PMID- 29382083 TI - Large Variations in Declared Serving Sizes of Packaged Foods in Australia: A Need for Serving Size Standardisation? AB - Declared serving sizes on food packaging are unregulated in Australia, and variations in serving size within similar products reduces the usability of this information. This study aimed to (i) assess the variations in declared serving sizes of packaged foods from the Five Food Groups, and (ii) compare declared serving sizes to the Australian Dietary Guidelines standard serves and typical portion sizes consumed by Australian adults. Product information, including serving size, was collected for 4046 products from four major Australian retailers. Within product categories from the Five Food Groups, coefficients of variation ranged from 0% to 59% for declared serving size and 9% to 64% for energy per serving. Overall, 24% of all products displayed serving sizes similar (within +/-10%) to the standard serves, and 23-28% were similar to typical portion sizes consumed by adults, for females and males, respectively. In conclusion, there is substantial variation in the declared serving sizes of packaged foods from the Five Food Groups, and serving sizes are not aligned with either the Dietary Guidelines or typical portion sizes consumed. Future research into effective means of standardising serving sizes is warranted. PMID- 29382084 TI - The Pharmabiotic Approach to Treat Hyperammonemia. AB - Ammonia is constantly produced as a metabolic waste from amino acid catabolism in mammals. Ammonia, the toxic waste metabolite, is resolved in the liver where the urea cycle converts free ammonia to urea. Liver malfunctions cause hyperammonemia that leads to central nervous system (CNS) dysfunctions, such as brain edema, convulsions, and coma. The current treatments for hyperammonemia, such as antibiotics or lactulose, are designed to decrease the intestinal production of ammonia and/or its absorption into the body and are not effective, besides being often accompanied by side effects. In recent years, increasing evidence has shown that modifications of the gut microbiota could be used to treat hyperammonemia. Considering the role of the gut microbiota and the physiological characteristics of the intestine, the removal of ammonia from the intestine by modulating the gut microbiota would be an ideal approach to treat hyperammonemia. In this review, we discuss the significance of hyperammonemia and its related diseases and the efficacy of the current management methods for hyperammonemia to understand the mechanism of ammonia transport in the human body. The possibility to use the gut microbiota as pharmabiotics to treat hyperammonemia and its related diseases is also explored. PMID- 29382085 TI - Multifunctional Tannic Acid/Silver Nanoparticle-Based Mucoadhesive Hydrogel for Improved Local Treatment of HSV Infection: In Vitro and In Vivo Studies. AB - Mucoadhesive gelling systems with tannic acid modified silver nanoparticles were developed for effective treatment of herpes virus infections. To increase nanoparticle residence time after local application, semi solid formulations designed from generally regarded as safe (GRAS) excipients were investigated for their rheological and mechanical properties followed with ex vivo mucoadhesive behavior to the porcine vaginal mucosa. Particular effort was made to evaluate the activity of nanoparticle-based hydrogels toward herpes simplex virus (HSV) type 1 and 2 infection in vitro in immortal human keratinocyte cell line and in vivo using murine model of HSV-2 genital infection. The effect of infectivity was determined by real time quantitative polymerase chain reaction, plaque assay, inactivation, attachment, penetration and cell-to-cell assessments. All analyzed nanoparticle-based hydrogels exhibited pseudoplastic and thixotropic properties. Viscosity and mechanical measurements of hydrogels were found to correlate with the mucoadhesive properties. The results confirmed the ability of nanoparticle based hydrogels to affect viral attachment, impede penetration and cell-to-cell transmission, although profound differences in the activity evoked by tested preparations toward HSV-1 and HSV-2 were noted. In addition, these findings demonstrated the in vivo potential of tannic acid modified silver nanoparticle based hydrogels for vaginal treatment of HSV-2 genital infection. PMID- 29382086 TI - Exploring the Adherence to the Mediterranean Diet and Its Relationship with Individual Lifestyle: The Role of Healthy Behaviors, Pro-Environmental Behaviors, Income, and Education. AB - The reduction of diet-related diseases and the improvement of environmental sustainability represent two of the major 21st century food policy challenges. Sustainable diets could significantly contribute to achieving both of these goals, improving consumer health and reducing the environmental impact of food production and consumption. The Mediterranean diet (MD) represents an excellent example of sustainable diet, however recent evidence indicates that such a dietary pattern is now progressively disappearing in Mediterranean countries. In such a context, this paper explores how individual lifestyle and habits are related to a high/low adherence to the MD model. The goal is to examine whether there is a relationship between individuals' healthy and pro-environmental behaviors and their level of adherence to the MD. The analysis also explores the role of consumer income and education. The study is based on the Italian population (n = 42,000) and uses a structural equation model approach. The results outline that the MD is part of a sustainability-oriented lifestyle and stress the key role of both income and education in affecting adherence to MD. Future policy aimed at contrasting the gradual disappearance of the MD should emphasize the sustainable dimension of the MD, meanwhile reducing socio-economic disparities among different population segments. PMID- 29382087 TI - Comparison of Human Dermal Fibroblasts and HaCat Cells Cultured in Medium with or without Serum via a Generic Tissue Engineering Research Platform. AB - A generic research platform with 2-dimensional (2D) cell culture technology, a 3 dimensional (3D) in vitro tissue model, and a scaled-down cell culture and imaging system in between, was utilized to address the problematic issues associated with the use of serum in skin tissue engineering. Human dermal fibroblasts (HDFs) and immortalized keratinocytes (HaCat cells) mono- or co cultured in serum or serum-free medium were compared and analyzed via the platform. It was demonstrated that serum depletion had significant influence on the attachment of HaCat cells onto tissue culture plastic (TCP), porous substrates and cellulosic scaffolds, which was further enhanced by the pre-seeded HDFs. The complex structures formed by the HDFs colonized within the porous substrates and scaffolds not only prevented the seeded HaCat cells from filtering through the open pores, but also acted as cellular substrates for HaCat cells to attach onto. When mono-cultured on TCP, both HDFs and HaCat cells were less proliferative in medium without serum than with serum. However, both cell types were successfully co-cultured in 2D using serum-free medium if the initial cell seeding density was higher than 80,000 cells/cm2 (with 1:1 ratio). Based on the results from 2D cultures, co-culture of both cell types on modular substrates with small open pores (125 MUm) and cellulosic scaffolds with open pores of varying sizes (50-300 um) were then conducted successfully in serum-free medium. This study demonstrated that the generic research platform had great potential for in-depth understanding of HDFs and HaCat cells cultivated in serum-free medium, which could inform the processes for manufacturing skin cells or tissues for clinical applications. PMID- 29382088 TI - The Effect of Ultraviolet Irradiation on the Physicochemical Properties of Poly(vinyl Chloride) Films Containing Organotin(IV) Complexes as Photostabilizers. AB - Three organotin(IV) complexes containing ciprofloxacin as a ligand (Ph3SnL, Me2SnL2 and Bu2SnL2; 0.5% by weight) were used as additives to inhibit the photodegradation of polyvinyl chloride films (40 um thickness) upon irradiation with ultraviolet light (lambdamax = 313 at a light intensity = 7.75 * 10-7 ein dm 3 S-1) at room temperature. The efficiency of organotin(IV) complexes as photostabilizers was determined by monitoring the changes in the weight, growth of specific functional groups (hydroxyl, carbonyl and carbene), viscosity, average molecular weight, chain scission and degree of deterioration of the polymeric films upon irradiation. The results obtained indicated that organotin(IV) complexes stabilized poly(vinyl chloride) and the dimethyltin(IV) complex was the most efficient additive. The surface morphologies of poly(vinyl chloride) films containing organotin(IV) complexes were examined using an atomic force microscope and scanning electron microscopy. These showed that the surface of polymeric films containing organotin(IV) complexes were smoother and less rough, compared to the surface of the blank films. Some mechanisms that explained the role of organotin(IV) complexes in poly(vinyl chloride) photostabilization process were proposed. PMID- 29382089 TI - Estimation of the Land Surface Temperature over the Tibetan Plateau by Using Chinese FY-2C Geostationary Satellite Data. AB - During the process of land-atmosphere interaction, one of the essential parameters is the land surface temperature (LST). The LST has high temporal variability, especially in its diurnal cycle, which cannot be acquired by polar orbiting satellites. Therefore, it is of great practical significance to retrieve LST data using geostationary satellites. According to the data of FengYun 2C (FY 2C) satellite and the measurements from the Enhanced Observing Period (CEOP) of the Asia-Australia Monsoon Project (CAMP) on the Tibetan Plateau (CAMP/Tibet), a regression approach was utilized in this research to optimize the split window algorithm (SWA). The thermal infrared data obtained by the Chinese geostationary satellite FY-2C over the Tibetan Plateau (TP) was used to estimate the hourly LST time series. To decrease the effects of cloud, the 10-day composite hourly LST data were obtained through the approach of maximal value composite (MVC). The derived LST was used to compare with the product of MODIS LST and was also validated by the field observation. The results show that the LST retrieved through the optimized SWA and in situ data has a better consistency (with correlation coefficient (R), mean absolute error (MAE), mean bias (MB), and root mean square error (RMSE) values of 0.987, 1.91 K, 0.83 K and 2.26 K, respectively) than that derived from Becker and Li's SWA and MODIS LST product, which means that the modified SWA can be applied to achieve plateau-scale LST. The diurnal variation of the LST and the hourly time series of the LST over the Tibetan Plateau were also obtained. The diurnal range of LST was found to be clearly affected by the influence of the thawing and freezing process of soil and the summer monsoon evolution. The comparison between the seasonal and diurnal variations of LST at four typical underlying surfaces over the TP indicate that the variation of LST is closely connected with the underlying surface types as well. The diurnal variation of LST is the smallest at the water (5.12 K), second at the snow and ice (5.45 K), third at the grasslands (19.82 K) and largest at the barren or sparsely vegetated (22.83 K). PMID- 29382090 TI - On the Demographic and Selective Forces Shaping Patterns of Human Cytomegalovirus Variation within Hosts. AB - Human cytomegalovirus (HCMV) is a member of the beta -herpesvirus subfamily within Herpesviridae that is nearly ubiquitous in human populations, and infection generally results only in mild symptoms. However, symptoms can be severe in immunonaive individuals, and transplacental congenital infection of HCMV can result in serious neurological sequelae. Recent work has revealed much about the demographic and selective forces shaping the evolution of congenitally transmitted HCMV both on the level of hosts and within host compartments, providing insight into the dynamics of congenital infection, reinfection, and evolution of HCMV with important implications for the development of effective treatments and vaccines. PMID- 29382091 TI - Epilepsy: A Call for Help. AB - Epilepsy is a considerable individual and social economic burden. In properly selected patients, epilepsy surgery can provide significant relief from disease, including remission. However, the surgical treatment of epilepsy lags in terms of knowledge and technology. The problem arises due to its slow adaptation and dissemination. This article explores this issue of a wide treatment gap and its causes. It develops a framework for a rational decision-making process that is appropriate for extant circumstances and will result in the speedy delivery of surgical care for suitable patients with medically intractable epilepsy. PMID- 29382092 TI - Non-Destructive Spectroscopic Techniques and Multivariate Analysis for Assessment of Fat Quality in Pork and Pork Products: A Review. AB - Fat is one of the most important traits determining the quality of pork. The composition of the fat greatly influences the quality of pork and its processed products, and contribute to defining the overall carcass value. However, establishing an efficient method for assessing fat quality parameters such as fatty acid composition, solid fat content, oxidative stability, iodine value, and fat color, remains a challenge that must be addressed. Conventional methods such as visual inspection, mechanical methods, and chemical methods are used off the production line, which often results in an inaccurate representation of the process because the dynamics are lost due to the time required to perform the analysis. Consequently, rapid, and non-destructive alternative methods are needed. In this paper, the traditional fat quality assessment techniques are discussed with emphasis on spectroscopic techniques as an alternative. Potential spectroscopic techniques include infrared spectroscopy, nuclear magnetic resonance and Raman spectroscopy. Hyperspectral imaging as an emerging advanced spectroscopy-based technology is introduced and discussed for the recent development of assessment for fat quality attributes. All techniques are described in terms of their operating principles and the research advances involving their application for pork fat quality parameters. Future trends for the non-destructive spectroscopic techniques are also discussed. PMID- 29382093 TI - Plant Pest Detection Using an Artificial Nose System: A Review. AB - This paper reviews artificial intelligent noses (or electronic noses) as a fast and noninvasive approach for the diagnosis of insects and diseases that attack vegetables and fruit trees. The particular focus is on bacterial, fungal, and viral infections, and insect damage. Volatile organic compounds (VOCs) emitted from plants, which provide functional information about the plant's growth, defense, and health status, allow for the possibility of using noninvasive detection to monitor plants status. Electronic noses are comprised of a sensor array, signal conditioning circuit, and pattern recognition algorithms. Compared with traditional gas chromatography-mass spectrometry (GC-MS) techniques, electronic noses are noninvasive and can be a rapid, cost-effective option for several applications. However, using electronic noses for plant pest diagnosis is still in its early stages, and there are challenges regarding sensor performance, sampling and detection in open areas, and scaling up measurements. This review paper introduces each element of electronic nose systems, especially commonly used sensors and pattern recognition methods, along with their advantages and limitations. It includes a comprehensive comparison and summary of applications, possible challenges, and potential improvements of electronic nose systems for different plant pest diagnoses. PMID- 29382094 TI - Experimental Study on the Thermal Start-Up Performance of the Graphene/Water Nanofluid-Enhanced Solar Gravity Heat Pipe. AB - The solar gravity heat pipe has been widely used for solar thermal water heating because of its high efficient heat transfer and thermal diode characteristics. Operated on fluctuant and low intensity solar radiation conditions, a solar gravity heat pipe may frequently start up. This severely affects its solar collection performance. To enhance the thermal performance of the solar gravity heat pipe, this study proposes using graphene/water nanofluid as the working fluid instead of deionized water. The stability of the prepared graphene/water nanofluid added with PVP was firstly investigated to obtain the optimum mass ratios of the added dispersant. Thermophysical properties-including the thermal conductivity and viscosity-of nanofluid with various graphene nanoplatelets (GNPs) concentrations were measured at different temperatures for further analysis. Furthermore, based on the operational evaluation on a single heat pipe's start-up process, the performance of nanofluid-enhanced solar gravity heat pipes using different concentrations of GNPs were compared by using water heating experiments. Results indicated that the use of 0.05 wt % graphene/water nanofluid instead of water could achieve a 15.1% and 10.7% reduction in start-up time under 30 and 60 W input heating conditions, respectively. Consequently, a higher thermal efficiency for solar collection could be expected. PMID- 29382095 TI - Microarchitecture of the Augmented Bone Following Sinus Elevation with an Albumin Impregnated Demineralized Freeze-Dried Bone Allograft (BoneAlbumin) versus Anorganic Bovine Bone Mineral: A Randomized Prospective Clinical, Histomorphometric, and Micro-Computed Tomography Study. AB - Serum albumin has been identified as an endogenous protein that is integral to early bone regeneration. We hypothesized that albumin addition to allografts may result in better bone remodeling than what can be achieved with anorganic xenografts. Sinus elevations were performed at 32 sites of 18 patients with the lateral window technique. Sites either received filling with an anorganic bovine bone mineral (ABBM, BioOss, Geistlich, CH) or albumin impregnated allograft (BoneAlbumin, OrthoSera, AT). After 6-months patients received dental implants and 16 bone core biopsy samples were obtained from the ABBM filled, and 16 from the BoneAlbumin augmented sites. The biopsies were examined by histomorphometry and uCT. Percentage of the residual graft in the BoneAlbumin group was 0-12.7%, median 5.4% vs. ABBM 6.3-35.9%, median 16.9%, p < 0.05. Results of the uCT analysis showed that the microarchitecture of the augmented bone in the BoneAlbumin group resembles that of the native maxilla in morphometric parameters Trabecular Pattern Factor and Connectivity. Our data show that while ABBM successfully integrates into the newly formed bone tissue as persisting particles, BoneAlbumin is underway towards complete remodeling with new bone closely resembling that of the intact maxilla. PMID- 29382096 TI - Novel Topologically Complex Scaffold Derived from Alkaloid Haemanthamine. AB - The generation of natural product-like compound collections has become an important area of research due to low hit rates found with synthetic high throughput libraries. One method of generating compounds occupying the areas of chemical space not accessible to synthetic planar heterocyclic structures is the utilization of natural products as starting materials. In the current work, using a ring-closing iodoalkoxylation reaction, alkaloid haemanthamine was transformed into a unique structural framework possessing an intricate ring system and a large number of stereocenters. The structure of the new compound was confirmed with an X-ray analysis. A small number of derivatives of this new compound were synthesized as a demonstration of the possibility of generating a large natural product-like compound collection based on the new structural framework. PMID- 29382097 TI - Nigella damascena L. Essential Oil-A Valuable Source of beta-Elemene for Antimicrobial Testing. AB - The most commonly used plant source of beta-elemene is Curcuma wenyujin Y. H. Chen & C. Ling (syn. of Curcuma aromatic Salisb.) with its content in supercritical CO2 extract up to 27.83%. However, the other rich source of this compound is Nigella damascena L. essential oil, in which beta-elemene accounts for 47%. In this work, the effective protocol for preparative isolation of beta elemene from a new source-N. damascena essential oil-using high performance counter-current chromatography HPCCC was elaborated. Furthermore, since sesquiterpens are known as potent antimicrobials, the need for finding new agents designed to combat multi-drug resistant strains was addressed and the purified target compound and the essential oil were tested for its activity against a panel of Gram-positive and Gram-negative bacteria, fungi, and mycobacterial strains. The application of the mixture of petroleum ether, acetonitrile, and acetone in the ratio 2:1.5:0.5 (v/v) in the reversed phase mode yielded beta elemene with high purity in 70 min. The results obtained for antimicrobial assay clearly indicated that N. damascena essential oil and isolated beta-elemene exert action against Mycobacterium tuberculosis strain H37Ra. PMID- 29382098 TI - On the Design of an Efficient Cardiac Health Monitoring System Through Combined Analysis of ECG and SCG Signals. AB - Cardiovascular disease (CVD) is a major public concern and socioeconomic problem across the globe. The popular high-end cardiac health monitoring systems such as magnetic resonance imaging (MRI), computerized tomography scan (CT scan), and echocardiography (Echo) are highly expensive and do not support long-term continuous monitoring of patients without disrupting their activities of daily living (ADL). In this paper, the continuous and non-invasive cardiac health monitoring using unobtrusive sensors is explored aiming to provide a feasible and low-cost alternative to foresee possible cardiac anomalies in an early stage. It is learned that cardiac health monitoring based on sole usage of electrocardiogram (ECG) signals may not provide powerful insights as ECG provides shallow information on various cardiac activities in the form of electrical impulses only. Hence, a novel low-cost, non-invasive seismocardiogram (SCG) signal along with ECG signals are jointly investigated for the robust cardiac health monitoring. For this purpose, the in-laboratory data collection model is designed for simultaneous acquisition of ECG and SCG signals followed by mechanisms for the automatic delineation of relevant feature points in acquired ECG and SCG signals. In addition, separate feature points based novel approach is adopted to distinguish between normal and abnormal morphology in each ECG and SCG cardiac cycle. Finally, a combined analysis of ECG and SCG is carried out by designing a Naive Bayes conditional probability model. Experiments on Institutional Review Board (IRB) approved licensed ECG/SCG signals acquired from real subjects containing 12,000 cardiac cycles show that the proposed feature point delineation mechanisms and abnormal morphology detection methods consistently perform well and give promising results. In addition, experimental results show that the combined analysis of ECG and SCG signals provide more reliable cardiac health monitoring compared to the standalone use of ECG and SCG. PMID- 29382100 TI - Joint Interference Alignment and Power Allocation for K-User Multicell MIMO Channel through Staggered Antenna Switching. AB - In this paper, we characterise the joint interference alignment (IA) and power allocation strategies for a K-user multicell multiple-input multiple-output (MIMO) Gaussian interference channel. We consider a MIMO interference channel with blind-IA through staggered antenna switching on the receiver. We explore the power allocation and feasibility condition for cooperative cell-edge (CE) mobile users (MUs) by assuming that the channel state information is unknown. The new insight behind the transmission strategy of the proposed scheme is premeditated (randomly generated transmission strategy) and partial cooperative CE MUs, where the transmitter is equipped with a conventional antenna, the receiver is equipped with a reconfigurable multimode antenna (staggered antenna switching pattern), and the receiver switches between preset T modes. Our proposed scheme assists and aligns the desired signals and interference signals to cancel the common interference signals because the received signal must have a corresponding independent signal subspace. The capacity for a K-user multicell MIMO Gaussian interference channel with reconfigurable multimode antennas is completely characterised. Furthermore, we show that the proposed K-user multicell MIMO scheduling and K-user L-cell CEUs partial cooperation algorithms elaborate the generalisation of K-user IA and power allocation strategies. The numerical results demonstrate that the proposed intercell interference scheme with partial cooperative CE MUs achieves better capacity and signal-to-interference plus noise ratio (SINR) performance compared to noncooperative CE MUs and without intercell interference schemes. PMID- 29382099 TI - In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone Dependent Quorum Sensing in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti infective drug discovery programs. PMID- 29382101 TI - Enhanced Thermoelectric Properties of Polycrystalline SnSe via LaCl3 Doping. AB - LaCl3 doped polycrystalline SnSe was synthesized by combining mechanical alloying (MA) process with spark plasma sintering (SPS). It is found that the electrical conductivity is enhanced after doping due to the increased carrier concentration and carrier mobility, resulting in optimization of the power factor at 750 K combing with a large Seebeck coefficient over 300 MUvk-1. Meanwhile, all the samples exhibit lower thermal conductivity below 1.0 W/mK in the whole measured temperature. The lattice thermal conductivity for the doped samples was reduced, which effectively suppressed the increscent of the total thermal conductivity because of the improved electrical conductivity. As a result, a ZT value of 0.55 has been achieved for the composition of SnSe-1.0 wt % LaCl3 at 750 K, which is nearly four times higher than the undoped one and reveals that rare earth element is an effective dopant for optimization of the thermoelectric properties of SnSe. PMID- 29382102 TI - X-ray Absorption Fine Structure (XAFS) Studies of Oxide Glasses-A 45-Year Overview. AB - X-ray Absorption Fine Structure (XAFS) spectroscopy has been widely used to characterize the short-range order of glassy materials since the theoretical basis was established 45 years ago. Soon after the technique became accessible, mainly due to the existence of Synchrotron laboratories, a wide range of glassy materials was characterized. Silicate glasses have been the most studied because they are easy to prepare, they have commercial value and are similar to natural glasses, but borate, germanate, phosphate, tellurite and other less frequent oxide glasses have also been studied. In this manuscript, we review reported advances in the structural characterization of oxide-based glasses using this technique. A focus is on structural characterization of transition metal ions, especially Ti, Fe, and Ni, and their role in different properties of synthetic oxide-based glasses, as well as their important function in the formation of natural glasses and magmas, and in nucleation and crystallization. We also give some examples of XAFS applications for structural characterization of glasses submitted to high pressure, glasses used to store radioactive waste and medieval glasses. This updated, comprehensive review will likely serve as a useful guide to clarify the details of the short-range structure of oxide glasses. PMID- 29382103 TI - Green Synthesis of Three-Dimensional Hybrid N-Doped ORR Electro-Catalysts Derived from Apricot Sap. AB - Rapid depletion of fossil fuel and increased energy demand has initiated a need for an alternative energy source to cater for the growing energy demand. Fuel cells are an enabling technology for the conversion of sustainable energy carriers (e.g., renewable hydrogen or bio-gas) into electrical power and heat. However, the hazardous raw materials and complicated experimental procedures used to produce electro-catalysts for the oxygen reduction reaction (ORR) in fuel cells has been a concern for the effective implementation of these catalysts. Therefore, environmentally friendly and low-cost oxygen reduction electro catalysts synthesised from natural products are considered as an attractive alternative to currently used synthetic materials involving hazardous chemicals and waste. Herein, we describe a unique integrated oxygen reduction three dimensional composite catalyst containing both nitrogen-doped carbon fibers (N CF) and carbon microspheres (N-CMS) synthesised from apricot sap from an apricot tree. The synthesis was carried out via three-step process, including apricot sap resin preparation, hydrothermal treatment, and pyrolysis with a nitrogen precursor. The nitrogen-doped electro-catalysts synthesised were characterised by SEM, TEM, XRD, Raman, and BET techniques followed by electro-chemical testing for ORR catalysis activity. The obtained catalyst material shows high catalytic activity for ORR in the basic medium by facilitating the reaction via a four electron transfer mechanism. PMID- 29382104 TI - Action of Phytochemicals on Insulin Signaling Pathways Accelerating Glucose Transporter (GLUT4) Protein Translocation. AB - Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro- and macro-complications like heart disease, stroke, dementia, cancer, kidney failure and blindness. All these complications rise primarily due to consistent high blood glucose levels. Insulin and glucagon help to maintain the homeostasis of glucose and lipids through signaling cascades. Pancreatic hormones stimulate translocation of the glucose transporter isoform 4 (GLUT4) from an intracellular location to the cell surface and facilitate the rapid insulin dependent storage of glucose in muscle and fat cells. Malfunction in glucose uptake mechanisms, primarily contribute to insulin resistance in type 2 diabetes. Plant secondary metabolites, commonly known as phytochemicals, are reported to have great benefits in the management of type 2 diabetes. The role of phytochemicals and their action on insulin signaling pathways through stimulation of GLUT4 translocation is crucial to understand the pathogenesis of this disease in the management process. This review will summarize the effects of phytochemicals and their action on insulin signaling pathways accelerating GLUT4 translocation based on the current literature. PMID- 29382105 TI - Study of the Anti-Staphylococcal Potential of Honeys Produced in Northern Poland. AB - The antimicrobial activity of 144 samples of honeys including 95 products from apiaries located in Northern Poland was evaluated. The antibacterial activity of those natural products, their thermal stability, and activity in the presence of catalase was investigated by microdilution assays in titration plates. The MTT assay was performed for the determination of anti-biofilm activity. Spectrophotometric assays were used for the determination of antioxidant potential, total phenolic content, and ability to generate hydrogen peroxide. Some of the investigated honeys exhibited surprisingly high antimicrobial, especially anti-staphylococcal, potential, with Minimal Inhibitory Concentration (MIC) values of only 1.56% (v/v). Much higher resistance was observed in the case of staphylococci growing as biofilms. Lower concentrations of the product, up to 12.5% (v/v) stimulated its growth and effective eradication of biofilm required concentration of at least 25% (v/v). Hydrogen peroxide has been identified as a crucial contributor to the antimicrobial activity of honeys supplied by Polish beekeepers. However, some of the results suggest that phytochemicals, especially polyphenols, play an important role depending on botanical source (both positive, e.g., in the case of buckwheat honeys as well as negative, e.g., in the case of some rapeseed honeys) in their antimicrobial potential. PMID- 29382106 TI - Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection. AB - Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER) stress, glucose metabolism, and synaptic function. The interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases. PMID- 29382107 TI - Aedes Mosquitoes and Aedes-Borne Arboviruses in Africa: Current and Future Threats. AB - The Zika crisis drew attention to the long-overlooked problem of arboviruses transmitted by Aedes mosquitoes in Africa. Yellow fever, dengue, chikungunya and Zika are poorly controlled in Africa and often go unrecognized. However, to combat these diseases, both in Africa and worldwide, it is crucial that this situation changes. Here, we review available data on the distribution of each disease in Africa, their Aedes vectors, transmission potential, and challenges and opportunities for Aedes control. Data on disease and vector ranges are sparse, and consequently maps of risk are uncertain. Issues such as genetic and ecological diversity, and opportunities for integration with malaria control, are primarily African; others such as ever-increasing urbanization, insecticide resistance and lack of evidence for most control-interventions reflect problems throughout the tropics. We identify key knowledge gaps and future research areas, and in particular, highlight the need to improve knowledge of the distributions of disease and major vectors, insecticide resistance, and to develop specific plans and capacity for arboviral disease surveillance, prevention and outbreak responses. PMID- 29382108 TI - Food-Grade Synthesis of Maillard-Type Taste Enhancers Using Natural Deep Eutectic Solvents (NADES). AB - The increasing demand for healthier food products, with reduced levels of table salt, sugar, and mono sodium glutamate, reinforce the need for novel taste enhancers prepared by means of food-grade kitchen-type chemistry. Although several taste modulating compounds have been discovered in processed foods, their Maillard-type ex food production is usually not exploited by industrial process reactions as the yields of target compounds typically do not exceed 1-2%. Natural deep eutectic solvents (NADES) are reported for the first time to significantly increase the yields of the taste enhancers 1-deoxy-?-fructosyl-N-beta-alanyl-L histidine (49% yield), N-(1-methyl-4-oxoimidazolidin-2-ylidene) aminopropionic acid (54% yield) and N2-(1-carboxyethyl) guanosine 5'-monophosphate (22% yield) at low temperature (80-100 degrees C) within a maximum reaction time of 2 h. Therefore, NADES open new avenues to a "next-generation culinary chemistry" overcoming the yield limitations of traditional Maillard chemistry approaches and enable a food-grade Maillard-type generation of flavor modulators. PMID- 29382110 TI - Intraneural Platelet-Rich Plasma Injections for the Treatment of Radial Nerve Section: A Case Report. AB - : The radial nerve is the most frequently injured nerve in the upper extremity. Numerous options in treatment have been described for radial nerve injury, such as neurolysis, nerve grafts, or tendon transfers. Currently, new treatment options are arising, such as platelet-rich plasma (PRP), an autologous product with proved therapeutic effect for various musculoskeletal disorders. We hypothesized that this treatment is a promising alternative for this type of nerve pathology. The patient was a healthy 27-year-old man who suffered a deep and long cut in the distal anterolateral region of the right arm. Forty-eight hours after injury, an end-to-end suture was performed without a microscope. Three months after the surgery, an electromyogram (EMG) showed right radial nerve neurotmesis with no tendency to reinnervation. Four months after the trauma, serial intraneural infiltrations of PRP were conducted using ultrasound guidance. The therapeutic effect was assessed by manual muscle testing and by EMG. Fourteen months after the injury and 11 months after the first PRP injection, functional recovery was achieved. The EMG showed a complete reinnervation of the musculature of the radial nerve dependent. The patient remains satisfied with the result and he is able to practice his profession. CONCLUSIONS: PRP infiltrations have the potential to enhance the healing process of radial nerve palsy. This case report demonstrates the therapeutic potential of this technology for traumatic peripheral nerve palsy, as well as the apt utility of US-guided PRP injections. PMID- 29382109 TI - Chiral Drug Analysis in Forensic Chemistry: An Overview. AB - Many substances of forensic interest are chiral and available either as racemates or pure enantiomers. Application of chiral analysis in biological samples can be useful for the determination of legal or illicit drugs consumption or interpretation of unexpected toxicological effects. Chiral substances can also be found in environmental samples and revealed to be useful for determination of community drug usage (sewage epidemiology), identification of illicit drug manufacturing locations, illegal discharge of sewage and in environmental risk assessment. Thus, the purpose of this paper is to provide an overview of the application of chiral analysis in biological and environmental samples and their relevance in the forensic field. Most frequently analytical methods used to quantify the enantiomers are liquid and gas chromatography using both indirect, with enantiomerically pure derivatizing reagents, and direct methods recurring to chiral stationary phases. PMID- 29382111 TI - Yirui Capsules Alleviate Atherosclerosis by Improving the Lipid Profile and Reducing Inflammation in Apolipoprotein E-Deficient Mice. AB - Atherosclerosis (AS) is the main cause of cardiovascular diseases. This study investigated Yirui (YR) capsules, whose ingredients are available in health food stores, against AS and the underlying mechanisms. Male apolipoprotein E-deficient mice fed a high-fat diet for 10 weeks developed severe aortic lesions, but YR significantly decreased the plaque area in the total aorta and aortic root. YR affected the serum lipid profile by significantly reducing total cholesterol, low density lipoprotein cholesterol (LDL-C), triglyceride (TG), and oxidative modification of LDL-C (Ox-LDL) levels. In addition, multi-cytokine analysis revealed that higher serum levels of interleukin-1 alpha (IL-1alpha), interleukin 1 beta (IL-1beta), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-27 (IL 27), tumor necrosis factor alpha, interferon gamma, and regulated on activation, normal T cell expressed and secreted (RANTES), which were induced by a high-fat diet, declined with YR treatment. These results suggest that YR reduces the atherosclerotic plaque burden, thereby alleviating AS by modulating the lipid profile and inhibiting inflammation. PMID- 29382112 TI - Environmental Regulation, Foreign Direct Investment and Green Technological Progress-Evidence from Chinese Manufacturing Industries. AB - This study examines the spillover effects of foreign direct investment (FDI) on green technology progress rate (as measured by the green total factor productivity). The analysis utilizes two measures of FDI, labor-based FDI and capital-based FDI, and separately investigates four sets of industry classifications-high/low discharge regulation and high/low emission standard regulation. The results indicate that in the low discharge regulation and low emission standard regulation industry, labor-based FDI has a significant negative spillover effect, and capital-based FDI has a significant positive spillover effect. However, in the high-intensity environmental regulation industry, the negative influence of labor-based FDI is completely restrained, and capital-based FDI continues to play a significant positive green technological spillover effects. These findings have clear policy implications: the government should be gradually reducing the labor-based FDI inflow or increasing stringency of environmental regulation in order to reduce or eliminate the negative spillover effect of the labor-based FDI. PMID- 29382114 TI - Utility of Non-Invasive Monitoring of Cardiac Output and Cerebral Oximetry during Pain Management of Children with Sickle Cell Disease in the Pediatric Emergency Department. AB - Pain crisis in children with sickle cell disease (SCD) is typically managed with intravenous fluids and parenteral opioids in the pediatric emergency department. Electrical cardiometry (EC) can be utilized to measure cardiac output (CO) and cardiac index (CI) non-invasively. Near-infrared spectroscopy (NIRS) measuring cerebral (rCO2) and splanchnic regional (rSO2) mixed venous oxygenation non invasively has been utilized for monitoring children with SCD. We studied the value and correlation of NIRS and EC in monitoring hemodynamic status in children with SCD during pain crisis. We monitored EC and NIRS continuously for 2 h after presentation and during management. Forty-five children participated in the study. CO (D = 1.72), CI (D = 1.31), rSO2 (D = 11.6), and rCO2 (D = 9.3), all increased over time. CO max and CI max were achieved 1 h after starting resuscitation. rCO2 max attainment was quicker than rSO2, as monitored by NIRS. CI max correlated with rCO2 max (r = -0.350) and rSO2 max (r = -0.359). In adjustment models, initial CI significantly impacted initial rCO2 (p = 0.045) and rCO2 max (p = 0.043), while initial CO impacted rCO2 max (p = 0.030). Cardiac output monitoring and NIRS monitoring for cerebral and splanchnic oxygenation were feasible and improved the monitoring of therapeutic interventions for children with SCD during pain crisis. PMID- 29382113 TI - Association of Dietary Patterns with Components of Metabolic Syndrome and Inflammation among Middle-Aged and Older Adults with Metabolic Syndrome in Taiwan. AB - This study examined the correlation of dietary patterns with components of metabolic syndrome (MetS) and inflammation among middle-aged and older adults with MetS in Taiwan. This cross-sectional study used data from the Mei Jau International Health Management Institution in Taiwan between 2004 and 2013. A total of 26,016 subjects aged 35 years and above were selected for analysis. MetS was defined according to the International Diabetes Federation. Three dietary patterns were identified by principal component analysis. High intake of a meat instant food dietary pattern (rich in animal protein, saturated fat, sweets, sodium, and food additives) was positively associated with components of MetS and C-reactive protein (CRP), while high intake of a vege-seafood dietary pattern (rich in dietary fiber, vitamins, minerals, and unsaturated fat) or a cereal dairy dietary pattern (rich in dietary fiber, antioxidants, phytochemicals, complex carbohydrate, prebiotics, and probiotics) was inversely associated with components of MetS and CRP. Our findings suggested that intake of a vege-seafood dietary pattern or a cereal-dairy dietary pattern decreased the risk of developing MetS and inflammation among middle-aged and older adults with MetS. PMID- 29382115 TI - Extraction and Optimization of Potato Starch and Its Application as a Stabilizer in Yogurt Manufacturing. AB - Starch is increasingly used as a functional group in many industrial applications and foods due to its ability to work as a thickener. The experimental values of extracting starch from yellow skin potato indicate the processing conditions at 3000 rpm and 15 min as optimum for the highest yield of extracted starch. The effect of adding different concentrations of extracted starch under the optimized conditions was studied to determine the acidity, pH, syneresis, microbial counts, and sensory evaluation in stored yogurt manufactured at 5 degrees C for 15 days. The results showed that adding sufficient concentrations of starch (0.75%, 1%) could provide better results in terms of the minimum change in the total acidity, decrease in pH, reduction in syneresis, and preferable results for all sensory parameters. The results revealed that the total bacteria count of all yogurt samples increased throughout the storage time. However, adding different concentrations of optimized extracted starch had a significant effect, decreasing the microbial content compared with the control sample (YC). In addition, the results indicated that coliform bacteria were not found during the storage time. PMID- 29382116 TI - An Improved Method for Magnetic Nanocarrier Drug Delivery across the Cell Membrane. AB - One of the crucial issues in the pharmacological field is developing new drug delivery systems. The main concern is to develop new methods for improving the drug delivery efficiencies such as low disruptions, precise control of the target of delivery and drug sustainability. Nowadays, there are many various methods for drug delivery systems. Carbon-based nanocarriers are a new efficient tool for translocating drug into the defined area or cells inside the body. These nanocarriers can be functionalized with proteins, peptides and used to transport their freight to cells or defined areas. Since functionalized carbon-based nanocarriers show low toxicity and high biocompatibility, they are used in many nanobiotechnology fields. In this study, different shapes of nanocarrier are investigated, and the suitable magnetic field, which is applied using MRI for the delivery of the nanocarrier, is proposed. In this research, based on the force required to cross the membrane and MD simulations, the optimal magnetic field profile is designed. This optimal magnetic force field is derived from the mathematical model of the system and magnetic particle dynamics inside the nanocarrier. The results of this paper illustrate the effects of the nanocarrier's shapes on the percentage of success in crossing the membrane and the optimal required magnetic field. PMID- 29382117 TI - Growing Industries, Growing Invasions? The Case of the Argentine Ant in Vineyards of Northern Argentina. AB - The invasive Argentine ant causes ecological and economic damage worldwide. In 2011, this species was reported in vineyards of Cafayate, a wine-producing town in the Andes, Argentina. While the local xeric climate is unsuitable for Argentine ants, populations could establish in association with vineyards where human activity and irrigation facilitate propagule introduction and survival. In 2013-2014, we combined extensive sampling of the area using ant-baits with monitoring of the change in land use and vineyard cultivated area over the past 15 years. Our results revealed that the species has thus far remained confined to a relatively isolated small area, owing to an effective barrier of dry shrublands surrounding the infested vineyards; yet the recent expansion of vineyard acreage in this region will soon connect this encapsulated area with the rest of the valley. When this happens, vulnerable ecosystems and the main local industry will be put at risk. This case provides a rare opportunity to study early invasion dynamics and reports, to the best of our knowledge, for the first time, the Argentine ant in high altitude agroecosystems. PMID- 29382118 TI - Nitrogen Fertilizer Management in Dryland Wheat Cropping Systems. AB - Wheat is the most widely cultivated food crop in the world, which provides nutrition to most of the world population and is well adapted to a wide range of environmental conditions. Timely and efficient rates of nitrogen (N) application are vital for increasing wheat grain yield and protein content, and maintaining environmental sustainability. The goal of this study was to investigate the effect of using different rates and split application of N on the performance of spring wheat in dryland cropping systems. The experiment was conducted in three different locations in Montana and Idaho during two consecutive growing seasons. A split-plot experimental design was used with three at planting N fertilization application (0, 90 and 135 kg N ha-1) and two topdressing N fertilization strategies as treatments. A number of variables such as grain yield (GY), protein content (GP) in the grains and N uptake (NUP) were assessed. There was a significant effect of climate, N rate, and time application on the wheat performance. The results showed that at-planting N fertilizer application of 90 kg N ha-1 has significantly increased GY, GP and NUP. On the other hand, for these site-years, increasing at-planting N fertilizer rate to 135 kg N ha-1 did not further enhance wheat GY, GP and NUP values. For all six site-years, topdress N fertilizer applied at flowering did not improve wheat GY, GP and NUP compared to at-planting fertilizer alone. As the risk of yield loss is minimal with split N application, from these results we concluded the best treatment for study is treatments that had received 90 kg N ha-1 split as 45 kg N ha-1 at planting and 45 kg N ha-1 at flowering. PMID- 29382119 TI - The Emerging Role of Tractography in Deep Brain Stimulation: Basic Principles and Current Applications. AB - Diffusion tensor imaging (DTI) is an MRI-based technique that delineates white matter tracts in the brain by tracking the diffusion of water in neural tissue. This methodology, known as "tractography", has been extensively applied in clinical neuroscience to explore nervous system architecture and diseases. More recently, tractography has been used to assist with neurosurgical targeting in functional neurosurgery. This review provides an overview of DTI principles, and discusses current applications of tractography for improving and helping develop novel deep brain stimulation (DBS) targets. PMID- 29382120 TI - Cutting Pattern Identification for Coal Mining Shearer through a Swarm Intelligence-Based Variable Translation Wavelet Neural Network. AB - As a sound signal has the advantages of non-contacted measurement, compact structure, and low power consumption, it has resulted in much attention in many fields. In this paper, the sound signal of the coal mining shearer is analyzed to realize the accurate online cutting pattern identification and guarantee the safety quality of the working face. The original acoustic signal is first collected through an industrial microphone and decomposed by adaptive ensemble empirical mode decomposition (EEMD). A 13-dimensional set composed by the normalized energy of each level is extracted as the feature vector in the next step. Then, a swarm intelligence optimization algorithm inspired by bat foraging behavior is applied to determine key parameters of the traditional variable translation wavelet neural network (VTWNN). Moreover, a disturbance coefficient is introduced into the basic bat algorithm (BA) to overcome the disadvantage of easily falling into local extremum and limited exploration ability. The VTWNN optimized by the modified BA (VTWNN-MBA) is used as the cutting pattern recognizer. Finally, a simulation example, with an accuracy of 95.25%, and a series of comparisons are conducted to prove the effectiveness and superiority of the proposed method. PMID- 29382121 TI - Metal-Incorporated Mesoporous Silicates: Tunable Catalytic Properties and Applications. AB - A relatively new class of three-dimensional ordered mesoporous silicates, KIT-6, incorporated with Earth-abundant metals such as Zr, Nb, and W (termed as M-KIT 6), show remarkable tunability of acidity and metal dispersion depending on the metal content, type, and synthetic method. The metal-incorporation is carried out using one-pot synthesis procedures that are amenable to easy scale-up. By such tuning, M-KIT-6 catalysts are shown to provide remarkable activity and selectivity in industrially-significant reactions, such as alcohol dehydration, ethylene epoxidation, and metathesis of 2-butene and ethylene. We review how the catalytic properties of M-KIT-6 materials may be tailored depending on the application to optimize performance. PMID- 29382122 TI - A Triaxial Applicator for the Measurement of the Electromagnetic Properties of Materials. AB - The design, analysis, and fabrication of a prototype triaxial applicator is described. The applicator provides both reflected and transmitted signals that can be used to characterize the electromagnetic properties of materials in situ. A method for calibrating the probe is outlined and validated using simulated data. Fabrication of the probe is discussed, and measured data for typical absorbing materials and for the probe situated in air are presented. The simulations and measurements suggest that the probe should be useful for measuring the properties of common radar absorbing materials under usual in situ conditions. PMID- 29382123 TI - Analysis of Protein-Phenolic Compound Modifications Using Electrochemistry Coupled to Mass Spectrometry. AB - In the last decade, electrochemical oxidation coupled with mass spectrometry has been successfully used for the analysis of metabolic studies. The application focused in this study was to investigate the redox potential of different phenolic compounds such as the very prominent chlorogenic acid. Further, EC/ESI MS was used as preparation technique for analyzing adduct formation between electrochemically oxidized phenolic compounds and food proteins, e.g., alpha lactalbumin or peptides derived from a tryptic digestion. In the first step of this approach, two reactant solutions are combined and mixed: one contains the solution of the digested protein, and the other contains the phenolic compound of interest, which was, prior to the mixing process, electrochemically transformed to several oxidation products using a boron-doped diamond working electrode. As a result, a Michael-type addition led to covalent binding of the activated phenolic compounds to reactive protein/peptide side chains. In a follow-up approach, the reaction mix was further separated chromatographically and finally detected using ESI-HRMS. Compound-specific, electrochemical oxidation of phenolic acids was performed successfully, and various oxidation and reaction products with proteins/peptides were observed. Further optimization of the reaction (conditions) is required, as well as structural elucidation concerning the final adducts, which can be phenolic compound oligomers, but even more interestingly, quite complex mixtures of proteins and oxidation products. PMID- 29382124 TI - Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. AB - The renin-angiotensin-aldosterone system (RAAS) is a dominant player in several cardiovascular pathologies. This study investigated whether alterations induced by l-NAME, (NLG)-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, and the protective effect of melatonin are associated with changes in the RAAS. Four groups of 3-month-old male Wistar rats (n = 10) were treated as follows for four weeks: untreated controls, rats treated with melatonin (10 mg/kg/day), rats treated with l-NAME (40 mg/kg/day), and rats treated with l-NAME + melatonin. l-NAME administration led to hypertension and left ventricular (LV) fibrosis in terms of enhancement of soluble, insoluble and total collagen concentration and content. Melatonin reduced systolic blood pressure enhancement and lowered the concentration and content of insoluble and total collagen in the LV. The serum concentration of angiotensin (Ang) 1-8 (Ang II) and its downstream metabolites were reduced in the l-NAME group and remained unaltered by melatonin. The serum aldosterone level and its ratio to Ang II (AA2-ratio) were increased in the l-NAME group without being modified by melatonin. We conclude that l-NAME hypertension is associated with reduced level of Ang II and its downstream metabolites and increased aldosterone concentration and AA2-ratio. Melatonin exerts its protective effect in l-NAME-induced hypertension without affecting RAAS. PMID- 29382125 TI - Transplantation of High Hydrogen-Producing Microbiota Leads to Generation of Large Amounts of Colonic Hydrogen in Recipient Rats Fed High Amylose Maize Starch. AB - The hydrogen molecule (H2), which has low redox potential, is produced by colonic fermentation. We examined whether increased hydrogen (H2) concentration in the portal vein in rats fed high amylose maize starch (HAS) helped alleviate oxidative stress, and whether the transplantation of rat colonic microbiota with high H2 production can shift low H2-generating rats (LG) to high H2-generating rats (HG). Rats were fed a 20% HAS diet for 10 days and 13 days in experiments 1 and 2, respectively. After 10 days (experiment 1), rats underwent a hepatic ischemia-reperfusion (IR) operation. Rats were then categorized into quintiles of portal H2 concentration. Plasma alanine aminotransferase activity and hepatic oxidized glutathione concentration were significantly lower as portal H2 concentration increased. In experiment 2, microbiota derived from HG (the transplantation group) or saline (the control group) were orally inoculated into LG on days 3 and 4. On day 13, portal H2 concentration in the transplantation group was significantly higher compared with the control group, and positively correlated with genera Bifidobacterium, Allobaculum, and Parabacteroides, and negatively correlated with genera Bacteroides, Ruminococcus, and Escherichia. In conclusion, the transplantation of microbiota derived from HG leads to stable, high H2 production in LG, with the resultant high production of H2 contributing to the alleviation of oxidative stress. PMID- 29382126 TI - Erratum: Mei, Y., et al. Mechanics Based Tomography: A Preliminary Feasibility Study. Sensors 2017, 17, 1075. AB - The authors wish to correct Figures 12 and 14 in their paper published in Sensors [1], doi:10.3390/s17051075, http://www.mdpi.com/1424-8220/17/5/1075[...]. PMID- 29382127 TI - The Implication of the Brain Insulin Receptor in Late Onset Alzheimer's Disease Dementia. AB - Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid beta peptide (Abeta), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Abeta production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Abeta42 generated in the brain would impact negatively on the hypothalamus, accelerating the "peripheral" symptomatology of AD. In this situation, Abeta42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors. PMID- 29382128 TI - Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. AB - Hypoxia-inducible factor (HIF) plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD) as well as in multiple other disease states involving ischemia-reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI) in these patients. Additionally, articles reporting the clinical potential for HIF-PHIs in 'other' putative therapeutic areas, the tissue and intracellular distribution of HIF- and prolyl-hydroxylase domain (PHD) isoforms, and HIF isoforms targeted by the different PHDs, were identified. There is increasing uncertainty regarding the optimal treatment for anemia of CKD with poorer outcomes associated with treatment to higher hemoglobin targets, and the increasing use of iron and consequent risk of iron imbalance. Attainment and maintenance of more physiologic erythropoietin levels associated with HIF stabilization may improve the management of patients resistant to treatment with erythropoiesis-stimulating agents and improve outcomes at higher hemoglobin targets. PMID- 29382129 TI - An Online Survey of New Zealand Vapers. AB - Using electronic cigarettes (vaping) is controversial, but is increasingly widespread. This paper reports the results of an electronic survey of vapers in New Zealand, a country where the sale and supply of e-liquids containing nicotine is illegal, although vapers can legally access e-liquids from overseas. An on line survey was conducted, using vaper and smoking cessation networks for recruitment, with follow up surveys conducted 1 and 2 months after the initial survey. 218 participants were recruited. Almost all had been smokers, but three quarters no longer smoked, with the remainder having significantly reduced their tobacco use. Three participants were non-smokers before starting to vape, but none had gone on to become smokers. The overriding motivation to begin and continue vaping was to stop or to reduce smoking. The results were consistent with a progression from initially both vaping and smoking using less effective electronic cigarette types, then moving to more powerful devices, experimentation with flavors and nicotine strengths-all resulting in reducing or stopping tobacco use. Lack of access to nicotine and lack of support for their chosen cessation method were the main problems reported. Vaping had resulted in effective smoking cessation for the majority of participants. PMID- 29382130 TI - Challenges and Achievements in Prevention and Treatment of Smallpox. AB - Declaration of smallpox eradication by the WHO in 1980 led to discontinuation of the worldwide vaccination campaign. The increasing percentage of unvaccinated individuals, the existence of its causative infectious agent variola virus (VARV), and the recent synthetic achievements increase the threat of intentional or accidental release and reemergence of smallpox. Control of smallpox would require an emergency vaccination campaign, as no other protective measure has been approved to achieve eradication and ensure worldwide protection. Experimental data in surrogate animal models support the assumption, based on anecdotal, uncontrolled historical data, that vaccination up to 4 days postexposure confers effective protection. The long incubation period, and the uncertainty of the exposure status in the surrounding population, call for the development and evaluation of safe and effective methods enabling extension of the therapeutic window, and to reduce the disease manifestations and vaccine adverse reactions. To achieve these goals, we need to evaluate the efficacy of novel and already licensed vaccines as a sole treatment, or in conjunction with immune modulators and antiviral drugs. In this review, we address the available data, recent achievements, and open questions. PMID- 29382131 TI - Unravelling Immunoglobulin G Fc N-Glycosylation: A Dynamic Marker Potentiating Predictive, Preventive and Personalised Medicine. AB - Multiple factors influence immunoglobulin G glycosylation, which in turn affect the glycoproteins' function on eliciting an anti-inflammatory or pro-inflammatory response. It is prudent to underscore these processes when considering the use of immunoglobulin G N-glycan moieties as an indication of disease presence, progress, or response to therapeutics. It has been demonstrated that the altered expression of genes that encode enzymes involved in the biosynthesis of immunoglobulin G N-glycans, receptors, or complement factors may significantly modify immunoglobulin G effector response, which is important for regulating the immune system. The immunoglobulin G N-glycome is highly heterogenous; however, it is considered an interphenotype of disease (a link between genetic predisposition and environmental exposure) and so has the potential to be used as a dynamic biomarker from the perspective of predictive, preventive, and personalised medicine. Undoubtedly, a deeper understanding of how the multiple factors interact with each other to alter immunoglobulin G glycosylation is crucial. Herein we review the current literature on immunoglobulin G glycoprotein structure, immunoglobulin G Fc glycosylation, associated receptors, and complement factors, the downstream effector functions, and the factors associated with the heterogeneity of immunoglobulin G glycosylation. PMID- 29382132 TI - S1P Signalling Differentially Affects Migration of Peritoneal B Cell Populations In Vitro and Influences the Production of Intestinal IgA In Vivo. AB - Introduction: Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells (B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to S1P was studied in vitro. The role of S1P signalling was further explored in a s1p4-/- mouse strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4 (S1P1 and S1P4, respectively). S1P1 showed differential expression between the distinct peritoneal B cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration response to S1P. s1p4-/- mice displayed significant alterations in the composition of peritoneal B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA) in the gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P4 deficiency alters the composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies. PMID- 29382133 TI - Early and Late Onset Side Effects of Photodynamic Therapy. AB - Photodynamic Therapy (PDT) is a non-invasive treatment successfully used for neoplastic, inflammatory and infectious skin diseases. One of its strengths is represented by the high safety profile, even in elderly and/or immuno-depressed subjects. PDT, however, may induce early and late onset side effects. Erythema, pain, burns, edema, itching, desquamation, and pustular formation, often in association with each other, are frequently observed in course of exposure to the light source and in the hours/days immediately after the therapy. In particular, pain is a clinically relevant short-term complication that also reduces long-term patient satisfaction. Rare complications are urticaria, contact dermatitis at the site of application of the photosensitizer, and erosive pustular dermatosis. Debated is the relationship between PDT and carcinogenesis: the eruptive appearance of squamous cell carcinoma (SCC) in previously treated areas has been correlated to a condition of local and/or systemic immunosuppression or to the selection of PDT-resistant SCC. Here we review the literature, with particular emphasis to the pathogenic hypotheses underlying these observations. PMID- 29382134 TI - Phage-Bacterial Dynamics with Spatial Structure: Self Organization around Phage Sinks Can Promote Increased Cell Densities. AB - Bacteria growing on surfaces appear to be profoundly more resistant to control by lytic bacteriophages than do the same cells grown in liquid. Here, we use simulation models to investigate whether spatial structure per se can account for this increased cell density in the presence of phages. A measure is derived for comparing cell densities between growth in spatially structured environments versus well mixed environments (known as mass action). Maintenance of sensitive cells requires some form of phage death; we invoke death mechanisms that are spatially fixed, as if produced by cells. Spatially structured phage death provides cells with a means of protection that can boost cell densities an order of magnitude above that attained under mass action, although the effect is sometimes in the opposite direction. Phage and bacteria self organize into separate refuges, and spatial structure operates so that the phage progeny from a single burst do not have independent fates (as they do with mass action). Phage incur a high loss when invading protected areas that have high cell densities, resulting in greater protection for the cells. By the same metric, mass action dynamics either show no sustained bacterial elevation or oscillate between states of low and high cell densities and an elevated average. The elevated cell densities observed in models with spatial structure do not approach the empirically observed increased density of cells in structured environments with phages (which can be many orders of magnitude), so the empirical phenomenon likely requires additional mechanisms than those analyzed here. PMID- 29382135 TI - Synthesis, DNA Binding, and Anticancer Properties of Bis-Naphthalimide Derivatives with Lysine-Modified Polyamine Linkers. AB - A series of bis-naphthalimide derivatives with different diamine linkers were designed and synthesized. All of the synthesized bis-naphthalimide derivatives were characterized by NMR and HRMS spectra. The binding ability between the compounds and CT DNA was evaluated by using UV-Vis titration experiments. The bis naphthalimide compound with an ethylenediamine linker showed the largest binding constant with CT DNA. Hence, it was used as the model compound to study the DNA binding selectivity by UV-Vis titration aiming at different DNA duplexes. As a result, this compound showed binding preference to AT-rich duplexes. The DNA binding modes of the compounds were also measured by viscosity titration. The cytotoxicity of the compounds was evaluated by MTT assay. Compounds with 1,6 diaminohexane or 1,4-phenylenedimethanamine linkers showed higher cytotoxicity compared with other bis-naphthalimide derivatives. PMID- 29382136 TI - A New Strategy Involving the Use of Peptides and Graphene Oxide for Fluorescence Turn-on Detection of Proteins. AB - The detection of proteins is of great biological significance as disease biomarkers in early diagnosis, prognosis tracking and therapeutic evaluation. Thus, we developed a simple, sensitive and universal protein-sensing platform based on peptide and graphene oxide (GO). The design consists of a fluorophore (TAMRA, TAM), a peptide containing eight arginines and peptide ligand that could recognize the target protein, and GO used as a quencher. To demonstrate the feasible use of the sensor for target detection, Bcl-xL was evaluated as the model target. The sensor was proved to be sensitive and applied for the detection of the target proteins in buffer, 2% serum and living cells. PMID- 29382137 TI - Dietary Habits and Eating Practices and Their Association with Overweight and Obesity in Rural and Urban Black South African Adolescents. AB - The aim of this study was to investigate differences/similarities in dietary habits and eating practices between younger and older, rural and urban South African adolescents in specific environments (home, community and school) and their associations with overweight and obesity. Dietary habits, eating practices, and anthropometric measurements were performed on rural (n = 392, mean age = 13 years) and urban (n = 3098, mean age = 14 years) adolescents. Logistic regression analysis was used to examine the associations between dietary habits and eating practices, with overweight and obesity risk. Differences in dietary habits and eating practices by gender and by site within the three environments were identified. After adjusting for gender, site, dietary habits, and eating practices within the home, community and school environment, eating the main meal with family some days (OR = 1.78, 95% CI = 1.114-2.835; p <= 0.02), eating the main meal with family almost every day (OR = 1.61, 95% CI = 1.106-2.343; p <= 0.01), and irregular frequency of consuming breakfast on weekdays (OR = 1.38, 95% CI = 1.007-1.896; p <= 0.05) were all associated with increased risk of overweight and obesity. For "Year 15" adolescents, irregular frequency of consuming breakfast on weekends within the home environment (OR = 1.53, 95% CI = 1.099-2.129, p <= 0.01), was associated with increased risk of overweight and obesity. For both early- and mid-adolescents, being male (OR = 0.401, 95% CI = 0.299-0.537; p <= 0.00; OR = 0.29, 95% CI = 0.218-0.397; p <= 0.00) was associated with reduced risk of overweight and obesity, while residing in a rural setting (OR = 0.55, 95% CI = 0.324-0.924; p <= 0.02) was associated with reduced risk of overweight and obesity only among early-adolescents. Only dietary habits and eating practices within the home environment were associated with increased risk of overweight and obesity. PMID- 29382138 TI - Isolation and Quantification of Ginsenoside Rh23, a New Anti-Melanogenic Compound from the Leaves of Panax ginseng. AB - A new ginsenoside, named ginsenoside Rh23 (1), and 20-O-beta-d-glucopyranosyl 3beta,6alpha,12beta,20beta,25-pentahydroxydammar-23-ene (2) were isolated from the leaves of hydroponic Panax ginseng. Compounds were isolated by various column chromatography and their structures were determined based on spectroscopic methods, including high resolution quadrupole/time of flight mass spectrometry (HR-QTOF/MS), nuclear magnetic resonance (NMR) spectroscopy, and infrared (IR) spectroscopy. To determine anti-melanogenic activity, the change in the melanin content in melan-a cells treated with identified compounds was tested. Additionally, we investigated the melanin inhibitory effects of ginsenoside Rh23 on pigmentation in a zebrafish in vivo model. Compound 1 inhibited potent melanogenesis in melan-a cells with 37.0% melanogenesis inhibition at 80 uM and also presented inhibition on the body pigmentation in zebrafish model. Although compound 2 showed slightly lower inhibitory activity than compound 1, it also showed significantly decreased melanogenesis in melan-a cell and in zebrafish model. These results indicated that compounds isolated from hydroponic P. ginseng may be used as new skin whitening compound through the in vitro and in vivo systems. Furthermore, this study demonstrated the utility of MS-based compound 1 for the quantitative analysis. Ginsenoside Rh23 (1) was found at a level of 0.31 mg/g in leaves of hydroponic P. ginseng. PMID- 29382139 TI - Bone Response to Dietary Co-Enrichment with Powdered Whole Grape and Probiotics. AB - Nutrition is a primary modifiable determinant of chronic noncommunicable disease, including osteoporosis. An etiology of osteoporosis is the stimulation of bone resorbing osteoclasts by reactive oxygen species (ROS). Dietary polyphenols and probiotics demonstrate protective effects on bone that are associated with reduced ROS formation and suppressed osteoclast activity. This study tested the effect of dietary enrichment with powdered whole grape and probiotics (composed of equal parts Bifidobacterium bifidum, B. breve, Lactobacillus casei, L. plantarum, and L. bulgaricus) on bone microarchitecture in a mouse model of age related osteoporosis. Groups (n = 7 each) of 10-month-old male mice were fed one of six diets for 6 months: 10% grape powder with sugar corrected to 20%; 20% grape powder; 1% probiotic with sugar corrected to 20%; 10% grape powder + 1% probiotic with sugar corrected to 20%; 20% grape powder + 1% probiotic; 20% sugar control. Femur, tibia and 4th lumbar vertebrae from 10-month-old mice served as comparator baseline samples. Bone microarchitecture was measured by micro computed tomography and compared across diet groups using analysis of variance. Aging exerted a significant effect on tibia metaphysis trabecular bone, with baseline 10-month-old mice having significantly higher bone volume/total volume (BV/TV) and trabecular number measurements and lower trabecular spacing measurements than all 16-month-old groups (p < 0.001). Neither grape nor probiotic enrichment significantly improved bone microarchitecture during aging compared to control diet. The combination of 20% grape + 1% probiotic exerted detrimental effects on tibia metaphysis BV/TV compared to 10% grape + 1% probiotic, and trabecular number and trabecular spacing compared to 10% grape + 1% probiotic, 1% probiotic and control groups (p < 0.05). Femur metaphysis trabecular bone displayed less pronounced aging effects than tibia bone, but also showed detrimental effects of the 20% grape + 1% probiotic vs. most other diets for BV/TV, trabecular number, trabecular spacing and trabecular pattern factor (p < 0.05). Tibia and femur diaphysis cortical bone (cortical wall thickness and medullary area) displayed neither aging nor diet effects (p > 0.05). Vertebrae bone showed age-related deterioration in trabecular thickness and trabecular spacing and a trend toward preservation of trabecular thickness by grape and/or probiotic enrichment (p < 0.05). These findings demonstrate no benefit to bone of combined compared to independent supplementation with probiotics or whole grape powder and even suggest an interference of co-ingestion. PMID- 29382140 TI - The Effects of Digital Marketing of Unhealthy Commodities on Young People: A Systematic Review. AB - The marketing of unhealthy commodities through traditional media is known to impact consumers' product attitudes and behaviors. Less is known about the impacts of digital marketing (online promotional activities), especially among young people who have a strong online presence. This review systematically assesses the relationship between digital marketing and young people's attitudes and behaviors towards unhealthy commodities. Literature was identified in June 2017 by searches in six electronic databases. Primary studies (both qualitative and quantitative) that examined the effect of digital marketing of unhealthy food or beverages, alcohol and tobacco products on young people's (12 to 30 years) attitudes, intended and actual consumption were reviewed. 28 relevant studies were identified. Significant detrimental effects of digital marketing on the intended use and actual consumption of unhealthy commodities were revealed in the majority of the included studies. Findings from the qualitative studies were summarized and these findings provided insights on how digital marketing exerts effects on young people. One of the key findings was that marketers used peer-to peer transmission of messages on social networking sites (e.g., friends' likes and comments on Facebook) to blur the boundary between marketing contents and online peer activities. Digital marketing of unhealthy commodities is associated with young people's use and beliefs of these products. The effects of digital marketing varied between product types and peer endorsed marketing (earned media) may exert greater negative impacts than owned or paid media marketing. PMID- 29382141 TI - Zinc, Carnosine, and Neurodegenerative Diseases. AB - Zinc (Zn) is abundantly present in the brain, and accumulates in the synaptic vesicles. Synaptic Zn is released with neuronal excitation, and plays essential roles in learning and memory. Increasing evidence suggests that the disruption of Zn homeostasis is involved in various neurodegenerative diseases including Alzheimer's disease, a vascular type of dementia, and prion diseases. Our and other numerous studies suggest that carnosine (beta-alanyl histidine) is protective against these neurodegenerative diseases. Carnosine is an endogenous dipeptide abundantly present in the skeletal muscles and in the brain, and has numerous beneficial effects such as antioxidant, metal chelating, anti crosslinking, and anti-glycation activities. The complex of carnosine and Zn, termed polaprezinc, is widely used for Zn supplementation therapy and for the treatment of ulcers. Here, we review the link between Zn and these neurodegenerative diseases, and focus on the neuroprotective effects of carnosine. We also discuss the carnosine level in various foodstuffs and beneficial effects of dietary supplementation of carnosine. PMID- 29382142 TI - The Influence of Pre-Exercise Glucose versus Fructose Ingestion on Subsequent Postprandial Lipemia. AB - Ingestion of low glycemic index (LGI) carbohydrate (CHO) before exercise induced less insulin response and higher fat oxidation than that of high GI (HGI) CHO during subsequent exercise. However, the effect on the subsequent postprandial lipid profile is still unclear. Therefore, the aim of this study was to investigate ingestion of CHO drinks with different GI using fructose and glucose before endurance exercise on the subsequent postprandial lipid profile. Eight healthy active males completed two experimental trials in randomized double-blind cross-over design. All participants ingested 500 mL CHO (75 g) solution either fructose (F) or glucose (G) before running on the treadmill at 60% VO2max for 1 h. Participants were asked to take an oral fat tolerance test (OFTT) immediately after the exercise. Blood samples were obtained for plasma and serum analysis. The F trial was significantly lower than the G trial in TG total area under the curve (AUC; 9.97 +/- 3.64 vs. 10.91 +/- 3.56 mmol * 6 h/L; p = 0.033) and incremental AUC (6.57 +/- 2.46 vs. 7.14 +/- 2.64 mmol/L * 6 h, p = 0.004). The current data suggested that a pre-exercise fructose drink showed a lower postprandial lipemia than a glucose drink after the subsequent high-fat meal. PMID- 29382143 TI - Use of a Regression Model to Study Host-Genomic Determinants of Phage Susceptibility in MRSA. AB - Staphylococcus aureus is a major agent of nosocomial infections. Especially in methicillin-resistant strains, conventional treatment options are limited and expensive, which has fueled a growing interest in phage therapy approaches. We have tested the susceptibility of 207 clinical S. aureus strains to 12 (nine monovalent) different therapeutic phage preparations and subsequently employed linear regression models to estimate the influence of individual host gene families on resistance to phages. Specifically, we used a two-step regression model setup with a preselection step based on gene family enrichment. We show that our models are robust and capture the data's underlying signal by comparing their performance to that of models build on randomized data. In doing so, we have identified 167 gene families that govern phage resistance in our strain set and performed functional analysis on them. This revealed genes of possible prophage or mobile genetic element origin, along with genes involved in restriction-modification and transcription regulators, though the majority were genes of unknown function. This study is a step in the direction of understanding the intricate host-phage relationship in this important pathogen with the outlook to targeted phage therapy applications. PMID- 29382144 TI - Use of Acoustic Emission and Pattern Recognition for Crack Detection of a Large Carbide Anvil. AB - Large-volume cubic high-pressure apparatus is commonly used to produce synthetic diamond. Due to the high pressure, high temperature and alternative stresses in practical production, cracks often occur in the carbide anvil, thereby resulting in significant economic losses or even casualties. Conventional methods are unsuitable for crack detection of the carbide anvil. This paper is concerned with acoustic emission-based crack detection of carbide anvils, regarded as a pattern recognition problem; this is achieved using a microphone, with methods including sound pulse detection, feature extraction, feature optimization and classifier design. Through analyzing the characteristics of background noise, the cracked sound pulses are separated accurately from the originally continuous signal. Subsequently, three different kinds of features including a zero-crossing rate, sound pressure levels, and linear prediction cepstrum coefficients are presented for characterizing the cracked sound pulses. The original high-dimensional features are adaptively optimized using principal component analysis. A hybrid framework of a support vector machine with k nearest neighbors is designed to recognize the cracked sound pulses. Finally, experiments are conducted in a practical diamond workshop to validate the feasibility and efficiency of the proposed method. PMID- 29382145 TI - Compressive Multispectral Spectrum Sensing for Spectrum Cartography. AB - In the process of spectrum sensing applied to wireless communications, it is possible to build interference maps based on acquired power spectral values. This allows the characterization of spectral occupation, which is crucial to take management spectrum decisions. However, the amount of information both in the space and frequency domains that needs to be processed generates an enormous amount of data with high transmission delays and high memory requirements. Meanwhile, compressive sensing is a technique that allows the reconstruction of sparse or compressible signals using fewer samples than those required by the Nyquist criterion. This paper presents a new model that uses compressed multispectral sampling for spectrum sensing. The aim is to reduce the number of data required for the storage and the subsequent construction of power spectral maps with geo-referenced information in different frequency bands. This model is based on architectures that use compressive sensing to analyze multispectral images. The operation of a centralized manager is presented in order to select the power data of different sensors by binary patterns. These sensors are located in different geographical positions. The centralized manager reconstructs a data cube with the transmitted power and frequency of operation of all the sensors based on the samples taken and applying multispectral sensing techniques. The results show that this multispectral data cube can be built with 50% of the samples generated by the devices, and the spectrum cartography information can be stored using only 6.25% of the original data. PMID- 29382146 TI - Feature Extraction of Electronic Nose Signals Using QPSO-Based Multiple KFDA Signal Processing. AB - The aim of this research was to enhance the classification accuracy of an electronic nose (E-nose) in different detecting applications. During the learning process of the E-nose to predict the types of different odors, the prediction accuracy was not quite satisfying because the raw features extracted from sensors' responses were regarded as the input of a classifier without any feature extraction processing. Therefore, in order to obtain more useful information and improve the E-nose's classification accuracy, in this paper, a Weighted Kernels Fisher Discriminant Analysis (WKFDA) combined with Quantum-behaved Particle Swarm Optimization (QPSO), i.e., QWKFDA, was presented to reprocess the original feature matrix. In addition, we have also compared the proposed method with quite a few previously existing ones including Principal Component Analysis (PCA), Locality Preserving Projections (LPP), Fisher Discriminant Analysis (FDA) and Kernels Fisher Discriminant Analysis (KFDA). Experimental results proved that QWKFDA is an effective feature extraction method for E-nose in predicting the types of wound infection and inflammable gases, which shared much higher classification accuracy than those of the contrast methods. PMID- 29382147 TI - Enzymatic Fuel Cells: Towards Self-Powered Implantable and Wearable Diagnostics. AB - With the rapid progress in nanotechnology and microengineering, point-of-care and personalised healthcare, based on wearable and implantable diagnostics, is becoming a reality. Enzymatic fuel cells (EFCs) hold great potential as a sustainable means to power such devices by using physiological fluids as the fuel. This review summarises the fundamental operation of EFCs and discusses the most recent advances for their use as implantable and wearable self-powered sensors. PMID- 29382148 TI - Implementation and Operational Analysis of an Interactive Intensive Care Unit within a Smart Health Context. AB - In the context of hospital management and operation, Intensive Care Units (ICU) are one of the most challenging in terms of time responsiveness and criticality, in which adequate resource management and signal processing play a key role in overall system performance. In this work, a context aware Intensive Care Unit is implemented and analyzed to provide scalable signal acquisition capabilities, as well as to provide tracking and access control. Wireless channel analysis is performed by means of hybrid optimized 3D Ray Launching deterministic simulation to assess potential interference impact as well as to provide required coverage/capacity thresholds for employed transceivers. Wireless system operation within the ICU scenario, considering conventional transceiver operation, is feasible in terms of quality of service for the complete scenario. Extensive measurements of overall interference levels have also been carried out, enabling subsequent adequate coverage/capacity estimations, for a set of Zigbee based nodes. Real system operation has been tested, with ad-hoc designed Zigbee wireless motes, employing lightweight communication protocols to minimize energy and bandwidth usage. An ICU information gathering application and software architecture for Visitor Access Control has been implemented, providing monitoring of the Boxes external doors and the identification of visitors via a RFID system. The results enable a solution to provide ICU access control and tracking capabilities previously not exploited, providing a step forward in the implementation of a Smart Health framework. PMID- 29382149 TI - Anticancer Efficacy of Targeted Shikonin Liposomes Modified with RGD in Breast Cancer Cells. AB - Shikonin (SHK) has been proven to have a good anti-tumor effect. However, poor water solubility and low bioavailability limit its wide application in clinical practice. In this study, to overcome these drawbacks, RGD-modified shikonin loaded liposomes (RGD-SSLs-SHK) were successfully prepared. It exhibited excellent physicochemical characteristics including particle size, zeta potential, encapsulation efficiency, and delayed release time. Meanwhile, the targeting activity of the RGD-modified liposomes was demonstrated by flow cytometry and confocal microscopy in the alphavbeta3-positive MDA-MB-231 cells. Besides exhibiting greater cytotoxicity in vitro, compared with non-targeted shikonin-loaded liposomes (SSLs-SHK), RGD-SSLs-SHK could also evidently induce apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax. It could also inhibit cell proliferation, migration, invasion, and adhesion by reducing the expression of MMP-9 and the level of NF-kappaB p65, but did not affect the expression of MMP-2 in the MDA-MB-231 cells. Therefore, these findings indicated that the strategy to use RGD-modified liposomes as carriers for targeted delivery of shikonin is a very promising approach to achieve breast cancer targeted therapy. PMID- 29382150 TI - Cloning, Expression Analysis and Functional Characterization of Squalene Synthase (SQS) from Tripterygium wilfordii. AB - Celastrol is an active triterpenoid compound derived from Tripterygium wilfordii which is well-known as a traditional Chinese medicinal plant. Squalene synthase has a vital role in condensing two molecules of farnesyl diphosphate to form squalene, a key precursor of triterpenoid biosynthesis. In the present study, T. wilfordii squalene synthase (TwSQS) was cloned followed by prokaryotic expression and functional verification. The open reading frame cDNA of TwSQS was 1242 bp encoding 413 amino acids. Bioinformatic and phylogenetic analysis showed that TwSQS had high homology with other plant SQSs. To obtain soluble protein, the truncated TwSQS without the last 28 amino acids of the carboxy terminus was inductively expressed in Escherichia coliTransetta (DE3). The purified protein was detected by SDS-PAGE and Western blot analysis. Squalene was detected in the product of in vitro reactions by gas chromatograph-mass spectrometry, which meant that TwSQS did have catalytic activity. Organ-specific and inducible expression levels of TwSQS were detected by quantitative real-time PCR. The results indicated that TwSQS was highly expressed in roots, followed by the stems and leaves, and was significantly up-regulated upon MeJA treatment. The identification of TwSQS is important for further studies of celastrol biosynthesis in T. wilfordii. PMID- 29382151 TI - Novel Strategies Using Total Gastrodin and Gastrodigenin, or Total Gastrodigenin for Quality Control of Gastrodia elata. AB - Gastrodia elata Blume (G. elata), a traditional Chinese medicine, is widely used for treatment of various neuro dysfunctions. However, its quality control is still limited to the determination of gastrodin. In the present study, two novel strategies based on quantitative evaluation of total gastrodin and gastrodigenin with base hydrolysis and total gastrodigenin with base-enzymatic hydrolysis followed by HPLC-FLD were put forward and successfully applied to evaluate the quality of 47 batches of G. elata from eight localities. Meanwhile, a systematic comparison of the novel strategy with the multiple markers and the Pharmacopeia method was performed. The results showed that the parishins category could be completely hydrolyzed to gastrodin by sodium hydroxide solution, and gastrodin could further utterly hydrolyze to gastrodigenin with beta-d-glucosidase buffer solution. The contents of total gastrodin and gastrodigenin ranged from 1.311% to 2.034%, and total gastrodigenin from 0.748% to 1.120% at the eight localities. From the comparison, we can conclude that the two novel strategies can comprehensively reveal the characteristics of overall active ingredients in G. elata for quality control. The present study provides a feasible and credible strategy for the quality control of G. elata, suggesting a revision of the latest Chinese Pharmacopoeia or European Pharmacopoeia methods for the modernization of G. elata use. PMID- 29382152 TI - Evaluation of Melatonin Secretion and Metabolism Exponents in Patients with Ulcerative and Lymphocytic Colitis. AB - Inflammatory bowel diseases, particularly ulcerative colitis (UC) and lymphocytic colitis (LC), affect many people. The role of melatonin in the pathogenesis of UC is precisely determined, whereas in LC it remains unknown. The aim of this study was to compare the expression of the melatonin-synthesizing enzymes tryptophan hydroxylase (TPH1), arylalkylamine-N-acetyltransferase (AANAT), and N acetylserotonin methyltransferase (ASMT) in the colonic mucosa and urinary excretion of 6-sulfatoxymelatonin in patients with ulcerative and lymphocytic colitis. The study included 30 healthy subjects (group C), 30 patients with severe ulcerative colitis (group UC), and 30 patients with lymphocytic colitis (group LC). The diagnosis was based on endoscopic, histological, and laboratory examinations. Biopsy specimens were collected from right, transverse, and left parts of the colon. The levels of mRNA expression, TPH1, AANAT, and ASMT were estimated in the colonic mucosa with RT-PCR. The urine concentration of aMT6s was determined by the photometric method. The expression of TPH1, AANAT, and ASMT in colonic mucosa in UC and LC patients was significantly higher than in healthy subjects. Significant differences were found in the urinary aMT6s excretion: group C-13.4 +/- 4.8 ug/24 h, group UC-7.8 +/- 2.6 ug/24 h (p < 0.01), group LC 19.2 +/- 6.1 ug/24 h (p < 0.01). Moreover, a negative correlation was found between fecal calprotectin and MT6s-in patients with UC - r = -0.888 and with LC r = -0.658. These results indicate that patients with UC and those with LC may display high levels of melatonin-synthesizing enzymes in their colonic mucosa, which could possibly be related to increased melatonin synthesis as an adaptive antioxidant activity. PMID- 29382153 TI - Preparation, Characterization and Catalytic Activity of Nickel Molybdate (NiMoO4) Nanoparticles. AB - Nickel molybdate (NiMoO4) nanoparticles were synthesized via calcination of an oxalate complex in static air at 500 degrees C. The oxalate complex was analyzed by thermal gravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR). The as-synthesized nickel molybdate was characterized by Brunauer-Emmett Teller technique (BET), X-ray diffraction (XRD), and transmission electron microscopy (TEM) and its catalytic efficiency was tested in the reduction reaction of the three-nitrophenol isomers. The nickel molybdate displays a very high activity in the catalytic reduction of the nitro functional group to an amino. The reduction progress was controlled using Ultraviolet-Visible (UV-Vis) absorption. PMID- 29382154 TI - Chemical Constituents and Antioxidant, Anti-Inflammatory and Anti-Tumor Activities of Melilotus officinalis (Linn.) Pall. AB - Two new p-hydroxybenzoic acid glycosides, namely p-hydroxybenzoic acid-4-O-alpha d-manopyranosyl-(1 -> 3)-alpha-l-rhamnopyranoside (compound 1) and 4-O-alpha-l rhamnopyran-osyl-(1 -> 6)-alpha-d-manopyranosyl-(1 -> 3)-alpha-l-rhamnopyranoside (compound 2), and seven known compounds, compound 3, 6, 7 (acid components), compound 8, 9 (flavonoids), compound 4 (a coumarin) and compound 5 (an alkaloid), were isolated from the 70% ethanol aqueous extract of the aerial parts of Melilotus officinalis (Linn.) Pall. The structures of all compounds were elucidated by use of extensive spectroscopic methods Infrared Spectroscopy (IR), High resolution electrospray ionization mass spectrometry (HR-ESI-MS), and 1H and 13C-NMR). Sugar residues obtained after acid hydrolysis were identified by high performance liquid chromatography (HPLC). The antioxidant activity of all the compounds was evaluated by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) and 1,1-diphenyl-2-picrylhydrazyl (DPPH). The anti-inflammatory effects of the compounds were also evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. All compounds were shown to inhibit LPS-induced nitric oxide (NO) and prostaglandin E 2 (PGE 2) production by suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, in LPS stimulated RAW 264.7 cells. The inhibitory effect of all the compounds on MCF-7 cells was determined by Cell Counting Kit-8 (CCK-8) method. The results showed that compounds 1, 2, 7, 8, 9 exhibited better antioxidant activity compared to the other compounds. compounds 1-9 had different inhibitory effects on the release of NO, TNF-alpha and IL-6 in LPS-stimulated RAW264.7 cells by LPS, of which compound 7 was the most effective against inflammatory factors. compounds 1 and 2 have better antitumor activity compared to other compounds. Further research to elucidate the chemical composition and pharmacological effects of Melilotus officinalis (Linn.) Pall is of major importance towards the development and foundation of clinical application of the species. PMID- 29382155 TI - The Effect of Zeolite Composition and Grain Size on Gas Sensing Properties of SnO2/Zeolite Sensor. AB - In order to improve the sensing properties of tin dioxide gas sensor, four kinds of different SiO2/Al2O3 ratio, different particle size of MFI type zeolites (ZSM 5) were coated on the SnO2 to prepared zeolite modified gas sensors, and the gas sensing properties were tested. The measurement results showed that the response values of ZSM-5 zeolite (SiO2/Al2O3 = 70, grain size 300 nm) coated SnO2 gas sensors to formaldehyde vapor were increased, and the response to acetone decreased compared with that of SnO2 gas sensor, indicating an improved selectivity property. The other three ZSM-5 zeolites with SiO2/Al2O3 70, 150 and 470, respectively, and grain sizes all around 1 MUm coated SnO2 sensors did not show much difference with SnO2 sensor for the response properties to both formaldehyde and acetone. The sensing mechanism of ZSM-5 modified sensors was briefly analyzed. PMID- 29382156 TI - Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment. AB - ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main alpha secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of beta-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer's disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPalpha, which is neuroprotective. As increased ADAM10 activity protects the brain from beta-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review. PMID- 29382157 TI - Factors Associated with Cigarette Smoking and Motivation to Quit among Street Food Sellers in Vietnam. AB - Since 2013, smoke-free signs in public places, including in restaurants and food stores, have been introduced in Vietnam, aiming to prevent passive smoking. Although extensive research has been carried out on second-hand smoking among clients in public places (e.g., hospitals, restaurants) in Vietnam, no single study exists which captures the current practice of smoking among street food outlets. This study aims to estimate the prevalence of smoking and identify factors associated with smoking status and cessation motivation amongst food sellers in Vietnam. A cross-sectional study involving 1733 food providers at outlets was conducted in 29 districts in Hanoi capital, Vietnam, in 2015. The prevalence of smoking amongst food sellers was determined to be 8.5% (25% for men and 0.8% for women). The enforcement of the smoke-free policy remains modest, since only 7.9% observed outlets complied with the law, providing a room designated for smokers. Although approximately 80% of the participants were aware of the indoor smoke-free regulations in public places, such as restaurants and food stores, 40.2% of smokers reported no intention of quitting smoking. A percentage of 37.6% of current smokers reported that despite having intentions to quit, they did not receive any form of support for smoking cessation. Being male and having hazardous drinking habits and a poor quality of life were all factors that were significantly associated with smoking status. Additionally, having awareness of smoking's adverse effects and being frequently supervised by the authority were associated with a greater motivation to quit. This study highlights the importance of an accompanying education and smoking cessation program in addition to the frequent inspection and reinforcement of smoke-free policy in food stores. This research extends on our knowledge of smoking prevalence and its factors related to smoking events and motivation to quit among street food outlets. Overall, this study strengthens the idea that more government efforts towards preventing passive smoking and smoking cessation education are necessary in restaurants and other street food outlets. PMID- 29382158 TI - Rapid Characterization and Identification of Non-Diterpenoid Constituents in Tinospora sinensis by HPLC-LTQ-Orbitrap MSn. AB - Tinospora sinensis, a kind of Chinese folk medicine, has functions of harmonizing qi and blood, dredging the channels and collaterals, calming and soothing the nerves. In the present study, a method based on high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ Orbitrap) was developed for the systematical characterization of the non diterpenoid constituents which possessed remarkable biological activities in T. sinensis, like anti-tumor, anti-inflammatory, hypoglycemic activity and immunomodulatory activity. Based on the accurate mass measurement (<5 ppm), retention times and MS fragmentation ions, 60 non-diterpenoid constituents were unambiguously or tentatively characterized from T. sinensis extract, including 27 alkaloids, 23 phenylpropanoids, seven sesquiterpenoids and three other constituents. Among them, 13 compounds were tentatively identified as new compounds. Finally, three of the non-diterpenoid constituents were purified and identified, which further confirmed the validity of the results. This study demonstrated that the HPLC-LTQ-Orbitrap MSn platform was a useful and efficient analytical tool to screen and identify constituents in natural medicine. PMID- 29382159 TI - Targeted Therapies for Pancreatic Cancer. AB - Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach but our progress in treating pancreatic cancer has been incremental with median overall survival remaining less than one year. There is an urgent need for improved therapies with better efficacy and less toxicity. Small molecule inhibitors, monoclonal antibodies and immune modulatory therapies have been used. Here we review the progress that we have made with these targeted therapies. PMID- 29382160 TI - Tribological Behaviors of Graphene and Graphene Oxide as Water-Based Lubricant Additives for Magnesium Alloy/Steel Contacts. AB - The tribological behaviors of graphene and graphene oxide (GO) as water-based lubricant additives were evaluated by use of a reciprocating ball-on-plate tribometer for magnesium alloy-steel contacts. Three sets of test conditions were examined to investigate the effect of concentration, the capacity of carrying load and the endurance of the lubrication film, respectively. The results showed that the tribological behaviors of water can be improved by adding the appropriate graphene or GO. Compared with pure deionized water, 0.5 wt.% graphene nanofluids can offer reduction of friction coefficient by 21.9% and reduction of wear rate by 13.5%. Meanwhile, 0.5 wt.% GO nanofluids were found to reduce the friction coefficient and wear rate up to 77.5% and 90%, respectively. Besides this, the positive effect of the GO nanofluids was also more pronounced in terms of the load-carrying capacity and the lubrication film endurance. The wear mechanisms have been tentatively proposed according to the observation of the worn surfaces by field emission scanning electron microscope-energy dispersive spectrometer (FESEM-EDS) and Raman spectrum as well as the wettability of the nanofluids on the magnesium alloy surface by goniometer. PMID- 29382161 TI - Effect of Fluoride on the Morphology and Electrochemical Property of Co3O4 Nanostructures for Hydrazine Detection. AB - In this paper, we systematically investigated the influence of fluoride on the morphology and electrochemical property of Co3O4 nanostructures for hydrazine detection. The results showed that with the introduction of NH4F during the synthesis process of Co3O4, both Co(CO3)0.5(OH).0.11H2O and Co(OH)F precursors would be generated. To understand the influence of F on the morphology and electrochemical property of Co3O4, three Co3O4 nanostructures that were respectively obtained from bare Co(CO3)0.5(OH).0.11H2O, Co(OH)F and Co(CO3)0.5(OH).0.11H2O mixtures and bare Co(OH)F were successfully synthesized. The electrochemical tests revealed the sensing performance of prepared Co3O4 nanostructures decreased with the increase in the fluoride contents of precursors. The more that dosages of NH4F were used, the higher crystallinity and smaller specific surface area of Co3O4 was gained. Among these three Co3O4 nanostructures, the Co3O4 that was obtained from bare Co(CO3)0.5(OH).0.11H2O based hydrazine sensor displayed the best performances, which exhibited a great sensitivity (32.42 MUA.mM-1), a low detection limit (9.7 MUMU), and a wide linear range (0.010-2.380 mM), together with good selectivity, great reproducibility and longtime stability. To the best of our knowledge, it was revealed for the first time that the sensing performance of prepared Co3O4 nanostructures decreased with the increase in fluoride contents of precursors. PMID- 29382162 TI - The Microstructure and Mechanical Properties of Refractory High-Entropy Alloys with High Plasticity. AB - Refractory high-entropy alloys (RHEAs) are promising materials used at high temperature, but their low plasticity restricts their application. Based on the valence electron concentration (VEC) principle, four kinds of RHEAs (ZrTiHfV0.5Nb0.5, Zr2.0TiHfVNb2.0, ZrTiHfNb0.5Mo0.5, and ZrTiHfNb0.5Ta0.5) are designed (VEC < 4.5). The experimental results show that the plasticity of these alloys was greatly improved: the static compressive strain was higher than 50% at room temperature (RT), and some elongations were produced in the tensile process. Moreover, the microstructure and phase composition are discussed in detail. The addition of Nb, Mo, and Ta contributed to the high-temperature strength. Finally, the dynamic mechanical properties of these RHEAs with coordination between strength and plasticity are investigated. PMID- 29382163 TI - Interacting Environmental Stress Factors Affects Targeted Metabolomic Profiles in Stored Natural Wheat and That Inoculated with F. graminearum. AB - Changes in environmental stress impact on secondary metabolite (SM) production profiles. Few studies have examined targeted SM production patterns in relation to interacting environmental conditions in stored cereals. The objectives were to examine the effect of water activity (aw; 0.95-0.90) x temperature (10-25 degrees C) on SM production on naturally contaminated stored wheat and that inoculated with Fusarium graminearum. Samples were analysed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) on (a) total number of known SMs, (b) their concentrations and (c) changes under environmental stress. 24 Fusarium metabolites were quantified. Interestingly, statistical differences (ChisSq., p < 0.001) were observed in the number of SMs produced under different sets of interacting environmental conditions. The dominant metabolites in natural stored grain were deoxynivalenol (DON) and nivalenol (NIV) followed by a range of enniatins (A, A1, B, B1), apicidin and DON-3-glucoside at 10 degrees C. Increasing temperature promoted the biosynthesis of other SMs such as aurofusarin, moniliformin, zearalenone (ZEN) and their derivatives. Natural wheat + F. graminearum inoculation resulted in a significant increase in the number of metabolites produced (ChisSq., p < 0.001). For ZEN and its derivatives, more was produced under cooler storage conditions. Fusarin C was enhanced in contrast to that for the enniatin group. The relative ratios of certain groups of targeted SM changed with environmental stress. Both temperature and aw affected the amounts of metabolites present, especially of DON and ZEN. This study suggests that the dominant SMs produced in stored temperate cereals are the mycotoxins for which legislation exists. However, there are changes in the ratios of key metabolites which could influence the relative contamination with individual compounds. Thus, in the future, under more extreme environmental stresses, different dominant SMs may be formed which could make present legislation out of step with the future contamination which might occur. PMID- 29382165 TI - Lipase-Produced Hydroxytyrosyl Eicosapentaenoate is an Excellent Antioxidant for the Stabilization of Omega-3 Bulk Oils, Emulsions and Microcapsules. AB - In this study, several lipophilic hydroxytyrosyl esters were prepared enzymatically using immobilized lipase from Candida antarctica B. Oxidation tests showed that these conjugates are excellent antioxidants in lipid-based matrices, with hydroxytyrosyl eicosapentaenoate showing the highest antioxidant activity. Hydroxytyrosyl eicosapentaenoate effectively stabilized bulk fish oil, fish-oil in-water emulsions and microencapsulated fish oil. The stabilizing effect of this antioxidant may either be because it orients itself with the omega-3 fatty acids in the oil, thereby protecting them against oxidation, or because this unstable fatty acid can preferentially oxidise, thus providing an additional mechanism of antioxidant protection. Hydroxytyrosyl eicosapentaenoate itself was stable for one year when stored at -20 degrees C. PMID- 29382166 TI - Activation of Aflatoxin Biosynthesis Alleviates Total ROS in Aspergillus parasiticus. AB - An aspect of mycotoxin biosynthesis that remains unclear is its relationship with the cellular management of reactive oxygen species (ROS). Here we conduct a comparative study of the total ROS production in the wild-type strain (SU-1) of the plant pathogen and aflatoxin producer, Aspergillus parasiticus, and its mutant strain, AFS10, in which the aflatoxin biosynthesis pathway is blocked by disruption of its pathway regulator, aflR. We show that SU-1 demonstrates a significantly faster decrease in total ROS than AFS10 between 24 h to 48 h, a time window within which aflatoxin synthesis is activated and reaches peak levels in SU-1. The impact of aflatoxin synthesis in alleviation of ROS correlated well with the transcriptional activation of five superoxide dismutases (SOD), a group of enzymes that protect cells from elevated levels of a class of ROS, the superoxide radicals (O2-). Finally, we show that aflatoxin supplementation to AFS10 growth medium results in a significant reduction of total ROS only in 24 h cultures, without resulting in significant changes in SOD gene expression. Our findings show that the activation of aflatoxin biosynthesis in A. parasiticus alleviates ROS generation, which in turn, can be both aflR dependent and aflatoxin dependent. PMID- 29382167 TI - Synthesis and Characterization of "Ravine-Like" BCN Compounds with High Capacitance. AB - A series of "ravine-like" boron carbonitrides (abbreviation: BCN) were synthesized by a green precursor pyrolysis method at different temperatures (about 700-1100 degrees C). The highest electrochemical performance of BCN-800 (Named BCN-temperature) electrode was observed, because the "ravine-like" structure can significantly increase the contact area and improve the wettability between electrode and electrolyte. The BCN electrode exhibited ultrahigh specific capacitance 805.9 F/g (at a current density of 0.2 A/g), excellent rate capability, and good cycling stability (91%) after 3000 cycles at a current density of 8 A/g, showing high potential applications in supercapacitors. PMID- 29382168 TI - Synthesis and Self-Assembly of Chiral Cylindrical Molecular Complexes: Functional Heterogeneous Liquid-Solid Materials Formed by Helicene Oligomers. AB - Chiral cylindrical molecular complexes of homo- and hetero-double-helices derived from helicene oligomers self-assemble in solution, providing functional heterogeneous liquid-solid materials. Gels and liotropic liquid crystals are formed by fibril self-assembly in solution; molecular monolayers and fibril films are formed by self-assembly on solid surfaces; gels containing gold nanoparticles emit light; silica nanoparticles aggregate and adsorb double-helices. Notable dynamics appears during self-assembly, including multistep self-assembly, solid surface catalyzed double-helix formation, sigmoidal and stairwise kinetics, molecular recognition of nanoparticles, discontinuous self-assembly, materials clocking, chiral symmetry breaking and homogeneous-heterogeneous transitions. These phenomena are derived from strong intercomplex interactions of chiral cylindrical molecular complexes. PMID- 29382169 TI - Are Perceived and Objective Distances to Fresh Food and Physical Activity Resources Associated with Cardiometabolic Risk? AB - Perceived and objective measures of neighbourhood features have shown limited correspondence. Few studies have examined whether discordance between objective measures and individual perceptions of neighbourhood environments relates to individual health. Individuals with mismatched perceptions may benefit from initiatives to improve understandings of resource availability. This study utilised data from n = 1491 adult participants in a biomedical cohort to evaluate cross-sectional associations between measures of access (perceived, objective, and perceived-objective mismatch) to fruit and vegetable retailers (FVR) and public open space (POS), and clinically-measured metabolic syndrome and its component risk factors: central obesity, dyslipidaemia, hypertension and pre diabetes/diabetes. Access measures included perceived distances from home to the nearest FVR and POS, corresponding objectively-assessed road network distances, and the discordance between perceived and objective distances (overestimated (i.e., mismatched) distances versus matched perceived-objective distances). Individual and neighbourhood measures were spatially joined using a geographic information system. Associations were evaluated using multilevel logistic regression, accounting for individual and area-level covariates. Hypertension was positively associated with perceived distances to FVR (odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.02, 1.28) and POS (OR = 1.19, 95% CI = 1.05, 1.34), after accounting for covariates and objective distances. Hypertension was positively associated with overestimating distances to FVR (OR = 1.36, 95% CI = 1.02, 1.80). Overestimating distances to POS was positively associated with both hypertension (OR = 1.42, 95% CI = 1.11, 1.83) and dyslipidaemia (OR = 1.25, 95% CI = 1.00, 1.57). Results provide new evidence for specific associations between perceived and overestimated distances from home to nearby resources and cardiometabolic risk factors. PMID- 29382170 TI - Electrotransfer of Different Control Plasmids Elicits Different Antitumor Effectiveness in B16.F10 Melanoma. AB - Several studies have shown that different control plasmids may cause antitumor action in different murine tumor models after gene electrotransfer (GET). Due to the differences in GET protocols, plasmid vectors, and experimental models, the observed antitumor effects were incomparable. Therefore, the current study was conducted comparing antitumor effectiveness of three different control plasmids using the same GET parameters. We followed cytotoxicity in vitro and the antitumor effect in vivo after GET of control plasmids pControl, pENTR/U6 scr and pVAX1 in B16.F10 murine melanoma cells and tumors. Types of cell death and upregulation of selected cytosolic DNA sensors and cytokines were determined. GET of all three plasmids caused significant growth delay in melanoma tumors; nevertheless, the effect of pVAX1 was significantly greater than pControl. While DNA sensors in vivo were not upregulated significantly, cytokines IFN beta and TNF alpha were upregulated after GET of pVAX1. In vitro, the mRNAs of some cytosolic DNA sensors were overexpressed after GET; however, with no significant difference among the three plasmids. In summary, although differences in antitumor effects were observed among control plasmids in vivo, no differences in cellular responses to plasmid GET were detected in tumor cells in vitro. Thus, the tumor microenvironment as well as some plasmid properties are most probably responsible for the antitumor effectiveness. PMID- 29382171 TI - Xylosylated Detoxification of the Rice Flavonoid Phytoalexin Sakuranetin by the Rice Sheath Blight Fungus Rhizoctonia solani. AB - Sakuranetin (1) is a rice flavanone-type phytoalexin. We have already reported that the metabolites from the detoxification of 1 by Pyriculariaoryzae are naringenin (2) and sternbin. In this study, we investigated whether the rice sheath blight fungus Rhizoctoniasolani, another major rice pathogen, can detoxify 1. The extract of R. solani suspension culture containing 1 was analyzed by LC-MS to identify the metabolites of 1. Three putative metabolites of 1 were detected in the extract from the R. solani suspension culture 12 h after the addition of 1, and they were identified as 2, sakuranetin-4'-O-beta-d-xylopyranoside (3), and naringenin-7-O-beta-d-xylopyranoside (4) by NMR, LC-MS/MS, and GC-MS analyses. The accumulation of 2, 3, and 4 reached their maximum levels 9-12 h after the addition of 1, whereas the content of 1 decreased to almost zero within 9 h. The antifungal activities of 3 and 4 against R. solani were negligible, and 2 showed weaker antifungal activity than 1. We concluded that 2, 3, and 4 are metabolites from the detoxification of 1 by R. solani. Xylosylation is a rare and efficient detoxification method for phytoalexins. PMID- 29382172 TI - Dissecting the Structure-Activity Relationship of Galectin-Ligand Interactions. AB - Galectins are beta-galactoside-binding proteins. As carbohydrate-binding proteins, they participate in intracellular trafficking, cell adhesion, and cell cell signaling. Accumulating evidence indicates that they play a pivotal role in numerous physiological and pathological activities, such as the regulation on cancer progression, inflammation, immune response, and bacterial and viral infections. Galectins have drawn much attention as targets for therapeutic interventions. Several molecules have been developed as galectin inhibitors. In particular, TD139, a thiodigalactoside derivative, is currently examined in clinical trials for the treatment of idiopathic pulmonary fibrosis. Herein, we provide an in-depth review on the development of galectin inhibitors, aiming at the dissection of the structure-activity relationship to demonstrate how inhibitors interact with galectin(s). We especially integrate the structural information established by X-ray crystallography with several biophysical methods to offer, not only in-depth understanding at the molecular level, but also insights to tackle the existing challenges. PMID- 29382173 TI - Anti-Cancerous Effect of Inonotus taiwanensis Polysaccharide Extract on Human Acute Monocytic Leukemia Cells through ROS-Independent Intrinsic Mitochondrial Pathway. AB - Acute leukemia is one of the commonly diagnosed neoplasms and causes human death. However, the treatment for acute leukemia is not yet satisfactory. Studies have shown that mushroom-derived polysaccharides display low toxicity and have been used clinically for cancer therapy. Therefore, we set out to evaluate the anti cancerous efficacy of a water-soluble polysaccharide extract from Inonotus taiwanensis (WSPIS) on human acute monocytic leukemia THP-1 and U937 cell lines in vitro. Under our experimental conditions, WSPIS elicited dose-dependent growth retardation and induced apoptotic cell death. Further analysis showed that WSPIS induced apoptosis was associated with a mitochondrial apoptotic pathway, such as the disruption of mitochondrial membrane potential (MMP), followed by the activation of caspase-9, caspase-3, and PARP (poly(ADP-ribose) polymerase) cleavage. However, a broad caspase inhibitor, Z-VAD.fmk, could not prevent WSPIS induced apoptosis. These data imply that mechanism(s) other than caspase might be involved. Thus, the involvement of endonuclease G (endoG), a mediator arbitrating caspase-independent oligonucleosomal DNA fragmentation, was examined. Western blotting demonstrated that WSPIS could elicit nuclear translocation of endoG. MMP disruption after WSPIS treatment was accompanied by intracellular reactive oxygen species (ROS) generation. However, pretreatment with N-acetyl-l-cysteine (NAC) could not attenuate WSPIS-induced apoptosis. In addition, our data also show that WSPIS could inhibit autophagy. Activation of autophagy by rapamycin decreased WSPIS-induced apoptosis and cell death. Taken together, our findings suggest that cell cycle arrest, endonuclease G-mediated apoptosis, and autophagy inhibition contribute to the anti-cancerous effect of WSPIS on human acute monocytic leukemia cells. PMID- 29382174 TI - Exploring the Impacts of Housing Condition on Migrants' Mental Health in Nanxiang, Shanghai: A Structural Equation Modelling Approach. AB - Although rapid urbanization and associated rural-to-urban migration has brought in enormous economic benefits in Chinese cities, one of the negative externalities include adverse effects upon the migrant workers' mental health. The links between housing conditions and mental health are well-established in healthy city and community planning scholarship. Nonetheless, there has thusfar been no Chinese study deciphering the links between housing conditions and mental health accounting for macro-level community environments, and no study has previously examined the nature of the relationships in locals and migrants. To overcome this research gap, we hypothesized that housing conditions may have a direct and indirect effects upon mental which may be mediated by neighbourhood satisfaction. We tested this hypothesis with the help of a household survey of 368 adult participants in Nanxiang Town, Shanghai, employing a structural equation modeling approach. Our results point to the differential pathways via which housing conditions effect mental health in locals and migrants. For locals, housing conditions have direct effects on mental health, while as for migrants, housing conditions have indirect effects on mental health, mediated via neighborhood satisfaction. Our findings have significant policy implications on building an inclusive and harmonious society. Upstream-level community interventions in the form of sustainable planning and designing of migrant neighborhoods can promote sense of community, social capital and support, thereby improving mental health and overall mental capital of Chinese cities. PMID- 29382175 TI - Current Government Actions and Potential Policy Options for Reducing Obesity in Queensland Schools. AB - School nutrition policies provide promising avenues towards the improvement of children's eating habits and the prevention of obesity. Childhood obesity rates and related chronic diseases are increasing in Queensland, in part as a result of unhealthy eating habits and lack of physical activity. There is a very high investment by the Queensland government in maintaining healthy weight and promoting nutrition and physical activity among schoolchildren through delivering a range of initiatives across the state. However, there is a lack of evidence concerning the effectiveness of nutrition/physical education and parental involvement programs addressing obesity delivered in Queensland schools. This paper can be used to guide government and policy-makers regarding the most effective policy options that will promote healthy eating and physical activity among Queensland schoolchildren. The aim of this paper is to: (i) summarize current evidence on Queensland government responses to obesity; and (ii) discuss potential policy options that could support healthy eating and regular physical activity, and examine the evidence base for each option and suggest new areas for future research. PMID- 29382176 TI - Yacon (Smallanthus sonchifolius Poepp. & Endl.) as a Novel Source of Health Promoting Compounds: Antioxidant Activity, Phytochemicals and Sugar Content in Flesh, Peel, and Whole Tubers of Seven Cultivars. AB - The aim of this study was to evaluate the quality characteristics of seven yacon (Smallanthus sonchifolius Poepp. and Endl.) cultivars (Cajamarca, Cusco, Early White, Late Red, Morado, New Zealand and Quinault) cultivated in the southwest of Germany. The following phyto/chemical traits were investigated in different yacon tuber parts (flesh, peel, and whole tubers): total dry matter, sugar content (fructose, glucose, and sucrose content), total phenolic content (TPC), total flavonoid content (TFC), 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, and Ferric reducing antioxidant power (FRAP). The results indicated a significant interaction between cultivar and tuber part on all of the examined traits (p < 0.0001). Of flesh and whole tuber, cv. Late Red, cv. Morado, and cv. Cajamarca had the highest TPC, TFC, DPPH radical scavenging activity, and FRAP. They also had relatively higher total sugar content. Cv. New Zealand had the lowest amount of sugars, TPC, TFC, DPPH radical scavenging activity, and FRAP, but the highest ABTS radical scavenging activity content in its flesh and whole tuber. Moreover, the results indicated that the peel of yacon tubers contained considerably high amounts of phytochemicals while possessing low sugar contents. Overall, this study provides a broad insight into the phyto/chemical content of yacon tubers from different cultivars, which can be used for further breeding programs, and the selection of proper cultivars for specific food product development. PMID- 29382177 TI - Research on the Effects of Drying Temperature on Nitrogen Detection of Different Soil Types by Near Infrared Sensors. AB - Soil is a complicated system whose components and mechanisms are complex and difficult to be fully excavated and comprehended. Nitrogen is the key parameter supporting plant growth and development, and is the material basis of plant growth as well. An accurate grasp of soil nitrogen information is the premise of scientific fertilization in precision agriculture, where near infrared sensors are widely used for rapid detection of nutrients in soil. However, soil texture, soil moisture content and drying temperature all affect soil nitrogen detection using near infrared sensors. In order to investigate the effects of drying temperature on the nitrogen detection in black soil, loess and calcium soil, three kinds of soils were detected by near infrared sensors after 25 degrees C placement (ambient temperature), 50 degrees C drying (medium temperature), 80 degrees C drying (medium-high temperature) and 95 degrees C drying (high temperature). The successive projections algorithm based on multiple linear regression (SPA-MLR), partial least squares (PLS) and competitive adaptive reweighted squares (CARS) were used to model and analyze the spectral information of different soil types. The predictive abilities were assessed using the prediction correlation coefficients (RP), the root mean squared error of prediction (RMSEP), and the residual predictive deviation (RPD). The results showed that the loess (RP = 0.9721, RMSEP = 0.067 g/kg, RPD = 4.34) and calcium soil (RP = 0.9588, RMSEP = 0.094 g/kg, RPD = 3.89) obtained the best prediction accuracy after 95 degrees C drying. The detection results of black soil (RP = 0.9486, RMSEP = 0.22 g/kg, RPD = 2.82) after 80 degrees C drying were the optimum. In conclusion, drying temperature does have an obvious influence on the detection of soil nitrogen by near infrared sensors, and the suitable drying temperature for different soil types was of great significance in enhancing the detection accuracy. PMID- 29382178 TI - Preparation of Cuprous Oxide Mesoporous Spheres with Different Pore Sizes for Non Enzymatic Glucose Detection. AB - Mass transfer plays a significant role in a sensor's performance, because the substrate can be detected only when it contacts with the active catalytic surface. In this work, cuprous oxide mesoporous nanospheres (Cu2O MPNS) with different pore size distributions are fabricated and applied as electrocatalysts for glucose detection. The small pore Cu2O (SP-Cu2O, mean pore size of 5.3 nm) and large pore Cu2O (LP-Cu2O, mean pore size of 16.4 nm) spheres are prepared by the template method and an etching treatment. The obtained two kinds of Cu2O MPNS exhibit high porosity with a similar specific surface area of 61.2 and 63.4 (m2.g 1), respectively. The prepared Cu2O MPNS are used to construct an electrochemical non-enzymatic glucose sensor. The results show that the LP-Cu2O exhibits better performance than SP-Cu2O, which illustrates that the internal diffusion takes a great impact on the performance of the sensor. The LP-Cu2O modified electrode possesses a high and reproducible sensitivity of 2116.9 MUA mM-1.cm-2 at the applied potential of 0.6 V with a wide detection range of 0.003-7.8 mM and a low detection limit of 0.42 MUM. PMID- 29382179 TI - WNT9A Is a Conserved Regulator of Hematopoietic Stem and Progenitor Cell Development. AB - Hematopoietic stem cells (HSCs) differentiate into all cell types of the blood and can be used therapeutically to treat hematopoietic cancers and disorders. Despite decades of research, it is not yet possible to derive therapy-grade HSCs from pluripotent precursors. Analysis of HSC development in model organisms has identified some of the molecular cues that are necessary to instruct hematopoiesis in vivo, including Wnt9A, which is required during an early time window in zebrafish development. Although bona fide HSCs cannot be derived in vitro, it is possible to model human hematopoietic progenitor development by differentiating human pluripotent stem cells to hematopoietic cells. Herein, we modulate WNT9A expression during the in vitro differentiation of human embryonic stem cells to hematopoietic progenitor cells and demonstrate that WNT9A also regulates human hematopoietic progenitor cell development in vitro. Overexpression of WNT9A only impacts differentiation to CD34+/CD45+ cells during early time windows and does so in a dose-dependent manner. The cells that receive the Wnt signal-not the cells that secrete WNT9A-differentiate most efficiently to hematopoietic progenitors; this mimics the paracrine action of Wnt9a during in vivo hematopoiesis. Taken together, these data indicate that WNT9A is a conserved regulator of zebrafish and human hematopoietic development. PMID- 29382180 TI - Association between Drug Usage and Constipation in the Elderly Population of Greater Western Sydney Australia. AB - The low socioeconomic region of Greater Western Sydney (GWS) has higher than average rates of gastrointestinal symptoms. The relationship between prescription drug usage and constipation has not been explored. The aim of this study was to investigate the impact of drug use on constipation in the elderly population of GWS (NSW, Australia). A random selection of elderly residents completed a postal questionnaire for constipation and drug use (response 30.7%). Bivariate associations between constipation and number of drug use and number of drug use with constipation adverse effect were compared. For multivariate analysis multiple logistic regression was performed for constipation with the number of drugs, use of drugs with known constipation side effects, and each drug class (Anatomical Therapeutic Chemical Classification System (ATC) level 4) as independent variables. The prevalence of constipation was 33.9%. There was a dose response relationship between constipation and the number of drugs used (odds ratio 1.24, p < 0.001) and the usage of drugs with known constipation adverse effects (odds ratio 2.21, p = 0.009). These findings suggest that constipation is associated with the number of drugs used, particularly those with constipation adverse-effects, in the elderly of GWS. PMID- 29382181 TI - A Total Bounded Variation Approach to Low Visibility Estimation on Expressways AB - Low visibility on expressways caused by heavy fog and haze is a main reason for traffic accidents. Real-time estimation of atmospheric visibility is an effective way to reduce traffic accident rates. With the development of computer technology, estimating atmospheric visibility via computer vision becomes a research focus. However, the estimation accuracy should be enhanced since fog and haze are complex and time-varying. In this paper, a total bounded variation (TBV) approach to estimate low visibility (less than 300 m) is introduced. Surveillance images of fog and haze are processed as blurred images (pseudo-blurred images), while the surveillance images at selected road points on sunny days are handled as clear images, when considering fog and haze as noise superimposed on the clear images. By combining image spectrum and TBV, the features of foggy and hazy images can be extracted. The extraction results are compared with features of images on sunny days. Firstly, the low visibility surveillance images can be filtered out according to spectrum features of foggy and hazy images. For foggy and hazy images with visibility less than 300 m, the high-frequency coefficient ratio of Fourier (discrete cosine) transform is less than 20%, while the low frequency coefficient ratio is between 100% and 120%. Secondly, the relationship between TBV and real visibility is established based on machine learning and piecewise stationary time series analysis. The established piecewise function can be used for visibility estimation. Finally, the visibility estimation approach proposed is validated based on real surveillance video data. The validation results are compared with the results of image contrast model. Besides, the big video data are collected from the Tongqi expressway, Jiangsu, China. A total of 1,782,000 frames were used and the relative errors of the approach proposed are less than 10%. PMID- 29382182 TI - First-Principles Study on the Structural and Electronic Properties of Monolayer MoS2 with S-Vacancy under Uniaxial Tensile Strain. AB - Monolayer molybdenum disulfide (MoS2) has obtained much attention recently and is expected to be widely used in flexible electronic devices. Due to inevitable bending in flexible electronic devices, the structural and electronic properties would be influenced by tensile strains. Based on the density functional theory (DFT), the structural and electronic properties of monolayer MoS2 with a sulfur (S)-vacancy is investigated by using first-principles calculations under uniaxial tensile strain loading. According to the calculations of vacancy formation energy, two types of S-vacancies, including one-sulfur and two-sulfur vacancies, are discussed in this paper. Structural analysis results indicate that the existence of S-vacancies will lead to a slightly inward relaxation of the structure, which is also verified by exploring the change of charge density of the Mo layer and the decrease of Young's modulus, as well as the ultimate strength of monolayer MoS2. Through uniaxial tensile strain loading, the simulation results show that the band gap of monolayer MoS2 decreases with increased strain despite the sulfur vacancy type and the uniaxial tensile orientation. Based on the electronic analysis, the band gap change can be attributed to the pi bond-like interaction between the interlayers, which is very sensitive to the tensile strain. In addition, the strain-induced density of states (DOS) of the Mo-d orbital and the S-p orbital are analyzed to explain the strain effect on the band gap. PMID- 29382183 TI - A Compact Operational Amplifier with Load-Insensitive Stability Compensation for High-Precision Transducer Interface. AB - High-resolution electronic interface circuits for transducers with nonlinear capacitive impedance need an operational amplifier, which is stable for a wide range of load capacitance. Such operational amplifier in a conventional design requires a large area for compensation capacitors, increasing costs and limiting applications. In order to address this problem, we present a gain-boosted two stage operational amplifier, whose frequency response compensation capacitor size is insensitive to the load capacitance and also orders of magnitude smaller compared to the conventional Miller-compensation capacitor that often dominates chip area. By exploiting pole-zero cancellation between a gain-boosting stage and the main amplifier stage, the compensation capacitor of the proposed operational amplifier becomes less dependent of load capacitance, so that it can also operate with a wide range of load capacitance. A prototype operational amplifier designed in 0.13-MUm complementary metal-oxide-semiconductor (CMOS) with a 400-fF compensation capacitor occupies 900- MU m 2 chip area and achieves 0.022-2.78-MHz unity gain bandwidth and over 65 ? phase margin with a load capacitance of 0.1-15 nF. The prototype amplifier consumes 7.6 MU W from a single 1.0-V supply. For a given compensation capacitor size and a chip area, the prototype design demonstrates the best reported performance trade-off on unity gain bandwidth, maximum stable load capacitance, and power consumption. PMID- 29382184 TI - Economic Cost of Ovine Johne's Disease in Clinically Affected New Zealand Flocks and Benefit-Cost of Vaccination. AB - The aims of this study were to estimate the on-fam economic cost of ovine Johne's disease (OJD) based on collected incidence and mortality data, and the benefit cost of OJD vaccination in typical OJD affected flocks in New Zealand after having vaccinated for a number of years. Owners of 20 sheep breeding and finishing farms known to be clinically affected by ovine Johne's disease in New Zealand participated in the study and were monitored for up to two years. Farms were categorized as fine-wool (Merino, Half-Bred, Corriedale, n = 15), and other breeds (Romney, composite breeds, n = 5). Ovine JD was confirmed by gross- and histo-pathology in 358 ewes culled due to chronic progressive wasting. An additional 228 ewes with low body condition score (BCS), but not targeted for culling, were tested with ELISA to estimate the proportion of OJD in ewes in the lower 5% BCS of the flock. Calculations were done separately for fine-wool and other breeds. Based on the data, mortality due to OJD, its associated cost and the benefit-cost of vaccination were evaluated for a hypothetical farm with 2000 ewes by stochastic simulation. Total ewe mortality was similar in fine-wool and other breeds, but the estimated mortality due to OJD was 2.7 times as high in fine-wool (median 1.8%, interquartile range IQR 1.2-2.7%) than other breeds (median 0.69%, IQR 0.3-1.2%), but with large variation between farms. ELISA results demonstrated fine-wool sheep had a higher seroprevalence than other breeds (39%, 95% CI 18-61% vs. 9%, 95% CI 0-22%). Stochastic modelling indicated that the average annual cost of mortality due to OJD in a flock of 2000 ewes was NZD 13,100 (IQR 8900-18,600) in fine-wool and NZD 4300 (IQR 2200-7600) in other breeds. Vaccinating replacement lambs against OJD may be cost-effective in most flocks when the pre-vaccination annual ewe mortality due to OJD is >1%. To make the best-informed decision about vaccination it is therefore essential for farmers to accurately diagnose OJD to establish incidence. PMID- 29382185 TI - Genetic Variations in Sweet Taste Receptor Gene Are Related to Chocolate Powder and Dietary Fiber Intake in Obese Children and Adolescents. AB - Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary fibers, vitamins, and minerals, as well as lack of physical exercise have been associated with the rise of obesity prevalence. However, factors that contribute to the preference for foods rich in these nutrients are not well established. Taste is recognized as an important predictor of food choices, and polymorphisms in taste-related genes may explain the variability of taste preference and food intake. The aim of this research is to evaluate the influence of polymorphisms of the sweet taste receptor gene TAS1R2 on diet and metabolic profile in obese children and adolescents. A cross-sectional study with 513 obese children and adolescents and 135 normal-weight children was carried out. A molecular study was performed for the single nucleotide polymorphisms (SNPs) rs9701796 and rs35874116 of TAS1R2, and dietary intake, anthropometric parameters (weight, height, waist circumference, waist-to-height ratio (WHtR)), and metabolic profile (including fasting glucose, insulin, triglyceride, high-density lipoprotein (HDL)-cholesterol, and leptin levels) were analyzed. The variant rs9701796 was associated with increased waist-height ratio, as well as with a higher chocolate powder intake in obese children. The variant rs35874116 was associated with a lower dietary fiber intake. In conclusion, there was no relationship between genotypes and risk of obesity. Obese adolescents carrying the serine allele of SNP rs9701796 in TAS1R2 showed higher waist-to-height ratio and chocolate powder intake, whereas those carrying the valine allele of SNP rs35874116 in TAS1R2 were characterized by lower dietary fiber intake. PMID- 29382186 TI - Fear and Disgust of Spiders: Factors that Limit University Preservice Middle School Science Teachers. AB - Spiders perform many essential ecological services, yet humans often experience negative emotions toward spiders. These emotions can lead to the avoidance of beneficial events. These emotions may affect beliefs about what should or should not be included in a science curriculum. This study investigated how activities with living spiders affected preservice middle school science teachers' emotions and beliefs. Prior to the activities both groups (i.e., treatment and control) had moderate to extreme fear and disgust toward the spider. The teachers that participated in the spider activities (i.e., treatment group) had much lower levels of fear and disgust after performing the spider activities than the control group that did not participate in the spider activities. The control group continued to have elevated levels of fear and disgust toward the spider throughout the study. Before the spider activities neither group planned to incorporate information about spiders or information about the essential ecological services of spiders into their science classroom. After the treatment group participated in the spider activities, the teachers had definitive plans to teach their students about spiders and the essential ecological services that they provide. The control group remained unchanged and had no plans to teach this information to their students. PMID- 29382187 TI - Ultrasonography of acute flank pain: a focus on renal stones and acute pyelonephritis. AB - Ultrasonography is a useful tool for the differential diagnosis of acute flank pain. Renal stones appear as a focal area of echogenicity with acoustic shadowing on ultrasonography. In acute pyelonephritis (APN), the kidneys may be enlarged and have a hypoechoic parenchyma with loss of the normal corticomedullary junction. However, clinical and laboratory correlations are essential for the diagnosis of renal stones and APN through imaging studies. This review describes the typical ultrasonography features of renal stones and APN. Moreover, in daily practice, cross-sectional imaging is essential and widely used to confirm renal stones and APN and to differentiate them from other diseases causing flank pain. Other diseases causing acute flank pain are also described in this review. PMID- 29382188 TI - Immobilization by Surface Conjugation of Cyclic Peptides for Effective Mimicry of the HCV-Envelope E2 Protein as a Strategy toward Synthetic Vaccines. AB - Mimicry of the binding interface of antibody-antigen interactions using peptide based modulators (i.e., epitope mimics) has promising applications for vaccine design. These epitope mimics can be synthesized in a streamlined and straightforward fashion, thereby allowing for high-throughput analysis. The design of epitope mimics is highly influenced by their spatial configuration and structural conformation. It is widely assumed that for proper mimicry sufficient conformational constraints have to be implemented. This paper describes the synthesis of bromide derivatives functionalized with a flexible TEG linker equipped with a thiol-moiety that could be used to support cyclic or linear peptides. The cyclic and linear epitope mimics were covalently conjugated via the free thiol-moiety on maleimide-activated plate surfaces. The resulting covalent, uniform, and oriented coated surface of cyclic or linear epitope mimics were subjected to an ELISA to investigate the effect of peptide cyclization with respect to mimicry of an antigen-antibody interaction of the HCV E2 glycoprotein. To the best of our knowledge, the benefit of cyclized peptides over linear peptides has been clearly demonstrated here for the first time. Cyclic epitope mimics, and not the linear epitope mimics, demonstrated specificity toward their monoclonal antibodies HC84.1 and V3.2, respectively. The described strategy for the construction of epitope mimics shows potential for high-throughput screening of key binding residues by simply changing the amino acid sequences within synthetic peptides. In this way, leucine-438 has been identified as a key binding residue for binding monoclonal antibody V3.2. PMID- 29382189 TI - Quickly Screening for Potential alpha-Glucosidase Inhibitors from Guava Leaves Tea by Bioaffinity Ultrafiltration Coupled with HPLC-ESI-TOF/MS Method. AB - Guava leaves tea (GLT) has a potential antihyperglycemic effect. Nevertheless, it is unclear which compound plays a key role in reducing blood sugar. In this study, GLT extract (IC50 = 19.37 +/- 0.21 MUg/mL) exhibited a stronger inhibitory potency against alpha-glucosidase than did acarbose (positive control) at IC50 = 178.52 +/- 1.37 MUg/mL. To rapidly identify the specific alpha-glucosidase inhibitor components from GLT, an approach based on bioaffinity ultrafiltration combined with high performance liquid chromatography coupled to electrospray ionization-time-of-flight-mass spectrometry (BAUF-HPLC-ESI-TOF/MS) was developed. Under the optimal bioaffinity ultrafiltration conditions, 11 corresponding potential alpha-glucosidase inhibitors with high affinity degrees (ADs) were screened and identified from the GLT extract. Quercetin (IC50 = 4.51 +/- 0.71 MUg/mL) and procyanidin B3 (IC50 = 28.67 +/- 5.81 MUg/mL) were determined to be primarily responsible for the antihyperglycemic effect, which further verified the established screening method. Moreover, structure-activity relationships were discussed. In conclusion, the BAUF-HPLC-ESI-TOF/MS method could be applied to determine the potential alpha-glucosidase inhibitors from complex natural products quickly. PMID- 29382190 TI - Mobile and Fixed-Site Measurements To Identify Spatial Distributions of Traffic Related Pollution Sources in Los Angeles. AB - Mobile monitoring and fixed-site monitoring using passive sampling devices (PSD) are popular air pollutant measurement techniques with complementary strengths and weaknesses. This study investigates the utility of combining data from concurrent 2-week mobile monitoring and fixed-site PSD campaigns in Los Angeles in the summer and early spring to identify sources of traffic-related air pollutants (TRAP) and their spatial distributions. There were strong to moderate correlations between mobile and fixed-site PSD measurements of both NO2 and NO x in the summer and spring (Pearson's r between 0.43 and 0.79), suggesting that the two data sets can be reliably combined for source apportionment. PCA identified the major TRAP sources as light-duty vehicle emissions, diesel exhaust, crankcase vent emissions, and an independent source of combustion-derived ultrafine particle emissions. The component scores of those four sources at each site were significantly correlated across the two seasons (Pearson's r between 0.58 and 0.79). Spatial maps of absolute principal component scores showed all sources to be most prominent near major roadways and the central business district and the ultrafine particle source being, in addition, more prominent near the airport. Mobile monitoring combined with fixed-site PSD sampling can provide high spatial resolution estimates of TRAP and can reveal underlying sources of exposure variability. PMID- 29382191 TI - Early-Life Persistent Vitamin D Deficiency Alters Cardiopulmonary Responses to Particulate Matter-Enhanced Atmospheric Smog in Adult Mice. AB - Early life nutritional deficiencies can lead to increased cardiovascular susceptibility to environmental exposures. Thus, the purpose of this study was to examine the effect of early life persistent vitamin D deficiency (VDD) on the cardiopulmonary response to a particulate matter-enhanced photochemical smog. Mice were fed a VDD or normal diet (ND) after weaning. At 17 weeks of age, mice were implanted with radiotelemeters to monitor electrocardiogram, heart rate (HR), and heart rate variability (HRV). Ventilatory function was measured throughout the diet before and after smog exposure using whole-body plethysmography. VDD mice had lower HR, increased HRV, and decreased tidal volume compared with ND. Regardless of diet, HR decreased during air exposure; this response was blunted by smog in ND mice and to a lesser degree in VDD. When compared with ND, VDD increased HRV during air exposure and more so with smog. However, smog only increased cardiac arrhythmias in ND mice. This study demonstrates that VDD alters the cardiopulmonary response to smog, highlighting the possible influence of nutritional factors in determining responses to air pollution. The mechanism of how VDD induces these effects is currently unknown, but modifiable factors should be considered when performing risk assessment of complex air pollution atmospheres. PMID- 29382192 TI - Spermidine-Induced Attraction of Like-Charged Surfaces Is Correlated with the pH Dependent Spermidine Charge: Force Spectroscopy Characterization. AB - The ubiquitous molecule spermidine is known for its pivotal roles in the contact mediation, fusion, and reorganization of biological membranes and DNA. In our model system, borosilicate beads were attached to atomic force microscopy cantilevers and used to probe mica surfaces to study the details of the spermidine-induced attractions. The negative surface charges of both materials were largely constant over the measured pH range of pH 7.8 to 12. The repulsion observed between the surfaces turned into attraction after the addition of spermidine. The attractive force was correlated with the degree of spermidine protonation, which changed from +3 to +1 over the measured pH range. The force was maximal at pH 7.8. To explain the observed pH and spermidine concentration dependence, two different theoretical approaches were used: a chemical model of the charge equilibrium of spermidine and Monte-Carlo simulations of the orientation of the rodlike spermidine molecules in the gap between the borosilicate and mica surfaces. Monte-Carlo simulations of the orientational ordering of the rodlike spermidine molecules suggested the induction of attractive interactions between the surfaces if the gap was bridged by the molecules. For larger gaps, the orientational distribution function of the spermidine molecules predicted a considerable degree of parallel attachment of the molecules to the surfaces, resulting in reduced effective surface charge densities of both surfaces, which reduced their electrostatic repulsion. PMID- 29382193 TI - Deformation Modes of Giant Unilamellar Vesicles Encapsulating Biopolymers. AB - The shapes of giant unilamellar vesicles (GUVs) enclosing polymer molecules at relatively high concentration, used as a model cytoplasm, significantly differ from those containing only small molecules. Here, we investigated the effects of the molecular weights and concentrations of polymers such as polyethylene glycol (PEG), bovine serum albumin (BSA), and DNA on the morphology of GUVs deflated by osmotic pressure. Although small PEG (MW < 1000) does not alter the mode of shape transformation even at >10% (w/w), PEG with MW > 6000 induces budding and pearling transformation at above 1% (w/w). Larger PEG frequently induced small buddings and tubulation from the membrane of mother GUVs. A similar trend was observed with BSA, indicating that the effect is irrelevant to the chemical nature of polymers. More surprisingly, long strands of DNA (>105 bp) enclosed in GUVs induced budding transformation at concentrations as low as 0.01-0.1% (w/w). We expect that this molecular size dependency arises mainly from the depletion volume effect. Our results showed that curving, budding, and tubulation of lipid membranes, which are ubiquitous in living cells, can result from simple cell mimics consisting of the membrane and cytosolic macromolecules, but without specific shape-determining proteins. PMID- 29382194 TI - Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median Effect Principle. AB - Recombinant high-density lipoprotein (rHDL) displays a similar anti atherosclerotic effect with native HDL and could also be served as a carrier of cardiovascular drug for atherosclerotic plaque targeting. In our previous studies, rHDL has shown a more potent anti-atherosclerotic efficacy as compared to the other conventional nanoparticles with a payload of lovastatin (LS). Therefore, we hypothesized that a synergistic anti-atherosclerotic effect of the rHDL carrier and the encapsulated LS might exist. In this study, the dose-effect relationships and the combined effect of the rHDL and LS were quantitatively evaluated in RAW 264.7 macrophage cells using the median-effect analysis, in which the rHDL carrier was regarded as a drug combined. Median-effect analysis suggested that rHDL and LS exerted a desirable synergistic inhibition on the oxLDL internalization at a ratio of 6:1 ( Dm,LS: Dm,rHDL) in RAW 264.7 macrophage cells. About 50% of the reduction on the intracellular lipid contents was found when RAW264.7 cells were treated with LS-loaded rHDLs at their respective median effect dose ( Dm) concentrations and a synergistic effect on the mediating cholesterol efflux was also observed, which verified the accuracy of the results obtained from the median-effect analysis. The mechanism underlying the synergistic effect of the rHDL carrier and the drug might be attributed to their potent inhibitory effects on SR-A expression. In conclusion, the median-effect analysis was proven to be a feasible method to quantitatively evaluate the synergistic effect of the biofunctional carrier and the drug encapsulated. PMID- 29382195 TI - Vx3-Functionalized Alumina Nanoparticles Assisted Enrichment of Ubiquitinated Proteins from Cancer Cells for Enhanced Cancer Immunotherapy. AB - A simple and effective strategy was developed to enrich ubiquitinated proteins (UPs) from cancer cell lysate using the alpha-Al2O3 nanoparticles covalently linked with ubiquitin binding protein (Vx3) (denoted as alpha-Al2O3-Vx3) via a chemical linker. The functionalized alpha-Al2O3-Vx3 showed long-term stability and high efficiency for the enrichment of UPs from cancer cell lysates. Flow cytometry analysis results indicated dendritic cells (DCs) could more effectively phagocytize the covalently linked alpha-Al2O3-Vx3-UPs than the physical mixture of alpha-Al2O3 and Vx3-UPs (alpha-Al2O3/Vx3-UPs). Laser confocal microscopy images revealed that alpha-Al2O3-Vx3-UPs localized within the autophagosome of DCs, which then cross-presented alpha-Al2O3-Vx3-UPs to CD8+ T cells in an autophagosome-related cross-presentation pathway. Furthermore, alpha-Al2O3-Vx3 UPs enhanced more potent antitumor immune response and antitumor efficacy than alpha-Al2O3/cell lysate or alpha-Al2O3/Vx3-UPs. This work highlights the potential of using the Vx3 covalently linked alpha-Al2O3 as a simple and effective platform to enrich UPs from cancer cells for the development of highly efficient therapeutic cancer vaccines. PMID- 29382196 TI - Theoretical and Experimental Insights into the Dissociation of 2 Hydroxyethylhydrazinium Nitrate Clusters Formed via Electrospray. AB - Ionic liquids are used for myriad applications, including as catalysts, solvents, and propellants. Specifically, 2-hydroxyethylhydrazinium nitrate (HEHN) has been developed as a chemical propellant for space applications. The gas-phase behavior of HEHN ions and clusters is important in understanding its potential as an electrospray thruster propellant. Here, the unimolecular dissociation pathways of two clusters are experimentally observed, and theoretical modeling of hydrogen bonding and dissociation pathways is used to help rationalize those observations. The cation/deprotonated cation cluster [HEH2 - H]+, which is observed from electrospray ionization, is calculated to be considerably more stable than the complementary cation/protonated anion adduct, [HEH + HNO3]+, which is not observed experimentally. Upon collisional activation, a larger cluster [(HEHN)2HEH]+ undergoes dissociation via loss of nitric acid at lower collision energies, as predicted theoretically. At higher collision energies, additional primary and secondary loss pathways open, including deprotonated cation loss, ion pair loss, and double-nitric-acid loss. Taken together, these experimental and theoretical results contribute to a foundational understanding of the dissociation of protic ionic liquid clusters in the gas phase. PMID- 29382197 TI - Fully Anisotropic Rotational Diffusion Tensor from Molecular Dynamics Simulations. AB - We present a method to calculate the fully anisotropic rotational diffusion tensor from molecular dynamics simulations. Our approach is based on fitting the time-dependent covariance matrix of the quaternions that describe the rigid-body rotational dynamics. Explicit analytical expressions have been derived for the covariances by Favro, which are valid irrespective of the degree of anisotropy. We use these expressions to determine an optimal rotational diffusion tensor from trajectory data. The molecular structures are aligned against a reference by optimal rigid-body superposition. The quaternion covariances can then be obtained directly from the rotation matrices used in the alignment. The rotational diffusion tensor is determined by a fit to the time-dependent quaternion covariances, or directly by Laplace transformation and matrix diagonalization. To quantify uncertainties in the fit, we derive analytical expressions and compare them with the results of Brownian dynamics simulations of anisotropic rotational diffusion. We apply the method to microsecond long trajectories of the Dickerson Drew B-DNA dodecamer and of horse heart myoglobin. The anisotropic rotational diffusion tensors calculated from simulations agree well with predictions from hydrodynamics. PMID- 29382198 TI - Gold Nanorods Conjugated Porous Silicon Nanoparticles Encapsulated in Calcium Alginate Nano Hydrogels Using Microemulsion Templates. AB - Porous silicon nanoparticles (PSiNPs) and gold nanorods (AuNRs) can be used as biocompatible nanocarriers for delivery of therapeutics but undesired leakage makes them inefficient. By encapsulating the PSiNPs and AuNRs in a hydrogel shell, we create a biocompatible functional nanocarrier that enables sustained release of therapeutics. Here, we report the fabrication of AuNRs-conjugated PSi nanoparticles (AuNRsPSiNPs) through two-step chemical reaction for high-capacity loading of hydrophobic and hydrophilic therapeutics with photothermal property. Furthermore, using water-in-oil microemulsion templates, we encapsulate the AuNRsPSiNPs within a calcium alginate hydrogel nanoshell, creating a versatile biocompatible nanocarrier to codeliver therapeutics for biomedical applications. We find that the functionalized nanohydrogel effectively controls the release rate of the therapeutics while maintaining a high loading efficiency and tunable loading ratios. Notably, combinations of therapeutics coloaded in the functionalized nanohydrogels significantly enhance inhibition of multidrug resistance through synergism and promote faster cancer cell death when combined with photothermal therapy. Moreover, the AuNRs can mediate the conversion of near infrared laser radiation into heat, increasing the release of therapeutics as well as thermally inducing cell damage to promote faster cancer cell death. Our AuNRsPSiNPs functionalized calcium alginate nanohydrogel holds great promise for photothermal combination therapy and other advanced biomedical applications. PMID- 29382199 TI - Modular Approach to Kekule Diradicaloids Derived from Cyclic (Alkyl)(amino)carbenes. AB - A modular approach for the synthesis of Kekule diradicaloids is reported. The key step is the insertion of a carbene, namely, a cyclic (alkyl)(amino)carbene (CAAC), into the C-H bonds of two terminal alkynes linked by a spacer. Subsequent hydride abstraction, followed by two-electron reduction of the corresponding bis(iminium) salts, affords the desired diradicaloids. This synthetic route readily allows for the installation of communicating spacers, featuring different degrees of aromaticity and lengths, and gives the possibility of generating unsymmetrical compounds with two different CAACs. Electron paramagnetic resonance (EPR), NMR, UV-vis, and X-ray studies in combination with quantum-chemical calculations give insight into the electronic nature of the deeply colored Kekule diradicaloids. They feature a singlet ground state with varying degrees of diradical character in combination with small singlet/triplet gaps. Upon lengthening of the spacer, the properties of the compounds approach those of monoradicals in which steric protection of the propargyl radical moiety is necessary to inhibit decomposition pathways. Most of these diradicaloids are stable at room temperature, both in solution and in the solid state, but are highly oxygen-sensitive. They represent the first diradicaloids derived from iminium salts. PMID- 29382200 TI - Seed-Initiated Anisotropic Growth of Unidirectional Armchair Graphene Nanoribbon Arrays on Germanium. AB - It was recently discovered that the chemical vapor deposition (CVD) of CH4 on Ge(001) can directly yield long, narrow, semiconducting nanoribbons of graphene with smooth armchair edges. These nanoribbons have exceptional charge transport properties compared with nanoribbons grown by other methods. However, the nanoribbons nucleate at random locations and at random times, problematically giving rise to width and bandgap polydispersity, and the mechanisms that drive the anisotropic crystal growth that produces the nanoribbons are not understood. Here, we study and engineer the seed-initiated growth of graphene nanoribbons on Ge(001). The use of seeds decouples nucleation and growth, controls where growth occurs, and allows graphene to grow with lattice orientations that do not spontaneously form without seeds. We discover that when the armchair direction (i.e., parallel to C-C bonds) of the seeds is aligned with the Ge?110? family of directions, the growth anisotropy is maximized, resulting in the formation of nanoribbons with high-aspect ratios. In contrast, increasing misorientation from Ge?110? yields decreasingly anisotropic crystals. Measured growth rate data are used to generate a construction analogous to a kinetic Wulff plot that quantitatively predicts the shape of graphene crystals on Ge(001). This knowledge is employed to fabricate regularly spaced, unidirectional arrays of nanoribbons and to significantly improve their uniformity. These results show that seed initiated graphene synthesis on Ge(001) will be a viable route for creating wafer scale arrays of narrow, semiconducting, armchair nanoribbons with rationally controlled placement and alignment for a wide range of semiconductor electronics technologies, provided that dense arrays of sub-10 nm seeds can be uniformly fabricated in the future. PMID- 29382201 TI - Role of Extracellular Vesicle Surface Proteins in the Pharmacokinetics of Extracellular Vesicles. AB - Extracellular vesicles (EVs) are small membrane vesicles secreted from cells and have great potential as drug delivery carriers. Surface proteins on EV membranes might play roles in pharmacokinetics. One method which can be used to study the role of surface membrane of EV is to modify the inner space of EV. In the present study, we constructed a plasmid DNA expressing a fusion protein of Gag protein derived from Moloney murine leukemia virus (Gag) and Gaussia luciferase (gLuc) (Gag-gLuc) to modify the inner space of EVs. EVs were collected from B16BL6 melanoma cells, transfected with the plasmid, and isolated by a differential ultracentrifugation method. Gag-gLuc EVs were negatively charged globular vesicles with a diameter of approximately 100 nm. gLuc labeling of the Gag-gLuc EVs was stable in serum. gLuc activity of Gag-gLuc EVs was minimally decreased by proteinase K (ProK) treatment, indicating that gLuc was modified in the inner space of EV. Then, to evaluate the effect of the surface proteins of EVs on their pharmacokinetics, Gag-gLuc EVs treated with ProK were intravenously administered to mice. Volume of distribution (Vd) was significantly smaller for treated EVs than untreated EVs. Moreover, integrin alpha6beta1, an integrin known to be involved in lung targeting, was degraded after ProK treatment. The ProK treatment significantly reduced the lung distribution of EVs after intravenous injection. These results indicate that the surface proteins of EVs such as integrin alpha6beta1 play some roles in pharmacokinetics in terms of reducing Vd and their distribution to the lung. PMID- 29382202 TI - Sulfinate Based Selective Labeling of 5-Hydroxymethylcytosine: Application to Biotin Pull Down Assay. AB - We developed an enzyme-free, chemical method to selectively label the epigenetic base, 5-hydroxymethylcytosine (hmC) with versatile sulfinate reagents in aqueous solvent under mild reaction conditions. This method allows efficient single step conjugation of biotin to hmC site in DNA for enrichment and pull down assays. PMID- 29382203 TI - Visible Light-Controlled Inversion of Pickering Emulsions Stabilized by Functional Silica Microspheres. AB - A new class of donor-acceptor Stenhouse adduct (DASA)-functionalized silica microspheres (SMs) is designed and described to formulate Pickering emulsions with inversion property and large polarity change upon visible light irradiation. By tuning the hydrophilicity of the functional SM particles with visible light, these Pickering emulsions can easily perform inversion from water-in-oil to oil in-water. The inversion performance of the emulsions is ascribed to DASA photoisomerization from an extended, hydrophobic, and intensely purple-colored triene to a compact, zwitterionic, and colorless cyclopentenone upon irradiation with visible light. This unique inversion behavior has been applied to control encapsulation and the release of fluorescein sodium salt. PMID- 29382205 TI - Archaeal tetraether lipid coatings-A strategy for the development of membrane analog spacer systems for the site-specific functionalization of medical surfaces. AB - The primary goal of our investigation was the development of a versatile immobilization matrix based on archaeal tetraether lipids that meets the most important prerequisites to render an implant surface bioactive by binding specific functional groups or functional polymers with the necessary flexibility and an optimal spatial arrangement to be bioavailable. From this point of view, it appears obvious that numerous efforts made recently to avoid initial bacterial adhesion on catheter surfaces as an important prerequisite of material associated infection episodes have shown only a limited efficiency since the bioactive entities could not be presented in an optimal conformation and a stable density. A significant improvement of this situation can be achieved by highly specific biomimetic modifications of the catheter surfaces. The term "biomimetic" originates from the fact that specific archaeal tetraether lipids were introduced to form a membrane analog monomolecular spacer system, which (1) can be immobilized on nearly all solid surfaces and (2) chemically modified to present a tailor-made functionality in contact with aqueous media either to avoid or inhibit surface fouling or to equip any implant surface with the necessary chemical functionality to enable cell adhesion and tissue integration. Ultrathin films based on tetraether lipids isolated from archaea Thermoplasma acidophilum were used as a special biomimetic immobilization matrix on the surface of commercial medical silicon elastomers. A complete performance control of the membrane analog coatings was realized in addition to biofunctionality tests, including the proof of cytotoxicity and hemocompatibility according to DIN EN ISO 10993. In order to make sure that the developed immobilization matrix including the grafted functional groups are biocompatible under in vivo-conditions, specific animal tests were carried out to examine the in vivo-performance. It can be concluded that the tetraether lipid based coating systems on silicone have shown no signs of cytotoxicity and a good hemocompatibility. Moreover, no mutagenic effects, no irritation effects, and no sensitization effects could be demonstrated. After an implantation period of 28 days, no irregularities were found. PMID- 29382206 TI - TOF-SIMS analysis of an isocitrate dehydrogenase 1 mutation-associated oncometabolite in cancer cells. AB - The development of analytical tools for accurate and sensitive detection of intracellular metabolites associated with mutated metabolic enzymes is important in cancer diagnosis and staging. The gene encoding the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is mutated in various cancers, and mutant IDH1 could represent a good biomarker and potent target for cancer therapy. Owing to a mutation in an important arginine residue in the catalytic pocket, mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) instead of its wild type product alpha-ketoglutarate (alpha-KG), which is involved in multiple cellular pathways involving the hydroxylation of proteins, ribonucleic acid, and deoxyribose nucleic acid (DNA). Since 2-HG is an alpha-KG antagonist, inhibiting normal alpha-KG-dependent metabolism, high intracellular levels of 2-HG result in abnormal histone and DNA methylation. Therefore, accurate and sensitive analytical tools for the direct detection of 2-HG in cancer cells expressing mutant IDH1 would benefit this field, as it would minimize the need both for complicated experimental procedures and for large amounts of biological samples. Here, the authors describe a useful analytical method for the direct detection of 2-HG in lysates from a mutant IDH1-expressing cell line by time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis, a powerful surface analysis tool. In addition, the authors verified the efficacy of the specific mutant IDH1 inhibitor AGI-5198 by tracking the intracellular 2-HG concentration, which decreased in a dose-dependent manner. Our results demonstrate the large potential of TOF-SIMS as an analytical tool for the simple, direct detection of oncometabolites during cancer diagnosis, and for verifying the efficiency of the targeted cancer drugs. PMID- 29382207 TI - Revision Anterior Cruciate Ligament Reconstruction Outcomes in Younger Patients: Medial Meniscal Pathology and High Rates of Return to Sport Are Associated With Third ACL Injuries. AB - BACKGROUND: There are limited data evaluating the outcomes of revision anterior cruciate ligament (ACL) reconstruction surgery in younger patients despite recent reports that the rates of graft rupture are higher in young cohorts. PURPOSE: To explore the outcomes of revision ACL reconstruction surgery in younger patients with the specific aims of determining the rates of third ACL injury and whether knee pathology at the time of revision surgery and return to sport were associated with further injury. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The study cohort consisted of 151 consecutive patients who were aged 25 years or younger at the time of their first revision ACL reconstruction. The number of subsequent ACL injuries (graft rerupture or contralateral injury to the native ACL) was determined at a mean follow-up time of 4.5 years (range, 2-9 years). Surgical details were recorded, along with a range of sport participation outcomes. Contingency tables were used to assess the associations between subsequent ACL injury and return to sport, knee pathology, and the drilling of new femoral or tibial tunnels at revision surgery. RESULTS: The follow-up rate was 85% (128/151). Graft reruptures occurred in 20 patients (16%) at a mean time of 2 years after revision surgery. Contralateral ACL injuries occurred in 15 patients (12%) at a mean time of 3.9 years. The total number of patients who had a third ACL injury was 35 (27%). There was a significant association between having medial meniscal pathology and sustaining a graft rerupture ( P = .03), but there was no association between graft rerupture and using the same tunnels from the primary procedure at revision surgery. After revision reconstruction, 68% of patients (95% CI, 55%-71%) returned to their preinjury level of sport, compared with 83% (95% CI, 69%-84%) after primary reconstruction in the same patients. Those who had a third ACL injury had a significantly higher rate of return to preinjury sport (83%) after the revision procedure than did the group that did not have further ACL injuries (62%, P = .02). CONCLUSION: Younger patients are at significant risk of having multiple ACL injuries. The high rate of third ACL injuries presents a significant issue for future knee health in these young athletes. Medial meniscal pathology and returning to high-risk sport are factors that are significantly associated with the high multiple ACL injury rate in the young. PMID- 29382208 TI - A systematic review of school-based interventions targeting social communication behaviors for students with autism. AB - Initiating and responding to peers are social communication behaviors which are challenging for students with autism. We reviewed intervention studies set in mainstream elementary schools, which targeted these behaviors and reported on intervention outcomes as well as the resources required for their implementation. A total of 22 studies met the criteria for inclusion. Findings suggest that school-based interventions can increase the frequency and duration of initiating and responding behaviors in elementary school aged students with autism. These interventions were resource-intensive and usually delivered by researchers or teaching assistants away from the classroom. Future research should build on this emerging evidence base to consider interventions which could be implemented by classroom teachers as part of the classroom program. PMID- 29382209 TI - Distal Clavicular Osteochondral Autograft Augmentation for Glenoid Bone Loss: A Comparison of Radius of Restoration Versus Latarjet Graft. AB - BACKGROUND: Bone loss in shoulder instability is a well-recognized cause of failure after stabilization surgery. Many approaches have been described to address glenoid bone loss, including coracoid transfer. This transfer can be technically difficult and has been associated with high complication rates. An ideal alternative to coracoid transfer would be an autologous source of fresh osteochondral graft with enough surface area to replace significant glenoid bone loss. The distal clavicle potentially provides such a graft source that is readily available and low-cost. PURPOSE: To evaluate distal clavicular autograft reconstruction for instability-related glenoid bone loss, specifically comparing the width of the clavicular autograft with the width of an ipsilateral coracoid graft as prepared for a Latarjet procedure. Further, we sought to compare the articular cartilage thickness of the distal clavicle graft with that of the native glenoid. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-seven fresh-frozen cadaver specimens were dissected, and an open distal clavicle excision was performed. The coracoid process in each specimen was prepared as has been described for a classic Latarjet coracoid transfer. In each specimen, the distal clavicle graft was compared with the coracoid graft for size and potential of glenoid articular radius of restoration. The distal clavicle graft was also compared with the native glenoid for cartilage thickness. RESULTS: In all specimens, the distal clavicle grafts provided a greater radius of glenoid restoration than the coracoid grafts ( P < .0001). On average, the clavicular graft was able to reconstruct 44% of the glenoid diameter, compared with 33% for the coracoid graft ( P < .0001). The articular cartilage of the glenoid was significantly thicker (1.4 mm thicker, P < .0001) than that of the distal clavicular autograft (average +/- SD, 3.5 +/- 0.6 mm vs 2.1 +/- 0.8 mm, respectively). When specimens with osteoarthritis were excluded, this difference decreased to 0.97 mm when compared with the clavicular cartilage ( P = .0026). CONCLUSION: The distal clavicle autograft can restore a significantly greater glenoid bone deficit than the Latarjet procedure and has the additional benefit of restoring articular cartilage to the glenoid. The articular cartilage thickness of the distal clavicle is within 1.4 mm of that of the native glenoid. CLINICAL RELEVANCE: The distal clavicular autograft may be a suitable option for reconstruction of instability-related glenoid bone loss. This graft provides a structural osteochondral autograft with a broader radius of reconstruction than that of a coracoid graft, is locally available, has minimal donor site morbidity, is anatomic, and provides articular cartilage. PMID- 29382210 TI - Event-Related Potentials in the Clinical High-Risk (CHR) State for Psychosis: A Systematic Review. AB - There is emerging evidence that identification and treatment of individuals in the prodromal or clinical high-risk (CHR) state for psychosis can reduce the probability that they will develop a psychotic disorder. Event-related brain potentials (ERPs) are a noninvasive neurophysiological technique that holds promise for improving our understanding of neurocognitive processes underlying the CHR state. We aimed to systematically review the current literature on cognitive ERP studies of the CHR population, in order to summarize and synthesize the results, and their implications for our understanding of the CHR state. Across studies, amplitudes of the auditory P300 and duration mismatch negativity (MMN) ERPs appear reliably reduced in CHR individuals, suggesting that underlying impairments in detecting changes in auditory stimuli are a sensitive early marker of the psychotic disease process. There are more limited data indicating that an earlier-latency auditory ERP response, the N100, is also reduced in amplitude, and in the degree to which it is modulated by stimulus characteristics, in the CHR population. There is also evidence that a number of auditory ERP measures (including P300, MMN and N100 amplitudes, and N100 gating in response to repeated stimuli) can further refine our ability to detect which CHR individuals are most at risk for developing psychosis. Thus, further research is warranted to optimize the predictive power of algorithms incorporating these measures, which could help efforts to target psychosis prevention interventions toward those most in need. PMID- 29382211 TI - Depression Associated With Transitions Into and Out of Spousal Caregiving. AB - This study investigates depressive symptoms among spousal caregivers in three groups: those who become caregivers, those who continue care, and those who exit caregiving, compared with those who remain non-caregivers. We also examine depressive symptoms among widowed caregivers by length of bereavement. We use four waves of the U.S. Health and Retirement Study (2006, 2008, 2010, and 2012), for a total of 43,262 observations. Findings show elevated levels of depressive symptoms for new caregivers, continuing caregivers, and exit caregivers. Among exit caregivers, symptoms were elevated when measured in the first 15 months after the spouse's death but declined thereafter. These findings add to the evidence that spousal caregiving carries a risk for depression, and symptoms are likely to peak near the end of the caregiving episode. These results underscore the need to provide support to newly widowed individuals. PMID- 29382212 TI - Accuracy Between AJSM Author-Reported Disclosures and the Centers for Medicare and Medicaid Services Open Payments Database. AB - BACKGROUND: Inaccurate disclosures of physician and industry relationships in scientific reporting may create an asymmetry of information by hiding potential biases. The accuracy of conflict of interest disclosure in sports medicine research is unknown. PURPOSE: To compare author financial disclosures in published articles in 2016 in the American Journal of Sports Medicine ( AJSM) with the Centers for Medicare and Medicaid Services' Open Payments Database (OPD) to determine the percentage of payments values and percentage of eligible authors with discrepancies. STUDY DESIGN: Cross-sectional study; no level of evidence (nonclinical). METHODS: All articles published in 2016 in AJSM were screened to identify eligible authors. On the basis of OPD reporting, physician authors affiliated with a US institution were included. Stated disclosures in AJSM publications for these authors were identified and compared with industry reported payments on OPD. RESULTS: A total of 434 authors were included in this study. Mean and median total payments per author per year were $76,941 and $1692, respectively. The most commonly received payment was for food and beverage (81.3% of authors), followed by travel and lodging (45.4%) and consulting (31.8%). Authors with higher total payments were less likely to be discrepant in their reporting-notably, authors earning >$500,000 had 16.1% of payment values with discrepancy, as opposed to 85.3% for those earning <$10,000 ( P < .001). First authors had a lower percentage of payment values with discrepancy (13.8%) versus middle authors (31.9%, P = .001). Finally, men had a lower percentage of payment values with discrepancy (418 authors, 22.3% of payment values with discrepancy) as compared with women (16 authors, 95.3%; P < .001). Regarding industry payments specifically requested on the AJSM disclosure form for authors (royalties, consulting, research payments, and ownership and investments), only 25.3% of authors had a discrepancy in these payment categories in aggregate. CONCLUSION: Discrepancies exist between disclosures reported by authors publishing in AJSM and what is reported in the OPD. Authors receiving lower total payments, middle authors, and women are more likely to have disclosure discrepancies. Additionally, industry research funding support and ownership interest are most likely to go unreported. However, this study did not assess whether authors with industry payments preferentially published studies pertaining to products from companies from which they received funding. As national registries such as the OPD are increasingly utilized, physicians may benefit from referencing such databases before submitting conflict of interest disclosures. PMID- 29382213 TI - Ethnicity and HIV vulnerabilities among men who have sex with men in China. AB - Ethnic affiliation can define sociocultural boundaries and contribute to the HIV vulnerabilities faced by men who have sex with men (MSM). This study investigated the influence of ethnic affiliation on HIV vulnerabilities among MSM in North China. Our study analyzed a cross-sectional survey of MSM (n = 398) in two major North China cities. We examined associations between ethnic affiliation and (a) HIV status, (b) sexual behaviors and experiences, and (c) substance use. Compared to ethnic majority Han MSM: MSM belonging to ethnic minority groups of South China had significantly greater odds of HIV infection (AOR: 7.40; 95% CI: 2.33 23.47) and experience of forced sex (AOR: 3.27; 95% CI: 1.12-9.52). Compared to ethnic majority Han MSM, Ethnic Hui MSM had significantly lower odds of condomless anal sex (AOR: 0.41; 95% CI: 0.21-0.82) and significantly greater odds of circumcision (AOR: 2.62; 95% CI: 1.24-5.51). HIV prevalence and riskier sexual behaviors among MSM in China appear to vary significantly by ethnic affiliation. Current epidemiological practices of aggregating all ethnic minority groups in China into a single category may be masking important interethnic differences in HIV risk, and precluding opportunities for more culturally appropriate interventions. PMID- 29382214 TI - Successful treatment of Nerium oleander toxicity with titrated Digoxin Fab antibody dosing. PMID- 29382215 TI - Evaluation of the Distribution of Paclitaxel After Application of a Paclitaxel Coated Balloon in the Rabbit Urethra. AB - INTRODUCTION: Urethral strictures are a common urologic problem that could require complex reconstructive procedures. Urethral dilatation represents a frequent practiced intervention associated with high recurrence rates. Drug coated percutaneous angioplasty balloons (DCBs) with cytostatic drugs have been effectively used for the prevention of vascular restenosis after balloon dilatation. To reduce restenosis rates of urethral dilatation, these balloons could be used in the urethra. Nevertheless, the urothelium is different than the endothelium and these drugs may not be distributed to the outer layers of the urethra. Thus, an experiment was performed to evaluate the distribution of paclitaxel (PTX) in the rabbit urethra after the inflation of a PTX-coated balloon (PCB). MATERIALS AND METHODS: Eleven rabbits underwent dilatation of the posterior urethra with common endoscopic balloons after urethrography. Nine of these rabbits were additionally treated with PCB. The urethras of the two control animals were removed along with three more dilated with PCB urethras immediately after the dilatation. The remaining of the urethras were removed after 24 (n = 3) and 48 hours (n = 3). The posterior segments of the urethras were evaluated with hematoxylin and eosin staining as well as with immunohistochemistry with polyclonal anti-PTX antibody. RESULTS: The two control specimens showed denudation of the urothelium after balloon dilatations and no PTX was observed. All specimens from dilated PCB urethras showed distribution of PTX to all layers of the urethra. The specimens that were immediately removed exhibited denudation of the urothelium without any inflammation. The specimens removed at 24 and 48 hours showed mild acute inflammation. CONCLUSION: PTX was distributed to the urothelial, submucosal, and smooth muscle layers of the normal rabbit urethra immediately after dilatation with a DCB. PTX and mild inflammation were present at the site 24 and 48 hours after the dilatation. PMID- 29382216 TI - Preoperative Tibial Subchondral Bone Marrow Lesion Patterns and Associations With Outcomes After Isolated Meniscus Allograft Transplantation. AB - BACKGROUND: The association between preoperative tibial subchondral bone marrow lesion (BML) patterns and outcomes after isolated meniscus allograft transplantation (MAT) are unknown. PURPOSE: To determine (1) if a superior classification means exists (ie, high interrater reliability [IRR]) for grading tibial subchondral BML before isolated MAT and (2) whether quality and/or severity of preoperative tibial subchondral BML patterns was associated with clinical outcomes and/or failure rates after isolated MAT. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All patients who underwent isolated MAT with a single surgeon between October 2006 and February 2017 were identified. Three means were evaluated to quantify the degree of subchondral BML in the affected tibial-sided compartment: Welsch et al, based on maximum diameter of the lesion; Costa-Paz et al, based on appearance and location of the lesion; and Filardo et al, based on severity of findings. IRR was generated and compared among the 3 classifications. The preoperative magnetic resonance imaging (MRI) subchondral BML grading scheme with the highest IRR was then used to assess for associations with postoperative outcomes for those patients with >2-year follow up, per a Spearman correlation matrix with each reviewer's grades. RESULTS: In total, 60 MRI scans were available for subchondral BML grading. Grader 1 identified the presence of subchondral BML in the tibia of the affected compartment in 40 (66.7%) of the available MRI scans, as compared with 38 (63.3%) for grader 2. The calculated IRRs with the Welsch et al and Costa-Paz et al classifications were rated "strong/almost perfect" agreement. A significant correlation was demonstrated between grader 1 with the Welsch et al grading scheme and outcome measures of KOOS pain (Knee injury and Osteoarthritis Outcome Score; negative correlation, P = .05), WOMAC pain (Western Ontario and McMaster Universities Osteoarthritis Index; positive correlation, P = .026), and Marx Activity Rating Scale (negative correlation, P = .019). A significant correlation was demonstrated between grader 2 with the Costa-Paz et al grading scheme and postoperative satisfaction (positive correlation, P = .018). There were no significant differences in survivorship based on gradings. CONCLUSION: Nearly two thirds of patients who undergo isolated MAT have subchondral BML on preoperative MRI. Our findings suggest that increasing BML size (Welsch et al) is correlated with worse postoperative pain measures (KOOS pain, WOMAC pain) and worse activity ratings (Marx Activity Rating Scale). Additionally, increasing disruption or depression of the normal contour of the cortical surface, with or without lesion contiguity with the subjacent articular surface (Costa-Paz et al), is correlated with greater postoperative satisfaction. PMID- 29382217 TI - Xylarodons A and B, new hexaketides from the endophytic fungus Xylaria sp. SC1440. AB - Two new hexaketides, xylarodons B (1) and C (2), were isolated from solid cultures of the endophytic fungus Xylaria sp. SC1440. The structures of these compounds were elucidated on the basis of detailed 1D, 2D NMR, and HRESIMS analysis. Their absolute configurations were established by experimental and TDDFT calculated ECD spectra. The isolated compounds were evaluated for cytotoxic and tyrosinase inhibitory activity. PMID- 29382218 TI - Motor neuron disease mortality rates in New Zealand 1992-2013. AB - BACKGROUND: We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no studies have examined MND rates nationwide to corroborate this. METHODS: Death certificate data coded G12.2 by International Classification of Diseases (ICD)-10 coding, or 335.2 by ICD-9 coding were obtained. These codes specify amyotrophic lateral sclerosis, progressive bulbar palsy, or other motor neuron diseases as the underlying cause of death. Mortality rates for MND deaths in New Zealand were age-standardized to the European Standard Population and compared with rates from international studies that also examined death certificate data and were age-standardized to the same standard population. RESULTS AND CONCLUSION: The age-standardized mortality from MND in New Zealand was 2.3 per 100,000 per year from 1992-2007 and 2.8 per 100,000 per year from 2008-2013. These rates were 3.3 and 4.0 per 100,000 per year, respectively, for the population 20 years and older. The increase in rate between these two time periods was likely due to changes in MND death coding from 2008. Contrary to a previous regional study of MND incidence, nationwide mortality rates did not increase steadily over this time period once aging was accounted for. However, New Zealand MND mortality rate was higher than comparable studies we examined internationally (mean 1.67 per 100,000 per year), suggesting that further analysis of MND burden in New Zealand is warranted. PMID- 29382220 TI - Furylhydroquinones and miscellaneous compounds from the roots of Lithospermum erythrorhizon and their anti-inflammatory effect in HaCaT cells. AB - One new furylhydroquinone derivative (1) and seven known compounds (2-8) were isolated from the roots of Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae). The structure of 1 was elucidated by extensive spectroscopic methods using NMR and MS. The absolute configuration of shikonofuran J (1) was unambiguously determined by aid of comparison experimental ECD with predicted ECD spectra. All the isolates were tested for their inhibitory activities against IL 6 production in HaCaT cells stimulated by tumor necrosis factor (TNF)-alpha. It was found that gracicleistanthoside (5) and uridine (7) remarkably down-regulated the TNF-alpha-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in HaCaT cells. PMID- 29382221 TI - Triterpenoids, megastigmanes and hydroxycinnamic acid derivatives from Anisomeles indica. AB - Six triterpenoids (1-6), four megastigmanes (7-10) and five hydroxycinnamic acid derivatives (11-15) were isolated from the aerial part of Anisomeles indica (Lamiaceae). Of these components, compound 1 was identified to be a new triterpenoid with the structure of 2alpha,3alpha,19alpha-trihydroxyurs-12,20(30) dien-28-oic acid based on extensive analysis of MS, 1D and 2D NMR spectroscopic data, while compounds 2-13 were obtained for the first time from Anisomeles species. PMID- 29382222 TI - Antifungal effects of actinomycin D on Verticillium dahliae via a membrane splitting mechanism. AB - Antifungal bioassays led to the isolation of actinomycins D and A1 from Streptomyces luteus TRM45540 collected from Norpo in Xinjiang, and these compounds were identified by nuclear magnetic resonance spectroscopy. The antifungal activity of actinomycin D was higher than that of actinomycin A1. Actinomycin D clearly inhibited the spore germination, hyphal growth and biomass accumulation of Verticillium dahliae in a dose-dependent manner. Flow cytometric analysis with propidium iodide, total ergosterol measurement, cell leakage and scanning electron microscopy experiments demonstrated that the plasma membrane of this fungus was damaged by actinomycin D, resulting in swollen cells and cellular content leakage. Transmission electron microscopy revealed that parts of the plasma membrane infolded after being treated with actinomycin D. The antifungal activity of actinomycin D damaged the fungal plasma membrane of V. dahliae via a membrane-splitting mechanism, which provided new insights into the functional mechanism of actinomycin D. PMID- 29382223 TI - beta-Secretase inhibition by C-methylisoflavones from Abronia nana. AB - The methanol extract of Abronia nana suspension cultures were subjected to column chromatography to identify potential inhibitors of beta-secretase, which is a major factor in Alzheimer's disease development. Two new C-methylisoflavones boeravinone T (1) and U (4) were isolated with three knowns boeravinone B (2), J (3) and X (5). The half-maximal inhibitory concentration (IC50) values of compounds 1-5 were 18.29, 8.57, 7.87, 12.02 and 5.30 MUM, respectively. The most potent 5, non-competitively inhibited beta-secretase [inhibition constant (Ki) = 3.79 MUM]. Compounds 1-5 did not inhibit other proteases such as chymotrypsin, trypsin and elastase at concentrations up to 1 mM, indicating that they were relatively specific inhibitors of beta-secretase. A free hydroxyl group at C-3 position of the C-methylisoflavone skeleton appeared to be responsible for the stronger inhibitory activity against beta-secretase. PMID- 29382224 TI - Determinants of Stunting, Wasting, and Anemia in Guinean Preschool-Age Children: An Analysis of DHS Data From 1999, 2005, and 2012. AB - Wasting, stunting, and anemia are persistent and important forms of malnutrition in preschool-age children in the less developed world, in particular the Republic of Guinea, which was the site of a large outbreak of Ebola virus disease in 2014 to 2015. We analyzed data from 3 Demographic and Health Surveys done in Guinea in 1999, 2005, and 2012 to identify possible determinants of wasting, stunting, and anemia. All analyses, both bivariate and multivariate, were carried out separately for each of 3 age groups: less than 6 months, 6 to 23 months, and 24 to 59 months. Variables found statistically significantly associated with stunting, wasting, or anemia in bivariate analysis were placed in an age-specific logistic regression model for that outcome. Overall, anthropometric indices were available for 9228 children and hemoglobin concentrations were available for 5681 children. Logistic regression found relatively few variables associated with nutrition outcomes in children younger than 6 months. More variables were associated with nutrition outcomes in children aged 6 to 23 months. Such variables measured a wide variety of conditions, including estimated birth size, child health and nutritional status, child caring practices, mother's nutritional and health status, and household water source and sanitation. A similarly broad range of variables was statistically significantly associated with one or more nutrition outcomes in children aged 24 to 59 months. Few of the standard infant and young child feeding indicators were associated with any nutrition outcome. Improvement in the nutritional status of young children in Guinea may require a broad range of nutrition and health interventions. PMID- 29382225 TI - Provision of assistive technology devices among people with ALS in Germany: a platform-case management approach. AB - OBJECTIVE: The procurement of assistive technology devices (ATD) is an essential component of managed care in ALS. The objective was to analyze the standards of care for ATD and to identify challenges in the provision process. METHODS: A cohort study design was used. We investigated the provision of 11,364 ATD in 1494 patients with ALS at 12 ALS centers in Germany over four years. Participants were patients that entered a case management program for ATD including systematic assessment of ATD on a digital management platform. RESULTS: Wheelchairs (requested in 65% of patients), orthoses (52%), bathroom adaptations (49%), and communication devices (46%) were the most needed ATD. There was a wide range in the number of indicated ATD per patient: 1 to 4 ATD per patient in 45% of patients, 5 to 20 ATD in 48%, and >20 ATD in 7% of patients. Seventy percent of all requested ATD were effectively delivered. However, an alarming failure rate during procurement was found in ATD that are crucial for ALS patients such as powered wheelchairs (52%), communication devices (39%), or orthoses (21%). Leading causes for not providing ATD were the refusal by health insurances, the decision by patients, and the death of the patient before delivery of the device. CONCLUSIONS: The need for ATD was highly prevalent among ALS patients. Failed or protracted provision posed substantial barriers to ATD procurement. Targeted national strategies and the incorporation of ATD indication criteria in international ALS treatment guidelines are urgently needed to overcome these barriers. PMID- 29382226 TI - The Safety and Feasibility of the Single-Port Laparoscopic Repair of Intraperitoneal Bladder Rupture. AB - OBJECTIVE: To evaluate the efficacy and safety of laparoendoscopic single-site surgery (LESS) in the repair of intraperitoneal bladder rupture. PATIENTS AND METHODS: All consecutive patients who underwent LESS for intraperitoneal bladder rupture in three hospitals in Korea were included prospectively in this study. LESS was performed using a homemade single-port device composed of an Alexis wound retractor and a surgical glove. RESULTS: Of the 22 patients, 18 were male. The mean age was 40.50 +/- 11.83 years. The mean body mass index was 24.19 +/- 2.61 kg/m2. The cause of rupture was trauma (n = 21) or iatrogenic injury (n = 1). The mean bladder rupture diameter was 3.41 +/- 1.01 cm. LESS bladder rupture repair was completed effectively in all patients. The mean operative time was 89.05 +/- 11.29 minutes. The mean length of hospital stay was 2.91 +/- 0.53 days. Postoperatively, none of the patients required patient-controlled analgesia, and none developed major complications. The urethral Foley catheter was removed 7.68 +/- 2.08 days after surgery. CONCLUSIONS: LESS repair of intraperitoneal bladder rupture, which involves a homemade single-port device, was a feasible and safe alternative to conventional laparoscopy in this case series. PMID- 29382227 TI - New furostanol glycosides from Polygonatum multiflorum (L.) All. AB - The phytochemical investigation of the whole plant of Polygonatum multiflorum resulted in the isolation of two new steroidal glycosides, polmultoside A (4) and polmultoside B (5), along with three known glycosides protobioside (1), protodeltonin (2) and huangjiangsu A (3). The structures of the isolated compounds have been elucidated by extensive 1D (1H, 13C) and 2D (COSY, HSQC, HMBC) NMR spectral data analysis, as well as high-resolution mass determinations. PMID- 29382228 TI - Primary fibroblasts derived from sporadic amyotrophic lateral sclerosis patients do not show ALS cytological lesions. AB - OBJECTIVE: Sporadic amyotrophic lateral sclerosis (sALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons. In view of the heterogeneous presentation of the disease, one of the current challenges is to identify diagnostic and prognostic markers in order to diagnose sALS at early stage and to stratify patients in trials. In this study, we sought to identify cytological hallmarks of sALS in patient-derived fibroblasts with the aim of finding new clinical-related markers of the disease. METHODS: Primary fibroblasts were prospectively collected from patients affected with classical, rapid, and slow forms of sALS. TDP-43 localization, cytoskeleton distribution, mitochondrial network architecture, and stress granules formation were analyzed using 3D fluorescence microscopy and new super-resolution imaging. Intracellular reactive oxygen species (ROS) production was assessed using live imaging techniques. RESULTS: Six sALS patients (two classical, two rapid, and two slow) and four age matched controls were included. No difference in fibroblasts cell growth, morphology, and distribution was noticed. The analysis of TDP-43 did not reveal any mislocalization nor aggregation of the protein. The cytoskeleton was harmoniously distributed among the cells, without any inclusion noticed, and no difference was observed regarding the mitochondrial network architecture. Basal ROS production and response to induced stress were similar among patient and control fibroblasts. CONCLUSIONS: ALS cytological lesions are absent in patient derived fibroblasts and thus cannot contribute as diagnostic nor prognostic markers of the disease. PMID- 29382229 TI - Key team physical and technical performance indicators indicative of team quality in the soccer Chinese super league. AB - The aim of this study was to identify the key physical and technical performance variables related to team quality in the Chinese Super League (CSL). Teams' performance variables were collected from 240 matches and analysed via analysis of variance between end-of-season-ranked groups and multinomial logistic regression. Significant physical performance differences between groups were identified for sprinting (top-ranked group vs. upper-middle-ranked group) and total distance covered without possession (upper and upper-middle-ranked groups and lower-ranked group). For technical performance, teams in the top-ranked group exhibited a significantly greater amount of possession in opponent's half, number of entry passes in the final 1/3 of the field and the Penalty Area, and 50-50 challenges than lower-ranked teams. Finally, time of possession increased the probability of a win compared with a draw. The current study identified key performance indicators that differentiated end-season team quality within the CSL. PMID- 29382230 TI - How to optimize the prescription of laboratory tests? Success and failures in an academic hospital. AB - In the context of the flat-rate reimbursements in healthcare, we reviewed physicians' behavior towards laboratory test ordering. We demonstrated how it could be improved when a specific stage of the patient management is considered. We took a multi-step approach to analyze the laboratory test orders in the context of planned laparoscopic cholecystectomy in a general teaching hospital. A reference order set was defined through a collaborative analysis between clinicians and laboratory physicians. The clinical and financial impacts were then evaluated over a period of 24 months. After the introduction of the reference order set, the number of laboratory tests per order decreased significantly for patients with cholecystitis of low severity. Above the monitoring of repeated orderings during a single stay, the major impacts were achieved by a drastic reduction of inappropriate orders, particularly in the field of bacteriology. The main effects of the order set were maintained throughout a follow-up period of 24 months. Our study demonstrated that, when considering laboratory test ordering optimization, reference order sets could achieve high levels of efficiency. To ensure high compliance to reference order sets, extensive collaboration between clinicians and laboratory physician is mandatory even if very sophisticated information systems are available. PMID- 29382231 TI - Overexpression of Hepatocyte Growth Factor mRNA Induced by Gene Transfer Attenuates Neointimal Hyperplasia After Balloon Injury. AB - Hepatic growth factor (HGF) has been widely used in studies on arterial remodeling after injury, and results turn out to be inconsistent. The changes of endogenous HGF expression after injury also remain controversial. This study clarified the role of exogenous human HGF (hHGF) gene transfer in neointimal hyperplasia and investigated the associated alterations of endogenous HGF and c Met expressions under endothelial denudation with or without hHGF gene transfer using a balloon-injured rabbit aorta model. Sixty-one rabbits were randomly divided into normal controls, endothelial injury, endothelial injury with hHGF, or the control vector gene transfer groups. On weeks 1, 2, 4, and 8 after injury, neointimal hyperplasia and endothelialization were evaluated by the ratio of neointimal area to medial area (N/M ratio), CD31-positive staining, alpha-smooth muscle actin, and endothelial nitric oxide synthase expressions using histological analysis, immunohistochemistry staining, or real-time quantitative reverse transcriptase polymerase chain reaction. Endogenous rabbit HGF (rHGF) and c-Met expressions were detected with immunohistochemistry staining and quantitative reverse transcriptase polymerase chain reaction. It was found that expressions of endogeneous rHGF and c-Met in endothelial injury upregulated with peak levels on week 2 or week 4 after injury (p < 0.01). On week 1 after hHGF transfer, neointimal hyperplasia was significantly inhibited (p < 0.001), with decreased alpha-smooth muscle actin expression (p < 0.05) and improved endothelial cells regeneration and function (p < 0.01). More remarkable overexpression of endogenous rHGF and c-Met mRNAs were detected, and lowered positive staining of rHGF and c-Met was shown in the neointima (p < 0.05). These results demonstrated hHGF gene transfer induced further overexpression of endogenous rHGF and c-Met mRNAs but lowered immunoreactivities of rHGF and c-Met in the neointima, thus leading to significant attenuation of neointimal hyperplasia. PMID- 29382232 TI - What are the main predictors of in-hospital mortality in patients with infective endocarditis: a review. AB - OBJECTIVES: Infective endocarditis (IE) has a high 30-day mortality. Surgery is needed in many patients. The preoperative hemodynamic status (congestive heart failure, need for urgent/emergent surgery or mechanical support, NYHA class III/IV) could have an impact on postoperative outcome. Each of these parameters is an indication for the inadequacy of the left ventricle to maintain an adequate circulation Methods. A literature search was performed using "endocarditis AND hospital mortality OR outcome AND predictor" and "International Collaboration on Endocarditis - Prospective Cohort Study" in Web of Science database, from 2010 2017. The focus was hospital mortality and its predictors. Manuscripts were excluded if no logistic regression or propensity analysis was available. The predictors were ranked according the odds ratios. Articles with risk scores based on multivariate analysis were also added. RESULTS: Most studies are coming from one tertiary center and are retrospective, with different designs. Recruitment periods are long and sample sizes small. Definitions of preoperative events such as hemodynamic status are not uniform. Thirty-day mortality varies between 10 and 50%. In 8 of 18 papers where the hemodynamic status is included, it is ranked as first and in 3 as second. The scoring systems confirm in several occasions the importance of left ventricular factors. DISCUSSION: The heterogeneity of the included papers and lack of uniform definitions of preoperative events precludes a proper meta-analysis. Nevertheless, heart failure and a compromised hemodynamic status can be identified as the dominant predictor for 30-day mortality of IE. This seems avoidable by early surgery. PMID- 29382233 TI - An in vivo study of Hypericum perforatum in a niosomal topical drug delivery system. AB - The active compounds present in Hypericum perforatum L. (Hypericaceae) include hyperforin, hypericins and flavonoids, which are assumed to be responsible for the activity of the extract in the treatment of wounds and scars. The present study aimed to incorporate H. perforatum extract standardized to a known content of phloroglucinols, naphthodianthrones and polyphenolic compounds into an effective transdermal drug delivery system capable of entrapping both lipophilic and hydrophilic constituents in the form of niosomal gels for wound treatment. An 80% ethanol extract (HE) was prepared on a pilot scale using DIG-MAZ. An HPLC-DAD holistic profile was established for HE and was standardized to contain 3.4 +/- 4 rutin, 1.1 +/- 3 chlorogenic acid, 0.5 +/- 2 quercitrin, 2.8 +/- 2 hyperforin, and 0.51 +/- 3% w/w total hypericins. Niosomes were prepared using the modified reverse phase evaporation technique (REV). The wound healing effect of the gel was tested on 16 adult mongrel dogs. A significant decrease in the inflammatory cell count (18.4 +/- 5.3) was recorded in the niosomal gel 1.5% NaCMC-treated group at the 7th day post wounding. It induced a marked regression in the inflammatory phase and enhanced the early beginning of the proliferative phase of wound healing. After 21 days, it showed complete re-epithelization, formation of new matrix fibers and significant reduction in the wound size, compared to the control and the Panthenol(r) 2% cream treated groups. This is the first study of H. perforatum in a niosomal topical drug delivery system. PMID- 29382234 TI - Association between the Rosen and Lundborg Score and the Screening Activity Limitation and Safety Awareness scale in hand functional evaluation of patients with leprosy diagnosis. AB - PURPOSE: To evaluate the association of results from the Rosen and Lundborg Score and the screening activity limitation and Safety Awareness scale for the assessment of hand in patients diagnosed with leprosy. METHOD: An association between the Rosen and Lundborg Score and the Screening Activity Limitation and Safety Awareness scale for hand was evaluated in a cross-section study with 25 people of a mean age of 51 years old (SD 14), undergoing drug treatment for leprosy. RESULTS: The mean quantitative score in the Screening Activity Limitation and Safety Awareness scale was 27.9 (SD 10.5). Rosen and Lundborg Score for the median nerve were 2.43 (SD 0.38) on the right hand and 2.41 (SD 0.54) on the left hand whilst for the ulnar nerve, the scores observed were 2.33 (SD 0.42) for the right hand and 2.31 (SD 0.61) for the left hand. Significant correlations between the two instruments in assessment of the median and ulnar nerves on both hands were found. CONCLUSIONS: Due to the association found between the scales, the Rosen and Lundborg Score may be used in assessment of the hand in patients diagnosed with leprosy, as a tool to assist the result evaluation after the drug treatment, surgical treatment, rehabilitation and follow-up in the hand dysfunction in leprosy. Implications for Rehabilitation The leprosy inflammatory neuropathy may cause limitations and disabilities related to hand functions of patients. Instruments with quantitative scores provide a reliable basis for therapeutic intervention prognosis. New evaluation methods promote a better monitoring of treatment and hand function evolution of people with leprosy. PMID- 29382235 TI - Barriers and facilitators to physical activity participation for children with physical disability: comparing and contrasting the views of children, young people, and their clinicians. AB - PURPOSE: Existing research has explored the barriers and facilitators of physical activity participation for young people with disability from the perspective of young people and their families. However, little research has investigated the views of clinicians who facilitate access to physical activity programs and compared this with their child client's perspectives. METHOD: Interviews were conducted with six allied health and sports development professionals associated with a programme which supports access to recreation and sporting activities. Interviews explored facilitators and barriers to physical activity experienced by their clients. Open-ended survey questions investigating barriers and facilitators of physical activity participation were also completed by 28 young people with disability aged 10-17 years who were clients of this programme. RESULTS: The most salient facilitator of participation described by clinicians was "planning programs to promote success and inclusion." Young people described two main facilitators; "the right people make physical activity fun!" and, similar to clinicians, "appropriate and inclusive opportunities to be active." The most salient barriers identified by clinicians were "practical limitations" and "time constraints and priorities," and a novel barrier raised was "whose choice?" The "lack of accessible and inclusive opportunities" was the most pertinent barrier for young people. CONCLUSIONS: Clinicians should determine both parent and young person commitment to a physical activity before enrolment. Lack of commitment can act as a barrier to physical activity and a more appropriate intervention could focus on increasing awareness of the benefits of being active, drawing on a Stages of Change based model of service delivery. Implications for rehabilitation Rehabilitation professionals seeking to increase physical activity participation for young people with physical disability should discuss readiness and motivation to change prior to any activity/sports referral. Different behaviour change processes are required for young people and for their parents and both are important to achieve physical activity participation. Regular monitoring is important to identify on-going physical and psychological barriers to participation, even for those who were already active. Clinicians should be aware that teenagers may be more ready to be active as they develop greater independence and should raise awareness of the benefits of physical activity. PMID- 29382236 TI - Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation, characterization, in vitro, and in vivo study. AB - Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD50). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability. PMID- 29382238 TI - Factors affecting participation in physical activities in Saudi children with Down syndrome: mothers' perspectives. AB - PURPOSE: Physical activity provides a wide range of benefits. Several studies conducted in various countries have examined factors influencing participation in physical activities in children with Down syndrome. This study aimed to explore factors affecting participation in physical activities in Saudi children with DS, from their mothers' perspectives. MATERIALS AND METHODS: In-depth interviews were conducted with 36 mothers of children with Down syndrome to explore facilitators of and barriers to their children's participation in physical activities. All audio recordings were transcribed, validated, reviewed by the authors independently, and organized into themes. RESULTS: Transcript analysis resulted in four facilitators (mother's support and siblings' involvement, involvement of peers, type of physical activity experience, and child's physical ability, behavioral, and psychological status), and six barriers (conditions associated with Down syndrome, family responsibility, social barriers, environmental constraints, electronic devices, and mother's personal psychological barriers). CONCLUSIONS: The results regarding perceived barriers indicated a need to develop and implement programs involving family consultation. Environmental modifications should be made to accommodate the needs of children with Down syndrome. A well organized partnership should be established and activated between private investors and the Ministries of Education, Social Affairs, and Health, to support the promotion of physical activity. Implications for rehabilitation The efficacy of home- and Internet-based programs for Saudi children with Down syndrome (DS) should be evaluated. Cultural and climactic conditions in Saudi Arabia suggest the need for environmental modifications to help children with DS engage in physical activity. Well-organized partnerships between private investors and the Ministries of Education, Social Affairs, and Health may be required to achieve higher participation of children with DS. Planning and designing of strategies, policies, facilities, and programs are required to increase engagement in physical activity and maximize the benefits of participation of children with DS. PMID- 29382237 TI - In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates. AB - Nasal administration has been proposed as a potential approach for the delivery of drugs to the central nervous system. Ribavirin (RBV), an antiviral drug potentially useful to treat viral infections both in humans and animals, has been previously demonstrated to attain several brain compartments after nasal administration. Here, a powder formulation in the form of agglomerates comprising micronized RBV and spray-dried microparticles containing excipients with potential absorption enhancing properties, i.e. mannitol, chitosan, and alpha cyclodextrin, was developed for nasal insufflation. The agglomerates were characterized for particle size, agglomeration yield, and ex vivo RBV permeation across rabbit nasal mucosa as well as delivery from an animal dry powder insufflator device. Interestingly, permeation enhancers such as chitosan and mannitol showed a lower amount of RBV permeating across the excised nasal tissue, whereas alpha-cyclodextrin proved to outperform the other formulations and to match the highly soluble micronized RBV powder taken as a reference. In vivo nasal administration to rats of the agglomerates containing alpha-cyclodextrin showed an overall higher accumulation of RBV in all the brain compartments analyzed as compared with the micronized RBV administered as such without excipient microparticles. Hence, powder agglomerates are a valuable approach to obtain a nasal formulation potentially attaining nose-to-brain delivery of drugs with minimal processing of the APIs and improvement of the technological and biopharmaceutical properties of micronized API and excipients, as they combine optimal flow properties for handling and dosing, suitable particle size for nasal deposition, high surface area for drug dissolution, and penetration enhancing properties from excipients such as cyclodextrins. PMID- 29382239 TI - Dual-targeting for brain-specific drug delivery: synthesis and biological evaluation. AB - Ibuprofen is one of the most potent non-steroid anti-inflammatory drugs (NSAIDs) and plays an important role in the treatment of neurodegenerative diseases. However, its poor brain penetration and serious side effects at therapeutic doses, has hindered its further application. Thus, it is of great interest to develop a carrier-mediated transporter (CMT) system that is capable of more efficiently delivering ibuprofen into the brain at smaller doses to treat neurodegenerative diseases. In this study, a dual-mediated ibuprofen prodrug modified by glucose (Glu) and vitamin C (Vc) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to brain. Ibuprofen could be released from the prepared prodrugs when incubated with various buffers, mice plasma and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vitro and in vivo than ibuprofen. Our results suggest that chemical modification of therapeutics with warheads of glucose and Vc represents a promising and efficient strategy for the development of brain-targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads. PMID- 29382240 TI - Diagnostic yield is not influenced by the timing of screening endoscopy: morning versus afternoon. AB - BACKGROUND: Previous studies have shown the colonoscopy quality affected by the endoscopist's fatigue. This study was aimed to evaluate this potential factor in a colorectal cancer-screening cohort of Chinese patients. METHODS: The attendances at department of gastroenterology for colorectal cancer screening between 2013 and 2015 were retrospectively analyzed. The procedure time-of-day and hours elapse were recorded. The primary outcome was defined as adenoma detection rate (ADR). RESULTS: A total of 1342 screening colonoscopies were performed by 19 gastroenterologists in the study. Detection rates were 7.7% for all polyps and 20.0% for adenomas. Time-of-day was not significantly associated with ADR. With time elapsing, the first climax for ADR was presented at 09:00 10:00, and persistently rose again after the lunch break. Significant inclined trend in ADR was noted for each hour blocks of a full day (p = .0021). CONCLUSIONS: The procedure time-of-day, morning versus afternoon, did not affect the diagnostic efficacy of screening endoscopy in Chinese patients. PMID- 29382241 TI - Is standing balance altered in individuals with chronic low back pain? A systematic review. AB - PURPOSE: To examine the static standing balance of individuals with chronic low back pain when compared to a healthy control group. METHODS: A search of available literature was done using PubMed, SPORTDiscus, CINAHL, and Scopus databases. Studies were included if they contained the following: (1) individuals with chronic low back pain 3 months or longer; (2) healthy control group; (3) quantified pain measurement; and (4) center of pressure measurement using a force plate. Two authors independently reviewed articles for inclusion, and assessed for quality using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross Sectional Studies. Cohen's d effect size was calculated to demonstrate the magnitude of differences between groups. RESULTS: Nine articles were included in this review. Quality scores ranged from 5/8 to 8/8. Although center of pressure measures were nonhomogeneous, subjects with chronic low back pain had poorer performance overall compared to healthy controls. Despite inconsistencies in statistical significance, effect sizes were frequently large, indicating a lack of sufficient power in the included studies. Data were insufficiently reported among certain studies, limiting the ability of direct study comparison. CONCLUSIONS: Results suggest that balance is impaired in individuals with chronic low back pain when compared to healthy individuals. Implications for rehabilitation Static balance is affected in individuals with chronic low back pain. Balance assessments should be completed for individuals with chronic low back pain. Results from balance assessments should be used to indicate areas of improvement and help guide the course of treatment, as well as reassess as treatment progresses. PMID- 29382243 TI - Development of an exercise intervention as part of rehabilitation in a glioblastoma multiforme survivor during irradiation treatment: a case report. AB - INTRODUCTION: This case report describes the rationale and development of an exercise intervention in a patient with glioblastoma multiforme (GBM ) and discusses potential relations of observed effects in functional performance and quality of life (QOL). METHODS: A 54-year-old GBM survivor completed a supervised six-week exercise intervention during irradiation treatment beginning 42 d after resection. Exercise modalities of cardiorespiratory, resistance, and balance training were designed on generic recommendations of various cancer populations and literature review. RESULTS: Our case attended all possible sessions without experiencing adverse effects, and improved in aerobe power (24%), muscle strength (0-38%), standing balance (71%), walking ability (9%), and QOL domains of "Global Health Status/QoL" and "Physical functioning." CONCLUSIONS: Based on this single case, exercise rehabilitation has the ability to maintain or improve functional performance and QOL domains even during heavy treatments. It also implies that patients with GBM are capable and may be willing to participate in exercise rehabilitation if supervised by physical therapists. Implications for rehabilitation The use of exercise as part of rehabilitation still needs attention in strong methodology studies of patients with gliomas. Exercise rehabilitation may maintain or even improve functional performance and QOL domains during medical treatment regimens. Functional independent patients with GBM are capable to comply with generic exercise recommendations and may be willing to participate in exercise rehabilitation if supervised by physical therapists. PMID- 29382244 TI - Successful treatment of post-transplant relapsed adult T cell leukemia after cord blood transplantation with low-dose, short-term lenalidomide. PMID- 29382245 TI - Bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning could be a bad combination. PMID- 29382242 TI - Models of retinal diseases and their applicability in drug discovery. AB - INTRODUCTION: The impact of vision debilitating diseases is a global public health concern, which will continue until effective preventative and management protocols are developed. Two retinal diseases responsible for the majority of vision loss in the working age adults and elderly populations are diabetic retinopathy (DR) and age-related macular degeneration (AMD), respectively. Model systems, which recapitulate aspects of human pathology, are valid experimental modalities that have contributed to the identification of signaling pathways involved in disease development and consequently potential therapies. Areas covered: The pathology of DR and AMD, which serve as the basis for designing appropriate models of disease, is discussed. The authors also review in vitro and in vivo models of DR and AMD and evaluate the utility of these models in exploratory and pre-clinical studies. Expert opinion: The complex nature of non Mendelian diseases such as DR and AMD has made identification of effective therapeutic treatments challenging. However, the authors believe that while in vivo models are often criticized for not being a 'perfect' recapitulation of disease, they have been valuable experimentally when used with consideration of the strengths and limitations of the experimental model selected and have a place in the drug discovery process. PMID- 29382246 TI - Success is built on failures: tackling the challenge of ponatinib failure. PMID- 29382247 TI - Antibiotic-loaded cement spacers - lessons learned from the past 20 years. AB - INTRODUCTION: The use of antibiotic-impregnated cement spacers is an established method in the treatment of periprosthetic hip and knee joint infections. Over the past 20 years, the indications for spacer implantation have expanded, and various modified surgical techniques have been proposed to manage difficult anatomical situations. To ensure clinical success, knowledge about the cement impregnation and the pharmacokinetic properties of antibiotic-loaded bone cement is an indispensable premise. Areas covered: In this review, techniques for the fabrication of cement spacers, the incorporation of antibiotics into bone cement, elution kinetics, the clinical performance of spacers, individualized surgical techniques as well as possible postoperative complications are presented. Moreover, the possibility of bacterial colonization of cement spacers during the interim phase which might lead to persistence of infection is also discussed. Expert commentary: The use of articulating spacers is established in hip surgery. However, in knee surgery it is still debated whether articulating or static spacers provide more advantages. The concern about the possible colonization of antibiotic-loaded spacers during the interim phase does not seem to be actually substantiated by hard scientific data due to the lack of important information in the published studies. PMID- 29382248 TI - Future of human Chlamydia vaccine: potential of self-adjuvanting biodegradable nanoparticles as safe vaccine delivery vehicles. AB - INTRODUCTION: There is a persisting global burden and considerable public health challenge by the plethora of ocular, genital and respiratory diseases caused by members of the Gram-negative bacteria of the genus Chlamydia. The major diseases are conjunctivitis and blinding trachoma, non-gonococcal urethritis, cervicitis, pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and interstitial pneumonia. The failures in screening and other prevention programs led to the current medical opinion that an efficacious prophylactic vaccine is the best approach to protect humans from chlamydial infections. Unfortunately, there is no human Chlamydia vaccine despite successful veterinary vaccines. A major challenge has been the effective delivery of vaccine antigens to induce safe and effective immune effectors to confer long-term protective immunity. The dawn of the era of biodegradable polymeric nanoparticles and the adjuvanted derivatives may accelerate the realization of the dream of human vaccine in the foreseeable future. Areas covered: This review focuses on the current status of human chlamydial vaccine research, specifically the potential of biodegradable polymeric nanovaccines to provide efficacious Chlamydia vaccines in the near future. Expert commentary: The safety of biodegradable polymeric nanoparticles based experimental vaccines with or without adjuvants and the array of available chlamydial vaccine candidates would suggest that clinical trials in humans may be imminent. Also, the promising results from vaccine testing in animal models could lead to human vaccines against trachoma and reproductive diseases simultaneously. PMID- 29382249 TI - Methoxsalen as an in vitro phenotyping tool in comparison with 1 aminobenzotriazole. AB - The objective is to evaluate methoxsalen as an in vitro phenotyping tool in comparison to ABT as a nonspecific inactivator of P450 mediated metabolism. The reversible inhibition of methoxsalen and ABT against the P450, FMO, AO, MAO-A and -B, enzymes were evaluated using standard marker probe reactions. The time dependent inhibition of P450 enzymes was evaluated in human liver microsomes. CES1 activities were determined by monitoring the depletion of known substrate, the clopidogrel. The metabolism of P450 substrates in the presence and absence of methoxsalen or ABT was evaluated in human liver microsomes. Methoxsalen is a direct inhibitor and inhibited the activities (>90%) of all enzymes at a concentration of 300 uM except for CYP2C9. Methoxsalen is also a potent time dependent inhibitor of all P450 enzymes except for CYP2C19 (moderate) at a concentration of 300 uM. Methoxsalen inhibited the metabolism of P450 substrates in the pre-incubation mode. ABT is a potent TDI of several P450 except for CYP2C19 (47%) and CYP2C9 (27%). The results indicate that methoxsalen is a potent pan P450 inhibitor than ABT and can be a better tool in distinguishing P450 mediated metabolism form non-P450 metabolism in human liver microsomes. PMID- 29382250 TI - The effect of individual enabling and support on empowerment and depression severity in persons with affective disorders: outcome of a randomized control trial. AB - PURPOSE: To evaluate the effect of Individual Enabling and Support (IES) on empowerment and depression severity as compared to Traditional Vocational Rehabilitation (TVR) in people with affective disorders at 12 months follow-up. Additionally, longitudinal changes within the intervention groups and the correlation over time between empowerment and depression severity were evaluated. METHOD: A single-blind randomized controlled trial of two intervention groups, IES (n = 33) and TVR (n = 28), was performed with measurement points at baseline, 6, and 12 months. Individuals with affective disorders, including depression and bipolar disorder diagnoses were included. The Empowerment Scale and Montgomery Asberg Depression Self-Rating Scale were administered, and Intention-To-Treat analysis was applied. The study was registered with the trial number ISRCTN93470551. RESULT: There was a statistically significant difference between the intervention groups on empowerment and depression severity at 12 months. Within-group analysis showed that IES-participants increased their perceived empowerment and decreased their depression severity between measurement points, this was not seen among TVR-participants. A moderate, inverse relationship was detected between empowerment and depression. CONCLUSION: IES is more effective in increasing empowerment and decreasing depression severity after a 12-month intervention than is TVR. This study was limited by a small sample size and larger trials in different contexts are needed. PMID- 29382252 TI - Synthetic siRNA targeting human papillomavirus 16 E6: a perspective on in vitro nanotherapeutic approaches. AB - High-risk human papillomaviruses infect skin and mucosa, causing approximately 5% of cancers worldwide. In the search for targeted nanotherapeutic approaches, siRNAs against the viral E6 transcript have been molecules of interest but have not yet seen successful translation into the clinic. By reviewing the past approximately 15 years of in vitro literature, we identify the need for siRNA validation protocols which concurrently evaluate ranges of key treatment parameters as well as characterize downstream process restoration in a methodical, quantitative manner and demonstrate their implementation using our own data. We also reflect on the future need for more appropriate cell culture models to represent patient lesions as well as the application of personalized approaches to identify optimal treatment strategies. PMID- 29382251 TI - Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial - challenges, enablers and lessons learned. AB - A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research. PMID- 29382253 TI - Bacterial promoter prediction: Selection of dynamic and static physical properties of DNA for reliable sequence classification. AB - Predicting promoter activity of DNA fragment is an important task for computational biology. Approaches using physical properties of DNA to predict bacterial promoters have recently gained a lot of attention. To select an adequate set of physical properties for training a classifier, various characteristics of DNA molecule should be taken into consideration. Here, we present a systematic approach that allows us to select less correlated properties for classification by means of both correlation and cophenetic coefficients as well as concordance matrices. To prove this concept, we have developed the first classifier that uses not only sequence and static physical properties of DNA fragment, but also dynamic properties of DNA open states. Therefore, the best performing models with accuracy values up to 90% for all types of sequences were obtained. Furthermore, we have demonstrated that the classifier can serve as a reliable tool enabling promoter DNA fragments to be distinguished from promoter islands despite the similarity of their nucleotide sequences. PMID- 29382254 TI - MethyMer: Design of combinations of specific primers for bisulfite sequencing of complete CpG islands. AB - We present MethyMer, a Python-based tool aimed at selecting primers for amplification of complete CpG islands. These regions are difficult in terms of selecting appropriate primers because of their low-complexity, high GC content. Moreover, bisulfite treatment, in fact, leads to the reduction of the 4-letter alphabet (ATGC) to 3-letter one (ATG, except for methylated cytosines), and this also reduces region complexity and increases mispriming potential. MethyMer has a flexible scoring system, which optimizes the balance between various characteristics such as nucleotide composition, thermodynamic features (melting temperature, dimers [Formula: see text]G, etc.), the presence of CpG sites and polyN tracts, and primer specificity, which is assessed with aligning primers to the bisulfite-treated genome using bowtie (up to three mismatches are allowed). Users are able to customize desired or limit ranges of various parameters as well as penalties for non-desired values. Moreover, MethyMer allows picking up the optimal combination of PCR primer pairs to perform the amplification of a large genomic locus, e.g. CpG island or other hard-to-study region, with minimal overlap of the individual amplicons. MethyMer incorporates ENCODE genome annotation records (promoter/enhancer/insulator), The Cancer Genome Atlas (TCGA) CpG methylation data derived with Illumina Infinium 450K microarrays, and records on correlations between TCGA RNA-Seq and CpG methylation data for 20 cancer types. These databases are included in the MethyMer release. Our tool is available at https://sourceforge.net/projects/methymer/ . PMID- 29382255 TI - Warm and touching tears: tearful individuals are perceived as warmer because we assume they feel moved and touched. AB - Recent work investigated the inter-individual functions of emotional tears in depth. In one study (Van de Ven, N., Meijs, M. H. J., & Vingerhoets, A. (2017). What emotional tears convey: Tearful individuals are seen as warmer, but also as less competent. British Journal of Social Psychology, 56(1), 146-160. Https://doi.org/10.1111/bjso.12162) tearful individuals were rated as warmer, and participants expressed more intentions to approach and help such individuals. Simultaneously, tearful individuals were rated as less competent, and participants expressed less intention to work with the depicted targets. While tearful individuals were perceived as sadder, perceived sadness mediated only the effect on competence, but not on warmth. We argue that tearful individuals might be perceived as warm because they are perceived as feeling moved and touched. We ran a pre-registered extended replication of Van de Ven et al. Results replicate the warmth and helping findings, but not the competence and work effects. The increase in warmth ratings was completely mediated by perceiving feeling moved and touched. Possible functions of feeling moved and touched with regard to emotional tears are discussed. PMID- 29382256 TI - Extender Supplementation with Antioxidants Selected after the Evaluation of Sperm Susceptibility to Oxidative Challenges in Goats. AB - This study aimed to detect the most deleterious ROS for goat sperm and then supplemented the extender with a proper antioxidant. For this, 12 adult goats (aged 1-7) were used. Fresh samples were submitted to challenge with different ROS (superoxide anion, hydrogen peroxide, and hydroxyl radical) and malondialdehyde (MDA-toxic product of lipid peroxidation). After experiment 1, sperms were cryopreserved in extenders supplemented to glutathione peroxidase (Control: 0 UI/mL; GPx1: 1 UI/mL; GPx5: 5 UI/mL, and GPx10: 10 UI/mL) and catalase (Control: 0 UI/mL; CAT60: 60 UI/mL; CAT120: 120 UI/mL, and CAT240: 240 UI/mL). Each sample was evaluated by motility, plasma membrane integrity (eosin/nigrosin), acrosome integrity (fast green/rose bengal), sperm morphology, assay of the sperm chromatin structure, mitochondrial activity (3,3 diaminobenzidine), and measurement of lipid peroxidation (thiobarbituric acid reactive substances [TBARS]). It was possible to observe a mitochondrial dysfunction (DAB-Class IV) and low membrane integrity after hydrogen peroxide action. However, the high rates of TBARS were observed on hydroxyl radical. CAT240 presents the lower percentage of plasma membrane integrity. It was possible to attest that hydrogen peroxide and hydroxyl radical are the more harmful for goat sperm. Antioxidant therapy must be improving perhaps using combination between antioxidants. PMID- 29382257 TI - Evaluating anxiety and depression symptoms in children and adolescents with prior mild traumatic brain injury: Agreement between methods and respondents. AB - Psychological functioning can be adversely impacted after a mild traumatic brain injury (mTBI) and may be a potential target for intervention. Despite the use of symptom ratings or structured diagnostic interview to assess long-term anxiety and depression symptoms in children and adolescents post-injury, no known studies have considered the agreement between different assessment methods and between respondents. The objectives of this study were to investigate the agreement between symptom ratings and structured diagnostic interview and between children and parents' symptom reporting. Participants (N = 33; 9-18 years old) were recruited from the Emergency Department and assessed on average 22.8 months (SD = 5.6) after their mTBI. Anxiety and depression symptoms were evaluated via subscales of a questionnaire (Behavior Assessment System for Children) and parts of a computerized structured diagnostic interview (generalized anxiety disorder and major depressive episode; Diagnostic Interview Schedule for Children - C-DISC IV) administered individually to children and their parents. Results showed that the inter-method agreement to identify high levels of anxiety and depression was moderate to perfect in children while it was lower in parents. Although a similar percentage of participants with elevated anxiety or depression were identified by both children and parents, the agreement between youth and parents was variable, ranging from poor to good for anxiety and poor to moderate for depression. These results highlight the importance of collecting youth and parents' reports of anxiety and depression symptoms and considering potential discrepancies between informants' answers. PMID- 29382258 TI - School burnout and heart rate variability: risk of cardiovascular disease and hypertension in young adult females. AB - Emerging research documents the relationship between school burnout and some indicators of increased cardiovascular risk. Indicators of cardiovascular functioning assessed via ambulatory blood pressure and heart rate variability (HRV) have not been thoroughly explored in this research domain. Therefore, the current study examined relationships between school burnout and indicators of cardiac functioning via 24 h ambulatory blood pressure (BP) and electrocardiogram monitoring in a sample of young adult female undergraduates (N = 88). Two hypotheses were tested: (1) that independent of related negative affective symptomology (depression and anxiety), increased school burnout would be related to greater systolic and diastolic BP, higher low frequency (LF) HRV and lower very low frequency (VLF) HRV, and (2) that lower VLF would be related to greater school burnout independently of LF HRV. Hierarchical multiple regression analyzes showed that school burnout was significantly related to elevated ambulatory BP (systolic and diastolic) and HRV markers of increased cardiac sympathovagal tone. These findings support the hypotheses and suggest that school burnout might be implicated in the development of pre-hypertension or early cardiovascular disease. Study limitations and the need for future longitudinal research are discussed. PMID- 29382259 TI - ? PMID- 29382260 TI - Recommendations for Diagnostic and Prognostic Evaluation of Autosomal Dominant Polycystic Kidney Disease (ADPKD) with a Focus on Imaging. PMID- 29382261 TI - ? PMID- 29382262 TI - ? PMID- 29382263 TI - ? PMID- 29382264 TI - ? PMID- 29382265 TI - ? PMID- 29382266 TI - ? PMID- 29382267 TI - ? PMID- 29382268 TI - [CME: Acute Intermittent Porphyria: When to Think of It? What Must be Checked? How to Treat?] PMID- 29382269 TI - [CME: Sonografie 80 - Jaundice.] PMID- 29382270 TI - Promoting innovation: Enhancing transdisciplinary opportunities for medical and engineering students. AB - PURPOSE: Addressing current healthcare challenges requires innovation and collaboration. Current literature provides limited guidance in promoting these skills in medical school. One approach involves transdisciplinary training in which students from different disciplines work together toward a shared goal. We assessed the need for such a curriculum at Dartmouth College. METHODS: We surveyed medical and engineering students' educational values; learning experiences; professional goals; and interest in transdisciplinary education and innovation. Data were analyzed using descriptive statistics. RESULTS: Shared values among student groups included leadership development, innovation, collaboration, and resource sharing. Medical students felt their curriculum inadequately addressed creativity and innovation relative to their engineering counterparts (p < 0.05). Medical students felt less prepared for entrepreneurial activities (p < 0.05), while engineering students indicated a need for basic medical knowledge and patient-oriented design factors. Despite strong interest, collaboration was less than 50% of indicated interest. CONCLUSIONS: Medical and engineering students share an interest in the innovation process and need a shared curriculum to facilitate collaboration. A transdisciplinary course that familiarizes students with this process has the potential to promote physicians and engineers as leaders and innovators who can effectively work across industry lines. A transdisciplinary course was piloted in Spring 2017. PMID- 29382271 TI - Workers' exposure to electric fields during the task 'maintenance of an operating device of circuit breaker from a service platform' at 110-kV substations. AB - The objective of the study was to investigate occupational exposure to electric fields during the task 'maintenance of an operating device of circuit breaker from a service platform' at 110-kV substations. The aim was also to compare the results to Directive 2013/35/EU. At 16 substations, 255 electric field measurements were performed. The highest mean value of the electric fields was 9.6 kV?m-1. At 63% of substations the maximum values were over 10.0 kV?m-1, and at 31% of the substations the 75th percentiles were over 10.0 kV?m-1, which is the low action level (AL) according to Directive 2013/35/EU. All measured values were below the high AL (20.0 kV?m-1). In the future, it is important to take into account that the measurements were only taken at Finnish 110-kV substations; therefore, it is not possible to generalize these results to other countries and different types of substations. PMID- 29382272 TI - Mycotic aortic aneurysms treated by endovascular repair: initial experience in a single center. AB - INTRODUCTION: Mycotic aortic aneurysm (MAA) is an uncommon cause of aneurysmal aortic disease. However, it may have an aggressive presentation and a complicated early outcome. Endovascular aneurysm repair (EVAR) of MAA is emerging as an alternative to open repair (OR) for the treatment of these aneurysms, particularly in high-risk surgical patients. We report a single-center experience with the endovascular management of mycotic aortic aneurysms. MATERIAL AND METHODS: Two mycotic abdominal aortic aneurysms were treated with an endovascular stent graft at Centre Hospitalier Regional du Val de Sambre, Belgium. The mean follow-up was 15 months. Technical success was achieved in all two patients. CT scan follow up showed shrinkage of the aneurysm sac, with no evidence of infection along the stent graft and no signs of endoleakage in all patients. One patient died during the follow-up period from a cause unrelated to the aneurysm. CONCLUSION: EVAR is an effective and safe option and might be a suitable alternative to OR in the absence of predictors of poor prognosis for the treatment of non-complicated forms of MAA. PMID- 29382273 TI - Conflict of Interest in Journal Peer Review. PMID- 29382274 TI - An assessment of financial catastrophe and impoverishment from out-of-pocket health care payments in Swaziland. AB - BACKGROUND: As the drive towards universal coverage is gaining momentum globally, the need for assessing levels of financial health protection in countries, particularity the developing world, has increasingly become important. In Swaziland, the level of financial health protection is not clearly understood. OBJECTIVE: To assess financial catastrophe and impoverishment from out-of-pocket payments for health services in Swaziland. METHODS: The nationally representative Swaziland Household Income and Expenditure Survey (2009/2010) dataset is used for the analyses. Data are collected by the Central Statistics Office in Swaziland. The final dataset contains information on 3,167 households (i.e. about 14,145 individuals) out of the anticipated 3,750 households. Financial catastrophe is assessed using an initial threshold that is adjusted to increase with household income (i.e. rank-dependent). Payment for health services is considered catastrophic when they exceed the threshold. Impoverishment is assessed using a national poverty line and an international poverty line ($1.25/day). RESULTS: Using an initial threshold of 10.0% of household expenditure, 9.7% of Swazi households experience financial catastrophe while the proportion is estimated at 2.7% using an initial threshold of 40.0% of non-food expenditure. Between 1.0% and 1.6% of the Swazi population, representing between 10,000 and 16,000 people are pushed below the poverty line because of out-of-pocket payments. These findings indicate that financial health protection is not adequate in Swaziland. CONCLUSION: If Swaziland is to move towards achieving universal health coverage, there is a need to address the burden created by direct out-of-pocket payments. Among other things, this means that the country needs to consider financing mechanisms that guarantee equitable access to needed quality health services, which do not place undue hardship on the poor and vulnerable. PMID- 29382275 TI - Rebuilding people-centred maternal health services in post-Ebola Liberia through participatory action research. AB - During the March 2014-January 2016 Ebola crisis in Liberia, Redemption Hospital lost 12 staff and became a holding facility for suspected cases, prompting violent hostility from the surrounding New Kru Town community, in the capital city Monrovia. Inpatient services were closed for 6 months, leaving the population without maternity care. In January 2015, Redemption reopened, but utilization was low, especially for deliveries. A key barrier was community trust in health workers which worsened during the epidemic. The New Kru Town council, Redemption Hospital, the International Rescue Committee, and Training and Research Support Centre initiated participatory action research (PAR) in July 2015 to build communication between stakeholder groups, and to identify impacts of the epidemic and shared actions to improve the system. The PAR involved pregnant women, community-based trained traditional midwives (TTMs) and traditional birth attendants (TBAs), and community leaders, as well as health workers. Qualitative data and a pre-post survey of PAR participants and community members assessed changes in relationships and maternal health services. The results indicated that Ebola worsened community-hospital relations and pre existing weaknesses in services, but also provided an opportunity to address these when rebuilding the system through shared action. Findings suggest that PAR generated evidence and improved communication and community and health worker interaction. PMID- 29382276 TI - The Predictive Value of the Maximal Liver Function Capacity Test for the Isolation of Primary Human Hepatocytes. AB - The need for primary human hepatocytes is constantly growing for basic research, as well as for therapeutic applications. However, the isolation outcome strongly depends on the quality of liver tissue, and we are still lacking a preoperative test that allows the prediction of the hepatocyte isolation outcome. In this study, we evaluated the "maximal liver function capacity test" (LiMAx) as predictive test for the quantitative and qualitative outcome of hepatocyte isolation. This test is already used in clinical routine to measure preoperative and to predict postoperative liver function. The patient's preoperative mean LiMAx was obtained from the patient records, and preoperative computed tomography and magnetic resonance images were used to calculate the whole liver volume to adjust the mean LiMAx. The outcome parameters of the hepatocyte isolation procedures were analyzed in correlation with the adjusted mean LiMAx. Primary human hepatocytes were isolated from partial hepatectomies (n = 64). From these 64 hepatectomies we included 48 to our study and correlated their isolation outcome parameters with volume corrected LiMAx values. From a total of 11 hepatocyte isolation procedures, metabolic parameters (albumin, urea, and aspartate aminotransferase or AST) were assessed during the hepatocyte cultivation period of 5 days. The volume adjusted mean LiMAx showed a significant positive correlation with the total cell yield (p = 0.049; r = 0.242; n = 48). The correlations of volume adjusted LiMAx values with viable cell yield and cell viability did not reach statistical significance. To create a more homogenous study group regarding tumor entities, subgroup analyses were performed. A subgroup analysis of isolations from patients with colorectal metastasis revealed a significant correlation between volume adjusted mean LiMAx and total cell yield (p = 0.012; r = 0.488; n = 21) and viable cell yield (p = 0.034; r = 0.405; n = 21), whereas a subgroup analysis of isolations of patients with carcinoma of the biliary tree showed significant correlations of volume adjusted mean LiMAx with cell viability (r = 0.387; p = 0.046; n = 20) and lacked significant correlations with total cell yield (r = -0.060; p = 0.401; n = 20) and viable cell yield (r = 0.012; p = 0.480; n = 20). The volume-adjusted mean LiMAx did not show a significant correlation with any of the metabolic parameters. In conclusion, the LiMAx test might be a useful tool to predict the quantitative outcome of hepatocyte isolation, as long as underlying liver disease is taken into consideration. PMID- 29382277 TI - Mitochondrial variability in the Mediterranean area: a complex stage for human migrations. AB - CONTEXT: The Mediterranean area has always played a significant role in human dispersal due to the large number of migratory events contributing to shape the cultural features and the genetic pool of its populations. OBJECTIVE: This paper aims to review and diachronically describe the mitogenome variability in the Mediterranean population and the main demic diffusions that occurred in this area over time. METHODS: Frequency distributions of the leading mitochondrial haplogroups have been geographically and chronologically evaluated. The variability of U5b and K lineages has been focussed to broaden the knowledge of their genetic histories. RESULTS: The mitochondrial genetic makeup of Palaeolithic hunter-gatherers is poorly defined within the extant Mediterranean populations, since only a few traces of their genetic contribution are still detectable. The Neolithic lineages are more represented, suggesting that the Neolithic revolution had a marked effect on the peopling of the Mediterranean area. The largest effect, however, was provided by historical migrations. CONCLUSION: Although the mitogenome variability has been widely used to try and clarify the evolution of the Mediterranean genetic makeup throughout almost 50 000 years, it is necessary to collect whole genome data on both extinct and extant populations from this area to fully reconstruct and interpret the impact of multiple migratory waves and their cultural and genetic consequences on the structure of the Mediterranean populations. PMID- 29382278 TI - Mediterranean Y-chromosome 2.0-why the Y in the Mediterranean is still relevant in the postgenomic era. AB - CONTEXT: Due to its unique paternal inheritance, the Y-chromosome has been a highly popular marker among population geneticists for over two decades. Recently, the advent of cost-effective genome-wide methods has unlocked information-rich autosomal genomic data, paving the way to the postgenomic era. This seems to have announced the decreasing popularity of investigating Y chromosome variation, which provides only the paternal perspective of human ancestries and is strongly influenced by genetic drift and social behaviour. OBJECTIVE: For this special issue on population genetics of the Mediterranean, the aim was to demonstrate that the Y-chromosome still provides important insights in the postgenomic era and in a time when ancient genomes are becoming exponentially available. METHODS: A systematic literature search on Y-chromosomal studies in the Mediterranean was performed. RESULTS: Several applications of Y chromosomal analysis with future opportunities are formulated and illustrated with studies on Mediterranean populations. CONCLUSIONS: There will be no reduced interest in Y-chromosomal studies going from reconstruction of male-specific demographic events to ancient DNA applications, surname history and population wide estimations of extra-pair paternity rates. Moreover, more initiatives are required to collect population genetic data of Y-chromosomal markers for forensic research, and to include Y-chromosomal data in GWAS investigations and studies on male infertility. PMID- 29382280 TI - The genetic landscape of Mediterranean North African populations through complete mtDNA sequences. AB - BACKGROUND: The genetic composition of human North African populations is an amalgam of different ancestral components coming from the Middle East, Europe, south-Saharan Africa and autochthonous to North Africa. This complex genetic pattern is the result of migrations and admixtures in the region since Palaeolithic times. AIMS: The objective of the present study is to refine knowledge of the population history of North African populations through the analysis of complete mitochondrial sequences. SUBJECTS AND METHODS: This study has sequenced complete mitochondrial DNAs (mtDNAs) in several North African and neighbouring individuals. RESULTS: The mtDNA haplogroup classification and phylogeny shows a high genetic diversity in the region as a result of continuous admixture. The phylogenetic analysis allowed us to identify a new haplogroup characterised by positions 10 101 C and 146 C (H1v2), a sub-branch of H1v, which is restricted to North Africa and whose origins are estimated as ~4000 years ago. CONCLUSIONS: The analysis of the complete mtDNA genome has allowed for the identification of a North African sub-lineage that might be ignored by the analysis of partial mtDNA control region sequences, highlighting the phylogeographic relevance of mtDNA complete sequence analysis. PMID- 29382281 TI - Human population genetics of the Mediterranean. PMID- 29382282 TI - Enlarging the gene-geography of Europe and the Mediterranean area to STR loci of common forensic use: longitudinal and latitudinal frequency gradients. AB - BACKGROUND: Tetranucleotide Short Tandem Repeats (STRs) for human identification and common use in forensic cases have recently been used to address the population genetics of the North-Eastern Mediterranean area. However, to gain confidence in the inferences made using STRs, this kind of analysis should be challenged with changes in three main aspects of the data, i.e. the sizes of the samples, their distance across space and the genetic background from which they are drawn. AIM: To test the resilience of the gradients previously detected in the North-Eastern Mediterranean to the enlargement of the surveyed area and population set, using revised data. SUBJECTS AND METHODS: STR genotype profiles were obtained from a publicly available database (PopAffilietor databank) and a dataset was assembled including >7000 subjects from the Arabian Peninsula to Scandinavia, genotyped at eight loci. Spatial principal component analysis (sPCA) was applied and the frequency maps of the nine alleles which contributed most strongly to sPC1 were examined in detail. RESULTS: By far the greatest part of diversity was summarised by a single spatial principal component (sPC1), oriented along a SouthEast-to-NorthWest axis. The alleles with the top 5% squared loadings were TH01(9.3), D19S433(14), TH01(6), D19S433(15.2), FGA(20), FGA(24), D3S1358(14), FGA(21) and D2S1338(19). These results confirm a clinal pattern over the whole range for at least four loci (TH01, D19S433, FGA, D3S1358). CONCLUSIONS: Four of the eight STR loci (or even alleles) considered here can reproducibly capture continental arrangements of diversity. This would, in principle, allow for the exploitation of forensic data to clarify important aspects in the formation of local gene pools. PMID- 29382283 TI - Mitochondrial DNA structure of an isolated Tunisian Berber population and its relationship with Mediterranean populations. AB - BACKGROUND: Douiret is an isolated Berber population from South-Eastern Tunisia. The strong geographic and cultural isolation characterising this population might have contributed to remarkable endogamy and consanguinity, which were practiced for several centuries. AIM: The objective of this study is to evaluate the mitochondrial DNA (mtDNA) genetic structure of Douiret and to compare it to other Mediterranean populations with a special focus on major haplogroup T. SUBJECTS AND METHODS: Genomic DNA was extracted from blood samples of 58 unrelated individuals collected from the different patrilineal lineages of the population. The hypervariable region 1 of the mtDNA was amplified and sequenced. For comparative analyses, additional HVS1 sequences (n = 4857) were compiled from previous studies. RESULTS: The maternal background of the studied sample from Douiret was mainly of Eurasian origin (74%) followed by Sub-Saharan (17%) and North African (3%) lineages. Douiret harbours the highest frequency of haplogroup T in the Mediterranean region, assigned to the unique subclade T1a (38%). Phylogenetic analysis showed an outlier position of Douiret at the Mediterranean level. CONCLUSIONS: The genetic structure of Douiret highlights the presence of founders, most likely of Near/Middle Eastern origin, who conquered this area during the Middle/Late Upper Palaeolithic and Neolithic dispersals. PMID- 29382284 TI - Reconstructing the genetic history of Italians: new insights from a male (Y chromosome) perspective. AB - BACKGROUND: Due to its central and strategic position in Europe and in the Mediterranean Basin, the Italian Peninsula played a pivotal role in the first peopling of the European continent and has been a crossroad of peoples and cultures since then. AIM: This study aims to gain more information on the genetic structure of modern Italian populations and to shed light on the migration/expansion events that led to their formation. SUBJECTS AND METHODS: High resolution Y-chromosome variation analysis in 817 unrelated males from 10 informative areas of Italy was performed. Haplogroup frequencies and microsatellite haplotypes were used, together with available data from the literature, to evaluate Mediterranean and European inputs and date their arrivals. RESULTS: Fifty-three distinct Y-chromosome lineages were identified. Their distribution is in general agreement with geography, southern populations being more differentiated than northern ones. CONCLUSIONS: A complex genetic structure reflecting the multifaceted peopling pattern of the Peninsula emerged: southern populations show high similarity with those from the Middle East and Southern Balkans, while those from Northern Italy are close to populations of North-Western Europe and the Northern Balkans. Interestingly, the population of Volterra, an ancient town of Etruscan origin in Tuscany, displays a unique Y chromosomal genetic structure. PMID- 29382285 TI - Dinucleotide (CA)n tandem repeats on the human X-chromosome and the history of the Mediterranean populations. AB - BACKGROUND: Tandem repeats (STRs) are genomic markers of particular interest in forensic and population genetics. Most of the population data currently available correspond to the variation of STRs of forensic panels, which barely include dinucleotide tandem repeats. AIMS: The aim of the study is to test the usefulness of a battery of dinucleotide STRs on the X chromosome for population and forensic studies. SUBJECTS AND METHODS: A total of 672 individuals from 12 Mediterranean populations and two external references were analysed for 15 X-STR following the instructions of the commercial company and using control DNA from the CEPH centre whose sequences are published in GenBank. Genotypic results were analysed using standard population genetics methods including estimates of linkage disequilibrium, population structure and gene flow. Common forensic efficiency parameters were calculated. RESULTS: The analysed X-STRs show high values of genetic diversity, comparable to other STRs of more common use. No significant associations between markers were found. A slight population structure was detected between the two shores of the Mediterranean. The X-STRs studied here present a similar degree of variability to that of other X-STRs used in forensics. CONCLUSION: Tandem-repeated dinucleotides are a good tool for evidencing population differences here. Forensic parameters indicate that the dinucleotide X-STRs are suitable for forensic use. PMID- 29382286 TI - A New Delay Connection for Long Short-Term Memory Networks. AB - Connections play a crucial role in neural network (NN) learning because they determine how information flows in NNs. Suitable connection mechanisms may extensively enlarge the learning capability and reduce the negative effect of gradient problems. In this paper, a new delay connection is proposed for Long Short-Term Memory (LSTM) unit to develop a more sophisticated recurrent unit, called Delay Connected LSTM (DCLSTM). The proposed delay connection brings two main merits to DCLSTM with introducing no extra parameters. First, it allows the output of the DCLSTM unit to maintain LSTM, which is absent in the LSTM unit. Second, the proposed delay connection helps to bridge the error signals to previous time steps and allows it to be back-propagated across several layers without vanishing too quickly. To evaluate the performance of the proposed delay connections, the DCLSTM model with and without peephole connections was compared with four state-of-the-art recurrent model on two sequence classification tasks. DCLSTM model outperformed the other models with higher accuracy and F1[Formula: see text]score. Furthermore, the networks with multiple stacked DCLSTM layers and the standard LSTM layer were evaluated on Penn Treebank (PTB) language modeling. The DCLSTM model achieved lower perplexity (PPL)/bit-per-character (BPC) than the standard LSTM model. The experiments demonstrate that the learning of the DCLSTM models is more stable and efficient. PMID- 29382287 TI - Liposomology: delivering the message. PMID- 29382288 TI - American College of Toxicology 2017 Annual Meeting Poster Abstracts. PMID- 29382289 TI - Editor's Note. PMID- 29382292 TI - Interpreting challenge data from early phase malaria blood stage vaccine trials. AB - INTRODUCTION: As the quest for an effective blood stage malaria vaccine continues, there is increasing reliance on the use of controlled human malaria infections (CHMI) in non-endemic settings to test vaccine efficacy at the earliest possible time. This is seen as a way to accelerate vaccine research and quickly eliminate candidates with poor efficacy. Areas covered: The data from these studies need to be carefully examined and interpreted in light of the very different roles that antibody and cellular immunity play in protection and within the context of the distinct clinical sensitivities of volunteers living in malaria-non-endemic countries compared to those living in endemic countries. With current strategies, it is likely that vaccines with protective immunological 'signatures' will be missed and potentially good candidates discarded. Expert commentary: Efficacy data from early phase vaccine trials in non-endemic countries should not be used to decide whether or not to proceed to vaccine trials in endemic countries. PMID- 29382293 TI - Midterm outcome of partial radial head replacement with a contoured iliac crest bone graft in complex elbow dislocation. AB - PURPOSE: To report the midterm outcome of a novel reconstructive technique using a contoured iliac crest bone graft for partial radial head replacement in the treatment of complex elbow dislocation. MATERIAL AND METHODS: Between January 2008 and December 2013, 10 patients (5 women, 5 men; mean age, 43.8 years; mean follow-up duration, 65.9 months) with complex elbow dislocation who underwent the partial radial head replacement with the contoured bone graft were included in the study. The irreparable radial head defects averaged 49% of the articular surface (range, 36-60%). The fracture involved the entire head in four patients and partial head in six patients. RESULTS: At the final follow-up, the mean elbow extension was 8 degrees , flexion 143 degrees , supination 76.5 degrees , and pronation 73 degrees . The mean Mayo elbow performance index was 93.2 points and the Broberg-Morrey functional rating score was 94.1 points, with seven excellent cases, two good cases, and one fair case. Radiographic union was achieved in all but one, at an average time of 6.89 weeks (range, 6-10 weeks). The final radiographs demonstrated no evidence of degenerative change in eight patients, mild arthritis in one patient, and moderate arthritis in one patient. CONCLUSION: This technique is a viable option in the treatment of the large radial head defect in complex elbow dislocation when more than 40% of the original head is still available for incorporation. PMID- 29382294 TI - Medium-term follow-up of 149 mobile-bearing total knee arthroplasties and evaluation of prognostic factors influencing outcomes. AB - OBJECTIVE: To evaluate the medium-term outcomes of a posterior-stabilized mobile bearing total knee arthroplasty (PS-MB-TKA) and the role of different prognostic factors. METHODS: Patients indicated for a primary cemented PS-MB-TKA between 2002 and 2010 were included and prospectively evaluated using the Knee Society Scoring System (KSS) and the Hospital for Special Surgery (HSS) knee scores. The Knee Society Roentgenographic Evaluation form was used for the radiological evaluation. Different variables were collected and divided into patient- and surgery-related. Logistic regression was used to analyze the correlation between these variables and implants outcomes and survivorship. RESULTS: In total, 149 cases were included (67.8% female, average age 70.4 years, SD +/-9.4). The patella was resurfaced in 12.1% of the cases. All the implants were cemented. The average follow-up was 87.3 months (SD +/-21.2). Postoperatively, there was a statistically significant improvement in all the scores. The cumulative survival was 96.2% (SD +/-0.02%). At the regression analysis, female gender was associated to worse satisfaction KSS (OR = 0.26), functional KSS (OR = 0.22), and HSS (OR = 0.37) scores. Patellar resurfacing and subsequent contralateral procedures were associated to better functional KSS score (OR = 4.13, OR = 2.21), as well as varus preoperative alignment (OR = 2.12). On contrary, valgus preoperative alignment was associated to worse objective KSS score (OR = 0.23). No variables were correlated to failure or presence of radiolucent lines. CONCLUSION: Good medium-term outcomes were obtained using PS-MB-TKA, with a cumulative survivorship of 96.5%. Female gender and valgus preoperative alignment were associated to worse objective and subjective outcomes. Conversely, patellar replacement, subsequent contralateral TKA, and varus preoperative alignment were associated to better functional outcomes. PMID- 29382295 TI - Arthroscopic percutaneous inverted mattress suture fixation of isolated greater tuberosity fracture of humerus. AB - OBJECTIVE: The purpose of the study was to evaluate the clinical and radiographic outcomes of treatment in patients with isolated greater tuberosity (GT) fractures of humerus using arthroscopic percutaneous inverted mattress suture fixation technique. MATERIALS AND METHODS: We attempted to use the arthroscopic percutaneous inverted mattress suture fixation technique in 17 consecutive cases with isolated displaced GT fractures. Fourteen patients were successfully treated without switching to other methods and were available for follow-up at a mean of 22 months (range: 17-38 months) after surgery. For assessment of clinical outcomes, we evaluated the range of motion and the visual analog scale (VAS) score, the shoulder index of the American Shoulder and Elbow Surgeons (ASES), and the Korean Shoulder Scale (KSS). RESULTS: At the final follow-up, the VAS improved to 1.0 points (range: 0-3), the mean ASES score improved to 86.9 points (range: 78.3-100) and the KSS improved to 88.6 points (range: 82-100) postoperatively. Mean union time was 10 weeks. Mean forward flexion was 167.8 degrees (range: 140-180 degrees ), mean external rotation in neutral position was 36 degrees (range: 20-70 degrees ), and mean internal rotation was at the 12th thoracic level (range: T6-L3) at final follow-up. Three cases were switched to open surgery after attempted arthroscopic technique due to large fragment or osteoporosis. CONCLUSION: In select cases, the arthroscopic percutaneous inverted mattress suture fixation of GT fracture is a simple and reproducible technique with encouraging early results. PMID- 29382296 TI - Treatment of implant-related methicillin-resistant Staphylococcus aureus osteomyelitis with vancomycin-loaded VK100 silicone cement: An experimental study in rats. AB - INTRODUCTION: The purpose of this present study is to investigate the efficacy of vancomycin-loaded VK100 silicone cement drug delivery system in the treatment of implant-related methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in rats. MATERIALS AND METHODS: Thirty-six adult (18-20 weeks old) female Sprague Dawley rats were included in the study. All rats underwent experimental osteomyelitis surgery via injecting 100 uL bacterial suspension of MRSA into the medullary canal. After a 2-week duration for the formation of osteomyelitis model, rats were assigned randomly into four groups: control (C), systemic vancomycin (V), local vancomycin-loaded VK100 silicone cement (vVK100), and systemic vancomycin and local vancomycin-loaded VK100 silicone cement (V+vVK100). The following treatment protocols were administered to each group for 4 weeks. For group C, 0.9% saline solution equivalent to the volume of vancomycin dose (approximately 1 ml/kg) was administered intraperitoneally twice daily (12-h intervals). For group V, 15 mg/kg of vancomycin was administered intraperitoneally twice daily (12-h intervals). For group vVK100, vVK100 polymer was included so that the intramedullary canal of the rats are affected. For group V+vVK100, vVK100 polymer was included so that the intramedullary canal of the rats are affected and 15 mg/kg of vancomycin was administered intraperitoneally twice daily (12-h intervals). After 4 weeks of treatment, clinical, radiologic, microbiologic, and histopathologic evaluations were performed for all groups. RESULTS: Results of this study revealed that all scores of the evaluation criteria for the treatment groups (groups V, vVK100, and V+vVK100) decreased due to the treatment protocols when compared to group C. These results show the effectiveness of all treatment protocols for the implant-related chronic MRSA osteomyelitis. However, there were no statistical difference between these three protocols. CONCLUSIONS: vVK100 polymer, as a local antibiotic delivery system, seems to be an effective method for the treatment of implant-related chronic MRSA osteomyelitis. PMID- 29382297 TI - Awareness of middle sacral artery pathway: A cadaveric study of the presacral area. AB - PURPOSE: To assess the anatomic path of the middle sacral artery (MSA) at the presacral area and its relationship to the spinal midline during an axial lumbar interbody fusion (AxiaLif) approach. METHODS: Fifty human cadavers (25 males, 25 females) were used in this study. A transabdominal approach was used to expose the anterior aspect of the L5/S1 intervertebral disc and the presacral space. We measured the size and distance from the spinal midline at the following positions: (a) middle of the L5/S1 disc level, (b) 1 cm below the sacral promontory (SP), and (c) 2 cm below the SP. Each parameter was measured three times by two observers, and the mean value analyzed. RESULTS: The MSA was present and originated from the left common iliac artery in all cadavers with a mean width of 2.14 mm. The position of the MSA in relation to the midline was most commonly on the left side (LS, 56%) followed by the right side (RS, 34%) and midline (ML, 10%). In the LS group, the distance from the midline is relatively constant in the three measured positions with a mean value of (a) 1.78 mm (range, 0-8.17 mm), (b) 2.08 mm (range, 0-7.10 mm), and (c) 2.06 mm (range, 0-9.76 mm). In the RS group, the distance from the midline increased from cephalad to caudad, with a mean value of (a) 1.44 mm (range, 0-9.64 mm), (b) 2.19 mm (range, 0-9.95 mm), and (c) 2.92 mm (range, 0-10.03 mm). CONCLUSIONS: Our study found the presacral anatomic path of the MSA was most commonly at the left of midline. In addition, the right-sided MSA variant had increasing distance from the midline along its anatomic path from cephalad to caudad. Our findings suggest an AxiaLif approach at the left of midline may place the MSA at greatest risk. PMID- 29382298 TI - Improving physical activity after stroke via treadmill training and self management (IMPACT): a protocol for a randomised controlled trial. AB - BACKGROUND: The level of physical activity undertaken by stroke survivors living in the community is generally low. The main objectives of the IMPACT trial are to determine, in individuals undergoing rehabilitation after stroke, if 8 weeks of high-intensity treadmill training embedded in self-management education (i) results in more physical activity than usual physiotherapy gait training and (ii) is more effective at increasing walking ability, cardiorespiratory fitness, self efficacy, perception of physical activity, participation, and health-related quality of life as well as decreasing cardiovascular risk, and depression, at 8 and 26 weeks. METHODS: A prospective, two-arm, parallel-group, randomised trial with concealed allocation, blinded measurement and intention-to-treat analysis, will be conducted. 128 stroke survivors undergoing rehabilitation who are able to walk independently will be recruited and randomly allocated to either the experimental or control group, who will both undergo gait training for 30 min, three times a week for 8 weeks under the supervision of a physiotherapist. Outcomes will be measured at baseline (Week 0), on completion of the intervention (Week 8) and beyond the intervention (Week 26). This study has obtained ethical approval from the relevant Human Research Ethics Committees. DISCUSSION: Improving stroke survivors' walking ability and cardiorespiratory fitness is likely to increase their levels of physical activity. Furthermore, if education in self-management results in sustained high levels of physical activity, this should result in improved participation and quality of life. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12613000744752 ) on 4th July, 2013. PMID- 29382299 TI - Genomic prediction using DArT-Seq technology for yellowtail kingfish Seriola lalandi. AB - BACKGROUND: Genomic prediction using Diversity Arrays Technology (DArT) genotype by sequencing platform has not been reported in yellowtail kingfish (Seriola lalandi). The principal aim of this study was to address this knowledge gap and to assess predictive ability of genomic Best Linear Unbiased Prediction (gBLUP) for traits of commercial importance in a yellowtail kingfish population comprising 752 individuals that had DNA sequence and phenotypic records for growth traits (body weight, fork length and condition index). The gBLUP method was used due to its computational efficiency and it showed similar predictive performance to other approaches, especially for traits whose variation is of polygenic nature, such as body traits analysed in this study. The accuracy or predictive ability of the gBLUP model was estimated for three growth traits: body weight, folk length and condition index. RESULTS: The prediction accuracy was moderate to high (0.44 to 0.69) for growth-related traits. The predictive ability for body weight increased by 17.0% (from 0.69 to 0.83) when missing genotype was imputed. Within population prediction using five-fold across validation approach showed that the gBLUP model performed well for growth traits (weight, length and condition factor), with the coefficient of determination (R2) from linear regression analysis ranging from 0.49 to 0.71. CONCLUSIONS: Collectively our results demonstrated, for the first time in yellowtail kingfish, the potential application of genomic selection for growth-related traits in the future breeding program for this species, S. lalandi. PMID- 29382300 TI - Co-circulation and simultaneous co-infection of dengue, chikungunya, and zika viruses in patients with febrile syndrome at the Colombian-Venezuelan border. AB - BACKGROUND: In Colombia, the dengue virus (DENV) has been endemic for decades, and with the recent entry of the chikungunya virus (CHIKV) (2014) and the Zika virus (ZIKV) (2015), health systems are overloaded because the diagnosis of these three diseases is based on clinical symptoms, and the three diseases share a symptomatology of febrile syndrome. Thus, the objective of this study was to use molecular methods to identify their co-circulation as well as the prevalence of co-infections, in a cohort of patients at the Colombian-Venezuelan border. METHODS: A total of 157 serum samples from patients with febrile syndrome consistent with DENV were collected after informed consent and processed for the identification of DENV (conventional PCR and real-time PCR), CHIKV (conventional PCR), and ZIKV (real-time PCR). DENV-positive samples were serotyped, and some of those positive for DENV and CHIKV were sequenced. RESULTS: Eighty-two patients were positive for one or more viruses: 33 (21.02%) for DENV, 47 (29.94%) for CHIKV, and 29 (18.47%) for ZIKV. The mean age range of the infected population was statistically higher in the patients infected with ZIKV (29.72 years) than in those infected with DENV or CHIKV (21.09 years). Both co-circulation and co infection of these three viruses was found. The prevalence of DENV/CHIKV, DENV/ZIKV, and CHIKV/ZIKV co-infection was 7.64%, 6.37%, and 5.10%, with attack rates of 14.90, 12.42, and 9.93 cases per 100,000 inhabitants, respectively. Furthermore, three patients were found to be co-infected with all three viruses (prevalence of 1.91%), with an attack rate of 4.96 cases per 100,000 inhabitants. CONCLUSION: Our results demonstrate the simultaneous co-circulation of DENV, CHIKV, ZIKV and their co-infections at the Colombian-Venezuelan border. Moreover, it is necessary to improve the differential diagnosis in patients with acute febrile syndrome and to study the possible consequences of this epidemiological overview of the clinical outcomes of these diseases in endemic regions. PMID- 29382301 TI - Decreased global myocardial perfusion at adenosine stress as a potential new biomarker for microvascular disease in systemic sclerosis: a magnetic resonance study. AB - BACKGROUND: Patients with systemic sclerosis (SSc) have high cardiovascular mortality even though there is no or little increase in prevalence of epicardial coronary stenosis. First-pass perfusion on cardiovascular magnetic resonance (CMR) have detected perfusion defects indicative of microvascular disease, but the quantitative extent of hypoperfusion is not known. Therefore, we aimed to determine if patients with SSc have lower global myocardial perfusion (MP) at rest or during adenosine stress, compared to healthy controls, quantified with CMR. METHODS: Nineteen SSc patients (17 females, 61 +/- 10 years) and 22 controls (10 females, 62 +/- 11 years) underwent CMR. Twelve patients had limited cutaneous SSc and 7 patients had diffuse cutaneous SSc. One patient had pulmonary arterial hypertension (PAH). MP was quantified using coronary sinus flow (CSF) measurements at rest and during adenosine stress, divided by left ventricular mass (LVM). RESULTS: There was no difference in MP at rest between patients and controls (1.1 +/- 0.5 vs. 1.1 +/- 0.3 ml/min/g, P = 0.85) whereas SSc patients showed statistically significantly lower MP during adenosine stress (3.1 +/- 0.9 vs. 4.2 +/- 1.3 ml/min/g, P = 0.008). Three out of the 19 SSc patients showed fibrosis in the right ventricle insertion points despite absence of PAH. None had signs of myocardial infarction. CONCLUSIONS: Patients with SSc have decreased MP during adenosine stress compared to healthy controls. Thus hypoperfusion at stress may be a sensitive marker of cardiac disease in SSc patients possibly signifying microvascular myocardial disease. PMID- 29382302 TI - Clinical management and outcome of patients with advanced NSCLC carrying EGFR mutations in Spain. AB - BACKGROUND: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real life diagnostic and clinical management and outcome of patients with advanced non small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. METHODS: All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. RESULTS: Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. CONCLUSION: EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC. PMID- 29382303 TI - Genetic variation of the gene coding for microRNA-204 (miR-204) is a risk factor in acute myeloid leukaemia. AB - BACKGROUND: MicroRNAs (miRNAs or miRs) are small molecules known to be involved in post-transcriptional gene expression. Many of them have been shown to influence risk for various diseases. Recent studies suggest that lower expression of miR-204, a gene coding for miRNA-204, is correlated with shorter survival in patients with acute myeloid leukaemia (AML). This observation prompted us to analyse the effect of two polymorphisms of the miR-204 gene, one in the upstream flanking region (rs718447 A > G) and the other inside the gene itself (rs112062096 A > G), both also in intron 3 of the TRPM3 gene. METHODS: The study was conducted on DNA samples isolated from AML patients (n = 95) and healthy individuals (n = 148), who were genotyped using the Light SNiP assays. RESULTS: The miR-204 rs718447 GG homozygosity was found to constitute a risk factor associated with susceptibility to AML (73/95 vs 92/148, AML patients vs healthy controls, OR = 2.020, p = 0.017). Additionally, this genotype was more frequent in patients with subtypes M0-M1 in the French-American-British (FAB) classification as compared to patients with subtypes M2-M7 (23/25 vs 39/57, p = 0.026). We also found that presence of allele A was linked to longer survival of AML patients. CONCLUSIONS: Our results show that polymorphism in miR-204 flanking region may constitute a risk and prognostic factor in AML. PMID- 29382304 TI - Factors influencing the use of contraceptives through the lens of teenage women: a qualitative study in Iran. AB - BACKGROUND: One out of seven teenage girls in developing countries marries before the age of 15. While the fertility rate of teenage girls is high, the rate of contraceptive use remains low; therefore, this group of teenagers needs reproductive healthcare. This study was undertaken to explore factors influencing the use of contraceptives from the perspective of teenage women living in the city of Ardabil in Iran. METHODS: This qualitative study was conducted with 14 married women aged 13-19 years who attended in urban-rural healthcare centers in Ardabil. Eligible women were recruited using purposive sampling and were invited to take part in individual in-depth semi-structured interviews. The duration of the interviews varied from 45 to 90 min with an average of 55 min. Sampling continued until data saturation was reached and no new data was collected. Each interview was tape-recorded after obtaining the participant's permission, transcribed verbatim and analyzed for identifying categories and themes using conventional content analysis. RESULTS: Three themes and eight subthemes were developed. The themes were as follows: "insufficient familiarity with contraceptive methods", "pressure to become pregnant" and "misconceptions". CONCLUSION: Despite the high prevalence of early marriage in Iranian society, teenage women are not empowered or prepared for marriage and birth control. Sexual and reproductive healthcare services to teenage women should be improved to meet their needs. PMID- 29382305 TI - Correction to: Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin. AB - After publication of the original article [1] it was identified that order of the author list had been presented incorrectly. The author Robert Gniadecki's surname was also incorrect in the original article. PMID- 29382306 TI - Quality medicines in maternal health: results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits. AB - BACKGROUND: The high level of maternal mortality and morbidity as a result of complications due to childbirth is unacceptable. The impact of quality medicines in the management of these complications cannot be overemphasized. Most of those medicines are sensitive to environmental conditions and must be handled properly. In this study, the quality of oxytocin injection, misoprostol tablets, magnesium sulfate, and calcium gluconate injections was assessed across the six geopolitical zones of Nigeria. METHOD: Simple, stratified random sampling of health facilities in each of the political zones of Nigeria. Analysis for identification and content of active pharmaceutical ingredient was performed using high-performance liquid chromatography procedures of 159 samples of oxytocin injection and 166 samples of misoprostol tablets. Titrimetric methods were used to analyze 164 samples of magnesium sulfate and 148 samples of calcium gluconate injection. Other tests included sterility, pH measurement, and fill volume. RESULTS: Samples of these commodities were procured mainly from wholesale and retail pharmacies, where these were readily available, while the federal medical centers reported low availability. Approximately, 74.2% of oxytocin injection samples failed the assay test, with the northeast and southeast zones registering the highest failure rates. Misoprostol tablets recorded a percentage failure of 33.7%. Magnesium sulfate and Calcium gluconate injection samples recorded a failure rate of 6.8% and 2.4%, respectively. CONCLUSION: The prevalence of particularly of oxytocin and misoprostol commodities was of substandard quality. Strengthening the supply chain of these important medicines is paramount to ensuring their effectiveness in reducing maternal deaths in Nigeria. PMID- 29382307 TI - Emphysematous change with scleroderma-associated interstitial lung disease: the potential contribution of vasculopathy? AB - BACKGROUND: Pulmonary emphysema combined with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) occurs more often in smokers but also in never smokers. This study aimed to describe a new finding characterized by peculiar emphysematous change with SSc-associated ILD (SSc-ILD). METHODS: We conducted a retrospective review of 21 consecutive patients with SSc-ILD diagnosed by surgical lung biopsy and focused on the radio-pathological correlation of the emphysematous change. RESULTS: Pathological pulmonary emphysema (p-PE) with SSc ILD was the predominant complication in 16 patients (76.2%) with/without a smoking history, of whom 62.5% were never-smokers. A low attenuation area (LAA) within interstitial abnormality on high-resolution computed tomography (HRCT) was present in 31.3%. Diffusing capacity of the lung for carbon monoxide (DLCO) was lower, disease extent on HRCT higher, and intimal/medial thickening in muscular pulmonary arteries more common in the patients with p-PE with SSc-ILD. However, forced vital capacity (FVC) was well preserved regardless of whether p-PE was observed. Most SSc-ILD patients had pulmonary microvasculature changes in arterioles (90.5%), venules (85.7%), and interlobular veins (81.0%). CONCLUSIONS: Pulmonary emphysematous changes (LAA within interstitial abnormalities on HRCT and destruction of fibrously thickened alveolar walls) are specific and novel radio-pathological features of SSc-ILD. Peripheral vasculopathy may help to destroy the fibrously thickened alveolar walls, resulting in emphysematous change in SSc-ILD. PMID- 29382308 TI - Endomyocardial biopsy guided by intracardiac echocardiography as a key step in intracardiac mass diagnosis. AB - BACKGROUND: Based on a plenty of different applications, intracardiac echocardiography (ICE) is now a well-established technology in complex electrophysiological procedures. Recently, ICE has become the most widely used ultrasound-based imaging tool to guide diagnostic endomyocardial biopsy (EMB). EMB of cardiac mass guided by ICE is an interesting application of ICE. Allowing a correct positioning of the bioptome, ICE reduce the procedure-related risks and the need of a diagnostic open-chest procedure reserving the more invasive approach to selected cases. CASE PRESENTATION: Hereby we report a case series of right ventricular masses in which the EMB was safely and effectively performed under ICE guidance giving essential information for planning the therapeutic strategy. CONCLUSIONS: The diagnosis of both metastatic and primary cardiac tumors relies on the histopathological analyses. The endomyocardial biopsy is a valuable tool for preoperative diagnosis and surgical planning of intracardiac masses suspected for tumors. In our experience, the use of ICE for right ventricle EMB of an intracardiac mass is an attractive modality thanks to the precise localization of the cardiac structures and the ability to guide bioptic withdrawal in the target area. PMID- 29382309 TI - Sex-related illness perception and self-management of a Thai type 2 diabetes population: a cross-sectional descriptive design. AB - BACKGROUND: Increased knowledge concerning the differences in the illness perception and self-management among sexes is needed for planning proper support programs for patients with diabetes. The aim of this study was to investigate the illness perception and self-management among Thai women and Thai men with type 2 diabetes and to investigate the psychometric properties of the translated instruments used. METHODS: In a suburban province of Thailand, 220 women and men with type 2 diabetes participated in a cross-sectional descriptive study. The participants were selected using a multistage sampling method. Data were collected through structured interviews and were analyzed using group comparisons, and psychometric properties were tested. RESULTS: Women and men with type 2 diabetes demonstrated very similar experiences regarding their illness perception and no differences in self-management. Women perceived more negative consequences of the disease and more fluctuation in the symptoms than men, whereas men felt more confident about the treatment effectiveness than women. Furthermore, the translated instruments used in this study showed acceptable validity and reliability. CONCLUSIONS: The Thai sociocultural context may influence people's perceptions and affect the self-care activities of Thai individuals, both women and men, with type 2 diabetes, causing differences from those found in the Western environment. Intervention programs that aim to improve the effectiveness of the self-management of Thai people with diabetes might consider a holistic and sex-related approach as well as incorporating Buddhist beliefs. PMID- 29382310 TI - Venous invasion as a risk factor for recurrence after gastrectomy followed by chemotherapy for stage III gastric cancer. AB - BACKGROUND: Although adjuvant chemotherapy with S-1 after curative gastrectomy has been performed as a standard treatment for Stage II and III gastric cancer (GC) in Japan, patients with Stage III GC still have a high incidence of recurrence and a poor prognostic outcome. The aim of this study was to investigate risk factors for recurrence in patients with Stage III GC despite of curative gastrectomy followed by adjuvant chemotherapy, suggesting an indicator for more intensive management. METHODS: A total of 97 patients with pathological Stage III GC underwent adjuvant chemotherapy after curative gastrectomy between 2001 and 2014, were enrolled in this study. We retrospectively analyzed their hospital records from our hospital. RESULTS: The 5-year relapse-free survival (RFS) rates of patients with pStage III GC were 42.0%. Univariate and multivariate analyses for RFS revealed that venous invasion (v+) was an independent factor predicting a shorter RFS (v + vs. v-, 36.5% vs. 47.4%, P = 0.034, HR 1.82, 95% CI: 1.01-3.37). Venous invasion also predicted a shorter overall survival (OS) (v + vs. v-, 33.7% vs. 50.4%, P = 0.027). Regarding the patterns of recurrence, hematogenous recurrence was significantly occurred in patients with v + GC than those without (P = 0.022). CONCLUSIONS: Stage III GC with venous invasion is a high-risk subgroup for hematogenous recurrence after curative surgery followed by adjuvant chemotherapy. More intensive and effective adjuvant chemo and/or molecular targeted therapy for Stage III GC patients with venous invasion should be considered to improve their outcomes. PMID- 29382311 TI - Correction to: Impact of new generation hormone-therapy on cognitive function in elderly patients treated for a metastatic prostate cancer: Cog-Pro trial protocol. AB - CORRECTION: After publication of the original article [1] the authors found that Table 2 had been formatted incorrectly, meaning that some rows in the Table did not display the correct information. An updated version of Table 2 is included with this Correction. The original article has also been updated. PMID- 29382312 TI - Stem cells and beta cell replacement therapy: a prospective health technology assessment study. AB - BACKGROUND: Although current beta cell replacement therapy is effective in stabilizing glycemic control in highly selected patients with refractory type 1 diabetes, many hurdles are inherent to this and other donor-based transplantation methods. One solution could be moving to stem cell-derived transplant tissue. This study investigates a novel stem cell-derived graft and implant technology and explores the circumstances of its cost-effectiveness compared to intensive insulin therapy. METHODS: We used a manufacturing optimization model based on work by Simaria et al. to model cost of the stem cell-based transplant doses and integrated its results into a cost-effectiveness model of diabetes treatments. The disease model simulated marginal differences in clinical effects and costs between the new technology and our comparator intensive insulin therapy. The form of beta cell replacement therapy was as a series of retrievable subcutaneous implant devices which protect the enclosed pancreatic progenitors cells from the immune system. This approach was presumed to be as effective as state of the art islet transplantation, aside from immunosuppression drawbacks. We investigated two different cell culture methods and several production and delivery scenarios. RESULTS: We found the likely range of treatment costs for this form of graft tissue for beta cell replacement therapy. Additionally our results show this technology could be cost-effective compared to intensive insulin therapy, at a willingness-to-pay threshold of $100,000 per quality-adjusted life year. However, results also indicate that mass production has by far the best chance of providing affordable graft tissue, while overall there seems to be considerable room for cost reductions. CONCLUSIONS: Such a technology can improve treatment access and quality of life for patients through increased graft supply and protection. Stem cell-based implants can be a feasible way of treating a wide range of patients with type 1 diabetes. PMID- 29382313 TI - Opsin expression patterns coincide with photoreceptor development during pupal development in the honey bee, Apis mellifera. AB - BACKGROUND: The compound eyes of insects allow them to catch photons and convert the energy into electric signals. All compound eyes consist of numerous ommatidia, each comprising a fixed number of photoreceptors. Different ommatidial types are characterized by a specific set of photoreceptors differing in spectral sensitivity. In honey bees, males and females possess different ommatidial types forming distinct retinal mosaics. However, data are lacking on retinal ontogeny and the mechanisms by which the eyes are patterned. In this study, we investigated the intrinsic temporal and circadian expression patterns of the opsins that give rise to the ultraviolet, blue and green sensitive photoreceptors, as well as the morphological maturation of the retina during pupal development of honey bees. RESULTS: qPCR and histological labeling revealed that temporal opsin mRNA expression differs between sexes and correlates with rhabdom elongation during photoreceptor development. In the first half of the pupal stage, when the rhabdoms of the photoreceptors are still short, worker and (dorsal) drone retinae exhibit similar expression patterns with relatively high levels of UV (UVop) and only marginal levels of blue (BLop) and green (Lop1) opsin mRNA. In the second half of pupation, when photoreceptors and rhabdoms elongate, opsin expression in workers becomes dominated by Lop1 mRNA. In contrast, the dorsal drone eye shows high expression levels of UVop and BLop mRNA, whereas Lop1 mRNA level decreases. Interestingly, opsin expression levels increase up to 22-fold during early adult life. We also found evidence that opsin expression in adult bees is under the control of the endogenous clock. CONCLUSIONS: Our data indicate that the formation of the sex-specific retinal composition of photoreceptors takes place during the second half of the pupal development, and that opsin mRNA expression levels continue to increase in young bees, which stands in contrast to Drosophila, where the highest expression levels are found during the late pupal stage and remain constant in adults. From an evolutionary perspective, we hypothesize that the delayed retinal maturation during the early adult phase is linked to the delayed transition from indoor to outdoor activities in bees, when vision becomes important. PMID- 29382314 TI - Assessing the feasibility of integration of self-care for filarial lymphoedema into existing community leprosy self-help groups in Nepal. AB - BACKGROUND: Lymphatic filariasis (LF) and leprosy are disabling infectious diseases endemic in Nepal. LF infection can lead to lymphoedema and hydrocoele, while secondary effects of leprosy infection include impairments to hands, eyes and feet. The disabling effects of both conditions can be managed through self care and the supportive effects of self-help groups (SHGs). A network of SHGs exists for people affected by leprosy in four districts in Nepal's Central Development Region, however no such service exists for people affected by LF. The aim of this study was to determine the feasibility of integrating LF affected people into existing leprosy SHGs in this area. METHODS: A survey was conducted using a semi-structured questionnaire to elicit information on: (i) participant characteristics, clinical manifestation and disease burden; (ii) participants' knowledge of management of their condition and access to services; and (iii) participants' knowledge and perceptions of the alternate condition (LF affected participants' knowledge of leprosy and vice versa) and attitudes towards integration. RESULTS: A total of 52 LF affected and 53 leprosy affected participants were interviewed from 14 SHGs. On average, leprosy affected participants were shown to have 1.8 times greater knowledge of self-care techniques, and practiced 2.5 times more frequently than LF affected participants. Only a quarter of LF affected participants had accessed a health service for their condition, compared with 94.3% of leprosy affected people accessing a service (including SHGs), at least once a week. High levels of stigma were perceived by both groups towards the alternate condition, however, the majority of LF (79%) and leprosy (94.3%) affected participants stated that they would consider attending an integrated SHG. CONCLUSIONS: LF affected participants need to increase their knowledge of self-care and access to health services. Despite stigma being a potential barrier, attitudes towards integration were positive, suggesting that the SHGs may be a good platform for LF affected people to start self-care in this area. TRIAL REGISTRATION: This is not a registered trial. PMID- 29382315 TI - Genetic engineering of Escherichia coli to improve L-phenylalanine production. AB - BACKGROUND: L-phenylalanine (L-Phe) is an essential amino acid for mammals and applications expand into human health and nutritional products. In this study, a system level engineering was conducted to enhance L-Phe biosynthesis in Escherichia coli. RESULTS: We inactivated the PTS system and recruited glucose uptake via combinatorial modulation of galP and glk to increase PEP supply in the Xllp01 strain. In addition, the HTH domain of the transcription factor TyrR was engineered to decrease the repression on the transcriptional levels of L-Phe pathway enzymes. Finally, proteomics analysis demonstrated the third step of the SHIK pathway (catalyzed via AroD) as the rate-limiting step for L-Phe production. After optimization of the aroD promoter strength, the titer of L-Phe increased by 13.3%. Analysis of the transcriptional level of genes involved in the central metabolic pathways and L-Phe biosynthesis via RT-PCR showed that the recombinant L-Phe producer exhibited a great capability in the glucose utilization and precursor (PEP and E4P) generation. Via systems level engineering, the L-Phe titer of Xllp21 strain reached 72.9 g/L in a 5 L fermenter under the non optimized fermentation conditions, which was 1.62-times that of the original strain Xllp01. CONCLUSION: The metabolic engineering strategy reported here can be broadly employed for developing genetically defined organisms for the efficient production of other aromatic amino acids and derived compounds. PMID- 29382316 TI - A model for predicting bacteremia in patients with community-acquired pneumococcal pneumonia: a retrospective observational study. AB - BACKGROUND: Pneumococcal pneumonia causes high morbidity and mortality among adults. This study aimed to identify risk factors for bacteremic pneumococcal pneumonia, and to construct a prediction model for the development of bacteremia in patients with community-acquired pneumococcal pneumonia. METHODS: We retrospectively analyzed data from patients hospitalized with community-acquired pneumococcal pneumonia between April 2007 and August 2015. Logistic regression models were applied to detect risk factors for pneumococcal bacteremia, and a receiver operating characteristic curve was used to devise a prediction model. RESULTS: Based on the results of sputum cultures, urine antigen tests, and/or blood cultures, 389 patients were diagnosed with pneumococcal pneumonia, 46 of whom had bacteremia. In the multivariate analysis, age < 65 years, serum albumin level < 3.0 g/dL, need for intensive respiratory or vasopressor support (IRVS), and C-reactive protein level > 20 mg/dL were identified as independent risk factors for the development of pneumococcal bacteremia. The bacteremia prediction score based on receiver operating characteristic curve analysis had a sensitivity of 0.74 and a specificity of 0.78 in patients with two risk factors. The area under the receiver operating characteristic curve was 0.77 (95% confidence interval (CI), 0.70-0.85). CONCLUSIONS: Age < 65 years, hypoalbuminemia, IRVS, and high C-reactive protein level on admission are independent risk factors for the development of bacteremia in patients with community-acquired pneumococcal pneumonia. A prediction model based on these four risk factors could help to identify patients with community-acquired pneumococcal pneumonia at high risk of developing bacteremia; this can be used to guide antibiotic choices. TRIAL REGISTRATION: UMIN-CTR UMIN 000004353 . Registered 7 October 2010. Retrospectively registered. PMID- 29382317 TI - The prevalence, burden and risk factors associated with chronic obstructive pulmonary disease in Commonwealth of Independent States (Ukraine, Kazakhstan and Azerbaijan): results of the CORE study. PMID- 29382318 TI - Patients' satisfaction with dental care: a qualitative study to develop a satisfaction instrument. AB - BACKGROUND: To explore and better understand how patients evaluate satisfaction in dental care and elicit information from them to develop a dental satisfaction instrument. METHODS: Patients currently receiving dental treatment in a teaching hospital were invited to be part of a qualitative research project which involved focus group discussion. Focus groups were conducted in Cantonese and discussions were recorded (audio and video) and later transcribed. RESULTS: Thirty patients participated and a thematic analysis of data from four focus groups helped generate a questionnaire on dental satisfaction. Six themes were extracted from the contents of the focus group: (i) attitude, (ii) cost, (iii) convenience, (iv) pain management, (v) quality, and (vi) patients' perceived need for prevention of oral disease. Compared to the existing Dental Satisfaction Questionnaire (DSQ), majority of the dental satisfaction aspects mentioned in focus group discussions were similar to items in DSQ supporting its content validity. Focus groups covered more aspects including attitude of dental supporting staff, convenience of emergency services, admission of patients and treatment duration. Consideration of the clinical skills of the operator, hospital infection control, and knowledge on prevention of oral disease were also expressed. CONCLUSIONS: The focus group discussions elicited the views of patients not covered by DSQ items thereby suggesting areas for development of a new satisfaction questionnaire. PMID- 29382319 TI - C-reactive protein for late-onset sepsis diagnosis in very low birth weight infants. AB - BACKGROUND: Late-onset sepsis in very low birth weight (VLBW) infants is a diagnostic challenge. We aimed to evaluate the diagnostic utility of the C Reactive protein (CRP) and the complete blood count (CBC) for late-onset sepsis in VLBW infants. METHODS: In a 5-year retrospective cohort of 416 VLBW infants born at less than 1500 g, there were 590 separate late-onset sepsis evaluations. CRP and CBC were drawn at time of initial blood culture (T0), at 16-24 h (T24) and 40-48 h (T48) after. The positive cut-off values for abnormal values were the following: CRP >=10 mg/L and CBC with at least one anomaly, including white blood cell count < 5000/mm3, immature neutrophil/total neutrophil ratio > 0.10, or platelet count < 100,000/uL. Sensitivity and specificity for predicting late onset sepsis were calculated for each laboratory test and their combinations. Receiver operating characteristics curves were obtained for each test and for the absolute change from T0 to T24 in the laboratory value of CRP, white blood cell count and immature neutrophil/total neutrophil. RESULTS: At T0, combining the CBC and the CRP had the highest sensitivity of 66% (95% confidence interval [CI], 58 73) compared to both individual tests for predicting late onset sepsis. At T24, CRP's sensitivity was 84% (95% CI, 78-89) and was statistically higher than the CBC's 59% (95% CI, 51-67). The combination of CBC at T0 and CRP at T24 offered the greatest sensitivity of 88% (95% CI, 82-92) and negative predictive value 93% (95% CI, 89-96), with fewer samples, compared to any other combination of tests. The area under the curve for the change in the white blood cell count from T0 to T24 was 0.82. CONCLUSION: At initial sepsis evaluation (T0), both CBC and CRP should be performed to increase sensitivity. A highly negative predictive value is reachable with only two tests: a CBC at T0 and a CRP a T24. PMID- 29382320 TI - Large scale analysis of protein conformational transitions from aqueous to non aqueous media. AB - BACKGROUND: Biocatalysis in organic solvents is nowadays a common practice with a large potential in Biotechnology. Several studies report that proteins which are co-crystallized or soaked in organic solvents preserve their fold integrity showing almost identical arrangements when compared to their aqueous forms. However, it is well established that the catalytic activity of proteins in organic solvents is much lower than in water. In order to explain this diminished activity and to further characterize the behaviour of proteins in non-aqueous environments, we performed a large-scale analysis (1737 proteins) of the conformational diversity of proteins crystallized in aqueous and co-crystallized or soaked in non-aqueous media. RESULTS: Using proteins' experimentally determined conformational diversity taken from CoDNaS database, we found that proteins in non-aqueous media display much lower conformational diversity when compared to the corresponding conformers obtained in water. When conformational diversity is compared between conformers obtained in different non-aqueous media, their structural differences are larger and mostly independent of the presence of cognate ligands. We also found that conformers corresponding to non-aqueous media have larger but less flexible cavities, lower number of disordered regions and lower active-site residue mobility. CONCLUSIONS: Our results show that non aqueous media conformers have specific structural features and that they do not adopt extreme conformations found in aqueous media. This makes them clearly different from their corresponding aqueous conformers. PMID- 29382321 TI - Inferring synteny between genome assemblies: a systematic evaluation. AB - BACKGROUND: Genome assemblies across all domains of life are being produced routinely. Initial analysis of a new genome usually includes annotation and comparative genomics. Synteny provides a framework in which conservation of homologous genes and gene order is identified between genomes of different species. The availability of human and mouse genomes paved the way for algorithm development in large-scale synteny mapping, which eventually became an integral part of comparative genomics. Synteny analysis is regularly performed on assembled sequences that are fragmented, neglecting the fact that most methods were developed using complete genomes. It is unknown to what extent draft assemblies lead to errors in such analysis. RESULTS: We fragmented genome assemblies of model nematodes to various extents and conducted synteny identification and downstream analysis. We first show that synteny between species can be underestimated up to 40% and find disagreements between popular tools that infer synteny blocks. This inconsistency and further demonstration of erroneous gene ontology enrichment tests raise questions about the robustness of previous synteny analysis when gold standard genome sequences remain limited. In addition, assembly scaffolding using a reference guided approach with a closely related species may result in chimeric scaffolds with inflated assembly metrics if a true evolutionary relationship was overlooked. Annotation quality, however, has minimal effect on synteny if the assembled genome is highly contiguous. CONCLUSIONS: Our results show that a minimum N50 of 1 Mb is required for robust downstream synteny analysis, which emphasizes the importance of gold standard genomes to the science community, and should be achieved given the current progress in sequencing technology. PMID- 29382322 TI - Trauma, attachment style, and somatization: a study of women with dyspareunia and women survivors of sexual abuse. AB - BACKGROUND: Evidence points toward shared characteristics between female survivors of sexual abuse and women with dyspareunia. This study explored, for the first time, similarities and differences between women who were exposed to sexual abuse to those with dyspareunia, in order to examine whether insecure attachment styles and high somatization level are associated with trauma among women with dyspareunia. METHODS: Attachment styles were explored using the Experience in Close Relationships Scale to reflect participants' levels of anxiety and avoidance. Somatization was assessed using the Brief Symptom Inventory focusing on the frequency of painful and non-painful bodily complaints. Trauma was categorized into three levels: sexual trauma, nonsexual trauma, and no trauma. RESULTS: Sexually abused (SA) women (n = 21) compared to women with dyspareunia (dys) (n = 44) exhibited insecure attachment styles, as expressed by high levels of avoidance (SA 4.10 +/- 0.99 vs. dys 3.08 +/- 1.04, t(61) = 2.66, p = .01) and anxiety (SA 4.29 +/- 1.22 vs. dys 3.49 +/- 1.04, t(61) = 3.61, p = .001), and higher somatization (21.00 +/- 8.25 vs. 13.07 +/- 7.57, t(59) = 3.63, p = .001). Attachment and somatization level did not differ significantly between women with dyspareunia without trauma to those with nonsexual trauma. CONCLUSIONS: Our findings emphasized the unique role of sexual trauma as a contributing factor to the augmentation of perceived bodily symptoms and to insecure attachment style. This illuminates the importance of disclosing previous sexual abuse history among women with dyspareunia. PMID- 29382323 TI - Prevalence of high-risk HPV genotypes, categorised by their quadrivalent and nine valent HPV vaccination coverage, and the genotype association with high-grade lesions. AB - BACKGROUND: The new nine-valent vaccine against human papillomavirus (HPV) includes the four HPV genotypes (6, 11, 16, and 18) that are targeted by the older quadrivalent HPV vaccine, plus five additional oncogenic types (31, 33, 45, 52, and 58) remain significantly associated with high grade lesions. We aimed to determine the prevalence of high-risk HPV genotypes in unvaccinated subjects and the association of these genotypes with the incidence of high-grade lesions. We also assessed which, if either, of these two HPV vaccines could have prevented these cases. METHODS: This cross-sectional study, conducted from 4 January 2010 to 30 December 2011, was composed of 595 women attending the Hospital General Universitario de Elche (Spain) gynaecology department who were positively screened for opportunistic cervical cancer by pap smears and HPV detection during a routine gynaecological health check. The pap smear results were classified using the Bethesda system. HPV genotyping was performed with the Linear Array HPV genotyping test, and viruses were classified by the International Agency for Research on Cancer assessment of HPV carcinogenicity. Odds ratios (ORs) with their 95% confidence intervals (95% CI) were estimated by logistic regression, adjusting for age and immigrant status. The prevented fraction among those exposed (PFe-adjusted) was determined as a measure of impact. RESULTS: At least one of the additional five high-risk HPV genotypes present in the nine-valent HPV vaccine was detected in 20.5% of subjects. After excluding women with genotype 16 and/or 18 co-infection, high-risk genotypes (31, 33, 45, 52, and 58) were associated with a higher risk of intraepithelial lesion or malignancy: adjusted OR = 3.51 (95% CI, 1.29-9.56), PFe-adjusted = 0.72 (95% CI, 0.22-0.90). Genotypes that are still non-vaccine-targeted were detected in 17.98% of the women, but these were not significantly associated with high-grade lesions. CONCLUSION: The greater protection of the nine-valent HPV vaccine is likely to have a positive impact because, in the absence of genotype 16 or 18 infection, these five genotypes on their own remained significantly associated with high-grade lesions. PMID- 29382324 TI - APOB codon 4311 polymorphism is associated with hepatitis C virus infection through altered lipid metabolism. AB - BACKGROUND: It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. METHODS: Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequence-specific oligonucleotide probe-Luminex method. RESULTS: An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). CONCLUSION: An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR. PMID- 29382325 TI - Metastatic renal cell carcinoma initially presenting with hematochezia and subsequently with vaginal bleeding: a case report. AB - BACKGROUND: We report an unusual case of a synchronous rectal and metachronous vaginal metastatic renal cell carcinoma. CASE PRESENTATION: A 78-year-old woman presented with hematochezia and a colonoscopy revealed a metastatic clear-cell renal cell carcinoma rectal polyp biopsy-proven. Abdominal computed tomography identified a 9.0-cm left renal mass with renal vein thrombosis, for which she underwent a laparoscopic radical nephrectomy. Histopathological examination confirmed a pT3a clear-cell renal cell carcinoma. Seven months later, the patient presented with vaginal bleeding. Physical examination revealed a vaginal polypoid mass and biopsy confirmed a clear-cell renal cell carcinoma metastasis. CONCLUSIONS: This case represents unusual manifestations of metastatic renal cell carcinoma and is a reminder of the wide spectrum of clinical course of this disease. PMID- 29382326 TI - Study on the inhibition of Mfn1 by plant-derived miR5338 mediating the treatment of BPH with rape bee pollen. AB - BACKGROUND: Recent studies have found that plant derived microRNA can cross kingdom regulate the expression of genes in humans and other mammals, thereby resisting diseases. Can exogenous miRNAs cross the blood-prostate barrier and entry prostate then participate in prostate disease treatment? METHODS: Using HiSeq sequencing and RT-qPCR technology, we detected plant miRNAs that enriched in the prostates of rats among the normal group, BPH model group and rape bee pollen group. To forecast the functions of these miRNAs, the psRobot software and TargetFinder software were used to predict their candidate target genes in rat genome. The qRT-PCR technology was used to validate the expression of candidate target genes. RESULTS: Plant miR5338 was enriched in the posterior lobes of prostate gland of rats fed with rape bee pollen, which was accompanied by the improvement of BPH. Among the predicted target genes of miR5338, Mfn1 was significantly lower in posterior lobes of prostates of rats in the rape bee pollen group than control groups. Further experiments suggested that Mfn1 was highly related to BPH. CONCLUSIONS: These results suggesting that plant-derived miR5338 may involve in treatment of rat BPH through inhibiting Mfn1 in prostate. These results will provide more evidence for plant miRNAs cross-kingdom regulation of animal gene, and will provide preliminary theoretical and experimental basis for development of rape bee pollen into innovative health care product or medicine for the treatment of BPH. PMID- 29382327 TI - A systematic review of care management interventions targeting multimorbidity and high care utilization. AB - BACKGROUND: Evidence supporting the effectiveness of care management programs for complex patients has been inconclusive. However, past reviews have not focused on complexity primarily defined by multimorbidity and healthcare utilization. We conducted a systematic review of care management interventions targeting the following three patient groups: adults with two or more chronic medical conditions, adults with at least one chronic medical condition and concurrent depression, and adults identified based solely on high past or predicted healthcare utilization. METHODS: Eligible studies were identified from PubMed, published between 06/01/2005 and 05/31/2015, and reported findings from a randomized intervention that tested a comprehensive, care management intervention. Identified interventions were grouped based on the three "complex" categories of interest (described above). Two investigators extracted data using a structured abstraction form and assessed RCT quality. RESULTS: We screened 989 article titles for eligibility from which 847 were excluded. After reviewing the remaining 142 abstracts, 83 articles were excluded. We reviewed the full-text of 59 full-text articles and identified 15 unique RCTs for the final analysis. Of these 15 studies, two focused on patients with two or more chronic medical conditions, seven on patients with at least one chronic medical condition and depression, and six on patients with high past or predicted healthcare utilization. Measured outcomes included utilization, chronic disease measures, and patient-reported outcomes. The seven studies targeting patients with at least one chronic medical condition and depression demonstrated significant improvement in depression symptoms (ranging from 9.2 to 48.7% improvement). Of the six studies that focused on high utilizers, two showed small reductions in utilization. The quality of the research methodology in most of the studies (12/15) was rated fair or poor. CONCLUSIONS: Interventions were more likely to be successful when patients were selected based on having at least one chronic medical condition and concurrent depression, and when patient-reported outcomes were assessed. Future research should focus on the role of mental health in complex care management, finding better methods for identifying patients who would benefit most from care management, and determining which intervention components are needed for which patients. PMID- 29382328 TI - Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II. AB - BACKGROUND: We attempted to determine whether the inflammatory pathway HMGB1-TLR4 and the downstream pro-inflammatory cytokines is upregulated in focal cortical dysplasia (FCD) type II and whether there is a correlation between the TLR4 upregulation and disease duration or frequency of epileptic seizures. METHODS: FCD type II and peri-FCD paired tissues resected from eight children with refractory epilepsy were collected. Through real-time qPCR, Western blot, and co immunoprecipitation, we examined the differences between FCD lesions and peri-FCD tissues with respect to mRNA expression, protein expression, and protein interaction in HMGB1-TLR4 pathway biomarker and downstream pro-inflammatory factors in whole brain tissue. Then, we used immunofluorescence to examine the difference between FCD lesions and peri-FCD tissues with respect to protein expression and intracellular distribution of HMGB1-TLR4 pathway biomarker in neurons, astrocytes, and oligodendrocytes. Correlation between level of TLR4 expression and disease duration or frequency of epileptic seizures in patients was also analyzed. RESULTS: The protein expression levels of TLR4, cytoplasm HMGB1, TLR4/MyD88 complex, ubiquitination of TRAF6, p-IKK, p-IkappaB-alpha, p-NF kappaB p65, and IL-1beta and TNF-alpha in lesion tissues were significantly higher than those in peri-FCD controls. Total mRNA expression levels of TLR4, IL 1beta, and TNF-alpha in lesion tissues were significantly higher than those in peri-FCD controls, but HMGB1 had no significant change. In neurons and astrocytes inside the lesions, the expression of TLR4 protein was significantly higher than that in peri-FCD tissues, and HMGB1 was mainly expressed in the cytoplasm, while expressed in the nuclei in peri-FCD tissues. But in oligodendrocytes, there was no upregulation of HMGB1-TLR4 pathway in both lesions and peri-FCD tissues. We did not identify the correlation between the level of TLR4 activation and disease duration or frequency of epileptic seizures. CONCLUSION: The HMGB1-TLR4 pathway was upregulated in the neurons and astrocytes inside FCD type II lesions, which led to an increase in the release of downstream pro-inflammatory cytokines. Correlation between the level of TLR4 activation and duration or frequency of epileptic seizures was not identified. PMID- 29382329 TI - The economic impact of sight loss and blindness in the UK adult population. AB - BACKGROUND: To quantify the economic impact of sight loss and blindness in the United Kingdom (UK) population, including direct and indirect costs, and its burden on health. METHODS: Prevalence data on sight loss and blindness by condition, Census demographic data, data on indirect costs, and healthcare cost databases were used. Blindness was defined as best corrected visual acuity (BCVA) of < 6/60, and sight loss as BCVA < 6/12 to 6/60, in the better-seeing eye. RESULTS: Sight loss and blindness from age-related macular degeneration (AMD), cataract, diabetic retinopathy, glaucoma and under-corrected refractive error are estimated to affect 1.93 (1.58 to 2.31) million people in the UK. Direct health care system costs were L3.0 billion, with inpatient and day care costs comprising L735 million (24.6%) and outpatient costs comprising L771 million (25.8%). Indirect costs amounted to L5.65 (5.12 to 6.22) billion. The value of the loss of healthy life associated with sight loss and blindness was estimated to be L19.5 (15.9 to 23.3) billion or L7.2 (5.9 to 8.6) billion, depending on the set of disability weights used. For comparison with other published results using 2004 disability weights and the 2008 estimates, the total economic cost of sight loss and blindness was estimated to be L28.1 (24.0 to 32.5) billion in 2013. Using 2010 disability weights, the estimated economic cost of sight loss and blindness was estimated to be L15.8 (13.5 to 18.3) billion in 2013. CONCLUSIONS: The large prevalence of sight loss and blindness in the UK population imposes significant costs on public funds, private expenditure, and health. Prevalence estimates relied on dated epidemiological studies and may not capture recent advances in treatment, highlighting the need for population-based studies that track the prevalence of sight-impairing eye conditions and treatment effects over time. PMID- 29382330 TI - Two novel deep-sea sediment metagenome-derived esterases: residue 199 is the determinant of substrate specificity and preference. AB - BACKGROUND: The deep-sea environment harbors a vast pool of novel enzymes. Owing to the limitations of cultivation, cultivation-independent has become an effective method for mining novel enzymes from the environment. Based on a deep sea sediment metagenomics library, lipolytic-positive clones were obtained by activity-based screening methods. RESULTS: Two novel esterases, DMWf18-543 and DMWf18-558, were obtained from a deep-sea metagenomic library through activity based screening and high-throughput sequencing methods. These esterases shared 80.7% amino acid identity with each other and were determined to be new members of bacterial lipolytic enzyme family IV. The two enzymes showed the highest activities toward p-nitrophenyl (p-NP) butyrate at pH 7.0 and 35-40 degrees C and were found to be resistant to some metal ions (Ba2+, Mg2+, and Sr2+) and detergents (Triton X-100, Tween 20, and Tween 80). DMWf18-543 and DMWf18-558 exhibited distinct substrate specificities and preferences. DMWf18-543 showed a catalytic range for substrates of C2-C8, whereas DMWf18-558 presented a wider range of C2-C14. Additionally, DMWf18-543 preferred p-NP butyrate, whereas DMWf18 558 preferred both p-NP butyrate and p-NP hexanoate. To investigate the mechanism underlying the phenotypic differences between the esterases, their three dimensional structures were compared by using homology modeling. The results suggested that residue Leu199 of DMWf18-543 shortens and blocks the substrate binding pocket. This hypothesis was confirmed by the finding that the DMWf18-558 A199L mutant showed a similar substrate specificity profile to that of DMWf18 543. CONCLUSIONS: This study characterized two novel homologous esterases obtained from a deep-sea sediment metagenomic library. The structural modeling and mutagenesis analysis provided insight into the determinants of their substrate specificity and preference. The characterization and mechanistic analyses of these two novel enzymes should provide a basis for further exploration of their potential biotechnological applications. PMID- 29382331 TI - Using regulatory enforcement theory to explain compliance with quality and patient safety regulations: the case of internal audits. AB - BACKGROUND: Implementing an accredited quality and patient safety management system is inevitable for hospitals. Even in the case of an obligatory rule system, different approaches to implement such a system can be used: coercive (based on monitoring and threats of punishment) and catalytic (based on dialogue and suggestion). This study takes these different approaches as a starting point to explore whether and how implementation actions are linked to compliance. By doing so, this study aims to contribute to the knowledge on how to increase compliance with obligatory rules and regulations. METHODS: The internal audit system (the 'tracer system') of a large Dutch academic hospital is used as a case to investigate different implementation approaches and their effect on compliance. This case allowed us to use a multi-actor and multi-method approach for data collection. Internal audits (N = 16) were observed, audit reports were analyzed, and semi-structured interviews were conducted with both the internal auditors (N = 23) and the ward leaders (N = 14) responsible for compliance. Framework analysis was used to analyze the data. RESULTS: Although all auditors use catalytic enforcement actions, these do not lead to (intended) compliance of all ward leaders. Rather, the catalytic actions contribute to (intended) compliance of ward leaders that are motivated, whereas they do not for the ward leaders that are not motivated. For the motivated ward leaders, catalytic enforcement actions contribute to (intended) compliance by increasing ward leaders' knowledge of the rules and how to comply with them. CONCLUSIONS: Our findings suggest that the effectiveness of implementation actions depends not only on the actions themselves, but also on the pre-existing motivation to comply. These findings imply that there is not one 'best' approach to the implementation of obligatory rules. Rather, the most effective approach depends on the willingness to comply with rules and regulations. PMID- 29382332 TI - Nanographene oxide-methylene blue as phototherapies platform for breast tumor ablation and metastasis prevention in a syngeneic orthotopic murine model. AB - BACKGROUND: In the photodynamic therapy (PDT), the photosensitizer absorbs light and transfers the energy of the excited state to the oxygen in the cell environment producing reactive oxygen species (ROS), that in its turn, may cause cell damage. In the photothermal therapy (PTT), light also is responsible for activating the photothermal agent, which converts the absorbed energy in heat. Graphene oxide is a carbon-based material that presents photothermal activity. Its physical properties allow the association with the photosensitizer methylene blue and consequently the production of ROS when submitted to light irradiation. Therefore, the association between nanographene oxide and methylene blue could represent a strategy to enhance therapeutic actions. In this work, we report the nanographene oxide-methylene blue platform (NanoGO-MB) used to promote tumor ablation in combination with photodynamic and photothermal therapies against a syngeneic orthotopic murine breast cancer model. RESULTS: In vitro, NanoGO-MB presented 50% of the reactive oxygen species production compared to the free MB after LED light irradiation, and a temperature increase of ~ 40 degrees C followed by laser irradiation. On cells, the ROS production by the nanoplatform displayed higher values in tumor than normal cells. In vivo assays demonstrated a synergistic effect obtained by the combined PDT/PTT therapies using NanoGO-MB, which promoted complete tumor ablation in 5/5 animals. Up to 30 days after the last treatment, there was no tumor regrowth compared with only PDT or PTT groups, which displayed tumoral bioluminescence 63-fold higher than the combined treatment group. Histological studies confirmed that the combined therapies were able to prevent tumor regrowth and liver, lung and spleen metastasis. In addition, low systemic toxicity was observed in pathologic examinations of liver, spleen, lungs, and kidneys. CONCLUSIONS: The treatment with combined PDT/PTT therapies using NanoGO-MB induced more toxicity on breast carcinoma cells than on normal cells. In vivo, the combined therapies promoted complete tumor ablation and metastasis prevention while only PDT or PTT were unable to stop tumor development. The results show the potential of NanoGO-MB in combination with the phototherapies in the treatment of the breast cancer and metastasis prevention. PMID- 29382333 TI - Q&A: Trash talk: disposal and remote degradation of neuronal garbage. AB - Caenorhabditis elegans neurons have recently been found to throw out cellular debris for remote degradation and/or storage, adding an "extracellular garbage elimination" option to known intracellular protein and organelle degradation pathways. This Q&A describes initial insights into the biology of seemingly selective protein and organelle elimination by challenged neurons, highlighting mysteries of how garbage is distinguished and sorted in the sending neuron, how the garbage-filled "exophers" appear to elicit degradative responses as they transit neighboring tissue, and how non-digestible materials get thrown out of cells again via processes that may be highly relevant to human neurodegenerative disease mechanisms. PMID- 29382334 TI - Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. AB - BACKGROUND: Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in colorectal cancer (CRC) remains unknown. METHODS: We performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues. RESULTS: We identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC. CONCLUSIONS: We for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer. PMID- 29382335 TI - Role of neuronal nitric oxide synthase (nNOS) at medulla in tachycardia induced by repeated administration of ethanol in conscious rats. AB - BACKGROUND: Intake of ethanol (alcohol) has been shown to influence cardiovascular function; the underlying brain mechanism remains unclear. Noting that nitric oxide (NO) system in the CNS is involved in the regulation of cardiovascular function, the present study examined the role of NO in medulla in ethanol-induced cardiovascular changes. METHODS: Ethanol was administered by oral gavage at dose of 3.2 g/kg once every day for 8 consecutive days. Changes in blood pressure (BP) and heart rate (HR) in response to ethanol were measured by radiotelemetry method in freely moving female Sprague-Dawley rats. NO modulators were applied by intracerebroventricular (ICV) injection. The protein levels of nitric oxide synthase (NOS) and NO content in rostroventral medulla were measured by Western blot and nitrate/nitrite colorimetric assay kit, respectively. RESULTS: Ethanol intake had little effects on basal BP and HR following 8 consecutive day treatments. A significant increase in HR but not BP following ethanol intake was observed at 6th and 8th, but not at 1st and 4th day treatments as compared with saline group. A decrease in the protein expression of neuronal NOS (nNOS) but not inducible NOS or endothelial NOS and a decline in the level of NO in the medulla 30 min after ethanol administration was observed at 8th day treatment. ICV treatment with NO donors attenuated ethanol-induced tachycardia effects at 8th day treatment. Ethanol produced significantly tachycardia responses when ICV nNOS inhibitors were given at 1st day treatment. CONCLUSION: Our results suggest that medulla nNOS/NO pathways play an important role in ethanol regulation of HR. PMID- 29382336 TI - Impacts of incorporating personal genome sequencing into graduate genomics education: a longitudinal study over three course years. AB - BACKGROUND: To address the need for more effective genomics training, beginning in 2012 the Icahn School of Medicine at Mount Sinai has offered a unique laboratory-style graduate genomics course, "Practical Analysis of Your Personal Genome" (PAPG), in which students optionally sequence and analyze their own whole genome. We hypothesized that incorporating personal genome sequencing (PGS) into the course pedagogy could improve educational outcomes by increasing student motivation and engagement. Here we extend our initial study of the pilot PAPG cohort with a report on student attitudes towards genome sequencing, decision making, psychological wellbeing, genomics knowledge and pedagogical engagement across three course years. METHODS: Students enrolled in the 2013, 2014 and 2015 course years completed questionnaires before (T1) and after (T2) a prerequisite workshop (n = 110) and before (T3) and after (T4) PAPG (n = 66). RESULTS: Students' interest in PGS was high; 56 of 59 eligible students chose to sequence their own genome. Decisional conflict significantly decreased after the prerequisite workshop (T2 vs. T1 p < 0.001). Most, but not all students, reported low levels of decision regret and test-related distress post-course (T4). Each year baseline decisional conflict decreased (p < 0.001) suggesting, that as the course became more established, students increasingly made their decision prior to enrolling in the prerequisite workshop. Students perceived that analyzing their own genome enhanced the genomics pedagogy, with students self-reporting being more persistent and engaged as a result of analyzing their own genome. More than 90% of respondents reported spending additional time outside of course assignments analyzing their genome. CONCLUSIONS: Incorporating personal genome sequencing in graduate medical education may improve student motivation and engagement. However, more data will be needed to quantitatively evaluate whether incorporating PGS is more effective than other educational approaches. PMID- 29382337 TI - Built environmental characteristics and diabetes: a systematic review and meta analysis. AB - BACKGROUND: The built environment influences behaviour, like physical activity, diet and sleep, which affects the risk of type 2 diabetes mellitus (T2DM). This study systematically reviewed and meta-analysed evidence on the association between built environmental characteristics related to lifestyle behaviour and T2DM risk/prevalence, worldwide. METHODS: We systematically searched PubMed, EMBASE.com and Web of Science from their inception to 6 June 2017. Studies were included with adult populations (>18 years), T2DM or glycaemic markers as outcomes, and physical activity and/or food environment and/or residential noise as independent variables. We excluded studies of specific subsamples of the population, that focused on built environmental characteristics that directly affect the cardiovascular system, that performed prediction analyses and that do not report original research. Data appraisal and extraction were based on published reports (PROSPERO-ID: CRD42016035663). RESULTS: From 11,279 studies, 109 were eligible and 40 were meta-analysed. Living in an urban residence was associated with higher T2DM risk/prevalence (n = 19, odds ratio (OR) = 1.40; 95% CI, 1.2-1.6; I2 = 83%) compared to living in a rural residence. Higher neighbourhood walkability was associated with lower T2DM risk/prevalence (n = 8, OR = 0.79; 95% CI, 0.7-0.9; I2 = 92%) and more green space tended to be associated with lower T2DM risk/prevalence (n = 6, OR = 0.90; 95% CI, 0.8-1.0; I2 = 95%). No convincing evidence was found of an association between food environment with T2DM risk/prevalence. CONCLUSIONS: An important strength of the study was the comprehensive overview of the literature, but our study was limited by the conclusion of mainly cross-sectional studies. In addition to other positive consequences of walkability and access to green space, these environmental characteristics may also contribute to T2DM prevention. These results may be relevant for infrastructure planning. PMID- 29382338 TI - Modeling livestock population structure: a geospatial database for Ontario swine farms. AB - BACKGROUND: Infectious diseases in farmed animals have economic, social, and health consequences. Foreign animal diseases (FAD) of swine are of significant concern. Mathematical and simulation models are often used to simulate FAD outbreaks and best practices for control. However, simulation outcomes are sensitive to the population structure used. Within Canada, access to individual swine farm population data with which to parameterize models is a challenge because of privacy concerns. Our objective was to develop a methodology to model the farmed swine population in Ontario, Canada that could represent the existing population structure and improve the efficacy of simulation models. RESULTS: We developed a swine population model based on the factors such as facilities supporting farm infrastructure, land availability, zoning and local regulations, and natural geographic barriers that could affect swine farming in Ontario. Assigned farm locations were equal to the swine farm density described in the 2011 Canadian Census of Agriculture. Farms were then randomly assigned to farm types proportional to the existing swine herd types. We compared the swine population models with a known database of swine farm locations in Ontario and found that the modeled population was representative of farm locations with a high accuracy (AUC: 0.91, Standard deviation: 0.02) suggesting that our algorithm generated a reasonable approximation of farm locations in Ontario. CONCLUSION: In the absence of a readily accessible dataset providing details of the relative locations of swine farms in Ontario, development of a model livestock population that captures key characteristics of the true population structure while protecting privacy concerns is an important methodological advancement. This methodology will be useful for individuals interested in modeling the spread of pathogens between farms across a landscape and using these models to evaluate disease control strategies. PMID- 29382339 TI - The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK) dependent signaling pathways. AB - BACKGROUND: Hesperidin is a flavonoid with antioxidant, anti-inflammatory, and immune modulatory activities. Photoaging is a consequence of chronic exposure to the sun and ultraviolet (UV) radiation. This study was designed to evaluate the efficacy of hesperidin against photoaging of dorsal skin in hairless mice. METHODS: Hairless male mice (6-week-old) were divided into three groups (n = 7): control, UVB-treated vehicle, and UVB-treated hesperidin groups. UVB-irradiated mice from hesperidin group were orally administered 0.1 mL of water containing 100 mg/kg body weight per day hesperidin. RESULTS: The mean length and depth of wrinkles in the UVB-treated hesperidin group significantly improved after the oral administration of hesperidin, which significantly inhibited the increase in epidermal thickness and epidermal hypertrophy (P < 0.05). UVB irradiation of mice induced epidermal barrier dysfunction including an increase in the transepidermal water loss (TEWL); however, hesperidin decreased the TEWL. UVB irradiation increased the expression of MMP-9 and pro-inflammatory cytokines whereas UVB treated hesperidin group showed reduced expression. These results indicate that hesperidin showed anti-photoaging activity in the UVB-irradiated hairless mice. In conclusion, hesperidin inhibited the UVB-induced increase in skin thickness, wrinkle formation, and collagen fiber loss in male hairless mice. CONCLUSIONS: These results suggest that hesperidin shows potent anti-photoaging activity by regulating MMP-9 expression through the suppression of MAPK-dependent signaling pathways. PMID- 29382340 TI - 38.8 million additional modern contraceptive users: this, in fact, is "a never before opportunity to strengthen investment and action on adolescent contraception". AB - BACKGROUND: We thank Bijlmakers et al. for their interest in our article, "A never-before opportunity to strengthen investment and action on adolescent contraception, and what we must do to make full use of it", and are grateful for the opportunity to respond to their four key assertions. RESPONSE: First, we fully agree that sexual rights are controversial, which we discussed in depth in our original article. However, we reaffirm that there is global consensus on adolescent contraception as evidenced in part by recent data emerging from FP2020 on 38.8 million additional modern contraceptive users, the Global Goods and commitments emanating from the 2017 FP2020 summit, and their translated actions at the country level. Additionally, we clarify WHO's working definitions of sex, sexual health, and sexuality, and introduce WHO's newly released Operational Framework on Sexual Health and its Linkages to Reproductive Health. We welcome and agree with Bijlmakers et al.'s second point, which elaborates on the barrier of restrictive laws and policies. To address this barrier, we describe examples of resources that can help programmes understand the political/social context that drives these laws and policies at national and subnational levels, and identify programmatic gaps and best practices to address them within specific political/social contexts. We also welcome and agree with Bijlmakers et al.'s third point, which reiterates that discomfort around adolescent sexuality is a major barrier for sexuality education. In response, we point to four relevant reviews of CSE policies and their implementation, our original article's description of three programmes that have successfully addressed inadequate teacher skills, and our ongoing work on documenting strategies to build an enabling environment for CSE and deal with resistance. Lastly, we wholeheartedly agree that the harmful policies noted by Bijlmakers et al. are damaging to international efforts to improve adolescent SRH and rights. We argue, though, that these policies alone will not undermine efforts by countless other stakeholders around the world who are working in defence and promotion of adolescents' SRH and rights. CONCLUSION: Despite the many valid obstacles noted by Bijlmakers et al., we truly believe that this is "a never-before opportunity to strengthen investment and action on adolescent contraception". PMID- 29382341 TI - Stress-induced reproductive arrest in Drosophila occurs through ETH deficiency mediated suppression of oogenesis and ovulation. AB - BACKGROUND: Environmental stressors induce changes in endocrine state, leading to energy re-allocation from reproduction to survival. Female Drosophila melanogaster respond to thermal and nutrient stressors by arresting egg production through elevation of the steroid hormone ecdysone. However, the mechanisms through which this reproductive arrest occurs are not well understood. RESULTS: Here we report that stress-induced elevation of ecdysone is accompanied by decreased levels of ecdysis triggering hormone (ETH). Depressed levels of circulating ETH lead to attenuated activity of its targets, including juvenile hormone-producing corpus allatum and, as we describe here for the first time, octopaminergic neurons of the oviduct. Elevation of steroid thereby results in arrested oogenesis, reduced octopaminergic input to the reproductive tract, and consequent suppression of ovulation. ETH mitigates heat or nutritional stress induced attenuation of fecundity, which suggests that its deficiency is critical to reproductive adaptability. CONCLUSIONS: Our findings indicate that, as a dual regulator of octopamine and juvenile hormone release, ETH provides a link between stress-induced elevation of ecdysone levels and consequent reduction in fecundity. PMID- 29382342 TI - Strain distribution of repaired articular cartilage defects by tissue engineering under compression loading. AB - BACKGROUND: It is difficult to repair cartilage damage when cartilage undergoes trauma or degeneration. Cartilage tissue engineering is an ideal treatment method to repair cartilage defects, but at present, there are still some uncertainties to be researched in cartilage tissue engineering including the mechanical properties of the repaired region. METHODS: In this study, using an agarose gel as artificial cartilage implanted into the cartilage defect and gluing the agarose gel to cartilage by using the medical bio-adhesive, the full-thickness and half-thickness defects models of articular cartilage in vitro repaired by tissue engineering were constructed. Strain behaviors of the repaired region were analyzed by the digital correlation technology under 5, 10, 15, and 20% compressive load. RESULTS: The axial normal strain (Ex) perpendicular to the surface of the cartilage and lateral normal strain (Ey) as well as shear strain (Exy) appeared obviously heterogeneous in the repaired region. In the full-defect model, Ex showed depth-dependent strain profiles where maximum Ex occurs at the low middle zone while in the half-defect mode, Ex showed heterogeneous strain profiles where maximum Ex occurs at the near deep zone. Ey and Exy at the interface site of both models present significantly differed from the host cartilage site. Ey and Exy exhibited region-specific change at the host, interface, and artificial cartilage sites in the superficial, middle, and deep zones due to the artificial cartilage implantation. CONCLUSION: Both defect models of cartilage exhibited a heterogeneous strain field due to the engineered cartilage tissue implant. The abnormal strain field can cause the cells within the repaired area to enter complex mechanical states which will affect the restoration of cartilage defects. PMID- 29382343 TI - Evidence to service gap: cardiac rehabilitation and secondary prevention in rural and remote Western Australia. AB - BACKGROUND: Cardiovascular disease (CVD), a leading cause of morbidity and mortality, has similar incidence in metropolitan and rural areas but poorer cardiovascular outcomes for residents living in rural and remote Australia. Cardiac Rehabilitation (CR) is an evidence-based intervention that helps reduce subsequent cardiovascular events and rehospitalisation. Unfortunately CR attendance rates are as low as 10-30% with rural/remote populations under represented. This in-depth assessment investigated the provision of CR and secondary prevention services in Western Australia (WA) with a focus on rural and remote populations. METHODS: CR and Aboriginal Community Controlled Health Services were identified through the Directory of Western Australian Cardiac Rehabilitation and Secondary Prevention Services 2012. Structured interviews with CR coordinators included questions specific to program delivery, content, referral and attendance. RESULTS: Of the 38 CR services identified, 23 (61%) were located in rural (n = 11, 29%) and remote (n = 12, 32%) regions. Interviews with coordinators from 34 CR services (10 rural, 12 remote, 12 metropolitan) found 77% of rural/remote services were hospital-based, with no service providing a comprehensive home-based or alternative method of program delivery. The majority of rural (60%) and remote (80%) services provided CR through chronic condition exercise programs compared with 17% of metropolitan services; only 27% of rural/remote programs provided education classes. Rural/remote coordinators were overwhelmingly physiotherapists, and only 50% of rural and 33% of remote programs had face-to-face access to multidisciplinary support. Patient referral and attendance rates differed greatly across WA and referrals to rural/remote services generally numbered less than 5 per month. Program evaluation was reported by 33% of rural/remote coordinators. CONCLUSION: Geography, population density and service availability limits patient access to CR services in rural/remote WA. Current inadequacies in delivering comprehensive centre-based CR in rural/remote settings impedes management of cardiovascular risk and opportunities for event reduction. Health pathways that ensure referral and continuity of care are needed, with emerging technology-based CR support to supplement centre-based CR services requiring assessment. Implementing systematic data collection across services to establish benchmarks and enable service monitoring and evaluation is needed. PMID- 29382344 TI - Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation. AB - BACKGROUND: Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. METHODS: Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. RESULTS: Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro inflammatory (IL-1beta and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. CONCLUSIONS: Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age related cognitive impairments. PMID- 29382345 TI - Investigation of genetic variation and lifestyle determinants in vitamin D levels in Arab individuals. AB - BACKGROUND: Differences in the concentrations of circulating 25-hydroxyvitamin D [25(OH)D] are associated with a wide range of health outcomes; however, most studies on genetic variants that impact 25(OH)D levels have been conducted in European populations. Here we aimed to identify common genetic variants that affect vitamin D concentrations in individuals of self-reported Arab ethnicity. METHODS: The study included 1151 Arab subjects living in Kuwait. Common variants of single-nucleotide polymorphisms and genes previously associated with vitamin D levels, such as GC, PDE3B, CYP2R1, and NADSYN1, were genotyped. Raw vitamin D level data were corrected for age, body mass index, and sex and then normalized. Regression tree analyses were performed to identify the impact of genetic variants on vitamin D levels. RESULTS: Compared with other gene variants, the GC gene variants exhibited the greatest impact on vitamin D levels in our study population, of which rs2298850 had the lowest p value (0.003). Individuals homozygous for the derived allele C had lower vitamin D levels. Analyses of the interaction between the number of years for which the subjects had lived in Kuwait and genetic variation in the GC gene showed that those with the CC genotype of rs2298850 who had lived in Kuwait for < 51 years had a mean 25(OH)D level of 10 ng/ml, whereas those who were homozygous for the ancestral allele had a mean 25(OH)D level of 17 ng/ml. Furthermore, subjects who had lived in Kuwait for > 51 years had higher vitamin D levels (mean 28 ng/ml) regardless of the genotype of their GC gene. CONCLUSIONS: The GC gene may play a major role in determining vitamin D levels in Arab populations. PMID- 29382346 TI - Correction to: Validation of the German version of the late adolescence and young adulthood survivorship-related quality of life measure (LAYA-SRQL). AB - ERRATUM: The original article contained the following errors. PMID- 29382347 TI - Plants of the Cerrado with antimicrobial effects against Staphylococcus spp. and Escherichia coli from cattle. AB - BACKGROUND: Both diarrhea in calves and mastitis in cows limit cattle production. The bacteria involved in these diseases have shown multi-resistance to antimicrobials, however plant metabolites therefore can provide an alternative method of control. This study selected and characterized Cerrado plant extracts showing inhibitory effects against Escherichia coli and Staphylococcus spp. from cattle. Thirteen leaf extracts were initially screened and diameters of inhibition zones produced against the pathogens were recorded using an agar disk diffusion method. Total condensed tannin contents were determined and antibacterial activities were analyzed after tannin removal from the five selected extracts. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) were evaluated by macro-dilution antimicrobial susceptibility tests, and the extracts were characterized by high performance liquid chromatography. RESULTS: Inter- and intra-specific bacterial variations in the susceptibility to the extracts were detected. The aqueous extract (AE) from Caryocar brasiliense Cambess. leaves produced larger inhibition zones against E. coli strains than did other selected extracts. However, the AE from Schinopsis brasiliensis was the most effective against Staphylococcus spp. strains (P < 0.001). The MIC of ethanolic extracts (EE) from C. brasiliense (0.27 mg/mL) and S. brasiliensis (0.17 mg/mL) were lower than those of other extracts. The MIC and MBC of the Annona crassiflora EE were 6.24 mg/mL for all bacteria. Flavonoids were the main metabolites detected in the A. crassiflora EE as well as in the AE and EE from C. brasiliense, while tannins were the main metabolites in the S. brasiliensis leaf extracts. CONCLUSION: The AE from C. brasiliense was more effective against Gram-negative bacteria, while the AE from S. brasiliensis was more effective against Gram-positive bacteria. A. crassiflora EE and S. brasiliensis extracts are potent bactericide. After removal of the tannins, no antimicrobial effects were observed, indicating that these metabolites are the main active antibacterial components. PMID- 29382348 TI - Estimates of global research productivity in using nicotine replacement therapy for tobacco cessation: a bibliometric study. AB - BACKGROUND: Tobacco use is a major healthcare problem worldwide. Tobacco smoking remains the most important risk factor for both cancer and heart diseases. This study was initiated due to the lack of published data concerning the real progress in research output in the use of nicotine replacement therapy (NRT) for tobacco cessation. This study was aimed to use bibliometric analysis to estimate the NRT literature indexed in Scopus database at global level. METHODS: Core of the search strategy was the documents that contained specific words or phrases regarding NRT as keywords in the title. Publication output of most prolific countries was adjusted to the gross domestic product and population size. All citations analysis were accomplished on December 22, 2017. RESULTS: A total of 2138 references were retrieved and published from 56 countries, which were published between 1970 and 2016. The USA has the most number of published articles accounted to 986, followed by the UK (312 publications) and then Australia (102 publications), and Sweden (102 publications). No data related to NRT were published from 156 countries. No significant correlation was found between the country population size or 2016 gross domestic product values and the number of publications of the top-10 most prolific countries in the field of NRT (r = - 0.156, P = 0.664; and r = - 0.173, P = 0.632, respectively). Furthermore, there is no correlation between prevalence of tobacco smoking and number of publications of the top-10 most prolific countries in the field of NRT (r = - 0.235, P = 0.514). CONCLUSIONS: The present data reveal a solid mass of research activity on NRT. The USA was by far the predominant country in the amount of NRT based research activity. NRT-based research activities were low or not available in most countries. The results of this study delineate a framework for better understanding the situations of current NRT research and prospective directions of the research in this field which could be applied for managing and prioritizing future research efforts in NRT research. PMID- 29382349 TI - Systemic arteriosclerosis is associated with left ventricular remodeling but not atherosclerosis: a TASCFORCE study. AB - BACKGROUND: Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events, with this effect postulated to be due to its effect on cardiac afterload, atherosclerosis (plaque formation) progression or both, but with limited evidence examining these early in disease formation. The aim of the current study is to examine the association between arteriosclerosis, atherosclerosis and ventricular remodelling in a population at low-intermediate cardiovascular risk. METHODS: One thousand six hundred fifty-one subjects free of clinical cardiovascular disease and with a < 20% 10 year cardiovascular risk score underwent a cardiovascular magnetic resonance (CMR) study and whole body CMR angiogram. Arteriosclerosis was measured using total arterial compliance (TAC) - calculated as the indexed stroke volume divided by the pulse pressure. Atherosclerosis was quantified using a standardised atheroma score (SAS) which was calculated by scoring 30 arterial segments within the body based on the degree of stenosis, summating these scores and normalising it to the number of assessable segments. Left ventricular remodelling was measured using left ventricular mass to volume ratio (LVMVR). RESULTS: One thousand five hundred fifteen (38% male, 53.8 +/- 8.2 years old) completed the study. On univariate analysis TAC was associated with SAS but this was lost after accounting for cardiovascular risk factors in both males (B = - 0.001 (- 0.004-0.002),p = 0.62) and females (B = 0.000(95%CI -0.002--0.002),p = 0.78). In contrast compliance correlated with LVMVR after accounting for cardiovascular risk factors (B = - 0.12(95%CI -0.16--0.091),p < 0.001 in males; B = - 0.12(95%CI -0.15--0.086),p < 0.001 in females). CONCLUSION: Systemic arteriosclerosis is associated with left ventricular remodelling but not atherosclerosis. Future efforts in cardiovascular risk prevention should thus seek to address both arteriosclerosis and atherosclerosis individually. PMID- 29382350 TI - Developing a model of family focused practice with consumers, families, practitioners and managers: a community based participatory research approach. AB - BACKGROUND: While governments are urging adult mental health services to support consumers in the context of their family, there is little information about what family focused practice is, nor how it might be enacted. METHODS: Informed by the principles of Community Based Participatory Research, workshops were held in three rural Australian communities in 2015 to discuss the meaning of family focused practice and how such practices might be promoted. RESULTS: Participants described the need to raise community awareness about mental illness and provide practical support to the family. Participants emphasized the importance of practitioners genuinely communicating with consumers and their families about mental illness and the need for collaborative care and treatment planning. They also highlighted the challenges of living in rural places and posed some solutions. CONCLUSION: On the basis of the results and previous literature, we developed a model of family focused practice that outlined various stakeholders and their enactments. The model has the potential to inform policy, professional development and practice guidelines. PMID- 29382351 TI - The crystal structure of titanium dioxide nanoparticles influences immune activity in vitro and in vivo. AB - BACKGROUND: The use of engineered nanoparticles (NP) is widespread and still increasing. There is a great need to assess their safety. Newly engineered NP enter the market in a large variety; therefore safety evaluation should preferably be in a high-throughput fashion. In vitro screening is suitable for this purpose. TiO 2 NP exist in a large variety (crystal structure, coating and size), but information on their relative toxicities is scarce. TiO 2 NP may be inhaled by workers in e.g. paint production and application. In mice, inhalation of TiO 2 NP increases allergic reactions. Dendritic cells (DC) form an important part of the lung immune system, and are essential in adjuvant activity. The present study aimed to establish the effect of a variety of TiO 2 NP on DC maturation in vitro. Two NP of different crystal structure but similar in size, uncoated and from the same supplier, were evaluated for their adjuvant activity in vivo. METHODS: Immature DC were differentiated in vitro from human peripheral blood monocytes. Exposure effects of a series of fourteen TiO 2 NP on cell viability, CD83 and CD86 expression, and IL-12p40 and TNF-alpha production were measured. BALB/c mice were intranasally sensitized with ovalbumin (OVA) alone, OVA plus anatase TiO 2 NP, OVA plus rutile TiO 2 NP, and OVA plus Carbon Black (CB; positive control). The mice were intranasally challenged with OVA. OVA specific IgE and IgG1 in serum, cellular inflammation in bronchoalveolar lavage fluid (BALF) and IL-4 and IL-5 production in draining bronchial lymph nodes were evaluated. RESULTS: All NP dispersions contained NP aggregates. The anatase NP and anatase/rutile mixture NP induced a higher CD83 and CD86 expression and a higher IL-12p40 production in vitro than the rutile NP (including coated rutile NP and a rutile NP of a 10-fold larger primary diameter). OVA-specific serum IgE and IgG1 were increased by anatase NP, rutile NP, and CB, in the order rutile T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. CONCLUSIONS: Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects. PMID- 29382363 TI - Identifying co-endemic areas for major filarial infections in sub-Saharan Africa: seeking synergies and preventing severe adverse events during mass drug administration campaigns. AB - BACKGROUND: Onchocerciasis and lymphatic filariasis (LF) are major filarial infections targeted for elimination in most endemic sub-Saharan Africa (SSA) countries by 2020/2025. The current control strategies are built upon community directed mass administration of ivermectin (CDTI) for onchocerciasis, and ivermectin plus albendazole for LF, with evidence pointing towards the potential for novel drug regimens. When distributing microfilaricides however, considerable care is needed to minimise the risk of severe adverse events (SAEs) in areas that are co-endemic for onchocerciasis or LF and loiasis. This work aims to combine previously published predictive risk maps for onchocerciasis, LF and loiasis to (i) explore the scale of spatial heterogeneity in co-distributions, (ii) delineate target populations for different treatment strategies, and (iii) quantify populations at risk of SAEs across the continent. METHODS: Geographical co-endemicity of filarial infections prior to the implementation of large-scale mass treatment interventions was analysed by combining a contemporary LF endemicity map with predictive prevalence maps of onchocerciasis and loiasis. Potential treatment strategies were geographically delineated according to the level of co-endemicity and estimated transmission intensity. RESULTS: In total, an estimated 251 million people live in areas of LF and/or onchocerciasis transmission in SSA, based on 2015 population estimates. Of these, 96 million live in areas co-endemic for both LF and onchocerciasis, providing opportunities for integrated control programmes, and 83 million live in LF-monoendemic areas potentially targetable for the novel ivermectin-diethylcarbamazine-albendazole (IDA) triple therapy. Only 4% of the at-risk population live in areas co-endemic with high loiasis transmission, representing up to 1.2 million individuals at high risk of experiencing SAEs if treated with ivermectin. In these areas, alternative treatment strategies should be explored, including biannual albendazole monotherapy for LF (1.4 million individuals) and 'test-and-treat' strategies (8.7 million individuals) for onchocerciasis. CONCLUSIONS: These maps are intended to initiate discussion around the potential for tailored treatment strategies, and highlight populations at risk of SAEs. Further work is required to test and refine strategies in programmatic settings, providing the empirical evidence needed to guide efforts towards the 2020/2025 goals and beyond. PMID- 29382364 TI - Treatment of immunoglobulin G4-related sialadenitis: outcomes of glucocorticoid therapy combined with steroid-sparing agents. AB - BACKGROUND: Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity. METHODS: IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed. RESULTS: Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow up period was 24.6 +/- 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P < 0.001). For long term, relapse occurred in 32.5% patients within 55 months in the regularly treated group, while all seven irregularly treated patients relapsed. However, the relapse-free survival curves were not significantly different between the steroid monotherapy and the combination therapy groups (P = 0.566). Submandibular glands, lacrimal glands, sublingual glands, nasal and paranasal cavity were commonly relapsing organs. In clinically stable patients, a serologically unstable condition occurred in 54.9% patients within 55 months and medication adjustment was performed accordingly. Volume changes in the submandibular and parotid glands were associated with serum IgG4 levels and time of follow up (R2adjusted = 0.905, P < 0.0001 and R2adjusted = 0.9334, P < 0.0001, respectively). CONCLUSIONS: The combination of glucocorticoid and steroid-sparing agents could be effective for treating IgG4-RS, and restoring salivary gland function. Serum IgG4 levels could predict disease activity. PMID- 29382365 TI - Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which dysregulation of B cells has been recognized. Here, we searched for potential biomarkers of SLE using liquid chromatography-tandem mass spectrometry (LC-MS). METHODS: Lymph nodes from SLE patients and controls were analyzed by LC-MS. To validate the identified molecules, immunoblotting and immunohistochemistry were performed and B cells from SLE patients were analyzed by quantitative RT-PCR. B-cell subsets from NZB/W F1 mice, which exhibit autoimmune disease resembling human SLE, were analyzed by flow cytometry. Endoplasmic reticulum (ER) stress was induced by tunicamycin and the serum concentration of anti-dsDNA antibodies was determined by ELISA. TUNEL methods and immunoblotting were used to assess the effect of tunicamycin. RESULTS: MZB1, which comprises part of a B-cell-specific ER chaperone complex and is a key player in antibody secretion, was one of the differentially expressed proteins identified by LC-MS and confirmed by immunoblotting. Immunohistochemically, larger numbers of MZB1+ cells were located mainly in interfollicular areas and scattered in germinal centers in specimens from SLE patients compared with those from controls. MZB1 colocalized with CD138+ plasma cells and IRTA1+ marginal zone B cells. MZB1 mRNA was increased by 2.1-fold in B cells of SLE patients with active disease (SLE Disease Activity Index 2000 >= 6) compared with controls. In aged NZB/W F1 mice, splenic marginal zone B cells and plasma cells showed elevated MZB1 levels. Tunicamycin induced apoptosis of MZB1+ cells in target organs, resulting in decreased serum anti-dsDNA antibody levels. Additionally, MZB1+ cells were increased in synovial tissue specimens from patients with rheumatoid arthritis. CONCLUSIONS: MZB1 may be a potential therapeutic target in excessive antibody-secreting cells in SLE. PMID- 29382366 TI - Age and fecal microbial strain-specific differences in patients with spondyloarthritis. AB - BACKGROUND: Prior studies have demonstrated abnormalities in the composition of the gastrointestinal microbiota in pediatric and adult patients with spondyloarthritis (SpA). In particular, diminished fecal abundance of Faecalibacterium prausnitzii and abnormalities in both directions in the abundance of the Bacteroides genus have been identified. METHODS: We obtained fecal specimens from 30 children with treatment-naive enthesitis-related arthritis (ERA) and 19 healthy controls, as well as specimens from 11 adult patients with longstanding SpA and 10 adult healthy controls. All of the samples underwent sequencing of the 16S ribosomal DNA. A subset of the pediatric fecal samples was subjected to shotgun metagenomics sequencing. RESULTS: ERA patients had decreased abundance of the anti-inflammatory F. prausnitzii A2-165 strain (41 +/- 28% versus 54 +/- 20% of all sequences matching F. prausnitzii, p = 0.084) and an increased abundance of the control F. prausnitzii L2/6 strain (28 +/- 28% versus 15 +/- 15%, p = 0.038). Similar trends were observed in adults with longstanding SpA (n = 11) and controls (n = 10). In contrast, the fecal abundance of Bacteroides fragilis was increased in ERA subjects (2.0 +/- 4.0% versus 0.45 +/- 0.7% of all sequences, p = 0.045), yet was diminished in adult subjects (0.2 +/- % versus 1.0 +/- % of all sequences, p = 0.106). Shotgun metagenomics sequencing of the fecal DNA in the pediatric subjects revealed diminished coverage of the butanoate pathway (abundance normalized to controls of 1 +/- 0.48 versus 0.72 +/- 0.33 in ERA, p = 0.037). CONCLUSIONS: The anti-inflammatory F. prausnitzii A2-165 strain appears to be depleted in both pediatric and adult SpA. In contrast, B. fragilis may be depleted in adult disease yet abundant in pediatric SpA, suggesting developmental effects on the immune system. PMID- 29382367 TI - Effects of automated smartphone mobile recovery support and telephone continuing care in the treatment of alcohol use disorder: study protocol for a randomized controlled trial. AB - BACKGROUND: New smartphone communication technology provides a novel way to provide personalized continuing care support following alcohol treatment. One such system is the Addiction version of the Comprehensive Health Enhancement Support System (A-CHESS), which provides a range of automated functions that support patients. A-CHESS improved drinking outcomes over standard continuing care when provided to patients leaving inpatient treatment. Effective continuing care can also be delivered via telephone calls with a counselor. Telephone Monitoring and Counseling (TMC) has demonstrated efficacy in two randomized trials with alcohol-dependent patients. A-CHESS and TMC have complementary strengths. A-CHESS provides automated 24/7 recovery support services and frequent assessment of symptoms and status, but does not involve regular contact with a counselor. TMC provides regular and sustained contact with the same counselor, but no ongoing support between calls. The future of continuing care for alcohol use disorders is likely to involve automated mobile technology and counselor contact, but little is known about how best to integrate these services. METHODS/DESIGN: To address this question, the study will feature a 2 * 2 design (A-CHESS for 12 months [yes/no] * TMC for 12 months [yes/no]), in which 280 alcohol-dependent patients in intensive outpatient programs (IOPs) will be randomized to one of the four conditions and followed for 18 months. We will determine whether adding TMC to A-CHESS produces fewer heavy drinking days than TMC or A-CHESS alone and test for TMC and A-CHESS main effects. We will determine the costs of each of the four conditions and the incremental cost-effectiveness of the three active conditions. Analyses will also examine secondary outcomes, including a biological measure of alcohol use, and hypothesized moderation and mediation effects. DISCUSSION: The results of the study will yield important information on improving patient alcohol use outcomes by integrating mobile automated recovery support and counselor contact. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02681406 . Registered on 2 September 2016. PMID- 29382368 TI - A panoramic view of RNA modifications: exploring new frontiers. AB - Meeting report on the Cold Spring Harbor Asia conference on RNA Modifications and Epitranscriptomics, held in Suzhou, China, 13-17 November, 2017. PMID- 29382369 TI - HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors. AB - BACKGROUND: Approximately one in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer. We set out to understand the genomics of HER2 amplification independent of subtype, and the underlying drivers and biology of HER2E tumors. METHODS: We investigated published genomic data from 3155 breast tumors and 5391 non-breast tumors. RESULTS: HER2 amplification is a distinct driver event seen in all breast cancer subtypes, rather than a subtype marker, with major characteristics restricted to amplification and overexpression of HER2 and neighboring genes. The HER2E subtype has a distinctive transcriptional landscape independent of HER2A that reflects androgen receptor signaling as replacement for estrogen receptor (ER)-driven tumorigenesis. HER2 amplification is also an event in 1.8% of non-breast tumors. CONCLUSIONS: These discoveries reveal therapeutic opportunities for combining anti-HER2 therapy with anti androgen agents in breast cancer, and highlight the potential for broader therapeutic use of HER2 inhibitors. PMID- 29382370 TI - Supraclavicular Subclavian access for Sapien Transcatheter aortic valve replacement- a novel approach. AB - BACKGROUND: Within the trans-subclavian approach, procedural techniques can vary widely, and reported access generally refers to an infraclavicular axillary approach. We describe and report the use of a novel supraclavicular true subclavian approach for transcatheter aortic valve replacement (TAVR) exclusively for implantation of Sapien 3 valves. CASE PRESENTATION: We report our first five consecutive patients undergoing TAVR with a Sapien 3 valve using a standardized subclavian approach at a single center. In-hospital and 30-day complications were reported. The use of this approach resulted in successful implantation in 100% of patients in a safe manner with 0% mortality, stroke, and vascular injury during hospitalization and at 30 day follow-up. The in-hospital pacemaker implantation rate was 20%. The average length of stay was 3 days. CONCLUSIONS: TAVR with Sapien implant can be safely performed with a standardized supraclavicular subclavian approach in patients with unfavorable femoral access. PMID- 29382371 TI - Common drug review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand. AB - BACKGROUND: Public payer reimbursement for non-oncology drugs in Canada, including orphan drugs, is based on recommendations by the Common Drug Review (CDR) (with the exception of Quebec). CDR has been criticized for negative recommendations for orphan drugs and contributing to delays in patient access to these drugs. However, it is unclear how CDR makes recommendations for orphan drugs and the role clinical and economic factors play in decision making. The objective of the present study was to analyze the basis for CDR orphan drug recommendations and to compare recommendations to those in other jurisdictions. METHODS: A list of orphan drugs reviewed by CDR (between 2004 and 2017) was compiled and final recommendations (list/do not list) assessed. The basis of each recommendation was categorized as clinical only, price only or combined clinical and price factors, based on the ranking of clinical and price parameters in recommendation summaries. The reimbursement status of the same drugs was determined in Quebec and other jurisdictions and level of agreement with CDR decisions assessed using a kappa analysis. RESULTS: Sixty eight orphan drug submissions were identified in the CDR database. Clinical, clinical and price and price parameters were the basis of 48.5%, 44.1% and 7.4% of the reviews, respectively, and corresponding positive recommendation rates were 45.5%, 86.7% and 40.0% (p = 0.0008); overall positive recommendation rate was 63.2%. Positive recommendation rate increased from 50.0% for drugs reviewed between 2004 and 2009 to 86.7% in 2016; however, 84.6% of the latter were conditional on a price reduction. Of the drugs reviewed by CDR, 80.9%, 88.2%, 80.9% and 58.8% were reviewed for the same indications by health technology assessment agencies in Quebec, Scotland, Australia and New Zealand, respectively, with positive listing rates ranging from 60.0% (Quebec) to 92.7% (Australia) with fair (kappa coefficient 0.3307) to poor (kappa coefficient 0.0611) agreement with CDR in listing decisions, respectively. CONCLUSIONS: The positive CDR recommendation rate for orphan drugs was highest when clinical and price parameters supported the assessment. Over time there has been an increase in CDR positive recommendation rates for orphan drugs, although most are conditional on a price reduction. It is unclear if this change in CDR recommendations will impact equitable and timely access to orphan drugs across Canada. PMID- 29382372 TI - Skilled delivery service utilization and its association with the establishment of Women's Health Development Army in Yeky district, South West Ethiopia: a multilevel analysis. AB - BACKGROUND: Because of the unacceptably high maternal and perinatal morbidity and mortality, the government of Ethiopia has established health extension program with a community-based network involving health extension workers (HEWs) and a community level women organization which is known as "Women's Health Development Army" (WHDA). Currently, the HEWs and WHDA network is the approach preferred by the government to register pregnant women and encourage them to link in the healthcare system. However, its association with skilled delivery service utilization is not well known. METHODS: A community-based cross-sectional study was conducted from January to February 2015. Within 380 clusters of WHDA, a total of 748 reproductive-age women who gave birth in 1 year preceding the study, were included using multistage sampling technique. The data were entered into EPI info version 7 statistical software and exported to STATA version 11 for analysis. Multilevel analysis technique was applied to check for an association of selected variables with a utilization of skilled delivery service. RESULTS: About 45% of women have received skilled delivery care. A significant heterogeneity was observed between "Women's Health Development Teams (clusters)" for skilled delivery care service utilization which explains about 62% of the total variation. Individual-level predictors including urban residence [AOR (95% CI) 35.10 (4.62, 266.52)], previous exposure of complications [AOR (95% CI) 3.81 (1.60, 9.08)], at least four ANC visits [AOR (95% CI) 7.44 (1.48, 37.42)] and preference of skilled personnel [AOR (95% CI) 8.11 (2.61, 25.15)] were significantly associated with skilled delivery service use. Among cluster level variables, the distance of clusters within 2 km radius from the nearest health facility was significantly associated [AOR (95% CI) 6.03 (1.92, 18.93)] with skilled delivery service utilization. CONCLUSIONS: In this study, significant variation among clusters of WHDA was observed. Both individual and cluster level variables were identified to predict skilled delivery service utilization. Encouraging women to have frequent ANC visits (- 4 and above), enhancing awareness creation towards the delivery care attendance, constructing more health facilities and roads in hard to reach areas and establishing telemedicine services are recommended. PMID- 29382373 TI - Refeeding syndrome in adults with celiac crisis: a case report. AB - BACKGROUND: Refeeding syndrome is a rare and life-threatening pathology with polyvisceral manifestations occurring in severely malnourished patients. It is rarely described in adults with celiac disease. CASE PRESENTATION: We report the case of a 28-year-old Tunisian woman followed up for celiac disease, who did not adhere to the gluten-free diet. She presented to our hospital with celiac crisis manifested by severe diarrhea, and metabolic and electrolyte disturbances. The treatment of electrolyte abnormalities, hydration, and nutritional support was marked by the occurrence on the fifth day of refeeding syndrome with psychomotor agitation followed by respiratory distress and a state of cardiogenic shock. CONCLUSIONS: Refeeding syndrome is still under-recognized. It should be systematically prevented for high-risk patients. Nutritional support in patients with celiac crisis should be monitored carefully since the risk of refeeding syndrome is very high with a poor prognosis. PMID- 29382374 TI - Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis. AB - BACKGROUND: Role of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently. However, their involvement in human rheumatoid arthritis (RA) is not conclusive. Pathogenesis of RA is complex and involves various T cell subsets and neutrophils. Here, we aimed at understanding the impact of IL-9 on infiltrating immune cells and their eventual role in synovial inflammation in RA. METHODS: In vitro stimulation of T cells was performed by engagement of anti-CD3 and anti CD28 monoclonal antibodies. Flow cytometry was employed for measuring intracellular cytokine, RORgammat in T cells, evaluating apoptosis of neutrophils. ELISA was used for measuring soluble cytokine, Western blot analysis and confocal microscopy were used for STAT3 phosphorylation and nuclear translocation. RESULTS: We demonstrated synovial enrichment of Th9 cells and their positive correlation with disease activity (DAS28-ESR) in RA. Synovial IL-9 prolonged the survival of neutrophils, increased their matrix metalloprotienase-9 production and facilitated Th17 cell differentiation evidenced by induction of transcription factor RORgammat and STAT3 phosphorylation. IL-9 also augmented the function of IFN-gamma + and TNF-alpha + synovial T cells. CONCLUSIONS: We provide evidences for critical role of IL-9 in disease pathogenesis and propose that targeting IL-9 may be an effective strategy to ameliorate synovial inflammation in RA. Inhibiting IL-9 may have wider impact on the production of pathogenic cytokines involved in autoimmune diseases including RA and may offer better control over the disease. PMID- 29382375 TI - What is the impact on health and wellbeing of interventions that foster respect and social inclusion in community-residing older adults? A systematic review of quantitative and qualitative studies. AB - BACKGROUND: Many interventions have been developed to promote respect and social inclusion among older people, but the evidence on their impacts on health has not been synthesised. This systematic review aims to appraise the state of the evidence across the quantitative and qualitative literature. METHODS: Eligible studies published between 1990 and 2015 were identified by scanning seven bibliographic databases using a pre-piloted strategy, searching grey literature and contacting experts. Studies were included if they assessed the impact (quantitatively) and/or perceived impact (qualitatively) of an intervention promoting respect and social inclusion on the physical or mental health of community-residing people aged 60 years and older. Titles and abstracts were screened for eligibility by one reviewer. A second reviewer independently screened a 10% random sample. Full texts were screened for eligibility by one reviewer, with verification by another reviewer. Risk of bias was assessed using standardised tools. Findings were summarised using narrative synthesis, harvest plots and logic models to depict the potential pathways to health outcomes. RESULTS: Of the 27,354 records retrieved, 40 studies (23 quantitative, 6 qualitative, 11 mixed methods) were included. All studies were conducted in high and upper middle-income countries. Interventions involved mentoring, intergenerational and multi-activity programmes, dancing, music and singing, art and culture and information-communication technology. Most studies (n = 24) were at high or moderate risk of bias. Music and singing, intergenerational interventions, art and culture and multi-activity interventions were associated with an overall positive impact on health outcomes. This included depression (n = 3), wellbeing (n = 3), subjective health (n = 2), quality of life (n = 2), perceived stress and mental health (n = 2) and physical health (n = 2). Qualitative studies offered explanations for mediating factors (e.g. improved self-esteem) that may lead to improved health outcomes and contributed to the assessment of causation. CONCLUSIONS: Whilst this review suggests that some interventions may positively impact on the health outcomes of older people, and identified mediating factors to health outcomes, the evidence is based on studies with heterogeneous methodologies. Many of the interventions were delivered as projects to selected groups, raising important questions about the feasibility of wider implementation and the potential for population-wide benefits. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42014010107. PMID- 29382376 TI - Psychometric properties of the Alcohol Use Disorders Identification Test (AUDIT) and prevalence of alcohol use among Iranian psychiatric outpatients. AB - BACKGROUND: Iran is a developing and Islamic country where the consumption of alcoholic beverages is banned. However, psychiatric disorders and alcohol use disorders are often co-occurring. We used the Alcohol Use Disorders Identification Test (AUDIT) to estimate the prevalence of alcohol use and examined the psychometric properties of the test among psychiatric outpatients in Teheran, Iran. METHODS: AUDIT was completed by 846 consecutive (sequential) patients. Descriptive statistics, internal consistency (Cronbach alpha), confirmatory and exploratory factor analyses were used to analyze the prevalence of alcohol use, reliability and construct validity. RESULTS: 12% of men and 1% of women were hazardous alcohol consumers. Internal reliability of the Iranian version of AUDIT was excellent. Confirmatory factor analyses showed that the construct validity and the fit of previous factor structures (1, 2 and 3 factors) to data were not good and seemingly contradicted results from the explorative principal axis factoring, which showed that a 1-factor solution explained 77% of the co-variances. CONCLUSIONS: We could not reproduce the suggested factor structure of AUDIT, probably due to the skewed distribution of alcohol consumption. Only 19% of men and 3% of women scored above 0 on AUDIT. This could be explained by the fact that alcohol is illegal in Iran. In conclusion the AUDIT exhibited good internal reliability when used as a single scale. The prevalence estimates according to AUDIT were somewhat higher among psychiatric patients compared to what was reported by WHO regarding the general population. PMID- 29382377 TI - Lateral cervical thymic cyst in a child: a case report. AB - BACKGROUND: Cervical thymic cysts are uncommon lesions, rarely considered in the differential diagnosis of neck cysts in children. CASE PRESENTATION: We report a rare case of multiloculated thymic cyst in an 8-year-old boy on the right side of the neck. Perioperative diagnosis was a cystic hygroma. Macroscopic examination showed a cystic mass measuring 6.5 cm in total length. Histopathology of the excised specimen revealed thymic tissue with prominent Hassall's corpuscles associated with multiloculated cyst. The cyst wall is bordered by a flattened or multilayered epithelium, often abraded. CONCLUSION: This case is presented here for its rarity and should be included in the differential diagnosis of neck masses in children. So, it's a lesion to be well aware of, particularly by pathologists. PMID- 29382378 TI - Filter forensics: microbiota recovery from residential HVAC filters. AB - BACKGROUND: Establishing reliable methods for assessing the microbiome within the built environment is critical for understanding the impact of biological exposures on human health. High-throughput DNA sequencing of dust samples provides valuable insights into the microbiome present in human-occupied spaces. However, the effect that different sampling methods have on the microbial community recovered from dust samples is not well understood across sample types. Heating, ventilation, and air conditioning (HVAC) filters hold promise as long term, spatially integrated, high volume samplers to characterize the airborne microbiome in homes and other climate-controlled spaces. In this study, the effect that dust recovery method (i.e., cut and elution, swabbing, or vacuuming) has on the microbial community structure, membership, and repeatability inferred by Illumina sequencing was evaluated. RESULTS: The results indicate that vacuum samples captured higher quantities of total, bacterial, and fungal DNA than swab or cut samples. Repeated swab and vacuum samples collected from the same filter were less variable than cut samples with respect to both quantitative DNA recovery and bacterial community structure. Vacuum samples captured substantially greater bacterial diversity than the other methods, whereas fungal diversity was similar across all three methods. Vacuum and swab samples of HVAC filter dust were repeatable and generally superior to cut samples. Nevertheless, the contribution of environmental and human sources to the bacterial and fungal communities recovered via each sampling method was generally consistent across the methods investigated. CONCLUSIONS: Dust recovery methodologies have been shown to affect the recovery, repeatability, structure, and membership of microbial communities recovered from dust samples in the built environment. The results of this study are directly applicable to indoor microbiota studies utilizing the filter forensics approach. More broadly, this study provides a better understanding of the microbial community variability attributable to sampling methodology and helps inform interpretation of data collected from other types of dust samples collected from indoor environments. PMID- 29382379 TI - Can baseline ultrasound results help to predict failure to achieve DAS28 remission after 1 year of tight control treatment in early RA patients? AB - BACKGROUND: At present, there are no prognostic parameters unequivocally predicting treatment failure in early rheumatoid arthritis (RA) patients. We investigated whether baseline ultrasonography (US) findings of joints, when added to baseline clinical, laboratory, and radiographical data, could improve prediction of failure to achieve Disease Activity Score assessing 28 joints (DAS28) remission (<2.6) at 1 year in newly diagnosed RA patients. METHODS: A multicentre cohort of newly diagnosed RA patients was followed prospectively for 1 year. US of the hands, wrists, and feet was performed at baseline. Clinical, laboratory, and radiographical parameters were recorded. Primary analysis was the prediction by logistic regression of the absence of DAS28 remission 12 months after diagnosis and start of therapy. RESULTS: Of 194 patients included, 174 were used for the analysis, with complete data available for 159. In a multivariate model with baseline DAS28 (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.2 2.2), the presence of rheumatoid factor (OR 2.3, 95% CI 1.1-5.1), and type of monitoring strategy (OR 0.2, 95% CI 0.05-0.85), the addition of baseline US results for joints (OR 0.96, 95% CI 0.89-1.04) did not significantly improve the prediction of failure to achieve DAS28 remission (likelihood ratio test, 1.04; p = 0.31). CONCLUSION: In an early RA population, adding baseline ultrasonography of the hands, wrists, and feet to commonly available baseline characteristics did not improve prediction of failure to achieve DAS28 remission at 12 months. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01752309 . Registered on 19 December 2012. PMID- 29382380 TI - Systemic sclerosis associated interstitial lung disease - individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group. AB - BACKGROUND: Interstitial lung disease in systemic sclerosis (SSc-ILD) is a major cause of SSc-related death. Imunosuppressive treatment (IS) is used in patients with SSc for various organ manifestations mainly to ameliorate progression of SSc ILD. Data on everyday IS prescription patterns and clinical courses of lung function during and after therapy are scarce. METHODS: We analysed patients fulfilling American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2013 criteria for SSc-ILD and at least one report of IS. Types of IS, pulmonary function tests (PFT) and PFT courses during IS treatment were evaluated. RESULTS: EUSTAR contains 3778/11,496 patients with SSc-ILD (33%), with IS in 2681/3,778 (71%). Glucocorticoid (GC) monotherapy was prescribed in 30.6% patients with GC combinations plus cyclophosphamide (CYC) (11.9%), azathioprine (AZA) (9.2%), methotrexate (MTX) (8.7%), or mycophenolate mofetil (MMF) (7.3%). Intensive IS (MMF + GC, CYC or CYC + GC) was started in patients with the worst PFTs and ground glass opacifications on imaging. Patients without IS showed slightly less worsening in forced vital capacity (FVC) when starting with FVC 50 75% or >75%. GC showed negative trends when starting with FVC <50%. Regarding diffusing capacity for carbon monoxide (DLCO), negative DLCO trends were found in patients with MMF. CONCLUSIONS: IS is broadly prescribed in SSc-ILD. Clusters of clinical and functional characteristics guide individualised treatment. Data favour distinguished decision-making, pointing to either watchful waiting and close monitoring in the early stages or start of immunosuppressive treatment in moderately impaired lung function. Advantages of specific IS are difficult to depict due to confounding by indication. Data do not support liberal use of GC in SSc-ILD. PMID- 29382381 TI - Genetic polymorphisms of autophagy-related gene 5 (ATG5) rs473543 predict different disease-free survivals of triple-negative breast cancer patients receiving anthracycline- and/or taxane-based adjuvant chemotherapy. AB - BACKGROUND: Autophagy plays a crucial role in chemotherapy resistance of triple negative breast cancer (TNBC). Hence, autophagy-related gene 5 (ATG5), an essential molecule involved in autophagy regulation, is presumably associated with recurrence of TNBC. This study was aimed to investigate the potential influence of single-nucleotide polymorphisms in ATG5 on the disease-free survival (DFS) of early-stage TNBC patients treated with anthracycline- and/or taxane based chemotherapy. METHODS: We genotyped ATG5 SNP rs473543 in a cohort of 316 TNBC patients treated with anthracycline- and/or taxane-based chemotherapy using the sequenom's MassARRAY system. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to analyze the association between ATG5 rs473543 genotypes and the clinical outcome of TNBC patients. RESULTS: Three genotypes, AA, GA, and GG, were detected in the rs473543 of ATG5 gene. The distribution of ATG5 rs473543 genotypes was significantly different between patients with and without recurrence (P = 0.024). Kaplan-Meier survival analysis showed that patients carrying A allele of ATG5 rs473543 had an increased risk of recurrence and shorter DFS compared with those carrying the variant genotype GG in rs473543 (P = 0.034). In addition, after adjusting for clinical factors, multivariate Cox regression analyses revealed that the AA/GA genotype of rs473543 was an independent predictor for DFS (hazard risk [HR], 1.73; 95% confidence interval [CI], 1.04-2.87; P = 0.034). In addition, DFS was shorter in node-negative patients with the presence of A allele (AA/GA) than in those with the absence of A allele (P = 0.027). CONCLUSION: ATG5 rs473543 genotypes may serve as a potential marker for predicting recurrence of early-stage TNBC patients who received anthracycline-and/or taxane-based regimens as adjuvant chemotherapy. PMID- 29382382 TI - Resolution of unilateral sensorineural hearing loss in a pediatric patient with a severe phenotype of Muckle-Wells syndrome treated with Anakinra: a case report and review of the literature. AB - BACKGROUND: Muckle-Wells syndrome (MWS) is a rare auto-inflammatory disease characterized by the presence of recurrent urticaria, deafness and amyloidosis. Progressive sensorineural hearing loss (SNHL) is reported to occur in up to 85% of patients occurring in the second and third decades and as early as the first decade in patients with a more severe phenotype, thus potentially having a significant impact on a child's development. IL-1 inhibitors, such as Anakinra, have been described to improve systemic inflammation, and stabilize or improve hearing status as well. However, complete resolution of hearing loss has been rarely reported. The objective of this article is to highlight the clinical presentation of a pediatric patient with a severe form of MWS and report on the complete resolution of SNHL with the use of Anakinra. CASE PRESENTATION: A 3-year old boy was referred to our hospital to assess for the possibility of MWS given a history of hives and recurrent episodes of fever with a family history of MWS in his mother. Of note, the patient's history was significant for conductive hearing loss, speech delay, as well as recurrent acute otitis media episodes. Genetic analysis was performed and diagnosis of MWS was confirmed due to the presence of a NLRP3 gene mutation. Further work-up demonstrated the presence of papilledema and elevation of systemic inflammatory markers for which Canakinumab was initiated. Despite initiation of this treatment, audiogram evaluation demonstrated a new right-sided SNHL. Lumbar puncture also revealed aseptic meningitis. Canakinumab was eventually discontinued and Anakinra initiated. Within 7 months of treatment with Anakinra at 5 mg/kg sc daily, resolution of the SNHL was observed. With further escalation of the Anakinra dose, there was also complete resolution of the aseptic meningitis. CONCLUSIONS: Progressive hearing loss is a significant finding in patients with MWS. Early screening as well as initiation of Anakinra can lead to complete resolution of SNHL even in a patient with a severe spectrum of MWS. However, as this case demonstrates, longer treatment duration and higher doses of Anakinra may be required to achieve this. PMID- 29382383 TI - Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab. AB - BACKGROUND: Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. CASE PRESENTATION: A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma. CONCLUSION: Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma. PMID- 29382384 TI - Modeling the therapeutic efficacy of NFkappaB synthetic decoy oligodeoxynucleotides (ODNs). AB - BACKGROUND: Transfection of NF kappaB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF kappaB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. RESULTS: In this work, we show how a systems pharmacology model of NF kappaB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF kappaB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates. Both deterministic mass action simulations and stochastic simulations of the systems biology model show that the therapeutic efficacy of synthetic decoy ODNs is inversely correlated with unbinding kinetic rates, nuclease-induced degradation rates and molecular stripping rates, but is positively correlated with dose. We show that the temporal coherence of the stochastic dynamics of NF kappaB regulatory networks is most sensitive to adding NF kappaB synthetic decoy ODNs having unbinding time-scales that are in-resonance with the time-scale of the limit cycle of the network. CONCLUSIONS: The pharmacokinetics/pharmacodynamics (PK/PD) predicted by the systems-level model should provide quantitative guidance for in-depth translational research of optimizing the thermodynamics/kinetic properties of synthetic decoy ODNs. PMID- 29382385 TI - Meeting report of the 2017 KidGen Renal Genetics Symposium. AB - The 2017 KidGen Renal Genetics Symposium was held at the Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, from 6 to 8 December 2017. This meeting addressed clinical, diagnostic, and research aspects of inherited kidney disease. More than 100 clinicians, researchers, and patient representatives attended the conference. The overall goal was to improve the understanding and direction of genomics in renal medicine in Australia and discuss barriers to the use of genomic testing within this area. It also aimed to strengthen collaborations between local, state, and global research and diagnostic and clinical groups. PMID- 29382386 TI - How dislocation and professional anxiety influence readiness for change during the implementation of hospital-based home care for children newly diagnosed with diabetes - an ethnographic analysis of the logic of workplace change. AB - BACKGROUND: In 2013-14, the evidence based care model Hospital-based Home Care for children newly diagnosed with diabetes was implemented at a large paediatric diabetes care facility in the south of Sweden. The first step of the implementation was to promote readiness for change among the professionals within the diabetes team through regular meetings. The aim was to analyse the implicit facilitators and barriers evident on a cultural micro level in discussions during the course of these meetings. What conceptions, ideals and identities might complicate, or facilitate, implementation? METHODS: A case study was conducted during the implementation process. This article draw on ethnographic observations carried out at team meetings (n = 6) during the introductory element of implementation. From a discourse theoretical perspective, the verbal negotiations during these meetings were analysed. RESULTS: Three aspects were significant in order to understand the dislocation during this element of implementation: an epistemological disagreement that challenged the function of information within care practice; a paradoxical understanding of the time-knowledge intersection; and expressions of professional anxiety. More concretely, the professionals exhibited an unwillingness to give up the opportunity to provide structured, age independent information; a resistance against allowing early discharge; and a professional identity formed both by altruistic concern and occupational guardiancy. The findings suggest the necessity of increased awareness of the conceptions and ideals that constitute the basis of a certain professional practice; a deeper understanding of the cultural meaning that influences care practice within a specific logic in order to predict in what way these ideals might be challenged by the implemented evidence. CONCLUSIONS: Our main contribution is the argument that the implemented evidence in itself needs to be examined and problematized from a cultural analytical perspective before initiation in order to be able to actively counter negative connotations and resistance. PMID- 29382387 TI - Hospital costs associated with psychiatric comorbidities: a retrospective study. AB - BACKGROUND: Psychiatric comorbidities are relevant for the diagnostic and therapeutic regimes in somatic hospital care. The main aim of this study was to analyse the association between psychiatric comorbidities and hospital costs per inpatient episode. A further aim was to discuss and address the methodological challenges in the estimation of these outcomes based on retrospective data. METHODS: The study included 338,162 inpatient episodes consecutively discharged between 2011 and 2014 at a German university hospital. We used detailed resource use data to calculate day-specific hospital costs. We adjusted analyses for sex, age, somatic comorbidities and main diagnoses. We addressed potential time related bias in retrospective diagnosis data with sensitivity analyses. RESULTS: Psychiatric comorbidities were associated with an increase in hospital costs per episode of 40% and an increase of reimbursement per episode of 28%, representing marginal effects of 1344 ? and 1004 ?, respectively. After controlling for length of stay, sensitivity analyses provided a lower bound increase in daily costs and reimbursement of 207 ? and 151 ?, respectively. CONCLUSION: If differences in hospital costs between patient groups are not adequately accounted for in DRG systems, perverse incentives are created that can reduce the efficiency of care. Therefore, we suggest intensifying the inclusion of psychiatric comorbidities in the German DRG system. Future research should investigate the appropriate inclusion of psychiatric comorbidities in other health care systems' payment schemes. PMID- 29382388 TI - Multi-country assessment of residual bio-efficacy of insecticides used for indoor residual spraying in malaria control on different surface types: results from program monitoring in 17 PMI/USAID-supported IRS countries. AB - BACKGROUND: Indoor residual spraying (IRS) is the application of insecticide to the interior walls of household structures that often serve as resting sites for mosquito vectors of malaria. Human exposure to malaria vectors is reduced when IRS involves proper application of pre-determined concentrations of the active ingredient specific to the insecticide formulation of choice. The impact of IRS can be affected by the dosage of insecticide, spray coverage, vector behavior, vector susceptibility to insecticides, and the residual efficacy of the insecticide applied. This report compiles data on the residual efficacy of insecticides used in IRS campaigns implemented by the United States President's Malaria Initiative (PMI)/United States Agency for International Development (USAID) in 17 African countries and compares observed length of efficacy to ranges proposed in World Health Organization (WHO) guidelines. Additionally, this study provides initial analysis on variation of mosquito mortality depending on the surface material of sprayed structures, country spray program, year of implementation, source of tested mosquitoes, and type of insecticide. METHODS: Residual efficacy of the insecticides used for PMI/USAID-supported IRS campaigns was measured in Benin, Burkina Faso, Ethiopia, Ghana, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia and Zimbabwe. The WHO cone bioassay tests were used to assess the mortality rate of mosquitoes exposed to insecticide-treated mud, wood, cement, and other commonly used housing materials. Baseline tests were performed within weeks of IRS application and follow-up tests were continued until the mortality of exposed mosquitoes dropped below 80% or the program monitoring period ended. Residual efficacy in months was then evaluated with respect to WHO guidelines that provide suggested ranges of residual efficacy for insecticide formulations recommended for use in IRS. Where the data allowed, direct comparisons of mosquito mortality rates were then made to determine any significant differences when comparing insecticide formulation, country, year, surface type, and the source of the mosquitoes used in testing. RESULTS: The residual efficacy of alpha-cypermethrin ranged from 4 to 10 months (average = 6.4 months), with no reported incidents of underperformance when compared to the efficacy range provided in WHO guidelines. Deltamethrin residual efficacy results reported a range of 1 to 10 months (average = 4.9 months), with two instances of underperformance. The residual efficacy of bendiocarb ranged from 2 weeks to 7 months (average = 2.8 months) and failed to achieve proposed minimum efficacy on 14 occasions. Lastly, long-lasting pirimiphos-methyl efficacy ranged from 2 months to 9 months (average = 5.3 months), but reported 13 incidents of underperformance. CONCLUSIONS: Much of the data used to determine application rate and expected efficacy of insecticides approved for use in IRS programs are collected in controlled laboratory or pilot field studies. However, the generalizability of the results obtained under controlled conditions are limited and unlikely to account for variation in locally sourced housing materials, climate, and the myriad other factors that may influence the bio-efficacy of insecticides. Here, data are presented that confirm the variation in residual efficacy observed when monitoring household surfaces sprayed during PMI/USAID-supported IRS campaigns. All insecticides except alpha cypermethrin showed evidence of failing to meet the minimum range of residual efficacy proposed in WHO criteria at least once. However, this initial effort in characterizing program-wide insecticide bio-efficacy indicates that some insecticides, such as bendiocarb and pirimiphos-methyl, may be vulnerable to variations in the local environment. Additionally, the comparative analysis performed in this study provides evidence that mosquito mortality rates differ with respect to factors including: the types of insecticide sprayed, surface material, geographical location, year of spraying, and tested mosquitoes. It is, therefore, important to locally assess the residual efficacy of insecticides on various surfaces to inform IRS programming. PMID- 29382389 TI - The political dimension of sexual rights. : Commentary on the paper by Chandra Mouli et al.: a never-before opportunity to strengthen investment and action on adolescent contraception, and what we must do to make full use of it. AB - BACKGROUND: The recent commentary article in this journal by Chandra-Mouli et al. speaks of a never-before opportunity to strengthen investment and action on adolescent contraception. We endorse the positive 'can-do' tone of the article, but noticed that at least four issues, which in our view are crucial, merit a comment. MAIN BODY: First of all, the article suggests that there is some sort of shared interest, based on a presumed global consensus around the use of contraceptives by adolescents - which is not the case: sexual rights are controversial. Secondly, for real progress in adolescent contraception to occur, we believe it is critical to thoroughly investigate and mention the factors, including political ones, that would need to be overcome. Thirdly, new avenues need to be explored that allow for accurate and positive teaching of adolescents about contraception in socio-cultural and political environments that are ambivalent about the issue. Fourthly, barriers at the global level that we already know of should not be silenced. There is sufficient evidence to call upon donors and international agencies to choose position and stop obstructing women's - including young women's - access to a broad range of contraceptives. The 'She Decides' movement is a heartening example. CONCLUSION: It is crucial to acknowledge the political dimension of sexual rights. It requires solutions not only at national levels, but also at the global level. PMID- 29382390 TI - Study design and the estimation of the size of key populations at risk of HIV: lessons from Viet Nam. AB - BACKGROUND: Estimation of the size of populations at risk of HIV is a key activity in the surveillance of the HIV epidemic. The existing framework for considering future research needs may provide decision-makers with a basis for a fair process of deciding on the methods of the estimation of the size of key populations at risk of HIV. This study explores the extent to which stakeholders involved with population size estimation agree with this framework, and thus, the study updates the framework. METHODS: We conducted 16 in-depth interviews with key informants from city and provincial governments, NGOs, research institutes, and the community of people at risk of HIV. Transcripts were analyzed and reviewed for significant statements pertaining to criteria. Variations and agreement around criteria were analyzed, and emerging criteria were validated against the existing framework. RESULTS: Eleven themes emerged which are relevant to the estimation of the size of populations at risk of HIV in Viet Nam. Findings on missing criteria, inclusive participation, community perspectives and conflicting weight and direction of criteria provide insights for an improved framework for the prioritization of population size estimation methods. CONCLUSIONS: The findings suggest that the exclusion of community members from decision-making on population size estimation methods in Viet Nam may affect the validity, use, and efficiency of the evidence generated. However, a wider group of decision-makers, including community members among others, may introduce diverse definitions, weight and direction of criteria. Although findings here may not apply to every country with a transitioning economy or to every emerging epidemic, the principles of fair decision-making, value of community participation in decision-making and the expected challenges faced, merit consideration in every situation. PMID- 29382392 TI - Serum DNA integrity index as a potential molecular biomarker in endometrial cancer. AB - BACKGROUND: Circulating cell-free DNA (cfDNA) and its integrity index may represent a rapid and noninvasive "liquid biopsy" biomarker, which gives important complementary information for diagnosis, prognosis, and treatment stratification in cancer patients. The aim of our study was to evaluate the possible role of cfDNA and its integrity index as a complementary tool for endometrial cancer (EC) management. METHODS: Alu-quantitative real-time PCR (qPCR) analysis wasprformed on 60 serum samples from preoperative EC patients randomly recruited. Both cfDNA content and DNA integrity index were measured by qPCR-Alu115 (representing total cfDNA) and qPCR-Alu247 (corresponding to high molecular weight DNA) and correlated with clinicopathologic characteristics. Lymphovascular space invasion (LVSI) was detected by hematoxylin and eosin staining. In case of doubt, LVSI status was further evaluate by immunohistochemistry using anti-CD31 and anti-CD34 antibodies. RESULTS: Total cfDNA content significantly increases in high grade EC. A significant decrease of DNA integrity index was detected in the subset of hypertensive and obese high grade EC. Serum DNA integrity was higher in samples with LVSI. The ordinal regression analysis predicted a significant correlation between decreased integrity index values and hypertension specifically in tumors presenting LVSI. CONCLUSIONS: Our study supports the utility of serum DNA integrity index as a noninvasive molecular biomarker in EC. We show that a correlation analysis between cfDNA quantitative and qualitative content and clinicopathologic features, such as blood pressure level, body mass index (BMI) and LVSI status, could represent a potential predictive signature to help stratification approaches in EC. PMID- 29382391 TI - Treatment of Middle East Respiratory Syndrome with a combination of lopinavir ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. AB - BACKGROUND: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-beta1b (IFN-beta1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-beta1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. DISCUSSION: This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24 2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016. PMID- 29382393 TI - Modified double patch repair with infarct exclusion technique for ventricular septal perforation: a case study. AB - BACKGROUND: Ventricular septal perforation (VSP) after acute myocardial infarction (AMI) is accompanied by the worsening of rapid hemodynamics, resulting in a poor prognosis. In our department, infarct lesions are preoperatively detected with electrocardiogram (ECG)-synchronized contrast computed tomography, and the scope of approach and exclusion is determined. Furthermore, to effectively prevent a residual shunt, modified double patch repair and infarct exclusion techniques were used in combination to preserve left ventricular (LV) function. This method is reported because it considers both techniques as a surgical procedure that can be accomplished relatively easily and simultaneously. CASE PRESENTATION: We targeted two consecutive VSP patients who underwent this procedure. It took an average of 1 day from the onset of VSP to surgery. We performed double patch and infarct exclusion for VSP using bovine pericardium via an LV incision. Two patches were marked with a skin pen to anastomose eight mattresses equally. In addition, a one piece-coupled patch was made for infarct exclusion. The two patients were extubated on the day after surgery and intra aortic balloon pump assistance was also withdrawn. Without perioperative complications, they could leave the intensive care unit after 6.5 days on average. Early postoperative ECG and magnetic resonance angiography showed good LV wall contraction, except at the infarcted area, with no evidence of a residual shunt. CONCLUSION: The modified double patch repair with infarct exclusion technique is more effective for preventing a residual shunt and maintaining postoperative cardiac function than either of the techniques alone. PMID- 29382394 TI - Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study. AB - BACKGROUND: The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). METHODS: Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa. RESULTS: A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC <= 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis. CONCLUSIONS: We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing. TRIAL REGISTRATION: Clincialtrials.gov, NCT02287493 . PMID- 29382395 TI - Mathematical modeling of tumor-associated macrophage interactions with the cancer microenvironment. AB - BACKGROUND: Immuno-oncotherapy has emerged as a promising means to target cancer. In particular, therapeutic manipulation of tumor-associated macrophages holds promise due to their various and sometimes opposing roles in tumor progression. It is established that M1-type macrophages suppress tumor progression while M2 types support it. Recently, Tie2-expressing macrophages (TEM) have been identified as a distinct sub-population influencing tumor angiogenesis and vascular remodeling as well as monocyte differentiation. METHODS: This study develops a modeling framework to evaluate macrophage interactions with the tumor microenvironment, enabling assessment of how these interactions may affect tumor progression. M1, M2, and Tie2 expressing variants are integrated into a model of tumor growth representing a metastatic lesion in a highly vascularized organ, such as the liver. Behaviors simulated include M1 release of nitric oxide (NO), M2 release of growth-promoting factors, and TEM facilitation of angiogenesis via Angiopoietin-2 and promotion of monocyte differentiation into M2 via IL-10. RESULTS: The results show that M2 presence leads to larger tumor growth regardless of TEM effects, implying that immunotherapeutic strategies that lead to TEM ablation may fail to restrain growth when the M2 represents a sizeable population. As TEM pro-tumor effects are less pronounced and on a longer time scale than M1-driven tumor inhibition, a more nuanced approach to influence monocyte differentiation taking into account the tumor state (e.g., under chemotherapy) may be desirable. CONCLUSIONS: The results highlight the dynamic interaction of macrophages within a growing tumor, and, further, establish the initial feasibility of a mathematical framework that could longer term help to optimize cancer immunotherapy. PMID- 29382396 TI - Higher cut-off serum procalcitonin level for sepsis diagnosis in metastatic solid tumor patients. AB - OBJECTIVE: The current study aimed to know procalcitonin levels in patients with metastatic tumor, and to discover the cut-off point for sepsis in this population. A cross-sectional study was conducted with patients with solid tumor. Sepsis and systemic inflammation response syndrome (SIRS) were identified using clinical, laboratory, and microbiological criteria. The cut-off point was determined using receiver operating characteristic (ROC) curve. RESULTS: A total of 112 subjects enrolled in this study, 51% male, mean age 47.9 +/- 12.47 years. Among 71 (63.4%) patients who had metastasis, 36 (32.1%) had sepsis and 6 (5.3%) experienced SIRS. In the absence of sepsis, the procalcitonin levels were significantly higher in patients with metastatic tumor compared to those without [0.25 ng/mL (0.07-1.76) vs. 0.09 ng/mL (0.03-0.54); p < 0.001]. The ROC curve showed that levels of procalcitonin for sepsis in metastatic solid tumors were in the area under curve (AUC) [0.956; CI 0.916-0.996]. Cut-off point of procalcitonin for sepsis was 1.14 ng/mL, Sn 86%, and Sp 88%. Thus, the results show that metastatic tumor affects the patients' procalcitonin level, even in the absence of sepsis. The cut-off point of procalcitonin level for diagnosing sepsis in the meta-static solid tumor was higher compared to the standard value. PMID- 29382397 TI - Exploiting graph kernels for high performance biomedical relation extraction. AB - BACKGROUND: Relation extraction from biomedical publications is an important task in the area of semantic mining of text. Kernel methods for supervised relation extraction are often preferred over manual feature engineering methods, when classifying highly ordered structures such as trees and graphs obtained from syntactic parsing of a sentence. Tree kernels such as the Subset Tree Kernel and Partial Tree Kernel have been shown to be effective for classifying constituency parse trees and basic dependency parse graphs of a sentence. Graph kernels such as the All Path Graph kernel (APG) and Approximate Subgraph Matching (ASM) kernel have been shown to be suitable for classifying general graphs with cycles, such as the enhanced dependency parse graph of a sentence. In this work, we present a high performance Chemical-Induced Disease (CID) relation extraction system. We present a comparative study of kernel methods for the CID task and also extend our study to the Protein-Protein Interaction (PPI) extraction task, an important biomedical relation extraction task. We discuss novel modifications to the ASM kernel to boost its performance and a method to apply graph kernels for extracting relations expressed in multiple sentences. RESULTS: Our system for CID relation extraction attains an F-score of 60%, without using external knowledge sources or task specific heuristic or rules. In comparison, the state of the art Chemical-Disease Relation Extraction system achieves an F-score of 56% using an ensemble of multiple machine learning methods, which is then boosted to 61% with a rule based system employing task specific post processing rules. For the CID task, graph kernels outperform tree kernels substantially, and the best performance is obtained with APG kernel that attains an F-score of 60%, followed by the ASM kernel at 57%. The performance difference between the ASM and APG kernels for CID sentence level relation extraction is not significant. In our evaluation of ASM for the PPI task, ASM performed better than APG kernel for the BioInfer dataset, in the Area Under Curve (AUC) measure (74% vs 69%). However, for all the other PPI datasets, namely AIMed, HPRD50, IEPA and LLL, ASM is substantially outperformed by the APG kernel in F-score and AUC measures. CONCLUSIONS: We demonstrate a high performance Chemical Induced Disease relation extraction, without employing external knowledge sources or task specific heuristics. Our work shows that graph kernels are effective in extracting relations that are expressed in multiple sentences. We also show that the graph kernels, namely the ASM and APG kernels, substantially outperform the tree kernels. Among the graph kernels, we showed the ASM kernel as effective for biomedical relation extraction, with comparable performance to the APG kernel for datasets such as the CID-sentence level relation extraction and BioInfer in PPI. Overall, the APG kernel is shown to be significantly more accurate than the ASM kernel, achieving better performance on most datasets. PMID- 29382398 TI - Comparison of Unmanned Aerial Vehicle Technology Versus Standard Practice in Identification of Hazards at a Mass Casualty Incident Scenario by Primary Care Paramedic Students. AB - : IntroductionThe proliferation of unmanned aerial vehicles (UAV) has the potential to change the situational awareness of incident commanders allowing greater scene safety. The aim of this study was to compare UAV technology to standard practice (SP) in hazard identification during a simulated multi-vehicle motor collision (MVC) in terms of time to identification, accuracy and the order of hazard identification. METHODS: A prospective observational cohort study was conducted with 21 students randomized into UAV or SP group, based on a MVC with 7 hazards. The UAV group remained at the UAV ground station while the SP group approached the scene. After identifying hazards the time and order was recorded. RESULTS: The mean time (SD, range) to identify the hazards were 3 minutes 41 seconds (1 minute 37 seconds, 1 minute 48 seconds-6 minutes 51 seconds) and 2 minutes 43 seconds (55 seconds, 1 minute 43 seconds-4 minutes 38 seconds) in UAV and SP groups corresponding to a mean difference of 58 seconds (P=0.11). A non parametric permutation test showed a significant (P=0.04) difference in identification order. CONCLUSION: Both groups had 100% accuracy in hazard identification with no statistical difference in time for hazard identification. A difference was found in the identification order of hazards. (Disaster Med Public Health Preparedness. 2018;12:631-634). PMID- 29382399 TI - Triage by Resource Allocation for INpatients: A Novel Disaster Triage Tool for Hospitalized Pediatric Patients. AB - OBJECTIVE: To develop a disaster triage tool for the evacuation of hospitalized neonatal and pediatric populations. METHODS: We expanded an existing neonatal disaster triage tool for the evacuation of a children's hospital. We assessed inpatients using bedside visual assessments and chart review to categorize patients transport level based on local emergency medical services protocols and expert opinion. The tool was refined by using multiple Plan Do Study Act cycles. Primary outcome was the number of each level of transport required for hospital evacuation. Secondary outcome was improved efficiency of obtaining information about specific transport needs for evacuation. RESULTS: We evaluated 1382 patients both visually and through electronic chart review over 10 random days. Accordance between visual assessment and electronic chart review reached 96.3%. During a 2 hour statewide disaster drill, no hospital units completed self assessed transport needs for their patients; a single nurse used Triage by Resource Allocation in INpatients to determine transportation needs in less than 1 hour. (Disaster Med Public Health Preparedness. 2018;page 1 of 5). PMID- 29382400 TI - Comparative Antimicrobial Efficacy of Two Hand Sanitizers in Intensive Care Units Common Areas: A Randomized, Controlled Trial. AB - OBJECTIVE Contaminated hands of healthcare workers (HCWs) are an important source of transmission of healthcare-associated infections. Alcohol-based hand sanitizers, while effective, do not provide sustained antimicrobial activity. The objective of this study was to compare the immediate and persistent activity of 2 hand hygiene products (ethanol [61% w/v] plus chlorhexidine gluconate [CHG; 1.0% solution] and ethanol only [70% v/v]) when used in an intensive care unit (ICU). DESIGN Prospective, randomized, double-blinded, crossover study SETTING Three ICUs at a large teaching hospital PARTICIPANTS In total, 51 HCWs involved in direct patient care were enrolled in and completed the study. METHODS All HCWs were randomized 1:1 to either product. Hand prints were obtained immediately after the product was applied and again after spending 4-7 minutes in the ICU common areas prior to entering a patient room or leaving the area. The numbers of aerobic colony-forming units (CFU) were compared for the 2 groups after log transformation. Each participant tested the alternative product after a 3-day washout period. RESULTS On bare hands, use of ethanol plus CHG was associated with significantly lower recovery of aerobic CFU, both immediately after use (0.27 +/- 0.05 and 0.88 +/- 0.08 log10 CFU; P = .035) and after spending time in ICU common areas (1.81 +/- 0.07 and 2.17 +/- 0.05 log10 CFU; P<.0001). Both the antiseptics were well tolerated by HCWs. CONCLUSIONS In comparison to the ethanol only product, the ethanol plus CHG sanitizer was associated with significantly lower aerobic bacterial counts on hands of HCWs, both immediately after use and after spending time in ICU common areas. CLINICAL TRIAL IDENTIFIER Clinicaltrials.gov identifier NCT02258412 Infect Control Hosp Epidemiol 2018;39:267-271. PMID- 29382401 TI - Communication barrier in family linked to increased risks for food insecurity among deaf people who use American Sign Language. AB - OBJECTIVE: Food security is defined as being able to access enough food that will help maintain an active, healthy lifestyle for those living in a household. While there are no studies on food security issues among deaf people, research shows that communication barriers early in life are linked to poor physical and mental health outcomes. Childhood communication barriers may also risk later food insecurity. Design/Setting/Subjects A single food security screener question found to have 82 % sensitivity in classifying families who are at risk for food insecurity was taken from the six-item US Household Food Security Survey Module. Questions related to food insecurity screener, depression diagnosis and retrospective communication experience were translated to American Sign Language and then included in an online survey. Over 600 deaf adult signers (18-95 years old) were recruited across the USA. RESULTS: After adjusting for covariates, deaf adults who reported being able to understand little to none of what their caregiver said during their formative years were about five times more likely to often experience difficulty with making food last or finding money to buy more food, and were about three times more likely to sometimes experience this difficulty, compared with deaf adults who reported to being able to understand some to all of what their caregiver said. CONCLUSIONS: Our results have highlighted a marked risk for food insecurity and related outcomes among deaf people. This should raise serious concern among individuals who have the potential to effect change in deaf children's access to communication. PMID- 29382402 TI - Associations of physical activity with anxiety symptoms and status: results from The Irish longitudinal study on ageing. AB - AIMS: Anxiety is debilitating and associated with numerous mental and physical comorbidities. There is a need to identify and investigate low-risk prevention and treatment strategies. Therefore, the purpose of this study was to investigate cross-sectional and longitudinal associations between different volumes of moderate-to-vigorous physical activity (PA) and anxiety symptoms and status among older adults in Ireland. METHODS: Participants (n = 4175; 56.8% female) aged ?50 years completed the International PA Questionnaire (IPAQ) at baseline, and the anxiety subscale of the Hospital Anxiety and Depression Scale at baseline and follow-up (2009-2013). Participants were classified according to meeting World Health Organisation PA guidelines, and divided into IPAQ categories. Respondents without anxiety at baseline (n = 3165) were included in prospective analyses. Data were analysed in 2017. RESULTS: Anxiety symptoms were significantly higher among females than males (p < 0.001). Models were adjusted for age, sex, waist circumference, social class, smoking status and pain. In cross-sectional analyses, meeting PA guidelines was associated with 9.3% (OR = 0.91, 95% confidence interval 0.78-1.06) lower odds of anxiety. Compared with the inactive group, the minimally- and very-active groups were associated with 8.4% (OR = 0.92, 0.76-1.10) and 18.8% (OR = 0.81, 0.67-0.98) lower odds of anxiety, respectively. In prospective analyses, meeting guidelines was associated with 6.3% (OR = 0.94, 0.63-1.40) reduced odds of anxiety. Compared with the inactive group, the minimally and very-active groups were associated with 43.5% (OR = 1.44, 0.89-2.32) increased, and 4.3% (OR = 0.96, 0.56-1.63) reduced odds of anxiety. The presence of pain, included in models as a covariate, was associated with a 108.7% (OR = 2.09, 1.80-2.42) increase in odds of prevalent anxiety, and a 109.7% (OR = 2.10, 1.41-3.11) increase in odds of incident anxiety. CONCLUSION: High volumes of PA are cross-sectionally associated with lower anxiety symptoms and status, with a potential dose-response apparent. However, significant associations were not observed in prospective analyses. The low absolute number of incident anxiety cases (n = 109) potentially influenced these findings. Further, as older adults may tend to experience and/or report more somatic anxiety symptoms, and the HADS focuses primarily on cognitive symptoms, it is plausible that the HADS was not an optimal measure of anxiety symptoms in the current population. PMID- 29382403 TI - Involuntary psychiatric hospitalisation, stigma stress and recovery: a 2-year study. AB - AIMS: Compulsory admission can be experienced as devaluing and stigmatising by people with mental illness. Emotional reactions to involuntary hospitalisation and stigma-related stress may affect recovery, but longitudinal data are lacking. We, therefore, examined the impact of stigma-related emotional reactions and stigma stress on recovery over a 2-year period. METHOD: Shame and self-contempt as emotional reactions to involuntary hospitalisation, stigma stress, self-stigma and empowerment, as well as recovery were assessed among 186 individuals with serious mental illness and a history of recent involuntary hospitalisation. RESULTS: More shame, self-contempt and stigma stress at baseline were correlated with increased self-stigma and reduced empowerment after 1 year. More stigma stress at baseline was associated with poor recovery after 2 years. In a longitudinal path analysis more stigma stress at baseline predicted poorer recovery after 2 years, mediated by decreased empowerment after 1 year, controlling for age, gender, symptoms and recovery at baseline. CONCLUSION: Stigma stress may have a lasting detrimental effect on recovery among people with mental illness and a history of involuntary hospitalisation. Anti-stigma interventions that reduce stigma stress and programs that enhance empowerment could improve recovery. Future research should test the effect of such interventions on recovery. PMID- 29382404 TI - Indexes of Caring for Elderly in Earthquakes According to the Iranian Experience: A Qualitative Study. AB - OBJECTIVE: The elderly are especially susceptible to death and injury in disasters. This study aimed to identify indexes of caring for elderly people in an earthquake according to the Iranian experience. METHODS: This qualitative study was conducted during 2014-2016 by use of the content analysis technique. Data were collected through individual deep interviews with the elderly and people with experience providing services to the elderly during earthquakes in an urban area of Iran. The data were analyzed by use of the Graneheim and Lundman method. RESULTS: Seven categories emerged: vulnerability of elderly people, physiological indexes, psychological indexes, economic indexes, religious and spiritual indexes, health indexes, and security indexes. There were 3 uncategorized issues: "There is no specific protocol for the elderly," "The need to design plans based on age care," and "Aid organizations." CONCLUSIONS: Implementing a comprehensive plan would not only save lives but decrease suffering and enable effective use of available resources. Due to the crucial role of the prehospital care system in disasters, there is a need for further investigation based on the results of this study to develop strategies for improving the system. (Disaster Med Public Health Preparedness. 2018;12:493-501). PMID- 29382405 TI - Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia. AB - BACKGROUND: Neuromuscular disorders are a phenotypically and genotypically diverse group of diseases that can be difficult to diagnose accurately because of overlapping clinical features and nonspecific muscle pathology. Next-generation sequencing (NGS) is a high-throughput technology that can be used as a more time- and cost-effective tool for identifying molecular diagnoses for complex genetic conditions, such as neuromuscular disorders. METHODS: One hundred and sixty-nine patients referred to a Canadian neuromuscular clinic for evaluation of possible muscle disease were screened with an NGS panel of muscular dystrophy-associated genes. Patients were categorized by the reason of referral (1) muscle weakness (n=135), (2) recurrent episodes of rhabdomyolysis (n=18), or (3) idiopathic hyperCKemia (n=16). RESULTS: Pathogenic and likely pathogenic variants were identified in 36.09% of patients (61/169). The detection rate was 37.04% (50/135) in patients with muscle weakness, 33.33% (6/18) with rhabdomyolysis, and 31.25% (5/16) in those with idiopathic hyperCKemia. CONCLUSIONS: This study shows that NGS can be a useful tool in the molecular workup of patients seen in a neuromuscular clinic. Evaluating the utility of large panels of a muscle disease specific NGS panel to investigate the genetic susceptibilities of rhabdomyolysis and/or idiopathic hyperCKemia is a relatively new field. Twenty-eight of the pathogenic and likely pathogenic variants reported here are novel and have not previously been associated with disease. PMID- 29382406 TI - Temporal Relationship Between Healthcare-Associated and Nonhealthcare-Associated Norovirus Outbreaks and Google Trends Data in the United States. AB - Healthcare-associated norovirus outbreaks increase later but have a more pronounced seasonality than nonhealthcare norovirus outbreaks. Healthcare associated norovirus outbreaks had higher correlation with Google Trends activity than nonhealthcare outbreaks (R2=0.68 vs 0.39). Google Trends data may have the potential to supplement existing norovirus surveillance due to its real-time availability. Infect Control Hosp Epidemiol 2018;39:355-358. PMID- 29382407 TI - Changes in cannabis potency and first-time admissions to drug treatment: a 16 year study in the Netherlands. AB - BACKGROUND: The number of people entering specialist drug treatment for cannabis problems has increased considerably in recent years. The reasons for this are unclear, but rising cannabis potency could be a contributing factor. METHODS: Cannabis potency data were obtained from an ongoing monitoring programme in the Netherlands. We analysed concentrations of delta-9-tetrahydrocannabinol (THC) from the most popular variety of domestic herbal cannabis sold in each retail outlet (2000-2015). Mixed effects linear regression models examined time dependent associations between THC and first-time cannabis admissions to specialist drug treatment. Candidate time lags were 0-10 years, based on normative European drug treatment data. RESULTS: THC increased from a mean (95% CI) of 8.62 (7.97-9.27) to 20.38 (19.09-21.67) from 2000 to 2004 and then decreased to 15.31 (14.24-16.38) in 2015. First-time cannabis admissions (per 100 000 inhabitants) rose from 7.08 to 26.36 from 2000 to 2010, and then decreased to 19.82 in 2015. THC was positively associated with treatment entry at lags of 0-9 years, with the strongest association at 5 years, b = 0.370 (0.317-0.424), p < 0.0001. After adjusting for age, sex and non-cannabis drug treatment admissions, these positive associations were attenuated but remained statistically significant at lags of 5-7 years and were again strongest at 5 years, b = 0.082 (0.052-0.111), p < 0.0001. CONCLUSIONS: In this 16-year observational study, we found positive time-dependent associations between changes in cannabis potency and first-time cannabis admissions to drug treatment. These associations are biologically plausible, but their strength after adjustment suggests that other factors are also important. PMID- 29382408 TI - Hiding in Plain Sight: Contaminated Ice Machines Are a Potential Source for Dissemination of Gram-Negative Bacteria and Candida Species in Healthcare Facilities. AB - BACKGROUND Contaminated ice machines have been linked to transmission of pathogens in healthcare facilities. OBJECTIVE To determine the frequency and sites of contamination of ice machines in multiple healthcare facilities and to investigate potential mechanisms of microorganism dispersal from contaminated ice machines to patients. DESIGN Multicenter culture survey and simulation study. SETTING The study took place in 5 hospitals and 2 nursing homes in northeastern Ohio. METHODS We cultured multiple sites on ice machines from patient care areas. To investigate potential mechanisms of microbial dispersal from contaminated ice machines, we observed the use of ice machines and conducted simulations using a fluorescent tracer and cultures. RESULTS Samples from 64 ice machines in the 5 hospitals and 2 nursing homes (range, 3-16 per facility) were cultured. Gram negative bacilli and/or Candida spp were recovered from 100% of drain pans, 52% of ice and/or water chutes, and 72% of drain-pan grilles. During the operation of ice machines, ice often fell through the grille, resulting in splattering, with dispersal of contaminated water from the drain pan to the drain-pan grille, cups, and the hands of those using the ice machine. Contamination of the inner surface of the ice chute resulted in contamination of ice cubes exiting the chute. CONCLUSIONS Our findings demonstrate that ice machines in healthcare facilities are often contaminated with gram-negative bacilli and Candida species, and provide a potential mechanism by which these organisms may be dispersed. Effective interventions are needed to reduce the risk of dissemination of pathogenic organisms from ice machines. Infect Control Hosp Epidemiol 2018;39:253 258. PMID- 29382409 TI - Exploring the Role of the Bedside Nurse in Antimicrobial Stewardship: Survey Results From Five Acute-Care Hospitals. PMID- 29382410 TI - Influence of Ligula intestinalis plerocercoids (Cestoda: Diphyllobothriidea) on the occurrence of eyeflukes in roach (Rutilus rutilus) from a lake in south-east England. AB - Vertebrate hosts commonly harbour concurrent infections of different helminth species which may interact with each other in a synergistic, antagonistic or negligible manner. Direct interactions between helminths that share a common site in the host have been regularly reported, but indirect interactions between species that occur in different sites are rarely described, especially in fish hosts. Plerocercoids of Ligula intestinalis are common infections of the peritoneal (body) cavity of roach (Rutilus rutilus) in freshwater habitats. These larval cestodes can cause extensive systemic pathologies to the fish host, which in turn may alter its susceptibility as a target host for other helminth species. The present study, using an existing dataset, investigates the influence of L. intestinalis (ligulosis) on frequently occurring eyefluke infections in roach sampled from a lake in south-east England. The occurrence of two species of eyefluke (Diplostomum sp. and Tylodelphys sp.) in the roach population demonstrated no significant levels of interaction with each other. The prevalence but not mean intensity or abundance of Diplostomum sp. was significantly increased in ligulosed roach, while the incidence of Tylodelphys sp. remained unchanged. Analyses of bilateral asymmetry in the occurrence of eyeflukes in left and right eyes of infected fish demonstrate that Tylodelphys sp. shows significant asymmetry in non-ligulosed roach, which is not replicated in ligulosed individuals. In contrast, Diplostomum sp. shows no evidence of asymmetry in either ligulosed or non-ligulosed fish. PMID- 29382411 TI - The epidemiology of trichinellosis in the Arctic territories of a Far Eastern District of the Russian Federation. AB - Trichinellosis, a zoonotic disease caused by nematodes of the genus Trichinella, is still a public health concern in the Arctic. The aims of this study were to investigate the seroprevalence of anti-Trichinella IgG in aboriginal peoples of two settlements in the Chukotka Autonomous Okrug (Russian Federation) on the Arctic coast of the Bering Sea, and to evaluate the survival of Trichinella nativa larvae in local fermented and frozen meat products. A seroprevalence of 24.3% was detected in 259 people tested by an enzyme-linked immunosorbent assay (ELISA). The highest prevalence was detected among people who consumed traditional local foods made from the meat of marine mammals. Trichinella nativa larvae were found to survive for up to 24 months in a fermented and frozen marine mammal meat product called kopalkhen. Since the T. nativa life cycle can be completed in the absence of humans, it can be expected to persist in the environment and therefore remain a cause of morbidity in the human populations living in Arctic regions. PMID- 29382413 TI - Persistence of schistosomal transmission linked to the Cavu river in southern Corsica since 2013. AB - Seven cases of urogenital schistosomiasis occurred in Corsica in 2015 and 2016. The episodes were related to exposure to the same river and involved the same parasite strain as an outbreak with 106 cases in summer 2013. The connection calls for further investigations on the presence of an animal reservoir and the survival of infested snails during winter. However, recontamination of the river from previously infected bathers remains the most likely hypothesis. PMID- 29382412 TI - Review of Cryptosporidium and Giardia in the eastern part of Europe, 2016. AB - IntroductionThis paper reviews the current knowledge and understanding of Cryptosporidium spp. and Giardia spp. in humans, animals and the environment in 10 countries in the eastern part of Europe: Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Latvia, Poland, Romania, Serbia and Slovenia. Methods: Published scientific papers and conference proceedings from the international and local literature, official national health service reports, national databases and doctoral theses in local languages were reviewed to provide an extensive overview on the epidemiology, diagnostics and research on these pathogens, as well as analyse knowledge gaps and areas for further research. Results:Cryptosporidium spp. and Giardia spp. were found to be common in eastern Europe, but the results from different countries are difficult to compare because of variations in reporting practices and detection methodologies used. Conclusion: Upgrading and making the diagnosis/detection procedures more uniform is recommended throughout the region. Public health authorities should actively work towards increasing reporting and standardising reporting practices as these prerequisites for the reported data to be valid and therefore necessary for appropriate control plans. PMID- 29382414 TI - Local amplification of highly pathogenic avian influenza H5N8 viruses in wild birds in the Netherlands, 2016 to 2017. AB - IntroductionHighly pathogenic avian influenza (HPAI) viruses of subtype H5N8 were re-introduced into the Netherlands by late 2016, after detections in south-east Asia and Russia. This second H5N8 wave resulted in a large number of outbreaks in poultry farms and the deaths of large numbers of wild birds in multiple European countries. Methods: Here we report on the detection of HPAI H5N8 virus in 57 wild birds of 12 species sampled during active (32/5,167) and passive (25/36) surveillance activities, i.e. in healthy and dead animals respectively, in the Netherlands between 8 November 2016 and 31 March 2017. Moreover, we further investigate the experimental approach of wild bird serology as a contributing tool in HPAI outbreak investigations. Results: In contrast to the first H5N8 wave, local virus amplification with associated wild bird mortality has occurred in the Netherlands in 2016/17, with evidence for occasional gene exchange with low pathogenic avian influenza (LPAI) viruses. Discussion: These apparent differences between outbreaks and the continuing detections of HPAI viruses in Europe are a cause of concern. With the current circulation of zoonotic HPAI and LPAI virus strains in Asia, increased understanding of the drivers responsible for the global spread of Asian poultry viruses via wild birds is needed. PMID- 29382415 TI - [Fasudil improves cognition of APP/PS1 transgenic mice via inhibiting the activation of microglia and shifting microglia phenotypes from M1 to M2]. AB - Objective To examine the regulatory effects of Rho kinase inhibitor fasudil on cognition and microglia polarization in APP/PS1 transgenic (APP/PS1 Tg) mice, a widely used model of Alzheimer's disease (AD). Methods Male APP/PS1 Tg mice at 8 months of age were randomly divided into two groups: Fasudil (25 mg/kg) and saline, i.p., once daily for 2 months; age- and gender-matched wild type (WT) mice without treatment were used as the controls. The Morris water maze (MWM) test was applied to examine spatial cognition of mice. Abeta1-42 deposition, the microglia surface marker CD11b, and the M1 and M2 microglia surface markers [iNOS, arginase 1 (ARG1) and CD206] in the hippocampus and cerebral cortex were analyzed by immunohistochemistry and Western blotting. Results Compared with WT controls, APP/PS1 Tg mice (10 months old at the time of testing) treated with saline displayed increases in the latency to target, mean distance to target, latency 1st entrance to SW quadrant during the MWM test; they also showed increased latency and mean distance entering to the target in the MWM test, indicating their impaired cognition, which was reversed by fasudil. In addition, fasudil decreased the expressions of Abeta1-42 and iNOS and increased ARG1/CD206 in the hippocampus and cerebral cortex. further, the microglia marker CD11b had an overlap with the M1 marker iNOS or the M2 markers ARG1/CD206 in the cerebral cortex of the AD mice following fasudil treatment. Conclusion Fasudil reverses spatial cognitive dysfunction in APP/PS1 Tg mice via facilitating the transformation of Abeta1-42-activated microglia from the M1 to M2 phenotype. PMID- 29382416 TI - [Caspase-1 inhibitor AC-YVAD-CMK blocks IL-1beta secretion of bone marrow-derived macrophages induced by Acinetobacter baumannii]. AB - Objective To explore the effect of caspase-1 selective inhibitor AC-YVAD-CMK on IL-1beta secretion of bone marrow-derived macrophages (BMDMs) induced by Acinetobacter baumannii (A. baumannii). Methods Macrophages were separated from C57BL/6 mice which were stimulated using different concentrations of A. baumannii. The level of IL-1beta in the culture supernatant was detected by ELISA. The expression of pro-IL-1beta mRNA and protein were detected using the real-time quantitative PCR and Western blot analysis, respectively. The role of caspase-1 in the secretion of IL-1beta was tested by AC-YVAD-CMK treatment to block caspase-1. Pneumonia models in C57BL/6 mice were prepared by A. baumannii inoculation. The level of IL-1beta in bronchoalveolar lavage fluid (BALF) and the morphology of lung were detected by ELISA or HE staining, respectively. Results IL-1beta level in the culture supernatant was up-reregulated by A. baumannii stimulation in a dose-dependent manner. The expression of pro-IL-1beta mRNA and protein were not significantly changed with A. baumannii stimulation. Mature IL 1beta secretion was blocked by AC-YVAD-CMK either in vitro or in vivo. The damage of lung induced by A. baumannii infection in mice was ameliorated by AC-YVAD-CMK. Conclusion AC-YVAD-CMK alleviates pulmonary pathological damage by reducing the caspase-1-mediated IL-1beta secretion. PMID- 29382417 TI - [Ulinastatin attenuates hyper-permeability of vascular endothelialium cells induced by serum from patients with sepsis]. AB - Objective To study the effect of ulinastatin (UTI) on the hyper-permeability of human umbilical vein endothelial cell induced by the serum from patients with severe sepsis. Methods The serum level of tumor necrosis factor alpha (TNF-alpha) was examined by ELISA in 5 healthy volunteers and 5 patients with septic shock. EA.hy926 human umbilical vein endothelial cells were cultured in vitro and treated with different concentrations of UTI (10, 100, 1000 U/mL), 300 MUL serum of septic shock patients and 22 ng/mL TNF-alpha. The permeability and the electrical resistance (TER) of EA.hy926 cells were detected by a TranswellTM chamber system and epithelial volt-ohm meter (EVOM) method, respectively. The morphological characteristics and distribution of F-actin were measured by immunofluorescence technique. Results The serum level of TNF-alpha in sepsis patients was significantly higher than that in healthy volunteers. After EA.hy926 cells were treated with the serum of septic shock patients, the TER significantly decreased; the cell permeability significantly increased; F-actin cytoskeleton was significantly redistributed; and intracellular stress fibers increased. But UTI could attenuate the above changes. Conclusion UTI attenuates the hyper permeability of EA.hy926 cells induced by the serum of septic shock patients in a dose-dependent manner. PMID- 29382418 TI - [Knockdown of indoleamine 2, 3-dioxygenase 2 (IDO2)gene inhibits tumor growth and enhances immune function in mice bearing melanoma]. AB - Objective To study the role of indoleamine 2, 3-dioxygenase 2 (IDO2) in anti tumor therapy and its effect on the immune response when using IDO2 as therapeutic target. Methods B16-BL6 cells were used to construct mouse xenografted melanoma model. IDO2-shRNA that contained IDO2-siRNA or control shRNA (scrambled-shRNA) was injected hydrodynamically via the tail vein to treat melanoma. The tumor size was measured by vernier caliper. Flow cytometry was performed to analyze the percentage of regulatory T cells (Tregs), T cell apoptosis rate in draining lymph nodes and the expressions of co-stimulatory molecules on splenic dendritic cells (DCs) from different treatment groups. The lactate dehydrogenase (LDH) assay was used to determine the CD8+ cytotoxic T lymphocyte (CTL) activity. The serum levels of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN-gamma) were detected by ELISA. Results In the IDO2-shRNA treated group, the tumor formation time was delayed, tumor grew slowly, and excised tumor mass was significantly reduced. IDO2-shRNA treatment also decreased the percentage of Tregs and T cell apoptosis in draining lymph nodes and increased the expressions of co-stimulatory molecules CD80 and CD86 on splenic DCs. The capacity of CD8+ T cells to kill B16-BL6 cells was enhanced and the serum levels of TNF-alpha and IFN-gamma were upregulated. Conclusion Silencing IDO2 can effectively inhibit the growth of melanoma and improve the anti-tumor immune response in vivo. PMID- 29382419 TI - [Alpinetin promotes the binding of PPAR and methyltransferase]. AB - Objective To screen the nucleus located-methyltransferase in murine macrophages (RAW246.7 cells) after peroxisome proliferator-activated receptors (PPAR) is activated by alpinetin so as to prove the epigenetic modification effect of alpinetin. Methods RAW246.7 cells were divided into control group, alpinetin group (final concentrations including 100, 200, 500, 1000 MUg/mL) and 1000 MUg/mL alpinetin combined with 0.1 mmol/mL GW9662 group. Firstly, bioinformatics database String was searched for the methyltransferases which might interact with PPAR. Then co-immunoprecipitation was used to screen the specific nucleus-located methyltransferase interacting with PPAR. Finally, the expressions of the related methyltransferases were validated by fluorescent quantitative PCR. Results Co immunoprecipitation proved that EZH2, DNMT3alpha and TDG were the specific methyltransferases which interacted with the activated PPAR in the nucleus when induced by a certain concentration of alpinetin, which was basically consistent with the search result of the String database. No methyltransferase was found to interact with PPAR if GW9662 was added. Furthermore, only by a high concentration of alpinetin (1 000 MUg/mL), could the synthesis of TDG mRNA be promoted, yet the synthesis of DNMT3alpha and EZH2 were not influenced. Conclusion Alpinetin, the PPAR activator, could promote the synthesis and interaction of specific methyltransferases with PPAR in the nucleus, which indicates that methylation modification on histone or cytosine may be the interpretation for the effect of gene expression regulation caused by alpinetin. PMID- 29382420 TI - [Blood extracts from pilose antler changes the proportion of immune cells in mammary tumor-bearing mice and inhibit the growth of transplanted tumor]. AB - Objective To study the influence of blood extracts from pilose antler on the immune system in healthy mice and tumor-bearing mice. Methods A mouse mammary tumor transplantation model was established and both the healthy and the tumor bearing mice were gavaged with the blood extracts of pilose antler. The percentages of mouse peripheral blood CD3+ T cells, CD4+ T cells, CD8+ T cells, B220+ B cells and myeloid-derived suppressor cells (MDSCs) in the healthy and tumor-bearing mice were analyzed by flow cytometry. Results The blood extracts of pilose antler quantitatively up-regulated the helper T (CD4+) cell numbers, elevated the total T cell and B cell numbers, reduced the MDSC number and inhibited tumor growth. Conclusion The blood extracts of pilose antler can enhance mouse immune functions and inhibit transplanted tumor growth. PMID- 29382421 TI - [The oxLDL/beta2GPI/anti-beta2GPI antibody complex promotes A7r5 chemotaxis, migration and lipid accumulation]. AB - Objective To explore the effect of the oxidized low-density lipoprotein/beta2 glycoprotein I/beta2 glycoprotein I antibody (oxLDL/beta2GPI/beta2GPI-Ab) complex on the migration, chemotaxis and lipid accumulation of rat thoracic aortic smooth muscle A7r5 cell line, and unveil the role of Toll-like receptor 4 (TLR4) pathway during the process. Methods A7r5 cells were cultured in vitro with or without the pretreatment of TAK-242, a TLR4 inhibitor. Then the cells were stimulated by oxLDL, oxLDL/beta2GPI complex, beta2GPI, beta2GPI-Ab, beta2GPI/beta2GPI-Ab complex or oxLDL/beta2GPI/beta2GPI-Ab complex. Total RNA was extracted from the cells and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and acetyl-CoA acetyltransferase 1 (ACAT1) were evaluated by real-time quantitative PCR. The cell supernatants were collected, and the protein levels of MCP-1 and MMP-9 were determined by ELISA. The migration of A7r5 was observed through wound-healing test. A7r5 cells pretreated with or without TAK-242 were stimulated by oxLDL or oxLDL/beta2GPI/beta2GPI-Ab complex, and the content of total cholesterol (TC) and free cholesterol (FC) in them were measured by corresponding test kits. Then the level of intracellular cholesterol ester (CE) was calculated. Results The oxLDL/beta2GPI/beta2GPI-Ab complex promoted the migration and cholesterol accumulation, and up-regulated the expressions of MCP-1, MMP-9 and ACAT1 in A7r5 cells. In addition, the application of TLR4 inhibitor, TAK-242, suppressed these effects. Conclusion oxLDL/beta2GPI/beta2GPI-Ab complex contributes to the process of atherosclerosis through promoting the migration, chemotaxis and lipid accumulation of a7r5 in a TLR4-dependent manner. PMID- 29382422 TI - [Knockdown of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) inhibits proliferation and promotes apoptosis in MGC-803 gastric cancer cells]. AB - Objective To investigate the effect of knockdown of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) on cell proliferation, cell cycle and apoptosis of MGC 803 human gastric cancer cells in vitro. Methods The TCGA database was downloaded from UCSC Cancer Browser and to search for the differential expressions of YTHDF2 mRNA in gastric cancer tissues. Short hairpin RNA (shRNA) targeting YTHDF2 was designed and cloned into lentivirus expression vector pLKO.1. Furthermore, MGC 803 gastric cancer cells were transfected with pLKO.1-shRNA to knockdown the expression of YTHDF2, which was confirmed by the detection of YTHDF2 mRNA and protein expression using real-time quantitative PCR and Western blotting, respectively. Then cell proliferation was observed by CCK-8 assay, and cell cycle and apoptosis were examined by flow cytometry. Results According to the TCGA database, the expression of YTHDF2 mRNA in gastric cancer was significantly higher than that in the normal tissues. MGC-803 stably expressing YTHDF2-shRNA was successfully established. Furthermore, the proliferation capacity of YTHDF2 shRNA-expressing MGC-803 cells was significantly inhibited compared with the controls. Similarly, the percentage of YTHDF2-shRNA-expressing MGC-803 cells in G1 phase increased and in S phase decreased compared with the controls. Meanwhile, apoptosis ratio of YTHDF2-shRNA-expressing MGC-803 cells was significantly higher compared with the control groups. Conclusion Knockdown of YTHDF2 in MGC-803 cells inhibits cell proliferation and promotes apoptosis. PMID- 29382423 TI - [Huangjiao granules ameliorate brain injury in rats with cerebral ischemia/reperfusion injury by stimulating PI3K/AKT/mTOR signaling pathway]. AB - Objective To investigate the protective effect of Huangjiao granules on rats with cerebral ischemia/reperfusion injury and the effect on phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Methods The rat models of cerebral ischemia/reperfusion injury were established by suture method and treated with Huangjiao granules. ZeaLonga scoring was used to evaluate the neurological function of rats. The percentage of cerebral infarction was detected by triphenyl tetrazolium chloride (TTC) staining. The pathological changes of brain tissues were observed by HE staining. The levels of interleukin 10 (IL-10), IL-1beta and tumor necrosis factor-alpha (TNF-alpha) in the brain tissues were detected by ELISA. The expression levels of PI3K, AKT, phosphorylated AKT (p-AKT), mTOR and phosphorylated mTOR (p-mTOR) proteins were detected by Western blot analysis. Results Huangjiao granules could reduce the degree of neurological deficits, decrease the percentage of cerebral infarction, and lessen brain tissue pathological damage in the model rats. The expressions of IL-10, PI3K, p-AKT and p-mTOR in the brain tissues of the model rats were significantly up-regulated by Huangjiao granules, but the expressions of IL-1beta and TNF-alpha in the brain tissues of the model rats were significantly down-regulated by Huangjiao granules. Conclusion The protective effect of Huangjiao granules on rat models of cerebral ischemia/reperfusion injury may be related to the activation of PI3K/AKT/mTOR signaling pathway. PMID- 29382424 TI - [Inhibition of autophagy initiation stage enhances camptothecin-induced apoptosis in NCI-H1975 cells]. AB - Objective To explore the effect of autophagic inhibitors chloroquine (CQ) and 3 methyl adenine (3-MA) on apoptosis of non-small cell lung adenocarcinoma NCI H1975 cells induced by camptothecin (CPT). Methods After NCI-H1975 cells were treated with CPT, cell proliferation was detected by CCK-8 assay, morphological changes of cells were observed by PI staining, and the apoptosis of NCI-H1975 cells was determined by flow cytometry. The levels of autophagy-and apoptosis related proteins LC3I, LC3II, P62, caspase-3 and poly ADP-ribose polymerase (PARP) and transforming growth factor beta 1 (TGF-beta 1) were detected by Western blot analysis. Results After CPT treatment, the ratio of LC3II to LC3I was raised. The apoptotic protease caspase-3 and substrate PARP were obviously degraded, which could be enhanced by 3-MA but inhibited by CQ. It was also found that the intracellular TGF-beta 1 was reduced after CPT treatment. Conclusion Inhibition of autophagy initiation stage in NCI-H1975 cells can increase the sensitivity of cell apoptosis induced by CPT. PMID- 29382425 TI - [Knockdown of DNA-PKcs inhibits cell cycle and its mechanism of drug-resistant Bel7402/5-Fu hepatocellular carcinoma cells]. AB - Objective To study the effect of the knock-down of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on the cell cycle of the multidrug-resistant (MDR) Bel7402/5-Fu hepatocellular carcinoma cells and its MDR mechanism. Methods After cationic liposome-mediated siDNA-PKcs oligonucleotide transfection, the drug sensitivity of Bel7402/5-Fu cells to 5-fluorouracil (5-Fu) and adriamycin (ADM) was determined by MTT assay; the cell cycle were detected by flow cytometry; meanwhile, the protein expressions of cell cycle-related proteins P21, cell cycle protein B1 (cyclin B1), cell cycle division protein 2 (CDC2) were tested by Western blotting; the expressions of ataxia telangiectasia mutated (ATM) and p53 at both mRNA and protein levels were detected by real-time PCR and Western blot analysis. Results The MTT results showed siDNA-PKcs increased the chemotherapeutic sensitivity of Bel7402/5-Fu cells to 5-Fu and ADM. The flow cytometric analysis showed siDNA-PKcs decreased the percentage of S-phase cells but increased the percentage of G2/M phase cells. Western blotting showed siDNA PKcs increased the protein expression of P21 but decreased cyclinB1 and CDC2 proteins. In addition, siDNA-PKcs also increased the expressions of ATM and p53. Conclusion DNA-PKcs silencing increases P21 while decreases cyclin B1 and CDC2 expressions, and finally induces G2/M phase arrest in Bel7402/5-Fu cells, which may be related to ATM-p53 signaling pathway. PMID- 29382426 TI - [Subcutaneous transplants of juvenile rat testicular tissues continue to develop and secret androgen in adult rats]. AB - Objective To explore the effects of subcutaneous microenvironment of adult rats on survival, development and androgen secretion of Leydig cells of transplanted juvenile rat testis. Methods Healthy adult SD rats were randomly divided into control group, sham group, castrated group and non-castrated group. Rats in the control group were kept intact, no testis was transplanted subcutaneously after adult recipients were castrated in the sham group; 5-7-day juvenile rat testes were transplanted subcutaneously in the castrated group, with one testis per side; Testes resected from juvenile rats were directly transplanted subcutaneously on both sides of the recipients in the non-castrated group. The grafts were obtained and weighed 4 weeks later. Then the histological features of the grafts were examined by HE staining; the expression and distribution of hydroxysteroid 17-beta dehydrogenase 1 (HSD-17beta1) were investigated by immunohistochemistry; and the serum androgen level was determined by ELISA. Results The average mass of grafts obtained from the castrated group was significantly higher than that of the non-castrated group. Immunohistochemistry indicated that Leydig cells were visible in the tissues from both the castrated and non-castrated groups, but the number of HSD-17beta1-posotive cells in the castrated group was larger than that in the non-castrated group. ELISA results showed that the serum androgen level was higher in the control group and non castrated group than in the sham group and castrated group, and compared with the sham group, the serum androgen level in the castrated group was significantly higher. Conclusion The juvenile rat testis subcutaneously transplanted could further develop under the adult recipient rat skin, and the Leydig cells of grafts harbored the ability to produce and secret androgen. PMID- 29382427 TI - [HUVECs respond to low shear stress stimulation by activating Wnt/beta-catenin signaling pathway]. AB - Objective To investigate the influence of different fluid shear stress (FSS) on Wnt/beta signaling pathway in human umbilical vein endothelial cells (HUVECs) and its relationship with atherosclerosis. Methods HUVECs were subjected to different FSS (0, 1, 15 dynes/cm2) for various durations (6, 12, 18, 24 hours) using a shear stress device. Subsequently, real-time quantitative PCR was used to observe the mRNA expression levels of dishevelled 2 (Dvl2) and beta-catenin in the Wnt signaling pathway, and immunofluorescence technology to observe their protein expression and localization. Results The low FSS promoted the expression and recruitment of Dvl2 as well as the translocation of beta-catenin into the nucleus at the early stage of loading low FSS. Conversely, laminar FSS inhabited their expression and nuclear translocation of beta-catenin. Conclusion Wnt signaling pathway participates in the stress response of vascular endothelial cells to low shear stress. PMID- 29382428 TI - [Construction and identification of nanobody phage display library targeting Middle East respiratory syndrome coronavirus]. AB - Objective To construct a phage display library of specific nano-antibodies against the Middle East respiratory syndrome coronavirus (MERS-CoV) and apply it to the screening of neutralizing nano-antibodies. Methods MERS-CoV receptor binding domain (RBD) recombinant protein was used to immunize alpaca. After the last immunization, peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood and total RNA was extracted. The VHH gene was amplified by PCR and used to construct recombinant phages. TG1 Escherichia coli was transformed by these recombinant phages. A phage display library of specific nano-antibodies against the MERS-CoV were obtained and used to screen and characterize the nano antibodies. Results The volume of this library of nano-antibodies was 1.31*108 and its abundance rate was 5.65*1010/mL. The ratio of VHH insertion in the constructed library reached 96%. There was a rich diversity of nano-antibodies in this library. Nano-antibodies with neutralizing activity were identified and expressed from this library. Conclusion We successfully constructed a library of phages which could be effectively applied to the screening of nano-antibodies against MERS-CoV virus. PMID- 29382429 TI - [Knockdown of SIRT1 enhances the sensitivity to cisplatin by inhibiting autophagy in A549 cells]. AB - Objective To inhibit cisplatin-induced autophagy and improve the cisplatin sensitivity of A549 cells by knockdown the silent information regulator of transcription 1 (SIRT1). Methods Both mRNA and protein levels of SIRT1 in BEAS 2B, A549 and A549/DDP cells were detected by real-time quantitative PCR and Western blotting. After cisplatin treatment, the protein levels of SIRT1, LC3, P62 and beclin-1 in A549 cells were detected by Western blotting. A549 cells were transfected by siRNA to silence SIRT1 expression. Then, the apoptotic morphology was observed by fluorescence microscopy with Hoechst33258 staining. The apoptotic rate was analyzed by flow cytometry. The expressions of SIRT1, LC3, P62, cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) were measured by Western blotting. Results Both mRNA and protein levels of SIRT1 in A549 cells and A549/DDP cells were significantly higher than those in BEAS-2B cells, and they were higher in A549/DDP cells than in A549 cells. After cisplatin treatment, the protein levels of SIRT1, LC3 and beclin-1 in A549 cells increased, while P62 decreased. After transfected with SIRT1-siRNA, the expression of SIRT1 in A549 cells decreased. Compared with cisplatin group, the number of the apoptotic cells increased with the obvious occurrence of pyknosis and nuclear fragmentation in cisplatin plus SIRT1-siRNA group. Moreover, the expressions of P62, cleaved caspase-3 and PARP were up-regulated accompanied with LC3 decrease. Conclusion SIRT1 is highly expressed in A549 cells. The sensitivity of A549 cells to cisplatin can be improved by inhibiting the cisplatin-induced autophagy through knockdown of SIRT1. PMID- 29382430 TI - [Genetic polymorphisms of ARL15 and HLA-DMA are associated with rheumatoid arthritis in Han population from northwest China]. AB - Objective To establish the methods for detecting single nucleotide polymorphisms (SNPs) of ADP-ribosylation factor-like GTPase 15 (ARL15), major histocompatibility complex class II-DM alpha (HLA-DMA ) and nuclear factor kappa B subunit 2 (NFKB2) genes using high resolution melting (HRM) technology, and to explore the association of those SNPs with the susceptibility of rheumatoid arthritis (RA) in northwestern Han Chinese population. Methods The PCR-HRM detection system for four SNPs (rs255758, rs1063478, rs397514331 and rs397514332) was established for genotyping, and gene sequencing was performed to validate the genotyping ability of the system. 588 RA cases and 200 controls were enrolled in a case-control study to analyze the associations of ARL15 and HLA-DMA gene polymorphisms with RA risk. Results The direct sequencing validated that the established PCR-HRM detection system could be used for genotyping clinical samples correctly. The mutated genotype of rs397514331 and rs397514332 from NFKB2 gene are not found in this study. The genotype frequencies of rs255758 and rs1063478 had statistical difference between the cases and controls, but no statistical difference in allelic frequencies. Under the dominant model (AA vs AC/CC), the AA genotype of rs255758 decreases the RA risk (OR=0.666, 95%CI=0.478 0.927, P=0.016). Conclusion The method of PCR-HRM we established can be applied to the routine detection of rs255758, rs1063478, rs397514331 and rs397514332. The ARL15 and HLA-DMA gene polymorphisms are associated with RA risk in Northwestern Han Chinese population. PMID- 29382431 TI - [Identification and application of Mycobacterium tuberculosis esxN-specific cell epitopes in the diagnosis of pulmonary tuberculosis]. AB - Objective To identify Mycobacterium tuberculosis ESAT-6 protein esxN-specific HLA A*0201-restricted CTL epitopes and assess the diagnostic potential of the identified epitopes in pulmonary tuberculosis. Methods The esxN-specific HLA A*0201-restricted CTL epitopes were predicted by the T epitope prediction software SYFPEITHI and further synthesized. The binding affinity of the candidate epitopes for HLA-A*0201 was detected using MHC-peptide complex stabilization assay. The immunogenicity of candidate epitopes were assessed using ELISPOT in HLA-A*0201 transgenic mice. Based on identified CTL epitopes, ESAT-6 and culture filtrate protein-10 (CFP-10), the ELISPOT was performed to detect the frequency of epitope/protein-specific CTL. Results In six CTL epitope candidates we tested, two epitopes, esxN15-24 (AMIRAQAASL) and esxN48-57 (VACQEFITQL), were found to have a high affinity for HLA-A*0201. In the HLA-A*0201 transgenic mice immunized with the epitope candidates, esxN48-57 induced T-cell response with a significantly high IFN-gamma secretion. The IFN-gamma-producing T cells directed to esxN15-24 and esxN48-57 were found to be correlated with the presence of ESAT 6 and CFP-10 in positive pulmonary tuberculosis patients. The sensitivity of these tests for the esxN15-24 and esxN48-57 epitopes was similar to that of ESAT 6 and CFP-10. Conclusion Two novel Mycobacterium tuberculosis protein esxN derived HLA-A*0201-restricted CTL epitopes have potential for the diagnosis of tuberculosis. PMID- 29382432 TI - [Highly expressed CHAF1A and PCNA are positively associated with malignancy of cervical squamous cell carcinoma]. AB - Objective To investigate the expressions of chromatin assembly factor 1 subunit A (CHAF1A) and proliferating cell nuclear antigen (PCNA) in cervical squamous cell carcinoma (CSCC) and their clinical implication. Methods Real-time quantitative PCR was performed to detect the mRNA levels of CHAF1A and PCNA in CSCC and corresponding paracancerous tissues. Immunohistochemistry was used to detect the expressions of CHAF1A and PCNA proteins in normal cervical epithelium tissues (NC), cervical intraepithelial neoplasia tissues (CIN), and CSCC. The correlation between CHAF1A and PCNA expressions and the relationship of the two proteins to the clinical pathological features of cervical cancer were analyzed. Results The expressions of CHAF1A and PCNA in CIN and CSCC were significantly higher than those in NC. In addition, CHAF1A and PCNA expressions were positively correlated in the CSCC tissues. Furthermore, overexpression of CHAF1A was significantly associated with the degree of differentiation, tumor size, depth of cancer invasion and HPV infection. Finally, the up-regulated expression of PCNA was correlated with the degree of differentiation, International Federation of Gynecology and Obstetrics (FIGO) grade, lymph node metastasis, depth of cancer invasion and HPV infection. Conclusion CHAF1A and PCNA are highly expressed in CSCC and associated with the malignancy. PMID- 29382433 TI - A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme. AB - PURPOSE: The Biopharmaceutics Classification System (BCS) based biowaiver is a scientific model which enables the substitution of in vivo bioequivalence studies with in vitro data as evidence of therapeutic equivalence subject to certain conditions. Despite being based on the same principles, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies. In this survey, the Bioequivalence Working Group (BEWG) of the International Generic Drug Regulators Programme (IGDRP) compared the criteria for BCS-based biowaivers applied by the participating regulators and organisations. METHODS: Differences and similarities regarding solubility, permeability, dissolution, excipients and fixed-dose combination products, were identified and compared in a detailed survey of each participant's criteria for BCS-based biowaivers. These criteria were determined based upon the participants' respective regulatory guidance documents, policies and practices. RESULTS: This review has, with the exception of two participants who do not accept BCS-based biowaivers, revealed that most IGDRP participants interpret the BCS principles and conditions similarly but notable differences exist in the application of these principles. Conclusion: Although many similarities exist, this review identifies several opportunities for greater convergence of regulatory requirements amongst the surveyed jurisdictions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29382434 TI - Diclofenac--Acetaminophen Combination Induced Acute Kidney Injury In Postoperative Pain Relief. AB - PURPOSE: The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury (AKI) in postoperative pain relief 2) the average cost and length of hospital stay for patients in AKI group and non-AKI group. METHODS: All patients with no prior history of chronic kidney disease (CKD) and normal serum creatinine [44~130 MUmol /l] who received diclofenac and acetaminophen combination as a single agent intramuscularly (IM) between January and December 2015 in The Second Xiangya Hospital, Changsha, Hunan, China were included in this retrospective own-control study. Baseline serum creatinine (SCr) and SCr during NSAID use were collected. AKI is defined as an increased of Scr over 1.5 times the baseline. Multivariate analyses were performed with a logistic regression model to assess the significant risk factors of AKI. RESULTS: A total of 821 patients were included in the study with 63 [7.7%] patients had diclofenac/acetaminophen combination single agent induced AKI. Multivariate analysis confirmed that using diclofenac/acetaminophen combination after surgeries within 24 h were significantly associated with AKI [odds ratio, OR, 2.173; 95% CI, 1.113-4.243; P=0.023]. The average cost and length of hospitalization in AKI group was 1.87 times [p=0.000] and 1.2 times [p=0.043] comparison than non-AKI group, respectively. CONCLUSIONS: The incidence of diclofenac/acetaminophen combination single agent induced AKI in postoperative pain relief was 7.7%. Patients with hypertension or liver cirrhosis was more likely to develop AKI and using diclofenac/acetaminophen combination after surgeries within 24 h was significant risk factors for AKI. AKI prolonged the cost and length of hospitalization. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29382435 TI - Programme AUQ 2017. PMID- 29382436 TI - ABSTRAITS AUQ 2017. PMID- 29382437 TI - Northeastern Section of the American Urological Association 69th Annual Meeting, Savannah, GA: Scientific Program. PMID- 29382438 TI - 2017 NSAUA Abstracts. PMID- 29382440 TI - Lifelong learning, our membership, and the CUA cua guideline. PMID- 29382439 TI - PSA screening: Time to overcome our brand confusion. PMID- 29382442 TI - Hilar control during laparoscopic donor nephrectomy: Practice patterns in Canada. AB - INTRODUCTION: In recent years, the method of vascular control during laparoscopic donor nephrectomy (LDN) has come under scrutiny due to catastrophic consequences of a device failure. This study sought to examine the surgical preferences of Canadian donor surgeons with regards to vascular control and their perception on the safety of these modalities. We also surveyed the experience with device malfunction and their subsequent management during LDN. METHODS: An online survey was sent out to donor surgeons registered with the Canadian Society of Transplantation. Surveys were anonymous and voluntary. Descriptive statistics were used to analyze the collected responses. Recollection of the sequelae and outcomes from device malfunction were also queried. RESULTS: Twenty-eight of 37 surgeons (76% response rate) responded to the survey. At least one surgeon from every institution in Canada performing LDN responded to the survey. Laparoscopic stapler is the most commonly used device for securing the renal artery (61%) and renal vein (67%). Overall, surgeons felt the stapler was the safest method of securing the renal artery. Stapler misfire and clip slippage were reported by eight (28.5%) and 12 (43%) surgeons, respectively. Most cases were salvageable: laparoscopically (30%), open conversion (30%), and by hand port (5%). Slippage of a plastic locking clip resulted in one emergent laparotomy on POD#1 and one stapler misfire was converted to open resulting in donor death. CONCLUSIONS: Although rare, hemorrhagic complications can occur from device malfunction resulting in poor outcomes for healthy volunteers undergoing LDN. Surgeons need to remain vigilant when selecting the appropriate modality for vascular control. PMID- 29382443 TI - All vascular closure technologies can fail: Urologists need to be prepared. PMID- 29382441 TI - Management of advanced kidney cancer: Canadian Kidney Cancer Forum (CKCF) consensus update 2017. PMID- 29382444 TI - Intraureteral lidocaine for ureteral stent symptoms post-ureteroscopy: A randomized, phase 2, placebo-controlled trial. AB - INTRODUCTION: Ureteral stent and ureteral manipulation-related pain is a significant complication for patients undergoing ureteroscopy. Herein, we report a phase 2, randomized trial to assess efficacy of direct instillation of intraureteral lidocaine in reducing postoperative pain and ureteral stent symptoms. METHODS: We performed a randomized, double-blinded trial of patients undergoing elective ureteroscopy for ureteral calculi. Patients were randomized to direct instillation of 2% lidocaine plus bicarbonate, or to normal saline as control. The primary outcome of interest was early postoperative pain scores. Patients completed10-point visual analog pain scale at one-hour, two-hour, four hour, 24-hours, four- and seven-day time points. Other outcome measurements collected included a medication diary and voiding questionnaire. RESULTS: A total of 41 patients were randomized in the study. Mean flank pain scores at one hour were 2.2 (+/-2.9) vs.1.9 (+/-2.4) in the intervention and placebo group, respectively (p=0.84). There was no significant difference at any time point between the intervention and placebo groups in patient-reported pain scores. Patients reported lower dysuria scores at all time points in the lidocaine group, however, none reached statistical significance. There was no difference in complication rates or adverse effects between groups. CONCLUSIONS: In this randomized, phase 2 study, direct instillation of lidocaine into the ureter did not appear to significantly improve pain or voiding symptoms following stented ureteroscopy. PMID- 29382445 TI - Feasibility of expert and crowd-sourced review of intraoperative video for quality improvement of intracorporeal urinary diversion during robotic radical cystectomy. AB - INTRODUCTION: Development of uretero-ileal stricture (UIS) after robotic-assisted radical cystectomy (RARC) may be dependent on surgical technique. Video review of intraoperative technique is an emerging paradigm for surgical quality improvement. We examined whether surgeon-perceived risk of UIS or crowd-sourced assessment of robotic skill are associated with the development of UIS. METHODS: We conducted a case-control study comparing the operative technique of uretero ileal anastomoses resulting in clinically significant UIS with the contralateral anastomosis for the same patient. De-identified videos were analyzed by 1) five high-volume surgeons; and 2) crowd workers (Crowd-Sourced Assessment of Technical Skill, C-SATS) to determine Global Evaluative Assessment of Robotic Skill (GEARS) score. Mantel-Haenszel common odds ratio (OR) estimates were calculated to assess the association between surgeon performance and the development of UIS. Logistic regression models were used to examine the association between GEARS scores and the development of UIS. RESULTS: A total of 10 UIS videos were compared to eight control videos by five surgeons and 2142 crowd workers. Expert surgeons systematically evaluated intraoperative footage, however, no association between the expert mode response and UIS (OR 0.42; 95% confidence interval [CI] 0.05 3.45; p=0.91) was identified. Crowd-sourced assessment was not predictive of UIS (p=0.62). CONCLUSIONS: We used video review to systematically analyze procedure specific content and technique. The inability of surgeons to predict UIS may reflect the questionnaire, uncontrolled patient factors, or a lack of power. Crowd-sourced GEARS score was unsuccessful in predicting UIS after RARC. PMID- 29382446 TI - Video replay in surgery: Can we make the "right call" in predicting outcomes? PMID- 29382447 TI - Biopsychosocial impact of prostate cancer and androgen-deprivation therapy. AB - INTRODUCTION: Prostate cancer is the most non-cutaneous malignancy in men, and androgen-deprivation therapy (ADT) is a cornerstone of management in advanced disease. The aim of this study was to evaluate the association of ADT with changes in depression and mental and physical quality of life (QoL) within a prospective patient cohort design. METHODS: Patients were prospectively recruited and consented at a single academic health sciences centre in Ontario, Canada. Inclusion criteria included those men with adenocarcinoma of the prostate and either on watchful waiting or initiating ADT as palliation or as an adjuvant therapy for high-risk localized disease. All three cohorts were followed in routine care and completed psychosocial evaluations, including depression, social support, anxiety, and QoL measures. RESULTS: In comparison to the control cohort of patients with prostate cancer on watchful waiting, initiation of ADT over a two-year period of time was not associated with any changes in depression or mental QoL. Instead, all patients, regardless of treatment cohort, showed increased depression scores and reduced mental QoL scores over time; however, for patients receiving ADT, a significant reduction in physical QoL compared to patients who did not receive ADT was demonstrated. CONCLUSIONS: ADT does not appear to significantly impact depressive symptoms and mental QoL over a two-year period; however, the depressive symptoms in this limited sample of men with prostate cancer was higher than expected and monitoring for these may be advisable for those who care for such patients. PMID- 29382448 TI - Ipsilateral renal function preservation following minimally invasive partial nephrectomy: The effect of tumour characteristics and warm ischemic time. AB - INTRODUCTION: The relative impact of preoperative and perioperative variables on renal function following partial nephrectomy (PN) is controversial. To further investigate, we assess the effects of tumour complexity, warm ischemic time (WIT), and volume of resected renal parenchyma on ipsilateral renal function (IRF) outcomes following minimally invasive PN. METHODS: Of patients who underwent laparoscopic or robotic-assisted PN between 2002 and 2011 at our institution, 99 met our inclusion criteria. The effects of preoperative tumour complexity (using RENAL nephrometry score), perioperative WIT, and pathological tumour volumes on ipsilateral renal function preservation (%IRF) were analyzed. %IRF was defined as the proportion of postoperative to preoperative ipsilateral renal function calculated using MAG3 nuclear renography. RESULTS: Increasing RENAL nephrometry score (RNS) and WIT were independently predictive of inferior %IRF at 6-12-week postoperative followup in univariate and multivariate analyses. Of RNS properties, masses that were endophytic, near the collecting system, or central in location were associated with inferior %IRF, with nearness to collecting system as the strongest predictor; however, RNS was no longer predictive of %IRF in cases requiring more than 30 minutes of WIT. CONCLUSIONS: In renal masses amenable to resection by minimally invasive PN, longer WIT was the most important predictor of inferior %IRF. Although increasing RNS score influenced %IRF, the overall clinical significance of RNS is limited and should not influence operative decision-making in efforts to preserve renal function. Furthermore, small volumes of renal parenchyma can be safely resected without impairment of long-term IRF. PMID- 29382449 TI - A population-based study of the use of radium 223 in metastatic castration resistant prostate cancer: Factors associated with treatment completion. AB - INTRODUCTION: Radium 223 (Ra223) given for six cycles has proven efficacy in clinical trials, but its population-level generalizability has not been well described. The objectives of this study were to describe population-based Ra223 use in the abiraterone and enzalutamide era and identify factors associated with completion. METHODS: All Ra223 patients at the British Columbia Cancer Agency between September 2013 and February 2016 were identified. Patients who completed <5 vs. >=5 cycles were compared on patient characteristics, lines of prior therapy, prostate-specific antigen (PSA) and alkaline phosphatase (ALP) decline >30% from baseline (R30%), and survival, to identify factors associated with therapy completion. RESULTS: Ninety-one patients were identified; 48 (52.7%) completed >5 cycles. Median overall survival (mOS) was 10.7 months, PSA and ALP R30% were 21% and 52%, respectively. Completion of <5 cycles was associated with higher baseline ALP (p=0.05) and lower baseline hemoglobin (Hb) levels (p=0.03). Patients in the >=5 cycles group had longer mOS than those in the <5 cycles group (16.2 vs. 5.9 months; p<0.0001), as well as higher PSA R30% (33.3% vs. 7.0%; p=0.002) and ALP R30% (66.7% vs. 34.9%; p=0.03). Patients with ALP >=220 and Hb <=118 had 3.85 times the odds of not completing >=5 cycles vs. ALP <220 and Hb >118. CONCLUSIONS: Compared to clinical trials, patients in a population-based setting had more lines of therapy and shorter survival. Lower ALP and higher hemoglobin were associated with completion of >5 cycles, longer mOS, and greater incidence of PSA and ALP response. PMID- 29382450 TI - CUA/EUREP Exchange Program: Prague 2017. PMID- 29382451 TI - Formation permanente, l'AUC et ses membres. PMID- 29382452 TI - Dr. Graham Glezerson. PMID- 29382453 TI - Accuracy of kidney cancer diagnosis and histological subtype within Canadian cancer registry data. AB - INTRODUCTION: Provincial/territorial cancer registries (PTCRs) are the mainstay for Canadian population-based cancer statistics. Each jurisdiction captures this data in a population-based registry, including the Nova Scotia Cancer Registry (NSCR). The goal of this study was to describe data from the NSCR regarding renal cell carcinoma (RCC) pathology subtype and method of diagnosis and compare it to the actual pathology reports to determine the accuracy of diagnosis and histological subtype assignment. METHODS: This retrospective analysis included patients diagnosed with RCC in the NSCR from 2006-2010 with an ICD-O-3 code C64.9 seen or treated in the largest NS health district. From the NSCR, method of diagnosis and pathological diagnosis was recorded. All diagnoses of non-clear cell RCC (nonccRCC) from NSCR were compared to the actual pathology report for descriptive comparison and reasons for discordance. RESULTS: 723 patients make up the study cohort. 81.3% of patients were diagnosed by nephrectomy, 11.1% radiography, 6.9 % biopsy, and 0.7% autopsy. By NSCR data, 52.8% had clear-cell (ccRCC), 20.5% RCC not otherwise specified (NOS), 12.7% papillary, 4% chromophobe, and the rest had other nonccRCC subtypes. By pathology reports, 69.5% had clear-cell, 15% papillary, 5% chromophobe, only 2.7% RCC NOS. There was a discordance rate of 15.4% between NSCR data and diagnosis from pathology report. Reasons for discordance were not enough information by the pathologist in 45.5%, misinterpretation of report by data coder in 22.2%, and true coding error in 32.3%. CONCLUSIONS: When using PTCR for RCC incidence data, it is important to understand how the diagnosis is made, as not all are based on pathological confirmation; in this cohort 11% were based on radiology. One must also be aware that clear-cell and non-clear-cell subtypes may differ between the PTCR data and pathology reports. In this study, ccRCC made up 52.8% of the registry diagnoses, but increased to 69.6% on pathology report review. Use of synoptic reporting and ongoing education may improve accuracy of registry data. PMID- 29382454 TI - Transrectal ultrasound-guided biopsy for prostate cancer detection: Systematic and/or magnetic-resonance imaging-targeted. AB - INTRODUCTION: Magnetic resonance imaging (MRI) is being more widely used in the detection of prostate cancer (PCa), particularly after an initial negative biopsy. In this study, we compared 12-core systematic biopsy (SYS), MRI-targeted biopsy (TAR), and the association of systematic and MRI-targeted (SYS+TAR) prostate biopsy in patients with previous biopsy and those who were biopsy-naive to evaluate the differences in terms of cancer detection and clinically significant cancer detection between the three modalities. METHODS: Overall, 203 consecutive patients with suspicion of PCa were analyzed; 48.2% were biopsy-naive and 51.7% had at least one previous negative prostate biopsy. The median age was 66 years, median prostate-specific antigen (PSA) level was 7.9 ng/mL and median prostate volume was 46 mL. 38.9% had SYS, 19.2% TAR only, and 41.8% had SYS+TAR biopsy. RESULTS: Overall, the PCa detection (PCaDR) was 63%. The SYS+TAR biopsy detected significantly more cancer than SYS and TAR only biopsies (72.9% vs. 56.9% and 53.8% respectively; p=0.03). Detection rate of clinically significant cancer (csPCaDR) was 50.7% overall; 65.8% in the SYS+TAR biopsy vs. 39.2% in the SYS and 48.7% in the TAR groups (p=0.002). In the biopsy-naive group, PCaDR and csPCaDR were significantly higher in the SYS+TAR group than in the SYS and TAR groups (p=0.01). In the repeat biopsy group, PCaDR and csPCaDR were equivalent in the TAR and SYS+TAR groups and higher than in the SYS group (p=0.001). CONCLUSIONS: TAR biopsy, when added to SYS biopsy, was associated with a higher detection rate of csPCa in biopsy-naive patients when compared to TAR and SYS only biopsies. In patients after previous negative biopsy, detection rates of csPCa were equivalent for SYS+TAR and TAR only biopsies, but higher than SYS. PMID- 29382455 TI - Can a supervised algorithmic assessment of men for prostate cancer improve the quality of care? A retrospective evaluation of a prostate assessment pathway in Saskatchewan. AB - INTRODUCTION: The Saskatoon Prostate Assessment Pathway (SPAP) was developed in 2013 in part to decrease the wait times between physician referral and biopsy for patients with suspected prostate cancer. Using an algorithm carefully designed to optimize appropriate prostate biopsy rates, physicians can directly refer patients for biopsy through the SPAP without seeing a urologist. All other patients are referred to the Saskatoon Urology Associates (SUA). The present study evaluates the performance of the algorithm. METHODS: 971 patients seen at the SUA and 302 patients seen through the SPAP were identified. Information on age, biopsy status and outcome, risk stratification, and time between referral and biopsy was collected. Biopsy wait time data was analyzed using gamma distribution. Association between referral method and biopsy rate, and between referral method and risk stratification, was analyzed using Z-test. RESULTS: The expected wait time from referral to biopsy for patients seen through SUA was 2.63 times longer than those seen through SPAP (34 vs. 91 days). The biopsy rate of patients seen in the SPAP was significantly higher than those by SUA (88% vs. 69%, 95% confidence interval [CI] 0.14-0.26; p<0.00001). There was no significant difference in positive biopsy rates for patients seen through the SPAP vs. SUA (81% vs. 74%, 95% CI -0.011,0.14; p=0.095), for detection of low-risk cancer, (12% vs. 10%, 95% CI -0.034,0.080; p=0.44), or for clinically relevant cancer, i.e., intermediate- and high-risk cancer, for SPAP vs. SUA (56.54% vs. 56.68%, 95% CI -0.091,0.089; p=0.49). CONCLUSIONS: The algorithm used in the SPAP is effective in decreasing wait time to prostate biopsy and has the same cancer/pre cancer detection rate, but at the cost of a higher biopsy rate. Both referral mechanisms result in few low-risk cancer detection biopsies, finding primarily cases of high- or intermediate-risk cancer. PMID- 29382456 TI - A contemporary population-based study of testicular sex cord stromal tumours: Presentation, treatment patterns, and predictors of outcome. AB - INTRODUCTION: We aimed to characterize demographic distribution, patient outcomes, and prognostic features of testicular sex cord stromal tumours (SCST) using a large statewide database. METHODS: Adult male patients diagnosed with SCST between 1988 and 2010 were identified within the California Cancer Registry (CCR). Baseline demographic variables and disease characteristics were reported. Primary outcome measures were cancer-specific survival (CSS) and overall survival (OS). Bivariate and multivariate Cox proportional hazards models were employed to identify predictors of survival. RESULTS: A total of 67 patients with SCST were identified, of which 45 (67%) had Leydig cell and 19 (28%) had Sertoli cell tumours. Median age was 40 years and the majority of patients (84%) presented with localized disease. Following orchiectomy, nine patients (15%) underwent retroperitoneal lymph node dissection (RPLND), whereas 54 patients (80%) had no further treatment. With a median followup of 75 months, two-year OS and CSS was 91% and 95%, respectively, for those presenting with stage I disease. For those presenting with stage II disease, two-year OS and CSS was 30%. Predictors of worse OS included age >60 (hazard ratio [HR] 5.64; p<0.01) and metastatic disease (HR 8.56; p<0.01). Presentation with metastatic disease was the only variable associated with worse CSS (HR 13.36; p<0.01). Histology was not found to be a significant predictor of either CSS or OS. CONCLUSIONS: We present the largest reported series to date for this rare tumour and provide contemporary epidemiological and treatment data. The primary driver of prognosis in patients with SCST is disease stage, emphasizing the importance of early detection and intervention. PMID- 29382457 TI - Gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on intermittent catheterization. AB - INTRODUCTION: This study aimed to determine if gentamicin bladder instillations reduce the rate of symptomatic urinary tract infection (UTI) in neurogenic bladder (NGB) patients on intermittent self-catheterization (ISC) who have recurrent UTIs. Secondary aims were to examine the effects of intravesical gentamicin on the organism resistance patterns. METHODS: We retrospectively reviewed our prospective NGB database. Inclusion criteria were NGB patients performing ISC exclusively for bladder drainage with clinical data available for six months before and six months after initiating prophylactic intravesical gentamicin instillations. Symptomatic UTIs were defined as symptoms consistent with UTI plus the need for antibiotic treatment. RESULTS: Twenty-two patients met inclusion criteria; etiology of NGB was 63.6% spinal cord injury, 13.6% multiple sclerosis. Median time since injury/diagnosis was 14 years and 6/22 (27.3%) had undergone urological reconstruction. Patients had fewer symptomatic UTI's (median 4 vs. 1 episodes; p<0.004) and underwent fewer courses of oral antibiotics after initiating gentamicin (median 3.5 vs. 1; p<0.01). Days of oral antibiotic therapy decreased from 15 before to five after gentamicin, but this did not reach significance. There were fewer telephone encounters for UTI concerns per patient (median 3 vs. 0; p=0.03). The proportion of multi-drug-resistant organisms in urine cultures decreased from 58.3% to 47.1% (p=0.04) and the rate of gentamicin resistance did not increase. Adverse events were mild and rare. CONCLUSIONS: Gentamicin bladder instillations decrease symptomatic UTI episodes and reduce oral antibiotics in patients with NGB on ISC who were suffering from recurrent UTIs. Antibiotic resistance decreased while on gentamicin instillations. PMID- 29382458 TI - Widespread use of internet, applications, and social media in the professional life of urology residents. AB - INTRODUCTION: Digital media have revolutionized communication and information dissemination in healthcare. We aimed to quantify and evaluate professional digital media use among urology residents. METHODS: We designed a 17-item survey to assess usage and perceived usefulness of digital media, as well as communication type and device type and distributed it via email to 143 Canadian and 721 German urology residents. RESULTS: In total, 58 (41% response rate) residents from Canada and 170 (24% response rate) from Germany reported professional usage rates of 100% on the internet, 89% on apps, and 46% on social media (SoMe). For professional use, residents spent a median of 30 minutes per day on the internet, 10 minutes on apps, and 15 minutes on SoMe. 100% rated the internet, 89% apps, and 31% SoMe as useful for clinical practice. Most (94%) used digital media for communication with colleagues and 23% for communication with patients. Digital media use was allocated to desktop computers (55%) and mobile devices (45%). Canadian residents had higher usage rates of apps (96% vs. 86%; p=0.042) and SoMe (65% vs. 39%; p=0.002) and longer daily usage times for the internet, apps, and SoMe than German residents (p<0.001 each). CONCLUSIONS: Digital media are an integral part of the daily professional practice of urology residents, reflected by high usage rates and perceived usefulness of the internet and apps, and the growing importance of SoMe. Urologists should strive to progressively exhaust the vast potential of digital media for academic and clinical practice. PMID- 29382459 TI - Chronic prostatitis/chronic pelvic pain syndrome is associated with previous colonoscopy. AB - INTRODUCTION: This study aimed to examine the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and receipt of a prior colonoscopic examination using a population-based database. METHODS: We used the Taiwan Longitudinal Health Insurance Database 2005 to retrieve the study sample. This study included 3933 patients with CP/CPPS and 3933 age-matched controls. We designated the date of receiving the first diagnosis of CP/CPPS as the index date for cases. We defined the first an ambulatory care visit occurring in the matched year as the index date for the controls. Conditional logistic regressions was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for having previously received colonoscopy between cases and controls. RESULTS: We found that 349 (4.44%) of the 7866 sampled patients had previously undergone colonoscopy, including 223 (5.67%) cases and 126 (3.20%) controls (p<0.001). A conditional logistic regression analysis revealed that the adjusted OR of receiving a colonoscopy within three years before the index date was 1.77 (95% CI 1.42-2.23) for cases compared to controls. Furthermore, we found that the youngest group of cases (<40 years) had the greatest adjusted OR for having received colonoscopy within three years before the index date compared to controls (OR 2.81; 95% CI 1.45-5.44); however, in contrast, no significant difference in the adjusted odds of having previously received colonoscopy was observed between cases and controls among the oldest age group (>=60 years). CONCLUSIONS: We concluded that there was an association between antecedent colonoscopy and CP/CPPS. PMID- 29382460 TI - Management of iatrogenic urorectal fistulae in men with pelvic cancer. AB - INTRODUCTION: Urorectal fistula (URF) is a devastating complication of pelvic cancer treatments and a surgical challenge for the reconstructive surgeon. We report a series of male patients with URF resulting from pelvic cancer treatments, specifically prostate (PCa), bladder (BCa), and rectal cancer (RCa), and explore the differences and impact on outcomes between purely surgical and non-surgical treatment modalities. METHODS: Between October 2008 and June 2015, 15 male patients, aged 59-78 years (mean 67), with URF induced by pelvic cancer treatments were identified in our institutions. Patients with a history of diverticulitis, inflammatory bowel disease, or other benign conditions were excluded. We reviewed the patients' medical records for symptoms, diagnostic tests performed, type and etiology of the fistula, type of surgical reconstruction, followup, and outcomes. RESULTS: Fourteen patients underwent surgical reconstruction. One patient developed metastatic disease before URF repair and, therefore, was excluded from this study. Mean followup (FU) was 32.7 months (14-79). All patients received diverting colostomy and temporary urinary diversion. An exclusively transperineal approach was used in nine (64.3%) patients and a combined abdominoperineal in five (35.7%). Overall successful URF closure was achieved in 12 (85.7%) patients, nine (64.3%) of whom at the first reconstructive attempt, two (14.3%) after two attempts (in our institution), and one (7.1%) after three attempts (two of which elsewhere). An interposition flap was used in seven (50%) patients. Surgical reconstruction failed ultimately in two (14.3%) patients who still have a colostomy and do not wish any further reconstruction. CONCLUSIONS: Our study has several limitations, including its retrospective nature and the heterogeneity of our small patient cohort. Nonetheless, although surgical reconstruction of URF may be extremely difficult and complex in the non-surgical/energy ablation patients, its successful reconstruction is possible in most through a transperineal, or a more aggressive abdominoperineal, approach with tissue interposition in selected patients. PMID- 29382461 TI - Case: Metastatic Crohn's disease of the genitalia in a prepubescent male: An illustrative case of an uncommon diagnosis. PMID- 29382462 TI - Case: Anuria and acute renal failure post-endoscopic valve ablation and Foley catheter insertion in a newborn with a small-capacity, non-compliant bladder. PMID- 29382463 TI - Case: Primary erectile dysfunction due to congenital isolated cavernous bodies. PMID- 29382464 TI - Techniques: Shockwave lithotripsy may not be a good option in patients with previous renal superselective embolization. PMID- 29382465 TI - Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan. AB - BACKGROUND AND AIMS: Gastroduodenal and biliary obstruction may occur synchronously or asynchronously in advanced pancreatic cancer, and endoscopic double stent placement may be required. EUS-guided biliary drainage (EUS-BD) often is performed after unsuccessful placement of an endoscopic transpapillary stent (ETS), and EUS-BD may be beneficial in double stent placement. This retrospective multicenter cohort study compared the outcomes of ETS placement and EUS-BD in patients with an indwelling gastroduodenal stent (GDS). METHODS: We recorded the clinical outcomes of patients at 5 tertiary-care medical centers who required biliary drainage after GDS placement between March 2009 and March 2014. RESULTS: Thirty-nine patients were included in this study. Patients' mean age was 68.5 years; 23 (59.0%) were men. The GDS overlay the papilla in 23 patients (59.0%). The overall technical success rate was significantly higher with EUS-BD (95.2%) than with ETS placement (56.0%; P < .01). Furthermore, the technical success rate was significantly higher with EUS-BD (93.3%) than with ETS placement (22.2%; P < .01) when the GDS overlies the papilla. The overall clinical success rate of EUS-BD also was significantly higher than for ETS placement (90.5% vs 52.0%, respectively; P = .01), and there was no significant difference in the incidence of adverse events (ETS, 32.0% vs EUS-BD, 42.9%; P = .65). CONCLUSION: Endoscopic double stent placement with EUS-BD is technically and clinically superior to ETS placement in patients with an indwelling GDS. EUS-BD should be considered the first-line treatment option for patients with an indwelling GDS that overlies the papilla. ETS placement remains a reasonable alternative when the papilla is not covered by the GDS. PMID- 29382466 TI - Characterization of sentinel node-derived antibodies from breast cancer patients. AB - Autoantibodies to breast and other cancers are commonly present in cancer patients. A method to rapidly produce these anti-cancer autoantibodies in the lab would be valuable for understanding immune events and to generate candidate reagents for therapy and diagnostics. The purpose of this report is to evaluate sentinel nodes (SNs) of breast cancer patients as a source of anti-cancer antibodies. Radiotracer lymphatic mapping in 29 patients with breast cancer confirmed the identity of the SNs which provided source cells for this study. Flow cytometry demonstrated ~28% of the MNCs were B cells and ~44% of the B cells were class switched memory B cells. EBV-induced proliferation of B cells yielded tumor binding antibodies from 3 wells per 1000 but cultures were too unstable for detailed evaluations. Hybridomas generated by electrofusion produced IgG (48%), IgM (34%) and IgA (18%) antibody isotypes which were screened for binding to a panel of breast cancer cells of the major molecular subtypes. Tumor lysate binding was observed in 28% of the hybridoma clones and 10% of these bound whole tumor cells with unique binding patterns. More detailed evaluation of selected clones showed binding to the patient's own tumor. SNs are removed from more than 100,000 breast cancer patients in the US per year. Samples from these lymph nodes represent a substantial opportunity to generate anticancer antibodies. PMID- 29382467 TI - The Efficacy of Plasma Rich in Growth Factors for the Treatment of Alveolar Osteitis: A Randomized Controlled Trial. AB - PURPOSE: To investigate the efficacy of plasma rich in growth factors (PRGF; BTI Biotechnology Institute, San Antonio, Spain) for the treatment of alveolar osteitis compared with a positive control (Alvogyl; Septodont, Maidstone, Kent, UK). MATERIALS AND METHODS: This single-center, single-blinded, randomized, 2 treatment, parallel study was conducted in a UK dental hospital. All healthy adults who presented with alveolar osteitis after tooth extraction over a 3-month period were invited to participate. Each socket was randomized and treated with 1 of 2 treatment modalities, a test treatment (PRGF) or a positive control (Alvogyl). After treatment, patients were reviewed at 3 and 7 days by a second clinician blinded to the treatment given. Outcome measures included pain, exposed bone, inflammation, halitosis, dysgeusia, and quality-of-life assessment. RESULTS: Thirty-eight patients with data from 44 sockets (22 in the PRGF group and 22 in the Alvogyl group) were analyzed. The PRGF group showed significantly faster bone coverage and significantly decreased inflammation and halitosis (P < .05) compared with the control group receiving Alvogyl. There was no significant difference for pain, quality-of-life measures, or dysgeusia between groups. CONCLUSION: PRGF predictably treated alveolar osteitis after tooth extraction compared with the conventional standard treatment of Alvogyl, which has been used for many years. PRGF could be considered an alternative treatment for alveolar osteitis and indeed appears to have considerable advantages over Alvogyl. PMID- 29382468 TI - Zeolitic imidazolate framework-based biosensor for detection of HIV-1 DNA. AB - ZIF-8(zinc-methylimidazolate framework-8), one of the zeolitic imidazolate frameworks (ZIFs), as quenching platforms for detection of HIV-1 DNA, which was identified to be effective for highly sensitive detection of HIV-1 DNA. The enhanced fluorescence signal has a relationship with the ssDNA concentration, the detection limit is as low as 1.2 nmol L-1 with good selectivity. This study is an important step toward rational design of materials to achieve specific interactions between biomolecules and synthetic particle surfaces. PMID- 29382469 TI - Eight human OPA1 isoforms, long and short: What are they for? AB - OPA1 is a dynamin-related GTPase that controls mitochondrial dynamics, cristae integrity, energetics and mtDNA maintenance. The exceptional complexity of this protein is determined by the presence, in humans, of eight different isoforms that, in turn, are proteolytically cleaved into combinations of membrane-anchored long forms and soluble short forms. Recent advances highlight how each OPA1 isoform is able to fulfill "essential" mitochondrial functions, whereas only some variants carry out "specialized" features. Long forms determine fusion, long or short forms alone build cristae, whereas long and short forms together tune mitochondrial morphology. These findings offer novel challenging therapeutic potential to gene therapy. PMID- 29382470 TI - Diagnostic implications of enumerating and reporting beta fraction(s) for the detection of beta-migrating monoclonal immunoglobulins in serum protein electrophoresis. AB - BACKGROUND: Modern serum protein electrophoresis (SPE) resolves serum proteins in 6 major fractions, splitting beta (B) into beta1 (B1) and beta2 (B2). Beta migrating monoclonal immunoglobulins (B-MC) commonly integrate into normal looking peak shape(s) but may increase the fraction value, forming the basis for reflex testing. The objectives of this study were (1) to ascertain the value of beta fraction(s) reporting, and (2) to compare the diagnostic performance between different beta-flagging approaches, particularly ?B versus ?B1 and/or ?B2. METHODS: We retrospectively studied 22,900 consecutive SPEs, and identified 3974 paired SPE and immunofixation electrophoresis (IFE) results obtained from the Sebia CapillarysTM 2 and HydrasysTM electrophoresis systems respectively. ?B, ?B1 and ?B2 were defined as fraction concentrations >11, 6 and 5 g/L respectively, and their respective diagnostic metrics calculated using IFE as the reference standard. RESULTS: 32 beta-gamma bridges were B-MC negative and thus excluded. Of 3942 cases, 142, 18, 285 and 300 had ?B, ?B1, ?B2 and ?B1 and/or ?B2 respectively, while their corresponding sensitivities for B-MC were 0.38, 0.09, 0.45 and 0.54 respectively. Comparing ?B and ?B1 and/or ?B2, ?B had significantly lower sensitivity but higher specificity (0.98 Vs 0.95) and positive predictive value (0.47 Vs 0.31). All 4 beta fraction increases had odds ratios ranged from 14 to 118. CONCLUSION: Beta increases were associated with increased odds for B MC, hence providing value and justification for their reporting and reflex testing. ?B1 and/or ?B2 detected more B-MC than ?B, supporting separate reporting of B1 and B2. PMID- 29382471 TI - Establishing reference intervals for ALT, AST, UR, Cr, and UA in apparently healthy Chinese adolescents. AB - BACKGROUND: The current child-specific reference intervals (RIs) are inadequate or even unavailable for many analyses in China. Many of the RIs used in Chinese laboratories were derived from Chinese adult standards or from foreign studies. The aim of this study was to establish specific RIs for alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (UR), creatinine (Cr) and uric acid (UA) for apparently healthy Chinese adolescents. METHODS: Overall, 1682 apparently healthy adolescents were enrolled. Serum ALT, AST, UR, Cr and UA were measured by an ARCHITECT C-8000 automated chemistry analyzer. The 2.5th and 97.5th percentile RIs were determined using non-parametric methods. RESULTS: The established reference intervals for ALT, AST, UR, CR and UA were 7.5-42.8 U/L, 12.8-40.2 U/L, 3.12-6.38 mmol/L, 42.7-91.2 MUmol/L, and 180.2-409.6 MUmol/L in boys and 6.5-32.8 U/L, 10.4-32.5 U/L, 3.05-6.47 mmol/L, 40.2-88.8 MUmol/L and 176.5-394.0 MUmol/L in girls, respectively. The median and upper and lower limits for the RIs of ALT, AST, Cr and UA were higher in boys than they were in girls (P < 0.05). CONCLUSION: RIs based on adult criteria are not applicable to adolescents. It was necessary to establish specific, accurate and suitable RIs for Chinese adolescents. We have established reference intervals of ALT, AST, UR, Cr and UA that are defined specifically for Chinese adolescents and are appropriate for universal use among Chinese laboratories. PMID- 29382472 TI - Exercise-Induced Pulmonary Hypertension: Translating Pathophysiological Concepts Into Clinical Practice. AB - Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output < 10 L/min and a total pulmonary vascular resistance> 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise. PMID- 29382473 TI - Investigation of Public Perception of Brain Death Using the Internet. AB - BACKGROUND: Brain death is a difficult concept for the public to comprehend, resulting in a reliance on alternative resources for clarity. This study aims to understand the public's perception of brain death via analysis of information on the Internet, determine the accuracy of that information, and understand how its perception affects the physician-patient relationship. METHODS: We conducted a prospective cross-sectional study to evaluate information available to the public about brain death. The top 10 Google websites were analyzed for language complexity and accuracy in describing brain death. The top 10 YouTube videos were examined for content and the comments qualitatively analyzed for themes. RESULTS: Inaccuracies describing brain death inconsistent with national guidelines were prevalent amongst 4 of 10 Google websites, 6 of 10 YouTube videos, and 80% of YouTube comments. On average, Google websites were written at a 12th grade level and 90% mentioned organ donation. Videos were frequently emotional (78%); 33% included negative comments toward physicians, of which 50% mentioned organ donation. All videos included clarification comments questioning the differences between brain death, death, coma, and persistent vegetative states. CONCLUSIONS: The study revealed a significant amount of inaccurate information about brain death, affecting the public's understanding of the concept of brain death and resulting in negative emotions specifically toward physicians, and the link between brain death and organ donation. The medical community can improve understanding through consistent, simplified language, dissociating brain death from organ donation, and recognizing the emotions tied to discussions of brain death. PMID- 29382474 TI - [Archibald Cochrane: evidence, effectiveness and decision-making in health]. AB - Nowadays, Evidence-Based Medicine plays a fundamental role while making medical decisions, considering that through the methods of science, it attempts to justify the variety of alternatives that may be offered to patients. In order to understand the historical evolution of this way of practicing medicine, it is necessary to review the contribution of one of the main participants in this cultural movement: Archibald Leman Cochrane, who helped to define the theoretical framework that has allowed the integration of science into the practice of medicine. Since he insisted in the need of integrating scientific evidence into clinical experience, his role became a fundamental and decisive element in the development of a new discipline: Evidence-Based Medicine. PMID- 29382475 TI - [Autoimmune hepatitis in the pediatric age]. AB - In pediatrics, autoimmune hepatitis and sclerosing cholangitis are liver disorders with an immunological damage mechanism. Autoimmune hepatitis is a disease of unknown etiology characterized by interface hepatitis, hypergammaglobulinemia, circulating autoantibodies and a favorable response to immunosuppression. It is an eminently pediatric disease with a prevalent condition in young women. Therapy should be instituted promptly to prevent rapid deterioration, promote remission of disease and long-term survival. The persistent lack of response or lack of adherence to treatment results in terminal liver failure; these patients, and those with fulminant hepatic insufficiency at the time of diagnosis, will require liver transplantation. PMID- 29382476 TI - [Factors associated with epilepsy in children in Mexico: A case-control study]. AB - BACKGROUND: Epilepsy is the most common chronic neurological disease in the world. In Mexico, epilepsy is among the diseases more related to mortality due to non-infectious diseases in children. The objective of the study was to identify the factors associated with epilepsy in children entitled to the Mexican Social Security Institute (IMSS), in Acapulco, Mexico. METHODS: We carried out a case control study from April 2010 to April 2011. We selected 118 cases from the database of outpatient pediatric neurology with epilepsy diagnostic with two year of evolution according to the International League Against Epilepsy criteria. We selected 118 controls from the same Medical Units where cases were detected. Data collected throughout an interview with the mothers included information on history of epilepsy among relatives, prenatal, perinatal and postnatal history. Bivariate and multivariate analysis was performed using Mantel-Haenszel process. RESULTS: Multivariate analysis identified three factors associated with epilepsy: family history of epilepsy in first-degree relatives (adjusted Odds ratio (ORa) 2.44, 95%CI 1.18 -5.03), birth asphyxia (ORa 2.20, 95%CI 1.16-34.18), and urinary tract infection in the prenatal stage (ORa, 1.80, 95%CI 1.0 - 3.24). CONCLUSIONS: Preventing birth asphyxia and urinary tract infections during pregnancy reduces the risk of epilepsy regardless of the history of epilepsy in first-degree relatives. PMID- 29382477 TI - [Tolerance, safety and efficacy of the one-day preparation of PEG3350 + bisacodyl compared to 2 days of PEG3350 + bisacodyl in pediatric patients]. AB - BACKGROUND: Multiple intestinal preparations have been used in children undergoing colonoscopy, with variable limitation due to acceptance, tolerance, and proper cleaning. The objective of this study was to compare the tolerability, safety and efficacy of the colonoscopy preparation with 1 day with PEG 3350 (poliethylenglycol) (4g/kg/day) + bisacodyl compared to 2 days of preparation with PEG 3350 (2g/kg/day) + bisacodyl in pediatric patients. METHODS: A clinical, randomized, and blind trial was performed. Patients aged 2 to 18 years scheduled for colonoscopy were included. Patients were randomized into two groups: 1 day of preparation with PEG 3350 4g/kg/day + bisacodyl and 2 days of preparation with PEG 3350 2g/kg/day + bisacodyl. Through a questionnaire, physical examination and endoscopic evaluation (Boston scale), the tolerance, safety and efficacy of the 2 preparations to be evaluated were determined. Student's t test was performed for quantitative variables and chi2 for qualitative variables. RESULTS: There were no significant differences in compliance rates, adverse effects, and extent of colonoscopic evaluation. CONCLUSIONS: Tolerance and safety between the intestinal preparation for 1-day colonoscopy with PEG 3350 (4g/kg/day) + bisacodyl and the 2 day preparation with PEG 3350 (2g/kg/day) + bisacodyl were similar. The quality of cleanliness was good in both groups, being partially more effective in the 1 day group with PEG 3350 (4g/kg/day). PMID- 29382478 TI - [The counseling of nursing decreases symptomatology and relapses in pediatric patients with allergic rhinitis]. AB - BACKGROUND: Allergic rhinitis (AR) is considered to be a public health problem, therefore it is essential to test health education strategies such as nursing counseling (NC) aimed at population groups such as children with allergic rhinitis and their tutors. This study aimed to measure the health benefits of children with this disease for a year. METHODS: Longitudinal, randomized, comparative study with a sample of 100 pediatric patients of both sexes, aged 6 to 12 years, with diagnosis of allergic rhinitis, with counseling (study group) and without counseling (control group). In both groups, an informed consent letter signed by both tutors was obtained, in addition to knowledge and assessment papers; the latter included a scale of symptomatology and Morisky Green (adherence to treatment). The children in the study group received intervention based on personalized education, didactic material, support of the multidisciplinary group if necessary (doctor, dermatologist and psychologist). The control group received usual care. In both groups, telephone follow-up was performed, which allowed the number of relapses to be identified in one year. RESULTS: The Wilcoxon rank-sum test (Mann-Whitney) was used to compare the results; the presence of relapses in the control group was statistically significant compared to the study group. CONCLUSIONS: It was found that the infant population that receives NC, has as a better benefit the control of the symptomatology and decrease of relapses per year. PMID- 29382479 TI - [Does a Physical Education lesson affect the foot morphology in school-aged children?] AB - BACKGROUND: To analyze the changes in foot morphology in school-age children, after a Physical Education lesson. METHODS: A total of 10 school-age children (5 girls and 5 boys) were recruited with a mean age of 9.3 +/- 0.5 years that voluntary participated in this study. Measurements of both feet were obtained using a 3D foot digitizer model IFU-S-01 (Japan) in two different moments, before and after a physical education lesson (per-exercise and post-exercise), where different activities involving displacements, jumps and landings were performed. RESULTS: By comparing foot morphology before and after exercise, significant differences in the arch height were found, which increased after exercise (p<0.05). The ball width shows greater changes after exercise but without significant differences (p= 0.07; effect size [ES] = 0.2). Furthermore, a positive correlation between the ball width and the arch height (p<0.05) and negative correlation between the distance from the heel to the first metatarsal and the ball width (r = - 0.7; p<0.05), were observed. CONCLUSIONS: The type of activities undertaken during physical education lesson (displacements, jumps and landings) increased the pressure on the forefoot, which would lead to a lager arch height. Development of children's sport footwear systems should take into account the foot lengths, widths and heights, for a better fit, preventing future musculoskeletal injuries. PMID- 29382480 TI - [Association between homozygous c.318A>GT mutation in exon 2 of the EIF2B5 gene and the infantile form of vanishing white matter leukoencephalopathy]. AB - BACKGROUND: Vanishing white matter disease is one of the most frequent leukodystrophies in childhood with an autosomal recessive inheritance. A mutation in one of the genes encoding the five subunits of the eukaryotic initiation factor 2 (EIF2B5) is present in 90% of the cases. The diagnosis can be accomplished by the clinical and neuroradiological findings and molecular tests. CASE REPORT: We describe a thirteen-month-old male with previous normal neurodevelopment, who was hospitalized for vomiting, hyperthermia and irritability. On examination, cephalic perimeter and cranial pairs were normal. Hypotonia, increased muscle stretching reflexes, generalized white matter hypodensity on cranial tomography were found. Fifteen days after discharge, he suffered minor head trauma presenting drowsiness and focal seizures. Magnetic resonance showed generalized hypointensity of white matter. Vanishing white matter disease was suspected, and confirmed by sequencing of the EIF2B5 gene, revealing a homozygous c.318A> T mutation in exon 2. Subsequently, visual acuity was lost and cognitive and motor deterioration was evident. The patient died at six years of age due to severe pneumonia. CONCLUSIONS: This case contributes to the knowledge of the mutational spectrum present in Mexican patients and allows to extend the phenotype associated to this mutation. PMID- 29382481 TI - [Disseminated aspergillosis due to Aspergillus flavus in a pediatric patient with a recent diagnosis of acute lymphoblastic leukemia]. PMID- 29382482 TI - [Facing a new generation of hospital pathogens in Pediatrics]. PMID- 29382483 TI - Clinical Proteomics in Mexico: where do we stand? PMID- 29382484 TI - Mitochondrial proteomic profile of complex IV deficiency fibroblasts: rearrangement of oxidative phosphorylation complex/supercomplex and other metabolic pathways. AB - BACKGROUND: Mitochondriopathies are multisystem diseases affecting the oxidative phosphorylation (OXPHOS) system. Skin fibroblasts are a good model for the study of these diseases. Fibroblasts with a complex IV mitochondriopathy were used to determine the molecular mechanism and the main affected functions in this disease. METHODS: Skin fibroblast were grown to assure disease phenotype. Mitochondria were isolated from these cells and their proteome extracted for protein identification. Identified proteins were validated with the MitoMiner database. RESULTS: Disease phenotype was corroborated on skin fibroblasts, which presented a complex IV defect. The mitochondrial proteome of these cells showed that the most affected proteins belonged to the OXPHOS system, mainly to the complexes that form supercomplexes or respirosomes (I, III, IV, and V). Defects in complex IV seemed to be due to assembly issues, which might prevent supercomplexes formation and efficient substrate channeling. It was also found that this mitochondriopathy affects other processes that are related to DNA genetic information flow (replication, transcription, and translation) as well as beta oxidation and tricarboxylic acid cycle. CONCLUSIONS: These data, as a whole, could be used for the better stratification of these diseases, as well as to optimize management and treatment options. PMID- 29382485 TI - Proteomic changes in a childhood acute lymphoblastic leukemia cell line during the adaptation to vincristine. AB - INTRODUCTION: Relapse occurs in approximately 20% of Mexican patients with childhood acute lymphoblastic leukemia (ALL). In this group, chemoresistance may be one of the biggest challenges. An overview of complex cellular processes like drug tolerance can be achieved with proteomic studies. METHODS: The B-lineage pediatric ALL cell line CCRF-SB was gradually exposed to the chemotherapeutic vincristine until proliferation was observed at 6nM, control cells were cultured in the absence of vincristine. The proteome from each group was analyzed by nanoHPLC coupled to an ESI-ion trap mass spectrometer. The identified proteins were grouped into overrepresented functional categories with the PANTHER classification system. RESULTS: We found 135 proteins exclusively expressed in the presence of vincristine. The most represented functional categories were: Toll receptor signaling pathway, Ras Pathway, B and T cell activation, CCKR signaling map, cytokine-mediated signaling pathway, and oxidative phosphorylation. CONCLUSIONS: Our study indicates that signal transduction and mitochondrial ATP production are essential during adaptation of leukemic cells to vincristine, these processes represent potential therapeutic targets. PMID- 29382486 TI - Characterization of Cry toxins from autochthonous Bacillus thuringiensis isolates from Mexico. AB - BACKGROUND: Chemical pesticides, widely used in agriculture and vector-borne disease control, have shown toxic effects on the environment and the people in contact with them. Bacillus thuringiensis is a widely used bacterium for alternative and safer control of insect pests. Its toxins are specific for insects but innocuous for mammals and may be used as powerful adjuvants when applied with vaccines. The objective of this work was to characterize some autochthonous B. thuringiensis strains, which could be used for the control of a local pest (Diatraea considerata Heinrich) that affects sugar cane crops in Sinaloa, Mexico. Also, to evaluate these strains as a source of Cry toxins, which may be used in the future as adjuvants for some vaccines. METHODS: Eight strains from field-collected dead insects were isolated. These were microbiologically identified as B. thuringiensis and confirmed by amplification and sequencing of 16S rDNA. Bioassays were performed to evaluate their pathogenicity against D. considerata, and Cry toxins were identified by proteomic analyses. RESULTS: An increased mortality among larvae infected with strain Bt-D was observed, and its toxin was identified as Cry1Ac. CONCLUSIONS: The observed data showed that the selected strain was pathogenic to D. considerata and seemed to produce Cry1Ac protein, which has been reported as an adjuvant in different types of immunization. PMID- 29382487 TI - Displacers improve the selectivity of phosphopeptide enrichment by metal oxide affinity chromatography. AB - BACKGROUND: A key process in cell regulation is protein phosphorylation, which is catalyzed by protein kinases and phosphatases. However, phosphoproteomics studies are difficult because of the complexity of protein phosphorylation and the number of phosphorylation sites. METHODS: We describe an efficient approach analyzing phosphopeptides in single, separated protein by two-dimensional gel electrophoresis. In this method, a titanium oxide (TiO2)-packed NuTip is used as a phosphopeptide trap, together with displacers as lactic acid in the loading buffer to increase the efficiency of the interaction between TiO2 and phosphorylated peptides. RESULTS: The results were obtained from the comparison of mass spectra of proteolytic peptides of proteins with a matrix-assisted laser desorption-ionization-time of flight (MALDI-TOF) instrument. CONCLUSIONS: This method has been applied to identifying phosphoproteins involved in the symbiosis Rhizobium etli-Phaseolus vulgaris. PMID- 29382488 TI - The dawn and the first twenty-five years of proteomics in Mexico: a personal chronicle. AB - This review does not aim to be an up-to-date of proteomics in Mexico; it simply tries to trace its development, exposing the story of the researchers, laboratories and some institutions that have contributed to the establishment and development of this science in Mexico. PMID- 29382489 TI - MALDI imaging: beyond classic diagnosis. AB - Mass spectrometry has been the focus of technology development and application for imaging for several decades. Imaging mass spectrometry using matrix-assisted laser desorption ionization is a new and effective tool for molecular studies of complex biological samples such as tissue sections. As histological features remain intact throughout the analysis of a section, distribution maps of multiple analytes can be correlated with histological and clinical features. Spatial molecular arrangements can be assessed without the need for target-specific reagents, allowing the discovery of diagnostic and prognostic markers of different cancer types and enabling the determination of effective therapies. PMID- 29382490 TI - Omics-based biomarkers: current status and potential use in the clinic. AB - In recent years, the use of high-throughput omics technologies has led to the rapid discovery of many candidate biomarkers. However, few of them have made the transition to the clinic. In this review, the promise of omics technologies to contribute to the process of biomarker development is described. An overview of the current state in this area is presented with examples of genomics, proteomics, transcriptomics, metabolomics and microbiomics biomarkers in the field of oncology, along with some proposed strategies to accelerate their validation and translation to improve the care of patients with neoplasms. The inherent complexity underlying neoplasms combined with the requirement of developing well-designed biomarker discovery processes based on omics technologies present a challenge for the effective development of biomarkers that may be useful in guiding therapies, addressing disease risks, and predicting clinical outcomes. PMID- 29382491 TI - Omics techniques and biobanks to find new biomarkers for the early detection of acute lymphoblastic leukemia in middle-income countries: a perspective from Mexico. AB - Acute lymphoblastic leukemia (ALL) affects the quality of life of many children in the world and particularly in Mexico, where a high incidence has been reported. With a proper financial investment and with well-organized institutions caring for those patients, together with solid platforms to perform high throughput analyses, we propose the creation of a Mexican repository system of serum and cells from bone marrow and blood samples derived from tissues of pediatric patients with ALL diagnosis. This resource, in combination with omics technologies, particularly proteomics and metabolomics, would allow longitudinal studies, offering an opportunity to design and apply personalized ALL treatments. Importantly, it would accelerate the development of translational science and will lead us to further discoveries, including the identification of new biomarkers for the early detection of leukemia. PMID- 29382492 TI - Proteomics: a tool to develop novel diagnostic methods and unravel molecular mechanisms of pediatric diseases. AB - Proteomics is the study of the expression of changes and post-translational modifications (PTM) of proteins along a metabolic condition either normal or pathological. In the field of health, proteomics allows obtaining valuable data for treatment, diagnosis or pathophysiological mechanisms of different illnesses. To illustrate the aforementioned, we describe two projects currently being performed at the Instituto Nacional de Pediatria: The immuno-proteomic study of cow milk allergy and the Proteomic study of childhood cataract. Cow's milk proteins (CMP) are the first antigens to which infants are exposed and generate allergy in some of them. In Mexico, the incidence of CMP allergy has been estimated at 5-7%. Clinical manifestations include both gastrointestinal and extra-gastrointestinal symptoms, making its diagnosis extremely difficult. An inappropriate diagnosis affects the development and growth of children. The goals of the study are to identify the main immune-reactive CMP in Mexican pediatric population and to design more accurate diagnostic tools for this disease. Childhood cataract is a major ocular disease representing one of the main causes of blindness in infants; in developing countries, this disease promotes up to 27% of cases related to visual loss. From this group, it has been estimated that close to 60% of children do not survive beyond two years after vision lost. PTM have been pointed out as the main cause of protein precipitation at the crystalline and, consequently, clouding of this tissue. The study of childhood cataract represents an outstanding opportunity to identify the PTM associated to the cataract-genesis process. PMID- 29382493 TI - A model and analysis for the nonlinear amplification of waves in the cochlea. AB - A nonlinear three-dimensional model for the amplification of a wave in the cochlea is analyzed. Using the long-slender geometry of the cochlea, and the relatively high frequencies in the hearing spectrum, an asymptotic approximation of the solution is derived for linear, but spatially inhomogeneous, amplification. From this, a nonlinear WKB approximation is constructed for the nonlinear problem, and this is used to derive an efficient numerical method for solving the amplification problem. The advantage of this approach is that the very short waves needed to resolve the wave do not need to calculated as they are represented in the asymptotic solution. PMID- 29382494 TI - [Clinical-epidemiological study in children with cleft lip palate in a secondary level hospital]. AB - BACKGROUND: One of the most common congenital disorders that affects the facial structures is the cleft lip palate (CLP). The aim of this study was to generate the clinical-epidemiological profile of CLP patients from Hospital de Especialidades del Nino y la Mujer (HENM) Dr. Felipe Nunez Lara, from the Ministry of Health, Queretaro, Mexico, from 2011 to 2014, who received treatment from the Cleft Lip Palate Clinic in order to provide interdisciplinary treatments for CLP patients based on the information from the pediatric records. METHODS: Retrospective, cross-sectional, observational study using univariate analysis frequencies for qualitative variables; central statistical and dispersion for quantitative variables and clinical profile. One hundred records were reviewed, from which 15 were discarded for being syndromic cases. Epidemiological, clinical, and socio-demographic variables were studied. RESULTS: The epidemiological profile (variables associated with mother's pregnancy, patient's health at birth, nutritional and psychomotor development; family medical records, addictions, and socioeconomic factors) and clinical profile (disease classification by sex, structure, and side; surgeries classification and order in which they took place) of the treated population were registered. CONCLUSIONS: The results showed the need to standardize the data registration on medical records to improve the monitoring and treatment of patients and emphasize actions to maintain low incidence of CLP in Queretaro. PMID- 29382495 TI - [Cytopathologic features of childhood acute leukemia at the Hospital de Especialidades Pediatricas, Chiapas, Mexico]. AB - BACKGROUND: Childhood acute leukemia cytological features are unknown in Chiapas, Mexico. Defining these features is important because this is a relatively isolated population with high consanguinity index, and these aspects could determine differences in responses to treatment and outcome. METHODS: Eighty-one childhood acute leukemia cases treated at the Hospital de Especialidades Pediatricas in Chiapas were characterized by morphology, immunophenotype, genotype, initial risk assignment and status at the time of the study. RESULTS: The proportion of leukemic cell types found in this study was B cell, 75.3%; myeloid, 16%; T cell, 3.7% and NK 1.2%. In B cell leukemia, genetic alterations were present in 40.6% of cases and had a specific outcome regardless of initial risk assessment. Cases with MLL gene alteration died within a month from diagnosis. Translocations were present in 17.5% B cases; t(1;19) was present in those with a favorable outcome. The t(12;21) translocation was related to initial remission and midterm relapse and dead. Hyperdiploidy was present in 20% of B cell cases with good outcome. In 38.5%of myeloid cases were translocations and karyotypic abnormalities. Short-term outcome in this group has been poor; 69% have died or abandoned treatment in relapse from 15 days to 37 months after diagnosis. CONCLUSIONS: Relative frequency of different types of acute leukemia in patients treated at a tertiary level pediatric hospital in Chiapas, Mexico, was similar to the one found in other parts of the country. Patients' outcome, under a standardized treatment, differs according to the group, the subgroup and the presence and type of genetic alterations. PMID- 29382496 TI - [Orbital cellulitis complicated by subperiosteal abscess due to Streptococcus pyogenes infection]. AB - BACKGROUND: Orbital cellulitis is an infectious disease that is very common in pediatric patients, in which severe complications may develop. Etiological agents related to this disease are Haemophilus influenzae B, Staphylococcus aureus, Streptococcus pneumoniae and Moraxella catarrhalis, which correspond to 95% of cases. Moreover, Streptococcus beta hemolytic and anaerobic microorganisms may also be present corresponding to < 5% of the cases. We present an uncommon case of cellulitis complicated by sub-periosteal abscess caused by Streptococcus pyogenes (Group A beta hemolytic streptococcus). CASE REPORT: A 9-year-old male patient with a history of deficit disorder and hyperactivity since 5 years of age. His current condition started with erythema in the external edge of the right eye, increase in peri-orbicular volume with limitation of eyelid opening, progression to proptosis, pain with eye movements and conjunctival purulent discharge. Image studies reported subperiosteal abscess and preseptal right with extraocular cellulitis. The patient started with empirical antibiotic treatment, surgical drainage and culture of purulent material from which Streptococcus pyogenes was isolated. CONCLUSIONS: Due to the implementation of vaccination schemes against H. influenza and S. pneumoniae since the 90s, the cases by these pathogens have decreased, causing new bacteria to take place as the cause of the infection. The importance of considering S. pyogenes as an etiology of orbital cellulitis is the rapid progression to abscess formation, and the few cases described in the literature. PMID- 29382497 TI - [Evans syndrome in infants]. AB - BACKGROUND: Evans syndrome is characterized by the reduction of at least two blood cell lineages in the absence of other diagnoses; it was previously described as the simultaneous or sequential development of autoimmune hemolytic anemia and immune thrombocytopenia with unknown etiology. An incidence of 37% and mortality rate of 10% were reported for Evans syndrome. CLINICAL CASES: We report the clinical presentation and evolution of Evans syndrome in two infants who were initially diagnosed with immune thrombocytopenia. The clinical diagnosis was supported on complementary studies, where hematological disorders were corroborated. Both cases received treatment with steroids and intravenous immunoglobulin. CONCLUSIONS: For the management of children with thrombocytopenia, the pediatrician must analyze for other cell lineage disorders. In the cases that we report here, we found the presence of autoimmune hemolytic anemia and monocytosis. Therefore, infectious and immunological studies must be included. The first-line treatment of choice are steroids, and intravenous immunoglobulin can be considered if severe immune thrombocytopenia is associated, as observed in these cases. PMID- 29382498 TI - [Pontine glioma. Pediatric gliomas and the new World Health Organization classification of tumors of the central nervous system]. PMID- 29382499 TI - [The jibarization of logos: how medical reductionism can kill]. AB - In recent decades, a disciplinary and subdisciplinary proliferation has triggered both in the medical fields and science in general. This trend may be partially explained by two diachronic, dialectically interconnected facts: the deepening of technical, social and international division of labor in the globalized capitalist world, and the triumph of the reductionist program, mainly developed by the logical empiricism of the Vienna Circle. This paper aims to deepen the debate on the intricate links between medicine, biology, philosophy, reductionism and complex thought, by using two examples: a case report of current medicine and the situation experienced by a famous American scientist, Stephen Jay Gould, about his first cancer, an abdominal mesothelioma. We have witnessed how the two above-mentioned historical facts have been operating as a super-structure like a pair of "tweezers", dismembering and compressing at the same moment the object of knowledge, the theories that allow their study, and the subject that receives the knowledge. This jibarization of logos is a real problem for public health, from the moment that it impacts, omnipresent, in the actual hegemonic medical model, leading to potentially dangerous attitudes to the various components of health systems. PMID- 29382500 TI - [Education in our time: competency or aptitude? The case for medicine. Part I]. AB - This paper begins with a statement: It is necessary to characterize the respective society to be able to understand the education's core. Distinctive features of the present-day world lead us to define it as the ruin of a civilization based on limitless financial gain, where education has a passive quality, responsible of maintaining the status quo as well as preserving the degrading attributes of actual societies: individualism, passivity, competitiveness, consumerism and high vulnerability to control and manipulation. About the dilemma: competency or aptitude, these are not synonyms but concepts pertaining radically different approaches to the practice and understanding of education. Competency represents the actual tendencies of passive education, where knowledge is just about acquiring information. Aptitude refers to participatory education, described in the second part of this essay. The passive education is present in the professional competencies model, specified in terms of curricula, profiles, levels, school activities, evaluation, concept of progress and social consequences. This paradigm does not foster real progress defined as the primacy of values sustaining spiritual, intellectual and moral development but as an "accomplice" of the civilization's collapse. PMID- 29382501 TI - [Childcare and child development in Mexico: progress and challenges]. PMID- 29382502 TI - [Advances in early childhood development: from neurons to big scale programs]. AB - Early childhood development (ECD) is the basis of countries' economic and social development and their ability to meet the Sustainable Development Goals (SDGs). Gestation and the first three years of life are critical for children to have adequate physical, psychosocial, emotional and cognitive development for the rest of their lives. Nurturing care and protection of children during gestation and early childhood are necessary for the development of trillions of neurons and trillions of synapses necessary for development. ECD requires access to good nutrition and health services from gestation, responsive caregiving according to the child's developmental stage, social protection and child welfare, and early stimulation and learning opportunities. Six actions are recommended to improve national ECD programs: expand political will and funding; create a supportive, evidence-based policy environment; build capacity through inter-sectoral coordination; ensure fair and transparent governance of programs and services; increase support for multidisciplinary research; and promote the development of leaders. Mexico has made significant progress under the leadership of the Health Ministry, but still faces significant challenges. The recent creation of a national inter-sectoral framework to enable ECD with support of international organizations and the participation of civil society organizations can help overcome these challenges. PMID- 29382503 TI - [Association between time of permanence at early education program (Estancias Infantiles) and developmental level for children in situation of poverty]. AB - BACKGROUND: Early education program (EEP) was created to support parents with 1 to 3 year olds living in poverty situation in Mexico, and includes education and child daycare for 8h five days per week. The objective of this study was to evaluate the association between length of stay in EEP and the level of development in children. METHODS: Cross sectional, population-based study conducted in two Mexican states. All children aged between 12 to 48 months enrolled in EEP from November 2014 to January 2015 were included. Child Development Evaluation (CDE) test was used to screen early development in every child. Normal early development prevalence odds ratio (OR) was calculated adjusted by gender, impairment and state, using as a reference those children with less than 30 days in the program. RESULTS: The study included 3,387 children from 177 EEP nurseries, from which 53% were male; age by group was divided in 12 24 months (22.3%), 25-36 months (37.6%) and 37-42 months (40.1%). Normal development adjusted OR by age was 1.9 (CI95%: 1.30-2.78) for 6-11 months, 2.36 (CI95%: 1.60-3.50) for 12-17 months, 2.78 (CI95%: 1.65-4.65) for 18-23 months and 3.46 (CI95%: 2.13-5.60) for >24 months. By area of development, a greater probability of having a normal result for language and social areas was observed after 6 months in the program, and for motor (both gross and fine) and knowledge areas after 12 months. CONCLUSION: The length of the stay in the EEP after 6 months significantly and progressively increases the probability of normal development regardless of gender and age. PMID- 29382504 TI - Balanced high fat diet reduces cardiovascular risk in obese women although changes in adipose tissue, lipoproteins, and insulin resistance differ by race. AB - BACKGROUND: We previously reported that consuming a balanced high fat diet (BHFD) wherein total saturated fat was reduced and total unsaturated fat increased by proportionately balancing the type of fat (1/3 saturated, 1/3 monounsaturated, 1/3 polyunsaturated) led to significant improvements in inflammatory burden, blood pressure, and vascular function in obese premenopausal European American (EA) and African American (AA) women. OBJECTIVE: Here we compared changes in adipose tissue, lipoproteins, insulin resistance, and cardiovascular risk between EA and AA women. METHODS: Dietary intakes, plasma fatty acids, lipids, apolipoproteins, lipoproteins, HOMA-IR and ASCVD risk was measured in 144 women who consumed BHFD for 16 weeks. Generalized linear modeling was performed while controlling for change in body weight. RESULTS: EA women had greater reductions in visceral adipose tissue. Only EA women had significant reductions in fasting insulin levels (?24.8%) and HOMA-IR (?29%) scores. In EA women, the most significant improvements occurred in VLDL particle size (?), apolipoprotein B levels (?), serum TG (?), number of plasma LDL particles (?), and serum LDL cholesterol (?). In AA women, significant improvements occurred in HDL particle size (?), number of large HDL particles (?), and apolipoprotein AI levels (?). Consequently, both groups had improved ASCVD risk scores (?5.5%). CONCLUSIONS: Consuming the balanced high fat diet led to significant reduction in cardiovascular risk factors in both groups. However, the pattern of response to BHFD differed with EA women responding more in components of the apolipoprotein B pathway versus AA women responding more in components of the apolipoprotein AI pathway. PMID- 29382505 TI - Independent relationships between cardinal features of obstructive sleep apnea and glycometabolism: a cross-sectional study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with abnormal glycometabolism; however, the cardinal features of OSA, such as sleep fragmentation (SF) and intermittent hypoxia (IH), have yet to show clear, independent associations with glycometabolism. METHODS: We enrolled 1834 participants with suspected OSA from July 2008 to July 2013 to participate in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected for each participant. Multiple linear regression analyses were used to evaluate independent associations between cardinal features of OSA and glycometabolism. Logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose metabolism across microarousal index (MAI) and oxygen desaturation index (ODI) quartiles. The effect of the interaction between MAI and ODI on glycometabolism was also evaluated. RESULTS: The MAI was independently associated with fasting insulin levels (beta = 0.024, p = 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR; beta = 0.006, p = 0.002) after multiple adjustments of confounding factors. In addition, the ORs for hyperinsulinemia across higher MAI quartiles were 1.081, 1.349, and 1.656, compared with the lowest quartile (p = 0.015 for a linear trend). Similarly, the ODI was independently associated with fasting glucose levels (beta = 0.003, p < 0.001), fasting insulin levels (beta = 0.037, p < 0.001), and the HOMA-IR (beta = 0.010, p < 0.001) after adjusting for multiple factors. The ORs for hyperglycemia across higher ODI quartiles were 1.362, 1.231, and 2.184, compared with the lowest quartile (p < 0.05 for a linear trend). In addition, the ORs for hyperinsulinemia and abnormal HOMA-IR across ODI quartiles had the same trends. There was no interaction between MAI and ODI with respect to glycometabolism. CONCLUSION: SF was independently associated with hyperinsulinemia, and IH was independently associated with hyperglycemia, hyperinsulinemia, and an abnormal HOMA-IR. We found no interaction between SF and IH with respect to OSA-related abnormal glycometabolism. PMID- 29382506 TI - Klinefelter syndrome: more than hypogonadism. AB - Klinefelter syndrome (KS) is the most frequent chromosome disorder in males (1:650 newborn males), defined by 47,XXY karyotype. The classical phenotype is that of a tall male with relatively long legs, small, firm testes and gynecomastia. Azoospermia and infertility are almost inevitably present, but may be overcome by TESE and ICSI. Nevertheless, a broad spectrum of phenotypes has been described and more than 70% of the actually existing KS men may remain undiagnosed throughout their lifespan. Accordingly, hypogonadism is usually not evident until early adulthood and progresses with ageing. KS patients present a series of comorbidities that increase morbidity and mortality by 40%. Such disturbances are the impaired metabolic profile (obesity, dyslipidemia, insulin resistance) and a tendency to thrombosis, which all favor cardiovascular disease. They also present susceptibility for specific neoplasias (breast cancer, extragonadal germ cell tumors), autoimmune diseases as well as osteoporosis and bone fractures. Moreover, KS has been associated with verbal processing and attention deficits as well as social skill impairments, leading KS individuals to academic and professional achievements inferior to those of their peers of comparable socio-economic status. Nevertheless, the majority fall within the average range regarding their intellectual abilities and adaptive functioning. Testosterone replacement therapy (TRT) is the mainstay of treatment in hypogonadal KS patients; however, randomized trials are needed to determine optimal therapeutic regimens and follow-up schedules. PMID- 29382507 TI - Spontaneous Pneumomediastinum After Electronic Cigarette Use. AB - Spontaneous pneumomediastinum is an uncommon condition typically occurring in young men presenting with pleuritic pain, dyspnea, and subcutaneous emphysema. We report an exceptional case of spontaneous pneumomediastinum after electronic cigarette use in an otherwise healthy young man. PMID- 29382508 TI - Good at One or Good at All? Variability of Coronary and Valve Operation Outcomes Within Centers. AB - BACKGROUND: The technical expertise required for treatment of coronary and structural heart valve disease differs. Correlation between center-specific mortality rates after coronary artery bypass grafting (CABG) and valve operations has not been demonstrated. This study tested the hypothesis that risk-adjusted outcomes between coronary and valve procedures do not correlate within centers. METHODS: Records of patients undergoing isolated CABG, isolated aortic valve replacement (AVR), or isolated mitral valve replacement (MVR) procedures from 2008 to 2015 in a multi-institutional Society of Thoracic Surgeons (STS) database were used to generate observed-to-expected (O/E) ratios for morbidity and death. Ratios were based on the STS predicted risks of morbidity and death and were calculated by procedure for each institution. Linear regression models evaluated the relationship between institutional performance in CABG and valve operations. RESULTS: A total of 22,258 records from 18 institutions were analyzed: 17,026 CABG, 3,238 isolated AVR, and 1,994 MVR procedures. With respect to deaths, the correlation coefficients were weak; for AVR and CABG, it was 0.22 and was 0.26 for MVR and CABG. With respect to morbidity, a strong relationship was seen between the morbidity O/E ratios, with coefficients of 1.03 for AVR and 0.97 for MVR, suggesting a nearly 1:1 relationship between morbidities observed in an institution's CABG and valve operations. CONCLUSIONS: Sites that perform CABG with low mortality rates may not have similarly low mortality rates with valve operations. Most striking, however, is the nearly identical O/E ratio for morbidity for CABG and valve operations at each center. These findings suggest postoperative care as a major determinant for morbidity after cardiac operation. PMID- 29382509 TI - Active Chest Tube Clearance After Cardiac Surgery Is Associated With Reduced Reexploration Rates. AB - BACKGROUND: Ineffective evacuation of intrathoracic fluid after cardiac surgery (retained blood syndrome [RBS]) might increase postoperative complications, morbidity, and mortality. Active tube clearance (ATC) technology using an intraluminal clearing apparatus aims at increasing chest tube drainage efficiency. This study evaluated whether ATC reduces RBS in an all-comers collective undergoing scheduled cardiac surgery with cardiopulmonary bypass and full or partial median sternotomy. METHODS: In this nonrandomized prospective trial, 581 consecutive patients undergoing scheduled cardiac surgery with median sternotomy between January 2016 and December 2016 were assigned to receive conventional chest tubes (control group) or a combination of conventional tubes and as many as two ATC devices (ATC group), depending on their operation date. Postoperative occurrence of RBS (one or more of the following: reexploration for bleeding or tamponade, pericardial drainage procedure, pleural drainage procedure) and other endpoints were compared. Propensity score matching was applied. RESULTS: In 222 ATC patients and 222 matched control patients, RBS occurrence did not differ between the groups (ATC 16%, control 22%; p = 0.15). However, reexploration rate for bleeding or tamponade was significantly reduced in the ATC group compared with the control group (4.1% versus 9.1%, respectively; p = 0.015). The mortality of RBS patients (21%) was higher compared with patients without RBS (3.9%, p < 0.001). Among the RBS components, only reexploration (odds ratio 16, 95% confidence interval: 5.8 to 43, p < 0.001) was relevant for inhospital mortality (ATC 6.8%, control 7.7%; p = 0.71). CONCLUSIONS: Active tube clearance is associated with reduced reexploration rates in an all-comers collective undergoing cardiac surgery. Reexploration is the only RBS component relevant for mortality. The ATC effect does not translate into improved overall survival. PMID- 29382510 TI - Preoperative Renal Functional Reserve Predicts Risk of Acute Kidney Injury After Cardiac Operation. AB - BACKGROUND: Although acute kidney injury (AKI) frequently complicates cardiac operations, methods to determine AKI risk in patients without underlying kidney disease are lacking. Renal functional reserve (RFR) can be used to measure the capacity of the kidney to increase glomerular filtration rate under conditions of physiologic stress and may serve as a functional marker that assesses susceptibility to injury. We sought to determine whether preoperative RFR predicts postoperative AKI. METHODS: We enrolled 110 patients with normal resting glomerular filtration rates undergoing elective cardiac operation. Preoperative RFR was measured by using a high oral protein load test. The primary end point was the ability of preoperative RFR to predict AKI within 7 days of operation. Secondary end points included the ability of a risk prediction model, including demographic and comorbidity covariates, RFR, and intraoperative variables to predict AKI, and the ability of postoperative cell cycle arrest markers at various times to predict AKI. RESULTS: AKI occurred in 15 patients (13.6%). Preoperative RFR was lower in patients who experienced AKI (p < 0.001) and predicted AKI with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval [CI]: 0.70 to 0.96). Patients with preoperative RFRs not greater than 15 mL . min-1 . 1.73 m-2 were 11.8 times more likely to experience AKI (95% CI: 4.62 to 29.89 times, p < 0.001). In addition, immediate postoperative cell cycle arrest biomarkers predicted AKI with an AUC of 0.87. CONCLUSIONS: Among elective cardiac surgical patients with normal resting glomerular filtration rates, preoperative RFR was highly predictive of AKI. A reduced RFR appears to be a novel risk factor for AKI, and measurement of RFR preoperatively can identify patients who are likely to benefit from preventive measures or to select for use of biomarkers for early detection. Larger prospective studies to validate the use of RFR in strategies to prevent AKI are warranted. ClinicalTrials.gov identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. PMID- 29382511 TI - Mitral Valve-in-Valve Implantation as an Elective or Rescue Procedure in High Risk Patients. AB - BACKGROUND: Transapical transcatheter mitral valve-in-valve implantation (TA MVIVI) for bioprosthetic valve failure is an emerging alternative to reoperation in high-risk patients. We report our outcomes in a patient population with a high proportion of cardiogenic shock. METHODS: Retrospective review was performed of all patients undergoing TA-MVIVI with an Edwards Sapien (Edwards Life sciences, Irvine, CA) prosthesis at our center between the years 2013 and 2017. RESULTS: Nineteen patients with bioprosthetic mitral valve failure were included (mean age 78 +/- 12 years). All patients were New York Heart Association functional class III or greater; The Society of Thoracic Surgeons mean score was 22.0 +/- 17.5. The TA-MVIVI was performed in the setting of cardiogenic shock in 12 of 19 patients (63%). The primary mechanism for valve failure was regurgitation in 58%, stenosis in 21%, and mixed in 21%. All patients underwent successful TA-MVIVI with no deaths, strokes, or myocardial infarctions at 30 days. Two patients had brief postprocedural cardiac arrest but had full recovery. Mean transmitral gradient decreased from 12 +/- 5 mm Hg to 5 +/- 3 mm Hg (p = 0.0005). There was 1 death from unknown causes within the first year (5.2%). At a mean follow-up of 339 days (range, 30 to 1291), trace transvalvular regurgitation had developed in 3 of 19 patients (15.8%). There was no paravalvular regurgitation. At last follow up, 89.5% of patients were New York Heart Association class I or II. CONCLUSIONS: Transapical transcatheter mitral valve-in-valve implantation can safely be performed in a patient population with a high proportion of cardiogenic shock with favorable clinical outcomes. PMID- 29382512 TI - Steroids Limit Myocardial Edema During Ex Vivo Perfusion of Hearts Donated After Circulatory Death. AB - BACKGROUND: Normothermic ex vivo heart perfusion (EVHP) has been shown to improve the preservation of hearts donated after circulatory arrest and to facilitate clinical successful transplantation. Steroids are added to the perfusate solution in current clinical EVHP protocols; however, the impact of this approach on donor heart preservation has not been previously investigated. We sought to determine the impact of steroids on the inflammatory response and development of myocardial edema during EVHP. METHODS: Thirteen pigs were anesthetized, mechanical ventilation was discontinued, and a hypoxemic cardiac arrest ensued. A 15-minute warm-ischemic standoff period was observed, and then hearts were resuscitated with a cardioplegic solution. Donor hearts were then perfused ex vivo in a normothermic beating state for 6 hours with 500 mg of methylprednisolone (steroid: n = 5) or without (control: n = 8). RESULTS: The addition of steroids to the perfusate solution reduced the generation of proinflammatory cytokines (interleukin-6, -8, -1beta, and tumor necrosis factor-alpha) and the development of myocardial edema during EVHP (percentage of weight gain: control = 26% +/- 7% versus steroid = 16% +/- 10%, p = 0.049). Electron microscopy suggested less endothelial cell edema in the steroid group (injury score: control = 1.8 +/- 0.2 versus steroid = 1.2 +/- 0.2, p = 0.06), whereas perfusate troponin-I (control = 11.9 +/- 1.9 ng/mL versus steroid = 9.5 +/- 2.4 ng/mL, p = 0.448) and myocardial function were comparable between the groups. CONCLUSIONS: The addition of methylprednisolone to the perfusion solution minimizes the generation of proinflammatory cytokines and development of myocardial edema during normothermic ex vivo perfusion of hearts donated after circulatory arrest. PMID- 29382513 TI - [Urinary tract infection: a prevalent problem in Pediatrics]. PMID- 29382514 TI - [Epigenetic alterations in acute lymphoblastic leukemia]. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL. PMID- 29382515 TI - Clinical characterization and antimicrobial resistance of Escherichia coli in pediatric patients with urinary tract infection at a third level hospital of Quito, Ecuador. AB - BACKGROUND: Urinary tract infections (UTI) are among the most common infections in pediatric patients. The main etiopathogenic agent is Escherichia coli. The purpose of this study was to determine the antimicrobial resistance pattern of E. coli in pediatric patients and to understand their main clinical and laboratory manifestations. METHODS: Fifty-nine patients were included in the study and classified into two groups: hospitalization (H) and external consultation (EC). Every patient presented urine cultures with the isolation of E. coli that included an antibiogram. Clinical signs and symptoms, urinalysis, complete blood count (CBC) and serum inflammatory markers were analyzed. RESULTS: The most common clinical manifestations were fever (H: 76.5%; EC: 88%), vomiting (H: 32.4%; EC: 32%), hyporexia (H: 20.6%; EC: 16%), abdominal pain (H: 20.6%: EC: 28%), and dysuria (H: 14.7%; EC: 32%). Ten patients (16.95%) presented UTI for extended spectrum beta-lactamase (ESBL) E. coli. Ampicillin, nalidixic acid, and trimethoprim-sulfamethoxazole showed a higher resistance rate, being ampicillin the most significant (H: 88.2%; EC: 92%). Leukocyturia, bacteriuria and urine nitrites were frequent alterations in urinalysis (H: 52.9%; EC: 92%). In ESBL E. coli patients, a positive correlation was found between leukocytes in CBC and C reactive protein (r = 0.9, p < 0.01). Diarrhea and foul-smelling urine were associated with E. coli resistance. CONCLUSIONS: The presence of leukocytes, bacteria, nitrites and the Gram stain are the most common indicators. Nitrofurantoin and phosphomycin are good therapeutic options. However, an antibiogram must be conducted to determine the best therapeutic agent. PMID- 29382516 TI - [Accelerometry does not match with self-reported physical activity and sedentary behaviors in Mexican children]. AB - BACKGROUND: An accurate assessment of physical activity in schoolchildren is necessary to implement strategies that promote active lifestyles. The objective of this study was to validate a self-administered questionnaire to assess physical activity and sedentary behaviors and to analyze differences in the validity according to nutritional status in Mexican schoolchildren. METHODS: Schoolchildren of 8-12 years of age answered a self-report physical activity and sedentary behaviors questionnaire to evaluate sedentary and light physical activity (SLPA) and moderate to vigorous physical activity (MVPA). The data of children who wore a triaxial accelerometer days was analyzed. Concordance between both methods to determine the time schoolchildren spend watching television was assessed using intraclass correlation coefficients and Bland-Altman method. RESULTS: The estimation of MVPA by questionnaires was higher than that of accelerometers by 117.6minutes per week, and the estimation of SLPA was lower by 1,924.7minutes per week. No correlation between the time assessed by accelerometers and the time reported in the questionnaires for SLPA and MVPA was detected. In normal-weighted children, a low correlation between the time dedicated to play videogames with sedentary activities (ric=0.29, p=0.031) assessed by accelerometers was observed. CONCLUSIONS: Schoolchildren over estimate MVPA and under-estimate SLPA. Body weight can be a factor influencing such bias. PMID- 29382517 TI - [Fluid balance and acute kidney injury in septic shock]. AB - BACKGROUND: In patients with septic shock, excessive fluid administration can lead to increased morbidity and mortality. The aim of this study was to evaluate the association between fluid balance, acute kidney injury and mortality in patients with septic shock. METHODS: A study of cases and controls was conducted in a Pediatric Intensive Care Unit. The fluid balance in the first 72h and the presence of acute kidney injury was compared in patients diagnosed with septic shock who died against patients who survived the same condition. Univariate and multivariate analyses were performed. RESULTS: Forty-five cases and forty-five controls were included in the analysis. Mortality was associated with Pediatric Risk of Mortality (PRISM III) >= 26 points (OR 7.5, 95% CI 2.8-18.7; p=0.000), Pediatric Logistic Organ Dysfunction (PELOD) >= 24 points (OR 11.0, 95% CI 4.1 29.4; p=0.000), creatinine >= 0.65mg/dl (OR 5.6, 95% CI 2.2-13.9; p=0.000), lactate >= 2.5 mmol/l (OR 2.5, 95% CI 1.1-5.9; p=0.033), SvO2 < 60% (OR 4.6, 95% CI 4.5-4.5; p=0.001), positive balance > 9% in 72h (OR 4.3, 95% CI 1.6-11.7; p=0.003), acute kidney injury (OR 5.7, 95% CI: 2.2-15.1; p=0.000). In the multivariate model, the values of PRISM >=26 and PELOD >=24 points were significant. CONCLUSIONS: In patients who died due to septic shock, the multivariate model showed an association with PRISM >=26 and PELOD >=24 and a trend toward association with SvO2 <60% and positive balance of liquids > 9%. PMID- 29382518 TI - [Risk factors associated with complications that required the removal of peripherally inserted central venous catheters in a tertiary pediatric hospital]. AB - BACKGROUND: In pediatrics, complications of the peripherally inserted central venous catheters (PICC) are reported in 30% to 40% of cases, with the most frequent risk factors being the age of the patient and the location of PICC. The aim of this study was to describe the characteristics of PICCs and to identify factors related to their withdrawal due to complications. METHODS: Prospective cohort study. Patients from 2 months to 18 years of age were included and followed-up until PICC was withdrawn. Age, sex, medications administered, PICC location, caliber, the number of lumens, days PICC was on the patient, and the reason for withdrawal was recorded. Univariate and multivariate analyses were performed. RESULTS: Two hundred and twenty-five patients were included. In 33.02%, PICC were withdrawn due to complications. In the bivariate analysis, age and location were factors associated with complications. A Cox proportional hazards model was performed. It was identified that only the caliber thickness (hazard ratio (HR): 0.5, confidence interval (CI)95%: 0.35-0.99) was associated with any complication, and age (HR: 1.02, CI95%: 1-1.04) only to the withdrawal of PICC due to suspected phlebitis. CONCLUSIONS: PICC withdrawal due to complications was performed in 33% of the patients. Risk factors related to complications were PICC caliber thickness and age. PMID- 29382519 TI - [Acrodermatitis enteropathica]. AB - INTRODUCTION: Acrodermatitis enteropathica is a low-incidence disease due to inherited or acquired zinc deficiency. It is characterized by acral dermatitis, alopecia, diarrhea and growth retardation. The dermatological condition may mimic a cutaneous fungal infection or other pathogen-related skin diseases. CASE REPORT: We report the case of a female patient of 7 months of age, who was sent to Centro Medico Nacional 20 de Noviembre for suspicion of immunodeficiency and cutaneous mycosis. Her condition began with dermatosis disseminated to the head, trunk and genital region; initial treatment with antifungal and broad spectrum antibiotics was given, without improvement. Upon admission, immunodeficiency and fungal infection were discarded. Acrodermatitis enteropathica was suspected, and corroborated later by low serum zinc levels. Immediately after the start of oral treatment with zinc, the patient showed improvement. CONCLUSIONS: There are multiple differential diagnoses of acrodermatitis enteropathica, which includes cutaneous infections. Therefore, the early recognition of the characteristic lesions favors suspicion, diagnosis and appropriate treatment. PMID- 29382520 TI - [Congenital malformations at birth: Mexico, 2008-2013]. PMID- 29382521 TI - [Education in our time: competency or aptitude? The case for medicine. Part II]. AB - Part II is focused on participatory education (PE), a distinctive way to understand and practice education in contrast to passive education. The core of PE is to develop everyone's own cognitive potentialities frequently mutilated, neglected or ignored. Epistemological and experiential basis of PE are defined: the concept of incisive and creative criticism, the idea of knowledge as each person's own construct and life experience as the main focus of reflection and cognition. The PE aims towards individuals with unprecedented cognitive and creative faculties, capable of approaching a more inclusive and hospitable world. The last part criticizes the fact that medical education has remained among the passive education paradigm. The key role of cognitive aptitudes, both methodological and practical (clinical aptitude), in the progress of medical education and practice is emphasized. As a conclusion, the knowhow of education is discussed, aiming towards a better world away from human and planetary degradation. PMID- 29382522 TI - [Screening of adverse childhood experiences in preschoolers: scoping review]. AB - The aim of the present article was to describe available scientific publications detailing strategies and screening tools for Adverse Childhood Experiences in preschoolers (2 to 5 years of age). A scoping review of the topic was carried out through investigative articles published in peer review journals from January 1998 to June 2017 and indexed in seven international databases (Cochrane Library, EBSCO, PubMed, Science Direct, Springer, Web of Science and Scielo). The articles were selected based on predefined criteria, using limiters and manual screening. Twenty articles published between 1999 and 2017 were selected. The screening of adverse childhood experiences is performed through opportunistic recruitment in a professional context aimed at caregivers and children, which integrates training actions, application of screening tools and reception of identified cases. Screening tools differ between interviews and questionnaires. Furthermore, we report the periodicity of the screening, the behaviors and beliefs of the professionals against it and the barriers to its implementation. This review confirms that the screening of Adverse Childhood Experiences is an emerging topic in the research field. We emphasize the need to systematize and evaluate the strategies and tools for screening Adverse Childhood Experiences, as well as to develop local approaches to respond to the needs of children exposed to adversity. PMID- 29382523 TI - [Cultural order, disease and health care]. AB - With the appearance of Homo sapiens, the biological order was gradually replaced by the anthropocentric cultural order (CO), in which traditions, appreciations, preferences and desires for possession and domination guided their interactions with nature (predation or care), within the group (ranks, classes) and with others groups (commerce, wars). Current CO, characterized by unlimited profit interests, extreme wealth concentration and inequality where moral degradation hits rock bottom and planetary ecosystem is devastated, shows a collapsed civilization with a background of a global media controlled anesthetized societies. Regarding the health field, control works by prevalent ideas and practices: sickness as a strange object to the body, health as an imperative vital ideal and technologically based suppressive medicine shaping life's medicalization, main control "device" and health industry support. Other alternative ideas and practices are discussed: sickness as an inner harmony disturbance or as a differentiated and particular way of human beings, and stimulating medicine, that targets sick people with the purpose of strengthening and harmonizing them so they may recover, alleviate or appease. Considerations about possibilities and significance of stimulating medicine are made at the end. PMID- 29382524 TI - A nationwide study on the prevalence of functional gastrointestinal disorders in school-children. AB - INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are highly prevalent worldwide and are thought to result from the interplay of multiple factors that can vary from region to region. Nationwide studies can help understand the regional epidemiology and the pathogenesis of FGIDs. The objectives of this study were to determine the prevalence of FGIDs in school-children of Colombia and assess associated factors. METHODS: A cross-sectional study was carried out at twelve private and public schools in ten cities distributed through the four main geographic regions of Colombia. School-children completed a validated questionnaire to assess functional gastrointestinal disorders according to Rome III criteria. Demographic information and past medical and family history was obtained from the parents. RESULTS: A total of 4394/5062 (86.8%) children participated in the study, with ages ranging from 8-18 years (mean = 11.9, SD = 2.3). The percentage of children with al least on FGID was 23.7%. Disorders of defecation were the most common category FGID (11.7%) followed by abdominal pain related-functional gastrointestinal disorders (10.4%). Children have increased odds of FGIDs if they have separated parents (OR 1.22, P=0.007), attend private school (OR 1.54, P<0.001), or have nausea (OR 3.16, P<0.001). CONCLUSIONS: This large epidemiological study of pediatric FGIDs is the first to evaluate a broad cross-section of children throughout a nation in the Americas. High prevalence of FGIDs and identified associations with their likelihood are relevant when providing medical care and when planning public health efforts. PMID- 29382525 TI - [Active form of vitamin D in overweight and obese pediatric patients in northwest Mexico]. AB - BACKGROUND: Low levels of vitamin D have been associated with a range of clinical conditions such as obesity, insulin resistance, and diabetes mellitus, among others. There are few studies that measure the active form of vitamin D (1,25 (OH)2 vitamin D) in obese children. However, published data are inconclusive. The aim of this study was to determine the active levels of vitamin D in obese and overweight children and to find an association between low levels of vitamin D, obesity and impaired glucose metabolism. METHODS: A cross-sectional, analytical study was conducted in 6 to 12-year-old children with excess adiposity determined by waist-stature index and body mass index. Levels of glucose, insulin, complete lipid profile, homeostatic model assessment and the active form of vitamin D were measured in each patient. Levels < 30 pg/ml were considered as low levels of vitamin D. RESULTS: The prevalence of low levels of active vitamin D was 36%. A significant association between low levels of active vitamin D and high levels of insulin was found. No significant association was found between vitamin levels and adiposity measures. CONCLUSIONS: Low levels of active vitamin D were found in 36% of the population studied. A significant association with insulin resistance and hyperinsulinemia was demonstrated. PMID- 29382526 TI - [Recurrent wheezing: prevalence and associated factors in infants from Buenos Aires City, Argentina]. AB - BACKGROUND: The episodes of bronchial obstruction at early age constitute a frequent problem in Pediatrics. The aim of this study was to evaluate the prevalence of recurrent wheezing in infants in Buenos Aires City, as well as to identify any associated factors. METHODS: Cross-sectional study performed from 2011 to 2012 in the Children Hospital Ricardo Gutierrez, Buenos Aires City, as part of the International Study of Wheezing in Infants. A validated questionnaire was applied to parents of infants aged between 12 and 15 months. The prevalence of wheezing, mostly the recurrent episodes (three or more), and their probable associated factors were evaluated. Data were statistically analyzed with chi2, Fisher's test, binary and logistics multiple regression analysis. The significance level was 0.05. RESULTS: Over 1063 infants, 58.9% (confidence interval (CI) 95% 55.9-61.9) presented at least one episode of wheezing and 26.3% (CI95% 23.8-29.9) three or more episodes (recurrent wheezing). Risk factors associated to wheezing were male gender (p=0.001), six or more episodes of cold during the first year of life (p <0.0001), age at first cold <4 months (p <0.0001); pneumonia (p <0.0001) and smoking during pregnancy (tobacco) (p=0.01). For recurrent wheezing, risk factors we considered as six or more episodes of cold during the first year of life (p <0.0001), early (< 4 month of age) onset wheezing (p <0.0001) and nocturnal wheezing (p <0.0001). CONCLUSIONS: The prevalence of recurrent wheezing among infants in Buenos Aires Ciy was high (26.3%). Some identified associated factors can be preventable. PMID- 29382527 TI - [Proteomic analysis of the excretion-secretion products of four Trichinella spiralis isolates obtained from accidental hosts]. AB - BACKGROUND: Trichinella spiralis is an intestinal and tissue nematode specific for mammalian skeletal muscle, causing a series of physiological alterations. T. spiralis excretory-secretion products play an important role in the appearance and regulation of these alterations. However, the effect of these products on the infection and invasion of the parasite to the host is unknown. METHODS: Differences and similarities between antigenic proteins and surface proteins of four accidental hosts isolates (dogs) of T. spiralis and the reference strain isolated from pigs (MSUS/MEX/91/CM) were assessed by electrophoresis, western blot and mass spectrometry. RESULTS: Using gene ontology, five proteins exclusive to the accidental hosts were analyzed. The results showed that these proteins are part of the extracellular matrix of the parasite, present catalytic activity, and bind to host cells. The antigenic activity the four strains showed the antigenic triplet characteristic of T. spiralis of 43, 45 and 47 kDa. CONCLUSIONS: Five proteins exclusive to dog isolates provided information to understand the mechanism of action of this parasite to penetrate the muscle and evade the immune response in the host. PMID- 29382528 TI - [Community-acquired pneumonia with infrequent presentation]. PMID- 29382529 TI - Homology modeling and docking of AahII-Nanobody complexes reveal the epitope binding site on AahII scorpion toxin. AB - Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively charged residues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 - AahII residue interactions (Gln38 - Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom. PMID- 29382530 TI - Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to isoleucine substitution at codon 180 on the prion protein gene. AB - Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrPres at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrPres in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrPres were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease. PMID- 29382531 TI - Gonadal hormone receptors underlie the resistance of female rats to inflammatory and cardiovascular complications of endotoxemia. AB - The male gender is more vulnerable to immunological complications of sepsis. Here, we tested the hypotheses that female rats are protected against endotoxemia evoked hypotension and cardiac autonomic dysfunction, and that gonadal hormone receptors account for such protection. Changes in blood pressure, heart rate, and cardiac sympathovagal balance caused by i.v. lipopolysaccharide (LPS) were determined. In male rats, LPS elevated serum TNFalpha together with falls in blood pressure and rises in heart rate. The spectral index of cardiac sympathovagal balance (low-frequency/high-frequency ratio, LF/HF) was reduced by LPS, suggesting an enhanced parasympathetic dominance. Remarkably, none of these LPS effects was evident in female rats. We also report that pretreatment of female rats with fulvestrant (nonselective estrogen receptor blocker), PHTPP (estrogen receptor beta blocker), or mifepristone (progesterone receptor blocker) uncovered clear inflammatory (increased serum TNFalpha), hypotensive and tachycardic responses to LPS. However, these female rats, contrary to their male counterparts, exhibited increases in LF/HF ratio. On the other hand, LPS failed to modify inflammatory or cardiovascular states in rats pretreated with MPP (estrogen receptor alpha blocker). In females treated with formestane (aromatase inhibitor), LPS increased LF/HF ratio but had no effect on blood pressure. In male rats, the hypotensive and cardiac autonomic effects of LPS were (i) eliminated after treatment with estrogen, and (ii) intensified and inhibited, respectively, in flutamide (androgen receptor blocker)-pretreated rats. These findings highlight important roles for female gonadal hormones and functional estrogen receptor beta and progesterone receptors in offsetting inflammatory and cardiovascular derangements caused by endotoxemia in female rats. PMID- 29382532 TI - Cordycepin rescues lidocaine-induced neurotoxicity in dorsal root ganglion by interacting with inflammatory signaling pathway MMP3. AB - Application of local anesthetic reagents, such as lidocaine (Lid), could cause significant neurotoxicity in spinal cord dorsal root ganglia neurons (DRGNs). In this study, we investigated the potential rescuing effect of cordycepin (CDC) in an in vitro explant model of lidocaine-induced apoptosis in DRGNs. Explant of rat neonatal DRGNs was prepared, and treated with Lid in vitro to induce neuronal apoptosis. Prior to Lid treatment, DRGN explant was pre-incubated with various concentrations of CDC to evaluate its rescuing effect on Lid-induced apoptosis. We found that, in cultured DRGNs, Lid caused significant neuronal apoptosis whereas pre-incubation of CDC rescued Lid-induced neurotoxicity. In addition, gene and protein expressions of Caspase-9 and Matrix metalloproteinase 3 (MMP3), a key component of inflammatory signal pathway, were both upregulated by Lid but downregulated by CDC pre-incubation. We further overexpressed MMP3 in cultured DRGNs. And discovered that forced MMP3 overexpression upregulated endogenous MMP3 and caspase-9, and reversed the rescuing effect of CDC on Lid-induced neurotoxicity in DRGNs. Therefore, we concluded that CDC has protective effect on local anesthesia induced spinal cord neurotoxicity, possibly through the inverse regulation on inflammatory signaling pathway. PMID- 29382533 TI - Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes. AB - Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3. PMID- 29382534 TI - Salvianolic acid B improves airway hyperresponsiveness by inhibiting MUC5AC overproduction associated with Erk1/2/P38 signaling. AB - Salvianolic acid B (SalB) is one of the main water-soluble composites from Chinese medicine Dansen (Radix miltiorrhiza). It is used for clinical treatment of various diseases including cardiovascular, lung, Liver, renal and cancers. However, the effects of SalB to allergy induced airway mucin hypersecretion, inflammation and hyperresponsiveness (AHR) remains not clear. Overproduction of airway MUC5AC is a central effector of inflammation that is strongly associated with AHR in asthmatic attack. In this study, we investigated the anti-asthmatic activity and mechanism of SalB in a murine model and human epithelial cells by monitoring changes in mucin expression and secretion, airway inflammation, AHR, and signaling pathways. SalB was administered by intragastric administration (i.g) daily for a week, starting at 21 days after sensitization of ovalbumin (OVA). All examinations were performed 24h after the last antigen challenge. We found that treatments with SalB significantly inhibited increase in the tracheobronchial secretion, glycosaminoglycan levels, interleukin (IL)-13, IL-4, and IL-5 cytokines mRNA and protein expression, and decrease in mucociliary clearance in lung tissues. Histological results demonstrated that SalB attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, and MUC5AC and MUC5B mRNA and protein expression in lung tissues. SalB exhibited protective effects against AHR in OVA-challenged animals. In vitro, SalB significantly inhibited IL-13-induced MUC5AC and MUC5B mRNA and protein expression in human epithelial cells. These effects were blocked by SalB by downregulating the Erk1/2 and P38 signaling pathways. Taken together, these data indicate that treatment with SalB may improve AHR by inhibiting MUC5AC overproduction. PMID- 29382535 TI - MEHP promotes the proliferation of cervical cancer via GPER mediated activation of Akt. AB - Cervical cancer is the fourth leading cause of cancer death in females worldwide and the second leading cause of mortality among women. Estrogenic signals can regulate the progression of cervical cancer, however, little is known about the mono-2-ethyhexyl phthalate (MEHP), an environmental xenoestrogen, on the development of cervical cancers. Our present data showed that nanomolar concentrations of MEHP can trigger the proliferation, while not invasion, of cervical cancer HeLa and SiHa cells, which was confirmed by the results that MEHP can also increase the expression of proliferating cell nuclear antigen (PCNA). MEHP treatment can increase the phosphorylation and nuclear localization of Akt, while had no effect on the activation of ERK1/2 or p65. Targeted inhibition of Akt via its specific siRNA or inhibitor can reverse MEHP induced cell proliferation. In addition, the inhibitor of G protein coupled estrogen receptor (GPER), while not estrogen receptor alpha (ERalpha), can abolish MEHP induced phosphorylation of Akt and cell proliferation, suggesting that GPER is involved in MEHP induced activation of Akt. Collectively, our data showed that MEHP can trigger the progression of cervical cancer via activation of GPER/Akt. It suggested that MEHP exposure is also an important risk factor for development and progression of cervical cancers. PMID- 29382536 TI - Epigenetic modification of Nrf2 by sulforaphane increases the antioxidative and anti-inflammatory capacity in a cellular model of Alzheimer's disease. AB - Sulforaphane was reported to exert neuroprotective effects via upregulating expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and has received increasing attention as an alternative candidate for treatment of Alzheimer's disease (AD). However, the mechanism to account for Nrf2 upregulation by sulforaphane in AD remains unknown. Herein, we found that sulforaphane upregulated Nrf2 expression and promoted Nrf2 nuclear translocation via decreasing DNA methylation levels of the Nrf2 promoter in mouse neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APPswe cells), a cellular model of AD. Furthermore, sulforaphane (1.25 and 2.5 MUM) decreased the levels of amyloid beta 1-40 (Abeta1-40) (21.7% and 33.4% decrease for intracellular Abeta1-40; 22.0% and 30.2% decrease in culture medium), Abeta1-42 (26.4% and 42.9% decrease for intracellular Abeta1-42; 25.8% and 43.8% decrease in culture medium), reactive oxygen species (15.0% and 28.5% decrease), and malondialdehyde (MDA) (34.4% and 39.2% decrease) and increased superoxide dismutase (SOD) (60.0% and 89.3% increase) activity in N2a/APPswe cells. Sulforaphane also decreased the levels of pro-inflammatory cytokines interleukin 1beta (IL-1beta) (16.5% and 33.6% decrease) and IL-6 (15.6% and 26.1% decrease) and reduced phosphorylated nuclear factor-kappaB (NF-kappaB) p65 (19.2% and 32.2% decrease), cyclooxygenase-2 (COX-2) (20.5% and 28.6% decrease), and iNOS protein (40.2% and 54.7% decrease) expression levels in N2a/APPswe cells. Our study suggested that sulforaphane upregulated the expression of Nrf2 and promoted the nuclear translocation of Nrf2 by decreasing DNA demethylation levels of the Nrf2 promoter, thus leading to antioxidative and anti-inflammatory effects in a cellular model of AD. PMID- 29382537 TI - RE: "Letter to the Editor concerning Roddy et al. Exp Eye Res 165:175-181, 2017". PMID- 29382538 TI - Effects of mating patterns on genealogical trees: Assessment of the high carrier rate of Familial Mediterranean Fever in rural Israeli districts. AB - We investigate the spread from ancestors to descendants, under a model of sexual reproduction, of hereditary elements distinguishing individuals from their fellow human beings. These hereditary elements, termed labels, are either symbolic, implying a socio-cultural or ethnic self-determined category, or biological, i.e. a DNA sequence (for example founder mutations). The impact of various modes of preferential (assortative) mating on the dissemination of a known ancestral label was studied for both kinds of labels, the symbolic and the biological. For the socio-cultural based labeling, both mathematical modeling and simulation studies were carried out, and disclosed a marked delay in the spread of the labels in future generations, compared to the case where mating was random. The transmission of biological labels (founder mutations) from an ancestor to descendants under various modes and degrees of assortative mating was investigated by simulations and supplemented by an in-depth analysis of allele frequencies of Familial Mediterranean Fever (FMF) in an Israeli Muslim Arab village. The high carrier frequency of FMF in this village was satisfactorily explained solely by the presence of a founder effect and a pronounced high factor of selective mating, causing segregation and consanguinity among its inhabitants. Contribution of further evolutionary mechanisms such as heterozygote advantage, drift, differential reproductive success or selection pressure was not essential to explain these results. PMID- 29382539 TI - Molecular cloning and distribution of oxytocin/vasopressin-like mRNA in the blue swimming crab, Portunus pelagicus, and its inhibitory effect on ovarian steroid release. AB - This study was aimed to characterize the full length of mRNA of oxytocin/vasopressin (OT/VP)-like mRNA in female Portunus pelagicus (PpelOT/VP like mRNA) using a partial PpelOT/VP-like sequence obtained previously in our transcriptome analysis (Saetan, 2014) to construct the primers. The PpelOT/VP like mRNA was 626 bp long and it encoded the preprohormones containing 158 amino acids. This preprohormone consisted of a signal peptide, an active nonapeptide (CFITNCPPG) followed by the dibasic cleavage site (GKR), and the neurophysin domain. Sequence alignment of the PpelOT/VP-like peptide with those of other animals revealed strong molecular conservation. Phylogenetic analysis of encoded proteins revealed that the PpelOT/VP-like peptide was clustered within the group of crustacean OT/VP-like peptide. Analysis by RT-PCR revealed the expression of mRNA transcripts in the eyestalk, brain, ventral nerve cord (VNC), ovary, intestine and gill. The in situ hybridization demonstrated the cellular localizations of the transcripts in the central nervous system (CNS) and ovary tissues. In the eyestalk, the mRNA expression was observed in the neuronal clusters 1-5 but not in the sinus gland complex. In the brain and the VNC, the transcripts were detected in all neuronal clusters but not in the glial cell. In the ovary, the transcripts were found in all stages of oocytes (Oc1, Oc2, Oc3, and Oc4). In addition, synthetic PpelOT/VP-like peptide could inhibit steroid release from the ovary. The knowledge gained from this study will provide more understanding on neuro-endocrinological controls in this crab species. PMID- 29382540 TI - A Contraception Quality Improvement Initiative with Detained Young Women: Counseling, Initiation, and Utilization. AB - STUDY OBJECTIVE: To assess the effect of providing standardized counseling to improve the rates of contraception initiation and utilization among detained young women. This was a quality improvement (QI) project conducted at a large urban juvenile short-term detention center. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The intervention included educating all staff and care providers, counseling detained young women on various contraceptive options, and offering contraception initiation with oral contraceptive pills or depot medroxyprogesterone acetate injection. Retrospective chart review before February 2012 established baseline contraception initiation and utilization rates. The QI intervention began in February 2012 and continued for 6 months followed by chart review. Outcomes measured included number of patients counseled about contraception, started contraception, and overall contraception utilization. RESULTS: We reviewed 120 and 186 charts before and after intervention, respectively. Compared with baseline data, the intervention group had statistically significant (P < .05) higher proportions of patients counseled (10% [10/120] baseline vs 84% [156/186] intervention) and who started contraception (7% [8/120] baseline vs 52% [97/186] intervention). CONCLUSION: This contraception QI intervention showed significant improvement in the rates of contraception counseling, contraception initiation, and utilization among detained young women. Most of youths' guardians were supportive and approved contraception initiation. This project showed it is feasible for health care providers to include contraception services for all intake assessments at juvenile detention facilities. PMID- 29382541 TI - Palliative Sedation for Existential Suffering: A Systematic Review of Argument Based Ethics Literature. AB - CONTEXT: Although unanimity exists on using palliative sedation (PS) for controlling refractory physical suffering in end-of-life situations, using it for controlling refractory existential suffering (PS-ES) is controversial. Complicating the debate is that definitions and terminology for existential suffering are unclear, ambiguous, and imprecise, leading to a lack of consensus for clinical practice. OBJECTIVES: To systematically identify, describe, analyze, and discuss ethical arguments and concepts underpinning the argument-based bioethics literature on PS-ES. METHODS: We conducted a systematic search of the argument-based bioethics literature in PubMed, CINAHL, Embase(r), The Philosopher's Index, PsycINFO(r), PsycARTICLES(r), Scopus, ScienceDirect, Web of Science, Pascal-Francis, and Cairn. We included articles published in peer reviewed journals till December 31, 2016, written in English or French, which focused on ethical arguments related to PS-ES. We used Peer Review of Electronic Search Strategies protocol, Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and The Qualitative Analysis Guide of Leuven for data extraction and synthesis of themes. RESULTS: We identified 18 articles that met the inclusion criteria. Our analysis revealed mind-body dualism, existential suffering, refractoriness, terminal condition, and imminent death as relevant concepts in the ethical debate on PS-ES. The ethical principles of double effect, proportionality, and the four principles of biomedical ethics were used in argumentations in the PS-ES debate. CONCLUSION: There is a clear need to better define the terminology used in discussions of PS-ES and to ground ethical arguments in a more effective way. Anthropological presuppositions such as mind body dualism underpin the debate and need to be more clearly elucidated using an interdisciplinary approach. PMID- 29382542 TI - Prevalence and Characteristics of Pruritus and Association With Quality of Life in People Living With HIV: A Cross-Sectional Study. PMID- 29382543 TI - Coupling and segregation of large-scale brain networks predict individual differences in delay discounting. AB - Decision-making about rewards, which requires us to choose between different time points, generally refers to intertemporal choice. Converging evidence suggests that some of the brain networks recruited in the delay discounting task have been well characterized for intertemporal choice. However, little is known about how the connectivity patterns of these large-scale brain networks are associated with delay discounting. Here, we use a resting-state functional connectivity MRI (rs fcMRI) and a graph theoretical analysis to address this question. We found that the delay discounting rates showed a positive correlation with the functional network connectivity (FNC) between the cingulo-opercular network (CON) and the default mode network (DMN), while they showed a negative correlation with the FNC of both the CON-SAN (salience network) and the SAN-FPN (fronto-parietal network). Our results showed the association of both coupling and segregating processes with large-scale brain networks in delay discounting. Thus, the present study highlights the pivotal role of the functional connectivity patterns of intrinsic large-scale brain networks in delay discounting and extends our perspective on the neural mechanism of delay discounting. PMID- 29382544 TI - Pushing and recognizing the limits of nonresponse to cardiac resynchronization therapy: A valuable "negative" trial. PMID- 29382545 TI - A novel mechanism for regulation of cardiac Ca2+ current by estradiol: cAMP-ing out at the basal epicardium. PMID- 29382546 TI - Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. AB - Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and evaluated. Such strategies generally address subsets of tumor cells, still allowing the progressive growth of tumor cells not expressing the target. Moreover, tumor stem cells and tumor supportive cells, such as cancer associated fibroblasts and cancer associated macrophages, are left unaffected by this approach. In this review, we discuss an alternative targeting strategy aimed at delivery of anti tumor drugs to the tumoral extracellular matrix with the potential to eliminate all cell types. The extracellular matrix of tumors is vastly different from that of healthy tissue and offers hooks for targeted drug delivery. It is concluded that matrix targeting is promising, but that clinical studies are required to evaluate translation. PMID- 29382547 TI - "Click" chemistry in polymeric scaffolds: Bioactive materials for tissue engineering. AB - Polymeric scaffolds have attracted great interests in recent years, due to their fascination with a large variety of examples with promising utilization. Recently, extensive efforts have been devoted to the exploitation of robust and functional polymer-based biomaterial scaffolds with high efficiency. The recent entry of so-called "click" reactions that include kinds of selective and orthogonal reactions under mild conditions have generated real stimulus not only in preparing elegant bioactive materials of choice but also in making the leap to industrial scale build-up of multifunctional products. In this review paper, we account several kinds of polymeric scaffolds prepared/modified via "click" reactions, with emphasis on their synthetic/functionalized strategies, tunable properties, and biomedical applications. PMID- 29382548 TI - Development of pharmacological screening method for evaluation of effect of drug on elevated pulse pressure and arterial stiffness. AB - INTRODUCTION: Elevated pulse pressure (PP) and amplification of arterial stiffness (AS) are responsible for various cardiovascular disease and deaths. Numerous investigations have identified that different antihypertensive agents influence PP and AS differently. None of the previous studies described any reliable animal model particularly to screen drugs having effects on PP and AS. In present study, we developed an animal model to screen such drugs particularly affecting PP and AS. METHODS: Elevation of PP and amplification of AS were induced in rats by uninephrectomy along with high salt intake (NaCl 4% w/v) for a period of six weeks, and weekly changes in body weight, PP, systolic, diastolic, mean pressure and pulse wave velocity (PWV) were estimated. After six weeks, collagen elastin ratio of aortic segment was estimated. Histomorphometry of abdominal aortic section of rats was done using trinocular microscope. RESULTS: After six weeks, uninephrectomized rats that were kept on high salt drinking water shown significant increase (P < 0.001) in MAP, PP and PWV indicates that hypertension along with elevated PP developed in rats, and increase in collagen/elastin ratio (P < 0.001) as well as PWV as compared to normal rats indicates the increase in AS. CONCLUSION: The development of condition of hypertension in conjunction with increase in PP and AS in rats can be used as in vivo screening model to determine the potency of drugs for the treatment of hypertension or other cardiovascular diseases associated with high PP and AS. PMID- 29382550 TI - Neuroprotective Effect of Sirt2-specific Inhibitor AK-7 Against Acute Cerebral Ischemia is P38 Activation-dependent in Mice. AB - Cerebral ischemia is the most common cause of stroke with high morbidity, disability and mortality. Sirtuin-2 (Sirt2), a vitally important NAD+-dependent deacetylase which has been widely researched in central nervous system diseases, has also been identified as a promising treatment target using its specific inhibitors such as AK-7. In this study, we found that P38 was specifically activated after focal cerebral ischemic injury, and it was also significantly activated after AK-7 administration in a concentration-dependent manner in vitro and in vivo. AK-7 decreased the infarction volume remarkably and promoted the recovery of neurological function efficiently in the mice evaluated by behavior tests. In contrast, pP38 inhibition increased the infarct volume and exacerbated the symptoms of paralysis. Herein, we suggest AK-7 improves the outcome of brain ischemia in dependence on the P38 activation in mice, which may serve as a strategy for the treatment of stroke. PMID- 29382549 TI - Human TUBB3 Mutations Disrupt Netrin Attractive Signaling. AB - Heterozygous missense mutations in human TUBB3 gene result in a spectrum of brain malformations associated with defects in axon guidance, neuronal migration and differentiation. However, the molecular mechanisms underlying mutation-related axon guidance abnormalities are unclear. Recent studies have shown that netrin-1, a canonical guidance cue, induced the interaction of TUBB3 with the netrin receptor deleted in colorectal cancer (DCC). Furthermore, TUBB3 is required for netrin-1-induced axon outgrowth, branching and pathfinding. Here, we provide evidence that TUBB3 mutations impair netrin/DCC signaling in the developing nervous system. The interaction of DCC with most TUBB3 mutants (eight out of twelve) is significantly reduced compared to the wild-type TUBB3. TUBB3 mutants R262C and A302V exhibit decreased subcellular colocalization with DCC in the growth cones of primary neurons. Netrin-1 increases the interaction of endogenous DCC with wild-type human TUBB3, but not R262C or A302V, in primary neurons. Netrin-1 also increases co-sedimentation of DCC with polymerized microtubules (MTs) in primary neurons expressing the wild-type TUBB3, but not R262C or A302V. Expression of either R262C or A302V not only suppresses netrin-1-induced neurite outgrowth, branching and attraction in vitro, but also causes defects in spinal cord commissural axon (CA) projection and pathfinding in ovo. Our study reveals that missense TUBB3 mutations specifically disrupt netrin/DCC-mediated attractive signaling. PMID- 29382551 TI - Multiple proteins differing between laboratory stocks of mammalian orthoreoviruses affect both virus sensitivity to interferon and induction of interferon production during infection. AB - In the course of previous works, it was observed that the virus laboratory stock (T3DS) differs in sequence from the virus encoded by the ten plasmids currently in use in many laboratories (T3DK), and derived from a different original virus stock. Seven proteins are affected by these sequence differences. In the present study, replication of T3DK was shown to be more sensitive to the antiviral effect of interferon. Infection by the T3DK virus was also shown to induce the production of higher amount of beta and alpha-interferons compared to T3DS. Two proteins, the MU2 and lambda2 proteins, were found to be responsible for increased sensitivity to interferon while both MU2 and lambda1 are responsible for increased interferon secretion. Altogether this supports the idea that multiple reovirus proteins are involved in the control of induction of interferon and virus sensitivity to the interferon-induced response. While interrelated, interferon induction and sensitivity can be separated by defined gene combinations. While both MU2 and lambda2 were previously suspected of a role in the control of the interferon response, other proteins are also likely involved, as first shown here for lambda1. This also further stresses that due caution should be exerted when comparing different virus isolates with different genetic background. PMID- 29382552 TI - Protein disulfide isomerases as potential therapeutic targets for influenza A and B viruses. AB - Seasonal flu as well as potential pandemic flu outbreaks continuously underscores the importance of the preventive and therapeutic measures against influenza viruses. During screening of natural and synthetic small molecules against influenza A and B virus, we identified juniferdin as a highly effective inhibitor against both viruses in cells. Since juniferdin is known to inhibit protein disulfide isomerases (PDIs), multiple PDI inhibitors were tested against these viruses. Among PDI inhibitors, 16F16, PACMA31, isoquercetin, epigallocatechin-3 gallate or nitazoxanide significantly reduced the replication of influenza A and B viruses in MDCK and A549 cells. Furthermore, siRNAs specific to three PDI family members (PDI1, PDIA3 or PDIA4) also significantly reduced the replication of influenza A and B viruses in cells. These results suggest that PDIs may serve as excellent targets for the development of new anti-influenza drugs. PMID- 29382553 TI - Maternal and child dietary intake: The role of maternal healthy-eater self schema. AB - BACKGROUND: Mothers play a key role in shaping the dietary intake of their young children through their own dietary intake and the foods they make available at home. Therefore, understanding the mechanisms underlying maternal food choices is crucial. Cognitions about the self as a healthy eater, referred to as healthy eater self-schema (HESS), predict dietary intake in diverse samples, but the linkage has not been investigated in mothers and their feeding behaviors. This study examined the relationship between a maternal HESS, maternal and child intake of fruits, vegetables, saturated fat, and added sugar, and home food availability. METHODS: A cross-sectional, descriptive design was used with mothers and their 2-5 year old children (N = 124 dyads). Kendzierski's Healthy Eater Self-Schema questionnaire was used to measure HESS. Block Food Frequency Screeners were used to measure diets (mother and child) and the Home Environment Survey was used to measure home availability of fruits/vegetables and fats/sweets. Multiple regression and multiple mediation analyses were performed. RESULTS: Maternal HESS was positively associated with maternal intake of fruits and vegetables, and negatively associated with intake of added sugar. Maternal HESS was not directly associated with child dietary intake, but was indirectly associated with child intake of fruits, vegetables, and added sugar through maternal intake of the same foods. Home food availability was not significantly associated with HESS. CONCLUSION: This study found that a mother's HESS was positively associated with her diet, which was subsequently associated with aspects of her child's diet. Interventions to foster development of HESS in mothers may be an effective means to promote healthy dietary intake in mothers and their young children. PMID- 29382554 TI - Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. AIM OF THE STUDY: To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. MATERIALS AND METHODS: The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT1A and 5-HT2A receptor in the mouse brain regions were quantified by western blot analysis. RESULTS: A single administration of fluvoxamine (5-20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5 HT2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. CONCLUSION: The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of anxiety disorders. PMID- 29382555 TI - Reliability and robustness of feedback-evoked brain-heart coupling after placebo, dopamine, and noradrenaline challenge. AB - External and internal performance feedback triggers not only neural but also cardiac modulations, suggesting communication between brain and heart during feedback processing. Using Cardio-Electroencephalographic Covariance Tracing (CECT), it has accordingly been shown that feedback-evoked centromedial single trial EEG at the P300 latency intraindividually predicts subsequent changes in heart period - the so called N300H phenomenon. While previous findings suggest that the N300H depends on serotonin, its relationship to central dopamine and noradrenaline is currently unknown. Here, we tested (1) the psychometric properties of this CECT-based component and (2) its putative catecholaminergic mechanisms. N = 54 healthy male participants received either a alpha2 adrenoceptor antagonist (yohimbine, 10 mg; n = 18), D2-dopamine-receptor antagonist (sulpiride, 200 mg; n = 18), or a placebo (n = 18). Afterwards, they performed a gambling task with feedback after each trial, while EEG and ECG were recorded. Feedback successfully evoked a significant N300H both across all 54 participants and within each substance group. Importantly, we show that N300H can be reliably measured in a priori defined time windows with as few as 240 feedback trials and is relatively unaffected when removing extreme single-trial values. However, we could not find any significant substance effects on N300H magnitude as well as on univariate feedback-related measures (FRN, P300, heart period). Altogether, the N300H component proves as a robust and reliable marker of cortico cardiac coupling evoked by feedback. Furthermore, these findings suggest a subordinate role of catecholamines (i.e., noradrenaline and dopamine) and sympathetic pathways in feedback-evoked brain-heart communication as measured with N300H. PMID- 29382556 TI - Using DNase Hi-C techniques to map global and local three-dimensional genome architecture at high resolution. AB - The folding and three-dimensional (3D) organization of chromatin in the nucleus critically impacts genome function. The past decade has witnessed rapid advances in genomic tools for delineating 3D genome architecture. Among them, chromosome conformation capture (3C)-based methods such as Hi-C are the most widely used techniques for mapping chromatin interactions. However, traditional Hi-C protocols rely on restriction enzymes (REs) to fragment chromatin and are therefore limited in resolution. We recently developed DNase Hi-C for mapping 3D genome organization, which uses DNase I for chromatin fragmentation. DNase Hi-C overcomes RE-related limitations associated with traditional Hi-C methods, leading to improved methodological resolution. Furthermore, combining this method with DNA capture technology provides a high-throughput approach (targeted DNase Hi-C) that allows for mapping fine-scale chromatin architecture at exceptionally high resolution. Hence, targeted DNase Hi-C will be valuable for delineating the physical landscapes of cis-regulatory networks that control gene expression and for characterizing phenotype-associated chromatin 3D signatures. Here, we provide a detailed description of method design and step-by-step working protocols for these two methods. PMID- 29382557 TI - Koala immunology and infectious diseases: How much can the koala bear? AB - Infectious diseases are contributing to the decline of the iconic Australian marsupial, the koala (Phascolarctos cinereus). Infections with the obligate intracellular bacteria, Chlamydia pecorum, cause debilitating ocular and urogenital-tract disease while the koala-retrovirus (KoRV) has been implicated in host immunosuppression and exacerbation of chlamydial pathogenesis. Although histological studies have provided insight into the basic architecture of koala immune tissues, our understanding of the koala immune response to infectious disease has been limited, until recently, by a lack of species-specific immune reagents. Recent advances in the characterisation of key immune genes have focused on advancing our understanding of the immune response to Chlamydia infection, revealing commonalities in disease pathologies and immunity between koalas and other hosts and paving the way for the development of a koala Chlamydia vaccine. This review summarises these recent findings and highlights key aspects of the koala immune system requiring further attention with particular regard to their most prominent infectious diseases. PMID- 29382558 TI - Damage to the ventromedial prefrontal cortex is associated with impairments in both spontaneous and deliberative moral judgments. AB - Implicit moral evaluations-spontaneous, unintentional judgments about the moral status of actions or persons-are thought to play a pivotal role in moral experience, suggesting a need for research to model these moral evaluations in clinical populations. Prior research reveals that the ventromedial prefrontal cortex (vmPFC) is a critical area underpinning affect and morality, and patients with vmPFC lesions show abnormalities in moral judgment and moral behavior. We use indirect measurement and multinomial modeling to understand differences in implicit moral evaluations among patients with vmPFC lesions. Our model quantifies multiple processes of moral judgment: implicit moral evaluations in response to distracting moral transgressions (Unintentional Judgment), accurate moral judgments about target actions (Intentional Judgment), and a directional tendency to judge actions as morally wrong (Response Bias). Compared to individuals with non-vmPFC brain damage and neurologically healthy comparisons, patients with vmPFC lesions showed a dual deficit in processes of moral judgment. First, patients with vmPFC lesions showed reduced Unintentional Judgment about moral transgressions, but not about non-moral negative affective distracters. Second, patients with vmPFC lesions showed reduced Intentional Judgment about target actions. These findings highlight the utility of a formal modeling approach in moral psychology, revealing a dual deficit in multiple component processes of moral judgment among patients with vmPFC lesions. PMID- 29382560 TI - Shared Decision-Making in Acute Surgical Illness: The Surgeon's Perspective. AB - BACKGROUND: Surgical patients increasingly have more comorbidities and are of an older age, complicating surgical decision-making in emergent situations. Little is known about surgeons' perceptions of shared decision-making in these settings. STUDY DESIGN: Twenty semi-structured interviews were conducted with practicing surgeons at 2 large academic medical centers. Thirteen questions and 2 case vignettes were used to assess perceptions of decision-making, considerations when deciding whether to offer to operate, and communication patterns with patients and families. RESULTS: Thematic analysis revealed 6 major themes: responsibility for the decision to operate, perceived futility, surgeon judgment, surgeon introspection, pressure to operate, and costs of the operation. Perceived futility was universally considered a contraindication to surgical intervention. However, the challenge of defining futility led participants to emphasize the importance of patients' self-determined risk-to-benefit analysis when considering surgical intervention. More experienced surgeons reported greater comfort with communicating to patients that a condition was not amenable to an operation and reserved the right to refuse to operate. CONCLUSIONS: Due to external pressures and uncertainty, some providers err on the side of operative intervention, despite suspected futility. Greater experience allows surgeons to withstand external pressures, be confident in their assessments of perceived futility, and guide patients and their families away from additional interventions. PMID- 29382559 TI - RIFM fragrance ingredient safety assessment 2-Benzylheptanol, CAS Registry Number 92368-90-6. PMID- 29382561 TI - Optimal Timing of Initiation of Thromboprophylaxis after Nonoperative Blunt Spinal Trauma: A Propensity-Matched Analysis. AB - BACKGROUND: Patients with spinal trauma have the highest risk of a venous thromboembolism. Although anticoagulation is recommended, its optimal timing is not well-defined. We aimed to assess the impact of early initiation of thromboprophylaxis in spinal trauma patients who were managed nonoperatively. STUDY DESIGN: A 2-year (2013 to 2014) analysis of all isolated spinal trauma patients managed nonoperatively who received thromboprophylaxis in the American College of Surgeons Trauma Quality Improvement Program. Patients were divided into 2 groups based on timing of initiation of thromboprophylaxis: early (<48 hours) and late (>=48 hours), and were matched in a 1:1 ratio using propensity score matching for demographic characteristics, admission vitals, injury severity, level of spine injury, and type of prophylaxis. Outcomes were prevalence of deep venous thrombosis (DVT) and pulmonary embolism, packed RBC requirement, and mortality. RESULTS: We included 20,106 patients, of which 8,552 (early, n = 4,276; late, n = 4,276) were matched. Matched groups were similar in demographic characteristics, vital and injury parameters, and type of prophylaxis. Patients in the early group were less likely to have DVT (1.7% vs 7.6%; p < 0.001) or pulmonary embolism (0.8% vs 2.2%; p < 0.001) develop compared with the late group. In addition, there was no difference in packed RBC requirement (p = 0.61) and mortality (p = 0.49). Patients who received unfractionated heparin had a similar rate of DVT (p = 0.26) and pulmonary embolism (p = 0.35) compared with those who received low-molecular-weight heparin. CONCLUSIONS: In patients with nonoperative spinal trauma, early initiation of thromboprophylaxis is associated with decreased rates of DVT and pulmonary embolism. In addition, we did not find any association between the type of pharmacologic agents and venous thromboembolism rates. Additional prospective clinical trials should be undertaken to define guidelines for the timing of initiation of thromboprophylaxis. PMID- 29382562 TI - Behavioural characterization of C57BL/6N and BALB/c female mice in social home cage - Effect of mixed housing in complex environment. AB - Developing reliable mouse models for social behaviour is challenging. Different tests have been proposed, but most of them consist of rather artificial confrontations of unfamiliar mice in novel arenas or are relying on social stress induced by aggressive conspecifics. Natural social interaction in home cage in laboratory has not been investigated well. IntelliCage is a fully automated home cage system, where activity of the group-housed mice can be monitored along with various cognitive tasks. Here we report the behavioural profile of C57BL/6N (B6) and BALB/c (BALB) female mice in IntelliCage when separated by strain, followed by monitoring of activity and formation of 'home-base' after mixing two strains. For that purpose, 3 cages were connected. Significant differences between the strains were established in baseline behaviour in conventional tests and in IntelliCage. The B6 mice showed reduced anxiety-like behaviour in open field and light-dark box, slightly enhanced exploratory activity in IntelliCage during initial adaptation and clearly distinct circadian activity. Mixing of two strains resulted in reduction of body weight and anhedonia in B6 mice. In addition, the B6 mice showed clear preference to previous home-cage, and formed a new home-base faster than BALB mice. In contrast, BALB mice showed enhanced activity and moving between the cages without showing any preference to previous home-cage. It could be argued that social challenge caused changes in both strains and different coping styles are responsible for behavioural manifestations. Altogether, this approach could be useful in modelling and validating mouse models for disorders with disturbed social behaviour. PMID- 29382563 TI - Is regular exercise an effective strategy for weight loss maintenance? AB - Weight regain after weight loss is one of the most significant challenges to successful obesity treatment. Regular exercise has long been touted as a strategy for weight loss maintenance, but the lack of clear evidence in clinical trials has caused some to question its effectiveness. In this review, we present the arguments both questioning and in support of exercise as an obesity therapeutic. Our purpose is to bring clarity to the literature, present a unified perspective, and identify the gaps in knowledge that need to be addressed in future studies. Critical questions remain including sex differences, individual variability and compensatory behaviors in response to exercise, exercise adherence, the role of energy flux and the molecular mechanisms mediating the beneficial effects of exercise after weight loss and during weight regain. Future research should focus on these critical questions to provide a more complete understanding of the potential benefits of exercise on weight loss maintenance. PMID- 29382564 TI - Diabetic cognitive dysfunction is associated with increased bile acids in liver and activation of bile acid signaling in intestine. AB - Impaired regulation of bile acid (BA) homeostasis has been suggested to be associated with adverse metabolic consequences. However, whether BA homeostasis is altered in diabetes-induced cognitive dysfunction (DCD) remains unknown. In the present study, mice were divided into four groups, namely normal control (NC) group, high-fat diet (HFD) group, diabetes without cognitive dysfunction (unDCD) group, and DCD group. Compared to HFD mice, the concentration of total BAs in liver was higher in unDCD and DCD mice, due to increased intestinal BA absorption. DCD mice tended to have higher BA concentrations in both liver and ileum than unDCD mice. Consequently, DCD mice had increased basolateral BA efflux (Ostalpha, Ostbeta, and Mrp4) and decreased BA synthesis (Cyp7a1, Cyp8b1, and Cyp7b1) in the liver as well as activated Fxr-Fgf15 signaling in the ileum. DCD mice also had increased BA hydroxylation (Cyp3a11) and BA sulfation (Sult2a1) in the liver compared to HFD mice. Furthermore, the bacterial community composition was altered in the cecum of DCD mice, characterized with a marked increase in Defferribacteres and Candidatus Saccharibacteria. In summary, the present study provides the first comprehensive analysis of BA homeostasis in DCD mice, and revealed a potential role of BAs in DCD development. PMID- 29382565 TI - Excess ventilation in COPD: Implications for dyspnoea and tolerance to interval exercise. AB - Interval exercise delays critical mechanical-ventilatory constraints with positive consequences on Dyspnoea and exercise tolerance in COPD. We hypothesized that those advantages of interval exercise would be partially off-set in patients showing excessive ventilation (VE) to metabolic demand (VCO2). Sixteen men (FEV1 = 42.3 +/- 8.9%) performed, on different days, 30 s and 60 s bouts at 100% peak (on) interspersed by moderate exercise at 40% (off). Nine patients did not sustain exercise for 30 min irrespective of on duration. They presented with higher VE/VCO2 nadir (35 +/- 3 vs. 30 +/- 5) and dead space/tidal volume (0.39 +/ 0.05 vs. 0.34 +/- 0.06) compared to their counterparts (p < 0.05). [Lactate], operating lung volumes and symptom burden (dyspnoea and leg effort) were also higher (p < 0.05). Unloading off decreased the metabolic-ventilatory demands, thereby allowing 7/9 patients to exercise for 30 min. Increased wasted ventilation accelerates the rate at which critical mechanical constraints and limiting dyspnoea are reached during interval exercise in patients with COPD. PMID- 29382566 TI - Overexpression of the 14-3-3gamma protein in uterine leiomyoma cells results in growth retardation and increased apoptosis. AB - Protein 14-3-3gamma was significantly reduced in human uterine leiomyoma compared to the adjacent normal myometrium tissue. To investigate the possible link between the reduced 14-3-3gamma expression and uterine leiomyoma growth, we have overexpressed 14-3-3gamma protein in uterine leiomyomal cells and its effects on cell proliferation and apoptosis were analyzed. Over-expression of 14-3-3gamma was achieved by transducing into two types of uterine leiomyoma cells (primary culture cells and immortal stem cells) with a 14-3-3gamma expressing adenovirus vector. Differentially expressed proteins were screened by the proteomics tool (TMT-LCTMS), followed by PANTHER database analysis to single out specifically modified signaling pathway proteins, which were confirmed by Phospho-MAPK Antibody Array and Western blots analysis. The results showed that increase in 14 3-3gamma expression in both two types of human uterine leiomyoma cells inhibited cell proliferation and induced apoptosis. Proteomic screening has found 42 proteins, among 5846, that were significantly affected. PANTHER database and GeneMANIA analysis of the differentially expressed proteins have found that proteins involved in apoptosis signaling and cytoskeletal/adhesion were among the ones affected the most. Further analysis of the key signaling pathways have found that over-expression of 14-3-3gamma resulted in reductions in the phosphorylations of multiple signaling molecules, including AKT, pan, ERK1/2, GSK 3 alpha/beta, MEK1/2, Foxo1 and Vimentin. In conclusion, the loss of 14-3-3gamma may have causal effects on the growth of uterine leiomyoma, which may function through modifying multiple signaling pathways, including AKT-Foxo and/or MEK1/2 ERK1/2. PMID- 29382567 TI - Fibroblast growth factor type 1 receptor stimulation of T-type Ca2+ channels in sensory neurons requires the phosphatidylinositol 3-kinase and protein kinase A pathways, independently of Akt. AB - Fibroblast growth factor-23 (FGF-23) secreted by osteocytes is known as a circulating factor that is essential for phosphate homeostasis. Recent studies have implicated FGF-23 in the nociceptive signalling of peripheral sensory neurons. However, the relevant mechanisms underlying this effect are not known. In this study, we determine the role of FGF-23 in regulating T-type Ca2+ channels (T-type channels) in small-diameter dorsal root ganglion (DRG) neurons in mice. Our results show that FGF-23 increases T-type channel currents in a concentration dependent manner. This FGF-23-induced response was dependent on FGF type 1 receptor (FGFR1) and was accompanied by a depolarizing shift in the steady-state inactivation curve. Pretreatment of neurons with the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 prevented the FGF-23-mediated T-type channel response. Analysis of phospho-Akt (p-Akt) revealed that FGF-23 significantly activated Akt, but Akt inhibition did not affect the FGF-23-induced T-type channel current increase. The cell-permeable protein kinase A (PKA) inhibitor KT 5720 pretreatment and intracellular application of PKI 6-22 both abolished the stimulatory effects of FGF-23 on T-type channels, but inhibition of PKC had no effect. In summary, these findings indicate that FGF-23 stimulates T-type channel activity via activation of FGFR1, which is coupled to the PI3K-dependent PKA signalling cascade in small DRG neurons. PMID- 29382568 TI - Reply to: In a subset of PEA patients, do continuous infusions of adrenergic agents improve chances of ROSC? PMID- 29382569 TI - Improved Base Editor for Efficiently Inducing Genetic Variations in Rice with CRISPR/Cas9-Guided Hyperactive hAID Mutant. PMID- 29382570 TI - Regulation of the replication initiator DnaA in Caulobacter crescentus. AB - The decision to initiate DNA replication is a critical step in the cell cycle of all organisms. In nearly all bacteria, replication initiation requires the activity of the conserved replication initiation protein DnaA. Due to its central role in cell cycle progression, DnaA activity must be precisely regulated. This review summarizes the current state of DnaA regulation in the asymmetrically dividing alpha-proteobacterium Caulobacter crescentus, an important model for bacterial cell cycle studies. Mechanisms will be discussed that regulate DnaA activity and abundance under optimal conditions and in coordination with the asymmetric Caulobacter cell cycle. Furthermore, we highlight recent findings of how regulated DnaA synthesis and degradation collaborate to adjust DnaA abundance under stress conditions. The mechanisms described provide important examples of how DNA replication is regulated in an alpha-proteobacterium and thus represent an important starting point for the study of DNA replication in many other bacteria. This article is part of a Special Issue entitled: Dynamic gene expression, edited by Prof. Patrick Viollier. PMID- 29382571 TI - FGF2 and FAM201A affect the development of osteonecrosis of the femoral head after femoral neck fracture. AB - Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease associated with high disability, and femoral neck fracture (FNF) is one of the most common reasons for traumatic ONFH. This study was designed to reveal the mechanisms underlying ONFH. Using fastx_toolkit and prinseq-lite tools, quality control was conducted for the sequencing data. The differentially expressed genes (DEGs, including both mRNAs and lncRNAs) between ONFH and FNF samples were identified using the edgeR package in R, and were then subjected to enrichment analysis using the BioCloud platform. Subsequently, protein-protein interaction (PPI) networks were constructed using Cytoscape software. After the target genes of DE-lncRNAs were predicted based on Spearman's rank correlation coefficient, lncRNA-gene coexpression network was visualized using the Cytoscape software. Furthermore, functional enrichment analysis was carried out for the target genes using the clusterprofiler package in R. Additionally, the key genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 2965 DEGs were identified from the ONFH samples, including 602 DE-lncRNAs (such as downregulated FAM201A). In the PPI networks, eight upregulated genes (including FGF2, IGF1, SOX9, and COL2A1) and 11 downregulated genes were among the top 20 genes according to all of the scores, such as degree centrality, closeness centrality, and betweenness centrality scores. Functional enrichment analysis showed that IGF1, SOX9, and COL2A1 were significantly enriched during skeletal system development. Moreover, qRT-PCR experiments detected the upregulation of FGF2 and downregulation of FAM201A in ONFH samples. FGF2 and FAM201A were correlated with the development of ONFH. Besides, IGF1, SOX9, and COL2A1 might also affect the pathogenesis of ONFH. PMID- 29382572 TI - Dopamine D2-like receptors (DRD2 and DRD4) in chickens: Tissue distribution, functional analysis, and their involvement in dopamine inhibition of pituitary prolactin expression. AB - Dopamine (DA) D2-like (and D1-like) receptors are suggested to mediate the dopamine actions in the anterior pituitary and/or CNS of birds. However, the information regarding the structure, functionality, and expression of avian D2 like receptors have not been fully characterized. In this study, we cloned two D2 like receptors (cDRD2, cDRD4) from chicken brain using RACE PCR. The cloned cDRD4 is a 378-amino acid receptor, which shows 57% amino acid (a.a.) identity with mouse DRD4. As in mammals, two cDRD2 isoforms, cDRD2L (long isoform, 437 a.a.) and cDRD2S (short isoform, 408 a.a.), which differ in their third intracellular loop, were identified in chickens. Using cell-based luciferase reporter assays or Western blot, we demonstrated that cDRD4, cDRD2L and cDRD2S could be activated by dopamine and quinpirole (a D2-like receptor agonist) dose-dependently, and their activation inhibits cAMP signaling pathway and stimulates MAPK/ERK signaling cascade, indicating that they are functional receptors capable of mediating dopamine actions. Quantitative real-time PCR revealed that cDRD2 and cDRD4 are widely expressed in chicken tissues with abundant expression noted in anterior pituitary, and their expressions are likely controlled by their promoters near exon 1, as demonstrated by dual-luciferase reporter assays in DF-1 cells. In accordance with cDRD2/cDRD4 expression in the pituitary, DA or quinpirole could partially inhibit vasoactive intestinal peptide-induced prolactin expression in cultured chick pituitary cells. Together, our data proves the functionality of DRD2 and DRD4 in birds and aids to uncover the conserved roles of DA/D2-like receptor system in vertebrates, such as its action on the pituitary. PMID- 29382573 TI - Studies on reproductive stress caused by candidate Gram positive and Gram negative bacteria using model organism, Caenorhabditis elegans. AB - Microbial association with a host using model system C. elegans have been widely studied based on factors such as host survival, the mode of infection, disease pathogenesis and the role of various players regulated during infection. The influence of pathogenic microorganism on reproduction and associated issues has not been explored fully. The present study focuses on the impact of bacterial infection on male reproductive parameters such as spermatogenesis and spermiogenesis, including physiological aspects like tail morphology defect and underlying molecular mechanisms that have been perturbed. In order to compare the consequence of infection caused by Gram positive and negative bacteria, Staphylococcus aureus and Vibrio alginolyticus were chosen as candidate pathogens, respectively. Microscopic observations revealed notable changes in tail morphology during 24 h of infection, as along with change in sperm size and activation. The Real Time-PCR results suggest the plausible down regulation of DBL-1/TGF-beta pathway suggesting the morphological change in the tail. Shotgun proteomics further lead to the identification of MAG-1, Magonashi Protein a candidate regulatory player that affects spermatogenesis and HIF-1 that regulate during stress in both Gram positive and Gram negative infection. The protein protein interaction with detected proteins revealed RACK-1 protein and mTOR pathway in S. aureus and V. alginolyticus respectively interacting with MAG-1 protein, which plays an important role in spermatogenesis termination in hermaphrodites during L4 to adult switch. This study paves a way to understand the candidate players that regulate reproduction during bacterial infection. PMID- 29382574 TI - Dynamic regulation of six histone H3 lysine (K) methyltransferases in response to prolonged anoxia exposure in a freshwater turtle. AB - The importance of histone lysine methylation is well established in health, disease, early development, aging, and cancer. However, the potential role of histone H3 methylation in regulating gene expression in response to extended periods of oxygen deprivation (anoxia) in a natural, anoxia-tolerant model system is underexplored. Red-eared sliders (Trachemys scripta elegans) can tolerate and survive three months of absolute anoxia and recover without incurring detrimental cellular damage, mainly by reducing the overall metabolic rate by 90% when compared to normoxia. Stringent regulation of gene expression is a vital aspect of metabolic rate depression in red-eared sliders, and as such we examined the anoxia-responsive regulation of histone lysine methylation in the liver during 5 h and 20 h anoxia exposure. Interestingly, this is the first study to illustrate the existence of histone lysine methyltransferases (HKMTs) and corresponding histone H3 lysine methylation levels in the liver of anoxia-tolerant red-eared sliders. In brief, H3K4me1, a histone mark associated with active transcription, and two corresponding histone lysine methyltransferases that modify H3K4me1 site, significantly increased in response to anoxia. On the contrary, H3K27me1, another transcriptionally active histone mark, significantly decreased during 20 h anoxia, and a transcriptionally repressive histone mark, H3K9me3, and the corresponding KMTs, similarly increased during 20 h anoxia. Overall, the results suggest a dynamic regulation of histone H3 lysine methylation in the liver of red eared sliders that could theoretically aid in the selective upregulation of genes that are necessary for anoxia survival, while globally suppressing others to conserve energy. PMID- 29382575 TI - Transcriptomic approach: A promising tool for rapid screening nanomaterial mediated toxicity in the marine bivalve Mytilus edulis-Application to copper oxide nanoparticles. AB - The extensive development of nanotechnologies will inevitably lead to the release of nanomaterials (NMs) in the environment. As the aquatic environments represent the ultimate sink for various contaminants, it is highly probable that they also constitute a reservoir for NMs and hence aquatic animals represent potential targets. In a regulatory perspective, it is necessary to develop tools to rapidly screen the impact of NMs on model organisms, given that the number of NMs on the market will be increasing. In this context High Throughput Screening approaches represent relevant tools for the investigation of NM-mediated toxicity. The objective of this work was to study the effects of copper oxide nanoparticles (CuONPs) in the marine bivalve Mytilus edulis, using a transcriptomic approach. Mussels were exposed in vivo to CuONPs (10 MUg.L-1CuO NPs) for 24 h and analysis of mRNA expression levels of genes implicated in immune response, antioxidant activities, cell metabolism, cell transport and cytoskeleton was investigated by qPCR on hemocytes and gills. Results showed common effects of CuONPs and its ionic counterpart. However, greater effects of CuONPs on GST, SOD, MT, Actin, ATP synthase gene expressions were observed compared to ionic form indicating that toxicity of CuONPs is not solely due to the release of Cu2+. Even though M. edulis genome is not fully characterized, this study provides additional knowledge on the signaling pathways implicated in CuONP-mediated toxicity and demonstrates the reliability of using a qPCR approach to go further in the cellular aspects implicated in response to NPs in marine bivalves. PMID- 29382576 TI - Toxic activity and protein identification from the parotoid gland secretion of the common toad Bufo bufo. AB - Anuran toxins released from the skin glands are involved in defence against predators and microorganisms. Secretion from parotoid macroglands of bufonid toads is a rich source of bioactive compounds with the cytotoxic, cardiotoxic and hemolytic activity. Bufadienolides are considered the most toxic components of the toad poison, whereas the protein properties are largely unknown. In the present work, we analysed the cardio-, myo-, and neurotropic activity of extract and the selected proteins from Bufo bufo parotoids in in vitro physiological bioassays carried out on two standard model organisms: beetles and frogs. Our results demonstrate a strong cardioactivity of B. bufo gland extract. The toad poison stimulates (by 16%) the contractility of the insect heart and displays the cardioinhibitory effect on the frog heartbeat frequency (a 27% decrease), coupled with an irreversible cardiac arrest. The gland extract also exhibits significant myotropic properties (a 10% decrease in the muscle contraction force), whereas its neuroactivity remains low (a 4% decrease in the nerve conduction velocity). Among identified peptides present in the B. bufo parotoid extract are serine proteases, muscle creatine kinase, phospholipid hydroperoxide glutathione peroxidase, cytotoxic T-lymphocyte protein, etc. Some proteins contribute to the cardioinhibitory effect. Certain compounds display the paralytic (myo- and neurotropic) properties. As the toad gland extract exhibits a strong cardiotoxic activity, we conclude that the poison is a potent agent capable of slaying a predator. Our results also provide the guides for the use of toad poison-peptides in therapeutics and new drug development. PMID- 29382577 TI - Penaeus vannamei protease stabilizing process of ZnS nanoparticles. AB - The protease enzyme purified from the Penaeus vannamei shrimp has unique properties, so improving the stability of this enzyme can improve their practical applications. In this study, ZnS nanoparticles, which have special properties for enzyme immobilization, were synthesized using a chemical precipitation method, and Penaeus vannamei protease was successfully immobilized on them. The size, structure, and morphology of the ZnS nanoparticles, and the immobilization of the protease were studied, using Transmission Electron Microscopy (TEM), Fourier Transform Infrared (FT-IR) spectroscopy, UV-Vis spectroscopy and Dynamic Light Scattering (DLS) analysis. We show that the immobilized enzyme has improved functionality at high temperatures, extreme pH conditions (pH3 and 12), and during storage. Immobilization increased the optimum temperature range of the enzyme, but did not change the pH optimum, which remained at pH7. Immobilization of P. vannamei protease enzyme increased the Km and decreased kcat/Km. These results indicate that P. vannamei protease immobilized on ZnS nanoparticles, has improved properties due to its high stability and unique properties, can be used for biotechnology applications. PMID- 29382578 TI - The pectinases from Sphenophorus levis: Potential for biotechnological applications. AB - Pectinases represent about one fifth of the enzyme worldwide market due their wide range of biotechnological applications. Current commercial pectinases are exclusively obtained from microbial sources, but here we report a pectin methylesterase (Sl-PME) and an endo-polygalacturonase (Sl-EPG) bioprospected from the sugarcane weevil, Sphenophorus levis, which revealed good potential for industrial applications. Sl-PME and Sl-EPG were overexpressed in Pichia pastoris, purified and enzymatically characterized. Sl-EPG presents optimal activity at pH 4-5 and 50 degrees C, showing that it can be used for juice extraction and clarification. On the other hand, Sl-PME presents optimal activity at pH 6-8 and 40 degrees C, and thus, suitable for both acidic and alkaline processing, such as coffee and tea fermentation. Sl-EPG shows Vmax = 3.23 mM/min, KM = 2.4 g/L and kcat = 418.6 s-1. While Sl-PME shows Vmax = 0.14 mM/min, KM = 4.1 g/L and kcat = 1.7 s-1. A PG inhibitor (PGIP2) weakly interfered in the Sl-EPG activity and Sl PME was not affected by a usual PME inhibitor. Moreover, these enzymes manifested synergistic action towards methylesterified pectin. Here, we propose these enzymes as novel alternative tools for the current commercial pectinases. PMID- 29382579 TI - Preparation and immunological activity of polysaccharides and their derivatives. AB - Polysaccharide is a kind of natural macromolecule polymer, which is widely existed in animals, plants and microorganisms, has a variety of biological activities, such as anti-tumor, anti-virus, anti-oxidation and immune regulation. Polysaccharides can affect macrophages, cells and other immune cells to improve the body's immune function, and have no toxic and side effects on normal cells, which make the polysaccharides receive widespread attention. In recent years, studies have shown that structural modification of polysaccharides can improve the immunological activity of polysaccharides. The common chemical modifications are sulfation, carboxymethylation, acetylation, phosphorylation, and so on. The chemical modification of polysaccharides and the immunomodulation of polysaccharides and polysaccharide derivatives were analyzed and discussed. PMID- 29382580 TI - Bioluminescence and kinetic aspects of double mutated aequorin variants. AB - Aequorin as an old small calcium-sensitive photoprotein is a blue fluorescence protein which converts coelenterazine (a substrate) to coelenteramide with a flash type emission. The decay kinetics and emission properties of this protein can be changed using directed mutagenesis of crucial amino acid residue. In this work, we prepared three double mutants: Y82F/W86F, Y82F/D153G, and W86F/D153G. According to our results, it seems that presence of Y82F mutation results in shift of emission to longer wavelengths while the W86F mutation shifts the emission to shorter wavelengths. Furthermore, comparison of the variants for light half-life indicated decreased t1/2 for the two variants of Y82F/D153G and W86F/D153G. But in compared to wild type aequorin, the Y82F/W86F variant displayed a 2-fold increase of light half-life. On the other hand, the thermostability properties of double mutants confirmed that only Y82F/D153G variant of apoaequorin is higher stability than others. Also, the single W86F mutant reached the highest stability against thermal shock. Our data suggest that replacement of single or few point mutations in the binding pocket or active site of aequorin affects its bioluminescence and kinetic properties and so could be used for new reporter production of this photoprotein with the feasibility and limited substitutions. PMID- 29382581 TI - Chitosan-based nanoparticles of avermectin to control pine wood nematodes. AB - Pine wood nematode disease is a most devastating disease of pine trees. Avermectin (AVM) is a widely used bio-nematocide which can effectively to kill the pine wood nematode (PWN). However, its poor solubility in water and rapid photolysis are responsible for its poor bioavailability, which causes environmental pollution because of excessive applied rates. Here, a simple electrostatic interaction method was used to encapsulate AVM within nanoparticles composed of poly-gamma-glutamic acid (gamma-PGA) and chitosan (CS). The loading capacity of the resulting AVM-CS/gamma-PGA nanoparticles was as much as 30.5%. The encapsulation of AVM within these nanoparticles reduced its losses by more than 20.0% through photolysis. An in vitro test showed that the rate of release of AVM from the nanoparticles was dependent on the ambient pH, with rapid release occurring in an alkaline environment. The mortality rate of nematodes which were treated with 1ppm of AVM content of AVM-CS/gamma-PGA was 98.6% after 24h, while one of free AVM was only 69.9%. In addition, FITC-labeled CS/gamma-PGA nanoparticles (FITC-CS/gamma-PGA) showed that the nanoparticles could enrich in intestines and head of nematodes. All of these results showed that those nanoparticles of AVM are a potential multifunctional formulation to control the pest and reduce environment pollution. PMID- 29382582 TI - Structure-function studies of prothrombin Amrita, a dysfunctional prothrombin characterized by point mutation at Arg553 -> Gln. AB - A dysfunctional prothrombin gene characterized by novel point mutation at Arg553 to Gln residue in Deep vein thrombosis (DVT) patient which we designated as "Prothrombin Amrita" was previously reported from our lab. The mutation occurred at nucleotide 20030 in exon 14 and was confirmed by restriction enzyme digestion. Arg553 has been reported as one of the key residues for the binding of cofactor Na+ ion in the thrombin protein. Structural analysis revealed the molecular mechanism behind the coagulant form of thrombin due to point Arg553Gln mutation near the cofactor Na+ ion region. Molecular electrostatic potential maps and molecular dynamics (MD) simulation of the wild type and mutated thrombin showed the key role played by the Na+ ion for its coagulant mechanism by analysing the charge distribution and nature of the hydrogen bonding at the mutated region of interest. We observed maintenance of the fast or procoagulant form of dysfunctional prothrombin due to changes in the charge distribution by this mutation and thereby also keeping strong hydrogen bonding network revealed by MD simulation between prothrombin and Na+ ion. This molecular mechanism might be the main cause for DVT in patients with this dysfunctional prothrombin gene. PMID- 29382583 TI - A novel IgG1 monoclonal antibody against xanthine oxidase alleviates inflammation induced by potassium oxonate in mice. AB - Xanthine oxidase (XOD) is a key enzyme that catalyzes xanthine to uric acid. Most of the urate-lowering medicines targeting XOD have a limited effect on alleviating inflammation in spite of significant effects on decreasing serum uric acid level. In this study, we produced and characterized a novel monoclonal antibody (Anti-XOD mAb) using hybridoma technology based on a novel peptide OI5P 1(O-IA2(5)-P2-1),which containing a B-cell epitope of XOD and a novel Th2 built in adjuvant I5P-1(IA2(5)-P2-1). Results of western blotting and cross-reactivity assay indicated that the mAb binds specifically to XOD and the affinity was 2.523*1010L/mol. The mAb reduced serum uric acid level and hepatic xanthine oxidase activity in potassium oxonate induced mice. A decreased methane dicarboxylic aldehyde level and an improved superoxide dismutase level in mAb treated mice indicated anti-lipid peroxidation effects of the mAb. Moreover, the mAb showed a significant immunomodulatory effect which could shift Th1/Th2 balance to Th2-dominant immunity. The mAb treatment alleviates inflammation induced by potassium oxonate, superior to the small molecule allopurinol treatment. For the first time, these results showed that the anti-XOD mAb may serve as a promising therapeutic approach for inflammatory response related to uric acid. PMID- 29382584 TI - Incidence of diabetic foot ulcer in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry. AB - AIMS: Although diabetic foot ulcer (DFU) is a serious diabetic complication, there have been no large-scale epidemiological studies of DFU in Japan. We prospectively investigated the incidences of DFU and limb amputation, the risk for developing DFU, and mortality in Japanese patients with type 2 diabetes. METHODS: We followed 4870 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 97.7%). The primary outcome was the development of DFU. RESULTS: During the follow-up period, DFU occurred in 74 participants (incidence rate, 2.9/1000 person-years) and limb amputation in 12 (incidence rate, 0.47/1000 person-years). DFU recurrence was observed in 21.4% of participants with history of DFU. History of DFU, chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2), depressive symptoms, and poor glycemic control were significant risk factors for developing DFU. Survival was significantly lower in participants with DFU and/or history of DFU compared with those without (5-year survival rates: with DFU, 87.7%, without DFU, 95.3%; P < .0001). The hazard ratio for death was 1.80 (95% confidence interval, 1.13-2.73, P = .014) in those with DFU and/or history of DFU in a multi-adjusted model. The most common cause of death was cardiovascular disease among participants with DFU, whereas it was malignant neoplasm among those without. CONCLUSIONS: Incidences of DFU and limb amputation were 0.3% and 0.05% per year in this Japanese cohort, respectively. Mortality significantly increased approximately 2-fold in those with DFU and/or history of DFU compared with those without. PMID- 29382585 TI - Interleukin-10 -1082A > G (rs1800896) polymorphism is associated with diabetic retinopathy in type 2 diabetes. AB - AIM: To investigate whether the -1082A > G polymorphism (rs1800896) in the interleukin-10 (IL10) gene is associated with diabetic retinopathy (DR) in Brazilians with type 2 diabetes mellitus. METHODS: This case-control study included 847 outpatients with type 2 diabetes and 145 healthy blood donors. Four hundred and two patients had no DR, 253 had non-proliferative DR (NPDR), and 192 had proliferative DR (PDR). Genotyping was done by real-time PCR. RESULTS: Genotype and allele frequencies were similar in patients and blood donors. In relation to the presence and severity of DR, the AA genotype was overrepresented among patients with NPDR, whereas the GG genotype was more frequent among patients with PDR. Multiple logistic regression analysis showed that the AA genotype was independently associated with increased risk of NPDR, after controlling for duration of diabetes, body mass index, and insulin use (adjusted OR = 1.50; 95% CI = 1.04-2.17). The GG genotype, however, did not remain associated with increased risk of PDR (adjusted OR = 1.49; 95% CI = 0.78-2.86). CONCLUSIONS: This study identified, for the first time, an independent association of the -1082A > G polymorphism in the IL10 gene with NPDR in type 2 diabetes. This finding provides additional evidence supporting that genetic variants of IL10 are involved in the pathogenesis of DR. PMID- 29382586 TI - Electrical changes during hypoglycaemia in patients with type 1 and type 2 diabetes and high cardiovascular risk. AB - The relationship between glycaemia, arrhythmia and changes in electrocardiogram (ECG) has been addressed showing mixed results. The objective of this study was to evaluate the changes in ECG, evaluated by Holter monitoring, induced by clinical hypoglycaemia in patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM), aged 50 or older, with high cardiovascular risk. Five-lead Holter monitoring (BL-900 Braemar, Inc, Norav Medical NH301-2.4.5 software), and blinded interstitial continuous glucose monitoring (CGM) (Dexcom G4-Platinum, range 40-400 mg/dl) was performed with time synchronization. In the Holter registry, in patients with hypoglycemic episodes, mean QTc during hypoglycaemia was longer compared to mean QTc in total group (+4.6 ms, p = 0.037) and T1DM patients (+5.5 ms, p = 0.048) but not in T2DM patients (+3 ms, p = 0.459). During hypoglycaemia, non-clinical significant disturbances in heart rhythm were observed. In conclusion, we observed a prolongation in QTc during hypoglycemia, mainly in T1DM. However, our study does not show a relationship between episodes of hypoglycaemia and clinical arrhythmias, at least in T1DM and T2DM patients with high cardiovascular risk. PMID- 29382587 TI - Comparison of nutrient intakes in South Asians with type 2 diabetes mellitus and controls living in the United States. AB - AIMS: Despite having a high risk for type 2 diabetes mellitus (T2DM), little is known about the relationship between nutrient intakes and T2DM in South Asians (SA) in the U.S. In addition, the available data are limited to a few macronutrients and collected using subjective measures. Therefore, we compared macro- and micro-nutrient intakes of SA migrants with and without T2DM using an objective measure. METHODS: SA in the U.S. with T2DM (n = 44) and controls (n = 33) reported their dietary intake using image-assisted dietary assessment method. They took pictures of all foods/drinks consumed on two weekdays and one weekend day. Age, gender distribution, and body mass index were similar across the two groups. RESULTS: SA with T2DM, as compared to controls, consumed less total energy (mean difference: 499 kcal/d; p < .0001), linoleic acid (3.6 g/d; p = .003), dietary fiber (8.6 g/d; p < .0001), vitamin A (262 ug/d; p = .003), vitamin E (2.7 mg/d; p = .007), calcium (133 mg/d; p = .01), magnesium (116 mg/d; p < .0001), zinc (1.4 mg/d; p = .004), potassium (754 mg/d; p < .0001), and beta carotene (1761 ug/d; p = .03). SA with T2DM, as compared to controls, were significantly more likely not to meet the requirements for linoleic acid, dietary fiber, vitamin E, calcium, magnesium, zinc, and potassium (p < .05). CONCLUSIONS: SA with T2DM, compared to controls, consume less total energy and have lower consumption of many nutrients associated with reduced risk of T2DM. Dietary interventions to reduce risk for T2DM are warranted in SA. PMID- 29382588 TI - Association of proton pump inhibitor use with the risk of the development or progression of albuminuria among Japanese patients with diabetes: A prospective cohort study [Diabetes Distress and Care Registry at Tenri (DDCRT 16)]. AB - AIMS: We aimed to determine the prospective association between proton pump inhibitor (PPI) use and the subsequent risk of the development or progression of albuminuria or eGFR. METHODS: Longitudinal data of patients with diabetes were obtained from a large Japanese diabetes registry. To assess the independent correlation between PPI use and the development or progression of urine microalbuminuria, the time-varying Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: The mean patient age, body-mass index (BMI), and hemoglobin A1c (HbA1c) levels were 65.7 y, 24.5 kg/m2, and 7.5% (57.9 mmol/mol), respectively. In 1711 patients without albuminuria, we observed 599 cases with development of albuminuria over median follow-up of 4.0 years, and in 1279 patients with microalbuminuria, 290 cases with urinary albuminuria progression over 4.0 years, and 257 eGFR decline cases over 3.8 years. PPI use was not associated with the development of albuminuria (HR = 0.88; 95%CI, 0.77 1.01; p = .058), progression of albuminuria (HR = 1.24; 95%CI, 0.87-1.79; p = .236), nor eGFR decline (HR = 1.05; 95%CI, 0.81-1.34; p = .973) even in a propensity score-adjusted model with time-varyingly updating PPI use information. CONCLUSIONS: In conclusion, PPI use was not associated with the subsequent risk of development or progression of albuminuria, or eGFR decline in patients with diabetes. PMID- 29382589 TI - The prevalence and determinants of active tuberculosis among diabetes patients in Cape Town, South Africa, a high HIV/TB burden setting. AB - AIMS: Studies addressing the association between diabetes mellitus (DM) and tuberculosis (TB) in sub-Saharan Africa are limited. We assessed the prevalence of active TB among DM patients at a primary care clinic, and identified risk factors for prevalent TB. METHODS: A cross-sectional study was conducted in adult DM patients attending a clinic in Khayelitsha, Cape Town. Participants were screened for active TB (symptom screening and microbiological diagnosis) and HIV. RESULTS: Among 440 DM patients screened, the active TB prevalence was 3.0% (95% CI 1.72-5.03). Of the 13 prevalent TB cases, 53.9% (n = 7; 95% CI 27.20-78.50) had no TB symptoms, and 61.5% (n = 8; 95% CI 33.30-83.70) were HIV-1 co-infected. There were no significant differences in either fasting plasma glucose or HbA1c levels between TB and non-TB participants. On multivariate analysis, HIV-1 infection (OR 11.3, 95% CI 3.26-39.42) and hemoptysis (OR 31.4, 95% CI 3.62 273.35) were strongly associated with prevalent active TB, with no differences in this association by age or gender. CONCLUSIONS: The prevalence of active TB among DM patients was 4-fold higher than the national prevalence; suggesting the need for active TB screening, particularly if hemoptysis is reported. Our results highlight the importance of HIV screening in this older population group. The high prevalence of sub-clinical TB among those diagnosed with TB highlights the need for further research to determine how best to screen for active TB in high risk TB/HIV population groups and settings. PMID- 29382590 TI - Association between QTc interval prolongation and outcomes of diabetic foot ulcers: Data from a 4-year follow-up study in China. AB - OBJECTIVES: To examine whether QTc interval prolongation is an independent risk factor of outcomes in patients with diabetic foot ulcers (DFU). RESEARCH DESIGN AND METHODS: 331 patients with type 2 diabetes and DFU hospitalized in a Chinese tertiary hospital were recruited. ECG was done at baseline and QTc interval was calculated through Bazett's formula. Participants were classified into 2 groups according to the QTc interval as prolonged (>=440 ms) or not (<440 ms). These patients were followed-up for an average of 48 months to observe the outcomes, including ulcer healing, ulcer recurrence, nonfatal cerebral or cardiovascular events (NCCVE), cerebral cardiovascular death, cardiac death and all-cause death. The associations between the risk of outcomes and QTc interval prolongation, as well as per 1-SD increase in QTc interval were analyzed by Cox proportional hazards models. RESULTS: In terms of the univariate Cox proportional hazard models, patients with QTc interval prolongation had a higher all-cause mortality (HR = 1.621, 95%CI: 1.040-2.526, P = .013), higher cardiac mortality (HR = 2.011 95%CI: 1.106-3.657, P = .019), higher cerebral cardiovascular mortality (HR = 1.525, 95%CI: 0.8151-2.852, P = .045). The multivariate analysis showed that QTc prolongation was an independent risk factor for cardiac death (HR = 5.465, 95%CI: 2.818-8.112, P = .039). Similar results were obtained when QTc interval was used as a continue variable, a 1-SD increase in QTc interval was associated with an 5.883 times risk for cardiac mortality (HR = 6.883, 95%CI: 4.153-9.613, P = .012). The association between QTc interval prolongation with ulcer healing, recurrence and NCCVE were not observed either in univariate or multivariate analysis (P > .05). CONCLUSION: QTc interval prolongation was a plausible predictor for cardiac death in DFU patients, but it cannot accurately predict ulcer healing or recurrence. PMID- 29382591 TI - Protein corona-mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses. AB - BACKGROUND: Nanoparticle (NP)-based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen presenting cells. Their cellular distribution and serum protein interaction ("protein corona") after systemic administration and their effect on the functional properties of NPs is poorly understood. OBJECTIVES: We analyzed the relevance of the protein corona on cell type-selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy. METHODS: The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxis and allergic asthma were assessed. RESULTS: DEX NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG2a production. Treatment of OVA-sensitized mice with the DEX NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition. CONCLUSIONS: Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses. PMID- 29382592 TI - The obese-asthma phenotype in children: An exacerbating situation? AB - BACKGROUND: Current evidence regarding the relationship between childhood obesity, decreased response to inhaled corticosteroids (ICSs), and poor asthma control is conflicting. OBJECTIVES: We assessed whether obesity (1) is associated with time to first exacerbation among children with asthma initiating step 3 maintenance therapies and (2) modifies the effectiveness of step 3 therapies. METHODS: A retrospective cohort study was conducted from clinical data linked to health and drug administrative databases. The cohort consisted of children aged 2 to 18 years with specialist-confirmed asthma who initiated medium/high-dose ICS monotherapy or low/medium-dose ICS with leukotriene receptor antagonist/long acting beta-agonist (combination therapy) at the Montreal Children's Hospital Asthma Center from 2000 to 2007. Children were classified as exposed to step 3 therapies when they were dispensed a corresponding drug claim during follow-up, whereas those without claims were classified as nonadherers. Marginal structural Cox models were used to estimate the effect of obesity (body mass index > 97th percentile) and treatment on time to exacerbation, which was defined as any emergency department visit, hospitalization, or use of oral corticosteroids for asthma. RESULTS: Of the 4621 cohort patients, 231 initiated ICS monotherapy, and 97 initiated combination therapy. The hazard ratio (HR) for obesity was 1.67 (95% CI, 1.41-1.98). Compared with nonobese nonadherers, the HR for obese nonadherers was 1.54 (95% CI, 0.97-2.45); the HR for ICS monotherapy in obese and nonobese children was 0.85 (95% CI, 0.47-1.52) and 0.58 (95% CI, 0.37-0.91), respectively; and the HR for combination therapy in obese and nonobese children was 0.50 (95% CI, 0.13-1.89) and 0.46 (95% CI, 0.23-0.92), respectively. CONCLUSION: Obesity might be a determinant of shorter exacerbation-free time in children with asthma; however, we could not rule out a differential response to step 3 therapies by obesity status, potentially because of a lack of precision. PMID- 29382593 TI - Benralizumab attenuates airway eosinophilia in prednisone-dependent asthma. PMID- 29382594 TI - Toll-like receptor 2 ligation of mesenchymal stem cells alleviates asthmatic airway inflammation. PMID- 29382595 TI - Activation of protease-activated receptor 2 leads to impairment of keratinocyte tight junction integrity. PMID- 29382596 TI - Age-dependent effect of ambient ozone on emergency asthma hospitalizations in Hong Kong. PMID- 29382597 TI - Incidence and sociodemographic characteristics of eczema diagnosis in children: A cohort study. PMID- 29382598 TI - Group 2 innate lymphoid cells promote airway hyperresponsiveness through production of VEGFA. PMID- 29382599 TI - Mentoring: An art and a responsibility. PMID- 29382600 TI - Highly efficient transformation of a (hemi-)cellulases-producing fungus Eupenicillium parvum 4-14 by Agrobacterium tumefaciens. AB - The mesophilic fungus Eupenicillium parvum 4-14 is an important producer of thermotolerant hemicellulolytic and cellulolytic enzymes. The aim of this study was to establish a method for genetic manipulation of the fungus by Agrobacterium tumefaciens. The promotor PgpdA of a glyceraldehyde-3-phosphate dehydrogenase gene was isolated from E. parvum 4-14. To transform the fungus, an expression plasmid containing a superfolder green fluorescent protein (sfGFP) gene under the control of PgpdA promotor was constructed using the plasmid pAg1-H3 as a parental plasmid. Using the fungal ascospores as receptor and hygromycin B resistance as a selection marker, the recombinant plasmid was successfully introduced into the fungal cells by A. tumefaciens-mediated transformation (ATMT) method. Acetosyringone (AS) was essential to the successful transformation. The transformation frequency was significantly affected by the co-culture temperature and time, the quantity of fungal spores and the AS concentration. The highest transformation frequency was up to 373 transformants per 105 fungal spores, which was higher than those of other fungal species. The fungal transformants were genetically stable after five subcultures in the absence of antibiotic. GFP protein was strongly expressed in the hypha of fungal transformants. In conclusion, the ATMT is a highly efficient method for genetic manipulation of E. parvum 4-14, and will improve the molecular researches on the fungus. PMID- 29382601 TI - Visual diagnostic of Helicobacter pylori based on a cascade amplification of PCR and G-quadruplex DNAzyme as a color label. AB - Helicobacter pylori is a spiral-shaped, Gram-negative, microaerophilic and fastidious bacterium. It is the main cause of chronic gastritis as well as gastric and duodenal ulcers. The diagnosis of H. pylori infection is significant for the selection of therapy and for the follow up of eradication success. A simple and robust strategy based on the cascade of PCR and DNAzyme catalyzed reaction was utilized to detect H. pylori. The design of the primer pair would enable PCR to synthesize aptamer of DNAzyme at the 3' end of PCR products. G quadruplex DNAzyme as a color label can exhibit peroxidase-like activity to amplify the specific signal and demonstrate a colorimetric signal to indicate the diagnostic result. This assay can detect genomic DNA of H. pylori specifically with as low as 100 pg/reaction by the naked eye. This is a powerful demonstration of G-quadruplex DNAzyme to be used for PCR-based assay with significant advantages of high sensitivity, low cost and simple manipulation over existing approaches and offers the potential opportunity for clinical application. PMID- 29382602 TI - Autofluorescence of yeast Saccharomyces cerevisiae cells caused by glucose metabolism products and its methodological implications. AB - Autofluorescence is the natural fluorescence emitted by cellular compounds which have light emission properties. The main examples of these compounds, identified as an endogenous fluorophores, include aromatic amino acids, vitamins, coenzymes and electron acceptors. As many of them play a critical role in cell metabolism, changes in their content may provide important information on the physiological status of the cell. Nevertheless, the simultaneous occurrence of different endogenous fluorophores in cells makes it difficult to interpret the autofluorescence signal. Autofluorescence values may also be imposed on values obtained through exogenous fluorescent dyes. This study evaluates the origin and the methodological implications of autofluorescence observed in yeast cells. The results show that the level of autofluorescence may differ between yeast cells, which are a result of different concentrations of endogenous fluorophores, including tryptophan, pyridoxine and riboflavin. The study also shows an important influence of autofluorescence on the results obtained by methods based on external fluorescent dyes. PMID- 29382603 TI - Sonication of orthopaedic implants: A valuable technique for diagnosis of prosthetic joint infections. AB - INTRODUCTION: Accurate and prompt microbiological diagnosis of prosthetic joint infection (PJI) is crucial for successful antimicrobial treatment. Studies have shown the diagnostic utility of sonication of explanted implants in total joint arthroplasty but all did not use consensus statements for defining PJI. We evaluated the diagnostic utility of culture of samples obtained by sonication of explanted implants compared with periprosthetic tissue cultures (PTC) for the diagnosis of PJI using Musculoskeletal Infection Society (MSIS) consensus criteria. We also assessed the utility of culture of sonicate fluid for determining the microbial profile of PJI compared with standard culture methods. MATERIALS AND METHODS: Forty consecutive revision arthroplasty cases were enrolled. Three to five periprosthetic tissue samples were obtained during each explant procedure. The 40 explanted implants were collected in sterile containers and sonicated under sterile conditions. MSIS criteria were used for the definition of PJI. RESULTS: Twenty - seven patients had PJI and thirteen were aseptic failures. Of the PJI cases, there were nine cases of early PJI's, 10 of delayed PJI's and eight of late PJI's. Twenty-five (92.5%) of the twenty-seven patients with PJI, had positive cultures in the sonicate fluid of implants and in 18 (66.7%) of them cultures of the periprosthetic tissues were also positive. Both PTC and SFC cultures of implants were negative in all the 13 cases of aseptic failure. Sensitivity of sonicate fluid culture (SFC) of implants was greater than PTC (92.5% vs. 66.7%), P = .02. The specificity of both was 100%. The incidence of gram-positive and gram-negative bacteria was nearly equal by both methods. However, SFC showed an increased ability to detect Gram-positive pathogens which was evidenced by better recovery of coagulase-negative staphylococci. CONCLUSIONS: Sonication of explanted implants is a simple and valuable microbiological technique and its routine use improves the diagnostic sensitivity of PJI. PMID- 29382604 TI - Relationships between in vivo dynamic knee joint loading, static alignment and tibial subchondral bone microarchitecture in end-stage knee osteoarthritis. AB - OBJECTIVE: To study, in end-stage knee osteoarthritis (OA) patients, relationships between indices of in vivo dynamic knee joint loads obtained pre operatively using gait analysis, static knee alignment, and the subchondral trabecular bone (STB) microarchitecture of their excised tibial plateau quantified with 3D micro-CT. DESIGN: Twenty-five knee OA patients scheduled for total knee arthroplasty underwent pre-operative gait analysis. Mechanical axis deviation (MAD) was determined radiographically. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four subregions (anteromedial, posteromedial, anterolateral, posterolateral). Regional differences in STB microarchitecture and relationships between joint loading and microarchitecture were examined. RESULTS: STB microarchitecture differed among subregions (P < 0.001), anteromedially exhibiting highest bone volume fraction (BV/TV) and lowest structure model index (SMI). Anteromedial BV/TV and SMI correlated strongest with the peak external rotation moment (ERM; r = -0.74, r = 0.67, P < 0.01), despite ERM being the lowest (by factor of 10) of the moments considered, with majority of ERM measures below accuracy thresholds; medial-to lateral BV/TV ratios correlated with ERM, MAD, knee adduction moment (KAM) and internal rotation moment (|r|-range: 0.54-0.74). When controlling for walking speed, KAM and MAD, the ERM explained additional 11-30% of the variations in anteromedial BV/TV and medial-to-lateral BV/TV ratio (R2 = 0.59, R2 = 0.69, P < 0.01). CONCLUSIONS: This preliminary study suggests significant associations between tibial plateau STB microarchitecture and knee joint loading indices in end-stage knee OA patients. Particularly, anteromedial BV/TV correlates strongest with ERM, whereas medial-to-lateral BV/TV ratio correlates strongest with indicators of medial-to-lateral joint loading (MAD, KAM) and rotational moments. However, associations with ERM should be interpreted with caution. PMID- 29382605 TI - Development of a prediction model for future risk of radiographic hip osteoarthritis. AB - OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA. PMID- 29382606 TI - Outcomes of infective endocarditis in the current era: Early predictors of a poor prognosis. AB - BACKGROUND: The early identification of patients at risk of complications of infective endocarditis (IE) using parameters obtained as part of routine practice is essential for guiding clinical decision-making. This study aimed to identify a parameter at hospital admission that predicts the outcome, adding value to other well-known factors of a poor prognosis in IE. METHODS: Two hundred and three patients with IE were included in this study. Clinical evaluation, echocardiography, blood cultures, and routine laboratory tests were performed at hospital admission. The endpoint was in-hospital mortality. RESULTS: The mean age of the patients was 48.2+/-16.6 years; 62% were male and 38% had rheumatic heart disease. During treatment, cardiac surgery was performed in 111 patients (55%), and the overall in-hospital mortality rate was 32%. In the multivariable analysis, the independent predictors of death were age (odds ratio (OR) 1.07, 95% confidence interval (CI) 1.02-1.13), C-reactive protein (CRP) at hospital admission (OR 1.12, 95% CI 1.04-1.21), length of the vegetation at diagnosis (OR 1.15, 95% CI 1.03-1.28), development of heart failure (OR 6.43, 95% CI 2.14 19.33), and embolic events during antimicrobial therapy (OR 12.14, 95% CI 2.11 71.89). CONCLUSIONS: An elevated CRP level at hospital admission and vegetation length at diagnosis were strong predictors of in-hospital mortality in IE, independent of other prognostic parameters, specifically taking into account patient characteristics and complications during therapy. PMID- 29382608 TI - Metabolic syndrome, autoimmunity and rheumatic diseases. AB - Metabolic syndrome (MetS) is a cluster of metabolic and cardiovascular (CV) risk factors including obesity and visceral adiposity, insulin resistance, dyslipidemia and hypertension contributing to CV mortality. The interface between the metabolic and immune systems has been of great interest recently. These interactions are regulated through genetics, nutritional status, and the intestinal microbiome. Alterations in the immune-metabolic cross-talk contribute to the development of autoimmune diseases. Adipokines exert a variety of metabolic activities contributing to the ethiopathogenesis of MetS and are involved in the regulation of both inflammatory processes and autoimmunity occurring in rheumatic diseases. Patients with autoinflammatory disease such as gout and those with autoimmune rheumatic diseases (ARD), such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, ankylosing spondylitis and vasculitis among others, have increased prevalence of MetS. Despite recent advances in treatment of ARD, incidence of CVD remains high. MetS and altered secretion patterns of proinflammatory adipokines could be the link between CVDs and ARD. In addition, in ARD the activation of proinflammatory signalling pathways results in the induction of several biological markers of chronic inflammation contributing to CVD. In the present paper, we review recent evidences of the interactions between MetS and ARD, as well as novel therapeutic targets. PMID- 29382607 TI - Investigation of an isolated case of human Crimean-Congo hemorrhagic fever in Central Uganda, 2015. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is the most geographically widespread tick-borne viral infection. Outbreaks of CCHF in sub-Saharan Africa are largely undetected and thus under-reported. On November 9, 2015, the National Viral Hemorrhagic Fever Laboratory at the Uganda Virus Research Institute received an alert for a suspect VHF case in a 33-year-old male who presented with VHF compatible signs and symptoms at Mengo Hospital in Kampala. METHODS: A blood sample from the suspect patient was tested by RT-PCR for CCHF and found positive. Serological testing on sequential blood specimens collected from this patient showed increasing anti-CCHFV IgM antibody titers, confirming recent infection. Repeat sampling of the confirmed case post recovery showed high titers for anti CCHFV-specific IgG. An epidemiological outbreak investigation was initiated following the initial RT-PCR positive detection to identify any additional suspect cases. RESULTS: Only a single acute case of CCHF was detected from this outbreak. No additional acute CCHF cases were identified following field investigations. Environmental investigations collected 53 tick samples, with only 1, a Boophilus decoloratus, having detectable CCHFV RNA by RT-PCR. Full-length genomic sequencing on a viral isolate from the index human case showed the virus to be related to the DRC (Africa 2) lineage. CONCLUSIONS: This is the fourth confirmed CCHF outbreak in Uganda within 2 years after more than 50 years of no reported human CCHF cases in this country. Our investigations reaffirm the endemicity of CCHFV in Uganda, and show that exposure to ticks poses a significant risk for human infection. These findings also reflect the importance of having an established national VHF surveillance system and diagnostic capacity in a developing country like Uganda, in order to identify the first cases of VHF outbreaks and rapidly respond to reduce secondary cases. Additional efforts should focus on implementing effective tick control methods and investigating the circulation of CCHFV throughout the country. PMID- 29382609 TI - Role of proteoglycans in neuro-inflammation and central nervous system fibrosis. AB - Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans. PMID- 29382610 TI - Lactation induces increases in the RANK/RANKL/OPG system in maxillary bone. AB - The underlying causes of maxillary bone loss during lactation remain poorly understood. We evaluated the impact of lactation on physiological and mechanically-induced alveolar bone remodeling. Nulliparous non-lactating (N-LAC) and 21-day lactating (LAC) mice underwent mechanically-induced bone remodeling by orthodontic tooth movement (OTM). Micro-computed tomography (microCT) was performed in the maxilla, femur and vertebra. Tartrate-resistant-acid phosphatase (TRAP) and Masson's trichrome labelling was performed in the maxillary bone and gene expression was determined in the periodontal ligament. The effect of prolactin on osteoclast (OCL) and osteoblast (OBL) differentiation was also investigated in N-LAC and LAC mice. Lactation increased alveolar bone loss in the maxilla, femur and vertebra, while OTM was enhanced. The number of OCL and OBL was higher in the maxilla of LAC mice. OTM increased OCL in both groups; while OBL was increased only in N-LAC but not in LAC mice, in which cell numbers were already elevated. The alveolar bone loss during lactation was associated with increased expression of receptor activator of nuclear factor-KappaB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in the maxilla. OTM induced the same responses in N-LAC mice, whereas it had no further effect in LAC mice. Lactation enhanced differentiation of OCL and OBL from bone marrow cells, and prolactin recapitulated OCL differentiation in N-LAC mice. Thus, lactation increases physiological maxillary bone remodeling and OTM, and both require activation of RANK/RANKL/OPG system. These findings expand our knowledge of lactation-induced osteopenia and have possible impact on clinical practice regarding orthodontic treatments and dental implants in lactating women. PMID- 29382611 TI - Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. AB - Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by low bone density and recurrent fractures with a wide genotypic and phenotypic spectrum. Common features include short stature, opalescent teeth, blue sclerae and hearing impairment. The majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2, which lead to defects in type 1 collagen. More recently, numerous recessive variants involving other genes have also been identified. Sp7/Osx gene, is a protein coding gene that encodes a zinc finger transcription factor, osterix, which is a member of the Sp subfamily of sequence specific DNA-binding proteins. Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation. In animal models, Sp7/Osx has also been shown to regulate biomineralization of otoliths, calcium carbonate structures found in the inner ear of vertebrates. Until recently, only one report of a boy with an Sp7/Osx pathogenic variant presenting with bone fragility, limb deformities and normal hearing has been described in the literature. We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature. Progressive moderate-to severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings. A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys). Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover. This is the second report to describe children with OI associated with an Sp7/Osx variant. However, it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype. Early audiology screening in these children is therefore warranted. PMID- 29382612 TI - Familial resemblance in trabecular and cortical volumetric bone mineral density and bone microarchitecture as measured by HRpQCT. AB - To estimate the heritability of bone geometry, volumetric bone mineral density (vBMD) and microarchitecture of trabecular (Tb) and cortical (Ct) bone measured by high resolution peripheral quantitative computerised tomography (HRpQCT) at the distal radius and tibia and to investigate the genetic correlations of these measures. Participants were 177 mother-offspring pairs from 162 families (mothers, mean age (SD) = 52.1 (4.7) years; offspring, 25.6 (0.73) years). Trabecular and cortical bone measures were obtained by HRpQCT. Multivariable linear regression was used to analyse the association of bone measures between mother and offspring. Sequential Oligogenic Linkage Analysis Routines (SOLAR) software was utilised to conduct quantitative genetic analyses. All maternal bone measures were independently associated with the corresponding bone measures in the offspring before and after adjustment for age, sex, weight and height. Heritability estimates ranged from 24% to 67% at the radius and from 42% to 74% at the tibia. The relationship for most bone geometry measures was significantly stronger in mother-son pairs (n = 107) compared with mother-daughter pairs (n = 70) (p < 0.05). In contrast, the heritability for most vBMD and microarchitecture measures were higher in mother-daughter pairs. Bivariate analyses found moderate to strong genetic correlations across all measures between radius and tibia (Rg = 0.49 to 0.93). Genetic factors have an important role in the development of bone geometry, vBMD and microarchitecture. These factors are strongly shared for the radius and tibia but vary by sex implying a role for imprinting. PMID- 29382613 TI - Changes of Facet Joints After Dynamic Stabilization: Continuous Degeneration or Slow Fusion? AB - BACKGROUND: The nonfusion pedicle-screw system Dynesys stabilization (DS) for lumbar degenerative disease aims to better preserve range of motion (ROM) than fixation and fusion systems. However, decreased ROM and unexpected facet fusion at the index level were observed after DS was applied with unknown etiology. The aim of this study is using radiologic parameters to explain the phenomenon of facet arthrodesis. METHODS: The patients who underwent surgery for L4-5 spinal stenosis were sorted retrospectively into 2 groups: DS and microdiskectomy (MicD). Radiologic parameters including facet degeneration, evaluated by computed tomography or magnetic resonance image, and ROM, evaluated by dynamic radiographs, were compared perioperatively. A linear regression model was fitted to data points to calculate correlation over time. Postoperative facet arthrodesis at the index level was detected by computed tomography. Functional outcomes were also compared between groups. RESULTS: A total of 61 patients (DS to-MicD = 38:23) were followed 36.9 +/- 16.8 months postoperatively. After surgery, both groups of patients had significant clinical improvement without difference between the 2 groups (all P > 0.05). In the DS group, significantly decreased ROM was observed after 24-month follow-up (P < 0.05). The correlation coefficient of facet degeneration over time and the facet fusion rate in the DS group were both significantly higher than in the MicD group (both P < 0.05). CONCLUSIONS: The patients who underwent DS for L4-5 grade 1 spondylolisthesis experienced significantly reduced ROM and a positive correlation of facet degeneration over time postoperatively. The limited ROM at the index level could be a potential risk of facet degeneration and cause unexpected arthrodesis. PMID- 29382614 TI - Giant Tumefactive Perivascular Spaces: A Case Report and Literature Review. AB - BACKGROUND: Perivascular spaces (PVS), also known as Virchow-Robin spaces, are pial-lined, interstitial fluid-filled structures in the brain that accompany cerebral vessels as they penetrate the cerebral substance. In healthy individuals, a PVS diameter of <2 mm is considered normal and can typically be seen within the white matter on magnetic resonance imaging (MRI). When PVS dilate, they are considered benign lesions and are associated with aging and other risk factors. These dilated PVS can cause neurologic symptoms, depending on their size and location. Symptomatic, massive enlargement of PVS are referred to as "giant" or "tumefactive" PVS; these are extremely rare and require neurosurgical intervention. CASE DESCRIPTION: We present a rare case of giant tumefactive PVS (GTPVS) associated with hydrocephalus in a female patient who presented with progressive headache for 6 months. The patient was found to have giant tumefactive dilatation of PVS involving the right midbrain, with extension to the pons and thalamus, and with supratentorial moderate hydrocephalus. She was treated with cerebrospinal fluid diversion alone. CONCLUSIONS: PVS are found on MRI in healthy people; rarely, they may dilate and cause neurologic symptoms. GTPVS are rare and can be misdiagnosed as central nervous system tumors; however, their imaging characteristics facilitate diagnosis. It has been postulated that these expanding PVS are due to defects in the drainage of interstitial fluid, where it enters into the ventricular system, and they are not the result of increased intraventricular pressure. We hypothesize that this may have been the case for the patient in our study, as the GTPVS collapsed following the insertion of a ventriculoperitoneal shunt. However, more recent literature provides evidence to support the idea that hydrocephalus is the consequence, and not the cause, of aqueduct compression by the lesion. PMID- 29382615 TI - Pain-Free Outcomes and Durability of Surgical Intervention for Trigeminal Neuralgia: A Comparison of Gamma Knife and Microvascular Decompression. AB - OBJECTIVE: Treatment options for trigeminal neuralgia include microvascular decompression (MVD) and Gamma Knife surgery (GKS). There is no consensus which option is more effective at providing immediate and long-lasting pain relief. This study evaluated the differences between these 2 options in terms of rates of complete pain relief and pain-free recurrence. METHODS: A systematic review was conducted of published studies of MVD and GKS for treatment of trigeminal neuralgia from 2004 to 2014. Studies were selected using a MEDLINE/PubMed search and from subsequent inspection of references from articles found in the initial search. Common outcome measures reported in the studies were used for meta analysis to make conclusions based on current available data. RESULTS: The MVD group included 18 articles with 2650 patients, and the GKS group included 25 articles with 2846 patients. MVD was found to have a significantly higher rate of initial pain-free outcomes (Barrow Neurological Institute grade I) compared with GKS (92.22% vs. 61.46%, P < 0.0001). MVD was also found to have a significantly higher rate of long-term pain-free outcomes at last follow-up compared with GKS (79.37% vs. 41.62%, P < 0.0001). MVD was found to have a similar rate of pain free recurrence compared with GKS (14.93% vs. 19.38%, P = 0.2536). CONCLUSIONS: MVD may be a more effective intervention than GKS owing to higher rates of initial pain-free outcomes and long-term pain-free outcomes. There is a need for more consistent data reporting of outcomes for treatment of trigeminal neuralgia. PMID- 29382616 TI - World Health Organization Grade III (Nonanaplastic) Meningioma: Experience in a Series of 23 Cases. AB - OBJECTIVE: Rhabdoid meningioma (RM) and papillary meningioma (PM) are rare variants of World Health Organization grade III meningiomas. In this study, we presented a series of 23 cases from our institution to investigate adverse factors of and appropriate treatment for RM and PM. METHODS: Clinical data from 23 cases of PM and RM between January 2011 and December 2015 were retrospectively reviewed. RESULTS: The median follow-up was 38.0 months for World Health Organization grade III meningiomas. The mean progression-free survival (PFS) was 37.6 months, with 1-year, 3-year, and 5-year PFS of 78.3%, 50.8%, and 43.6%, respectively. The mean overall survival (OS) was 48.8 months, with 1-year, 3 year, and 5-year OS of 95.7%, 82.6%, and 44.0%, respectively. Univariate analysis showed that a ki-67 proliferation index >20% (hazard ratio [HR], 4.190; 95% confidence interval [CI], 1.033-17.001; P = 0.045) and PM (HR, 3.375; 95% CI, 0.998-11.408; P = 0.005) were related to worse PFS. Patients administered postoperative radiotherapy (PRT) after surgery had longer OS than did patients who did not receive PRT (median, 60.7 vs. 35.1 months; P = 0.029). Multivariate analysis showed that PRT was an independent factor for PFS (HR, 0.147; 95% CI, 0.033-0.657; P = 0.012) and OS (HR, 0.130; 95% CI, 0.025-0.691; P = 0.017) and that RM was an independent factor for PFS (HR, 7.312; 95% CI, 1.587-33.688; P = 0.011) and OS (HR, 6.447; 95% CI, 1.310-31.740; P = 0.022). CONCLUSIONS: We recommended adjuvant radiation regardless of the extent of resection. Individuals with PM or RM were at increased risk of recurrence and death; appropriate treatment for these patients should be further studied, and close follow-up is needed. PMID- 29382617 TI - Hypertrophic Olivary Degeneration: Neurosurgical Perspective and Literature Review. AB - BACKGROUND: Hypertrophic olivary degeneration (HOD) occurs because of posterior fossa or brainstem lesions that disrupt the dentato-rubro-olivary tract, well known as the Guillain-Mollaret triangle. Clinical and radiologic hallmarks of this condition are palatal myoclonus and T2 hyperintensity of the inferior olivary complex on magnetic resonance imaging (MRI), respectively. Because symptomatic HOD can complicate the recovery of patients with posterior fossa or brainstem lesions, the purpose of this study is to evaluate clinical and imaging findings of patients with HOD. METHODS: Sixteen patients (8 female and 8 male) with a mean age of 40.7 years, (range, 5-83 years) years were included in this study based on clinical symptoms and MRI findings. RESULTS: We reviewed the clinical and imaging findings in 16 cases of HOD at our institution. Seven patients (43.7%) had posterior fossa tumors, 6 patients (37.5%) had cavernoma, 2 patients (12.5%) sustained traumatic brain injury, and only 1 patient (6.2%) had cerebellar infarction. Posterior fossa surgery was performed in 13 (81.2%) of these patients. HOD was detected a mean of 7.2 months (range, 0.5-18 months) after surgery or primary neurologic insult. Unilateral HOD was observed in 10 patients (62.5%), while bilateral HOD was observed in only 6 patients (37.5%). Seven patients (43.7%) were asymptomatic for HOD, whereas 5 patients (31.2%) had symptoms attributable to HOD. Two patients died because of primary tumors, although mean follow-up after detection of HOD on MRI was 52.2 months (range, 1 120 months) in the remaining 14 patients. In these cases, no change in clinical symptoms or imaging findings was detected during follow-up. CONCLUSIONS: In this series, posterior fossa tumors and cavernomas were the most common causes of HOD. Although most of the patients with HOD remained asymptomatic, HOD complicated the course of recovery in almost one quarter of the patients included in this study. Neurosurgeons should be aware of HOD, which has characteristic clinical and imaging findings. In addition, HOD can complicate the recovery of patients with disruption to the dentato-rubro-olivary tract. PMID- 29382618 TI - Primary Meningeal Melanocytoma in Sellar Region, Simulating a Nonfunctioning Pituitary Adenoma: Case Report and Literature Review. AB - BACKGROUND: Primary meningeal melanocytoma is a benign lesion in the central nervous system derived from leptomeningeal melanocytes, most commonly growing in the posterior fossa and cervical spinal cord. The sellar primary meningeal melanocytoma (SPMM) is an exceptionally rare tumor. Here we report the ninth published case of an SPMM, and also discuss the problems of differential diagnosis and management of these tumors. CASE DESCRIPTION: The patient presented with visual impairment and irregular menstruation with no other symptoms. Her general examination was otherwise unremarkable. Endocrine tests disclosed normal endocrine function except for slight hyperprolactinemia. Magnetic resonance imaging revealed a sellar lesion. The patient underwent a successful total transsphenoidal removal of the tumor without neurologic sequelae. Based on this case report, SPMM should be included in the differential diagnosis of malignant and/or metastatic melanoma. CONCLUSIONS: SPMM is an exceptionally rare tumor. Differentiating sellar melanocytic tumors from other sellar diseases through clinical and radiologic investigations is very difficult. The treatment of choice for SPMM is complete surgical resection via a transsphenoidal approach. For patients with a partially resected tumor, radiotherapy is an effective complementary treatment modality. PMID- 29382619 TI - The Effects of Memantine on Glutamic Receptor-Associated Nitrosative Stress in a Traumatic Brain Injury Rat Model. AB - BACKGROUND: The main aim of this study is to elucidate whether the neuroprotective effect of memantine, a noncompetitive N-methyl-d-aspartate receptor 2B (NR2B) antagonist, affects neuronal nitrosative stress, apoptosis, and NR2B expression and improves functional outcomes. METHODS: Immediately after the onset of fluid percussion traumatic brain injury (TBI), anesthetized male Sprague-Dawley rats were divided into sham-operated, TBI + vehicle, and TBI + memantine groups. TBI rats were treated with a memantine intraperitoneal injection dose of 20 mg/kg intraperitoneally and then 1 mg/kg every 12 hours intraperitoneally for 6 doses. The motor function, proprioception, infarction volume, and neuronal apoptosis were then measured. Immunofluorescence was used to evaluate astrogliosis, microgliosis, nitrosative stress, and NR2A and NR2B expression in cortical cells. All the parameters were assessed 72 hours after TBI. RESULTS: Compared with the sham-operated controls, the TBI-induced motor and proprioception deficits, and increased infraction volume after TBI were significantly attenuated by memantine therapy. The TBI-induced neuronal apoptosis, astrogliosis, and microgliosis, the numbers of neuronal NO synthase and 3-nitro-l-tyrosine expression in neurons, and inducible NO synthase expression in microglia and astrocyte cells in the ischemic cortex after TBI were significantly improved by memantine therapy. Simultaneously, without affecting the NR2A expression in neuronal cells, the NR2B expression significantly decreased after memantine therapy, as evaluated by an immunofluorescence stain. CONCLUSIONS: Intraperitoneal injection of memantine in the acute stage may ameliorate TBI in rats by affecting NR2B expression and decreasing neuronal apoptosis and nitrosative stress in the injured cortex. These effects might represent 1 mechanism by which functional recovery occurred. PMID- 29382620 TI - Brain Abscess of Basal Ganglia Presenting with Persistent Hiccups. AB - BACKGROUND: Brain abscesses are well-known to neurologic surgeons with well recognized presentations, which include seizures, neurologic deficit, and headache. Rare symptoms may lead to a delay in diagnosis, which can be life threatening in the setting of a brain abscess. CASE DESCRIPTION: We present the case of a 46-year-old male with intractable hiccups found to have an abscess of the right basal ganglia. The brain abscess was treated by frameless stereotactic guided aspiration. The patient's hiccups improved after surgical aspiration and medical management. CONCLUSIONS: A comprehensive literature review confirmed brain abscess as a rare cause of intractable hiccups. In addition, there are few reports of lesions of the basal ganglia causing intractable hiccups. Aspiration and medical therapy resulted in resolution of the hiccups. Knowledge of the hiccup reflex arc and unusual presentation of basal ganglia lesions may shorten time to diagnosis. PMID- 29382621 TI - Case of Primary Central Nervous System Lymphoma Arising at Site of Remote Herpes Encephalitis. AB - BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare malignancy that usually arises in the context of severe immunosuppression but has incompletely understood etiology, limiting effective treatments. CASE DESCRIPTION: We present the case of an 81-year-old immunocompetent man who developed a PCNSL in the right temporal lobe, at the site of a remote episode of herpes simplex virus (HSV) encephalitis 8 years prior. There are numerous viruses with known oncogenic associations; however, to our knowledge, this is the first reported case of PCNSL with an antecedent HSV infection. CONCLUSIONS: We discuss this case in the context of our current understandings of the pathogenesis of HSV encephalitis and PCNSL and postulate mechanisms through which the 2 could be associated. PMID- 29382622 TI - The Pathogenesis of Subacute Subdural Hematoma: A Report of 3 Cases and Literature Review. AB - OBJECTIVE: To discuss the pathologic mechanism of subacute subdural hematoma (sASDH). METHODS: Three typical cases of sASDH were reported, and related literature in Chinese published in the past 15 years was reviewed. RESULTS: Intervals from onset of acute subdural hematoma to surgery or symptom deterioration resulting in sASDH were 12.5-15.5 days (mean 14.1 days). Delayed liquefaction of hematoma clots occurred in all 3 reported cases. One patient achieved good curative effect after administration of dexamethasone, and another patient relapsed owing to poor drainage after evacuation of hematoma. CONCLUSIONS: The conversion of acute subdural hematoma to sASDH is an inflammatory reaction process with very regular in time, and it is speculated that the pathologic mechanism may be a delayed hypersensitivity reaction. Antigen released during the liquefaction process of blood clot, with subdural neomembrane cells as antigen-presenting cells, is presented to the T lymphocytes released from the capillaries in the neomembrane and forms sensitized T lymphocytes. When the subsequent antigen is released from the blood clots with a delayed liquefaction and is exposed to sensitized T lymphocytes, the delayed hypersensitivity process occurs. PMID- 29382623 TI - Improving Refill Adherence in Medicare Patients With Tailored and Interactive Mobile Text Messaging: Pilot Study. AB - BACKGROUND: Nonadherence is a major concern in the management of chronic conditions such as hypertension, cardiovascular disease, and diabetes where patients may discontinue or interrupt their medication for a variety of reasons. Text message reminders have been used to improve adherence. However, few programs or studies have explored the benefits of text messaging with older populations and at scale. In this paper, we present a program design using tailored and interactive text messaging to improve refill rates of partially adherent or nonadherent Medicare members of a large integrated health plan. OBJECTIVE: The aim of this 3-month program was to gain an understanding of whether tailored interactive text message dialogues could be used to improve medication refills in Medicare patients with one or more chronic diseases. METHODS: We used the mPulse Mobile interactive text messaging solution with partially adherent and nonadherent Medicare patients (ie, over age 65 years or younger with disabilities) of Kaiser Permanente Southern California (KP), a large integrated health plan, and compared refill rates of the text messaging group (n=12,272) to a group of partially adherent or nonadherent Medicare patients at KP who did not receive text messages (nontext messaging group, n=76,068). Both groups were exposed to other forms of refill and adherence outreach including phone calls, secure emails, and robo-calls from December 2016 to February 2017. RESULTS: The text messaging group and nontext messaging group were compared using an independent samples t test to test difference in group average of refill rates. There was a significant difference in medication refill rates between the 2 groups, with a 14.07 percentage points higher refill rate in the text messaging group (P<.001). CONCLUSIONS: The results showed a strong benefit of using this text messaging solution to improve medication refill rates among Medicare patients. These findings also support using interactive text messaging as a cost effective, convenient, and user-friendly solution for patient engagement. Program outcomes and insights can be used to enhance the design of future text-based solutions to improve health outcomes and promote adherence and long-term behavior change. PMID- 29382624 TI - Implementing a Mobile Health System to Integrate the Treatment of Addiction Into Primary Care: A Hybrid Implementation-Effectiveness Study. AB - BACKGROUND: Despite the near ubiquity of mobile phones, little research has been conducted on the implementation of mobile health (mHealth) apps to treat patients in primary care. Although primary care clinicians routinely treat chronic conditions such as asthma and diabetes, they rarely treat addiction, a common chronic condition. Instead, addiction is most often treated in the US health care system, if it is treated at all, in a separate behavioral health system. mHealth could help integrate addiction treatment in primary care. OBJECTIVE: The objective of this paper was to report the effects of implementing an mHealth system for addiction in primary care on both patients and clinicians. METHODS: In this implementation research trial, an evidence-based mHealth system named Seva was introduced sequentially over 36 months to a maximum of 100 patients with substance use disorders (SUDs) in each of three federally qualified health centers (FQHCs; primary care clinics that serve patients regardless of their ability to pay). This paper reports on patient and clinician outcomes organized according to the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RESULTS: The outcomes according to the RE-AIM framework are as follows: Reach-Seva reached 8.31% (268/3226) of appropriate patients. Reach was limited by our ability to pay for phones and data plans for a maximum of 100 patients per clinic. Effectiveness-Patients who were given Seva had significant improvements in their risky drinking days (44% reduction, (0.7-1.25)/1.25, P=.04), illicit drug-use days (34% reduction, (2.14-3.22)/3.22, P=.01), quality of life, human immunodeficiency virus screening rates, and number of hospitalizations. Through Seva, patients also provided peer support to one another in ways that are novel in primary care settings. Adoption-Patients sustained high levels of Seva use-between 53% and 60% of the patients at the 3 sites accessed Seva during the last week of the 12-month implementation period. Among clinicians, use of the technology was less robust than use by patients, with only a handful of clinicians using Seva in each clinic and behavioral health providers making most referrals to Seva in 2 of the 3 clinics. Implementation-At 2 sites, implementation plans were realized successfully; they were delayed in the third. Maintenance-Use of Seva dropped when grant funding stopped paying for the mobile phones and data plans. Two of the 3 clinics wanted to maintain the use of Seva, but they struggled to find funding to support this. CONCLUSIONS: Implementing an mHealth system can improve care among primary care patients with SUDs, and patients using the system can support one another in their recovery. Among clinicians, however, implementation requires figuring out how information from the mHealth system will be used and making mHealth data available in the electronic health (eHealth) record. In addition, paying for an mHealth system remains a challenge. PMID- 29382625 TI - Smartphone App-Based Assessment of Gait During Normal and Dual-Task Walking: Demonstration of Validity and Reliability. AB - BACKGROUND: Walking is a complex cognitive motor task that is commonly completed while performing another task such as talking or making decisions. Gait assessments performed under normal and "dual-task" walking conditions thus provide important insights into health. Such assessments, however, are limited primarily to laboratory-based settings. OBJECTIVE: The objective of our study was to create and test a smartphone-based assessment of normal and dual-task walking for use in nonlaboratory settings. METHODS: We created an iPhone app that used the phone's motion sensors to record movements during walking under normal conditions and while performing a serial-subtraction dual task, with the phone placed in the user's pants pocket. The app provided the user with multimedia instructions before and during the assessment. Acquired data were automatically uploaded to a cloud-based server for offline analyses. A total of 14 healthy adults completed 2 laboratory visits separated by 1 week. On each visit, they used the app to complete three 45-second trials each of normal and dual-task walking. Kinematic data were collected with the app and a gold-standard instrumented GAITRite mat. Participants also used the app to complete normal and dual-task walking trials within their homes on 3 separate days. Within laboratory based trials, GAITRite-derived heel strikes and toe-offs of the phone-side leg aligned with smartphone acceleration extrema, following filtering and rotation to the earth coordinate system. We derived stride times-a clinically meaningful metric of locomotor control-from GAITRite and app data, for all strides occurring over the GAITRite mat. We calculated stride times and the dual-task cost to the average stride time (ie, percentage change from normal to dual-task conditions) from both measurement devices. We calculated similar metrics from home-based app data. For these trials, periods of potential turning were identified via custom developed algorithms and omitted from stride-time analyses. RESULTS: Across all detected strides in the laboratory, stride times derived from the app and GAITRite mat were highly correlated (P<.001, r2=.98). These correlations were independent of walking condition and pocket tightness. App- and GAITRite-derived stride-time dual-task costs were also highly correlated (P<.001, r2=.95). The error of app-derived stride times (mean 16.9, SD 9.0 ms) was unaffected by the magnitude of stride time, walking condition, or pocket tightness. For both normal and dual-task trials, average stride times derived from app walking trials demonstrated excellent test-retest reliability within and between both laboratory and home-based assessments (intraclass correlation coefficient range .82-.94). CONCLUSIONS: The iPhone app we created enabled valid and reliable assessment of stride timing-with the smartphone in the pocket-during both normal and dual-task walking and within both laboratory and nonlaboratory environments. Additional work is warranted to expand the functionality of this tool to older adults and other patient populations. PMID- 29382626 TI - Web-Based Decision Aid to Assist Help-Seeking Choices for Young People Who Self Harm: Outcomes From a Randomized Controlled Feasibility Trial. AB - BACKGROUND: Adolescents who self-harm are often unsure how or where to get help. We developed a Web-based personalized decision aid (DA) designed to support young people in decision making about seeking help for their self-harm. OBJECTIVE: The aim of this study was to evaluate the feasibility and acceptability of the DA intervention and the randomized controlled trial (RCT) in a school setting. METHODS: We conducted a two-group, single blind, randomized controlled feasibility trial in a school setting. Participants aged 12 to 18 years who reported self-harm in the past 12 months were randomized to either a Web-based DA or to general information about mood and feelings. Feasibility of recruitment, randomization, and follow-up rates were assessed, as was acceptability of the intervention and study procedures. Descriptive data were collected on outcome measures examining decision making and help-seeking behavior. Qualitative interviews were conducted with young people, parents or carers, and staff and subjected to thematic analysis to explore their views of the DA and study processes. RESULTS: Parental consent was a significant barrier to young people participating in the trial, with only 17.87% (208/1164) of parents or guardians who were contacted for consent responding to study invitations. Where parental consent was obtained, we were able to recruit 81.7% (170/208) of young people into the study. Of those young people screened, 13.5% (23/170) had self-harmed in the past year. Ten participants were randomized to receiving the DA, and 13 were randomized to the control group. Four-week follow-up assessments were completed with all participants. The DA had good acceptability, but qualitative interviews suggested that a DA that addressed broader mental health problems such as depression, anxiety, and self-harm may be more beneficial. CONCLUSIONS: A broad based mental health DA addressing a wide range of psychosocial problems may be useful for young people. The requirement for parental consent is a key barrier to intervention research on self-harm in the school setting. Adaptations to the research design and the intervention are needed before generalizable research about DAs can be successfully conducted in a school setting. TRIAL REGISTRATION: International Standard Randomized Controlled Trial registry: ISRCTN11230559; http://www.isrctn.com/ISRCTN11230559 (Archived by WebCite at http://www.webcitation.org/6wqErsYWG). PMID- 29382627 TI - Migration Influences on the Allostatic Load of Children: Systematic Review Protocol. AB - BACKGROUND: Migration is a worldwide phenomenon in recent times. Recently, documented studies suggest that the change in environments involved in migration may have an influence on children's allostatic load related to health and well being. OBJECTIVE: The aim of this review is to systematically search the extant literature and critically examine the evidence on how migration affects allostatic load in children and describe the relevant methods in measuring allostatic load. METHODS: A systematic review will be conducted to recapitulate the evidence on the influence of migration on allostatic load and describe the methods employed in measuring allostatic load parameters among migrant children using the following search terms combinations: 1) allostasis OR allostatic OR allostatic load OR allosta*; 2) migration OR migrant OR immigration OR immigrant OR migra* OR *migra*; and 3) children OR child* OR adolescen*. We will search for peer-reviewed articles in English using a three-step process: title and abstract review, individual article review, and reference hand-searching among the following databases: Medline, CINAHL, ProQuest, PubMed, Science Direct and BioMed Central. Two independent review authors will analyze for data quality, level of evidence and risk of bias; a third review author will be consulted if consensus cannot be met. Data on study details, participant characteristics, allostatic load operationalization and description, methods, and results summary will be extracted. Evidence will be synthesized statistically when possible and narratively clustered into themes. RESULTS: At present, we have conducted only a preliminary search to test out our search terms. The systematic search, appraisal, synthesis and analysis will be finished by June 2018. It is projected that the manuscript that describes the systematic review will be available by the last quarter of 2018. CONCLUSIONS: The results of this systematic review have implications on supporting the concept of allostasis as a mechanism underlying the adaptive processes related to migration. Furthermore, our findings can lead to the development of innovative evidence-informed evaluation and intervention programs aimed at migrant children's needs. Likewise, it is hoped that this review can be an impetus to inform health and sociopolitical policies responsive of migrant children's current contexts. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO): CRD42017068895; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68895 (Archived by WebCite at http://www.webcitation.org/6wprRkxvA). PMID- 29382628 TI - Using the Inflammacheck Device to Measure the Level of Exhaled Breath Condensate Hydrogen Peroxide in Patients With Asthma and Chronic Obstructive Pulmonary Disease (The EXHALE Pilot Study): Protocol for a Cross-Sectional Feasibility Study. AB - BACKGROUND: Asthma and Chronic Obstructive Pulmonary Disease (COPD) are common conditions that affect over 5 million people in the United Kingdom. These groups of patients suffer significantly from breathlessness and recurrent exacerbations that can be difficult to diagnose and go untreated. A common feature of COPD and asthma is airway inflammation that increases before and during exacerbations. Current methods of assessing airway inflammation can be invasive, difficult to perform, and are often inaccurate. In contrast, measurement of exhaled breath condensate (EBC) hydrogen peroxide (H2O2) is performed during normal tidal breathing and is known to reflect the level of global inflammation in the airways. There is a need for novel tools to diagnose asthma and COPD earlier and to detect increased airway inflammation that precedes an exacerbation. OBJECTIVE: The aim of this study was to explore the use of a new handheld device (called Inflammacheck) in measuring H2O2 levels in EBC. We will study whether it can measure EBC H2O2 levels consistently and whether it can be used to differentiate asthma and COPD from healthy controls. METHODS: We will perform a cross sectional, feasibility, pilot study of EBC H2O2 levels, as measured by Inflammacheck, and other markers of disease severity and symptom control in patients with asthma and COPD and volunteers with no history of lung disease. Participants will be asked to provide an exhaled breath sample for measurement of their EBC H2O2 using Inflammacheck. The result will be correlated with disease stage, spirometry, fractional exhaled nitric oxide (FeNO), and symptom control scores. RESULTS: This study's recruitment is ongoing; it is anticipated that the results will be available in 2018. CONCLUSIONS: The EXhaled Hydrogen peroxide As a marker of Lung diseasE (EXHALE) pilot study will provide an evaluation of a new method of measuring EBC H2O2. It will assess the device's consistency and ability to distinguish airway inflammation in asthma and COPD compared with healthy controls. PMID- 29382629 TI - Examining Influences of Parenting Styles and Practices on Physical Activity and Sedentary Behaviors in Latino Children in the United States: Integrative Review. AB - BACKGROUND: Research indicates that parents influence their children's physical activity (PA) and sedentary behaviors (SB) through their parenting styles and practices. OBJECTIVE: The objectives of this paper were to evaluate existing research examining the associations between parenting styles, parenting practices, and PA and SB among Latino children aged between 2 and 12 years, highlight limitations of the existing research, and generate suggestions for future research. METHODS: The method of this integrative review was informed by methods developed by Whittemore and Knafl, which allow for the inclusion of qualitative, quantitative, and mixed-methods studies. Using the Preferred Reporting Items for Systematic Reviews Meta-Analyses guidelines, five electronic academic databases (PubMed, SPORTDiscus, PsycINFO, PsycARTICLES, and CINAHL) were searched for peer-reviewed, full-text papers published in English. Of the 641 unique citations identified, 67 full-text papers were retrieved, and 16 were selected for review. RESULTS: The majority of the 16 reviewed studies were conducted with predominantly Mexican American or Mexican immigrant samples, and only 1 study examined the association between parenting styles and Latino children's PA and SB. Most (n=15) reviewed studies assessed the influence of parenting practices on children's PA and SB, and they provide good evidence that parenting practices such as offering verbal encouragement, prompting the child to be physically active, providing logistic support, engaging and being involved in PA, monitoring, and offering reinforcement and rewards encourage, facilitate, or increase children's PA. The examined studies also provide evidence that parenting practices, such as setting rules and implementing PA restrictions due to safety concerns, weather, and using psychological control discourage, hinder, or decrease children's PA. CONCLUSIONS: Because this review found a very small number of studies examining the relationship between parenting styles and Latino children's PA and SB, additional research is needed. Given that the majority of reviewed studies were conducted with predominantly Mexican American or Mexican immigrant samples, additional research examining parenting styles, parenting practices, and PA and SB among multiethnic Latino groups is needed to design interventions tailored to the needs of this ethnically diverse population group. PMID- 29382630 TI - Motivational Interviewing and Medication Review in Coronary Heart Disease (MIMeRiC): Intervention Development and Protocol for the Process Evaluation. AB - BACKGROUND: Trials of complex interventions are often criticized for being difficult to interpret because the effects of apparently similar interventions vary across studies dependent on context, targeted groups, and the delivery of the intervention. The Motivational Interviewing and Medication Review in Coronary heart disease (MIMeRiC) trial is a randomized controlled trial (RCT) of an intervention aimed at improving pharmacological secondary prevention. Guidelines for the development and evaluation of complex interventions have recently highlighted the need for better reporting of the development of interventions, including descriptions of how the intervention is assumed to work, how this theory informed the process evaluation, and how the process evaluation relates to the outcome evaluation. OBJECTIVE: This paper aims to describe how the intervention was designed and developed. The aim of the process evaluation is to better understand how and why the intervention in the MIMeRiC trial was effective or not effective. METHODS: The research questions for evaluating the process are based on the conceptual model of change processes assumed in the intervention and will be analyzed by qualitative and quantitative methods. Quantitative data are used to evaluate the medication review in terms of drug-related problems, to describe how patients' beliefs about medicines are affected by the intervention, and to evaluate the quality of motivational interviewing. Qualitative data will be used to analyze whether patients experienced the intervention as intended, how cardiologists experienced the collaboration and intervention, and how the intervention affected patients' overall experience of care after coronary heart disease. RESULTS: The development and piloting of the intervention are described in relation to the theoretical framework. Data for the process evaluation will be collected until March 2018. Some process evaluation questions will be analyzed before, and others will be analyzed after the outcomes of the MIMeRiC RCT are known. CONCLUSIONS: This paper describes the framework for the design of the intervention tested in the MIMeRiC trial, development of the intervention from the pilot stage to the complete trial intervention, and the framework and methods for the process evaluation. Providing the protocol of the process evaluation allows prespecification of the processes that will be evaluated, because we hypothesize that they will determine the outcomes of the MIMeRiC trial. This protocol also constitutes a contribution to the new field of process evaluations as made explicit in health services research and clinical trials of complex interventions. PMID- 29382631 TI - One Pass Thalamic and Subthalamic Stimulation for Patients with Tremor-Dominant Idiopathic Parkinson Syndrome (OPINION): Protocol for a Randomized, Active Controlled, Double-Blinded Pilot Trial. AB - BACKGROUND: Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. OBJECTIVE: This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. METHODS: This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson's Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson's disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. RESULTS: At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. CONCLUSIONS: The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the "quality of life" outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients' quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL). PMID- 29382632 TI - A Smartphone App (BlueIce) for Young People Who Self-Harm: Open Phase 1 Pre-Post Trial. AB - BACKGROUND: Recent years have seen a significant increase in the availability of smartphone apps for mental health problems. Despite their proliferation, few apps have been specifically developed for young people, and almost none have been subject to any form of evaluation. OBJECTIVE: This study aimed to undertake a preliminary evaluation of a smartphone app (BlueIce), coproduced with young people and designed to help young people manage distress and urges to self-harm. We aimed to assess the acceptability, safety, and use of BlueIce and to explore the effects on the primary outcome of self-harm and the secondary outcomes of psychological functioning. METHODS: We undertook an open trial where we recruited young people aged 12 to 17 years attending specialist child and adolescent mental health services (CAMHS) who were currently self-harming or had a history of self harm. Eligible participants were assessed at baseline and then given BlueIce. They were assessed 2 weeks later (post familiarization) and again at 12 weeks (post use). A behavior-screening questionnaire (Strengths and Difficulties Questionnaire) was completed along with standardized measures of depression (Mood and Feelings Questionnaire or MFQ) and anxiety (Revised Child Anxiety and Depression Scale or RCADS), taking into account self-reports of self-harm, app helpfulness, and safety. RESULTS: All core CAMHS professional groups referred at least 1 young person. Out of 40 young people recruited, 37 (93%) elected to use BlueIce after familiarization, with 29 out of 33 (88%) wanting to keep it at the end of the study. No young person called the emergency numbers during the 12-week trial, and no one was withdrawn by his or her clinician due to increased risk of suicide. Almost three-quarters (73%) of those who had recently self-harmed reported reductions in self-harm after using BlueIce for 12 weeks. There was a statistically significant mean difference of 4.91 (t31=2.11; P=.04; 95% CI 0.17 9.64) on postuse symptoms of depression (MFQ) and 13.53 on symptoms of anxiety (RCADS) (t30=3.76; P=.001; 95% CI 6.17-20.90), which was evident across all anxiety subscales. Ratings of app acceptability and usefulness were high. CONCLUSIONS: Our study has a number of methodological limitations, particularly the absence of a comparison group and a prospective way of assessing self-harm. Nonetheless, our findings are encouraging and suggest that BlueIce, used alongside a traditional CAMHS face-to-face intervention, can help young people manage their emotional distress and urges to self-harm. PMID- 29382634 TI - Smartphone GP consultation app cost CCG L150 000 in first two months. PMID- 29382633 TI - Prediction of Incident Hypertension Within the Next Year: Prospective Study Using Statewide Electronic Health Records and Machine Learning. AB - BACKGROUND: As a high-prevalence health condition, hypertension is clinically costly, difficult to manage, and often leads to severe and life-threatening diseases such as cardiovascular disease (CVD) and stroke. OBJECTIVE: The aim of this study was to develop and validate prospectively a risk prediction model of incident essential hypertension within the following year. METHODS: Data from individual patient electronic health records (EHRs) were extracted from the Maine Health Information Exchange network. Retrospective (N=823,627, calendar year 2013) and prospective (N=680,810, calendar year 2014) cohorts were formed. A machine learning algorithm, XGBoost, was adopted in the process of feature selection and model building. It generated an ensemble of classification trees and assigned a final predictive risk score to each individual. RESULTS: The 1 year incident hypertension risk model attained areas under the curve (AUCs) of 0.917 and 0.870 in the retrospective and prospective cohorts, respectively. Risk scores were calculated and stratified into five risk categories, with 4526 out of 381,544 patients (1.19%) in the lowest risk category (score 0-0.05) and 21,050 out of 41,329 patients (50.93%) in the highest risk category (score 0.4-1) receiving a diagnosis of incident hypertension in the following 1 year. Type 2 diabetes, lipid disorders, CVDs, mental illness, clinical utilization indicators, and socioeconomic determinants were recognized as driving or associated features of incident essential hypertension. The very high risk population mainly comprised elderly (age>50 years) individuals with multiple chronic conditions, especially those receiving medications for mental disorders. Disparities were also found in social determinants, including some community-level factors associated with higher risk and others that were protective against hypertension. CONCLUSIONS: With statewide EHR datasets, our study prospectively validated an accurate 1-year risk prediction model for incident essential hypertension. Our real-time predictive analytic model has been deployed in the state of Maine, providing implications in interventions for hypertension and related diseases and hopefully enhancing hypertension care. PMID- 29382636 TI - Knotty issues in postpyloric feeding. PMID- 29382635 TI - Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. AB - OBJECTIVE: To investigate associations of physical activity at age 11 years with chronic disabling fatigue (CDF) at ages 13 and 16 years. DESIGN: Longitudinal birth cohort. SETTING: South-West England. PARTICIPANTS: Adolescents enrolled in the Avon Longitudinal Study of Parents and Children. OUTCOMES AND EXPOSURES: We identified adolescents who had disabling fatigue of >6 months' duration without a known cause at ages 13 and 16 years. Total and moderate-to-vigorous physical activity and sedentary time at age 11 years were measured by accelerometry over a 7-day period. RESULTS: A total physical activity level 100 counts/min higher at age 11 years was associated with 25% lower odds of CDF at age 13 years (OR=0.75 (95% CI 0.59 to 0.95)), a 1% increase in the proportion of monitored time spent in moderate-to-vigorous activity was associated with 16% lower odds of CDF (OR=0.84 (95% CI 0.69 to 1.01)) and a 1-hour increase in sedentary time was associated with 35% higher odds of CDF (OR=1.35 (95% CI 1.02 to 1.79)). Disabling fatigue of only 3-5 months' duration at age 13 years had weaker associations with physical activity, and CDF at age 16 years was not associated with physical activity at age 11 years. CONCLUSIONS: Children who had chronic disabling fatigue at age 13 years had lower levels of total and moderate-to-vigorous physical activity and more sedentary time 2 years previously, but this association could be explained by reverse causation. PMID- 29382637 TI - When paediatricians and families can't agree. PMID- 29382638 TI - Observations on the case of Charlie Gard. PMID- 29382639 TI - Response to: 'Detection of myositis-specific antibodies' by Vulsteke et al. PMID- 29382640 TI - Healthcare professionals must demand action on the social determinants of preventable low fetal growth and preterm birth. PMID- 29382641 TI - First WHO antimicrobial surveillance data reveal high levels of resistance globally. PMID- 29382642 TI - Government to investigate damage caused by mesh implants. PMID- 29382643 TI - Relative survival reaches a plateau in hairy cell leukemia: a population-based analysis in The Netherlands. PMID- 29382644 TI - Venetoclax Data Prompt Rethink of CLL Therapy. AB - The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease. PMID- 29382645 TI - First PARP Inhibitor Ok'd for Breast Cancer. AB - The FDA has approved olaparib, a PARP inhibitor, for use in patients with metastatic breast cancer who also carry a germline BRCA1 or BRCA2 mutation. With the January 12 approval, olaparib becomes the first targeted therapy for patients with breast cancer with mutated BRCA. PMID- 29382646 TI - Doctors can stop ventilating 11 month old boy brain damaged at birth. PMID- 29382647 TI - Optimizing Amplification of the GC-Rich TERT Promoter Region Using 7-Deaza-dGTP for Droplet Digital PCR Quantification of TERT Promoter Mutations. PMID- 29382648 TI - Why are preterm newborns at increased risk of infection? AB - One in 10 newborns will be born before completion of 36 weeks' gestation (premature birth). Infection and sepsis in preterm infants remain a significant clinical problem that represents a substantial financial burden on the healthcare system. Many factors predispose premature infants for having the greatest risk of developing and succumbing to infection as compared with all other age groups across the age spectrum. It is clear that the immune system of preterm infants exhibits distinct, rather than simply deficient, function as compared with more mature and older humans and that the immune function in preterm infants contributes to infection risk. While no single review can cover all aspects of immune function in this population, we will discuss key aspects of preterm neonatal innate and adaptive immune function that place them at high risk for developing infections and sepsis, as well as sepsis-associated morbidity and mortality. PMID- 29382649 TI - Control of Maize Vegetative and Reproductive Development, Fertility, and rRNAs Silencing by HISTONE DEACETYLASE 108. AB - Histone deacetylases (HDACs) catalyze the removal of acetyl groups from acetylated histone tails that consequently interact more closely with DNA, leading to chromatin state refractory to transcription. Zea mays HDA108 belongs to the Rpd3/HDA1 HDAC family and is ubiquitously expressed during development. The newly isolated hda108/hda108 insertional mutant exhibited many developmental defects: significant reduction in plant height, alterations of shoot and leaf development, and alterations of inflorescence patterning and fertility. Western blot analyses and immunolocalization experiments revealed an evident increase in histone acetylation, accompanied by a marked reduction in H3K9 dimethylation, in mutant nuclei. The DNA methylation status, in the CHG sequence context, and the transcript level of ribosomal sequences were also affected in hda108 mutants, while enrichment in H3 and H4 acetylation characterizes both repetitive and nonrepetitive transcriptional up-regulated loci. RNA-Seq of both young leaf and anthers indicated that transcription factor expression is highly affected and that the pollen developmental program is disrupted in hda108 mutants. Crosses between hda108/hda108 and epiregulator mutants did not produce any double mutant progeny indicating possible genetic interactions of HDA108 with distinct epigenetic pathways. Our findings indicate that HDA108 is directly involved in regulation of maize development, fertility, and epigenetic regulation of genome activity. PMID- 29382651 TI - Chronic Kidney Disease in India: A Clarion Call for Change. PMID- 29382650 TI - Beyond Thermodynamic Constraints: Evolutionary Sampling Generates Realistic Protein Sequence Variation. AB - Biological evolution generates a surprising amount of site-specific variability in protein sequences. Yet, attempts at modeling this process have been only moderately successful, and current models based on protein structural metrics explain, at best, 60% of the observed variation. Surprisingly, simple measures of protein structure, such as solvent accessibility, are often better predictors of site-specific variability than more complex models employing all-atom energy functions and detailed structural modeling. We suggest here that these more complex models perform poorly because they lack consideration of the evolutionary process, which is, in part, captured by the simpler metrics. We compare protein sequences that are computationally designed to sequences that are computationally evolved using the same protein-design energy function and to homologous natural sequences. We find that, by a wide variety of metrics, evolved sequences are much more similar to natural sequences than are designed sequences. In particular, designed sequences are too conserved on the protein surface relative to natural sequences, whereas evolved sequences are not. Our results suggest that evolutionary simulation produces a realistic sampling of sequence space. By contrast, protein design-at least as currently implemented-does not. Existing energy functions seem to be sufficiently accurate to correctly describe the key thermodynamic constraints acting on protein sequences, but they need to be paired with realistic sampling schemes to generate realistic sequence alignments. PMID- 29382652 TI - Crafting the Prescription for Patients Starting Peritoneal Dialysis. PMID- 29382653 TI - Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma. AB - Smoking perpetuates in cytologically normal airways a molecular "field of injury" that is pertinent to lung cancer and early detection. The evolution of airway field changes prior to lung oncogenesis is poorly understood largely due to the long latency of lung cancer in smokers. Here, we studied airway expression changes prior to lung cancer onset in mice with knockout of the Gprc5a gene (Gprc5a-/-) and tobacco carcinogen (NNK) exposure and that develop the most common type of lung cancer, lung adenocarcinoma, within 6 months following exposure. Airway epithelial brushings were collected from Gprc5a-/- mice before exposure and at multiple times post-NNK until time of lung adenocarcinoma development and then analyzed by RNA sequencing. Temporal airway profiles were identified by linear models and analyzed by comparative genomics in normal airways of human smokers with and without lung cancer. We identified significantly altered profiles (n = 926) in the NNK-exposed mouse normal airways relative to baseline epithelia, a subset of which were concordantly modulated with smoking status in the human airway. Among airway profiles that were significantly modulated following NNK, we found that expression changes (n = 22) occurring as early as 2 months following exposure were significantly associated with lung cancer status when examined in airways of human smokers. Furthermore, a subset of a recently reported human bronchial gene classifier (Percepta; n = 56) was enriched in the temporal mouse airway profiles. We underscore evolutionarily conserved profiles in the normal-appearing airway that develop prior to lung oncogenesis and that comprise viable markers for early lung cancer detection in suspect smokers. Cancer Prev Res; 11(4); 237-48. (c)2018 AACR. PMID- 29382654 TI - Shuttle mission in the mitochondrial intermembrane space. PMID- 29382655 TI - UK ranks in the middle of European healthcare survey. PMID- 29382656 TI - Why we should be concerned about accountable care organisations in England's NHS. PMID- 29382657 TI - Union vows to support NHS staff who refuse to act as "border guards". PMID- 29382658 TI - Plasma Connective Tissue Growth Factor (CTGF/CCN2) Levels Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort. AB - OBJECTIVE: Connective tissue growth factor (CTGF), also known as CCN2, is a potent chemotactic and extracellular matrix-inducing matricellular protein that has been implicated in progression of inflammatory and fibroproliferative disorders. An emerging role of CTGF/CCN2 is that of a prosclerotic factor implicated in the development of cardiac disease. Our objective was to determine the role of CTGF/CCN2 as a predictor of cardiovascular events in type 2 diabetes in the Veterans Affairs Diabetes Trial (VADT) cohort. RESEARCH DESIGN AND METHODS: Levels of CTGF/CCN2 were measured in 952 VADT patients a median of 1.9 years after entry into the study. Participants were followed for an average of 3.3 years for vascular outcomes. CTGF/CCN2 categories were defined as below the detectable limit (referent, 54.5%), lower half of detectable values (22.8%), and upper half of detectable values (22.7%). Hazard ratios (HRs) for cardiovascular end points in relation to CTGF/CCN2 categories were calculated by Cox proportional hazards models. RESULTS: During follow-up, 4.8% had a myocardial infarction (MI), 6.9% had an MI or cardiovascular death, and 6.9% died. After adjustments by conventional risk factors, individuals in the highest category of CTGF/CCN2 were at higher risk of MI (HR 2.43 [95% CI 1.15, 5.14]), MI or cardiovascular death (HR 2.71 [95% CI 1.44, 5.08]), and all-cause mortality (HR 2.70 [95% CI 1.43, 5.08]) relative to individuals with CTGF below the detectable limit. CONCLUSIONS: Our study indicates that high levels of CTGF/CCN2 predict future MI and cardiovascular death in patients with type 2 diabetes. PMID- 29382659 TI - Prognostic Value of the Acute-to-Chronic Glycemic Ratio at Admission in Acute Myocardial Infarction: A Prospective Study. AB - OBJECTIVE: Acute hyperglycemia is a powerful predictor of poor prognosis in acute myocardial infarction (AMI), particularly in patients without diabetes. This emphasizes the importance of an acute glycemic rise rather than glycemia level at admission alone. We investigated in AMI whether the combined evaluation of acute and chronic glycemic levels, as compared with admission glycemia alone, may have a better prognostic value. RESEARCH DESIGN AND METHODS: We prospectively measured admission glycemia and estimated average chronic glucose levels (mg/dL) by the following formula: [(28.7 * glycosylated hemoglobin %) - 46.7], and calculated the acute-to-chronic (A/C) glycemic ratio in 1,553 consecutive AMI patients (mean +/- SD age 67 +/- 13 years). The primary end point was the combination of in hospital mortality, acute pulmonary edema, and cardiogenic shock. RESULTS: The primary end point rate increased in parallel with A/C glycemic ratio tertiles (5%, 8%, and 20%, respectively; P for trend <0.0001). A parallel increase was observed in troponin I peak value (15 +/- 34 ng/mL, 34 +/- 66 ng/mL, and 68 +/- 131 ng/mL; P < 0.0001). At multivariable analysis, A/C glycemic ratio remained an independent predictor of the primary end point and of troponin I peak value, even after adjustment for major confounders. At reclassification analyses, A/C glycemic ratio showed the best prognostic power in predicting the primary end point as compared with glycemia at admission in the entire population (net reclassification improvement 12% [95% CI 4-20]; P = 0.003) and, particularly, in patients with diabetes (27% [95% CI 14-40]; P < 0.0001). CONCLUSIONS: In AMI patients with diabetes, A/C glycemic ratio is a better predictor of in-hospital morbidity and mortality than glycemia at admission. PMID- 29382660 TI - Effect of High-Deductible Insurance on High-Acuity Outcomes in Diabetes: A Natural Experiment for Translation in Diabetes (NEXT-D) Study. AB - OBJECTIVE: High-deductible health plans (HDHPs) are now the predominant commercial health insurance benefit in the U.S. We sought to determine the effects of HDHPs on emergency department and hospital care, adverse outcomes, and total health care expenditures among patients with diabetes. RESEARCH DESIGN AND METHODS: We applied a controlled interrupted time-series design to study 23,493 HDHP members with diabetes, aged 12-64, insured through a large national health insurer from 2003 to 2012. HDHP members were enrolled for 1 year in a low deductible (<=$500) plan, followed by 1 year in an HDHP (>=$1,000 deductible) after an employer-mandated switch. Patients transitioning to HDHPs were matched to 192,842 contemporaneous patients whose employers offered only low-deductible coverage. HDHP members from low-income neighborhoods (n = 8,453) were a subgroup of interest. Utilization measures included emergency department visits, hospitalizations, and total (health plan plus member out-of-pocket) health care expenditures. Proxy health outcome measures comprised high-severity emergency department visit expenditures and high-severity hospitalization days. RESULTS: After the HDHP transition, emergency department visits declined by 4.0% (95% CI 7.8, -0.1), hospitalizations fell by 5.6% (-10.8, -0.5), direct (nonemergency department-based) hospitalizations declined by 11.1% (-16.6, -5.6), and total health care expenditures dropped by 3.8% (-4.3, -3.4). Adverse outcomes did not change in the overall HDHP cohort, but members from low-income neighborhoods experienced 23.5% higher (18.3, 28.7) high-severity emergency department visit expenditures and 27.4% higher (15.5, 39.2) high-severity hospitalization days. CONCLUSIONS: After an HDHP switch, direct hospitalizations declined by 11.1% among patients with diabetes, likely driving 3.8% lower total health care expenditures. Proxy adverse outcomes were unchanged in the overall HDHP population with diabetes, but members from low-income neighborhoods experienced large, concerning increases in high-severity emergency department visit expenditures and hospitalization days. PMID- 29382661 TI - Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients. AB - BACKGROUND: The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100-300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition. METHODS AND RESULTS: Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (<=45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68+/-10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT <=19.8% or serum iron <=13 umol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively (P<0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction <=45%). In these patients, TSAT <=19.8% and serum iron <=13 umol/L, and not ferritin, were independently associated with mortality. CONCLUSIONS: A TSAT <=19.8% or a serum iron <=13 umol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin. PMID- 29382662 TI - Expert urges doctors to report themselves to GMC. PMID- 29382663 TI - Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis. AB - Mammalian genomes encode a huge number of long noncoding RNAs (lncRNAs) with unknown functions. This study determined the role and mechanism of a new lncRNA, lncRNA suppressor of hepatic gluconeogenesis and lipogenesis (lncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and patients with nonalcoholic fatty liver disease, the expression levels of mouse lncSHGL and its human homologous lncRNA B4GALT1-AS1 were reduced. Hepatic lncSHGL restoration improved hyperglycemia, insulin resistance, and steatosis in obese diabetic mice, whereas hepatic lncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. lncSHGL overexpression increased Akt phosphorylation and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas lncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, lncSHGL recruited heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) to enhance the translation efficiency of CALM mRNAs to increase calmodulin (CaM) protein level without affecting their transcription, leading to the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway and repression of the mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated the CaM/Akt pathway and repressed the mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, lncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating the lncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis. PMID- 29382664 TI - Hypertensive Disorders of Pregnancy and Offspring Cardiometabolic Health at Midchildhood: Project Viva Findings. AB - BACKGROUND: Exposure to preeclampsia or gestational hypertension is associated with higher offspring systolic blood pressure (SBP), but less is known about associations with other cardiometabolic risk markers. METHODS AND RESULTS: We studied 1097 children from the Project Viva cohort born 1999-2002. Exposures were preeclampsia or gestational hypertension and mean maternal SBP in each trimester from prenatal records. Outcomes were research measures in midchildhood (mean 8.0 years) of SBP, overall adiposity, and a global cardiometabolic risk score comprising measures of SBP, waist circumference, glycemia, and lipids. We conducted linear regression analyses adjusted for maternal characteristics and offspring sex and age. In adjusted models, maternal preeclampsia or gestational hypertension (n=98, 9.1%) versus normal blood pressure was associated with slightly higher offspring SBP z-score (0.15 units; 95% confidence interval [CI] 0.03, 0.32) but otherwise predicted better cardiometabolic health markers including metabolic risk z-score (-0.23 units; -95% CI 0.44, -0.03) and several of its components as well as lower body mass index z-score (-0.27 units; 95% CI 0.48, -0.06) and lower fat mass index (-0.91 kg/m2; 95% CI -1.35, -0.47). Similarly, higher mean third-trimester maternal SBP was associated with higher offspring SBP z-score (0.09 units per 10 mm Hg; 95% CI 0.02, 0.16) and lower overall and central adiposity but not with biomarkers of metabolic risk. Results for second-trimester SBP were generally similar. First-trimester blood pressure was associated with higher offspring blood pressure but not with other outcomes. CONCLUSIONS: Higher maternal late-pregnancy SBP and hypertensive disorders of pregnancy were associated with higher offspring SBP but otherwise better cardiometabolic health. PMID- 29382665 TI - Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the beta-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway. AB - BACKGROUND: As a monoamine neurotransmitter, 5-hydroxytryptamine (5-HT) or serotonin modulates mood, appetite, and sleep. Besides, 5-HT also has important peripheral functions. 5-HT receptor 2B (5-HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5-HT2BR in neointimal hyperplasia, a key pathological process in restenosis. METHODS AND RESULTS: The expression of 5 HT2BR was upregulated in wire-injured mouse femoral arteries. In addition, BW723C86, a selective 5-HT2BR agonist, promoted the injury response during restenosis. 5-HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5-HT-induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5-HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a beta arrestin2-dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5-HT2BR-mediated smooth muscle cell migration. Mice with deficiency of 5-HT2BR showed significantly reduced neointimal formation in wire-injured arteries. CONCLUSIONS: These results demonstrated that activation of 5-HT2BR and beta-arrestin2-biased downstream signaling are key pathological processes in neointimal formation, and 5-HT2BR may be a potential target for the therapeutic intervention of vascular restenosis. PMID- 29382666 TI - Long-Term Outcome of Consecutive Patients With Previous Coronary Bypass Surgery, Treated With Newer-Generation Drug-Eluting Stents. AB - BACKGROUND: Percutaneous coronary intervention (PCI) in patients with previous coronary artery bypass grafting (CABG) is associated with adverse clinical events. Although newer generation drug-eluting stents showed favorable short-term safety profiles, there is a lack of long-term outcome data. We evaluated the impact of previous CABG on 5-year clinical outcomes of patients treated with PCI using newer-generation drug-eluting stents. METHODS AND RESULTS: In this patient level pooled analysis of the prospective TWENTE (The Real-World Endeavor Resolute versus Xience V Drug-Eluting Stent Study in Twente) trial and nonenrolled TWENTE registry, we assessed a consecutive series of patients who underwent PCI with newer-generation drug-eluting stents for non-ST-segment-elevation acute coronary syndromes or stable angina. Of all 1709 patients, 202 (11.8%) had a history of CABG. Patients with previous CABG had significantly higher 5-year rates of cardiac death (10.4% versus 4.3%; P<0.001) and target vessel revascularization (25.0% versus 8.1%; P<0.001). These differences remained statistically significant after adjustment for differences in baseline characteristics. Landmark analysis revealed that from 1- to 5-year follow-up, the rates of cardiac death (8.1% versus 3.2%; P<0.001) and target vessel revascularization (17.1% versus 5.9%; P<0.001) were significantly higher in patients with previous CABG. Among patients with a history of CABG, PCI of an obstructed vein graft was associated with a higher rate of 5-year target vessel revascularization (P=0.003). CONCLUSIONS: At 5-year follow-up after PCI with newer-generation drug eluting stents, the risk of cardiac death and target vessel revascularization was significantly higher in patients with previous CABG. The target vessel revascularization rate was highest in patients who underwent PCI of obstructed vein grafts. PMID- 29382667 TI - Inhibiting Integrin alpha5 Cytoplasmic Domain Signaling Reduces Atherosclerosis and Promotes Arteriogenesis. AB - BACKGROUND: Fibronectin in endothelial basement membranes promotes endothelial inflammatory activation and atherosclerosis but also promotes plaque stability and vascular remodeling. The fibronectin receptor alpha5 subunit is proinflammatory through binding to and activating phosphodiesterase 4D5, which inhibits anti-inflammatory cyclic adenosine monophosphate and protein kinase A. Replacing the alpha5 cytoplasmic domain with that of alpha2 resulted in smaller atherosclerotic plaques. Here, we further assessed plaque phenotype and compensatory vascular remodeling in this model. METHODS AND RESULTS: alpha5/2 mice in the hyperlipidemic apolipoprotein E null background had smaller plaques in the aortic root, with reduced endothelial NF-kappaB activation and inflammatory gene expression, reduced leukocyte content, and much lower metalloproteinase expression. However, smooth muscle cell content, fibrous cap thickness, and fibrillar collagen were unchanged, indicating no shift toward vulnerability. In vivo knockdown of phosphodiesterase 4D5 also decreased endothelial inflammatory activation and atherosclerotic plaque size. alpha5/2 mice showed improved recovery from hindlimb ischemia after femoral artery ligation. CONCLUSIONS: Blocking the fibronectin-Integrin alpha5 pathway reduces atherosclerotic plaque size, maintains plaque stability, and improves compensatory remodeling. This pathway is therefore a potential therapeutic target for treatment of atherosclerosis. PMID- 29382668 TI - The relation between publication rate and financial conflict of interest among physician authors of high-impact oncology publications: an observational study. AB - BACKGROUND: Despite the abundant research on financial conflict of interest regarding provider behaviour and the interpretation and results of research, little is known about the relation between these conflicts in academia and the trajectory of one's academic career. We performed a study to examine whether the presence of financial ties to drug makers among academics is associated with research productivity. METHODS: We hand-searched 3 high-impact general medical journals (New England Journal of Medicine, JAMA and The Lancet) and 3 high-impact oncology journals that publish original science (The Lancet Oncology, Journal of Clinical Oncology and Journal of the National Cancer Institute) to identify physicians based in the United States who were first or last authors on original papers on hematologic or oncologic topics that appeared in 2015. We ascertained their publication history from Scopus and their personal and research payments from the Centers for Medicare & Medicaid Services' Open Payments Web site (2013 2015). The strength of association between general (personal) financial payments from 2013 to 2015 and publications from 2013 to 2016 was determined by multivariate regression. RESULTS: Our sample consisted of 435 physicians who had authored a median of 140 publications, earning a median h-index of 36 and a median of 5639 citations. The median total of general payments from 2013 to 2015 was US$3282 (range $0-$3.4 million), and the median amount of research payments was US$3500 (range $0-$23 million). General payments were associated with contemporary publications, with an increase of 1.99 papers (95% confidence interval [CI] 1.1 to 2.9) per $10 000 in payments. This association persisted in multivariate analysis after adjustment for prior publications, seniority and research payments (0.84 papers [95% CI 0.15 to 1.5] per $10 000 in payments). INTERPRETATION: The findings suggest that there is a positive association between personal payments from drug makers and publications, and that this association persists after adjustment for prior publications, time since medical school graduation and research payments. PMID- 29382669 TI - Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center. AB - We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 1-7. (c)2018 AACR. PMID- 29382670 TI - YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma. AB - Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8+ T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription. Both BRAFi-resistant and YAP-5SA-expressing melanoma cells suppress the cytotoxic function and cytokine production of Melan-A-specific CD8+ T cells, whereas anti PD-1 antibody reverses the YAP-mediated T-cell suppression. Moreover, nuclear enrichment of YAP in clinical melanoma samples correlates with increased PD-L1 expression. Our findings show that YAP directly mediates evasion of cytotoxic T cell immune responses in BRAFi-resistant melanoma cells by upregulating PD-L1, and targeting of YAP-mediated immune evasion may improve prognosis of melanoma patients. Cancer Immunol Res; 6(3); 1-12. (c)2018 AACR. PMID- 29382671 TI - Mast Cell-Dependent CD8+ T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in ApcMin/+ Mice. AB - The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (ApcMin/+) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2-/ ApcMin/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell-deficient ACKR2-/-SA-/-ApcMin/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2-/- mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8+ T cells. Mast cell-derived leukotriene B4 (LTB4) was found to be required for CD8+ T lymphocyte recruitment, as mice lacking the LTB4 receptor (ACKR2-/-BLT1-/ ApcMin/+) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB4/BLT1-regulated CD8+ T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors. Cancer Immunol Res; 6(3); 1 16. (c)2018 AACR. PMID- 29382672 TI - Time in therapeutic range and stability over time for warfarin users in clinical practice: a retrospective cohort study using linked routinely collected health data in Alberta, Canada. AB - OBJECTIVES: Whether warfarin-treated patients with non-valvular atrial fibrillation (NVAF) who exhibit good control will experience deterioration in control over time is uncertain. We designed this study to examine the time in therapeutic range (TTR) in a population-based cohort of patients with NVAF recently initiated on warfarin. DESIGN: Retrospective cohort study using routinely collected health data from 2008 to 2015. SETTING: The Canadian province of Alberta. PARTICIPANTS: All adults with NVAF who were taking warfarin for >1 month. MAIN OUTCOME MEASURES: Frequency of international normalised ratio (INR) monitoring and the Rosendaal TTR with time zero set at 31 days after the first warfarin dispensation. RESULTS: Of 57 669 patients with NVAF dispensed warfarin for >1 month, 17 099 (29.7%) had <3 INRs measured in months 1-6. Of the 40 570 who went for regular INR monitoring in months 1-6 (median number of INRs 11, IQR 7-16), 16 639 (41.0%) met the definition of good control (TTR > 65%); good control continued to be exhibited by 8177 (57.1% of those who remained on warfarin) during months 7-12 and 6804 (56.8% of continuing warfarin users) in months 13-18. Good control in the first 6 months predicted good control over the subsequent year: adjusted OR (aOR) 4.0(95%CI 3.8 to 4.2), c index 0.685(95%CI 0.679 to 0.691) for months 7-12 and aOR 3.2(95%CI 3.1 to 3.3), c index 0.665(95%CI 0.659 to 0.671) for months 13-18. CONCLUSIONS: Nearly one-third of warfarin-treated patients had insufficient INR monitoring-this could influence the initial choice of anticoagulant and identifies a target for future quality improvement efforts. Of those warfarin-treated patients who went for regular INR monitoring, 41% exhibited levels of control similar to that in randomised trials and this deteriorated by half over time. However, in patients who have already exhibited adherence with regular monitoring and good TTR, warfarin may still be a reliable anticoagulation option. PMID- 29382673 TI - Effectiveness of an internet-based perioperative care programme to enhance postoperative recovery in gynaecological patients: cluster controlled trial with randomised stepped-wedge implementation. AB - OBJECTIVE: To evaluate the implementation and effectiveness of an internet-based perioperative care programme for patients following gynaecological surgery for benign disease. DESIGN: Stepped-wedge cluster randomised controlled trial. SETTING: Secondary care, nine hospitals in the Netherlands, 2011-2014. PARTICIPANTS: 433 employed women aged 18-65 years scheduled for hysterectomy and/or laparoscopic adnexal surgery. INTERVENTIONS: An internet-based care programme was sequentially rolled out using a multifaceted implementation strategy. Depending on the implementation phase of their hospital, patients were allocated to usual care (n=206) or the care programme (n=227). The care programme included an e-health intervention equipping patients with tailored personalised convalescence advice. MAIN OUTCOME MEASURES: The primary outcome was duration until full sustainable return to work (RTW). The degree of implementation of the care programme was evaluated at the level of the patient, healthcare provider and organisation by indicators measuring internet-based actions by patients and providers. RESULTS: Median time until RTW was 49 days (IQR 27-76) in the intervention group and 62 days (42-85) in the control group. A piecewise Cox model was fitted to take into account non-proportionality of hazards. In the first 85 days after surgery, patients receiving the intervention returned to work faster than patients in the control group (HR 2.66, 95% CI 1.88 to 3.77), but this effect was reversed in the small group of patients that did not reach RTW within this period (0.28, 0.17 to 0.46). Indicators showed that the implementation of the care programme was most successful at the level of the patient (82.8%) and professional (81.7%). CONCLUSIONS: Implementation of an internet-based care programme has a large potential to lead to accelerated recovery and improved RTW rates following different types of gynaecological surgeries. TRIAL REGISTRATION NUMBER: NTR2933; Results. PMID- 29382674 TI - Study protocol for a randomised, controlled platform trial estimating the effect of autobiographical Memory Flexibility training (MemFlex) on relapse of recurrent major depressive disorder. AB - INTRODUCTION: Major depressive disorder (MDD) is a chronic condition. Although current treatment approaches are effective in reducing acute depressive symptoms, rates of relapse are high. Chronic and inflexible retrieval of autobiographical memories, and in particular a bias towards negative and overgeneral memories, is a reliable predictor of relapse. This randomised controlled single-blind trial will determine whether a therapist-guided self-help intervention to ameliorate autobiographical memory biases using Memory Flexibility training (MemFlex) will increase the experience of depression-free days, relative to a psychoeducation control condition, in the 12 months following intervention. METHODS AND ANALYSIS: Individuals (aged 18 and above) with a diagnosis of recurrent MDD will be recruited when remitted from a major depressive episode. Participants will be randomly allocated to complete 4 weeks of a workbook providing either MemFlex training, or psychoeducation on factors that increase risk of relapse. Assessment of diagnostic status, self-report depressive symptoms, depression-free days and cognitive risk factors for depression will be completed post-intervention, and at 6 and 12 months follow-up. The cognitive target of MemFlex will be change in memory flexibility on the Autobiographical Memory Test- Alternating Instructions. The primary clinical endpoints will be the number of depression-free days in the 12 months following workbook completion, and time to depressive relapse. ETHICS AND DISSEMINATION: Ethics approval has been granted by the NHS National Research Ethics Committee (East of England, 11/H0305/1). Results from this study will provide a point-estimate of the effect of MemFlex on depressive relapse, which will be used to inform a fully powered trial evaluating the potential of MemFlex as an effective, low-cost and low-intensity option for reducing relapse of MDD. TRIAL REGISTRATION NUMBER: NCT02614326. PMID- 29382675 TI - Randomised controlled trial on the effect of internet-delivered computerised cognitive-behavioural therapy on patients with insomnia who remain symptomatic following hypnotics: a study protocol. AB - INTRODUCTION: Insomnia has severe consequences for health. Primary care physicians in Japan commonly provide hypnotics, which is far from optimal. The recommended treatment for insomnia is cognitive-behavioural therapy (CBT). Access to trained therapists, however, is limited. Rather than face-to-face CBT, several researchers have studied internet-delivered computerised CBT (ICBT). This paper describes the study protocol for a randomised controlled trial (RCT) to evaluate effectiveness and feasibility of our newly developed five-step ICBT as an adjunct to usual care (UC) compared with UC alone for patients with insomnia who remain symptomatic following hypnotics. METHODS AND ANALYSIS: This proposed exploratory RCT comprises two parallel groups (ICBT+UC and UC alone) consisting of 15 participants each (n=30) diagnosed with insomnia who remain symptomatic after pharmacotherapy. We aim to evaluate the effectiveness of six intervention weeks. The primary outcome of insomnia severity will be the Pittsburgh Sleep Quality Index (PSQI) at week 6. Secondary outcomes include sleep onset latency, total sleep time, sleep efficiency extracted from PSQI, current feeling of refreshment and perceived soundness of sleep measured using visual analogue scale, number of awakenings, anxiety by Hospital Anxiety and Depression Scale, depression by Center for Epidemiologic Studies Depression Scale and quality of life by Euro Qol 5D. All measures will be assessed at weeks 0 (baseline), 6 (postintervention) and 12 (follow-up), and intention-to-treat analysis will be applied. The statistical analysis plan has been developed considering design of field materials. ETHICS AND DISSEMINATION: This study will be conducted at the academic outpatient clinic of Chiba University Hospital, Japan. Ethics approval was granted by the Institutional Review Board of Chiba University Hospital. All participants will be required to provide written informed consent. The trial will be implemented and reported in accordance with Consolidated Standards of Reporting Trials recommendations. TRIAL REGISTRATION NUMBER: UMIN000021509; Pre-results. PMID- 29382676 TI - Patient engagement in hospital health service planning and improvement: a scoping review. AB - OBJECTIVES: Patient engagement (PE) improves patient, organisation and health system outcomes, but most research is based on primary care. The primary purpose of this study was to describe the characteristics of published empirical research that evaluated PE in hospital health service improvement. DESIGN: Scoping review. METHODS: Five databases were searched from 2006 to September 2016. English language studies that evaluated patient or provider beliefs, participation in PE, influencing factors or impact were eligible. Screening and data extraction were done in triplicate. PE characteristics, influencing factors and impact were extracted and summarised. RESULTS: From a total of 3939 search results, 227 studies emerged as potentially relevant; of these, 217 were not eligible, and 10 studies were included in the review. None evaluated behavioural interventions to promote or support PE. While most studies examined involvement in standing committees or projects, patient input and influence on decisions were minimal. Lack of skill and negative beliefs among providers were PE barriers. PE facilitators included careful selection and joint training of patients and providers, formalising patient roles, informal interaction to build trust, involving patients early in projects, small team size, frequent meetings, active solicitation of patient input in meetings and debriefing after meetings. Asking patients to provide insight into problems rather than solutions and deploying provider champions may enhance patient influence on hospital services. CONCLUSIONS: Given the important role of PE in improving hospital services and the paucity of research on this topic, future research should develop and evaluate behavioural interventions for PE directed at patients and providers informed by the PE barriers and facilitators identified here. Future studies should also assess the impact on various individual and organisational outcomes. PMID- 29382677 TI - Computerised decision to reduce inappropriate medication in the elderly: a systematic review with meta-analysis protocol. AB - INTRODUCTION: Life expectancy continues to increase in developed countries. Elderly people are more likely to consume more medications and become vulnerable to age-related changes in drugs' pharmacokinetics and pharmacodynamics. Recent studies have identified opportunities and barriers for deprescribing potentially inappropriate medications. It has already been demonstrated that computerised decision support systems can reduce physician orders for unnecessary tests. We will systematically review the available literature to understand if computerised decision support is effective in reducing the use of potentially inappropriate medications, thus having an impact on health outcomes. METHODS AND ANALYSIS: A systematic review will be conducted using MEDLINE, CENTRAL, EMBASE and Web of Science databases, as well as the grey literature assessing the effectiveness of computer decision support interventions in deprescribing inappropriate medication, with an impact on health outcomes in the elderly. The search will be performed during January and February 2018. Two reviewers will conduct articles' screening, selection and data extraction, independently and blind to each other. Eligible sources will be selected after discussing non-conformities. All extracted data from the included articles will be assessed based on studies' participants, design and setting, methodological quality, bias and any other potential sources of heterogeneity. This review will be conducted and reported in adherence to the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement of quality for reporting systematic reviews and meta-analyses. ETHICS AND DISSEMINATION: As a systematic review, this research is exempt from ethical approval. We intend to publish the full article in a related peer reviewed journal and present it at international conferences. PROSPEROREGISTRATION NUMBER: CRD42017067021. PMID- 29382678 TI - Fatty liver index, albuminuria and the association with chronic kidney disease: a population-based study in China. AB - OBJECTIVES: The effects of lipid metabolism disorder on renal damage have drawn much attention. Using the fatty liver index (FLI) as a validated indicator of hepatic steatosis, this study aims to provide insight about the possible links between fatty liver and the development of chronic kidney disease (CKD). SETTING: Hospital. PARTICIPANTS: We performed a population-based study on 9436 subjects aged 40 years or older. PRIMARY AND SECONDARY OUTCOME MEASURES: FLI is calculated using an algorithm based on body mass index, waist circumference, triglycerides and gamma-glutamyltransferase. Increased urinary albumin excretion was defined according to the urinary albumin to creatinine ratio ranges >=30 mg/g. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or presence of albuminuria. RESULTS: There were 620 (6.6%) subjects categorised to have increased urinary albumin excretion and 753 (8.0%) subjects categorised to have CKD. Participants with higher FLI had increased age, blood pressure, low density lipoprotein cholesterol, fasting plasma glucose, fasting insulin and decreased eGFR level. Prevalence of increased urinary albumin excretion and CKD tended to increase with the elevated FLI quartiles. In logistic regression analysis, compared with subjects in the lowest quartile of FLI, the adjusted ORs in the highest quartile were 2.30 (95% CI 1.36 to 3.90) for increased urinary albumin excretion and 1.93 (95% CI 1.18 to 3.15) for CKD. CONCLUSION: Hepatic steatosis evaluated by FLI is independently associated with increased urinary albumin excretion and prevalence of CKD in middle-aged and elderly Chinese. PMID- 29382679 TI - Opportunities and barriers in paediatric pulse oximetry for pneumonia in low resource clinical settings: a qualitative evaluation from Malawi and Bangladesh. AB - OBJECTIVE: To gain an understanding of what challenges pulse oximetry for paediatric pneumonia management poses, how it has changed service provision and what would improve this device for use across paediatric clinical settings in low income countries. DESIGN: Focus group discussions (FGDs), with purposive sampling and thematic analysis using a framework approach. SETTING: Community, front-line outpatient, and hospital outpatient and inpatient settings in Malawi and Bangladesh, which provide paediatric pneumonia care. PARTICIPANTS: Healthcare providers (HCPs) from Malawi and Bangladesh who had received training in pulse oximetry and had been using oximeters in routine paediatric care, including community healthcare workers, non-physician clinicians or medical assistants, and hospital-based nurses and doctors. RESULTS: We conducted six FGDs, with 23 participants from Bangladesh and 26 from Malawi. We identified five emergent themes: trust, value, user-related experience, sustainability and design. HCPs discussed the confidence gained through the use of oximeters, resulting in improved trust from caregivers and valuing the device, although there were conflicts between the weight given to clinical judgement versus oximeter results. HCPs reported the ease of using oximeters, but identified movement and physically smaller children as measurement challenges. Challenges in sustainability related to battery durability and replacement parts, however many HCPs had used the same device longer than 4 years, demonstrating robustness within these settings. Desirable features included back-up power banks and integrated respiratory rate and thermometer capability. CONCLUSIONS: Pulse oximetry was generally deemed valuable by HCPs for use as a spot-check device in a range of paediatric low income clinical settings. Areas highlighted as challenges by HCPs, and therefore opportunities for redesign, included battery charging and durability, probe fit and sensitivity in paediatric populations. TRIAL REGISTRATION NUMBER: NCT02941237. PMID- 29382680 TI - Are trends in billing for high-intensity emergency care explained by changes in services provided in the emergency department? An observational study among US Medicare beneficiaries. AB - OBJECTIVE: There has been concern that an increase in billing for high-intensity emergency care is due to changes in coding practices facilitated by electronic health records. We sought to characterise the trends in billing for high intensity emergency care among Medicare beneficiaries and to examine the degree to which trends in high-intensity billing are explained by changes in patient characteristics and services provided in the emergency department (ED). DESIGN, SETTING AND PARTICIPANTS: Observational study using traditional Medicare claims to identify ED visits at non-federal acute care hospitals for elderly beneficiaries in 2006, 2009 and 2012. OUTCOMES MEASURES: Billing intensity was defined by emergency physician evaluation and management (E&M) codes. We tested for overall trends in high-intensity billing (E&M codes 99285, 99291 and 99292) and in services provided over time using linear regression models, adjusting for patient characteristics. Additionally, we tested for time trends in rates of admission to the hospital and to the intensive care unit (ICU). Next, we classified outpatient visits into 39 diagnosis categories and analysed the change in proportion of high-intensity visits versus the change in number of services. Finally, we quantified the extent to which trends in high-intensity billing are explained by changes in patient demographics and services provided in the ED using multivariable modelling. RESULTS: High-intensity visits grew from 45.8% of 671 103 visits in 2006 to 57.8% of 629 010 visits in 2012 (2.0% absolute increase per year; 95% CI 1.97% to 2.03%) as did the mean number of services provided for admitted (1.28 to 1.41; +0.02 increase in procedures per year; 95% CI 0.018 to 0.021) and discharged ED patients (7.1 to 8.6; +0.25 increase in services per year; 95% CI 0.245 to 0.255). There was a reduction in hospital admission rate from 40.1% to 35.9% (-0.68% per year; 95% CI -0.71% to -0.65%; P<0.001), while the ICU rate of admission rose from 11.7% to 12.3% (+0.11% per year; 95% CI 0.09% to 0.12%; P<0.001). When we stratified by diagnosis category, there was a moderate correlation between change in visits billed as high intensity and the change in mean number of services provided per visit (r=0.38; 95% CI 0.07 to 0.63). Trends in patient characteristics and services provided accounted moderately for the trend in practice intensity for outpatient visits (pseudo R2 of 0.47) but very little for inpatient visits (0.051) and visits overall (0.148). CONCLUSIONS: Increases in services provided in the ED moderately account for the trends in billing for high-intensity emergency care for outpatient visits. PMID- 29382681 TI - Evaluating the role of prereduction hip traction in the management of infants and children with developmental dysplasia of the hip (DDH): protocol for a systematic review and planned meta-analysis. AB - INTRODUCTION: Developmental dysplasia of the hip (DDH) affects 4-6 per 1000 live births in developed countries. Effective treatment to realign the hip is necessary to avoid long-term morbidities and maximise functional outcome. Treatment options depend on patient age but typically involve hip bracing and/or reduction under general anaesthetic. Some centres also employ prereduction hip traction. Historical papers suggest traction reduces risk of avascular necrosis (AVN) femoral head and reduces requirement for open reduction. However, several studies including a large retrospective cohort study, dispute this. We propose to perform the first systematic review and meta-analysis to clarify the value of prereduction hip traction in the management of DDH in children under the age of 3 years by identifying whether it impacts on the rate of successful closed reduction (CR) and risk of AVN. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to identify potentially relevant studies. Studies reporting on incidence of successful CR, AVN femoral head and complications associated with prereduction hip traction in children of less than 3 years with DDH will be eligible for inclusion. Only randomised controlled trials, prospective and retrospective case-control and comparative cohort studies will be included in quantitative review. There will be no study design restrictions for inclusion in qualitative review. Following study selection, full-text paper retrieval, data extraction and synthesis, studies will be assessed for risk of bias and heterogeneity. If the included studies are sufficiently homogeneous, then we will perform meta-analysis. A narrative synthesis of the systematic review's results will also be presented. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary patient data will not be collected. The systematic review's results will be disseminated through a peer-reviewed publication. TRIAL REGISTRATION NUMBER: CRD42017064254; Pre-results. PMID- 29382682 TI - Health science communication strategies used by researchers with the public in the digital and social media ecosystem: a systematic scoping review protocol. AB - INTRODUCTION: The optimisation of health science communication (HSC) between researchers and the public is crucial. In the last decade, the rise of the digital and social media ecosystem allowed for the disintermediation of HSC. Disintermediation refers to the public's direct access to information from researchers about health science-related topics through the digital and social media ecosystem, a process that would otherwise require a human mediator, such as a journalist. Therefore, the primary aim of this scoping review is to describe the nature and the extent of the literature regarding HSC strategies involving disintermediation used by researchers with the public in the digital and social media ecosystem. The secondary aim is to describe the HSC strategies used by researchers, and the communication channels associated with these strategies. METHODS AND ANALYSIS: We will conduct a scoping review based on the Joanna Briggs Institute's methodology and perform a systematic search of six bibliographical databases (CINAHL, EMBASE, IBSS, PubMed, Sociological Abstracts and Web of Science), four trial registries and relevant sources of grey literature. Relevant journals and reference lists of included records will be hand-searched. Data will be managed using the EndNote software and the Rayyan web application. Two review team members will perform independently the screening process as well as the full text assessment of included records. Descriptive data will be synthesised in a tabular format. Data regarding the nature and the extent of the literature, the HSC strategies and the associated communication channels will be presented narratively. ETHICS AND DISSEMINATION: This review does not require institutional review board approval as we will use only collected and published data. Results will allow the mapping of the literature about HSC between researchers and the public in the digital and social media ecosystem, and will be published in a peer reviewed journal. PMID- 29382684 TI - Correction: Incidence of laboratory-confirmed influenza disease among infants under 6 months of age: a systematic review. PMID- 29382683 TI - Accelerated induction regimens of TNF-alpha inhibitors in patients with inflammatory bowel disease: a scoping review protocol. AB - INTRODUCTION: Tumour necrosis factor (TNF)-alpha inhibitors are commonly used to treat inflammatory bowel disease (IBD). In patients with IBD who are unresponsive to their first induction dose, the implementation of an 'accelerated' induction dose schedule (doses more frequent than recommended in product monographs) is becoming increasingly common. It is unclear whether this practice results in favourable patient outcomes, such as avoidance of surgery and disease remission. As such, there is a need to identify and map the current evidence base on accelerated induction schedules of these medications in the treatment of IBD. METHODS AND ANALYSIS: A scoping review will be employed to systematically identify and characterise the nature of scientific literature on accelerated induction regimens of TNF-alpha inhibitors. MEDLINE, Embase, International Pharmaceutical Abstracts and grey literature will be searched to identify relevant studies. The titles/abstracts of all records and full text of potentially relevant articles will be independently screened for inclusion by two reviewers. Data will be abstracted from included studies by one reviewer and verified for accuracy by another. The findings will be synthesised descriptively. ETHICS AND DISSEMINATION: We intend to report the findings of this scoping review in a peer-reviewed journal and a scientific conference. TRIAL REGISTRATION: This research was registered prospectively with the Open Science Framework (https://osf.io/z7n2d/). PMID- 29382686 TI - Reducing Unnecessary Imaging and Pathology Tests: A Systematic Review. AB - CONTEXT: Unnecessary imaging and pathology procedures represent low-value care and can harm children and the health care system. OBJECTIVE: To perform a systematic review of interventions designed to reduce unnecessary pediatric imaging and pathology testing. DATA SOURCES: We searched Medline, Embase, Cinahl, PubMed, Cochrane Library, and gray literature. STUDY SELECTION: Studies we included were: reports of interventions to reduce unnecessary imaging and pathology testing in pediatric populations; from developed countries; written in the English language; and published between January 1, 1996, and April 29, 2017. DATA EXTRACTION: Two researchers independently extracted data and assessed study quality using a Cochrane group risk of bias tool. Level of evidence was graded using the Oxford Centre for Evidence-Based Medicine grading system. RESULTS: We found 64 articles including 44 before-after, 14 interrupted time series, and 1 randomized controlled trial. More effective interventions were (1) multifaceted, with 3 components (mean relative reduction = 45.0%; SD = 28.3%) as opposed to 2 components (32.0% [30.3%]); or 1 component (28.6%, [34.9%]); (2) targeted toward families and clinicians compared with clinicians only (61.9% [34.3%] vs 30.0% [32.0%], respectively); and (3) targeted toward imaging (41.8% [38.4%]) or pathology testing only (48.8% [20.9%]), compared with both simultaneously (21.6% [29.2%]). LIMITATIONS: The studies we included were limited to the English language. CONCLUSIONS: Promising interventions include audit and feedback, system based changes, and education. Future researchers should move beyond before-after designs to rigorously evaluate interventions. A relatively novel approach will be to include both clinicians and the families they manage in such interventions. PMID- 29382685 TI - Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction. AB - Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF-beta1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo, EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD. PMID- 29382687 TI - Choosing Better: Standard of Care Should Be Data-driven, Not Just Habit-forming. PMID- 29382688 TI - No Cause for Alarm: Decreasing Inappropriate Pulse Oximetry Use in Bronchiolitis. PMID- 29382689 TI - The unmasking of the lipid binding face of sphingosine kinase 1. PMID- 29382690 TI - Man in his 50s with chest pain and dyspnoea. AB - CLINICAL INTRODUCTION: A man in his 50s with sudden-onset chest pain and dyspnoea was transferred to the emergency room. He had a history of aortic valve replacement due to aortic regurgitation with a mechanical valve 6 years previously. Heart rate was 90 bpm, and blood pressure was too low to measure. In the emergency room, he presented with severe dyspnoea and a chest X-ray showed severe lung congestion (figure 1A). ECG showed complete left bundle branch block. His respiratory status rapidly worsened, and he went into cardiopulmonary arrest. After cardiopulmonary resuscitation, transthoracic echocardiography was performed (figure 1B, online supplementary video 1).DC1SP110.1136/heartjnl-2017 312477.supp1Supplementary file 1 heartjnl;104/10/868/F1F1F1Figure 1(A) Chest X ray. (B) Colour Doppler image from apical five-chamber view. QUESTION: What is the most likely cause of the patient's cardiopulmonary arrest?Myocardial infarction in left main trunkAortic dissectionProsthetic valve thrombosisProsthetic valve embolisationPulmonary embolism. PMID- 29382691 TI - Resting heart rate: what is normal? PMID- 29382692 TI - Plant Temperature Acclimation and Growth Rely on Cytosolic Ribosome Biogenesis Factor Homologs. AB - Arabidopsis (Arabidopsis thaliana) REI1-LIKE (REIL) proteins, REIL1 and REIL2, are homologs of a yeast ribosome biogenesis factor that participates in late cytoplasmic 60S ribosomal subunit maturation. Here, we report that the inhibited growth of the reil1-1 reil2-1 mutant at 10 degrees C can be rescued by the expression of amino-terminal FLUORESCENT PROTEIN (FP)-REIL fusions driven by the UBIQUITIN10 promoter, allowing the analysis of REIL function in planta. Arabidopsis REIL1 appears to be functionally conserved, based on the cytosolic localization of FP-REIL1 and the interaction of native REIL1 with the 60S subunit in wild-type plants. In contrast to its yeast homologs, REIL1 also was present in translating ribosome fractions. Systems analysis revealed that wild-type Arabidopsis remodels the cytosolic translation machinery when grown at 10 degrees C by accumulating cytosolic ribosome subunits and inducing the expression of cytosolic ribosomal RNA, ribosomal genes, ribosome biogenesis factors, and translation initiation or elongation factors. In the reil1-1 reil2-1 mutant, all processes associated with inhibited growth were delayed, although the plants maintained cellular integrity or acquired freezing tolerance. REIL proteins also were implicated in plant-specific processes: nonacclimated reil1-1 reil2-1 exhibited cold-acclimation responses, including activation of the DREB/CBF regulon. In addition, acclimated reil1-1 reil2-1 plants failed to activate FLOWERING LOCUS T expression in mature leaves. Therefore, in the wild type, REIL function may contribute to temperature perception by suppressing premature cold responses during growth at nonstressful temperatures. In conclusion, we suggest that Arabidopsis REIL proteins influence cold-induced plant ribosome remodeling and enhance the accumulation of cytosolic ribosome subunits after cold shift either by de novo synthesis or by recycling them from the translating ribosome fraction. PMID- 29382693 TI - Synthetic MicroProteins: Versatile Tools for Posttranslational Regulation of Target Proteins. AB - MicroProteins are small, single-domain proteins that regulate multidomain proteins by sequestering them into novel, often nonproductive, complexes. Several microProteins have been identified in plants and animals, most of which negatively regulate transcription factors. MicroProtein candidates that potentially target a wide range of different protein classes were recently identified in a computational approach. Here, we classified all Arabidopsis (Arabidopsis thaliana) microProteins and developed a synthetic microProtein approach to target specific protein classes, such as hydrolases, receptors, and lyases, in a proof-of-concept approach. Our findings reveal that microProteins can be used to influence different physiological processes, which makes them useful tools for posttranslational regulation in plants and potentially also in animals. PMID- 29382694 TI - Sickness absence due to different musculoskeletal diagnoses by occupational class: a register-based study among 1.2 million Finnish employees. AB - OBJECTIVES: Those in lower occupational classes have an increased risk of sickness absence due to musculoskeletal diseases (MSDs), but studies examining the associations simultaneously across specified diagnostic groups within MSDs are lacking. We examined occupational class differences in the occurrence and length of long-term sickness absence due to different musculoskeletal diagnoses. METHODS: A 70% random sample of employed Finns aged 25-64 years old at the end of 2013 was linked to data on sickness absence of over 10 working days obtained from The Social Insurance Institution of Finland and occupational class from Statistics Finland. Sickness absences due to MSDs initiated in 2014 were followed until the end of each episode for female (n=675 636) and male (n=604 715) upper non-manuals, lower non-manuals and manual workers. Negative binomial hurdle models were used to analyse the associations. RESULTS: Within the studied MSDs, the most common causes of absence were back disorders, particularly back pain, and shoulder disorders. Osteoarthritis, disc disorders and rheumatoid arthritis induced the longest episodes of absence. Clear hierarchical class differences were found throughout, but the magnitude of the differences varied across the diagnostic causes. The largest class differences in the occurrence were detected in shoulder disorders and back pain. The class differences in length were greatest in rheumatoid arthritis, disc disorders and, among men, also in hip osteoarthritis. CONCLUSIONS: Hierarchical occupational class differences were found across different MSDs, with large differences in back and shoulder disorders. Occupational class and diagnosis should be considered when attempting to reduce sickness absence due to MSDs. PMID- 29382695 TI - Regulation of amyloid-beta dynamics and pathology by the circadian clock. AB - Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer's Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-beta (Abeta) dynamics and pathology, we used a mouse model of beta-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Bmal1 Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Abeta oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral Bmal1 in the brain parenchyma increases expression of Apoe and promotes fibrillar plaque deposition. These results provide evidence that both central circadian rhythms and local clock function influence Abeta dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis. PMID- 29382696 TI - Contextual control of skin immunity and inflammation by Corynebacterium. AB - How defined microbes influence the skin immune system remains poorly understood. Here we demonstrate that Corynebacteria, dominant members of the skin microbiota, promote a dramatic increase in the number and activation of a defined subset of gammadelta T cells. This effect is long-lasting, occurs independently of other microbes, and is, in part, mediated by interleukin (IL)-23. Under steady-state conditions, the impact of Corynebacterium is discrete and noninflammatory. However, when applied to the skin of a host fed a high-fat diet, Corynebacterium accolens alone promotes inflammation in an IL-23-dependent manner. Such effect is highly conserved among species of Corynebacterium and dependent on the expression of a dominant component of the cell envelope, mycolic acid. Our data uncover a mode of communication between the immune system and a dominant genus of the skin microbiota and reveal that the functional impact of canonical skin microbial determinants is contextually controlled by the inflammatory and metabolic state of the host. PMID- 29382697 TI - Metformin attenuates effects of cyclophilin A on macrophages, reduces lipid uptake and secretion of cytokines by repressing decreased AMPK activity. AB - Growing evidence implicates cyclophilin A secreted by vascular wall cells and monocytes as a key mediator in atherosclerosis. Cyclophilin A in addition to its proliferative effects, during hyperglycemic conditions, increases lipid uptake in macrophages by increasing scavenger receptors on the cell's surface. It also promotes macrophage migration across endothelial cells and conversion of macrophages into foam cells. Given the known effects of metformin in reducing vascular complications of diabetes, we investigated the effect of metformin on cyclophilin A action in macrophages. Using an ex vivo model of cultured macrophages isolated from patients with type 2 diabetes with and without coronary artery disease (CAD), we measured the effect of metformin on cyclophilin A expression, lipid accumulation, expression of scavenger receptors, plasma cytokine levels and AMP-activated protein kinase (AMPK) activity in macrophages. In addition, the effects of metformin on migration of monocytes, reactive oxygen species (ROS) formation, lipid uptake in the presence of cyclophilin A inhibitors and comparison with pioglitazone were studied using THP-1 monocytes. Metformin reduced cyclophilin A expression in human monocyte-derived macrophages. Metformin also decreased the effects of cyclophilin A on macrophages such as oxidized low density lipoprotein (oxLDL) uptake, scavenger receptor expression, ROS formation and secretion of inflammatory cytokines in high-glucose conditions. Metformin reversed cyclophilin A-induced decrease in AMPK-1alpha activity in macrophages. These effects of metformin were similar to those of cyclophilin A inhibitors. Metformin can thus function as a suppressor of pro-inflammatory effects of cyclophilin A in high-glucose conditions by attenuating its expression and repressing cyclophilin A-induced decrease in AMPK-1alpha activity in macrophages. PMID- 29382698 TI - Concatenated nicotinic acetylcholine receptors: A gift or a curse? AB - Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are vital for normal mammalian brain function. Cys-loop receptors are pentameric ligand-gated ion channels formed from five identical or homologous subunits oriented around a central ion-conducting pore, which result in homomeric or heteromeric receptors, respectively. Within a given Cys-loop receptor family, many different heteromeric receptors can assemble from a common set of subunits, and understanding the properties of these heteromeric receptors is crucial for the continuing quest to generate novel treatments for human diseases. Yet this complexity also presents a hindrance for studying Cys-loop receptors in heterologous expression systems, where full control of the receptor stoichiometry and assembly is required. Therefore, subunit concatenation technology is commonly used to control receptor assembly. In theory, this methodology should facilitate full control of the stoichiometry. In reality, however, we find that commonly used constructs do not yield the expected receptor stoichiometries. With ternary or more complex receptors, concatenated subunits must assemble uniformly in only one orientation; otherwise, the resulting receptor pool will consist of receptors with mixed stoichiometries. We find that typically used constructs of alpha4beta2 nAChR dimers, tetramers, and pentamers assemble readily in both the clockwise and the counterclockwise orientations. Consequently, we investigate the possibility of successfully directing the receptor assembly process using concatenation. We begin by investigating the three-dimensional structures of the alpha4beta2 nAChR. Based on this, we hypothesize that the minimum linker length required to bridge the C terminus of one subunit to the N terminus of the next is shortest in the counterclockwise orientation. We then successfully express receptors with a uniform stoichiometry by systematically shortening linker lengths, proving the hypothesis correct. Our results will significantly aid future studies of heteromeric Cys-loop receptors and enable clarification of the current contradictions in the literature. PMID- 29382699 TI - Mitotic spindles revisited - new insights from 3D electron microscopy. AB - The mitotic spindle is a complex three-dimensional (3D) apparatus that functions to ensure the faithful segregation of chromosomes during cell division. Our current understanding of spindle architecture is mainly based on a plethora of information derived from light microscopy with rather few insights about spindle ultrastructure obtained from electron microscopy. In this Review, we will provide insights into the history of imaging of mitotic spindles and highlight recent technological advances in electron tomography and data processing, which have delivered detailed 3D reconstructions of mitotic spindles in the early embryo of the nematode Caenorhabditis elegans Tomographic reconstructions provide novel views on spindles and will enable us to revisit and address long-standing questions in the field of mitosis. PMID- 29382700 TI - Tom70 enhances mitochondrial preprotein import efficiency by binding to internal targeting sequences. AB - The biogenesis of mitochondria depends on the import of hundreds of preproteins. N-terminal matrix-targeting signals (MTSs) direct preproteins to the surface receptors Tom20, Tom22, and Tom70. In this study, we show that many preproteins contain additional internal MTS-like signals (iMTS-Ls) in their mature region that share the characteristic properties of presequences. These features allow the in silico prediction of iMTS-Ls. Using Atp1 as model substrate, we show that iMTS-Ls mediate the binding to Tom70 and have the potential to target the protein to mitochondria if they are presented at its N terminus. The import of preproteins with high iMTS-L content is significantly impaired in the absence of Tom70, whereas preproteins with low iMTS-L scores are less dependent on Tom70. We propose a stepping stone model according to which the Tom70-mediated interaction with internal binding sites improves the import competence of preproteins and increases the efficiency of their translocation into the mitochondrial matrix. PMID- 29382701 TI - Factors Associated with False Positive Results on Screening Mammography in a Population of Predominantly Hispanic Women. AB - Background: Potential harms of screening mammography include false positive results, such as recall breast imaging or biopsies.Methods: We recruited women undergoing screening mammography at Columbia University Medical Center in New York, New York. They completed a questionnaire on breast cancer risk factors and permitted access to their medical records. Breast cancer risk status was determined using the Gail model and a family history screener. High risk was defined as a 5-year invasive breast cancer risk of >=1.67% or eligible for BRCA genetic testing. False positive results were defined as recall breast imaging (BIRADS score of 0, 3, 4, or 5) and/or biopsies that did not yield breast cancer.Results: From November 2014 to October 2015, 2,361 women were enrolled and 2,019 were evaluable, of whom 76% were Hispanic and 10% non-Hispanic white. Fewer Hispanic women met high-risk criteria for breast cancer than non-Hispanic whites (18.0% vs. 68.1%), but Hispanics more frequently engaged in annual screening (71.9% vs. 60.8%). Higher breast density (heterogeneously/extremely dense vs. mostly fat/scattered fibroglandular densities) and more frequent screening (annual vs. biennial) were significantly associated with false positive results [odds ratio (OR), 1.64; 95% confidence interval (CI), 1.32-2.04 and OR, 2.18; 95% CI, 1.70-2.80, respectively].Conclusions: We observed that women who screened more frequently or had higher breast density were at greater risk for false positive results. In addition, Hispanic women were screening more frequently despite having a lower risk of breast cancer compared with whites.Impact: Our results highlight the need for risk-stratified screening to potentially minimize the harms of screening mammography. Cancer Epidemiol Biomarkers Prev; 27(4); 446 53. (c)2018 AACR. PMID- 29382702 TI - Genome-Wide Association Studies in Glioma. AB - Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation. Cancer Epidemiol Biomarkers Prev; 27(4); 418-28. (c)2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer." PMID- 29382704 TI - Testicular transcriptional signatures associated with high fertility. AB - Factors of high fertility are poorly described. The majority of transgenic or knockout models with a reproductive phenotype are subfertile or infertile phenotypes. Few genotypes have been linked to improved reproductive performance (0.2%) or increased litter size (1%). In this study, we used a unique mouse model, fertility line FL1, selected for 'high fertility' for more than 170 generations. This strain has almost doubled the number of littermates as well as their total birth weight accompanied by an elevated ovulation rate and increased numbers of corpora lutea compared to a randomly mated and unselected control line (Ctrl). Here, we investigate whether the gonadal tissue of FL1 males are affected by 'co-evolution' after more than 40 years of female-focused selection. Using microarrays, we analysed the testicular transcriptome of the FL1 and Ctrl mice. These data were also compared with previously published female gonadal transcriptional alterations. We detected alterations in testicular gene expression, which are partly associated with female reproductive performance. Thus, female-focused selection for litter size has not only affected the female side, but also has been manifested in transcriptional alterations on the male gonadal organ. This suggests consequences for the entire mouse lines in the long run and emphasizes the perspective of inevitably considering both genders about mechanisms of high fertility. PMID- 29382703 TI - Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future. AB - Breast cancer is the most common cancer among women in the United States, with up to 30% of those diagnosed displaying a family history of breast cancer. To date, 18% of the familial risk of breast cancer can be explained by SNPs. This review summarizes the discovery of risk-associated SNPs using candidate gene and genome wide association studies (GWAS), including discovery and replication in large collaborative efforts such as The Collaborative Oncologic Gene-environment Study and OncoArray. We discuss the evolution of GWAS studies, efforts to discover additional SNPs, and methods for identifying causal variants. We summarize findings associated with overall breast cancer, pathologic subtypes, and mutation carriers (BRCA1, BRCA2, and CHEK2). In addition, we summarize the development of polygenic risk scores (PRS) using the risk-associated SNPs and show how PRS can contribute to estimation of individual risks for developing breast cancer. Cancer Epidemiol Biomarkers Prev; 27(4); 380-94. (c)2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer." PMID- 29382705 TI - Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer. AB - The myotonic dystrophy-related Cdc42-binding kinases MRCKalpha and MRCKbeta contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here, we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphologic changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent antiproliferative effects with greatest activity in hematologic cancer cells. Mass spectrometry identified MRCKalpha S1003 as an autophosphorylation site, enabling development of a phosphorylation sensitive antibody tool to report on MRCKalpha status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKalpha S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.Significance: The development of selective small-molecule inhibitors of the Cdc42-binding MRCK kinases reveals their essential roles in cancer cell viability, migration, and invasive character. Cancer Res; 78(8); 2096-114. (c)2018 AACR. PMID- 29382706 TI - HER2 Overexpression Triggers an IL1alpha Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance. AB - Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1alpha and IL6 that stimulated NFkappaB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1alpha/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1alpha signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1alpha signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040-51. (c)2018 AACR. PMID- 29382707 TI - Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates. AB - AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS 16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS 16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. Cancer Res; 78(8); 2115-26. (c)2018 AACR. PMID- 29382708 TI - Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies. AB - Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied antiproliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum-tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.Significance: By using drug dose modulation or treatment vacations, adaptive therapy strategies control the emergence of tumor drug resistance by spatially suppressing less fit resistant populations in favor of treatment sensitive ones. Cancer Res; 78(8); 2127-39. (c)2018 AACR. PMID- 29382709 TI - Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma. AB - Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. (c)2018 AACR. PMID- 29382710 TI - Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After Olig2 Deletion. AB - NG2 cells are a resident glial progenitor cell population that is uniformly distributed throughout the developing and mature mammalian CNS. Those in the postnatal CNS generate exclusively myelinating and non-myelinating oligodendrocytes and are thus equated with oligodendrocyte precursor cells. Prenatally, NG2 cells in the ventral gray matter of the forebrain generate protoplasmic astrocytes as well as oligodendrocytes. The fate conversion from NG2 cells into protoplasmic astrocytes is dependent on downregulation of the key oligodendrocyte transcription factor Olig2. We showed previously that constitutive deletion of Olig2 in NG2 cells converts NG2 cells in the neocortex into protoplasmic astrocytes at the expense of oligodendrocytes. In this study, we show that postnatal deletion of Olig2 caused NG2 cells in the neocortex but not in other gray matter regions to become protoplasmic astrocytes. However, NG2 cells in the neocortex became more resistant to astrocyte fate switch over the first 3 postnatal weeks. Fewer NG2 cells differentiated into astrocytes and did so with longer latency after Olig2 deletion at postnatal day 18 (P18) compared with deletion at P2. The high-mobility group transcription factor Sox10 was not downregulated for at least 1 month after Olig2 deletion at P18 despite an early transient upregulation of the astrocyte transcription factor NFIA. Furthermore, inhibiting cell proliferation in slice culture reduced astrocyte differentiation from Olig2-deleted perinatal NG2 cells, suggesting that cell division might facilitate nuclear reorganization needed for astrocyte transformation.SIGNIFICANCE STATEMENT NG2 cells are glial progenitor cells that retain a certain degree of lineage plasticity. In the normal postnatal neocortex, they generate mostly oligodendrocyte lineage cells. When the oligodendrocyte transcription factor Olig2 is deleted in NG2 cells in the neocortex, they switch their fate to protoplasmic astrocytes. However, the efficiency of the fate switch decreases with age over the first 3 postnatal weeks and is reduced when cell proliferation is inhibited. As the neocortex matures, sustained expression of the oligodendrocyte lineage-specific key transcription factor Sox10 becomes less dependent on Olig2. Together, our findings suggest a gradual stabilization of the oligodendrocyte lineage genes and loss of lineage plasticity during the first 3 weeks after birth, possibly due to nuclear reorganization. PMID- 29382711 TI - Differential Sampling of Visual Space in Ventral and Dorsal Early Visual Cortex. AB - A fundamental feature of cortical visual processing is the separation of visual processing for the upper and lower visual fields. In early visual cortex (EVC), the upper visual field is processed ventrally, with the lower visual field processed dorsally. This distinction persists into several category-selective regions of occipitotemporal cortex, with ventral and lateral scene-, face-, and object-selective regions biased for the upper and lower visual fields, respectively. Here, using an elliptical population receptive field (pRF) model, we systematically tested the sampling of visual space within ventral and dorsal divisions of human EVC in both male and female participants. We found that (1) pRFs tend to be elliptical and oriented toward the fovea with distinct angular distributions for ventral and dorsal divisions of EVC, potentially reflecting a radial bias; and (2) pRFs in ventral areas were larger (~1.5*) and more elliptical (~1.2*) than those in dorsal areas. These differences potentially reflect a tendency for receptive fields in ventral temporal cortex to overlap the fovea with less emphasis on precise localization and isotropic representation of space compared with dorsal areas. Collectively, these findings suggest that ventral and dorsal divisions of EVC sample visual space differently, likely contributing to and/or stemming from the functional differentiation of visual processing observed in higher-level regions of the ventral and dorsal cortical visual pathways.SIGNIFICANCE STATEMENT The processing of visual information from the upper and lower visual fields is separated in visual cortex. Although ventral and dorsal divisions of early visual cortex (EVC) are commonly assumed to sample visual space equivalently, we demonstrate systematic differences using an elliptical population receptive field (pRF) model. Specifically, we demonstrate that (1) ventral and dorsal divisions of EVC exhibit diverging distributions of pRF angle, which are biased toward the fovea; and (2) ventral pRFs exhibit higher aspect ratios and cover larger areas than dorsal pRFs. These results suggest that ventral and dorsal divisions of EVC sample visual space differently and that such differential sampling likely contributes to different functional roles attributed to the ventral and dorsal pathways, such as object recognition and visually guided attention, respectively. PMID- 29382712 TI - Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression. AB - Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress. PMID- 29382713 TI - Structural determinants controlling 14-3-3 recruitment to the endocytic adaptor Numb and dissociation of the Numb.alpha-adaptin complex. AB - Traffic of cargo across membranes helps establish, maintain, and reorganize distinct cellular compartments and is fundamental to many metabolic processes. The cargo-selective endocytic adaptor Numb participates in clathrin-dependent endocytosis by attaching cargoes to the clathrin adaptor alpha-adaptin. The phosphorylation of Numb at Ser265 and Ser284 recruits the regulatory protein 14-3 3, accompanied by the dissociation of Numb from alpha-adaptin and Numb's translocation from the cortical membrane to the cytosol. However, the molecular mechanisms underlying the Numb-alpha-adaptin interaction and its regulation by Numb phosphorylation and 14-3-3 recruitment remain poorly understood. Here, biochemical and structural analyses of the Numb.14-3-3 complex revealed that Numb phosphorylation at both Ser265 and Ser284 is required for Numb's efficient interaction with 14-3-3. We also discovered that an RQFRF motif surrounding Ser265 in Numb functions together with the canonical C-terminal DPF motif, required for Numb's interaction with alpha-adaptin, to form a stable complex with alpha-adaptin. Of note, we provide evidence that the phosphorylation-induced binding of 14-3-3 to Numb directly competes with the binding of alpha-adaptin to Numb. Our findings suggest a potential mechanism governing the dynamic assembly of Numb with alpha-adaptin or 14-3-3. This dual-site recognition of Numb by alpha adaptin may have implications for other alpha-adaptin targets. We propose that the newly identified alpha-adaptin-binding site surrounding Ser265 in Numb functions as a triggering mechanism for the dynamic dissociation of the Numb.alpha-adaptin complex. PMID- 29382714 TI - An N-terminal motif unique to primate tau enables differential protein-protein interactions. AB - Compared with other mammalian species, humans are particularly susceptible to tau mediated neurodegenerative disorders. Differential interactions of the tau protein with other proteins are critical for mediating tau's physiological functions as well as tau-associated pathological processes. Primate tau harbors an 11-amino acid-long motif in its N-terminal region (residues 18-28), which is not present in non-primate species and whose function is unknown. Here, we used deletion mutagenesis to remove this sequence region from the longest human tau isoform, followed by glutathione S-transferase (GST) pulldown assays paired with isobaric tags for relative and absolute quantitation (iTRAQ) multiplex labeling, a quantitative method to measure protein abundance by mass spectrometry. Using this method, we found that the primate-specific N-terminal tau motif differentially mediates interactions with neuronal proteins. Among these binding partners are proteins involved in synaptic transmission (synapsin-1 and synaptotagmin-1) and signaling proteins of the 14-3-3 family. Furthermore, we identified an interaction of tau with a member of the annexin family (annexin A5) that was linked to the 11-residue motif. These results suggest that primate Tau has evolved specific residues that differentially regulate protein-protein interactions compared with tau proteins from other non-primate mammalian species. Our findings provide in vitro insights into tau's interactions with other proteins that may be relevant to human disease. PMID- 29382715 TI - Stat3 and CCAAT enhancer-binding protein beta (C/ebpbeta) activate Fanconi C gene transcription during emergency granulopoiesis. AB - Interferon consensus sequence-binding protein (Icsbp) is required for terminating emergency granulopoiesis, an episodic event responsible for granulocyte production in response to infections and a key component of the innate immune response. Icsbp inhibits the expression of Stat3 and C/ebpbeta, transcription factors essential for initiating and sustaining granulopoiesis, and activates transcription of Fanconi C (FANCC), a DNA repair protein. In prior studies, we noted accelerated bone marrow failure in Fancc-/- mice undergoing multiple episodes of emergency granulopoiesis, associated with apoptosis of bone marrow cells with unrepaired DNA damage. Additionally, we found increased expression of Fanconi C and F proteins during emergency granulopoiesis. These findings suggest that Icsbp protects the bone marrow from DNA damage by increasing activity of the Fanconi DNA repair pathway, but the mechanisms for FANCC activation during initiation of emergency granulopoiesis are unclear. In this study, we observed that Stat3 and C/ebpbeta activate FANCC transcription and contribute to DNA repair. Our findings indicate that FancC expression is increased during Stat3- and C/ebpbeta-induced initiation of emergency granulopoiesis by these transcription factors and is maintained through termination by Icsbp. Our work reveals that Stat3- and C/ebpbeta-mediated FancC expression is a critical component for initiating and sustaining key innate immune responses. PMID- 29382716 TI - Structure-function analyses of a PL24 family ulvan lyase reveal key features and suggest its catalytic mechanism. AB - Ulvan is a major cell wall component of green algae of the genus Ulva, and some marine bacteria encode enzymes that can degrade this polysaccharide. The first ulvan-degrading lyases have been recently characterized, and several putative ulvan lyases have been recombinantly expressed, confirmed as ulvan lyases, and partially characterized. Two families of ulvan-degrading lyases, PL24 and PL25, have recently been established. The PL24 lyase LOR_107 from the bacterial Alteromonadales sp. strain LOR degrades ulvan endolytically, cleaving the bond at the C4 of a glucuronic acid. However, the mechanism and LOR_107 structural features involved are unknown. We present here the crystal structure of LOR_107, representing the first PL24 family structure. We found that LOR_107 adopts a seven-bladed beta-propeller fold with a deep canyon on one side of the protein. Comparative sequence analysis revealed a cluster of conserved residues within this canyon, and site-directed mutagenesis disclosed several residues essential for catalysis. We also found that LOR_107 uses the His/Tyr catalytic mechanism, common to several PL families. We captured a tetrasaccharide substrate in the structures of two inactive mutants, which indicated a two-step binding event, with the first substrate interaction near the top of the canyon coordinated by Arg320, followed by sliding of the substrate into the canyon toward the active site residues. Surprisingly, the LOR_107 structure was very similar to that of the PL25 family PLSV_3936, despite only ~14% sequence identity between the two enzymes. On the basis of our structural and mutational analyses, we propose a catalytic mechanism for LOR_107 that differs from the typical His/Tyr mechanism. PMID- 29382717 TI - Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation. AB - Limb-girdle muscular dystrophy type 2a arises from mutations in the Ca2+ activated intracellular cysteine protease calpain-3. This calpain isoform is abundant in skeletal muscle and differs from the main isoforms, calpain-1 and -2, in being a homodimer and having two short insertion sequences. The first of these, IS1, interrupts the protease core and must be cleaved for activation and substrate binding. Here, to learn how calpain-3 can be regulated and inhibited, we determined the structures of the calpain-3 protease core with IS1 present or proteolytically excised. To prevent intramolecular IS1 autoproteolysis, we converted the active-site Cys to Ala. Small-angle X-ray scattering (SAXS) analysis of the C129A mutant suggested that IS1 is disordered and mobile enough to occupy several locations. Surprisingly, this was also true for the apo version of this mutant. We therefore concluded that IS1 might have a binding partner in the sarcomere and is unstructured in its absence. After autoproteolytic IS1 removal from the active Cys129 calpain-3 protease core, we could solve its crystal structures with and without the cysteine protease inhibitors E-64 and leupeptin covalently bound to the active-site cysteine. In each structure, the active state of the protease core was assembled by the cooperative binding of two Ca2+ ions to the equivalent sites used in calpain-1 and -2. These structures of the calpain-3 active site with residual IS1 and with bound E-64 and leupeptin may help guide the design of calpain-3-specific inhibitors. PMID- 29382718 TI - Endoplasmic reticulum-retained podocin mutants are massively degraded by the proteasome. AB - Podocin is a key component of the slit diaphragm in the glomerular filtration barrier, and mutations in the podocin-encoding gene NPHS2 are a common cause of hereditary steroid-resistant nephrotic syndrome. A mutant allele encoding podocin with a p.R138Q amino acid substitution is the most frequent pathogenic variant in European and North American children, and the corresponding mutant protein is poorly expressed and retained in the endoplasmic reticulum both in vitro and in vivo To better understand the defective trafficking and degradation of this mutant, we generated human podocyte cell lines stably expressing podocinwt or podocinR138Q Although it has been proposed that podocin has a hairpin topology, we present evidence for podocinR138QN-glycosylation, suggesting that most of the protein has a transmembrane topology. We find that N-glycosylated podocinR138Q has a longer half-life than non-glycosylated podocinR138Q and that the latter is far more rapidly degraded than podocinwt Consistent with its rapid degradation, podocinR138Q is exclusively degraded by the proteasome, whereas podocinwt is degraded by both the proteasomal and the lysosomal proteolytic machineries. In addition, we demonstrate an enhanced interaction of podocinR138Q with calnexin as the mechanism of endoplasmic reticulum retention. Calnexin knockdown enriches the podocinR138Q non-glycosylated fraction, whereas preventing exit from the calnexin cycle increases the glycosylated fraction. Altogether, we propose a model in which hairpin podocinR138Q is rapidly degraded by the proteasome, whereas transmembrane podocinR138Q degradation is delayed due to entry into the calnexin cycle. PMID- 29382719 TI - Tyrosine phosphorylation switching of a G protein. AB - Heterotrimeric G protein complexes are molecular switches relaying extracellular signals sensed by G protein-coupled receptors (GPCRs) to downstream targets in the cytoplasm, which effect cellular responses. In the plant heterotrimeric GTPase cycle, GTP hydrolysis, rather than nucleotide exchange, is the rate limiting reaction and is accelerated by a receptor-like regulator of G signaling (RGS) protein. We hypothesized that posttranslational modification of the Galpha subunit in the G protein complex regulates the RGS-dependent GTPase cycle. Our structural analyses identified an invariant phosphorylated tyrosine residue (Tyr166 in the Arabidopsis Galpha subunit AtGPA1) located in the intramolecular domain interface where nucleotide binding and hydrolysis occur. We also identified a receptor-like kinase that phosphorylates AtGPA1 in a Tyr166 dependent manner. Discrete molecular dynamics simulations predicted that phosphorylated Tyr166 forms a salt bridge in this interface and potentially affects the RGS protein-accelerated GTPase cycle. Using a Tyr166 phosphomimetic substitution, we found that the cognate RGS protein binds more tightly to the GDP bound Galpha substrate, consequently reducing its ability to accelerate GTPase activity. In conclusion, we propose that phosphorylation of Tyr166 in AtGPA1 changes the binding pattern with AtRGS1 and thereby attenuates the steady-state rate of the GTPase cycle. We coin this newly identified mechanism "substrate phosphoswitching." PMID- 29382720 TI - The protonation states of GTP and GppNHp in Ras proteins. AB - The small GTPase Ras transmits signals in a variety of cellular signaling pathways, most prominently in cell proliferation. GTP hydrolysis in the active center of Ras acts as a prototype for many GTPases and is the key to the understanding of several diseases, including cancer. Therefore, Ras has been the focus of intense research over the last decades. A recent neutron diffraction crystal structure of Ras indicated a protonated gamma-guanylyl imidodiphosphate (gamma-GppNHp) group, which has put the protonation state of GTP in question. A possible protonation of GTP was not considered in previously published mechanistic studies. To determine the detailed prehydrolysis state of Ras, we calculated infrared and NMR spectra from quantum mechanics/molecular mechanics (QM/MM) simulations and compared them with those from previous studies. Furthermore, we measured infrared spectra of GTP and several GTP analogs bound to lipidated Ras on a membrane system under near-native conditions. Our findings unify results from previous studies and indicate a structural model confirming the hypothesis that gamma-GTP is fully deprotonated in the prehydrolysis state of Ras. PMID- 29382721 TI - Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog. AB - Mechanistic details of intramembrane aspartyl protease (IAP) chemistry, which is central to many biological and pathogenic processes, remain largely obscure. Here, we investigated the in vitro kinetics of a microbial intramembrane aspartyl protease (mIAP) fortuitously acting on the renin substrate angiotensinogen and the C-terminal transmembrane segment of amyloid precursor protein (C100), which is cleaved by the presenilin subunit of gamma-secretase, an Alzheimer disease (AD)-associated IAP. mIAP variants with substitutions in active-site and putative substrate-gating residues generally exhibit impaired, but not abolished, activity toward angiotensinogen and retain the predominant cleavage site (His-Thr). The aromatic ring, but not the hydroxyl substituent, within Tyr of the catalytic Tyr Asp (YD) motif plays a catalytic role, and the hydrolysis reaction incorporates bulk water as in soluble aspartyl proteases. mIAP hydrolyzes the transmembrane region of C100 at two major presenilin cleavage sites, one corresponding to the AD-associated Abeta42 peptide (Ala-Thr) and the other to the non-pathogenic Abeta48 (Thr-Leu). For the former site, we observed more favorable kinetics in lipid bilayer-mimicking bicelles than in detergent solution, indicating that substrate-lipid and substrate-enzyme interactions both contribute to catalytic rates. High-resolution MS analyses across four substrates support a preference for threonine at the scissile bond. However, results from threonine-scanning mutagenesis of angiotensinogen demonstrate a competing positional preference for cleavage. Our results indicate that IAP cleavage is controlled by both positional and chemical factors, opening up new avenues for selective IAP inhibition for therapeutic interventions. PMID- 29382722 TI - The scaffolding protein JADE1 physically links the acetyltransferase subunit HBO1 with its histone H3-H4 substrate. AB - The human enzyme histone acetyltransferase binding to ORC1 (HBO1) regulates DNA replication, cell proliferation, and development. HBO1 is part of a multiprotein histone acetyltransferase (HAT) complex that also contains inhibitor of growth family member (ING) 4/5, MYST/Esa1-associated factor (MEAF) 6, and the scaffolding proteins Jade family PHD finger (JADE) 1/2/3 or bromodomain and PHD finger-containing protein (BRPF) 2/3 to acetylate histone H4 H4K5/8/12 or H3K14, respectively. Within this four-protein complex, JADE1 determines histone H4 substrate specificity of the HBO1-HAT complex. However, the mechanism by which JADE1 controls the H4-specific acetyltransferase activity of HBO1 is unknown. Here we used recombinant proteins in vitro to dissect the specific regions and activities of HBO1 and JADE1 that mediate histone H3-H4 acetylation via the HBO1 HAT domain. We found that JADE1 increases the catalytic efficiency of HBO1 acetylation of an H3-H4 substrate by about 5-fold through an N-terminal, 21 residue HBO1- and histone-binding domain and a nearby second histone core-binding domain. We also demonstrate that HBO1 contains an N-terminal histone-binding domain (HBD) that makes additional contacts with H3-H4 independent of JADE1 interactions with histones and that the HBO1 HBD does not significantly contribute to HBO1's overall HAT activity. Experiments with JADE1 deletions in vivo recapitulated these in vitro interactions and their roles in HBO1 histone acetylation activity. Together, these results indicate that the N-terminal region of JADE1 functions as a platform that brings together the catalytic HBO1 subunit with its cognate H3-H4 substrate for histone acetylation. PMID- 29382723 TI - Dimerization of sortilin regulates its trafficking to extracellular vesicles. AB - Extracellular vesicles (EVs) play a critical role in intercellular communication by transferring microRNAs, lipids, and proteins to neighboring cells. Sortilin, a sorting receptor that directs target proteins to the secretory or endocytic compartments of cells, is found in both EVs and cells. In many human diseases, including cancer and cardiovascular disorders, sortilin expression levels are atypically high. To elucidate the relationship between cardiovascular disease, particularly vascular calcification, and sortilin expression levels, we explored the trafficking of sortilin in both the intracellular and extracellular milieu. We previously demonstrated that sortilin promotes vascular calcification via its trafficking of tissue-nonspecific alkaline phosphatase to EVs. Although recent reports have noted that sortilin is regulated by multiple post-translational modifications, the precise mechanisms of sortilin trafficking still need to be determined. Here, we show that sortilin forms homodimers with an intermolecular disulfide bond at the cysteine 783 (Cys783) residue, and because Cys783 can be palmitoylated, it could be shared via palmitoylation and an intermolecular disulfide bond. Formation of this intermolecular disulfide bond leads to trafficking of sortilin to EVs by preventing palmitoylation, which further promotes sortilin trafficking to the Golgi apparatus. Moreover, we found that sortilin-derived propeptide decreased sortilin homodimers within EVs. In conclusion, sortilin is transported to EVs via the formation of homodimers with an intermolecular disulfide bond, which is endogenously regulated by its own propeptide. Therefore, we propose that inhibiting dimerization of sortilin acts as a new therapeutic strategy for the treatment of EV-associated diseases, including vascular calcification and cancer. PMID- 29382724 TI - Spontaneous self-segregation of Rad51 and Dmc1 DNA recombinases within mixed recombinase filaments. AB - During meiosis, the two DNA recombinases Rad51 and Dmc1 form specialized presynaptic filaments that are adapted for performing recombination between homologous chromosomes. There is currently a limited understanding of how these two recombinases are organized within the meiotic presynaptic filament. Here, we used single molecule imaging to examine the properties of presynaptic complexes composed of both Rad51 and Dmc1. We demonstrate that Rad51 and Dmc1 have an intrinsic ability to self-segregate, even in the absence of any other recombination accessory proteins. Moreover, we found that the presence of Dmc1 stabilizes the adjacent Rad51 filaments, suggesting that cross-talk between these two recombinases may affect their biochemical properties. Based upon these findings, we describe a model for the organization of Rad51 and Dmc1 within the meiotic presynaptic complex, which is also consistent with in vivo observations, genetic findings, and biochemical expectations. This model argues against the existence of extensively intermixed filaments, and we propose that Rad51 and Dmc1 have intrinsic capacities to form spatially distinct filaments, suggesting that additional recombination cofactors are not required to segregate the Rad51 and Dmc1 filaments. PMID- 29382725 TI - The small heat shock protein Hsp27 binds alpha-synuclein fibrils, preventing elongation and cytotoxicity. AB - Proteostasis, or protein homeostasis, encompasses the maintenance of the conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are key elements of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intracellular and extracellular deposits. Deposits containing fibrillar forms of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies. Here we show that the sHsp Hsp27 (HSPB1) binds to alpha-syn fibrils, inhibiting fibril growth by preventing elongation. Using total internal reflection fluorescence (TIRF)-based imaging methods, we show that Hsp27 binds along the surface of alpha syn fibrils, decreasing their hydrophobicity. Binding of Hsp27 also inhibits cytotoxicity of alpha-syn fibrils. Our results demonstrate that the ability of sHsps, such as Hsp27, to bind fibrils represents an important mechanism through which they may mitigate cellular toxicity associated with aberrant protein aggregation. Fibril binding may represent a generic mechanism by which chaperone active sHsps interact with aggregation-prone proteins, highlighting the potential to target sHsp activity to prevent or disrupt the onset and progression of alpha syn aggregation associated with alpha-synucleinopathies. PMID- 29382726 TI - OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR. AB - Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which DEPTOR stability is regulated are still elusive. Here, we report that OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR in a deubiquitination assay. We found that OTUB1 directly interacted with DEPTOR via its N-terminal domain, deubiquitinated DEPTOR, and thereby stabilized DEPTOR in a Cys-91-independent but Asp-88 dependent manner, suggesting that OTUB1 targets DEPTOR for deubiquitination via a deubiquitinase activity-independent non-canonical mechanism. The interaction between OTUB1 and DEPTOR was enhanced when the cells were treated with amino acids. Moreover, OTUB1 suppressed amino acid-induced activation of mTORC1 in a DEPTOR-dependent manner and thereby ultimately controlled cellular autophagy, cell proliferation, and size. Our findings reveal a mechanism that stabilizes the mTORC1 inhibitor DEPTOR via OTUB1's deubiquitinase activity. Our insights may inform research into various mTOR activity-related diseases, such as cancer, and may contribute to the identification of new diagnostic markers and therapeutic strategies for cancer treatments. PMID- 29382727 TI - Membrane-embedded substrate recognition by cytochrome P450 3A4. AB - Cytochrome P450 3A4 (CYP3A4) is the dominant xenobiotic-metabolizing enzyme in the liver and intestine and is involved in the disposition of more than 50% of drugs. Because of its ability to bind multiple substrates, its reaction kinetics are complex, and its association with the microsomal membrane confounds our understanding of how this enzyme recognizes and recruits diverse substrates. Testosterone (TST) hydroxylation is the prototypical CYP3A4 reaction, displaying positive homotropic cooperativity with three binding sites. Here, exploiting the capability of accelerated molecular dynamics (aMD) to sample events in the millisecond regime, I performed >25-MUs aMD simulations in the presence of three TST molecules. These simulations identified high-occupancy surface-binding sites as well as a pathway for TST ingress into the CYP3A4 active site originating in the membrane. Adaptive biasing force analysis of the latter pathway revealed a metastable intermediate that could constitute a third binding site at high TST concentrations. Prompted by the observation that interactions between TST and the G'-helix mobilize the ligand into the active site, a free-energy analysis of TST distribution in the membrane was conducted and revealed that the depth of the G' helix is optimal for extracting TST. In summary, these simulations confirm separate, but adjacent substrate-binding sites within the enzyme and the existence of an auxiliary TST-binding site. The broader impact of these simulations is that they support a mechanism in which cytochromes P450 directly recruit membrane-solubilized substrates. PMID- 29382728 TI - The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. AB - p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53 like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential. PMID- 29382729 TI - Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges. AB - Increasing incidences of multidrug resistance in pathogenic bacteria threaten our ability to treat and manage bacterial infection. The development and FDA approval of novel antibiotics have slowed over the past decade; therefore, the adoption and improvement of alternative therapeutic strategies are critical for addressing the threat posed by multidrug-resistant bacteria. Host-directed therapies utilize small-molecule drugs and proteins to alter the host response to pathogen infection. Here, we highlight strategies for modulating the host inflammatory response to enhance bacterial clearance, small-molecule potentiation of innate immunity, and targeting of host factors that are exploited by pathogen virulence factors. Application of state-of-the-art "omic" technologies, including proteomics, transcriptomics, and image-omics (image-based high-throughput phenotypic screening), combined with powerful bioinformatics tools will enable the modeling of key signaling pathways in the host-pathogen interplay and aid in the identification of host proteins for therapeutic targeting and the discovery of host-directed small molecules that will regulate bacterial infection. We conclude with an outlook on research needed to overcome the challenges associated with transitioning host-directed therapies into a clinical setting. PMID- 29382730 TI - Translation Stress Positively Regulates MscL-Dependent Excretion of Cytoplasmic Proteins. AB - The apparent mislocalization or excretion of cytoplasmic proteins is a commonly observed phenomenon in both bacteria and eukaryotes. However, reports on the mechanistic basis and the cellular function of this so-called "nonclassical protein secretion" are limited. Here we report that protein overexpression in recombinant cells and antibiotic-induced translation stress in wild-type Escherichia coli cells both lead to excretion of cytoplasmic protein (ECP). Condition-specific metabolomic and proteomic analyses, combined with genetic knockouts, indicate a role for both the large mechanosensitive channel (MscL) and the alternative ribosome rescue factor A (ArfA) in ECP. Collectively, the findings indicate that MscL-dependent protein excretion is positively regulated in response to both osmotic stress and arfA-mediated translational stress.IMPORTANCE Protein translocation is an essential feature of cellular organisms. Bacteria, like all single-cell organisms, interact with their environment by translocation of proteins across their cell membranes via dedicated secretion pathways. Proteins destined for secretion are directed toward the secretion pathways by the presence of specific signal peptides. This study demonstrates that under conditions of both osmotic stress and translation stress, E. coli cells undergo an excretion phenomenon whereby signal peptide-less proteins are translocated across both the inner and outer cell membranes into the extracellular environment. Confirming the presence of alternative translocation/excretion pathways and understanding their function and regulation are thus important for fundamental microbiology and biotechnology. PMID- 29382731 TI - Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to Invasive Chlamydia trachomatis Biovars. AB - Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes blinding trachoma and sexually transmitted disease. C. trachomatis isolates are classified into 2 biovars-lymphogranuloma venereum (LGV) and trachoma-which are distinguished biologically by their natural host cell infection tropism. LGV biovars infect macrophages and are invasive, whereas trachoma biovars infect oculo-urogenital epithelial cells and are noninvasive. The C. trachomatis plasmid is an important virulence factor in the pathogenesis of these infections. Central to its pathogenic role is the transcriptional regulatory function of the plasmid protein Pgp4, which regulates the expression of plasmid and chromosomal virulence genes. As many gene regulatory functions are post-transcriptional, we employed a comparative proteomic study of cells infected with plasmid-cured C. trachomatis serovars A and D (trachoma biovar), a L2 serovar (LGV biovar), and the L2 serovar transformed with a plasmid containing a nonsense mutation in pgp4 to more completely elucidate the effects of the plasmid on chlamydial infection biology. Our results show that the Pgp4-dependent elevations in the levels of Pgp3 and a conserved core set of chromosomally encoded proteins are remarkably similar for serovars within both C. trachomatis biovars. Conversely, we found a plasmid dependent, Pgp4-independent, negative regulation in the expression of the chlamydial protease-like activity factor (CPAF) for the L2 serovar but not the A and D serovars. The molecular mechanism of plasmid-dependent negative regulation of CPAF expression in the LGV serovar is not understood but is likely important to understanding its macrophage infection tropism and invasive infection nature.IMPORTANCE The Chlamydia trachomatis plasmid is an important virulence factor in the pathogenesis of chlamydial infection. It is known that plasmid protein 4 (Pgp4) functions in the transcriptional regulation of the plasmid virulence protein 3 (Pgp3) and multiple chromosomal loci of unknown function. Since many gene regulatory functions can be post-transcriptional, we undertook a comparative proteomic analysis to better understand the plasmid's role in chlamydial and host protein expression. We report that Pgp4 is a potent and specific master positive regulator of a common core of plasmid and chromosomal virulence genes shared by multiple C. trachomatis serovars. Notably, we show that the plasmid is a negative regulator of the expression of the chlamydial virulence factor CPAF. The plasmid regulation of CPAF is independent of Pgp4 and restricted to a C. trachomatis macrophage-tropic strain. These findings are important because they define a previously unknown role for the plasmid in the pathophysiology of invasive chlamydial infection. PMID- 29382732 TI - QStatin, a Selective Inhibitor of Quorum Sensing in Vibrio Species. AB - Pathogenic Vibrio species cause diseases in diverse marine animals reared in aquaculture. Since their pathogenesis, persistence, and survival in marine environments are regulated by quorum sensing (QS), QS interference has attracted attention as a means to control these bacteria in aquatic settings. A few QS inhibitors of Vibrio species have been reported, but detailed molecular mechanisms are lacking. Here, we identified a novel, potent, and selective Vibrio QS inhibitor, named QStatin [1-(5-bromothiophene-2-sulfonyl)-1H-pyrazole], which affects Vibrio harveyi LuxR homologues, the well-conserved master transcriptional regulators for QS in Vibrio species. Crystallographic and biochemical analyses showed that QStatin binds tightly to a putative ligand-binding pocket in SmcR, the LuxR homologue in V. vulnificus, and changes the flexibility of the protein, thereby altering its transcription regulatory activity. Transcriptome analysis revealed that QStatin results in SmcR dysfunction, affecting the expression of SmcR regulon required for virulence, motility/chemotaxis, and biofilm dynamics. Notably, QStatin attenuated representative QS-regulated phenotypes in various Vibrio species, including virulence against the brine shrimp (Artemia franciscana). Together, these results provide molecular insights into the mechanism of action of an effective, sustainable QS inhibitor that is less susceptible to resistance than other antimicrobial agents and useful in controlling the virulence of Vibrio species in aquacultures.IMPORTANCE Yields of aquaculture, such as penaeid shrimp hatcheries, are greatly affected by vibriosis, a disease caused by pathogenic Vibrio infections. Since bacterial cell to-cell communication, known as quorum sensing (QS), regulates pathogenesis of Vibrio species in marine environments, QS inhibitors have attracted attention as alternatives to conventional antibiotics in aquatic settings. Here, we used target-based high-throughput screening to identify QStatin, a potent and selective inhibitor of V. harveyi LuxR homologues, which are well-conserved master QS regulators in Vibrio species. Structural and biochemical analyses revealed that QStatin binds tightly to a putative ligand-binding pocket on SmcR, the LuxR homologue in V. vulnificus, and affects expression of QS-regulated genes. Remarkably, QStatin attenuated diverse QS-regulated phenotypes in various Vibrio species, including pathogenesis against brine shrimp, with no impact on bacterial viability. Taken together, the results suggest that QStatin may be a sustainable antivibriosis agent useful in aquacultures. PMID- 29382733 TI - Virulence Role of the GlcNAc Side Chain of the Lancefield Cell Wall Carbohydrate Antigen in Non-M1-Serotype Group A Streptococcus. AB - Classification of streptococci is based upon expression of unique cell wall carbohydrate antigens. All serotypes of group A Streptococcus (GAS; Streptococcus pyogenes), a leading cause of infection-related mortality worldwide, express the group A carbohydrate (GAC). GAC, the classical Lancefield antigen, is comprised of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc) side chains. The immunodominant GlcNAc epitope of GAC is the basis of all rapid diagnostic testing for GAS infection. We previously identified the 12-gene GAC biosynthesis gene cluster and determined that the glycosyltransferase GacI was required for addition of the GlcNAc side chain to the polyrhamnose core. Loss of the GAC GlcNAc epitope in serotype M1 GAS resulted in attenuated virulence in two animal infection models and increased GAS sensitivity to killing by whole human blood, serum, neutrophils, and antimicrobial peptides. Here, we report that the GAC biosynthesis gene cluster is ubiquitous among 520 GAS isolates from global sources, representing 105 GAS emm serotypes. Isogenic DeltagacI mutants were constructed in M2, M3, M4, M28, and M89 backgrounds and displayed an array of phenotypes in susceptibility to killing by whole human blood, baby rabbit serum, human platelet releasate, human neutrophils, and antimicrobial peptide LL-37. The contribution of the GlcNAc side chain to GAS survival in vivo also varied by strain, demonstrating that it is not a prerequisite for virulence in the murine infection model. Thus, the relative contribution of GAC to virulence in non-M1 serotypes appears to depend on the quorum of other virulence factors that each strain possesses.IMPORTANCE The Lancefield group A carbohydrate (GAC) is the species-defining antigen for group A Streptococcus (GAS), comprising ~50% of the cell wall of this major human pathogen. We previously showed that the GlcNAc side chain of GAC contributes to the innate immune resistance and animal virulence phenotypes of the globally disseminated strain of serotype M1 GAS. Here, we use isogenic mutagenesis to examine the role of GAC GlcNAc in five additional medically relevant GAS serotypes. Overall, the GlcNAc side chain of GAC contributes to the innate immune resistance of GAS, but the relative contribution varies among individual strains. Moreover, the GAC GlcNAc side chain is not a universal prerequisite for GAS virulence in the animal model. PMID- 29382734 TI - Conditional Protein Splicing Switch in Hyperthermophiles through an Intein-Extein Partnership. AB - Inteins are intervening proteins that undergo an autocatalytic splicing reaction that ligates flanking host protein sequences termed exteins. Some intein containing proteins have evolved to couple splicing to environmental signals; this represents a new form of posttranslational regulation. Of particular interest is RadA from the archaeon Pyrococcus horikoshii, for which long-range intein-extein interactions block splicing, requiring temperature and single stranded DNA (ssDNA) substrate to splice rapidly and accurately. Here, we report that splicing of the intein-containing RadA from another archaeon, Thermococcus sibericus, is activated by significantly lower temperatures than is P. horikoshii RadA, consistent with differences in their growth environments. Investigation into variations between T. sibericus and P. horikoshii RadA inteins led to the discovery that a nonconserved region (NCR) of the intein, a flexible loop where a homing endonuclease previously resided, is critical to splicing. Deletion of the NCR leads to a substantial loss in the rate and accuracy of P. horikoshii RadA splicing only within native exteins. The influence of the NCR deletion can be largely overcome by ssDNA, demonstrating that the splicing-competent conformation can be achieved. We present a model whereby the NCR is a flexible hinge which acts as a switch by controlling distant intein-extein interactions that inhibit active site assembly. These results speak to the repurposing of the vestigial endonuclease loop to control an intein-extein partnership, which ultimately allows exquisite adaptation of protein splicing upon changes in the environment.IMPORTANCE Inteins are mobile genetic elements that interrupt coding sequences (exteins) and are removed by protein splicing. They are abundant elements in microbes, and recent work has demonstrated that protein splicing can be controlled by environmental cues, including the substrate of the intein containing protein. Here, we describe an intein-extein collaboration that controls temperature-induced splicing of RadA from two archaea and how variation in this intein-extein partnership results in fine-tuning of splicing to closely match the environment. Specifically, we found that a small sequence difference between the two inteins, a flexible loop that likely once housed a homing endonuclease used for intein mobility, acts as a switch to control intein-extein interactions that block splicing. Our results argue strongly that some inteins have evolved away from a purely parasitic lifestyle to control the activity of host proteins, representing a new form of posttranslational regulation that is potentially widespread in the microbial world. PMID- 29382735 TI - Mucolipin-2 Cation Channel Increases Trafficking Efficiency of Endocytosed Viruses. AB - Receptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells. The stages of entry are well described for certain viruses, but the host factors that mediate each step are less well characterized. We previously identified endosomal cation channel mucolipin-2 (MCOLN2) as a host factor that promotes viral infection. Here, we assign a role for MCOLN2 in modulating viral entry. We show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require transport to late endosomes for infection, including influenza A virus, yellow fever virus, and Zika virus. We further identify a rare allelic variant of human MCOLN2 that has a loss-of function phenotype with respect to viral enhancement. These findings establish a mechanistic link between an endosomal cation channel and late stages of viral entry.IMPORTANCE Viruses must co-opt cellular processes to complete their life cycle. To enter cells, viruses frequently take advantage of cellular receptor mediated endocytosis pathways. A growing number of host proteins are implicated in these viral uptake pathways. Here, we describe a new role for the gated cation channel MCOLN2 in viral entry. This endosomal protein modulates viral entry by enhancing the efficiency of viral trafficking through the endosomal system. Thus, MCOLN2-mediated enhancement of infection may represent a key vulnerability in the viral life cycle that could be targeted for therapeutic intervention. PMID- 29382736 TI - Pseudomonas aeruginosa AlgR Phosphorylation Status Differentially Regulates Pyocyanin and Pyoverdine Production. AB - Pseudomonas aeruginosa employs numerous, complex regulatory elements to control expression of its many virulence systems. The P. aeruginosa AlgZR two-component regulatory system controls the expression of several crucial virulence phenotypes. We recently determined, through transcriptomic profiling of a PAO1 DeltaalgR mutant strain compared to wild-type PAO1, that algZR and hemCD are cotranscribed and show differential iron-dependent gene expression. Previous expression profiling was performed in strains without algR and revealed that AlgR acts as either an activator or repressor, depending on the gene. Thus, examination of P. aeruginosa gene expression from cells locked into different AlgR phosphorylation states reveals greater physiological relevance. Therefore, gene expression from strains carrying algR alleles encoding a phosphomimetic (AlgR D54E) or a phosphoablative (AlgR D54N) form were compared by microarray to PAO1. Transcriptome analyses of these strains revealed 25 differentially expressed genes associated with iron siderophore biosynthesis or heme acquisition or production. The PAO1 algR D54N mutant produced lower levels of pyoverdine but increased expression of the small RNAs prrf1 and prrf2 compared to PAO1. In contrast, the algR D54N mutant produced more pyocyanin than wild-type PAO1. On the other hand, the PAO1 algR D54E mutant produced higher levels of pyoverdine, likely due to increased expression of an iron-regulated gene encoding the sigma factor pvdS, but it had decreased pyocyanin production. AlgR specifically bound to the prrf2 and pvdS promoters in vitro AlgR-dependent pyoverdine production was additionally influenced by carbon source rather than the extracellular iron concentration per se AlgR phosphorylation effects were also examined in a Drosophila melanogaster feeding, murine acute pneumonia, and punch wound infection models. Abrogation of AlgR phosphorylation attenuated P. aeruginosa virulence in these infection models. These results show that the AlgR phosphorylation state can directly, as well as indirectly, modulate the expression of iron acquisition genes that may ultimately impact the ability of P. aeruginosa to establish and maintain an infection.IMPORTANCE Pyoverdine and pyocyanin production are well-known P. aeruginosa virulence factors that obtain extracellular iron from the environment and from host proteins in different manners. Here, we show that the AlgR phosphorylation state inversely controls pyoverdine and pyocyanin production and that this control is carbon source dependent. P. aeruginosa expressing AlgR D54N, mimicking the constitutively unphosphorylated state, produced more pyocyanin than cells expressing wild-type AlgR. In contrast, a strain expressing an AlgR phosphomimetic (AlgR D54E) produced higher levels of pyoverdine. Pyoverdine production was directly controlled through the prrf2 small regulatory RNA and the pyoverdine sigma factor, PvdS. Abrogating pyoverdine or pyocyanin gene expression has been shown to attenuate virulence in a variety of models. Moreover, the inability to phosphorylate AlgR attenuates virulence in three different models, a Drosophila melanogaster feeding model, a murine acute pneumonia model, and a wound infection model. Interestingly, AlgR-dependent pyoverdine production was responsive to carbon source, indicating that this regulation has additional complexities that merit further study. PMID- 29382737 TI - UDP-Glucuronic Acid Transport Is Required for Virulence of Cryptococcus neoformans. AB - Glycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions. For pathogens, they are also often required for virulence and survival in the host. In Cryptococcus neoformans, an opportunistic pathogen of humans, the acidic monosaccharide glucuronic acid (GlcA) is a critical component of multiple essential glycoconjugates. One of these glycoconjugates is the polysaccharide capsule, a major virulence factor that enables this yeast to modulate the host immune response and resist antimicrobial defenses. This allows cryptococci to colonize the lung and brain, leading to hundreds of thousands of deaths each year worldwide. Synthesis of most glycans, including capsule polysaccharides, occurs in the secretory pathway. However, the activated precursors for this process, nucleotide sugars, are made primarily in the cytosol. This topological problem is resolved by the action of nucleotide sugar transporters (NSTs). We discovered that Uut1 is the sole UDP GlcA transporter in C. neoformans and is unique among NSTs for its narrow substrate range and high affinity for UDP-GlcA. Mutant cells with UUT1 deleted lack capsule polysaccharides and are highly sensitive to environmental stress. As a result, the deletion mutant is internalized and cleared by phagocytes more readily than wild-type cells are and is completely avirulent in mice. These findings expand our understanding of the requirements for capsule synthesis and cryptococcal virulence and elucidate a critical protein family.IMPORTANCECryptococcus neoformans causes lethal meningitis in almost two hundred thousand immunocompromised patients each year. Much of this fungal pathogen's ability to resist host defenses and cause disease is mediated by carbohydrate structures, including a complex polysaccharide capsule around the cell. Like most eukaryotic glycoconjugates, capsule polysaccharides are made within the secretory pathway, although their precursors are generated in the cytosol. Specific transporters are therefore required to convey these raw materials to the site of synthesis. One precursor of particular interest is UDP glucuronic acid, which donates glucuronic acid to growing capsule polysaccharides. We discovered a highly specific, high-affinity transporter for this molecule. Deletion of the gene encoding this unusual protein abolishes capsule synthesis, alters stress resistance, and eliminates fungal virulence. In this work, we have identified a novel transporter, elucidated capsule synthesis and thereby aspects of fungal pathogenesis, and opened directions for potential antifungal therapy. PMID- 29382739 TI - Microbial Unmasking of Plant Glycosides. AB - The therapeutic potential of plants is widely recognized and harnessed in plant based remedies and drug discovery. However, the factors that modulate the bioavailability and bioactivities of plant-derived phytochemicals are poorly understood. In a recent article in mBio, M. C. Theilmann et al. (mBio 8:e01421 17, 2017, https://doi.org/10.1128/mBio.01421-17) describe how one gut microbe, Lactobacillus acidophilus, catalytically unwraps plant glucosides to make deglucosylated bioactive aglycones available to human tissues. They demonstrate that understanding the metabolism of plant glycosides by intestinal bacteria is essential to appreciating how bacteria manipulate the levels of bioactive plant metabolites in the human host. PMID- 29382738 TI - Metagenomes Reveal Global Distribution of Bacterial Steroid Catabolism in Natural, Engineered, and Host Environments. AB - Steroids are abundant growth substrates for bacteria in natural, engineered, and host-associated environments. This study analyzed the distribution of the aerobic 9,10-seco steroid degradation pathway in 346 publically available metagenomes from diverse environments. Our results show that steroid-degrading bacteria are globally distributed and prevalent in particular environments, such as wastewater treatment plants, soil, plant rhizospheres, and the marine environment, including marine sponges. Genomic signature-based sequence binning recovered 45 metagenome assembled genomes containing a majority of 9,10-seco pathway genes. Only Actinobacteria and Proteobacteria were identified as steroid degraders, but we identified several alpha- and gammaproteobacterial lineages not previously known to degrade steroids. Actino- and proteobacterial steroid degraders coexisted in wastewater, while soil and rhizosphere samples contained mostly actinobacterial ones. Actinobacterial steroid degraders were found in deep ocean samples, while mostly alpha- and gammaproteobacterial ones were found in other marine samples, including sponges. Isolation of steroid-degrading bacteria from sponges confirmed their presence. Phylogenetic analysis of key steroid degradation proteins suggested their biochemical novelty in genomes from sponges and other environments. This study shows that the ecological significance as well as taxonomic and biochemical diversity of bacterial steroid degradation has so far been largely underestimated, especially in the marine environment.IMPORTANCE Microbial steroid degradation is a critical process for biomass decomposition in natural environments, for removal of important pollutants during wastewater treatment, and for pathogenesis of bacteria associated with tuberculosis and other bacteria. To date, microbial steroid degradation was mainly studied in a few model organisms, while the ecological significance of steroid degradation remained largely unexplored. This study provides the first analysis of aerobic steroid degradation in diverse natural, engineered, and host-associated environments via bioinformatic analysis of an extensive metagenome data set. We found that steroid-degrading bacteria are globally distributed and prevalent in wastewater treatment plants, soil, plant rhizospheres, and the marine environment, especially in marine sponges. We show that the ecological significance as well as the taxonomic and biochemical diversity of bacterial steroid degradation has been largely underestimated. This study greatly expands our ecological and evolutionary understanding of microbial steroid degradation. PMID- 29382740 TI - A plastidial pantoate transporter with a potential role in pantothenate synthesis. AB - The pantothenate (vitamin B5) synthesis pathway in plants is not fully defined because the subcellular site of its ketopantoate -> pantoate reduction step is unclear. However, the pathway is known to be split between cytosol, mitochondria, and potentially plastids, and inferred to involve mitochondrial or plastidial transport of ketopantoate or pantoate. No proteins that mediate these transport steps have been identified. Comparative genomic and transcriptomic analyses identified Arabidopsis thaliana BASS1 (At1g78560) and its maize (Zea mays) ortholog as candidates for such a transport role. BASS1 proteins belong to the bile acid : sodium symporter family and share similarity with the Salmonella enterica PanS pantoate/ketopantoate transporter and with predicted bacterial transporters whose genes cluster on the chromosome with pantothenate synthesis genes. Furthermore, Arabidopsis BASS1 is co-expressed with genes related to metabolism of coenzyme A, the cofactor derived from pantothenate. Expression of Arabidopsis or maize BASS1 promoted the growth of a S. enterica panB panS mutant strain when pantoate, but not ketopantoate, was supplied, and increased the rate of [3H]pantoate uptake. Subcellular localization of green fluorescent protein fusions in Nicotiana tabacum BY-2 cells demonstrated that Arabidopsis BASS1 is targeted solely to the plastid inner envelope. Two independent Arabidopsis BASS1 knockout mutants accumulated pantoate ~10-fold in leaves and had smaller seeds. Taken together, these data indicate that BASS1 is a physiologically significant plastidial pantoate transporter and that the pantoate reduction step in pantothenate biosynthesis could be at least partly localized in plastids. PMID- 29382741 TI - Mechanistic insights into the allosteric regulation of Pseudomonas aeruginosa aspartate kinase. AB - In plants and microorganisms, aspartate kinase (AK) catalyzes an initial commitment step of the aspartate family amino acid biosynthesis. Owing to various structural organizations, AKs from different species show tremendous diversity and complex allosteric controls. We report the crystal structure of AK from Pseudomonas aeruginosa (PaAK), a typical alpha2beta2 hetero-tetrameric enzyme, in complex with inhibitory effectors. Distinctive features of PaAK are revealed by structural and biochemical analyses. Essentially, the open conformation of Lys /Thr-bound PaAK structure clarifies the inhibitory mechanism of alpha2beta2-type AK. Moreover, the various inhibitory effectors of PaAK have been identified and a general amino acid effector motif of AK family is described. PMID- 29382742 TI - 5alpha-dihydrotestosterone reduces renal Cyp24a1 expression via suppression of progesterone receptor. AB - Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5alpha-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor alpha expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase via transcriptional regulation because Cyp24a1 gene has a progesterone receptor binding site on promoter. When male kidneys preferentially hydroxylate 25 hydroxyvitamin D3 using 24-hydroxylase rather than 25-hydroxyvitamin D3-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D3 levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders. PMID- 29382743 TI - Correction for Ferrari et al., Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. PMID- 29382744 TI - Heterogeneity within the frontoparietal control network and its relationship to the default and dorsal attention networks. AB - The frontoparietal control network (FPCN) plays a central role in executive control. It has been predominantly viewed as a unitary domain general system. Here, we examined patterns of FPCN functional connectivity (FC) across multiple conditions of varying cognitive demands, to test for FPCN heterogeneity. We identified two distinct subsystems within the FPCN based on hierarchical clustering and machine learning classification analyses of within-FPCN FC patterns. These two FPCN subsystems exhibited distinct patterns of FC with the default network (DN) and the dorsal attention network (DAN). FPCNA exhibited stronger connectivity with the DN than the DAN, whereas FPCNB exhibited the opposite pattern. This twofold FPCN differentiation was observed across four independent datasets, across nine different conditions (rest and eight tasks), at the level of individual-participant data, as well as in meta-analytic coactivation patterns. Notably, the extent of FPCN differentiation varied across conditions, suggesting flexible adaptation to task demands. Finally, we used meta analytic tools to identify several functional domains associated with the DN and DAN that differentially predict activation in the FPCN subsystems. These findings reveal a flexible and heterogeneous FPCN organization that may in part emerge from separable DN and DAN processing streams. We propose that FPCNA may be preferentially involved in the regulation of introspective processes, whereas FPCNB may be preferentially involved in the regulation of visuospatial perceptual attention. PMID- 29382745 TI - Iterative near-term ecological forecasting: Needs, opportunities, and challenges. AB - Two foundational questions about sustainability are "How are ecosystems and the services they provide going to change in the future?" and "How do human decisions affect these trajectories?" Answering these questions requires an ability to forecast ecological processes. Unfortunately, most ecological forecasts focus on centennial-scale climate responses, therefore neither meeting the needs of near term (daily to decadal) environmental decision-making nor allowing comparison of specific, quantitative predictions to new observational data, one of the strongest tests of scientific theory. Near-term forecasts provide the opportunity to iteratively cycle between performing analyses and updating predictions in light of new evidence. This iterative process of gaining feedback, building experience, and correcting models and methods is critical for improving forecasts. Iterative, near-term forecasting will accelerate ecological research, make it more relevant to society, and inform sustainable decision-making under high uncertainty and adaptive management. Here, we identify the immediate scientific and societal needs, opportunities, and challenges for iterative near term ecological forecasting. Over the past decade, data volume, variety, and accessibility have greatly increased, but challenges remain in interoperability, latency, and uncertainty quantification. Similarly, ecologists have made considerable advances in applying computational, informatic, and statistical methods, but opportunities exist for improving forecast-specific theory, methods, and cyberinfrastructure. Effective forecasting will also require changes in scientific training, culture, and institutions. The need to start forecasting is now; the time for making ecology more predictive is here, and learning by doing is the fastest route to drive the science forward. PMID- 29382746 TI - Endoplasmic reticulum acyltransferase with prokaryotic substrate preference contributes to triacylglycerol assembly in Chlamydomonas. AB - Understanding the unique features of triacylglycerol (TAG) metabolism in microalgae may be necessary to realize the full potential of these organisms for biofuel and biomaterial production. In the unicellular green alga Chlamydomonas reinhardtii a chloroplastic (prokaryotic) pathway has been proposed to play a major role in TAG precursor biosynthesis. However, as reported here, C. reinhardtii contains a chlorophyte-specific lysophosphatidic acid acyltransferase, CrLPAAT2, that localizes to endoplasmic reticulum (ER) membranes. Unlike canonical, ER-located LPAATs, CrLPAAT2 prefers palmitoyl-CoA over oleoyl-CoA as the acyl donor substrate. RNA-mediated suppression of CrLPAAT2 indicated that the enzyme is required for TAG accumulation under nitrogen deprivation. Our findings suggest that Chlamydomonas has a distinct glycerolipid assembly pathway that relies on CrLPAAT2 to generate prokaryotic-like TAG precursors in the ER. PMID- 29382748 TI - Correction for Noh et al., ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons. PMID- 29382747 TI - Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. AB - Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603). PMID- 29382749 TI - Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer. AB - Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 A) and DPP9 (3.0 A) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one beta-propeller and alpha/beta hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an alpha helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets. PMID- 29382750 TI - Nature and evolution of incommensurate charge order in manganites visualized with cryogenic scanning transmission electron microscopy. AB - Incommensurate charge order in hole-doped oxides is intertwined with exotic phenomena such as colossal magnetoresistance, high-temperature superconductivity, and electronic nematicity. Here, we map, at atomic resolution, the nature of incommensurate charge-lattice order in a manganite using scanning transmission electron microscopy at room temperature and cryogenic temperature ([Formula: see text]93 K). In diffraction, the ordering wave vector changes upon cooling, a behavior typically associated with incommensurate order. However, using real space measurements, we discover that the ordered state forms lattice-locked regions over a few wavelengths interspersed with phase defects and changing periodicity. The cations undergo picometer-scale ([Formula: see text]6 pm to 11 pm) transverse displacements, suggesting that charge-lattice coupling is strong. We further unearth phase inhomogeneity in the periodic lattice displacements at room temperature, and emergent phase coherence at 93 K. Such local phase variations govern the long-range correlations of the charge-ordered state and locally change the periodicity of the modulations, resulting in wave vector shifts in reciprocal space. These atomically resolved observations underscore the importance of lattice coupling and phase inhomogeneity, and provide a microscopic explanation for putative "incommensurate" order in hole-doped oxides. PMID- 29382753 TI - Evidence that asymmetry of the membrane/cytoskeletal complex in human red blood cell ghosts is responsible for their biconcave shape. AB - The main conclusion of the results reported in this article is that during centrifugation, sphered red blood cell ghosts become oriented in their attachment to a coverslip such that a dense band within the ghosts lies parallel to the centrifugal field. The result of the orientation of this dense band is that when the attached spherical ghosts are shrunken to become biconcave discs, they do so by directly collapsing on themselves without any lateral motion. This result is interpreted to suggest that a dense band, relative to the dimple, resides in the rim of the ghost and is responsible for its biconcave shape. These results confirm the conclusions reached in a previous publication in which there was the uncertainty that the shape change of the spherical ghosts to discs could not be directly imaged. The present work corrects this limitation by use of a chamber in which the tonicity of the solutions in the ghosts' surround could be altered by perfusion coupled with constant microscopic imaging. The identity of the components that are responsible for the differences in the density (mass) between the rim and the dimple regions of the cytoskeletal/membrane complex in the biconcave disk are unknown. It is also unknown what forces apply or what the explanation is for the unique orientation of the dense band during the ghosts' centrifugation, as described in this article. Nevertheless, the results reported in this article indicate the membrane's underlying cytoskeletal complex is asymmetrically distributed. PMID- 29382752 TI - Brain-state dependent astrocytic Ca2+ signals are coupled to both positive and negative BOLD-fMRI signals. AB - Astrocytic Ca2+-mediated gliovascular interactions regulate the neurovascular network in situ and in vivo. However, it is difficult to measure directly both the astrocytic activity and fMRI to relate the various forms of blood-oxygen level-dependent (BOLD) signaling to brain states under normal and pathological conditions. In this study, fMRI and GCaMP-mediated Ca2+ optical fiber recordings revealed distinct evoked astrocytic Ca2+ signals that were coupled with positive BOLD signals and intrinsic astrocytic Ca2+ signals that were coupled with negative BOLD signals. Both evoked and intrinsic astrocytic calcium signal could occur concurrently or respectively during stimulation. The intrinsic astrocytic calcium signal can be detected globally in multiple cortical sites in contrast to the evoked astrocytic calcium signal only detected at the activated cortical region. Unlike propagating Ca2+ waves in spreading depolarization/depression, the intrinsic Ca2+ spikes occurred simultaneously in both hemispheres and were initiated upon the activation of the central thalamus and midbrain reticular formation. The occurrence of the intrinsic astrocytic calcium signal is strongly coincident with an increased EEG power level of the brain resting-state fluctuation. These results demonstrate highly correlated astrocytic Ca2+ spikes with bidirectional fMRI signals based on the thalamic regulation of cortical states, depicting a brain-state dependency of both astrocytic Ca2+ and BOLD fMRI signals. PMID- 29382751 TI - Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes. AB - Precise translation of glycan-encoded information into cellular activity depends critically on highly specific functional pairing between glycans and their human lectin counter receptors. Sulfoglycolipids, such as sulfatides, are important glycolipid components of the biological membranes found in the nervous and immune systems. The optimal molecular and spatial design aspects of sulfated and nonsulfated glycans with high specificity for lectin-mediated bridging are unknown. To elucidate how different molecular and spatial aspects combine to ensure the high specificity of lectin-mediated bridging, a bottom-up toolbox is devised. To this end, negatively surface-charged glycodendrimersomes (GDSs), of different nanoscale dimensions, containing sulfo-lactose groups are self assembled in buffer from a synthetic sulfatide mimic: Janus glycodendrimer (JGD) containing a 3'-O-sulfo-lactose headgroup. Also prepared for comparative analysis are GDSs with nonsulfated lactose, a common epitope of human membranes. These self-assembled GDSs are employed in aggregation assays with 15 galectins, comprising disease-related human galectins, and other natural and engineered variants from four families, having homodimeric, heterodimeric, and chimera architectures. There are pronounced differences in aggregation capacity between human homodimeric and heterodimeric galectins, and also with respect to their responsiveness to the charge of carbohydrate-derived ligand. Assays reveal strong differential impact of ligand surface charge and density, as well as lectin concentration and structure, on the extent of surface cross-linking. These findings demonstrate how synthetic JGD-headgroup tailoring teamed with protein engineering and network assays can help explain how molecular matchmaking operates in the cellular context of glycan and lectin complexity. PMID- 29382754 TI - Path integration in place cells of developing rats. AB - Place cells in the hippocampus and grid cells in the medial entorhinal cortex rely on self-motion information and path integration for spatially confined firing. Place cells can be observed in young rats as soon as they leave their nest at around 2.5 wk of postnatal life. In contrast, the regularly spaced firing of grid cells develops only after weaning, during the fourth week. In the present study, we sought to determine whether place cells are able to integrate self motion information before maturation of the grid-cell system. Place cells were recorded on a 200-cm linear track while preweaning, postweaning, and adult rats ran on successive trials from a start wall to a box at the end of a linear track. The position of the start wall was altered in the middle of the trial sequence. When recordings were made in complete darkness, place cells maintained fields at a fixed distance from the start wall regardless of the age of the animal. When lights were on, place fields were determined primarily by external landmarks, except at the very beginning of the track. This shift was observed in both young and adult animals. The results suggest that preweaning rats are able to calculate distances based on information from self-motion before the grid-cell system has matured to its full extent. PMID- 29382755 TI - Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria. AB - The emergence and ongoing spread of multidrug-resistant bacteria puts humans and other species at risk for potentially lethal infections. Thus, novel antibiotics or alternative approaches are needed to target drug-resistant bacteria, and metabolic modulation has been documented to improve antibiotic efficacy, but the relevant metabolic mechanisms require more studies. Here, we show that glutamate potentiates aminoglycoside antibiotics, resulting in improved elimination of antibiotic-resistant pathogens. When exploring the metabolic flux of glutamate, it was found that the enzymes that link the phosphoenolpyruvate (PEP)-pyruvate AcCoA pathway to the TCA cycle were key players in this increased efficacy. Together, the PEP-pyruvate-AcCoA pathway and TCA cycle can be considered the pyruvate cycle (P cycle). Our results show that inhibition or gene depletion of the enzymes in the P cycle shut down the TCA cycle even in the presence of excess carbon sources, and that the P cycle operates routinely as a general mechanism for energy production and regulation in Escherichia coli and Edwardsiella tarda These findings address metabolic mechanisms of metabolite-induced potentiation and fundamental questions about bacterial biochemistry and energy metabolism. PMID- 29382756 TI - Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma. AB - Capicua (CIC) regulates a transcriptional network downstream of the RAS/MAPK signaling cascade. In Drosophila, CIC is important for many developmental processes, including embryonic patterning and specification of wing veins. In humans, CIC has been implicated in neurological diseases, including spinocerebellar ataxia type 1 (SCA1) and a neurodevelopmental syndrome. Additionally, we and others have reported mutations in CIC in several cancers. However, whether CIC is a tumor suppressor remains to be formally tested. In this study, we found that deletion of Cic in adult mice causes T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Using hematopoietic-specific deletion and bone marrow transplantation studies, we show that loss of Cic from hematopoietic cells is sufficient to drive T-ALL. Cic-null tumors show up regulation of the KRAS pathway as well as activation of the NOTCH1 and MYC transcriptional programs. In sum, we demonstrate that loss of CIC causes T-ALL, establishing it as a tumor suppressor for lymphoid malignancies. Moreover, we show that mouse models lacking CIC in the hematopoietic system are robust models for studying the role of RAS signaling as well as NOTCH1 and MYC transcriptional programs in T-ALL. PMID- 29382758 TI - Auxetic metamaterials from disordered networks. AB - Recent theoretical work suggests that systematic pruning of disordered networks consisting of nodes connected by springs can lead to materials that exhibit a host of unusual mechanical properties. In particular, global properties such as Poisson's ratio or local responses related to deformation can be precisely altered. Tunable mechanical responses would be useful in areas ranging from impact mitigation to robotics and, more generally, for creation of metamaterials with engineered properties. However, experimental attempts to create auxetic materials based on pruning-based theoretical ideas have not been successful. Here we introduce a more realistic model of the networks, which incorporates angle bending forces and the appropriate experimental boundary conditions. A sequential pruning strategy of select bonds in this model is then devised and implemented that enables engineering of specific mechanical behaviors upon deformation, both in the linear and in the nonlinear regimes. In particular, it is shown that Poisson's ratio can be tuned to arbitrary values. The model and concepts discussed here are validated by preparing physical realizations of the networks designed in this manner, which are produced by laser cutting 2D sheets and are found to behave as predicted. Furthermore, by relying on optimization algorithms, we exploit the networks' susceptibility to tuning to design networks that possess a distribution of stiffer and more compliant bonds and whose auxetic behavior is even greater than that of homogeneous networks. Taken together, the findings reported here serve to establish that pruned networks represent a promising platform for the creation of unique mechanical metamaterials. PMID- 29382757 TI - RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism. AB - Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells. PMID- 29382759 TI - Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome. AB - The CARMA1-BCL10-MALT1 (CBM) signalosome is a central mediator of T cell receptor and B cell receptor-induced NF-kappaB signaling that regulates multiple lymphocyte functions. While caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) nucleates B cell lymphoma 10 (BCL10) filament formation through interactions between CARDs, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a paracaspase with structural similarity to caspases, which recruits TNF receptor-associated factor 6 (TRAF6) for K63-linked polyubiquitination. Here we present cryo-electron microscopy (cryo EM) structure of the BCL10 CARD filament at 4.0-A resolution. The structure redefines CARD-CARD interactions compared with the previous EM structure determined from a negatively stained sample. Surprisingly, time-lapse confocal imaging shows that BCL10 polymerizes in a unidirectional manner. CARMA1, the BCL10 nucleator, serves as a hub for formation of star-shaped filamentous networks of BCL10 and significantly decreases the lag period of BCL10 polymerization. Cooperative MALT1 interaction with BCL10 filaments observed under EM suggests immediate dimerization of MALT1 in the BCL10 filamentous scaffold. In addition, TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, likely resulting in all-or-none activation of the downstream pathway. Collectively, these data reveal biophysical mechanisms in the assembly of the CARMA1-BCL10-MALT1-TRAF6 complex for signal transduction. PMID- 29382760 TI - Restoring GABAergic inhibition rescues memory deficits in a Huntington's disease mouse model. AB - Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ~15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl--extruding cotransporter KCC2 is accompanied by an increase in the Cl--importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests. PMID- 29382761 TI - Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence. AB - Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts DeltandhDeltanuoAN and DeltandhADeltanuoAN were constructed. The DeltandhDeltandhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Deltandh and DeltandhDeltanuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of DeltandhA, DeltanuoAN, and DeltandhADeltanuoAN were similar to the parental strain. Interestingly, although DeltanuoAN had no phenotype in vivo, DeltandhDeltanuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development. PMID- 29382762 TI - Oxidation of dCTP contributes to antibiotic lethality in stationary-phase mycobacteria. AB - Growing evidence shows that generation of reactive oxygen species (ROS) derived from antibiotic-induced metabolic perturbation contribute to antibiotic lethality. However, our knowledge of the mechanisms by which antibiotic-induced oxidative stress actually kills cells remains elusive. Here, we show that oxidation of dCTP underlies ROS-mediated antibiotic lethality via induction of DNA double-strand breaks (DSBs). Deletion of mazG-encoded 5-OH-dCTP-specific pyrophosphohydrolase potentiates antibiotic killing of stationary-phase mycobacteria, but did not affect antibiotic efficacy in exponentially growing cultures. Critically, the effect of mazG deletion on potentiating antibiotic killing is associated with antibiotic-induced ROS and accumulation of 5-OH-dCTP. Independent lines of evidence presented here indicate that the increased level of DSBs observed in the DeltamazG mutant is a dead-end event accounting for enhanced antibiotic killing. Moreover, we provided genetic evidence that 5-OH-dCTP is incorporated into genomic DNA via error-prone DNA polymerase DnaE2 and repair of 5-OH-dC lesions via the endonuclease Nth leads to the generation of lethal DSBs. This work provides a mechanistic view of ROS-mediated antibiotic lethality in stationary phase and may have broad implications not only with respect to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria. PMID- 29382763 TI - Phosphatidylinositol-(4, 5)-bisphosphate regulates calcium gating of small conductance cation channel TMEM16F. AB - TMEM16F, which is activated by elevation of intracellular calcium to trigger phospholipid scrambling and the collapse of lipid bilayer asymmetry to mediate important cellular functions such as blood coagulation, also generates a small conductance calcium-activated cation current. How TMEM16F activation may be regulated is an open question. By recording TMEM16F Ca2+-activated current, we found that the TMEM16F Ca2+-response is desensitized by a brief exposure to high intracellular Ca2+, which is associated with depletion of phosphatidylinositol (4, 5)-bisphosphate (PIP2) from the inner leaflet of the membrane. Application of artificial or natural PIP2 restores TMEM16F channel activity. PIP2 modulation of TMEM16F requires the presence of several positively charged amino acids in its cytoplasmic N-terminal domain. TMEM16F interaction with PIP2 works synergistically with membrane depolarization to facilitate Ca2+-gating of TMEM16F. Our study reveals the dependence of TMEM16F activity on phosphoinositides and provides one mechanism for TMEM16F activation to be strictly regulated in the cell membrane. PMID- 29382764 TI - Efficiency of quantum vs. classical annealing in nonconvex learning problems. AB - Quantum annealers aim at solving nonconvex optimization problems by exploiting cooperative tunneling effects to escape local minima. The underlying idea consists of designing a classical energy function whose ground states are the sought optimal solutions of the original optimization problem and add a controllable quantum transverse field to generate tunneling processes. A key challenge is to identify classes of nonconvex optimization problems for which quantum annealing remains efficient while thermal annealing fails. We show that this happens for a wide class of problems which are central to machine learning. Their energy landscapes are dominated by local minima that cause exponential slowdown of classical thermal annealers while simulated quantum annealing converges efficiently to rare dense regions of optimal solutions. PMID- 29382765 TI - Superior colliculus neuronal ensemble activity signals optimal rather than subjective confidence. AB - Recent studies suggest that neurons in sensorimotor circuits involved in perceptual decision-making also play a role in decision confidence. In these studies, confidence is often considered to be an optimal readout of the probability that a decision is correct. However, the information leading to decision accuracy and the report of confidence often covaried, leaving open the possibility that there are actually two dissociable signal types in the brain: signals that correlate with decision accuracy (optimal confidence) and signals that correlate with subjects' behavioral reports of confidence (subjective confidence). We recorded neuronal activity from a sensorimotor decision area, the superior colliculus (SC) of monkeys, while they performed two different tasks. In our first task, decision accuracy and confidence covaried, as in previous studies. In our second task, we implemented a motion discrimination task with stimuli that were matched for decision accuracy but produced different levels of confidence, as reflected by behavioral reports. We used a multivariate decoder to predict monkeys' choices from neuronal population activity. As in previous studies on perceptual decision-making mechanisms, we found that neuronal decoding performance increased as decision accuracy increased. However, when decision accuracy was matched, performance of the decoder was similar between high and low subjective confidence conditions. These results show that the SC likely signals optimal decision confidence similar to previously reported cortical mechanisms, but is unlikely to play a critical role in subjective confidence. The results also motivate future investigations to determine where in the brain signals related to subjective confidence reside. PMID- 29382766 TI - Relevance of packing to colloidal self-assembly. AB - Since the 1920s, packing arguments have been used to rationalize crystal structures in systems ranging from atomic mixtures to colloidal crystals. Packing arguments have recently been applied to complex nanoparticle structures, where they often, but not always, work. We examine when, if ever, packing is a causal mechanism in hard particle approximations of colloidal crystals. We investigate three crystal structures composed of their ideal packing shapes. We show that, contrary to expectations, the ordering mechanism cannot be packing, even when the thermodynamically self-assembled structure is the same as that of the densest packing. We also show that the best particle shapes for hard particle colloidal crystals at any finite pressure are imperfect versions of the ideal packing shape. PMID- 29382768 TI - Farming the mitochondrial ancestor as a model of endosymbiotic establishment by natural selection. AB - The origin of mitochondria was a major evolutionary transition leading to eukaryotes, and is a hotly debated issue. It is unknown whether mitochondria were acquired early or late, and whether it was captured via phagocytosis or syntrophic integration. We present dynamical models to directly simulate the emergence of mitochondria in an ecoevolutionary context. Our results show that regulated farming of prey bacteria and delayed digestion can facilitate the establishment of stable endosymbiosis if prey-rich and prey-poor periods alternate. Stable endosymbiosis emerges without assuming any initial metabolic benefit provided by the engulfed partner, in a wide range of parameters, despite that during good periods farming is costly. Our approach lends support to the appearance of mitochondria before any metabolic coupling has emerged, but after the evolution of primitive phagocytosis by the urkaryote. PMID- 29382769 TI - Polaronic behavior in a weak-coupling superconductor. AB - The nature of superconductivity in the dilute semiconductor SrTiO3 has remained an open question for more than 50 y. The extremely low carrier densities ([Formula: see text]-[Formula: see text] cm-3) at which superconductivity occurs suggest an unconventional origin of superconductivity outside of the adiabatic limit on which the Bardeen-Cooper-Schrieffer (BCS) and Migdal-Eliashberg (ME) theories are based. We take advantage of a newly developed method for engineering band alignments at oxide interfaces and access the electronic structure of Nb doped SrTiO3, using high-resolution tunneling spectroscopy. We observe strong coupling to the highest-energy longitudinal optic (LO) phonon branch and estimate the doping evolution of the dimensionless electron-phonon interaction strength ([Formula: see text]). Upon cooling below the superconducting transition temperature ([Formula: see text]), we observe a single superconducting gap corresponding to the weak-coupling limit of BCS theory, indicating an order of magnitude smaller coupling ([Formula: see text]). These results suggest that despite the strong normal state interaction with electrons, the highest LO phonon does not provide a dominant contribution to pairing. They further demonstrate that SrTiO3 is an ideal system to probe superconductivity over a wide range of carrier density, adiabatic parameter, and electron-phonon coupling strength. PMID- 29382767 TI - Effects of the ecto-ATPase apyrase on microglial ramification and surveillance reflect cell depolarization, not ATP depletion. AB - Microglia, the brain's innate immune cells, have highly motile processes which constantly survey the brain to detect infection, remove dying cells, and prune synapses during brain development. ATP released by tissue damage is known to attract microglial processes, but it is controversial whether an ambient level of ATP is needed to promote constant microglial surveillance in the normal brain. Applying the ATPase apyrase, an enzyme which hydrolyzes ATP and ADP, reduces microglial process ramification and surveillance, suggesting that ambient ATP/ADP maintains microglial surveillance. However, attempting to raise the level of ATP/ADP by blocking the endogenous ecto-ATPase (termed NTPDase1/CD39), which also hydrolyzes ATP/ADP, does not affect the cells' ramification or surveillance, nor their membrane currents, which respond to even small rises of extracellular [ATP] or [ADP] with the activation of K+ channels. This indicates a lack of detectable ambient ATP/ADP and ecto-ATPase activity, contradicting the results with apyrase. We resolve this contradiction by demonstrating that contamination of commercially available apyrase by a high K+ concentration reduces ramification and surveillance by depolarizing microglia. Exposure to the same K+ concentration (without apyrase added) reduced ramification and surveillance as with apyrase. Dialysis of apyrase to remove K+ retained its ATP-hydrolyzing activity but abolished the microglial depolarization and decrease of ramification produced by the undialyzed enzyme. Thus, applying apyrase affects microglia by an action independent of ATP, and no ambient purinergic signaling is required to maintain microglial ramification and surveillance. These results also have implications for hundreds of prior studies that employed apyrase to hydrolyze ATP/ADP. PMID- 29382770 TI - Ethylene Represses Gene Transcription via Histone Deacetylases. PMID- 29382772 TI - Outcome of transarterial treatment of dural arteriovenous fistulas with direct or indirect cortical venous drainage. AB - BACKGROUND AND PURPOSE: Transarterial Onyx embolization is an effective treatment for patients with intracranial dural arteriovenous fistula (DAVF). A study was performed to determine whether the clinical and radiological outcomes after transarterial Onyx treatment were affected by the type of cortical venous drainage (direct vs indirect) of high-grade DAVF. MATERIALS AND METHODS: Between May 2006 and December 2014, demographic data, clinical presentation, angiographic characteristics, and treatment-related outcomes were collected for 54 patients divided into two groups (intracranial DAVF with direct and indirect cortical venous drainage). Continuous variables were compared with the two-tailed t test and categorical variables with the chi2 test. Statistical significance was set at P<0.05. RESULTS: Fifty-two patients (71% with direct and 29% with indirect cortical venous drainage) underwent Onyx embolization. Immediate complete occlusion after treatment was observed in about 55% of patients without between group difference. During the long-term follow-up, complete angiographic occlusion was achieved in 83% of patients. Specifically, 15 additional patients (40%) in the direct cortical venous drainage group progressed to complete occlusion, but only one (6%) in the indirect cortical venous drainage group. Overall, the rate of complete occlusion was higher in patients with DAVF with direct cortical venous drainage (92%) than in those with DAVF with indirect cortical venous drainage (62.5%) (P=0.01). The rate of permanent treatment-related complications was 4%, mostly related to ischemic events. Overall, 80.5% of patients had a good neurological outcome (modified Rankin Scale score 0-2). CONCLUSIONS: Transarterial Onyx embolization of intracranial high-grade DAVF is safe and effective, particularly for lesions with direct cortical venous drainage. PMID- 29382773 TI - Spinal artery aneurysms: clinical presentation, radiological findings and outcome. AB - BACKGROUND AND PURPOSE: Spinal arterial aneurysms are a rare cause of spinal subarachnoid hemorrhage (SAH). We performed a retrospective review of spinal arterial aneurysms not associated with spinal arteriovenus shunts from three institutions in order to better understand the clinical and imaging characteristics of these lesions. MATERIALS AND METHODS: We performed a retrospective review of spinal arterial aneurysms managed at three North American institutions. For each patient, the following information was collected: demographic data, clinical presentation, comorbidities, imaging findings, and neurological status at the last follow-up. Treatment strategies and outcomes were reported. RESULTS: 11 patients were included; 7 were women and median age was 60 years. The most common presentation was sudden back pain (81.8%). We found 3 aneurysms on the radiculomedullary artery and 8 along the radiculopial arteries. Of the 3 aneurysms on the radiculomedullary artery, 1 was treated conservatively, 1 was treated with coiling of the aneurysm and sacrifice of the radiculomedullary artery, and 1 was treated with surgical trapping. The 8 aneurysms on the radiculopial artery were treated endovascularly in 4 cases, surgically in 1 case, and conservatively in 3 cases. One surgically treated patient had a spinal subdural hematoma. There were no other complications. Mean clinical follow-up time was 20 months, and 87.5% of patients were functionally independent. CONCLUSIONS: Spinal arterial aneurysms are lesions which commonly present with sudden back pain and spinal SAH. Conservative, surgical, and endovascular treatment options are safe and effective. Long term outcomes in these patients are generally good. PMID- 29382771 TI - Defended to the Nines: 25 Years of Resistance Gene Cloning Identifies Nine Mechanisms for R Protein Function. AB - Plants have many, highly variable resistance (R) gene loci, which provide resistance to a variety of pathogens. The first R gene to be cloned, maize (Zea mays) Hm1, was published over 25 years ago, and since then, many different R genes have been identified and isolated. The encoded proteins have provided clues to the diverse molecular mechanisms underlying immunity. Here, we present a meta analysis of 314 cloned R genes. The majority of R genes encode cell surface or intracellular receptors, and we distinguish nine molecular mechanisms by which R proteins can elevate or trigger disease resistance: direct (1) or indirect (2) perception of pathogen-derived molecules on the cell surface by receptor-like proteins and receptor-like kinases; direct (3) or indirect (4) intracellular detection of pathogen-derived molecules by nucleotide binding, leucine-rich repeat receptors, or detection through integrated domains (5); perception of transcription activator-like effectors through activation of executor genes (6); and active (7), passive (8), or host reprogramming-mediated (9) loss of susceptibility. Although the molecular mechanisms underlying the functions of R genes are only understood for a small proportion of known R genes, a clearer understanding of mechanisms is emerging and will be crucial for rational engineering and deployment of novel R genes. PMID- 29382774 TI - Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. AB - OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5 year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes. PMID- 29382775 TI - Potential of butyrate to influence food intake in mice and men. PMID- 29382777 TI - Matters of interest to medical professionals. PMID- 29382776 TI - Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population. AB - OBJECTIVE: Gastric infection with Helicobacter pylori is a strong risk factor for non-cardia gastric adenocarcinoma. The aim of this study was to assess whether the risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma decreases after eradication treatment for H. pylori in a Western population. DESIGN: This was a nationwide, population-based cohort study in Sweden in 2005 2012. Data from the Swedish Prescribed Drug Registry provided information on H. pylori eradication treatment, whereas information concerning newly developed gastric adenocarcinoma was retrieved from the Swedish Cancer Registry. The risk of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in individuals who had received H. pylori eradication treatment was compared with the background population of the corresponding age, sex and calendar year distribution, yielding standardised incidence ratios (SIRs) with 95% CIs. RESULTS: During the follow-up of 95 176 individuals who had received eradication treatment (351 018 person years at risk), 75 (0.1%) developed gastric adenocarcinoma and 69 (0.1%) developed non-cardia gastric adenocarcinoma. The risk of gastric adenocarcinoma decreased over time after eradication treatment to levels below that of the corresponding background population. The SIRs were 8.65 (95% CI 6.37 to 11.46) for 1-3 years, 2.02 (95% CI 1.25 to 3.09) for 3-5 years and 0.31 (95% CI 0.11 to 0.67) for 5-7.5 years after eradication treatment. When restricted to non-cardia adenocarcinoma, the corresponding SIRs were 10.74 (95% CI 7.77 to 14.46), 2.67 (95% CI 1.63 to 4.13) and 0.43 (95% CI 0.16 to 0.93). CONCLUSION: Eradication treatment for H. pylori seems to counteract the development of gastric adenocarcinoma and non-cardia gastric adenocarcinoma in this Western population. PMID- 29382779 TI - Correction: 'Is this knowledge mine and nobody else's? I don't feel that.' Patient views about consent, confidentiality and information-sharing in genetic medicine. PMID- 29382778 TI - Correction: Is current practice around late termination of pregnancy eugenic and discriminatory? Maternal interests and abortion. PMID- 29382780 TI - Correction: Going above and beneath the call of duty: the luck egalitarian claims of healthcare heroes, and the accomodation of professionally-motivated treatment refusal. PMID- 29382781 TI - Ethics briefing. PMID- 29382782 TI - Approval of Ogivri. PMID- 29382783 TI - SILAC identifies LAD1 as a filamin-binding regulator of actin dynamics in response to EGF and a marker of aggressive breast tumors. AB - Mutations mimicking growth factor-induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel currently unknown players in these processes, we performed phosphoproteomic analysis on untransformed mammary epithelial cells (MCF10A) that were stimulated in culture with epidermal growth factor (EGF). We identified ladinin-1 (LAD1), a largely uncharacterized protein to date, as a phosphorylation-regulated mediator of the EGF-to-ERK pathway. Further experiments revealed that LAD1 mediated the proliferation and migration of mammary cells. LAD1 was transcriptionally induced, phosphorylated, and partly colocalized with actin stress fibers in response to EGF. Yeast two-hybrid, proximity ligation, and coimmunoprecipitation assays revealed that LAD1 bound to actin-cross-linking proteins called filamins. Cosedimentation analyses indicated that LAD1 played a role in actin dynamics, probably in collaboration with the scaffold protein 14-3-3sigma (also called SFN). Depletion of LAD1 decreased the expression of transcripts associated with cell survival and inhibited the growth of mammary xenografts in an animal model. Furthermore, LAD1 predicts poor patient prognosis and is highly expressed in aggressive subtypes of breast cancer characterized as integrative clusters 5 and 10, which partly correspond to triple negative and HER2-positive tumors. Thus, these findings reveal a cytoskeletal component that is critically involved in cell migration and the acquisition of oncogenic attributes in human mammary tumors. PMID- 29382784 TI - KIF22 coordinates CAR and EGFR dynamics to promote cancer cell proliferation. AB - The coxsackievirus and adenovirus receptor (CAR) is a transmembrane receptor that plays a key role in cell-cell adhesion. CAR is found in normal epithelial cells and is increased in abundance in various human tumors, including lung carcinomas. We investigated the potential mechanisms by which CAR contributes to cancer cell growth and found that depletion of CAR in human lung cancer cells reduced anchorage-independent growth, epidermal growth factor (EGF)-dependent proliferation, and tumor growth in vivo. EGF induced the phosphorylation of CAR and its subsequent relocalization to cell junctions through the activation of the kinase PKCdelta. EGF promoted the binding of CAR to the chromokinesin KIF22. KIF22-dependent regulation of microtubule dynamics led to delayed EGFR internalization, enhanced EGFR signaling, and coordination of CAR dynamics at cell-cell junctions. These data suggest a role for KIF22 in the coordination of membrane receptors and provide potential new therapeutic strategies to combat lung tumor growth. PMID- 29382786 TI - EGFR-induced cytoskeletal changes drive complex cell behaviors: The tip of the iceberg. AB - Cytoskeletal networks are dramatically reorganized upon EGF stimulation to enable complex cell behaviors such as cell-cell communication, migration and invasion, and cell division. In this issue of Science Signaling, Roth et al. and Pike et al. use proteomic methods to identify several effectors of EGF responses. The findings show the interdependent nature of growth factor signaling and the cytoskeleton and identify potential new therapeutic targets for treating cancer and other growth factor-driven diseases. PMID- 29382785 TI - Fluorescent Ca2+ indicators directly inhibit the Na,K-ATPase and disrupt cellular functions. AB - Fluorescent Ca2+ indicators have been essential for the analysis of Ca2+ signaling events in various cell types. We showed that chemical Ca2+ indicators, but not a genetically encoded Ca2+ indicator, potently suppressed the activity of Na+- and K+-dependent adenosine triphosphatase (Na,K-ATPase), independently of their Ca2+ chelating activity. Loading of commonly used Ca2+ indicators, including Fluo-4 acetoxymethyl (AM), Rhod-2 AM, and Fura-2 AM, and of the Ca2+ chelator BAPTA AM into cultured mouse or human neurons, astrocytes, cardiomyocytes, or kidney proximal tubule epithelial cells suppressed Na,K-ATPase activity by 30 to 80%. Ca2+ indicators also suppressed the agonist-induced activation of the Na,K-ATPase, altered metabolic status, and caused a dose dependent loss of cell viability. Loading of Ca2+ indicators into mice, which is carried out for two-photon imaging, markedly altered brain extracellular concentrations of K+ and ATP. These results suggest that a critical review of data obtained with chemical Ca2+ indicators may be necessary. PMID- 29382787 TI - Correction for del Toro et al., "Potato Virus Y HCPro Suppression of Antiviral Silencing in Nicotiana benthamiana Plants Correlates with Its Ability To Bind In Vivo to 21- and 22-Nucleotide Small RNAs of Viral Sequence". PMID- 29382788 TI - Do swingers self-identify as swingers when attending STI services for testing? A cross-sectional study. AB - OBJECTIVES: Swingers, that is, members of a heterosexual couple who, as a couple, had sex with other couples and/or singles within the swinger's subculture, are a hidden population with substantial rates of sexually transmitted infections (STIs) and high-risk sexual behaviour. Information on swingers' self identification to be a swinger, their risk perception and attitudes about STI testing and safe sex will help to reveal swingers who are hidden while in care, to address them with targeted strategies. METHODS: We used data from a convenience sample of 289 swingers from our Dutch STI clinic patient registry between 2009 and 2012 (median age 45 years; 49% women; STI positivity 13%, no condom in vaginal sex: 57%). Participants filled in a self-administered questionnaire on sexual behaviour and answered statements about self identification, risk perception and attitudes about STI testing and safe sex. RESULTS: Of all participating registered swingers, 56% self-identified as a swinger. Safe sex was reportedly deemed important (77%). Overall, 72%, 62% and 56% reported that STI testing, partner notification and condom use is the norm in the swinger community. The latter was reported more often by self-identified swingers compared with non-self-identified swingers. Self-identified swingers further swinged more often, had more partners and more often swinged at home parties than non-self-identified swingers. CONCLUSIONS: About half of STI clinic attending swingers whose sexual behaviour agrees with the definition of swinging are neutral/do not identify themselves to be a swinger. As many STI clinics internationally not specifically ask clients about their swinging behaviour, swingers may be a missed target population in care. Implementation of routine questions addressing behaviour (thus not only asking whether someone is a swinger) in STI clinics is feasible and facilitated by swingers' positive norm towards STI prevention and testing. Implementing routine swinger questions contribute to effective STI services including appropriate testing, counselling and partner notification. PMID- 29382789 TI - Science and Culture: Cancer researcher looks to artists for inspiration. PMID- 29382790 TI - Inner Workings: Smart-sensor network keeps close eye on lake ecosystem. PMID- 29382794 TI - Helmet Versus Nasal-Prong CPAP in Infants With Acute Bronchiolitis. AB - BACKGROUND: Nasal prongs are frequently used to deliver noninvasive CPAP in bronchiolitis, especially in the youngest children. A helmet interface is an alternative that might be comparable to nasal prongs. We sought to compare these interfaces. METHODS: We performed a prospective, randomized, crossover, single center study in an 8-bed multidisciplinary pediatric ICU in a university hospital. Infants age <3 months who were consecutively admitted to the pediatric ICU during a bronchiolitis epidemic season and fulfilled inclusion criteria were recruited. Subjects were randomly allocated to receive CPAP via a helmet or nasal prongs for 60 min. The subjects were then placed on the other CPAP system for another 60-min period (helmet then nasal prongs [H-NP] or nasal prongs then helmet [NP-H]). Measurements were taken at 30, 60, 90, and 120 min. Failure was defined as the need for further respiratory support. RESULTS: Sixteen subjects were included, with 9 in the H-NP group and 7 in the NP-H group. CPAP significantly reduced respiratory distress, showing no differences between the H NP and NP-H groups in terms of improving the Modified Wood's Clinical Asthma Score from 4.8 +/- 1 to 3 +/- 0.9 and 2.7 +/- 1.7 points at 60 min and 120 min in the H-NP group, respectively, and from 4.2 +/- 0.9 to 2.8 +/- 0.9 and to 2.9 +/- 0.9 at 60 min and 120 min, respectively, in the NP-H group. Sedatives were used in only 3 subjects (2 in the NP-H group, P = .77). The failure rate was similar in both groups (3 of 9 subjects vs 3 of 7 subjects, P = .70). No significant differences were seen for heart rate, breathing frequency, FIO2 , or transcutaneous oxygen saturation response. CONCLUSIONS: Our results suggest that CPAP delivered by nasal prongs and CPAP delivered by helmet are similar in terms of efficacy in young infants with acute bronchiolitis. PMID- 29382793 TI - Frequent Versus Infrequent Monitoring of Endotracheal Tube Cuff Pressures. AB - BACKGROUND: Currently there is no accepted standard of practice for the optimal frequency of endotracheal tube cuff pressure monitoring in mechanically ventilated patients. Therefore, we conducted a study to compare infrequent endotracheal tube cuff pressure monitoring (immediately after intubation and when clinically indicated for an observed air leak or due to tube migration) with frequent endotracheal tube cuff pressure monitoring (immediately after intubation, every 8 h, and when clinically indicated). METHODS: We performed a prospective clinical trial with subjects assigned to study groups based on room assignment. The primary outcome was the occurrence of a ventilator-associated event (VAE) and was adjudicated by individuals blinded to the conduct of this study. RESULTS: We enrolled 305 subjects, with 166 (54.4%) assigned to frequent monitoring and 139 (45.6%) assigned to infrequent monitoring. The total number of endotracheal tube cuff pressure monitoring events for both groups was 1,531 versus 336, respectively. The occurrence of VAEs was infrequent and similar for both groups (3.6% vs 5.8%, P = .37). Witnessed aspiration events (0.6% vs 0%, P = .36), ventilator-associated pneumonia (0% vs 0.7%, P = .27), 30-d mortality (31.3% vs 30.2%, P = .83), and hospital length of stay (10 d [6 d, 21 d] vs 11 d [6 d, 21 d], P = .34) were also similar for both study groups. The 30-d hospital readmission rate was statistically lower for the group that received infrequent monitoring (15.1% vs 6.5%, P = .02). CONCLUSIONS: More frequent cuff pressure monitoring was not associated with any identifiable clinical outcome benefit. PMID- 29382792 TI - Prolonged Mechanical Ventilation as a Predictor of Mortality After Cardiac Surgery. AB - BACKGROUND: Mortality among the small percentage of cardiac surgery patients receiving prolonged mechanical ventilation is high, but this issue appears to be inadequately addressed in guidelines. METHODS: This study is a retrospective analysis of prospective, multi-center, and observational study in Spain including all adults undergoing cardiac surgery in 3 Andalusian hospitals between June 2008 and December 2012. RESULTS: The study included 3,588 adults with mean +/- SD age of 63.5 +/- 12.8 y and with median (interquartile range) EuroSCORE of 5 (3-7) points. Prolonged mechanical ventilation (> 24 h) was required by 415 subjects (11.6%), with ICU mortality of 44.3% (184 subjects), and was not required by 3,173 subjects (88.4%), with ICU mortality of 3.1% (99 subjects, P < .001). Prolonged mechanical ventilation was associated with more complications and was required by 4.5% of subjects with a EuroSCORE <5, 11.2% with a score of 5-7, 27.2% with a score of 8-10, and 32.2% with a score > 10. In the multivariable analysis, ICU mortality was associated with illness severity, duration of bypass surgery, surgery type, and prolonged mechanical ventilation (odds ratio 15.19, 95% CI 11.56-22.09). The main cause of death was multiple organ failure and sepsis in subjects who required prolonged mechanical ventilation (50.3%) and cardiogenic shock in those who did not (59.2%). CONCLUSION: Prolonged postoperative mechanical ventilation was required by 10-20% of cardiac surgery subjects, who constitute a specific group that represents most of the postoperative mortality, which is associated with multiple organ failure and sepsis. PMID- 29382795 TI - Evaluation of a Low-Cost Bubble CPAP System Designed for Resource-Limited Settings. AB - BACKGROUND: Respiratory compromise is a leading contributor to global neonatal death. CPAP is a method of treatment that helps maintain lung volume during expiration, promotes comfortable breathing, and improves oxygenation. Bubble CPAP is an effective alternative to standard CPAP. We sought to determine the reliability and functionality of a low-cost bubble CPAP device designed for low resource settings. METHODS: The low-cost bubble CPAP device was compared to a commercially available bubble CPAP system. The devices were connected to a lung simulator that simulated neonates of 4 different weights with compromised respiratory mechanics (~1, ~3, ~5, and ~10 kg). The devices' abilities to establish and maintain pressure and flow under normal conditions as well as under conditions of leak were compared. Multiple combinations of pressure levels (5, 8, and 10 cm H2O) and flow levels (3, 6, and 10 L/min) were tested. The endurance of both devices was also tested by running the systems continuously for 8 h and measuring the changes in pressure and flow. RESULTS: Both devices performed equivalently during the no-leak and leak trials. While our testing revealed individual differences that were statistically significant and clinically important (>10% difference) within specific CPAP and flow-level settings, no overall comparisons of CPAP or flow were both statistically significant and clinically important. Each device delivered pressures similar to the desired pressures, although the flows delivered by both machines were lower than the set flows in most trials. During the endurance trials, the low-cost device was marginally better at maintaining pressure, while the commercially available device was better at maintaining flow. CONCLUSIONS: The low-cost bubble CPAP device evaluated in this study is comparable to a bubble CPAP system used in developed settings. Extensive clinical trials, however, are necessary to confirm its effectiveness. PMID- 29382796 TI - Friend or foe? The dual role of neutrophils in lung injury and repair. PMID- 29382798 TI - Oleothorax. PMID- 29382797 TI - Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury. AB - BACKGROUND: Tumour necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-alpha, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807. PMID- 29382799 TI - Body mass index status and peripheral airway obstruction in school-age children: a population-based cohort study. AB - BACKGROUND: Few large prospective studies have investigated the impact of body mass index (BMI) on lung function during childhood. METHODS: Using data collected between 2002 and 2013, we analysed associations between BMI status and lung function (assessed by spirometry) from 8 to 16 years, as well as cross-sectional associations with small airway function (impulse oscillometry) at 16 years in the BAMSE cohort (n=2889). At 16 years, cross-sectional associations with local and systemic inflammation were investigated by analysing FENO, blood eosinophils and neutrophils. RESULTS: Overweight and obesity at 8 years were associated with higher FVC, but lower FEV1/FVC ratio at 8 and 16 years. In boys, but not girls, obesity at 8 years was associated with a further reduction in FEV1/FVC between 8 and 16 years. In cross-sectional analyses, overweight and obesity were associated with higher frequency dependence of resistance (R5-20) and larger area under the reactance curve (AX0.5) at 16 years. Increased blood neutrophil counts were seen in overweight and obese girls, but not in boys. No association was found between BMI status and FENO. Persistent, but not transient, overweight/obesity between 8 and 16 years was associated with higher R5-20 and AX0.5 and lower FEV1/FVC (-2.8% (95% CI -4.1 to -1.2) in girls and -2.7% (95% CI -4.4 to -1.1) in boys) at 16 years, compared with persistent normal weight. CONCLUSION: In childhood and adolescence, overweight and obesity, particularly persistent overweight, were associated with evidence of airway obstruction, including the small airways. PMID- 29382800 TI - Case of paediatric neuromuscular disease with a surprising clinical outcome: time to challenge the dogma? PMID- 29382801 TI - Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation. AB - Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD. PMID- 29382802 TI - Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke. AB - BACKGROUND AND PURPOSE: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. METHODS: We tested the efficacy of acute (1.5 hours) or delayed (1-3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7-14 weeks) and aged mice (20-22 months) of both sexes, as well as adult marmosets of either sex. RESULTS: We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. CONCLUSIONS: Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery. PMID- 29382804 TI - Association of Progression of Carotid Artery Wall Volume and Recurrent Transient Ischemic Attack or Stroke: A Magnetic Resonance Imaging Study. AB - BACKGROUND AND PURPOSE: This study aimed to investigate the association between carotid plaque progression and subsequent recurrent events using magnetic resonance imaging. METHODS: Sixty-three symptomatic patients with ipsilateral carotid atherosclerotic stenosis (30%-69% stenosis) determined by ultrasound underwent first and second carotid artery magnetic resonance imaging for carotid artery at baseline and >=6 months after the first scan, respectively. All the patients had clinical follow-up after the second magnetic resonance scan for <=5 years until the onset of recurrent transient ischemic attack or stroke. Presence/absence of carotid plaque compositional features, particularly intraplaque hemorrhage and fibrous cap rupture was identified. The annual progression of carotid wall volume between 2 magnetic resonance scans was measured. Univariate and multivariate Cox regression was used to calculate the hazard ratio and corresponding 95% confidence interval of carotid plaque features in discriminating recurrent events. Receiver-operating-characteristic-curve analysis was conducted to determine the area-under-the-curve of carotid plaque features in predicting recurrent events. RESULTS: Sixty-three patients (mean age: 66.5+/-10.0 years old; 54 males) were eligible for final statistics analysis. During a mean follow-up duration of 55.1+/-13.6 months, 14.3% of patients (n=9) experienced ipsilateral recurrent transient ischemic attack/stroke. The annual progression of carotid wall volume was significantly associated with recurrent events before (hazard ratio, 1.14 per 10 mm3; 95% confidence interval, 1.02-1.27; P=0.019) and after (hazard ratio, 1.19 per 10 mm3; 95% confidence interval, 1.03 1.37; P=0.022) adjusted for confounding factors. In discriminating the recurrence of transient ischemia attack/stroke, receiver-operator curve analysis indicated that combined with annual progression of wall volume, there was a significant incremental improvement in the area-under-the-curve of intraplaque hemorrhage (area-under-the-curve: 0.69-0.81) and fibrous cap rupture (area-under-the-curve: 0.73-0.84). CONCLUSIONS: The annual progression of carotid wall volume is independently associated with recurrent ischemic cerebrovascular events, and this measurement has added value for intraplaque hemorrhage and fibrous cap rupture in predicting future events. PMID- 29382803 TI - Outcome After Reperfusion Therapies in Patients With Large Baseline Diffusion Weighted Imaging Stroke Lesions: A THRACE Trial (Mechanical Thrombectomy After Intravenous Alteplase Versus Alteplase Alone After Stroke) Subgroup Analysis. AB - BACKGROUND AND PURPOSE: Stroke patients with large diffusion-weighted imaging (DWI) volumes are often excluded from reperfusion because of reckoned futility. In those with DWIvolume >70 mL, included in the THRACE trial (Mechanical Thrombectomy After Intravenous Alteplase Versus Alteplase Alone After Stroke), we report the associations between baseline parameters and outcome. METHODS: We examined 304 patients with anterior circulation stroke and pretreatment magnetic resonance imaging. Variables were extracted from the THRACE database, and DWI volumes were measured semiautomatically. RESULTS: Among 53 patients with DWIvolume >70 mL, 12 had favorable outcome (modified Rankin Scale score, <=2) at 3 months; they had less coronary disease (0/12 versus 12/38; P=0.046) and less history of smoking (1/10 versus 12/31; P=0.013) than patients with modified Rankin Scale score >2. None of the 8 patients >75 years of age reached modified Rankin Scale score <=2. Favorable outcome occurred in 12 of 37 M1-occluded patients but in 0 of 16 internal carotid-T/L-occluded patients (P=0.010). Favorable outcome was more frequent (6/13) when DWI lesion was limited to the superficial middle cerebral artery territory than when it extended to the deep middle cerebral artery territory (6/40; P=0.050). CONCLUSIONS: Stroke patients with DWI lesion >70 mL may benefit from reperfusion therapy, especially those with isolated M1 occlusion or ischemia restricted to the superficial middle cerebral artery territory. The benefit of treatment seems questionable for patients with carotid occlusion or lesion extending to the deep middle cerebral artery territory. PMID- 29382807 TI - Correction for Phosphorylation of multiple sites within an acidic region of Alcadein alpha is required for kinesin-1 association and Golgi exit of Alcadein alpha cargo. PMID- 29382805 TI - Exploring new routes for secretory protein export from the trans-Golgi network. AB - Sorting of soluble proteins for transport to intracellular compartments and for secretion from cells is essential for cell and tissue homeostasis. The trans Golgi network (TGN) is a major sorting station that sorts secretory proteins into specific carriers to transport them to their final destinations. The sorting of lysosomal hydrolases at the TGN by the mannose 6-phosphate receptor is well understood. The recent discovery of a Ca2+-based sorting of secretory cargo at the TGN is beginning to uncover the mechanism by which cells sort secretory cargoes from Golgi residents and cargoes destined to the other cellular compartments. This Ca2+-based sorting involves the cytoplasmic actin cytoskeleton, which through membrane anchored Ca2+ ATPase SPCA1 and the luminal Ca2+ binding protein Cab45 sorts of a subset of secretory proteins at the TGN. We present this discovery and highlight important challenges that remain unaddressed in the overall pathway of cargo sorting at the TGN. PMID- 29382806 TI - Same but different: pleiotropy in centrosome-related microcephaly. AB - An intimate link between centrosome function and neurogenesis is revealed by the identification of many genes with centrosome-associated functions that are mutated in microcephaly disorders. Consistent with the major role of the centrosome in mitosis, mutations in these centrosome-related microcephaly (CRM) genes are thought to affect neurogenesis by depleting the pool of neural progenitor cells, primarily through apoptosis as a consequence of mitotic failure or premature differentiation as a consequence of cell cycle delay and randomization of spindle orientation. However, as suggested by the wide range of microcephaly phenotypes and the multifunctional nature of many CRM proteins, this picture of CRM gene function is incomplete. Here, we explore several examples of CRM genes pointing to additional functions that contribute to microcephaly, including regulation of cell cycle signaling, actin cytoskeleton, and Hippo pathway proteins, as well as functions in postmitotic neurons and glia. As these examples are likely just the tip of the iceberg, further exploration of the roles of microcephaly-related genes are certain to reveal additional unforeseen functions important for neurodevelopment. PMID- 29382808 TI - Protein Immunodepletion and Complementation in Xenopus laevis Egg Extracts. AB - The Xenopus egg extract system has been widely used to study cell cycle events, including DNA replication, nuclear envelope formation, spindle assembly, chromosome condensation and kinetochore formation. The functional roles of the proteins involved in these processes can be determined by immunodepleting a protein of interest from the extract. As immunodepletion may result in co depletion of other proteins, the protein of interest can be added back to the extract to verify its function. Additionally, proteins harboring point mutations or domain deletions may be added to assess their functions. Here we outline the immunodepletion procedure and two separate methods for restoring a protein of interest: addition of either a recombinant protein or an mRNA that supports translation in egg extracts. The tradeoffs between these two methods are discussed. PMID- 29382809 TI - Patch-Clamp and Perfusion Techniques to Study Ion Channels Expressed in Xenopus Oocytes. AB - The Xenopus oocyte expression system is ideal for electrophysiological characterization of voltage-dependent and ligand-dependent ion channels because of its relatively low background of endogenous channels and the large size of the cell. Here, we present a protocol to study voltage- and ligand-dependent activation of ion channels expressed in Xenopus oocytes using patch-clamp techniques designed to control both the membrane voltage and the intracellular solution. In this protocol, the large conductance voltage- and Ca2+-activated K+ (BK) channel is studied as an example. After injection of BK channel mRNA, oocytes are incubated for 2-7 d at 18 degrees C. Inside-out membrane patches containing single or multiple BK channels are excised with perfusion of different solutions during recording. The protocol can be used to study structure-function relations for ion channels and neurotransmitter receptors. PMID- 29382810 TI - Isolation and Analysis of Xenopus Germinal Vesicles. AB - The giant nucleus or germinal vesicle (GV) of Xenopus oocytes provides an unusual opportunity to analyze nuclear structure and function in exquisite detail by light microscopy. Detailed here are two rapid procedures for using manually isolated GVs in combination with fluorescent reporter proteins to investigate the lampbrush chromosomes and nuclear bodies of oocytes. One procedure provides spreads of nuclear components in an unfixed and life-like, although not living, form. The other describes the isolation of intact, functional GVs directly into mineral oil offering possibilities for direct observation of nuclear dynamics. PMID- 29382811 TI - RNAi-Mediated Loss of Function of Xenopus Immune Genes by Transgenesis. AB - Generation of transgenic frogs through the stable integration of foreign DNA into the genome is well established in Xenopus This protocol describes the combination of transgenesis with stable RNA interference as an efficient reverse genetic approach to study gene function in Xenopus Initially developed in the fish medaka and later adapted to Xenopus, this transgenic method uses the I-SceI meganuclease, a "rare-cutter" endonuclease with an 18 bp recognition sequence. In this protocol, transgenic X. laevis with knocked down expression of a specific gene are generated using a double promoter expression cassette. This cassette, which is flanked by I-SceI recognition sites, contains the shRNA of choice under the control of the human U6 promoter and a green fluorescent protein (GFP) reporter gene under the control of the human EF-1alpha promoter. Prior to microinjection the plasmid is linearized by digestion with I-SceI and the entire reaction is then microinjected into one-cell stage eggs. The highly stringent recognition sequence of I-SceI is thought to maintain the linearized plasmid in a nonconcatamerized state, which promotes random integration of the plasmid transgene in the genome. The injected embryos are reared until larval stage 56 and then screened for GFP expression by fluorescence microscopy and assessed for effective knockdown by quantitative RT-PCR using a tail biopsy. Typically, the I SceI meganuclease transgenesis technique results in 35%-50% transgenesis efficiency, a high survival rate (>35%) and bright nonmosaic GFP expression. A key advantage of this technique is that the high efficiency and nonmosaic transgene expression permit the direct use of F0 animals. PMID- 29382812 TI - Evaluation and Management of Spinal Subarachnoid Hemorrhage in a Patient with Lupus Vasculitis. AB - BACKGROUND Isolated spinal artery subarachnoid hemorrhage is a rare occurrence in the general population, but occurs more commonly as one of many neurologic sequela of systemic lupus erythematosus (SLE). The etiology of a neurologic deficit in an SLE patient is often multifactorial. Comorbid conditions, such as antiphospholipid antibody syndrome, predispose to stroke. Other diagnoses, including transverse myelitis, may also be attributed to local inflammation. CASE REPORT A 37-year-old woman with SLE and antiphospholipid antibody syndrome experienced severe back pain followed by sudden paralysis and sensory loss below the T2 level. She remained alert and oriented on examination, with neurologic exam positive for diminished strength in the arms and with total loss of sensation and strength in the legs. Diagnostic workup was limited due to a contrast allergy and severe lupus nephritis; however, initial imaging showed increased cervical-thoracic spinal cord signal and concern for acute blood in the subarachnoid space. No neurosurgical intervention occurred, and the patient was treated with high-dose steroids and plasmapheresis for a possible transverse myelitis and non-aneurysmal subarachnoid hemorrhage. The patient received further neurologic and rheumatologic workup and remained neurologically stable, with improvement in proximal arm strength on physical exam. CONCLUSIONS We highlight the diagnostic challenges in treating a patient with SLE with acute paralysis and sensory loss. In this case, aggressive early treatment of the patient's myelitis and myelopathy were successful in leading to mild neurological improvement. PMID- 29382813 TI - Acute Hypervolemic Infusion Can Improve Splanchnic Perfusion in Elderly Patients During Laparoscopic Colorectal Surgery. AB - BACKGROUND There is no adequate evidence on how the long duration of laparoscopic surgery affects splanchnic perfusion in elderly patients or the efficacy of acute hypervolemic fluid infusion (AHFI) during the induction of anesthesia. Our aim was to observe the effects of AHFI during the induction of general anesthesia on splanchnic perfusion. MATERIAL AND METHODS Seventy elderly patients receiving laparoscopic colorectal surgery were randomly divided into three groups: lactated Ringer's solution group (group R), succinylated gelatin group (group G), and hypertonic sodium chloride hydroxyethyl starch 40 injection group (group H). Thirty minutes after the induction of general anesthesia, patients received an infusion of target dose of these three solutions. Corresponding hemodynamic parameters, arterial blood gas analysis, and gastric mucosal carbon dioxide tension were monitored in sequences. RESULTS In all three groups, gastric arterial partial CO2 pressure gaps (Pg-aCO2) were decreased at several beginning stages and then gradually increased, Pg-aCO2 also varied between groups due to certain time points. The pH values of gastric mucosa (pHi) decreased gradually after the induction of pneumoperitoneum in the three groups. CONCLUSIONS The AHFI of succinylated gelatin (12 ml/kg) during the induction of anesthesia can improve splanchnic perfusion in elderly patients undergoing laparoscopic surgery for colorectal cancer and maintain good splanchnic perfusion even after a long period of pneumoperitoneum (60 minutes). AHFI can improve splanchnic perfusion in elderly patients undergoing laparoscopic colorectal surgery. PMID- 29382814 TI - Social affective context reveals altered network dynamics in schizophrenia patients. AB - Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks' NCI dynamic during the social affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another's' distress may underlie social-affective deficits in schizophrenia. PMID- 29382815 TI - Extended amygdala connectivity changes during sustained shock anticipation. AB - The bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) of the extended amygdala are small, anatomically interconnected brain regions. They are thought to mediate responses to sustained, unpredictable threat stimuli and phasic, predictable threat stimuli, respectively. They perform these operations largely through their interconnected networks. In two previous studies, we mapped and contrasted the resting functional connectivity networks of the BNST and CeA at 7 Tesla with high resolution. This follow-up study investigates the changes in functional connectivity of these structures during sustained anticipation of electric shock. Results show that the BNST and CeA become less strongly coupled with the ventromedial prefrontal cortex (vmPFC), cingulate, and nucleus accumbens in shock threat relative to a safety condition. In addition, the CeA becomes more strongly coupled with the thalamus under threat. An exploratory, whole-brain connectivity analysis reveals that, although the BNST/CeA exhibits generally decreased connectivity, many other cortical regions demonstrate greater coupling under threat than safety. Understanding the differential network structures of these two regions and how they contribute to processing under threat will help elucidate the building blocks of the anxious state. PMID- 29382816 TI - A carbon nanotube tape for serial-section electron microscopy of brain ultrastructure. AB - Automated tape-collecting ultramicrotomy in conjunction with scanning electron microscopy (SEM) is a powerful approach for volume electron microscopy and three dimensional neuronal circuit analysis. Current tapes are limited by section wrinkle formation, surface scratches and sample charging during imaging. Here we show that a plasma-hydrophilized carbon nanotube (CNT)-coated polyethylene terephthalate (PET) tape effectively resolves these issues and produces SEM images of comparable quality to those from transmission electron microscopy. CNT tape can withstand multiple rounds of imaging, offer low surface resistance across the entire tape length and generate no wrinkles during the collection of ultrathin sections. When combined with an enhanced en bloc staining protocol, CNT tape-processed brain sections reveal detailed synaptic ultrastructure. In addition, CNT tape is compatible with post-embedding immunostaining for light and electron microscopy. We conclude that CNT tape can enable high-resolution volume electron microscopy for brain ultrastructure analysis. PMID- 29382817 TI - Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology. AB - Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCalpha as the kinase responsible for the early stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCalpha via PLCgamma, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease. PMID- 29382818 TI - Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration. AB - During development, mesodermal progenitors from the first heart field (FHF) form a primitive cardiac tube, to which progenitors from the second heart field (SHF) are added. The contribution of FHF and SHF progenitors to the adult zebrafish heart has not been studied to date. Here we find, using genetic tbx5a lineage tracing tools, that the ventricular myocardium in the adult zebrafish is mainly derived from tbx5a+ cells, with a small contribution from tbx5a- SHF progenitors. Notably, ablation of ventricular tbx5a+-derived cardiomyocytes in the embryo is compensated by expansion of SHF-derived cells. In the adult, tbx5a expression is restricted to the trabeculae and excluded from the outer cortical layer. tbx5a lineage tracing revealed that trabecular cardiomyocytes can switch their fate and differentiate into cortical myocardium during adult heart regeneration. We conclude that a high degree of cardiomyocyte cell fate plasticity contributes to efficient regeneration. PMID- 29382820 TI - Similar neural responses predict friendship. AB - Human social networks are overwhelmingly homophilous: individuals tend to befriend others who are similar to them in terms of a range of physical attributes (e.g., age, gender). Do similarities among friends reflect deeper similarities in how we perceive, interpret, and respond to the world? To test whether friendship, and more generally, social network proximity, is associated with increased similarity of real-time mental responding, we used functional magnetic resonance imaging to scan subjects' brains during free viewing of naturalistic movies. Here we show evidence for neural homophily: neural responses when viewing audiovisual movies are exceptionally similar among friends, and that similarity decreases with increasing distance in a real-world social network. These results suggest that we are exceptionally similar to our friends in how we perceive and respond to the world around us, which has implications for interpersonal influence and attraction. PMID- 29382819 TI - RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. AB - Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the beta-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP-TEAD and beta-catenin-TCF3 complexes on the Oct4 distal enhancer. However, during differentiation, promoter demethylation allows GATA1 mediated RASSF1A expression which prevents YAP from contributing to the TEAD/beta catenin-TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP-p73 transcriptional programme that enables differentiation. Together, our findings demonstrate that RASSF1A mediates transcription factor selection of YAP in stem cells, thereby acting as a functional "switch" between pluripotency and initiation of differentiation. PMID- 29382821 TI - Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. AB - The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models. PMID- 29382823 TI - Publisher Correction: Ticks parasitised feathered dinosaurs as revealed by Cretaceous amber assemblages. AB - The originally published version of this Article was updated shortly after publication to add the word 'Ticks' to the title, following its inadvertent removal during the production process. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29382824 TI - Genetic estimators of DNA methylation provide insights into the molecular basis of polygenic traits. AB - The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits. PMID- 29382822 TI - Bismuth antimicrobial drugs serve as broad-spectrum metallo-beta-lactamase inhibitors. AB - Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-beta-lactamases (MBLs), e.g., New Delhi metallo-beta-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL positive bacterial infection in conjunction with existing carbapenems. PMID- 29382825 TI - Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer's disease by exerting anti inflammatory and neuroprotective effects. AB - In an aging society, Alzheimer's disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month old) and adult (12-month-old) 3*Tg-AD mice that received ultramicronized PEA (um PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription-polymerase chain reaction (RT PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3*Tg-AD mice. Moreover, it reduces Abeta formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use. PMID- 29382826 TI - Ubiquitin C decrement plays a pivotal role in replicative senescence of bone marrow mesenchymal stromal cells. AB - Human bone marrow-mesenchymal stromal cells (hBM-MSCs) undergo cellular senescence during in vitro culture. In this study, we defined this replicative senescence as impaired proliferation, deterioration in representative cell characteristics, accumulated DNA damage, and decreased telomere length and telomerase activity with or without genomic abnormalities. The UBC gene expression gradually decreased during passaging along with the reduction in series of molecules including hub genes; CDK1, CCNA2, MCM10, E2F1, BRCA1, HIST1H1A and HIST1H3B. UBC knockdown in hBM-MSCs induced impaired proliferation in dose-dependent manner and showed replicative senescence-like phenomenon. Gene expression changes after UBC knockdown were similar to late passage hBM-MSCs. Additionally, UBC overexpession improved the proliferation activity of hBM-MSCs accompanied by increased expression of the hub genes. Consequently, UBC worked in higher-order through regulation of the hub genes controlling cell cycle and proliferation. These results indicate that the decrement of UBC expression plays a pivotal role in replicative senescence of hBM-MSCs. PMID- 29382827 TI - Probability of phenotypically detectable protein damage by ENU-induced mutations in the Mutagenetix database. AB - Computational inference of mutation effects is necessary for genetic studies in which many mutations must be considered as etiologic candidates. Programs such as PolyPhen-2 predict the relative severity of damage caused by missense mutations, but not the actual probability that a mutation will reduce/eliminate protein function. Based on genotype and phenotype data for 116,330 ENU-induced mutations in the Mutagenetix database, we calculate that putative null mutations, and PolyPhen-2-classified "probably damaging", "possibly damaging", or "probably benign" mutations have, respectively, 61%, 17%, 9.8%, and 4.5% probabilities of causing phenotypically detectable damage in the homozygous state. We use these probabilities in the estimation of genome saturation and the probability that individual proteins have been adequately tested for function in specific genetic screens. We estimate the proportion of essential autosomal genes in Mus musculus (C57BL/6J) and show that viable mutations in essential genes are more likely to induce phenotype than mutations in non-essential genes. PMID- 29382828 TI - Cardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES. AB - Master cell fate determinants are thought to induce specific cell lineages in gastrulation by orchestrating entire gene programs. The T-box transcription factor EOMES (eomesodermin) is crucially required for the development of the heart-yet it is equally important for endoderm specification suggesting that it may act in a context-dependent manner. Here, we define an unrecognized interplay between EOMES and the WNT signaling pathway in controlling cardiac induction by using loss and gain-of-function approaches in human embryonic stem cells. Dose dependent EOMES induction alone can fully replace a cocktail of signaling molecules otherwise essential for the specification of cardiogenic mesoderm. Highly efficient cardiomyocyte programming by EOMES mechanistically involves autocrine activation of canonical WNT signaling via the WNT3 ligand, which necessitates a shutdown of this axis at a subsequent stage. Our findings provide insights into human germ layer induction and bear biotechnological potential for the robust production of cardiomyocytes from engineered stem cells. PMID- 29382829 TI - Type IX secretion system PorM and gliding machinery GldM form arches spanning the periplasmic space. AB - Type IX secretion system (T9SS), exclusively present in the Bacteroidetes phylum, has been studied mainly in Flavobacterium johnsoniae and Porphyromonas gingivalis. Among the 18 genes, essential for T9SS function, a group of four, porK-N (P. gingivalis) or gldK-N (F. johnsoniae) belongs to a co-transcribed operon that expresses the T9SS core membrane complex. The central component of this complex, PorM (or GldM), is anchored in the inner membrane by a trans membrane helix and interacts through the outer membrane PorK-N complex. There is a complete lack of available atomic structures for any component of T9SS, including the PorKLMN complex. Here we report the crystal structure of the GldM and PorM periplasmic domains. Dimeric GldM and PorM, each contain four domains of ~180-A length that span most of the periplasmic space. These and previously reported results allow us to propose a model of the T9SS core membrane complex as well as its functional behavior. PMID- 29382831 TI - Single-cell replication profiling to measure stochastic variation in mammalian replication timing. AB - Mammalian DNA replication is regulated via multi-replicon segments that replicate in a defined temporal order during S-phase. Further, early/late replication of RDs corresponds to active/inactive chromatin interaction compartments. Although replication origins are selected stochastically, variation in replication timing is poorly understood. Here we devise a strategy to measure variation in replication timing using DNA copy number in single mouse embryonic stem cells. We find that borders between replicated and unreplicated DNA are highly conserved between cells, demarcating active and inactive compartments of the nucleus. Fifty percent of replication events deviated from their average replication time by +/- 15% of S phase. This degree of variation is similar between cells, between homologs within cells and between all domains genomewide, regardless of their replication timing. These results demonstrate that stochastic variation in replication timing is independent of elements that dictate timing or extrinsic environmental variation. PMID- 29382832 TI - Structure-guided design of an Hsp90beta N-terminal isoform-selective inhibitor. AB - The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90beta, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90beta-selective inhibitors as a method to overcome the detriments associated with pan-inhibition. PMID- 29382830 TI - Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. AB - Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing. PMID- 29382833 TI - Extension of the growing season increases vegetation exposure to frost. AB - While climate warming reduces the occurrence of frost events, the warming-induced lengthening of the growing season of plants in the Northern Hemisphere may actually induce more frequent frost days during the growing season (GSFDs, days with minimum temperature < 0 degrees C). Direct evidence of this hypothesis, however, is limited. Here we investigate the change in the number of GSFDs at latitudes greater than 30 degrees N using remotely-sensed and in situ phenological records and three minimum temperature (Tmin) data sets from 1982 to 2012. While decreased GSFDs are found in northern Siberia, the Tibetan Plateau, and northwestern North America (mainly in autumn), ~43% of the hemisphere, especially in Europe, experienced a significant increase in GSFDs between 1982 and 2012 (mainly during spring). Overall, regions with larger increases in growing season length exhibit larger increases in GSFDs. Climate warming thus reduces the total number of frost days per year, but GSFDs nonetheless increase in many areas. PMID- 29382834 TI - Metabolite identification in fecal microbiota transplantation mouse livers and combined proteomics with chronic unpredictive mild stress mouse livers. AB - Major depressive disorder (MDD) is a common mood disorder. Gut microbiota may be involved in the pathogenesis of depression via the microbe-gut-brain axis. Liver is vulnerable to exposure of bacterial products translocated from the gut via the portal vein and may be involved in the axis. In this study, germ-free mice underwent fecal microbiota transplantation from MDD patients and healthy controls. Behavioral tests verified the depression model. Metabolomics using gas chromatography-mass spectrometry, nuclear magnetic resonance, and liquid chromatography-mass spectrometry determined the influence of microbes on liver metabolism. With multivariate statistical analysis, 191 metabolites were distinguishable in MDD mice from control (CON) mice. Compared with CON mice, MDD mice showed lower levels for 106 metabolites and higher levels for 85 metabolites. These metabolites are associated with lipid and energy metabolism and oxidative stress. Combined analyses of significantly changed proteins in livers from another depression model induced by chronic unpredictive mild stress returned a high score for the Lipid Metabolism, Free Radical Scavenging, and Molecule Transports network, and canonical pathways were involved in energy metabolism and tryptophan degradation. The two mouse models of depression suggest that changes in liver metabolism might be involved in the pathogenesis of MDD. Conjoint analyses of fecal, serum, liver, and hippocampal metabolites from fecal microbiota transplantation mice suggested that aminoacyl-tRNA biosynthesis significantly changed and fecal metabolites showed a close relationship with the liver. These findings may help determine the biological mechanisms of depression and provide evidence about "depression microbes" impacting on liver metabolism. PMID- 29382835 TI - A clean and membrane-free chlor-alkali process with decoupled Cl2 and H2/NaOH production. AB - Existing chlor-alkali processes generally use asbestos, mercury or fluorine containing ion-exchange membranes to separate the simultaneous chlorine production on the anode and hydrogen production on the cathode, and form sodium hydroxide in the electrolyte. Here, using the Na+ de-intercalation/intercalation of a Na0.44MnO2 electrode as a redox mediator, we decouple the chlor-alkali process into two independent steps: a H2 production step with the NaOH formation in the electrolyte and a Cl2 production step. The first step involves a cathodic H2 evolution reaction (H2O -> H2) and an anodic Na+ de-intercalation reaction (Na0.44MnO2 -> Na0.44-xMnO2), during which NaOH is produced in the electrolyte solution. The second step depends on a cathodic Na+ intercalation reaction (Na0.44-xMnO2 -> Na0.44MnO2) and an anodic Cl2 production (Cl -> Cl2). The cycle of the two steps provides a membrane-free process, which is potentially a promising direction for developing clean chlor-alkali technology. PMID- 29382837 TI - Author Correction: Induced unconventional superconductivity on the surface states of Bi2Te3 topological insulator. AB - The original version of this Article contained an error in Fig. 6b. In the top scattering process, while the positioning of both arrows was correct, the colours were switched: the first arrow was red and the second arrow was blue, rather than the correct order of blue then red. PMID- 29382836 TI - Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody. AB - Tick-borne encephalitis virus (TBEV) causes 13,000 cases of human meningitis and encephalitis annually. However, the structure of the TBEV virion and its interactions with antibodies are unknown. Here, we present cryo-EM structures of the native TBEV virion and its complex with Fab fragments of neutralizing antibody 19/1786. Flavivirus genome delivery depends on membrane fusion that is triggered at low pH. The virion structure indicates that the repulsive interactions of histidine side chains, which become protonated at low pH, may contribute to the disruption of heterotetramers of the TBEV envelope and membrane proteins and induce detachment of the envelope protein ectodomains from the virus membrane. The Fab fragments bind to 120 out of the 180 envelope glycoproteins of the TBEV virion. Unlike most of the previously studied flavivirus-neutralizing antibodies, the Fab fragments do not lock the E-proteins in the native-like arrangement, but interfere with the process of virus-induced membrane fusion. PMID- 29382838 TI - Identification of OsGGR2, a second geranylgeranyl reductase involved in alpha tocopherol synthesis in rice. AB - Tocopherol (Toc) and tocotrienol (T3) are abundant in rice bran. Geranylgeranyl reductase (GGR) is an essential enzyme for Toc production that catalyzes the reduction of geranylgeranyl pyrophosphate and geranylgeranyl-chlorophyll. However, we found that a rice mutant line with inactivated Os02g0744900 (OsGGR1/LYL1/OsChl P) gene produces Toc, suggesting that rice plants may carry another enzyme with GGR activity. Using an RNA-mediated interference technique, we demonstrated that the Os01g0265000 ("OsGGR2") gene product has GGR activity. This result supports the existence of two GGR genes (OsGGR1 and OsGGR2) in rice, in contrast to Arabidopsis thaliana (thale cress) and cyanobacterium Synechocystis that each have only one GGR gene. We also produced rice callus with inactivated OsGGR1 and OsGGR2 that produced T3 but not Toc. Such rice callus could be used as a resource for production of pure T3 for nutraceutical applications. PMID- 29382839 TI - Towards the scale-up of the formation of nanoparticles on alpha-Ag2WO4 with bactericidal properties by femtosecond laser irradiation. AB - In recent years, complex nanocomposites formed by Ag nanoparticles coupled to an alpha-Ag2WO4 semiconductor network have emerged as promising bactericides, where the semiconductor attracts bacterial agents and Ag nanoparticles neutralize them. However, the production rate of such materials has been limited to transmission electron microscope processing, making it difficult to cross the barrier from basic research to real applications. The interaction between pulsed laser radiation and alpha-Ag2WO4 has revealed a new processing alternative to scale up the production of the nanocomposite resulting in a 32-fold improvement of bactericidal performance, and at the same time obtaining a new class of spherical AgxWyOz nanoparticles. PMID- 29382840 TI - Author Correction: Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1. AB - The original version of this Article contained an error in the spelling of the author Alvaro Sebastian-Serrano, which was incorrectly given as Alvaro Sebastian Serrano. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29382841 TI - Topology-dependent self-structure mediation and efficient energy conversion in heat-flux-driven rotors of cholesteric droplets. AB - When heat flux is applied to a chiral liquid crystal, unidirectional rotation is induced around the flux axis, as first discovered by Otto Lehmann in 1900. In recent years, this heat-flux-induced phenomenon has been studied mostly in droplets of cholesteric liquid crystals undergoing phase transition from the isotropic to cholesteric phase, i.e., in the coexistence region, which occurs over a very narrow temperature range. Here, we report that the heat-flux-induced rotation can be stabilised by the use of a dispersion system, in which the cholesteric droplets are dispersed in a viscous and poorly miscible isotropic solvent. Interestingly, the phenomenon is found to be topology dependent. Moreover, the rotation is not only stable but also more efficient than that in the known systems. We describe in detail how the dynamics of the heat-flux induced rotation are altered in the present dispersion system. PMID- 29382842 TI - The SR protein B52/SRp55 regulates splicing of the period thermosensitive intron and mid-day siesta in Drosophila. AB - Similar to many diurnal animals, Drosophila melanogaster exhibits a mid-day siesta that is more robust as temperature increases, an adaptive response that aims to minimize the deleterious effects from exposure to heat. This temperature dependent plasticity in mid-day sleep levels is partly based on the thermal sensitive splicing of an intron in the 3' untranslated region (UTR) of the circadian clock gene termed period (per). In this study, we evaluated a possible role for the serine/arginine-rich (SR) splicing factors in the regulation of dmpi8 splicing efficiency and mid-day siesta. Using a Drosophila cell culture assay we show that B52/SRp55 increases dmpi8 splicing efficiency, whereas other SR proteins have little to no effect. The magnitude of the stimulatory effect of B52 on dmpi8 splicing efficiency is modulated by natural variation in single nucleotide polymorphisms (SNPs) in the per 3' UTR that correlate with B52 binding levels. Down-regulating B52 expression in clock neurons increases mid-day siesta and reduces dmpi8 splicing efficiency. Our results establish a novel role for SR proteins in sleep and suggest that polymorphisms in the per 3' UTR contribute to natural variation in sleep behavior by modulating the binding efficiencies of SR proteins. PMID- 29382843 TI - Comparative genomic and transcriptomic analyses of Family-1 UDP glycosyltransferase in three Brassica species and Arabidopsis indicates stress responsive regulation. AB - In plants, UGTs (UDP-glycosyltransferases) glycosylate various phytohormones and metabolites in response to biotic and abiotic stresses. Little is known about stress-responsive glycosyltransferases in plants. Therefore, it is important to understand the genomic and transcriptomic portfolio of plants with regard to biotic and abiotic stresses. Here, we identified 140, 154, and 251 putative UGTs in Brassica rapa, Brassica oleracea, and Brassica napus, respectively, and clustered them into 14 major phylogenetic groups (A-N). Fourteen major KEGG pathways and 24 biological processes were associated with the UGTs, highlighting them as unique modulators against environmental stimuli. Putative UGTs from B. rapa and B. oleracea showed a negative selection pressure and biased gene fractionation pattern during their evolution. Polyploidization increased the intron proportion and number of UGT-containing introns among Brassica. The putative UGTs were preferentially expressed in developing tissues and at the senescence stage. Differential expression of up- and down-regulated UGTs in response to phytohormone treatments, pathogen responsiveness and abiotic stresses, inferred from microarray and RNA-Seq data in Arabidopsis and Brassica broaden the glycosylation impact at the molecular level. This study identifies unique candidate UGTs for the manipulation of biotic and abiotic stress pathways in Brassica and Arabidopsis. PMID- 29382844 TI - Deciphering microvascular changes after myocardial infarction through 3D fully automated image analysis. AB - The microvasculature continuously adapts in response to pathophysiological conditions to meet tissue demands. Quantitative assessment of the dynamic changes in the coronary microvasculature is therefore crucial in enhancing our knowledge regarding the impact of cardiovascular diseases in tissue perfusion and in developing efficient angiotherapies. Using confocal microscopy and thick tissue sections, we developed a 3D fully automated pipeline that allows to precisely reconstruct the microvasculature and to extract parameters that quantify all its major features, its relation to smooth muscle actin positive cells and capillary diffusion regions. The novel pipeline was applied in the analysis of the coronary microvasculature from healthy tissue and tissue at various stages after myocardial infarction (MI) in the pig model, whose coronary vasculature closely resembles that of human tissue. We unravelled alterations in the microvasculature, particularly structural changes and angioadaptation in the aftermath of MI. In addition, we evaluated the extracted knowledge's potential for the prediction of pathophysiological conditions in tissue, using different classification schemes. The high accuracy achieved in this respect, demonstrates the ability of our approach not only to quantify and identify pathology-related changes of microvascular beds, but also to predict complex and dynamic microvascular patterns. PMID- 29382845 TI - HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition. AB - Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome. PMID- 29382846 TI - A novel human induced pluripotent stem cell blood-brain barrier model: Applicability to study antibody-triggered receptor-mediated transcytosis. AB - We have developed a renewable, scalable and transgene free human blood-brain barrier model, composed of brain endothelial cells (BECs), generated from human amniotic fluid derived induced pluripotent stem cells (AF-iPSC), which can also give rise to syngeneic neural cells of the neurovascular unit. These AF-iPSC derived BECs (i-BEC) exhibited high transendothelial electrical resistance (up to 1500 Omega cm2) inducible by astrocyte-derived molecular cues and retinoic acid treatment, polarized expression of functional efflux transporters and receptor mediated transcytosis triggered by antibodies against specific receptors. In vitro human BBB models enable pre-clinical screening of central nervous system (CNS)-targeting drugs and are of particular importance for assessing species specific/selective transport mechanisms. This i-BEC human BBB model discriminates species-selective antibody- mediated transcytosis mechanisms, is predictive of in vivo CNS exposure of rodent cross-reactive antibodies and can be implemented into pre-clinical CNS drug discovery and development processes. PMID- 29382848 TI - Design of an acoustic superlens using single-phase metamaterials with a star shaped lattice structure. AB - We propose a single-phase super lens with a low density that can achieve focusing of sound beyond the diffraction limit. The super lens has a star-shaped lattice structure made of steel that offers abundant resonances to produce abnormal dispersive effects as determined by negative parameter indices. Our analysis of the metamaterial band structure suggests that these star-shaped metamaterials have double-negative index properties, that can mediate these effects for sound in water. Simulations verify the effective focusing of sound by a single-phase solid lens with a spatial resolution of approximately 0.39 lambda. This superlens has a simple structure, low density and solid nature, which makes it more practical for application in water-based environments. PMID- 29382847 TI - Activated CD8+ T cell extracellular vesicles prevent tumour progression by targeting of lesional mesenchymal cells. AB - Fibroblastic tumour stroma comprising mesenchymal stem cells (MSCs) and cancer associated fibroblasts (CAFs) promotes the invasive and metastatic properties of tumour cells. Here we show that activated CD8+ T cell-derived extracellular vesicles (EVs) interrupt fibroblastic stroma-mediated tumour progression. Activated CD8+ T cells from healthy mice transiently release cytotoxic EVs causing marked attenuation of tumour invasion and metastasis by apoptotic depletion of mesenchymal tumour stromal cells. Infiltration of EV-producing CD8+ T cells is observed in neovascular areas with high mesenchymal cell density, and tumour MSC depletion is associated with preferential engulfment of CD8+ T cell EVs in this setting. Thus, CD8+ T cells have the capacity to protect tumour progression by EV-mediated depletion of mesenchymal tumour stromal cells in addition to their conventional direct cytotoxicity against tumour cells. PMID- 29382849 TI - Population-Wide Genetic Risk Prediction of Complex Diseases: A Pilot Feasibility Study in Macau Population for Precision Public Healthcare Planning. AB - The genetic bases of many common diseases have been identified through genome wide association studies in the past decade. However, the application of this approach on public healthcare planning has not been well established. Using Macau with population of around 650,000 as a basis, we conducted a pilot study to evaluate the feasibility of population genomic research and its potential on public health decisions. By performing genome-wide SNP genotyping of over a thousand Macau individuals, we evaluated the population genetic risk profiles of 47 non-communicable diseases and traits, as well as two traits associated with influenza infection. We found that for most of the diseases, the genetic risks of Macau population were different from those of Caucasian, but with similar profile with mainland Chinese. We also identified a panel of diseases that Macau population may have a high or elevated genetic risks. This pilot study showed that (1) population genomic study is feasible in Asian regions like Macau; (2) Macau may have different profile of population-based genetic risks than Caucasians, (3) the different prevalence of genetic risk profile indicates the importance of Asian-specific studies for Asian populations; and (4) the results generated may have an impact for going forward healthcare planning. PMID- 29382850 TI - A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome. AB - A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPARgamma and ADIPOR2. Changes in the expression of Nr4a2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement. PMID- 29382852 TI - A peak in the critical current for quantum critical superconductors. AB - Generally, studies of the critical current Ic are necessary if superconductors are to be of practical use, because Ic sets the current limit below which there is a zero-resistance state. Here, we report a peak in the pressure dependence of the zero-field Ic, Ic(0), at a hidden quantum critical point (QCP), where a continuous antiferromagnetic transition temperature is suppressed by pressure toward 0 K in CeRhIn5 and 4.4% Sn-doped CeRhIn5. The Ic(0)s of these Ce-based compounds under pressure exhibit a universal temperature dependence, underlining that the peak in zero-field Ic(P) is determined predominantly by critical fluctuations associated with the hidden QCP. The dc conductivity sigmadc is a minimum at the QCP, showing anti-correlation with Ic(0). These discoveries demonstrate that a quantum critical point hidden inside the superconducting phase in strongly correlated materials can be exposed by the zero-field Ic, therefore providing a direct link between a QCP and unconventional superconductivity. PMID- 29382851 TI - Gimap5-dependent inactivation of GSK3beta is required for CD4+ T cell homeostasis and prevention of immune pathology. AB - GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3beta (GSK3beta) following T cell activation. In the absence of Gimap5, constitutive GSK3beta activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3beta, thereby limiting DNA damage in CD4+ T cells. Importantly, pharmacological inhibition and genetic targeting of GSK3beta can override Gimap5 deficiency in CD4+ T cells and ameliorates immunopathology in mice. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors. Given that the expression of Gimap5 is lymphocyte-restricted, we propose that its control of GSK3beta is an important checkpoint in lymphocyte proliferation. PMID- 29382853 TI - On the tunneling time of ultracold atoms through a system of two mazer cavities. AB - We study the resonant tunneling of ultraslow atoms through a system of high quality microwave cavities. We find that the phase tunneling time across the two coupled cavities exhibits more frequent resonances as compared to the single cavity interaction. The increased resonances are instrumental in the display of an alternate sub and superclassical character of the tunneling time along the momentum axis with increasing energies of the incident slow atoms. Here, the intercavity separation appears as an additional controlling parameter of the system that provides an efficient control of the superclassical behavior of the phase tunneling time. Further, we find that the phase time characteristics through two cavity system has the combined features of the tunneling through a double barrier and a double well arrangements. PMID- 29382854 TI - Computer-aided Discovery of Peptides that Specifically Attack Bacterial Biofilms. AB - Biofilms represent a multicellular growth state of bacteria that are intrinsically resistant to conventional antibiotics. It was recently shown that a synthetic immunomodulatory cationic peptide, 1018 (VRLIVAVRIWRR-NH2), exhibits broad-spectrum antibiofilm activity but the sequence determinants of antibiofilm peptides have not been systematically studied. In the present work, a peptide library consisting of 96 single amino acid substituted variants of 1018 was SPOT synthesized on cellulose arrays and evaluated against methicillin resistant Staphylococcus aureus (MRSA) biofilms. This dataset was used to establish quantitative structure-activity relationship (QSAR) models relating the antibiofilm activity of these peptides to hundreds of molecular descriptors derived from their sequences. The developed 3D QSAR models then predicted the probability that a peptide would possess antibiofilm activity from a library of 100,000 virtual peptide sequences in silico. A subset of these variants were SPOT synthesized and their activity assessed, revealing that the QSAR models resulted in ~85% prediction accuracy. Notably, peptide 3002 (ILVRWIRWRIQW-NH2) was identified that exhibited an 8-fold increased antibiofilm potency in vitro compared to 1018 and proved effective in vivo, significantly reducing abscess size in a chronic MRSA mouse infection model. This study demonstrates that QSAR modeling can successfully be used to identify antibiofilm specific peptides with therapeutic potential. PMID- 29382855 TI - A heralded and error-rejecting three-photon hyper-parallel quantum gate through cavity-assisted interactions. AB - Hyper-parallel quantum computation is a promising and fruitful area of research with its high capacity and low loss rate characters. In this paper, we propose a heralded, compact, scalable, and deterministic error-rejecting scheme for implementing three-photon hyper-parallel Toffoli gate simultaneously acting on polarization and spatial degrees of freedom. It is a practical and unity gate without strong coupling strength limitations, since the undesired performances caused by the side leakage and the limited coupling strength are detected by the single-photon detectors. The success of our proposal can be heralded by the detectors, and the efficiency can be further improved by repeating the operation processes when the detectors are clicked. The evaluation of gate performance with experimental parameters shows that it is feasible with current experimental technology. PMID- 29382856 TI - Dynamic cellular phynotyping defines specific mobilization mechanisms of human hematopoietic stem and progenitor cells induced by SDF1alpha versus synthetic agents. AB - Efficient mobilization of hematopoietic stem and progenitor cells (HSPC) is one of the most crucial issues for harvesting an adequate amount of peripheral HSPC for successful clinical transplantation. Applying well-defined surrogate models for the bone marrow niche, live cell imaging techniques, and novel tools in statistical physics, we have quantified the functionality of two mobilization agents that have been applied in the clinic, NOX-A12 and AMD3100 (plerixafor), as compared to a naturally occurring chemokine in the bone marrow, SDF1alpha. We found that NOX-A12, an L-enantiomeric RNA oligonucleotide to SDF1, significantly reduced the adhesion of HSPC to the niche surface mediated via the CXCR4 SDF1alpha axis, and stretched the migration trajectories of the HSPC. We found that the stretching of trajectories by NOX-A12 was more prominent than that by SDF1alpha. In contrast, plerixafor exhibited no detectable interference with adhesion and migration. We also found that the deformation of HSPC induced by SDF1alpha or plerixafor was also drastically suppressed in the presence of NOX A12. This novel technology of quantitative assessment of "dynamic phenotypes" by physical tools has therefore enabled us to define different mechanisms of function for various extrinsic factors compared to naturally occurring chemokines. PMID- 29382857 TI - Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence. AB - Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma. PMID- 29382858 TI - Changes in Distribution of Dry Eye Disease by the New 2016 Diagnostic Criteria from the Asia Dry Eye Society. AB - Dry eye disease (DED) is a disorder of the tear film. Here, we delineate the changes in distribution of DED after diagnostic criteria changes from the 2006 Japanese Diagnostic Criteria to the 2016 Asia Dry Eye Society criteria. We included 250 right eyes of 250 patients and all patients completed ophthalmic assessments for DED. The 2006 criteria classified patients into definite DED, probable DED, and non-DED based on subjective symptoms, tear function, and/or vital staining. The 2016 criteria eliminated probable DED and classified patients into definite DED or non-DED based on subjective symptoms and decreased tear break-up time. We examined how probable DED patients were reclassified by the 2016 criteria. By the 2006 criteria, 38.8% (97/250) of patients had definite DED, 35.6% (89/250) had probable DED, and 25.6% (64/250) had non-DED. By the 2016 criteria, 66.8% (167/250) had definite DED and 31.2% (83/250) had non-DED. Among patients with probable DED using the 2006 criteria, 79.8% (71/89) were reclassified as definite DED and 20.2% (18/89) were reclassified as non-DED using the 2016 criteria. Our data revealed that prevalence of definite DED increased because most probable DED patients were reclassified as definite DED after changes in the diagnostic criteria. PMID- 29382859 TI - Evaluation of the osteogenesis and osseointegration of titanium alloys coated with graphene: an in vivo study. AB - The aim of this study was to investigate whether a surface coating with graphene could enhance the surface bioactivation of titanium alloys (Ti6Al4V) to further accelerate in vivo osteogenesis and osseointegration at the implant surface. In this study, a New Zealand white rabbit femoral condyle defect model was established. After 4, 12 and 24 weeks, biomechanical testing, micro-computed tomography (Micro-CT) analyses and histological observations were performed. At the highest push-out forces during the test, microstructure parameters, such as the bone volume/total volume fraction (BV/TV) and mineral apposition rate (MAR), of the new bone were significantly higher in the graphene-coated Ti6Al4V group (G Ti6Al4V) than in the Ti6Al4V group (P < 0.05). Van Gieson (VG) staining showed that the G-Ti6Al4V group had more new bone formation than the Ti6Al4V group, and the G-Ti6Al4V group showed a closer fit between the bone and implant. In conclusion, graphene might be a novel type of nano-coating material for enhancing the surface biological activity of Ti-based alloy materials and may further promote in vivo osteogenesis and osseointegration. PMID- 29382860 TI - Ergodicity breaking transition in a glassy soft sphere system at small but non zero temperatures. AB - While the glass transition at non-zero temperature seems to be hard to access for experimental, theoretical, or simulation studies, jamming at zero temperature has been studied in great detail. Motivated by the exploration of the energy landscape that has been successfully used to investigate athermal jamming, we introduce a new method that includes the possibility of the thermally excited crossing of energy barriers. We then determine whether the ground state configurations of a soft sphere system are accessible or not and as a consequence whether the system is ergodic or effectively non-ergodic. Interestingly, we find an transition where the system becomes effectively non-ergodic if the density is increased. The transition density in the limit of small but non-zero temperatures is independent of temperature and below the transition density of athermal jamming. This confirms recent computer simulation studies where athermal jamming occurs deep inside the glass phase. In addition, we show that the ergodicity breaking transition is in the universality class of directed percolation. Therefore, our approach not only makes the transition from an ergodic to an effectively non-ergodic systems easily accessible and helps to reveal its universality class but also shows that it is fundamentally different from athermal jamming. PMID- 29382861 TI - Activated Biomass-derived Graphene-based Carbons for Supercapacitors with High Energy and Power Density. AB - Here, we present a facile and low-cost method to produce hierarchically porous graphene-based carbons from a biomass source. Three-dimensional (3D) graphene based carbons were produced through continuous sequential steps such as the formation and transformation of glucose-based polymers into 3D foam-like structures and their subsequent carbonization to form the corresponding macroporous carbons with thin graphene-based carbon walls of macropores and intersectional carbon skeletons. Physical and chemical activation was then performed on this carbon to create micro- and meso-pores, thereby producing hierarchically porous biomass-derived graphene-based carbons with a high Brunauer Emmett-Teller specific surface area of 3,657 m2 g-1. Owing to its exceptionally high surface area, interconnected hierarchical pore networks, and a high degree of graphitization, this carbon exhibited a high specific capacitance of 175 F g-1 in ionic liquid electrolyte. A supercapacitor constructed with this carbon yielded a maximum energy density of 74 Wh kg-1 and a maximum power density of 408 kW kg-1, based on the total mass of electrodes, which is comparable to those of the state-of-the-art graphene-based carbons. This approach holds promise for the low-cost and readily scalable production of high performance electrode materials for supercapacitors. PMID- 29382862 TI - Spin-Orbit Effects on the Dynamical Properties of Polarons in Graphene Nanoribbons. AB - The dynamical properties of polarons in armchair graphene nanoribbons (GNR) is numerically investigated in the framework of a two-dimensional tight-binding model that considers spin-orbit (SO) coupling and electron-lattice (e-l) interactions. Within this physical picture, novel polaron properties with no counterparts to results obtained from conventional tight-binding models are obtained. Our findings show that, depending on the system's width, the presence of SO coupling changes the polaron's charge localization giving rise to different degrees of stability for the charge carrier. For instance, the joint action of SO coupling and e-l interactions could promote a slight increase on the charge concentration in the center of the lattice deformation associated to the polaron. As a straightforward consequence, this process of increasing stability would lead to a depreciation in the polaron's motion by decreasing its saturation velocity. Our finds are in good agreement with recent experimental investigations for the charge localization in GNR, mostly when it comes to the influence of SO coupling. Moreover, the contributions reported here provide a reliable method for future works to evaluate spin-orbit influence on the performance of graphene nanoribbons. PMID- 29382863 TI - Visualization of human karyopherin beta-1/importin beta-1 interactions with protein partners in mitotic cells by co-immunoprecipitation and proximity ligation assays. AB - Karyopherin beta-1/Importin beta-1 is a conserved nuclear transport receptor, acting in protein nuclear import in interphase and as a global regulator of mitosis. These pleiotropic functions reflect its ability to interact with, and regulate, different pathways during the cell cycle, operating as a major effector of the GTPase RAN. Importin beta-1 is overexpressed in cancers characterized by high genetic instability, an observation that highlights the importance of identifying its partners in mitosis. Here we present the first comprehensive profile of importin beta-1 interactors from human mitotic cells. By combining co immunoprecipitation and proteome-wide mass spectrometry analysis of synchronized cell extracts, we identified expected (e.g., RAN and SUMO pathway factors) and novel mitotic interactors of importin beta-1, many with RNA-binding ability, that had not been previously associated with importin beta-1. These data complement interactomic studies of interphase transport pathways. We further developed automated proximity ligation assay (PLA) protocols to validate selected interactors. We succeeded in obtaining spatial and temporal resolution of genuine importin beta-1 interactions, which were visualized and localized in situ in intact mitotic cells. Further developments of PLA protocols will be helpful to dissect importin beta-1-orchestrated pathways during mitosis. PMID- 29382864 TI - Bioengineered polyester beads co-displaying protein and carbohydrate-based antigens induce protective immunity against bacterial infection. AB - The efficacy of protein and carbohydrate antigens as vaccines can be improved via particulate delivery strategies. Here, protein and carbohydrate antigens used in formulations of vaccines against Neisseria menigitidis were displayed on in vivo assembled polyester beads using a combined bioengineering and conjugation approach. An endotoxin-free mutant of Escherichia coli was engineered to produce translational fusions of antigens (Neisseria adhesin A (NadA) and factor H binding protein (fHbp) derived from serogroup B) to the polyhydroxybutyrate synthase (PhaC), in order to intracellularly assemble polyester beads displaying the respective antigens. Purified beads displaying NadA showed enhanced immunogenicity compared to soluble NadA. Both soluble and particulate NadA elicited functional antibodies with bactericidal activity associated with protective immunity. To expand the antigen repertoire and to design a more broadly protective vaccine, NadA-PhaC beads were additionally conjugated to the capsular polysaccharide from serogroup C. Co-delivery of surface displayed NadA and the capsular polysaccharide induced a strong and specific Th1/Th17 mediated immune response associated with functional bactericidal antibodies. Our findings provide the foundation for the design of multivalent antigen-coated polyester beads as suitable carriers for protein and polysaccharide antigens in order to induce protective immunity. PMID- 29382865 TI - Frequency of EBV associated classical Hodgkin lymphoma decreases over a 54-year period in a Brazilian population. AB - The epidemiology of classical Hodgkin lymphoma varies significantly in populations with different socioeconomic conditions. Among other changes, improvement in such conditions leads to a reduction in the association with EBV infection and predominance of the nodular sclerosis subtype. This study provides an overview of the epidemiology of 817 cases of classical Hodgkin lymphoma diagnosed in five reference hospitals of the State of Sao Paulo, Brazil, over 54 years (1954-2008). The cases were distributed in 3 periods (1954-1979; 1980-1999; and 2000-2008). EBV-positive cases decreased from 87% to 46%. In children and adolescents (<15 years) and in young adults (15-45 years), EBV-positive cases decreased respectively from 96% to 64%, and from 85% to 32%. The percentage of male patients declined from 80% to 58%. In older patients (>45 years), the decrease in EBV infection was not significant. Nodular Sclerosis was the most common subtype in all periods. These results support the hypothesis that, in the Brazilian State of Sao Paulo, classical Hodgkin lymphoma has changed and now shows characteristics consistent with Pattern III observed in populations that experienced a similar socioeconomic transition. PMID- 29382866 TI - Modulation of Neurally Mediated Vasodepression and Bradycardia by Electroacupuncture through Opioids in Nucleus Tractus Solitarius. AB - Stimulation of vagal afferent endings with intravenous phenylbiguanide (PBG) causes both bradycardia and vasodepression, simulating neurally mediated syncope. Activation of u-opioid receptors in the nucleus tractus solitarius (NTS) increases blood pressure. Electroacupuncture (EA) stimulation of somatosensory nerves underneath acupoints P5-6, ST36-37, LI6-7 or G37-39 selectively but differentially modulates sympathoexcitatory responses. We therefore hypothesized that EA-stimulation at P5-6 or ST36-37, but not LI6-7 or G37-39 acupoints, inhibits the bradycardia and vasodepression through a u-opioid receptor mechanism in the NTS. We observed that stimulation at acupoints P5-6 and ST36-37 overlying the deep somatosensory nerves and LI6-7 and G37-39 overlying cutaneous nerves differentially evoked NTS neural activity in anesthetized and ventilated animals. Thirty-min of EA-stimulation at P5-6 or ST36-37 reduced the depressor and bradycardia responses to PBG while EA at LI6-7 or G37-39 did not. Congruent with the hemodynamic responses, EA at P5-6 and ST36-37, but not at LI6-7 and G37-39, reduced vagally evoked activity of cardiovascular NTS cells. Finally, opioid receptor blockade in the NTS with naloxone or a specific MU-receptor antagonist reversed P5-6 EA-inhibition of the depressor, bradycardia and vagally evoked NTS activity. These data suggest that point specific EA stimulation inhibits PBG induced vasodepression and bradycardia responses through a MU-opioid mechanism in the NTS. PMID- 29382867 TI - Molecular epidemiology and comparative genomics of Campylobacter concisus strains from saliva, faeces and gut mucosal biopsies in inflammatory bowel disease. AB - Campylobacter concisus is an emerging pathogen associated with inflammatory bowel disease (IBD), yet little is known about the genetic diversity of C. concisus in relation to host niches and disease. We isolated 104 C. concisus isolates from saliva, mucosal biopsies and faecal samples from 41 individuals (26 IBD, 3 Gastroenteritis (GE), 12 Healthy controls (HC)). Whole genomes were sequenced and the dataset pan-genome examined, and genomic information was used for typing using multi-locus-sequence typing (MLST). C. concisus isolates clustered into two main groups/genomospecies (GS) with 71 distinct sequence types (STs) represented. Sampling site (p < 0.001), rather than disease phenotype (p = 1.00) was associated with particular GS. We identified 97 candidate genes associated with increase or decrease in prevalence during the anatomical descent from the oral cavity to mucosal biopsies to faeces. Genes related to cell wall/membrane biogenesis were more common in oral isolates, whereas genes involved in cell transport, metabolism and secretory pathways were more prevalent in enteric isolates. Furthermore, there was no correlation between individual genetic diversity and clinical phenotype. This study confirms the genetic heterogeneity of C. concisus and provides evidence that genomic variation is related to the source of isolation, but not clinical phenotype. PMID- 29382868 TI - Error-Gated Hebbian Rule: A Local Learning Rule for Principal and Independent Component Analysis. AB - We developed a biologically plausible unsupervised learning algorithm, error gated Hebbian rule (EGHR)-beta, that performs principal component analysis (PCA) and independent component analysis (ICA) in a single-layer feedforward neural network. If parameter beta = 1, it can extract the subspace that major principal components span similarly to Oja's subspace rule for PCA. If beta = 0, it can separate independent sources similarly to Bell-Sejnowski's ICA rule but without requiring the same number of input and output neurons. Unlike these engineering rules, the EGHR-beta can be easily implemented in a biological or neuromorphic circuit because it only uses local information available at each synapse. We analytically and numerically demonstrate the reliability of the EGHR-beta in extracting and separating major sources given high-dimensional input. By adjusting beta, the EGHR-beta can extract sources that are missed by the conventional engineering approach that first applies PCA and then ICA. Namely, the proposed rule can successfully extract hidden natural images even in the presence of dominant or non-Gaussian noise components. The results highlight the reliability and utility of the EGHR-beta for large-scale parallel computation of PCA and ICA and its future implementation in a neuromorphic hardware. PMID- 29382869 TI - Enhancing Thermal Transport in Layered Nanomaterials. AB - A comprehensive rational thermal material design paradigm requires the ability to reduce and enhance the thermal conductivities of nanomaterials. In contrast to the existing ability to reduce the thermal conductivity, methods that allow to enhance heat conduction are currently limited. Enhancing the nanoscale thermal conductivity could bring radical improvements in the performance of electronics, optoelectronics, and photovoltaic systems. Here, we show that enhanced thermal conductivities can be achieved in semiconductor nanostructures by rationally engineering phonon spectral coupling between materials. By embedding a germanium film between silicon layers, we show that its thermal conductivity can be increased by more than 100% at room temperature in contrast to a free standing thin-film. The injection of phonons from the cladding silicon layers creates the observed enhancement in thermal conductivity. We study the key factors underlying the phonon injection mechanism and find that the surface conditions and layer thicknesses play a determining role. The findings presented here will allow for the creation of nanomaterials with an increased thermal conductivity. PMID- 29382870 TI - Resilience management during large-scale epidemic outbreaks. AB - Assessing and managing the impact of large-scale epidemics considering only the individual risk and severity of the disease is exceedingly difficult and could be extremely expensive. Economic consequences, infrastructure and service disruption, as well as the recovery speed, are just a few of the many dimensions along which to quantify the effect of an epidemic on society's fabric. Here, we extend the concept of resilience to characterize epidemics in structured populations, by defining the system-wide critical functionality that combines an individual's risk of getting the disease (disease attack rate) and the disruption to the system's functionality (human mobility deterioration). By studying both conceptual and data-driven models, we show that the integrated consideration of individual risks and societal disruptions under resilience assessment framework provides an insightful picture of how an epidemic might impact society. In particular, containment interventions intended for a straightforward reduction of the risk may have net negative impact on the system by slowing down the recovery of basic societal functions. The presented study operationalizes the resilience framework, providing a more nuanced and comprehensive approach for optimizing containment schemes and mitigation policies in the case of epidemic outbreaks. PMID- 29382871 TI - Detection of tick-borne bacteria and babesia with zoonotic potential in Argas (Carios) vespertilionis (Latreille, 1802) ticks from British bats. AB - Ticks host a wide range of zoonotic pathogens and are a significant source of diseases that affect humans and livestock. However, little is known about the pathogens associated with bat ticks. We have collected ectoparasites from bat carcasses over a seven year period. Nucleic acids (DNA and RNA) were extracted from 296 ticks removed from bats and the species designation was confirmed in all ticks as Argas (Carios) vespertilionis. A subset of these samples (n = 120) were tested for the presence of zoonotic pathogens by molecular methods. Babesia species, Rickettsia spp., within the spotted fever group (SFG), and Ehrlichia spp. were detected in ticks removed from 26 bats submitted from 14 counties across England. The prevalence of Rickettsia spp. was found to be highest in Pipistrellus pipistrellus from southern England. This study suggests that the tick species that host B. venatorum may include the genus Argas in addition to the genus Ixodes. As A. vespertilionis has been reported to feed on humans, detection of B. venatorum and SFG Rickettsia spp. could present a risk of disease transmission in England. No evidence for the presence of flaviviruses or Issyk Kul virus (nairovirus) was found in these tick samples. PMID- 29382873 TI - Sub-parts-per-trillion level sensitivity in trace gas detection by cantilever enhanced photo-acoustic spectroscopy. AB - An exceptional property of photo-acoustic spectroscopy is the zero-background in wavelength modulation configuration while the signal varies linearly as a function of absorbed laser power. Here, we make use of this property by combining a highly sensitive cantilever-enhanced photo-acoustic detector, a particularly stable high-power narrow-linewidth mid-infrared continuous-wave optical parametric oscillator, and a strong absorption cross-section of hydrogen fluoride to demonstrate the ability of cantilever-enhanced photo-acoustic spectroscopy to reach sub-parts-per-trillion level sensitivity in trace gas detection. The high stability of the experimental setup allows long averaging times. A noise equivalent concentration of 650 parts-per-quadrillion is reached in 32 minutes. PMID- 29382872 TI - Embryonic exposure to ethanol increases the susceptibility of larval zebrafish to chemically induced seizures. AB - Prenatal ethanol exposure is known to cause neurodevelopmental disorders. While high prevalence of epilepsy is observed among the children whose mothers abused alcohol during pregnancy, the results from animal studies are conflicting. Here, we investigated whether embryonic exposure to ethanol can increase the susceptibility to pentylenetetrazole (PTZ)-induced seizures in larval zebrafish. Embryos at 3 hours post-fertilization (hpf) were exposed to ethanol at the concentrations ranging from 0.25% to 1% for 21 hours. Control and ethanol-exposed larvae were challenged with PTZ at 7 days post-fertilization (dpf) at the concentrations of 2.5, 5 or 15 mM. The seizure behavior of larvae was recorded and analyzed using EthoVision XT 11. We found that embryonic ethanol exposure increased the percentage of larvae exhibiting typical stage II and III seizure and resulted in a significant reduction in stage I, II and III seizure latency in an ethanol concentration-dependent manner. Embryonic exposure to ethanol also significantly increased the severity of PTZ-induced seizures in larvae, as demonstrated by increased total distance traveled and the duration of mobility. This is the first demonstration that ethanol exposure during early embryonic stage can reduce the threshold for chemically induced seizures and increase the severity of seizure behavior in larval fish. PMID- 29382874 TI - Phase space volume scaling of generalized entropies and anomalous diffusion scaling governed by corresponding non-linear Fokker-Planck equations. AB - Many physical, biological or social systems are governed by history-dependent dynamics or are composed of strongly interacting units, showing an extreme diversity of microscopic behaviour. Macroscopically, however, they can be efficiently modeled by generalizing concepts of the theory of Markovian, ergodic and weakly interacting stochastic processes. In this paper, we model stochastic processes by a family of generalized Fokker-Planck equations whose stationary solutions are equivalent to the maximum entropy distributions according to generalized entropies. We show that at asymptotically large times and volumes, the scaling exponent of the anomalous diffusion process described by the generalized Fokker-Planck equation and the phase space volume scaling exponent of the generalized entropy bijectively determine each other via a simple algebraic relation. This implies that these basic measures characterizing the transient and the stationary behaviour of the processes provide the same information regarding the asymptotic regime, and consequently, the classification of the processes given by these two exponents coincide. PMID- 29382875 TI - Template-free synthesis of porous carbon from triazine based polymers and their use in iodine adsorption and CO2 capture. AB - A series of novel triazine-containing pore-tunable carbon materials (NT-POP@800-1 6), which was synthesized via pyrolysis of porous organic polymers (POPs) without any templates. NT-POP@800-1-6 possess moderate BET surface areas of 475-736 m2 g 1, have permanent porosity and plenty of nitrogen units in the skeletons as effective sorption sites, and display relatively rapid guest uptake of 56-192 wt% in iodine vapour in the first 4 h. In addition, all the samples exhibit the outstanding CO2 adsorption capacity of 2.83-3.96 mmol g-1 at 273 K and 1.05 bar. Furthermore, NT-POP@800-1-6 show good selectivity ratios of 21.2-36.9 and 3.3-7.5 for CO2/N2 or CH4/N2, respectively. We believe that our new building block design provides a general strategy for the construction of triazine-containing carbon materials from various extended building blocks, thereby greatly expanding the range of applicable molecules. PMID- 29382876 TI - Generation of all-male-like sterile zebrafish by eliminating primordial germ cells at early development. AB - Production of all-male and sterile fish may not only substantially improve yield but also be crucial for the application of genome modified species in aquaculture. Previously, it was reported that the fish lacking primordial germ cells (PGCs) becomes infertile, and nitroreductase, an enzyme converting non toxic metronidazole (MTZ) into toxic metabolites, induces targeted toxicity to kill the cells expressing it. In this study, we generated a transgenic zebrafish line of Tg(nanos3:nfsB-mCherry-nanos3 3'UTR) in which the NfsB nitroreductase is solely expressed in PGCs. Treating the embryos derived from the female transgenic zebrafish with MTZ from 0 through 2 dpf (days post fertilization), we found that the germ cells were completely eliminated in the ones older than 2.5 dpf. At 20 dpf, the MTZ-treated juvenile had no germ cells in their gonads. At 100 dpf, the MTZ-treated adult exhibited male-like morphology and showed normal mating behaviors although they had no germ cells but only supporting cells in their gonads. Taken together, our results demonstrated that conditional elimination of PGCs during early development make the zebrafish male-like and infertile. It may provide an alternative strategy to make sterile and all-male farmed fish that is good for increasing aquaculture yield and preventing the genome modified species from potential ecological risks. PMID- 29382877 TI - High surface recombination velocity limits Quasi-Fermi level splitting in kesterite absorbers. AB - Kelvin Probe Force Microscopy, Photoluminescence imaging and numerical simulations are used to study the surfaces of Cu2ZnSnSe4 absorber layers. In particular, the effect of NH4OH and annealing under ambient conditions is investigated. We observe drastic changes in the measured quasi Fermi-level splitting (QFLs) after chemical cleaning of the absorber surface with NH4OH, which is traced back to a removal of the surface inversion. Air annealing recovers surface inversion, which reduces the recombination current at the surface. Annealing above 200 degrees C leads to a permanent change in the work function which cannot be modified by NH4OH etching anymore. This modification makes the QFLs insensitive to surface cleaning and explains why air annealing in Cu2ZnSnSe4 is important. From numerical simulations we find that a large surface recombination velocity needs to be present in order to describe the experimental observations. PMID- 29382878 TI - Early bone tissue aging in human auditory ossicles is accompanied by excessive hypermineralization, osteocyte death and micropetrosis. AB - Within the mineralized bone, osteocytes form a multifunctional mechanosensitive network orchestrating bone remodelling. A preserved osteocyte population is a crucial determinant of bone quality. In human auditory ossicles, the early decrease in osteocyte numbers but maintained integrity remains an unexplained phenomenon that might serve for sound transmission from air to the labyrinth. Here we analysed the frequency, size and composition of osteocyte lacunae in the auditory ossicles of 22 individuals from early postnatal period to old age. Mineralization of the bone matrix was determined using backscattered electron imaging. No signs of bone remodelling were observed above the age of 1 year. We detected characteristics of early bone tissue aging, such as decrease in osteocytes, lower total lacunar density and lacunar area, as well as high matrix mineralization accompanied by distinct accumulation of micropetrotic lacunae and decreased indentation depths. The majority of these changes took place in the first months and years of life, while afterwards only minor reorganization was present. With osteocyte apoptosis potentially being a consequence of low mechanical stimuli, the early loss of osteocytes without initiation of bone remodelling indicates an adaptive response conserving the architecture of the auditory ossicles and ensuring stable sound transmission throughout life. PMID- 29382879 TI - Borrelia burgdorferi surface protein Lmp1 facilitates pathogen dissemination through ticks as studied by an artificial membrane feeding system. AB - In its natural infection cycle, the pathogen of Lyme borreliosis transits between a tick vector and a mammalian host. As relatively a minor fraction of spirochetes transits between the host and the vector precluding their reliable detection at early infection, artificial membrane feeders emerged as useful tools to study roles of spirochete proteins in pathogen entry, persistence, and exit through ticks. Here we report the development of a modified membrane feeder to study the role of a Borrelia burgdorferi surface protein called Lmp1 in spirochete transitions between the murine host and ticks. We show that our membrane feeder supports the blood meal engorgement process where ticks can acquire spirochetes from the feeder containing extremely low levels of pathogens (102 cells/ml of blood). Our data revealed that in comparison to wild-type spirochetes, lmp1 deletion mutants are significantly impaired for acquisition in naive ticks as well as transmission from infected ticks. Taking together, our data suggest that Lmp1 plays an essential role in spirochete transitions between hosts and the vector. These studies also underscore the usefulness of artificial membrane feeding system as a valuable tool to study the role of B. burgdorferi gene products in pathogen persistence in and passage through vector ticks. PMID- 29382880 TI - Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity. AB - The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcgammaRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus. PMID- 29382881 TI - Dynamical Transitions and Diffusion Mechanism in DODAB Bilayer. AB - Dioctadecyldimethylammonium bromide (DODAB), a potential candidate for applications in drug transport or DNA transfection, forms bilayer in aqueous media exhibiting a rich phase behavior. Here, we report the detailed dynamical features of DODAB bilayer in their different phases (coagel, gel and fluid) as studied by neutron scattering techniques. Elastic intensity scans show dynamical transitions at 327 K in the heating and at 311 K and 299 K during cooling cycle. These results are consistent with calorimetric studies, identified as coagel fluid phase transition during heating, and fluid-gel and gel-coagel phase transitions during cooling. Quasielastic Neutron Scattering (QENS) data analysis showed presence of only localized internal motion in the coagel phase. However, in the gel and fluid phases, two distinct motions appear, namely lateral motion of the DODAB monomers and a faster localized internal motion of the monomers. The lateral motion of the DODAB molecule is described by a continuous diffusion model and is found to be about an order of magnitude slower in the gel phase than in the fluid phase. To gain molecular insights, molecular dynamics simulations of DODAB bilayer have also been carried out and the results are found to be in agreement with the experiment. PMID- 29382882 TI - Convergent and Divergent Migratory Patterns of Human Neutrophils inside Microfluidic Mazes. AB - Neutrophils are key cellular components of the innate immune response and characteristically migrate from the blood towards and throughout tissues. Their migratory process is complex, guided by multiple chemoattractants released from injured tissues and microbes. How neutrophils integrate the various signals in the tissue microenvironment and mount effective responses is not fully understood. Here, we employed microfluidic mazes that replicate features of interstitial spaces and chemoattractant gradients within tissues to analyze the migration patterns of human neutrophils. We find that neutrophils respond to LTB4 and fMLF gradients with highly directional migration patterns and converge towards the source of chemoattractant. We named this directed migration pattern convergent. Moreover, neutrophils respond to gradients of C5a and IL-8 with a low directionality migration pattern and disperse within mazes. We named this alternative migration pattern divergent. Inhibitors of MAP kinase and PI-3 kinase signaling pathways do not alter either convergent or divergent migration patterns, but reduce the number of responding neutrophils. Overlapping gradients of chemoattractants conserve the convergent and divergent migration patterns corresponding to each chemoattractant and have additive effects on the number of neutrophils migrating. These results suggest that convergent and divergent neutrophil migration-patterns are the result of simultaneous activation of multiple signaling pathways. PMID- 29382883 TI - Integrated transcriptomic and proteomic analyses reveal potential mechanisms linking thermal stress and depressed disease resistance in the turbot Scophthalmus maximus. AB - A worldwide increase in the reports of diseases affecting marine organisms has paralleled the climate warming over the past few decades. In this study, we applied omics to explore the mechanisms underlying thermo-linked epizootics, by comparing both the transcriptome- and proteome-wide response of turbots to a mimic pathogen (poly I:C) between high temperature and low temperature using a time-course approach. Our results showed that myeloperoxidase (MPO) and insulin were differentially expressed transcripts shared by all five time-points post poly I:C-injection between high and low temperature and also had a consistent expression trend as differentially expressed proteins at 24 h post injection. Combined with other data, it was suggested that the elevated temperature enhanced neutrophil-mediated immunity and the resultant MPO-mediated oxidative stress, which lasted for at least 5 days. The contents of malondialdehyde and protein carbonyls, markers of oxidative damage for lipids and proteins, respectively, were compared between different temperature groups, and the results further implied the emergence of oxidative damage under high temperature. It was also suggested that metabolism disorder likely occur considering the sustained expression changes of insulin. Hence, prolonged MPO-mediated oxidative stress and metabolic disorder might be involved in the thermo-linked epizootic. PMID- 29382884 TI - Optimizing critical parameters for the directly measurement of particle flow with PF-SIBS. AB - A novel measurement technology named as particle flow-spark induced breakdown spectroscopy (PF-SIBS) was reported for real-time measurement of solid materials. Critical measurement parameters of PF-SIBS were optimized and a set of fly ashes with different carbon content were measured for evaluation of measurement performance. Four electrode materials, tungsten, copper, molybdenum and platinum, were compared in the aspects of signal stability, line interference and electrode durability. Less line interference and better signal stability were obtained with W and Cu electrode, while W electrode has better durability. Quartz sand with diameters from 48 MUm to 180 MUm were tested to investigate the influence of particle size. As the particle diameter increased, the intensity of Si 288.16 nm line decreased while that of ambient air constituents increased. To reduce the particle effect, the sum intensity from sample and ambient air were introduced to correct. The RSD of line intensity between the five diameters were reduced from 67.30% to 16.59% with Cu electrodes and from 63.21% to 13.64% with W electrodes. With the optimal measurement parameters and correction, fly ash samples with different carbon content were tested and the correlation coefficients R2 of multivariate calibration achieved 0.987. PMID- 29382885 TI - Comparative Analysis of Natural Radioactivity Content in Tiles made in Nigeria and Imported Tiles from China. AB - In this investigation, natural radioactive contents in tiles manufactured in Nigeria and tiles imported from China were measured using gamma ray spectroscopy. High Purity Germanium detector was used to estimate the concentrations of some radioisotopes present in 17 samples of various tiles from Nigeria and China. The average activity concentrations of 226Ra, 232Th, and 40K for the tiles were found to be 68.2 +/- 0.5; 173.9 +/- 9.2 and 490 +/- 15 Bq/kg and 58.2 +/- 0.5, 161.5 +/ 9.4 and 455.7 +/- 15.1 Bq/kg for the tiles from Nigeria and China respectively. Radiological hazard indices such as absorbed dose rate, radium equivalent activity, external Hazard Index (Hex), internal Hazard Index (Hin), Annual Effective Dose (mSv/y), Gamma activity Index (Igamma) and Alpha Index (Ialpha) were determined for both kind of tiles from Nigeria and China. The mean values obtained were: 354.56 and 317.16 Bq/kg; 169.22 nGyh-1 and 153.92 nGyh-1; 0.95 and 0.87; 1.14 and 1.08; 1.59 mSv/y and 1.52 mSv/y; 1 and 1.15 and; 0.34 and 0.29 respectively. The mean value of radium equivalent obtained in this study is less than that of the international reference value of 370 Bq/kg for the both kind of tiles. PMID- 29382886 TI - An efficient copper-based magnetic nanocatalyst for the fixation of carbon dioxide at atmospheric pressure. AB - In the last few decades, the emission of carbon dioxide (CO2) in the environment has caused havoc across the globe. One of the most promising strategies for fixation of CO2 is the cycloaddition reaction between epoxides and CO2 to produce cyclic carbonates. For the first time, we have fabricated copper-based magnetic nanocatalyst and have applied for the CO2 fixation. The prepared catalyst was thoroughly characterized using various techniques including XRD, FT-IR, TEM, FE SEM, XPS, VSM, ICP-OES and elemental mapping. The reactions proceeded at atmospheric pressure, relatively lower temperature, short reaction time, solvent- less and organic halide free reaction conditions. Additionally, the ease of recovery through an external magnet, reusability of the catalyst and excellent yields of the obtained cyclic carbonates make the present protocol practical and sustainable. PMID- 29382887 TI - Effect of the consumption of green tea extract during pregnancy and lactation on metabolism of mothers and 28d-old offspring. AB - The objective was to investigate the effects of the maternal consumption of the green tea extract during pregnancy and lactation on mothers and offspring metabolism. The female Wistar rats, on the first day of pregnancy until the end of lactation, was divided into groups: MC- received water and ME- received green tea extract (400 mg/kg body weight/day), both ingested control diet. After lactation, at day 28th post-partum, the mothers and pups from each mother were euthanized and composed the groups: FC- pup from mother received water and FE- pup from mother received green tea extract. The ME group increased IL-10/TNF alpha ratio and IL-1beta content in the mesenteric and IL-1beta content in retroperitoneal adipose tissues, and decreased catalase activity. The FE group decreased the retroperitoneal adipose tissue relative weight and SOD activity, but increased adiponectin, LPS, IL-10 and IL-6 content and IL-10/TNF-alpha ratio in retroperitoneal, IL-10 and TNF-alpha content in gonadal, and IL-6 content in mesenteric adipose tissues. In summary, the maternal consumption of green tea extract associated with control diet ingestion during pregnancy and lactation altered the inflammatory status of mothers and 28d-old offspring. These data elucidate the effects of green tea during pregnancy and lactation on maternal and offspring metabolism. PMID- 29382888 TI - A unique inbred rat strain with sustained cephalic hypersensitivity as a model of chronic migraine-like pain. AB - Animal models of migraine-like pain enabling ongoing study of behaviour typically involve the systemic administration of chemical vasodilators or dural administration of inflammatory algogens. However, neither method mediates prolonged effects on behavior indicative of enduring pathophysiological changes occurring within dural or trigeminal pain circuits. We generated successive generations of a unique inbred rat strain, spontaneous trigeminal allodynia (STA) rats, previously reported to exhibit an episodic migraine-like behavioural phenotype. We show that both male and female STA rats display robust and sustained reductions in periorbital thresholds to cutaneous mechanical stimulation. Otherwise, the general behavior (e.g. locomotor, grooming) of these rats appeared normal. In female STA rats, the mechanical hypersensitivity was confined to the cephalic region, manifested after puberty through adolescence, and was sustained into adulthood recapitulating the clinical manifestation of migraine. We exploited this hitherto unidentified chronic phenotype to show that the migraine-specific drugs sumatriptan (5-HT1B/1D receptor agonist) and olcegepant (CGRP receptor antagonist) could completely reverse cephalic hypersensitivity using a within subject cross-over paradigm. Our findings indicate that STA rats actually possess a phenotype indicative of migraine chronicity which is exquisitely sensitive to migraine therapeutics. This unique strain could prove to be an invaluable resource in preclinical migraine drug discovery. PMID- 29382889 TI - Proactive Locomotor Adjustments Are Specific to Perturbation Uncertainty in Below Knee Prosthesis Users. AB - Sensory-motor deficits associated with below-knee amputation impair reactions to external perturbations. As such, below-knee prosthesis users rely on proactive control strategies to maintain locomotor stability. However, there are trade-offs (metabolic, comfort, etc.) associated with proactive strategies. We hypothesize that because proactive control strategies are costly, prosthesis users and non impaired participants will use a priori knowledge (timing, direction) of an impending lateral perturbation to make specific gait adaptations only when the timing of the perturbation is known and the adaptation can be temporally-limited. This hypothesis was partially supported. When the perturbation timing was predictable, only prosthesis users, and only on their impaired side, increased their lateral margin of stability during the steps immediately preceding the perturbation when perturbation direction was either unknown or known to be directed towards their impaired side. This strategy should reduce the likelihood of requiring a corrective step to maintain stability. However, neither group exhibited substantial proactive adaptations compared to baseline walking when perturbation timing was unpredictable, independent of perturbation direction knowledge. The absence of further proactive stabilization behaviors observed in prosthesis users in anticipation of a certain but temporally unpredictable perturbation may be partially responsible for impaired balance control. PMID- 29382890 TI - Damage-free plasma etching of porous organo-silicate low-k using micro-capillary condensation above -50 degrees C. AB - The micro-capillary condensation of a new high boiling point organic reagent (HBPO), is studied in a periodic mesoporous oxide (PMO) with ~34 % porosity and k value ~2.3. At a partial pressure of 3 mT, the onset of micro-capillary condensation occurs around +20 degrees C and the low-k matrix is filled at -20 degrees C. The condensed phase shows high stability from -50 < T <=-35 degrees C, and persists in the pores when the low-k is exposed to a SF6-based plasma discharge. The etching properties of a SF6-based 150W-biased plasma discharge, using as additive this new HBPO gas, shows that negligible damage can be achieved at -50 degrees C, with acceptable etch rates. The evolution of the damage depth as a function of time was studied without bias and indicates that Si-CH3 loss occurs principally through Si-C dissociation by VUV photons. PMID- 29382891 TI - Pre-revascularization coronary wedge pressure as marker of adverse long-term left ventricular remodelling in patients with acute ST-segment elevation myocardial infarction. AB - The aim of this study was to investigate the relationship between coronary wedge pressure (CWP), measured as a marker of pre-procedural microvascular obstruction, and left ventricular remodelling in high-risk ST-segment elevation myocardial infarction (STEMI) patients. Pre-revascularization CWP was measured in 25 patients with high-risk anterior STEMI. Left ventricular volumes and ejection fraction were echocardiographically measured at discharge and at follow-up. A 20% increase in left ventricular volumes was used to define remodelling. Patients with CWP <= 38 mmHg were characterized by late ventricular remodelling. Patients with CWP > 38 mmHg developed a progressive remodelling process which was associated with a significant 60 months increase in left ventricular volumes (P = 0.01 for end-systolic volume and 0.03 for end-diastolic volume) and a significant decrease in left ventricular ejection fraction (P = 0.05). A significant increase in both left ventricular end-systolic (P = 0.009) and end-diastolic volume (P = 0.02) from baseline to 60 months follow-up was recorded in patients with extracted thrombus length >=2 mm. Pre-revascularization elevated CWP was associated with increased left ventricular volumes and decreased ejection fraction at long-term follow-up. CWP was a predictor of severe left ventricular enlargement, besides extracted thrombus quantity. PMID- 29382892 TI - Analysis of Staphylococcus aureus wall teichoic acid glycoepitopes by Fourier Transform Infrared Spectroscopy provides novel insights into the staphylococcal glycocode. AB - Surface carbohydrate moieties are essential for bacterial communication, phage bacteria and host-pathogen interaction. Most Staphylococcus aureus produce polyribitolphosphate type Wall teichoic acids (WTAs) substituted with alpha- and/or beta-O-linked N-acetyl-glucosamine (alpha-/beta-O-GlcNAc) residues. GlcNAc modifications have attracted particular interest, as they were shown to govern staphylococcal adhesion to host cells, to promote phage susceptibility conferring beta-lactam resistance and are an important target for antimicrobial agents and vaccines. However, there is a lack of rapid, reliable, and convenient methods to detect and quantify these sugar residues. Whole cell Fourier transform infrared (FTIR) spectroscopy could meet these demands and was employed to analyse WTAs and WTA glycosylation in S. aureus. Using S. aureus mutants, we found that a complete loss of WTA expression resulted in strong FTIR spectral perturbations mainly related to carbohydrates and phosphorus-containing molecules. We could demonstrate that alpha- or beta-O-GlcNAc WTA substituents can be clearly differentiated by chemometrically assisted FTIR spectroscopy. Our results suggest that whole cell FTIR spectroscopy represents a powerful and reliable method for large scale analysis of WTA glycosylation, thus opening up a complete new range of options for deciphering the staphylococcal pathogenesis related glycocode. PMID- 29382893 TI - Molecular Role of Ca2+ and Hard Divalent Metal Cations on Accelerated Fibrillation and Interfibrillar Aggregation of alpha-Synuclein. AB - alpha-Synuclein (alphaSyn) is an intrinsically disordered protein, the aggregation of which is highly related to the pathology of diverse alpha synucleinopathies. Various hard divalent metal cations have been shown to affect alphaSyn aggregation. Especially, Ca2+ is suggested to be a crucial ion due to its physiological relevance to alpha-synucleinopathies. However, the molecular origin of alphaSyn aggregation mediated by the metal ions is not fully elucidated. In this study, we revealed that hard divalent metal ions had almost identical influences on alphaSyn aggregation. Based on these similarities, the molecular role of Ca2+ was investigated as a representative metal ion. Herein, we demonstrated that binding of multiple Ca2+ ions induces structural transition of alphaSyn monomers to extended conformations, which promotes rapid alphaSyn fibrillation. Additionally, we observed that Ca2+ induced further interfibrillar aggregation via electrostatic and hydrophobic interactions. Our results from multiple biophysical methods, including ion mobility-mass spectrometry (IM-MS), synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), provide detailed information on the structural change of alphaSyn and the aggregation process mediated by Ca2+. Overall, our study would be valuable for understanding the influence of Ca2+ on the aggregation of alphaSyn during the pathogenesis of alpha-synucleinopathies. PMID- 29382894 TI - Zika virus infection elicits auto-antibodies to C1q. AB - Zika virus (ZIKV) causes mostly asymptomatic infection or mild febrile illness. However, with an increasing number of patients, various clinical features such as microcephaly, Guillain-Barre syndrome and thrombocytopenia have also been reported. To determine which host factors are related to pathogenesis, the E protein of ZIKV was analyzed with the Informational Spectrum Method, which identifies common information encoded by primary structures of the virus and the respective host protein. The data showed that the ZIKV E protein and the complement component C1q cross-spectra are characterized by a single dominant peak at the frequency F = 0.338, suggesting similar biological properties. Indeed, C1q-specific antibodies were detected in sera obtained from mice and monkeys infected with ZIKV. As C1q has been known to be involved not only in immunity, but also in synaptic organization and different autoimmune diseases, a ZIKV-induced anti-C1q antibody response may contribute to the neurological complications. These findings might also be exploited for the design of safe and efficacious vaccines in the future. PMID- 29382895 TI - Incubation temperature affects the expression of young precocial birds' fear related behaviours and neuroendocrine correlates. AB - The influence of embryonic microclimate on the behavioural development of birds remains unexplored. In this study, we experimentally tested whether chronic exposure to suboptimal temperatures engendered plasticity in the expression of fear-related behaviours and in the expression of the corticotropin-releasing factor in the brains of domestic chicks (Gallus g. domesticus). We compared the neurobehavioural phenotypes of a control group of chicks incubated in an optimal thermal environment (37.8 degrees C) with those of a group of experimental chicks exposed chronically in ovo to suboptimal temperatures (27.2 degrees C for 1 hour twice a day). Chronic exposure to a suboptimal temperature delayed hatching and decreased growth rate and experimental chicks had higher neophobic responses than controls in novel food and novel environment tests. In addition, experimental chicks showed higher expression of corticotropin-releasing factor than did controls in nuclei of the amygdala, a structure involved in the regulation of fear-related behaviours. In this study, we report the first evidence of the strong but underappreciated role of incubation microclimate on the development of birds' behaviour and its neurobiological correlates. PMID- 29382896 TI - Extracellular DNA as a genetic recorder of microbial diversity in benthic deep sea ecosystems. AB - Extracellular DNA in deep-sea sediments represents a major repository of genes, which previously belonged to living organisms. However, the extent to which these extracellular genes influence current estimates of prokaryotic biodiversity is unknown. We investigated the abundance and diversity of 16S rDNA sequences contained within extracellular DNA from continental margins of different biogeographic regions. We also compared the taxonomic composition of microbial assemblages through the analysis of extracellular DNA and DNA associated with living cells. 16S rDNA contained in the extracellular DNA pool contributed up to 50% of the total 16S rDNA copy number determined in the sediments. Ca. 4% of extracellular Operational Taxonomic Units (OTUs) were shared among the different biogeographic regions revealing the presence of a core of preserved OTUs. A higher fraction of OTUs was exclusive of each region potentially due to its geographic and thermohaline characteristics. Ca. one third of the OTUs identified in the extracellular DNA were absent from living prokaryotic assemblages, possibly representing the signatures of past assemblages. Our findings expand the knowledge of the contribution of extracellular microbial sequences to current estimates of prokaryotic diversity obtained through the analyses of "environmental DNA", and open new perspectives for understanding microbial successions in benthic ecosystems. PMID- 29382898 TI - Evaluation of cell penetrating peptide coated Mn:ZnS nanoparticles for paclitaxel delivery to cancer cells. AB - This work aimed at formulating paclitaxel (PTX) loaded cell penetrating peptide (CPP) coated Mn doped ZnS nanoparticles (Mn:ZnS NPs) for improved anti-cancer efficacy in vitro and in vivo. The developed PTX loaded Mn:ZnS NPs with different CPPs (PEN, pVEC and R9) showed enhanced anti-cancer effect compared to bare PTX, which has been validated by MTT assay followed by apoptosis assay and DNA fragmentation analysis. The in vivo bio-distribution and anti-cancer efficacy was studied on breast cancer xenograft model showing maximum tumor localization and enhanced therapeutic efficacy with R9 coated Mn:ZnS NPs (R9:Mn:ZnS NPs) and was confirmed by H/E staining. Thus, R9:Mn:ZnS NPs could be an ideal theranostic nano carrier for PTX with enhanced the rapeutic efficacy toward cancer cells, where penetration and sustainability of therapeutics are essential. PMID- 29382899 TI - Elevated pulse amplification in hypertensive patients with advanced kidney disease. AB - The progression of chronic kidney disease (CKD) inverts the arterial stiffness gradient. However, central hemodynamic pressure profiles in CKD have not been fully examined. A cross-sectional study was performed to assess the relationship between the CKD stage and central hemodynamic processes. The study enrolled 2020 hypertensive patients who had undergone echocardiography and measurement of their serum creatinine levels. Radial tonometry was applied to all patients to measure central blood pressure. Patients were classified according to six CKD stages based on their estimated glomerular filtration rate. Central (PP2) and brachial pulse pressure (PP) were elevated at stages 3a and 3b, respectively. Diastolic blood pressure (DBP) was higher at stage 1 compared to the other stages. The left ventricular mass index was greater at CKD stages 3b-5 than that at stage 1. Either PP or PP2 was sensitive for detecting the presence of left ventricular hypertrophy (LVH). Age, weight, pulse rate, brachial blood pressure, and antihypertensive medication differed among the six stages. Pulse amplification (PA) adjusted for these confounders was the lowest in CKD stages 3a and 3b. The present observations support that cardiovascular risk is higher in CKD stages 3b and later. Our findings indicate that PA is inverted in CKD stages 4 and 5. The present results suggest that aortic stiffening and the subsequent elevation in PA during CKD progression relate to a reduction in the ability of PP2 to predict LVH. PMID- 29382897 TI - Integrative genomic analysis of methylphenidate response in attention deficit/hyperactivity disorder. AB - Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies. PMID- 29382900 TI - Seasonal variation in nocturnal home blood pressure fall: the Nagahama study. AB - Abnormalities in circadian blood pressure (BP) variation have been suggested to be associated with cardiovascular diseases and mortality. Factors affecting this variability need to be clarified to precisely evaluate the risk of circadian BP abnormalities. Given the seasonal differences in casual BP, it was hypothesized that nocturnal BP may also differ by season. Here, we aimed to clarify the seasonality of circadian BP variation, as well as the factors associated with this seasonality, in a large-scale general population (n = 4780). This is a cross sectional study based on multiday BP values measured in the evening, during sleep, and in the morning. Measurements were taken at home using an automatic cuff-oscillometric device. The sleeping period was objectively defined by actigraphy. The nocturnal systolic BP fall was significantly less in individuals whose BP was measured during the summer season (summer, -5.8 +/- 7.8%; middle (spring or autumn), -8.2 +/- 7.5%; winter, -11.0 +/- 7.7%; p < 0.001), resulting in higher frequencies of riser (summer, 19.9; middle, 12.8; winter, 7.8%) and non dipper (summer, 51.4; middle, 46.3; winter, 37.0%) patterns in the summer season (p < 0.001). The results of linear regression analysis identified the middle (beta = 0.154, p < 0.001) and summer season (beta = 0.261, p < 0.001) as strong positive determinants for decreasing the nocturnal SBP fall. No seasonality was observed in day-to-day variability of the dipping pattern (Kendall's coefficient: winter, 0.527; middle, 0.539; summer, 0.515). The nocturnal BP fall was largely different by season, with a higher frequency of riser and non-dipper patterns in the summer. The seasonality might not be due to the seasonal difference in day-to day variability of nocturnal BP changes. PMID- 29382901 TI - Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry. AB - Much of the recent excitement in the cancer immunotherapy approach has been generated by the recognition that immune checkpoint proteins, like the receptor PD-1, can be blocked by antibody-based drugs with profound effects. Promising clinical data have already been released pointing to the efficiency of the drug pembrolizumab to block the PD-1 pathway, triggering the T-lymphocytes to destroy the cancer cells. Thus, a deep understanding of this drug/receptor complex is essential for the improvement of new drugs targeting the protein PD-1. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT), we investigate in silico the binding energy features of the receptor PD-1 in complex with its drug inhibitor. Our computational results give a better understanding of the binding mechanisms, being also an efficient alternative towards the development of antibody-based drugs, pointing to new treatments for cancer therapy. PMID- 29382902 TI - Cognitive Impairment In Treatment-Naive Bipolar II and Unipolar Depression. AB - Cognition dysfunction may reflect trait characteristics of bipolarity but cognitive effects of medications have confounded previous comparisons of cognitive function between bipolar II and unipolar depression, which are distinct clinical disorders with some overlaps. Therefore, we examined the executive function (WCST), attention, cognitive speed (TMT-A) and memory (CAVLT, WMS-Visual reproduction) of 20 treatment-naive bipolar II patients (BPII), 35 treatment naive unipolar depressed (UD) patients, and 35 age/sex/education matched healthy controls. The subjects were young (aged 18-35), and had no history of psychosis or substance use, currently depressed and meeting either RDC criteria for Bipolar II Disorder or DSM-IV-TR criteria for Major Depressive Disorder. The patients were moderately depressed (MADRS) and anxious(HAM-A), on average within 3.44 years of illness onset. Sociodemographic data and IQ were similar between the groups. UD patients had significantly slower cognitive speed and cognitive flexibility (WCST perseverative error). BPII depressed patients showed relatively intact cognitive function. Verbal memory (CAVLT List A total) correlated with illness chronicity only in BPII depression, but not UD. In conclusion, young and treatment-naive BPII depressed patients differed from unipolar depression by a relatively intact cognitive profile and a chronicity-cognitive correlation that suggested a stronger resemblance to Bipolar I Disorder than Unipolar Depression. PMID- 29382903 TI - Developmental delays and psychiatric diagnoses are elevated in offspring staying in prisons with their mothers. AB - The aim of the study was to describe the sociodemographic and clinical features of the mothers and their offspring staying with them in prison. The study was planned as a cross-sectional, single-center study of mothers residing in Tarsus Closed Women's Prison of Turkish Ministry of Justice along with their 0 to 6 years old offspring. Mothers were evaluated via Structured Clinical Interview for DSM-IV Axis I Disorders. A psychologist blind to maternal evaluations applied the Denver Developmental Screening Test II (DII-DST). Children/mothers were also evaluated by a child and adolescent psychiatrist via K-SADS-PL. Twenty-four mothers with a mean age of 29.3 years were included. Most common diagnoses in mothers were nicotine abuse (n = 17, 70.8%), specific phobia (n = 8, 33.3%), alcohol abuse (n = 7, 29.2%) and substance abuse (n = 5, 20.8%). Twenty-six children (53.9% female) were living with their mothers in prison, and the mean age of those was 26.3 months. Results of the D-II-DST were abnormal in 33.3% of the children. Most common diagnoses in children were adjustment disorder (n = 7, 26.9%) separation anxiety disorder (n = 3, 11.5%) and conduct disorder (n = 2, 7.7%). A multi-center study is necessary to reach that neglected/under-served population and address the inter-generational transmission of abuse, neglect, and psychopathology. PMID- 29382904 TI - Evaluation of dried blood spot samples for screening of hepatitis C and human immunodeficiency virus in a real-world setting. AB - Both hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection are underdiagnosed, particularly in low-income countries and in difficult-to-access populations. Our aim was to develop and evaluate a methodology for the detection of HCV and HIV infection based on capillary dry blood spot (DBS) samples taken under real-world conditions. We carried out a cross-sectional study of 139 individuals (31 healthy controls, 68 HCV monoinfected patients, and 40 HCV/HIV-coinfected patients). ELISA was used for anti-HCV and anti-HIV antibody detection; and SYBR Green RT-PCR was used for HCV RNA detection. The HIV serological analysis revealed 100% sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The HCV serological analysis revealed a sensitivity of 92.6%, specificity of 100%, PPV of 100%, and NPV of 79.5%. Finally, the HCV-RNA detection test revealed a detection limit of 5 copies/ul with an efficiency of 100% and sensitivity of 99.1%, specificity of 100%, PPV of 100%, and NPV of 96.9%. In conclusion, our methodology was able to detect both HCV infection and HIV infection from the same DBS sample with good diagnostic performance. Screening for HCV and HIV using DBS might be a key strategy in the implementation of national programs for the control of both infections. PMID- 29382905 TI - Biological corneal inlay for presbyopia derived from small incision lenticule extraction (SMILE). AB - Corneal inlays are a relatively new treatment option for presbyopia. Using biological inlays, derived from lenticules extracted from small incision lenticule extraction, may offer advantages over commercialized synthetic inlays in the aspect of biocompatibility. We conducted a non-human primate study to evaluate the safety, predictability, efficacy and tissue response after autogeneic, decellularized xenogeneic and xenogeneic lenticule implantation. The lenticule implantation effectively resulted in central corneal steepening (simulated keratometric values increased by 1.8-2.3 diopters), central hyper prolate changes (asphericity Q values changed by -0.26 to -0.36), corneal anterior surface elevation (7.7-9.3 MUm) and reasonable effective zone (1.5-1.8 times of the lenticule physical diameter), with no differences among the three groups. Slit lamp microscopy, transmission electron microscopy, confocal microscopy, histology and immunohistochemistry analyses confirmed the biocompatibility of the autogeneic and decellularized lenticules, whereas one eye in the xenogeneic group developed corneal stromal rejection during the study period. Our results showed that lenticule implantation has the potential for the management of presbyopia, and provide the basis for future clinical studies. The decellularization process may increase the potential utilization of lenticules without changing the efficacy. PMID- 29382906 TI - A viroid-derived system to produce large amounts of recombinant RNA in Escherichia coli. AB - Viruses have been engineered into useful biotechnological tools for gene therapy or to induce the synthesis of products of interest, such as therapeutic proteins and vaccines, in animal and fungal cells, bacteria or plants. Viroids are a particular class of infectious agents of higher plants that exclusively consist of a small non-protein-coding circular RNA molecule. In the same way as viruses have been transformed into useful biotechnological devices, can viroids be converted into beneficial tools? We show herein that, by expressing Eggplant latent viroid (ELVd) derived RNAs in Escherichia coli together with the eggplant tRNA ligase, this being the enzyme involved in viroid circularization in the infected plant, RNAs of interest like aptamers, extended hairpins, or other structured RNAs are produced in amounts of tens of milligrams per liter of culture. Although ELVd fails to replicate in E. coli, ELVd precursors self-cleave through the embedded hammerhead ribozymes and the resulting monomers are, in part, circularized by the co-expressed enzyme. The mature viroid forms and the protein likely form a ribonucleoprotein complex that transitorily accumulates in E. coli cells at extraordinarily amounts. PMID- 29382907 TI - Role of P2X4 Receptor in Mouse Voiding Function. AB - Purinergic signalling plays an important role in the regulation of bladder smooth muscle (BSM) contractility, and P2X4 receptor is expressed in the bladder wall, where it may act by forming heteromeric receptors with P2X1, the major purinergic force-generating muscle receptor. To test this hypothesis, we examined mouse BSM contractile properties in the absence and presence of selective P2X1 (NF449 & NF279) and P2X4 antagonists (5-BDBD). These drugs inhibited BSM purinergic contraction only partially, suggesting the possibility of a heteromeric receptor. However, carefully controlled co-immunoprecipitation experiments indicated that P2X1 and P2X4 do not form physically linked heteromers. Furthermore, immunofluorescence staining showed that P2X4 is not present in mouse BSM per se, but in an unknown cellular structure among BSM bundles. To investigate whether deletion of P2X4 could impact voiding function in vivo, P2X4 null mice were characterized. P2X4 null mice had normal bladder weight and morphology, normal voiding spot size and number by voiding spot assay, normal voiding interval, pressure and compliance by cystometrogram, and normal BSM contractility by myography. In conclusion, these data strongly suggest that P2X4 is not present in mouse BSM cells, does not affect smooth muscle contractility and that mice null for P2X4 exhibit normal voiding function. PMID- 29382908 TI - Limits of Kirchhoff's Laws in Plasmonics. AB - The validity of Kirchhoff's laws in plasmonic nanocircuitry is investigated by studying a junction of plasmonic two-wire transmission lines. We find that Kirchhoff's laws are valid for sufficiently small values of a phenomenological parameter kappa relating the geometrical parameters of the transmission line with the effective wavelength of the guided mode. Beyond such regime, for large values of the phenomenological parameter, increasing deviations occur and the equivalent impedance description (Kirchhoff's laws) can only provide rough, but nevertheless useful, guidelines for the design of more complex plasmonic circuitry. As an example we investigate a system composed of a two-wire transmission line and a nanoantenna as the load. By addition of a parallel stub designed according to Kirchhoff's laws we achieve maximum signal transfer to the nanoantenna. PMID- 29382909 TI - Analysis of chimera states as drive-response systems. AB - Chimera states are spatiotemporal segregations - stably coexisting coherent and incoherent groups - that can occur in systems of identical phase oscillators. Here we demonstrate that this remarkable phenomenon can also be understood in terms of Pecora and Carroll's drive-response theory. By calculating the conditional Lyapunov exponents, we show that the incoherent group acts to synchronize the coherent group; the latter playing the role of a response. We also compare the distributions of finite-time conditional Lyapunov exponents to the characteristic distribution that was reported previously for chimera states. The present analysis provides a unifying explanation of the inherently frustrated dynamics that gives rise to chimera states. PMID- 29382910 TI - Lnc2Catlas: an atlas of long noncoding RNAs associated with risk of cancers. AB - Lnc2Catlas ( http://lnc2catlas.bioinfotech.org/ ) is an atlas of long noncoding RNAs (lncRNAs) associated with cancer risk. LncRNAs are a class of functional noncoding RNAs with lengths over 200 nt and play a vital role in diverse biological processes. Increasing evidence shows that lncRNA dysfunction is associated with many human cancers/diseases. It is therefore important to understand the underlying relationship between lncRNAs and cancers. To this end, we developed Lnc2Catlas to compile quantitative associations between lncRNAs and cancers using three computational methods, assessing secondary structure disruption, lncRNA-protein interactions, and co-expression networks. Lnc2Catlas was constructed based on 27,670 well-annotated lncRNAs, 31,749,216 SNPs, 1,473 cancer-associated proteins, and 10,539 expression profiles of 33 cancers from The Cancer Genome Atlas (TCGA). Lnc2Catlas contains 247,124 lncRNA-SNP pairs, over two millions lncRNA-protein interactions, and 6,902 co-expression clusters. We deposited Lnc2Catlas on Alibaba Cloud and developed interactive, mobile device compatible, user-friendly interfaces to help users search and browse Lnc2Catlas with ultra-low latency. Lnc2Catlas can aid in the investigation of associations between lncRNAs and cancers and can provide candidate lncRNAs for further experimental validation. Lnc2Catlas will facilitate an understanding of the associations between lncRNAs and cancer and will help reveal the critical role of lncRNAs in cancer. PMID- 29382911 TI - Peach RNA viromes in six different peach cultivars. AB - Many recent studies have demonstrated that several known and unknown viruses infect many horticultural plants. However, the elucidation of a viral population and the understanding of the genetic complexity of viral genomes in a single plant are rarely reported. Here, we conducted metatranscriptome analyses using six different peach trees representing six individual peach cultivars. We identified six viruses including five viruses in the family Betaflexiviridae and a novel virus belonging to the family Tymoviridae as well as two viroids. The number of identified viruses and viroids in each transcriptome ranged from one to six. We obtained 18 complete or nearly complete genomes for six viruses and two viroids using transcriptome data. Furthermore, we analyzed single nucleotide variations for individual viral genomes. In addition, we analyzed the amount of viral RNA and copy number for identified viruses and viroids. Some viruses or viroids were commonly present in different cultivars; however, the list of infected viruses and viroids in each cultivar was different. Taken together, our study reveals the viral population in a single peach tree and a comprehensive overview for the diversities of viral communities in different peach cultivars. PMID- 29382912 TI - Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers. AB - Efforts to improve existing anti-HIV-1 therapies or develop preventatives have identified CCR5 as an important target and CCL5 as an ideal scaffold to sculpt potent HIV-1 entry inhibitors. We created novel human CCL5 variants that exhibit exceptional anti-HIV-1 features using recombinant lactobacilli (exploited for live microbicide development) as a screening platform. Protein design, expression and anti-HIV-1 activity flowed in iterative cycles, with a stepwise integration of successful mutations and refinement of an initial CCL5 mutant battery towards the generation of two ultimate CCL5 derivatives, a CCR5 agonist and a CCR5 antagonist with similar anti-HIV-1 potency. The CCR5 antagonist was tested in human macrophages and against primary R5 HIV-1 strains, exhibiting cross-clade low picomolar IC50 activity. Moreover, its successful combination with several HIV-1 inhibitors provided the ground for conceiving therapeutic and preventative anti-HIV-1 cocktails. Beyond HIV-1 infection, these CCL5 derivatives may now be tested against several inflammation-related pathologies where the CCL5:CCR5 axis plays a relevant role. PMID- 29382913 TI - Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy. AB - It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive to acute exercise demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/memory. PMID- 29382914 TI - Hydroxylamine released by nitrifying microorganisms is a precursor for HONO emission from drying soils. AB - Nitrous acid (HONO) is an important precursor of the hydroxyl radical (OH), the atmosphere's primary oxidant. An unknown strong daytime source of HONO is required to explain measurements in ambient air. Emissions from soils are one of the potential sources. Ammonia-oxidizing bacteria (AOB) have been identified as possible producers of these HONO soil emissions. However, the mechanisms for production and release of HONO in soils are not fully understood. In this study, we used a dynamic soil-chamber system to provide direct evidence that gaseous emissions from nitrifying pure cultures contain hydroxylamine (NH2OH), which is subsequently converted to HONO in a heterogeneous reaction with water vapor on glass bead surfaces. In addition to different AOB species, we found release of HONO also in ammonia-oxidizing archaea (AOA), suggesting that these globally abundant microbes may also contribute to the formation of atmospheric HONO and consequently OH. Since biogenic NH2OH is formed by diverse organisms, such as AOB, AOA, methane-oxidizing bacteria, heterotrophic nitrifiers, and fungi, we argue that HONO emission from soil is not restricted to the nitrifying bacteria, but is also promoted by nitrifying members of the domains Archaea and Eukarya. PMID- 29382915 TI - Dielectric Breakdown and Post-Breakdown Dissolution of Si/SiO2 Cathodes in Acidic Aqueous Electrochemical Environment. AB - Understanding the conducting mechanisms of dielectric materials under various conditions is of increasing importance. Here, we report the dielectric breakdown (DB) and post-breakdown mechanism of Si/SiO2, a widely used semiconductor and dielectric, in an acidic aqueous electrochemical environment. Cathodic breakdown was found to generate conduction spots on the Si/SiO2 surface. Using scanning electrochemical microscopy (SECM), the size and number of conduction spots are confirmed to increase from nanometer to micrometer scale during the application of negative voltage. The morphologies of these conduction spots reveal locally recessed inverted-pyramidal structures with exposed Si{111} sidewalls. The pits generation preceded by DB is considered to occur via cathodic dissolution of Si and exfoliation of SiO2 that are induced by local pH increases due to the hydrogen evolution reaction (HER) at the conduction spots. The HER at the conduction spots is more sluggish due to strongly hydrogen-terminated Si{111} surfaces. PMID- 29382916 TI - Genetic diversity and kelp forest vulnerability to climatic stress. AB - Genetic diversity confers adaptive capacity to populations under changing conditions but its role in mediating impacts of climate change remains unresolved for most ecosystems. This lack of knowledge is particularly acute for foundation species, where impacts may cascade throughout entire ecosystems. We combined population genetics with eco-physiological and ecological field experiments to explore relationships among latitudinal patterns in genetic diversity, physiology and resilience of a kelp ecosystem to climate stress. A subsequent 'natural experiment' illustrated the possible influence of latitudinal patterns of genetic diversity on ecosystem vulnerability to an extreme climatic perturbation (marine heatwave). There were strong relationships between physiological versatility, ecological resilience and genetic diversity of kelp forests across latitudes, and genetic diversity consistently outperformed other explanatory variables in contributing to the response of kelp forests to the marine heatwave. Population performance and vulnerability to a severe climatic event were thus strongly related to latitudinal patterns in genetic diversity, with the heatwave extirpating forests with low genetic diversity. Where foundation species control ecological structure and function, impacts of climatic stress can cascade through the ecosystem and, consequently, genetic diversity could contribute to ecosystem vulnerability to climate change. PMID- 29382917 TI - Nitrogen enrichment regulates straw decomposition and its associated microbial community in a double-rice cropping system. AB - Litter bag method was conducted to investigate the decomposition characteristics of rice straw (6000 kg ha-1) and its associated microbial community under different nitrogen (N) addition rates (0, 90, 180 and 270 kg N ha-1) under double rice rotation. Generally, straw mass reduction and nutrient release of rice straw were faster in early stage of decomposition (0-14 days after decomposition), when easily-utilized carbohydrates and amines were the preferential substrates for involved decomposers. Straw-associated N-acetyl-glucosamidase and L-leucine aminopeptidase activities, which were higher under 180 and 270 kg N ha-1 addition, showed more activities in the early stage of decomposition. Gram positive bacteria were the quantitatively predominant microorganisms, while fungi and actinomycetes played a key role in decomposing recalcitrant compounds in late decomposition stage. Straw residue at middle decomposition stage was associated with greater cbhI and GH48 abundance and was followed by stronger beta glucosidase, beta-cellobiohydrolase and beta-xylosidase activities. Although enzyme activities and cellulolytic gene abundances were enhanced by 180 and 270 kg N ha-1 application, microbial communities and metabolic capability associated with rice straw were grouped by sampling time rather than specific fertilizer treatments. Thus, we recommended 180 kg N ha-1 application should be the economical rate for the current 6000 kg ha-1 rice straw returning. PMID- 29382918 TI - Individual neural transfer function affects the prediction of subjective depth of focus. AB - Attempts to accurately predict the depth of focus (DoF) based on objective metrics have failed so far. We investigated the effect of the individual neural transfer function (iNTF) on the quality of the prediction of the subjective DoF from objective wavefront measures. Subjective DoF was assessed in 22 participants using subjective through focus curves of visual acuity (VA). Objective defocus curves were calculated for visual Strehl metrics of the optical (VSOTFa) and the modulation transfer function as well as the point spread function. DoF was computed for residual lower order aberrations (rLoA) and incorporation of iNTF. Correlations between subjective and objective DoF did not reach significance, when a) standard metrics were used and b) rLoA were considered (r max = 0.33, p all > 0.05). By incorporating the iNTF of the individuals in the calculation of the objective DoF from the VSOTFa metric, a moderate statistically significant correlation was found (r = 0.43, p < 0.01, Pearson). The iNTF of the individual's eye is fundamental for the prediction of subjective DoF using the VSOTFa metric. Individualized predictions could aid future application in the correction of refractive errors like presbyopia using intraocular lenses. PMID- 29382919 TI - Simultaneous Realization of Anomalous Reflection and Transmission at Two Frequencies using Bi-functional Metasurfaces. AB - The capability to manipulating electromagnetic (EM) waves at the sub-wavelength scale has been enabled by metamaterials and their two-dimensional counterparts, metasurfaces. Especially, integrating two or more diverse functionalities into a single metasurface-based device is of great significance to meet the stringent requirements imposed by today's high frequency components and systems. Here, we present a dual-band bi-functional metasurface structure that could simultaneously achieve anomalous reflection and transmission at two terahertz (THz) frequencies, respectively, under linearly-polarized incident waves. To demonstrate the property of the proposed metasurface, a number of dual-band bi-functional metasurface-based components that could tailor the reflected and transmitted waves simultaneously are designed and verified numerically. Moreover, it is shown that both the amplitude and phase responses of the reflected and transmitted waves at two operating frequency bands (wavelengths) can be manipulated using the proposed metasurface, providing a new and convenient way to construct multi functional metasurfaces and corresponding electromagnetic devices. PMID- 29382922 TI - ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients. AB - Rho guanine nucleotide exchange factor 39 (ARHGEF39), also called C9orf100, is a new member of the Dbl-family of guanine nucleotide exchange factors. Although ARHGEF39 has been proven to regulate tumor progression in hepatocellular carcinoma, the downstream signaling pathway of ARHGEF39 and its clinical associations in non-small cell lung cancer (NSCLC) are currently unknown. In the present study, using MTT, colony formation, flow cytometry, mice xenografts, wound healing, and transwell assays, we showed that ARHGEF39 promoted tumor proliferation, migration, and invasion. Furthermore, ARHGEF39 promoted the expression of Cyclin A2, Cyclin D1, and MMP2 by activating Rac1, leading to increased phosphorylation of P38 and ATF2. Treatment with a P38 inhibitor counteracted the effect of ARHGEF39 overexpression on the increase in Cyclin A2, Cyclin D1, and MMP2 expression. Moreover, the elevated levels of p-P38 and p-ATF2 caused by ARHGEF39 overexpression could be inhibited by expression of a dominant negative Rac1 mutant (T17N). In addition, the inhibition of the expression of p P38 and p-ATF2 by ARHGEF39 RNAi could be restored by the expression of a constitutively active Rac1 mutant (Q61L). A similar impact on cell growth and invasion was observed after ARHGEF39 overexpression combined with the P38 inhibitor, Rac1 T17N, or Rac1 Q61L. Using immunohistochemistry, ARHGEF39 expression was observed to correlate positively with larger tumor size in clinical samples from 109 cases of NSCLC (P = 0.008). The Kaplan-Meier test revealed that ARHGEF39 expression significantly affected the overall survival of patients with NSCLC (52.55 +/- 6.40 months vs. 64.30 +/- 5.40 months, P = 0.017). In conclusion, we identified that ARHGEF39 promotes tumor growth and invasion by activating the Rac1-P38-ATF2 signaling pathway, as well as increasing the expression of Cyclin A2, Cyclin D1, and MMP2 in NSCLC cells. ARHGEF39 may be a useful marker to predict poor prognosis of patients with NSCLC. PMID- 29382921 TI - Diverse functions of clusterin promote and protect against the development of pulmonary fibrosis. AB - Pulmonary fibrosis is a progressive scarring disorder of the lung with dismal prognosis and no curative therapy. Clusterin, an extracellular chaperone and regulator of cell functions, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic human lung are incompletely characterized. Immunohistochemical localization of clusterin revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localized with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF beta1 is capable of down-regulating fibroblast clusterin expression. shRNA mediated down-regulation of clusterin did not affect TGF-beta1-induced fibroblast myofibroblast differentiation but inhibited fibroblast proliferative responses and sensitized to apoptosis. Down-regulation of clusterin in fibrotic lung fibroblasts at least partly due to increased TGF-beta1 may therefore represent an appropriate but insufficient response to limit fibroproliferation. Reduced expression of clusterin in the lung may also limit its extracellular chaperoning activity contributing to dysregulated deposition of extracellular matrix proteins. PMID- 29382920 TI - A systematic analysis highlights multiple long non-coding RNAs associated with cardiometabolic disorders. AB - Genome-wide association studies (GWAS) have identified many susceptibility loci for cardiometabolic disorders. Most of the associated variants reside in non coding regions of the genome including long non-coding RNAs (lncRNAs), which are thought to play critical roles in diverse biological processes. Here, we leveraged data from the available GWAS meta-analyses on lipid and obesity-related traits, blood pressure, type 2 diabetes, and coronary artery disease and identified 179 associated single-nucleotide polymorphisms (SNPs) in 102 lncRNAs (p-value < 2.3 * 10-7). Of these, 55 SNPs, either the lead SNP or in strong linkage disequilibrium with the lead SNP in the related loci, were selected for further investigations. Our in silico predictions and functional annotations of the SNPs as well as expression and DNA methylation analysis of their lncRNAs demonstrated several lncRNAs that fulfilled predefined criteria for being potential functional targets. In particular, we found evidence suggesting that LOC157273 (at 8p23.1) is involved in regulating serum lipid-cholesterol. Our results showed that rs4841132 in the second exon and cg17371580 in the promoter region of LOC157273 are associated with lipids; the lncRNA is expressed in liver and associates with the expression of its nearby coding gene, PPP1R3B. Collectively, we highlight a number of loci associated with cardiometabolic disorders for which the association may act through lncRNAs. PMID- 29382923 TI - Effect of a fish oil-based lipid emulsion on intestinal failure-associated liver disease in children. AB - BACKGROUND/OBJECTIVES: The aim of this study was to assess the effects of a fish oil-based lipid emulsion on intestinal failure-associated liver disease (IFALD) in children. SUBJECTS/METHODS: From January 2014 through June 2017, we enrolled 32 children with IF on long-term parenteral nutrition (PN). When the levels of any three of seven liver indicators (TBA, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, gamma glutamyl transferase (gamma-GT), total bilirubin (TB), or direct bilirubin (DB)) were two times higher than normal levels, we switched a 50:50 mix of soybean oil and medium-chain triglycerides (MCT) lipid emulsion (with an average dose of 1.30 g/kg/day) to a fish oil-based lipid emulsion (1 g/kg/day) and measured liver function in the children. Meanwhile, inflammation and oxidative stress-related markers were also measured. RESULTS: The average fish oil therapy duration was 26 +/- 21 days, and the median duration of PN support was 84 days. With fish oil therapy, levels of TBA, ALT, AST, gamma-GT, TB, and DB all significantly decreased. Enteral nutrition was introduced following fish oil resulting in higher energy intake (99.88 +/- 31.06 kcal/kg/day) compared with before fish oil (67.90 +/- 27.31 kcal/kg/day, P = 0.001). No significant difference was found in average PN energy (P = 0.147). In addition, levels of inflammatory indicators like tumor necrosis factor-alpha (TNF alpha), C-reactive protein (CRP), and white blood cell (WBC) significantly decreased. CONCLUSIONS: Fish oil therapy alleviates IFALD in children. PMID- 29382924 TI - Sodium excretion and health-related quality of life: the results from the Korea National Health and Nutrition Examination Survey 2010-2011. AB - BACKGROUND/OBJECTIVES: Little is known about the effect of sodium intake on health-related quality of life (HR-QOL). In this study, we investigated the association between estimated 24-h urine sodium and HR-QOL in Korean adults. SUBJECTS/METHODS: In this cross-sectional study, we analyzed 10,672 participants from Korea National Health and Nutrition Examination Survey (KNHANES) 2010~2011. To assess sodium intake, 24-h urine sodium excretion was estimated from random urine sodium and creatinine using the Kawasaki formula. HR-QOL was assessed using EQ-5D (EuroQol five-dimension) index calculated from Korean version of the EQ-5D questionnaire. Low HR-QOL was defined as the lowest quartile of the EQ-5D index. Participants were divided into three groups according to their estimated 24-h urine sodium level (low, <2.0 g/day; moderate, 2.0~3.9 g/day; high, >4.0 g/day). RESULTS: Adjusted means of EQ-5D index were 0.975, 0.995, and 0.991 in the low, moderate, and high estimated 24-h urine sodium group, respectively (P = 0.003 for low vs. moderate, P = 0.078 for high vs. moderate). In a multiple logistic analysis, the odds ratio (OR) for low EQ-5D index in the low estimated 24-h urine sodium group compared to the moderate group was 1.87 (95% confidence interval (CI), 1.33-2.64; P < 0.001). The OR in the high estimated 24-h urine sodium group compared to the moderate group was 1.09 (95% CI, 0.95-1.24; P = 0.218). CONCLUSIONS: Low estimated 24-h urine sodium rather than high estimated 24-h urine sodium was associated with low HR-QOL in representative Korean adults. Further studies are warranted to verify the effect of sodium intake on HR-QOL and the adequate-level sodium restriction in terms of HR-QOL. PMID- 29382925 TI - Macro-/Micro-Controlled 3D Lithium-Ion Batteries via Additive Manufacturing and Electric Field Processing. AB - This paper presents a new concept for making battery electrodes that can simultaneously control macro-/micro-structures and help address current energy storage technology gaps and future energy storage requirements. Modern batteries are fabricated in the form of laminated structures that are composed of randomly mixed constituent materials. This randomness in conventional methods can provide a possibility of developing new breakthrough processing techniques to build well organized structures that can improve battery performance. In the proposed processing, an electric field (EF) controls the microstructures of manganese based electrodes, while additive manufacturing controls macro-3D structures and the integration of both scales. The synergistic control of micro-/macro structures is a novel concept in energy material processing that has considerable potential for providing unprecedented control of electrode structures, thereby enhancing performance. Electrochemical tests have shown that these new electrodes exhibit superior performance in their specific capacity, areal capacity, and life cycle. PMID- 29382926 TI - Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99. AB - Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents. CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy. We screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth. We identified two structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it can function through inhibiting CD99 independent of DNA metabolism. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of three different ES xenografts. Our findings provide a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities. PMID- 29382927 TI - Formation of Multi-Component Extracellular Matrix Protein Fibers. AB - The extracellular matrix (ECM) consists of polymerized protein monomers that form a unique fibrous network providing stability and structural support to surrounding cells. We harnessed the fibrillogenesis mechanisms of naturally occurring ECM proteins to produce artificial fibers with a heterogeneous protein makeup. Using ECM proteins as fibril building blocks, we created uniquely structured multi-component ECM fibers. Sequential incubation of fibronectin (FN) and laminin (LAM) resulted in self-assembly into locally stacked fibers. In contrast, simultaneous incubation of FN with LAM or collagen (COL) produced molecularly stacked multi-component fibers because both proteins share a similar assembly mechanism or possess binding domains specific to each other. Sequential incubation of COL on FN fibers resulted in fibers with sandwiched layers because COL molecules bind to the external surface of FN fibers. By choosing proteins for incubation according to the interplay of their fibrillogenesis mechanisms and their binding domains (exposed when they unfold), we were able to create ECM protein fibers that have never before been observed. PMID- 29382928 TI - Sewable soft shields for the gamma-ray radiation. AB - Soft shields are required to protect the human body during a radioactive accident. However, the modulus of most soft shields, such as HDPE and epoxy, is high, thereby making it difficult to process them in wearable forms like gloves and clothes. We synthesized a soft shield based on a hydrogel that is very compliant, stretchable, and biocompatible. The shields were fabricated by integrating gamma-ray-shield particles into hydrogels with an interpenetrating network. The soft shields containing 3.33 M of PbO2 exhibited a high attenuation coefficient (0.284 cm-1) and were stretched to 400% without a rupture. Furthermore, the fabricated soft shield can be sewn without a fabric support due to its high energy-dispersion ability. A wearable arm shield for the gamma-ray radiation was demonstrated using a direct sewing of the soft-shield materials. PMID- 29382929 TI - Energy savings, emission reductions, and health co-benefits of the green building movement. AB - Buildings consume nearly 40% of primary energy production globally. Certified green buildings substantially reduce energy consumption on a per square foot basis and they also focus on indoor environmental quality. However, the co benefits to health through reductions in energy and concomitant reductions in air pollution have not been examined.We calculated year by year LEED (Leadership in Energy and Environmental Design) certification rates in six countries (the United States, China, India, Brazil, Germany, and Turkey) and then used data from the Green Building Information Gateway (GBIG) to estimate energy savings in each country each year. Of the green building rating schemes, LEED accounts for 32% of green-certified floor space and publically reports energy efficiency data. We employed Harvard's Co-BE Calculator to determine pollutant emissions reductions by country accounting for transient energy mixes and baseline energy use intensities. Co-BE applies the social cost of carbon and the social cost of atmospheric release to translate these reductions into health benefits. Based on modeled energy use, LEED-certified buildings saved $7.5B in energy costs and averted 33MT of CO2, 51 kt of SO2, 38 kt of NOx, and 10 kt of PM2.5 from entering the atmosphere, which amounts to $5.8B (lower limit = $2.3B, upper limit = $9.1B) in climate and health co-benefits from 2000 to 2016 in the six countries investigated. The U.S. health benefits derive from avoiding an estimated 172-405 premature deaths, 171 hospital admissions, 11,000 asthma exacerbations, 54,000 respiratory symptoms, 21,000 lost days of work, and 16,000 lost days of school. Because the climate and health benefits are nearly equivalent to the energy savings for green buildings in the United States, and up to 10 times higher in developing countries, they provide an important and previously unquantified societal value. Future analyses should consider these co-benefits when weighing policy decisions around energy-efficient buildings. PMID- 29382930 TI - Red fluorescent cAMP indicator with increased affinity and expanded dynamic range. AB - cAMP is one of the most important second messengers in biological processes. Cellular dynamics of cAMP have been investigated using a series of fluorescent indicators; however, their sensitivity was sub-optimal for detecting cAMP dynamics at a low concentration range, due to a low ligand affinity and/or poor dynamic range. Seeking an indicator with improved detection sensitivity, we performed insertion screening of circularly permuted mApple, a red fluorescent protein, into the cAMP-binding motif of PKA regulatory subunit Ialpha and developed an improved cAMP indicator named R-FlincA (Red Fluorescent indicator for cAMP). Its increased affinity (Kd = 0.3 MUM) and expanded dynamic range (860% at pH 7.2) allowed the detection of subtle changes in the cellular cAMP dynamics at sub-MUM concentrations, which could not be easily observed with existing indicators. Increased detection sensitivity also strengthened the advantages of using R-FlincA as a red fluorescent indicator, as it permits a series of applications, including multi-channel/function imaging of multiple second messengers and combinatorial imaging with photo-manipulation. These results strongly suggest that R-FlincA is a promising tool that accelerates cAMP research by revealing unobserved cAMP dynamics at a low concentration range. PMID- 29382931 TI - Chemical camouflage: a key process in shaping an ant-treehopper and fig-fig wasp mutualistic network. AB - Different types of mutualisms may interact, co-evolve and form complex networks of interdependences, but how species interact in networks of a mutualistic community and maintain its stability remains unclear. In a mutualistic network between treehoppers-weaver ants and fig-pollinating wasps, we found that the cuticular hydrocarbons of the treehoppers are more similar to the surface chemical profiles of fig inflorescence branches (FIB) than the cuticular hydrocarbons of the fig wasps. Behavioral assays showed that the cuticular hydrocarbons from both treehoppers and FIBs reduce the propensity of weaver ants to attack treehoppers even in the absence of honeydew rewards, suggesting that chemical camouflage helps enforce the mutualism between weaver ants and treehoppers. High levels of weaver ant and treehopper abundances help maintain the dominance of pollinating fig wasps in the fig wasp community and also increase fig seed production, as a result of discriminative predation and disturbance by weaver ants of ovipositing non-pollinating fig wasps (NPFWs). Ants therefore help preserve this fig-pollinating wasp mutualism from over exploitation by NPFWs. Our results imply that in this mutualistic network chemical camouflage plays a decisive role in regulating the behavior of a key species and indirectly shaping the architecture of complex arthropod-plant interactions. PMID- 29382932 TI - Improvement of penile neurogenic and endothelial relaxant responses by chronic administration of resveratrol in rabbits exposed to unpredictable chronic mild stress. AB - Chronic stress is an important public health problem known as a risk factor for depression, cognitive deficits, and also erectile dysfunction (ED). Resveratrol, a plant polyphenol, was reported to activate constitutive endothelial nitric oxide synthase (eNOS). Although resveratrol has been proven to exert beneficial effects on the unpredictable chronic mild stress (UCMS)-induced decline in cognitive functions, its potential protecting effect on the penile tissue subjected to UCMS was in fact not investigated. Therefore, restorative effects of resveratrol on neurogenic and endothelium-dependent relaxations were evaluated in the corpus cavernosum of rabbits exposed to UCMS. Eighteen male New Zealand white rabbits were assigned into three groups (n = 6 in each group): controls; UCMS; and UCMS rabbits treated with resveratrol (20 mg/kg/day, i.p.) for 12-week period of stress induction. UCMS was induced by a couple of defined adverse conditions applied in a shuffled order for 12 weeks. Neurogenic and endothelium-dependent relaxations of corpus cavernosum were assessed by using organ bath studies. Both the electrical field stimulation (EFS)-induced neurogenic and carbachol-induced endothelium-dependent relaxant responses significantly decreased in physiological stress and resveratrol treatment exhibited a marked improvement in these relaxation responses in vitro. Our results indicated that chronic psychological stress could lead to ED by reducing neurogenic and endothelium-dependent relaxations and resveratrol prevents impairment of the functional responses, suggesting a potential new treatment approach for treatment of ED during psychological stress. PMID- 29382933 TI - Characterization of soil bacterial, archaeal and fungal communities inhabiting archaeological human-impacted layers at Monte Iato settlement (Sicily, Italy). AB - Microbial communities in human-impacted soils of ancient settlements have been proposed to be used as ecofacts (bioindicators) of different ancient anthropogenic activities. In this study, bacterial, archaeal and fungal communities inhabiting soil of three archaic layers, excavated at the archaeological site on Monte Iato (Sicily, Italy) and believed to have been created in a chronological order in archaic times in the context of periodic cultic feasts, were investigated in terms of (i) abundance (phospholipid fatty acid (PLFA) analysis and quantitative PCR)), (ii) carbon(C)-source consumption patterns (Biolog-Ecoplates) and (iii) diversity and community composition (Illumina amplicon sequencing). PLFA analyses demonstrated the existence of living bacteria and fungi in the soil samples of all three layers. The upper layer showed increased levels of organic C, which were not concomitant with an increment in the microbial abundance. In taxonomic terms, the results indicated that bacterial, archaeal and fungal communities were highly diverse, although differences in richness or diversity among the three layers were not detected for any of the communities. However, significantly different microbial C-source utilization patterns and structures of bacterial, archaeal and fungal communities in the three layers confirmed that changing features of soil microbial communities reflect different past human activities. PMID- 29382934 TI - Insights into earthquake hazard map performance from shaking history simulations. AB - Why recent large earthquakes caused shaking stronger than shown on earthquake hazard maps for common return periods is under debate. Explanations include: (1) Current probabilistic seismic hazard analysis (PSHA) is deficient. (2) PSHA is fine but some map parameters are wrong. (3) Low-probability events consistent with a map sometimes occur. This issue has two parts. Verification involves how well maps implement PSHA ("have we built the map right?"). Validation asks how well maps forecast shaking ("have we built the right map?"). We explore how well a map can ideally perform by simulating an area's shaking history and comparing "observed" shaking to that predicted by a map generated for the same parameters. The simulations yield shaking distributions whose mean is consistent with the map, but individual shaking histories show large scatter. Infrequent large earthquakes cause shaking much stronger than mapped, as observed. Hence, PSHA seems internally consistent and can be regarded as verified. Validation is harder because an earthquake history can yield shaking higher or lower than the hazard map without being inconsistent. As reality gives only one history, it is hard to assess whether misfit between a map and actual shaking reflects chance or a map biased by inappropriate parameters. PMID- 29382935 TI - Contaminant-Activated Visible Light Photocatalysis. AB - Pristine titanium dioxide (TiO2) absorbs ultraviolet light and reflects the entire visible spectrum. This optical response of TiO2 has found widespread application as white pigments in paper, paints, pharmaceuticals, foods and plastic industries; and as a UV absorber in cosmetics and photocatalysis. However, pristine TiO2 is considered to be inert under visible light for these applications. Here we show for the first time that a bacterial contaminant (Staphylococcus aureus-a MRSA surrogate) in contact with TiO2 activates its own photocatalytic degradation under visible light. The present study delineates the critical role of visible light absorption by contaminants and electronic interactions with anatase in photocatalytic degradation using two azo dyes (Mordant Orange and Procion Red) that are highly stable because of their aromaticity. An auxiliary light harvester, polyhydroxy fullerenes, was successfully used to accelerate photocatalytic degradation of contaminants. We designed a contaminant-activated, transparent, photocatalytic coating for common indoor surfaces and conducted a 12-month study that proved the efficacy of the coating in killing bacteria and holding bacterial concentrations generally below the benign threshold. Data collected in parallel with this study showed a substantial reduction in the incidence of infections. PMID- 29382936 TI - White matter hyperintensity shape and location feature analysis on brain MRI; proof of principle study in patients with diabetes. AB - Cerebral small vessel disease is a heterogeneous disease in which various underlying etiologies can lead to different types of white matter hyperintensities (WMH). WMH shape features might aid in distinguishing these different types. In this proof of principle study in patients with type 2 diabetes mellitus (T2DM), we present a novel approach to assess WMH using shape features. Our algorithm determines WMH volume and different WMH shape and location features on 3T MRI scans. These features were compared between patients with T2DM (n = 60) and a matched control group (n = 54). Although a more traditional marker (WMH volume) was not significantly different between groups (natural log transformed Beta (95% CI): 0.07 (-0.11<->0.24)), patients with T2DM showed a larger number of non-punctuate WMH (median (10th-90th percentile), patients: 40 lesions per person (16-86); controls: 26 (5-58)) and a different shape (eccentricity) of punctuate deep WMH (Beta (95% CI): 0.40 (0.23<->0.58)) compared to controls. In conclusion, our algorithm identified WMH features that are not part of traditional WMH assessment, but showed to be distinguishing features between patients with T2DM and controls. Future studies could address these features to further unravel the etiology and functional impact of WMH. PMID- 29382938 TI - A presumed homologue of the regulatory subunits of eIF2B functions as ribose-1,5 bisphosphate isomerase in Pyrococcus horikoshii OT3. AB - The homologues of the regulatory subunits of eukaryotic translation initiation factor 2B (eIF2B) are assumed to be present in archaea. Likewise, an ORF, PH0208 in Pyrococcus horikoshii OT3 have been proposed to encode one of the homologues of regulatory subunits of eIF2B. However, PH0208 protein also shares sequence similarity with a functionally non-related enzyme, ribose-1,5-bisphosphate isomerase (R15Pi), involved in conversion of ribose-1,5-bisphosphate (R15P) to ribulose-1,5-bisphosphate (RuBP) in an AMP-dependent manner. Herein, we have determined the crystal structure of PH0208 protein in order to decipher its true function. Although structurally similar to the regulatory subunits of eIF2B, the ability to bind R15P and RuBP suggests that PH0208 would function as R15Pi. Additionally, this study for the first time reports the binding sites of AMP and GMP in R15Pi. The AMP binding site in PH0208 protein clarified the role of AMP in providing structural stability to R15Pi. The binding of GMP to the 'AMP binding site' in addition to its own binding site indicates that GMP might also execute a similar function, though with less specificity. Furthermore, we have utilized the resemblance between PH0208 and the regulatory subunits of eIF2B to propose a model for the regulatory mechanism of eIF2B in eukaryotes. PMID- 29382939 TI - Mechanisms of disease: Consequences of mitoribosome overload. PMID- 29382937 TI - The genetic prehistory of the Baltic Sea region. AB - While the series of events that shaped the transition between foraging societies and food producers are well described for Central and Southern Europe, genetic evidence from Northern Europe surrounding the Baltic Sea is still sparse. Here, we report genome-wide DNA data from 38 ancient North Europeans ranging from ~9500 to 2200 years before present. Our analysis provides genetic evidence that hunter gatherers settled Scandinavia via two routes. We reveal that the first Scandinavian farmers derive their ancestry from Anatolia 1000 years earlier than previously demonstrated. The range of Mesolithic Western hunter-gatherers extended to the east of the Baltic Sea, where these populations persisted without gene-flow from Central European farmers during the Early and Middle Neolithic. The arrival of steppe pastoralists in the Late Neolithic introduced a major shift in economy and mediated the spread of a new ancestry associated with the Corded Ware Complex in Northern Europe. PMID- 29382940 TI - The future of CRISPR technologies in agriculture. PMID- 29382941 TI - Density-matrix evaluation of the enhancement to resonant Raman scattering and fluorescence of molecules confined in metallic nanoparticle dimers. AB - In the present work we study the surface-enhanced resonant Raman scattering (SERRS) and fluorescence (SEF) spectra of a general model molecule confined in metallic dimers consisting of Ag, Au and hybrid AuAg nanoparticles (NPs). The electromagnetic (EM) enhancement factors were simulated by the generalized Mie scatting method and the scattering cross section of the molecules were obtained by density-matrix calculations. The influence of the size of the NPs and the separation between the dimer on the Raman scattering and fluorescence were systematically studied and analyzed in detail. It was found that the SERRS mainly related to EM enhancement and the SEF depended on the competition between EM enhancement and quantum yield, both of which could be controlled by tuning the radius and separation of the metallic dimers. The optimal radius of the NPs for SERRS were found to be around 30 nm for AgNPs, 40 nm for AuNPs and 50 nm for hybrid AuAgNPs. The strongest Raman enhancement as predicted by the theoretical simulations were 6.2 * 1010, 1.5 * 107 and 5.2 * 108 for the three types of structures, respectively. These results could offer valuable information for the design of metallic substrates for surface enhanced Raman and fluorescence measurements. PMID- 29382942 TI - Eye region surface temperature reflects both energy reserves and circulating glucocorticoids in a wild bird. AB - Body temperature of endotherms shows substantial within- and between-individual variation, but the sources of this variation are not fully understood in wild animals. Variation in body temperature can indicate how individuals cope with their environment via metabolic or stress-induced effects, both of which may relate to depletion of energy reserves. Body condition can reflect heat production through changes to metabolic rate made to protect energy reserves. Additionally, changes in metabolic processes may be mediated by stress-related glucocorticoid secretion, which is associated with altered blood-flow patterns that affect regional body temperatures. Accordingly, both body condition and glucocorticoid secretion should relate to body temperature. We used thermal imaging, a novel non-invasive method of temperature measurement, to investigate relationships between body condition, glucocorticoid secretion and body surface temperature in wild blue tits (Cyanistes caeruleus). Individuals with lower body condition had lower eye-region surface temperature in both non-breeding and breeding seasons. Eye-region surface temperature was also negatively correlated with baseline circulating glucocorticoid levels in non-breeding birds. Our results demonstrate that body surface temperature can integrate multiple aspects of physiological state. Consequently, remotely-measured body surface temperature could be used to assess such aspects of physiological state non-invasively in free-living animals at multiple life history stages. PMID- 29382943 TI - Optimized targeted sequencing of cell-free plasma DNA from bladder cancer patients. AB - Analysis of plasma cell-free DNA (cfDNA) may provide important information in cancer research, though the often small fraction of DNA originating from tumor cells makes the analysis technically challenging. Digital droplet PCR (ddPCR) has been utilized extensively as sufficient technical performance is easily achieved, but analysis is restricted to few mutations. Next generation sequencing (NGS) approaches have been optimized to provide comparable technical performance, especially with the introduction of unique identifiers (UIDs). However, the parameters influencing data quality when utilizing UIDs are not fully understood. In this study, we applied a targeted NGS approach to 65 plasma samples from bladder cancer patients. Laboratory and bioinformatics parameters were found to influence data quality when using UIDs. We successfully sequenced 249 unique DNA fragments on average per genomic position of interest using a 225 kb gene panel. Validation identified 24 of 38 mutations originally identified using ddPCR across several plasma samples. In addition, four mutations detected in associated tumor samples were detected using NGS, but not using ddPCR. CfDNA analysis of consecutively collected plasma samples from a bladder cancer patient indicated earlier detection of recurrence compared to radiographic imaging. The insights presented here may further the technical advancement of NGS mediated cfDNA analysis. PMID- 29382944 TI - APLP1 is endoproteolytically cleaved by gamma-secretase without previous ectodomain shedding. AB - Regulated intramembrane proteolysis of the amyloid precursor protein (APP) and its homologs, the APP like proteins APLP1 and APLP2, is typically a two-step process, which is initiated by ectodomain-shedding of the substrates by alpha- or beta-secretases. Growing evidence, however, indicates that the cleavage process for APLP1 is different than for APP. Here, we describe that full-length APLP1, but not APP or APLP2, is uniquely cleaved by gamma-secretase without previous ectodomain shedding. The new fragment, termed sAPLP1gamma, was exclusively associated with APLP1, not APP, APLP2. We provide an exact molecular analysis showing that sAPLP1gamma was uniquely generated by gamma-secretase from full length APLP1. Mass spectrometry analysis showed that the sAPLP1gamma fragment and the longest Abeta-like peptide share the C-terminus. This novel mechanism of gamma-secretase action is consistent with an epsilon-cut based upon the nature of the reaction in APP. We further demonstrate that the APLP1 transmembrane sequence is the critical determinant for gamma-shedding and release of full-length APLP1. Moreover, the APLP1 TMS is sufficient to convert larger type-I membrane proteins like APP into direct gamma-secretase substrates. Taken together, the direct cleavage of APLP1 is a novel feature of the gamma-secretase prompting a re thinking of gamma-secretase activity modulation as a therapeutic strategy for Alzheimer disease. PMID- 29382945 TI - Coordinated gene expression between Trichodesmium and its microbiome over day night cycles in the North Pacific Subtropical Gyre. AB - Trichodesmium is a widespread, N2 fixing marine cyanobacterium that drives inputs of newly fixed nitrogen and carbon into the oligotrophic ecosystems where it occurs. Colonies of Trichodesmium ubiquitously occur with heterotrophic bacteria that make up a diverse microbiome, and interactions within this Trichodesmium holobiont could influence the fate of fixed carbon and nitrogen. Metatranscriptome sequencing was performed on Trichodesmium colonies collected during high-frequency Lagrangian sampling in the North Pacific Subtropical Gyre (NPSG) to identify possible interactions between the Trichodesmium host and microbiome over day-night cycles. Here we show significantly coordinated patterns of gene expression between host and microbiome, many of which had significant day night periodicity. The functions of the co-expressed genes suggested a suite of interactions within the holobiont linked to key resources including nitrogen, carbon, and iron. Evidence of microbiome reliance on Trichodesmium-derived vitamin B12 was also detected in co-expression patterns, highlighting a dependency that could shape holobiont community structure. Collectively, these patterns of expression suggest that biotic interactions could influence colony cycling of resources like nitrogen and vitamin B12, and decouple activities, like N2 fixation, from typical abiotic drivers of Trichodesmium physiological ecology. PMID- 29382946 TI - Suppression of the activity of arbuscular mycorrhizal fungi by the soil microbiota. AB - Arbuscular mycorrhizal fungi (AMF) colonise roots of most plants; their extra radical mycelium (ERM) extends into the soil and acquires nutrients for the plant. The ERM coexists with soil microbial communities and it is unresolved whether these communities stimulate or suppress the ERM activity. This work studied the prevalence of suppressed ERM activity and identified main components behind the suppression. ERM activity was determined by quantifying ERM-mediated P uptake from radioisotope-labelled unsterile soil into plants, and compared to soil physicochemical characteristics and soil microbiome composition. ERM activity varied considerably and was greatly suppressed in 4 of 21 soils. Suppression was mitigated by soil pasteurisation and had a dominating biotic component. AMF-suppressive soils had high abundances of Acidobacteria, and other bacterial taxa being putative fungal antagonists. Suppression was also associated with low soil pH, but this effect was likely indirect, as the relative abundance of, e.g., Acidobacteria decreased after liming. Suppression could not be transferred by adding small amounts of suppressive soil to conducive soil, and thus appeared to involve the common action of several taxa. The presence of AMF antagonists resembles the phenomenon of disease-suppressive soils and implies that ecosystem services of AMF will depend strongly on the specific soil microbiome. PMID- 29382947 TI - Living apart together-bacterial volatiles influence methanotrophic growth and activity. AB - Volatile organic compounds play an important role in microbial interactions. However, little is known about how volatile-mediated interactions modulate biogeochemical processes. In this study, we show the effect of volatile-mediated interaction on growth and functioning of aerobic methane-oxidizing bacteria, grown in co-culture with five different heterotrophs. Both growth and methane oxidation of Methylobacter luteus were stimulated by interaction with specific heterotrophs. In Methylocystis parvus, we observed significant growth promotion, while methane oxidation was inhibited. Volatolomics of the interaction of each of the methanotrophs with Pseudomonas mandelii, revealed presence of a complex blend of volatiles, including dimethylsulfide, dimethyldisulfide, and bicyclic sesquiterpenes. Although the ecological role of the detected compounds remains to be elucidated, our results provide unprecedented insights into interspecific relations and associated volatiles for stimulating methanotroph functioning, which is of substantial environmental and biotechnological significance. PMID- 29382948 TI - Locality and diel cycling of viral production revealed by a 24 h time course cross-omics analysis in a coastal region of Japan. AB - Viruses infecting microorganisms are ubiquitous and abundant in the ocean. However, it is unclear when and where the numerous viral particles we observe in the sea are produced and whether they are active. To address these questions, we performed time-series analyses of viral metagenomes and microbial metatranscriptomes collected over a period of 24 h at a Japanese coastal site. Through mapping the metatranscriptomic reads on three sets of viral genomes ((i) 878 contigs of Osaka Bay viromes (OBV), (ii) 1766 environmental viral genomes from marine viromes, and (iii) 2429 reference viral genomes), we revealed that all the local OBV contigs were transcribed in the host fraction. This indicates that the majority of viral populations detected in viromes are active, and suggests that virions are rapidly diluted as a result of diffusion, currents, and mixing. Our data further revealed a peak of cyanophage gene expression in the afternoon/dusk followed by an increase of genomes from their virions at night and less-coherent infectious patterns for viruses putatively infecting various groups of heterotrophs. This suggests that cyanophages drive the diel release of cyanobacteria-derived organic matter into the environment and viruses of heterotrophic bacteria might have adapted to the population-specific life cycles of hosts. PMID- 29382949 TI - JhI-21 plays a role in Drosophila insulin-like peptide release from larval IPCs via leucine transport. AB - Insulin is present all across the animal kingdom. Its proper release after feeding is of extraordinary importance for nutrient uptake, regulation of metabolism, and growth. We used Drosophila melanogaster to shed light on the processes linking dietary leucine intake to insulin secretion. The Drosophila genome encodes 8 insulin-like peptides ("Dilps"). Of these, Dilp2 is secreted after the ingestion of a leucine-containing diet. We previously demonstrated that Minidiscs, related to mammalian system-L transporters, acts as a leucine sensor within the Dilp2-secreting insulin-producing cells ("IPCs") of the brain. Here, we show that a second leucine transporter, JhI-21, of the same family is additionally necessary for proper leucine sensing in the IPCs. Using calcium imaging and ex-vivo cultured brains we show that knockdown of JhI-21 in IPCs causes malfunction of these cells: they are no longer able to sense dietary leucine or to release Dilp2 in a leucine dependent manner. JhI-21 knockdown in IPCs further causes systemic metabolic defects including defective sugar uptake and altered growth. Finally, we showed that JhI-21 and Minidiscs have no cumulative effect on Dilp2 release. Since system-L transporters are expressed by mammalian beta-cells our results could help to better understand the role of these proteins in insulin signaling. PMID- 29382951 TI - Hepatitis: No cure for hepatitis B and D without targeting integrated viral DNA? PMID- 29382953 TI - Detection of secondary malignancy following high-dose chemotherapy in germ cell tumors: prospects and limitations. PMID- 29382952 TI - Establishing rapid analysis of Pu isotopes in seawater to study the impact of Fukushima nuclear accident in the Northwest Pacific. AB - In order to assess the impact of the Fukushima derived Pu isotopes on seawater, a new analytical method to rapidly determine Pu isotopes in seawater by SF-ICP-MS including Fe(OH)2 primary co-precipitation, CaF2/LaF3 secondary co-precipitation and TEVA+UTEVA+DGA extraction chromatographic separation was established. High concentration efficiency (~100%) and high U decontamination factor (~107) were achieved. The plutonium chemical recoveries were 74-88% with the mean of 83 +/- 5%. The precisions for both 240Pu/239Pu atom ratios and 239+240Pu activity concentrations were less than 5% when 15 L of seawater samples with the typical 239+240Pu activity of the Northwest Pacific were measured. It just needs 12 hours to determine plutonium using this new method. The limit of detection (LOD) for 239Pu and 240Pu were both 0.08 fg/mL, corresponding to 0.01 mBq/m3 for 239Pu and 0.05 mBq/m3 for 240Pu when a 15 L volume of seawater was measured. This method was applied to determine the seawater samples collected 446-1316 km off the FDNPP accident site in the Northwest Pacific in July of 2013. The obtained 239+240Pu activity concentrations of 1.21-2.19 mBq/m3 and the 240Pu/239Pu atom ratios of 0.198-0.322 suggested that there was no significant Pu contamination from the accident to the Northwest Pacific. PMID- 29382950 TI - Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. AB - Neutrophil extracellular traps (NETs) have an important role during infection by helping neutrophils to capture and kill pathogens. However, evidence is accumulating that uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. In this Review, we focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects. The latest mechanistic insights in NET formation, interactions between microorganisms and NETs and the relationship between neutrophil subtypes and their functions are also discussed. Additionally, we describe the potential importance of NET-related molecules, including cell-free DNA and hypercitrullinated histones, as biomarkers and targets for therapeutic intervention in gastrointestinal diseases. PMID- 29382954 TI - Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation. PMID- 29382955 TI - Ocular findings and ocular graft-versus-host disease after allogeneic stem cell transplantation without total body irradiation. AB - Patients treated with allogeneic stem cell transplantation (allo-SCT) often develop ocular complications. To investigate the ocular findings in young long term survivors after allo-SCT without TBI, we examined 96 patients more than 5 years after transplantation. All patients were under 30 years of age at transplantation. The mean follow-up time was 16.8 years (range 6.0-26.1 years). The study was a part of the Norwegian Allo Survivorship Study investigating health impairments in young survivors after allo-SCT. Ophthalmological examination included visual acuity, tear break-up time, corneal fluorescein staining, Schirmer I test, tear film osmolarity, biomicroscopy and dilated ophthalmoscopy. In patients with known systemic chronic GVHD (cGVHD), ocular GVHD (oGVHD) diagnosed by clinical examination was compared with diagnosis using National Institutes of Health (NIH) or International Chronic Ocular Graft-vs-Host Disease (ICCGVHD) Consensus Group criteria. We diagnosed dry eye disease (DED) in 52 patients (54%), cataract in 3 patients (3%) and retinopathy in 1 patient (1%). Systemic cGVHD was a risk factor for DED (OR 4.40, CI 1.33-14.56, p = 0.02). Comparison of diagnostic criteria suggests that the more stringent ICCGVHD criteria can better differentiate DED from oGVHD after allo-SCT as compared with the NIH criteria. PMID- 29382956 TI - Vgll3 and the Hippo pathway are regulated in Sertoli cells upon entry and during puberty in Atlantic salmon testis. AB - Vgll3 is linked to age at maturity in Atlantic salmon (Salmo salar). However, the molecular mechanisms involving Vgll3 in controlling timing of puberty as well as relevant tissue and cell types are currently unknown. Vgll3 and the associated Hippo pathway has been linked to reduced proliferation activity in different tissues. Analysis of gene expression reveals for the first time that vgll3 and several members of the Hippo pathway were down-regulated in salmon testis during onset of puberty and remained repressed in maturing testis. In the gonads, we found expression in Sertoli and granulosa cells in males and females, respectively. We hypothesize that vgll3 negatively regulates Sertoli cell proliferation in testis and therefore acts as an inhibitor of pubertal testis growth. Gonadal expression of vgll3 is located to somatic cells that are in direct contact with germ cells in both sexes, however our results indicate sex biased regulation of vgll3 during puberty. PMID- 29382957 TI - Major Depression Comorbid with Medical Conditions: Analysis of Quality of Life, Functioning, and Depressive Symptom Severity. AB - Background: The presence of Major Depressive Disorder (MDD) is often comorbid in patients with a variety of general medical conditions (GMCs) which could lead to less favorable outcomes. Objective: The goal of this analysis is to examine functional outcomes of QOL and functioning before and after antidepressant treatment among patients with MDD with and without GMCs. Methods: We performed a secondary analysis based on the STAR*D database. The analysis included two patient groups from the STAR*D trial: 1,198 patients comorbid with MDD and GMCs (MDD + GMC) and 1,082 patients with MDD and no GMCs (MDDnoGMC), as defined by the Cumulative Illness Rating Scale. We analyzed depressive symptom severity, functioning and quality of life (QOL) before and after level 1 treatment with citalopram. Results: At baseline, the MDD + GMC group had significantly lower QOL (p < 0.001) and functioning (p = 0.001) than the MDDnoGMC group, although depressive symptom severity was not significantly different. Following antidepressant treatment, QOL, functioning and depressive symptom severity significantly improved for both MDD + GMC and MDDnoGMC groups. However, patients with MDD + GMC were more likely to experience severe impairments in QOL in (56.8% vs. 43.5% for MDDnoGMC, p < 0.001) and functioning (42.5% vs. 29.3% for MDDnoGMC, p < 0.001) following treatment. The remission rate was significantly lower for MDD + GMC (30.6% vs. 41.1% for MDDnoGMC, p < 0.001). Conclusions: Our findings suggest that antidepressant treatment had a positive impact on patients with and without GMCs. However, those with GMCs experienced not only a lower remission rate, but also continued to experience more significantly severe impairments in QOL and functioning. PMID- 29382958 TI - Effective Vortioxetine Dose Varies with Extent of Antidepressant Use Across Countries. AB - Objective: One of the possible explanations for the antidepressant resistance is tolerance to the effect of increasing synaptic serotonin. Vortioxetine is thought to work through a combination of two pharmacological modes of action: serotonin reuptake inhibition and modification of serotonin receptor activity, in a dose dependent manner. This mechanism of action allows for examination of the hypothesis that antidepressant non-response may be due to exposure to persistently elevated synaptic amine levels. Methods: We hypothesized that lower doses of vortioxetine, which exclusively inhibit serotonin reuptake, would not be effective in the setting of prolonged exposure to antidepressants, but higher doses, which interact in various ways to multiple post-synaptic serotonin receptors, would be relatively more effective in the setting of prolonged, prestudy antidepressant exposure. We examined the relationship between Defined Daily Dose (DDD), which is a measure of the extent of antidepressant use in each country, and the minimal effective dose of vortioxetine. Principal Observation: There is a significant relationship between the DDD and effective vortioxetine dose (P = 0.035). Conclusions: In countries with high antidepressant utilization, higher doses of vortioxetine were required, and obverse was true in countries with lower antidepressant utilization. These data support the hypothesis that tolerance to serotonin reuptake inhibition drives poor antidepressant response. PMID- 29382959 TI - The Use of Complementary Alternative Medicine in Children and Adolescents with Autism Spectrum Disorder. AB - Complementary alternative medicine (CAM) is used to a greater degree in children and adolescents with autism spectrum disorder (ASD), when compared to children and adolescents without this diagnosis. There is limited evidence supporting the use of many of these treatments in ASD, despite their popularity. Current FDA approved medications for ASD target associated behavioral symptoms of the diagnosis, not the core symptoms of social communication deficits and restricted/repetitive behaviors. These medications are also associated with concerning adverse effects. Evidence-based therapies for core symptoms, such as applied behavior analysis (ABA), are sometimes difficult for families to access for various reasons. Families are sometimes hesitant to discuss their interest in CAM with physicians. Physicians report knowledge gaps about CAM and their use in ASD and concerns about potential conflict with parents regarding differing beliefs of CAM's role in the management of ASD. It is important for physicians to know the current evidence which examines the use of CAM treatments in children and adolescents with autism so that they may have conversations with families which are informed and evidence-based. PMID- 29382961 TI - Retraction. PMID- 29382962 TI - Microscopic validation of whole mouse micro-metastatic tumor imaging agents using cryo-imaging and sliding organ image registration. AB - We created a metastasis imaging, analysis platform consisting of software and multi-spectral cryo-imaging system suitable for evaluating emerging imaging agents targeting micro-metastatic tumor. We analyzed CREKA-Gd in MRI, followed by cryo-imaging which repeatedly sectioned and tiled microscope images of the tissue block face, providing anatomical bright field and molecular fluorescence, enabling 3D microscopic imaging of the entire mouse with single metastatic cell sensitivity. To register MRI volumes to the cryo bright field reference, we used our standard mutual information, non-rigid registration which proceeded: preprocess -> affine -> B-spline non-rigid 3D registration. In this report, we created two modified approaches: mask where we registered locally over a smaller rectangular solid, and sliding organ. Briefly, in sliding organ, we segmented the organ, registered the organ and body volumes separately and combined results. Though sliding organ required manual annotation, it provided the best result as a standard to measure other registration methods. Regularization parameters for standard and mask methods were optimized in a grid search. Evaluations consisted of DICE, and visual scoring of a checkerboard display. Standard had accuracy of 2 voxels in all regions except near the kidney, where there were 5 voxels sliding. After mask and sliding organ correction, kidneys sliding were within 2 voxels, and Dice overlap increased 4%-10% in mask compared to standard. Mask generated comparable results with sliding organ and allowed a semi-automatic process. PMID- 29382965 TI - Development and optimization of a cell-associated challenge model for Mycoplasma hyorhinis in 7-week-old cesarean-derived, colostrum-deprived pigs. AB - Mycoplasma hyorhinis (MHR) causes polyserositis and lameness in grower pigs. While herd-specific vaccines for this bacterium are being marketed, there are currently no licensed, commercially available vaccines for MHR. The objective of this study was to develop a challenge model in cesarean-derived, colostrum deprived (CDCD) pigs using cell-associated MHR that results in both severe pericarditis and lameness, in order to evaluate suitable vaccine candidates. We investigated administering MHR to 7-week-old pigs over 3 d using 3 different routes compared to administering MHR on a single day using 1 of 3 routes. Pigs were monitored for 21 d for signs of lameness and well-being. At the end of the study, pigs were examined for evidence of polyserositis and arthritis associated with Mycoplasma. Results indicate that clinical manifestation of disease depended more on the route of administration than on the total dose given. A single intravenous (IV) administration of MHR resulted in extensive polyserositis, while a single intranasal (IN) administration showed little to no signs of disease. A single intraperitoneal (IP) administration did not induce the same level of polyserositis as observed in the IV group, but did result in an increased incidence of lameness. Furthermore, pigs administered MHR by IP (Day 0), IV (Day 1), and IN (Day 2) on 3 consecutive days showed a more robust disease manifestation, which resulted in both polyserositis and lameness. Optimization of this group showed that elimination of the 3rd-day IN challenge had no detrimental effect on clinical outcomes. The consecutive day administration of cell associated MHR will allow polyserositis and lameness to be simultaneously evaluated in future vaccine trials. PMID- 29382964 TI - Safety evaluation of a new anxiolytic product containing botanicals Souroubea spp. and Platanus spp. in dogs. AB - Separation anxiety and noise aversion are common behavioral problems in dogs. They elicit fear responses such as cowering, seeking out the owner, and attempting to escape. This can result in property damage, injury to the dog, and disruption of the owner-pet bond, possibly leading to pet abandonment or euthanasia. A novel botanical anxiolytic product was evaluated for safety in dogs as the target animal species. Its intended use is for the treatment and prevention of anxiety and noise aversion in dogs. It contains a defined mixture of Souroubea spp. vine and Platanus spp. bark, delivering the active principle, betulinic acid, at a recommended dose of 1 mg/kg body weight (BW). In the current target animal safety study, 16 healthy male beagle dogs were administered either a placebo or the newly formulated botanical tablets at 0.5*, 2.5*, or 5* the recommended dose (1 mg/kg BW) over 28 d. The dogs were monitored for occurrence of any systemic or local adverse events. In the investigation presented here, there were no clinically significant adverse effects following treatment, as determined by clinical observations, physical examinations, BW, hematology, clinical biochemistry, and urinalysis. Pharmacokinetic analysis demonstrated that the concentration of betulinic acid in serum was below 0.020 MUg/mL in treated animals. Under the conditions of these studies, the formulated blend of S. sympetala and P. occidentalis, when administered up to 5* the intended dose for 28 consecutive d, showed no adverse effects on the health of dogs. PMID- 29382966 TI - Comparison of antimicrobial resistance genes in feedlots and urban wastewater. AB - The use of antibiotics in livestock production in North America and possible association with elevated abundance of detectable antimicrobial resistance genes (ARG) is a growing concern. Real-time, quantitative PCR (RT-qPCR) was used to determine the relative abundance and diversity of ARG in fecal composite and catch basin samples from 4 beef feedlots in Alberta. Samples from a surrounding waterway and municipal wastewater treatment plants were also included to compare the ARG profile of urban environments and fresh water with that of feedlots. The relative abundance of 18 resistance genes across 5 antibiotic families including sulfonamides, tetracyclines, macrolides, fluoroquinolones, and beta-lactams was examined. Sulfonamide, fluoroquinolone, and beta-lactam resistance genes predominated in wastewater treatment samples, while tetracycline resistance genes predominated in cattle fecal composite samples. These results reflect the types of antibiotic that are used in cattle versus humans, but other factors such as co selection of ARG and variation in the composition of bacterial communities associated with these samples may also play a role. PMID- 29382967 TI - Comparison of 3 vaccination strategies against porcine reproductive and respiratory syndrome virus, Mycoplasma hyopneumoniae, and porcine circovirus type 2 on a 3 pathogen challenge model. AB - The objective of this study was to compare clinical, microbiologic, immunologic, and pathologic parameters in pigs each concurrently administered porcine reproductive and respiratory syndrome virus (PRRSV), Mycoplasma hyopneumoniae, and porcine circovirus type 2 (PCV2) vaccine from 1 of 2 commercial sources at 21 days of age and challenged with field strains of each of the 3 pathogens. Pigs were challenged with PRRSV and M. hyopneumoniae at 42 days of age (-14 days post challenge, dpc) followed by a challenge with PCV2 at 56 days of age (0 dpc). Significant differences were observed between vaccinated challenged and unvaccinated challenged groups in clinical (average daily gain and clinical signs), microbiologic (viremia and nasal shedding), immunologic (antibodies and interferon-gamma secreting cells), and pathologic (lesions) outcomes. Significant differences were observed among the 3 vaccinated challenged groups in microbiologic (nasal shedding of M. hyopneumoniae and viremia of PCV2) and immunologic (M. hyopneumoniae- and PCV2-specific interferon-gamma secreting cells) outcomes. The vaccination regimen for PRRSV vaccine, M. hyopneumoniae vaccine, and PCV2 vaccine is efficacious for controlling triple challenge with PRRSV, M. hyopneumoniae, and PCV2 from weaning to finishing period. PMID- 29382968 TI - Biological characteristics and conjugated antigens of ClfA A-FnBPA and CP5 in Staphylococcus aureus. AB - To obtain immunogenic conjugate antigens, adipic acid dihydrazide (ADH), as a bridge, and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDAC), as a coupling agent, were used to conjugate the purified fusion protein, clumping factor A-fibronectin binding protein ClfA A-FnBPA, and type 5 capsular polysaccharide (CP5). The conjugates were mixed with an adjuvant, and mice were immunized 3 times and challenged with Staphylococcus aureus 1 week later. Antibody titers were determined by indirect enzyme-linked immunosorbent assay (ELISA). At 14 days after the first immunization, antibodies against the purified protein and conjugate were detected; after 28 days, antibody levels increased; and a week after the third immunization, antibody levels continued to increase. However, the conjugate antibody titers were higher than those of the purified protein during the study, and no IgG antibodies against purified CP5 were detected during the entire experiment. The protection rate increased to 90% in the conjugate group, indicating that the conjugate imparts a relatively higher protective efficacy than the purified protein and purified CP5. PMID- 29382969 TI - Comparison of the oral and rectal mucosal and colonic serosal microcirculations of healthy, anesthetized horses. AB - The objectives of the study were to: i) determine baseline microvascular perfusion indices (MPI) and assess their repeatability in healthy horses under general anesthesia, and ii) compare the MPIs of 3 microvascular beds (oral mucosa, colonic serosa, and rectal mucosa). Healthy adult horses were anesthetized and sidestream dark field microscopy was used to collect video loops of the oral mucosa, rectal mucosa, and colonic serosa under normotensive conditions without cardiovascular support drugs; videos were later analyzed to produce MPIs. Baseline MPI values were determined for each site, which included the total vessel density (TVD), perfused vessel density (PVD), portion perfused vessels (PPV), and microcirculatory flow index (MFI). Differences in MPIs between microvascular beds were not statistically significant. Repeatability of the measurements varied for each MPI. In particular, the site of sampling had a profound effect on the repeatability of the PPV measurements and should be considered in future studies. PMID- 29382970 TI - Histological structure and age-related changes in the luminal diameter of the excurrent duct system of guinea cocks (Numida meleagris) and associated changes in testosterone concentrations. AB - As little information is available on the reproductive system of guinea fowl (Numida meleagris), a study was conducted on 49 male guinea fowl to document the histological structure and developmental changes in the luminal diameter of the ducts within the excurrent duct system and associated changes in concentrations of testosterone. Age-related changes were analyzed using the Kruskal-Wallis test and medians separated by the Mann-Whitney U-test. Tubuli recti were clearly visible in the guinea fowl and the rete testes were both intracapsular and extracapsular. Regardless of age, the luminal diameter of the proximal ductuli efferentes was the largest, while that of the connecting duct was the smallest. The luminal diameter of all ducts within the epididymal region increased (P < 0.001) monthly until 20 wk of age, and then increased marginally every month thereafter. Peripheral testosterone concentrations also peaked at 20 wk of age and declined thereafter. In adult birds, the ductus deferens enlarged posteriorly, from an average of about 279 MUm cranially to 678 MUm caudally. Peripheral testosterone concentrations strongly and positively correlated with the luminal diameter of ducts within the excurrent duct system. The pattern of increase in the luminal diameter of all ducts followed the pattern of testosterone secretion in these birds, which indicates that testosterone concentrations may be closely related to the development of the excurrent duct system in male guinea fowl. PMID- 29382971 TI - Livestock-associated methicillin-resistant Staphylococcus aureus and Clostridium difficile in wild Norway rats (Rattus norvegicus) from Ontario swine farms. AB - Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile are important human pathogens that are also carried by animals. The role of wild mammals on farms in their maintenance and transmission, however, is poorly understood. To determine if Norway rats (Rattus norvegicus) are potential carriers of these bacteria on Canadian farms, we tested 21 rats from swine farms in Ontario. The MRSA spa type t034 was isolated from 1 (4.8%) rat. This livestock associated strain often colonizes pigs and pig farmers, suggesting that transmission among rats and pigs or environmental transmission is possible on pig farms. Clostridium difficile ribotype 078 was isolated from 1 rat from a different farm. This strain is associated with infection in piglets, calves, and humans. The identification of MRSA and C. difficile in Norway rats on farms in Canada adds to the growing knowledge about the role of rats in the ecology of these pathogens. Further studies are required to determine if rats play a part in the epidemiology of these pathogens on farms. PMID- 29382972 TI - Development and application of a droplet digital polymerase chain reaction (ddPCR) for detection and investigation of African swine fever virus. AB - The aim of this study was to develop a droplet digital polymerase chain reaction (ddPCR) method to detect African swine fever virus (ASFV). The methods of ASFV real-time PCR and ddPCR were established and optimal reaction conditions were confirmed. Each method was evaluated for linearity, limit of detection, and specificity. The results indicated that ASFV ddPCR had a high degree of linearity (R2 >= 0.998) and specificity. The detection limit was 10 copies/reaction, which was approximately a 10-fold greater sensitivity than real-time PCR. This sensitive method could be used as an efficient molecular biology tool to diagnose ASFV, which is very important for preventing the spread of diseases across borders. PMID- 29382975 TI - Standards of Medical Care in Diabetes-2018 Abridged for Primary Care Providers. PMID- 29382974 TI - By What Standard Should We Manage Diabetes? PMID- 29382973 TI - Effect of transoral tracheal wash on respiratory mechanics in dogs with respiratory disease. AB - The purpose of this study was to determine the impact of a transoral tracheal wash (TOTW) on respiratory mechanics in dogs and to describe the use of a critical care ventilator (CCV) to determine respiratory mechanics. Fourteen client-owned dogs with respiratory diseases were enrolled. Respiratory mechanics, including static compliance (Cstat) and static resistance (Rstat), were determined before and after TOTW. Pre- and post-wash results were compared, with a P-value of < 0.05 considered significant. The mean +/- standard deviation (SD) value of Cstat pre-TOTW was 1.59 +/- 0.94 mL/cmH2O/kg while the mean +/- SD of Cstat post-TOTW was 1.29 +/- 0.71 mL/cmH2O/kg (P = 0.045). The median Rstat was not significantly different pre- and post-wash. The transoral tracheal wash altered respiratory mechanics, as observed by a reduction in Cstat, presumably due to airway flooding and collapse. While no long-lasting effects were noted in these clinical patients, this effect should be considered when performing TOTW on dogs with respiratory diseases. Respiratory mechanics testing using a CCV was feasible and may be a useful clinical testing approach. PMID- 29382977 TI - Comparison of Insulin Dose Adjustments by Primary Care Physicians and Endocrinologists. AB - IN BRIEF Insulin dose adjustment decisions in 20 simulated patients by nine primary care physicians (PCPs) and nine endocrinologists were compared to the algorithms used in a diabetes program in a large safety-net clinic. The number of dose changes was similar in the PCP and endocrinologist groups; however, the amounts of the dose changes in the PCP group were significantly closer to the diabetes program algorithms than the amounts in the endocrinologist group. Time constraints, rather than lack of ability, seem to be the major barrier to PCPs treating patients with insulin. PMID- 29382978 TI - Comparison of Diabetes Management by Certified Diabetes Educators via Telephone Versus Mixed Modalities of Care. AB - IN BRIEF This pilot program evaluates the impact of telephone versus mixed modalities of care on A1C. A retrospective chart review was conducted to evaluate mean baseline and follow-up A1C values for all patients who received telephone care, video-conferencing, or in-person clinic appointments with certified diabetes educators at a single, rural U.S. Department of Veterans Affairs clinic. The results of this evaluation showed that glycemic control was improved both in patients who received diabetes management through telephone care alone and in those who received mixed modalities of care. PMID- 29382979 TI - Adoption Barriers for Continuous Glucose Monitoring and Their Potential Reduction With a Fully Implanted System: Results From Patient Preference Surveys. AB - IN BRIEF A patient-centered approach to device design can provide important advantages in optimizing diabetes care technology for broadened adoption and improved adherence. Results from two surveys of people with diabetes and the parents of children with diabetes (n = 1,348) regarding continuous glucose monitoring (CGM) devices reveal the importance of the concept of "user burden" in patients' and caregivers' evaluations of the acceptability of available devices. Survey respondents' strongly favorable reactions to a proposed 1-year, fully implanted CGM device with no skin-attached components further confirm that minimizing system obtrusiveness will likely be of significant value in reducing hurdles to CGM device use and adherence. PMID- 29382980 TI - Preventing Diabetes in Primary Care: Providers' Perspectives About Diagnosing and Treating Prediabetes. AB - IN BRIEF Offering patient-centered care to prevent diabetes will require collaborative decision-making between patients with prediabetes and their health care providers. From the perspective of primary care providers, prediabetes detection should be targeted to patients who are most likely to benefit from diagnosis and treatment. Improving access to lifestyle intervention programs and educating providers about evidence-based treatments for prediabetes and how to effectively discuss treatment options with patients may improve both providers' and patients' engagement in diabetes prevention. PMID- 29382981 TI - Preoperative Diabetes Optimization Program. AB - IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes a successful effort to improve glycemic control in presurgical patients with an A1C >8%. PMID- 29382982 TI - GOOD TO KNOW: Standards of Care. PMID- 29382983 TI - Sugar. PMID- 29382984 TI - Delayed Response to U-500 Regular Insulin. PMID- 29382985 TI - Drug-Induced Falsely Low A1C: Report of a Case Series From a Diabetes Clinic. PMID- 29382986 TI - Prolonged Severe Hypoglycemia in a Pediatric Patient With Type 1 Diabetes. PMID- 29382987 TI - Vascular Anomalies of the Head and Neck Region. AB - Vascular anomalies of the head and neck region are a complex group of lesions that challenge the head and neck physicians. From the very understanding of the difference between its two distinct forms, hemangiomas and vascular malformations to its management remain confusing. The review of this anomaly attempts at comprehensively understanding the disease. Vascular anomalies are easily diagnosed by their clinical presentation, but choice of imaging and management for this spectrum of lesions is varied. The author attempts to categorize the required imaging for the lesion with suggestions on the management of both hemangiomas and vascular malformations. The available treatment options are discussed, and a comprehensive algorithm for management is suggested. Further research in developing drugs that could restrict the growth of these lesions would be the future of the management of vascular lesions. PMID- 29382988 TI - Bone regeneration with recombinant human bone morphogenetic protein 2: a systematic review. AB - Aim: The aim of this work was to perform a systematic literature review on the clinical application of rhBMP-2 in bone reconstruction prior to placing implants. Materials and Methods: A PUBMED search was made about the subject and nine clinical trials were selected according to strict inclusion criteria. Results: Overall success rates of bone regeneration with rhBMP-2 was 81.4% and success of implants placed was 87.4%. Most frequent adverse events were pain, edema and erythema. Conclusion: It was concluded that the treatment with rhBMP-2 foi satisfactory in most cases and the placement of dental implants in the bone regenerated with rhBMP-2 is feasible. PMID- 29382989 TI - Protocol for Antibiotic Administration in Mandibular Trauma: A Prospective Clinical Trial. AB - Purpose: The purpose of this study is to determine the necessity and/or effectiveness of antibiotics in cases with maxillofacial trauma and emphasise the administration of antibiotics in maxillofacial fractures indicated for open reduction and rigid internal fixation (ORIF). Materials and Methods: This study is a single blind, prospective, randomized clinical trial composed of subjects who presented with non-comminuted, linear fractures of the mandible and were treated by ORIF via an intraoral approach. One hundred and forty-four subjects (2011-2015) who belonged to the above entities were randomly categorized into 2 groups of 72 each, on lottery method. Patients in Group A were administered a 5 day course of antibiotic (1 day IV antibiotics followed by 4 days oral) while patients in Group B received a 1 day course of IV antibiotic (1 dose post op). Both the groups were followed up on the 1st day, 3rd day, 1st week, 1st month, 3rd month post operatively and were evaluated for pain, swelling, infection, fever, spontaneous wound dehiscence, purulent discharge and any other adverse effects. Results: Post operative infection when measured clinically and radiographically was comparatively higher in Group B. Out of 72 patients in both the groups, 5 patients each in Group A and Group B reported with wound dehiscence, 9 patients in both groups developed pyrexia. Conclusion: Though the post operative infection was slightly more in Group B compared to Group A, 1 day antibiotic regimen was found to be equally effective when compared to 5 day regimen and helps in reducing the after effects, superinfection and antibiotic resistance. It has better patient compliance and is cost effective. PMID- 29382990 TI - Clinical Spectrum, Treatment and Relapse Patterns in 353 Patients with Squamous Cell Carcinoma of the Alveobuccal Complex Treated with a Curative Intent: A Retrospective Study. AB - Aims and Objectives: Oral cancer is one of the most common cancers in Indian subcontinent with alveobuccal complex as most common cancer sub site. Cancers of Alveobuccal complex provides maximum challenge and management guidelines are not clear. The aim of the present study is to provide comprehensive demographic, clinical and treatment outcome data of alveobuccal squamous cell carcinoma (SCC) patients treated at a tertiary care cancer center in North India. Materials and Methods: An analysis of prospectively maintained database in department of surgical oncology at Dr BRA-IRCH, AIIMS, Delhi, India was performed. All alveobuccal cancer patients who had undergone surgery from 1995 to 2010 were included for analysis. Results: A total of 353 patients were included for analysis. Mean age was 49.75 years (SD +/-12.04) with male and female ratio of 4:1. Composite resection without mandible was done in 25 % patients and 75 % underwent mandibular resection. Neck dissection was performed in 347 patients. Nodal deposits were identified in 124 (35.73 %) neck dissection specimens. Margin negative resection was performed in 89.5 % cases. After a median follow up of 30 months, 87 (24.64 %) patients developed disease relapse and 25 (7.08 %) patients developed second primaries. Overall 5-year disease free survival (DFS) was 57.65 % and 5 year overall survival (OS) was 59.86 %. Conclusion: Among Indian oral cancer patients alveobuccal complex is most common sub site. Majority presents in locally advanced stage and reasonably good outcomes can be achieved with quality control surgery and judicious use of radiotherapy. PMID- 29382991 TI - Psychosocial Support Following Maxillofacial Trauma and its Impact on Trauma Recurrence. AB - Background: Injuries sustained to the maxillofacial region can result in significant physical trauma and long lasting psychosocial impairment. Maxillofacial trauma has been reported in literature to be a potentially recurrent disease. Patients who suffer maxillofacial trauma can benefit from psychological support. Aim: This study aims to identify maxillofacial trauma patient characteristics, investigate maxillofacial re-injury rate after provision of psychological support and report incidence of post traumatic stress disorder symptoms after maxillofacial trauma. Method: A total of 100 patients were identified from the departmental trauma database over two time periods at Royal Darwin Hospital; 50 patients did not have psychosocial intervention and 50 patients received intervention. Data on demographics, trauma pattern and aetiology were collected. A brief counselling session was conducted on second patient group by a trained mental health nurse and a survey using Trauma Screening Questionnaire was completed one month following injury. Results: The most common cause of injuries was assault in both groups followed by falls and the most common site of injuries was in the mandible in both groups. Almost half of all patients were in the15-24 and 25-34 age groups. 17 % of patients in pre intervention period and 4 % of patients in intervention period had injury recurrence at 3 year follow up. Patient groups at risk of developing post traumatic symptoms included male, non-indigenous population, employed group with no alcohol involvement. Conclusion: Maxillofacial trauma can cause considerable psychological morbidity and expose the patient to high risk of post traumatic disorder symptoms. This type of injury was found to affect particular groups of population and is associated with high rate of recurrence. Psychological support should be provided to these patients as a routine part of trauma aftercare. PMID- 29382992 TI - Osteosarcomas of the Head and Neck Region: A Case Series with a Review of Literature. AB - Background: Osteosarcomas of head and neck region have unique biology and exhibit a clinical behavior and natural history that is distinct from osteosarcomas of the trunk and extremities. Our understanding of this malignant bone tumor is largely based on data from single institutions or compiled from registries, and hence the clinical practice guidelines seem confusing and conflicting. Aims and Objectives: To analyze the demographic profile, disease characteristics and survival outcomes of osteosarcoma of head and neck region. Materials and Methods: Retrospective analysis of the patients treated for osteosarcoma of head and neck region with curative intent in the period between the years 2001-2013 at a tertiary cancer center from South India. Results: A total of 14 patients were treated in the said period with a mean age of 37 years. The most common site was mandible (n = 9 patients) followed by maxilla (n = 4) and paranasal sinuses (n = 1). Conventional osteoblastic variant of OS was the most common histological variant (n = 8) followed by the chondroblastic variant (n = 5). The median disease-free survival was 41.7 months, whereas the median overall survival of our patient cohort was 47.6 months. A formal analysis of various prognostic factors showed only postoperative margin positivity to be the single important factor affecting the survival outcomes. Conclusion: Head and neck osteosarcoma that most commonly afflicts the jaw bones occurs in the fourth decade of life. Despite being a small series, our study does highlight the importance of achieving a margin-negative resection as a part of the multimodality treatment of head and neck osteosarcomas. Considering the relative paucity of data, there is a need for multi-institutional collaborative studies to refine the therapeutic strategies for the management of patients with head and neck osteosarcomas. PMID- 29382993 TI - Comparative Evaluation of the Intranasal Spray Formulation of Midazolam and Dexmedetomidine in Patients Undergoing Surgical Removal of Impacted Mandibular Third Molars: A Split Mouth Prospective Study. AB - Purpose: The purpose of this prospective randomized single blinded split mouth study was to conduct a comparative evaluation of the efficacy of intranasal atomised spray formulation of Dexmedetomidine with Midazolam in patients undergoing surgical removal of bilaterally impacted mandibular third molars. Methods: This prospective study was conducted in twenty volunteers. Each volunteer underwent the surgical removal of an impacted mandibular third molar at two separate appointments at an interval of two weeks. The first third molar surgery was conducted using either intranasal Midazolam (Group M) or intranasal Dexmedetomidine (Group D). At the second appointment the surgical procedure was performed using the sedative agent not used at the first appointment. The primary testing outcome variables were Plasma oxygen saturation (SpO2), pulse and blood pressure and Modified Observer's Assessment of Alertness/Sedation (OAA/S) scale. These were recorded at predetermined intervals starting 10 min before the administration of local anaesthesia and continued up to 10 min after completion of the procedure. In addition surgeon's opinion regarding the patient cooperation, event amnesia, post operative nausea & vomiting were obtained. Results: The sample composed of twenty patients (M = 9 and F = 11). There was statistically no significant difference between Group M and Group D with respect to mean SpO2. Minor differences were however noted at 20 and 30 min after sedation. There was no significant difference between the groups with respect to mean pulse rate, blood pressure, OAA/S, event amnesia, post operative nausea and vomiting and patient cooperation. Conclusion: We conclude that Midazolam and Dexmedetomidine are equivalent and can be used in minor oral surgery with minimal complications. These drugs can be used intranasally using nasal atomization device in routine outpatient basis in otherwise normal healthy but anxious patients. All procedures must however be performed in the presence of an anaesthesiologist and with ready availability of emergency drugs and equipment. PMID- 29382994 TI - Clinical and MRI Evaluation of Orthodontic Mini-Screws for Disc Repositioning in Internal Derangement of TMJ: A Prospective Study. AB - Purpose: The purpose of this study was to assess the efficacy of orthodontic mini screws as a modified suture anchor for disc repositioning in cases of internal derangement of the temporomandibular joint. Patients and Methods: A prospective evaluation of ten patients was undertaken for a period of 6 months using this modified approach from Jan 2014 to Jun 2016. Symptomatic patients with clinical and MRI features suggestive of internal derangement of TMJ and willing to undergo surgical repositioning of articular disc to alleviate symptoms of temporomandibular dysfunction were taken up for the study. Post-operatively, functional outcomes were assessed in terms of reduction in pain, joint movement and absence of joint noise and clicking sounds. Post-operative MRI was used to assess the disc position and morphological changes in the disc and arthritic changes in the condyle. Results: All patients underwent a surgical repositioning of the anteriorly displaced disc by the modified orthodontic suture anchor. Patients were post-surgically followed up at intervals of 1, 3 and 6 months. Immediate complications in terms of pain, restriction of functional motion and transient facial nerve palsy were noted. Late complications include temporal nerve palsy in one case. All patients experienced significant improvement with good functional outcomes and stable repositioning of disc was noticed at the end of 6 months. Conclusion: The modified disc repositioning using an orthodontic screw via a mini preauricular approach provided a good functional outcome in all patients as assessed over a period of 6 months. However, the long-term functional sequel of the procedure and changes in the articular disc needs to be assessed. PMID- 29382995 TI - Perineural Invasion of Oral Squamous Cell Carcinoma: A New Hurdle for Surgeons. AB - The high rate of mortality associated with cancer is due to its inherent nature to metastasize. Perineural invasion (PNI) is a relatively rare mode of metastasis, and a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion which is still shrouded by mystery. PNI is a marker of poor prognosis. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of mechanisms behind PNI. The purpose of this article is to make surgeons aware of caudad to cephalad metastasis of oral cancer along trigeminal nerve. PMID- 29382996 TI - Nasal Mucosal Cyst a Clinical and Surgical Dilemma. AB - A mucous cyst is a lesion which can show a wide range of symptoms but is benign and most of them can even appear several months or even years after nasal surgeries. Size of the displaced epithelial fragment is a crucial factor for the development of the mucous cyst. Complete resection of the mucous cyst is the ideal treatment. Surfing through the literature we came across 18 cases of mucous cyst formation following nasal surgery. Here we describe a mucous cyst which had resulted from a rhinoplasty procedure the patient had undergone earlier in her life. PMID- 29382998 TI - Reduction of Palatal Midline and Para-Midline Fractures Using Intra-arch Wire Fixation Versus Transmucosal Miniplate Stabilization: Prospective Randomized Clinical Study to Evaluate Postoperative Occlusion. AB - Purpose: The aim of the study is to compare the post reduction squealae of transmucosal miniplate fixation technique for stabilization of palatal fractures with intra-arch wiring technique. Materials and Method: This study was prospectively undertaken on 16 patients, dividing them into two treatment arms based on random sampling methodology (Group A & B). For patients in Group A, intra-arch wire stabilization technique and in Group B trans-mucosal miniplate stabilization technique was used. The pre-operative and post-operative occlusion and time taken for stabilization in both the techniques was compared. Results: The mean time taken for reduction and stabilization of palatal fracture in group A was 10.9 +/- 2.21 min and in group B was 14.2 +/- 1.13 min. Four out of eight study patients in group A required post reduction interception to stabilize occlusion postoperatively, whereas none of the patients in group B needed any post operative intervention. Conclusion: The post operative occlusal stability was found better in study patients included in group B when compared to group A patients, although satisfactory post-operative occlusion was obtained even in group A with post-operative interception for occlusal stability. PMID- 29382997 TI - Leech related Aeromonas veronii complex infection after reconstruction with a microvascular forearm flap. AB - Medical leeches (Hirudo medicinalis) in plastic and reconstructive surgery are often used for the treatment of vascular failure after microvascular surgery. Leeches are a reservoir for bacteria of the Aeromonas group that help digesting the blood meal. In some cases these bacteria are able to cause severe wound infections that can lead to loss of tissue transplants. We report about a patient with a common microvascular forearm flap after resection of an oral squamous cell carcinoma which got infected by Aeromonas spp. after treatment with medical leeches. Most of these species are resistant for common antibiotic treatment after surgery. This report shows the importance of an early concomitant antibiotic prophylaxis in the treatment of venous congestion with medical leeches. PMID- 29382999 TI - Clinical and Radiographic Outcomes of Apical Surgery: A Clinical Study. AB - Background: Endodontic treatment is usually indicated when teeth with periapical lesions are encountered. However, sometimes root canal treatment results in failure. In that case, one of the treatment choices is retreatment by an orthograde approach. Surgical endodontic therapy is also an alternative to preserve the tooth. Various techniques have been suggested in the literature which has more predictable results. The introduction of modern surgical techniques have enhanced the results of apical surgery procedures. Operating microscopes, magnifying loupes, microinstruments, ultrasonic tips, and biologically acceptable root-end filling materials (such as MTA and SuperEBA) have been introduced to this field with the modern technique, thus the success rates of modern apical surgery has increased significantly. Objective: The aim of the present study was to evaluate the clinical and radiographic outcomes and periotest values of apical surgery treatment. Methods: A total of 112 teeth were included. SuperEBA and MTA were used as root-filling materials. The recorded parameters were gender, age, location of the tooth, the presence/absence of a post, coronal restoration of the tooth, previous surgical/nonsurgical treatment of the tooth, the size of periapical lesions, histopathology of periapical lesions, smoking habits. Also the periotest values were recorded. Results: The overall success rate was 88.4%. With regard to the evaluated variables, only one parameter (tooth type) was found statistically significant. Although the periotest values were decreased after 6 months compared to immediately postoperative measurements, the values were still significantly higher than preoperative measurements. Conclusion: In this study, apical surgery performed with the modern instruments has significantly successful results with 88.4% success rate. PMID- 29383000 TI - Evaluation of a New Surgical Technique for Closing Oroantral Fistula Using Auto transplanted Upper Third Molar: A 1-Year Follow-Up Study. AB - Background: Oroantral fistula (OAF) is considered a frequent complication in dental practice. Many surgical techniques/methods have been proposed to close it. The aim of this study was to evaluate the auto-transplantation of upper third molar for closing OAF. Materials and Methods: Twenty patients participated in this study aged between 20 and 40 years old. The OAF was closed by auto transplantation of upper third molar placed directly in the socket of the extracted tooth. Results were evaluated clinically and radiographically through the period of observation which lasted for 1 year. Results: Final results showed that the success rate of closing OAF was 95% while the success rate of upper third molar auto-transplantation was 90%. Conclusion: This technique is simple, applicable, provides immediate replacement of the missing tooth, and does not require complicated instruments or procedures. PMID- 29383001 TI - Efficacy of Multimodal Therapy in the Survival Outcomes of Advanced-Stage (Stage III-Stage IV) Oral Carcinoma Patients: An Institutional Experience in Asian Indian Population. AB - Aim: Primary ablative surgery followed by post-op radiotherapy (S-RT) remains the mainstay of treatment for stage III-stage IV oral carcinoma. A retrospective analysis of survival rates of advanced-stage OSCC patients treated with multimodal therapies (S-RT or combined chemoradiation) was performed to analyse the outcome for patient survival and whether addition of adjuvant chemotherapy (S CRT) improves survival. Materials and Methods: Demographic, pathological, treatment and follow-up data of 128 patients were included in the study. Sixty nine patients received S-RT, while 55 patients were opted for S-CRT. Overall survival, disease-specific survival and disease-free survival were estimated with Kaplan-Meier analysis and compared between groups with Cox regression analysis. Results: Survival was significantly influenced by the type of modality and regional spread of disease. S-CRT group had improved overall, disease-specific, disease-free and metastasis-free survival compared to S-RT group. A survival advantage of 10% was achieved in S-CRT group compared to S-RT group even in patients with extracapsular spread and perineural invasion. Conclusion: Addition of adjuvant chemotherapy to S-RT improves survival outcomes in advanced OSCC, especially in patients with regional spread of disease. PMID- 29383002 TI - Chronic Recurrent Temporomandibular Joint Dislocation: A Comparison of Various Surgical Treatment Options, and Demonstration of the Versatility and Efficacy of the Dautrey's Procedure. AB - Introduction: There has been a changing trend of treating temporomandibular joint subluxation, which range from conservative non-surgical measures to various soft and hard tissue surgical procedures aimed at either augmenting or restricting the condylar path. Aim: This study was aimed at comparing the efficacy of three major surgical treatment modalities: condylar obstruction creation, obstruction removal and anti-translatory procedures. Also, the location, anatomy and morphology of the TMJs pre- and post-surgery were evaluated and compared using radiographs, sagittal and 3-D Computed Tomographic scans. Materials and Methods: A 6-year study was carried out on seventy-five patients of various age groups. Twenty-five were operated by the Dautrey's procedure, 25 by articular eminectomy alone and the remaining 25 by eminectomy followed by meniscal plication and tethering. The distribution of patients in the three groups was random. Effectiveness of the surgical procedure and incidence of complications including recurrence were carefully compiled and compared between the three groups. Results and Conclusion: Dautrey's procedure yielded more gratifying and stable results, leading to a successful and permanent correction of chronic recurrent dislocation of the TMJs, with practically nil complications, thus demonstrating it to be an extremely safe, effective and versatile technique, making the joints function normally and securing sufficient volume of mouth opening. There was observed an average increase in articular tubercle height by 3.65 mm and a mean anterior shift of its lowest point by 4.5 mm following the Dautrey's procedure, which were statistically significant findings. The upper age limit to carry out the Dautrey's procedure can be safely taken up to 45 years. PMID- 29383003 TI - Intermaxillary Fixation with a Single Wire. AB - Intermaxillary fixation (IMF) is required before plating to achieve premorbid relationship of mandibular and maxillary teeth. We recommended the use of single wire for achieving IMF using 24 gauze stainless steel wire, which is an easy, fast, economical and minimally invasive technique. PMID- 29383004 TI - Screw and Wire Technique for Condylar Fracture Reduction. AB - In case of displaced condylar fractures, ideal reduction during open reduction and internal fixation poses a challenge to the surgeon. This article describes a simple technique to aid reduction with the use of a screw and wire during open treatment. PMID- 29383005 TI - A Cost-Effective, In-House, Positioning and Cutting Guide System for Orthognathic Surgery. AB - Introduction: Technological advances in 3D printing can dramatically improve orthognathic surgical planning workflow. Custom positioning and cutting guides enable intraoperative reproduction of pre-planned osteotomy cuts and can result in greater surgical accuracy and patient safety. Objectives: This short paper describes the use of freeware (some with open-source) combined with in-house 3D printing facilities to produce reliable, affordable osteotomy cutting guides. Methods: Open-source software (3D Slicer) is used to visualise and segment three dimensional planning models from imported conventional computed tomography (CT) scans. Freeware (Autodesk Meshmixer (c)) allows digital manipulation of maxillary and mandibular components to plan precise osteotomy cuts. Bespoke cutting guides allow exact intraoperative positioning. These are printed in polylactic acid (PLA) using a fused-filament fabrication 3D printer. Fixation of the osteotomised segments is achieved using plating templates and four pre-adapted plates with planned screw holes over the thickest bone. We print maxilla/ mandible models with desired movements incorporated to use as a plating template. Results: A 3D printer capable of reproducing a complete skull can be procured for L1000, with material costs in the region of L10 per case. Our production of models and guides typically takes less than 24 hours of total print time. The entire production process is frequently less than three days. Externally sourced models and guides cost significantly more, frequently encountering costs totalling L1500-L2000 for models and guides for a bimaxillary osteotomy. Conclusion: Three-dimensional guided surgical planning utilising custom cutting guides enables the surgeon to determine optimal orientation of osteotomy cuts and better predict the skeletal maxilla/mandible relationship following surgery. The learning curve to develop proficiency using planning software and printer settings is offset by increased surgical predictability and reduced theatre time, making this form of planning a worthy investment. PMID- 29382960 TI - The Black Book of Psychotropic Dosing and Monitoring. PMID- 29383006 TI - Role of Radiotherapy in Mucosal Kaposi Sarcoma. PMID- 29383008 TI - Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation. AB - Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair (MMR) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this. PMID- 29383009 TI - Letter to the Editor Re: Enstrom JE. Fine particulate and total mortality in Cancer Prevention Study cohort reanalysis. Dose-Response. 2017;15(1):1-12. PMID- 29383010 TI - Present and Future Prospects of Radiation Therapy Using alpha-Emitting Nuclides. AB - Therapy with alpha-radiation has issues associated with internal exposure; its clinical use has been avoided. However, phase III clinical tests of the alpha emitting nuclide 223Ra on patients with cancer have been conducted, and results were reported in 2011 to 2012. Since then, research has being carried out on targeted internal therapy by introducing alpha-emitting nuclides directly into the cancers. For many decades, nontargeted radon therapy has been carried out and is controversial because its mechanism of action is stimulation. The low-level radiation sends powerful signals to upregulate many biological protection systems, which protect against the effects of radiogenic and nonradiogenic toxins. These vital systems prevent, repair, and remove DNA and other biomolecular damage being produced endogenously at a very high rate by the very abundant reactive oxygen species associated with aerobic metabolism. Stimulation of protection systems results in beneficial effects, including a lower risk of cancer. This article reports the results of treatments on 4 patients with cancer and reviews the clinical use of alpha-radiation from 223Ra and radon. It discusses the prospect of using the novel 225Ac-prostate-specific membrane antigen ligand-617 ligand as a therapeutic agent for prostate cancer. It presents a new treatment system that we developed, alpha-Radiorespiro-Rn, which seems to be extremely effective in treating cancer. PMID- 29383007 TI - Myopia in Chinese families shows linkage to 10q26.13. AB - Purpose: To determine genetic linkage between myopia and Han Chinese patients with a family history of the disease. Methods: One hundred seventy-six Han Chinese patients from 34 extended families were given eye examinations, and mean spherical equivalent (MSE) in diopters (D) was calculated by adding the spherical component of the refraction to one-half the cylindrical component and taking the average of both eyes. The MSE was converted to a binary phenotype, where all patients with an MSE of -1.00 D or less were coded as affected. Unaffected individuals had an MSE greater than 0.00 D (ages 21 years and up), +1.50 (ages 11 20), or +2.00 D (ages 6-10 years). Individuals between the given upper threshold and -1.00 were coded as unknown. Patients were genotyped on an exome chip. Three types of linkage analyses were performed: single-variant two-point, multipoint, and collapsed haplotype pattern (CHP) variant two-point. Results: The CHP variant two-point results identified a significant peak (heterogeneity logarithm of the odds [HLOD] = 3.73) at 10q26.13 in TACC2. The single-variant two-point and multipoint analyses showed highly suggestive linkage to the same region. The single-variant two-point results identified 25 suggestive variants at HTRA1, also at 10q26.13. Conclusions: We report a significant genetic linkage between myopia and Han Chinese patients at 10q26.13. 10q26.13 contains several good candidate genes, such as TACC2 and the known age-related macular degeneration gene HTRA1. Targeted sequencing of the region is planned to identify the causal variant(s). PMID- 29383011 TI - Regulating Ionizing Radiation Based on Metrics for Evaluation of Regulatory Science Claims. AB - This article attempts to reconcile differences within the relevant scientific community on the effect of exposure to low levels of ionizing radiation notably the applicability of linear nonthreshold (LNT) process at exposures below a certain limit. This article applies an updated version of Metrics for Evaluation of Regulatory Science Claims (MERSC) derived form Best Available Regulatory Science (BARS) to the arguments provided by the proponents and opponents of LNT. Based on BARS/MERSC, 3 categories of effects of exposure to ionizing radiation are identified. One category (designated as S) consists of reproducible and undisputed adverse effects. A second category (designated as U) consists of areas where the scientific evidence for potential adverse effects includes uncertainties. The scientific evidence in the U category leads to a threshold. In contrast, the scientific foundation of the third category (designated as P) is questionable, as the scientific evidence indicates that adverse effects of the exposure at this level are not only questionable but may be helpful. This article claims that the third area is the domain of policy makers including regulators. This article describes Jeffersonian Principle that categorizes the affected community into specialists, knowledgeable nonspecialists, and the general public. Based on Jeffersonian Principle, the relevant scientific information, particularly the U and P areas, must be translated into a language that at a minimum is understandable to the knowledgeable group. Once this process is completed, the policy makers including regulators may select exposure limits based on their judgment. PMID- 29383013 TI - The JAK2 V617F mutation in isolated neutropenia. PMID- 29383012 TI - Homogenous and Microbeam X-Ray Radiation Induces Proteomic Changes in the Brains of Irradiated Rats and in the Brains of Nonirradiated Cage Mate Rats. AB - To evaluate microbeam radiation therapy (MRT), for brain tumor treatment, the bystander effect in nonirradiated companion animals was investigated. Adult rats were irradiated with 35 or 350 Gy at the European Synchrotron Research Facility using homogenous irradiation (HR) or MRT to the right brain hemisphere. The irradiated rats were housed with nonirradiated rats. After 48 hours, all rats were euthanized and the frontal lobe proteome was analyzed using 2-dimensional electrophoresis and mass spectrometry. Proteome changes were determined by analysis of variance (P < .05). Homogenous irradiation increased serum albumin, heat shock protein 71 (HSP-71), triosephosphate isomerase (TPI), fructose bisphosphate aldolase (FBA), and prohibitin and decreased dihydrolipoyl dehydrogenase (DLD) and pyruvate kinase. Microbeam radiation therapy increased HSP-71, FBA, and prohibitin, and decreased aconitase, dihydropyrimidinase, TPI, tubulin DLD, and pyruvate kinase. Cage mates with HR irradiated rats showed increased HSP-71 and FBA and decreased pyruvate kinase, DLD, and aconitase. Cage mates with MRT irradiated rats showed increased HSP-71, prohibitin, and FBA and decreased aconitase and DLD. Homogenous irradiation proteome changes indicated tumorigenesis, while MRT proteome changes indicated an oxidative stress response. The bystander effect of proteome changes appeared antitumorigenic and inducing radioresistance. This investigation also supports the need for research into prohibitin interaction with HSP-70/71 chaperones and cancer therapy. PMID- 29383014 TI - Association between single nucleotide polymorphisms in the PI3K/AKT/mTOR pathway and bladder cancer risk in a sample of Iranian population. AB - In the past few years several investigations have focused on the role of PI3K/AKT/mTOR pathway and its deregulations in different cancers. This study aimed to examine genetic polymorphisms of this pathway in bladder cancer (BC). In this case-control study, 235 patients with pathologically confirmed bladder cancer and 254 control subjects were examined. PIK3CA, AKT1 and mTOR variants were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The findings proposed that the PIK3CA rs6443624 SNP significantly decreased the risk of BC (OR=0.44, 95 % CI=0.30-0.65, p<0.0001 CA vs CC; OR=0.35, 95 % CI=0.16-0.78, p=0.0107, AA vs CC; OR=0.60, 95 % CI=0.46 0.79, p=0.0002, A vs T). The AKT1 rs2498801 variant is associated with a decreased risk of BC (OR=0.57, 95 % CI=0.39-0.82, p=0.003, AG vs AA; OR=0.74, 95 % CI=0.56-0.97, p=0.032, G vs A) while, AKT1 rs1130233 polymorphism considerably increased the risk of BC (OR=3.70, 95 % CI=2.52-5.43, p<0.0001, GA vs GG; OR=5.81, 95 % CI=1.53-21.97, p=0.010, AA vs GG; OR=2.71, 95 % CI=1.98-3.70, p<0.0001, A vs G). Additionally, mTOR rs2295080 variant notably increased the risk of BC (OR=2.25, 95 % CI=1.50-3.38, p<0.0001, GT vs GG; OR=4.75, 95 % CI=2.80 8.06, p<0.0001, TT vs GG; OR=3.10, 95 % CI=2.34-4.10, p<0.0001, T vs G). None of the other examined polymorphisms (AKT1 rs1130214, AKT1 rs3730358, mTOR rs1883965) revealed significant association with BC. In conclusion, our findings suggest that PIK3CA rs6443624, AKT1 rs2498801, AKT1 rs1130233, as well mTOR rs2295080 polymorphism may be related to bladder cancer development in a sample of Iranian population. Validation of our findings in larger sample sizes of different ethnicities would provide evidence on the role of variants of PI3K/AKT/mTOR pathway in developing BC. PMID- 29383015 TI - Protective effects of hydrogen sulfide on chronic kidney disease by reducing oxidative stress, inflammation and apoptosis. AB - The current study aimed to examine the renoprotective effects of long-term treatment with sodium hydrosulfide (NaHS), a prominent hydrogen sulfide donor, in 5/6 nephrectomy animal model. Twenty-four rats were randomly divided into 3 groups including sham-operated group (Sham), 5/6-nephrectomized group (5/6 Nx), and NaHS-treated group (5/6Nx+NaHS). NaHS (30 micromol/l) was added twice daily into the drinking water and renal failure was induced by 5/6 nephrectomy. Twelve weeks after surgical procedure, blood pressure, creatinine clearance (CCr), urine concentration of neutrophil gelatinase associated lipocalin (NGAL) and tissue concentration of malondialdehyde (MDA), superoxide dismutase (SOD), as well as renal morphological changes, apoptosis (cleaved caspase-3) and inflammation (p-NF kappaB) were measured. Five-sixth nephrectomy induced severe renal damage as indicated by renal dysfunction, hypertension and significant histopathological injury which were associated with increased NGAL and MDA levels, oxidant/antioxidant imbalance, decreased SOD activity and CCr and also overexpression of p-NF-kappaB and cleaved caspase-3 proteins. Instead, NaHS treatment attenuated renal dysfunction through reduction of NGAL concentration, hypertension, CCr, oxidant/antioxidant imbalance, inflammation and apoptosis. These findings suggest that long term NaHS treatment can be useful in preventing the progression of CKD by improving oxidant/antioxidant balance and reducing inflammation and apoptosis in the kidney. PMID- 29383016 TI - An update on the biological and pharmacological activities of diosgenin. PMID- 29383017 TI - Highly potent antioxidant Olea europaea L. leaf extract affects carotid and renal haemodynamics in experimental hypertension: The role of oleuropein. AB - Haemodynamic alterations in carotid and renal arteries are associated with the severity of target organ damage in patients with hypertension. Dietary habits, such as the Mediterranean diet, regulate blood pressure and oxidative stress, thus reduce the mortality rate due to cardiovascular diseases. In this study, our aim was to evaluate the reducing activity, antioxidant capacity and metal chelating ability of standardized Olea europaea L. leaf extract (OLE), and to test its (5, 25, 50 mg/kg) acute in vivo effects, as well as oleuropein's (OP, 10 mg/kg) on oxidative stress, carotid, renal and systemic haemodynamic parameters (blood pressure, heart rate, cardiac output, peripheral resistance) in spontaneously hypertensive rats (SHR). OLE has a higher antioxidative capacity than BHT, higher reducing ability than vitamin C, and 23 times lower capacity for metal ion chelation than EDTA. All three doses of OLE, and OP, improved oxidative stress in SHR. OLE5 improved carotid and renal haemodynamics, without significant effects on systemic haemodynamics. Two different mechanisms of antihypertensive responses to OLE were observed, OLE25 was most effective in reducing cardiovascular risks by improving systemic and regional (carotid and renal) haemodynamics, peripheral and regional vascular resistance. OLE50 causes the improvement of blood pressure and cardiac performances, but tends to retain elevated vascular resistance, therefore, reducing the inflow of blood into the brain and kidneys of the SHR. The OP did not alter systemic or regional haemodynamics, suggesting others constituents responsible for changes of cardiac function, as well as carotid and renal haemodynamics in response to OLE50. PMID- 29383018 TI - Different effects of metformin and insulin on primary and secondary chemoprevention of colorectal adenoma in diabetes type 2: Traditional and Bayesian meta-analysis. AB - Metformin and insulin differently affect the risk of colon cancer in type 2 diabetic patients, however their effects on colon adenoma is not clear. PubMed, ISI, Scopus and Cochrane databases were searched for studies reporting. The outcomes were total adenoma; advanced adenoma and recurrent adenoma. Traditional and Bayesian meta-analysis were conducted via random-effects models. Odds ratios (OR) with 95 % confidence intervals (CIs) / or credible intervals (CrI) were used to describe the ratio of different events. A random-effects model described by DerSimonian and Laird was performed, when significant between-study heterogeneity existed. Alternatively, an inverse variance fixed effects model was used, when there was no significant heterogeneity across studies. The potential publication bias was assessed with funnel plot, Egger and Begg's regression asymmetry tests. Moreover, "trim and fill" procedure was used to assess the possible effect of publication bias. For metformin intake, 11 studies (51991 patients) were included. The results showed that metformin significantly decreased the risk of advance adenoma (OR= 0.51, p< 0.001). The risk of total adenoma was not associated with metformin use (OR= 0.86, p=0.274), and metformin did not affect the risk of adenoma recurrence (OR= 0.89, p=0.137). Five studies (2678 patients) were included in the analysis to determine the effect of insulin therapy. Insulin significantly increased the risk of colorectal adenoma (OR= 1.43, p=0.002). These findings indicate that metformin has no protective effect on total and recurrent adenoma, whilst it significantly reduces the risk of advanced adenoma, but insulin increases the risk of total adenoma. PMID- 29383019 TI - Alteration of hepatocellular antioxidant gene expression pattern and biomarkers of oxidative damage in diazinon-induced acute toxicity in Wistar rat: A time course mechanistic study. AB - In the present survey, the plasma level of diazinon after acute exposure was measured by HPLC method at a time-course manner. In addition, the impact of diazinon on the expression of the key genes responsible for hepatocellular antioxidative defense, including PON1, GPx and CAT were investigated. The increase in oxidative damages in treated rats was determined by measuring LPO, protein carbonyl content and total antioxidant power in plasma. After administration of 85 mg/kg diazinon in ten groups of male Wistar rats at different time points between 0-24 hours, the activity of AChE enzyme was inhibited to about 77.94 %. Significant increases in carbonyl groups and LPO after 0.75 and 1 hours were also observed while the plasma antioxidant power was significantly decreased. Despite the dramatic reduction of GPX and PON1 gene expression, CAT gene was significantly upregulated in mRNA level by 1.1 fold after 4 hours and 1.5-fold after 24 hours due to diazinon exposure, compared to control group. Furthermore, no significant changes in diazinon plasma levels were found after 4 hours in the treated rats. The limits of detection and quantification were 137.42 and 416.52 ng/mL, respectively. The average percentage recoveries from plasma were between 90.62 % and 95.72 %. In conclusion, acute exposure to diazinon increased oxidative stress markers in a time-dependent manner and the changes were consistent with effects on hepatic antioxidant gene expression pattern. The effect of diazinon even as a non-lethal dose was induced on the gene expression of antioxidant enzymes. The change in antioxidant defense system occurs prior to diazinon plasma peak time. These results provide biochemical and molecular evidence supporting potential acute toxicity of diazinon and is beneficial in the evaluation of acute toxicity of other organophosphorus pesticides as well. PMID- 29383020 TI - Data mining for the identification of metabolic syndrome status. AB - Metabolic syndrome (MS) is a condition associated with metabolic abnormalities that are characterized by central obesity (e.g. waist circumference or body mass index), hypertension (e.g. systolic or diastolic blood pressure), hyperglycemia (e.g. fasting plasma glucose) and dyslipidemia (e.g. triglyceride and high density lipoprotein cholesterol). It is also associated with the development of diabetes mellitus (DM) type 2 and cardiovascular disease (CVD). Therefore, the rapid identification of MS is required to prevent the occurrence of such diseases. Herein, we review the utilization of data mining approaches for MS identification. Furthermore, the concept of quantitative population-health relationship (QPHR) is also presented, which can be defined as the elucidation/understanding of the relationship that exists between health parameters and health status. The QPHR modeling uses data mining techniques such as artificial neural network (ANN), support vector machine (SVM), principal component analysis (PCA), decision tree (DT), random forest (RF) and association analysis (AA) for modeling and construction of predictive models for MS characterization. The DT method has been found to outperform other data mining techniques in the identification of MS status. Moreover, the AA technique has proved useful in the discovery of in-depth as well as frequently occurring health parameters that can be used for revealing the rules of MS development. This review presents the potential benefits on the applications of data mining as a rapid identification tool for classifying MS. PMID- 29383021 TI - Micronucleus cytome assay in the differential assessment of cytotoxicity and genotoxicity of cadmium and lead in Amietophrynus regularis. AB - Amphibians are increasingly being used as bio-indicator of contamination in ecosystems due to their sensitivity to xenobiotics in the environment. Cadmium and lead compounds, ubiquitous mutagens and carcinogens, are capable of eliciting genome instability in adult toads which may enhance amphibian decline. Micronucleus cytome (MN-cyt) assay, a comprehensive cytogenetic test for the assessment of genome instability induced by xenobiotics in organisms, was utilized in the differential cytogenotoxic evaluation of Cd and Pb in adult Amietophrynus regularis. A. regularis was exposed to six concentrations (8 - 512 mg/L) of the metal solutions to determine 96 h acute toxicity. Four toads per group were exposed to five sub-lethal concentrations (5 - 75 %) of the 96 h LC50 of the metals for 14 days. At post exposure, bone marrow and peripheral erythrocytes were collected for MN-cyt analysis. The metals induced differential concentration and time-dependent increase in mortality with 96 h LC50 of 36.36 mg/L (Cd) and 112.06 mg/L (Pb). No observable effective concentrations (NOEC); Cd=8 and Pb=32 (mg/L) and Lowest observable effective concentrations (LOEC); Cd=16 and Pb=64 (mg/L) were recorded for the metals. Derived toxicity factor (TF) showed that Cd was 3.08 times more toxic to the toads than Pb. The metal solutions induced significant (p<0.05) increase in frequencies of MN, binucleated, nuclear bud, notch, lobe, vacuolated erythrocytes, apoptosis and necrosis compared to the negative control. Cd elicited 1.42 and 3.26 folds increase in MN and NAs respectively, than Pb. MN-cyt assay is a suitable cytogenetic tool for assessing genome instability in A. regularis. Increased genetic instability induced by Cd and Pb may be associated with genetic related syndromes; neoplasms, reproductive dysfunctions and mortality. This suggests threat to amphibian health and may enhance population decline. PMID- 29383022 TI - Endoscopic full-thickness biopsy, a novel method in the work up of complicated abdominal symptoms. AB - Gastrointestinal complaints without obvious organic causes confirmed by clinical laboratory analyses, endoscopy or radiology are often referred to functional entities. Irritable bowel syndrome (IBS) is the most common functional disorder in the gut. Careful examination of these patients may reveal other diagnoses of defined etiologies, e.g., enteric neuropathy, microscopic colitis, and primary Sjogre's syndrome. The present case describes a young patient with incapacitating gastrointestinal symptoms presumed to be IBS, who underwent endoscopic full thickness biopsy in sigmoid colon. Histopathological examination revealed degenerative enteric neuropathy, possibly secondary to chronic ischemia. PMID- 29383023 TI - Of mice and men: a novel dietary supplement for the treatment of ulcerative colitis. AB - Background: Curcumin, green tea polyphenols and selenium possess anti inflammatory and anti-oxidant properties. Individually they have demonstrated some efficacy in animal models and human subjects with inflammatory bowel disease (IBD). To evaluate the efficacy and safety of Coltect [Curcumin (500 mg), green tea (250 mg) and selenium (100 ug)] in vivo and in patients with ulcerative colitis (UC). Methods: Each component was compared to placebo in a DSS mice colitis model. The efficacy was validated in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) rat colitis model. Twenty patients with mild-to-moderate UC received two Coltect tablets twice daily for 8 weeks. Enrollees underwent sigmoidoscopy at study entrance and closure, and physical and laboratory evaluation at baseline, 4 and 8 weeks. Results: Coltect showed a synergistic therapeutic effect in the DSS and TNBS models. Disease activity was significantly higher in the placebo versus the treated group (p < 0.05). Selenium was the more active component. The contribution of green tea was minor. In the TNBS model, the Wallace scores for macroscopic lesions were 4.8 +/- 1.5 (treatment) and 8.2 +/- 0.5 (placebo) (p = 0.01). In humans, Coltect was well tolerated and effective. Fourteen subjects (70%) improved: nine (45%) went into complete remission, four (20%) experienced marked improvement and one (5%) experienced moderate improvement at the end of the trial. Clinical activity index decreased significantly at 4 and 8 weeks (p < 0.001). Two patients had no change in their symptoms, and one withdrew after 4 weeks. Flare-up in four subjects caused three to withdraw from the study after less than 4 weeks. Endoscopic improvement was observed in 11 (69%) patients, and four patients (25%) achieved complete remission. Conclusions: Coltect may serve as a first-line or add-on therapy in patients with mild-to-moderate UC. PMID- 29383024 TI - Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients. AB - Background: Episodes of hepatic encephalopathy (HE) have been related to low survival rate. However, the relation between its clinical evolution and mortality has not been assessed. Methods: A retrospective analysis of 245 cirrhotic patients admitted for an acute episode of HE (?grade 2) or who developed an HE episode after an upper gastrointestinal bleeding (UGIB) event was performed to assess the relation between time in HE and transplant-free survival. Results: Median (IQR25-75) time in HE was 48 h (24-96 h) in the whole cohort. Patients who presented a longer time in HE (>48 h; n = 89) exhibited a lower transplant-free survival at 28 days (67.2% versus 88.9%, p < 0.001), 90 days (48.7% versus 73.8%, p < 0.001) and 365 days (30.3% versus 53.2%, p < 0.001), as compared to those with less time in HE (?48 h; n = 156). Survival rates remained significantly different, with lower percentages in the group with time in HE >48 h, when comparing patients according to baseline HE grade (2 versus ?3) or model for end stage liver disease (MELD) function (?15 versus >15). Time in HE was also an independent risk factor for mortality at each time point, hazard ratio (HR) (95 CI%) 28 days 2.59 (1.39-4.84); 90 days 1.98 (1.28-3.1) and 365 days 1.5 (1.08 2.19). Conclusions: The duration of the acute HE episode determines survival in cirrhotic patients independently of liver function and baseline HE grade. PMID- 29383025 TI - Diminished bile acids excretion is a risk factor for coronary artery disease: 20 year follow up and long-term outcome. AB - Background: Patients with coronary artery disease (CAD) had significantly lower bile acid excretion (BAE) compared with non-CAD patients, leading to the hypothesis that the inability to efficiently excrete bile acids leads to coronary atherosclerosis development. We investigated the long-term role of BAE in CAD development and related mortality in 50 patients with proven CAD compared with that of 50 patients with chest pain and no CAD (controls) matched for clinical and laboratory characteristics. Methods: All subjects received a 4-day standard diet that included ~500 mg of cholesterol. Fecal bile acids from 24-h stool collections were measured by gas liquid chromatography. Results: CAD patients excreted lower amounts of total bile acids than controls (p < 0.001), less deoxycholic acid (p < 0.0001) and less lithocholic acid (p < 0.01). BAE was the best significant independent laboratory factor that predicted CAD (p < 0.05). Mortality and CAD development rates were significantly lower for the controls at the 20-year follow up. Conclusions: These results showed that CAD patients had markedly decreased BAE levels compared with non-CAD controls. BAE <415 mg/day was associated with increased CAD long-term mortality. Impaired ability to excrete cholesterol might be considered an additional independent risk factor for CAD development. PMID- 29383026 TI - Factors affecting clinical decision-making in inflammatory bowel disease and the role of point-of-care calprotectin. AB - Objectives: Patient-reported symptoms correlate poorly with mucosal inflammation. Clinical decision-making may, therefore, not be based on objective evidence of disease activity. We conducted a study to determine factors associated with clinical decision-making in a secondary care inflammatory bowel disease (IBD) population, using a cross-sectional design. Methods: Decisions to request investigations or escalate medical therapy were recorded from outpatient clinic encounters in a cohort of 276 patients with ulcerative colitis (UC) or Crohn's disease (CD). Disease activity was assessed using clinical indices, self-reported flare or faecal calprotectin >= 250 ug/g. Demographic, disease-related and psychological factors were assessed using validated questionnaires. Logistic regression was performed to determine the association between clinical decision making and symptoms, mucosal inflammation and psychological comorbidity. Results: Self-reported flare was associated with requesting investigations in CD [odds ratio (OR) 5.57; 95% confidence interval (CI) 1.84-17.0] and UC (OR 10.8; 95% CI 1.8-64.3), but mucosal inflammation was not (OR 1.62; 95% CI 0.49-5.39; and OR 0.21; 95% CI 0.21-1.05, respectively). Self-reported flare (OR 7.96; 95% CI 1.84 34.4), but not mucosal inflammation (OR 1.67; 95% CI 0.46-6.13) in CD, and clinical disease activity (OR 10.36; 95% CI 2.47-43.5) and mucosal inflammation (OR 4.26; 95% CI 1.28-14.2) in UC were associated with escalation of medical therapy. Almost 60% of patients referred for investigation had no evidence of mucosal inflammation. Conclusions: Apart from escalation of medical therapy in UC, clinical decision-making was not associated with mucosal inflammation in IBD. The use of point-of-care calprotectin testing may aid clinical decision-making, improve resource allocation and reduce costs in IBD. PMID- 29383027 TI - Inflammatory bowel disease: towards a personalized medicine. AB - The management of inflammatory bowel disease (IBD) has been transformed over the last two decades by the arrival of tumor necrosis factor (TNF) antagonist agents. Recently, alternative drugs have been approved, directed at leukocyte-trafficking molecules (vedolizumab) or other inflammatory cytokines (ustekinumab). New therapeutics are currently being developed in IBD and represent promising targets as they involve other mechanisms of action (JAK molecules, Smad 7 antisense oligonucleotide etc.). Beyond TNF antagonist agents, these alternative drugs are needed for early-stage treatment of patients with aggressive IBD or when the disease is resistant to conventional therapy. Personalized medicine involves the determination of patients with a high risk of progression and complications, and better characterization of patients who may respond preferentially to specific therapies. Indeed, more and more studies aim to identify factors predictive of drug response (corresponding to a specific signaling pathway) that could better manage treatment for patients with IBD. Once treatment has started, disease monitoring is essential and remote patient care could in some circumstances be an attractive option. Telemedicine improves medical adherence and quality of life, and has a positive impact on health outcomes of patients with IBD. This review discusses the current application of personalized medicine to the management of patients with IBD and the advantages and limits of telemedicine in IBD. PMID- 29383028 TI - Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date. AB - Potassium-competitive acid blocker (P-CAB) is a class of drug that competitively blocks the potassium-binding site of H+, K+-adenosine triphosphate (ATP)ase. Although the history of this class of drugs started over 30 years ago, clinical use of two P-CABs, revaprazan and vonoprazan, were only recently approved in Korea and Japan, respectively. Among them, vonoprazan has several advantages over conventional proton-pump inhibitors (PPIs), including rapid onset of action, long duration of acid suppression, fewer interindividual variations in terms of acid suppression, and minimum dietary influence on its action. These advantages of vonoprazan have been proved in clinical trials conducted for license approvals for several acid-related diseases. In this review article, current evidence of vonoprazan in the management of gastroesophageal reflux disease (GERD) will be summarized. Since the clinical trial data, as well as postmarketed clinical data, have consistently demonstrated superiority of vonoprazan over conventional PPIs in terms of achieving healing of mucosal breaks and maintaining the healing, it may provide an excellent, if not complete, option for fulfilling some of the unmet needs for current GERD therapy. The safety problem of vonoprazan is also discussed, as more pronounced hypergastrinemia inevitably ensues with its use. PMID- 29383029 TI - Can technology increase adenoma detection rate? AB - Colorectal cancer is the third most common cancer worldwide and the second most common cause of cancer-related death in Europe and North America. Colonoscopy is the gold standard investigation for the colon but is not perfect, and small or flat adenomas can be missed which increases the risk of patients subsequently developing colorectal cancer. Adenoma detection rate is the most widely used marker of quality, and low rates are associated with increased rates of post colonoscopy colorectal cancer. Standards of colonoscopy and adenoma detection vary widely between different endoscopists. Interventions to improve adenoma detection rate are therefore required. Many devices have been purported to increase adenoma detection rate. This review looks at current available evidence for device technology to improve adenoma detection rate during colonoscopy. PMID- 29383030 TI - Immunogenicity of biologics in inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10-14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required. PMID- 29383031 TI - Treatment of ulcerative compared to non-ulcerative interstitial cystitis with hyperbaric oxygen: a pilot study. AB - Background: The etiology of interstitial cystitis (IC) is often idiopathic but can be due to Hunner's ulcers. Hyperbaric oxygen (HBO) is used to treat ulcerative disease of the superficial skin. We hypothesized that HBO can treat ulcerative IC (UIC) but would be less efficacious for non-ulcerative IC (NIC). Methods: Patients with NIC and UIC enrolled in this study. Following informed consent, demographic information was collected. A visual analog pain scale and validated questionnaires were collected; each patient underwent cystoscopy prior to treatment. Each subject met with a hyperbaric specialist and after clearance underwent 30 treatments over 6 weeks. Adverse events were monitored. Patients repeated questionnaires, visual analog pain scale and global response assessment (GRA) immediately, 2 weeks, 3, 6 and 12 months after treatment. Patients also underwent cystoscopy 6 months after treatment. Differences before and after treatment were compared. Results: Nine patients were recruited to this study. One was unable to participate, leaving two subjects with NIC and six with UIC. All patients completed HBO without adverse events. Three patients completed HBO but pursued other therapies 7, 8.5 and 11 months after treatment. On GRA, 83% of patients with UIC were improved. This treatment effect persisted, as 66% of UIC patients remained better at 6 months. In contrast, only one patient in the NIC group improved. Questionnaire scores improved in both groups. Pain scores improved by 2 points in the UIC group but worsened by 1.5 points in the NIC group. Two patients with ulcers resolved at 6-month cystoscopy. Conclusion: HBO appeared beneficial for both UIC and NIC. Data shows slightly better benefit in patients with UIC compared to NIC; both groups showed improvement. Given the small sample size, it is difficult to draw definitive conclusions from these data. Larger studies with randomization would be beneficial to show treatment effect. PMID- 29383032 TI - Comparison of objective and subjective factors in the adherence to antimuscarinics when treating overactive bladder in employed persons. AB - Background: This study examines subjective reasons for the refusal of treatment and the state of objective status markers of various factors influencing the resistance of patients when treating overactive bladder by antimuscarinic drugs (AMs). Methods: The socioeconomic and medical parameters were studied in 2465 patients aged 18-60 years (1446 women (58.7%), 1019 men (41.3%); mean age was 52.1) taking AMs during the year. The study control was carried out by studying passport data, employers' income certificates, patients' ambulatory medical records, the use of OABq-SF and MOS SF-36 questionnaires, voiding diaries and uroflowmetry. Results: The average time to reach the 30-day break in the AM administration was 177 days. During the 12-month follow up, 74.7% of patients discontinued their participation. In total, 35.9% of patients stated medical reasons for the refusal of AM treatment; in 31.9% of individuals in the group the deviation of objective health status markers from average sample values was established. Economic reasons for the refusal were given by 20.4% of patients; in 18.5% of individuals economic status markers were different from average sample values. In 24.1% of cases of refusal of treatment, patients indicated social and psychological reasons; objective social and psychological status markers were altered in 35.9%. Conclusions: The percentage of patients indicating economic and medical reasons for the refusal of AM treatment is statistically uniform with respect to the percentage of patients with objective disturbances of health and economic statuses. The percentage of patients indicating social and psychological factors as a reason for the refusal of treatment was significantly lower than the percentage of patients with altered social and psychological status markers. These results can be used in practical healthcare when predicting adherence to AM use. PMID- 29383034 TI - Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC). AB - Treatment for advanced non-small cell lung cancer (NSCLC) has been significantly improved in recent years with the incorporation of drugs targeting antiangiogenesis and more specifically genomic alterations such as the EGFR mutations and ALK translocations. However, most patients invariably progress and die. The emergence of immune checkpoint inhibitors targeting the pathways involved in tumor-induced immunosuppression have redefined the management of the disease, achieving significant long-lasting responses with manageable safety profiles, regardless of histology. Still, response rates with immunotherapy are deemed suboptimal. Current efforts are focusing on new potential combination strategies with synergistic antitumor activity, using immune checkpoint blockade as a partner for targeted agents. Herein we discuss the available data on the combined use of immunotherapy, including PD-1/PD-L1 and CTLA-4 inhibitors, with EGFR and ALK inhibitors and comment on the current status of immunotherapy plus antiangiogenic drugs for molecularly unselected advanced NSCLC. PMID- 29383035 TI - Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer: a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes. AB - Background: The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes. Methods: This was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- versus post-docetaxel). Multivariable Cox proportional hazards models assessed factors associated with progression-free survival (PFS) and overall survival (OS). Results: Overall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ? 10 ng/ml (p = 0.007), Gleason Score >7 (p = 0.008), Eastern Cooperative Oncology Group (ECOG) performance status (PS)1-2 (p = 0.002), duration of androgen deprivation therapy (ADT) ? 43.2 months (p = 0.01), and body mass index (BMI) > 25 (p = 0.03) were associated with worse PFS; presence of pain (p = 0.01), ECOG PS1-2 (p = 0.004), duration of ADT ? 43.2 (p = 0.05), and BMI > 25 (p = 0.042) were associated with worse OS. Incidence of CVEs was as follows: hypertension 17.1%, fluid retention 4.8%, cardiac disorders 8.6%. 16.2% of patients developed hypokalemia. Age ? 75 years was associated with higher probability of cardiac disorders (p = 0.001) and fluid retention (p = 0.03). CVEs did not impact on PFS or OS. Hypokalemia was associated with better median OS (p = 0.036). Similar associations were observed after stratification by subgroup. Conclusions: Median PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series. PMID- 29383033 TI - Radiation effects on antitumor immune responses: current perspectives and challenges. AB - Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies. PMID- 29383036 TI - Development of a personalized therapeutic strategy for ERBB-gene-mutated cancers. AB - Background: The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations. Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer. Methods: We used www.cbioportal.org to determine the frequency of ERBB mutations in solid tumors. We then determined the sensitivity of a panel of cell lines to clinically available PI3K inhibitors. Using proliferation and apoptosis assays as well as functional interrogation with reverse phase protein arrays we demonstrated the impact of targeting ERBB-mutant cancers with the combination of a PI3K inhibitor and the pan-HER family inhibitor afatinib. Results: In over 14,000 patients we found that 12% of their tumors have an ERBB family gene mutation (EGFR, ERBB2, ERBB3 and ERBB4). In cancers not commonly associated with HER family protein overexpression, such as ovarian, endometrial, melanoma and head and neck cancers (n = 2116), we found that ERBB family mutations are enriched, occurring at rates from 14% to 34% and commonly co-occur with PIK3CA mutations. Importantly, we demonstrate that ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors. Finally we show that the combination of afatinib and copanlisib represents a novel therapeutic strategy for patients whose cancers harbor both ERBB family and PIK3CA mutation. Conclusions: We demonstrate that ERBB family mutations are common in cancers not associated with overexpression or amplification of HER family proteins. These ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors, and when combined with pan-HER inhibitors have synergistic antiproliferative effects. PMID- 29383038 TI - Evaluation of PD-L1/PD-1 on circulating tumor cells in patients with advanced non small cell lung cancer. AB - Background: Circulating tumor cells (CTCs) could escape from the immune system through the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD 1) axis leading to the development of metastasis. The current study investigated the expression of PD-1/PD-L1 on CTCs isolated from non-small cell lung cancer (NSCLC) patients treated with chemotherapy. Patients and methods: CTCs were isolated from 30 chemo-naive stage IV NSCLC patients before and after front-line chemotherapy using the ISET filtration platform. CTCs were detected by Giemsa and immunofluorescence (IF) staining. Samples were analyzed with the ARIOL system. Results: Giemsa staining revealed that 28 (93.3%) out of 30 and 9 (81.8%) out of 11 patients had detectable CTCs at baseline and after the third chemotherapy cycle, respectively. Cytokeratin (CK)+/CD45- CTCs by IF could be detected in 17 of 30 (56.7%) patients at baseline and in 8 of 11 (72.7%) after the third chemotherapy cycle. Spearman analysis revealed a significant correlation (p = 0.001) between Giemsa-positive and IF-positive (CK+/CD45-) CTCs. At baseline, PD 1 and PD-L1 expression was observed in 53% and in 47% CK-positive patients, respectively. After the third treatment cycle the corresponding numbers were 13% and 63% respectively. Median progression-free survival (PFS) was significantly shorter in patients with >3 PD-1(+) CTCs at baseline compared with those with <3 PD-1(+) CTCs (p = 0.022) as well as in patients with >1 Giemsa-positive tumor cells (p = 0.025). Conclusion: PD-1(+) and PD-L1(+) CTCs could be detected before and after front-line chemotherapy in patients with metastatic NSCLC. The presence of high PD-1(+) CTC numbers before treatment is associated with a poor patient clinical outcome. PMID- 29383037 TI - Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. AB - Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-gamma). We have explored whether the expression of IFNG, the gene encoding IFN-gamma, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-gamma is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1. PMID- 29383039 TI - Diverse cutaneous adverse eruptions caused by anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies: clinical features and management. AB - Background: The anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies have shown exceptional activity in many cancers. However, these immunotherapies can also result in diverse adverse cutaneous eruptions that need to be better characterized for ongoing management. The objective was to provide clinical and histopathologic descriptions of the variety of cutaneous adverse events seen in patients who received anti-PD-1/PD-L1 treatment and discuss their management. Methods: Patients with advanced cancers in clinical trials at University of California Los Angeles (UCLA), receiving anti PD-1/PD-L1 treatment between 2012 and 2016 who developed cutaneous eruptions and were evaluated in the dermatology clinic were included in this retrospective case series study. A total of 16 patients were included in this study; of these, five were treated with pembrolizumab alone, two with avelumab alone, eight with nivolumab plus ipilimumab and one with nivolumab plus T-Vec. Of these 16 patients, eight had received systemic chemotherapy, six had received radiotherapy, and one had received trememlimumab prior to the immunotherapies described in this study. Results: Cutaneous eruptions occurred at variable times, from week 1 to 88, with a median of 11.5 weeks; the morphologies included lichenoid, bullous, psoriasiform, macular, morbiliform appearances, and alopecia which were confirmed histopathologically in several of the cases. All cutaneous immune-related adverse events were either grade 1 or 2. Ten patients were treated with topical corticosteroids, and one also received NBUVB. Four patients eventually required systemic steroids. Three required discontinuation of their anti-PD-1/PD-L1 therapy secondary to the cutaneous eruptions. Conclusions: There are several different types of adverse cutaneous morphologies that may be seen with administration of PD-1 and PD-L1 inhibitors. Identifying the patterns of eruption may assist in prompt treatment. Most eruptions could be managed with topical corticosteroids and without discontinuation of the systemic treatment. PMID- 29383040 TI - A prospective study on the diagnosis of peripheral lung cancer using endobronchial ultrasonography with a guide sheath and computed tomography-guided transthoracic needle aspiration. AB - Background: It is difficult to collect peripheral lung cancer samples. This study analyzed the applicability of endobronchial ultrasonography with a guide sheath (EBUS-GS) and computed tomography-guided transthoracic needle aspiration (CT TTNA) for the diagnosis of peripheral lung cancer. Methods: A prospective analysis of peripheral lung cancer patients was performed. The study included 150 cases in the EBUS-GS group and 177 cases in the CT-TTNA group. The diagnostic rate, pathological type, genetic status and complications were analyzed. Results: The diagnosis rates were 64.0% and 97.7% in the EBUS-GS and CT-TTNA groups, respectively. The EBUS-GS group had undergone the most operations of the upper lobes of both lungs, while there was no significant difference in the operation distribution among the lobes in the CT-TTNA group. Adenocarcinoma (64 cases versus 51 cases) was most commonly observed in both groups, followed by squamous cell carcinoma. The detection rates of patients who were given a genetic test were 96.1% and 98.9% in the EBUS-GS and CT-TTNA groups, respectively. The incidence of complications in the EBUS-GS group was significantly less than that in the CT-TTNA group. Conclusions: EBUS-GS and CT-TTNA both had operational limitations. The diagnostic rate of EBUS-GS was lower than that of CT-TTNA, but there were fewer complications. CT-TTNA had better tolerance. According to the specific location of the lesion, we recommend EBUS-GS for lesions with a diameter ?30 mm and CT-TTNA for lesions with a diameter >30 mm. CT-TTNA specimens were advantageous for genetic testing. PMID- 29383041 TI - Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors. AB - Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles. Therefore, there is a strong imperative to optimize the sequence of TKIs in order to maximize their clinical benefit. Osimertinib has demonstrated striking efficacy as a second-line treatment option in patients with T790M-positive tumors, and also confers efficacy and tolerability advantages over first-generation TKIs in the first-line setting. However, while accrual of T790M is the most predominant mechanism of resistance to erlotinib, gefitinib and afatinib, resistance mechanisms to osimertinib have not been clearly elucidated, meaning that possible therapy options after osimertinib failure are not clear. At present, few data comparing sequential regimens in patients with EGFR mutation-positive NSCLC are available and prospective clinical trials are required. This article reviews the similarities and differences between EGFR TKIs, and discusses key considerations when assessing optimal sequential therapy with these agents for the treatment of EGFR mutation-positive NSCLC. PMID- 29383042 TI - New chemistry of transition metal oxyhydrides. AB - In this review we describe recent advances in transition metal oxyhydride chemistry obtained by topochemical routes, such as low temperature reduction with metal hydrides, or high-pressure solid-state reactions. Besides the crystal chemistry, magnetic and transport properties of the bulk powder and epitaxial thin film samples, the remarkable lability of the hydride anion is particularly highlighted as a new strategy to discover unprecedented mixed anion materials. PMID- 29383043 TI - Unconventional aspects of electronic transport in delafossite oxides. AB - The electronic transport properties of the delafossite oxides [Formula: see text] are usually understood in terms of two well-separated entities, namely the triangular [Formula: see text] and ([Formula: see text] layers. Here, we review several cases among this extensive family of materials where the transport depends on the interlayer coupling and displays unconventional properties. We review the doped thermoelectrics based on [Formula: see text] and [Formula: see text], which show a high-temperature recovery of Fermi-liquid transport exponents, as well as the highly anisotropic metals [Formula: see text], [Formula: see text], and [Formula: see text], where the sheer simplicity of the Fermi surface leads to unconventional transport. We present some of the theoretical tools that have been used to investigate these transport properties and review what can and cannot be learned from the extensive set of electronic structure calculations that have been performed. PMID- 29383044 TI - Synthesis of core-shell structured FAU/SBA-15 composite molecular sieves and their performance in catalytic cracking of polystyrene. AB - Composite molecular sieves, FAU/SBA-15, having core-shell structure were synthesized. The synthesized composite sieves were characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), pyrolysis fourier transform infrared (Py-FTIR) spectroscopy, temperature programmed desorption spectra (NH3-TPD), UV Raman spectroscopy, nuclear magnetic resonance (NMR) and other techniques. XRD, SEM, TEM, N2 adsorption-desorption, mass spectrometry, NMR and EDS results showed that the composite molecular sieve contained two pore channels. Py-FTIR results showed that the addition of HY molecular sieves improved the acidity of the composite zeolite. The crystallization mechanism during the growth of FAU/SBA-15 shell was deduced from the influence of crystallization time on the synthesis of FAU/SBA-15 core-shell structured composite molecular sieve. HY dissociated partially in H2SO4 solution, and consisted of secondary structural units. This framework structure was more stable than its presence in the isolated form on the same ring or in the absence of Al. Thus it played a guiding role and connected with SBA-15 closely through the Si-O bond. This resulted in the gradual covering of the exterior surface of FAU phase by SBA-15 molecular sieves. The presence of SBA-15 restricted the formation of the other high mass components and increased the selectivity towards ethylbenzene. PMID- 29383045 TI - Effect of amine structure on CO2 capture by polymeric membranes. AB - Poly(amidoamine)s (PAMAMs) incorporated into a cross-linked poly(ethylene glycol) exhibited excellent CO2 separation properties over H2. However, the CO2 permeability should be increased for practical applications. Monoethanolamine (MEA) used as a CO2 determining agent in the current CO2 capture technology at demonstration scale was readily immobilized in poly(vinyl alcohol) (PVA) matrix by solvent casting of aqueous mixture of PVA and the amine. The resulting polymeric membranes can be self-standing with the thickness above 3 MUm and the amine fraction less than 80 wt%. The gas permeation properties were examined at 40 degrees C and under 80% relative humidity. The CO2 separation performance increased with increase of the amine content in the polymeric membranes. When the amine fraction was 80 wt%, the CO2 permeability coefficient of MEA containing membrane was 604 barrer with CO2 selectivity of 58.5 over H2, which was much higher than the PAMAM membrane (83.7 barrer and 51.8, respectively) under the same operation conditions. On the other hand, ethylamine (EA) was also incorporated into PVA matrix to form a thin membrane. However, the resulting polymeric membranes exhibited slight CO2-selective gas permeation properties. The hydroxyl group of MEA was crucial for high CO2 separation performance. PMID- 29383046 TI - Nanocellulose-stabilized Pickering emulsions and their applications. AB - Pickering emulsion, which is an emulsion stabilized by solid particles, offers a wide range of potential applications because it generally provides a more stable system than surfactant-stabilized emulsion. Among various solid stabilizers, nanocellulose may open up new opportunities for future Pickering emulsions owing to its unique nanosizes, amphiphilicity, and other favorable properties (e.g. chemical stability, biodegradability, biocompatibility, and renewability). In this review, the preparation and properties of nanocellulose-stabilized Pickering emulsions are summarized. We also provide future perspectives on their applications, such as drug delivery, food, and composite materials. PMID- 29383047 TI - Double perovskite cathodes for proton-conducting ceramic fuel cells: are they triple mixed ionic electronic conductors? AB - 18O and 2H diffusion has been investigated at a temperature of 300 degrees C in the double perovskite material PrBaCo2O5+delta (PBCO) in flowing air containing 200 mbar of 2H216O. Secondary ion mass spectrometry (SIMS) depth profiling of exchanged ceramics has shown PBCO still retains significant oxygen diffusivity (~1.3 * 10-11 cm2s-1) at this temperature and that the presence of water (2H216O), gives rise to an enhancement of the surface exchange rate over that in pure oxygen by a factor of ~3. The 2H distribution, as inferred from the 2H216O- SIMS signal, shows an apparent depth profile which could be interpreted as 2H diffusion. However, examination of the 3-D distribution of the signal shows it to be nonhomogeneous and probably related to the presence of hydrated layers in the interior walls of pores and is not due to proton diffusion. This suggests that PBCO acts mainly as an oxygen ion mixed conductor when used in PCFC devices, although the presence of a small amount of protonic conductivity cannot be discounted in these materials. PMID- 29383048 TI - Getting Published in Medical Education: Overcoming Barriers to Scholarly Production. PMID- 29383049 TI - Jack of All Trades, Masters of One? PMID- 29383050 TI - Replacing Lectures with Small Groups: The Impact of Flipping the Residency Conference Day. AB - The flipped classroom, an educational alternative to the traditional lecture, has been widely adopted by educators at all levels of education and across many disciplines. In the flipped classroom, learners prepare in advance of the face-to face meeting by learning content material on their own. Classroom time is reserved for application of the learned content to solving problems or discussing cases. Over the past year, we replaced most residency program lectures with small group discussions using the flipped-classroom model, case-based learning, simulation and procedure labs. In the new model, residents prepared for conference by reviewing a patient case and studying suggested learning materials. Conference day was set aside for facilitated small-group discussions about the case. This is a cross-cohort study of emergency medicine residents who experienced the lecture-based curriculum to residents in the new flipped classroom curriculum using paired comparisons (independent t-tests) on in training exam scores while controlling for program year level. We also compared results of the evaluation of various program components. We observed no differences between cohorts on in-training examination scores. Small-group methods were rated the same across program years. Two program components in the new curriculum, an updated format of both adult and pediatric case conferences, were rated significantly higher on program quality. In preparation for didactics, residents in the new curriculum report spending more time on average with outside learning materials, including almost twice as much time reviewing textbooks. Residents found the new format of the case conferences to be of higher quality because of the inclusion of rapid-fire case discussions with targeted learning points. PMID- 29383051 TI - Tracking Student Mistreatment Data to Improve the Emergency Medicine Clerkship Learning Environment. AB - Introduction: Medical student mistreatment is a prevalent and significant challenge for medical schools across the country, associated with negative emotional and professional consequences for students. The Association of American Medical Colleges and Liaison Committee on Medical Education have increasingly emphasized the issue of mistreatment in recent years, and medical schools are tasked with creating a positive learning climate. Methods: The authors describe the efforts of an emergency department (ED) to improve its clerkship learning environment, using a multifaceted approach for collecting mistreatment data and relaying them to educators and clerkship leadership. Data are gathered through end-of-rotation evaluations, teaching evaluations, and an online reporting system available to medical students. Mistreatment data are then relayed to the ED during semi-annual meetings between clerkship leadership and medical school assistant deans, and through annual mistreatment reports provided to department chairs. Results: Over a two-year period, students submitted a total of 56 narrative comments related to mistreatment or unprofessional behavior during their emergency medicine (EM) clerkship. Of these comments, 12 were submitted in 2015-16 and 44 were submitted in 2016-17. The most frequently observed themes were students feeling ignored or marginalized by faculty (14 comments); students being prevented from speaking or working with patients and/or attending faculty (11 comments); and students being treated in an unprofessional manner by staff (other than faculty, 8 comments). Conclusion: This article details an ED's efforts to improve its EM clerkship learning environment by tracking mistreatment data and intentionally communicating the results to educators and clerkship leadership. Continued mistreatment data collection and faculty development will be necessary for these efforts to have a measurable effect on the learning environment. PMID- 29383052 TI - The Flipped Journal Club. AB - Introduction: Educators struggle to develop a journal club format that promotes active participation from all levels of trainees. The explosion of social media compels residencies to incorporate the evaluation and application of these resources into evidence-based practice. We sought to design an innovative "flipped journal club" to achieve greater effectiveness in meeting goals and objectives among residents and faculty. Methods: Each journal club is focused on a specific clinical question based on a landmark article, a background article, and a podcast or blog post. With the "flipped" model, residents are assigned to prepare an in-depth discussion of one of these works based on their level of training. At journal club, trainees break into small groups and discuss their assigned readings with faculty facilitation. Following the small-group discussions, all participants convene to summarize key points. In redesigning our journal club, we sought to achieve specific educational outcomes, and improve participant engagement and overall impressions. Results: Sixty-one residents at our emergency medicine program participated in the flipped journal club during the 2015-2016 academic year, with supervision by core faculty. Program evaluation for the flipped journal club was performed using an anonymous survey, with response rates of 70% and 56% for residents and faculty, respectively. Overall, 95% of resident respondents and 100% of faculty respondents preferred the flipped format. Conclusion: The "flipped journal club" hinges upon well-selected articles, incorporation of social media, and small-group discussions. This format engages all residents, holds learners accountable, and encourages greater participation among residents and faculty. PMID- 29383053 TI - Taking Advantage of the Teachable Moment: A Review of Learner-Centered Clinical Teaching Models. AB - When working in a chaotic Emergency Department (ED) with competing priorities, clinical teaching may be sacrificed for the sake of patient flow and throughput. An organized, efficient approach to clinical teaching helps focus teaching on what the learner needs at that moment, incorporates regular feedback, keeps the department on track, and prevents over-teaching. Effective clinical teaching in a busy environment is an important skill for senior residents and faculty to develop. This review will provide a critique and comparison of seven structured teaching models to better prepare readers to seize the teachable moment. PMID- 29383054 TI - Self vs. Other Focus: Predicting Professionalism Remediation of Emergency Medicine Residents. AB - Introduction: Unprofessionalism is a major reason for resident dismissal from training. Because of the high stakes involved, residents and educators alike would benefit from information predicting whether they might experience challenges related to this competency. Our objective was to correlate the outcome of professionalism-related remedial actions during residency with the predictor variable of resident response to a standardized interview question: "Why is Medicine important to you?" Methods: We conducted a professional development quality improvement (QI) initiative to improve resident education and mentorship by achieving a better understanding of each resident's reasons for valuing a career in medicine. This initiative entailed an interview administered to each resident beginning emergency medicine training at San Antonio Military Medical Center during 2006-2013. The interviews uniformly began with the standardized question "Why is Medicine important to you?" The residency program director documented a free-text summary of each response to this question, the accuracy of which was confirmed by the resident. We analyzed the text of each resident's response after a review of the QI data suggested an association between responses and professionalism actions (retrospective cohort design). Two associate investigators blinded to all interview data, remedial actions, and resident identities categorized each text response as either self-focused (e.g., "I enjoy the challenge") or other-focused (e.g., "I enjoy helping patients"). Additional de-identified data collected included demographics, and expressed personal importance of politics and religion. The primary outcome was a Clinical Competency Committee professionalism remedial action. Results: Of 114 physicians starting residency during 2006-2013, 106 (93.0%) completed the interview. There was good inter-rater reliability in associate investigator categorization of resident responses as either self-focused or other-focused (kappa coefficient 0.85). Thirteen of 50 residents (26.0%) expressed self-focus versus three of 54 (5.4%) residents expressed other-focus experienced professionalism remedial actions (p<0.01). This association held in a logistic regression model controlling for measured confounders (p=0.02). Conclusion: Self-focused responses to the question "Why is Medicine important to you?" correlated with professionalism remedial actions during residency. PMID- 29383055 TI - Intern as Patient: A Patient Experience Simulation to Cultivate Empathy in Emergency Medicine Residents. AB - Introduction: Prior work links empathy and positive physician-patient relationships to improved healthcare outcomes. The objective of this study was to analyze a patient experience simulation for emergency medicine (EM) interns as a way to teach empathy and conscientious patient care. Methods: We conducted a qualitative descriptive study on an in situ, patient experience simulation held during EM residency orientation. Half the interns were patients brought into the emergency department (ED) by ambulance and half were family members. Interns then took part in focus groups that discussed the experience. Data collected during these focus groups were coded by two investigators using a grounded theory approach and constant comparative methodology. Results: We identified 10 major themes and 28 subthemes in the resulting qualitative data. Themes were in three broad categories: the experience as a patient or family member in the ED; application to current clinical practice; and evaluation of the exercise itself. Interns experienced firsthand the physical discomfort, emotional stress and confusion patients and families endure during the ED care process. They reflected on lessons learned, including the importance of good communication skills, frequent updates on care and timing, and being responsive to the needs and concerns of patients and families. All interns felt this was a valuable orientation experience. Conclusion: Conducting a patient experience simulation may be a practical and effective way to develop empathy in EM resident physicians. Additional research evaluating the effect of participation in the simulation over a longer time period and assessing the effects on residents' actual clinical care is warranted. PMID- 29383056 TI - ACGME Clinical and Educational Work Hour Standards: Perspectives and Recommendations from Emergency Medicine Educators. AB - Introduction: The American College of Emergency Physicians (ACEP) and the Council of Emergency Medicine Residency Directors (CORD) were invited to contribute to the 2016 Accreditation Council for Graduate Medical Education's (ACGME) Second Resident Duty Hours in the Learning and Working Environment Congress. We describe the joint process used by ACEP and CORD to capture the opinions of emergency medicine (EM) educators on the ACGME clinical and educational work hour standards, formulate recommendations, and inform subsequent congressional testimony. Methods: In 2016 our joint working group of experts in EM medical education conducted a consensus-based, mixed-methods process using survey data from medical education stakeholders in EM and expert iterative discussions to create organizational position statements and recommendations for revisions of work hour standards. A 19-item survey was administered to a convenience sample of 199 EM residency training programs using a national EM educational listserv. Results: A total of 157 educational leaders responded to the survey; 92 of 157 could be linked to specific programs, yielding a targeted response rate of 46.2% (92/199) of programs. Respondents commented on the impact of clinical and educational work-hour standards on patient safety, programmatic and personnel costs, resident caseload, and educational experience. Using survey results, comments, and iterative discussions, organizational recommendations were crafted and submitted to the ACGME. Conclusion: EM educators believe that ACGME clinical and educational work hour standards negatively impact the learning environment and are not optimal for promoting patient safety or the development of resident professional citizenship. PMID- 29383057 TI - Fantastic Learning Moments and Where to Find Them. AB - Introduction: Experiential learning is crucial for the development of all learners. Literature exploring how and where experiential learning happens in the modern clinical learning environment is sparse. We created a novel, web-based educational tool called "Learning Moment" (LM) to foster experiential learning among our learners. We used data captured by LM as a research database to determine where learning experiences were occuring within our emergency department (ED). We hypothesized that these moments would occur more frequently at the physician workstations as opposed to the bedside. Methods: We implemented LM at a single ED's medical student clerkship. The platform captured demographic data including the student's intended specialty and year of training as well as "learning moments," defined as logs of learner self-selected learning experiences that included the clinical "pearl," clinical scenario, and location where the "learning moment" occurred. We presented data using descriptive statistics with frequencies and percentages. Locations of learning experiences were stratified by specialty and training level. Results: A total of 323 "learning moments" were logged by 42 registered medical students (29 fourth-year medical students (MS 4) and 13 MS 3 over a six-month period. Over half (52.4%) intended to enter the field of emergency medicine (EM). Of these "learning moments," 266 included optional location data. The most frequently reported location was patient rooms (135 "learning moments", 50.8%). Physician workstations hosted the second most frequent "learning moments" (67, 25.2%). EM-bound students reported 43.7% of "learning moments" happening in patient rooms, followed by workstations (32.8%). On the other hand, non EM-bound students reported that 66.3% of "learning moments" occurred in patient rooms and only 8.4% at workstations (p<0.001). Conclusion: LM was implemented within our ED as an innovative, web-based tool to fulfill and optimize the experiential learning cycle for our learners. In our environment, patient rooms represented the most frequent location of "learning moments," followed by physician workstations. EM-bound students were considerably more likely to document "learning moments" occurring at the workstation and less likely in patient rooms than their non EM-bound colleagues. PMID- 29383058 TI - The National Clinical Assessment Tool for Medical Students in the Emergency Department (NCAT-EM). AB - Introduction: Clinical assessment of medical students in emergency medicine (EM) clerkships is a highly variable process that presents unique challenges and opportunities. Currently, clerkship directors use institution-specific tools with unproven validity and reliability that may or may not address competencies valued most highly in the EM setting. Standardization of assessment practices and development of a common, valid, specialty-specific tool would benefit EM educators and students. Methods: A two-day national consensus conference was held in March 2016 in the Clerkship Directors in Emergency Medicine (CDEM) track at the Council of Residency Directors in Emergency Medicine (CORD) Academic Assembly in Nashville, TN. The goal of this conference was to standardize assessment practices and to create a national clinical assessment tool for use in EM clerkships across the country. Conference leaders synthesized the literature, articulated major themes and questions pertinent to clinical assessment of students in EM, clarified the issues, and outlined the consensus-building process prior to consensus-building activities. Results: The first day of the conference was dedicated to developing consensus on these key themes in clinical assessment. The second day of the conference was dedicated to discussing and voting on proposed domains to be included in the national clinical assessment tool. A modified Delphi process was initiated after the conference to reconcile questions and items that did not reach an a priori level of consensus. Conclusion: The final tool, the National Clinical Assessment Tool for Medical Students in Emergency Medicine (NCAT-EM) is presented here. PMID- 29383059 TI - Tit-For-Tat Strategy for Increasing Medical Student Evaluation Response Rates. AB - Introducation: It is essential for faculty to receive feedback on their teaching for the purpose of improvement as well as promotion. It can be challenging to motivate students to provide feedback to preceptors and fill out evaluation forms when not a clerkship requirement. Furthermore, there is concern that making the evaluations a requirement can compromise the quality of the feedback. The objective of this study was to identify an increase in the number of faculty and resident evaluations completed by students rotating through their Emergency Medicine clerkship following the implementation of a tit-for-tat incentive strategy. Method: Prior to the implementation of Tit-for-Tat, students rotating through their emergency medicine clerkship were asked to fill out evaluations of residents and faculty members with whom they worked. These were encouraged but voluntary. Beginning in the 2014-2015 academic year, a tit-for-tat strategy was employed whereby students had to complete a resident or faculty evaluation in order to view the student assessment completed by that resident or faculty preceptor. Results: Students submitted 1101 evaluations in the control, with a mean of 3.60 evaluations completed per student and 3.77 evaluations received per preceptor. Following the implementation of tit-for-tat, students submitted 2736 evaluations, with a mean of 8.19 evaluations completed per student and 7.52 evaluations received per preceptor. Both the increase in evaluations completed per student and evaluations received per preceptor were statistically significant with p-value <0.001. Conclusion: The tit-for-tat strategy significantly increased the number of evaluations submitted by students rotating through their emergency medicine clerkship. This has served as an effective tool to increase the overall number of evaluations completed, the number of evaluations each instructor received on average and the proportion of students that completed evaluations. Further work could be done to attempt to better assess the quality of the feedback from these evaluations. PMID- 29383060 TI - Feasibility and Usability of Tele-interview for Medical Residency Interview. AB - Every year in the United States, medical students and residency programs dedicate millions of dollars to the residency matching process. On-site interviews for training positions involve tremendous financial investment, and time spent detracts from educational pursuits and clinical responsibilities. Students are usually required to fund their own travel and accommodations, adding additional financial burdens to an already costly medical education. Similarly, residency programs allocate considerable funds to interview-day meals, tours, staffing, and social events. With the rapid onslaught of innovations and advancements in the field of telecommunication, technology has become ubiquitous in the practice of medicine. Internet applications have aided our ability to deliver appropriate, evidence-based care at speeds previously unimagined. Wearable medical tech allows physicians to monitor patients from afar, and telemedicine has emerged as an economical means by which to provide care to all corners of the world. It is against this backdrop that we consider the integration of technology into the residency application process. This article aims to assess the implementation of technology in the form of web-based interviewing as a viable means by which to reduce the costs and productivity losses associated with traditional in-person interview days. PMID- 29383061 TI - Training in Emergency Obstetrics: A Needs Assessment of U.S. Emergency Medicine Program Directors. AB - Introduction: Obstetrical emergencies are a high-risk yet infrequent occurrence in the emergency department. While U.S. emergency medicine (EM) residency graduates are required to perform 10 low-risk normal spontaneous vaginal deliveries, little is known about how residencies prepare residents to manage obstetrical emergencies. We sought to profile the current obstetrical training curricula through a survey of U.S. training programs. Methods: We sent a web based survey covering the four most common obstetrical emergencies (pre eclampsia/eclampsia, postpartum hemorrhage (PPH), shoulder dystocia, and breech presentation) through email invitations to all program directors (PD) of U.S. EM residency programs. The survey focused on curricular details as well as the comfort level of the PDs in the preparation of their graduating residents to treat obstetrical emergencies and normal vaginal deliveries. Results: Our survey had a 55% return rate (n=105/191). Of the residencies responding, 75% were in the academic setting, 20.2% community, 65% urban, and 29.8% suburban, and the obstetrical curricula were 2-4 weeks long occurring in post-graduate year one. The most common teaching method was didactics (84.1-98.1%), followed by oral cases for pre-eclampsia (48%) and PPH (37.2%), and homemade simulation for shoulder dystocia (37.5%) and breech delivery (33.3%). The PDs' comfort about residency graduate skills was highest for normal spontaneous vaginal delivery, pre-eclampsia, and PPH. PDs were not as comfortable about their graduates' skill in handling shoulder dystocia or breech delivery. Conclusion: Our survey found that PDs are less comfortable in their graduates' ability to perform non-routine emergency obstetrical procedures. PMID- 29383062 TI - Flipping the Classroom in Medical Student Education: Does Priming Work? AB - Introduction: The emergency medicine (EM) clerkship curriculum at Los Angeles County + University of Southern California Medical Center includes monthly lectures on pediatric fever and shortness of breath (SOB). This educational innovation evaluated if learning could be enhanced by "priming" the students with educational online videos prior to an in-class session. Factors that impacted completion rates were also evaluated (planned specialty and time given for video viewing). Methods: Twenty-minute videos were to be viewed prior to the didactic session. Students were assigned to either the fever or SOB group and received links to those respective videos. All participating students took a pre-test prior to viewing the online lectures. For analysis, test scores were placed into concordant groups (test results on fever questions in the group assigned the fever video and test results on SOB questions in the group assigned the SOB video) and discordant groups (crossover between video assigned and topic tested). Each subject contributed one set of concordant results and one set of discordant results. Descriptive statistics were performed with the Mann-Whitney U test. Lecture links were distributed to students two weeks prior to the in-class session for seven months and three days prior to the in-class session for eight months (in which both groups included both EM-bound and non-EM bound students). Results: In the fifteen-month study period, 64% of students rotating through the EM elective prepared for the in class session by watching the videos. During ten months where exclusively EM-bound students were rotating (n=144), 71.5% of students viewed the lectures. In four months where students were not EM-bound (n=54), 55.6% of students viewed the lectures (p=0.033). Participation was 60.2% when lecture links were given three days in advance and 68.7% when links were given two weeks in advance (p=0.197). In the analysis of concordant scores, the pre-test averaged 56.7% correct, the immediate post-test averaged 78.1% correct, and the delayed post-test was 67.2%. In the discordant groups, the pretest averaged 51.9%, the immediate posttest was 67.1% and the delayed by 68.8%. In the concordant groups, the immediate post-test scores improved by 21.4%, compared with 15.2% in the discordant groups (p = 0.655). In the delayed post-test the concordant scores improved by 10.5% and discordant scores by 16.9 percent (p=0.609). Sixty-two percent of students surveyed preferred the format of online videos with in-class case discussion to a traditional lecture format. Conclusion: Immediate post-tests and delayed post-tests improved but priming was not demonstrated to be a statistically superior educational method in this study. Medical student completion of the preparatory materials for the EM rotation session increased when the students were EM-bound. Participation rates were not significantly different when given at two weeks versus three days. PMID- 29383063 TI - Does the Podcast Video Playback Speed Affect Comprehension for Novel Curriculum Delivery? A Randomized Trial. AB - Introduction: Medical education is a rapidly evolving field that has been using new technology to improve how medical students learn. One of the recent implementations in medical education is the recording of lectures for the purpose of playback at various speeds. Though previous studies done via surveys have shown a subjective increase in the rate of knowledge acquisition when learning from sped-up lectures, no quantitative studies have measured information retention. The purpose of this study was to compare mean test scores on written assessments to objectively determine if watching a video of a recorded lecture at 1.5* speed was significantly different than 1.0* speed for the immediate retention of novel material. Methods: Fifty-four University of Kentucky medical students volunteered to participate in this study. The subjects were divided into two separate groups: Group A and Group B. Each group watched two separate videos, the first at 1.5* speed and the second at 1.0* speed, then completed assessments following each. The topics of the two videos were ultrasonography artifacts and transducers. Group A watched the artifacts video first at 1.5* speed followed by the transducers video at 1.0* speed. Group B watched the transducers video first at 1.5* speed followed by the artifacts video at 1.0* speed. The percentage correct on the written assessment were calculated for each subject at each video speed. The mean and standard deviation were also calculated using a t-test to determine if there was a significant difference in assessment scores between 1.5* and 1.0* speeds. Results: There was a significant (p=0.0188) detriment in performance on the artifacts quiz at 1.5* speed (mean 61.4; 95% confidence interval [CI]-53.9, 68.9) compared to the control group at normal speed (mean 72.7; 95% CI-66.8, 78.6). On the transducers assessment, there was not a significant (p=0.1365) difference in performance in the 1.5* speed group (mean 66.9; CI- 59.8, 74.0) compared to the control group (mean 73.8; CI- 67.7, 79.8). Conclusion: These findings suggest that, unlike previously published studies that showed subjective improvement in performance with sped-up video-recorded lectures compared to normal speed, objective performance may be worse. PMID- 29383064 TI - Emergency Medicine Residency Applicant Characteristics Associated with Measured Adverse Outcomes During Residency. AB - Introduction: Negative outcomes in emergency medicine (EM) programs use a disproportionate amount of educational resources to the detriment of other residents. We sought to determine if any applicant characteristics identifiable during the selection process are associated with negative outcomes during residency. Methods: Primary analysis consisted of looking at the association of each of the descriptors including resident characteristics and events during residency with a composite measure of negative outcomes. Components of the negative outcome composite were any formal remediation, failure to complete residency, or extension of residency. Results: From a dataset of 260 residents who completed their residency over a 19-year period, 26 (10%) were osteopaths and 33 (13%) were international medical school graduates A leave of absence during medical school (p <.001), failure to send a thank-you note (p=.008), a failing score on United States Medical Licensing Examination Step I (p=.002), and a prior career in health (p=.034) were factors associated with greater likelihood of a negative outcome. All four residents with a "red flag" during their medicine clerkships experienced a negative outcome (p <.001). Conclusion: "Red flags" during EM clerkships, a leave of absence during medical school for any reason and failure to send post-interview thank-you notes may be associated with negative outcomes during an EM residency. PMID- 29383065 TI - A Randomized Trial of SMART Goal Enhanced Debriefing after Simulation to Promote Educational Actions. AB - Introduction: Goal setting is used in education to promote learning and performance. Debriefing after clinical scenario-based simulation is a well established practice that provides learners a defined structure to review and improve performance. Our objective was to integrate formal learning goal generation, using the SMART framework (Specific, Measurable, Attainable, Realistic, and Time-bound), into standard debriefing processes (i.e., "SMART Goal Enhanced Debriefing") and subsequently measure the impact on the development of learning goals and execution of educational actions. Methods: This was a prospective multicenter randomized controlled study of 80 emergency medicine residents at three academic hospitals comparing the effectiveness of SMART Goal Enhanced Debriefing to a standard debriefing. Residents were block randomized on a rolling basis following a simulation case. SMART Goal Enhanced Debriefing included five minutes of formal instruction on the development of SMART learning goals during the summary/application phase of the debrief. Outcome measures included the number of recalled learning goals, self-reported executed educational actions, and quality of each learning goal and educational action after a two-week follow-up period. Results: The mean number of reported learning goals was similar in the standard debriefing group (mean 2.05 goals, SD 1.13, n=37 residents), and in the SMART Goal Enhanced Debriefing group (mean 1.93, SD 0.96, n=43), with no difference in learning goal quality. Residents receiving SMART Goal Enhanced Debriefing completed more educational actions on average (Control group actions completed 0.97 (SD 0.87), SMART debrief group 1.44 (SD 1.03) p=0.03). Conclusion: The number and quality of learning goals reported by residents was not improved as a result of SMART Goal Enhanced Debriefing. Residents did, however, execute more educational actions, which is consistent with the overarching intent of any educational intervention. PMID- 29383066 TI - Do End-of-Rotation and End-of-Shift Assessments Inform Clinical Competency Committees' (CCC) Decisions? AB - Introduction: Clinical Competency Committees (CCC) require reliable, objective data to inform decisions regarding assignment of milestone proficiency levels, which must be reported to the Accreditation Council for Graduate Medical Education. After the development of two new assessment methods, the end-of-shift (EOS) assessment and the end-of-rotation (EOR) assessment, we sought to evaluate their performance. We report data on the concordance between these assessments, as well as how each informs the final proficiency level determined in biannual CCC meetings. We hypothesized that there would be a high concordance level between the two assessment methods, including concordance of both the EOS and EOR with the final proficiency level designation by the CCC. Methods: The residency program is an urban academic four-year emergency medicine residency with 48 residents. After their shifts in the emergency department (ED), residents handed out EOS assessment forms asking about individual milestones from 15 subcompetencies to supervising physicians, as well as triggered electronic EOR doctor (EORd) assessments to supervising doctors and EOR-nurse (EORn) to nurses they had worked with after each two-week ED block. EORd assessments contained the full proficiency level scale from 16 subcompetencies, while EORn assessments contained four subcompetencies. Data reports were generated after each six-month assessment period and data was aggregated. We calculated Spearman's rank order correlations for correlations between assessment types and between assessments and final CCC proficiency levels. Results: Over 24 months, 5,234 assessments were completed. The strongest correlations with CCC proficiency levels were the EORd for the immediate six-month assessment period prior (rs 0.71-0.84), and the CCC proficiency levels from the previous six-months (rs 0.83-0.92). EOS assessments had weaker correlations (rs 0.49 to 0.62), as did EORn (rs 0.4 to 0.73). Conclusion: End-of-rotation assessments completed by supervising doctors are most highly correlated with final CCC proficiency level designations, while end-of shift assessments and end-of-rotation assessments by nurses did not correlate strongly with final CCC proficiency levels, both with overestimation of levels noted. Every level of proficiency the CCC assigned appears to be highly correlated with the designated level in the immediate six-month period, perhaps implying CCC members are biased by previous level assignments. PMID- 29383067 TI - Experience Within the Emergency Department and Improved Productivity for First Year Residents in Emergency Medicine and Other Specialties. AB - Introduction: Resident productivity is an important educational and operational measure in emergency medicine (EM). The ability to continue effectively seeing new patients throughout a shift is fundamental to an emergency physician's development, and residents are integral to the workforce of many academic emergency departments (ED). Our previous work has demonstrated that residents make gains in productivity over the course of intern year; however, it is unclear whether this is from experience as a physician in general on all rotations, or specific to experience in the ED. Methods: This was a retrospective cohort study, conducted in an urban academic hospital ED, with a three-year EM training program in which first-year residents see new patients ad libitum. We evaluated resident shifts for the total number of new patients seen. We constructed a generalized estimating equation to predict productivity, defined as the number of new patients seen per shift, as a function of the week of the academic year, the number of weeks spent in the ED, and their interaction. Off-service residents' productivity in the ED was analyzed in a secondary analysis. Results: We evaluated 7,779 EM intern shifts from 7/1/2010 to 7/1/2016. Interns started at 7.16 (95% confidence interval [CI] [6.87 - 7.45]) patients per nine-hour shift, with an increase of 0.20 (95% CI [0.17 - 0.24]) patients per shift for each week in the ED, over 22 weeks, leading to 11.5 (95% CI [10.6 - 12.7]) patients per shift at the end of their training in the ED. The effects of the week of the academic year and its interaction with weeks in the ED were not significant. We evaluated 2,328 off-service intern shifts, in which off-service residents saw 5.43 (95% CI [5.02 - 5.84]) patients per nine-hour shift initially, with 0.46 additional patients per week in the ED (95% CI [0.25 - 0.68]). The weeks of the academic year were not significant. Conclusion: Intern productivity in EM correlates with time spent training in the ED, and not with experience on other rotations. Accordingly, an EM intern's productivity should be evaluated relative to their aggregate time in the ED, rather than the time in the academic year. PMID- 29383068 TI - Emergency Medicine Student End-of-Rotation Examinations: Where Are We Now? PMID- 29383069 TI - Implementing a Team-Based Fourth-Year Medical Student Rotation in Emergency Medicine. PMID- 29383070 TI - Development of a Case-based Reading Curriculum and Its Effect on Resident Reading. AB - Textbook reading plays a foundational role in a resident's knowledge base. Many residency programs place residents on identical reading schedules, regardless of the clinical work or rotation the resident is doing. We sought to develop a reading curriculum that takes into account the clinical work a resident is doing so their reading curriculum corresponds with their clinical work. Preliminary data suggests an increased amount of resident reading and an increased interest in reading as a result of this change to their reading curriculum. PMID- 29383071 TI - Free Open Access Medical Education (FOAM) Resources in a Team-Based Learning Educational Series. AB - Although Free Open Access Medical Education (FOAM) has become popular within emergency medicine, concerns exist regarding its role in resident education. We sought to develop an educational intervention whereby residents could review FOAM resources while maintaining faculty oversight. We created a novel curriculum pairing FOAM from the Academic Life in Emergence Medicine (ALiEM) Approved Instructional Resources (Air) series with a team-based learning (TBL) format. Residents have an opportunity to engage with FOAM in a structured setting with faculty input on possible practice changes. This series has been well-received by residents and appears to have increased engagement with core content material. Qualitative feedback from residents on this series has been positive and we believe this is the first described use of TBL in emergency medicine. PMID- 29383072 TI - Bringing the Flipped Classroom to Day 1: A Novel Didactic Curriculum for Emergency Medicine Intern Orientation. AB - Most emergency medicine (EM) residency programs provide an orientation program for their incoming interns, with the lecture being the most common education activity during this period. Our orientation program is designed to bridge the gap between undergraduate and graduate medical education by ensuring that all learners demonstrate competency on Level 1 Milestones, including medical knowledge (MK). To teach interns core medical knowledge in EM, we reformulated orientation using the flipped-classroom model by replacing lectures with small group, case-based discussions. Interns demonstrated improvement in medical knowledge through higher scores on a posttest. Evaluation survey results were also favorable for the flipped-classroom teaching format. PMID- 29383073 TI - Using Medical Student Quality Improvement Projects to Promote Evidence-Based Care in the Emergency Department. AB - Introduction: The Association of American Medical Colleges' (AAMC) initiative for Core Entrustable Professional Activities for Entering Residency includes as an element of Entrustable Professional Activity 13 to "identify system failures and contribute to a culture of safety and improvement." We set out to determine the feasibility of using medical students' action learning projects (ALPs) to expedite implementation of evidence-based pathways for three common patient diagnoses in the emergency department (ED) setting (Atrial fibrillation, congestive heart failure, and pulmonary embolism). Methods: These prospective quality improvement (QI) initiatives were performed over six months in three Northeastern PA hospitals. Emergency physician mentors were recruited to facilitate a QI experience for third-year medical students for each project. Six students were assigned to each mentor and given class time and network infrastructure support (information technology, consultant experts in lean management) to work on their projects. Students had access to background network data that revealed potential for improvement in disposition (home) for patients. Results: Under the leadership of their mentors, students accomplished standard QI processes such as performing the background literature search and assessing key stakeholders' positions that were involved in the respective patient's care. Students effectively developed flow diagrams, computer aids for clinicians and educational programs, and participated in recruiting champions for the new practice standard. They met with other departmental clinicians to determine barriers to implementation and used this feedback to help set specific parameters to make clinicians more comfortable with the changes in practice that were recommended. All three clinical practice guidelines were initiated at consummation of the students' projects. After implementation, 86% (38/44) of queried ED providers felt comfortable with medical students being a part of future ED QI initiatives, and 84% (26/31) of the providers who recalled communicating with students on these projects felt they were effective. Conclusion: Using this novel technique of aligning small groups of medical students with seasoned mentors, it is feasible for medical students to learn important aspects of QI implementation and allows for their engagement to more efficiently move evidence-based medicine from the literature to the bedside. PMID- 29383074 TI - Exploratory Application of Augmented Reality/Mixed Reality Devices for Acute Care Procedure Training. AB - Introduction: Augmented reality (AR), mixed reality (MR), and virtual reality devices are enabling technologies that may facilitate effective communication in healthcare between those with information and knowledge (clinician/specialist; expert; educator) and those seeking understanding and insight (patient/family; non-expert; learner). Investigators initiated an exploratory program to enable the study of AR/MR use-cases in acute care clinical and instructional settings. Methods: Academic clinician educators, computer scientists, and diagnostic imaging specialists conducted a proof-of-concept project to 1) implement a core holoimaging pipeline infrastructure and open-access repository at the study institution, and 2) use novel AR/MR techniques on off-the-shelf devices with holoimages generated by the infrastructure to demonstrate their potential role in the instructive communication of complex medical information. Results: The study team successfully developed a medical holoimaging infrastructure methodology to identify, retrieve, and manipulate real patients' de-identified computed tomography and magnetic resonance imagesets for rendering, packaging, transfer, and display of modular holoimages onto AR/MR headset devices and connected displays. Holoimages containing key segmentations of cervical and thoracic anatomic structures and pathology were overlaid and registered onto physical task trainers for simulation-based "blind insertion" invasive procedural training. During the session, learners experienced and used task-relevant anatomic holoimages for central venous catheter and tube thoracostomy insertion training with enhanced visual cues and haptic feedback. Direct instructor access into the learner's AR/MR headset view of the task trainer was achieved for visual-axis interactive instructional guidance. Conclusion: Investigators implemented a core holoimaging pipeline infrastructure and modular open-access repository to generate and enable access to modular holoimages during exploratory pilot stage applications for invasive procedure training that featured innovative AR/MR techniques on off-the-shelf headset devices. PMID- 29383075 TI - Creating a Vision for Education Leadership. PMID- 29383076 TI - Calling All Curators: A Novel Approach to Individualized Interactive Instruction. AB - With the increasing influence of the "Free Open Access Medical Education" (FOAM or FOAMed) movement, it is critical that medical educators be engaged with FOAM in order to better inform and direct their learners, who likely regularly consume these materials. In 2012, the Accreditation Council for Graduate Medical Education (ACGME)/Residency Review Committee (RRC) began to permit 20% of emergency medicine (EM) residents' didactics hours to be earned outside of weekly conference, as "Individualized Interactive Instruction" (III) credits.1 We describe a digital course in EM, "Asynchrony," as an approach to FOAM to meet these III standards. Asynchrony is geared toward EM residents using FOAM and other online learning tools, curated by faculty into narrative, topic-specific educational modules. Each module requires residents to complete a topic assignment, participate in a discussion board, and pass a quiz to earn ACGME approved III didactic credit; all of this is tracked and filed in an online learning management system. PMID- 29383077 TI - Development of a Novel Ultrasound-guided Peritonsillar Abscess Model for Simulation Training. AB - Introduction: Peritonsillar abscess (PTA) is the most common deep space infection of the head and neck presenting to emergency departments.1 No commercial PTA task trainer exists for simulation training. Thus, resident physicians often perform their first PTA needle aspiration in the clinical setting, knowing that carotid artery puncture and hemorrhage are serious and devastating complications. While several low-fidelity PTA task trainers have been previously described, none allow for ultrasound image acquisition.6-9 We sought to create a cost-effective and realistic task trainer that allows trainees to acquire both diagnostic ultrasound and needle aspiration skills while draining a peritonsillar abscess. Methods: We built the task trainer with low-cost, replaceable, and easily cleanable materials. A damaged airway headskin was repurposed to build the model. A mesh wire cylinder attached to a wooden base was fashioned to provide infrastructure. PTAs were simulated with a water and lotion solution inside a water balloon that was glued to the bottom of a paper cup. The balloon was fully submerged with ordnance gelatin to facilitate ultrasound image acquisition, and an asymmetric soft palate and deviated uvula were painted on top after setting. PTA cups were replaced after use. We spent eight hours constructing three task trainers and used 50 PTA cups for a total cost <$110. Results: Forty-six emergency medicine (EM) residents performed PTA needle aspirations using the task trainers and were asked to rate ultrasound image realism, task trainer realism, and trainer ease of use on a five-point visual analog scale, with five being very realistic and easy. Sixteen of 46 (35%) residents completed the survey and reported that ultrasound images were representative of real PTAs (mean 3.41). They found the model realistic (mean 3.73) and easy to use (mean 4.08). Residents rated their comfort with the drainage procedure as 2.07 before and 3.64 after practicing on the trainer. Conclusion: This low-cost, easy-to-construct simulator allows for ultrasound image acquisition while performing PTA needle aspirations and is the first reported of its kind. Educators from EM and otolaryngology can use this model to educate inexperienced trainees, thus ultimately improving patient safety in the clinical setting. PMID- 29383078 TI - Anything but Shadowing! Early Clinical Reasoning in Emergency Department Improves Clinical Skills. AB - Introduction: Transitioning from the pre-clinical environment to clerkships poses a challenge to students and educators alike. Students along with faculty developed the Clinical Reasoning Elective (CRE) to provide pre-clinical students exposure to patients in the emergency department and the opportunity to build illness scripts and practice clinical skills with longitudinal mentorship in a low-stakes environment before entering clerkships. It is a voluntary program. Each year, the CRE has received overwhelming positive feedback from students. The objective of this study is to determine if the CRE improved students' clinical skills and reported comfort in their skills. Methods: We examined the relationships between students' self-reported participation in the CRE and their individual scores on a comprehensive clinical assessment (CCA) at the end of the pre-clerkship period. A total of 178 students took the CCA exam in 2016. Of these, 113 participated in the CRE and 65 did not. Seven students who participated in CRE did not complete the exit survey and were omitted from analysis. We performed regression analysis and dichotomous (participants/nonparticipants) comparisons of means with t-tests. Survey of student reactions was collected. Results: Participants completed an average of 10 sessions over the course of the program (range=1-20). Involvement in the CRE was associated with significantly increased scores on Abdominal History; Pulmonary Physical Exam; Overall History-Taking; Overall Communication; and Overall Physical Exam (p<0.05). Nearly all students (97%) reported that the program offered opportunities to enhance clinical skills, increased their comfort with patients, and better prepared them for their clinical years. Conclusion: There were measurable improvements in clinical skills performance for students who participated in CRE. As many schools seek to incorporate early clinical exposure to their curricula, this program provides a successful framework to provide meaningful clinical exposure to real patients that also shows objective benefits to students' clinical skills. PMID- 29383079 TI - Interprofessional Emergency Training Leads to Changes in the Workplace. AB - Introduction: Preventable mistakes occur frequently and can lead to patient harm and death. The emergency department (ED) is notoriously prone to such errors, and evidence suggests that improving teamwork is a key aspect to reduce the rate of error in acute care settings. Only a few strategies are in place to train team skills and communication in interprofessional situations. Our goal was to conceptualize, implement, and evaluate a training module for students of three professions involved in emergency care. The objective was to sensitize participants to barriers for their team skills and communication across professional borders. Methods: We developed a longitudinal simulation-enhanced training format for interprofessional teams, consisting of final-year medical students, advanced trainees of emergency nursing and student paramedics. The training format consisted of several one-day training modules, which took place twice in 2016 and 2017. Each training module started with an introduction to share one's roles, professional self-concepts, common misconceptions, and communication barriers. Next, we conducted different simulated cases. Each case consisted of a prehospital section (for paramedics and medical students), a handover (everyone), and an ED section (medical students and emergency nurses). After each training module, we assessed participants' "Commitment to Change." In this questionnaire, students were anonymously asked to state up to three changes that they wished to implement as a result of the course, as well as the strength of their commitment to these changes. Results: In total, 64 of 80 participants (80.0%) made at least one commitment to change after participating in the training modules. The total of 123 commitments was evenly distributed over four emerging categories: communication, behavior, knowledge and attitude. Roughly one third of behavior- and attitude-related commitments were directly related to interprofessional topics (e.g., "acknowledge other professions' work"), and these were equally distributed among professions. At the two-month follow-up, 32 participants (50%) provided written feedback on their original commitments: 57 of 62 (91.9%) commitments were at least partly realized at the follow-up, and only five (8.1%) commitments lacked realization entirely. Conclusion: A structured simulation-enhanced intervention was successful in promoting change to the practice of emergency care, while training teamwork and communication skills jointly. PMID- 29383080 TI - A Novel Approach to Medical Student Peer-assisted Learning Through Case-based Simulations. AB - Introduction: Peer-assisted learning (PAL) is the development of new knowledge and skills through active learning support from peers. Benefits of PAL include introduction of teaching skills for students, creation of a safe learning environment, and efficient use of faculty time. We present a novel approach to PAL in an emergency medicine (EM) clerkship curriculum using an inexpensive, tablet-based app for students to cooperatively present and perform low-fidelity, case-based simulations that promotes accountability for student learning, fosters teaching skills, and economizes faculty presence. Methods: We developed five clinical cases in the style of EM oral boards. Fourth-year medical students were each assigned a unique case one week in advance. Students also received an instructional document and a video example detailing how to lead a case. During the 90-minute session, students were placed in small groups of 3-5 students and rotated between facilitating their assigned cases and participating as a team for the cases presented by their fellow students. Cases were supplemented with a half mannequin that can be intubated, airway supplies, and a tablet-based app (SimMon, $22.99) to remotely display and update vital signs. One faculty member rotated among groups to provide additional assistance and clarification. Three EM faculty members iteratively developed a survey, based on the literature and pilot tested it with fourth-year medical students, to evaluate the course. Results: 135 medical students completed the course and course evaluation survey. Learner satisfaction was high with an overall score of 4.6 on a 5-point Likert scale. In written comments, students reported that small groups with minimal faculty involvement provided a safe learning environment and a unique opportunity to lead a group of peers. They felt that PAL was more effective than traditional simulations for learning. Faculty reported that students remained engaged and required minimal oversight. Conclusion: Unlike other simulations, our combination of brief, student-assisted cases using low-fidelity simulation provides a cost-, resource- and time-effective way to implement a medical student clerkship educational experience. PMID- 29383081 TI - A Cognitive Apprenticeship-Based Faculty Development Intervention for Emergency Medicine Educators. AB - In just a few years of preparation, emergency medicine (EM) trainees must achieve expertise across the broad spectrum of skills critical to the practice of the specialty. Though education occurs in many contexts, much learning occurs on the job, caring for patients under the guidance of clinical educators. The cognitive apprenticeship framework, originally described in primary and secondary education, has been applied to workplace-based medical training. The framework includes a variety of teaching methods: scaffolding, modeling, articulation, reflection, and exploration, applied in a safe learning environment. Without understanding these methods within a theoretical framework, faculty may not apply the methods optimally. Here we describe a faculty development intervention during which participants articulate, share, and practice their own applications of cognitive-apprenticeship methods to learners in EM. We summarize themes identified by workshop participants, and provide suggestions for tailoring the application of these methods to varying levels of EM learners. The cognitive apprenticeship framework allows for a common understanding of the methods used in clinical teaching toward independence. Clinical educators should be encouraged to reflect critically on their methods, while being offered the opportunity to share and learn from others. PMID- 29383082 TI - Filling the Gap: Simulation-based Crisis Resource Management Training for Emergency Medicine Residents. AB - Introduction: In today's team-oriented healthcare environment, high-quality patient care requires physicians to possess not only medical knowledge and technical skills but also crisis resource management (CRM) skills. In emergency medicine (EM), the high acuity and dynamic environment makes CRM skills of physicians particularly critical to healthcare team success. The Accreditation Council of Graduate Medicine Education Core Competencies that guide residency program curriculums include CRM skills; however, EM residency programs are not given specific instructions as to how to teach these skills to their trainees. This article describes a simulation-based CRM course designed specifically for novice EM residents. Methods: The CRM course includes an introductory didactic presentation followed by a series of simulation scenarios and structured debriefs. The course is designed to use observational learning within simulation education to decrease the time and resources required for implementation. To assess the effectiveness in improving team CRM skills, two independent raters use a validated CRM global rating scale to measure the CRM skills displayed by teams of EM interns in a pretest and posttest during the course. Results: The CRM course improved leadership, problem solving, communication, situational awareness, teamwork, resource utilization and overall CRM skills displayed by teams of EM interns. While the improvement from pretest to posttest did not reach statistical significance for this pilot study, the large effect sizes suggest that statistical significance may be achieved with a larger sample size. Conclusion: This course can feasibly be incorporated into existing EM residency curriculums to provide EM trainees with basic CRM skills required of successful emergency physicians. We believe integrating CRM training early into existing EM education encourages continued deliberate practice, discussion, and improvement of essential CRM skills. PMID- 29383083 TI - Preparing Emergency Medicine Residents to Disclose Medical Error Using Standardized Patients. AB - Introduction: Emergency Medicine (EM) is a unique clinical learning environment. The American College of Graduate Medical Education Clinical Learning Environment Review Pathways to Excellence calls for "hands-on training" of disclosure of medical error (DME) during residency. Training and practicing key elements of DME using standardized patients (SP) may enhance preparedness among EM residents in performing this crucial skill in a clinical setting. Methods: This training was developed to improve resident preparedness in DME in the clinical setting. Objectives included the following: the residents will be able to define a medical error; discuss ethical and professional standards of DME; recognize common barriers to DME; describe key elements in effective DME to patients and families; and apply key elements during a SP encounter. The four-hour course included didactic and experiential learning methods, and was created collaboratively by core EM faculty and subject matter experts in conflict resolution and healthcare simulation. Educational media included lecture, video exemplars of DME communication with discussion, small group case-study discussion, and SP encounters. We administered a survey assessing for preparedness in DME pre-and post-training. A critical action checklist was administered to assess individual performance of key elements of DME during the evaluated SP case. A total of 15 postgraduate-year 1 and 2 EM residents completed the training. Results: After the course, residents reported increased comfort with and preparedness in performing several key elements in DME. They were able to demonstrate these elements in a simulated setting using SP. Residents valued the training, rating the didactic, SP sessions, and overall educational experience very high. Conclusion: Experiential learning using SP is effective in improving resident knowledge of and preparedness in performing medical error disclosure. This educational module can be adapted to other clinical learning environments through creation of specialty-specific scenarios. PMID- 29383084 TI - Sphingosine 1-Phosphate signaling controls mitosis. PMID- 29383085 TI - Day-to-day blood pressure variability and dementia. PMID- 29383086 TI - Targeting RIG-I or STING promotes epithelial regeneration. PMID- 29383087 TI - Nucleotide excision repair as a targetable vulnerability in leukemia. PMID- 29383088 TI - Tailoring treatment for MALT lymphoma patients: where do we stand now? PMID- 29383089 TI - Consequences of cure: subsequent therapy-related cancers. PMID- 29383090 TI - Expert central review in lymphoma diagnosis. Is there a need? PMID- 29383091 TI - Sodium fluoride induces apoptosis in mouse splenocytes by activating ROS dependent NF-kappaB signaling. AB - In this study, we investigated the roles of reactive oxygen species (ROS) and nuclear factor-kappaB (NF-kappaB) signaling in sodium fluoride-induced DNA damage and apoptosis in mouse splenocytes. Intragastric administration of 12, 24 or 48 mg/kg sodium fluoride resulted in a time- and dose-dependent increase in DNA fragmentation and apoptosis in mouse splenocytes on days 21 and 42. High ROS levels correlated with increased levels of phosphorylated IkappaB kinase and NF kappaB p65 and decreased levels of inhibitory kappa B protein in splenocytes from mice treated with sodium fluoride. Moreover, splenocytes from sodium fluoride treated mice showed high expression of pro-apoptotic proteins, including Bim, Bax, Bak, caspase-3 and poly ADP-ribose polymerase, and low expression of the anti-apoptotic proteins BcL-2 and BcL-xL. These results show that sodium fluoride induces apoptosis in mouse splenocytes by enhancing ROS-dependent NF-kappaB signaling. PMID- 29383093 TI - Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model. AB - Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China, accounting for 90% of all esophageal carcinoma cases. Hence, identifying drug targets for prevention and treatment of ESCC is essential. Due to its critical role in the regulation of cell apoptosis, Mcl-1 holds great potential as a target for treatment against ESCC. In current study, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model of test whether A-1210477, a Mcl-1 small molecular inhibitor, could repress ESCC development. We showed that A-1210477 treatment decreased ESCC formation and animal weight loss in a dose dependent manner. We detected decreased cellular proliferation in A-1210477-treated ESCC tissue by Ki67 expression. Moreover, A-1210477 treatment increased the number of apoptotic cells in ESCC tissues. Our study clearly demonstrates the contribution of Mcl-1 to ESCC development through promoting cell proliferation and inhibition of apoptosis, and provides a strong evidence for further evaluation of A-1210477 for treating ESCC. PMID- 29383092 TI - Identification of the histone lysine demethylase KDM4A/JMJD2A as a novel epigenetic target in M1 macrophage polarization induced by oxidized LDL. AB - Oxidized low density lipoprotein (oxLDL) induces macrophage activation, an event essential for atherosclerosis. Emerging evidence supports that epigenetic regulation plays important roles in macrophage activation and function. However, it remains unclear which epigenetic modulator is responsible for oxLDL-induced macrophage activation. Here, we identify for the first time KDM4A (JMJD2A) as an epigenetic modifying enzyme that controls oxLDL-induced pro-inflammatory M1 polarization of macrophages. OxLDL triggered M1 polarization of murine and human macrophages, characterized by expression of iNOS and robust production of inflammatory cytokines (e.g., TNF-alpha, MCP-1, IL-1beta). In contrast, protein level of the M2 marker Arg1 was clearly decreased after treated with oxLDL. Notably, exposure to oxLDL resulted in markedly increased expression of KDM4A in macrophages. Functionally, shRNA knockdown of KDM4A significantly impaired M1 polarization and expression of inflammatory cytokines induced by oxLDL, accompanied by increased expression of Arg1 and VEGF. However, inhibition of KDM4A by shRNA or the pan-selective KDM inhibitor JIB-04 did not affect oxLDL mediated activation of the NF-kappaB and hypoxia inducible factor (HIF) pathways, and vice versa. In addition, JIB-04 induced apoptosis of macrophages in a dose dependent manner, an event attenuated by oxLDL. Together, these findings argue that KDM4A might represent a novel epigenetic modulator that acts to direct oxLDL induced M1 polarization of macrophages, while its up-regulation is independent of NF-kappaB and HIF activation, two signals critical for pro-inflammatory activation of macrophages. They also suggest that KDM4A might serve as a potential target for epigenetic therapy in prevention and treatment of inflammatory diseases such as atherosclerosis. PMID- 29383094 TI - Simultaneous detection of genetic and copy number alterations in BRCA1/2 genes. AB - Germline mutations in BRCA1 and BRCA2 genes (BRCA1/2) predispose to hereditary breast and ovarian cancer syndrome (HBOC), and their dysregulation increases the risk of cancers. The detection of pathogenic BRCA1/2 variants is essential for the diagnosis and prevention of HBOC, and for offering treatment decisions for patients. Therefore, there is a growing demand for the development of accurate, rapid assay systems that simultaneously detect pathogenic variants and copy number alterations. Here, we tested Thermo Fisher Scientific's newly developed Oncomine(r)BRCA1/2 Panel. We showed that all mutations in standard reference DNA were detected with high accuracy, and that values of allelic fractions were detected with high concordance (R2 = 0.9986). The Oncomine(r)BRCA1/2 Panel detected 21 pathogenic germline variants in 147 patients with breast and/or ovarian cancer, of which 20 were detected by the previously-launched Ion AmpliSeqTM BRCA1/2 Panel, except for one frameshift mutation. The Oncomine(r)BRCA1/2 Panel precisely captured one additional frameshift mutation, which is difficult to detect because of the homopolymer site. Large genomic deletion was identified in one sample, which was previously detected by multiplex ligation-dependent probe amplification. Oncomine(r)BRCA1/2 Panel could accurately detect pathogenic variant and copy number alteration, and be an alternative assay to investigate BRCA1/2 germline and somatic mutations. PMID- 29383095 TI - Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas. AB - Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ~500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade ("double hit") diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas. PMID- 29383096 TI - Hypoxia-inducible factor-1alpha promotes cell survival during ammonia stress response in ovarian cancer stem-like cells. AB - Ammonia is a toxic by-product of metabolism that causes cellular stresses. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism to survive against its toxicity have yet to be identified. We demonstrated that the hypoxia-inducible factor-1alpha (HIF-1alpha) is stabilized and activated by ammonia stress. HIF-1alpha activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation under ammonia stress and glutamine-dependent metabolism in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1alpha counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1alpha in a biphasic ammonia stress management in the cancer stem-like cells where GS facilitates cell proliferation and HIF-1alpha contributes to the metabolic remodeling in energy fuel usage resulting in attenuated proliferation but conversely promoting cell survival. PMID- 29383097 TI - Efficacy of decitabine-loaded gelatinases-stimuli nanoparticles in overcoming cancer drug resistance is mediated via its enhanced demethylating activity to transcription factor AP-2 epsilon. AB - Hypermethylation of the transcription factor AP-2 epsilon (TFAP2E) gene affects 5 fluorouridine (5-FU) resistance in gastric cancer (GC) patients. The epigenetic inhibitor 5-Aza-2'-deoxycytidine (DAC), which reverses DNA methylation by targeting DNA methyltransferases (DNMTs), has potential to sensitize GC to 5-FU. Nevertheless, DNA demethylation only DAC transiently occurs since DAC is unstable in aqueous solutions, which limits its potential. Here we developed intelligent nanoparticles (NPs) comprising gelatinase with polyethylene glycol (PEG) and poly epsilon-caprolactone) (PCL) to specifically deliver DAC (DAC-TNPs) to tumors. DAC carrying PEG-PCL NPs (DAC-NPs) lacking gelatinase features served as controls. 72 hours after administration of DAC-TNPs or DAC-NPs, 5-FU was sequentially applied to GC cells and human GC xenografts in nude mice. Both in vitro and in vivo evaluations demonstrated that the combination treatment of DAC-TNPs and 5-FU greatly improved tumor suppression in GC cells and mouse xenograft models with hypermethylation TFAP2E (MKN45 cells). We thus propose that the sequential administration of DAC-TNPs and 5-FU could be significant in the development of novel targeted therapies. PMID- 29383098 TI - CAPE-pNO2 ameliorated diabetic nephropathy through regulating the Akt/NF-kappaB/ iNOS pathway in STZ-induced diabetic mice. AB - Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. This study aimed to determine the effects and potential mechanism of caffeic acid para-nitro phenethyl ester (CAPE-pNO2), a derivative of caffeic acid phenethyl ester (CAPE), on DN; In vivo, intraperitoneal injections of streptozotocin (STZ) were used to induce diabetes in mice; then, the mice were intraperitoneally injected daily with CAPE or CAPE-pNO2 for 8 weeks. The mice were sacrificed, and blood samples and kidney tissues were collected to measure biological indexes. The results showed that CAPE and CAPE-pNO2 could lower serum creatinine, blood urea nitrogen, 24-h albumin excretion, malondialdehyde and myeloperoxidase levels and increase superoxide dismutase activity in diabetic mice. According to HE, PAS and Masson staining, these two compounds ameliorated structural changes and fibrosis in the kidneys. In addition, the immunohistochemical and western blot results showed that CAPE and CAPE-pNO2 inhibited inflammation through the Akt/NF-kappaB pathway and prevented renal fibrosis through the TGF-beta/Smad pathway. In vitro, CAPE and CAPE-pNO2 inhibited glomerular mesangial cell (GMC) proliferation, arrested cell cycle progression and suppressed ROS generation. These compounds also inhibited ECM accumulation via regulating the TGF-beta1, which was a similar effect to that of the NF-kappaB inhibitor PDTC. More importantly, CAPE and CAPE-pNO2 could up regulate nitric oxide synthase expression in STZ-induced diabetic mice and HG induced GMCs. CAPE-pNO2 had stronger effects than CAPE both in vivo and in vitro. These data suggest that CAPE-pNO2 ameliorated DN by suppressing oxidative stress, inflammation, and fibrosis via the Akt/NF-kappaB/ iNOS pathway. PMID- 29383099 TI - Oncogenic dependency on beta-catenin in liver cancer cell lines correlates with pathway activation. AB - Hepatocellular carcinoma (HCC) represents a serious public health challenge with few therapeutic options available to cancer patients.Wnt/beta-catenin pathway is thought to play a significant role in HCC pathogenesis. In this study, we confirmed high frequency of CTNNB1 (beta-catenin) mutations in two independent cohorts of HCC patients and demonstrated significant upregulation of beta-catenin protein in the overwhelming majority of HCC patient samples, patient-derived xenografts (PDX) and established cell lines. Using genetic tools validated for target specificity through phenotypic rescue experiments, we went on to investigate oncogenic dependency on beta-catenin in an extensive collection of human HCC cells lines. Our results demonstrate that dependency on beta-catenin generally tracks with its activation status. HCC cell lines that harbored activating mutations in CTNNB1 or displayed elevated levels of non-phosphorylated (active) beta-catenin were significantly more sensitive to beta-catenin siRNA treatment than cell lines with wild-type CTNNB1 and lower active beta-catenin. Finally, significant therapeutic benefit of beta-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system. beta-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of beta catenin, and decreased cancer cell proliferation as measured by Ki67 staining. Taken together, our data highlight fundamental importance of aberrant beta catenin signaling in the maintenance of oncogenic phenotype in HCC. PMID- 29383100 TI - SIRT1 regulates Mxd1 during malignant melanoma progression. AB - In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, gammaH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression. PMID- 29383101 TI - CXCR2+ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion. AB - Although myeloid-derived suppressor cells (MDSCs) have been demonstrated to contribute to tumor initiation, progression and metastasis, however, which MDSC subsets are preferentially expanded and activated, and what's the key molecular mechanism responsible for specific MDSC subsets in promoting tumor progression need to be fully addressed. Here we identify that Ly6GmiLy6CloCD11b+CXCR2+ subpopulation (named CXCR2+ MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis. The proportion of CXCR2+ MDSCs is inversely correlated with the infiltration of CD4+ or CD8+ T cells. Besides, CXCR2+ MDSCs promote breast cancer growth and metastasis to lung and/or lymph node in vivo. Furthermore, CXCR2+ MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6. Moreover, CXCR2+ MDSCs upregulate the expression of immunosuppressive molecules programmed cell death protein 1(PD1), PD1 ligand 1 (PDL1), lymphocyte activation gene 3 protein (LAG3), cytotoxic T lymphocyte antigen 4 (CTLA4), and T cell immunoglobulin domain and mucin domain protein 3 (TIM3) on CD4+ or CD8+ T cells, and induce exhaustion of the activated T cells partially via IFN-gamma. These results demonstrate that CXCR2+ MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2+ MDSCs may be a potential therapeutic target of breast cancer. PMID- 29383102 TI - LncRNA BANCR facilitates vascular smooth muscle cell proliferation and migration through JNK pathway. AB - Deregulated migration and proliferation of vascular smooth muscle cells (VSMCs) acts a crucial role in the pathogenesis of many cardiovascular diseases such as atherosclerosis, coronary heart disease and hypertension. Long noncoding RNAs (lncRNAs) play crucial functional roles in a lot of biological processes such as cell development, cell proliferation, differentiation and invasion. In our study, we demonstrated that the BANCR expression level was upregulated in the atherosclerotic plaques tissues compared to in the normal vessels tissues. TNF alpha could emhance the VSMCs proliferation. The expression level of BANCR and p JNK were upregulated and activated in the proliferating VSMCs. Overexpression of BANCR enhanced VSMCs proliferation and migration. Elevated expression of BANCR induced JNK activation, which can be decreased by the specific JNK inhibitor SP600125. We demonstrated that ectopic expression of BANCR increased the VSMCs proliferation and migration through activating JNK pathway. These data suggested that lncRNA BANCR acts a crucial role in the regulating VSMCs proliferation and migration partly by activating the JNK pathway. PMID- 29383103 TI - YAP regulates PD-L1 expression in human NSCLC cells. AB - Programmed death-ligand 1 (PD-L1) is a membrane protein on tumor cells that binds to the PD-1 receptor expressed on immune cells, leading to the immune escape of tumor cells. Yes-associated protein (YAP) is a main effector of the Hippo/YAP signaling pathway, which plays important roles in cancer development. Here we show that YAP regulates PD-L1 expression in human non-small cell lung cancer (NSCLC) cells. First, we investigated YAP and PD-L1 expression at the protein level in 142 NSCLC samples and 15 normal lung samples. In tumor tissue, immunohistochemistry showed positive staining for YAP and PD-L1, which correlated significantly (n = 142, r = 0.514, P < 0.001). Second, in cell lines that express high levels of PD-L1 (H460, SKLU-1, and H1299), the ratio of p-YAP/YAP was lower and GTIIC reporter activity of the Hippo pathway was higher than those in three cell lines expressing low levels of PD-L1 (A549, H2030, and PC9) (P < 0.05). Third, in the same three cell lines, inhibition of YAP by two small interfering RNAs (siRNAs) decreased the mRNA and protein level of PD-L1 (P < 0.05). Fourth, forced overexpression of the YAP gene rescued the PD-L1 mRNA and protein level after siRNA knockdown targeting 3'UTR of the endogenous YAP gene. Finally, chromatin immunoprecipitation (ChIP) assays using a YAP-specific monoclonal antibody resulted in the precipitation of PD-L1 enhancer region encompassing two putative TEAD binding sites. Our results indicate that YAP regulates the transcription of PD-L1 in NSCLC. PMID- 29383104 TI - CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2 eIF2alpha-ATF4 pathway. AB - Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells. Moreover, cystine starvation induced mitochondrial fragmentation, dysfunction, and ROS production. A mitochondrial ROS scavenger, Necrox-5, can prevent cystine starvation-induced cell death. In addition, cystine starvation was found to activate GCN2, but not PERK, to increase the phosphorylation of eIF2alpha at serine 51, the protein expression of ATF4, and the expression of ATF4 target genes such as CHAC1, which might be downstream of the RIP1/RIP3-MLKL pathway and contribute to cystine-starvation-induced cell death. Knockdown of CHAC1 rescued the cystine-starvation-induced reduction in glutathione (GSH) levels and cell death. Furthermore, N-acetyl-cysteine (NAC), Trolox, and Nec-1 significantly prevented the cystine-starvation-induced increase in intracellular ROS levels, mitochondrial fragmentation and cell death. In summary, these results suggest that CHAC1 degradation of GSH enhances cystine-starvation-induced necroptosis and ferroptosis through the activated GCN2-eIF2alpha-ATF4 pathway in TNBC cells. Our findings improve our understanding of the mechanism underlying cystine-starvation induced TNBC cell death. PMID- 29383105 TI - LncNetP, a systematical lncRNA prioritization approach based on ceRNA and disease phenotype association assumptions. AB - Our knowledge of lncRNA is very limited and discovering novel disease-related long non-coding RNA (lncRNA) has been a major research challenge in cancer studies. In this work, we developed an LncRNA Network-based Prioritization approach, named "LncNetP" based on the competing endogenous RNA (ceRNA) and disease phenotype association assumptions. Through application to 11 cancer types with 3089 common lncRNA and miRNA samples from the Cancer Genome Atlas (TCGA), our approach yielded an average area under the ROC curve (AUC) of 83.87%, with the highest AUC (95.22%) for renal cell carcinoma, by the leave-one-out cross validation strategy. Moreover, we demonstrated the excellent performance of our approach by evaluating the influencing factors including disease phenotype associations, known disease lncRNAs and the numbers of cancer types. Comparisons with previous methods further suggested the integrative importance of our approach. Taking hepatocellular carcinoma (LIHC) as a case study, we predicted four candidate lncRNA genes, RHPN1-AS1, AC007389.1, LINC01116 and BMS1P20 that may serve as novel disease risk factors for disease diagnosis and prognosis. In summary, our lncRNA prioritization strategy can efficiently identify disease related lncRNAs and help researchers better understand the important roles of lncRNAs in human cancers. PMID- 29383106 TI - Analysis of differential gene expression profile identifies novel biomarkers for breast cancer. AB - Breast cancer is the most prevalent cancer diagnosis in women. We aimed to identify biomarkers for breast cancer prognosis. mRNA expression profiling was performed using Gene Chip Human Transcriptome Array 2.0. Microarray analysis and series test of cluster (STC) analysis were used to screen the differential expressed mRNAs and the expression trend of genes. Immumohistochemical staining with 100 clinical specimens was used to validate two differentially expressed genes, ITGA11 and Jab1. In the present study, significantly enriched Gene Ontology (GO) terms and pathways were identified. 26 model profiles were used to summarize the expression pattern of differentially expressed genes. Results of immunohistochemistry were consistent with those of the microarray, in that ITGA11 and Jab1 were differentially expressed with the same trend. Survival analyses using the Kaplan-Meier method demonstrated that breast cancer patients with high levels of either ITGA11 or Jab1 had a significant association with worse prognosis. Our study identified ITGA11 and Jab1 as novel biomarkers for breast cancer. PMID- 29383107 TI - Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers. AB - In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the NEIL2 gene previously identified as "cancer risk modifier" for BRCA2 mutation carriers. To that end, we studied the role of this SNP (rs804271) on NEIL2 transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six BRCA1 and BRCA2 mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on NEIL2 gene expression and oxidative DNA damage accumulation. The second was a set of twenty lymphoblastoid cell lines (LCLs), thirteen BRCA1 mutation carriers and seven non-carriers control, that were used to analyze the correlation between NEIL2 mRNA and/or protein levels, the oxidative and the double stranded break (DSB) DNA damage levels. Our results suggest that an excessive production of NEIL2 enzyme, associated with the SNP, may have a deleterious effect modifying cancer risk susceptibility in BRCA2 mutation carriers. We hypothesize that due to the SNP impact on NEIL2 transcriptional upregulation, a cascade of events may converge in the accumulation of oxidative DNA damage and its posterior conversion into DSBs for this specific group of patients. PMID- 29383108 TI - Sevoflurane preconditioning promotes activation of resident CSCs by transplanted BMSCs via miR-210 in a rat model for myocardial infarction. AB - Objective: To assess the effect of sevoflurane preconditioning (SFpre) on bone marrow mesenchymal stem cells (BMSCs) for the treatment of acute myocardial infarction. Results: 24 hours after the transplantation, decreased apoptosis of implanted BMSCs and up-regulation of cytokines expression were found within the ischemic area in SFpreBMSCs group compared with BMSCs group (P < 0.05). 4 weeks later, SFpreBMSCs group showed more viable implanted BMSCs, CSC-derived cardiomyocytes, and higher vessel and myocardial density within the infarcted region and improved cardiac function, compared with control and BMSCs groups (P < 0.05). Compared with untreated BMSCs, promoted migration, inhibited apoptosis, increased cytokine secretion, and enhanced activation to CSCs were detected in SFpreBMSCs exposed to profound hypoxia and serum deprivation, via up-regulating miR-210 expression (P < 0.05). Conclusions: Sevoflurane preconditioning can protect BMSCs against hypoxia by activating miR-210 expression and promote their paracrine functions and effects on resident CSCs. Methods: After the preconditioning, rat BMSCs (SFpreBMSCs group) were transplanted into rat AMI models, while BMSCs group received unconditioned BMSCs. Apoptosis and paracrine functions of the transplanted BMSCs, angiogenesis, resident cardiac stem cells (CSCs) derived myocardial regeneration, cardiac function and remodeling were assessed at various time points. In vitro experiments were performed to determine the expression of miR-210 in BMSCs exposed to sevoflurane and the effect of sevoflurane on BMSCs' migration, apoptosis and secretion of cytokines under hypoxic condition, as well as cytokine-induced CSCs activation. PMID- 29383109 TI - Landscape of genome-wide age-related DNA methylation in breast tissue. AB - Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm's. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication. 1,214 aDNAm's were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm's with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm's identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm's showed borderline significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51-17.23) and DHRS12 (OR 6.08, 95% CI: 2.33-15.86). A subset of aDNAm's co-localized within vulnerable regions for somatic mutations in cancers including breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm's were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, aDNAm's may be one pathway for increased breast cancer risk with age. PMID- 29383110 TI - EGFR expression in patients with stage III colorectal cancer after adjuvant chemotherapy and on cancer cell function. AB - The epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway plays a crucial role in the carcinogenesis, invasion and metastasis of colorectal cancer (CRC). However, its role in the prognosis and prediction of relapse in patients with stage III CRC after adjuvant chemotherapy remains controversial. In the present study, the clinicopathological features of 173 patients with stage III CRC who underwent radical resection and adjuvant chemotherapy with the fluoropyrimidine/folinic acid, and oxaliplatin (FOLFOX) regimen, and their prognostic values of EGFR expression were retrospectively analyzed. By conducting an in vitro CRC cell line study through the knockdown of EGFR expression, we analyzed cell proliferation, colony formation and migration. Positive EGFR expression and an abnormal postoperative serum carcinoembryonic antigen (CEA) level were found to be significant independent negative predictive factors for postoperative relapse. Furthermore, positive EGFR expression was a significant independent negative prognostic factor for disease-free survival (DFS) and overall survival (OS). Additionally, an in vitro cell line study showed that the knockdown of EGFR expression significantly reduced CRC cell proliferation, colony formation and migration. The results of in vitro and in vivo experiments demonstrated that EGFR expression had a prognostic value for OS and DFS, as well as predictive roles for postoperative relapse, in patients with stage III CRC. By analyzing both EGFR expression and the postoperative CEA, the patients with stage III CRC who were at a high risk of postoperative relapse, or mortality following adjuvant chemotherapy could be identified. In short, CRC cells with EGFR expression would exhibit a highly malignant behavior. PMID- 29383111 TI - MicroRNA-182 targets protein phosphatase 1 regulatory inhibitor subunit 1C in glioblastoma. AB - Glioblastoma (GBM) is an incurable cancer, with mean post-diagnosis survival time of 14-16 months. Metagenomic analysis by The Cancer Genome Atlas (TCGA) program has identified microRNA-182-5p (miR-182-5p or miR-182) as the only miRNA associated with favorable disease prognosis and temozolomide (TMZ) susceptibility. Previous reports have indicated that miR-182 down regulates expression of BCL2L12, c-MET, and HIF2A. However, other messenger RNA (mRNA) targets of miR-182 have not been validated which would explain its association with a favorable disease prognosis. In situ analysis revealed that protein phosphatase 1 regulatory inhibitor subunit 1C (PPP1R1C) is a putative target of miR-182. PPP1R1C protein and RNA expression as assessed by tissue microarray and quantitative real time PCR, respectively, was inversely correlated to miR-182 expression in glioblastoma patients and in the metastatic glioblastoma cell line U87-MG. Reporter assays using PPP1R1C 3' untranslated region (UTR) showed that miR-182 can interact with the wild-type but not a miR-182-5-seed mutant. Ectopic expression of miR-182 mimic in the U87-MG cell line significantly decreased proliferation as well as suppressed in vitro migration and invasion. Opposite observations were made when the non-malignant neuronal cell line HCN-2 was transfected with anti-miR-182 antagomir. The miR-182 mimic or siRNA targeting PPP1R1C induced TMZ susceptibility indicating that decreased susceptibility to TMZ in GBM patients might be attributed to high expression of PPP1R1C. Inverse correlation of PPP1R1C mRNA and miR-182 levels in 20 GBM patients confirmed the same. Cumulatively, our results indicate that loss of miR-182 leads to increased expression of PPP1R1C which in part explain disease progression and resistance to TMZ therapy. PMID- 29383112 TI - Unique circulating microRNAs in relation to EGFR mutation status in Japanese smoker male with lung adenocarcinoma. AB - The incidence of lung adenocarcinoma has been increasing recently in smokers. The molecular target therapy has been developed for lung adenocarcinoma patients harboring EGFR gene mutation. However, the treatment modalities for patients without mutation are currently limited. Thus, analysis of EGFR gene mutation status at early stage is important strategy to classify the patients for improving treatments and prognosis efficiently. This study aimed to identify microRNA (miRNA) signature in relation to mutation status in EGFR gene in early stage of lung adenocarcinoma male patients with smoking history. MiRNA profiles were assessed by microarray in paired plasma and tissue pooled from 10 EGFR wild type (EGFR-wt) and 10 EGFR mutated (EGFR-mut) patients. Expressions of selected miRNAs were verified further by real-time qRT-PCR in 83 plasma samples consisting of 55 EGFR-wt patients and 28 EGFR-mut patients and their correlation with clinicopathological parameters and EGFR gene mutation status were evaluated. We found that seven miRNAs (miR-16-5p, miR-23a-3p, miR-103a-3p, miR122-5p, miR-223 3p, miR-346 and miR-451a) were differentially expressed in stage I and stage I+II. Especially, miR-23a-3p was only miRNA shown higher expression in EGFR-wt patients than EGFR-mut patients. Thus, our findings could be useful non-invasive biomarkers to differentiate mutation status in EGFR gene in smoker lung adenocarcinoma male patients. PMID- 29383113 TI - Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma. AB - HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed ~60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed ~60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion. PMID- 29383114 TI - Pir-B inhibits the DC function and disturbs the Th17/Treg balance in lung cancer murine model. AB - Paired immunoglobulin-like receptor B (Pir-B) was an inhibitory receptor expressed on the surfaces of dendritic cells (DCs). Pir-B inhibit T helper (Th) 1 response and induce Th2 cell differentiation, leading to the imbalance of Th1/Th2 cells. However, the role and potential mechanism of Pir-B on the balance of Th17/regulatory T cells (Tregs) is still largely unknown in lung cancer murine model. In the present study, the DC function and Th17/Treg balance were destroyed during the progression of lung cancer and this was accompanied by an increased expression of Pir-B. After transfection with Pir-B siRNA or administration of IL 6 in vitro, the decreased response of Th17 cells were restored, whereas the augmented differentiation of Tregs was diminished. Further, the transfer of Pir-B silenced DCs or the injection of IL-6 in vivo increased Th17 response and decreased Treg differentiation. Our study has demonstrated that Pir-B inhibits the DC function and disturbs the Th17/Treg balance via IL-6 pathway during the progression of lung cancer, contributing to inhibited antitumor immunity. PMID- 29383115 TI - Circulating CD9+/GFAP+/survivin+ exosomes in malignant glioma patients following survivin vaccination. AB - Glioma cells release exosomes in culture and into the extracellular matrix in vivo. These nanobodies transport an array of biomolecules and are capable of mediating cell-cell communication. Circulating exosomes in cancer patients may be indicative of disease status and response to therapy. The inhibitor of apoptosis protein (IAP) survivin (SVN) promotes cancer cell proliferation, local immune suppression and resistance to chemotherapy and it is a potential cancer biomarker. We used imaging flow cytometry to perform quantitative measurements of circulating SVN+ exosomes in the serum of malignant glioma patients undergoing investigational treatment with an anti-survivin vaccine (SurVaxM). Serum from glioma patients contained abundant CD9+ exosomes with both SVN and glial fibrillary acidic protein (GFAP) on their surface. Survivin and GFAP were evaluated both independently and together as possible tumor markers on CD9+ exosomes. Patients with longer time to tumor progression generally exhibited a decrease in circulating CD9+/SVN+ and CD9+/GFAP+/SVN+ exosomes immediately following survivin vaccination; whereas, those with early tumor progression had an increase in exosomes, despite anti-survivin immunotherapy. Serum from non cancer healthy control individuals had very few detectable CD9+/GFAP+/SVN+ exosomes, although CD9+/GFAP+ exosomes were detectable in small numbers. This study demonstrates that patients with malignant gliomas have CD9+/GFAP+/SVN+ and CD9+/SVN+ exosomes that are released into the circulation and that early reductions in their numbers following anti-survivin immunotherapy might be associated with longer progression-free survival. PMID- 29383117 TI - Magnetic resonance tumor regression grade (MR-TRG) to assess pathological complete response following neoadjuvant radiochemotherapy in locally advanced rectal cancer. AB - This study aims to evaluate the feasibility of a magnetic resonance (MR) automatic method for quantitative assessment of the percentage of fibrosis developed within locally advanced rectal cancers (LARC) after neoadjuvant radiochemotherapy (RCT). A total of 65 patients were enrolled in the study and MR studies were performed on 3.0 Tesla scanner; patients were followed-up for 30 months. The percentage of fibrosis was quantified on T2-weighted images, using automatic K-Means clustering algorithm. According to the percentage of fibrosis, an optimal cut-off point for separating patients into favorable and unfavorable pathologic response groups was identified by ROC analysis and tumor regression grade (MR-TRG) classes were determined and compared to histopathologic TRG. An optimal cut-off point of 81% of fibrosis was identified to differentiate between favorable and unfavorable pathologic response groups resulting in a sensitivity of 78.26% and a specificity of 97.62% for the identification of complete responders (CRs). Interobserver agreement was good (0.85). The agreement between P-TRG and MR-TRG was excellent (0.923). Significant differences in terms of overall survival (OS) and disease free survival (DFS) were found between favorable and unfavorable pathologic response groups. The automatic quantification of fibrosis determined by MR is feasible and reproducible. PMID- 29383116 TI - Overexpression of HSD17B4 exerts tumor suppressive function in adrenocortical carcinoma and is not associated with hormone excess. AB - Aim: Adrenocortical carcinoma (ACC) is characterized with excessive hormone production. We therefore investigated expression of hormone-related genes in ACC. Results: We queried status of 14 key genes directly involved in adrenal hormone production and found HSD17B4 expression was upregulated in 39% of ACC cases on top of all queried genes. Overexpression of HSD17B4 was significantly associate with a normo-hormonal phenotype. Constitutive HSD17B4 expression was higher in ACC cell line NCI-H295R than in adrenocortical small cell carcinoma cell line SW13. NCI-H295R cells with HSD17B4-knockdown (KD) demonstrated significantly inhibited proliferation, increased apoptosis, and increased cell cycle arrest. Enrichment analysis for mRNA expression in ACC samples with or without HSD17B4 overexpression showed significant change in p53 pathway. Replenish of HSD17B4 in SW13 cells and knockdown of HSD17B4 in H295R cells confirmed alterations in MDM4, ATR, and IE24 with alterations more contrasting in H295R cells. HSD17B4-KD inhibited cell invasion, migration and anchorage independent growth of NCI-H295R cells, but not of SW13 cells. Materials and Methods: Clinical and genetic data of ACC samples were reproduced from the ACC dataset of The Cancer Genome Atlas (TCGA) database using cBioPortal. Genes participating in adrenal hormone production were queried. Association between gene status and hormone release were studied and in vitro assays using RNA interference were carried out. Conclusions: Overexpression of HSD17B4 exerted tumor suppressive function in adrenocortical carcinoma and was not related to hormone excess. Crosstalk between HSD17B4 and p53 warrants further investigation. PMID- 29383118 TI - Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer. AB - Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified. We observed that peptides phosphorylated by elements of JAK-STAT signaling pathway and PKC signaling pathways are subject to extensive kinase activity in MCF7Res cells as compared to chemotherapy-sensitive MCF cells; and Western blotting confirmed relatively strong activation of these signaling pathways in chemoresistant cells. Importantly, treatment of cells with Tofacitinib, a FDA approved JAK inhibitor, converted chemoresistant cells to chemosensitive cells, inducing apoptosis when used in conjunction with doxorubicin. Thus our results reveal that chemoresistance in breast cancer is associated with activation of JAK/STAT signaling and suggest that JAK2 may be useful for combating chemoresistance in breast cancer. PMID- 29383119 TI - Snail1-expressing cancer-associated fibroblasts induce lung cancer cell epithelial-mesenchymal transition through miR-33b. AB - Lung cancer has a high propensity for metastasis. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in cancer tissue, are activated by tumor cells, and play a significant role in tumor development. However, whether CAFs induce lung cancer cell metastasis, as well as pathway involved in CAF induced lung cancer cell metastasis, is uncertain. Snail1 is a transcriptional factor whose expression in the stroma is associated with lower survival rates in patients with cancer. However, how Snail1 regulates the crosstalk between stromal cells and tumor cells when it is expressed in the stroma has not been determined. Altered microRNA (miRNA) expression is correlated with lung cancer metastasis. Our previous study of microRNAs showed that miR-33b levels were clearly reduced in lung cancer cell lines and lung cancer tissues, and miR-33b suppressed tumor cell epithelial-mesenchymal transition (EMT) when its expression was elevated. In this study, we found that co-culturing CAFs with lung cancer cells induced miR 33b downregulation and promoted epithelial cells EMT. Moreover, we found that miR 33b overexpression in lung cancer cells counteracted CAF-induced EMT. Interestingly, Snail1 expression in fibroblasts activate the inductive effects of CAFs on lung cancer cell EMT. Hence, understanding the molecular mechanism underlying the communication between stromal cells and tumor cells mediated by miR-33b may lead to the identification of novel targets for the treatment of lung cancer. Additionally, understanding the role of Snail1 driving CAFs to induce lung cancer cell EMT may provide with a new perspective on the treatment of lung cancer. PMID- 29383120 TI - Integrated analysis of mRNA and miRNA expression profiles in livers of Yimeng black pigs with extreme phenotypes for backfat thickness. AB - Fat deposition is an important economic trait in farm animals as well as obesity related diseases in humans, and the liver is a central organ involved in regulating lipid synthesis and metabolism in mammals. In this study, the pig liver transcriptome of two groups (H and L) showing differences in backfat thickness were profiled using RNA-Seq and miRNA-Seq to further explore the molecular mechanism of fat deposition. A total of 238 differentially expressed genes (DEGs) and 58 differentially expressed miRNAs were identified between the H and L group. These genes and miRNAs were functionally related to lipid metabolism, including CYP1A1/2, HMGCS2, ACSS2, UBE2L6, miR-27a, and miR-31. Functional enrichment analysis revealed that genes associated with oxidative stress might be responsible for fat deposition in pigs. Two miRNA-mRNA interaction networks involved in lipid metabolism were identified, and these provided new insights into the molecular regulation that determines fat content in these pigs. Overall, our study furthers our understanding of the molecular mechanisms involved in fat deposition, and these results may help in the design of selection strategies to improve the quality of pork meat and to combat obesity in humans. PMID- 29383121 TI - Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer. AB - Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway repressed CD44 and cleared the CSC population, mediated through SUMO-unconjugated TFAP2A. We sought to evaluate effects of inhibiting the SUMO pathway in ATC. ATC cell lines and primary ATC tumor samples were evaluated. The SUMO pathway was inhibited by knockdown of PIAS1 and use of SUMO inhibitors anacardic acid and PYR-41. The expression of TFAP2A in primary ATC was examined by immunohistochemistry. All ATC cell lines expressed TFAP2A but only 8505C expressed SUMO-conjugated TFAP2A. In 8505C only, inhibition of the SUMO pathway by knockdown of PIAS1 or treatment with SUMO inhibitors repressed expression of CD44 with a concomitant loss of SUMO conjugated TFAP2A. The effect of SUMO inhibition on CD44 expression was dependent upon TFAP2A. Treatment with SUMO inhibitors resulted in a statistically improved tumor-free survival in mice harboring 8505C xenografts. An examination of primary ATC tissue determined that TFAP2A was expressed in 4 of 11 tumors surveyed. We conclude that inhibition of the SUMO pathway repressed the CSC population, delaying the outgrowth of tumor xenografts in ATC. The effect of SUMO inhibition was dependent upon expression of SUMO-conjugated TFAP2A, which may serve as a molecular marker for therapeutic effects of SUMO inhibitors. The findings provide pre-clinical evidence for development of SUMO inhibitors for the treatment of ATC. PMID- 29383123 TI - Circular RNA circ-NT5C2 acts as an oncogene in osteosarcoma proliferation and metastasis through targeting miR-448. AB - Circular RNAs (circRNAs) are a type of endogenous noncoding RNA which have been verified to participate in numerous pathophysiological processes. However, the underlying role of circRNAs in osteosarcoma tissue is still unidentified. Our study aims to investigate the circRNA expression profiles in osteosarcoma tissue and investigate the physiological functions of circRNAs. Human circRNAs microarray analysis showed that 785 differently expressed circRNAs were distinguished in osteosarcoma tissue and adjacent non-tumor tissue with 2 fold change. Circ-NT5C2 was validated to be up-regulated expressed in 52 pairs of osteosarcoma tissue and cell lines. Furthermore, the enforced expression of circ NT5C2 could act as a valuable diagnostic marker for osteosarcoma detection with AUC (area under the ROC curve) value of 0.753. Functional validation experiments verified that circ-NT5C2 silencing suppressed the proliferation and invasion, and promoted apoptosis of osteosarcoma cells in vitro. In vivo, circ-NT5C2 silencing inhibited the tumor growth. Bioinformatics analysis and rescue experiments indicated that circ-NT5C2 sponged miR-448, which was confirmed by luciferase reporter assay and RT-PCR assay. Overall, our study investigates the circRNAs expression profiles and determines the function of circ-NT5C2 in osteosarcoma tumorigenesis, which might serve as a novel therapeutic target of osteosarcoma patients. PMID- 29383122 TI - Antioxidant and pro-angiogenic effects of corilagin in rat cerebral ischemia via Nrf2 activation. AB - The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway has been considered as a potential target for neuroprotection in stroke. The aim of present study was to determine whether corilagin, a novel Nrf2 activator, can protect against ischemia-reperfusion injury and explore the underlying mechanism involved. In vivo, rats exposed to middle cerebral artery occlusion were applied to establish an ischemic stroke model. Posttreatment of corilagin significantly reduced infarct volumes and apoptotic cells as well as improved neurologic score after reperfusion, together with increased vascular density in the ischemic penumbra. Meanwhile, posttreatment with corilagin in MCAO rats significantly decreased malondialdehyde levels, restored the superoxide dismutase and glutathione activity, elevating the Nrf2, heme oxygenase-1, the vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. However, consecutive intrathecal injection of short interference RNAs targeting Nrf2 at 24-h intervals 72 h before ischemia reduced the beneficial effects of corilagin. In primary cultured neurons, corilagin dose-dependently protected against oxygen and glucose deprivation-induced insult, but the protective effect of corilagin was attenuated by knockdown of Nrf2. In conclusion, these findings indicate that corilagin exerts protective effects against cerebral ischemic injury by attenuating oxidative stress and enhancing angiogenesis via activation of Nrf2 signaling pathway. PMID- 29383124 TI - Genetic association between 1425G/A SNP in PRKCH and hypertrophic cardiomyopathy in a Chinese population. AB - Hypertrophic cardiomyopathy is a heterogeneous myocardial disorder with a broad spectrum of clinical presentation and morphologic features. Previous reports indicated that protein kinase C pathway as a major determinant of cardiac hypertrophy and heart failure. Population-based analyses of the association between PRKCH gene (encoded PKCeta) and HCM has not been performed yet. The purpose of this study is to investigate the association of the nonsynonymous SNP (1425G/A) in PRKCH gene and hypertrophic cardiomyopathy in a Chinese population. 323 patients with HCM and 326 controls were examined using a case-control methodology. The 1425G/A SNP in PRKCH was genotyped by allele-specific real-time PCR assay. The 1425G/A SNP in PRKCH increased the risk of HOCM (hypertrophic obstructive cardiomyopathy) (OR=1.427, 95% confidence interval, 1.013 to 2.012, P=0.046) under a dominant model. After age- and sex-adjustment, the significant associations remained in HOCM (for GG +AG versus AA, OR= 2.497, 95% confidence interval, 1.01 to 6.17; P=0.047). The 1425G/A SNP in PRKCH increases the risk of hypertrophic obstructive cardiomyopathy in the Chinese population. PMID- 29383125 TI - Transcriptomic features of primary prostate cancer and their prognostic relevance to castration-resistant prostate cancer. AB - Although various mechanisms of castration-resistant prostate cancer (CRPC) have been discovered, reliable biomarkers for monitoring CRPC progression are lacking. We sought to identify molecules that predict the progression of advanced prostate cancer (AdvPC) into CRPC. The study used primary-site samples (N=45 for next generation sequencing (NGS); N=243 for real-time polymerase chain reaction) from patients with prostate cancer (PC). Five public databases containing microarray data of AdvPC and CRPC samples were analyzed. The NGS data showed that each progression step in PC associated with distinct gene expression profiles. Androgen receptor (AR) associated with tumorigenesis, advanced progression, and progression into CRPC. Analysis of the paired and unpaired AdvPC and CRPC samples in the NGS cohort showed that 15 genes associated with progression into CRPC. This was validated by cohort-1 and public database analyses. Analysis of the third cohort with AdvPC showed that higher serine peptidase inhibitor, Kazal type 1 (SPINK1) and lower Sp8 transcription factor (SP8) expression associated with progression into CRPC (log-rank test, both P<0.05). Multivariate regression analysis showed that higher SPINK1 (Hazard Ratio (HR)=4.506, 95% confidence intervals (CI)=1.175-17.29, P=0.028) and lower SP8 (HR=0.199, 95% CI=0.063-0.632, P=0.006) expression independently predicted progression into CRPC. Gene network analysis showed that CRPC progression may be mediated through the AR-SPINK1 pathway by a HNF1A-based gene network. Taken together, our results suggest thatSPINK1 and SP8 may be useful for classifying patients with AdvPC who have a higher risk of progressing to CRPC. PMID- 29383127 TI - Comparing the genomes of cutaneous melanoma tumors to commercially available cell lines. AB - Insulated culture environment and prolonged propagation contribute to known limitations of cell lines, and selection is often limited to availability or favorable growth characteristics. To better characterize and improve selection of cell lines, we compared 60 melanoma cell lines profiled by the Cancer Cell Line Encyclopedia and 472 cutaneous melanoma tumors profiled by The Cancer Genome Atlas by DNA sequence and copy number alterations. All samples were scored for stromal and immune cell composition by the ESTIMATE algorithm, and 412 tumors with >= 60% tumor cell fraction were compared to cell lines. Uncharacterized early passage cell lines that lacked BRAF, NRAS, or NF1 mutations had near zero mean Pearson correlation of copy number alterations per gene to tumors and also tended to have higher stromal scores. The Comet Exact Test was applied to tumors and cell lines identifying three pairs of genes mutated in a mutually exclusive pattern in tumors but not cell lines: BRAF and NRAS, BRAF and NF1, as well as NRAS and PTEN. Additionally, 31 genes were more frequently mutated in cell lines than tumors. Avoiding cell lines with co-occurring mutually exclusive mutations and the fewest differentially mutated genes within a known distribution of genetic similarity to tumors by copy number alterations may optimize selection. PMID- 29383126 TI - Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-beta signaling and malignant features in vitro and in vivo. AB - Breast cancer is the most prevalent malignancy in women and there is an urgent need for new therapeutic drugs targeting aggressive and metastatic subtypes, such as hormone-refractory triple-negative breast cancer (TNBC). Control of protein synthesis is vital to cell growth and tumour progression and permits increased resistance to therapy and cellular stress. Hypoxic cancer cells attain invasive and metastatic properties and chemotherapy resistance, but the regulation and role of protein synthesis in this setting is poorly understood. We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. Integrin beta 3 (ITGB3) was translationally activated in hypoxia and its knockdown increased apoptosis and reduced survival and migration, particularly under hypoxic conditions. Moreover, ITGB3 was required for sustained TGF-beta pathway activation and for the induction of Snail and associated epithelial-mesenchymal transition markers. ITGB3 downregulation significantly reduced lung metastasis and improved overall survival in mice. Collectively, these data suggest that ITGB3 is translationally activated in hypoxia and regulates malignant features, including epithelial mesenchymal transition and cell migration, through the TGF-beta pathway, revealing a novel angle for the treatment of therapy-resistant hypoxic tumours. PMID- 29383128 TI - Genome-wide identification of long non-coding RNA and mRNA profiling using RNA sequencing in subjects with sensitive skin. AB - Sensitive skin (SS) is a condition of subjective cutaneous hyper-reactivity. The role of long non-coding RNAs (lncRNAs) in subjects with SS is unclear. Therefore, the aim of the present study was to provide a comprehensive profile of the mRNAs and lncRNAs in subjects with SS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis presented the characteristics of associated protein-coding genes. In addition, a co-expression network of lncRNA and mRNA was constructed to identify potential underlying regulation targets; the results were verified by quantitative real-time PCR (qRT-PCR) and RNA-seq analyses in patients with SS and normal samples. Compared with the normal skin group, 266 novel lncRNAs and 6750 annotated lncRNAs were identified in the SS group. A total of 71 lncRNA transcripts and 2615 mRNA transcripts were differentially expressed (P < 0.05). The heat signature of the SS samples could be distinguished from the normal skin samples, whereas the majority of the genes that were present in enriched pathways were those that participated in focal adhesion, PI3K-Akt signaling, and cancer-related pathways. Five transcripts were selected for qRT PCR analysis and the results were consistent with RNA-seq. The results suggested that LNC_000265 may play a role in the epidermal barrier structure of patient with SS. The data suggest novel genes and pathways that may be involved in the pathogenesis of SS and highlight potential targets that could be used for individualized treatment applications. PMID- 29383129 TI - CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues. AB - The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2 overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach. PMID- 29383130 TI - GSK-3beta inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents. AB - The complexities of GSK-3beta function and interactions with PI3K/AKT/mTOR signaling, cell cycling, and apoptotic pathways are poorly understood in the context of lymphomagenesis and cancer therapeutics. In this study, we explored the anti-tumor effects of the GSK-3beta inhibitor, 9-ING-41, in lymphoma cell lines as a single agent and in combination with novel agents comprising BCL-2 inhibitor (Venetoclax), CDK-9 inhibitor (BAY-1143572) and p110delta-PI3K inhibitor (Idelalisib). Treatment of Daudi, SUDHL-4, Karpas 422, KPUM-UH1, and TMD8 lymphoma cell lines with 1 MUM 9-ING-41 reduced cell viability by 40-70% (p<0.05) and halted proliferation. Luminex analysis of apoptotic pathways revealed a significant increase in active caspase 3 in all lymphoma cell lines (p<0.001) except TMD8 cells. Co-treating SUDHL-4 and KPUM-UH1 lymphoma cells with 0.5 MUM 9-ING-41 showed 8-and 2-fold reduction in IC50 values of Venetoclax, respectively. No significant benefit for this combination was seen in other lymphoma cells tested. The combination of BAY-1143572 with 0.5 MUM 9-ING-41 showed an 8-fold reduction in the IC50 value of the former in SUDHL-4 lymphoma cells alone. No significant changes in IC50 values of Idelalisib were measured across all cell lines for the combination of 9-ING-41 and Idelalisib. Further, signaling analysis via Western blot in the double-hit lymphoma cell line, KPUM UH1, suggests that phospho-c-MYC is modified with 9-ING-41 treatment. Altogether, our data show that 9-ING-41 results in increased apoptosis and decreased proliferation in aggressive B-cell lymphoma cells and enhances the antitumor effects of BCL-2 and CDK-9 antagonists. PMID- 29383131 TI - Development of a reliable and accurate algorithm to quantify the tumor immune stroma (QTiS) across tumor types. AB - The tumor microenvironment plays an important role in the tumor biology. Overall survival of tumor patients after resection is influenced by tumor-infiltrating lymphocytes (TILs) as a component of the tumor stroma. However, it is not clear how to assess TILs in the tumor stroma due to heterogeneous methods in different cancer types. Therefore, we present a novel Quantification of the Tumor immune Stroma (QTiS) Algorithm to reliably and accurately quantify cells in the tumor stroma. Immunohistochemical staining of CD3 and CD8 cells in sections of metastatic colorectal cancer (mCRC), ovarian cancer (OvCa), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC), alltogether N = 80, was performed. Hot spots of infiltrating immune cells are reported in the literature. Reliability of the hot spot identification of TILs was examined by two blinded observers. Accuracy was tested in 1 and 3 hot spots using computed counting methods (ZEN 2 software counting (ZC), ImageJ software with subjective threshold (ISC) and ImageJ with color deconvolution (IAC)) and compared to manual counting. All tumor types investigated showed an accumulation of TILs in the tumor stroma (peri- and intratumoral). Reliability between observers indicated a high level consistency. Accuracy for CD8+/CD3+ ratio and absolute cell count required 1 and 3 hot spots, respectively. ISC was found to be the best for paraffin sections, whereas IAC was ideal for frozen sections. ImageJ software is cost-effective and yielded the best results. In conclusion, an algorithm for quantification of tumoral stroma could be established. With this QTiS Algorithm counting of tumor stromal cells is reliable, accurate, and cost-effective. PMID- 29383132 TI - Norcantharidin alone or in combination with crizotinib induces autophagic cell death in hepatocellular carcinoma by repressing c-Met-mTOR signaling. AB - There is an urgent need for effective molecular therapies for hepatocellular carcinoma (HCC), the third-leading cause of cancer-related deaths worldwide. Norcantharidin (NCTD), a demethylated derivative of cantharidin, reportedly exhibits anticancer activity against various types of tumors, including HCC, though the mechanisms involved remain largely unknown. Here, we report that NCTD reduces viability of human MHCC-97H (97H) and HepG2 HCC cells, and induces cell death by triggering high levels of autophagy. Moreover, a significant attenuation of tumor growth was observed after NCTD treatment of HepG2 tumors in vivo, and this effect was enhanced by co-treatment with the c-Met inhibitor crizotinib. Interestingly, western blot analyses showed that the cytotoxic autophagy induced by NCTD correlates with a reduction in the phosphorylation status of both c-Met and m-TOR. These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in HCC by combined NCTD and crizotinib administration. Further studies to validate the therapeutic potential of this approach are warranted. PMID- 29383133 TI - miR-455-5p promotes cell growth and invasion by targeting SOCO3 in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. miR 455-5p has increased expression and the ability to promote tumorigenesis in certain cancers. However, the role of miR-455-5p in NSCLC has not been sufficiently investigated. SOCS3 (suppressor of cytokine signaling 3), an important tumor suppressor, is often aberrantly inactivated in various tumors, but it is currently unclear whether SOCO3 is a target of miR-455-5p. In the present study, we investigated the role of miR-455-5p in NSCLC. We found that the expression of miR-455-5p was up-regulated in NSCLC tumor tissues compared to corresponding noncancerous tissues, and its expression was correlated with metastasis and tumor node metastasis in NSCLC tissue. We then showed that miR-455 5p promoted migration, invasion and proliferation in NSCLC cell lines. Additionally, we also found that SOCS3 was the direct target gene of miR-455-5p. Consistently, the expression of SOCS3 was negatively correlated with the expression of miR-455-5p in NSCLC tissues. We further show that aberrant miR-455 5p expression is partially controlled by activated ERK signaling in NSCLC. Therefore, miR-455-5p could enhance the growth and metastasis of NSCLC by inhibiting SOCS3, thus providing a potential molecular therapeutic target for the treatment of NSCLC patients. PMID- 29383134 TI - Long non-coding RNA deep sequencing reveals the role of macrophage in liver disorders. AB - Liver disorders such as hepatitis, cirrhosis and hepatocellular carcinoma are a series of the most life threatening diseases along with extensive inflammatory cellular infiltrations. Macrophage has been proved to be key regulators and initiators of inflammation, and long non-coding RNAs (lncRNAs) are recommended to play critical roles in the occurrence and development of a variety of diseases. To uncover the role of macrophage in liver disorders via lncRNA sequencing method, we first applied a lncRNA classification pipeline to identify 1247 lncRNAs represented on the Affymetrix Mouse Genome 430/430A 2.0 array. We then analyzed the lncRNA expression patterns in a set of previously published gene expression profiles of silica particle exposed macrophages and liver respectively, and identified and validated sets of differentially expressed lncRNAs shared by macrophages and liver. The functional enrichment analysis of these lncRNAs was processed on the basis of their expression signatures, three aspects including cis, trans and co-acting proteins were proposed. This is the first time to correlate macrophage with liver disorders via co-expressed lncRNAs. Our findings indicated that roles of macrophage in liver disorders were double edged, the differentially expressed lncRNAs and their corresponding regulatory genes or proteins may serve as potential diagnostic biomarkers and therapeutic targets. PMID- 29383135 TI - Upregulation of RSPO2-GPR48/LGR4 signaling in papillary thyroid carcinoma contributes to tumor progression. AB - The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines. R-spondin 2, and GPR48/LGR4 were expressed at significantly higher levels in thyroid cancer than in normal controls. Elevated GPR48/LGR4 expression was significantly associated with tumor size (P=0.049), lymph node metastasis (P=0.004), recurrence (P=0.037), and the BRAFV600E mutation (P=0.003). Moreover, high GPR48/LGR4 expression was an independent risk factor for lymph node metastasis (P=0.027) and the BRAFV600E mutation (P=0.009). in vitro assays demonstrated that elevated expression of GPR48/LGR4 promoted proliferation and migration of thyroid cancer cells, whereas downregulation of GPR48/LGR4 decreased proliferation and migration by inhibition of the beta-catenin pathway. Moreover, treatment of thyroid cancer cells with exogenous R-spondin 2 induced activation of the beta-catenin pathway through GPR48/LGR4. The R-spondin 2-GPR48/LGR4 signaling axis also induced the phosphorylation of ERK, as well as phosphorylation of LRP6 and serine 9 of GSK3beta. Our findings demonstrate that upregulation of the R-spondin 2 GPR48/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer. PMID- 29383136 TI - Association of RTEL1 gene polymorphisms with stroke risk in a Chinese Han population. AB - We investigated the associations between single nucleotide polymorphisms (SNPs) in the regulator of telomere elongation helicase 1 (RTEL1) gene and stroke in the Chinese population. A total of 400 stroke patients and 395 healthy participants were included in this study. Five SNPs in RTEL1 were genotyped and the association with stroke risk was analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to identify SNPs that correlated with stroke. Rs2297441 was associated with an increased risk of stroke in an allele model (odds ratio [OR] = 1.24, 95% confidence interval [95% CI] = 1.01-1.52, p = 0.043). Rs6089953 was associated with an increased risk of stroke under the genotype model ([OR] = 1.862, [CI] = 1.123-3.085, p = 0.016). Rs2297441 was associated with an increased risk of stroke in an additive model (OR = 1.234, 95% CI = 1.005, p = 0.045, Rs6089953, Rs6010620 and Rs6010621 were associated with an increased risk of stroke in the recessive model (Rs6089953:OR = 1.825, 95% CI = 1.121-2.969, p =0.01546; Rs6010620: OR = 1.64, 95% CI = 1.008 2.669, p =0.04656;Rs6010621:OR = 1.661, 95% CI = 1.014-2.722, p =0.04389). Our findings reveal a possible association between SNPs in the RTEL1 gene and stroke risk in Chinese population. PMID- 29383137 TI - Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes. AB - Genetic lesions affecting epigenetic regulators are frequent in myelodysplastic syndromes (MDS). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in MDS and AML, little is known about the role of PRC1. To analyze the role of PRC1, we have taken a functional approach testing PRC1 components in loss- and gain-of-function experiments that we found overexpressed in advanced MDS patients or dynamically expressed during normal hematopoiesis. This approach allowed us to identify the enzymatically active component RING1A as the key PRC1 component in hematopoietic stem cells and MDS. Specifically, we found that RING1A is expressed in CD34+ bone marrow progenitor cells and further overexpressed in high-risk MDS patients. Knockdown of RING1A in an MDS-derived AML cell line facilitated spontaneous and retinoic acid-induced differentiation. Similarly, inactivation of RING1A in primary CD34+ cells augmented erythroid differentiation. Treatment with a small compound RING1 inhibitor reduced the colony forming capacity of CD34+ cells from MDS patients and healthy controls. In MDS patients higher RING1A expression associated with an increased number of dysplastic lineages and blasts. Our data suggests that RING1A is deregulated in MDS and plays a role in the erythroid development defect. PMID- 29383138 TI - SF3B1 mutation is a poor prognostic indicator in luminal B and progesterone receptor-negative breast cancer patients. AB - The purpose of this study was to explore the relationship between SF3B1 mutations and the prognoses of patients with breast cancer. Clinical and SF3B1 mutation data from The Cancer Genome Atlas were analyzed. SF3B1 mutations were evaluated as prognostic factors in all breast cancer patients and specific subgroups through Cox regression and Kaplan-Meier analyses. We also investigated the relationship between traditional parameters and SF3B1 mutations. Receiver operating characteristics curves were used to analyze common risk factors for their sensitivity and specificity in predicting SF3B1 mutations. SF3B1 mutations were a poor prognostic factor in luminal B and progesterone receptor (PR) negative breast cancer (P < 0.01). Age at diagnosis and estrogen receptor (ER) status were associated with SF3B1 mutations in all breast cancers (P < 0.01) and in luminal B and PR-negative subgroups (P < 0.01). The age at diagnosis and ER status combined had a higher sensitivity and specificity for predicting SF3B1 mutations than each factor alone. SF3B1 mutations are a poor prognostic factor in luminal B and PR-negative breast cancer patients. These mutations are significantly associated with age at diagnosis and ER status. SF3B1 mutations may therefore be a novel therapeutic target for breast cancer patients. PMID- 29383139 TI - Dihydroartemisinin attenuates autoimmune thyroiditis by inhibiting the CXCR3/PI3K/AKT/NF-kappaB signaling pathway. AB - Dihydroartemisinin (DHA) is the first generation of naturally occurring artemisinin derivatives with antimalarial activity. Recent research showed that this drug also features immunosuppressive and anti-inflammatory properties. Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with no available effective drug treatment. In this study, we investigated effects of DHA on AIT in vitro and in vivo. Results showed that DHA can visibly reduce antithyroglobulin antibody and thyroid peroxidase antibody levels and regulate T helper cells (Th) 1/Th2 imbalance of experimental AIT mice. DHA also dose dependently suppressed proliferation of lymphocytes induced by lipopolysaccharide and concanavalin A. DHA inhibited binding of C-X-C chemokine ligand 10 (CXCL10) and its receptor (C-X-C motif) receptor 3 (CXCR3), thus inhibiting calcium flow. DHA can also reduce expression levels of PI3-kinase (PI3K), p-PI3K, protein kinase B (AKT), p-AKT, nuclear factor (NF)-kappaB/p65, and p-NF-kappaB/p65. In conclusion, DHA may serve as treatment drug for AIT by inhibiting the CXCR3/PI3K/AKT/NF-kB signaling pathway. PMID- 29383140 TI - INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis. AB - The INO80 chromatin-remodeling complex performs functions in many chromosomal processes that are crucial for genome stability, such as DNA replication and stalled replication fork recovery. Although these functions suggest that INO80 acts as a tumor suppressor, its specific role in tumorigenesis has remained obscure. Here, we show that a haploinsufficient mutation of Ino80, the catalytic ATPase of the INO80 complex, decreased intestinal adenomatous polyps and increased survival in an Apcmin/+ mouse model of colon cancer. Experiments using tumors obtained from Apcmin/+ mice and cells from human colon cancers showed that this Ino80 defect induced stalled replication forks, the concomitant activation of ATR-Chk1 signaling and an increase in apoptosis, suggesting that Ino80 haploinsufficiency inhibited colon cancer tumorigenesis by activating replication stress-induced ATR-Chk1 signaling to increase apoptosis. Importantly, in human colon cancer, we observed that the INO80 subunits were frequently present in high copy numbers and exhibited a high rate of amplification and increased protein expression. These results show that in contrast to our original prediction that INO80 acts as a tumor suppressor, INO80 actually functions oncogenically to promote colon tumorigenesis. INO80 therefore represents a novel therapeutic target in colon cancer. The results of this study also reinforce the emerging notion that while genomic instability can promote tumorigenesis, in certain genetic contexts, it can also act as a tumor suppressor. PMID- 29383141 TI - YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth. AB - Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2 and DNMT3a to YAP1 promoter, thereby promoting DNA methylation and the repression of YAP1 gene transcription. Following ADT treatment or when AR activity is antagonized by Bicalutamide or Enzalutamide, YAP1 gene expression is switched on. In turn, YAP1 promotes SOX2 and Nanog expression and the de-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion, our data reveals that AR suppresses YAP1 gene expression through a novel epigenetic mechanism, which is critical for PCa cells self-renewal and the development of CRPC. PMID- 29383142 TI - 2,2'-Methylenebis (6-tert-butyl 4-methylphenol) enhances the antitumor efficacy of belotecan, a derivative of camptothecin, by inducing autophagy. AB - Autophagy regulation is important for tumor cell survival. Activation and inhibition of autophagy can sensitize tumor cells to anticancer drugs. However, few autophagy-regulating small molecules are available to increase the efficacy of anticancer drugs. Here, we report that 2,2'-methylenebis (6-tert-butyl 4 methylphenol), hereafter referred to as methylenebis, is a novel autophagy regulating small molecule that sensitizes tumor cells to belotecan, which is a derivative of camptothecin, a topoisomerase I inhibitor. Methylenebis activates autophagic flux by increasing the level of LC3-II and forming autolysosome puncta. Moreover, methylenebis enhances the antitumor efficacy of belotecan by activating both autophagy and apoptosis. Interestingly, methylenebis increased the level of LC3-II and belotecan independently decreased the level of p62, suggesting that methylenebis and belotecan target different steps of autophagy. Finally, we searched for compounds that are structurally similar to methylenebis. Our results imply that the specific structure of methylenebis contributes to its ability to activate autophagy. PMID- 29383143 TI - Functional characterization of a unique cytochrome P450 in Toxoplasma gondii. AB - The basic metabolic cytochrome P450 (CYP) proteins are essential for the biotransformation of sterols and xenobiotics. By contrast, the Toxoplasma gondii genome contains only one CYP gene, and the role of this enzyme in the physiology and biochemistry of apicomplexan parasites is unknown. Because it is a potential resistance gene, identifying the functionality of P450 in T. gondii is particularly important. Knocking out Tg-P450 had no significant effect on T. gondii survival, but mice infected with parasites overexpressing Tg-P450 exhibited significantly enhanced pathogenicity. Enzyme activity analyses demonstrated that this protein has mammalian CYP2B and CYP3A enzymatic activity. In addition, T. gondii lacking the P450 gene exhibited reduced resistance to quinine, mefloquine and clarithromycin compared with parasites overexpressing Tg P450. These results suggest that P450 functions in T. gondii metabolism and detoxification is involved in vitally important processes in parasitic organisms, making this enzyme a potential drug target. PMID- 29383144 TI - Insufficient microwave ablation-induced promotion of distant metastasis is suppressed by beta-catenin pathway inhibition in breast cancer. AB - Microwave ablation (MWA), a thermal ablation, is an effective treatment for breast cancer. However, residual breast cancer is still detected. The biological characteristics of residual breast cancer after thermal ablation remain unknown. To mimic insufficient MWA in vitro, breast cancer cells were treated at 37 degrees C, 42 degrees C, 45 degrees C, 47 degrees C and 50 degrees C for 10 mins, the 37 degrees C as control group. Insufficient MWA induced EMT-like changes of residual breast cancer by down-regulation of E-cadherin and up-regulation of vimentin and N-cadherin in vitro and in vivo. For the first time, we reported insufficient MWA promoted distant metastasis of residual breast cancer in vivo. Reduced beta-catenin expression by siRNA diminished the EMT-like phenotype and enhanced migration capability induced by heat treatment in breast cancer cells. Moreover, ICG001, a special inhibitor of beta-catenin pathway, depressed EMT of residual tumor and distant metastasis in an insufficient MWA nude mice model of breast cancer. In conclusion, our results demonstrate that insufficient MWA promotes EMT of residual breast cancer by activating beta-catenin signal pathway, resulting in enhanced distant metastasis of residual breast cancer. In addition, the effectiveness of ICG001 in suppressing enhanced metastasis of residual breast cancer is preliminarily validated. PMID- 29383145 TI - Discovering drugs to overcome chemoresistance in ovarian cancers based on the cancer genome atlas tumor transcriptome profile. AB - Ovarian cancer accounts for the highest mortality among gynecologic cancers, mainly due to intrinsic or acquired chemoresistance. While mechanistic-based methods have been used to identify compounds that can overcome chemoresistance, an effective comprehensive drug screening has yet to be developed. We applied a transcriptome based drug sensitivity prediction method, to the Cancer Genome Atlas (TCGA) ovarian cancer dataset to impute patient tumor response to over 100 different drugs. By stratifying patients based on their predicted response to standard of care (SOC) chemotherapy, we identified drugs that are likely more sensitive in SOC resistant ovarian tumors. Five drugs (ABT-888, BIBW2992, gefitinib, AZD6244 and lenalidomide) exhibit higher efficacy in SOC resistant ovarian tumors when multi-platform of transcriptome profiling methods were employed. Additional in vitro and clinical sample validations were carried out and verified the effectiveness of these agents. Our candidate drugs hold great potential to improve clinical outcome of chemoresistant ovarian cancer. PMID- 29383146 TI - Tumor exome sequencing and copy number alterations reveal potential predictors of intrinsic resistance to multi-targeted tyrosine kinase inhibitors. AB - Multi-targeted tyrosine kinase inhibitors (TKIs) have broad efficacy and similar FDA-approved indications, suggesting shared molecular drug targets across cancer types. Irrespective of tumor type, 20-30% of patients treated with multi-targeted TKIs demonstrate intrinsic resistance, with progressive disease as a best response. We conducted a retrospective cohort study to identify tumor (somatic) point mutations, insertion/deletions, and copy number alterations (CNA) associated with intrinsic resistance to multi-targeted TKIs. Using a candidate gene approach (n=243), tumor next-generation sequencing and CNA data was associated with resistant and non-resistant outcomes. Resistant individuals (n=11) more commonly harbored somatic point mutations in NTRK1, KDR, TGFBR2, and PTPN11 and CNA in CDK4, CDKN2B, and ERBB2 compared to non-resistant (n=26, p<0.01). Using a random forest classification model for variable reduction and a decision tree classification model, we were able to differentiate intrinsically resistant from non-resistant patients. CNA in CDK4 and CDKN2B were the most important analytical features, implicating the cyclin D pathway as a potentially important factor in resistance to multi-targeted TKIs. Replication of these results in a larger, independent patient cohort has potential to inform personalized prescribing of these widely utilized agents. PMID- 29383147 TI - Cigarette smoke enhances initiation and progression of lung cancer by mutating Notch1/2 and dysregulating downstream signaling molecules. AB - Lung cancer is the primary cause of cancer related deaths in the western world and smoking significantly increases the risk of developing lung cancer. Smoking enhances lung cancer initiation and progression. The effects of cigarette smoke on lung cancer are mediated by the presence of highly mutagenic substances, including nicotine, leading to mutations in oncogenes and tumor suppressor genes. An emerging pathway in cancer is the Notch signaling pathway which is essential for embryonic lung development and tissue homeostasis. The role of Notch signaling in lung cancer remains controversial and no studies have directly linked cigarette exposure to mutations in Notch. Therefore, we investigated the direct effect of Notch signaling pathways on cigarette-induced lung tumors and the correlation between smoking and mutations in Notch leading to altered downstream signaling. Human cell lines, mouse models and clinical lung cancer samples were utilized in this study. Cigarette-induced in vitro human lung cancer models and in vivo mouse models demonstrated strong effects of cigarette exposure on the Notch signaling pathway. Immunohistochemistry (IHC) of 50 clinical samples collected from smokers and non-smokers with and without lung cancer also demonstrated a link between smoking and changes in Notch signaling. Finally, 34 lung cancer samples analyzed through direct sequencing indicated smoking significantly increased small nucleotide polymorphisms (SNPs) in Notch 1 and 2 and specific SNPs significantly modulated expression levels of downstream signaling pathway molecules. Taken together, these results demonstrate a direct effect of smoking on the Notch signaling pathway leading to lung cancer initiation and progression. PMID- 29383148 TI - Hypoxia-activated prodrug enhances therapeutic effect of sunitinib in melanoma. AB - Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia-a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox ) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma. PMID- 29383149 TI - Prognostic significance of cystatin SN associated nomograms in patients with colorectal cancer. AB - Colorectal cancer (CRC) is one of most malignant tumors, mainly due to its high rate of metastasis and recurrence. The prognosis of CRC is difficult due to early CRC patients have no specific symptoms. Therefore, it is emergent to identify a biomarker for CRC prognosis. Cystatin SN (CST1) shows elevated expression in many tumors, but its role in CRCs is still unknown. Through immunohistochemistry analysis, we found that CST1 was upregulated in CRC samples. The survival analysis had demonstrated that high CST1 expression was closely associated with poor clinical status, providing that CST1 plays a role in CRC tumorigenesis. Furthermore, nomograms were generated using CST1 levels and other factors to evaluate survival of CRCs. We evaluated the reliabilities of these nomograms using an independent cohort of 141 CRC cases and found that high CST1 expression is linked to low survival, which is consistent with the clinical results. Thus, we could predict the survival of a CRC patient via these nomograms. In addition, the multivariate analysis identified CST1 as an independent prognostic factor for CRCs, providing CST1 as a biomarker for CRC prognosis. Taken together, our studies revealed a close relationship between CST1 and CRCs, suggesting that CST1 possibly acts as a marker for CRC prognosis and a target for CRC therapy. PMID- 29383150 TI - Molecular crosstalk between ferroptosis and apoptosis: emerging role of ER stress induced p53-independent PUMA expression. AB - Ferroptosis is a type of programmed cell death that depends on iron and is characterized by the accumulation of lipid peroxides. In the present study, we investigated the nature of the interplay between ferroptosis and other forms of cell death such as apoptosis. Human pancreatic cancer PANC-1 and BxPC-3 and human colorectal cancer HCT116 cells were treated with ferroptotic agents such as erastin and artesunate (ART) in combination with the apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We observed synergistic interaction of erastin or ART with TRAIL as determined by cell death assay, caspase activation, poly [ADP-ribose] polymerase 1 (PARP-1) cleavage, flow cytometry analysis, and lipid peroxidation assay. Moreover, erastin and ART induced endoplasmic reticulum (ER) stress and promoted p53 upregulated modulator of apoptosis (PUMA) expression via C/EBP-homologous protein (CHOP). Synergy of erastin/ART and TRAIL was abolished in PUMA-deficient HCT116 cells and CHOP deficient mouse embryonic fibroblasts, but not in p53-deficient HCT116 cells. The results suggest the involvement of the p53-independent CHOP/PUMA axis in response to ferroptosis inducers, which may play a key role in ferroptotic agent-mediated sensitization to TRAIL-induced apoptosis. PMID- 29383151 TI - High protein and mRNA expression levels of TUBB3 (class III beta-tubulin) are associated with aggressive tumor features in esophageal adenocarcinomas. AB - Background: Esophageal adenocarcinomas show an increasing incidence in the Western world and their overall survival remains low. Microtubules are multifunctional cytoskeletal proteins involved in crucial cellular roles, including maintenance of cell shape, intracellular transport, meiosis, and mitosis. Microtubulus-TUBB3 was found overexpressed in several carcinomas suggesting a significant role in cancer development. High levels of TUBB3 expression were also described to be associated with poor clinical outcome in various cancers. It was shown that overexpression of TUBB3 could be related to reduced efficiency of taxane-based targeting anticancer drugs in several cancer types. Results: There is a statistically significant association between high TUBB3 protein and TUBB3 mRNA expression and shortened survival (p<0,0001). Prognostic impact of TUBB3 expression is seen in patients with and without multimodal treatment. Multivariate analysis revealed a strong TUBB3 expression to be an independent prognosis factor. Validation of protein expression by mRNA in situ hybridization underlines the credibility of the immunohistochemical results. Discussion: Our study emphasized the significant importance of TUBB3 in esophageal adenocarcinoma. TUBB3 serves as an independent prognostic marker and may be a valuable biomarker for routine application in esophageal adenocarcinoma especially to address the need for adjuvant treatment in individuals following neoadjuvant therapy and surgery. Future prospective studies are needed which include the results of TUBB3 in preoperative biopsy material to proof the prognostic impact of TUBB3. Materials and Methods: 280 esophageal adenocarcinomas that underwent primary surgical resection or resection after neoadjuvant therapy were analyzed by mRNA-in-situ-hybridization (RNAscope(r)) and by immunohistochemistry (TUBB3 rabbit monoclonal antibody; Epitomics). PMID- 29383152 TI - Zinc improves learning and memory abilities of fetal growth restriction rats and promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 axis activity. AB - Fetal growth restriction (FGR) is a well-known risk factor for cognitive dysfunction, especially for learning and memory abilities. However, knowledge about prevention and treatment methods of learning and memory abilities of fetal are limit. Here, Morris water maze and passive avoidance tests showed zinc supplementation could protect the impairment of the learning and memory abilities caused by FGR. As accumulating evidence suggested that insufficiency of placental trophoblast cell invasion was closely related to FGR fetal neurodevelopmental dysplasia, we further explored the relationship between zinc supplementation during pregnancy and placental trophoblast. Microarray identified 346 differently expressed genes in placental tissues with and without zinc supplementation, and GO and KEGG analyses showed these differently expressed genes were highly enriched in cell invasion and migration and STAT3 pathway. Protein-protein interaction(PPI) analysis found that STAT3 interacted with matrix metalloproteinase-2/9 (MMP-2/9). In vivo, western blot results authenticated that the expression levels of phospho-STAT3, STAT3, MMP-2 and MMP-9 were up-regulated in placental tissues after zinc treatment. To validate whether zinc could promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 activity. In vitro, Transwell assay was performed, and we observed that abilities of invasion and migration were obviously increased in zinc treated trophoblast cells. And phospho-STAT3, STAT3, MMP-2 and MMP-9 expression levels were correspondingly increased in zinc treated trophoblast cells, which were dose dependent. Moreover, gain-of-function and loss-of-function of STAT3 confirmed that zinc promotes cell invasion and migration via regulating STAT3 mediated up regulation of MMP-2/9 activity. We propose that activation of MMP-2/9 mediated by STAT3 may contribute to invasion and migration of trophoblast cells, which improved neurodevelopmental impairment of FGR rats probably via contributing to placental development. Our findings are the first to show a possible mechanism of reversing neurodevelopmental impairment of FGR rats by zinc supplementation, holding promise for the development of novel therapeutic modalities for learning and memory abilities impairment caused by FGR. PMID- 29383153 TI - Reciprocal crosstalk between endometrial carcinoma and mesenchymal stem cells via transforming growth factor-beta/transforming growth factor receptor and C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 aggravates malignant phenotypes. AB - Designated for cyclic shedding, the endometrial stroma is rich in endometrial mesenchymal stem cells (EMSCs) and may play an important role in the development of endometrial carcinoma (EC). This study characterized the crosstalk of EC cells with EMSCs and the resultant effects on malignant phenotypes. The cultured EMSCs expressed CD73, CD90, and CD105, but not CD14, CD19, CD34, CD45, or human leukocyte antigen-antigen D related markers. These EMSCs also showed osteogenic, adipogenic, and chondrogenic differentiation ability. Transforming growth factor (TGF)-beta1 and C-X-C motif chemokine ligand 12 (CXCL12) secretion or expression were reciprocally enhanced in EC cells and EMSCs, as well as in their tissues. By acting on the receptors expressed in their mutual target cells, the interaction between TGF-beta and CXCL12 results in the enhanced migration, invasion, tumorigenesis, and epithelial-mesenchymal transition of EC cells, which can be blocked by neutralizing the antibody of either CXCL12 or C-X-C chemokine receptor type 4. The study revealed unprecedented paracrine interactions between EC cells and EMSCs that resulted in the enhancement of transformation phenotypes. Thus, the blocking of TGF-beta or CXCL12 signaling can be a therapeutic target for EC. PMID- 29383154 TI - An ultrastructural investigation of tumors undergoing regression mediated by immunotherapy. AB - While immunotherapy employing chimeric antigen receptor (CAR) T cells can be effective against a variety of tumor types, little is known about what happens within the tumor at an ultrastructural level during tumor regression. Here, we used transmission electron microscopy to investigate morphologic and cellular features of tumors responding to immunotherapy composed of adoptive transfer of dual-specific CAR T cells and a vaccine, supported by preconditioning irradiation and interleukin-2. Tumors responded rapidly, and large areas of cell death were apparent by 4 days after treatment. The pleomorphic and metabolically active nature of tumor cells and phagocytic activity of macrophages were apparent in electron microscopic images of tumors prior to treatment. Following treatment, morphologic features of various types of tumor cell death were observed, including apoptosis, paraptosis and necrosis. Large numbers of lipid droplets were evident in tumor cells undergoing apoptosis. Macrophages were the predominant leukocyte type infiltrating tumors before treatment. Macrophages decreased in frequency and number after treatment, whereas an increasing accumulation of neutrophils and T lymphocytes was observed following treatment. Phagocytic activity of macrophages and neutrophils was apparent, while T cells could be observed in close association with tumor cells with potential immunological synapses present. These observations highlight the cellular composition and ultrastructural appearance of tumors undergoing regression mediated by immunotherapy. PMID- 29383155 TI - Circulating cell-free DNA content as blood based biomarker in endometrial cancer. AB - Background: Altered circulating cell-free DNA (cfDNA) levels are related to cancer development and aggressiveness. Up to now, very few studies have been performed for evaluating cfDNA content in endometrial cancer (EC). Methods: First, we measured cfDNA release in blood serum of EC cancer patients collected before surgery and before the beginning of any treatment by SYBR Gold assay and correlated it with tumor aggressiveness. We also assessed the relative mitochondrial cell-free DNA (cfmtDNA) content by qRT-PCR. Next, we correlated cfDNA levels with BMI, age, hypertension and inflammation markers. Results: CfDNA levels are higher in G2 and G3 compared with G1 EC sera. A significant modulation of cfDNA content was detected in sera from patients with BMI>30 compared with those with BMI<30. We observed a further and significant alteration in cfDNA level in hypertensive patients with G2-G3, but not in G1 EC. Analysis of preoperative neutrophil-to-lymphocyte (NLR) and monocyte-to-lymphocyte (MLR) ratios suggests a contribution of the host response in the altered cfDNA levels in EC. Conclusions: Our data indicate that assessment of total and mitochondrial cfDNA levels in blood sera and the relative NLR and MLR in blood obtained from preoperative patients may help clinical management and prognosis in EC. PMID- 29383156 TI - Expression of CCR6 in esophageal squamous cell carcinoma and its effects on epithelial-to-mesenchymal transition. AB - Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis. We detected the expression of C-C motif chemokine receptor 6 (CCR6) and epithelial-to-mesenchymal transition (EMT) markers in esophageal tissues/cells, and evaluated the effects of CCR6 on ESCC cells proliferation, migration and invasion in response to C-C motif chemokine ligand 20 (CCL20) treatment. Our data showed CCR6 was highly expressed in ESCC cell lines (ECA-109 and TE-1), whereas kept in a low expression in normal cell lines HEEC (P < 0.001). CCL20 stimulus induced a significant decrease in the proliferation ability of ESCC (P < 0.05). The healing speed of CCL20 group was significantly higher than control in ECA-109 (P < 0.01), whereas significantly lower in alphaCCR6+CCL20 group than CCL20 group (P < 0.05).The number of cells permeabling through the polycarbonate membrane in CCL20 group was higher than control (P < 0.01). The cell number in alphaCCR6+CCL20 group was significantly reduced compared to CCL20 group in ECA-109 (P < 0.05). Moreover, after CCL20 stimulated in ECA-109, both mRNA and protein level of E-cadherin significantly decreased compared to control, while Vimentin was significantly higher. In alphaCCR6+CCL20 group, mRNA and protein level of E-cadherin significantly increased compared to CCL20 group, while Vimentin was much lower than CCL20 group. There was no significant difference in TE-1. In summary, high expression of CCR6 existed in the lymph node metastasis and TNM stage of ESCC. CCR6 play an important role in the regulation of tumor cell proliferation, invasion and migration. CCR6 may participate in regulating the occurrence of EMT in ESCC. PMID- 29383157 TI - Celecoxib targets breast cancer stem cells by inhibiting the synthesis of prostaglandin E2 and down-regulating the Wnt pathway activity. AB - Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs is responsible for tumor initiation, progression, recurrence and chemo-resistance. Celecoxib is one of the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs), which have chemo-preventive activity against cancers, including breast cancer and colorectal cancer. However, the mechanisms by which NSAIDs exert its cancer prevention effects have yet been completely understood. In the present study, we investigated for the first time the effect of celecoxib on breast CSCs inhibition and its potential molecular mechanisms. Our results demonstrated that celecoxib suppresses CSC self-renewal, sensitizes chemo-resistance, inhibits epithelial to mesenchymal transition (EMT), and attenuates metastasis and tumorigenesis. Further exploring the underlying mechanism revealed that celecoxib targets breast CSCs by inhibiting the synthesis of prostaglandin E2 and down regulating the Wnt pathway activity. Our findings suggest that celecoxib, by targeting CSCs, may be used as an adjuvant chemotherapy drug to improve breast cancer treatment outcomes. PMID- 29383158 TI - The serum activity of thioredoxin reductases 1 (TrxR1) is correlated with the poor prognosis in EGFR wild-type and ALK negative non-small cell lung cancer. AB - Background: The thioredxin reductases 1 (TrxR1) is one of the major antioxidant and redox regulators in mammalian cells. Studies have shown that TrxR1 is over expressed in many malignancy diseases. However, few studies have evaluated the role of TrxR1 in non-small cell lung cancer (NSCLC). Methods: Serum levels of TrxR1 and CEA in 142 patients with EGFR wild type and ALK negative advanced NSCLC was measured by ELISA assay before first line standard doublet chemotherapy from June 2013 to February 2016 in Hunan Cancer Hospital. Clinical characteristics and Survival data were collected and analyzed according to serum TrxR1 levels. Results: No significant differences were founded from clinic pathological variables. With the cut-off value of 12U/mL, the lower serum TrxR1 activity patients had long progression-free survival (PFS) and overall survival (OS) compared with higher patients (PFS: 5.3m vs. 3.6m p=0.044, OS: 14.5m vs. 11m p<0.001). In subgroup, lower serum TrxR1 activity patients had long OS both in adenocarcinoma (ADC) (17m vs. 8m, p=0.003) and squamous cell carcinoma (SCC) (13m vs. 11m, p=0.035). While combining with TrxR1 activity and serum CEA concentrations, we founded that patients with lower serum TrxR1 activity and serum CEA concentrations had long OS compared with higher group patients (20m vs. 7m, p<0.001). Conclusions: Serum TrxR1 activity was not affected by clinic pathological variables. Measurement of serum TrxR1 activity might be an independent prognostic factor for EGFR wild type and ALK negative advanced NSCLC patients. Combination of serum TrxR1 activity and serum CEA concentrations need to be further profiled from bench to beside. PMID- 29383159 TI - Role of DDX3 in the pathogenesis of inflammatory bowel disease. AB - When crypt stem cells of the gastrointestinal tract become injured, the result is increased synthesis of pro-inflammatory cytokines and matrix metalloproteinases by their progeny - the colonic epithelium. Chronic inflammation of the gastrointestinal tract is a characteristic of inflammatory bowel disease, which includes Crohn's Disease and Ulcerative Colitis. In our ongoing investigation to decipher the characteristic functions of a RNA helicase gene, DDX3, we identified high DDX3 expression by immunohistochemistry of colon biopsy samples, which included chronic/mild Morbus Crohn, active Morbus Crohn, Chronic/mild Colitis Ulcerosa and active Colitis Ulcerosa in epithelium and stromal compartments. We used a small molecule inhibitor of DDX3, RK-33, on two human colonic epithelial cell lines, HCEC1CT and HCEC2CT and found that RK-33 was able to decrease expression of MMP-1, MMP-2, MMP-3, and MMP-10. Moreover, forced differentiation of a human colonic cancer cell line, HT29, resulted in decreased DDX3 levels, indicating that DDX3 contributes to the modulation of colonic epithelium differentiation. In conclusion, our results revealed novel functions of DDX3 in inflammatory bowel disease and indicate a potential for using RK-33 as a systemic therapy to promote not only differentiation of transformed colonic epithelium but also to reduce MMP expression and thus elicit a decreased inflammatory response. PMID- 29383160 TI - HMGA2 overexpression predicts relapse susceptibility of blastemal Wilms tumor patients. AB - Wilms tumor (WT) is an embryonal malignant neoplasm of the kidney that accounts for 6-7% of all childhood cancers. WT seems to derive from multipotent embryonic renal stem cells that have failed to differentiate properly. Since mechanisms underlying WT tumorigenesis remain largely unknown, the aim of this study was to explore the expression of embryonic stem cell (ESC) markers in samples of WT patients after chemotherapy treatment SIOP protocol, as the gene expression patterns of ESC are like those of most cancer cells. We found that expression of ESC markers is heterogeneous, and depends on histological WT components. Interestingly, among ESC markers, HMGA2 was expressed significantly stronger in the blastemal component than in the stromal and the normal kidney. Moreover, two subsets of patients of WT blastemal type were identified, depending on the expression levels of HMGA2. High HMGA2 expression levels were significantly associated with a higher proliferation rate (p=0.0345) and worse patient prognosis (p=0.0289). The expression of HMGA2 was a stage-independent factor of clinical outcome in blastemal WT patients. Our multivariate analyses demonstrated the association between LIN28B-LET7A-HMGA2 expression, and the positive correlation between HMGA2 and SLUG expression (p=0.0358) in blastemal WT components. In addition, patients with a poor prognosis and high HMGA2 expression presented high levels of MDR3 (multidrug resistance transporter). Our findings suggest that HMGA2 plays a prominent role in the pathogenesis of a subset of blastemal WT, strongly associated with relapse and resistance to chemotherapy. PMID- 29383161 TI - Impact of prenatal cold stress on placental physiology, inflammatory response, and apoptosis in rats. AB - Prenatal cold stress is one of the earliest factors affecting mammalian health, and is associated with neonatal growth retardation and immune dysfunction, thus increasing disease susceptibility. The mechanisms underlying these observations remain unclear; hence, the objective of this study was to elucidate placental responses to cold stress. 60 maternal rats were randomly allocated to either stressed (n = 30) or non-stressed (control, n = 30) treatment conditions and 30 pubs (n=15) were used for the pups analysis. We found that maternal exposure to cold stress resulted in decreased body temperature, increased food intake without body weight gain, and a high level of plasma corticosterone (CORT) between gestational day (GD) 14 and GD21. In addition, gestation cold stress induced the placental expression of heat shock protein 70 (HSP70), IkappaBalpha, glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11beta hydroxysteroid dehydrogenase 2 (11beta-HSD2), interferon (IFN) regulatory factor 3 (IRF3), Caspase-3 proteins and altered the ratio of B-cell lymphoma-extra large (Bcl-xL) to Bcl-associated x (Bax) proteins on gestational GD15, GD17, GD19, and GD21, also resulted in the production of interleukin (IL)-1beta. Next, gestational cold stress provoked a decrease in plasma GH levels of 21-day-old offspring, and the body weights of offspring were have no differences from postnatal day (PD) 1-21. Taken together, our results indicate that gestational cold stress induces placental apoptosis and the activation of NF-kB via HSP70/TLR4/NF-kappaB signaling pathways in the placenta, these changes may affect placental function and fetus development. PMID- 29383162 TI - Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion. AB - Gemcitabine, an anti-cancer chemotherapy drug, has additionally shown the antiviral activity against a broad range of viruses and we also have previously reported its synergistic antiviral activity with ribavirin against enteroviruses. As a cytidine analog, gemcitabine has been reported to have an inhibitory activity on the pyrimidine biosynthesis. In addition, a few inhibitors of the pyrimidine biosynthesis have shown to induce the innate immunity in a yet-to-be determined manner and inhibit the virus infection. Thus, we also investigated whether the anti-enteroviral activity of gemcitabine is mediated by innate immunity, induction of which is related with the inhibition of the pyrimidine synthesis. In this study, we found that the addition of exogenous cytidine, uridine and uridine mono-phosphate (UMP) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon harboring cells, demonstrating gemcitabine's targeting of the salvage pathway. Moreover, the expression of several interferon (IFN)-stimulated genes (ISGs) was significantly induced by the treatment of gemcitabine, which was also suppressed by the co-treatment with cytidine. These results suggest that the antiviral activity of gemcitabine involves ISGs induced by the inhibition of the pyrimidine biosynthesis. PMID- 29383163 TI - Reduced representation bisulfite sequencing (RRBS) of dairy goat mammary glands reveals DNA methylation profiles of integrated genome-wide and critical milk related genes. AB - DNA methylation (DNAm), a major element of epigenetics, plays critical roles in individual development. Reduced representation bisulfite sequencing (RRBS) is an effective and economical method for analyzing the DNA methylation of a single base. The aims of this study were to determine the DNAm profiles of the methylation contexts (CGs and non-CGs) of lactation and dry periods of goat mammary glands using the RRBS, and to identify potential milk-related genes. The proportion of CG was the highest among all the sequence contexts. The highest CG levels (72.44% to 75.24%) occurred in the 3' UTR region, followed by the gene body region (61.14% to 65.45%). The non-CG levels were low compared to the CG levels. Bioinformatic analysis demonstrated that the CGs were mainly enriched at high methylation levels (>90%), while non-CGs were enriched at low methylation levels. Methylation levels of 95 and 54 genes in the lactation period were up- or downregulated, respectively, relative to the dry period, such as PPARalpha, RXRalpha and NPY genes. The bisulfite sequencing PCR results showed that the methylation level of goat PPARalpha gene during the lactation period was significant lower than in the dry period, while the methylation level of the RXRalpha gene was lower in the dry period than in the lactation period. Meanwhile, the methylation levels of human PPARalpha and NPY genes were significantly higher in MCF-7 than in MCF-10A cells. These findings provide essential information for DNA methylation profiles of goat mammary gland and detect some potential milk-related genes in dairy goats. PMID- 29383164 TI - Regulation of macrophage migration in ischemic mouse hearts via an AKT2/NBA1/SPK1 pathway. AB - The role of the AKT2/NBA1/SPK1 signaling cascade in macrophage migration regulation and post-ischemic cardiac remodeling was investigated. We determined that the AKT2/NBA1/SPK1 signaling cascade regulated macrophage migration. A novel role for NBA1 in macrophage migration was discovered. Elevated AKT2 phosphorylation, NBA1, SPK1 (along with phosphorylated SPK1) levels, macrophage recruitment, apoptosis, and fibrosis were found within the infarct area. Atorvastatin had a beneficial effect on cardiac remodeling following myocardial infarction by inhibiting AKT2/NBA1/SPK1-mediated macrophage recruitment, apoptosis, and collagen deposition while increasing angiogenesis in the infarct area. Atorvastatin-related protection of cardiac remodeling following myocardial infarction was abolished in SPK1-KO mice. The AKT2/NAB1/SPK1 pathway is a novel regulating factor of macrophage migration and cardiac remodeling after myocardial infarction. PMID- 29383165 TI - Gefitinib enhances sensitivity of endometrial cancer cells to progestin therapy via dual-specificity phosphatase 1. AB - In this study, we investigated if Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, augments endometrial cancer (EC) therapy with medroxyprogesterone acetate (MPA). Combined treatment with Gefitinib plus MPA decreased the proliferation and invasiveness of the Ishikawa and RL952 EC cell lines more effectively than MPA treatment alone. Moreover, combined treatment with Gefitinib plus MPA reduced growth of EC xenografts in Balb/c nude mice more than either Gefitinib or MPA alone. The therapeutic efficacy of combined Gefitinib plus MPA treatment was dependent on expression of dual-specificity phosphatase 1 (DUSP1). DUSP1 knockdown in Ishikawa cells treated with Gefitinib plus MPA showed greater proliferation and invasiveness than parental Ishikawa cells treated similarly. EC cells treated with the combination of Gefitinib plus MPA also showed DUSP1-dependent reductions in phospho-ERK1/2 and increases in E Cadherin. Thus, Gefitinib appears to DUSP1-dependently enhance the therapeutic efficacy of progestin in EC cells. PMID- 29383166 TI - GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis. AB - Dysregulated JAK/STAT signaling has been implicated in the molecular pathogenesis of gastric cancer. However, downstream effectors of STAT signaling that facilitate gastric carcinogenesis remain to be explored. We previously identified the Drosophila ortholog of human GRAMD1B in our genome-wide RNAi screen to identify novel components of the JAK/STAT signaling pathway in Drosophila. Here, we examined the involvement of GRAMD1B in JAK/STAT-associated gastric carcinogenesis. We found that GRAMD1B expression is positively regulated by JAK/STAT signaling and GRAMD1B inhibition decreases STAT3 levels, suggesting the existence of a positive feedback loop. Consistently, GRAMD1B and JAK/STAT signaling acted synergistically to promote gastric cancer cell survival by upregulating the expression of the anti-apoptotic molecule Bcl-xL. Interestingly, our immunohistochemical analysis for GRAMD1B revealed a gradual loss of cytoplasmic staining but an increase in the nuclear accumulation of GRAMD1B, as gastric tissue becomes malignant. GRAMD1B expression levels were also found to be significantly associated with clinicopathological features of the gastric cancer patients, particularly the tumor grades and lymph node status. Moreover, GRAMD1B and pSTAT3 (Tyr705) showed a positive correlation in gastric tissues, thereby confirming the existence of a close link between these two signaling molecules in vivo. This new knowledge about JAK/STAT-GRAMD1B regulation deepens our understanding of JAK/STAT signaling in gastric carcinogenesis and provides a foundation for the development of novel biomarkers in gastric cancer. PMID- 29383167 TI - Dual roles of IL-22 at ischemia-reperfusion injury and acute rejection stages of rat allograft liver transplantation. AB - Interleukin-22 (IL-22) is a recently identified regulator of inflammation, but little is known about its role in liver transplantation. Therefore, in this study, we explored the roles and the underlying mechanisms of IL-22 in acute allograft rejection by using a rat allogeneic liver transplantation model. Results showed that allograft liver transplantation led to damage of the parent liver and to significantly increased IL-22 expression in the allograft liver and plasma of the recipient rats compared with the rats who received isografts. Moreover, the significantly increased IL-22 expression was accompanied by markedly increased level of phospho-STAT3 in the allogeneic liver tissues after transplantation. Of note, neutralization of the IL-22 protein in recipient rats significantly worsened the function of the allograft liver at 1 day post transplantation (ischemia-reperfusion injury, IRI) but improved the function at 7 days post-transplantation (acute rejection, AR). At IRI stage, IL-22 protected liver function through the increase of anti-apoptosis and pro-regeneration cytokines. However, IL-22 led to the increase of pro-inflammation factors at AR stage, accompanied by the marked increase of the Th17 and the marked decrease of Treg cells in allograft recipient rats through modulating the expression of chemokines for different cell types, which however were reversed by in vivo IL-22 neutralization. Results indicate the dual roles of IL-22 and suggest the differential potential clinical application of IL-22 at different stage of allograft liver transplantation. PMID- 29383168 TI - Cryptotanshinone induces ROS-mediated apoptosis in human gastric cancer cells. AB - Cryptotanshinone (CT), isolated from the plant Salvia miltiorrhiza Bunge, has been reported to have potential anticancer effects on human prostate and breast cancer cells. However, the mechanisms of action of CT on gastric cancer (GC) cells are not well understood. Here we investigated the antitumor effects of CT on GC cells and its possible molecular mechanism. We found CT suppressed viability of twelve GC cell lines in a dose-dependent manner. CT induced cell cycle arrest at the G2/M phase and mitochondrial apoptosis accompanying the accumulation of reactive oxygen species (ROS). Pretreatment with ROS inhibitor N acetyl-L-cysteine (NAC) blocked CT-induced apoptosis. CT increased p-JNK and p p38, and decreased p-ERK and p-STAT3 protein expression, these effects were prevented by NAC. Furthermore, a xenograft assay showed that CT significantly inhibited MKN-45 cell-induced tumor growth in vivo by increasing expression of pro-apoptotic proteins (p-JNK, p-38 and cleaved-caspase-3) and reducing expression of anti-apoptotic proteins (p-ERK and p-STAT3) without adverse effects on nude mice weight. In conclusion, CT induced apoptosis and cell cycle arrest in GC cells via ROS-mediated MAPK and AKT signaling pathways, and this CT may be a useful compound for the developing anticancer agents for GC. PMID- 29383169 TI - P53-derived hybrid peptides induce apoptosis of synovial fibroblasts in the rheumatoid joint. AB - Loss of p53-mediated suppression by its dominant-negative counterpart is commonly observed in human cancers, and activating p73 is a therapeutic strategy in p53 mutated oncological patients. In synovial fibroblasts (SFs) from rheumatoid arthritis (RA), mutant p53 can lead to the transformation-like features with resistance to the apoptosis induction. We examined whether intra-articular (i.a.) administration of p53-derived hybrid peptides to activate p73 can induce apoptosis of SFs by using adenoviral vectors encoding 37 amino acid (Ad37AA), a p53-derived hybrid peptide capable of activating p73, to transduce SFs in vitro and inject collagen-induced arthritis (CIA) joints in vivo. Increased p73 expression was found in synovial lining layers and SFs of RA patients and CIA rats. Higher expression of p53 up-regulated modulator of apoptosis (PUMA) and Bax with enhanced apoptosis were found in Ad37AA-transduced SFs, and silencing p73 abrogated the up-regulation of PUMA and Bax. Articular indexes and histologic scores were reduced in Ad37AA-injected joints with decreased SF densities, increased apoptotic cell numbers, and higher PUMA expression levels. We demonstrate that i.a. administration of p53-derived hybrid peptides can activate p73 to induce apoptosis of SFs and ameliorate the rheumatoid joint, implicating an enhancement of the p73-dependent apoptotic mechanism as a pharmacological strategy in the RA therapy. PMID- 29383170 TI - Dimeric and tetrameric forms of muscle fructose-1,6-bisphosphatase play different roles in the cell. AB - Muscle fructose 1,6-bisphosphatase (FBP2), besides being a regulatory enzyme of glyconeogenesis also protects mitochondria against calcium stress and plays a key role in regulation of the cell cycle, promoting cardiomyocytes survival. However, in cancer cells, FBP2 acts as an anti-oncogenic/anti-proliferative protein. Here, we show that the physiological function of FBP2 depends both on its level of expression in a cell as well as its oligomerization state. Animal fructose-1,6 bisphosphatases are thought to function as tetramers. We present evidence that FBP2 exists in an equilibrium between tetramers and dimers. The dimeric form is fully active and insensitive to AMP, the main allosteric inhibitor of FBP2. Tetramerization induces the sensitivity of the protein to AMP, but it requires the presence of a hydrophobic central region in which leucine 190 plays a crucial role. Only the tetrameric form of FBP2 is retained in cardiomyocyte cell nucleus whereas only the dimeric form associates with mitochondria and protects them against stress stimuli, such as elevated calcium and H2O2 level. Remarkably, in hypoxic conditions, which are typical for many cancers, FBP2 ceases to interact with mitochondria and loses its pro-survival potential. Our results throw new light on the basis of the diverse role of FBP2 in cells. PMID- 29383171 TI - Synergistic neuroprotective effects of Danshensu and hydroxysafflor yellow A on cerebral ischemia-reperfusion injury in rats. AB - Ischemic stroke is a common cerebrovascular disease with substantial morbidity and mortality worldwide. However, therapeutic options to minimize the cerebral ischemia-reperfusion (I/R) injury are limited. In China, combination of herb Danshen (Salvia miltiorrhiza Bge) and Honghua (Carthamus tinctorius L.) is effective for stroke treatment in patients but its underlying mechanism requires further investigation. Our study was conducted to evaluate and explore the synergistic effects of two herb ingredients Danshensu and hydroxysafflor yellow A (HSYA) on cerebral ischemia-reperfusion (I/R) injury in rats. Rats were randomly assigned to the following five groups: sham group, model group, Danshensu group, HSYA group, and Danshensu+HSYA group. Under our experimental conditions in vitro, oxygen-glucose deprivation (OGD) model was established to determine the synergistic neuroprotective effects of Danshensu and HSYA. With such methods as neurological deficits scoring, TTC, HE and TUNEL staining, and ELISA detection, the results demonstrated that administration of either Danshensu or HSYA improved neurological defects and alleviated pro-inflammatory and oxidative stress reactions. Notably, combination of Danshensu and HSYA exerted more effective results than that used alone. Furthermore, western blot analysis results showed that Danshensu and HSYA combination displayed synergistic regulation on TLR4/NF kappaB and Nrf2/HO-1 pathways. Consistently, Danshensu +HSYA group exhibits better neuroprotection in primary neurons with OGD model compared with Danshensu or HSYA group. Taken together, we found for the first time that Danshensu plus HSYA could achieve remarkable synergistic neuroprotective effects on I/R injury, which is related to the anti-inflammatory and antioxidant pathways. PMID- 29383172 TI - Novel prognostic marker PRMT1 regulates cell growth via downregulation of CDKN1A in HCC. AB - Hepatocellular carcinoma (HCC) is a major type of liver cancer caused by the hepatitis B and C viruses, alcohol and exposure to aflatoxin. For HCC treatment, anticancer drugs have been widely used, but drug resistance in advanced HCC is an important problem, resulting in a continuous need for novel therapeutic targets. Therefore, in this study, we established a screening pipeline based on RNA-seq to screen novel therapeutic/prognostic targets in HCC and identified PRMT1 (Protein Arginine Methyltransferase 1). In the prognostic analysis, the overexpression of PRMT1 was clearly associated with poor prognosis in a number of HCC patient cohorts. Moreover, after PRMT1 knockdown, HCC cell lines exhibited cell growth and spheroid formation suppression, an increase in Sub-G1 cells by FACS analysis, and enrichment of the cell cycle pathway via functional enrichment analysis. With these results, we demonstrated that PRMT1 could be a novel prognostic marker and therapeutic target for HCC therapy. PMID- 29383173 TI - Clinical relevance of LINC00152 and its variants in western Chinese tuberculosis patients. AB - Recent studies indicate that the long intergenic non-coding RNA LINC00152 plays crucial roles in various human diseases. Here, we investigated whether levels of LINC00152 or its genetic variants correlate with the clinical features of tuberculosis (TB) in western Chinese patients. We genotyped the single nucleotide polymorphism LINC00152 rs80292941 in 476 TB patients and 475 healthy subjects using a custom-by-design 48-Plex SNPscan Kit, and measured relative levels of LINC00152 using RT-qPCR. We observed that LINC00152 levels were lower in TB patients than controls. Moreover, rs80292941 TT genotype carriers had the lowest LINC00152 levels among TB patients, and rs80292941 AA genotype carriers are more likely to suffer from hepatotoxicity induced by antituberculosis therapy [OR = 3.97, 95% = 1.53-10.13, p = 0.002]. Our findings strongly suggest that LINC00152 may promote TB progression and highlight rs80292941 single nucleotide polymorphism as a novel predisposition marker for antituberculosis drug-induced hepatotoxicity. PMID- 29383174 TI - Addition of 5-fluorouracil to docetaxel/cisplatin does not improve survival in locoregionally advanced nasopharyngeal carcinoma. AB - Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) is a potentially effective approach for treating locoregionally advanced nasopharyngeal carcinoma (NPC). In this study, we compared the efficacy and toxicity of IC regimens consisting of docetaxel plus cisplatin with (TPF) or without (TP) 5-fluorouracil followed by CCRT in these patients. Clinical data from 245 propensity score-matched pairs of newly diagnosed non-metastatic NPC patients who received either TPF or TP IC before CCRT were retrospectively reviewed. After a median follow-up of 60 months, 5-year locoregional relapse free, distant metastasis-free, progression-free, and overall survival rates were 95.6%, 94.7%, 90.4%, and 92.9% in TPF arm patients and 96.7%, 94.2%, 91.7%, and 91.0% in TP arm patients, respectively. There were thus no differences in survival between the two arms. Multivariate analysis revealed that IC regimen was not an independent prognostic factor for any of the survival outcomes. However, patients who received TP experienced lower incidences of grade 3/4 toxicities than those who received TPF. These results indicate that omission of 5 fluorouracil from TPF-based IC did not affect survival outcomes, but was associated with reduced toxicity, in patients with locoregionally advanced NPC. PMID- 29383175 TI - Apancreatic pigs cloned using Pdx1-disrupted fibroblasts created via TALEN mediated mutagenesis. AB - Pancreatic and duodenal homeobox 1 (PDX1) plays a crucial role in pancreas development, beta-cell differentiation, and maintenance of mature beta-cell function. In this study, we designed a strategy to produce PDX1-knockout (KO) pigs. A transcription activator-like effector nuclease (TALEN) pair targeting exon 1 of the swine PDX1 gene was constructed. Porcine fetal fibroblasts (PFFs) were transfected with the TALEN plasmids plus a surrogate reporter plasmid. PDX1 mutated PFFs were enriched by magnetic separation and used to produce homozygous PDX1-KO pigs via a two-step somatic cell nuclear transfer (SCNT) cloning process. In the first SCNT step, we obtained eight fetuses, established PFF cell lines, and analyzed PDX1 gene mutations by T7 endonuclease 1 assays and Sanger sequencing. Five fetuses showed mutations at the PDX1 loci with two biallelic mutations and three monoallelic mutations (mutation rate of 62.5%). In the second step, a PDX1 biallelic mutant PFF cell line with a 2 bp deletion in one allele and a 4 bp insertion in the other allele was used as a donor to generate cloned pigs via SCNT. From 462 cloned embryos transferred into two surrogates, nine live piglets were delivered. These piglets at birth were not clearly distinguishable phenotypically from wild-type piglets, but soon developed severe diarrhea and vomiting and all died within 2 days after birth. Dissection of PDX1-KO piglets revealed that the liver, gallbladder, spleen, stomach, common bile duct, and other viscera were present and normal, but the pancreas was absent in all cases. PMID- 29383176 TI - Antidepressants, sertraline and paroxetine, increase calcium influx and induce mitochondrial damage-mediated apoptosis of astrocytes. AB - The impacts of antidepressants on the pathogenesis of dementia remain unclear despite depression and dementia are closely related. Antidepressants have been reported may impair serotonin-regulated adaptive processes, increase neurological side-effects and cytotoxicity. An 'astroglio-centric' perspective of neurodegenerative diseases proposes astrocyte dysfunction is involved in the impairment of proper central nervous system functioning. Thus, defining whether antidepressants are harmful to astrocytes is an intriguing issue. We used an astrocyte cell line, primary cultured astrocytes and neuron cells, to identify the effects of 11 antidepressants which included selective serotonin reuptake inhibitors, a serotonin-norepinephrine reuptake inhibitor, tricyclic antidepressants, a tetracyclic antidepressant, a monoamine oxide inhibitor, and a serotonin antagonist and reuptake inhibitor. We found that treatment with 10 MUM sertraline and 20 MUM paroxetine significantly reduced cell viability. We further explored the underlying mechanisms and found induction of the [Ca2+]i level in astrocytes. We also revealed that sertraline and paroxetine induced mitochondrial damage, ROS generation, and astrocyte apoptosis with elevation of cleaved-caspase 3 and cleaved-PARP levels. Ultimately, we validated these mechanisms in primary cultured astrocytes and neuron cells and obtained consistent results. These results suggest that sertraline and paroxetine cause astrocyte dysfunction, and this impairment may be involved in the pathogenesis of neurodegenerative diseases. PMID- 29383177 TI - A novel KCND3 mutation associated with early-onset lone atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in the clinic. While previous studies have identified AF-associated mutations in several genes, the genetic basis for AF remains unclear. Here, we identified a novel T361S missense mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) from a Chinese Han family ancestor with lone AF. The wild-type (WT) or mutant T361S of Kv4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K+ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (Ito) were recorded using patch-clamp methods, and the surface or total protein levels of Kv4.3 were analyzed by western blot. Ito density, measured at 60 mV, for T361S was significantly higher than that for WT. Both the steady-state activation and inactivation curves showed a remarkable hyperpolarizing shift in T361S. Moreover, recovery from inactivation after a 500-ms depolarizing pulse was significantly delayed for T361S compared with that for WT. Mechanistically, the gain of function of Ito elicited by T361S was associated with the increased expression of cell surface and total cell protein of Kv4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased Itoin Human Atrial Model. In conclusion, we identified a novel T361S mutation in KCND3 associated with AF in the Chinese Han family. The T361S mutant result in the changes in channel kinetics as well as the up-regulation of Kv4.3 protein, which may be a critical driver for lone AF as observed in the patient. PMID- 29383178 TI - Predictive value of 1H MR spectroscopy and 18F-FDG PET/CT for local control of advanced oropharyngeal and hypopharyngeal squamous cell carcinoma receiving chemoradiotherapy: a prospective study. AB - Purpose: To determine whether pretreatment in vivo 1H magnetic resonance (MR) spectroscopy at 3 Tesla (T) and 18F-FDG PET/CT can offer predictive power regarding the local control of oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) patients. Materials and Methods: 1H MR spectroscopy was performed in addition to conventional MR imaging before definitive chemoradiotherapy in 58 patients with advanced OHSCC. The relationship of local control with the 1H MR spectroscopy and 18F-FDG PET/CT parameters was analyzed. Results: With a median follow-up of 17.6 months, 13 (22.4%) patients exhibited local failure; whereas the remaining 45 achieved local control. Kaplan-Meier analysis identified age > 60 years, creatine level on MRS ? 6.02 mM, glutamine and glutamate (Glx) level on MRS > 3.31 mM, and total lesion glycolysis (TLG) on 18F-FDG PET/CT > 217.18 g/mL * mL as significant adverse predictors for 2-year local control. Multivariate Cox regression analysis showed that age (p=0.017), Glx level on MRS (p=0.021), and TLG on 18F-FDG PET/CT (p=0.028) retained their independent prognostic significance. A scoring system was constructed based on the sum of these three factors. We found that patients with scores of 2-3 had significantly poorer local control rates than patients with scores of 0-1 (33.3% versus 86.8%, p=0.003). Conclusion: We conclude that Glx on 1H MR spectroscopy at 3 T was the independent prognostic factor for local control of OHSCC patients treated with chemoradiotherapy, and its combination with age and TLG may help identify a subgroup of patients at high risk for developing local failure. PMID- 29383179 TI - Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer. AB - Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-kappaB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer. PMID- 29383180 TI - Significance of intratissue estrogen concentration coupled with estrogen receptors levels in colorectal cancer prognosis. AB - Dysregulation of estrogen related pathways is implicated colorectal cancer (CRC) development. However, significance of intratissue concentration of estrone (E1) and 17beta-estradiol (E2) in relation to estrogen receptor (ESR) expression level was not addressed so far. Herein, we measured E1 and E2 intratissue concentration using liquid chromatography electrospray ionization tandem mass spectrometry (ESI LC/MS) and mRNA levels of ESR1 and ESR2 using RT-qPCR in cancerous and histopathologically unchanged tissue from 75 and 110 CRC patients, respectively. The obtained results were associated with clinicopathological factors, expression of estrogen dependent genes (CTNNB1, CCND1) and prognostic significance. We found no statistically significant differences in E1 or E2 concentration between cancerous tissue and histopathologically unchanged counterparts. Moreover, mRNA levels of ESR1 and ESR2 were significantly decreased in cancerous tissue compared with histopathologically unchanged (p=0.00001). Log rank analysis revealed no benefit of low E1 to E2 ratio, high E1, E2 concentration or ESR1, ESR2 mRNA level for patients' overall (OS) and disease free survival (DFS). Interestingly, we have observed that patients with low ESR1 mRNA level coupled with low E1 intratissue concentration had a significant decrease in DFS compared with group of patients with high ESR1 mRNA level and high E1 concentration (HR=0.16, 95% CI 0.02-1.05; p=0.06). Furthermore, patients with low E1 concentration and low ESR1 transcript had significantly higher CTNNB1 and CCND1 mRNA level compare with subgroup with high level of both grouping factors. Our study indicates a potential value of estrogen intratissue concentration and its receptor expression level for CRC patients' prognosis. PMID- 29383182 TI - Transcriptomic analysis in pediatric spinal ependymoma reveals distinct molecular signatures. AB - Pediatric spinal ependymomas (SEPN) are important albeit uncommon malignant central nervous system tumors with limited treatment options. Our current knowledge about the underlying biology of these tumors is limited due to their rarity. To begin to elucidate molecular mechanisms that give rise to pediatric SEPN, we compared the transcriptomic landscape of SEPNs to that of intracranial ependymomas using genome-wide mRNA and microRNA (miRNA) expression profiling in primary tumour samples. We found that pediatric SEPNs are characterized by increased expression of genes involved in developmental processes, oxidative phosphorylation, cellular respiration, electron transport chain, and cofactor metabolic process. Next, we compared pediatric spinal and intracranial ependymomas with the same tumours in adults and found a relatively low number of genes in pediatric tumours that were shared with adult tumours (12.5%). In contrast to adult SEPN, down-regulated genes in pediatric SEPN were not enriched for position on chromosome 22. At the miRNA level, we found ten miRNAs that were perturbed in pediatric SEPN and we identified regulatory relationships between these miRNAs and their putative targets mRNAs using the integrative miRNA-mRNA network and predicted miRNA target analysis. These miRNAs include the oncomiR hsa miR-10b and its family member hsa-miR-10a, both of which are upregulated and target chromatin modification genes that are down regulated in pediatric SEPN. The tumor suppressor, hsa-miR-124, was down regulated in pediatric SEPN and it normally represses genes involved in cell-cell communication and metabolic processes. Together, our findings suggest that pediatric SEPN is characterized by a distinct transcriptional landscape from that of pediatric intracranial EPNs or adult tumors (both SEPNs and intracranial EPNs). Although confirmatory studies are needed, our study reveals novel molecular pathways that may drive tumorigenesis and could serve as biomarkers or rational therapeutic targets. PMID- 29383181 TI - The value of systemic inflammatory markers in identifying malignancy in mucinous pancreatic cystic neoplasms. AB - The treatment decision-making of mucinous pancreatic cystic neoplasm (PCN) has become a common clinical problem since the diagnostic accuracy of current tests in identifying malignancies in pancreatic cysts is limited. In this study, we aimed to validate the predictive value of systemic inflammatory factors in detecting malignant PCNs. Two hundred and forty-five patients with pathologically confirmed mucinous PCNs in a single Chinese institution were retrospectively analyzed. Receiver operating characteristic (ROC) curves were calculated to determine the optimal cut-off values and measure the diagnostic value. The results showed that neutrophil count (P = 0.009), lymphocyte count (P = 0.002), neutrophil-to-lymphocyte ratio (NLR, P < 0.001), platelet-to-lymphocyte ratio (PLR, P < 0.001) and lymphocyte-to-monocyte ratio (LMR, P < 0.001) were distributed differently among the various differentiation groups of PCN. The univariate analyses indicated that a neutrophil count >= 2.8 * 109/L (P = 0.024), lymphocyte count <= 1.9 * 109/L (P < 0.001), PLR >= 125 (P < 0.001), NLR >= 1.96 (P < 0.001), and LMR <= 4.29 (P < 0.001) were significantly associated with invasive carcinomas in PCN patients. In addition, the multivariate analyses demonstrated that PLR >= 125 and LMR <= 4.29 were independent predictors of invasive malignancies. The ROC curves exhibited the malignant detection utility of the independent factor-based predictive model with an area under the curve (AUC) of 0.858 (P < 0.001). In conclusion, systemic inflammatory markers provide a supportive and easily accessible tool for the preoperative diagnoses of malignant PCNs. PMID- 29383183 TI - Multi-color RGB marking enables clonality assessment of liver tumors in a murine xenograft model. AB - We recently introduced red-green-blue (RGB) marking for clonal cell tracking based on individual color-coding. Here, we applied RGB marking to study clonal development of liver tumors. Immortalized, non-tumorigenic human fetal hepatocytes expressing the human telomerase reverse transcriptase (FH-hTERT) were RGB-marked by simultaneous transduction with lentiviral vectors encoding mCherry, Venus, and Cerulean. Multi-color fluorescence microscopy was used to analyze growth characteristics of RGB-marked FH-hTERT in vitro and in vivo after transplantation into livers of immunodeficient mice with endogenous liver damage (uPA/SCID). After initially polyclonal engraftment we observed oligoclonal regenerative nodules derived from transplanted RGB-marked FH-hTERT. Some mice developed monochromatic invasive liver tumors; their clonal origin was confirmed both on the molecular level, based on specific lentiviral-vector insertion sites, and by serial transplantation of one tumor. Vector insertions in proximity to the proto-oncogene MCF2 and the transcription factor MITF resulted in strong upregulation of mRNA expression in the respective tumors. Notably, upregulated MCF2 and MITF expression was also observed in 21% and 33% of 24 human hepatocellular carcinomas analyzed. In conclusion, liver repopulation with RGB marked FH-hTERT is a useful tool to study clonal progression of liver tumors caused by insertional mutagenesis in vivo and will help identifying genes involved in liver cancer. PMID- 29383184 TI - Stabilization of Sur8 via PKCalpha/delta degradation promotes transformation and migration of colorectal cancer cells. AB - Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells. Fibroblast growth factor 2 (FGF2) is identified as an external regulator that stabilizes Sur8. Protein kinase C-alpha and -delta (PKCalpha/delta) are also identified as specific mediators of FGF2 regulation of Sur8 stability. PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. Sur8 mutations, which mimic phosphorylation by PKCalpha/delta and destabilized Sur8, suppress the FGF2 induced transformation and migration of CRC cells. The clinical relevance of Sur8 regulation by PKCalpha/delta is indicated by the inverse relationship between PKCalpha/delta and Sur8 expression in human CRC patient tissues. Overall, our findings demonstrate for the first time a regulatory mechanism of Sur8 stability involving cellular transformation and migration in CRC. PMID- 29383185 TI - GPER-independent inhibition of adrenocortical cancer growth by G-1 involves ROS/Egr-1/BAX pathway. AB - We previously demonstrated that treatment of the H295R adrenocortical cancer cell line with the non-steroidal, high-affinity GPER (G protein-coupled estrogen receptor 1) agonist G-1 reduced tumor growth in vitro and in vivo through a GPER independent action. Moreover, we observed that G-1 treatment induces cell-cycle arrest and apoptosis following a sustained ERK1/2 activation. However, the precise mechanisms causing these effects were not clarified. Starting from our preliminary published results, we performed a microarray study that clearly evidenced a strong and significative up-regulation of EGR-1 gene in H295R cells treated for 24h with micromolar concentration of G-1. The microarray findings were confirmed by RT-PCR and Western-blot analysis as well as by immunofluorescence that revealed a strong nuclear staining for EGR-1 after G-1 treatment. EGR-1 is a point of convergence of many intracellular signaling cascades that control tumor cell growth and proliferation as well as others that relate to cell death machinery. Here we found that the increased Egr-1 expression was a consequence of G-1-mediated ROS-dependent ERK activation that were promptly reversed by the presence of the antioxidant n-acetyl-cysteine. Finally, we observed that silencing EGR-1 gene expression reversed the main effects induced by G-1 in ACC cells, including upregulation of the negative regulator of cell cycle, p21Waf1/Cip1 and the positive regulator of mitochondrial apoptotic pathway, BAX, as well as the cell growth inhibition. The identified ROS/MAPK/Egr 1/BAX pathway as a potential off-target effect of the G-1 could be useful in implementing the pharmacological approach for ACC therapy. PMID- 29383186 TI - Bisphenol A induces cell cycle arrest in primary and prostate cancer cells through EGFR/ERK/p53 signaling pathway activation. AB - Bisphenol A (BPA) belongs to the class of chemicals known as endocrine disruptors and has been also involved in the pathogenesis and progression of endocrine related cancer such as breast and prostate cancers. Here, we have investigated the effect of BPA in human prostate cancer LNCaP cells and in human non transformed epithelial prostate EPN cells. Our data showed that BPA induces the down regulation of cyclin D1 expression and the upregulation of the cell cycle inhibitors p21 and p27, leading to cell cycle arrest. Interestingly, we found that the BPA anti-proliferative response depends on a strong and rapid activation of epidermal growth factor receptor (EGFR), which stimulates ERK-dependent pathway. This, in turn, induces expression of p53 and its phosphorylation on residue Ser15, which is responsible for cell cycle arrest. EGFR activation occurs upon a cross talk with androgen (AR) and estradiol receptor-beta (ERbeta) which are known to bind BPA. Altogether, these findings show a novel signaling pathway in which EGFR activation plays a key role on BPA-induced cell cycle inhibition through a pathway involving AR and ERbeta/EGFR complexes, ERK and p53. Our results provide new insights for understanding the molecular mechanisms in human prostate cancer. On the other, they could allow the development of new compounds that may be used to overcome human prostate cancer resistance to endocrine therapy in promising target therapeutic approaches. PMID- 29383187 TI - Anti-tumor efficacy of oncolytic reovirus against gastrointestinal stromal tumor cells. AB - Imatinib, a multitargeted receptor tyrosine kinase inhibitor, is used as the standard initial therapy against inoperable gastrointestinal stromal tumor (GIST). However, GIST can acquire resistance to imatinib within several years of therapy. The development of oncolytic reovirus as an anticancer agent has expanded to many clinical trials for various tumors. Here, we investigated whether reovirus has antitumor activity against GIST cells in the setting of imatinib sensitivity in vitro and in vivo. Cell proliferation and apoptosis assays were performed using a human GIST cell line, GIST-T1, and imatinib resistant GIST (GIST-IR) cells that we established. The molecular pathways responsible for cell damage by reovirus were explored using PCR-arrays and Western blots. Reovirus significantly induced apoptotic cell death in GIST-T1 and GIST-IR cells in vitro, despite differences in the activation of receptor tyrosine kinase pathways between GIST-T1 and GIST-IR. Molecular assays indicated the possibility that reovirus induces apoptotic cell death via Fas signaling. Furthermore, in vivo mouse tumor xenograft models demonstrated a significant anti tumor effect of reovirus on both GIST-T1 and GIST-IR cells. Our results demonstrate the therapeutic potential of reovirus against GIST. PMID- 29383188 TI - Microarray analysis of lung long non-coding RNAs in cigarette smoke-exposed mouse model. AB - Several studies have demonstrated the function of long nona?'coding RNAs (lncRNAs) in various biological processes, yet their role underlying the susceptibility to cigarette smoke (CS)-induced airway inflammation remains limited. In the present study, we aimed to profile the expression of lncRNAs and mRNAs in CS-exposed mice. C57BL/6 mice were assigned into a single cigarette smoking machine with or without CS exposure for 4 weeks, followed by lung tissue harvest and RNA isolation. Microarray analysis identified 108 lncRNAs and 119 mRNAs with differential expression levels in CS-exposed mouse lung tissue compared with those in control mice. The expression patterns of several lncRNAs were further confirmed by qRT-PCR. GO and pathway analyses showed that the altered mRNAs were mainly related to the processes of immune response, defense response and cell chemotaxis, cytokine-cytokine receptor interaction and chemokine signaling pathway. Moreover, a single lncRNA may co-expressed with several mRNAs, and so was the mRNA. Our findings uncovered the expression profile of lncRNAs and mRNAs in the lungs of CS-exposed mice, which may offer new insights into pathogenesis of CS-associated airway inflammatory disorders. PMID- 29383189 TI - Clinicopathological analysis of HOXD4 expression in diffuse gliomas and its correlation with IDH mutations and 1p/19q co-deletion. AB - Backgrounds: HOX (homologous box) is known as the dominant gene of vertebrate growth and cell differentiation. Abnormal expression of HOX gene in various tumors has attracted the attention of scholars. As a component of HOX clusters, HOXD4 plays a controversial role in the tumorigenesis of central nervous system. Results: The data demonstrated that and the results demonstrated that HOXD4 was overexpressed in glioma tissues compared to that of normal brain tissues. patients with high HOXD4 expression had a significant shorter survival than those with low HOXD4 expression in total glioma cohort (p<0.001), WHO Grade II cohort (p=0.003) and Grade III cohort (p<0.001), but not in Grade IV cohort when OS (overall survival) was analyzed (p=0.216). The findings were confirmed by the large-scale omics data analysis including lower-grade glioma (LGG) and glioblastoma multiforme (GBM) in TCGA (the cancer genome atlas) and CGGA (Chinese glioma genome atlas). Moreover, it was revealed that the expression of HOXD4 have a significant impact on the OS of Grade IV glioma with IDH wild-type and 1p/19q intact according to TCGA data. Methods: Clinicopathological analysis of HOXD4 expression in 453 glioma patients was performed in the current study. Expression of HOXD4 was evaluated by qPCR and immunohistochemical (IHC) staining. Univariate and multivariate analysis were conducted to investigate the prognostic role of HOXD4 in glioma patients. Conclusions: Expression of HOXD4 was closely related to the clinical outcomes of patients with gliomas, and HOXD4 may be a potential prognostic biomarker of gliomas. PMID- 29383190 TI - Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis. AB - Background: Organic cation transporters (OCT) are responsible for the uptake of a broad spectrum of endogenous and exogenous substrates. Downregulation of OCT is frequently observed in human hepatocellular carcinoma (HCC) and is associated with a poor outcome. The aim of our current study was to elucidate the impact of OCT3 on hepatocarcinogenesis. Methods: Transcriptional and functional loss of OCT was investigated in primary murine hepatocytes, derived from Oct3-knockout (Oct3 /-; FVB.Slc22a3tm1Dpb ) and wildtype (WT) mice. Liver tumors were induced in Oct3 /- and WT mice with Diethylnitrosamine and Phenobarbital over 10 months and characterized macroscopically and microscopically. Key survival pathways were investigated by Western Blot analysis. Results: Loss of Oct3-/- in primary hepatocytes resulted in significantly reduced OCT activity determined by [3H]MPP+ uptake in vivo. Furthermore, tumor size and quantity were markedly enhanced in Oct3-/- mice (p<0.0001). Oct3-/- tumors showed significant higher proliferation (p<0.0001). Ki-67 and Cyclin D expression were significantly increased in primary Oct3-/- hepatocytes after treatment with the OCT inhibitors quinine or verapamil (p<0.05). Functional inhibition of OCT by quinine resulted in an activation of c Jun N-terminal kinase (Jnk), especially in Oct3-/- hepatocytes. Conclusion: Loss of Oct3 leads to enhanced proliferation and hepatocarcinogenesis in vivo. PMID- 29383191 TI - Comparison of transanal endoscopic microsurgery with or without neoadjuvant therapy and standard total mesorectal excision in the treatment of clinical T2 low rectal cancer: a meta-analysis. AB - Some clinical trials demonstrated local resection for clinical T1 rectal cancer was safe and effective. But for clinical T2 rectal cancer, the results were controversial. Neoadjuvant therapy (NT) is proven to reduce the opportunity of advanced rectal cancer recurrence in various researches. The objective of this Meta-Analysis was to evaluate the oncological outcomes of transanal endoscopic microsurgery (TEM) with or without NT comparing with conventional total mesorectal excision (TME) for the treatment of clinical T2 rectal cancer.To search for the relevant studies, an electronic search was done from the databases of Pubmed, Embase, and the Cochrane Library in this meta-analysis. We compared the effectiveness of transanal endoscopic microsurgery with or without NT and standard total mesorectal excision in the treatment of T2 Rectal Cancer. 1RCT and 3nRCTs including 121 TEM patients (TEM + NT: 59, TEM: 62) and 174 TME patients with T2 rectal cancer were retrieved. Compared with TME, there were no significant differences in the outcomes of local recurrence, overall recurrence, overall survival between TEM + NT group. However in compassion with TME, TEM without NT was associated with an increased local recurrence, overall recurrence, and a shorter overall survival, with individual ORs being 3.04 (95% Cl: 1.17 7.90; I2 = 0%), 5.67 (95% Cl: 1.58-20.38; I2 = 0%) and 0.12 (95% Cl: 0.02-0.65; I2 = 0%), respectively. Compared with TME, TEM after NT may be a feasible and safe organ preservative approach for patients with clinical T2 low rectal cancer. But for those without NT, TEM always seem be associated with worse oncological outcomes. PMID- 29383192 TI - Meta-analysis of the correlation between Helicobacter pylori infection and autoimmune thyroid diseases. AB - Objective: This study presents a systematic meta-analysis of the correlation between Helicobacter pylori (H. pylori) infection and autoimmune thyroid diseases (AITD). Materials and Methods: Fifteen articles including 3,046 cases were selected (1,716 observational and 1,330 control cases). These data were analyzed using Stata12.0 meta-analysis software. Results: H. pylori infection was positively correlated with the occurrence of AITD (OR = 2.25, 95% CI: 1.72-2.93). Infection with H. pylori strains positive for the cytotoxin-associated gene A (CagA) were positively correlated with AITD (OR = 1.99, 95% CI: 1.07-3.70). There was no significant difference between infections detected using enzyme-linked immunosorbent assay (ELISA) and other methods (chi2 = 2.151, p = 0.143). Patients with Grave's disease (GD) and Hashimoto's thyroiditis (HT) were more susceptible to H. pylori infection (GD: OR = 2.78, 95% CI: 1.68-4.61; HT: OR = 2.16, 95% CI: 1.44-3.23), while the rate of H. pylori infection did not differ between GD and HT (chi2 = 3.113, p = 0.078). Conclusions: H. pylori infection correlated with GD and HT, and the eradication of H. pylori infection could reduce thyroid autoantibodies. PMID- 29383193 TI - Prognostic significance of the pretreatment serum gamma-glutamyltransferase levels in Chinese patients with non-metastatic cervical cancer. AB - This study was performed to evaluate the prognostic significance of the pretreatment serum gamma-glutamyltransferase (GGT) levels in a Chinese cohort of patients with early-stage or locally advanced cervical cancer. The pretreatment serum GGT levels were examined in 290 cervical cancer patients with stage I-III disease and 230 healthy controls selected from a cancer-free population in the same region. Patients were assigned to normal or high-risk GGT groups, as previously described, and the GGT levels were correlated to clinicopathologic parameters and survival data. The GGT levels in cervical cancer patients were significantly higher than those in healthy controls (35.6 +/- 29.1 vs. 24.1 +/- 14.7 U/L, P < 0.001). In addition, the pretreatment serum GGT levels were associated with the histology type (P = 0.023), lymph node involvement (P = 0.040), stage (P = 0.029), recurrence (P = 0.015) and death (P = 0.005), but not with age (P = 0.432), tumor size (P = 0.067) or degree of differentiation (P = 0.901). Moreover, univariate survival analysis revealed that patients with high GGT levels tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.721; 95% confidence interval (CI), 1.189-2.491; P = 0.004] and overall survival (OS) (HR, 1.929; 95% CI, 1.294-2.876; P = 0.001) compared to those with normal GGT levels. However, a multivariate Cox-regression model did not support these data (HR, 1.373; 95% CI, 0.925-2.039; P = 0.116 for DFS and HR, 1.357; 95% CI, 0.887-2.078; P = 0.160 for OS, respectively) after adjusting for other confounding variables. High pretreatment serum GGT was associated with more advanced tumor behavior, but could not serve as an independent prognostic indicator in patients with early-stage or locally advanced cervical cancer. PMID- 29383194 TI - Combined effect of obesity and diabetes on early breast cancer outcome: a prospective observational study. AB - Background: Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods: Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi square test and survival data by the log-rank test. Results: At diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1-3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for disease-free survival (hazard ratio=2.62, 95% CI 1.23-5.60) but not for overall survival. Conclusions: At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cancer. PMID- 29383195 TI - The safety of fertility and ipsilateral ovary procedures for borderline ovarian tumors. AB - Objective: To explore the optimal treatment options for women with borderline ovarian tumors (BOTs). Materials and Methods: The medical records of consecutive patients with BOTs in two academic institutions were retrospectively collected. The pertinent data, including clinicopathological characteristics and, treatment and prognostic information were evaluated. Results: A total of 281 cases of BOTs were included in this analysis. For the entire series, the 5- year disease-free survival (DFS) and overall survival (OS) rates were 91.8% and 98.5%, respectively. In the multivariate analysis, reservation of the ipsilateral ovary (HR: 0.104 [95% CI, 0.036-0.304], p = 0.000) and FIGO stage II-III (HR: 6.811 [95% CI, 2.700-17.181], p = 0.000) were the independent risk factors for recurrence. Ovarian surface involvement (HR: 64.996 [95% CI, 4.054-1041.941], p = 0.003) was the only independent prognostic factor for OS. Lymphadenectomy and adjunct chemotherapy had no significant impact on patients' recurrence and survival (recurrence: p = 0.332 and 0.290, respectively, survival: p = 0.896 and 0.216, respectively). Conclusions: Fertility-sparing surgery with healthy ovarian preservation seems safe and feasible for young women who prefer fertility-sparing treatment. Ovarian cystectomy to conserve the affected ovary/ovaries without ovarian surface involvement may be cautiously performed under fully informed consent for young women with bilateral BOTs who strongly prefer fertility-sparing treatment and have no evidence of infertility. However, long-term follow-up is necessary due to the relapse susceptibility of the ovary. PMID- 29383196 TI - Glioblastoma research: US and international networking achievements. AB - Being the most aggressive type of brain tumor, glioblastoma is estimated to be diagnosed in about 12,400 new cases in 2017. The diagnosis is dramatic to patients and relatives and leaves open many unanswered questions for them. One is the big question why there is no cure as in other tumors. This review illustrates the US and global research efforts that have been made over the past century. It demonstrates the great magnitude of energy invested by US clinicians and scientists but undoubtedly, more research is needed and funding by NIH and other sources should be continued on the same level. PMID- 29383197 TI - Rethinking the bile acid/gut microbiome axis in cancer. AB - Dietary factors, probiotic agents, aging and antibiotics/medicines impact on gut microbiome composition leading to disturbances in localised microbial populations. The impact can be profound and underlies a plethora of human disorders, including the focus of this review; cancer. Compromised microbiome populations can alter bile acid signalling and produce distinct pathophysiological bile acid profiles. These in turn have been associated with cancer development and progression. Exposure to high levels of bile acids, combined with localised molecular/genome instability leads to the acquisition of bile mediated neoplastic alterations, generating apoptotic resistant proliferation phenotypes. However, in recent years, several studies have emerged advocating the therapeutic benefits of bile acid signalling in suppressing molecular and phenotypic hallmarks of cancer progression. These studies suggest that in some instances, bile acids may reduce cancer phenotypic effects, thereby limiting metastatic potential. In this review, we contextualise the current state of the art to propose that the bile acid/gut microbiome axis can influence cancer progression to the extent that classical in vitro cancer hallmarks of malignancy (cell invasion, cell migration, clonogenicity, and cell adhesion) are significantly reduced. We readily acknowledge the existence of a bile acid/gut microbiome axis in cancer initiation, however, in light of recent advances, we focus exclusively on the role of bile acids as potentially beneficial molecules in suppressing cancer progression. Finally, we theorise that suppressing aggressive malignant phenotypes through bile acid/gut microbiome axis modulation could uncover new and innovative disease management strategies for managing cancers in vulnerable cohorts. PMID- 29383198 TI - Platelet-inspired medicine for tumor therapy. AB - As the number of patients with tumor increases dramatically recent years, traditional therapies expose more and more problems which can even lead to death. Many researchers and clinicians quest for an efficient drug delivery system to deal with tumor as a result. With the researches further develop, we find that platelet can interact with tumor cells through a variety of ways. So it can be used as a carrier broadly to deliver different anti-tumor drugs for tumor treatment. In the present review, we summarize the interaction of tumor cells and platelet. At the same time, we focus on recent progress on the application of platelet drug-loaded system in the anti-tumor prospects. PMID- 29383199 TI - MicroRNAs as regulators of cisplatin-resistance in non-small cell lung carcinomas. AB - With more than 80% of all diagnosed lung cancer cases, non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. Exact diagnosis is mostly very late and advanced-stage NSCLCs are inoperable at admission. Tailored therapies with tyrosine kinase inhibitors are only available for a minority of patients. Thus, chemotherapy is often the treatment of choice. As first-line chemotherapy for NSCLCs, platinum-based substances (e.g. cisplatin, CDDP) are mainly used. Unfortunately, the positive effects of CDDP are frequently diminished due to development of drug resistance and negative influence of microenvironmental factors like hypoxia. MicroRNAs (miRNAs) are small, non-coding molecules involved in the regulation of gene expression and modification of biological processes like cell proliferation, apoptosis and cell response to chemotherapeutics. Expression of miRNAs is often deregulated in lung cancer compared to corresponding non-malignant tissue. In this review we summarize the present knowledge about the effects of miRNAs on CDDP-resistance in NSCLCs. Further, we focus on miRNAs deregulated by hypoxia, which is an important factor in the development of CDDP-resistance in NSCLCs. This review will contribute to the general understanding of miRNA-regulated biological processes in NSCLC, with special focus on the role of miRNA in CDDP-resistance. PMID- 29383200 TI - Next-generation metabolomics in lung cancer diagnosis, treatment and precision medicine: mini review. AB - Lung cancer is the leading cause of cancer-related death. Next-generation metabolomics is becoming a powerful emerging technology for studying the systems biology and chemistry of health and disease. This mini review summarized the main platforms of next-generation metabolomics and its main applications in lung cancer including early diagnosis, pathogenesis, classifications and precision medicine. The period covers between 2009 and August, 2017. The major issues and future directions of metabolomics in lung cancer research and clinical applications were also discussed. PMID- 29383203 TI - Over-expression of PPAR-gamma2 gene enhances the adipogenic differentiation of hemangioma-derived mesenchymal stem cells in vitro and in vivo. AB - Background: Most of infantile hemangiomas involute into fibrofatty tissue in childhood, which indicates adipogenesis during this period. Mesenchymal stem cells (MSCs) contribute to the adipogenesis in IH. In this study, we investigated the effects of overexpression of PPAR-gamma2 gene on the adipogenic differentiation of Hemangioma-derived MSCs (Hem-MSCs), and discussed the possibility of targeted therapy via PPAR-gamma pathway. Methods: MSCs were isolated from proliferating hemangioma by their selective adhesion to plastic culture dishes. Recombinant lentivirus with PPAR-gamma2 gene were prepared, and used to transfect Hem-MSCs. Transfected cells were cultured in adipogenic medium to observe the differentiation in vitro. And the cells were mixed with Matrigel, then subcutaneously injected into the back of nude mice to observe the differentiation in vivo. Results: In the in vitro tests, Hem-MSCs with overexpression of PPAR-gamma2 gene showed enhanced adipogenic differentiation with increased expression of adipogenic-related genes, including PPAR-gamma2, ADD1, LPL, and CEBPA genes. In the in vivo tests, Hem-MSCs/Matrigel plugs with overexpression of PPAR-gamma2 gene also showed accelerated adipogenesis and time phased changes of above genes. Conclusions: Overexpression of PPAR-gamma2 gene enhances and accelerates the adipogenic differentiation of Hem-MSCs in vitro and in vivo. The results may provide the preliminary evidences for the targeted therapy of IH via PPAR-gamma signal pathway. PMID- 29383204 TI - Sedentary Lifestyle and Cardiovascular Health. PMID- 29383202 TI - Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/beta-catenin signaling. AB - Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1 3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5 fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shbeta-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled beta-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT 8/VCR cells compared to HCT-8. Dishevelled1-3 bound to beta-catenin in nucleus, and promoted nuclear complex formation and transcription activity of beta catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/beta-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of beta catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer. PMID- 29383201 TI - MicroRNAs in cancer metastasis and angiogenesis. AB - Cancer metastasis is a malignant process by which tumor cells migrate from their primary site of origin to other organs. It is the main cause of poor prognosis in cancer patients. Angiogenesis is the process of generating new blood capillaries from pre-existing vasculature. It plays a vital role in primary tumor growth and distant metastasis. MicroRNAs are small non-coding RNAs involved in regulating normal physiological processes as well as cancer pathogenesis. They suppress gene expression by specifically binding to the 3'-untranslated region (3'-UTR) of their target genes. They can thus act as oncogenes or tumor suppressors depending on the function of their target genes. MicroRNAs have shown great promise for use in anti-metastatic cancer therapy. In this article, we review the roles of various miRNAs in cancer angiogenesis and metastasis and highlight their potential for use in future therapies against metastatic cancer. PMID- 29383205 TI - Efficacy of Boric Acid as a Treatment of Choice for Chronic Suppurative Otitis Media and Its Ototoxicity. AB - Chronic suppurative otitis media (CSOM) is one of the most common chronic infectious diseases worldwide, especially affecting children. The patients or the parents of the affected children are often worried about the cost of medical visits, prescription medicines, or inconsistently effective medication. The complications of CSOM have been greatly reduced because of the development of antibiotics; however, the irrational use of antibiotics has led to the emergence of organisms resistant to the commonly used drugs. Owing to the increase in antibiotic resistance, the development of new treatments that will efficiently eradicate infectious microorganisms has become imperative. Boric acid solutions are effective in the treatment of CSOM because of their acidic effect. Various databases, such as the PubMed, The Cochrane Library, and SciELO, were searched for references related to the efficacy of boric acid in the treatment of mucosal CSOM, as well as its ototoxicity. The search revealed that boric acid is relatively effective in treating CSOM, especially at a high concentration. Boric acid in distilled water was found safe in animal studies. However, the ototoxicity of boric acid concentrations higher than 4% needs further evaluation, considering the effectivity of boric acid at high concentrations. PMID- 29383206 TI - Association between Female Urinary Incontinence and Geriatric Health Problems: Results from Korean Longitudinal Study of Ageing (2006). AB - Background: Urinary incontinence (UI) is highly prevalent in the aging population. UI is one of the most common geriatric syndromes and affects overall health, quality of life, and economical burden in patients. The aims of this study were to investigate the characteristics of patients with UI and to assess its association with other geriatric health problems. Methods: We used data from the Korean Longitudinal Study of Ageing obtained in 2006. Among the 10,254 individuals aged 45 years and older, we analyzed data from 2,418 women aged 65 years and older. Data were obtained using questionnaires for UI, comorbidities, and lifestyle factors. Results: Among the 2,418 women aged 65 years and older, 506 (20.9%) had UI. Cerebrovascular disease (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.26 to 3.23), arthritis (OR, 1.44; 95% CI, 1.18 to 1.77), and fear of falling (OR, 1.62; 95% CI, 1.18 to 2.22) were significantly associated with UI, while chronic lung disease, psychiatric disease, difficulty in daily living due to visual and hearing problems, and experiencing a fall in the last 2 years were not associated with UI. Conclusion: Cerebrovascular disease, arthritis, and especially fear of falls were significantly associated with UI in elderly Korean women. PMID- 29383207 TI - Understanding Dieting and Previous Weight Loss Attempts among Overweight and Obese Participants: Insights into My Body Is Fit and Fabulous at Work Program. AB - Background: A qualitative study providing an in-depth exploration of people's view and the increasing burden of overweight and obesity is required. This study aimed to explore the understanding of dieting and previous experiences on weight loss attempts among overweight and obese government employees in Kelantan, Malaysia, prior to recruitment into the intervention program. Methods: Thirteen focus group discussions involving 129 participants from a weight-loss intervention program were conducted within the first 1 month of recruitment. These discussions were moderated by two trained researchers in the Malay language and assisted by an interview guide. They were audio-recorded and transcribed verbatim. A thematic analysis was performed, and codes and themes from each discussion were constructed. Results: The participants understood dieting with various meanings, including skipping meals and removing rice from daily diets. They applied numerous methods to lose weight and achieved various outcomes. Health and appearance, social support, and compliance with current trends were the factors motivating these participants to lose weight. Their determination to lose weight was limited by lack of self-control and motivation, experiences of unpleasant effects, influence on weight, and environmental and health factors. Conclusion: Real-life weight loss experiences and perceptions provided relevant insights into current weight loss management strategies. Some of these issues and misunderstandings should be emphasized in weight loss strategies during health promotion. PMID- 29383208 TI - Effects of Module Development and Role Play Course on Clinical Practice Examination Scores during a 4th Year Clerkship. AB - Background: After introduction of clinical skills assessment in the Korean Medical Licensing Examination, medical schools have reinforced both experiential learning with real patients and preparatory programs. This study was conducted to investigate whether a clinical practice examination (CPX) preparation program improves students' CPX score in terms of case specificity. Methods: One hundred and thirteen senior students in a medical school participated in this study. During the fourth-year clerkship, 28 students (24.8%) from three rotation groups took a 3-day CPX preparation course consisting of module development, role play, and comprehensive physical exam skills training. Eleven rotation groups (n=85) were compared as control. Both the intervention and control group took two comprehensive CPXs before and after the clerkship was completed. Results: There was no significant difference in age, sex, and school type between the two groups. On pre-test CPX, there was no significant difference in total and sectional scores between the two groups. On post-test CPX, total scores of the intervention group were higher than those of the control groups (69.5+/-4.3 vs. 67.5+/-4.4, P<0.05). History taking scores were higher in intervention groups (70.0+/-6.0 vs. 66.0+/-6.6, P=0.01). The station scores of vaginal discharge with case similarity were higher in the intervention groups (73.0+/-6.3 vs. 68.9+/ 9.3, P=0.03). Conclusion: A short CPX preparation course improved history taking ability, but its effect was greater only in a specific case, similar to the pre course case. Whether this effect was due to the test experience or true improvement in competency requires further investigation. PMID- 29383209 TI - Association between Sedentary Time and Cardiovascular Risk Factors in Korean Adults. AB - Background: Sedentary behavior has been shown to have deleterious effects on cardiovascular outcomes. This study aimed to examine the association between sedentary time and cardiovascular risk factors in Korean adults. Methods: A cross sectional study was performed using data from adults aged 19 years and above in the 2013 Korean National Health and Nutrition Examination Survey. Sedentary time was self-reported and categorized into quintiles. Cardiovascular risk factors, including blood pressure (BP), total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein cholesterol, and fasting glucose levels, were categorized into dichotomous variables according to the Adult Treatment Panel III criteria. Multivariate logistic regression was performed with adjustment for various demographic and lifestyle variables, body mass index (BMI), waist circumference (WC), and moderate-to-vigorous physical activity. Complex sampling design was used, and survey weights and sample design variables were applied in analyses. Results: A total of 3,301 individuals were included in the analyses, and mean sedentary time was 6.1 h/d. Prolonged sedentary time was significantly associated with high diastolic BP (top vs. bottom quintile: adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.09-2.68; Ptrend=0.03) and low HDL cholesterol level (top vs. bottom quintile: adjusted OR, 1.42; 95% CI, 1.02-1.98; Ptrend=0.02) after adjustment for BMI, WC, moderate-to-vigorous physical activity, and other variables. No significant associations were found between sedentary time and other cardiovascular risk factors. Conclusion: Prolonged sedentary time was significantly associated with high diastolic BP and low HDL cholesterol level in Korean adults. The associations were independent of general and abdominal obesity and moderate-to vigorous physical activities. PMID- 29383210 TI - Analysis of Clinical Manifestations and Laboratory Findings in Children with Influenza B-Associated Myositis: A Single Center Study. AB - Background: Influenza-associated myositis (IAM) is a rare and poorly recognized complication of influenza infection in children, and is characterized by acute onset of severe pain in the lower extremities and a refusal to ambulate walk. We sought to understand the association between IAM and influenza B infection and to investigate its clinical and laboratory characteristics in affected children. Methods: Influenza B-associated myositis (IBAM) cases diagnosed in the pediatrics department of Wonkwang University Hospital from January 2010 and March 2016 were analyzed retrospectively. Results: Medical records of affected children were examined, and clinical characteristics and laboratory findings were recorded. Of the 536 children diagnosed with influenza B infection, 47 children complained of bilateral calf pain with or without gait disturbance. All children exhibited elevated serum aspartate aminotransferase (AST) level. The median serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels, reportedly elevated in myositis, were 2,597 IU/L and 678 IU/L, respectively. While the immunofluorescence test results were negative for some patients, the polymerase chain reaction test results indicated influenza B infection in all 47 children. At the time of hospital discharge, the patients' symptoms had resolved, and their CK levels had improved. Conclusion: IBAM was generally benign and short, and although the blood AST, CK, and LDH levels were markedly high, the erythrocyte sedimentation rate and C-reactive protein levels were normal. Further, the duration of IBAM symptoms correlated with the duration of fever. The IBAM associated clinical and laboratory findings are highly characteristic and may allow its rapid diagnosis during the influenza season. PMID- 29383211 TI - Association of Fasting Glucose Level with Neutrophil-Lymphocyte Ratio Compared to Leukocyte Count and Serum C-Reactive Protein. AB - Background: The neutrophil-lymphocyte ratio (NLR) is often used as an inflammatory marker in chronic diseases such as cancer or cardiovascular diseases. However, there are few studies about the association between the NLR and diabetes mellitus (DM) or impaired fasting glucose (IFG) patients in Korea. This study investigated the association between the fasting plasma glucose (FPG) level and NLR in Koreans. Methods: This cross-sectional retrospective study included 3,219 healthy subjects who visited Konyang University Hospital in South Korea for regular health examinations. Participants with a history of insulin administration, anti-diabetic drugs, anti-inflammatory drugs, or underlying diseases related to inflammation were excluded. Results: All statistical evaluation was performed by dividing participants into males and females. Based on FPG levels, the subjects were classified into three groups, with normal fasting glucose (n=1,969), IFG (n=1,138), and DM (n=122). The NLR had no significant mean differences among these groups for both sexes. Multiple linear regression analysis between FPG level and NLR showed an independent and significantly negative association (beta+/-standard error, -0.67+/-0.24; P=0.006) in normal subjects after adjustment. Log(serum C-reactive protein [S-CRP]) showed an independently and significantly positive association with FPG in male IFG/DM patients. Total leukocyte (white blood cell [WBC]) showed an independently and significantly positive association with FPG in female IFG/DM patients. Conclusion: In normal subjects, NLR shows an independently and significantly negative association with FPG. In IFG/DM patients, NLR was not significantly related to FPG. WBC count in female patients and S-CRP level in male patients were significantly positively associated with FPG only in IFG/DM. PMID- 29383212 TI - A Possible Case of Statin-Induced Ichthyosis in an Elderly Woman. AB - Ichthyosis is a heterogeneous group of hereditary or acquired skin disorders, characterized by increased stratum corneum production. Several systemic diseases and many drugs can occasionally cause acquired ichthyosis. We report a case of statin-induced ichthyosis in which the causality between statin and ichthyosis was found possible by using the Naranjo scale. A 79-year-old woman presented with pruritic skin lesions on both legs that appeared erythematous, scaly, and cracked. A clinical diagnosis of acquired ichthyosis was made and the statin was suspected as the cause. The skin lesions improved after 6 weeks of dose reduction of the statin. PMID- 29383213 TI - A Case of a Girl with Arnold-Chiari Type 1 Malformation with Precocious Puberty. AB - A small percentage of individuals have the neurological anomaly of central precocious puberty (CPP). Common neurologic causes of CPP include a tumor or congenital lesions. Although Arnold-Chiari malformation can be caused by congenital or acquired causes, it is unusual in patients with CPP. We present the case of a girl aged 4.5 years who complained of breast budding. Her neurological examination and growth pattern were normal. She had no endocrinological abnormality, except for true precocious puberty. We performed brain magnetic resonance imaging, which showed an Arnold-Chiari type 1 malformation. Currently, this case represents the youngest girl who exhibited both Arnold-Chiari type 1 malformation and precocious puberty. Furthermore, it is likely that there is a meaningful association between the brain lesion and precocious puberty in this case. PMID- 29383215 TI - Economic Status Inequality Is a Predictor for Screening and Health Utilization. PMID- 29383214 TI - Beneficial Effects of Appropriate Sleep Duration on Depressive Symptoms and Perceived Stress Severity in a Healthy Population in Korea. AB - Background: Recently, several institutions, including the American Academy of Sleep Medicine, the Sleep Research Society, and the National Sleep Foundation, have made consensus recommendations concerning appropriate sleep duration for adults. Although numerous studies conducted in Western populations have provided evidence of the harmful effects of short or long sleep duration on mental health, it is still unclear whether these consensus recommendations are appropriate in Korean culture. Methods: Data from 1,892 subjects with no history of medical or psychiatric diagnoses were selected from the Korea National Health and Nutrition Examination Survey of 2014. Subjects were divided into seven groups based on their sleep duration (<=4, 5, 6, 7, 8, 9, and >=10 hours). Depressive symptoms were measured using the Patient Health Questionnaire-9 and perceived stress severity was evaluated using a Likert-type scale. Group differences in depressive symptoms and severity of stress were analyzed using an analysis of covariance. Results: Depressive symptoms in subjects with sleep duration of <=4 hours (5.7+/ 5.9) or 5 hours (3.4+/-3.9) were higher than in subjects with a sleep duration of 7 (2.2+/-2.9) or 8 hours (2.2+/-2.9) (corrected P<0.05). Furthermore, subjects with a short sleep duration (5 hours or below) had greater perceived stress severity than subjects with a sleep duration of 7 or 8 hours (corrected P<0.05). Conclusion: Our results suggest that maintaining an appropriate sleep duration as found in the recent consensus recommendation is important for mental health, even in healthy subjects without any medical or psychiatric illnesses, in Korea. PMID- 29383216 TI - Psychometric testing of immigrants and natives in an acute psychiatry facility. PMID- 29383217 TI - Reluctance to change and end psychotherapy. PMID- 29383218 TI - Social anxiety disorder and its impact in undergraduate students at Jazan University, Saudi Arabia. PMID- 29383219 TI - Initiation of complementary feeding and associated factors among children of age 6-23 months in Sodo town, Southern Ethiopia: Cross-sectional study. PMID- 29383220 TI - Pectus updates and special considerations in Marfan syndrome. PMID- 29383221 TI - Zinc supplementation enhances linear growth in school-aged children: A randomized controlled trial. PMID- 29383222 TI - Zika virus infection in a pediatric patient with acute gastrointestinal involvement. PMID- 29383223 TI - A boy with recurrent swelling of the jaw. PMID- 29383224 TI - Haploidentical hematopoietic stem cell transplantation in a myelofibrosis patient with primary graft failure. PMID- 29383225 TI - A rare case of de novo CD5+ diffuse large B-cell lymphoma in leukemic phase and positive for CD13. PMID- 29383226 TI - Double heterozygocity for hemoglobin C and beta thalassemia dominant: A rare case of thalassemia intermedia. PMID- 29383227 TI - Determining the role of intravenous hydration on hospital readmissions for acute congestive heart failure. PMID- 29383228 TI - Heterotaxy syndrome with intestinal malrotation, polysplenia and azygos continuity. PMID- 29383229 TI - Primary hypoparathyroidism presenting as basal ganglia calcification secondary to extreme hypocalcemia. PMID- 29383230 TI - Peripheral giant cell granuloma recurring as an exclusively intra-osseous lesion: An unusual clinical presentation. PMID- 29383231 TI - Variables affecting factors associated with primary headache. PMID- 29383232 TI - Ecology of Floristic Quality Assessment: testing for correlations between coefficients of conservatism, species traits and mycorrhizal responsiveness. AB - Many plant species are limited to habitats relatively unaffected by anthropogenic disturbance, so protecting these undisturbed habitats is essential for plant conservation. Coefficients of conservatism (C values) were developed as indicators of a species' sensitivity to anthropogenic disturbance, and these values are used in Floristic Quality Assessment as a means of assessing natural areas and ecological restoration. However, assigning of these values is subjective and improved quantitative validation of C values is needed. We tested whether there are consistent differences in life histories between species with high and low C values. To do this, we grew 54 species of tallgrass prairie plants in a greenhouse and measured traits that are associated with trade-offs on the fast-slow continuum of life-history strategies. We also grew plants with and without mycorrhizal fungi as a test of these species' reliance on this mutualism. We compared these traits and mycorrhizal responsiveness to C values. We found that six of the nine traits we measured were correlated with C values, and together, traits predicted up to 50 % of the variation in C values. Traits including fast growth rates and greater investment in reproduction were associated with lower C values, and slow growth rates, long-lived leaves and high root:shoot ratios were associated with higher C values. Additionally, plants with high C values and a slow life history were more responsive to mutualisms with mycorrhizal fungi. Overall, our results connect C values with life-history trade offs, indicating that high C value species tend to share a suite of traits associated with a slow life history. PMID- 29383233 TI - Wetland seed dispersal by white-tailed deer in a large freshwater wetland complex. AB - Mechanisms of long-distance dispersal are important in establishing and maintaining plant populations in isolated wetland habitats. White-tailed deer (Odocoileus virginianus) have been cited as long-distance dispersers of both native and exotic plant species in North America; however, knowledge regarding their influence in wetlands is limited. Given traditional classification methods for seed dispersal, white-tailed deer are not likely viewed as important dispersal mechanism for wetland plants. We collected naturally deposited white tailed deer faecal pellet piles from wetlands in Canaan Valley, West Virginia, USA. Pellet piles were cold-stratified and germinated seedlings over a layer of sterile potting mix. The percentage of germinated seedlings with a facultative wetland (FACW) or obligate wetland (OBL) plant indicator status were compared to the frequency of occurrence to those of germinated plants with facultative upland (FACU) or upland (UPL) indicator status. We identified 38 species. Of these, 1 % were UPL, 38 % were FACU, 18 % were FACW and 21 % were OBL. Graminoid species accounted for 42 %; forbs and woody species accounted for 29 % each. Our research has suggested that endozoochory by herbivores contributes to long-distance dispersal of wetland plants. PMID- 29383234 TI - Isotropic and anisotropic processes influence fine-scale spatial genetic structure of a keystone tropical plant. AB - Limited seed or pollen dispersal enhances spatial genetic relatedness between individuals (fine-scale spatial genetic structure, FSGS), which usually decreases as a function of physical distance. However, such isotropic pattern of FSGS may not always occur when spatially asymmetric processes, for instance, wind direction during dispersal, are considered in wind-pollinated and -dispersed plants. This study assessed the pattern of FSGS in the keystone tropical wetland plant Cyperus papyrus (papyrus) as a function of these isotropic and anisotropic processes. We tested the hypothesis that the FSGS would be influenced by predominant wind direction during pollen and seed dispersal, as well as by the physical distance between individuals. We genotyped a total of 510 adults and 407 juveniles from three papyrus swamps (Ethiopia) using 15 microsatellite markers. In addition, the contemporary directional dispersal by wind was evaluated by seed release-recapture experiments and complemented with parentage analysis. Adults and juveniles differed in the strength of isotropic FSGS ranging from 0.09 to 0.13 and 0.12 to 0.16, respectively, and this suggests variation in dispersal distance. Anisotropic FSGS was found to be a function of asymmetric wind direction during dispersal/pollination that varied between sites. Historical gene dispersal distance was astoundingly low (<4 m), possibly due to localized seed rain. According to our contemporary dispersal estimates, mean pollen dispersal distances were longer than those of seed dispersal (101 and <55 m, respectively). More than two-thirds of seeds and half of pollen grains were locally dispersed (<=80 m). The difference in historical and contemporary dispersal distance probably resulted from the asymmetric wind direction due to change in vegetation cover in the surrounding matrix. We further concluded that, in addition to wind direction, post-dispersal processes could influence gene dispersal distance inferred from the FSGS. PMID- 29383235 TI - Can Rotational Grouping Be Determined by the Initial Conditions? AB - Objects rotating in depth with an ambiguous rotation direction frequently appear to rotate together. Corotation is especially strong when the objects are interpretable as having a shared axis. We manipulated the initial conditions of the experiment by having pairs of objects initially appear to be unambiguous, and then make either a sudden or gradual transition to ambiguous spin. We find that in neither case do coaxial counter-rotating objects persist in being perceived as counter-rotating. This implies that the perceptual constraint that favors coaxial corotation overrides the initial perceptual state of the objects. PMID- 29383236 TI - Amyand's hernia managed with open repair and laparoscopic appendicectomy. AB - We present a rare case of Amyand's hernia that was surgically managed using an open repair of hernia combined with laparoscopic appendicectomy. A 68-year-old man presented with an irreducible recurrent right-sided inguinal hernia and abdominal pain. This gentleman had undergone three previous inguinal hernia repairs on the right, and one on the left using the open mesh technique. Ultrasound suggested the possibility of the appendix within the hernial sac and clinical correlation was advised. An open groin approach was taken to repair the incarcerated hernia. This revealed an indirect inguinal hernia containing the appendix with signs of inflammation. The base of the appendix was not visible due to there being a long appendix with fixed cecum in the abdomen. To safely resect the appendix, a laparoscopy was performed and the appendix was successfully removed. The inguinal hernia was repaired using a sutured technique without mesh. There were no post-operative complications. PMID- 29383237 TI - Cervical left pulmonary artery. AB - We detail what we believe to be the first reported case of a congenital 'Cervical Left Pulmonary Artery' in which an aberrant left pulmonary artery courses cranially into the mid-cervical neck before descending back into the thorax to the left pulmonary hilum. Due to the location and course of the artery, we believe that this anomaly is likely due to a developmental error of the sixth pharyngeal arch. Ultimately, the use of a reconstructed 3D computed tomography image provided detailed characterization of the unique anatomical variant, aiding in a successful surgical repair of the defect. PMID- 29383238 TI - Do all type 2 aortic dissection require emergency surgery? AB - We represent a case of asymptomatic isolated chronic ascending aortic dissection that lasted for 15 years in which a patient was only followed up with medical therapy that saved him from early surgical intervention. PMID- 29383239 TI - Abnormal distance of the extralaryngeal bifurcation point of the recurrent laryngeal nerve from the cricothyroid joint. AB - The extralaryngeal bifurcation point of the recurrent laryngeal nerve (RLN) is typically located in a mean distance of 0-2 cm from the cricothyroid joint (CTJ). In the presented case though, the left RLN was unexpectedly identified bifurcating in a mean distance of 7 cm from the left CTJ in a young woman with multinodular goiter during total thyroidectomy. The RLN was carefully exposed throughout its course for the avoidance of iatrogenic injury of the nerval structure. The operation was uneventful. The present manuscript aims to highlight a scarce anatomic variation and its implications for thyroidectomy. Rare anatomic variations of the RLN such as the presented one encumber thyroid surgery and represent a severe risk factor of RLN injury. Meticulous operative technique combined with surgeons' perpetual awareness concerning this peculiar anatomical aberration leads to an injury-free thyroid surgery. PMID- 29383240 TI - Intrabilary obstruction by colorectal metastases. AB - Intrabiliary colorectal metastases are rare. We present a case of an 84-year-old man who developed obstructive jaundice secondary to intrabiliary growth of colorectal metastases. The patient presented with three weeks of jaundice and significant weight loss in the preceding months. The patient's background included metastatic colorectal carcinoma, with a previous right hemicolectomy and left hepatectomy for liver metastases. A MRCP showed an obstruction of the biliary tract transitioning at the ampulla. Histology confirmed a malignant adenocarcinoma. When compared to the patient's previous resected colorectal liver metastases, morphology and immunohistochemistry was consistent with colorectal metastases. This case highlights the importance of differentiating a new intraductal papillary neoplasm from a colorectal metastasis. Correctly identifying these lesions requires the use of MRCP and ERCP, as well as immunohistochemistry. This is a priority for clinicians to ensure appropriate therapy. PMID- 29383241 TI - Co-existing infantile hepatic hemangioma and mesenchymal hamartoma in a neonate. AB - Infantile hepatic hemangioma (IHH) and mesenchymal hamartoma (MH) form the first and second most common benign hepatic tumors in children. In this case report, we present a newborn child in whom a growing hepatic mass was discovered at the age of 7 days. She suffered also from anemia, respiratory and renal failure. No signs of heart disease or cutaneous lesions were detected. Alpha-fetoprotein was elevated for her age (3562.2 ng/ml). Imaging studies showed multifocal large cystic lesions associated with heterogeneous small solid lesions with arterial enhancement of the liver. Non-anatomical liver resection was performed initially and synchronous MH and IHH GLUT-1 positive were discovered in the pathological analysis. Segmental IV hepatic resection and later on selective cysts excision were done for persistent hepatic lesion despite medical treatment. After 14 months of beta-blockers treatment, clinical follow-up shows a healthy child with no residual cystic lesions. PMID- 29383242 TI - Metastatic squamous cell cancer of the lung presenting as a perforated cecal cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of diagnoses. Metastasis occurs in ~50% of cases but clinically evident isolated gastrointestinal (GI) metastasis is rare. We present a 78-year-old female who underwent an urgent right hemi-colectomy after cross-sectional imaging revealed a perforated cecal mass. Final pathology demonstrated squamous cell cancer of lung origin. We review the literature on NSCLC with clinically evident metastases to the GI tract, as well as important diagnostic considerations. PMID- 29383243 TI - A Brodie's abscess with soft tissue collection-complicating an already difficult diagnosis. AB - A healthy 14-year-old boy with a 3-month history of thigh pain and swelling is referred to a specialist centre with an uncertain diagnosis. After extensive tests and imaging a Brodie's abscess is diagnosed. The abscess is complicated by a fistula (cloaca) through the cortical bone of the femur, resulting in a large complex soft tissue collection. This is a presentation, we are unaware has been documented in any literature. After specialist multi-team combined management (Paediatric Trauma and Orthopaedic and Paediatric Infectious Diseases), the patient undergoes two surgical procedures, and extensive antibiotic cover. The patient makes a good recovery with no long lasting sequelae to date. PMID- 29383244 TI - A novel safe approach to laparoscopic colorectal cancer resection in patients with ventriculoperitoneal shunt: report of two cases and literature review. AB - There is ongoing challenges regarding the safety of performing laparoscopic surgery with the presence of ventriculoperitoneal (VP) shunts, especially in patients treated for cancer disease. To date, only one case has been reported in the English literature. Herein, we report an additional two cases of patients with previous insertion of a VP shunt, diagnosed with colon cancer. Both our patients underwent successful laparoscopic colectomies, without clamping or removal of the VP shunt, with no reported perioperative complications or postoperative neurological deficits. Laparoscopic bowel resection for cancer, in patients with a pre-existing VP shunt, could be considered a potentially safe and feasible procedure. Furthermore, due to the increasing number of patients with VP shunts, additional case reports and investigations are warranted to further confirm safety of this procedure. PMID- 29383245 TI - Spontaneous closure of multiple enterocutaneous fistula due to abdominal tuberculosis using negative pressure wound therapy: a case report. AB - Enterocutaneous fistula (ECF) is one of the most challenging abdominal complications, for surgeons and other healthcare members, which involves significant morbidity and potentially mortality. Despite advancements in both operative and non-operative therapy, fistula-related complications are still unavoidable. Negative pressure wound therapy (NPWT) had been used years to treat chronic wound, to decrease tissue edema, improve circulation, promote healthy granulation tissue and inhibit bacterial growth. We report a 29-year-old male with complicated ECF due to abdominal tuberculosis, that was healed after treated using NPWT. This was the first ECF patient in our hospital treated using NPWT. PMID- 29383246 TI - Pancreaticoduodenectomy with hepatic arterial revascularization for pancreatic head cancer with stenosis of the celiac axis due to compression by the median arcuate ligament: a case report. AB - A 71-year-old woman presented to our hospital because pancreatic head cancer was suspected on a medical checkup. Computed tomography showed a 30 mm low-density lesion in the pancreatic head, and the stenosis of the celiac axis (CA) due to the median arcuate ligament (MAL) compression. We made a preoperative diagnosis of pancreatic head cancer and performed laparotomy. Transection of the MAL failed to restore adequate hepatic arterial flow, necessitating arterial revascularization, which was achieved by end-to-end anastomosis between the gastroduodenal artery and the middle colic artery. After reconstruction, Doppler ultrasonography showed improved hepatic arterial signal. The patient was discharged 16 days after surgery with no complications. When planning pancreaticoduodenectomy (PD) for such patients with CA stenosis due to MAL compression, surgeons should simulate a situation of insufficient hepatic arterial flow after division of the MAL, and prepare for reconstruction of the hepatic artery during PD. PMID- 29263780 TI - GAC: Gene Associations with Clinical, a web based application. AB - We present GAC, a shiny R based tool for interactive visualization of clinical associations based on high-dimensional data. The tool provides a web-based suite to perform supervised principal component analysis (SuperPC), an approach that uses both high-dimensional data, such as gene expression, combined with clinical data to infer clinical associations. We extended the approach to address binary outcomes, in addition to continuous and time-to-event data in our package, thereby increasing the use and flexibility of SuperPC. Additionally, the tool provides an interactive visualization for summarizing results based on a forest plot for both binary and time-to-event data. In summary, the GAC suite of tools provide a one stop shop for conducting statistical analysis to identify and visualize the association between a clinical outcome of interest and high dimensional data types, such as genomic data. Our GAC package has been implemented in R and is available via http://shinygispa.winship.emory.edu/GAC/. The developmental repository is available at https://github.com/manalirupji/GAC. PMID- 29375809 TI - The long reads ahead: de novo genome assembly using the MinION. AB - Nanopore technology provides a novel approach to DNA sequencing that yields long, label-free reads of constant quality. The first commercial implementation of this approach, the MinION, has shown promise in various sequencing applications. This review gives an up-to-date overview of the MinION's utility as a de novo sequencing device. It is argued that the MinION may allow for portable and affordable de novo sequencing of even complex genomes in the near future, despite the currently error-prone nature of its reads. Through continuous updates to the MinION hardware and the development of new assembly pipelines, both sequencing accuracy and assembly quality have already risen rapidly. However, this fast pace of development has also lead to a lack of overview of the expanding landscape of analysis tools, as performance evaluations are outdated quickly. As the MinION is approaching a state of maturity, its user community would benefit from a thorough comparative benchmarking effort of de novo assembly pipelines in the near future. An earlier version of this article can be found on bioRxiv. PMID- 29375810 TI - Optimal cutoff for the evaluation of insulin resistance through triglyceride glucose index: A cross-sectional study in a Venezuelan population. AB - Background: Insulin resistance (IR) evaluation is a fundamental goal in clinical and epidemiological research. However, the most widely used methods are difficult to apply to populations with low incomes. The triglyceride-glucose index (TGI) emerges as an alternative to use in daily clinical practice. Therefore the objective of this study was to determine an optimal cutoff point for the TGI in an adult population from Maracaibo, Venezuela. Methods: This is a sub-study of Maracaibo City Metabolic Syndrome Prevalence Study, a descriptive, cross sectional study with random and multi-stage sampling. For this analysis, 2004 individuals of both genders >=18 years old with basal insulin determination and triglycerides < 500 mg/dl were evaluated.. A reference population was selected according to clinical and metabolic criteria to plot ROC Curves specific for gender and age groups to determine the optimal cutoff point according to sensitivity and specificity.The TGI was calculated according to the equation: ln [Fasting triglyceride (mg / dl) x Fasting glucose (mg / dl)] / 2. Results: The TGI in the general population was 4.6+/-0.3 (male: 4.66+/-0.34 vs. female: 4.56+/ 0.33, p=8.93x10 -10). The optimal cutoff point was 4.49, with a sensitivity of 82.6% and specificity of 82.1% (AUC=0.889, 95% CI: 0.854-0.924). There were no significant differences in the predictive capacity of the index when evaluated according to gender and age groups. Those individuals with TGI>=4.5 had higher HOMA2-IR averages than those with TGI <4.5 (2.48 vs 1.74, respectively, p<0.001). Conclusions: The TGI is a measure of interest to identify IR in the general population. We propose a single cutoff point of 4.5 to classify individuals with IR. Future studies should evaluate the predictive capacity of this index to determine atypical metabolic phenotypes, type 2 diabetes mellitus and even cardiovascular risk in our population. PMID- 29375811 TI - Initial study of three different pathogenic microorganisms by gas chromatography mass spectrometry. AB - Background: Diagnoses of respiratory tract infections usually happen in the late phase of the disease and usually result in reduction of the pathogen load after broad-spectrum antibiotic therapy, but not in eradication of the pathogen. The development of a non-invasive, fast, and accurate method to detect pathogens has always been of interest to researchers and clinicians alike. Previous studies have shown that bacteria produce organic gases. The current study aimed to identify the volatile organic compounds (VOCs) produced by three respiratory tract pathogens, including Staphylococcus aureus, Escherichia coli and Candida albicans.Methods: The VOCs produced were identified by gas chromatography-mass spectrometry (GC-MS), with prior collection of microbial volatile compounds using solid phase microextraction (SPME) fiber. The volatile compounds were collected by obtaining bacterial headspace samples. Results: Results showed that these three organisms have various VOCs, which were analyzed under different conditions. By ignoring common VOCs, some species-specific VOCs could be detected. The most important VOC of E. coli was Indole, also some important VOCs produced by S. aureus were 2,3-Pentandione, cis-Dihydro-alpha terpinyl acetate, 1-Decyne, 1,3-Heptadiene-3-yne, 2,5-dimethyl Pyrazine, Ethyl butanoate and Cyclohexene,4-ethenyl furthermore, most of identified compounds by C. albicans are alcohols. Conclusions: The detection of VOCs produced by infectious agents maybe the key to make a rapid and precise diagnosis of infection, but more comprehensive studies must be conducted in this regard. PMID- 29375812 TI - TicTimer software for measuring tic suppression. AB - Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. The present article describes a Java program that automates record keeping and reward dispensing during the several experimental conditions of the TSP. The software can optionally be connected to a commercial reward token dispenser to further automate reward delivery to the participant. The timing of all tics, 10-second tic-free intervals, and dispensed rewards is recorded in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders. PMID- 29375816 TI - The rise and fall of machine learning methods in biomedical research. AB - In the era of explosion in biological data, machine learning techniques are becoming more popular in life sciences, including biology and medicine. This research note examines the rise and fall of the most commonly used machine learning techniques in life sciences over the past three decades. PMID- 29383254 TI - Monitoring ovarian cycles, pregnancy and post-partum in captive marsh deer (Blastocerus dichotomus) by measuring fecal steroids. AB - The marsh deer is an endangered species from the marshlands of central South America. This study aimed to characterize certain aspects of the reproductive physiology of marsh deer hinds, including the duration and fecal progestins profile of the estrous cycle, pregnancy and post-partum periods, and evaluate the effect of cloprostenol administration on this species. The experimental group consisted of six females and one fertile male marsh deer. During monitoring of the estrous cycle, the fresh fecal samples were collected daily and, during pregnancy, they were collected twice weekly. The hormonal profile obtained from daily fecal samples indicated that the mean duration of the estrous cycle was 21.3 +/- 1.3 days (6.4 days inter-luteal phase and 14.8 days luteal phase; n = 16 estrous cycles). The mean concentration of fecal progestins in the inter-luteal phase was 834 +/- 311 ng g-1, in the luteal phase was 3979 +/- 1611 ng g-1, value between them was 1457 ng g-1. No significant difference in fecal estrogen concentrations was determined during the estrous cycle. The corpora luteum was not responsive to cloprostenol until Day 6 of the estrous cycle, the period previously described as the inter-luteal phase. Half the females became pregnant following treatment with cloprostenol and two others were fertilized in their natural estrous cycle. Four females delivered fawns, and the mean duration of pregnancy was 253 +/- 4 days. Fecal progestin concentrations were similar to those of the estrous cycle during the first 11 weeks of pregnancy and increased significantly ( > 15250 ng g-1) thereafter, providing a presumptive diagnosis guideline. Within 60 days of post-partum analyses, 75% of the deer exhibited behavioural estrus and/or ovarian activity. This study generated a broader understanding of the marsh deer species concerning the production of consistent data related to its reproduction. This knowledge can be used to assist the reproductive management of this species and, consequently, to promote its conservation. PMID- 29383253 TI - Body water conservation through selective brain cooling by the carotid rete: a physiological feature for surviving climate change? AB - Some mammals have the ability to lower their hypothalamic temperature below that of carotid arterial blood temperature, a process termed selective brain cooling. Although the requisite anatomical structure that facilitates this physiological process, the carotid rete, is present in members of the Cetartiodactyla, Felidae and Canidae, the carotid rete is particularly well developed in the artiodactyls, e.g. antelopes, cattle, sheep and goats. First described in the domestic cat, the seemingly obvious function initially attributed to selective brain cooling was that of protecting the brain from thermal damage. However, hyperthermia is not a prerequisite for selective brain cooling, and selective brain cooling can be exhibited at all times of the day, even when carotid arterial blood temperature is relatively low. More recently, it has been shown that selective brain cooling functions primarily as a water-conservation mechanism, allowing artiodactyls to save more than half of their daily water requirements. Here, we argue that the evolutionary success of the artiodactyls may, in part, be attributed to the evolution of the carotid rete and the resulting ability to conserve body water during past environmental conditions, and we suggest that this group of mammals may therefore have a selective advantage in the hotter and drier conditions associated with current anthropogenic climate change. A better understanding of how selective brain cooling provides physiological plasticity to mammals in changing environments will improve our ability to predict their responses and to implement appropriate conservation measures. PMID- 29383255 TI - Elevated seawater temperature, not pCO2, negatively affects post-spawning adult mussels (Mytilus edulis) under food limitation. AB - Pre-spawning blue mussels (Mytilus edulis) appear sensitive to elevated temperature and robust to elevated pCO2; however, the effects of these stressors soon after investing energy into spawning remain unknown. Furthermore, while studies suggest that elevated pCO2 affects the byssal attachment strength of Mytilus trossulus from southern latitudes, pCO2 and temperature impacts on the byssus strength of other species at higher latitudes remain undocumented. In a 90 day laboratory experiment, we exposed post-spawning adult blue mussels (M. edulis) from Atlantic Canada to three pCO2 levels (pCO2 ~625, 1295 and 2440 MUatm) at two different temperatures (16 degrees C and 22 degrees C) and assessed energetic reserves on Day 90, byssal attachment strength on Days 30 and 60, and condition index and mortality on Days 30, 60 and 90. Results indicated that glycogen content was negatively affected under elevated temperature, but protein, lipid, and overall energy content were unaffected. Reduced glycogen content under elevated temperature was associated with reduced condition index, reduced byssal thread attachment strength, and increased mortality; elevated pCO2 had no effects. Overall, these results suggest that the glycogen reserves of post spawning adult M. edulis are sensitive to elevated temperature, and can result in reduced health and byssal attachment strength, leading to increased mortality. These results are similar to those reported for pre-spawning mussels and suggest that post-spawning blue mussels are tolerant to elevated pCO2 and sensitive to elevated temperature. In contrast to previous studies, however, elevated pCO2 did not affect byssus strength, suggesting that negative effects of elevated pCO2 on byssus strength are not universal. PMID- 29383256 TI - Assessment of chronic kidney disease using skin texture as a key parameter: for South Indian population. AB - Periodical monitoring of renal function, specifically for subjects with history of diabetic or hypertension would prevent them from entering into chronic kidney disease (CKD) condition. The recent increase in numbers may be due to food habits or lack of physical exercise, necessitates a rapid kidney function monitoring system. Presently, it is determined by evaluating glomerular filtration rate (GFR) that is mainly dependent on serum creatinine value and demographic parameters and ethnic value. Attempted here is to develop ethnic parameter based on skin texture for every individual. This value when used in GFR computation, the results are much agreeable with GFR obtained through standard modification of diet in renal disease and CKD epidemiology collaboration equations. Once correlation between CKD and skin texture is established, classification tool using artificial neural network is built to categorise CKD level based on demographic values and parameter obtained through skin texture (without using creatinine). This network when tested gives almost at par results with the network that is trained with demographic and creatinine values. The results of this Letter demonstrate the possibility of non-invasively determining kidney function and hence for making a device that would readily assess the kidney function even at home. PMID- 29383257 TI - Secured remote health monitoring system. AB - Wireless medical sensor network is used in healthcare applications that have the collections of biosensors connected to a human body or emergency care unit to monitor the patient's physiological vital status. The real-time medical data collected using wearable medical sensors are transmitted to a diagnostic centre. The data generated from the sensors are aggregated at this centre and transmitted further to the doctor's personal digital assistant for diagnosis. The unauthorised access of one's health data may lead to misuse and legal complications while unreliable data transmission or storage may lead to life threatening risk to patients. So, this Letter combines the symmetric algorithm and attribute-based encryption to secure the data transmission and access control system for medical sensor network. In this work, existing systems and their algorithm are compared for identifying the best performance. The work also shows the graphical comparison of encryption time, decryption time and total computation time of the existing and the proposed systems. PMID- 29383258 TI - Anti-jamming communication for body area network using chaotic frequency hopping. AB - The healthcare industries research trends focus on patient reliable communication and security is a paramount requirement of healthcare applications. Jamming in wireless communication medium has become a major research issue due to the ease of blocking communication in wireless networks and throughput degradation. The most commonly used technique to overcome jamming is frequency hopping (FH). However, in traditional FH pre-sharing of key for channel selection and a high throughput overhead is required. So to overcome this pre-sharing of key and to increase the security chaotic frequency hopping (CFH) has been proposed. The design of chaos-based hop selection is a new development that offers improved performance in transmission of information without pre-shared key and also increases the security. The authors analysed the performance of proposed CFH system under different reactive jamming durations. The percentage of error reduction by the reactive jamming for jamming duration 0.01 and 0.05 s for FH and CFH is 55.03 and 84.24%, respectively. The obtained result shows that CFH is more secure and difficult to jam by the reactive jammer. PMID- 29383259 TI - Monitoring of atopic dermatitis using leaky coaxial cable. AB - In our daily life, inadvertent scratching may increase the severity of skin diseases (such as atopic dermatitis etc.). However, people rarely pay attention to this matter, so the known measurement behaviour of the movement is also very little. Nevertheless, the behaviour and frequency of scratching represent the degree of itching, and the analysis of scratching frequency is helpful to the doctor's clinical dosage. In this Letter, a novel system is proposed to monitor the scratching motion of a sleeping human body at night. The core device of the system is just a leaky coaxial cable (LCX) and a router. Commonly, LCX is used in the blind field or semi-blindfield in wireless communication. The new idea is that the leaky cable is placed on the bed, and then the state information of physical layer of wireless communication channels is acquired to identify the scratching motion and other small body movements in the human sleep process. The results show that it can be used to detect the movement and its duration. Channel state information (CSI) packet is collected by card installed in the computer based on the 802.11n protocol. The characterisation of the scratch motion in the collected CSI is unique, so it can be distinguished from the wireless channel amplitude variation trend. PMID- 29383260 TI - Penile Mondor's disease in a patient treated with radical chemoradiation for anal cancer. AB - Penile Mondor's disease is a rare condition characterized by sclerosing thrombophlebitis of the superficial dorsal penile vein. Usually its causes are benign, but it is also evident in cancer patients. We report the case of a 62 year-old man with a cT4 anal cancer (infiltration of corpora spongiosa and penile bulb), associated with extensive loco-regional lymphadenopathy, who developed painful lumps in the midline of the anterior penile surface while receiving radical chemoradiotherapy. Physical examination revealed two palpable cord-like swellings located 2 cm from the pubic symphysis. Color Doppler ultrasound established the diagnosis of Mondor's disease. The patient was successfully managed with non-steroidal anti-inflammatory drugs. The causative factors were pelvic malignancy and radiotherapy. The diagnosis was challenging since Mondor's disease is a rare condition and the differential diagnosis included malignancy progression. This is the first case report describing penile Mondor's disease in a patient with anal cancer under chemoradiotherapy. PMID- 29383261 TI - Case report of a patient with 'one-and-a-half plus syndrome: nine syndrome'. AB - This case talks about 'One-and-a-half plus syndrome', a clinical syndrome affecting binocular vision and facial nerve. One-and-a-half plus syndrome is a less known clinical syndrome which constitutes of a conjugate horizontal gaze palsy in one direction and an internuclear ophthalmoplegia in the other direction. Despite the known association between ischemia, autoimmune disorders, multiple sclerosis, with mono neuritis multiplex resulting in extra ocular movement disorder, one-and-a-half plus syndrome is rarely considered in the differential diagnosis of eye ball movement disorders, as many clinicians are not able to diagnose such a case as ' the eyes don't see what the mind doesn't know'. Our report aims to raise awareness about connective tissue disorders presenting as neuro-ophthalmological syndrome, as early recognition can accelerate diagnosis and decrease the morbidity. PMID- 29383262 TI - The role of external eyelid weights in acute facial palsy: functional and aesthetic considerations. AB - Purpose: Patients with acute paralytic lagophthalmos are at high risk for ocular surface breakdown due to exposure. External eyelid weights are a temporary solution for paralytic lagophthalmos that aim to reduce exposure and optimize blink excursion. Despite easy application and high efficacy, this product is under-utilized in clinical practice with few physicians employing this treatment adjunct. Results: Ocular surface health was maintained in all patients, and overall aesthetic satisfaction was high. Conclusion: External eyelid weights are a valuable adjunct in the treatment of facial palsy but are under-utilized in clinical practice. This article highlights the benefits of external eyelid weights as an accessible adjunct to restore eyelid function and maintain cosmesis. The device can be implemented without specialist involvement and adds a dimension of independence for general practitioners to manage ocular complications of facial palsy. PMID- 29383263 TI - Intracardiac ultrasound to detect aneurysm in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a genetic disorder characterized by fibrofattty replacement of the right ventricular myocardium. In the revised 2010 Task Force Criteria, a major criteria for ARVD/C is the presence of RV aneurysm by 2D echo. Our report demonstrates that intracardiac ultrasound can detect RV aneurysms and also focal absence of trabeculations which brings additional value to the diagnosis of ARVD/C. A 26-year-old male patient suffering from multiple sustained episodes of ventricular tachycardia was implanted with an internal cardiac defibrillator after confirmation of the disease by cardiac magnetic resonance imaging. Intracardiac ultrasound was performed using a 6F, 9 MHz catheter and the iLAB intravascular system (Boston Scientific). Images of right ventricular inflow tract, outflow tract, apex and pulmonary artery were taken and saved on videotape. ICE revealed loss of trabecular structure at the right ventricular outflow tract with an antero-septal aneurysm at this level. Intravascular ultrasound provides useful information on the presence of aneurysms and of tissue characterization. PMID- 29383264 TI - Acute duodenal intramural hematoma complicated by acute pancreatitis-a rare complication of endoscopic epinephrine injection therapy. AB - Intramural duodenal hematoma (IDH) is a rare complication in endoscopic management of ulcer hemorrhage. Usually noted in cases of blunt abdominal trauma, non-traumatic IDHs have been reported in individuals on anticoagulation, with blood disorders, pancreatic diseases and in endoscopic procedures such as biopsy, sclerotherapy and argon plasma coagulation. Patients may be asymptomatic or present with acute blood loss anemia, abdominal pain or vomiting. We report a case of an 83-year-old man with melena and syncope who underwent endoscopy for bleeding ulcer control and subsequently developed acute pancreatitis due to an acute IDH. Computed tomography (CT) scan confirms the diagnosis. Most cases are conservatively managed however when unsuccessful, laparoscopic surgical drainage or ultrasound or CT guided drainage can be performed. PMID- 29383265 TI - Apparent diffusion coefficient value for a B-cell central nervous system lymphoma in a cat. AB - Case summary: This report involves a 10-year-old male mixed-breed cat with a B cell central nervous system (CNS) lymphoma. The cat presented with ataxia progressing to left hemiparesis. While haematological findings were normal, serum biochemistry showed a high creatine phosphokinase concentration. MRI revealed a homogeneously enhancing well-demarcated extra-axial lesion involving the region of the left lateral aperture with oedema in left flocculus and left medulla oblongata. On diffusion-weighted imaging, the lesion margins showed marked hyperintensity relative to the right cerebellar hemisphere. On an apparent diffusion coefficient map, the lesion appeared hypointense, with an apparent diffusion coefficient value of 0.57 +/- 0.01 * 10-3 mm2/s. Cerebrospinal fluid (CSF) analysis and cytology, and genetic analysis of CSF lymphoblasts confirmed a diagnosis of B-cell lymphoma. The owner opted for palliative treatment with prednisolone (1 mg/kg q12h); however, the cat died of dyspnoea 10 days after presentation. Relevance and novel information: CNS lymphomas, which are the second most common intracranial tumours in cats, are highly infiltrative lesions and radical surgical excision is not recommended. Therefore, accurate diagnosis is crucial. However, contrast-enhanced MRI cannot always differentiate these lesions from other conditions, including other CNS tumours and strokes. To the best of our knowledge, this is the first report to document the diffusion weighted imaging features and apparent diffusion coefficient value for a feline CNS lymphoma. These findings are expected to improve the diagnostic accuracy of these lesions in cats. PMID- 29383266 TI - Movement measurements at home for multiple sclerosis: walking speed measured by a novel ambient measurement system. AB - Background: Gait disturbance is a major contributor to clinical disability in multiple sclerosis (MS). A sensor was developed to assess walking speed at home for people with MS using infrared technology in real-time without the use of wearables. Objective: To develop continuous in-home outcome measures to assess gait in adults with MS. Methods: Movement measurements were collected continuously for 8 months from six people with MS. Average walking speed and peak walking speed were calculated from movement data, then analyzed for variability over time, by room (location), and over the course of the day. In-home continuous gait outcomes and variability were correlated with standard in-clinic gait outcomes. Results: Measured in-home average walking speed of participants ranged from 0.33 m/s to 0.96 m/s and peak walking speed ranged from 0.89 m/s to 1.51 m/s. Mean total within-participant coefficient of variation for daily average walking speed and peak walking speed were 10.75% and 10.93%, respectively. Average walking speed demonstrated a moderately strong correlation with baseline Timed 25-Foot Walk (rs = 0.714, P = 0.111). Conclusion: New non-wearable technology provides reliable and continuous in-home assessment of walking speed. PMID- 29383268 TI - Mysterious Pisotriquetral Joint. PMID- 29383267 TI - Geriatric Cyclists: Assessing Risks, Safety, and Benefits. AB - Nearly 1 in every 3 Americans ride bicycles each year, but only 20% of the reported 100 million cyclists ride on a weekly basis. Bicycling is a common form of transportation and recreation and has gained popularity among the elderly patients. In recent years, the number of elderly cyclists has increased steadily and studies have cited ease of use, need for exercise, and enjoyment as important contributing factors. The benefits of physical activity on health is well documented, and elderly individuals are encouraged to remain active to reduce the progression of age-related weakness and loss of muscle mass. Safety concerns, however, have been a prevalent public health issue. According to the Center for Disease Control and Prevention, elderly and teenage cyclists account for the highest number of head injuries and fatalities among all cyclists. Safety measures that include wearing protective gear such as helmets and choosing the appropriate bicycle have been recommended to minimize the risk of sustaining injuries while riding. Despite these concerns, bicycling has remained a popular and exciting activity for the elderly patients. PMID- 29383269 TI - Treatment of Pisotriquetral Arthritis by Pyrocarbon Interposition Arthroplasty. AB - Purpose Pisiformectomy is the baseline treatment for pisotriquetral arthritis when medical treatment fails to address the problem. This operation may lead to loss of mobility and strength in the wrist. This study reports the short-term outcomes of a new technique for treating pisotriquetral arthritis using a pisotriquetral interposition arthroplasty with a pyrocarbon implant. Patients and Methods We performed a clinical and radiographic study on a series of eight patients who received this treatment at a mean follow-up of 2.8 years. We also studied the mobility of the implant and did assessed articular instability using dynamic radiology and fluoroscopy. Results We observed one proximal dislocation of the implant in one hand which was reoperated to reposition the implant and strengthen the capsule. All patients were satisfied or very satisfied with their operation and had an average functional recovery period of 1.6 months. At the last follow-up, the Mayo Wrist Score (MWS), Quick Disability of Arm Shoulder and Hand (QDASH), and Patient-Rated Wrist Evaluation (PRWE) scores were 89, 18, and 20, respectively. Postoperatively, there was a 22% improvement in the grip strength of the wrists as well as improved mobility, mainly as regards the radioulnar deviation (47% improvement) and the Visual Analogue Scale (VAS) pain scores decreased from 8 preoperatively to 2 at the latest follow-up. The functional radiologic and fluoroscopic study reported good adaptive mobility of the implant in all the patients, without any indication of pisotriquetral joint instability. Conclusion The short-term results of pisotriquetral arthroplasty using the Pyrocardan implant are encouraging. This new surgical solution appears to be a valid alternative to pisiformectomy or pisotriquetral arthrodesis. Long term studies are required to confirm these preliminary findings. PMID- 29383270 TI - Combined Fractures of the Scaphoid and Distal Radius: Evaluation of Early Surgical Fixation (21 Patients with 22 Wrists). AB - Introduction The purpose of this retrospective study, is to evaluate the clinical and functional results of early surgical fixation of the ipsilateral distal radius and scaphoid fractures in 22 of 21 patients. Patients and Methods Overall, 22 combined ipsilateral scaphoid, and distal radius fracture treatments between 2002 and 2015 were evaluated. The mean age was 34.9 (range: 19-82) years. One patient had bilateral injuries. In 17 patients the injury was due to a fall from a height, and in 4 patients due to a motorcycle accident. According to the AO classification, there were 2 type B and 20 type C fractures of the distal radius. The volar locking plate fixation technique was applied in 14 wrists, screw fixation technique in 1, external fixation combined with Kirschner wires (K wire) stabilization technique was used in 3 wrists, and only K-wire pinning technique was used in 4 wrists. All scaphoid fractures were type B (21 type B2, 1 type B1) according to the Herbert-Fischer classification. K-wire fixation was applied in 2 and cannulated screw fixation was performed in 20 fractures. Clinical evaluation was performed with measuring the pinch power, grip power, and range of motions. Functional evaluation was performed using patient-rated wrist evaluation score (PRWE). Results The average follow-up period was 25 (range: 12 97) months. All radius and scaphoid fractures healed. The mean active wrist motions were found to be 45 degrees of flexion, 48.5 degrees of extension, 20 degrees of radial deviation, and 43 degrees ulnar deviation. Mean grip/pinch strengths were 31/8.5 kg. Mean PRWE score was 5.5 (range: 0-8.5). All patients returned to preoperative activity level and can do preinjury jobs. Conclusion Combined ipsilateral fractures of distal radius and scaphoid are complex and rare injuries due to high energy traumas. Stable early primary fracture fixation in these injuries can be expected with good functional results. Level of Evidence Level IV. PMID- 29383271 TI - Survivorship of Revision Wrist Replacement. AB - Purpose This study aims to report the 5-year survivorship of revision wrist arthroplasties and to report midterm clinical and radiological results. Materials and Methods All patients receiving a revision wrist arthroplasty in our unit between January 1, 1997 and October 31, 2010 were identified, and clinical notes retrospectively analyzed for Quick Disabilities of the Arm, Shoulder and Hand (quickDASH), Patient Evaluation Method (PEM), Patient-Rated Wrist Evaluation (PRWE), the range of movement, and visual analog score (VAS). In cases where patient review had not occurred within the past year, they were invited for assessment, and this data was included in the analysis. Plain radiographs were analyzed for loosening of each component. The 5-year survival was plotted using Kaplan-Meier analysis. Results Of the 19 patients identified, 1 was lost to follow-up and therefore excluded from all analyses. Mean age at revision wrist arthroplasty was 55.8 years and the mean time from primary to revision wrist arthroplasty was 6.7 years. At revision arthroplasty, 7 patients received the Biaxial implant (DePuy, Inc., Warsaw, IN) and 11 received the Universal II implant (Integra, Inc., Plainsboro, NJ). The 5-year implant revision survivorship was 83%. Depending on the variable of interest, clinical data were available for either three, four or five patients. At final follow-up (mean: 10.4 years), mean visual analog score was 2.9, mean quickDASH 57, mean PEM 49, mean PRWE 61, and mean arc of flexion/extension was 26 degrees. Radiological data were available for 12 patients, with evidence of gross loosening present in around 60% of the carpal components and 50% of the radial components at mean 6.7 years. Conclusion Revision wrist replacement implant survival is acceptable, but the majority of the surviving implants are radiologically loose. It is not clear at this time whether they are better or worse than a fusion after a failed primary wrist arthroplasty. Clinical Relevance It is reasonable to offer revision wrist arthroplasty in selective cases, but regular clinical and radiological follow-up is recommended. PMID- 29383272 TI - Angular Stable Miniplate Fixation of Chronic Unstable Scaphoid Nonunion. AB - Background Around 5 to 15% of all scaphoid fractures result in nonunion. Treatment of long-lasting scaphoid nonunion remains a challenge for the treating surgeon. Healing of scaphoid nonunion is essential for prevention of scaphoid nonunion advanced collapse and the subsequent predictable pattern of radiocarpal osteoarthritis. Purpose The purpose of this study was to investigate the feasibility of fixation of the scaphoid nonunion with a volar angular stable miniplate and cancellous bone grafting. We hypothesized that this technique could be successful, even in patients with previous surgery for nonunion and in patients with a long duration of nonunion. Patients and Methods A total of 21 patients enrolled in a single-center prospective cohort study. Healing of nonunion was assessed on multiplanar computed tomography scan of the wrist at a 3 month interval. Functional outcome was assessed by measuring grip strength, range of motion, and by means of the patient-rated wrist and hand evaluation (PRWHE) questionnaire. Results During follow-up, 19 out of 21 patients (90%) showed radiological healing of the nonunion. The range of motion did not improve significantly. Postoperative PRWHE scores decreased by 34 points. Healing occurred regardless of the length of time of the nonunion (range: 6-183 months) and regardless of previous surgery (38% of patients). Conclusion Volar angular stable miniplate fixation with autologous cancellous bone grafting is a successful technique for the treatment of chronic unstable scaphoid nonunion, even in patients with long-lasting nonunion and in patients who underwent previous surgery for a scaphoid fracture. Rotational interfragmentary stability might be an important determining factor for the successful treatment of unstable scaphoid nonunion. Level of Evidence Level IV. PMID- 29383273 TI - Pulley Reconstruction for Symptomatic Instability of the Tendons of the First Extensor Compartment Following de Quervain's Release. AB - Background Surgical management of de Quervain's tenosynovitis is based on decompression of the first extensor compartment. A simple release of the first compartment can cause instability of the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons in zone seven of the extensors. The WHAT test (wrist hyperflexion and abduction of the thumb) is very effective in diagnosing this instability. Patients and Methods In this retrospective monocentric study, we analyzed a case series of 10 patients all of whom underwent a reconstruction of the first extensor compartment using a retinacular graft because of symptomatic instability after decompression surgery. The reconstruction was a modified technique of the sixth compartment. Functional outcome and characteristics of the newly reconstructed pulley were examined by physical examination with the aid of ultrasound and internationally validated questionnaires. Results Four patients had a good-to-excellent functional outcome, all of those had a maximum of two surgical procedures performed on the first extensor compartment. Six patients presented poor functional outcome. In four of them, more than two surgical procedures were performed. Minor residual instability was noted in six cases, found in both the groups. Conclusion The reconstruction procedures on the first compartment seemed to be satisfactory in treating instability of the EPB and APL tendons after primary surgical release for de Quervain's disease. Level of Evidence Level IV, observational study without controls. PMID- 29383274 TI - Importance of Computed Tomography in Determining Displacement in Scaphoid Fractures. AB - Background Displaced scaphoid fractures have a relatively high rate of nonunion. Detection of displacement is vital in limiting the risk of nonunion when treating scaphoid fractures. Questions/Purpose We evaluated the ability to diagnose displacement on radiographs and computed tomography (CT), hypothesizing that displacement is underestimated in assessing scaphoid fracture by radiograph compared with CT. Materials and Methods Thirty-five preoperative radiographs and CT scans of acute scaphoid fractures were evaluated by two blinded observers. Displacement and angular deformity were measured, and the fracture was judged as displaced or nondisplaced. Scapholunate, radiolunate, and intrascaphoid angles were measured. Radiograph and CT measurements between nondisplaced and displaced fractures were compared. Intraobserver reliability was measured. Results Reader 1 identified 12 fractures as nondisplaced on radiograph, but displaced on CT (34%). Reader 2 identified 9 fractures as nondisplaced on radiograph, but displaced on CT (26%). For displaced fractures, the mean intrascaphoid angle was over three times greater when measured on CT than on radiograph (56 vs. 16 degrees). Scapholunate angle >65 degrees and radiolunate angle >16 degrees were significantly associated with displacement on CT. Interobserver reliability for diagnosing displacement was perfect on CT but less reliable on radiograph. Conclusion Scaphoid fracture displacement on CT was identified in 26 to 34% of fractures that were nondisplaced on radiograph, confirming that radiographic evaluation alone underestimates displacement. These results underscore the importance of CT scan in determining displacement and angular deformity when evaluating scaphoid fractures, as it may alter the decision on treatment and surgical approach to the fracture. We recommend considering CT scan to evaluate all scaphoid fractures. Level of Evidence Level III. PMID- 29383275 TI - Outcomes after Arthroscopic Debridement of the Triangular Fibrocartilage Complex in Adolescents. AB - Background To the best of our knowledge, we are not aware of any reports focusing on results of arthroscopic debridement of triangular fibrocartilage complex (TFCC) tears in immature patients. Purpose The purpose of this study was to evaluate our results after arthroscopic debridement of TFCC tears in adolescents. Materials and Methods We retrospectively identified all patients of 18 years or less, who received an arthroscopic TFCC debridement due to a traumatic or degenerative tear according to Palmer. These cases were clinically re-evaluated after a mean period of 6.7 years (SD +/- 3.9 years). All patients completed the Modified Mayo Wrist Score (MMWS), Disabilities of the Arm, Shoulder and Hand (DASH) inventory, and Patient-Rated Wrist Evaluation (PRWE). Results Thirteen adolescent patients (mean age: 15.6 +/- 2.2 years at surgery) were included. The mean MMWS increased significantly from 70 +/- 13.6 to 90 +/- 6.5 after the TFCC debridement; mean postoperative DASH and PRWE scores of 17 +/- 15.2 and 21 +/- 18.5, respectively, indicated good and excellent outcomes for the majority of the cohort. The mean pain level decreased significantly from a mean of 5.7 +/- 2.0 to 1.8 +/- 2.0 at follow-up. Six patients needed a reoperation to achieve a successful outcome. Conclusion Arthroscopic debridement of TFCC tears, performed as a concomitant wrist surgery in adolescents, efficiently reduced wrist pain and yielded good to excellent results in the long term. However, under certain circumstances, its results are unpredictable and further surgery may be necessary to eventually achieve the satisfying outcomes. Further studies are needed to confirm these findings. Level of Evidence Level IV, therapeutic case series. PMID- 29383276 TI - Long-Term Outcome and Secondary Operations after Proximal Row Carpectomy or Four Corner Arthrodesis. AB - Background Proximal row carpectomy (PRC) and four-corner arthrodesis (FCA) are common surgical procedures used to treat degenerative wrist conditions; however, complications and failures can occur. Purpose This study aimed to investigate and compare the long-term rate of secondary surgeries including conversion to total wrist arthrodesis in patients who underwent PRC or FCA. Materials and Methods A retrospective chart review of all patients who underwent PRC or FCA in the past 20 years at a tertiary referral institution and associated Veterans Affairs (VA) hospital was performed. Patient demographics, comorbidities, surgical indications, and associated complications were tabulated. Patients were contacted via phone to obtain additional follow-up information regarding any additional surgeries, 10-point visual analog scale (VAS) for pain, quick Disabilities of the Arm, Shoulder, and Hand (quickDASH) scores, hand dominance, and occupational data. Results A total of 123 wrists made up the final dataset. Sixty-two wrists treated with PRC and 61 wrists treated with FCA were reviewed at a mean follow-up of 8.2 years. We did not find a significant difference in the rate of conversion to total wrist arthrodesis between the PRC (14.5%) and FCA (19.5%, p = 0.51) cohorts. Secondary operations were significantly greater in the FCA group (34.4%) compared with the PRC group (16.1%, p = 0.02). Females were 2.6 times more likely than males to undergo secondary operations when controlling for surgical procedure and smoking status ( p = 0.04). We did not detect a significant difference in VAS pain or in quickDASH scores between the two groups ( p = 0.35, 0.48, respectively). Conclusion PRC and FCA have comparable patient reported outcomes and wrist arthrodesis conversion rates at a mean follow-up of 8.2 years. In contrast, the FCA patient group had a significantly higher rate of secondary operations, including those for nonunion, symptomatic hardware, and other implant-related issues, when combined with wrist arthrodesis conversion. Level of Evidence Level IV, therapeutic study. PMID- 29383277 TI - Perilunate Dislocations and Perilunate Fracture Dislocations in the U.S. Military. AB - Background Perilunate dislocations and perilunate fracture dislocations (PLDs/PLFDs) are rare and often associated with poor outcomes. Heretofore, these outcomes have not been evaluated in a high-demand military population. Questions/Purpose The purpose of this study was to evaluate the outcomes in a young, active population after sustaining PLD/PLFD injuries. Patients and Methods We retrospectively reviewed the U.S. military service members who underwent surgical treatment for a PLD/PLFD (Current Procedural Terminology codes 25695 and 25685) between June 1, 2010, and June 1, 2014 through the Military Health System Management Analysis and Reporting Tool (M2) database, capturing patients with a minimum 2-year follow-up. Patient characteristics and outcomes were gathered; however, radiographic analysis was not possible. Results In this study, 40 patients (40 wrists) were included with an average follow-up of 47.8 months. The average age was 28.8 years. Twenty-two injuries (55%) were PLFD and 22 (55%) cases involved the nondominant extremity. On initial presentation, 11 (27.5%) were missed and 50% of patients were presented with acute carpal tunnel syndrome. Range of motion (ROM) was 74% and grip strength was 65% compared with the contralateral wrist; 78% reported pain with activity and only 55% remained on active duty status at final follow-up. Injuries to the nondominant extremity were significantly more likely to experience a good to excellent outcome and regained a more ROM. Patients with ligamentous PLD had less pain at rest and were more likely to return to sport. Conclusion Worse outcomes can be expected for PLD/PLFD of the dominant extremity, transscaphoid PLFD, greater arc injuries, and those undergoing pinning alone. A high-demand patient may expect worse functional results with a higher degree of limitation postoperatively. Level of Evidence The level of evidence is therapeutic IV. PMID- 29383278 TI - Variable Bone Density of Scaphoid: Importance of Subchondral Screw Placement. AB - Background Ideal internal fixation of the scaphoid relies on adequate bone stock for screw purchase; so, knowledge of regional bone density of the scaphoid is crucial. Questions/Purpose The purpose of this study was to evaluate regional variations in scaphoid bone density. Materials and Methods Three-dimensional CT models of fractured scaphoids were created and sectioned into proximal/distal segments and then into quadrants (volar/dorsal/radial/ulnar). Concentric shells in the proximal and distal pole were constructed in 2-mm increments moving from exterior to interior. Bone density was measured in Hounsfield units (HU). Results Bone density of the distal scaphoid (453.2 +/- 70.8 HU) was less than the proximal scaphoid (619.8 +/- 124.2 HU). There was no difference in bone density between the four quadrants in either pole. In both the poles, the first subchondral shell was the densest. In both the proximal and distal poles, bone density decreased significantly in all three deeper shells. Conclusion The proximal scaphoid had a greater density than the distal scaphoid. Within the poles, there was no difference in bone density between the quadrants. The subchondral 2-mm shell had the greatest density. Bone density dropped off significantly between the first and second shell in both the proximal and distal scaphoids. Clinical Relevance In scaphoid fracture ORIF, optimal screw placement engages the subchondral 2-mm shell, especially in the distal pole, which has an overall lower bone density, and the second shell has only two-third the density of the first shell. PMID- 29383279 TI - Ulnar Neck Fractures Associated with Distal Radius Fractures. AB - Background There is little published data to guide management of ulnar neck fractures associated with fractures of the distal radius. Purpose As unplanned surgery usually reflects adverse events and this injury combination is relatively uncommon, we used a large database to study the incidence of unplanned surgeries after surgical and nonsurgical treatment of distal metaphyseal ulna fractures associated with a distal radius fracture and identify factors associated with these unplanned surgeries. Patients and Methods We identified 277 patients with an ulnar neck fracture associated with a distal radius fracture. Fifty-six (20%) ulnar neck fractures were initially treated operatively and six of them (11%) had a second, unplanned surgery. Of the 221 initially nonoperatively treated fractures, only one (0.45%) had a subsequent unplanned surgery that seemed unrelated to the fracture (ulnar nerve neurolysis). Results Bivariate analysis showed that younger age, open fracture, multifragmentary fractures, and initial operative treatment of the ulnar neck fracture were significantly associated with unplanned surgery. A multivariable analysis was not feasible due to the small number of unplanned surgeries. Conclusion Eighty percent of ulnar neck fractures associated with a fracture of the distal radius was treated nonoperatively in our region, and subsequent surgery for problems was very uncommon. Operative treatment and fracture complexity were associated with unplanned surgery, which reflected some measure of injury severity, technical inadequacy, and inherent problems associated with surgery. Level of Evidence Level II, prognostic study. PMID- 29383280 TI - A Biomechanical Comparison of Screw and Plate Fixations for Scaphoid Fractures. AB - Background Headless screw fixation is the current gold standard of surgical repair for scaphoid fractures. However, maintaining reduction of certain types of scaphoid fractures is challenging with a compression screw. Plate fixation may offer superior fixation in some scaphoid fractures, particularly those with comminution, nonunion, segmental bony defects, and osteopenic or osteoporotic bone. Purpose This study questions whether method of fixation is a determinant in load to failure in segmental scaphoid fractures, and whether any fixation provides a greater mechanical advantage in simulated normal versus osteoporotic bone. Materials and Methods Polyurethane models were fashioned to simulate scaphoids with 3-mm segmental defects. Defects were bridged by one of three constructs: a locking plate, a nonlocking plate, or a headless compression screw. Three models for each fixation construct were tested for both simulated normal and osteoporotic bone density. Load to failure was recorded as the load at which the 3-mm segmental defect was closed. Results Gap closure occurred in all trials. In simulated normal bone, there were no statistically significant differences in load to failure between fixation methods. In simulated osteoporotic bone, the locking plate had a 28% greater load to failure as compared with screw fixation. Conclusion While biomechanical testing shows that plate and screw fixations are equivalent in normal density bone for fixation of a segmental scaphoid defect, locking plates are superior to screw fixation in simulated osteoporotic bone models. Clinical Relevance Plate fixation may provide superior fixation for complex scaphoid fractures, particularly in osteopenic bone. PMID- 29383281 TI - Spontaneous Healing of a Pediatric Scaphoid Proximal Pole Fracture Nonunion. AB - Background Scaphoid fractures in the pediatric population are rare. The majority of nondisplaced fractures tend to unite; however, there is an increased risk of nonunion in proximal pole fractures. Limited evidence exists in their outcomes, owing to the scarcity of the fracture pattern. Case Description A 13-year-old boy who presented late after developing a traumatic proximal pole scaphoid fracture developed nonunion. He was treated conservatively owing to it being asymptomatic and developed union at 18 months. Literature Review No previous case of proximal pole pediatric scaphoid fractures with established nonunion that has developed union with conservative management has been described. Clinical Relevance The authors highlight a unique case of an established proximal pole scaphoid nonunion in a child progressing to union with nonoperative intervention. Owing to its rarity and difficulty in obtaining research, we recommend consideration of nonoperative management of asymptomatic nondisplaced proximal pole fractures in children. PMID- 29383282 TI - A Posttraumatic Distal Radius Allograft: 10 Years Follow-Up. AB - Background Wrist osteoarthritis is a common disease often resulting from malunited fractures of the distal radius. The primary treatment purpose is to provide pain relief, while maintaining strength and mobility whenever possible. In a patient presenting a posttraumatic degeneration of the wrist, deciding which surgical technique, which joints to sacrifice and which to preserve is crucial to optimizing the outcome. Case Description We describe a 10-year follow-up of an osteoarticular allograft of the distal radius proposed to treat an isolated distal radius posttraumatic degeneration. The patient was young and active. No or slight articular degeneration of the carpal rows was present. The surgical technique was based on a periarticular step-cut that allowed the preservation of the dorsal capsule and the maximum contact between the bone and the allograft. Literature Review In the literature, the allograft of the radius is described as a solution to an oncologic problem. Considering a posttraumatic scenario other techniques are usually performed. However, compared with artificial interbody fusion devices and prosthetic implants, structural bone allograft retains an advantage in biologic performance. It has osteoconductive properties and is similar to native tissues providing a progressive incorporation by the host. Clinical Relevance This surgical technique provide a metaphyseal step-cut able to ensure a secure stabilization and a wide contact surface between the allograft and the native bone. Integration of the allograft with good functional and radiological outcome seen after 10 years supports this technique. PMID- 29383283 TI - Arthroscopic Scaphoid 3D Test for Scapholunate Instability. AB - Background Patients with scapholunate instability usually have pain in the dorsal wrist. This pain may occur due to the impingement between the scaphoid and the dorsal rim of the radius when the scaphoid is detached from the lunate. This pain appears as the scaphoid is displaced over the dorsal rim of the radius. The arthroscopic scaphoid 3D (dorsal, dynamic, displacement) test is described here to check this pathologic dorsal displacement of the scaphoid. Surgical Technique The test should be performed both in the radiocarpal and midcarpal joints. Traction is released and the arthroscope is set under the lunate when tested in the radiocarpal joint and on the lunate when tested in the midcarpal joint. The scaphoid is manually pushed dorsally at the scaphoid tubercle. If there was no scapholunate instability, all the proximal row bones are minimally displaced: a negative test. If there was scapholunate instability, the scaphoid is displaced dorsally while the lunate remains static: evaluated as positive. Clinical Relevance This test can add information to the arthroscopic classifications of the scapholunate instability, which explore both the proximal to distal displacement of the scaphoid (the step-off) and the ulnar to radial displacement (the gap), as this test explores the volar to dorsal displacement. PMID- 29383284 TI - Erratum. AB - [This corrects the article on p. 14 in vol. 6.]. PMID- 29383285 TI - The oldest Archaeopteryx (Theropoda: Avialiae): a new specimen from the Kimmeridgian/Tithonian boundary of Schamhaupten, Bavaria. AB - The iconic primeval bird Archaeopteryx was so far mainly known from the Altmuhltal Formation (early Tithonian) of Bavaria, southern Germany, with one specimen having been found in the overlying Mornsheim Formation. A new specimen (the 12th skeletal specimen) from the earliest Tithonian Painten Formation of Schamhaupten (Bavaria) represents the so far oldest representative of the genus. The new specimen shows several interesting anatomical details, including the presence of a postorbital in contact with the jugal, the presence of a separate prefrontal and coronoid, and opisthocoelous mid-cervical vertebrae. Based on observations on the new specimen, we discuss several problematic issues concerning Archaeopteryx, including the monophyly and diagnosis of the genus, the absence/presence of the sternum, the position of the gastralia, and variation in morphometrics and dental morphology in that genus. Based on a new diagnosis for the genus Archaeopteryx, the Berlin, Eichstatt, Solnhofen, Munich, Daiting, Thermopolis, 11th, and 12th specimens can be referred to this genus with high certainty. The Maxberg specimen is very probably also an Archaeopteryx, based on overall similarity, although none of the diagnostic characters can be evaluated with certainty. The ninth specimen ('chicken wing') might be Archaeopteryx, but cannot be referred to the genus with any certainty. In comparison with other paravians, the presence of distally thickened anterior pectoral ribs indicates that a rather large cartilagenous sternum was present in this taxon. In contrast to non-opisthopubic theropods, opisthopubic taxa, such as Archaeopteryx and many other paravians, have the posterior end of the gastral basket preserved at about half-length of the pubis, which might reflect the post-mortem collapse of enlarged abdominal air sacs in these taxa. Specimens that can be referred to Archaeopteryx show a high amount of variation, both in the morphometrics of the limb bones as well as in the dentition. In respect to the latter aspect, variation is found in tooth number, spacing, orientation, and morphology, with no two specimens showing the exact same pattern. The significance of this variation is unclear, and possible explanations reach from high intraspecific (and possibly ontogenetic and/or sexual dimorphic) variation to the possibility that the known specimens represent a 'species flock' of Archaeopteryx, possibly due to island speciation after the initial dispersal of the genus into the Solnhofen Archipelago. PMID- 29383286 TI - Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors. AB - Targeting tyrosinase is considered to be an effective way to control the production of melanin. Tyrosinase inhibitor is anticipated to provide new therapy to prevent skin pigmentation, melanoma and neurodegenerative diseases. Herein, we report our results in identifying new tyrosinase inhibitors. The shape-based virtual screening was performed to discover new tyrosinase inhibitors. Thirteen potential hits derived from virtual screening were tested by biological determinations. Compound 5186-0429 exhibited the most potent inhibitory activity. It dose-dependently inhibited the activity of tyrosinase, with the IC50 values 6.2 +/- 2.0 uM and 10.3 +/- 5.4 uM on tyrosine and L-Dopa formation, respectively. The kinetic study of 5186-0429 demonstrated that this compound acted as a competitive inhibitor. We believe the discoveries here could serve as a good starting point for further design of potent tyrosinase inhibitor. PMID- 29383287 TI - Remote collection of microorganisms at two depths in a freshwater lake using an unmanned surface vehicle (USV). AB - Microorganisms are ubiquitous in freshwater aquatic environments, but little is known about their abundance, diversity, and transport. We designed and deployed a remote-operated water-sampling system onboard an unmanned surface vehicle (USV, a remote-controlled boat) to collect and characterize microbes in a freshwater lake in Virginia, USA. The USV collected water samples simultaneously at 5 and 50 cm below the surface of the water at three separate locations over three days in October, 2016. These samples were plated on a non-selective medium (TSA) and on a medium selective for the genus Pseudomonas (KBC) to estimate concentrations of culturable bacteria in the lake. Mean concentrations ranged from 134 to 407 CFU/mL for microbes cultured on TSA, and from 2 to 8 CFU/mL for microbes cultured on KBC. There was a significant difference in the concentration of microbes cultured on KBC across three sampling locations in the lake (P = 0.027), suggesting an uneven distribution of Pseudomonas across the locations sampled. There was also a significant difference in concentrations of microbes cultured on TSA across the three sampling days (P = 0.038), demonstrating daily fluctuations in concentrations of culturable bacteria. There was no significant difference in concentrations of microbes cultured on TSA (P = 0.707) and KBC (P = 0.641) across the two depths sampled, suggesting microorganisms were well-mixed between 5 and 50 cm below the surface of the water. About 1 percent (7/720) of the colonies recovered across all four sampling missions were ice nucleation active (ice+) at temperatures warmer than -10 degrees C. Our work extends traditional manned observations of aquatic environments to unmanned systems, and highlights the potential for USVs to understand the distribution and diversity of microbes within and above freshwater aquatic environments. PMID- 29383288 TI - Establishment of an immortalized mouse dermal papilla cell strain with optimized culture strategy. AB - Dermal papilla (DP) plays important roles in hair follicle regeneration. Long term culture of mouse DP cells can provide enough cells for research and application of DP cells. We optimized the culture strategy for DP cells from three dimensions: stepwise dissection, collagen I coating, and optimized culture medium. Based on the optimized culture strategy, we immortalized primary DP cells with SV40 large T antigen, and established several immortalized DP cell strains. By comparing molecular expression and morphologic characteristics with primary DP cells, we found one cell strain named iDP6 was similar with primary DP cells. Further identifications illustrate that iDP6 expresses FGF7 and alpha-SMA, and has activity of alkaline phosphatase. During the process of characterization of immortalized DP cell strains, we also found that cells in DP were heterogeneous. We successfully optimized culture strategy for DP cells, and established an immortalized DP cell strain suitable for research and application of DP cells. PMID- 29383289 TI - Retraction: Thoracic Vertebral Actinomycosis Secondary to a Pulmonary Origin. AB - [This retracts the article DOI: 10.7759/cureus.391.]. PMID- 29383290 TI - Retraction: Staged Surgical Management in the Treatment of Primary Epidural Hydatidosis of the Spine: A Case Series and Review. AB - [This retracts the article DOI: 10.7759/cureus.401.]. PMID- 29383291 TI - Orbital Apex Metastasis from Adenoid Cystic Carcinoma: Acute Loss of Vision and Subsequent Recovery with the Radiation. AB - Orbital apex metastasis from adenoid cystic carcinoma (ACC) is rare. We present a patient with known metastatic ACC presented with a rapidly declining vision with visual acuity oculus dexter (OD) equal to counting fingers at two feet. On imaging, she was found to have a right orbital apex tumor causing compressive optic neuropathy. She received the intensity modulated radiation therapy (IMRT). After completion of the therapy, she had regained essentially a full vision with visual acuity OD of 20/30 without corrective lenses. The treatment rationale and pertinent literature are discussed in this article. PMID- 29383292 TI - Clinical Research Skills Assessment: An Investigation into the Determinants of Effective Research. AB - Background Developing individual research skills and enhancing the institutional research culture leads to quality research capabilities and research excellence at the national level. We aim to assess the educational needs of healthcare providers regarding research skills at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia. Methods From February 2016 to October 2016, we conducted a cross sectional study using a self-administered questionnaire of the healthcare providers at KFMC. The questionnaire targeted staff who have not been involved in research (n=353; "category-1"), staff who received Institutional Review Board (IRB) approval (n=94; "category-2"), and staff who have completed and published their research (n=53; "category-3"). A descriptive analysis was used to measure the frequency, and the chi-square test was used to test significance when comparing categorical data. Results The final analysis contained 500 questionnaires. The number of women was higher than that of men in "category-2 "and "category-3" (53.2%, 62.3%), respectively. Approximately 62.4% of "category 1" participants reported good, poor, and very poor knowledge of epidemiology. Participants in "category-1" and "category-2" stated poor and very poor levels when writing a manuscript (43%, 23.4%), respectively. Only 37% of participants in "category-3" showed very good to excellent research skills. However, there was a significant correlation between the mean scores of research skill and research stage (p-value < 0.001). Conclusion The results showed a significant variation in research skills needs among research stage categories; therefore, meeting the educational needs of healthcare providers aimed at effective research shall be constructed based on their stage of research. PMID- 29383293 TI - A Pilot Study in the Use of Activity Trackers for Assessing Response to Palliative Radiotherapy. AB - Purpose Radiation therapy (RT) has been a frequently used treatment for painful bone metastasis. The aim of this study was to determine the feasibility of using activity trackers (AT) to assess the patient prognosis and the effects of palliative RT. Methods and materials Twelve patients planned to receive palliative RT for axial metastases and were prospectively recruited to participate in this pilot clinical trial. The patients were eligible if there was no intent to change the analgesic medications prior to or within seven days of palliative RT. All the patients were lent a Misfit FlashTM activity tracker (Misfit, Burlingame, California, United States of America) and were asked to wear it from the time of baseline assessment prior to RT until seven days after RT. The patients completed the European Organisation for Research and Treatment of Cancer quality of life (QOL) questionnaire (EORTC-QLQ C30) and the Short Form Brief Pain Inventory (SF-BPI) before the treatment and at days seven, 30 and 90 after completion of the RT. The patients' Karnofsky Performance Status (KPS) was assessed at each visit. The patients' overall survival at the end of the RT was recorded. Average daily steps before and after RT were compared using paired Wilcoxon signed-rank test. The patients' overall survival was estimated using the Kaplan-Meier curve and analyzed using the Log-Rank test. Results The median age of the patients was 62 years (range: 40-79 years). Of the 12 patients, there were five prostate, three breasts, three lungs, and one colon cancer-related patients. Six patients received 20 Gray (Gy) in five fractions and six received 8 Gy in one fraction. By day seven, post-RT, there was a 30% (p <0.02) reduction in the patients' daily activity level. There was no correlation between improvements in the QOL or with the level of pain and with the number of daily steps. While baseline KPS was not prognostic of the patient survival, the patients who on average took more than 7800 steps per day prior to RT lived significantly (p=0.034) longer than those who were less active. Conclusions The baseline activity level is associated with the patient prognosis. A significant decline in the physical activity was observed at one week after palliative RT. The use of activity trackers was to prognosticate and to monitor the patients' response to the palliative RT and should be evaluated further. PMID- 29383294 TI - Hydrodissection of Wiltse's Plane to Facilitate Exposure During Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - Traditional posterior lumbar approaches in a transforaminal lumbar interbody fusion (TLIF) require subperiosteal dissection of bilateral paraspinal muscles to provide adequate exposure. This may traumatize the multifidus muscle and its afferent innervations leading to postoperative paraspinal muscle atrophy. Minimizing such intraoperative trauma has been identified as an important factor in the reduction of postoperative lumbar pain. An approach via a blunt dissection through Wiltse's plane, which lies between the longissimus and multifidus muscles, may minimize postoperative pain. Definition of this plane may be facilitated by local injection of 1% lidocaine within the plane itself, as well as in the musculature defining its borders. In this paper, we demonstrate this technique with a 55-year-old female patient who presented with left-sided radicular leg pain in an L5 distribution. Wiltse plane hydrodissection was utilized in performing an L4-5 TLIF. Ultrasound images of the patient's sub fascial musculature were obtained pre- and posthydrodissection to assess the elucidation of this plane through this technique. Intraoperative images were obtained following dissection of Wiltse's plane to further illustrate the facilitation of exposure of Wiltse's plane through hydrodissection. Postoperatively the patient did well citing a complete resolution of her radicular pain. She did not require intravenous (IV) pain medication, as her postoperative pain was well controlled with oral pain medication. She was mobilized on post-op day one, and discharged home on post-op day two with minimal back pain. Our initial experience supports the feasibility, safety, and effectiveness of hydrodissection of Wiltse's plane to facilitate exposure during a minimally invasive TLIF and thereby reducing postoperative pain. PMID- 29383296 TI - A Combined Open and Endovascular Approach for the Treatment of a Torcular Dural Arteriovenous Fistula. AB - Cranial dural arteriovenous fistulae (dAVFs) are complex vascular lesions, rarely encountered within the pediatric population. Endovascular embolization has revolutionized the management of these lesions and should be regarded as the first-line treatment for the majority of dAVFs; however, in a subset of particularly complicated lesions, traditional routes of access either do not exist or have been eliminated in the course of prior embolization attempts. We describe the case of an 11-year-old boy with a complicated torcular dAVF refractory to multiple attempts at standard endovascular treatment. He was cured after direct surgical puncture of the superior sagittal sinus to obtain vascular access for coil embolization of the venous sac. We review the technical aspects of this particular case while highlighting the anatomic features of those dAVFs that require nontraditional, surgical access for appropriate treatment. We also describe a simple algorithm, which may help in identifying the small subset of dAVF that requires a hybrid open and endovascular approach to effectively access the fistulous point and achieve disconnection. PMID- 29383295 TI - Alteration of the Ki-67 Proliferative Index following Surgical Resection with or without Radiation Therapy of Intracranial Meningiomas. AB - The Ki-67 proliferative index is a widely accepted assay for cycling cells within tumor specimens of multiple histological subtypes. While it is not a substitute for the World Health Organization (WHO) grading, the Ki-67 proliferative index is thought to correlate with the biological activity of selected tumors. In the case of intracranial meningiomas, many lesions may be resected multiple times, with radiation therapy juxtaposed between surgical procedures. A retrospective review of 3,900 consecutive patients undergoing intracranial surgical resection at the University of Pittsburgh Medical Center over a five year period was undertaken. Of these patients, 604 had multiple resections. Multiple Ki-67 index scores were available for 42 patients with WHO grade I and II meningiomas, who suffered a recurrence or progression after their initial resection. Evidence of radiation therapy in the interval between pathology reports was also recorded. Data was evaluated for significant differences (p<0.05). WHO grade II meningiomas were more likely to have a higher Ki-67 index score on second resection than WHO grade I tumors (p=0.051). Furthermore, radiation-treated meningiomas demonstrated similar first Ki-67 index scores and higher second Ki-67 index scores (p=0.057 and p=0.022). Male patients tended to have less change in proliferation rates than female patients between the first and second resections (p=0.083), with a greater proportion of female patient tumors demonstrating accelerating proliferation rates. Treatment with radiation was associated with diminishing changes in meningioma proliferation rates compared to non-treated patients for tumors showing both accelerating rates (p=0.067) and decelerating rates (p=0.081). Ki-67 proliferation indices of recurrent or progressive meningiomas indicate that there are potentially distinct types of growth patterns of meningiomas, consisting of accelerating and decelerating proliferation rates. Meningioma growth is related to WHO grade, patient gender, and treatment with radiation. Radiation treatment appears to stabilize or "inactivate" tumor proliferation and thus normalize changes in meningioma growth rates. PMID- 29383297 TI - Burnout of Physicians Working in Primary Health Care Centers under Ministry of Health Jeddah, Saudi Arabia. AB - Introduction The levels of physicians' job satisfaction and burnout directly affect their professionalism, punctuality, absenteeism, and ultimately, patients' care. Despite its crucial importance, little is known about professional burnout of the physicians in Saudi Arabia. The objectives of this research are two-fold: (1) To assess the prevalence of burnout in physicians working in primary health care centers under Ministry of Health; and (2) to find the modifiable factors which can decrease the burnout ratio. Methodology Through a cross-sectional study design, a representative sample of the physicians working in primary health care centers (PHCCs) Jeddah (n=246) was randomly selected. The overall burnout level was assessed using the validated abbreviated Maslach burnout inventory (aMBI) questionnaire. It measures the overall burnout prevalence based on three main domains i.e., emotional exhaustion, depersonalization, and personal accomplishment. Independent sample T-test, analysis of variance (ANOVA), and multivariate regression analysis were performed using Statistical Package for the Social Sciences (SPSS Version 22, IBM, Armonk, NY). Results Overall, moderate to high burnout was prevalent in 25.2% of the physicians. Emotional exhaustion was noted in 69.5%. Multivariate regression analysis showed that patient pressure/violence (p <0.001), unorganized patients flow to clinics (p=0.021), more paperwork (p<0.001), and less co-operative colleague doctors (p=0.045) were the significant predictors for high emotional exhaustion. A positive correlation was noted between the number of patients per day and burnout. The patient's pressure/violence was the only significant independent predictor of overall burnout. Conclusion Emotional exhaustion is the most prominent feature of overall burnout in the physicians of primary health care centers. The main reasons include patient's pressure/violence, unorganized patient flow, less cooperative colleague doctors, fewer support services at the PHCCs, more paperwork, and less cooperative colleagues. Addressing these issues could lead to a decrease in physician's burnout. PMID- 29383298 TI - Treatment of Minimal Residual Disease in Breast Cancer: A Longitudinal Case Study. AB - The presence of micrometastatic disease will ultimately determine the breast cancer-specific mortality of patients treated according to current guidelines. Minimal residual disease (i.e., occult tumor, not detected by conventional tests) may exist in two forms: a dormant form of only micrometastasis and a more aggressive "awakened" form where CTCs (circulating tumor cells) are actively disseminating. The hypothesis is that patients with CTCs have a more advanced or aggressive disease (that the cancer has "awoken" and there is active dissemination), whereas those patients with only micrometastasis have "dormant" disease and, although at risk of future relapse, may not do so for many years. This case study shows how determining the presence of both CTCs and bone marrow micrometastasis could be used to monitor disease activity and determine treatment changes before the appearance of metastatic disease. Presented is the case of a 53-year-old postmenopausal woman who presented with a T2N1M0 invasive ductal breast cancer. She had been treated with partial mastectomy, axillary dissection, local radiotherapy, and adjuvant chemotherapy. As the cancer was estrogen receptor-positive, she was taking tamoxifen. Two years into treatment, she was assessed for minimal residual disease and was found to be positive for CTCs and bone marrow micrometastasis. Her treatment was changed to letrozole and differing bisphosphonates. The minimal residual disease was finally eliminated, and at 16 years post-initial treatment, there was no evidence of relapse. The detection of minimal residual disease can be used to monitor treatment effect and change therapy in order to maintain the asymptomatic status of the patient and prevent disease progression. PMID- 29383300 TI - Enteral Nutrition in Pediatric Patients. AB - Pediatric patients require specialized attention and have diverse demands for proper growth and development, and thus need a different approach and interest in nutritional assessment and supply. Enteral nutrition is the most basic and important method of nutritional intervention, and its indications should be identified. Also, the sites, modes, types, and timing of nutritional intervention according to the patient's condition should be determined. In addition, various complications associated with enteral nutrition supply should be identified, and prevention and treatment are required. This approach to enteral nutrition and proper administration can help in the proper growth and recovery of pediatric patients with nutritional imbalances or nutritional needs. PMID- 29383299 TI - Early Biologic Treatment in Pediatric Crohn's Disease: Catching the Therapeutic Window of Opportunity in Early Disease by Treat-to-Target. AB - The emergence of mucosal healing as a treatment goal that could modify the natural course of Crohn's disease and the accumulating evidence showing that biologics are most effective in achieving mucosal healing, along with the success of early treatment regimens for rheumatoid arthritis, have led to the identification of early Crohn's disease and development of the concept of catching the therapeutic window during the early disease course. Thus, an increasing number of pediatric gastroenterologists are adopting an early biologic treatment strategy with or without an immunomodulator. Although early biologic treatment is effective, cost and overtreatment are issues that limit its early use. Currently, there are insufficient data on who will benefit most from early biologics, as well as on who will not need early or even any biologics. For now, top-down biologics should be considered for patients with currently known high risk factors of poor outcomes. For other patients, close, objective monitoring and accelerating the step-up process by means of a treat-to-target approach seems the best way to catch the therapeutic window in early pediatric Crohn's disease. The individual benefits of immunomodulator addition during early biologic treatment should be weighed against its risks and decision on early combination treatment should be made after comprehensive discussion with each patient and guardian. PMID- 29383301 TI - Association between Minimal Change Esophagitis and Gastric Dysmotility: A Single Center Electrogastrography and Endoscopy Study in Children. AB - Purpose: Minimal change esophagitis (MCE) is a reflux disease without mucosal breaks, known to be partially associated with abnormal gastric motor function. Electrogastrography (EGG) is commonly applied to assess gastric motor function in a noninvasive fashion. We aimed to determine the relationship between MCE and gastric myoelectrical activity (GME) recorded on EGG in children. Methods: We retrospectively assessed the records of 157 children without underlying disease who underwent both EGG and upper gastrointestinal endoscopy at Gachon University Gil Medical Center between January 2010 and June 2015. The children were stratified according to the appearance of the esophagus (normal vs. MCE). Between group differences in EGG parameters and their correlation with each MCE finding were statistically analyzed. Results: Only the power ratio, one of the EGG parameters analyzed, differed significantly between the two groups (MCE, 1.68+/ 3.37 vs. normal, 0.76+/-1.06; p<0.05), whereas the other parameters, such as dominant frequency, dominant power, and the ratio of abnormal rhythm, showed no differences. Among children with MCE, significant correlations were noted between erythema and power ratio (p<0.05), friability and postprandial dominant frequency (p<0.05), and edema and/or accentuation of mucosal folds and pre-prandial frequency (p<0.05). Helicobacter pylori infection correlated with postprandial arrhythmia (MCE, 33.59+/-15.52 vs. normal, 28.10+/-17.23; p<0.05). EGG parameters did not differ between children with normal esophagus and those with biopsy proven chronic esophagitis. Conclusion: In children with MCE, gastric dysmotility may affect the development of MCE, manifesting as EGG abnormalities. H. pylori infection may also affect GME. However, larger prospective investigations are needed to confirm these findings. PMID- 29383302 TI - A Synbiotic Infant Formula with High Magnesium Content Improves Constipation and Quality of Life. AB - Purpose: To evaluate the efficacy of synbiotic formula with partial whey hydrolysate and high magnesium content in infants presenting with functional constipation. Methods: Sixty-five infants with functional constipation were included. Forty infants were treated during one month with parental reassurance and the intervention formula and were compared to a control group of 25 infants treated with parental reassurance only. Parents completed a quality of life (QoL) questionnaire at baseline and during the last week of the study. Results: At inclusion, stool characteristics and QoL were similar in both groups. The control group was slightly older than the intervention group (7.5+/-3.9 vs. 6.2+/-3.6 weeks). At onset, stool composition was "hard and tight" (Bristol stool scale 1 and 2) in all infants. After one month, stool composition remained unchanged in the control group except in two infants that developed "creamy" stools (Bristol stool scale type 3 and 4). In the intervention group, stools remained "hard and tight" in 27.5%, and became "creamy" in 47.5%, "loose" (Bristol stool scale type 5) in 22.5% and "watery" (Bristol stool type 6 and 7) in 2.5%. The benefit of the intervention formula was estimated to be "very important" in 70%. The median scores for QoL improved significantly in the intervention group for all parameters and for one in the control group. Conclusion: The intervention formula significantly improved functional constipation resulting in a better QoL of the parents and infants. PMID- 29383303 TI - Higher Morbidity of Monogenic Inflammatory Bowel Disease Compared to the Adolescent Onset Inflammatory Bowel Disease. AB - Purpose: Monogenic inflammatory bowel disease (IBD) patients do not respond to conventional therapy and are associated with a higher morbidity. We summarized the clinical characteristics of monogenic IBD patients and compared their clinical outcomes to that of non-monogenic IBD patients. Methods: We performed a retrospective cohort study of all children <18 years old who were diagnosed with IBD between 2005 and 2016. A total of 230 children were enrolled. Monogenic IBD was defined as a presentation age less than 6 years old with confirmation of a genetic disorder. We subdivided the groups into monogenic IBD (n=18), non monogenic very early-onset IBD (defined as patients with a presentation age <6 years old without a confirmed genetic disorder, n=12), non-monogenic IBD (defined as all patients under 18 years old excluding monogenic IBD, n=212), and severe IBD (defined as patients treated with an anti-tumor necrosis factor excluding monogenic IBD, n=92). We compared demographic data, initial pediatric Crohn disease activity index/pediatric ulcerative colitis activity index (PCDAI/PUCAI) score, frequency of hospitalizations, surgical experiences, and height and weight under 3rd percentile among the patients enrolled. Results: The initial PCDAI/PUCAI score (p<0.05), incidence of surgery per year (p<0.05), and hospitalization per year (p<0.05) were higher in the monogenic IBD group than in the other IBD groups. Additionally, the proportion of children whose weight and height were less than the 3rd percentile (p<0.05 and p<0.05, respectively) was also higher in the monogenic IBD group. Conclusion: Monogenic IBD showed more severe clinical manifestations than the other groups. PMID- 29383304 TI - Clostridium difficile Infection at Diagnosis and during the Disease Course of Pediatric Inflammatory Bowel Disease. AB - Purpose: Clostridium difficile colonization and infection are commonly associated with poor outcomes in patients with pediatric inflammatory bowel disease (PIBD). We aimed to investigate the prevalence of C. difficile colonization and infection at the time of diagnosis and to evaluate risk factors associated with the development of C. difficile infection during the course of PIBD treatment. Methods: We retrospectively enrolled a total of 59 children who were newly diagnosed with PIBD at the tertiary medical center. All patients underwent C. difficile toxin assays and cultures initially and at every follow-up during the disease course. Kaplan-Meier survival analysis and Cox regression test were used for statistical analysis. Results: Initial cultures for C. difficile were positive in 13 (22.0%) of 59 PIBD patients, whereas initial toxin assays were positive in 3 patients (5.1%). During treatment, C. difficile cultures converted to positive in 28 (47.5%) in addition to 13 patients who were initially culture positive, and C. difficile toxins converted to positive in 13 (22.0%) in addition to 3 originally toxin-positive patients. Antibiotic usage alone was significantly associated with the development of C. difficile colonization (p=0.011), and the length of hospitalization was associated with the development of C. difficile infection (p=0.032). Conclusion: C. difficile colonization and infection occur frequently during the disease course of PIBD. Antibiotic usage and longer hospital stay were significant risks factors for the conversion of C. difficile status in PIBD patients undergoing treatment. PMID- 29383305 TI - Different Clinical Features and Lower Scores in Clinical Scoring Systems for Appendicitis in Preschool Children: Comparison with School Age Onset. AB - Purpose: To clarify the clinical features of appendicitis in preschool children and to explore clinical appendicitis scoring systems in this age group. Methods: We retrospectively collected data on 142 children, aged 10 years or younger, with confirmed diagnosis of appendicitis based on surgical and pathologic findings. Enrolled subjects were divided into two groups: Group 1 (preschool children aged <=5 years, n=41) and Group 2 (school children aged >5 to <=10 years, n=101). Data analyzed included clinical presentation, laboratory findings, the pediatric appendicitis score (PAS), and the modified Alvarado score (MAS). Results: The most common presenting symptom was abdominal pain in both groups (92.7% vs. 97.0%). Other presenting symptoms were as follows: fever (65.9%), vomiting (68.3%), right lower quadrant (RLQ) localization (24.4%), anorexia (14.6%), and diarrhea (7.3%) in Group 1, and RLQ localization (74.3%), vomiting (71.3%), anorexia (52.5%), fever (47.5%), and diarrhea (11.9%) in Group 2. Perforation and abscess occurred more frequently in Group 1 than in Group 2 (43.9% vs. 12.9%, p<0.001; 34.1% vs. 5.0%, p<0.001; respectively). PAS and MAS were lower in Group 1 than in Group 2 (4.09+/-1.97 vs. 6.91+/-1.61, p=0.048; 4.65+/-1.79 vs. 6.51+/ 1.39, p=0.012; respectively). Conclusion: In preschool children, appendicitis often presents with atypical features, more rapid progression, and higher incidence of complications. This age group is more likely to have lower PAS and MAS than those of school children. PMID- 29383306 TI - Different Criteria for the Definition of Insulin Resistance and Its Relation with Dyslipidemia in Overweight and Obese Children and Adolescents. AB - Purpose: to compare cut off points corrected for age and gender (COOP) with fixed cut off points (FCOP) for fasting plasma insulin and Homeostatic model assessment insulin resistance (HOMA-IR) for the diagnosis of IR in obese children and adolescents and their correlation with dyslipidemia. Methods: A multicenter, cross-sectional study including 383 subjects aged 7 to 18 years, evaluating fasting blood glucose, plasma insulin, and lipid profile. Subjects with high insulin levels and/or HOMA-IR were considered as having IR, based on two defining criteria: FCOP or CCOP. The frequency of metabolic abnormalities, the presence of IR, and the presence of dyslipidemia in relation to FCOP or CCOP were analyzed using Fisher and Mann-Whitney exact tests. Results: Using HOMA-IR, IR was diagnosed in 155 (40.5%) and 215 (56.1%) patients and, using fasting insulin, 150 (39.2%) and 221 (57.7%), respectively applying FCOP and CCOP. The use of CCOP resulted in lower insulin and HOMA-IR values than FCOP. Dyslipidemia was not related to FCOP or CCOP. Blood glucose remained within normal limits in all patients with IR. There was no difference in the frequency of IR identified by plasma insulin or HOMA-IR, both for FCOP and CCOP. Conclusion: The CCOP of plasma insulin or of HOMA-IR detected more cases of IR as compared to the FCOP, but were not associated with the frequency of dyslipidemia. As blood glucose has almost no fluctuation in this age group, even in the presence of IR, fasting plasma insulin detected the same cases of IR that would be detected by HOMA-IR. PMID- 29383307 TI - Colonic Angioectasia in an Adolescent Boy with Hoyeraal-Hreidarsson on Long-Term Anabolic Steroid Therapy. AB - Androgen therapy has proven efficacy in treating patients with bone marrow failure who are not candidates for bone marrow transplantation. Herein, we report on a case of colonic angioectasia secondary to oxymetholone use in an adolescent patient with Hoyeraal-Hreidarsson syndrome (HHS). A 13-year-old Caucasian male with HHS characterized by cerebellar hypoplasia, developmental delay, microcephaly, esophageal strictures and myelodysplasia presented with severe hematochezia from colonic angioectasia secondary to long-term oxymetholone therapy. These vascular lesions resolved spontaneously once this anabolic steroid was discontinued. While androgen therapy is often recommended for certain anemias and myelodysplastic syndromes, clinicians should be aware of the potential complication in developing these perceived uncommon colonic angioectasias. Moreover, pediatric gastroenterologists should familiarize themselves in identifying these vascular lesions by colonoscopy, especially among the high risk groups on long-term anabolic steroid therapy. PMID- 29383309 TI - Prevalence and Management of Functional Gastrointestinal Disorders in Infants: An Asian Perspective. PMID- 29383308 TI - An Unusual Presentation of Rectal Carcinoma in a Child. AB - Colorectal carcinoma is a well-known malignancy in adults. However, it is rare in children. Besides, it also has different behaviour in paediatric age-group and usually presents with non-specific symptoms like abdominal pain, weight loss, and anaemia. This usually leads to delay in diagnosis. Adenocarcinoma in children has unfavourable tumour histology (mucinous subtype) and advanced disease stage at presentation which lead to poorer prognosis in children. Family history, genetic typing and sibling screening are essential components of management as this malignancy is frequently seen associated with hereditary syndromes. We describe a case of unusual presentation of rectal carcinoma in a 12-year-old girl. PMID- 29383310 TI - Total Endoscopic Approach in Glomus Tympanicum Surgery. AB - Introduction: Glomus tympanicum (GT) is a benign primary tumor of the middle ear. The evolution of endoscopic ear surgery has allowed for an alternative approach to managing this vascular tumor. The purpose of this study was to evaluate an endoscopic approach in GT surgery, and also to investigate its applicability and feasibility. Materials and Methods: Prospectively, 13 class I and II patients, according to the Glasscock-Jackson glomus classification, were candidates for management via a transcanal endoscopic approach. Patients were categorized into three groups according to the location of the tumor in the middle ear. Group A consisted of patients with tumors located anteriorly while occupying the Eustachian tube. Group B were patients with tumors located on the promontory with entirely visible tumor borders. Patients in Group C had tumors that occupied the entire middle ear. Under specially designed flap elevation and hemostasis, the tumors were completely removed using an endoscopic technique. Results: Based on the classification criteria, three patients fell into Group A (30%), six into Group B (46%), and three into Group C (23%). The principal chief complaint was pulsatile tinnitus that disappeared after surgery in most cases. Hearing status was mostly mixed hearing loss. No change was detected in bone conduction after surgery, but air conduction was improved in nine cases. No major complication or recurrence was observed over 30 months of follow up. Conclusion: Improved exposure and access in the endoscopic transcanal approach to GT leads to safe, rapid, and reliable tumor removal, as well as allowing comfortable surgery for both the surgeon and most patients. PMID- 29383311 TI - A Comparison between Cold Dissection Tonsillectomy and Harmonic Scalpel Tonsillectomy. PMID- 29383312 TI - Pattern of Gustatory Impairment and its Recovery after Head and Neck Irradiation. AB - Introduction: The majority of patients receiving concurrent chemoradiotherapy frequently complain of changes in their taste perception, and other distressing symptoms affecting their quality of life. This study was undertaken to determine the pattern of gustatory impairment and its recovery in irradiated head and neck cancer patients in India. Materials and Methods: Thirty patients undergoing radical head and neck irradiation were enrolled and assessed for the four basic taste quality (sweet, salt, sour and bitter) by a forced three-choice stimulus drop technique measuring their taste recognition thresholds at baseline, weekly during radiation therapy (RT) and every month for 6 months following completion of RT. Results: The maximum taste loss for any taste quality developed after the third week of RT. Irrespective of the taste quality, the majority of patients developed their maximum taste loss in the fourth to sixth week. The maximum taste loss was highest (100%) for the bitter taste and least (40.7%) for the sweet taste. Taste recovery for sweet, salt and sour taste qualities started from the first month onwards, but not for bitter taste. All taste qualities were severely affected in patients with primary involvement of the oral cavity and oropharynx as compared with nasopharynx, hypopharynx and laryngeal tumors. Conclusions: Taste dysfunction is a frequently ignored adverse effect of head and neck cancer treatment, seriously affecting the patient's quality of life. Clinicians must make patients aware of this specific gustatory dysfunction and its pattern of recovery. Future efforts should be directed towards minimizing this dysfunction, specifically in tumors arising from the oral cavity and oropharynx. PMID- 29383313 TI - Otologic Manifestations and Progression in Patients with Wegener's granulomatosis: A Survey in 55 Patients. AB - Introduction: Granulomatosis with polyangiitis (GPA; also known as Wegener's granulomatosis) is a primary systemic vasculitis involving the ear, nose and throat system (ENT) and lower respiratory tract. Because of the lack of knowledge regarding the clinical findings of GPA due to the limited number of studies, the current study was designed to investigate the prevalence and nature of the otology manifestations in the disease course. Materials and Methods: In the current prospective study, patients with a diagnosis of GPA from 2012-2016 were included. A definitive diagnosis was made based on the history, physical examination (otomicroscopy, Rinne and Weber test), audiometry, tympanometry, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibody (C-ANCA and P ANCA) investigations, and pathologic studies. Results: Twenty-seven male and 28 female patients aged 41.6+/-15.3 years were enrolled. Ear involvement was found in 20 patients (36.3%), and the most prevalent symptom was loss of hearing followed by otalgia and tinnitus. Tinnitus improved in none of the patients. The most prevalent sign was otitis serous followed by mastoiditis and external otitis. The most important audiometry finding was sensorineural hearing loss. Pathological studies using pulmonary samples were more useful for diagnosis. Conclusions: Precise clinical examination is crucial for the early diagnosis of GPA. Otological manifestations are common, especially loss of hearing and otitis serous, and can be the first sign of this disease. Early diagnosis can lead to better treatment of Wegener's granulomatosis. PMID- 29383314 TI - Controlled vs Spontaneous Ventilation for Bronchoscopy in Children with Tracheobronchial Foreign Body. AB - Introduction: Tracheobronchial foreign body aspiration is a common life threatening condition in children. There are controversies in the management of this condition, including the type of ventilation during bronchoscopy. This study aims to compare anesthesia with controlled ventilation versus spontaneous ventilation in rigid bronchoscopy in children with foreign body aspiration. Materials and Methods: Patients who were candidates for rigid bronchoscopy due to foreign body aspiration were randomly assigned to either anesthesia with spontaneous ventilation or controlled ventilation. End tidal CO2 (ETCO2), electrocardiogram (ECG), heart rate (HR), oxygen saturation (SpO2), non-invasive blood pressure (NIBP) and complications and accidents during the surgery and recovery were recorded for each patient. Surgeon comfort during the procedure was also evaluated for each patient. A 20% change in HR or NIBP was considered significant. SpO2 values under 90% are considered desaturation. Results: Fifty one patients (31 male and 20 female) entered the study. The mean age was 26.76 months, ranging from 6 to 100 months. Choking and cough were present in 94% and 96.1% of the patients, respectively. Nuts were the most common foreign body (76.9%). The controlled ventilation group had significantly fewer complications, and surgeon comfort was significantly higher in this group. Oxygen desaturation was significantly more prevalent in the spontaneous ventilation group during laryngoscopy and bronchoscopy (P<0.001). Conclusion: Controlled ventilation has the potential to be used as an effective alternative option in anesthesia for patients with suspected foreign body aspiration. PMID- 29383316 TI - Solitary Head and Neck Cysticercosis: A Series of Rare Cases. AB - Introduction: Cysticercosis is a disease which is caused by the infestation of the larvae Taenia solium, with humans acting as an intermediate host instead of a definitive host. Head and neck involvement including maxillofacial and oral involvement of cysticercosis is quite rare. Case Report: We report a series of rare cases of cysticercosis of the head and neck region encountered in a tertiary hospital in Northern India with a brief review of literature and its diagnosis and management. The patients had undergone ultrasonography, FNAC and CT scan. All the cases were treated by Oral Albendazole tablets. The period of study was from August 2014 to August 2015. FNAC proved to be a highly effective way of diagnosis corroborated by imaging evidence. Treatment with albendazole was curative in all the cases. Conclusions: Cytopathology has emerged as an excellent diagnostic modality for cysticercosis. Medical treatment with antihelminthics produces excellent results, as illustrated in our case, and can eliminate the need of surgery. PMID- 29383315 TI - Methylprednisolone versus Dexamethasone for Control of Vertigo in Patients with Definite Meniere's disease. AB - Introduction: Definite Meniere's disease is associated with two or more definitive periods of vertigo along with hearing loss, plus tinnitus or aural fullness or both. This study aimed to compare the effect of intratympanic dexamethasone and methylprednisolone on the functional-level scale of pure-tone audiometry (PTA), and class outcome measures of vertigo. Materials and Methods: In this clinical study, 69 patients with definite Meniere's disease, referred to the tertiary otolaryngology center, were randomly assigned to two groups: 36 patients were treated with intratympanic dexamethasone (4mg/dl) and 33 patients were treated with intratympanicmethylprednisolone (40mg/dl). Each group received three weekly injections. After a follow-up of 1 and 6 months, PTA changes and vertigo control were evaluated. Results: There was no statistically significant difference between the two groups with regard to control of vertigo (P=0.866, P=0.879 for 1 and 6 months post injection, respectively). PTA improvement was statistically significantly higher in the methylprednisolone group (P=0.006). Conclusion: In summary, intratympanic corticosteroid is an effective treatment for Meniere's disease and can prevent other invasive treatments. Intratympanic methylprednisolone can improve hearing level to a greater extent than intratympanic dexamethasone, but the two groups were similarly beneficial in controlling vertigo. However, there was a trend toward a more sustained benefit with methylprednisolone. PMID- 29383317 TI - Retropharyngeal Space Schwannoma: A Rare Entity. AB - Introduction: Retropharyngeal space schwannomas are rare entities. About 20-45% of schwannomas occur in the head and neck region; however, they represent less than 1% of all head and neck tumors. Case Report: We present the case of a 36 year-old woman complaining of dysphagia caused by a large schwannoma arising in the posterior pharyngeal wall with remarkable reduction of the oropharyngeal space. The tumor was resected through a combined transoral and cervicotomic transmandibular approach due to its dimension. No recurrence was observed after a two-year follow up. This case represents the thirteenth case reported in international literature. Conclusion: Preoperative settings for rare tumors such as retropharyngeal schwannomas should include radiological investigations and preoperative biopsy. In order to obtain a successful result in terms of radicality, a combined surgical approach may be necessary to completely control the extension of the lesion. PMID- 29383318 TI - Missing Aspirated Impacted Denture Requiring Tracheotomy for Removal. AB - Introduction: Aspirated foreign bodies continue to present challenges to otorhinolaryngologists. Removal of impacted airway foreign bodies via conventional methods can at times pose difficulty. This may be related to the location and type of foreign body, experience of the surgeon and anesthetist, and the availability of appropriate instruments. In adults, especially in edentulous patients, a swallowed denture usually gets lodged in the esophagus and entrance into the airway is uncommon. Case Report: We report a case of an uncommon foreign body (3-toothed artificial denture plate) impacted in the trachea of a 40-year old male following an acute episode of an epileptic attack in which conventional methods of foreign body removal had failed. It was eventually removed via a direct laryngoscopy and tracheotomy technique. Conclusion: This type of impaction of a large denture in the trachea is uncommon and late presentation after aspiration is even more rare. This unusual case of a foreign body in the airway is interesting due to its rarity, mode of entry, site of impaction, variable clinical presentation, and method of removal; and hence, prompted the authors to report this case. PMID- 29383319 TI - Xanthoma Disseminatum Presenting with Hoarseness. AB - Introduction: Xanthoma disseminatum (XD) is a rare, benign, non-Langerhans cell histiocytic disorder with unknown etio-pathology. It manifests with multiple, grouped, red-brown to yellow papules and nodules involving the skin, mucous membranes, and internal organs with a predilection for flexures and the face. Case Report: We report a patient who presented with disseminated xanthomatous papules and nodules involving the face, neck, trunk, axilla, groin, and oral cavity, along with hoarseness of voice. Video laryngoscopy revealed multiple yellowish nodules over the base of the tongue, vallecula, laryngeal surface of the epiglottis, ary-epiglottic folds, interarytenoid region, and subglottic region. Histopathology was suggestive of xanthoma disseminatum and the patient was treated with tablet acitretin 25mg daily for three months without any response. Following this, the patient was prescribed tablet thalidomide 100 mg daily without any significant improvement at the end of two months. Conclusion: Xanthoma disseminatum is a very rare form of non-Langerhans cell histiocytosis that classically presents with cutaneous xanthomas, mucosal xanthomas, and diabetes insipidus. Hoarseness of voice due to lesions involving the larynx is a rare symptom. Because the disease has punctated, numerous relapses and causes morbidity to the patient, its multisystem manifestations have to be known. Therefore, xanthoma disseminatum has to be kept in mind as a differential diagnosis for hoarseness of voice. PMID- 29383320 TI - Assessment of genetic diversity of an endangered tooth-carp, Aphanius farsicus (Teleostei: Cyprinodontiformes: Cyprinodontidae) using microsatellite markers. AB - Genetic structure of an endemic tooth-carp fish, Aphanius farsicus from four different water bodies in the Maharlu Lake basin was investigated by applying five microsatellite markers. All of the five examined microsatellite loci showed polymor-phism pattern. A total of four alleles were detected at five microsatellite loci, with an average of 2.8 to 3.5 alleles per locus. Average values of observed and expected heterozygosity were 0.95+/-0.09 and 0.64+/-0.02 respectively. None of the tests of linkage disequilibrium were significant between each pair of loci and no deviation from Hardy-Weinberg equilibrium were detected to test for heterozygote deficiency within populations. The Nei's genetic distance values ranged between 0.03 - 0.13. Analysis of pairwise genetic differentiation between each pair of the populations revealed that fixation index (FST) values ranged from 0.013 to 0.039 and RST ranged from 0.005 to 0.065. High genetic diversity observed within the populations (99%) and low diversity (1%) among them indicating probably high level of gene flow among the studied populations of Fars tooth-carp at the present time or in the past. Regarding low genetic differentiation among the studied populations and results of population assignment test, two hypotheses are suggested and supporting evidence for each hypothesis are provided. PMID- 29383321 TI - Transcript analysis of some defense genes of tomato in response to host and non host bacterial pathogens. AB - The transcript levels of six defense genes including pathogenesis-related gene 1 (PR-1), pathogenesis-related gene 2 (PR-2), pathogenesis-related gene 5 (PR-5), lipoxygenase (LOX), phenylalanine ammonia-lyase (PAL) and catalase (CAT) were investigated in tomato plants inoculated with Xanthomonas axonopodis pv. phaseoli as a non-host pathogen and X. euvesicatoria as a host pathogen. Activation of all the genes was confirmed in both host and non-host treatments. Additionally, the results showed stronger expression of majority of the genes (PR-1, PR-2, LOX, PAL and CAT) in non-host treatment compared to host treatment at least at early hours after inoculation. These data suggest that faster and more expression of PR-1, PR 2, LOX, PAL and CAT might have a role in non-host resistance of tomato against X. axonopodis pv. phaseoli. PMID- 29383322 TI - Chronicity of Anterior Cruciate Ligament Deficiency, Part 1: Effects on the Tibiofemoral Relationship Before and Immediately After Anatomic ACL Reconstruction With Autologous Hamstring Grafts. AB - Background: It remains unclear whether the tibiofemoral relationship in the sagittal plane is restored after anatomic anterior cruciate ligament (ACL) reconstruction, particularly in cases of chronic ACL deficiency (ACLD). Hypothesis: Patients with long-term ACLD will exhibit an anteriorly subluxed tibia both preoperatively and immediately postoperatively, even after anatomic reconstruction. Study Design: Cohort study; Level of evidence, 2. Methods: In total, 358 patients who had undergone anatomic ACL reconstruction with autologous semitendinosus grafts were divided into 5 groups based on chronicity of ACLD: (1) 0 to 6 months, (2) 6 months to 1 year, (3) 1 to 2 years, (4) 2 to 5 years, and (5) longer than 5 years. Preoperatively and immediately postoperatively, all patients underwent lateral radiography in extension to evaluate the tibiofemoral relationship, specifically with regard to anterior tibial subluxation (ATS), space for the ACL (sACL), and extension angle. Demographic and radiographic factors were compared among the 5 groups. Results: Preoperative ATS values in groups 4 (mean +/- SD, 2.9 +/- 2.1 mm) and 5 (2.6 +/- 1.9 mm) were significantly greater than in group 1 (1.6 +/- 1.9 mm). Postoperatively, the tibia was posteriorly overconstrained in all groups, and there was no difference in immediately postoperative ATS among the 5 groups. Further evaluation of the tibiofemoral relationship in the sagittal plane revealed that the mean preoperative side-to-side difference in sACL (sACL-SSD) was greater in groups 4 (2.5 +/- 1.6 mm) and 5 (2.2 +/- 1.7 mm) than in group 1 (1.2 +/- 1.5 mm). Immediately after ACL reconstruction, however, there were no group-dependent differences in sACL-SSD. No significant group-dependent differences were found for extension deficit. Conclusion: Chronicity of ACLD had an effect on the preoperative tibiofemoral relationship in the sagittal plane, including ATS and sACL-SSD, especially in patients with ACLD longer than 2 years. However, preoperative extension deficit was not influenced by chronicity. Immediately postoperatively, chronicity did not affect the ability of anatomic ACL reconstruction to reduce subluxation. PMID- 29383323 TI - An Unusual Cluster of Neuroinvasive Lyme Disease Cases Presenting With Bannwarth Syndrome in the Midwest United States. AB - Bannwarth syndrome (BWS), an infrequent manifestation of neuroinvasive Lyme disease (LD) characterized by radiculopathy, neuropathy, and lymphocytic pleocytosis, is more commonly documented in Europe than North America. Here, we describe a cluster of 5 neuroinvasive LD cases with BWS in the upper Midwest United States between July and August 2017. PMID- 29383326 TI - Protection of Children's Human Rights and Health: A Legacy of Julian Kramsztyk, Janusz Korczak, and Ludwik Rajchman. AB - Tutor of generations of Warsaw medical doctors, Julian Kramsztyk (1851-1926) was son of Rabbi Izaak Kramsztyk, Polish patriot and fighter for independent Poland. Julian Kramsztyk graduated in medicine from Warsaw University in 1873 to soon work as a supervisor of the Internal Diseases Department of Bersohns and Baumans Children's Hospital from 1878 to 1910, and despite of refusing professorship from Imperial Warsaw University, he worked as a lecturer of pediatric disorders from 1880 with strong association of his medical practice with scientific and editorial tasks as well as engaging in charity. This article focuses on selective retrieval of biographical data of social and scientific achievements of followers of Julian Kramsztyk: his student, pioneer of children human rights, and pioneer of healthy patterns of nutrition of children, pediatrician Janusz Korczak (Henryk Goldszmit; 1878 or 1879-1942); and a skilled bacteriologist and a brilliant epidemiologist who was a prominent activist of the League of Nations (later United Nations Organization), cofounder of the UNICEF (United Nations Children's Emergency Fund), and the first chairman of the Organization from 1946 to 1950, which was primarily dedicated to "provide emergency food and health care to children in postwar time," Ludwik Rajchman (1881-1965). Janusz Korczak works laid foundation for international recognition of children rights to health, respect, education, privacy, and all the other human rights to be included in the United Nations Convention on the Rights of the Child (UNCRC). In 1989, nutrition and vaccination issues were the main medical interests of these medical doctors and still remain major fields of UNICEF actions. PMID- 29383324 TI - A Predictive Algorithm to Detect Opioid Use Disorder: What Is the Utility in a Primary Care Setting? AB - Purpose: The purpose of this study was to determine the clinical utility of an algorithm-based decision tool designed to assess risk associated with opioid use in the primary care setting. Methods: A prospective, longitudinal study was conducted to assess the utility of precision medicine testing in 1822 patients across 18 family medicine/primary care clinics in the United States. Using the profile, patients were categorized into low, moderate, and high risk for opioid use. Physicians who ordered testing were asked to complete patient evaluations and document their actions, decisions, and perceptions regarding the utility of the precision medicine tests. Results: Approximately 47% of primary care physicians surveyed used the profile to guide clinical decision-making. These physicians rated the benefit of the profile on patient care an average of 3.6 on a 5-point scale (1 indicating no benefit and 5 indicating significant benefit). Eighty-eight percent of all clinicians surveyed felt the test exhibited some benefit to their patient care. The most frequent utilization for the profile was to guide a change in opioid prescribed. Physicians reported greater benefit of profile utilization for minority patients. Patients whose treatment was guided by the profile had pain levels that were reduced, on average, 2.7 levels on the numeric rating scale. Conclusions: The profile provided primary care physicians with a useful tool to stratify the risk of opioid use disorder and was rated as beneficial for decision-making and patient improvement by the majority of physicians surveyed. Physicians reported the profile resulted in greater clinical improvement for minorities, highlighting the objective use of this profile to guide judicial use of opioids in high-risk patients. Significantly, when physicians used the profile to guide treatment decisions, patient-reported pain was greatly reduced. PMID- 29383325 TI - Acceptability of Health Kiosks Within African American Community Settings: A Pilot Study. AB - Introduction: Health kiosks have been increasingly adopted to provide health-care services to those with limited access. Kiosks have the potential to reach people who may have undiagnosed health conditions or those who are not under regular physician care. Thus far, there is limited research assessing the usefulness of health kiosks in the community. This study aimed to explore the acceptability, usability, usefulness, and overall satisfaction of health kiosks in African American majority community settings. Methods: Two health kiosks were placed in predominantly African American low-income areas in an urban city in Western Pennsylvania. After the kiosk interaction, participants 18 years and older were recruited to complete a survey on their overall kiosk use experience. The technology acceptance model was adapted to develop the survey. Survey responses were analyzed using descriptive statistics. Qualitative survey responses were analyzed using content analysis. Results: Seventy-seven percent of the 31 survey respondents were female and 37.8% were ages 60 to 69 years old. Overall, 90% of participants were satisfied with their kiosk experience and 97% found the kiosk useful for health self-management, with 94% stating that they would use the kiosk again. Conclusion: This study showed that health kiosks are accepted among African Americans in community settings such as churches and community centers. Participants found the kiosks easy to use and an overall useful tool to help manage their health. Future studies are needed to provide a better understanding of health kiosk acceptance among minority populations and in community settings. PMID- 29383327 TI - Editorial: Rethinking the Failure to Replicate. PMID- 29383329 TI - Iliac Artery-Uretero-Colonic Fistula Presenting as Gastrointestinal Hemorrhage and Hematuria: A Case Report. AB - Background: The experience with uretero-arterial fistulas has been limited. However, the aggressive treatment of pelvic tumors with surgical resection and radiotherapy, along with liberal use of ureteral catheters, has been attributed to an increase in their incidence. Unless they are promptly diagnosed and treated, uretero-arterial fistulas are associated with considerably high rates of morbidity and mortality. Urologists need maintain a high degree of suspicion for uretero-arterial fistula in high-risk patients. We herein present the clinical course of an iliac artery-uretero-colonic fistula. Case Presentation: A 67-year old woman with a history of colon cancer who underwent laparoscopic high anterior resection in July 2010. A ureteral stent inserted to right ureteral stricture, which developed as a result of local recurrence of the tumor in September 2010. She had undergone chemoradiotherapy, but the lesion had slowly increased in size. During the replacement of the ureteral stent in April 2016, she immediately experienced bladder tamponade, bloody bowel discharge, and hypotension. Contrast CT revealed a complex fistula between the right distal ureter and the right internal iliac artery. Furthermore, contrast medium flowed into the intestinal tract through the tumor. The patient was therefore diagnosed with internal iliac artery-uretero-colonic fistula. Arteriography revealed a right uretero-internal iliac artery fistula, and the embolization of the right internal iliac artery was performed. The right ureteral stent was removed. Her hematuria and bloody bowel discharge disappeared, but right nephrostomy was performed because she presented with acute pyelonephritis to ureteral obstruction. Conclusion: In the present case, the uretero-arterial fistula was caused by the long use of an indwelling stent, chemoradiotherapy, infection, and an increase in the size of the lesion. When a suspected uretero-arterial fistula is accompanied by bloody bowel discharge, we should consider the possibility of traffic to the intestinal tract. PMID- 29383328 TI - Mitochondrial Ultrastructure Is Coupled to Synaptic Performance at Axonal Release Sites. AB - Mitochondrial function in neurons is tightly linked with metabolic and signaling mechanisms that ultimately determine neuronal performance. The subcellular distribution of these organelles is dynamically regulated as they are directed to axonal release sites on demand, but whether mitochondrial internal ultrastructure and molecular properties would reflect the actual performance requirements in a synapse-specific manner, remains to be established. Here, we examined performance determining ultrastructural features of presynaptic mitochondria in GABAergic and glutamatergic axons of mice and human. Using electron-tomography and super resolution microscopy we found, that these features were coupled to synaptic strength: mitochondria in boutons with high synaptic activity exhibited an ultrastructure optimized for high rate metabolism and contained higher levels of the respiratory chain protein cytochrome-c (CytC) than mitochondria in boutons with lower activity. The strong, cell type-independent correlation between mitochondrial ultrastructure, molecular fingerprints and synaptic performance suggests that changes in synaptic activity could trigger ultrastructural plasticity of presynaptic mitochondria, likely to adjust their performance to the actual metabolic demand. PMID- 29383330 TI - Bilateral Prone Percutaneous Nephrolithotomy Under Epidural in Candidate for Lung Transplant: Case Report and Review of Literature. AB - Background: Percutaneous nephrolithotomy (PCNL) is a procedure typically performed under general anesthesia (GA); however, many patients might be considered unfit for GA and locoregional anesthesia is their only chance to have the procedure done. Case Presentation: A 60-year-old Middle-Eastern female with end-stage lung disease underwent evaluation for lung transplant; she was found to have severe restrictive pattern on steroid and continuous oxygen therapy, pulmonary hypertension with dilated right ventricle, chronic anemia, and asthma. She had kidney stones for 10 years, having spontaneously passed several in the past. During work-up for a lung transplant, she was found to have bilateral staghorn calculi and was referred to urology for stone management before lung transplant. After insertion of a Double-J stent for management of worsening right hydronephrosis, antibiotic therapy for extended spectrum beta-lactamases Klebsiella pneumoniae, and optimization after two procedure cancellations because of new onset of cardiovascular issues, she had a simultaneous bilateral PCNL under thoracic epidural anesthesia in two stages within 48 hours without significant complications. She was rendered stone-free and a candidate to be added to the lung transplant list. Conclusion: Bilateral prone PCNL under epidural is a safe and effective option in high anesthetic risk patients. PMID- 29383332 TI - Ventricular Fibrillation Associated With Dynamic Changes in J-Point Elevation in a Patient With Silent Thyroiditis. AB - A J wave is a common electrocardiographic finding in the general population. Individuals with prominent J waves in multiple electrocardiogram (ECG) leads have a higher risk of lethal arrhythmias than those with low-amplitude J waves. There are few reports about the relationship between thyroid function and J-wave amplitude. We report the case of a 45-year-old man who had unexpected ventricular fibrillation (VF). He had dynamic J-point elevation in multiple ECG leads. Possible early repolarization syndrome was diagnosed. He also had thyrotoxicosis caused by silent thyroiditis, and his J-wave amplitude decreased according to changes in thyroid function because of spontaneous remission of silent thyroiditis. There was a positive correlation between serum triiodothyronine levels and J-wave amplitudes. The findings in case suggested silent thyroiditis may contribute to the occurrence of VF in a patient with dynamic changes in J point elevation in multiple ECG leads. Thyrotoxicosis is a relatively common endocrine disease; therefore, clinicians should pay attention to J-wave amplitude in the ECG of patients with thyrotoxicosis. PMID- 29383333 TI - Embryonic Exposure to Dexamethasone Affects Nonneuronal Cells in the Adult Paraventricular Nucleus of the Hypothalamus. AB - Neurons in the paraventricular nucleus of the hypothalamus (PVN) integrate peripheral signals and coordinate responses that maintain numerous homeostatic functions. An excess of glucocorticoids during fetal development results in long lasting consequences tied to disrupted PVN development. The PVN contains a distinct neuronal population and a threefold greater vascular density than the surrounding brain regions that prepubertally is reduced in offspring exposed to excess glucocorticoids in utero. This study expands the examination of sex specific nonneuronal PVN composition by examining astrocytes, astrocytic endfeet, and pericytes. Blood-brain barrier (BBB) competency and composition were examined along with depressive-like behavior and hypothalamic-pituitary-adrenal function in male and female mice. For PVN vasculature, female offspring of vehicle (veh) treated mothers had significantly more astrocytes and pericytes than male offspring from the same litters. Female offspring from dexamethasone (dex) treated mothers had significantly lower levels of astrocytes than female offspring from veh-treated mothers, whereas male offspring from dex-treated mothers had greater levels of pericytes compared with veh-treated male offspring. Using the tail-suspension test, male and female offspring from dex-treated mothers had significantly shorter latencies to immobility, indicating an increase in depression-like behavior, and showed greater plasma corticosterone after restraint stress, which was significantly greater in female offspring from dex treated mothers even after recovery. Therefore, in addition to long-term sex differences in cellular components of the BBB in the PVN that were differentially regulated by fetal glucocorticoid exposure, there were behavioral differences observed into early adulthood in a sex-specific manner. PMID- 29383331 TI - Children's Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia. AB - Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO 2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO 2TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%. Clinical trial registration: ISRCTN15622505 Trial status: Recruiting. PMID- 29383334 TI - Effects of Toremifene, a Selective Estrogen Receptor Modulator, on Spontaneous and Stimulated GH Secretion, IGF-I, and IGF-Binding Proteins in Healthy Elderly Subjects. AB - Context: Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish GH-dependent insulin-like growth factor (IGF)-I in a dose-dependent manner. Selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene, are widely adjunctively used in breast and prostate cancer. Although some endocrine effects of tamoxifen are known, few data are available for toremifene. Objective: To explore sex-dependent effects of toremifene on spontaneous 10-hour overnight GH secretion, followed by GH releasing hormone-ghrelin stimulation. Additionally, effects on IGF-I, its binding proteins, and sex hormone-binding globulin (SHBG) were quantified. Participants and Design: Twenty men and 20 women, within an allowable age range of 50 to 80 years, volunteered for this double-blind, placebo-controlled prospective crossover study. Ten-minute blood sampling was done for 10 hours overnight and then for 2 hours after combined GH-releasing hormone-ghrelin injection. Main Outcome Measures: Pulsatile GH and stimulated GH secretion, and fasting levels of IGF-I, IGF-binding protein (IGFBP)1, IGFBP3, and SHBG. Results: Toremifene did not enhance pulsatile or stimulated GH secretion, but decreased IGF-I by 20% in men and women. IGFBP3 was unchanged, whereas while IGFBP1 and SHBG increased in both sexes to a similar extent. Conclusions: The expected rise in spontaneous and stimulated GH secretion under the diminished negative feedback restraint of powered IGF-I favors a central inhibitory antiestrogenic effect of toremifene. Estrogenic effects of toremifene on the liver were present, as evidenced by increased IGFBP1 and SHBG levels. Men and women responded to this SERM comparably. PMID- 29383335 TI - pH-Triggered nanostructural transformations in antimicrobial peptide/oleic acid self-assemblies. AB - The delivery of poorly water-soluble antimicrobial peptides (AMPs) that are sensitive to degradation is a major challenge in the pharmaceutical field. In this study, we design and characterize a pH-sensitive nanocarrier with the potential for delivery of AMPs and their protection from degradation. These nanobiointerfaces are prepared through the self-assembly of oleic acid (OA) with the human cathelicidin LL-37 in excess water. Advanced experimental methods including synchrotron small angle X-ray scattering, cryogenic transmission electron microscopy, and dynamic light scattering were used to characterize the OA/LL-37 self-assemblies and their structural alterations in response to changes in pH and composition. Experimental findings reveal colloidal transformations from normal emulsions via micellar cubosomes and hexosomes to vesicles upon increasing the pH from 6.0 to 8.0 at a LL-37 content around 10 wt% relative to OA. Increasing the LL-37 content to 30 wt% in OA led to diminishing of micellar cubosomes and hexosomes in this narrow pH range, favoring the formation of micelles and vesicles of various shapes and sizes. Upon increasing the pH, with the strongest effect around pH 7.5, charge repulsions among the gradually deprotonating carboxylic groups of OA modified the geometric packing of the molecules, significantly affecting the nanostructure. These detailed insights into the formation of this unique family of nanobiointerfaces and their tunable structural features may contribute to the rational design of pH-responsive antimicrobial systems for the delivery of peptides, particularly poorly water soluble AMPs. PMID- 29383337 TI - Scanning electrochemical microscopy at the nanometer level. AB - This review describes how one can perform nanometer (nm)-scale SECM experiments through advances in tip fabrication and positioning and instrumentation design. Basic SECM methodology including instrumentation and feedback and generation/collection modes are discussed. Aspects of nanoscale SECM including fabrication of nm-sized electrodes and nano SECM instrumentation are also described. State of the art applications related to nanogaps (i.e., rapid homogeneous reactions and short-lived intermediates; heterogeneous electron transfer kinetics; nanoparticles (NPs) and clusters) and nanoscale imaging (e.g., single NPs, single biological samples, combined methods) are described. Future possibilities and prospects are suggested that might lead to even better resolution, thus introducing SECM electrochemical imaging to the single atom level. PMID- 29383336 TI - Concentric electrodes improve microfluidic droplet sorting. AB - Microfluidic droplet sorting allows selection of subpopulations of cells, nucleic acids, and biomolecules with soluble assays. Dielectrophoresis is widely used for sorting because it generates strong forces on droplets, actuates rapidly, and is easy to integrate into microfluidic chips. However, existing device designs apply a short force, limiting the deflection of droplets, and therefore the speed and reliability of sorting. We describe a concentric design that applies a long force, allowing large deflections and increased reliability. We demonstrate the utility of this design by sorting polydisperse emulsions, which are typically difficult to sort with high purity. PMID- 29383338 TI - An allylated firefly luciferin analogue with luciferase specific response in living cells. AB - An allylated firefly luciferin was successfully synthesized and its bioluminescence properties were evaluated. When applied to cellular imaging in combination with Eluc, which is one of the commercially available luciferases, this analogue displayed a luciferase-specific bioluminescence signal with prolonged emission (>100 min). PMID- 29383339 TI - Arylboronate esters mediated self-healable and biocompatible dynamic G-quadruplex hydrogels as promising 3D-bioinks. AB - Extrudable G-quadruplex hydrogels were prepared at physiological pH. Gels with suitable mechanical properties were explored as 3D-bioinks. The 3D printing process is driven by injectability and the highly thixotropic and self-healable nature of the gel. High cell viability and homogeneous cell distribution within the gel make it a promising material as a 3D bioink. PMID- 29383340 TI - Multifunctional HA/Cu nano-coatings on titanium using PPy coordination and doping via pulse electrochemical polymerization. AB - The incorporation of hydroxyapatite nanoparticles onto the surface of titanium is an effective method to improve its osteoinductive ability. However, there are still issues with the hydroxyapatite nanoparticle coatings fabricated using current methods, such as particle aggregation and unsatisfactory binding ability with the matrix, in addition to the difficulties in the multi-functionalization of antibacterial, anti-wear and bioinductive ability. In the present study, we propose a strategy to fabricate a refined hydroxyapatite nanoparticles/copper nanoparticles co-deposition titanium matrix by the mediation of pulse electrochemical polymerized pyrrole through its coordination and doping of cations and anions. During this process, PO43- in the electrolyte is doped into the corresponding anion structure in the polypyrrole chain and forms HA with Ca2+ and OH- because of electrostatic interaction. The bioactivity investigation indicates that the composite coatings are able to induce the formation of apatite in supersaturated calcium phosphate solution. Furthermore, the friction and wear tests show that the composite coatings improve the friction properties of the material to a certain extent. The composites also exhibit an antibacterial rate of 97% in the antibacterial test. Finally, in virtue of the dual regulation of polypyrrole by coordination and doping, we successfully fabricate multifunctional hydroxyapatite/copper nano-coatings on titanium surfaces. PMID- 29383341 TI - Adsorption and decomposition of dimethyl methylphosphonate on size-selected (MoO3)3 clusters. AB - The adsorption and decomposition of dimethyl methylphosphonate (DMMP), a chemical warfare agent (CWA) simulant, on size-selected molybdenum oxide trimer clusters, i.e. (MoO3)3, was studied both experimentally and theoretically. X-ray photoelectron spectroscopy (XPS), temperature programmed reaction (TPR), and density functional theory (DFT)-based simulations were utilized in this study. The XPS and TPR results showed both, desorption of intact DMMP, and decomposition of DMMP through the elimination of methanol at elevated temperatures on (MoO3)3 clusters. Theoretical investigation of DMMP on (MoO3)3 clusters suggested that, in addition to pure (MoO3)3 clusters, reduced molybdenum oxide clusters and hydroxylated molybdenum oxide clusters also play an important role in decomposing DMMP via a "reverse Mars-van Krevelen mechanism". The present study, which focused on oxide clusters, underlines the importance of surface defects, e.g., the oxygen vacancies and surface hydroxyls, in determining the reaction pathway of DMMP, in agreement with previous studies on thin films. In addition, the structural fluxionality and the Lewis acidity of molybdenum oxide clusters, i.e. (MoO3)3, may make them good candidates for adsorption and decomposition of chemical warfare agents with similar structures to DMMP. PMID- 29383343 TI - Promising half-metallicity in ductile NbF3: a first-principles prediction. AB - Materials with half-metallicity are long desired in spintronics. Using first principles calculations, we predicted that the already-synthesized NbF3 crystal is a promising half-metal with a large exchange splitting and stable ferromagnetism. The mechanical stability, ductility and softness of the NbF3 crystal were confirmed by its elastic constants and moduli. The Curie temperature (TC = 120 K) estimated from the Monte Carlo simulations based on the 3D Ising model is above the liquid nitrogen temperature (78 K). The ferromagnetism and half-metallicity can be preserved on the surfaces of NbF3. The NbOF2 formed by substituting F with O atoms, however, has an antiferromagnetic ground state and a normal metallic band structure. This work opens an avenue for half-metallic materials and may find applications in spintronic devices. PMID- 29383342 TI - Reactivity of hydropersulfides toward the hydroxyl radical unraveled: disulfide bond cleavage, hydrogen atom transfer, and proton-coupled electron transfer. AB - Hydropersulfides (RSSH) are highly reactive as nucleophiles and hydrogen atom transfer reagents. These chemical properties are believed to be key for them to act as antioxidants in cells. The reaction involving the radical species and the disulfide bond (S-S) in RSSH, a known redox-active group, however, has been scarcely studied, resulting in an incomplete understanding of the chemical nature of RSSH. We have performed a high-level theoretical investigation on the reactions of the hydroxyl radical (OH) toward a set of RSSH (R = -H, -CH3, -NH2, C(O)OH, -CN, and -NO2). The results show that S-S cleavage and H-atom abstraction are the two competing channels. The electron inductive effect of R induces selective OH substitution at one sulfur atom upon S-S cleavage, forming RSOH and SH for the electron donating groups (EDGs), whereas producing HSOH and SR for the electron withdrawing groups (EWGs). The H-Atom abstraction by OH follows a classical hydrogen atom transfer (hat) mechanism, producing RSS and H2O. Surprisingly, a proton-coupled electron transfer (pcet) process also occurs for R being an EDG. Although for RSSH having EWGs hat is the leading channel, S-S cleavage can be competitive or even dominant for the EDGs. The overall reactivity of RSSH toward OH attack is greatly enhanced with the presence of an EDG, with CH3SSH being the most reactive species found in this study (overall rate constant: 4.55 * 1012 M-1 s-1). Our results highlight the complexity in RSSH reaction chemistry, the extent of which is closely modulated by the inductive effect of the substituents in the case of the oxidation by hydroxyl radicals. PMID- 29383344 TI - T and V-shaped donor-acceptor-donor molecules involving pyridoquinoxaline: large Stokes shift, environment-sensitive tunable emission and temperature-induced fluorochromism. AB - The intramolecular charge transfer-driven emission properties of T and V-shaped donor-acceptor-donor molecules involving a new acceptor core of pyridoquinoxaline were demonstrated. The T-shaped molecule exhibits a large Stokes shift, red emission in the solid state and remarkable viscosity and temperature-dependent tunable fluorescence including a thermally-induced single-component near white light emission. PMID- 29383345 TI - Palladium-catalyzed regioselective hydroboration of aryl alkenes with B2pin2. AB - A palladium(ii)-catalyzed hydroboration of aryl alkenes with stable and easy-to handle (pinacolato)diboron (B2pin2) under mild conditions has been developed. Acetic acid acted as the solvent and the hydrogen source, which has been identified by deuterium experiments. Notably, isomerization-hydroboration of allyl benzene derivatives was observed. As a result, a series of benzyl boronic esters were obtained in moderate to excellent yields with exclusive regioselectivity. PMID- 29383346 TI - Excited-state dynamics of mononucleotides and DNA strands in a deep eutectic solvent. AB - The photophysics of several mono- and oligonucleotides were investigated in a deep eutectic solvent for the first time. The solvent glyceline, prepared as a 1 : 2 mole ratio mixture of choline chloride and glycerol, was used to study excited-state deactivation in a non-aqueous solvent by the use of steady-state and time-resolved spectroscopy. DNA strands in glyceline retain the secondary structures that are present in aqueous solution to some degree, thus enabling a study of the effects of solvent properties on the excited states of stacked bases and stacked base pairs. The excited-state lifetime of the mononucleotide 5'-AMP in glyceline is 630 fs, or twice as long as in aqueous solution. Even slower relaxation is seen for 5'-TMP in glyceline, and a possible triplet state with a lifetime greater than 3 ns is observed. Circular dichroism spectra show that the single strand (dA)18 and the duplex d(AT)9.d(AT)9 adopt similar structures in glyceline and in aqueous solution. Despite having similar conformations in both solvents, femtosecond transient absorption experiments reveal striking changes in the dynamics. Excited-state decay and vibrational cooling generally take place more slowly in glyceline than in water. Additionally, the fraction of long-lived excited states in both oligonucleotide systems is lower in glyceline than in aqueous solution. For a DNA duplex, water is suggested to favor decay pathways involving intrastrand charge separation, while the deep eutectic solvent favors interstrand deactivation channels involving neutral species. Slower solvation dynamics in the viscous deep eutectic solvent may also play a role. These results demonstrate that the dynamics of excitations in stacked bases and stacked base pairs depend not only on conformation, but are also highly sensitive to the solvent. PMID- 29383347 TI - A theoretical study on the mechanism of hydrogenation of carboxylic acids catalyzed by the Saito catalyst. AB - The mechanism of the ruthenium carboxylate-catalyzed hydrogenation of carboxylic acids was investigated by using density functional theory (DFT) calculations. The novel mechanism including two hydrogenation cycles was proposed for this reaction. The first cycle is the hydrogenation of the carboxylic acid to an aldehyde, while the second cycle is the hydrogenation of the aldehyde to an alcohol. These two catalytic cycles share similar elementary steps, including H2 heterolysis, hydride migration of the carboxylic acid or aldehyde, and catalyst regeneration. In this hydrogenation mechanism, the carboxylic acid is not only a reactant, but also an important proton source. Furthermore, the noncovalent interaction (e.g. hydrogen bonding interaction) between the ligand and carboxylic acid substrate could promote the hydrogenation of the carboxylic acid through stabilizing the transition state of the most energy-demanding step (i.e., hydride migration in the first catalytic cycle). Besides, the strong electron-donating ability of the dppb ligand could also facilitate the hydride migration. PMID- 29383348 TI - Development and utility of a new 3-D magnetron source for high rate deposition of highly conductive ITO thin films near room temperature. AB - As transparent conductive films, indium tin oxide (ITO) materials are being extensively used as electrodes in various technological and optoelectronic applications. The demand for ITO films is firmly increasing because of the widespread market growth in these industries, but the available solutions only partly fulfill the prerequisites of high transmittance, low resistivity, large area process, cost-effective manufacturing, high growth rate and low-temperature process. The present work demonstrates a possible framework for the detailed study of ITO coatings in addition to the development of a novel highly confined 3 D magnetron source (3DMS) that can be simply used for tailored products. In this work, the deposition conditions are optimized through plasma chemistry by utilizing various in situ plasma diagnostics. The emphasis is given to studying the effects of different deposition conditions such as power density and oxygen (O2) flow. Measurements show that the 3DMS can efficiently produce very high density plasmas at a low-discharge voltage. The combined effect of high electron density and energy flux favors high growth rate deposition up to ~1.75 nm s-1. By controlling the plasma parameters, energy flux on the substrate, In3+, Sn4+, oxygen vacancies, and mobility, highly transparent ITO film with a very low resistivity of ~4.2 * 10-4 Omega cm is fabricated at low-temperature using a 3DMS process with the incorporation of O2 flow. PMID- 29383349 TI - Synthesis of carborane-fused carbo- and heterocycles via zirconacyclopentane intermediates. AB - A variety of carborane-fused carbo- and heterocycles were prepared in good to high isolated yields via the reaction of carborane-fused zirconacyclopentane with a series of substrates such as S8, Se, Te, CO, XylNC, MeOOC-CH[double bond, length as m-dash]N2, PhPCl2, nBu2SnCl2 and Me2GeCl2. However, it was found that the Zr-C bond in the zirconacyclopentane did not show any reactivity towards PhBCl2, PhCN and PhCH[double bond, length as m-dash]NPh. This approach represents a promising route to functionalized carboranes that are difficult to access by conventional methods. PMID- 29383350 TI - Bound and continuum-embedded states of cyanopolyyne anions. AB - Cyanopolyyne anions were among the first anions discovered in the interstellar medium. The discovery has raised questions about the routes of formation of these anions in space. Some of the proposed mechanisms assumed that anionic excited electronic states, either metastable or weakly bound, play a key role in the formation process. The verification of this hypothesis requires detailed knowledge of the electronic states of the anions. Here we investigate the bound and continuum states of four cyanopolyyne anions, CN-, C3N-, C5N-, and C7N-, by means of ab initio calculations. We employ the equation-of-motion coupled-cluster method augmented with complex absorbing potential. We predict that already in CN , the smallest anion in the family, there are several low-lying metastable states of both singlet and triplet spin symmetry. These states, identified as shape resonances, are located between 6.3-8.5 eV above the ground state of the anion (or 2.3-4.5 eV above the ground state of the parent radical) and have widths of a few tenths of eV up to 1 eV. We analyze the identified resonances in terms of leading molecular orbital contributions and Dyson orbitals. As the carbon chain length increases in the C2n+1N- series, these resonances gradually become stabilized and eventually turn into stable valence bound states. The trends in the energies of the transitions leading to both resonance and bound excited states can be rationalized by means of the Huckel model. Apart from valence excited states, some of the cyanopolyynes can also support dipole bound states and dipole stabilized resonances, owing to a large dipole moment of the parent radicals in the lowest 2Sigma+ state. PMID- 29383351 TI - Hexagonal SiC with spatially separated active sites on polar and nonpolar facets achieving enhanced hydrogen production from photocatalytic water reduction. AB - Sufficient spatial separation of photo-generated electrons and holes plays a significant role in affecting the efficiency for solar energy conversion. Non equivalent facets of a catalyst are known to possess different charge distribution properties. Here, we report that hexagonal 6H-SiC, a metal-free, environmentally friendly, polar semiconductor, exhibits different charge distribution and photocatalytic properties on naturally occurring Si-{0001} and {10-10} facets. Very strong selectivity of metals in situ photodeposition occurs in these two facets, demonstrating that the photo-excited electrons are assembled only on polar Si-{0001} facets while the holes are assembled on non-polar {10-10} facets. Consequently, reduction reactions occur only on the Si-{0001} facets with noble metals, and meantime oxidation occurs only in {10-10} with metal oxide. We show that the activity of photocatalytic water splitting is significantly enhanced by this kind of selective depositions resulting from the charge spatial separation. The underlying mechanism is investigated in terms of experimental evidence and first principles calculations. Our results demonstrate that the utilization of facets with opposite catalytic characteristics could be a feasible means to enhance the photocatalytic performance in diverse semiconducting materials. This is, in particular, of interest for polar semiconductors, as their particles always naturally occur in both polar facets and non-polar ones without needing facet engineering. PMID- 29383352 TI - Atomistic insights into the nanofluid transport through an ultra-confined capillary. AB - Nanofluid or nanoparticle (NP) transport in confined channels is of great importance for many biological and industrial processes. In this study, molecular dynamics simulation has been employed to investigate the spontaneous two-phase displacement process in an ultra-confined capillary controlled by the surface wettability of NPs. The results clearly show that the presence of NPs modulates the fluid-fluid meniscus and hinders the displacement process compared with the NP-free case. From the perspective of motion behavior, hydrophilic NPs disperse in the water phase or adsorb on the capillary, while hydrophobic and mixed-wet NPs are mainly distributed in the fluid phase. The NPs dispersed into fluids tend to increase the viscosity of the fluids, while the adsorbed NPs contribute to the wettability alteration of the solid capillary. Via capillary number calculations, it is uncovered that the viscosity increase of fluids is responsible for the hindered spontaneous displacement process by hydrophobic and mixed NPs. The wettability alteration of the capillary induced by adsorbed NPs dominates the enhanced displacement in the case of hydrophilic NPs. Our findings provide guidance for modifying the rate of capillary filling and reveal the microscopic mechanism transporting NPs into porous media, which is significant to the design of NPs for target applications. PMID- 29383353 TI - Efficient perovskite/organic integrated solar cells with extended photoresponse to 930 nm and enhanced near-infrared external quantum efficiency of over 50. AB - Enhancing the light-harvesting activity is an effective way to improve the power conversion efficiency of solar cells. Although rapid enhancement in the PCE up to a value of 22.1% has been achieved for perovskite solar cells, only part of the sunlight, i.e., with wavelengths below 800-850 nm is utilized due to the limited bandgap of the perovskite materials, resulting in most of the near infrared light being wasted. To broaden the photoresponse of perovskite solar cells, we demonstrate an efficient perovskite/organic integrated solar cell containing both CH3NH3PbI3 perovskite and PBDTTT-E-T:IEICO organic photoactive layers. By integrating a low band gap PBDTTT-E-T:IEICO active layer on a perovskite layer, the maximum wavelength for light harvesting of the ISC increased to 930 nm, sharply increasing the utilization of near infrared radiation. In addition, the external quantum efficiency of the integrated device exceeded 50% in the near infrared range. The MAPbI3/PBDTTT-E-T:IEICO ISCs show an enhanced short-circuit current density of over 24 mA cm-2, which is the highest existing value among perovskite/organic integrated solar cells and much higher than the traditional MAPbI3 based perovskite solar cells. The results reveal that a perovskite/organic integrated structure is a promising strategy to extend and enhance sunlight utilization for perovskite solar cells. PMID- 29383354 TI - Applying macromolecular crowding to 3D bioprinting: fabrication of 3D hierarchical porous collagen-based hydrogel constructs. AB - Native tissues and/or organs possess complex hierarchical porous structures that confer highly-specific cellular functions. Despite advances in fabrication processes, it is still very challenging to emulate the hierarchical porous collagen architecture found in most native tissues. Hence, the ability to recreate such hierarchical porous structures would result in biomimetic tissue engineered constructs. Here, a single-step drop-on-demand (DOD) bioprinting strategy is proposed to fabricate hierarchical porous collagen-based hydrogels. Printable macromolecule-based bio-inks (polyvinylpyrrolidone, PVP) have been developed and printed in a DOD manner to manipulate the porosity within the multi layered collagen-based hydrogels by altering the collagen fibrillogenesis process. The experimental results have indicated that hierarchical porous collagen structures could be achieved by controlling the number of macromolecule based bio-ink droplets printed on each printed collagen layer. This facile single step bioprinting process could be useful for the structural design of collagen based hydrogels for various tissue engineering applications. PMID- 29383355 TI - New carbon allotropes in sp + sp3 bonding networks consisting of C8 cubes. AB - We identify using ab initio calculations new types of three-dimensional carbon allotrope constructed by inserting acetylenic or diacetylenic bonds into a body centered cubic C8 lattice. The resulting sp + sp3-hybridized cubane-yne and cubane-diyne structures consisting of C8 cubes can be characterized as a cubic crystalline modification of linear carbon chains, but energetically more favorable than the simplest linear carbyne chain and the cubic tetrahedral diamond and yne-diamond consisting of C4 tetrahedrons. Electronic band calculations indicate that these new carbon allotropes are semiconductors with an indirect band gap of 3.08 eV for cubane-yne and 2.53 eV for cubane-diyne. The present results establish new types of carbon phases consisting of C8 cubes and offer insights into their outstanding structural and electronic properties. PMID- 29383356 TI - The effect of solvent relaxation in the ultrafast time-resolved spectroscopy of solvated benzophenone. AB - Benzophenone (BP) despite its relatively simple molecular structure is a paradigmatic sensitizer, featuring both photocatalytic and photobiological effects due to its rather complex photophysical properties. In this contribution we report an original theoretical approach to model realistic, ultra-fast spectroscopy data, which requires describing intra- and intermolecular energy and structural relaxation. In particular we explicitly simulate time-resolved pump probe spectra using a combination of state-of-the art hybrid quantum mechanics/molecular mechanics dynamics to treat relaxation and vibrational effects. The comparison with experimental transient absorption data demonstrates the efficiency and accuracy of our approach. Furthermore the explicit inclusion of the solvent, water for simulation and methanol for experiment, allows us, despite the inherent different behavior of the two, to underline the role played by the H-bonding relaxation in the first hundreds of femtoseconds after optical excitation. Finally we predict for the first time the two-dimensional electronic spectrum (2DES) of BP taking into account the vibrational effects and hence modelling partially symmetric and asymmetric ultrafast broadening. PMID- 29383357 TI - Global quasi-linearization (GQL) versus QSSA for a hydrogen-air auto-ignition problem. AB - A recently developed automatic reduction method for systems of chemical kinetics, the so-called Global Quasi-Linearization (GQL) method, has been implemented to study and reduce the dimensions of a homogeneous combustion system. The results of application of the GQL and the Quasi-Steady State Assumption (QSSA) are compared. A number of drawbacks of the QSSA are discussed, i.e. the selection criteria of QSS-species and its sensitivity to system parameters, initial conditions, etc. To overcome these drawbacks, the GQL approach has been developed as a robust, automatic and scaling invariant method for a global analysis of the system timescale hierarchy and subsequent model reduction. In this work the auto ignition problem of the hydrogen-air system is considered in a wide range of system parameters and initial conditions. The potential of the suggested approach to overcome most of the drawbacks of the standard approaches is illustrated. PMID- 29383358 TI - Rational construction of an ssa-type of MOF through pre-organizing the ligand's conformation and its exceptional gas adsorption properties. AB - Ssa-type MOFs constructed from dicopper paddlewheels and bent diisophthalate ligands exhibit a promising potential for gas adsorption which benefits from their rich open copper sites and polyhedron-based cages with suitable sizes. However, the rational construction of such types of MOFs is exceedingly challenging because the bent diisophthalate ligands employed are inclined to exhibit various conformations and thus are prone to form MOFs with varied topologies. In this work, by pre-organizing the ligand's conformation, we successfully targeted an ssa-type MOF ZJNU-57 from a bent diisophthalate ligand. More significantly, ZJNU-57 exhibits excellent hydrolytic stability and high C2H2 and CO2 uptake capacities as well as impressive C2H2/CH4 and CO2/CH4 adsorption selectivities, indicating its promising potential for C2H2/CH4 and CO2/CH4 separation, which are relevant to acetylene production and natural gas purification. This work not only provides a rare water-stable MOF based on the Cu2(COO)4 cluster for highly selective adsorption of C2H2 and CO2 from CH4, but also demonstrates that the ligand conformation-controlled assembly strategy may be an efficient approach toward the construction of MOF materials with definite topologies for specific applications. PMID- 29383359 TI - Importance of protein flexibility in molecular recognition: a case study on Type I1/2 inhibitors of ALK. AB - Anaplastic lymphoma kinase (ALK) has been regarded as a promising target for the therapy of various cancers. A large number of ALK inhibitors with diverse scaffolds have been discovered, and most of them belong to Type-I inhibitors that only occupy the ATP-binding pocket. Recently, we reported a series of novel and potent Type-I1/2 inhibitors of ALK with the 1-purine-3-piperidinecarboxamide scaffold, which can bind to both the ATP-binding site of ALK and the adjacent hydrophobic allosteric pocket. In this study, the binding mechanisms of these Type-I1/2 ALK inhibitors were elucidated by multiple molecular modeling techniques. The calculation results demonstrate that the ensemble docking based on multiple protein structures and the MM/PB(GB)SA calculations based on molecular dynamics (MD) simulations yield better predictions than conventional rigid receptor docking (Glide, Surflex-Dock, and Autodock Vina), highlighting the importance of incorporating receptor flexibility in the predictions of binding poses and binding affinities of Type-I1/2 ALK inhibitors. Furthermore, the umbrella sampling (US) simulations and MM/GBSA binding free energy decomposition analyses indicate that Leu1122, Leu1198, Gly1202 and Glu1210 in the hinge region and Glu1197, Ile1171, Phe1174, Ile1179, His1247, Ile1268, Asp1270 and Phe1271 in the allosteric pocket of ALK are the key residues for determining the relative binding strength of the studied inhibitors. Besides, we found that the most potent inhibitor (001-017) tends to form stronger transient interactions with residues along the dissociation channel due to the high electronegativity of its bulky 4-(trifluoromethoxy) phenylamine tail. As a whole, both the stronger binding affinity and the higher energetic barrier (which may prolong the drug target residence time) of 001-017 contribute to its excellent anti-proliferation activity against ALK-positive cancer cells. PMID- 29383360 TI - A crystalline and 3D periodically ordered mesoporous quaternary semiconductor for photocatalytic hydrogen generation. AB - We have prepared the first crystalline and 3D periodically ordered mesoporous quaternary semiconductor photocatalyst in an evaporation-induced self-assembly assisted soft-templating process. Using lab synthesized triblock-terpolymer poly(isoprene-b-styrene-b-ethylene oxide) (ISO) a highly ordered 3D interconnected alternating gyroid morphology was achieved exhibiting near and long-range order, as evidenced by small angle X-ray scattering (SAXS) and electron microscopy (TEM/SEM). Moreover, we reveal the formation process on the phase-pure construction of the material's pore-walls with its high crystallinity, which proceeds along a highly stable W5+ compound, by both in situ and ex situ analyses, including X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and electron paramagnetic resonance (EPR). The resulting photocatalyst CsTaWO6 with its optimum balance between surface area and ordered mesoporosity ultimately shows superior hydrogen evolution rates over its non ordered reference in photocatalytic hydrogen production. This work will help to advance new self-assembly preparation pathways towards multi-element multifunctional compounds for different applications, including improved battery and sensor electrode materials. PMID- 29383361 TI - Binding kinetics of ultrasmall gold nanoparticles with proteins. AB - Synthetic ultrasmall nanoparticles (NPs) can be designed to interact with biologically active proteins in a controlled manner. However, the rational design of NPs requires a clear understanding of their interactions with proteins and the precise molecular mechanisms that lead to association/dissociation in biological media. Although much effort has been devoted to the study of the kinetics mechanism of protein corona formation on large NPs, the nature of NP-protein interactions in the ultrasmall regime is radically different and poorly understood. Using a combination of experimental and computational approaches, we studied the interactions of a model protein, CrataBL, with ultrasmall gold NPs passivated with p-mercaptobenzoic acid (AuMBA) and glutathione (AuGSH). We have identified this system as an ideal in vitro platform to understand the dependence of binding affinity and kinetics on NP surface chemistry. We found that the structural and chemical complexity of the passivating NP layer leads to quite different association kinetics, from slow and reaction-limited (AuGSH) to fast and diffusion-limited (AuMBA). We also found that the otherwise weak and slow AuGSH-protein interactions measured in buffer solution are enhanced in macromolecular crowded solutions. These findings advance our mechanistic understanding of biomimetic NP-protein interactions in the ultrasmall regime and have implications for the design and use of NPs in the crowded conditions common to all biological media. PMID- 29383363 TI - Dearylation of arylphosphine oxides using a sodium hydride-iodide composite. AB - A new protocol for the dearylation of arylphosphine oxides was developed using sodium hydride (NaH) in the presence of lithium iodide (LiI). The transient sodium phosphinite could be functionalized with a range of electrophiles in a one pot fashion. PMID- 29383362 TI - Dithioamide substitutions in proteins: effects on thermostability, peptide binding, and fluorescence quenching in calmodulin. AB - Thioamide substitutions in the backbones of proteins can modulate their structure and thermostability, or serve as spectroscopic probes in fluorescence quenching experiments. Using native chemical ligation, we have produced the first examples of a protein (calmodulin) containing two thioamides. Dithioamide variants were made to explore the effects of combining stabilizing, neutral, and destabilizing single thioamide substitutions. One of the dithioamide calmodulin variants exhibited stabilization greater than any monothioamide variant, although the effect could not easily be anticipated from the results of single substitutions. Each of the calmodulin variants retained the ability to bind a target peptide, and the dithioamide proteins exhibited an increase in fluorescence quenching of tryptophan relative to their single thioamide counterparts. These results show that multiply thioamidated proteins can be synthesized, and that properly placed thioamides can be used to increase protein thermostability or enhance fluorecsence quenching in peptide binding experiments. PMID- 29383364 TI - The effect of shape on the fracture of a soft elastic gel subjected to shear load. AB - For brittle solids, the fracture energy is the energy required to create a unit area of new surface through the process of division. For crosslinked materials, it is a function of the intrinsic properties like crosslinking density and bond strength of the crosslinks. Here we show that the energy released due to fracture can depend also on the shape of a joint made of this material. Our experiment involves two gel blocks connected via a thin gel disk. The disk is formed into different regular and exotic shapes, but with identical areas of cross-section. When one of the blocks is sheared with respect to the other, the shear load increases with vertical displacement, eventually causing a fracture at a threshold load. The maximum fracture load is different for different disks and among different regularly shaped disks, it is at a maximum for pentagon and hexagon shapes. The fracture energy release rate of the joint depends also on the aspect ratio (height/width) of the shapes. Our experiments also throw light on possible reasons for such a dependence on the shape of the joints. PMID- 29383365 TI - Surface elastic constants of a soft solid. AB - Solid interfaces have intrinsic elasticity. However, in most experiments, this is obscured by bulk stresses. Through microscopic observations of the contact-line geometry of a partially wetting droplet on an anisotropically stretched substrate, we measure two surface-elastic constants that quantify the linear dependence of the surface stress of a soft polymer gel on its strain. With these two parameters, one can predict surface stresses for general deformations of the material in the linear-elastic limit. PMID- 29383366 TI - Electrical current nanogeneration driven by spontaneous nanofluidic oscillations. AB - Exploiting natural phenomena is a central route for providing electricity to sustainably drive wearable electronics. Here we report a nano-scale water-driven energy generator that produces tiny electrical currents from spontaneous wetting drying oscillations in mesoporous thin films. The system was fabricated with a wormlike mesoporous silica film, which was packed in between Cu and silicon contacts. The nanogenerator runs autonomously when a water droplet is laid over the film close to the Cu electrode, as water infiltration into the film under the electrode produces a direct-current. Wetting-drying cycles, which are spontaneously triggered by water evaporation, are perfectly correlated to the generated electrical current. The autonomous water displacement through the film yields a sustained energy conversion until the droplet reservoir vanishes. This novel water-driven nanogenerator opens new alternatives for versatile, mobile and cost-effective self-powering of nanosystems and nanodevices. PMID- 29383367 TI - Self-diffusiophoresis induced by fluid interfaces. AB - The influence of a fluid-fluid interface on self-phoresis of chemically active, axially symmetric, spherical colloids is analyzed. Distinct from the studies of self-phoresis for colloids trapped at fluid interfaces or in the vicinity of hard walls, here we focus on the issue of self-phoresis close to a fluid-fluid interface. In order to provide physically intuitive results highlighting the role played by the interface, the analysis is carried out for the case that the symmetry axis of the colloid is normal to the interface; moreover, thermal fluctuations are not taken into account. Similarly to what has been observed near hard walls, we find that such colloids can be set into motion even if their whole surface is homogeneously active. This is due to the anisotropy along the direction normal to the interface owing to the partitioning by diffusion, among the coexisting fluid phases, of the product of the chemical reaction taking place at the colloid surface. Different from results corresponding to hard walls, in the case of a fluid interface the direction of motion, i.e., towards the interface or away from it, can be controlled by tuning the physical properties of one of the two fluid phases. This effect is analyzed qualitatively and quantitatively, both by resorting to a far-field approximation and via an exact, analytical calculation which provides the means for a critical assessment of the approximate analysis. PMID- 29383368 TI - Direct observation of the external force mediated conformational dynamics of an IHF bound Holliday junction. AB - We have investigated the isomerization dynamics and plausible energy landscape of 4-way Holliday junctions (4WHJs) bound to integration host factor (IHF, a DNA binding protein), considering the effect of applied external force, by single molecule FRET methods. A slowing down of the forward as well as the backward rates of the isomerization process of the protein bound 4WHJ has been observed under the influence of an external force, which indicates an imposed restriction on the conformational switching. This has also been reflected by an increase in rigidity, as observed from the increase in the single-molecule FRET (smFRET) anisotropy values (0.270 +/- 0.012 to 0.360 +/- 0.008). The application of an external force has assisted the conformational transitions to share the unstacked open structure intermediate, with different rate-limiting steps and a huge induced variation in the energy landscape. Furthermore, the associated landscape of the 4WHJ is visualized in terms of rarely interconverting states embedded into the two isoforms by using nonlinear dynamics analysis, which shows that the chaoticity of the system increases at intermediate force (0.4 to 1.6 pN). The identification of chaos in our investigation provides useful information for a comprehensive explanation of the origin of the complex behavior of the system, which effectively helps us to perceive the dynamics of IHF bound 4WHJs under the influence of external force, and also demonstrates the applicability of nonlinear dynamics analysis in the field of biology. PMID- 29383369 TI - On-a-chip tryptic digestion of transthyretin: a step toward an integrated microfluidic system for the follow-up of familial transthyretin amyloidosis. AB - A microfluidic microreactor for trypsin mediated transthyretin (TTR) digestion has been developed as a step towards the elaboration of a fully integrated microdevice for the detection of a rare and disabling disease, the familial transthyretin amyloidosis (ATTR) which is related to specific TTR mutations. Therefore, an enzymatic microreactor coupled to an analytical step able to monitor the mutation of TTR on specific peptide fragments would allow an accurate monitoring of the treatment efficiency of ATTR. In this study, two types of immobilized trypsin microreactors have been investigated: a new miniaturized, microfluidic fluidized bed packed with trypsin functionalized magnetic particles (MPs), and a thiol-ene (TE) monolith-based chip. Their performances were first demonstrated with N-benzoyl-dl-arginine-4-nitroanilide hydrochloride BApNA, a low molecular weight substrate. High reaction yields (75.2%) have been reached within 0.6 min for the TE-based trypsin microreactor, while a lower yield (12.4%) was obtained for the micro-fluidized bed within a similar residence time. Transposition of the optimized conditions, developed with BApNA, to TTR digestion in the TE-based trypsin microreactor was successfully performed. We demonstrated that the TE-chip can achieve an efficient and reproducible digestion of TTR. This has been assessed by MS detection. In addition, TTR hydrolysis led to the production of a fragment of interest allowing the therapeutic follow-up of more than twenty possible ATTR mutations. High sequence coverage (90%), similar to those obtained with free trypsin, was achieved in a short time (2.4 min). Repeated experiments showed good reproducibility (RSD = 6.8%). These promising results open up the route for an innovative treatment follow-up dedicated to ATTR. PMID- 29383370 TI - Simultaneous uniaxial extensional deformation and cylindrical confinement of block copolymers using non-equilibrium molecular dynamics. AB - Using coarse-grained nonequilibrium molecular dynamics, symmetric block copolymers are simulated under the combined effects of cylindrical confinement and uniaxial extensional deformation. For a given confinement diameter, a block copolymer (BCP) will self-assemble into a fixed number of concentric cylinder lamellae at equilibrium. The changing diameter during uniaxial extensional deformation therefore is expected to affect the morphology of the BCPs. The aim of this study is to investigate the interplay of deformation and confinement on BCP morphology by varying the simulation strain rate and diameter. Two different simulation approaches are conducted: constant time simulations with varying initial diameter and constant strain simulations with varying simulation time. A comparison of self-assembly at different strain rates shows that for low strain rates, near-equilibrium morphology can form despite the deformation, while for progressively higher strain rates, extra lamellae and disordered morphologies appear. By defining a Weissenberg number based on the deformation and polymer self-assembly time-scales, the morphologies at different strain rates and diameters are explained. Using the time scale analysis, ordered morphologies appear for Wi < 1, while extra lamellae and disordered morphologies occur at Wi > 1. For the latter case, the cylinder diameter shrinks too quickly for polymers to form the equilibrium morphology, which results in a mixture of lamellar structures along the cylinder length. PMID- 29383371 TI - Bilayer sheet protrusions and budding from bilayer membranes induced by hydrolysis and condensation reactions. AB - Shape transformations of flat bilayer membranes and vesicles induced by hydrolysis and condensation reactions of amphiphilic molecules are studied using coarse-grained molecular dynamics simulations. The hydrolysis and condensation reactions result in the formation and dissociation of amphiphilic molecules, respectively. Asymmetric reactions between the inner and outer leaflets of a vesicle can transport amphiphilic molecules between the leaflets. It is found that the resulting area difference between the two leaflets induces bilayer sheet protrusion (BP) and budding at low reduced volumes of the vesicles, whereas BP only occurs at high reduced volumes. The probabilities of these two types of transformations depend on the shear viscosity of the surrounding fluids compared to the membrane as well as the reaction rates. A higher surrounding fluid viscosity leads to more BP formation. The inhomogeneous spatial distribution of the hydrophobic reaction products forms the nuclei of BP formation, and faster diffusion of the products enhances BP formation. Our results suggest that adjustment of the viscosity is important to control membrane shape transformations in experiments. PMID- 29383372 TI - Effectiveness of a Method for Teaching Self-Compassion to Communication Sciences and Disorders Graduate Students. AB - Purpose: The purpose of this study is to explore the effects of a daily mindfulness practice and 2 types of journaling on participants' development of self-compassion. Method: This was a between-groups design. All participants in a graduate counseling course engaged in a short daily mindfulness practice at the beginning of every class. Participants were randomly assigned to a counseling journal or a gratitude journal group. Participants were to write in their journals 2 to 5 times a week for the duration of the class. Participants completed the Self-Compassion Scale (Neff, 2003) and a questionnaire created by the 1st author before any mindfulness sessions were held and again at the completion of the course. Results: Participants' level of self-compassion increased from pretest to posttest. The self-compassion scores of participants who kept counseling journals increased more than did those of participants who kept gratitude journals. Qualitative data indicated that participants believed that mindfulness was an important quality for clinicians to possess and that they were accepting of the daily mindfulness practice. Conclusions: Engaging in a 12 min daily mindfulness practice utilizing simple yoga postures, breath work, reflective writing, and journaling done at a separate time appears to be an effective technique for increasing students' levels of self-compassion. Maintaining a counseling journal as opposed to a gratitude journal appears to enhance the effect of the daily mindfulness practice on self-compassion. PMID- 29383373 TI - ASO Therapy: Hope for Genetic Neurological Diseases. PMID- 29383374 TI - Validation of a Custom Instrumented Retainer Form Factor for Measuring Linear and Angular Head Impact Kinematics. AB - Head impact exposure in popular contact sports is not well understood, especially in the youth population, despite recent advances in impact-sensing technology which has allowed widespread collection of real-time head impact data. Previous studies indicate that a custom-instrumented mouthpiece is a superior method for collecting accurate head acceleration data. The objective of this study was to evaluate the efficacy of mounting a sensor device inside an acrylic retainer form factor to measure six-degrees-of-freedom (6DOF) head kinematic response. This study compares 6DOF mouthpiece kinematics at the head center of gravity (CG) to kinematics measured by an anthropomorphic test device (ATD). This study found that when instrumentation is mounted in the rigid retainer form factor, there is good coupling with the upper dentition and highly accurate kinematic results compared to the ATD. Peak head kinematics were correlated with r2 > 0.98 for both rotational velocity and linear acceleration and r2 = 0.93 for rotational acceleration. These results indicate that a rigid retainer-based form factor is an accurate and promising method of collecting head impact data. This device can be used to study head impacts in helmeted contact sports such as football, hockey, and lacrosse as well as nonhelmeted sports such as soccer and basketball. Understanding the magnitude and frequency of impacts sustained in various sports using an accurate head impact sensor, such as the one presented in this study, will improve our understanding of head impact exposure and sports-related concussion. PMID- 29383375 TI - Reevaluating Order Effects in the Binaural Bithermal Caloric Test. AB - Purpose: The purpose of this study was to determine whether a significant order effect exists in the binaural bithermal caloric test. Method: Fifteen volunteers (mean age = 24.3 years, range = 18-38 years) with no history of vestibular disorder, hearing loss, concussion, or neurological disease underwent caloric testing on 3 occasions. Irrigations were randomized using 8 possible order combinations. The parameters of interest included unilateral weakness, directional preponderance, total response from the right ear, and total response from the left ear. Results: Order effects were analyzed using 2 methods. The first analysis was done looking at the 8 possible orders. We also had an a priori established hypothesis that the first irrigation tested would influence the calculation of unilateral weakness more than the other 3 irrigations. To test this hypothesis, the 8 orders were condensed into 4 order conditions based on the first irrigation. The effect of order was determined using analysis of variance tests. Although the first irrigation tended to be the largest, no significant effects were observed. Conclusions: This experiment demonstrated that while there is great inter-individual and intra-individual variability in caloric test results, the order of irrigations had no significant effect in the test. Future studies may explore the effects of nonphysiological factors on test results. PMID- 29383376 TI - Are Medicaid Work Requirements Legal? PMID- 29383377 TI - Performance on Auditory and Visual Tasks of Inhibition in English Monolingual and Spanish-English Bilingual Adults: Do Bilinguals Have a Cognitive Advantage? AB - Purpose: Bilingual individuals have been shown to be more proficient on visual tasks of inhibition compared with their monolingual counterparts. However, the bilingual advantage has not been evidenced in all studies, and very little is known regarding how bilingualism influences inhibitory control in the perception of auditory information. The purpose of the current study was to examine inhibition of irrelevant information using auditory and visual tasks in English monolingual and Spanish-English bilingual adults. Method: Twenty English monolinguals and 19 early balanced Spanish-English bilinguals participated in this study. All participants were 18-30 years of age, had hearing thresholds < 25 dB HL from 250 to 8000 Hz, bilaterally (American National Standards Institute, 2003), and were right handed. Inhibition was measured using a forced-attention dichotic consonant-vowel listening task and the Simon task, a nonverbal visual test. Results: Both groups of participants demonstrated a significant right ear advantage on the dichotic listening task; however, no significant differences in performance were evidenced between the monolingual and bilingual groups in any of the dichotic listening conditions. Both groups performed better on the congruent trial than on the incongruent trial of the Simon task and had significantly faster response times on the congruent trial than on the incongruent trial. However, there were no significant differences in performance between the monolingual and bilingual groups on the visual test of inhibition. Conclusions: No significant differences in performance on auditory and visual tests of inhibition of irrelevant information were evidenced between the monolingual and bilingual participants in this study. These findings suggest that bilinguals may not exhibit an advantage in the inhibition of irrelevant information compared with monolinguals. PMID- 29383378 TI - Counseling Issues: Addressing Behavioral and Emotional Considerations in the Treatment of Communication Disorders. AB - Purpose: Counseling is an important fundamental professional activity and an established component of the speech-language pathology/audiology scope of practice as documented by the American Speech-Language-Hearing Association (2004a, 2016a). Appropriate incorporation of counseling into practice can optimize service provision, help address comorbid behavioral and emotional reactions to communication disorders, and enhance prognosis. Practitioner insecurity in incorporating counseling into practice has been documented by Phillips and Mendel (2008), as well as Atkins (2007). This tutorial seeks to present general counseling constructs and treatment applications primarily utilizing a humanistic counseling perspective. Method: This tutorial incorporated relevant publications from communication disorders and counseling psychology literature databases over a 3-year period. The tutorial evolved through interviews with practicing speech-language pathology practitioners and educators and was undertaken to provide transparency and clarity to support the assertions and recommendations offered. Results: This tutorial organizes and presents general counseling considerations along with specific suggestions, which can help practitioners who are seeking to expand their understanding, skill, and confidence in incorporating counseling into their practice. The tutorial identifies some of the potential and impactful comorbid emotional and behavioral responses to experiencing a communication disorder and/or to the treatment process for the communication disorder issue(s). Theoretically grounded considerations for mitigating such potentially impactful responses are offered. Conclusion: Continued and enhanced efforts may be necessary to meet American Speech-Language-Hearing Association's mandate for universal incorporation of empirically supported counseling approaches and in advancing universal speech language pathology/audiology training in this area. It is hoped that this tutorial serves as an initial guide for addressing this need until universal preparation and practice is achieved. PMID- 29383379 TI - Effect of Local Coil Density on Blood Flow Stagnation in Densely Coiled Cerebral Aneurysms: A Computational Study Using a Cartesian Grid Method. AB - Aneurysm recurrence is the most critical concern following coil embolization of a cerebral aneurysm. Adequate packing density (PD) and coil uniformity are believed necessary to achieve sufficient flow stagnation, which decreases the risk of aneurysm recurrence. The effect of coil distribution on the extent of flow stagnation, however, especially in cases of dense packing (high PD), has received less attention. Thus, the cause of aneurysm recurrence despite dense packing is still an open question. The primary aim of this study is to evaluate the effect of local coil density on the extent of blood flow stagnation in densely coiled aneurysms. For this purpose, we developed a robust computational framework to determine blood flow using a Cartesian grid method, by which the complex fluid pathways in coiled aneurysms could be flexibly treated using an implicit function. This tool allowed us to conduct blood flow analyses in two patient specific geometries with 50 coil distribution patterns in each aneurysm at clinically adequate PD. The results demonstrated that dense packing in the aneurysm may not necessarily block completely the inflow into the aneurysm and local flow that formed in the neck region, whose strength was inversely related to this local PD. This finding suggests that local coil density in the neck region still plays an important role in disturbing the remaining local flow, which possibly prevents thrombus formation in a whole aneurysm sac, increasing the risk of aneurysm regrowth and subsequent recurrence. PMID- 29383380 TI - Concurrent Validity and Reliability for the Communication Complexity Scale. AB - Purpose: The Communication Complexity Scale (CCS; Brady et al., 2012) was created to fill a void in measures of expressive communication skills in individuals who communicate primarily with presymbolic or early symbolic means. CCS scores reflect expressive communication observed during interactive communication contexts. Method: Two studies were completed to examine the reliability and validity of the revised CCS scores. Participants in both studies had minimal verbal skills (i.e., produced less than 20 functional words). Study 1 examined interobserver agreement, test-retest reliability, and concurrent validity for 239 participants with intellectual disabilities between the ages of 3-66 years, assessed with the protocol developed at the University of Kansas (KU CCS). CCS scores were compared with scores from the Vineland Adaptive Behavior Scales Second Edition (Sparrow, Cicchetti, & Balla, 2005) and the Communication Matrix (Rowland & Fried-Oken, 2010). Study 2 examined the reliability and concurrent validity for CCS scores derived from 110 children (chronological age = 3-9) with autism from diverse backgrounds. These children were assessed with the Early Social Communication Scale (Mundy et al., 2003). CCS scores were compared with rates of communication derived from the Early Social Communication Scale. Results: CCS scores were moderately correlated with scores from existing measures of early communication. In addition, CCS scores from different raters were reliable, and test-retest scores were highly similar. Conclusions: These findings support the validity and reliability of the CCS when used with individuals across a wide range of ages and with various types of disabilities. The CCS can be used in research and clinical practice to describe extant communication levels in individuals with minimal verbal skills. PMID- 29383381 TI - A Family-Centered Feeding Intervention to Promote Food Acceptance and Decrease Challenging Behaviors in Children With ASD: Report of Follow-Up Data on a Train the-Trainer Model Using EAT-UP. AB - Purpose: This research note outlines the usefulness of Easing Anxiety Together with Understanding and Perseverance (EAT-UP), a train-the-trainer, family centered feeding intervention, for promoting food acceptance of children with autism spectrum disorder (ASD). This report is a follow-up on a pilot study (n = 4) of the EAT-UP intervention previously completed by the same authors. Method: Participants were 3 families of children with ASD receiving services from an outpatient department of a larger rehabilitation hospital in the northeastern United States. Three professionals working with the families were also recruited and trained by the first author, a speech-language pathologist experienced with the EAT-UP method. Initial assessment was followed by a baseline period for each participant. An individual mealtime plan was drafted for each family. Data on acceptance of less preferred food and the presence of challenging mealtime behaviors were recorded using direct observation and pre-, mid-, and postintervention measures and questionnaires. Results: All children demonstrated increased food acceptance and dietary diversity and decreased challenging behaviors. Caregivers reported decreases in the frequency of problem behaviors and in the number of problem mealtime behaviors. Measures of procedural fidelity increased from 50% to 100% for registered behavior technicians and parents over the course of the EAT-UP intervention period. Conclusions: EAT-UP is an effective model for training professionals who work with families of children with ASD and challenging mealtime behavior. Implications for interprofessional practice and research are discussed. PMID- 29383382 TI - Promoting Peer Interaction for Preschool Children With Complex Communication Needs and Autism Spectrum Disorder. AB - Purpose: This study investigates the impact of a multicomponent intervention on the social communication and engagement of preschool children with complex communication needs (CCN) and autism spectrum disorder (ASD) and peers without disabilities. Method: Five dyads of children participated in this research. A multiple probe design across dyads was used to evaluate the effects of intervention on the frequency of communicative turns expressed by children with CCN and ASD in interactions with peers. Frequency of peer turns, percentage of turns taken by peers, and joint engagement were investigated to assess the quality of the interaction. The intervention included (a) provision of a communication app on an Apple iPad Air 2 and (b) dyadic turn-taking training. Results: Four of the 5 participants with CCN completed training and increased independent communicative turn-taking with peers. The 5th participant showed increased turn-taking during training but little change in independent turn taking. All peers took more turns in intervention than in baseline, with no negative impact on the turn balance between participants. Average joint engagement increased for all dyads, although session-to-session variability was high. Conclusion: The results from this study provide support for the use of this intervention to promote peer interaction for children with CCN and ASD. Supplemental Material: https://doi.org/10.23641/asha.5829678. PMID- 29383383 TI - Self-rated health in Europe and its determinants: Does generation matter? AB - OBJECTIVES: To analyse the influence of micro- and macro-factors on self-rated health, and the role of generation on this relationship. METHODS: Cross-sectional study using data from European Health Interview Surveys from 14 European countries. Individuals were divided into four generations ("silent generation", "baby boomers", and "generation X" and "Y"). We conducted multilevel analyses for each generation to study the influence of individual and national explanatory variables on self-rated health. RESULTS: Age showed an exponential effect in older generations. Education and employment presented the strongest association with low self-rated health, especially in "baby boomers" and women (low education: OR 3.5; 95% CI 3.2-3.9). Tobacco showed a negative effect in younger generations. Overweight and low physical activity were negatively associated with self-rated health regardless of generation. Countries from the Eastern welfare system showed the highest risk of low self-rated health and this association was higher in men for "silent generation" (OR 4.7; 95% CI 3.0-7.6). CONCLUSIONS: The influence of individual and national factors on self-rated health varies regarding generation. The target generation and the demographic structure of a country should be taken into account to develop more accurate health policies. PMID- 29383384 TI - The contribution of behavioural and metabolic risk factors to socioeconomic inequalities in mortality: the Italian Longitudinal Study. AB - OBJECTIVES: The aim of this study was to assess social inequalities in overall mortality in a representative sample of the Italian population, and to evaluate the contribution of behavioural and metabolic risk (BMF) factors to these inequalities. METHODS: 85,308 participants aged 25-74 years from the Italian Longitudinal Study were included in the study population and followed up for mortality (1999-2012). Level of education was used as a proxy for socioeconomic status. The contribution of BMF was estimated assessing the attenuation of the risk by education produced by the inclusion of BMF in regression model. RESULTS: Men with the lowest education had 62% and women had 57% greater risk of dying than those with the highest education. Among men, adjustment for BMF produced an attenuation of the mortality risk between extreme classes of education by 22%, while among women the risk attenuation was 7%. CONCLUSIONS: Large educational differences in mortality were observed for both men and women. BMF reduced by approximately 20% differences in mortality relative risk between extreme classes of education in men. In contrast, a very low contribution was observed in women. PMID- 29383385 TI - Effects of Experimental Lead Exposure on Testis of the Chestnut Capped Blackbird Chrysomus ruficapillus. AB - Lead (Pb) effects on testis histology, as well as sperm quality and oxidative status were evaluated in male Chestnut Capped Blackbird (Chrysomus ruficapillus). Wild blackbirds were captured, immediately sampled (field group) or kept in captivity and treated with a single intraperitoneal injection of saline solution (control) or saline solution with Pb acetate (50 or 100 mg/kg Pb). Seven days after injection, whole blood, ductus deferens and testis samples were collected. Increased Pb concentrations were observed in whole blood and testis of Pb-exposed blackbirds with respect to those from field and control blackbirds. Sperm cells of Pb-exposed blackbirds showed loss of membrane integrity, mitochondrial functionality, and DNA integrity. Also, oxidative damage was observed in testis of blackbirds injected with 100 mg/kg Pb. These findings indicate that Pb is accumulated in testis of C. ruficapillus, inducing severe morphological and biochemical injury that can compromise the reproductive performance of male blackbirds. Although the exposure scenario (Pb acetate, high dosage and intraperitoneal injection) tested in the present study would likely not occur in the wild, it was adequate to show potential and relevant toxic effects of Pb in wild birds. PMID- 29383386 TI - [Alcohol intoxication in emergency medicine]. AB - Every year more than 100,000 people with an alcohol intoxication are admitted to German hospitals. Many of them refuse inpatient observation or treatment. Therefore the physician in charge at the emergency room has to decide, how to proceed. The capacity to consent has to be judged, especially if the patient insists on being discharged. In this context the risks of injuries, complicated alcohol withdrawal, aggressive and suicidal behavior must be evaluated. In this article the juridical aspects and the necessary mental and physical assessments especially in case of discharge of the patient against medical advice are presented. Essential aspects are summarized in checklists. PMID- 29383387 TI - [Medical examination: preparation for ENT specialisation : Part 34]. PMID- 29383388 TI - [Interactive augmented reality systems : Aid for personalized patient education and rehabilitation]. AB - BACKGROUND: During patient education, information exchange plays a critical role both for patient compliance during medical or rehabilitative treatment and for obtaining an informed consent for an operative procedure. OBJECTIVE: In this article the augmented reality system "Magic Mirror" as an additive tool during patient education, rehabilitation as well as anatomical education is highlighted. MATERIAL AND METHODS: The Magic Mirror system allows the user of the system to inspect both a detailed model of the 3-dimensional anatomy of the human body and volumetric slice images in a virtual mirror environment. RESULTS: First preliminary results from the areas of rehabilitation and learning anatomy indicate the broad potential of the Magic Mirror. Similarly, the system also provides interesting advantages for patient education situations in comparison to traditional methods of information exchange. CONCLUSION: Novel technologies, such as augmented reality are a door opener for many innovations in medicine. In the future, patient-specific systems, such as the Magic Mirror will be used increasingly more in areas such as patient education and rehabilitation. In order to maximize the benefits of such systems, further evaluation studies are necessary to find out about the best use cases and to start an iterative optimization process of these systems. PMID- 29383389 TI - Gout as a risk factor for osteoporosis: epidemiologic evidence from a population based longitudinal study involving 108,060 individuals. AB - : Is gout a risk factor for future osteoporosis? This large population-based study comprising two matched groups of individuals with and without gout demonstrates that patients with gout have a 20% increase in the risk of developing osteoporosis in future through an 8-year follow-up. INTRODUCTION: To examine if gout is associated with an increased risk of osteoporosis. METHODS: We conducted a nationwide population-based retrospective matched-cohort study. Two matched cohorts (n = 36,458 with gout and 71,602 without gout) assembled and recruited from the Longitudinal Health Insurance Dataset containing 1 million subjects. Exclusion criteria were missing data, age < 20 years, short follow-up period, and pre-existing osteoporosis. Both cohorts were followed up until incident osteoporosis, death, or the end of the study. Person-year data and incidence rates were evaluated. A multivariable Cox model was used to derive an adjusted hazard ratio (aHR) after controlling for socioeconomic proxy, geographical difference, glucocorticoid and allopurinol exposure, various prespecified medical conditions, and comorbidities. RESULTS: Men comprised 72.8% of the cohorts. With a follow-up of 183,729 and 359,900 person-years for the gout and non-gout cohorts, 517 and 811 incidents of osteoporosis occurred, respectively, after excluding osteoporosis incidents in the first 3 years of follow-up. The cumulative incidence of osteoporosis was statistically higher in the gout cohort than in the non-gout cohort, at 3.3 versus 2.1% (P = 0.0036, log rank). Our Cox model showed a 1.2-fold increase in the incidence of osteoporosis in the gout cohort, with an aHR of 1.2 (95% confidence interval, 1.06-1.35). CONCLUSIONS: This first population-based epidemiologic study supports the hypothesis that compared with individuals without gout; those with gout have a modest increase in the risk of developing osteoporosis in future. PMID- 29383390 TI - Prevalence of prone position use and complications among ventilated ARDS patients. PMID- 29383391 TI - A misplaced dialysis catheter. PMID- 29383392 TI - [Ethical perspectives on E-health and health apps : Is all that is achievable desirable?] AB - The aim of technical innovation-and the standpoint from which to assess technology-must be to expand human spaces of action and improve social coexistence. Although many current developments have the potential for furthering this aim, they also imply the danger of being misused. The potential for misuse can be recognized and dealt with at an early stage if ethics is an integral part of technology development. Relevant evaluation criteria include benefit and damage potential, possible repercussions on the physician-patient relationship, self-efficacy, and self-determination (autonomy) of the actors based on full knowledge, appropriate attribution of responsibility, and the access and distribution of rights.This report meditates on the ethical evaluation of E health and the role of ethics in developing new medical technologies. It first discusses the effects of the digitalization of the healthcare market on patients and health workers and then reconsiders the potential, framework, and instruments of ethical evaluation from a theoretical and application-oriented point of view. PMID- 29383393 TI - [From idea to standard care-a field report]. AB - Digital health products and services have started to fundamentally change healthcare and prevention. Products intended for a medical use require CE-marking and potentially certification (ISO 13485) of the company. Startups play an important role in the development of new digital products and services. Two startups share their experience with these processes. Becoming a part of standard care and hence being reimbursed is a challenge for startups. For this reason, startups pursue alternative sources of income, too. The statutory health insurance's procedures for assessing new products and services are perceived as long. Startups are required to provide evidence of the benefit of their product at an early stage in the procedure. This requires time-consuming and costly studies. Startups would therefore appreciate support in generating this evidence, e. g. through adequate procedures for testing. PMID- 29383394 TI - [Legal framework for E-health products on the European market]. AB - Legitimately categorizing software in the healthcare sector is complex. According to European medical devices law, software can be considered a medical device. The decisive factor is whether the software is used for directly controlling a therapeutic or diagnostic medical device or as stand-alone software that achieves specific medical purposes, as they are described in the legal definition of a medical device. A contribution of the software to diagnosis or therapy can be sufficient for the categorization; it does not have to provide the complete diagnosis or the complete therapy itself.This principle will continue to be the same with the new Regulation on Medical Devices (EU) 2017/745, even though the classification rules have been more closely and more specifically tailored to software and more stringent requirements for essential safety and performance requirements have to be met. PMID- 29383395 TI - Bacterial sepsis : Diagnostics and calculated antibiotic therapy. AB - The mortality of patients with sepsis and septic shock is still unacceptably high. An effective calculated antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed infection and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account during the selection of anti-infective treatment. Many pathophysiologic alterations influence the pharmacokinetics (PK) of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM, but for continuous infusion, TDM is generally necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug-resistant (MDR) pathogens in the intensive care unit. For effective treatment, antibiotic stewardship teams (ABS teams) are becoming more established. Interdisciplinary cooperation of the ABS team with infectious disease (ID) specialists, microbiologists, and clinical pharmacists leads not only to rational administration of antibiotics, but also has a positive influence on treatment outcome. The gold standards for pathogen identification are still culture-based detection and microbiologic resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction(PCR)-based procedures for pathogen identification and resistance determination are currently only an adjunct to routine sepsis diagnostics, due to the limited number of studies, high costs, and limited availability. In complicated septic courses with multiple anti-infective therapies or recurrent sepsis, PCR-based procedures can be used in addition to treatment monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically (still) absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation). (Contribution available free of charge by "Free Access" [ https://link.springer.com/article/10.1007/s00101-017-0396-z ].). PMID- 29383396 TI - Differential effects of alpha4beta2 nicotinic receptor antagonists and partial agonists on contextual fear extinction in male C57BL/6 mice. AB - RATIONALE: Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction OBJECTIVES: In the present study, we examined the effects of inhibition and desensitization of alpha4beta2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (DhbetaE)) and two alpha4beta2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice. METHODS: We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of DhbetaE, varenicline, and sazetidine-A. RESULTS: Our results demonstrated that lower doses of DhbetaE (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of DhbetaE, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction. CONCLUSIONS: Overall, these results suggest that inhibition and desensitization of alpha4beta2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of alpha4beta2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction processes. PMID- 29383397 TI - NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease. AB - OBJECTIVES: To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. METHODS: Administrative data from five Italian geographic areas were analyzed. Patients aged >= 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with >= 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. RESULTS: Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. CONCLUSIONS: NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted. PMID- 29383398 TI - Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways. AB - Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+ neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment. PMID- 29383399 TI - Influence of dual-task constraints on the interaction between posture and movement during a lower limb pointing task. AB - One of the challenges regarding human motor control is making the movement fluid and at a limited cognitive cost. The coordination between posture and movement is a necessary requirement to perform daily life tasks. The present experiment investigated this interaction in 20 adult men, aged 18-30 years. The cognitive costs associated to postural and movement control when kicking towards a target was estimated using a dual-task paradigm (secondary auditory task). Results showed that addition of the attentional demanding cognitive task yielded a decreased kicking accuracy and an increased timing to perform the movement, mainly during the backswing motion. In addition, significant differences between conditions were found for COP and COM displacement (increased amplitude, mean speed) on the anteroposterior axis. However, no significant differences between conditions were found on the mediolateral axis. Finally, EMG analysis showed that dual-task condition modified the way anticipatory postural adjustments (APAs) were generated. More specifically, we observed an increase of the peroneus longus activity, whereas the temporal EMG showed a decrease of its latency with respect to movement onset. These results suggested a functional adaptation resulting in an invariance of overall APAs, emphasizing that cognitive, postural, and motor processes worked dependently. PMID- 29383400 TI - Individual differences and the effect of face configuration information in the McGurk effect. AB - The McGurk effect, which denotes the influence of visual information on audiovisual speech perception, is less frequently observed in individuals with autism spectrum disorder (ASD) compared to those without it; the reason for this remains unclear. Several studies have suggested that facial configuration context might play a role in this difference. More specifically, people with ASD show a local processing bias for faces-that is, they process global face information to a lesser extent. This study examined the role of facial configuration context in the McGurk effect in 46 healthy students. Adopting an analogue approach using the Autism-Spectrum Quotient (AQ), we sought to determine whether this facial configuration context is crucial to previously observed reductions in the McGurk effect in people with ASD. Lip-reading and audiovisual syllable identification tasks were assessed via presentation of upright normal, inverted normal, upright Thatcher-type, and inverted Thatcher-type faces. When the Thatcher-type face was presented, perceivers were found to be sensitive to the misoriented facial characteristics, causing them to perceive a weaker McGurk effect than when the normal face was presented (this is known as the McThatcher effect). Additionally, the McGurk effect was weaker in individuals with high AQ scores than in those with low AQ scores in the incongruent audiovisual condition, regardless of their ability to read lips or process facial configuration contexts. Our findings, therefore, do not support the assumption that individuals with ASD show a weaker McGurk effect due to a difficulty in processing facial configuration context. PMID- 29383402 TI - ? PMID- 29383401 TI - Stereospecific Interactions of Cholesterol in a Model Cell Membrane: Implications for the Membrane Dipole Potential. AB - Cholesterol is a major constituent of the plasma membrane in higher order eukaryotes. The effect of cholesterol on the structure and organisation of cell membranes has been studied extensively by both experimental and computational means. In recent years, a wealth of data has been accumulated illustrating how subtle differences in the structure of cholesterol equate to considerable changes in the physical properties of the membrane. The effect of cholesterol stereoisomers, in particular, has been established, identifying a direct link with the activity of specific membrane proteins. In this study, we perform extensive molecular dynamics simulations of phospholipid bilayers containing three isomers of cholesterol, the native form (nat-cholesterol), the enantiomer of the native form (ent-cholesterol), and an epimer of cholesterol that differs by the orientation of the polar hydroxyl group (epi-cholesterol). Based on these simulations, an atomic-level description of the stereospecific cholesterol phospholipid interactions is provided, establishing a potential mechanism for the perturbation of membrane properties, specifically the membrane dipole potential. PMID- 29383403 TI - [Unplanned admission or readmission to the intensive care unit : Avoidable or fateful?] AB - BACKGROUND: Unplanned admissions or readmissions to the intensive care unit lead to a poorer outcome and present medical, logistic and economic challenges for a clinic. How often and what are the reasons for readmission to the intensive care unit? Which strategies and guidelines to avoid readmission are recommended. MATERIAL AND METHODS: Analysis and discussion of available studies and recommendations of national and international societies. RESULTS: Many studies show that unplanned admissions and readmissions to the intensive care unit represent an independent risk factor for a poor outcome for patients. Different factors that increase the probability of readmission can be identified. Structural changes concerning the normal wards, intensive care unit or the clinic internal emergency service could positively effect readmission rates and/or patient outcome while other studies failed to show any effect of these arrangements. CONCLUSION: Patient transition from the intensive care unit to a lower level of care is a critical point of time and has to be accompanied by a high quality handover. Unstable patients on normal wards have to be identified and treated as soon as possible but effects of standardized medical emergency teams are controversial. PMID- 29383404 TI - Response of the respiratory mucosal cells to mycobacterium avium subsp. Hominissuis microaggregate. AB - Mycobacterium avium: subsp. hominissuis (MAH) is an opportunistic pathogen that commonly infects immunocompromised individuals. Recently, we described an invasive phenotypic change MAH undergoes when incubated with lung airway epithelial host cells for 24 h, which is accompanied with microaggregate formation in vitro. The microaggregate phenotype also resulted in higher colonization in the lungs of mice early during infection. Previously, we identified genes highly regulated during microaggregate formation and further characterized the function of two highly upregulated bacterial proteins, mycobacterial binding protein-1 (MBP-1) and mycobacterial inversion protein-1 (MIP-1), which were found to be involved in binding and invasion of the respiratory mucosa. While these studies are valuable in understanding the pathogenesis of MAH, they primarily investigated the bacteria during microaggregate infection without commenting on the differences in the host response to microaggregate and planktonic infection. The bacteria-host interaction between microaggregates and epithelial cells was examined in a variety of assays. Using a transwell polarized epithelial cell model, microaggregates translocated through the monolayer more efficiently than planktonic bacteria at set timepoints. In addition, during infection with microaggregate and planktonic bacteria, host phosphorylated proteins were identified revealing differences in immune response, glutathione synthesis, and apoptosis. The host immune response was further investigated by measuring pro inflammatory cytokine secretion during microaggregate and planktonic infection of BEAS-2B bronchial epithelial cells. The epithelial cells secreted more CCL5 during infection with microaggregates suggesting that this chemokine may play an important role during microaggregate invasion. Subsequent experiments showed that microaggregates are formed more efficiently in the presence of CCL5, suggesting that MAH had evolved a strategy to use the host response in its benefit. Collectively, this study establishes the different nature of infection by planktonic bacteria and microaggregates. PMID- 29383405 TI - Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer : A systematic review. AB - PURPOSE: To review the evidence regarding post-mastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NACT) for breast cancer, with a special focus on individualization of adjuvant radiotherapy based on treatment response. METHODS: A systematic literature search using the PubMed/Medline database was performed. We included prospective and retrospective reports with a minimum of 10 patients that had been published since 1st January 2000, and provided clinical outcome data analyzed by treatment response and radiotherapy. RESULTS: Out of 763 articles identified via PubMed/Medline and hand search, 68 full text-articles were assessed for eligibility after screening of title and abstract. 13 studies were included in the systematic review, 9 for PMRT and 5 for RNI. All included studies were retrospective reports. CONCLUSIONS: There is a considerable lack of evidence regarding the role of adjuvant radiotherapy and its individualization based on treatment response after NACT. Results of prospective randomized trials such as NSABP B-51/RTOG 1304 and Alliance A11202 are eagerly awaited. PMID- 29383407 TI - A Novel microCT Method for Bone and Marrow Adipose Tissue Alignment Identifies Key Differences Between Mandible and Tibia in Rats. AB - Bone homeostasis is influenced by the bone marrow adipose tissue (BMAT). BMAT distribution varies from one anatomical location in the skeleton to another. We developed an advanced microfocus computed tomography imaging and analysis protocol that allows accurate alignment of both the BMAT distribution and bone micro-architecture as well as calculation of the distance of the BMAT adipocytes from the bone surface. Using this protocol, we detected a different spatial BMAT distribution between the rat tibia and mandible: in the proximal metaphysis of the tibia a large amount of BMAT (~ 20% of the total BMAT) was located close to the bone surface (< 20 um), whereas in the alveolar ridge ~ 30% of the total BMAT was located between 40 and 60 um from the bone surface. In the alveolar ridge of rats, the trabecular bone volume was 48.3% higher compared to the proximal metaphysis of the tibia (p < 0.0001) and the percentage of adiposity determined to the relative marrow volume was lower (1.5%) compared to the proximal metaphysis of the tibia (9%, p = 0.0002). Interestingly, in the tibia a negative correlation was found between the percentage of adiposity in the total volume and the trabecular thickness (r =- 0.74, p = 0.037). The present study highlights that in comparison to tibial proximal metaphysis, the mandibular bone exhibits a massive trabecular network and a low BMAT content with almost no contact with the bone surface. These findings are of great interest because of the importance of the fat-bone interaction and its potential relevance to several resorptive bone diseases. PMID- 29383406 TI - Use of androgen deprivation and salvage radiation therapy for patients with prostate cancer and biochemical recurrence after prostatectomy. AB - AIM: Overview on the use of androgen deprivation therapy (ADT) added to salvage radiation therapy (SRT) for prostate cancer patients with biochemical recurrence after prostatectomy. METHODS: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published between January 2009 and May 2017, and assessed the validity of the information on outcome parameters including overall survival (OS) and treatment-related toxicity. RESULTS: Two randomized controlled trials and nine relevant retrospective analyses were identified. The RTOG 9601 trial showed an OS improvement for the combination of 2 years of bicalutamide and SRT compared to SRT alone after a median follow-up of 13 years. This improvement appeared to be restricted to those patients with a prostate specific antigen (PSA) level before SRT of >=0.7 ng/mL. The GETUG AFU-16 trial showed that after a median follow-up of 5 years, the addition of 6 months of goserelin to SRT improved progression-free survival (PFS; based on biochemical recurrence) as compared to SRT alone. ADT in both trials was not associated with increased major late toxicities. Results of retrospective series were inconsistent with a suggestion that the addition of ADT improved biochemical PFS especially in patients with high-risk factors such as Gleason Score >=8 and in the group with initially negative surgical margins. CONCLUSIONS: ADT combined with SRT appears to improve OS in patients with a PSA level before SRT of >=0.7 ng/mL. In patients without persistent PSA after prostatectomy and PSA levels of <0.7 ng/mL, ADT should not routinely be used, but may be considered in patients with additional risk factors such as Gleason Score >=8 and negative surgical margins. PMID- 29383408 TI - Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia. AB - Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400 IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25 dihydroxyvitamin D, and TmP/GFR were made over 27 h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production. PMID- 29383409 TI - Correction to: Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide. AB - The article Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide, written by Michael R. McClung, Gregory C. Williams, Gary Hattersley, Lorraine A. Fitzpatrick, Yamei Wang, Paul D. Miller, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 28 December 2017 without open access. PMID- 29383410 TI - [Pharmacogenetics in psychiatry: state of the art]. AB - In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients. PMID- 29383411 TI - [Neuromyelitis optica spectrum disorder and pregnancy]. AB - BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory diseases of the central nervous system that mainly affect women. In some of these patients NMOSD occurs during fertile age. For this reason, treating physicians may be confronted with questions concerning family planning, pregnancy and birth. OBJECTIVE: This study provides an overview on the influence of NMOSD on fertility, pregnancy complications and pregnancy outcome. The effect of pregnancy on NMOSD course and therapy options during pregnancy are discussed. MATERIAL AND METHODS: A search of the current literature was carried out using the PubMed database. RESULTS AND CONCLUSION: Animal studies have shown lower fertility rates in NMOSD; however, studies investigating fertility in NMOSD patients are lacking. Pregnancy in NMOSD patients are associated with an increase in postpartum disease activity and a higher grade of disability after pregnancy. Some studies showed higher risks of pregnancy complications e. g. spontaneous abortions and preeclampsia. With a few limitations, acute relapses during pregnancy can be treated with methylprednisolone and/or plasma exchange/immunoadsorption. Stopping or continuing immunosuppressive therapy with azathioprine or rituximab during pregnancy should be critically weighed considering previous and current disease activity. Therefore, a joint supervision by a specialized center is recommended, particularly in specific situations such as pregnancy. PMID- 29383412 TI - [Anxiety disorders: which psychotherapy for whom?] AB - According to the Federal Healthcare Survey (Bundesgesundheitssurvey), approximately 15% of the German population fulfil the diagnostic criteria for at least one anxiety disorder within (any) 1 year. Women are affected approximately twice as often as men. The study by the Robert Koch Institute included the systematic assessment of panic disorder, agoraphobia, generalized anxiety disorder, social anxiety disorder and specific phobias; therefore, the question for both those affected and the treating therapist is "anxiety disorders: which psychotherapy for whom?" is of great clinical and healthcare political importance. We therefore review the available literature for answering three more specific questions: 1) what are the most suitable forms of psychotherapy, 2) which psychotherapy is most promising for an individual patient and diagnosis (differential evaluation of indications) and 3) what is the best approach to nonresponse or avoidance of the treatment offered? National and international guidelines agree that cognitive behavioral therapy is the psychotherapy of first choice in most patients with anxiety disorders. In cases of nonresponse or lack of availability of the appropriate therapy, psychodynamic therapy or pharmacotherapy can also be recommended. For individualized treatment recommendations we do not have empirical evidence. Also, no evidence-based (individual) recommendations are available for non-responders;however, there are some preferred strategies based on a clinical consensus. PMID- 29383413 TI - [Psychotherapy for people with bipolar disorders : An overview of evidence-based procedures and new developments]. AB - Many individual studies and meta-analyses have shown that psychotherapeutic interventions for people with bipolar disorders can positively influence the course of the disease. This article gives an overview of the development of psychotherapy for people with bipolar disorders. According to the current guidelines the evidence-based procedures with their mechanisms of action are presented and new developments in psychotherapy research in this field are outlined. PMID- 29383414 TI - [Psychotherapy of depressive disorders : Procedures, evidence and perspectives]. AB - BACKGROUND: Depressive disorders are associated with a high burden of suffering and significantly reduce the well-being and the self-esteem of affected patients. Psychotherapy is one of the main treatment options for depressive disorders. OBJECTIVE: The aim of this article is to present the current evidence for antidepressive psychotherapeutic treatments. MATERIAL AND METHODS: During the revision of the German S3- and National Disease Management Guideline (NDMG) on unipolar depression in 2015, a comprehensive and systematic evidence search was conducted. The results of this search along with a systematic update are summarized. RESULTS: The most intensively investigated psychotherapeutic method is cognitive behavioral therapy (CBT), which proved to be effective in many trials. Evidence also exists for psychodynamic psychotherapy and interpersonal therapy (IPT), followed by systemic therapy and client-centered psychotherapy; however, the evidence is less robust. CONCLUSION: Psychotherapy alone or in combination with pharmacotherapy was shown to be an effective treatment option. Psychotherapy represents a key element in the treatment of depressive disorders. PMID- 29383415 TI - Autologous Fibroblast-Seeded Amnion for Reconstruction of Neo-vagina in Male-to Female Reassignment Surgery. AB - BACKGROUND: Plastic surgeons have used several methods for the construction of neo-vaginas, including the utilization of penile skin, free skin grafts, small bowel or recto-sigmoid grafts, an amnion graft, and cultured cells. PURPOSE: The aim of this study is to compare the results of amnion grafts with amnion seeded with autograft fibroblasts. MATERIALS AND METHODS: Over 8 years, we compared the results of 24 male-to-female transsexual patients retrospectively based on their complications and levels of satisfaction. Sixteen patients in group A received amnion grafts with fibroblasts, and the patients in group B received only amnion grafts without any additional cellular lining. The depths, sizes, secretions, and sensations of the vaginas were evaluated. The patients were monitored for any complications, including over-secretion, stenosis, stricture, fistula formation, infection, and bleeding. RESULTS: The mean age of group A was 28 +/- 4 years and group B was 32 +/- 3 years. Patients were followed up from 30 months to 8 years, (mean 36 +/- 4) after surgery. The depth of the vaginas for group A was 14-16 and 13-16 cm for group B. There was no stenosis in neither group. The diameter of the vaginal opening was 34-38 mm in group A and 33-38 cm in group B. We only had two cases of stricture in the neo-vagina in group B, but no stricture was recorded for group A. All of the patients had good and acceptable sensation in the neo vagina. Seventy-five percent of patients had sexual experience and of those, 93.7% in group A and 87.5% in group B expressed satisfaction. CONCLUSION: The creation of a neo-vaginal canal and its lining with allograft amnion and seeded autologous fibroblasts is an effective method for imitating a normal vagina. The size of neo-vagina, secretion, sensation, and orgasm was good and proper. More than 93.7% of patients had satisfaction with sexual intercourse. Amnion seeded with fibroblasts extracted from the patient's own cells will result in a vagina with the proper size and moisture that can eliminate the need for long-term dilatation. The constructed vagina has a two-layer structure and is much more resistant to trauma and laceration. No cases of stenosis or stricture were recorded. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29383417 TI - Pediatric hepatoblastoma and hepatocellular carcinoma: lessons learned in the last decade. PMID- 29383416 TI - Calcium receptor signaling and citrate transport. AB - The calcium sensing receptor (CaSR) in the distal nephron decreases the propensity for calcium stones. Here we investigate if the apical CaSR in the proximal tubule also prevents stone formation acting via regulation of apical dicarboxylate and citrate transport. Urinary citrate, partially reabsorbed as a dicarboxylate in the proximal tubule lumen, inhibits stone formation by complexing calcium. We previously demonstrated a novel apical calcium-sensitive dicarboxylate transport system in OK proximal tubule cells. This calcium sensitive process has the potential to modulate the amount of citrate available to complex increased urinary calcium. Using isotope labeled succinate uptake in OK cells along with various pharmacologic tools we examined whether the CaSR alters apical dicarboxylate transport and through which signal transduction pathways this occurs. Our results indicate that in the proximal tubule CaSR adjusts apical dicarboxylate transport, and does so via a CaSR -> Gq -> PKC signaling pathway. Thus, the CaSR may decrease the propensity for stone formation via actions in both proximal and distal nephron segments. PMID- 29383419 TI - Extensor indicis proprius muscle and its variants together with the extensor digitorum brevis manus muscle: a common classification. Clinical significance in hand and reconstructive surgery. AB - PURPOSE: The extensor indicis proprius (EIP) is a muscle of the forearm that originates from the posterior surface of the ulna and the adjacent interosseous membrane and attaches to the index finger. Many anatomical variations of this muscle have been reported in the literature. The extensor digitorum brevis manus (EDBM) is a variant muscle found on the back of the wrist and hand. These muscle variants should be considered in the context of clinical syndromes and reconstructive hand surgery. The aim of the present study was to describe in detail the normal and variant anatomy of these muscles and propose new systematic classifications. MATERIALS AND METHODS: Formol-carbol-fixed Europid upper limbs (n = 176) were examined in the Department of Anatomy, Histology and Embryology at the Medical University of Sofia for variations of the EIP and occurrences of the EDBM. RESULTS: We found normal anatomy in 147 (84%) of the specimens examined and we measured the length and width of the muscle belly and tendon of the EIP. Variations of the EIP in the other 29 upper limbs (16%) included replacement of the EIP by an EIB, coexistence of the EIP and EIB, presence of accessory tendons, and additional muscles. CONCLUSIONS: Knowledge of anatomical variations of forearm muscles is important because they can cause clinical syndromes or have implications for reconstructive surgery, most often as tendon transfers in response to functional loss of other forearm muscles. PMID- 29383420 TI - The Energy & Raw Materials Factory: Role and Potential Contribution to the Circular Economy of the Netherlands. AB - Water is an abundant resource worldwide, but fresh and clean water is scarce in many areas of the world. Increases in water consumption and climate change will affect global water security even further in the near future. With increasing numbers of people living in metropolitan areas, water, energy, and materials need to be used carefully, reused and renewed. Resource scarcity is the driver behind the circular economy. The recovery of materials and energy can add significant new value streams and improve cost recovery and water quality. In this paper, we present the creation of the Energy & Raw Materials Factory (ERMF) of the Dutch Water Authorities, also known as the Resource Factory, as one of the solutions to this global challenge of water in the circular economy. Resources like cellulose, bioplastics, phosphate, alginate-like exopolymers from aerobic granular sludge (bio-ALE), and biomass can be recovered. Bio-ALE is an alginate-like polymer of sugars and proteins and can be used in agriculture and horticulture, the paper industry, medical, and construction industries. The ERMF demands significant investments but the return on investment is high both from a financial and environmental perspective, provided that markets can be realized. Experiences in the Netherlands show that the concept of the ERMF is viable and adds to the creation of a circular economy. Achieving climate neutrality and production of new and promising resources like bio-ALE are possible. The ERMF can contribute to the sustainable development goals (SDGs) of the United Nations on water and sanitation, once fully operational. PMID- 29383421 TI - Correction to: Delayed manifestations of abdominal trauma: follow-up abdominopelvic CT in posttraumatic patients. AB - The original version of this article unfortunately contained few mistakes. Under the subheading "Data extraction and review process", in line 12 the word "prospective" is incorrectly given by the author. The correct word is "retrospective". In Fig. 2D, the label should read as RA instead of LA. In Table 6, the word "ischemic/gangrenous" should read as "ischemia/gangrene" in 9th row, column 6. The revised Fig 2 and Table 6 are available in the correction article. PMID- 29383422 TI - Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease. AB - Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Low-dose copper increased the spatial memory impairment of these animals, increased accumulation of intracellular amyloid 1-42 (Abeta1-42), decreased ATP content, increased the positive staining of 8-hydroxyguanosine (8 OHdG), a marker of DNA oxidative damage, and caused apoptosis and a decrease in synaptic proteins. Mitochondrial proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) revealed modulation of 24 hippocampal mitochondrial proteins (14 increased and 10 decreased) in copper treated vs. untreated 3xTg-AD mice. Nuclear proteomic analysis revealed 43 modulated hippocampal nuclear proteins (25 increased and 18 decreased) in copper treated 3xTg-AD vs. untreated mice. Classification of modulated mitochondrial and nuclear proteins included functional categories such as energy metabolism, synaptic-related proteins, DNA damage and apoptosis-related proteins, and oxidative stress-related proteins. Among these differentially expressed mitochondrial and nuclear proteins, nine proteins were abnormally expressed in both hippocampus mitochondria and nuclei, including electron transport chain related proteins NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUAA), cytochrome b-c1 complex subunit Rieske (UCRI), cytochrome c oxidase subunit 5B (COX5B), and ATP synthase subunit d (ATP5H), glycolytic-related pyruvate kinase PKM (KPYM) and pyruvate dehydrogenase E1 component subunit alpha (ODPA). Furthermore, we found coenzyme Q10 (CoQ10), an endogenous mitochondrial protective factor/antioxidant, modulated the expression of 12 differentially expressed hippocampal proteins (4 increased and 8 decreased), which could be classified in functional categories such as glycolysis and synaptic-related proteins, oxidative stress-related proteins, implying that CoQ10 improved synaptic function, suppress oxidative stress, and regulate glycolysis. For the proteomics study, we validated the expression of several proteins related to synapses, DNA and apoptosis. The data confirmed that synapsin-2, a synaptic related protein, was significantly decreased in both mitochondria and nuclei of copper-exposed 3xTg-AD mice. In mitochondria, dynamin-1 (DYN1), an apoptosis related proteins, was significantly decreased. In the cellular nuclei, paraspeckle protein 1 (PSPC1) and purin-rich element-binding protein alpha (Puralpha), two DNA damage-related proteins, were significantly decreased and increased, respectively. We conclude that low-dose copper exposure exacerbates the spatial memory impairment of 3xTg-AD mice and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome. Exposure to copper might therefore contribute to the evolution of AD. PMID- 29383424 TI - Enhanced Recovery After Surgery for Low- and Middle-Income Countries. PMID- 29383423 TI - Cervical Lymph Node Metastases of Papillary Thyroid Carcinoma, in the Central and Lateral Compartments, in Children and Adolescents: Predictive Factors. AB - PROBLEM STATEMENT: The aim of our study was to identify predictive factors for lymph node metastases (LNM) in children and adolescents with papillary thyroid carcinoma (PTC) and their impact on survival. METHODS: The authors conducted an Italian multicentric retrospective analysis on 132 pediatric patients (0-18 years old) affected by PTC between 2000 and 2014. The investigated variables were demographic characteristics of the patients, clinicopathological features of PTCs, and persistence/recurrence of disease. The female/male ratio was 3.1:1. The median age was 14.3 +/- 3.5 years (range 4-18 years). Total thyroidectomy was performed in all the patients, followed by lymph node dissection in 87 patients (65.9%). Metastatic lymph node involvement was confirmed in 73 patients (55.3%): lateral compartment (LC) in 25 patients (34.2%), central compartment (CC) in 17 patients (23.3%), and both compartments in 31 patients (42.5%). RESULTS: Multifocality (P < .00), vascular invasion (P = .04), infiltration of the thyroid capsule (P < .00), minimal extrathyroidal extension (P < .00), diffuse sclerosing variant of PTC (P = .02), and presence of LNM in the LC (P < .00) were significantly associated with LNM in CC. Infiltration of the thyroid capsule (P < .00), massive extrathyroidal extension (P = .03), distant metastases (P = .02), PTC, not otherwise specified (P < .00), and presence of LNM in the CC (P < .00) were significantly associated with LNM in LC. Age, sex and size of PTC were not correlated with the presence of cervical LNM. Moreover, presence of LNM in CC increases the risk of persistence (P < .01) and recurrence (P < .02) of PTC in children and adolescents. CONCLUSIONS: Most predictors, unfortunately, are only identified post-operatively by histopathologic examination: Just a small part of them can be pre-operatively detected with a low-sensitivity neck ultrasonography. In PTC patients with pre-operative predictors, we suggest an accurate pre- and intra-operative evaluation of CC and/or LC to find suspicious lymph nodes. The presence of LNM in CC has an impact on disease/progression/relapse-free survival. We suggest performing RAI therapy and an accurate follow-up for pediatric patients with only post-operative predictors. PMID- 29383425 TI - Adrenal Ganglioneuroma: Features and Outcomes of 42 Cases in a Chinese Population. AB - BACKGROUND: Adrenal ganglioneuromas (AGNs) are extremely rare benign neoplasms. This study is to share our experience regarding diagnostic and operative management of these tumors. METHODS: Clinical details as well as follow-up data were retrospectively analyzed in 42 primary AGN patients who received operative resection at a tertiary referral hospital in China between May 2005 and July 2016. RESULTS: The mean age of the patients at diagnosis was 35.3 years (range 13 59 years). Among the patients, 28 were asymptomatic. The mean preoperative size was 5.3 +/- 2.2 cm (range 2.1-14.0 cm), and 17 cases were larger than 5 cm. All patients underwent operative resection as open adrenalectomy in 20 patients and laparoscopy in 22 patients. The mean tumor size on pathologic examination was 6.0 +/- 2.6 cm (range 2.2-17.0 cm). Laparoscopic operation showed its advantages over open surgery on the postoperative duration (5.0 vs. 7.3 days, p < 0.001) and estimated blood loss (69.5 vs. 157.5 ml, p = 0.047). No patient had recurrence or metastasis during a median follow-up of 70.5 months (range 3.7-164.3 months). CONCLUSIONS: We describe the largest AGN series reported to date. The preoperative diagnosis of AGN remains difficult despite of the progression of imaging examination. After complete resection, the prognosis of AGN patients is excellent. Laparoscopic approach has its advantages in the resection of AGNs. PMID- 29383426 TI - Prospective Randomized Trial of Use of In-House Prepared Low-Cost Radiopharmaceutical Versus Commercial Radiopharmaceutical for Sentinel Lymph Node Biopsy in Patients with Early Stage Invasive Breast Cancer. AB - BACKGROUND: The current standard-of-care for surgical staging of the axilla in clinically node-negative (N0) early breast cancers is sentinel lymph node biopsy (SLNB), which requires expensive radiopharmaceuticals for efficacious results. In house produced low-cost radiopharmaceuticals may be the solution and have shown efficacy in earlier observational/pilot studies. We compared SLNB using in-house prepared radiopharmaceutical (99mTc-Antimony-colloid) versus commercially marketed radiopharmaceutical (99mTc-Sulphur-colloid) in this prospective randomized study. STUDY DESIGN: 78 clinically N0 early breast cancer patients (T1/2, N0 stages), undergoing primary surgery were prospectively randomized 1:1 into two groups; to receive SLNB using methylene blue, and either 99mTc-Antimony colloid (Group-1) or 99mTc-Sulphur colloid (Group-2). Completion axillary dissection was done in all (validation SLNB). SLNB indices were compared between the groups. RESULTS: The groups were comparable with regard to age, stage, tumour size, hormone receptors and HER2neu status. Cost of the in-house prepared 99mTc antimony colloid was 16-times lesser compared to 99mTc-sulphur colloid. SLN identification rates (IR) in Groups 1 and 2 were 100 and 97.4% respectively, (p > 0.05). False negative rates (FNR) in Group 1 and 2 were 6.3% (1/16 patients) and 7.7% (1/13 patients), respectively, (p > 0.05). There were no major allergic reactions in either group. CONCLUSION: In this prospective randomized trial on early breast cancer patients, accuracy of SLNB was comparable using in-house prepared, 99mTc-antimony colloid and commercially marketed 99mTc-sulphur colloid as radiopharmaceutical, while 99mTc-antimony colloid was much cheaper than 99mTc sulphur colloid. PMID- 29383427 TI - Blunt Cerebrovascular Artery Injury and Stroke in Severely Injured Patients: An International Multicenter Analysis. PMID- 29383428 TI - From Initial Description by Wermer to Present-Day MEN1: What have We Learned? AB - INTRODUCTION: Pancreas, parathyroid, and pituitary, are referred to as the "3 Ps" of MEN1. The time has come to move beyond those Ps and begin to discuss (1) prediction, (2) pausing progression, and (3) prevention of MEN1. METHODS: In preparation for the International Association of Endocrine Surgeons State of the Art address, updates and uncertainties of MEN were reviewed. This included a detailed examination of the MEN1 gene and the library of implicated mutations, exon sequencing databases and cell cycle pathways. Therapeutic options including radiofrequency ablation, systemic therapy, peptide receptor radionuclide therapy, immune checkpoint inhibitor mechanisms and preimplantation genetic testing were described. RESULTS: Several key points included mutations in exon 2 are suspected of being associated with a higher rate of distant metastases, a higher rate of PNET development, and more aggressive disease. The suggestion that missense mutations involving loss of interaction with CHES1 (associated with DNA repair) correlates with more aggressive disease and is more closely associated with death related to PNET than to death from other causes was mentioned. For advanced NETs, optimism for agents under study include lanreotide, a long-acting somatostatin analog, and everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor. The NETest shows the potential value of being a multidimensional tumor marker for response to therapy. Preimplantation genetic diagnosis (PGD) is applicable. CONCLUSION: Adjunct modalities and determination of the effect of therapy for MEN1 is needed. Prediction through early detection of aggressive disease is an idea worth spreading. We are called us to engage with our patients about prevention, the only true cure. PMID- 29383429 TI - Long-Term Outcomes After Pancreatectomy for Pancreatic Ductal Adenocarcinoma in Elderly Patients: Special Reference to Postoperative Adjuvant Chemotherapy. AB - BACKGROUND: The benefit of pancreatectomy for elderly patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. Moreover, adjuvant chemotherapy (AC) for elderly patients has not been fully evaluated. We investigated the long-term outcomes after pancreatectomy for PDAC in elderly patients with special reference to AC. METHODS: The medical records of 123 patients who underwent pancreatectomy for PDAC from 2007 to 2016 were retrospectively reviewed. The patients were divided into two groups: young (<75 years) and elderly patients (>=75 years). RESULTS: The study population comprised 91 young and 32 elderly patients. The postoperative clinical courses were not different between the two groups. AC was more frequently administered to young (85%) than elderly patients (66%; P = 0.04). The weekly dose of tegafur/gimeracil/oteracil potassium (S1) for AC was significantly lower in elderly (median 423 mg/m2) than young patients (median 491 mg/m2; P = 0.02). The prevalence of adverse events and the completion rate of AC were not significantly different between the two groups. There were no significant differences in recurrence-free survival (P = 0.73) or overall survival (P = 0.68) between the two groups in univariate analysis. Receipt of AC was not a significant independent factor for survival, and completion of planned AC was a significant independent factor for recurrence-free survival and overall survival in multivariate analysis. CONCLUSIONS: The benefit of pancreatectomy for PDAC was the same between young and elderly patients. Completion of planned AC was important, and lowered-dose AC using S1 for elderly patients might be safe and therapeutically useful. PMID- 29383430 TI - Urea and urine are a viable and cost-effective nitrogen source for Yarrowia lipolytica biomass and lipid accumulation. AB - Yarrowia lipolytica is an industrial yeast that has been used in the sustainable production of fatty acid-derived and lipid compounds due to its high growth capacity, genetic tractability, and oleaginous properties. This investigation examines the possibility of utilizing urea or urine as an alternative to ammonium sulfate as a nitrogen source to culture Y. lipolytica. The use of a stoichiometrically equivalent concentration of urea in lieu of ammonium sulfate significantly increased cell growth when glucose was used as the carbon source. Furthermore, Y. lipolytica growth was equally improved when grown with synthetic urine and real human urine. Equivalent or better lipid production was achieved when cells are grown on urea or urine. The successful use of urea and urine as nitrogen sources for Y. lipolytica growth highlights the potential of using cheaper media components as well as exploiting and recycling non-treated human waste streams for biotechnology processes. PMID- 29383433 TI - Volumetric assessment of tumor size changes in pediatric low-grade gliomas: feasibility and comparison with linear measurements. AB - PURPOSE: We report a retrospective comparison between bi-dimensional RANO criteria and manual volumetric segmentation (MVS) in pediatric low-grade gliomas. METHODS: MRI FLAIR or T1 post contrast images were used for assessment of tumor response. Seventy patients were included in this single center study, for each patient two scans were assessed ("time 0" and "end of therapy") and response to therapy was evaluated for both methods. Inter-reader variability and average time for volumetric assessment were also calculated. RESULTS: Fourteen (20%) of the 70 patients had discordant results in terms of response assessment between the bi dimensional measurements and MVS. All volumetric response assessments were in keeping with the subjective analysis of tumor (radiology report). Of the 14 patients, 6 had stable disease (SD) on MVS and progressive disease (PD) on 2D assessment, 5 patients had SD on MVS and partial response (PR) on 2D assessment, 2 patients had PD on MVS and SD on 2D assessment, and 1 patient had PR on MVS and SD on 2D analysis. The number of discordant results rises to 21(30%) if minor response is integrated in the response assessment. MVS was relatively fast and showed high inter-reader concordance. CONCLUSION: Our analysis shows that therapeutic response classification may change in a significant number of children by performing a volumetric tumor assessment. Furthermore, MVS is not particularly time consuming and has very good inter-reader concordance. PMID- 29383434 TI - Age-related early/late variations of functional connectivity across the human lifespan. AB - PURPOSE: Many questions remain regarding how the brain develops, matures, and ages across the lifespan. The functional connectivity networks in the resting state brain can reflect many of the characteristic changes in the brain that are associated with increasing age. Functional connectivity has been shown to be time dependent over the course of a lifespan and even over the course of minutes. The lifespan strategies of all cognitive networks and how dynamic functional connectivity is associated with age are unclear. METHODS: In this paper, studies employing both linear and quadratic models to define new specific lifespan strategies, including early/late increase/decrease models, were conducted to explore the lifespan functional changes. A large data sample was retrieved from the publicly available data from the Nathan Kline Institute (N = 149 and ages 9 85). Both static and dynamic functional connectivity indexes were calculated including the static functional connectivity, the mean of the dynamic functional connectivity and variations in dynamic functional connectivity. RESULTS: The between-network connectivity results revealed early increases in the default-mode (DF) and cingulo-opercular network (CO)-associated network connectivities and a late increase in the fronto-parietal (FP)-associated network connectivity. These results depicted various lifespan strategies for different development stages and different cognitive networks across the lifespan. Additionally, the static FC and mean dynamic FC exhibited consistent results, and their variation exhibited a constant decrease with age across the entire age range. CONCLUSION: These results (FDR-corrected p value < 0.05) suggest that the early/late variations in lifespan strategies could reflect an association between varied and complex circumstances and brain development. PMID- 29383435 TI - Fibrolipomatous hamartomas of the median nerve in infancy and early childhood imaging hallmarks, symptomatology, and treatment. AB - : A fibrolipomatous hamartoma (FLH) is a rare lesion leading to an enlargement of the affected nerve and commonly manifests at the median nerve. Symptomatic patients are mostly adolescents or adults. In children below 10 years, this entity is rather unknown and likely to be misdiagnosed. We report three children with FLH, two severely and one mildly symptomatic, all below 4 years of age at the time of first presentation. Two of three children were initially misdiagnosed. We provide a review of the pertinent clinical and radiological findings of the entity. Two patients had a characteristic macrodactyly. The two symptomatic children underwent surgical carpal tunnel decompression. The intervention relived their symptoms with a long-lasting effect. Surgical reduction of the hamartoma mass is not indicated and medical treatment non existent. CONCLUSION: A symptomatic FLH of the median nerve is rare in children below the age of 5 years but has to be kept in mind as differential diagnosis in case of wrist and/or palm swelling, macrodactyly, and pain in hand or forearm. MRI is diagnostic, with very characteristic features, which can also be identified in high-resolution nerve ultrasound. This article aims to increase the knowledge about the entity including the diagnostic features and the management options. What is Known: * Fibrolipomatous hamartomas (FLHs) of the median nerve are rare, possibly associated with macrodactyly and tissue growth at the wrist and thenar side of the palm. * An associated carpal tunnel syndrome typically occurs, if at all, in adulthood. What is New: * We describe two children below 4 years with symptomatic carpal tunnel syndrome, experiencing a long-lasting favorable outcome after carpal tunnel decompression. In this age group, only one other child undergoing surgery has been published so far. * MRI and high resolution ultrasound demonstrate the characteristic features of FLHs and are the diagnostic modalities of choice. Biopsy is not recommended. PMID- 29383436 TI - Knowledge of allergies and performance in epinephrine auto-injector use: a controlled intervention in preschool teachers. AB - : Epinephrine auto-injectors are used for first aid in anaphylactic emergencies by non-healthcare professionals, e.g., (pre-)school teachers. We developed an education session for preschool teachers addressing allergies, anaphylactic emergencies, and administering auto-injectors. We assessed their attitudes and knowledge in allergies and anaphylactic emergency by a questionnaire and monitored their practical performance in administering auto-injectors before the education session, directly after, and 4-12 weeks after the session. From 75 teachers giving their consent to participate, 81% had children with allergies under their supervision and 3% had already administered medication from an available rescue kit. The knowledge of triggers of allergies increased from 9 to 55% directly and to 33% 4-12 weeks after the session (both p < 0.001, compared to baseline). Directly after the session, the number of teachers who felt well prepared for an anaphylactic emergency rose from 11 to 88%, which decreased to 79% 4-12 weeks thereafter (each p < 0.001). The number of auto-injector administrations without any drug-related problems increased from 3 to 35% directly after the session and shrunk to 16% 4-12 weeks afterwards (both p < 0.025). CONCLUSION: A single education session substantially improved preschool teachers' attitudes and knowledge in allergies and anaphylactic emergencies. Additionally, their practical performance in auto-injector administration increased. What is Known: * Food allergies are increasing among children. * The knowledge about allergies and anaphylactic emergencies is poor. What is New: * The proportion of teachers who felt well-prepared for an anaphylactic emergency increased after a single education session. * The proportion of auto-injector administrations without any drug-related problems additionally increased due to an education session. PMID- 29383437 TI - Is the presence of endometriosis associated with a survival benefit in pure ovarian clear cell carcinoma? AB - BACKGROUND: The purpose of this study was to compare the prognoses of women with pure ovarian clear cell carcinoma (OCCC) arising from endometriosis to those of women with pure OCCC not arising from endometriosis treated in the same manner. METHODS: A dual-institutional, retrospective database review was performed to identify patients with pure OCCC who were treated with maximal or optimal cytoreductive surgery (CRS) followed by paclitaxel/carboplatin chemotherapy between January 2006 and December 2016. Patients were divided into two groups according to the detection of cancer arising in endometriosis or not, on the basis of pathological findings. Demographic, clinicopathological, and survival data were collected, and prognosis was compared between the two groups. RESULTS: Ninety-three women who met the inclusion criteria were included. Of these patients, 48 (51.6%) were diagnosed with OCCC arising in endometriosis, while 45 (48.4%) had no concomitant endometriosis. OCCC arising in endometriosis was found more frequently in younger women and had a higher incidence of early stage disease when compared to OCCC patients without endometriosis. The 5-year overall survival (OS) rate of the patients with OCCC arising in endometriosis was found to be significantly longer than that of women who had OCCC without endometriosis (74.1 vs. 46.4%; p = 0.003). Although univariate analysis revealed the absence of endometriosis (p = 0.003) as a prognostic factor for decreased OS, the extent of CRS was identified as an independent prognostic factor for both recurrence-free survival (hazard ratio (HR) 8.7, 95% confidence interval (CI) 3.15-24.38; p < 0.001) and OS (HR 11.7, 95% CI 3.68-33.71; p < 0.001) on multivariate analysis. CONCLUSION: Our results suggest that endometriosis per se does not seem to affect the prognosis of pure OCCC. PMID- 29383438 TI - A cohort study on self-reported role stressors at work and poor sleep: does sense of coherence moderate or mediate the associations? AB - AIM: The aim of the present study was to examine the bidirectional associations between subjective role ambiguity and role conflicts at work, respectively, and self-reported sleep 2 years later. In addition, we also examine whether sense of coherence (SOC) moderate or mediate the association between role stressors and poor sleep and between poor sleep and role stressors. METHODS: We used questionnaire data collected in 2006 and 2008 from the Workplace Bullying and Harassment cohort. In 2006, 3363 responded to the questionnaire and in 2008 1671 responded. In total, 1569 participants responded in both 2006 and 2008 to the questions on role stressors (in terms of role ambiguity and role conflicts at work) and sleep problems in both 2006 and 2008. Sleep problems were assessed with the awakening index (AWI) and the disturbed sleep index (DSI). Moderation and mediation analyses of the association were estimated using structural equation modelling. RESULTS: We found a prospective association between role stressors and sleep problems [beta values were 0.07 (95% CI 0.03-0.11) and 0.05 (CI 0.01-0.10) for DSI and AWI, respectively] when adjusting for sleep problems at baseline, age, sex, and life style factors (i.e. alcohol, smoking, and leisure time physical activity). SOC moderated the association showing that participants with lower SOC scores who reported higher role ambiguity reported sleep problems to a higher extent than participants with high SOC scores. SOC also mediated the association between role stressors and sleep problems. We also found support for sleep problems at baseline and role stressors 2 years later [DSI 0.04 (CI 0.00 0.08) and 0.15 (CI 0.09-0.21)] for role ambiguity and role conflicts, respectively. Similar results were observed for AWI. CONCLUSION: Subjective role stressors were prospectively associated with sleep problems. Yet, sleep problems could also prospectively predict subjective role stressors (i.e. reverse causation). The analyses also showed that SOC may be regarded as both a mediating and a moderating factor of the association between subjective role conflicts and poor sleep. We found that SOC moderated the prospective association so participants with low SOC report more sleep problems with subjective role conflicts compared to participants with high SOC. Finally, we also found SOC mediated the prospective association between subjective role stressors and sleep problems and the reverse association. PMID- 29383439 TI - Impact of generalized anxiety disorder (GAD) on prehospital delay of acute myocardial infarction patients. Findings from the multicenter MEDEA study. AB - BACKGROUND: Anxiety has been identified as a cardiac risk factor. However, less is known about the impact of generalized anxiety disorder (GAD) on prehospital delay during an acute myocardial infarction (AMI). This study assessed the impact of GAD on prehospital delay and delay related cognition and behavior. METHODS: Data were from the cross-sectional Munich examination of delay in patients experiencing acute myocardial infarction (MEDEA) study with a total of 619 ST elevated myocardial infarction (STEMI) patients. Data on socio-demographic, clinical and psycho-behavioral characteristics were collected at bedside. The outcome was assessed with the Generalized Anxiety Disorder scale (GAD-7). A GAD-7 score greater than or equal to 10 indicates general anxiety disorder. RESULTS: A total of 11.47% (n = 71) MI patients suffered from GAD. GAD was associated with decreased odds of delay compared to patients without GAD (OR 0.58, 95% CI 0.35 0.96), which was more significant in women (112 vs. 238 min, p = 0.02) than in men (150 vs. 198 min, p = 0.38). GAD was highly correlated with acute anxiety (p = 0.004) and fear of death (p = 0.005). Nevertheless, the effect remained significant after controlling for these two covariates. GAD patients were more likely to perceive a higher cardiovascular risk (OR 2.56, 95% CI 1.37-4.76) in 6 months before MI, which leads to the higher likelihood of making self-decision to go to the hospital (OR 2.68, 95% CI 1.48-4.85) in the acute phase. However, GAD was also highly associated with impaired psychological well-being, stress and fatigue (p < 0.0001). CONCLUSIONS: In AMI patients, GAD was independently associated with less prehospital delay, but led to an impaired psychological state. PMID- 29383440 TI - [Revised version of the statement by the DGRh on biosimilars-update 2017]. AB - The treatment of rheumatic diseases with bioloics has significantly improved the prognosis of patients. Currently, there are 13 preparations available in Germany for the treatment of patients with inflammatory rheumatic diseases. These original preparations generally have-depending on the individual country-15 years of patent protection. As soon as the patent has expired, approved biosimilars can be brought into use. For the approval of a biosimilar, authorities such as the European Medical Agency or the American Food and Drug Administration require proof of the best possible comparability with respect to efficacy and safety in comparison to the original or reference product. Since 2015, biosimilars of inifliximab, adalimumab, etanercept and rituximab have been granted approval in the European Union, the USA, Japan and in other countries. Further biosimilar products for these reference products are in development for treatment in rheumatology. From a societal and medical point of view, this opens up the possibility to increase the availability of biopharmaceutical products for patients through lower prices. In Germany, this possibility has already occurred statutory health insurance physicians have introduced quotas for biosimilars, which will ultimately decrease spending and healthcare costs. This can lead to price reductions of the original products, which has already happened in Germany. Biosimilars can be prescribed for new patients or as a change from the original to the generic drug. When switching, a distinction is made between individual switching (interchangeability), which is made in individual consultation between the physician and the patient, and nonmedical switching (substitution) made at the societal or governmental level, which is made in the context of health care cost containment, and then, for example, implemented at the pharmacy level. Preliminary data from Norway and Denmark are available for substitution on the basis of results from large studies or registries in which systematic changes were made. The previous conclusion was that this does not lead to new problems for the patients. The German Society for Rheumatology recognizes the advantages of introducing biosimilars in Germany, but recommends that their use be based primarily on a joint decision by the treating physician and patient. PMID- 29383441 TI - Intra-ligamentary autologous conditioned plasma and healing response to treat partial ACL ruptures. AB - INTRODUCTION: Conservative treatment of partial ACL ruptures is associated with a high failure rate, and often patients undergo ACL reconstruction. ACL preservation by trephination of the ACL origin and application of Autologous Conditioned Plasma (ACP) seems to be an intriguing new treatment option to favour ACL tissue healing and avoid traditional reconstruction. The aim of this study was to describe the mid-term outcomes of this new ACL preserving technique. MATERIALS AND METHODS: Twenty-four patients (mean age 41.8 years) affected by partial rupture of one or both ACL bundles were included in the present trial. The partial ACL tears were arthroscopically assessed and classified according to a new five step grading system. All patients were treated by trephination of the femoral ACL stump and intra-ligamentary application of ACP. The postoperative outcome was evaluated by both subjective scores and stability testing up to a mean of 25.1 months' follow-up. Adverse events and failure rate were also documented. RESULTS: Clinical outcome was good to excellent with IKDC subjective 82.7 (SD 11.8), Lysholm 87.6 (SD 8.1), Tegner 5.3 (SD 2.1), Cincinnati 88.7 (SD 14.8). The failure rate (i.e. persisting knee instability assessed clinically or by rolimeter) was 12.5%. At objective measurements, knee joints showed a firm endpoint in Lachman test, negative pivot shift phenomenon and a significant reduction in AP-laxity compared to pre-operative status by rolimeter testing (p = 0.002). Return to sport practice was achieved after mean 4.8 months (SD 4.1). CONCLUSIONS: ACL stump trephination and concomitant intra-ligamentary application of ACP revealed promising results at mid-term follow-up to treat partial ACL lesions. PMID- 29383442 TI - Diagnostic performance of magnifying endoscopy with narrow-band imaging in differentiating neoplastic colorectal polyps from non-neoplastic colorectal polyps: a meta-analysis. AB - Colorectal polyps are commonly seen in colonoscopy and the management of neoplastic polyps and non-neoplastic polyps are different. It is necessary to distinguish neoplastic polyps from non-neoplastic polyps in real-time. Therefore, we conducted a meta-analysis to assess the diagnostic accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) in diagnosing neoplastic colorectal polyps from non-neoplastic colorectal polyps. PubMed and EMBASE were searched for trials that used magnifying endoscopy with ME-NBI for diagnosing neoplastic colorectal polyps. Sixteen articles and 20 fourfold tables were obtained. Sensitivity (Sen), specificity (Spe), positive likelihood ratios (+ LRs), negative likelihood ratios (- LRs) and diagnostic odds ratios (DORs) were calculated. A summary receiver-operating characteristic (SROC) curve was constructed, and the area under the ROC curve (AUC) was calculated. We performed subgroup analyses based on polyp size and assessment criteria: (1) According to data extracted from 20 fourfold tables, the pooled Sen and Spe of ME-NBI for diagnosing neoplastic colorectal polyps < 10 mm were 0.94 (95% CI 0.92-0.95) and 0.76 (95% CI 0.72-0.80),respectively. The pooled Sen and Spe of ME-NBI for diagnosing all neoplastic polyps were 0.98 (95% CI 0.98-0.99) and 0.88 (95% CI 0.85-0.90), respectively. (2) Data pertaining to the following three assessment methods were analysed from 15 fourfold tables: surface pattern (SP), vessel pattern (VP) and the combination of SP and VP. The AUCs for these assessment criteria were 0.9533, 0.9518 and 0.9954, respectively. Conclusions were made that ME-NBI has high diagnostic accuracy in diagnosing neoplastic colorectal polyps based on the combination of SP with VP and is helpful in making real-time diagnoses. PMID- 29383443 TI - Establishment and validation of a novel risk model for estimating time to first treatment in 120 patients with chronic myelomonocytic leukaemia. AB - Chronic myelomonocytic leukaemia is a rare disease and data on the treatment are often extrapolated from myelodysplastic syndrome studies. Although several scores exist for the prognosis of overall survival in chronic myelomonocytic leukaemia, so far there is no designated score for the prediction of the time to first treatment. We tested clinical parameters and cytogenetic information for their ability to predict the time to first treatment in our single center cohort of 55 unselected consecutive chronic myelomonocytic leukaemia patients. In multivariate analysis we identified elevated lactate dehydrogenase (>=223 U/l), higher bone marrow blast percentage (>=7.5%) and thrombocytopenia (<55 G/l) at initial diagnosis as the most relevant parameters for the time to first treatment. Using these three parameters we developed a risk score that efficiently estimates the time to treatment initiation with azacitidine or hydroxyurea (p < 0.001; log rank). In the high-risk group (>=2 risk factors) 85% of patients required treatment within 1 year, whereas this was the case in 48% in the intermediate risk (1 risk factor) and in 0% in the low-risk group (0 risk factors). Our risk model was validated in an external test cohort of 65 patients and may serve as a simplified and easily applicable tool for identifying patients who may not require early treatment initiation. PMID- 29383444 TI - The role of macrophages during acute kidney injury: destruction and repair. AB - Acute kidney injury (AKI) is defined by a rapid decline in renal function. Regardless of the initial cause of injury, the influx of immune cells is a common theme during AKI. While an inflammatory response is critical for the initial control of injury, a prolonged response can negatively affect tissue repair. In this review, we focus on the role of macrophages, from early inflammation to resolution, during AKI. These cells serve as the innate defense system by phagocytosing cellular debris and pathogenic molecules and bridge communication with the adaptive immune system by acting as antigen-presenting cells and secreting cytokines. While many immune cells function to initiate inflammation, macrophages play a complex role throughout AKI. This complexity is driven by their functional plasticity: the ability to polarize from a "pro-inflammatory" phenotype to a "pro-reparative" phenotype. Importantly, experimental and translational studies indicate that macrophage polarization opens the possibility to generate novel therapeutics to promote repair during AKI. A thorough understanding of the biological roles these phagocytes play during both injury and repair is necessary to understand the limitations while furthering the therapeutic application. PMID- 29383445 TI - Neutrophils in tissue injury and repair. AB - As one of the first defenders of innate immune response, neutrophils make a rapid and robust response against infection or harmful agents. While traditionally regarded as suicidal killers that cause collateral tissue damage, recent findings on neutrophil extracellular trap formation, heterogeneity and plasticity and novel reparative functions have expanded our understanding of their diverse roles in health and disease. This review summarizes our current understanding of neutrophil-associated tissue injury, highlighting the emerging roles of neutrophil extracellular traps. This review will also focus on scrutinizing the roles of neutrophils in tissue repair and regeneration and will examine data on unexpected aspects of involvement of neutrophils in regulating normal tissue homeostasis. PMID- 29383447 TI - [Visual recovery as the target for glaucoma]. AB - BACKGROUND: Visual recovery is an established but poorly studied phenomenon in glaucoma. OBJECTIVE: To provide insights into functional recovery of retinal ganglion cells (RGCs) with a view to providing information on the development of forms of treatment that improve RGC function after injury. METHOD: A model of recoverable RGC function in the mouse eye, induced by short-term elevation of intraocular pressure (IOP). RESULTS: The RGCs manifest near complete functional recovery after a prolonged period of dysfunction following acute IOP elevation. Increasing age and a high fat diet were subsequently found to impair recovery, whereas exercise substantially improved recovery such that older mice recovered in a similar way to young mice. CONCLUSION: Injured RGCs have the capacity to restore function after periods of functional impairment. Therapies that specifically target injured RGCs and enhance their capacity to recover function may provide a new approach for treating glaucoma. PMID- 29383446 TI - The neurobiology of impulse control disorders in Parkinson's disease: from neurotransmitters to neural networks. AB - Impulse control disorders (ICD) are common neuropsychiatric disorders that can arise in Parkinson's disease (PD) patients after commencing dopamine replacement therapy. Approximately 15% of all patients develop these disorders and many more exhibit subclinical symptoms of impulsivity. ICD is thought to develop due to an interaction between the use of dopaminergic medication and an as yet unknown neurobiological vulnerability that either pre-existed before PD onset (possibly genetic) or is associated with neural alterations due to the PD pathology. This review discusses genes, neurotransmitters and neural networks that have been implicated in the pathophysiology of ICD in PD. Although dopamine and the related reward system have been the main focus of research, recently, studies have started to look beyond those systems to find new clues to the neurobiological underpinnings of ICD and come up with possible new targets for treatment. Studies on the whole-brain connectome to investigate the global alterations due to ICD development are currently lacking. In addition, there is a dire need for longitudinal studies that are able to disentangle the contributions of individual (genetic) traits and secondary effects of the PD pathology and chronic dopamine replacement therapy to the development of ICD in PD. PMID- 29383448 TI - A comparison of CRISPR/Cas9 and siRNA-mediated ALDH2 gene silencing in human cell lines. AB - Gene knockdown and knockout using RNAi and CRISPR/Cas9 allow for efficient evaluation of gene function, but it is unclear how the choice of technology can influence the results. To compare the phenotypes obtained using siRNA and CRISPR/Cas9 technologies, aldehyde dehydrogenase 2 (ALDH2) was selected as an example. In this study, we constructed one HepG2 cell line with a homozygous mutation in the fifth exon of ALDH2 (ALDH2-KO1 cell) using the eukaryotic CRISPR/Cas9 expression system followed by the limited dilution method and one HepG2 cell line with different mutations in the ALDH2 gene (ALDH2-KO2 cell) using the lentivirus CRISPR/Cas9 system. Additionally, one ALDH2-knockdown (KD) HepG2 cell line was created using siRNA. The reproducibility of these methods was further verified in the HEK293FT cell line. We found that the mRNA expression level of ALDH2 was significantly decreased and the protein expression level of ALDH2 was completely abolished in the ALDH2-KO cell lines, but not in ALDH2-KD cells. Furthermore, the functional activity of ALDH2 was also markedly disrupted in the two ALDH2-KO cell lines compared with ALDH2-KD and wild-type cells. The lack of ALDH2 expression mediated by CRIPSR/Cas9 resulted in a more dramatic increase in the cellular susceptibility to chemical-induced reactive oxygen species generation, cytotoxicity, apoptosis, and inflammation, especially at low concentrations compared with ALDH2-KD and WT cells. Therefore, we consider the gene knockout cell line created by CRISPR/Cas9 to be a more useful tool for identifying the function of a gene. PMID- 29383449 TI - No difference in the prevalence of Alzheimer-type neurodegenerative changes in the brains of suicides when compared with controls: an explorative neuropathologic study. AB - Suicide ranks among the leading causes of death for individuals of all ages with highest rates in the elderly. The cause of suicide is considered a multifactorial phenomenon. A variety of neurodegenerative diseases, notably Alzheimer's disease, or, more recently, tauopathies as frontotemporal lobar degeneration or chronic traumatic encephalopathy, has been suggested as risk factor for suicide. Accordingly, we hypothesized that neurodegenerative changes typical of these diseases should be more prevalent in the brains of suicides when compared with controls. Suicides from the German federal state of Hamburg (n = 162) were compared with age- and sex-matched controls who died of other cause. Neuropathological assessment included semiquantitative analysis of neuritic plaques and neurofibrillary tangles visualized with silver stains; in addition, quantitative immunohistochemical analysis of beta-amyloid load and counts of tau positive neurofibrillary tangles and neuropil threads was done. Univariate analysis and multivariable conditional logistic regression models did not show an effect of any parameter associated with the odds of committing suicide. On the contrary, after stratification for age, older suicide victims (over 48 years) showed lower beta-amyloid loads when compared to controls in the univariate analysis (suicides: 4.7 +/- 12.9; controls: 9.9 +/- 20.9; p = 0.031; r = - 0.17). In conclusion, neuropathological characteristics of Alzheimer's disease and common tauopathies associated with age seem to be of limited relevance for suicides. However, intact cognition when planning and carrying out complex acts may be of importance in the context of suicide. PMID- 29383451 TI - Chronic Myeloid Leukemia: What Is the Best Strategy to Start and Monitor Treatment Outside Academic Centers? AB - The introduction of tyrosine kinase inhibitors (TKI) has dramatically changed the outcome of chronic myeloid leukemia (CML). Over the last decade, imatinib positioned itself as the gold standard of care, until second-generation TKIs were introduced as first-line treatment. Multiple therapeutic options available today in CML make the decision of the first-line therapy a difficult choice. However, a gap still exists, in the management of CML outside academic centers. Important advances in molecular monitoring have been developed worldwide; nevertheless, monitoring in the "real world" continues to be a challenge in part because international scale (IS) standardized laboratories are not available worldwide, and also because physicians still have some resource barriers and lack of familiarity restricting guideline adoption and consider optimal molecular monitoring a challenge. This review addresses CML first-line treatment, monitoring aspects and giving practical advice, identifying prognostic factors, and guiding management of CML for non-academic centers. PMID- 29383450 TI - Genome-wide identification, classification, and expression of phytocyanins in Populus trichocarpa. AB - MAIN CONCLUSION: 74 phytocyanin genes were identified in the Populus trichocarpa genome. Phylogenetic analysis grouped the PC proteins into four subfamilies (UCs, PLCs, SCs, and ENODLs). Closely related PC proteins share similar motifs, implying similar functions. Expression profiles of PtPC genes were analyzed in response to drought and salt-stress. Phytocyanins (PCs) are blue copper proteins associated with electron carrier activity that have a large influence on plant growth and resistance. The majority of PCs are chimeric arabinogalactan proteins (AGPs). In this work, we identified 74 PC genes in Populus trichocarpa and analyzed them comprehensively. Based on the ligands composition of copper-binding sites, glycosylation state, the domain structure and spectral characteristics of PC genes, PCs were divided into four subfamilies [uclacyanins (UCs), plantacyanins (PLCs), stellacyanins (SCs) and early nodulin-like proteins (ENODLs)], and phylogenetic relationship analysis classified them into seven groups. All PtPCs are randomly distributed on 17 of the 19 poplar chromosomes, and they appear to have undergone expansion via segmental duplication. Eight PtPCs do not contain introns, and each group has a similar conserved motif structure. Promoter analysis revealed cis-elements related to growth, development and stress responses, and established orthology relationships of PCs between Arabidopsis and poplar by synteny analysis. Expression profile analysis and qRT PCR analysis showed that PtPCs were expressed widely in various tissues. Quantitative real-time RT-PCR analysis of PC genes expression in response to salt and drought stress revealed their stress-responses profiles. This work provides a theoretical basis for a further study of stress resistance mechanisms and the function of PC genes in poplar growth and development. PMID- 29383452 TI - Clinical and Pathologic Features of Primary Angiosarcoma of the Kidney. AB - PURPOSE OF REVIEW: Primary angiosarcoma of the kidney is extremely rare; hence, relatively little is known regarding its clinicopathologic features and prognosis. Herein, we review the literature on primary renal angiosarcoma with emphasis on the clinical and pathologic features. RECENT FINDINGS: Approximately 64 cases have been reported in the literature, and most cases occur in the 6th 7th decade with a strong male predominance. The aetiology is unknown. Patients present with flank pain, haematuria, abdominal mass and weight loss. A considerable number of patients develop metastatic disease at diagnosis or shortly afterwards. Grossly, the tumour comprises ill-defined haemorrhagic spongy masses often with necrosis. Microscopically, the tumour is composed of anastomosing capillary-sized vessels which are lined by malignant endothelial cells. The mainstay of treatment is surgery followed by radiation therapy with or without chemotherapy. Renal angiosarcomas are highly aggressive tumours with dismal outcome, and they must be distinguished from morphologically similar lesions of the kidney. PMID- 29383453 TI - Safety of the concomitant use of methotrexate and a prophylactic dose of trimethoprim-sulfamethoxazole. AB - The objective of this study was to investigate risk factors for cytopenia when a prophylactic dose of trimethoprim-sulfamethoxazole (TMP-SMX) was co-administered with methotrexate (MTX). Patients who received MTX with or without a prophylactic dose of TMP-SMX were included. Patients who received a therapeutic dose of TMP SMX were excluded. The MTX-alone and MTX with TMP-SMX groups (MTX group and MTX + TMP-SMX group, respectively) were matched in a 4:1 ratio according to age, creatinine level, mean corpuscular volume and MTX dose. Cytopenia was defined as a haemoglobin level decrease by > 2 g/dl, platelet count of < 150,000/mm3 or white blood cell count of < 3500/mm3. The Cox proportional hazards model was used to evaluate risk factors for cytopenia in patients administered with MTX. The incidence of cytopenia did not significantly differ between the MTX group and MTX + TMP-SMX group (5.0 vs 5.7%, p > 0.999). According to the Cox proportional hazards model, chronic liver disease (hazard ratio [HR] 5.829, 95% confidence interval [CI] 1.211-28.063, p = 0.028) was associated with an increased risk of cytopenia. However, the concomitant use of a prophylactic dose of TMP-SMX (HR 1.717, 95% CI 0.352-8.371, p = 0.504) was not significantly associated with an increased risk of cytopenia. Compared with the use of MTX alone, the concomitant use of MTX with a prophylactic dose of TMP-SMX was not significantly associated with an increased risk of cytopenia. Thus, a prophylactic dose of TMP-SMX can be safely used with MTX. PMID- 29383454 TI - Increased frequency of temporal acoustic window failure in rheumatoid arthritis: a manifestation of altered bone metabolism? AB - Assessment of intracranial vessels includes transcranial Doppler (TCD). TCD performance requires intact temporal acoustic windows (TAW). Failure of TAW (TAWF) is present in 8-20% of people. There have been no reports on TAWF in rheumatoid arthritis (RA). Altogether, 62 female RA patients were included. Among them, 20 were MTX-treated and biologic-free, 20 received infliximab, and 22 tocilizumab. The controls included 60 non-RA women. TAWF, temporal bone thickness, and texture were determined by ultrasound and CT. BMD and T-scores of multiple bones were determined by DEXA. Several bone biomarkers were assessed by ELISA. In RA, 54.8% of the patients had TAWF on at least one side. Neither TAW could be identified in 34% of RA subjects. In contrast, only 20.0% of control subjects had TAWF on either or both sides (p < 0.001). In RA vs controls, 53.0 vs 2.9% of subjects exerted the trilayer, "sandwich-like" structure of TAW (p < 0.001). Finally, in RA vs controls, the mean temporal bone thickness values of the right TAW were 3.58 +/- 1.43 vs 2.92 +/- 1.22 mm (p = NS), while those of the left TAW were 4.16 +/- 1.56 vs 2.90 +/- 1.16 mm (p = 0.001). There was close association between TAWF, bone thickness, and texture (p < 0.05). These TAW parameters all correlated with age; however, TAW failure and texture also correlated with serum osteoprotegerin. TAW bone thickness inversely correlated with hip BMD (p < 0.05). TAWF, thicker, and heterogeneous temporal bones were associated with RA. These features have been associated with bone loss and OPG production. Bone loss seen in RA may result in OPG release and stimulation of bone formation around TAW. PMID- 29383455 TI - Study of the radiologic features of Legionnaires' disease with mediastinal adenopathy: Legionella or lymphoma? AB - An index case of Legionnaires's disease with mediastinal adenopathy prompted us to review our recent experience with Legionnaires' disease to determine the incidence of mediastinal adenopathy of this finding in Legionnaires' disease. We reviewed the radiographic findings of 90 hospitalized adults with Legionnaires' disease from 2015 to 2017. Excluded were 11 patients with mediastinal adenopathy due to non-Legionnaires' disease causes, e.g., lymphoma. Thirty-seven of the remaining patients had both chest films and chest computed tomography (CT) scans. Of the 37 Legionnaires' disease cases, 13/37 (35%) had mediastinal adenopathy and 8/27 (24%) also had unilateral hilar adenopathy. These chest CT findings were not seen on chest films. Chest CT scans are needed to detect mediastinal adenopathy in Legionnaires' disease. Mediastinal adenopathy may be due to Legionnaires' disease or a malignancy. Some findings in Legionnaires' disease are also present in mediastinal adenopathy due to lymphomas, e.g., highly elevated erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and ferritin. Hospitalized adults with Legionnaires' disease and mediastinal adenopathy should have serial chest CT scans to monitor resolution of the mediastinal adenopathy. In hospitalized adults with otherwise unexplained persistent mediastinal adenopathy, they should be considered as being due to another etiology, e.g., lymphoma, until proven otherwise. PMID- 29383456 TI - Continuous culture techniques as simulators for standard cells: Jacques Monod's, Aron Novick's and Leo Szilard's quantitative approach to microbiology. AB - Continuous culture techniques were developed in the early twentieth century to replace cumbersome studies of cell growth in batch cultures. In contrast to batch cultures, they constituted an open concept, as cells are forced to proliferate by adding new medium while cell suspension is constantly removed. During the 1940s and 1950s new devices have been designed-called "automatic syringe mechanism," "turbidostat," "chemostat," "bactogen," and "microbial auxanometer"-which allowed increasingly accurate quantitative measurements of bacterial growth. With these devices cell growth came under the external control of the experimenters and thus accessible for developing a mathematical theory of growth kinetics-developed mainly by Jacques Monod, Aron Novick and Leo Szilard in the early 1950s and still in use today. The paper explores the development of continuous culture devices and claims that these devices are simulators for standard cells following specific requirements, in particular involving mathematical constraints in the design and setting of the devices as well as experiments. These requirements have led to contemporary designs of continuous culture techniques realizing a specific event-based flow algorithm able to simulate directed evolution and produce artificial cells and microorganisms. This current development is seen as an alternative approach to today's synthetic biology. PMID- 29383457 TI - Adverse drug reactions triggered by the common HLA-B*57:01 variant: virtual screening of DrugBank using 3D molecular docking. AB - BACKGROUND: Idiosyncratic adverse drug reactions have been linked to a drug's ability to bind with a human leukocyte antigen (HLA) protein. However, due to the thousands of HLA variants and limited structural data for drug-HLA complexes, predicting a specific drug-HLA combination represents a significant challenge. Recently, we investigated the binding mode of abacavir with the HLA-B*57:01 variant using molecular docking. Herein, we developed a new ensemble screening workflow involving three X-ray crystal derived docking procedures to screen the DrugBank database and identify potentially HLA-B*57:01 liable drugs. Then, we compared our workflow's performance with another model recently developed by Metushi et al., which proposed seven in silico HLA-B*57:01 actives, but were later found to be experimentally inactive. METHODS: After curation, there were over 6000 approved and experimental drugs remaining in DrugBank for docking using Schrodinger's GLIDE SP and XP scoring functions. Docking was performed with our new consensus-like ensemble workflow, relying on three different X-ray crystals (3VRI, 3VRJ, and 3UPR) in presence and absence of co-binding peptides. The binding modes of HLA-B*57:01 hit compounds for all three peptides were further explored using 3D interaction fingerprints and hierarchical clustering. RESULTS: The screening resulted in 22 hit compounds forecasted to bind HLA-B*57:01 in all docking conditions (SP and XP with and without peptides P1, P2, and P3). These 22 compounds afforded 2D-Tanimoto similarities being less than 0.6 when compared to the structure of native abacavir, whereas their 3D binding mode similarities varied in a broader range (0.2-0.8). Hierarchical clustering using a Ward Linkage revealed different clustering patterns for each co-binding peptide. When we docked Metushi et al.'s seven proposed hits using our workflow, our screening platform identified six out of seven as being inactive. Molecular dynamic simulations were used to explore the stability of abacavir and acyclovir in complex with peptide P3. CONCLUSIONS: This study reports on the extensive docking of the DrugBank database and the 22 HLA-B*57:01 liable candidates we identified. Importantly, comparisons between this study and the one by Metushi et al. highlighted new critical and complementary knowledge for the development of future HLA-specific in silico models. PMID- 29383458 TI - Nutrition and Cardiovascular Disease-an Update. AB - PURPOSE OF REVIEW: This review summarizes recent developments in nutrition and cardiovascular disease (CVD) prevention. RECENT FINDINGS: Contemporary dietary guidance recommends healthy dietary patterns with emphasis on food-based recommendations because the totality of the diet (i.e., the combinations and quantities of foods and nutrients consumed) is an important determinant of health. In many guidelines, recommendations are still made for saturated fat, added sugar, sodium, and dietary cholesterol because these are over-consumed by many people and are related to chronic disease development. Epidemiological research illustrates the importance of considering the total diet and the interrelatedness of nutrients in a dietary pattern. Traditionally, epidemiological research focused on individual nutrients in isolation, which can result in erroneous conclusions. An example of this, which has led to substantial controversy, is the evidence from studies evaluating the association between saturated fat and CVD without considering the replacement nutrient. Another controversial topic is the relationship between dietary cholesterol and CVD, which is confounded by saturated fat intake. Finally, the totality of evidence shows that high sodium intake is associated with greater CVD risk; however, some epidemiological research has suggested that a low-sodium intake is detrimental, which has caused some controversy. Overall, this reductionist approach has led to a debate about recommendations for saturated fat, cholesterol, and sodium. However, if approaches that accounted for the interrelatedness of nutrients had been taken, it is likely that there would be less controversy about these nutrients. To encourage dietary pattern-based approaches and consideration of total intake, dietary guidelines should emphasize food-based recommendations that meet nutrient targets. Thus, nutrient targets should underpin food-based dietary guidelines, and recommended dietary patterns should comply with nutrient-based targets. The evidence reviewed shows that it is imperative to consider total dietary patterns for CVD prevention. Dietary guidance should be aligned with nutrient targets and recommendations should be food and dietary pattern based. PMID- 29383459 TI - Alterations in mitochondrial respiration and reactive oxygen species in patients poisoned with carbon monoxide treated with hyperbaric oxygen. AB - BACKGROUND: Carbon monoxide (CO) poisoning is the leading cause of poisoning mortality and morbidity in the USA. Carboxyhemoglobin (COHb) levels are not predictive of severity or prognosis. At this time, the measurement of mitochondrial respiration may serve as a biomarker in CO poisoning. The primary objective of this study was to assess changes in mitochondrial function consisting of respiration and generation of reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) obtained from patients with CO poisoning. METHODS: PBMCs from patients having confirmed CO exposure treated with hyperbaric oxygen or HBO (CO group) and healthy controls (control group) were analyzed with high-resolution respirometry. PBMCs were placed in a 2-ml chamber at a final concentration of 3-4 * 106 cells/ml to simultaneously obtain both respiration and hydrogen peroxide (H2O2) production. In the CO group, we performed measurements before and after patients underwent their first HBO treatment. RESULTS: We enrolled a total of 17 subjects, including 7 subjects with confirmed CO poisoning and 10 subjects in the control group. The CO group included five (71.4%) men and two (28.6%) women having a median COHb of 28%. There was a significant decrease in respiration as measured in pmol O2 * s- 1 * 10- 6 PBMCs in the CO group (pre-HBO) when compared to the control group: maximal respiration (18.4 +/- 2.4 versus 35.4 +/- 2.8, P < 0.001); uncoupled Complex I respiration (19.8 +/- 1.8 versus 41.1 +/- 3.8, P < 0.001); uncoupled Complex I + II respiration (32.3 +/- 3.2 versus 58.3 +/- 3.1, P < 0.001); Complex IV respiration (43.5 +/- 2.9 versus 63.6 +/- 6.31, P < 0.05). There were also similar differences measured in the CO group before and after HBO treatment with an overall increase in respiration present after treatment. We also determined the rate of H2O2 production simultaneously with the measurement of respiration. There was an overall significant increase in the H2O2 production in the CO group after HBO treatment when compared to prior HBO treatment and the control group. CONCLUSIONS: In this study, PBMCs obtained from subjects with CO poisoning have an overall decrease in respiration (similar H2O2 production) when compared to controls. The inhibition of Complex IV respiration is from CO binding leading to a downstream decrease in respiration at other complexes. PBMCs obtained from CO poisoned individuals immediately following initial HBO therapy displayed an overall increase in both respiration and H2O2 production. The study findings demonstrate that treatment with HBO resulted in improved cellular respiration but a higher H2O2 production. It is unclear if the increased production of H2O2 in HBO treatment is detrimental. PMID- 29383460 TI - Patterns of Asexuality in China: Sexual Activity, Sexual and Romantic Attraction, and Sexual Desire. AB - This study examined patterns of asexuality in Chinese asexual people in terms of sexual activities, sexual/romantic attraction, and sexual desire. The sample included 227 (64 men and 163 women) asexual participants and 57 (26 men and 31 women) uncertain asexual participants recruited from social networks for asexual people. The control group included 217 (115 men and 102 women) heterosexual participants recruited from general social networks. Participants scoring 40 or higher on the Asexuality Identification Scale were classified as asexual. Asexual participants reported having less frequent masturbation, sexual intercourse experience, and sexual and romantic attraction compared to heterosexual participants. Lower sexual attraction among asexuals indicated that "people who experience little or no sexual attraction" would be a more appropriate definition of asexuality. The pattern of uncertain asexual participants' sexual/romantic attraction and sexual desire was intermediate between heterosexual and asexual participants. Asexual participants scored significantly lower on dyadic sexual desire and slightly lower on solitary sexual desire than heterosexual participants. There were significant differences in sexual activities and solitary sexual desire among romantic orientation categories. Homoromantic participants showed higher dyadic sexual desire and were more likely to engage in masturbation, indicating the heterogeneity among asexual people. The findings indicated that Chinese asexual people showed similar patterns of asexuality as in Western nations. Specifically, asexual people have little or no sexual attraction, non-partner-orientated sexual desire, and are heterogeneous in sexual activities and sexual desire. This implies similar mechanisms underlying the etiology of asexuality across cultures. PMID- 29383461 TI - Corynebacterium fournierii sp. nov., isolated from the female genital tract of a patient with bacterial vaginosis. AB - Strain Marseille-P2948T, a novel Gram-positive, catalase-positive bacterium was isolated from a vaginal sample of a patient with bacterial vaginosis. It was characterised using the taxonogenomic approach. Phylogenetic analysis revealed that the 16S rRNA and the rpoB genes exhibit 98.7 and 93.4% similarity, respectively, with those of Corynebacterium ureicelerivorans strain IMMIB RIV 301T. Biochemical tests of strain Marseille-P2948T gave results that were similar to those of other validly named Corynebacterium species, whereas chemotaxonomic tests showed the presence of C16:0, C18:1n9, C18:0, and C18:2n6 in the fatty acid profile. The draft genome of strain Marseille-P2948T is 2,383,644 bp long in size with a G+C content of 65.03%. Of the 2210 predicted genes, 2147 are protein coding genes and 63 are RNAs. Based on phenotypic, phylogenic and genomic results, it was concluded that the isolate represents a new species within the genus Corynebacterium. The name Corynebacterium fournierii sp. nov. is proposed and the type strain is Marseille-P2948T (= CSUR P2948 = DSM 103271). PMID- 29383462 TI - Amycolatopsis cappadoca sp. nov., isolated from soil. AB - An Amycolatopsis strain, designated AG28T, isolated from a soil sample collected from Acigol, Kapadokya, Turkey, was examined using a polyphasic taxonomic approach. Phylogenetic analysis based on an almost-complete 16S rRNA gene sequence showed that the strain is closely related to the type strains of Amycolatopsis deserti GY024T (97.1%), Amycolatopsis taiwanensis 0345 M-7T (96.9%) and Amycolatopsis pigmentata TT00-43T (96.9%). Strain AG28T was found to have chemotaxonomic and phylogenetic properties consistent with its classification in the genus Amycolatopsis. The strain was found to contain meso-diaminopimelic acid as the diagnostic diamino acid. The whole cell sugars identified were rhamnose, ribose, arabinose and galactose. The polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. The predominant menaquinone was identified as MK-9(H4). Major fatty acids (> 10%) were identified as iso-C15:0, iso-C16:0 and iso-C16:0 2OH. Consequently, on the basis of the data from this polyphasic study, it is proposed that strain AG28T represents a novel Amycolatopsis species for which the name Amycolatopsis cappadoca sp. nov. is proposed. The type strain is AG28T (= KCTC 39884T = DSM 104280T). PMID- 29383463 TI - Primary desmoplastic small round cell tumor in the left orbit: a case report and literature review. AB - PURPOSE: Desmoplastic small round cell tumor is a rare malignant neoplasm that most often occurs in the abdomen or pelvis of young men. We herein describe a rare case of desmoplastic small round cell tumor arising from the left orbit in a 16-year-old male. METHODS AND RESULTS: A biopsy was performed and the histology showed the nests of tumor cells with small round cell morphology. The tumor cells showed immunopositivity for desmin, CD99, CD56, SMA, NSE, CgA, SYN, Ki67 and vimentin. Fluorescence in situ hybridization study using EWSR1 break-apart probe was positive for EWSR1 gene rearrangement. After complete surgical resection of the tumor, we did not find tumor recurrence or metastasis with one-year follow up. Furthermore, a review of the relevant English literature has been discussed. CONCLUSIONS: In the present study, for the first time, we report a case of desmoplastic small round cell tumor which is located in the orbital region. PMID- 29383464 TI - Patient-Centered Values and Experiences with Emergency Department and Mental Health Crisis Care. AB - Little is known about what patients value in psychiatric crisis services or how they compare community-based services with those received in the emergency department. Three focus groups (n = 27) were held of participants who had received psychiatric crisis services in emergency departments or a community mental health center. Participants described care experiences and preferences. Focus groups were audio recorded, transcribed, and coded using a value-based lens. Themes included appreciation for feeling respected, basic comforts, and shared decision-making as foundations of quality care. Participants preferred the community mental health center. Research should address long-term outcomes to motivate change in psychiatric crisis care. PMID- 29383465 TI - The feasibility of tricuspid annular plane systolic excursion performed by transesophageal echocardiography throughout heart surgery and its interchangeability with transthoracic echocardiography. AB - Tricuspid annular plane systolic excursion (TAPSE) is a robust measure of RV function, but the performance of transesophageal echocardiography (TEE) measured TAPSE during surgery is not well established. We aim to evaluate feasibility of various TEE views before, during and after surgery. Furthermore, we compare performance of individual TEE measurements depending on view and method (AMM- and M-mode as well as 2D) as well as TAPSE measured using TEE with transthoracic echocardiography (TTE) TAPSE. The study was conducted from January 2015 through September 2016. In 47 patients with normal left ventricular ejection fraction, TEE was prospectively performed during coronary artery bypass grafting surgery. TAPSE and tricuspid annulus tissue Doppler imaging (TDI) were recorded in five different views at pre-specified time points during surgery. Data were analyzed for availability (obtainable/readable images) and reliability (intra-/inter observer bias and precision). Finally, TEE TAPSE was compared to TTE TAPSE immediately before and after surgery. TAPSE and TDI with TEE was achievable in > 90% of patients in the transgastric view during surgery. The AM- and M-mode had the best reliability and the best correlation with TAPSE measured with TTE. The deep transgastric view was achievable in less than 50% after sternotomy, and TAPSE measured from 2D had a poorer performance compared to the AM- and M-mode. TDI demonstrated a high reliability throughout surgery. RV function can be evaluated by TAPSE and TDI using TEE during surgery. TEE values from the transgastric view demonstrated high performance throughout surgery and a good agreement with TTE TAPSE measurements. PMID- 29383466 TI - Structure-based drug design, synthesis and biological assays of P. falciparum Atg3-Atg8 protein-protein interaction inhibitors. AB - The proteins involved in the autophagy (Atg) pathway have recently been considered promising targets for the development of new antimalarial drugs. In particular, inhibitors of the protein-protein interaction (PPI) between Atg3 and Atg8 of Plasmodium falciparum retarded the blood- and liver-stages of parasite growth. In this paper, we used computational techniques to design a new class of peptidomimetics mimicking the Atg3 interaction motif, which were then synthesized by click-chemistry. Surface plasmon resonance has been employed to measure the ability of these compounds to inhibit the Atg3-Atg8 reciprocal protein-protein interaction. Moreover, P. falciparum growth inhibition in red blood cell cultures was evaluated as well as the cyto-toxicity of the compounds. PMID- 29383467 TI - Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control. AB - While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional (3D) ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamp's ability to screen more than 12 million commercially available molecules and identify potent in vivo inhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the 3D structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis-that presence of an alkyl sulfate side chain results in high activity identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening. PMID- 29383468 TI - The Influence of Social Communication Impairments on Gaze in Adolescents with Social Anxiety Disorder. AB - Adolescents with social anxiety disorder (SAD) often present distorted beliefs related to expected social rejection, coupled with avoidance of social stimuli including interpersonal interactions and others' gaze. Social communication (SC) deficits, often seen in SAD, may play a role in avoidance of social stimuli. The present study evaluated whether SC impairment uniquely contributes to diminished or heightened attention to social stimuli. Gaze patterns to social stimuli were examined in a sample of 41 adolescents with SAD (12-16 years of age; 68% female). Unexpectedly, no significant relationship was observed between SC impairment and fixation duration to angry or neutral faces. However, SC impairment did predict greater fixation duration to happy faces, after controlling for social anxiety severity [adjusted R 2 = 0.201, F(2, 38) = 4.536, p = 0.018]. Clinical implications are discussed, focusing on the potential utility of targeting SC impairments directly in light of the role of SC difficulties in youth with SAD. PMID- 29383469 TI - Challenges in assessing the real incidence of chronic lymphocytic leukemia: 16 years of epidemiological data from the province of Girona, Spain. AB - Determining chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) incidence is challenging for two reasons: cancer registries tend to underreport CLL cases and its diagnostic criteria changed markedly in 2008. No studies have reported incidence rates dealing with both difficulties, and thus CLL/SLL burden in Europe is currently uncertain. Herein, we present accurate CLL/SLL incidence in a Spanish region during 1998-2013, using the population-based Girona Cancer Registry (GCR). We detected an 18.2% under-reporting of CLL/SLL cases when combining records from the GCR and additional information sources (i.e., records of flow cytometry laboratories, hospital registries and hematologists' databases). In addition, age-adjusted rates (using the 2013 European population) changed from 7.57 (95% CI 6.87; 8.30) in 1998-2008 to 6.35 (95% CI 5.51; 7.30) in 2009-2013. Overall, completeness of CLL/SLL data requires accurate diagnosis and reporting of cases. Revision of cancer registry operations to include CLL/SLL specific surveillance is likely to ensure that the monitoring of this malignancy is entirely accurate. PMID- 29383470 TI - Purification of virus-like particles (VLPs) expressed in the silkworm Bombyx mori. AB - Virus-like particles (VLPs) are a promising and developing option for vaccination and gene therapy. They are also interesting as shuttles for drug targeting. Currently, several different gene expression systems are available, among which the silkworm expression system is known for its mass production capacity. However, cost-effective purification with high purity of the target protein is a particular bottleneck for this system. The present review evaluates the advances in the purification of VLPs, especially from silkworm larval hemolymph. Beginning with applicable pre-treatments for VLPs over to chromatography methods and quality control of the purified VLPs. Whereupon the main focus is on the different chromatography approaches for the purification, but the structure of the VLPs and their intended use for humans make also the quality control important. Within this, the stability of the VLPs which has to be considered for the purification is as well discussed. PMID- 29383471 TI - PKM2 knockdown influences SREBP activation and lipid synthesis in bovine mammary gland epithelial MAC-T cells. AB - OBJECTIVE: The purpose of the article is to evaluate the changes in lipid metabolism in bovine mammary-gland epithelial MAC-T cells after PKM2 knockdown. RESULTS: MAC-T cells stably expressing low levels of PKM2 were established with lentivirus-mediated small hairpin RNA. Although the knockdown of PKM2 had no effect on MAC-T cell growth, the reduced expression of PKM2 attenuated the mRNA and protein expression of key enzymes involved in sterol synthesis through the SREBP pathway. CONCLUSIONS: The downregulation of PKM2 significantly influenced lipid synthesis in bovine mammary-gland epithelial MAC-T cells. These findings extend our understanding of the crosstalk between glycolysis and lipid metabolism in bovine mammary-gland epithelial cells. PMID- 29383472 TI - Harvesting Chlorella vulgaris via rapid sedimentation induced by combined coagulants and tapered shear. AB - OBJECTIVES: In this study, a rapid sedimentation induced by combined coagulants and gradual shear was developed to harvest Chlorella vulgaris. RESULTS: The microalgal harvesting efficiency was observably promoted by the synergistic effect between FeCl3 and PAM, especially in the first 10 min. A higher harvesting efficiency, 95.61%, could be achieved within approximately 3 min due to the large and dense flocs generated by the combined coagulants. In contrast, the efficiencies were only 54.25 and 60.20% with FeCl3 and PAM, independently. When coagulation was performed under gradually reduced shear (from 50 to 30 rpm), smaller clusters or cells filled the pores of the aggregates via interception, which caused the flocs to become larger and more compact. CONCLUSIONS: The sedimentation time was shortened to 30 s for microalgal coagulation induced by the simultaneous use of combined coagulants and tapered shear, providing an effective approach to harvesting microalgae. PMID- 29383473 TI - Response to risk of hydroxychloroquine retinopathy is not related to systemic lupus erythematosus or rheumatoid arthritis. PMID- 29383474 TI - Retinopathy from hydroxychloroquine is not related to lupus or rheumatoid arthritis. PMID- 29383475 TI - Spontaneous rupture of urinary bladder diverticulum with pseudo-acute renal failure. PMID- 29383476 TI - Apoplexy in nonfunctioning pituitary adenomas. AB - Pituitary apoplexy is an uncommon event, occurring due to the infarction and/or haemorrhage usually of a previously unknown pituitary adenoma. It can occur in all adenoma subtypes but is more common in nonfunctioning pituitary adenomas. The physiopathology is not completely clear, and precipitating factors, such as major surgeries, anticoagulant use or pituitary dynamic tests, can be found in up to 40% of patients. The clinical presentation is characterized by a rapid onset with a headache as the main symptom, but visual disturbances can also be present as well as meningism and intracranial hypertension. The diagnosis is based on imaging evaluations, mainly using magnetic resonance imaging, which can show various patterns depending on the timeframe following the occurrence of the apoplectic event. Pituitary hormonal deficits are also common, and the evaluation of hormonal levels is mandatory. Pituitary apoplexy can be managed by surgery or conservative treatment, and a multidisciplinary team is essential for the decision-making process. The outcome is usually positive with both surgical and conservative approaches, but surveillance is needed due to the risk of re bleeding or tumour recurrence. PMID- 29383477 TI - Physiological and RNA-seq analyses provide insights into the response mechanism of the Cf-10-mediated resistance to Cladosporium fulvum infection in tomato. AB - KEY MESSAGE: Based on the physiological and RNA-seq analysis, some progress has been made in elucidating the Cf-10-mediated resistance responses to C. fulvum infection in tomato. GO and KEGG enrichment analysis revealed that the DEGs were significantly associated with defense-signaling pathways like oxidation-reduction processes, oxidoreductase activity and plant hormone signal transduction. Leaf mold, caused by the fungus Cladosporium fulvum, is one of the most common diseases affecting tomatoes worldwide. Cf series genes including Cf-2, Cf-4, Cf 5, Cf-9 and Cf-10 play very important roles in resisting tomato leaf mold. Understanding the molecular mechanism of Cf gene-mediated resistance is thus the key to facilitating genetic engineering of resistance to C. fulvum infection. Progress has been made in elucidating two Cf genes, Cf -19 and Cf -12, and how they mediate resistance responses to C. fulvum infection in tomato. However, the mechanism of the Cf-10- mediated resistance response is still unclear. In the present study, RNA-seq was used to analyze changes in the transcriptome at different stages of C. fulvum infection. A total of 2,242 differentially expressed genes (DEGs) responsive to C. fulvum between 0 and 16 days post infection (dpi) were identified, including 1,501 upregulated and 741 downregulated genes. The majority of DEGs were associated with defense-signaling pathways including oxidation-reduction processes, oxidoreductase activity and plant hormone signal transduction. Four DEGs associated with plant-pathogen interaction were uniquely activated in Cf-10 tomato and validated by qRT-PCR. In addition, physiological indicators including reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) were measured at 0-21 dpi, and hormone expression [Jasmonic acid (JA) and salicylic acid (SA)] was estimated at 0 and 16 dpi to elucidate the mechanism of the Cf-10-mediated resistance response. C. fulvum infection induced the activities of POD, CAT and SOD, and decreased ROS levels. JA was determined to participate in the resistance response to C. fulvum during the initial infection period. The results of this study provide accountable evidence for the physiological and transcriptional regulation of the Cf-10-mediated resistance response to C. fulvum infection, facilitating further understanding of the molecular mechanism of Cf-10-mediated resistance to C. fulvum infection. PMID- 29383478 TI - Generation of a biotinylatable Sox2 mouse model to identify Sox2 complexes in vivo. AB - Sox2 is a Sry-box containing family member of related transcription factors sharing homology in their DNA binding domain. Sox2 is important during different stages of development, and previously we showed that Sox2 plays an important role in branching morphogenesis and epithelial cell differentiation in lung development. The transcriptional activity of Sox2 depends on its interaction with other proteins, leading to 'complex-specific' DNA binding and transcriptional regulation. In this study, we generated a mouse model containing a biotinylatable tag targeted at the translational start site of the endogenous Sox2 gene (bioSox2). This tag was biotinylated by the bacterial birA protein and the resulting bioSox2 protein was used to identify associating partners of Sox2 at different phases of lung development in vivo (the Sox2 interactome). Homozygous bioSox2 mice are viable and fertile irrespective of the biotinylation of the bio tag, indicating that the bioSox2 gene is normally expressed and the protein is functional in all tissues. This suggests that partners of Sox2 are most likely able to associate with the bioSox2 protein. BioSox2 complexes were isolated with high affinity using streptavidin beads and analysed by MALDI-ToF mass spectrometry analysis. Several of the identified binding partners are already shown to have a respiratory phenotype. Two of these partners, Wdr5 and Tcf3, were validated to confirm their association in Sox2 complexes. This bioSox2 mouse model will be a valuable tool for isolating in vivo Sox2 complexes from different tissues. PMID- 29383479 TI - Magnetic resonance imaging as an adjunct diagnostic tool in computed tomography defined Bosniak IIF-III renal cysts: a multicenter study. AB - INTRODUCTION: CT imaging is the standard examination for renal cystic lesions and defines the Bosniak category, which dictates further management. Given that Bosniak II/IIF/III renal cystic lesions can potentially harbor renal cell carcinoma (RCC), additional diagnostic modalities may be required in management decision making. AIM: To determine the value of additional magnetic resonance imaging in CT-defined Bosniak IIF-III renal cystic lesions. MATERIALS AND METHODS: This a multicenter retrospective study of 46 consecutive patients, diagnosed with cystic renal lesions between 2009 and 2016. The inclusion criteria were: (1) cystic renal lesion classified as Bosniak IIF-III on CT, (2) a subsequent MRI examination, and (3) documented outcome via surgery for cystic renal mass or follow-up. RESULTS: 46 patients (35 males, 11 females) were included. The mean size of the cystic lesion was 3.92 cm (0.7-10 cm). According to the CT findings, Bosniak IIF and III were found in 12 (26.1%) and 34 (73.9%) cases. Reclassification of Bosniak category was done after MRI examination in 31 cases (67.4%). An upgrade rate of 58.7% (27 cases) to a higher category was made, while the downgrade rate to a lower category was achieved in 4 cases (8.7%). As a result, significant therapeutic management change was made in 12/31 patients (38.7%), of whom 8 underwent subsequent surgery. CONCLUSION: MRI study may reduce the use of Bosniak IIF category (in comparison with CT), which has a direct impact on therapeutic management (surgery vs. surveillance) in a significant proportion of patients. PMID- 29383480 TI - Prostatic injection of botulinum toxin is not inferior to optimized medical therapy in the management of lower urinary tract symptoms due to benign prostatic hyperplasia: results of a randomized clinical trial. AB - OBJECTIVE: To explore efficacy and safety of Botulinum Neurotoxin Type A (BoNT-A) prostatic injection in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperperplasia. MATERIALS AND METHODS: A phase 3 multicenter open-labeled study randomised patients to receive BoNT-A prostatic injection or optimized medical therapy. BoNT-A injection consisted in trans-rectal injections of 200 UI in the transitional zone of the prostate. Optimal medical therapy consisted in oral medication with any drug patented for LUTS. One month (M1) after randomisation patients in the BoNT-A group were asked to stop any medical therapy related to LUTS. The main judgment criterion was the IPSS score at M4. Per-protocol analysis was performed with a non-inferiority hypothesis (DeltaIPSS < 3). RESULTS: 127 patients were randomised to BoNT-A (n = 64) or medical therapy (n = 63). At randomisation mean IPSS was 16.9 +/- 7.2 in the BoNT-A group vs 15.7 +/- 7.3 in control. In the BoNT-A group, 44 patients (73.3%) could interrupt medical therapy for LUTS from M1 to M4. At M4, mean IPSS score was 12.0 +/- 6.7 in the BoNT-A group vs 11.8 +/- 6.9 in control. After adjustment for baseline IPSS, delta IPSS between groups was 0.01; 95% CI [- 2.14; 2.11] leading to accept the non-inferiority hypothesis. CONCLUSIONS: Four months after BoNT-A injection, most of the patients could interrupt LUTS-related medical treatments. In these patients, IPSS improvement was not inferior to optimized medical treatment, but the study design did not allow to conclude that this improvement was related with study drug rather than with sustained placebo effect. TRIAL REGISTRATION: NCT01275521. PMID- 29383481 TI - Patterns and timing of artificial urinary sphincter failure. AB - PURPOSE: To assess population-based trends in artificial urinary sphincter (AUS) placement after prostatectomy and determine the effect of timing on device survival and complications. METHODS: We identified patients who underwent prostatectomy and AUS placement in SEER-Medicare from 2002 to 2011. We analyzed factors affecting the time of reoperation from AUS implantation and prostatectomy using multivariable Cox proportional hazard models. RESULTS: In total, 841 men underwent AUS placement at a median 23 months after prostatectomy. Patients who underwent reoperation (28.5%) had higher clinical stage, more likely underwent open prostatectomy, or had prior sling placement (p < 0.03). There were no differences in rates of diabetes, smoking status, prior radiation therapy, or Charlson Comorbidity Index between those requiring reoperation vs. not (all p > 0.15). Patients with AUS placement > 15 months after prostatectomy (75%) initially experienced less need for operative reinterventions. Patients with later AUS placement were significantly more likely to have received radiation therapy [22.9 vs. 3.8% (p < 0.01)]. Nonetheless, late implantation was confirmed to be protective on multivariate analysis during the first 5 years after AUS placement [HR 0.79 (95% CI 0.67-0.92); p < 0.01]. Factors independently associated with a shorter interval time until reoperation included history of radiation [HR 1.93 (95% CI 1.33-2.80); p < 0.01] and history of prior sling [HR 1.70 (95% CI 1.08-2.68); p = 0.02]. Even for patients who underwent radiation therapy, delayed AUS implantation reduced reoperative risk. CONCLUSIONS: Late AUS implantation in the Medicare population is associated with prolonged device survival initially, while radiation and prior sling surgery predict for earlier reoperation. Patients with delayed AUS implantation experience less immediate complications. Further work is required to identify patient-specific factors which may explain variability in timing for AUS. PMID- 29383482 TI - Docetaxel, cisplatin and S-1 (DCS) combination chemotherapy for gastric cancer patients with peritoneal metastasis: a retrospective study. AB - PURPOSE: Peritoneal metastasis (PM) in advanced or recurrent gastric cancer (AGC) is the most frequent cause of death from this disease. However, current treatments remain unsatisfactory. We previously conducted studies of docetaxel, cisplatin and S-1 (DCS) combination chemotherapy for AGC. The aim of this study was to investigate the benefits and tolerability of DCS in PM patients. METHODS: Patients were divided into three groups: patients without PM (non-PM); PM patients without ascites, or mild to moderate ascites (None-Mod); and PM patients with massive ascites (Massive). Patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14, and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Drug exposure, adverse events, tumor response, progression free and overall survival (OS) rates were evaluated. RESULTS: Of the 111 AGC patients who received DCS as first-line therapy, 37 cases had complicated PM, 15 of whom displayed massive ascites. The response rate for PM patients was 81.5%. Drug exposure and toxicities were not meaningfully different among the groups. The MSTs were also similar: 22.6 months for the non-PM, 21.7 months for the None Mod PM, and 16.8 months for the Massive, respectively. Ten (27.0%) patients with PM achieved downstaging and underwent curative surgery, subsequently demonstrating an excellent MST of 28.0 months. An independent prognostic factor for OS, as revealed by multivariate analyses. was a good performance status. CONCLUSION: DCS is feasible and efficacious for AGC with PM, especially when patients present with a good PS. PMID- 29383483 TI - Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma. AB - PURPOSE: The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC). METHODS: We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m2, day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m2/day, days 1-4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first. RESULTS: The median follow-up was 10.5 (range 1.2-34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3-4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal. CONCLUSION: The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC. PMID- 29383484 TI - 2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human gastric cancer cells through downregulating JNK-mediated cytoprotective autophagy. AB - PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) resistance significantly limits its use in clinical practice. It has been reported that 2-deoxy-D-glucose (2-DG) can enhance TRAIL's cytotoxicity. Our studies were designed to investigate the mechanisms of 2-DG reversing TRAIL resistance therapy in gastric cancer cells. METHODS: Gastric cancer cells (MGC803, SGC7901) were treated with 2-DG and TRAIL. Cell viability was determined by CCK-8 assay and detection of apoptosis by flow cytometry. Autophagic and apoptosis protein expression and c-Jun NH2 terminal kinase (JNK) phosphorylation were determined by Western blotting. Autophagy response and JNK activities were inhibited by specific inhibitor, 3MA or SP600125, respectively. LDH release assay was used to detect cytotoxicity. RESULTS: We confirmed that TRAIL triggered an autophagic response in TRAIL resistant gastric cancer cells, MGC803 and SGC7901, and depended on JNK activation. Blocking autophagy or JNK activation with specific inhibitor, 3MA or SP600125, potentiated cell death and caspase-3 activation. Furthermore, we confirmed that 2-DG inhibited the viability of gastric cancer cells, phosphorylation of JNK induced by TRAIL and increased gastric cancer cells to TRAIL-induced apoptosis. CONCLUSIONS: Taken together, we show that 2-DG can sensitize TRAIL-induced apoptosis, at least in part, through suppressing JNK mediated cytoprotective autophagic signaling in MGC803 and SGC7901cells. These results may have significant implications for the development of new strategies to reverse TRAIL resistance in gastric tumor. PMID- 29383485 TI - Answer to the Letter to the Editor of Qi Sun et al. concerning "Robot-assisted and conventional freehand pedicle screw placement: a systematic review and meta analysis of randomized controlled trials" by Gao ST, et al. (Eur Spine J; 2017: DOI 10.1007/s00586-017-5333-y). PMID- 29383486 TI - Focal disorders of the spine with compensatory deformities: how to define them. AB - PURPOSE: In this paper, the authors propose classifying the epiphenomenon of spinal deformity in two different categories: structural deformity, when the main driver of the observed deformity is a fixed and stiff alteration of the spinal segments, and compensatory deformity, which includes cases where the observed deformity is due to focal abnormalities. This last category comprises, but is not limited to, spinal stenosis, spondylolisthesis, disc herniation, infection or tumor, hip disease or neurological disease (such as Parkinson's disease). METHOD: Narrative review article. RESULTS: We analyzed the focal diseases of the spine that may cause a compensatory deformity inducing adaptation in the unaffected part of the spine. CONCLUSION: The compensatory mechanisms involved in adaptive deformity represent an attempt to maintain a global alignment, to escape from pain or to control body posture. These slides can be retrieved under Electronic Supplementary material. PMID- 29383487 TI - 102 lumbar pedicle subtraction osteotomies: one surgeon's learning curve. AB - PURPOSE: Pedicle Subtraction Osteotomy (PSO) is an effective surgical technique for the correction of fixed sagittal malalignment of the spine. It is a demanding technique that requires a long learning curve. The aim of this study is to analyze a surgeon's learning curve for lumbar PSO in relation to the preoperative, perioperative, and postoperative management, with assessment of the global outcome. MATERIALS AND METHODS: 102 patients operated over an 8-year period were included, distributed in 3 groups over the time, and retrospectively analyzed. The following data were collected: demographic characteristics, preoperative and postoperative radiological parameters, operative technical details, and complications. Multiple regression analysis was performed, and while the number of cases was the predictor, other variables such as demographic, radiographical, and surgical variables were considered as a covariate in the final model. RESULTS: When comparing the first group and the last group of patients, the mean surgical time had decreased by 50 min, the estimated blood loss was decreased by 655 ml, and a significant decrease in dural tear occurrence was noticed. In addition, we found a significant decrease in the hospital stay length. Multivariate linear regression analysis showed that when the surgeon's experience doubles, the operative time decreases by 29 min, the blood loss by 281 ml, and the odds of hospital stay >= 21 days decrease by 0.66 times. CONCLUSION: PSO technique has a relatively long learning curve. This study showed that accumulating the experience over the years, while performing cases on a regular basis, is definitely the key in mastering this complex and risky technique, with significant improvements in the perioperative parameters that directly impact the recovery and global outcome. These slides can be retrieved under Electronic Supplementary Material. PMID- 29383488 TI - [Diagnostic and predictive molecular pathology of head and neck neoplasms]. AB - As a result of some seminal observations as well as a consequence of increasing use of modern and innovative molecular diagnostic technologies, a variety of new genetic aberrations have been discovered in head and neck neoplasms of different anatomic locations and histogenetic origins. These advances resulted in the establishment of new molecularly defined disease entities. On the other hand, some of these new genetic biomarkers paved the way to potentially promising novel therapeutic opportunities. Diverse old (well known in other entities) and newly discovered translocations and gene fusions represent the leading subgroup of these genetic aberrations. They have been detected not only in malignant epithelial neoplasms (carcinomas) of the salivary glands, but also in carcinomas from other head and neck sites as well as diverse mesenchymal tumors. In addition to these gene fusions, several activating mutations (such as CTNNB1 in sinonasal glomangiopericytoma) as well as inactivating mutations or deletions (like SMARCB1 loss in sinonasal carcinomas) were detected as new molecular markers. In the present review we summarize the relevant molecular alterations in topographically and histopathologically distinct tumors of the head and neck region with emphasis on recently established molecular markers. PMID- 29383489 TI - Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia. AB - Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37*. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component. PMID- 29383490 TI - Altered goblet cell function in Hirschsprung's disease. AB - AIMS AND OBJECTIVES: Hirschsprung's disease-associated enterocolitis (HAEC) is the most serious complication of Hirschsprung's disease (HSCR). HAEC occurs in 17 50% of patients with HSCR and may occur before or after a properly performed pull through operation. The pathogenesis of HAEC is poorly understood. It is well recognized that a complex mucosal barrier protects, as the first line of defense, the surface of healthy intestinal tract from adhesion and invasion by luminal micro-organisms. Within the intestinal epithelium, goblet cells secrete gel forming mucins, the major component of mucus, which block the direct attachment of commensal bacteria to the epithelial layer. Mucin 2 (MUC2) is the predominant mucin expressed in humans. Trefoil factor 3 (TFF3) synergizes with mucin and enhances the protective barrier properties of the mucus layer. SAM pointed domain containing ETS transcription factor (SPDEF) drives terminal differentiation and maturation of secretory progenitors into goblet cells. Krueppel-like factor 4 (KLF4) is a goblet cell-specific differentiation factor in the colon and controls goblet cell differentiation and activates mucin synthesis. We hypothesized that the goblet cell function in the ganglionic pulled-through bowel in HSCR is abnormal and, therefore, we investigated the changes in goblet cell differentiation and functional expression of mucin in the bowel specimens from patients with HSCR. MATERIAL AND METHODS: We investigated MUC2, TFF3, SPDEF and KLF4 expression, and the goblet cell population in the ganglionic and aganglionic bowel of HSCR patients (n = 10) and controls (n = 10) by qPCR, Western blotting, confocal immunofluorescence, and alcian blue staining. RESULTS: The qPCR and Western blotting analysis revealed that TFF3, SPDEF and KLF4 expressions were significantly downregulated in the aganglionic and ganglionic colon of patients with HSCR as compared to controls (p < 0.05). Alcian blue staining revealed that the goblet cell population was significantly decreased in aganglionic and ganglionic colon as compared to controls (p < 0.05). Confocal microscopy revealed a markedly decreased expression of TFF3, SPDEF and KLF4 in colonic epithelium of patients with HSCR as compared to controls. CONCLUSION: This is, to our knowledge, the first report of decreased expression of TFF3, SPDEF, KLF4, and goblet cell population in the colon of patients with HSCR. Altered goblet cell function may result in intestinal barrier dysfunction contributing to the development of HAEC. PMID- 29383491 TI - Catheter ablation of symptomatic idiopathic ventricular arrhythmias : A five-year single-centre experience. AB - AIMS: This study was designed to gain insight into the patient characteristics, results and possible complications of ablation procedures for symptomatic idiopathic premature ventricular complexes (PVC) and idiopathic ventricular tachycardia (VT). METHODS: Data were collected from all patients who underwent radiofrequency catheter ablation for symptomatic PVCs and idiopathic VT in the Catharina Hospital between 1 January 2011 and 31 December 2015. The procedural endpoint was elimination or non-inducibility of the clinical arrhythmia. Successful sustained ablation was defined as the persistent elimination of at least 80% of the PVCs or the absence of VTs at follow-up. In case of suspected PVC-induced cardiomyopathy, the systolic left ventricular function was reassessed 3 months post procedure. RESULTS: Our cohort consisted of 131 patients who underwent one or more ablation procedures; 99 because of symptomatic premature ventricular complexes, 32 because of idiopathic VT. In total 147 procedures were performed. The procedural ablation success rate was 89%. Successful sustained ablation rate was 82%. Eighteen (13.2%) patients had suspected PVC-induced cardiomyopathy. In 15 of them (83%), successful sustained ablation was achieved and the left ventricular ejection fraction improved from a mean of 39% (+/-8.8) to 55.4% (+/-8.1). Most arrhythmias originated from the right ventricular outflow tract (60%) or aortic cusps (13%). Complications included three tamponades. CONCLUSION: Catheter ablation therapy for idiopathic ventricular arrhythmias is very effective with a sustained success rate of 82%. In patients with PVC-induced cardiomyopathy, it leads to improvement of systolic left ventricular function. However, risk for complications is not negligible, even in experienced hands. PMID- 29383492 TI - Correction to: Circumstances and causes of sudden circulatory arrests in the Dutch province of Limburg and the involvement of citizen rescuers. AB - Correction to:Neth Heart J 2017 https://doi.org/10.1007/s12471-017-1057-1 In the version of the article originally published online, there was an error in the last section of the Discussion. It is stated that 'In 42% of the OHCAs a volunteer alert would have been appropriate, but the alert system .... PMID- 29383493 TI - Treatment with Botulinum Toxin for Refractory Fever Caused by Severe Spasticity: A Case Series. AB - INTRODUCTION: Brain and spinal cord injuries may cause very severe spasticity that occasionally may be associated with persistent fever. CASE SERIES: We present 14 patients with spasticity and persistent fever, treated with botulinum toxin type A. Their spasticity improved and the fever resolved within a period no greater than 48 h. In all cases, infectious and other non-infectious causes were ruled out. CONCLUSIONS: When sustained tonic muscular activity is associated with a significant increase in body temperature and is refractory to the usual drugs used for hyperpyrexia, type A botulinum toxin may be an effective treatment option to control both spasticity and fever. PMID- 29383494 TI - Two-step progression of varenicline-induced autoimmune hepatitis. AB - We describe a rare case of drug-induced hepatitis due to the smoking cessation agent varenicline in a 46-year-old Asian woman. The liver injury progressed in two steps. First, the liver injury started in the absence of viral/autoimmune responses, and withdrawal of varenicline lowered the increase in the levels of liver enzymes immediately. Such findings suggested varenicline-induced liver injury. Second, hepatitis recurred in association with conversion of antinuclear antibody from negative to positive about 8 weeks after the initial episode. Histology upon recurrence of liver injury revealed interface hepatitis with lymphocytic and lymphoplasmacytic portal inflammatory infiltrates extending into lobules. Such findings suggested autoimmune hepatitis. Corticosteroid treatment was effective for recurrent hepatitis. The clinical course suggests that varenicline caused drug-induced liver injury and subsequent autoimmune hepatitis. Some autoimmune changes were probably involved in the mechanism of varenicline induced liver injury. PMID- 29383495 TI - Per-oral endoscopic myotomy for esophageal achalasia in a case of Allgrove syndrome. AB - Allgrove syndrome, also known as Triple A syndrome, is a rare autosomal recessive genetic disease characterized by three signs: esophageal achalasia, adrenocorticotropic hormone refractoriness, and alacrima. A 31-year-old male presented to our hospital for treatment of difficulty swallowing caused by esophageal achalasia. Because he had complicating alacrima, a neurologic disease, and a family history of consanguineous marriage, a genetic neurologic disease was suspected. Then, a mutation in the achalasia-addisonianism-alacrima syndrome gene was identified. With the diagnosis of Allgrove syndrome, a per-oral endoscopic myotomy (POEM) was performed for esophageal achalasia. After the POEM, the symptoms and the esophageal pressure findings ameliorated quickly, with no recurrence noted throughout a follow-up of more than 1 year. Here, we report the first case of POEM performed for esophageal achalasia in Allgrove syndrome. PMID- 29383496 TI - Candidemia after endoscopic therapy with lumen-apposing metal stent for pancreatic walled-off necrosis. AB - Necrotizing pancreatitis remains a challenging and unpredictable condition accompanied by various complications. Endoscopic ultrasound-guided transmural drainage and necrosectomy have become the standard treatment for patients with walled-off necrosis (WON). Endoscopic therapy via lumen-apposing metal stents (LAMS) with large diameters has shown success in the management of pancreatic fluid collections, but there are few data on specific complications of that therapy. We report a case of infected WON and concomitant fungemia following LAMS placement and necrosectomy. In addition, a systematic literature review of current related studies has been provided. PMID- 29383497 TI - Microfluidic quantification of multiple enteric and opportunistic bacterial pathogens in roof-harvested rainwater tank samples. AB - Potable and non-potable uses of roof-harvested rainwater (RHRW) are increasing due to water shortages. To protect human health risks, it is important to identify and quantify disease-causing pathogens in RHRW so that appropriate treatment options can be implemented. We used a microfluidic quantitative PCR (MFQPCR) system for the quantitative detection of a wide array of fecal indicator bacteria (FIB) and pathogens in RHRW tank samples along with culturable FIB and conventional qPCR analysis of selected pathogens. Among the nine pathogenic bacteria and their associated genes tested with the MFQPCR, 4.86 and 2.77% samples were positive for Legionella pneumophila and Shigella spp., respectively. The remaining seven pathogens were absent. MFQPCR and conventional qPCR results showed good agreement. Therefore, direct pathogen quantification by MFQPCR systems may be advantageous for circumstances where a thorough microbial analysis is required to assess the public health risks from multiple pathogens that occur simultaneously in the target water source. PMID- 29383499 TI - Applications of Bioengineered 3D Tissue and Tumor Organoids in Drug Development and Precision Medicine: Current and Future. AB - Over the past decade, advances in biomedical and tissue engineering technologies, such as cell culture techniques, biomaterials, and biofabrication, have driven increasingly widespread use of three-dimensional (3D) cell culture platforms and, subsequently, the use of organoids in a variety of research endeavors. Given the 3D nature of these organoid systems, and the frequent inclusion of extracellular matrix components, these constructs typically have more physiologically accurate cell-cell and cell-matrix interactions than traditional 2D cell cultures. As a result, 3D organoids can serve as better model systems than their 2D counterparts. Moreover, as organoids can be biofabricated from highly functional human cells, they have certain advantages over animal models, being human in nature and more easily manipulated in the laboratory. In this review, we describe such organoid technologies and their deployment in drug development and precision medicine efforts. Organoid technologies are rapidly being developed for these applications and now represent a wide variety of tissue types and diseases. Evidence is emerging that organoids are poised for widespread adoption, not only in academia but also in the pharmaceutical industry and in clinical diagnostic applications, positioning them as indispensable tools in medicine. PMID- 29383498 TI - Episodic bouts of hyperaemia and shear stress improve arterial blood flow and endothelial function. AB - INTRODUCTION: Exercise and heat stress lead to systemic improvements in arterial endothelial function, vascular stiffness, and cardiopulmonary capacity. The improvements in endothelial function may be primarily mediated via increases in shear stress. This study examined whether improvements in arterial function may be achieved in the absence of systemic vascular adaptations. Specifically, we hypothesized that repeated bouts of brief occlusion would improve arterial endothelial function via shear stress-dependent mechanisms. METHODS: Eleven healthy males underwent a shear stress intervention (5 s brachial occlusion, 10 s rest) for 30 min, five times weekly for 6 weeks on one arm while the other acted as an untreated control. Ultrasound was used to assess brachial arterial forearm blood flow (FBF) and vascular conductance (FVC), diameter, and shear rate (SR), while endothelial function was assessed by flow-mediated dilatation (FMD). Post occlusive reactive hyperaemia and pulse wave velocity (PWV) were also measured. RESULTS: There were no changes in any of the measures in the control arm (all d < 0.2, p > 0.05). After 3 weeks of the intervention, FMD was increased from baseline (7.6 +/- 0.6 vs. 5.9 +/- 0.9%; d = 1.3, p = 0.038) and further increased after 6 weeks to 9.5 +/- 2.6% (d = 1.7, p < 0.001). SR was also increased following the 6-week intervention (all d >= 0.6, p < 0.001). Resting and peak FBF and FVC were also increased in response to the intervention (all d >= 0.6, p < 0.001) and PWV was reduced. CONCLUSIONS: These data demonstrate that episodic increases in shear stress elicit marked increases in arterial endothelial function and vascular reactivity. PMID- 29383500 TI - Prevalence and genetic characterization of eimeriid coccidia from feces of black necked cranes, Grus nigricollis. AB - Disseminated visceral coccidiosis (DVC) is a widely distributed intestinal and extraintestinal disease of cranes caused by eimeriid coccidia and has lethal pathogenicity to several crane species. Here, feces of 164 black-necked cranes collected in Dashanbao Black-necked Crane National Nature Reserve, China, were examined to determine the prevalence of coccidial oocysts. Of the 164 fecal samples, 76 (46.3%) were positive for oocysts of Eimeria, including E. gruis in 59 (35.9%), E. reichenowi in 52 (31.7%), and E. bosquei in 47 (28.7%) by microscopic observation. Sixty-eight (89.5%) of these positive samples included two or more morphologically identifiable species of Eimeria. The nearly full length 18S rRNA gene (18S rRNA; about 1.8 kb) and partial mitochondrial cytochrome c oxidase I gene (COX1; about 1.3 kb) from oocysts of each morphologically distinct species of Eimeria were amplified, sequenced, and analyzed. BLAST searches using these new 18S rRNA sequences for E. gruis, E. reichenowi, or E. bosquei showed the most similar sequences were those of E. gruis (98.7-99.7% identity), E. reichenowi (97.9-100% identity), or E. gruis (98.6-99.6% identity) isolated from different species of Grus. BLAST searches using the new COX1 sequences for the three species of Eimeria showed that no nucleotide sequences of Eimeria and Isospora coccidia in GenBank have more than 83.0% identity with these species. Identities among the new COX1 sequences were 91.8% for E. gruis and E. reichenowi, 94.5% for E. gruis and E. bosquei, and 91.3% for E. reichenowi and E. bosquei. Phylogenetic analysis based on 18S rRNA or COX1 sequences indicated that Eimeria spp. in black-necked cranes were clustered together with other previously identified Eimeria species from different cranes. PMID- 29383501 TI - Parasites of small Indian mongoose, Herpestes auropunctatus, on St. Kitts, West Indies. AB - Herpestes auropunctatus, the small Indian mongoose, is an invasive omnivore introduced to the Caribbean, including the island of St. Kitts over 150 years ago. It has played a role in changing native fauna and can carry zoonotic pathogens of public health importance. The aim of the current study was to estimate the prevalence of parasites harbored by mongooses. In total, 87 mongooses trapped from April to July 2015 were examined for parasites using (1) hair plucks (N = 79), ear swabs (N = 79), and general coat and skin examination (N = 87) for mites, ticks, lice, and fleas; (2) dissection of the trachea, bronchi, and lungs for lungworms and flukes (N = 76); (3) a double centrifugation fecal flotation method for parasites of the gastrointestinal tract (N = 75); and (4) PCR of heart homogenates for Toxoplasma gondii (N = 60). The only ectoparasite seen was Ctenocephalides felis (79.3%; 69/87), with most mongooses having > 10 fleas (based on a subjective assessment) but insufficient numbers to result in signs of pruritus or anemia. On fecal flotation, coccidial oocysts were found with a prevalence of 69.3% (52/75). Neither T. gondii, lungworm, nor fluke infections were detected with the methods used. The high number of C. felis infested mongooses and the infestation level of the individual mongooses suggest that they could serve as a reservoir for these potential vectors of pathogens. No evidence was found to support that mongooses are a component of T. gondii cycles on St. Kitts, although this finding needs to be confirmed with a larger sample size from other geographic locations. PMID- 29383502 TI - Influences of different lower cervical bone graft heights on the size of the intervertebral foramen: multiple planar dynamic measurements with laser scanning. AB - The aim of this study is to evaluate the influences of different bone graft heights on the size of the intervertebral foramen, which will help determine the optimal graft height in clinical practice. Six fresh adult cadavers were used, with the C5-C6 vertebral column segment defined as the functional spinal unit (FSU). After discectomy, the C5/6 intervertebral height was set as the baseline height (normal disc height). We initially used spiral computed tomography (CT) to scan and measure the middle area of the intervertebral foramen when at the baseline height. Data regarding the spatial relationship of C5-C6 were subsequently collected with a laser scanner. Grafting with four different sized grafts, namely, grafts of 100, 130, 160, and 190% of the baseline height, was implanted. Moreover, we scanned to display the FSU in the four different states using Geomagic8.0 studio software. Multiple planar dynamic measurements (MPDM) were adopted to measure the intervertebral foramen volume, middle area, and areas of internal and external opening. MPDM with a laser scanner precisely measured the middle area of the intervertebral foramen as spiral CT, and it is easy to simulate the different grafts implanted. With the increase of the bone graft height, the size of the intervertebral foramen began to decrease after it increased to a certain point, when grafts of 160% of the baseline height implanted. MPDM of the intervertebral foramens with laser scanning three dimensional (3D) reconstitution are relatively objective and accurate. The recommended optimal graft height of cervical spondylosis is 160% of the mean height of adjacent normal intervertebral spaces. PMID- 29383503 TI - A prospective randomized trial of total synovectomy versus limited synovectomy in primary total knee arthroplasty: evaluation of bleeding, postoperative pain, and quality of life with SF-12 v2. AB - BACKGROUND: During total knee arthroplasty (TKA), total synovectomy (TS) as a part of the surgical technique has been proposed to reduce the inflammatory tissue after the procedure, but there is a controversy about it because of the risk of major postsurgical bleeding. The aim of this study was to compare postoperative bleeding, pain, and health-related quality of life (HRQOL) after a TKA when a TS is performed and when it is not. METHODS: The difference in pre and postoperative hemoglobin was measured, as well as postoperative pain using visual analogue scale (VAS) scores at 24 and 48 h post-surgical, HRQOL was measured prior to surgery and at one year using the SF-12V2 questionnaire. RESULTS: We assessed a total of 148 patients (73 for TS and 75 for limited synovectomy). We have found a difference of 0.9 mg/dl of pre- and postoperative hemoglobin between both groups, with a higher bleeding amount for the TS group (P = 0.0000647); VAS scores were slightly lower for the TS group at 24 and 48 h after surgery, but not relevant. The TS group required transfusion in 13.3% and the limited synovectomy group in 6.8%. No significant differences in HRQOL were found in both groups at 1 year follow-up. CONCLUSIONS: Performing a TS in TKA in patients with osteoarthrosis does not result in a relevant lower postoperative pain, or in an improvement in HRQOL, and it does increase the amount of bleeding after the procedure. PMID- 29383504 TI - Plant and herbivore ontogeny interact to shape the preference, performance and chemical defense of a specialist herbivore. AB - The amount of damage that herbivorous insects impose on plants varies as a function of plant ontogenetic trajectories in tissue quality and defenses, and the herbivores' own developmental trajectories in body size, mandible shape and detoxification enzymes, among others. However, little is known about how host plant and herbivore ontogeny interact. Using four ontogenetic stages of Plantago lanceolata (Plantaginaceae) and three to five larval stages of the specialist caterpillar Junonia coenia (Nymphalidae), we evaluated how ontogenies in both of these trophic levels shape: (i) caterpillar feeding choice, (ii) performance, and (iii) sequestration of plant allelochemicals. Plant physical (leaf toughness) and chemical (iridoid glycosides) defenses increased, while nutritional quality (water and nitrogen content) decreased, as plants aged. These plant ontogenetic trajectories strongly altered the behavior and physiology of this specialist herbivore, but the magnitude of the response varied with larval stage. In feeding experiments, while first instar larvae showed little preference among plant stages, older larvae significantly preferred juvenile over reproductive stages. In turn, larval consumption increased and digestive efficiency decreased, potentially explaining their decrease in relative growth rate, as larvae and host plant aged, but differences were greater for younger than older caterpillars. Finally, sequestration of plant allelochemicals increased through plant and larval development; however, the major differences due to diet occurred earlier during larval development. Our results highlight that changes in plant ontogeny most strongly influence early herbivore instars, emphasizing the need to consider the developmental stage of both trophic levels to better understand temporal variation in herbivore damage. PMID- 29383505 TI - Glycoalkaloid composition explains variation in slug resistance in Solanum dulcamara. AB - In natural environments, plants have to deal with a wide range of different herbivores whose communities vary in time and space. It is believed that the chemical diversity within plant species has mainly arisen from selection pressures exerted by herbivores. So far, the effects of chemical diversity on plant resistance have mostly been assessed for arthropod herbivores. However, also gastropods, such as slugs, can cause extensive damage to plants. Here we investigate to what extent individual Solanum dulcamara plants differ in their resistance to slug herbivory and whether this variation can be explained by differences in secondary metabolites. We performed a series of preference assays using the grey field slug (Deroceras reticulatum) and S. dulcamara accessions from eight geographically distinct populations from the Netherlands. Significant and consistent variation in slug preference was found for individual accessions within and among populations. Metabolomic analyses showed that variation in steroidal glycoalkaloids (GAs) correlated with slug preference; accessions with high GA levels were consistently less damaged by slugs. One, strongly preferred, accession with particularly low GA levels contained high levels of structurally related steroidal compounds. These were conjugated with uronic acid instead of the glycoside moieties common for Solanum GAs. Our results illustrate how intraspecific variation in steroidal glycoside profiles affects resistance to slug feeding. This suggests that also slugs should be considered as important drivers in the co-evolution between plants and herbivores. PMID- 29383506 TI - Effectiveness of predator satiation in masting oaks is negatively affected by conspecific density. AB - Variation in seed availability shapes plant communities, and is strongly affected by seed predation. In some plant species, temporal variation in seed production is especially high and synchronized over large areas, which is called 'mast seeding'. One selective advantage of this phenomenon is predator satiation which posits that masting helps plants escape seed predation through starvation of predators in lean years, and satiation in mast years. However, even though seed predation can be predicted to have a strong spatial component and depend on plant densities, whether the effectiveness of predator satiation in masting plants changes according to the Janzen-Connell effect has been barely investigated. We studied, over an 8-year period, the seed production, the spatiotemporal patters of weevil seed predation, and the abundance of adult weevils in a holm oak (Quercus ilex) population that consists of trees interspersed at patches covering a continuum of conspecific density. Isolated oaks effectively satiate predators, but this is trumped by increasing conspecific plant density. Lack of predator satiation in trees growing in dense patches was caused by re-distribution of insects among plants that likely attenuated them against food shortage in lean years, and changed the type of weevil functional response from type II in isolated trees to type III in trees growing in dense patches. This study provides the first empirical evaluation of the notion that masting and predator satiation should be more important in populations that start to dominate their communities, and is consistent with the observation that masting is less frequent and less intense in diverse forests. PMID- 29383507 TI - Time-lagged intraspecific competition in temporally separated cohorts of a generalist insect. AB - Competition can have far-reaching consequences for insect fitness and dispersion. Time-lagged interspecific competition is known to negatively affect fitness, yet time-lagged intraspecific competition is rarely studied outside of outbreak conditions. We tested the impact of competition between larval cohorts of the western tent caterpillar (Malacosoma californicum) feeding on chokecherry (Prunus virginiana). We reared larvae on host plants that either had or did not have feeding damage from tent caterpillars the previous season to test the bottom-up fitness effects of intraspecific competition. We measured host-plant quality to test potential mechanisms for bottom-up effects and conducted field oviposition surveys to determine if female adult tent caterpillars avoided host plants with evidence of prior tent caterpillar presence. We found that time-lagged intraspecific competition impacted tent caterpillar fitness by reducing female pupal mass, which is a predictor of lifetime fitness. We found that plants that had been fed upon by tent caterpillars the previous season had leaves that were significantly tougher than plants that had not been fed upon by tent caterpillars, which may explain why female tent caterpillars suffered reduced fitness on these plants. Finally, we found that there were fewer tent caterpillar egg masses on plants that had tent caterpillars earlier in the season than plants without tent caterpillars, which suggests that adult females avoid these plants for oviposition. Our results confirm that intraspecific competition occurs among tent caterpillars and suggests that time-lagged intraspecific competition has been overlooked as an important component of insect fitness. PMID- 29383509 TI - Oral health impact profile of head and neck cancer patients after or before oncologic treatment: an observational analytic case-control study. AB - PURPOSE: The objective of this study was to investigate the impact of oral health on the quality of life of patients with head and neck cancer (HNC) before and after oncologic treatment. METHODS: Forty cancer-free individuals (Cf group) and 40 HNC patients (Hnc group) were included in this study. Hnc group was also divided into two subgroups: Hnc 1 (pre-cancer therapy, n = 20) and Hnc 2 (post cancer therapy, n = 20). Participants were asked to complete a short form of Oral Health Impact Profile (OHIP-14). The results were statistically analyzed with the multivariate analysis of variance with post-hoc Scheffe multiple comparison. RESULTS: It was observed a moderate impact on the quality of life on HNC patients, with values on Hnc 2 group significantly higher in the functional limitation when compared to the Hnc 1 group (p < 0.05). When compared to the Cf group, the values found on Hnc group were higher on functional limitation (p < 0.01) and at the total score (p < 0.05), whereas Hnc 2 group had significant superior values on functional limitation (p < 0.01), physical pain (p < 0.05), and total score (p < 0.01) CONCLUSION: These results show that there is an oral impairment that depreciates the quality of life of patients with an experience of HNC, principally after treatment, indicating the importance of the inclusion of professionals responsible for dental and oral care with the oncologic team to monitor the oral condition of these patients. PMID- 29383508 TI - Physical activity barriers, preferences, and beliefs in childhood cancer patients. AB - PURPOSE: Childhood cancer patients report low physical activity levels despite the risk for long-term complications that may benefit from exercise. Research is lacking regarding exercise barriers, preferences, and beliefs among patients (1) on- and off-therapy and (2) across the age spectrum. METHODS: Cross-sectional study in the Yale Pediatric Hematology-Oncology Clinic (October 2013-October 2014). Participants were >= 4 years old, > 1 month after cancer diagnosis at < 20 years, not acutely ill, expected to live > 6 months, and received chemotherapy and/or radiation. Participants (or parents if < 13 years) completed a survey. RESULTS: The 162 patients (99% participated) were 34% children (4.0-12.9 years), 31% adolescents (13.0-17.9 years), and 35% adults (>= 18 years). Most had leukemia/lymphoma (66%); 32% were on-therapy. On-therapy patients were more likely than off-therapy patients (73 vs. 48%; p = 0.003) to report >= 1 barrier related to physical complaints, such as "just too tired" (46 vs. 28%; p = 0.021) or "afraid" of injury (22 vs. 9%; p = 0.027). The majority preferred walking (73%), exercising at home (91%), exercising in the afternoon (79%), and a maximum travel time of 10-20 min (54%); preferences did not vary significantly by therapy status or age. Most respondents (94%) recognized the benefits of exercise after cancer, but 50% of on- vs. 12% of off-therapy patients believed "their cancer diagnosis made it unsafe to exercise regularly" (p < 0.001). CONCLUSIONS: Physical activity barriers pertaining to physical complaints and safety concerns were more pronounced in on-therapy childhood cancer patients but persisted off therapy. Preferences and beliefs were relatively consistent. Our data can inform interventions in different patient subgroups. PMID- 29383510 TI - Epidemiology, causes, evolution and outcome in a single-center cohort of 1116 critically ill patients with hypoxic hepatitis. AB - BACKGROUND: Hypoxic hepatitis (HH) is a type of acute hepatic injury that is histologically characterized by centrilobular liver cell necrosis and that is caused by insufficient oxygen delivery to the hepatocytes. Typical for HH is the sudden and significant increase of aspartate aminotransferase (AST) in response to cardiac, circulatory or respiratory failure. The aim of this study is to investigate its epidemiology, causes, evolution and outcome. METHODS: The screened population consisted of all adults admitted to the intensive care unit (ICU) at the Ghent University Hospital between January 1, 2007 and September 21, 2015. HH was defined as peak AST > 5 times the upper limit of normal (ULN) after exclusion of other causes of liver injury. Thirty-five variables were retrospectively collected and used in descriptive analysis, time series plots and Kaplan-Meier survival curves with multi-group log-rank tests. RESULTS: HH was observed in 4.0% of the ICU admissions at our center. The study cohort comprised 1116 patients. Causes of HH were cardiac failure (49.1%), septic shock (29.8%), hypovolemic shock (9.4%), acute respiratory failure (6.4%), acute on chronic respiratory failure (3.3%), pulmonary embolism (1.4%) and hyperthermia (0.5%). The 28-day mortality associated with HH was 45.0%. Mortality rates differed significantly (P = 0.007) among the causes, ranging from 33.3% in the hyperthermia subgroup to 52.9 and 56.2% in the septic shock and pulmonary embolism subgroups, respectively. The magnitude of AST increase was also significantly correlated (P < 0.001) with mortality: 33.2, 44.4 and 55.4% for peak AST 5-10* ULN, 10-20* ULN and > 20* ULN, respectively. CONCLUSION: This study surpasses by far the largest cohort of critically ill patients with HH. HH is more common than previously thought with an ICU incidence of 4.0%, and it is associated with a high all-cause mortality of 45.0% at 28 days. The main causes of HH are cardiac failure and septic shock, which include more than 3/4 of all episodes. Clinicians should search actively for any underlying hemodynamic or respiratory instability even in patients with moderately increased AST levels. PMID- 29383511 TI - Is Regenerative Medicine Ready for Prime Time in Diabetic Polyneuropathy? AB - PURPOSE OF REVIEW: After a prolonged warm-up period of basic research, several modalities of cell replacement therapies are under development for diseases with no available cure. Diabetic polyneuropathy (DPN) is one of the most prevalent chronic diabetes complications that causes sensorimotor dysfunction, subsequent high risks for lower limb amputations, and high mortality. Currently, no disease modifying therapy exists for DPN. RECENT FINDINGS: Several types of well documented stem/progenitor cells have been utilized for cell transplantation therapies in DPN model rodents: mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and cells with similar characteristics of MSCs or EPCs derived from embryonic stem cells or induced pluripotent stem cells. Some recent experimental studies reported that these immature cells may have beneficial effects on DPN. Although the role of nerve regeneration in the pathology of DPN has not been sufficiently elucidated, many intervention studies attempting regenerative therapy of DPN have been reported. Further studies are needed to better evaluate the potential of regeneration in reversing the pathology of DPN. PMID- 29383512 TI - New MR perfusion features in primary central nervous system lymphomas: pattern and prognostic impact. AB - PURPOSE: Some MR perfusion features predict overall survival (OS) and progression free survival (PFS) in glioblastomas. Prognostic value of MR perfusion in primary CNS lymphomas (PCNSL) remains unexplored being the aim of this investigation. METHODS: We retrospectively analyzed 3Tesla dynamic susceptibility contrast MR perfusion in 37 pre-surgical PCNSL for normalized regional cerebral blood volume rCBVmean and rCBVmax and for a PCNSL-typical shoulder-like increase of the time signal intensity curve ("TSIC-shoulder"), indicating moderate vessel permeability. These MR perfusion features, tumor and edema size, number of lesions and patient characteristics were correlated with OS and PFS. RESULTS: Only patient's age was prognostic for OS (p = 0.0037) and PFS (p = 0.0088). 23 PCNSL had the TSIC-shoulder, a middle-sized diameter (39.5 +/- 10.8 mm), volume (15.7 +/- 11.3 ml), peritumoral edema (23 +/- 8.7 mm) and moderately increased rCBVmean and rCBVmax (1.7 +/- 0.5; 3.9 +/- 1.2). Seven PCSNL with the TSIC shoulder presented a sun-like pattern ("rCBV-sun") with a rim of marginally high rCBV. These unifocal PCNSL were larger (43 +/- 11.2 mm; 25.62 +/- 19.2 ml), with more peritumoral edema (32.8 +/- 7.6 mm) and lower CBVmean (0.8 +/- 0.3) and rCBVmax (2.2 +/- 0.7), compared to the remaining six multifocal PCNSL without the TSIC-shoulder (26.3 +/- 8.3 mm; 4.7 +/- 4 ml; 16.3 +/- 6.4 mm; 2.4 +/- 1.6; 4.4 +/- 2.3). CONCLUSIONS: Only patient age was predictive for OS and PFS of PCNSL; MR perfusion parameters and features were not. Most PCNSL revealed the TSIC shoulder, moderate size, peritumoral edema and rCBV increase. However, larger, solitary PCNSL additionally had a rCBV-sun pattern and more edema, maybe due to a centrifugal vessel proliferation, whereas smaller, multifocal PCNSL contain apparently more concentrated and less permeable blood vessels represented by higher rCBV, no TSIC-shoulder and less edema. PMID- 29383513 TI - A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome. AB - The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity. PMID- 29383514 TI - Closure of patent foramen ovale for cryptogenic stroke patients: an updated systematic review and meta-analysis of randomized trials. AB - OBJECTIVE: This systematic review and meta-analysis was performed to investigate the efficacy and safety of transcatheter device closure (TDC) plus anti thrombotic drugs over medical management alone for patients with cryptogenic stroke and patent foramen oval. METHODS: PubMed, Embase and Cochrane Library database were searched for randomized controlled clinical trials (RCTs). The primary endpoint is the composite of stroke and transient ischemic attack. The secondary endpoints are all-cause mortality, total serious adverse events, atrial fibrillation and bleeding. RESULTS: Five RCTs with a total of 3440 participants were included. TDC significantly decreased the risk of primary endpoint when compared to medical therapy alone (RR 0.54, 95% CI 0.43-0.69). Further subgroup analyses showed that patients with male gender and with substantial shunt size of foramen ovale significantly benefited from TDC as compared to those with female gender and with no substantial shunt size of foramen oval separately. Moreover, TDC was superior to medical therapy with anti-platelet drug alone (not with anti coagulation). On the other hand, the incidence of atrial fibrillation was higher in TDC group (RR 4.49, 95% CI 2.02-9.97), with the risk of other adverse events equivalent between the two groups. CONCLUSIONS: TDC plus anti-thrombotic drugs is superior than medical therapy alone for secondary prevention of stroke, especially for those with male gender and with substantial shunt size of foramen ovale. Though it may increase the risk of postoperative atrial fibrillation, it would not bring higher risk of all-cause mortality, total adverse events and bleeding. PMID- 29383515 TI - Diffusion tensor imaging in metachromatic leukodystrophy. AB - OBJECTIVE: We aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up. METHODS: Four late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and nonparametric permutation analyses (randomise) for TBSS data, considering family-wise error corrected p < 0.05 significant. RESULTS: Throughout white matter (WM), FA was decreased and MD and RD increased in both patient groups compared to controls, while AD was decreased in NAWM and corpus callosum. In the thalamus, no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally (median follow-up 3.9 years), diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients. INTERPRETATION: The observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss vs. intracellular sulfatide storage in macrophages, depending on region and disease stage. PMID- 29383516 TI - Glioblastoma as differential diagnosis of autoimmune encephalitis. AB - OBJECTIVE: To identify the clinical and radiological features that should raise suspicion for the autoimmune encephalitis (AE)-like presentation of glioblastoma. METHODS: This is an observational, retrospective case series of patients referred to the French National Reference Center on Paraneoplastic Neurological Diseases for suspected AE (possible, probable or definite, using the 2016 criteria) who later received a final diagnosis of glioblastoma according to 2016 WHO criteria. An extensive literature search was also conducted for similar existing cases. RESULTS: Between 2014 and 2016, 306 patients were referred to our center for suspected AE. Six of these patients (2%) later developed pathologically confirmed glioblastoma. Thirteen patients (9 male) were included for analysis (6 from the present series and 7 from the literature); median age was 63. Initially, a diagnosis of AE was clinically suspected based on: working memory deficits (77%), seizures (62%) (including status epilepticus in 23%), and psychiatric symptoms (46%). Initial brain MRI was not in favor of a typical glioblastoma pattern and showed bilateral (54%) or unilateral selective limbic involvement. Five patients exhibited initial slight contrast enhancement. A clear inflammatory CSF was present in five patients and three from the literature showed autoantibody positivity (NMDAR, VGKC, GluRepsilon2). Median delay between suspicions of AE to GBM diagnosis was 3 months (range 1.5-24) and one patient from the literature was diagnosed post-mortem. CONCLUSIONS: An alternative diagnosis of glioblastoma should be considered in patients presenting initially as AE, especially in patients who do not fulfill the criteria for definite AE and in those with a poor clinical evolution despite initial improvement. PMID- 29383517 TI - Phosphorus magnetic resonance spectroscopic imaging using flyback echo planar readout trajectories. AB - OBJECT: To present and evaluate a fast phosphorus magnetic resonance spectroscopic imaging (MRSI) sequence using echo planar spectroscopic imaging with flyback readout gradient trajectories. MATERIALS AND METHODS: Waveforms were designed and implemented using a 3 Tesla MRI system. 31P spectra were acquired with 2 * 2 cm2 and 3 * 3 cm2 resolution over a 20- and 21-cm field of view and spectral bandwidths up to 1923 Hz. The sequence was first tested using a 20-cm diameter phosphate phantom, and subsequent in vivo tests were performed on healthy human calf muscles and brains from five volunteers. RESULTS: Flyback EPSI achieved 10* and 7* reductions in acquisition time, with 68.0 +/- 1.2 and 69.8 +/ 2.2% signal-to-noise ratio (SNR) per unit of time efficiency (theoretical SNR efficiency was 74.5 and 76.4%) for the in vivo experiments, compared to conventional phase-encoded MRSI for the 2 * 2 cm2 and 3 * 3 cm2 resolution waveforms, respectively. Statistical analysis showed no difference in the quantification of most metabolites. Time savings and SNR comparisons were consistent across phantom, leg and brain experiments. CONCLUSION: EPSI using flyback readout trajectories was found to be a reliable alternative for acquiring 31P-MRSI data in a shorter acquisition time. PMID- 29383518 TI - Prediction of post-TACE necrosis of hepatocellular carcinoma usingvolumetric enhancement on MRI and volumetric oil deposition on CT, with pathological correlation. AB - OBJECTIVE: To investigate whether volumetric enhancement on baseline MRI and volumetric oil deposition on unenhanced CT would predict HCC necrosis and response post-TACE. METHOD: Of 115 retrospective HCC patients (173 lesions) who underwent cTACE, a subset of 53 HCC patients underwent liver transplant (LT). Semiautomatic volumetric segmentation of target lesions was performed on dual imaging to assess the accuracy of predicting tumour necrosis after TACE in the whole cohort and at pathology in the LT group. Predicted percentage tumour necrosis is defined as 100 % - (%baseline MRI enhancement - %CT oil deposition). RESULTS: Mean predicted tumour necrosis by dual imaging modalities was 61.5 % +/- 31.6%; mean percentage tumour necrosis on follow-up MRI was 63.8 % +/- 31.5 %. In the LT group, mean predicted tumour necrosis by dual imaging modalities was 77.6 % +/- 27.2 %; mean percentage necrosis at pathology was 78.7 % +/- 31.5 %. There was a strong significant correlation between predicted tumour necrosis and volumetric necrosis on MRI follow-up (r = 0.889, p<0.001) and between predicted tumour necrosis and pathological necrosis (r = 0.871, p<0.001). CONCLUSION: Volumetric pre-TACE enhancement on MRI and post-TACE oil deposition in CT may accurately predict necrosis in treated HCC lesions. KEY POINTS: * Imaging-based tumour response can assist in therapeutic decisions. * Lipiodol retention as carrier agent in cTACE is a tumour necrosis biomarker. * Predicting tumour necrosis with dual imaging potentially obviates immediate post-treatment MRI. * Predicting tumour necrosis would facilitate further therapeutic decisions in HCC post-cTACE. * Pre-TACE MRI and post-TACE CT predict necrosis in treated HCC. PMID- 29383519 TI - PET/CT predicts bone marrow involvement in paediatric non-Hodgkin lymphoma and may preclude the need for bone marrow biopsy in selected patients. AB - OBJECTIVES: To investigate the role of 18F-FDG PET/CT to detect bone marrow (BM) involvement in paediatric non-Hodgkin lymphoma (NHL). METHODS: Pretreatment PET/CT scans from 93 consecutive paediatric patients with NHL were retrospectively reviewed. Patterns of BM FDG uptake and standardized uptake value of the fifth lumbar vertebra (SUVBM) were compared with bone marrow biopsy (BMB) for diagnosis of BM involvement. RESULTS: Of 93 patients, 41 were judged to have BM involvement. Thirty-nine were identified by PET/CT, versus 23 by BMB. Sensitivity and specificity were 95 % and 98 % for PET/CT and 56 % and 100 % for BMB, respectively. None of the patients with BM FDG uptake lower than liver had positive BMB. In 45 patients presenting homogeneously increased BM uptake, positive BMB was achieved in 93 % (14/15) of patients with FDG uptake expanding to the distal portion of extremities, compared to 7 % (2/30) of those without. A multifocal pattern was observed in 25 patients and 18 had negative BMB. SUVBM differentiated BM involvement from benign BM activation with an area under the curve of 0.885 (p < 0.001). CONCLUSIONS: PET/CT had a high level of accuracy for detecting BM involvement in paediatric NHL. BMB might be omitted in selected patients. KEY POINTS: * PET/CT allows for accurate detection of bone marrow involvement. * Patterns of bone marrow FDG uptake are highly correlated with marrow disease. * Bone marrow biopsy could be omitted in selected paediatric patients. PMID- 29383520 TI - The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib. AB - OBJECTIVES: To identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib. METHODS: Thirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis. RESULTS: A higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used. CONCLUSIONS: DCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS. KEY POINTS: * DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy. * The change in blood volume measured by DCE-US was predictive of OS/PFS. * Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS. PMID- 29383521 TI - Standard diffusion-weighted, diffusion kurtosis and intravoxel incoherent motion MR imaging of sinonasal malignancies: correlations with Ki-67 proliferation status. AB - OBJECTIVES: To explore the correlations of parameters derived from standard diffusion-weighted imaging (DWI), diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) with the Ki-67 proliferation status. METHODS: Seventy five patients with histologically proven sinonasal malignancies who underwent standard DWI, DKI and IVIM were retrospectively reviewed. The mean, minimum, maximum and whole standard DWI [apparent diffusion coefficient (ADC)], DKI [diffusion kurtosis (K) and diffusion coefficient (Dk)] and IVIM [pure diffusion coefficient (D), pseudo-diffusion coefficient (D*) and perfusion fraction (f)] parameters were measured and correlated with the Ki-67 labelling index (LI). The Ki-67 LI was categorised as high (> 50%) or low (<= 50%). RESULTS: The K and f values were positively correlated with the Ki-67 LI (rho = 0.295~0.532), whereas the ADC, Dk and D values were negatively correlated with the Ki-67 LI (rho = 0.443~-0.277). The ADC, Dk and D values were lower, whereas the K value was higher in sinonasal malignancies with a high Ki-67 LI than in those in a low Ki 67 LI (all p < 0.05). A higher maximum K value (Kmax > 0.977) independently predicted a high Ki-67 status [odds ratio (OR) = 7.614; 95% confidence interval (CI) = 2.197-38.674; p = 0.017]. CONCLUSION: ADC, Dk, K, D and f are correlated with Ki-67 LI. Kmax is the strongest independent factor for predicting Ki-67 status. KEY POINTS: * DWI-derived parameters from different models are capable of providing different pathophysiological information. * DWI, DKI and IVIM parameters are associated with Ki-67 proliferation status. * K max derived from DKI is the strongest independent factor for the prediction of Ki-67 proliferation status. PMID- 29383522 TI - Staging liver fibrosis with DWI: is there an added value for diffusion kurtosis imaging? AB - OBJECTIVES: To assess liver fibrosis in patients with chronic liver disease using diffusion kurtosis imaging (DKI) in comparison with conventional diffusion weighted imaging, with histology as reference standard. METHODS: This prospective study included 81 patients and DKI with b-values of 0, 200, 500, 1,000, 1,500, 2,000 s/mm2 were performed. Mean diffusivity (MD), mean kurtosis (MK) and apparent diffusion coefficient (ADC) maps were calculated. The diagnostic efficacy of MD, MK and ADC for predicting stage 2 fibrosis or greater, and stage 3 fibrosis or greater were compared. RESULTS: The MD (rho=-0.491, p<0.001), MK (rho=0.537, p<0.001) and ADC (rho=-0.496, p<0.001) correlated significantly with fibrosis stages, and ADC exhibited a strong negative correlation with MK (rho= 0.968; p<0.001) and a moderate association with MD (rho=0.601, p<0.001). Areas under the curves (AUCs) for predicting stage 2 fibrosis or greater were not significantly different (p>0.05) between MK (0.809) and ADC (0.797) as well as between MD (0.715) and ADC. AUCs were also similar for MD (0.710), MK (0.768) and ADC (0.747) for predicting stage 3 fibrosis or greater. CONCLUSION: Although DKI is feasible for predicting liver fibrosis in patients with chronic liver disease, MD and MK offer similar diagnostic performance to ADC values. KEY POINTS: * Diffusion kurtosis imaging is feasible for staging liver fibrosis. * Diffusion kurtosis and monoexponential model are highly correlated. * The kurtosis model offers no added value to the conventional, monoexponential model. PMID- 29383523 TI - A simple method for bone age assessment: the capitohamate planimetry. AB - OBJECTIVES: To determine if the capitohamate (CH) planimetry could be a reliable indicator of bone age, and to compare it with Greulich-Pyle (GP) method. METHODS: This retrospective study included 391 children (age, 1-180 months). Two reviewers manually measured the areas of the capitate and hamate on plain radiographs. CH planimetry was defined as the measurement of the sum of areas of the capitate and hamate. Two reviewers independently applied the CH planimetry and GP methods in 109 children whose heights were at the 50th percentile of the growth chart. RESULTS: There was a strong positive correlation between chronological age and CH planimetry measurement (right, r = 0.9702; left, r = 0.9709). There was no significant difference in accuracy between CH planimetry (84.39-84.46 %) and the GP method (85.15-87.66 %) (p >= 0.0867). The interobserver reproducibility of CH planimetry (precision, 4.42 %; 95 % limits of agreement [LOA], -10.5 to 13.4 months) was greater than that of the GP method (precision, 8.45 %; LOA, -29.5 to 21.1 months). CONCLUSIONS: CH planimetry may be a reliable method for bone age assessment. KEY POINTS: * Bone age assessment is important in the work-up of paediatric endocrine disorders. * Radiography of the left hand is widely used to estimate bone age. * Capitatohamate planimetry is a reliable and reproducible method for assessing bone age. PMID- 29383524 TI - DNA double-strand breaks in blood lymphocytes induced by two-day 99mTc-MIBI myocardial perfusion scintigraphy. AB - OBJECTIVES: To investigate DNA double-strand breaks (DSBs) in blood lymphocytes induced by two-day 99mTc-MIBI myocardial perfusion scintigraphy (MPS) using y H2AX immunofluorescence microscopy and to correlate the results with 99mTc activity in blood samples. METHODS: Eleven patients who underwent two-day MPS were included. DSB blood sampling was performed before and 5min, 1h and 24h after the first and second radiotracer injections. 99mTc activity was measured in each blood sample. For immunofluorescence microscopy, distinct foci representing DSBs were quantified in lymphocytes after staining for the phosphorylated histone variant y-H2AX. RESULTS: The 99mTc-MIBI activity measured on days one and two was similar (254+/-25 and 258+/-27 MBq; p=0.594). Compared with baseline DSB foci (0.09+/-0.05/cell), a significant increase was found at 5min (0.19+/-0.04/cell) and 1h (0.18+/-0.04/cell) after the first injection and at 5min and 1h after the second injection (0.21+/-0.03 and 0.19+/-0.04/cell, respectively; p=0.003 for both). At 24h after the first and second injections, the number of DSB foci had returned to baseline (0.06+/-0.02 and 0.12+/-0.05/cell, respectively). 99mTc activity levels in peripheral blood samples correlated well with DSB counts (r=0.451). CONCLUSIONS: DSB counts reflect 99mTc-MIBI activity after injection for two-day MPS, and might allow individual monitoring of biological effects of cardiac nuclear imaging. KEY POINTS: * Myocardial perfusion scintigraphy using 99mTc induces time-dependent double-strand breaks (DSBs) * gamma-H2AX immunofluorescence microscopy shows DSB as an early response to radiotracer injection * Activity measurements of 99mTc correlate well with detected DSB * DSB foci induced by 99mTc return to baseline 24h after radiotracer injection. PMID- 29383525 TI - Contrast-enhanced cadaver-specific computed tomography in gross anatomy teaching. AB - OBJECTIVES: To establish contrast-enhanced (CE) cadaver-specific post-mortem computed tomography (PMCT) in first-year gross anatomy teaching and quantitatively evaluate its learning benefit. METHODS: 132 first-year medical students were included in this IRB-approved study and randomly assigned to an intervention group (n=59) provided with continuous access to CE and non-enhanced (NE) cadaver-specific PMCT-scans during the first-semester gross anatomy course, and a control group (n=73) that had only NE cadaver-specific PMCT data available. Four multiple-choice tests were carried out (15 questions each) subsequent to completion of the corresponding anatomy module: Head and neck anatomy, extremities, thorax, and abdomen. Median test results were compared in each module between the groups using the Wilcoxon rank-sum test. Additionally, participants of the intervention group answered a 15-item feedback-questionnaire. RESULTS: The intervention group achieved significantly higher test scores in head and neck anatomy (median=12.0, IQR=10.0-13.0) versus the control group (median=10.5, IQR=9.0-12.0) (p<0.01). There were no significant differences in the comparison of other modules. CEPMCT was highly appreciated by undergraduate medical students. CONCLUSIONS: The incorporation of contrast-enhanced cadaver specific PMCT-scans in gross anatomy teaching was proven to be feasible in the framework of the medical curriculum and significantly improved the students' learning performance in head and neck anatomy. KEY POINTS: * Cadaver-specific contrast-enhanced post-mortem CT (CEPMCT) is feasible in the medical curriculum. * CEPMCT yields significantly improved learning performance in head and neck anatomy (p<0.01). * CEPMCT is highly appreciated by medical students and used in tutor- or self-guided modes. PMID- 29383527 TI - Early percutaneous vertebroplasty helps motorsport professionals to resume competition soon after vertebral fracture. PMID- 29383526 TI - Leveraging the coronary calcium scan beyond the coronary calcium score. AB - : Non-contrast cardiac computed tomography in order to obtain the coronary artery calcium score has become an established diagnostic procedure in the clinical setting, and is commonly employed in clinical and population-based research. This state-of-the-art review paper highlights the potential gain in information that can be obtained from the non-contrast coronary calcium scans without any necessary modifications to the scan protocol. This includes markers of cardio metabolic health, such as the amount of epicardial fat and liver fat, but also markers of general health including bone density and lung density. Finally, this paper addresses the importance of incidental findings and of radiation exposure accompanying imaging with non-contrast cardiac computed tomography. Despite the fact that coronary calcium scan protocols have been optimized for the visualization of coronary calcification in terms image quality and radiation exposure, it is important for radiologists, cardiologists and medical specialists in the field of preventive medicine to acknowledge that numerous additional markers of cardio-metabolic health and general health can be readily identified on a coronary calcium scan. KEY POINTS: * The coronary artery calcium score substantially increased the use of cardiac CT. * Cardio-metabolic and general health markers may be derived without changes to the scan protocol. * Those include epicardial fat, aortic valve calcifications, liver fat, bone density, and lung density. * Clinicians must be aware of this potential additional yield from non-contrast cardiac CT. PMID- 29383528 TI - Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T. AB - OBJECTIVES: The purpose was to implement a fast 3D glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) sequence at 7 T, test stability and reproducibility in cartilage in the knee in healthy volunteers, and evaluate clinical applicability in cartilage repair patients. METHODS: Experiments were carried out on a 7-T scanner using a volume transmit coil and a 32-channel receiver wrap-around knee coil. The 3D gagCEST measurement had an acquisition time of 7 min. Signal stability and reproducibility of the GAG effect were assessed in eight healthy volunteers. Clinical applicability of the method was demonstrated in five patients before cartilage repair surgery. RESULTS: Coefficient of variation of the gagCEST signal was 1.9%. The reproducibility of the GAG effect measurements was good in the medial condyle (ICC = 0.87) and excellent in the lateral condyle (ICC = 0.97). GAG effect measurements in healthy cartilage ranged from 2.6%-12.4% compared with 1.3%-5.1% in damaged cartilage. Difference in GAG measurement between healthy cartilage and damaged cartilage was significant (p < 0.05). CONCLUSIONS: A fast 3D gagCEST sequence was applied at 7 T for use in cartilage in the knee, acquired within a clinically feasible scan time of 7 min. We demonstrated that the method has high stability, reproducibility and clinical applicability. KEY POINTS: * gagCEST measurements are stable and reproducible * A non-invasive GAG measurement with gagCEST can be acquired in 7 min * gagCEST is able to discriminate between healthy and damaged cartilage. PMID- 29383529 TI - Accelerated real-time cardiac MRI using iterative sparse SENSE reconstruction: comparing performance in patients with sinus rhythm and atrial fibrillation. AB - OBJECTIVES: To compare accelerated real-time cardiac MRI (CMR) using sparse spatial and temporal undersampling and non-linear iterative SENSE reconstruction (RT IS SENSE) with real-time CMR (RT) and segmented CMR (SEG) in a cohort that included atrial fibrillation (AF) patients. METHODS: We evaluated 27 subjects, including 11 AF patients, by acquiring steady-state free precession cine images covering the left ventricle (LV) at 1.5 T with SEG (acceleration factor 2, TR 42 ms, 1.8 * 1.8 * 6 mm3), RT (acceleration factor 3, TR 62 ms, 3.0 * 3.0 * 7 mm3), and RT IS SENSE (acceleration factor 9.9-12, TR 42 ms, 2.0 * 2.0 * 7 mm3). We performed quantitative LV functional analysis in sinus rhythm (SR) patients and qualitatively scored image quality, noise and artefact using a 5-point Likert scale in the complete cohort and AF and SR subgroups. RESULTS: There was no difference between LV functional parameters between acquisitions in SR patients. RT IS SENSE short-axis image quality was superior to SEG (4.5 +/- 0.6 vs. 3.9 +/- 1.1, p = 0.007) and RT (3.8 +/- 0.4, p = 0.003). There was reduced artefact in RT IS SENSE compared to SEG (4.4 +/- 0.6 vs. 3.8 +/- 1.2, p = 0.04), driven by arrhythmia performance. RT IS SENSE short-axis image quality was superior to SEG (4.6 +/- 0.5 vs. 3.1 +/- 1.0, p < 0.001) in the AF subgroup. CONCLUSION: Accelerated real-time CMR with iterative sparse SENSE provides excellent clinical performance, especially in patients with AF. KEY POINTS: * Iterative sparse SENSE significantly accelerates real-time cardiovascular MRI acquisitions. * It provides excellent qualitative and quantitative performance in sinus rhythm patients. * It outperforms standard segmented acquisitions in patients with atrial fibrillation. * It improves the trade-off between temporal and spatial resolution in real-time imaging. PMID- 29383530 TI - Microvascular Coronary Dysfunction-an Overview. AB - PURPOSE OF REVIEW: We will review the available data on the epidemiology, pathophysiology, diagnosis, and management of microvascular coronary dysfunction (MCD). RECENT FINDINGS: The study of MCD was pioneered by the Women's Ischemia Syndrome Evaluation (WISE) cohort. New techniques in the diagnosis of this condition, using invasive and noninvasive means, are helping to increase awareness of this condition as well as ways in which to treat it. Microvascular coronary disease without epicardial involvement has become an increasingly recognized cause of cardiac chest pain, particularly in women. Dysfunction of the microvasculature related to endothelium-dependent and endothelial-independent factors likely results in symptoms and/or evidence of ischemia. Although there is a growing body of research, there is still much about MCD that we do not understand. PMID- 29383531 TI - Ricoseius loxocheles (Acari: Phytoseiidae) is not a predator of false spider mite on coffee crops: What does it eat? AB - Ricoseius loxocheles (De Leon) (Acari: Phytoseiidae) is often found in coffee crops and is known to feed on coffee leaf rust, Hemileia vastatrix Berkeley and Broome (Uredinales). As the occurrence of coffee leaf rust is limited primarily to the rainy season, the mite may use other food sources to survive during the periods of low pathogen prevalence. It is well known that phytoseiid mites can survive on a variety of food sources, such as herbivorous mites, fungi and pollen. We evaluated the ability of R. loxocheles to survive and reproduce on a diet of Brevipalpus phoenicis Geijskes (Acari: Tenuipalpidae), cattail pollen (Typha spp.), clover rust (Puccinia oxalidis), bee pollen (Santa Barbara(r) dehydrated pollen, Santa Barbara, MG, Brazil) and coffee leaf rust. Ricoseius loxocheles did not survive or reproduce on any B. phoenicis stages tested (egg, larva, adult). The survival and oviposition of R. loxocheles were directly affected by the presence of coffee rust urediniospores, but not by the presence of the prey. Survival and oviposition of the phytoseiid were similar when fed cattail pollen, clover rust and coffee leaf rust but was lower when fed bee pollen. Our results show that R. loxocheles is not a predator of B. phoenicis but it is able to utilize other resources besides coffee leaf rust. PMID- 29383532 TI - First report of Borrelia miyamotoi in an Ixodes ricinus tick in Augsburg, Germany. AB - Borrelia miyamotoi, a spirochete found in the hard tick Ixodes ricinus, is thought to cause relapsing fever. The disease caused by this bacterium can manifest with high fever, fatigue and other symptoms. It may also lead to central nervous system involvement with symptoms similar to meningoencephalitis. DNA from ticks from the greater Augsburg region in Germany was subjected to qPCR for Borrelia spp., followed by nested PCR and subsequent sequencing for species identification of the qPCR positive samples. From 112 ticks, 20 were found to be positive for Borrelia. The DNA sequenced showed 50% Borrelia afzelli, 15% Borrelia garinii, 5% Borrelia valaisiana and one sequence was identified as Borrelia miyamotoi. The positive identification of Borrelia miyamotoi is unlikely to be due to contamination. In conclusion, Borrelia miyamotoi has been found in a tick in the Augsburg region for the first time. This follows on from previous reports of a low incidence of this bacterium in southern Germany around Lake Constance and in the Munich region. This infectious agent should be taken into account when patients present with recurring fever or neurological symptoms which cannot be otherwise explained. Tick-borne relapsing fever should now be considered as a cause of such symptoms and medical professionals should contemplate differential Borrelia testing when presented with corresponding symptoms. PMID- 29383533 TI - Ticks (Acari: Ixodidae) of the state of Amazonas, Brazil. AB - The tick fauna of Brazil is currently composed by 72 species. The state of Amazonas is the largest of Brazil, with an area of ~ 19% of the Brazilian land. Besides its vast geographic area, only 19 tick species have been reported for Amazonas. Herein, lots containing ticks from the state of Amazonas were examined in three major tick collections from Brazil. A total of 5933 tick specimens were examined and recorded, comprising 2693 males, 1247 females, 1509 nymphs, and 484 larvae. These ticks were identified into the following 22 species: Amblyomma cajennense sensu lato, Amblyomma calcaratum, Amblyomma coelebs, Amblyomma dissimile, Amblyomma dubitatum, Amblyomma geayi, Amblyomma goeldii, Amblyomma humerale, Amblyomma latepunctatun, Amblyomma longirostre, Amblyomma naponense, Amblyomma oblongoguttatum, Amblyomma ovale, Amblyomma rotundatum, Amblyomma scalpturatum, Amblyomma varium, Dermacentor nitens, Haemaphysalis juxtakochi, Ixodes cf. Ixodes fuscipes, Ixodes luciae, Rhipicephalus microplus, Rhipicephalus sanguineus sensu lato. Ticks were collected from 17 (27.4%) out of the 62 municipalities that currently compose the state of Amazonas. The following four species are reported for the first time in the state of Amazonas: A. coelebs, A. dubitatum, H. juxtakochi, and Ixodes cf. I. fuscipes. The only tick species previously reported for Amazonas and not found in the present study is Amblyomma parvum. This study provides a great expansion of geographical and host records of ticks for the state of Amazonas, which is now considered to have a tick fauna composed by 23 species. It is noteworthy that we report 1391 Amblyomma nymphs that were identified to 13 different species. PMID- 29383534 TI - Psychosocial complications of HIV/AIDS-metabolic disorder comorbidities among patients in a rural area of southeastern United States. AB - As people living with HIV experience longer life-expectancies resulting from antiretroviral therapy, comorbid conditions are increasing, particularly metabolic disorders. There is potential for psychosocial factors such as stigma experiences, depression, and alcohol use to complicate both HIV infection and metabolic disorders, including diabetes mellitus and hyperlipidemia. While the impact of these psychosocial factors on HIV infection alone are widely studied, their role in potentially complicating HIV co-morbid metabolic conditions has received little attention. This study examined the association between HIV related stigma and depression, and the potential role of alcohol use as a mediating factor in a clinical sample of patients with comorbid HIV infection and metabolic conditions. Results demonstrated that HIV stigma is associated with depression and this relationship is in part accounted for by alcohol use. Our results indicate that interventions aiming to improve the health of people living with HIV and co-morbid metabolic disorders should prioritize addressing alcohol use as it is related to sources of stress, such as stigma, and depression. PMID- 29383535 TI - Time spent outdoors, activity levels, and chronic disease among American adults. AB - Chronic diseases-including cancer, cardiovascular diseases, and metabolic conditions such as diabetes and obesity-account for over 60% of overall global mortality. Sedentary time increases the risk for chronic disease incidence and mortality, while moderate to vigorous physical activity is known to decrease risk. Most Americans spend at least half of their time sedentary, with a trend toward increasingly sedentary lifestyles, and few Americans achieve recommended levels of physical activity. Time spent outdoors has been associated with reduced sedentary time and increased physical activity among children/youth and the elderly, but few population-based studies have examined this relationship among working age adults who may face greater constraints on active, outdoor time. This study examines the relationship between time spent outdoors, activity levels, and several chronic health conditions among a population-based sample of working age American adults in the National Health and Nutrition Examination Survey (NHANES) for 2009-2012. Findings provide evidence that time spent outdoors, on both work days and non-work days, is associated with less time spent sedentary and more time spent in moderate to vigorous physical activity. Further, findings indicate that time spent outdoors is associated with lower chronic disease risk; while these associations are partially explained by activity levels, controlling for activity levels does not fully attenuate the relationship between time outdoors and chronic disease risk. While cross-sectional, study findings support the notion that increasing time spent outdoors could result in more active lifestyles and lower chronic disease risk. Future work should examine this relationship longitudinally to determine a causal direction. Additional work is also needed to identify mechanisms beyond physical activity, such as psychosocial stress, that could contribute to explaining the relationship between time spent outdoors and chronic disease risk. PMID- 29383536 TI - Which method is more suitable for advanced gastric cancer with enlarged lymph nodes, laparoscopic radical gastrectomy or open gastrectomy? AB - BACKGROUND: The oncologic outcome of laparoscopic radical gastrectomy (LG) with open radical gastrectomy (OG) for gastric cancer with preoperative enlarged lymph nodes (LNs) remains ambiguous. METHODS: The long-term outcomes of LG (n = 855) versus OG (n = 154) in gastric adenocarcinoma patients were analyzed retrospectively. Patients were stratified according to enlarged (> 10 mm) and small (<= 10 mm) LNs (ELN and SLN) based on the long-axis diameter of the LNs. RESULTS: The violin plot indicates that the distribution of ELN size was similar between two groups. Survival curves demonstrated that the overall survival (OS) in LG is enhanced compared with OG (p = 0.034). A stratified analysis revealed that the OS was better in the LG group compared with the OG group for patients with ELNs (p = 0.038). In a forest map analysis, the actual 3-year OS rate for LG was significantly increased compared with OG in enlarged suprapancreatic LN (ESLNs) patients. Stratified analysis based on different diameters of ESLNs revealed that the actual 3-year OS and cancer-specific survival (CSS)rate for LG was significant increased compared to OG with a diameter from 1.0 to 1.9 cm for pII or pIII stage patients. However, the actual 3-year OS and CSS rate for LG was significantly reduced compared with OG when the size exceeded 2.5 cm. CONCLUSIONS: For advanced gastric cancer with an ESLN diameter from 1.0 to 1.9 cm, LG could be chosen preferentially; nevertheless, LG is not safe if ESLN are > 2.5 cm. PMID- 29383537 TI - Changes in refractive characteristics in Japanese children with Down syndrome. AB - PURPOSE: To investigate the refractive characteristics of Japanese children with Down syndrome. STUDY DESIGN: Retrospective study. METHODS: The clinical records of refractive errors and ocular manifestations in children with Down syndrome who visited the Aichi Children's Health and Medical Center between November 2001 and January 2016 were retrospectively reviewed. The children were divided into the 3 following groups depending on their age: group 1 (<= 6 years), group 2 (7-12 years), and group 3 (13-19 years). The collection of refractive error data was performed only for the right eyes and only once for each child, when the children were last examined with their pupils dilated. RESULTS: The study included 416 children (224 boys, 192 girls; average age, 6.1 +/- 4.1 years). Group 3 had significantly stronger myopia than did groups 1 and 2. The mean cylindrical power in all the children was - 2.1 +/- 1.2 diopters (D), and cylindrical power <= - 1.0 D (stronger than - 1.0 D) was seen in 366 eyes (88%). No significant difference in cylindrical power was found among the 3 groups. CONCLUSIONS: The spherical equivalent refraction showed an age-dependent myopic shift. Given that the amount of astigmatism did not show age-dependent differences, the age dependent myopic shift could be due mainly to the change in spherical power. PMID- 29383538 TI - Outcomes of bee sting injury: comparison of hornet and paper wasp. AB - PURPOSE: To compare the outcomes of ocular injuries of hornets and paper wasps' stings. STUDY DESIGN: Retrospective case series. METHODS: Patients diagnosed with ocular injuries sustained by bee stings at Miyata Eye Hospital (Miyazaki, Japan) between August 2000 and July 2016 were enrolled. Retrospective data regarding type of bee, visual acuity, and treatment were collected from medical records. Outcomes of the hornet and wasp groups were compared. RESULTS: Five eyes of 5 patients (3 men, 2 women; mean age 44.6+/-21.2 years [range 9-62 years]) were enrolled. The mean follow-up period was 50.6 +/- 57.6 months (range 4 days to 121 months). The causative bee was hornet in 3 cases and wasp in 2. The anterior chamber was irrigated in 2 patients, both from the hornet group. The best corrected visual acuity at the final visit was no light perception, light perception, and (0.02) in the hornet group, (1.5) and (1.2) in the wasp group. CONCLUSIONS: The hornet group exhibited significantly worse prognosis than the wasp group. Identifying the type of bee is important in establishing prognosis. PMID- 29383539 TI - Retinal thinning after internal limiting membrane peeling for idiopathic macular hole. AB - PURPOSE: To determine the changes in retinal thickness and whether they correlate with the size of the macular hole (MH) after vitrectomy with internal limiting membrane peeling. STUDY DESIGN: Retrospective, interventional case series METHODS: Consecutive patients with an MH and undergoing pars plana vitrectomy with internal limiting membrane peeling were studied. The retinal thicknesses in the inner 4 sectors as defined by the Early Treatment of Diabetic Retinopathy Study were measured using spectral-domain optical coherence tomography (SD-OCT) before and at 2 weeks and 1, 3, 6, and 12 months after the surgery. The basal and minimum diameters of the MHs were measured. The correlations between the retinal thicknesses and the size of the MH were determined. RESULTS: Thirty-three eyes of 32 consecutive patients (18 women; mean age, 64.2 +/- 8.8 years) with an MH were studied. Thirteen eyes had a stage-2 MH; 12 eyes, a stage-3 MH; and 8 eyes, a stage-4 MH. The mean retinal thickness in the temporal sector was 362.8 +/- 29.9 um preoperatively, 337.9 +/- 20.6 um at 2 weeks postoperatively, and 307.6 +/- 20.2 um at 12 months postoperatively (P < .001 for both, paired t tests). The respective mean thicknesses in the superior, inferior, and nasal sectors were 373.9 +/- 34.9, 367 +/- 28.7, and 385.5 +/- 35.9 um preoperatively; 361.6 +/- 22.7, 359.4 +/- 20.6, and 383.4 +/- 29.0 um at 2 weeks postoperatively (P = .0087, P = .049, P = .635); and 339.4 +/- 18.9, 331.6 +/- 21.4, and 371.3 +/- 23.2 um at 12 months postoperatively (P < .001, P < .001, P = .033). The changes in the retinal thickness at 2 weeks and 12 months in all 4 sectors were significantly correlated with the basal and minimum diameters of the MH. CONCLUSIONS: Retinal thinning was observed soon after the MH surgery mainly in the temporal sector but also in the superior and inferior sectors. The thinning was greater in eyes with a larger MH, indicating that retinal structures dynamically change after internal limiting membrane peeling. PMID- 29383540 TI - Visualization of microaneurysms using optical coherence tomography angiography: comparison of OCTA en face, OCT B-scan, OCT en face, FA, and IA images. AB - PURPOSE: To compare the visualization of microaneurysms (MAs) in patients with diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA) with that using fluorescein angiography (FA). STUDY DESIGN: Prospective, clinical, and experimental. METHODS: This study was a prospective evaluation of imaging technology. Thirty-seven eyes of 33 patients with DR were scanned using an OCTA instrument. The 83 MAs that were confirmed on OCT B-scan and OCT en face images were evaluated using OCTA, and these findings were compared with those evaluated using FA. RESULTS: Of the 83 MAs confirmed on OCT B-scan images, 73 (88%) were clearly visualized on the OCTA en face images as nodular or comma shaped structures, while the remaining 12% did not present with a typical MA or vascular structure on the OCTA en face images at the relevant positions. Seventy four of the 83 MAs (87%) confirmed on the OCT B-scan images presented as punctate hyperfluorescent spots on the FA images. On the FA images, 8 of 9 (88%) MAs absent on the OCTA en face images presented as hyperfluorescent spots. Visualization of the MAs on the OCTA en face images did not correlate with the OCT B-scan images of the MA lumens (open, closed, or heterogeneous). CONCLUSIONS: For diabetic maculopathy, OCTA en face images do not present with comprehensive MAs images, indicating that some MAs might be overlooked with OCTA en face images. PMID- 29383541 TI - Comparison of the characteristics of patients with intermittent exotropia according to response to diagnostic monocular occlusion. AB - PURPOSE: To compare the characteristics of intermittent exotropia patients according to their response to the diagnostic monocular occlusion test. STUDY DESIGN: Retrospective study. METHODS: A retrospective review was performed of 141 patients with intermittent exotropia who had taken a monocular occlusion test before surgery. We classified the patients into 3 groups based on the response to monocular occlusion. The increase group was defined as those patients having an increase in deviation of >= 5 prism diopters (PD) after monocular occlusion as compared with the maximum measured angle. The decrease group was defined as those patients having a decrease in deviation of >= 5 PD. Otherwise, patients were classified as having no change. The patients' characteristics were compared among the groups. RESULTS: At distance fixation, 9 patients (6.5%) were classified as increase, 92 patients (66.7%) as no change, and 37 patients (26.8%) as decrease after monocular occlusion. At near fixation, 50 patients (35.5%) were classified as increase, 65 patients (46.1%) as no change, and 26 patients (18.4%) as decrease. At distance fixation, no significant differences were found between the parameters of the patients in the increase group and those of the patients in the other 2 groups. In patients with a small maximum angle of exodeviation at near fixation and with few visits, the deviation at near fixation significantly increased after diagnostic occlusion. CONCLUSION: Fifty-two patients (36.8%) showed an increase of >= 5 PD during distance or near fixation after monocular occlusion. In patients with a small maximum angle at near fixation and with few visits, it would be beneficial to perform the monocular occlusion test before surgery to reveal the maximal deviation angle, regardless of exotropia type. PMID- 29383542 TI - Ulinastatin Protects against CVB3-Induced Acute Viral Myocarditis through Nrf2 Activation. AB - Inflammation and oxidative stress are implicated in the pathogenesis of acute viral myocarditis (AVM). Ulinastantin (UTI), an inhibitor of serine protease widely used in treatment of pancreatitis and various inflammatory disorders, displays cardioprotective properties in experimental animals. Although the specific mechanism through which UTI regulates cardiac function is not well explored, evidence suggests that UTI might activate nuclear factor E2-related factor 2 (Nrf2) signaling. In this study, we investigated the role of Nrf2 in mediating UTI's cardioprotection in a mouse model of AVM. We found that UTI is an activator of Nrf2 signaling. It markedly increased Nrf2 nuclear translocation, Nrf2 transcription capacity, and the downstream protein expression. In addition, UTI possessed strong protective functions in coxsackievirus B3 (CVB3)-induced AVM. UTI treatment effectively reduced the cardiac damage, decreased the expression of inflammatory cytokines, and balanced oxidative stress via improving the activity of anti-oxidant and detoxifying enzymes. Even more impressively, UTI achieved its cardioprotective activities in an Nrf2-dependent manner. Taken together, our study has identified a novel pathway through which UTI exerts its cardioprotective functions and provides a molecular basis for UTI potential applications in the treatment of AVM and other inflammatory disorders. PMID- 29383543 TI - Soluble fibrin is a useful marker for predicting extracorporeal membrane oxygenation circuit exchange because of circuit clots. AB - A circuit clot is one of the most frequent complications during extracorporeal membrane oxygenation (ECMO) support. We identify coagulation/fibrinolysis markers for predicting ECMO circuit exchange because of circuit clots during ECMO support. Ten patients with acute pulmonary failure who underwent veno-venous ECMO were enrolled between January 2014 and December 2016. ECMO support lasted 106 days. The 6 days on which the ECMO circuits were exchanged were considered as circuit clot (+) group, while the remaining 100 days were considered as circuit clot (-) group. The predictors of ECMO circuit exchange because of circuit clots were identified. The mean duration of ECMO support was 10 +/- 13 days, and the mean number of ECMO circuit exchange was 0.6 +/- 1.1 times per patient. Thrombin antithrombin complex (TAT) and soluble fibrin (SF) were higher in the circuit clot (+) group than in the circuit clot (-) group (both P < 0.01). According to a multivariate analysis, SF was the only independent predictor of ECMO circuit exchange (P < 0.01). The odds ratio (confidence intervals) for SF (10 ug/ml) was 1.20 (1.06-1.36). The area under the curve and optimal cut-off value were 0.95 and 101 ng/ml for SF (sensitivity, 100%; specificity, 89%). SF may be useful in predicting ECMO circuit exchange because of circuit clots. PMID- 29383544 TI - Emerging Technologies for the Management of Type 1 Diabetes in Pregnancy. AB - PURPOSE OF REVIEW: The purpose of the study is to discuss emerging technologies available in the management of type 1 diabetes in pregnancy. RECENT FINDINGS: The latest evidence suggests that continuous glucose monitoring (CGM) should be offered to all women on intensive insulin therapy in early pregnancy. Studies have additionally demonstrated the ability of CGM to help gain insight into specific glucose profiles as they relate to glycaemic targets and pregnancy outcomes. Despite new studies comparing insulin pump therapy to multiple daily injections, its effectiveness in improving glucose and pregnancy outcomes remains unclear. Sensor-integrated insulin delivery (also called artificial pancreas or closed-loop insulin delivery) in pregnancy has been demonstrated to improve time in target and performs well despite the changing insulin demands of pregnancy. Emerging technologies show promise in the management of type 1 diabetes in pregnancy; however, research must continue to keep up as technology advances. Further research is needed to clarify the role technology can play in optimising glucose control before and during pregnancy as well as to understand which women are candidates for sensor-integrated insulin delivery. PMID- 29383545 TI - Children's at Home: Pilot Study Assessing Dedicated Social Media for Parents of Adolescents with Neurofibromatosis Type 1. AB - The aim of this pilot study was to evaluate Children's at Home (C@H), a dedicated social media website for parents of adolescents with neurofibromatosis type 1 (NF1). The interventional study included two phases: (1) creating video intervention/prevention assessment (VIA) visual narratives about having an adolescent with NF1 and (2) interacting on C@H, a secure, medically moderated social media website. C@H was evaluated qualitatively at three time points. At enrollment (T0, N = 17), participants reported needing C@H to break their isolation, connect with other families, and receive accurate information, advice, and support from others facing similar challenges. At T1, after creating VIA during 6 months (N = 13, 145 videos), participants mostly valued the opportunity to speak about the challenges they face with NF1 and their journey since diagnosis. At T2, after interacting on C@H for 7 weeks (N = 10, two sign ins/week/parent), participants reported connecting with other parents of children with NF1 for the first time, valuing the "real faces" and emotions of other parents with shared experiences providing a sense of normalcy. Qualitative analysis suggested that C@H decreased feelings of isolation, provided relief to talk about NF1 without having to explain it, provided new knowledge about NF1 and the opportunity to address non-medical issues of NF1 never discussed in clinic, and helped participants with putting their lives into perspective. C@H allowed parents of adolescents with NF1 to overcome previous isolation and connect for the first time. Innovative applications of social media dedicated to those who care for children with chronic conditions can provide peer-to-peer support, shared experience, and reliable medical information. PMID- 29383546 TI - Talking with Children About Adult-Onset Hereditary Cancer Risk: A Developmental Approach for Parents. AB - Families often express difficulty to their providers and request guidance regarding the task of communicating with children about potential adult-onset inherited cancer risks. This disclosure is often complicated by the parent's ongoing adjustment to their mutation status, guilt at potential transmission of the mutation to the child, concern over inciting distress in children, and the varied capacities of children in the home to understand genetic information. Providers often do not have adequate resources to support or facilitate disclosure of genetic test results to children. Optimally, communication about inherited cancer risk is an open, ongoing process within the family. We recommend that parents tailor conversations to the child's developmental, cognitive, emotional, and behavioral abilities to support comprehension. Based on well established theories of child development, empirical research on family communication of hereditary cancer risk, and clinical counseling experience, we offer recommendations for parental disclosure of genetic risk to children, case examples with critical discussion of relevant topics, common child questions with sample scripted responses, and additional printed and online resources. PMID- 29383547 TI - New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells. AB - Neural stem cells (NSCs) undergo self-renewal and generate neurons and glial cells under the influence of specific signals from surrounding environments. Glioblastoma multiforme (GBM) is a highly lethal brain tumor arising from NSCs or glial precursor cells owing to dysregulation of transcriptional and epigenetic networks that control self-renewal and differentiation of NSCs. Highly tumorigenic glioblastoma stem cells (GSCs) constitute a small subpopulation of GBM cells, which share several characteristic similarities with NSCs. GSCs exist atop a stem cell hierarchy and generate heterogeneous populations that participate in tumor propagation, drug resistance, and relapse. During multimodal treatment, GSCs de-differentiate and convert into cells with malignant characteristics, and thus play critical roles in tumor propagation. In contrast, differentiation therapy that induces GBM cells or GSCs to differentiate into a neuronal or glial lineage is expected to inhibit their proliferation. Since stem cell differentiation is specified by the cells' epigenetic status, understanding their stemness and the epigenomic situation in the ancestor, NSCs, is important and expected to be helpful for developing treatment modalities for GBM. Here, we review the current findings regarding the epigenetic regulatory mechanisms of NSC fate in the developing brain, as well as those of GBM and GSCs. Furthermore, considering the similarities between NSCs and GSCs, we also discuss potential new strategies for GBM treatment. PMID- 29383548 TI - An Unusual Cause of Horner Syndrome. PMID- 29383549 TI - Response to Capsule Commentary. PMID- 29383550 TI - Improving Rates of Outpatient Influenza Vaccination Through EHR Portal Messages and Interactive Automated Calls: A Randomized Controlled Trial. AB - BACKGROUND: Patient reminders for influenza vaccination, delivered via electronic health record (EHR) patient portal messages and interactive voice response (IVR) calls, offer an innovative approach to improving patient care. OBJECTIVE: To test the effectiveness of portal and IVR outreach in improving rates of influenza vaccination. DESIGN: Randomized controlled trial of EHR portal messages and IVR calls promoting influenza vaccination. PARTICIPANTS: Adults with no documented influenza vaccination 2 months after the start of influenza season (2014-2015). INTERVENTION: Using a factorial design, we assigned 20,000 patients who were active portal users to one of four study arms: (a) receipt of a portal message promoting influenza vaccines, (b) receipt of IVR call with similar content, (c) both a and b, or (d) neither (usual care). We randomized 10,000 non-portal users to receipt of IVR call or usual care. In all intervention arms, information on pneumococcal vaccination was included if the targeted patient was overdue for pneumococcal vaccine. MAIN MEASURES: EHR-documented influenza vaccination during the 2014-2015 influenza season, measured April 2015. KEY RESULTS: Among portal users, 14.0% (702) of those receiving both portal messages and calls, 13.4% (669) of message recipients, 12.8% (642) of call recipients, and 11.6% (582) of those with usual care received vaccines. On multivariable analysis of portal users, those receiving portal messages alone (OR 1.20, 95% CI 1.06-1.35) or IVR calls alone (OR 1.15 95% CI 1.02-1.30) were more likely than usual care recipients to be vaccinated. Those receiving both messages and calls were also more likely than the usual care group to be vaccinated (ad hoc analysis, using a Bonferroni correction: OR 1.29, 97.5% CI 1.13, 1.48). Among non-portal users, 8.5% of call recipients and 8.6% of usual care recipients received influenza vaccines (p = NS). Pneumococcal vaccination rates showed no significant improvement. CONCLUSIONS: Our outreach achieved a small but significant improvement in influenza vaccination rates. Registration: ClinicalTrials.gov Identifier NCT02266277 ( https://clinicaltrials.gov/ct2/show/NCT02266277 ). PMID- 29383551 TI - Development and Validation of Machine Learning Models for Prediction of 1-Year Mortality Utilizing Electronic Medical Record Data Available at the End of Hospitalization in Multicondition Patients: a Proof-of-Concept Study. AB - BACKGROUND: Predicting death in a cohort of clinically diverse, multicondition hospitalized patients is difficult. Prognostic models that use electronic medical record (EMR) data to determine 1-year death risk can improve end-of-life planning and risk adjustment for research. OBJECTIVE: Determine if the final set of demographic, vital sign, and laboratory data from a hospitalization can be used to accurately quantify 1-year mortality risk. DESIGN: A retrospective study using electronic medical record data linked with the state death registry. PARTICIPANTS: A total of 59,848 hospitalized patients within a six-hospital network over a 4-year period. MAIN MEASURES: The last set of vital signs, complete blood count, basic and complete metabolic panel, demographic information, and ICD codes. The outcome of interest was death within 1 year. KEY RESULTS: Model performance was measured on the validation data set. Random forests (RF) outperformed logisitic regression (LR) models in discriminative ability. An RF model that used the final set of demographic, vitals, and laboratory data from the final 48 h of hospitalization had an AUC of 0.86 (0.85 0.87) for predicting death within a year. Age, blood urea nitrogen, platelet count, hemoglobin, and creatinine were the most important variables in the RF model. Models that used comorbidity variables alone had the lowest AUC. In groups of patients with a high probability of death, RF models underestimated the probability by less than 10%. CONCLUSION: The last set of EMR data from a hospitalization can be used to accurately estimate the risk of 1-year mortality within a cohort of multicondition hospitalized patients. PMID- 29383552 TI - Towards understanding and acting on risk factors for developmental psychopathology. PMID- 29383553 TI - Examining the intertwined development of prosocial skills and ASD symptoms in adolescence. AB - Autism spectrum disorder (ASD) and reduced prosocial behaviour are strongly intertwined. However, social interactions with peers may be increasingly practiced over the course of development and may instigate a reduction in ASD symptoms and vice versa. We, therefore, sought to determine if, during adolescence, possible improvements in prosocial behaviours and ASD symptoms may benefit one another over time. Participants were 2773 adolescents from the Tracking Adolescents' Individual Lives Survey (TRAILS) cohorts. Measurements took place over three waves (mean ages: 11.1, 13.4, and 16.2 years). Longitudinal associations between teacher-rated classroom prosocial skills and parent-rated ASD symptoms were examined using the random intercept cross-lagged panel model (RI-CLPM). In addition to estimating the stable, between-person associations, the dynamical effects between prosocial skills and ASD symptoms over time were estimated at the within-person level. At the between-person level, prosocial skills and ASD symptoms were substantially negatively correlated. At the within person level, a small and unexpected positive cross-lagged effect from wave 1 ASD symptoms on wave 2 prosocial skills was observed. We added to the existing literature by showing that, in addition to replicating the already firmly established between-person association between low prosocial skills and ASD, within-person gains in prosocial skills do not lead to subsequent reduction of ASD symptoms, and reductions in ASD symptoms do not lead to subsequent enhancement of prosocial skills. We, therefore, conclude from our findings that the inverse association between autistic symptoms and prosocial skills in adolescence is highly stable. PMID- 29383554 TI - "We Went Out to Explore, But Gained Nothing But Illness": Immigration Expectations, Reality, Risk and Resilience in Chinese-Canadian Women with a History of Suicide-Related Behaviour. AB - Suicide is a complex and tragic outcome driven by biological, psychological, social and cultural factors. Women of Chinese descent and women who have immigrated to other countries have higher rates of suicidal ideation and behaviour, and immigration-related stress may contribute. To understand the experiences of immigration and their relationship with distress and suicide related behaviour in Chinese women who have immigrated to Canada. 10 semi structured qualitative interviews with Chinese women who have immigrated to Toronto, Canada and have a history of suicide-related behaviour were completed and analyzed using a constructivist grounded theory methodology. Immigration related and acculturation stress stemmed from unmet expectations and harsh realities. These repeated experiences resulted in hopelessness, helplessness, and alienation, which are risk factors for suicide and suicide-related behaviour. However, immigration-related support can also increase hope, self-efficacy and connectedness to foster recovery and resilience. This is the first qualitative study focusing on immigration experiences and its relationship to suicide-related behaviour in Chinese immigrant women. Knowledge of immigration and acculturation stressors can a) help identify and support women at risk for suicide and b) form a target for social intervention for all immigrant women, regardless of suicide risk. PMID- 29383555 TI - Superb microvascular imaging (SMI) findings of splenic artery pseudoaneurysm: a report of two cases. AB - Splenic artery pseudoaneurysm (SAPA) is a relatively infrequently encountered but clinically important vascular change, because it carries a high risk of rupture that warrants prompt treatment regardless of its size. Thus, sufficient knowledge is indispensable when seeing chronic pancreatitis patients or post-traumatic patients. Here, we report two such cases. The first case was a 52-year-old woman known to have chronic pancreatitis who presented with hematemesis and hemodynamic instability in which X-ray computed tomography (CT) and color Doppler sonography (CDS) had difficulty visualizing slow blood flow in SAPA, but superb microvascular imaging (SMI) clearly demonstrated the slow blood flow in SAPA, prompting our therapeutic decision to perform rapid embolization. The second case was a 51-year-old woman with post-traumatic SAPA in which 3D SMI enabled us to understand more clearly the topographic relationship between multiple SAPAs as compared with conventional US, leading to a decision to provide immediate surgical treatment. SMI was thought to provide a new insight into the US diagnosis of SAPA. When examining patients suspected of having a SAPA, SMI is an indispensable diagnostic tool at present. PMID- 29383556 TI - Simultaneous nitrification and denitrification with different mixed nitrogen loads by a hypothermia aerobic bacterium. AB - Microorganism with simultaneous nitrification and denitrification ability plays a significant role in nitrogen removal process, especially in the eutrophic waters with excessive nitrogen loads. The nitrogen removal capacity of microorganism may suffer from low temperature or nitrite nitrogen source. In this study, a hypothermia aerobic nitrite-denitrifying bacterium, Pseudomonas tolaasii strain Y 11, was selected to determine the simultaneous nitrification and denitrification ability with mixed nitrogen source at 15 degrees C. The sole nitrogen removal efficiencies of strain Y-11 in simulated wastewater were obtained. After 24 h of incubation at 15 degrees C, the ammonium nitrogen fell below the detection limit from an initial value of 10.99 mg/L. Approximately 88.0 +/- 0.33% of nitrate nitrogen was removed with the initial concentration of 11.78 mg/L and the nitrite nitrogen was not detected with the initial concentration of 10.75 mg/L after 48 h of incubation at 15 degrees C. Additionally, the simultaneous nitrification and denitrification nitrogen removal ability of P. tolaasii strain Y-11 was evaluated using low concentration of mixed NH4+-N and NO3--N/NO2--N (about 5 mg/L-N each) and high concentration of mixed NH4+-N and NO3--N/NO2--N (about 100 mg/L-N each). There was no nitrite nitrogen accumulation at the time of evaluation. The results demonstrated that P. tolaasii strain Y-11 had higher simultaneous nitrification and denitrification capacity with low concentration of mixed inorganic nitrogen sources and may be applied in low temperature wastewater treatment. PMID- 29383558 TI - Peri-procedural antithrombotic management: time to burn the bridge? AB - Emerging evidence suggests the use of peri-procedural bridging during interruptions in warfarin therapy increases bleed risk without reducing thromboembolic events. We implemented a peri-procedural anticoagulant management risk assessment tool in a single, outpatient anticoagulation clinic within an academic teaching institution. In this retrospective, pre-post observational study, we evaluated adults who required an interruption in warfarin therapy for an invasive procedure. The primary outcome was the proportion of patients who received bridging prior to and following implementation of the tool. Secondary outcomes included major bleeding, clinically relevant non-major bleeding, thromboembolic events, and other surgical complications within 30 days of the index procedure. In total, 149 patients were included. Bridging was recommended in 60% of the pre-intervention group and in 39.3% of the post-intervention group (p = 0.012). There were no significant differences in the secondary outcomes between the groups. However, patients who received bridging had numerically more bleeding events than patients who did not (12.3 vs. 3.9%, p = 0.102), and patients who received therapeutic dose bridging had more bleeding events than those who received modified dose bridging (10.9 vs. 1.4%, p = 0.466). Following implementation of the tool, there was a statistically significant decrease in the number of patients who received bridging without an increase in thromboembolic events. There were numerically higher rates of bleeding in those who received bridging. Additional research is needed to evaluate efficacy and safety of prophylactic versus treatment dose bridging and how implementation of peri procedural antithrombotic tools reflecting the emerging evidence will affect patient outcomes, satisfaction and healthcare costs. PMID- 29383559 TI - A Paradigm Shift in the Implementation of Ethics Codes in Construction Organizations in Hong Kong: Towards an Ethical Behaviour. AB - Due to the economic globalization which is characterized with business scandals, scholars and practitioners are increasingly engaged with the implementation of codes of ethics as a regulatory mechanism for stimulating ethical behaviours within an organization. The aim of this study is to examine various organizational practices regarding the effective implementation of codes of ethics within construction contracting companies. Views on ethics management in construction organizations together with the recommendations for improvement were gleaned through 19 semi-structured interviews, involving construction practitioners from various construction companies in Hong Kong. The findings suggested some practices for effective implementation of codes of ethics in order to diffuse ethical behaviours in an organizational setting which include; introduction of effective reward schemes, arrangement of ethics training for employees, and leadership responsiveness to reported wrongdoings. Since most of the construction companies in Hong Kong have codes of ethics, emphasis is made on the practical implementation of codes within the organizations. Hence, implications were drawn from the recommended measures to guide construction companies and policy makers. PMID- 29383557 TI - Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism. AB - In patients receiving anticoagulant therapy for venous thromboembolism (VTE), the important issue of anemia influence on the risk of bleeding has not been consistently studied. We used the large registry data RIETE (Registro Informatizado Enfermedad Tromboembolica) to compare the rate of major bleeding in patients receiving anticoagulant therapy for VTE according to the presence or absence of anemia at baseline. Patients with or without cancer were separately studied. Until August 2016, 63492 patients had been enrolled. Of these, 21652 (34%) had anemia and 14312 (23%) had cancer. Anemia was found in 57% of the patients with cancer and in 28% without (odds ratio 3.46; 95% CI 3.33-3.60). During the course of anticoagulant therapy, 680 patients with cancer had a major bleeding event (gastrointestinal tract 43%, intracranial 14%, hematoma 12%). Cancer patients with anemia had a higher rate of major bleeding (rate ratio [RR]: 2.52; 95% CI 2.14-2.97) and fatal bleeding (RR 2.73; 95% CI 1.95-3.86) than those without anemia. During the course of anticoagulation, 1133 patients without cancer had major bleeding (gastrointestinal tract 32%, hematoma 24%, intracranial 21%). Patients with anemia had a higher rate of major bleeding (RR 2.84; 95% CI 2.52-2.39) and fatal bleeding (RR 2.76; 95% CI 2.07-3.67) than those without. On a multivariable analysis, anemia independently predicted the risk for major bleeding in patients with and without cancer (hazard ratios: 1.66; 95% CI 1.40 1.96 and 1.95; 95% CI 1.72-2.20, respectively). During anticoagulation for VTE, both cancer- and non-cancer anemic patients had a higher risk for major bleeding than those without anemia. In anemic patients (with or without cancer), the rate of major bleeding during the course of anticoagulant therapy exceeded the rate of VTE recurrences. In patients without anemia the rate of major bleeding was lower than the rate of VTE recurrences. PMID- 29383560 TI - Expression profiles of Sox transcription factors within the postnatal rodent testes. AB - SRY-related box (Sox) transcription factors are conserved among vertebrate species. These proteins regulate multiple processes including sex determination and testis differentiation of the male embryo. Members of the Sox family have been identified in pre- and postnatal testis and are known to play an important role in sex determination (Sry, Sox9), male gonadal development, and fertility (Sox4, Sox8, Sox30). However, their expression profiles per cell types remain elusive. The objectives of this research were to characterize the expression profiles of Sox family members within adult testes using publically available datasets and to determine whether these findings are consistent with literature as well as immunofluorescence and in situ hybridization results. We have found that Sox4, Sox8, Sox9, and Sox12 are highly expressed in Sertoli cells, whereas Sox5, Sox6, and Sox30 were typically expressed in spermatocytes and spermatids. Spermatogonia were characterized by the expressions of Sox3, Sox4, Sox12, Sox13, and Sox18. Hence, these results suggest that Sox transcription factors may play different roles according to cell types of the adult mammalian testis. PMID- 29383561 TI - Betaine promotes lipid accumulation in adipogenic-differentiated skeletal muscle cells through ERK/PPARgamma signalling pathway. AB - Betaine, a neutral zwitterionic compound, could regulate intramuscular fat (IMF) deposition and meat quality. However, the efficacy is controversial. Moreover, the regulatory mechanism of betaine on lipid metabolism in skeletal muscle cells remains unclear. Therefore, in this study, we examined the effects and regulatory mechanism of betaine on lipid accumulation in adipogenic-differentiated C2C12 cells. We found that adipogenic-induced C2C12 cells treated with 10 mM betaine for 24 and 48 h had more lipid accumulation than the control group. Real-time PCR and Western blot results revealed that betaine treatment did not alter the expression of lipolysis and lipid oxidation-related genes, but dramatically increased the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and its target genes such as fatty acid binding protein 4 (aP2), fatty acid synthase (FAS) and lipoprteinlipase (LPL). Furthermore, betaine combined with PPARgamma inhibitor GW9662 treatment showed that betaine elevated C2C12 lipid accumulation through upregulation of PPARgamma. Mechanistically, we found that betaine promoted PPARgamma expression and lipid accumulation through inhibition of extracellular regulated protein kinases1/2 (ERK1/2) signalling pathway. These results demonstrate that betaine acts through ERK1/2-PPARgamma signalling pathway to regulate lipid metabolism in adipogenic-differentiated skeletal muscle cells, which could provide some useful information for controlling muscle lipid accumulation by manipulating ERK1/2 and PPARgamma signalling pathway. PMID- 29383563 TI - Homology Modeling of 5-alpha-Reductase 2 Using Available Experimental Data. AB - 5-Alpha-reductase 2 is an interesting pharmaceutical target for the treatment of several diseases, including prostate cancer, benign prostatic hyperplasia, male pattern baldness, acne, and hirsutism. One of the main approaches in computer aided drug design is structure-based drug discovery. However, the experimental 3D structure of 5-alpha-reductase 2 is not available at present. Therefore, a homology modeling method and molecular dynamics simulation were used to develop a reliable model of 5-alpha-reductase 2 for inhibitor pose prediction and virtual screening. Despite the low sequence identity between the target and template sequences, a useful 3D model of 5-alpha-reductase 2 was generated by the inclusion of experimental data. PMID- 29383562 TI - Obesity Surgery Score (OSS) for Prioritization in the Bariatric Surgery Waiting List: a Need of Public Health Systems and a Literature Review. AB - BACKGROUND: In the last decades, we have experienced an increase in the prevalence of obesity in western countries with a higher demand for bariatric surgery and consequently prolonged waiting times. Currently, in many public hospitals, the only criterion that establishes priority for bariatric surgery is waiting time regardless of obesity severity. METHODS: We propose a new, simple, and homogeneous clinical prioritization system, the Obesity Surgery Score (OSS), which takes into account simultaneously and equitably the time on surgical waiting list and the obesity severity based on three variables: body mass index, obesity-related comorbidities, and functional limitations. We have reviewed the current literature related to obesity clinical staging systems, and we have carried out an analysis of our patients in waiting list and divided their characteristics according to their degree of severity (A, B, or C) in the OSS. Patients with OSS grade C have a higher mean BMI, greater severity in comorbidities, and greater socio-labor impact. The current surgery waiting time of our series is of 26 months. Currently, 27 patients (51.9%) with OSS grade B and 15 patients (51.7%) with OSS grade C have been on our waiting list for more than 1 year. CONCLUSION: Since the obesity severity, the waiting time and its clinical consequences are associated with an increase in morbidity and mortality, it is important to apply a structured prioritization system for bariatric surgery waiting list. This allows prioritization of patients at greater risk, improves patient prognosis, and optimizes costs and available health resources. PMID- 29383564 TI - Large Scale Analyses and Visualization of Adaptive Amino Acid Changes Projects. AB - When changes at few amino acid sites are the target of selection, adaptive amino acid changes in protein sequences can be identified using maximum-likelihood methods based on models of codon substitution (such as codeml). Although such methods have been employed numerous times using a variety of different organisms, the time needed to collect the data and prepare the input files means that tens or hundreds of coding regions are usually analyzed. Nevertheless, the recent availability of flexible and easy to use computer applications that collect relevant data (such as BDBM) and infer positively selected amino acid sites (such as ADOPS), means that the entire process is easier and quicker than before. However, the lack of a batch option in ADOPS, here reported, still precludes the analysis of hundreds or thousands of sequence files. Given the interest and possibility of running such large-scale projects, we have also developed a database where ADOPS projects can be stored. Therefore, this study also presents the B+ database, which is both a data repository and a convenient interface that looks at the information contained in ADOPS projects without the need to download and unzip the corresponding ADOPS project file. The ADOPS projects available at B+ can also be downloaded, unzipped, and opened using the ADOPS graphical interface. The availability of such a database ensures results repeatability, promotes data reuse with significant savings on the time needed for preparing datasets, and effortlessly allows further exploration of the data contained in ADOPS projects. PMID- 29383565 TI - An Across-Target Study on Visual Attentions in Facial Expression Recognition. AB - As a simulation of human expression recognition, the studies on automatic expression recognition expect to draw useful enlightenment through close, accurate observation on human expression processing via advanced devices. Eye trackers are mostly used devices that are technically designed to obtain eye movement data. However, due to the discrepancy between target faces, across target analysis is limited in these studies, and this much reduces the chance of finding the latent eye-behavior patterns. Through the utilization of correspondences between targets, this study achieves an across-target analysis to explore the attention pattern in expression recognition. The fixations from different targets are mapped onto a synthetic face to generate an across-target fixation map, and then tokenized with area of interests (AOI), measured in receiver operating characteristic (ROC) space, modeled by linear regression and compared through Pearson's correlation. The resulted averaged correlation values vary in the range (0.60, 0.86), and illustrate that there is significant similarity between subjects when recognizing the same expression classes. PMID- 29383566 TI - Functional Categorization of Disease Genes Based on Spectral Graph Theory and Integrated Biological Knowledge. AB - Interaction of multiple genetic variants is a major challenge in the development of effective treatment strategies for complex disorders. Identifying the most promising genes enhances the understanding of the underlying mechanisms of the disease, which, in turn leads to better diagnostic and therapeutic predictions. Categorizing the disease genes into meaningful groups even helps in analyzing the correlated phenotypes which will further improve the power of detecting disease associated variants. Since experimental approaches are time consuming and expensive, computational methods offer an accurate and efficient alternative for analyzing gene-disease associations from vast amount of publicly available genomic information. Integration of biological knowledge encoded in genes are necessary for identifying significant groups of functionally similar genes and for the sufficient biological elucidation of patterns classified by these clusters. The aim of the work is to identify gene clusters by utilizing diverse genomic information instead of using a single class of biological data in isolation and using efficient feature selection methods and edge pruning techniques for performance improvement. An optimized and streamlined procedure is proposed based on spectral clustering for automatic detection of gene communities through a combination of weighted knowledge fusion, threshold-based edge detection and entropy-based eigenvector subset selection. The proposed approach is applied to produce communities of genes related to Autism Spectrum Disorder and is compared with standard clustering solutions. PMID- 29383567 TI - Risk Factors Analysis and Death Prediction in Some Life-Threatening Ailments Using Chi-Square Case-Based Reasoning (chi2 CBR) Model. AB - A wealth of data are available within the health care system, however, effective analysis tools for exploring the hidden patterns in these datasets are lacking. To alleviate this limitation, this paper proposes a simple but promising hybrid predictive model by suitably combining the Chi-square distance measurement with case-based reasoning technique. The study presents the realization of an automated risk calculator and death prediction in some life-threatening ailments using Chi-square case-based reasoning (chi2 CBR) model. The proposed predictive engine is capable of reducing runtime and speeds up execution process through the use of critical chi2 distribution value. This work also showcases the development of a novel feature selection method referred to as frequent item based rule (FIBR) method. This FIBR method is used for selecting the best feature for the proposed chi2 CBR model at the preprocessing stage of the predictive procedures. The implementation of the proposed risk calculator is achieved through the use of an in-house developed PHP program experimented with XAMP/Apache HTTP server as hosting server. The process of data acquisition and case-based development is implemented using the MySQL application. Performance comparison between our system, the NBY, the ED-KNN, the ANN, the SVM, the Random Forest and the traditional CBR techniques shows that the quality of predictions produced by our system outperformed the baseline methods studied. The result of our experiment shows that the precision rate and predictive quality of our system in most cases are equal to or greater than 70%. Our result also shows that the proposed system executes faster than the baseline methods studied. Therefore, the proposed risk calculator is capable of providing useful, consistent, faster, accurate and efficient risk level prediction to both the patients and the physicians at any time, online and on a real-time basis. PMID- 29383568 TI - Decreased aluminium tolerance in the growth of Saccharomyces cerevisiae with SSO2 gene disruption. AB - Aluminium ions inhibit growth of the budding yeast Saccharomyces cerevisiae. Disruption of the SSO2 gene increased the susceptibility to aluminium. Sso2p belongs to the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SSO2 has one paralogue, SSO1, which encodes Sso1p. The SNARE complex containing Sso1/2p plays a role in the recognition of plasma membrane targeted vesicle transport. The susceptibility to aluminium stress was not increased in the Deltasso1 strain. The phenotype of aluminium ion influx between the wild-type and Deltasso2 strains was not different, suggesting that Sso2p was involved in the elimination of cellular aluminium. However, the cellular lipid constitution of Deltasso2 was richer in unsaturated fatty acids than the wild type, indicating that Sso2p is associated with lipid homeostasis of the plasma membrane. Aluminium treatment increased the production of reactive oxygen species (ROS) during proliferation. ROS production was increased in the Deltasso2 strain after 3 h of aluminium treatment compared with the wild type. These results suggested that Sso2p plays a role in maintaining the lipid composition of the plasma membrane and the increase in unsaturated fatty acids amplified the production of ROS in the acute phase of aluminium stress. ROS derived from aluminium stress inhibited growth and resulted in the susceptibility of the Deltasso2 strain. PMID- 29383569 TI - Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects. AB - BACKGROUND AND OBJECTIVES: Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses. METHODS: Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food. RESULTS: Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (Cmax) and a 33.6% lower minimum steady state plasma concentration (Css min) than IR tablet intake, while the median time to Cmax (tmax) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC0-t), AUC from zero to infinity (AUC0-infinity), AUC at steady state (AUCss, tau = 24 h), Cmax at steady state (Css max) and average concentration at steady state (Css av) were contained within the 80-125% range of bioequivalence. The Cmax and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher Cmax. The 90% confidence interval (CIs) of the fed/fasted ratios for Cmax and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the tmax was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst. CONCLUSIONS: After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the tmax was significantly delayed, and the Cmax and Css min were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the Cmax increased and the tmax was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects. PMID- 29383570 TI - Correction to: Age at menarche and age at natural menopause in East Asian women: a genome-wide association study. AB - The original version of this article unfortunately contained a mistake. PMID- 29383572 TI - Cognitive Function of Children and Adolescents with Attention Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate. AB - BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756. PMID- 29383571 TI - Variation in the speech signal as a window into the cognitive architecture of language production. AB - The pronunciation of words is highly variable. This variation provides crucial information about the cognitive architecture of the language production system. This review summarizes key empirical findings about variation phenomena, integrating corpus, acoustic, articulatory, and chronometric data from phonetic and psycholinguistic studies. It examines how these data constrain our current understanding of word production processes and highlights major challenges and open issues that should be addressed in future research. PMID- 29383573 TI - Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management. AB - Fatigue is a frequently reported symptom in major depressive disorder, occurring in over 90% of patients. Clinical presentations of fatigue within major depressive disorder encompass overlapping physical, cognitive and emotional aspects. While this review addresses the epidemiology, burden, functional impact and management of fatigue in major depressive disorder, the main focus is on available pharmacotherapy options and their comparative efficacies. Our review of the effects of pharmacological treatments on fatigue in major depressive disorder found that medications with dopaminergic and/or noradrenergic action such as modafinil, flupenthixol and atomoxetine were most effective in improving symptoms of fatigue and low energy. However, significant variation across studies in assessment tools and study inclusion/exclusion criteria may have contributed to inconsistent findings. The efficacy of non-pharmacological interventions is also discussed, including light therapy and exercise. PMID- 29383574 TI - A Fatal Case of Candida auris and Candida tropicalis Candidemia in Neutropenic Patient. AB - We report a fatal case of Candida auris that was involved in mixed candidemia with Candida tropicalis, isolated from the blood of a neutropenic patient. Identification of both isolates was confirmed by amplification and sequencing of internal transcribed spacer and D1/D2 domain of large subunit in rRNA gene. Antifungal susceptibility test by E-test method revealed that C. auris was resistant to amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole and voriconazole. On the other hand, C. tropicalis was sensitive to all antifungal tested. The use of chromogenic agar as isolation media is vital in detecting mixed candidemia. PMID- 29383575 TI - Antifungal Susceptibility, Morphological and Molecular Characterization of Lasiodiplodia theobromae Isolated from a Patient with Keratitis. AB - Lasiodiplodia theobromae is a rare ocular pathogen. We report a patient with fungal keratitis caused by L. theobromae. The patient was a 75-year-old male, a farmer with diabetes type II, and no previous history of ocular trauma. Histopathology analysis revealed the presence fungi invading Descemet's membrane of the cornea. The fungus was characterized by septate, highly bulged fungal filaments involving full corneal thickness in the corresponding histopathology specimens. A dematiaceous mold was isolated and initally identified as L. theobromae by microscopic and macroscopic morphology, and further confirmed by PCR-based determination of internal transcribed spacer (ITS) regions of ribosomal DNA. Antifungal susceptibility tests showed sensitivity to amphotericin B (AMB) and voriconazole ( VRC), and resistance to other azoles, including itraconazole (ITC) and fluconazole (FLC). Corneal transplant was performed. Despite in vitro itraconazole resistance, the patient was successfully treated with oral itraconazole, topical voriconazole and natamycin, combined with ocular injections of amphotericin B and voriconazole. PMID- 29383576 TI - Behavioral studies and veterinary management of orangutans at Bukit Merah Orang Utan Island, Perak, Malaysia. AB - The Bukit Merah Orang Utan Island (OUI) Foundation has been conducting behavioral and veterinary research on orangutans as an attempt at ex situ conservation. Since 2010, the Primate Research Institute, Kyoto University has been collaborating with OUI to promote environmental enrichment and infant rearing by biological mothers in addition to the continuous efforts of refining the veterinary management of the endangered species. In 2011, three Bornean orangutans (Pongo pygmaeus pygmaeus) were released on an island, called BJ Island, adjacent to OUI. This island is approximately 5.6 ha in size, and 635 trees belonging to 102 plant species were identified prior to their release. Behavioral monitoring of the released individuals has been conducted to evaluate their behavioral adaptation to the new environment. Two of the three released orangutans were born in the wild, whereas the youngest individual was born on OUI and expected to learn forest survival strategies from the two older individuals. One of the orangutans was pregnant at the time of release and subsequently gave birth to two male infants on BJ Island. The behavioral monitoring indicated that these orangutans traveled more and spent more time on trees following their release onto BJ Island. However, resting was longer for two females both on OUI and BJ Island when compared to other populations. The orangutans consumed some natural food resources on BJ Island. The release into a more naturalistic environment may help the orangutans to develop more naturalistic behavioral patterns that resemble their wild counterparts. PMID- 29383577 TI - A case of ABO-incompatible blood transfusion treated by plasma exchange therapy and continuous hemodiafiltration. AB - ABO-incompatible blood transfusion is potentially a life-threatening event. A 74 year-old type O Rh-positive male was accidentally transfused with 280 mL type B Rh-positive red blood cells during open right hemicolectomy, causing ABO incompatible blood transfusion. Immediately after the transfusion, the patient experienced a hypotension episode followed by acute hemolytic reaction, disseminated intravascular coagulation and acute kidney injury. Plasma exchange therapy was performed to remove anti-B antibody and free hemoglobin because they caused acute hemolytic reaction, disseminated intravascular coagulation, and acute kidney injury. Free hemoglobin levels decreased from 13 to 2 mg/dL for 2 h. Continuous hemodiafiltration was used to stabilize hemodynamics. The patient was successfully treated for acute hemolytic reaction, disseminated intravascular coagulation, and acute kidney injury. Plasma exchange therapy and continuous hemodiafiltration are likely to be effective treatments for ABO-incompatible blood transfusion, and further studies are required to assess this effectiveness in future. PMID- 29383578 TI - The do's, don't and don't knows of supporting transition to more independent practice. AB - INTRODUCTION: Transitions are traditionally viewed as challenging for clinicians. Throughout medical career pathways, clinicians need to successfully navigate successive transitions as they become progressively more independent practitioners. In these guidelines, we aim to synthesize the evidence from the literature to provide guidance for supporting clinicians in their development of independence, and highlight areas for further research. METHODS: Drawing upon D3 method guidance, four key themes universal to medical career transitions and progressive independence were identified by all authors through discussion and consensus from our own experience and expertise: workplace learning, independence and responsibility, mentoring and coaching, and patient perspectives. A scoping review of the literature was conducted using Medline database searches in addition to the authors' personal archives and reference snowballing searches. RESULTS: 387 articles were identified and screened. 210 were excluded as not relevant to medical transitions (50 at title screen; 160 at abstract screen). 177 full-text articles were assessed for eligibility; a further 107 were rejected (97 did not include career transitions in their study design; 10 were review articles; the primary references of these were screened for inclusion). 70 articles were included of which 60 provided extractable data for the final qualitative synthesis. Across the four key themes, seven do's, two don'ts and seven don't knows were identified, and the strength of evidence was graded for each of these recommendations. CONCLUSION: The two strongest messages arising from current literature are first, transitions should not be viewed as one moment in time: career trajectories are a continuum with valuable opportunities for personal and professional development throughout. Second, learning needs to be embedded in practice and learners provided with authentic and meaningful learning opportunities. In this paper, we propose evidence-based guidelines aimed at facilitating such transitions through the fostering of progressive independence. PMID- 29383579 TI - Selenium (Na2SeO3) Upregulates Expression of Immune Genes and Blood-Testis Barrier Constituent Proteins of Bovine Sertoli Cell In Vitro. AB - Sertoli cells were isolated from newborn calves and cultured in a medium supplemented with 0, 0.25, 0.50, 0.75, and 1.00 mg/L of sodium selenite to study their immune stimulatory effect, influence on cell's viability, and expression of blood-testis barrier proteins (occludin, connexin-43, zonula occluden, E cadherin) using quantitative PCR and western blot analyses. Results showed that medium supplemented with 0.50 mg/L of selenium significantly (P < 0.05) promoted cell viability, upregulated toll-like receptor gene (TLR4), anti-inflammatory cytokines (IL-4, IL-10, TGFbeta1), and expressions of blood-testis barrier proteins, and modulated expressions of pro-inflammatory cytokines (TNF-alpha, IL 1beta, IFN-gamma). Sertoli cells grown in culture medium supplemented with 0.25 mg/L of selenium significantly upregulated TLR4, IL-4, IL-10, TGFbeta1, and blood testis barrier proteins compared to the control group. Sodium selenite supplementation at 0.75 and 1.00 mg/L levels was cytotoxic and temporarily downregulated the expression of blood-testis barrier protein within 24 h after culture; however, commencing from 72 h post culture, increased cell viability and upregulation of expression of blood-testis barrier proteins were observed. In conclusion, the results of this study showed that selenium supplementation in the culture medium up to 0.50 mg/L concentration upregulates immune genes and blood testis barrier constituent proteins of bovine Sertoli cells. PMID- 29383580 TI - Sickle cell nephropathy: an update on pathophysiology, diagnosis, and treatment. AB - Sickle cell nephropathy is a major complication of sickle cell disease. It manifests in different forms, including glomerulopathy, proteinuria, hematuria, and tubular defects, and frequently results in end-stage renal disease (ESRD). Different pathophysiologic mechanisms have been proposed to explain the development of nephropathy in SCD, where hemolysis and vascular occlusion are the main contributors in the manifestations of this disease. Markers of renal injury, such as proteinuria and tubular dysfunction, have been associated with outcomes among patients with sickle cell nephropathy and provide means for early detection of nephropathy and screening prior to progression to renal failure. In small sized clinical trials, hydroxyurea has demonstrated to be effective in slowing the progression to ESRD. Dialysis and renal transplantation represent the last resort for patients with sickle cell nephropathy. Nevertheless, despite the availability of diagnostic and therapeutic strategies, sickle cell nephropathy remains a challenging and under-recognized complication for patients with sickle cell disease. PMID- 29383581 TI - Genome-wide microRNA profiling of bovine milk-derived exosomes infected with Staphylococcus aureus. AB - Bovine milk is rich in exosomes, which contain abundant miRNAs and play important roles in the regulation of neonatal growth and development of adaptive immunity. Here, we analyzed miRNA expression profiles of bovine milk exosomes from three healthy and three mastitic cows, and then six miRNA libraries were constructed. Interestingly, we detected no scRNAs and few snRNAs in milk exosomes; this result indicated a potential preference for RNA packaging in milk exosomes. A total of 492 known and 980 novel exosomal miRNAs were detected, and the 10 most expressed miRNAs in the six samples accounted for 80-90% of total miRNA-associated reads. Expression analyses identified 18 miRNAs with significantly different expression between healthy and infected animals; the predicted target genes of differentially expressed miRNAs were significantly enriched in immune system process, response to stimulus, growth, etc. Moreover, target genes were significantly enriched in several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including inflammatory, immune, and cancer pathways. Our survey provided comprehensive information about milk exosomes and exosomal miRNAs involved in mastitis. Moreover, the differentially expressed miRNAs, especially miR-223 and miR-142-5p, could be considered as potential candidates for mastitis. PMID- 29383582 TI - Trend and causes of neonatal mortality in a level III children's hospital in Shanghai: a 15-year retrospective study. AB - BACKGROUND: To determine the trend and causes of neonatal mortality in a large level III neonatal intensive care unit in Shanghai during a 15-year period. METHODS: This is a retrospective, single-centered study. All neonates who died during the period from January 1, 1999 to December 31, 2013 at Children's Hospital of Fudan University were included. We extracted relevant clinical information from their medical records, analyzed neonatal mortality rate and the characteristics of these patients, and compared neonatal deaths between different periods and populations. RESULTS: Among a total of 50,957 admissions during the study period, there were 929 neonatal deaths. The neonatal mortality rate was 1.82%. Trends in neonatal mortality rate showed an increase in the period from 1.0% in 2003 to 2.2% in 2013. The main causes of neonatal mortality were complications of preterm birth (33.6%), congenital anomalies (21.3%), infections (12.6%), and birth asphyxia (9.1%). The proportions of complications of preterm birth (P < 0.001) and congenital anomalies (P = 0.018) increased yearly, while the proportions of birth asphyxia (P < 0.001) and infections (P < 0.001) decreased. Proportions of deaths caused by birth asphyxia (P = 0.005) and infections (P < 0.001) were both higher in the migrating population than in the permanent residents. CONCLUSIONS: Neonatal mortality rate increased from 2003 to 2013 in our study. The proportion of preterm infants in neonatal deaths also increased within the same period. Complications of preterm birth were the main cause of neonatal mortality and the percentage increased year by year. Neonates in the migrating population appeared to be at a higher risk of death during the neonatal period compared to those in the permanent residents, and efforts should be made towards improving perinatal care to prevent infections and birth asphyxia in this vulnerable population. PMID- 29383583 TI - Pediatrics in China: challenges and prospects. PMID- 29383584 TI - Asymptotic Relative Risk Results from a Simplified Armitage and Doll Model of Carcinogenesis. AB - We examine basic asymptotic properties of relative risk for two families of generalized Erlang processes (where each one is based off of a simplified Armitage and Doll multistage model) in order to predict relative risk data from cancer. The main theorems that we are able to prove are all corroborated by large clinical studies involving relative risk for former smokers and transplant recipients. We then show that at least some of these theorems do not extend to other Armitage and Doll multistage models. We conclude with suggestions for lifelong increased cancer screening for both former smoker and transplant recipient subpopulations of individuals and possible future directions of research. PMID- 29383585 TI - No selection, but higher satisfaction of people participating in the disease management programme diabetes type 2 in Germany. AB - AIMS: We analysed metabolic control, complications and satisfaction in people with and without DMP participation. METHODS: We retrospectively analysed the German data of the GUIDANCE study. The general practices included (n = 38) were selected from the physicians' register of the Thuringian Association of Statutory Health Insurance Physicians. Half of the practices (n = 19) participated in the DMP "Diabetes mellitus type 2". RESULTS: Nine hundred and fifty-nine people were included in the analysis. Of these, 541 (56.4%) were enrolled in the DMP and 418 (43.6%) not. There was no difference between the two groups (DMP vs. no DMP) regarding age (67.8 vs. 67.6y), gender (female 50.6 vs. 52.2%), diabetes duration (9.8 vs. 9.5y), BMI (31.3 vs. 30.7 kg/m2), HbA1c (7.2 vs. 7.2%), systolic blood pressure (139 vs. 140 mm Hg) or antihypertensive drug (89.5 vs. 88.8%). More DMP participants had regular screening of diabetic late complications: retinopathy 84.7 versus 69.9% (p < 0.001); polyneuropathy 93.0 versus 52.6% (p < 0.001). Chronic kidney disease was more frequent in DMP participants (15.0 vs. 9.3%, p = 0.005). Treatment satisfaction was higher in participants enrolled in the DMP (31.1 vs. 30.0; p = 0.002). CONCLUSIONS: DMP participants do not exhibit positive selection. Process quality and treatment satisfaction are higher in DMP participants. PMID- 29383586 TI - The 1-h post-load plasma glucose as a novel biomarker for diagnosing dysglycemia. AB - Identifying the earliest moment for intervention to avert progression to prediabetes and diabetes in high-risk individuals is a substantial challenge. As beta-cell function is already compromised in prediabetes, attention should therefore be focused on identifying high-risk individuals earlier in the so called pre-prediabetes stage. Biomarkers to monitor progression and identify the time point at which beta-cell dysfunction occurs are therefore critically needed. Large-scale population studies have consistently shown that the 1-h plasma glucose (1-h PG) >= 155 mg/dl (8.6 mmol/l) during the oral glucose tolerance test detected incident type 2 diabetes and associated complications earlier than fasting plasma glucose or 2-h plasma glucose levels. An elevated 1-h PG level appears to be a better alternative to HbA1c [5.7-6.4% (37-47 mmol/mol)] or traditional glucose criteria for identifying high-risk individuals at a stage when beta-cell function is substantially more intact than in prediabetes. Diagnosing high-risk individuals earlier proffers the opportunity for potentially reducing progression to diabetes, development of microvascular complications and mortality, thereby advancing benefit beyond that which has been demonstrated in global diabetes prevention programs. PMID- 29383587 TI - Claimed effects, outcome variables and methods of measurement for health claims proposed under European Community Regulation 1924/2006 in the area of blood glucose and insulin concentrations. AB - Most requests for authorization to bear health claims under Articles 13(5) and 14 related to blood glucose and insulin concentration/regulation presented to the European Food Safety Authority (EFSA) receive a negative opinion. Reasons for such decisions are mainly ascribable to poor substantiation of the claimed effects. In this scenario, a project was carried out aiming at critically analysing the outcome variables (OVs) and methods of measurement (MMs) to be used to substantiate health claims, with the final purpose to improve the quality of applications provided by stakeholders to EFSA. This manuscript provides a position statement of the experts involved in the project, reporting the results of an investigation aimed to collect, collate and critically analyse the information relevant to claimed effects (CEs), OVs and MMs related to blood glucose and insulin levels and homoeostasis compliant with Regulation 1924/2006. The critical analysis of OVs and MMs was performed with the aid of the pertinent scientific literature and was aimed at defining their appropriateness (alone or in combination with others) to support a specific CE. The results can be used to properly select OVs and MMs in a randomized controlled trial, for an effective substantiation of the claims, using the reference method(s) whenever available. Moreover, results can help EFSA in updating the guidance for the scientific requirements of health claims. PMID- 29383588 TI - Investigation of the effects of a prevention of mother-to-child HIV transmission program among Iranian neonates. AB - Human immunodeficiency virus (HIV) infection is mostly spreading in developing countries. One of the most important pathways of HIV infection in these nations is the vertical route, from mother to infant. Therefore, this study evaluated the effectiveness of the prevention of mother-to-child transmission (PMTCT) program for HIV among Iranian neonates born to HIV-positive mothers. A total of 54 neonates born to HIV-1 positive mothers, all of whom were in a PMTCT program for HIV, as per the Iranian guidelines, were enrolled in this descriptive cross sectional study from March 2014 to July 2017. After RNA extraction of a plasma specimen, HIV-1 viral load was tested by an Artus HIV-1 RG RT-PCR Kit. Out of 54 evaluated neonates, 32 (59.3%) were male. The mean age of the HIV-infected mothers was 30.1 +/- 5.4 (range: 19-47) years, and 36 (66.7%) of the mothers were in the age group 26-34 years. In the present study, it was found that none of the neonates whose mothers had previously entered PMTCT programs had HIV. 15 children were found who were born to HIV-positive mothers who had not entered the PMTCT program. Three of these children were infected with HIV (CRF35_AD), and none of them carried HIV-1 variants with SDRMs. The results of this study indicate that if HIV-positive pregnant women enter the PMTCT program for HIV, they can realistically hope to give birth to a non-infected child. PMID- 29383589 TI - Detection and genetic characterization of classic human astroviruses in Brazil, 2010-2012. AB - The aims of this study were to monitor human astrovirus (HAstV) infections in patients presenting with acute gastroenteritis in Brazil and to determine the HAstV genotypes of these viruses. From May 2010 to July 2012, a total of 140 samples that were negative for both rotaviruses and noroviruses were randomly selected and tested for the presence of HAstV using an RT-PCR assay specific for the ORF2 region. Viral genotypes were identified and genetic diversity was investigated by sequencing. HAstV infection was detected in 2.9% of samples (4/140). The viruses in three samples were shown by phylogenetic analysis to belong to HAstV-4 lineage "c", clustering together with strains detected in Europe and the Middle East. The virus in one sample was genotyped as HAstV-1 lineage "a", clustering with strains from Uruguay, Brazil and Russia. Our findings provide further evidence for a global distribution of HAstV-1a and suggest a possible emergent importance of the HAstV-4c lineage in this country. The present study does not suggest that HAstVs currently have a major epidemiological impact, even after the introduction of a rotavirus vaccine in 2006. PMID- 29383590 TI - Diversity of partial RNA-dependent RNA polymerase gene sequences of soybean blotchy mosaic virus isolates from different host-, geographical- and temporal origins. AB - Infection of soybean by the plant cytorhabdovirus soybean blotchy mosaic virus (SbBMV) results in significant yield losses in the temperate, lower-lying soybean production regions of South Africa. A 277 bp portion of the RNA-dependent RNA polymerase gene of 66 SbBMV isolates from different: hosts, geographical locations in South Africa, and times of collection (spanning 16 years) were amplified by RT-PCR and sequenced to investigate the genetic diversity of isolates. Phylogenetic reconstruction revealed three main lineages, designated Groups A, B and C, with isolates grouping primarily according to geographic origin. Pairwise nucleotide identities ranged between 85.7% and 100% among all isolates, with isolates in Group A exhibiting the highest degree of sequence identity, and isolates of Groups A and B being more closely related to each other than to those in Group C. This is the first study investigating the genetic diversity of SbBMV. PMID- 29383591 TI - The Son's Fault: Martin Luther King, Jr.'s Search for and Recovery of Sonship. AB - This article examines the role of sonship in the psychological and spiritual development of men. In using the methodology of psychobiography, I explore the life history of Martin Luther King, Jr. to analyze his search for and recovery of sonship. I propose that sonship helps men rebel against and, in the end, overcome the feelings of inadequacy that are experienced in their struggles to achieve manhood, particularly within the father-son dyad. The scholarship of pastoral theologian Donald Capps is instructive in this regard, in that he suggests that sons should be allowed to search for a male figure, a father-substitute, who can affirm, not disdain or reject, this state of sonship. In the end, what is often viewed as a negative act of regression-i.e., the recovery of and return to sonship-is recognized instead as a positive one that assists a man in his journey toward wholeness. PMID- 29383592 TI - Prayer: A Helpful Aid in Recovery from Depression. AB - Depression is a growing issue within the field of medicine. It negatively impacts individuals' lives and the people they are most connected to. For decades, medical professionals have been searching for solutions to assist those who are suffering from this illness. The use of drugs has not been a sufficient means of treatment to alleviate depression and its symptoms. There is a dire need to expand therapeutic interventions that can attribute meaningful recovery for victims of depression. One means of positive treatment is the use of prayer. Prayer, one of the most ancient forms of meditation, aligns and relaxes the mental state of the mind. The uses of drugs are limited by physiological focus, but prayer is a mechanism that brings human beings into a unique state of oneness. Oneness comprises the holistic nature of a human being and asserts the triad of well-being: mind, body, and spirit. As the emergence of humanities and holism continues in medicine, centering/meditative prayer and similar practices like mindfulness-based cognitive therapy can be useful therapeutic interventions specifically for major depressed patients. PMID- 29383593 TI - Scanning number and brightness yields absolute protein concentrations in live cells: a crucial parameter controlling functional bio-molecular interaction networks. AB - Biological function results from properly timed bio-molecular interactions that transduce external or internal signals, resulting in any number of cellular fates, including triggering of cell-state transitions (division, differentiation, transformation, apoptosis), metabolic homeostasis and adjustment to changing physical or nutritional environments, amongst many more. These bio-molecular interactions can be modulated by chemical modifications of proteins, nucleic acids, lipids and other small molecules. They can result in bio-molecular transport from one cellular compartment to the other and often trigger specific enzyme activities involved in bio-molecular synthesis, modification or degradation. Clearly, a mechanistic understanding of any given high level biological function requires a quantitative characterization of the principal bio molecular interactions involved and how these may change dynamically. Such information can be obtained using fluctation analysis, in particular scanning number and brightness, and used to build and test mechanistic models of the functional network to define which characteristics are the most important for its regulation. PMID- 29383594 TI - Detection of alternative subpleural lymph flow pathways using indocyanine green fluorescence. AB - PURPOSE: Pulmonary lymphatic fluid predominately flows along the bronchi. However, there are reports suggesting that an alternative lymphatic pathway exist, which may result in skip metastases. The aim of this study was to evaluate the subpleural lymph flow in vivo using indocyanine green (ICG) fluorescence. METHODS: One hundred cases were enrolled. ICG was injected into the macroscopically healthy subpleural space. Intraoperative fluorescence images were then observed in real time. RESULTS: ICG fluorescence was observed moving through subpleural channels in 58/100 cases. ICG flowed into adjacent lobes over interlobar lines in 18 cases and flowed from the visceral pleura directly into the mediastinum in 5 cases. The frequency of mediastinal detection without hilar lymph node detection was significantly higher in the left lung compared to the right (p < 0.05). The subpleural lymph flow detection rates were significantly lower in patients with smoking pack-years >= 40 than those with < 40 (p < 0.05). CONCLUSIONS: The flow of lymphatic fluid directly into the mediastinum suggests one mechanism of skip metastasis. In addition, the reduction of the subpleural lymph flows in smokers with >= 40 pack-years suggests that smoking might modify lymph flow patterns. These findings may assist in selecting the optimal therapy for patients with possible skip metastasis. PMID- 29383595 TI - The impact of the Charlson comorbidity index on the prognosis of esophageal cancer patients who underwent esophagectomy with curative intent. AB - PURPOSE: The aim of this study was to clarify the influence of Charlson comorbidity index (CCI) on treatment options, and on short- and mid-term outcomes in esophageal cancer patients who underwent esophagectomy. METHODS: Patients who underwent curative-intent esophagectomy from 2009 to 2014 were classified by CCI. A CCI of >= 2 was defined as high, while a CCI of 0 or 1 was classified as low. Clinicopathological parameters, including overall survival (OS) and disease specific survival (DSS), were compared between the groups. RESULTS: Among 548 patients, the most frequent comorbidity was chronic obstructive pulmonary disease (n = 142, 25.9%), followed by solid tumor (n = 79, 14.4%). A high CCI was significantly correlated with older age (P < 0.001), surgery alone (P = 0.020), a lower number of dissected lymph nodes (P < 0.001), lower rate of R0 resection (P = 0.048), and prolonged hospital stay (P < 0.001). In the low group, OS after surgery was favorable in comparison to the the high group. Although DSS was comparable between the groups, the CCI was significantly associated with a poor prognosis in patients with stage >= II disease. CONCLUSIONS: The CCI was significantly correlated with the prognosis of esophageal cancer patients who underwent curative-intent esophagectomy. PMID- 29383596 TI - Postoperative therapy with infliximab for Crohn's disease: a 2-year prospective randomized multicenter study in Japan. AB - PURPOSE: The prevention of postoperative recurrence is a critical issue in surgery for Crohn's disease. Prospective randomized trials in Western countries have shown that the postoperative use of anti-tumor necrosis factor alpha antibodies was effective in reducing the recurrence rate. We investigated the efficacy of infliximab (IFX) for the prevention of postoperative Crohn's disease recurrence. METHODS: We performed a prospective randomized multicenter study. Patients who underwent intestinal resection were assigned to groups treated with or without IFX. Immediately after surgery, patients in the IFX group received IFX at 5 mg/kg at 0, 2, and 6 weeks, followed by every 8 weeks for 2 years. The primary study outcome was the proportion of patients with endoscopic and/or clinical recurrence at 2 years after surgery. RESULTS: Thirty-eight eligible patients participated in this study: 19 in the IFX group and 19 in the non-IFX group. The disease recurrence rate in the IFX group was 52.6% (10/19), which was significantly lower than that in the non-IFX group (94.7% [18/19]). CONCLUSION: The postoperative use of IFX is effective in preventing Crohn's disease recurrence for 2 years. PMID- 29383598 TI - Athletes with inguinal disruption benefit from endoscopic totally extraperitoneal (TEP) repair. AB - PURPOSE: Inguinal disruption, a common condition in athletes, is a diagnostic and therapeutic challenge. The aim of this study was to evaluate the effect of endoscopic totally extraperitoneal (TEP) repair in athletes with inguinal disruption, selected through a multidisciplinary, systematic work-up. METHODS: An observational, prospective cohort study was conducted in 32 athletes with inguinal disruption. Athletes were assessed by a sports medicine physician, radiologist and hernia surgeon and underwent subsequent endoscopic TEP repair with placement of polypropylene mesh. The primary outcome was pain reduction during exercise on the numeric rating scale (NRS) 3 months postoperatively. Secondary outcomes were sports resumption, physical functioning and long-term pain intensity. Patients were assessed preoperatively, 3 months postoperatively and after a median follow-up of 19 months. RESULTS: Follow-up was completed in 30 patients (94%). The median pain score decreased from 8 [interquartile range (IQR) 7-8] preoperatively to 2 (IQR 0-5) 3 months postoperatively (p < 0.001). At long term follow-up, the median pain score was 0 (IQR 0-3) (p < 0.001). At 3 months, 60% of patients were able to complete a full training and match. The median intensity of sport was 50% (IQR 20-70) preoperatively, 95% (IQR 70-100) 3 months postoperatively (p < 0.001), and 100% (IQR 90-100) at long-term follow-up (p < 0.001). The median frequency of sport was 4 (IQR 3-5) times per week before development of symptoms and 3 (IQR 3-4) times per week 3 months postoperatively (p = 0.025). Three months postoperatively, improvement was shown on all physical functioning subscales. CONCLUSIONS: Athletes with inguinal disruption, selected through a multidisciplinary, systematic work-up, benefit from TEP repair. PMID- 29383597 TI - The attenuation value of preoperative computed tomography as a novel predictor for pancreatic fistula after pancreaticoduodenectomy. AB - PURPOSE: Pancreatic fistula (PF) is the most serious complication following pancreaticoduodenectomy (PD). This study was performed to identify new clinical factors that may predict the development of PF after PD to improve perioperative management. METHODS: Seventy-five consecutive patients who underwent PD from 2012 to 2015 were evaluated. The patients' perioperative data including the computed tomography (CT) parameters were collected. The minimum, maximum, and mean CT attenuation values (HUmin, HUmax, and HUmean, respectively) were extracted from the pancreatic parenchyma (>= 100 pixels), and the standard deviation of these values (HUSD) was determined from the slice in which the superior mesenteric and splenic veins were merged. PF was defined as grade B or C according to the International Study Group for Pancreatic Fistula criteria. RESULTS: The PF occurrence rate (grade B or C) was 25.3% in 75 patients. A multivariate analysis identified a larger HUSD (odds ratio 3.092; 95% CI 1.018-9.394) and higher amylase concentration in drainage fluid on postoperative day 1 (odds ratio 1.0001; 95% CI 1.00001-1.00022) as significant risk factors for PF. CONCLUSIONS: The HUSD of preoperative CT attenuation values in the pancreatic parenchyma was found to be an independent predictor for PF after PD and it might therefore positively contribute to the perioperative management of PD. PMID- 29383599 TI - Age-related differences in the use of spatial and categorical relationships in a visuo-spatial working memory task. AB - Research examining object identity and location processing in visuo-spatial working memory (VSWM) has yielded inconsistent results on whether age differences exist in VSWM. The present study investigated whether these inconsistencies may stem from age-related differences in VSWM sub-processes, and whether processing of component VSWM information can be facilitated. In two experiments, younger and older adults studied 5 * 5 grids containing five objects in separate locations. In a continuous recognition paradigm, participants were tested on memory for object identity, location, or identity and location information combined. Spatial and categorical relationships were manipulated within grids to provide trial level facilitation. In Experiment 1, randomizing trial types (location, identity, combination) assured that participants could not predict the information that would be queried. In Experiment 2, blocking trials by type encouraged strategic processing. Thus, we manipulated the nature of the task through object categorical relationship and spatial organization, and trial blocking. Our findings support age-related declines in VSWM. Additionally, grid organizations (categorical and spatial relationships), and trial blocking differentially affected younger and older adults. Younger adults used spatial organizations more effectively whereas older adults demonstrated an association bias. Our finding also suggests that older adults may be less efficient than younger adults in strategically engaging information processing. PMID- 29383601 TI - Fluorescein-assisted stereotactic needle biopsy of brain tumors: a single-center experience and systematic review. AB - Over the last years, fluorescence-based technology has begun an emergent intraoperative method for diagnostic confirmation of brain tumor tissue in stereotactic needle biopsy. However, the actual level of evidence is quite low, especially about fluorescein sodium (FL) application. This method needs to be further validated and better analyzed about its impact in clinical practice. Retrospective analysis of 11 cases with contrast-enhancing brain tumors, underwent awake stereotactic needle biopsy with intraoperative FL assistance (group 1), was verified under the operative microscope filter. This group was matched with a control group of 18 patients (group 2). In addition, a systematic literature review was performed in PubMed/Medline database according to PRISMA statement. All studies concerning FL or 5-ALA application in stereotactic biopsy as intraoperative confirmation of brain tumor tissue were included. The primary endpoint was the evaluation of diagnostic accuracy. In group 1, all fluorescent specimens were diagnostic. The number of samplings was the useful minimum and non use of intraoperative neuropathological examination allowed to significantly reduce procedure time (42.09 vs 69.72 min of group 2). No complications occurred, and the average hospitalization time after procedure was 1.09 days (vs 2.33 of group 2). Literature analysis supports the usefulness of photodiagnosis and its high diagnostic yield especially at the core of high-grade/contrast-enhancing tumors. FL assistance during stereotactic biopsy of contrast-enhancing brain tumors may give a real-time confirmation of tumor tissue, maximizing the diagnostic yield, and reducing time of procedure, morbidity, and hospitalization. PMID- 29383600 TI - The role of surgery in intracranial PCNSL. AB - This aimed to evaluate the effect of surgery for overall survival (OS) and progression-free survival (PFS) in intracranial primary CNS lymphoma (PCNSL) of all patients diagnosed at a single center. A prospective database at Oslo University Hospital of PCNSL was reviewed over a 12-year period (2003-2014). Seventy-nine patients with intracranial PCNSL were identified. Deep brain involvement was shown in 63 patients. Thirty-two patients underwent craniotomy with resection, while all other patients had a biopsy. Fifty-seven patients were given chemotherapy: 18 were treated with the MSKCC (Memorial Sloan-Kettering Cancer Center) with rituximab, 21 with the MSKCC without rituximab, and 14 within a Nordic prospective phase II protocol. Forty-four patients achieved complete response (CR) and had OS of 46.3 months. Patients who underwent resection had a median OS of 28.6 versus 11.7 months for those who had a biopsy performed. Resection showed an insignificant prolongation of OS. Multivariate analysis confirmed statistical significance of deep brain involvement only (p < 0.005). Neither chemotherapy regimen, Karnofsky Performance Status (KPS), type of surgery, nor patient age was significant factors for OS or PFS. Resective surgery played no role in significantly improving either OS or PFS and therefore it is not recommended as treatment for PCNSL. PMID- 29383602 TI - Recurrence of Gastric Masses in a Neonate with Congenital Myotonic Dystrophy. PMID- 29383603 TI - Goltz-Gorlin Syndrome: Revisiting the Clinical Spectrum. AB - OBJECTIVE: To describe the varying phenotypic spectrum of Focal Dermal Hypoplasia (FDH) and to emphasize the need for identifying the condition in mildly affected females which is crucial for offering a prenatal diagnosis in subsequent pregnancy owing to the risk of having a severely affected baby. METHODS: The phenotype-genotype correlation of 4 patients with FDH, over a period of 11 y from the genetic clinic in a tertiary care centre from Kerala, India was done. RESULTS: All four mutation proven patients were females (2 adults and 2 children). One of the adult female subjects were mildly affected, though she had a history of having a severely affected female child who expired on day six. Among the 2 affected children, one of them had an unaffected mother and the other had an affected mother. CONCLUSIONS: FDH has a wide clinical spectrum from very subtle findings to severe manifestations. The lethality of the condition in males and the disfigurement and multisystem involvement in females highlights the importance of confirmation of diagnosis by molecular analysis so that the family can be offered prenatal diagnosis in subsequent pregnancy. PMID- 29383604 TI - Cyclic fatigue resistances of Hyflex EDM, WaveOne gold, Reciproc blue and 2shape NiTi rotary files in different artificial canals. AB - The aim of the present study was to compare the cyclic fatigue resistances of HyFlex EDM (HEDM), WaveOne Gold (WOG), Reciproc Blue (RB), and 2Shape (TS) NiTi systems having different metallurgic properties. HEDM, WOG, RB, and TS instruments were rotated in artificial canals which were made of stainless steel with an inner diameter of 1.5 mm, 45 degrees , and 90 degrees angles of curvatures and a radius of curvature of 5 mm until fracture occurred, and the time to fracture (TTF) was recorded in seconds. Also, number of cycles to fracture was calculated (NCF). Data were statistically analyzed using Kruskal Wallis and t test. The statistical significance level was set at P < 0.05. When comparing the TTF of all the instruments tested in the artificial canal with 45 degrees curvature, RB had statistically the highest cyclic fatigue resistance followed by HEDM and TS (P < 0.05), while the WOG showed the lowest cyclic fatigue resistance (P < 0.05). In artificial canal with 90 degrees curvature, RB showed a significantly higher cyclic fatigue resistance than the other tested files (P < 0.05), while there was no significant difference among the TS, WOG and HEDM groups (P > 0.05). When the NCF values were taken into consideration, HEDM reported a significantly higher cyclic fatigue resistance than TS in both canal curvatures analyzed (P < 0.05). Within the limitations of the present study, RB NiTi files showed statistically higher cyclic fatigue resistance in artificial canals with 45 degrees and 90 degrees than the other NiTi files tested. PMID- 29383605 TI - Hemolysis in Alcoholic Liver Disease: Zieve's Syndrome. PMID- 29383606 TI - Clinical Effectiveness of Submucosal Injection with Indigo Carmine Mixed Solution for Colon Endoscopic Mucosal Resection. AB - BACKGROUND/AIMS: Submucosal injection with indigo carmine mixed solution can improve the delineation of colorectal neoplasia during endoscopic mucosal resection (EMR). Thus, the aim of this study was to evaluate the efficacy of submucosal injection with indigo carmine mixed solution during EMR of colorectal neoplasia. METHODS: This was a prospective, randomized, controlled study of a total of 212 neoplastic colon polyps (5-20 mm) subjected to EMR in a single tertiary university hospital. The patients were randomized into two groups according to whether or not indigo carmine mixed solution was used, and the complete resection rate (CRR) after EMR was evaluated. RESULTS: A total of 212 neoplastic polyps (normal saline group, 115; indigo carmine group, 97) were successfully removed by EMR. There was no significant difference in the CRR (92.8 vs. 89.6%, p = 0.414) or macroscopic delineation (86.0 vs. 93.8%, p = 0.118) between the two groups. In a separate analysis of sessile serrated adenomas/polyps (SSAs/Ps), macroscopic delineation was better in the indigo carmine group than the normal saline group (87.5 vs. 53.8%), albeit not significantly (p = 0.103). In univariate analyses, the CRR was significantly related to polyp location, polyp morphology, macroscopic delineation, and pathologic findings. In a multiple logistic regression analysis, macroscopic delineation (odds ratio (OR), 7.616, p = 0.001) and polyp pathology (OR, 8.621; p < 0.001) were significantly associated with the CRR. CONCLUSIONS: Submucosal injection with indigo carmine mixed solution did not improve the CRR or macroscopic delineation of EMR of colorectal neoplasias. PMID- 29383607 TI - Prevalence of Nausea and Vomiting in Adults Using Ropinirole: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Nausea and vomiting are commonly associated with medication use. Dopaminergic agonists have been associated with these symptoms, but their impact in patients without Parkinson's disease, such as those with restless legs syndrome (RLS), is not well characterized. AIMS: We sought to determine whether the non-ergoline dopamine agonist ropinirole is associated with nausea and vomiting in adults with RLS. METHODS: We conducted a systematic review using PUBMED, EMBASE, and clinical trial databases to identify placebo-controlled clinical trials of ropinirole for RLS treatment. We extracted data including dosing schedule and the proportion of patients reporting nausea and/or vomiting. We also determined hazard ratios (HR) using a random effects proportional hazard model. RESULTS: We extracted data from a pool of 13 studies. The prevalence of nausea in the ropinirole-treated RLS group (RLS-R; N = 1528) was 37.2% compared to 9.4% in the placebo-treated RLS group (RLS-P; N = 1395) (p < 0.0001). The prevalence of vomiting in the RLS-R group was 10.9% compared to 2.6% in the RLS-P group (p < 0.0001). Ropinirole use was associated with a higher risk of reporting nausea (HR 5.924 [4.410-7.959], p < 0.001) and experiencing vomiting (HR 4.628 [3.035-7.057], p < 0.0001). Nausea and vomiting represented nearly 50% of all adverse events reported. CONCLUSIONS: Nausea and vomiting are quite common side effects in those using ropinirole for RLS. As RLS is more widely recognized and treated; the prevalence of ropinirole-induced nausea and vomiting could grow substantially. Ropinirole use should be considered as a cause of chronic nausea and vomiting. PMID- 29383608 TI - Aldo-Keto Reductases as Early Biomarkers of Hepatocellular Carcinoma: A Comparison Between Animal Models and Human HCC. AB - BACKGROUND: The intrinsic heterogeneity of hepatocellular carcinoma (HCC) represents a great challenge for its molecular classification and for detecting predictive biomarkers. Aldo-keto reductase (Akr) family members have shown differential expression in human HCC, while AKR1B10 overexpression is considered a biomarker; AKR7A3 expression is frequently reduced in HCC. AIMS: To investigate the time-course expression of Akr members in the experimental hepatocarcinogenesis. METHODS: Using DNA-microarray data, we analyzed the time course gene expression profile from nodules to tumors (4-17 months) of 17 Akr members induced by the resistant hepatocyte carcinogenesis model in the rat. RESULTS: The expression of six members (Akr1c19, Akr1b10, Akr7a3, Akr1b1, Akr1cl1, and Akr1b8) was increased, comparable to that of Ggt and Gstp1, two well known liver cancer markers. In particular, Akr7a3 and Akr1b10 expression also showed a time-dependent increment at mRNA and protein levels in a second hepatocarcinogenesis model induced with diethylnitrosamine. We confirmed that aldo-keto reductases 7A3 and 1B10 were co-expressed in nine biopsies of human HCC, independently from the presence of glypican-3 and cytokeratin-19, two well known HCC biomarkers. Because it has been suggested that expression of Akr members is regulated through NRF2 activity at the antioxidant response element (ARE) sequences, we searched and identified at least two ARE sites in Akr1b1, Akr1b10, and Akr7a3 from rat and human gene sequences. Moreover, we observed higher NRF2 nuclear translocation in tumors as compared with non-tumor tissues. CONCLUSIONS: Our results demonstrate that Akr7a3 mRNA and protein levels are consistently co-expressed along with Akr1b10, in both experimental liver carcinogenesis and some human HCC samples. These results highlight the presence of AKR7A3 and AKR1B10 from early stages of the experimental HCC and introduce them as a potential application for early diagnosis, staging, and prognosis in human cancer. PMID- 29383609 TI - Public Awareness and Practice of Responsible Gambling in Macao. AB - Responsible gambling (RG) is a relatively new concept to the Macao gambling industry. Although recent studies reported a heightened public awareness of RG, the prevalence of disordered gambling is still high. This discrepancy may suggest an existing gap between RG awareness and gambling practices, pinpointing aspects that need to be improved by different RG stakeholders. The gap may be attributable to people's limited knowledge toward practices favoring RG. To explore means for enhancing the RG campaign, we studied Macao residents' interpretation and adoption of RG practices. In Study 1, a random community sample was collected to assess the extent to which common RG practices were adopted. Results suggested that there was a fair proportion of gamblers not adhering to them and gambling disorder tendency was related to the adoption of RG practices. It implied a successful promotion of RG practices may reduce gambling problems. In Study 2, focus group discussions were conducted to explore how RG was conceptualized. Twenty-five participants (including 11 casino employees) took part in four focus group interviews. All participants were aware of RG but their knowledge of RG practices was limited. Very few of them were able to identify major practices such as putting constraints on gambling amount and time and the application for self-exclusion. We argue that future RG promotion needs to be more specific and behavior-oriented and it should also address various procedural concerns on how RG practices can be implemented. PMID- 29383610 TI - Are Treatment Outcomes Determined by Type of Gambling? A UK Study. AB - One of the main difficulties faced in treating gambling disorder is compliance with psychological treatment. Gambling takes many forms and can differ greatly in its features such as speed of play and skill requirements. The type of gambling a pathological gambler opts for may play a key role in treatment compliance. The aim of the present study was to determine whether within treatment seeking sample of gambling disorder clients, gambling activity has any correlation with their resultant treatment outcomes. The study incorporated 524 treatment-seeking individuals who are clients of the National Problem Gambling Clinic in London. All of the clients were assessed prior to treatment and fulfilled the Problem Gambling Severity Index criteria for problem gambling. Data concerning clients' gambling behavior over the previous year was gathered using self-reports. Subsequently, the data was fitted to a multinomial logistic regression model, with the treatment outcome (i.e. pre-treatment dropouts, during treatment dropouts, and completed treatment) as the dependent variable and gambling behavior as the independent variable, whilst controlling for socio-demographic factors. The use of gaming machines was a significant predictor of dropping out pre-treatment (p < 0.05, RRR 1.616), whilst betting on sports events was a significant predictor of dropping out during treatment (p < 0.01, RRR 2.435). Treatment outcomes have been found to significantly differ based on participation in certain gambling activities. Further research into the salient features of these gambling activities may help to further explain pre-treatment and during treatment dropouts within this population. PMID- 29383611 TI - Desmoplastic Small Round Cell Tumor Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Results of a Phase 2 Trial. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that primarily affects adolescents and young adults. Patients can present with many peritoneal implants. We conducted a phase 2 clinical trial utilizing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with cisplatin for DSRCT and pediatric-type abdominal sarcomas. PATIENTS AND METHODS: A prospective cohort study was performed on 20 patients, who underwent CRS-HIPEC procedures, with cisplatin from 2012 to 2013. All patients were enrolled in the phase 2 clinical trial. Patients with extraabdominal disease and in whom complete cytoreduction (CCR0-1) could not be achieved were excluded. All outcomes were recorded. RESULTS: Fourteen patients had DSRCT, while five patients had other sarcomas. One patient had repeat HIPEC. Patients with DSRCT had significantly longer median overall survival after surgery than patients with other tumors (44.3 vs. 12.5 months, p = 0.0013). The 3-year overall survival from time of diagnosis for DSRCT patients was 79 %. Estimated median recurrence-free survival (RFS) was 14.0 months. However, RFS for patients with DSRCT was significantly longer than for non-DSRCT patients (14.9 vs. 4.5 months, p = 0.0012). Among DSRCT patients, those without hepatic or portal metastases had longer median RFS than those with tumors at these sites (37.9 vs. 14.3 months, p = 0.02). In 100 % of patients without hepatic or portal metastasis, there was no peritoneal disease recurrence after CRS-HIPEC. CONCLUSIONS: Complete CRS-HIPEC with cisplatin is effective in select DSRCT patients. DSRCT patients with hepatic or portal metastasis have poorer outcomes. PMID- 29383612 TI - Palliative Management of Peritoneal Metastases. AB - Despite significant recent advances in the management of peritoneal carcinomatosis, this diagnosis still is accompanied frequently by a grim survival prognosis, often measured in weeks to months. The poor prognosis also is accompanied often by complications and symptoms that have a dramatic impact on quality of life and are challenging to the managing health care provider and devastating to loved ones caring for the person who is suffering. Consequently, management of carcinomatosis often revolves around palliation of symptoms such as bowel obstruction, nausea, pain, fatigue, and cachexia as well as emotional and existential concerns. This article reviews several palliative treatment options for some of the more common symptoms and complications associated with advanced, incurable peritoneal carcinomatosis. Although readers should recognize that carcinomatosis is no longer an imminent death sentence, providers caring for patients with peritoneal carcinomatosis also must be well-versed in the palliative management of this condition and recognize the utility of early palliative care referral in this setting. PMID- 29383613 TI - Surgical Risk Factors for the Delayed Initiation of Adjuvant Chemotherapy in Breast Cancer. AB - BACKGROUND: Timely administration of adjuvant chemotherapy for breast cancer is associated with a survival benefit. Specific elements of surgical management may lead to delays initiating chemotherapy, resulting in unfavorable outcomes. The purpose of this study was to determine the correlation between surgical factors and delayed chemotherapy in breast cancer patients. METHODS: A retrospective analysis of the National Cancer Database was performed. The study cohort consisted of female patients with stage 1-3 breast cancer diagnosed between 2010 and 2014. Initiation of chemotherapy beyond 90 days after surgery was defined as delayed. Multivariable logistic regression modeling was performed to establish associations between delayed chemotherapy and clinical and demographic factors of interest. Survival analysis was performed using the Kaplan-Meier estimation and Cox proportional hazards regression to evaluate potential 5-year overall survival disadvantage of delayed initiation of chemotherapy. RESULTS: Of 166,681 women assessed, 4.3% had a delay in the initiation of chemotherapy. Surgery-specific risk factors included unplanned readmission in the postoperative period, lower surgical volume, mastectomy with immediate autologous reconstruction, and positive surgical margins. Adjusted survival analysis showed a survival disadvantage of delayed initiation of chemotherapy (hazard ratio [HR] 1.46; p < 0.01). CONCLUSIONS: Risk factors for delayed initiation of chemotherapy specific to the surgical process were identified. Delayed initiation of adjuvant chemotherapy was associated with a survival detriment. Efforts should be made to address these surgical management issues and optimize the perioperative process to ensure timely patient treatment. PMID- 29383615 TI - Broken dynasty: how Jean Batiste Charcot relinquished his father's neurological empire to conquer the seven seas. AB - The authors review the relationship between Jean-Martin Charcot, the most celebrate Professor of Neurology of the XIX century, and his son, Jean-Baptiste Charcot, former a physician and neurologist and after Professor Charcot's death, a worldwide famous maritime explorer, the "Commander Charcot." PMID- 29383614 TI - Comparison of odor identification among amnestic and non-amnestic mild cognitive impairment, subjective cognitive decline, and early Alzheimer's dementia. AB - Olfactory impairment might be an important clinical marker and predictor of Alzheimer's disease (AD). In the present study, we aimed to compare the degree of olfactory identification impairment in each mild cognitive impairment (MCI) subtype, subjective memory impairment, and early AD dementia and assessed the relationship between olfactory identification and cognitive performance. We consecutively included 50 patients with amnestic MCI, 28 patients with non amnestic MCI, 20 patients with mild AD, and 17 patients with subjective memory impairment (SMI). All patients underwent clinical and neuropsychological assessments. A multiple choice olfactory identification cross-cultural smell identification test was also utilized. Controlling for age and gender, olfactory impairment was significantly more severe in patients with AD and amnestic MCI compared with the results from the non-amnestic MCI and SMI groups. Higher scores on MMSE, verbal and non-verbal memory, and frontal executive function tests were significantly related to olfactory identification ability. In conclusion, olfactory identification is impaired in amnestic MCI and AD. These findings are consistent with previous studies. In amnestic MCI patients, this dysfunction is considered to be caused by underlying AD pathology. PMID- 29383616 TI - Assessment of Snaith-Hamilton Pleasure Scale (SHAPS): the dimension of anhedonia in Italian healthy sample. AB - The Snaith-Hamilton Pleasure Scale (SHAPS) is a rapid screening battery created for assessing the presence of anhedonia, namely the inability to experience pleasure. Although, this symptom has widely been investigated in clinical settings, individual differences in anhedonia are also present in healthy population. The aim of present study was to validate the translated Italian version of this test. One thousand six hundred ninety-seven consecutive healthy subjects (55% female) of different ages (age 18-82 years) underwent SHAPS. Participants who showed mild level of anhedonia also completed the Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), Toronto Alexithymia Scale-20 (TAS), Mood Disorders Insight Scale (MDIS), and Beck Hopelessness Scale (BHS). The SHAPS showed good internal consistency and discriminant validity; moreover, the factorial analysis highlighted that SHAPS had a three-factor structure for explaining the anhedonic construct. 14.9% showed a significant reduction of hedonic tone (SHAPS >= 3). Finally, the degree of anhedonia was significantly correlated with BDI and BHS scores, but not with age or gender. Although anhedonia is a prominent feature of many psychiatric and neurological disorders, the presence of this symptom in the healthy population highlighted the importance to develop reliable tool. SHAPS shows good psychometric properties to assess multidimensional anhedonia symptoms also in Italian healthy population. PMID- 29383617 TI - Famous people recognition through personal name: a normative study. AB - In this normative study, we investigated famous people recognition through personal name, using as stimuli the names of the same 40 Italian famous persons whose faces and voices had been utilized for the normative study of the Famous People Recognition Battery. For each famous people, we assessed name familiarity, person identification (when the name had been considered as familiar), and false alarms. The investigation was carried out on 143 normal subjects who varied in age and education. Name familiarity and semantic scores were affected by educational level, whereas age influenced false alarms. A comparison between results obtained with names in this research and with faces and voices of the same famous people in our previous study showed that familiarity scores were higher for personal names than those for faces and voices, which obtained the worst scores. Person identification scores were not significantly different from names and from faces, but both these scores were significantly higher than the semantic scores obtained by voices. Taken together, these results are inconsistent with the influential interactive activation and competition model of person recognition. PMID- 29383618 TI - Multiple brain metastases: a surgical series and neurosurgical perspective. AB - Despite review papers claim for radical treatment of oligometastatic patients, only few surgical series have been published. In this study, we analyze results and actual role of surgical resection for the management of patients with multiple brain metastases. This retrospective study compares surgical results of two groups of patients consecutively treated in our Institute from January 2004 to June 2015. The first group comprises all 32 patients with multiple brain metastases with only 2-3 lesions who underwent surgical resection of all lesions; the second group comprises 30 patients with a single surgically treated brain mestastasis compatible with the first group (match-paired control series). Median survival was 14.6 months for patients with multiple brain metastases (range 1-28 months) and 17.4 months for patients with a single brain metastasis (range 4-38 months); the difference was not statistically significant (P = 0.2). Neurological condition improved in 59.4% of patients with multiple metastases, it remained unchanged in 37.5% and worsened in 3.1%. In our series, selected patients with only 2-3 lesions with well-controlled systemic disease, life expectancy of more than 3 months, Karnofsky's performance status > 60, and surgically accessible lesions, benefited from surgical treatment in terms of survival and quality of life, with reduction or disappearance of significant neurological deficits. The prognosis for these patients is similar to that of patients with a single metastasis. It seems that patients with breast cancer included in our series had the worst prognosis if compared to other histotypes. PMID- 29383620 TI - Correction to: The sternalis muscle: radiologic findings on MDCT. AB - In the original publication of the article, the seventh author name was incorrectly published as Hidehumi Aoyama. The correct author name should read as Hidefumi Aoyama. PMID- 29383619 TI - The Role of Clinics in Determining Older Recent Immigrants' Use of Health Services. AB - Immigrants are ineligible for federally-funded Medicaid in the U.S. until at least 5 years after arrival. There is little information on where they receive care in light of this restriction. Using Blinder-Oaxaca decomposition, this study examines whether the setting in which older recent immigrants receive care (i.e., health clinic, emergency room or doctor's office) explains delays in care. Among older adults with a usual source of care, 13.5% of recent immigrants had not seen a health professional in the past year compared to 8.6% of non-recent immigrants and 6.3% of native-born. Approximately 23% of these differences is attributable to recent immigrants' tendency to receive care in clinics and community health centers. Even when older recent immigrants manage to find a usual source of care, it is of lower quality than that received by their non-recent immigrant and native-born counterparts. PMID- 29383621 TI - Diffusion tensor imaging changes following mild, moderate and severe adult traumatic brain injury: a meta-analysis. AB - Diffusion tensor imaging quantifies the asymmetry (fractional anisotropy; FA) and amount of water diffusion (mean diffusivity/apparent diffusion coefficient; MD/ADC) and has been used to assess white matter damage following traumatic brain injury (TBI). In healthy brains, diffusion is constrained by the organization of axons, resulting in high FA and low MD/ADC. Following a TBI, diffusion may be altered; however the exact nature of these changes has yet to be determined. A meta-analysis was therefore conducted to determine the location and extent of changes in DTI following adult TBI. The data from 44 studies that compared the FA and/or MD/ADC data from TBI and Control participants in different regions of interest (ROIs) were analyzed. The impact of injury severity, post-injury interval (acute: <= 1 week, subacute: 1 week-3 months, chronic: > 3 months), scanner details and acquisition parameters were investigated in subgroup analyses, with the findings indicating that mild TBI should be examined separately to that of moderate to severe injuries. Lower FA values were found in 88% of brain regions following mild TBI and 92% following moderate-severe TBI, compared to Controls. MD/ADC was higher in 95% and 100% of brain regions following mild and moderate-severe TBI, respectively. Moderate to severe TBI resulted in larger changes in FA and MD/ADC than mild TBI. Overall, changes to FA and MD/ADC were widespread, reflecting more symmetric and a higher amount of diffusion, indicative of white matter damage. PMID- 29383622 TI - Favorable survival in lung transplant recipients on preoperative low-dose, as compared to high-dose corticosteroids, after hematopoietic stem cell transplantation. AB - Although the number of patients developing pulmonary complications after hematopoietic stem cell transplantation (HSCT) necessitating lung transplantation (LT) is increasing, a little information is available about factors influencing the prognosis after LT in these patients. Corticosteroids represent the first line therapy for pulmonary complications after HSCT; however, prolonged corticosteroid treatment prior to LT increases the potential risks of LT. In this study, we assessed the effect of preoperative corticosteroid therapy on long-term survival in patients undergoing LT after HSCT. We retrospectively investigated data from 13 patients who had received high-dose corticosteroid therapy and nine who had received low-dose corticosteroid therapy prior to LT for pulmonary complications after HSCT. Other than the preoperative corticosteroid dose, patient clinical characteristics did not differ. The incidence of postoperative complications within the first year after LT was significantly lower in the low dose corticosteroid group (p = 0.026). Survival after LT was also significantly better in the low-dose corticosteroid group than in the high-dose corticosteroid group (p = 0.034). In recipients of LT after HSCT, preoperative low-dose corticosteroid use, as compared to preoperative high-dose corticosteroid use, could limit the risks of postoperative complications developing within the first year after the LT, leading to improved long-term survival after LT. PMID- 29383623 TI - NK cell therapy for hematologic malignancies. AB - Natural killer (NK) cells are part of the innate immune system and represent the first line of defense against infections and tumors. In contrast to T cells, NK cells do not require prior antigen sensitization to induce cytotoxicity and do not cause graft-versus-host disease. These, along with other advantages, make NK cells an attractive candidate for adoptive cellular therapy. Herein, we describe the mechanisms of NK cell cytotoxicity, which is governed by an intricate balance between various activating and inhibitory receptors, including the killer cell immunoglobulin-like receptors (KIRs). We illustrate the advantages of NK alloreactivity as demonstrated in various types of hematopoietic stem cell transplants (HSCT), such as haploidentical, human leukocyte antigen-matched related or unrelated donor and umbilical cord blood transplant. We elaborate on different models used to predict NK cell alloreactivity in these studies, which are either based on the absence of the ligands for inhibitory KIRs, presence of activating NK cell receptors and KIR genes content in donors, or a combination of these. We will review clinical studies demonstrating anti-tumor efficacy of NK cells used either as a stand-alone immunotherapy or as an adjunct to HSCT and novel genetic engineering strategies to improve the anti-tumor activity of NK cells. PMID- 29383625 TI - Genetic analysis of a novel missense mutation (Gly542Ser) with factor XII deficiency in a Chinese patient of consanguineous marriage. AB - Coagulation factor XII deficiency is a rare autosomal recessive disorder, which could be found in a consanguineous family. We studied a Chinese family in which the activated partial thromboplastin time (APTT) of the proband had clearly prolonged up to 101.7 s, associated with low FXII activity of 3% and FXII antigen < 1%. To analyze the gene mutation in this FXII-deficient patient, we performed FXII mutation screening, and analyzed the DNA sequence of the F12 gene. A ClustalX-2.1-win and four online bioinformatics software services were used to study the conservatism and effects of the mutation. A transient in vitro expression study was performed to elucidate the possible pathological mechanism. Sequence analysis revealed a homozygous c.1681 G > A point mutation in exon 14, causing a novel Gly542Ser mutation in the catalytic domain. The results of the conservatism and bioinformatics analyses both indicated that the mutation likely affects the function of the protein. Additional expression studies in COS-7 cells showed that the antigen level of mutant FXII (FXII-Gly542Ser) was lower than wild type in culture medium, whereas the corresponding level of FXII antigen in cell lysates was equivalent. These results suggest that the Gly542Ser mutation causes FXII deficiency through intracellular degradation. PMID- 29383624 TI - Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan. AB - In paroxysmal nocturnal hemoglobinuria (PNH), various symptoms due to intravascular hemolysis exert a negative impact on patients' quality of life (QOL). To determine clinical factors related with improvements in QOL in PNH patients treated, we analyzed changes in QOL scales in PNH patients treated with eculizumab based on data collected from post-marketing surveillance in Japan. Summary statistics were obtained using figures from QOL scoring systems and laboratory values, and evaluated by t test. One-year administration of eculizumab improved the most QOL items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values. Changes in serum lactate dehydrogenase (LDH) and hemoglobin showed strong correlations with QOL improvement. Quality of life improvement was independent of patients' baseline characteristics of co-occurrence of bone marrow failure (BMF), or the degree of LDH. In this analysis, we found that the degree of QOL improvement was independent of the baseline LDH before eculizumab treatment and of co-occurrence of BMF. Paroxysmal nocturnal hemoglobinuria patients who have not received eculizumab treatment due to mild hemolysis may benefit from eculizumab treatment. PMID- 29383626 TI - Continuous infusions of B domain-truncated recombinant factor VIII, turoctocog alfa, for orthopedic surgery in severe hemophilia A: first case report. AB - Continuous infusions (CI) of factor (F)VIII are preferable to the conventional bolus injections for the maintenance of consistent FVIII levels during surgery in patients with severe hemophilia A. A third generation, B domain-truncated recombinant FVIII (turoctocog alfa, Novo Nordisk, NovoEight(r)), was approved for clinical use in 2014. The hemostatic efficacy and safety of bolus injections of turoctocog alfa in patients undergoing surgery have been reported, but no reports on CI therapy have been published. We describe a 43-year-old patient with severe hemophilia A who required arthroscopic synovectomy of the right elbow and arthrodesis of the right ankle. He was treated with a bolus injection of turoctocog alfa (36 IU/kg) immediately before operation, followed by CI (infusion rate; 2.9 IU/kg/h) to maintain FVIII activity > 80 IU/dl throughout the perioperative period. Surgery was completed successfully with uncomplicated hemostatic control. CIs were continued until post-operative day (POD) 4. Further bolus injections were given from POD5. No anti-FVIII inhibitor has been detected post-operation. This case provides important information on CI therapy using turoctocog alfa during surgery for patients with severe hemophilia A. PMID- 29383627 TI - Chronic postsurgical pain following breast reconstruction: a commentary and critique. AB - In line with other major surgeries including breast cancer surgery (BCS), recent studies suggest a striking rate of chronic postsurgical pain (CPSP) following breast reconstruction. This commentary will critically examine evidence for the degree to which the prevalence of CPSP following breast reconstruction is directly attributable to reconstructive surgery. The discussion will trace similarities and distinctions between breast reconstruction and BCS in considering the risk for CPSP, and describe recent advances in the definition of CPSP, highlighting methodological limitations in the general investigation of CPSP, which also characterize the study of CPSP more specifically for breast reconstruction outcome. A convenience sample of relevant studies examining CPSP following breast reconstruction reveals inadequate evidence to support a serious concern for reconstruction-induced CPSP and further that these studies fail to adhere to recommended methodological standards to effectively isolate surgery as the etiology of persistent pain reported by women following reconstructive surgery. Suggestions for future exploration of problematic chronic pain after breast reconstruction are considered. PMID- 29383628 TI - Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database. AB - PURPOSE: To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. METHODS: Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. CONCLUSION: Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS. PMID- 29383629 TI - The frequency of missed breast cancers in women participating in a high-risk MRI screening program. AB - PURPOSE: To evaluate the frequency of missed cancers on breast MRI in women participating in a high-risk screening program. METHODS: Patient files from women who participated in an increased risk mammography and MRI screening program (2003 2014) were coupled to the Dutch National Cancer Registry. For each cancer detected, we determined whether an MRI scan was available (0-24 months before cancer detection), which was reported to be negative. These negative MRI scans were in consensus re-evaluated by two dedicated breast radiologists, with knowledge of the cancer location. Cancers were scored as invisible, minimal sign, or visible. Additionally, BI-RADS scores, background parenchymal enhancement, and image quality (IQ; perfect, sufficient, bad) were determined. Results were stratified by detection mode (mammography, MRI, interval cancers, or cancers in prophylactic mastectomies) and patient characteristics (presence of BRCA mutation, age, menopausal state). RESULTS: Negative prior MRI scans were available for 131 breast cancers. Overall 31% of cancers were visible at the initially negative MRI scan and 34% of cancers showed a minimal sign. The presence of a BRCA mutation strongly reduced the likelihood of visible findings in the last negative MRI (19 vs. 46%, P < 0.001). Less than perfect IQ increased the likelihood of visible findings and minimal signs in the negative MRI (P = 0.021). CONCLUSION: This study shows that almost one-third of cancers detected in a high-risk screening program are already visible at the last negative MRI scan, and even more in women without BRCA mutations. Regular auditing and double reading for breast MRI screening is warranted. PMID- 29383630 TI - Shmuel Malkin (1934-2017) : Listening to photosynthesis and making music. AB - We present here the life and work of Shmuel Malkin (1934-2017), an accomplished scientist and a gifted musician who touched the lives of many around the world. His early scientific work addressed the dynamics of light harvesting and electron transport in photosynthesis. Later, he used photoacoustic and photothermal methodologies to explore all aspects of photosynthesis. As a musician, Shmuel played the piano often for family and friends but after his formal retirement, he produced a body of original musical compositions, many of which were performed publicly. Throughout his life, Shmuel was a caring and deeply thoughtful man, respected and loved by colleagues, family, and friends. This tribute presents a summary of Shmuel's work as well as remembrances written by his wife, Nava Malkin, their son, Eyal Malkinson, and many of his colleagues: Michael Havaux from France; Sandra and Marcel Jansen from Ireland; David Cahen, Marvin Edelmann, Joop and Onnie de Graaf, Jonathan Gressel, Uri Pick, Yona Siderer, and Elisha Tel Or from Israel; Ulrich Schreiber from Germany; James Barber and Alison Telfer from the UK; Govindjee, Stephen Herbert and Thomas Sharkey from the USA. Minnie Ho and Iris Malkin of the USA wrote contributions about Shmuel's music. PMID- 29383632 TI - Protective Effect of Ellagic Acid Against Sodium Arsenite-Induced Cardio- and Hematotoxicity in Rats. AB - Ellagic acid (EA) is a phenolic constituent in certain fruits and nuts with wide range of biological activities, including potent antioxidant, antidiabetic, anti inflammatory, anticancer and antimutagen properties. The aim of this study was to evaluate the effect of EA on sodium arsenic (SA)-induced cardio- and hematotoxicity in rats. Animals were divided into five groups. The first group was used as control. Group 2 was orally treated with sodium arsenite (SA, 10 mg/kg) for 21 days. Group 3 was orally treated with EA (30 mg/kg) for 14 days. Groups 4 and 5 were orally treated with SA for 7 days prior to EA (10 and 30 mg/kg, respectively) treatment and continued up to 21 days simultaneous with SA administration. Various biochemical, histological and molecular biomarkers were assessed in blood and heart. The results indicate that SA-intoxicated rats display significantly higher levels of plasma cardiac markers (AST, CK-MB, LDH and cTnI) than normal control animals. Moreover, an increase in MDA and NO with depletion of GSH and activities of CAT, SOD and GPx occurred in the heart of rats treated with SA. Furthermore, SA-treated rats showed significantly lower WBC, RBC, HGB, HCT and PLT and significantly higher MCV and MCH. Administration of EA (30 mg/kg) resulted in a significant reversal of hematological and cardiac markers in arsenic-intoxicated rats. These biochemical disturbances were supported by histopathological observations of the heart. In conclusion, the results of this study suggest that EA treatment exerts a significant protective effect on SA-induced cardio- and hematotoxicity. PMID- 29383631 TI - Wheat plant selection for high yields entailed improvement of leaf anatomical and biochemical traits including tolerance to non-optimal temperature conditions. AB - Assessment of photosynthetic traits and temperature tolerance was performed on field-grown modern genotype (MG), and the local landrace (LR) of wheat (Triticum aestivum L.) as well as the wild relative species (Aegilops cylindrica Host.). The comparison was based on measurements of the gas exchange (A/ci, light and temperature response curves), slow and fast chlorophyll fluorescence kinetics, and some growth and leaf parameters. In MG, we observed the highest CO2 assimilation rate [Formula: see text] electron transport rate (Jmax) and maximum carboxylation rate [Formula: see text]. The Aegilops leaves had substantially lower values of all photosynthetic parameters; this fact correlated with its lower biomass production. The mesophyll conductance was almost the same in Aegilops and MG, despite the significant differences in leaf phenotype. In contrary, in LR with a higher dry mass per leaf area, the half mesophyll conductance (gm) values indicated more limited CO2 diffusion. In Aegilops, we found much lower carboxylation capacity; this can be attributed mainly to thin leaves and lower Rubisco activity. The difference in CO2 assimilation rate between MG and others was diminished because of its higher mitochondrial respiration activity indicating more intense metabolism. Assessment of temperature response showed lower temperature optimum and a narrow ecological valence (i.e., the range determining the tolerance limits of a species to an environmental factor) in Aegilops. In addition, analysis of photosynthetic thermostability identified the LR as the most sensitive. Our results support the idea that the selection for high yields was accompanied by the increase of photosynthetic productivity through unintentional improvement of leaf anatomical and biochemical traits including tolerance to non-optimal temperature conditions. PMID- 29383633 TI - A Fatal Case of Amlodipine Toxicity Following Iatrogenic Hypercalcemia. AB - Using calcium salts in management of amlodipine overdose is challenging. A 25 year-old male with known history of adult polycystic kidney disease presented with hypotension, tachycardia, and intact neurological status after ingestion of 450 mg of amlodipine. Immediately, normal saline infusion and norepinephrine were initiated. Two grams of calcium gluconate was injected, followed by intravenous infusion of 1.16 mg/kg/h. The patient was put on insulin-glucose protocol to maintain euglycemia and hyperinsulinemia. Electrocardiography demonstrated junctional rhythm. Serum creatinine was 2.5 mg/dL with metabolic acidosis. By the end of 24 h post-admission, his consciousness, blood pressure, and urine output were normal. Almost 32 h post-admission, he became disoriented and his oxygen saturation decreased and therefore was mechanically ventilated. Second chest X ray showed pulmonary edema. Serum calcium level increased to 26.1 mg/dL. Calcium was discontinued, and furosemide infusion and calcitonin were intravenously administrated. Urine output increased and hemodialysis improved pulmonary edema and serum calcium level with no change in consciousness. Three days after admission, the patient became anuric and developed multi-organ failure and died 5 days post-admission. To avoid the consequences of excessive infusion of calcium in renal failure patients, the minimum calcium dose with close monitoring is recommended. PMID- 29383634 TI - Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells. AB - AIM: Delta-like 1 homolog (DLK1) is a non-canonical ligand of Notch signaling, which plays a pivotal role in vascular development and tumor angiogenesis. This study aimed to elucidate the function and mechanism of DLK1 in angiogenesis. METHODS AND RESULTS: By using in situ hybridization and immunohistochemical studies, expression analysis revealed a unique vascular tropism of DLK1 in vasculature of neuroblastoma and vascular tumors. Thus, it was hypothesized that DLK1 may be cleaved and then bound to endothelial cells, thereby regulating the endothelial function. To test such hypothesis, soluble DLK1 encompassing DLK1 extracellular domain (DLK1-EC) was generated and validated by its inhibitory function in adipogenesis assay. Recombinant DLK1-EC exhibited the preferential binding capability toward endothelial cells and stimulated the microvessels sprouting in aorta rings. Above all, implantation of DLK1-EC dose-dependently elicited the cornea neovascularization in rats. By using various angiogenesis assays, it was delineated that DLK1-EC stimulated the angiogenesis by promoting the proliferation, motility and tube formation of endothelial cells. By immunoblot and luciferase analysis, it was elucidated that DLK1-EC enhanced the expression and activities of Notch1/Akt/eNOS/Hes-1 signaling in dose- and time dependent manners. Pharmaceutical blockage of Notch signaling using gamma secretase inhibitor DAPT abrogated the DLK1-EC-induced endothelial migration and Hes-1-driven luciferase activities. Furthermore, Notch1 inactivation by neutralizing antibodies or RNA interference reversed the DLK1-EC-induced angiogenesis. CONCLUSIONS: The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells. PMID- 29383636 TI - The dark side of the kidney in cardio-renal syndrome: renal venous hypertension and congestive kidney failure. AB - Renal involvement in some forms of acute or chronic diseases, such as heart failure or sepsis, presents with a complex pathophysiological basis that is not always clearly distinguishable. In these clinical settings, kidney failure is traditionally and almost exclusively attributed to renal hypoperfusion and it is commonly accepted that causal elements are pre-renal, such as a reduction in the ejection fraction or absolute or relative hypovolemia acting directly on oxygen transport mechanisms and renal autoregulation systems, causing a reduction of glomerular filtration rate. Nevertheless, the concept emerging from accumulating clinical and experimental evidence is that in complex clinical pictures, kidney failure is strongly linked to the hemodynamic alterations occurring in the renal venous micro and macrocirculation. Accordingly, the transmission of the increased venous pressure to the renal venous compartment and the consequent increasing renal afterload has a pivotal role in determining and sustaining the kidney damage. The aim of this review was to clarify the physiopathological aspects of the link between worsening renal function and renal venous hypertension, analyzing the prognostic and therapeutic implications of the so-called congestive kidney failure in cardio-renal syndrome and in other clinical contexts of its possible onset. PMID- 29383635 TI - miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. AB - The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF 1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions. PMID- 29383637 TI - Biomarkers in cancer therapy related cardiac dysfunction (CTRCD). AB - Biomarkers are at the cornerstone of preventive measures and contribute to the screening process. More recently, biomarkers have been used to gauge the biological response to the employed therapies. Since it is ubiquitously used to detect subclinical disease process, biomarkers also have found its place in cancer therapy related cardiac dysfunction (CTRCD). The aim of this review is to comprehensively present up-to-date knowledge of biomarkers in CTRCD and highlight some of the future biomedical technologies that may strengthen the screening process, and/or provide new insight in pathological mechanisms behind CTRCD. PMID- 29383638 TI - Possible mechanisms of direct cardiovascular impact of GLP-1 agonists and DPP4 inhibitors. AB - Diabetes mellitus is a leading cause of cardiovascular morbidity and mortality worldwide. Traditional antidiabetic therapies targeting hyperglycemia reduce diabetic microvascular complications but have minor effects on macrovascular complications, including cardiovascular disease. Instead, cardiovascular complications are improved by antidiabetic medications (metformin) and other therapies (statins, antihypertensive medications) ameliorating insulin resistance and other associated metabolic abnormalities. Novel classes of antidiabetic drugs have proven efficacious in improving glycemia, while at the same time exert beneficial effects on pathophysiologic mechanisms of diabetes-related cardiovascular disease. In the present review, we will present current evidence of the cardiovascular effects of two new classes of antidiabetic medications, glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, focusing from mechanistic preclinical and clinical investigation to late-phase clinical testing. PMID- 29383639 TI - Clinical correlates and pharmacological management of Asian patients with concomitant diabetes mellitus and heart failure. AB - Asia is the center of convergence of the twin epidemics of diabetes mellitus (DM) and heart failure (HF). The regional and ethnic diversity across Asia, along with a high prevalence of a young, lean diabetic phenotype, emphasizes the importance of targeted public health strategies that address the unique needs of Asian patients with DM and HF. This review discusses the epidemiology, clinical correlates, pharmacological management, and outcomes of Asian patients with concomitant DM and HF. PMID- 29383640 TI - Fungi extracellular enzyme-containing microcapsules enhance degradation of sulfonamide antibiotics in mangrove sediments. AB - Mangroves represent a special coastal vegetation along the coastlines of tropical and subtropical regions. Sulfonamide antibiotics (SAs) are the most commonly used antibiotics. The application of white-rot fungi extracellular enzyme-containing microcapsules (MC) for aerobic degradation of SAs in mangrove sediments was investigated in this study. Degradation of three SAs, sulfamethoxazole (SMX), sulfadimethoxine (SDM), and sulfamethazine (SMZ), was enhanced by adding MC to the sediments. The order of SA degradation in batch experiments was SMX > SDM > SMZ. Bioreactor experiments revealed that SA removal rates were higher with than without MC. The enhanced SA removal rates with MC persisted with three re additions of SAs. Thirteen bacteria genera (Achromobacter, Acinetobacter, Alcaligenes, Aquamicrobium, Arthrobacter, Brevundimonas, Flavobacterium, Methylobacterium, Microbacterium, Oligotropha, Paracoccus, Pseudomonas, and Rhodococcus) were identified to be associated with SA degradation in mangrove sediments by combination of next-generation sequencing, bacterial strain isolation, and literature search results. Results of this study suggest that MC could be used for SA removal in mangrove sediments. PMID- 29383641 TI - Assessment of sulforaphane-induced protective mechanisms against cadmium toxicity in human mesenchymal stem cells. AB - Cd is a hazardous substance and carcinogen that is present in the environment; it is known to cause toxic effects in living organisms. Sulforaphane is a naturally available phytochemical with antioxidant, anti-inflammatory, and anticarcinogenic properties. However, the effects of sulforaphane on Cd toxicity in human mesenchymal stem cells (hMSCs) are unknown. In the present study, we investigated the molecular mechanisms of the effects of sulforaphane on Cd toxicity in hMSCs by using MTT assays, acridine orange/ethidium bromide staining, Hoechst staining, LysoRed staining, assessment of mitochondrial membrane potential, and gene expression analysis. Cd decreased hMSC viability in a dose-dependent manner with an IC50 value of 56.5 MUM. However, sulforaphane did not induce any significant reduction in cell viability. Nuclear morphological analysis revealed that Cd induced necrotic cell death. Additionally, Cd caused mitochondrial membrane potential loss in hMSCs. The treatment of Cd-exposed cells with sulforaphane (Cd sulforaphane co-treatment) resulted in a significant recovery of the cell viability and nuclear morphological changes compared with that of cells treated with Cd only. The gene expression pattern of cells co-treated with Cd sulforaphane was markedly different from that of Cd-treated cells, owing to the reduction in Cd toxicity. Our results clearly indicated that sulforaphane reduced Cd-induced toxic effects in hMSCs. Overall, the results of our study suggested that sulforaphane-rich vegetables and fruits can help to improve human health through amelioration of the molecular effects of Cd poisoning. PMID- 29383642 TI - Iron doped fibrous-structured silica nanospheres as efficient catalyst for catalytic ozonation of sulfamethazine. AB - Sulfonamide antibiotics are ubiquitous pollutants in aquatic environments due to their large production and extensive application. In this paper, the iron doped fibrous-structured silica (KCC-1) nanospheres (Fe-KCC-1) was prepared, characterized, and applied as a catalyst for catalytic ozonation of sulfamethazine (SMT). The effects of ozone dosage, catalyst dosage, and initial concentration of SMT were examined. The experimental results showed that Fe-KCC-1 had large surface area (464.56 m2 g-1) and iron particles were well dispersed on the catalyst. The catalyst had high catalytic performance especially for the mineralization of SMT, with mineralization ratio of about 40% in a wide pH range. With addition of Fe-KCC-1, the ozone utilization increased nearly two times than single ozonation. The enhancement of SMT degradation was mainly due to the surface reaction, and the increased mineralization of SMT was due to radical mechanism. Fe-KCC-1 was an efficient catalyst for SMT degradation in catalytic ozonation system. PMID- 29383643 TI - The effect of anthropogenic and natural factors on the prevalence of physicochemical parameters of water and bacterial water quality indicators along the river Bialka, southern Poland. AB - This study was aimed to determine the anthropogenic and natural factors affecting spatial and temporal changes in the physicochemical parameters and bacterial indicators of water quality in the river Bialka. The impact of intensive development of the tourist infrastructure on the quality of river water and the potential health threats to tourists was also assessed. Water samples were collected over a period of 2.5 years, once per each month in four sites along the river. Temperature, electrolytic conductivity, pH, and water level were measured onsite; flow rate data were acquired from the Institute of Meteorology and Water Management; chemical analyses allowed to determine the amount of fourteen ions, while microbiological indicators included total and thermotolerant coliforms, total and thermotolerant Escherichia coli, and mesophilic and psychrophilic bacteria. The combination of hydrological, hydrochemical, and microbiological methods generated large amount of data, which were processed by multivariate statistical analysis. A downstream cumulative effect was observed in the contamination of the river water. Fecal coliforms and E. coli were detected in all sites, suggesting the source of fecal contamination even in the protected areas. Intensive development of a ski resort and the related infrastructure, together with the need to accommodate numerous tourists in the examined region, has an evident environmental impact. The resulting deterioration of water quality poses health risks to tourists, as water from the Bialka river is used for a variety of purposes, including as a raw drinking water or for artificial snowing of ski slopes. The seasonal changes in the physicochemical parameters mainly result from varying natural factors that shape the water quality in the studied region. The differences in the number of analyzed microorganisms result from seasonal variation in touristic activity and are affected mostly by point sources of sewage inflow. PMID- 29383644 TI - The spatio-temporal dynamic pattern of rural domestic solid waste discharge of China and its challenges. AB - At present, construction of rural domestic waste treatment facilities is seriously lagging, and in many cases, treatment facilities do not yet exist in some villages of China. Serious rural waste pollution has not only impacted the quality of surface water and groundwater but also the atmosphere and the living environment of farmers of China. There are relatively few studies of rural domestic waste pollution, especially with respect to the spatio-temporal dynamic pattern of rural domestic waste discharge. Using survey data and income per capita, we calculated rural domestic waste discharge per capita per day. From this, we calculated provincial rural domestic waste discharge. According to our study, rural domestic waste discharge was 1.42 * 108 t/year in 2000. This number increased to 2.3 * 108 t/year in 2006 and to 2.47 * 108 t/year in 2010. Rural domestic waste increased dramatically while the actual rural population and the proportion of the rural population declined. When examining the eight regions, the rural domestic waste discharge of northeastern China, Qinghai-Tibet, middle China, and southwestern China had increased dramatically, while that of northern China, southern China, and eastern China increased relatively slowly. The economies of northern China, southern China, and eastern China are more developed; their rural domestic waste discharge has been high since 2000 and has continued to increase slowly. In northeastern China, Qinghai-Tibet, middle China, and southwestern China, rural domestic waste discharge was low in 2000; however, in the ten-year period from 2000 to 2010, their rural domestic waste discharge increased dramatically. PMID- 29383645 TI - Regenerable, innovative porous silicon-based polymer-derived ceramics for removal of methylene blue and rhodamine B from textile and environmental waters. AB - The presence of residual color in treated textile wastewater above the regulation limits is still a critical issue in many textile districts. Innovative, polymer derived ceramics of the Si-C-O system were here synthesized in order to obtain porous nanocomposite materials where a free carbon phase is dispersed into a silicon carbide/silicon oxycarbide network. The sorbents were comprehensively characterized for the removal of two model water-soluble dyes (i.e., the cation methylene blue and the zwitterion rhodamine B). Adsorption is very rapid and controlled by intra-particle and/or film diffusion, depending on dye concentration. Among the nanocomposites studied, the SiOC aerogel (total capacity about 45 mg/g, is easily regenerated under mild treatment (250 degrees C, 2 h). Adsorption of dyes is not affected by the matrix composition: removals of 150 mg/L methylene blue from river water and simulated textile wastewater with high content of metal ions (2-50 mg/L) and chemical oxygen demand (800 mg/L) were higher than 92% and quantitative for a dye concentration of 1 mg/L. PMID- 29383646 TI - The efficacy of bacterial species to decolourise reactive azo, anthroquinone and triphenylmethane dyes from wastewater: a review. AB - The industrial dye-contaminated wastewater has been considered as the most complex and hazardous in terms of nature and composition of toxicants that can cause severe biotic risk. Reactive azo, anthroquinone and triphenylmethane dyes are mostly used in dyeing industries; thus, the unfixed hydrolysed molecules of these dyes are commonly found in wastewater. In this regard, bacterial species have been proved to be highly effective to treat wastewater containing reactive dyes and heavy metals. The bio-decolourisation of dye occurs either by adsorption or through degradation in bacterial metabolic pathways under optimised environmental conditions. The bacterial dye decolourisation rates vary with the type of bacteria, reactivity of dye and operational parameters such as temperature, pH, co-substrate, electron donor and dissolved oxygen concentration. The present paper reviews the efficiency of bacterial species (individual and consortia) to decolourise wastewater containing reactive azo, anthroquinone and triphenylmethane dyes either individually or mixed or with metal ions. It has been observed that bacteria Pseudomonas spp. are comparatively more effective to treat reactive dyes and metal-contaminated wastewater. In recent studies, either immobilised cell or isolated enzymes are being used to decolourise dye at a large scale of operations. However, it is required to investigate more potent bacterial species or consortia that could be used to treat wastewater containing mixed reactive dyes and heavy metals like chromium ions. PMID- 29383647 TI - Normalization of ADC does not improve correlation with overall survival in patients with high-grade glioma (HGG). AB - Mixed reports leave uncertainty about whether normalization of apparent diffusion coefficient (ADC) to a within-subject white matter reference is necessary for assessment of tumor cellularity. We tested whether normalization improves the previously reported correlation of resection margin ADC with 15-month overall survival (OS) in HGG patients. Spin-echo echo-planar DWI was retrieved from 3 T MRI acquired between maximal resection and radiation in 37 adults with new-onset HGG (25 glioblastoma; 12 anaplastic astrocytoma). ADC maps were produced with the FSL DTIFIT tool (Oxford Centre for Functional MRI). 3 neuroradiologists manually selected regions of interest (ROI) in normal appearing white matter (NAWM) and in non-enhancing tumor (NT) < 2 cm from the margin of residual enhancing tumor or resection cavity. Normalized ADC (nADC) was computed as the ratio of absolute NT ADC to NAWM ADC. Reproducibility of nADC and absolute ADC among the readers' ROI was assessed using intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wCV). Correlations of ADC and nADC with OS were compared using receiver operating characteristics (ROC) analysis. A p value 0.05 was considered statistically significant. Both mean ADC and nADC differed significantly between patients subgrouped by 15-month OS (p = 0.0014 and 0.0073 respectively). wCV and ICC among the readers were similar for absolute and normalized ADC. In ROC analysis of correlation with OS, nADC did not perform significantly better than absolute ADC. Normalization does not significantly improve the correlation of absolute ADC with OS in HGG, suggesting that normalization is not necessary for clinical or research ADC analysis in HGG patients. PMID- 29383648 TI - Is there a role of breast pathologist in diagnostic challenges of discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis? PMID- 29383649 TI - Network Analysis of Anxiety in the Autism Realm. AB - The anxiety and autism realms are each complicated and heterogeneous, and relationships between the two areas are especially complex. Network analysis offers a promising approach to the phenotypic complexities of typical and atypical human behavior. The Revised Children's Anxiety and Depression Scale (RCADS) was used to assess anxiety in 126 high-functioning 9-13 year-olds with ASDs. Network graphs of Autism Diagnostic Observation Schedule items and RCADS anxiety total score, social, generalized, panic and separation anxiety subscores consistently found the anxiety node (score) to be highly peripheral. Also, the networks of RCADS anxiety items themselves were similar for the ASDs group and a general population comparison group (n = 2017). The results suggest anxiety is not a central part of autism and that anxiety is dynamically similar (aspects of anxiety relate to one another in a similar manner) in high-functioning autism and the general population. PMID- 29383650 TI - Rate and Risk Factors Associated with Autism Spectrum Disorder in Congenital Diaphragmatic Hernia. AB - To determine the rate and predictors of autism spectrum disorder (ASD) in congenital diaphragmatic hernia (CDH). Between 06/2004 and 09/2015 a total of 110 CDH survivors underwent neurodevelopmental (ND) testing and screening for ASD, followed by a full autism diagnostic evaluation if indicated at our institution. We found a 9 time higher rate of ASD in CDH children compared to the general population (P = 0.0002). Multiple patient-related and clinical variables risk factors of ASD were identified by univariate analysis. However, only short-term and long-term neurodevelopmental delays were strongly associated with ASD in CDH by multivariate comparisons. There is a striking prevalence of ASD in CDH survivors and our findings suggest that all CDH children should be regularly screened for ASD. PMID- 29383651 TI - Rickettsia parkeri infections diagnosed by eschar biopsy, Virginia, USA. AB - BACKGROUND: Infection with Rickettsia parkeri is an emerging tick-borne illness, often accompanied by fever and an eschar at the site of tick attachment. We present three cases of R. parkeri in Virginia residents. CASE PRESENTATIONS: Case 1 presented initially afebrile, failed to seroconvert to rickettsial antigens, and was diagnosed by DNA testing of the eschar. Case 2 presented febrile with eschar, no serologies were performed, and was diagnosed by DNA testing of the eschar. Case 3 presented febrile with eschar, serologies were negative for rickettsial antigens, and was diagnosed by DNA testing of the eschar. CONCLUSION: DNA testing of eschars represents an under-utilized diagnostic test and may aid in cases where the diagnosis is not made clinically. PMID- 29383652 TI - The Differential Mortality of Undesired Infants in Sub-Saharan Africa. AB - With high rates of infant mortality in sub-Saharan Africa, investments in infant health are subject to tough prioritizations within the household, in which maternal preferences may play a part. How these preferences will affect infant mortality as African women have ever-lower fertility is still uncertain, as increased female empowerment and increased difficulty in achieving a desired gender composition within a smaller family pull in potentially different directions. I study how being born at a parity or of a gender undesired by the mother relates to infant mortality in sub-Saharan Africa and how such differential mortality varies between women at different stages of the demographic transition. Using data from 79 Demographic and Health Surveys, I find that a child being undesired according to the mother is associated with a differential mortality that is not due to constant maternal factors, family composition, or factors that are correlated with maternal preferences and vary continuously across siblings. As a share of overall infant mortality, the excess mortality of undesired children amounts to 3.3 % of male and 4 % of female infant mortality. Undesiredness can explain a larger share of infant mortality among mothers with lower fertility desires and a larger share of female than male infant mortality for children of women who desire 1-3 children. Undesired gender composition is more important for infant mortality than undesired childbearing and may also lead couples to increase family size beyond the maternal desire, in which case infants of the surplus gender are particularly vulnerable. PMID- 29383654 TI - Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer: an Update Meta-Analysis of Randomized Clinical Trials. AB - Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have showed clinical benefit in combination with chemotherapeutic cytotoxic drugs in the first-line therapy of metastatic colorectal cancer (mCRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unknown. This study aimed to evaluate the impact of the combination of anti-epidermal growth factor receptor (anti-EGFR) therapy and anti vascular endothelial growth factor therapy on mCRC patient outcomes by combining the data from randomized clinical trials. Three trials meeting the eligibility criteria, and four randomized studies were included in the meta-analysis. For MCRC patients with KRAS wild type (KRAS-WT), the ORR was superior in patients treated with anti-EGFR compared with those who treated with anti-VEGF therapy. This effect was even better for all RAS-WT patients. Progression-free survival (PFS) rates were not significantly different for KRAS-WT mCRC and all RAS-WT mCRC between the two groups. The overall survival (OS) was higher for RAS wild-type (RAS-WT) mCRC patients who received anti-EGFR, but the KRAS-WT patients compared to the anti-VEGF therapy. The results of our research indicate that superior ORR and OS between the addition of anti-EGFR therapy VS anti-VEGF therapy in all RAS WT patients with MCRC. There was no significant difference in OS and PFS between the two groups for KRAS-WT mCRC. These results suggest that anti- EGFR monoclonal antibodies can achieve an equivalent efficacy when compared with anti-VEGF therapy of all RAS-WT mCRC patients. PMID- 29383653 TI - Alterations of Hippocampal Myelin Sheath and Axon Sprouting by Status Convulsion and Regulating Lingo-1 Expression with RNA Interference in Immature and Adult Rats. AB - Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage. PMID- 29383656 TI - The use of ultrasound imaging for brachial plexus injury assessment following operative clavicle repair. PMID- 29383655 TI - Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases. The mechanism for trehalose-induced autophagy enhancement is not clear, and its therapeutic effect on TAR DNA-binding protein-43 (TDP-43) proteinopathies has been poorly investigated. Here we examined the effect of trehalose on TDP-43 clearance in a cell culture model and identified that trehalose treatment significantly reduced TDP-43 accumulation in vitro through modulation of the autophagic degradation pathway. Further studies revealed that activation of TFEB induced by trehalose was responsible for the enhancement of autophagy and clearance of TDP-43 level. These results gave us the notion that TFEB is a central regular in trehalose-mediated autophagic clearance of TDP-43 aggregates, representing an important step forward in the treatment of TDP-43 related ALS diseases. PMID- 29383657 TI - Preservation of the infected thoracic aortic endograft with thoracoscopic drainage and continuous irrigation. AB - The gold standard for aortic endograft infection includes the excision of infected endograft, debridement, and reconstruction. However, these methods are not always the best option for patients with poor clinical status. We assessed the suitability of alternative methods for managing aortic endograft infection. The patient was a 72-year-old man whose previous abdominal surgeries provoked recurrent cholangitis. The patient had also undergone thoracic endovascular aortic repair (TEVAR). One month after the TEVAR, he was readmitted with high grade fever and diagnosed with endograft infection. Due to his frail condition, we chose a less invasive and conservative strategy; thoracoscopic drainage with endograft preservation, followed by continuous irrigation. He recovered well, and has survived more than 2 years after the drainage procedure. In unstable patients or those with severe comorbidities who cannot tolerate endograft excision, thoracoscopic drainage with endograft preservation is less invasive, and can be a bridging or temporary solution. PMID- 29383658 TI - COPD Patients as Vulnerable Subpopulation for Exposure to Ambient Air Pollution. AB - PURPOSE OF REVIEW: The prevalence of chronic obstructive pulmonary disease (COPD) is increasing worldwide with no known cure and an increasing number of triggers that exacerbate symptoms and speed up progression. This review aims to summarize the evidence for COPD patients being more vulnerable to air pollution exposure assessed as acute effects. RECENT FINDINGS: Several recent systematic reviews show consistently increased risks for COPD mortality and COPD hospital admission, ranging between 2 and 3% with increasing PM2.5 or PM10. Similar adverse impacts were shown for NO2. Also, adverse health effects among COPD patients were also found for other gaseous pollutants such as ozone and SO2; most of these studies could not be included in the meta-analysis we reviewed. Data from ten panel studies of COPD patients reported a small but statistically significant decline of FEV1 [- 3.38 mL (95% CI - 6.39 to - 0.37)] per increment of 10 MUg/m3 PM10, supporting an impact on respiratory health with increasing PM10 exposure. The combined information from systematic reviews and more recent findings lead us to conclude that COPD patients are more vulnerable to ambient air pollution than healthier people. PMID- 29383660 TI - Economic Burden of Clostridium difficile Infection in European Countries. AB - Clostridium difficile infection (CDI) remains a considerable challenge to health care systems worldwide. Although CDI represents a significant burden on healthcare systems in Europe, few studies have attempted to estimate the consumption of resources associated with CDI in Europe. The reported extra costs attributable to CDI vary widely according to the definitions, design, and methodologies used, making comparisons difficult to perform. In this chapter, the economic burden of healthcare facility-associated CDI in Europe will be assessed, as will other less explored areas such as the economic burden of recurrent CDI, community-acquired CDI, pediatric CDI, and CDI in outbreaks. PMID- 29383659 TI - An Electrophysiological Study of Cognitive and Emotion Processing in Type I Chiari Malformation. AB - Type I Chiari malformation (CMI) is a neurological condition in which the cerebellar tonsils descend into the cervical spinal subarachnoid space resulting in cervico-medullary compression. Early case-control investigations have indicated cognitive deficits in the areas of attention, memory, processing speed, and visuospatial function. The present study further examined cognitive and emotional processing deficits associated with CMI using a dual-task paradigm. Nineteen CMI patients were recruited during pre-surgical consultation and 19 matched control participants identified emotional expressions in separate single and asynchronous dual-task designs. To extend earlier behavioral studies of cognitive effects in CMI, we recorded event-related potentials (ERPs) in the dual task design. Though response times were slower for CMI patients across the two tasks, behavioral and ERP analyses indicated that patients did not differ from matched controls in the ability to allocate attentional resources between the two tasks. P1 ERP component analyses provided no indication of an emotional arousal deficit in our CMI sample while P3 ERP component analyses suggested a CMI-related deficit in emotional regulation. P3 analysis also yielded evidence for a frontalization of neurophysiological activity in CMI patients. Pain and related depression and anxiety factors accounted for CMI deficits in single-task, but not dual-task, response times. Results are consistent with a dysfunctional fronto parietal attentional network resulting from either the indirect effects of chronic pain or the direct effects of CMI pathophysiology stemming from cervico medullary compression. PMID- 29383661 TI - The Need for European Surveillance of CDI. AB - Since the turn of the millennium, the epidemiology of Clostridium difficile infection (CDI) has continued to challenge. Over the last decade there has been a growing awareness that improvements to surveillance are needed. The increasing rate of CDI and emergence of ribotype 027 precipitated the implementation of mandatory national surveillance of CDI in the UK. Changes in clinical presentation, severity of disease, descriptions of new risk factors and the occurrence of outbreaks all emphasised the importance of early diagnosis and surveillance.However a lack of consensus on case definitions, clinical guidelines and optimal laboratory diagnostics across Europe has lead to the underestimation of CDI and impeded comparison between countries. These inconsistencies have prevented the true burden of disease from being appreciated.Acceptance that a multi-country surveillance programme and optimised diagnostic strategies are required not only to detect and control CDI in Europe, but for a better understanding of the epidemiology, has built the foundations for a more robust, unified surveillance. The concerted efforts of the European Centre for Disease Prevention and Control (ECDC) CDI networks, has lead to the development of an over-arching long-term CDI surveillance strategy for 2014-2020. Fulfilment of the ECDC priorities and targets will no doubt be challenging and will require significant investment however the hope is that both a national and Europe-wide picture of CDI will finally be realised. PMID- 29383662 TI - Diagnostic Guidance for C. difficile Infections. AB - Diagnosis of Clostridium difficile infection (CDI) can be challenging. First of all, there has been debate on which of the two reference assays, cell cytotoxicity neutralization assay (CCNA) or toxigenic culture (TC) should be considered the gold standard for CDI detection. Although the CCNA suffers most from suboptimal storage conditions and subsequent toxin degradation, TC is reported to falsely increase CDI detection rates as it cannot differentiate CDI patients from patients asymptomatically colonised by toxigenic C. difficile. Several rapid assays are available for CDI detection and fall into three broad categories: (1) enzyme immunoassays for glutamate dehydrogenase, (2) enzyme immunoassays for toxins A/B and (3) nucleic acid amplification tests detecting toxin genes. All three categories have their own limitations, being suboptimal specificity and/or sensitivity or the inability to discern colonised patients from CDI patients. In light of these limitations, multi-step algorithmic testing has now been advocated by international guidelines in order to optimize diagnostic accuracy. Despite these recommendations, testing methods between hospitals vary widely, which impacts CDI incidence rates. CDI incidence rates are also influenced by sample selection criteria, as several studies have shown that if not all unformed stool samples are tested for CDI, many cases may be missed due to an absence of clinical suspicion. Since methods for diagnosing CDI remain imperfect, there has been a growing interest in alternative testing strategies like faecal biomarkers, immune modulating interleukins, cytokines and imaging methods. At the moment, these alternative methods might play an adjunctive role, but they are not suitable to replace conventional CDI testing strategies. PMID- 29383663 TI - Ribotypes and New Virulent Strains Across Europe. AB - Clostridium difficile is a major bacterial cause of post-antibiotic diarrhoea. The epidemiology of C. difficile infections (CDI) has dramatically changed since the early 2000s, with an increasing incidence and severity across Europe. This trend is partly due to the emergence and rapid worldwide spread of the hypervirulent and epidemic PCR ribotype 027. Profiles of patients with CDI have also evolved, with description of community-acquired (CA) infections in patients with no traditional risk factors for CDI. However, recent epidemiological studies indicated that some European countries have successfully controlled the dissemination of the 027 clone whereas other countries recently reported the emergence of other virulent or unusual strains. The aims of this review are to summarize the current European CDI epidemiology and to describe the new virulent C. difficile strains circulating in Europe, as well as other potential emerging strains described elsewhere. Standardized typing methods and surveillance programmes are mandatory for a better understanding and monitoring of CDI in Europe. PMID- 29383664 TI - Comparative Genomics of Clostridium difficile. AB - Clostridium difficile, a gram-positive spore-forming anaerobic bacterium, has rapidly emerged as the leading cause of nosocomial diarrhoea in hospitals. The availability of genome sequences in large numbers, mainly due to the use of next generation sequencing methods, have undoubtedly shown their immense advantages in the determination of the C. difficile population structure. The implementation of fine-scale comparative genomic approaches have paved the way to global transmission and recurrence studies, but also more targeted studies such as the PaLoc or the CRISPR/Cas systems. In this chapter, we provide an overview of the recent and significant findings on C. difficile using comparative genomics studies with implication for the epidemiology, infection control and understanding of the evolution of C. difficile. PMID- 29383665 TI - Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins. AB - Research on the human gut pathogen Clostridium difficile and its toxins has gained much attention, particularly as a consequence of the increasing threat to human health presented by emerging hypervirulent strains. Toxin A (TcdA) and B (TcdB) are the two major virulence determinants of C. difficile. Both are single chain proteins with a similar multidomain architecture. Certain hypervirulent C. difficile strains also produce a third toxin, namely binary toxin CDT (Clostridium difficile transferase). As C. difficile toxins are the causative agents of C. difficile-associated diseases (CDAD), such as antibiotics-associated diarrhea and pseudomembranous colitis, considerable efforts have been expended to unravel their molecular mode-of-action and the cellular mechanisms responsible for their uptake. Notably, a high proportion of studies on C. difficile toxins were performed in European laboratories. In this chapter we will highlight important recent advances in C. difficile toxins research. PMID- 29383666 TI - Clostridium difficile Biofilm. AB - Clostridium difficile infection (CDI) is an important healthcare-associated disease worldwide, mainly occurring after antimicrobial therapy. Antibiotics administered to treat a number of infections can promote C. difficile colonization of the gastrointestinal tract and, thus, CDI. A rise in multidrug resistant clinical isolates to multiple antibiotics and their reduced susceptibility to the most commonly used antibiotic molecules have made the treatment of CDI more complicated, allowing the persistence of C. difficile in the intestinal environment.Gut colonization and biofilm formation have been suggested to contribute to the pathogenesis and persistence of C. difficile. In fact, biofilm growth is considered as a serious threat because of the related increase in bacterial resistance that makes antibiotic therapy often ineffective. However, although the involvement of the C. difficile biofilm in the pathogenesis and recurrence of CDI is attracting more and more interest, the mechanisms underlying biofilm formation of C. difficile as well as the role of biofilm in CDI have not been extensively described.Findings on C. difficile biofilm, possible implications in CDI pathogenesis and treatment, efficacy of currently available antibiotics in treating biofilm-forming C. difficile strains, and some antimicrobial alternatives under investigation will be discussed here. PMID- 29383667 TI - European Practice for CDI Treatment. AB - Clostridium difficile infection (CDI) remains a significant cause of morbidity and mortality worldwide. Historically, two antibiotics (metronidazole and vancomycin) and a recent third (fidaxomicin) have been used routinely for CDI treatment; convincing data are now available showing that metronidazole is the least efficacious agent. The European Society of Clinical Microbiology and Infectious Diseases CDI treatment guidelines outline the treatment options for a variety of CDI clinical scenarios, including use of the more traditional anti-CDI therapies (e.g., metronidazole, vancomycin), the role of newer anti-CDI agents (e.g., fidaxomicin), indications for surgical intervention and for non antimicrobial management (e.g., faecal microbiota transplantation, FMT). A 2017 survey of 20 European countries found that while the majority (n = 14) have national CDI guidelines that provide a variety of recommendations for CDI treatment, only five have audited guideline implementation. A variety of restrictions are in place in 13 (65%) countries prior to use of new anti-CDI treatments, including committee/infection specialist approval or economic review/restrictions. Novel anti-CDI agents are being evaluated in Phase III trials; it is not yet clear what will be the roles of these agents. Prophylaxis is an optimum approach to reduce the impact of CDI especially in high-risk populations; monoclonal antibodies, antibiotic blocking approaches and multiple vaccines are currently in advanced clinical trials. The treatment of recurrent CDI is particularly troublesome, and several different live bio therapeutics are being developed, in addition to FMT. PMID- 29383668 TI - Antibiotic Resistances of Clostridium difficile. AB - The rapid evolution of antibiotic resistance in Clostridium difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matter of concern for public health. Antibiotic resistance plays an important role in driving C. difficile epidemiology. Emergence of new types is often associated with the emergence of new resistances and most of epidemic C. difficile clinical isolates is currently resistant to multiple antibiotics. In particular, it is to worth to note the recent identification of strains with reduced susceptibility to the first-line antibiotics for CDI treatment and/or for relapsing infections. Antibiotic resistance in C. difficile has a multifactorial nature. Acquisition of genetic elements and alterations of the antibiotic target sites, as well as other factors, such as variations in the metabolic pathways and biofilm production, contribute to the survival of this pathogen in the presence of antibiotics. Different transfer mechanisms facilitate the spread of mobile elements among C. difficile strains and between C. difficile and other species. Furthermore, recent data indicate that both genetic elements and alterations in the antibiotic targets can be maintained in C. difficile regardless of the burden imposed on fitness, and therefore resistances may persist in C. difficile population in absence of antibiotic selective pressure. PMID- 29383669 TI - Probiotics for Prevention and Treatment of Clostridium difficile Infection. AB - Probiotics have been claimed as a valuable tool to restore the balance in the intestinal microbiota following a dysbiosis caused by, among other factors, antibiotic therapy. This perturbed environment could favor the overgrowth of Clostridium difficile and, in fact, the occurrence of C. difficile-associated infections (CDI) is being increasing in recent years. In spite of the high number of probiotics able to in vitro inhibit the growth and/or toxicity of this pathogen, its application for treatment or prevention of CDI is still scarce since there are not enough well-defined clinical studies supporting efficacy. Only a few strains, such as Lactobacillus rhamnosus GG and Saccharomyces boulardii have been studied in more extent. The increasing knowledge about the probiotic mechanisms of action against C. difficile, some of them reviewed here, makes promising the application of these live biotherapeutic agents against CDI. Nevertheless, more effort must be paid to standardize the clinical studied conducted to evaluate probiotic products, in combination with antibiotics, in order to select the best candidate for C. difficile infections. PMID- 29383670 TI - Faecal Microbiota Transplantation as Emerging Treatment in European Countries. AB - Clostridium difficile infection (CDI) is one of the most common healthcare associated infections in the world and is a leading cause of morbidity and mortality in hospitalized patients.Although several antibiotics effectively treat CDI, some individuals do not respond to these drugs and may be cured by transplanting stool from healthy donors. This procedure, termed Faecal Microbiota Transplantation (FMT), has demonstrated remarkable efficacy as a treatment for recurrent CDI.FMT has also been investigated in other diseases and disorders where perturbations to the gut microbiota have been theorized to play a causative role in pathogenesis and severity, such as inflammatory bowel disease (IBD). Although FMT is currently not recommended to cure IBD patients in clinical practice, several studies have recently been carried out with promising results. The aim of future research is therefore to standardize protocols and develop FMT as a therapeutic option for these patients.This review summarizes data on the use of FMT as a treatment for CDI and IBD, with special attention given to studies conducted in European countries. PMID- 29383671 TI - Immunization Strategies Against Clostridium difficile. AB - C. difficile infection (CDI) is an important healthcare- but also community associated disease. CDI is considered a public health threat and an economic burden. A major problem is the high rate of recurrences. Besides classical antibiotic treatments, new therapeutic strategies are needed to prevent infection, to treat patients and prevent recurrences. If fecal transplantation has been recommended to treat recurrences, another key approach is to restore immunity against C. difficile and its virulence factors. Here, after a summary concerning the virulence factors, the host immune response against C. difficile and its role in the outcome of disease, we review the different approaches of passive immunotherapies and vaccines developed against CDI. Passive immunization strategies are designed in function of the target antigen, the antibody-based product and its administration route. Similarly, for active immunization strategies, vaccine antigens can target toxins or surface proteins and immunization can be performed by parenteral or mucosal routes. For passive immunization and vaccination as well, we first present immunization assays performed in animal models and second in humans and associated clinical trials. The different studies are presented according to the mode of administration either parenteral or mucosal and the target antigens, either toxins or colonization factors. PMID- 29383672 TI - Non-human C. difficile Reservoirs and Sources: Animals, Food, Environment. AB - Clostridium difficile is ubiquitous and is found in humans, animals and in variety of environments. The substantial overlap of ribotypes between all three main reservoirs suggests the extensive transmissions. Here we give the overview of European studies investigating farm, companion and wild animals, food and environments including water, soil, sediment, waste water treatment plants, biogas plants, air and households. Studies in Europe are more numerous especially in last couple of years, but are still fragmented in terms of countries, animal species or type of environment covered. Soil seem to be the habitat of divergent unusual lineages of C. difficile. But the most important aspect of animals and environment is their role in C. difficile transmissions and their potential as a source for human infection is discussed. PMID- 29383673 TI - The ESCMID Study Group for Clostridium difficile: History, Role and Perspectives. AB - C. difficile is a major nosocomial pathogen, but is also increasingly recognised as an important diarrhoeal pathogen in the community, not always associated with antibiotics. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Clostridium difficile (ESGCD) is a group of clinicians and scientists from many European countries and further afield, who share a common interest in C. difficile. The aims of the Study Group are centred around raising the profile of CDI in humans and animals, fostering collaboration amongst centres in different European countries and providing a forum for discussing and disseminating information. One of the principal aims of the Study Group is to raise awareness of C. difficile infections in European hospitals. ESGCD has a particular interest in the development and dissemination of European guidance on prevention, diagnosis and treatment of CDI. This chapter will discuss the organisation of ESGCD within the ESCMID Study Group structure, the origins of the Study Group, the aims and objectives of the group, and will highlight some of the past and present activities of ESGCD in relation to these. PMID- 29383674 TI - Choriocapillaris Vascular Density Changes in Patients with Drusen: Cross Sectional Study Based on Optical Coherence Tomography Angiography Findings. AB - INTRODUCTION: The purpose of this study was to investigate the extent and morphology of the choriocapillaris' density defect in patients with drusen in non neovascular age-related macular degeneration (AMD). METHODS: Participants in this study were 36 patients with non-neovascular AMD and drusen. All patients underwent best-corrected visual acuity, slit-lamp examination, spectral domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA). RESULTS: In all studied cases, the presence of drusen was associated with choriocapillaris' reduced blood flow signal of different extent and severity. Three types of choriocapillaris' non-perfusion were observed, along with an association between the size of drusen and the morphology of choriocapillaris' density defect. Moreover, the extent of choriocapillaris' density change has been related to ellipsoid zone disruption and therefore to visual impairment. CONCLUSIONS: Our study showed that in patients with drusen due to non-neovascular AMD, there is choriocapillaris' impairment of different morphology in OCTA, which is mainly related to the size and location of the drusen. PMID- 29383675 TI - Effects of Corrective Feedback on EFL Learners' Acquisition of Third-Person Singular Form and the Mediating Role of Cognitive Style. AB - The present study investigated the effectiveness of recasts and prompts on the acquisition of the English third-person singular form and the mediating role of cognitive style on the effects of feedback. One hundred and seventy-five college students from four intact classes were assigned to four groups: form-focused instruction with recast (FFI-recast), FFI with prompt (FFI-prompt), FFI, and control. The group embedded figures test (Witkin et al. in Rev Educ Res 47:1-64, 1977) was adopted to test learners' cognitive style (field dependence/independence). The results show that the FFI-prompt group outperformed the FFI-recast group and the control group on the immediate post-test; the FFI prompt group also achieved significantly higher scores than the other groups on the delayed post-test in the written test. However, no significant difference was found among groups in the text-completion test. Regression analyses reveal that in the text-completion test, field dependence/independence mediates the effect of recasts on the immediate post-test. PMID- 29383677 TI - Pasireotide treatment reduces cardiometabolic risk in Cushing's disease patients: an Italian, multicenter study. AB - PURPOSE: Patients with Cushing's disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients. METHODS: This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200-1800 mcg/daily). RESULTS: Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values. CONCLUSIONS: Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus. PMID- 29383676 TI - Regulation, signalling and functions of hormonal peptides in pulmonary vascular remodelling during hypoxia. AB - Hypoxic state affects organism primarily by decreasing the amount of oxygen reaching the cells and tissues. To adjust with changing environment organism undergoes mechanisms which are necessary for acclimatization to hypoxic stress. Pulmonary vascular remodelling is one such mechanism controlled by hormonal peptides present in blood circulation for acclimatization. Activation of peptides regulates constriction and relaxation of blood vessels of pulmonary and systemic circulation. Thus, understanding of vascular tone maintenance and hypoxic pulmonary vasoconstriction like pathophysiological condition during hypoxia is of prime importance. Endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and renin angiotensin system (RAS) function, their receptor functioning and signalling during hypoxia in different body parts point them as disease markers. In vivo and in vitro studies have helped understanding the mechanism of hormonal peptides for better acclimatization to hypoxic stress and interventions for better management of vascular remodelling in different models like cell, rat, and human is discussed in this review. PMID- 29383678 TI - Hepatic intra-arterial therapies in metastatic neuroendocrine tumors: lessons from clinical practice. AB - BACKGROUND: Liver metastases are common in patients with neuroendocrine tumors (NETs), having a negative impact on disease prognosis. The options for selective therapy in patients with unresectable multiple liver metastases are limited to TACE (transarterial chemoembolization), TAE (transarterial embolization), or SIRT (selective internal radiation therapy). AIM: To explore the clinical outcome, survival and safety of these therapies in NETs patients. METHODS: Retrospective case series of consecutive patients (mean age 56.6 years, 59% male) treated at two tertiary university medical centers from 2005 to 2015. RESULTS: Fifty-seven patients with G1, G2, and low G3 NETs with liver metastases were investigated (pancreatic NET (pNET), 24; small bowel, 16; unknown origin (UKO), 9; rectal, 3; lung, 3; and gastric, 2). Fifty-three patients underwent TACE, three patients underwent TAE, and one patient underwent SIRT. Clinical improvement and tumor response were observed in 54/57 patients (95%), together with marked decreased in tumor markers. The median time to tumor progression following the first treatment was 14 +/- 16 months. The median overall survival was 22 +/- 18 months, more pronounced in the pNET, followed by small bowel and UKO subgroups. There was a trend for a better survival in patients with disease limited to the liver and in whom the primary tumor was resected. CONCLUSION: Hepatic intra-arterial therapies are well tolerated in the majority of patients with NETs and liver metastases and associated with both clinical improvement and tumor stabilization for prolonged periods. These therapies should be always considered, irrespective of the presence of extrahepatic metastasis. PMID- 29383679 TI - miR15a and miR16 in Chilean type 1 diabetes patients: possible association with apoptosis, inflammatory, or autoimmunity markers. AB - AIM: Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by the progressive destruction of beta cells, mediated by the interaction between T cells and several cytokines. The pathogenesis of T1D has established its possible relationship with miRNAs. In this study, we analyze the expression profile of miR 15a and miR-16 in peripheral blood mononuclear cells (PBMCs) and their possible association with apoptosis, inflammation, or autoimmunity markers. PATIENTS AND METHODOLOGY: 38 T1D patients and 41 control subjects were recruited. mRNAs were analyzed by means of qPCR and TaqMan probes. PBMCs were treated with different concentrations of glucose (baseline, 11 and 25 mM) with or without an inflammatory stimulus as TNF-alpha (10 ng/ml). RESULTS: A decrease in the levels of the miR-15a expression in basal conditions is observed in T1D patients compared to healthy control subjects (relative units 0.5 vs. 1.8, p < 0.05). This change in miR-15a and miR-16 is not affected by the addition of TNF-alpha. No association is observed with inflammatory markers (IL-6, TNF-alpha, vCAM) or apoptosis (bcl2 expression). The relationship with immunological markers shows an interaction effect between miR16 and IA-2 (p < 0.03). CONCLUSION: TNF-alpha does not affect the expression profile of miR-15a and miR16 in PBMCs. A weak correlation is observed between miR-16 and with the autoimmunity profile (IA-2 autoantibody). PMID- 29383681 TI - Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+ Channel Gating. AB - Over one hundred mutations in the Kv7.2 (KCNQ2) gene encoding for phosphatidylinositol 4,5-bisphosphate (PIP2)-sensitive voltage-gated K+ channel subunits have been identified in early-onset epilepsies with wide phenotypic variability. By contrast, only few mutations in the closely related Kv7.3 (KCNQ3) gene have been reported, mostly associated with typical benign familial neonatal seizures (BFNS). We herein describe a patient affected by early onset epileptic encephalopathy (EOEE) carrying two Kv7.3 missense mutations (p.Val359Leu/V359L and p.Asp542Asn/D542N) in compound heterozygosis, each inherited from an asymptomatic parent. Patch-clamp recordings from transiently transfected CHO cells showed that, when incorporated in physiologically relevant Kv7.2 + Kv7.3 heteromeric channels, expression of Kv7.3 V359L or Kv7.3 D542N subunits failed to affect current density, whereas a significant decrease was instead observed when these mutant subunits were both simultaneously present. Modeling and functional experiments revealed that each variant decreased PIP2-dependent current regulation, with additive effects when the two were co-expressed. Moreover, expression of Kv7.2 subunits carrying the D535N variant previously described in three sporadic EOEE cases prompted functional changes more dramatic when compared to those of the corresponding D542N variant in Kv7.3, but similar to those observed when both Kv7.3 V359L and Kv7.3 D542N subunits were expressed together. Finally, the Kv7 activator retigabine restored channel dysfunction induced by each Kv7.2 or Kv7.3 variant(s). These results provide a plausible molecular explanation for the apparent recessive inheritance of the phenotype in the family investigated, and a rational basis for personalized therapy with Kv7 channel activators in EOEE patients carrying loss-of-function mutations in Kv7.2 or Kv7.3. PMID- 29383682 TI - Disruption of De Novo Serine Synthesis in Muller Cells Induced Mitochondrial Dysfunction and Aggravated Oxidative Damage. AB - De novo serine synthesis plays important roles in normal mitochondrial function and cellular anti-oxidative capacity. It is reported to be mainly activated in glial cells of the central nervous system, but its role in retinal Muller glia remains unclear. In this study, we inhibited de novo serine synthesis using CBR 5884, a specific inhibitor of phosphoglycerate dehydrogenase (PHGDH, a rate limiting enzyme in de novo serine metabolism) in MIO-M1 cells (immortalized human Muller cells) and huPMCs (human primary Muller cells) under mild oxidative stress. Alamar blue and LDH (lactate dehydrogenase) assays showed significantly reduced metabolic activities and increased cellular damage of Muller cells, when exposed to CBR-5884 accompanied by mild oxidative stress; however, CBR-5884 alone had little effect. The increased cellular damage was partially reversed by supplementation with exogenous serine/glycine. HSP72 (an oxidative stress marker) and reactive oxygen species (ROS) levels were significantly increased; glutathione and NADPH/NADP+ levels were pronouncedly reduced under PHGDH inhibition accompanied by oxidative stress. JC-1 staining and Seahorse respiration experiments showed that inhibition of de novo serine synthesis in Muller cells can also increase mitochondrial stress and decrease mitochondrial ATP production. qPCR and Western blot demonstrated an increased expression of HSP60 (a key mitochondrial stress-related gene), and this was further validated in human retinal explants. Our study suggests that de novo serine synthesis is important for Muller cell survival, particularly when they are exposed to mild oxidative stress, possibly by maintaining mitochondrial function and generating glutathione and NADPH to counteract ROS. PMID- 29383680 TI - Frailty and emergency surgery in the elderly: protocol of a prospective, multicenter study in Italy for evaluating perioperative outcome (The FRAILESEL Study). AB - Improvements in living conditions and progress in medical management have resulted in better quality of life and longer life expectancy. Therefore, the number of older people undergoing surgery is increasing. Frailty is often described as a syndrome in aged patients where there is augmented vulnerability due to progressive loss of functional reserves. Studies suggest that frailty predisposes elderly to worsening outcome after surgery. Since emergency surgery is associated with higher mortality rates, it is paramount to have an accurate stratification of surgical risk in such patients. The aim of our study is to characterize the clinicopathological findings, management, and short-term outcome of elderly patients undergoing emergency surgery. The secondary objectives are to evaluate the presence and influence of frailty and analyze the prognostic role of existing risk-scores. The final FRAILESEL protocol was approved by the Ethical Committee of "Sapienza" University of Rome, Italy. The FRAILESEL study is a nationwide, Italian, multicenter, observational study conducted through a resident-led model. Patients over 65 years of age who require emergency surgical procedures will be included in this study. The primary outcome measures are 30 day postoperative mortality and morbidity rates. The Clavien-Dindo classification system is used to categorize complications. The secondary outcome measures include length of hospital stay, length of stay in intensive care unit, and predictive value for morbidity and mortality of several frailty and surgical risk scores. The results of the FRAILESEL study will be disseminated through national and international conference presentations and peer-reviewed journals. The study is also registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02825082). PMID- 29383683 TI - Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats. AB - Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder. PMID- 29383684 TI - Dynorphin and kappa-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics. AB - Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/kappa-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2 containing pathways which may lead to the negative affective state in human alcoholics. PMID- 29383685 TI - Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex. AB - Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex. PMID- 29383686 TI - Expected Paradigm Shift in Brain Metastases Therapy-Immune Checkpoint Inhibitors. AB - Brain metastasis (BM) is one of the dreadful complications of malignancies. The prognosis after BM is extremely poor and life expectancy is meager. Currently, our treatment modalities are limited to radiotherapy and surgical resection, which also has poor outcomes and leads to various neurological deficits and affects the quality of life of patients. New treatment modality, i.e., immune checkpoint inhibitors, has brought revolution in management of melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors basically enhance the immune response of the body to fight against cancers. Immune response in the brain is highly regulated; therefore, it is challenging to use immune-modulator drugs in BM. The microenvironment of BM is rich in cytotoxic T lymphocytes and which is the target of immune checkpoint inhibitors. Few studies have shown some hope regarding use of immune checkpoint inhibitors in management of BM. It works through inhibiting immune check point gates, i.e., CTLA-4 (cytotoxic T-lymphocyte-associated protein) and PD-1/PD-L1 (programmed cell death protein-1/program death ligand-1). This article explains the basic mechanism of immune check point inhibitors, rationale behind their usage in BM, and some of the clinical studies which have shown the efficacy of immune check point inhibitors in BM. PMID- 29383687 TI - Transcranial Ultrasound Stimulation Improves Long-Term Functional Outcomes and Protects Against Brain Damage in Traumatic Brain Injury. AB - The purpose of this study was to assess the long-term treatment efficacy of low intensity pulsed ultrasound (LIPUS) on functional outcomes, brain edema, and the possible involvement of reactions in mice following traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury received LIPUS treatment daily for a period of 4 weeks. The effects of LIPUS on edema were detected by MR imaging in the mouse brain at 148 days following TBI. Long-term functional outcomes of LIPUS stimulation were evaluated by behavioral analyses. One-way or two-way analysis of variance and Student's t test were used for statistical analyses, with a significant level of .05. Up to post-injury day 148, treatment with LIPUS significantly improved functional outcomes (all p < 0.05). LIPUS also significantly attenuated brain edema and neuronal death at day 148 after TBI (all p < 0.05). Furthermore, LIPUS reduced MMP9 activity, neutrophil infiltration, and microglial activation at day 1 or day 4 following TBI (all p < 0.05). Meanwhile, LIPUS increased the Bcl-2/Bax ratio and enhanced the phosphorylation of Bad and FOXO-1 at day 1 or day 4 following TBI (all p < 0.05). Almost 5 months of follow up showed that the treatment efficacy of post-injury LIPUS stimulation on reduced brain edema and improved functional outcomes persisted over time after TBI. The neuroprotective effects of LIPUS are associated with a reduction of early inflammatory events and inhibition of apoptotic progression. PMID- 29383688 TI - Role of Amyloid Precursor Protein (APP) and Its Derivatives in the Biology and Cell Fate Specification of Neural Stem Cells. AB - Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (eta-secretase, delta-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPalpha (sAPPalpha), soluble APPbeta (sAPPbeta), beta-amyloid (Abeta) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described. PMID- 29383689 TI - Magnesium Reduces Blood-Brain Barrier Permeability and Regulates Amyloid-beta Transcytosis. AB - Poor Mg status is a risk factor for Alzheimer's disease (AD), and the underlying mechanisms remain elusive. Here, we provided the first evidence that elevated Mg levels significantly reduced the blood-brain barrier (BBB) permeability and regulated its function in vitro. Transient receptor potential melastatin 7 (TRPM7) and magnesium transporter subtype 1 (MagT1) were two major cellular receptors mediating entry of extracellular Mg2+ into the cells. Elevated Mg levels also induced an accelerated clearance of amyloid-beta peptide (Abeta) from the brain to the blood side via BBB transcytosis through low-density lipoprotein receptor-related protein (LRP) and phosphatidylinositol binding clathrin assembly protein (PICALM), while reduced the influx of Abeta from the blood to the brain side involving receptor for advanced glycation end products (RAGE) and caveolae. Mg enhanced BBB barrier properties and overall expression of LRP1 and PICALM whereas reduced that of RAGE and caveolin-1. Apical-to-basolateral and vice versa steady-state Abeta flux achieved an equilibrium of 18 and 0.27 fmol/min/cm2, respectively, about 30 min after the initial addition of physiological levels of free Abeta. Knockdown of caveolin-1 or disruption of caveolae membrane microdomains reduced RAGE-mediated influx significantly, but not LRP1-mediated efflux of Abeta. Stimulating endothelial cells with vascular endothelial growth factor (VEGF) enhanced caveolin-1 phosphorylation and RAGE expression. Co immunoprecipitation demonstrated that RAGE, but not LRP1, was physically associated with caveolin-1. Thus, Mg can reduce BBB permeability and promote BBB clearance of Abeta from the brain by increasing the expression of LRP1 and PICALM while reducing the level of RAGE and caveolin-1. PMID- 29383690 TI - Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1alpha Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease affecting over five million individuals worldwide. The exact molecular events underlying PD pathogenesis are still not clearly known. Glia maturation factor (GMF), a neuroinflammatory protein in the brain plays an important role in the pathogenesis of PD. Mitochondrial dysfunctions and oxidative stress trigger apoptosis leading to dopaminergic neuronal degeneration in PD. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha or PPARGC alpha) acts as a transcriptional co-regulator of mitochondrial biogenesis and energy metabolism by controlling oxidative phosphorylation, antioxidant activity, and autophagy. In this study, we found that incubation of immortalized rat dopaminergic (N27) neurons with GMF influences the expression of peroxisome PGC 1alpha and increases oxidative stress, mitochondrial dysfunction, and apoptotic cell death. We show that incubation with GMF reduces the expression of PGC-1alpha with concomitant decreases in the mitochondrial complexes. Besides, there is increased oxidative stress and depolarization of mitochondrial membrane potential (MMP) in these cells. Further, GMF reduces tyrosine hydroxylase (TH) expression and shifts Bax/Bcl-2 expression resulting in release of cytochrome-c and increased activations of effector caspase expressions. Transmission electron microscopy analyses revealed alteration in the mitochondrial architecture. Our results show that GMF acts as an important upstream regulator of PGC-1alpha in promoting dopaminergic neuronal death through its effect on oxidative stress mediated apoptosis. Our current data suggest that GMF is a critical risk factor for PD and suggest that it could be explored as a potential therapeutic target to inhibit PD progression. PMID- 29383691 TI - Early Treatment with Poly(ADP-Ribose) Polymerase-1 Inhibitor (JPI-289) Reduces Infarct Volume and Improves Long-Term Behavior in an Animal Model of Ischemic Stroke. AB - In patients with stroke and neurodegenerative diseases, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) causes harmful effects by inducing apoptosis, necrosis, neuroinflammation, and immune dysregulation. The current study investigated the neuroprotective effect of a novel PARP-1 inhibitor, JPI 289, in an animal model of ischemic stroke. A transient middle cerebral artery occlusion (tMCAO, 2 h) model was used to determine the therapeutic effect and the most effective dose and time window of administration of JPI-289. We also investigated the long-term outcomes of treatment with JPI-289 by diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI and by measuring neurological function at 24 h, 7 days, and 28 days after MCAO. The most effective dose and time window of administration of JPI-289 was 10 mg/kg administered 2 h after MCAO with reperfusion. Twenty-four hours after MCAO, infarct volume was reduced by 53% and the number of apoptotic cells was reduced by 56% compared with control. JPI-289 also reduced infarct volume by 16% in the permanent MCAO model. In an MRI-based study, initial infarct volume, as measured using DWI, was similar in the control and JPI-289-treated groups. However, infarct volume and brain swelling were significantly reduced in the group treated with JPI-289 (2 h) at 24 h and 7 days after MCAO. Neurological functions also improved in the group treated with JPI-289 (2 h) until 28 days after MCAO. Inhibition of PARP-1 has neuroprotective effects (reduction of infarct volume and brain swelling) in both tMCAO and pMCAO models of ischemic stroke. PMID- 29383693 TI - Distinct Roles of Protein Phosphatase 1 Bound on Neurabin and Spinophilin and Its Regulation in AMPA Receptor Trafficking and LTD Induction. AB - Protein phosphatase-1 (PP1) constrains learning and memory formation in part through its effects on the induction threshold of long-term potentiation (LTP) and depression (LTD). LTD induction requires both the enzymatic activity of PP1 and its proper anchoring to synaptic spines. We have shown previously that neurabin, a major synaptic scaffolding protein, targets PP1 to synapses for LTD induction. Here, we show that PP1 bound on spinophilin, a close homolog of neurabin and another major synaptic PP1 anchoring protein, does not play a role in LTD induction, which suggests that neurabin plays a privileged role in nanodomain targeting of PP1 in LTD induction. We found that protein kinase A can significantly weaken the neurabin-PP1 interaction in neurons via phosphorylation of neurabin at serine 461, a phosphorylation site adjacent to the PP1-binding motif that is not conserved in spinophilin. Finally, we found that a neurabin mutation (S461E), which mimics phosphorylation, blocked AMPA receptor endocytosis and LTD induction. The results indicate the critical importance of nanodomain targeting of PP1 within synaptic spines and its regulation in LTD induction. PMID- 29383692 TI - A Fragment of Adhesion Molecule L1 Binds to Nuclear Receptors to Regulate Synaptic Plasticity and Motor Coordination. AB - Proteolytic cleavage of the neuronal isoform of the murine cell adhesion molecule L1, triggered by stimulation of the cognate L1-dependent signaling pathways, results in the generation and nuclear import of an L1 fragment that contains the intracellular domain, the transmembrane domain, and part of the extracellular domain. Here, we show that the LXXLL and FXXLF motifs in the extracellular and transmembrane domain of this L1 fragment mediate the interaction with the nuclear estrogen receptors alpha (ERalpha) and beta (ERbeta), peroxisome proliferator activated receptor gamma (PPARgamma), and retinoid X receptor beta (RXRbeta). Mutations of the LXXLL motif in the transmembrane domain and of the FXXLF motif in the extracellular domain disturb the interaction of the L1 fragment with these nuclear receptors and, when introduced by viral transduction into mouse embryos in utero, result in impaired motor coordination, learning and memory, as well as synaptic connectivity in the cerebellum, in adulthood. These impairments are similar to those observed in the L1-deficient mouse. Our findings suggest that the interplay of nuclear L1 and distinct nuclear receptors is associated with synaptic contact formation and plasticity. PMID- 29383694 TI - Evaluation of Midkine Expression in Dentigerous Cysts, Odontogenic Keratocysts and Different Types of Ameloblastoma. AB - OBJECTIVE: Midkine is a heparin-binding growth factor whose expression is increased in most tumors, namely ameloblastomas. This study aimed to compare Midkine expression in different odontogenic lesions. MATERIAL AND METHOD: This analytical cross-sectional study was performed on 52 definitely diagnosed odontogenic lesions including 15 dentigerous cysts, 13 odontogenic keratocysts, and 17 unicystic and 5 multicystic ameloblastomas archived from 1997 to 2015. Midkine expression was examined in tissue samples through immunohistochemistry. The nonparametric Kruskal-Wallis and Mann-Whitney tests were run as appropriate (P < 0.05). RESULTS: The frequency of Midkine expression was < 20% in 7.7%, 20 50% in 25%, and > 50 % in 67.3% of the samples, indicating significant differences among the groups (P = 0.002). Moreover, the expression intensity was strong in 63.5%, moderate in 23.1%, and weak in 13.5% of odontogenic lesion samples (P = 0.071). The total staining score was weak in 3.8%, moderate in 48.1%, and strong in 48.1% of the cells, displaying significant differences between the study groups in this regard (P = 0.043). CONCLUSION: Midkine can be considered as both a differentiating factor and a molecular-targeted therapy in odontogenic lesions. Yet, further studies are required to approve the role of this cytokine in different biological and pathological stages of the tumors. PMID- 29383695 TI - Bioactive glass induced osteogenic differentiation of human adipose stem cells is dependent on cell attachment mechanism and mitogen-activated protein kinases. AB - Bioactive glasses (BaGs) are widely utilised in bone tissue engineering (TE) but the molecular response of cells to BaGs is poorly understood. To elucidate the mechanisms of cell attachment to BaGs and BaG-induced early osteogenic differentiation, we cultured human adipose stem cells (hASCs) on discs of two silica-based BaGs S53P4 (23.0 Na2O - 20.0 CaO - 4.0 P2O5 - 53.0 SiO2 (wt-%)) and 1-06 (5.9 Na2O - 12.0 K2O - 5.3 MgO - 22.6 CaO - 4.0 P2O5 - 0.2 B2O3 - 50.0 SiO2) in the absence of osteogenic supplements. Both BaGs induced early osteogenic differentiation by increasing alkaline phosphatase activity (ALP) and the expression of osteogenic marker genes RUNX2a and OSTERIX. Based on ALP activity, the slower reacting 1-06 glass was a stronger osteoinducer. Regarding the cell attachment, cells cultured on BaGs had enhanced integrinbeta1 and vinculin production, and mature focal adhesions were smaller but more dispersed than on cell culture plastic (polystyrene). Focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK)-induced c-Jun phosphorylations were upregulated by glass contact. Moreover, the BaG-stimulated osteoinduction was significantly reduced by FAK and mitogen-activated protein kinase (MAPK) inhibitors, indicating an important role for FAK and MAPKs in the BaG-induced early osteogenic commitment of hASCs. Upon indirect insert culture, the ions released from the BaG discs could not reproduce the observed cellular changes, which highlighted the role of direct cell-BaG interactions in the osteopotential of BaGs. These findings gave valuable insight into the mechanism of BaG-induced osteogenic differentiation and therefore provided knowledge to aid the future design of new functional biomaterials to meet the increasing demand for clinical bone TE treatments. PMID- 29383697 TI - A resource reallocation model for school dental screening: taking advantage of teledentistry in low-risk areas. AB - OBJECTIVE: To estimate the scale of resource transfer that could be achieved by screening low-risk schoolchildren using teledentistry rather than using traditional visual dental examination. METHODS: This study was based on a previous cost-minimisation study that compared the costs of two dental-screening approaches (visual and teledentistry). The data for the population of children 5 14 years of age was obtained from the Australian Bureau of Statistics and was divided across Australia according to statistical local area (SA2). The cost models (for teledentistry and visual screening) for each SA2 relative to the state, Remoteness Area (RA) and Socio-Economic Index for Area (SEIFA) indexes were estimated. The geographical information system was used to superimpose modelled cost data on the geographical map to provide a visual presentation of the data. Resource transfer scenarios, based on risk minimisation, were then developed and analysed. RESULTS: This study demonstrated a suboptimal allocation of dental-care resources, such that children living in high socio-economic areas (major cities) with low disease burdens consuming half of the estimated resources of a universal visual dental screening system. The findings suggest that utilising teledentistry screening for low-risk children has the potential to free up $40 million per annum. Such resources can be reallocated to increase care access and improve the quality of dental services for vulnerable children. CONCLUSION: To reduce inequalities in dental health within a community, scarce health-care resources should be targeted at the population at most risk. These findings can be used to inform policymakers, guide the appropriate distribution of scarce resources and target dental services to benefit high-need children. PMID- 29383696 TI - TRAP1 regulates autophagy in lung cancer cells. AB - BACKGROUND: Expression of TRAP1, a member of the HSP90 chaperone family, has been implicated in tumour protective effects, based on its differential mitochondrial localization and function. DESIGN: This work was designed to provide new insights into the pathways involved in TRAP1-provided cytoprotection on NSCLC. For this, TRAP1-depleted A549 human NSCLC cells and MRC-5 normal lung fibroblasts were produced using a siRNA approach and main cellular quality control mechanisms were investigated. RESULTS: TRAP1-depleted A549 cells displayed decreased cell viability likely due to impaired mitochondrial function including decreased ATP/AMP ratio, oxygen consumption and membrane potential, as well as increased apoptotic indicators. Furthermore, the negative impact of TRAP1 depletion on mitochondrial function was not observed in normal MRC-5 lung cells, which might be due to the differential intracellular localization of the chaperone in tumour versus normal cells. Additionally, A549 TRAP1-depleted cells showed increased autophagic flux. Functionally, autophagy inhibition resulted in decreased cell viability in both TRAP1-expressing and TRAP1-depleted tumour cells with minor effects on MRC-5 cells. Conversely, autophagy stimulation decreased cell viability of both A549 and MRC-5 TRAP1-expressing cells while in A549 TRAP1 depleted cells, increased autophagy augmented viability. CONCLUSIONS: Our results show that even though TRAP1 depletion affects both normal MRC-5 and tumour A549 cell proliferation, inhibition of autophagy per se led to a decrease in tumour cell mass, while having a reduced effect on the normal cell line. The strategy of targeting TRAP1 in NSCLC shows future potential therapeutic applications. PMID- 29383698 TI - Infusion-fill method versus standard auto-fill trial of void protocol following a TVT-exact procedure: A randomised controlled trial. AB - OBJECTIVE: To establish whether the infusion method trial of void (TOV) after a mid-urethral sling procedure, in contrast to the standard auto-fill TOV, permits discharge home from recovery, as these procedures are eminently suited to same day discharge, and the delay in achieving a successful TOV often keeps the patient in hospital overnight. METHOD: A randomised controlled trial performed between December 2014 and April 2016 at the University Hospital, enrolling 40 women undergoing a mid-urethral sling procedure for stress urinary incontinence. The women were randomised to infusion method or auto-fill method TOV. The primary outcome was discharge home from the recovery area of theatre. RESULTS: Discharge from recovery was not different between the two groups (odds ratio (OR) 1.3 95% CI: 0.3-5.9, P = 0.71). The rate of TOV being successfully passed in recovery was higher in the infusion-fill group compared to the standard auto-fill group (OR 4.5 95% CI 1.2-17.4, P = 0.025). This means that three women will undergo the infusion-fill to achieve one more successful TOV in recovery. CONCLUSIONS: The infusion method resulted in more women passing their TOV in recovery but this did not translate into more discharges from recovery. PMID- 29383699 TI - Socio-demographic predictors of unintended pregnancy and late antenatal booking in Honiara, Solomon Islands. AB - BACKGROUND: The Solomon Islands is a Pacific nation with a maternal mortality of 114 per 100 000 births. Around 57% of pregnancies are unintended and only 15% of women attend their first antenatal visit in the first 12 weeks as recommended by the World Health Organization. AIMS: We sought to examine the socio-demographic predictors of unintended pregnancy and late antenatal booking (>18 weeks) among women attending antenatal care in Honiara. MATERIALS AND METHODS: From January 2014 to May 2015 we undertook a cross-sectional survey using a structured questionnaire on women presenting to the National Referral Hospital and community clinics in Honiara for antenatal care. RESULTS: Of 1441 women, 41.0% of pregnancies were intended, 55.7% were ambivalent and 3.3% were fully unintended. Unintended pregnancy was significantly associated with being unemployed (adjusted odds ratio (aOR) 1.45, P = 0.024), being a teenager at first intercourse (aOR 1.53; P = 0.004), shared family planning decision making (aOR 0.54; P = 0.006) living with a husband (aOR 0.31 P < 0.001) and a short interpregnancy interval (OR 4.48, P <= 0.001). Late booking occurred in 1168 (84.7%) women and independent predictors of this included ambivalent or unintended pregnancy (aOR 1.74, P = 0.005) and multiparity (aOR 2.05, P = 0.001). CONCLUSIONS: Unintended pregnancy and late antenatal booking remain a challenge to improving maternal health in the Solomon Islands. Investments in family planning could target reproductive health education and post-partum family planning. Improving the quality of antenatal care as well as addressing social determinants of health, including gender equity, education and employment of women, is required if maternal mortality is to be reduced. PMID- 29383700 TI - Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma. PMID- 29383701 TI - Demographic profile, Oral Health Impact Profile and Dental Anxiety Scale in patients with chronic periodontitis: a case-control study. AB - OBJECTIVES: To examine whether dental anxiety (DA) and oral health-related quality of life (OHRQoL) differ between persons with and those without chronic periodontitis. METHODS: One-hundred patients with chronic periodontitis and 50 age- and- sex-matched controls were included. Data were collected on the following: demographics; smoking habits; Numerical Rating Scale (NRS) for dental pain assessment; Corah's Dental Anxiety Scale (DAS); Oral Health Impact Profile 14 (OHIP-14); Decayed, Missing and Filled Teeth (DMFT) index; Plaque Index (PI); probing depth (PD); bleeding on probing (BOP); and radiographic bone loss. RESULTS: Patients with chronic periodontitis exhibited a significantly higher percentage of high anxiety and phobia compared with subjects in the control group. Furthermore, patients with chronic periodontitis were statistically significantly more likely to consider themselves as suffering from dental anxiety (68.7% vs. 14.3%, P < 0.001) as well as more likely to have fear of receiving dental injections, hearing the dental drill noise and feeling a foreign object in the mouth. Patients with chronic periodontitis exhibited worse OHIP-14 global scores as well as worse scores in the following individual domains: functional limitation (P = 0.005); physical disability (P = 0.003); psychological disability (P = 0.010); social disability (P = 0.011); and handicap (P = 0.012). CONCLUSIONS: Compared with controls, patients with chronic periodontitis had higher levels of dental anxiety and worse OHRQoL. It is important to consider dental anxiety and OHRQoL assessment as an integral component of the evaluation of patients with chronic periodontitis. Communication between dental and behavioral health professionals is needed to implement a multidisciplinary team approach involving behavioural and psychological interventions. PMID- 29383702 TI - The validity and reliability of the Test of Arm Selective Control for children with cerebral palsy: a prospective cross-sectional study. AB - AIM: This study examined the reliability and validity of the Test of Arm Selective Control (TASC) to examine upper extremity selective voluntary motor control in children and adolescents with all types of spastic cerebral palsy (CP). METHOD: Fifty-six participants with CP, ranging in age from 5 years 9 months to 18 years 11 months (average 11y 7mo, SD 3y 9mo; 25 males, 31 females), participated in this prospective cross-sectional study. They were evaluated using the TASC and several clinical measures. RESULTS: TASC and Manual Ability Classification System (r=-0.529, p<0.001), TASC and ABILHAND-Kids (r=0.596, p<0.001), and TASC and affected extremities (r=-0.486, p=0.001) were moderately correlated. There was a weak correlation between the TASC and Gross Motor Function Classification System (r=-0.363, p=0.006) and no correlation between the TASC and age (p=0.366) or rater (p=0.713). Interrater reliability for upper extremity total score (intraclass correlation coefficient [ICC]=0.92-0.94) and upper extremity limb scores (ICC=0.92-0.96) was high for two independent rater groups (p<=0.001). Average time to administer was 16 minutes, 18 seconds. INTERPRETATION: The TASC is a reliable and valid tool for objective assessment of selective voluntary motor control. Clinically this measure may guide the selection of medical, surgical, or therapy interventions and may improve outcome prognosis. WHAT THIS PAPER ADDS: The Test of Arm Selective Control (TASC) demonstrates a high degree of reliability and multiple aspects of validity when assessing upper extremity selective control in those with cerebral palsy. The TASC is an upper limb companion to the Selective Control Assessment of the Lower Extremity. PMID- 29383703 TI - Epigenetic changes and their implications in autoimmune hepatitis. AB - BACKGROUND: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. MATERIALS AND METHODS: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. RESULTS: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. CONCLUSIONS: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences. PMID- 29383704 TI - Platelets at the crossroads of thrombosis, inflammation and haemolysis. AB - Platelets play a critical role at the interphase of thrombosis and inflammation, key features in haemolysis-associated disorders. Exercising this role requires expression of pattern recognition receptors by platelets, including toll-like receptor 4 (TLR4) and nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3), the latter forming intraplatelet multiprotein inflammasome complexes. Platelets are a potential target of various damage-associated molecular pattern (DAMP) molecules, such as free haem, a degradation by-product of haemoglobin oxidation during haemolysis, and high-mobility group box 1 (HMGB1), a DNA-binding protein released by dying or stressed cells and activated platelets. We have recently identified platelet TLR4, NLRP3, and Bruton tyrosine kinase (BTK) as critical regulators of platelet aggregation and thrombus formation, suggesting that the BTK inhibitor ibrutinib is a potential therapeutic target. Increasing evidence suggests that these and other DAMP-driven signalling mechanisms employed by platelets might be key in mediating inflammation and thrombosis encountered in haemolytic disorders. However, the precise regulatory triggers and their clinical relevance are poorly understood. We provide new insights into these less-well characterised platelet mechanisms, which are potentially targetable in haemolytic disorders. PMID- 29383705 TI - Reflectance difference microscopy for nanometre thickness microstructure measurements. AB - The discontinuity of medium at the boundary produces optically anisotropic response which makes reflectance difference microscopy (RDM) a potential method for nanometre-thickness microstructure measurements. Here, we present the methodology of RDM for the edge measurement of ultrathin microstructure. The RD signal of microstructure's boundary is mathematically deduced according to boundary condition and polarization optics theory. A normal-incidence RDM setup was built simply with one linear polarizer, one liquid crystal variable retarder and one 5 * objective. Then, the performance of the developed setup was identified using homogenous reflection mirror and high quality linear polarizer. For demonstration, microstructures array with 100 nm step height was measured. The results show that the RD signal is sensitive to the edge and its sign reflects the change direction of the edge. Furthermore, a height sensitivity of better than 10 nm and a spatial resolution of ~3 MUm offer this technique a good candidate for characterizing ultrathin microstructures. PMID- 29383706 TI - Influence of Diabetes on Antiplatelet Drug Efficacy. PMID- 29383707 TI - Is TWEAK a valid screening questionnaire to identify alcohol risk drinkers among pregnant women in Denmark? AB - INTRODUCTION: Identification of pregnant alcohol risk drinkers is crucial to prevent adverse birth outcomes. The TWEAK screening instrument has shown promising results for identifying risk drinkers. However, as the effectiveness of the screening questionnaire has only been investigated among American women with mainly low socioeconomic status, we aimed to investigate the ability of TWEAK to identify alcohol risk drinkers among pregnant Danish women. MATERIAL AND METHODS: During 2000, Danish-speaking women referred to the Midwife Center at Aarhus University Hospital (n = 1554) and Fredericia Hospital (n = 499) for routine antenatal care were invited to participate in the study at their first visit. The women were interviewed about their periconceptional and current drinking habits including average weekly alcohol consumption and binge drinking. Additionally, the women were also asked the questions related to the TWEAK questionnaire. RESULTS: We found that the sensitivity of TWEAK to identify periconceptional risk drinking was quite low, but its ability to identify risk drinkers during pregnancy was marginally higher. Our results suggested that older age (odds ratio 1.46, 95% confidence interval 0.95-2.23), current smoking (odds ratio 2.33, 95% confidence interval 1.63-3.33), being single (odds ratio 2.38, 95% confidence interval 1.38-4.11) and a TWEAK score with a cut-off score of >=1 (odds ratio 2.75, 95% confidence interval 2.02-3.76) increased the risk of high-risk drinking during pregnancy. CONCLUSIONS: In a Danish setting, TWEAK does not seem as an optimal screening tool to identify periconceptional risk drinkers but it may be useful in identifying high-risk drinking during pregnancy. PMID- 29383708 TI - Preschoolers' Saving Behavior: The Role of Planning and Self-Control. AB - Planning and self-control were examined in relation to preschoolers' (41- to 74 months) saving behavior. Employing a marble run paradigm, 54 children participated in two trials in which they could use their marbles immediately on a less desirable run, or save for a more desirable run. Twenty-nine children received the opportunity to create a budget. On Trial 1, children in the budgeting condition saved significantly more than did children in the control condition, and their planning ability related to saving (after controlling for age and language). Those who consistently budgeted at least one marble for the more desirable run were more likely to save. Control children's performance improved across trials, with no between-condition differences on Trial 2. Self control was not related to saving. PMID- 29383709 TI - Neural Correlates of Risk Processing Among Adolescents: Influences of Parental Monitoring and Household Chaos. AB - Adolescent risky behavior is related to developmental changes in decision-making processes and their neural correlates. Yet, research investigating how the family environment relates to risk processing in the adolescent brain is limited. In this study, longitudinal data were collected from 167 adolescents (13-15 years, 53% male) who self-reported household chaos and their parent's monitoring practices, and completed a decision-making task during functional MRI at Time 1 and Time 2 (1 year apart). Parental knowledge was positively related to insular risk processing only among adolescents in low-chaos environments at both time points. Results highlight environmental correlates of insular risk processing in the developing brain. PMID- 29383711 TI - Subsequent primary malignancies after endometrial cancer diagnosed in American cancer registries. PMID- 29383710 TI - Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke. AB - BACKGROUND: Children's exposure to other people's tobacco smoke (environmental tobacco smoke, or ETS) is associated with a range of adverse health outcomes for children. Parental smoking is a common source of children's exposure to ETS. Older children in child care or educational settings are also at risk of exposure to ETS. Preventing exposure to ETS during infancy and childhood has significant potential to improve children's health worldwide. OBJECTIVES: To determine the effectiveness of interventions designed to reduce exposure of children to environmental tobacco smoke, or ETS. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register and conducted additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Education Resource Information Center (ERIC), and the Social Science Citation Index & Science Citation Index (Web of Knowledge). We conducted the most recent search in February 2017. SELECTION CRITERIA: We included controlled trials, with or without random allocation, that enrolled participants (parents and other family members, child care workers, and teachers) involved in the care and education of infants and young children (from birth to 12 years of age). All mechanisms for reducing children's ETS exposure were eligible, including smoking prevention, cessation, and control programmes. These include health promotion, social-behavioural therapies, technology, education, and clinical interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies and extracted data. Due to heterogeneity of methods and outcome measures, we did not pool results but instead synthesised study findings narratively. MAIN RESULTS: Seventy-eight studies met the inclusion criteria, and we assessed all evidence to be of low or very low quality based on GRADE assessment. We judged nine studies to be at low risk of bias, 35 to have unclear overall risk of bias, and 34 to have high risk of bias. Twenty-one interventions targeted populations or community settings, 27 studies were conducted in the well-child healthcare setting and 26 in the ill-child healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether visits were made to well- or ill children, and another included visits to both well- and ill-children. Forty-five studies were reported from North America, 22 from other high-income countries, and 11 from low- or middle-income countries. Only 26 of the 78 studies reported a beneficial intervention effect for reduction of child ETS exposure, 24 of which were statistically significant. Of these 24 studies, 13 used objective measures of children's ETS exposure. We were unable to pinpoint what made these programmes effective. Studies showing a significant effect used a range of interventions: nine used in-person counselling or motivational interviewing; another study used telephone counselling, and one used a combination of in-person and telephone counselling; three used multi-component counselling-based interventions; two used multi-component education-based interventions; one used a school-based strategy; four used educational interventions, including one that used picture books; one used a smoking cessation intervention; one used a brief intervention; and another did not describe the intervention. Of the 52 studies that did not show a significant reduction in child ETS exposure, 19 used more intensive counselling approaches, including motivational interviewing, education, coaching, and smoking cessation brief advice. Other interventions consisted of brief advice or counselling (10 studies), feedback of a biological measure of children's ETS exposure (six studies), nicotine replacement therapy (two studies), feedback of maternal cotinine (one study), computerised risk assessment (one study), telephone smoking cessation support (two studies), educational home visits (eight studies), group sessions (one study), educational materials (three studies), and school-based policy and health promotion (one study). Some studies employed more than one intervention. 35 of the 78 studies reported a reduction in ETS exposure for children, irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure but rather sought to reduce symptoms of asthma, and found a significant reduction in symptoms among the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions. AUTHORS' CONCLUSIONS: A minority of interventions have been shown to reduce children's exposure to environmental tobacco smoke and improve children's health, but the features that differentiate the effective interventions from those without clear evidence of effectiveness remain unclear. The evidence was judged to be of low or very low quality, as many of the trials are at a high risk of bias, are small and inadequately powered, with heterogeneous interventions and populations. PMID- 29383712 TI - Trait independence primes convergent trait loss. AB - The repeated, independent evolution of traits (convergent evolution) is often attributed to shared environmental selection pressures. However, developmental dependencies among traits can limit the phenotypic variation available to selection and bias evolutionary outcomes. Here, we determine how changes in developmentally correlated traits may impact convergent loss of the tympanic middle ear, a highly labile trait within toads that currently lack adaptive explanation. The middle ear's lability could reflect evolutionary trade-offs with other skull features under selection, or the middle ear may evolve independently of the rest of the skull, allowing it to be modified by active or passive processes without pleiotropic trade-offs with other skull features. We compare the skulls of 55 species (39 eared, 16 earless) within the family Bufonidae, spanning six hypothesized independent middle ear transitions. We test whether shared or lineage-specific changes in skull shape distinguish earless species from eared species and whether earless skulls lack other late-forming skull bones. We find no evidence for pleiotropic trade-offs between the middle ear and other skull structures. Instead, middle ear loss in anurans may provide a rare example of developmental independence contributing to evolutionary lability of a sensory system. PMID- 29383713 TI - Prognostic factors for soft tissue sarcoma patients with lung metastases only who are receiving first-line chemotherapy: An exploratory, retrospective analysis of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). AB - The prognosis of adult soft tissue sarcoma (STS) patients with metastases is generally poor. As little is known about the impact of the involvement of different metastatic sites and the extent of pulmonary lesions on the outcome for patients receiving first-line chemotherapy, we aimed to establish prognostic factors for STS patients with lung metastases only. A retrospective, exploratory analysis was performed on 2,913 metastatic STS patients who received first-line chemotherapy. Detailed information from 580 patients who had lung metastases only, was used for prognostic factor analysis. Patients with lung metastases only were more often asymptomatic and had undergone complete primary tumor resection more frequently compared to patients with additional metastases outside the lung or without lung metastases. For extremity STS, the incidence of lung metastases only was much higher compared to non-extremity STS. Lung involvement only was an independent favorable prognostic factor for overall survival (OS) with regard to metastatic site. Within this subgroup, in a multivariate model, other factors associated with improved OS included: good performance status (PS), no progression at primary site, low histological grade, younger age, long interval between initial diagnosis and trial registration, and smaller diameter of the largest lung lesion. This unique analysis on prognostic factors in STS patients with lung metastases confirms well-known patient factors (such as age and PS), and tumor characteristics (including tumor grade, interval between primary diagnosis, and metastases), but also identifies diameter of the largest lung lesion as a new prognostic factor. Knowledge about these factors may support decision-making within multidisciplinary tumor boards. PMID- 29383715 TI - Erratum. PMID- 29383716 TI - Erratum. PMID- 29383714 TI - Disclosure of cardiac variants of uncertain significance results in an exome cohort. AB - This study examined the impact of disclosing subclassifications of genetic variants of uncertain significance (VUS) on behavioral intentions. We studied return of VUS results to 79 individuals with a cardiomyopathy-associated VUS, subclassified into VUS-high or VUS-low. Primary outcomes were perceived risk (absolute and comparative), perceived severity, perceived value of information, self-efficacy, decision regret, and behavioral intentions to share results and change behaviors. There was no significant difference between the 2 subclasses in overall behavioral intentions (t = 0.023, P = .982) and each of the individual items on the behavioral intentions scale; absolute (t = -1.138, P = .259) or comparative (t = -0.463, P = .645) risk perceptions; perceived value of information (t = 0.582, P = .563) and self-efficacy (t = -0.733, P = .466). Decision regret was significantly different (t = 2.148, P = .035), with VUS-low (mean = 17.24, SD = 16.08) reporting greater regret. Combining the subclasses, perceived value of information was the strongest predictor of behavioral intentions (beta = 0.524, P < .001). Participants generally understood the meaning of a genetic VUS result classification and reported satisfaction with result disclosure. No differences in behavioral intentions were found, but differences in decision regret suggest participants distinguish subclasses of VUS results. The perceived value of VUS may motivate recipients to pursue health related behaviors. PMID- 29383717 TI - Topographic principles of cortical fluid-attenuated inversion recovery signal in temporal lobe epilepsy. AB - OBJECTIVE: In drug-resistant temporal lobe epilepsy (TLE), relative to the large number of whole-brain morphological studies, neocortical T2 changes have not been systematically investigated. The aim of this study was to assess the anatomical principles that govern the distribution of neocortical T2-weighted fluid attenuated inversion recovery (FLAIR) signal intensity and uncover its topographic principles. METHODS: Using a surface-based sampling scheme, we mapped neocortical FLAIR intensity of 61 TLE patients relative to 38 healthy controls imaged at 3 T. To address topographic principles of the susceptibility to FLAIR signal changes in TLE, we assessed associations with normative data on tissue composition using 2 complementary approaches. First, we evaluated whether the degree of TLE-related FLAIR intensity changes differed across cytoarchitectonic classes as defined by Von Economo-Koskinas taxonomy. Second, as a proxy to map regions with similar intracortical composition, we carried out a FLAIR intensity covariance paradigm in controls by seeding systematically from all cortical regions, and identified those networks that were the best spatial predictors of the between-group FLAIR changes. RESULTS: Increased intensities were observed in bilateral limbic and paralimbic cortices (hippocampus, parahippocampus, cingulate, temporopolar, insular, orbitofrontal). Effect sizes were highest in periallocortical limbic and insular classes as defined by the Von Economo Koskinas cytoarchitectonic taxonomy. Furthermore, systematic FLAIR intensity covariance analysis in healthy controls revealed that similarity patterns characteristic of limbic cortices, most notably the hippocampus, served as sensitive predictors for the topography of FLAIR hypersignal in patients. FLAIR intensity findings were robust against correction for morphological confounds. Patients with a history of febrile convulsions showed more marked signal changes in parahippocampal and retrosplenial cortices, known to be strongly connected to the hippocampus. SIGNIFICANCE: FLAIR intensity mapping and covariance analysis provide a model of TLE gray matter pathology based on shared vulnerability of periallocortical and limbic cortices. PMID- 29383718 TI - Urine test for HPV genotypes as a predictor of precancerous cervical lesions and for cervical cancer screening. AB - OBJECTIVE: To assess the sensitivity of a urine test for high-risk HPV DNA genotypes in the detection of high-grade squamous intra-epithelial lesion (HSIL) and its correlation with pathologic precancerous lesions. METHODS: The present prospective cross-sectional study included women referred to Kasr AlAiny Medical School, Cairo, Egypt, for cervical smear anomalies, a history of cervical smear anomalies, or for suspicious cervix between May 1, 2015, and April 30, 2017. Paired urine tests and cervical smears were performed. HPV DNA was detected in urine using polymerase chain reaction and cervical smears were performed with a cervical spatula and a cytobrush. Agreement between urine test results and pathology was examined. RESULTS: In total, 1375 women were included. Urine test for high-risk HPV DNA demonstrated 97.8% (95% confidence interval [CI] 92.1% 99.7%) sensitivity and 100% (95% CI 99.7%-100.0%) specificity for HSIL. Overall, 87 women had a positive urine test for high-risk HPV; of these, 82 (94.3%, 95% CI 87.1%-98.1%) had pathologic findings of cervical intra-epithelial neoplasia 2 or 3 (CIN2/3). Similarly, 89 women had HSIL cytology; again, 82 had CIN2/3 (92.1%; 95% CI, 84.3%-96.4%). CONCLUSION: There was good agreement between a positive urine test for high-risk HPV DNA genotypes and pathologic findings of CIN2/3. PMID- 29383719 TI - CrossTalk proposal: CNNM proteins are Na+ /Mg2+ exchangers playing a central role in transepithelial Mg2+ (re)absorption. PMID- 29383720 TI - The Brazilian experience of nucleic acid testing to detect human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infections in blood donors. AB - BACKGROUND: The history of the development and implementation of the Brazilian nucleic acid testing (NAT) platform to detect and discriminate among human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections in blood donors is described here. The results for the sensitivity, reproducibility, and NAT yield of the platform since program implementation are provided. STUDY DESIGN AND METHODS: The Brazilian NAT HIV, HCV, and HBV kit was developed and evaluated with regard to analytical sensitivity, specificity, intralot and interlot reproducibility, interfering substances, and genotype and diagnostic sensitivity. Additionally, a sample of identified NAT-yield cases was characterized with regard to viral load. RESULTS: The 95% limits of detection for HIV, HCV, and HBV were 68.02, 102.35, and 9.08 IU/mL, respectively. All replicates were detected with reproducibility assays between the acceptable values. A total of 13,610,536 blood donors was screened from 2010 to 2016, and 63 HIV-yield cases and 28 HCV-yield cases were detected. Among 5,795,424 blood donors screened for HBV from 2014 to 2016, 42 yield cases were found. CONCLUSION: The Brazilian NAT HIV, HCV, and HBV kit is an automated NAT system suitable for routine blood donor screening in a completely traceable process. The analytical sensitivity as well as the diagnostic sensitivity fulfilled all requirements set by the health ministry for blood donor screening. A significant number of transmission cases were prevented by the implementation of this important program. PMID- 29383721 TI - Initial evaluation of Advanced Collapsed cone Engine dose calculations in water medium for I-125 seeds and COMS eye plaques. AB - PURPOSE: To investigate the dose calculation accuracy in water medium of the Advanced Collapsed cone Engine (ACE) for three sizes of COMS eye plaques loaded with low-energy I-125 seeds. METHODS: A model of the Oncura 6711 I-125 seed was created for use with ACE in Oncentra(r) Brachy (OcB) using primary-scatter separated (PSS) point dose kernel and Task Group (TG) 43 datasets. COMS eye plaque models of diameters 12, 16, and 20 mm were introduced into the OcB applicator library based on 3D CAD drawings of the plaques and Silastic inserts. To perform TG-186 level 1 commissioning, treatment plans were created in OcB for a single source in water and for each COMS plaque in water for two scenarios: with only one centrally loaded seed, or with all seed positions loaded. ACE dose calculations were performed in high accuracy mode with a 0.5 * 0.5 * 0.5 mm3 calculation grid. The resulting dose data were evaluated against Monte Carlo (MC) calculated doses obtained with MCNP6, using both local and global percent differences. RESULTS: ACE doses around the source for the single seed in water agreed with MC doses on average within < 5% inside a 6 * 6 * 6 cm3 region, and within < 1.5% inside a 2 * 2 * 2 cm3 region. The PSS data were generated at a higher resolution within 2 cm from the source, resulting in this improved agreement closer to the source due to fewer approximations in the ACE dose calculation. Average differences in both investigated plaque loading patterns in front of the plaques and on the plaque central axes were <= 2.5%, though larger differences (up to 12%) were found near the plaque lip. CONCLUSIONS: Overall, good agreement was found between ACE and MC dose calculations for a single I-125 seed and in front of the COMS plaques in water. More complex scenarios need to be investigated to determine how well ACE handles heterogeneous patient materials. PMID- 29383722 TI - Mechanisms of red blood cell transfusion-related immunomodulation. AB - Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions. PMID- 29383723 TI - Rebuttal from Yosuke Funato, Kazuharu Furutani, Yoshihisa Kurachi and Hiroaki Miki. PMID- 29383724 TI - Knowledge translation in transfusion medicine. Part 1: The basics and the frameworks. PMID- 29383725 TI - ERP components and behavior in the auditory equiprobable go/no-go task: Inhibition in young adults. AB - Previous research suggests that young adults do not need active and effortful inhibition to successfully complete the auditory equiprobable go/no-go task, a view that was incorporated into Barry and De Blasio's sequential processing schema for this task. However, recent evidence in children suggests that view could be incorrect. The present research aims to clarify the functionality of the N2 and P3 subcomponents within the proposed schema, assessing the role of inhibition in this task. To optimize the quantification of the N2 and P3 subcomponents, separate temporal PCAs were applied to the go/no-go ERP data from 40 young adults. Correlations were then used to link subcomponent amplitudes with performance outcomes, informing a functional interpretation of each subcomponent. Larger N2b and P3a amplitudes were each linked to fewer commission errors. N2c amplitude also increased with intraindividual reaction time variability, but no performance outcomes were associated with P3b. These findings link the young adult N2b and P3a with inhibition in the auditory equiprobable task, confirming the importance of control for successful nontarget processing in that paradigm. The functionality of N2c and P3b remain unclear from our results. However, these outcomes improve our understanding of cognitive processing in equiprobable tasks, and contribute to an improved conceptualization of the sequential processing schema. PMID- 29383726 TI - Boat builders' occupational contact dermatitis - 11-year data from the Finnish register of occupational diseases. PMID- 29383727 TI - Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance. AB - KEY POINTS: The cardiac metabolic reprogramming seen in heart diseases such as myocardial infarction and hypertrophy shares similarities with that seen in chronic hypoxia, but understanding of how the hypoxic heart responds to further hypoxic challenge - hypoxic tolerance - is limited. The pyruvate dehydrogenase complex serves to control irreversible decarboxylation of pyruvate within mitochondria, and is a key regulator of substrate metabolism, potentially regulating hypoxic tolerance. Acute activation of the pyruvate dehydrogenase complex did not improve cardiac function during acute hypoxia; however, simultaneous activation of the pyruvate dehydrogenase complex during chronic hypoxic exposure improved tolerance to subsequent acute hypoxia. Activation of the pyruvate dehydrogenase complex during chronic hypoxia stockpiled cardiac acetylcarnitine, and this was used during acute hypoxia. This maintained cardiac ATP and glycogen, and improved hypoxic tolerance as a result. These findings demonstrate that pyruvate dehydrogenase complex activation can improve cardiac function under hypoxia. ABSTRACT: The pattern of metabolic reprogramming in chronic hypoxia shares similarities with that following myocardial infarction or hypertrophy; however, the response of the chronically hypoxic heart to subsequent acute injury, and the role of metabolism is not well understood. Here, we determined the myocardial tolerance of the chronically hypoxic heart to subsequent acute injury, and hypothesised that activation of a key regulator of myocardial metabolism, the pyruvate dehydrogenase complex (PDC), could improve hypoxic tolerance. Mouse hearts, perfused in Langendorff mode, were exposed to 30 min of hypoxia, and lost 80% of pre-hypoxic function (P = 0.001), with only 51% recovery of pre-hypoxic function with 30 min of reoxygenation (P = 0.046). Activation of the PDC with infusion of 1 mm dichloroacetate (DCA) during hypoxia and reoxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in hypoxia for 3 weeks. Chronic hypoxia reduced cardiac tolerance to subsequent acute hypoxia, with recovery of function 22% of pre-acute hypoxic levels vs. 39% in normoxic control hearts (P = 0.012). DCA feeding in chronic hypoxia (per os, 70 mg kg-1 day-1 ) doubled cardiac acetylcarnitine content, and this fell following acute hypoxia. This acetylcarnitine use maintained cardiac ATP and glycogen content during acute hypoxia, with hypoxic tolerance normalised. In summary, chronic hypoxia renders the heart more susceptible to acute hypoxic injury, which can be improved by activation of the PDC and pooling of acetylcarnitine. This is the first study showing functional improvement of the chronically hypoxic heart with activation of the PDC, and offers therapeutic potential in cardiac disease with a hypoxic component. PMID- 29383728 TI - Nano-amylose-2,3-bis(3,5-dimethylphenylcarbamate)-silica hybrid sol immobilized on open tubular capillary column for capillary electrochromatography enantioseparation. AB - The chiral organic-inorganic hybrid materials can exhibit a high loading, and the chiral selector nanoparticles can create efficient stationary phases for open tubular capillary electrochromatography (OT-CEC). Hence, a novel protocol for the preparation of an OT column coated with nano-amylose-2,3-bis(3,5 dimethylphenylcarbamate) (nano-ABDMPC)-silica hybrid sol through in situ layer-by layer self-assembly method was developed for CEC enantioseparation. By controlling the assembly cycle number of nano-ABDMPC-silica hybrid sol, a homogeneous, dense and stable coating was successfully prepared, which was confirmed by SEM and elemental analysis. As the main parameter influencing the chiral separating effect, the nano-ABDMPC bearing 3-(triethoxysilyl)propyl residues concentration was investigated. The experimental results showed that 10.0 mg/mL nano-ABDMPC bearing 3-(triethoxysilyl)propyl residues coated OT capillary column possessed chiral recognition ability toward the six enantiomers (phenylalanine, tyrosine, tryptophan, phenethyl alcohol, 1-phenyl-2-propanol, and Troger's base) at some of the different conditions tested. Additionally, the coated OT column revealed adequate repeatability concerning run-to-run, day-to day and column-to-column. These results demonstrated the promising applicability of nano-ABDMPC-silica hybrid sol coated OT column in CEC enantioseparations. PMID- 29383729 TI - CrossTalk opposing view: CNNM proteins are not Na+ /Mg2+ exchangers but Mg2+ transport regulators playing a central role in transepithelial Mg2+ (re)absorption. PMID- 29383730 TI - Capacitive coupling synchronizes autonomous microfluidic oscillators. AB - Even identically designed autonomous microfluidic oscillators have device-to device oscillation variability that arises due to inconsistencies in fabrication, materials, and operation conditions. This work demonstrates, experimentally and theoretically, that with appropriate capacitive coupling these microfluidic oscillators can be synchronized. The size and characteristics of the capacitive coupling needed and the range of input flow rate differences that can be synchronized are also characterized. In addition to device-to-device variability, there is also within-device oscillation noise that arises. An additional advantage of coupling multiple fluidic oscillators together is that the oscillation noise decreases. The ability to synchronize multiple autonomous oscillators is also a first step towards enhancing their usefulness as tools for biochemical research applications where multiplicate experiments with identical temporal-stimulation conditions are required. PMID- 29383732 TI - A New Concept to Achieve Optimal Weight Gain in Malnourished Infants on Total Parenteral Nutrition. AB - BACKGROUND: Infants with intestinal failure (IF) are at increased risk of malnutrition and require adapted nutrition support. Optimal weight gain during nutrition rehabilitation should occur at the velocity of statural age (adjusted to the 50th percentile of height) and not chronological age. The aim of this study was to assess the relationship between weight gain during catch-up growth, nonprotein energy intake (NPEI) provided by total parenteral nutrition (TPN), and resting energy expenditure (REE) in children with severe malnutrition due to IF. MATERIALS AND METHODS: This retrospective study included all infants with severe malnutrition treated with TPN for IF between January 1, 2010, and December 31, 2013. They all had no or minimal oral intake (<10% REE). The REE was calculated using the Schofield equations. RESULTS: Seventeen children were included (11 boys) with a mean age at TPN onset of 5 mo. They were followed for a mean duration of 39 days. On admission, body weight and height were -3.1 +/- 0.9 and 3.3 +/- 1.3 SD, respectively. The indications for TPN were short bowel syndrome (n = 10), congenital enteropathy (microvillous inclusion disease, n = 6) and chronic intestinal pseudo-obstruction syndrome (n = 1). After 28 days of nutrition rehabilitation with full NPEI from TPN, the observed weight gain was 110 +/- 5% of optimal weight gain for statural age. The mean NPEI from TPN was 104.3 +/- 8.0 kcal/kg/d. The mean ratio of NPEI over REE was 2.1 +/- 0.2. CONCLUSION: Optimal weight gain was achieved with NPEI from TPN twice the REE in severely malnourished infants with IF. NPEI values were adequate and not excessive for age. PMID- 29383731 TI - Ca2+ signalling in mouse urethral smooth muscle in situ: role of Ca2+ stores and Ca2+ influx mechanisms. AB - KEY POINTS: Contraction of urethral smooth muscle cells (USMCs) contributes to urinary continence. Ca2+ signalling in USMCs was investigated in intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMCs. USMCs were spontaneously active in situ, firing intracellular Ca2+ waves that were asynchronous at different sites within cells and between adjacent cells. Spontaneous Ca2+ waves in USMCs were myogenic but enhanced by adrenergic or purinergic agonists and decreased by nitric oxide. Ca2+ waves arose from inositol trisphosphate type 1 receptors and ryanodine receptors, and Ca2+ influx by store-operated calcium entry was required to maintain Ca2+ release events. Ca2+ release and development of Ca2+ waves appear to be the primary source of Ca2+ for excitation-contraction coupling in the mouse urethra, and no evidence was found that voltage-dependent Ca2+ entry via L-type or T-type channels was required for responses to alpha adrenergic responses. ABSTRACT: Urethral smooth muscle cells (USMCs) generate myogenic tone and contribute to urinary continence. Currently, little is known about Ca2+ signalling in USMCs in situ, and therefore little is known about the source(s) of Ca2+ required for excitation-contraction coupling. We characterized Ca2+ signalling in USMCs within intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMCs. USMCs fired spontaneous intracellular Ca2+ waves that did not propagate cell-to-cell across muscle bundles. Ca2+ waves increased dramatically in response to the alpha1 adrenoceptor agonist phenylephrine (10 MUm) and to ATP (10 MUm). Ca2+ waves were inhibited by the nitric oxide donor DEA NONOate (10 MUm). Ca2+ influx and release from sarcoplasmic reticulum stores contributed to Ca2+ waves, as Ca2+ free bathing solution and blocking the sarcoplasmic Ca2+ -ATPase abolished activity. Intracellular Ca2+ release involved cooperation between ryanadine receptors and inositol trisphosphate receptors, as tetracaine and ryanodine (100 MUm) and xestospongin C (1 MUm) reduced Ca2+ waves. Ca2+ waves were insensitive to L-type Ca2+ channel modulators nifedipine (1 MUm), nicardipine (1 MUm), isradipine (1 MUm) and FPL 64176 (1 MUm), and were unaffected by the T-type Ca2+ channel antagonists NNC-550396 (1 MUm) and TTA-A2 (1 MUm). Ca2+ waves were reduced by the store operated Ca2+ entry blocker SKF 96365 (10 MUm) and by an Orai antagonist, GSK-7975A (1 MUm). The latter also reduced urethral contractions induced by phenylephrine, suggesting that Orai can function effectively as a receptor-operated channel. In conclusion, Ca2+ waves in mouse USMCs are a source of Ca2+ for excitation-contraction coupling in urethral muscles. PMID- 29383733 TI - Impact of missing attenuation and scatter corrections on 99m Tc-MAA SPECT 3D dosimetry for liver radioembolization using the patient relative calibration methodology: A retrospective investigation on clinical images. AB - PURPOSE: To investigate the clinical implication of performing pre-treatment dosimetry for 90 Y-microspheres liver radioembolization on 99m Tc-MAA SPECT images reconstructed without attenuation or scatter correction and quantified with the patient relative calibration methodology. METHODS: Twenty-five patients treated with SIR-Spheres(r) at Istituto Europeo di Oncologia and 31 patients treated with TheraSphere(r) at Istituto Nazionale Tumori were considered. For each acquired 99m Tc-MAA SPECT, four reconstructions were performed: with attenuation and scatter correction (AC_SC), only attenuation (AC_NoSC), only scatter (NoAC_SC) and without corrections (NoAC_NoSC). Absorbed dose maps were calculated from the activity maps, quantified applying the patient relative calibration to the SPECT images. Whole Liver (WL) and Tumor (T) regions were drawn on CT images. Injected Liver (IL) region was defined including the voxels receiving absorbed dose >3.8 Gy/GBq. Whole Healthy Liver (WHL) and Healthy Injected Liver (HIL) regions were obtained as WHL = WL - T and HIL = IL - T. Average absorbed dose to WHL and HIL were calculated, and the injection activity was derived following each Institute's procedure. The values obtained from AC_NoSC, NoAC_SC and NoAC_NoSC images were compared to the reference value suggested by AC_SC images using Bland-Altman analysis and Wilcoxon paired test (5% significance threshold). Absorbed-dose maps were compared to the reference map (AC_SC) in global terms using the Voxel Normalized Mean Square Error (%VNMSE), and at voxel level by calculating for each voxel the normalized difference with the reference value. The uncertainty affecting absorbed dose at voxel level was accounted for in the comparison; to this purpose, the voxel counts fluctuation due to Poisson and reconstruction noise was estimated from SPECT images of a water phantom acquired and reconstructed as patient images. RESULTS: NoAC_SC images lead to activity prescriptions not significantly different from the reference AC_SC images; the individual differences (<0.1 GBq for all IEO patients, <0.6 GBq for all but one INT patients) were comparable to the uncertainty affecting activity measurement. AC_NoSC and NoAC_NoSC images, instead, yielded significantly different activity prescriptions and wider 95% confidence intervals in the Bland-Altman analysis. Concerning the absorbed dose map, AC_NoSC images had the smallest %VNMSE value and the highest fraction of voxels differing less than 2 standard deviations from AC_SC. CONCLUSIONS: The patient relative calibration methodology can compensate for the missing attenuation correction when performing healthy liver pre-treatment dosimetry: safe treatments can be planned even on NoAC_SC images, suggesting activities comparable to AC_SC images. Scatter correction is recommended due to its heavy impact on healthy liver dosimetry. PMID- 29383734 TI - Rebuttal from Francisco J. Arjona and Jeroen H. F. de Baaij. PMID- 29383735 TI - Transfusion-transmitted and community-acquired babesiosis in New York, 2004 to 2015. AB - BACKGROUND: Babesiosis is a potentially life-threatening zoonotic infection most frequently caused by the intraerythrocytic parasite Babesia microti. The pathogen is usually tickborne, but may also be transfusion or vertically transmitted. Healthy persons, including blood donors, may be asymptomatic and unaware they are infected. Immunocompromised patients are at increased risk for symptomatic disease. STUDY DESIGN AND METHODS: All reported community-acquired babesiosis cases in New York from 2004 to 2015 were evaluated, enumerated, and characterized. All potential transfusion-transmitted babesiosis (TTB) cases reported through one or more of three public health surveillance systems were investigated to determine the likelihood of transfusion transmission. In addition, host-seeking ticks were actively collected in public parks and other likely sites of human exposure to B. microti. RESULTS: From 2004 to 2015, a total of 3799 cases of babesiosis were found; 55 (1.4%) of these were linked to transfusion. The incidence of both community-acquired babesiosis and TTB increased significantly during the 12-year study period. The geographic range of both ticks and tickborne infections also expanded. Among TTB cases, 95% of recipients had at least one risk factor for symptomatic disease. Implicated donors resided in five states, including in 10 New York counties. More than half of implicated donors resided in counties known to be B. microti endemic. CONCLUSION: The increasing incidence of TTB correlated with increases in community-acquired babesiosis and infection of ticks with B. microti. Surveillance of ticks and community-acquired cases may aid identification of emerging areas at risk for Babesia transfusion transmission. PMID- 29383736 TI - Pharmacokinetics of cefquinome in healthy and Pasteurella multocida-infected rabbits. AB - The pharmacokinetics of cefquinome were studied in healthy and Pasteurella multocida-infected rabbits after a single intramuscular (IM) injection at 2 mg/kg of its sulfate salt. Twelve female New Zealand white rabbits (2.0-2.5 kg) were used; six of them served as controls, and the other six had been infected with P. multocida; the experiments were conducted 1-2 days after nasal inoculation of P. multocida when rabbits showed the signs of respiratory infection. Plasma concentrations of cefquinome were determined using high-performance liquid chromatography. The values of elimination half-life, area under the curve, area under the first moment curve, and mean residence time were significantly lower in infected rabbits (0.48 hr, 4.54 hr*MUg/ml, 3.63 hr* hr*MUg/ml and 0.8 hr, respectively) than healthy rabbits (0.72 hr, 9.11 hr*MUg/ml, 9.85 hr* hr*MUg/ml and 1.1 hr, respectively), whereas total body clearance was significantly higher in infected than healthy rabbits. Therefore, P. multocida infection caused significant changes in some of the pharmacokinetic parameters of cefquinome in rabbits. These pharmacokinetic changes may affect dose regimen when used in P. multocida-infected rabbits. PMID- 29383737 TI - Quality evaluation of no-reference MR images using multidirectional filters and image statistics. AB - PURPOSE: This study aimed to develop a fully automatic, no-reference image quality assessment (IQA) method for MR images. METHODS: New quality-aware features were obtained by applying multidirectional filters to MR images and examining the feature statistics. A histogram of these features was then fitted to a generalized Gaussian distribution function for which the shape parameters yielded different values depending on the type of distortion in the MR image. Standard feature statistics were established through a training process based on high-quality MR images without distortion. Subsequently, the feature statistics of a test MR image were calculated and compared with the standards. The quality score was calculated as the difference between the shape parameters of the test image and the undistorted standard images. RESULTS: The proposed IQA method showed a >0.99 correlation with the conventional full-reference assessment methods; accordingly, this proposed method yielded the best performance among no reference IQA methods for images containing six types of synthetic, MR-specific distortions. In addition, for authentically distorted images, the proposed method yielded the highest correlation with subjective assessments by human observers, thus demonstrating its superior performance over other no-reference IQAs. CONCLUSION: Our proposed IQA was designed to consider MR-specific features and outperformed other no-reference IQAs designed mainly for photographic images. Magn Reson Med 80:914-924, 2018. (c) 2018 International Society for Magnetic Resonance in Medicine. PMID- 29383738 TI - Detection of human papillomavirus in actinic keratosis. PMID- 29383739 TI - Circulating microRNAs in plasma as potential biomarkers for the early detection of prostate cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have been linked to prostate cancer (PC) risk; however, their role as a screening biomarker for PC has yet to be determined. We examined whether circulating miRNAs in plasma could be potential biomarkers for the early detection of PC among men undergoing prostate needle biopsy. METHODS: Men who had a prostate biopsy due to an abnormal screening test were recruited. Linear regression was used to examine the association between miRNAs in plasma and PC status and to model individual miRNA expression on serum PSA and age to calculate the partial correlation coefficient (r). RESULTS: There were 134 men, aged 46-86 years, included, with 66 men with a PC diagnosis (cases), eight men with no PC diagnosis but atypical lesion, and 60 men without a PC diagnosis (controls). The most statistically significant PC circulating miRNAs were miR 381, miR-34a, miR-523, miR-365, miR-122, miR-375, miR-1255b, miR-34b, miR-450b 5p, and miR-639 after adjusting for age (P-values <=0.05); however, they were no longer statistically significant after P-value adjustment for multiple comparisons. MiR-671-3p was differentially expressed between black and white cases (P-value = 0.03). Moderate positive correlations with serum PSA were observed for miR-381 overall and among controls (r = 0.43-0.60; P-values <=0.05) and miR-34a among cases (r = 0.46; P-value = 0.02). CONCLUSIONS: There was no miRNA associated with PC diagnosis after adjusting for age and P-values; however, moderate correlations between miRNAs and serum PSA were observed. Further investigation between miRNAs and PC risk is warranted in a larger population at high risk for PC. PMID- 29383740 TI - Flexible multistate models for interval-censored data: Specification, estimation, and an application to ageing research. AB - Continuous-time multistate survival models can be used to describe health-related processes over time. In the presence of interval-censored times for transitions between the living states, the likelihood is constructed using transition probabilities. Models can be specified using parametric or semiparametric shapes for the hazards. Semiparametric hazards can be fitted using P-splines and penalised maximum likelihood estimation. This paper presents a method to estimate flexible multistate models that allow for parametric and semiparametric hazard specifications. The estimation is based on a scoring algorithm. The method is illustrated with data from the English Longitudinal Study of Ageing. PMID- 29383741 TI - Chart stalking, list making, and physicians' efforts to track patients' outcomes after transitioning responsibility. AB - CONTEXT: Transitions of patient care responsibility occur frequently between physicians. Resultant discontinuities make it difficult for physicians to observe clinical outcomes. Little is known about what physicians do to overcome the practical challenges to learning these discontinuities create. This study explored physicians' activities in practice as they sought follow-up information about patients. METHODS: Using a constructivist grounded theory approach, semi structured interviews with 18 internal medicine hospitalist and resident physicians at a single tertiary care academic medical center explored participants' strategies when deliberately conducting follow-up after they transitioned responsibility for patients to other physicians. Following open coding, the authors used activity theory (AT) to explore interactions among the social, cultural and material influences related to follow-up. RESULTS: The authors identified three themes related to follow-up: (i) keeping lists to track patients, (ii) learning to create tracking systems and (iii) conducting follow up. Analysis of participants' follow-up processes as an activity system highlighted key tensions in the system and participants' work adaptations. Tension within functionality of electronic health records for keeping lists (tools) to find information about patients' outcomes (object) resulted in using paper lists as workarounds. Tension between paper lists (tools) and protecting patients' health information (rules) led to rule-breaking or abandoning activities of locating information. Finding time to conduct desired follow-up produced tension between this and other activity systems. CONCLUSION: In clinical environments characterised by discontinuity, lists of patients served as tools for guiding patient care follow-up. The authors offer four recommendations to address the tensions identified through AT: (i) optimise electronic health record tracking systems to eliminate the need for paper lists; (ii) support physicians' skill development in developing and maintaining tracking systems for follow-up; (iii) dedicate time in physicians' work schedules for conducting follow-up; and (iv) engage physicians and patients in determining guidelines for longitudinal tracking that optimise physicians' learning and respect patients' privacy. PMID- 29383742 TI - Crystal structure of yeast nitronate monooxygenase from Cyberlindnera saturnus. AB - Nitronate monooxygenase (NMO) is an FMN-dependent enzyme that oxidizes the neurotoxin propionate 3-nitronate (P3N) and represents the best-known system for P3N detoxification in different organisms. The crystal structure of the first eukaryotic Class I NMO from Cyberlindnera saturnus (CsNMO) has been solved at 1.65 A resolution and refined to an R-factor of 14.0%. The three-dimensional structures of yeast CsNMO and bacterial PaNMO are highly conserved with the exception of three additional loops on the surface in the CsNMO enzyme and differences in four active sites residues. A PEG molecule was identified in the structure and formed extensive interactions with CsNMO, suggesting a specific binding site; however, 8% PEG showed no significant effect on the enzyme activity. This new crystal structure of a eukaryotic NMO provides insight into the function of this class of enzymes. PMID- 29383743 TI - Investigating the effect of key mutations on the conformational dynamics of toll like receptor dimers through molecular dynamics simulations and protein structure networks. AB - The Toll-like receptors (TLRs) are critical components of the innate immune system due to their ability to detect conserved pathogen-associated molecular patterns, present in bacteria, viruses, and other microorganisms. Ligand detection by TLRs leads to a signaling cascade, mediated by interactions among TIR domains present in the receptors, the bridging adaptors and sorting adaptors. The BB loop is a highly conserved region present in the TIR domain and is crucial for mediating interactions among TIR domain-containing proteins. Mutations in the BB loop of the Toll-like receptors, such as the A795P mutation in TLR3 and the P712H mutation (Lpsd mutation) in TLR4, have been reported to disrupt or alter downstream signaling. While the phenotypic effect of these mutations is known, the underlying effect of these mutations on the structure, dynamics and interactions with other TIR domain-containing proteins is not well understood. Here, we have attempted to investigate the effect of the BB loop mutations on the dimer form of TLRs, using TLR2 and TLR3 as case studies. Our results based on molecular dynamics simulations, protein-protein interaction analyses and protein structure network analyses highlight significant differences between the dimer interfaces of the wild-type and mutant forms and provide a logical reasoning for the effect of these mutations on adaptor binding to TLRs. Furthermore, it also leads us to propose a hypothesis for the differential requirement of signaling and bridging adaptors by TLRs. This could aid in further understanding of the mechanisms governing such signaling pathways. PMID- 29383744 TI - Comparative anatomy of the clasper of the subfamily Potamotrygoninae (Chondrichthyes: Myliobatiformes). AB - Claspers of stingrays (Myliobatiformes) are poorly documented in comparison to claspers of skates, with our knowledge restricted mainly to external morphological characters and skeletal components included in descriptions of new species; more encompassing morphological comparative analyses are lacking. Concerning potamotrygonins, clasper morphology has been described for a handful of species, but without elucidating their variation and systematic potential. The present article analyzed clasper structures in all genera of the subfamily Potamotrygoninae (Potamotrygon, Paratrygon, Plesiotrygon, and Heliotrygon), which were compared to the clasper of Styracura and some dasyatid genera. Potamotrygon shows some morphometric variation among the species analyzed. Anatomically, we found variation mainly in the dorsal terminal 1 and accessory terminal 1 cartilages, which are considered diagnostic among potamotrygonin genera; external morphological structures did not present significant differences among potamotrygonins. PMID- 29383745 TI - Clinical experience of ingenol mebutate gel for the treatment of Bowen's disease. AB - There are only a few anecdotal case reports about Bowen's disease (BD) treated with ingenol mebutate (IM) gel but no clinical study has been published yet. The aim of this study was to evaluate the effectiveness of IM gel in the treatment of BD and to observe the therapeutic efficacy of IM alone or IM with ablative fractional laser pretreatment. Nineteen patients with BD or squamous cell carcinoma in situ confirmed by skin biopsy were enrolled. IM was applied with 0.015% gel on facial lesions for 3 days consecutively and 0.05% gel on other sites for 2 days consecutively, with a 5-mm application margin around the visible lesion. Nine patients applied IM gel immediately following fractional CO2 laser treatment. Two patients were lost to follow up and a total of 17 patients were enrolled. Nine patients (9/17, 52.9%) had a clinically complete response at 2 months after treatment. Among the patients treated with the fractional CO2 laser before applying IM gel, eight (8/9, 88.9%) showed a complete response and one (1/9, 11.1%) showed partial response. Among the patients treated with IM gel alone, only one patient (1/8, 12.5%) showed a complete response, four (4/8, 50%) showed a partial response and three (3/8, 37.5%) did not respond to therapy. IM gel alone seems to have limited value for treatment of BD; however, a combination therapy with the ablative fractional laser can increase its therapeutic effectiveness. PMID- 29383746 TI - Vector competence of Culex antennatus and Anopheles coustani mosquitoes for Rift Valley fever virus in Madagascar. AB - Culex antennatus (Diptera: Culicidae), Anopheles coustani (Diptera: Culicidae) and Anopheles squamosus/cydippis were found to be infected with Rift Valley fever virus (RVFV) during an epidemic that occurred in 2008 and 2009 in Madagascar. To understand the roles played by Cx. antennatus and An. coustani in virus maintenance and transmission, RVFV vector competence was assessed in each species. Mosquito body parts and saliva of mosquitoes that fed on RVFV-infected blood were tested for RVFV using real-time quantitative polymerase chain reaction (RT-qPCR) assays. Overall, viral RNA was detected in body parts and saliva at 5 days post-infection (d.p.i.) in both species. At 5 d.p.i., infection rates were 12.5% (3/24) and 15.8% (6/38), disseminated infection rates were 100% (3/3) and 100% (6/6), transmission rates were 33.3% (1/3) and 83.3% (5/6), and transmission efficiencies were 4.2% (1/24) and 13.2% (5/38) in Cx. antennatus and An. coustani, respectively. Although RVFV detected in saliva did not propagate on to Vero cells, these results support potential roles for these two mosquito species in the transmission of RVFV. PMID- 29383747 TI - Fatal work-related falls in the United States, 2003-2014. AB - BACKGROUND: Falls are the second leading cause of work-related fatalities among US workers. We describe fatal work-related falls from 2003 to 2014, including demographic, work, and injury event characteristics, and changes in rates over time. METHODS: We identified fatal falls from the Bureau of Labor Statistics (BLS), Census of Fatal Occupational Injuries and estimated rates using the BLS Current Population Survey. RESULTS: From 2003 to 2014, there were 8880 fatal work related falls, at an annual rate of 5.5 per million FTE. Rates increased with age. Occupations with the highest rates included construction/extraction (42.2 per million FTE) and installation/maintenance/repair (12.5 per million FTE). Falls to a lower level represented the majority (n = 7521, 85%) compared to falls on the same level (n = 1128, 13%). CONCLUSIONS: Falls are a persistent source of work-related fatalities. Fall prevention should continue to focus on regulation adherence, Prevention through Design, improving fall protection, training, fostering partnerships, and increasing communication. PMID- 29383748 TI - Paralysis of the external popliteal sciatic nerve associated with daptomycin administration. AB - WHAT IS KNOWN AND OBJECTIVE: Peripheral neuropathy has been associated with the administration of certain drugs. Few reports have described the association of daptomycin with the development of peripheral neuropathy, none of them with peroneal nerve involvement. CASE SUMMARY: We report a case of a 62-year-old man who developed external popliteal sciatic nerve paralysis after 22 days of therapy with daptomycin. WHAT IS NEW AND CONCLUSION: We present an uncommon and not previously reported adverse event. We have also analysed a possible alteration in a metabolic pathway (ABCB1 gene polymorphisms) that, in some patients, could explain certain drug adverse events. WHAT IS NEW AND CONCLUSION: We present an uncommon and not previously reported adverse event. We have also analysed a possible alteration in a metabolic pathway (ABCB1 gene polymorphisms) that, in some patients, could explain certain drug adverse events. PMID- 29383749 TI - Probing subtle conformational changes induced by phosphorylation and point mutations in the TIR domains of TLR2 and TLR3. AB - Extensive research performed on Toll-like receptor (TLR) signaling has identified residues in the Toll/interleukin-1 receptor (TIR) domains that are essential for its proper functioning. Among these residues, those in BB loop are particularly significant as single amino acid mutations in this region can cause drastic changes in downstream signaling. However, while the effect of these mutations on the function is well studied (like the P681H mutation in TLR2, the A795P mutation in TLR3, and the P714H mutation in TLR4), their influence on the dynamics and inter-residue networks is not well understood. The effects of local perturbations induced by these mutations could propagate throughout the TIR domain, influencing interactions with other TIR domain-containing proteins. The identification of these subtle changes in inter-residue interactions can provide new insights and structural rationale for how single-point mutations cause drastic changes in TIR TIR interactions. We employed molecular dynamics simulations and protein structure network (PSN) analyses to investigate the structural transitions with special emphasis on TLR2 and TLR3. Our results reveal that phosphorylation of the Tyr 759 residue in the TIR domain of TLR3 introduces rigidity to its BB loop. Subtle differences in the intra BB loop hydrogen bonding network between TLR3 and TLR2 are also observed. The PSN analyses indicate that the TIR domain is highly connected and pinpoints key differences in the inter-residue interactions between the wild-type and mutant TIR domains, suggesting that TIR domain structure is prone to allosteric effects, consistent with the current view of the influence of allostery on TLR signaling. PMID- 29383750 TI - Electron microscopic characterization of nuclear egress in the sea urchin gastrula. AB - Nuclear egress, also referred to as nuclear envelope (NE) budding, is a process of transport in which vesicles containing molecular complexes or viral particles leave the nucleus through budding from the inner nuclear membrane (INM) to enter the perinuclear space. Following this event, the perinuclear vesicles (PNVs) fuse with the outer nuclear membrane (ONM), where they release their contents into the cytoplasm. Nuclear egress is thought to participate in many functions such as viral replication, cellular differentiation, and synaptic development. The molecular basis for nuclear egress is now beginning to be elucidated. Here, we observe in the sea urchin gastrula, using serial section transmission electron microscopy, strikingly abundant PNVs containing as yet unidentified granules that resemble the ribonucleoprotein complexes (RNPs) previously observed in similar types of PNVs. Some PNVs were observed in the process of fusion with the ONM where they appeared to release their contents into the cytoplasm. These vesicles were abundantly observed in all three presumptive germ layers. These findings indicate that nuclear egress is likely to be an important mechanism for nucleocytoplasmic transfer during sea urchin development. The sea urchin may be a useful model to characterize further and gain a better understanding of the process of nuclear egress. PMID- 29383751 TI - Osteoblast-derived factors promote metastatic potential in human prostate cancer cells, in part via non-canonical transforming growth factor beta (TGFbeta) signaling. AB - BACKGROUND: Transforming growth factor beta (TGFbeta) functions as a double-edged sword in prostate cancer tumorigenesis. In initial stages of the disease, TGFbeta acts as a growth inhibitor upon tumor cells, whereas it in later stages of disease rather promotes invasion and metastatic potential. One well-known cellular source of TGFbeta in the bone metastatic site is the bone-forming osteoblasts. Here we have studied the effects by osteoblast-derived factors on metastatic potential in several human prostate cancer cell lines. METHODS: Effects on metastatic potential in prostate cancer cells by osteoblast-derived factors were studied in vitro using several methods, including Transwell migration and evaluation of formation of pro-migratory protrusions. Confocal microscopy was used to evaluate possible changes in differentiation state in tumor cells by analysis of markers for epithelial-to-mesenchymal transition (EMT). The Matrigel-on-top 3D culture method was used for further assessment of metastatic characteristics in tumor cells by analysis of formation of filopodium like protrusions (FLPs). RESULTS: Osteoblast-derived factors increased migration of PC-3U cells, an effect less prominent in cells overexpressing a mutated type I TGFbeta receptor (TbetaRI) preventing non-canonical TRAF6-dependent TGFbeta signaling. Osteoblast-derived factors also increased the formation of long protrusions and loss of cell-cell contacts in PC-3U cells, suggesting induction of a more aggressive phenotype. In addition, treatment with TGFbeta or osteoblast derived factors of PC-3U cells in Matrigel-on-top 3D cultures promoted formation of FLPs, previously shown to be essential for metastatic establishment. CONCLUSIONS: These findings suggests that factors secreted from osteoblasts, including TGFbeta, can induce several cellular traits involved in metastatic potential of PC-3U cells, further strengthening the role for bone cells to promote metastatic tumor cell behavior. PMID- 29383753 TI - Hydrophobic residues can identify native protein structures. AB - Evaluation of protein structures needs a trustworthy potential function. Although several knowledge-based potential functions exist, the impact of different types of amino acids in the scoring functions has not been studied yet. Previously, we have reported the importance of nonlocal interactions in scoring function (based on Delaunay tessellation) in discrimination of native structures. Then, we have questioned the structural impact of hydrophobic amino acids in protein fold recognition. Therefore, a Hydrophobic Reduced Model (HRM) was designed to reduce protein structure of FS (Full Structure) into RS (Reduced Structure). RS is considered as a reduced structure of only seven hydrophobic amino acids (L, V, F, I, A, W, Y) and all their interactions. The presented model was evaluated via four different performance metrics including the number of correctly identified natives, the Z-score of the native energy, the RMSD of the minimum score, and the Pearson correlation coefficient between the energy and the model quality. Results indicated that only nonlocal interactions between hydrophobic amino acids could be sufficient and accurate enough for protein fold recognition. Interestingly, the results of HRM is significantly close to the model that considers all amino acids (20-amino acid model) to discriminate the native structure of the proteins on eleven decoy sets. This indicates that the power of knowledge-based potential functions in protein fold recognition is mostly due to hydrophobic interactions. Hence, we suggest combining a different well-designed scoring function for non hydrophobic interactions with HRM to achieve better performance in fold recognition. PMID- 29383752 TI - Metastatic prostate cancer-associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6. AB - BACKGROUND: P62 (also named sequestosome-1, SQSTM1) is involved in autophagy regulation through multiple pathways. It interacts with autophagosomes-associated LC3-II and ubiquitinated protein aggregates to engulf the aggregates in autophagosomes, interacts with HDAC6 to inhibit its deacetylase activity to maintain the levels of acetylated alpha-tubulin and stabilities of microtubules to enhance autophagosome trafficking, and regulates autophagy initiation and cell survival. We performed immunohistochemistry staining of P62 in prostate tissues from prostate cancer patients and found that levels of P62 in patients with prostate adenocarcinomas (PCA) are significantly higher than those in patients with benign prostate hyperplasia (BPH). High levels of P62 predict high tumor grade and high intensity of metastasis. METHODS: We created prostate cancer cell lines stably overexpressing P62 and then suppress the expression of P62 in the cell line stably overexpressing P62 with CRISPR technology. Cell proliferation assay with crystal violet, cell migration assay, cell invasion assay, Western blot analysis, and confocal fluorescent microscopy were conducted to test the impact of altered levels of P62 on the growth, migration, invasion, epithelial-to mesenchymal transition, autophagy flux, HDAC6 activity, and microtubular acetylation of cancer cells. RESULTS: P62 increased the levels of HDAC6 and reduced the acetylation of alpha-tubulin and the stability of microtubules. Consequently, high levels of P62 caused a promotion of epithelial-to-mesenchymal transition in addition to an impairment of autophagy flux, and further led to an enhancement of proliferation, migration, and invasion of prostate cancer cells. CONCLUSION: P62 promotes metastasis of PCA by sustaining the level of HDAC6 to inhibit autophagy and promote epithelial-to-mesenchymal transition. PMID- 29383754 TI - The effect of a practical nutrition education programme on feeding skills of caregivers of children with cerebral palsy at Muhimbili National Hospital, in Tanzania. AB - BACKGROUND: Feeding children with cerebral palsy (CP) is challenging and can lead to poor health outcomes. Using a facility-based intervention, we assessed the effect of a practical nutrition programme on feeding skills in caregivers of children with CP attending a pediatric clinic in urban Tanzania. METHODS: A randomized-controlled intervention study, involving 2-block stratified sample of under-5 CP children attending a specialized pediatric clinic at the Muhimbili National Hospital was done. One hundred ten moderate-to-severe, new and follow-up cases of children with CP were randomly allocated to the intervention (N = 63) and control groups (N = 47). A short nutrition education on feeding and positioning skills was provided to caregivers and occupational therapy sessions to CP children. Bivariate and multivariable logistic regression analyses of collected data were done. Statistical significance was assessed at p < .05. FINDINGS: The intervention significantly improved feeding skills of caregiver in the select indicators assessed. More caregivers appropriately positioned the children (AOR = 5.29; 95% CI: 2.00-13.96), fed children slowly (AOR: 5.17, 95% CI: 1.99-13.44), and involved the child during the feeding process (AOR = 3.46; 95% CI: 1.42-8.44). During feeding, caregiver's reported being less stressed (AOR = 2.53, 95% CI: 1.04-6.13) and the child's mood was more likely to be reported as improved (AOR = 3.15, 95% CI: 1.33-7.474). Although changes were observed in oral motor feeding skills (AOR = 1.67; 95% CI: 0.72-3.91) and functional feeding skills (AOR = 2.28; 95% CI: 0.86-6.06), they did not reach statistical significance in the multivariable models. CONCLUSION: Strengthening nutrition education and services for caregivers of children with CP has great value in the care of children with special needs and may improve the health outcomes of children as well as reduce stress among parents/caregivers. PMID- 29383755 TI - Hydrodynamic radius coincides with the slip plane position in the electrokinetic behavior of lysozyme. AB - The zeta potential (zeta) is the effective charge energy of a solvated protein, describing the magnitude of electrostatic interactions in solution. It is commonly used in the assessment of adsorption processes and dispersion stability. Predicting zeta from molecular structure would be useful to the structure-based molecular design of drugs, proteins, and other molecules that hold charge dependent function while remaining suspended in solution. One challenge in predicting zeta is identifying the location of the slip plane (XSP ), a distance from the protein surface where zeta is theoretically defined. This study tests the hypothesis that the XSP can be estimated by the Stokes-Einstein hydrodynamic radius (Rh ), using globular hen egg white lysozyme as a model system. Although the XSP and Rh differ in their theoretical definitions, with the XSP being the position of the zeta during electrokinetic phenomena (e.g., electrophoresis) and the Rh being a radius pertaining to the edge of solvation during diffusion, they both represent the point where water and ions no longer adhere to a molecule. This work identifies the limited range of ionic strengths in which the XSP can be determined using diffusivity measurements and the Stokes-Einstein equation. In addition, a computational protocol is developed for determining the zeta from a protein crystal structure. At low ionic strengths, a hyperdiffusivity regime exists, requiring direct measurement of electrophoretic mobility to determine zeta. This work, therefore, supports a basic tenant of EDL theory that the electric double layer during diffusion and electrophoresis are equivalent in the Stokes-Einstein regime. PMID- 29383756 TI - Predicted accommodative response from image quality in young eyes fitted with different dual-focus designs. AB - PURPOSE: To investigate the separated and combined influences of inner zone (IZ) diameter and effective add power of dual-focus contact lenses (CL) in the image quality at distance and near viewing, in a functional accommodating model eye. METHODS: Computational wave-optics methods were used to define zonal bifocal pupil functions, representing the optic zones of nine dual-focus centre-distance CLs. The dual-focus pupil functions were defined having IZ diameters of 2.10 mm, 3.36 mm and 4.00 mm, with add powers of 1.5 D, 2.0 D and 2.5 D (dioptres), for each design, that resulted in a ratio of 64%/36% between the distance and treatment zone areas, bounded by a 6 mm entrance pupil. A through-focus routine was implemented in MATLAB to simulate the changes in image quality, calculated from the Visual Strehl ratio, as the eye with the dual-focus accommodates, from 0 to -3.00 D target vergences. Accommodative responses were defined as the changes in the defocus coefficient, combined with a change in fourth and sixth order spherical aberration, which produced a peak in image quality at each target vergence. RESULTS: Distance viewing image quality was marginally affected by IZ diameter but not by add power. Near image quality obtained when focussing the image formed by the near optics was only higher by a small amount compared to the other two IZ diameters. The mean +/- standard deviation values obtained with the three adds were 0.28 +/- 0.02, 0.23 +/- 0.02 and 0.22 +/- 0.02, for the small, medium and larger IZ diameters, respectively. On the other hand, near image quality predicted by focussing the image formed by the distance optics was considerably lower relatively to the other two IZ diameters. The mean +/- standard deviation values obtained with the three adds were 0.15 +/- 0.01, 0.38 +/- 0.00 and 0.54 +/- 0.01, for the small, medium and larger IZ diameters, respectively. CONCLUSIONS: During near viewing through dual-focus CLs, image quality depends on the diameter of the most inner zone of the CL, while add power only affects the range of clear focus when focussing the image formed by the CL near optics. When only image quality gain is taken into consideration, medium and large IZ diameters designs are most likely to promote normal accommodative responses driven by the CL distance optics, while a smaller IZ diameter design is most likely to promote a reduced accommodative response driven by the dual-focus CL near optics. PMID- 29383757 TI - Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an Alexander disease model. AB - Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca2+ responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca2+ homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca2+ signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca2+ . Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis. PMID- 29383759 TI - Bioinspired, Spine-Like, Flexible, Rechargeable Lithium-Ion Batteries with High Energy Density. AB - The rapid development of flexible and wearable electronics proposes the persistent requirements of high-performance flexible batteries. Much progress has been achieved recently, but how to obtain remarkable flexibility and high energy density simultaneously remains a great challenge. Here, a facile and scalable approach to fabricate spine-like flexible lithium-ion batteries is reported. A thick, rigid segment to store energy through winding the electrodes corresponds to the vertebra of animals, while a thin, unwound, and flexible part acts as marrow to interconnect all vertebra-like stacks together, providing excellent flexibility for the whole battery. As the volume of the rigid electrode part is significantly larger than the flexible interconnection, the energy density of such a flexible battery can be over 85% of that in conventional packing. A nonoptimized flexible cell with an energy density of 242 Wh L-1 is demonstrated with packaging considered, which is 86.1% of a standard prismatic cell using the same components. The cell also successfully survives a harsh dynamic mechanical load test due to this rational bioinspired design. Mechanical simulation results uncover the underlying mechanism: the maximum strain in the reported design (~0.08%) is markedly smaller than traditional stacked cells (~1.1%). This new approach offers great promise for applications in flexible devices. PMID- 29383758 TI - Circadian expression and functional characterization of PEA-15 within the mouse suprachiasmatic nucleus. AB - The circadian timing system influences the functional properties of most, if not all, physiological processes. Central to the mammalian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN functions as a 'master clock' that sets the phasing of ancillary circadian oscillator populations found throughout the body. Further, via an entraining input from the retina, the SCN ensures that the clock oscillators are synchronized to the daily light/dark cycle. A critical component of the SCN timing and entrainment systems is the p44/42 mitogen-activated protein kinase (ERK/MAPK) pathway. Here, we examined the expression and function of phosphoprotein-enriched in astrocytes (PEA-15), an ERK scaffold protein that serves as a key regulator of MAPK signaling. A combination of immunolabeling and Western blotting approaches revealed high levels of PEA-15 within the SCN. PEA-15 expression was enriched in distinct subpopulations of SCN neurons, including arginine vasopressin (AVP)-positive neurons of the SCN shell region. Further, expression profiling detected a significant circadian oscillation in PEA-15 expression within the SCN. Brief photic stimulation during the early subjective night led to a significant increase in PEA-15 phosphorylation, an event that can trigger ERK/PEA-15 dissociation. Consistent with this, co-immunoprecipitation assays revealed that PEA-15 is directly bound to ERK in the SCN and that photic stimulation leads to their dissociation. Finally, we show that PEA-15 regulates ERK/MAPK-dependent activation of the core clock gene period1. Together, these data raise the prospect that PEA-15 functions as a key regulator of the SCN timing system. PMID- 29383760 TI - High-frequency ultrasonography-New non-invasive method in assessment of skin lymphomas. AB - BACKGROUND: Mycosis fingoides (MF) is the most common subtype of primary cutaneous T-cell lymphomas. Current evaluation of disease extent and severity is based on mSWAT scoring system, which seems to be relatively subjective. The aim of this subject was to present the usefulness of 20 MHz in objective 5-year long monitoring of response to therapy in MF patients. MATERIALS AND METHODS: The 5 years long follow-up based on 19 skin USG images of patients diagnosed as early stages of MF was studied. The assessed USG parameter was the mean diameter of subepidermal low echogenic band (SLEB). RESULTS: In every MF patient during exacerbation within lesional skin we could observe SLEB, which thinning or complete disappearance was detected after finishing the therapy. Lack of complete absence of SLEB was related to the lack of complete remission assessed by mSWAT. CONCLUSION: We present for the first time the possibility of monitoring patients' clinical state on the base of non-invasive USG imaging. We recommend additional use of 20 MHz USG to reduce intra-observer variability and to assess residual disease. USG imaging can complement evaluation of skin lesions in MF and can support clinical judgement. PMID- 29383761 TI - Reducing intra-abdominal pressure in peritoneal dialysis patients to avoid transient hemodialysis. AB - Patients treated with peritoneal dialysis (PD) are often required to switch to hemodialysis (HD) temporarily when they develop abdominal wall hernias and dialysate leaks, peritonitis or undergo thoracic or abdominal surgeries. There are significant risks associated with incident hemodialysis including possible central venous catheter infections, thrombosis, and need for invasive procedures. Therefore, strategies to avoid temporary transfer to hemodialysis are desirable. The increased intra-abdominal pressure associated with PD is largely responsible for the issues requiring withholding PD. However, the high intra-abdominal pressure, due to dialysate and body position, can be minimized by making changes to the peritoneal dialysis prescription. The lower intra-abdominal pressure may allow dialysate leaks, hernia repairs, and abdominal incisions time to heal as well as to facilitate earlier resumption of PD after catheter replacement. These strategies help to decrease morbidity and minimize cost to the health care system associated with modality switches and its complications. PMID- 29383762 TI - Exploring additivity effects of double mutations on the binding affinity of protein-protein complexes. AB - Additivity in binding affinity of protein-protein complexes refers to the change in free energy of binding (DeltaDeltaGbind ) for double (or multiple) mutations which is approximately equal to the sum of their corresponding single mutation DeltaDeltaGbind values. In this study, we have explored the additivity effect of double mutants, which shows a linear relationship between the binding affinity of double and sum of single mutants with a correlation of 0.90. However, the comparison of DeltaDeltaGbind values showed a mean absolute deviation of 0.86 kcal/mol, and 25.6% of the double mutants show a deviation of more than 1 kcal/mol, which are identified as non-additive. The additivity effects have been analyzed based on the influence of structural features such as accessible surface area, long range order, binding propensity change, surrounding hydrophobicity, flexibility, atomic contacts between the mutations and distance between the 2 mutations. We found that non-additive mutations tend to be closer to each other and have more contacts. We have also used machine learning methods to discriminate additive and non-additive mutations using structure-based features, which showed the accuracies in the range of 0.77-0.92 for protein-protein complexes belonging to different functions. Further, we have compared the additivity effects of protein stability along with binding affinity and explored the similarities and differences between them. The results obtained in this study provide insights into the effects of various structural features on binding affinity of double mutants, and will aid the development of accurate methods to predict the binding affinity of double mutants. PMID- 29383763 TI - A Zwitterionic Ligand-Based Cationic Metal-Organic Framework for Rapidly Selective Dye Capture and Highly Efficient Cr2 O72- Removal. AB - A cationic metal-organic framework (MOF), [Cu2 L(H2 O)2 ]?(NO3 )2 ?5.5 H2 O (1) has been successfully synthesized from a zwitterionic ligand 1,1'-bis(3,5 dicarboxyphenyl)-4,4'-bipyridinium chlorine ([H4 L]Cl2 ). The framework of compound 1 contains classical {Cu2 (O2 C)4 } paddlewheels, and possesses typical nbo-type topology and two types of channels with sizes of 5.0 and 15.54 A. Benefitting from the 3D cationic framework and high pore volume, compound 1 shows interesting selective adsorption ability for anionic dyes. Such material can be successfully employed in a chromatographic column to efficiently separate mixed dyes of Fluorescein Sodium and Methylene Blue. In addition, compound 1 exhibits excellent Cr2 O72- removal capacity with maximum adsorption amount of 222.5 mg g 1 , which ranks among the higher Cr2 O72- adsorption amounts of MOF materials ever reported, based on ion-exchange. The strategy to construct cationic MOFs based on zwitterionic ligands will promote the development of functional porous materials for the capture and removal of anionic pollutant species from contaminated liquid. PMID- 29383764 TI - Access to kidney transplantation in European adults aged 75-84 years and related outcomes: an analysis of the European Renal Association-European Dialysis and Transplant Association Registry. AB - To what extent access to, and allocation of kidney transplants and survival outcomes in patients aged >=75 years have changed over time in Europe is unclear. We included patients aged >=75-84 years (termed older adults) receiving renal replacement therapy in thirteen European countries between 2005 and 2014. Country differences and time trends in access to, and allocation of kidney transplants were examined. Survival outcomes were determined by Cox regression analyses. Between 2005 and 2014, 1392 older adult patients received 1406 transplants. Access to kidney transplantation varied from ~0% (Slovenia, Greece and Denmark) to ~4% (Norway and various Spanish regions) of all older adult dialysis patients, and overall increased from 0.3% (2005) to 0.9% (2014). Allocation of kidney transplants to older adults overall increased from 0.8% (2005) to 3.2% (2014). Seven-year unadjusted patient and graft survival probabilities were 49.1% (95% confidence interval, 95% CI: 43.6; 54.4) and 41.7% (95% CI: 36.5; 46.8), respectively, with a temporal trend towards improved survival outcomes. In conclusion, in the European dialysis population aged >=75-84 years access to kidney transplantation is low, and allocation of kidney transplants remains a rare event. Though both are increasing with time and vary considerably between countries. The trend towards improved survival outcomes is encouraging. This information can aid informed decision-making regarding treatment options. PMID- 29383765 TI - Rational Syntheses and Serendipity: Complexes [LSnPtCl2 (SMe2 )]2 , [{LSnPtCl(SMe2 )}2 SnCl2 ], [(LSn)3 (PtCl2 )(PtClSnCl){LSn(Cl)OH}], and [O(SnCl)2 (SnL)2 ] with L=MeN(CH2 CMe2 O)2. AB - Syntheses and molecular structures of the dimeric tin-platinum complex [LSnPtCl2 (SMe2 )]2 (2), the tin-platinum clusters [{LSnPtCl(SMe2 )}2 SnCl2 )] (3) and [(LSn)3 (PtCl2 )(PtClSnCl)(LSnOHCl)] (6) (L=MeN(CH2 CMe2 O- )2 ), and of the unprecedented tin(II) aminoalkoxide-tin oxide chloride complex [O(SnCl)2 ?(SnL)2 ] (5) are reported. The compounds were characterized by NMR spectroscopy (1 H, 13 C, 119 Sn, 195 Pt), 119 Sn Mossbauer spectroscopy (1-3, 6), electrospray ionization mass spectrometry, elemental analyses, and single-crystal X-ray diffraction analyses (2?CH2 Cl2 , 3?2 C4 H8 O, 5, 6?3CH2 Cl2 ). The tin(II) aminoalkoxide [MeN(CH2 CMe2 O)2 Sn]2 (1) behaves like a neutral ligand, inserts into a Pt-Cl bond, or is involved in rearrangement reactions with the different behavior occurring even within one compound (3, 6). DFT calculations show that the tin-platinum compounds behave like electronic chameleons. PMID- 29383766 TI - A method of evaluating facial pores using optical 2D images and analysis of age dependent changes in facial pores in Koreans. AB - BACKGROUND: Enlarged facial pores and changes in pore area are of concern for cosmetic reasons. To evaluate pores, measuring tools based on 3D methodology are used. Yet, these methods are limited by their measuring ranges. In this study, we performed pore analysis by measuring the whole face using 2D optical images. We further sought to understand how the pores of Korean women change with age. MATERIALS AND METHODS: One hundred sixteen Korean female subjects aged 20-60 years were recruited for this study. Facial images were taken using the VISIA CR(r) adjusted light source. Images were processed using Image-Pro Plus 9.2. Statistical significance was assumed when P < .05. RESULTS: The pore area, as indicated by pixel count, gradually increased in patients through their 40s, but decreased through their 50s and 60s. Facial pores generally exhibited directionality through the patients' 30s, but this isotropic feature was more prominent in their 50s. Pore elongation increased stepwise. The first increase occurred during the transition from patients' 30s to their 40s and the second increase occurred during the transition from patients' 50s to their 60s. This indicated that the pores deformed from a circular shape to a long elliptic shape over time. CONCLUSION: A new evaluation method using 2D optical images facilitates the analysis of pore distribution and elongation throughout the entire cheek. This is an improvement over an analysis of pores over a narrow region of interest. PMID- 29383767 TI - Entropy-Driven Reversible Agglomeration of Crown Ether Capped Gold Nanoparticles. AB - It is shown that plasmonic gold nanoparticles functionalised with a thiolated 18 crown-6 ligand shell agglomerate spontaneously from aqueous dispersion at elevated temperatures. This process takes place over a narrow temperature range, is accompanied by a colour change from red to purple-blue and is fully reversible. Moreover, the temperature at which it occurs can be adjusted by the degree of complexation of the crown ether moiety with appropriate cations. More complexation leads to higher transition temperatures. The process has been studied by UV/Vis spectroscopy, electron microscopy, dynamic light scattering and zeta potential measurements. A thermodynamic rationale is provided to suggest an entropy-driven endothermic agglomeration process based on attractive hydrophobic interactions of the complexed crowns that are competing against electrostatic repulsion of the charged ligand shells. PMID- 29383768 TI - Effects of the supplementation with an high-polyphenols extra-virgin olive oil on kinetic sperm features and seminal plasma oxidative status in healthy dogs. AB - The aim of this work was to evaluate the effects of the supplementation of two extra-virgin olive oils (EVOO) having different polyphenols content, on canine spermatozoa kinetic parameters and seminal plasma oxidative status. The study was conducted on 12 clinically healthy dogs of different breeds (2-7 years, 5-48 kg of body weight) divided into two groups: an experimental group supplemented with EVOO (Coratina cultivar) high in polyphenols (H-P) and a control group fed EVOO (Cima di Bitonto cultivar) low in polyphenols (L-P). The oil was daily administered per os (1 ml/3 kg BW) before meal. Semen collection was made twice at 15 days distance (D01 and D02 ) and then at 30 (D30), 60 (D60) and 90 (D90) days. Semen concentration and kinetic parameters were measured using computer assisted sperm analysis (CASA) system to evaluate: sperm total count, sperm motile (MOT%), progressive motility (PROGR%) and its fractions, straight-line velocity (VSL, MUm/s), curvilinear velocity (VCL, MUm/s), average path velocity (VAP, MUm/s), amplitude of lateral head displacement (ALH, MUm), beat cross frequency (BCF, Hz), straightness (STR%) and linearity (LIN%). On seminal plasma, reactive oxygen species (ROS) and biological antioxidant potential (BAP) were tested. From findings, no differences were found for sperm MOT, VSL, VCL, VAP, ALH, BCF, STR, LIN and BAP. A gradual enhancement of PROGR% was observed in H-P group (p < .01). The ROS levels were higher in dogs H-P compared to the other group (p < .05). In conclusion, our results highlight the positive effects of EVOO polyphenols on sperm PROGR% in healthy dogs. PMID- 29383769 TI - Serum intestinal fatty acid-binding protein in the noninvasive diagnosis of celiac disease. AB - Current diagnostic guidelines for celiac disease (CD) in pediatric patients require a duodenal biopsy if the IgA anti-tissue transglutaminase (tTG) is below 10x the upper limit of normal (ULN). Additional markers may enable a noninvasive diagnosis in this group. Serum intestinal-fatty acid-binding protein (I-FABP), a marker for intestinal epithelial damage, could be useful in this respect. A total of 95 children with a clinical suspicion of CD and tTG 1-10x ULN were investigated. All had a duodenal biopsy and analysis of serum I-FABP. A control group of 161 children with familial short stature and normal tTG was included. I FABP levels in the 71 patients with tTG 1-10x ULN and biopsy-proven CD (median 725 pg/mL) were not significantly different (p = 0.13) from the levels in the 24 patients with a tTG 1-10x ULN but a normal biopsy (median 497 pg/mL). However, when combining tTG and I-FABP levels, 11/24 patients could have been diagnosed noninvasively if tTG is >= 50 U/mL and I-FABP >=880 pg/mL or in 12/19 patients if tTG is >= 60 U/mL and I-FABP >= 620 pg/mL. Therefore, addition of I-FABP to the diagnostic procedure of CD may provide a noninvasive diagnosis in patients with a tTG >= 50 U/mL. PMID- 29383770 TI - Phenylene Bridged Cyclic Azaacenes: Dimers and Trimers. AB - The synthesis and characterization of novel macrocyclic, phenylene-bridged azaacenes is reported. These species were obtained either by a conventional benzoin- diamine condensation, as shown for the case of the cyclotrimers, in which the azaacene units are separated by meta-connected phenylene bridges, or by a Buchwald-Hartwig-type Pd-catalyzed coupling, which employs 1,2,5,6 tetrabromodibenzocyclooctatetraene as the substrate and bis-TIPS-ethynylated diaminobenzene, -naphthalene or -anthracene as the coupling partner to give the double coupling products azaacene-annulated dibenzocyclooctatetraenes in moderate yields. The macrocycles show strong emission and light emitting diodes have been built with brightnesses exceeding 1600 cd m-2 . We evaluated the optical and electronic properties and the solid-state structures of the molecules and discuss their properties through comparison with their linear and tetrameric N heteroacene counterparts. PMID- 29383771 TI - Coccidioidomycosis: Imported and possible domestic cases in China: A case report and review, 1958-2017. AB - We report a case of imported pulmonary coccidioidomycosis caused by Coccidioides posadasii in a patient who was misdiagnosed as tuberculosis and mistreated with antituberculosis medications for 18 months. The symptoms were not relieved until antifungal treatment was started. An extensive review of the coccidioidomycosis cases occurring in China reveals 38 cases, 16 of which had no associated history of travel to any traditional endemic areas. We speculate that some factors may drive Coccidioides spp. transference to China, which then causes those domestic infections. Moreover, we indicate the first, to the best of our knowledge, possible endemic areas in China. PMID- 29383772 TI - Effects of two freezing methods and two cryopreservation media on post-thaw quality of stallion spermatozoa. AB - Glycerol-based extenders are widely utilized for freezing equine semen, but media combining methylformamide may better preserve sperm motility and mitochondrial function. Semen is cryopreserved utilizing either a Styrofoam box filled with liquid nitrogen or an automatic freezer. The objective of this experiment was to compare the post-thaw characteristics of the same ejaculates cryopreserved in a Styrofoam box or in an automatic freezer, utilizing a glycerol-based extender (Gent) and an extender that combines methylformamide and glycerol (BotuCrio(r) ). For that, one ejaculate from 30 stallions collected in two different centres was used. For data analysis, a mixed linear model with laboratory, medium and freezing method and respective interactions as fixed effects was used. Stallion was taken into account as a random effect. There was no influence (p > .05) of laboratory, while stallion effect was marked. Semen frozen in BotuCrio(r) in the automatic freezer had higher (p < .001) VCL than semen cryopreserved in Gent using the Styrofoam box. VCL was also higher (p = .068) for semen frozen in BotuCrio(r) in the Styrofoam box than for semen cryopreserved in Gent using the same method. The difference between percentage of sperm with intact plasma membrane frozen in Gent using the Styrofoam box (44.43% +/- 2.44%) compared to spermatozoa cryopreserved in BotuCrio(r) using the same method (40.78% +/- 2.42%) approached significance (p = .0507). The percentage of sperm with intact acrosome membrane was higher (p < .05) in semen frozen in BotuCrio(r) (79.08% +/- 1.79%) than semen frozen in Gent (75.15% +/- 1.80%). A higher (p = .0125) percentage (32.24% +/- 2.18%) of semen extended in Gent and cryopreserved in the Styrofoam box had high mitochondrial membrane potential than semen frozen in BotuCrio(r) using the same method (26.02% +/- 2.15%). Fertility studies are warranted to assess whether differences found have any effect on the fertility of inseminated mares. PMID- 29383773 TI - A framework for testing the equality between the health concentration curve and the 45-degree line. AB - The health concentration curve is the standard graphical tool to depict socioeconomic health inequality in the literature on health inequality. This paper shows that testing for the absence of socioeconomic health inequality is equivalent to testing if the conditional expectation of health on income is a constant function that is equal to average health status. In consequence, any test for parametric specification of a regression function can be used to test for the absence of socioeconomic health inequality (subject to regularity conditions). Furthermore, this paper illustrates how to test for this equality using a test for parametric regression functional form and applies it to health related behaviors from the National Health Survey 2014. PMID- 29383774 TI - Suppression of DELLA signaling induces procambial cell formation in culture. AB - The post-embryonic growth of plants requires the activities of apical meristems and lateral meristems. In the meristems, self-proliferation and differentiation of stem cells is tightly modulated by plant hormone signaling networks and specific transcription factors. Despite extensive studies on stem cell maintenance in plants, the mechanism by which stem cells are initially established is largely unknown. Vascular stem cells consisting of procambial/cambial cells give rise to xylem and phloem cells. In this study, we analyzed the establishment of procambial cells using the in vitro culture system VISUAL, in which mesophyll cells rapidly differentiate into xylem tracheary elements and phloem sieve elements via procambial cells. We found that procambial cell formation in VISUAL is initiated by light, which can be replaced by application of gibberellin (GA). Gibberellin was able to promote procambial cell formation through degradation of DELLA, whereas light did not elevate the endogenous GA content. Indeed, light in combination with bikinin reduced the accumulation of DELLA protein in VISUAL. Consistently, overexpression of a constitutively active DELLA protein repressed vascular cell differentiation even under light. These combined results suggest that DELLA signaling suppresses procambial cell formation during vascular development in VISUAL. PMID- 29383775 TI - Diagnostic validity of flow cytometry vs manual counting of polymorphonuclear leukocytes in spontaneous bacterial peritonitis. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is frequently occurring infection among patients with liver cirrhosis, defined by polymorphonuclear (PMN) leukocytic count >=250 cell/mm3 with or without a positive ascitic fluid (AF) bacterial culture. So, this study aimed to investigate the diagnostic value of flow cytometry versus manual counting of ascitic fluid PMNL in cirrhotic patients, with clinical suspicion of SBP. METHODS: A hospital-based cross sectional study was carried out on 320 cirrhotic patients with clinical suspicion of SBP. Abdominal paracentesis was performed in all cases for microscopic manual and flow cytometry counting of PMNL. Anti-HLA-DR, anti-CD15, anti-CD16, and anti CD45 monoclonal antibodies were used for flow cytometry method. RESULTS: Flow cytometric PMNL count had 100% sensitivity and specificity, while manual PMNL count had a sensitivity of 65.52% and specificity of 90% with significant difference (P value < .05). CONCLUSION: Flow cytometry is more reliable rapid method for PMNL counting, than the manual method that is less accurate and time consuming in diagnosing clinically suspected SBP. PMID- 29383776 TI - Temperature-controlled laminar airflow (TLA) device in the treatment of children with severe atopic eczema: Open-label, proof-of-concept study. AB - BACKGROUND: Children with severe, persistent atopic eczema (AE) have limited treatment options, often requiring systemic immunosuppression. OBJECTIVE: To evaluate the effect of the temperature-controlled laminar airflow (TLA) treatment in children/adolescents with severe AE. METHODS: We recruited 15 children aged 2 16 years with long-standing, severe AE and sensitization to >=1 perennial inhalant allergen. Run-in period of 6-10 weeks (3 visits) was followed by 12 month treatment with overnight TLA (Airsonett(r) , Sweden). The primary outcome was eczema severity (SCORAD-Index and Investigator Global Assessment-IGA). Secondary outcomes included child/family dermatology quality of life and family impact questionnaires (CDQLI, FDQLI, DFI), patient-oriented eczema measure (POEM), medication requirements and healthcare contacts. The study is registered as ISRCTN65865773. RESULTS: There was a significant reduction in AE severity ascertained by SCORAD and IGA during the 12-month intervention period (P < .001). SCORAD was reduced from a median of 34.9 [interquartile range 28.75-45.15] at Baseline to 17.2 [12.95-32.3] at the final visit, and IGA improved significantly from 4 [3-4] to 2 [1-3]. We observed a significant improvement in FDQLI (16.0 [12.25-19.0] to 12 [8-18], P = .023) and DFI (P = .011), but not CDQLI or POEM. Compared to 6-month period prior to enrolment, there was a significant reduction at six months after the start of the intervention in potent topical corticosteroids (P = .033). The exploratory cluster analysis revealed two strongly divergent patterns of response, with 9 patients classified as responders, and 6 as non-responders. CONCLUSION AND CLINICAL RELEVANCE: Addition of TLA device to standard pharmacological treatment may be an effective add-on to the management of difficult-to-control AE. PMID- 29383778 TI - Obese asthmatics are characterized by altered adipose tissue macrophage activation. AB - BACKGROUND: Adipose tissue-derived inflammation is linked to obesity-related comorbidities. This study aimed to quantify and immuno-phenotype adipose tissue macrophages (ATMs) from obese asthmatics and obese non-asthmatics and to examine associations between adipose tissue, systemic and airway inflammation. METHODS: Visceral (VAT) adipose tissue and subcutaneous (SAT) adipose tissue were collected from obese adults undergoing bariatric surgery and processed to obtain the stromovascular fraction. Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages were quantified by flow cytometry. Cytospins of induced sputum were stained for differential cell counts. Plasma C-reactive protein (CRP) and CD163 were measured by ELISA. RESULTS: VAT contained a higher number of ATMs compared to SAT. A higher percentage of M1 ATMs was observed in VAT of obese asthmatics compared to obese non-asthmatics. The M1:M2 ratio in VAT was negatively associated with FEV1 %. Sputum macrophage count was correlated positively with M1 ATMs and negatively with M2 ATMs in VAT. In obese asthmatics, CRP was positively associated with M1:M2 ratio in VAT. There were no associations with CD163. An elevated ratio of M1:M2 ATMs was observed in VAT of obese asthmatics with increased disease severity. CONCLUSIONS AND CLINICAL RELEVANCE: Visceral inflammation with increased pro-inflammatory macrophages (M1) occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity. PMID- 29383779 TI - Erythema-directed digital photography for the enhanced evaluation of topical treatments for acne vulgaris. AB - BACKGROUND: Erythema-directed digital photography is a novel method for evaluating the efficacy and tolerability of topical acne treatments. Here, we describe three case reports in which erythema-directed digital photography was used to evaluate acne before and after up to 12 weeks of treatment with clindamycin 1%/tretinoin 0.025% (Clin-RA). MATERIALS AND METHODS: Erythema directed digital photography was used to evaluate acne in three patients with mild-to-moderate facial acne, two of whom had refused to continue previous topical acne treatment (benzoyl peroxide 5% and clindamycin 1%/benzoyl peroxide 5%) due to persistent irritation. Acne lesions and erythema were evaluated using standard clinical photography and erythema-directed digital photography (VISIA CRTM system) before and after 8-12 weeks of treatment with Clin-RA. RESULTS: Erythema-directed digital photography revealed background erythema from previous topical acne treatments that was not evident from standard clinical photographs and allowed a better visualization of both inflammatory and non-inflammatory lesions. In all patients, there was a clear improvement in background erythema and a reduction in acne lesions following treatment with Clin-RA. CONCLUSION: This study has demonstrated for the first time that erythema-directed digital photography can enhance the evaluation of the efficacy and tolerability of topical acne treatments. These cases show that Clin-RA was associated with improved efficacy and tolerability vs previous treatments with topical monotherapy (benzoyl peroxide 5%) or a topical fixed-dose combination (clindamycin 1%/benzoyl peroxide 5%). PMID- 29383777 TI - Long noncoding RNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia. AB - Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known whether long, noncoding RNAs (lncRNAs) are involved in the contribution of hypoxia to GC metastasis. In the present study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia-induced GC cell metastasis. Furthermore, BC005927 is frequently upregulated in GC samples and increased BC005927 expression was correlated with a higher tumor-node-metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments showed that BC005927 expression is induced by hypoxia inducible factor-1 alpha (HIF-1alpha); ChIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF 1alpha. Next, we found that EPHB4, a metastasis-related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia-induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression. PMID- 29383780 TI - Dual-Crosslink Physical Hydrogels with High Toughness Based on Synergistic Hydrogen Bonding and Hydrophobic Interactions. AB - Constructing dual or multiple noncovalent crosslinks is highly effective to improve the mechanical and stimuli-responsive properties of supramolecular physical hydrogels, due to the synergistic effects of different noncovalent bonds. Herein, a series of tough physical hydrogels are prepared by solution casting and subsequently swelling the films of poly(ureidopyrimidone methacrylate co-stearyl acrylate-co-acrylic acid). The hydrophobic interactions between crystallizable alkyl chains and the quadruple hydrogen bonds between ureidopyrimidone (UPy) motifs serve as the dual crosslinks of hydrogels. Synergistic effects between the hydrophobic interactions and hydrogen bonds render the hydrogels excellent mechanical properties, with tensile breaking stress up to 4.6 MPa and breaking strain up to 680%. The UPy motifs promote the crystallization of alkyl chains and the hydrophobic alkyl chains also stabilize UPy-UPy hydrogen bonding. The resultant hydrogels are responsive to multiple external stimuli, such as temperature, pH, and ion; therefore, they show the thermal-induced dual and metal ion-induced triple shape memory behaviors. PMID- 29383781 TI - Morpho-palynological study of Cyperaceae from wetlands of Azad Jammu and Kashmir using SEM and LM. AB - In this study 12 species of Cyperaceae have been studied for quantitative and qualitative observation of pollen grains through Light and scanning electron microscopy. Pollens of 12 species of Cyperaceae from different wetlands of Azad Jammu and Kashmir were collected. Morphological characters of pollen grains were then investigated under the Light and Scanning electron microscope. Two pollen types have been observed apolar and heteropolar. Shape of pollens was prolate (4 spp), sub-spheroidal (7 spp), and oblate (1 spp). Variation observed in exine sculpturing granular (4 spp), reticulate (1 spp), areolate-punctate (3 spp), and psilate (2 spp). Polar to equatorial ratio and fertility percentage of the pollens were also studied. Based on these micromorphlogical characters of pollens taxonomic keys have been made for the accurate identification of the members of Cyperaceae. The characteristics studied in present research work are very much valuable taxonomically and phytochemically for the identification of species of family Cyperaceae. Light microscope (LM) and Scanning electron microscope (SEM) were used for pollen observation, which play vital role in the taxonomical identification of species and provide sufficient information for taxonomist. PMID- 29383782 TI - Step-down of inhaled corticosteroids in non-eosinophilic asthma: A prospective trial in real life. AB - BACKGROUND: While non-eosinophilic asthmatics are usually considered poorly responsive to inhaled corticosteroids (ICSs), studies assessing a step-down of ICS in this specific population are currently lacking. OBJECTIVES: To assess the proportion of non-eosinophilic asthmatics in whom ICS may be withdrawn without any clinical degradation and to determine the predictive markers of a failure to stop treatment with ICS. METHODS: This prospective study was completed by 36 non eosinophilic asthmatics, defined by sputum eosinophils <3% and blood eosinophils <400/MUL. In these patients, whichever the baseline asthma control level, the dose of ICS was gradually reduced every 3 months until they met the failure criteria or successfully discontinued ICS for 6 months. The failure criteria were an ACQ score >=1.5 with an increase from baseline >0.5 or a number of severe exacerbations during the study which was greater than the number during the year prior to the baseline visit. Receiver-operating characteristic (ROC) curves were constructed to assess predictors of a failure to stop ICS. This study is registered with ClinicalTrials.gov, number NCT02169323. RESULTS: In 14 patients (39%), ICSs were completely withdrawn, and in 10 further patients (28%), ICS were stepped-down to a reduced ICS dose without any deterioration of asthma control and exacerbation rate. Baseline predictors of a failure to stop ICS were a greater age (area under ROC curve [ROC AUC] and [95% CI]: 0.77 [0.62-0.93]) and elevated blood eosinophils (ROC AUC [95% CI]: 0.77 [0.61-0.93]). After the first step-down of ICS, the best predictor was an elevated blood eosinophil count (ROC AUC [95% CI]: 0.85 [0.72-0.99]). CONCLUSIONS & CLINICAL RELEVANCE: Withdrawing or reducing the dose of ICS is feasible in two-thirds of non-eosinophilic asthmatics irrespective of baseline asthma control. An elevated blood eosinophil count may predict the failure to stop ICS. PMID- 29383783 TI - DIVARICATA AND RADIALIS INTERACTING FACTOR (DRIF) also interacts with WOX and KNOX proteins associated with wood formation in Populus trichocarpa. AB - DIVARICATA AND RADIALIS INTERACTING FACTOR (DRIF) from snapdragon (Antirrhinum majus) is a MYB/SANT protein that interacts with related MYB/SANT proteins, RADIALIS and DIVARICATA, through its N-terminal MYB/SANT domain. In addition to the MYB/SANT domain, DRIF contains a C-terminal domain of unknown function (DUF3755). Here we describe novel protein-protein interactions involving a poplar (Populus trichocarpa) homolog of DRIF, PtrDRIF1. In addition to interacting with poplar homologs of RADIALIS (PtrRAD1) and DIVARICATA (PtrDIV4), PtrDRIF1 interacted with members of other families within the homeodomain-like superfamily, including PtrWOX13c, a WUSCHEL-RELATED HOMEOBOX protein, and PtrKNAT7, a KNOTTED1-LIKE HOMEOBOX protein. PtrRAD1 and PtrDIV4 interacted with the MYB/SANT-containing N-terminal portion of PtrDRIF1, whereas DUF3755 was both necessary and sufficient for interactions with PtrWOX13c and PtrKNAT7. Of the two MYB/SANT domains present in PtrDIV4, only the N-terminal MYB/SANT domain interacted with PtrDRIF1. GFP-PtrDRIF1 expressed alone or with PtrRAD1 localized to the cytoplasm, whereas co-expression of GFP-PtrDRIF1 with PtrDIV4, PtrWOX13c or PtrKNAT7 resulted in nuclear localization of GFP-PtrDRIF1. Modified yeast two hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) experiments using PtrDRIF1 as a bridge protein revealed that PtrDRIF1 simultaneously interacted with PtrRAD1 and PtrWOX13c, but could not form a heterotrimeric complex when PtrDIV4 was substituted for PtrRAD1. Moreover, a Y2H competition assay indicated that PtrKNAT7 inhibits the interaction between PtrRAD1 and PtrDRIF1. The discovery of an additional protein-protein interaction domain in DRIF proteins, DUF3755, and its ability to form heterodimers and heterotrimers involving MYB/SANT and wood-associated homeodomain proteins, implicates DRIF proteins as mediators of a broader array of processes than previously reported. PMID- 29383784 TI - Sexual harassment. PMID- 29383786 TI - Divergent functions of the GAGA-binding transcription factor family in rice. AB - OsGBPs are a small family of four genes in rice (Oryza sativa L.) that function as transcription factors recognizing the GAGA motif; however, their functions in plant growth and development remain unclear. Here we report the functions of OsGBPs in plant growth and grain development. Knock-down and knock-out of OsGBP1 promoted seedling growth and enhanced grain length, whereas overexpression of OsGBP1 exhibited the opposite effect on seedling growth and grain length, indicating that OsGBP1 repressed grain length and seedling growth. In addition, overexpression of OsGBP1 led to delayed flowering time and suppressed plant height. OsGBP1 could regulate OsLFL1 expression through binding to the (GA)12 element of its promoter. In contrast, OsGBP3 induced grain length and plant height. Grain length and plant height were decreased in OsGBP3RNAi lines and were increased in OsGBP3 overexpression lines. We also found a synergistic effect of these two genes on grain width and plant growth. RNAi of both OsGBP1 and OsGBP3 resulted in severe dwarfism, compared with RNAi of a single gene. These results suggest the presence of functional divergence of OsGBPs in the regulation of grain size and plant growth; these results enrich our understanding of the roles of GAGA-binding transcription factors in the regulatory pathways of plant development. PMID- 29383785 TI - Neutrophilia, gelatinase release and microvascular leakage induced by human mast cell tryptase in a mouse model: Lack of a role of protease-activated receptor 2 (PAR2). AB - BACKGROUND: Tryptase, the most abundant protease of the human mast cell, has been implicated as a key mediator of allergic inflammation that acts through activation of PAR2. OBJECTIVES: To investigate the contribution of PAR2 in the pro-inflammatory actions mediated by tryptase in a mice model. METHODS: We have injected recombinant human betaII-tryptase into the peritoneum of PAR2-deficient and wild-type C57BL/6 mice. After 6, 12 and 24 hours, mice were killed, peritoneal lavage performed and inflammatory changes investigated. RESULTS: Tryptase stimulated an increase in neutrophil numbers in the peritoneum, but responses did not differ between PAR2-deficient and wild-type mice. Heat inactivation of tryptase or pre-incubation with a selective tryptase inhibitor reduced neutrophilia, but neutrophil accumulation was not elicited with a peptide agonist of PAR2 (SLIGRL-NH2 ). Zymography indicated that tryptase stimulated the release of matrix metalloproteinases (MMP) 2 and 9 in the peritoneum of both mouse strains. Studies involving immunomagnetic isolation of neutrophils suggested that neutrophils represent the major cellular source of tryptase induced MMP2 and MMP9. At 24 hours after tryptase injection, there was increased microvascular leakage as indicated by high levels of albumin in peritoneal lavage fluid, and this appeared to be partially abolished by heat-inactivating tryptase or addition of a protease inhibitor. There was no corresponding increase in levels of histamine or total protein. The extent of tryptase-induced microvascular leakage or gelatinase release into the peritoneum did not differ between PAR2-deficient and wild-type mice. CONCLUSIONS: Our findings indicate that tryptase is a potent stimulus for neutrophil accumulation, MMP release and microvascular leakage. Although these actions required an intact catalytic site, the primary mechanism of tryptase in vivo would appear to involve processes independent of PAR2. PMID- 29383787 TI - Prevalence of sleep disturbances in Chinese university students: a comprehensive meta-analysis. AB - This is a meta-analysis of the pooled prevalence of sleep disturbances and its associated factors in Chinese university students. English (PubMed, PsycINFO, Embase) and Chinese (SinoMed, Wan Fang Database and Chinese National Knowledge Infrastructure) databases were systematically and independently searched from inception until 16 August 2016. The prevalence of sleep disturbances was pooled using random-effects model. Altogether 76 studies involving 112 939 university students were included. The overall pooled prevalence of sleep disturbances was 25.7% (95% CI: 22.5-28.9%). When using the screening scales Pittsburgh Sleep Quality Index, Athens Insomnia Scale and Self-Rating Sleeping State Scale, and the diagnostic criteria of the Chinese Classification of Mental Disorders (Second Edition), the pooled prevalence of sleep disturbances was 24.1% (95% CI: 21.0 27.5%) and 18.1% (95% CI: 16.4-20.0%), respectively. The percentages of students dissatisfied with sleep quality and those suffering from insomnia symptoms were 20.3% (95% CI: 13.0-30.3%) and 23.6% (95% CI: 18.9-29.0%), respectively. Subgroup analyses revealed that medical students were more vulnerable to sleep disturbances than other student groups. There was no significant difference between males and females, and across geographic locations. Sleep disturbances are common in Chinese university students. Appropriate strategies for prevention and treatment of sleep disturbances in this population need greater attention. PMID- 29383788 TI - Shift work with and without night work as a risk factor for fatigue and changes in sleep length: A cohort study with linkage to records on daily working hours. AB - We examined shift work with or without night work as a risk factor for fatigue and short or long sleep. In a prospective cohort study with 4- and 6-year follow ups (the Finnish Public Sector study), we linked survey responses of 3,679 full time hospital employees on sleep duration and fatigue to records on daily working hours in 2008 (baseline), 2012 and 2014. We used logistic regression to estimate risk ratios and their confidence intervals to examine whether continuous exposure to shift work or changes between shift work and day work were associated with short (<=6.5 hr) or long (>=9.0 hr) sleep over 24 hr and fatigue at work and during free days. Compared with continuous day work and adjusting for age, gender, education and fatigue/sleep duration at baseline, continuous shift work with night shifts was associated with increased fatigue during free days (risk ratio = 1.38, 95% confidence interval 1.17-1.63) and long sleep (risk ratio = 8.04, 95% confidence interval 2.88-22.5, without adjustment for education) after 6-year follow-up. Exposure to shift work without night shifts increased only long sleep after 6 years (risk ratio = 5.87, 95% confidence interval 1.94-17.8). A change from day work to shift work with or without night shifts was associated with an increased risk for long sleep, and a change from shift work to day work with a decreased risk for long sleep and fatigue. This study suggests that irregular shift work is a modifiable risk factor for long sleep and increased fatigue, probably reflecting a higher need for recovery. PMID- 29383789 TI - Enhancing heterologous expression in Chlamydomonas reinhardtii by transcript sequence optimization. AB - Various species of microalgae have recently emerged as promising host-organisms for use in biotechnology industries due to their unique properties. These include efficient conversion of sunlight into organic compounds, the ability to grow in extreme conditions and the occurrence of numerous post-translational modification pathways. However, the inability to obtain high levels of nuclear heterologous gene expression in microalgae hinders the development of the entire field. To overcome this limitation, we analyzed different sequence optimization algorithms while studying the effect of transcript sequence features on heterologous expression in the model microalga Chlamydomonas reinhardtii, whose genome consists of rare features such as a high GC content. Based on the analysis of genomic data, we created eight unique sequences coding for a synthetic ferredoxin hydrogenase enzyme, used here as a reporter gene. Following in silico design, these synthetic genes were transformed into the C. reinhardtii nucleus, after which gene expression levels were measured. The empirical data, measured in vivo show a discrepancy of up to 65-fold between the different constructs. In this work we demonstrate how the combination of computational methods and our empirical results enable us to learn about the way gene expression is encoded in the C. reinhardtii transcripts. We describe the deleterious effect on overall expression of codons encoding for splicing signals. Subsequently, our analysis shows that utilization of a frequent subset of preferred codons results in elevated transcript levels, and that mRNA folding energy in the vicinity of translation initiation significantly affects gene expression. PMID- 29383790 TI - XPNPEP3 is a novel transcriptional target of canonical Wnt/beta-catenin signaling. AB - Canonical Wnt/beta-catenin signaling plays important roles in embryonic development and adult tissue regeneration while aberrant Wnt activation is the major driver of sporadic colorectal cancer (CRC). Thus, it is important to characterize the complete beta-catenin target transcriptome. We previously performed microarray-based mRNA profiling of rectal cancer samples stratified for Wnt status. In addition to AXIN2 and EPHB2, XPNPEP3 transcripts were significantly elevated in tumors exhibiting activated Wnt/beta-catenin signaling, validated by Q-PCR. Three different cell lines supported elevated XPNPEP3 transcript levels upon activation of Wnt signaling, confirmed using promoter luciferase assays. Ectopic expression of XPNPEP3 promoted tumorigenic properties in CRC cells. Immunohistochemistry on a CRC tissue microarray revealed significant correlation between beta-catenin nuclear localization and XPNPEP3 levels. More importantly, XPNPEP3 expression was upregulated compared to normal samples in published expression data sets from several cancers including CRC. Finally, XPNPEP3 expression correlated with poor survival in many cancers. Our results therefore suggest XPNPEP3 to be a transcriptional target of Wnt/beta catenin pathway with particular significance for CRC. PMID- 29383791 TI - Irish clinical and counselling psychologists' experiences and views of mandatory personal therapy during training: A polarisation of ethical concerns. AB - Although there have been some recent changes in Ireland, the practice of mandating personal therapy during training has traditionally differed between counselling and clinical psychologists. Irish psychologists (n = 258: 170 clinical, 88 counselling) took part in a survey study of experiences and views regarding this practice. Counselling psychologists reported higher rates of lifetime and current attendance at personal therapy compared to clinical psychologists, and nearly all had experienced mandated personal therapy compared to a minority of the clinical group. However, the clinical psychologists had a high rate of attendance at personal therapy compared to that reported for their British peers, indicating a high regard for personal therapy amongst Irish clinicians despite the absence of a training mandate. Five factors were found to be independent predictors of agreement with mandating personal therapy during training-lifetime experience of personal therapy, being a counselling psychologist, experience of mandated therapy, being more recently qualified, and longer attendance at personal therapy. Thematic analysis of the psychologists' open responses regarding mandated therapy indicated that the majority believed that personal therapy was an important part of ethical, effective practice, and valuable in enhancing self-awareness and learning from the client experience. Ethical concerns about a mandate were polarised between the two psychology specialisms, more counselling psychologists emphasising the dangers and questionable efficacy of psychologists practising psychotherapy without personal therapy experience, and more clinical psychologists questioning the efficacy and ethics of imposing a mandate on trainees. Recommendations are made regarding this issue for trainers of both specialisms. PMID- 29383792 TI - Repeated vaccination with tetanus toxoid of plasma donors with pre-existing specific IgE transiently elevates tetanus-specific IgE but does not induce allergic symptoms. PMID- 29383793 TI - Nasal variation in relation to high-altitude adaptations among Tibetans and Andeans. AB - OBJECTIVES: High-altitude (>2500 m) populations face several pressures, including hypoxia and cold-dry air, resulting in greater respiratory demand to obtain more oxygen and condition inspired air. While cardiovascular and pulmonary adaptations to high-altitude hypoxia have been extensively studied, adaptations of upper respiratory structures, e.g., nasal cavity, remain untested. This study investigates whether nasal morphology presents adaptations to hypoxic (larger noses) and/or cold-dry (tall/narrow noses) conditions among high-altitude samples. METHODS: CT scans of two high- and four low-altitude samples from diverse climates were collected (n = 130): high-altitude Tibetans and Peruvians; low-altitude Peruvians, Southern Chinese (temperate), Mongolian-Buriats (cold dry), and Southeast Asians (hot-wet). Facial and nasal distances were calculated from 3D landmarks placed on digitally-modeled crania. Temperature, precipitation, and barometric pressure data were also obtained. RESULTS: Principal components analysis and analyses of variance primarily indicate size-related differences among the cold-dry (Mongolian-Buriats) and hot-wet (Southeast Asians) adapted groups. Two-block partial least squares (PLS) analysis show weak relationships between size-standardized nasal dimensions and environmental variables. However, among PLS1 (85.90% of covariance), Tibetans display relatively larger nasal cavities related to lower temperatures and barometric pressure; regression analyses also indicate high-altitude Tibetans possess relatively larger internal nasal breadths and heights for their facial size. CONCLUSIONS: Overall, nasal differences relate to climate among the cold-dry and hot-wet groups. Specific nasal adaptations were not identified among either Peruvian group, perhaps due to their relatively recent migration history and population structure. However, high altitude Tibetans seem to exhibit a compromise in nasal morphology, serving in increased oxygen uptake, and air-conditioning processes. PMID- 29383794 TI - Fabrication of Polymer-Protein Hybrids. AB - Rapid developments in organic chemistry and polymer chemistry promote the synthesis of polymer-protein hybrids with different structures and biofunctionalities. In this feature article, recent progress achieved in the synthesis of polymer-protein conjugates, protein-nanoparticle core-shell structures, and polymer-protein nanogels/hydrogels is briefly reviewed. The polymer-protein conjugates can be synthesized by the "grafting-to" or the "grafting-from" approach. In this article, different coupling reactions and polymerization methods used in the synthesis of bioconjugates are reviewed. Protein molecules can be immobilized on the surfaces of nanoparticles by covalent or noncovalent linkages. The specific interactions and chemical reactions employed in the synthesis of core-shell structures are discussed. Finally, a general introduction to the synthesis of environmentally responsive polymer protein nanogels/hydrogels by chemical cross-linking reactions or molecular recognition is provided. PMID- 29383795 TI - Ice Melting to Release Reactants in Solution Syntheses. AB - Aqueous solution syntheses are mostly based on mixing two solutions with different reactants. It is shown that freezing one solution and melting it in another solution provides a new interesting strategy to mix chemicals and to significantly change the reaction kinetics and thermodynamics. For example, a precursor solution containing a certain concentration of AgNO3 was frozen and dropped into a reductive NaBH4 solution at about 0 degrees C. The ultra-slow release of reactants was successfully achieved. An ice-melting process can be used to synthesize atomically dispersed metals, including cobalt, nickel, copper, rhodium, ruthenium, palladium, silver, osmium, iridium, platinum, and gold, which can be easily extended to other solution syntheses (such as precipitation, hydrolysis, and displacement reactions) and provide a generalized method to redesign the interphase reaction kinetics and ion diffusion in wet chemistry. PMID- 29383796 TI - Structural Change of a Single Ag Nanoparticle Observed by Dark-field Microspectroscopy. AB - Silver nanoparticles (AgNPs) have been widely used as photocatalysts and nanosensors. Observation of the spectroscopy of a single AgNP greatly helps us understand the catalytic characteristics and morphology change of the AgNP during reactions. In the present study, AgNPs physically adsorbed on indium tin oxide (ITO) conductive glass were electrochemically reduced and oxidized, and the plasmonic resonance Rayleigh scattering (PRRS) spectrum of an individual AgNP was observed under a dark-field microscopy (DFM) equipped with a spectrometer. The electrochemical oxidization of the AgNP under constant potential caused a redshift of the PRRS peak for 30+/-5 nm. However, electrochemical reduction of the AgNP could not make the PRRS peak completely shift back to the initial position. In situ AFM and SEM characterization confirmed that very small Ag fragments (<10 nm) formed around the AgNP core during electrochemical oxidization. Results showed that dark-field microspectroscopy could be used as a sensitive tool for estimating the morphology/structural changes of nanoparticles that can hardly be observed through the cyclic voltammograms of multiple AgNPs. PMID- 29383797 TI - High-Speed 3D Printing of High-Performance Thermosetting Polymers via Two-Stage Curing. AB - Design and direct fabrication of high-performance thermosets and composites via 3D printing are highly desirable in engineering applications. Most 3D printed thermosetting polymers to date suffer from poor mechanical properties and low printing speed. Here, a novel ink for high-speed 3D printing of high-performance epoxy thermosets via a two-stage curing approach is presented. The ink containing photocurable resin and thermally curable epoxy resin is used for the digital light processing (DLP) 3D printing. After printing, the part is thermally cured at elevated temperature to yield an interpenetrating polymer network epoxy composite, whose mechanical properties are comparable to engineering epoxy. The printing speed is accelerated by the continuous liquid interface production assisted DLP 3D printing method, achieving a printing speed as high as 216 mm h-1 . It is also demonstrated that 3D printing structural electronics can be achieved by combining the 3D printed epoxy composites with infilled silver ink in the hollow channels. The new 3D printing method via two-stage curing combines the attributes of outstanding printing speed, high resolution, low volume shrinkage, and excellent mechanical properties, and provides a new avenue to fabricate 3D thermosetting composites with excellent mechanical properties and high efficiency toward high-performance and functional applications. PMID- 29383799 TI - Diagnostic patterns and delays in autoimmune blistering diseases of the mouth: A cross-sectional study. AB - OBJECTIVES: To describe the natural history and factors influencing diagnostic delays among patients with autoimmune blistering diseases of the mouth. MATERIALS AND METHODS: In this cross-sectional study, 27 newly diagnosed patients were interviewed, and professional and patient delays were calculated. Disease extent and severity scores were determined using Saraswat scoring system. RESULTS: Twenty-seven patients were interviewed and examined. Patient delay was significantly longer in patients who had desquamative gingivitis as initial presentation, in those who tried to use home remedies and over the counter medications, and in patients with less severe disease. Most patients (n = 21 [77.7%]) made more than one consultation, and the mean time needed to reach a definitive diagnosis (i.e. professional delay) was 83.2 +/- 21.4 days (range from 21 to 130 days). Professional delay was significantly correlated with the number of previous consultations (r = .78) and was significantly longer in patients who had desquamative gingivitis as initial presentation. CONCLUSION: Diagnosis of oral blistering diseases is often delayed. Diagnostic delay is more common in patients presenting with desquamative gingivitis and those with less severe disease. Improving patients and healthcare professionals' awareness about oral blistering diseases might help reduce diagnostic delay. PMID- 29383798 TI - Reverse of non-small cell lung cancer drug resistance induced by cancer associated fibroblasts via a paracrine pathway. AB - The tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of the tumor microenvironment, cancer-associated fibroblasts (CAF) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer-associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of CAF, which induces upregulation of P-glycoprotein expression and the drug resistance of non-small cell lung cancer cells. Our results demonstrated that CAF cells constitute a mechanism for cancer drug resistance. Thus, traditional chemotherapy combined with insulin-like growth factor 2 (IGF2) signaling inhibitor may present an innovative therapeutic strategy for non-small cell lung cancer therapy. PMID- 29383800 TI - Designed Long-Lived Emission from CdSe Quantum Dots through Reversible Electronic Energy Transfer with a Surface-Bound Chromophore. AB - The size-tunable emission of luminescent quantum dots (QDs) makes them highly interesting for applications that range from bioimaging to optoelectronics. For the same applications, engineering their luminescence lifetime, in particular, making it longer, would be as important; however, no rational approach to reach this goal is available to date. We describe a strategy to prolong the emission lifetime of QDs through electronic energy shuttling to the triplet excited state of a surface-bound molecular chromophore. To implement this idea, we made CdSe QDs of different sizes and carried out self-assembly with a pyrene derivative. We observed that the conjugates exhibit delayed luminescence, with emission decays that are prolonged by more than 3 orders of magnitude (lifetimes up to 330 MUs) compared to the parent CdSe QDs. The mechanism invokes unprecedented reversible quantum dot to organic chromophore electronic energy transfer. PMID- 29383802 TI - Reversal of visceral hypersensitivity in rat by Menthacarin(r) , a proprietary combination of essential oils from peppermint and caraway, coincides with mycobiome modulation. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder associated with altered gastrointestinal microflora and increased nociception to colonic distension. This visceral hypersensitivity can be reversed in our rat maternal separation model by fungicides. Menthacarin(r) is a proprietary combination of essential oils from Mentha x piperita L. and Carum carvi. Because these oils exhibit antifungal and antibacterial properties, we investigated whether Menthacarin(r) can reverse existing visceral hypersensitivity in maternally separated rats. METHODS: In non-handled and maternally separated rats, we used the visceromotor responses to colorectal distension as measure for visceral sensitivity. We evaluated this response before and 24 hours after water avoidance stress and after 7 days treatment with Menthacarin(r) or control. The pre- and post-treatment mycobiome and microbiome were characterized by sequencing of fungal internal transcribed spacer 1 (ITS-1) and bacterial 16s rDNA regions. In vitro antifungal and antimicrobial properties of Menthacarin(r) were studied with radial diffusion assay. KEY RESULTS: Menthacarin(r) inhibited in vitro growth of yeast and bacteria. Water-avoidance caused visceral hypersensitivity in maternally separated rats, and this was reversed by treatment. Multivariate analyses of ITS-1 and 16S high throughput data showed that maternal separation, induced changes in the myco- and microbiome. Menthacarin(r) treatment of non handled and maternally separated rats shifted the mycobiomes to more similar compositions. CONCLUSIONS & INFERENCES: The development of visceral hypersensitivity in maternally separated rats and the Menthacarin(r) -mediated reversal of hypersensitivity is associated with changes in the mycobiome. Therefore, Menthacarin(r) may be a safe and effective treatment option that should be tested for IBS. PMID- 29383801 TI - Preserving salivary gland physiology against genotoxic damage - the Tousled way. AB - Tousled and its homologs are evolutionarily conserved serine/threonine kinases present in plants and animals. Human Tousled-like kinases, TLK1 and TLK2, are implicated in chromatin assembly during DNA replication, chromosome segregation during mitosis, as well as in DNA damage response and repair. They share a high degree of sequence similarity, but have few non-redundant functions. Our laboratory has studied TLK1 and found that it increases the resistance of cells to ionizing radiation (IR) damage through expedited double-strand break (DSB) repair. DSBs are life-threatening lesions which when repaired restore DNA integrity and promote cell survival. A major focus in our laboratory is to dissect TLK1's role in DSB response and repair and study its usefulness in averting salivary gland hypofunction, a condition that invariably afflicts patients undergoing regional radiotherapy. The identification of anti-silencing factor 1 (ASF1), histone H3, and Rad9 as substrates of TLK1 links the protein to chromatin organization and DNA damage response and repair. However, recent findings of new interacting partners that include NEK1 suggest that TLK1 may play a broader role in DSB repair. This review provides a brief overview of the DNA damage response and DSB repair, and it highlights our current understanding of TLK1 in the process. PMID- 29383804 TI - 11th Annual Congress of the European Association for Haemophilia and Allied Disorders 2018, 7-9 February 2018, Madrid, Spain. PMID- 29383803 TI - Diabetes distress is more strongly associated with HbA1c than depressive symptoms in adolescents with type 1 diabetes: Results from Diabetes MILES Youth-Australia. AB - BACKGROUND: Glycated hemoglobin (HbA1c) is higher during adolescence than at any other life stage. Some research among adolescents indicates that depressive symptoms are associated with suboptimal HbA1c. However, research among adults suggests diabetes distress is a stronger predictor of HbA1c than depressive symptoms. OBJECTIVE: To determine the relative contributions of depressive symptoms and diabetes distress to explain the variance in HbA1c among adolescents with type 1 diabetes. PARTICIPANTS AND METHODS: Diabetes MILES Youth Study respondents aged 13 to 19 years completed questionnaires assessing depressive symptoms (Patient Health Questionnaire for Adolescents: PHQA-8), diabetes distress (Problem Areas in Diabetes-Teen version: PAID-T), and self-reported socio-demographic and clinical variables, including their most recent HbA1c. Stepwise hierarchical multiple regression was conducted to examine the contributions of depressive symptoms and diabetes distress to HbA1c. RESULTS: Participants (N = 450) had a (mean +/- SD) age of 15.7 +/- 1.9 years; diabetes duration of 6.9 +/- 4.3 years; and 38% (n = 169) were male. Twenty-one percent (n = 96) experienced moderate-to-severe depressive symptoms (PHQA-8 >= 11) and 36% (n = 162) experienced high diabetes distress (PAID-T > 90). In the final regression model, HbA1c was explained by: diabetes duration (beta = .14, P = .001), self-monitoring of blood glucose (beta = -.20, P < .001), and diabetes distress (beta = .30, P < .001). Following the addition of diabetes distress, depressive symptoms were no longer significantly associated with HbA1c (P = .551). The final model explained 18% of the variance in HbA1c. CONCLUSIONS: Consistent with evidence from studies among adults, diabetes distress mediated the relationship between depressive symptoms and HbA1c among adolescents with type 1 diabetes. These findings suggest that clinicians need to be aware of diabetes distress. PMID- 29383805 TI - Exogenous hydrogen sulfide inhibits oral mucosal wound-induced macrophage activation via the NF-kappaB pathway. AB - OBJECTIVE: This study includes exploring (i) the production of endogenous hydrogen sulfide (H2 S) after mucosal wound generation and (ii) the role of compensating the change in H2 S level postmucosal wound generation. METHODS AND MATERIALS: A mucosal wound model was established in female C57BL/6J mice. Wound tissues were collected to examine the change in the endogenous H2 S level. To examine the effect of decreased H2 S, GYY4137 was intraperitoneally injected into mice at 50 mg kg-1 day-1 before mucosal wounding to compensate for the decreased endogenous H2 S. Finally, we confirmed the role of GYY4137 in inhibiting the M1 phenotype macrophage activation induced by LPS in peritoneal macrophages and RAW264.7. RESULTS: The production of endogenous H2 S and the expression of cystathionine b-synthase and cystathionine g-lyase in vivo were reduced significantly in early stage after wound. GYY4137 significantly inhibited the activation of the M1 phenotype induced by mucosal wound inflammation in vivo and LPS in vitro. Finally, we confirmed that GYY4137 inhibited iNOS expression via the NF-kappaB signaling pathway. CONCLUSION: The exogenous H2 S donor GYY4137 compensated for the reduced endogenous H2 S postmucosal wound generation and inhibited the induced M1 macrophage activation. Thus, appropriate H2 S supplementation may aid in controlling inflammation associated with mucosal wounds. PMID- 29383806 TI - Comprehensive human leukocyte antigen genotyping of patients with type 1 diabetes mellitus in Taiwan. AB - BACKGROUND: Type 1 diabetes (T1D) mellitus is an autoimmune disorder involving both complex genetic and environmental factors. The incidence rates are low in Asian countries, and the specific, explanatory genetic factors underlying this have been investigated. The aim of this study was to elucidate the association of human leukocyte antigen (HLA) alleles/haplotypes with T1D in Taiwan. METHODS: We performed direct comprehensive genotyping of 6 classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) to 4-digit resolution in 104 unrelated T1D patients and 504 controls. Twenty-four of the 104 patients also exhibited thyroid autoimmunity. RESULTS: Three major susceptibility haplotypes were identified: DRB1*03:01-DQB1*02:01 (odds ratio [OR] = 5.39 under the dominant model, P = 2.3 * 10-13 ), DRB1*04:05-DQB1*04:01 (OR = 2.44, P = 5.0 * 10-4 ), and DRB1*09:01 DQB1*03:03 (OR = 2.02, P = 1.4 * 10-3 ); one protective haplotype was identified: DRB1*08:03-DQB1*06:01 (OR = 0.10, P = 1.6 * 10-3 ). DRB1*03:01-DQB1*02:01, the major T1D susceptibility haplotype, was found at a lower frequency in T1D patients with thyroid autoimmunity. The T1D protective allele DRB1*12:02 was shown to be protective against Graves' disease in our previous report. CONCLUSION: In addition to clarifying the roles of several known T1D HLA alleles and haplotypes, we discovered that the DRB1*08:03-DQB1*06:01 haplotype is protective against T1D. The DRB1*12:02 allele protected against both T1D and Graves' disease. PMID- 29383807 TI - RBMX is a component of the centromere noncoding RNP complex involved in cohesion regulation. AB - Satellite I RNA, a noncoding (nc)RNA transcribed from repetitive regions in human centromeres, binds to Aurora kinase B and forms a ncRNP complex required for chromosome segregation. To examine its function in this process, we purified satellite I ncRNP complex from nuclear extracts prepared from asynchronized or mitotic (M) phase-arrested HeLa cells and then carried out LC/MS to identify proteins bound to satellite I RNA. RBMX (RNA-binding motif protein, X-linked), which was isolated from M phase-arrested cells, was selected for further characterization. We found that RBMX associates with satellite I RNA only during M phase. Knockdown of RBMX induced premature separation of sister chromatid cohesion and abnormal nuclear division. Likewise, knockdown of satellite I RNA also caused premature separation of sister chromatids during M phase. The amounts of RBMX and Sororin, a cohesion regulator, were reduced in satellite I RNA depleted cells. These results suggest that satellite I RNA plays a role in stabilizing RBMX and Sororin in the ncRNP complex to maintain proper sister chromatid cohesion. PMID- 29383808 TI - Palladium-Catalyzed C-H Silylation through Palladacycles Generated from Aryl Halides. AB - A highly efficient palladium-catalyzed disilylation reaction of aryl halides through C-H activation has been developed for the first time. The reaction has broad substrate scope. A variety of aryl halides can be disilylated by three types of C-H activation, including C(sp2 )-H, C(sp3 )-H, and remote C-H activation. In particular, the reactions are also unusually efficient. The yields are essentially quantitative in many cases, even in the presence of less than 1 mol % catalyst and 1 equivalent of the silylating reagent under relatively mild conditions. The disilylated biphenyls can be converted into disiloxane-bridged biphenyls. PMID- 29383809 TI - A single night of sleep loss impairs objective but not subjective working memory performance in a sex-dependent manner. AB - Acute sleep deprivation can lead to judgement errors and thereby increases the risk of accidents, possibly due to an impaired working memory. However, whether the adverse effects of acute sleep loss on working memory are modulated by auditory distraction in women and men are not known. Additionally, it is unknown whether sleep loss alters the way in which men and women perceive their working memory performance. Thus, 24 young adults (12 women using oral contraceptives at the time of investigation) participated in two experimental conditions: nocturnal sleep (scheduled between 22:30 and 06:30 hours) versus one night of total sleep loss. Participants were administered a digital working memory test in which eight digit sequences were learned and retrieved in the morning after each condition. Learning of digital sequences was accompanied by either silence or auditory distraction (equal distribution among trials). After sequence retrieval, each trial ended with a question regarding how certain participants were of the correctness of their response, as a self-estimate of working memory performance. We found that sleep loss impaired objective but not self-estimated working memory performance in women. In contrast, both measures remained unaffected by sleep loss in men. Auditory distraction impaired working memory performance, without modulation by sleep loss or sex. Being unaware of cognitive limitations when sleep-deprived, as seen in our study, could lead to undesirable consequences in, for example, an occupational context. Our findings suggest that sleep-deprived young women are at particular risk for overestimating their working memory performance. PMID- 29383810 TI - Salivary proteomics in lichen planus: A relationship with pathogenesis? AB - OBJECTIVES: Oral lichen planus is a chronic, T-cell-mediated, inflammatory disease that affects the oral cavity. The oral lichen planus pathogenesis is still unclear, however, the main evidence is that the mechanisms of activation of different T lymphocyte pathway induce apoptosis with an increase in Th1 and Th17 subtypes cells, triggered by the release of cytokines. This study analysed saliva proteomics to identify protein markers that might be involved in the pathogenesis and development of the disease. MATERIAL AND METHODS: Proteins differentially expressed by oral lichen planus and healthy controls were screened using mass spectrometry; the proteins found in oral lichen planus were subjected to bioinformatics analysis, including gene ontology and string networks analysis. The multiplex analysis validation allowed the correlation between the proteins identified and the involved cytokines in Th17 response. RESULTS: One hundred and eight proteins were identified in oral lichen planus, of which 17 proteins showed a high interaction between them and indicated an association with the disease. Expression of these proteins was correlated with the triggering of cytokines, more specifically the Th17 cells. CONCLUSION: Proteins, such as S100A8, S100A9, haptoglobin, can trigger cytokines and might be associated with a pathological function and antioxidant activities in oral lichen planus. PMID- 29383811 TI - An Intracellular H2 O2 -Responsive AIEgen for the Peroxidase-Mediated Selective Imaging and Inhibition of Inflammatory Cells. AB - Inflammatory cells have gained widespread attention because inflammatory diseases increase the risk for many types of cancer. Therefore, it is urgent and important to implement detection and treatment methods for inflammatory cells. Herein, we constructed a theranostic probe with aggregation-induced emission (AIE) characteristics, in which tetraphenylethene (TPE) was modified with two tyrosine (Tyr) moieties. Owing to the H2 O2 -dependent, enzyme-catalyzed dityrosine formation, Tyr-containing TPE (TT) molecules crosslink through dityrosine linkages to induce the formation of hydrophobic aggregates, activating the AIE process in inflammatory cells that contain H2 O2 and overexpress myeloperoxidase. The emission turn-on resulting from the crosslinking of TT molecules could be used to distinguish between inflammatory and normal cells. Moreover, the massive TT aggregates induced mitochondria damage and cell apoptosis. This study demonstrates that the H2 O2 -responsive peroxidase-activated AIEgen holds great promise for inflammatory-cell selective imaging and inhibition. PMID- 29383812 TI - Socioeconomic disparities in clinical trials on Alzheimer's disease: a systematic review. AB - BACKGROUND AND PURPOSE: There is now a wide consensus at recognizing social and economic circumstances as main determinants of an individual's health status. Nevertheless, characteristics relating to socioeconomic status (SES) are poorly described in research reports. The aim of the present review was to verify whether the SES of participants is adequately reported in interventional studies targeting Alzheimer's disease (AD), and to explore the impact of SES proxy measures on the efficacy of the considered medications. METHODS: A systematic review of available randomized controlled trials (RCTs) on the currently marketed drugs for AD (i.e. cholinesterase inhibitors and memantine) was conducted by performing a structured search on PubMed and the Cochrane databases. The following indicators of SES were considered in the retained studies: (i) educational level, (ii) lifetime job category, (iii) income and (iv) wealth. The study quality was assessed using the Cochrane Risk of Bias Tool for Randomized Controlled Trials. RESULTS: A total of 48 articles were finally selected. Overall, only eight RCTs reported data concerning the four considered SES indicators. Indeed, only information pertaining to the educational level of participants was provided. Only one RCT (n = 60) performed ad hoc, secondary analyses accounting for the SES of participating subjects. CONCLUSIONS: The research and clinical relevance of SES has mistakenly been overlooked by the vast majority of RCTs on AD. A greater effort should be made to collect and report data on those SES indicators that may significantly affect the clinical manifestations and trajectories of patients with cognitive disturbances. PMID- 29383813 TI - Higher body mass index predicts cardiac autonomic dysfunction: A longitudinal study in adolescent type 1 diabetes. AB - BACKGROUND: Obesity is associated with an increased risk of cardiovascular morbidity in adults with diabetes. OBJECTIVE: To examine the predictive role of body mass index (BMI) and adiposity on cardiac autonomic function in childhood onset type 1 diabetes. SUBJECTS: Two hundred and fifty-three participants with type 1 diabetes (aged 8-30 years) were assessed for diabetes complications at a tertiary hospital, and followed over 7 years (total 922 visits). METHODS: Heart rate variability (HRV) measures assessed by 10-minute electrocardiography recording using LabChart Pro were standard deviation of RR intervals, time between consecutive QRS complexes, [SDNN], root mean squared difference of successive RR intervals (RMSSD), triangular index (TI), and low to high frequency ratio [LF:HF]. Multivariable generalized estimating equations were used to model the longitudinal associations between HRV measures and clinical variables (BMI standard deviation scores [SDS], waist:height ratio, total daily insulin dose/kg (TDD) and hemoglobin A1c [HbA1c]). RESULTS: At baseline, mean age was 14.4 +/- 2.7 years, diabetes duration 7.1 +/- 3.7 years, HbA1c 8.3% +/- 1.5% (67 +/- 16 mmol/mol), and 33% were overweight/obese (BMI >=85th percentile). At final visit, mean age was 18.5 +/- 2.7 years, duration 11.3 +/- 3.9 years, HbA1c 9.0% +/- 1.8% (75 +/- 20 mmol/mol), and 40% were overweight/obese. Adiposity (higher BMI SDS or waist: height ratio) was a significant predictor of worse HRV (lower SDNN, RMSSD; P < .05), while higher HbA1c and TDD predicted all adverse HRV measures (lower SDNN, RMSSD, TI; P < .05) and abnormal sympathovagal balance (higher LF:HF ratio; P < .05). CONCLUSIONS: Higher BMI and central adiposity are associated with cardiac autonomic dysfunction in childhood onset type 1 diabetes, after adjusting for HbA1c. Interventions targeting overweight/obesity during adolescence may optimize long-term vascular health in type 1 diabetes. PMID- 29383814 TI - Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals. AB - Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome. PMID- 29383815 TI - Viral safety of coagulation factor concentrates: memoirs from an insider. AB - The purpose of this essay is to recall the actions taken globally to improve the viral safety of coagulation factor concentrates, mainly in the years 1985-1990, at a time of confusing and often contradictory information on bloodborne viral infections in multitransfused patients with hemophilia (PWHs). I shall first recall the problem of the transmission and control of the hepatitis viruses, and then that of HIV: not only for temporal reasons, but also because understanding the progress of knowledge on hepatitis and the poor success of the early measures taken to tackle this problem in PWHs is essential to understand how the problem of HIV transmission was ultimately dealt with successfully. PMID- 29383816 TI - Effects of insulin resistance on the association between the circulating retinol binding protein 4 level and clustering of pediatric cardiometabolic risk factors. AB - OBJECTIVES: Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children's susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. METHODS: We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n = 2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. RESULTS: Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310 cm, 1.384 MUg/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (beta for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). CONCLUSIONS: HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components. PMID- 29383817 TI - Highly Efficient Artificial Light-Harvesting Systems Constructed in Aqueous Solution Based on Supramolecular Self-Assembly. AB - Highly efficient light-harvesting systems were successfully fabricated in aqueous solution based on the supramolecular self-assembly of a water-soluble pillar[6]arene (WP6), a salicylaldehyde azine derivative (G), and two different fluorescence dyes, Nile Red (NiR) or Eosin Y (ESY). The WP6-G supramolecular assembly exhibits remarkably improved aggregation-induced emission enhancement and acts as a donor for the artificial light-harvesting system, and NiR or ESY, which are loaded within the WP6-G assembly, act as acceptors. An efficient energy transfer process takes place from the WP6-G assembly not only to NiR but also to ESY for these two different systems. Furthermore, both of the WP6-G-NiR and WP6-G ESY systems show an ultrahigh antenna effect at a high donor/acceptor ratio. PMID- 29383818 TI - A recursive partitioning approach for subgroup identification in individual patient data meta-analysis. AB - BACKGROUND: Motivated by the setting of clinical trials in low back pain, this work investigated statistical methods to identify patient subgroups for which there is a large treatment effect (treatment by subgroup interaction). Statistical tests for interaction are often underpowered. Individual patient data (IPD) meta-analyses provide a framework with improved statistical power to investigate subgroups. However, conventional approaches to subgroup analyses applied in both a single trial setting and an IPD setting have a number of issues, one of them being that factors used to define subgroups are investigated one at a time. As individuals have multiple characteristics that may be related to response to treatment, alternative exploratory statistical methods are required. METHODS: Tree-based methods are a promising alternative that systematically searches the covariate space to identify subgroups defined by multiple characteristics. A tree method in particular, SIDES, is described and extended for application in an IPD meta-analyses setting by incorporating fixed effects and random-effects models to account for between-trial variation. The performance of the proposed extension was assessed using simulation studies. The proposed method was then applied to an IPD low back pain dataset. RESULTS: The simulation studies found that the extended IPD-SIDES method performed well in detecting subgroups especially in the presence of large between-trial variation. The IPD-SIDES method identified subgroups with enhanced treatment effect when applied to the low back pain data. CONCLUSIONS: This work proposes an exploratory statistical approach for subgroup analyses applicable in any research discipline where subgroup analyses in an IPD meta-analysis setting are of interest. PMID- 29383819 TI - Validity and Test-Retest Reliability of the Dutch Modified Perceived Deficits Questionnaire to Examine Cognitive Symptoms in Women with Chronic Whiplash, Chronic Idiopathic Neck Pain, and Fibromyalgia. AB - INTRODUCTION: Until now, only reliability and validity of the English version of the modified Perceived Deficits Questionnaire (mPDQ) have been investigated. OBJECTIVE: The aim of this study was to translate the mPDQ into Dutch and evaluate its validity and reliability as an assessment tool for self-perceived cognitive problems in patients with chronic whiplash-associated disorders (CWAD), chronic idiopathic neck pain (CINP), and fibromyalgia (FM). METHODS: A case control study was performed with a volunteer sample of 13 women with CWAD, 18 with CINP, and 33 with FM, and 33 women who were healthy and free of pain. The mPDQ was first translated into Dutch, and its test-retest reliability, internal consistency, and discriminative power were examined. RESULTS: The intraclass correlation coefficients were higher than 0.74. Cronbach's alpha values ranged between 0.71 and 0.95. Total mPDQ scores were significantly higher (P < 0.017) in FM and CWAD patients compared to healthy controls. Furthermore, participants performed the Stroop task and the psychomotor vigilance task (PVT), 2 neuropsychological computer-based cognitive performance tests. Correlations between the mPDQ total score and the cognitive performance tests were evaluated. Significant moderate to high correlations were found in all study samples between total mPDQ score and objective cognitive tests (Spearman correlation coefficient = 0.35 to 0.80; P < 0.05). CONCLUSION: Therefore, the Dutch version of the mPDQ showed high test-retest reliability and high internal consistency, and was able to distinguish CWAD and FM patients from healthy controls. PERSPECTIVE: This article presents the validity and test-retest reliability of the Dutch mPDQ. This measure could help clinicians who seek a reliable and user-friendly way to assess cognitive symptoms in chronic pain patients. PMID- 29383820 TI - When all other doors are closed: Telenurses' experiences of encountering care seekers with mental illnesses. AB - The aim of the study was to describe the telephone nurses' experiences of encountering callers with mental illnesses. Telenursing services are solely staffed with telenurses, who with the support of a decision support system (CDSS) independently triage callers based on the severity of the main symptoms presented by the care seeker. The system focuses on somatic symptoms, while information regarding mental health and mental illnesses is limited. Information about telenurses' experiences of encountering care seekers with mental illnesses is scarce, despite the increase in mental illnesses in the population. The study used a descriptive design with a qualitative approach. Twenty telenurses were interviewed, and the data were then analysed using inductive qualitative content analysis. The results are elaborated in the following three categories: (i) Experiences of encountering care seekers with mental illnesses; (ii) Experiences of facing difficulties and challenges; and (iii) Experiences of facing dissatisfaction and threats. Encountering care seekers with mental illnesses is metaphorically addressed as 'when all other doors are closed'. Encountering care seekers with mental illnesses was perceived as time-consuming and did not adequately correspond to the resources given by the service. Even though telenurses strive to achieve agreement, there is a collision between human needs and organizational structures. The study pinpoints the lack of resources for and education about mental illnesses and the limitations of the decision system, which needs to be updated in order to provide all care seekers care on equal terms. PMID- 29383821 TI - Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice. AB - : Essentials Two basic carboxypeptidases are present in plasma, B2 (CPB2) and N (CPN). Cpb2-/- and Cpn-/- mice were challenged in a hemolytic uremic syndrome (HUS) model vs. wild type. Cpb2-/- exacerbates HUS while Cpn-/- exacerbates cobra venom factor challenge vs. wild type mice. CPB2 and CPN have overlapping but non redundant roles. SUMMARY: Background There are two basic carboxypeptidases in plasma. Carboxypeptidase B2 (CPB2) is activated from a circulating zymogen, proCPB2, and carboxypeptidase N (CPN) is constitutively active with both inactivating complement C3a and C5a. Aims To test the roles of CPB2 and CPN in complement-driven mouse models of cobra venom factor (CVF) challenge and hemolytic-uremic syndrome (HUS). Methods Cpb2-/- , Cpn-/- and wild-type (WT) mice were compared in an HUS model induced by Shiga toxin and lipopolysaccharide administration and following CVF administration. Results HUS was exacerbated in Cpb2-/- mice more than in Cpn-/- mice, compared with WT mice. Cpb2-/- mice developed the HUS clinical triad of microangiopathic hemolytic anemia, uremia and thrombocytopenia. Treatment with anti-C5 antibody improved survival of both Cpb2 /- and Cpn-/- mice. In contrast, when challenged acutely with CVF, the reverse phenotype was observed. Cpn-/- mice had markedly worse disease than Cpb2-/- mice, whereas the WT mice were resistant. Conclusions CPN and CPB2 play overlapping but non-redundant roles in regulating complement activation in vivo. The constitutively active CPN is key for inactivation of systemic C5a, whereas CPB2 functions as an on-demand supplementary anaphylatoxin inhibitor in inactivating excessive C5a formed locally. PMID- 29383822 TI - Comparison of diode laser trans-scleral cyclophotocoagulation versus implantation of a 350-mm2 Baerveldt glaucoma drainage device for the treatment of glaucoma in dogs (a retrospective study: 2010-2016). AB - OBJECTIVE: To compare outcomes following trans-scleral cyclophotocoagulation (TSCP) and 350-mm2 Baerveldt implantation in the treatment of canine refractory glaucoma. DESIGN: Retrospective case study. CASE SELECTION: Client owned dogs undergoing surgical treatment of glaucoma within a veterinary referral hospital. PROCEDURES: Eighty-six glaucoma surgeries were performed on 83 eyes (69 dogs) diagnosed with primary or secondary glaucoma. Medical records were retrieved, and baseline data, surgery, medications, intraocular pressures (IOPs), vision, and complications were extracted. RESULTS: Fifty-four eyes (44 dogs) were treated with TSCP and placement of an anterior chamber suture shunt; 28 eyes (24 dogs) were implanted with a Baerveldt glaucoma drainage device (GDD); and four eyes (4 dogs) underwent GDD implantation after failure of TSCP to manage IOP. Following TSCP, IOP control (<20 mmHg) and vision retention occurred in 81.5% and 42.6%, respectively, for 16.1 +/- 1.36 months. Following GDD implantation, 71.4% maintained IOP <20 mmHg and 69.6% maintained vision for 11.0 +/- 0.94 months. IOP control without loss of vision was more likely following Baerveldt implantation (17/28; 60.7%) than TSCP (19/54; 35.2%) (P = 0.027). One eye had functional vision restored following GDD placement. IOP control without adjunctive medications was more likely following Baerveldt implantation (P = 0.02). CONCLUSIONS: In this study, eyes treated with Baerveldt GDD implantation were more likely to maintain IOP control and retain vision compared to eyes treated with TSCP and placement of an anterior chamber suture shunt. Lack of formal randomization, inconsistencies in surgical techniques and TSCP protocols, and potential unmeasured confounders must be considered when extrapolating from this retrospective study. PMID- 29383823 TI - Perthes disease: A new finding in Floating-Harbor syndrome. AB - Floating-Harbor Syndrome (FHS; OMIM #136140) is an ultra-rare autosomal dominant genetic condition characterized by expressive language delay, short stature with delayed bone mineralization, a triangular face with a prominent nose, and deep set eyes, and hand anomalies. First reported in 1973, FHS is associated with mutations in the SRCAP gene, which encodes SNF2-related CREBBP activator protein. Mutations in the CREBBP gene cause Rubinstein-Taybi Syndrome (RSTS; OMIM #180849, #613684), another rare disease characterized by broad thumbs and halluces, facial dysmorphisms, short stature, and intellectual disability, which has a phenotypic overlap with FHS. We describe a case of FHS associated with a novel SRCAP mutation and characterized by Perthes disease, a skeletal anomaly described in approximately 3% of patients with RSTS. Thus Perthes disease can be added to the list of clinical features that overlap between FHS and RSTS. PMID- 29383824 TI - Clinical therapeutic efficacy of mycophenolate mofetil in the treatment of SARDS in dogs-a prospective open-label pilot study. AB - OBJECTIVE: Sudden acquired retinal degeneration syndrome (SARDS) is a leading cause of irreversible blindness in dogs, yet no treatment has been objectively evaluated, or proven to be effective. Consensus of opinion is that SARDS is immune-mediated, although corticosteroid medications may exacerbate associated systemic signs. We examined the effect of sole-agent treatment with mycophenolate mofetil (MMF), a potent immunosuppressive medication unlikely to exacerbate associated systemic signs. ANIMALS STUDIED: Ten client-owned dogs with SARDS prospectively recruited within 6 weeks of vision loss. PROCEDURES: Clinical history, findings of systemic and ophthalmic examinations, blood parameters, visual navigation ability, electroretinography, and optical coherence tomography (OCT) were collected at baseline and at recheck after approximately 6 weeks of treatment with 10 mg/kg q 12 h of oral MMF. RESULTS: Twenty percent of dogs (2/10) experienced side effects (diarrhea, vomiting, lethargy), which resolved with reduction in dose to 8 mg/kg q12 h. No significant changes in systemic signs, physical examination findings, or laboratory test results were detected at the recheck examination. Compared with baseline, visual ability significantly declined at the recheck examination, and the amplitude of a slow-onset negative waveform noted on dark-adapted electroretinography was reduced at the recheck examination. The outer retinal layers were significantly thinner at the recheck examination as measured by OCT. CONCLUSIONS: Mycophenolate mofetil as a sole agent has no measureable positive effect on physical health, vision, or retinal structure following a 6-week trial period. Further studies are needed to evaluate other treatment options for SARDS. PMID- 29383825 TI - Ablation of PPARgamma in subcutaneous fat exacerbates age-associated obesity and metabolic decline. AB - It is well established that aging is associated with metabolic dysfunction such as increased adiposity and impaired energy dissipation; however, the transcriptional mechanisms regulating energy balance during late life stages have not yet been fully elucidated. Here, we show that ablation of the nuclear receptor PPARgamma specifically in inguinal fat tissue in aging mice is associated with increased fat tissue expansion and insulin resistance. These metabolic effects are accompanied by decreased thermogenesis, reduced levels of brown fat genes, and browning of subcutaneous adipose tissue. Comparative studies of the effects of PPARgamma downregulation in young and mid-aged mice demonstrate a preferential regulation of brown fat gene programs in inguinal fat in an age dependent manner. In conclusion, our study uncovers an essential role for PPARgamma in maintaining energy expenditure during the aging process and suggests the possibility of targeting PPARgamma to counteract age-associated metabolic dysfunction. PMID- 29383826 TI - Variation in practice of pouch surgery in England - using SWORD data to cut to the chase and justify centralization. AB - AIM: Increasing scrutiny on both individual and unit outcomes after surgical procedures is now expected. In the field of inflammatory bowel disease, this is particularly pertinent for outcomes after ileoanal pouch surgery. METHOD: The Surgical Workload and Outcomes Research Database (SWORD) relies on administrative data derived from Hospital Episode Statistics collected in England. The platform was interrogated for pouch procedures undertaken in England between April 2009 and December 2016 to assess national caseload and, between April 2012 and December 2016, to assess variation in caseload and outcomes after pouch surgery. RESULTS: In England there is a suggestion that numbers of pouch procedures may be decreasing. Over 80% of Trusts offering pouch surgery do so at very low volume with less than five procedures per year. There is also a clear phenomenon of the occasional pouch surgeon with 126 surgeons undertaking just one pouch operation during the study period of almost 5 years. Laparoscopic practice varies but 60% of pouches overall were done via an open approach. Mean length of stay was 10.1 days and average 30-day readmission rates were 27.4%. Outside London there appears to be an increasing trend for higher volume units to do more adult pouch procedures and lower volume units to do fewer. CONCLUSION: Low volume units and occasional pouch surgeons present a strong argument for centralization of pouch surgery. Data from England outside London suggest that this may already be happening. PMID- 29383827 TI - Mild case of Hailey-Hailey disease caused by a novel ATP2C1 mutation. PMID- 29383828 TI - Investigating energy-based pool structure selection in the structure ensemble modeling with experimental distance constraints: The example from a multidomain protein Pub1. AB - The structural variations of multidomain proteins with flexible parts mediate many biological processes, and a structure ensemble can be determined by selecting a weighted combination of representative structures from a simulated structure pool, producing the best fit to experimental constraints such as interatomic distance. In this study, a hybrid structure-based and physics-based atomistic force field with an efficient sampling strategy is adopted to simulate a model di-domain protein against experimental paramagnetic relaxation enhancement (PRE) data that correspond to distance constraints. The molecular dynamics simulations produce a wide range of conformations depicted on a protein energy landscape. Subsequently, a conformational ensemble recovered with low energy structures and the minimum-size restraint is identified in good agreement with experimental PRE rates, and the result is also supported by chemical shift perturbations and small-angle X-ray scattering data. It is illustrated that the regularizations of energy and ensemble-size prevent an arbitrary interpretation of protein conformations. Moreover, energy is found to serve as a critical control to refine the structure pool and prevent data overfitting, because the absence of energy regularization exposes ensemble construction to the noise from high-energy structures and causes a more ambiguous representation of protein conformations. Finally, we perform structure-ensemble optimizations with a topology-based structure pool, to enhance the understanding on the ensemble results from different sources of pool candidates. PMID- 29383829 TI - Failure load effect of molar axial wall height with CAD/CAM ceramic crowns with moderate occlusal convergence. AB - OBJECTIVES: To evaluate the significance of axial wall height (AWH) in molar fracture resistance involving CAD/CAM adhesively bonded, all-ceramic full coverage restorations on preparations with moderate total occlusal convergence (TOC) (16 degrees ). MATERIALS AND METHODS: 60 newly extracted maxillary third molars were divided into 5 groups (n = 12). Specimens were prepared for full coverage, all ceramic restorations with occlusal cervical AWHs of 4, 3, 2, 1 as well as a flat preparation (0 mm AWH) with all preparations with AWH containing a moderate 16 degrees TOC. Scanned preparations were fitted with a lithium disilicate restoration with a self-adhesive resin luting agent after intaglio surface preparation with hydrofluoric acid and silanation. Specimens were stored at 37 degrees C/98% humidity for 24 hours and tested to failure at a 45 degrees angle applied to the palatal cusp on a universal testing machine. Mean results were analyzed using ANOVA/Tukey's (P = .05). RESULTS: Preparations containing 2, 3, and 4 millimeters of AWH demonstrated similar and higher resistance to fracture than the 1 and zero millimeter AWH groups. CONCLUSIONS: Under the conditions of this study, results suggest that adhesive CAD/CAM technology may compensate for reduced axial wall height. However, more definitive results depend on fatigue testing. CLINICAL SIGNIFICANCE: These in vitro results suggest that adhesive CAD/CAM technology may compensate for less than optimal AWH. PMID- 29383831 TI - Patterns of care of superficial soft tissue sarcomas: it is not always just a lump. AB - AIM: Superficial soft tissue sarcomas (S-STS) are generally considered low-risk tumors and have an excellent prognosis when treated with appropriate surgery and adjuvant therapy. However, they are often misdiagnosed then mistreated, leading to significant morbidity. This study aims to examine the patterns of care and outcomes of patients with S-STS, comparing those initially managed through sarcoma units versus elsewhere. METHODS: Patients with S-STS from Prince of Wales Hospital in NSW (1995-2013) and Peter MacCallum Cancer Centre in Victoria (2009 2013) were identified from a national sarcoma database. Baseline variables, treatment and disease outcomes were recorded. Statistical tests performed included univariate and multivariate analyses, chi-square tests, as well as the Kaplan-Meier method for 5-year local recurrence and survival rates. RESULTS: Eighty-nine patients were identified, with 35% initially managed at a sarcoma unit and 65% elsewhere. Patients initially managed at sarcoma units had larger tumors (>5 cm 39% vs 17%; P = 0.036) with a trend to higher grade (61% vs 48%; P = 0.39). Patients that were initially managed outside a sarcoma unit more often underwent open surgical biopsies (P < 0.0005), had multiple operations (P < 0.0005) and had higher rates of local recurrences (24% vs 6.5%, P = 0.038). They also had lower 5-year local recurrence-free survival rates (P = 0.022), but had higher metastasis-free survival (P = 0.014). On multivariate analysis, only larger STS size and male gender predicted for poorer metastasis-free survival (P = 0.042 and 0.018, respectively). CONCLUSION: Patients with S-STS initially managed outside specialized sarcoma units undergo more operations, with risk of greater morbidity, and have greater risk of local recurrence. PMID- 29383832 TI - Long-lasting pathological consequences of overexpression-induced alpha-synuclein spreading in the rat brain. AB - Increased expression of alpha-synuclein can initiate its long-distance brain transfer, representing a potential mechanism for pathology spreading in age related synucleinopathies, such as Parkinson's disease. In this study, the effects of overexpression-induced alpha-synuclein transfer were assessed over a 1 year period after injection of viral vectors carrying human alpha-synuclein DNA into the rat vagus nerve. This treatment causes targeted overexpression within neurons in the dorsal medulla oblongata and subsequent diffusion of the exogenous protein toward more rostral brain regions. Protein advancement and accumulation in pontine, midbrain, and forebrain areas were contingent upon continuous overexpression, because death of transduced medullary neurons resulted in cessation of spreading. Lack of sustained spreading did not prevent the development of long-lasting pathological changes. Particularly remarkable were findings in the locus coeruleus, a pontine nucleus with direct connections to the dorsal medulla oblongata and greatly affected by overexpression-induced transfer in this model. Data revealed progressive degeneration of catecholaminergic neurons that proceeded long beyond the time of spreading cessation. Neuronal pathology in the locus coeruleus was accompanied by pronounced microglial activation and, at later times, astrocytosis. Interestingly, microglial activation was also featured in another region reached by alpha-synuclein transfer, the central amygdala, even in the absence of frank neurodegeneration. Thus, overexpression-induced spreading, even if temporary, causes long-lasting pathological consequences in brain regions distant from the site of overexpression but anatomically connected to it. Neurodegeneration may be a consequence of severe protein burden, whereas even a milder alpha-synuclein accumulation in tissues affected by protein transfer could induce sustained microglial activation. PMID- 29383833 TI - Adipose-derived stem cells decrease cardiomyocyte damage induced by porphyromonas gingivalis endotoxin through suppressing hypertrophy, apoptosis, fibrosis, and MAPK markers. AB - Heart failure is one of the complications related to periodontal disease. In addition to drugs or herbal medicines, stem cell therapy shows potential in the treatment of cardiomyopathy. This study investigates if stem cells exhibit beneficial effects on cardiomyocyte damage induced by porphyromonas gingivalis endotoxin (Pg-LPS). From the experimental results we find that Pg-LPS reduce cardiomyocyte viability via the activation of apoptosis, hypertrophy, fibrosis and MAPK signaling. Pg-LPS damaged cardiomyocytes co-cultured with adipose derived stem cells (ADSC) increases cardiomyocyte viability through suppressing the pathological markers described above. Further evidence implies that survival marker, IGF1, secreted from ADSC, may play an important role in the Pg-LPS induced protective effect on cardiomyocyte damage. PMID- 29383834 TI - Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes. AB - Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2. PMID- 29383835 TI - FLT3-ITD positive acute myeloid leukemia: A retrospective analysis of the role of allogeneic transplant and allelic ratio in patient management. AB - AIM: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) positive AML is associated with increased relapse risk and reduced overall survival (OS) compared to non-FLT3-mutated AML. The aim of this study was to evaluate the impact of allelic ratio and allogeneic transplant on outcomes in FLT3-ITD+ AML. METHODS: A retrospective study across five centers in Queensland, Australia, was conducted to examine survival outcomes and impact of FLT3-ITD allelic ratio and allograft. RESULTS: Seventy-one patients were included in the study. OS was significantly better for patients who were able to be allografted in first complete remission (CR1; 50.1 months vs 8.5 months; P = 0.0002). We did not find allelic ratio to be predictive of outcome. CONCLUSION: Transplantation in first complete remission is associated with improved outcomes for patients with FLT3+ AML. When feasible transplantation in CR1 is recommended. We do not currently recommend using allelic ratio to stratify risk unless this has been validated by local results. PMID- 29383836 TI - Physician Awareness of Immune Responses to Polyethylene Glycol-Drug Conjugates. AB - Antibodies against polyethylene glycol (PEG) can critically jeopardize the efficacy and safety of PEGylated therapeutics. For some PEG-drugs, a sizeable fraction of patients develop anti-PEG antibodies (APA), leading to reduced efficacy and potential adverse events. We surveyed physicians from several specialties to assess their awareness of APA. Overall, 83% of the physicians surveyed indicated that they have recently prescribed PEGylated drugs. Although 91% of respondents were aware of antidrug antibodies in general, only 22% were aware of APA responses. Further, there was limited awareness (35%) of PEG's inclusion in prescribed PEGylated therapeutics. These findings bring to light a need for improved awareness of APA, potentially via targeted education of physicians who prescribe specific PEGylated therapeutics that could induce or are otherwise affected by APA. Finally, it will be critical to quantitate the extent of knowledge transfer from the research community to clinicians, especially on topics of patient safety. PMID- 29383837 TI - Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities. AB - Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability. PMID- 29383838 TI - Response to 'The evolving mystery of why skeletal muscle is spared in seropositive neuromyelitis optica'. PMID- 29383840 TI - Addressing unmeasured confounding in comparative observational research. AB - PURPOSE: Observational pharmacoepidemiological studies can provide valuable information on the effectiveness or safety of interventions in the real world, but one major challenge is the existence of unmeasured confounder(s). While many analytical methods have been developed for dealing with this challenge, they appear under-utilized, perhaps due to the complexity and varied requirements for implementation. Thus, there is an unmet need to improve understanding the appropriate course of action to address unmeasured confounding under a variety of research scenarios. METHODS: We implemented a stepwise search strategy to find articles discussing the assessment of unmeasured confounding in electronic literature databases. Identified publications were reviewed and characterized by the applicable research settings and information requirements required for implementing each method. We further used this information to develop a best practice recommendation to help guide the selection of appropriate analytical methods for assessing the potential impact of unmeasured confounding. RESULTS: Over 100 papers were reviewed, and 15 methods were identified. We used a flowchart to illustrate the best practice recommendation which was driven by 2 critical components: (1) availability of information on the unmeasured confounders; and (2) goals of the unmeasured confounding assessment. Key factors for implementation of each method were summarized in a checklist to provide further assistance to researchers for implementing these methods. CONCLUSION: When assessing comparative effectiveness or safety in observational research, the impact of unmeasured confounding should not be ignored. Instead, we suggest quantitatively evaluating the impact of unmeasured confounding and provided a best practice recommendation for selecting appropriate analytical methods. PMID- 29383839 TI - Interplay between Trx-1 and S100P promotes colorectal cancer cell epithelial mesenchymal transition by up-regulating S100A4 through AKT activation. AB - We previously reported a novel positive feedback loop between thioredoxin-1 (Trx 1) and S100P, which promotes the invasion and metastasis of colorectal cancer (CRC). However, the underlying molecular mechanisms remain poorly understood. In this study, we examined the roles of Trx-1 and S100P in CRC epithelial-to mesenchymal transition (EMT) and their underlying mechanisms. We observed that knockdown of Trx-1 or S100P in SW620 cells inhibited EMT, whereas overexpression of Trx-1 or S100P in SW480 cells promoted EMT. Importantly, S100A4 and the phosphorylation of AKT were identified as potential downstream targets of Trx-1 and S100P in CRC cells. Silencing S100A4 or inhibition of AKT phosphorylation eliminated S100P- or Trx-1-mediated CRC cell EMT, migration and invasion. Moreover, inhibition of AKT activity reversed S100P- or Trx-1-induced S100A4 expression. The expression of S100A4 was higher in human CRC tissues compared with their normal counterpart tissues and was significantly correlated with lymph node metastasis and poor survival. The overexpression of S100A4 protein was also positively correlated with S100P or Trx-1 protein overexpression in our cohort of CRC tissues. In addition, overexpression of S100P reversed the Trx-1 knockdown induced inhibition of S100A4 expression, EMT and migration and invasion in SW620 cells. The data suggest that interplay between Trx-1 and S100P promoted CRC EMT as well as migration and invasion by up-regulating S100A4 through AKT activation, thus providing further potential therapeutic targets for suppressing the EMT in metastatic CRC. PMID- 29383841 TI - Magnetic separation coupled with high-performance liquid chromatography-mass spectrometry for rapid separation and determination of lignans in Schisandra chinensis. AB - Despite the strong antihepatotoxic, antioxidant, and antitumor properties of lignans from Schisandra chinensis, their applications in new drug development, bioscience and functional foods, etc. are limited because of their low abundance and complex coextractions. In this study, a magnetic separation method has been developed based on polyethylenimine-modified magnetic nanoparticles to rapidly and effectively separate and purify the lignans from S. chinensis crude extracts through cation-pi interaction and electrostatic adsorption. The magnetic nanoparticles were characterized by transmission electron microscopy, vibrating sample magnetometry, Fourier transform infrared spectroscopy, and X-ray diffraction. Polyethylenimine-modified magnetic nanoparticles showed a spherical shaped morphology and the average size was about 10 nm with superparamagnetism. Under the pH 7.4, polyethylenimine modified magnetic nanoparticles can remove a lot of coextracts. The range of detection limits and quantification limits was 0.27-0.34 and 0.89-1.13 ng/mL, respectively. Compared with other common methods, the magnetic separation method proposed in this study is much simpler and more effective through both strong cation-pi interaction and electrostatic interaction. PMID- 29383842 TI - A new mutation in the C-terminal end of TTC37 leading to a mild form of syndromic diarrhea/tricho-hepato-enteric syndrome in seven patients from two families. AB - Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital enteropathy with seven main clinical features: intractable diarrhea of infancy, hair abnormalities, intrauterine growth restriction (IUGR), facial dysmorphism, immune dysfunction, and liver and skin abnormalities. SD/THE is caused by mutations in TTC37 or SKIV2L, two genes encoding components of the human SKI complex. To date, approximately 50 SD/THE patients have been described with a wide spectrum of mutations, and only one recurrent mutation has been identified in independent families. We present a detailed description of seven patients of Turkish origin with the same new mutation in TTC37: c.4572 G>A p.(Trp1524X). All seven patients were homozygous for this mutation and presented the typical clinical features of SD/THE, but with a milder presentation than usual. All seven patients were alive at the last follow-up. Four out of seven patients had no IUGR, and four patients never required parenteral nutrition. All patients presented a better growth rate than previously described in patients with SD/THE, with 4/7 above the 3rd percentile. The mutation is localized only forty amino acids from the end of TTC37, and as TTC37 is longer than the yeast SKI3, it is possible that a truncated protein is expressed and plays a reduced role in the SKI complex. PMID- 29383845 TI - Flexible Transparent and Free-Standing SiC Nanowires Fabric: Stretchable UV Absorber and Fast-Response UV-A Detector. AB - Transparent and flexible materials are desired for the construction of photoelectric multifunctional integrated devices and portable electronics. Herein, 2H-SiC nanowires are assembled into a flexible, transparent, self standing nanowire fabric (FTS-NWsF). The as-synthesized ultralong nanowires form high-quality crystals with a few stacking faults. The optical transmission spectra reveal that FTS-NWsF absorbs most incident 200-400 nm light, but remains transparent to visible light. A polydimethylsiloxane (PDMS)-SiC fabric-PDMS sandwich film device exhibits stable electrical output even when repeatedly stretched by up to 50%. Unlike previous SiC nanowires in which stacking faults are prevalent, the transparent, stretchable SiC fabric shows considerable photoelectric activity and exhibits a rapid photoresponse (rise and decay time < 30 ms) to 340-400 nm light, covering most of the UV-A spectral region. These advances represent significant progress in the design of functional optoelectronic SiC nanowires and transparent and stretchable optoelectronic systems. PMID- 29383846 TI - Modeling and predicting chiral stationary phase enantioselectivity: An efficient random forest classifier using an optimally balanced training dataset and an aggregation strategy. AB - Predicting whether a chiral column will be effective is a daily task for many analysts. Moreover, finding the best chiral column for separating a particular racemic compound is mostly a matter of trial and error that may take up to a week in some cases. In this study we have developed a novel prediction approach based on combining a random forest classifier and an optimized discretization method for dealing with enantioselectivity as a continuous variable. Using the optimization results, models were trained on data sets divided into four enantioselectivity classes. The best model performances were achieved by over sampling the minority classes (alpha <= 1.10 and alpha >= 2.00), down-sampling the majority class (1.2 <= alpha < 2.0), and aggregating multicategory predictions into binary classifications. We tested our method on 41 chiral stationary phases using layered fingerprints as descriptors. Experimental results show that this learning methodology was successful in terms of average area under the Receiver Operating Characteristic curve, Kappa indices and F-measure for structure-based prediction of the enantioselective behavior of 34 chiral columns. PMID- 29383843 TI - Efficacy and safety of sunitinib alternate day regimen in patients with metastatic renal cell carcinoma in Japan: Comparison with standard 4/2 schedule. AB - AIM: Sunitinib is a standard agent for metastatic renal cell carcinoma (mRCC). The standard schedule, 4 weeks-on followed by 2 weeks-off (4/2 schedule), often does not maintain an adequate dosage because of the severe adverse events (AEs). We compared the efficacy and safety of an alternative every other day (q.a.d.) dosing with that of the 4/2 schedule in mRCC patients. METHODS: Of the 55 Japanese patients, 32 and 23 were administered 4/2 (standard group) and q.a.d. schedules (50 or 37.5 mg, every other day; experimental groups), respectively. The AEs, anticancer effects, and trough plasma concentrations of sunitinib were compared between them. RESULTS: The most common AE in the standard group was thrombocytopenia (43.2%), but it was observed in only two patients in the experimental group (8.7%). Although leukopenia and hand-foot syndrome were both detected in six patients (18.8%) in the standard group, no patients had these AEs in the experimental group. The incidence of dose interruption in the experimental group (21.7%) was significantly lower than that in the standard group was (59.4%, P = 0.005). Time to progression (TTP) and overall survival (OS) of the experimental group were better than those of the standard group (P < 0.001 and P = 0.002, respectively). Mean plasma levels in the experimental group (64.83 ng/mL) were significantly lower than those in the standard group (135.82 ng/mL, P < 0.001) were. CONCLUSION: Sunitinib administered q.a.d. was safe and effective for mRCC patients. We speculate that the persistent optimal drug plasma concentrations contributed to these effects. PMID- 29383847 TI - Growth pattern of Rahman syndrome. AB - Recently, in a cohort study with "overgrowth syndrome with intellectual disability," five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This "lack of overgrowth in overgrowth syndrome" is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome. PMID- 29383848 TI - Higher Ca2+ -sensitivity of arterial contraction in 1-week-old rats is due to a greater Rho-kinase activity. AB - AIM: During early post-natal development, arterial contraction depends less on Ca2+ -signalling pathways but more on changes in Ca2+ -sensitivity compared to adult animals. Whether this difference is related to Rho-kinase, one of the major players affecting Ca2+ -sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca2+ sensitivity of contraction in intact arteries of 1-week-old rats. METHODS: We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca2+ -fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia. RESULTS: In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in [Ca2+ ]i and Ca2+ -sensitivity. In contrast, in 1 week-old rats these contractions were accompanied only by an increase in Ca2+ sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y 27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1 week-old rats. CONCLUSION: Our results suggest that the higher Ca2+ -sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses. PMID- 29383849 TI - Interfacial Generation of a Carbanion: The Key Step of PTC Reaction Directly Observed by Second Harmonic Generation. AB - We present the first unambiguous evidence of the interfacial mechanism of phase transfer catalysis (PTC) by direct observation of the formation of carbanions in the interfacial region between the aqueous and the organic phase by using a surface-sensitive spectroscopic method known as second harmonic generation (SHG). Ion exchange of carbanions adsorbed at the surface after addition of lipophilic tetraalkylammonium salts (TAA) to organic phase and transport of the lipophilic ion-pairs to the organic phase is observed. Results allow for the formulation of a more detailed mechanism of PTC. PMID- 29383850 TI - Adoptive transfer of CD3+ T cells and CD4+ CD44high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice. AB - The immunopathogenesis of autoimmune pancreatitis (AIP) is poorly understood. Here, we have used MRL/MpJ mice, a model of spontaneous AIP, to address the role of cellular autoimmune processes in the initiation and progression of the disease. Therefore, different T cell subpopulations were adoptively transferred from sick to still healthy (but susceptible) MRL/MpJ mice. Unpurified splenocytes and CD3+ T cells both efficiently induced AIP, while CD4+ and CD8+ T cells alone, as well as splenocytes from healthy mice, were insufficient to trigger the disease. Strikingly, CD4+ CD44high memory T cells, although transferred at lower numbers than other T cells, also induced AIP in recipient mice. Employing a modified experimental design, we also evaluated the effects of regulatory T cells (Tregs ) on the progression of AIP in already diseased mice. Under the given experimental conditions, there was no significant suppressive effect of adoptively transferred Tregs on pancreatic histopathology. The results of our studies suggest a key role of T cell-mediated processes in murine AIP. The effects of CD4+ CD44high memory T cells are in accordance with genetic studies of our group, which had previously implicated this cell type into the pathogenesis of AIP. In follow-up studies, we will focus on the interplay of cellular and humoral autoimmunity in the context of AIP. PMID- 29383851 TI - Chromogenic Photonic Crystal Sensors Enabled by Multistimuli-Responsive Shape Memory Polymers. AB - Here novel chromogenic photonic crystal sensors based on smart shape memory polymers (SMPs) comprising polyester/polyether-based urethane acrylates blended with tripropylene glycol diacrylate are reported, which exhibit nontraditional all-room-temperature shape memory (SM) effects. Stepwise recovery of the collapsed macropores with 350 nm diameter created by a "cold" programming process leads to easily perceived color changes that can be correlated with the concentrations of swelling analytes in complex, multicomponent nonswelling mixtures. High sensitivity (as low as 10 ppm) and unprecedented measurement range (from 10 ppm to 30 vol%) for analyzing ethanol in octane and gasoline have been demonstrated by leveraging colorimetric sensing in both liquid and gas phases. Proof-of-concept tests for specifically detecting ethanol in consumer medical and healthcare products have also been demonstrated. These sensors are inexpensive, reusable, durable, and readily deployable with mobile platforms for quantitative analysis. Additionally, theoretical modeling of solvent diffusion in macroporous SMPs provides fundamental insights into the mechanisms of nanoscopic SM recovery, which is a topic that has received little examination. These novel sensors are of great technological importance in a wide spectrum of applications ranging from environmental monitoring and workplace hazard identification to threat detection and process/product control in chemical, petroleum, and pharmaceutical industries. PMID- 29383852 TI - Building a developmental toxicity ontology. AB - BACKGROUND: As more information is generated about modes of action for developmental toxicity and more data are generated using high-throughput and high content technologies, it is becoming necessary to organize that information. This report discussed the need for a systematic representation of knowledge about developmental toxicity (i.e., an ontology) and proposes a method to build one based on knowledge of developmental biology and mode of action/ adverse outcome pathways in developmental toxicity. METHODS: This report is the result of a consensus working group developing a plan to create an ontology for developmental toxicity that spans multiple levels of biological organization. RESULTS: This report provide a description of some of the challenges in building a developmental toxicity ontology and outlines a proposed methodology to meet those challenges. As the ontology is built on currently available web-based resources, a review of these resources is provided. Case studies on one of the most well understood morphogens and developmental toxicants, retinoic acid, are presented as examples of how such an ontology might be developed. DISCUSSION: This report outlines an approach to construct a developmental toxicity ontology. Such an ontology will facilitate computer-based prediction of substances likely to induce human developmental toxicity. PMID- 29383854 TI - Core-Shell Nitrogen-Doped Carbon Hollow Spheres/Co3 O4 Nanosheets as Advanced Electrode for High-Performance Supercapacitor. AB - Co3 O4 /nitrogen-doped carbon hollow spheres (Co3 O4 /NHCSs) with hierarchical structures are synthesized by virtue of a hydrothermal method and subsequent calcination treatment. NHCSs, as a hard template, can aid the generation of Co3 O4 nanosheets on its surface; while SiO2 spheres, as a sacrificed-template, can be dissolved in the process. The prepared Co3 O4 /NHCS composites are investigated as the electrode active material. This composite exhibits an enhanced performance than Co3 O4 itself. A higher specific capacitance of 581 F g 1 at 1 A g-1 and a higher rate performance of 91.6% retention at 20 A g-1 are achieved, better than Co3 O4 nanorods (318 F g-1 at 1 A g-1 and 67.1% retention at 20 A g-1 ). In addition, the composite is employed as a positive electrode to fabricate an asymmetric supercapacitor. The device can deliver a high energy density of 34.5 Wh kg-1 at the power density of 753 W kg-1 and display a desirable cycling stability. All of these attractive results make the unique hierarchical Co3 O4 /NHCS core-shell structure a promising electrode material for high-performance supercapacitors. PMID- 29383853 TI - A toolkit for studying cellular reorganization during early embryogenesis in Arabidopsis thaliana. AB - Considerable progress has been made in understanding the influence of physical and genetic factors on the patterns of cell division in various model systems. However, how each of these factors directs changes in subcellular structures has remained unclear. Generic machineries for the execution of cell expansion and division have been characterized, but how these are influenced by genetic regulators and physical cell properties remains an open question. To a large degree, the complexity of growing post-embryonic tissues and a lack of precise predictability have prevented the extraction of rigid correlations between subcellular structures and future orientation of cell division. The Arabidopsis embryo offers an exquisitely predictable and simple model for studying such correlations, but so far the tools and methodology for studying subcellular structures in the early embryo have been lacking. Here, we describe a set of markers to visualize a range of subcellular structures in the early Arabidopsis embryo. We have designed a series of fluorescent cellular reporters optimized for embryos, and demonstrate the effectiveness of using these 'ACE' reporters with simple three-dimensional imaging procedures that preserve delicate cellular structures. We describe the ontogeny of subcellular structures in the early embryo and find that central/peripheral cell polarity is established much earlier than suspected. In addition, we show that the actin and microtubule cytoskeleton has distinct topologies in the embryo. These tools and methods will allow detailed analysis of the events of cellular reorganization that underlie morphogenesis in the Arabidopsis embryo. PMID- 29383855 TI - Therapeutic applications of group I intron-based trans-splicing ribozymes. AB - Since the breakthrough discovery of catalytic RNAs (ribozymes) in the early 1980s, valuable ribozyme-based gene therapies have been developed for incurable diseases ranging from genetic disorders to viral infections and cancers. Ribozymes can be engineered and used to downregulate or repair pathogenic genes via RNA cleavage mediated by trans-cleaving ribozymes or repair and reprograming mediated by trans-splicing ribozymes, respectively. Uniquely, trans-splicing ribozymes can edit target RNAs via simultaneous destruction and repair (and/or reprograming) to yield the desired therapeutic RNAs, thus selectively inducing therapeutic gene activity in cells expressing the target RNAs. In contrast to traditional gene therapy approaches, such as simple addition of therapeutic transgenes or inhibition of disease-causing genes, the selective repair and/or reprograming abilities of trans-splicing ribozymes in target RNA-expressing cells facilitates the maintenance of endogenous spatial and temporal gene regulation and reduction of disease-associated transcript expression. In molecular imaging technologies, trans-splicing ribozymes can be used to reprogram specific RNAs in living cells and organisms by the 3'-tagging of reporter RNAs. The past two decades have seen progressive improvements in trans-splicing ribozymes and the successful application of these elements in gene therapy and molecular imaging approaches for various pathogenic conditions, such as genetic, infectious, and malignant disease. This review provides an overview of the current status of trans-splicing ribozyme therapeutics, focusing on Tetrahymena group I intron based ribozymes, and their future prospects. This article is categorized under: RNA in Disease and Development > RNA in Disease. PMID- 29383856 TI - Detecting the Presence of Bacterial DNA and RNA by Polymerase Chain Reaction to Diagnose Suspected Periprosthetic Joint Infection after Antibiotic Therapy. AB - OBJECTIVE: To explore the diagnostic efficiency of DNA-based and RNA-based quantitative polymerase chain reaction (qPCR) analyses for periprosthetic joint infection (PJI). METHODS: To determine the detection limit of DNA-based and RNA based qPCR in vitro, Staphylococcus aureus and Escherichia coli strains were added to sterile synovial fluid obtained from a patient with knee osteoarthritis. Serial dilutions of samples were analyzed by DNA-based and RNA-based qPCR. Clinically, patients who were suspected of having PJI and eventually underwent revision arthroplasty in our hospital from July 2014 to December 2016 were screened. Preoperative puncture or intraoperative collection was performed on patients who met the inclusion and exclusion criteria to obtain synovial fluid. DNA-based and RNA-based PCR analyses and culture were performed on each synovial fluid sample. The patients' demographic characteristics, medical history, and laboratory test results were recorded. The diagnostic efficiency of both PCR assays was compared with culture methods. RESULTS: The in vitro analysis demonstrated that DNA-based qPCR assay was highly sensitive, with the detection limit being 1200 colony forming units (CFU)/mL of S. aureus and 3200 CFU/mL of E. coli. Meanwhile, The RNA-based qPCR assay could detect 2300 CFU/mL of S. aureus and 11 000 CFU/mL of E. coli. Clinically, the sensitivity, specificity, and accuracy were 65.7%, 100%, and 81.6%, respectively, for the culture method; 81.5%, 84.8%, and 83.1%, respectively, for DNA-based qPCR; and 73.6%, 100%, and 85.9%, respectively, for RNA-based qPCR. CONCLUSIONS: DNA-based qPCR could detect suspected PJI with high sensitivity after antibiotic therapy. RNA-based qPCR could reduce the false positive rates of DNA-based assays. qPCR-based methods could improve the efficiency of PJI diagnosis. PMID- 29383857 TI - Physical Polyurethane Hydrogels via Charge Shielding through Acids or Salts. AB - Physical hydrogels with tunable stress-relaxation and excellent stress recovery are formed from anionic polyurethanes via addition of acids, monovalent salts, or divalent salts. Gel properties can be widely adjusted through pH, salt valence, salt concentration, and monomer composition. We propose and investigate a novel gelation mechanism based on a colloidal system interacting through charge repulsion and chrage shielding, allowing a broad use of the material, from acidic (pH 4-5.5) to pH-neutral hydrogels with Young's moduli ranging from 10 to 140 kPa. PMID- 29383858 TI - Generalized boosted modeling to identify subgroups where effect of dabigatran versus warfarin may differ: An observational cohort study of patients with atrial fibrillation. AB - PURPOSE: To explore generalized boosted modeling (GBM) as a method for identifying subgroups with greater benefit or harm with dabigatran versus warfarin for treatment of atrial fibrillation. METHODS: We identified new initiators of warfarin or dabigatran with nonvalvular atrial fibrillation in 2 healthcare claims databases (2009-2013) and used GBM within 1 data source (development cohort) to explore subgroups where their effect on thromboembolism and major bleeding may differ. Identified subgroups were evaluated in the second data source (validation cohort) with stabilized-inverse-probability-of-treatment weights to adjust for confounding. RESULTS: Development and validation cohorts included 13 624 (28% dabigatran) and 62 596 (29% dabigatran) initiators, respectively. In development data, the strongest exposure interactions were prior thromboembolism and renal disease. In validation data, reduction in thromboembolism with dabigatran was greater for patients with versus without a history of thromboembolism by 2.8 (95% CI, -0.5 to 5.4) events per 100 patient years. Major bleeding was reduced by 1.6/100 patient-years for dabigatran compared to warfarin initiators, without evidence of variation by renal disease. CONCLUSIONS: We explored use of GBM to identify potential subgroups with different treatment effect. Dabigatran's superiority to warfarin at prevention of thromboembolism may be greater in secondary than primary prevention. In practice, secondary prevention patients are more often treated with warfarin. PMID- 29383859 TI - Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15. AB - Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF kappaB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects. PMID- 29383860 TI - Risk of stroke and bleeding in patients with heart failure and chronic kidney disease: a nationwide cohort study. AB - AIMS: The aim of this study was to assess the prognostic value of chronic kidney disease (CKD) in relation to ischaemic stroke, intracranial haemorrhage, major bleeding, and all-cause death in heart failure patients without atrial fibrillation. METHODS AND RESULTS: In this observational cohort study, heart failure patients without atrial fibrillation were identified using Danish nationwide registries. Risk of stroke, major haemorrhage, and death were calculated after 1 and 5 years to compare patients with and without CKD, +/ dialysis [dialysis: CKD with renal replacement therapy (CKD-RRT); no dialysis: CKD-no RRT]. A total of 43 199 heart failure patients were included, among which 0.8% had CKD-RRT and 5.9% had CKD-no RRT. When compared with heart failure patients without CKD, both CKD-RRT and CKD-no RRT were associated with a higher 5 year rate of major bleeding (CKD-RRT: adjusted hazard ratio (aHR): 2.91, 95% confidence interval (CI): 2.29 to 3.70; CKD-no RRT: aHR: 1.28, 95% CI: 1.13 to 1.45) and all-cause death (CKD-RRT: aHR: 2.40, 95% CI: 2.07 to 2.77; CKD-no RRT: aHR: 1.63, 95% CI: 1.55 to 1.73). For the endpoints of ischaemic stroke and intracranial bleeding, only CKD-no RRT was associated with significantly higher 5 year rates (ischaemic stroke: aHR: 1.31, 95% CI: 1.13 to 1.52; intracranial haemorrhage: aHR: 1.66, 95% CI: 1.04 to 2.65). CONCLUSIONS: Compared with patients without CKD, among incident heart failure patients without atrial fibrillation, CKD both with and without dialysis was associated with a higher rate of major bleeding and all-cause death. Only CKD-no RRT was associated with a higher rate of ischaemic stroke and intracranial bleeding. PMID- 29383861 TI - Functional requirement for human pitrilysin metallopeptidase 1 arginine 183, mutated in amyloidogenic neuropathy. AB - Here we report the enzymologic characterization of recombinant human pitrilysin metallopeptidase 1 (Pitrm1) and derivative mutants including the arginine-to glutamine substitution mutant Pitrm1 R183Q, which has been implicated in inherited amyloidogenic neuropathy. Recombinant Pitrm1 R183Q was readily expressed in and purified from Escherichia coli, but was less active than the recombinant wild-type enzyme against recombinant amyloid beta-peptide (Abeta 1 40). A novel fluorogenic substrate derived from the reported Abeta 1-40 core peptide cleavage sequence, Mca-KLVFFAEDK-(Dnp)-OH, was synthesized and applied to real-time kinetic study of Pitrm1 and derivative mutants including Pitrm1 R183Q. The Pitrm1 R183Q mutant exhibited significantly decreased rate of fluorogenic peptide hydrolysis, yet retained similar binding affinity by comparison with the wild-type enzyme. Targeted mutagenic analysis revealed a functional requirement for uncharged or electropositive residues in place of Pitrm1 R183. Residue R183 is positioned within an N-terminal strand-loop-strand motif that is conserved among M16C, but not M16A or M16B family metallopeptidases. Truncation analysis revealed that this strand-loop-strand motif inclusive of residue R183 is essential Pitrm1 function. A requirement for charged residues within 4.5 A of residue R183 was demonstrated, and Pitrm1 R183Q was found to exhibit increased sensitivity to heat inactivation. Our findings indicate that charge sharing in the vicinity of Pitrm1 R183 is critical to enzyme activity, providing potential insight into a molecular basis of Pitrm1 dysfunction. PMID- 29383862 TI - Comparing human and mouse salivary glands: A practice guide for salivary researchers. AB - Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many ways to human salivary glands (i.e., in terms of their anatomy, histology, and physiology) and are both readily available and relatively easy and affordable to maintain. However, there are some significant differences between the two organisms, and by extension, the salivary glands derived from them must be taken into account for translational studies. The current review details pertinent similarities and differences between human and mouse salivary glands and offers practical guidelines for using both for research purposes. PMID- 29383863 TI - Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience. AB - Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1-57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen. PMID- 29383864 TI - Local barriers to optimal pediatric kidney transplantation. PMID- 29383865 TI - Fisetin induces apoptosis through mitochondrial apoptosis pathway in human uveal melanoma cells. AB - Fisetin, a diatery flavonoid, been reported that possess anticancer effects in various cancers. The purpose of the study was to investigate the antitumor effects of fisetin in cultured uveal melanoma cell lines and compared with normal retinal pigment epithelial (RPE) cells. MTT assay was used for evaluating cytotoxic effects of fisetin. Flow cytometry study was used for the determination of apoptosis. JC-1 fluorescent reader was used to determine mitochondrial transmembrane potential changes. The results shown that fisetin dose-dependently decreased the cell viability of uveal melanoma cells but not influenced the cell viability of RPE cells. Apoptosis of uveal melanoma cells was induced by fisetin efficiently. Fisetin inhibited antiapoptotic Bcl-2 family proteins and damaged the mitochondrial transmembrane potential. The levels of proapoptotic Bcl-2 proteins, cytochrome c, and various caspase activities were increased by fisetin. In conclusion, fisetin induces apoptosis of uveal melanoma cells selectively and may be a promising agent to be explored for the treatment of uveal melanoma. PMID- 29383866 TI - Light-Driven Water Splitting Mediated by Photogenerated Bromine. AB - Light-driven water splitting was achieved using a dye-sensitized mesoporous oxide film and the oxidation of bromide (Br- ) to bromine (Br2 ) or tribromide (Br3- ). The chemical oxidant (Br2 or Br3- ) is formed during illumination at the photoanode and used as a sacrificial oxidant to drive a water oxidation catalyst (WOC), here demonstrated using [Ru(bda)(pic)2 ], (1; pic=picoline, bda=2,2' bipyridine-6,6'-dicarboxylate). The photochemical oxidation of bromide produces a chemical oxidant with a potential of 1.09 V vs. NHE for the Br2 /Br- couple or 1.05 V vs. NHE for the Br3- /Br- couple, which is sufficient to drive water oxidation at 1 (RuV/IV ~1.0 V vs. NHE at pH 5.6). At pH 5.6, using a 0.2 m acetate buffer containing 40 mm LiBr and the [Ru(4,4'-PO3 H2 -bpy)(bpy)2 ]2+ (RuP2+ , bpy=2,2'-bipyridine) chromophore dye on a SnO2 /TiO2 core-shell electrode resulted in a photocurrent density of around 1.2 mA cm-2 under approximately 1 Sun illumination and a Faradaic efficiency upon addition of 1 of 77 % for oxygen evolution. PMID- 29383867 TI - Human-simulation-based learning to prevent medication error: A systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: In the past 2 decades, there has been an increasing interest in simulation-based learning programs to prevent medication error (ME). To improve knowledge, skills, and attitudes in prescribers, nurses, and pharmaceutical staff, these methods enable training without directly involving patients. However, best practices for simulation for healthcare providers are as yet undefined. By analysing the current state of experience in the field, the present review aims to assess whether human simulation in healthcare helps to reduce ME. METHODS: A systematic review was conducted on Medline from 2000 to June 2015, associating the terms "Patient Simulation," "Medication Errors," and "Simulation Healthcare." Reports of technology-based simulation were excluded, to focus exclusively on human simulation in nontechnical skills learning. RESULTS: Twenty-one studies assessing simulation based learning programs were selected, focusing on pharmacy, medicine or nursing students, or concerning programs aimed at reducing administration or preparation errors, managing crises, or learning communication skills for healthcare professionals. The studies varied in design, methodology, and assessment criteria. Few demonstrated that simulation was more effective than didactic learning in reducing ME. This review highlights a lack of long-term assessment and real-life extrapolation, with limited scenarios and participant samples. These various experiences, however, help in identifying the key elements required for an effective human simulation-based learning program for ME prevention: ie, scenario design, debriefing, and perception assessment. The performance of these programs depends on their ability to reflect reality and on professional guidance. CONCLUSION: Properly regulated simulation is a good way to train staff in events that happen only exceptionally, as well as in standard daily activities. By integrating human factors, simulation seems to be effective in preventing iatrogenic risk related to ME, if the program is well designed. PMID- 29383868 TI - Impact of testosterone replacement therapy on thromboembolism, heart disease and obstructive sleep apnoea in men. AB - OBJECTIVES: To assess the association of testosterone replacement therapy (TRT) with thromboembolism, cardiovascular disease (stroke, coronary artery disease and heart failure) and obstructive sleep apnoea (OSA). METHODS: A cohort of 3 422 male US military service members, retirees and their dependents, aged 40-64 years, was identified, who were prescribed TRT between 2006 and 2010 for low testosterone levels. The men in this cohort were matched on a 1:1 basis for age and comorbidities to men without a prescription for TRT. Event-free survival and rates of thromboembolism, cardiovascular events and OSA were compared between men using TRT and the control group, with a median follow-up of 17 months. RESULTS: There was no difference in event-free survival with regard to thromboembolism (P = 0.239). Relative to controls, men using TRT had improved cardiovascular event free survival (P = 0.004), mainly as a result of lower incidence of coronary artery disease (P = 0.008). The risk of OSA was higher in TRT users (2-year risk 16.5% [95% confidence interval 15.1-18.1] in the TRT group vs 12.7% [11.4-14.1] in the control group. CONCLUSIONS: This study adds to growing evidence that the cardiovascular risk associated with TRT may be lower than once feared. The elevated risk of OSA in men using TRT is noteworthy. PMID- 29383869 TI - Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. AB - Administration of metformin increases healthspan and lifespan in model systems, and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70-year-old participants (n = 14) in a randomized, double blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed-meal challenge test was performed. As expected, metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and nonmetabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR and SREBP signaling, mitochondrial fatty acid oxidation, and collagen trimerization in adipose. While each tissue had a signature reflecting its own function, we identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFbeta1, and miRNA-29b that may explain tissue-specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and nonmetabolic effects linked to aging. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways. PMID- 29383870 TI - The beer and biofuels laboratory: A report on implementing and supporting a large, interdisciplinary, yeast-focused course-based undergraduate research experience. AB - Course-integrated Undergraduate Research Experiences (CUREs) involve large numbers of students in real research. We describe a late-year microbiology CURE in which students use yeast to address a research question around beer brewing or synthesizing biofuel; the interdisciplinary student-designed project incorporates genetics, bioinformatics, biochemistry, analytical chemistry, and microbiology. Students perceived significant learning gains around multiple technical and "becoming a scientist" aspects of the project. The project is demanding for both the students and the academic implementers. We examine the rich landscape of support and interaction that this CURE both encourages and requires while also considering how we can support the exercise better and more sustainably. The findings from this study provide a picture of a CURE implementation that has begun to reach the limits of both the students' and the academics' capacities to complete it. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):213-222, 2018. PMID- 29383871 TI - Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non cardiac surgery: an observational cohort study. AB - : Essentials An increasing number of patients requiring surgery receive antiplatelet therapy (APT). We analyzed 181 patients receiving presurgery platelet transfusions to reverse APT. No coronary thrombosis occurred after platelet transfusion. This justifies a prospective trial to test preoperative platelet transfusions to reverse APT. SUMMARY: Background Patients receiving antiplatelet therapy (APT) have an increased risk of perioperative bleeding and cardiac adverse events (CAE). Preoperative platelet transfusions may reduce the bleeding risk but may also increase the risk of CAE, particularly coronary thrombosis in patients after recent stent implantation. Objectives To analyze the incidence of perioperative CAE and bleeding in patients undergoing non-cardiac surgery using a standardized management of transfusing two platelet concentrates preoperatively and restart of APT within 24-72 h after surgery. Methods A cohort of consecutive patients on APT treated with two platelet concentrates before non cardiac surgery between January 2012 and December 2014 was retrospectively identified. Patients were stratified by the risk of major adverse cardiac and cerebrovascular events (MACCE). The primary objective was the incidence of CAE (myocardial infarction, acute heart failure and cardiac troponine T increase). Secondary objectives were incidences of other thromboembolic events, bleedings, transfusions and mortality. Results Among 181 patients, 88 received aspirin, 21 clopidogrel and 72 dual APT. MACCE risk was high in 63, moderate in 103 and low in 15 patients; 67 had cardiac stents. Ten patients (5.5%; 95% CI, 3.0-9.9%) developed a CAE (three myocardial infarctions, four cardiac failures and three troponin T increases). None was caused by coronary thrombosis. Surgery-related bleeding occurred in 22 patients (12.2%; 95% CI, 8.2-17.7%), making 12 re interventions necessary (6.6%; 95% CI, 3.8-11.2%). Conclusion Preoperative platelet transfusions and early restart of APT allowed urgent surgery and did not cause coronary thromboses, but non-thrombotic CAEs and re-bleeding occurred. Randomized trials are warranted to test platelet transfusion against other management strategies. PMID- 29383872 TI - Novel Transparent and Self-Powered UV Photodetector Based on Crossed ZnO Nanofiber Array Homojunction. AB - A novel self-powered UV photodetector based on electrospun ZnO nanofiber arrays is introduced. Aligned pure ZnO nanofibers and Ag-doped p-type ZnO nanofibers are processed perpendicular to each other, and p-n junction arrays of ZnO nanofibers are fabricated as a result. Owing to the intrinsic intervals between nanofibers, the device is fully transparent on quartz substrate. Various characterization methods including TEM, XRD, and XPS are used to testify the existence form of Ag element in ZnO nanofibers, and a field effect transistor is constructed to judge their conductivity. It is discovered that the Ag doping process not only transforms ZnO to p-type conductivity, making it possible to build this self powered photodetector, but also forms Ag nanoparticles in ZnO nanofibers and thus helps reduce the response time. Benefiting from the abovementioned dual effects, this UV detector is found to have an enhanced performance, with the on-off ratio up to 104 at zero bias and a rather short rise/decay time of 3.90 s/4.71 s. PMID- 29383873 TI - Supporting international graduates to success. PMID- 29383874 TI - Synovial fibroblast-targeting liposomes encapsulating an NF-kappaB-blocking peptide ameliorates zymosan-induced synovial inflammation. AB - Synovial fibroblasts (SFs) play a crucial role in the inflammatory process of rheumatoid arthritis (RA). The highly activated NF-kappaB signal in SFs is responsible for most of the synovial inflammation associated with this disease. In this study, we have developed an SF-targeting liposomal system that encapsulates the NF-kappaB-blocking peptide (NBD peptide) HAP-lipo/NBD. HAP lipo/NBDs demonstrated efficient SF-specific targeting in vitro and in vivo. Our study also showed a significant inhibitory effect of HAP-lipo/NBD on NF-kappaB activation, inflammatory cytokine release and SF migration capability after zymosan stimulation. Furthermore, the systemic administration of HAP-lipo/NBDs significantly inhibited synovial inflammation and improved the pathological scores of arthritis induced by zymosan. Thus, these results suggest that an SF targeting NF-kappaB-blocking strategy is a potential approach for the development of alternative, targeted anti-RA therapies. PMID- 29383875 TI - Multiple roles of Ring 1 and YY1 binding protein in physiology and disease. AB - Ring 1 and YY1 binding protein (RYBP) was first identified in 1999, and its structure includes a conserved Npl4 Zinc finger motif at the N-terminus, a central region that is characteristically enriched with arginine and lysine residues and a C-terminal region enriched with serine and threonine amino acids. Over nearly 20 years, multiple studies have found that RYBP functions as an organ developmental adaptor. There is also evidence that RYBP regulates the expression of different genes involved in various aspects of biological processes, via a mechanism that is dependent on interactions with components of PcG complexes and/or through binding to different transcriptional factors. In addition, RYBP interacts directly or indirectly with apoptosis-associated proteins to mediate anti-apoptotic or pro-apoptotic activity in both the cytoplasm and nucleus of various cell types. Furthermore, RYBP has also been shown to act as tumour suppressor gene in different solid tumours, but as an oncogene in lymphoma and melanoma. In this review, we summarize our current understanding of the functions of this multifaceted RYBP in physiological and pathological conditions, including embryonic development, apoptosis and cancer, as well as its role as a component of polycomb repressive complex 1. PMID- 29383877 TI - Medical Student Resilience: a symposium approach. PMID- 29383876 TI - Histone Methyltransferase Setd7 Regulates Nrf2 Signaling Pathway by Phenethyl Isothiocyanate and Ursolic Acid in Human Prostate Cancer Cells. AB - SCOPE: This study aims to investigate the role of the epigenetic regulator SET domain-containing lysine methyltransferase 7 (Setd7) in regulating the antioxidant Nrf2 pathway in prostate cancer (PCa) cells and examines the effects of two phytochemicals, phenethyl isothiocyanate (PEITC) and ursolic acid (UA). METHODS AND RESULTS: Lentivirus-mediated shRNA knockdown of Setd7 in LNCaP and PC 3 cells decreases the expression of downstream Nrf2 targets, such as NAD(P)H: quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase theta 2 (Gstt2). Downregulation of Setd7 decreases soft agar colony formation ability of PCa cells. Knockdown of Setd7 increases reactive oxygen species (ROS) generation. Furthermore, Setd7 knockdown attenuates Nqo1 and Gstt2 expression in response to H2 O2 challenge, whereas increased DNA damage is observed in Setd7 knockdown cells in comet assay. Interestingly, Setd7 expression could be induced by the dietary phytochemicals PEITC and UA. Chromatin immunoprecipitation (ChIP) assays show that Setd7 knockdown decreased H3K4me1 enrichment in the Nrf2 and Gstt2 promoter regions, while PEITC and UA treatments elevated the enrichment. CONCLUSION: Taken together, these results indicate that Setd7 knockdown decreases Nrf2 and Nrf2-target genes expression and that PEITC and UA induce Setd7 expression, which activates the Nrf2/antioxidant response element (ARE) signaling pathway and protects DNA from oxidative damage. PMID- 29383878 TI - Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model. AB - Anal incontinence is a devastating condition that significantly reduces the quality of life. Our aim was to evaluate the effect of human adipose stem cell (hASC) injections in a rat model for anal sphincter injury, which is the main cause of anal incontinence in humans. Furthermore, we tested if the efficacy of hASCs could be improved by combining them with polyacrylamide hydrogel carrier, Bulkamid. Human ASCs derived from a female donor were culture expanded in DMEM/F12 supplemented with human platelet lysate. Female virgin Sprague-Dawley rats were randomized into four groups (n = 14-15/group): hASCs in saline or Bulkamid (3 * 105 /60 MUl) and saline or Bulkamid without cells. Anorectal manometry (ARM) was performed before anal sphincter injury, at two (n = 58) and at four weeks after (n = 33). Additionally, the anal sphincter tissue was examined by micro-computed tomography (MUCT) and the histological parameters were compared between the groups. The median resting and peak pressure during spontaneous contraction measured by ARM were significantly higher in hASC treatment groups compared with the control groups without hASCs. There was no statistical difference in functional results between the hASC-carrier groups (saline vs. Bulkamid). No difference was detected in the sphincter muscle continuation between the groups in the histology and MUCT analysis. More inflammation was discovered in the group receiving saline with hASC. The hASC injection therapy with both saline and Bulkamid is a promising nonsurgical treatment for acute anal sphincter injury. Traditional histology combined with the 3D MUCT image data lends greater confidence in assessing muscle healing and continuity. Stem Cells Translational Medicine 2018;7:295-304. PMID- 29383879 TI - Clostridium difficile toxin B induces autophagic cell death in colonocytes. AB - Toxin B (TcdB) is a major pathogenic factor of Clostridum difficile. However, the mechanism by which TcdB exerts its cytotoxic action in host cells is still not completely known. Herein, we report for the first time that TcdB induced autophagic cell death in cultured human colonocytes. The induction of autophagy was demonstrated by the increased levels of LC3-II, formation of LC3+ autophagosomes, accumulation of acidic vesicular organelles and reduced levels of the autophagic substrate p62/SQSTM1. TcdB-induced autophagy was also accompanied by the repression of phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) complex 1 activity. Functionally, pharmacological inhibition of autophagy by wortmannin or chloroquine or knockdown of autophagy-related genes Beclin 1, Atg5 and Atg7 attenuated TcdB-induced cell death in colonocytes. Genetic ablation of Atg5, a gene required for autophagosome formation, also mitigated the cytotoxic effect of TcdB. In conclusion, our study demonstrated that autophagy serves as a pro-death mechanism mediating the cytotoxic action of TcdB in colonocytes. This discovery suggested that blockade of autophagy might be a novel therapeutic strategy for C. difficile infection. PMID- 29383880 TI - An analysis of stigma and suicide literacy in responses to suicides broadcast on social media. AB - INTRODUCTION: Broadcasting a suicide attempt on social media has become a public concern in China. Stigmatizing attitudes around such broadcast can limit help seeking and increase the likelihood of death. To reduce stigmatizing attitudes, this paper aims to detect stigma expressions in social media posts through language use patterns and then identify suicide literacy in responses to such broadcast. METHODS: Firstly, to examine linguistic patterns of stigma expressions, 6632 Weibo posts with keywords were collected and analyzed. Using 102 linguistic features, 2 classification models were built: one for differentiating between stigmatizing and nonstigmatizing attitudes, and one for differentiating between specific types of stigmatizing attitudes. Secondly, to identify the levels of suicide literacy, a content analysis was conducted on 4969 Weibo posts related to social media suicide. RESULTS: Firstly, the model accuracy ranged from 66.15% to 72.79%. Secondly, a total of 11.67% of the Weibo posts (n = 580) contained misinformation about suicide. In the category of knowledge of signs, 27.93% and 18.10% of posts endorsed the stigmatizing views that "suicide happens without warning" and "people who want to attempt suicide cannot change their mind quickly," both of which were related to a stigmatizing belief that a suicide attempt on social media is not genuine. In the category of knowledge of treatments, 35.17% of posts endorsed the stigmatizing view that "people who have thoughts about suicide should not tell others about it." DISCUSSION: This paper presents an opportunity for the dissemination of targeted online campaigns to increase mental health literacy and help-seeking. PMID- 29383881 TI - Introduction to Volume 10, Issue 1 of topiCS. PMID- 29383882 TI - Probability Theory Plus Noise: Descriptive Estimation and Inferential Judgment. AB - We describe a computational model of two central aspects of people's probabilistic reasoning: descriptive probability estimation and inferential probability judgment. This model assumes that people's reasoning follows standard frequentist probability theory, but it is subject to random noise. This random noise has a regressive effect in descriptive probability estimation, moving probability estimates away from normative probabilities and toward the center of the probability scale. This random noise has an anti-regressive effect in inferential judgement, however. These regressive and anti-regressive effects explain various reliable and systematic biases seen in people's descriptive probability estimation and inferential probability judgment. This model predicts that these contrary effects will tend to cancel out in tasks that involve both descriptive estimation and inferential judgement, leading to unbiased responses in those tasks. We test this model by applying it to one such task, described by Gallistel et al. ). Participants' median responses in this task were unbiased, agreeing with normative probability theory over the full range of responses. Our model captures the pattern of unbiased responses in this task, while simultaneously explaining systematic biases away from normatively correct probabilities seen in other tasks. PMID- 29383883 TI - Editors' Introduction: Cognitive Modeling at ICCM: Advancing the State of the Art. AB - Cognitive modeling is the effort to understand the mind by implementing theories of the mind in computer code, producing measures comparable to human behavior and mental activity. The community of cognitive modelers has traditionally met twice every 3 years at the International Conference on Cognitive Modeling (ICCM). In this special issue of topiCS, we present the best papers from the ICCM meeting. (The full proceedings are available on the ICCM website.) These best papers represent advances in the state of the art in cognitive modeling. Since ICCM was for the first time also held jointly with the Society for Mathematical Psychology, we use this preface to also reflect on the similarities and differences between mathematical psychology and cognitive modeling. PMID- 29383884 TI - How Does Rumination Impact Cognition? A First Mechanistic Model. AB - Rumination is a process of uncontrolled, narrowly focused negative thinking that is often self-referential, and that is a hallmark of depression. Despite its importance, little is known about its cognitive mechanisms. Rumination can be thought of as a specific, constrained form of mind-wandering. Here, we introduce a cognitive model of rumination that we developed on the basis of our existing model of mind-wandering. The rumination model implements the hypothesis that rumination is caused by maladaptive habits of thought. These habits of thought are modeled by adjusting the number of memory chunks and their associative structure, which changes the sequence of memories that are retrieved during mind wandering, such that during rumination the same set of negative memories is retrieved repeatedly. The implementation of habits of thought was guided by empirical data from an experience sampling study in healthy and depressed participants. On the basis of this empirically derived memory structure, our model naturally predicts the declines in cognitive task performance that are typically observed in depressed patients. This study demonstrates how we can use cognitive models to better understand the cognitive mechanisms underlying rumination and depression. PMID- 29383886 TI - [Effect of Electroacupuncture and Moxibustion Pretreatment on Expression of Autophagy Related Proteins LC 3 and Beclin 1 in Rats with Myocardial Ischemia reperfusion Injury]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) and moxibustion (Moxi) pretreatment on myocardial pathological and structural changes and expression of autophagy related protein LC 3 I/II and Beclin 1 in rats with myocardial ischemia-reperfusion injury (MI/RI), so as to explore their mechanisms underlying improving MI/RI. METHODS: Forty SD rats were randomly divided into sham operation, model, ischemic preconditioning (IP), EA and Moxi groups (n=8 in each group). EA (10 Hz/50 Hz,1 mA) or Moxi (ignited moxa stick) was respectively applied to bilateral "Neiguan"(PC 6) for 20 min, once daily for 7 days. The MI/RI model was established by occlusion of the anterior descending branch of the left coronary artery for 40 min, followed by reperfusion for 60 min. The left ventricular (LV) tissue samples were collected and analyzed for pathological (H.E. staining) and ultrastructural changes, for myocardial apoptosis (apoptotic index= number of apoptotic cells/total number of cardiomyocytes*100%) with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method, and for the expression of LC 3 and Beclin 1 in myocardial cells with Western blot. RESULTS: Following MI/RI, H.E. staining revealed a disorder of arrangement of cardiomyocytes with vague border, inflammatory cell infiltration, intracellular swelling with bleeding, necrosis and dissolution of partial striated muscles of the left ventricle under light microscope, and dual staining of Uranyl acetate and leadnitrate showed atrophy, arrangement disorder, dissolution, necrosis, and interstitial edema of partial myocardial fibers, mitochondrial structural disorder, vacolation, and large body of autophagosomes with bilayers, etc. in ultrastructure, which was relatively lighter in both EA and Moxi groups. The apoptosis index, expression levels of myocardial LC 3 II and Beclin 1 and the ratio of LC 3 II/LC 3 I were significantly higher in the model group than those in the sham operation group (P<0.01), but the expression level of LC 3 I was considerably down-regulated in the model group relevant to the sham operation group (P<0.01). Following the intervention and MI preconditioning, the increased apoptosis index and expression levels of LC 3II and Beclin 1 proteins and the ratio of LC 3II/LC 3 I were obviously down-regulated in the IP, EA and Moxi groups relevant to the model group (P<0.01), and the decreased expression of LC 3 I protein was up-regulated obviously in the 3 treatment groups (P<0.05,P<0.01). The effects of EA were significantly superior to those of IP and Moxi groups in down-regulating apoptosis index and expression of LC 3 II and Beclin 1 and the ratio of LC 3 II/LC 3 I and in up-regulating expression of LC 3 I (P<0.05, P<0.01). CONCLUSION: Both EA and Moxi preconditioning of PC 6 have a protective effect on ischemic myocardium in MI/RI rats, which is probably related to their effects in regulating expression of myocardial autophagy proteins as LC 3 I/II and Beclin 1. PMID- 29383885 TI - Increased FXYD1 and PGC-1alpha mRNA after blood flow-restricted running is related to fibre type-specific AMPK signalling and oxidative stress in human muscle. AB - AIM: This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC-1alpha (total, 1alpha1, and 1alpha4) and Na+ ,K+ -ATPase isoforms (NKA; alpha1-3 , beta1-3 , and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type-specific AMPK and CaMKII signalling, in human skeletal muscle. METHODS: In a randomized, crossover fashion, 8 healthy men (26 +/- 5 year and 57.4 +/- 6.3 mL kg-1 min-1 ) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and alpha-AMPK Thr172 /alpha AMPK, ACC Ser221 /ACC, CaMKII Thr287 /CaMKII, and PLBSer16 /PLB ratios in type I and II fibres. RESULTS: Muscle hypoxia (assessed by near-infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P < .05). The mRNA levels of FXYD1 and PGC-1alpha isoforms (1alpha1 and 1alpha4) increased in BFR only (P < .05) and were associated with increases in indicators of oxidative stress and type I fibre ACC Ser221 /ACC ratio, but dissociated from muscle hypoxia, lactate, and CaMKII signalling. CONCLUSION: Blood flow restriction augmented exercise-induced increases in muscle FXYD1 and PGC-1alpha mRNA in men. This effect was related to increased oxidative stress and fibre type dependent AMPK signalling, but unrelated to the severity of muscle hypoxia, lactate accumulation, and modulation of fibre type-specific CaMKII signalling. PMID- 29383887 TI - [Effect of Eletroacupuncture Intervention on Insulin Resistance, Lipid Metabolic Disorder and Expression of Hepatic SREBP-1 c and Fatty Acid Synthase Proteins in Rats with Hyperlipidemia]. AB - OBJECTIVE: To observe the effect of electroacupuncture(EA) of "Fenglong" (ST 40) and "Sanyinjiao" (SP 6) on lipid metabolic disorder, insulin resistance (IR) and expression of sterol regulatory element blinding protein-1 (SREBP-1) c and fatty acid synthase (FAS) proteins in the liver tissue in hyperlipidemia rats with IR, so as to reveal its mechanisms underlying improvement of IR. METHODS: Forty male SD rats were randomly divided into blank control, model, medication and EA groups (n=8 in each group). The IR model was established by feeding the rat with high fat diet. Rats of the medication group were treated by intragastric administration of pioglitazone (10 mL/kg). For rats of the EA group, EA (2 Hz/100 Hz,1 mA) was applied to bilateral ST 40 and SP 6, once daily for 14 days. The insulin sensitivity index (ISI) was assessed by calculating 60-120 min glucose infusion rate (GIR 60-120) with euglycemic hyperinsulinemic clamp in reference to Kraegen's and colleagues' methods. Fasting blood samples (10 mL) were collected and analyzed for fasting blood glucose (FBG) using enzyme method, serum fasting insulin(FINS) using ELISA, free fatty acid(FFA) using spectrophotometry, and total triglyceride(TG) and total cholesterol(TC) employing glycerine phosphate oxidase peroxidase (GPO-PAP) assay, low density lipoprotein(LDL), high density lipoprotein(HDL) levels using combined filiter paper activity and lipase activity methods, respectively. The IR level was assessed by calculating homeostatic model assessment of insulin resistance (HOMA-IR) using the formula (FBG*FINS)/22.5. The expression levels of SREBP-1 c and FAS proteins in the liver tissue were detected by Western blot. RESULTS: Following modeling, the GIR 60-120 and serum HDL were significantly decreased(P<0.01), and the HOMA-IR, serum FBG, FINS, FFA, TG, TC and LDL, and the expression levels of hepatic SREBP-1 c and FAS proteins were significantly increased in comparison with the blank control group(P<0.01). After the intervention, the decreased GIR 60-120 and serum HDL levels were considerably up-regulated (P<0.01), and the increased FBG, FINS, FFA, TG, TC and LDL, and hepatic SREBP-1 c and FAS protein levels were notably down-regulated in both EA and medication groups relevant to the model group (P<0.05, P<0.01). No significant differences were found between the EA and medication groups in all the indexes mentioned above (P>0.05). CONCLUSION: EA intervention is able to improve the disorder of lipid metabolism of IR rats, which may be associated with its effects in reducing the expression of SREBP-1 c and FAS proteins and in lowering the synthesis of fatty acid. PMID- 29383888 TI - [Effect of Electroacupuncture on Pain Reaction and Content of Proteinase activated Receptors 2 in Dorsal Root Ganglion in Hyperalgesia Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on mechanical hyperalgesia threshold (MHTs) and thermal hyperalgesia threshold (THTs) and content of proteinase-activated receptors 2 (PAR 2) in dorsal root ganglia (DRG) in rats with inflammatory pain, so as to explore its peripheral mechanism underlying improvement of inflammatory pain. METHODS: The present study contains two parts. 1) In the first part, 27 male SD rats were randomized into sham hyperalgesic priming (sham-HP) group and real hyperalgesic priming (HP) group (n=5 in the sham-HP group and n=6 in the HP group for the test of MHTs, n=8 in the two groups for the test of THTs). The sham-HP model was established by subcutaneous injection of normal saline into the left plantar part of the hind paw, and the HP model established by subcutaneous injection of 1% carragenan (the first injection) into the same left hind paw, followed by injection of PGE2 (100 ng/25 MUL, the second injection) into the dorsum pedis of the same hind paw 7 days after the first injection. The ipsilateral paw withdrawal latencies (MHTs and THTs) were detected before and 5 h, 3 d and 6 d after the first injection, 0.5, 4 and 24 h after the second injection. 2) In the second part, 64 male SD rats were randomly divided into sham-HP, HP, sham-EA and EA groups (n=16 in each group). The sham-HP and HP models were made in the same way as the first part. Both"Zusanli"(ST 36)and "Kunlun"(BL 60) were punctured with filiform needles in the sham-EA group and also stimulated with EA: 2 Hz/100 Hz, 0.5-1.5 mA (0.5 mA increase per 10 min) for 30 min in the EA group, 1 time/d for 7 d. Both ipsilateral MHTs and THTs were observed at the same time-points of the first part and the PAR 2 protein content in the L 4-L 6 DRGs was assayed by ELISA 24 h after the second injection. RESULTS: 1) In the first part of the study, compared with the sham-HP group, the MHTs at 5 h and 3 d, and THT at 5 h after the first injection, and MHTs, and THTs at 4 and 24 h after the se-cond injection were significantly decreased in the HP group (P<0.01, P<0.05). 2) In the second part of the study, compared with the HP group, the MHTs at 4 and 24 h after the second injection and the THTs at 3 d after the first injection, 4 and 24 h after the second injection were significantly up-regulated in the EA group (P<0.01, P<0.05). The content of PAR 2 in the DRGs (L 4-L 6) was significantly higher in the HP group than in the sham-HP group (P<0.05), but considerably lower in the EA group than in the HP group (P<0.05). CONCLUSION: EA can suppress hyperalgesia priming in inflammatory pain rats which may be related to its effect in down regulating PAR 2 level in the lumbar DRGs. PMID- 29383889 TI - [Effect of Electroacupuncture on Levels of beta-amyloid and Neprilysin Proteins in the Cerebral Cortex of Alzheimer's Disease Mice Based on "Mutual Assistance of Kidney and Brain" Theory]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on the levels of Abeta 1-40 and Abeta 1-42 and neprilysin (NEP) protein in the temporal cortex of SAMP 8 mice with Alzheimer's disease (AD), so as to explore its mechanism underlying improvement of AD based on the theory of "mutual assistance of kidney and brain" in traditional Chinese medicine. METHODS: Eighteen male SAMP 8 mice were randomly assigned to 3 groups: model, EA and medication (memantine, n=6/group), and 6 male homologous SAMR 1 mice were used as the normal control group. According to the "mutual assistance of kidney and brain" theory, EA (2 Hz,0.6 mA) was applied at "Baihui"(GV 20), bilateral "Shenshu"(BL 23) and "Taixi"(KI 3) for 15 min, once daily for 8 consecutive weeks. Mice of the medication group were treated with intragastric administration of memantine (20 mg*kg-1*d-1) for 8 weeks. The contents of Abeta 1-40 and Abeta 1-42 in the temporal cortex were assayed using ELISA, and the expression of NEP protein in the temporal cortex was detected using immunohistochemistry and Western blot (WB), separately. RESULTS: The contents of Abeta 1-40 and Abeta 1-42 were significantly higher in the model group than in the control group (P<0.05), and notably lower in both EA and medication groups than in the model group (P<0.05). WB assay showed that the expression level of NEP was significantly down-regulated in the model group relevant to the control group (P<0.05), and obviously up regulated in both EA and medication groups relevant to the model group (P<0.05). No significant differences were found between the EA and medication groups in the contents of Abeta 1-40 and Abeta 1-42 and in the up-regulated expression levels of NEP protein (P>0.05). Immunohistochemistry stain showed that NEP-positive products mainly expressed in the perikaryon of neurons of the temporal cortex. CONCLUSION: EA intervention based on "mutual assistance of kidney and brain" theory has a good efficacy in up-regulating NEP expression and down-regulating Abeta 1-40 and Abeta 1-42 levels in the temporal cortex of AD mice, suggesting a potential effectiveness in the prevention and treatment of AD. PMID- 29383890 TI - [Effect of Electroacupuncture at "Neiguan" (PC 6) and "Tianshu" (ST 25) for Colonic Motility and D 2 Receptor in Irritable Bowel Syndrome Rats]. AB - OBJECTIVE: To observe and compare the effects of electroacupuncture (EA) at "Tianshu" (ST 25) and "Neiguan" (PC 6) for colonic motility and the expression of colon dopamine D 2 in irritable bowel syndrome (IBS) rats, and to explore the specificity of different meridians and different acupoints. METHODS: Forty Wistar newborn rats were randomly divided into blank, model, Tianshu and Neiguan groups. Separation of mother and child and acetic acid coloclyster combined with colorectal distension were used to establish IBS model in the model, Tianshu and Neiguan groups. At the age of 9 weeks, EA at bilateral ST 25 and PC 6 were applied in the corresponding groups 5 times, once every other day. After the intervention, the Bristol fecal score, the latent period of abdominal retraction reflex and the number of contraction waves were recorded. The expression of dopamine D 2 receptor was detected by immunohistochemistry. RESULTS: Compared with the blank group, the Bristol fecal score of the model group was higher (P<0.01), the 1st contraction wave latent period was shorter (P<0.01), the number of contraction waves in 90 s increased (P<0.01), the immunoreactive expression of D 2 receptor in colon decreased (P<0.01). Compared with the model group, the Bristol fecal scores of the Tianshu and Neiguan groups decreased (P<0.01), the 1st contraction wave latent periods were longer (P<0.01), the numbers of contraction waves in 90 s decreased (P<0.01), the positive expressions of D 2 receptor in colon increased (P<0.01, P<0.05). Compared with the Tianshu group, the immunoreactive expression of D 2 receptor in the Neiguan group decreased (P<0.01). CONCLUSION: EA at ST 25 and PC 6 can improve the symptoms of colonic motility in IBS rats. The effect of EA at ST 25 is better, which indicates that different meridians and different acupoints play specific effects. PMID- 29383891 TI - [Effects of the Acupoint Catgut Embedding on Nerve-Endocrine-Immune Network in Dysmenorrhea Rats]. AB - OBJECTIVE: To explore the underlying mechanism of acupoint catgut embedding in improving primary dysme-norrhea (PD) in rats based on functional activities of the neuro-endocrine-immune (NEI) network. METHODS: Forty female rats were equally randomized into blank control, PD model, medication, and acupoint catgut embedding groups. The PD model was established by subcutaneous injection of estradiol benzoate (0.5 mg/rat on the 1st and 10th d, and 0.2 mg/rat from 2nd to 9th d) and oxytocin (2 U/rat, i.p.). Rats of the medication group were treated by intragastric perfusion of fenbid (0.8 mL/rat, 125 mg/100 mL), once daily for 10 days. The catgut embedding was applied to bilateral "Ciliao" (BL 32), "Sanyinjiao" (SP 6) and "Guanyuan" (CV 4) before modeling. The body writhing times in 30 minutes were recorded, plasma beta-endorphin(beta-EP) content, and prostaglandin E 2 (PGE2) and prostaglandin F 2 alpha (PGF2alpha) contents in the uterus tissue were assayed using ELISA, and the activity of natural killer cell (NK cell) in the spleen tissue was detected using 3-(4,5-dimethyl-2-thiazolyl) 2,5-diphenyl-2-H-tetrazolium bromide (MTT) method after isolation and co-culture with K 562 cells. RESULTS: The body writhing times were no-tably more in the model group than in the control group (P<0.01), and obviously fewer in both medication and catgut embedding groups than in the model group (P<0.01). After modeling, the plasma beta-EP and uterus PGE2 contents and splenic NK cell activity were significantly decreased (P<0.01), while the uterus PGF2alpha content was evidently increased in the model group relevant to the control group (P<0.01). Following the treatment, plasma beta-EP and uterus PGE2 contents and splenic NK cell activity were considerably up-regulated (P<0.01), and uterus PGF2alpha content was markedly down-regulated in both medication and acupoint catgut embedding groups (P<0.01), suggesting an involvement of the NEI network in catgut embedding-induced improvement of PD. The therapeutic effect of catgut embedment was markedly superior to that of medication in up-regulating splenic NK cell activity (P<0.01). No significant differences were found between the medication and catgut embedding groups in the body writhing times within 30 min, and in the levels of plasma beta-EP and uterus PGE2 and PGF2alpha (P>0.05). CONCLUSION: The acupoint catgut embedding has a significant efficacy in relieving PD in rats, which may be related to its effect in up-regulating plasma beta-EP, uterus PGE2 contents and splenic NK cell activity and in down-regulating uterus PGF2alpha level. PMID- 29383892 TI - [Effect of Warm Acupuncture on the Levels of Serum Immunoglobulin E, Interleukin 1 beta and Tumor Necrosis Factor-alpha in Rats with Allergic Rhinitis]. AB - OBJECTIVE: To observe the effect of warm acupuncture on behavior and contents of serum immunoglobulin E(IgE), interleukin-1 beta(IL-1 beta) and tumor necrosis factor-alpha(TNF-alpha) in allergic rhinitis(AR) rats, so as to explore its mechanism underlying improving AR. METHODS: Forty Wistar rats were randomly divided into four groups: control group, model group, medication group and warm acupuncture group(10 rats/group). The AR model was established by intraperitoneal injection of sensitization and nasal drip. The rats in the medication group were given fluticasone propionate nasal spray, daily for 10 days. Warm acupuncture was applied to "Fengchi"(GB 20), "Yintang"(GV 29), "Yingxiang"(LI 20) for 60 seconds, once daily for 10 days. Behavioral scores were used to evaluate behavioral changes in rats. Enzyme linked immunosorbent assay (ELISA) was used to detect the expression levels of serum IgE, IL-1 beta and TNF-alpha. RESULTS: Behavioral scores of the model group were significantly higher than those of the control group 0, 3, 7 and 10 days after modeling (P<0.05). After treatment, the behavioral scores of medication group and the warm acupuncture group were lower than those of the model group (P<0.05), and the score was more lower in the warm acupuncture group than in the medication group (P<0.05). Compared with the control group, the levels of serum IgE, IL-1 beta and TNF-alpha in the model group were all increased (P<0.01), while the levels of serum IgE, IL-1 beta and TNF-alpha were decreased in the medication and warm acupuncture groups after treatment in comparison with the model group (P<0.05, P<0.01). Compared with the medication group, the levels of serum IgE, IL-1 beta and TNF-alpha were significantly lower in the warm acupuncture group (P<0.05, P<0.01). CONCLUSION: The expression levels of IgE, IL-1 beta and TNF-alpha were elevated in serum after AR attack. Warm acupuncture can improve the symptoms of AR rats, which may be associated to its effect in inhibiting the expression of serum IgE, IL-1 beta and TNF-alpha. PMID- 29383893 TI - [Effect of Tiaoshen Kaiyu Acupuncture (Regulating Vitality and Dredging Stasis) Combined with Psychological Intervention on Patients of Mild Depression After Stroke]. AB - OBJECTIVE: To observe the effect of Tiaoshen Kaiyu acupuncture (regulating vitality and dredging stasis) combined with psychological intervention for treating mild depression after stroke. METHODS: Ninety-four patients were enrolled and were randomly divided into acupuncture (48 cases) and control (46 cases) groups. Patients in the control group were given standard treatment plus psychological intervention, while patients in the acupuncture group were treated with Tiaoshen Kaiyu acupuncture plus standard treatment and psychological intervention. Acupoints of Sishencong(EX-HN 1), Baihui(GV 20), and Yintang(EX-HN 3) were selected in the acupuncture group. Each group received treatment once daily, five times weekly, for a total of 6 weeks. A self-rating depression scale (SDS), Hamilton depression scale (HAMD), simplified Fugl-Meyer motor function assessment (FMA), and modified Barthel index (MBI) were used before and after treatment to evaluate the efficacy. RESULTS: After the treatment the four indexes were improved significantly compared with those before treatment in the acupuncture and control groups (P<0.01). The FMA and MBI scores in the acupuncture group were higher than those in the control group (P<0.05). The HAMD and SDS scores were significantly lower in the acupuncture group than in the control group (P<0.01). In both the acupuncture and control groups, the differences before and after treatment of the HAMD and FMA scores (rs=0.332, P<0.01) and the HAMD and MBI scores (rs=0.356, P<0.01) were positively correlated. CONCLUSION: Tiaoshen Kaiyu acupuncture combined with psychological intervention is more effective than psychological intervention therapy alone. The efficacy is correlated with motor function and mild depression scores of patients after stroke. PMID- 29383894 TI - [Effects of Transcutaneous Electrical Acupoint Stimulation for Depression in Late Pregnancy and Impacts on Inflammatory Cytokines]. AB - OBJECTIVE: To assess the safety and efficacy of transcutaneous electrical acupoint stimulation (TEAS) for depression in late pregnancy and impacts on inflammatory cytokines. METHODS: A total of 150 pregnant women with depression in late pregnancy were randomized into a high intensity group (n=52), a low intensity group (n=49) and a control group (n=49). TEAS was applied at bilateral Neiguan (PC 6) and Shenmen (HT 7) for 6 weeks. The intensities of TEAS in the high intensity group, the low intensity group and the control group were 10, 5 and 0 mA, respectively. During the process of TEAS, the blood pressure, pulse, uterine contraction and the fetal heart rate were recorded. Depression was evaluated by 24-item Hamilton depression scale (HAMD) before TEAS and after 2 week, 4-week, 6-week treatment. Serum levels of tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta) and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA) before and after 6-week treatment. Delivery outcomes were observed. The correlation was analyzed between HAMD difference value and the diffe-rence values of TNF-alpha, IL-1 beta and IL-6, respectively. RESULTS: The blood pressure, pulse and fetal heart rate had no statistical significance before and after treatment in the three groups (P>0.05). The HAMD scores at all the time points were lower than that before treatment in the high intensity group (P<0.05), which were lower compared with those in the low intensity group and the control group (P<0.05). The HAMD score in the low intensity group decreased after 6-week treatment compared with that before treatment and was lower than that in the control group (P<0.05). The serum levels of IL-1 beta and IL-6 in the high intensity group decreased compared with those before treatment and were lower compared with those in the low intensity group and the control group after 6-week treatment (P<0.05). There was no significant difference in the deliver outcomes among the three groups (P>0.05). The variation of HAMD score did not have significant correlation with those of TNF-alpha, IL-1 beta and IL-6 (P>0.05). CONCLUSION: TEAS is safe and effective for depression in late pregnancy and can regulate the serum levels of IL-1 beta and IL-6 without influencing on delivery outcome. PMID- 29383895 TI - [Analgesic Effect of Deqi Induced by Needling at Sanyinjiao (SP 6) Acupoint on Primary Dysmenorrheal Patients with Cold Damp Stagnation Syndrome]. AB - OBJECTIVE: To observe the analgesic effect of deqi induced by needling at Sanyinjiao (SP 6) on primary dysmenorrheal (PD) patients with cold damp stagnation syndrome (CDSS). METHODS: A total of 64 PD patients with CDSS experiencing abdominal pain (>=40 mm in visual analogue scale ,VAS) were randomly assigned into deqi-expectation(DE) group(n=15) and no-deqi-expectation(NDE) group(n=49). On the first day of abdominal pain attack, bilateral SP 6 were punctured respectively with thicker needles with deeper insertion for deqi expectation patients and thin filiform needles with shallow insertion for no-deqi expectation patients. The needles were removed after 30 minutes, a deqi scale was used to evaluate the deqi condition. According to the results, patients in the DE group were further divided into deqi DE group and no-deqi DE group, patients in the NDE group were also divided into deqi NDE group and no-deqi NDE group. The VAS was used to evaluate the patients' abdominal pain severity before treatment and 0, 10, 20, 30 min after acupuncture needle withdrawal. RESULTS: The rate of deqi in the DE group was higher than that in the NDE group(P<0.05). The VAS scores of abdominal pain in the four groups were decreased at all time-points after needle withdrawal compared with those before treatment (P<0.01), while the VAS score in the deqi DE group were lower than in the no-deqi NDE group 30 min after needle withdrawal (P<0.05). CONCLUSION: The intervention method of thick needle, deep insertion and some manipulation is easier in inducing deqi than that of thin needle, shallow insertion and no manipulation. The analgesic effect of deqi is better than that of no-deqi for PD patients with CDSS. PMID- 29383896 TI - [Effect of Acupuncture on Inflammatory Cytokines in Patients with Acute Pelvic Inflammatory Disease]. AB - OBJECTIVE: To observe the effect of acupuncture on inflammatory indices and symptoms in patients with acute pelvic inflammatory disease, and investigate its mechanism. METHODS: Seventy-nine patients with acute pelvic inflammatory disease were randomly assigned to a control group (n=37) given conventional treatment and an observation group (n=42) given conventional treatment and acupuncture therapy. In the observation group, acupionts of Zhongji(CV 3), Guanyuan(CV 4), Zigong(EX CA 1), Zusanli(ST 36), Sanyinjiao(SP 6), etc. were selected. Each group received treatment once daily, for a total of 7 days. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-10 and C-reactive protein (CRP) in the serum, white blood cell (WBC) and neutrophil counts, size of pelvic mass and depth of pelvic effusion, and clinical symptoms were assayed pretreatment and on days 3 and 7. RESULTS: WBC and neutrophils were significantly decreased after treatment in both groups (P<0.05), and more in the observation group than in the control group (P<0.05). After treatment, the size of pelvic mass and depth of effusion were less in both groups (P<0.05), and the efficacy in the observation group was superior to that in the control group (P<0.05). In the observation group, serum TNF-alpha, and CRP on day 3 and day 7 were significantly lower than those before treatment (P<0.05). Se-rum TNF-alpha and CRP were significantly down-regulated in the observation group compared with those in the control group on both day 3 and day 7 (P<0.05). In the observation group, serum IL-10 was higher on both day 3 and day 7 than that before treatment (P<0.05), and was statistically different from that in the control group on both days (P<0.05). The clinical efficacy in the observation group was superior to that in the control group (95.24% vs 81.08%, P<0.05). CONCLUSION: Acupuncture can regulate the levels of inflammatory markers in patients with acute pelvic inflammatory disease, and improve clinical symptoms. PMID- 29383897 TI - [Progress of the Mechanism of Acupuncture to Promote Repair of Facial Nerve Injury]. AB - Facial nerve injury results in facial muscle movement disorders that interferes with patient's life. Acupuncture is an effective therapy for facial nerve injury, but its mechanism has not been clarified. The evidence supports that acupuncture can accelerate the repair of facial nerve injury by adjusting the electric wave of patient's facial muscle, improving facial blood circulation, and promoting the expression of cell and protein molecule. PMID- 29383898 TI - [10 Years of Experience in Living Donation for Liver Transplantation in Pediatric Patients - A Single Centre Study]. AB - Living donor liver transplantation poses new issues related to the performance of a major surgery on a healthy person - the living donor. Thus, it requires precise logistics to ensure positive outcome for both the donor and the recipient, outweighing the risks associated with donation and transplantation. For this purpose, we developed an original three phase protocol for evaluation of candidate donors with set of mandatory assays. This paper aims to analyze the outcomes of this protocol. 89 candidates have been examined for the performance of 23 living donor liver transplantations. The procedure was successfully completed by 25 candidates (28.1%), including two cases of procedure suspension due to occurrence of a suitable deceased donor. The majority of exclusions occurred in the third phase, generally due to anatomical variations: arterial (17%), portal (9.68%), venous (18.15%) and biliary (18.15%), and for several reasons simultaneously (6.7%). NO exclusions occurred due to inadequate potential graft or residual volume. All living donors underwent left lateral resection and the measured volumes were enough for both the recipients and the donors. No significant complications occurred in the donors (Clavien 1: 21%, Clavien II: 4%), with no need of transfusion, reoperation or re-hospitalization. The laboratory parameters were restored to normal values within the 10th postoperative day as the average hospital stay was 14.7 days. All donors were discharged with normal laboratory, instrumental and physical parameters. No abnormalities were observed at long-term follow-up. No primary graft dysfunction was observed. The large proportion of declined candidates requires strict adherence to the precise sequence of the evaluation protocol. The main reasons for decline are anatomical variation. Los level of complicatons was registered, with short postoperative stay, normal laboratory results at discharge and normal physiological parameters at long-term follow-up. The concept of donor advocate was introduced for the first time in Bulgaria. His task is to defend the interests of the candidate donor and to provide assistance in making an informed decision. PMID- 29383899 TI - [About Clinical Applicatoin of Local Rotation Plasty]. AB - Introduction: Local rotation plasty is a well-known and well-accepted plastic surgery tool for the body surface defects treatment. Because of some new theoretical streams in the literature, authors performed their own researches among oncological, non-oncological cases in which the method was performed as a part of surgical treatment. Aim: The aim of this study is a clinical analysis of local plasty application in different anatomical regions of the human body. Material and Methods: A retrospective study was performed among 54 consecutives local plasty surgical cases. Results and discussion: Between 01.2010 and 01.2015 54 consecutive patients were treated with local plasty surgical approach. 39 of them were man and 15 - women. The median age of the participants was 62,5 years for the man and 57.5 years for the women. In the 24,07 % of all cases the rotation angle chosen was 90 degrees , and in the other 75,93% of all cases this one was lower 90 degrees . Postoperative complication were established in 9,26 % +/-4,25 % mainly in the greater angle rotation group. All of them were conservatively managed without reconstructive failure. We discuss our results with those obtained in the literature focused on some new streams in the local plasty applications. PMID- 29383900 TI - [Subclinical Pheochromocytoma: The Surgeons Point fo View - A Single-Institution Experience]. AB - Background: Pheochromocytoma is a rare neuroendocrine tumor. Most of the autopsy studies indicate that large numbers of these tumors remain undiagnosed during life. The most obvious explanation for this fact is its rather non-specific clinical presentation or the absence of any symptoms - the presence of subclinical pheochromocytoma. We report our institution experience with silent pehochromocytomas - their preoperative characteristics, intraoperative management and postoperative complications. Material and Methods: A total of 104 patients underwent operation for pheochromocytoma between 19780 and 2010 in our department. Eleven of them had no clinical symptoms. We describe and analyze retrospectively: indication for diagnosis and surgery, length of hospital stay, intra and postoperative complications. Results: In total, 11 of the 104 patent operated in our department had no clinical symptoms. From the classical triad (headache, palpitation and diaphoresis) only five of those patients had occasional palpitation when they felt severe anger, which is rather unspecific. When we analyzed the data of these patients we found a longer operative time (p = 0.04), more intraoperative complication (p = 0.02) - higher estimated blood loss and larger transfusion requirement. Postoperative complications however showed no statistical significance. Conclusion: Pheochromocytoma can have variable presentation. Patients with small incidentalomas schedules for surgery should be closely evaluated and medically treated preoperatively to ensure an excellent outcome. PMID- 29383901 TI - [Comparing Onset Times and Vascular Punctures in axillary Blocks with Nerve Stimulation or Ultrasound: Randomised Trial]. AB - The use of ultrasound (US) guidance in regional anaesthesia has evolved in the last then years and has even been considered the fatest and safest way to identify peripheral nerves and vascular structures thus eliminating the risk of injuring them. Prior to US guidance, peripheral nerve stimulation (PNS) was the gold standard procedure of the last twenty years, still being used in the present alone or alongside US guidance. However, sometimes -especially in vessel rich areas such as the axillary plexus- it is hard to avoid injuring vascular structures with blind techniques such as PNS. The study's hypothesis was that out of-plane US guided peri-neural axillary plexus block has a better success rate, faster onset and less intravascular punctures than the PNS method. PMID- 29383902 TI - [Teaching management disciplines in nursing education in Brazil: the experience of a group of teachers from the Federal University of Minas Gerais]. AB - Nursing education in Brazil is based on the following principles that guide profession : assistance, management, education and research. These activities can not be developed separately as the intersection between them is an important factor to provide nursing care to the population with safety and quality. Even recognizing the importance of this articulation, in this study it is highlighted the professional managerial training. The aim of this paper is to describe the management disciplines teaching in the training of nurses from a critical and reflective analysis of a group of teachers from the Federal University of Minas Gerais, Brazil. The Brazilian Health Reform Movement and the implementation of the National Curriculum Guidelines have resulted in significant advances in teaching Nursing Management, considering that currently content and practical activities take place at different moments of nursing training. It is concluded that, in this new context, teachers have sought more contemporary theoretical references, which focus on a more participative manage in order to train competent professionals who have a more humane and ethical practice. PMID- 29383903 TI - [Nursing education in Spain: background and current program]. AB - Spanish nursing has experienced many changes since the early twentieth century. At first, the nurse was simply a medical assistant, then they studied at university, and nowadaysthey are able to specialize in seven different areas.In the last decade, Spanish nurses have had access to master studies in different fields of the scope of nursing to reach the doctoral degree. This has stimulated research in nursing as well as nurse autonomy. PMID- 29383904 TI - ? PMID- 29383906 TI - ? PMID- 29383905 TI - ? PMID- 29383907 TI - ? PMID- 29383908 TI - ? PMID- 29383909 TI - ? PMID- 29383910 TI - ? PMID- 29383911 TI - ? PMID- 29383912 TI - ? PMID- 29383913 TI - [Nursing science education: a non audible discipline with variable geometry]. AB - How to teach sciences of nurses if words science and nurse are not placed in their meaning and history of their evolution ? Even with doctoral training of high level academic or postdoctoral, it is impressive to see that experienced researchers are still dependent for understanding of their works, the dominant visions of collective representations and the weight of the past.The occupation may no longer think only care or sick, but it must also consider the conditions of knowledge production within its Hautes Ecoles and its use within the health system. PMID- 29383914 TI - [Teaching Nursing science in France: programs and strategies]. AB - The nursing education in academic contexts reinforces the need for students to take ownership and control discipline " nursing ". In some countries the nursing education is well established and fits as well as teaching other scientific disciplines with its epistemology, its authors, methods etc. In other countries it is emerging and ways of doing are not stabilized.The seminar on " The sciences of nursing education " identifies the epistemological fundamentals, clinical and scientific of the discipline to support its development in France. It aims to identify the basic content related to nursing to be acquired in initial training and mastered by all nurses.The answers to questions relating to epistemology and paradigms in nursing, learning clinical, scientific culture and research, nursing education are based on the review of models from other countries, sharing of experiences, discussions in a prospective vision. The recommendations take into account the changes required and consistent with public health goals and service to society. They are supplemented strategies for their appropriation by nurses themselves and other professions and other fields. PMID- 29383915 TI - [Nursing education at the university in Brazil: three experiences]. AB - The ways of forming the nursing professional are linked to the history and to the socio-political and economic context. The article discusses the academic training for nurses in Brazil in three different public universities : University of Sao Paulo, Ribeirao Preto ; Federal University of Goias, Catalao and Federal University of Minas Gerais, Belo Horizonte. It notes the challenges and their differences and similarities. The networks of health services, the universities and university training for nurses are too much different in Brazilian territory. A national law that regulates the training of nurses but the universities has some autonomy to apply these programs. How this structure the nurses formation in this three different universities that we'll compared ? Even with the resources and different histories, the programs of formation have the objectives the management of integral quality care in all health and social services in the country. The achievement of this project is conditioned in each university to the reality and the situation of the health care system and universities as well the work of the professor and nurses. PMID- 29383916 TI - [Nursing Science Education at BachelorAca?!a?cs level: the process for developing a shared vision]. AB - The development and the implementation for a project in nursing science education at a Bachelor?s level is related to the recommendations published in the new curriculum framework (PEC 2012) of the University of Applied Sciences Western Switzerland. Considering the issues raised by the professors concerning the fundamentals in nursing science to be taught at a bachelor?s level, in line with a Master and Doctorate in nursing science, the management of the institution HEDS has given a mandate to two master students in nursing science to brainstorm with professors to develop and improve a plan of action for nursing science education. By relying on a rigorous methodology based on a systemic approach, interviews with national and international nursing experts, nursing faculty deans and professors concerned by those recommendations highlight two priorities for action : incorporate a conception of nursing discipline within the faculty of nursing and set up the curriculum according to the conceptual model chosen. This original project has allowed an important change for the renewal of a shared vision of nursing science education at three levels : the teachers? educational practices, the curriculum and the institution. PMID- 29383917 TI - [A socioconstructivist and humanistic approach to continuing education nurses caring for people with complex needs]. AB - In order to care for persons with complex needs, such as those living with a chronic illness and at risk for complications when hospitalized, nurses must possess multiple sorts of knowledge and skills. After a description of the prevalent schools of thought in pedagogy, the case is made for the use of narrative pedagogy - an educational approach based on nursing science research and congruent with the socio-constructivist and humanist schools of thought?in continuing professional development for nurses. Through the sharing of lived experiences from nurses, care recipients and their families, this educational approach fosters active listening, interpretation, questioning, and perspectival openness. It was tested with nurses caring for hospitalized older persons at risk of presenting signs of acute confusional state and found to be promising. Consequently, it is hoped that educators responsible for the continuing education of nurses in clinical settings will explore this novel educational option in order to adjust their teaching to the knowledge and experience of nurses and to the changing needs of care recipients. PMID- 29383918 TI - [Home care situationsA : discontinuity of trajectories]. AB - Introduction :The aging of the population in Western Europe led to a substantial increase of home-based care services. These services are quite simple in nature, but very complex to provide in the community. Little is known about how they are actually provided.Aim :By the mean of trajectory and arc of work analysis, the aim of this qualitative sociological study is to understand how support and care activities are ran in their local context.Method :Eight home care situations where observed during a period of three months, in three different home-based centers of one French speaking canton of Switzerland. Data collection included semi-structured and ethnographic interviews, service documents, key reference documents and observation of work practices in natural settings.Results :Data analysis showed that the standardization of evaluation practices - and a common frame of reference oriented by administrative principles - limited the possibility to problematize situations as a whole, from a caring point of view. As a consequence, services are mainly delivered in a fractionated way - and work organization is presently driven by compliance concerns.Conclusion :The ongoing standardization of care processes is a challenge to individualized and community based care. PMID- 29383919 TI - [Nursing students assessment in simulated conditionsA : in search of meaning and ethics]. AB - A thought about the assessment in simulated conditions is at the origin of this research-action conducted at the Institute of Nursing Education of Chambery, France. Indeed, the differences in the assessment procedures between units that require this kind of validation and the disappointing rate of success at the examinations in simulated situations have led the trainers to raise the following question : " How can these assessments be meaningful and consistent with the goal of training (help to become autonomous and reflexive practitioners) " ?This issue was addressed with concepts such as socioconstructivism, simulation in health, assessment and ethical principles. The change of practices has been the application of the principles of ?educative? assessment according to G. Nunziatti which strongly involves the students in the assessment?s process.In order to estimate the impact of these changes of practices, an unidentified online survey was offered to all students who benefited from this kind of assessment. The results between two classes of students having had different evaluation procedures have also been compared.The objectives were, after the implementation of this new kind of evaluation, to assess the students? satisfaction, to compare the failure rate at the tests in simulated conditions and to verify the compliance with the ethical principles.This study has shown the students? satisfaction about these new forms of assessment in simulated conditions, an increased success rate in the tests and the applicability of the ethical principles with this way of proceeding. However, the principles of justice and non-maleficence are difficult to implement. Nevertheless, this critical thinking on the procedures of assessment in simulated conditions has helped to change the practices and the assessment design by the teachers. PMID- 29383920 TI - [Learning nursing by short vignette clinical reasoningA : exploratory study]. AB - Introduction : finding ways to teach clinical reasoning has been an important concern of nursing educators for many years.Context : hypothesis generation is a critical milestone in clinical nursing reasoning which students are still struggling with at the end of their program.Aim : the study aimed at documenting nursing student?s capacity to formulate hypotheses during a vignette-based activity.Method : for this qualitative exploratory study, seventeen nursing students in the last semester of their program were recruited and divided in four groups. Each group participated once to the activity. The combined methods used for data collection were participative observation, videotaping the activity and a written questionnaire immediately after the activity. The clinical nursing reasoning skills described by Fonteyn (1998) were used as the theoretical framework to analyse data.Results : results suggest that the vignette-based activity does stimulate students to formulate hypotheses. It also stimulates sharing and recollection of knowledge amongst students.Discussion : further research would be necessary to verify if the activity could be used with students at the beginning of their nursing education.Conclusion : this type of activity could be useful in promoting the development of clinical reasoning as a complement to other educative activities used in nursing education programs.. PMID- 29383921 TI - ? PMID- 29383922 TI - [A cooperation learning program to improve health promotion approach]. AB - Cooperation in the health and social welfare sectors enables the users to be taken care of, as a part of a health promotion approach. The aim of L'IRFSS Auvergne is to promote cooperation between future nurses and social workers within its training sessions. Based on that work, the objective was to implement a framework integrated to both the nursing and social work curriculum, enabling the students to develop team working skills on the field. A survey of nurses and social workers leads to the creation of a pedagogical tool adapted to issues encountered on the field. " the cooperation toolbox kit "In addition to this project, the study raised the question of the role of health promotion in the social work curriculum, the organization of the lifelong training department in a given area, and the role of coordination in the training of managerial staff. PMID- 29383923 TI - [Reflexive analysis of practices and new skills development]. AB - Reflexive approach, as training process has now gained most fields involving the issue of relationship. In the field of healthcare, official texts for the reference training schemes (July 29th, 2009) encourage associating a reflexive process dealing with ability " to analyze any situation of healthcare ". Within the master degree curricula " teacher training to functions of professional accompaniment " of which the authors are co-persons in charge at the University of Cergy Pontoise, they train head nurses, eager to be trained to this approach. In this context, the authors clarify, from their experience, the approach of accompaniment and training in reference to clinical social psychology. They analyze how the training group acquires professional skills in relation to reflexive capacity and identify the process involved in the professional posture transformation. After presenting the device of reflexive analysis of the practice, they highlight the symbolic force of the frame and show the effects of an accompaniment of the new posture with thanks to a meta-analysis process. At each step of the process ; new professional skills identified are put to work, accompanying and accelerating individual and group change process. PMID- 29383924 TI - [Professional development of nurses in promoting health]. AB - This research aims to help the nursing staff and it will help them to develop the skills to use among the school community. On top of her ordinary skills and beyond simple prescriptions, a nurse also has to teach and promote health. It is believed that there is a link between the professional and the personal development. This research deals with the different approaches of (N=30) nurses working within different schools in " Ille et Vilaine ". Nurses ?experiences have been questioned to identify how this professional development centered on three issues : awareness ; identity process and what group they belong to. This qualitive research lies on varied tools that use a compared analysis based on two different types : an oral interview and a pondering written part. PMID- 29383925 TI - [Difficulties/suffering experienced by nurses : strategies for maintaining their mental health, the calling of the profession and their job performance]. AB - The nursing profession is faced with an issue of growing concern, that of the mental health of its practitioners. The many difficulties that nurses experience in the workplace may prove to be detrimental to the maintenance of an optimal mental state. With respect to these difficulties, several strategies can be implemented and used by nurses and managers. The present literature review aims to identify the difficulties and suffering experienced by nurses and the strategies employed to ensure the preservation of mental health, as well as maintaining the calling of the profession and job performance. It also aims to provide nurses and managers of the health care system with ideas to promote optimal mental health for nurses. In this context, " psychodynamique du travail " was chosen as the framework to structure the analysis of the literature dealing with elements surrounding the suffering and difficulties experienced by nurses. The use of this theoretical framework deepens and supports the relationship between the suffering experienced at work and the mental health of nurses. PMID- 29383926 TI - Piperacillin-tazobactam anaphylaxis: a rare cause of occupational disease. AB - Summary: Piperacillin is a beta-lactam antibiotic of penicillin family. Some penicillins were report-ed as occupational diseases cause, but piperacillin anaphylaxis with occupational sensi-tization is rare. We describe the case of a female nurse with recurrent anaphylaxis in last few months without apparent cause, only in work environment. Latex allergy was excluded after negative latex glove provocation. Later during diagnostic workup, the patient reported a similar reaction minutes after piperacillin preparation. She denied any previous antibiotic therapeutic exposure. Skin prick tests (SPT) to beta-lactams were positive to piperacillin, penicillin G and major and minor determinants. SPT to cefuroxime was negative but intradermic test was positive. The patient has indication for beta-lactams eviction and for adrenaline auto-injector kit. No further reactions occurred after patient's transfer to another department with minimum possible exposure. Allergic risk prevention is essential and must be rapidly implemented to avoid incapacitating occupational diseases development. PMID- 29383927 TI - The effect and mechanism of Bushenyiqi prescriptions on learning and memory in aged rats. PMID- 29383928 TI - The future of choline pet in the era of PMSA. AB - Radiolabeled choline was the first radiopharmaceutical agent employed in prostate cancer patients. It has been considered a metabolic agent able to detect the presence of prostate cancer cell, both in the initial phase of the disease and in the restaging setting. Three agents are now available in clinical practice: one radiolabeled with 11C (called 11C-Choline) and two with 18F (either as 18F methylcholine or 18F-ethylcholine). During the years, different studies have been performed with 11C -Choline and 18F- Choline demonstrating their performance for the detection of prostate cancer, in different settings of the disease. However, recently, new radiopharmaceutical agents for prostate cancer have been developed, gaining an important role for the diagnosis of prostate cancer, particularly in the restaging setting. The present review has been conceived in order to discuss the current role of radiolabeled choline PET/CT in the era of new agents for prostate cancer, in particular in the era of radiolabeled PSMA. PMID- 29383929 TI - [Firs Case Report of Intraoperative Radiotherapy (IORT) for Early Breast Cancer in Bulgaria]. AB - The intraoperative radiotherapy (IORT) is an innovative method for treatment of breast cancer, which can be used as a substitute of postoperative external beam radiotherapy )EBRT), or boost treatment to EBRT (1). Radiobiological advantages of IORT compared to EBRT are higher relative biologic effectiveness of low-dose radiation therapy and the presence of high dose in the tumor bed (where the possibility of remaining vital tumor cells is the highest), as this dose reduces rapidly with the distance from the applicator (2). Important feature of IORT alone is that it can be applied as a single fraction during the surgical intervention and spares 3 to 5 weeks of following radiation therapy. This means less time spent in hospital for the patients and for the radiotherapeutical units - reduced waiting lists and more machine time for other patients. Prolonged operative time as well as the need of additional staff are assumed as relative flaws of IORT (3). The INTRABEAM(r) system (Carl Zeiss Surgical Gmbh, Oberkochen, Germany) uses a single high dose of low-energy X-rays (mas 50kV), applied to the tumor bed immediately after the surgical excision of the tumor. These rays have high degree of absorption and low penetrating ability. This determines their advantage in comparison to EBRT to protect the surrounding healthy tissues (2). The data from the Targeted Intraoperative radioTherapy (TARGIT-A) and the Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomized controlled equivalence trial show that when following the recommendations of The Groupe Europeen de Curietherapie European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) Breast Cancer Working Group (2009) for an accelerated partial breast irradiation (APBI), IORT can be used as an equivalent of the postoperative radiotherapy (1,4,5,6). The purpose of this article is to show the results of the performed on 15 December 2015 for the first time in Bulgaria breast conserving surgery with intraoperative radiotherapy on a patient with early breast cancer. PMID- 29383930 TI - An Epidermis-like Hierarchical Smart Coating with a Hardness of Tooth Enamel. AB - We overcome the fundamental dilemma in achieving hard materials with self-healing capability by integrating an epidermis-like hierarchical stratified structure with attractive mechanical and barrier properties of graphene oxide and show that such biomimetic design enables a smart hierarchical coating system with a synergetic healing effect and a record-high stiffness (31.4 +/- 1.8 GPa)/hardness (2.27 +/- 0.09 GPa) among all self-healable polymeric films even comparable to that of tooth enamel. A quasi-linear layer-by-layer (LBL) film with constituent graphene oxide is deposited on top of an exponential LBL counterpart as a protective hard layer, forming a hierarchical stratified assembly mimicking the structure of epidermis. The hybrid multilayers can achieve a complete restoration after scratching thanks to the mutual benefit: The soft underneath cushion can provide additional polymers to assist the recovery of the outer hard layer, which in turn can be a sealing barrier promoting the self-healing of the soft layer during stimulated polymer diffusion. The presenting hybridization mode of LBL assembly represents a promising tool for integrating seemingly contradictory properties in artificial materials with potential performances surpassing those in nature. PMID- 29383931 TI - Bacterial Analysis Using an Electrochemical DNA Biosensor with Poly-Adenine Mediated DNA Self-Assembly. AB - The spatial arrangement of DNA probes on the electrode surface is of critical significance for the performance of electrochemical biosensors. However, rational control of the probe surface remains challenging. In this work, we develop a capture probe carrying a poly-adenine anchoring block to construct a programmable self-assembled monolayer for a "sandwich-type" electrochemical biosensor. We show that with a co-assembling strategy using a polyA capture probe and 6-mercapto-1 hexanol, the density of the probes on the gold electrode can be simply adjusted by the length of polyA. The electron-transfer effect and thus the hybridization efficiency can as well be optimized by tuning the polyA length. As a result, we obtained an excellent biosensor performance with a limit of detection as low as 5 fM for a synthetic DNA target. We demonstrate the practicability of this system by analyzing a PCR product from Escherichia coli genomic DNA (0.2 pg/MUL). On the basis of the ideal electrochemical interface, our polyA-based biosensor exhibited excellent reusability and stability, which is important for potential applications in the onsite analysis for a wide range of targets. PMID- 29383932 TI - Water Stress from High-Volume Hydraulic Fracturing Potentially Threatens Aquatic Biodiversity and Ecosystem Services in Arkansas, United States. AB - Demand for high-volume, short duration water withdrawals could create water stress to aquatic organisms in Fayetteville Shale streams sourced for hydraulic fracturing fluids. We estimated potential water stress using permitted water withdrawal volumes and actual water withdrawals compared to monthly median, low, and high streamflows. Risk for biological stress was considered at 20% of long term median and 10% of high- and low-flow thresholds. Future well build-out projections estimated potential for continued stress. Most water was permitted from small, free-flowing streams and "frack" ponds (dammed streams). Permitted 12 h pumping volumes exceeded median streamflow at 50% of withdrawal sites in June, when flows were low. Daily water usage, from operator disclosures, compared to median streamflow showed possible water stress in 7-51% of catchments from June November, respectively. If 100% of produced water was recycled, per-well water use declined by 25%, reducing threshold exceedance by 10%. Future water stress was predicted to occur in fewer catchments important for drinking water and species of conservation concern due to the decline in new well installations and increased use of recycled water. Accessible and precise withdrawal and streamflow data are critical moving forward to assess and mitigate water stress in streams that experience high-volume withdrawals. PMID- 29383933 TI - Chemically Active, Porous 3D-Printed Thermoplastic Composites. AB - Metal-organic frameworks (MOFs) exhibit exceptional properties and are widely investigated because of their structural and functional versatility relevant to catalysis, separations, and sensing applications. However, their commercial or large-scale application is often limited by their powder forms which make integration into devices challenging. Here, we report the production of MOF thermoplastic polymer composites in well-defined and customizable forms and with complex internal structural features accessed via a standard three-dimensional (3D) printer. MOFs (zeolitic imidazolate framework; ZIF-8) were incorporated homogeneously into both poly(lactic acid) (PLA) and thermoplastic polyurethane (TPU) matrices at high loadings (up to 50% by mass), extruded into filaments, and utilized for on-demand access to 3D structures by fused deposition modeling. Printed, rigid PLA/MOF composites display a large surface area (SAavg = 531 m2 g 1) and hierarchical pore features, whereas flexible TPU/MOF composites achieve a high surface area (SAavg = 706 m2 g-1) by employing a simple method developed to expose obstructed micropores postprinting. Critically, embedded particles in the plastic matrices retain their ability to participate in chemical interactions characteristic of the parent framework. The fabrication strategies were extended to other MOFs and illustrate the potential of 3D printing to create unique porous and high surface area chemically active structures. PMID- 29383934 TI - Titanocene-Mediated Dinitrile Coupling: A Divergent Route to Nitrogen-Containing Polycyclic Aromatic Hydrocarbons. AB - A general synthetic strategy for the construction of large, nitrogen-containing polycyclic aromatic hydrocarbons (PAHs) is reported. The strategy involves two key steps: (1) a titanocene-mediated reductive cyclization of an oligo(dinitrile) precursor to form a PAH appended with di(aza)titanacyclopentadiene functionality; (2) a divergent titanocene transfer reaction, which allows final-step installation of one or more o-quinone, diazole, or pyrazine units into the PAH framework. The new methodology enables rational, late-stage control of HOMO and LUMO energy levels and thus photophysical and electrochemical properties, as revealed by UV/vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations. More generally, this contribution presents the first productive use of di(aza)metallacyclopentadiene intermediates in organic synthesis, including the first formal [2 + 2 + 2] reaction to form a pyrazine ring. PMID- 29383935 TI - Transition-Metal-Triggered High-Efficiency Lithium Ion Storage via Coordination Interactions with Redox-Active Croconate in One-Dimensional Metal-Organic Anode Materials. AB - Coordination polymers (CPs) have powerful competence as anode materials for lithium-ion batteries (LIBs) owing to their structural diversity, tunable functionality, and facile and mild synthetic conditions. Here, we show that two isostructural one-dimensional croconate-based CPs, namely, [M(C5O5)(H2O)3]n (M = Mn for 1 and Co for 2; C5O52- = croconate dianion), can work as high-performance electrode materials for rechargeable LIBs. By means of the coordination between the redox-active transition metal ion and the ligand, the anode materials were stable in the electrolyte and showed high capacities, impressive rate capabilities, and excellent cycling performance during the discharging/charging processes. The chain-based supramolecular structures of the CPs also make them stand out from a crowd of porous three-dimensional molecular materials due to their free channels between the chains for lithium ion diffusion. When tested in a voltage window of 0.01-2.4 V at 100 mA g-1, CPs 1 and 2 demonstrated high discharge specific capacities of 729 and 741 mA h g-1, respectively. The synergistical redox reactions on both metal centers and the organic moieties play a crucial role in the high electrochemical performance of CPs 1 and 2. After undergoing elevated discharging/charging rates to 2 A g-1, the electrodes could finally recover their capabilities as those in the initial stage when the current rate was back to 100 mA g-1, indicating excellent rate performance and outstanding cycling stabilities of the materials. PMID- 29383936 TI - Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/beta-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling. AB - Renal fibrosis is a common end point of the progression of chronic kidney disease (CKD). Suppressing the development and progression of renal fibrosis is essential in the treatment of kidney disease. Our previous study demonstrated that the ethyl acetate extract of the surface layer of Poria cocos exhibited beneficial antitubulointerstitial fibrosis. In this study, we isolated new diterpene (PZF) and triterpenes (PZG and PZH) and examined their antifibrotic effect. TGF-beta1 upregulated the collagen I protein expression in HK-2 cells, and PZG and PZH treatment significantly inhibited the upregulated collagen I expression (TGF group 0.59 +/- 0.08 vs TGF+PZG group 0.36 +/- 0.08, P < 0.01; TGF+PZH group 0.39 +/- 0.12, P < 0.01). Triterpenes, PZG and PZH, exhibited a stronger inhibitory effect on renal fibrosis and podocyte injury than PZF. PZG and PZH further showed a stronger inhibitory effect on the activation of the renin-angiotensin system (RAS) than PZF. Additionally, PZG and PZH markedly inhibited the activation of Wnt/beta-catenin signaling, which played an important role in fibrogenesis. Interestingly, PZG and PZH suppressed the TGF-beta/Smad pathway by selectively inhibiting the phosphorylation of Smad3 through blocking the interactions of SARA with TGFbetaI and Smad3. The analysis of the structure-activity relationship demonstrated that their antifibrotic effects were closely associated with the first six-membered ring structure and the number of carboxyl groups in this type of compounds. Additionally, fifteen known triterpenes were identified. These novel tetracyclic triterpenoid compounds provided the potential lead compounds for the research and development of antifibrosis drug, and they possessed the potential to be utilized as RAS inhibitors. PMID- 29383937 TI - Chemical Structures of Polyphenols That Critically Influence the Toxicity of ZnO Nanoparticles. AB - Recent studies suggested that phytochemicals as natural antioxidants in food could alleviate nanoparticle (NP) toxicity. This study investigated the combined toxicity of ZnO NPs and a panel of polyphenols. Surprisingly, polyphenols with both high and almost no radical scavenging activities could elicit cytoprotective effects against NP exposure in Caco-2 cells, which were primarily influenced by the positions of the hydroxyl group. Polyphenols with different chemical structures variously influenced the hydrodynamic size, zeta potential, and solubility of ZnO NPs as well as NP-induced intracellular superoxide and Zn ions, which could all contribute to the combined effects. Responses of human endothelial cells appeared to be different from the responses of Caco-2 cells, which may indicate cell-type dependent responses to combined exposure of NPs and phytochemicals. In conclusion, the data from this study suggested a pivotal role of chemical structures of phytochemicals in determining their capacity to affect ZnO NP toxicity. PMID- 29383938 TI - Total Synthesis of Clavilactones. AB - Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a gamma-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-) clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D. PMID- 29383941 TI - Cochrane corner: hearing aids for mild to moderate hearing loss in adults. AB - This Cochrane corner features the review entitled "Hearing aids for mild to moderate hearing loss in adults" published in 2017. In their review, Ferguson et al. identified five randomised controlled trials (RCTs) involving 825 participants, with moderate quality of evidence shown for all domains except adverse effects. Results showed a large beneficial effect of hearing aids on hearing-specific health-related quality of life and listening ability, and a small yet significant beneficial effect on overall health-related quality of life. Ferguson et al. concluded that according to the available evidence, hearing aids are effective at improving hearing-specific health-related quality of life, general health-related quality of life and listening ability in adults with mild to moderate hearing loss. The evidence supports the widespread provision of hearing aids as the first-line clinical management for those seeking help for hearing difficulties. PMID- 29383942 TI - The association between trans fatty acids, infertility and fetal life: a review. AB - Trans fatty acids (TFAs) are thought to affect reproductive health by causing adverse effects on sperm morphology and ovum quality as a result of changing membrane lipid composition which, in turn, leads to impairment in metabolic pathways. This literature review examines the evidence for the effects of dietary TFAs on male and female infertility. Studies conducted between 2007 and 2017 on the effect of dietary TFAs on human reproductive health and fetal life have been included. They indicate that TFA intakes are inversely proportional to sperm concentration and total sperm count and exhibit a positive correlation with asthenospermia, as well as an adverse association on sperm concentration and semen quality. In the female TFAs intakes are associated with an increase in the risk of ovulatory infertility, adversely affect the length of gestation leading to fetal developmental defects and fetal loss. The findings suggest that high TFA intake (more than 1% of energy consumption) constitute a risk factor for infertility in both sexes. PMID- 29383939 TI - The validation of Implicit Association Test measures for smartphone and Internet addiction in at-risk children and adolescents. AB - Background Potential concerns are increasing that smartphone and Internet addictions may have deleterious effects on the mental health. Despite the recognition of the important role that implicit associations may have over explicit processes in addiction, such implicit associations have not been comprehensively investigated with respect to Internet addiction. Therefore, we modified the Implicit Association Test (IAT) for smartphone and Internet addictions and investigated its validity in children and adolescents. Methods In this experimental study, 78 at-risk children and adolescents ranging in age from 7 to 17 years completed an IAT modified with pictures captured from the most popular Internet games among youth. Furthermore, measures of Internet and smartphone addictions, mental health and problem behaviors, impulsive tendencies, self-esteem, daily stress, and quality of life were assessed simultaneously. Results Significant correlations were found between IAT D2SD scores and standardized scales for Internet (r = .28, p < .05) and smartphone (r = .33, p < .01) addictions. There were no significant correlations between IAT parameters and other scales measuring the constructs that are less relevant to the features of addiction, such as daily stress levels, impulsivity, and quality of life. Multiple regression analysis revealed that the IAT D2SD was independently and positively associated with smartphone addiction (p = .03) after controlling for other clinical correlates. Conclusions This study demonstrated good convergent and discriminant validity of this IAT as a novel measurement relating to Internet and smartphone addictions. Further longitudinal and prospective studies are needed to evaluate its potential utility in clinical and community settings. PMID- 29383940 TI - Adaptation and validation of the Hungarian version of the Yale Food Addiction Scale for Children. AB - Background Childhood obesity proves to be an important public health issue, since it serves as a potential risk factor for multiple diseases. Food addiction could also serve as an important etiological factor. As childhood obesity plays a serious issue also in Hungary, we aimed to adapt and validate the Hungarian version of the Yale Food Addiction Scale for Children (H-YFAS-C). Methods A total of 191 children were assessed with the H-YFAS-C and the Eating Disorder Inventory (EDI). The following psychometric properties were analyzed: internal consistency, construct validity, convergent, and discriminant validity. Results A good construct validity was revealed by confirmatory factor analysis (RMSEA = 0.0528, CFI = 0.896, chi2 value = 279.06). Question 25 proved to have no significant effect on its group and was removed from further analyses. The Kuder-Richardson 20 coefficient indicated good internal consistency (K20 = 0.82). With the use of the eight EDI subscales, a good convergent and discriminant validity could be determined. Food addiction was diagnosed in 8.9% of children. The mean symptom count was 1.7 +/- 1.2 (range: 0-7). Females were more often diagnosed with food addiction than males (p = .016; OR = 3.6, 95% CI: 1.2-10.6). BMI percentiles were significantly higher in children with diagnosed food addiction (p = .003). There proved to be no correlation between age and the occurrence of food addiction. Discussion and conclusion Our results show that H-YFAS-C is a good and reliable tool for addictive-like behavior assessment. PMID- 29383944 TI - The Effects of a Culturally Tailored, Patient-Centered Psychosocial Intervention in South Korean Cancer Survivors. AB - This study aimed to develop a culturally tailored, patient-centered psychosocial intervention program and to investigate the effects of the program on health related quality of life, sleep disturbance, and depression in cancer survivors. This was a one-group pretest and posttest design. A total of 19 cancer survivors participated in the program. The program was designed to have an 8-week duration with one class per week. Every class was composed of a 90-min education session and a 90-min exercise. Among the health-related quality of life subscales, the scores of global health status/quality of life, physical functioning, and emotional functioning at posttest were statistically increased than those at pretest. Fatigue scores significantly decreased, whereas no changes were observed in sleep disturbance or depression scores. The findings of this study suggested that a culturally tailored, patient-centered psychosocial intervention could be applied in clinical settings to improve health-related quality of life in cancer survivors. PMID- 29383943 TI - Complications of surgery for infectious lung cavities. AB - Background Infectious lung cavities are a common entity for the respiratory physician. Sometimes these lesions require surgical treatment, but surgery is challenging, and complications are common. Methods Patients with infectious lung cavities amenable to surgical treatment were included in a case-control study. The control group included patients with no complications. The cases group comprised patients with any of the following complications up to 90 days after surgery: death, persistence of hemoptysis, empyema, operative blood loss > 500 mL, vascular lesion requiring repair, massive transfusion (>5 units of packed red blood cells per 48 h) or reoperation for bleeding, postoperative mechanical ventilation, intensive care unit stay > 48 h, prolonged air leak, and persistent atelectasis. The potential risk factors for complications analyzed were demographic data, exposure to contaminants, comorbidities, preoperative embolization, surgical indication, spirometry results, and sputum test positive for Mycobacterium tuberculosis. Results Forty-five patients were included in the study and divided into 24 cases and 21 controls. We found a significant difference in the time to removal of chest tubes in favor of the noncomplicated cases (6.45 vs. 4.05 days, p = 0.030), and persistent active infection at the time of surgery tended to be a risk factor for complications (odds ratio = 6.6, 95% confidence interval: 0.7-60, p = 0.061). Conclusion The presence of persistent active infection at the time of surgery could be a risk factor for complications in resection surgery for infectious lung cavities. PMID- 29383945 TI - Assessment of cortical bone fracture resistance curves by fusing artificial neural networks and linear regression. AB - Bone injures (BI) represents one of the major health problems, together with cancer and cardiovascular diseases. Assessment of the risks associated with BI is nontrivial since fragility of human cortical bone is varying with age. Due to restrictions for performing experiments on humans, only a limited number of fracture resistance curves (R-curves) for particular ages have been reported in the literature. This study proposes a novel decision support system for the assessment of bone fracture resistance by fusing various artificial intelligence algorithms. The aim was to estimate the R-curve slope, toughness threshold and stress intensity factor using the two input parameters commonly available during a routine clinical examination: patients age and crack length. Using the data from the literature, the evolutionary assembled Artificial Neural Network was developed and used for the derivation of Linear regression (LR) models of R curves for arbitrary age. Finally, by using the patient (age)-specific LR models and diagnosed crack size one could estimate the risk of bone fracture under given physiological conditions. Compared to the literature, we demonstrated improved performances for estimating nonlinear changes of R-curve slope (R2 = 0.82 vs. R2 = 0.76) and Toughness threshold with ageing (R2 = 0.73 vs. R2 = 0.66). PMID- 29383946 TI - Nanoscale modification of chrysin for improved of therapeutic efficiency and cytotoxicity. AB - Chrysin, as a flavone, is a promising drug candidate because of its multifaceted properties, such as anti-inflammatory, antioxidant and anticancer. However, its poor bioavailability is a bottleneck for pharmaceutical applications. To enhance the bioactive effects, chrysin-loaded poly (D,L-lactic-co-glycolic acid) and polyvinyl alcohol were successfully prepared to overcome problems associated with chrysin. The properties of modified nanochrysin were analysed by in vitro dissolution study, XRD, FTIR and SEM. Free radical scavenging potentials of the modified nanochrysin against DPPH were confirmed based on its stable antioxidant effects. A DNA instability enhancement was observed after H2O2 exposure, whereas chrysin decreased the H2O2 activity, and modified nanochrysin was more potent in this regard. Blood compatibility on red blood cells was confirmed by haemolytic and in vitro cytotoxicity assays. The in vitro anticancer activity of the modified nanochrysin towards MCF-7 and SKOV-3 cell lines using various parameters was investigated. The nanochrysin was found to exert cell growth arrest against both cancer cells in a dose-dependent manner. IC50 value was significantly decreased in nanochrysin in comparison with pure chrysin and induced apoptotic cell death pathway. The results of this study suggest that the nanochrysin might be used for medical applications and offer a beneficial formulation for chemotherapy. PMID- 29383947 TI - Development of a Comprehensive Quality-of-Life Measure for Facial and Torso Acne. AB - : Background Acne is a chronic skin disorder which generally presents in adolescence but continues into adulthood, and negatively affects both physical and psychosocial well-being. Presently, there are no validated acne-specific quality-of-life (QoL) measures that include dimensions for both facial and torso acne. OBJECTIVE: The objective of this study was to develop a QoL instrument for both facial and torso acne (CompAQ) in accordance with recommended standards. METHODS: A literature review and Delphi survey of patients and clinicians were used to develop the conceptual framework for outcomes perceived important to acne patients. An initial version of the measure was developed, CompAQ-v1, and pilot tested with patients via cognitive interviews. RESULTS: The Delphi survey generated 4 domains (physical, psychological, sociological, and treatment) and 54 items. These, along with a literature review and input from clinical experts, informed the development of the CompAQ-v1. Eleven cognitive interviews were conducted, resulting in the second version of the measure, CompAQ-v2. Psychometric validation resulted in the final 20-item CompAQ measure comprising 5 domains. An abbreviated 5-item measure was also developed (CompAQ-SF). CONCLUSION: CompAQ and CompAQ-SF are instruments intended to evaluate QoL in patients with acne on their face or torso. The former is a 21-item QoL intended for research, while the latter is intended for clinical practice. PMID- 29383948 TI - Nevoid Basal Cell Carcinomata Mimicking Melanocytic Nevi: Case Report. PMID- 29383950 TI - Hemoglobin A2 (HbA2) has a measure of unreliability in diagnosing beta thalassemia trait (beta-TT). AB - INTRODUCTION: Detection of beta-thalassemia trait or carriers (beta-TT) depends significantly on an increase in Hemoglobin A2 (HbA2) levels, which is found at low levels (<3%) in normal healthy individuals and elevated levels (>=3.5%) in beta-TT individuals. The study was designed to evaluate the reliability of the diagnostic parameter HbA2 in the differentiation of beta-TT and non-beta-TT in Saudis. METHODS: The widely used high performance liquid chromatography (Variant II Bio-Rad) was used to measure HbA2 levels in blood. Sanger sequencing was used to screen the variation in globin genes (HBB, HBD, HBA1, and HBA2). All the study subjects were divided into betaTT and non-betaTT (wild) categories based on the presence or absence of HBB variations and further sub-divided into false positive, true positive, false negative, and true negative, based on HbA2 values. RESULTS: Out of 288 samples, 96 had HBB gene mutations. Of the 96 beta-TT samples, sickle cell trait (SCT) samples (n = 58) were excluded, while the remaining (38 beta-TT) were included in the detailed analysis: seven subjects with the HBB mutation had normal HbA2 (<3%), and three were borderline (3.1 3.9%). The remainder (n = 28) had an elevated HbA2 level (>4%). Based on HbA2 analysis alone, both these groups would be incorrectly diagnosed as normal. Similarly, of the 189 non-beta-TT samples, 179 had normal HbA2, eight had borderline HbA2, and two had a HbA2 level above 4%. Based on HbA2 analysis alone, borderline and >4% HbA2 individuals, negative for beta-TT, can be incorrectly diagnosed as carriers. CONCLUSION: Given the percentage of samples falling in the HbA2 "borderline" and "normal" categories, it can be concluded that HbA2 has a measure of unreliability in the diagnosis of beta-thalassemia carriers. PMID- 29383951 TI - Gustatory Function in Patients With Chronic Rhinosinusitis. AB - OBJECTIVES: Recent research has shown that taste receptors in airway epithelial cells are involved in defending against upper respiratory tract infection. The aim of the present study was to investigate gustatory function in patients with chronic rhinosinusitis (CRS). METHODS: Taste function was assessed using the extended "taste strip" test in 37 patients with CRS (20 males, 17 females; mean age = 32.1 years; range, 20-82 years) and 135 healthy controls (70 males, 65 females; mean age = 29.5 years; range, 18-84 years). RESULTS: The mean (+/-SD) total extended taste score was 12.8 (+/-3.5) in patients and 14.5 (+/-3.2) in controls. Analysis of variance indicated an interaction of sinusitis and gender ( P < .05) with significantly lower total scores and significantly poorer results for the bitter taste among male patients compared to controls ( P < .01). In addition, CRS patients exhibited a trend toward decreased sweet taste perception compared to controls, but this did not reach significance ( P = .051). CONCLUSIONS: Patients with CRS exhibited decreased gustatory function compared to healthy controls. The effect was most pronounced for bitter taste. Thus, the assessment of gustatory function seems to be useful for detecting potential risk factors for recurrent upper respiratory tract infection. PMID- 29383949 TI - Recent developments on triazole nucleus in anticonvulsant compounds: a review. AB - Epilepsy is one of the common diseases seriously threatening life and health of human. More than 50 million people are suffering from this condition and anticonvulsant agents are the main treatment. However, side effects and intolerance, and a lack of efficacy limit the application of the current anticonvulsant agents. The search for new anticonvulsant agents with higher efficacy and lower toxicity continues to be the focus and task in medicinal chemistry. Numbers of triazole derivatives as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have proved the importance of this heterocyclic nucleus in drug design and discovery. Recently many endeavours were made to involve the triazole into the anticonvulsants design, which have brought lots of active compounds. This work is an attempt to systematically review the research of triazole derivatives in the design and development of anticonvulsant agents during the past two decades. PMID- 29383952 TI - Helmet Clasp Cracks Larynx? A Case Series and Literature Review. AB - INTRODUCTION: Helmet use is well known to greatly reduce the risk of head injury in both bicycle and motorcycle riding. However, helmet buckle position may increase the risk of injury to the neck cartilages. We present a series of cases in which thyroid cartilage fracture is presumed to arise from the position of the helmet buckle during a crash. Our objective with this case series is to outline an unusual series of cases and review the literature regarding laryngeal injuries secondary to helmet impact. DESIGN: Single institution case series. MATERIALS AND METHODS: We present 3 adult patients with laryngeal fractures following bicycle and motorcycle accidents. Medical records were reviewed for history. RESULTS: All patients in this series presented with voice or swallowing complaints and were found to have thyroid cartilage fractures. It was determined that the buckle of the helmet was positioned overlying the larynx during these accidents, so the impact and flexion of the head and neck may have produced sufficient force against it to fracture the cartilage. A literature search yielded works supporting helmet use for head and brain protection but only a single report of laryngeal injuries secondary to helmet use. CONCLUSIONS: Though wearing a helmet is protective against head injuries, it may create serious risk to the neck cartilages when the buckle is positioned adjacent to the larynx. Rare but serious, neck cartilage fracture should be considered in helmeted cycling accidents. It may be reasonable to advance a helmet design that positions the buckle and other nonpliable components laterally, away from neck cartilages. PMID- 29383953 TI - Personality traits predict and moderate the outcome of Internet-based cognitive behavioural therapy for chronic tinnitus. AB - OBJECTIVE: The aim of this study is to investigate whether the Big Five personality traits predict the outcome of Internet-based cognitive behavioural therapy (ICBT) and whether they moderate the outcome between ICBT and face-to face group cognitive behavioural therapy (GCBT). DESIGN: This study investigated the Big Five personality traits as predictors and moderators of the outcome (tinnitus handicap) in a trial comparing ICBT and GCBT for chronic tinnitus. STUDY SAMPLE: N = 84 patients with chronic tinnitus were randomised to either ICBT (n = 41) or GCBT (n = 43). RESULTS: A multilevel model for discontinuous change was performed. Higher scores on the "openness" scale of the Big Five Personality Inventory (BFI-10) predicted a lower tinnitus handicap (Tinnitus Handicap Inventory, THI) at post-treatment in ICBT (p < 0.05). Openness moderated the outcome at post-treatment in favour of ICBT (p < 0.05). Higher scores on the BFI-10 "conscientiousness" scale predicted a more favourable outcome in ICBT at 6 month (p < 0.05) and 12-month follow-up (p < 0.05), but the BFI-10 "conscientiousness" scale was positively associated with the THI at baseline (p < 0.05). CONCLUSIONS: ICBT might be the preferred treatment choice for tinnitus patients being open towards new experiences. Moreover, ICBT requires autonomous work and self-motivation by the patient in order to have an impact. PMID- 29383955 TI - Helicobacter pylori eradication: poor medical compliance from East to West of the world. PMID- 29383954 TI - N-thioalkylcarbazoles derivatives as new anti-proliferative agents: synthesis, characterisation and molecular mechanism evaluation. AB - Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which showed several pharmaceutical properties and occupied a promising place as antitumour tools in preclinical studies. They target several cellular key-points, e.g. DNA and Topoisomerases I and II. The most studied representative, i.e. Ellipticine, was introduced in the treatment of metastatic breast cancer. However, because of the onset of dramatic side effects, its use was almost dismissed. Many efforts were made in order to design and synthesise new carbazole derivatives with good activity and reduced side effects. The major goal of the present study was to synthesise a series of new N-thioalkylcarbazole derivatives with anti-proliferative effects. Two compounds, 5a and 5c, possess an interesting anti-proliferative activity against breast and uterine cancer cell lines without affecting non-tumoural cell lines viability. The most active compound (5c) induces cancer cells death triggering the intrinsic apoptotic pathway by inhibition of Topoisomerase II. PMID- 29383956 TI - The macrophage activation marker sMR as a diagnostic and prognostic marker in patients with acute infectious disease with or without sepsis. AB - Sepsis is a leading cause of mortality. This study aims to assess the utility of the soluble mannose receptor (sMR) as a biomarker of sepsis and mortality in patients hospitalized with suspected infection. Using an in-house ELISA assay the concentration of sMR was analyzed in the serum of patients from three prospective studies. Using Sepsis-3 guidelines, patients were stratified as no infection (NI, n = 68), verified infection without sepsis (NSEP, n = 133) and verified infection with sepsis (SEP, n = 190). Adverse outcome was assessed as death before 28 days. We show that the sensitivity of sMR to predict mortality [area under curve (AUC) = 0.77] exceeded the sensitivity of procalcitonin (PCT, AUC = 0.63), C-reactive protein (CRP, AUC = 0.61) and the macrophage soluble receptor, CD163 (sCD163, AUC = 0.74), while it was less accurate to predict diagnosis of sepsis [AUC(sMR) = 0.69 vs. AUC(PCT) = 0.79, AUC(CRP) = 0.71 and AUC(sCD163) = 0.66]. Median sMR was significantly higher in the group with SEP (0.55 mg/L), compared with the groups without sepsis (NI and NSEP) (0.39 mg/L, p < .0001), and among those who died compared to those who survived (0.89 mg/L vs. 0.44 mg/L, p < .0001). Our results, and the current literature, support further evaluation of sMR as a biomarker of sepsis and mortality among patients hospitalized with suspected infection. PMID- 29383957 TI - Physician perceptions of pharmacologic treatment options for chorea associated with Huntington disease in the United States. AB - OBJECTIVE: To survey neurologists and obtain clinical perceptions of tetrabenazine for the treatment of chorea in patients with Huntington disease (HD). METHODS: Board-certified/board-eligible neurologists, in practice for >=5 years, who had treated treat >=3 HD patients in the past 2 years, were recruited from an online physician panel to participate in a cross-sectional, web-based survey. Respondents provided information about themselves, their practice, approaches to HD chorea management and perceptions of available treatments. RESULTS: Two hundred neurologists responded to the survey. Based on clinician responses, the most common reasons to treat chorea are impairment in activities of daily living (54%) and quality of life (41%). Although tetrabenazine was the only approved treatment for chorea in HD patients at the time of this analysis, it was only prescribed to ~50% of patients with HD-related chorea. More than half of physicians perceive tetrabenazine as having minimal or no effectiveness in improving chorea. More than 40% of physicians consider tetrabenazine to be a non optimal treatment, and 51% of physicians agree that they are unable to titrate to efficacious doses due to adverse side effects or tolerability concerns. Physicians report that side effects leading to dose interruptions (33%) and reductions (30%) occur in their patients "often" or "almost always". The most common side effects that led to insufficient dosing and disruptions in titration were sedation and somnolence (41%), depression (24%) and anxiety (22%). CONCLUSIONS: Many physicians who treat HD-related chorea report that tolerability issues with tetrabenazine impact their ability to effectively use tetrabenazine in their clinical practice. PMID- 29383958 TI - Copper oxide nanoparticles induce collagen deposition via TGF-beta1/Smad3 signaling in human airway epithelial cells. AB - Use and application of nanoparticles has increased in recent years. Copper oxide nanoparticles (CuONPs) are one of the most common types of nanoparticles, and they are mainly used as catalysts and preservatives. However, limited toxicity data are available on the toxicity of CuONPs to the respiratory system. We investigated fibrotic responses induced by CuONPs in the respiratory tract and elucidated its underlying mechanism of action in vivo and in vitro experiments. In the mouse model, CuONPs exposure markedly increased transforming growth factor beta1 (TGF-beta1) and collagen I expression and Smad3 phosphorylation, combined with elevation of inflammatory mediators including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). These alterations were also observed in histological analysis of lung tissue. CuONPs markedly increased inflammatory responses and collagen deposition, accompanied by the elevation of TGF-beta1 and collagen I expression in lung tissue. In addition, CuONPs-treated H292 cells showed significantly increased mRNA and protein production of TGF-beta1, collagen I, IL-6, and TNF-alpha; this response was markedly decreased by treatment of a TGF-beta1 inhibitor (SB-431542). Taken together, CuONPs induced fibrotic responses in the respiratory tract, closely related to TGF-beta1/Smad3 signaling. Therefore, our results raise the necessity of further investigation for the present state of its risk by providing useful information of the toxicity of CuONPs. PMID- 29383959 TI - Investigation into factors affecting the mechanical behaviours of a patient specific vertebral body replacement. AB - Most vertebral body implants that are currently designed and produced in batches have difficulty meeting the patient-specific demands. Moreover, several complications, including a low fusion rate, subsidence occurrence, and rod displacement, are associated with these implants. This study aims to investigate the effects of patient-specific geometric and clinical parameters on the biomechanics of a vertebral body replacement. A three-dimensional patient specific vertebral body replacement model was established as the basic model for parametric studies, including the anatomic design of the endplates, tilting angle, thickness, and dislocation of the vertebral body implant. A finite element analysis was applied to determine the stress distribution of the vertebral body implant when under various loading conditions. The model with an anatomical interfacing design generates 75% less stress concentration compared to a flat design; the peak stress of the model with a tilted angle closely matching the replaced vertebra segment is decreased by 30%; and the thickness close to the cortical bone can offer better bone growth capability and long-term stability. Patient-specific geometrical parameters were found to significantly affect the biomechanics of a vertebral body replacement, and therefore, a design customized especially for the endplates is necessary for better stability and long-term longevity of the prostheses. Regardless of such progress, how to balance the stability of a vertebral body implant and the safety of the peripheral nervous system remains a clinical challenge. PMID- 29383960 TI - Spatial analyses of ALS incidence in Denmark over three decades. AB - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor neuron with very few known risk factors. We conducted a spatial epidemiologic analysis of ALS incidence in Denmark to assess the contribution of sociodemographic determinants to geographic variation. METHODS: We analyzed 4249 ALS cases (1982-2013), each with 100 controls matched on sex and birth year. Odds ratio and 95% confidence bands at birth and diagnosis/index locations were calculated using generalized additive models. We included a bivariate spatial smooth for location in our conditional logistic regression adjusted for socioeconomic status and marital status. We also conducted analyses adjusted for both birth and diagnosis addresses to separate location effects. RESULTS: We observed significantly elevated ALS odds near Copenhagen for both the birth and diagnosis period analyses. Sociodemographic factors did not explain the observed patterns. When we further adjusted our spatial analyses by including both birth and diagnosis addresses, the significant area of elevated male ALS odds by birth address shifted to northwest Denmark away from Copenhagen, and there was little evidence of variation among women. Geographic variation at diagnosis differed between male and females, suggesting that patterns are not just due to regional variation in case ascertainment. CONCLUSION: ALS incidence in Denmark is associated with both location at birth and diagnosis, suggesting that geographic variation may be due to exposures occurring at birth or closer to diagnosis, although the latter could relate to case ascertainment issues. PMID- 29383961 TI - Nano-engineered microcapsules boost the treatment of persistent pain. AB - Persistent pain remains a major health issue: common treatments relying on either repeated local injections or systemic drug administration are prone to concomitant side-effects. It is thought that an alternative could be a multifunctional cargo system to deliver medicine to the target site and release it over a prolonged time window. We nano-engineered microcapsules equipped with adjustable cargo release properties and encapsulated the sodium-channel blocker QX-314 using the layer-by-layer (LbL) technology. First, we employed single-cell electrophysiology to establish in vitro that microcapsule application can dampen neuronal excitability in a controlled fashion. Secondly, we used two-photon excitation imaging to monitor and adjust long-lasting release of encapsulated cargo in target tissue in situ. Finally, we explored an established peripheral inflammation model in rodents to find that a single local injection of QX-314 containing microcapsules could provide robust pain relief lasting for over a week. This was accompanied by a recovery of the locomotive deficit and the amelioration of anxiety in animals with persistent inflammation. Post hoc immunohistology confirmed biodegradation of microcapsules over a period of several weeks. The overall remedial effect lasted 10-20 times longer than that of a single focal drug injection. It depended on the QX-314 encapsulation levels, involved TRPV1-channel-dependent cell permeability of QX-314, and showed no detectable side-effects. Our data suggest that nano-engineered encapsulation provides local drug delivery suitable for prolonged pain relief, which could be highly advantageous compared to existing treatments. PMID- 29383962 TI - Heterogeneity of estrogen receptor alpha and progesterone receptor distribution in lesions of deep infiltrating endometriosis of untreated women or during exposure to various hormonal treatments. AB - Deep infiltrating endometriosis (DIE) responds variably to hormonal therapy. Mutations in cancer driver genes have been identified in a fraction of the ectopic endometrial epithelial cells, suggesting a functional heterogeneity of these lesions. To evaluate the phenotype heterogeneity of cells in DIE, we measured the expression of estrogen receptor alpha (ERalpha) and of progesterone receptor (PR) in DIE of untreated women or under various treatments. We analyzed the luminal epithelial height (LEH), immunoreactive epithelial staining (IRS) and stromal staining intensity (SSI) of ERalpha and PR. We observed a high variability in the same gland, among distinct glands in the same sample and among distinct patients receiving the same treatment. LEH variability was primarily due to epithelial cells heterogeneity in a gland, secondarily to the glands randomly evaluated on the same section, and tertiary to the patient category. Variability in IRS and SSI scores was primarily the consequence of their heterogeneity in the same woman and to a lesser extent to variability among patients. LEH and SSI were not modified according to treatment. IRS for PR was lower in treated patients. This heterogeneity of ERalpha and PR distribution could explain why endocrine treatments are unable to cure this condition. PMID- 29383963 TI - Addendum to Hricak H. MR imaging and MR spectroscopic imaging in the pre treatment evaluation of prostate cancer. Br J Radiol 2005; 78: S103-S111. PMID- 29383964 TI - Acute intermittent porphyria: general aspects with focus on pain. AB - Despite medical advances, the diagnosis and management of acute intermittent porphyria continues to be challenging. Acute pain is one of the most important clinical manifestations in acute intermittent porphyria, but management and pain assessment have been poorly studied in these patients. The lack of information and evidence based recommendations regarding these topics in the medical literature is certainly surprising. Furthermore, pain management is discussed based on extrapolating concepts adopted for other pain syndromes. An important arsenal of medications, including reportedly safe opioid and non-opioid analgesics, is available for use in this type of patient. In addition to conducting an extensive review of the current literature, the present article aims to show the general aspects of a disease that generates a challenge for the clinician, emphasizing what is related to pain as a cardinal symptom and to create awareness about the need for studies supporting the development of guidelines, based on evidence obtained from analgesic management in patients presenting with this disorder. A systematic assessment directed at understanding the physiopathological processes underlying acute pain combined with a stepwise approach to pain management with safe opioid and non-opioid drugs constitutes the fundamental basis for a successful pain management program in patients with acute intermittent porphyria. PMID- 29383965 TI - The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia. AB - BACKGROUND: Prevention of hemarthrosis is the key factor in the adequate management of people with hemophilia (PWH). If hemarthrosis occurs, early diagnosis of joint damage is essential to make personalized treatments. This study is aimed at gaining an understanding of the ability of point-of-care ultrasound (US) using the 'Hemophilia Early Arthropathy Detection with Ultrasound' (HEAD-US) protocol to detect abnormalities in joints without history of hemarthrosis and clinically asymptomatic joints of PWH. METHODS: The sample included 976 joints from 167 PWH (mean age 24.86 years). Data were collected from routine practice over a 3-year period and analyzed based on history of hemarthrosis and results of clinical (HJHS 2.1) and HEAD-US examinations. RESULTS: In our series, 14% of patients exhibited HEAD-US signs of incipient arthropathy in joints with no history of bleeding and with a HJHS 2.1 score of 0. The most severely involved joint was the right ankle. Synovitis, articular cartilage and subchondral bone damage scores in joints with subclinical findings were slower than in joints with previous hemarthroses or HJHS 2.1 > 1 Conclusions: Our study demonstrates that HEAD-US is better than hemarthrosis records and the HJHS 2.1 scale in detecting the early signs of joint damage in PWH. PMID- 29383966 TI - Antero posterior elongation of midbrain in traumatic brain injury- significant sign yet a mistaken entity. AB - BACKGROUND: Antero posterior elongation of the midbrain is observed occasionally in severe traumatic brain injury and generally implies a bad outcome. The objective of the study was to document midbrain elongation and identify the implications of this finding. METHODS: This prospective study included 100 patients with traumatic intracranial haematoma of more than 20 cc in volume. Key measurements were taken in the midbrain and pontine regions and the status of perimesencephalic basal cisterns was noted. All the predictors were analyzed for the outcome. RESULTS: In twenty-nine patients the distorted midbrain appeared to be elongated in the antero posterior direction on visual inspection of CT head images. However, on statistical analysis, it was made out that there is no demonstrable anteroposterior lengthening of the midbrain. The factors influencing the appearance and outcome were discussed. CONCLUSIONS: Although not a true sign, the finding of the elongated appearance of the midbrain in traumatic brain injury still holds significance as a predictor of mortality. Hence, this finding should alert neurosurgeons or intensivists to expedite the administration of suitable interventions in a salvageable patient. PMID- 29383967 TI - Developing FAITHH: Methods to Develop a Faith-Based HIV Stigma-Reduction Intervention in the Rural South. AB - Human immunodeficiency virus (HIV) disproportionately affects Blacks/African Americans, particularly those residing in the southern United States. HIV-related stigma adversely affects strategies to successfully engage people in HIV education, prevention, and care. Interventions targeting stigma reduction are vital as additional tools to move toward improved outcomes with HIV prevention and care, consistent with national goals. Faith institutions in the South have been understudied as partners in HIV stigma-reduction efforts, and some at-risk, Black/African American communities are involved with southern faith institutions. We describe the collaborative effort with rural, southern faith leaders from various denominations to develop and pilot test Project Faith-based Anti-stigma Initiative Towards Healing HIV/AIDS (FAITHH), an HIV stigma-reduction intervention that built on strategies previously used with other nonrural, Black/African American faith communities. The eight-module intervention included educational materials, myth-busting exercises to increase accurate HIV knowledge, role-playing, activities to confront stigma, and opportunities to develop and practice delivering a sermon about HIV that included scripture-based content and guidance. Engaging faith leaders facilitated the successful tailoring of the intervention, and congregation members were willing participants in the research process in support of increased HIV awareness, prevention, and care. PMID- 29383968 TI - Language in individuals with left hemisphere tumors: Is spontaneous speech analysis comparable to formal testing? AB - BACKGROUND: The relationship between spontaneous speech and formal language testing in people with brain tumors (gliomas) has been rarely studied. In clinical practice, formal testing is typically used, while spontaneous speech is less often evaluated quantitatively. However, spontaneous speech is quicker to sample and may be less prone to test/retest effects, making it a potential candidate for assessing language impairments when there is restricted time or when the patient is unable to undertake prolonged testing. AIM: To assess whether quantitative spontaneous speech analysis and formal testing detect comparable language impairments in people with gliomas. Specifically, we addressed (a) whether both measures detected comparable language impairments in our patient sample; and (b) which language levels, assessment times, and spontaneous speech variables were more often impaired in this subject group. METHOD: Five people with left perisylvian gliomas performed a spontaneous speech task and a formal language assessment. Tests were administered before surgery, within a week after surgery, and seven months after surgery. Performance on spontaneous speech was compared with that of 15 healthy speakers. RESULTS: Language impairments were detected more often with both measures than with either measure independently. Lexical-semantic impairments were more common than phonological and grammatical impairments, and performance was equally impaired across assessment time points. Incomplete sentences and phonological paraphasias were the most common error types. CONCLUSIONS: In our sample both spontaneous speech analysis and formal testing detected comparable language impairments. Currently, we suggest that formal testing remains overall the better option, except for cases in which there are restrictions on testing time or the patient is too tired to undergo formal testing. In these cases, spontaneous speech may provide a viable alternative, particularly if automated analysis of spontaneous speech becomes more readily available in the future. These results await replication in a bigger sample and/or other populations. PMID- 29383969 TI - Contouring pudendal nerves. PMID- 29383970 TI - Long non-coding RNA nuclear paraspeckle assembly transcript 1 inhibits the apoptosis of retina Muller cells after diabetic retinopathy through regulating miR-497/brain-derived neurotrophic factor axis. AB - BACKGROUND: The role of long non-coding RNA in diabetic retinopathy, a serious complication of diabetes mellitus, has attracted increasing attention in recent years. The purpose of this study was to explore whether long non-coding RNA nuclear paraspeckle assembly transcript 1 was involved in the context of diabetic retinopathy and its underlying mechanisms. RESULTS: Our results revealed that nuclear paraspeckle assembly transcript 1 was significantly downregulated in the retina of diabetes mellitus rats. Meanwhile, miR-497 was significantly increased in diabetes mellitus rats' retina and high glucose-treated Muller cells, but brain-derived neurotrophic factor was increased. We also found that high glucose induced apoptosis of Muller cells was accompanied by the significant downregulation of nuclear paraspeckle assembly transcript 1 in vitro. Further study demonstrated that high glucose-promoted Muller cells apoptosis through downregulating nuclear paraspeckle assembly transcript 1 and downregulated nuclear paraspeckle assembly transcript 1 mediated this effect via negative regulating miR-497. Moreover, brain-derived neurotrophic factor was negatively regulated by miR-497 and associated with the apoptosis of Muller cells under high glucose. CONCLUSION: Our results suggested that under diabetic conditions, downregulated nuclear paraspeckle assembly transcript 1 decreased the expression of brain-derived neurotrophic factor through elevating miR-497, thereby promoting Muller cells apoptosis and aggravating diabetic retinopathy. PMID- 29383972 TI - Knowledge of an inflammatory biomarker of cardiovascular risk leads to biomarker based decreased risk in pre-diabetic and diabetic patients. AB - Objective Diabetes is a risk equivalent for cardiovascular events. The increase in vascular inflammation with diabetes is believed to be responsible for increased risk of ischemic events in diabetic patients. Our goal was to assess whether knowledge of vascular inflammation alters cardiovascular risk over time, and how knowledge of vascular inflammation changes risk in non-diabetic, pre diabetic and diabetic patients. Methods We retrospectively studied >100,000 primary-care patients per annum for 5 years (baseline in 2011 through 2015) with tests including lipoprotein profile, hemoglobin A1C and the vascular-specific inflammation risk marker myeloperoxidase. Results were obtained during the patient's MD Value In Prevention (MDVIP) annual wellness program physical. Results We show that rates of patients with elevated myeloperoxidase levels were reduced from 14.4%, 15.2% and 21.3% to 4.0%, 4.0% and 6.7% in non-diabetic, pre diabetic and diabetic patients, respectively, over the 5-year period. Decreases in vascular inflammation were achieved without decreases in the prevalence of pre diabetes (hemoglobin A1C 5.7%-6.4%) or diabetes (hemoglobin A1C >6.4%) and were observed in patients below or above guideline low-density lipoprotein targets. Conclusions These data demonstrate that physicians informed of elevated markers of vascular inflammation can lower vascular inflammation correlating with biomarker-based decreased risk of cardiovascular events. PMID- 29383971 TI - Evaluation of the oxidative stress-related genes ALOX5, ALOX5AP, GPX1, GPX3 and MPO for contribution to the risk of type 2 diabetes mellitus in the Han Chinese population. AB - AIM: Type 2 diabetes mellitus is a polygenic metabolic disorder resulting from oxidative stress, the root cause of insulin resistance, beta-cell dysfunction and impaired glucose tolerance. The aim of this study was to investigate the role of oxidative stress-related genes ALOX5, ALOX5AP, GPX1, GPX3 and MPO in type 2 diabetes mellitus susceptibility in the Chinese Han population. METHODS: A total of 396 type 2 diabetes mellitus patients and 678 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222, GPX1 rs1050450, GPX3 rs3828599 and MPO rs2107545 gene polymorphisms were genotyped. RESULTS: We found one single nucleotide polymorphism in the MPO gene was associated with type 2 diabetes mellitus susceptibility [rs2107545: odds ratio = 1.563 (1.166-2.096); p = 0.003], after adjusting for covariates. Furthermore, we also considered the likely complexity of effects of genetic and conventional risk factors in type 2 diabetes mellitus-related vascular complications, such as carotid plaques. Our analysis revealed that the GPX1 rs1050450 and MPO rs2107545 were significantly associated with increased risk of carotid plaques in type 2 diabetes mellitus patients. CONCLUSION: Our study presents novel evidence for main effects of MPO gene on type 2 diabetes mellitus susceptibility. Furthermore, our study supported the association between variants of oxidative stress-related genes ( GPX1 and MPO) and carotid plaques in type 2 diabetes mellitus patients, which indicated a modulation of type 2 diabetes mellitus-related vascular complication susceptibility by genetic predisposition. PMID- 29383973 TI - Insulin- and quercetin-loaded liquid crystalline nanoparticles: implications on oral bioavailability, antidiabetic and antioxidant efficacy. AB - AIM: The present study reports insulin (INS)- and quercetin (QT)-lyotropic liquid crystalline nanoparticles (LCNPs) with improved bioavailability, antidiabetic and antioxidant efficacy following oral administration. MATERIALS & METHODS: The developed INS-QT-LCNPs were evaluated for simulated gastric fluid stability. In vitro Caco-2 uptake studies were also performed. Furthermore, in vivo pharmacokinetics and pharmacodynamics of INS-QT-LCNPs were evaluated. RESULTS & CONCLUSION: INS entrapped within LCNPs demonstrated excellent stability in simulated gastric fluid. Higher uptake of fluorescein isothiocyanate-INS-LCNPs were observed in Caco-2 cells. INS-LCNPs demonstrated approximately 20% relative bioavailability compared with subcutaneously administered INS. Significant decrease in oxidative stress was confirmed by reduction in malondialdehyde level. Overall, combination strategy not only overcomes poor oral bioavailability of INS and QT, but also prevents the generation of reactive oxygen species, responsible for diabetes-mediated complications. PMID- 29383974 TI - Is the accuracy of preoperative MRI stage in rectal adenocarcinoma influenced by tumour height? AB - AIM: To our knowledge, no prior studies have addressed the possible effects of tumour height on the accuracy of preoperative magnetic resonance imaging (MRI) based staging relative to postoperative histopathological assessments in patients with adenocarcinoma of the rectum (RC). This study aimed to investigate whether the accuracy of preoperative MRI stage in RC is influenced by tumour height. METHODS: A total of 489 consecutive RC patients scheduled for curative treatment between 2009 and 2013 were included. Of the 489 patients, 133 patients had preoperative chemoradiotherapy (CRT), and 356 patients underwent primary surgery. Low, mid and high RC were defined as a tumour <5 cm, 5-10 cm and >10 cm from the anal verge, respectively. Diagnostic MRI and, for patients with CRT, re-staging MRI features including tumour T-stage (mrT), distance between the tumour border and the distance to the mesorectal fascia (mrMRF), extramural tumour depth (mrEMD), extramural vascular invasion (mrEMVI) and nodal involvement (mrN) were correlated with the corresponding postoperative histopathological findings. RESULTS: There were 115, 186 and 188 patients with low RC, mid RC and high RC, respectively. For all patients, the correlations between mrT and pT and between mrMRF and pCRM were not influenced by tumour height. None of the correlations between mrEMD, mrEMVI and mrN and the corresponding postoperative histopathological findings significantly differed for tumours of different heights. For patients with CRT, a remarkable proportion with low RC were overstaged as ymrT3 compared to ypT0-2. CONCLUSIONS: The ability to preoperatively use MRI to accurately stage is not influenced by tumour height. For patients with preoperative CRT, low RC may be MRI overstaged due to post radiation fibrosis. We found that mrEMD predicts pEMD reliably and should therefore be considered in treatment decisions. Although new MRI techniques are emerging, preoperative RC staging remains incompletely definitive in daily clinical practice. PMID- 29383975 TI - Fenestration of the supraclinoid internal carotid artery connecting the neck of the paraclinoid aneurysm and the origin of the posterior communicating artery: A case report. AB - Fenestration of the supraclinoid internal carotid artery is extremely rare and frequently associated with aneurysms at the fenestrated segment or other vascular anomalies. We present a rare case of fenestration of the right supraclinoid internal carotid artery in which a small fenestrated segment arose from the neck portion of the paraclinoid aneurysm and fused with the origin of the posterior communicating artery. PMID- 29383976 TI - The dynamic natural history of cerebral aneurysms from cardiac myxomas: A review of the natural history of myxomatous aneurysms. AB - We describe two contrasting patients with multiple cerebral aneurysms and a previous history of resected cardiac myxomas with no cardiac recurrence on follow up echocardiography. Both patients presented with stroke- like symptoms; one with a left visual defect and the other with right hemiplegia. Magnetic resonance imaging of the brain of both patients showed the presence of multiple cerebral aneurysms that was later confirmed on conventional angiography. Both patients' aneurysms were managed conservatively. Serial angiograms were performed during their follow-up, which spanned several years. One patient's aneurysms remained static while the evolution of the other patient's aneurysms displayed a dynamic quality with some increasing in size while others diminished. This is the first description in which some aneurysms progressed while others regressed simultaneously in the same patient. Aneurysms in patients with a history of cardiac myxoma can be active years after primary tumor resection and it is difficult to predict how they will develop. We reviewed the literature of all patients with multiple myxomatous aneurysms who were treated conservatively to better understand the natural history of this rare disease. Long-term follow-up of these patients may be necessary. PMID- 29383977 TI - Does Self-Licensing Benefit Self-Regulation Over Time? An Ecological Momentary Assessment Study of Food Temptations. AB - Self-licensing, employing reasons to justify indulgence, may help resolve the conflict between immediate temptations and long-term goals in favor of the former. It was hypothesized that this conflict-resolving potential of self licensing may benefit self-regulation over time. With a momentary assessment design, we examined how self-licensing affects self-regulatory ability and the capacity to deal with subsequent self-regulatory conflicts. One hundred thirty six female participants filled out surveys eight times per day for one week. Food temptation strength, conflict, resistance, and enactment were assessed, as well as license opportunity and perceived self-regulatory ability. When self-licensing opportunity was high (vs. low), a weaker association between temptation strength and conflict was observed. High license opportunity was associated with higher perceived self-regulatory ability for instances of low degrees of temptation enactment and predicted better handling of subsequent conflict after high degrees of prior temptation enactment. These results suggest that self-licensing can support self-regulation after initial failure. PMID- 29383979 TI - Recruiting the best into medical careers. PMID- 29383978 TI - Of two minds or one? A registered replication of Rydell et al. (2006). AB - Evaluative conditioning (EC) is proposed as a mechanism of automatic preference acquisition in dual-process theories of attitudes (Gawronski, B., & Bodenhausen, G. V. (2006). Associative and propositional processes in evaluation: An integrative review of implicit and explicit attitude change. Psychological Bulletin, 132(5), 692-731. doi: 10.1037/0033-2909.132.5.692 ). Evidence for the automaticity of EC comes from studies claiming EC effects for subliminally presented stimuli. An impression-formation study showed a selective influence of briefly presented primes on implicitly measured attitudes, whereas supraliminally presented behavioural information about the target person was reflected in explicit ratings (Rydell, R. J., McConnell, A. R., Mackie, D. M., & Strain, L. M. (2006). Of two minds forming and changing valence-inconsistent implicit and explicit attitudes. Psychological Science, 17(11), 954-958. doi:10.1111/j.1467 9280.2006.01811.x) This finding is considered one of the strongest pieces of evidence for dual process theories (Sweldens, S., Corneille, O., & Yzerbyt, V. (2014). The role of awareness in attitude formation through evaluative conditioning. Personality and Social Psychology Review, 18(2), 187-209. doi: 10.1177/1088868314527832 ), and it is therefore crucial to assess its reliability and robustness. The present study presents two registered replications of the Rydell et al. (2006) study. In contrast to the original findings, the implicit measures did not reflect the valence of the subliminal primes in both studies. PMID- 29383980 TI - Optimizing Anti-VEGF Treatment Outcomes for Patients with Neovascular Age-Related Macular Degeneration. AB - BACKGROUND: The introduction of anti-vascular endothelial growth factor (anti VEGF) drugs to ophthalmology has revolutionized the treatment of neovascular age related macular degeneration (nAMD). Despite this significant progress, gaps and challenges persist in the diagnosis of nAMD, initiation of treatment, and management of frequent intravitreal injections. Thus, nAMD remains a leading cause of blindness in the United States. OBJECTIVE: To present current knowledge, evidence, and expert perspectives on anti-VEGF therapies in nAMD to support managed care professionals and providers in decision making and collaborative strategies to overcome barriers to optimize anti-VEGF treatment outcomes among nAMD patients. SUMMARY: Three anti-VEGF therapies currently form the mainstay of treatment for nAMD, including 2 therapies approved by the FDA for treatment of nAMD (aflibercept and ranibizumab) and 1 therapy approved by the FDA for oncology indications and used off-label for treatment of nAMD (bevacizumab). In clinical trials, each of the 3 agents maintained visual acuity (VA) in approximately 90% or more of nAMD patients over 2 years. However, in long-term and real-world settings, significant gaps and challenges in diagnosis, treatment, and management pose barriers to achieving optimal outcomes for patients with nAMD. Many considerations, including individual patient characteristics, on-label versus off label treatment, repackaging, and financial considerations, add to the complexity of nAMD decision making and management. Many factors may contribute to additional challenges leading to suboptimal long-term outcomes among nAMD patients, such as delays in diagnosis and/or treatment approval and initiation, individual patient response to different anti-VEGF therapies, lapses in physician regimentation of anti-VEGF injection and monitoring, and inadequate patient adherence to treatment and monitoring. These latter factors highlight the considerable logistical, emotional, and financial burdens of long-term, frequent intravitreal injections and the vital importance of personalized approaches to anti-VEGF treatment decision making and management for patients with nAMD. To address these challenges and reduce the number of yearly injections, studies have examined alternative dosing regimens, including extended fixed intervals, as needed, and treat-and-extend strategies in specific nAMD patient populations. New clinical evidence and insights into expert clinical practice discussed in this article can support managed care professionals in the key role they play in addressing challenges in nAMD treatment and management and optimizing patient outcomes through appropriate management of anti-VEGF treatment. DISCLOSURES: PRIME Education is an independent medical education company and has been an accredited provider of continuing education for 23 years. There is no fee for this activity as it is sponsored by PRIME through an educational grant from Regeneron. All authors contributed to the writing and reviewing of the article. Wykoff reports consultancies/research grants from Alcon Laboratories, Genentech/Roche, Clearside, and Iconic Therapeutics; consultancies/honoraria, research grants, and speaker fees from Allergan and Regeneron; research grants from Allegro, Apellis, Aura, NEI, NIH, Novartis, OHR Pharmaceuticals, Ophthotech, pSivida, Roche, Santen, SciFluor, Tyrogenex; and consultancies for Alimera Sciences, Alnylam Pharmaceuticals, Bayer, DORC, ONL Therapeutics, Thrombogenics, and Valeant. Clark reports advisory board work, consultancies, research grants, and speaker fees from Genentech/Roche and Regeneron and consultancy for Bayer. Brill reports consultancies for Aries Pharma, Avella, BaroNova, Braeburn Pharmaceuticals, Cardinal Health, Endogastric Solutions, GeneNews, Halt Medical, Lumendi, Medtronic, Monteris Medical, Natera, Phosphorus, Rebiotix, Seno Medical, UCB, Vermillion, Echosens, and HAP Innovations. Brill is a shareholder in EndoChoice, GeneNews, SonarMD, and SynerZ and reports advisory board work with Nestle Health Sciences, Indivior Pharmaceuticals, Eli Lilly, Blue Earth Diagnostics, Bayer, and AstraZeneca. Nielson reports advisory board work/consultancy and research grants for Genentech/Roche; advisory board work and research grants from Regeneron; and research grants from Alcon and Ophthotech. PMID- 29383981 TI - Comparison of Different In Vivo Incubation Sites to Produce Tissue-Engineered Small Intestine. AB - OBJECTIVE: The objective of this study was to compare the impact of different in vivo incubation sites on the production of tissue-engineered small intestine (TESI). MATERIALS AND METHODS: Green fluorescent protein transgenic rat pups (3-5 days) were used as donors of intestinal organoids. Harvested intestine was exposed to enzymatic digestion to release intestinal stem cell-containing organoids. Organoids were purified, concentrated, and seeded onto tubular polyglycolic acid scaffolds. Seeded scaffolds were implanted in each of five locations in recipient female nude rats: wrapped with omentum, wrapped with intestinal mesentery, wrapped with uterine horn membrane, attached to the abdominal wall, and inserted into the subcutaneous space. After 4 weeks of in vivo incubation, specimens from each site were explanted for evaluation. RESULTS: Wrapping seeded scaffolds with vascularized membranes produced TESI with variable lengths of vascularized pedicles, with the longest pedicle length from uterine horn membrane, the shortest pedicle length from intestinal mesentery, and intermediate length from omentum. The quantity of TESI, as expressed by volume and neomucosal length, was identical in TESI produced by wrapping with any of the three membranes. The smallest quantity of TESI was found in TESI produced from insertion into the subcutaneous space, with an intermediate quantity of TESI produced from attachment to the abdominal wall. Periodic acid-Schiff and immunofluorescence (IF) staining confirmed the presence of all intestinal epithelial cell lineages in TESI produced at all incubation sites. Additional IF staining demonstrated the presence of enteric nervous system components and blood vessels. Wrapping of seeded scaffolds with vascularized membranes significantly increased the density of blood vessels in the TESI produced. CONCLUSION: Wrapping of seeded scaffolds in vascularized membranes produced the largest quantity and highest quality of TESI. Attaching seeded scaffolds to the abdominal wall produced an intermediate quantity of TESI, but the quality was still comparable to TESI produced in vascularized membranes. Insertion of seeded scaffolds into the subcutaneous space produced the smallest quantity and lowest quality of TESI. In summary, wrapping seeded scaffolds with vascularized membranes is favorable for the production of TESI, and wrapping with omentum may produce TESI that is most easily anastomosed with host intestine. PMID- 29383982 TI - The Impact of motivational interviewing on illness perception in patients with stable coronary artery disease. A randomised controlled study AB - Background: Coronary heart disease (CHD) constitutes one of the most frequent causes of death for individuals > 60 years. Lifestyle dependent risk factors are key. Hence, cardiac rehabilitation is essential for optimal CHD treatment. However, individuals rarely comprehend their illness. Motivational interviewing promotes illness perception. Aim/Methods: A randomised-controlled study was conducted to determine the effect of motivational interviewing on illness perception. Patients with stable coronary heart disease were consecutively recruited after elective percutaneous transluminal coronary angioplasty (PTCA). The intervention group received a short motivational interview (MI) about the disease and related risk factors as an intervention. The control group had usual treatment. Illness perception was assessed (Illness Perception Questionnaire Revised) prior to the intervention and six months afterwards. Results: A total of 312 patients (intervention group: n = 148, control group: n = 164) were recruited into the study (mean age: 66.2 years). After the intervention, a significant change was observed in the domain of emotional reactions regarding the disease. Conclusion: To improve illness perception in patients with stable CHD, one short intervention with MI may have an effect. Whether intensifying the MI-intervention is more effective, requires further research. PMID- 29383983 TI - The role of the gut microbiota in schizophrenia: Current and future perspectives. AB - OBJECTIVES: Schizophrenia is a poorly understood chronic disease. Its pathophysiology is complex, dynamic, and linked to epigenetic mechanisms and microbiota involvement. Nowadays, correlating schizophrenia with the environment makes sense owing to its multidimensional implications: temporal and spatial variability. Microbiota involvement and epigenetic mechanisms are factors that are currently being considered to better understand another dimension of schizophrenia. METHODS: This review summarises and discusses currently available information, focussing on the microbiota, epigenetic mechanisms, technological approaches aimed at performing exhaustive analyses of the microbiota, and psychotherapies, to establish future perspectives. RESULTS: The connection between the microbiota, epigenetic mechanisms and technological developments allows for formulating new approaches objectively oriented towards the development of alternative psychotherapies that may help treat schizophrenia. CONCLUSIONS: In this review, the gut microbiota and epigenetic mechanisms were considered as key regulators, revealing a potential new aetiology of schizophrenia. Likewise, continuous technological advances (e.g. culturomics), aimed at the microbiota-gut-brain axis generate new evidence on this concept. PMID- 29383985 TI - Chitosan-coated nanoparticles enhanced lung pharmacokinetic profile of voriconazole upon pulmonary delivery in mice. AB - AIM: Chitosan-coated polylactic-co-glycolic acid nanoparticles of voriconazole (VChNP) were developed to increase residence time and provide sustained drug release locally to treat recurrent lung-fungal infection. MATERIALS & METHODS: VChNP has been developed using a simple, unique technique and characterized. Pharmacokinetics, lung deposition with time and gamma imaging were conducted with optimized formulations. RESULTS: The deposition of fluorescein isothiocyanate labeled VChNP in lung was confirmed by confocal microscopy. Gamma-scintigraphic images showed that Tc-99m-labeled VChNP had better pulmonary retention for longer period than that of noncoated formulation. Drastic improvement in pharmacokinetic profile of VChNP than noncoated formulation was observed. CONCLUSION: Thus, VChNP may be useful for effective pulmonary delivery with improved bioavailability. Such chitosan-coated nanoparticles may open up a new avenue for efficacious treatment of lung-fungal infection. PMID- 29383984 TI - Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. AB - The present study examined whether preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. Among 65 adult patients with ischemic moyamoya disease, 19 had misery perfusion in the precentral region on preoperative 15O positron emission tomography and underwent arterial bypass surgery for that region. Brain technetium-99 m-labeled ethyl cysteinate dimer single-photon emission computed tomography (SPECT) was preoperatively performed with and without hyperventilation challenge and relative cerebrovascular contractile reactivity to hypocapnia (RCVCRhypocap) (%/mmHg) was calculated in the precentral region. Development of cerebral hyperperfusion syndrome was determined using perioperative changes of symptoms and brain N isopropyl-p-[123I]-iodoamphetamine SPECT performed after surgery. RCVCRhypocap was significantly lower in the 6 patients with cerebral hyperperfusion syndrome ( 2.85 +/- 1.10%/mmHg) than in the 13 patients without cerebral hyperperfusion syndrome (0.18 +/- 1.97%/mmHg; p = 0.0050). Multivariate analysis demonstrated low RCVCRhypocap as an independent predictor of cerebral hyperperfusion syndrome (95% confidence interval, 0.04-0.96; p = 0.0433). Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. PMID- 29383986 TI - Neuroprotective and tumoricidal activities of cardiac glycosides. Could oleandrin be a new weapon against stroke and glioblastoma? AB - Cardiac glycosides induce a strong immunological cancer cell cytotoxicity, in which the released intracellular components of dying tumor cells (e.g. calreticulin, HMGB1 and ATP) stimulate immunity and help in eradicating cancer. Among the cardiac glycosides, oleandrin is an inhibitor of P-glycoprotein expression and exerts excellent penetration through the blood-brain barrier which also harbors neuroprotective and anti-glioma efficacies. Cardiac glycosides also exert neuroprotective activities, one explanation for such an action is the metabolic arrest as a defense strategy against hypoxia. Recently, it was also shown that oleandrin increases survival of glioma-implanted mice alone and in synergy with temozolomide, which also associated with the release of brain derived neurotrophic factor and activation of its receptor TrkB. In conclusion, oleandrin strongly deserves to be studied as a candidate molecule in treatment of neurodegenerative and neurooncological diseases. PMID- 29383987 TI - Results of an Arctic Council survey on water and sanitation services in the Arctic. AB - As part of a project endorsed by the Arctic Council's Sustainable Development Working Group (SDWG), a survey was conducted to describe the current status of water, sanitation and hygiene (WASH) services in the Arctic region. The English language internet-based survey was open from April to September, 2016 and drew 142 respondents from seven Arctic nations. Respondents provided information on access to WASH services, notification requirements for water-related infectious diseases, and examples of environmental- or climate-change related events that impact the provision of WASH services. Many remote Arctic and sub-Arctic residents lack WASH services, and these disparities are often not reflected in national summary data. Environmental changes impacting WASH services were reported by respondents in every Arctic nation. Participants at an international conference co-sponsored by SDWG reviewed these results and provided suggestions for next steps to improve health of Arctic residents through improved access to water and sanitation services. Suggestions included ongoing reporting on WASH service availability in underserved populations to measure progress towards UN Sustainable Development Goal #6; evaluations of the health and economic consequences of disparities in WASH services; and Arctic-specific forums to share innovations in WASH technology, improved management and operations, and adaptation strategies for environmental or climate change. PMID- 29383989 TI - Performance of the fixed-bed of granular activated carbon for the removal of pesticides from water supply. AB - : The application of a fixed bed adsorption column of granular activated carbon (FBAC-GAC), in the removal of carbaryl, methomyl and carbofuran at a concentration of 25 MUg L-1 for each carbamate, from the public water supply was investigated. For the determination of the presence of pesticides in the water supply, the analytical technique of high-performance liquid chromatography with post-column derivatization was used. Under conditions of constant diffusivity, the FBAC-GAC was saturated after 196 h of operation on a pilot scale. The exhaust rate of the granular activated carbon (GAC) in the FBAC-GAC until the point of saturation was 0.02 kg GAC m-3 of treated water. By comparing a rapid small-scale column test and FBAC-GAC, it was confirmed that the predominant intraparticle diffusivity in the adsorption column was constant diffusivity. Based on the results obtained on a pilot scale, it was possible to estimate the values to be applied in the FBAC-GAC (full scale) to remove the pesticides, which are particle size with an average diameter of 1.5 mm GAC; relationship between the internal diameter of the column and the average diameter of GAC >=50 in order to avoid preferential flow near the adsorption column wall; surface application rate 240 m3 m-2 d-1 and an empty bed contact time of 3 min. ABBREVIATIONS: BV: bed volume; CD: constant diffusivity; EBCT: empty bed contact time; FBAC-GAC: fixed bed adsorption column of granular activated carbon; GAC: granular activated carbon; MPV: maximum permitted values; NOM: natural organic matter; PD: proportional diffusivity; pHPCZ: pH of the zero charge point; SAR: surface application rate; RSSCT: rapid small-scale column test; WTCS: water treated conventional system. PMID- 29383990 TI - Separating variability in healthcare practice patterns from random error. AB - Improving the quality of care that patients receive is a major focus of clinical research, particularly in the setting of cardiovascular hospitalization. Quality improvement studies seek to estimate and visualize the degree of variability in dichotomous treatment patterns and outcomes across different providers, whereby naive techniques either over-estimate or under-estimate the actual degree of variation. Various statistical methods have been proposed for similar applications including (1) the Gaussian hierarchical model, (2) the semi parametric Bayesian hierarchical model with a Dirichlet process prior and (3) the non-parametric empirical Bayes approach of smoothing by roughening. Alternatively, we propose that a recently developed method for density estimation in the presence of measurement error, moment-adjusted imputation, can be adapted for this problem. The methods are compared by an extensive simulation study. In the present context, we find that the Bayesian methods are sensitive to the choice of prior and tuning parameters, whereas moment-adjusted imputation performs well with modest sample size requirements. The alternative approaches are applied to identify disparities in the receipt of early physician follow-up after myocardial infarction across 225 hospitals in the CRUSADE registry. PMID- 29383988 TI - Effect of a combination of inulin and polyphenol-containing adzuki bean extract on intestinal fermentation in vitro and in vivo. AB - The effect of a combination of inulin (INU) and polyphenol-containing adzuki bean extract (AE) on intestinal fermentation was examined in vitro using fermenters for 48 h and in vivo using rats for 28 d. The total short-chain fatty acid concentrations in the fermenters were decreased by a combination of INU and AE, but the concentration in the INU + AE group was higher than the cellulose (CEL) and CEL + AE groups. The cecal propionate concentration was increased by a combination of INU and AE compared with their single supplement. The ammonia nitrogen concentration in the fermenters and rat cecum was decreased by INU and AE. Cecal mucin levels were increased by INU and AE respectively. Therefore, our observations suggested that the combination of INU and AE might be a material of functional food that includes several healthy effects through intestinal fermentation. PMID- 29383991 TI - Preparation of non-sintered fly ash filter (NSFF) for ammonia nitrogen adsorption. AB - In accordance with China's goal of 'treating wastes with wastes, turning wastes into treasure', a non-sintered fly ash filter (NSFF) with sewage sludge as additive was prepared. It consists of 70.9% fly ash, 7% sewage sludge, 9% cement, 7.1% CaO, 1% NaHCO3 and 5% sodium silicate solution. After mixing, 34 g/(100 g dry material) water was added, and then was granulated and steam cured under 80 degrees C for 16 h. NSFF's main performance indexes include specific surface area (SSA) of 17.038 m2 g-1, filter media breaking rate (FMBR) of 2.2%, apparent density (AD) of 1140 kg m-3, and porosity of 41.67%, meeting the Chinese Standard CJ/T 299-2008. This NSFF has a larger SSA and a lower AD comparing with the other similar non-sintered fly ash ceramsite products. Moreover, leaching toxicity of the NSFF has met the Chinese Standards for Hazardous Wastes (GB5085.3-2007). Therefore, the NSFF is effective and safe to use as a water treatment filter media. The NSFF's adsorption characteristics for ammonia nitrogen was investigated. Results showed that the optimized parameters for ammonia nitrogen adsorption are as follows, NSFF dosage at 5 g, initial ammonia nitrogen concentration of 225 mg L-1, pH at 7, contact time of 12 h and temperature at 30 degrees C. Under the optimum conditions, the adsorption capacity of NSFF for ammonia nitrogen was 4.25 mg g-1. The adsorption process can be best described by Langmuir isotherm and pseudo-second-order kinetic model. The proposed adsorption mechanism include adsorption and cation exchange. PMID- 29383992 TI - From the President. PMID- 29383994 TI - Upcoming RANZCP conferences. PMID- 29383995 TI - Metformin prescription in psychiatry. PMID- 29383997 TI - Two new College networks established. PMID- 29383998 TI - Addiction Psychiatry and Manufactured Epiphanies. PMID- 29384000 TI - The Medical Board of Australia releases its new Professional Performance Framework. PMID- 29384001 TI - Submitting your 2017 CPD claim via My CPD. PMID- 29384003 TI - RANZCP congratulates new President of the World Psychiatric Association. PMID- 29384002 TI - The multiple facets of addiction in psychiatry. PMID- 29384004 TI - Management of acute severe behavioural disturbance in Australia and in the UK. PMID- 29384005 TI - Which audit? PMID- 29384006 TI - RANZCP response to the NT Royal Commission into the protection and detention of children. PMID- 29384007 TI - Obituary: Dr Pramila Fernandez (1947-2016). PMID- 29384008 TI - Bullying in public psychiatry. PMID- 29384009 TI - Talking with Dr Denise Riordan. PMID- 29384010 TI - Telepsychiatry in the Australian Defence Force: a success story. PMID- 29384012 TI - Nurse-led diabetic retinopathy screening: a pilot study to evaluate a new approach to vision care for Canadian Aboriginal peoples. AB - Diabetic retinopathy is the most common cause of new cases of blindness and is pandemic among Aboriginal people around the world. To reduce health inequities, accessible vision screening among these high-risk populations is essential. To assess cardio-metabolic co-morbidities associated with type 2 diabetes and the use of a portable fundus camera as a novel approach for convenient, earlier and more accessible vision screening for Aboriginal peoples living with type 2 diabetes in northern and remote Canadian communities. This quantitative pilot study screened participants diagnosed with type 2 diabetes for commonly associated cardio-metabolic co-morbidities using anthropometrical measurements, blood pressure and a A1c (HbA1c) blood glucose test, followed by vision exams conducted first by a trained nurse and then by an ophthalmologist to screen for signs of retinopathy using fundus photography. Large numbers of the participants presented with overweight/obese (84.8%), pre-hypertension/hypertension (69.7%) and an elevated A1C (78.8%). Inter-rater reliability demonstrated substantial agreement between vision exam judgements made by the nurse and ophthalmologist (k = .67). Nurse-led vision screening in remote or northern communities can improve the standard of care by extending access to health services, lowering the costs to families by reducing travel expenses and preventing vision loss in a family member. PMID- 29384013 TI - Public Health Practice Report: water supply and sanitation in Chukotka and Yakutia, Russian Arctic. AB - Information from 2013-2015 have been analysed on water accessibility, types of water service to households, use of water pretreatment, availability of sewerage, use of sewage treatment in Chukotka Autonomous Okrug and Yakutia Republic, based on evaluation information accessible in open sources, such as regional statistics and sanitary-epidemiologic reports. The main causes of the poor state of water supply and sanitation in the study regions include: very limited access to in home running water (one-quarter of settlements in Chukotka and half of settlements in Yakutia have no regular water supply) and lack of centralised sewerage (78% and 94% of settlements correspondingly have no sewerage); lack of water pretreatment and sewage treatment, outdated technologies and systems; serious deterioration of facilities and networks, frequent accidents; secondary pollution of drinking water. Lack of open objective information on Russian Arctic water supply and sanitation in the materials of the regional and federal statistics hampers the assessment of the real state of affairs. The situation for water and sanitation supply in these Russian Arctic regions remains steadily unfavourable. A comprehensive intervention from national and regional governmental levels is urgently needed. PMID- 29384014 TI - Campylobacter coli meningitis in a 57-year-old patient. AB - Campylobacter coli is a major pathogen rarely responsible for extra-intestinal infections. We report a case of Campylobacter coli bacteremia and meningitis in a 57-year-old immunocompetent Belgian man. The strain, isolated from cerebrospinal fluid, belonged to the unusual sequence type 8418 (ST8418). The patient fully recovered after meropenem treatment. PMID- 29384016 TI - Corrigendum. PMID- 29384015 TI - The neuroprotective effect of rat adipose tissue-derived mesenchymal stem cell conditioned medium on cortical neurons using an in vitro model of SCI inflammation. AB - Objectives In this study, a new approach was used with an in vitro model in which neural cells were exposed to conditioned media from the injured spinal cord (SCI CM) mimicking a local inflammatory microenvironment . Subsequently, the neuroprotective effect of rat adipose tissue-derived msesenchymal stem cell conditioned media (ATMSC-CM) was investigated through a cell-free based therapy, which was used to treat cortical neurons and astrocytes under inflammation. Methods Primary cell cultures isolated from postnatal day (P6) Wistar rat brain cortex were exposed to SCI-CM derived from the central lesion, rostral and caudal segments of injured spinal cord. After 48 h incubation, the SCI-CM was replaced and primary cultures were cultivated either in DMEM media alone or in ATMSC-CM for 72 h. The impact of ATMSC-CM on the viability of neurons and astrocytes was assessed using a CyQUANT(r) Direct Cell Proliferation Assay Kit as well as immunocytochemistry analysis. Results Immunocytochemical analysis revealed significant decrease in the number of MAP2 positive neurons exposed to SCI-CM compared to Control. Protection by ATMSC-CM was associated with increased survival of neurons compared to primary culture cultivated in DMEM media alone. The ATMSC-CM effect on astrocytes was more variable and without any significant impact. Conclusion The results demonstrate that SCI-CM mimicking inflammation can reduce cortical neuron survival, and subsequent exposure to ATMSC-CM can stabilize the neuronal population most likely via released neuroprotective and trophic factors. In addition, astrogliosis was not affected by ATMSC-CM. PMID- 29384017 TI - Adsorption and biodegradation functions of novel microbial embedding polyvinyl alcohol gel beads modified with cyclodextrin: a case study of benzene. AB - A novel microorganism embedding material was developed to enhance the benzene removal through adsorption and biodegradation, by introducing beta-cyclodextrin (CD) to traditional polyvinyl alcohol gel beads. Results show that the optimal ratio of sucrose/benzene was 1.25 for co-metabolism biodegradation of benzene, and the maximum exogenous microbial respiration rate was 260.13 mgO2/(gVSS h) for gel beads with CD. The positive effects of CD on benzene removal mainly resulted from the adsorption characteristics of CD as well as the stimulation of CD on microbial activity. Adsorption tests indicate that CD addition increased the adsorption function of gel beads to benzene with its dispersion coefficient of 5.1 * 10-7 cm2/s. Respiration tests show that gel beads with CD possessed the highest maximum specific exogenous respiration rates. Moreover, a high-throughput sequencing analysis confirms that CD addition could obviously enhance microbial diversity with domain microbial of Zoogloea (17.0%). Finally, microbial embedding gel beads could remove certain benzene after lyophilization and storage for one month. Overall, the novel microbial embedding gel beads modified with CD (a favorable additional agent to traditional embedding materials) have been proved as an efficient method for removing benzene under suitable sucrose/benzene ratio. PMID- 29384018 TI - Effect and mechanism of modification treatment on ammonium and phosphate removal by ferric-modified zeolite. AB - In this study, the reason for the decline of ammonium sorption capacity by zeolite after ferric modification and the effect of modification treatment on ammonium and phosphate removal by ferric-modified zeolite were studied. Modification treatment media (Na salt and HCl) and Na concentration (0.1 and 0.9 mol/L) have been investigated. Zeolites have been characterized by SEM, XRD, BET and XRF; meanwhile, CEC and pHpzc have been also determined. Equilibrium batch sorption for ammonium and phosphate individually and kinetics batch sorption for ammonium were conducted. The results showed a decline in sorption capacity or diffusion coefficients for ammonium but an increase for phosphate after ferric modification. The decrease of surface negative charge was the main contributor for the former, but iron loading did not well account for the latter. The performance of 0.1 mol/L Na modification treatment was better than other treatments for ammonium sorption and equal to HCl modification treatment for phosphate sorption, and the enhancement extent increased for ammonium but declined for phosphate when Na concentration increased. The advantage of Na modification treatment for ammonium was due to the enhancement of textural properties and high exchange rate with ammonium. PMID- 29384019 TI - The tear turnover and tear clearance tests - a review. AB - INTRODUCTION: The aim is to provide a summary of methods available for the assessment of tear turnover and tear clearance rates. The review defines tear clearance and tear turnover and describes their implication for ocular surface health. Additionally, it describes main types of techniques for measuring tear turnover, including fluorescein tear clearance tests, techniques utilizing electromagnetic spectrum and tracer molecule and novel experimental techniques utilizing optical coherence tomography and fluorescein profilometry. Areas covered: Internet databases (PubMed, Science Direct, Google Scholar) and most frequently cited references were used as a principal resource of information on tear turnover rate and tear clearance rate, presenting methodologies and equipment, as well as their definition and implications for the anterior eye surface health and function. Keywords used for data-search were as follows: tear turnover, tear clearance, fluorescein clearance, scintigraphy, fluorophotometry, tear flow, drainage, tear meniscus dynamics, Krehbiel flow and lacrimal functional unit. Expert commentary: After decades, the topic of tear turnover assessment has been reintroduced. Recently, new techniques have been developed to propose less invasive, less time consuming and simpler methodologies for the assessment of tear dynamics that have the potential to be utilized in clinical practice. PMID- 29384020 TI - Influence of warm-up duration on physical performance and psychological perceptions in handball players. AB - The purpose of the study was to analyse the effect of two warm-up protocols of different duration on physical performance, perceived load and perception of being ready for a match in handball players. Eighteen handball players were randomly divided into two groups (Wup34min, warm-up protocol of 34 min, Wup17min, warm-up protocol of 17 min). Before and after the warm-up protocols, they performed a battery of physical tests and recorded their perception of feeling ready for a match. At the end of the warm-up protocols, all the players evaluated their differentiated perceived effort (dRPE). The results showed that neither of the protocols significantly modified (p > 0.05) the players' physical performance. However, the Wup34min group showed higher values in the differentiated warm-up perceived load (dRPE-WL) (p < 0.01, TE = 0.97-1.27, high) than the Wup17min group. The players with a greater perceived muscular load (RPEMUSC) experienced a greater decrease in their acceleration capacity (r = 0.48 0.49, p < 0.05). In spite of the fact that neither of the warm-up protocols significantly modified the players' physical performance, a greater perceived muscular load may cause a greater decrease in acceleration capacity. PMID- 29384022 TI - Clinical and Economic Benefits of Pharmacist Involvement in a Community Hospital Affiliated Patient-Centered Medical Home. AB - BACKGROUND: The primary goals of an accountable care organization (ACO) are to reduce health care spending and increase quality of care. Within an ACO, pharmacists have a unique opportunity to help carry out these goals within patient-centered medical homes (PCMHs). Pharmacy presence is increasing in these integrated care models, but the pharmacist's role and benefit is still being defined. OBJECTIVE: To exhibit the clinical and economic benefit of pharmacist involvement in ACOs and PCMHs as documented by clinical interventions (CIs) and drug cost reductions. METHODS: This is a retrospective quality improvement study. All interventions made by the pharmacist during the study period were documented using TAV Health. The interventions were then analyzed. Specific identified endpoints included the total number of documented interventions and number of CIs from each category, transition of care (TOC) medication reconciliations performed, discrepancies identified during TOC medication reconciliation, and cost savings generated from generic and therapeutic alternative use. CI categories were collaborative drug therapy management, medication therapy management (MTM), medication reconciliation, patient and provider education, and drug cost management. RESULTS: During the study period (October 2016-March 2017), a pharmacist was in clinic 8 hours per week. Sixty-three patients were included in the study. There were 283 CIs documented, with a majority of the interventions associated with MTM or cost management (94 and 88 CIs, respectively). There were 37 education CIs, 36 TOC medication reconciliations performed, and 28 collaborative drug therapy management CIs. From the 36 TOC medication reconciliations, 240 medication discrepancies were found, with a majority associated with medication omission. A cost savings of $118,409 was gained from generic and therapeutic alternative substitutions. CONCLUSIONS: Clinical benefit of pharmacy services was demonstrated through documented CIs. Pharmacists can have a dramatic and quantitative effect on reducing drug costs by recommending less expensive generic or therapeutic alternatives. Documenting CIs allows pharmacists to provide valuable evidence of avoided drug misadventures and identification of medication discrepancies. Such evidence supports an elevated quality of care. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by Tate and Hopper, along with Bergeron. Tate collected and interpreted the data, as well wrote the manuscript, which was revised by all the authors. PMID- 29384023 TI - Prevalence and Management of Drug-Related Problems in Chronic Kidney Disease Patients by Severity Level: A Subanalysis of a Cluster Randomized Controlled Trial in Community Pharmacies. AB - BACKGROUND: Drug-related problems (DRPs) are prevalent among chronic kidney disease (CKD) patients. However, little is known about their severity and management by community pharmacists. OBJECTIVES: To (a) describe the prevalence of DRPs by severity level in CKD patients and (b) assess the effect of a training and-communication network program in nephrology (ProFiL) on these DRPs. METHODS: This is a secondary analysis of a cluster randomized controlled trial evaluating the effect of the ProFiL-program. In 6 CKD clinics, patients at CKD stage 3 or 4 and their community pharmacists were recruited and assigned to the ProFiL group or a usual care (UC) group. Using validated criteria, 2 pharmacists identified DRPs and assessed their severity at baseline and after 12 months. The mean annual change in the number of DRPs per patient by severity level was assessed using a 2 level multivariable linear mixed-effects model. RESULTS: A total of 494 pharmacists and 442 patients participated. At baseline, the prevalence (mean number of DRPs per patient [SD]) of mild DRPs (e.g., requiring dosage adjustment) and moderate DRPs (e.g., drug adherence requiring a monitoring plan) were 0.55 (0.98) and 1.04 (1.51), respectively. After 12 months, an unadjusted incremental annual reduction of 0.34 moderate DRPs (95% CI = -0.66 to -0.01) was observed in the ProFiL group compared with the UC group. After adjustment, no between-group differences were observed. CONCLUSIONS: Among patients followed in CKD clinics, most DRPs have a moderate severity requiring specific monitoring by pharmacists. The benefit of continuing education programs, such as ProFiL, to reduce moderate DRPs remains to be determined. DISCLOSURES: This study was supported by the Canadian Institutes of Health Research (grant number: MOP-230207). Part of the study was also funded by Pfizer Canada, Leo Pharma, and Amgen. The authors declare that they have no relevant financial interests. Study concept and design were contributed by Quintana-Barcena, Lord, and Lalonde. Quintana-Barcena, Lord, and Lizotte were responsible for the data analysis, and Quintana-Barcena and Berbiche performed the statistical analysis. The manuscript was written by Quintana-Barcena and Lalonde and revised by Quintana-Barcena and Lalonde, along with the other authors. PMID- 29384024 TI - Clinical and Economic Effects of a Pharmacist-Administered Antiretroviral Therapy Adherence Clinic for Patients Living with HIV. AB - BACKGROUND: Pharmacists have demonstrated the ability to improve patient adherence to antiretroviral therapy (ART). OBJECTIVE: To determine the clinical and economic effects of a pharmacist-administered ART adherence clinic for patients living with human immunodeficiency virus (HIV). METHODS: This pilot study with a pretest-posttest design examined the effect of a pharmacy adherence clinic on patient HIV viral load and CD4 count over a 6-month period. Patients with documented adherence problems were referred to the clinic. The pharmacist counseled patients at baseline and met with patients 1-2 weeks, 6 weeks, 3 months, and 6 months after starting ART. A societal perspective net cost analysis of the pharmacy adherence clinic was conducted to assess the economic efficiency of the intervention. RESULTS: Twenty-eight patients were enrolled in the study, and 16 patients reached completion. Median HIV RNA significantly decreased from 48,000 copies/mL (interquartile range [IQR] = 16,750-139,000) to undetectable (< 20 copies/mL) at 6 months for all study participants who completed the full intervention (P = 0.001). In the 3 months following the intervention, we estimated that it prevented approximately 0.13 secondary HIV infections among the sexual partners of the 16 participants who completed the intervention. The total cost of the intervention was $16,811 ($1,051 per patient), which was less than the future savings in averted HIV-related medical care expenditures ($49,702). CONCLUSIONS: A pharmacy adherence clinic that focused on early and sustained ART adherence interventions helped patients with documented medication adherence problems achieve an undetectable HIV RNA. The intervention was highly cost saving, with a return of nearly $3 in future medical care savings per dollar spent on the intervention. DISCLOSURES: This work was supported in part by a research grant to Dilworth, Mercier, and Borrego from the American Society of Health-System Pharmacists Foundation. Klein and Pinkerton were supported in part by grants T32-MH19985 and P30-MH52776, respectively, from the National Institute of Mental Health. No funding bodies had any role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Health Resources and Services Administration. The authors have no conflicts of interest to disclose. Study concept and design were contributed primarily by Dilworth, Mercier, and Borrego, along with the other authors. Dilworth took the lead in data collection, along with Pinkerton, Klein, Mercier, and Jakeman. Data interpretation was performed by Dilworth and Pinkerton, along with the other authors. The manuscript was written by Dilworth, Klein, and Jakeman, with assistance from the other authors, and revised by Dilworth, Jakeman, and Klein, with assistance from the other authors. The results from this study were presented in part at the 2015 United States Conference on AIDS in Washington, DC, on September 10-13, 2015. PMID- 29384025 TI - Failure of a Best Practice Alert to Reduce Antibiotic Prescribing Rates for Acute Sinusitis Across an Integrated Health System in the Midwest. AB - BACKGROUND: Antimicrobial resistance is a growing concern, and in recent years, there has been increased interest in ambulatory antimicrobial stewardship. Acute rhinosinusitis (ARS) is one of the most common outpatient diagnoses that results in an antibiotic prescription. OBJECTIVE: To determine if a best practice alert (BPA) will affect the percentage of oral antibiotic prescriptions for adults with ARS. METHODS: A prospective, pre/post study was initiated to evaluate the percentage of oral antibiotic prescriptions for ARS in 117 primary care clinics in the Midwest. Included in the study results were 16,570 adults who had an office visit for ARS: 8,106 patients from December 1, 2015, to February 28, 2016, were in the pre-intervention group without an active BPA, and 8,464 patients from December 1, 2016, to February 28, 2017, were in the post-intervention group when the BPA was active. The primary outcome was the number of oral antibiotic prescriptions for ARS compared with the number of office visits for ARS in the pre- and postintervention groups. RESULTS: The percentage of oral antibiotics prescribed for the pre- and postintervention groups were 94.8% and 94.3%, respectively (P = 0.152). The BPA displayed for 7,780 visits, prompting discontinuation of an antibiotic for 10 (0.1%) visits in the postintervention group. CONCLUSIONS: This study suggests that, although an electronic alert may be attractive to facilitate antimicrobial stewardship, it may be ineffective. These results warrant alternative measures to facilitate ambulatory antimicrobial stewardship. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. Study concept and design were contributed by Hansen, D. Leedahl, and N. Leedahl. Hansen and N. Leedahl took the lead in data collection, with assistance from Carson and D. Leedahl. Data interpretation was performed by all the authors. The manuscript was written by Hansen, along with the other authors, and revised by all the authors. PMID- 29384026 TI - Evaluation of an Academic-Community Partnership to Implement MTM Services in Rural Communities to Improve Pharmaceutical Care for Patients with Diabetes and/or Hypertension. AB - BACKGROUND: Although the current methods of medication therapy management (MTM) delivery have demonstrably improved therapeutic, safety, economic, and humanistic health outcomes, patient- and prescriber-level barriers persist, limiting its reach and effectiveness. OBJECTIVE: To assess telephonic- and community-based clinical pharmacy services in improving health indicators for rural, underserved patients. METHODS: In 2014, an established MTM provider created a novel, collaborative pilot program with independent retail and community health center pharmacies to provide comprehensive, telephonic MTM services to rural Arizonans. This pilot program used a combined telephonic- and community-based pharmacist approach in the provision of MTM services for rural, underserved Arizona populations. Adults with diabetes mellitus and/or hypertension, seen by a prescriber or who filled prescriptions at a contracted, rural facility in 2014, were eligible to participate. Initial MTM telephonic consultations were conducted, and recommendations were communicated to patients' prescribers and/or pharmacists. Patients received a follow-up telephone call at standard intervals, depending on risk severity. RESULTS: A total of 517 patients participated, and 237 medication-related and 1,102 health promotion interventions were completed. Positive trends were observed in fasting blood glucose, postprandial glucose, and diastolic blood pressure. Broad variation in prescriber acceptance of pharmacist recommendations was observed (27%-60%). CONCLUSIONS: Study results provide initial evidence to support the efficacy of collaborative efforts in the provision of MTM services for improving health indicators and safety measures while potentially reducing health care disparities. While the results are encouraging, future research is warranted in more diverse populations and settings. DISCLOSURES: This work was supported in part by funding from the Centers for Disease Control and Prevention via a multiyear, interagency grant from the Arizona Department of Health Services. The findings and conclusions presented in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention nor the Arizona Department of Health Services. Study concept and design were contributed by M. Johnson, Jastrzab, Hall-Lipsy, Martin, and Warholak. M. Johnson took the lead in data collection, along with K. Johnson, Martin, Jastrzab, and Hall-Lipsy. Data interpretation was performed by Jastrzab, Warholak, and Taylor. The manuscript was written by K. Johnson, M. Johnson, and Jastrzab, along with the other authors, and revised by M. Johnson, Tate, and Taylor, along with Jastrzab, K. Johnson, and Hall-Lipsy. The data from this manuscript were previously presented in poster and podium format by Jastrzab and Johnson at the American Public Health Annual Meeting; Chicago, Illinois; October 31-November 4, 2015. PMID- 29384027 TI - An Evaluation of the Cost-effectiveness of Comprehensive MTM Integrated with Point-of-Care Phenotypic and Genetic Testing for U.S. Elderly Patients After Percutaneous Coronary Intervention. AB - BACKGROUND: Poor health outcomes after percutaneous coronary intervention (PCI) in elderly patients is an area of concern among policymakers and administrators. In an effort to determine the best strategy to improve outcomes among elderly patients who underwent PCI, several studies have evaluated the cost-effectiveness of genotype-guided antiplatelet therapy compared with universal use of any one of the antiplatelet drugs indicated for patients with acute coronary syndrome (ACS) who underwent PCI. The results have either been in favor of genotype-guided antiplatelet therapy or universal use of ticagrelor. However, no study has yet evaluated the cost-effectiveness of pharmacist-provided face-to-face medication therapy management (MTM) combined with point-of-care genotype-guided antiplatelet therapy (POCP) when compared with universal use of ticagrelor or clopidogrel for the elderly after PCI. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist integration of MTM with POCP (MTM-POCP) when compared with universal use of ticagrelor or clopidogrel combined with MTM (MTM-ticagrelor or MTM clopidogrel). METHODS: We conducted a cost-effectiveness analysis from the perspective of the U.S. health care system. A hybrid model, consisting of a 1 year decision tree and a 20-year Markov model, was used to simulate a cohort of elderly patients (aged at least 65 years) with ACS who underwent PCI. Treatment strategies available to patients were POCP, POCP-MTM, MTM-clopidogrel, or MTM ticagrelor. Data used to populate the model were obtained from the PLATO trial and other published studies. Outcome measures were costs, quality-adjusted life years (QALYs) and incremental cost per QALY gained. A deterministic and probabilistic sensitivity analysis was conducted to account for the joint uncertainty around the key parameters of the model. Finally, a benchmark willingness to pay of $50,000-200,000 was considered. RESULTS: The use of PCOP (with dual antiplatelet therapy) resulted in 5.29 QALYs, at a cost of $50,207. MTM-clopidogrel resulted in 5.34 QALYs, at a cost of $50,011. The use of POCP-MTM resulted in 5.36 QALYs, at a cost of $50,270. Finally, MTM-ticagrelor resulted in 5.42 QALYs, at a cost of $53,346. MTM-ticagrelor was found to be cost-effective compared with MTM-clopidogrel or MTM-POCP, irrespective of the willingness to pay. The deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. CONCLUSIONS: The combination of MTM ticagrelor was cost-effective when compared with MTM-POCP or MTM-clopidogrel. The transitional probabilities, however, were mostly based on published studies. Analysis based on a prospective randomized clinical study, comparing all the treatment strategies included in this study, is warranted to confirm our findings. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. Study concept and design were contributed by Okere and Diaby. Ezendu took the lead in data collection, along with Okere. Data interpretation was performed by all the authors. The manuscript was written by Okere, Diaby, and Berthe and revised by Okere and Diaby. PMID- 29384028 TI - Budget Impact Analysis of a Pharmacist-Provided Transition of Care Program. AB - BACKGROUND: Postdischarge medication management services have been shown to reduce the incidence of medication-related problems during the transition from inpatient to outpatient care. A pharmacist-run transition of care (TOC) program has been developed to reduce the unplanned readmissions of a high-risk managed Medicaid population after hospitalization. OBJECTIVE: To estimate the budget impact of adding an outpatient pharmacy-based TOC program to a medical benefit from the payer perspective. METHODS: A budget impact analysis was conducted using a decision-tree model developed in Microsoft Excel. The effect on inpatient and total health care costs from the payer perspective was estimated for the 2-year period following initial hospital discharge. Inputs were based on a total plan population of 240,000 lives, with a high-risk population of 7.5%, of whom 37% were hospitalized and potentially qualified for TOC services, resulting in an eligible population of 6,660 patients. The TOC program was assumed to initially cover 30% of the eligible population, with expansion to 60% over the 2 years. We previously reported that this program reduced the risk of readmission by 32% within 6 months and saved the health plan $2,139 per patient referred to the program, inclusive of program cost, compared with patients receiving usual discharge care. Sensitivity analyses were performed to test the impact of uncertainty of model inputs on the results, with the cost of TOC services ranging from $99 to $2,000 per patient referred. RESULTS: The model showed that the TOC program was cost saving at over $3 per member per month in the first 6 months, which translates to over $25 million in total health care cost savings over 2 years. These results were primarily driven by the estimated reduction in inpatient costs associated with the program, which were estimated at $20 million over the 2 years. Sensitivity analyses illustrated that within all the reasonable ranges of model input parameters, including the upper limit of TOC services set to $2,000 per patient referred, the TOC program resulted in cost savings to the health plan. CONCLUSIONS: The TOC program resulted in potential cost savings of over $25 million to the managed Medicaid plan over a period of 2 years, corresponding to over $4 per member per month. DISCLOSURES: Funding for this study was contributed by the Komoto Family Foundation, which provided fellowships to Ni and McCombs during the time of this study. Colayco is employed by Synergy Pharmacy Solutions and by the Komoto Family Foundation. Hashimoto and Komoto are employed by Synergy Pharmacy Solutions. Gowda and Wearda report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Study concept and design were contributed by Ni, Colayco, and McCombs, along with the other authors. Hashimoto, Komoto, and Wearda took the lead in data collection, assisted by Ni, Colayco, and Gowda. Data interpretation was performed by Ni, Colayco, and McCombs, along with the other authors. The manuscript was written by Ni and Colayco and revised by Gowda and McCombs, along with the other authors. PMID- 29384029 TI - Evaluation of a Pharmacist-Managed Diabetes Program in a Primary Care Setting Within an Integrated Health Care System. AB - BACKGROUND: Pharmacists have important roles in managing the therapy of patients with type 2 diabetes and improving patient care. Pharmacists titrate medications; reinforce patient education; and address care gaps, such as medication adherence, vaccinations, and overdue health screenings. Through these efforts and more, pharmacists help to improve patient care and achieve Healthcare Effectiveness Data and Information Set (HEDIS) measures. Thus, it is important to demonstrate improved health outcomes through pharmacist contributions to diabetes management, which can then provide an opportunity to expand the role of clinical pharmacists in other medical centers and practice settings within an integrated health care system. OBJECTIVE: To evaluate the effect of a pharmacist-managed program within a primary care setting by determining the percentage of patients who reached the HEDIS goal of hemoglobin A1c (A1c) < 8.0%, the time needed to reach this goal, and A1c reduction in patients with type 2 diabetes. METHODS: This retrospective cohort study identified patients aged 18-74 years who had uncontrolled A1c >= 8.0%. Patients in the Complete Care Program (CCP) had their diabetes therapy managed by a pharmacist and were propensity score matched to a comparison group of usual care (UC) patients. Multivariate regression analyses and a Cox proportional hazards model compared the change in A1c from baseline and the time to A1c goal between the 2 groups. RESULTS: There were no significant differences in baseline characteristics between the CCP and UC patients (n = 980 patients per group). CCP patients were significantly more likely to achieve the HEDIS goal of A1c < 8% at 3 months (OR = 2.44, 95% CI = 1.93-3.10, P < 0.0001) and at 6 months (OR = 1.32, 95% CI = 1.08-1.61, P = 0.007) compared with the UC patients. CCP patients also reached the A1c goal significantly faster: 3.4 months versus 4.6 months (P < 0.0001), even after controlling for covariates (HR = 1.24, 95% CI = 1.09-1.41, P = 0.001). Change in baseline A1c was -0.95% versus -0.54% (P < 0.0001) at 3 months and -1.19% versus -0.99% (P = 0.008) at 6 months for CCP versus UC patients, respectively. CONCLUSIONS: Type 2 diabetes therapy management by clinical pharmacists was associated with a greater percentage of patients achieving the HEDIS goal of A1c < 8.0%, reaching the A1c goal faster, and a greater A1c reduction from baseline at 3 and 6 months of follow-up compared with patients receiving usual care. DISCLOSURES: No funding was provided to support this research study. The authors report no potential conflicts of interest relevant to this article. All authors contributed to the study concept and design. Benedict and Spence performed data analysis and interpretation. The manuscript was written by Benedict, with assistance from Spence and Rashid. All authors reviewed and contributed to manuscript revisions. Spence is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Parts of this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; San Francisco, California; April 19-22, 2016. PMID- 29384030 TI - The Effect of Florida Medicaid's State-Mandated Formulary Provision on Prescription Drug Use and Health Plan Costs in a Medicaid Managed Care Plan. AB - BACKGROUND: Formulary or preferred drug list (PDL) management is an effective strategy to ensure clinically efficient prescription drug management by managed care organizations (MCOs). Medicaid MCOs participating in Florida's Medicaid program were required to use a state-mandated PDL between May and August 2014. OBJECTIVE: To examine differences in prescription drug use and plan costs between a single Florida Medicaid managed care (MMC) health plan that implemented a state mandated PDL policy on July 1, 2014, and a comparable MMC health plan in another state without a state-mandated PDL, controlling for sociodemographic confounders. METHODS: A retrospective analysis with a pre-post design was conducted using deidentified administrative claims data from a large pharmacy benefit manager. The prepolicy evaluation period was January 1 through June 30, 2014, and the postpolicy period was January 1 through June 30, 2015. Continuously eligible Florida MMC plan members were matched on sociodemographic and health characteristics to their counterparts enrolled in a comparable MMC health plan in another state without a state-mandated formulary. Outcomes were drug use, measured as the number of 30-day adjusted nonspecialty drug prescriptions per member per period, and total drug plan costs per member per period for all drugs, with separate measures for generic and brand drugs. Bivariate comparisons were conducted using t-tests. Employing a difference-in-differences (DID) analytic approach, multivariate negative binomial regression and generalized estimating equation models were used to analyze prescription drug use and costs. RESULTS: The final analytical sample consisted of 18,372 enrollees, evenly divided between the 2 groups. In the postpolicy evaluation period, overall and generic use declined, while brand use increased for members in the Florida health plan. Drug costs, especially for brands, significantly increased for Florida health plan members. No significant changes were observed over the same time period in the control health plan members. DID analyses indicated that the decline in overall drug use was 6% lower (P = 0.020), and the increase in plan costs was 27% higher (P = 0.002) among Florida health plan members compared with control group members. CONCLUSIONS: Members in a Florida Medicaid health plan with a state mandated PDL saw declines in overall and generic drug use and an increase in drug plan costs. States considering a state-mandated PDL should take into account potential effects of decreased generic drug use and increases in prescription drug plan costs. DISCLOSURES: Funding for this study was provided internally by Express Scripts Holding Company. The authors and acknowledged contributors are employees of Express Scripts Holding Company. All authors contributed to the study concept, and study design was provided by Munshi, Mager, and Henderson. Munshi and Mager collected the data, and Munshi provided the statistical analysis. Data interpretation was performed by Munshi, Mager, and Henderson. The manuscript was written by Munshi, Henderson, and Mager and revised by Munshi, Ward, Mischel, and Henderson. PMID- 29384031 TI - Racial and Ethnic Disparities in Meeting MTM Eligibility Criteria Based on Star Ratings Compared with the Medicare Modernization Act. AB - BACKGROUND: Previous research found racial and ethnic disparities in meeting medication therapy management (MTM) eligibility criteria implemented by the Centers for Medicare & Medicaid Services (CMS) in accordance with the Medicare Modernization Act (MMA). OBJECTIVE: To examine whether alternative MTM eligibility criteria based on the CMS Part D star ratings quality evaluation system can reduce racial and ethnic disparities. METHODS: This study analyzed the Beneficiary Summary File and claims files for Medicare beneficiaries linked to the Area Health Resource File. Three million Medicare beneficiaries with continuous Parts A, B, and D enrollment in 2012-2013 were included. Proposed star ratings criteria included 9 existing medication safety and adherence measures developed mostly by the Pharmacy Quality Alliance. Logistic regression and the Blinder-Oaxaca approach were used to test disparities in meeting MMA and star ratings eligibility criteria across racial and ethnic groups. Multinomial logistic regression was used to examine whether there was a disparity reduction by comparing individuals who were MTM-eligible under MMA but not under star ratings criteria and those who were MTM-eligible under star ratings criteria but not under the MMA. Concerning MMA-based MTM criteria, main and sensitivity analyses were performed to represent the entire range of the MMA eligibility thresholds reported by plans in 2009, 2013, and proposed by CMS in 2015. Regarding star ratings criteria, meeting any 1 of the 9 measures was examined as the main analysis, and various measure combinations were examined as the sensitivity analyses. RESULTS: In the main analysis, adjusted odds ratios for non Hispanic blacks (backs) and Hispanics to non-Hispanic whites (whites) were 1.394 (95% CI = 1.375-1.414) and 1.197 (95% CI = 1.176-1.218), respectively, under star ratings. Blacks were 39.4% and Hispanics were 19.7% more likely to be MTM eligible than whites. Blacks and Hispanics were less likely to be MTM-eligible than whites in some sensitivity analyses. Disparities were not completely explained by differences in patient characteristics based on the Blinder-Oaxaca approach. The multinomial logistic regression of each main analysis found significant adjusted relative risk ratios (RRR) between whites and blacks for 2009 (RRR = 0.459, 95% CI = 0.438-0.481); 2013 (RRR = 0.449, 95% CI = 0.434 0.465); and 2015 (RRR = 0.436, 95% CI = 0.425-0.446) and between whites and Hispanics for 2009 (RRR = 0.559, 95% CI = 0.528-0.593); 2013 (RRR = 0.544, 95% CI = 0.521-0.569); and 2015 (RRR = 0.503, 95% CI = 0.488-0.518). These findings indicate a significant reduction in racial and ethnic disparities when using star ratings eligibility criteria; for example, black-white disparities in the likelihood of meeting MTM eligibility criteria were reduced by 55.1% based on star ratings compared with MMA in 2013. Similar patterns were found in most sensitivity and disease-specific analyses. CONCLUSIONS: This study found that minorities were more likely than whites to be MTM-eligible under the star ratings criteria. In addition, MTM eligibility criteria based on star ratings would reduce racial and ethnic disparities associated with MMA in the general Medicare population and those with specific chronic conditions. DISCLOSURES: Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award number R01AG049696. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Cushman reports an Eli Lilly grant and uncompensated consulting for Takeda Pharmaceuticals outside this work. The other authors have no potential conflicts of interest to report. Study concept and design were contributed by Wang and Shih, along with Wan, Kuhle, Spivey, and Cushman. Wang, Qiao, and Wan took the lead in data collection, with assistance from the other authors. Data interpretation was performed by Wang, Kuhle, and Qiao, with assistance from the other authors. The manuscript was written by Spivey and Qiao, along with the other authors, and revised by Cushman, Dagogo-Jack, and Chisholm-Burns, along with the other authors. PMID- 29384033 TI - An Employee-Centered Care Model Responds to the Triple Aim: Improving Employee Health. AB - Health care expenditures, patient satisfaction, and timely access to care will remain problematic if dramatic changes in health care delivery models are not developed and implemented. To combat this challenge, a Triple Aim approach is essential; Innovation in payment and health care delivery models is required. Using the Donabedian framework of structure, process, and outcome, this article describes a nurse-led employee-centered care model designed to improve consumers' health care experiences, improve employee health, and increase access to care while reducing health care costs for employees, age 18 and older, in a corporate environment. PMID- 29384032 TI - Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients. AB - Doxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control; and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p = 0.0054, p = 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivo study to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS. PMID- 29384034 TI - Development of pulmonary tuberculosis following treatment with anti-PD-1 for non small cell lung cancer. PMID- 29384036 TI - The exciting field of neuro-repair in multiple sclerosis: an interview with Sarah I Sheikh. AB - Sarah Isabel Sheikh speaks to Laura Dormer, Commissioning Editor: Sarah I Sheikh, MD, MSc, MRCP, is a Senior Medical Director in Late Stage Clinical Development at Biogen. Her current focus is on developing therapies for multiple sclerosis/neuroinflammation, remyelination and neuro-repair. Prior to Biogen, Dr Sheikh was an attending in Neurology at Brigham and Women's Hospital. She completed her internship at Massachusetts General Hospital and residency in Neurology and Neuromuscular fellowship at Massachusetts General Hospital and Brigham and Women's Hospital. She received her medical degree from Oxford University Medical School, and a Masters in cell physiology from Oxford University, Corpus Christi College. She is a member of the Royal College of Physicians, London. PMID- 29384035 TI - Loss of life expectancy derived from a standardized mortality ratio in Denmark, Finland, Norway and Sweden. AB - AIMS: The standardized mortality ratio (SMR) is a widely used measure. A recent methodological study provided an accurate approximate relationship between an SMR and difference in lifetime expectancies. This study examines the usefulness of the theoretical relationship, when comparing historic mortality data in four Scandinavian populations. METHODS: For Denmark, Finland, Norway and Sweden, data on mortality every fifth year in the period 1950 to 2010 were obtained. Using 1980 as the reference year, SMRs and difference in life expectancy were calculated. The assumptions behind the theoretical relationship were examined graphically. The theoretical relationship predicts a linear association with a slope, [Formula: see text], between log(SMR) and difference in life expectancies, and the theoretical prediction and calculated differences in lifetime expectancies were compared. We examined the linear association both for life expectancy at birth and at age 30. All analyses were done for females, males and the total population. RESULTS: The approximate relationship provided accurate predictions of actual differences in lifetime expectancies. The accuracy of the predictions was better when age was restricted to above 30, and improved if the changes in mortality rate were close to a proportional change. Slopes of the linear relationship were generally around 9 for females and 10 for males. CONCLUSIONS: The theoretically derived relationship between SMR and difference in life expectancies provides an accurate prediction for comparing populations with approximately proportional differences in mortality, and was relatively robust. The relationship may provide a useful prediction of differences in lifetime expectancies, which can be more readily communicated and understood. PMID- 29384037 TI - Validation of cardiovascular diagnoses in the Greenlandic Hospital Discharge Register for epidemiological use. AB - Cardiovascular disease (CVD) is one of the leading causes of death worldwide. In Greenland, valid estimates of prevalence and incidence of CVD do not exist and can only be calculated if diagnoses of CVD in the Greenlandic Hospital Discharge Register (GHDR) are correct. Diagnoses of CVD in GHDR have not previously been validated specifically. The objective of the study was to validate diagnoses of CVD in GHDR. The study was conducted as a validation study with primary investigator comparing information in GHDR with information in medical records. Diagnoses in GHDR were considered correct and thus valid if they matched the diagnoses or the medical information in the medical records. A total of 432 online accessible medical records with a cardiovascular diagnosis according to GHDR from Queen Ingrid's Hospital from 2001 to 2013 (n=291) and from local health care centres from 2007 to 2013 (n=141) were reviewed. Ninety-nine and ninety-two percent of discharge diagnosis in GHDR from Queen Ingrid's Hospital and local health care centres were correct in comparison with diagnoses in the medical record indicating valid registration practice. The correctness of cardiovascular diagnoses in GHDR was considered high in terms of acceptable agreement between medical records and diagnoses in GHDR. Cardiovascular diagnoses are valid for epidemiological use. PMID- 29384038 TI - It may not be time to clean out the sample closets. PMID- 29384039 TI - Future perspectives of genome-scale sequencing. AB - INTRODUCTION: In recent decades, we witnessed a revolution in genetic technology. Some 20 years ago, analysing a single gene was quite laborious and time consuming. In addition, diagnostic testing was only available for selected genes. Nowadays, whole exome analysis - a technique enabling sequencing of all protein coding sequences in the entire genome - is gradually introduced in a clinical setting. Whole genome sequencing forms the ultimate exponent of this evolution and offers an even broader application. METHODS: A review of the application of these technologies in a diagnostic setting is presented. RESULTS: Whole exome sequencing has a prominent place in modern clinical diagnostics. It offers a cost and time-efficient way to interrogate all protein coding portions of the genome leading to a quick and adequate diagnosis, also in cases of phenotypic heterogeneity. As sequencing costs continue to drop, whole genome sequencing will take over in the near future guaranteeing a further improvement of the quality of genetic testing. CONCLUSION: Due to technological advances in the past decades, the field of clinical diagnostics has changed dramatically. With techniques such as whole exome and whole genome sequencing, the diagnostic yield increases serving both the patient and the health care system. PMID- 29384040 TI - Facile synthesis of silver nanoparticles in a crosslinked polymeric system by in situ reduction method for catalytic reduction of 4-nitroaniline. AB - In this study, poly(N-isopropylmethacrylamide-co-methacrylic acid) microgels prepared by free radical precipitation polymerization were used as micro-reactors for the synthesis and stabilization of silver nanoparticles. UV-Visible spectroscopy, Transmission Electron Microscopy and Fourier-transform infrared spectroscopy were used to characterize both pure and hybrid microgels. The catalytic reduction of 4-nitroaniline was carried out in the presence of hybrid microgels to test their catalytic activity, and the catalysis mechanism was explored by varying the concentrations of reacting species like 4-nitroaniline and NaBH4, as well as the dose of the catalyst. The kinetic data indicates that this reaction follows pseudo-first order. The variation in apparent rate constant (kapp) with respect to NaBH4 concentration also discloses it to be the following Langmuir-Hinshelwood mechanism. The relationship between catalyst concentration and apparent rate constant was found to be increasing in a linear manner. The data obtained also confirmed that silver nanoparticles loaded microgels have the potential to be used as an excellent micro-reactor for selective reduction of 4 nitroaniline to p-phenylenediamine. PMID- 29384041 TI - Two G-box-like elements essential to high gene expression of SlAKR4B in tomato leaves. AB - Aldo-keto reductases (AKRs) play important roles in aldehyde detoxification as well as primary and secondary metabolism in plants. We previously reported inducible expression of a Solanum lycopersicum AKR4B (SlAKR4B) in tomato leaves treated with salicylic acid and jasmonic acid, and high promoter activity of SlAKR4B in tomato leaf protoplasts. In this study, we investigated the expression response of SlAKR4B in the tomato leaves with infiltration treatment and the cis element(s) involved in high promoter activity. Gene expression analysis in tomato leaf protoplasts and buffer-infiltrated tomato leaves suggested that cell damage caused the increased expression of SlAKR4B. Promoter activity of SlAKR4B was significantly reduced by mutation of two G-box like elements. It is suggested that the two G-box like elements are responsible for the high promoter activity. PMID- 29384042 TI - Transformed low-rank ANOVA models for high-dimensional variable selection. AB - High-dimensional data are often encountered in biomedical, environmental, and other studies. For example, in biomedical studies that involve high-throughput omic data, an important problem is to search for genetic variables that are predictive of a particular phenotype. A conventional solution is to characterize such relationships through regression models in which a phenotype is treated as the response variable and the variables are treated as covariates; this approach becomes particularly challenging when the number of variables exceeds the number of samples. We propose a general framework for expressing the transformed mean of high-dimensional variables in an exponential distribution family via ANOVA models in which a low-rank interaction space captures the association between the phenotype and the variables. This alternative method transforms the variable selection problem into a well-posed problem with the number of observations larger than the number of variables. In addition, we propose a model selection criterion for the new model framework with a diverging number of parameters, and establish the consistency of the selection criterion. We demonstrate the appealing performance of the proposed method in terms of prediction and detection accuracy through simulations and real data analyses. PMID- 29384044 TI - History of Cardiac Surgery in Belgium. PMID- 29384043 TI - Reference-free error estimation for multiple measurement methods. AB - We present a computational framework to select the most accurate and precise method of measurement of a certain quantity, when there is no access to the true value of the measurand. A typical use case is when several image analysis methods are applied to measure the value of a particular quantitative imaging biomarker from the same images. The accuracy of each measurement method is characterized by systematic error (bias), which is modeled as a polynomial in true values of measurand, and the precision as random error modeled with a Gaussian random variable. In contrast to previous works, the random errors are modeled jointly across all methods, thereby enabling the framework to analyze measurement methods based on similar principles, which may have correlated random errors. Furthermore, the posterior distribution of the error model parameters is estimated from samples obtained by Markov chain Monte-Carlo and analyzed to estimate the parameter values and the unknown true values of the measurand. The framework was validated on six synthetic and one clinical dataset containing measurements of total lesion load, a biomarker of neurodegenerative diseases, which was obtained with four automatic methods by analyzing brain magnetic resonance images. The estimates of bias and random error were in a good agreement with the corresponding least squares regression estimates against a reference. PMID- 29384045 TI - Letter to the Editor. PMID- 29384046 TI - Inflammatory Myofibroblasts Tumour (IMT) of the Liver: A Report of Two Cases. AB - Inflammatory myofibroblastic tumour (IMT) is an uncommon mass lesion composed of myofibroblasts and mixed inflammatory infiltrate that rarely undergoes malignant transformation. Although IMT was originally reported in the lung, it is now recognised that it can occur in a variety of organs. Hepatic localisation of IMT is less frequent. Here we report two cases of IMT in the liver. They underwent hepatic resections with the diagnosis of FNH and Klatskin tumour. The pathological diagnosis of the tumour was IMT. We conclude that in the management of IMT in the liver, surgical excision is the primary choice, in order to obtain a definitive diagnosis as well as to relieve symptoms, and strict follow-up after surgery is required for the timely detection of recurrence. PMID- 29384047 TI - Physiochemical and Thermodynamic Characterization of Highly Active Mutated Aspergillus niger beta-glucosidase for Lignocellulose Hydrolysis. AB - BACKGROUND: Cellulose represents a major source of fermentable sugars in lignocellulosic biomass and a combined action of hydrolytic enzymes (exoglucanases , endoglucanases and beta-glucosidases) is required to effectively convert cellulose to glucose that can be fermented to bio-ethanol. However, in order to make the production of bio-ethanol an economically feasible process, the costs of the enzymes to be used for hydrolysis of the raw material need to be reduced and an increase in specific activity or production efficiency of cellulases is required. Among the cellulases, beta-glucosidase not only hydrolyzes cellobiose to glucose but it also reduces the cellobiose inhibition, resulting in efficient functioning of endo- and exo-glucanases. Therefore, in the current study kinetic and thermodynamic characteristics of highly active beta glucosidase from randomly mutated Aspergillus niger NIBGE-06 have been evaluated for its industrial applications. OBJECTIVE: The main objective of this study was the identification of mutations and determination of their effect on the physiochemical, kinetic and thermodynamic characteristics of beta-glucosidase activity and stability. METHODS: Pure cultures of Aspergillus niger NIBGE and its 2-Deoxy-D-glucose resistant gamma-rays mutant Aspergillus niger NIBGE-06 were grown on Vogel's medium containing wheat bran (3% w/v), at 30+/-1 degrees C for 96-108 h. Crude enzymes from both strains were subjected to ammonium sulfate precipitation and column chromatography on Fast Protein Liquid Chromatography (FPLC) system. The purified beta-glucosidases from both fungal sources were characterized for their native and subunit molecular mass through FPLC and SDS PAGE, respectively. The purified enzymes were then comparatively characterized for their optimum temperature, activation energy (Ea), temperature quotient (Q10), Optimum pH, Heat of ionization (DeltaHI) of active site residues , Michaelis-Menten constants (Vmax, Km, kcat and kcat/Km) and thermodynamics of irreversible inactivation through various enzyme assays. The genomic DNA from both fungal strains was also extracted by SDS-method and full length beta- glucosidase genes (bgl) were amplified through PCR. The PCR products were cloned in TA cloning vector followed by the sequencing of potentially full length clones using the commercial services of Macrogen, Korea. The in silico analyses of the sequences thus obtained were also performed using various online tools such as blastn, blastp, GeneWise, SignalP, Inter- ProScan. RESULTS: The extracellular beta-glucosidases (BGL) from both fungal sources were purified to homogeneity level by ammonium sulfate precipitation and FPLC system. The BGLs from both strains were dimeric in nature, with subunit and native molecular masses of 130 kDa and 252 kDa, respectively. The comparative analysis of nucleotides of bgl genes revealed 8 point mutations. Significant improvement was observed in the kinetic properties of the mutant BGL relative to the wild type enzyme. Arrhenius plot for energy of activation (Ea) showed a biphasic trend and ES-complex formation required Ea of 50 and 42 kJ mol-1 by BGL from parent and mutant, respectively. The pKa1 and pKa2 of the active site residues were 3.4 & 5.5 and 3.2 & 5.6, respectively. The heat of ionization for the acidic limb (DeltaHI-AL) and the basic limb (DeltaHI-BL) of BGL from both strains were equal to 56 & 41 and 71 & 45 kJ mol-1, respectively. Kinetic constants of cellobiose hydrolysis for BGL from both strains were determined as follows: kcat = 2,589 and 4,135 s-1, Km = 0.24 and 0.26 mM cellobiose, kcat/Km = 10,872 and 15,712 s-1 mM-1 cellobiose, respectively. Thermodynamic parameters for cellobiose hydrolysis also suggested that mutant BGL is more efficient compared to the parent enzyme. Comparative analysis of Ea(d), DeltaH* and DeltaG* for irreversible thermostability indicated that the thermostabilization of mutant enzyme was due to higher functional energy (free energy), which enabled the enzyme to resist against unfolding of its transition state. CONCLUSION: Physiochemical and thermodynamic characterization of extracellular beta-glucosidases (BGL) from 2 Deoxy-Dglucose resistant mutant derivative of A. niger showed that mutagenesis did not greatly affect the physiochemical properties of the BGL enzyme, like temperature optima, pH optima and molecular mass, while the catalytic efficiency for cellobiose hydrolysis was significantly improved (High kcat and kcat/Km). Furthermore, the mutant BGL was more thermostable than the parent enzyme. This shows that random mutagenesis has changed the BGL structural gene, resulting in improvement within its stability- function characteristics. Hence, directed evolution or random mutagenesis with careful selection can result in the engineering of highly efficient enzymes for intended industrial applications. PMID- 29384048 TI - Effect of Various Polyols on the Acid-Denatured States of Champedak Galactose Binding Lectin. AB - BACKGROUND: Champedak galactose-binding (CGB) lectin is a tetrameric protein with noncovalently bound monomers, isolated from Artocarpus integer fruit seeds. We had previously reported existence of a structured monomer and an unfolded monomer of CGB lectin at pH 2.5 and pH 1.5, respectively. Polyols are known to induce significant refolding in denatured proteins and stabilize proteins against environmental stresses. Studies on the effect of various polyols on the acid denatured states of CGB lectin are lacking. OBJECTIVE: The objective of this study was to investigate the effects of four different polyols, namely, ethylene glycol, erythritol, xylitol and sorbitol on the acid-denatured states of CGB lectin. METHODS: CGB lectin was subjected to acid denaturation at pH 2.5 and pH 1.5, both in the absence and presence of 30% (w/v) polyols, i.e. ethylene glycol, erythritol, xylitol and sorbitol. Thermal denaturation of the acid-denatured states was also studied in the absence and presence of these polyols. Different spectroscopic probes such as tryptophan fluorescence, ANS fluorescence and far-UV CD spectral signal were used to monitor structural changes in the acid-denatured states of CGB lectin in the presence of polyols. RESULTS: Presence of erythritol, xylitol and sorbitol in the incubation mixture was found to stabilize the lectin at both pH 2.5 and pH 1.5, as evident from the burial of the hydrophobic clusters and decreased polarity around Trp residues. These polyols also stabilized the acid-denatured states of CGB lectin against thermal denaturation by shifting the thermal transition curves towards higher temperatures. Exposure of the acid denatured states of CGB lectin, obtained at pH 2.5 and pH 1.5 to 61 degrees C and 51 degrees C, respectively, induced formation of non-native beta-structures, compared to that present at 25 degrees C, and this phenomenon was significantly suppressed in the presence of these polyols. Based on the spectral data, both sorbitol and erythritol appeared to exude better stabilizing effect. On the other hand, ethylene glycol was shown to destabilize the aciddenatured states of CGB lectin. CONCLUSION: Thermal stabilization of the lectin was noticed in the presence of erythritol, xylitol and sorbitol at both pH 2.5 and pH 1.5. These polyols also stabilize the secondary and tertiary structures of the acid denatured CGB lectin at 25 degrees C. Ethylene glycol was proved to be a destabilizer of the acid-denatured CGB lectin. PMID- 29384049 TI - Immunomodulatory Effects of the Water-soluble Lectin from Moringa oleifera Seeds (WSMoL) on Human Peripheral Blood Mononuclear Cells (PBMC). AB - BACKGROUND: Moringa oleifera is used in traditional medicine as well as in food, cosmetic, and pharmaceutical industries. Water-soluble M. oleifera lectin (WSMoL) is an anionic protein isolated from the seeds of this tree. Until now, immune responses promoted by this lectin in human PBMC have not been investigated. OBJECTIVE: The main objective of this study was to investigate the immunomodulatory effects of WSMoL on human PBMC through measurement of lymphocytes subsets, cytokine and nitric oxide levels. METHODS: Human peripheral blood mononuclear cells (PBMC) were isolated through Ficoll technique, were incubated with WSMoL (10 ug/mL) for 24, 48 and 72 hours, and was performed immunophenotyping assay of lymphocytes and monocytes. Culture supernatants were used to determined cytokine and nitric oxide levels. Assays with cells subsets and cytokine production were performed through cytometry. Nitric oxide release assay was determinate by spectrophotometry. RESULTS: WSMoL induced the release of the cytokines TNF-alpha, IL-2, IL-6, IL-10 as well as nitric oxide. Incubation of PBMC with this lectin also led to activation of CD8+ T lymphocytes. CONCLUSION: WSMoL promotes immunomodulation in human PBMC inducing a potential wound healing profile and, in future in vivo assays, can be evaluated as adjuvant in immunosuppressive diseases and wound repair. PMID- 29384050 TI - Polyphenols: Potential Use in the Prevention and Treatment of Cardiovascular Diseases. AB - BACKGROUND: Polyphenols are bioactive compounds that can be found mostly in foods like fruits, cereals, vegetables, dry legumes, chocolate and beverages such as coffee, tea and wine. They are extensively used in the prevention and treatment of cardiovascular disease (CVD) providing protection against many chronic illnesses. Their effects on human health depend on the amount consumed and on their bioavailability. Many studies have demonstrated that polyphenols have also good effects on the vascular system by lowering blood pressure, improving endothelial function, increasing antioxidant defences, inhibiting platelet aggregation and low-density lipoprotein oxidation, and reducing inflammatory responses. METHODS: This review is focused on some groups of polyphenols and their effects on several cardiovascular risk factors such as hypertension, oxidative stress, atherogenesis, endothelial dysfunction, carotid artery intima media thickness, diabetes and lipid disorders. RESULTS: It is proved that these compounds have many cardio protective functions: they alter hepatic cholesterol absorption, triglyceride biosynthesis and lipoprotein secretion, the processing of lipoproteins in plasma, and inflammation. In some cases, human long-term studies did not show conclusive results because they lacked in appropriate controls and in an undefined polyphenol dosing regimen. CONCLUSION: Rigorous evidence is necessary to demonstrate whether or not polyphenols beneficially impact CVD prevention and treatment. PMID- 29384051 TI - Current Status of Molecular Imaging in Inflammatory and Autoimmune Disorders. AB - In the field of inflammation imaging, nuclear medicine techniques can be considered as a non-invasive tool to early detect pathophysiological changes in affected tissues. These changes usually occur before clinical onset of symptoms and before the development of anatomical changes, that are commonly detected by radiological procedures. This is particularly important for prognostic purposes, therapy decision making and for therapy follow-up. Here we review the current state-of-the art of nuclear medicine for diagnostic purposes in different conditions characterized by a chronic inflammation, such as vulnerable atherosclerotic plaques, vasculitis, rheumatoid arthritis, Sjogren syndrome, autoimmune thyroid diseases, inflammatory bowel diseases, Coeliac disease, Type 1 diabetes mellitus and other immunological diseases. Overall, we describe several different approaches based on radiolabeled cells, peptides and antibodies or FDG. It emerges the role of PET and of hybrid cameras in particular (SPECT/CT and PET/CT) for diagnosis of these disorders and for therapy decision making and followup. PMID- 29384052 TI - Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth. AB - BACKGROUND: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. METHODS: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. RESULTS: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-kappaB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. CONCLUSION: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge. PMID- 29384053 TI - Viral Infections in Pregnancy: A Focus on Ebola Virus. AB - During gestation, the immune response of the placenta to viruses and other pathogens plays an important role in determining a pregnant woman's vulnerability toward infectious diseases. Located at the maternalfetal interface, trophoblast cells serve to minimize the spread of viruses between the host and developing fetus through an intricate system of innate antiviral immune signaling. Adverse pregnancy outcomes, ranging from learning disabilities to preterm birth and fetal death, are all documented results of a viral breach in the placental barrier. Viral infections during pregnancy can also be spread through blood and vaginal secretions, and during the post-natal period, via breast milk. Thus, even in the absence of vertical transmission of viral infection to the fetus, maternal health can still be compromised and threaten the pregnancy. The most common viral DNA isolates found in gestation are adenovirus, cytomegalovirus, and enterovirus. However, with the recent pandemic of Ebola virus, and the first documented case of a neonate to survive due to experimental therapies in 2017, it is becoming increasingly apparent that the changing roles and impacts of viral infection during pregnancy needs to be better understood, while strategies to minimize adverse pregnancy outcomes need to be identified. This review focuses on the adverse impacts of viral infection during gestation, with an emphasis on Ebola virus. PMID- 29384054 TI - Toll-like Receptor-4: A New Target for Preterm Labour Pharmacotherapies? AB - Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered <=34 weeks' gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery. PMID- 29384055 TI - Investigating the Et-1/SphK/S1P Pathway as a Novel Approach for the Prevention of Inflammation-Induced Preterm Birth. AB - BACKGROUND: Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed. METHODS: Our group has used an in vivo model of inflammation-driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB. RESULTS: We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET 1 action, pharmacologically or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the proinflammatory response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis. CONCLUSION: The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB. PMID- 29384056 TI - Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR 2 Inhibitors. AB - BACKGROUND: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention. METHODS: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. RESULTS: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 uM). CONCLUSION: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure based virtual screening method for drug discovery. PMID- 29384057 TI - Synthesis of Novel Derivatives of Quinazoline Schiff base Compound Promotes Epithelial Wound Healing. AB - Quinazoline is an aromatic bicyclic compound exhibiting several pharmaceutical and biological activities. This study was conducted to investigate the potential wound healing properties of Synthetic Quinazoline Compound (SQC) on experimental rats. The toxicity of SQC was determined by MTT cell proliferation assay. The healing effect of SQC was assessed by in vitro wound healing scratch assay on the skin fibroblast cells (BJ-5ta) and in vivo wound healing experiment of low and high dose of SQC on adult Sprague-Dawley rats compared with negative (gum acacia) and positive control (Intrasite-gel). Hematoxylin and Eosin (H&E), Masson's Trichrome (MT) staining and immunohistochemistry analysis were performed to evaluate the histopathological alterations and proteins expression of Bax and Hsp70 on the wound tissue after 10 days. In addition, levels of antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase), and malondialdehyde (MDA) were measured in wound tissue homogenates. The SQC significantly enhanced BJ-5ta cell proliferation and accelerated the percentage of wound closure, with less scarring, increased fibroblast and collagen fibers and less inflammatory cells compared with the negative control. The compound also increases endogenous enzymes and decline lipid peroxidation in wound homogenate. PMID- 29384058 TI - Inflammation, Atrial Fibrillation and Cardiac Surgery: Current Medical and Invasive Approaches for the Treatment of Atrial Fibrillation. AB - Atrial fibrillation (AF) is a cardiac dysrhythmia commonly seen in clinical practice especially after cardiac surgery. It is associated with increased morbidity and mortality for the patients. The pathogenesis of AF is not exactly understood yet, but there is growing data about the relationship between AF and inflammation. Cardiac surgery itself is a big source for inflammation. It causes major surgical trauma, ischemia/reperfusion injury, hypothermia, low arterial pressure, and the equipment of cardiopulmonary bypass makes a large foreign surface thus it activates inflammatory response. There is a large number of data about the treatment options of AF and there are also strategies, which are related to reduction of inflammatory activation during cardiopulmonary bypass. In order to review the relationship between cardiac surgery, inflammation, AF and treatment strategies in patients with AF, we conducted a search through Pubmed for articles in English using the keywords: "atrial fibrillation, cardiac surgery, inflammation, medical therapy, surgical therapy, ablation therapy" from January 2012 to present. We also searched separately for each alternative treatment modality on Pubmed. To identify further articles, we also looked into related citations in review articles and commentaries. We searched thoroughly the guidelines published by the European Society of Cardiology (2016), and the American Heart Association/ American College of Cardiology/ Heart Rhythm Surgery (2014). Many studies concluded that inflammation contributes in the occurrence of AF. Inflammatory markers, such as CRP, interleukins and complements have high sensitivity and specificity for prediction of AF whether the patient having cardiac surgery or not. Betablockers, diltiazem and amiodarone are the most commonly used drugs for rate control in AF following surgery. Although there are some new therapeutic approaches to reduce postoperative inflammatory activation, such as the use of vitamins, fatty acids, statins, or technical improvements to cardiopulmonary bypass unit like miniaturized bypass circuits, heparin coating of the circuits, leukocyte filters, or various surgical approaches like off-pump coronary bypass surgery, we still need more effective strategies to reduce both postoperative inflammation and postoperative AF risk after cardiac surgery. Today we use more advanced invasive and surgical treatment strategies for AF although we need far more advanced technics to reduce perioperative inflammatory activation, which actually causes AF. PMID- 29384059 TI - Recombinant Protein Expression in Escherichia coli (E.coli): What We Need to Know. AB - BACKGROUND: Host, vector, and culture conditions (including cultivation media) are considered among the three main elements contributing to a successful production of recombinant proteins. Accordingly, one of the most common hosts to produce recombinant therapeutic proteins is Escherichia coli. METHODOLOGY: A comprehensive literature review was performed to identify important factors affecting production of recombinant proteins in Escherichia coli. RESULTS: Escherichia coli is taken into account as the easiest, quickest, and cheapest host with a fully known genome. Thus, numerous modifications have been carried out on Escherichia coli to optimize it as a good candidate for protein expression and; as a result, several engineered strains of Escherichia coli have been designed. In general; host strain, vector, and cultivation parameters are recognized as crucial ones determining success of recombinant protein expression in Escherichia coli. In this review, the role of host, vector, and culture conditions along with current pros and cons of different types of these factors leading to success of recombinant protein expression in Escherichia coli were discussed. CONCLUSION: Successful protein expression in Escherichia coli necessitates a broad knowledge about physicochemical properties of recombinant proteins, selection among common strains of Escherichia coli and vectors, as well as factors related to media including time, temperature, and inducer. PMID- 29384060 TI - Nanocarrier Based Advances in Drug Delivery to Tumor: An Overview. AB - BACKGROUND: Nanotechnology deals with the manufacturing of materials at the atomic and molecular scale. According to the National Nanotechnology Initiative, nanotechnology denotes those structures which are nearly in 1-100 nm size regime in at least one dimension. OBJECTIVE: Nanotechnology in drug delivery has been evidenced into nanocarriers that possess distinct properties both in vitro and in vivo, which may be used in targeting drugs to various diseases especially tumors. In the last few years, there has been a keen concern in the formulation of various new drug delivery systems employing nanotechnology. Different nanodevices or nanocarriers like liposomes, dendrimers, polymersomes, transfersomes, and nanoparticles etc. have been employed for the targeted drug delivery. CONCLUSION: This review summarizes the advances in nanocarriers in terms of their methods of preparation and potential applications especially in tumors. PMID- 29384061 TI - PPARgamma-targeting Potential for Radioprotection. AB - BACKGROUND: Peroxisomal proliferator receptor gamma (PPARgamma) is a class of nuclear hormone receptor family involved in insulin sensitization. In addition, PPARgamma has a key role in the protection against oxidative stress and inflammation through regulation of NFkappaB levels and crosstalk with the Nrf2 pathway. Also, its role in the modulation of immune response is substantial. OBJECTIVE: Radiation-induced oxidative stress is the sole determinant of damage to hematopoietic, gastrointestinal system and immune system suppression. Uncontrolled exposure to normal cells during radiotherapy raises the demand for novel and efficient radioprotectors. In this review, we will present an overview of the involvement of PPARgamma in radiation-induced damage and inflammation with major emphasis on whether PPARgamma can serve as a suitable radiomodification target. CONCLUSION: Through this review, we have justified that PPARgamma having both radioprotective as wells as radiotherapeutic potential, may serve as an attractive target for the development of novel and more effective therapies. PMID- 29384062 TI - Melatonin differentially modulates NF-KB expression in breast and liver cancer cells. AB - Background NF-kB (nuclear factor kappa B) is a transcription factor composed of two subunits, p50 and p65, which plays a key role in the inflammatory process. Melatonin has oncostatic, antiangiogenic and antimetastatic properties, and some recent studies have indicated an inhibitory effect of melatonin on NF-kB in some types of cancer. This work aims to investigate the effects of melatonin treatment on the expression of NF-kB in breast and liver cancer models. Methods The breast cancer xenographic model was performed using female Balb/c nude athymic mice injected with MDA-MB-231 cells. The animals were treated with 40 mg/Kg of melatonin for 21 days. Volume of the tumors was measured with a digital capiler. Hepatocarcinoma model was developed by using the HepG2 cells in vitro, treated with 1 mM melatonin for 24 h. The expression of NF-kB protein was verified by immunohistochemistry and immunocytochemistry and quantified by optical densitometry, in vivo study and in vitro study, respectively. NF-kB gene expression was performed by quantitative RT-PCR. Results The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size (P=0.0022). There was a decrease in NF-kB protein staining (P=0.0027) and gene expression (P=0.0185) in mice treated with melatonin. The opposite results were observed for the hepatocarcinoma model. HepG2 cells treated with melatonin showed an increase in the NF-kB immunostaining when compared to control cells (P=0.0042). Conclusion Our results indicated that treatment with melatonin was able to decrease both gene and protein expressions of NF-kB in breast cancer cells and, conversely, increase the transcription factor protein expression in hepatocarcinoma cells. These data highlighted a double role in the expression of NF-kB, depending on the cell type. Further studies are needed to better elucidate the action of melatonin in NF-kB, since this transcription factor acts on different signaling pathways that are fundamental for carcinogenesis. PMID- 29384063 TI - Potential Pharmacological Inhibitors Of Pim Kinase Under Clinical Trials. AB - Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, It has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials. PMID- 29384064 TI - Investigating the Therapeutic Effects of Alginate Nanogel Co-loaded with Gold Nanoparticles and Cisplatin on U87-MG Human Glioblastoma Cells. AB - BACKGROUND AND PURPOSE: It has been well-known both gold nanoparticles (AuNPs) and cisplatin are potential radiosensitizers for radiotherapy of cancer. In this in vitro study, we investigated the chemoradiotherapeutic effects of alginate nanogel co-loaded with AuNPs and cisplatin (ACA) on U87-MG human glioblastoma cells. METHODS: Based on the accomplished pilot studies, U87-MG cells were incubated with ACA and cisplatin at 10% inhibitory concentration (IC10) for 4h. Then, the cells were irradiated to different doses of 6MV X-rays (2 and 10 Gy). MTT assay was performed to evaluate the cell survival rate. Apoptosis was determined by flow cytometry using an annexinV-fluorescein isothiocyanate/propidium iodide apoptosis detection kit. RESULTS: The results showed that ACA at the concentration of 4 ug/ml (per cisplatin) and free cisplatin at concentration of 15 MUg/ml have the same effects on U87-MG cells (survival rate: 90%). The combination of ACA with radiation resulted in a significant decrease in cell viability (survival rate: 30%). The flow cytometry assay also showed that such a combination therapy induces more apoptosis than necrosis. CONCLUSION: It may be concluded that co-delivery of AuNPs and cisplatin with a single nanoplatform like ACA nanocomplex enhances the therapeutic ratio of human glioblastoma radiation therapy. PMID- 29384065 TI - IGF-1R Inhibitor Ameliorates Diabetic Nephropathy with Suppressed HMGN1/TLR4 Pathway. AB - OBJECTIVE: This study was established to investigate the contribution of high mobility group nucleosome-binding protein 1 (HMGN1)/ Toll-like receptor 4 (TLR4) pathway in diabetic nephropathy (DN). And as an intervention of the potential mechanism above, the insulin growth factor 1 receptor (IGF-1R) inhibitor was examined for its therapeutic effect in the diabetic mice. METHOD: Male C57BL/6J mice were administered streptozotocin(STZ) to induce diabetes and thus divided into 5 groups: the untreated group (DN group), the benazepril-treated group (BEN DN group), the insulin-treated group (INS-DN group) and the IGF-1R inhibitor treated group (IGF-DN group). Immunohistochemistry and in situ hybrization were performed to detect the expression of HMGN1 and TLR4 in renal tissue. To evaluate the effect of IGF-1R inhibitor, levels of blood glucose and kidney/ body weight (KW/BW) were measured. And morphological changes and mesangial matrix expansion in kidneys were also detected. RESULTS: Increased expression of HMGN1 and TLR4 in renal tissue of STZ-induced type1 diabetic mellitus (T1DM) mice models was observed. IGF-1R inhibitor attenuate the established nephropathy with reduced expression of TLR4 protein, as revealed by a decrease in mesangial index. CONCLUSION: IGF-1R inhibitor might have therapeutic potential in DN through inhibition of HMGN1/TLR4 pathway. PMID- 29384066 TI - Relationship between Proinflammatory Cytokines/Chemokines and Adipokines in Serum of Young Adults with Obesity. AB - BACKGROUND AND OBJECTIVE: The adipose tissue has been recognized as an important endocrine organ, which is metabolically active and expresses and secretes various inflammatory cytokines. Inflammation is involved in obesity-related complications. As such, the present study investigated the correlation between biochemical parameters, serum proinflammatory cytokines and adipokines in individuals with obesity. METHODS: Based on the body mass index (BMI), 30 subjects were divided into 3 groups: eutrophic (GC, n = 10), overweight (GOW, n = 10) and obese (GOB, n = 10). Serum glucose, cholesterol (total-C, HDLC and LDL C), triglycerides, total proteins, uric acid and insulin were determined, as well as cytokines IL-8, TNF-alpha, IL-1beta, and IL-6, leptin and adiponectin. RESULTS: GOB showed the highest glucose, total and LDL-C, triglycerides, uric acid, insulin, leptin, IL- 8, IL-1beta, IL-6, TNF-alpha and lowest adiponectin levels. In general, adiponectin exhibited an inverse correlation with BMI, abdominal circumference, LDL-C, IL-6, TNF-alpha, leptin and leptin-adiponectin ratio (LAR) and a positive correlation with HDL-C. Leptin was positively correlated with BMI, abdominal circumference, insulin, IL-6, TNF-alpha and LAR and negatively correlated with HDL-C and adiponectin. The LAR was positively correlated with BMI, waist circumference, insulin, TNF-alpha and negatively associated with HDL-C. CONCLUSION: The results confirm that obesity changes the lipid and glycemic profiles of individuals, increases the proinflammatory adipokine levels and reduces those of anti-inflammatory adipokines, promoting a state of chronic inflammation. PMID- 29384067 TI - Interplay of Gut Microbiota, Probiotics in Obesity: A Review. AB - BACKGROUND AND OBJECTIVE: Excess caloric intake and less energy expenditure (e.g. physical inactivity) are associated with acquired metabolic disorders due to sedentary life style. Pharmacological treatments are less effective in preventing obesity. Type of diet influences the gut microbiome alteration and it is interrelated with obesity, insulin resistance and type 2 diabetes. Modified gut microbiota by the harmful bacterial components (e.g: lipopolysaccharides) is linked with the metabolic endotoxemia (low-grade inflammation) which results in damage to the gut barrier function. Administration of probiotics (lactobacilli and bifidobacteria) as live micro-organisms or fermented products achieves proper gut environment. In addition, administration of prebiotics along with probiotics improves the body weight, abdominal fat and intestinal barrier function. METHODS: We compiled all the available literature in the present review in relation to altered gut microbiota by different type of diets, effect of probiotics on obesity and its accompanying diseases in animal and clinical studies. CONCLUSION: Studies are indicating that anti-hyperglycemic and hyperlipidemic effects of probiotics are strain dependent as well as type of animal models. To improve against metabolic disorders, probiotics, need to be administered through prebiotics and requires more clinical studies in this area. PMID- 29384068 TI - Thyroid and Assisted Reproduction Technologies: A Brief Clinical Update with Recommendations for Practice. AB - BACKGROUND AND OBJECTIVE: Infertility is a common disease that in about one third of cases has a female cause and often requires assisted reproduction technologies (ART) to conceive. Also thyroid autoimmunity (TAI), with or without hypothyroidism, is a common disease, particularly in females, and referral for endocrine consultation is not infrequent. DISCUSSION: In the last 15 years a remarkable amount of studies has been published that investigated the pathophysiology of women suffering from TAI, who undergo ART. Due to insufficient sample size, data about the association between infertility and TAI/subclinical hypothyroidism are conflicting. In relation to pregnancy rate, miscarriage, and live births (primary outcomes) data of the literature do not allow to clearly demonstrating an unfavorable impact attributable to TAI/subclinical hypothyroidism; however, secondary outcomes like ovarian reserve or oocytes quality look like worsened. CONCLUSION: For sure, the therapeutic regimens used for controlled ovarian hyperstimulation (COH) induce a deterioration of thyroid function in patients suffering from TAI [with or without Levothyroxine (LT4) treatment]. This picture places patients in a condition of increased risk of developing untimely TSH elevation during fertilization; then, it is reasonable that a patient, above all if thyroid antibody positive, would have a TSH value <2.5mIU/L before undergoing COH, and that would be strictly monitored to start or increase LT4 treatment, when necessary. PMID- 29384070 TI - PART I: FIGHTING CANCER WITH DEADLY BACTERIA. AB - A 200-year-old observation might provide a new way to eliminate tumors by infecting cancer patients with bacteria. Kristie Nybo explores a new approach that could transform cancer treatment. PMID- 29384071 TI - PART II: BREAKTHROUGHS IN TUMOR-SEEKING BACTERIA. AB - Newly engineered bacterial strains propel an immune-mediated cancer therapy toward clinical applications. Hannah Martin Lawrenz reports on the latest developments. PMID- 29384069 TI - Exploration of Global Trend on Biomedical Application of Polyhydroxyalkanoate (PHA): A Patent Survey. AB - BACKGROUND: Polyhydroxyalkanoates are bio-based, biodegradable naturally occurring polymers produced by a wide range of organisms, from bacteria to higher mammals. The properties and biocompatibility of PHA make it possible for a wide spectrum of applications. In this context, we analyze the potential applications of PHA in biomedical science by exploring the global trend through the patent survey. The survey suggests that PHA is an attractive candidate in such a way that their applications are widely distributed in the medical industry, drug delivery system, dental material, tissue engineering, packaging material as well as other useful products. OBJECTIVE: In our present study, we explored patents associated with various biomedical applications of polyhydroxyalkanoates. METHOD: Patent databases of European Patent Office, United States Patent and Trademark Office and World Intellectual Property Organization were mined. We developed an intensive exploration approach to eliminate overlapping patents and sort out significant patents.We demarcated the keywords and search criterions and established search patterns for the database request. We retrieved documents within the recent 6 years, 2010 to 2016 and sort out the collected data stepwise to gather the most appropriate documents in patent families for further scrutiny. RESULTS: By this approach, we retrieved 23,368 patent documents from all the three databases and the patent titles were further analyzed for the relevance of polyhydroxyalkanoates in biomedical applications. This ensued in the documentation of approximately 226 significant patents associated with biomedical applications of polyhydroxyalkanoates and the information was classified into six major groups. Polyhydroxyalkanoates has been patented in such a way that their applications are widely distributed in the medical industry, drug delivery system, dental material, tissue engineering, packagingmaterial as well as other useful products. CONCLUSION: There are many avenues through which PHA & PHB could be used. Our analysis shows patent information can be used to identify various applications of PHA and its representatives in the biomedical field. Upcoming studies can focus on the application of PHA in the different field to discover the related topics and associate to this study.We believe that this approach of analysis and findings can initiate new researchers to undertake similar kind of studies in their represented field to fill the gap between the patent articles and research publications. PMID- 29384074 TI - Standardized cloning vectors for protein production and generation of large gene libraries in Escherichia coli. AB - Here, we modified the multiple cloning sites from commonly used expression vectors to create a new suite of cloning plasmids that simplify and speed up cloning procedures in Escherichia coli. Each of our standardized plasmids contains two BsaI restriction sites, allowing for highly efficient cloning of genes and bringing their expression under control of either a T7 (pET21a_BsaI, pET28a_BsaI, and pMAL-c5T_BsaI) or T5 promoter (pUR22 and pUR23). Another plasmid in our suite (pTNA_BsaI) allows for generation of large gene libraries containing >108 variants, which can be constitutively expressed in selection experiments using metabolic complementation of auxotrophic E. coli strains. Coupling restriction and ligation with the BsaI restriction enzyme minimizes hands-on time, while the need for only three different primers to clone a target gene into the six different vectors keeps overall cloning costs low. PMID- 29384072 TI - Vital ex vivo tissue labeling and pathology-guided micropunching to characterize cellular heterogeneity in the tissue microenvironment. AB - Cellular heterogeneity within the tissue microenvironment may underlie chemotherapeutic resistance and response, enabling tumor evolution; however, this heterogeneity it is difficult to characterize. Here, we present a new approach pathology-guided micropunching (PGM)-that enables identification and characterization of heterogeneous foci identified in viable human and animal model tissue slices. This technique consists of live-cell tissue labeling using fluorescent antibodies/small molecules to identify heterogeneous foci (e.g., immune infiltrates or cells with high levels of reactive oxygen species) in viable tissues, coupled with a micropunch step to isolate cells from these heterogeneous foci for downstream molecular or vital functional analysis. Micropunches obtained from epithelial or stromal fibroblast foci in human prostate tissue show 6- to 12-fold enrichment in transcripts specific for EpCam/cytokeratin 8 and vimentin/a-smooth muscle actin/integrin 1-alpha, respectively. Transcriptional enrichment efficiency agrees with epithelial and stromal laser capture microdissection samples isolated from human prostate. Micropunched foci show a loss of cellular viability in the periphery, but centrally localized cells retained viability before and after dissociation and grew out in culture. PMID- 29384073 TI - General and facile purification of dye-labeled oligonucleotides by pH-controlled extraction. AB - Previously, we reported a method for facile purification of oligonucleotides labeled with hydrophobic dyes, based on the solubility difference between the hydrophilic DNA and unreacted dye. Here, we present a new purification method applicable to any dye regardless of its hydrophobicity. We exploited the population shift of a fluorescent dye in a low-pH aqueous solution from its anionic form toward its neutral form. When the pH of an aqueous solution containing dye-labeled DNA and unreacted free dye is lowered, and the solution is mixed with a hydrophobic organic solvent (butanol), the neutral free dye is preferentially dissolved in the organic phase, leaving behind the hydrophilic dye labeled DNA in the aqueous phase. We experimentally verified that our new method results in high yields of dye-labeled oligonucleotides and the efficient removal of free dye. PMID- 29384075 TI - A gas trapping method for high-throughput metabolic experiments. AB - Research into cellular metabolism has become more high-throughput, with typical cell-culture experiments being performed in multiwell plates (microplates). This format presents a challenge when trying to collect gaseous products, such as carbon dioxide (CO2), which requires a sealed environment and a vessel separate from the biological sample. To address this limitation, we developed a gas trapping protocol using perforated plastic lids in sealed cell-culture multiwell plates. We used this trap design to measure CO2 production from glucose and fatty acid metabolism, as well as hydrogen sulfide production from cysteine-treated cells. Our data clearly show that this gas trap can be applied to liquid and solid gas-collection media and can be used to study gaseous product generation by both adherent cells and cells in suspension. Since our gas traps can be adapted to multiwell plates of various sizes, they present a convenient, cost-effective solution that can accommodate the trend toward high-throughput measurements in metabolic research. PMID- 29384076 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 7: understanding the potential impacts of dissemination bias. AB - BACKGROUND: The GRADE-CERQual (Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations, (2) coherence, (3) adequacy of data and (4) relevance. This paper is part of a series providing guidance on how to apply CERQual and focuses on a probable fifth component, dissemination bias. Given its exploratory nature, we are not yet able to provide guidance on applying this potential component of the CERQual approach. Instead, we focus on how dissemination bias might be conceptualised in the context of qualitative research and the potential impact dissemination bias might have on an overall assessment of confidence in a review finding. We also set out a proposed research agenda in this area. METHODS: We developed this paper by gathering feedback from relevant research communities, searching MEDLINE and Web of Science to identify and characterise the existing literature discussing or assessing dissemination bias in qualitative research and its wider implications, developing consensus through project group meetings, and conducting an online survey of the extent, awareness and perceptions of dissemination bias in qualitative research. RESULTS: We have defined dissemination bias in qualitative research as a systematic distortion of the phenomenon of interest due to selective dissemination of studies or individual study findings. Dissemination bias is important for qualitative evidence syntheses as the selective dissemination of qualitative studies and/or study findings may distort our understanding of the phenomena that these syntheses aim to explore and thereby undermine our confidence in these findings. Dissemination bias has been extensively examined in the context of randomised controlled trials and systematic reviews of such studies. The effects of potential dissemination bias are formally considered, as publication bias, within the GRADE approach. However, the issue has received almost no attention in the context of qualitative research. Because of very limited understanding of dissemination bias and its potential impact on review findings in the context of qualitative evidence syntheses, this component is currently not included in the GRADE-CERQual approach. CONCLUSIONS: Further research is needed to establish the extent and impacts of dissemination bias in qualitative research and the extent to which dissemination bias needs to be taken into account when we assess how much confidence we have in findings from qualitative evidence syntheses. PMID- 29384077 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 5: how to assess adequacy of data. AB - BACKGROUND: The GRADE-CERQual (Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations; (2) coherence; (3) adequacy of data; and (4) relevance. This paper is part of a series providing guidance on how to apply CERQual and focuses on CERQual's adequacy of data component. METHODS: We developed the adequacy of data component by searching the literature for definitions, gathering feedback from relevant research communities and developing consensus through project group meetings. We tested the CERQual adequacy of data component within several qualitative evidence syntheses before agreeing on the current definition and principles for application. RESULTS: When applying CERQual, we define adequacy of data as an overall determination of the degree of richness and the quantity of data supporting a review finding. In this paper, we describe the adequacy component and its rationale and offer guidance on how to assess data adequacy in the context of a review finding as part of the CERQual approach. This guidance outlines the information required to assess data adequacy, the steps that need to be taken to assess data adequacy, and examples of adequacy assessments. CONCLUSIONS: This paper provides guidance for review authors and others on undertaking an assessment of adequacy in the context of the CERQual approach. We approach assessments of data adequacy in terms of the richness and quantity of the data supporting each review finding, but do not offer fixed rules regarding what constitutes sufficiently rich data or an adequate quantity of data. Instead, we recommend that this assessment is made in relation to the nature of the finding. We expect the CERQual approach, and its individual components, to develop further as our experiences with the practical implementation of the approach increase. PMID- 29384078 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 3: how to assess methodological limitations. AB - BACKGROUND: The GRADE-CERQual (Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations, (2) coherence, (3) adequacy of data and (4) relevance. This paper is part of a series providing guidance on how to apply CERQual and focuses on CERQual's methodological limitations component. METHODS: We developed the methodological limitations component by searching the literature for definitions, gathering feedback from relevant research communities and developing consensus through project group meetings. We tested the CERQual methodological limitations component within several qualitative evidence syntheses before agreeing on the current definition and principles for application. RESULTS: When applying CERQual, we define methodological limitations as the extent to which there are concerns about the design or conduct of the primary studies that contributed evidence to an individual review finding. In this paper, we describe the methodological limitations component and its rationale and offer guidance on how to assess methodological limitations of a review finding as part of the CERQual approach. This guidance outlines the information required to assess methodological limitations component, the steps that need to be taken to assess methodological limitations of data contributing to a review finding and examples of methodological limitation assessments. CONCLUSIONS: This paper provides guidance for review authors and others on undertaking an assessment of methodological limitations in the context of the CERQual approach. More work is needed to determine which criteria critical appraisal tools should include when assessing methodological limitations. We currently recommend that whichever tool is used, review authors provide a transparent description of their assessments of methodological limitations in a review finding. We expect the CERQual approach and its individual components to develop further as our experiences with the practical implementation of the approach increase. PMID- 29384079 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to the series. AB - The GRADE-CERQual ('Confidence in the Evidence from Reviews of Qualitative research') approach provides guidance for assessing how much confidence to place in findings from systematic reviews of qualitative research (or qualitative evidence syntheses). The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. Confidence in the evidence from qualitative evidence syntheses is an assessment of the extent to which a review finding is a reasonable representation of the phenomenon of interest. CERQual provides a systematic and transparent framework for assessing confidence in individual review findings, based on consideration of four components: (1) methodological limitations, (2) coherence, (3) adequacy of data, and (4) relevance. A fifth component, dissemination (or publication) bias, may also be important and is being explored. As with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach for effectiveness evidence, CERQual suggests summarising evidence in succinct, transparent, and informative Summary of Qualitative Findings tables. These tables are designed to communicate the review findings and the CERQual assessment of confidence in each finding. This article is the first of a seven-part series providing guidance on how to apply the CERQual approach. In this paper, we describe the rationale and conceptual basis for CERQual, the aims of the approach, how the approach was developed, and its main components. We also outline the purpose and structure of this series and discuss the growing role for qualitative evidence in decision making. Papers 3, 4, 5, 6, and 7 in this series discuss each CERQual component, including the rationale for including the component in the approach, how the component is conceptualised, and how it should be assessed. Paper 2 discusses how to make an overall assessment of confidence in a review finding and how to create a Summary of Qualitative Findings table. The series is intended primarily for those undertaking qualitative evidence syntheses or using their findings in decision-making processes but is also relevant to guideline development agencies, primary qualitative researchers, and implementation scientists and practitioners. PMID- 29384080 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 6: how to assess relevance of the data. AB - BACKGROUND: The GRADE-CERQual (Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations, (2) coherence, (3) adequacy of data and (4) relevance. This paper is part of a series providing guidance on how to apply CERQual and focuses on CERQual's relevance component. METHODS: We developed the relevance component by searching the literature for definitions, gathering feedback from relevant research communities and developing consensus through project group meetings. We tested the CERQual relevance component within several qualitative evidence syntheses before agreeing on the current definition and principles for application. RESULTS: When applying CERQual, we define relevance as the extent to which the body of data from the primary studies supporting a review finding is applicable to the context (perspective or population, phenomenon of interest, setting) specified in the review question. In this paper, we describe the relevance component and its rationale and offer guidance on how to assess relevance in the context of a review finding. This guidance outlines the information required to assess relevance, the steps that need to be taken to assess relevance and examples of relevance assessments. CONCLUSIONS: This paper provides guidance for review authors and others on undertaking an assessment of relevance in the context of the CERQual approach. Assessing the relevance component requires consideration of potentially important contextual factors at an early stage in the review process. We expect the CERQual approach, and its individual components, to develop further as our experiences with the practical implementation of the approach increase. PMID- 29384081 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 4: how to assess coherence. AB - BACKGROUND: The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE working group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision-making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations, (2) relevance, (3) coherence and (4) adequacy of data. This paper is part of a series providing guidance on how to apply CERQual and focuses on CERQual's coherence component. METHODS: We developed the coherence component by searching the literature for definitions, gathering feedback from relevant research communities and developing consensus through project group meetings. We tested the CERQual coherence component within several qualitative evidence syntheses before agreeing on the current definition and principles for application. RESULTS: When applying CERQual, we define coherence as how clear and cogent the fit is between the data from the primary studies and a review finding that synthesises that data. In this paper, we describe the coherence component and its rationale and offer guidance on how to assess coherence in the context of a review finding as part of the CERQual approach. This guidance outlines the information required to assess coherence, the steps that need to be taken to assess coherence and examples of coherence assessments. CONCLUSIONS: This paper provides guidance for review authors and others on undertaking an assessment of coherence in the context of the CERQual approach. We suggest that threats to coherence may arise when the data supporting a review finding are contradictory, ambiguous or incomplete or where competing theories exist that could be used to synthesise the data. We expect the CERQual approach, and its individual components, to develop further as our experiences with the practical implementation of the approach increase. PMID- 29384082 TI - Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 2: how to make an overall CERQual assessment of confidence and create a Summary of Qualitative Findings table. AB - BACKGROUND: The GRADE-CERQual (Confidence in Evidence from Reviews of Qualitative research) approach has been developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. The approach has been developed to support the use of findings from qualitative evidence syntheses in decision making, including guideline development and policy formulation. CERQual includes four components for assessing how much confidence to place in findings from reviews of qualitative research (also referred to as qualitative evidence syntheses): (1) methodological limitations, (2) coherence, (3) adequacy of data and (4) relevance. This paper is part of a series providing guidance on how to apply CERQual and focuses on making an overall assessment of confidence in a review finding and creating a CERQual Evidence Profile and a CERQual Summary of Qualitative Findings table. METHODS: We developed this guidance by examining the methods used by other GRADE approaches, gathering feedback from relevant research communities and developing consensus through project group meetings. We then piloted the guidance on several qualitative evidence syntheses before agreeing on the approach. RESULTS: Confidence in the evidence is an assessment of the extent to which a review finding is a reasonable representation of the phenomenon of interest. Creating a summary of each review finding and deciding whether or not CERQual should be used are important steps prior to assessing confidence. Confidence should be assessed for each review finding individually, based on the judgements made for each of the four CERQual components. Four levels are used to describe the overall assessment of confidence: high, moderate, low or very low. The overall CERQual assessment for each review finding should be explained in a CERQual Evidence Profile and Summary of Qualitative Findings table. CONCLUSIONS: Structuring and summarising review findings, assessing confidence in those findings using CERQual and creating a CERQual Evidence Profile and Summary of Qualitative Findings table should be essential components of undertaking qualitative evidence syntheses. This paper describes the end point of a CERQual assessment and should be read in conjunction with the other papers in the series that provide information on assessing individual CERQual components. PMID- 29384084 TI - [medecine/sciences 2018, a journal at the very heart of the debates and of the current and future research challenges]. PMID- 29384083 TI - Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: a diagnostic accuracy study. AB - BACKGROUND: Progressive optic nerve damage in glaucoma results in vision loss, quantifiable with visual field (VF) testing. VF measurements are, however, highly variable, making identification of worsening vision ('progression') challenging. Glaucomatous optic nerve damage can also be measured with imaging techniques such as optical coherence tomography (OCT). OBJECTIVE: To compare statistical methods that combine VF and OCT data with VF-only methods to establish whether or not these allow (1) more rapid identification of glaucoma progression and (2) shorter or smaller clinical trials. DESIGN: Method 'hit rate' (related to sensitivity) was evaluated in subsets of the United Kingdom Glaucoma Treatment Study (UKGTS) and specificity was evaluated in 72 stable glaucoma patients who had 11 VF and OCT tests within 3 months (the RAPID data set). The reference progression detection method was based on Guided Progression AnalysisTM (GPA) Software (Carl Zeiss Meditec Inc., Dublin, CA, USA). Index methods were based on previously described approaches [Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS), Permutation analyses Of Pointwise Linear Regression (PoPLR) and structure-guided ANSWERS (sANSWERS)] or newly developed methods based on Permutation Test (PERM), multivariate hierarchical models with multiple imputation for censored values (MaHMIC) and multivariate generalised estimating equations with multiple imputation for censored values (MaGIC). SETTING: Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). PARTICIPANTS: UKGTS participants were newly diagnosed glaucoma patients randomised to intraocular pressure-lowering drops or placebo. RAPID participants had glaucomatous VF loss, were on treatment and were clinically stable. INTERVENTIONS: 24-2 VF tests with the Humphrey Field Analyzer and optic nerve imaging with time-domain (TD) Stratus OCTTM (Carl Zeiss Meditec Inc., Dublin, CA, USA). MAIN OUTCOME MEASURES: Criterion hit rate and specificity, time to progression, future VF prediction error, proportion progressing in UKGTS treatment groups, hazard ratios (HRs) and study sample size. RESULTS: Criterion specificity was 95% for all tests; the hit rate was 22.2% for GPA, 41.6% for PoPLR, 53.8% for ANSWERS and 61.3% for sANSWERS (all comparisons p <= 0.042). Mean survival time (weeks) was 93.6 for GPA, 82.5 for PoPLR, 72.0 for ANSWERS and 69.1 for sANSWERS. The median prediction errors (decibels) when the initial trend was used to predict the final VF were 3.8 (5th to 95th percentile 1.7 to 7.6) for PoPLR, 3.0 (5th to 95th percentile 1.5 to 5.7) for ANSWERS and 2.3 (5th to 95th percentile 1.3 to 4.5) for sANSWERS. HRs were 0.57 [95% confidence interval (CI) 0.34 to 0.90; p = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; p = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; p = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; p = 0.012) for sANSWERS. Sample size estimates were not reduced using methods including OCT data. PERM hit rates were between 8.3% and 17.4%. Treatment effects were non-significant in MaHMIC and MaGIC analyses; statistical significance was altered little by incorporating imaging. LIMITATIONS: TD OCT is less precise than current imaging technology; current OCT technology would likely perform better. The size of the RAPID data set limited the precision of criterion specificity estimates. CONCLUSIONS: The sANSWERS method combining VF and OCT data had a higher hit rate and identified progression more quickly than the reference and other VF-only methods, and produced more accurate estimates of the progression rate, but did not increase treatment effect statistical significance. Similar studies with current OCT technology need to be undertaken and the statistical methods need refinement. TRIAL REGISTRATION: Current Controlled Trials ISRCTN96423140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 4. See the NIHR Journals Library website for further project information. Data analysed in the study were from the UKGTS. Funding for the UKGTS was provided through an unrestricted investigator-initiated research grant from Pfizer Inc. (New York, NY, USA), with supplementary funding from the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. Imaging equipment loans were made by Heidelberg Engineering, Carl Zeiss Meditec and Optovue (Fremont, CA, USA). Pfizer, Heidelberg Engineering, Carl Zeiss Meditec and Optovue had no input into the design, conduct, analysis or reporting of any of the UKGTS findings or this work. The sponsor for both the UKGTS and RAPID data collection was Moorfields Eye Hospital NHS Foundation Trust. David F Garway-Heath, Tuan-Anh Ho and Haogang Zhu are partly funded by the NIHR Biomedical Research Centre based at Moorfields Eye Hospital and UCL Institute of Ophthalmology. David F Garway-Heath's chair at University College London (UCL) is supported by funding from the International Glaucoma Association. PMID- 29384085 TI - [Towards a personalized pretransplantation conditioning in patients with myelodysplastic syndromes]. PMID- 29384086 TI - [The Ras-related GTPase RhoB, a relevant actor in the adaptive resistance to EGFR tyrosine kinase inhibitors in lung cancers]. PMID- 29384087 TI - [Paradoxical effects of cannabis on memory: for once, it's better to be old!] PMID- 29384088 TI - [Super-resolution STED imaging reveals a new type of axonal plasticity]. PMID- 29384089 TI - [KCNQ1: a new regulator of the epithelio-mesenchymal transition in colorectal cancers]. PMID- 29384090 TI - [Dual tumor suppressive and oncogenic roles for Notch signaling in small cell lung cancer]. PMID- 29384091 TI - [The neuropeptide FF: a signal for M1 to M2 type switching in macrophages from the adipose tissue]. PMID- 29384092 TI - [Biological clocks: a rythm can hide another one]. PMID- 29384093 TI - [Spatial orientation in the primate: I see, there I am]. PMID- 29384094 TI - [Eating and sleeping, two vital tumor activities favoring anticancer treatment failure]. PMID- 29384095 TI - [Some scientific highlights from early 2018: a selection by MD/Pharmacy-PhD students]. PMID- 29384096 TI - [Regulation of the NLRP3 inflammasome]. AB - The innate immunity constitutes an efficient barrier by rapidly detecting pathogens and tissue damages through pattern recognition receptors including NLRP3. Moreover, inappropriate NLRP3 activation causes deleterious inflammation and contributes to various conditions including atherosclerosis, diabetes, gout and Alzheimer's diseases. NLRP3 assembles a multimeric inflammasome complex serving as an activation platform for caspase-1 that controls processing and release of cytosolic inflammatory factors and cytokines including IL-1beta Inflammasome assembly is tightly controlled and requires coordinated NLRP3 priming, through cytokine or other pattern recognition receptors, followed by activation by cellular stress. Here, we describe recent advances in the understanding of the signalling pathways supporting the priming and activation of NLRP3, with a special focus on the key role of post-translational modifications of NLRP3, including phosphorylation and ubiquitination, in inflammasome regulation. PMID- 29384097 TI - [Osteocalcin, a key molecule for bone endocrine functions]. AB - The maintenance of our physiological functions and their adaptive response to environmental changes depend on precise crosstalk between organs. Recent advances in mouse genetics have helped demonstrate that this holistic view of physiology extends to the skeletal system, where many unexpected signaling axes are found to play essential roles affecting numerous organs. After being long regarded as a static tissue, functioning merely as a structural support system, the skeleton has seen its image evolve into a much more complex picture. The skeleton reveals itself as a key endocrine organ for the homeostasis of our body, both by its central position in our body, but also by the large number of physiological functions it influences. In this review, we discuss the multiple endocrine roles of osteocalcin, an osteoclast-derived molecule (Ocn), where its functional importance has steadily increased over the last 15 years. PMID- 29384098 TI - [Cell complexity should be placed at the heart of cancer research]. AB - Genetic and most likely epigenetic alterations occurring during tumor progression and metastatic process lead to a broad deregulation of major cellular functions. However, the molecular mechanisms involved are still poorly understood. To understand them, the cell, the basic unit of life, remains more than ever the essential level to integrate the functional impact of genetics and epigenetics processes in the light of the global economy of the normal and cancerous cell, and of its interactions with its microenvironment. PMID- 29384099 TI - [Which future for B lymphocytes infiltrating solid tumors: prognostic biomarker and/or therapeutic target?] AB - The role of B lymphocytes in tumor immuno-surveillance has been neglected for a long time because it has been often considered to be ineffective if not pro tumoral. Extensive studies of the tumor immune microenvironment, particularly in humans, has now made it possible to specify the nature of the interactions between B cells and their cellular partners. This review will present a number of parameters that dictate the fate of B cells toward a pro-tumor versus an anti tumor function. Thus, the ability to elicit a B cell-and/or an antibody-dependent anti-tumor immunity involves a wide variety of molecular and cellular mechanisms, some of which may represent novel therapeutic targets in oncology. PMID- 29384100 TI - [EBV/KSHV co-infection: an effective partnership]. AB - Kaposi's sarcoma human herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL) in which Epstein-Barr virus (EBV) is also very often present. By using a humanized mouse model, Pr. Munz's team has been able to demonstrate that EBV/KSHV co-infection increases KSHV persistence and cell transformation through the stimulation of EBV replication. This is the first model of PEL in small animals, opening up exciting prospects for future studies on this unique lymphoma. PMID- 29384101 TI - [Evolution, determinants and regulation of drug expenditures in France]. AB - According to the Organization for Economic Co-operation and Development (OECD), drug expenditures account for about 20 % of all health expenditures in high income countries. The increase of these drug expenditures which has been observed in all these countries over a long period is due to the combination of aging populations, changes in medical practices and the dynamics of the pharmaceutical market, in particular the hospital market. France is no exception. Its consumption of drugs (which accounted for 17.5 % of health expenditures in 2014), historically among the highest in volume, has grown slower in the last decade than in other OECD countries. However, the particularly rapid and wide adoption of pharmaceutical innovations, which has always characterized France, has had in recent years a very significant effect on the soaring drug expenditures covered by the social protection system (plus 1.1 billion in 2014, a year marked by the introduction of new therapies against hepatitis C). This significant effect should continue with the introduction of new and very expensive therapies, particularly in oncology. PMID- 29384102 TI - [John Locke, philosopher who did not want "to get involved in medicine"...]. PMID- 29384103 TI - [A question of colour]. AB - GWAS analyses for skin colour performed on a series of diverse African groups reveal new loci involved in this phenotype and, surprisingly, the presence within several African populations of the "light" allele of the SLC24A5 gene at significant frequency. This underlines the complexity of skin colour genetics and the interest of studying a wide range of populations. PMID- 29384104 TI - Successful rapid subcutaneous desensitization to anakinra in a case with a severe immediate-type hypersensitivity reaction. AB - Summary: Anakinra, one of the novel biological agents, is a recombinant human IL 1 receptor antagonist. It is preferred as an alternative drug for familial Mediterranean fever cases where colchicine is not sufficient or cannot be used due to its side effects. Like all other biologics, hypersensitivity reactions to anakinra are quite rare. This is the first case which was successfully desensitized with anakinra after a severe immediate-type hypersensitivity reaction. PMID- 29384105 TI - An unusual case of wheat dependent exercise induced anaphylaxis (WDEIA) triggered by Tri a 14 in a pediatric patient: a case report. AB - Summary: Anakinra, one of the novel biological agents, is a recombinant human IL 1 receptor antagonist. It is preferred as an alternative drug for familial Mediterranean fever cases where colchicine is not sufficient or cannot be used due to its side effects. Like all other biologics, hypersensitivity reactions to anakinra are quite rare. This is the first case which was successfully desensitized with anakinra after a severe immediate-type hypersensitivity reaction. We report a case of WDEIA in an asthmatic boy admitted to our Unit with suspected mushroom acute toxicity. The symptoms occurred during a gym session, approximately 2 hours after the ingestion of a meal based on pasta and cooked mushroom found in the family's garden. Acute toxicity due to mushroom ingestion was then excluded. Triptase serum levels resulted elevated in acute phase and normal after 24 hours. Food specific IgE showed a sensitization to lipid transfer protein Pru p 3 and to Tri a 14. This case highlights that WDEIA is underdiagnosed, especially when patients are firstly visited in Emergency Unit. Moreover, Tri a 14 is seldom described as responsible for WDEIA, compared to omega 5 gliadin. PMID- 29384106 TI - Recommendations for the use of molecular diagnostics in the diagnosis of allergic dis-eases. AB - Summary: The Study Group on Allergology of the Italian Society of Clinical Pathology and Laboratory Medicine (SIPMeL) and the Associazione Italiana degli Allergologi e Immunologi Territoriali e Ospedalieri (AAIITO) developed the present recommendations on the diagnosis of allergic diseases based on the use of molecular allergenic components, whose purpose is to provide the pathologists and the clinicians with information and algorithms enabling a proper use of this second-level diagnostics. Molecular diagnostics allows definition of the exact sensitization profile of the allergic patient. The methodology followed to develop these recommendations included an initial phase of discussion between all the components to integrate the knowledge derived from scientific evidence, a revision of the recommendations made by Italian and foreign experts, and the subsequent production of this document to be disseminated to all those who deal with allergy diagnostics. PMID- 29384107 TI - Restoration of aspirin tolerance following omalizumab treatment in a patient with chronic spontaneous urticaria. AB - Summary: Up to 30% of cases of chronic spontaneous urticaria (CSU) are exacerbated by COX-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAID); this clinical picture is termed NECD (NSAID-exacerbated cutaneous disease). On the other hand, multiple NSAID hypersensitivity may occur in the absence of an underlying CSU also, a situation that is termed NIUA (NSAID-induced urticaria / angioedema). The present study reports a case of multiple NSAID hypersensitivity that occurred in a man much before he developed severe CSU. Omalizumab treatment eventually induced a remission of the cutaneous disease which was associated with aspirin tolerance, as assessed by open oral challenge with the drug. Altogether, this case suggests that it might be worth to investigate tolerance to aspirin or other strong COX-1 inhibitors NECD patients showing a complete response to omalizumab, and maybe also the effects of omalizumab in NIUA patients as well. PMID- 29384108 TI - Patch testing in a case of eslicarbazepine and carbamazepine induced cutaneous reaction. AB - Summary: Anticonvulsants are among the drugs most commonly involved in cutaneous adverse drug reactions (CADRs). Eslicarbazepine is a new anti-epileptic drug, chemically related to carbamazepine but with a more favorable safety profile. We report the clinical case of a woman who developed a skin rash on day 10 of eslicarbazepine with further exacerbation with eosinophilia on day 2 of carbamazepine. Epicutaneous tests were positive with eslicarbazepine. PMID- 29384109 TI - Local anesthetics allergy: who should be tested? AB - Summary: Objective. To document the test results of patients referred to our clinic for testing with local anesthetics (LAs) in real life conditions and provide data related to the necessity of these tests. Methods. All consecutive subjects who were referred to be evaluated for LA allergy during a two-year follow up were included in the analysis. All subjects underwent skin prick / intradermal tests followed by a subcutaneous provocation test with the LAs tested. Results. A total of 228 subjects were included. The main referral reason was the presence of a history of drug hypersensitivity reaction (DHR) to drugs other than LAs (n = 128; 56%), whereas a history of LA allergy constituted the second most common referral reason (n = 64, 28.1%). In the majority of cases (n = 39; 60.9%), the culprit LA was not known by the patients. Asthma was the third most common referral reason, presented in 49 cases (21.5%). Ten cases had positivity to the tested LA in skin testing / challenges. Nine out of 10 patients had a history of DHR to drugs other than LA, whereas 5 of them had also a history of DHR to LA. Six of the 10 patients had a history of multiple DHR. None of the asthma patients without any DHR history were positive in the LA tests. Eight out of 10 cases who underwent skin testing / challenge with an alternative LA, tolerated the alternative LA. Conclusion. The most common referral reason for testing with LA was a history of DHR to drugs other than LAs, whereas asthma was the third most common referral reason. Patients with a history of multiple DHR may be considered for testing with LAs. Asthmatics and those with other allergic diseases without a history of drug / LA allergy do not need to be tested with LA. PMID- 29384110 TI - Systematic investigation for underlying causes of recurrent infections in children: surveillance of primary immunodeficiency. AB - Summary: Recurrent infections seem to be a common complaint in children who are referred to general practitioners and pediatricians offices. Detection of primary immunodeficiencies (PID) etiology is very important for achieving appropriate diagnosis and treatment of these patients. The absence of appropriate treatment could lead to subsequent complications, in a hospital inpatient and/or outpatient settings. This study was performed in a group of children with recurrent infections to identify patients with underlying PID. A cross-sectional study was designed to evaluate the final clinical diagnosis obtained in 100 pediatric patients with a history of recurrent infections referred to Children s Medical Center, Tehran, Iran, during one year (2011-2012). History taking and physical examination, complementary laboratory tests including immunological investigations were done to confirm the main causes of disease according to our previously published stepwise approach to recurrent infections. Among all studied patients, 21% (11 males and 10 females) were diagnosed to have PID. Parental consanguinity (p = 0.001) and soft tissue infections (p = 0.004) were significantly higher in PID group, comparing to other causes of recurrent infections. Gender and location of infections were also linked to the type of PID including antibody deficiency, combined immunodeficiency and phagocytosis disorders. The real rate of PID as a cause of recurrent infection appears to be much higher than what is generally considered in a se-lected group of pediatric patients; so, following the suggested stepwise guideline can im-prove timely diagnosis and appropriate treatment of these patients. PMID- 29384111 TI - Immunogenetics of cytokine genes in parthenium dermatitis: a review. AB - Summary: Parthenium dermatitis is a chronic immuno-inflammatory, distressing skin disease and is mediated by activated T-lymphocyte which is primarily manifested on the exposed sites of the face, neck, hand and flexures. Parthenium hysterophorus is ubiquitous, hence it is diffi-cult to avoid the aero-allergenic antigen parthenin, responsible for the contact dermatitis. The pathogenesis of parthenium dermatitis is characterized by infiltration of T-lymphocytes into challenged skin sites and the development of a cutaneous inflammation due to altered regulatory network of pro and anti-inflammatory cytokines. Regulation of inflammatory events perpetuated by cytokines continues to complicate efforts to analyze both the function of individual cytokine and the influence of candidate gene polymorphism on expression and disease severity. The genetic polymorphisms in these cytokines are significantly affecting immunological parameters and, subsequently, modulation and polarization of immune responses. This review has focused mainly on understanding of the mechanisms of genetic susceptibility of cytokine genes in this disease and, further, this process is likely to achieve significant advances in the diagnosis and management of parthenium dermatitis. PMID- 29384112 TI - Dog allergy: can a prevalent or exclusive sensitization to Can f 5 be considered a lucky or negative event in real life? AB - Summary: Recent studies have shown the increasing relevance of allergic sensitization to Can f 5 (a prostatic kallikrein), which is an androgen-regulated protein expressed in the prostate and detectable only in male dogs. Can f 5 can be a prevalent or exclusive sensitizing agent in a considerable percentage of dog allergic patients. Its specific allergenic characteristics are able to induce possible negative as well as positive clinical effects in individuals sensitized to dogs. In the present article we pointed out the possible pros or cons of sensitization to this allergen in real life. Further studies should be carried out to correctly assess some peculiar characteristics of Can f 5, in order to support the most of positive aspects and remedy at best the negative effects. PMID- 29384113 TI - Hypersensitivity to antiretroviral drugs. AB - Summary: Background. Antiretroviral therapy (ART) may be responsible for hypersensitivity reactions varying in severity, clinical manifestations and frequency. Case report. We report the case of a 47-year-old woman with HIV infection who developed a delayed mucocutaneous reaction after treatment with ART. Hypersensitivty reaction (HR) to emtricitabine and tenofovir was considered probable based on positive patch tests (PT) and hypersensitivity reaction to nevirapine was confirmed by drug provocation test. Discussion. The diagnosis of HR to ART remains a diagnostic challenge, partly due to unknown mechanism and the absence of validated diagnostic tools. Patch testing may represent a useful method for confirming hypersensitivity. Further investigation in this area is required, so that successful management strategies can be offered, preventing loss of potent and viable antiretroviral agents. PMID- 29384114 TI - Freshly squeezed: anaphylaxis caused by drone larvae juice. AB - Summary: Drone larvae are mostly considered a by-product of beekeeping, but have recently been advo-cated as a high-protein source of food. There are as yet no data concerning their allergenic potential. We report on a 29-year old bee keeper who experienced an anaphylactic reaction following the consumption of a freshly prepared beverage from raw drone larvae. Larvae-specific sensitization was confirmed by prick-to-prick and basophil activation testing. Bee stings and classical bee products including honey and royal jelly were tolerated. This is the hitherto first report on IgE-mediated allergy to drone larvae. We suggest that a certain awareness towards the allergenicity of bee larvae is required. PMID- 29384115 TI - Food protein-induced enterocolitis syndrome in children: what's known? What's new? AB - Summary: Food protein-induced enterocolitis syndrome (FPIES) is an under recognized and frequently misdiagnosed non-IgE mediated food allergy syndrome. Affected infants show gastrointestinal symptoms few hours after ingestion of the incriminating food. Pathophysiology of FPIES has not yet been clearly defined and needs further characterization. The common allergy tests are not helpful for this disorder and tests for food specific IgE are usually negative. A diagnostic oral food challenge (OFC) is the method to confirm the diagnosis of FPIES. This review summarizes what is known about epidemiology, pathophysiology, clinical characteristics and diagnosis and what's new about therapeutic options of FPIES. PMID- 29384116 TI - Anaphylaxis in a food allergy outpatient department: one-year review. AB - Summary: Background. Anaphylaxis is an acute, potentially fatal, multi-organ allergic reac-tion. Our aim was to characterize the population with food induced anaphylaxis followed over a one-year period. Methods. Retrospective analysis of clinical files of patients with food anaphylaxis observed in our food allergy consultation during 2016. Results. Sixty-two patients were included. In the pediatric group, the implicated allergens were cow's milk, egg and fish and in the adults' group, the commonest allergens were nuts and wheat. Allergy to shrimp affected equally children and adults. The most frequent symptoms were urticaria (85.5%), angioedema (64.5%) and dyspnea (62.9%). Cofactors were present in 32.6% of patients, mainly exercise. Asthma and/or rhinitis were the most frequent comorbidities. Conclusion. In accordance to other studies, milk and egg were the most implicated allergens in children. Anaphylaxis in adults reflects the Mediterranean sensitization pattern. Exercise was the most relevant cofactor. PMID- 29384117 TI - Vitamin D receptor variants and uncontrolled asthma. AB - Summary: Background. Asthma is a common childhood respiratory disease, affecting around 20% of Irish children. In other populations, vitamin D receptor (VDR) polymorphisms have been associated with asthma risk. We aimed to investigate the association between 2 VDR polymorphisms and uncontrolled paediatric asthma. Methods. 44 asthmatic children and 57 healthy volunteers were studied. The VDR TaqI gene variant in exon 9 (T/C) (rs731236) and ApaI (rs7975232) in intron 8 (C/T) were determined, using TaqMan(r) Assays. The lung function, serum 25 hydroxyvitamin D (25OHD) levels and other biomarkers of allergy, immunity, airway and systemic inflammation were as-sessed. Results. The distribution of T and C alleles and genotype frequencies differed significantly between asthmatics and controls for both polymorphisms (p < 0.05). A significant association was found between both TaqI [OR = 2.37, 95% CI (1.27 - 4.45), p = 0.007] and ApaI polymorphisms, and asthma risk [OR = 2.93, 95% CI (1.62 - 5.3), p = 0.0004]. No association was observed between genotypes and 25OHD levels, lung function and other biomarkers, with the exception of Interleukin-10 (IL-10) and white blood cells count (WBC). IL-10 levels were lower in asthmatics with TC genotype for TaqI polymorphism (p < 0.01) and were higher in patients with TT genotype for ApaI (p < 0.01). WBC were higher in patients with TC and CC genotypes for TaqI (p < 0.05) and lower in TT genotype for ApaI (p < 0.05). Conclusion. TaqI and ApaI polymorphisms are associated with asthma in Irish children. Further studies are warranted to investigate the importance of decreased IL-10 levels in paediatric asthmatics with specific genotypes. PMID- 29384118 TI - Paediatric case series of drug reaction with eosinophilia and systemic symptoms (DRESS): 12-year experience at a single referral centre in Hong Kong and the first reported use of infliximab. AB - Summary: DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare but potentially life-threatening disorder characterized by fever, skin eruption, haematological abnormalities and multi-organ dysfunction after drug exposure. The pathophysiology is thought to be related to interactions between culprit drugs, viral reactivation and T-lymphocytes activation. We report 4 paediatric patients with DRESS who were treated at our centre over the past 12 years. Most cases improved after corticosteroids. Other immunosuppressive medications were attempted in refractory cases with varied outcomes. Patient 3 was the first reported case that involved the use of infliximab, a TNF-alpha inhibitor, for DRESS. Although clinical efficacy was not observed for this one patient, a previous study demonstrated that patients with DRESS, disease progression and HHV 6 reactivation had elevated pre-treatment TNF- alpha and IL-6 levels. Further research is needed to explore the role of these cytokines in DRESS. PMID- 29384119 TI - Localized salt-dependent aquagenic urticaria, a rare subtype of urticaria: a case report. AB - Summary: Aquagenic urticaria (AU) is a rare form of chronic inducible urticaria elicited by water at any temperature. We describe the case of a 25-year-old atopic woman who presented to our unit with a 4-year history of recurrent urticarial rashes, highly pruritic, confined to the neck and lower part of the face, occurring solely on contact with sea water. The lesions were reproduced by challenge tests with aqueous 3.5% NaCl and other hypertonic aqueous solutions but not with 20% glucose neither tap water. Our case supports the existence of a distinct salt-dependent subtype of aquagenic urticaria (SDAU), which seems to be triggered mostly by sea bathing, affects young women and has a characteristic localization on the inferior facial contours and neck. To the best of our knowledge, only eight cases of SDAU have been reported in the literature. PMID- 29384120 TI - [Seventy years of life and validity of a legendary scientific article of universal resonance]. PMID- 29384121 TI - [Malnutrition]. PMID- 29384122 TI - [Neonatal acute suppurative submandibular sialadenitis. Literature reports from 1950-2015]. AB - BACKGROUND: Submandibular salivary gland infections are uncommon. For this reason, neonatal acute suppurative submandibular sialadenitis non-coincident with parotitis is considered as a rare entity. The aim of this work was to verify if there have been changes in the clinical and microbiological aspects of this infection from its first descriptions. METHODS: A review of the international literature from different sources was performed from the earliest reports until April, 2016, in order to collect all the cases reported with this infection up to the present date. RESULTS: We found 39 neonate patients reported in 30 articles for this review. Most articles came from the United States of America and Europe, whereas in Latin America there was only one case declared in Cuba. Some of the clinical aspects of the presentation and evolution of this infection in the reported patients are described. CONCLUSIONS: Neonatal acute suppurative submandibular sialadenitis is an uncommon infection that presents similar clinical features through the years. As microbiological feature, this infection is usually caused by Staphylococcus aureus, although some methicillin-resistant Staphylococcus aureus have been implicated during the last 16 years. In general, it presents a satisfactory evolution with an early and appropriate antibiotic treatment. PMID- 29384123 TI - [Comparative study of the conventional scheme and prolonged treatment with steroids on primary steroid-sensitive nephrotic syndrome in children]. AB - BACKGROUND: In the steroid-sensitive nephrotic syndrome (SSNS) the prolonged treatment with steroids could decrease the frequency of relapses. We conducted a comparative study of prolonged steroid scheme and the usual treatment of primary SSNS to assess: the number of patients with relapses, mean time to treatment initiation, to remission and to first relapse, total number of relapses, total cumulative dose of steroids, and the steroid toxicity. METHODS: Patients were divided into two groups: group A (27 patients) received 16-beta methylprednisolone for 12 weeks, reducing the steroid until week 24. Group B (29 patients) received 16-beta-methylprednisolone for 12 weeks and placebo until week 24. RESULTS: Cumulative incidence rate of relapse (person/years) for group A was of 36/100 and 66/100 for group B (p=0.04). Average elapsed time to first relapse was of 114 days for group A and of 75 days to for group B (p=0.01). The difference in time for initial response to treatment and up to achieve remission between both groups was not significant. Total cumulative relapses were 9 for group A and 17 for group B (p=0.04). Total patients with relapses were 3 for group A and 7 for group B (p=0.17). Cumulative average dose per patient was 5,243mg/m2 for group A and 4,306mg/m2 for group B (p=0.3), and serum cortisol was 14MUg/dl for group A and 16MUg/dl for group B (p=0.4). There were no steroid toxicity differences between groups. CONCLUSIONS: The duration of the treatment had an impact on the number of relapses without increasing steroid toxicity. PMID- 29384124 TI - [Pulmonary complications associated with mechanical ventilation in neonates]. AB - BACKGROUND: To determine the incidence of0 associated with mechanical ventilation in patients admitted to a service in a second level hospital NICU. METHODS: Retrospective analytical study records of newborns admitted to NICU room and receiving mechanical ventilation in a secondary hospital health care. Demographic data, of mechanical ventilation, intubation and complications reported in the clinical record were collected and analyzed in SPSS 20. RESULTS: 53 patients selected a total of 40 complications found. The annual incidence of pulmonary complications associated with mechanical ventilation in the area of service neonatology NICU, at a second level hospital at Sonora was 49.05% (95% CI 0.35 to 0.62). The most frequent pulmonary complications were atelectasis 35%, pneumonia 27.5%, pneumothorax 15%, bronchopulmonary dysplasia 15%, pneumomediastinum 15% and pulmonary hemorrhage 2.5%. CONCLUSIONS: The presentation of pulmonary complications secondary to mechanical ventilation in neonatal patients is similar to that reported in developing countries. Atelectasis is the most common pulmonary complication in neonatal patients undergoing mechanical ventilation. PMID- 29384125 TI - [Functional echocardiography in the neonatal intensive care unit; experience in a tertiary level hospital]. AB - BACKGROUND: The Hospital Infantil de Mexico Federico Gomez is a tertiary level hospital with a neonatal intensive care unit (NICU), which is one of the most important units in the treatment of newborn's diseases in Mexico. In this unit, the decisions are taken based on some clinic parameters such as respiratory rate, heart rate, arterial pressure, urinary output and lactate levels. The functional echocardiography is a useful tool which improves the hemodynamic evaluation and decisions in neonatal care. Data on its use in neonatal units in Mexico is lacking. METHODS: A prospective study conducted in NICU patients during 3 months from August to October 2015 at the Hospital Infantil de Mexico Federico Gomez. Gestational age, birth weight, admission criteria, days of life at examination, indication for functional echocardiography and changes in treatment were evaluated and finally, we performed a new study 24hours later. Echocardiographic evaluation included: assessment of presence/hemodynamic significance of PDA; myocardial function: ejection fraction/shortening fraction, left ventricular output, right ventricular output, systemic blood flow; and signs of pulmonary hypertension. RESULTS: 30 echocardiographic studies were performed in 15 patients. The average age was 9.6 days, the variability in gestational ages were 37 to 42 weeks; the average weight was 2.583kg. The most frequent diagnosis was respiratory distress, and the principal indications for echocardiography were hemodynamic instability and sepsis (53.3%). In 11 cases (73.3%), the treatment was modified posteriorly to functional echocardiography, and in 10 cases we observed improvements in the 24hours after control. CONCLUSIONS: Functional echocardiography is a useful tool in NICU, which may assist with clinical decision-making. PMID- 29384126 TI - [Pseudo-Bartter syndrome as manifestation of cystic fibrosis with DF508 mutation]. AB - BACKGROUND: Pseudo Bartter syndrome (PBS) is defined as hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. Children with cystic fibrosis (CF) are at risk of developing electrolyte abnormalities and even PBS may occur. CASE REPORT: 5 months old female infant with a history of two events of dehydration with vomit, refusal to eat, chronic cough, polyuria, malnutrition, metabolic alkalosis, hypokalemia, hyponatremia, hypochloremia and acute renal failure. Chronic cough study was performed, discarding pulmonary tuberculosis, gastroesophageal reflux disease and impaired swallowing. PBS was diagnosed due to hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. CF was corroborated by electrolytes in sweat and through molecular analysis of the delta F508 mutation. This is one of the few reported cases linking PBS and this mutation. CONCLUSIONS: In patients with hyponatremic dehydration episodes with hypokalaemic hypochloraemic metabolic alkalosis, PBS should be considered as differential diagnosis. CF could be presented as PBS, mainly in patients younger than 2 years. PMID- 29384127 TI - [Use of Hemospray(r) in post-sclerotherapy bleeding]. AB - BACKGROUND: Hemospray(r) is a new device for endoscopic hemostasis used for non variceal gastrointestinal bleeding. It enables hemostasis and platelet activation by increasing the concentration of clotting factors and forming a mechanical barrier on the wall of a bleeding vessel creating a mechanical plug at the site of bleeding. Within the main indications for use are: injuries with difficult endoscopic access, massive gastrointestinal bleeding, multiple bleeding sites, modification of the anatomy by previous endoscopic therapy, presence of coagulopathy, difficulty in having direct visualization or when it is impossible to have contact with the bleeding lesion. However, its use in children has not been approved yet by the FDA. There is a case report of an 11-month-old patient successfully treated with Hemospray(r) for non-variceal gastrointestinal bleeding. CLINICAL CASE: We report the case of a 2-year-old female with acute liver failure and primary biliary cirrhosis with portal hypertension and bleeding after sclerotherapy. We analyzed the case to support new therapies for massive bleeding control in post-sclerotherapy esophageal ulcers. CONCLUSIONS: The application showed to be safe without side effects. Using Hemospray(r) is an effective alternative in controlling gastrointestinal bleeding. PMID- 29384129 TI - [Biographical sketch of Roberto Nunez Andrade MD (1905-1979): the first dermatologist in the Hospital Infantil de Mexico]. AB - Roberto Nunez Andrade (1905-1979) was a prominent Mexican dermatologist who focused a big part of his clinical practice to the treatment and knowledge of cutaneous disorders of children; because of his scientific contributions, he is considered a pioneer of pediatric dermatology in Mexico. PMID- 29384128 TI - [Guidelines for complementary feeding in healthy infants]. AB - A proper nutrition during the first two years of life is critical to reach the full potential of every human being; now, this period is recognized as a critical window for promoting optimal growth, development, and good health. Therefore, adequate feeding at this stage of life has an impact on health, nutritional status, growth and development of children; not only in the short term, but in the medium and long term. This paper provides recommendations on complementary feeding (CF) presented as questions or statements that are important for those who take care for children during this stage of life. For example: When to start complementary feedings: 4 or 6 months of age?; Exposure to potentially allergenic foods; Introduction of sweetened beverages; Use of artificial sweeteners and light products; Food introduction sequence; Food consistency changes according to neurological maturation; Number of days to test acceptance and tolerance to new foods; Amounts for each meal; Inadequate complementary feeding practices; Myths and realities of complementary feeding; Developmental milestones; Practice of "Baby Led Weaning" and practice of vegetarianism. PMID- 29384131 TI - Hydrogen-assisted post-growth substitution of tellurium into molybdenum disulfide monolayers with tunable compositions. AB - Herein we report the successful doping of tellurium (Te) into molybdenum disulfide (MoS2) monolayers to form MoS2x Te2(1-x) alloy with variable compositions via a hydrogen-assisted post-growth chemical vapor deposition process. It is confirmed that H2 plays an indispensable role in the Te substitution into as-grown MoS2 monolayers. Atomic-resolution transmission electron microscopy allows us to determine the lattice sites and the concentration of introduced Te atoms. At a relatively low concentration, tellurium is only substituted in the sulfur sublattice to form monolayer MoS2(1 x)Te2x alloy, while with increasing Te concentration (up to ~27.6% achieved in this study), local regions with enriched tellurium, large structural distortions, and obvious sulfur deficiency are observed. Statistical analysis of the Te distribution indicates the random substitution. Density functional theory calculations are used to investigate the stability of the alloy structures and their electronic properties. Comparison with experimental results indicate that the samples are unstrained and the Te atoms are predominantly substituted in the top S sublattice. Importantly, such ultimately thin Janus structure of MoS2(1 x)Te2x exhibits properties that are distinct from their constituents. We believe our results will inspire further exploration of the versatile properties of asymmetric 2D TMD alloys. PMID- 29384132 TI - Integrated nanomaterials for extreme thermal management: a perspective for aerospace applications. AB - Nanomaterials will play a disruptive role in next-generation thermal management for high power electronics in aerospace platforms. These high power and high frequency devices have been experiencing a paradigm shift toward designs that favor extreme integration and compaction. The reduction in form factor amplifies the intensity of the thermal loads and imposes extreme requirements on the thermal management architecture for reliable operation. In this perspective, we introduce the opportunities and challenges enabled by rationally integrating nanomaterials along the entire thermal resistance chain, beginning at the high heat flux source up to the system-level heat rejection. Using gallium nitride radio frequency devices as a case study, we employ a combination of viewpoints comprised of original research, academic literature, and industry adoption of emerging nanotechnologies being used to construct advanced thermal management architectures. We consider the benefits and challenges for nanomaterials along the entire thermal pathway from synthetic diamond and on-chip microfluidics at the heat source to vertically-aligned copper nanowires and nanoporous media along the heat rejection pathway. We then propose a vision for a materials-by-design approach to the rational engineering of complex nanostructures to achieve tunable property combinations on demand. These strategies offer a snapshot of the opportunities enabled by the rational design of nanomaterials to mitigate thermal constraints and approach the limits of performance in complex aerospace electronics. PMID- 29384130 TI - Lithography-based fabrication of nanopore arrays in freestanding SiN and graphene membranes. AB - We report a simple and scalable technique for the fabrication of nanopore arrays on freestanding SiN and graphene membranes based on electron-beam lithography and reactive ion etching. By controlling the dose of the single-shot electron-beam exposure, circular nanopores of any size down to 16 nm in diameter can be fabricated in both materials at high accuracy and precision. We demonstrate the sensing capabilities of these nanopores by translocating dsDNA through pores fabricated using this method, and find signal-to-noise characteristics on par with transmission-electron-microscope-drilled nanopores. This versatile lithography-based approach allows for the high-throughput manufacturing of nanopores and can in principle be used on any substrate, in particular membranes made out of transferable two-dimensional materials. PMID- 29384133 TI - Modification of graphene oxide films by radiofrequency N2 plasma. AB - The effect of treatment in nitrogen plasma on the properties of partially reduced graphene oxide (rGO) was studied. A comparison is made between two different sample locations in the reaction chamber. It is shown that in the case when rGO films were turned towards the inductor of the plasma system, the etching rate is much higher. Effective nitrogen functionalization of rGO was established in the second position, when the rGO films were turned in the opposite direction. In this case, the nitrogen content increases to 5 at% of the initial value. The change in the current-voltage characteristics is observed under illumination, which is independent of the wavelength. On and off daylight changes the resistance to 30% of the initial value. The magnitude of the photocurrent increases depending on the applied voltage. The effect is most noticeable for thin rGO films 10-15 nm in thickness. PMID- 29384135 TI - Fabrication of metal nanopatterns for organic field effect transistor electrodes by cracking and transfer printing. AB - In this paper, we demonstrate a novel method for fabricating metal nanopatterns using cracking to address the limitations of traditional techniques. Parallel crack arrays were created in a polydimethylsiloxane (PDMS) mold using a combination of surface modification and control of strain fields. The elastic PDMS containing the crack arrays was subsequently used as a stamp to prepare nanoscale metal patterns on a substrate by transfer printing. To illustrate the functionality of this technique, we employed the metal patterns as the source and drain contacts of an organic field effect transistor. Using this approach, we fabricated transistors with channel lengths ranging from 70-600 nm. The performance of these devices when the channel length was reduced was studied. The drive current density increases as expected, indicating the creation of operational transistors with recognizable properties. PMID- 29384134 TI - Nanoscale density variations induced by high energy heavy ions in amorphous silicon nitride and silicon dioxide. AB - The cylindrical nanoscale density variations resulting from the interaction of 185 MeV and 2.2 GeV Au ions with 1.0 MUm thick amorphous SiN x :H and SiO x :H layers are determined using small angle x-ray scattering measurements. The resulting density profiles resembles an under-dense core surrounded by an over dense shell with a smooth transition between the two regions, consistent with molecular-dynamics simulations. For amorphous SiN x :H, the density variations show a radius of 4.2 nm with a relative density change three times larger than the value determined for amorphous SiO x :H, with a radius of 5.5 nm. Complementary infrared spectroscopy measurements exhibit a damage cross-section comparable to the core dimensions. The morphology of the density variations results from freezing in the local viscous flow arising from the non-uniform temperature profile in the radial direction of the ion path. The concomitant drop in viscosity mediated by the thermal conductivity appears to be the main driving force rather than the presence of a density anomaly. PMID- 29384136 TI - Semiclassical transport properties of IrGa3: a promising thermoelectric material. AB - IrGa3 is an intermetallic compound which is expected to be a metal, but a study on the electronic properties of this material to confirm its metallic character is not available in the literature. In this work, we report for the first time a first-principles density functional theory and semiclassical Boltzmann theory study of the structural, electronic and transport properties of this material. The inclusion of the spin-orbit coupling term is crucial to calculate accurately the electronic properties of this compound. We have established that IrGa3 is an indirect semiconductor with a narrow gap of 0.07 eV. From semiclassical Boltzmann transport theory, it is inferred that this material, with the appropriate hole concentration, could have a thermoelectric figure of merit at room temperature comparable to other intermetallic compounds such as FeGa3, though the transport properties of IrGa3 are highly anisotropic. PMID- 29384137 TI - Capillary electrophoresis-driven synthesis of water-soluble CdTe quantum dots in nanoliter scale. AB - 'Green nanotechnology' is a term used for the design of nanomaterials and processes that reduce or eliminate the use and/or generation of hazardous substances. In this paper, a capillary electrophoresis (CE)-driven synthesis of CdTe quantum dots (QDs) and their subsequent conjugation with a metal-binding protein metallothionein (isofom MT1) is reported. Even though the toxic materials (cadmium and potassium borohydride) were used for synthesis, the proposed method can be labeled as 'environmentally friendly' because the whole process (synthesis of QDs and MT1 conjugation) was carried out under mild conditions: ultra-low volume (nanoliter scale), relatively low temperature (50 degrees C), atmospheric pressure, and completed in a short time (under 90 s). Prepared QDs were also characterized by classical fluorescence spectroscopy and transmission electron microscopy. This study opens up new possibilities for the utilization of classical CE in the synthesis of nanoparticles and on-line labeling of biomolecules in the nanoliter scale in short period of time. PMID- 29384138 TI - Conduction properties of thin films from a water soluble carbon nanotube/hemicellulose complex. AB - We have examined the conductive properties of carbon nanotube based thin films, which were prepared via dispersion in water by non-covalent functionalization of the nanotubes with xylan, a type of hemicellulose. Measurements of low temperature conductivity, Kelvin probe force microscopy, and high frequency (THz) conductivity elucidated the intra-tube and inter-tube charge transport processes in this material. The measurements show excellent conductive properties of the as prepared thin films, with bulk conductivity up to 2000 S cm-1. The transport results demonstrate that the hemicellulose does not seriously interfere with the inter-tube conductance. PMID- 29384139 TI - Highly selective and sensitive methanol gas sensor based on molecular imprinted silver-doped LaFeO3 core-shell and cage structures. AB - Silver-doped LaFeO3 molecularly imprinted polymers (SLMIPs) were synthesized by a sol-gel method combined with molecularly imprinted technology as precursors. The precursors were then used to prepare SLMIPs cage (SLM-cage) and SLMIPs core-shell (SLM-core-shell) structures by using a carbon sphere as the template and hydrothermal synthesis, respectively. The structures, morphologies, and surface areas of these materials were determined, as well as their gas-sensing properties and related mechanisms. The SLM-cage and SLM-core-shell samples exhibited good responses to methanol gas, with excellent selectivity. The response and optimum working temperature were 16.98 degrees C and 215 degrees C, 33.7 degrees C and 195 degrees C, respectively, with corresponding response and recovery times of 45 and 50 s (SLM-cage) and 42 and 57 s (SLM-core-shell) for 5 ppm methanol gas. Notably, the SLM-cage and SLM-core-shell samples exhibited lower responses (<=5 and <=7, respectively) to other gases, including ethanol, ammonia, benzene, acetone, and toluene. Thus, these materials show potential as practical methanol detectors. PMID- 29384140 TI - Immediate and late effects of chronic stress in the testes of prepubertal and adult rats. AB - The objective of this study was to investigate the effects of chronic stress on the testes of prepubertal and adult rats and to evaluate whether any alterations could be reversed when stress induction is ended. Seventy-six male rats were assigned to eight groups depending on the type of treatment (control or stressed), the age at which stress was initiated (prepubertal or adult), and the time of evaluation (immediate or late). Stress stimuli were applied for 6 weeks. Stressed prepubertal and adult rats evaluated immediately after the last stress stimulus were included in SP-I and SA-I groups, respectively. The late prepubertal (SP-L) and adult (SA-L) groups of stressed rats were evaluated 6 weeks after the last stress stimulus. Age-matched rats were used as controls (CP I, CA-I, CP-L, and CA-L groups). Application of stress stimuli to rats in the SP I group resulted in body weight and seminiferous tubule diameter reduction. The rats in the SA-I group also showed several functional (testosterone level and sperm parameter) and morphological (testicular weight and seminiferous tubule diameter) reductions. The rats in the SP-L group showed increased body weight and intertubular compartment volumetric and absolute densities and reduced tubular compartment volumetric density. The rats in the SA-L group presented only reduced sperm viability. Stress stimuli promoted changes in the rats in all the study groups. The testes of the adult rats were the most affected by chronic stress. However, the stressed adult rats recovered well from the testicular alterations. PMID- 29384141 TI - Would male hormonal contraceptives affect cardiovascular risk? AB - The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives. This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, lipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk. However, as all trials have been relatively short (< 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception. The potential adverse effects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contraceptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential. PMID- 29384142 TI - Endogenous testosterone and mortality risk. AB - In men, obesity and metabolic complications are associated with lower serum testosterone (T) and dihydrotestosterone (DHT) and an increased risk of, and mortality from, multiple chronic diseases in addition to cardiovascular disease (CVD). The causal interrelationships between these factors remain a matter of debate. In men with untreated congenital and lifelong forms of hypogonadotropic hypogonadism, there appears to be no increased risk. Men with Klinefelter's syndrome have an increased risk of various types of cancers, as well as CVD, which persist despite T therapy. In the absence of pathology of the hypothalamic pituitary-gonadal axis, the effect of modest reductions in serum T in aging men is unclear. The prevalence of low serum T concentrations is high in men with cancer, renal disease, and respiratory disease and is likely to be an indicator of severity of systemic disease, not hypogonadism. Some population-based studies have found low serum T to be associated with a higher risk of deaths attributed to cancer, renal disease, and respiratory disease, while others have not. Although a meta-analysis of longitudinal studies has shown an association between low serum T and all-cause mortality, marked heterogeneity between studies limited a firm conclusion. Therefore, while a decrease in T particularly occurring later in life may be associated with an increase in all-cause and specific types of mortality in men, the differential effects, if any, of T and other sex steroids as compared to health and lifestyle factors are unknown at the current time. PMID- 29384144 TI - Immunotherapy: Oncolytic viruses prime antitumour immunity. PMID- 29384145 TI - Approvals in 2017: gene therapies and site-agnostic indications. PMID- 29384143 TI - Expression and Comparison of Cbl-b in Lung Squamous Cell Carcinoma and Adenocarcinoma. AB - BACKGROUND Non-small cell lung carcinoma (NSCLC) mainly includes lung squamous cell carcinoma and adenocarcinoma. This study aimed to investigate the difference between the expression of Cbl-b in lung squamous cell carcinoma and adenocarcinoma. MATERIAL AND METHODS The clinical features and survival data of NSCLC patients and Cbl-b mRNA (FPKM) were obtained from the TCGA database. Then, lung squamous cell carcinoma and adenocarcinoma cell lines were transfected with lentivirus-mediated RNA interference vector to knockdown the expression of Cbl-b. Next, a Transwell assay was performed to study the effect of Cbl-b shRNA on migration and invasion of lung squamous cell carcinoma and adenocarcinoma cells. Finally, Western blot analysis was performed to measure the expressions of PI3K, p-PI3K, AKT, p-AKT, ERK1/2, p-ERK1/2, GSK3beta, p-GSK3beta, mTOR, and p-mTOR protein in lung adenocarcinoma and squamous cell carcinoma cells. RESULTS The correlation of Cbl-b expression and OS was different between NSCLC adenocarcinoma and squamous carcinoma. After transfection, the expression of Cbl-b was inhibited in A549, H1975, and SW900 cells. Cbl-b shRNA promoted the migration and invasion of lung adenocarcinoma A549 and H1975 cells, but it inhibited the invasion of lung squamous cell carcinoma SW900 cells. In addition, Cbl-b regulated the expression of PI3K and ERK1/2-GSK3beta pathway proteins in A549 and SW900 cells. CONCLUSIONS The OS of Cbl-b mRNA low expression in lung adenocarcinoma and squamous cell carcinoma was different. The difference in signal pathways may be one of the reasons for the difference in the correlation between Cbl-b expression and the survival rate of these 2 pathological types of lung cancer. PMID- 29384146 TI - Immunotherapy: Targeting MDSCs with LXR agonists. PMID- 29384147 TI - Immunotherapy: Desmoplasia is no barrier to PD-1 blockade in melanoma. PMID- 29384148 TI - Paediatrics: Addressing the health burden of childhood cancer survivors - improvements are needed. PMID- 29384149 TI - Haematological cancer: TGFbeta-insensitive T cells provide sustained remissions in HL. PMID- 29384150 TI - Multiple sclerosis in 2017: Progress in multiple sclerosis - from diagnosis to therapy. PMID- 29384151 TI - Scale up of a Plasmodium falciparum elimination program and surveillance system in Kayin State, Myanmar. AB - Background: Myanmar has one of the largest malaria burdens in the Greater Mekong Subregion (GMS). Throughout the GMS, Plasmodium falciparum parasites are increasingly resistant to artemisinin combination therapies. Given that there are no current alternative treatment therapies, one proposed solution to the threat of untreatable P. falciparum malaria is to eliminate the parasite from the region. Several small-scale elimination projects have been piloted in the GMS, including along the Myanmar-Thailand border. Following the success of the pilot elimination project along the Myanmar-Thailand border, there was a scale up to a broad area of Eastern Kayin State, Myanmar. Here we describe the establishment of the scale up elimination project in Easter Kayin State. Methods: The scale up relied on geographic reconnaissance and a geographic information system, community engagement, generalized access to community-based early diagnosis and treatment, near real-time epidemiological surveillance, cross sectional malaria prevalence surveys and targeted mass drug administration in villages with high prevalence of P. falciparum malaria. Molecular markers of drug resistance were also monitored in individuals with symptomatic and asymptomatic infections. Discussion: This protocol illustrates the establishment of an elimination project and operational research in a remote, rural area encompassing several armed groups, multiple political organizations and a near-absent health care infrastructure. The establishment of the project relied on a strong rapport with the target community, on-the-ground knowledge (through geographic surveys and community engagement), rapid decision making and an approach that was flexible enough to quickly adapt to a complex landscape. The elimination project is ongoing, now over three years in operation, and assessment of the impact of this operational research will follow. This project has relevance not only for other malaria elimination projects but also for operational research aimed at eliminating other diseases. PMID- 29384152 TI - Monitoring dynamic spiculation in red blood cells with scanning ion conductance microscopy. AB - Phospholipids are critical structural components of the membrane of human erythrocytes and their asymmetric transbilayer distribution is essential for normal cell functions. Phospholipid asymmetry is maintained by transporters that shuttle phospholipids between the inner leaflet and the outer leaflet of the membrane bilayer. When an exogenous, short acyl chain, phosphatidylcholine (PC) or phosphatidylserine (PS) is incorporated into erythrocytes, a discocyte-to echinocyte shape change is induced. PC treated cells remain echinocytic, while PS treated cells return to discocytes, and eventually stomatocytes, due to the action of an inwardly directed transporter. These morphological changes have been well studied by light microscopy and scanning electron microscopy in the past few decades. However, most of this research is based on the glutaraldehyde fixed cells, which limits the dynamic study in discrete time points instead of continuous single cell measurements. Scanning ion conductance microscopy (SICM) is a scanning probe technique which is ideal for live cell imaging due to high resolution, in situ and non-contact scanning. To better understand these phospholipid-induced morphological changes, SICM was used to scan the morphological change of human erythrocytes after the incorporation of exogenous dilauroylphosphatidylserine (DLPS) and the results revealed single cell dynamic morphological changes and the movement of spicules on the membrane surface. PMID- 29384153 TI - Advances, challenges and opportunities for point-of-need screening of mycotoxins in foods and feeds. AB - The assurance of food and feed safety, including the identification and effective monitoring of multiple biological and chemical hazards, is a major societal challenge, given the increasing pace at which food commodities are demanded, produced and traded across the globe. Within this context, mycotoxins are globally widespread secondary fungal metabolites, which can contaminate crops either in the field or during storage and have serious human and animal health impacts such as carcinogenic, teratogenic and hepatotoxic effects. Therefore, their presence in a wide range of foods and feeds is strictly regulated, particularly in the European Union. In order to perform effective and routine monitoring of mycotoxin levels in the field prior to further processing, during transport or during processing, rapid, simple, portable and sensitive means of screening of regulated mycotoxins are in high demand. This review focuses on (1) discussing the relevance of mycotoxins and the standard approaches for their sampling and monitoring; and (2) compiling and discussing recent advances in miniaturized analytical tools for mycotoxin detection. This provides insights into current research efforts and opportunities to develop a truly integrated and fit-for-purpose analytical tool, suitable for use at critical points of the food, feed and raw material processing and distribution chains. PMID- 29384154 TI - Structural transformations of carbon and boron nitride nanoscrolls at high impact collisions. AB - The behavior of nanostructures under high strain-rate conditions has been the object of theoretical and experimental investigations in recent years. For instance, it has been shown that carbon and boron nitride nanotubes can be unzipped into nanoribbons at high-velocity impacts. However, the response of many nanostructures to high strain-rate conditions is still unknown. In this work, we have investigated the mechanical behavior of carbon (CNS) and boron nitride nanoscrolls (BNS) colliding against solid targets at high velocities, using fully atomistic reactive (ReaxFF) molecular dynamics (MD) simulations. CNS (BNS) are graphene (boron nitride) membranes rolled up into papyrus-like structures. Their open-ended topology leads to unique properties not found in their close-ended analogs, such as nanotubes. Our results show that collision products are mainly determined by impact velocities and by two orientation angles, which define the position of the scroll (i) axis and (ii) open edge relative to the target. Our MD results showed that for appropriate velocities and orientations, large-scale deformations and nanoscroll fractures could occur. We also observed unscrolling (scrolls going back to quasi-planar membranes), scroll unzipping into nanoribbons, and significant reconstruction due to breaking and/or formation of new chemical bonds. For particular edge orientations and velocities, conversion from open to close-ended topology is also possible, due to the fusion of nanoscroll walls. PMID- 29384155 TI - Enzymatically-stable oxetane-based dipeptide hydrogels. AB - Low molecular weight gelators that are not easily degraded by enzymes have a range of potential applications. Here, we report new Fmoc-protected dipeptides in which the amide carbonyl group has been replaced by an oxetane ring. Remarkably one of these peptidomimetics, but not the corresponding dipeptide, is an effective gelator, forming hydrogels at a concentration of 3 mg mL-1. On assembly, there is a lack of beta-sheet structure, implying that there is no requirement for this motif in such a gel. Furthermore, the modified dipeptide is also stable to proteolysis compared to the parent dipeptide. PMID- 29384156 TI - Cl-Loss dynamics in the dissociative photoionization of CF3Cl with threshold photoelectron-photoion coincidence imaging. AB - The dissociative photoionization of CF3Cl was investigated in the photon energy range of 12.30-18.50 eV. The low-lying electronic states of CF3Cl+ cations were prepared by the method of threshold photoelectron-photoion coincidence (TPEPICO). The threshold photoelectron spectrum and the coincident time-of-flight mass spectra at the specific photon energies were recorded. Only a CF3+ fragment was observed at lower energy, while a CF2Cl+ fragment appeared for C2E and D2E states. As Cl-loss from the ground ionic state is statistical, the total kinetic energy release distribution (KERD) is represented as a Boltzmann profile, and a 0 K appearance energy of AP0 =12.79 +/- 0.02 eV is derived from the statistical modelling of the breakdown diagram from 12.60 to 12.85 eV without taking into account the kinetic shift. For the A2A1 and B2A2 states of CF3Cl+ cations, the total KERDs are bimodal, where a parallel faster dissociation appears together with the statistical distribution. At higher energies like the C2E and D2E ionic states, a bimodal distribution similar to that of the A2A1 and B2A2 states is also observed for the KERD. With the aid of the calculated Cl-loss potential energy curves, the dissociative mechanisms of internal energy-selected CF3Cl+ cations are proposed. PMID- 29384157 TI - Specific circularly polarized luminescence of Eu(iii), Sm(iii), and Er(iii) induced by N-acetylneuraminic acid. AB - Recently, we found that the Raman optical activity (ROA) technique can be used to monitor even a weak lanthanide luminescence including circular polarization. In the present study we compare circularly polarized luminescence (CPL) spectra of Eu(iii), Sm(iii), and Er(iii) induced by aqueous solution of sialic acid. For Eu providing the strongest signal a chelation model was proposed where the carboxyl adopts the axial conformation and carboxyl oxygen is attached to Eu(iii). PMID- 29384158 TI - A dynamical process of optically trapped singlet ground state 85Rb133Cs molecules produced via short-range photoassociation. AB - We investigate the dynamical process of optically trapped X1Sigma+ (v'' = 0) state 85Rb133Cs molecules distributed in J'' = 1 and J'' = 3 rotational states. The considered molecules, formed from short-range photoassociation of mixed cold atoms, are subsequently confined in a crossed optical dipole trap. Based on a phenomenological rate equation, we provide a detailed study of the dynamics of 85Rb133Cs molecules during the loading and holding processes. The inelastic collisions of 85Rb133Cs molecules in the X1Sigma+ (v'' = 0, J'' = 1 and J'' = 3) states with ultracold 85Rb (or 133Cs) atoms are measured to be 1.0 (2) * 10-10 cm3 s-1 (1.2 (3) * 10-10 cm3 s-1). Our work provides a simple and generic procedure for studying the dynamical process of trapped cold molecules in the singlet ground states. PMID- 29384159 TI - Understanding interface (odd-even) effects in charge tunneling using a polished EGaIn electrode. AB - Charge transport across large area molecular tunneling junctions is widely studied due to its potential in the development of quantum electronic devices. Large area junctions based on eutectic gallium indium (used in the form of a conical tip top electrode) have emerged as a reliable platform for delineating structure-property relationships. Discrepancies, however, arise from different tip-morphologies and fabrication techniques. It can be, therefore, challenging to make reliable conclusions based on molecular features. Of particular note is the discrepancy between the behaviors of hydrocarbons containing odd and even numbered carbons across different EGaIn electrodes. Moreover, inconsistencies in tip roughness and oxide thickness can lead to more than a 100* increase in current densities with narrow distribution in data. Besides effects on the precision vs. accuracy of data, a theoretically predicted length-dependent limit to observation of the odd-even effect has not been realized experimentally. We developed a method to chemically polish the EGaIn tip to allow formation of smooth conformal contact due to re-establishment of liquid character at the point of contact though tension-driven reconstruction of a thin oxide layer. To evaluate the polished tip, we measured charge transport behavior across n alkanethiolate SAMs and observed good correlation in the odd-even oscillation behavior to that observed from wetting studies. Since these molecules are homologues of each other, only differing in the orientation of the terminal CH2CH3 moiety, the odd-even effects are governed by orientation induced differences in the absences of SAM (gauche) defects. Comparison of obtained data with the literature shows significant difference between odd-numbered SAMs across Ag and Au. PMID- 29384160 TI - In situ tribochemical sulfurization of molybdenum oxide nanotubes. AB - MoS2 nanoparticles are typically obtained by high temperature sulfurization of organic and inorganic precursors under a S rich atmosphere and have excellent friction reduction properties. We present a novel approach for making the sulfurization unnecessary for MoO3 nanotubes during the synthesis process for friction and wear reduction applications while simultaneously achieving a superb tribological performance. To this end, we report the first in situ sulfurization of MoO3 nanotubes during sliding contact in the presence of sulfur-containing lubricant additives. The sulfurization leads to the tribo-chemical formation of a MoS2-rich low-friction tribofilm as verified using Raman spectroscopy and can be achieved both during sliding contact and under extreme pressure conditions. Under sliding contact conditions, MoO3 nanotubes in synergy with sulfurized olefin polysulfide and pre-formed zinc dialkyl dithiophosphate tribofilms achieve an excellent friction performance. Under these conditions, the tribochemical sulfurization of MoO3 nanotubes leads to a similar coefficient of friction to the one obtained using a model nanolubricant containing MoS2 nanotubes. Under extreme pressure conditions, the in situ sulfurization of MoO3 nanotubes using sulfurized olefin polysulfide results in a superb load carrying capacity capable of outperforming MoS2 nanotubes. The reason is that while MoO3 nanotubes are able to continuously sulfurize during sliding contact conditions, MoS2 nanotubes progressively degrade by oxidation thus losing lubricity. PMID- 29384161 TI - Fully transparent conformal organic thin-film transistor array and its application as LED front driving. AB - A fully transparent conformal organic thin-film field-effect transistor array is demonstrated based on a photolithography-compatible ultrathin metallic grid gate electrode and a solution-processed C8-BTBT film. The resulting organic field effect transistor array exhibits a high optical transparency of >80% over the visible spectrum, mobility up to 2 cm2 V-1 s-1, on/off ratio of 105-106, switching current of >0.1 mA, and excellent light stability. The transparent conformal transistor array is demonstrated to adhere well to flat and curved LEDs as front driving. These results present promising applications of the solution processed wide-bandgap organic semiconductor thin films in future large-scale transparent conformal active-matrix displays. PMID- 29384162 TI - In situ FTIR studies on the oxidation of isopropyl alcohol over SnO2 as a function of temperature up to 600 degrees C and a comparison to the analogous plasma-driven process. AB - This paper reports the application of in situ reflectance Fourier Transform InfraRed spectroscopy to the study of the thermal and plasma driven reaction of IsoPropyl Alcohol (IPA) at SnO2-coated Macor, the latter a ceramic material comprised of the oxides of Al, Mg and Si. The data so obtained were compared to those obtained using uncoated Macor. When uncoated Macor was employed, no reaction of the IPA was observed up to 600 degrees C in the thermal experiments, whereas a number of products were observed in the plasma-driven experiments. The results obtained using coated Macor were somewhat different, with no reaction taking place in the plasma-driven experiments, whilst significant reaction took place in the thermally-driven process. In the latter experiments, the chemistry was observed to show four distinct temperature regions, with electron injection into the conduction band of the SnO2 playing a significant role, culminating in the production of CO2. The data were interpreted in terms of a model in which physisorbed IPA was converted to two forms of isopropoxide: this was converted to acetone and acetaldehyde via adsorbed enolate. The data clearly support the catalytic activity of Macor in the plasma-driven conversion of IPA. PMID- 29384163 TI - Solvent switchable nanostructures and the function of a pi-amphiphile. AB - This manuscript reports solvent tunable functional nano-assemblies of an unsymmetrical bola-shaped pi-amphiphile (NDI-PY) which consists of a hydrophobic naphthalene-diimide (NDI) chromophore connected to a non-ionic hydrophilic wedge and a pyridine group at its two opposite arms. Importantly, it contains a hydrazide group located at the hydrophobic domain between the NDI-chromophore and the hydrophilic-wedge to drive the supramolecular assembly by directional H bonding. NDI-PY exhibits spontaneous assembly in water as well as in a highly non polar solvent like tetra-chloroethylene (TCE) by the synergistic effect of H bonding and pi-stacking interaction. Spectroscopy studies reveal almost identical self-assembly features in water and TCE with critical aggregation concentrations in the range of 0.3 mM, which matches the values obtained from the isothermal calorimetry (ITC) dilution experiment. Differential scanning calorimetry (DSC) experiments reveal a single endothermic peak at 31 degrees C (DeltaH = -12.3 kJ mol-1) and 40 degrees C (DeltaH = -5.35 kJ mol-1) for water and TCE, respectively, indicating marginally higher thermal stability in TCE, which is consistent with the FT-IR data, suggesting stronger H-bonding in TCE. Although the molecular assembly features appear to be similar, NDI-PY produces distinctly different mesoscopic structures in water and TCE. In water, it forms vesicles (Dh = 150-180 nm) with the pyridine groups displayed at the outer surface, while in TCE it generates a transparent gel (CGC = 8.0 mM) with a nanotubular (width ~50 nm, wall thickness ~10 nm) morphology. Powder X-ray diffraction studies show clearly different packing structures; in water a single sharp peak at the low angle (d = 19.3 A, a little shorter than the extended length of the molecule) suggests the formation of a monolayer membrane, while in TCE several sharp peaks appear with the d values maintaining a ratio of 1 : 1/?3 : 1/2 : 1/?7 : 1/3 : 1/?12, indicating the formation of a 2D hexagonal lattice. Photoconductivity measurements reveal moderate electronic conduction in both cases. However, it shows a remarkable enhancement of the life time of the charge-carriers for the nanotubular structure compared to the vesicular morphology. On the other hand, the vesicles in water display antimicrobial activity against Gram-positive S. aureus with a highly promising MICLB value of 29.4 MUg mL-1. In contrast, it does not lyse human red blood cells even at as high a concentration as 2.5 mg mL-1 (HC50 > 2.5 mg mL-1), implying high selectivity of the NDI-PY vesicles towards bacterial cells over mammalian cells. Display of the pyridine groups at the outer surface of the membrane enables molecular recognition by complementary H-bonding with a carboxylic acid group and thereby facilitates uptake of the attached pyrene chromophores in the NDI-membrane by charge-transfer interaction between the NDI acceptor and the pyrene donor. In fact a Job's plot experiment reveals maximum uptake at a 1 : 1 ratio of the NDI-PY and the pyrene guest, indicating all the pyridine groups are accessible at the vesicular surface. PMID- 29384164 TI - Achieving rapid Li-ion insertion kinetics in TiO2 mesoporous nanotube arrays for bifunctional high-rate energy storage smart windows. AB - Smart electrochromic windows integrated with electrochemical energy storage capacity are receiving increasing interest for green buildings. However, the fabrication of bifunctional devices that demonstrate high-rate capability with stable and desirable optical modulation still remains a great challenge. Herein, a facile sacrificial template-accelerated hydrolysis approach is presented to prepare a designed lithium-ion insertion-type material layer on a fluorine-doped tin oxide substrate, with TiO2 mesoporous nanotube array (MNTA) film as an example, with rapid Li-ion insertion kinetics and without sacrificing window transparency, to meet requirements. A bifunctional device is assembled to exhibit the optical-electrochemical superiority of MNTA nanostructures. The as-assembled bifunctional smart window exhibits strong electrochromic contrast and high-rate capability in the fast galvanostatic charge/discharge process. For instance, at 1 A g-1, it completes the charge or discharge process within only 232 s and delivers a high, reversible and stable specific capacity of 60 mA h g-1, accompanying obvious transmittance modulation in the visible spectrum, with a typical value of ca. 30.4% at 700 nm, and strong color changes between deep blue and transparency. PMID- 29384165 TI - Photochemical transformation of dimethyl phthalate (DMP) with N(iii)(H2ONO+/HONO/NO2-) in the atmospheric aqueous environment. AB - The photochemical transformation of dimethyl phthalate (DMP) with N(iii)(NO2 /HONO/H2ONO+) was investigated using 365 nm steady-state irradiation and 355 nm laser flash photolysis (LFP) techniques. The results showed that N(iii) concentration, DMP initial concentration and pH values all strongly affected the oxidation efficiency of DMP. The primary step of the reaction was the attack of OH radicals on the aromatic ring to form a DMP-OH adduct, and the bimolecular rate constant was determined to be (5.5 +/- 0.4) * 109 M-1 s-1. The DMP-OH adduct not only underwent monomolecular self-decay with a rate constant of (1.6 +/- 0.3) * 104 s-1 but also interacted with HONO, H2ONO+ and O2 with rate constants of (6.4 +/- 0.4) * 106 M-1 s-1, (8.8 +/- 0.5) * 106 M-1 s-1 and (1.6 +/- 0.1) * 108 M-1 s-1, respectively. Major transformation products including methyl salicylate, monomethyl phthalate, dimethyl 4-hydroxyphthalate and dimethyl 4-nitrophthalate were identified by GC-MS and characteristics of these secondary contaminants required extra attention. PMID- 29384166 TI - Domain alignment within ferroelectric/dielectric PbTiO3/SrTiO3 superlattice nanostructures. AB - The ferroelectric domain pattern within lithographically defined PbTiO3/SrTiO3 ferroelectric/dielectric heteroepitaxial superlattice nanostructures is strongly influenced by the edges of the structures. Synchrotron X-ray nanobeam diffraction reveals that the spontaneously formed 180 degrees ferroelectric stripe domains exhibited by such superlattices adopt a configuration in rectangular nanostructures in which domain walls are aligned with long patterned edges. The angular distribution of X-ray diffuse scattering intensity from nanodomains indicates that domains are aligned within an angular range of approximately 20 degrees with respect to the edges. Computational studies based on a time dependent Landau-Ginzburg-Devonshire model show that the preferred direction of the alignment results from lowering of the bulk and electrostrictive contributions to the free energy of the system due to the release of the lateral mechanical constraint. This unexpected alignment appears to be intrinsic and not a result of distortions or defects caused by the patterning process. Our work demonstrates how nanostructuring and patterning of heteroepitaxial superlattices allow for pathways to create and control ferroelectric structures that may appear counterintuitive. PMID- 29384167 TI - Floating-gate controlled programmable non-volatile black phosphorus PNP junction memory. AB - To meet the increasing requirements of minimizing circuits, the development of novel device architectures that use ultra-thin two-dimensional materials is encouraged. Here, we demonstrate a non-volatile black phosphorus (BP) PNP junction in a BP/h-BN/graphene heterostructure in which BP acts as a transport channel layer, hexagonal boron nitride (h-BN) serves as a tunnel barrier layer and graphene is the charge-trapping layer. The device architecture is designed such that only the middle part of the BP is aligned over the graphene flake, enabling the flexible tuning of the charge carriers in the BP over the graphene charge-trapping layer. Thus, the device exhibits the ability to work in two different operating modes (PNP and PP+P). Each operating mode can be retained well and demonstrates non-volatile behavior, and each can be programmed by using the control-gate. PMID- 29384168 TI - Analysis of redox states of protic and aprotic solutions irradiated by low linear energy transfer carbon-ion beams using a 2,2-diphenyl-1-picrylhydrazyl radical. AB - The quantitative evaluation of changes in the redox state induced by low linear energy transfer (LET) radiations such as the plateau region of heavy-ion beams via formation of reactive oxygen species is of considerable importance to eliminate the adverse effects of radiation therapy on normal tissues adjacent to a tumour. In this study, a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) was used as a redox probe to estimate the redox states of protic and aprotic solutions irradiated by low LET carbon-ion (C-ion) beams. The dose dependence of the decrease in the absorption band due to DPPH (which was solubilised by beta cyclodextrin (beta-CD) in water) after irradiation with low LET C-ion beams (13 keV MUm-1) was similar to that after X-irradiation. Similar results were obtained when H2O was replaced with methanol or acetonitrile although the slope values of the plots of the absorbance changes vs. radiation doses were twice larger as compared to the case in beta-CD-containing H2O. Moreover, DPPH was more susceptible to the C-ion beam than to X-rays in isopropyl myristate (IPM), which is one of the saturated fatty acid esters. PMID- 29384169 TI - An intramolecular oxa-Michael reaction on alpha,beta-unsaturated alpha-amino delta-hydroxycarboxylic acid esters. Synthesis of functionalized 1,3-dioxanes. AB - A highly diastereoselective intramolecular oxa-Michael reaction on alpha,beta unsaturated alpha-amino-delta-hydroxycarboxylic acid esters is presented; 1,3 dioxanes functionalized in positions 2,4 and 6 were obtained in good yields and with excellent selectivities; an experimental and computational study was carried out to understand the reaction course in terms of yields and selectivities. This reaction proceeds under mild reaction conditions using highly electrophilic aldehydes and ketones. PMID- 29384170 TI - An implanted paramagnetic metallofullerene probe within a metal-organic framework. AB - Paramagnetic endohedral metallofullerene can be used as a molecular probe because of its sensitive electron spin characters, one of which is to sense its surroundings. Metal-organic framework (MOF) materials have significant applications in selective adsorption owing to their porous structures. Herein, we report a Sc3C2@C80 spin probe implanted in MOF-177 to detect the unusual host guest interaction between the guest molecules of metallofullerene and the host pores of the MOF. Paramagnetic Sc3C2@C80 molecules were incorporated into the pores of MOF-177 via absorption method, and there was strong pi-pi interaction between oleophilic metallofullerene and aromatic framework. The electron paramagnetic resonance (EPR) signals of Sc3C2@C80 in MOF-177 exhibit anisotropic properties caused by the restricted motion of implanted Sc3C2@C80. This unusual host-guest interaction between Sc3C2@C80 and MOF-177 is gradually strengthened with decreasing temperature as revealed by the EPR signals. In addition, the gas desorption from the MOF-177 pores under subatmospheric pressure can weaken the host-guest interaction and lead to slightly enhanced Sc3C2@C80 EPR signals. Furthermore, the changes in the host-guest interaction between Sc3C2@C80 and MOF 177 at different temperatures and pressures exhibit reversibility, as shown by cycling EPR measurements. These results will inspire material design and applications of fullerene and MOF complexes. PMID- 29384171 TI - Cyclic trimers of phosphinic acids in polar aprotic solvent: symmetry, chirality and H/D isotope effects on NMR chemical shifts. AB - The hydrogen-bonded self-associates of dimethylphosphinic (1), diphenylphosphoric (2), phenylphosphinic (3), and bis(2,4,4-trimethylpentyl)phosphinic (4) acids have been studied by using liquid-state NMR down to 100 K in a low-freezing polar solvent, CDF3/CDClF2. The H/D isotope effects on 1H NMR chemical shifts caused by partial deuteration of hydroxyl groups unambiguously reveal the stoichiometry of the self-associates and the cooperativity of their hydrogen bonds. In all cases, cyclic trimers are the dominant form, while cyclic dimers are present as a minor form for 1 and 2. Due to the asymmetry of substituents, cyclic trimers of 3 exist in two isomeric forms, depending on the orientation of the phenyl groups with respect to the plane of the hydrogen bonds. The racemic mixture of 4 leads to the coexistence of up to 64 isomers of cyclic trimers, many of which are chemically equivalent or effectively isochronous. The mole fractions of such isomers deviate from the statistically expected values. This feature could provide information about the relative stabilization energies of hydrogen-bonded chiral self associates. The complexation of 4 with SbCl5 (complex 5) suppresses the self association and 5 exists exclusively in the monomeric form with chemically non equivalent 31P nuclei in RS, SR and RR/SS forms. PMID- 29384172 TI - ITO nanoparticles enhanced upconversion luminescence in Er3+/Yb3+-codoped silica glasses. AB - Upconversion (UC) materials have shown many applications in the solar cell industry, biomedical imaging, and LED lighting. For the first time, we report enhanced UC in Er3+/Yb3+-codoped silica glasses induced by the energy transfer between rare earth ions and indium tin oxide nanoparticles (ITO NPs), introduced by an in situ growth approach. The enhancements of the intensities of the emissions of red and green light were all more than 10 fold and in some cases up to 42 fold. This work in our opinion has contributed a novel method and materials for UC enhancement in Er3+/Yb3+-codoped silica glasses. PMID- 29384174 TI - A self-assembled CdSe QD-organogel hybrid: photophysical and thermoresponsive properties. AB - A luminescent hybrid gel was prepared by incorporating organic ligand capped CdSe quantum dots (QDs) into a steroid-dimer derived organogel. Photophysical measurements and electron microscopy studies allowed us to understand the nature of the hybrid. Detailed analysis of the excited state dynamics of the hybrid was carried out using a kinetic decay model. The luminescence of the QDs in the hybrid was unaltered by taking it through a gel-sol-gel cycle induced by thermal stimuli. We believe that the results obtained herein provide a route to develop a thermoresponsive device for practical applications, because of the spatial assembly between soft organic scaffolds and colloidal QDs. PMID- 29384173 TI - Comparative studies on the hypolipidemic, antioxidant and hepatoprotective activities of catechin-enriched green and oolong tea in a double-blind clinical trial. AB - This study aimed to compare the beneficial effect of catechin-enriched green tea and oolong tea on mildly hypercholesterolemic subjects. Sixty mildly hypercholesterolemic subjects (180-220 mg dL-1) were enrolled and divided into three groups as catechin-enriched green tea (CEGT), catechin-enriched oolong tea (CEOT) or placebo. The subjects were instructed to drink 2 * 300 mL of CEGT (780.6 mg of catechin), CEOT (640.4 mg of catechin) or placebo beverage for 12 weeks. Drinking CEGT and CEOT significantly decreased (p < 0.05) the body weight, fat, and BMI, lipid peroxidation as well as lipid profile (TC, LDL-c, HDL-c, and TG). Also, intervention with CEGT and CEOT significantly improved (p < 0.05) the oxidative indices (TEAC and GSH) and antioxidant enzymes (SOD, CAT, GPx, and GR). Moreover, ultrasound examination endorsed the hepatoprotective activity of CEGT and CEOT by reverting mild fatty liver to the normal hepatic condition because of antioxidant and hypolipidemic activities. To summarize, both CEGT and CEOT showed similar antioxidant and hepatoprotective activities. However, CEOT displayed superior lipid-lowering activity compared to CEGT or placebo, and hence it could be used to amend the wellness condition of mildly hypercholesterolemic subjects. PMID- 29384175 TI - Tailoring the gas separation efficiency of metal organic framework ZIF-8 through metal substitution: a computational study. AB - The influence of a zeolitic imidazolate framework (ZIF)'s metal identity on its gas separation performance is studied extensively through molecular simulations for a variety of gases. ZIF-8 is used as the original framework for alterations of different metal substitutes of the Zn2+ metal. ZIF-8 consists of cages connected by narrow apertures that exhibit flexibility through "swelling", allowing for relatively large penetrants to diffuse. Replacing the central metal atom in the basic tetrahedral unit of ZIF-8 with Cd, Co or Be results in three different structures with increasing bonding stiffness with their neighboring atoms. The metal modification approach offers a way to control the flexibility and the size of the aperture, which constitutes the main energy barrier of the penetrant's hop-like diffusion between the framework's cages. Newly developed force fields are reported and utilized here; the new frameworks are compared to the original one, in terms of the diffusivity of various gas molecules as a function of their size (from He to n-butane). The correlation of the gas diffusivity with the aperture flexibility-molecular size relation is investigated. The results reveal that the aperture flexibility-molecular size relation governs the diffusivity, which shapes a common trend along all modifications. Furthermore, a new generalized method is employed for the screening of the various modifications for specific gas separations. This method is useful to detect optimum separation performance for the various modifications: CdIF-1 (Cd) for n-butane/iso-butane mixture; ZIF-67 (Co) for propylene/n-propane and ethylene/ethane mixtures; BeIF-1 (Be) for CO2/C2H6, CO2/CH4 and CO2/N2 mixtures. PMID- 29384183 TI - Regulating morphologies and near-infrared photothermal conversion of perylene bisimide via sequence-dependent peptide self-assembly. AB - The assembly behavior of perylene bisimide (PBI) can be precisely organised by the conjugation of sequence-dependent di-peptides in aqueous media. The assembled nanostructures and consequent properties of PBI aggregates can be tuned by the use of different peptide sequences with improved yield of radical anions and enhanced photothermal conversion efficiency. PMID- 29384186 TI - Intentional herniation technique with the Neuroform EZ stent system for preservation of aneurysmal neck branch: a case report. AB - PURPOSE: Endovascular treatment of bifurcation aneurysms is difficult and complicated because arterial branches may arise from the aneurysmal neck. We treat these cases with complex techniques such as Y or T stenting. In this report, we deployed one Neuroform EZ stent using the intentional herniation technique for the preservation of arterial branches. CASE PRESENTATION: A 78-year old female presented with two unruptured aneurysms. One was an 8 mm aneurysm located at the bifurcation of the internal carotid artery and the posterior communicating artery (PcomA). The other was an 11 mm aneurysm located at the cavernous segment of the internal carotid artery. RESULTS: A 4.5 * 20 mm Neuroform EZ stent was placed across the aneurysm neck. The delivery wire and microcatheter were pushed during deployment, similar to braided stents. High resolution cone beam CT after stenting revealed the stent strut to be vertically aligned near the aneurysmal sac, and the PcomA orifice was preserved. We performed coil embolization easily and achieved acceptable obliteration. CONCLUSIONS: Our intentional herniation technique may be useful in some cases. Open cell stents have some advantages depending on the method of deployment. PMID- 29384187 TI - Investigating the levels of soluble extracellular domain of HER2 protein in the sera of meningioma patients. AB - AIM: Meningiomas are the most frequently diagnosed primary central nervous system (CNS) neoplasms. Considering slightly higher incidence of meningiomas in breast cancer patients and breast cancer in meningioma patients, it can be assumed that both tumors share similar risk factors. HER2 gene amplification and/or over expression have been found in several human cancers, but it has been most widely studied in breast carcinomas. Bearing in mind the association of breast cancer and meningioma, the present study aimed to investigate the levels of the soluble extracellular domain of HER2 protein in meningioma cases and control group. Besides, in the present research, its associations with pathological features and prognostic indicators of meningioma were examined. MATERIAL AND METHODS: In the present study, 68 meningioma patients along with 20 healthy age-sex matched individuals, as controls, were selected. Levels of HER2 in the sera were measured by a quantitative enzyme-linked immunosorbent assay (ELISA). RESULTS: The observations showed that HER2 serum levels in meningioma patients were significantly lower than normal controls. However, outlier quantities were mostly observed in the cases. Furthermore, in meningiomas with higher histological grade (grade II, III), statistically significant elevated serum levels of HER2 were observed compared to patients with low-grade meningiomas (grade I). CONCLUSION: The results showed that serum HER2 levels were a poor biomarker for determination of pathological and prognostic characteristics of meningiomas and coupling serum HER2 levels with immuno-histo-chemistry (IHC) examination of HER2 in meningioma tissue samples would be helpful in future studies. PMID- 29384188 TI - In Vitro Effects of Mesenchymal Stem Cells and Various Agents on Apoptosis of Glioblastoma Cells. PMID- 29384189 TI - Percutaneous Endoscopic Interlaminar Discectomy for L5-S1 Adolescent Lumbar Disc Herniation. AB - AIM: L5/S1 Adolescent lumbar disc herniation (ALDH) is usually ignored for its low incidence. Recently, percutaneous endoscopic procedures have been widely used. To investigate the surgical techniques and clinical outcomes of percutaneous endoscopic interlaminar discectomy (PEID) in the treatment of adolescent L5-S1 disc herniation (ALDH). MATERIAL AND METHODS: A retrospective study was performed between May 2012 and September 2014, which included 23 adolescent patients who underwent PEID for L5/S1 lumbar disc herniation. Ten females and 13 males were included, with a mean age of 15.4 years and a mean BMI of 25.1 kg/m2. The pre- and postoperative visual analogue scale (VAS), Japanese Orthopaedic Association (JOA), and modified MacNab scores, as well as perioperative data, were collected. RESULTS: The mean follow-up period was 19.7 months. The average operation time and hospital stay were 80.9 +/- 7.3 minutes and 5.8 +/- 1.2 days, respectively. During the follow-up period, the VAS for back and leg pain decreased significantly, and JOA scores greatly increased (p < 0.05). In terms of modified MacNab criteria, 86.9% of patients showed excellent or good results. After surgery, two patients complained of leg numbness, and another patient underwent a subsequent open discectomy due to recurrent disc herniation. CONCLUSION: Considering specific anatomical peculiarities and expectation for rapid recovery, PEID is a safe and effective minimally invasive technique for ALDH at the L5-S1 level. PMID- 29384190 TI - Miescher nevus as devil's mark, but also as beauty mark. PMID- 29384191 TI - Histoid leprosy: clinical and histopathological analysis of patients in follow-up in University Clinical Hospital of endemic country. AB - BACKGROUND: Histoid leprosy (HL) is a rare form of lepromatous leprosy, characterized by hyperchromic indurated nodules above normal skin. Its main histopathological aspect is spindle cells. Because it may simulate other aspects, such as dermatofibroma and neurofibroma, histoid leprosy poses itself as a diagnostic challenge. METHODS: This is a retrospective study with all patients having been selected from the leprosy clinic of the Hospital das Clinicas da Universidade de Sao Paulo from 2006 to 2016. RESULTS: There were 12 patients in this study, eight in the histoid group and four in the lepromatous leprosy group. The prevalence of HL was 1.12% in all leprosy subjects. All individuals from HL group were "de novo" cases, and the histopathological analysis of skin lesions presented spindle cells generating a storiform pattern. Immunohistochemistry for CD68, vimentin, and anti-BCG were positive in all 12 cases. Factor XIIIa was visualized only in the papillary dermis, and S100 protein was negative in all biopsies. Smooth-muscle actin was present in 62.5% of the HL samples. CONCLUSION: The prevalence of HL was similar to previous reports. However, all histoid patients were "de novo" cases, differing from published studies. Fusocellular macrophage transformation could be explained by the differences in cytoskeleton proteins expressed in histoid lesions in comparison to other leprosy variants, with emphasis on vimentin and smooth muscle actin. PMID- 29384192 TI - Public Health Policy Strategies to Address the Opioid Epidemic. AB - Public health policy responses to the opioid epidemic require addressing both opioid supply and opioid demand. The growth in prescriptions of opioid analgesics, for example, is associated with escalating opioid overdose fatalities.1 Enhanced access to opioid agonist treatment, conversely, is required to curb demands driven by opioid use disorders. Oregon's multidimensional approaches toward opioid misuse and abuse achieved 20% reductions in opioid prescribing and a 30% reduction in the opioid overdose fatality rate. PMID- 29384193 TI - BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy. PMID- 29384194 TI - Application of hydrocarbon and perfluorocarbon oxygen vectors to enhance heterologous production of hyaluronic acid in engineered Bacillus subtilis. AB - In microbial cultivations for hyaluronic acid (HA) production, oxygen can be a limiting substrate due to its poor solubility in aqueous medium and the substantial increase in culture viscosity at relatively low HA titers. Shear stress due to the high agitation and aeration rates required to overcome oxygen limitation may reduce the quality (i.e., molecular weight) of HA, and production costs associated with power consumption and supplemental oxygen may be excessive. Here, we report the application of oxygen vectors to the heterologous production of HA in engineered Bacillus subtilis, leading to significantly improved culture performance. We first derived an improved HA-producing strain of B. subtilis through engineering of the promoter driving coexpression of seHas and tuaD, leading to high-level HA production. Out of seven potential oxygen vectors evaluated in a preliminary screening, significant improvements to the HA titer and/or cell density were observed in cultures containing n-heptane, n-hexadecane, perfluoromethyldecalin, and perfluoro-1,3-dimethylcyclohexane. Adjustments to the vector concentration, timing of vector addition, and the agitation rate resulted in further enhancements, with the HA titer reaching up to 4.5 g/L after only 10 hr cultivation. Moreover, our results indicate that certain vectors may alter the functional expression of Class I hyaluronan synthase (HAS) in B. subtilis, and that higher shear rates may drive more carbon flux through the HA biosynthetic pathway without negatively affecting the MW. Our study demonstrates the efficacy of oxygen vectors to enhance heterologous HA production in B. subtilis, and provides valuable insight for future bioprocess development in microbial HA production. PMID- 29384195 TI - Multi-facet implications of PEGylated lysozyme stabilized-silver nanoclusters loaded recombinant PTEN cargo in cancer theranostics. AB - Amalgamation of delivery and tracking of therapeutically relevant moieties on a single platform is made possible by the application of metal nanoclusters, an innovative class of luminescent nanomaterials. Metal nanoclusters, possessing molecule-like attributes, display extraordinary size and shape tunable properties befitting theranostic applications. Herein, we report successful assembly of therapeutically significant phosphatase protein PTEN and fluorescent lysozyme stabilized silver nanoclusters to accomplish delivery and tracking of the protein. Down-regulation of PTEN perturbs the cellular networking leading to copious pathological conditions. The integration of purified recombinant PTEN with silver nanoclusters was evaluated by fluorescence spectroscopy study. A key feature of this study is the use of polyethylene glycol coating that allows fabrication of the assembly into spherical nanocomposites as characterized by transmission electron microscope along with retention of both optical functionality of the cluster and biological activity of the protein. Prior to cellular application, the functional integrity of PTEN in the composite was determined in vitro, by enzymatic assay employing para-nitrophenylphosphate as substrate. Cellular internalization of the cargo was studied by confocal microscopy and flow cytometry analysis. The efficacy of the payload on modulation of cellular signaling was assessed on cell lines that expressed PTEN differentially. PTEN null U-87 MG and PTEN expressing MCF7 cell lines displayed successful alteration of AKT and FAK signaling proteins culminating in cell cycle arrest and reduced wound healing capacity. A dose dependent reduction in cell proliferation of MCF7 cells was achieved. For U-87 MG, treatment with the payload resulted in chemosensitization toward anti-cancer drug erlotinib. Thus, PEG coated GST-PTEN loaded silver nanoclusters serves as a comprehensive system encompassing cellular imaging and protein delivery with potential biomedical implications. PMID- 29384196 TI - Anomalies in target-controlled infusion: an analysis after 20 years of clinical use. AB - Although target-controlled infusion has been in use for more than two decades, its benefits are being obscured by anomalies in clinical practice caused by a number of important problems. These include: a variety of pharmacokinetic models available in open target-controlled infusion systems, which often confuse the user; the extrapolation of anthropomorphic data which provokes anomalous adjustments of dosing by such systems; and the uncertainty of regulatory requirements for the application of target-controlled infusion which causes uncontrolled exploitation of drugs and pharmacokinetic models in target controlled infusion devices. Comparison of performance of pharmacokinetic models is complex and mostly inconclusive. However, a specific behaviour of a model in a target-controlled infusion system that is neither intended nor supported by scientific data can be considered an artefact or anomaly. Several of these anomalies can be identified in the current commercially available target controlled infusion systems and are discussed in this review. PMID- 29384198 TI - Retrospective review of 18 British South Asian women with frontal fibrosing alopecia. PMID- 29384197 TI - If or when? Uncertainty's role in anxious anticipation. AB - Uncertainty is often associated with subjective distress and a potentiated anxiety response. Occurrence uncertainty, or the inability to predict if a threat will occur, has rarely been compared experimentally with temporal uncertainty, or the inability to predict when a threat will occur. The current study aimed to (a) directly compare the anxiogenic effects of anticipating these two types of uncertain threat, as indexed by the eyeblink startle response, and (b) assess the relationship between startle response to occurrence and temporal uncertainty and individual differences in self-reported intolerance of uncertainty and anxiety. The findings indicated that anticipation during occurrence uncertainty elicited a larger startle response than anticipating a certain threat, but anticipation during temporal uncertainty was superior at potentiating startle blink overall. Additional analyses of the effects of order and habituation further highlighted temporal uncertainty's superiority in eliciting greater startle responding. This suggests that, while uncertainty is physiologically anxiety provoking, some level of certainty that the threat will occur enhances the robustness of the physiological anxiety response. However, self-reported anxiety was equivalent for temporal and occurrence uncertainty, suggesting that, while defensive responding may be more affected by temporal uncertainty, people perceive both types of uncertainty as anxiogenic. Individual differences in the intolerance of uncertainty and other anxiety measures were not related to anticipatory startle responsivity during any of the conditions. PMID- 29384199 TI - Development of an electrophoretic method based on nanostructured materials for HbA1c determination. AB - Glycosylated hemoglobin (HbA1c) detection is performed routinely in hospitals as it is the most widespread confirmatory diagnosis of diabetes mellitus. Here we present a novel CE method for measuring HbA1c by introducing silica nanoparticles (NPs) modified with a boronic acid derivative (sugar loadings of 51 +/- 2 MUg/mg) as pseudo-stationary phase. Before the sample injection, SiO2 NP?B(OH)2 were introduced via pressure. Electrophoretic separation was explored through variation of the buffer pH and separation voltage, being the best separation, resolution and shorter separation time achieved with a 25 mM phosphate buffer pH 6.5. The calibration curve obtained was expressed as Area = 182.05%-1 * HbA1c - 377.02; R2 = 0.9826, using a UV/VIS absorbance detector at 415 nm (diode array). No interferences were observed from carbamylated or acetylated hemoglobin and the method shows a noteworthy stability. A paired t-test was applied to compare the developed CE method with a commercial HbA1c test and no significant variations have been observed at a 90% significance level. PMID- 29384200 TI - Mercury tolerance and biosorption in bacteria isolated from Ny-Alesund, Svalbard, Arctic. AB - Mercury tolerant bacteria Pseudarthrobacter oxydans strain MM20 and Pseudomonas frederiksbergensis strain SS18 were isolated from the tundra ecosystem of Ny Alesund, Svalbard, where commercial exploitation of the coal existed till 1960s. Minimum inhibitory concentration (MIC), mercury removal, mercury biosorption, and antibiotic resistance of these strains were analyzed. P. frederiksbergensis strain SS18 showed high tolerance (2.0 ppm) to mercury than P. oxydans strain MM20 (1.5 ppm). Mercury removal and biosorption studies were carried out in liquid media containing 1.0 ppm mercury. More than 90% of mercury was removed from the culture media by the selected strains. The mercury biosorption assay revealed that a part of mercury was accumulated in cell pellets and was 22 and 25% respectively for P. oxydans strain MM20 and P. frederiksbergensis strain SS18. Fourier transform infrared study revealed that alkyl halide, alkynes, alcoholic, aliphatic and aromatic amines, alkanes, nitro compound, primary amines, carboxylic acid, alkenes, and amide groups play a major role in the development of tolerance towards mercury. Out of eleven antibiotics tested, P. oxydans strain MM20 was found to be resistant to lincomycin and novobiocin while P. frederiksbergensis strain SS18 was found to be resistant to seven antibiotics. Our study demonstrates that under experimental conditions, bacterial isolates undergo detailed structural and functional changes to tolerate as well as immobilize toxic elements like mercury. PMID- 29384201 TI - Extended duration of treatment with peginterferon alfa-2a in patients with chronic hepatitis B, HBeAg-negative and E genotype: A retrospective analysis. AB - An alternative approach in the treatment of chronic hepatitis B (CHB) with pegylated (PEG)-interferon (IFN) is the prolonged course to 96 weeks of therapy, with higher sustained response (SR) than patients treated for 48 weeks. This result was confirmed in patients with CHB and D genotype, while no data are currently available about the prolonged course of PEG-IFN in E genotype. This retrospective analysis reported the role of different treatment duration of PEG IFN on the SR in patients affected by CHB and E genotype. A total of 86 subjects with CHB and E genotype were considered in this analysis; different treatment durations were: 48 weeks (control group, 41 patients), 72 weeks (25 patients), and 96 weeks (19 patients). Treatment effectiveness was evaluated with sustained response (SR) and serological response. SR was significantly higher in patients who underwent PEG-IFN for 96 weeks in comparison to 48 weeks: 14.6% versus 26.3% (P = 0.016). HBsAg loss rate was 5.3% in patients treated for 96 weeks and 2.4% in the control group. In the multivariate analysis only the 72 and 96 weeks of therapy (OR 2.335, 95% CI 1.550-4.578; P = 0.020 and (OR 3.890, 95% CI 1.991 10.961; P = 0003) were predictive of SR. The extended duration of PEG-IFN course in patients with CHB and genotype E is a promising approach to increase the SR and HBsAg clearance. PMID- 29384202 TI - Pediatric Drug Development: Outlook for Science-Based Innovation. AB - There has been significant progress in pediatric drug development during the past 15 years. Results from 1,200 pediatric studies have been submitted to the US Food and Drug Administration (FDA). Over 700 drug labels have been revised with information to guide pediatric use. Two international pediatric trial networks have been established.1,2 The failure rate for pediatric efficacy trials has fallen from over 40%3 to about 20%. Taken together, the outlook for pediatric drug development is positive. PMID- 29384203 TI - Improving the recombinant human erythropoietin glycosylation using microsome supplementation in CHO cell-free system. AB - Cell-Free Protein Synthesis (CFPS) offers many advantages for the production of recombinant therapeutic proteins using the CHO cell-free system. However, many complex proteins are still difficult to express using this method. To investigate the current bottlenecks in cell-free glycoprotein production, we chose erythropoietin (40% glycosylated), an essential endogenous hormone which stimulates the development of red blood cells. Here, we report the production of recombinant erythropoietin (EPO) using CHO cell-free system. Using this method, EPO was expressed and purified with a twofold increase in yield when the cell free reaction was supplemented with CHO microsomes. The protein was purified to near homogeneity using an ion-metal affinity column. We were able to analyze the expressed and purified products (glycosylated cell-free EPO runs at 25-28 kDa, and unglycosylated protein runs at 20 kDa on an SDS-PAGE), identifying the presence of glycan moieties by PNGase shift assay. The purified protein was predicted to have ~2,300 IU in vitro activity. Additionally, we tested the presence and absence of sugars on the cell-free EPO using a lectin-based assay system. The results obtained in this study indicate that microsomes augmented in vitro production of the glycoprotein is useful for the rapid production of single doses of a therapeutic glycoprotein drug and to rapidly screen glycoprotein constructs in the development of these types of drugs. CFPS is useful for implementing a lectin-based method for rapid screening and detection of glycan moieties, which is a critical quality attribute in the industrial production of therapeutic glycoproteins. PMID- 29384204 TI - Frenkel-exciton decomposition analysis of circular dichroism and circularly polarized luminescence for multichromophoric systems. AB - Recently, a method to calculate the absorption and circular dichroism (CD) spectra based on the exciton coupling has been developed. In this work, the method was utilized for the decomposition of the CD and circularly polarized luminescence (CPL) spectra of a multichromophoric system into chromophore contributions for recently developed through-space conjugated oligomers. The method which has been implemented using rotatory strength in the velocity form and therefore it is gauge-invariant, enables us to evaluate the contribution from each chromophoric unit and locally excited state to the CD and CPL spectra of the total system. The excitonic calculations suitably reproduce the full calculations of the system, as well as the experimental results. We demonstrate that the interactions between electric transition dipole moments of adjacent chromophoric units are crucial in the CD and CPL spectra of the multichromophoric systems, while the interactions between electric and magnetic transition dipole moments are not negligible. (c) 2018 Wiley Periodicals, Inc. PMID- 29384205 TI - Mitigating Litigating: An Examination of Psychosocial Impacts of Compensation Processes Associated with the 2010 BP Deepwater Horizon Oil Spill. AB - During the past four decades, a number of social science scholars have conceptualized technological disasters as a social problem. More specifically, research in this arena has identified individual and collective stress as a secondary trauma of processes intended to provide compensation and economic relief from disasters in general and, more specifically, technological disasters. Based on data from a 2013 household telephone survey of 1,216 residents of coastal Alabama, this article examines the relationship between psychosocial stress and compensation processes related to the 2010 BP Deepwater Horizon oil spill. We examine involvement with claims, settlement, and litigation activities; vulnerability and exposure to the spill; ties to resources; resource loss and gain; perceptions of risk and recreancy; and intrusive stress and avoidance behaviors as measured by the impact of event scale. Regression analysis reveals that the strongest contributors to intrusive stress were being part of the compensation process, resource loss, concerns about air quality, and income. Although being involved with compensation processes was a significant predictor of avoidance behaviors, the strongest contributors to avoidance behaviors were resource loss, air quality concern, income, being male, minority status, and community attachment. Beliefs that the compensation process was as distressing as the oil spill also significantly contributed to intrusive stress and avoidance behaviors. This research represents a step toward filling a gap in empirical evidence regarding the extent to which protracted compensation processes exacerbate adverse psychosocial impacts of disasters and hinder community recovery. PMID- 29384207 TI - Influence of internet addiction on executive function and learning attention in Taiwanese school-aged children. AB - PURPOSE: This study aims to evaluate the executive function and learning attention in children with internet addiction (IA). DESIGN AND METHODS: Children aged 10-12 were screened by Chinese Internet Addiction Scale to compose the IA group and internet nonaddiction group. Their executive functions were evaluated by Stroop color and word test, Wisconsin card sorting test, and Wechsler digit span test. Learning attention was evaluated by Chinese concentration questionnaire. FINDINGS: Executive function and learning attention were lower in the IA group than in the internet nonaddiction group. PRACTICE IMPLICATIONS: Executive function and learning attention are compromised by IA in children. Early interventions into the IA should be planned to maintain the normal development of executive function and learning attention in childhood. PMID- 29384208 TI - On the Relationship between Safety and Decision Significance. AB - Risk analysts are often concerned with identifying key safety drivers, that is, the systems, structures, and components (SSCs) that matter the most to safety. SSCs importance is assessed both in the design phase (i.e., before a system is built) and in the implementation phase (i.e., when the system has been built) using the same importance measures. However, in a design phase, it would be necessary to appreciate whether the failure/success of a given SSC can cause the overall decision to change from accept to reject (decision significance). This work addresses the search for the conditions under which SSCs that are safety significant are also decision significant. To address this issue, the work proposes the notion of a theta-importance measure. We study in detail the relationships among risk importance measures to determine which properties guarantee that the ranking of SSCs does not change before and after the decision is made. An application to a probabilistic safety assessment model developed at NASA illustrates the risk management implications of our work. PMID- 29384206 TI - Bone Marrow Micro-Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies. AB - Various cell types cooperate to create a highly organized and dynamic micro environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy. PMID- 29384209 TI - Early vedolizumab trough levels predict mucosal healing in inflammatory bowel disease: a multicentre prospective observational study. AB - BACKGROUND: The correlation between vedolizumab trough levels during induction therapy and mucosal healing remains unknown. AIM: To compare early vedolizumab trough levels in patients with and without mucosal healing within the first year after treatment initiation. METHODS: We prospectively collected vedolizumab trough levels in all inflammatory bowel disease patients at weeks 2, 6 and 14 of vedolizumab treatment in three French referral centres between 1 June 2014 and 31 March 2017. Results of every patient that underwent mucosal assessment by magnetic resonance imaging and/or endoscopy in the first year after treatment initiation were analysed. RESULTS: Median vedolizumab trough levels in the overall population (n = 82) were 27 MUg/mL (interquartile range, IQR 21.2-33.8 MUg/mL) at week 2, 23 MUg/mL (IQR 15-34.5 MUg/mL) at week 6 and 10.7 MUg/mL (IQR 4.6-20.4 MUg/mL) at week 14. Only median vedolizumab trough levels at week 6 differed between patients with and without mucosal healing within the first year after treatment initiation (26.8 vs 15.1 MUg/mL, P = 0.035). A cut-off trough level of 18 MUg/mL at week 6 predicted mucosal healing within the first year after the start of vedolizumab with an area under the receiver operating curve of 0.735 (95% confidence interval 0.531-0.939). A vedolizumab trough level above 18 MUg/mL at week 6 was the only independent variable associated with mucosal healing within the first year of treatment (odds ratio 15.7, 95% confidence interval 2.4-173.0, P = 0.01). CONCLUSION: Early therapeutic drug monitoring might improve timely detection of vedolizumab-treated patients in need for an intensified dosing regimen. PMID- 29384210 TI - Generation of hematopoietic cells from mouse pluripotent stem cells in a 3D culture system of self-assembling peptide hydrogel. AB - In vitro generation of HSCs from pluripotent stem cells (PSCs) can be regarded as novel therapeutic approaches for replacing bone marrow (BM) transplantation without immune rejection or graft versus host disease(GVHD). To date, many differentiation approaches have been evaluated in terms of directing PSCs toward different hematopoietic cell types, yet, low efficiency and no function restrict the further hematopoietic differentiation study, our research aim to develop a three dimention (3D) hematopoietic differentiation approach that serve as recapitulation of embryonic development in vitro to a degree of complexity not achievable in a two dimention (2D) culture system. We first found that mouse PSCs could be efficiently induced to hematopoietic differentiation with expression of hematopoietic makers such as c-kit, CD41 and CD45 within self-assembling peptide hydrogel. Colony-forming cells assay results suggested mPSCs could differentiated into multipotential progenitor cells and 3D induction system derived hematopoietic colonies owned potential of differentiating into lymphocyte cells. In addition, in vivo animal transplantation experiment showed that mPSCs(CD45.2) could embedded into NOD/SCID mice(CD45.1) with about 3% engraftment efficiency after 3 weeks transplantation. This study demonstrated that we developed the 3D induction approach that could efficiently promoted the hematopoietic differentiation of mPSCs in vitro and obtained the multipotential progenitors that possessed the short-term engraftment potential. This article is protected by copyright. All rights reserved. PMID- 29384211 TI - The importance of miRNAs and epigenetics in acute lymphoblastic leukemia prognosis. AB - Acute lymphoblastic leukemia (ALL), one of the most common malignant human disorders, originates in different important genetic lesions in T-cell or B-cell progenitors. ALL is a malignant lymphoid progenitor with peak prevalence in children (2-5 years). The rate of survival when one is suffering from ALL depends on various agents including the age of the patient, responses to anti-leukemic therapy, and cell biology. miRNAs and epigenetics are important regulatory factors in the expression of genes. miRNAs are noncoding RNA with inhibitory effectors on specific mRNA. Patterns of DNA methylation are profoundly changed in ALL by epigenetic mechanisms. The deciphering of miRNA and the epigenetic pathogenesis in ALL could revolutionize response to the therapy and outcome, and create an enormous promise for novel approaches to reduce the toxic side-effects of intensive leukemia. Hence, pathogenetic miRNAs and epigenetics leading to the initiation and the progression of ALL are summarized in this review. PMID- 29384212 TI - Increased N6-methyladenosine causes infertility is associated with FTO expression. AB - The N6-methyladenosine (m6A) modification plays a central role in epigenetic regulation of the mammalian transcriptome. m6A can be demethylated by the fat mass- and obesity-associated (FTO) protein and the alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein. Much less is known about that whether m6A content is involved in POI (premature ovarian insufficiency) disease. In this case-controlled study, 69 POI and 53 tubal occlusion patients were recruited from the reproduction centers in our hospital. For the POI animal model experiment, ovarian tissue was obtained from ten POI and nine healthy mice. An m6A test kit was developed to determine the m6A content in the RNA, and qPCR and western blot were used to examine the mRNA and protein expression levels of FTO and ALKBH5. FACS was used to measure the levels of proliferation and apoptosis, and siRNA was used to establish FTO and ALKBH5 knockdown cell lines. Our results showed that the m6A content in the RNA from POI patients and POI mice was significantly higher than control groups and that POI was characterized by the content of m6A. The mRNA and protein expression levels of FTO were significantly lower in the POI patients than control group and were associated with a risk of POI. These data suggest that the decreased mRNA and protein expression levels of FTO may be responsible for the increase in m6A in POI, which may further increase the risk of complications of POI. High m6A should be investigated further as a novel potential biomarker of POI. PMID- 29384213 TI - FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation. AB - Fat mass and obesity-associated protein (FTO) is a RNA demethylase, whether FTO regulates fat metabolism through its demethylation is unclear. The results of this study confirmed that N6-methyladenosine (m6 A) is associated with fat accumulation both in vivo and in vitro. The data showed that FTO down-regulated m6 A levels, decreased mitochondrial content, and increased triglyceride (TG) deposition. However, an FTO (R316A) mutant lacking demethylation activity could not regulate mitochondria and TG content, indicating that FTO affects mitochondrial content and fat metabolism by modulating m6 A levels in hepatocytes. In addition, the regulatory roles of cycloleucine (methylation inhibitor) and betaine (methyl donor) could regulate m6 A levels and fat deposition. This work clarified that the demethylation function of FTO plays an essential role in the fat metabolism of hepatocytes and links the epigenetic modification of RNA with fat deposition, thereby providing a new target (m6 A) for regulation of hepatic fat metabolism. PMID- 29384214 TI - Effects of insulin on transcriptional response and permeability in an in vitro model of human blood-brain barrier. AB - Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. Active and passive immune therapies targeting beta amyloid (Abeta) have shown very limited evidence in human studies of clinical benefits from these approaches. Epidemiological studies have shown that subjects with type 2 diabetes (T2D) are at higher risk of developing AD. However, whether and how these two conditions are causally linked is unknown. With the purpose of confirming the relationship between T2D and AD, this study specifically focused on effects of insulin in an in vitro model of the human blood-brain barrier (BBB) and on potential mechanisms of action in the treatment of AD. By using a series of assays to establish a BBB model, we demonstrated that insulin treatment alone could induce the increase of brain endothelial barrier properties. The transcriptional response of hCMEC/D3 cells to activation with different concentrations of insulin was determined by RT-PCR, and expression levels of genes involved in the control of barrier permeability, including inter-brain endothelial junctions, integrin-focal adhesions complexes, and transporter system, were found to be altered by the treatment. Notably, the influence of insulin on expression of the ATP-binding cassette (ABC) transporter which contributes to the clearance of Abeta was investigated. Insulin up-regulated adherens junction and tight junction transmembrane proteins, as well as the ABC transporter. By treatment with insulin, the models have major advantages: it is fast, it has low cost, it is fit for considerable samples, and its conditions are under control. PMID- 29384215 TI - Mechanical regulation of breast cancer migration and apoptosis via direct and indirect osteocyte signaling. AB - Bone metastases, the migration of cancers to bone, occur in 65-80% of patients with advanced breast cancer. Metastasized cancer cells interact with cells such as the bone-resorbing osteoclasts to alter bone remodeling. Exercise, often suggested as an intervention for cancer patients, regulates bone remodeling via osteocytes. Osteocytes also signal to endothelial cells, which may affect cancer cell extravasation. Therefore, we hypothesize that mechanically stimulated osteocytes can regulate processes in breast cancer bone metastasis. To test this, we exposed osteocytes to oscillatory fluid flow in vitro using parallel-plate flow chambers. We observed that conditioned medium from flow-stimulated osteocytes increased migration (by 45%) and reduced apoptosis (by 12%) of breast cancer cells. Conditioned medium from osteoclasts conditioned in flowed osteocytes' conditioned medium reduced migration (by 47%) and increased apoptosis (by 55%) of cancer cells. Cancer cell trans-endothelial migration was reduced by 34% toward flowed osteocytes' conditioned medium. This difference was abolished with ICAM-1 or IL-6 neutralizing antibodies. Conditioned medium from endothelial cells conditioned in flowed osteocytes' conditioned medium increased cancer cell apoptosis by 29%. To summarize, this study demonstrated mechanically stimulated osteocytes' potential to affect breast cancer cells not only through direct signaling, but also through osteoclasts and endothelial cells. The anti metastatic potential of the indirect signalings is particularly exciting since osteocytes are further away from metastasizing cancer cells than osteoclasts and endothelial cells. Future studies into the effect of bone mechanical loading on metastases and its mechanism will assist in designing cancer intervention programs that lowers the risk for bone metastases. PMID- 29384216 TI - MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1. AB - MicroRNA let-7 family acts as the key regulator of the differentiation of mesenchymal stem cells (MSCs). However, the influence of let-7b on biological characteristics of stem cells from apical papilla (SCAPs) is still controversial. In this study, the expression of hsa-let-7b was obviously downregulated during the osteogenic differentiation of SCAPs. SCAPs were then infected with hsa-let-7b or hsa-let-7b inhibitor lentiviruses. The proliferation ability was determined by CCK-8 and flow cytometry. The odonto/osteogenic differentiation capacity was analyzed by alkaline phosphatase (ALP) activity, alizarin red staining, Western blot assay, and real-time RT-PCR. Bioinformatics analysis was used to screen out the target of hsa-let-7b and the target relationship was confirmed by dual luciferase reporter assay. Hsa-let-7b was of no influence on the proliferation of SCAPs. Interferential expression of hsa-let-7b increased the ALP activity as well as the formation of calcified nodules of SCAPs. Moreover, the mRNA levels of osteoblastic markers (ALP, RUNX2, OSX, OPN, and OCN) were upregulated while the protein levels of DSPP, ALP, RUNX2, OSX, OPN, and OCN also increased considerably. Conversely, overexpression of hsa-let-7b inhibited the odonto/osteogenic differentiation capacity of SCAPs. Bioinformatics analysis revealed a putative binding site of hsa-let-7b in the matrix metalloproteinase 1 (MMP1) 3'-untranslated region (3'-UTR). Dual luciferase reporter assay confirmed that hsa-let-7b targets MMP1. The odonto/osteogenic differentiation ability of SCAPs ascended after repression of hsa-let-7b, which was then reversed after co transfection with siMMP1. Together, hsa-let-7b can suppress the odonto/osteogenic differentiation capacity of SCAPs by targeting MMP1. PMID- 29384217 TI - Lysine-specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC-803. AB - B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer. PMID- 29384218 TI - microRNA-130a suppresses breast cancer cell migration and invasion by targeting FOSL1 and upregulating ZO-1. AB - FOSL1 is frequently overexpressed in multiple types of human cancers including invasive breast cancers and implicated in cancer invasion and metastasis. However, how FOSL1 is overexpressed in cancers remains to be elucidated. Several microRNAs (miRNAs) have been shown to target FOSL1 and are downregulated in human cancers. Here, we report that miR-130a is a novel FOSL1 targeting miRNA. Using gene expression microarray analysis, we found that FOSL1 is among the most up regulated genes in cells transfected with miR-130a inhibitors. Transient transfection-immunoblot, RNA-immunoprecipitation, and luciferase reporter assays revealed that miR-130a directly targets FOSL1 mRNA at its 3'-UTR. Overexpression of miR-130a significantly reduced the levels of FOSL1 in invasive breast cancer MDA-MB-231 and Hs578T cell lines and suppresses their migration and invasion. This inhibition can be rescued by ectopic expression of miR-130a-resistant FOSL1. Interestingly, we show that overexpression of miR-130a increased the levels of tight-junction protein ZO-1 while inhibition of miR-130a reduced the levels of ZO 1. We further show that miR-130a expression is significantly reduced in cancer tissues from triple-negative breast cancer (TNBC) patients, correlating significantly with the upregulation of FOSL1 expression, compared to non-TNBC tissues. Together, our results reveal that miR-130a directly targets FOSL1 and suppresses the inhibition of ZO-1, thus inhibiting cancer cell migration and invasion, in TNBCs. PMID- 29384219 TI - piRNA-19128 regulates spermatogenesis by silencing of KIT in chicken. AB - Spermatogenesis is a complex process. Some studies have shown that Piwi interacting RNAs (piRNAs) play an important role in spermatogenesis. To verify the evaluate between piRNAs and PIWI proteins in chicken and its possible role in spermatogenesis and reproductive stem cell proliferation and differentiation, we performed immunoprecipitation and deep sequencing analyses and determined the expression profiles of small RNAs in primordial germ cells (PGCs), spermatogonial stem cells (SSCs), spermatogonia (Sa) cells, and spermatozoa. Length analysis showed that piRNAs bound to PIWIL1 mainly contained 23-30 nt. Base preference analysis showed "1U-10A"; moreover, base preference of piRNAs was obvious in all of germline cells. Here we reported the TE family of gallus gallus, and targeted by piRNA. Target gene of piRNA annotation enrichment analysis identified candidate genes KIT, SRC, WNT4, and HMGB2. Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes were associated with steroid hormone biosynthesis, Notch signaling pathway, and melanogenesis. These results indicate that chicken piRNAs perform important regulatory roles during spermatogenesis similar to mice piRNAs. Chicken piRNAs interacted with PIWI proteins and regulated spermatogenesis and germ cell proliferation and differentiation. Further, we observed a negative correlation between piRNA-19128 and KIT expression. Results of dual-luciferase reporter assay confirmed that piRNA-19128 directly interacted with KIT, suggesting that it plays a key role in the regulation spermatogenesis by inhibiting KIT expression. Thus, the present study provides information on the length and base preference of chicken piRNAs and suggests that piRNA-19128 regulates spermatogenesis in chicken by silencing KIT. PMID- 29384220 TI - Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt/mTOR-independent pathway. AB - Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to exert antitumor activities in some types of cells. Whether compound C can exert antitumor effects in human cholangiocarcinoma (CCA) remains unknown. Here, we demonstrated that compound C is a potent inducer of cell death and autophagy in human CCA cells. Autophagy inhibitors increased the cytotoxicity of compound C towards human CCA cells, as confirmed by increased LDH release, and PARP cleavage. It is notable that compound C treatment increased phosphorylated Akt, sustained high levels of phosphorylated p70S6K, and decreased mTOR regulated p-ULK1 (ser757). Based on the data that blocking PI3K/Akt or mTOR had no apparent influence on autophagic response, we suggest that compound C induces autophagy independent of Akt/mTOR signaling in human CCA cells. Further study demonstrated that compound C inhibited the phosphorylation of JNK and its target c-Jun. Blocking JNK by SP600125 or siRNA suppressed autophagy induction upon compound C treatment. Moreover, compound C induced p38 MAPK activation, and its inhibition promoted autophagy induction via JNK activation. In addition, compound C induced p53 expression, and its inhibition attenuated compound C-induced autophagic response. Thus, compound C triggers autophagy, at least in part, via the JNK and p53 pathways in human CCA cells. In conclusion, suppresses autophagy could increase compound C sensitivity in human CCA. PMID- 29384221 TI - The effect of chronic high insulin exposure upon metabolic and myogenic markers in C2C12 skeletal muscle cells and myotubes. AB - Skeletal muscle is an insulin sensitive tissue and accounts for approximately 80% of post-prandial glucose disposal. This study describes the effects of insulin, delivered for 72 h, to skeletal muscle myoblasts during differentiation or to skeletal muscle myotubes. After chronic treatment, cultures were acutely stimulated with insulin and analyzed for total and phosphorylated Akt (Ser473 ), mRNA expression of metabolic and myogenic markers and insulin-stimulated glucose uptake. Skeletal muscle cells differentiated in the presence of insulin chronically, reduced acute insulin stimulated phosphorylation of Akt Ser473 . In addition, there was a reduction in mRNA expression of Hexokinase II (HKII), GLUT4 and PGC-1alpha. Insulin-stimulated glucose uptake was attenuated when cells were differentiated in the presence of insulin. In contrast, myotubes exposed to chronic insulin showed no alterations in phosphorylation of Akt Ser473 . Both HKII and GLUT4 mRNA expression were reduced by chronic exposure to insulin; while PGC-1alpha was not different between culture conditions and was increased by acute insulin stimulation. These data suggest that there are differential responses in insulin signalling, transcription, and glucose uptake of skeletal muscle cells when cultured in either the presence of insulin during differentiation or in myotube cultures. PMID- 29384222 TI - RNA interference-mediated silencing of S100B improves nerve function recovery and inhibits hippocampal cell apoptosis in rat models of ischemic stroke. AB - Ischemic stroke is the leading cause of worldwide mortality and long-term disability in adults. This study aims to explore the effects of RNA interference (RNAi)-mediated silencing of the S100B gene on nerve function recovery and morphological changes of hippocampus cells in rat models with ischemic stroke. Sixty Wistar rats were assigned into different group. S100B and Caspase 3 mRNA and protein expressions were evaluated by RT-qPCR and Western blotting. Positive rate of S100B, NeuN, and MAP2 expressions were detected by immunohistochemistry (IHC). Water content, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activity in brain tissues were measured. Enzyme-linked immunosorbent assay (ELISA) was employed to detect serum levels of TNF-alpha and IL-1beta. A neurological severity score (NSS) was used to test nerve function. TUNEL assay was used to determine hippocampal cell apoptosis. Downregulation of S100B showed a lower number of S100B immune positive cells, but higher NeuN and MAP2-positive cells, increased SOD level, declined MDA level, prominently faster recovery of neurological function, decreased TRCS, TCTP, TCFP, and IE levels, an obvious increase in the number of survival neurons, a decrease in the number of apoptotic cells, notably decreased TNF-alpha and IL-1beta contents, as well as infarct volume, an obvious decrease in positive hippocampal cell Caspase 3 expression and protein expressions of Caspase 3 and cleaved Caspase 3. This study provides data to suggest that RNAi-mediated silencing of S100B gene could improve the recovery of nerve function while inhibiting apoptosis of hippocampal cells in rats with ischemic stroke. PMID- 29384223 TI - Total Synthesis of Parvineostemonine by Structure Pattern Recognition: A Unified Approach to Stemona and Sarpagine Alkaloids. AB - Through structure pattern recognition based total synthesis we designed a synthesis in which two biogenetically unrelated natural product families (Stemona and Sarpagine alkaloids) share 50 % of their synthetic sequence. In this report, the efficiency of such a strategic approach is demonstrated in the total synthesis of the Stemona alkaloid parvineostemonine, proceeding through a privileged intermediate that we have previously transformed into biogenetically completely unrelated Sarpagine alkaloids. In addition, we capitalized on the symmetry properties of the privileged intermediate, which was obtained as two regioisomers. After their separation by column chromatography the two regioisomers were converted to the corresponding pair of enantiomers by one transformation. To the best of our knowledge, this feature (conversion of regioisomers to enantiomers) has never been applied to natural product synthesis, and proved to be very valuable, since it allowed to obtain both optical antipodes of parvineostemonine in a single synthetic campaign. This not only enabled the determination of the previously undisclosed absolute configuration of the natural product, but gave 60-200 mg amounts of both enantiomers of the natural product. PMID- 29384224 TI - Curcumin on the "flying carpets" to modulate different signal transduction cascades in cancers: Next-generation approach to bridge translational gaps. AB - Curcumin, a bioactive and pharmacologically efficient component isolated from Curcuma longa has attracted considerable attention because of its ability to modulate diverse cellular and physiological pathways. WNT, TGF/SMAD, NOTCH, and SHH are fundamentally different signaling cascades, but their choreographed activation is strongly associated with cancer development and progression. In this review we have attempted to set spotlight on regulation of different cell signaling pathways by curcumin in different cancers. We partition this multi component review into in-depth biological understanding of various signal transduction cascades and how curcumin targets intracellular signal transducers of deregulated pathways to inhibit cancer development and progression. Rapidly broadening landscape of both established and candidate oncogenic driver mutations identified in different cancers is a major stumbling block in the standardization of drugs having significant clinical outcome. Intra and inter-tumor heterogeneity had leveraged the complexity of therapeutic challenges to another level. Multi pronged approach and molecularly guided treatments will be helpful in improving the clinical outcome. PMID- 29384225 TI - Jolkinolide B inhibits glycolysis by downregulating hexokinase 2 expression through inactivating the Akt/mTOR pathway in non-small cell lung cancer cells. AB - Jolkinolide B (JB), a bioactive compound isolated from herbal medicine, has been found to inhibit tumor growth by altering glycolysis. However, whether glycolysis is influenced by JB in non-small cell lung cancer (NSCLC) cells and the mechanism remain unknown. The aim of the present study was to evaluate the effect of JB on the glycolysis in NSCLC cells and the underlying molecular mechanism. The results showed that JB treatment inhibited cell viability of A549 and H1299 cells in a concentration-dependent manner. JB reduced the glucose consumption, lactate production, and HK2 expression. The expressions of p-Akt and p-mTOR were also decreased by JB treatment. Knockdown of HK2 reduced glucose consumption and lactate production. Inhibition of the Akt/mTOR pathway decreased HK2 expression and inhibited glycolysis. In conclusion, the results indicated that JB inhibits glycolysis by down-regulating HK2 expression through inactivating the Akt/mTOR pathway in NSCLC cells, suggesting that JB might be a potential therapeutic agent for the treatment of NSCLC. PMID- 29384226 TI - Long non-coding RNA XIST promotes osteosarcoma progression by targeting YAP via miR-195-5p. AB - The lncRNA XIST (X inactive-specific transcript) is an oncogenic lncRNA that is present in various malignant tumors; however, its role and molecular mechanisms in osteosarcoma (OS) progression remain unclear. In the current study, 40 pairs of OS tissues and matched adjacent non-tumor tissues were collected. qRT-PCR was conducted to investigate the differences in XIST expression in tissues and OS cell lines. The proliferation, invasion, and EMT status of OS cells after transfection were assessed with WST-1 assays, Transwell assays, and Western blot analysis, respectively. Whether miR-195-5p was a direct downstream target of XIST was verified by both bioinformatics target gene prediction and dual-luciferase report analysis. A mouse model was established to evaluate tumor proliferation in vivo. Our results demonstrated that XIST expression was significantly upregulated in OS tissues and cell lines and negatively correlated with clinical prognosis. XIST knockdown inhibited cancer cell proliferation and invasion in vitro, inhibited the EMT of OS cells in vitro, and suppressed subcutaneous tumor growth in vivo. Further analysis demonstrated that XIST regulated YAP expression by functioning as a competing endogenous RNA that sponged miR-195-5p in OS cells. XIST directly interacted with miR-195-5p and decreased the binding of miR-195-5p to the YAP 3'UTR, which suppressed the degradation of YAP mRNA by miR-195-5p. In conclusion, this work demonstrates that lncRNA XIST enhances OS cancer cell proliferation and invasion in part through the miR-195-5p/YAP pathway. Therefore, lncRNA XIST might be a promising therapeutic target for OS. PMID- 29384227 TI - A mitogenic lectin from Rhizoctonia bataticola arrests growth, inhibits metastasis, and induces apoptosis in human colon epithelial cancer cells. AB - The correlation between colorectal cancer (CRC) progression and altered expression of N-glycans can be considered in search for new biomarkers and anticancer agents to control CRC. Earlier N-glycan specific mitogenic lectin from Rhizoctonia bataticola (RBL) has been reported which has growth inhibitory and apoptotic effect on human ovarian and leukemic cells, but mitogenic effect on normal PBMCs revealing its clinical potential. Here, we report the effect of RBL on human colon cancer HT 29, SW480, and SW620 cell growth and its differential binding to human normal colon and cancer tissues. RBL has strong binding to both primary and metastatic colon cancer cells with MFI of 403, 404, and 192, respectively for HT 29, SW480, and SW620 cells. RBL shows dose and time dependent growth inhibitory effect with IC50 of 5, 6.4, and 6.8 ug/mL, respectively for HT 29, SW480, and SW620 cells. RBL inhibited the clonogenicity of colon carcinoma cells. RBL arrests metastatic SW620 cell growth at S phase, increased hypodiploid population by 6.1%, 14.3%, and 23.2%, respectively at 12, 24, and 36 h. Further, RBL induces SW620 cell apoptosis in time dependent manner, showed increased release of ROS and nuclear degradation compared to lectin untreated control. Adhesion, wound healing, invasion, and migration assays demonstrated anti metastasis effect of RBL in SW620 cells apart from its growth inhibitory effect. Anti angiogenic effect of RBL was demonstrated by CAM assay. All these results show the promising potential of RBL both as diagnostic and therapeutic agent. PMID- 29384228 TI - NTPDase activities: possible roles on Leishmania spp infectivity and virulence. AB - Nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes that belong to the GDA1/CD39 protein superfamily. These enzymes catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP). Biochemical characterization of the nucleotidases/NTPDases from various types of cells, including those from plants, animals, and pathogenic organisms, has revealed the existence of several isoforms with different specificities with respect to divalent cations (magnesium, calcium, manganese, and zinc) and substrates. In mammals, the NTPDases play important roles in the regulation of thrombosis and inflammation. In parasites of the genus Leishmania, the causative agents of leishmaniasis, two NTPDase isoforms, termed NTPDase-1 and NTPDase-2 have been described. Independently of their cellular localization, whether cell-surface localized, secreted or targeted to other organelles, in some Leishmania species these NTPDases could be involved in parasite growth, infectivity, and virulence. Experimental evidence has suggested that the hydrolysis of ATP and ADP by parasite ecto-nucleotidases can down-modulate the host immune response. In this context, the present work provides an overview of recent works that show strong evidence not only of the involvement of the nucleotidases/NTPDases in Leishmania spp infectivity and virulence but also of the molecular mechanisms that lead to the success of the parasitic infection. PMID- 29384229 TI - Computational Study of the Aza-Michael Addition of the Flavonoid (+)-Taxifolin in the Inhibition of beta-Amyloid Fibril Aggregation. AB - Inhibition of abnormal protein self-aggregation is an attractive strategy against amyloidogenic diseases, but has found limited success due to the complexity of protein self-assembly, the absence of fully reproducible aggregation assays, and the scarce knowledge of the inhibition mechanisms by small molecules. In this context, catechol-containing compounds may lead to covalent adducts with amyloid fibrils that interfere with the aggregation process. In particular, the covalent adduct formed between the oxidized form of (+)-taxifolin and an beta-amyloid (Abeta42) suggests the involvement of a specific recognition motif that enables the chemical reaction with Abeta42. In this study, we have examined the mechanisms implicated in the aza-Michael addition of the o-quinone species of (+) taxifolin with Abeta42 fibrils. The results support the binding of (+)-taxifolin to the hydrophobic groove delimited by the edges defined by Lys16 and Glu22 residues in the fibril. The chemical reaction proceeds through the nucleophilic attack of the deprotonated amino group of a Lys16 residue in a process activated by the interaction between the o-quinone ring with a vicinal Lys16 residue, as well as by a water-assisted proton transfer, which is the rate-limiting step of the reaction. This specific inhibition mechanism, which may explain the enhanced anti-aggregating activity of oxidized flavonoids compared to fresh compounds, holds promise for developing disease-modifying therapies. PMID- 29384230 TI - Describing one generic and two new species record to the flora of Pakistan using LM and SEM methods. AB - Common mulberry weed (Fatoua villosa (Thunb.) Nakai) and creeping amaranth (Amaranthus crassipes Schlecht) are reported for the first time in Pakistan's flora as these were not listed in any other literature nor identified before in Pakistan. Plants were found as a result of taxonomic studies performed in 2013 in Peshawar, Pakistan. Detail study was performed for the exact identification. Morphological results were compared with Flora of China and Flora of North America. Plant distribution along with its habitat and adjacent species was also recorded. Scanning electron and light microscopy was performed for the confirmation of epidermal appendages on leaf epidermis and palyno-morphological characters. PMID- 29384231 TI - Xenotopic expression of alternative electron transport enzymes in animal mitochondria and their impact in health and disease. AB - The mitochondrial respiratory chain in vertebrates and arthropods is different from that of most other eukaryotes because they lack alternative enzymes that provide electron transfer pathways additional to the oxidative phosphorylation (OXPHOS) system. However, the use of diverse experimental models, such as human cells in culture, Drosophila melanogaster and the mouse, has demonstrated that the transgenic expression of these alternative enzymes can impact positively many phenotypes associated with human mitochondrial and other cellular dysfunction, including those typically presented in complex IV deficiencies, Parkinson's, and Alzheimer's. In addition, these enzymes have recently provided extremely valuable data on how, when, and where reactive oxygen species, considered by many as "by products" of OXPHOS, can contribute to animal longevity. It has also been shown that the expression of the alternative enzymes is thermogenic in cultured cells, causes reproductive defects in flies, and enhances the deleterious phenotype of some mitochondrial disease models. Therefore, all the reported beneficial effects must be considered with caution, as these enzymes have been proposed to be deployed in putative gene therapies to treat human diseases. Here, we present a brief review of the scientific data accumulated over the past decade that show the benefits and the risks of introducing alternative branches of the electron transport into mammalian and insect mitochondria, and we provide a perspective on the future of this research field. PMID- 29384232 TI - Complicated Grief Among Military Service Members and Veterans Who Served After September 11, 2001. AB - Minimal research is available on the prevalence and impact of complicated grief (CG) in military service members and veterans, despite high reported rates of loss in this population. The present study aimed to examine prevalence rates of CG in a sample of treatment-seeking military service and members and veterans who served after September 11, 2001. Additionally, the study aimed to examine characteristics associated with CG as well as the association between CG and quality of life. In a sample of 622 military service members and veterans who served after September 11, 2001, 502 reported a significant loss (80.7%). Usable data were available for a total of 468 participants. Of these 468 participants, 30.3% (n = 142) met diagnostic criteria for CG, as defined by a score of 30 or more on the Inventory of Complicated Grief (ICG; Prigerson et al., 1995). We conducted a series of t tests and chi-square tests to examine the differences between individuals who met criteria for CG and those who did not. The presence of CG was associated with worse PTSD, d = 0.68, p < .001; depression, d = -1.10, p < .001; anxiety, d = -1.02, p < .001; stress, d = 0.99, p < .001; and quality of life, d = 0.76, p < .001. Multiple regression analyses examined the independent impact of CG on quality of life. Complicated grief was associated with poorer quality of life above and beyond PTSD, beta = -.12, p = .017. In addition, in a separate regression, CG was associated with poorer quality of life above and beyond depression, beta = -.13, p < .001. Overall, our findings highlight the impact of CG on this population, and have implications for assessment and treatment. PMID- 29384233 TI - Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration. AB - BACKGROUND AND AIM: It has been well documented that Notch signaling is involved in liver regeneration. However, the exact molecular mechanism mediating this process is not fully elucidated. The current study aimed to investigate the role of Notch signaling regulating cell cycle in proliferating hepatocytes in liver regeneration after partial hepatectomy (PHx, 67% resection) and the related molecular mechanism. METHODS: Partial hepatectomy was performed in Sprague Dawley rats, and remnant livers were harvested 0, 1, 3, 5, and 7 days after operation, and primary hepatocytes were isolated to investigate the molecular mechanism. RESULTS: Notch signaling activation and hepatocyte proliferation were significantly increased after PHx, while treatment with FLI-06, the inhibitor of gamma-secreting enzyme, blocked these trends. Besides, inhibition of Notch signaling led to dysregulation of cell cycle and cell-cycle components. Furthermore, Akti-1/2 (a selective Akt inhibitor) and PX-478 (a selective Hif 1alpha inhibitor) inhibited hepatocyte proliferation and liver regeneration after PHx, and the effect of downstream molecules activation by Jagged-1 (Notch-1 ligand) in hepatocytes was abolished by FLI-06, Akti-1/2, and PX-478. CONCLUSION: The current study demonstrated for the first time that Notch signaling regulated cell cycle in proliferating hepatocytes involved in liver regeneration through NICD/Akt Akt/Hif-1alpha pathway. PMID- 29384234 TI - Development and Evaluation of the Thinking About Recovery Scale: Measure of Parent Posttraumatic Cognitions Following Children's Exposure to Trauma. AB - Researchers have recently suggested that parent posttraumatic appraisals potentially contribute to the development of posttraumatic stress in both parents and children following children's exposure to trauma. However, a single instrument, multidimensional measure of parent posttraumatic cognitions as they relate to their child's recovery has yet to be operationalized. This study described the development and evaluation of a parent-report questionnaire of parent posttraumatic cognitions, designed to be used after a child's exposure to trauma. We generated an initial pool of items in reference to existing theories and subjected this list to an iterative process of item writing and revision. Items were subjected to expert review to maximize construct validity. The 33-item Thinking About Recovery Scale (TARS), which measures three domains (My child has been permanently damaged; The world is dangerous for my child; Parents should always promote avoidance) demonstrated good internal consistency (Cronbach's alpha = .74-88) and convergent validity (r 2 range = .08-.40) when piloted in a sample of 116 parents of children who had been exposed to a serious accidental injury. The TARS augments the available literature by providing a brief measure of parent posttraumatic cognitions, an area which is currently understudied in childhood posttraumatic stress and could have broad clinical and research use. PMID- 29384235 TI - miR147b: A novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes. AB - Astrocytes are important mediators of inflammatory processes in the brain and seem to play an important role in several neurological disorders, including epilepsy. Recent studies show that astrocytes produce several microRNAs, which may function as crucial regulators of inflammatory pathways and could be used as therapeutic target. We aim to study which miRNAs are produced by astrocytes during IL-1beta mediated inflammatory conditions in vitro, as well as their functional role and to validate these findings in human epileptogenic brain tissue. Sequencing was used to assess miRNA and mRNA expression in IL-1beta stimulated human fetal astrocyte cultures. miRNAs were overexpressed in cell cultures using miRNA mimics. Expression of miRNAs in resected brain tissue from patients with tuberous sclerosis complex or temporal lobe epilepsy with hippocampal sclerosis was examined using in situ hybridization. Two differentially expressed miRNAs were found: miR146a and miR147b, which were associated with increased expression of genes related to the immune/inflammatory response. As previously reported for miR146a, overexpression of miR147b reduced the expression of the pro-inflammatory mediators IL-6 and COX-2 after IL-1beta stimulation in both astrocyte and tuberous sclerosis complex cell cultures. miR146a and miR147b overexpression decreased proliferation of astrocytes and promoted neuronal differentiation of human neural stem cells. Similarly to previous evidence for miR146a, miR147b was increased expressed in astrocytes in epileptogenic brain. Due to their anti-inflammatory effects, ability to restore aberrant astrocytic proliferation and promote neuronal differentiation, miR146a and miR147b deserve further investigation as potential therapeutic targets in neurological disorders associated with inflammation, such as epilepsy. PMID- 29384236 TI - Incidence and risk factors associated with hepatocellular carcinoma surveillance failure. AB - BACKGROUND AND AIM: Surveillance for hepatocellular carcinoma (HCC) intends to detect tumors at an early stage to improve survival. The study aims were to assess the frequency and risk factors associated with HCC surveillance failure. METHODS: The study analyzed data from 188 consecutive patients diagnosed with HCC within a surveillance program conducted among 1,242 cirrhotic patients and based on ultrasonography and alpha-fetoprotein (AFP) testing every 3 or 6 months. Program failure was defined as the detection of HCC exceeding the Milan criteria. Variables recorded at entry into the program, during follow-up and at HCC diagnosis, were analyzed. RESULTS: At diagnosis, 50 (26.6%) HCC tumors were beyond the Milan criteria. In univariate analysis, Child-Pugh B at entry (P = 0.03), development of complications of portal hypertension before tumor diagnosis (P = 0.03), and failure to complete the prior screening round (P = 0.02), Child Pugh B/C (P = 0.001) and AFP >= 100 ng/mL (P = 0.03) at diagnosis, were associated with failure. In multivariate analysis, only Child-Pugh B/C (hazard ratio, 3.18; 95% confidence interval, 1.66-6.10, P < 0.001) and AFP >= 100 ng/mL, both at diagnosis (hazard ratio, 2.80; 95% confidence interval, 1.37-5.71, P = 0.005), were independently associated with failure. Survival was higher among patients with tumors within the Milan criteria than those with program failure (33.9 vs 7.6 months, P < 0.001). CONCLUSIONS: Approximately 25% of HCC cases diagnosed among patients included in a surveillance program were beyond the Milan criteria. Child-Pugh B/C and AFP >= 100 ng/mL at diagnosis were associated with program failure. However, Child-Pugh B at entry and development of liver-related complications during follow-up can be early predictors of failure. PMID- 29384237 TI - Uptake of maternal vaccinations by Indigenous women in Central Australia. PMID- 29384238 TI - A citizens' jury on regulation of McDonald's products and operations in Australia in response to a corporate health impact assessment. AB - OBJECTIVES: 1) To report outcomes from a citizens' jury examining regulatory responses to the health impacts of McDonald's Australia; 2) To determine the value of using citizens' juries to develop policy recommendations based on the findings of health impact assessment of transnational corporations (TNCs). METHODS: A citizens' jury engaged 15 randomly selected and demographically representative jurors from metropolitan Adelaide to deliberate on the findings of a Corporate Health Impact Assessment, and to decide on appropriate policy actions. RESULTS: Jurors unanimously called for government regulation to ensure that transnational fast food corporations pay taxes on profits in the country of income. A majority (two-thirds) also recommended government regulation to reduce fast food advertising, and improve standards of consumer information including a star-ratings system. A minority held the view that no further regulation is required of the corporate fast food industry in Australia. CONCLUSION: The jury's recommendations can help inform policy makers about the importance of ending the legal profit-shifting strategies by TNCs that affect taxation revenue. They also endorse regulating the fast food industry to provide healthier food, and employing forms of community education and awareness-raising. Implications for public health: Citizens' juries can play an important role in providing feedback and policy recommendations in response to the findings of a health impact assessment of transnational corporations. PMID- 29384239 TI - Awareness and use of family planning methods among iTaukei women in Fiji and New Zealand. AB - OBJECTIVE: iTaukei women's awareness and practice of family planning methods was investigated in New Zealand and Fiji to ascertain differences in behaviour within the context of changing developmental settings. METHODS: The study was cross sectional in nature and recruited women aged 18 years and over from three suburbs in Suva, Fiji, and five cities in New Zealand. RESULTS: Overall, 352 women participated in the study, 212 in Fiji and 140 in New Zealand. The study found that living in New Zealand was significantly associated with lower odds of being aware of family planning (OR 0.4, 95%CI 0.2-0.9, p=0.029) and using family planning methods (OR 0.5, 95%CI 0.2-0.9, p=0.027). Tertiary education was found to increase the odds of being aware (OR 2.8, 95%CI 1.3-6.2, p=0.009) and of using (OR 3.9, 95%CI 1.9-7.8, p=0.000) family planning. CONCLUSIONS: Despite the greater availability of services and higher standards of living experienced in New Zealand compared with Fiji, there was no improvement in awareness and use of family planning among New Zealand participants. Implications for public health: Reduced awareness and use of family planning in New Zealand indicates a need for better targeting of services among minority Pacific ethnic groups. PMID- 29384240 TI - Age and cause-of-death contributions to area socioeconomic, sex and remoteness differences in life expectancy in New South Wales, 2010-2012. AB - OBJECTIVES: To determine age group- and cause-of-death-specific contributions to area socioeconomic status (SES), sex and remoteness life expectancy inequalities. METHODS: Mortality and estimated residential population data from New South Wales, Australia, over 2010-2012 was used to calculate life expectancy. Inequalities by sociodemographic groups were partitioned into age group- and cause-of-death-specific contributions. RESULTS: The largest contributions to SES differentials in life expectancy were observed at 60-84 years of age; for cancer, cardiovascular, endocrine and respiratory causes of death; and additionally external causes of death for males. Sex inequalities ranged from 3.6 to 5.2 years, with common causes of death such as cardiovascular disease and cancer in late adulthood (60+ years) accounting for the bulk of the differences. Smaller differences in life expectancy were observed by remoteness, with the largest contributions observed in ages 85 years and above, and for cardiovascular, mental, cancer and external causes of death. CONCLUSIONS: Common causes of death in late adulthood accounted for the bulk of life expectancy inequalities. Implications for public health: Development of policy and interventions aimed at addressing social determinants, such as proposed by the WHO's Global Plan of Action, are needed to help reduce sociodemographic inequalities in lifespan. PMID- 29384241 TI - Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux. AB - Hematophagous organisms undergo remarkable metabolic changes during the blood digestion process, increasing fermentative glucose metabolism, and reducing respiratory rates, both consequence of functional mitochondrial remodeling. Here, we review the pathways involved in energy metabolism and mitochondrial functionality in a comparative framework across different hematophagous species, and consider how these processes regulate redox homeostasis during blood digestion. The trend across distinct species indicate that a switch in energy metabolism might represent an important defensive mechanism to avoid the potential harmful interaction of oxidants generated from aerobic energy metabolism with products derived from blood digestion. Indeed, in insect vectors, blood feeding transiently reduces respiratory rates and oxidant production, irrespective of tissue and insect model. On the other hand, a different scenario is observed in several unrelated parasite species when exposed to blood digestion products, as respiratory rates reduce and mitochondrial oxidant production increase. The emerging picture indicates that re-wiring of energy metabolism, through reduced mitochondrial function, culminates in improved tolerance to redox insults and seems to represent a key step for hematophagous organisms to cope with the overwhelming and potentially toxic blood meal. PMID- 29384242 TI - Circulating molecules that control brown/beige adipocyte differentiation and thermogenic capacity. AB - Obesity may be counteracted by increased energy expenditure. Circulating molecules act in the adipose tissue to influence brown and beige adipocyte function, differentiation, and thermogenic capacity, which in turn affects substrate utilization and impacts energy balance at the organismal level. These molecules have been envisioned as biomarkers and potential candidates for pharmacological interventions to treat obesity. Here we summarize studies that demonstrate the roles of endogenous circulating molecules of a wide variety in regulating the thermogenic potential of brown and beige fat cells. This review describes the state-of-the-art in the field and helps researchers to prioritize their targets in future studies. PMID- 29384243 TI - Ambulatory blood pressure in the dash diet trial: Effects of race and albuminuria. AB - We evaluated whether low-grade albuminuria or black race modulates ambulatory blood pressure (BP) or nocturnal BP response to the DASH diet. Among 202 adults enrolled in the DASH multicenter trial who were fed the DASH or control diet for 8 weeks, reductions in 24-hour daytime and nighttime SBP and DBP were significantly larger for DASH compared to control. Median changes in nocturnal BP dipping were not significant. Compared to urine albumin excretion of <7 mg/d, >=7 mg/d was associated with larger significant median reductions in 24-hour SBP ( 7.3 vs -3.1 mm Hg), all measures of DBP (24-hour: -5.9 vs -1.8 mm Hg; daytime: 9.9 vs -4.0 mm Hg; nighttime -9.0 vs -2.0 mm Hg), and with increased nocturnal SBP dipping (2.3% vs -0.5%). Black race was associated with larger median reduction in 24-hour SBP only (-5.5 vs -2.4 mm Hg). This analysis suggests greater effect of DASH on ambulatory BP in the presence of low-grade albuminuria. PMID- 29384244 TI - Rapid and dynamic arginylation of the leading edge beta-actin is required for cell migration. AB - beta-actin plays key roles in cell migration. Our previous work demonstrated that beta-actin in migratory non-muscle cells is N-terminally arginylated and that this arginylation is required for normal lamellipodia extension. Here, we examined the function of beta-actin arginylation in cell migration. We found that arginylated beta-actin is concentrated at the leading edge of lamellipodia and that this enrichment is abolished after serum starvation as well as in contact inhibited cells in confluent cultures, suggesting that arginylated beta-actin at the cell leading edge is coupled to active migration. Arginylated actin levels exhibit dynamic changes in response to cell stimuli, lowered after serum starvation and dramatically elevating within minutes after cell stimulation by readdition of serum or lysophosphatidic acid. These dynamic changes require active translation and are not seen in confluent contact-inhibited cell cultures. Microinjection of arginylated actin antibodies into cells severely and specifically inhibits their migration rates. Together, these data strongly suggest that arginylation of beta-actin is a tightly regulated dynamic process that occurs at the leading edge of locomoting cells in response to stimuli and is integral to the signaling network that regulates cell migration. PMID- 29384245 TI - Isolation of a Cationic Platinum(II) sigma-Silane Complex. AB - The platinum complex [Pt(It Bui Pr')(It Bui Pr)][BArF ] interacts with tertiary silanes to form stable (<0 degrees C) mononuclear PtII sigma-SiH complexes [Pt(It Bui Pr')(It Bui Pr)(eta1 -HSiR3 )][BArF ]. These compounds have been fully characterized, including X-ray diffraction methods, as the first examples for platinum. DFT calculations (including electronic topological analysis) support the interpretation of the coordination as an unusual eta1 -SiH. However, the energies required for achieving a eta2 -SiH mode are rather low, and is consistent with the propensity of these derivatives to undergo Si-H cleavage leading to the more stable silyl species [Pt(SiR3 )(It Bui Pr)2 ][BArF ] at room temperature. PMID- 29384246 TI - Kinetic Resolution of sec-Thiols by Enantioselective Oxidation with Rationally Engineered 5-(Hydroxymethyl)furfural Oxidase. AB - Various flavoprotein oxidases were recently shown to oxidize primary thiols. Herein, this reactivity is extended to sec-thiols by using structure-guided engineering of 5-(hydroxymethyl)furfural oxidase (HMFO). The variants obtained were employed for the oxidative kinetic resolution of racemic sec-thiols, thus yielding the corresponding thioketones and nonreacted R-configured thiols with excellent enantioselectivities (E>=200). The engineering strategy applied went beyond the classic approach of replacing bulky amino acid residues with smaller ones, as the active site was additionally enlarged by a newly introduced Thr residue. This residue established a hydrogen-bonding interaction with the substrates, as verified in the crystal structure of the variant. These strategies unlocked HMFO variants for the enantioselective oxidation of a range of sec thiols. PMID- 29384247 TI - Effect of oral exposure to the acaricide pirimicarb, a new varroacide candidate, on Apis mellifera feeding rate. AB - BACKGROUND: The ectoparasitic honey bee mite Varroa destructor is a main cause of the gradual decline in honey bees Apis mellifera. Beekeepers currently utilize a wide range of different synthetic acaricides, organic acids and essential oils to keep mite populations under control. Previous work has indicated that pirimicarb may be a new varroacide candidate. The aim of this study was to observe chronic effects on feeding activity in worker honey bees after oral exposure to 1.05 mm pirimicarb. The long-term effects of 24 h exposure to pirimicarb were also tested. RESULTS: After three successive trials, no mortality could be detected at the tested concentration, although oral exposure to pirimicarb had a significant effect on honey bees feeding behavior. Pirimicarb added to a sucrose solution led to a rapid decrease in food intake. These tendencies may be reversed when the pesticide is removed. However, recovery seemed to be trial dependent. CONCLUSION: This study highlights seasonal variation in honey bee susceptibility, which should be considered in toxicology studies. (c) 2018 Society of Chemical Industry. PMID- 29384248 TI - Improving the public health impact of eHealth and mHealth interventions. PMID- 29384249 TI - A point-prevalence survey of alcohol-related presentations to Australasian emergency departments. PMID- 29384250 TI - Factors relating to high psychological distress in Indigenous Australians and their contribution to Indigenous-non-Indigenous disparities. AB - OBJECTIVE: To explore factors associated with high psychological distress among Aboriginal and non-Aboriginal Australians and their contribution to the elevated distress prevalence among Aboriginal people. METHODS: Questionnaire data from 1,631 Aboriginal and 233,405 non-Aboriginal 45 and Up Study (NSW, Australia) participants aged >=45 years were used to calculate adjusted prevalence ratios for high psychological distress (Kessler-10 score >=22) for socio-demographic, health and disability-related factors, and to quantify contributions to differences in distress prevalence. RESULTS: While high-distress prevalence was increased around three-fold in Aboriginal versus non-Aboriginal participants, distress-related risk factors were similar. Morbidity and physical disability had the strongest associations; high distress affected 43.8% of Aboriginal and 20.9% of non-Aboriginal participants with severe physical limitations and 9.5% and 3.9% of those without limitations, respectively. Differences in distress prevalence between Aboriginal and non-Aboriginal participants were essentially attributable to differences in SES, morbidity, disability/functional limitations and social support (fully-adjusted PR 1.19 [95% 1.08, 1.30]); physical morbidity and disability explained the bulk. CONCLUSIONS: The markedly elevated prevalence of high distress among older Aboriginal Australians appears largely attributable to greater physical morbidity and disability. Implications for public health: Addressing upstream determinants of physical morbidity and improved integration of social and emotional wellbeing care into primary care and chronic disease management are essential. PMID- 29384251 TI - From tolerance to resistance: mechanisms governing the differential response to glyphosate in Chloris barbata. AB - BACKGROUND: Susceptibility and the mechanism (s) governing tolerance/resistance to glyphosate were characterized in two putative-glyphosate-resistant Chloris barbata populations (R1 and R2), collected in Persian lime orchards from Colima State, Mexico, comparing them with one non-treated population (referred to as S). RESULTS: Glyphosate doses required to reduce fresh weight or cause mortality by 50% were 4.2-6.4 times higher in resistant populations than in the S population. The S population accumulated 4.3 and 5.2 times more shikimate than the R2 and R1 populations, respectively. There were no differences in 14 C-glyphosate uptake between R and S populations, but the R plants translocated at least 12% less herbicide to the rest of plant and roots 96 h after treatment. Insignificant amounts of glyphosate were metabolized to aminomethyl phosphonate and glyoxylate in both R and S plants. The 5-enolpyruvylshikimate-3-phosphate synthase gene of the R populations contained the Pro106-Ser mutation, giving them a resistance 12 (R2) and 14.7 (R1) times greater at target-site level compared with the S population. CONCLUSION: The Pro106-Ser mutation governs the resistance to glyphosate of the R1 and R2 C barbata populations, but the impaired translocation could contribute to the resistance. These results confirm the first case of glyphosate resistance evolved in this species. (c) 2018 Society of Chemical Industry. PMID- 29384252 TI - New modifications of the blood pressure-to-height ratio for the diagnosis of high blood pressure in children. PMID- 29384253 TI - Differential accumulation of leucine and methionine in red and green pea aphids leads to different fecundity in response to nitrogen fertilization. AB - BACKGROUND: Nitrogen fertilization affects plants directly and herbivorous insects indirectly. Although insect species and even genotypes are known to differ in their responses to nitrogen fertilization, the physiological and molecular mechanisms remain unclear. This study assessed the fecundity and related regulatory signaling pathways in the green and red morphs of pea aphid (Acyrthosiphon pisum) feeding on Medicago truncatula with and without nitrogen fertilization. RESULTS: Nitrogen fertilization significantly increased foliar amino acid concentrations and consequently increased the concentrations of several individual essential amino acids in body tissue of the green morph. The increased concentration of Leu, Ile, Met and Val was consistent with enhanced biosynthesis of these amino acids in the endosymbiont Buchnera. Under nitrogen fertilization, Leu and Met accumulated in the green morph enhanced the target of rapamycin (TOR) signaling pathway, which consequently increased fecundity by promoting vitellogenin synthesis. In the red morph, however, nitrogen fertilization did not change the concentration of essential amino acids, TOR signaling or fecundity. CONCLUSION: Specific amino acids accumulation and the nutrient transduction pathway in pea aphids are responsible for genotype-specific fecundity in response to nitrogen fertilization, which could be used as potential target for pest control. (c) 2018 Society of Chemical Industry. PMID- 29384254 TI - Design, synthesis, fungicidal property and QSAR studies of novel beta-carbolines containing urea, benzoylthiourea and benzoylurea for the control of rice sheath blight. AB - BACKGROUND: Rice sheath blight is a globally important rice disease. Unfortunately, this critical disease has not been effectively controlled, and the intensive and continuous use of the same fungicide might increase the risk of resistance development in the pathogen. To discover new active agents against rice sheath blight, in this study, three series of beta-carboline urea, benzoylurea and benzoylthiourea derivatives were designed, synthesized and evaluated for in vitro and in vivo fungicidal activity against Rhizoctonia solani. RESULTS: All these compounds (EC50 : 0.131-1.227 mmol L-1 ) exhibited better fungicidal activity than harmine itself (EC50 : 2.453 mmol L-1 ). Significantly, compound 17c (EC50 : 0.131 mmol L-1 ) displayed the best efficacy in vitro and superior fungicidal activity compared with validamycin A (EC50 : 0.397 mmol L-1 ). Moreover, the in vivo bioassay also indicated that compound 17c could be effective for the control of rice sheath blight. CONCLUSION: Based on the bioassay result and quantitative structure-activity relationship (QSAR) information, structure modification in beta-carboline warrants further investigation and its benzoylurea derivative 17c, which showed the best fungicidal activities, could emerge as a potential fungicide against rice sheath blight. (c) 2018 Society of Chemical Industry. PMID- 29384256 TI - Isotropic/Anisotropic NMR Editing by Resolution-Enhanced NMR Spectroscopy. AB - Modern resolution-enhanced NMR techniques can monitor the in situ discrimination of co-existing isotropic and anisotropic contributions of small molecules dissolved in weakly aligning PMMA/CDCl3 media. The simultaneous sign-sensitive determination of accurate Deltadeltaiso-aniso (1 H), Deltadeltaiso-aniso (13 C) and/or isotropic 1 JCH and anisotropic 1 TCH coupling constants (and consequently 1 H-13 C residual dipolar couplings and 1 H/13 C residual chemical shift anisotropies) can be performed from spectral-aliased heteronuclear single-quantum correlation spectra. PMID- 29384255 TI - Pyridone Luciferins and Mutant Luciferases for Bioluminescence Imaging. AB - New applications for bioluminescence imaging require an expanded set of luciferase enzymes and luciferin substrates. Here, we report two novel luciferins for use in vitro and in cells. These molecules comprise regioisomeric pyridone cores that can be accessed from a common synthetic route. The analogues exhibited unique emission spectra with firefly luciferase, although photon intensities remained weak. Enhanced light outputs were achieved by using mutant luciferase enzymes. One of the luciferin-luciferase pairs produced light on par with native probes in live cells. The pyridone analogues and complementary luciferases add to a growing set of designer probes for bioluminescence imaging. PMID- 29384257 TI - How Does the Encapsulation of Porphyrinic Photosensitizers into Polymer Matrices Affect Their Self-Association and Dynamic Properties? AB - Photodynamic therapy (PDT) with porphyrinic photosensitizers largely relies on efficient drug formulations to prevent porphyrin aggregation and to enhance water solubility and stability in physiologic environments. In this study, we compare two polymeric carrier systems, polyvinylpyrrolidone (PVP) and block copolymer micelles (BCMs) formed by the poloxamer Kolliphor P188 (KP), for their encapsulation efficiencies of porphyrin (xPP) and chlorin e6 (xCE) derivatives. Monomerization, loading efficiency, and dynamic properties were examined by 1 H NMR spectroscopy chemical shift titration, DOSY, and T2 relaxation time measurements. Binding affinity was determined by UV/Vis spectroscopy. Both PVP and KP-BCMs were well suited to disaggregate and encapsulate amphiphilic xCE, whereas they were less efficient for the xPP compounds. PVP exhibited higher monomerization efficiency than KP-BCMs. Significant differences were found in the dynamic behavior of the carriers. PVP formed rather stable complexes with the porphyrinic compounds, whereas a dynamic equilibrium between free and bound porphyrins was found to exist in the presence of KP-BCMs. This may have a considerable impact on the pharmacokinetic properties of the corresponding delivery systems. PMID- 29384258 TI - Analyzing Xyloglucan Endotransglycosylases by Incorporating Synthetic Oligosaccharides into Plant Cell Walls. AB - The plant cell wall is a cellular exoskeleton consisting predominantly of a complex polysaccharide network that defines the shape of cells. During growth, this network can be loosened through the action of xyloglucan endotransglycosylases (XETs), glycoside hydrolases that "cut and paste" xyloglucan polysaccharides through a transglycosylation process. We have analyzed cohorts of XETs in different plant species to evaluate the substrate specificities of xyloglucan acceptors by using a set of synthetic oligosaccharides obtained by automated glycan assembly. The ability of XETs to incorporate the oligosaccharides into polysaccharides printed as microarrays and into stem sections of Arabidopsis thaliana, beans, and peas was assessed. We found that single xylose substitutions are sufficient for transfer, and xylosylation of the terminal glucose residue is not required by XETs, independent of plant species. To obtain information on the potential xylosylation pattern of the natural acceptor of XETs, that is, the nonreducing end of xyloglucan, we further tested the activity of xyloglucan xylosyl transferase (XXT) 2 on the synthetic xyloglucan oligosaccharides. These data shed light on inconsistencies between previous studies towards determining the acceptor substrate specificities of XETs and have important implications for further understanding plant cell wall polysaccharide synthesis and remodeling. PMID- 29384259 TI - Tuning of Thermoresponsivity of a Poly(2-alkyl-2-oxazoline) Block Copolymer by Interaction with Surface-Active and Chaotropic Metallacarborane Anion. AB - Thermoresponsive nanoparticles based on the interaction of metallacarboranes, bulky chaotropic and surface-active anions, and poly(2-alkyl-2-oxazoline) block copolymers were prepared. Recently, the great potential of metallacarboranes have been recognized in biomedicine and many delivery nanosystems have been proposed. However, none of them are thermoresponsive. Therefore, a thermoresponsive block copolymer, poly(2-methyl-2-oxazoline)-block-poly(2-n-propyl-2-oxazoline) (PMeOx PPrOx), was synthesized to encapsulate metallacarboranes. Light scattering, NMR spectroscopy, isothermal titration calorimetry, and cryogenic TEM were used to characterize all solutions of the formed nanoparticles. The cloud-point temperature (TCP ) of the block copolymer was observed at 30 degrees C and polymeric micelles formed above this temperature. Cobalt bis(dicarbollide) anion (COSAN) interacts with both polymeric segments. Depending on the COSAN concentration, this affinity influenced the phase transition of the thermoresponsive PPrOx block. The TCP shifted to lower values at a lower COSAN content. At higher COSAN concentrations, the hybrid nanoparticles are fragmented into relatively small pieces. This system is also thermoresponsive, whereby an increase in temperature leads to higher polymer mobility and COSAN release. PMID- 29384260 TI - Decoupling Hydrogen and Oxygen Production in Acidic Water Electrolysis Using a Polytriphenylamine-Based Battery Electrode. AB - Hydrogen production through water splitting is considered a promising approach for solar energy harvesting. However, the variable and intermittent nature of solar energy and the co-production of H2 and O2 significantly reduce the flexibility of this approach, increasing the costs of its use in practical applications. Herein, using the reversible n-type doping/de-doping reaction of the solid-state polytriphenylamine-based battery electrode, we decouple the H2 and O2 production in acid water electrolysis. In this architecture, the H2 and O2 production occur at different times, which eliminates the issue of gas mixing and adapts to the variable and intermittent nature of solar energy, facilitating the conversion of solar energy to hydrogen (STH). Furthermore, for the first time, we demonstrate a membrane-free solar water splitting through commercial photovoltaics and the decoupled acid water electrolysis, which potentially paves the way for a new approach for solar water splitting. PMID- 29384261 TI - The status of dermoscopy in Germany - results of the cross-sectional Pan-Euro Dermoscopy Study. AB - BACKGROUND: Survey on the current status of dermoscopy in Germany. METHODS: In the context of a pan-European internet-based study (n = 7,480) conducted by the International Dermoscopy Society, 880 German dermatologists were asked to answer questions with respect to their level of training as well as their use and perceived benefit of dermoscopy. RESULTS: Seven hundred and sixty-two (86.6 %) participants practiced dermatology in a publicly funded health care setting; 98.4 % used a dermoscope in routine clinical practice. About 93 % (n = 814) stated to have had more than five years of experience in the use of dermoscopy. Dermoscopy was considered useful in the diagnosis of melanoma by 93.6 % (n = 824); for pigmented skin tumors, by 92.4 % (n = 813); in the follow-up of melanocytic lesions, by 88.6 % (n = 780); for non-pigmented lesions, by 71.4 % (n = 628), in the follow-up of non-melanocytic lesions, by 52.7 % (n = 464); and for inflammatory skin lesions, by 28.5 % (n = 251). Overall, 86.5 % (n = 761) of participants felt that - compared to naked-eye examination - dermoscopy increased the number of melanomas diagnosed; 77,7 % (n = 684) considered the number of unnecessary excisions of benign lesions to be decreased. Participants who personally felt that dermoscopy improved their ability to diagnose melanoma were significantly i) younger, ii) had been practicing dermatology for a shorter period of time, iii) were less commonly employed by an university-affiliated dermatology department, iv) were more frequently working in an office-based public health care setting, and v) had more frequently been trained in dermoscopy during their dermatology residency. CONCLUSIONS: The findings presented herein ought to be integrated into future residency and continuing medical education programs with the challenge to improve dermato-oncological care and to expand the diagnostic spectrum of dermoscopy to include inflammatory skin diseases. PMID- 29384262 TI - A novel frameshift mutation in the MPL gene in congenital amegakaryocytic thrombocytopenia. PMID- 29384263 TI - Possible involvement of IL-6-producing tissue-resident macrophages in early-onset pericardial effusion pathogenesis after hematopoietic stem cell transplantation. AB - PURPOSE: Pericardial effusion (PE) is a potentially life-threatening complication following hematopoietic stem cell transplantation (HCT). A higher incidence of early-onset PE, unrelated to graft-versus-host disease, before day 100 after HCT has been reported in pediatric patients, but the pathogenic mechanism is poorly understood. Aiming to determine the pathogenesis of early-onset PE in pediatric patients, we analyzed the cytokine concentration and cell population in the pericardial fluid of four pediatric patients with PE. METHODS: Between January 2009 and December 2015, four patients requiring pericardiocentesis for clinically significant PE were identified in 60 patients. We evaluated the interleukin-6 (IL 6), interferon-gamma, IL-1beta, and tumor necrosis factor-alpha levels in PE. Two patients were available for analysis with intracellular cytokine flow cytometry and a chimerism assay. RESULTS: All patients showed the accumulation of pericardial macrophages and high concentrations of IL-6 in PE. Notably, the accumulated pericardial macrophages were CD163+ CD15+ CD14+ cells of host origin that produced IL-6. CONCLUSION: These IL-6-producing tissue-resident macrophages may be key players in the pathogenesis of early-onset PE. PMID- 29384264 TI - The ASPHO 2018 Distinguished Career Award goes to Dr. Michael P. Link. PMID- 29384265 TI - Development of the "Day 100 Talk": Addressing existing communication gaps during the early cancer treatment period in childhood cancer. AB - BACKGROUND: Families' communication needs during the early cancer treatment period (ECTP) may not be optimally met by current practices. We sought to identify potential communication gaps and to ameliorate these by developing a novel in-depth conversation between families and their pediatric oncologists, the "Day 100 Talk" (D100), during the ECTP. PROCEDURE: We conducted semistructured interviews with parents and patients undergoing childhood cancer treatment for < 7 months. Interviews sought to elicit perceived communication gaps regarding cancer care and inform D100 development. Following qualitative analysis of interview responses, we developed a three-part D100 conversation tool consisting of a preparatory family worksheet, a conversation guide, and a family summary sheet. We presented the tool during interviews and a focus group with pediatric oncology providers and revised it to incorporate provider input. RESULTS: Twenty two stakeholders (six parents, five adolescents, and 11 providers) participated in interviews or a focus group. Parents and patients perceived insufficient anticipatory guidance as the most important communication gap. They also reported sometimes withholding worries and cancer-related beliefs. Meanwhile, oncology providers worried about "opening Pandora's Box" and limited clinical time. Additionally, providers reported employing indirect methods such as surmising to determine families' needs and relying on psychosocial clinicians to engage families around potentially "taboo" issues of emotional coping and spirituality. CONCLUSION: Creating a communication occasion (D100), ensuring complementary disciplinary expertise through joint participation by oncologists and psychosocial clinicians, and providing a conversation tool to prompt disclosure by families and facilitate anticipatory guidance may ameliorate existing communication gaps during the ECTP. PMID- 29384266 TI - Pazopanib therapy for desmoid tumors in adolescent and young adult patients. AB - BACKGROUND: Desmoid tumors/aggressive fibromatosis (DT/AF) lack a reliably effective medical therapy. Surgical resection may be morbid and does not preclude recurrence. Radiation may carry severe late effects, particularly detrimental in young patients. At our institution, we recently observed promising results with pazopanib therapy for DT/AF in adolescent and young adult (AYA) patients. PROCEDURE: Retrospective single-institution chart review. RESULTS: Six DT/AF patients of 3-21 years with previously treated DT/AF received pazopanib; 31 DT/AF patients received established therapies only. In both groups, median age at diagnosis was 16 years, female patients comprised 50%, and most common DT/AF site was extremity. Established therapies showed few objective responses and most patients therefore received multiple therapies. Surgical resection had a 68% recurrence rate. Of eight patients who received vinblastine/methotrexate, only one had a partial response (PR) by RECIST 1.1 and five had stable disease (SD); 62.5% required additional therapy. Of seven patients who received sulindac/tamoxifen, none showed objective improvement. In contrast, pazopanib demonstrated best responses by RECIST of PR in two of seven and SD in six of seven tumors. A PR of 66% was observed in a patient who had failed multiple prior therapies. The mesenteric DT/AF also showed PR. Maximum volumetric decrease by T2 weighted magnetic resonance imaging (MRI) was 97%. Dramatically increased fibrosis was seen on T2-weighted MRI. Patients reported pain relief and improvement in function within 1 month. Except for one case of edema, all other toxicities responded to dose reduction without sacrificing objective treatment response. CONCLUSION: Pazopanib provides a promising, well-tolerated therapy for DT/AF in the AYA population and warrants further study. PMID- 29384267 TI - A cool response-The influence of ambient temperature on capillary refill time. AB - OBJECTIVE: To describe the effect of low ambient temperature on skin temperature and capillary refill (CR) time in forehead, sternum and finger pulp. METHODS: An observational, nonrandomized experimental study on 15 healthy subjects (6 females) in a cold room (8 degrees C). Outcome measures were skin temperature and quantified CR test after application of a standardized blanching pressure (9 N/cm2 ) using digital photographic polarization spectroscopy to generate CR times. RESULTS: The finger pulp showed marked temperature fall and prolonged CR times (>10 seconds). The CR registrations of the forehead and sternum were more comparable to curves observed in a control material at room temperature, and skin temperature falls were less marked. CR times were not prolonged in forehead measurements. At the sternum, some individuals showed CR times beyond guideline recommendations despite only a marginal reduction in skin temperature. CONCLUSIONS: Low ambient temperature is a strong independent factor for CR time at peripheral sites. Reservation about sternum as a site of measurement is warranted since cold provocation produced prolonged CR times in some individuals. We found that the forehead is the most thermostable of the 3 sites and thus the preferred site to avoid ambient temperature artifact in measuring CR time. PMID- 29384269 TI - 17th Chromosome-Centric Human Proteome Project Symposium in Tehran. AB - This report describes the 17th Chromosome-Centric Human Proteome Project which was held in Tehran, Iran, April 27 and 28, 2017. A brief summary of the symposium's talks including new technical and computational approaches for the identification of novel proteins from non-coding genomic regions, physicochemical and biological causes of missing proteins, and the close interactions between Chromosome- and Biology/Disease-driven Human Proteome Project are presented. A synopsis of decisions made on the prospective programs to maintain collaborative works, share resources and information, and establishment of a newly organized working group, the task force for missing protein analysis are discussed. PMID- 29384268 TI - Dating phototrophic microbial lineages with reticulate gene histories. AB - Phototrophic bacteria are among the most biogeochemically significant organisms on Earth and are physiologically related through the use of reaction centers to collect photons for energy metabolism. However, the major phototrophic lineages are not closely related to one another in bacterial phylogeny, and the origins of their respective photosynthetic machinery remain obscured by time and low sequence similarity. To better understand the co-evolution of Cyanobacteria and other ancient anoxygenic phototrophic lineages with respect to geologic time, we designed and implemented a variety of molecular clocks that use horizontal gene transfer (HGT) as additional, relative constraints. These HGT constraints improve the precision of phototroph divergence date estimates and indicate that stem green non-sulfur bacteria are likely the oldest phototrophic lineage. Concurrently, crown Cyanobacteria age estimates ranged from 2.2 Ga to 2.7 Ga, with stem Cyanobacteria diverging ~2.8 Ga. These estimates provide a several hundred Ma window for oxygenic photosynthesis to evolve prior to the Great Oxidation Event (GOE) ~2.3 Ga. In all models, crown green sulfur bacteria diversify after the loss of the banded iron formations from the sedimentary record (~1.8 Ga) and may indicate the expansion of the lineage into a new ecological niche following the GOE. Our date estimates also provide a timeline to investigate the temporal feasibility of different photosystem HGT events between phototrophic lineages. Using this approach, we infer that stem Cyanobacteria are unlikely to be the recipient of an HGT of photosystem I proteins from green sulfur bacteria but could still have been either the HGT donor or the recipient of photosystem II proteins with green non-sulfur bacteria, prior to the GOE. Together, these results indicate that HGT-constrained molecular clocks are useful tools for the evaluation of various geological and evolutionary hypotheses, using the evolutionary histories of both genes and organismal lineages. PMID- 29384271 TI - Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review. PMID- 29384270 TI - Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8. AB - Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 -/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 -/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice. PMID- 29384272 TI - ? PMID- 29384273 TI - [Ultrasound in the emergency department as an extension of the practitioner's clinical examination]. AB - Ultrasound in the emergency department and general practice can be used as an extension of the physical examination, answering simple questions. It requires a short basic training that is easily accessible. This article illustrates with a few examples (kidney, lung and fractures) the interest of this formidable tool becoming unavoidable in the emergency department and general practice. PMID- 29384274 TI - [Understanding renal functional reserve]. AB - Renal function is usually estimated through the blood measurement of creatinine, which allows estimating the glomerular filtration rate (GFR). However, this value only decreases when half the nephrons are damaged, limiting the detection of early renal disease. The ingestion of an important amount of protein can increase the GFR. The renal functional reserve concept is the difference between the maximal GFR, stimulated by an important protein intake, and the baseline GFR. A diminished renal functional reserve could mean glomerular hyperfiltration and early renal disease. This value could help predicting patients more likely to present with acute renal injury and evaluating the capacity of the kidney to increase their function before a nephrectomy. PMID- 29384275 TI - [Femoral hernia in geriatric patient]. AB - When facing an elderly patient with cognitive impairment and unspecific digestive symptoms, the physical examination should include the research of a groin hernia. Additional radiological exam may be required to confirm the diagnosis. Femoral hernia is a diagnostic pitfall, as clinical signs are not always obvious. It occurs late in life and is often found to be already complicated when the patient seeks attention. While the elective surgical treatment is simple, it needs an emergency surgical repair when it is incarcerated that is often associated with intestinal resection and post-operative complications including death. PMID- 29384276 TI - [Long-term non-invasive ventilation in chronic obstructive pulmonary disease patients]. AB - Non-invasive ventilation (NIV) is recognized as first line therapy in acute hypercapnic respiratory failure and chronic alveolar hypoventilation caused by several diseases (restrictive thoracic disorders, neuromuscular disease and obesity-hypoventilation syndrome). In Switzerland and other European countries, long-term NIV has also been applied in hypercapnic patients with chronic obstructive pulmonary disease (COPD). However, only recently has conclusive evidence showing benefits of long-term NIV become available. Long-term NIV in COPD has now shown its efficacy in many studies. However, despite these findings, indications, ventilatory settings and monitoring remain poorly known and topic of debate. PMID- 29384277 TI - [VIPoma : a rare etiology of diarrhea with hypokalemia]. AB - VIPoma or Verner Morrison syndrome is a very rare disease with an incidence rate of 1 case per 10 000 000 person-years. It is a neuroendocrine tumor issue from beta-pancreatic islets leading to profuse diarrhea, hypokalemia and gastric achlorydria due to secretion of vasoactive intestinal polypeptide (VIP) hormone. Diagnosis is based on histology of tumor and the dosage of VIP in a blood sample. Somatostatin analog is a simple and efficient treatment for diarrhea. Curative treatment with surgery could be proposed for a localized disease. For disseminated disease, there are different treatments and a multimodal assessment that should be discussed in a multidisciplinary team might be curative. PMID- 29384278 TI - [Fever in a returning traveler from Tuscany]. AB - Arbovirus infections are emerging pathogens leading sometimes to severe disease. This virus is transmitted by sandflies in the Mediterranean countries during the summer season. The disease is often asymptomatic but can also cause an influenza like illness and aseptic meningitis or encephalitis. The treatment is supportive and preventive measures should be taken in order to avoid an infection when travelling to the affected areas. The differential diagnosis of fever in the returning traveler from southern European countries should include Toscana virus. PMID- 29384279 TI - [Boerhaave syndrome: update on physiopathology, diagnosis and early management]. AB - Boerhaave syndrome is a rare condition, usually associated with a delay in diagnosis. It is fatal in the absence of therapy. The nonspecific nature of the clinical signs contributes to the poor outcome. This syndrome should be suspected in patients with severe chest or abdominal pain, associated with a history of vomiting, clinical signs of pneumomediastinum (subcutaneous emphysema, pleural effusion) and rapid clinical deterioration. Prompt diagnosis and initial management by the primary care physician and the emergency department physician are key elements of a better outcome. This article will review the pathogenesis, clinical manifestations, diagnosis and treatment of Boerhaave syndrome in adults. PMID- 29384280 TI - ? PMID- 29384281 TI - ? PMID- 29384282 TI - ? PMID- 29384283 TI - ? PMID- 29384284 TI - ? PMID- 29384285 TI - ? PMID- 29384286 TI - ? PMID- 29384287 TI - ? PMID- 29384288 TI - Role of central venous pressure monitoring in critical care settings. AB - Central venous pressure (CVP) monitoring is used to assess the fluid status of patients in critical care settings. This article explains CVP monitoring, discussing the rationale for its use, the ways CVP can be measured, and the physiological factors that can affect the reliability and validity of CVP measurement. It also discusses the complications associated with CVP monitoring and the nursing responsibilities in relation to this activity. PMID- 29384289 TI - Principles and nursing management of anticoagulation. AB - Anticoagulant drugs are widely used in hospital and community settings. Anticoagulation is the first-line treatment for venous thromboembolism, and anticoagulant drugs have an important role in the treatment and prevention of blood clots. However, maintaining the equilibrium between clotting and bleeding can be challenging and anticoagulants have been identified as a class of drug associated with preventable patient harm. Direct oral anticoagulants (DOACs) have become the first-line treatment for many patients requiring an anticoagulant, removing the burden of frequent tests and the many food and drug interactions associated with vitamin K antagonists such as warfarin sodium. However, DOACs have increased the complexity of decision-making regarding treatment, which also increases the risk of drug errors. This article discusses the uses, modes of action and potential side effects of anticoagulants, to improve nurses' understanding and enable them to have an active role in limiting the risk of harm from these drugs. PMID- 29384290 TI - [Novelties in the Treatment of Colorectal Diseases - An Echo from the 10-th ESCP Congress]. AB - Treatment of colorectal pathology stands continuous development. One of the promotional leaders of the new therapeutic approaches is the European Society of Coloproctology (ESCP). The annual congress of the organization held in Dublin, Ireland and it unites the elite of European Community countries. The most advanced scientific knowledge of the diseases of the colon and rectum, anal canal and perineum was presented. PMID- 29384291 TI - ? PMID- 29384292 TI - ? PMID- 29384293 TI - ? PMID- 29384294 TI - ? PMID- 29384295 TI - [Evaluation of the perception of postpartum stressors at the Marseille Gynepole]. AB - INTRODUCTION: Maternity stay following childbirth corresponds to the early postpartum period. Birth-related events may be perceived as a major source of stress by women and these events can cause certain disorders during this period, such as anxiety and postnatal depression. The aim of this study was to investigate women's perception of post-delivery stress factors. METHODS: An overall descriptive study of the target population (n = 206) was carried out and primiparous (n = 96) and multiparous (n = 110) women were then compared in two level III public maternity units in the Marseille Gynepole. The Post-Delivery Perceived Stress Inventory (PDPSI) was the psychometric scale used to collect data. A correlation between the various items of the PDPSI was investigated. RESULTS: The experience of childbirth is perceived as the main stress factor by 45% of mothers. This factor was significantly correlated (p < 0.05) with 3 items of the PDPSI and very significantly correlated (p < 0.001) with 11 of the 16 items constituting the other 4 factors of the PDPSI. Primiparous women significantly perceived (p < 0.05) childbirth as being more stressful than multiparous women. They also felt very significantly (p < 0.001) more stressed by care activities (bathing, changing) related to the relationship with the newborn factor. CONCLUSION: These results encourage implementation of guidelines and the organization of informal ?conversations? in the maternity unit, and to conduct an early postnatal consultation at home for these mothers concerning their childbirth experience, which could be ensured by adequate social support based on empathic listening and reassuring actions about parenting. PMID- 29384296 TI - [Design an educational intervention to prevent falls of older people in social housing: description of a research method]. AB - INTRODUCTION: In a social environment in which prevention of falls in older people has become a public health issue, adaptation of housing for older people is particularly important. Based on the home-identity concept, the objective of this research was to design an educational model specifically adapted to the context of a Social Housing Company (SHC), focussing on elderly tenants who have experienced a fall in order to allow them to adapt their lodgings and avoid subsequent falls. METHOD: This article describes design-based research (DBR), which enabled the research committee (composed of professionals, tenants, and researchers) to construct the educational intervention based on analysis of the SHC context. RESULTS: The creation of a common approach within the research committee and the production of design-linked intentions enabled the creation of a formal intervention composed of four educational sessions, involving a private occupational therapist, an SHC social worker and a caretaker. DISCUSSION: The use of DBR can be justified by the research goal, i.e. validation of an educational model (based on the theoretical home-identity model) that can be transposed to a SHC. As this research is still underway, its quality criteria will only be partially described and will be completed by field experimentation. CONCLUSION: This exploratory study could eventually result in interventional research designed to assess this model in a multifactorial therapeutic patient education programme for older people at high risk of falls (e.g.: Personnes Agees En Risque de Perte d'Autonomie device). PMID- 29384297 TI - [An illustrated guide to dental screening: a school survey]. AB - AIM: Marked social inequalities in oral health are observed right from early childhood. A mandatory complete health check-up, including dental screening, is organized at school for 6-year-old children. School healthcare professionals are not well trained in dental health. The aim of this study was to assess the relevance of an illustrated guide as a simple and rapid dental screening training tool in order to ensure effective, standardized and reproducible screening. METHODS: A cross-sectional study was conducted in the context of the dental examination performed as part of the health check-up. Two examiners (Doctor E1 and Nurse E2) were trained in dental screening by means of the illustrated guide. This reference guide, comprising pictures and legends, presents the main oral pathology observed in children. RESULTS: 109 consent forms for oral screening were delivered, and 102 children agreed to participate (93.57%). The sensitivity of detection of tooth decay by examiners E1 and E2 was 81.48% with a specificity of 96%. No correlation was observed between the child's age (+/- 6 years) and correct detection rates. CONCLUSIONS: The illustrated guide is an appropriate and rapid tool for dental screening that can improve the quality of dental check-up and increase the number of children detected. PMID- 29384298 TI - [Strengthening Families Program: key points for the French adaptation]. AB - OBJECTIVE: The Strengthening Families Program (SFP) is an American evidence-based family skills training intervention, developed in 35 countries around the world.The aim of this study was to identify potential key-points to ensure successful implantation of SFP in France. METHODS: SFP was implemented in three cities of Alpes Maritimes to test acceptability and feasibility, and to identify an efficient implementation protocol. Each step was accompanied by necessary adaptations. The trial was completed by assessment of immediate efficacy. RESULTS: SFP was tested with four groups of families, providing positive results in terms of family retention rate and immediate efficacy.Cultural adaptation of the programme identified the need for a local partnership, information and training in order to support implementation of SFP. CONCLUSION: This very positive experience shows that it is possible to use successfully standardized programmes in France. This adaptation must now be validated by a larger scale study. PMID- 29384299 TI - [Interventions to support the return-to-work process after cancer: a literature review]. AB - : Returning to work after cancer can be challenging for cancer survivors and little is known about interventions designed to support survivors returning to work. PURPOSE: The objective of this review was to identify interventions designed to support the return-to-work process after a cancer diagnosis. METHODS: A literature review was performed mainly done by consulting bibliographical databases. Systematic analysis and interpretation of the results were then performed. RESULTS: Twenty-two articles were identified. The first finding is that very few interventions are specifically devoted to return to work after cancer and are usually administered in the clinical setting by healthcare practitioners. The activities proposed to support return to work in these interventions are individual counselling, provision of information and support groups. These activities are provided by various multidisciplinary teams composed of one or more professionals: occupational physicians, social workers and nurses. A second finding is that even with the use of experimental and quasi-experimental approaches, no effect was observed on return to work. CONCLUSION: This integrative review highlights two recommendations for the development of future interventions. First, to improve the efficacy of future interventions on return to work of cancer survivors, these interventions must be developed and supported by an intervention theory. Second, future interventions must include and mobilize workplaces. PMID- 29384300 TI - [Care pathway of children managed by the Bouches-du-Rhone Child Welfare Services]. AB - AIM: To describe the care pathway of children managed by the Bouches-du-Rhone Child Welfare Services and to propose ways to improve this care pathway. METHODS: ESSPER-ASE 13 survey is a descriptive and cross-sectional survey carried out between April 2013 and April 2014, which included 1,092 children under the age of 18 years placed in a Bouches-du-Rhone Child Welfare Services children's home or foster care. This survey studied the physical and mental health and the medical follow-up characteristics of these children. This article focuses on care pathway data. RESULTS: 82% of children were followed by general practitioners, while 15% of children, essentially children under the age of 6 years in child care, were followed by Maternal and Infant Protection (Protection Maternelle et Infantile). The care pathway of these children involved multiple actors and was dominated by psychological follow-up. On average, the children were followed by 2 professionals (specialist or paramedical professional) in addition to the medical examiner. In terms of prevention, children's immunization coverage rates were better than national rates. CONCLUSION: Coordination of the numerous actors is essential, including the creation of a referring physician. PMID- 29384301 TI - [Dental care for disabled people]. AB - CONTEXT: Patients with disabilities represent a population with special needs whose dental care management constitutes a public health problem. This article describes dental care of disabled people in a hospital dental care unit to highlight the difficulties encountered and propose ways to improve this care. METHODS: A retrospective descriptive study was carried out on patients followed between 2010 and 2016 as part of the partnership between the Albert Chenevier Hospital odontology department and the RHAPSOD'IF network. The data collected by means of ?follow-up sheets? described the procedures performed and any medication used. These anonymised records were analysed by Excel software. RESULTS: Dental care sessions for the 434 disabled persons consisted of visits (42 to 57%), restorations and scalings each represented 1/6 of all procedures performed (14 to 19% and 14 to 18%), and surgery and radiography each represented 1/8 of procedures (4 to 12% and 6 to 11%). There were almost no dental prostheses (0 to 1%). Most dental care sessions were performed without premedication (61 to 76%). CONCLUSION: This type of dental care requires training of families and caregivers, a good interpersonal approach and time to build a relationship of trust. Participation in a network is important to help, support, and advise the practitioner and to provide financial support. PMID- 29384302 TI - [Safety culture in Tunisian primary health care: A multicenter study]. AB - AIMS: To assess safety culture in primary healthcare centres and to explore its associated factors. METHODS: This multicentre cross-sectional descriptive study was conducted in the 30 primary healthcare centres in central Tunisia and used the validated French version of the Hospital Survey on Patient Safety Culture questionnaire' (HSOPSC). RESULTS: A total of 214 professionals participated, corresponding to a response rate of 85%. The ?Teamwork within centres? dimension had the highest score (71.5%). However, two safety dimensions had very low scores: ?Frequency of event reporting?, ?Non-punitive response to errors? with percentages of 31.4% and 35.4%, respectively. Among the associated factors, the ?Frequency of reported events? dimension was significantly higher among professionals involved in risk management committees (p = 0.01). CONCLUSION: This study demonstrates that the level of safety culture needs to be improved in primary healthcare centres in Tunisia and also highlights the need to implement a quality management system in primary healthcare centres. PMID- 29384303 TI - [Overlapping, interdependence or complementarity, interprofessional collaboration between nurse practitioners and other health professionals in Ontario]. AB - OBJECTIVE: The Naylor Report (2015) states that nurse practitioners (NP) are still underutilized in Canada despite positive evidence of their work and the benefits they provide to health systems and, more generally, the health of the population. METHODS: Why are nurse practitioners not more actively involved in the Canadian health care system? A socio-historical literature review showed that there is overlap, interdependence or complementarity between the role of NPs and that of other health professionals and that this concerns their status, training as well as the scope of their practice. The development of an interprofessional collaborative approach, although supported by most professional nursing associations in Canada, is difficult to establish in NP practice and training. RESULTS: This article describes the emergence of the role of NPs in Canada and provides an update on the current status of their integration in the health system with reference to the Ontario example. It provides insight into the overlap and zones of complementarity or interdependence between NPs and other health professionals. CONCLUSION: In conclusion, the authors call for improved governance by the contribution of a new collaborative contract with other health professionals. This contract should be based on the interdependence of practices and the complementarity of roles between all health professionals including NPs. PMID- 29384304 TI - [Role of functional rehabilitation in preventive and interceptive orthodontic management]. AB - Orofacial dysfunction and parafunctions are responsible for many orthodontic abnormalities right from the stage of deciduous teeth.Incisor malocclusion, dental malposition and alveolar arch malformations are the most common abnormalities.Functional rehabilitation for prevention or as part of interceptive orthodontics significantly reduces the risk of appearance or progression of these abnormalities to more extensive malocclusions that are more difficult to manage.Functional rehabilitation consists of re-educating and restoring physiological orofacial functions, such as speech and swallowing, breathing and/or chewing disorders. PMID- 29384305 TI - [Abortion practices in high school students in Yamoussoukro, Cote d'Ivoire]. AB - INTRODUCTION: Induced abortion is illegal in Cote d'Ivoire, except when the mother's life is in danger. The primary objective of this study was to describe abortion practices among Yamoussoukro high school students. More specifically, this study estimated the prevalence of induced abortion, described the pathway and the methods used for abortion and determined any abortion-related complications. MATERIAL AND METHODS: This cross-sectional study was conducted in July 2011 on 312 randomly selected girls attending the Lycee Jeunes Filles in Yamoussoukro. RESULTS: These girls had a mean age (SD) of 16.1 (4.7) years; 258 (82.7%) of them had already had sexual intercourse and 81 (31.4%) had already been pregnant. Fifty (61.7% [56.3-67.1%]) of these 81 girls had already had an abortion. The abortion pathway was as follows: the main method was self prescribed medication (70%) as first attempt, followed, in case of failure, by traditional healers (56.4%). Healthcare practitioners were usually consulted at the third attempt (85.7%). The most commonly used methods of abortion were drugs (91.9%), ingestion of plants/beverages (68.5%) and introduction of devices into the uterine cavity (62.3%). Twenty-two (44%) out of 50 induced abortions resulted in complications, mostly infectious complications (81.8%), and bleeding (68.2%). Complications were significantly associated with self-induced abortions or abortions performed by traditional healers (p < 0.001). CONCLUSION: More intensive sexual education, access to modern methods of contraception, awareness campaigns concerning the risks related to unwanted pregnancies and abortions performed by non-medical personnel need to be implemented to prevent school abortions. The quality and accessibility of post-abortion services also need to be reinforced. PMID- 29384306 TI - [Understanding failure of obstetric referral to the Cotonou University gynaecology and obstetrics clinic]. AB - INTRODUCTION: Since 2000, in the context of the Millennium development goals, Benin has reinforced its obstetric referral system in order to reduce maternal mortality. However, structural, sociocultural and economic problems continue to affect this strategy. The Cotonou University gynaecology and obstetrics clinic (CUGO), at the top of the health pyramid, is emblematic of this situation. This study was designed to elucidate the stakes involved in referral to this hospital based on analysis of the perceptions and experiences of referral personnel. METHODS: Essentially qualitative data collection was conducted by means of in depth semi-structured interviews from July to December 2015 involving 37 people, including referred women, healthcare personnel and caregivers. RESULTS: The poor quality of information given to women concerning the reasons for referral, the fear of caesarean section, considered to be inevitable, and the difficult relationships with health workers contribute to failure to comply with referral. Rumours concerning reception, waiting times and hospitalization conditions are other factors that must be taken into account. Finally, the distance from the woman's home is a decisive element in acceptance of referral by women and their families. CONCLUSION: Referral is generally perceived as necessary in the case of complications during pregnancy, by both referred women and healthcare personnel. However, differences in points of view are observed when the woman is referred to CUGO. PMID- 29384307 TI - [Analysis of interventions designed to improve clinical supervision of student nurses in Benin]. AB - INTRODUCTION: The absence of an explicit and coherent conception of the articulation between theory and practice in the reform of nursing training in Benin has resulted in poor quality clinical supervision of student nurses. The objective of this article is to analyze two interventions designed to improve the quality of supervision. METHODS: A student welcome booklet developed by means of a consultative and provocative participatory approach was tested with twelve student nurses versus a control group. Content analysis of the data collected by individual semi-directed interviews and during two focus groups demonstrated the value of this tool. Student nurses were also taught to use to training diaries inspired by the ?experiential learning? MODEL: Training diaries were analysed using a grid based on the descriptive elements of the five types of Scheepers training diaries (2008). RESULTS: According to the student nurses, the welcome booklet provided them with structured information to be used as a reference during their training and a better understanding of their teachers, and allowed them to situate the resources of the training course with a lower level of stress. Fifty-eight per cent of the training diaries were are mosaics, reflecting the reflective practice and self-regulated learning of student nurses. This activity also promoted metacognitive dialogue with their supervisors. CONCLUSION: The student welcome booklet appeared to facilitate integration of student nurses into the clinical setting and promoted professional and organizational socialization. The training diary improved the quality of clinical learning by repeated reflective observation of student nurses and helped to maintain permanent communication with the supervisors. PMID- 29384308 TI - [Water, sanitation and diarrheal risk in Nouakchott Urban Community, Mauritania]. AB - INTRODUCTION: Drinking water and sanitation are two factors of inter-linked inextricably public health especially in the city of Nouakchott where the low availability of these services leads to a multitude of use and hygiene practices involving a complex socio-ecological system with an increased risk of waterborne diseases transmission (diarrhea, cholera, etc.). METHODS: Thus, this contribution analyzes the impact of socio-ecological system on the development of diarrheal diseases by using socio-environmental and epidemiological data from various sources (national surveys and registries consultation). RESULTS: Overall, the results show that only 25.6% of households have access to drinking water sources while 69.8% of the populations dispose improved latrines. Hence, the weakness in environmental sanitation conditions explains the level of diarrheal morbidity averring 12.8% at the urban level, with an unequal spatial distribution showing less affected communes such as Tevragh Zeina (9.1%) and municipalities more affected like Sebkha (19.1%). The distribution according to the age categories shows that children under 5 years are the most affected with 51.7% followed by people aged over 14 with 34.2%. The correlation analysis between socio-economic, environmental and epidemiological variables reveals a number of significant associations: untreated water consumption and diarrhea (R = 0.429); collection of wastewater and occurrence of diarrhea ; existence of improved latrine and reduction of diarrheal risk (R = 0.402). DISCUSSION: Therefore, exposure to diarrheal diseases through the prism of water and sanitation is a real public health problem that requires a systemic and integrated approach to improving environmental health. PMID- 29384310 TI - ? PMID- 29384309 TI - [A plea for introduction of hepatitis B vaccination at birth in Cote d'Ivoire]. AB - The Cote d'Ivoire National Immunization Technical Advisory Group 2015 work plan included elaboration of an opinion on inclusion of hepatitis B vaccination at birth in the Expanded Program on Immunization (EPI) in Cote d'Ivoire. A task force was set up to conduct this assessment according to a systematized method. The task force analysed scientific articles on the burden of hepatitis B in Cote d'Ivoire, the burden of mother-child transmission, the impact of hepatitis B vaccination at birth in countries which have adopted this strategy, the efficacy and safety of hepatitis B vaccine in newborns, the cost-effectiveness of hepatitis B vaccination at birth, and the best strategy to introduce hepatitis B vaccination at birth in the EPI. The National Immunization Technical Advisory Group of Cote d'Ivoire finally recommended introduction of a dose of hepatitis B vaccine at birth in the context of the Expanded Program on Immunization with maintenance of three doses of pentavalent vaccine (DPT-HepB-Hib) at 6, 10, and 14 weeks of age. PMID- 29384311 TI - Consumption and sources of added sugar in Thailand: a review. AB - BACKGROUND AND OBJECTIVES: The present review examined the best available evidence regarding consumption levels and sources of added sugar in different population groups in Thailand. METHODS AND STUDY DESIGN: Information was extracted from food balance sheets, household expenditure surveys, food consumption surveys, government reports, published and unpublished studies. RESULTS: A total of 24 references were obtained, comprising 8 nationally representative reports and 16 individual studies. Results were inconsistent. The National Statistical Office reported an available supply of 83 g sugar per capita per day in 2010. The 2009 Food Consumption Survey of Thai Population showed median intake of sugar and sweeteners for all age groups ranging from 2.0 to 20.0 g per day among males and from 2.0 to 15.7 g per day among females (below the Thai recommendation of 40 to 55 g/day). Studies on children suggested intake levels between 25 to 50 g/day, while studies on adults were inconsistent. Frequently consumed sources were table sugar, sweetened beverages, and sweet snacks (traditional desserts, baked products, crispy snacks). CONCLUSIONS: Insufficient evidence exists regarding intake levels and sources of added sugar in Thailand. Limitations were the use of food frequency questionnaires or a single 24-h recall to assess intake, and outdated studies with small sample sizes. An updated nationally representative survey using improved methods is needed to determine the levels and sources of sugar intake in different population groups. These include biomarkers to establish levels of consumption and multiple 24-h recalls (at least two) to identify food sources that contribute significantly to excess sugar intake. PMID- 29384312 TI - Selenium in infant formula milk. AB - Formula-based animal milk is an alternative source of infant nutrition in many cases when breastfeeding is unacceptable or inaccessible; however, these replacements often have low selenium levels. The composition of infant formula milk should be as close as possible to that of human breast milk, both in content and chemical speciation. Selenium is an essential trace element for infants. Generally, human breast milk is the ideal food to ensure adequate infant Se intake. However, to date, sodium selenite or sodium selenate has been used as selenium supplementation in infant formula milk in most countries. This inorganic Se, which is not a natural component of food, may not be the optimal speciation for Se supplementation in infant formula milk. Advances in speciation in foods, especially in animal milk, suggest that future proposals for selenium speciation in human breast milk can lead to discussions regarding the most favorable methods of selenium supplementation in infant formula milk. PMID- 29384313 TI - Associations of postprandial lipemia with trunk/leg fat ratio in young normal weight women independently of fat mass and insulin resistance. AB - BACKGROUND AND OBJECTIVES: To determine whether postprandial lipemia is associated with fat distribution even in young, normal weight women independently of fat mass, adipokines, insulin resistance and systemic inflammation. METHODS AND STUDY DESIGN: Female college students (ages 21-24, n=35) underwent dual energy X-ray absorptiometry and a standardized breakfast providing 17 g triglycerides (TG). Serum lipids, lipoproteins, apolipoproteins, adipokines and markers of insulin resistance and inflammation were measured in fasting blood samples. RESULTS: In crude analyses, postprandial lipemia, as assessed by 0-2 h area under the curve of serum TG (TG-AUC), was positively associated with fasting TG, trunk/leg fat ratio, apolipoprotein B, leptin/adiponectin ratio and log high sensitivity CRP. Multiple linear regression analysis with these 5 variables as independent variables revealed that fasting TG (p<0.001) and trunk/ leg fat ratio (p=0.001), were independent positive predictors of TG-AUC (R2=0.923). Women with high compared to low TG-AUC were characterized by higher trunk/leg fat ratio, elevated apolipoprotein B and leptin/adiponectin ratio. CONCLUSION: Trunk/leg fat ratio, a marker of central adiposity, is a significant predictor of postprandial lipemia even in young women who are normal weight and insulin- sensitive, suggesting a modifiable pathway to postprandial hypertriglyceridemia, a cardiometabolic risk factor. These findings should be confirmed in studies employing more participants. PMID- 29384314 TI - Relevance of the Mini Nutritional Assessment in cirrhotic liver disease patients. AB - BACKGROUND AND OBJECTIVES: Malnutrition is an important prognostic factor for patients with liver disease and a novel nutritional assessment tool is required for these patients. The aim of this study was to validate the Mini Nutritional Assessment (MNA) as a nutritional screening tool for patients with liver disease, by comparing MNA scores with other nutrition-related parameters. METHODS AND STUDY DESIGN: Patients who were hospitalized at the gastroenterology division of Kyushu and Beppu Medical Center were enrolled. The study included 77 patients with liver disease (male/female, 46/31; mean+/-SD age, 68.5+/-10.7 years; liver cirrhosis, 64.9%; liver cancer, 61.0%). Correlations of MNA score at hospital admission with anthropometric parameters and blood test data were evaluated. RESULTS: In patients with liver disease, MNA scores demonstrated that 18 (23.4%) had normal nutritional status, 41 (53.2%) were at risk of malnutrition, and 18 (23.4%) were malnourished, indicating that up to 76.6% of the liver disease group were malnourished. Especially, patients with liver cirrhosis had lower scores of nutritional markers and MNA. The MNA score in liver cirrhotic patients correlated with the following parameters: % arm circumference, % triceps skinfolds, ratio of % maximum grasp strength and arm circumference, maximum grasp strength, arm muscle circumference, calf circumference, serum albumin levels, the controlling nutritional status score, and Onodera's prognostic index, while patients without liver cirrhosis did not show such correlation. CONCLUSIONS: MNA scores correlated with nutrition-related data in patients with liver cirrhosis. The MNA is an appropriate tool for nutritional screening assessment in these cirrhotic patients of any etiology. PMID- 29384315 TI - The efficacy of parenteral fish oil in critical illness patients with sepsis: a prospective, non-randomized, observational study. AB - BACKGROUND AND OBJECTIVES: To investigate the clinical outcomes in septic patients receiving parenteral fish oil. METHODS AND STUDY DESIGN: A prospective, non-randomized, observational clinical study was carried out in 112 patients with sepsis from March, 2013 to May, 2015 in the surgical intensive care unit (SICU) of a tertiaryreferral hospital. The patients were put into one of two groups; either the control or the study group. Patients received the standard treatment of sepsis based on guidelines in the control group. In the study group, patients received parenteral nutrition (PN) containing fish oil. The Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the length of ICU and hospital stay, duration of mechanical ventilation, mortality, and readmission into the ICU were recorded. Tumor necrosis factor (TNF)-alpha and procalcitonin (PCT) levels were also evaluated. RESULTS: The study group showed a significant reduction for all-cause mortality (20.0% vs 10.0% in study and control groups, p=0.034) and APACHE II score on day 5 (p=0.015), day 7 (p=0.036) and day out of SICU (p=0.045) compared with the control group. The study group tended to show a shortened length of stay in the ICU compared to the control group. However, TNF-alpha and PCT level, 28 d mortality, the length of hospital stay and the duration of mechanical ventilation did not show statistical differences between the two groups. There were no drug-related adverse effects shown during the study. CONCLUSIONS: PN with fish oil is probably safe and may improve clinical outcome in critical ill patients with sepsis. PMID- 29384316 TI - Continuous tube feeding versus intermittent oral feeding for intermediate position enterostomy in infants. AB - BACKGROUND AND OBJECTIVES: The stoma of intermediate position enterostomy (IPE) often leads to high output, which is related to electrolyte abnormalities, and prolongs patient recovery post-operatively. The continuous nasogastric tube feeding method has the advantage of reducing the risk of feeding intolerance, and improves nutrient absorption. In the current study, we review our experience with continuous tube feeding and compare the clinical outcomes with intermittent oral feeding in patients with an IPE post-operatively. METHODS AND STUDY DESIGN: This was a retrospective review of 118 infants with IPEs in our hospital. The infants were categorized into two groups (intermittent oral feeding [OF] group [n=68 infants, 1-14 days of age] and continuous tube feeding [TF] group [n=50 infants, 1-14 days of age]). Differences in stool volume, daily intravenous fluid infusion, weight gain, nutrition indices, and post-operative complications were reviewed. RESULTS: The stool volume and intravenous fluid infusion in the TF group were less than the OF group from week 2. The weight gain was higher in the TF group than the OF group from week 3. The pre-albumin and retinol binding protein levels were significantly higher in the TF group than the OF group in weeks 3-4 post-operatively. The incidence of cholestasis and waterelectrolyte disturbances in the TF group was significantly lower than the OF group, and the incidence of intestinal obstruction was lower than the control group, but the differences were not significant. CONCLUSIONS: Continuous tube feeding had better clinical outcomes than intermittent oral feeding in IPE patients. PMID- 29384317 TI - Contributors to nutritional status in continuous ambulatory peritoneal dialysis as practised in Henan Province, China. AB - BACKGROUND AND OBJECTIVES: To investigate the nutritional status of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and the factors involved. METHODS AND STUDY DESIGN: We used the Subjective Global Assessment (SGA) of nutritional status, a general questionnaire, dietary records, and laboratory parameters from 3 consecutive days to develop a NS assessment with it, we assessed 240 patients undergoing CAPD at a dialysis center in Henan Province. RESULTS: In this setting, the prevalence of malnutrition in patients undergoing CAPD was 11.7%. Univariate analysis showed that patient characteristics related to NS included energy and protein intakes, weight and BMI, dialysis duration, urinary creatinine, and total creatinine clearance rate. Multiple linear regression analysis revealed that dialysis duration (p<0.001) and energy intake (p=0.01) were the principal predictors of nutritional status and allowed 81% of the variance in nutritional status to be explained. CONCLUSIONS: Effective collaboration between nutritionists and other health care workers to minimise dialysis duration and optimize energy intake should improve the nutritionally related quality of life and well-being among CAPD patients. PMID- 29384318 TI - Effects of eating frequency on respiratory quotient in patients with liver cirrhosis: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Respiratory quotient (RQ) is a good marker of substrate oxidation. Low RQ is fre-quently found in patients with liver cirrhosis and is associated with poor outcome. The purpose of this study was to demonstrate the effects of eating frequency on RQ in patients with cirrhosis. METHODS AND STUDY DESIGN: We performed a randomized controlled trial to assess the effects of eating frequency on RQ in patients with cirrhosis. Seventy patients and 30 healthy controls were enrolled, and patients were further randomized to receive either normal eating frequency (NEF) meals at 08:00, 12:00 and 18:00 h, or high eating frequency (HEF) meals at 08:00, 10:00, 12:00, 15:00, 18:00 and 20:00 h. The two groups had equivalent energy intake. Fasting RQ was measured at 07:30 h and daytime RQ was measured at 11:30 and 17:30 h. Disease severity was evaluated using the Child-Turcotte-Pugh (CTP) classification. RESULTS: Fasting RQ and daytime RQ were significantly lower in patients with cirrhosis than in healthy controls. Patients in the HEF group had a higher RQ than patients in the NEF group at three time points. In patients with CTP-A, no significant differences in daytime RQ were observed between the two groups. However, in CTP-C patients, daytime RQ was significantly higher in the HEF group than in the NEF group. Serum free fatty acid levels were significantly decreased and albumin was significantly increased after HEF intervention. CONCLUSIONS: HEF strategy is effective in improvement of RQ and is beneficial to patients with cirrhosis. PMID- 29384319 TI - Refeeding hypophosphataemia after enteral nutrition in a Malaysian intensive care unit: risk factors and outcome. AB - BACKGROUND AND OBJECTIVES: Refeeding hypophosphataemia (RH) is characterized by an acute electrolyte derangement following nutrition therapy. Complications associated include heart failure, respiratory failure, paraesthesia, seizure and death. We aim to assess its incidence, risk factors, and outcome in our local intensive care unit (ICU). METHODS AND STUDY DESIGN: A prospective observational cohort study was conducted at the mixed medical- surgical of a tertiary ICU in Kuantan, Malaysia. The study was registered under the National Medical Research Register (NMRR-14-803-19813) and has received ethical approval. Inclusion criteria include adult admission longer than 48 hours who were started on enteral feeding. Chronic renal failure patients and those receiving dialysis were excluded. RH was defined as plasma phosphate less than 0.65 mmol/L and a drop of more than 0.16 mmol/L following feeding. RESULTS: A total of 109 patients were recruited, of which 44 (42.6%) had RH. Patients with RH had higher SOFA score compared to those without (p=0.04). There were no differences in the APACHE II and NUTRIC scores. Serum albumin was lower in those with RH (p=0.04). After refeeding, patients with RH had lower serum phosphate, magnesium and albumin, and higher supplementation of phosphate, potassium and calcium. There were no differences in mortality, length of hospital or ICU stay. CONCLUSIONS: Refeeding hypophosphataemia occurs in almost half of ICU admission. Risk factors for refeeding include high organ failure score and low albumin. Refeeding was associated with imbalances in phosphate, magnesium, potassium and calcium. Future larger study may further investigate these risk factors and long-term outcomes. PMID- 29384320 TI - Effects of grass jelly on glycemic control: hydrocolloids may inhibit gut carbohydrase. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to investigate (1) the hydrocolloid properties of grass jelly on reducing glycaemic response, (2) the impact of phenolic compounds in Mesona chinensis L. on glycaemic response. METHODS AND STUDY DESIGN: A total of 15 healthy Chinese men were recruited to this study. On each visit, subjects consumed one of the following three treatments, i.e. glucose solution (T1), grass jelly (Mesona chinensis L.) solution with glucose (T2) or grass jelly gel with glucose (T3). Capillary blood glucose and venous plasma insulin were analysed over a period of 180 min. RESULTS: The incremental area under the curve for capillary glucose and venous plasma insulin for glucose group, grass jelly solution group and grass jelly gel was found to be statistically not significant (p>0.05). In a previous study the co-ingestion of grass jelly with complex carbohydrate was found to reduce glycaemic response. The key difference between the two studies was the use of monosaccharide glucose in the present study, compared to complex carbohydrates in the other. The present study suggests that the glycaemic lowering effect of grass jelly may be dependent on the inhibition of carbohydrase enzymes. CONCLUSIONS: The co-ingestion of Mesona chinensis L. appears to reduce glycaemic response of only complex carbohydrates through the inhibition of carbohydrase. This conclusion was arrived at by the lack of any effect of Mesona chinensis L. on the monosaccharide glucose. PMID- 29384321 TI - Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVES: This randomized, placebo-controlled trial was performed for 8 weeks to investigate the potential effects of astaxanthin (AST) supplementation on the adiponectin concentration, lipid peroxidation, glycemic control, insulin sensitivity, and anthropometric indices in participants with type 2 diabetes mellitus. METHODS AND STUDY DESIGN: We enrolled 44 participants with type 2 diabetes who met our inclusion criteria. Eight milligrams of AST supplementation or a placebo were randomly administered once daily for 8 weeks to these participants. RESULTS: The 8-week administration of AST supplementation increased the serum adiponectin concentration and reduced visceral body fat mass (p<0.01), serum triglyceride and very-low-density lipoprotein cholesterol concentrations, and systolic blood pressure (p<0.05). Furthermore, AST significantly reduced the fructosamine concentration (p<0.05) and marginally reduced the plasma glucose concentration (p=0.057). CONCLUSIONS: We demonstrated that because participants with type 2 diabetes often have hypertriglycemia and uncontrolled glucose metabolism; our findings of dual beneficial effects are clinically valuable. Our results may provide a novel complementary treatment with potential impacts on diabetic complications without adverse effects. PMID- 29384322 TI - The effects of green kiwifruit combined with isoflavones on equol production, bone turnover and gut microflora in healthy postmenopausal women. AB - BACKGROUND AND OBJECTIVES: Isoflavone (daidzein and genistein) interventions in postmenopausal women have produced inconsistent skeletal benefits, partly due to population heterogeneity in daidzein metabolism to equol by enteric bacteria. This study assessed changes in microflora and bone turnover in response to isoflavone and ki-wifruit supplementation in New Zealand postmenopausal women. METHODS AND STUDY DESIGN: Healthy women 1-10 years post-menopause were randomly allocated to group A (n=16) or B (n=17) for a 16-week crossover trial. Two consecutive 6-week treatment periods had a 2-week lead-in period at intervention commencement and a 2-week washout period between treatments. Treatments prescribed either (1) daily isoflavone supplementation (50 mg/day aglycone daidzein and genistein) alone, or (2) with two green kiwifruit. At treatment baseline and end-point (four time points) the serum bone markers C Telopeptide of Type I collagen (CTx), undercarboxylated os-teocalcin (unOC), and serum and urinary daidzein and equol, were measured. Changes in gut microflora were monitored in a subgroup of the women. RESULTS: Equol producers made up 30% of this study population (equol producers n=10; non-equol producers n=23) with serum equol rising significantly in equol producers. Serum ucOC decreased by 15.5% (p<0.05) after the kiwifruit and isoflavone treatment. There were no changes in serum CTx or in the diversity of the gut microflora. CONCLUSIONS: 50 mg/day isoflavones did not reduce bone resorption but kiwifruit and isoflavone consumption decreased serum ucOC levels, possibly due to vitamin K1 and/or other bioactive components of green kiwifruit. PMID- 29384323 TI - Regular egg consumption at breakfast by Japanese woman university students improves daily nutrient intakes: open-labeled observations. AB - BACKGROUND AND OBJECTIVES: Eggs, an important source of high-quality protein, contain a variety of key nutrients and antioxidants. Here we conducted an intervention study to evaluate whether the additional consumption of one egg per day would affect the daily nutritional intakes and blood antioxidant status in Japanese woman university students. METHODS AND STUDY DESIGN: For 4 weeks, the 14 subjects were provided a nutritious breakfast including one boiled egg, and they were asked to keep a daily dietary record. RESULTS: The subjects' daily energy intake during the intervention did not differ compared to the baseline, whereas the protein energy ratio and cholesterol intake were significantly increased. The subjects' consumption of confectionery during the intervention was significantly decreased compared to the pre-trial period. The total score of adherence to the food-based Japanese dietary guidelines for a healthy diet during the intervention was higher than that at baseline. The analysis of fasting blood samples showed that the subjects' serum lipids levels were not altered, whereas their malondialdehyde modified low-density lipoprotein (MDA-LDL) levels and the oxidative susceptibility of LDL were significantly reduced after the intervention. More importantly, serum folic acid levels were significantly increased. CONCLUSIONS: Our results suggest that regular egg consumption at breakfast can help improve the daily nutritional status and dietary habits and also ameliorate certain indices of antioxidant status in young women. PMID- 29384324 TI - Dietary patterns, dietary biomarkers, and kidney disease in patients with type 2 diabetes: a repeated-measure study in Taiwan. AB - BACKGROUND AND OBJECTIVES: Western dietary patterns have been linked with kidney disease. This study investigated the association between Chinese dietary patterns and kidney disease in a Taiwanese population with type 2 diabetes and evaluated dietary fatty acid patterns, a kidney-related dietary biomarker. METHODS AND STUDY DESIGN: We recruited 838 patients with type 2 diabetes and used their dietary and renal data obtained from three repeated measures in 2008, 2009 and 2010. Diet was assessed using food-frequency questionnaires, and factor analysis was performed to identify dietary patterns. Albuminuria was defined by having an albumin-to-creatinine ratio >=30 mg/g and kidney dysfunction by estimated glomerular filtration rate <60 mL/min/1.73m2. Generalized estimating equation models were used to estimate ORs (95% CIs) of kidney disease adjusted for covariates. Erythrocyte fatty acids were only measured in blood samples collected in 2008. RESULTS: Three dietary patterns were identified: high fat-meat, traditional Chinese food-snack, and fish-vegetable. In the adjusted model, the high fat-meat and traditional Chinese food-snack diets were not associated with any kidney outcomes. The fishvegetable diet was inversely associated with kidney dysfunction (quartile 4 vs 1, OR: 0.75, 0.58-0.97), but not associated with albuminuria. A higher fish-vegetable diet factor score was associated with higher n-3 fatty acid levels. CONCLUSION: In patients with diabetes, we found greater adherence to a fish-vegetable diet to be associated with better kidney function and greater n-3 fatty acid profiles. The inclusion of repeated dietary assessments and dietary biomarker measurements in future diet-disease research, especially in patient populations, may provide more definitive risk evaluation. PMID- 29384325 TI - Dietary glycemic load and metabolic status in newly diagnosed type 2 diabetes in southeastern China. AB - BACKGROUND AND OBJECTIVES: Large-scale epidemiological investigations worldwide have shown that dietary glycemic load is associated with metabolic diseases, including diabetes. However, only a few studies have examined the correlations between glycemic load and blood glucose and lipids in Chinese diabetic patients. Therefore, this study aimed to determine these correlations in southeastern China. METHODS AND STUDY DESIGN: 201 patients with newly diagnosed type 2 diabetes and 126 participants with normal blood glucose were enrolled at the Sun Yat-sen Memorial Hospital, Guangdong Province. Carbohydrate intake and glycemic load were assessed based on 3-day dietary records. Using glycemic load as the dependent variable, a correlation analysis and multiple regression analyses were used to analyze the correlations between glycemic load and blood glucose and lipids. RESULTS: The mean glycemic load in diabetic patients was significantly higher than that in the control group (p<0.05). Correlation analysis showed that glycemic load was positively correlated with body mass index and glycated hemoglobin in diabetic patients (p<0.05) but negatively correlated with high density lipoprotein cholesterol in all subjects (p<0.05). Multivariable regression analysis indicated that, among participants in southeastern China, a higher glycemic load increased the odds of having diabetes, a low high-density lipoprotein cholesterol, and higher Charlson weighted index of comorbidities score, as well as being overweight. CONCLUSIONS: A high-glycemic load diet may be associated with a risk of diabetes, glycemic control, lipid metabolism, prognosis of diseases, and body composition. It is necessary to control dietary glycemic load for both patients with diabetes and healthy people in southeastern China. PMID- 29384326 TI - Prevalence of gestational diabetes mellitus and associated risk factors in pregnant Chinese women: a cross-sectional study in Huangdao, Qingdao, China. AB - BACKGROUND AND OBJECTIVES: This study explored the prevalence of gestational diabetes mellitus (GDM) in Chinese pregnant women and identified risk factors for GDM after the implementation of the universal two-child policy. METHODS AND STUDY DESIGN: On the basis of income and population, we randomly selected three hospitals through stratified and cluster sampling. From January 1 to July 31, 2016, 4959 women who had been registered within 12 weeks of gestation received a 75-g 2-h oral glucose tolerance test (OGTT) at 24-28 gestational weeks. International Association of Diabetes and Pregnancy Study Group criteria were used for the diagnosis of GDM. RESULTS: The OGTT was positive in 1080 (21.8%; 1080/4959) women, who were then diagnosed as having GDM on the basis of their results. GDM was positively associated with the following factors: advanced maternal age (p<0.001; adjusted odds ratio [OR]=4.88; 95% confidence interval [CI]=2.38-10.0, pre-pregnancy body mass index overweight (OR=2.44, 95% CI=1.78 3.34)/obesity (OR=10.9, 95% CI=6-19.6; p<0.001), paternal history of diabetes (p=0.003; OR=2.54, 95% CI=1.38-4.67), and maternal history of diabetes (p<0.001; OR=3.6, 95% CI=2.16-5.98). CONCLUSIONS: Qingdao has an exceptionally high estimated prevalence of GDM. Widely recognized risk factors for GDM were advanced age, pre-pregnancy overweight/obesity, and a family history of diabetes in first degree relatives. More options to prevent and manage GDM must be explored. PMID- 29384327 TI - Differences in brain-derived neurotrophic factor between neonates born to mothers with normal and low ferritin. AB - BACKGROUND AND OBJECTIVES: Maternal iron deficiency in late pregnancy, labor, and the postpartum period has an indirect impact to decrease neurotrophin concentration in the fetal hippocampus, namely brain-derived neurotrophic factor (BDNF). It plays an important role in the development of learning, memory, and behavior. The aim of this study was to determine the differences in BDNF between neonates born to mothers with normal and low ferritin. METHODS AND STUDY DESIGN: This was an observational study with a cross-sectional design involving 20 term pregnant women with normal ferritin (>=12 ng/mL) and 20 term pregnant women with low ferritin (<12 ng/mL). Samples were taken from Yarsi hospital, BMC hospital, and Hardi clinic located in Padang, from August 2015 to February 2016. Umbilical cord plasma was examined directly after delivery using an enzymelinked immunosorbent assay (ELISA) employed at the Biomedical Laboratory of Andalas University. Mean differences were statistically assessed by independent samples t test. RESULTS: Plasma BDNF concentrations in neonates born to mothers with normal and low ferritin were 3.81+/-1.37 ng/mL and 2.78+/-1.19 ng/mL, respectively (p=0.015). CONCLUSIONS: Plasma BDNF was lower in neonates born to mothers with low serum ferritin. PMID- 29384328 TI - Breast milk and infant iodine status during the first 12 weeks of lactation in Tianjin City, China. AB - BACKGROUND AND OBJECTIVES: The present study investigated the iodine status of breast milk and breast-fed infants during the first 12 weeks postpartum in Tianjin, China. METHODS AND STUDY DESIGN: A total of 175 pregnant women were recruited before delivery. Their breastmilk and 24-h urine samples were collected at 4, 8, and 12 weeks postpartum; spot urine samples were simultaneously collected from their infants. The iodine content of the samples was measured. RESULTS: The mean breast milk iodine concentrations (BMICs) at 4, 8, and 12 weeks were 221.7+/-103.5 MUg/L, 175.2+/-76.2 MUg/L, and 148.1+/-66.2 MUg/L, respectively. Significant differences existed between the mean BMICs of the three sampling times (F=12.449, p<0.001). The BMIC showed a decreasing trend during the first 12 weeks postpartum. The median urinary iodine concentrations (UICs) of the mothers were 152, 112, and 109 MUg/L at the different sampling times. The BMIC and UIC were not correlated in the mothers. The median UICs in the infants were 251, 183, and 164 MUg/L. The infant UICs were statistically different at the three sampling times (p=0.001). Moreover, the infant UICs correlated with the BMICs (Rs=0.205, p=0.010) but not with the maternal UICs (Rs=0.131, p=0.067). CONCLUSION: The BMIC in and infant iodine intake from breast milk decreased in the first 12 weeks. Breastfed infants could receive adequate iodine from breast milk in Tianjin City. PMID- 29384329 TI - Childhood overweight and obesity amongst primary school children in Hai Phong City, Vietnam. AB - BACKGROUND AND OBJECTIVES: Childhood obesity is a rising health concern in Vietnam, however, research in this area is not extensive. The aim of this study was to determine the prevalence of childhood overweight and obesity, and to study associations between weight status and selected lifestyle factors, such as diet and physical activity levels, among children aged 6-10 years in Hai Phong City, Vietnam. METHODS AND STUDY DESIGN: Two hundred and seventy-six children from an urban and a rural primary school participated in this cross-sectional study. Data on weight, height and waist circumference were used to calculate BMI, and waist height ratio to determine the proportion of children who were overweight, obese and had high central adiposity. Information on diet, physical activity and socioeconomic status of families was collected using questionnaires. RESULTS: Prevalences of overweight, obesity and high abdominal adiposity were 11.2%, 10.1% and 19.9%, respectively. Children who completed >=60 minutes of physical activity daily were 50% and 80% less likely to be overweight and have high abdominal adiposity, respectively. Computer usage increased the odds of overweight and high abdominal adiposity by 4.5 and 3.9 times, respectively. Mothers with higher education and income levels increased the risk of their children being overweight (p<0.05). CONCLUSIONS: Physical inactivity and high maternal education and income levels increased the risk of childhood overweight and obesity in this cohort. Future interventions should target parents and their children by providing both with educational modules centred on healthy eating habits, parental feeding practices and strategies for increasing physical activity. PMID- 29384330 TI - Dietary patterns and obesity in preschool children in Australia: a cross sectional study. AB - BACKGROUND AND OBJECTIVES: Dietary patterns have been linked to the risk of obesity in adults but little is known about such a link in young children. To examine the association between dietary patterns, nutrient intake and obesity in a representative population of preschool children in Australia. METHODS AND STUDY DESIGN: Dietary intake was assessed using a 3-day weighed food diary. Dietary patterns were identified by factor analysis. Children were classified as overweight or obesity if their BMI z-score was between the 85th-95th percentiles or was above the 95th percentile, respectively. RESULTS: Three dietary patterns were identified. The 'Traditional' pattern was characterised by grains, fruit, vegetables, and red meat. The 'Processed' pattern was characterised by processed meats, snack foods and confectionary. The 'Health conscious' pattern was characterised by eggs, fish, polyunsaturated margarines and low fat dairy products. The 'Traditional' pattern was positively associated with protein and zinc intake while the 'Processed' pattern was inversely associated. Both patterns were inversely associated with calcium intake. No associations were found between the 'Health conscious' pattern and macronutrients and key micronutrients intakes. The 'Traditional' pattern was positively associated with obesity but the association became non-significant after adjustment for energy and protein intake. No association was observed between the other two dietary patterns and weight status. CONCLUSIONS: In this cross-sectional study, dietary patterns were not associated with obesity. Longitudinal follow up will help to better understand the relationship between dietary patterns in early childhood and the risk of obesity later in life. PMID- 29384331 TI - Factors which may limit the value of dietary diversity and its association with nutritional outcomes in preschool children in high burden districts of India. AB - BACKGROUND AND OBJECTIVES: Dietary diversity plays a critical role in infants as they need energy and nutrient dense foods for both physical and mental development. This study examines whether three dietary diversity indices validate against Nutrient Adequacy Ratio (NAR) and Mean Adequacy Ratio (MAR) and studies the relationship of dietary diversity with nutritional status of preschool children, in two districts of India: Wardha district in Maharashtra state and Koraput district in Odisha state. METHODS AND STUDY DESIGN: Dietary diversity was calculated using: individual food scores calculated using 24 hour diet recall (FS24hr) data; household dietary diversity using Berry's index (DDI) and food scores calculated using food frequency data (FSFFQ). Nutritional status was assessed by anthropometric indices. RESULTS: It was observed that 42.7% of 1 to 5 years children were underweight, 38% stunted and 27.6% wasted across both locations. The dietary diversity was found to be relatively better in Wardha when compared with Koraput with mean diversity of FS24hr 7, DDI 90 and FSFFQ 63 in both locations. Preschool children in both locations consumed a cereal based diet. Apart from protein in both locations and energy in Koraput, the NAR of all nutrients consumed was <70% of requirement. MAR showed lower consumption of nutrients than the recommended levels (50% adequacy). NAR and MAR correlate with FS24hr indicating that dietary diversity calculated using 24 hour diet recall ensures nutrient adequacy but showed association only with Height-for-Age scores. CONCLUSION: Dietary diversity calculated using three methods did not show any correlation with nutritional status of 1 to 5 years children. PMID- 29384332 TI - Breakfast consumption among Malaysian primary and secondary school children and relationship with body weight status - Findings from the MyBreakfast Study. AB - BACKGROUND AND OBJECTIVES: This study aimed to determine the relationship between breakfast consumption and body weight status among primary and secondary school children in Malaysia. METHODS AND STUDY DESIGN: This nationwide cross-sectional study involved 5,332 primary school children aged 6 to 12 years and 3,000 secondary school children aged 13 to 17 years. Height and weight were measured and BMI-for-age was determined. Socio-demographic backgrounds, breakfast habits and physical activity levels were assessed using questionnaires. Breakfast frequency was defined as follows: breakfast skippers (ate breakfast 0-2 days/week), irregular breakfast eaters (ate breakfast 3-4 days/week) and regular breakfast eaters (ate breakfast >=5 days/week). RESULTS: The overall prevalence of breakfast skippers and irregular breakfast eaters was 11.7% and 12.7% respectively. Breakfast skipping was related to age, sex, ethnicity, income and physical activity level. Among primary school boys and secondary school girls, the proportion of overweight/obesity was higher among breakfast skippers (boys: 43.9%, girls: 30.5%) than regular breakfast eaters (boys: 31.2%, girls: 22.7%). Among primary school children, only boys who skipped breakfast had a higher mean BMI-for-age z-score than regular breakfast eaters. Among secondary school boys and girls, BMI-for-age z-score was higher among breakfast skippers than regular breakfast eaters. Compared to regular breakfast eaters, primary school boys who skipped breakfast were 1.71 times (95% CI=1.26-2.32, p=0.001) more likely to be overweight/obese, while the risk was lower in primary school girls (OR=1.36, 95% CI=1.02-1.81, p=0.039) and secondary school girls (OR=1.38, 95% CI=1.01-1.90, p=0.044). CONCLUSION: Regular breakfast consumption was associated with a healthier body weight status and is a dietary behaviour which should be encouraged. PMID- 29384333 TI - Intake ratio and major food sources of n-3 and n-6 fatty acids in Korea: a study based on the sixth Korea national health and nutrition examination survey (2013 2014). AB - BACKGROUND AND OBJECTIVES: In addition to the intake ratio of omega 6 (n-6) to omega 3 (n-3) fatty acids, their intake amount has an effect on health. This study evaluated the n-6:n-3 intake ratio as well as the food sources and association of these fatty acids with demographic characteristics based on sixth Korea National Health and Nutrition Examination Survey data. METHODS AND STUDY DESIGN: This study included 13,937 participants from the survey. The weighted mean intake and major food groups of n-3 and n-6 fatty acids were determined. The 10 chief food sources of n-3 and n-6 fatty acid were expressed as percent contribution to total intake. RESULTS: alpha- Linolenic acid constituted approximately 80% of total n-3 intake, followed by docosahexaenoic acid (10.5%) and eicosapentaenoic acid (6.1%). Linoleic acid constituted 97% of total n-6 intake. After adjustment for cofactors (age, sex, and energy intake), education level (p<0.01), alcohol consumption frequency (p<0.05) and monthly income (p<0.01) were significant variables determining n-3 and n-6 FA intake by Korean people. The average n- 6:n-3 intake ratio was 7.49:1. The major source of alpha linolenic acid and linoleic acid was soybean oil, whereas that of docosahexaenoic acid and eicosapentaenoic acid was mackerel. Pork (70.0%) and egg (38.7%) were the major food sources of arachidonic acid and dihomo-gamma-linolenic acid, respectively. CONCLUSION: Monthly income, alcohol consumption frequency, and education level significantly affected n-3 FA intake. The dietary n-6: n-3 intake ratio in Korea is 7.49:1; however, eicosapentaenoic acid and docosahexaenoic acid intake remains inadequate (0.27 g/day). PMID- 29384334 TI - Prevalence and characteristics of misreporting of energy intake in Japanese adults: the 2012 National Health and Nutrition Survey. AB - BACKGROUND AND OBJECTIVES: Information on a whole array of characteristics associated with dietary misreporting in a representative sample in each country is still limited. Using data from the 2012 National Health and Nutrition Survey, Japan, we investigated the prevalence and characteristics of under- and over reporting of energy intake among 19,986 Japanese adults aged >=20 years. METHODS AND STUDY DESIGN: Each individual's energy intake was calculated based on a 1-day semi-weighed dietary record. Under-, plausible, and over-reporters were identified based on the 95% confidence limits 1) for agreement between the ratio of energy intake to basal metabolic rate and a physical activity level for sedentary lifestyle (1.55), and 2) of the expected ratio of energy intake to estimated energy requirement of 1.0, assuming 'low active' level of physical activity. RESULTS: Almost all subjects (>=92.8%) were classified as plausible reporters by any of the methods applied, with very low percentages of under- and over-reporters (<=6.3% and <=2.0%, respectively). Under-reporting was associated with younger age, overweight and obesity (compared with normal weight), current smoking (compared with never smoking), no alcohol drinking (compared with drinking everyday), and household consisting of a single person (compared with that consisting of two persons). Over-reporting was associated with gender (female), normal weight (compared with overweight), and household consisting of a single person. CONCLUSIONS: Overall mean energy intake obtained in this sample of Japanese adults appears to be plausible, but caution should be exercised when assessing the plausibility of energy intake in some subgroups. PMID- 29384335 TI - Dietary patterns, dietary lead exposure and hypertension in the older Chinese population. AB - BACKGROUND AND OBJECTIVES: With rapid population ageing and an increasing rate of hypertension in China, this study aims to examine the association between dietary patterns, dietary lead and hypertension among older Chinese population. METHODS AND STUDY DESIGN: We analysed the 2009 China Health and Nutrition Survey data (2,634 individuals with dietary and hypertension measurement data, aged >=60 years). Dietary data were obtained using 24 hour-recall over three consecutive days. Dietary lead intake is based on a published systematic review of food lead concentration and dietary lead exposure in China. Factor analysis was used to identify dietary patterns. Poisson regression and multinomial logistic regression models were used to explore the association between dietary patterns and hypertension. RESULTS: The prevalence of hypertension was 47.0% in men and 48.9% in women. Traditional dietary pattern (high intake of rice, pork and vegetables) was significantly inversely associated with known hypertension. In the fully adjusted model, compared with the lowest quartile of traditional dietary pattern, the highest quartile had a lower risk of known hypertension, with Relative Risk Ratio=0.69 (95% CI: 0.50; 0.95). However, associations between modern dietary pattern and hypertension differed by urbanization; an inverse, positive and null association was seen in low, medium and high urbanization. Additionally, dietary lead showed a significant positive association with hypertension and known hypertension. CONCLUSIONS: Policies that facilitate and promote healthy diets, and the availability of healthy foods particularly at the regional and local levels, are important for the prevention of hypertension. PMID- 29384336 TI - Assessing self-reported green tea and coffee consumption by food frequency questionnaire and food record and their association with polyphenol biomarkers in Japanese women. AB - BACKGROUND AND OBJECTIVES: Despite the demonstrated protective effects of green tea and coffee intake against several chronic diseases, finding between studies have not been consistent. One potential reason of this discrepancy is the imprecision in the measurement of tea or coffee consumption using food frequency questionnaire (FFQ) and food record (FR) in epidemiological studies. METHODS AND STUDY DESIGN: In a sample of 57 healthy Japanese women, intake of green tea and coffee was estimated by a validated FFQ and a 3-day FR, while their plasma and urine concentrations of polyphenol biomarkers were measured by HPLC. The polyphenols assessed included (-)-epigallocatechin gallate (EGCG), (-) epicatechin gallate (ECG), (-)-epigallocatechin (EGC) and (-)- epicatechin (EC), caffeic acid (CA) and chlorogenic acid (CGA). RESULTS: Green tea consumption estimated by FFQ and FR showed moderate association, while strong association was detected for coffee consumption. Urinary green tea polyphenol concentrations were moderately-strongly associated with FR-estimated intake, while the associations were weak with FFQ. Similarly, coffee polyphenols in urine were moderately associated with FR-estimated coffee intake, whereas FFQ showed poor correlation. The associations between urinary and plasma polyphenols ranged from moderate to high. CONCLUSIONS: The results indicated that firstly, the FFQ tends to overestimate green tea intake. Secondly, the urinary polyphenols are preferred over plasma polyphenols as a potential surrogate marker of the short-term green tea and coffee intake, while their use as an indicator of long-term consumption is not reliable. PMID- 29384337 TI - Role of behavioural feedback in nutrition education for enhancing nutrition knowledge and improving nutritional behaviour among adolescents. AB - BACKGROUND AND OBJECTIVES: The integration of nutrition knowledge into nutritional behaviour can help children to develop a healthy lifestyle that may be carried forward into adulthood. E-learning enables students to take ownership of recording their dietary intake and modify their diets by making their own decisions regarding food choices and portion sizes through reflective feedback. This study investigated the role of behavioural feedback in nutrition education in modifying students' nutrition knowledge and behaviour. METHODS AND STUDY DESIGN: Ninety-five secondary students studying from Secondary 1 to Secondary 3 were recruited from five schools. Moreover, 50 and 45 students were randomly assigned to experimental and control groups, respectively. Nutrition education delivered through e-learning (NeL) was adopted to record students' diets. Online reports with behavioural feedback were provided for the experimental group but not for the control group. NeL sessions lasted for 12 weeks. The energy and nutrient profiles of the students were recorded as pre-post measurements. Pre post nutrition knowledge was assessed using a self-administered questionnaire at the baseline and after intervention. RESULTS: The experimental group had significantly higher scores in the 'dietary recommendation' and 'food choices' domains of the questionnaire and demonstrated significant dietary improvement in the intake of all studied macronutrients and micronutrients. CONCLUSIONS: Nutrition education conducted with behavioural feedback can effectively improve adolescents' nutrition knowledge and nutritional behaviour. PMID- 29384338 TI - Nutritional quality and patterns of lunch menus at child care centers in South Korea and Japan. AB - BACKGROUND AND OBJECTIVES: This study aimed to investigate the nutritional quality and patterns of lunch menus provided by child care centers in South Korea and Japan. METHODS AND STUDY DESIGN: The weekly lunch menus from Monday to Saturday that child care centers provided in November 2014 in South Korea and Japan were analyzed. For Korea, a total of 72 meals provided by 12 centers in Seoul were analyzed by referring to the homepage of the Center for Children's Foodservice Management, which serviced menus for child care centers. For Japan, a total of 30 meals provided by 5 child care centers in Tokyo were analyzed. Nutrient content and pattern in lunch menus were evaluated. RESULTS: The lunch menus in Korea and Japan provided 359.5 kcal (25.7% of the estimated energy requirement) and 376.3 kcal (29.5% of the estimated energy requirement), respectively. 'Rice + Soup + Main dish + Side dish I + Side dish II' were provided in 66.7% of meals in Korea, while various patterns with rice and soup as their bases were provided in Japan. CONCLUSIONS: The lunch menus of child care centers in Korea and Japan provide similar amounts of energy, protein, carbohydrate, vitamin A, calcium, and other nutrients. However, there were significant differences in the lunch menu patterns in Korea and Japan. This study provides information about the nutritional content and pattern of lunch menus at child care centers in Asian countries with rice as a staple food. PMID- 29384339 TI - Taste perception and diet in people of Chinese ancestry. AB - BACKGROUND AND OBJECTIVES: Taste perception plays a key role in consumer acceptance and food choice, which has an important impact on human health. Our aim was to examine the relationship between taste intensities and preferences of sweet (sucrose), salty (sodium chloride and potassium chloride), sour (citric acid), and bitter (quinine and phenylthiocarbamide) in relation to dietary intake and dietary patterns in people of Chinese ancestry. METHODS AND STUDY DESIGN: This cross-sectional study included 100 adult Singaporean Chinese (50 women). A validated taste methodology was used with taste solutions provided by Monell Chemical Senses Center. Dietary intake and patterns were assessed by dietary recalls. RESULTS: There was little relationship between taste intensity and tastant preference in regard to background dietary intake or pattern. Tastant differentiation was reliable, but there was some confusion in regard to the rating of saltiness as sourness. CONCLUSIONS: There was a salty-sour confusion among Singaporean Chinese unlike the bitter-sour confusion reported for Caucasians. Most sodium came from sauces and was added during food preparation. In programs to address sodium: potassium ratio excess among Chinese prone to hypertension and stroke, sour as well as salty taste may need to be considered. PMID- 29384340 TI - Ambient temperature-related exaggerated post-prandial insulin response in a young athlete: a case report and implications for climate change. AB - The objective is to present the case of a 21-yr-old athlete observed with non physiological immediate postprandial insulin response (1162 pmol/l; normal glucose excursion: 6.6 mmol/l), in a warm environment. No suspicion or evidence of any underlying pathology was found in this well-trained Afro-Caribbean male runner. He never reported any hypoglycemic episode. When performing the same protocol performed in a cooler environment (21.0 degrees C vs 30.3 degrees C), only physiological responses were observed. We conclude that 1) youth, leanness and regular exercise training are not absolutely protective against glucose metabolism impairment in apparently healthy subjects; 2) ambient temperature should be regarded as a potential source of glucose metabolism impairment. PMID- 29384341 TI - The Subject of Enhancement: Augmented Capacities, Extended Cognition, and Delicate Ecologies of the Mind. AB - This paper argues for an inflationary and capacity-relative understanding of human enhancement technology. In doing so it echoes the approach followed by Buchanan (2011a, 2011b). Particular emphasis is placed on the point that capacities themselves are relative to demands placed on the organism by its environment. In the case of human beings, this environment is to a very large extent institutionally structured. On the basis of the inflationary and capacity relative concept of enhancement, I argue that the subject of enhancement must be understood in terms of a bundle of capacities that is both extended (Clark 1998) and ecological. This consequence of the inflationary enhancement concept has some surprising upshots, namely that the subject itself must be considered as a technological enhancement and not a 'platform' or subjectum upon which the enhancement enterprise builds. This conclusion clashes, I argue, with some of the presuppositions of liberal philosophy, which starts by assuming a reflective subject. The paper ends with some reflection on the desirability of reflective subjectivity for human flourishing and addressing the ecological crisis. PMID- 29384342 TI - 'Just a Bit of Fun': How Recreational is Direct-to-Customer Genetic Testing? AB - Direct to consumer (DTC) genetic testing has given rise to much controversy, especially in relation to testing for health diagnostic purposes. This paper will consider whether consumers' use of DTC genetic testing should be understood as predominantly recreational. It will be argued that recreational testing can encompass all information domains, including most kinds of predictive health risk information. In relation to recreational testing the potential identity implications for the consumer become a significant concern, more so than the risks more traditionally associated with genetic testing. It will be concluded that while the DTC genetic testing sector is beset by numerous problems and an increase in consumers' genetic literacy is highly desirable, consumers' engagement with DTC genetic testing may be less problematic than sometimes assumed. PMID- 29384343 TI - Voicing Unease: Care Ethics in the Professionalization of Social Care. AB - In her work on moral reasoning, Carol Gilligan identifies two distinct models which she terms the 'voice of care' and the 'voice of justice'. The 'voice of justice' informs a professional practice grounded in fairness and objectivity and is principally concerned with rights and obligations. It can motivate the drive for legislation and codes of ethics that provide clear rules and regulations to govern social care practice. In contrast, the 'voice of care' prioritises relationships, requiring practitioners to pay attention to the particularity of each moral situation. As a result, the demand to commit to upholding universal principles and rights cannot be met. This paper explores the nature of the conflict between the moral voice of care and justice, applying insights from these diverging voices to deepen our understanding of the kind of professionalization appropriate in social care. PMID- 29384344 TI - Alcohol and Controlling Risks through Nudges. AB - This article examines the relation of risks and public policy through the lens of alcohol and crime. Alcohol thus lives a double-life as a fountain of celebration while also a wellspring of potentially serious harms. The issue of how risks might be managed much better is approached through considering three different arenas within the criminal law concluding that it is a crude mechanism for grappling with complex issues of criminal responsibility for any higher risks associated with becoming under the influence. The article defends the use of nudges as an under explored area for public policy decision-making and proposes new policies based on them. PMID- 29384345 TI - Autonomy as Ideology: Towards an Autonomy Worthy of Respect. AB - Recent criticism of the role of respect for autonomy in bioethics has focused on that principle's status as 'dogma' or 'ideology'. I suggest that lying beneath many applications of respect for autonomy in medical ethics are some influential dogmas - propositions accepted, not as explicit premises or as a consequence of reasoned argument, but simply because moral problems are so frequently framed in such terms. Furthermore, I will argue that rejecting these dogmas is vital to secure and protect an autonomy worthy of respect. The concept of autonomy that is widely applied in clinical ethics emphasises decision-making competence, at the expense of considering the authenticity of those decisions. Respect for such autonomy is interpreted in largely synchronic and individual terms - concerned with the isolated decisions of individual agents - and thus neglects the diachronic and social dimensions of many moral dilemmas arising in the health care context. I will examine how these unwritten rules lead to an impoverished understanding of respect and a systematic neglect in bioethics of certain kinds of ethical consideration, and draw on insights from feminist and communitarian work on autonomy to sketch an alternative approach to understanding respect, modelled on the norms of respectful conversation - a respect that is firstly concerned with engaging with the another as a potential giver and bearer or reasons, and working with them to promote both individual and social flourishing. PMID- 29384346 TI - To What Extent Does or Should a Woman's Autonomy Overrule the Interests of Her Baby? A Study of Autonomy-related Issues in the Context of Caesarean Section. AB - Approaches to supporting autonomy in medicine need to be able to support complex and sensitive decision-making, incorporating reflection on the patient's values and goals. This should involve deliberation in partnership between physician and patient, allowing the patient to take responsibility for her decision. Nowhere is this truer than in decisions around pregnancy and Caesarean section where maternal autonomy can seem to directly conflict with foetal interests. Medical and societal expectations and norms such as the expectations of a 'mother', constraints of making decisions in an emergency, and the role of technology in viewing the foetus as a separate patient and surgery as a guarantor of results can all act to limit a woman's autonomy. In considering decisions about Caesarean section, maternal interests in bodily integrity can be dismissed as being less important than the foetus's own interests and the mother's duties to it, despite the inherent risks and impacts of such a major surgical procedure. Maternal autonomy must be respected through support for informed deliberation, incorporating patients' own values and risk tolerance, with the aim of minimizing the effect of those factors that would tend to limit autonomy. PMID- 29384347 TI - Human Dignity in Healthcare: A Virtue Ethics Approach. AB - The term 'dignity' is used in a variety of ways but always to attribute or recognize some status in the person. The present paper concerns not the status itself but the virtue of acknowledging that status. This virtue, which Thomas Aquinas calls 'observantia', concerns how dignity is honoured, respected, or observed. By analogy with justice (of which it is a part) observantia can be thought of both as a general virtue and as a special virtue. As a general virtue observantia refers to that respect for human dignity that is implicit in all acts of justice. As a special virtue it concerns the specific way we show esteem for people. Healthcare represents a challenge to observantia because those in need of healthcare are doubly restricted in expressing their dignity in action: in the first place by their ill health, and in the second place by the conditions required by healthcare (hence the sick are termed 'patients' rather than 'agents'). To be understood properly, especially in the context of healthcare, the virtue of observantia needs both to qualify and to be qualified by the virtue of misericordia, empathy, or compassion for affliction. The unity of the virtues requires a simultaneous recognition of the common dignity and common neediness of human existence. PMID- 29384348 TI - Correction to Determining Transport Efficiency for the Purpose of Counting and Sizing Nanoparticles via Single Particle Inductively Coupled Plasma Mass Spectrometry PMID- 29384350 TI - Characterization of a Prenyltransferase for Iso-A82775C Biosynthesis and Generation of New Congeners of Chloropestolides. AB - Chloropupukeananin and chloropestolides are novel metabolites of the plant endophyte Pestalotiopsis fici, showing antimicrobial, antitumor, and anti-HIV activities. Their highly complex and unique skeletons were generated from the coisolated pestheic acid (1) and iso-A82775C (10) based on our previous studies. Here, we identified the biosynthetic gene cluster iac of 10 and characterized an iacE encoded prenyltransferase. Deletion of iacE abolished iso-A82775C production, accumulated the prenyl group-lacking siccayne (2), and generated four new chloropestolides (3-6). Compounds 5 and 6 showed antibacterial effects against Staphylococcus aureus and Bacillus subtilis, and 5 was also cytotoxic to human tumor cell lines HeLa, MCF-7, and SW480. These results provided the first genetic and biochemical insights into the biosynthesis of natural prenylepoxycyclohexanes and demonstrated the feasibility for generation of diversified congeners by manipulating the biosynthetic genes of 10. PMID- 29384351 TI - Comparison of Biological Responses of Polymers Based on Imine and Disulfide Backbones for siRNA Delivery. AB - To achieve a successful delivery of siRNA by carriers in vivo, the degradation of polymers in response to tiny intracellular changes should be seriously considered. In addition, the balance between degradation and stability of polymers is another key point for high performance of carriers. In this study, imine and disulfide linkages, which are sensitive to pH changes and redox environment, respectively, were constructed as the main backbone of polymers to deliver siRNA at the intracellular and animal level. Comparisons were made between performances of these two different polymers. Both of the polymers synthesized here have good ability to condense siRNA. However, polyplexes formed by the imine backbone-based polymer (TPSP) showed a larger particle size and a higher zeta potential than that of the disulfide backbone-based polymer (DTDPS). Although both TPSP and DTDPS could deliver the target siRNA into 7721 cells, polyplexes formed by TPSP showed a higher silence efficiency in vitro and accomplished more accumulation in tumors. In conclusion, we believe TPSP is superior to be used for siRNA delivery and promises a potential for widespread use. PMID- 29384352 TI - FRET Effect between Fluorescent Polydopamine Nanoparticles and MnO2 Nanosheets and Its Application for Sensitive Sensing of Alkaline Phosphatase. AB - As an essential and universal hydrolase, alkaline phosphatase (ALP) has been identified as a crucial indicator of various diseases. Herein, we, for the first time, expanded the application of fluorescent polydopamine (F-PDA) nanoparticles to nanoquencher-based biosensing system, as well as discovered the reversible quenching effect of manganese dioxide (MnO2) nanosheets on the fluorescence of F PDA nanoparticles and intensively confirmed the quenching mechanism of Forster resonance energy transfer by using transmission electron microscopy, UV-vis, Fourier transform infrared spectroscopy, and fluorescence lifetime experiments. By means of the ALP-triggered generation of ascorbic acid (AA) from the substrate ascorbic acid 2-phosphate, the AA-triggered reduction of MnO2 nanosheets to Mn2+, as well as the clear quenching mechanism of F-PDA nanoparticles by MnO2 nanosheets, we have developed a label-free, low-cost, visual, and facile synthetic fluorescent biosensor for convenient assay of ALP activity. The fluorescent bioassay shows a good linear relationship from 1 to 80 mU/mL (R2 = 0.999), with a low detection limit of 0.34 mU/mL, and the excellent applicability in human serum samples demonstrates potential applications in clinical diagnosis and biomedical research. PMID- 29384353 TI - 3D Foam-Like Composites of Mo2C Nanorods Coated by N-Doped Carbon: A Novel Self Standing and Binder-Free O2 Electrode for Li-O2 Batteries. AB - The development of self-standing and binder-free O2 electrodes is significant for enhancing the total specific energy density and suppressing parasitic reactions for Li-O2 batteries, which is still a formidable challenge thus far. Here, a three-dimensional foam-like composite composed of Mo2C nanorods decorated by different amounts of N-doped carbon (Mo2C-NR@xNC (x = 5, 11, and 16 wt %)) was directly employed as the O2 electrode without applications of any binders and current collectors. Mo2C-NR@xNC presents a network microstructure with interconnected macropore and mesoporous channels, which is beneficial to achieving fast Li+ migration and O2 diffusion, facilitating the electrolyte impregnation, and providing enough space for Li2O2 storage. Additionally, the coated N-doped carbon layer can largely improve the electrochemical stability and conductivity of Mo2C. The cell with Mo2C-NR@11NC shows a considerable cyclability of 200 cycles with an overpotential of 0.28 V in the first cycle at a constant current density of 100 mA g-1, a superior reversibility associated with the formation and decomposition of Li2O2 as desired, and a high electrochemical stability. On the basis of the experimental results, the electrochemical mechanism for the cell using Mo2C-NR@11NC is proposed. These results represent a promising process in the development of a self-standing and binder-free foam based electrode for Li-O2 batteries. PMID- 29384354 TI - Mechanisms of Degradation and Strategies for the Stabilization of Cathode Electrolyte Interfaces in Li-Ion Batteries. AB - Undesired reactions at the interface between a transition metal oxide cathode and a nonaqueous electrolyte bring about challenges to the performance of Li-ion batteries in the form of compromised durability. These challenges are especially severe in extreme conditions, such as above room temperature or at high potentials. The ongoing push to increase the energy density of Li-ion batteries to break through the existing barriers of application in electric vehicles creates a compelling need to address these inefficiencies. This goal requires a combination of deep knowledge of the mechanisms underpinning reactivity, and the ability to assemble multifunctional electrode systems where different components synergistically extend cycle life by imparting interfacial stability, while maintaining, or even increasing, capacity and potential of operation. The barriers toward energy storage at high density apply equally in Li-ion, the leading technology in the battery market, and in related, emerging concepts for high energy density, such as Na-ion and Mg-ion, because they also conceptually rely on electroactive transition metal oxides. Therefore, their relevance is broad and the quest for solutions inevitable. In this Account, we describe mechanisms of reaction that can degrade the interface between a Li-ion battery electrolyte and the cathode, based on an oxide with transition metals that can reach high formal oxidation states. The focus is placed on cathodes that deliver high capacity and operate at high potential because their development would enable Li-ion battery technologies with high capacity for energy storage. Electrode-electrolyte instabilities will be identified beyond the intrinsic potential windows of stability, by linking them to the electroactive transition metals present at the surface of the electrode. These instabilities result in irreversible transformations at these interfaces, with formation of insulating layers that impede transport or material loss due to corrosion. As a result, strategies that screen the reactive surface of the oxide, while reducing the transition metal content by introducing inactive ions emerge as a logical means toward interfacial stability. Yet they must be implemented in the form of thin passivating barriers to avoid unacceptable losses in storage capacity. This Account subsequently describes our current ability to build composite structures that include the active material and phases designed to address deleterious reactions. We will discuss emerging strategies that move beyond the application of such barriers on premade agglomerated powders of the material of interest. The need for these strategies will be rationalized by the goal to effectively passivate all interfaces while fully controlling the chemistry that results at the surface and its homogeneity. Such outcomes would successfully minimize interfacial losses, thereby leading to materials that exceed the charge storage and life capabilities possible today. Practically speaking, it would create opportunities to design batteries that break the existing barriers of energy density. PMID- 29384355 TI - Biobased, Internally pH-Sensitive Materials: Immobilized Yellow Fluorescent Protein as an Optical Sensor for Spatiotemporal Mapping of pH Inside Porous Matrices. AB - The pH is fundamental to biological function and its measurement therefore crucial across all biosciences. Unlike homogenous bulk solution, solids often feature internal pH gradients due to partition effects and confined biochemical reactions. Thus, a full spatiotemporal mapping for pH characterization in solid materials with biological systems embedded in them is essential. In here, therefore, a fully biocompatible methodology for real-time optical sensing of pH within porous materials is presented. A genetically encoded ratiometric pH sensor, the enhanced superfolder yellow fluorescent protein (sYFP), is used to functionalize the internal surface of different materials, including natural and synthetic organic polymers as well as silica frameworks. By using controlled, tailor-made immobilization, sYFP is homogenously distributed within these materials and so enables, via self-referenced imaging analysis, pH measurements in high accuracy and with useful spatiotemporal resolution. Evolution of internal pH is monitored in consequence of a proton-releasing enzymatic reaction, the hydrolysis of penicillin by a penicillin acylase, taking place in solution or confined to the solid surface of the porous matrix. Unlike optochemical pH sensors, which often interfere with biological function, labeling with sYFP enables pH sensing without altering the immobilized enzyme's properties in any of the materials used. Fast response of sYFP to pH change permits evaluation of biochemical kinetics within the solid materials. Thus, pH sensing based on immobilized sYFP represents a broadly applicable technique to the study of biology confined to the internally heterogeneous environment of solid matrices. PMID- 29384356 TI - Atomically Resolved Electronic States and Correlated Magnetic Order at Termination Engineered Complex Oxide Heterointerfaces. AB - We map electronic states, band gaps, and interface-bound charges at termination engineered BiFeO3/La0.7Sr0.3MnO3 interfaces using atomically resolved cross sectional scanning tunneling microscopy. We identify a delicate interplay of different correlated physical effects and relate these to the ferroelectric and magnetic interface properties tuned by engineering the atomic layer stacking sequence at the interfaces. This study highlights the importance of a direct atomically resolved access to electronic interface states for understanding the intriguing interface properties in complex oxides. PMID- 29384357 TI - Composition-Dependent Aspect Ratio and Photoconductivity of Ternary (BixSb1-x)2S3 Nanorods. AB - The chemical composition, size and shape, and surface engineering play key roles in the performance of electronic, optoelectronic, and energy devices. V2VI3 (V = Sb, Bi; VI = S, Se) group materials are actively studied in these fields. In this paper, we introduce a colloidal method to synthesize uniform ternary (BixSb1 x)2S3 (0 < x < 1) nanorods. These nanorods show composition-dependent aspect ratios, enabling their composition, size, and shape control by varying Bi/Sb precursor ratios. It is found that the surface passivation by various thiols (L SH) efficiently enhances the photoconductivity and optical responsive capability of (BixSb1-x)2S3 nanorods when used as active materials in indium tin oxide (ITO)/(BixSb1-x)2S3/ITO optoelectronic devices. Meanwhile, the increase of Sb content causes a gradual deterioration of photoconductivity of thiol-passivated nanorods. We propose that the thiol passivation is able to reduce the number of S vacancies, which act as the recombination centers (trapped states) for photogenerated electrons and holes, and thus boosts the carrier transport in (BixSb1-x)2S3 nanorods, and in particular that the composition-related conductivity deterioration is attributed to the increase of unpassivated S vacancies and surface oxidation due to the rise of Sb content. PMID- 29384358 TI - Smoothing Surface Trapping States in 3D Coral-Like CoOOH-Wrapped-BiVO4 for Efficient Photoelectrochemical Water Oxidation. AB - Highly efficient oxygen evolution driven by abundant sunlight is a key to realize overall water splitting for large-scale conversion of renewable energy. Here, we report a strategy for the interfacial atomic and electronic coupling of layered CoOOH and BiVO4 to deactivate the surface trapping states and suppress the charge carrier recombination for high photoelectrochemical (PEC) water oxidation activity. The successful synthesis of a 3D ultrathin-CoOOH-overlayer-coated coral like BiVO4 photoanode effectively tailors the migration route of photocarriers on the semiconductor/liquid interface to realize a great increase of ~200% in the photovoltage relative to bare BiVO4, consequently decreasing the corresponding onset potential of PEC water splitting from 0.60 to 0.20 VRHE. As a result, the unique CoOOH/BiVO4 photoanode could efficiently perform PEC water oxidation in a neutral aqueous solution (pH = 7) with a high photocurrent density of 4.0 mA/cm2 at 1.23 VRHE and a prominent quantum efficiency of 65% at 450 nm. Electronic structural characterizations and theoretical calculations reveal that the combination of layered CoOOH and BiVO4 forming interfacial oxo-bridge bonding could greatly eliminate surface trapping states and promote the direct transfer of photogenerated holes from the valence band to the surface water redox potential for water oxidation. PMID- 29384359 TI - Highly Stretchable Core-Sheath Fibers via Wet-Spinning for Wearable Strain Sensors. AB - Lightweight, stretchable, and wearable strain sensors have recently been widely studied for the development of health monitoring systems, human-machine interfaces, and wearable devices. Herein, highly stretchable polymer elastomer wrapped carbon nanocomposite piezoresistive core-sheath fibers are successfully prepared using a facile and scalable one-step coaxial wet-spinning assembly approach. The carbon nanotube-polymeric composite core of the stretchable fiber is surrounded by an insulating sheath, similar to conventional cables, and shows excellent electrical conductivity with a low percolation threshold (0.74 vol %). The core-sheath elastic fibers are used as wearable strain sensors, exhibiting ultra-high stretchability (above 300%), excellent stability (>10 000 cycles), fast response, low hysteresis, and good washability. Furthermore, the piezoresistive core-sheath fiber possesses bending-insensitiveness and negligible torsion-sensitive properties, and the strain sensing performance of piezoresistive fibers maintains a high degree of stability under harsh conditions. On the basis of this high level of performance, the fiber-shaped strain sensor can accurately detect both subtle and large-scale human movements by embedding it in gloves and garments or by directly attaching it to the skin. The current results indicate that the proposed stretchable strain sensor has many potential applications in health monitoring, human-machine interfaces, soft robotics, and wearable electronics. PMID- 29384360 TI - Exposing the {010} Planes by Oriented Self-Assembly with Nanosheets To Improve the Electrochemical Performances of Ni-Rich Li[Ni0.8Co0.1Mn0.1]O2 Microspheres. AB - A modified Ni-rich Li[Ni0.8Co0.1Mn0.1]O2 cathode material with exposed {010} planes is successfully synthesized for lithium-ion batteries. The scanning electron microscopy images have demonstrated that by tuning the ammonia concentration during the synthesis of precursors, the primary nanosheets could be successfully stacked along the [001] crystal axis predominantly, self-assembling like multilayers. According to the high-resolution transmission electron microscopy results, such a morphology benefits the growth of the {010} active planes of final layered cathodes during calcination treatment, resulting in the increased area of the exposed {010} active planes, a well-ordered layer structure, and a lower cation mixing disorder. The Li-ion diffusion coefficient has also been improved after the modification based on the results of potentiostatic intermittent titration technique. As a consequence, the modified Li[Ni0.8Co0.1Mn0.1]O2 material exhibits superior initial discharges of 201.6 mA h g-1 at 0.2 C and 185.7 mA h g-1 at 1 C within 2.8-4.3 V (vs Li+/Li), and their capacity retentions after 100 cycles reach 90 and 90.6%, respectively. The capacity at 10 C also increases from 98.3 to 146.5 mA h g-1 after the modification. Our work proposes a novel approach for exposing high-energy {010} active planes of the layered cathode material and again confirms its validity in improving electrochemical properties. PMID- 29384361 TI - High-Performance Silicon Photoanode Enhanced by Gold Nanoparticles for Efficient Water Oxidation. AB - Ni catalyst is a low-cost catalyst for oxygen evolution reaction (OER) on silicon metal-insulator-semiconductor photoanode. We found that Au nanoparticles incorporated with Ni nanoparticles can enhance the OER activity and stability of Ni nanoparticles due to the local surface plasmon resonance (LSPR) effect of the Au nanoparticles. The efficiency of NiAu/TiO2/n-Si photoanode can be boosted at least three times under the illumination (100 mW/cm2) by LSPR effect of the Au nanoparticles. A small onset potential of 1.03 V versus reversible hydrogen electrode (overpotential, eta0 = -0.20 V) and a current density of 18.80 mA/cm2 at 1.23 V versus reversible hydrogen electrode can be obtained. The NiAu/TiO2/n Si photoanode exhibits a high saturation current density of 35 mA/cm2, which is greater than that of most of the state-of-the-art silicon photoanodes. PMID- 29384362 TI - Enhanced Electrochemical Stability of a Zwitterionic-Polymer-Functionalized Electrode for Capacitive Deionization. AB - In capacitive deionization, the salt-adsorption capacity of the electrode is critical for the efficient softening of brackish water. To improve the water deionization capacity, the carbon electrode surface is modified with ion-exchange resins. Herein, we introduce the encapsulation of zwitterionic polymers over activated carbon to provide a resistant barrier that stabilizes the structure of electrode during electrochemical performance and enhances the capacitive deionization efficiency. Compared to conventional activated carbon, the surface modified activated carbon exhibits significantly enhanced capacitive deionization, with a salt adsorption capacity of ~2.0 * 10-4 mg/mL and a minimum conductivity of ~43 MUS/cm in the alkali-metal ions solution. Encapsulating the activated-carbon surface increased the number of ions adsorption sites and the surface area of the electrode, which improved the charge separation and deionization efficiency. In addition, the coating layer suppresses side reactions between the electrode and electrolyte, thus providing a stable cyclability. Our experimental findings suggest that the well-distributed coating layer leads to a synergistic effect on the enhanced electrochemical performance. In addition, density functional theory calculation reveals that a favorable binding affinity exists between the alkali-metal ion and zwitterionic polymer, which supports the preferable salt ions adsorption on the coating layer. The results provide useful information for designing more efficient capacitive-deionization electrodes that require high electrochemical stability. PMID- 29384364 TI - Multiscale Principles To Boost Reactivity in Gas-Involving Energy Electrocatalysis. AB - Various gas-involving energy electrocatalysis, including oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER), has witnessed increasing concerns recently for the sake of clean, renewable, and efficient energy technologies. However, these heterogeneous reactions exhibit sluggish kinetics due to multistep electron transfer and only occur at triple-phase boundary regions. Up to now, tremendous attention has been attracted to develop cost-effective and high-performance electrocatalysts to boost the electrocatalytic activities as promising alternatives to noble metal counterparts. In addition to the prolific achievements in materials science, the advances in interface chemistry are also very critical in consideration of the complex phenomena proceeded at triple-phase boundary regions, such as mass diffusion, electron transfer, and surface reaction. Therefore, insightful principles and effective strategies for a comprehensive optimization, ranging from active sites to electrochemical interface, are necessary to fully enhance the electrocatalytic performance aiming at practical device applications. In this Account, we give an overview of our recent attempts toward efficient gas involving electrocatalysis with multiscale principles from the respect of electronic structure, hierarchical morphology, and electrode interface step by step. It is widely accepted that the intrinsic activity of individual active sites is directly influenced by their electronic structure. Heteroatom doping and topological defects are demonstrated to be the most effective strategies for metal-free nanocarbon materials, while the cationic (e.g., Ni, Fe, Co, Sn) and anionic (e.g., O, S, OH) regulation is revealed to be a promising method for transition metal compounds, to alter the electronic structure and generate high activity. Additionally, the apparent activity of the whole electrocatalyst is significantly impacted by its hierarchical morphology. The active sites of nanocarbon materials are expected to be enriched on the surface for a full exposure and utilization; the hybridization of other active components with nanocarbon materials should achieve a uniform dispersion in nanoscale and a strongly coupled interface, thereby ensuring the electron transfer and boosting the activity. Furthermore, steady and favorable electrochemical interfaces are strongly anticipated in working electrodes for optimal reaction conditions. The powdery electrocatalysts are suggested to be constructed into self-supported electrodes for more efficient and stable catalysis integrally, while the local microenvironment can be versatilely modified by ionic liquids with more beneficial gas solubility and hydrophobicity. Collectively, with the all-round regulation of the electronic structure, hierarchical morphology, and electrode interface, the electrocatalytic performances are demonstrated to be comprehensively facilitated. Such multiscale principles stemmed from the in-depth insights on the structure-activity relationship and heterogeneous reaction characteristics will no doubt pave the way for the future development of gas involving energy electrocatalysis, and also afford constructive inspirations in a broad range of research including CO2 reduction reaction, hydrogen peroxide production, nitrogen reduction reaction, and other important electrocatalytic activation of small molecules. PMID- 29384363 TI - Isobaric Labeling of Intact Gangliosides toward Multiplexed LC-MS/MS-Based Quantitative Analysis. AB - Gangliosides are sialic acid-containing glycosphingolipids recognized to play essential role in biological processes. Both the glycan and lipid structures influence their biological function and thus necessitate their determination as intact molecular species. To our knowledge, no multiplexed method for intact gangliosides currently exists. In this paper, we aimed to demonstrate an approach for isobaric labeling of intact gangliosides. Specifically, we carried out the rapid, chemoselective oxidation of sialic acid side chain in common ganglioside core structures using NaIO4 followed by ligation with a carbonyl-reactive isobaric tandem mass tag (TMT) reagent and subsequent RPLC-MS/MS analysis. Attachment of the isobaric label was observed to improve the ionization efficiency of complex gangliosides using electrospray ionization. Fragmentation of the resulting [M + 2H]2+ ions of TMT-labeled gangliosides provided information rich spectra containing fragments from the glycan, lipid, and TMT reporter ions. This facile approach enabled simultaneous quantification of up to six samples as well as identification of glycan and lipid compositions in a single injection. As a proof-of-concept, using porcine brain total ganglioside extracts pooled at known ratios, we obtained overall sample-to-sample precision of <12% RSD and mean error of <10%. This showcased the great promise and feasibility of this strategy for high-throughput analysis of intact gangliosides in biological extracts. PMID- 29384365 TI - Ce-Doped NiFe-Layered Double Hydroxide Ultrathin Nanosheets/Nanocarbon Hierarchical Nanocomposite as an Efficient Oxygen Evolution Catalyst. AB - Developing convenient doping to build highly active oxygen evolution reaction (OER) electrocatalysts is a practical process for solving the energy crisis. Herein, a facile and low-cost in situ self-assembly strategy for preparing a Ce doped NiFe-LDH nanosheets/nanocarbon (denoted as NiFeCe-LDH/CNT, LDH = layered double hydroxide and CNT = carbon nanotube) hierarchical nanocomposite is established for enhanced OER, in which the novel material provides its overall advantageous structural features, including high intrinsic catalytic activity, rich redox properties, high, flexible coordination number of Ce3+, and strongly coupled interface. Further experimental results indicate that doped Ce into NiFe LDH/CNT nanoarrays brings about the reinforced specific surface area, electrochemical surface area, lattice defects, and the electron transport between the LDH nanolayered structure and the framework of CNTs. The effective synergy prompts the NiFeCe-LDH/CNT nanocomposite to possess superior OER electrocatalytic activity with a low onset potential (227 mV) and Tafel slope (33 mV dec-1), better than the most non-noble metal-based OER electrocatalysts reported. Therefore, the combination of the remarkable catalytic ability and the facile normal temperature synthesis conditions endows the Ce-doped LDH nanocomposite as a promising catalyst to expand the field of lanthanide-doped layered materials for efficient water-splitting electrocatalysis with scale-up potential. PMID- 29384366 TI - Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects. AB - There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small number of suitable target genes that have been shown by genetic or chemical methods to be essential for the parasite. In this perspective, we discuss the state of genetic target validation in the field of Leishmania research and review the 200 Leishmania genes and 36 Trypanosoma cruzi genes for which gene deletion attempts have been made since the first published case in 1990. We define a quality score for the different genetic deletion techniques that can be used to identify potential drug targets. We also discuss how the advances in genome-scale gene disruption techniques have been used to assist target-based and phenotypic based drug development in other parasitic protozoa and why Leishmania has lacked a similar approach so far. The prospects for this scale of work are considered in the context of the application of CRISPR/Cas9 gene editing as a useful tool in Leishmania. PMID- 29384367 TI - Tuning the Hydrolytic Stability of Next Generation Maleimide Cross-Linkers Enables Access to Albumin-Antibody Fragment Conjugates and tri-scFvs. AB - We describe investigations to expand the scope of next generation maleimide cross linkers for the construction of homogeneous protein-protein conjugates. Diiodomaleimides are shown to offer the ideal properties of rapid bioconjugation with reduced hydrolysis, allowing the cross-linking of even sterically hindered systems. The optimized linkers are exploited to link human serum albumin to antibody fragments (Fab or scFv) as a prospective half-life extension platform, with retention of antigen binding and robust serum stability. Finally, a triprotein conjugate is formed, by linking scFv antibody fragments targeting carcinoembryonic antigen. This tri-scFv is shown to infer a combination of greater antigen avidity and increased in vivo half-life, representing a promising platform for antibody therapeutic development. PMID- 29384368 TI - Electrocatalytic Reduction of CO2 to Formate by an Iron Schiff Base Complex. AB - The synthesis, structural characterization, and reactivity of an iron(III) chloride compound of 6,6'-di(3,5-di-tert-butyl-2-hydroxybenzene)-2,2'-bipyridine (Fe(tbudhbpy)Cl), under electrochemically reducing conditions is reported. In the presence of carbon dioxide (CO2) under anhydrous conditions in N,N dimethylformamide (DMF), this complex mediates the 2e- reductive disproportionation of two equivalents of CO2 to carbon monoxide (CO) and carbonate (CO32-). Upon addition of phenol (PhOH) as a proton source under CO2 saturation, catalytic current is observed; product analysis from controlled potential electrolysis experiments shows the majority product is formate (68 +/- 4% Faradaic efficiency), with H2 as a minor product (30 +/- 10% Faradaic efficiency) and minimal CO (1.1 +/- 0.3% Faradaic efficiency). On the basis of data obtained from cyclic voltammetry and infrared spectroelectrochemistry (IR SEC), the release of CO from intermediate Fe carbonyl species is extremely slow and undergoes competitive degradation, limiting the activity and lifetime of this catalyst. Mechanistic studies also indicate the phenolate moieties coordinated to Fe are sensitive to protonation in the reduced state, suggesting the possibility of cooperative pendent proton interactions being involved in CO2 reduction. PMID- 29384370 TI - DNA-Assembled Advanced Plasmonic Architectures. AB - The interaction between light and matter can be controlled efficiently by structuring materials at a length scale shorter than the wavelength of interest. With the goal to build optical devices that operate at the nanoscale, plasmonics has established itself as a discipline, where near-field effects of electromagnetic waves created in the vicinity of metallic surfaces can give rise to a variety of novel phenomena and fascinating applications. As research on plasmonics has emerged from the optics and solid-state communities, most laboratories employ top-down lithography to implement their nanophotonic designs. In this review, we discuss the recent, successful efforts of employing self assembled DNA nanostructures as scaffolds for creating advanced plasmonic architectures. DNA self-assembly exploits the base-pairing specificity of nucleic acid sequences and allows for the nanometer-precise organization of organic molecules but also for the arrangement of inorganic particles in space. Bottom-up self-assembly thus bypasses many of the limitations of conventional fabrication methods. As a consequence, powerful tools such as DNA origami have pushed the boundaries of nanophotonics and new ways of thinking about plasmonic designs are on the rise. PMID- 29384372 TI - Robust Bifunctional Lanthanide Cluster Based Metal-Organic Frameworks (MOFs) for Tandem Deacetalization-Knoevenagel Reaction. AB - A series of 12-connected lanthanide cluster based metal-organic frameworks (MOFs) have been constructed by [Ln6(MU3-OH)8(COO-)12] secondary building units (SBUs) and 2-aminobenzenedicarboxylate (BDC-NH2) ligands. These obtained materials exhibit high chemical stability and generic thermal stability, especially in acidic and basic conditions. They also present commendable CO2 adsorption capacity, and Yb-BDC-NH2 was further confirmed by a breakthrough experiment under both dry and wet conditions. Moreover, these materials possess both Lewis acid and Bronsted base sites that can catalyze one-pot tandem deacetalization Knoevenagel condensation reactions. PMID- 29384371 TI - Sterically Stabilized Terminal Hydride of a Diiron Dithiolate. AB - The kinetically robust hydride [t-HFe2(Me2pdt)(CO)2(dppv)2]+ ([t-H1]+) (Me2pdt2- = Me2C(CH2S-)2; dppv = cis-1,2-C2H2(PPh2)2) and related derivatives were prepared with 57Fe enrichment for characterization by NMR, FT-IR, and NRVS. The experimental results were rationalized using DFT molecular modeling and spectral simulations. The spectroscopic analysis was aimed at supporting assignments of Fe H vibrational spectra as they relate to recent measurements on [FeFe]-hydrogenase enzymes. The combination of bulky Me2pdt2- and dppv ligands stabilizes the terminal hydride with respect to its isomerization to the 5-16 kcal/mol more stable bridging hydride ([MU-H1]+) with t1/2(313.3 K) = 19.3 min. In agreement with the nOe experiments, the calculations predict that one methyl group in [t H1]+ interacts with the hydride with a computed CH...HFe distance of 1.7 A. Although [t-H571]+ exhibits multiple NRVS features in the 720-800 cm-1 region containing the bending Fe-H modes, the deuterated [t-D571]+ sample exhibits a unique Fe-D/CO band at ~600 cm-1. In contrast, the NRVS spectra for [MU-H571]+ exhibit weaker bands near 670-700 cm-1 produced by the Fe-H-Fe wagging modes coupled to Me2pdt2- and dppv motions. PMID- 29384374 TI - Chemical Vapor Deposition Growth and Applications of Two-Dimensional Materials and Their Heterostructures. AB - Two-dimensional (2D) materials have attracted increasing research interest because of the abundant choice of materials with diverse and tunable electronic, optical, and chemical properties. Moreover, 2D material based heterostructures combining several individual 2D materials provide unique platforms to create an almost infinite number of materials and show exotic physical phenomena as well as new properties and applications. To achieve these high expectations, methods for the scalable preparation of 2D materials and 2D heterostructures of high quality and low cost must be developed. Chemical vapor deposition (CVD) is a powerful method which may meet the above requirements, and has been extensively used to grow 2D materials and their heterostructures in recent years, despite several challenges remaining. In this review of the challenges in the CVD growth of 2D materials, we highlight recent advances in the controlled growth of single crystal 2D materials, with an emphasis on semiconducting transition metal dichalcogenides. We provide insight into the growth mechanisms of single crystal 2D domains and the key technologies used to realize wafer-scale growth of continuous and homogeneous 2D films which are important for practical applications. Meanwhile, strategies to design and grow various kinds of 2D material based heterostructures are thoroughly discussed. The applications of CVD grown 2D materials and their heterostructures in electronics, optoelectronics, sensors, flexible devices, and electrocatalysis are also discussed. Finally, we suggest solutions to these challenges and ideas concerning future developments in this emerging field. PMID- 29384373 TI - Catalytic Carbo- and Aminoboration of Alkenyl Carbonyl Compounds via Five- and Six-Membered Palladacycles. AB - A palladium(II)-catalyzed alkene difunctionalization reaction has been developed, wherein B2pin2 is used to trap chelation-stabilized alkylpalladium(II) intermediates that are formed upon nucleopalladation. A range of carbon and nitrogen nucleophiles were found to be suitable coupling partners in this transformation, providing moderate to high yields. Both 3-butenoic and 4 pentenoic acid derivatives were reactive substrate classes, affording beta,gamma- and gamma,delta-difunctionalized carboxylic acid derivatives. This work represents a new strategy to synthesize highly functionalized secondary boronates that complements existing methods. PMID- 29384369 TI - Hit Generation in TB Drug Discovery: From Genome to Granuloma. AB - Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell screening assays because biochemical, target-based inhibitor screens during the last two decades have not delivered new TB drugs. Mycobacterium tuberculosis (Mtb), the causative agent of TB, encounters diverse microenvironments and can be found in a variety of metabolic states in the human host. Due to the complexity and heterogeneity of Mtb infection, no single model can fully recapitulate the in vivo conditions in which Mtb is found in TB patients, and there is no single "standard" screening condition to generate hit compounds for TB drug development. However, current screening assays have become more sophisticated as researchers attempt to mirror the complexity of TB disease in the laboratory. In this review, we describe efforts using surrogates and engineered strains of Mtb to focus screens on specific targets. We explain model culture systems ranging from carbon starvation to hypoxia, and combinations thereof, designed to represent the microenvironment which Mtb encounters in the human body. We outline ongoing efforts to model Mtb infection in the lung granuloma. We assess these different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery. PMID- 29384375 TI - Nonprecious Metal Catalysts for Oxygen Reduction in Heterogeneous Aqueous Systems. AB - A comprehensive review of recent advances in the field of oxygen reduction electrocatalysis utilizing nonprecious metal (NPM) catalysts is presented. Progress in the synthesis and characterization of pyrolyzed catalysts, based primarily on the transition metals Fe and Co with sources of N and C, is summarized. Several synthetic strategies to improve the catalytic activity for the oxygen reduction reaction (ORR) are highlighted. Recent work to explain the active-site structures and the ORR mechanism on pyrolyzed NPM catalysts is discussed. Additionally, the recent application of Cu-based catalysts for the ORR is reviewed. Suggestions and direction for future research to develop and understand NPM catalysts with enhanced ORR activity are provided. PMID- 29384377 TI - Weak Directing Group Steered Formal Oxidative [2+2+2]-Cyclization for Selective Benzannulation of Indoles. AB - A double C-H activation and double insertion process to achieve the synthesis benzo[e]indole frameworks has been disclosed. This type of benzannulation is directed by a trifluoromethylketone moiety, which is easy to install on the indole C3-position. Overall the reaction takes places as an oxidative cyclization of two alkynes with the C4-C5 position of indole. PMID- 29384378 TI - Combining Electronic and Steric Effects To Generate Hindered Propargylic Alcohols in High Enantiomeric Excess. AB - Tethered ruthenium-TsDPEN complexes have been applied to the catalysis of the asymmetric transfer hydrogenation of a range of aryl/acetylenic ketones. The introduction of an ortho- substituent to the aryl ring of the substrate results in a reversal of the enantioselectivity, while the introduction of two o-fluoro substituents results in an improvement to the reduction enantioselectivity, as does the replacement of a phenyl ring on the alkyne with a trimethylsilyl group. These effects are rationalized as resulting from a change in the steric properties of the aryl ring and the electronic properties of the alkyne which, when matched in the reduction transition state, combine within a "window" of substrate/catalyst matching to generate products of high ee. PMID- 29384379 TI - Coalescence-Induced Jumping of Two Unequal-Sized Nanodroplets. AB - Coalescence-induced self-propelled jumping of droplets on superhydrophobic surfaces has potential applications for condensation heat transfer enhancement, anti-icing, self-cleaning, antidew, and so forth. However, most of the previous studies focused on two identical droplets which are not commonly encountered in the nature. In this work, coalescence-induced jumping phenomena of two unequal sized droplets on superhydrophobic surfaces were investigated theoretically and numerically. First, by introducing modified inertial-capillary velocity (uic*) and Ohnesorge number (Oh*) with consideration of radius ratio (r*) of two coalescing droplets, we proposed a generalized inertial-capillary scaling law for the jumping velocity of coalesced droplets, which is expected to be applicable for both two identical droplets and two unequal-sized droplets coalescing on superhydrophobic surfaces. Subsequently, we employed molecular dynamics simulations to investigate the coalescence-induced jumping process of two unequal sized nanodroplets. Our simulations showed that the dimensionless jumping velocity (vj/uic*) well follows the generalized inertial-capillary scaling law with vj/uic* ~ 0.127 in a specific Oh* range; however, it rapidly reduces and finally vanishes when the radius ratio of large droplet to small droplet is larger than a certain threshold value. Our simulations also revealed that nonjumping of two unequal-sized droplets with a very large radius ratio is due to that the larger droplet swallows the small one, so that the liquid bridge has no chance to impact the solid surface, and hence the "liquid bridge impacting substrate" mechanism fails in this circumstance. PMID- 29384380 TI - High-Content Surface and Total Expression siRNA Kinase Library Screen with VX-809 Treatment Reveals Kinase Targets that Enhance F508del-CFTR Rescue. AB - The most promising F508del-CFTR corrector, VX-809, has been unsuccessful as an effective, stand-alone treatment for CF patients, but the rescue effect in combination with other drugs may confer an acceptable level of therapeutic benefit. Targeting cellular factors that modify trafficking may act to enhance the cell surface density of F508-CFTR with VX-809 correction. Our goal is to identify druggable kinases that enhance F508del-CFTR rescue and stabilization at the cell surface beyond that achievable with the VX-809 corrector alone. To achieve this goal, we implemented a new high-throughput screening paradigm that quickly and quantitatively measures surface density and total protein in the same cells. This allowed for rapid screening for increased surface targeting and proteostatic regulation. The assay utilizes fluorogen-activating-protein (FAP) technology with cell excluded and cell permeant fluorogenic dyes in a quick, wash free fluorescent plate reader format on live cells to first measure F508del-CFTR expressed on the surface and then the total amount of F508del-CFTR protein present. To screen for kinase targets, we used Dharmacon's ON-TARGET plus SMARTpool siRNA Kinase library (715 target kinases) with and without 10 MUM VX 809 treatment in triplicate at 37 degrees C. We identified several targets that had a significant interaction with VX-809 treatment in enhancing surface density with siRNA knockdown. Select small-molecule inhibitors of the kinase targets demonstrated augmented surface expression with VX-809 treatment. PMID- 29384381 TI - Quantum Chemical Topology of the Electron Localization Function in the Field of Attosecond Electron Dynamics. AB - We report original analyses of attosecond electron dynamics of molecules subject to collisions by high energy charged particles based on Real-Time Time-Dependent Density-Functional-Theory simulations coupled to Topological Analyses of the Electron Localization Function (TA-TD-ELF). We investigate irradiation of water and guanine. TA-TD-ELF enables qualitative and quantitative characterizations of bond breaking and formation, of charge migration within topological basins, or of electron attachment to the colliding particle. Whereas the Lewis-VSEPR structure of gas phase water is blown out within a few attoseconds after collision, that of guanine is far more robust and reconstitutes rapidly after impact even though the molecule remains electronically excited. This difference is accounted by the presence of the electron bath surrounding the impact point which enables energy relaxation within the molecule. Our approach should stimulate future studies to unravel the early steps following irradiation of various types of systems (isolated molecules, biomolecules, nanoclusters, solids, etc.) and is also readily applicable to irradiation by photons of various energies. PMID- 29384382 TI - Sub-2 nm Single-Crystal Pt Nanoparticles via Sputtering onto a Liquid Polymer. AB - Matrix sputtering with the use of a low vapor pressure liquid as its matrix becomes a green technique to prepare nanoparticles dispersed in liquid. In the present study, we proposed using this method with polyethylene glycol (PEG, molecular weight = 600) as the liquid matrix to produce highly uniform Pt nanoparticles with a small size (below 2.0 nm) and a narrow size distribution. The results indicated that particle sizes were tailorable from 0.9 +/- 0.3 to 1.4 +/- 0.3 nm by varying the sputtering current (5-50 mA) with negligible particle aggregation that occurred in PEG during sputtering. The slight growth of the particle size observed after sputtering was attributed to the addition of free Pt atoms to the existing Pt nanoparticles. All samples formed stable dispersion in PEG for 5 month storage. This result suggested an advantage of using a liquid matrix to produce and stabilize nanoparticles. PMID- 29384376 TI - New Technologies for Analysis of Extracellular Vesicles. AB - Extracellular vesicles (EVs) are diverse, nanoscale membrane vesicles actively released by cells. Similar-sized vesicles can be further classified (e.g., exosomes, microvesicles) based on their biogenesis, size, and biophysical properties. Although initially thought to be cellular debris, and thus under appreciated, EVs are now increasingly recognized as important vehicles of intercellular communication and circulating biomarkers for disease diagnoses and prognosis. Despite their clinical potential, the lack of sensitive preparatory and analytical technologies for EVs poses a barrier to clinical translation. New analytical platforms including molecular ones are thus actively being developed to address these challenges. Recent advances in the field are expected to have far-reaching impact in both basic and translational studies. This article aims to present a comprehensive and critical overview of emerging analytical technologies for EV detection and their clinical applications. PMID- 29384383 TI - Diastereo- and Enantioselective Dearomative [3 + 2] Cycloaddition Reaction of 2 Nitrobenzofurans with 3-Isothiocyanato Oxindoles. AB - Enantioselective dearomative [3 + 2] cycloaddition reaction of 2-nitrobenzofurans with 3-isothiocyanato oxindoles was developed. The reaction employs a chiral bis(oxazoline)/Zn(OTf)2 catalyst, allowing a practical, straightforward access to structurally diverse spirooxindoles containing a 2,3-dihydrobenzofuran motif and three contiguous stereocenters with excellent diastereo- and enantioselectivities. The synthetic potentials of the method have been demonstrated by the scale-up experiment and transformations of the products. The preliminary mechanism was investigated with experimental observations, nonlinear effects studies, and MS experiments. PMID- 29384387 TI - Racial differences in dietary antioxidant intake and cardiac event-free survival in patients with heart failure. AB - BACKGROUND: Heart failure is a chronic, burdensome condition with higher re hospitalization rates in African Americans than Whites. Higher dietary antioxidant intake is associated with lower oxidative stress and improved endothelial function. Lower dietary antioxidant intake in African Americans may play a role in the re-hospitalization disparity between African American and White patients with heart failure. OBJECTIVE: The objective of this study was to examine the associations among race, dietary antioxidant intake, and cardiac event-free survival in patients with heart failure. METHODS: In a secondary analysis of 247 patients with heart failure who completed a four-day food diary, intake of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, lycopene, vitamins C and E, zinc, and selenium were assessed. Antioxidant deficiency was defined as intake below the estimated average requirement for antioxidants with an established estimated average requirement, or lower than the sample median for antioxidants without an established estimated average requirement. Patients were followed for a median of one year to determine time to first cardiac event (hospitalization or death). Survival analysis was used for data analysis. RESULTS: African American patients had more dietary antioxidant deficiencies and a shorter cardiac event-free survival compared with Whites ( p = .007 and p = .028, respectively). In Cox regression, race and antioxidant deficiency were associated with cardiac event-free survival before and after adjusting for covariates. CONCLUSION: African Americans with heart failure had more dietary antioxidant deficiencies and shorter cardiac event-free survival than Whites. This suggests that encouraging African American patients with heart failure to consume an antioxidant-rich diet may be beneficial in lengthening cardiac event-free survival. PMID- 29384388 TI - The stability of engagement over comprehensive neuropsychological assessment in student athletes diagnosed with sports related concussion. AB - We documented effort stability during neuropsychological (NP) testing examining failure rates on three Performance Validity Tests (PVTs). 65 student athletes, ages 8-21, were evaluated in an outpatient practice, following sports-related concussion over three sessions within 18 months of injury (mean=6 months). 7.7% of student athletes failed PVTs at all three test sessions, 7.7% failed PVTs at two test sessions, and 12.3% failed PVTs at one session; 28% of this sample was sub-optimally engaged for at least one test session, producing invalid neuropsychological data at the time of testing and 72% produced valid neuropsychological data across the comprehensive evaluation. PMID- 29384390 TI - Bittersweet: a qualitative exploration of mothers' experiences of raising a single surviving twin. AB - Loss of a child from a multiple birth pregnancy is not uncommon yet the idiographic experience of parents who have lost a single twin from a multiple birth pregnancy is underexplored. This novel study sought to explore the experiences of mothers bereaved after loss of a twin from a multiple birth pregnancy, focusing on the dual challenges of parenting and grieving. Eighteen mothers at least 12 months post loss were recruited from a private UK based Facebook page dedicated to supporting parents after loss from a multiple birth. Eligible mothers completed an independent qualitative open-ended survey to explore maternal experiences of loss. Data were analysed using Thematic Analysis. Findings represented a sense of duality for participants, with mothers experiencing conflict between roles and identities as well as the nature of their loss. Key themes identified include 'Narrating a story of family and loss', 'Finding a place for the twins within the family' and 'A changing sense of self'. Findings fit with theoretical conceptualisations of bereavement that acknowledge retaining relationships with the deceased. Practically, suggestions for supporting mothers to identify stock answers to often asked questions about family make up were suggested. PMID- 29384389 TI - A Multisite, Multidisciplinary Delphi Consensus Study Describing "Usual Care" Intervention Strategies for School-Age to Transition-Age Youth With Autism. AB - Understanding usual care is important to reduce health disparities and improve the dissemination of evidence-based practices for youth (ages 7-22 years) with autism spectrum disorder (ASD). A barrier to describing "usual ASD care" is the lack of a common vocabulary and inventory of the practices used by a diverse provider field. To address this barrier, we gathered input from expert providers to develop an inventory of usual care practices and assess expert familiarity and perceptions of these practices as interventions for anxiety, externalizing, and social difficulties in ASD. Purposeful sampling recruited 66 expert ASD providers representing multiple disciplines from 5 sites. Via a 2-round Delphi poll, experts reviewed, suggested revisions to and rated 49 literature-derived practices on several dimensions (familiarity, usefulness, common use, research support). A revised list of 55 practices and anonymous summary of group characteristics and ratings was then returned for further review. Results yielded 55 intervention practices, 48 of which were identified as "familiar" approaches by consensus (>= 75% endorsement). Greater variation was observed in practices identified by consensus as most often used, useful, and research supported, depending upon the target problem. Findings provide an inventory of practices, reflective of the multidisciplinary language and approaches of expert ASD providers. This inventory may be used to better assess what constitutes usual care for youth with ASD in the United States. Moreover, findings offer insights from clinical experts regarding the range and acceptability of practices that may inform and ground treatment research, dissemination, and implementation efforts. PMID- 29384391 TI - How can heart disease patients prevent complications from viral infections? PMID- 29384393 TI - Intralesional botulinum toxin-A injection for the treatment of multiple eccrine hidrocystomas. AB - BACKGROUND: Multiple eccrine hidrocystomas (MEH) are benign cystic lesions of the sweat gland ducts. They are characterized by translucent, skin-colored or bluish dome-shaped papules on the face, causing cosmetic concern. Recently, botulinum toxin-A, because of its antiperspirant properties, has been used to treat facial MEH. However, there are only some case reports in the literature. OBJECTIVE: Here, we conducted a prospective study to assess the efficacy and safety of intralesional injection of botulinum toxin-A (Dysport) for the treatment of MEH. MATERIAL AND METHODS: Twenty patients (3 men and 17 women), aged from 31 to 75 years old, participated in this study. A 300 unit vial of botulinum toxin-A (Dysport, Ipsenn Biopharm, United Kingdom) was diluted with 4 ml of saline solution without preservative to achieve a concentration of 7.5U/.1 ml. Up to 1.5 unit of botulinum toxin was injected intradermally at the base of each lesion to raise a visible wheal. The patients were evaluated 7 days later, and any clinical changes or adverse effects were recorded. RESULTS: In all patients, more than 75% of eccrine hidrocystoma lesions resolved without any scaring. The result sustained for 2-5 months. In two patients mild smile asymmetry and in one patient lagophthalmos were noted approximately 5-7 days after injection that gradually resolved in 3 weeks. CONCLUSION: Intralesional botulinum toxin-A for treatment of multiple hidrocystomas is a simple and well-tolerated procedure. It is accompanied by excellent results, a good postoperative course, and no risk of scarring. It can be considered in patients who did not respond to other treatment or even as the first line therapy. PMID- 29384392 TI - Factors associated with health-related quality of life in stable ambulatory congestive heart failure patients: Systematic review. AB - Background Since improved treatment of congestive heart failure has resulted in decreased mortality and hospitalisation rates, increasing self-perceived health related quality of life (HRQoL) has become a major goal of congestive heart failure treatment. However, an overview on predictieve factors of HRQoL is currently lacking in literature. Purpose The aim of this study was to identify key factors associated with HRQoL in stable ambulatory patients with congestive heart failure. Methods A systematic review was performed. MEDLINE, Web of Science and Embase were searched for the following combination of terms: heart failure, quality of life, health perception or functional status between the period 2000 and February 2017. Literature screening was done by two independent reviewers. Results Thirty-five studies out of 8374 titles were included for quality appraisal, of which 29 were selected for further data extraction. Four distinct categories grouping different types of variables were identified: socio demographic characteristics, clinical characteristics, health and health behaviour, and care provider characteristics. Within the above-mentioned categories the presence of depressive symptoms was most consistently related to a worse HRQoL, followed by a higher New York Heart Association functional class, younger age and female gender. Conclusion Through a systematic literature search, factors associated with HRQoL among congestive heart failure patients were investigated. Age, gender, New York Heart Association functional class and depressive symptoms are the most consistent variables explaining the variance in HRQoL in patients with congestive heart failure. These findings are partly in line with previous research on predictors for hard endpoints in patients with congestive heart failure. PMID- 29384394 TI - Prospective analysis of the port-wine stain patient population in the Netherlands in light of novel treatment modalities. AB - BACKGROUND: Pulsed dye laser is the gold standard for port-wine stain (PWS) treatment. However, pulsed dye lasers achieve suboptimal clinical results in a majority of patients. Patient demand for novel therapies and willingness to participate in clinical studies is currently unknown, yet, imperative for steering R&D activity. The objective of this study was to evaluate these two factors in relation to PWS patient demographics. METHODS: A questionnaire was used to assess patient and PWS characteristics, treatment history, efficacy, and satisfaction, stress level, willingness to travel and pay for an effective treatment, participation in clinical studies, and amenability to intravenous drug administration. Descriptive statistics and correlation analysis were performed. RESULTS: Of the respondents (N = 108), 65% would participate in clinical studies and 49% would accept intravenous drugs. For an effective treatment, 58% was prepared to pay over ?2,000 and 48% would travel more than 6 h. Travel time was inversely correlated with age, clearance rate, and satisfaction. Facial PWS patients had undergone more treatments, were less satisfied, and less willing to participate in studies or accept intravenous drugs. Stress levels were higher in females. CONCLUSION: There is considerable demand for new PWS therapies, and a substantial proportion of patients are willing to participate in clinical studies. PMID- 29384395 TI - Diffuse low-grade glioma mimicking ischaemic infarct: a case report. AB - Diffuse Low-Grade Gliomas (LGGs) include World Health Organization (WHO) grade II diffuse astrocytoma, oligodendroglioma and oligoastrocytoma. Since the neurological symptoms of LGGs are often subtle and deceptive, LGGs are easily overlooked at their early stage. Here, we report a case of a 49-year-old female with symptoms and imaging manifestations mimicking ischaemic infarct. After treatments for ischaemic stroke, the symptoms initially fluctuated and then aggravated. In addition, we found that the locations of the lesions did not match the vascular distribution and no obvious abnormalities were observed by Computed Tomography (CT) angiography and transcranial Doppler. The results from the Magnetic Resonance Spectroscopy (MRS) and from the stereotactic biopsy directed to the final diagnosis of WHO grade II, isocitrate dehydrogenase (IDH)-wild-type diffuse astrocytoma. This is the first reported LGG case with a stroke-like onset. This case illustrates how easy it is to misdiagnose an LGG as a stroke if just using cerebral CT and magnetic resonance imaging. MRS and biopsy can assist with the differential diagnosis process thereby avoiding inappropriate or delayed treatments. PMID- 29384396 TI - Psychophysiological biomarkers: Working around behavioral response limitations. PMID- 29384397 TI - Quaternary prevention: reviewing the concept. AB - BACKGROUND: According to the Wonca International Dictionary for General/Family Practice Quaternary Prevention is defined as: 'Action taken to identify patient at risk of overmedicalization, to protect him from new medical invasion, and to suggest to him interventions, which are ethically acceptable.' The concept of quaternary prevention was initially proposed by Marc Jamoulle and the targets were mainly patients with illness but without a disease. OBJECTIVES: The purpose of this opinion article is to open the debate around a new possible definition and a new conceptual model of quaternary prevention based on the belief that quaternary prevention should be present in physicians' minds for every intervention they suggest to a patient. DISCUSSION: The debate around quaternary prevention is vital in the context of contemporary medicine and has expanded worldwide. The human being may suffer harm from medical interventions from conception, during their childhood, during their entire healthy lifetime as well as during a self-limited disease, a chronic disease, or a terminal disease. The current definition of quaternary prevention has limitations because it excludes patients and medical interventions where a quaternary prevention perspective would be needed and useful to protect patients from harm. In this context, a new definition and conceptual model of quaternary prevention is proposed. CONCLUSION: In this new proposal, quaternary prevention is defined as an 'action taken to protect individuals (persons/patients) from medical interventions that are likely to cause more harm than good.' PMID- 29384398 TI - Children's appraisals of interparental conflict predict event-related potential components. AB - Interparental conflict and neural correlates of children's emotion processing were examined. Event-related potential (ERP) data were collected from 87 children (9-11 years old) with stimuli depicting interpersonal anger, happiness, and neutrality. Three ERP components were modulated by child-reported measures of conflict, reflecting a progression from early sensory attention to cognitive control to stimulus categorization. Negative conflict predicted larger N1 and N2 amplitudes on happy than on angry trials. Greater self-blame for conflict predicted larger N2 amplitudes across emotions and larger P3 amplitudes on angry than on neutral or happy trials. Results suggest conflict-related experiences shape processing of interpersonal emotion. PMID- 29384399 TI - FGFR1 rearranged hematological neoplasms - molecularly defined and clinically heterogeneous. PMID- 29384404 TI - A novel fusion of PDGFRB to TSC1, an intrinsic suppressor of mTOR-signaling pathway, in a chronic eosinophilic leukemia patient with t(5;9)(q32;q34). PMID- 29384405 TI - The clinical effectiveness and cost-effectiveness of fractional CO2 laser in acne scars and skin rejuvenation: A meta-analysis and economic evaluation. AB - INTRODUCTION: Fractional CO2 has many indications in medicine including in treatment of acne scars and rejuvenation. The aim of this study was to evaluate the safety, efficacy, and cost-effectiveness of Fractional CO2 Laser in comparison with other methods of rejuvenation and acne scar treatment. MATERIALS AND METHODS: Several databases including Medline, OVID, EMBASE, CINHAL, SCOPUS, Web of science, CRD, and Cochrane were searched. After conducting the search and evaluation of selected publications, critical appraisal was done and eligible studies were accepted for inclusion in the systematic review. RESULTS AND DISCUSSION: From 2667 identified publications two of the trials were eligible. The effectiveness and complications of Fractional CO2 laser were comparable with Er:YAG but Fractional CO2 laser was 14.7% (p = 0.01) more effective than Q Switched ND:YAG laser. Cost affectivity of this method was the same as other alternative lasers. In conclusion Fractional CO2 laser is an effective and safe method for curing of several kinds of skin diseases. Nevertheless there was not sufficient evidence to support its advantage. This device has equal or lower price in comparison to competent technologies except for the non- fractional ablative CO2 laser that has the same or lower price and comparable effects. PMID- 29384406 TI - The impact of micronized progesterone on breast cancer risk: a systematic review. AB - Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. The debate on bioidentical hormones including micronized progesterone has increased in recent years. Based on a systematic literature review on the impact of menopausal hormone therapy (MHT) containing micronized progesterone on the mammary gland, an international expert panel's recommendations are as follows: (1) estrogens combined with oral (approved) or vaginal (off-label use) micronized progesterone do not increase breast cancer risk for up to 5 years of treatment duration; (2) there is limited evidence that estrogens combined with oral micronized progesterone applied for more than 5 years are associated with an increased breast cancer risk; and (3) counseling on combined MHT should cover breast cancer risk - regardless of the progestogen chosen. Yet, women should also be counseled on other modifiable and non-modifiable breast cancer risk factors in order to balance the impact of combined MHT on the breast. PMID- 29384407 TI - Effect of aucubin on neural precursor cell survival during neuronal differentiation. AB - PURPOSE OF THE STUDY: Aucubin (ACB) is an iridoid glycoside with various biological activities. Previously, it is reported that ACB reduces cell survival and proliferation in many human tumors, whereas it facilitates cell survival and neuroprotection in damaged neuronal cells and disease models. However, its effects on cell survival in the non-proliferating or differentiated neurons are not known. MATERIALS AND METHODS: We examined whether ACB facilitated cell survival in differentiating neural precursor cells, HiB5, compared with the proliferating HiB5 cells at various concentrations. RESULTS: The cell viabilities were evaluated by measuring MTT values, cell numbers, amounts of neurotransmittersD1 and protein amounts of neuronal markers. Here, we showed that ACB promotes cell survival in differentiated neurons (10-200 MUg/mL), but reduces it in proliferating NPCs (200-400 MUg/mL). Protein amounts of neurofilament proteins, NF-H, NF-M, PSD-95 in post-synaptic density, GAP-43 in growing neurites and NeuN in differentiated neurons were upregulated by addition of ACB, indicating that cell survival increased in differentiated neurons, shown by immunoblot analysis. Especially, when PDGF was added into N2 media to facilitate neuronal differentiation of HiB5 cells, the viability of differentiated HiB5 cells was significantly elevated following the increase of ACB concentration. Furthermore, ACB promoted cell survival of specific neuron types, such as GABAergic neurons and glutamatergic neurons. When differentiated neurons were immunostained with markers for specific neurons, neuronal subtypes producing GABA and GAD 65/67 were immunostained more than subtypes producing glutamate and vGluT1. CONCLUSION: These results indicate that ACB improves neuronal cell survival in differentiated cells, suggesting it may be a therapeutic compound for neurodegenerative disorders. PMID- 29384408 TI - Octasomy 21 in a patient with secondary AML after CMML: the role of acquired NRAS mutations in triggering aneuploidy. PMID- 29384409 TI - Heterochronous occurrence of microsatellite instability in multiple myeloma - an implication for a role of defective DNA mismatch repair in myelomagenesis. PMID- 29384410 TI - Strategies for improving dabigatran adherence for stroke prevention in patients with non-valvular atrial fibrillation: education and drug intake reminders (FACILITA study). AB - Objective To assess the efficacy of a mixed intervention, educational, and reminder calendar of the intake, as a strategy to improve therapeutic adherence with dabigatran in patients with non-valvular atrial fibrillation (NVAF). Methods This was a prospective, longitudinal, multi-center study, carried out in 110 specialized healthcare centers in Spain. Seven hundred and twenty-six patients treated with dabigatran prescribed for stroke prevention were included. A cluster randomization was performed based on two groups: (1) Control Group (CG) as usual clinical practice, and (2) Intervention Group (IG) with a mixed strategy: (a) Healthcare education, and (b) Use of a reminder calendar for taking the anticoagulant medication. Three visits took place: baseline and follow-up at 6 and 12 months. Compliance was measured by using electronic monitors (MEMS). Average adherence percentage (%; Average AP) and daily compliance (%; Daily AP) was calculated. A patient was considered adherent when AP was 80-100%. Results Six hundred and twenty-five patients completed the study (315 in the IG and 310 in the CG). Daily AP was 91.97% at 6 months and 91.05% after 12 months in the IG and 82.26% and 82.63% in the CG. Average adherence was 90.79% and 89.20% in the IG and 64.51% and 63.22% in the CG at 6 and 12 months, respectively. Significant differences were observed in the Daily AP and Average AP, with higher percentages in the IG. In the non-adherents group, the number of concomitant drugs, baseline, and 6 months SBP values, 6 and 12 months DBP values, and weight, total cholesterol, and LDL cholesterol were significantly higher. The number needed to treat (NNT) was 3.84 patients to prevent one non-adherence. Conclusions A mixed intervention, consisting of patient education and a simple calendar reminder of drug intake, is an effective strategy to improve dabigatran therapeutic adherence in patients with NVAF. The percentage of adherence with dabigatran was high. PMID- 29384411 TI - Mass spectrometry analysis of plasma from amyotrophic lateral sclerosis and control subjects. AB - Mass spectrometry was used to study blood samples from patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Addenbrooke's cognitive examination III (ACE-III) was used to test for cognitive impairment (CI). Nano liquid chromatography and time of flight mass spectrometry (MS) were performed on samples from 42 ALS patients and 18 healthy controls. SWATHTM proteomic analysis was utilized to look for differences between groups. Western blot analysis was used to study levels of 4 proteins, selected as being of possible interest in ALS, in the MS discovery cohort and a second validation group of 10 ALS patients and 10 healthy controls. INGENUITY PATHWAY ANALYSIS (IPA) was applied to the final proteomic data. Between ALS patients and controls, there were significant differences in the expression of 30 proteins. Between controls and ALS patients without CI, there were significant differences in 15 proteins. Between controls and ALS patients with CI, there were significant differences in 32 proteins. Changes in levels of gelsolin, clusterin, and CD5L were validated by using western blot analysis in the discovery cohort. Changes in the expression of gelsolin, clusterin, and ficolin 3 were replicated in a validation group. In ALS, the LXR/RXR and coagulation pathways were downregulated whereas the complement pathway was upregulated. The proteomic data were used to produce two new networks, centered on IL1 and on NFkB, which showed altered levels in ALS. This study highlights the usefulness of MS of blood samples as a tool to study ALS. PMID- 29384412 TI - Severe hypofibrinogenemia associated with imatinib and prednisone therapy in Philadelphia chromosome-positive acute lymphoblastic leukemia. PMID- 29384413 TI - Having the "Headspace" for Compassion Toward Self and Others: A Qualitative Study of Medical Students' Views and Experiences. AB - : Phenomenon: Debate about compassion exhibited by healthcare professionals has escalated, following a perceived decline over recent years. At the same time, a growing interest in self-compassion has emerged, which is seen as facilitating compassion toward others. Little research has explored, in depth, what compassion to self and others means to medical students. Therefore, a study was designed to address this gap in knowledge. APPROACH: A qualitative study was conducted, involving students from all 4 years of a graduate-entry medical school in the United Kingdom. Focus groups were used to obtain the views of students on compassion for self and others (patients). Care was taken to achieve variation within the sample in terms of age, gender, and year of study. Focus groups were completed between September and October 2016. An inductive thematic analysis was performed. FINDINGS: A total of 31 students participated in 4 focus groups, each lasting between 60 and 90 minutes. Having the cognitive freedom-"headspace"-to be aware of and respond to one's own and others' difficulties and distress was identified as an overarching theme within the data. This was underpinned by the themes developed during analysis: (a) bringing humanity into the workplace; (b) compassion as a variable, innate resource; (c) zoning into an individual's current needs; and (d) collective compassion. Students talked about the importance of being adaptable and responsive to situational factors in relation to self-compassion and compassionate care. They also highlighted the contribution of role models in promoting compassion to self and others. Insights: It is important for medical educators to explore ways of enhancing students' compassion to self and others during their training and beyond. Integrating approaches to "well-being" into the curriculum can create opportunities for self-compassion development, but rigid protocols could derail these efforts. PMID- 29384414 TI - Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice. AB - We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been defined. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoa7 gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6v1b1 KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyperbicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoa7 KO compared with wild-type mice, a phenotype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans. PMID- 29384415 TI - Subclinical kidney injury induced by repeated cisplatin administration results in progressive chronic kidney disease. AB - Cisplatin is used to treat many solid cancers, but its dose-limiting side effect is nephrotoxicity, causing acute kidney injury in 30% of patients. Previously, we have developed a mouse model that better recapitulates the cisplatin dosing regimen humans receive and found that repeated dosing of cisplatin induces interstitial renal fibrosis. Chronic kidney disease is progressive and is characterized by chronic inflammation, worsening interstitial fibrosis, development of glomerulosclerosis, and endothelial dysfunction. To determine if damage caused by repeated cisplatin dosing results in bona fide chronic kidney disease, mice were treated with our repeated dosing regimen and then aged for 6 mo. These mice had progressive, chronic inflammation and worsened interstitial fibrosis compared with mice euthanized after day 24. Mice aged for 6 mo developed glomerular pathologies, and endothelial dysfunction was persistent. Mice treated with only two doses of cisplatin had little inflammation or kidney damage. Thus repeated dosing of cisplatin causes long-term effects that are characteristic of chronic kidney disease. This translational mouse model of cisplatin injury may better represent the 70% of patients that do not develop clinical acute kidney injury and can be used to identify both biomarkers for early injury, as well as novel therapeutic targets for the prevention of cisplatin-induced chronic kidney disease. PMID- 29384416 TI - Differential roles of WNK4 in regulation of NCC in vivo. AB - The Na+-Cl- cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl- concentration ([Cl-]i). WNK kinases bind Cl-, and Cl- binding decreases the catalytic activity. It is believed that hypokalemia under low K+ intake decreases [Cl-]i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl-]i. Whether [Cl-]i in DCT under low-K+ diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K+ intake, increased luminal NaCl delivery would tend to increase [Cl-]i. Thus we investigated the role of WNK4 and [Cl-]i in regulating NCC. We generated Wnk4-knockout mice and examined regulation of NCC by low K+ intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice. Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K+ intake increases NCC phosphorylation and functional activity in wild-type mice, but not in Wnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K+ intake, is not abolished in Wnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl-]i is not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl ]i. PMID- 29384417 TI - Salvianolic acid A ameliorates renal ischemia/reperfusion injury by activating Akt/mTOR/4EBP1 signaling pathway. AB - Salvianolic acid A (Sal A) has been shown to prevent and treat ischemic cardiovascular, as well as cerebral vascular diseases. However, little is known about Sal A in renal ischemia/reperfusion (I/R) injury. In this study, a renal I/R injury model in rats and a hypoxia/reoxygenation (H/R) model to damage proximal renal tubular cells (HK-2) were used to assess whether Sal A halts the development and progression of renal I/R injury. As compared with vehicle treatment, Sal A significantly attenuated kidney injury after renal I/R injury, accompanied by decreases in plasma creatinine, blood urea nitrogen levels, the number of apoptosis-positive tubular cells, and kidney oxidative stress. Sal A also activated phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) compared with vehicle-treated I/R injury rats. In H/R-injured HK-2 cells, Sal A can reduce the levels of reactive oxygen species in a dose-related manner. Similar to the results from in vivo experiments, in vitro Sal A also increased the protein expression of phosphorylated-eukaryotic initiation factor 4E binding protein 1 (p-4EBP1) compared with vehicle. Furthermore, the cytoprotective activity of Sal A was inhibited by LY294002 and rapamycin. These findings indicate that Sal A can ameliorate renal I/R injury and promote tubular cell survival partly via the Akt/mTOR/4EBP1pathway. Sal A could be a candidate compound to prevent ischemic tissue damage. PMID- 29384418 TI - Editor's presentation. PMID- 29384419 TI - Procedural Sedation and Analgesia in Trauma Patients in an Out-of-Hospital Emergency Setting: A Prospective Multicenter Observational Study. AB - BACKGROUND: The quality of procedural analgesia and sedation among trauma patients has not been studied much in the prehospital setting. The main objective of this study was to characterize the quality of procedural analgesia sedation practices in prehospital settings in trauma patients. METHODS: This was an open label observational prospective multicenter study (January 01, 2012-December 31, 2013). We included all consecutive trauma victims undergoing a potentially painful procedure on the accident scene. The primary endpoint was the procedural pain intensity. RESULTS: Data for 210 patients aged 11 to 98 years were analyzed. The most common lesions were limb fractures or dislocations. The most common procedures were limb realignment and splinting. Overall, 25 different drug combinations [with paracetamol [acetaminophen], non-steroidal anti-inflammatory drugs, nefopam, opioids, loco-regional anesthesia, Equimolar Mixture of Oxygen/Nitrous Oxide (EMONO), sedative drugs] were used by the emergency medical services (EMS). One hundred seventeen patients (55%) received either one or two sedative drugs (among ketamine, propofol, and midazolam), 171 patients (81%) received morphine that was combined with a sedative drug in 54% of cases. During the procedure, 95 patients, 45% [95% Confidence Interval (CI) 39-52] experienced intense to severe pain. Among patients who received sedative drugs, 27% (32/117) had intense to severe pain vs. 68% (63/93) in patients who did not, that is, 40% difference [95% CI 33.8-47.0]. Seventeen patients (8%) experienced 18 adverse events of which 6 were respiratory adverse events. A deep sedation occurred in 17 patients. No center had any specific protocols for procedural sedation analgesia. CONCLUSION: Procedural sedation-analgesia was inadequate in almost half of the trauma patients in the out-of-hospital setting. The reasons of these failures were probably multiple. The non-administration of a sedative drug despite an indication or non-adapted doses, in the context of a lack of specific protocols, was certainly one of them. PMID- 29384420 TI - Hearing loss before and after cisplatin-based chemotherapy in testicular cancer survivors: a longitudinal study. AB - BACKGROUND: Hearing loss is a well-known long-term effect after cisplatin-based chemotherapy (CBCT) in testicular cancer survivors (TCS), but longitudinal data are sparse. We evaluate hearing loss and the impact of age in TCS treated with CBCT in this longitudinal study. MATERIAL AND METHODS: Forty-six TCS treated with CBCT 1980-1994 with audiograms (0.25-8 kHz) pre-chemotherapy (PRE) and at a follow-up survey (SURV) after median 10 years were included (cases). Audiograms at SURV from 46 age-matched TCS without CBCT were included as controls. Linear regression was performed to evaluate predictors for change in the hearing threshold level (HTL) from PRE to SURV. Two definitions of a audiogram-defined hearing loss was applied if: (1) mean HTL for both ears exceeded 20 dB at any frequency 0.25-8 kHz (American Speech-Language-Hearing Association (ASHA) definition) and (2) average HTL for the frequencies 0.5, 1, 2 and 4 kHz exceeded 20 dB (WHO-M4 definition). Self-reported hearing impairment (SURV) was assessed by a questionnaire. RESULTS: Age and cisplatin dose was significantly associated with a greater change in HTL for the frequencies 2-8 kHz. For the 8 kHz frequency, each 100 mg increase in cumulative cisplatin dose was associated with a deterioration of 3.6 dB (95% CI 1.8-5.3, p < .001). The prevalence of hearing loss (ASHA) among cases was 33% PRE, 70% at SURV and 65% among controls at SURV (cases vs. controls, p = .66). According to M4, the prevalence of hearing loss among cases was 6.5% PRE, 13% at SURV and 2.2% among controls at SURV (cases vs. controls, p = .049). Twenty-nine percent of cases, and 33% of controls (p = .70) reported hearing impairment at SURV. CONCLUSION: Cisplatin is associated with a hearing loss particularly at higher frequencies. Age appear to be an important factor for hearing loss regardless of treatment. The ASHA definition overestimates the hearing problem. PMID- 29384421 TI - Relation of serum levels of homocysteine, vitamin B12 and folate to cognitive functions in multiple sclerosis patients. AB - BACKGROUND: Hyperhomocysteinemia, vitamin B12 and folate deficiency have been linked to cognitive dysfunction in multiple sclerosis (MS) patients. OBJECTIVE: This study aimed to investigate the relation of serum homocysteine (Hcy), vitamin B12 and folate to cognitive functions in MS patients. SUBJECTS AND METHODS: Forty five MS patients and twenty matched healthy controls were included. Subjects were submitted to cognitive assessment using a selected psychometric battery and measurement of serum levels of homocysteine, B12 and folic acid. RESULTS: MS patients showed significant worse performance in cognitive scales compared to controls (P <= 0.05). Serum homocysteine, vitamin B12 and folate showed no significant difference between patients and controls (P > 0.05). Serum homocysteine was negatively correlated with total score of Addenbrooke's Cognitive Examination (ACE), paced auditory serial addition test and controlled oral word association test scores. Serum vitamin B12 was positively correlated with ACE language, visuospatial and total scores and negatively correlated with trail making B score. Serum folate was significantly positively correlated with ACE language and total scores. Homocysteine was the only significant predictor for cognitive impairment in MS patients. CONCLUSION: Serum homocysteine may play a role in cognitive dysfunction in MS patients. PMID- 29384422 TI - The impact of documentation on communication during patient-physiotherapist interactions: A qualitative observational study. AB - Documentation is an essential component of physiotherapy practice for clinical, legal, and ethical reasons. Research in other healthcare contexts suggests that documentation impacts upon communication in patient-practitioner interactions. Thus, the objective of this qualitative study was to examine how physiotherapists and their patients communicate during episodes of documentation. The research was informed by ethnomethodology and ethnography. In total, 113 patient physiotherapist interactions were observed in Switzerland and Australia with video-recordings, audio-recordings, and field notes collected as data. Episodes of documentation within these interactions were transcribed, and both verbal and non-verbal communication were analyzed inductively. Analysis identified that communication during documentation was characterized by: pauses in conversation, pre-established order of questioning, minimal eye contact, use of direct communication, and an emphasis on objectivity. The use of documentation was observed to alter the wording of questioning as well as the sequence and flow of conversation between patient and physiotherapist. In addition, the observed communicative features seemed to restrict patient participation, and may hinder the achievement of a patient-centered approach. Recognizing the importance of documentation, we address the challenges that our research highlighted by proposing strategies to assist educators and clinicians to optimize communication with patients when incorporating documentation into practice. PMID- 29384423 TI - Analysis of carboxylesterase 2 transcript variants in cynomolgus macaque liver. AB - Carboxylesterase (CES) is important for the detoxification of a wide range of drugs and xenobiotics. In this study, the hepatic level of CES2 mRNA was examined in cynomolgus macaques used widely in preclinical studies for drug metabolism. Three CES2 mRNAs were present in cynomolgus macaque liver. The mRNA level was highest for cynomolgus CES2A (formerly CES2v3), much lower for cynomolgus CES2B (formerly CES2v1) and extremely low for cynomolgus CES2C (formerly CES2v2). Most various transcript variants produced from cynomolgus CES2B gene did not contain a complete coding region. Thus, CES2A is the major CES2 enzyme in cynomolgus liver. A new transcript variant of CES2A, CES2Av2, was identified. CES2Av2 contained exon 3 region different from wild-type (CES2Av1). In cynomolgus macaques expressing only CES2Av2 transcript, CES2A contained the sequence of CES2B in exon 3 and vicinity, probably due to gene conversion. On genotyping, this CES2Av2 allele was prevalent in Indochinese cynomolgus macaques, but not in Indonesian cynomolgus or rhesus macaques. CES2Av2 recombinant protein showed similar activity to CES2Av1 protein for several substrates. It is concluded that CES2A is the major cynomolgus hepatic CES2, and new transcript variant, CES2Av2, has similar functions to CES2Av1. PMID- 29384425 TI - The relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with progression of primary open-angle glaucoma. AB - BACKGROUND: Primary open-angle glaucoma (POAG) belongs to neurodegenerative diseases. Its etiology is not fully understood. However, a lot of reports have indicated that many biochemical molecules are involved in the retinal ganglion cell damage. Therefore, the purpose of this study was to evaluate a relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with the occurrence risk of POAG and its progression. MATERIALS AND METHODS: The study included 34 glaucoma patients and 32 subjects without glaucoma symptoms. RNA was isolated from peripheral blood lymphocytes. Level of mRNA expression was determined by real-time PCR method. RESULTS: Our results have shown significant association of the HDAC6 and SIRT1 expression levels with progression of POAG according to rim area (RA) value, p = 0.041; p = 0.012. Moreover, the analysis of the CXCR3 expression level showed a correlation with progression of POAG based on RA and cup disc ratio (c/d) value, p = 0.006 and p = 0.012, respectively. CONCLUSIONS: The expression level of HDAC6, CXCR3, and SIRT1 genes may be involved in the progression of POAG. PMID- 29384424 TI - Longitudinal assessment of gray matter volumes and white matter integrity in patients with medication-overuse headache. AB - Background Medication-overuse headache is a common clinical entity, but neuroimaging studies investigating volumetric and microstructural alterations of the brain in medication-overuse headache are rare. Therefore, in the current longitidunal study we evaluated gray matter volume and white matter integrity in patients with medication-overuse headache before and after drug withdrawal. Methods A prospective study evaluated 27 patients with medication-overuse headache and 27 age-, sex-, and education-matched healthy adults. High-resolution T1-weighted magnetic resonance imaging and diffusion tensor imaging were obtained from the control group and medication-overuse headache patients before and six months after drug withdrawal. Tract-based spatial statistics of multiple diffusivity indices and voxel-based morphometry were employed to investigate white and gray matter abnormalities. Results No correlation was found between age, gender, education and smoking status in both groups. The most commonly overused medications were simple analgesics (96.3%) and combined analgesics (3.7%). The mean duration of the history of medication overuse and headaches was 56.7 +/- 63.5 months. White matter diffusional and gray matter morphological alterations including volume, fractional anisotropy, radial diffusivity, and axial diffusivity analyses showed no significant relationship in the patients before and six months after withdrawal of analgesics. Also no difference was observed between the patients versus controls. Conclusion Our data demonstrated no structural alterations within the brain in medication-overuse headache. PMID- 29384426 TI - Korean clergy for healthy families: online intervention for preventing intimate partner violence. AB - BACKGROUND: Intimate partner violence (IPV) among immigrant women is a serious public health problem. Churches and clergy play a fundamental role in their lives, as a form of social organization and alternative to community services. PURPOSE: To describe the implementation and evaluation of an intervention for Korean American faith leaders designed to increase knowledge about IPV and about resources to handle IPV, strengthen attitudes that do not support IPV, enhance self-efficacy to handle IPV, and increase prevention and intervention behaviors about IPV. METHODS: Korean American faith leaders in a Southeastern state of the USA were invited to participate in the study ( n = 55). Participants completed two online assessments: baseline and a 3-month follow-up. After the baseline assessment, participants were randomized to either the intervention ( n = 27) or the control ( n = 28) group. The intervention consisted of three online modules, each taking approximately 30-45 min to complete. Modules were developed based on the researchers' work with Korean American faith leaders. Assessments and interventions were available in Korean and English. RESULTS: Compared to the control group, the intervention group significantly improved their knowledge of resources and enhanced attitudes against IPV. The intervention group increased their self-efficacy and behaviors to prevent IPV more than the control group, but these changes were not statistically significant. CONCLUSIONS: The online training provided a safe and convenient environment for the Korean American clergy, for whom anonymity and convenient access were important. Results are promising, but highlight the need to include more specific training of skills, which could be incorporated into the online modules in the form of an avatar. This online training could serve as a template to be adapted for other immigrant groups. PMID- 29384427 TI - Lessons from the COMPASS-3 Study. PMID- 29384428 TI - Telehealth at the US Department of Veterans Affairs after Hurricane Sandy. AB - Background Like other integrated health systems, the US Department of Veterans Affairs has widely implemented telehealth during the past decade to improve access to care for its patient population. During major crises, the US Department of Veterans Affairs has the potential to transition healthcare delivery from traditional care to telecare. This paper identifies the types of Veterans Affairs telehealth services used during Hurricane Sandy (2012), and examines the patient characteristics of those users. Methods This study conducted both quantitative and qualitative analyses. Veterans Affairs administrative and clinical data files were used to illustrate the use of telehealth services 12 months pre- and 12 months post- Hurricane Sandy. In-person interviews with 31 key informants at the Manhattan Veterans Affairs Medical Center three-months post- Hurricane Sandy were used to identify major themes related to telecare. Results During the seven-month period of hospital closure at the Manhattan Veterans Affairs Medical Center after Hurricane Sandy, in-person patient visits decreased dramatically while telehealth visits increased substantially, suggesting that telecare was used in lieu of in person care for some vulnerable patients. The most commonly used types of Veterans Affairs telehealth services included primary care, triage, mental health, home health, and ancillary services. Using qualitative analyses, three themes emerged from the interviews regarding the use of Veterans Affairs telecare post- Hurricane Sandy: patient safety, provision of telecare, and patient outreach. Conclusion Telehealth offers the potential to improve post-disaster access to and coordination of care. More information is needed to better understand how telehealth can change the processes and outcomes during disasters. Future studies should also evaluate key elements, such as adequate resources, regulatory and technology issues, workflow integration, provider resistance, diagnostic fidelity and confidentiality, all of which are critical to telehealth success during disasters and other crises. PMID- 29384429 TI - Assessment of expanded polystyrene as a separator in microbial fuel cell. AB - Separators are considered as an important component in microbial fuel cells (MFCs) to facilitate ion transport and to prevent electrode short circuiting. In the present study, expanded polystyrene (EPS) was evaluated for the first time as a separator in a single-chamber air cathode and dual chamber aqueous cathode MFCs. The characteristics and performance of EPS were analyzed and compared with other conventionally used separators used in MFCs and was found to be competitive. Initially, the EPS was less impermeable to protons, resulting in delayed process startup (17 days) and stabilization (57 days), but gradually exhibited improved and stable performance. In the air cathode MFC with the EPS as the separator and domestic wastewater as the substrate, power production was 391 mW/m2, while power output of the aqueous cathode MFC was 328 mW/m2. The characteristics and cost analysis of EPS indicate that it can be a potential candidate as a separator in scaled-up MFC applications. PMID- 29384430 TI - Molecular Insights into the Involvement of a Never Ripe Receptor in the Interaction Between Two Beneficial Soil Bacteria and Tomato Plants Under Well Watered and Drought Conditions. AB - Management of plant growth-promoting bacteria (PGPB) can be implemented to deal with sustainable intensification of agriculture. Ethylene is an essential component for plant growth and development and in response to drought. However, little is known about the effects of bacterial inoculation on ethylene transduction pathway. Thus, the present study sought to establish whether ethylene perception is critical for growth induction by two different PGPB strains under drought conditions and the analysis of bacterial effects on ethylene production and gene expression in tomatoes (Solanum lycopersicum). The ethylene-insensitive never ripe (nr) and its isogenic wild-type (wt) cv. Pearson line were inoculated with either Bacillus megaterium or Enterobacter sp. strain C7 and grown until the attainment of maturity under both well-watered and drought conditions. Ethylene perception is crucial for B. megaterium. However, it is not of prime importance for Enterobacter sp. strain C7 PGPB activity under drought conditions. Both PGPB decreased the expression of ethylene-related genes in wt plants, resulting in stress alleviation, while only B. megaterium induced their expression in nr plants. Furthermore, PGPB inoculation affected transcriptomic profile dependency on strain, genotype, and drought. Ethylene sensitivity determines plant interaction with PGPB strains. Enterobacter sp. strain C7 could modulate amino-acid metabolism, while nr mutation causes a partially functional interaction with B. megaterium, resulting in higher oxidative stress and loss of PGPB activity. PMID- 29384431 TI - Epigenetic mechanisms in health and disease: BCEC 2017. AB - The Barcelona Conference on Epigenetics and Cancer (BCEC) entitled "Epigenetic Mechanisms in Health and Disease" was held in Barcelona, October 26-26, 2017. The 2017 BCEC was the fifth and last edition of a series of annual conferences organized as a joint effort of five leading Barcelona research institutes together with B-Debate. This edition was organized by Albert Jordan from the Molecular Biology Institute of Barcelona (IBMB-CSIC) and Marcus Bushbeck from the Josep Carreras Leukaemia Research Institute (IJC). Jordi Bernues, Marian Martinez Balbas, and Ferran Azorin were also part of the scientific committee. In 22 talks and 51 posters, researchers presented their latest results in the fields of histone variants, epigenetic regulation, and chromatin 3D organization to an audience of around 250 participants from 16 countries. This year, a broad number of talks focused on the epigenetic causes and possible related treatments of complex diseases such as cancer. Participants at the 2017 BCEC elegantly closed the series, discussing progress made in the field of epigenetics and highlighting its role in human health and disease. PMID- 29384432 TI - Dysphagia and esophageal dysfunction due to dystrophin deficient muscular dystrophy in a male Spanish water spaniel. PMID- 29384433 TI - Regenerative potential of chitosan-coated poly-3-hydroxybutyrate conduits seeded with mesenchymal stem cells in a rat sciatic nerve injury model. AB - OBJECTIVES: A number of chemical and biological factors, including mesenchymal stem cells (MSCs), have been developed to enhance nerve regeneration by introduction through a variety of nerve conduits. This study was designed to assess the efficacy of using chitosan-coated poly-3-hydroxybutyrate (PHB) nerve conduits seeded with human bone marrow-derived MSCs (hMSC-bm) to augment repair in an experimental rat model of sciatic nerve injury. METHODS: A total of 30 rats were randomly assigned to one of three groups (n = 10). In each rat, a 10 mm segment of the sciatic nerve was removed and was replaced by a chitosan-coated PHB conduit seeded with hMSC-bm (PHB/chitosan-hMSC-bm group), a chitosan-coated PHB conduit (PHB/chitosan group), or an autograft (autograft group) as the control. The results were evaluated 8 weeks postoperatively by observation, electromyography and histologic examination with light microscopy and immunostaining. RESULTS: Histologic examination showed that both PHB/chitosan hMSC-bm conduits and PHB/chitosan conduits led the damaged axons through the injured area. When the effects were compared, the results with the PHB/chitosan hMSC-bm conduits were superior to those with the PHB/chitosan conduits (p < 0.05) but not as successful as with the autologous nerve grafts (p < 0.05). CONCLUSION: PHB/chitosan-hMSC-bm nerve conduits may be a useful artificial guide for nerve regeneration. PMID- 29384436 TI - Anti-N-methyl-D-aspartate receptor antibody encephalitis: An important cause of encephalitis in young adults. A report of two cases. AB - Encephalitis is a clinical syndrome which can include altered mental status, motor and sensory deficits, altered behavior including personality changes, speech and movement disorders and seizures. While the overall incidence of encephalitis is not known, it is common enough that most pediatric and adolescent medicine physicians will have seen at least one case. Peak times of risk include the newborn period and middle-to-late adolescence. 1 It is important for clinicians to have a working knowledge of the broad range of encephalitis etiologies: viral, post-viral, toxic, auto-immune, and paraneoplastic. We discuss two cases of encephalitis in young adult women with ovarian teratoma and production of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. PMID- 29384434 TI - The psychomotor vigilance test: a comparison of different test durations in elite athletes. AB - The 10-min Psychomotor Vigilance Test (PVT-10) is regarded as the gold-standard for assessing vigilant attention following sleep loss; however, other studies have investigated whether shorter versions of the test elicit similar results to the PVT-10. The present study compared the PVT-10 with 3-min (PVT-3) and 5-min (PVT-5) versions of the test in elite female basketball players. Athletes performed all three tests in the morning and evening for seven consecutive days. Response speed (mean reciprocal reaction time; mean 1/RT), number of errors and number of lapses were determined for each test and time point. The PVT-3 elicited significantly faster response speeds than the other two tests (p < 0.01), while the PVT-5 and PVT-10 were not different. The PVT-10 resulted in more lapses than the PVT-5, followed by the PVT-3, with all tests being significantly different to each other (p < 0.01). In conclusion, while the PVT-5 and PVT-10 were generally similar for response speed, the PVT-3 did not produce results comparable with the PVT-10 for response speed, lapses or errors, and should therefore not be used interchangeably. Further research is required to determine whether the shorter tests are a suitable replacement for the PVT-10 in professional basketball players. PMID- 29384437 TI - Acute exposure to sulfur dioxide and mortality: Historical data from Yokkaichi, Japan. AB - We examined the association between acute exposure to sulfur dioxide (SO2) and mortality, using historical data from 1972-1991 in Yokkaichi, Japan. We used a time-stratified case-crossover study design. We included all causes of death, excluding external causes, between 1972 and 1991 in Yokkaichi and the neighboring town, Kusu of the Mie Prefecture (N = 29,839). We obtained daily estimations of SO2 concentrations during the study period. We then conducted conditional logistic regression analysis to examine association between SO2 exposure and all cause and cause-specific mortality. Exposure to SO2 increased the risk of all cause and cause-specific mortality in a non-linear manner. The relationship between SO2 exposure and mortality outcomes remained after adjustment for co pollutants such as particulate matter and nitrogen dioxide. Historical data from Yokkaichi, Japan, showed that SO2 exposure increased the risk of all-cause and cause-specific mortality. PMID- 29384438 TI - Modular Organization of Exploratory Force Development Under Isometric Conditions in the Human Arm. AB - Muscle coordination of isometric force production can be explained by a smaller number of modules. Variability in force output, however, is higher during exploratory/transient force development phases than force maintenance phase, and it is not clear whether the same modular structure underlies both phases. In this study, eight neurologically-intact adults isometrically performed target force matches in 54 directions at hands, and electromyographic (EMG) data from eight muscles were parsed into four sequential phases. Despite the varying degree of motor complexity across phases (significant between-phase differences in EMG force correlation, angular errors, and between-force correlations), the number/composition of motor modules were found equivalent across phases, suggesting that the CNS systematically modulated activation of the same set of motor modules throughout sequential force development. PMID- 29384439 TI - Do Preschoolers Recognize The Emotional Expressiveness of Colors in Realistic and Abstract Art Paintings? AB - The present study was designed to examine preschoolers' ability to recognize the emotional expressiveness of an art painting, through its colors. To attain this aim 78 children, 3-5 years old were presented with realistic and abstract paintings conveying either happiness or sadness and were asked to choose those which matched the appropriate emotion. In total 16 paintings were used, which varied in color, while their subject matter was held as constant as possible after they had been previously rated by a group of adults to ensure that they conveyed the two emotions under investigation. Results showed that children's ability to recognize the emotional expressiveness of a painting through its colors appears at 3 years old and increases significantly at 4 and 5 years old. It was also found that the mood of happiness was more easily recognized than that of sadness, while the style of art paintings (realistic vs. abstract) did not affect children's ability to recognize emotions. PMID- 29384440 TI - Reciprocal Inuit and Western research training: facilitating research capacity and community agency in Arctic research partnerships. AB - Engaging community partners to work as co-researchers and research assistants for research involving Inuit communities or regions helps to ensure the equitable recognition of community and researcher priorities, mutual trust and respect, participation by local participants, inclusion of local knowledge and local uptake of research findings. However, research knowledge still in development among community members has been described as a barrier to effective Arctic community research partnerships. This paper describes two 3-day, cross-cultural research training workshops held in the Nunavut communities of Arviat and Iqaluit during Spring 2017. The purpose was to encourage reciprocity as a basis for research training that incorporates both Western and Inuit approaches and that emphasises relationship building to benefit both Inuit and non-Inuit research communities. A review of participant responses to the workshops suggests value in using an integrated Western-Inuit framework of educational objectives to guide the training. Responses suggest the workshops helped improve understanding of research practices and ethics rooted in different traditions for participants interested in assisting with or conducting research in Canada's Arctic communities. PMID- 29384442 TI - Improving student knowledge and perceptions of primary care providers at campus health centers. AB - OBJECTIVE: To examine current knowledge and perceptions toward primary care providers commonly staffed at student health centers (PAs and NPs), and also assess the effectiveness of information-rich provider biographies to improve knowledge and perceptions. PARTICIPANTS: One thousand six hundred forty six students from 2 universities in 2 states participated in this study from February to November, 2016. METHODS: An online survey. Students were exposed to an improved biography of an NP discussing how she can perform many of the same duties as primary care physicians. Changes in knowledge and perceptions were assessed pre- and post-biography exposure. RESULTS: More than half of students are unaware NPs and PAs can prescribe medications and diagnose illnesses. Students exposed to the biography increased their knowledge of NPs, and perceptions of their expertise. CONCLUSIONS: Results suggest improved provider biographies on student health centers' websites can help reduce the knowledge deficit that exists among students regarding common primary care providers. PMID- 29384443 TI - Not All Behaviors Are Attention Maintained. PMID- 29384444 TI - Predictors of Readiness for Mobility Transition in Older Drivers. AB - We administered the Assessment of Readiness for Mobility Transition (ARMT) to 301 older drivers and compared total scores with participant characteristics. Overall, 18% of participants were not attitudinally ready for mobility transition, while 19% were very ready. Notably, participants with hospitalizations in the past year were either very ready for mobility transition (20% vs 14% without hospitalizations) or not ready at all (30% vs 17%). Significant health events may polarize reactions towards mobility transition. Individualizing communication about driving cessation readiness could help address such differing views. To further consider its effectiveness, ARMT could be utilized in mobility transition counseling interventions. PMID- 29384445 TI - Identification of client involvement in sex trafficking in Mississippi. AB - OBJECTIVE: Sex trafficking is an unrelenting problem in Mississippi. No quantitative data currently exist on the prevalence of sex trafficking or the identification of victims in the state. METHOD: This study used the Trafficking in Victims Identification Tool (TVIT) (Short Version) to identify the extent to which a sample of clients (n = 28) receiving services at a non-profit social services agency in Jackson, Mississippi, were also victims of sex trafficking. RESULTS: The TVIT interview tool was completed during the intake phase at one social services agency in Mississippi. Over a 90-day period, 54% (n = 15) of participants were likely to have been trafficked for sex at some point. The researcher focused on three questions identified as predictors of sex trafficking. DISCUSSION: This research study provides a snapshot of the potential for identifying sex trafficking victims in Mississippi. PMID- 29384446 TI - Selection of Differential Isolates of Magnaporthe oryzae for Postulation of Blast Resistance Genes. AB - A set of differential isolates of Magnaporthe oryzae is needed for the postulation of blast resistance genes in numerous rice varieties and breeding materials. In this study, the pathotypes of 1,377 M. oryzae isolates from different regions of China were determined by inoculating detached rice leaves of 24 monogenic lines. Among them, 25 isolates were selected as differential isolates based on the following characteristics: they had distinct responses on the monogenic lines, contained the minimum number of avirulence genes, were stable in pathogenicity and conidiation during consecutive culture, were consistent colony growth rate, and, together, could differentiate combinations of the 24 major blast resistance genes. Seedlings of rice cultivars were inoculated with this differential set of isolates to postulate whether they contain 1 or more than 1 of the 24 blast resistance genes. The results were consistent with those from polymerase chain reaction analysis of target resistance genes. Establishment of a standard set of differential isolates will facilitate breeding for blast resistance and improved management of rice blast disease. PMID- 29384447 TI - Thermal Inactivation of Inoculum of Two Phytophthora Species by Intermittent Versus Constant Heat. AB - Research on solarization efficacy has examined the critical temperature and minimum exposure time to inactivate soilborne pathogens. Most mathematical models focus on survival of inoculum subjected to a constant heat regime rather than an intermittent heat regime that better simulates field conditions. To develop a more accurate predictive model, we conducted controlled lab experiments with rhododendron leaf disks infested with Phytophthora ramorum and P. pini. Focused in vitro experiments with P. ramorum showed significantly longer survival of inoculum exposed to intermittent versus constant heat, indicating that intermittent heat is less damaging. A similar trend was observed in soil. Damage was evaluated by comparing the reduction in subsequent survival time of inoculum subjected to different intensities of sublethal heat treatments. Inoculum exposure to continuous heat reflected an increasing rate of damage accumulation. Multiple sublethal heat events resulted in a constant rate of damage accumulation which allowed us to calculate total damage as the sum of damage from each heat event. A model including a correction for an intermittent heat regime significantly improved the prediction of thermal inactivation under a temperature regime that simulated field conditions. PMID- 29384448 TI - Characterization of Argentinian Endemic Aspergillus flavus Isolates and Their Potential Use as Biocontrol Agents for Mycotoxins in Maize. AB - Maize (Zea mays L.) is a highly valuable crop in Argentina, frequently contaminated with the mycotoxins produced by Aspergillus flavus. Biocontrol products formulated with atoxigenic (nontoxic) strains of this fungal species are well known as an effective method to reduce this contamination. In the present study, 83 A. flavus isolates from two maize regions of Argentina were characterized and evaluated for their ability to produce or lack of producing mycotoxins in order to select atoxigenic strains to be used as potential biocontrol agents (BCA). All of the isolates were tested for aflatoxin and cyclopiazonic acid (CPA) production in maize kernels and a liquid culture medium. Genetic diversity of the nonaflatoxigenic isolates was evaluated by analysis of vegetative compatibility groups (VCG) and confirmation of deletions in the aflatoxin biosynthesis cluster. Eight atoxigenic isolates were compared for their ability to reduce aflatoxin and CPA contamination in maize kernels in coinoculation tests. The A. flavus population was composed of 32% aflatoxin and CPA producers and 52% CPA producers, and 16% was determined as atoxigenic. All of the aflatoxin producer isolates also produced CPA. Aflatoxin and CPA production was significantly higher in maize kernels than in liquid medium. The 57 nonaflatoxigenic strains formed six VCG, with AM1 and AM5 being the dominant groups, with a frequency of 58 and 35%, respectively. In coinoculation experiments, all of the atoxigenic strains reduced aflatoxin from 54 to 83% and CPA from 60 to 97%. Members of group AM1 showed a greater aflatoxin reduction than members of AM5 (72 versus 66%) but no differences were detected in CPA production. Here, we described for the first time atoxigenic isolates of A. flavus that show promise to be used as BCA in maize crops in Argentina. This innovating biological control approach should be considered, developed further, and used by the maize industry to preserve the quality properties and food safety of maize kernels in Argentina. PMID- 29384450 TI - Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study. AB - Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes. PMID- 29384451 TI - Comparison of speed-accuracy tradeoff between linear and nonlinear filtering algorithms for myocontrol. AB - Nonlinear Bayesian filtering of surface electromyography (EMG) can provide a stable output signal with little delay and the ability to change rapidly, making it a potential control input for prosthetic or communication devices. We hypothesized that myocontrol follows Fitts' Law, and that Bayesian filtered EMG would improve movement times and success rates when compared with linearly filtered EMG. We tested the two filters using a Fitts' Law speed-accuracy paradigm in a one-muscle myocontrol task with EMG captured from the dominant first dorsal interosseous muscle. Cursor position in one dimension was proportional to EMG. Six indices of difficulty were tested, varying the target size and distance. We examined two performance measures: movement time (MT) and success rate. The filter had a significant effect on both MT and success. MT followed Fitts' Law and the speed-accuracy relationship exhibited a significantly higher channel capacity when using the Bayesian filter. Subjects seemed to be less cautious using the Bayesian filter due to its lower error rate and smoother control. These findings suggest that Bayesian filtering may be a useful component for myoelectrically controlled prosthetics or communication devices. NEW & NOTEWORTHY Whereas previous work has focused on assessing the Bayesian algorithm as a signal processing algorithm for EMG, this study assesses the use of the Bayesian algorithm for online EMG control. In other words, the subjects see the output of the filter and can adapt their own behavior to use the filter optimally as a tool. This study compares how subjects adapt EMG behavior using the Bayesian algorithm vs. a linear algorithm. PMID- 29384449 TI - Similar nicotinic excitability responses across the developing hippocampal formation are regulated by small-conductance calcium-activated potassium channels. AB - The hippocampal formation forms a cognitive circuit that is critical for learning and memory. Cholinergic input to nicotinic acetylcholine receptors plays an important role in the normal development of principal neurons within the hippocampal formation. However, the ability of nicotinic receptors to stimulate principal neurons across all regions of the developing hippocampal formation has not been determined. We show in this study that heteromeric nicotinic receptors mediate direct inward current and depolarization responses in principal neurons across the hippocampal formation of the young postnatal mouse. These responses were found in principal neurons of the CA1, CA3, dentate gyrus, subiculum, and entorhinal cortex layer VI, and they varied in magnitude across regions with the greatest responses occurring in the subiculum and entorhinal cortex. Despite this regional variation in the magnitude of passive responses, heteromeric nicotinic receptor stimulation increased the excitability of active principal neurons by a similar amount in all regions. Pharmacological experiments found this similar excitability response to be regulated by small-conductance calcium-activated potassium (SK) channels, which exhibited regional differences in their influence on neuron activity that offset the observed regional differences in passive nicotinic responses. These findings demonstrate that SK channels play a role to coordinate the magnitude of heteromeric nicotinic excitability responses across the hippocampal formation at a time when nicotinic signaling drives the development of this cognitive brain region. This coordinated input may contribute to the normal development, synchrony, and maturation of the hippocampal formation learning and memory network. NEW & NOTEWORTHY This study demonstrates that small conductance calcium-activated potassium channels regulate similar-magnitude excitability responses to heteromeric nicotinic acetylcholine receptor stimulation in active principal neurons across multiple regions of the developing mouse hippocampal formation. Given the importance of nicotinic neurotransmission for the development of principal neurons within the hippocampal formation, this coordinated excitability response is positioned to influence the normal development, synchrony, and maturation of the hippocampal formation learning and memory network. PMID- 29384452 TI - Modeling auditory-visual evoked eye-head gaze shifts in dynamic multisteps. AB - In dynamic visual or auditory gaze double-steps, a brief target flash or sound burst is presented in midflight of an ongoing eye-head gaze shift. Behavioral experiments in humans and monkeys have indicated that the subsequent eye and head movements to the target are goal-directed, regardless of stimulus timing, first gaze shift characteristics, and initial conditions. This remarkable behavior requires that the gaze-control system 1) has continuous access to accurate signals about eye-in-head position and ongoing eye-head movements, 2) that it accounts for different internal signal delays, and 3) that it is able to update the retinal ( TE) and head-centric ( TH) target coordinates into appropriate eye centered and head-centered motor commands on millisecond time scales. As predictive, feedforward remapping of targets cannot account for this behavior, we propose that targets are transformed and stored into a stable reference frame as soon as their sensory information becomes available. We present a computational model, in which recruited cells in the midbrain superior colliculus drive eyes and head to the stored target location through a common dynamic oculocentric gaze velocity command, which is continuously updated from the stable goal and transformed into appropriate oculocentric and craniocentric motor commands. We describe two equivalent, yet conceptually different, implementations that both account for the complex, but accurate, kinematic behaviors and trajectories of eye-head gaze shifts under a variety of challenging multisensory conditions, such as in dynamic visual-auditory multisteps. PMID- 29384453 TI - Three members of a peptide family are differentially distributed and elicit differential state-dependent responses in a pattern generator-effector system. AB - C-type allatostatins (AST-Cs) are pleiotropic neuropeptides that are broadly conserved within arthropods; the presence of three AST-C isoforms, encoded by paralog genes, is common. However, these peptides are hypothesized to act through a single receptor, thereby exerting similar bioactivities within each species. We investigated this hypothesis in the American lobster, Homarus americanus, mapping the distributions of AST-C isoforms within relevant regions of the nervous system and digestive tract, and comparing their modulatory influences on the cardiac neuromuscular system. Immunohistochemistry showed that in the pericardial organ, a neuroendocrine release site, AST-C I and/or III and AST-C II are contained within distinct populations of release terminals. Moreover, AST-C I/III-like immunoreactivity was seen in midgut epithelial endocrine cells and the cardiac ganglion (CG), whereas AST-C II-like immunoreactivity was not seen in these tissues. These data suggest that AST-C I and/or III can modulate the CG both locally and hormonally; AST-C II likely acts on the CG solely as a hormonal modulator. Physiological studies demonstrated that all three AST-C isoforms can exert differential effects, including both increases and decreases, on contraction amplitude and frequency when perfused through the heart. However, in contrast to many state-dependent modulatory changes, the changes in contraction amplitude and frequency elicited by the AST-Cs were not functions of the baseline parameters. The responses to AST-C I and III, neither of which is COOH-terminally amidated, are more similar to one another than they are to the responses elicited by AST-C II, which is COOH-terminally amidated. These results suggest that the three AST-C isoforms are differentially distributed in the lobster nervous system/midgut and can elicit distinct behaviors from the cardiac neuromuscular system, with particular structural features, e.g., COOH-terminal amidation, likely important in determining the effects of the peptides. NEW & NOTEWORTHY Multiple isoforms of many peptides exert similar effects on neural circuits. In this study we show that each of the three isoforms of C-type allatostatin (AST-C) can exert differential effects, including both increases and decreases in contraction amplitude and frequency, on the lobster cardiac neuromuscular system. The distribution of effects elicited by the nonamidated isoforms AST-C I and III are more similar to one another than to the effects of the amidated AST-C II. PMID- 29384455 TI - Reciprocal inhibition between motor neurons of the tibialis anterior and triceps surae in humans. AB - Motor neurons innervating antagonist muscles receive reciprocal inhibitory afferent inputs to facilitate the joint movement in the two directions. The present study investigates the mutual transmission of reciprocal inhibitory afferent inputs between the tibialis anterior (TA) and triceps surae (soleus and medial gastrocnemius) motor units. We assessed this mutual mechanism in large populations of motor units for building a statistical distribution of the inhibition amplitudes during standardized input to the motor neuron pools to minimize the effect of modulatory pathways. Single motor unit activities were identified using high-density surface electromyography (HDsEMG) recorded from the TA, soleus (Sol), and medial gastrocnemius (GM) muscles during isometric dorsi- and plantarflexion. Reciprocal inhibition on the antagonist muscle was elicited by electrical stimulation of the tibial (TN) or common peroneal nerves (CPN). The probability density distributions of reflex strength for each muscle were estimated to examine the strength of mutual transmission of reciprocal inhibitory input. The results showed that the strength of reciprocal inhibition in the TA motor units was fourfold greater than for the GM and the Sol motor units. This suggests an asymmetric transmission of reciprocal inhibition between ankle extensor and flexor muscles. This asymmetry cannot be explained by differences in motor unit type composition between the investigated muscles since we sampled low threshold motor units in all cases. Therefore, the differences observed for the strength of inhibition are presumably due to a differential reciprocal spindle afferent input and the relative contribution of nonreciprocal inhibitory pathways. NEW & NOTEWORTHY We investigated the mutual transmission of reciprocal inhibition in large samples of motor units using a standardized input (electrical stimulation) to the motor neurons. The results demonstrated that the disynaptic reciprocal inhibition exerted between ankle flexor and extensor muscles is asymmetric. The functional implication of asymmetric transmission may be associated with the neural strategies of postural control. PMID- 29384456 TI - Analysis of variability in length of sleep state bouts reveals memory-free sleep subcomponents consistent among primary insomnia patients. AB - The statistical distributions of bout lengths for the different (macro) sleep states (wake, N1, N2, N3, and REM sleep) are essential to understanding whether any memory-free subcomponent ("micro state") is involved in the organization of sleep. Micro state detection can be prevented by the fusion of data including various sources of variability, in particular by the differences in sleep architecture between individuals, along sleep time (or nighttime), or between different nights. In this analysis, a mathematical model of sleep was adopted to disentangle these features and advance the understanding of the dynamics and mechanisms of sleep and its states. The analysis involved 116 primary insomnia patients taking placebo before going to bed and undergoing polysomnography for one night. The individual sequences of macro sleep states had been previously modeled with a mixed-effect nonhomogeneous modified Markov chain model, from which individual conditional probability distributions for the bout durations were derived in this analysis as functions of sleep time. The probability distributions, affected by neither subject, night-time, nor multiple-night pooling, substantially changed at 1/4 and 3/4 sleep time, had modified exponential shape, and were best described as the sum of one to four exponentials, depending on the sleep state. The time constants and proportions of bouts contributing to each exponential were similar in the different subjects, changing over sleep time. Variability in bout durations thus indicated the presence of multiple memory-free sleep subcomponents whose mean residence times and access probabilities could be identified and shown to be consistent among the studied subjects. NEW & NOTEWORTHY We present a new methodology for deriving, from polysomnography data, the individual conditional probability for the duration of the bouts of wake, N1, N2, N3, and REM sleep. We evaluated the variability of this probability within and between primary insomnia patients and along sleep time. The multiexponential shapes of the probability distributions within the individuals revealed memory-free mechanisms and sleep subcomponents with consistent features in the studied population. PMID- 29384457 TI - Announcing a new Editor-in-Chief of Orbit. PMID- 29384458 TI - Out of touch: Interoceptive deficits are elevated in suicide attempters with eating disorders. AB - People with eating disorders have elevated interoceptive deficits and risk for self-injurious behaviors (SIBs). Across two eating disorder samples, the relationship between interoceptive deficits (IDs) and SIBs was tested. Study 1 (n = 100) found that suicide attempters and those engaging in non-suicidal self injury (NSSI) had greater IDs than those with no self-injury history. Lack of access to emotion regulation strategies accounted for the link between IDs and SIBs. In Study 2 (n = 92) multiple suicide attempters had greater IDs than single attempters and those engaging in NSSI; however, the latter two groups did not differ from one another. Interoceptive deficits may differentiate those who engage in severe SIBs from those who do not, and thus be a useful determinant of suicide risk severity among patients with eating disorders. Lack of access to emotion regulation strategies appears to be one pathway linking interoceptive deficits and self-injury. PMID- 29384454 TI - Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest alpha-motoneurons die before smaller alpha-motoneurons, and gamma motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of alpha-gamma coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS. PMID- 29384459 TI - Radically open DBT: Targeting emotional loneliness in Anorexia Nervosa. AB - This article conceptualizes Anorexia Nervosa (AN) as a prototypical overcontrolled disorder, characterized by low receptivity and openness, low flexible control, pervasive inhibited emotional expressiveness, low emotional awareness, and low social connectedness and intimacy with others. As a result, individuals with AN often report high levels of emotional loneliness. A new evidence-based treatment, Radically Open Dialectical Behavior Therapy (RO-DBT), and its underlying neuroregulatory theory, offer a novel way of understanding how self-starvation and social signaling deficits are used as maladaptive regulation strategies to reduce negative affect. RO-DBT proposes that rather than trying to be 'emotionally regulated' or achieving equanimity, long-term psychological well being is achieved by increasing social connectedness. RO-DBT skills, including body posture, gestures, and facial expressions, activate brain regions that increase social safety responses that function to automatically enhance the open minded and flexible social-signaling, which are crucial for establishing long term intimate bonds with others and becoming part of a "tribe." PMID- 29384460 TI - Negative urgency and expectancies increase vulnerability to binge eating in bulimia nervosa. AB - Negative urgency (NU), the tendency to act impulsively when distressed, is associated with binge eating. Women who believe that eating alleviates negative affect are also more likely to binge eat. Thus, it is hypothesized that the individuals with high levels of NU, and who endorse these eating expectancies, will binge eat the following acute distress. This study tested these hypotheses using ecological momentary assessment. Sixteen women with the symptoms of BN completed clinical assessments, and were asked to report on distress and binges multiple times daily for two weeks. NU moderated the temporal relationship of negative affect to binges, such that women with lower scores on NU experienced a sharper increase in affect prior to binges. Individual differences in eating expectancies also moderated the relationship of affect to binge eating. Results suggest that women with high levels of NU and expectancy endorsement are triggered to binge by smaller shifts in negative affect than women who do not endorse these traits. PMID- 29384461 TI - Restrictive eating is associated with emotion regulation difficulties in a non clinical sample. AB - The relationship between emotion regulation difficulties and restrictive eating has not been established in non-clinical samples. In this study, undergraduates (n = 98) provided information regarding general and specific emotion regulation difficulties on the Difficulties in Emotion Regulation Scale (DERS) and whether they had engaged in recent restrictive eating. Generalized linear models were used to determine if individuals endorsing versus denying recent restrictive eating differed on emotion regulation problems. Results indicated that individuals endorsing restrictive eating had elevated DERS Total (p < .001), Goals (p = .001), Impulse (p < .001), and Strategies (p < .001) scores. Results remained primarily unchanged after controlling for the related construct of dietary restraint. Findings indicate that endorsement of restrictive eating among non-clinical individuals is uniquely associated with emotion regulation deficits, especially those reflecting emotional under-control. Interventions targeting emotion regulation may enhance prevention and treatment of restrictive eating across severity. PMID- 29384462 TI - An open trial targeting emotional eating among adolescents with overweight or obesity. AB - Emotional eating is associated with obesity and disordered eating in adolescents, and thus, is an important target for treatment. We developed a program called PEER (Preventing Emotional Eating Routines), which incorporates emotion regulation skills with behavioral weight loss and parenting techniques for adolescents who are overweight or obese (OW/OB) and their parent. This open label trial evaluated the feasibility, acceptability, and initial efficacy of the PEER program. Thirty adolescents who were OW/OB (86.7% female; mean age = 14.6 years (SD = 1.2); Body Mass Index (BMI) = 34.0 kg/m2 (SD = 5.6); 33.3% White non Hispanic) and their parent (66.7% biological mother) participated in a 4-month treatment and 3-month follow-up. The PEER program was well accepted. Initial efficacy showed significant decreases in emotional eating, and there were trends towards weight loss and a decrease in emotion dysregulation. This trial provides preliminary evidence for the feasibility, acceptability, and initial efficacy of the PEER program among adolescents who are OW/OB and their parent. Further treatment development and randomized controlled studies are needed. PMID- 29384463 TI - Emotion dysregulation across the spectrum of pathological eating: Comparisons among women with binge eating, overeating, and loss of control eating. AB - Emotion regulation difficulties influence the etiology and maintenance of binge eating and eating disorders, but differential associations between emotion dysregulation and objective binge eating (OBE) components have not been examined. We compared emotion dysregulation dimensions in women with OBEs (n = 27), overeating only (n = 25), loss of control (LOC) only (n = 32), or no pathological eating (n = 137). Women with OBEs had significantly more difficulty with overall emotion dysregulation, access to strategies, and impulse control when upset than other groups. Women with OBEs and women with overeating did not differ on poor emotional clarity, whereas women with OBEs and women with LOC did not differ on non-acceptance of emotions. The combination of overeating and LOC eating is associated with the greatest emotion dysregulation, but certain emotion regulation facets may differentially relate to overeating and LOC. Identifying emotion-related treatment targets for core eating disorder symptoms is important. PMID- 29384464 TI - An introduction to the special issue on emotion regulation and eating disorders. PMID- 29384465 TI - A test of a state-based, self-control theory of binge eating in adults with obesity. AB - It has been theorized that state the levels of self-control depletion (as caused by negative affect and restraint) may lead to binge eating (BE) when individuals also endorse momentary expectancies that eating will make them feel better (EE). Given commonalities in precipitants of BE across populations, the current study tested this theory in a sample of adults with obesity using ecological momentary assessment (EMA). Fifty obese adults completed the EMA protocol during which they provided pre-eating episode ratings of negative affect, restraint, and EE, and post-eating episode ratings of BE. Generalized estimating equations (GEE) identified a 3-way interaction between within-person pre-eating episode variables: higher self-control depletion (e.g., higher restraint and higher negative affect) was predictive of BE episodes only when individuals also endorsed higher EE. To our knowledge, this is the first empirical test of this theory, highlighting the impact of momentary self-control depletion and EE on BE in obese adults. PMID- 29384467 TI - Speed of Processing Time Slowing in Eating Disorders. AB - We applied Brinley ( 1965 ) plot analysis to the eating disorders field. Across 23 studies and 165 experimental conditions [experienced by a total of 773 eating disorder (ED) participants, including anorexia nervosa (AN), binge eating (BE), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS) and 995 controls], the best-fit regression equation was Y (ED) = 1.08 X (CONTROL) - 31. This equation accounted for 98.2% of the variance. Thus, the ED subjects were only 1.08 times slower than the control subjects, suggesting little processing speed slowing in ED. We also examined simple reaction time [SRT; Y (ED) = .91 X (CONTROL) + 63; variance accounted for = 93.6%] and choice reaction time (CRT; Y (ED) = 1.12X (CONTROL) - 43, variance accounted for = 99.7%). These slopes are significantly different. ED subjects are more impacted when the task involves a decision component (CRT) than when it does not (SRT). PMID- 29384466 TI - Affective predictors of the severity and change in eating psychopathology in residential eating disorder treatment: The role of social anxiety. AB - Despite evidence documenting relationships between eating disorder (ED) psychopathology, depression, and anxiety, little is known regarding how social anxiety is related to ED symptoms in treatment. Therefore this study examined associations between depression, general anxiety, social anxiety, and ED psychopathology at the beginning and end of treatment (EOT) among patients (N = 380) treated in a residential ED program. Participants completed measures of ED psychopathology and affective variables. Higher depression and general anxiety, but not social anxiety, were related to higher ED psychopathology at baseline. However, social anxiety emerged as a unique predictor of ED psychopathology at EOT such that participants with higher social anxiety evidenced less improvement in ED psychopathology. Findings suggest that social anxiety has specific relevance to treatment in EDs, which may reflect shared mechanisms and underlying deficits in emotion regulation. PMID- 29384468 TI - Emotion Regulation and Empathy: Which Relation with Social Conduct? AB - A shared consensus among researchers deals with the positive association between the ability to effectively regulate and manage one's emotion and the engagement in empathic behavior and morally desirable actions. This study was designed to investigate how dispositional reliance on suppression and reappraisal differently impacted on the cognitive and affective components of empathy and on social conduct, distinguishing among prosocial, internalizing, and externalizing behaviors. Two hundred nineteen middle adolescents were enrolled and fulfilled self-reports assessing emotion regulation strategies, empathy, and social behaviors. The results suggest that there are important distinctions among the emotion regulation strategies and the components of empathy as they relate to one another and to prosocial behavior and problem conduct. Specifically, cognitive reappraisal was related to prosocial behavior through empathic concern. While internalizing behavior was associated with emotion regulation strategies, externalizing behavior was only related to perspective-taking ability. Delimitations and practical implications were discussed. PMID- 29384469 TI - Perceived need for care and mental health service utilization among college students with suicidal ideation. AB - OBJECTIVE: This study aimed to identify correlates of service utilization and perceived need for care among college students with suicidal ideation. PARTICIPANTS: Respondents were recruited from introductory psychology courses at an undergraduate college during the Fall 2014 semester. METHODS: Independent correlates of (1) mental health service utilization, (2) self-perceived need, and (3) other-perceived need for mental health services among college students (N = 190) with suicidal ideation were identified. RESULTS: Service utilization was associated with need for care as perceived by others. Perceived need for care by others was associated with suicidal ideation intensity and suicide attempt history. Perceived need by the respondents themselves was correlated with depression severity, sex, and race but was not independently associated with actual service utilization. CONCLUSIONS: Perceived need by others was the sole significant correlate of service utilization, suggesting it is an important target for public health interventions aimed at facilitating pathways into mental health treatment. PMID- 29384470 TI - The UK EndoVascular Aneurysm Repair (EVAR) randomised controlled trials: long term follow-up and cost-effectiveness analysis. AB - BACKGROUND: Short-term survival benefits of endovascular aneurysm repair (EVAR) compared with open repair (OR) of intact abdominal aortic aneurysms have been shown in randomised trials, but this early survival benefit is soon lost. Survival benefit of EVAR was unclear at follow-up to 10 years. OBJECTIVE: To assess the long-term efficacy of EVAR against OR in patients deemed fit and suitable for both procedures (EVAR trial 1; EVAR-1); and against no intervention in patients unfit for OR (EVAR trial 2; EVAR-2). To appraise the long-term significance of type II endoleak and define criteria for intervention. DESIGN: Two national, multicentre randomised controlled trials: EVAR-1 and EVAR-2. SETTING: Patients were recruited from 37 hospitals in the UK between 1 September 1999 and 31 August 2004. PARTICIPANTS: Men and women aged >= 60 years with an aneurysm of >= 5.5 cm (as identified by computed tomography scanning), anatomically suitable and fit for OR were randomly assigned 1 : 1 to either EVAR (n = 626) or OR (n = 626) in EVAR-1 using computer-generated sequences at the trial hub. Patients considered unfit were randomly assigned to EVAR (n = 197) or no intervention (n = 207) in EVAR-2. There was no blinding. INTERVENTIONS: EVAR, OR or no intervention. MAIN OUTCOME MEASURES: The primary end points were total and aneurysm-related mortality until mid-2015 for both trials. Secondary outcomes for EVAR-1 were reinterventions, costs and cost-effectiveness. RESULTS: In EVAR 1, over a mean of 12.7 years (standard deviation 1.5 years; maximum 15.8 years), we recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the OR group [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.97 to 1.27; p = 0.14]. At 0-6 months after randomisation, patients in the EVAR group had a lower mortality (adjusted HR 0.61, 95% CI 0.37 to 1.02 for total mortality; HR 0.47, 95% CI 0.23 to 0.93 for aneurysm-related mortality; p = 0.031), but beyond 8 years of follow-up patients in the OR group had a significantly lower mortality (adjusted HR 1.25, 95% CI 1.00 to 1.56, p = 0.048 for total mortality; HR 5.82, 95% CI 1.64 to 20.65, p = 0.0064 for aneurysm related mortality). The increased aneurysm-related mortality in the EVAR group after 8 years was mainly attributable to secondary aneurysm sac rupture, with increased cancer mortality also observed in the EVAR group. Overall, aneurysm reintervention rates were higher in the EVAR group than in the OR group, 4.1 and 1.7 per 100 person-years, respectively (p < 0.001), with reinterventions occurring throughout follow-up. The mean difference in costs over 14 years was L3798 (95% CI L2338 to L5258). Economic modelling based on the outcomes of the EVAR-1 trial showed that the cost per quality-adjusted life-year gained over the patient's lifetime exceeds conventional thresholds used in the UK. In EVAR-2, patients died at the same rate in both groups, but there was suggestion of lower aneurysm mortality in those who actually underwent EVAR. Type II endoleak itself is not associated with a higher rate of mortality. LIMITATIONS: Devices used were implanted between 1999 and 2004. Newer devices might have better results. Later follow-up imaging declined, particularly for OR patients. Methodology to capture reinterventions changed mainly to record linkage through the Hospital Episode Statistics administrative data set from 2009. CONCLUSIONS: EVAR has an early survival benefit but an inferior late survival benefit compared with OR, which needs to be addressed by lifelong surveillance of EVAR and reintervention if necessary. EVAR does not prolong life in patients unfit for OR. Type II endoleak alone is relatively benign. FUTURE WORK: To find easier ways to monitor sac expansion to trigger timely reintervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55703451. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the results will be published in full in Health Technology Assessment; Vol. 22, No. 5. See the NIHR Journals Library website for further project information. PMID- 29384471 TI - A novel approach to off-clamp partial nephrectomy demonstrates significant improvements in renal injury in an experimental porcine model. AB - INTRODUCTION: We sought to design a partial nephrectomy (PN) with contralateral total nephrectomy porcine model and assess the underlying mechanisms of ischemia reperfusion injury (IRI) after PN using a novel, clinically approved resection device. METHODS: Domestic male pigs (n=9) underwent left lower pole PN, allocated to either standard (Group 1) or no ischemia PN (Group 2), followed by contralateral nephrectomy. Biochemical studies were performed at baseline, Day 2, and Day 7; after sacrifice, kidneys were processed for histological analysis. Apoptotic markers were measured by Western blot analyses. Urinary biomarkers were measured to assess acute kidney injury. RESULTS: At Day 2 following PN, there was a significant rise in serum creatinine in Group 1 compared to Group 2 (355 vs. 136 mmol/L; p=0.008). Intra-renal tissue oxygen saturation after PN was inversely correlated with postoperative creatinine (rs -0.75; p=0.012) and the grade of acute tubular necrosis (rs -0.70; p=0.036). We observed a rise in expression of pro-apoptotic markers and pro-inflammatory markers in Group 1 following PN compared to Group 2. Histological analysis revealed higher grade of apoptosis in Group 1. CONCLUSIONS: IRI associated with standard PN has a deleterious impact on acute renal function, markers of tissue injury, and histological parameters, compared to off-clamp PN using the ALTRUS device. We identified several intraoperative and postoperative markers that may be used as predictors for functional and histological injury following PN. PMID- 29384472 TI - Montreal electronic artificial urinary sphincters: Our futuristic alternatives to the AMS800TM. AB - INTRODUCTION: We aimed to present three novel remotely controlled hydromechanical artificial urinary sphincters (AUSs) and report their in-vitro and ex-vivo results. METHODS: We successively developed three distinct hydromechanical AUSs on the basis of the existing AMS800TM device by incorporating an electronic pump. No changes were made to the cuff and balloon. The AUS#1 was designed as an electromagnetically controlled device. The AUS#2 and AUS#3 were conceived as Bluetooth 2.1 remotely controlled and Bluetooth 4.0 remotely-controlled, adaptive devices, respectively. In-vitro experiments profiled occlusive cuff pressure (OCP) during a complete device cycle, with different predetermined OCP. Ex-vivo experiments were performed on a fresh pig bladder with 4 cm cuff placed around the urethra. Leak point pressure with different predetermined OCP values was successively measured during cystometry via a catheter at the bladder dome. RESULTS: Our in-vitro and ex-vivo experiments demonstrated that these three novel AUSs provided stable and predetermined OCP - within the physiological range - and completely deflated the cuff, when required, in a limited time compatible with physiological voiding cycles. CONCLUSIONS: Our three novel, remotely controlled AUSs showed promising results that should be confirmed by in-vivo experiments focusing on efficacy and safety. PMID- 29384473 TI - The representational dynamics of task and object processing in humans. AB - Despite the importance of an observer's goals in determining how a visual object is categorized, surprisingly little is known about how humans process the task context in which objects occur and how it may interact with the processing of objects. Using magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI) and multivariate techniques, we studied the spatial and temporal dynamics of task and object processing. Our results reveal a sequence of separate but overlapping task-related processes spread across frontoparietal and occipitotemporal cortex. Task exhibited late effects on object processing by selectively enhancing task-relevant object features, with limited impact on the overall pattern of object representations. Combining MEG and fMRI data, we reveal a parallel rise in task-related signals throughout the cerebral cortex, with an increasing dominance of task over object representations from early to higher visual areas. Collectively, our results reveal the complex dynamics underlying task and object representations throughout human cortex. PMID- 29384474 TI - Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers. AB - RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development. PMID- 29384475 TI - Structural basis of ribosomal peptide macrocyclization in plants. AB - Constrained, cyclic peptides encoded by plant genes represent a new generation of drug leads. Evolution has repeatedly recruited the Cys-protease asparaginyl endopeptidase (AEP) to perform their head-to-tail ligation. These macrocyclization reactions use the substrates amino terminus instead of water to deacylate, so a peptide bond is formed. How solvent-exposed plant AEPs macrocyclize is poorly understood. Here we present the crystal structure of an active plant AEP from the common sunflower, Helianthus annuus. The active site contained electron density for a tetrahedral intermediate with partial occupancy that predicted a binding mode for peptide macrocyclization. By substituting catalytic residues we could alter the ratio of cyclic to acyclic products. Moreover, we showed AEPs from other species lacking cyclic peptides can perform macrocyclization under favorable pH conditions. This structural characterization of AEP presents a logical framework for engineering superior enzymes that generate macrocyclic peptide drug leads. PMID- 29384476 TI - Activity-induced Ca2+ signaling in perisynaptic Schwann cells of the early postnatal mouse is mediated by P2Y1 receptors and regulates muscle fatigue. AB - Perisynaptic glial cells respond to neural activity by increasing cytosolic calcium, but the significance of this pathway is unclear. Terminal/perisynaptic Schwann cells (TPSCs) are a perisynaptic glial cell at the neuromuscular junction that respond to nerve-derived substances such as acetylcholine and purines. Here, we provide genetic evidence that activity-induced calcium accumulation in neonatal TPSCs is mediated exclusively by one subtype of metabotropic purinergic receptor. In P2ry1 mutant mice lacking these responses, postsynaptic, rather than presynaptic, function was altered in response to nerve stimulation. This impairment was correlated with a greater susceptibility to activity-induced muscle fatigue. Interestingly, fatigue in P2ry1 mutants was more greatly exacerbated by exposure to high potassium than in control mice. High potassium itself increased cytosolic levels of calcium in TPSCs, a response which was also reduced P2ry1 mutants. These results suggest that activity-induced calcium responses in TPSCs regulate postsynaptic function and muscle fatigue by regulating perisynaptic potassium. PMID- 29384477 TI - The lawful imprecision of human surface tilt estimation in natural scenes. AB - Estimating local surface orientation (slant and tilt) is fundamental to recovering the three-dimensional structure of the environment. It is unknown how well humans perform this task in natural scenes. Here, with a database of natural stereo-images having groundtruth surface orientation at each pixel, we find dramatic differences in human tilt estimation with natural and artificial stimuli. Estimates are precise and unbiased with artificial stimuli and imprecise and strongly biased with natural stimuli. An image-computable Bayes optimal model grounded in natural scene statistics predicts human bias, precision, and trial-by trial errors without fitting parameters to the human data. The similarities between human and model performance suggest that the complex human performance patterns with natural stimuli are lawful, and that human visual systems have internalized local image and scene statistics to optimally infer the three dimensional structure of the environment. These results generalize our understanding of vision from the lab to the real world. PMID- 29384478 TI - Discrimination between bycatch and other causes of cetacean and pinniped stranding. AB - The challenge of identifying cause of death in discarded bycaught marine mammals stems from a combination of the non-specific nature of the lesions of drowning, the complex physiologic adaptations unique to breath-holding marine mammals, lack of case histories, and the diverse nature of fishing gear. While no pathognomonic lesions are recognized, signs of acute external entanglement, bulging or reddened eyes, recently ingested gastric contents, pulmonary changes, and decompression associated gas bubbles have been identified in the condition of peracute underwater entrapment (PUE) syndrome in previous studies of marine mammals. We reviewed the gross necropsy and histopathology reports of 36 cetaceans and pinnipeds including 20 directly observed bycaught and 16 live stranded animals that were euthanized between 2005 and 2011 for lesions consistent with PUE. We identified 5 criteria which present at significantly higher rates in bycaught marine mammals: external signs of acute entanglement, red or bulging eyes, recently ingested gastric contents, multi-organ congestion, and disseminated gas bubbles detected grossly during the necropsy and histologically. In contrast, froth in the trachea or primary bronchi, and lung changes (i.e. wet, heavy, froth, edema, congestion, and hemorrhage) were poor indicators of PUE. This is the first study that provides insight into the different published parameters for PUE in bycatch. For regions frequently confronted by stranded marine mammals with non-specific lesions, this could potentially aid in the investigation and quantification of marine fisheries interactions. PMID- 29384479 TI - Susceptibility of eastern water dragons Intellagama lesueurii lesueurii to Bohle iridovirus. AB - Ranaviruses infect and have been associated with mass mortality events in fish, amphibians and reptiles and are capable of interclass transmission. Eastern water dragons (EWDs), a semi-aquatic squamate, have an overlapping distribution with several species shown to be susceptible to Bohle iridovirus (BIV). However, this species has not been previously investigated, and no known mass mortalities have occurred in wild populations. Here we report the experimental infection of juvenile EWDs with BIV to investigate a water-dwelling lizards' susceptibility to a ranaviral strain present in northern Queensland, Australia. Lizards were exposed via oral inoculation, intramuscular injection, or cohabitation with orally infected lizards. All exposure methods were effective in establishing an infection as demonstrated by skin lesions and pathological changes in the internal organs. Necrosis, haemorrhage and inflammation were observed histologically in the pancreas, liver, spleen, kidney and submucosa of the gastrointestinal tract of BIV-exposed lizards. Variably sized basophilic intracytoplasmic inclusion bodies were observed in the liver of 6/14 BIV-exposed lizards. Virus was isolated from the liver and kidney of all BIV-infected lizards and confirmed with quantitative PCR (qPCR). The outcome of this study demonstrates that juvenile EWDs are susceptible to BIV, thereby adding Australian lizards to the broad host range of ranaviruses. Furthermore, this study provides additional evidence of BIV's ability to infect different classes of ecothermic vertebrates. PMID- 29384480 TI - Amphibian chytrid infection is influenced by rainfall seasonality and water availability. AB - Amphibians suffer from a number of factors that make them the most threatened group of vertebrates. One threat is the fungal disease chytridiomycosis caused by the emerging pathogen Batrachochytrium dendrobatidis (Bd), which has rapidly spread and caused the loss of massive amphibian biodiversity worldwide. Recently, Bd was associated with a few amphibian population declines and extinctions in some areas of the Brazilian Atlantic Forest. However, the mechanisms underlying such declines are not fully understood. Therefore, it is essential to improve our knowledge of abiotic factors that can possibly influence Bd prevalence and chytridiomycosis disease severity. Herein we tested the hypothesis that water availability (such as in perennial streams, where Bd is frequently present in larvae) and rainfall would increase the prevalence of Bd. To test this, we sampled frogs from 6 transects with different numbers of perennial waterbodies, and we report that the more water available in the area, the higher the probability of Bd infection on anurans. Seasonality also influenced both the Bd prevalence in the area and the intensity of infection in infected frogs. However, Bd prevalence was higher during the rainy months whereas the infection burden was lower. We suggest that Bd is likely spread during the summer, when most anuran species gather near the water for spawning and when rainfall overfills ephemeral wetlands. On the other hand, during the drier months, a higher infection burden may be explained by increased disease susceptibility. PMID- 29384481 TI - Morphology and molecular phylogeny of Ortholinea mullusi sp. nov. (Myxozoa) in Mullus barbatus from the Black Sea. AB - Myxosporeans of the genus Ortholinea have a worldwide distribution and infect organs and tissues of exclusively marine fishes. Here we describe the morphological and molecular characteristics of Ortholinea mullusi sp. nov. parasitizing the urinary bladder and kidney tubules of red mullet Mullus barbatus collected from the coastal zone of Sinop in the Black Sea, Turkey. Polysporic plasmodia with immature spores were either elongate, 37.0 +/- 4.5 SD (30-50) um long and 45.0 +/- 3.8 (40-55) um wide, or were round, up to 100.0 um in diameter. Mature, free spores were spherical in the frontal view and measured 9.3 +/- 0.2 (9.0-9.7) um in length, 8.7 +/- 0.3 (8.2-9.3) um in width and 7.7 +/- 0.1 (7.5 7.9) um in thickness. We observed 2 polar capsules of equal size, which measured 3.1 +/- 0.1 (3.0-3.2) um long by 2.5 +/- 0.1 (2.4-2.6) um wide, and the tips of the polar capsules were open towards the sutural line. The prevalence of infection by O. mullusi sp. nov. was 24.5%. Phylogenetic analysis based on nuclear small subunit ribosomal DNA (SSU rDNA) clearly suggested O. mullusi to be a new species, clustered within a lineage comprising O. labracis and O auratae. Pairwise nucleotide similarities and DNA distance values between O. mullusi sp. nov. and sister Ortholinea species also supported this suggestion. PMID- 29384482 TI - Tetrahymena glochidiophila n. sp., a new species of Tetrahymena (Ciliophora) that causes mortality to glochidia larvae of freshwater mussels (Bivalvia). AB - A ciliate protozoan was discovered whose presence coincided with a rapid decrease in the viability (i.e. ability to close valves) of glochidia of the freshwater mussel Lampsilis siliquoidea. Microscopic examination showed it to be a histophagous tetrahymenine ciliate. Small subunit (SSU) rRNA and cytochrome c oxidase subunit 1 (cox1) barcode sequences from cultured cells showed that it belongs to the same new species isolated from water samples as a free-living ciliate. Phylogenetic analyses place this new ciliate in the same clade with the macrostome species Tetrahymena paravorax, and we propose the name T. glochidiophila n. sp. for this new species. The phylogeny provides further support for the hypothesis that histophagy was a life history trait of the ancestor of Tetrahymena. PMID- 29384483 TI - Occlusive mycotic tracheobronchitis and systemic Alphaherpesvirus coinfection in a free-living striped dolphin Stenella coeruleoalba in Italy. AB - A juvenile female striped dolphin Stenella coeruleoalba live stranded on 4 March 2016 at Alassio, western Ligurian Sea coast, Italy. The dolphin died shortly after stranding, and a complete postmortem examination was performed. Necropsy revealed severe tracheal occlusion and unilateral bronchial stenosis with luminal accumulation of abundant green-yellow mucous-gelatinous material. Histological features suggestive of tracheobronchial aspergillosis were observed. Cultures of lung tissue and tracheo-bronchial exudate isolated Aspergillus fumigatus, identified by a Microseq D2 LSUrDNA fungal sequencing kit. A pan-Herpesvirus nested-PCR assay on frozen samples obtained from multiple organs was positive. Phylogenetic analysis on the partial DNA polymerase gene revealed that the striped dolphin isolate was closely related to known cetacean Alphaherpesvirus sequences from the same host species. Attempted virus isolation was unsuccessful. The tissue levels of different persistent organic pollutants and the toxicological stress, evaluated using a theoretical model, showed a severely impaired immune response. This study reports the first case of occlusive mycotic tracheobronchitis in a free-living cetacean and the first molecular identification of an Alphaherpesvirus in a free-ranging striped dolphin stranded on the coast of Italy. PMID- 29384484 TI - Brevetoxin exposure in sea turtles in south Texas (USA) during Karenia brevis red tide. AB - Five green (Chelonia mydas) and 11 Kemp's ridley (Lepidochelys kempii) sea turtles found dead, or that died soon after stranding, on the southern Texas (USA) coast during 2 Karenia brevis blooms (October 2015, September-October 2016) were tested for exposure to brevetoxins (PbTx). Tissues (liver, kidney) and digesta (stomach and intestinal contents) were analyzed by ELISA. Three green turtles found alive during the 2015 event and 2 Kemp's ridley turtles found alive during the 2016 event exhibited signs of PbTx exposure, including lethargy and/or convulsions of the head and neck. PbTx were detected in 1 or more tissues or digesta in all 16 stranded turtles. Detected PbTx concentrations ranged from 2 to >2000 ng g-1. Necropsy examination and results of PbTx analysis indicated that 10 of the Kemp's ridleys and 2 of the green turtles died from brevetoxicosis via ingestion. This is the first documentation of sea turtle mortality in Texas attributed to brevetoxicosis. PMID- 29384485 TI - Tetracapsuloides bryosalmonae persists in brown trout Salmo trutta for five years post exposure. AB - Tetracapsuloides bryosalmonae is a malacosporean parasite and the causative agent of proliferative kidney disease (PKD) that seriously impacts farmed and wild salmonids. The parasite's life cycle includes an invertebrate host, the bryozoan Fredericella sultana, and a vertebrate host, salmonid fish. The persistence of T. bryosalmonae in brown trout Salmo trutta for up to 2 yr following exposure is well documented. Results from the present study confirmed that one brown trout that had recovered from PKD did not completely clear the parasite from its tissues and that T. bryosalmonae could persist in brown trout for up to 5 yr post exposure. Furthermore, recovered infected brown trout can release viable T. bryosalmonae spores that are able to infect specific pathogen-free F. sultana colonies. T. bryosalmonae DNA was detected by PCR in every organ, and parasite stages were observed in the kidney, spleen and liver following immunohistochemistry. This finding indicates that T. bryosalmonae-infected brown trout can act as asymptomatic carriers and release the parasite for several years after the initial infection, acting as a reservoir of infection, and contributing to the dissemination of the parasite to new areas. PMID- 29384486 TI - Buoyancy disorders in pet axolotls Ambystoma mexicanum: three cases. AB - As far as we are aware, there are no previous reports on the pathologic conditions of buoyancy disorders in Ambystoma mexicanum. Herein, we describe various clinical test results, clinical outcomes, and the pathological findings of an experimental pneumonectomy procedure in 3 A. mexicanum exhibiting abnormal buoyancy. The 3 pet A. mexicanum were adults, and their respective ages and body weights were 1, 5, and 6 yr and 48, 55, and 56 g. Two of these cases were confirmed via radiographic examination to have free air within the body cavity, and all 3 cases were found via ultrasonography to have an acoustic shadow within the body cavity and were diagnosed with pneumocoelom. Lung perforations were detected macroscopically in 2 of the cases, and all 3 cases had fibrosis in the caudal ends of the lungs. Removal of the lung lesions eliminated the abnormal buoyancy in all 3 cases. We concluded that air had leaked into the body cavity from the lungs, and we propose that lung lesions are an important cause of buoyancy disorders in A. mexicanum. PMID- 29384487 TI - Facile morphology-controlled synthesis of nickel-coated graphite core-shell particles for excellent conducting performance of polymer-matrix composites and enhanced catalytic reduction of 4-nitrophenol. AB - We have developed a novel seed-mediated growth method to fabricate nickel-coated graphite composite particles (GP@Ni-CPs) with controllable shell morphology by simply adjusting the concentration of sodium hydroxide ([NaOH]). The fabrication of two kinds of typical GP@Ni-CPs includes adsorption of Ni2+ via electrostatic attraction, sufficient heterogeneous nucleation of Ni atoms by an in situ reduction, and shell-controlled growth by regulating the kinetics of electroless Ni plating in turn. High [NaOH] results in fast kinetics of electroless plating, which causes heterogeneous nuclei to grow isotropically. After fast and uniform growth of Ni nuclei, GP@Ni-CPs with dense shells can be achieved. The first typical GP@Ni-CPs exhibit denser shells, smaller diameters and higher conductivities than the available commercial ones, indicating their important applications in the conducting of polymer-matrix composites. On the other hand, low [NaOH] favors slow kinetics. Thus, the reduction rate of Ni2+ slows down to a relatively low level so that electroless plating is dominated thermodynamically instead of kinetically, leading to an anisotropic crystalline growth of nuclei and finally to the formation of GP@Ni-CPs with nanoneedle-like shells. The second typical samples can effectively catalyze the reduction of p-nitrophenol into p aminophenol with NaBH4 in comparison with commercial GP@Ni-CPs and RANEY(r) Ni, owing to the strong charge accumulation effect of needle-like Ni shells. This work proposes a model system for fundamental investigations and has important applications in the fields of electronic interconnection and catalysis. PMID- 29384488 TI - Optimization of photoelectrochemical performance in Pt modified p Cu2O/n-Cu2O nanocomposite. AB - As expected to be one of the most promising materials for utilizing solar energy, Cu2O has attracted extensive attention toward solar energy conversion. Until now, the photocurrent densities of all planar structure of the Cu2O photocathode are still not even close to the theoretical value of -14.7 mA cm-2 due to the incompatible light absorption and charge carrier diffusion lengths. Here, we have fabricated p-n Cu2O homojunction nanocomposite by multiple steps of electrochemical deposition (ECD) processing with the optimization of deposition periods. The p-Cu2O/n Cu2O nanocomposite fabricated by optimized pH (4.9) and deposition time (4 min) exhibited 2 times higher photocurrent density than that of the bare p-Cu2O photocathode. And the highest photocurrent density of nanostructured p-n Cu2O NR homojunction photocathode with a p Cu2O blocking layer reached up to -10.0 mA cm-2 at 0 V vs. RHE under simulated AM 1.5G illumination (100 mW cm-2). PMID- 29384489 TI - Designing magnetic droplet soliton nucleation employing spin polarizer. AB - We show by means of micromagnetic simulations that spin polarizer in nano-contact (NC) spin torque oscillators as the representative of the fixed layer in an orthogonal pseudo-spin valve can be employed to design and to control magnetic droplet soliton nucleation and dynamics. We found that using a tilted spin polarizer layer decreases the droplet nucleation time which is more suitable for high speed applications. However, a tilted spin polarizer increases the nucleation current and decreases the frequency stability of the droplet. Additionally, by driving the magnetization inhomogenously at the NC region, it is found that a tilted spin polarizer reduces the precession angle of the droplet and through an interplay with the Oersted field of the DC current, it breaks the spatial symmetry of the droplet profile. Our findings explore fundamental insight into nano-scale magnetic droplet soliton dynamics with potential tunability parameters for future microwave electronics. PMID- 29384490 TI - A microfluidic chip containing multiple 3D nanofibrous scaffolds for culturing human pluripotent stem cells. AB - In microfluidics-based lab-on-a-chip systems, which are used for investigating the effect of drugs and growth factors on cells, the latter are usually cultured within the device's channels in two-dimensional, and not in their optimal three dimensional (3D) microenvironment. Herein, we address this shortfall by designing a microfluidic system, comprised of two layers. The upper layer of the system consists of multiple channels generating a gradient of soluble factors. The lower layer is comprised of multiple wells, each deposited with 3D, nanofibrous scaffold. We first used a mathematical model to characterize the fluid flow within the system. We then show that induced pluripotent stem cells can be seeded within the 3D scaffolds and be exposed to a well-mixed gradient of soluble factors. We believe that utilizing such system may enable in the future to identify new differentiation factors, investigate drug toxicity, and eventually allow to perform analyses on patient-specific tissues, in order to fit the appropriate combination and concentration of drugs. PMID- 29384491 TI - A fabrication guide for planar silicon quantum dot heterostructures. AB - We describe important considerations to create top-down fabricated planar quantum dots in silicon, often not discussed in detail in literature. The subtle interplay between intrinsic material properties, interfaces and fabrication processes plays a crucial role in the formation of electrostatically defined quantum dots. Processes such as oxidation, physical vapor deposition and atomic layer deposition must be tailored in order to prevent unwanted side effects such as defects, disorder and dewetting. In two directly related manuscripts written in parallel we use techniques described in this work to create depletion-mode quantum dots in intrinsic silicon, and low-disorder silicon quantum dots defined with palladium gates. While we discuss three different planar gate structures, the general principles also apply to 0D and 1D systems, such as self-assembled islands and nanowires. PMID- 29384492 TI - Formation of tungsten oxide nanowires by ion irradiation and vacuum annealing. AB - Here we reported the fabrication of tungsten oxide (WO3-x ) nanowires by Ar+ ion irradiation of WO3 thin films followed by annealing in vacuum. The nanowire length increases with increasing irradiation fluence and with decreasing ion energy. We propose that the stress-driven diffusion of the irradiation-induced W interstitial atoms is responsible for the formation of the nanowires. Comparing to the pristine film, the fabricated nanowire film shows a 106-fold enhancement in electrical conductivity, resulting from the high-density irradiation-induced vacancies on the oxygen sublattice. The nanostructure exhibits largely enhanced surface-enhanced Raman scattering effect due to the oxygen vacancy. Thus, ion irradiation provides a powerful approach for fabricating and tailoring the surface nanostructures of semiconductors. PMID- 29384493 TI - Iterative reconstruction with boundary detection for carbon ion computed tomography. AB - In heavy ion radiation therapy, improving the accuracy in range prediction of the ions inside the patient's body has become essential. Accurate localization of the Bragg peak provides greater conformity of the tumor while sparing healthy tissues. We investigated the use of carbon ions directly for computed tomography (carbon CT) to create the relative stopping power map of a patient's body. The Geant4 toolkit was used to perform a Monte Carlo simulation of the carbon ion trajectories, to study their lateral and angular deflections and the most likely paths, using a water phantom. Geant4 was used to create carbonCT projections of a contrast and spatial resolution phantom, with a cone beam of 430 MeV/u carbon ions. The contrast phantom consisted of cranial bone, lung material, and PMMA inserts while the spatial resolution phantom contained bone and lung material inserts with line pair (lp) densities ranging from 1.67 lp cm-1 through 5 lp cm 1. First, the positions of each carbon ion on the rear and front trackers were used for an approximate reconstruction of the phantom. The phantom boundary was extracted from this approximate reconstruction, by using the position as well as angle information from the four tracking detectors, resulting in the entry and exit locations of the individual ions on the phantom surface. Subsequent reconstruction was performed by the iterative algebraic reconstruction technique coupled with total variation minimization (ART-TV) assuming straight line trajectories for the ions inside the phantom. The influence of number of projections was studied with reconstruction from five different sets of projections: 15, 30, 45, 60 and 90. Additionally, the effect of number of ions on the image quality was investigated by reducing the number of ions/projection while keeping the total number of projections at 60. An estimation of carbon ion range using the carbonCT image resulted in improved range prediction compared to the range calculated using a calibration curve. PMID- 29384494 TI - One-step formation of TiO2 hollow spheres via a facile microwave-assisted process for photocatalytic activity. AB - Mesoporous TiO2 hollow spherical nanostructures with high surface areas were successfully prepared using a microwave method. The prepared hollow spheres had a size range between 200 and 500 nm. The spheres consisted of numerous smaller TiO2 nanoparticles with an average diameter of 8 nm. The particles had an essentially mesoporous structure, with a pore size in the range of 2-50 nm. The results confirmed that the synthesised of anatase TiO2 nanoparticles with specific surface area approximately 172.3 m2 g-1. The effect of ultraviolet and visible light irradiation and catalyst dosage on the TiO2 photocatalytic activity was studied by measuring the degradation rate of methylene blue. The maximum dye degradation performances with low catalyst loading (30 mg) were 99% and 63.4% using the same duration of ultraviolet and visible light irradiation, respectively (120 min). PMID- 29384495 TI - Novel photocatalyst gold nanoparticles with dumbbell-like structure and their superiorly photocatalytic performance for ammonia borane hydrolysis. AB - Gold nanoparticles (Au NPs) have attracted remarkable research interests in heterogeneous catalysis due to their unique physical and chemical properties. However, only small-size Au NPs (<7 nm) exhibit promising catalytic activity. In this work, dumbbell-like Au NPs (D-Au NPs) with average size of 37 * 11 nm were prepared by a secondary seed-mediated growth method to serve as novel photocatalyst for ammonia borane (AB) hydrolysis in the solution with specific pH value. Our results demonstrate that i) the strengthened LSPR compensation effect could effectively remedy the loss of catalytic activity resulting from the size enlarging of D-Au NPs, proven by that the heating power of a single Au nanoparticle (Ps) and turnover frequency of AB molecules within 10 minutes of D Au NPs are 52.5 and 3.89 times higher than that of spherical Au NPs; ii) the extinction coefficient and Ps of D-Au NPs are almost 2.72 and 2.42 times as high as that of rod-like Au NPs, demonstrating the promoting structure-property relationship of dumbbell-like structure.; iii) when the pH value of AB solution was lower than 6.0, the hydrolysis rate was highly promoted, indicating that H+ ions play an active role in the hydrolysis process. This work greatly extends the application of noble metals and provides a new insight into AB hydrolysis. PMID- 29384496 TI - Anomalous DC Hall response in noncentrosymmetric tilted Weyl semimetals. AB - Weyl nodes come in pairs of opposite chirality. For broken time reversal symmetry (TR) they are displaced in momentum space by [Formula: see text] and the anomalous DC Hall conductivity [Formula: see text] is proportional to [Formula: see text] at charge neutrality. For finite doping there are additive corrections to [Formula: see text] which depend on the chemical potential as well as on the tilt ([Formula: see text]) of the Dirac cones and on their relative orientation. If inversion symmetry (I) is also broken the Weyl nodes are shifted in energy by an amount [Formula: see text]. This introduces further changes in [Formula: see text] and we provide simple analytic formulas for these modifications for both type I ([Formula: see text]) and type II ([Formula: see text], overtilted) Weyl. For type I when the Weyl nodes have equal magnitude but oppositely directed tilts, the correction to [Formula: see text] is proportional to the chemical potential MU and completely independent of the energy shift [Formula: see text]. When instead the tilts are parallel, the correction is linear in [Formula: see text] and MU drops out. For type II the corrections involve both MU and [Formula: see text], are nonlinear and also involve a momentum cut off. We discuss the implied changes to the Nernst coefficient and to the thermal Hall effect of a finite [Formula: see text]. PMID- 29384497 TI - An improved optimization algorithm of 3-compartmental model with spill over and partial volume corrections for dynamic FDG PET images of small animal heart in vivo. AB - The 3- Compartment model with spill-over (SP) and partial volume corrections (PV) has been widely used for noninvasive kinetic parameters study for dynamic FDG PET images of small animal heart in vivo. However, the approach still suffers from the estimation uncertainty or slow convergence caused by the commonly used optimization algorithms. The aim of the study was to develop an improved optimization algorithm with better estimation performance. Femoral artery blood samples, image derived input functions (IDIFs) from heart ventricles and myocardial time-activity curves (TACs) were derived from sixteen C57BL/6 mice data obtained from the UCLA Mouse Quantitation Program. Parametric equations of the average myocardium and the blood pool TACs with SP and PV corrections in a 3 compartment tracer kinetic model were formulated. A hybrid method integrating Artificial Immune System (AIS) and Interior-Reflective Newton (IRN) method were developed to solve the equations. Two penalty functions and one late time point tail vein blood sample were used to constrain the objective function. The estimation accuracy of the method was validated by comparing results with experimental values using the errors in the areas under the curves (AUC) of model corrected input function (MCIF) and the 18F-FDG influx constant Ki. Moreover, the elapsed time was used to measure the convergence speed. The overall AUC error of MCIF for 16 mice averaged -1.4+/-8.2%, with correlation coefficients of 0.9706. Similar result can be seen in overall Ki error percentage, which was 0.4+/-5.8% with correlation coefficient of 0.9912. The t-test P value for both showed no significant difference. The mean and standard deviation of MCIF AUC and Ki percentage errors have lower values compared to the previously published methods. The computation time of the hybrid method is also several fold lower than using just stochastic algorithm. The proposed method significantly improved the model estimation performance in terms of the accuracy of the MCIF and Ki, as well as the convergence speed. PMID- 29384498 TI - Imaging of vaporised sub-micron phase change contrast agents with high frame rate ultrasound and optics. AB - Phase-change ultrasound contrast agent (PCCA), or nanodroplet, shows promise as an alternative to the conventional microbubble agent over a wide range of diagnostic applications. Meanwhile, high-frame-rate (HFR) ultrasound imaging with microbubbles enables unprecedented temporal resolution compared to traditional contrast-enhanced ultrasound imaging. The combination of HFR ultrasound imaging and PCCAs can offer the opportunity to observe and better understand PCCA behaviour after vaporisation captures the fast phenomenon at a high temporal resolution. In this study, we utilised HFR ultrasound at frame rates in the kilohertz range (5-20 kHz) to image native and size-selected PCCA populations immediately after vaporisation in vitro within clinical acoustic parameters. The size-selected PCCAs through filtration are shown to preserve a sub-micron-sized (mean diameter < 200 nm) population without micron-sized outliers (>1 um) that originate from native PCCA emulsion. The results demonstrate imaging signals with different amplitudes and temporal features compared to that of microbubbles. Compared with the microbubbles, both the B-mode and pulse-inversion (PI) signals from the vaporised PCCA populations were reduced significantly in the first tens of milliseconds, while only the B-mode signals from the PCCAs were recovered during the next 400 ms, suggesting significant changes to the size distribution of the PCCAs after vaporisation. It is also shown that such recovery in signal over time is not evident when using size-selective PCCAs. Furthermore, it was found that signals from the vaporised PCCA populations are affected by the amplitude and frame rate of the HFR ultrasound imaging. Using high-speed optical camera observation (30 kHz), we observed a change in particle size in the vaporised PCCA populations exposed to the HFR ultrasound imaging pulses. These findings can further the understanding of PCCA behaviour under HFR ultrasound imaging. PMID- 29384499 TI - Carbon dots based immunosorbent assay for the determination of GFAP in human serum. AB - Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system and the level of GFAP normally rises with brain injury and astroglial tumors. So, serum GFAP is used as a marker for diagnosing various types of brain damage and astroglial tumors. In this study, a new sensor based on carbon dots (CDs) linked with antibodies to specifically detect GFAP in human serum was developed. Anti GFAP (Ab1) linked with protein A/G agarose resin (PA/G) as a capture antibody (PA/G-Ab1) and anti-GFAP (Ab2) labeled with CDs as a detection antibody (CDs-Ab2) were prepared firstly. Then the CD-linked antibody immunosorbent assay (CLAISA) method was constructed based on the sandwich conjunction reaction among PA/G-Ab1, GFAP, and CDs-Ab2. CLAISA, using the fluorescence of PA/G-Ab1-GFAP-Ab2-CDs as the direct signal, enabled the proposed immunosensor to detect GFAP sensitively with a linear range of 0.10-8.00 ng ml-1 and a detection limit of 25 pg ml-1. This method was applied to the determination of GFAP in human serum by the standard addition method, and the results showed high accuracy and precision. Considering the easy synthetic process and excellent performance of CLAISA, this method has great potential to be used to monitor GFAP in the clinic. PMID- 29384500 TI - Probing in-plane anisotropy in fewlayer ReS2 using low frequency noise measurement. AB - ReS2, a layered two-dimensional material popular for its in-plane anisotropic properties is emerging as one of the potential candidates for flexible electronics and ultrafast optical applications. It is an n-type semiconducting material having a layer independent bandgap of 1.55 eV. In this paper we have characterized the intrinsic electronic noise level of fewlayer ReS2 for the first time. Fewlayer ReS2 FET devices show 1/f nature of noise for frequency ranging over three orders of magnitude. We have also observed that not only the electrical response of the material is anisotropic; the noise level is also direction dependent. In fact the noise is found to be more sensitive towards the anisotropy. This fact has been explained by evoking the theory where the Hooge parameter is not a constant quantity, but has a distinct power law dependence on mobility along the two axes direction. The anisotropy in 1/f noise measurement will pave the way to quantify the anisotropic nature of two-dimensional (2D) materials, which will be helpful for the design of low noise transistor in future. PMID- 29384501 TI - Nonlinear optical and multi-photon absorption properties in graphene-ZnO nanocomposites. AB - Graphene-ZnO (GZO) nanocomposites were synthesized by a modified solvothermal method, and characterized by transmission electron microscopy, x-ray diffraction, Raman spectra, and UV-vis absorption spectra. The controllable nonlinear optical (NLO) properties of as-prepared GZO nanocomposites were tested by an open aperture Z-scan method with 1030 nm fs laser pulses; the tested results showed that there were five-photon absorption (5PA) at 46.8 GW cm-2, 3PA at 28.1 GW cm 2, 2PA at 18.7 GW cm-2, and a vital change from saturable absorption (SA) to reverse SA (RSA) with the increase of incident intensity. This was the first time that 5PA was found in GZO nanocomposites at such a low intensity, 46.8 GW cm-2. The tunable NLO property from SA to RSA and controllable multi-photon absorption provided a facile approach for their applications in optical, optoelectronic devices, and information storage. PMID- 29384502 TI - Optimization, evaluation and calibration of a cross-strip DOI detector. AB - This study depicts the evaluation of a SiPM detector with depth of interaction (DOI) capability via a dual-sided readout that is suitable for high-resolution positron emission tomography and magnetic resonance (PET/MR) imaging. Two different 12 * 12 pixelated LSO scintillator arrays with a crystal pitch of 1.60 mm are examined. One array is 20 mm-long with a crystal separation by the specular reflector Vikuiti enhanced specular reflector (ESR), and the other one is 18 mm-long and separated by the diffuse reflector Lumirror E60 (E60). An improvement in energy resolution from 22.6% to 15.5% for the scintillator array with the E60 reflector is achieved by taking a nonlinear light collection correction into account. The results are FWHM energy resolutions of 14.0% and 15.5%, average FWHM DOI resolutions of 2.96 mm and 1.83 mm, and FWHM coincidence resolving times of 1.09 ns and 1.48 ns for the scintillator array with the ESR and that with the E60 reflector, respectively. The measured DOI signal ratios need to be assigned to an interaction depth inside the scintillator crystal. A linear and a nonlinear method, using the intrinsic scintillator radiation from lutetium, are implemented for an easy to apply calibration and are compared to the conventional method, which exploits a setup with an externally collimated radiation beam. The deviation between the DOI functions of the linear or nonlinear method and the conventional method is determined. The resulting average of differences in DOI positions is 0.67 mm and 0.45 mm for the nonlinear calibration method for the scintillator array with the ESR and with the E60 reflector, respectively; Whereas the linear calibration method results in 0.51 mm and 0.32 mm for the scintillator array with the ESR and the E60 reflector, respectively; and is, due to its simplicity, also applicable in assembled detector systems. PMID- 29384503 TI - Transparent and stretchable strain sensors based on metal nanowire microgrids for human motion monitoring. AB - Optical transparency is increasingly considered as one of the most important characteristics required in advanced stretchable strain sensors for application in body-attachable systems. In this paper, we present an entirely solution processed fabrication route to highly transparent and stretchable resistive strain sensors based on silver nanowire microgrids (AgNW-MGs). The AgNW-MG strain sensors are readily prepared by patterning the AgNWs on a stretchable substrate into a MG geometry via a mesh-template-assisted contact-transfer printing. The MG has a unique architecture comprising the AgNWs and can be stretched to epsilon = 35%, with high gauge factors of ~6.9 for epsilon = 0%-30% and ~41.1 for epsilon = 30%-35%. The sensor also shows a high optical transmittance of 77.1% +/- 1.5% (at 550 nm) and stably maintains the remarkable optical performance even at high strains. In addition, the sensor responses are found to be highly reversible with negligible hysteresis and are reliable even under repetitive stretching-releasing cycles (1000 cycles at epsilon = 10%). The practicality of the AgNW-MG strain sensor is confirmed by successfully monitoring a wide range of human motions in real time after firmly laminating the device onto various body parts. PMID- 29384507 TI - How should the IACUC handle unanticipated deaths? PMID- 29384504 TI - Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation. AB - INTRODUCTION: Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine that supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences. METHODS: To further understand the association between L-carnitine induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1 year survivors and nonsurvivors within treatment groups. RESULTS: Mortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. L-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm. CONCLUSIONS: In human patients with septic shock, L-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to L carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment. PMID- 29384508 TI - Response to Protocol Review Scenario: Reporting is unnecessary, but preventing further unexpected deaths is key. PMID- 29384509 TI - Dark data see the light. PMID- 29384510 TI - Small structures on a big scale. PMID- 29384511 TI - Two opportunities to address regulatory burden. PMID- 29384512 TI - Modeling autism. PMID- 29384515 TI - Response to Protocol Review Scenario: The time for active post-approval monitoring is now. PMID- 29384514 TI - Love Animals? Support Animal Research. PMID- 29384516 TI - Response to Protocol Review Scenario: Make the leap of faith, but finish looking first. PMID- 29384518 TI - Response to Protocol Review Scenario: A Word from OLAW. PMID- 29384517 TI - Training mouse pathologists: 16th annual workshop on the pathology of mouse models of human disease. PMID- 29384519 TI - A polymorphism against prions. PMID- 29384521 TI - Prostate cancer: PROMs suggest a festival of benefits in LATITUDE. PMID- 29384520 TI - A new window sheds light on lung tumor metastasis. PMID- 29384522 TI - Stepwise sexual development of adolescents: the Dutch approach to sexuality education. PMID- 29384524 TI - Infection: Vaginal microbiota and infectious infertility. PMID- 29384523 TI - A practical guide to bladder cancer pathology. AB - Pathological assessment of bladder cancer is becoming an increasingly complex task owing to the growing availability of molecular data for different histological subtypes and the appreciation of their importance in determining outcomes of neoadjuvant chemotherapy. Urologists are aware of the need to closely collaborate with pathologists, and comprehensive sharing of information is crucial to achieve optimal patient management. Numerous steps towards this goal have been made during the past years. Important advances in the assessment and reporting of grading and staging, especially substaging of pT1 urothelial carcinomas, have been made. As part of the International Collaboration on Cancer Reporting (ICCR), an international expert group has suggested worldwide reporting standards for urothelial lesions. Nevertheless, several issues remain unresolved, for example, regarding the reporting of heterogeneous lesions and substaging as well as the gross handling and the reporting for lymphadenectomy specimens. During the past few years, major insights have been gained into the molecular changes that occur during bladder cancer development, but a consensus on how to integrate these data into daily practice has not been achieved. PMID- 29384526 TI - Reply to 'Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system". PMID- 29384525 TI - MTOR inhibitor-based combination therapies for pancreatic cancer. AB - BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor based therapies for subtype-specific intervention. PMID- 29384527 TI - Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation. AB - BACKGROUND: Radiotherapy remains one of the cornerstones to improve the outcome of colorectal cancer (CRC) patients. Radiotherapy of the CRC not only help to destroy cancer cells but also remodel the tumour microenvironment by enhancing tumour-specific tropism of bone marrow-derived mesenchymal stromal cell (BM-MSC) from the peripheral circulation. However, the role of local MSCs and recruited BM MSC under radiation were not well defined. Indeed, the functions of BM-MSC without irradiation intervention remained controversial in tumour progression: BM MSC was previously shown to modulate the immune function of major immune cells, resulting in an impaired immunological sensitivity and to induce an increased risk of tumour recurrence. In contrast, it could also secrete various cytokines and possess anticancer effect. METHODS: Three co-cultivation modules, 3D culture modules, and cancer organoids were established. The induction of cytokines secretion in hBM-MSCs after irradiation was analysed by ELISA array and flow cytometry. AutoMac separator was used to separate hBM-MSC and CRC automatically. Cells from the co-cultured group and the control group were then irradiated by UV C lamp and X-ray. Proliferation assay and viability assay were performed. RESULTS: In this study, we show that BM-MSCs can induce the EMT progression of CRC cells in vitro. When irradiated with low doses of ultraviolet radiation and X rays, BM-MSCs show an anti-tumour effect by secreting certain cytokine (TNF alpha, IFN-gamma) that lead to the inhibition of proliferation and induction of apoptosis of CRC cells. This was further verified in a 3D culture model of a CRC cell in vitro. Furthermore, irradiation on the co-culture system induced the cleavage of caspase3, and attenuated the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase in cancer cells. The signal pathways above might contribute to the cancer cell death. CONCLUSIONS: Taken together, we show that BM-MSC can potentially promote the effect of radiotherapy in CRC. PMID- 29384528 TI - Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system'. PMID- 29384529 TI - Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia. AB - BACKGROUND: High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown. METHODS: To reveal the role and mechanism of HMGA2 in differentiation arrest of myeloid leukaemia cells, the quantitative expression of HMGA2 and homeobox A9 (HOXA9) was analysed by real-time PCR (qRT PCR). The regulatory function of HMGA2 in blockage of differentiation in human myeloid leukaemia was investigated through in vitro assays (XTT assay, May Grunwald-Giemsa, flow cytometry analysis and western blot). RESULTS: We found that the expression of HMGA2 and HOXA9 was reduced during the process of granulo monocytic maturation of acute myeloid leukaemia (AML) cells, knockdown of HMGA2 promotes terminal (granulocytic and monocytic) differentiation of myeloid leukaemia primary blasts and cell lines, and HOXA9 was significantly downregulated in leukaemic cells with knockdown of HMGA2. Downregulation of HOXA9 in myeloid leukaemia cells led to increased differentiation capacity in vitro. CONCLUSIONS: Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia. PMID- 29384530 TI - Erratum: Being stressed outside the park-conservation of African elephants (Loxodonta africana) in Namibia. AB - [This corrects the article DOI: 10.1093/conphys/cox067.][This corrects the article DOI: 10.1093/conphys/cox067.]. PMID- 29384531 TI - Triphenylbismuth(v) di[(iso)nicotinates] - transmetallation agents or divergent organometalloligands? First organobismuth(v)-based silver(i) coordination polymers. AB - The reaction of Ph3BiCl2 with alkali salts of isonicotinic and nicotinic acids afforded Ph3Bi[O(O)CC5H4N-4]2 (1) and Ph3Bi[O(O)CC5H4N-3]2 (2), respectively, which were characterized by multinuclear NMR spectroscopy in solution, mass spectrometry and IR spectroscopy in the solid state. Their molecular structures were established by single-crystal X-ray diffraction. For both 1 and 2 the molecules contain a trigonal bipyramidal C3BiO2 core, with the phenyl groups in equatorial positions. The potential use of 1 and 2 as ditopic organometalloligands was investigated. The reaction of 1 or 2 with Me3SnCl (1 : 2 molar ratio) resulted in carboxylato ligand exchange and the formation of Me3Sn[O(O)CC5H4N-4] (3) and Me3Sn[O(O)CC5H4N-3] (4) besides Ph3BiCl2. The crystals of both 3 and 4 contain 1-D coordination polymers built through intermolecular N -> Sn interactions. The treatment of Ni[S2P(OiPr)2]2 with 1 and 2, respectively, resulted, in addition to di(carboxylato)nickel(ii) derivatives, in isolation of Ph3Bi and the disulphane [(iPrO)2P(S)S]2. New coordination polymers were obtained by reacting 1 and 2 with various silver(i) salts: [Ag{Ph3Bi[O(O)CC5H4N-4]2}(OTf)] (5), [Ag{Ph3Bi[O(O)CC5H4N-3]2}(OTf)].CH2Cl2 (6.CH2Cl2), [Ag{Ph3Bi[O(O)CC5H4N-4]2}](SbF6).2THF (7.2THF), [Ag{Ph3Bi[O(O)CC5H4N 3]2}](SbF6).CH2Cl2 (8.CH2Cl2) and [Ag{Ph3Bi[O(O)CC5H4N-3]2}(NO3)].CH2Cl2 (9.CH2Cl2). The crystal structures of 5 and 6 can be described as 1-D chains linked by triflate bridges in pairs of chains and 2-D networks, respectively. Compound 7 features a 2-D grid-like topology of the network, with tecton 1 acting as a tridentate ligand through both nitrogen and one oxygen atoms. The linker 2 molecules adopt either cis (compound 6) or trans (compounds 8 and 9) conformation. Complexes 8 and 9 are 1-D chain polymers exhibiting zig-zag and wavy motifs, respectively. The dimensionality of the structures is extended by the presence of supramolecular interactions (pipi, AgAg, AgO). PMID- 29384532 TI - Rise of A-site columnar-ordered A2A'A''B4O12 quadruple perovskites with intrinsic triple order. AB - A-site-ordered AA'3B4O12 quadruple perovskites (with twelve-fold coordinated A and square-planar coordinated A' sites) were discovered in 1967. Since then, there have been considerable research efforts to synthesize and characterize new members of such perovskites. These efforts have led to the discoveries of many interesting physical and chemical properties, such as inter-site charge transfer and disproportionation, giant dielectric constant, multiferroic properties, reentrant structural transitions and high catalytic activity. The first member of A-site columnar-ordered A2A'A''B4O12 quadruple perovskites (with ten-fold coordinated A, square-planar coordinated A' and tetrahedrally coordinated A'' sites), CaFeTi2O6, was discovered in 1995, and for 19 years it was the only representative of this family. In the last few years, A2A'A''B4O12 perovskites have experienced rapid growth. Herein, we present a brief overview of the recent developments in this field and highlight an under-investigated status and great potential of A2A'A''B4O12, which can be prepared mainly at high pressure and high temperature. The presence of the A'' site gives an additional degree of freedom in designing such perovskites. The A2A'A''B4O12 perovskites are discussed in comparison with well-known AA'3B4O12 perovskites. PMID- 29384533 TI - Slow magnetic relaxation influenced by change of symmetry from ideal Ci to D3d in cobalt(ii)-based single-ion magnets. AB - The coordination geometries of the Co(ii) site in the two complexes [Co(imidazole)6][BPh4]2.0.3CH3CN (1) and [Co(imidazole)6][NO3]2 (2) were observed to display the ideal symmetries Ci and D3d, respectively. Both complexes were shown to be field-induced single-ion magnets. The effective energy barrier was found to decrease as the local symmetry changed from low-symmetry Ci to high symmetry D3d. PMID- 29384534 TI - Direct monitoring of spin transitions in a dinuclear triple-stranded helicate iron(ii) complex through X-ray photoelectron spectroscopy. AB - A dinuclear helical iron(ii) complex of a new ditopic thiazolylimine ligand (L) has been synthesised via supramolecular assembly. The resulting dinuclear helical cylinder [Fe2L3].4BF4 was investigated by variable temperature X-ray crystallography, ESI high resolution mass spectrometry, CHN analysis, FT-IR and UV-Vis spectroscopy. The nature of the spin transition was investigated by magnetic susceptibility measurements, and confirmed by VT-SCXRD and X-ray photoelectron spectroscopy. [Fe2L3].4BF4 displays a complete spin transition with a gradual-abrupt character at T1/2 = 348 K and represents a new example of a dinuclear iron(ii) complex exhibiting a spin transition at high temperature. Both VT-SCXRD and XPS measurements show excellent correlation with the magnetic susceptibility experiments, demonstrating the power of XPS not just to confirm, but also to clearly follow the spin-state transition in Fe(ii) SCO complexes. PMID- 29384535 TI - Tracking HOCl concentrations across cellular organelles in real time using a super resolution microscopy probe. AB - BODIPY derivative, SF-1, exclusively shows a fluorescence ON response to HOCl and images endogenously generated HOCl in RAW 264.7 macrophages. Widefield and super resolution structured illumination microscopy images confirm localization in the Golgi complex and lysosomes, and hence specifically detects HOCl generated in these organelles. SF-1 is compatible with 3D-SIM imaging of individual cells. PMID- 29384536 TI - Hyper-cross-linked polymer supported rhodium: an effective catalyst for hydrogen evolution from ammonia borane. AB - Metal nanoparticles (NPs) have wide applications in hydrogen evolution from ammonia-borane (AB) hydrolysis because they can provide large surface active areas for reactants, and thus produce high catalytic activity. Here, a hyper cross-linked polymer (HCP-PPh3), which was synthesized through the Friedel-Crafts reaction of benzene and triphenylphosphine, was employed as a support to stabilize Rh NPs. The characterization results revealed that the Rh NPs were uniformly dispersed on the surface of HCP-PPh3, and that they had an average particle size of 2.1 nm. The as-prepared HCP-PPh3-Rh was used as an active catalyst for hydrogen generation from AB hydrolysis. This catalyst exhibited a high turnover frequency of 481 mol H2 (molRh min)-1 for AB hydrolysis under mild conditions. The high catalytic performance of HCP-PPh3-Rh can be attributed to the small size of Rh NPs and the strong interaction between the metal and HCP PPh3. This work highlights a potentially powerful strategy for preparing highly active HCP stabilized metal NPs for AB hydrolysis to generate hydrogen. PMID- 29384537 TI - Insight into vibrational circular dichroism of proteins by density functional modeling. AB - Vibrational circular dichroism (VCD) spectroscopy is an excellent method to determine the secondary structure of proteins in solution. Comparison of experimental spectra with quantum-chemical simulations represents a convenient and objective way to extract information on the structure. This has been difficult for such large molecules where approximate theoretical models have to be used. In the present study we applied the Cartesian-coordinate based tensor transfer (CCT) making it possible to extend the density functional theory (DFT) and model spectral intensities of large globular proteins nearly at quantum chemical precision. Indeed, comparison with experiment provided a better understanding of the dependence of VCD spectral shapes on the geometry, their sensitivity to fine structural details and interactions with the environment. On a model set of globular proteins the simulated spectra correlated well with experimental data and revealed which structural information can (and cannot) be obtained from this kind of spectroscopy. Although the VCD technique has been regarded as being rather insensitive to side-chain variations, we found that the spectra of human and hen lysozyme differing by a few amino acids only are quite distinct. This has been explained by long-distance coupling of the amide vibrations. Likewise, the modeling reproduced some spectral changes caused by protein deuteration even when the protein structure was conserved. PMID- 29384538 TI - Spectroscopic, electrochemical and photovoltaic properties of Pt(ii) and Pd(ii) complexes of a chelating 1,10-phenanthroline appended perylene diimide. AB - In this study, a bis-chelating bridging perylene diimide ditopic ligand, namely N,N'-di(1,10-phenanthroline)-1,6,7,12-tetrakis-(4-methoxyphenoxy)perylene tetracarboxylic acid diimide (1), was synthesized and characterized. Further reactions of 1 with d8 metal ions such as Pt(ii) and Pd(ii) having preferential square-planar geometry afforded the novel triads [(Cl2)M(ii)-(1)-M(ii)(Cl2)] where M(ii) = Pt(ii) (2), and Pd(ii) (3), respectively. The isolated triads and the key precursor were fully characterized by FT-IR, 1D-NMR (1H NMR and 13C DEPT NMR), 2D-NMR (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC), MALDI-TOF mass and UV/Vis spectroscopy. The electrochemical properties of 1, 2 and 3 were investigated by cyclic voltammetry as well as in situ spectroelectrochemistry and also in situ electrocolorimetric measurements. These compounds were shown to exhibit net colour changes suitable for electrochromic applications. The compounds exhibited remarkably narrow HOMO-LUMO gaps, leading to their ease of reduction at low negative potentials. More importantly, dye-sensitized solar cells (DSSCs) were also fabricated using 1-3 to clarify the potential use of these complexes as a sensitizer. Analysis of the experimental data indicated that 2 has good potential as a sensitizer material for DSSCs. PMID- 29384539 TI - Synthesis and catalytic activity of N-heterocyclic silylene (NHSi) cobalt hydride for Kumada coupling reactions. AB - The electron-rich silylene Co(i) chloride 5 was obtained through the reaction of CoCl(PMe3)3 with chlorosilylene. Complex 5 reacted with 1,3-siladiazole HSiMe(NCH2PPh2)2C6H4 to give the silylene Co(iii) hydride 6 through chelate assisted Si-H activation. To the best of our knowledge, complex 6 is the first example of Co(iii) hydride supported by N-heterocyclic silylene. Complexes 5 and 6 were fully characterized by spectroscopic methods and X-ray diffraction analysis. Complex 6 was used as an efficient precatalyst for Kumada cross coupling reactions. Compared with the related complex 3 supported by only trimethylphosphine, complex 6 as a catalyst supported by both chlorosilylene and trimethylphosphine exhibits a more efficient performance for the Kumada cross coupling reactions. A novel catalytic radical mechanism was suggested and experimentally verified. As an intermediate silylene cobalt(ii) chloride 6d was isolated and structurally characterized. PMID- 29384540 TI - s-Block metal complexes of PC(H)P-bridged chalcogen-centred methanides: comparisons with isoelectronic PNP-bridged monoanions. AB - The chemistry of the chalcogen-centred methanides [HC(PR2E)2]- (E = S, Se, Te; R = alkyl, aryl) (PC(H)P-bridged anions) is less well-developed than that of the isoelectronic imidodiphosphinates [N(PR2E)2]-, which are PNP-bridged analogues. The objective of this Perspective is to compare the chemistry of s-block metal complexes of the PC(H)P- and PNP-bridged anions in the context of synthetic approaches, X-ray (solid-state) structures, multinuclear NMR spectra, redox behaviour, and applications in coordination and inorganic heterocyclic chemistry. The related monochalcogeno-centred anions [HC(PR2)(PR2E)]- and [N(PR2)(PR2E)]- (E = S, Se, Te; R = alkyl, aryl) are also included in the discussion. Consideration of the similarities and, especially, the differences in the properties and reactions of the methanides with those of their imidodiphosphinate analogues reveals a number of areas in which the significance of the PC(H)P-bridged anions could be advanced. PMID- 29384541 TI - Intercalation of nanostructured CeO2 in MgAl2O4 spinel illustrates the critical interaction between metal oxides and oxides. AB - Heterogeneous catalytic oxidation arises from the prerequisite oxygen activation and transfer ability of metal oxide catalysts. Thus, engineering intercalated nanounits and heterophase metal oxide structures, and forming interstitial catalyst supports at the nanoscale level can drastically alter the catalytic performances of metal oxides. This is particularly important for ceria-based nanomaterial catalysts, where the interactions of reducible ceria (CeO2) and nonreducible oxides are fundamental for the preparation of enhanced catalysts for oxygen-involved reactions. Herein, we intercalated nanostructured CeO2 in the bulk phase of magnesium aluminate spinel (MgAl2O4, referred to as MgAl), produced the interstitial effect between CeO2 nanoparticles and MgAl crystallites, thus boosting their oxygen transfer and activation capability. This nanoscaled intercalation engineering significantly enhanced the number and quality of tight contact points between the nanostructured CeO2 and MgAl units. Therefore, the oxygen storage/release capability (OSC) is exceptionally improved as revealed by various characterizations and catalytic carbon oxidation reaction. A mechanism similar to the Mars-van Krevelen process at the nanoscale level was invoked to explain the catalytic oxidation mechanisms. The reactive oxygen species of gaseous O2 originate formed the bulk of the as-obtained nanomaterial, where strong interactions between the CeO2 and MgAl components occured, which were subsequently released and diffused to the catalyst-interface at elevated temperatures. Silver supported on Ce-MgAl produced an approximately 4-fold higher concentration of active oxygen species than Ag/MgAl, and gives the optimum low temperature oxidation at 229 degrees C. This study verifies the importance of the redox performance of ceria-spinel with enhanced OSC, which validates that the arrangement of contacts at the nanoscale can substantially boost the catalytic reactivity without varying the microscale structure and properties of spinel. PMID- 29384542 TI - In vitro digestion with bile acids enhances the bioaccessibility of kale polyphenols. AB - Kale (Brassica oleracea) is a leafy green vegetable belonging to the Brassicaceae family, and kale leaves have large amounts of dietary fiber and polyphenolics. Dietary fiber can bind bile acids, thus potentially decreasing cholesterol levels; however, whether the polyphenols from kale contribute to in vitro bile acid binding capacity remains unclear. In the present study, kale was extracted with hexane, acetone, and MeOH : water and the dried extracts, as well as the fiber-rich residue, were tested for their bile acid binding capacity. The fiber rich residue bound total bile acids in amounts equivalent to that bound by raw kale. The lyophilized acetone extract bound significantly more glycochenodeoxycholate and glycodeoxycholate and less of other bile acids. To test whether bile acid binding enhanced the bioaccessibility of polyphenolic compounds from kale, we used ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry to identify chemical constituents and measure their bioaccessibility in an in vitro digestion reaction. This identified 36 phenolic compounds in kale, including 18 kaempferol derivatives, 13 quercetin derivatives, 4 sinapoyl derivatives, and one caffeoylquinic acid. The bioaccessibility of these phenolics was significantly higher (69.4%) in digestions with bile acids. Moreover, bile acids enhanced the bioaccessibility of quercetin by 25 times: only 2.7% of quercetin derivatives were bioaccessible in the digestion without bile acids, but with bile acids, their accessibility increased to 69.5%. Bile acids increased the bioaccessibility of kaempferol from 37.7% to 69.2%. The extractability and biostability of total phenolics in the digested residue increased 1.8 fold in the digestions with bile acids. These results demonstrated the potential use of kale to improve human health. PMID- 29384543 TI - The effect of fucoidan on intestinal flora and intestinal barrier function in rats with breast cancer. AB - Recent research studies have shown that the intestinal flora are related to the occurrence and progress of breast cancer. This study investigates the effect of fucoidan on intestinal flora and intestinal barrier function in rats with 7,12 dimethylbenz[a]anthracene (DMBA)-induced breast cancers. Sixty female Sprague Dawley rats were randomly assigned to the control group, the model group, and the F1 and F2 groups, which were fed fucoidan at concentrations of 200 and 400 mg per kg bw (body weight), respectively. Intestinal histopathological analysis was performed and 16S rDNA high-throughput sequencing was used to provide an overview of the intestinal flora composition. The contents of d-lactic acid (d-LA), diamine oxidase (DAO) and endotoxin in plasma were detected by ELISA. Expression levels of the tight junction (TJ) proteins, phosphorylated p38 MAPK and ERK1/2 were measured using western blotting. Our results suggested that the intestinal wall of the model group was damaged. However, after fucoidan intervention, the villi were gradually restored. ELISA showed that the levels of plasma endotoxin, d-LA and DAO decreased in the F1 and F2 groups compared to those in the model group. Fucoidan treatment also increased the expressions of ZO-1, occludin, claudin-1 and claudin-8. Furthermore, the expression levels of phosphorylated p38 MAPK and ERK1/2 were upregulated in fucoidan treatment groups. The results of 16S rDNA high-throughput sequencing indicated that fucoidan increased the diversity of the intestinal microbiota and induced changes in microbial composition, with the increased Bacteroidetes/Firmicutes phylum ratio. In conclusion, the supplement of fucoidan could improve the fecal microbiota composition and repair the intestinal barrier function. The study suggested the use of fucoidan as an intestinal flora modulator for potential prevention of breast cancer. PMID- 29384544 TI - From genomics to metabolomics, moving toward an integrated strategy for the discovery of fungal secondary metabolites. AB - Fungal secondary metabolites are defined by bioactive properties that ensure adaptation of the fungus to its environment. Although some of these natural products are promising sources of new lead compounds especially for the pharmaceutical industry, others pose risks to human and animal health. The identification of secondary metabolites is critical to assessing both the utility and risks of these compounds. Since fungi present biological specificities different from other microorganisms, this review covers the different strategies specifically used in fungal studies to perform this critical identification. Strategies focused on the direct detection of the secondary metabolites are firstly reported. Particularly, advances in high-throughput untargeted metabolomics have led to the generation of large datasets whose exploitation and interpretation generally require bioinformatics tools. Then, the genome-based methods used to study the entire fungal metabolic potential are reported. Transcriptomic and proteomic tools used in the discovery of fungal secondary metabolites are presented as links between genomic methods and metabolomic experiments. Finally, the influence of the culture environment on the synthesis of secondary metabolites by fungi is highlighted as a major factor to consider in research on fungal secondary metabolites. Through this review, we seek to emphasize that the discovery of natural products should integrate all of these valuable tools. Attention is also drawn to emerging technologies that will certainly revolutionize fungal research and to the use of computational tools that are necessary but whose results should be interpreted carefully. PMID- 29384545 TI - Destruction of chemical warfare agent simulants by air and moisture stable metal NHC complexes. AB - The cooperative effect of both NHC and metal centre has been found to destroy chemical warfare agent (CWA) simulants. Choice of both the metal and NHC is key to these transformations as simple, monodentate N-heterocyclic carbenes in combination with silver or vanadium can promote stoichiometric destruction, whilst bidentate, aryloxide-tethered NHC complexes of silver and alkali metals promote breakdown under mild heating. Iron-NHC complexes generated in situ are competent catalysts for the destruction of each of the three targetted CWA simulants. PMID- 29384546 TI - Effect of Te substitution on crystal structure and transport properties of AgBiSe2 thermoelectric material. AB - Silver bismuth diselenide (AgBiSe2) has attracted much attention as an efficient thermoelectric material, owing to its intrinsically low lattice thermal conductivity. While samples synthesized using a solid-state reaction showed n type conductivity and their dimensionless figure of merit (ZT) reached ~1 by electron doping, theoretical calculations predicted that a remarkably high thermoelectric performance can be achieved in p-type AgBiSe2. In this paper, we present the effect of Te substitution on the crystal structure and thermoelectric properties of AgBiSe2, expecting p-type conductivity due to the shallowing of the energy potential of the valence band. We found that all AgBiSe2-xTex (x = 0-0.8) prepared using a solid-state reaction exhibits n-type conductivity from 300 to 750 K. The room-temperature lattice thermal conductivity decreased to as low as 0.3 W m-1 K-1 by Te substitution, which was qualitatively described using the point defect scattering model for the solid solution. We show that ZT reaches ~0.6 for x = 0.8 at a broad range of temperatures, from 550 to 750 K, due to the increased power factor, although the carrier concentration has not been optimized yet. PMID- 29384547 TI - Cyclometalated ruthenium complexes with carboxylated ligands from a combined experimental/computational perspective. AB - The syntheses and characterization of nine new cyclometalated ruthenium complexes are reported. These structures consist of Ru(ii) with bipyridine and phenylpyridine ligands which are substituted with ester or carboxylate groups. Two of the complexes were extensively studied and their properties were compared to those of two previously reported structures. The identities of the compounds were confirmed by NMR, HR-MS and single crystal XRD, and the electronic properties were investigated by UV-Vis spectroscopy. DFT and TD-DFT calculations showed that the intense absorbances in the visible region of the spectrum of these cyclometalated complexes are due to electronic excitations to virtual orbitals located on the carboxylated ligands. These results indicate that the compounds are promising candidates as sensitizers for more efficient photocatalysis with sunlight. Further, the carboxylate groups should facilitate their use as linkers in metal-organic frameworks. PMID- 29384548 TI - Structural characterization of two endopolysaccharides from Phellinus sp. and their immunologic effects by intragastric administration in a healthy mammalian model. AB - Two purified endopolysaccharides derived from cultured Phellinus sp., individually named SHIP-1 and 2, were structurally characterized, along with an evaluation of their in vivo influential immunomodulatory activity in a healthy mammalian model. The structure of SHIP-1 was mainly composed of ->4)-alpha-d-Fucp (1->, ->3,6)-alpha-d-Araf-(1-> and ->2,4)-beta-d-Galp-(->, with four residuals of alpha-d-Manp-(1-> and one alpha-d-Glcp-(1-> as sidegroups, while the planar structure and the heteronuclear multiple-bond correlation of SHIP-2 were not able to be analyzed. Biochemical analysis in the healthy mice model demonstrated that SHIP-1 increased the concentrations of the detected cytokines in a dosage dependent manner but not in a time-dependent way. SHIP-2 exerted a positive effect in a dose-dependent manner over time for interferon gamma (IFN-gamma) and interleukin (IL)-2 cytokine production at elevated dosages of 200, or 350 mg kg-1 d-1, while IFN-alpha(alpha) and IL-4 production was observed only in a dosage dependent manner even at high dosages. Thus, SHIP-1 and 2 significantly improved the immune response through the intragastric administration of the tested high dosages by increasing the production of cytokines in the healthy mice, and these polysaccharides could possibly be used as an immunopotentiator in health foods or dietary supplements. PMID- 29384549 TI - Phase engineering of seamless heterophase homojunctions with co-existing 3R and 2H phases in WS2 monolayers. AB - Self-organized semiconductor-semiconductor heterostructures (3R-2H) that coexist in atomically thin 2D monolayers forming homojunctions are of great importance for next-generation nanoelectronics and optoelectronics applications. Herein, we investigated the defect controlled growth of heterogeneous electronic structure within a single domain of monolayer WS2 to enable in-plane homojunctions consisting of alternate 2H semiconducting and 3R semiconducting phases of WS2. X ray photoelectron, Raman, and photoluminescence spectroscopy along with fluorescence and Kelvin probe force microscopy imaging confirm the formation of homojunctions, enabling a direct correlation between chemical heterogeneity and electronic heterostructure in the atomically thin WS2 monolayer. Quantitative analysis of phase fractions shows 59% stable 2H phase and 41% metastable 3R phase estimated over WS2 flakes of different sizes. Time-resolved fluorescence lifetime imaging confirms distinct contrast between 2H and 3R phases with two distinct lifetimes of 3.2 ns and 1.1 ns, respectively. Kelvin probe force microscopy imaging revealed an abrupt change in the contact potential difference with a depletion width of ~2.5 MUm, capturing a difference in work function of ~40 meV across the homojunction. Further, the thermal stability of coexisting phases and their temperature dependent optical behavior show a distinct difference among 2H and 3R phases. The investigated aspects of the controlled in plane growth of coexisting phases with seamless homojunctions, their properties, and their thermal stability will enable the development of nanoscale devices that are free from issues of lattice mismatch and grain boundaries. PMID- 29384550 TI - Combined brain Fe, Cu, Zn and neurometabolite analysis - a new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control. AB - Obesity is a chronic, multifactorial origin disease that has recently become one of the most frequent lifestyle disorders. Unfortunately, current obesity treatments seem to be ineffective. At present, transcranial direct current brain stimulation (tDCS) represents a promising novel treatment methodology that seems to be efficient, well-tolerated and safe for a patient. Unfortunately, the biochemical action of tDCS remains unknown, which prevents its widespread use in the clinical arena, although neurobiochemical changes in brain signaling and metal metabolism are frequently reported. Therefore, our research aimed at exploring the biochemical response to tDCS in situ, in the brain areas triggering feeding behavior in obese animals. The objective was to propose a novel neurochemical (serotoninergic and dopaminergic signaling) and trace metal analysis of Fe, Cu and Zn. In doing so, we used energy-dispersive X-ray fluorescence (EDXRF) and high-performance liquid chromatography (HPLC). Anodal type stimulation (atDCS) of the right frontal cortex was utilized to down regulate food intake and body weight gain in obese rats. EDXRF was coupled with the external standard method in order to quantify the chemical elements within appetite-triggering brain areas. Major dopamine metabolites were assessed in the brains, based on the HPLC assay utilizing the external standard assay. Our study confirms that elemental analysis by EDXRF and brain metabolite assay by HPLC can be considered as a useful tool for the in situ investigation of the interplay between neurochemical and Fe/Cu/Zn metabolism in the brain upon atDCS. With this methodology, an increase in both Cu and Zn in the satiety center of the stimulated group could be reported. In turn, the most significant neurochemical changes involved dopaminergic and serotoninergic signaling in the brain reward system. PMID- 29384554 TI - Scalable production of core-shell nanoparticles by flash nanocomplexation to enhance mucosal transport for oral delivery of insulin. AB - Scalable manufacturing continues to present a major barrier for clinical translation of nanotherapeutics. Methods available for fabricating protein encapsulating nanoparticles in a scalable fashion are scarce. Protein delivery often requires multiple functionalities to be incorporated into the same vehicle. Specifically for nanoparticle-mediated oral delivery of protein therapeutics, protection in GI tract, site-specific release, facilitating transmucosal permeation, and enhancing epithelial transport are a few desirable features to be engineered into a nanoparticle system. Here we devised a sequential flash nanocomplexation (FNC) technique for the scalable production of a core-shell structured nanoparticle system by combining materials choice and particle size and structure to fulfill these functions, therefore enhancing the delivery efficiency of insulin. This method is highly effective in controlling the size, generating core-shell structure with high encapsulation efficiency (97%) and payload capacity (67%) using insulin/l-penetratin complex nanoparticles as a core coated with hyaluronic acid (HA). Both the in vitro and in vivo models confirmed that the HA coating on these core-shell nanoparticles enhanced the permeation of nanoparticles through the intestinal mucus layer and improved trans-epithelial absorption of insulin nanoparticles; and the enhancement effect was most prominent using HA with the highest average molecular weight. The insulin-loaded nanoparticles were then encapsulated into enteric microcapsules (MCs) in an FNC process to provide additional protection against the acidic environment in the stomach while allowing rapid release of insulin nanoparticles when they reach small intestine. The optimized multifunctional MCs delivered an effective glucose reduction in a Type I diabetes rat model following a single oral administration, yielding a relative bioavailability of 11% in comparison with subcutaneous injection of free-form insulin. This FNC technique is highly effective in controlling particle size and structure to improve delivery properties and function. It can be easily extended to oral delivery for other protein therapeutics. PMID- 29384555 TI - Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation. AB - Split-hand/split-foot malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation. PMID- 29384556 TI - Spatiotemporal expression of MYD88 gene in pigs from birth to adulthood. AB - MYD88 plays an important role in the immune response against infections. To analyze MYD88 gene expression during different stages of pig development, we used real-time PCR. MYD88 was seen expressed in all tissues examined. MYD88 expression in spleen, lungs, and thymus reached its highest value from 7 to 14 days of age and decreased thereafter. Expression in lymph nodes was high until 28 days of age and then it declined after weaning, with stable low levels in adult pigs. MYD88 expression was high before 35 days of age in the small intestine (duodenum, jejunum, and ileum), where it reached its highest value from 7 to 14 days of age. MYD88 expression in the small intestine declined post-weaning and remained relatively low during adulthood. The results of this study suggest that weaning stress and development of the immune system might be positively correlated with MYD88 expression regulation. Moreover, this study provided evidence that the high expression of MYD88 may diminish weaning stress and increase disease resistance in Meishan pigs. PMID- 29384557 TI - The association between adult-type hypolactasia and symptoms of functional dyspepsia. AB - Functional dyspepsia and lactose intolerance (adult-type hypolactasia, ATH) are common conditions that may coexist or even be confounded. Their clinical presentation can be similar, however, lactose intolerance does not form part of the diagnostic investigation of functional dyspepsia. Studies on the association between functional dyspepsia and ATH are scarce. This study aimed to evaluate whether ATH is associated with symptoms of functional dyspepsia. Patients fulfilling the Rome III diagnostic criteria for functional dyspepsia underwent genetic testing for ATH. Dyspeptic symptoms were evaluated and scored according to a validated questionnaire. The diagnostic criteria for ATH was a CC genotype for the -13910C/T polymorphism, located upstream of the lactase gene. The mean scores for dyspeptic symptoms were compared between patients with ATH and those with lactase persistence. A total of 197 functional dyspeptic patients were included in the study. Mean age was 47.7 years and 82.7% patients were women. Eighty-eight patients (44.7%) had a diagnosis of ATH. Abdominal bloating scores were higher in ATH patients compared to the lactase persistent patients (P=0.014). The remaining dyspeptic symptom scores were not significantly different between the two groups. The study results demonstrate an association between ATH and bloating in patients with functional dyspepsia. PMID- 29384558 TI - The human cytomegalovirus tegument protein pp65 (pUL83): a key player in innate immune evasion. AB - The germline encoded proteins serving as "pattern recognition receptors" (PRRs) constitute the earliest step in the innate immune response by recognizing the "pathogen-associated molecular patterns" (PAMPs) that comprise microbe nucleic acids and proteins usually absent from healthy hosts. Upon detection of exogenous nucleic acid two different innate immunity signaling cascades are activated. The first culminates in the production of chemokines, cytokines, and type I interferons (IFN-I), while the second leads to inflammasome complex formation. Human cytomegalovirus (HCMV), a member of the b-herpesvirus subfamily, is a widespread pathogen that infects the vast majority of the world's population. The virion has an icosahedral capsid that contains a linear dsDNA genome of approximately 240 kb, surrounded by an outer lipid envelope and a proteinaceous tegument containing several viral proteins. Despite the numerous and multifaceted antiviral effects of IFNs and cytokines, HCMV is able to invade, multiply, and establish persistent infection in healthy human hosts. To achieve this goal the virus has developed different strategies to block the IFN-I response and to alter the physiological outcomes of the IFN-inducible genes. This article focuses on HCMV tegument pp65 by reviewing its mechanisms of action in favoring virus evasion from the host innate immune response. PMID- 29384559 TI - Neurobrucellosis: diagnostic and clinical management of an atypical case. AB - Brucellosis is the most common zoonosis in the world and it is caused by ingestion of foods contaminated by Brucella spp. that is able to avoid the immune system and can involve every organ system. The bacteria may affect the Central Nervous System (CNS) directly or using phagocytic cells with the way of the "Trojan Horse Model". Meningitis is the most common form of neuro-brucellosis (NB) but other neurological manifestation, with variable onset, such as severe encephalic involvement, neuropathy, vascular damage, radiculitis and hydrocephalus might happened. NB may manifest itself with an acute or chronic onset and could be the only manifestation of the infection or appearance during the systemic disease. Frequently the diagnosis might be very difficult and the clinical characteristics and the microbiological demonstration in the blood and in the CSF are necessary. The prognosis of brucella meningitis is generally better than other forms of chronic meningitis except for encephalitis or spinal cord involvement. The treatment is based on the combination of two or three antibiotics to achieve normalization of the cerebrospinal fluid parameters otherwise relapse are relatively frequent. We describe an atypical case of brucellar meningitis with many stroke-like signs, think as recurrent cerebrovascular events and treated with antithrombotic therapy, but without meningeal syndrome. PMID- 29384560 TI - Horner Syndrome After Epidural Catheter Placement in a 4-Month-Old Child. AB - Although there are reports of iatrogenic Horner syndrome in the adult population, pediatric cases are rare. The current report presents a case of acquired Horner syndrome that occurred after an epidural catheter was placed for pain control. Horner syndrome completely resolved after removing the catheter and no imaging or further work-up was necessary. [J Pediatr Ophthalmol Strabismus. 2018;55:e1-e3.]. PMID- 29384561 TI - Ocular Dipping in a Patient With Hemiplegic Migraine. AB - A 5-year-old girl presented with acute, rapidly progressive encephalopathy following minor head trauma and was found to have ocular dipping. Her encephalopathy was secondary to a channelopathy caused by a CACNA1A mutation. This is the first reported case of ocular dipping in an encephalopathic child with CACNA1A-confirmed hemiplegic migraine. [J Pediatr Ophthalmol Strabismus. 2018;55:e4-e6.]. PMID- 29384562 TI - Characteristics and Long-term Follow-up of Isolated Vertical Nystagmus in Infancy. AB - PURPOSE: To determine the clinical characteristics and long-term outcomes of infants who presented with isolated vertical nystagmus. METHODS: The medical records of 114 infants who were diagnosed as having nystagmus from 1996 to 2016 were screened. Patients with vertical nystagmus within the first year of life who had unremarkable magnetic resonance imaging of the brain and demonstrated age appropriate visual behavior were included. The parents of patients in the final study cohort were contacted by telephone to obtain long-term follow-up information. RESULTS: Eight patients comprised the final cohort. Vertical nystagmus was first observed at a mean age of 1.4 months (range: 1 to 2.5 months) and resolved in 87.5% of patients at a mean age of 3.8 months (range: 2 to 10 months). Vertical nystagmus was intermittent in 62.5%, upbeat in 62.5%, and pendular in 37.5% of patients. One patient's nystagmus did not resolve. Seventy five percent of patient guardians participated in the telephone questionnaire. The mean age of patients at follow-up was 3.5 years (range: 0.5 to 8.1 years). Isolated iris transillumination was discovered in one patient without other features of albinism. Fifty percent of patients had speech delay requiring intervention. No other developmental delays or general medical conditions were identified. CONCLUSIONS: Nystagmus resolved in 87.5% of patients, all before the first year of life, and speech delay was later identified in half of the patients. [J Pediatr Ophthalmol Strabismus. 2018;55(3):159-163.]. PMID- 29384563 TI - Optical Coherence Tomography in Children With Microtropia. AB - PURPOSE: To assess whether optical coherence tomography (OCT) could be useful for detecting and documenting fixation in patients with microtropia. METHODS: Retinal fixation observation was performed using spectral-domain OCT on amblyopic children with microtropia. The position between the retinal fixation point and the anatomical fovea was measured, in microns, using the system software tools. Only patients with a high level of cooperation, OCT scan quality signal of 7 or better, and visual acuity of 0.70 logarithm of the minimum angle of resolution (logMAR) or worse in the amblyopic eye were included. RESULTS: A total of 25 patients were included: 15 with microtropia (study group) and 10 without tropia and with foveal fixation and stereopsis (control group). In the study group, microtropia was previously diagnosed in 67% of cases through the cover test, and was predominantly in the left eye (73%). The average visual acuity of the sound eye was 0.03 decimal and 0.18 logMAR in the amblyopic eye. The microtropia was 3.73 +/- 3.34 prism diopters and eccentric fixation (387 +/- 199 um) with OCT was observed in all cases except one. Eccentricity was predominantly in the superonasal quadrant (57%). Both eyes in the control group and the contralateral eyes of the study group showed foveal fixation. CONCLUSIONS: OCT can play an important role in the diagnosis and measurement of eccentric fixation in eyes with microtropia, providing high sensitivity. [J Pediatr Ophthalmol Strabismus. 2018;55(3):171-177.]. PMID- 29384564 TI - Mitomycin C in Filtering Surgery for Primary Congenital Glaucoma: A Comparison of Exposure Durations. AB - PURPOSE: To compare the effect of two exposure durations of mitomycin C in combined angle and filtering surgery for primary congenital glaucoma. METHODS: This was a prospective study conducted in the Department of Ophthalmology at Alexandria Main University Hospital, Alexandria, Egypt, on 75 eyes with primary congenital glaucoma that underwent combined trabeculotomy-trabeculectomy with intraoperative mitomycin C application for 1 minute (MMC 1) or 2 minutes (MMC 2) and were followed up for 24 months. Success rates were studied and complications noted. Success was defined by a composite primary end point of an intraocular pressure (IOP) of less than 16 mm Hg under general anesthesia, without any IOP lowering medications and with no hypotony-related complications and/or lack of IOP-related progression of the disease as evidenced by worsening of the ocular biometric characteristics. RESULTS: The mean age of the study participants was 6.7 +/- 4.1 months (range: 2 to 16 months; median: 6 months) in the MMC 1 group (35 eyes) and 7.7 +/- 5.7 months (range: 1 to 32 months; median: 6.5 months) in the MMC 2 group (40 eyes). The initial surgery was successful in 32 (91.5%) and 31 (77.5%) eyes in the MMC 1 and MMC 2 groups, respectively. The mean IOP was 18.4 +/- 5.1 and 18.1 +/- 6.1 mm Hg preoperatively and 5.5 +/- 3.5 and 4.8 +/- 2.8 mm Hg at the end of follow-up in the MMC 1 and MMC 2 groups, respectively. There was no statistically significant difference in the clinical parameters between the two groups. Complications included cataracts in each group and hypotony optic disc edema in 3 eyes (7.5%) in the MMC 2 group. CONCLUSIONS: Both mitomycin C application durations were effective in combined trabeculotomy trabeculectomy with mitomycin C for primary congenital glaucoma. The longer duration was not advantageous in disease control and there were no significant differences in complications. [J Pediatr Ophthalmol Strabismus. 2018;55(3):164 170.]. PMID- 29384565 TI - Academic Freedom and Educational Responsibility. PMID- 29384566 TI - The Single-Group, Pre- and Posttest Design in Nursing Education Research: It's Time to Move on. AB - Studying the effectiveness of educational interventions is centrally important to building the science of nursing education. Yet, the design most commonly used in the study of nursing education interventions-the single-group, preand posttest design-provides limited evidence to support claims of intervention effectiveness. In this Methodology Corner installment, the limitations of the single-group, preand posttest design are outlined and a review of the requirements for establishing stronger arguments for causality is presented. To overcome the limitations of single-group, preand posttest designs, nursing education researchers are encouraged to employ study designs and procedures that can significantly strengthen researchers' claims of intervention effectiveness. [J Nurs Educ. 2018;57(2):69-71.]. PMID- 29384567 TI - A Philosophical Analysis of Clinical Decision Making in Nursing. AB - BACKGROUND: Clinical decision making is a fundamental aspect of nurses' clinical practice and has a direct impact on the health and well-being of each patient. METHOD: An exploratory analysis of the concept of clinical decision making in nursing will be provided from the two predominant theoretical perspectives: the systematic-positivist model and the intuitive-humanistic model. The origin, aim, value, ontology and epistemology, assumptions, communicability, and context specificity of these two models are discussed. RESULTS: As nurses work in ever changing health care environments, either the positivist model or the intuitive model is adequate to describe the dynamic processes nurses use in clinical decision making. Therefore, it was suggested that the cognitive processes used in decision making were neither completely analytical nor completely intuitive. CONCLUSION: Clinical decision making is complex. A combination of scientific evidence-based knowledge in conjunction with intuition and contextual factors could enable nurses to utilize excellent clinical decision making. [J Nurs Educ. 2018;57(2):73-78.]. PMID- 29384568 TI - Dishonest Behavior in the Classroom and Clinical Setting: Perceptions and Engagement. AB - BACKGROUND: Nursing students sometimes engage in academically dishonest behaviors despite honor codes and policies. We believe that learning more about nursing students' perceptions of and engagement in academically dishonest behaviors will aid faculty in crafting more effective codes, policies, and educational modules. METHOD: Baccalaureate nursing students from accredited programs across the nation were invited to participate in an online cross-sectional descriptive correlational survey. Data were analyzed using descriptive and correlational statistics. RESULTS: Nursing students do not perceive all academically dishonest behavior as dishonest. There is a positive relationship between perceptions of behaviors in the classroom and clinical setting. Students have higher rates of engagement in behaviors they do not perceive as dishonest. Those who engage in the behaviors considered dishonest have higher rates of rationalization. CONCLUSION: Faculty need to delineate to students what behaviors are deemed dishonest in a course. Eliminating ambiguity has potential to reduce engagement in dishonest behavior. [J Nurs Educ. 2018;57(2):79-87.]. PMID- 29384569 TI - Dementia Care Content in Prelicensure Nursing Curricula: A Pilot Mixed-Methods Study. AB - BACKGROUND: Having a nursing workforce equipped to provide quality care for patients living with dementia is essential. The purpose of this study was to investigate how undergraduate nursing programs integration of dementia care content into their curricula. METHOD: Using sequential explanatory mixed methods, a stratified sample of 137 representatives of programs in 11 states with dense elderly populations completed a quantitative survey. A subsample (n = 8) completed qualitative e-mail interviews. RESULTS: Most respondents indicated dementia care content was integrated into their curricula (n = 103, 92.8%). Clinical partnership with dementia care centers was associated with a greater proportion of students interacting with individuals having dementia (p = .02). Curriculum overload was the most significant challenge to integrating dementia content (n = 61, 43.9%). Qualitative themes supported the quantitative results. CONCLUSION: Future research is needed to identify best practices to ensure that nursing curricula provide essential content to meet the care needs of the growing population of individuals with dementia. [J Nurs Educ. 2018;57(2):88-95.]. PMID- 29384570 TI - Teaching Methodologies for End-of-Life Care in Undergraduate Nursing Students. AB - BACKGROUND: The purpose of this literature review was to explore methodologies for teaching end-of-life (EOL) care to undergraduate nursing students. METHOD: Articles were retrieved by searching CINAHL, Academic Search Complete, and MEDLINE databases using the terms terminal care, palliative care, end of life care, undergraduate nurs*, hospice care, baccalaureate nurs*, prelicensure nurs*, palliative nurs*, training, and undergraduate education. A total of 728 articles were preliminarily evaluated for inclusion, with 22 relevant to this literature review. RESULTS: A variety of teaching methods have been studied for efficacy in undergraduate nursing education. CONCLUSION: Comparisons are limited by inconsistencies in instrumentation and the use of multiple teaching strategies in individual studies. More information is needed regarding the effect of interventions on clinical practice. Educational activities should be integrated throughout the learning experience and include elements of didactic teaching, clinical experiences, and application in simulation, including a focus on interprofessional education. [J Nurs Educ. 2018;57(2):96-100.]. PMID- 29384571 TI - Interprofessional Education on Adverse Childhood Experiences for Associate Degree Nursing Students. AB - BACKGROUND: The health impact of adverse childhood experiences (ACEs) is significant. Nurses need knowledge and must work in multidisciplinary teams to address this problem. This study examined the effects of an interprofessional education (IPE) activity with nonhealth care students on associate degree nursing (ADN) students' ACEs knowledge and perspectives on IPE. METHOD: The mixed-methods approach used a quasi-experimental pretest-posttest design with an intervention and control group and thematic analysis of focus group data. RESULTS: Readiness for Interprofessional Learning scale mean scores indicated positive baseline IPE perspectives. Scores changed minimally for most measures in both the intervention and control groups on posttest. However, four major relevant themes related to ACEs knowledge and two related to interprofessional learning were identified. CONCLUSION: IPE with nonhealth care students is an effective way to teach ADN students about ACEs and infuse interprofessional learning in a nonuniversity setting. However, outcomes are best captured with qualitative data. [J Nurs Educ. 2018;57(2):101-105.]. PMID- 29384572 TI - Students' Knowledge of and Interest in Older Adults: Impact of a Geriatrics Course. AB - BACKGROUND: The number of older adults living with chronic conditions is steadily increasing, so nurses must be prepared to care for the needs of this population. However, only one third of nursing education programs include a stand-alone geriatrics course. METHOD: A cross-sectional mixed-methods design was used to compare two cohorts of 46 nursing students. Knowledge, attitude, and interest in older adults were examined using an online survey. The control cohort did not complete the geriatric course. RESULTS: No demographic differences were found between groups. Completing the geriatric course was not correlated with having greater aging-related knowledge. Decreased interest in working with the older adult population was found. CONCLUSION: Findings from this cross-sectional pilot study suggest that previous experience with an aging relative was associated with better aging-related knowledge. Further research exploring students' perceptions is needed to understand the relationship between the geriatric course and attitudes toward aging. [J Nurs Educ. 2018;57(2):106-109.]. PMID- 29384573 TI - Catalyst for Growth: The Implications of Co-Curricular Experiences for Nursing Education. AB - BACKGROUND: Co-curricular experiences provide an opportunity for learning outside of a university classroom. A co-curricular retreat was developed to engage students, faculty, and staff in learning about social justice. Through guided activities and deep discussions, participants explored privileged and oppressed identities in a safe environment. METHOD: Pre- and postsurveys were collected. Quantitative and qualitative data, including personal narratives from two nurse educators, were described. RESULTS: Participants reported feeling less confident about their knowledge about socially constructed identities after the retreat, with deepened awareness of a need to learn. CONCLUSION: Co-curricular retreat exercises led to new insights among student and nurse educator participants, which stimulated ongoing education. Exploration of personal identities is a beginning step toward cultural competence-an essential quality in the nursing profession. Co-curricular experiences focused on social justice having implications for promoting social justice-a core nursing value-as well as developing cultural competence among nursing students and nurse educators. [J Nurs Educ. 2018;57(2):110-114.]. PMID- 29384574 TI - Techniques to Promote Reflective Practice and Empowered Learning. AB - BACKGROUND: Health care environments are fraught with fast-paced critical demands and ethical dilemmas requiring decisive nursing actions. Nurse educators must prepare nursing students to practice skills, behaviors, and attitudes needed to meet the challenges of health care demands. Evidence-based, innovative, multimodal techniques with novice and seasoned nurses were incorporated into a baccalaureate (BSN) completion program (RN to-BSN) to deepen learning, complex skill building, reflective practice, teamwork, and compassion toward the experiences of others. METHOD: Principles of popular education for engaged teaching-learning were applied. Nursing students experience equitable access to content through co-constructing knowledge with four creative techniques. RESULTS: Four creative techniques include poem reading aloud to facilitate connectedness; mindfulness to cultivate self-awareness; string figure activities to demonstrate indigenous knowledge and teamwork; and cartooning difficult subject matter. CONCLUSION: Nursing school curricula can promote a milieu for developing organizational skills to manage simultaneous priorities, practice reflectively, and develop empathy and the authenticity that effective nursing requires. [J Nurs Educ. 2018;57(2):115-120.]. PMID- 29384575 TI - Promoting Faculty Scholarship: A Clinical Faculty Scholars Program. AB - BACKGROUND: The importance of supporting and promoting faculty scholarship in nursing is acknowledged, but the reality of scholarship for faculty engaged in clinical teaching can be challenging. METHOD: The article describes the development and initial results of the scholarly practice program. Mentorship, time, and limited funding are essentials for the program. RESULTS: After submitting detailed proposals, 15 faculty were chosen to be project leaders in the first 2 years of the program, resulting in 15 presentations, three posters, 19 publications, and a webinar, to date. External continuing funding has been secured by three projects. Additional dissemination efforts are awaiting peer review. CONCLUSION: The program has successfully increased the level of scholarship among clinical teaching faculty and contributed to the faculty's professional satisfaction. Faculty have increased experience and ability to conduct clinical quality improvement. Experience supports targeted, substantial support for projects, rather than a general average faculty allocation strategy to promote scholarship. [J Nurs Educ. 2018;57(2):121-125.]. PMID- 29384576 TI - Teaching About Zebras. PMID- 29384577 TI - Managing Online Groups With a Slice of Pie. PMID- 29384578 TI - Culturally Competent Communication: Building a Culture of Safety Through Online Role-Playing. PMID- 29384579 TI - You Say Tomato, I Say Tomato-But It Isn't the Same. PMID- 29384580 TI - Analyzing Gaps to Design Educational Interventions. AB - This article addresses how nursing professional development practitioners can meet educational design criterion 1 in the American Nurses Credentialing Center Primary Accreditation process and standards 1 and 2 in the Association for Nursing Professional Development Scope and Standards of Practice. J Contin Educ Nurs. 2018;49(1):4-6. PMID- 29384581 TI - Tips and Trends to Start the New Year. AB - With the New Year comes the opportunity to set goals and advance training and development opportunities for leaders. This article presents five tips and five trends that serve as prognosticators for the coming year, including tips to influence time management and leadership impact and trends, such as sexual harassment training and "soft" skills development, which are now core skills for team success. A shift from hierarchical structures to network- and relationship centered webs for advanced problem solving is also projected. J Contin Educ Nurs. 2018;49(1):7-9. PMID- 29384582 TI - Using a Role-Play Simulation Game to Promote Systems Thinking. AB - Learning is a dynamic process where the learner discovers new knowledge and constructs new insights. The "Friday Night in the ER"(c) role-play simulation game facilitates system thinking, data-based decision making, and collaboration. Nurse educators in academe and health care settings can use this game to practice the essential skills of nurse professionals. J Contin Nurs Educ. 2018;49(1):10 11. PMID- 29384583 TI - Using Evidence to Prepare Non-Oncology Nurses for Cancer Survivor Care. AB - BACKGROUND: Growing increases in current and projected cancer survivors demands a workforce that can safely meet their health care needs spanning a lifetime. The literature lacks sufficient evidence regarding the knowledge needed by non oncology nurses who care for cancer survivors in settings not designated for cancer care. This study identified this oncology knowledge and perceived barriers. METHOD: The Cancer Nursing Curriculum Survey was completed by a national pool of 302 oncology and 313 medical-surgical nurses who rated the depth and importance of 33 cancer concepts needed by non-oncology nurses for cancer survivor care. RESULTS: Concept means for depth and importance were similar between both groups, with importance rated higher. Major concepts focused on symptom management. Barriers included lack of time, knowledge, and access to resources. CONCLUSION: The findings indicate the understanding of knowledge needed by non-oncology nurses for survivor care and provide a first step to design continuing education to address needs. J Contin Educ Nurs. 2018;49(1):12 18. PMID- 29384584 TI - What's in a Word? Understanding Terms in Continuing Nursing Education and Professional Development. AB - Terminology used in the field of continuing nursing education and nursing professional development can be confusing. This article defines common terms and explains the importance of their correct usage. J Contin Nurs Educ. 2018;49(1):19 25. PMID- 29384585 TI - Continuing Education Preferences, Facilitators, and Barriers for Nursing Home Nurses. AB - BACKGROUND: The purpose of the study was to determine the continuing education needs for nursing home nurses in rural central Illinois and to determine any potential facilitators or barriers to obtaining continuing education. METHOD: Data were collected using the Educational Needs Assessment questionnaire. Descriptive statistics were computed to examine continuing education preferences, facilitators, and barriers among nursing home nurses. Independent samples t tests were used to compare preferences between administrative and staff nurses. RESULTS: The sample included 317 nurses from 34 facilities. The five top needs were related to clinical problems. Administrative nurses had greater needs for professional issues, managerial skills, and quality improvement than staff nurses. Barriers included rural settings, need for vacation time for programs, and inadequate staffing. CONCLUSION: Continuing education needs of nursing home nurses in Illinois are similar to previous studies conducted in Arizona and North Carolina. Continuing education barriers were mostly organizational, rather than personal. J Contin Nurs Educ. 2018;49(1):26-33. PMID- 29384586 TI - Emergency Patient Handoffs: Identifying Essential Elements and Developing an Evidence-Based Training Tool. AB - BACKGROUND: Patient handoffs between care teams have been recognized as a major patient safety risk due to inadequate exchange or loss of critical information, especially during emergent patient transfers. The purpose of this literature review was to identify the essential elements of effective patient handoffs in emergency situations to develop a standardized tool to support a structured patient handoff procedure capable of guiding education and training. METHOD: A literature search of handoff procedures and patient transfers was conducted using the Cumulative Index to Nursing and Allied Health Literature and PubMed between 2008 and 2015. RESULTS: Two global themes were identified-Crew Interactions, and Essential Data Elements-resulting in a tool containing 30 objective and five subjective items. CONCLUSION: Through the literature review, synthesis, and workgroup consensus, we developed a standardized tool to guide standardized education, training, and future inquiry in prehospital and emergent patient handoffs. J Contin Educ Nurs. 2018;49(1):34-41. PMID- 29384587 TI - Substance Use Disorder: Efficacy of Educational Strategies in Delaware. AB - BACKGROUND: Substance use disorder (SUD) is a national epidemic. The problem is underreported and gaps exist in nurses' knowledge pertaining to recognizing and reporting nurses with an SUD. The purpose of this research was to examine the effects of an educational intervention on SUD to meet the continuing education (CE) requirement for relicensure. METHOD: A quasi-experimental pretest-posttest design was used to determine whether an increase in scores occurred following completion of the National Council of State Boards of Nursing Learning Extension's online course, titled Understanding Substance Use Disorder in Nursing. Eighty-six nurses started the online course. RESULTS: Sixty-eight of the 86 nurses completed the online course. An increase of 22% (p < .001) was observed when pre- and posttest scores were compared, suggesting an increase in nurses' knowledge about SUD. CONCLUSION: Online CE courses are an effective means to increase SUD knowledge for nurses. J Contin Nurs Educ. 2018;49(1):42-48. PMID- 29384588 TI - Palladium-Catalyzed Formal Cross-Coupling of Diaryl Ethers with Amines: Slicing the 4-O-5 Linkage in Lignin Models. AB - Lignin is the second most abundant organic matter on Earth, and is an underutilized renewable source for valuable aromatic chemicals. For future sustainable production of aromatic compounds, it is highly desirable to convert lignin into value-added platform chemicals instead of using fossil-based resources. Lignins are aromatic polymers linked by three types of ether bonds (alpha-O-4, beta-O-4, and 4-O-5 linkages) and other C-C bonds. Among the ether bonds, the bond dissociation energy of the 4-O-5 linkage is the highest and the most challenging to cleave. To date, 4-O-5 ether linkage model compounds have been cleaved to obtain phenol, cyclohexane, cyclohexanone, and cyclohexanol. The first example of direct formal cross-coupling of diaryl ether 4-O-5 linkage models with amines is reported, in which dual C(Ar)-O bond cleavages form valuable nitrogen-containing derivatives. PMID- 29384589 TI - Who's still smoking? Disparities in adult cigarette smoking prevalence in the United States. AB - The continuing high prevalence of cigarette smoking among specific subpopulations, many of them vulnerable, is one of the most pressing challenges facing the tobacco control community. These populations include individuals in lower education and/or socioeconomic groups; from certain racial/ethnic groups; in the lesbian, gay, bisexual, and transgender community; with mental illness; and in the military, particularly among those in the lowest pay grades. Although traditional tobacco control measures are having positive health effects for most groups, the effects are not sufficient for others. More attention to and support for promising novel interventions, in addition to new attempts at reaching these populations through conventional interventions that have proven to be effective, are crucial going forward to find new ways to address these disparities. CA Cancer J Clin 2018;68:106-115. (c) 2018 American Cancer Society. PMID- 29384590 TI - Conformation change of hornet silk proteins in the solid phase in response to external stimulation. AB - Hornet silks adopt a variety of morphology such as fibers, sponge, films, and gels depending on the preparation methods. We have studied the conformation change of hornet silk proteins (Vespa mandarina) as regenerated films, using chiroptical spectrophotometer universal chiroptical spectrophotometer 1, which can measure true circular dichroism spectra without artifact signals that are intrinsic to solid-state samples. The spectra showed that the proteins in films alter the conformation rapidly from the alpha-helix to the coiled coil and then to a beta-sheet structure in response to heat/moisture treatment, but the transformation stopped at the coiled coil state when the sample was soaked in EtOH/water solution. Water is required for the alpha-helix to the coiled coil transition, and extra energy is required for the further transition to a beta sheet structure. This is the first successful circular dichroism study of fibril silk proteins to follow the conformation changes in the solid state. This work shows that proteins can undergo conformational changes easily even in the solid phase in response to external stimuli, and this can be traced by solid-phase feasible chiroptical spectrophotometers. Application of unnatural stress to proteins gives valuable insights into their structure and characteristics. PMID- 29384591 TI - A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration-resistant metastatic prostate cancer. AB - ADVERSE EVENT: Decreased abiraterone exposure after introducing carbamazepine. DRUGS IMPLICATED: Abiraterone acetate and carbamazepine. THE PATIENT: A 65-year old man with metastatic castration resistant prostate cancer, was treated with abiraterone acetate and prednisolone, and received concomitant carbamazepine for treatment of facial neuropathy. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The interaction was confirmed by a decrease in abiraterone exposure >2-fold (area under-the-curve and trough levels). After discontinuation of carbamazepine therapy, the abiraterone exposure normalized. No alternative causes were found that explain the decrease in abiraterone exposure. MECHANISM: Induction of CYP3A and potentially phase I metabolism (SULT2A1) by carbamazepine. IMPLICATIONS FOR THERAPY: Clinicians and pharmacists should be aware of this clinically relevant interaction. The national drug-drug interaction checker does not warn for this interaction, whereas both the Lexicomp(r) and Micromedex(r) advice to avoid if possible or to increase the abiraterone dose frequency to twice daily. Carbamazepine should not be combined with abiraterone to avoid underexposure and suboptimal therapy. Therapeutic drug monitoring of abiraterone is useful to guide therapy when drug-drug interactions cannot be avoided. PMID- 29384592 TI - Label-Free Quantitative Proteomic Screening of Candidate Plasma Biomarkers for the Prognosis of Breast Cancer with Different Lymph Node Statuses. AB - PURPOSE: Lymph node status is a crucial predictor for the overall survival of invasive breast cancer. However, lymph node involvement is only detected in about half of HER2-positive patients. Since patients with lymph node involvement has less favorable prognosis and higher risk of recurrence, it is important to develop plasma protein biomarkers for distinguishing lymph node metastasis. EXPERIMENTAL DESIGN: A label-free quantitative proteomic strategy to construct plasma proteomes of ten patients with small size HER2-positive breast cancer (five patients with lymph node metastasis versus five patients without lymph node metastasis) is applied. RESULTS: A total of 388 proteins are identified, of which 33 proteins are differentially expressed. Statistical analyses suggested the present strategy is low cost and highly efficient in initial screening of plasma biomarkers. In silico analyses using various bioinformatics databases show that these altered proteins are highly associated with breast disease, cancer pathway, lymph node morphology, metastasis, complement pathway, and immune regulation. CONCLUSIONS AND CLINICAL RELEVANCE: The present dataset provides a list of candidate biomarkers that could be used for early differentiation diagnosis and prognosis of breast cancer with lymph node metastasis. PMID- 29384593 TI - Variables That Influence US Midwife and Physician Management of the Third Stage of Labor. AB - INTRODUCTION: Midwives and physicians incorporate their knowledge, experiences, and other variables in making clinical decisions. Variations in the management of the third stage of labor may be a result of variables that influence providers' decision making. The purpose of this study was to describe variables that influence US midwives' and physicians' management of the third stage of labor. METHODS: A randomly selected national sample of certified nurse-midwives and certified midwives, certified professional midwives, obstetricians, and family physicians was surveyed about the extent to which maternal characteristics, maternal history, and current birth characteristics influence their third-stage management. The extent of influence was defined in terms of always to never altering management. Descriptive summaries, group comparisons, and partial correlations were used to determine differences in influences between midwives and physicians. One free-text question was analyzed using qualitative methods. RESULTS: A total of 1243 clinicians responded. There was considerable variability in the response patterns in that the same variable was reported to always alter management during the third stage of labor for some participants yet did not influence the management practices of others at all. Differences between responses from midwives and physicians were explored as a possible explanation for some of the variability. In response to the free-text inquiry about variables that most influenced changes in participants' usual management of the third stage, the participants most often included active bleeding, current recommendations or guidelines, and maternal or family preferences. DISCUSSION: This study identifies variables reported as influencing clinical decision making during the third stage of labor. Therefore, these variables are important to consider when evaluating interventions and outcomes related to management of the third stage of labor and any attempts to design new interventions. The findings are descriptive of practice; they are not intended to guide changes in practice. PMID- 29384594 TI - Prevalence and correlates of depressive symptoms in older adults across the glycaemic spectrum: the Atherosclerosis Risk in Communities (ARIC) study. AB - AIMS: To document the prevalence of current depressive symptoms and history of depression across the glycaemic spectrum in older adults, and examine if measures of health status and healthcare satisfaction, access and utilization explain differences in the prevalence of current depressive symptoms by diabetes status. METHODS: We conducted a cross-sectional study of 6226 participants aged 67-90 years who attended the 2011-2013 visit of the Atherosclerosis Risk in Communities (ARIC) study. Diabetes was based on self-report, medication use and HbA1c . Current depressive symptoms were defined using the Center for Epidemiologic Studies Depression 11-item questionnaire, and history of depression was assessed via self-report. We examined obesity, history of cardiovascular disease, hypertension, kidney disease, cognitive function, and self-reported health compared with others. Prevalence and prevalence ratios were estimated using age-, race-, and sex-adjusted Poisson regression. RESULTS: The prevalence of current depressive symptoms was 5.4% in people without diabetes and 11.0% in people with diabetes (prevalence ratio 2.04, 95% CI 1.60, 2.48); the prevalence of history of depression was 11% in people without diabetes and 17.7% in people with diabetes (prevalence ratio 1.61, 95% CI 1.28,1.95). Strong correlates of current depressive symptoms were history of depression (prevalence ratio 3.86, 95% CI 3.05, 4.90) and reporting poor health compared with others (prevalence ratio 3.88, 95% CI 2.93, 5.15). No variables had significantly different associations with depressive symptoms across glycaemic categories (P for interaction >0.10). CONCLUSIONS: In older adults, current depressive symptoms were twice as prevalent in people with diabetes compared with those without. Measures of health status and healthcare did not explain differences in depressive symptoms between people with and without diabetes. PMID- 29384595 TI - MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo HSCT response and prognostic factor of MLL 3' region mRNA expression. AB - OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). METHODS: Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes. Risk stratification and association of MLL genetic partner and gene expression to overall survival, in the context of received therapy, were performed. RESULTS: MLLr cohort showed to have an OS more similar to intermediate risk AML. Type of MLL genetic partner showed to be relevant in allo-HSCT response; having MLLT1 and MLLT3, a better benefit from it. Expression of MLL-3' region, EVI1 and FLT3, showed association with OS in patients undergoing allo HSCT. CONCLUSION: We show that the MLL genetic partner could have implications in allo-HSCT response, and we propose three genes whose expression could be useful for the prognosis of this leukemia in patients undergoing allo-HSCT: 3' region of MLL, EVI1, and FLT3. PMID- 29384596 TI - Eating jellyfish: safety, chemical and sensory properties. AB - BACKGROUND: People's preference for fish with a high trophic level, like Atlantic cod and tuna, leads to a large food footprint. Responsible seafood consumption should include underutilised local products; hence the culinary use of edible jellyfish can be an effective contribution. The present work focused on Catostylus tagi to contribute to the consumption of edible jellyfish in the West. RESULTS: A questionnaire conducted with 192 young people showed an interest in tasting jellyfish-based food (64.6%). The resulting product, obtained by an alternative cooking process to traditional Asian ones, was chemically characterised and underwent microbiological and heavy metals control. The results indicated its non-toxicity. Patients who were allergic to seafood as well as non allergic volunteers revealed no allergic reaction to the jellyfish umbrella product (intakes up to 5 mg/kg body weight and 8 mg/kg, respectively). Seafood trained panellists defined the product's main impact on the mouth as freshness (72 mg/kg body weight). The preliminary snack, a pate, was positively accepted by allergic (7 in 9; n = 20) and non-allergic volunteers (6 in 7; n = 21). CONCLUSION: The present study confirmed that jellyfish intake is safe, even for allergic individuals, and its organoleptic properties were accepted by the study population. (c) 2018 Society of Chemical Industry. PMID- 29384597 TI - Uniportal video-assisted thoracoscopic surgery for anatomical fissureless anterior segment resection (S3) of the right upper lobe followed by lymph node dissection. AB - Uniportal video-assisted thoracoscopic (UVATS) resections seem to offer real benefits over conventional surgery in terms of postoperative pain and better cosmetic results. The procedure described in this tutorial, an anterior segment resection of the right upper lobe, is rarely performed, and fissureless resection of this segment by means of UVATS has, at time of writing, never been described in the literature. Our patient was a 79-year-old female, admitted to our clinic for treatment of a solitary metachronous metastatic tumor of a colon carcinoma, located in the anterior segment of the right upper lobe. A fissureless anatomical anterior segment resection of the right upper lobe was conducted, followed by the radical lymph node dissection. The postoperative course was event free and the patient was discharged on the 4th postoperative day. Fissureless VATS operations have an advantage compared to conventional operations in terms of reduced risk of prolonged air leak. Moreover, these operations take no longer to perform than conventional surgery and have no notable disadvantages, apart from the potential for using more staples. PMID- 29384598 TI - Uniportal video-assisted thoracoscopic resection of anterior segment of the left upper lobe. AB - Anatomical segment resections are often technically more demanding than lobectomies. Anterior segment of the left upper lobe (S3) is usually removed within the standard resection of the upper three segments. Our patient in this case was a 56-year-old with a known oropharyngeal carcinoma, otherwise amenable to curative treatment, who was admitted to our clinic with a 1-cm nodule in the anterior segment of the left upper lobe. Distant metastases were excluded, and a decision was made to proceed with a uniportal video-assisted thoracoscopic segmentectomy and lymphadenectomy. The procedure was successfully conducted without any adverse effects and the patient's postoperative course was uneventful. The tumor was diagnosed as a primary solid 1-cm adenocarcinoma and the final stage was pT1aN0M0. PMID- 29384599 TI - Combination video-assisted mediastinoscopic lymphadenectomy and transcervical thoracoscopy. AB - Surgical staging of lung and pleural cancers is crucial for planning treatment and assessing prognosis. In some cases, we need to explore both the mediastinum and the pleural cavity to confirm or rule out tumor dissemination. The combination of video-assisted mediastinoscopic lymphadenectomy (VAMLA) and thoracoscopy through a single transcervical incision allows the surgeon to widen the range of the exploration and improve the staging for lung and pleural cancers. VAMLA consists of complete removal of the mediastinal fat and lymph nodes of the subcarinal space, the right paratracheal and pretracheal areas, and the left paratracheal space. Once this mediastinal tissue is removed, the right mediastinal pleura can be identified and incised. A 30o thoracoscope is then inserted through the video-mediastinoscope into the pleural cavity to obtain samples of pleural fluid and biopsies of the parietal pleura and lung nodules, if present. In the case of left-sided thoracoscopy the access route to the left pleural cavity is anterior to the aortic arch, as for extended cervical mediastinoscopy. The combination of VAMLA and thoracoscopy is useful for exploring the mediastinum and the pleural space from a single incision and in the same surgical setting as the transcervical approach. PMID- 29384600 TI - Thoracoabdominal aortic replacement with a bovine pericardial tube graft for aortobronchial fistulation 10 years after TEVAR. AB - Aortobronchial fistula after thoracic endovascular aortic repair is usually a late complication. It is associated with high mortality and its surgical management is technically challenging. This tutorial illustrates the steps involved in removing an infected stent graft and replacing it with a bovine pericardial tube graft. PMID- 29384601 TI - Enhancement of the Immune Function by Titanium Dioxide Nanorods and Their Application in Cancer Immunotherapy. AB - With the rapid development of nanotherapy, concerns surrounding the possible use of nanomaterials-mediated immunomodulation are growing. Thus, evaluating the effects of novel materials for potential application in nanotherapy is essential. Herein, we studied the effects of TiO2-nanorods (NRs) on the immune function and their potential application in immunotherapy. TiO2-NRs exerted specific immunomodulatory effects on the main immune cells. Cytokines TNF-alpha and IL-2, which play a key role in antitumor processes, were upregulated more significantly than other cytokines (IL-4, IL-5, IFN-gamma) in the main immune cells. The cells group treated with a high dose of TiO2-NRs (50 mg/L) for 12 h produced a higher TNF-alpha content of 530.4 pg/mL relative to that (238.2 pg/mL) treated with saline solution only. The TNF-alpha content increased to 2.2- and 4.9-fold for macrophages and lymphocytes, respectively. Also, we conclude that TiO2-NRs exposure may trigger T cell proliferation and bias toward Th1 immune response and cause a long-lasting activation of lymphocytes involved in adaptive immunity rather than an innate immunity in BALB/c mice. Furthermore, we explored the potential application of TiO2-NRs in immunotherapy. At a given dose of 1 mg/kg, the inhibition rate by TiO2-NRs (26.7%) was much higher than that by DOX (13.3%). PMID- 29384602 TI - Foreign Body Reaction to Biomaterial Nanotubular Surface and the Influence of Silver Loading. AB - The impacts of biomaterial surface properties (i.e., surface nanotopography) and dopants (i.e., silver (Ag)) on the biomaterial-associated foreign body reaction (FBR) remain unclear. In this study, an in vivo FBR that was induced by a titania nanotube array (NT) on titanium was examined with and without Ag loading. An NT with an 80 nm diameter that was fabricated by anodization, and the NT samples that were loaded with two Ag concentrations (NT-AgH and NT-AgL) and formed by electrodeposition exhibited high hydrophilicities. A relatively rapid initial Ag+ release with a subsequent gradual reduction was observed for NT-AgH and NT-AgL; the Ag+ release was higher for NT-AgH than for NT-AgL. We found that the NT decreased the biomaterial-associated FBR, evidenced by a decreased fibrous capsule thickness and a number of recruited macrophages. The effect of Ag loading on the FBR was considered acceptable because the FBR induced by the NT-Ag samples was still less severe than that of the PT control. Additionally, the temporary increases in the blood, brain, liver and kidney Ag+ concentrations did not produce general side effects and were considered to be in the safe range. This study demonstrates the ability of nanotopography to alleviate the biomaterial associated FBR and provides further evidence for future clinical applications of biomaterials with nanostructures and Ag loading. PMID- 29384603 TI - Toxicity Evaluation and Anti-Tumor Study of Docetaxel Loaded mPEG-Polyester Micelles for Breast Cancer Therapy. AB - In this work, docetaxel (DTX) was encapsulated in monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (mPEG-PCL) micelles and monomethoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PLA) micelles, respectively. For the further application, the acute/genetic toxicity evaluation and pharmacokinetic/pharmacodynamic study of the two kinds of micellar nanomedicines were performed. In the study of anticancer activity in vitro and in vivo, DTX micelles showed better tumorgrowth inhibition than free DTX. The pharmacokinetic and tissue distribution studies showed that the DTX incorporated in micelles (especially in DTX-mPEG-PCL) retained significantly higher concentration in plasma and tumor tissue compared with free DTX. The acute toxicity and genotoxicity studies indicated that DTX micelles were safer than the docetaxel injection in cancer therapy and DTX-mPEG-PCL had less damage to DNA than DTX-mPEG PLA. So the micelles had a pronounced effect on reducing acute toxicity and genotoxicity of docetaxel. In conclusion, DTX micelles were efficient and safe on breast carcinoma chemotherapy. PMID- 29384604 TI - Cytoskeletons of Two Reproductive Germ Cell Lines Response Differently to Titanium Dioxide Nanoparticles Mediating Vary Reproductive Toxicity. AB - Titanium dioxide nanoparticles (TiO2 NPs) have been widely used for many years. Their toxic effects on the male reproductive system had been reported, but the underlying mechanisms were still not clear. Here we utilized two germ cell lines (GC-2 and TM4) to explore the possible toxic effects of TiO2 NPs on male reproductive system. Our results showed that TiO2 NPs did not affect cell viability but induced cell apoptosis of both GC-2 and TM4 cells up to 100 MUg/ml. Microtubule networks and microtubule dynamics of GC-2 but not TM4 cells were changed. The microfilaments arrangement of TM4 cells altered after treated with TiO2 NPs, and the phagocytosis activity of TM4 cells decreased significantly. Although the microfilament network of GC-2 cells seemed normal, the migration ability of GC-2 cells was significantly impaired. Totally TiO2 NPs is toxic to GC 2 cells by inducing cell apoptosis, disturbing microtubule arrangement and microtubule dynamic, and impairing cell migration ability. In addition, they altered the microfilament network and reduced the phagocytic activity of TM4 cells. We firstly reported that cytoskeletons (microtubules and microfilaments) in different cells showed different responses to TiO2 NPs, which might mediate different toxic mechanisms. PMID- 29384605 TI - Statistically Optimal Multisensory Cue Integration: A Practical Tutorial. AB - Humans combine redundant multisensory estimates into a coherent multimodal percept. Experiments in cue integration have shown for many modality pairs and perceptual tasks that multisensory information is fused in a statistically optimal manner: observers take the unimodal sensory reliability into consideration when performing perceptual judgments. They combine the senses according to the rules of Maximum Likelihood Estimation to maximize overall perceptual precision. This tutorial explains in an accessible manner how to design optimal cue integration experiments and how to analyse the results from these experiments to test whether humans follow the predictions of the optimal cue integration model. The tutorial is meant for novices in multisensory integration and requires very little training in formal models and psychophysical methods. For each step in the experimental design and analysis, rules of thumb and practical examples are provided. We also publish Matlab code for an example experiment on cue integration and a Matlab toolbox for data analysis that accompanies the tutorial online. This way, readers can learn about the techniques by trying them out themselves. We hope to provide readers with the tools necessary to design their own experiments on optimal cue integration and enable them to take part in explaining when, why and how humans combine multisensory information optimally. PMID- 29384606 TI - Sounds Modulate the Perceived Duration of Visual Stimuli via Crossmodal Integration. AB - Previous studies have shown that the perceived duration of visual stimuli can be strongly distorted by auditory stimuli presented simultaneously. In this study, we examine whether sounds presented separately from target visual stimuli alter the perceived duration of the target's presentation. The participants' task was to classify the duration of the target visual stimuli as perceived by them into four categories. Our results demonstrate that a sound presented before and after a visual target increases or decreases the perceived visual duration depending on the inter-stimulus interval between the sounds and the visual stimulus. In addition, three tones presented before and after a visual target did not increase or decrease the perceived visual duration. This indicates that auditory perceptual grouping prevents intermodal perceptual grouping, and eliminates crossmodal effects. These findings suggest that the auditory-visual integration, rather than a high arousal state caused by the presentation of the preceding sound, can induce distortions of perceived visual duration, and that inter- and intramodal perceptual grouping plays an important role in crossmodal time perception. These findings are discussed with reference to the Scalar Expectancy Theory. PMID- 29384607 TI - Cross-Modal Correspondences Enhance Performance on a Colour-to-Sound Sensory Substitution Device. AB - Visual sensory substitution devices (SSDs) can represent visual characteristics through distinct patterns of sound, allowing a visually impaired user access to visual information. Previous SSDs have avoided colour and when they do encode colour, have assigned sounds to colour in a largely unprincipled way. This study introduces a new tablet-based SSD termed the 'Creole' (so called because it combines tactile scanning with image sonification) and a new algorithm for converting colour to sound that is based on established cross-modal correspondences (intuitive mappings between different sensory dimensions). To test the utility of correspondences, we examined the colour-sound associative memory and object recognition abilities of sighted users who had their device either coded in line with or opposite to sound-colour correspondences. Improved colour memory and reduced colour-errors were made by users who had the correspondence-based mappings. Interestingly, the colour-sound mappings that provided the highest improvements during the associative memory task also saw the greatest gains for recognising realistic objects that also featured these colours, indicating a transfer of abilities from memory to recognition. These users were also marginally better at matching sounds to images varying in luminance, even though luminance was coded identically across the different versions of the device. These findings are discussed with relevance for both colour and correspondences for sensory substitution use. PMID- 29384608 TI - Audiovisual Integration of Time-to-Contact Information for Approaching Objects. AB - Previous studies of time-to-collision (TTC) judgments of approaching objects focused on effectiveness of visual TTC information in the optical expansion pattern (e.g., visual tau, disparity). Fewer studies examined effectiveness of auditory TTC information in the pattern of increasing intensity (auditory tau), or measured integration of auditory and visual TTC information. Here, participants judged TTC of an approaching object presented in the visual or auditory modality, or both concurrently. TTC information provided by the modalities was jittered slightly against each other, so that auditory and visual TTC were not perfectly correlated. A psychophysical reverse correlation approach was used to estimate the influence of auditory and visual cues on TTC estimates. TTC estimates were shorter in the auditory than the visual condition. On average, TTC judgments in the audiovisual condition were not significantly different from judgments in the visual condition. However, multiple regression analyses showed that TTC estimates were based on both auditory and visual information. Although heuristic cues (final sound pressure level, final optical size) and more reliable information (relative rate of change in acoustic intensity, optical expansion) contributed to auditory and visual judgments, the effect of heuristics was greater in the auditory condition. Although auditory and visual information influenced judgments, concurrent presentation of both did not result in lower response variability compared to presentation of either one alone; there was no multimodal advantage. The relative weightings of heuristics and more reliable information differed between auditory and visual TTC judgments, and when both were available, visual information was weighted more heavily. PMID- 29384610 TI - Ponzo's Illusion in 3D: Perspective Gradients Dominate Differences in Retinal Size. AB - A common form of the Ponzo illusion involves two test probes of equal size, embedded in a planar linear perspective painting depicting a three-dimensional (3D) scene, where the probe perceived to be farther is judged to be larger than the probe perceived closer to the viewer. In this paper, the same perspective 3D scene was painted on three surfaces: (a) A 2D surface incongruent with the 3D painted scene (flat perspective). (b) A 3D surface with a geometry congruent with the 3D scene (proper perspective). (c) A 3D surface with an opposite depth arrangement to the 3D scene (reverse perspective). This last stimulus was bistable and could be perceived veridically, as it physically existed, or as a depth-inverting illusion. For all experiments, observers relied on perspective gradients to estimate the size of a test probe placed within the scene; objects placed in a 'far' position as defined by perspective cues were perceived to be larger regardless of their physical distance. Further, illusion strength was tied to retinal size; small retinal-size differences (Experiments 1 and 2) did not affect illusion strength, whereas larger retinal-size differences (Experiment 3) did play a minor role. PMID- 29384609 TI - Visual-Somatosensory Integration in Older Adults: Links to Sensory Functioning. AB - Research investigating multisensory integration (MSI) processes in aging is scarce, but converging evidence for larger behavioral MSI effects in older compared to younger adults exists. The current study employed a three-prong approach to determine whether inherent age-related sensory processing declines were associated with larger (i.e., worse) visual-somatosensory (VS) reaction time (RT) facilitation effects. Non-demented older adults ( n = 156 ; mean age = 77 years; 55% female) without any medical or psychiatric conditions were included. Participants were instructed to make speeded foot-pedal responses as soon as they detected visual, somatosensory, or VS stimulation. Visual acuity was assessed using the Snellen test while somatosensory sensitivity was determined using vibration thresholds. The aims of the current study were to: (1) replicate a reliable MSI effect; (2) investigate the effect of unisensory functioning on VS RT facilitation; and (3) determine whether sensory functioning combination groups manifested differential MSI effects. Results revealed a significant VS RT facilitation effect that was influenced by somatosensory sensitivity but not visual acuity. That is, older adults with poor somatosensory sensitivity demonstrated significantly larger MSI effects than those with intact somatosensory sensitivity. Additionally, a significant interaction between stimulus condition and sensory functioning group suggested that the group with poor visual acuity and poor somatosensory functioning demonstrated the largest MSI effect compared to the other groups. In summary, the current study reveals that worse somatosensory functioning is associated with larger MSI effects in older adults. To our knowledge, this is first study to identify potential mechanisms behind increased RT facilitation in aging. PMID- 29384611 TI - Downward and Parallel Perspectives in an Experimental Study of Out-of-Body Experiences. AB - Out-of-body experiences (OBEs) have been reported in patients with neurological or psychiatric disorders. According to these reports, the patients looked down on their body from overhead. Based on this phenomenon, we adopted a downward perspective in an experimentally induced OBE paradigm and compared responses to an OBE questionnaire (sensations of OBE) with self-location mapping (feelings of body drift). The results revealed a correlation between the sensation of an OBE and self-location under the downward-perspective condition but not under the parallel-perspective condition; however, no significant difference was observed between the two conditions. Thus, the effect of perspective on OBE illusion that has been reported in clinical research of OBE did not affect the results obtained in previous studies inducing OBE. PMID- 29384612 TI - Disambiguating the Stream/Bounce Illusion With Inference. AB - The 'stream/bounce' illusion refers to the perception of an ambiguous visual display in which two discs approach each other on a collision course. The display can be seen as two discs streaming through each other or bouncing off each other. Which perception dominates, may be influenced by a brief transient, usually a sound, presented around the time of simulated contact. Several theories have been proposed to account for the switching in dominance based on sensory processing, attention and cognitive inference, but a universally applicable, parsimonious explanation has not emerged. We hypothesized that only cognitive inference would be influenced by the perceptual history of the display. We rendered the display technically unambiguous by vertically offsetting the targets' trajectories and manipulated their history by allowing the objects to switch from one trajectory to the other up to four times before the potential collision point. As the number of switches increased, the number of 'bounce' responses also increased. These observations show that expectancy is a critical factor in determining whether a bounce or streaming is perceived and may form the basis for a universal explanation of instances of the stream/bounce illusion. PMID- 29384613 TI - No smoker left behind: it's time to tackle tobacco in Australian priority populations. PMID- 29384614 TI - Test-Retest Reliability and Concurrent Validity of an fMRI-Compatible Pneumatic Vibrator to Stimulate Muscle Proprioceptors. AB - Processing proprioceptive information in the brain is essential for optimal postural control and can be studied with proprioceptive stimulation, provided by muscle vibration, during functional magnetic resonance imaging (fMRI). Classic electromagnetic muscle vibrators, however, cannot be used in the high-strength magnetic field of the fMRI scanner. Pneumatic vibrators offer an fMRI-compatible alternative. However, whether these devices produce reliable and valid proprioceptive stimuli has not been investigated, although this is essential for these devices to be used in longitudinal research. Test-retest reliability and concurrent validity of the postural response to muscle vibration, provided by custom-made fMRI-compatible pneumatic vibrators, were assessed in a repeated measures design. Mean center of pressure (CoP) displacements during, respectively, ankle muscle and back muscle vibration (45-60 Hz, 0.5 mm) provided by an electromagnetic and a pneumatic vibrator were measured in ten young healthy subjects. The test was repeated on the same day and again within one week. Intraclass correlation coefficients (ICC) were calculated to assess (a) intra- and interday reliability of the postural responses to, respectively, pneumatic and electromagnetic vibration, and (b) concurrent validity of the response to pneumatic compared to electromagnetic vibration. Test-retest reliability of mean CoP displacements during pneumatic vibration was good to excellent (ICCs = 0.64 0.90) and resembled that of responses to electromagnetic vibration (ICCs = 0.64 0.94). Concurrent validity of the postural effect of pneumatic vibration was good to excellent (ICCs = 0.63-0.95). In conclusion, the proposed fMRI-compatible pneumatic vibrator can be used with confidence to stimulate muscle spindles during fMRI to study central processing of proprioception. PMID- 29384618 TI - Gd3+ Tethered Gold Nanorods for Combined Magnetic Resonance Imaging and Photo Thermal Therapy. AB - Near infrared (NIR) mediated photothermal therapy and magnetic resonance imaging (MRI) are promising treatment and imaging modalities in the field of cancer theranostics. Gold nanorods are the first choice of materials for NIR-mediated photothermal therapy due to their strong localized surface plasmon resonance (LSPR) at NIR region. Similarly, gadolinium based MRI contrast agents have an ability to increase the ionic and molecular relaxivity, thereby enhancing the solvent proton relaxation rate resulting in contrast enhancement. Herein, the effort has been made to engineer a dual front theranostic agent with combined photothermal and magnetic resonance imaging capacity using gadolinium tethered gold nanorods (Gd3+-AuNR). NIR-responsive gold nanorods were surface fabricated by means of Au-thiol interaction using a thiolated macrocyclic chelator that chelates Gd3+ ions, and further stabilized by thiolated polyethylene glycol (PEG SH). The magnetic properties of the Gd3+-AuNR displayed an enhanced r 1 relaxivity of 12.1 mM-1s-1, with higher biological stability, and contrast enhancement in both solution state and in cell pellets. In-vitro (cell-free) and ex-vivo (on pig skin) analysis of the Gd3+-AuNR shows enhanced photothermal properties as equivalent to that of the raw AuNR. Furthermore, Gd3+-AuNR showed competent cellular entry and intracellular distribution as revealed by hyperspectral microscopy. In addition, Gd3+-AuNR also exhibits significant thermal ablation of B16-F10 cells in the presence of NIR. Thus, Gd3+-AuNR features a significant theranostic potential with combined photothermal and imaging modality, suggesting a great potential in anticancer therapy. PMID- 29384619 TI - Biodegradable Self-Assembled Micelles Based on MPEG-PTMC Copolymers: An Ideal Drug Delivery System for Vincristine. AB - Despite advantageous properties, micelles using methoxy poly(ethylene glycol) poly(trimethylene carbonate) (MPEGPTMC) have not been widely studied. In this work, we aim to develop a novel vehicle for vincristine (VCR) based on a MPEG PTMC micelle system. MPEG-PTMC with a series of molecular weights were synthesized and screened for the appropriate range for forming stable VCR micelles. The prepared micelles were then characterized in vitro and in vivo . VCR micelles presented high stability and ideal sustained release profile. The passive targeting effect was also enhanced compared with liposomal VCR. These results provide critical data to give the first clues regarding novel VCR micelles which exhibit potential for clinical application. PMID- 29384620 TI - Novel Synthesized Nanofibrous Scaffold Efficiently Delivered hBMP-2 Encoded in Adenoviral Vector to Promote Bone Regeneration. AB - Treatment of bone defect, especially large bone defect, is still a challenge for physicians clinically. Bone morphogenetic protein 2 (BMP-2) can induce osteoblast differentiation and promote new bone formation. Recently, nanomaterials have been widely used as a carrier to hold and deliver biomolecules, like human bone morphogenetic protein 2 gene (hBMP-2) in target cells/tissues. Most nanomethods, however, need further modification in order to work more reliably in clinical applications. Therefore, in this study, we created a novel poly(lactic-co glycolic acid [PLGA]) nanofibrous scaffold using an electrospinning technique; then, using a lyophilization process to allow nanofibrous scaffold to adsorb hBMP 2 adenoviral vector, AdCMV-hBMP2. Results indicate that the lyophilized poly(lactic-co-glycolic acid) nanofibrous scaffold/AdCMVhBMP2 can efficiently release and transduce cells in vitro and in vivo, and secrete functional hBMP-2 to promote osteogenic differentiation in vitro, and new bone generation in vivo. Importantly, the amount of newly formed bone covered >80% of the bone defect area 8 weeks post-implantation in vivo, in which the defect could not be repaired without any treatment in general. Our data demonstrate that the lyophilized PLGA nanofibrous scaffold/AdCMV-hBMP2 created herein stably and efficiently release functional viral vector to transduce local cells, resulting in secretion of hBMP 2 and promote new bone formation in vivo. Our new nanodelivery method has potential clinical application for the repair of large bone defects. PMID- 29384621 TI - A Fresh Shine onCystic Fibrosis Inhalation Therapy: Antimicrobial Synergy of Polymyxin B in Combination with Silver Nanoparticles. AB - This in vitro study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with 2 nm silver nanoparticles (NPs) against Gram negative pathogens commonly isolated from the cystic fibrosis (CF) lung. The in vitro synergistic activity of polymyxin B with silver NPs was assessed using the checkerboard assay against polymyxinsusceptible and polymyxin-resistant Pseudomonas aeruginosa isolates from the lungs of CF patients. The combination was also examined against the Gram-negative species Haemophilus influenzae, Burkholderia cepacia, Burkholderia pseudomallei, Stenotrophomonas maltophilia, Klebsiella pneumoniae and Acinetobacter baumannii that are less common in the CF lung. The killing kinetics of the polymyxin B-silver NPs combinations was assessed against P. aeruginosa by static time-kill assays over 24 h. Polymyxin B and silver NPs alone were not active against polymyxin-resistant (MIC >=4 mg/L) P. aeruginosa. Whereas, the combination of a clinically-relevant concentration of polymyxin B (2 mg/L) with silver NPs (4 mg/L) successfully inhibited the growth of polymyxin-resistant P. aeruginosa isolates from CF patients as demonstrated by >=2 log10 decrease in bacterial count (CFU/mL) after 24 h. Treatment of P. aeruginosa cells with the combination induced cytosolic GFP release and an increase of cellular reactive oxygen species. In the nitrocefin assay, the combination displayed a membrane permeabilizing activity superior to each of the drugs alone. The combination of polymyxin B and silver NPs displays excellent synergistic activity against highly polymyxin-resistant P. aeruginosa and is potentially of considerable clinical utility for the treatment of problematic CF lung infections. PMID- 29384643 TI - Ordered Topographically Patterned Silicon by Insect-Inspired Capillary Submicron Stamping. AB - Insect-inspired capillary submicron stamping and subsequent surface-limited metal assisted chemical etching (MACE) with ammonium bifluoride as a HF source are employed for the high-throughput production of ordered topographically patterned silicon (tpSi). Insect feet often possess hairy contact elements through which adhesive secretion is deployed. Thus, arrays of adhesive secretion drops remain as footprints on contact surfaces. Stamps for insect-inspired capillary submicron stamping having surfaces topographically patterned with contact elements mimic the functional principles of such insect feet. They contain spongy continuous nanopore networks penetrating the entire stamps. Any ink (organic or aqueous) may be supplied from the backside of the nanoporous stamps to the contact elements. We generated ordered arrays of submicron AgNO3 dots extending square millimeters on Si by manual stamping with cycle times of a few seconds under ambient conditions; at higher load, ordered holey AgNO3 films were obtained. Surface limited MACE correspondingly yielded either macroporous tpSi or Si pillar arrays. Inkjet printing of polymer solutions onto the tpSi yielded patterns of polymer blots conformally covering the tpSi. Such blot patterns could potentially represent a starting point for the development of persistent and scratch resistant identity labels or quick response codes on silicon surfaces. PMID- 29384644 TI - Ionic Conductivity of Polyelectrolyte Hydrogels. AB - Polyelectrolytes have many important functions in both living organisms and man made applications. One key property of polyelectrolytes is the ionic conductivity due to their porous networks that allow the transport of water and small molecular solutes. Among polyelectrolytes, zwitterionic polymers have attracted huge attention for applications that involve ion transport in a polyelectrolyte matrix; however, it is still unclear how the functional groups of zwitterionic polymer side chains affect their ion transport and swelling properties. In this study, zwitterionic poly(carboxybetaine acrylamide), poly(2-methacryloyloxyethyl phosphorylcholine), and poly(sulfobetaine methacrylate) hydrogels were synthesized and their ionic conductivity was studied and compared to cationic, anionic, and nonionic hydrogels. The change of the ionic conductivity of zwitterionic and nonionic hydrogels in different saline solutions was investigated in detail. Zwitterionic hydrogels showed much higher ionic conductivity than that of the widely used nonionic poly(ethylene glycol) methyl ether methacrylate hydrogel in all tested solutions. For both cationic and anionic hydrogels, the presence of mobile counterions led to high ionic conductivity in low salt solutions; however, the ionic conductivity of zwitterionic hydrogels surpassed that of cationic and ionic hydrogels in high salt solutions. Cationic and anionic hydrogels showed much higher water content than that of zwitterionic hydrogels in deionized water; however, the cationic hydrogels shrank significantly with increasing saline concentration. This work provides insight into the effects of polyelectrolyte side chains on ion transport. This can guide us in choosing better polyelectrolytes for a broad spectrum of applications, including bioelectronics, neural implants, battery, and so on. PMID- 29384645 TI - Crystallographic Habit Tuning of Li2MnSiO4 Nanoplates for High-Capacity Lithium Battery Cathodes. AB - Li2MnSiO4 has attracted significant attention as a cathode material for lithium ion batteries because of its high theoretical capacity (330 mA h g-1 with two Li+ ions per formula unit), low cost, and environmentally friendly nature. However, its intrinsically poor Li diffusion, low electronic conductivity, and structural instability preclude its use in practical applications. Herein, elongated hexagonal prism-shaped Li2MnSiO4 nanoplates with preferentially exposed {001} and {210} facets have been successfully synthesized via a solvothermal method. Density functional theory calculations and experimental characterization reveal that the formation mechanism involves the decomposition of solid precursors to nanosheets, self-assembly into nanoplates, and Ostwald ripening. Hydroxyl containing solvents such as ethylene glycol and diethylene glycol play a crucial role as capping agents in tuning the preferential growth. Li2MnSiO4@C nanoplates demonstrate a near theoretical discharge capacity of 326.7 mA h g-1 at 0.05 C (1 C = 160 mA h g-1), superior rate capability, and good cycling stability. The enhanced electrochemical performance is ascribed to the electrochemically active {001} and {210} exposed facets, which provide short and fast Li+ diffusion pathways along the [001] and [100] axes, a conformal carbon nanocoating, and a nanoscaled platelike structure, which offers a large electrode/electrolyte contact interface for Li+ extraction/insertion processes. PMID- 29384646 TI - A New Class of Ternary Compound for Lithium-Ion Battery: from Composite to Solid Solution. AB - Searching for high-performance cathode materials is a crucial task to develop advanced lithium-ion batteries (LIBs) with high-energy densities for electrical vehicles (EVs). As a promising lithium-rich material, Li2MnO3 delivers high capacity over 200 mAh g-1 but suffers from poor structural stability and electronic conductivity. Replacing Mn4+ ions by relatively larger Sn4+ ions is regarded as a possible strategy to improve structural stability and thus cycling performance of Li2MnO3 material. However, large difference in ionic radii of Mn4+ and Sn4+ ions leads to phase separation of Li2MnO3 and Li2SnO3 during high temperature synthesis. To prepare solid-solution phase of Li2MnO3-Li2SnO3, a buffer agent of Ru4+, whose ionic radius is in between that of Mn4+ and Sn4+ ions, is introduced to assist the formation of a single solid-solution phase. The results show that the Li2RuO3-Li2MnO3-Li2SnO3 ternary system evolves from mixed composite phases into a single solid-solution phase with increasing Ru content. Meanwhile, discharge capacity of this ternary system shows significantly increase at the transformation point which is ascribed to the improvement of Li+/e- transportation kinetics and anionic redox chemistry for solid-solution phase. The role of Mn/Sn molar ratio of Li2RuO3-Li2MnO3-Li2SnO3 ternary system has also been studied. It is revealed that higher Sn content benefits cycling stability of the system because Sn4+ ions with larger sizes could partially block the migration of Mn4+ and Ru4+ from transition metal layer to Li layer, thus suppressing structural transformation of the system from layered-to-spinel phase. These findings may enable a new route for exploring ternary or even quaternary lithium rich cathode materials for LIBs. PMID- 29384647 TI - Parallels in Structural Chemistry between the Molecular and Metallic Realms Revealed by Complex Intermetallic Phases. AB - The structural diversity of intermetallic phases poses a great challenge to chemical theory and materials design. In this Account, two examples are used to illustrate how a focus on the most complex of these structures (and their relationships to simpler ones) can reveal how chemical principles underlie structure for broad families of compounds. First, we show how experimental investigations into the Fe-Al-Si system, inspired by host-guest like features in the structure of Fe25Al78Si20, led to a theoretical approach to deriving isolobal analogies between molecular and intermetallic compounds and a more general electron counting rule. Specifically, the Fe8Al17.6Si7.4 compound obtained in these syntheses was traced to a fragmentation of the fluorite-type structure (as adopted by NiSi2), driven by the maintenance of 18-electron configurations on the transition metal centers. The desire to quickly generalize these conclusions to a broader range of phases motivated the formulation of the reversed approximation Molecular Orbital (raMO) approach. The application of raMO to a diverse series of compounds allowed us recognize the prevalence of electron pair sharing in multicenter functions isolobal to classical covalent bonds and to propose the 18 n electron rule for transition metal-main group (T-E) intermetallic compounds. These approaches provided a framework for understanding the 14-electron rule of the Nowotny Chimney Ladder phases, a temperature-driven phase transition in GdCoSi2, and the bcc-structure of group VI transition metals. In the second story, we recount the development of the chemical pressure approach to analyzing atomic size and packing effects in intermetallic structures. We begin with how the stability of the Yb2Ag7-type structure of Ca2Ag7 over the more common CaCu5 type highlights the pressing need for approaches to assessing the role of atomic size in crystal structures, and inspired the development of the DFT-Chemical Pressure (CP) method. Examples of structural phenomena elucidated by this approach are then given, including the Y/Co2 dumbbell substitution in the Th2Zn17 type phase Y2Co17, and local icosahedral order in the Tsai-type quasicrystal approximant CaCd6. We next discuss how deriving relationships between the CP features of a structure and its phonon modes provided a way of both validating the method and visualizing how local arrangements can give rise to soft vibrational modes. The themes of structural mechanisms for CP relief and soft atomic motions merge in the discovery and elucidation of the incommensurately modulated phase CaPd5. In the conclusion of this Account, we propose combining raMO and CP methods for focused predictions of structural phenomena. PMID- 29384648 TI - Well-Coupled Nanohybrids Obtained by Component-Controlled Synthesis and in Situ Integration of Mn xPd y Nanocrystals on Vulcan Carbon for Electrocatalytic Oxygen Reduction. AB - Development of cheap, highly active, and robust bimetallic nanocrystal (NC)-based nanohybrid (NH) electrocatalysts for oxygen reduction reaction (ORR) is helpful for advancing fuel cells or other renewable energy technologies. Here, four kinds of well-coupled Mn xPd y(MnPd3, MnPd-Pd, Mn2Pd3, Mn2Pd3-Mn11Pd21)/C NHs have been synthesized by in situ integration of Mn xPd y NCs with variable component ratios on pretreated Vulcan XC-72 C using the solvothermal method accompanied with annealing under Ar/H2 atmosphere and used as electrocatalysts for ORR. Among them, the MnPd3/C NHs possess the unique "half-embedded and half-encapsulated" interfaces and exhibit the highest catalytic activity, which can compete with some currently reported non-Pt catalysts (e.g., Ag-Co nanoalloys, Pd2NiAg NCs, PdCo/N-doped porous C, G-Cu3Pd nanocomposites, etc.), and close to commercial Pt/C. Electrocatalytic dynamic measurements disclose that their ORR mechanism abides by the direct 4e- pathway. Moreover, their durability and methanol tolerant capability are much higher than that of Pt/C. As revealed by spectroscopic and electrochemical analyses, the excellent catalytic performance of MnPd3/C NHs results from the proper component ratio of Mn and Pd and the strong interplay of their constituents, which not only facilitate to optimize the d-band center or the electronic structure of Pd but also induce the phase transformation of MnPd3 active components and enhance their conductivity or interfacial electron transfer dynamics. This work demonstrates that MnPd3/C NHs are promising methanol-tolerant cathode electrocatalysts that may be employed in fuel cells or other renewable energy option. PMID- 29384649 TI - Beyond van der Waals Interaction: The Case of MoSe2 Epitaxially Grown on Few Layer Graphene. AB - Van der Waals heterojunctions composed of graphene and transition metal dichalcogenides have gain much attention because of the possibility to control and tailor band structure, promising applications in two-dimensional optoelectronics and electronics. In this report, we characterized the van der Waals heterojunction MoSe2/few-layer graphene with a high-quality interface using cutting-edge surface techniques scaling from atomic to microscopic range. These surface analyses gave us a complete picture of the atomic structure and electronic properties of the heterojunction. In particular, we found two important results: the commensurability between the MoSe2 and few-layer graphene lattices and a band-gap opening in the few-layer graphene. The band gap is as large as 250 meV, and we ascribed it to an interface charge transfer that results in an electronic depletion in the few-layer graphene. This conclusion is well supported by electron spectroscopy data and density functional theory calculations. The commensurability between the MoSe2 and graphene lattices as well as the band-gap opening clearly show that the interlayer interaction goes beyond the simple van der Waals interaction. Hence, stacking two-dimensional materials in van der Waals heterojunctions enables us to tailor the atomic and electronic properties of individual layers. It also permits the introduction of a band gap in few-layer graphene by interface charge transfer. PMID- 29384650 TI - Biosynthesis and Structure-Activity Relationship Studies of Okaramines That Target Insect Glutamate-Gated Chloride Channels. AB - Prenylated indole alkaloid okaramines selectively target insect glutamate-gated chloride channels (GluCls). Because of their highly complex structures, including azocine and azetidine rings, total synthesis of okaramine A or B has not been achieved, preventing evaluation of the biological activities of okaramines. Biosynthetic approaches provide alternatives to accessing structurally diverse derivatives and enabling the elucidation of structure-activity relationships. To explore the biosynthetic potential of okaramines, gene knockout experiments of an okaramine-producer fungus were performed. The deletion mutants of the oxygenase genes okaB, okaD, okaE, and okaG provided analogues that were unlikely to be accumulated in the normal biosynthetic process of the wild-type strain. Analysis of the structure-activity relationships of okaramines collected from the fungal cultures revealed that 1,4-dihydroazocine and N-aliphatic group attached to the indole were crucial for GluCl-activating activity. This provided insights into further derivatization of the complex structure of okaramines in order to facilitate the development of new insecticides. PMID- 29384651 TI - Advanced Glycation End Products Modulate Amyloidogenic APP Processing and Tau Phosphorylation: A Mechanistic Link between Glycation and the Development of Alzheimer's Disease. AB - Advanced glycation end products (AGEs) are implicated in the pathology of Alzheimer's disease (AD), as they induce neurodegeneration following interaction with the receptor for AGE (RAGE). This study aimed to establish a mechanistic link between AGE-RAGE signaling and AD pathology. AGE-induced changes in the neuro2a proteome were monitored by SWATH-MS. Western blotting and cell-based reporter assays were used to investigate AGE-RAGE regulated APP processing and tau phosphorylation in primary cortical neurons. Selected protein expression was validated in brain samples affected by AD. The AGE-RAGE axis altered proteome included increased expression of cathepsin B and asparagine endopeptidase (AEP), which mediated an increase in Abeta1-42 formation and tau phosphorylation, respectively. Elevated cathepsin B, AEP, RAGE, and pTau levels were found in human AD brain, coincident with enhanced AGEs. This study demonstrates that the AGE-RAGE axis regulates Abeta1-42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology. PMID- 29384652 TI - Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Mild Hyperthermia-Induced Bubble-Enhanced Oxygen-Sensitized Radiotherapy. AB - Alleviation of tumor hypoxia has been the premise for improving the effectiveness of radiotherapy, which hinges upon the advanced delivery and rapid release of oxygen within the tumor region. Herein, we propose a "bubble-enhanced oxygen diffusion" strategy to achieve whole tumor oxygenation for significant radiation enhancement based on the "bystander effect". Toward this end, sub-50 nm CuS modified and 64Cu-labeled hollow mesoporous organosilica nanoparticles were constructed for tumor-specific delivery of O2-saturated perfluoropentane (PFP). Through the aid of PFP gasification arising from NIR laser-triggered mild hyperthermia, simultaneous PET/PA/US multimodality imaging and rapid oxygen diffusion across the tumor can be achieved for remarkable hypoxic radiosensitization. Furthermore, the multifunctional oxygen-carrying nanotheranostics also allow for other oxygen-dependent treatments, thus greatly advancing the development of bubble-enhanced synergistic therapy platforms. PMID- 29384653 TI - Surface and Electrochemical Studies on Silicon Diphosphide as Easy-to-Handle Anode Material for Lithium-Based Batteries-the Phosphorus Path. AB - The electrochemical characteristics of silicon diphosphide (SiP2) as a new anode material for future lithium-ion batteries (LIBs) are evaluated. The high theoretical capacity of about 3900 mA h g-1 (fully lithiated state: Li15Si4 + Li3P) renders silicon diphosphide as a highly promising candidate to replace graphite (372 mA h g-1) as the standard anode to significantly increase the specific energy density of LIBs. The proposed mechanism of SiP2 is divided into a conversion reaction of phosphorus species, followed by an alloying reaction forming lithium silicide phases. In this study, we focus on the conversion mechanism during cycling and report on the phase transitions of SiP2 during lithiation and delithiation. By using ex situ analysis techniques such as X-ray powder diffraction, formed reaction products are identified. Magic angle spinning nuclear magnetic resonance spectroscopy is applied for the characterization of long-range ordered compounds, whereas X-ray photoelectron spectroscopy gives information of the surface-layer species at the interface of active material and electrolyte. Our SiP2 anode material shows a high initial capacity of about 2700 mA h g-1, whereas a fast capacity fading during the first few cycles occurs which is not necessarily expected. On the basis of our results, we conclude that besides other degradation effects, such as electrolyte decomposition and electrical contact loss, the rapid capacity fading originates from the formation of a low ion-conductive layer of LiP. This insulating layer hinders lithium-ion diffusion during lithiation and thereby mainly contributes to fast capacity fading. PMID- 29384654 TI - Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's Disease: Current Progress and Future Perspectives. AB - Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopaminergic neurons of the substantia nigra as well as degeneration of motor and nonmotor basal ganglia circuitries. Typically known for classical motor deficits (tremor, rigidity, bradykinesia), early stages of the disease are associated with a large nonmotor component (depression, anxiety, apathy, etc.). Currently, there are no definitive biomarkers of PD, and the measurement of dopamine metabolites does not allow for detection of prodromal PD nor does it aid in long-term monitoring of disease progression. Given that PD is increasingly recognized as complex and heterogeneous, involving several neurotransmitters and proteins, it is of importance that we advance interdisciplinary studies to further our knowledge of the molecular and cellular pathways that are affected in PD. This approach will possibly yield useful biomarkers for early diagnosis and may assist in the development of disease-modifying therapies. Here, we discuss preanalytical factors associated with metabolomics studies, summarize current mass spectrometric methodologies used to evaluate the metabolic signature of PD, and provide future perspectives of the rapidly developing field of MS in the context of PD. PMID- 29384655 TI - Phasing Gene Expression: mRNA N6-Methyladenosine Regulates Temporal Progression of Mammalian Cortical Neurogenesis. PMID- 29384656 TI - Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 MUM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy. PMID- 29384657 TI - Directed Evolution of Alcohol Dehydrogenase for Improved Stereoselective Redox Transformations of 1-Phenylethane-1,2-diol and Its Corresponding Acyloin. AB - Laboratory evolution of alcohol dehydrogenase produced enzyme variants with improved turnover numbers with a vicinal 1,2-diol and its corresponding hydroxyketone. Crystal structure and transient kinetics analysis aids in rationalizing the new functions of these variants. PMID- 29384659 TI - A Raman-Based Imaging Method for Characterizing the Molecular Adsorption and Spatial Distribution of Silver Nanoparticles on Hydrated Mineral Surfaces. AB - Although minerals are known to affect the environmental fate and transformation of heavy-metal ions, little is known about their interaction with the heavily exploited silver nanoparticles (AgNPs). Proposed here is a combination of hitherto under-utilized micro-Raman-based mapping and chemometric methods for imaging the distribution of AgNPs on various mineral surfaces and their molecular interaction mechanisms. The feasibility of the Raman-based imaging method was tested on two macro- and microsized mineral models, muscovite [KAl2(AlSi3O10)(OH)2] and corundum (alpha-Al2O3), under key environmental conditions (ionic strength and pH). Both AgNPs- and AgNPs+ were found to covalently attach to corundum (pHpzc = 9.1) through the formation of Ag-O-Al- bonds and thereby to potentially experience reduced environmental mobility. Because label-free Raman imaging showed no molecular interactions between AgNPs- and muscovite (pHpzc = 7.5), a label-enhanced Raman imaging approach was developed for mapping the scarce spatial distribution of AgNPs- on such mineral surfaces. Raman maps comprising of n = 625-961 spectra for each sample/control were rapidly analyzed in Vespucci, a free open-source software, and the results were confirmed via ICP-OES, AFM, and SEM-EDX. The proposed Raman-based imaging requires minimum to no sample preparation; is sensitive, noninvasive, cost effective; and might be extended to other environmentally relevant systems. PMID- 29384658 TI - Photoactivatable Sensors for Detecting Mobile Zinc. AB - Fluorescent sensors for mobile zinc are valuable for studying complex biological systems. Because these sensors typically bind zinc rapidly and tightly, there has been little temporal control over the activity of the probe after its application to a sample. The ability to control the activity of a zinc sensor in vivo during imaging experiments would greatly improve the time resolution of the measurement. Here, we describe photoactivatable zinc sensors that can be triggered with short pulses of UV light. These probes are prepared by functionalizing a zinc sensor with protecting groups that render the probe insensitive to metal ions. Photoinduced removal of the protecting groups restores the binding site, allowing for zinc-responsive changes in fluorescence that can be observed in live cells and tissues. PMID- 29384660 TI - H2MBH2 and M(MU-H)2BH2 Molecules Isolated in Solid Argon: Interelement M-B and M H-B Bonds (M = Ge, Sn). AB - Laser-ablated boron atoms react with GeH4 molecules to form novel germylidene borane H2GeBH2, which undergoes a photochemical rearrangement to the germanium tetrahydroborate Ge(MU-H)2BH2 upon irradiation with light of lambda = 405 nm. For comparison, the boron atom reactions with SnH4 only gave the tin tetrahydroborate Sn(MU-H)2BH2. Infrared matrix-isolation spectroscopy with deuterium substitution and the state-of-the-art quantum-chemical calculations are used to identify these species in solid argon. A planar structure of H2GeBH2 with an electron-deficient B-Ge bond with a partial multiple bond character (bond order = 1.5) is predicted by quantum-chemical calculations. In the case of M(MU-H)2BH2 (M = Ge, Sn) two 3c 2e B-H-M hydrogen bridged bonds are formed by donation of electrons from the B-H sigma-bonds into empty p-orbitals of M. PMID- 29384662 TI - A Triple Functional Approach To Simultaneously Determine the Type, Concentration, and Size of Titanium Dioxide Particles. AB - The large-scale manufacturing and use of titanium dioxide (TiO2) particles in food and consumer products significantly increase the likelihood of human exposure and release into the environment. We present a simple and innovative approach to rapidly identify the type (anatase or rutile), as well as to estimate, the size and concentration of TiO2 particles using Raman spectroscopy and surface-enhanced Raman spectroscopy (SERS). The identification and discrimination of rutile and anatase were based on their intrinsic Raman signatures. The concentration of the TiO2 particles was determined based on Raman peak intensity. Particle sizes were estimated based on the ratio between the Raman intensity of TiO2 and the SERS intensity of myricetin bound to the nanoparticles (NPs), which was proven to be independent of TiO2 nanoparticle concentrations. The ratio that was calculated from the 100 nm particles was used as a cutoff value when estimating the presence of nanosized particles within a mixture. We also demonstrated the practical use of this approach when determining the type, concentration, and size of E171: a mixture that contains TiO2 particles of various sizes which are commonly used in many food products as food additives. The presence of TiO2 anatase NPs in E171 was confirmed using the developed approach and was validated by transmission electron micrographs. TiO2 presence in pond water was also demonstrated to be an analytical capability of this method. Our approach shows great promise for the rapid screening of nanosized rutile and anatase TiO2 particles in complex matrixes. This approach will strongly improve the measurement of TiO2 quality during production, as well as the survey capacity and risk assessment of TiO2 NPs in food, consumer goods, and environmental samples. PMID- 29384661 TI - Charged Metallopolymer-Grafted Silica Nanoparticles for Antimicrobial Applications. AB - Inappropriate and frequent use of antibiotics has led to the development of antibiotic-resistant bacteria, which cause infectious diseases that are difficult to treat. With the rising threat of antibiotic resistance, the need to develop effective new antimicrobial agents is prominent. We report antimicrobial metallopolymer nanoparticles, which were prepared by surface-initiated reversible addition-fragmentation chain transfer polymerization of a cobaltocenium containing methacrylate monomer from silica nanoparticles. These particles are capable of forming a complex with beta-lactam antibiotics, such as penicillin, rejuvenating the bactericidal activity of the antibiotic. Disk diffusion assays showed significantly increased antibacterial activities against both Gram positive and Gram-negative bacteria. The improved efficiencies were attributed to the inhibition of hydrolysis of the beta-lactam antibiotics and enhancement of local antibiotics concentration on a nanoparticle surface. In addition, hemolysis evaluations demonstrated minimal toxicity to red blood cells. PMID- 29384663 TI - Electronic Structure and Spin Multiplicity of Iron Tetraphenylporphyrins in Their Reduced States as Determined by a Combination of Resonance Raman Spectroscopy and Quantum Chemistry. AB - Iron tetraphenylporphyrins are prime candidates as catalysts for CO2 reduction. Yet, even after 40 years of research, fundamental questions about the electronic structure of their reduced states remain, in particular as to whether the reducing equivalents are stored at the iron center or at the porphyrin ligand. In this contribution, we address this question by a combination of resonance Raman spectroscopy and quantum chemistry. Analysis of the data allows for an unequivocal identification of the porphyrin as the redox active moiety. Additionally, determination of the spin state of iron is possible by comparing the characteristic shifts of spin and oxidation-state-sensitive marker bands in the Raman spectrum with calculations of planar porphyrin model structures. PMID- 29384664 TI - Catalytic Silylation of N2 and Synthesis of NH3 and N2H4 by Net Hydrogen Atom Transfer Reactions Using a Chromium P4 Macrocycle. AB - We report the first discrete molecular Cr-based catalysts for the reduction of N2. This study is focused on the reactivity of the Cr-N2 complex, trans [Cr(N2)2(PPh4NBn4)] (P4Cr(N2)2), bearing a 16-membered tetraphosphine macrocycle. The architecture of the [16]-PPh4NBn4 ligand is critical to preserve the structural integrity of the catalyst. P4Cr(N2)2 was found to mediate the reduction of N2 at room temperature and 1 atm pressure by three complementary reaction pathways: (1) Cr-catalyzed reduction of N2 to N(SiMe3)3 by Na and Me3SiCl, affording up to 34 equiv N(SiMe3)3; (2) stoichiometric reduction of N2 by protons and electrons (for example, the reaction of cobaltocene and collidinium triflate at room temperature afforded 1.9 equiv of NH3, or at -78 degrees C afforded a mixture of NH3 and N2H4); and (3) the first example of NH3 formation from the reaction of a terminally bound N2 ligand with a traditional H atom source, TEMPOH (2,2,6,6-tetramethylpiperidine-1-ol). We found that trans [Cr(15N2)2(PPh4NBn4)] reacts with excess TEMPOH to afford 1.4 equiv of 15NH3. Isotopic labeling studies using TEMPOD afforded ND3 as the product of N2 reduction, confirming that the H atoms are provided by TEMPOH. PMID- 29384665 TI - Broad-Spectrum Antibacterial Activity of Proteolytically Stable Self-Assembled alphagamma-Hybrid Peptide Gels. AB - Bacterial infections pose a serious threat to mankind, and there is immense interest in the design and development of self-assembled peptide gels using ultrashort peptides for antibacterial applications. The peptide gels containing natural amino acids suffer from poor stability against proteolytic enzymes. Therefore, there is a need to design and develop peptide gels with improved stability against proteolytic enzymes. In the present work, we report the synthesis and characterization of alpha/gamma hybrid peptides Boc-D-Phe-gamma4-L Phe-PEA (NH007) and Boc-L-Phe-gamma4-L-Phe-PEA (NH009) to improve the proteolytic stability. Both of the dipeptides were found to self-assemble into gels in aqueous DMSO (3-5% w/v), and the self-assembly process was studied using FTIR and CD, which indicated antiparallel beta-sheet formation with random coils in NH007 gels and random or unordered conformation in NH009. The rheological studies indicated viscoelastic characteristics for both gels; the storage modulus ( G') for NH007 and NH009 gels (3% w/v) was estimated as 0.2 and 0.5 MPa, higher than the loss modulus ( G''). Also, both gels demonstrated self-healing characteristics for six consecutive cycles when subjected to varying strains of 0.1 and 30% (200 s each). The peptide gels were incubated with a mocktail of proteolytic enzymes, proteinase K, pepsin, and chymotrypsin, and stability was monitored using RP HPLC. Up to 23 and 40% degradation was observed for NH007 (3%, w/v) in 24 and 36 h, and 77 and 94% degradation was observed for NH009 (3%, w/v), within the same period. Thus alpha/gamma hybrid peptide gels containing D-Phe exhibited higher stability than gels fabricated using L-Phe. The use of D-residue in alpha/gamma hybrid peptide significantly enhanced the stability of peptides against proteolytic enzymes, as the stability data reported in this work are possibly the best in class. Both peptide gels exhibited broad-spectrum antibacterial activity against Gram-negative and Gram-positive bacteria, such as Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. The Pseudomonas aeruginosa and Staphylococcus aureus, in particular, are known to develop resistance. The NH007 (3%, w/v) demonstrated 65% inhibition, whereas NH009 (3%, w/v) showed 78% inhibition, with potent activity against Pseudomonas aeruginosa. Mechanistic studies, using SEM, HR-TEM, and bacterial live-dead assay, indicated entrapment of bacteria in gel networks, followed by interaction with cell membrane components and lysis. Cell viability (MTT assay) and toxicity (LDH assay) studies showed that both gels are not toxic to NIH 3T3 mouse embryonic fibroblast cells (mammalian). MTT assay showed >85% cell viability, and LDH assay exhibited not more than 15% cytotoxicity, even at higher concentrations (5%, w/v) and prolonged exposures (48 h). Overall, studies indicate the potential application of gels developed from the alpha/gamma hybrid peptides in preventing biomaterial-related infections. PMID- 29384666 TI - Unraveling Tetrazine-Triggered Bioorthogonal Elimination Enables Chemical Tools for Ultrafast Release and Universal Cleavage. AB - Recent developments in bond cleavage reactions have expanded the scope of bioorthogonal chemistry beyond click ligation and enabled new strategies for probe activation and therapeutic delivery. These applications, however, remain in their infancy, with further innovations needed to achieve the efficiency required for versatile and broadly useful tools in vivo. Among these chemistries, the tetrazine/ trans-cyclooctene click-to-release reaction has exemplary kinetics and adaptability but achieves only partial release and is incompletely understood, which has limited its application. Investigating the mechanistic features of this reaction's performance, we discovered profound pH sensitivity, exploited it with acid-functionalized tetrazines that both enhance and markedly accelerate release, and ultimately uncovered an unexpected dead-end isomer as the reason for poor release. Implementing facile methods to prevent formation of this dead end, we have achieved exceptional efficiency, with essentially complete release across the full scope of physiologic pH, potentiating drug-delivery strategies and expanding the dynamic range of bioorthogonal on/off control. PMID- 29384668 TI - Dual Nicotinic Acetylcholine Receptor alpha4beta2 Antagonists/alpha7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts. AB - We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were alpha4beta2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent alpha4beta2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the alpha4beta4 and alpha3beta4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at alpha4beta2, (R)-6c was a slightly more potent alpha4beta2 antagonist than the reference beta2-nAChR antagonist DHbetaEpsilon. The observation that the alpha4beta2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the alpha7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of alpha4beta2 nAChR antagonists for this indication. PMID- 29384667 TI - Effects of Simulated Smog Atmospheres in Rodent Models of Metabolic and Immunologic Dysfunction. AB - Air pollution is a diverse and dynamic mixture of gaseous and particulate matter, limiting our understanding of associated adverse health outcomes. The biological effects of two simulated smog atmospheres (SA) with different compositions but similar air quality health indexes were compared in a nonobese diabetic rat model (Goto-Kakizaki, GK) and three mouse immune models (house dust mite (HDM) allergy, antibody response to heat-killed pneumococcus, and resistance to influenza A infection). In GK rats, both SA-PM (high particulate matter) and SA-O3 (high ozone) decreased cholesterol levels immediately after a 4-h exposure, whereas only SA-O3 increased airflow limitation. Airway responsiveness to methacholine was increased in HDM-allergic mice compared with nonallergic mice, but exposure to SA-PM or SA-O3 did not significantly alter responsiveness. Exposure to SA-PM did not affect the IgM response to pneumococcus, and SA-O3 did not affect virus titers, although inflammatory cytokine levels were decreased in mice infected at the end of a 7-day exposure. Collectively, acute SA exposures produced limited health effects in animal models of metabolic and immune diseases. Effects of SA O3 tended to be greater than those of SA-PM, suggesting that gas-phase components in photochemically derived multipollutant mixtures may be of greater concern than secondary organic aerosol PM. PMID- 29384669 TI - Discovery of Glycosylated Genipin Derivatives as Novel Antiviral, Insecticidal, and Fungicidal Agents. AB - A series of novel genipin glycoside derivatives incorporating 11 glycosidic moieties at either the 1 or 10 position of genipin were designed and synthesized. These compounds exhibited moderate to excellent inhibitory activities against tobacco mosaic virus. Especially, the in vitro and in vivo activities of compounds 6e, 7c, 7d, 7f, 7h, and 7i were comparable to that of ribavirin. In particular, compound 7c, the mannosyl derivative of genipin at the 10 position, showed the best activity. The series of genipin glycosyl derivatives also displayed fungicidal activities against 14 kinds of phytopathogenic fungi, especially for Rhizoctonia cerealis and Sclerotinia sclerotiorum. Moreover, compound 6h exhibited good insecticidal activity against diamondback moth; compounds 7b, 7c, and 7g exhibited moderate insecticidal activity against three kinds of Lepidoptera pests (oriental armyworm, cotton bollworm, and corn borer); and compound 7e showed excellent larvacidal activities against mosquito. PMID- 29384670 TI - A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols. AB - A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products. PMID- 29384671 TI - Theoretical Investigation of the Reactivity of Sodium Dicyanamide with Nitric Acid. AB - There is a need to replace current hydrazine fuels with safer propellants, and dicyanamide (DCA-)-based systems have emerged as promising alternatives because they autoignite when mixed with some oxidizers. Previous studies of the hypergolic reaction mechanism have focused on the reaction between DCA- and the oxidizer HNO3; here, we compare the calculated pathway of DCA- + HNO3 with the reaction coordinate of the ion pair sodium dicyanamide with nitric acid, Na[DCA] + HNO3. Enthalpies and free energies are calculated in the gas phase and in solution using a quantum mechanical continuum solvation model, SMD-GIL. The barriers to the Na[DCA] + HNO3 reaction are dramatically lowered relative to those of the reaction with the bare anion, and an exothermic exit channel to produce NaNO3 and the reactive intermediate HDCA appears. These results suggest that Na[DCA] may accelerate the ignition reaction. PMID- 29384672 TI - Nickel-Catalyzed C(sp3)-H Arylation of Diarylmethane Derivatives with Aryl Fluorides. AB - A novel nickel-catalyzed C(sp3)-H arylation with nonactivated aryl fluorides is reported. The use of 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) as a ligand was found to be critical to the success of the reaction. This new method enables the synthesis of a wide range of triarylmethane derivatives. PMID- 29384673 TI - Charge-Displacement Analysis via Natural Orbitals for Chemical Valence in the Four-Component Relativistic Framework. AB - We have recently introduced a simple yet powerful tool for analyzing quantitatively the coordination bond in terms of the donation and back-donation constituents of the Dewar-Chatt-Duncanson model. Our approach is based on the decomposition, via natural orbitals for chemical valence (NOCV), of the so-called charge-displacement (CD) function into additive chemically meaningful components (Bistoni et al. J. Chem. Phys. 2015, 142, 084112 ). The method, referred to as NOCV/CD, provides clear-cut measures of donation and back-donation charge flows following bond formation, and its robustness has been demonstrated by a tight correlation of the related charge-transfer estimates with experimental observables. In this paper we extend the NOCV/CD analysis scheme to the four component relativistic framework, which includes spin-orbit coupling variationally. This formalism is incorporated into a recently developed, highly efficient parallel version of the relativistic Dirac-Kohn-Sham (DKS) program BERTHA (Rampino et al. J. Chem. Theory Comput. 2014, 10, 3766-3776 ). We test the accuracy and numerical stability of this new implementation through the analysis of the convergence properties of the basis sets employed to expand the DKS spinor solution and those used to linearize the electronic density in the density fitting algorithm speeding up the evaluation of the DKS matrix. An illustration of NOCV/CD analysis in the relativistic framework is also given through a study of the metal-carbonyl coordination bond in a series of [M-CO]+ (M = Cu, Ag, Au) complexes of group 11 metals, where relativistic effects, including spin-orbit coupling, are found to play an important role. PMID- 29384674 TI - Alkali Metal Ion Partitioning with Calix[4]arene-benzo-crown-6 Ionophore in Acidic Medium: Insights from Experiments, Statistical Mechanical Framework, and Molecular Dynamics Simulations. AB - The current work reports the experimental and predicted interfacial behavior of metal ion extraction from aqueous phase-diluent system using a newly synthesized calix-benzo-crown-6 (CBCBGA) ionophore. Conductor-like screening model for real solvents was used to predict the selectivity at infinite dilution for the metal ion complexes in both aqueous and diluent phases. The selectivity for Cs+-CBCBGA extraction was found to be higher than that of other metal ions, namely, K+, Na+, and Rb+. This was confirmed by the experimental distribution coefficients obtained in the diluents system at 3 M HNO3 along with 0.01 M CBCBGA/organic solvents. The high selectivity of Cs+-CBCBGA complex over other complexes (K+, Rb+, and Na+) in nitrobenzene was also confirmed and validated by the highest occupied molecular orbital-lowest unoccupied molecular orbital energy gap (i.e., 0.13114 > 0.12411 > 0.11719 > 0.11561 eV) and interaction energy (i.e., -68.25 > 57.11 > -55.52 > -52.37 kcal/mol). The interaction and free energies of the extraction were found to increase with the dielectric constant of the organic solvents, namely, nitrobenzene > o-nitrophenyl hexyl ether > 1-octanol > chloroform. Overall, a higher selectivity of Cs+ ion over that of other metal ions (K+, Na+, and Rb+) was obtained for the newly synthesized CBCBGA ionophore in a radioactive waste solution. PMID- 29384675 TI - Computational Study of the Isomerization Reactions of Borirane. AB - Borirane is isoelectronic to the cyclopropyl cation, but is stable toward electrocyclic ring opening to 2-bora-propa-1,3-diyl A, the boron analogue of the allyl cation. A computational investigation using density functional theory (B3LYP) in combination with highly correlated electronic structure theory methods of the coupled-cluster [CCSD(T)] and multireference configuration interaction (MRCI) type in conjunction with basis sets of up to quadruple-zeta quality reveal that formation of A is endothermic by roughly 15 kcal mol-1 and that A collapses almost without barrier (0.2 kcal mol-1) to borirane. The vinylborane isomer B is more stable than borirane and its formation is associated with a barrier of 36-38 kcal mol-1. Methyl methylideneborane E, only slightly less stable than B, can only be accessed by pathways involving barriers of at least 60 kcal mol-1. PMID- 29384676 TI - Electronic Structure of Biotin Conformers Studied with SAC-CI and OVGF Methods. AB - In this work, the study was performed with 37 gas-phase conformers of biotin and two biologically active conformers of biotin in the ligand-receptor complexes with astavidin and streptavidin. The ionization energies and photoelectron spectra of conformers were calculated by two methods: the general-R symmetry adapted cluster-configuration interaction (general-R-SAC-CI) method and the outer valence Green's function (OVGF) method. The photoelectron spectrum of each conformer was calculated using basis set D95 (df,pd) for both methods. The simulated photoelectron spectra of free molecules and bioactive conformers calculated by the two methods were compared. Natural bonding orbital (NBO) calculations were also performed for the assignment of ionization bands of each conformer. NBO calculation indicated that the first to five ionization bands correspond to ionizations from orbitals localized in the two rings. The most important point about the ionization of all conformers is that the removal of an electron from the sigma-bonding orbital (C-S) takes place above 10.0 eV. PMID- 29384677 TI - Base-Controlled Regiodivergent Azidation of Trifluoromethyl Alkenyl Triflates: Transition-Metal-Free Access to CF3-Containing Allyl Azides and Alkenyl Azides. AB - A base-controlled regiodivergent azidation of trifluoromethyl alkenyl triflates providing either (E)-3-azido-1-aryl-4,4,4-trifluorobut-1-ene (CF3-containing allyl azides) or (Z)-1-azido-1-aryl-4,4,4-trifluorobut-1-ene (CF3-containing alkenyl azides) is described. Catalyzed by Et3N, the azidation of trifluoromethyl alkenyl triflates with TMSN3 gave CF3-containing allyl azides. On the other hand, using stoichiometric DBU, the regioisomeric azidation products, CF3-containing alkenyl azides, were obtained in good yield. A further transformation for CF3 containing amines, triazoles, and azirines highlights the practical applicability of this transition-metal-free protocol. PMID- 29384678 TI - Synthesis and Properties of Subphthalocyanine-Tetracyanobutadiene-Ferrocene Triads. AB - A series of boron subphthalocyanine-tetracyanobutadiene-ferrocene (SubPc-TCBD-Fc) triads was synthesized by subjecting SubPcs with a ferrocenylethynyl substituent at either the axial or peripheral position to a [2 + 2] cycloaddition reaction with tetracyanoethylene followed by retroelectrocyclization. The ferrocenylethynyl unit was introduced at the axial position (at the boron atom) by a simple aluminum chloride-mediated alkynylation reaction, while functionalization at the SubPc periphery was accomplished by a Sonogashira coupling reaction. The conversion of one alkyne unit into a TCBD unit in combination with the location of the resulting TCBD-Fc moiety was found to have a strong influence on the optical and redox properties, which is ascribed to very different ground-state interactions between the individual donor/acceptor systems. The first electrochemical oxidation could thus be anodically shifted by as much as 0.4 V from the strongest donor molecule (with most unperturbed ferrocene character) to the poorest donor molecule (with strongly perturbed ferrocene character). Six redox states could be reached reversibly for the SubPc TCBD-Fc triads, -3, -2, -1, 0, + 1, + 2, and for one compound the formation of a tetraanion persistent at the time scale of slow scan voltammetry was observed. PMID- 29384679 TI - Multicolor Liposome Mixtures for Selective and Selectable Cargo Release. AB - Many approaches exist for stimuli-triggered cargo release from nanocarriers, but few can provide for on-demand release of multiple payloads, selectively. Here, we report the synthesis of purpurin-phospholipid (Pur-P), a lipid chromophore that has near-infrared absorbance red-shifted by 30 nm compared to a structurally similar pyropheophorbide-phospholipid (Pyr-P). Liposomes containing small amounts of either Pur-P or Pyr-P exhibited similar physical properties and fluorescence self-quenching. Loaded with distinct cargos, Pur-P and Pyr-P liposomes were mixed into a single colloidal suspension and selectively released cargo depending on irradiation wavelength. Spatiotemporal control of distinct cargo release was achieved by controlling multicolor laser placement. Using basic orange and doxorubicin anthraquinones, multidimensional cytotoxicity gradients were established to gauge efficacy against cancer cells using light-released drug. Wavelength selectivity of cargo release was maintained following intramuscular administration to mice. PMID- 29384680 TI - A Comparison of Common Mass Spectrometry Approaches for Paleoproteomics. AB - The last two decades have seen a broad diversity of methods used to identify and/or characterize proteins in the archeological and paleontological record. Of these, mass spectrometry has opened an unprecedented window into the proteomes of the past, providing protein sequence data from long extinct animals as well as historical and prehistorical artifacts. Thus, application of mass spectrometry to fossil remains has become an attractive source for ancient molecular sequences with which to conduct evolutionary studies, particularly in specimens older than the proposed limit of amplifiable DNA detection. However, "mass spectrometry" covers a range of mass-based proteomic approaches, each of which utilize different technology and physical principles to generate unique types of data, with their own strengths and challenges. Here, we discuss a variety of mass spectrometry techniques that have or may be used to detect and characterize archeological and paleontological proteins, with a particular focus on MALDI-MS, LC-MS/MS, TOF-SIMS, and MSi. The main differences in their functionality, the types of data they produce, and the potential effects of diagenesis on their results are considered. PMID- 29384682 TI - Determination of Fragility in Organic Small Molecular Glass Forming Liquids: Comparison of Calorimetric and Spectroscopic Data and Commentary on Pharmaceutical Importance. AB - The fragility index ( m) and conversely the strength parameter ( D) are widely used to categorize glass forming liquids and are used to characterize temperature dependency of viscosity and relaxation time as the supercooled liquid approaches glass transition. The currently used calorimetric methods in pharmaceutical literature lead to wide variability in measured values of m. In this work, a modulated differential scanning calorimetry (DSC) method is introduced that can directly determine m with minimal variability. Although calorimetric fragility is easy to measure due to availability and ease of use of DSC, there is no correlation between calorimetric and dielectric fragility (calculated spectroscopically from relaxation times). In addition, there is also no correlation between calorimetric fragility and the so-called "thermodynamic fragility" that can be calculated using only thermodynamic parameters. No relationship can be found between the crystallization propensity in the supercooled liquid state and D. However, the crystallization propensity shows a reasonable correlation with the Kohlrausch distribution parameter betak, which defines the breadth of the relaxation time distribution. PMID- 29384683 TI - Surface Adsorption of Suwannee River Humic Acid on TiO2 Nanoparticles: A Study of pH and Particle Size. AB - TiO2 nanoparticles are some of the most widely used metal oxide nanomaterials mainly because of their diverse industrial applications. Increasing usage of these nanoparticles raises concerns about the potential adverse effects on the environment. Humic acid is a ubiquitous component of the natural organic matter in the environment that is known to get adsorbed onto nanoparticle surfaces. In this study, adsorption of humic acid on TiO2 nanoparticles of two different sizes (5 and 22 nm) is studied at different environmentally relevant pH values using attenuated total reflectance Fourier transformation infrared spectroscopy. These vibrational spectra provide insights into the nature of the adsorption process (extent of adsorption and reversibility) as a function of pH as well as information about the bonding to the surface. Additionally, the impact of humic acid adsorption on surface charge and agglomeration has been investigated. Interestingly, the results show that the humic acid adsorption is strongly pH dependent and that adsorption of humic acid on TiO2 nanoparticles alters the extent of agglomeration and modifies the zeta potential and surface charges depending on the pH, thus potentially increasing the bioavailability of TiO2 nanoparticles in the environment. PMID- 29384681 TI - Peptide Solubility Limits: Backbone and Side-Chain Interactions. AB - We calculate the solubility limit of pentapeptides in water by simulating the phase separation in an oversaturated aqueous solution. The solubility limit order followed by our model peptides (GGRGG > GGDGG > GGGGG > GGVGG > GGQGG > GGNGG > GGFGG) is found to be the same as that reported for amino acid monomers from experiment (R > D > G > V > Q > N > F). Investigation of dynamical properties of peptides shows that the higher the solubility of a peptide is, the lower the time spent by the peptide in the aggregated cluster is. We also demonstrate that fluctuations in conformation and hydration number of peptide in monomeric form are correlated with the solubility of the peptide. We considered energetic mechanisms and dynamical properties of interbackbone CO-CO and CO...HN interactions. Our results confirm that CO-CO interactions more than the interbackbone H-bonds are important in peptide self-assembly and association. Further, we find that the stability of H-bonded peptide pairs arises mainly from coexisting CO-CO and CO...HN interactions. PMID- 29384684 TI - Oscillating Emission of [2]Rotaxane Driven by Chemical Fuel. AB - A molecular shuttle consisting of a dibenzo-24-crown-8 macrocycle and an axle with two degenerate peripheral triazolium stations, a central dibenzyl ammonium station, and two anthracenes stoppers was exposed to 2-cyano-2-phenylpropanoic acid as a chemical fuel. Protonation/deprotonation of the amine reversibly switches the rotaxane from a static and little emissive to a dynamic fluorescent shuttling device, the latter exhibiting rapid motion (15 kHz at 25 degrees C). Four fuel cycles were run. PMID- 29384685 TI - Enamines as Surrogates of Alkene Carbanions for the Reductive Alkenylation of Secondary Amides: An Approach to Allylamines. AB - A new strategy to construct allylamines through reductive alkenylation of secondary amides with enamines is reported. The method features the use of trifluoromethanesulfonic anhydride as an activation reagent of amides, and enamines as unconventional alkenylation reagents. In this manner, enamines serve as surrogates of alkene carbanions instead of the classical enolates equivalents. A possible mechanism involving a Hoffmann-like elimination of the amine-borane complex intermediate is proposed. PMID- 29384686 TI - Direct Difluorination-Hydroxylation, Trifluorination, and C(sp2)-H Fluorination of Enamides. AB - A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With the appropriate combination of an electrophilic fluorinating reagent and H2O, the most convenient and ecofriendly hydroxylating agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Bronsted acidic conditions. Suitable conditions for trifluorination as well as C(sp2)-H fluorination were also identified. Subsequent asymmetric functionalization of the obtained gem-difluorinated products has also been demonstrated. PMID- 29384687 TI - Synthesis of Dibenzothiophene and 1,4-Dihydrodibenzothiophene Derivatives via Allylic Phosphonium Salt Initiated Domino Reactions. AB - Two efficient synthetic protocols were developed for the synthesis of dibenzothiophene and 1,4-dihydrodibenzothiophene using thioaurones and allylic phosphonium salt. Mild reaction conditions, a one-pot procedure, and easily accessible starting materials make these protocols powerful tools for the synthesis of these compounds, which are often used in material and pharmaceutical sciences. PMID- 29384688 TI - Cobalt-Catalyzed Remote C-4 Functionalization of 8-Aminoquinoline Amides with Ethers via C-H Activation under Visible-Light Irradiation. Access to alpha Heteroarylated Ether Derivatives. AB - A cobalt-catalyzed selective remote C-4 alkylation of 8-aminoquinoline amides via C-H activation under irradiation with a CFL lamp in the presence of eosin Y at room temperature has been achieved. A series of pharmaceutically important C-4 quinoline amide-substituted ether derivatives has been obtained by this procedure. The C-4 functionalization of quinoline amides with inert ether is of much significance and was not reported earlier. PMID- 29384689 TI - Further Need for Evidence in Long-Term Oxygen Therapy. PMID- 29384690 TI - Augmented Reality Technology Using Microsoft HoloLens in Anatomic Pathology. AB - Context Augmented reality (AR) devices such as the Microsoft HoloLens have not been well used in the medical field. Objective To test the HoloLens for clinical and nonclinical applications in pathology. Design A Microsoft HoloLens was tested for virtual annotation during autopsy, viewing 3D gross and microscopic pathology specimens, navigating whole slide images, telepathology, as well as real-time pathology-radiology correlation. Results Pathology residents performing an autopsy wearing the HoloLens were remotely instructed with real-time diagrams, annotations, and voice instruction. 3D-scanned gross pathology specimens could be viewed as holograms and easily manipulated. Telepathology was supported during gross examination and at the time of intraoperative consultation, allowing users to remotely access a pathologist for guidance and to virtually annotate areas of interest on specimens in real-time. The HoloLens permitted radiographs to be coregistered on gross specimens and thereby enhanced locating important pathologic findings. The HoloLens also allowed easy viewing and navigation of whole slide images, using an AR workstation, including multiple coregistered tissue sections facilitating volumetric pathology evaluation. Conclusions The HoloLens is a novel AR tool with multiple clinical and nonclinical applications in pathology. The device was comfortable to wear, easy to use, provided sufficient computing power, and supported high-resolution imaging. It was useful for autopsy, gross and microscopic examination, and ideally suited for digital pathology. Unique applications include remote supervision and annotation, 3D image viewing and manipulation, telepathology in a mixed-reality environment, and real-time pathology-radiology correlation. PMID- 29384691 TI - Utility of Alternate, Noncentromeric Chromosome 17 Reference Probe for Human Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization Testing in Breast Cancer Cases. AB - Context PathVysion-a US Food and Drug Administration-approved dual-probe human epidermal growth factor receptor ( HER2) fluorescence in situ hybridization (FISH) assay-provides the HER2: CEP17 ratio, a centromeric enumeration probe ratio for determining HER2 status in breast cancers. However, pericentromeric amplifications might then skew the HER2: CEP17 ratio, underestimating the HER2 status, which calls into question the use of CEP17 as the reference probe. Objective To analyze the utility of a noncentromeric chromosome 17 reference locus ( D17S122) to assess HER2 gene status in cases showing "nonclassical" FISH patterns with the CEP17 probe. Design The HER2 status of breast cancers accessioned in the years 2015-2017, displaying "nonclassical" or "equivocal" results by the PathVysion (Abbott Molecular Inc, Des Plaines, Illinois) HER2 DNA Probe Kit were reflex tested using an alternate FISH probe (ZytoLight SPEC/D17S122, ZytoVision, Bremerhaven, Germany) and interpreted with American Society of Clinical Oncology/College of American Pathologists 2013 guidelines. Results Of 37 cases, 17 were FISH equivocal. With the alternate D17S122 probe, 13 (76.4%) were reclassified as amplified, 3 (17.6%) as nonamplified, and a single case retained an equivocal result. Of the 17 cases with a chromosome 17 polysomy pattern, disomy, polysomy, and monosomy patterns were seen with 14 cases, 2 cases, and 1 case, respectively. Within the 17 cases with polysomy pattern, 3 (17.6%) demonstrated an unusual colocalization pattern of HER2 and CEP17, which was not observed with the alternate probe. Conclusions The denominator-stable alternate probe is a useful adjunct in the diagnostic armamentarium to analyze HER2 status in cases with FISH equivocal and complex patterns. PMID- 29384692 TI - Reply: Further Need for Evidence in Long-Term Oxygen Therapy. PMID- 29384693 TI - Palmitate induces glycosylation of cyclooxygenase-2 in primary human vascular smooth muscle cells. AB - Vascular basal cyclooxygenase-2 (COX-2) expression and activity can be induced by endotoxin, hypoxia, or ischemia. During vascular pathologies such as atherosclerosis, increases in COX-2 activity result in prostanoid production, a contributor to the development and progression of vascular inflammation leading to unstable atherosclerotic plaques and increased risk for thrombotic events. Recent studies demonstrate that select free fatty acids, such as palmitate, can act as proinflammatory mediators. However, the effect of palmitate on COX-2 expression and activity, and its impact on the development and progression of vascular inflammation, are not well elucidated. We investigated the effect of palmitate on COX-2 expression and function in human vascular smooth muscle cells. Cells were treated with palmitate, COX-2 protein levels were assessed using Western analysis, and activity was assessed via ELISA. We observed that palmitate dose-dependently increased COX-2 levels and specifically enhanced band intensity of the COX-2 74 kDa band (slowest migrating band). This response was attenuated by N-linked glycosylation inhibition, suggesting that palmitate impacts expression of the fully activated glycoform of COX-2. Palmitate-induced increases in COX-2 levels correlated with an increase in prostaglandin E2 production that was also attenuated by a glycosylation inhibitor. Additionally, palmitate altered cell morphology and increased cell density which were reversed by selective COX-2 inhibition. Thus, we conclude that palmitate acts on COX-2 by two separate mechanisms of action in human vascular smooth muscle. It elicits dose-dependent increases in COX-2 protein expression and modulates regulation of COX-2 activity via modification of posttranslational glycosylation. PMID- 29384694 TI - Ectopic expression of aquaporin-5 in noncancerous epithelial MDCK cells changes cellular morphology and actin fiber formation without inducing epithelial-to mesenchymal transition. AB - Aquaporin-5 (AQP5) is a plasma membrane water channel mainly expressed in secretory glands. Increased expression of AQP5 is observed in multiple cancers, including breast cancer, where high expression correlates with the degree of metastasis and poor prognosis. Moreover, studies in cancer cells have suggested that AQP5 activates Ras signaling, drives morphological changes, and in particular increased invasiveness. To design intervention strategies, it is of utmost importance to characterize and dissect the cell biological changes induced by altered AQP5 expression. To isolate the effect of AQP5 overexpression from the cancer background, AQP5 was overexpressed in normal epithelial MDCK cells which have no endogenous AQP5 expression. AQP5 overexpression promoted actin stress fiber formation and lamellipodia dynamics. Moreover, AQP5 decreased cell circularity. Phosphorylation of AQP5 on serine 156 in the second intracellular loop has been shown to activate the Ras pathway. When serine 156 was mutated to alanine to mimic the nonphosphorylated state, the decrease in cell circularity was reversed, indicating that the AQP5-Ras axis is involved in the effect on cell shape. Interestingly, the cellular changes mediated by AQP5 were not associated with induction of epithelial-to-mesenchymal transition. Thus, AQP5 may contribute to cancer by altering cellular morphology and actin organization, which increase the metastatic potential. PMID- 29384696 TI - A social network analysis of Canadian food insecurity policy actors. AB - PURPOSE: This paper aims to: (i) visualize the networks of food insecurity policy actors in Canada, (ii) identify potential food insecurity policy entrepreneurs (i.e., individuals with voice, connections, and persistence) within these networks, and (iii) examine the political landscape for action on food insecurity as revealed by social network analysis. METHODS: A survey was administered to 93 Canadian food insecurity policy actors. They were each asked to nominate 3 individuals whom they believed to be policy entrepreneurs. Ego-centred social network maps (sociograms) were generated based on data on nominees and nominators. RESULTS: Seventy-two percent of the actors completed the survey; 117 unique nominations ensued. Eleven actors obtained 3 or more nominations and thus were considered policy entrepreneurs. The majority of actors nominated actors from the same province (71.5%) and with a similar approach to theirs to addressing food insecurity (54.8%). Most nominees worked in research, charitable, and other nongovernmental organizations. CONCLUSIONS: Networks of Canadian food insecurity policy actors exist but are limited in scope and reach, with a paucity of policy entrepreneurs from political, private, or governmental jurisdictions. The networks are divided between food-based solution actors and income-based solution actors, which might impede collaboration among those with differing approaches to addressing food insecurity. PMID- 29384697 TI - What messages can foster safer sex among young women? Experimental evidence concerning the role of emotions and moral norms. AB - Through a 2 * 2 * 2 quasi experimental design (N = 254), this research investigated if a social campaign eliciting positive emotions and activating moral norms might enhance condom negotiation skills, intended and estimated condom among young women with or without past sexual experience with casual partners. Emotions had a main effect on one of the six condom negotiation strategies we considered; for most of the other variables an interaction effect with moral norms and/or past behaviour emerged. Concerning estimated condom use, positive emotions worked better than negative ones when moral norms were salient. With respect to negotiations skills, positive rather than negative emotions seemed more effective for women with past causal sexual experience. In women without this kind of experience, positive emotions seemed to work better when moral norms were salient. Moral norms had a main effect on negotiation self efficacy, but not in the predicted direction: when moral norms were more salient women were found to be less confident about their negotiation ability. These results suggest that a message which makes moral norms salient should at the same time elicit positive emotions in order to be effective; moreover, messages should be carefully tailored according to women's past behaviour. PMID- 29384695 TI - Mouse models of SLC4-linked disorders of HCO3--transporter dysfunction. AB - The SLC4 family Cl-/[Formula: see text] cotransporters (NBCe1, NBCe2, NBCn1, and NBCn2) contribute to a variety of vital physiological processes including pH regulation and epithelial fluid secretion. Accordingly, their dysfunction can have devastating effects. Disorders such as epilepsy, hemolytic anemia, glaucoma, hearing loss, osteopetrosis, and renal tubular acidosis are all genetically linked to SLC4-family gene loci. This review summarizes how studies of Slc4 modified mice have enhanced our understanding of the etiology of SLC4-linked pathologies and the interpretation of genetic linkage studies. The review also surveys the novel disease signs exhibited by Slc4-modified mice which could either be considered to presage their description in humans, or to highlight interspecific differences. Finally, novel Slc4-modified mouse models are proposed, the study of which may further our understanding of the basis and treatment of SLC4-linked disorders of [Formula: see text]-transporter dysfunction. PMID- 29384698 TI - Cross-talk inhibition between 5-HT2B and 5-HT7 receptors in phrenic motor facilitation via NADPH oxidase and PKA. AB - Intermittent spinal serotonin receptor activation elicits phrenic motor facilitation (pMF), a form of spinal respiratory motor plasticity. Episodic activation of either serotonin type 2 (5-HT2) or type 7 (5-HT7) receptors elicits pMF, although they do so via distinct cellular mechanisms known as the Q (5-HT2) and S (5-HT7) pathways to pMF. When coactivated, these pathways interact via mutual cross-talk inhibition. Although we have a rudimentary understanding of mechanisms mediating cross-talk interactions between spinal 5-HT2 subtype A (5 HT2A) and 5-HT7 receptor activation, we do not know if similar interactions exist between 5-HT2 subtype B (5-HT2B) and 5-HT7 receptors. We confirmed that either spinal 5-HT2B or 5-HT7 receptor activation alone elicits pMF and tested the hypotheses that 1) concurrent activation of both receptors suppresses pMF due to cross-talk inhibition; 2) 5-HT7 receptor inhibition of 5-HT2B receptor-induced pMF requires protein kinase A (PKA) activity; and 3) 5-HT2B receptor inhibition of 5-HT7 receptor-induced pMF requires NADPH oxidase (NOX) activity. Selective 5 HT2B and 5-HT7 receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) to anesthetized, paralyzed, and ventilated rats. Whereas integrated phrenic nerve burst amplitude increased after selective spinal 5-HT2B or 5-HT7 receptor activation alone (i.e., pMF), pMF was no longer observed with concurrent 5-HT2B and 5-HT7 receptor agonist administration. With concurrent receptor activation, pMF was rescued by inhibiting either NOX or PKA activity, demonstrating their roles in cross-talk inhibition between these pathways to pMF. This report demonstrates cross-talk inhibition between 5-HT2B- and 5-HT7 receptor induced pMF and that NOX and PKA activity are necessary for that cross-talk inhibition. PMID- 29384699 TI - Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity. AB - Hindbrain catecholamine neurons convey gut-derived metabolic signals to an interconnected neuronal network in the hypothalamus and adjacent forebrain. These neurons are critical for short-term glycemic control, glucocorticoid and glucoprivic feeding responses, and glucagon-like peptide 1 (GLP-1) signaling. Here we investigate whether these pathways also contribute to long-term energy homeostasis by controlling obesogenic sensitivity to a high-fat/high-sucrose choice (HFSC) diet. We ablated hindbrain-originating catecholaminergic projections by injecting anti-dopamine-beta-hydroxylase-conjugated saporin (DSAP) into the paraventricular nucleus of the hypothalamus (PVH) of male rats fed a chow diet for up to 12 wk or a HFSC diet for 8 wk. We measured the effects of DSAP lesions on food choices; visceral adiposity; plasma glucose, insulin, and leptin; and indicators of long-term ACTH and corticosterone secretion. We also determined lesion effects on the number of carbohydrate or fat calories required to increase visceral fat. Finally, we examined corticotropin-releasing hormone levels in the PVH and arcuate nucleus expression of neuropeptide Y ( Npy), agouti related peptide ( Agrp), and proopiomelanocortin ( Pomc). DSAP-injected chow-fed rats slowly increase visceral adiposity but quickly develop mild insulin resistance and elevated blood glucose. DSAP-injected HFSC-fed rats, however, dramatically increase food intake, body weight, and visceral adiposity beyond the level in control HFSC-fed rats. These changes are concomitant with 1) a reduction in the number of carbohydrate calories required to generate visceral fat, 2) abnormal Npy, Agrp, and Pomc expression, and 3) aberrant control of insulin secretion and glucocorticoid negative feedback. Long-term metabolic adaptations to high-carbohydrate diets, therefore, require intact forebrain catecholamine projections. Without them, animals cannot alter forebrain mechanisms to restrain increased visceral adiposity. PMID- 29384701 TI - Evaluation of alveolar bone support around incisors in patients with unilateral cleft lip, alveolus, and palate in late mixed dentition using cone beam computed tomography. AB - OBJECTIVES: To evaluate alveolar bone support around cleft-adjacent maxillary central incisors (U1) in patients with unilateral cleft lip, alveolus and palate (UCLAP) in the late mixed dentition and to investigate the correlation between the alveolar bone thickness (ABT) and tooth inclination. MATERIALS AND METHODS: Cone beam computed tomography scans of 45 subjects with UCLAP (29 boys, 16 girls; mean age = 10.74 +/- 1.08 years) were assessed. The distance between the cementoenamel junction (CEJ) and alveolar bone crest (AC), and the ABTs at 3 mm, 6 mm, and the apex were measured on the labial, lingual and distal surfaces of U1. The cleft and normal sides were compared using a paired t-test and Pearson's chi2 test. Pearson's correlation was used to explore the association between the ABT and tooth inclination of cleft-adjacent U1 in the labiolingual and mesiodistal dimensions. RESULTS: The CEJ-AC distances were significantly greater in cleft-adjacent U1 ( P < .01), with more bone height reduction observed labially and distally ( P < .001). The labial, lingual, and apico-distal ABTs were decreased on the cleft side ( P < .01). A positive correlation was found between the apico-labial ABT and the labiolingual inclination ( r = 0.568, P < .01). CONCLUSIONS: Patients with UCLAP have reduced alveolar bone support around the cleft-adjacent U1, and the apico-labial ABT tends to decrease with increasing lingual tooth inclination; however, the correlation was weak. PMID- 29384702 TI - The correlations of psychological status, quality of life, self-esteem, social support and body image disturbance in Chinese patients with Systemic Lupus Erythematosus. AB - This study aimed (i) to complement existing research by focusing on body image disturbance issues in Chinese Systemic Lupus Erythematosus (SLE) patients; (ii) to investigate how Chinese patients make sense of disease diagnosis and perceived cultural influences within the context of their SLE. A total of 118 SLE patients underwent standardized laboratory examinations and completed several questionnaires. Independent sample t-test, Mann-Whitney U-test, Chi-square test, and multivariate analysis using backward stepwise logistic regression model were used to analyze these data. We found 18.3% SLE patients had BID, which were significantly higher than the control group (.8%). SLE patients are more concerned about their physical changes caused by disease. There were significant correlations among personal health insurance, complication of diabetes, appearance of new rash, depression, anxiety, self-esteem and BID in patients with SLE. Meanwhile, logistic regression analysis revealed that appearance of new rash and high anxiety were significantly associated with BID in SLE patients. In conclusion, it is beneficial to pay attention to the physical and mental health of patients with rheumatic disease from the perspective of body image, to understand their needs and to provide effective and effective service for them. PMID- 29384700 TI - Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice. AB - Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3-6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3-5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson's trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease. PMID- 29384703 TI - A Qualitative Evaluation of Contact Centre Dietitian Support and Electronic Motivational Messaging for eaTracker My Goals Users. AB - PURPOSE: To conduct a qualitative evaluation of adjunct supports (brief motivational messaging regarding goals delivered by email/website, contact centre dietitian assistance) offered by EatRight Ontario (ERO) for users of a website based nutrition/activity goal setting/tracking feature (eaTracker "My Goals"). METHODS: One-on-one semi-structured interviews were conducted with My Goals users in Ontario (n = 18) and Alberta (n = 5) recruited via the eaTracker website and ERO contact centre dietitians (n = 5). Interview transcripts were analyzed using content analysis. RESULTS: Participants had mixed experiences and perspectives with ERO motivational messaging. Messages targeted towards specific goals (e.g., tips, recipes) were generally well-liked, and generic messages (e.g., eaTracker login reminders) were less useful. No interviewed users had contacted ERO dietitians regarding goals, and dietitians reported encountering few callers asking for assistance while using My Goals. Limited user knowledge was one explanation for this finding. Participants provided suggestions to enhance these supports. CONCLUSION: Electronic motivational messaging and contact centre dietitian assistance have the potential to support achievement of goals set with website-based features. When considering using electronic messaging, researchers and practitioners should consider message content and delivery tailoring. Marketing that focuses on how contact centre dietitians can assist website users with their goals is needed when services are used in naturalistic settings. PMID- 29384705 TI - A self-efficacy enhancing intervention for pulmonary rehabilitation based on motivational interviewing for postoperative lung cancers patients: modeling and randomized exploratory trial. AB - The objective of this study was to evaluate the feasibility and preliminary efficacy of a self-efficacy enhancing intervention designed for pulmonary rehabilitation based on motivational interviewing (MI) for postsurgical non-small cell lung cancer (NSCLC) patients. This study was a 2-arm pilot randomized controlled trial and was conducted in two cardiothoracic surgery departments, a tertiary hospital in Fuzhou, China. 28 postsurgical NSCLC patients were randomized to a 3 month (6 session) self-efficacy enhancing intervention based on MI or usual care (UC). Data were measured at baseline and after intervention. The MI based self-efficacy enhancing intervention group was superior to the UC group for reducing anxiety and depression, improving self-efficacy, quality of life, confrontational coping, social support and functional capacity. However, no statistically significant difference was observed in subjective well-being, posttraumatic growth, body mass index and pulmonary function between the two groups. This pilot study demonstrated the feasibility of MI based self-efficacy enhancing intervention for postsurgical NSCLC patients. A larger randomized trial would demonstrate a more rigorous test of efficacy. PMID- 29384706 TI - The nursing workforce of the future. PMID- 29384707 TI - Late-onset psoriasis: diagnosis, assessment and management. PMID- 29384708 TI - Removing a sick patient to hospital. AB - District nurses sometimes encounter situations where a patient in need of hospital treatment, or their family, refuses to go. Richard Griffith considers the legal options available to a district nurse who believes their patient should be removed from home and taken to hospital for treatment against their wishes. PMID- 29384709 TI - Loss, grief and bereavement: an inescapable link in palliative care. PMID- 29384710 TI - Address hearing loss and improve wellbeing. PMID- 29384711 TI - Variation in the provision of health care. PMID- 29384712 TI - Community palliative care clinical nurse specialists as independent prescribers: part 1. AB - The Department of Health and Social Care has recently reiterated its commitment to improvement in the quality of end-of-life care and emphasised the importance of all patients having rapid access to medication. The aim of this study was to explore the lived experiences of clinical nurse specialists who are able to prescribe independently in their role in providing support for patients with palliative care needs within the community setting. Interpretive phenomenology was employed in order to understand and interpret the experiences of six nurse independent prescribers employed as community palliative care clinical nurse specialists. This purposive sampling was preferred with semi-structured interviews as the most appropriate data collection technique. This is the first of a two-part article. In this part, the authors describe how the study was undertaken. Part 2 will provide the results, outline the key themes that were extracted from the study, and discuss them. It will be published in the next issue of the Journal. PMID- 29384714 TI - The use of acuity and frailty measures for district nursing workforce plans. AB - This article discusses the use of Quest acuity and frailty measures for community nursing interventions to quantify and qualify the contributions of district nursing teams. It describes the use of a suite of acuity and frailty tools tested in 8 UK community service trusts over the past 5years. In addition, a competency assessment tool was used to gauge both capacity and capability of individual nurses. The consistency of the results obtained from the Quest audits offer significant evidence and potential for realigning community nursing services to offer improvements in efficiency and cost-effectiveness. The National Quality Board (NQB) improvement resource for the district nursing services ( NQB, 2017 ) recommends a robust method for classifying patient acuity/frailty/dependency. It is contended the Quest tools and their usage articulated here offer a suitable methodology. PMID- 29384713 TI - Taking a proactive approach to mild to moderate chronic oedema: a case study. AB - This case study demonstrates the benefits of early intervention and a proactive approach for a patient with chronic oedema living in the community. These benefited the patient and also supported value-based healthcare in the NHS. The patient's health and wellbeing significantly improved with an assessment of his chronic oedema and a management plan consisting of skincare, an exercise and movement programme and the introduction of a class 1 British standard compression garment. PMID- 29384715 TI - Balance in community nursing: leaving work at work. PMID- 29384716 TI - The use of early warning scores to recognise and respond to patient deterioration in district nursing. AB - This discussion article focuses on the literature surrounding early warning scoring systems and their use in primary care, specifically within district nursing. Patient deterioration is a global concern, associated with high mortality rates and avoidable deaths. Early recognition and response by nursing and other health care staff has been attributed to early warning scoring systems (EWSS) and tools. However, the use of equivalent tools in the community appears to be lacking. This review concludes that there is no consensus over the use of EWSS in district nursing and culture of practice is varied, rather than standardised. PMID- 29384718 TI - Vaccination without Litigation - Addressing Religious Objections to Hospital Influenza-Vaccination Mandates. PMID- 29384717 TI - False-positive HIV diagnoses: lessons from Ugandan and Russian research cohorts. AB - BACKGROUND: Research studies rely on accurate assessment of entry criteria in order to maintain study integrity and participant safety, however, challenges can exist with HIV studies in international settings. OBJECTIVE: Examine the unexpectedly high proportion of study participants with an undetectable HIV viral load found in Ugandan and Russian research cohorts meeting antiretroviral therapy (ART)-naive entry criteria. METHODS: Russian participants with documented HIV and ART-naive status were recruited between 2012 and 2015 from clinical and non clinical sites in St. Petersburg. Participants in Uganda were recruited from Mbarara Regional Referral Hospital from 2011 to 2014 with documented HIV infection via rapid diagnostic testing and recorded ART-naive in the clinic database. HIV viral load testing of baseline samples was performed; the lower limit of detection was 500 copies/mL in Russia and 40 in Uganda. Due to an unexpectedly high proportion of participants with undetectable viremia, additional tests were performed: enzyme-linked immunosorbent assay HIV testing and testing for ART. RESULTS: In Russia, 16% (58/360) had undetectable viremia; 3% (9/360) re-tested HIV-seronegative and 4% (13/360) tested positive for ART. In Uganda 11% (55/482) had undetectable viremia; 5% (26/482) re-tested HIV seronegative, while <1% (4/482) tested positive for ART. CONCLUSIONS: In both Russia & Uganda, undetectable viremia was much higher than would be expected for an HIV-infected ART-naive cohort. Misclassification of study participants was due to misdiagnosis of HIV with rapid diagnostic testing and inaccurate accounting of ART use. Confirmatory HIV testing could improve accuracy of participants meeting entry criteria for HIV infection as might increased scrutiny of medication use in an ART-naive cohort. PMID- 29384719 TI - Where There's Wildfire, There's Smoke. PMID- 29384720 TI - Meeting the Challenge: The National Cancer Institute's Central Institutional Review Board for Multi-Site Research. AB - The National Institutes of Health (NIH) issued a new policy that requires a single institutional review board (IRB) of record be used for all protocols funded by the NIH that are carried out at more than one site in the United States, effective January 2018. This policy affects several hundred clinical trials opened annually across the NIH. Limited data exist to compare the use of a single IRB to that of multiple local IRBs, so some institutions are resistant to or distrustful of single IRBs. Since 2001, the National Cancer Institute (NCI) has funded a central IRB (CIRB) that provides human patient reviews for its extensive national cancer clinical trials program. This paper presents data to show the adoption, efficiencies gained, and satisfaction of the CIRB among NCI trial networks and reviews key lessons gleaned from 16 years of experience that may be informative for others charged with implementation of the new NIH single IRB policy. PMID- 29384721 TI - Risk of Synchronous Distant Recurrence at Time of Locoregional Recurrence in Patients With Stage II and III Breast Cancer (AFT-01). AB - Purpose National Comprehensive Cancer Network guidelines recommend systemic staging imaging at the time of locoregional breast cancer recurrence. Limited data support this recommendation. We determined the rate of synchronous distant recurrence at the time of locoregional recurrence in high-risk patients and identified clinical factors associated with an increased risk of synchronous metastases. Methods A stage-stratified random sample of 11,046 patients with stage II to III breast cancer in 2006 to 2007 was selected from the National Cancer Database for participation in a Commission on Cancer special study. From medical record abstraction of imaging and recurrence data, we identified patients who experienced locoregional recurrence within 5 years of diagnosis. Synchronous distant metastases (within 30 days of locoregional recurrence) were determined. We used multivariable logistic regression to identify factors associated with synchronous metastases. Results Four percent experienced locoregional recurrence (n = 445). Synchronous distant metastases were identified in 27% (n = 120). Initial presenting stage ( P = .03), locoregional recurrence type ( P = .01), and insurance status ( P = .03) were associated with synchronous distant metastases. The proportion of synchronous metastases was highest for women with lymph node (35%), postmastectomy chest wall (30%), and in-breast (15%) recurrence; 54% received systemic staging imaging within 30 days of a locoregional recurrence. Conclusion These findings support current recommendations for systemic imaging in the setting of locoregional recurrence, particularly for patients with lymph node or chest wall recurrences. Because most patients with isolated locoregional recurrence will be recommended locoregional treatment, early identification of distant metastases through routine systemic imaging may spare them treatments unlikely to extend their survival. PMID- 29384723 TI - HIF2 Inhibitor Joins the Kidney Cancer Armamentarium. PMID- 29384722 TI - Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. AB - Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or >= four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high volume disease; however, for patients with low-volume disease, no OS benefit was discerned. PMID- 29384724 TI - Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia. AB - Sarcopenia is a well-known geriatric syndrome that has been endorsed over the years as a biomarker allowing for the discrimination, at a clinical level, of biological from chronological age. Multiple candidate mechanisms have been linked to muscle degeneration during sarcopenia. Among them, there is wide consensus on the central role played by the loss of mitochondrial integrity in myocytes, secondary to dysfunctional quality control mechanisms. Indeed, mitochondria establish direct or indirect contacts with other cellular components (e.g. endoplasmic reticulum, peroxisomes, lysosomes/vacuoles) as well as the extracellular environment through the release of several biomolecules. The functional implications of these interactions in the context of muscle physiology and sarcopenia are not yet fully appreciated and represent a promising area of investigation. Here, we present an overview of recent findings concerning the interrelation between mitochondrial quality control processes, inflammation and the metabolic regulation of muscle mass in the pathogenesis of sarcopenia highlighting those pathways that may be exploited for developing preventive and therapeutic interventions against muscle aging. PMID- 29384725 TI - Voices from the Field: Regional Nurses Speak About Motivations, Careers and How to Entice Others to Pursue Mental Health Nursing. AB - The aims of this study are three-fold: determine the factors that motivate nurses to pursue mental health nursing; identify the strategies that might attract nursing students and practising nurses to pursue mental health nursing as a professional career; and identify the difficulties of nurses in achieving their preferred clinical specialty. A descriptive qualitative study design with semi structured interviews was used. Fifteen mental health nurses from rural and regional South Australia were interviewed. Interviews were transcribed verbatim, and thematic analysis was undertaken. Of the fifteen participants, thirteen were females and two were males; their average age was 50 years. The factors that motivated the participants to pursue mental health nursing were categorized as intrinsic and extrinsic. There were many strategies that might attract nursing students and nurses to the field, but the most popular suggestion was the provision of high quality meaningful clinical placements. Other strategies were to convey the personal satisfaction derived from being a mental health nurse, promote mental health nursing aggressively, and provide employment incentives. The study also highlighted the importance of addressing stigma, and greater education and support for nurses to pursue a mental health career. PMID- 29384726 TI - Enhanced efficiency of hybrid amorphous silicon solar cells based on single walled carbon nanotubes and polymer composite thin film. AB - We report a simple approach to fabricate hybrid solar cells (HSCs) based on a single-walled carbon nanotube (SWCNT) film and thin film hydrogenated amorphous silicon (a-Si:H). Randomly oriented high-quality SWCNTs with conductivity enhanced by means of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate are used as a window layer and a front electrode. A series of HSCs are fabricated in ambient conditions with varying SWCNT film thicknesses. The polymethylmethacrylate layer drop-casted on fabricated HSCs reduces the reflection fourfold and enhances the short-circuit J sc , open-circuit V oc , and efficiency by nearly 10%. A state-of-the-art J-V performance is shown for SWCNT/a Si HSC with an open-circuit voltage of 900 mV and an efficiency of 3.4% under simulated one-sun AM 1.5 G direct illumination. PMID- 29384727 TI - Graphene nanoplatelet doping of P3HT:PCBM photoactive layer of bulk heterojunction organic solar cells for enhancing performance. AB - Hybrid organic photovoltaic (OPV) cells based on conjugated polymer photoactive materials are promising candidates for flexible, high-performance and low-cost energy sources owing to their inexpensive materials, cost-effective processing and ease of fabrication by simple solution processes. However, the modest PV performance obtained to date-in particular the low power conversion efficiency (PCE)-has impeded the large scale deployment of OPV cells. The low PCE in OPV solar cells is mainly attributed to the low carrier mobility, which is closely correlated to the transport diffusion length of the charge carriers within the photoactive layers. The 2D graphene material could be an excellent candidate for assisting charge transport improvement in the active layer of OPV cells, due to its huge carrier mobility, thermal and chemical stability, and its compatibility with the solution process. In this work, we report on the improvement of the optoelectronic properties and photovoltaic performance of graphene nanoplatelet (GNP)-doped P3HT:PCBM photoactive blended layers, integrated into a bulk heterojunction (BHJ) organic-photovoltaic-based device, using PEDOT:PSS on an ITO/glass substrate. First, the light absorption capacity was observed to increase with respect to the GNP content, while the photoluminescence showed clear quenching, indicating electron transfer between the graphene sheets and the polymeric matrix. Then, the incorporation of GNP into the BHJ active layer resulted in enhanced PV performance with respect to the reference cell, and the best PV performance was obtained with 3 wt.% of GNP loading, with an open-circuit voltage of 1.24 V, a short-circuit current density value of 6.18 mA cm-2, a fill factor of 47.12%, and a power conversion efficiency of about 3.61%. We believe that the obtained results contribute to the development of organic photovoltaic devices and to the understanding of the impact of sp2-bonded carbon therein. PMID- 29384728 TI - The ambipolar evolution of a high-performance WSe2 transistor assisted by a ferroelectric polymer. AB - In recent years, the electrical characteristics of WSe2 field-effect transistors (FETs) have been widely investigated with various dielectrics. Among them, being able to perfectly tune the polarity of WSe2 is meaningful and promising work. In this work, we systematically study the electrical properties of bilayer WSe2 FETs modulated by ferroelectric polymer poly(vinylidenefluoride-co-trifluoroethylene) (P(VDF-TrFE)). Compared to traditional gate dielectric SiO2, the P(VDF-TrFE) can not only tune both electron and hole concentrations to the same high level, but also improve the hole mobility of bilayer WSe2 to 265.96 cm2 V-1 s-1 under SiO2 gating. Its drain current on/off ratio is also improved to 2 * 105 for p-type and 4 * 105 for n-type driven by P(VDF-TrFE). More importantly, the ambipolar behaviors of bilayer WSe2 are effectively achieved and maintained because of the remnant polarization field of P(VDF-TrFE). This work indicates that WSe2 FETs with P(VDF-TrFE) gating have huge potential for complementary logic transistor applications, and paves an effective way to achieve in-plane p-n junctions. PMID- 29384729 TI - One-step oxidation preparation of unfolded and good soluble graphene nanoribbons by longitudinal unzipping of carbon nanotubes. AB - A simple one-step method to prepare graphene nanoribbon (GNR) is reported in this paper. Compared with water steam etching, the oxidation and co-etching of dilute sulfuric acid can result in the more complete longitudinal unzipping of carbon nanotube, although there is no other strong oxidant. As-prepared GNRs are more flat and have more oxygenated functional groups along the edge. Moreover, they can steadily disperse in a water system. These make them suitable as a carrier for supporting palladium (Pd) nanoparticles. The Pd/GNR composite exhibits a superior electrocatalytic activity for ethanol oxidation. PMID- 29384730 TI - End-to-end tests using alanine dosimetry in scanned proton beams. AB - This paper describes end-to-end test procedures as the last fundamental step of medical commissioning before starting clinical operation of the MedAustron synchrotron-based pencil beam scanning (PBS) therapy facility with protons. One in-house homogeneous phantom and two anthropomorphic heterogeneous (head and pelvis) phantoms were used for end-to-end tests at MedAustron. The phantoms were equipped with alanine detectors, radiochromic films and ionization chambers. The correction for the 'quenching' effect of alanine pellets was implemented in the Monte Carlo platform of the evaluation version of RayStation TPS. During the end to-end tests, the phantoms were transferred through the workflow like real patients to simulate the entire clinical workflow: immobilization, imaging, treatment planning and dose delivery. Different clinical scenarios of increasing complexity were simulated: delivery of a single beam, two oblique beams without and with range shifter. In addition to the dose comparison in the plastic phantoms the dose obtained from alanine pellet readings was compared with the dose determined with the Farmer ionization chamber in water. A consistent systematic deviation of about 2% was found between alanine dosimetry and the ionization chamber dosimetry in water and plastic materials. Acceptable agreement of planned and delivered doses was observed together with consistent and reproducible results of the end-to-end testing performed with different dosimetric techniques (alanine detectors, ionization chambers and EBT3 radiochromic films). The results confirmed the adequate implementation and integration of the new PBS technology at MedAustron. This work demonstrates that alanine pellets are suitable detectors for end-to-end tests in proton beam therapy and the developed procedures with customized anthropomorphic phantoms can be used to support implementation of PBS technology in clinical practice. PMID- 29384731 TI - Real-time volumetric relative dosimetry for magnetic resonance-image-guided radiation therapy (MR-IGRT). AB - The integration of magnetic resonance imaging (MRI) with linear accelerators (linac) has enabled the use of 3D MR-visible gel dosimeters for real-time verification of volumetric dose distributions. Several iron-based radiochromic 3D gels were created in-house then imaged and irradiated in a pre-clinical 1.5 T-7 MV MR-Linac. MR images were acquired using a range of balanced-fast field echo (b FFE) sequences during irradiation to assess the contrast and dose response in irradiated regions and to minimize the presence of MR artifacts. Out of four radiochromic 3D gel formulations, the FOX 3D gel was found to provide superior MR contrast in the irradiated regions. The FOX gels responded linearly with respect to real-time dose and the signal remained stable post-irradiation for at least 20 min. The response of the FOX gel also was found to be unaffected by the radiofrequency and gradient fields created by the b-FFE sequence during irradiation. A reusable version of the FOX gel was used for b-FFE sequence optimization to reduce artifacts by increasing the number of averages at the expense of temporal resolution. Regardless of the real-time MR sequence used, the FOX 3D gels responded linearly to dose with minimal magnetic field effects due to the strong 1.5 T field or gradient fields present during imaging. These gels can easily be made in-house using non-reusable and reusable formulations depending on the needs of the clinic, and the results of this study encourage further applications of 3D gels for MR-IGRT applications. PMID- 29384732 TI - A systematic review of odontological sex estimation methods. AB - BACKGROUND: In human identification sex estimation plays an important role in the search for ante-mortem data. AIM: To systematically review studies describing and testing/validating methods of odontological sex estimation. The set research question was: What odontological sex estimation method is the most accurate? MATERIALS AND METHODS: An electronic search until November 29th 2016 was performed in 5 databases: MEDLINE/PubMed, Cochrane, SciELO, LILACS and Grey literature. The PRISMA guidelines were used. Studies were assessed and included based on the reported data. In particular data criteria were set regarding the considered population, sample size, age range, sex estimation method, type of statistical analysis and study outcome. The extracted data enabled to classify the included studies. Meta-analysis was used to compare the study outcomes per obtained study group. RESULTS: The established search string detected 4720 studies. 103 were considered eligible after review of title, abstract and full text. The odontological sex estimation methods were classified based on dental metric and non-metric measurements (n=65), cephalometric analysis (n=13), frontal and maxillary sinuses (n=5), cheiloscopy (n=4), palatal features (n=3) and biochemical analysis of teeth (n=13). Teeth measurements for sex estimation were mainly performed on casts (n=34), followed by skeletal remains (n=13), medical imaging (n=5), intraoral measurements/ photography (n=4), and cascades of the above (n=4). CONCLUSION: The variety of published odontological sex estimation methods highlights the importance of sex estimation in human identification. Biochemical analysis of teeth proved to be the most accurate method, but in forensic practice, a need to select the most appropriate evidence based odontological sex estimation method exists. PMID- 29384733 TI - Prevalence of agenesis of frontal sinus in human skulls with metopism. AB - BACKGROUND: The frontal bone is an anatomical structure of the skull separated by the metopic suture in the childhood. The scientific literature indicates that metopic suture consolidates with closure in the early stages of life. Metopism is the term used to describe a metopic suture that persists up to the adulthood. Persistent metopic suture is associated potentially with the agenesis of the frontal sinus. AIM: To investigate the prevalence of absent frontal sinuses in dry skulls with metopism. MATERIALS AND METHODS: The present study was performed after the approval of the local Committee of Ethics in Research. The sample consisted of dry skulls (n=245), aging between 17 and 50 years old, of the Forensic Medical Institute of Goiania, Brazil. The skulls underwent anthropological exam in the search for metopism. Radiographic exam was performed in the skulls with metopism to verify the presence or absence of the frontal sinus. The radiographic assessment was performed with a Mobile DaRt Evolution device (Shimadzu, Kyoto, Japan) with protocol set in 64 kV and 16 mA). RESULTS: From the 245 dry skulls, 17 presented metopism. The length of the metopic suture in the skulls, considering the distances between nasio and bregma craniometric landmarks, ranged between 114 mm and 137 mm. Radiographic exams were performed on 16 skulls (one skull was not analysed radiographically because of extensive destruction). Only one skull (6.25%) had the frontal sinus absent. Besides the agenesis, the present study also found four (12.5%) skulls with aplasia and eight (25.0%) hyperplasia of the frontal sinus in dry skulls with metopism. CONCLUSION: The present study found a low prevalence rate of the agenesis of frontal sinuses in dry skulls with metopism. PMID- 29384734 TI - Extra-oral dental radiography for disaster victims using a flat panel X-ray detector and a hand-held X-ray generator. AB - BACKGROUND: Forensic odontologists commonly incise the skin for post-mortem dental examinations when it is difficult to open the victim's mouth. However, it is prohibited by law to incise dead bodies without permission in Japan. Therefore, we attempted using extra-oral dental radiography, using a digital X ray equipment with rechargeable batteries, to overcome this restriction. MATERIALS AND METHODS: A phantom was placed in the prone position on a table, and three plain dental radiographs were used per case: "lateral oblique radiographs" for left and right posterior teeth and a "contact radiograph" for anterior teeth were taken using a flat panel X-ray detector and a hand-held X-ray generator. The resolving power of the images was measured by a resolution test chart, and the scattered X-ray dose was measured using an ionization chamber-type survey meter. RESULTS: The resolving power of the flat panel X-ray detector was 3.0 lp/mm, which was less than that of intra-oral dental methods, but the three extra-oral plain dental radiographs provided the overall dental information from outside of the mouth, and this approach was less time-consuming. In addition, the higher dose of scattered X-rays was laterally distributed, but the dose per case was much less than that of intra-oral dental radiographs. CONCLUSION: Extra-oral plain dental radiography can be used for disaster victim identification by dental methods even when it is difficult to open the mouth. Portable and rechargeable devices, such as a flat panel X-ray detector and a hand-held X-ray generator, are convenient to bring and use anywhere, even at a disaster scene lacking electricity and water. PMID- 29384735 TI - Semi-automatic forensic approach using mandibular midline lingual structures as fingerprint: a pilot study. AB - BACKGROUND: Previous research proposed the use of the mandibular midline neurovascular canal structures as a forensic finger print. In their observer study, an average correct identification of 95% was reached which triggered this study. AIM: To present a semi-automatic computer recognition approach to replace the observers and to validate the accuracy of this newly proposed method. MATERIALS AND METHODS: Imaging data from Computer Tomography (CT) and Cone Beam Computer Tomography (CBCT) of mandibles scanned at two different moments were collected to simulate an AM and PM situation where the first scan presented AM and the second scan was used to simulate PM. Ten cases with 20 scans were used to build a classifier which relies on voxel based matching and results with classification into one of two groups: "Unmatched" and "Matched". This protocol was then tested using five other scans out of the database. Unpaired t-testing was applied and accuracy of the computerized approach was determined. RESULTS: A significant difference was found between the "Unmatched" and "Matched" classes with means of 0.41 and 0.86 respectively. Furthermore, the testing phase showed an accuracy of 100%. CONCLUSION: The validation of this method pushes this protocol further to a fully automatic identification procedure for victim identification based on the mandibular midline canals structures only in cases with available AM and PM CBCT/CT data. PMID- 29384736 TI - An automated technique to stage lower third molar development on panoramic radiographs for age estimation: a pilot study. AB - BACKGROUND: Automated methods to evaluate growth of hand and wrist bones on radiographs and magnetic resonance imaging have been developed. They can be applied to estimate age in children and subadults. Automated methods require the software to (1) recognise the region of interest in the image(s), (2) evaluate the degree of development and (3) correlate this to the age of the subject based on a reference population. For age estimation based on third molars an automated method for step (1) has been presented for 3D magnetic resonance imaging and is currently being optimised (Unterpirker et al. 2015). AIM: To develop an automated method for step (2) based on lower third molars on panoramic radiographs. MATERIALS AND METHODS: A modified Demirjian staging technique including ten developmental stages was developed. Twenty panoramic radiographs per stage per gender were retrospectively selected for FDI element 38. Two observers decided in consensus about the stages. When necessary, a third observer acted as a referee to establish the reference stage for the considered third molar. This set of radiographs was used as training data for machine learning algorithms for automated staging. First, image contrast settings were optimised to evaluate the third molar of interest and a rectangular bounding box was placed around it in a standardised way using Adobe Photoshop CC 2017 software. This bounding box indicated the region of interest for the next step. Second, several machine learning algorithms available in MATLAB R2017a software were applied for automated stage recognition. Third, the classification performance was evaluated in a 5-fold cross-validation scenario, using different validation metrics (accuracy, Rank-N recognition rate, mean absolute difference, linear kappa coefficient). RESULTS: Transfer Learning as a type of Deep Learning Convolutional Neural Network approach outperformed all other tested approaches. Mean accuracy equalled 0.51, mean absolute difference was 0.6 stages and mean linearly weighted kappa was 0.82. CONCLUSION: The overall performance of the presented automated pilot technique to stage lower third molar development on panoramic radiographs was similar to staging by human observers. It will be further optimised in future research, since it represents a necessary step to achieve a fully automated dental age estimation method, which to date is not available. PMID- 29384737 TI - Age estimation by facial analysis based on applications available for smartphones. AB - BACKGROUND: Forensic Dentistry has an important role in the human identification cases and, among the analyses that can be performed, age estimation has an important value in establishing an anthropological profile. Modern technology invests for new mechanisms of age estimation: software apps, based on special algorithms, because there is not interference based on personal knowledge, cultural and personal experiences for facial recognition. MATERIALS AND METHODS: This research evaluated the use of two different apps: "How Old Do I Look? - Age Camera" and "How Old Am I? - Age Camera, Do You Look Like in Selfie Face Pic?", for age estimation analysis in a sample of 100 people (50 females and 50 males). Univariate and multivariate statistical methods were used to evaluate data. RESULTS: A great reliability was seen when used for the male volunteers. However, for females, no equivalence was found between the real age and the estimated age. CONCLUSION: These applications presented satisfactory results as an auxiliary method, in male images. PMID- 29384738 TI - Are cervical vertebrae suitable for age estimation? AB - BACKGROUND: The ability of cervical vertebrae (CV) staging to contribute in forensic age estimation is being discussed controversially. The large variability of CV geometries in the end stage of development might be the reason for not reaching a performance competitive to hand or third molar methods. Here we study the geometry of adult CV and demonstrate that the description of their "typical" appearance is often not met. MATERIALS AND METHODS: Lateral cephalograms from clinical routine of 320 subjects aged 20 years or above (median 24 years, 52% female) were evaluated. The criteria for the end stage of CV development (Hassel Farman, Baccetti) were examined by assessing them in terms of metric measurements: (1) rectangular shape of C3/C4, (2) at least one of the height width ratios of C3/C4 > 1 (both not <1), (3) significant concavities at the inferior margin of C2, C3 and C4. Metric data of the adults were also compared to those of 100 children aged 8-10 years (50% female). RESULTS: Adult CV often violated the criteria of rectangular shape (44% C3, 36% C4), of height-width ratio (16% C3, 35% C4) and inferior concavity (10% C2, 10% C3, 19% C4). All of the criteria for adult CV were fulfilled in only 24% of the subjects (95%CI 19 28%). The variability of measures of the CV shapes was large; e.g., the 95% reference ranges for the height-width ratios were 0.81-1.19 (C3) and 0.77-1.14 (C4). There was a material overlap of ranges of CV measures of adults and children. CONCLUSION: While hand bones and teeth have well-defined appearances in the end stage of development, adult CV have a large biological variance of shapes; it is hard to define their "typical" appearance. Moreover, measures of CV geometry do not strictly separate adults from children. These facts might reason the limited usefulness of CV in age estimation. PMID- 29384739 TI - A radiographic study estimating age of mandibular third molars by periodontal ligament visibility. AB - BACKGROUND: Visibility of the periodontal ligament of mandibular third molars (M3) has been suggested as a method to estimate age. AIM: To assess the accuracy of this method and compare the visibility of the periodontal ligament in the left M3 with the right M3. The sample was archived panoramic dental radiographs of 163 individuals (75 males, 88 females, age 16-53 years) with mature M3's. MATERIALS AND METHODS: Reliability was assessed using Kappa. Accuracy was assessed by subtracting chronological age from estimated age for males and females. Stages were cross-tabulated against age stages younger than and at least 18 and 21 years of age. Stages were compared in the left M3 and right M3. RESULTS: Analysis showed excellent intra-observer reliability. Mean difference between estimated and chronological ages was 7.21 years (SD 5.16) for left M3 and 7.69 (SD 6.08) for right M3 in males and 6.87 (SD 5.83) for left M3 and 8.61 (SD 6.58) for right M3 in females. Minimum ages of stages 0 to 2 were younger than previously reported, despite a small sample of individuals younger than 18. The left and right M3 stage differed in 46% of the 85 individuals with readings from both side and estimated age differed from -10.5 to 12.2 years between left and right. CONCLUSION: Accuracy of this method was between 6 and 8 years with an error of 5 to 6 years. The number of individuals with mature M3 apices younger than 18 years was small. The stage of visibility of the periodontal ligament differed between left and right in almost half of our sample with both teeth present. Our findings question the use of this method to estimate age or to discriminate between age younger and at least 18 years. PMID- 29384740 TI - Periodontal Ligament Visibility (PLV): validation of PLV to determine adult status. AB - BACKGROUND: Gradual obliteration of the Periodontal Ligament Visibility (PLV) of lower third molars indicates increasing age. This is used to help determine whether or not an age disputed subject is above or below the 18 year threshold. AIM: The main focus was to determine, in test subjects of known age, whether the PLV system used 'blind' is able to reliably indicate whether the subject was a child (age < 18 years) or adult (age > 18). MATERIALS AND METHODS: A total of 250 normal subjects in the age range 16 to 26 years, from the archives of Guy's Hospital in London, UK, were used to validate the system of PLV. The radiographic assessment of PLV1 was used to categorize four grades of PLV. RESULTS: It was found that for both females and males PLV-C and PLV-D gave very high probabilities (p = 1.000) of the test subjects being of adult status. CONCLUSION: Periodontal Ligament Visibility has the potential to play an important part in the assessment of age disputed asylum seekers who look adult and claim to be children. PMID- 29384741 TI - A radiographic study of the mandibular third molar root development in different ethnic groups. AB - BACKGROUND: The nature of differences in the timing of tooth formation between ethnic groups is important when estimating age. AIM: To calculate age of transition of the mandibular third (M3) molar tooth stages from archived dental radiographs from sub-Saharan Africa, Malaysia, Japan and two groups from London UK (Whites and Bangladeshi). MATERIALS AND METHODS: The number of radiographs was 4555 (2028 males, 2527 females) with an age range 10-25 years. The left M3 was staged into Moorrees stages. A probit model was fitted to calculate mean ages for transitions between stages for males and females and each ethnic group separately. The estimated age distributions given each M3 stage was calculated. To assess differences in timing of M3 between ethnic groups, three models were proposed: a separate model for each ethnic group, a joint model and a third model combining some aspects across groups. The best model fit was tested using Bayesian and Akaikes information criteria (BIC and AIC) and log likelihood ratio test. RESULTS: Differences in mean ages of M3 root stages were found between ethnic groups, however all groups showed large standard deviation values. The AIC and log likelihood ratio test indicated that a separate model for each ethnic group was best. Small differences were also noted between timing of M3 between males and females, with the exception of the Malaysian group. These findings suggests that features of a reference data set (wide age range and uniform age distribution) and a Bayesian statistical approach are more important than population specific convenience samples to estimate age of an individual using M3. CONCLUSION: Some group differences were evident in M3 timing, however, this has some impact on the confidence interval of estimated age in females and little impact in males because of the large variation in age. PMID- 29384742 TI - Comparisons between skeletal and dental age assessment in unaccompanied asylum seeking children. AB - BACKGROUND: For children with disputed date of birth, age assessments based on skeletal and dental development are recommended. AIM: The aim of this retrospective study was to compare and contrast the results of age assessments from these two methods performed on unaccompanied asylum seeking children in Norway. In addition the aim of the analysis was to see if the skeletal age assessment from hand-wrist was operator sensitive. MATERIALS AND METHODS: Age assessments performed from January 2010 to December 2014 were analysed. Skeletal development of hand-wrist was graded according to Greulich and Pyle (1959). Dental development of the wisdom teeth was scored on orthopantomograms according to Moorrees, Fanning and Hunt (1963) and age assessed from tables published by Liversidge (2008) and Haavikko (1970). In the statistical analysis agreement between the two age assessments was defined according to the asylum seeker's age being assessed to be older or younger than 18 years. The statistical analysis included 3333 boys and 486 girls. RESULTS: The agreement was 83% for boys and 79% for girls. Approximately 70% of the boys and girls were 18 years or older by both methods. It was more common that the skeletal age was assessed older than 18 years and dental age younger than 18 years for both genders. It could be demonstrated that the age assessment based on skeletal maturation was not operator sensitive. CONCLUSION: The analyses demonstrate that there is good agreement between the two age assessments, but a method to combine the results would increase the reliability of the age assessments. PMID- 29384743 TI - Forensic age estimation based on development of third molars: a staging technique for magnetic resonance imaging. AB - BACKGROUND: The development of third molars can be evaluated with medical imaging to estimate age in subadults. The appearance of third molars on magnetic resonance imaging (MRI) differs greatly from that on radiographs. Therefore a specific staging technique is necessary to classify third molar development on MRI and to apply it for age estimation. AIM: To develop a specific staging technique to register third molar development on MRI and to evaluate its performance for age estimation in subadults. MATERIALS AND METHODS: Using 3T MRI in three planes, all third molars were evaluated in 309 healthy Caucasian participants from 14 to 26 years old. According to the appearance of the developing third molars on MRI, descriptive criteria and schematic representations were established to define a specific staging technique. Two observers, with different levels of experience, staged all third molars independently with the developed technique. Intra- and inter-observer agreement were calculated. The data were imported in a Bayesian model for age estimation as described by Fieuws et al. (2016). This approach adequately handles correlation between age indicators and missing age indicators. It was used to calculate a point estimate and a prediction interval of the estimated age. Observed age minus predicted age was calculated, reflecting the error of the estimate. RESULTS: One hundred and sixty-six third molars were agenetic. Five percent (51/1096) of upper third molars and 7% (70/1044) of lower third molars were not assessable. Kappa for inter-observer agreement ranged from 0.76 to 0.80. For intra-observer agreement kappa ranged from 0.80 to 0.89. However, two stage differences between observers or between staging sessions occurred in up to 2.2% (20/899) of assessments, probably due to a learning effect. Using the Bayesian model for age estimation, a mean absolute error of 2.0 years in females and 1.7 years in males was obtained. Root mean squared error equalled 2.38 years and 2.06 years respectively. The performance to discern minors from adults was better for males than for females, with specificities of 96% and 73% respectively. CONCLUSION: Age estimations based on the proposed staging method for third molars on MRI showed comparable reproducibility and performance as the established methods based on radiographs. PMID- 29384744 TI - The age estimation practice related to illegal unaccompanied minors immigration in Italy. AB - The migrants arrived to the Italian coasts in 2016 were 181.436, 18% more than the previous year and 6% more than the highest number ever since. An "unaccompanied minor" (UAM) is a third-country national or a stateless person under eighteen years of age, who arrives on the territory of the Member State unaccompanied by an adult responsible for him/her whether by law or by the practice of the Member State concerned, and for as long as he or she is not effectively taken into the care of such a person; it includes a minor who is left unaccompanied after he/she entered the territory of the Member States. As many as 95.985 UAMs applied for international protection in an EU member country just in 2015, almost four times the number registered in the previous year. The UAMs arrived in Italy were 28.283 in 2016; 94% of them were males, 92% unaccompanied, 8% of them under 15; the 53,6% is 17; the individuals between 16 and 17 are instead the 82%. Many of them (50%), 6561 in 2016, escaped from the sanctuaries, thus avoiding to be formally identified and registered in Italy in the attempt to reach more easily northern Europe countries, since The Dublin Regulations (2003) state that the asylum application should be held in the EU country of entrance or where parents reside. The age assessment procedures can therefore be considered as a relevant task that weighs in on the shoulders of the forensic experts with all the related issues and the coming of age is the important threshold. In the EU laws on asylum, the minors are considered as one of the groups of vulnerable persons towards whom Member States have specific obligations. A proper EU common formal regulation in the matter of age estimation procedures still lacks. According to the Italian legal framework in the matter, a medical examination should have been always performed but a new law completely changed the approach to the procedures of age estimation of the migrant (excluding the criminal cases) with a better adherence to the notions and concepts of vulnerability and psychological and social maturity. PMID- 29384745 TI - Forensic odontology education:from undergraduate to PhD - a Brazilian experience. AB - BACKGROUND: Forensic Odontology is a topic present in the majority of Dental Schools in Brazil, and due to this reality, some universities develop activities related to undergraduate and graduate students, from the Dentistry course until the Ph.D. degree. AIM: To present the education experience related to Forensic Odontology at School of Dentistry of Ribeirao Preto (USP - University of Sao Paulo), showing the strategies and activities in the different degrees (Dental course, Forensic Odontology Specialization Program, Specific Professional Training, Master, and Ph.D.). RESULTS: To the undergraduate students, many activities are developed in order to demonstrate all the possibilities that Forensic Dentistry allow, including theoretical and practical activities; in the Forensic Odontology Specialization Program, the dentists are trained to act as Forensic Odontologists in all its amplitude; in the Specific Professional Training, some courses are available, related to specific topics as DVI, Forensic Facial Reconstruction, Auditor in Dental Care Insurance and others; and in the Master and Ph.D. Programs, the professionals receive training in skills like teaching, research, student's guidance and others. CONCLUSION: In Brazil, Forensic Odontology is a well-known field in Dentistry and universities develop an important role in training a qualified workforce. PMID- 29384746 TI - Day to day issues in the forensic identification practice related to illegal immigration in Italy. AB - The migratory flows to Europe from the African countries, Asia and Middle East, have hugely intensified in the recent years. In 2016, more than 98,000 out of a total of 260,000 migrants across the Mediterranean Sea arrived in Italy and in May 2017, the trend of arrivals is: Italy +576%; Greece -39% compared to previous years. Some migrants die before touching the sole of the European continent, during the crossing, often afforded with ships, made available by unscrupulous smugglers or criminal organizations, which are unsuitable for this type of transportation. The tremendous occurrence of migrant casualties during the Mediterranean Sea crossing remains underestimated and nobody, country officers or databank, can provide a reliable number of dead bodies in such a large and now, endemic phenomenon. Forensic officers, who intervened to examine migrants' corpses, are ideally required to perform the usual activity and to answer the routine questions about the causes of death by detecting signs of possible crimes and body identification. In practice, several specific issues and limits challenge the activity of the forensic professionals addressed to ascertain both circumstances of death and possible related crimes and the identity of the corpses. Generally speaking, in case of examining up to a few dead bodies in Italy, a complete autopsy is performed, whilst, when several tens or hundreds of corpses are recovered, the lack of resources on one hand and clearer clues on incident, connected crimes, and cause of deaths on the other, push the public prosecutor to limit the request of complete autopsies. In some cases, the dead migrants were identified through visual recognition by relatives, friends, or travel companions. The DVI Interpol protocol is never completely applied to dead migrants for several reasons, mainly for the huge difficulties in retrieving AM data of the missing persons and for some limitations affecting both the primary and the secondary identifiers. The few chances of identification by dental data are further reduced by the systematic lack of an odontologist among the forensic teams charged of the PM; valuable dental data for body identification or for constructing the biological profile of the missing person (age, ancestry, country of provenance/residence, etc.) are likely to be overlooked. This approach implies a clear disparity with the approach applied when corpses of citizens of the EU or other developed countries are involved and undergo identification. The dead migrants' identification activity should be reconsidered for an improvement in the common international effort in accordance to an approach more respectful toward the legal rights and dignity of the dead migrants and their families. PMID- 29384747 TI - Iatrogenic Takotsubo. PMID- 29384748 TI - Volume at First Leak Is Associated With Sling Failure Among Women With Stress Urinary Incontinence. AB - INTRODUCTION: Stress urinary incontinence at a low bladder volume is a clinically observed phenomenon that is not well studied with regard to treatment outcomes. The primary aim of our study was to determine if the volume at first leak is associated with sling outcome. METHODS: This is a retrospective cohort study evaluating whether urodynamic stress urinary incontinence observed at low volumes is associated with sling failure using the Synthetic Derivative database. Sling failure was defined as (1) undergoing a subsequent surgery for stress incontinence (eg, urethral bulking agent, repeat sling) or (2) leakage that was subjectively worse or unchanged from baseline. Sling success was defined as subjective improvement in incontinence or being dry. Intrinsic sphincter deficiency was defined as maximum urethral closure pressure 20 cm H20 or less or abdominal leak point pressure less than 60 cm H20. RESULTS: Outcome data were available for 168 of 206 women who underwent a sling after urodynamic testing from 2006 to 2014. Of the 168 women, 80 were transobturator, 79 were retropubic, 8 lacked data regarding the approach to the midurethral sling, and 1 was an autologous pubovaginal sling. Similar failure rates were seen for transobturator (10%) and retropubic slings (7.6%). Preoperative urodynamic parameters, such as cystometric capacity and intrinsic sphincter deficiency, were similar among failed and successful slings. For every additional 50 mL in bladder volume at first leak (SUIvol), there was a 1.6 increased odds of having a successful sling (odds ratio, 1.576; 95% confidence interval, 1.014-2.450; P = 0.04). There was no statistically significant association between maximum urethral closure pressure, abdominal leak point pressure, body mass index, age, sling type, or whether a prior anti-incontinence procedure had been performed and sling success. CONCLUSIONS: Bladder volume at first leak is a strong predictor of sling failure. PMID- 29384749 TI - Whose Paper Is It Anyway? Authorship Criteria According to Established Scholars in Health Professions Education. AB - PURPOSE: The health professions education (HPE) community is a crossroad of scholars from various disciplines with potentially conflicting views on who qualifies as author. Established HPE scholars are expected to model ethical research conduct, but no research has investigated the extent to which authorship criteria are understood and applied by leaders in the field. This study investigated what leading scholars consider appropriate criteria for authorship and how often these criteria are ignored. METHOD: Directors of research and editors of HPE journals completed an anonymous survey between September 2015 and August 2016 with questions about authorship practices they experienced and recommended, common authorship criteria, and how often they had encountered unethical authorship decisions. RESULTS: Out of 82 invited scholars, 46 participated in the survey (response rate = 56.0%). They reported a stark contrast between current and recommended authorship practices. Twenty-two (51.2%) had experienced unethical pressure regarding authorship order, 15 (34.9%) had not been included as author when they qualified, and 25 (58.1%) had seen authors included who did not qualify. A slight majority (n = 25; 58.1%) correctly identified authorship standards widely adopted by biomedical journals. CONCLUSIONS: A surprising proportion of leaders in the HPE field had encountered unethical authorship practices. Despite widely disseminated authorship criteria, the findings suggest that offering authorship to those who do not qualify, or arguably worse, excluding those who should have been included, remains a common practice. The authors offer strategies to scholars, editors, and tenure and promotion committees to combat these practices. PMID- 29384750 TI - Delivering on the Promise of CLER: A Patient Safety Rotation That Aligns Resident Education With Hospital Processes. AB - PROBLEM: Residency programs must provide training in patient safety. Yet, significant gaps exist among published patient safety curricula. The authors developed a rotation designed to be scalable to an entire residency, built on sound pedagogy, aligned with hospital safety processes, and effective in improving educational outcomes. APPROACH: From July 2015 to May 2017, each second year resident completed the two-week rotation. Residents engaged the foundational science asynchronously via multiple modalities and then practiced applying key concepts during a mock root cause analysis. Next, each resident performed a special review of an actual adverse patient event and presented findings to the hospital's Special Review Committee (SRC). Multiple educational outcomes were assessed, including resident satisfaction and attitudes (postrotation survey), changes in knowledge via pre- and posttest, quality of the residents' written safety analyses and oral presentations (per survey of SRC members), and organizational changes that resulted from the residents' reviews. OUTCOMES: Twenty-two residents completed the rotation. Most components were rated favorably; 80% (12/15 respondents) indicated interest in future patient safety work. Knowledge improved by 44.3% (P < .0001; pretest mean 23.7, posttest mean 34.2). Compared to faculty, SRC members rated the quality of residents' written reviews as superior and the quality of the rated oral presentations as either comparable or superior. The reviews identified a variety of safety vulnerabilities and led to multiple corrective actions. NEXT STEPS: The authors will evaluate the curriculum in a controlled trial with better measures of change in behavior. Further tests of the curriculum's scalability to other contexts are needed. PMID- 29384752 TI - Curricular Transformation: The Case Against Global Change. AB - In this Commentary, the authors make the case for medical schools to pursue more circumscribed solutions to curricular redesign for undergraduate medical education rather than whole system changes-at least as first steps and perhaps as ultimate solutions. Although they focus primarily on the experience at the Warren Alpert Medical School of Brown University (AMS), they believe that the insights gleaned from their experiences are generalizable to other innovations and other medical schools. The authors describe the implementation of the Primary Care Population Medicine track at AMS as a working example of implementing circumscribed rather than global change, and they discuss the advantages and disadvantages of such an approach to curriculum transformation. PMID- 29384751 TI - Gender Differences in Academic Medicine: Retention, Rank, and Leadership Comparisons From the National Faculty Survey. AB - PURPOSE: Prior studies have found that women in academic medicine do not advance or remain in their careers in parity with men. The authors examined a cohort of faculty from the 1995 National Faculty Survey to identify predictors of advancement, retention, and leadership for women faculty. METHOD: The authors followed 1,273 faculty at 24 medical schools in the continental United States for 17 years to identify predictors of advancement, retention, and leadership for women faculty. Schools were balanced for public or private status and the four Association of American Medical Colleges geographic regions. The authors used regression models to adjust for covariates: seniority, department, academic setting, and race/ethnicity. RESULTS: After adjusting for significant covariates, women were less likely than men to achieve the rank of professor (OR = 0.57; 95% CI, 0.43-0.78) or to remain in academic careers (OR = 0.68; 95% CI, 0.49-0.94). When number of refereed publications was added to the model, differences by gender in retention and attainment of senior rank were no longer significant. Male faculty were more likely to hold senior leadership positions after adjusting for publications (OR = 0.49; 95% CI, 0.35-0.69). CONCLUSIONS: Gender disparities in rank, retention, and leadership remain across the career trajectories of the faculty cohort in this study. Women were less likely to attain senior-level positions than men, even after adjusting for publication-related productivity. Institutions must examine the climate for women to ensure their academic capital is fully utilized and equal opportunity exists for leadership. PMID- 29384753 TI - Determinants of self-rated health in older adults before and 3 months after an emergency department visit: a prospective study. AB - OBJECTIVES: Self-rated health (SRH) is an important patient-reported outcome, but little is known about SRH after a visit to the emergency department (ED). We investigated the determinants of decline in SRH during 3 months after an ED visit in older patients. DESIGN: This was a multicenter prospective cohort study including acutely presenting older (>=70 years) patients in the ED (the Netherlands). Patients were asked to self-rate their health between 0 and 10. The main outcome was a decline in SRH defined as a transition of a SRH of at least 6 to a SRH of less than 6, 3 months after the patient's visit to the ED. RESULTS: Three months after the ED visit, 870 (71.4%) patients had a stable SRH and 209 (11.5%) patients declined in SRH. Independent predictors with a decline in SRH were: male gender (OR 1.83) living alone (OR 1.56), living in residential care or nursing home (OR 2.75), number of different medications (OR 1.08), using a walking device (OR 1.70), and the Katz-ADL score (OR 1.22). Patients with functional decline 3 months after an ED visit show a steeper decline in the mean SRH (0.68 points) than patients with no functional decline (0.12 points, P<0.001). CONCLUSION: Decline in SRH after an ED visit in older patients is at least partly dependent on factors of functional capacity and functional decline. Preventive interventions to maintain functional status may be the solution to maintain SRH, but more research is needed to further improve and firmly establish the clinical usability of these findings. PMID- 29384754 TI - 'Knocking-fingers' chest compression technique in infant cardiac arrest: single rescuer manikin study. AB - OBJECTIVE: We designed a new chest compression technique, the 'knocking-fingers' chest compression (KF) technique, for a single rescuer in infant cardiac arrest. We compared the effectiveness and feasibility between the KF technique and the two-finger (TF) and two-thumb encircling hands (TT) techniques. PARTICIPANTS AND METHODS: A prospective, randomized, crossover study was carried out to compare the quality of chest compression and ventilation between the KF, TF, and TT techniques using a 30 : 2 compression-to-ventilation ratio and mouth-to-mouth ventilation. The area of chest compression, finger(s) pain, and fatigability were measured to compare safety and feasibility. RESULTS: The total frequency of chest compression for 5 min was the highest with the KF technique, followed by the TF and TT techniques. The total frequency of ventilation for 5 min was higher with the KF and TF techniques compared with the TT technique. The total hands-off time was the shortest with the KF technique, followed by the TF and TT techniques. The area of chest compression was the smallest in KF technique. Participants complained of severe finger pain and high fatigability in TF technique. CONCLUSION: The single-rescuer KF chest compression technique is an effective alternative to the TF or TT techniques for infant cardiac arrest. PMID- 29384755 TI - Direct Echocardiographic Imaging of Berlin Heart Valves Can Aid in Early Detection of Berlin Heart Valve Dysfunction. AB - Mechanical circulatory support options remain limited for pediatric patients, especially neonates. The only FDA-approved pediatric device remains the Berlin Heart EXCOR, which unfortunately carries with it a 20-30% risk of neurologic complications, such as strokes. We demonstrate a new technique of direct echocardiographic color-Doppler imaging of the Berlin Heart valves to detect valve regurgitation. Increases in valve regurgitation could indicate issues with pump-valve thrombosis or increased afterload leading to valve insufficiency. Early recognition of valve thrombosis or insufficiency may reduce neurologic complications and lead to timely pump adjustments or replacement. PMID- 29384759 TI - Harms of cigarette smoking: call to increase knowledge among children. AB - Although the major burden of disease caused by smoking is observed in the adult population, two-third of smokers start before the age of 18 years. Reducing the number of young smokers could lead to marked improvements to the health of the UK population and save billions of pounds in National Health Service finances. However, very little is known about what makes children decide to not smoke or to quit early. We believe that increased awareness of the health risks associated with smoking will reduce smoking uptake among children. This study identifies a significant lack of knowledge among children aged 11-17 years at two London secondary schools and potentially identifies an area for improving our antismoking programmes. Although 80% of pupils cited lung cancer as being a smoking-related disease, very few other conditions could be recalled. We must do all we can to reduce smoking uptake in children. Understanding their baseline knowledge is the first step towards addressing the deficits in our current antismoking programmes. PMID- 29384762 TI - The role of robotic gait training coupled with virtual reality in boosting the rehabilitative outcomes in patients with multiple sclerosis. AB - Motor impairment is the most common symptom in multiple sclerosis (MS). Thus, a variety of new rehabilitative strategies, including robotic gait training, have been implemented, showing their effectiveness. The aim of our study was to investigate whether an intensive robotic gait training, preceding a traditional rehabilitative treatment, could be useful in improving and potentiating motor performance in MS patients. Forty-five patients, who fulfilled the inclusion criteria, were enrolled in this study and randomized into either the control group (CG) or the experimental group (EG). A complete clinical evaluation, including the Expanded Disability Severity Scale, the Functional Independence Measure, the Hamilton Rating Scale for Depression, the time up and go test (TUG), and the Tinetti balance scale, was performed at baseline (T0), after 6 week (T1), at the end of rehabilitative training (T2), and 1 month later (T3). A significant improvement was observed in the EG for all the outcome measures, whereas the CG showed an improvement only in TUG. In contrast, from T1 to T2, only CG significantly improved in all outcomes, whereas the EG had an improvement only regarding TUG. From T2 to T3, no significant differences in Functional Independence Measure scores emerged for both the groups, but a significant worsening in Tinetti balance scale and TUG was observed for the CG and in TUG for the EG. Our study provides evidence that robotic rehabilitationn coupled with two dimensional virtual reality may be a valuable tool in promoting functional recovery in patients with MS. PMID- 29384763 TI - Helicobacter pylori among patients with uninvestigated dyspepsia: issues to be remembered. PMID- 29384766 TI - Utility of post-liver transplantation MELD and delta MELD in predicting early and late mortality: Erratum. PMID- 29384764 TI - Red blood cell distribution width: a potential prognostic index for short-term mortality of patients admitted to emergency department for acute decompensation of liver cirrhosis? PMID- 29384767 TI - A Tribute. PMID- 29384768 TI - Emergency Department Use of Contrast Computed Tomography in Patients With Renal Dysfunction. AB - The Research to Practice Column is designed to improve translational research critique skills of advanced practice nurses. In this issue, the article "Risk of Acute Kidney Injury After Intravenous Contrast Media Administration" () is discussed in the context of a patient presenting to the emergency department with acute abdominal pain. The study was designed to assess the risk of acute kidney injury and adverse clinical outcomes in patients receiving intravenous contrast for computed tomography. Advanced practice nurses need to be aware of advances in types of intravenous contrast and current recommendations for administration of intravenous contrast for diagnostic purposes in patients at risk for acute kidney injury to facilitate making timely and accurate diagnoses. PMID- 29384769 TI - Hip Fractures. AB - Hip fractures are associated with significant morbidity and mortality and a major health problem in the United States (). Eighty percent of hip fractures are experienced by 80-year-old women. Plain radiographs usually confirm the diagnosis, but if there is a high level of suspicion of an occult hip fracture, magnetic resonance imaging or bone scan is the next step to confirm the diagnosis. Areas of the hip bone have varied bone strength and blood supply, making the femoral neck one of the most vulnerable areas for fracture. A consultation to an orthopedic surgeon will determine surgical interventions. PMID- 29384771 TI - The Specialty of Emergency Nurse Practitioner Practice: Erratum. PMID- 29384770 TI - A Case of Drug-Induced Severe Endocrinopathies: What Providers in the Emergency Department Need to Know. AB - The purpose of this article is to present a discussion of immune checkpoint inhibitors (ICIs) that are relatively new, yet growing, form of cancer therapy. Immune checkpoint inhibitors increase host immune response against neoplastic cells. Strengthened immunological response increases the potential for adverse events such as life-threatening endocrinopathies. The case of a 66-year-old man with metastatic melanoma treated with nivolumab and ipilimumab presented to the emergency department with marked hyperglycemia and elevated anion gap 19 days after receiving both agents is discussed. The patient received a diagnosis of immune-mediated diabetes requiring ongoing insulin even after discontinuation of ICIs. As treatment with this class of agents expands, emergency department providers will need to become familiar with the identification of their adverse reactions to provide the proper management of care. PMID- 29384772 TI - Spontaneous Vertebral Artery Dissection in a Healthy 26 Year Old Female Patient: A Case Study. AB - Spontaneous vertebral artery dissection (SVAD) is an extremely rare, yet life threatening, event that can potentially result in ischemic stroke or subarachnoid hemorrhage, depending on the origin and extension of the dissection. Vertebral artery dissection is more commonly associated with traumatic injury to the neck, resulting in compromised structural integrity of the vertebral artery wall. This case study discusses the clinical presentation, physical examination, diagnosis, clinical course, and outcome for a young, otherwise healthy, female patient who presented to the emergency department with a SVAD. PMID- 29384773 TI - Tranexamic Acid: Promise or Panacea: The Impact of Air Medical Administration of Tranexamic Acid on Morbidity, Mortality, and Length of Stay. AB - The MATTERs and CRASH-2 studies demonstrate that tranexamic acid (TXA) reduces mortality in patients with traumatic hemorrhage. However, their results, conducted in foreign countries and with U.S. military soldiers, provoke concerns over generalizability to civilian trauma patients in the United States was reported. The evaluation of patient outcomes following treatment with TXA by a civilian air medical program. A retrospective chart review of trauma patients transported by air service to a Level 1 trauma center was conducted. For the purposes of intervention evaluation, patients meeting this criterion for the 2 years (2012-2014) prior to therapy implementation were compared with patients treated during the 2-year study period (2014-2016). Goals were to evaluate morbidity, mortality, and length of stay. During the review, 82 control and 49 study patients were identified as meeting inclusion criteria. Patients in the control group were found to be less acute, which correlated with shorter hospital stays and better discharge outcomes. Multiple patients in the study group who should have expired according to a significantly elevated Trauma Revised Injury Severity Score (TRISS) survived, whereas multiple patients in the control group expired despite a low TRISS calculation. This is the first outcome-based study conducted in a U.S. trauma system. The outcomes in civilian trauma patients in the United States do not follow that of the previous MATTERs and CRASH-2 studies. However, this study still shows benefit to TXA administration and reduced risk for administration to patients with head trauma and occurrence of venous thromboembolism. Randomized control trials are needed to evaluate the role of TXA administration in the United States. PMID- 29384774 TI - What the Advanced Practice Nurse in the Emergency Department Needs to Know About the Health Risks and Hazards of Electronic Cigarette Use by Youth. AB - Despite the decline in traditional tobacco use among teens and young adults, the rapid increase in electronic cigarette (EC) use has filled the gap, raising concern that this will usher in a new generation of tobacco users. Although long term effects have not been clearly established, EC use is not without risks or hazards that may be encountered by the advanced practice nurse in the emergency department (ED). The ED presents an opportune moment for health promotion and risk reduction education for patients and families, but there are also dangers to EC use that the practitioner should be aware of and prepared to manage. Nicotine, found in most EC liquids, is well known to be a neurotoxin that affects brain development in young people. It is important to inform young people and families that EC products may contain not only nicotine but also other harmful chemicals and are not just harmless water vapor. Other toxins found in EC liquids and vapors raise questions about the health impact of long-term EC use and add additional concerns for secondhand exposure for children and pregnant women. The EC is also used by youth to inhale concentrated forms of cannabis, which could be a precursor to EC use for other illicit drugs. Hazards to be prepared for in the ED are accidental ingestion of EC liquids by children and intentional overdose of concentrated liquids. Severe injuries have been reported from explosions of EC devices as well. The ED is a starting point for EC screening and education of young people and families. Advanced practice nurses must also anticipate and be prepared to handle any other untoward effects from exposures to devices and liquids. The purpose of this article is to inform and prepare advanced practice nurses with the latest information to manage these patient encounters. PMID- 29384775 TI - Implementation of an Asthma Self-Management Education Guideline in the Emergency Department: A Feasibility Study. AB - Patients often present to emergency departments (EDs) for the management of chronic asthma. Because of the nature of ED care, national guideline recommendations for asthma education are generally not initiated in the ED. There is evidence that asthma education can have a positive effect on patient outcomes (; ). This study examines the feasibility of implementing an asthma self management guideline in a tertiary care center ED. Despite protocol utilization by physicians (87%), nurse practitioners and physician assistants (66.7%), and nurses (41.7%), total compliance with national guideline was accomplished in only 25.93% of cases. Barriers to protocol implementation included staff education, high workload, rapid turnover, and competing initiatives within the department. Linear regression analysis identified high daily census as a predictor of protocol noncompliance (p = 0.033). PMID- 29384777 TI - What the Advanced Practice Nurse in the Emergency Department Needs to Know About the Health Risks and Hazards of Electronic Cigarette Use by Youth. PMID- 29384776 TI - Evaluating an Order Set for Improvement of Quality Outcomes in Diabetic Ketoacidosis. AB - The timely management of diabetic ketoacidosis (DKA) is essential to avoid lengthy hospitalizations and poor clinical outcomes. There is often an absence of ownership for glycemic management in hospitalized patients, most notably in those with a diagnosis other than diabetes. Evidence supports the use of evidence-based DKA protocols. The purpose of this project was to determine whether utilization of an evidence-based order set versus an individualized provider approach for the treatment and management of DKA decreases resolution time and occurrences of hypoglycemia and improves clinical outcomes. Preintervention and postintervention retrospective reviews of the electronic medical record of 150 nonpregnant adult patients diagnosed with DKA allowed retrieval of relevant outcome data. Multiple events provided an intensive orientation and development of health care professionals for a systems approach to utilization of the evidence-based order set. Implementation of the institutionally approved evidence-based order set affirmed anticipated outcomes. Results showed improvements in the (a) total length of stay, (b) arrival to intravenous fluid time, (c) intravenous insulin initiation to discontinuation (resolution) time, (d) arrival to subcutaneous insulin administration time, (e) time from initial to sequential laboratory testing, (f) use of a basal, prandial, and correction insulin approach (physiological mimic), and (g) the incidence of hypoglycemia. Outcomes substantiate the importance and need for maintaining an evidence-based and systems approach for the management of DKA. PMID- 29384778 TI - Whole Genome Methylation Analysis of Nondysplastic Barrett Esophagus that Progresses to Invasive Cancer. AB - OBJECTIVE: To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. BACKGROUND: Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potential utility of epigenetic markers for identifying this group. METHODS: A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. RESULTS: In all, 12 patients with "progressive" versus 12 with "nonprogressive" nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed. CONCLUSION: Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program. PMID- 29384779 TI - Long-Term Cognitive Outcome and Brain Imaging in Adults After Extracorporeal Membrane Oxygenation. AB - OBJECTIVES: To investigate the presence of cognitive dysfunction and brain lesions in long-term survivors after treatment with extracorporeal membrane oxygenation for severe respiratory failure, and to see whether patients with prolonged hypoxemia were at increased risk. DESIGN: A single-center retrospective cohort study. SETTING: Tertiary referral center for extracorporeal membrane oxygenation in Sweden. PATIENTS: Long-term survivors treated between 1995 and July 2009. Seven patients from a previously published study investigated with a similar protocol were included. INTERVENTIONS: Brain imaging, neurocognitive testing, interview. MEASUREMENTS AND MAIN RESULTS: Thirty-eight patients (i.e., n = 31 + 7) were enrolled and investigated in median 9.0 years after discharge. Only memory tests were performed in 10 patients, mainly due to a lack of formal education necessary for the test results to be reliable. Median full-scale intelligence quotient, memory index, and executive index were 97, 101, and 104, respectively (normal, 100 +/- 15). Cognitive function was not reduced in the group with prolonged hypoxemia. Brain imaging showed cerebrovascular lesions in 14 of 38 patients (37%), most commonly in the group treated with venoarterial extracorporeal membrane oxygenation (7/11, 64%). In this group, memory function and executive function were significantly reduced. CONCLUSIONS: Patients treated with extracorporeal membrane oxygenation for respiratory failure may have normal cognitive function years after treatment, if not affected by cerebrovascular lesions. Permissive hypoxemia was not correlated with long-term cognitive dysfunction in the present study. Further prospective studies with minimal loss to follow-up are direly needed to confirm our findings. PMID- 29384781 TI - Systemic Administration of Carbon Monoxide-Releasing Molecule-3 Protects the Skeletal Muscle in Porcine Model of Compartment Syndrome. AB - OBJECTIVES: Acute limb compartment syndrome, a complication of musculoskeletal trauma, results in muscle necrosis and cell death. Carbon monoxide, liberated from the carbon monoxide-releasing molecule-3, has been shown protective in a rat model of compartment syndrome. The purpose of this study was to test the effect of carbon monoxide-releasing molecule-3 in a preclinical large animal model of compartment syndrome, with the ultimate goal of developing a pharmacologic adjunct treatment for compartment syndrome. DESIGN: Animal research study. SETTING: Basic research laboratory in a hospital setting. SUBJECTS: Male Yorkshire-Landrace pigs (50-60 kg). INTERVENTIONS: Pigs underwent 6 hours of intracompartmental pressure elevation by infusing fluid into the anterior compartment of the right hind limb. Carbon monoxide-releasing molecule-3 was administered systemically (2 mg/kg, IV) at fasciotomy, followed by 3-hour reperfusion. MEASUREMENTS AND MAIN RESULTS: Muscle perfusion, inflammation, injury, and apoptosis were assessed in the skeletal muscle. Systemic leukocyte activation was assessed during compartment syndrome and reperfusion. Elevation of hind limb intracompartmental pressure resulted in significant microvascular perfusion deficits (44% +/- 1% continuously perfused capillaries in compartment syndrome vs 76% +/- 4% in sham; p < 0.001), increased tissue injury (ethidium bromide/bisbenzimide of 0.31 +/- 0.07 in compartment syndrome vs 0.17 +/- 0.03 in sham; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.26 +/- 0.06 in compartment syndrome vs 0.13 +/- 0.03 in sham; p < 0.05), and systemic leukocyte activation (14.7 relative luminescence units/10 polymorphonuclear leukocytes in compartment syndrome vs 1.0 +/- 0.1 in baseline; p < 0.001). Systemic application of carbon monoxide-releasing molecule-3 at fasciotomy increased the number of continuously perfused capillaries (68% +/- 3%; p < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.13 +/- 0.04; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.12 +/- 0.03; p < 0.05), and blocked systemic leukocyte activation (3.9 +/- 0.3 relative luminescence unit/10 polymorphonuclear leukocytes; p < 0.001). CONCLUSIONS: Administration of carbon monoxide-releasing molecule-3 at fasciotomy offered protection against compartment syndrome-induced microvascular perfusion deficit, tissue injury, and systemic leukocyte activation. The data suggest the potential therapeutic application of carbon monoxide-releasing molecule-3 to patients at risk of developing compartment syndrome. PMID- 29384780 TI - Effect of Emergency Department and ICU Occupancy on Admission Decisions and Outcomes for Critically Ill Patients. AB - OBJECTIVES: ICU admission delays can negatively affect patient outcomes, but emergency department volume and boarding times may also affect these decisions and associated patient outcomes. We sought to investigate the effect of emergency department and ICU capacity strain on ICU admission decisions and to examine the effect of emergency department boarding time of critically ill patients on in hospital mortality. DESIGN: A retrospective cohort study. SETTING: Single academic tertiary care hospital. PATIENTS: Adult critically ill emergency department patients for whom a consult for medical ICU admission was requested, over a 21-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient data, including severity of illness (Mortality Probability Model III on Admission), outcomes of mortality and persistent organ dysfunction, and hourly census reports for the emergency department, for all ICUs and all adult wards were compiled. A total of 854 emergency department requests for ICU admission were logged, with 455 (53.3%) as "accept" and 399 (46.7%) as "deny" cases, with median emergency department boarding times 4.2 hours (interquartile range, 2.8 6.3 hr) and 11.7 hours (3.2-20.3 hr) and similar rates of persistent organ dysfunction and/or death 41.5% and 44.6%, respectively. Those accepted were younger (mean +/- SD, 61 +/- 17 vs 65 +/- 18 yr) and more severely ill (median Mortality Probability Model III on Admission score, 15.3% [7.0-29.5%] vs 13.4% [6.3-25.2%]) than those denied admission. In the multivariable model, a full medical ICU was the only hospital-level factor significantly associated with a lower probability of ICU acceptance (odds ratio, 0.55 [95% CI, 0.37-0.81]). Using propensity score analysis to account for imbalances in baseline characteristics between those accepted or denied for ICU admission, longer emergency department boarding time after consult was associated with higher odds of mortality and persistent organ dysfunction (odds ratio, 1.77 [1.07-2.95]/log10 hour increase). CONCLUSIONS: ICU admission decisions for critically ill emergency department patients are affected by medical ICU bed availability, though higher emergency department volume and other ICU occupancy did not play a role. Prolonged emergency department boarding times were associated with worse patient outcomes, suggesting a need for improved throughput and targeted care for patients awaiting ICU admission. PMID- 29384783 TI - Glucocorticoid Equipoise. PMID- 29384782 TI - Impact of Telemedicine on Mortality, Length of Stay, and Cost Among Patients in Progressive Care Units: Experience From a Large Healthcare System. AB - OBJECTIVES: To determine whether Telemedicine intervention can affect hospital mortality, length of stay, and direct costs for progressive care unit patients. DESIGN: Retrospective observational. SETTING: Large healthcare system in Florida. PATIENTS: Adult patients admitted to progressive care unit (PCU) as their primary admission between December 2011 and August 2016 (n = 16,091). INTERVENTIONS: Progressive care unit patients with telemedicine intervention (telemedicine PCU [TPCU]; n = 8091) and without telemedicine control (nontelemedicine PCU [NTPCU]; n = 8000) were compared concurrently during study period. MEASUREMENTS AND MAIN RESULTS: Primary outcome was progressive care unit and hospital mortality. Secondary outcomes were hospital length of stay, progressive care unit length of stay, and mean direct costs. The mean age NTPCU and TPCU patients were 63.4 years (95% CI, 62.9-63.8 yr) and 71.1 years (95% CI, 70.7-71.4 yr), respectively. All Patient Refined-Diagnosis Related Group Disease Severity (p < 0.0001) and All Patient Refined-Diagnosis Related Group patient Risk of Mortality (p < 0.0001) scores were significantly higher among TPCU versus NTPCU. After adjusting for age, sex, race, disease severity, risk of mortality, hospital entity, and organ systems, TPCU survival benefit was 20%. Mean progressive care unit length of stay was lower among TPCU compared with NTPCU (2.6 vs 3.2 d; p < 0.0001). Postprogressive care unit hospital length of stay was longer for TPCU patients, compared with NTPCU (7.3 vs 6.8 d; p < 0.0001). The overall mean direct cost was higher for TPCU ($13,180), compared with NTPCU ($12,301; p < 0.0001). CONCLUSIONS: Although there are many studies about the effects of telemedicine in ICU, currently there are no studies on the effects of telemedicine in progressive care unit settings. Our study showed that TPCU intervention significantly decreased mortality in progressive care unit and hospital and progressive care unit length of stay despite the fact patients in TPCU were older and had higher disease severity, and risk of mortality. Increased postprogressive care unit hospital length of stay and total mean direct costs inclusive of telemedicine costs coincided with improved survival rates. Telemedicine intervention decreased overall mortality and length of stay within progressive care units without substantial cost incurrences. PMID- 29384784 TI - Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies. AB - OBJECTIVES: Transfusion-related acute lung injury is characterized by the onset of respiratory distress and acute lung injury following blood transfusion, but its pathogenesis remains poorly understood. Generally, a two-hit model is presumed to underlie transfusion-related acute lung injury with the first hit being risk factors present in the transfused patient (such as inflammation), whereas the second hit is conveyed by factors in the transfused donor blood (such as antileukocyte antibodies). At least 80% of transfusion-related acute lung injury cases are related to the presence of donor antibodies such as antihuman leukocyte or antihuman neutrophil antibodies. The remaining cases may be related to nonantibody-mediated factors such as biolipids or components related to storage and ageing of the transfused blood cells. At present, transfusion-related acute lung injury is the leading cause of transfusion-related fatalities and no specific therapy is clinically available. In this article, we critically appraise and discuss recent preclinical (bench) insights related to transfusion-related acute lung injury pathogenesis and their therapeutic potential for future use at the patients' bedside in order to combat this devastating and possibly fatal complication of transfusion. DATA SOURCES: We searched the PubMed database (until August 22, 2017). STUDY SELECTION: Using terms: "Transfusion-related acute lung injury," "TRALI," "TRALI and therapy," "TRALI pathogenesis." DATA EXTRACTION: English-written articles focusing on transfusion-related acute lung injury pathogenesis, with potential therapeutic implications, were extracted. DATA SYNTHESIS: We have identified potential therapeutic approaches based on the literature. CONCLUSIONS: We propose that the most promising therapeutic strategies to explore are interleukin-10 therapy, down-modulating C-reactive protein levels, targeting reactive oxygen species, or blocking the interleukin-8 receptors; all focused on the transfused recipient. In the long-run, it may perhaps also be advantageous to explore other strategies aimed at the transfused recipient or aimed toward the blood product, but these will require more validation and confirmation first. PMID- 29384785 TI - Interleukin-34 Ameliorates Survival and Bacterial Clearance in Polymicrobial Sepsis. AB - OBJECTIVES: Sepsis is a devastating condition with a high mortality rate and limited treatments. Sepsis is characterized by a failed host immune response to contain the infection, resulting in organ dysfunction. Interleukin-34 is new cytokine involved in infection and immunity. Whether interleukin-34 is beneficial or deleterious to sepsis and the underlying mechanisms remains unknown. DESIGN: Prospective randomized animal investigation and in vitro studies. SETTING: Research laboratory at a university hospital. SUBJECTS: Wild-type C57BL/6 mice were used for in vivo studies, and septic human patients and healthy human subjects were used to obtain blood for in vitro studies. INTERVENTIONS: Interleukin-34 concentrations were measured in human sepsis patients and healthy individuals. The effects of interleukin-34 administration on survival, bacterial burden, organ injury, and inflammatory response were assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. MEASUREMENTS AND MAIN RESULTS: Interleukin-34 levels were significantly elevated in human sepsis and cecal ligation and puncture-induced experimental sepsis. Interleukin-34 administration improved survival and bacterial clearance, although suppressed vascular leakage and organ injury after cecal ligation and puncture-induced polymicrobial sepsis. Neutralization of interleukin-34 increased mortality rate and decreased bacterial clearance in septic mice. An increased neutrophil and macrophage influx were developed in interleukin-34-treated mice at the site of infection, accompanied by elevated production of neutrophil chemokine chemokine (C-X-C motif) ligand 1 and macrophage chemokine C-C motif chemokine ligand 2 in the peritoneal cavity. Depletion of neutrophils or macrophages reversed interleukin-34-mediated protection against polymicrobial sepsis. CONCLUSIONS: We reported for the first time a potential therapeutic role for interleukin-34 in sepsis and suggested that interleukin-34 is a novel target for the development of therapeutic agents against sepsis. PMID- 29384787 TI - Generalizing Study Results: A Potential Outcomes Perspective: Erratum. PMID- 29384786 TI - Early Risk and Resiliency Factors Predict Chronic Posttraumatic Stress Disorder in Caregivers of Patients Admitted to a Neuroscience ICU. AB - OBJECTIVES: Informal caregivers-that is, close family and friends providing unpaid emotional or instrumental care-of patients admitted to ICUs are at risk for posttraumatic stress disorder. As a first step toward developing interventions to prevent posttraumatic stress disorder in ICU caregivers, we examined the predictive validity of psychosocial risk screening during admission for caregiver posttraumatic stress disorder at 3 and 6 months post hospitalization. DESIGN: An observational, prospective study. PARTICIPANTS: Ninety-nine caregivers were recruited as part of a longitudinal research program of patient-caregiver dyads in a neuroscience ICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Caregiver posttraumatic stress disorder symptoms were assessed during admission (baseline), 3 months, and 6 months post hospitalization. We 1) characterized prevalence of clinically significant symptoms at each time point 2); calculated sensitivity and specificity of baseline posttraumatic stress disorder screening in predicting posttraumatic stress disorder at 3 and 6 months; and 3) used recursive partitioning to select potential baseline factors and examine the extent to which they helped predict clinically significant posttraumatic stress disorder symptoms at each time point. Rates of caregiver posttraumatic stress disorder remained relatively stable over time (16-22%). Screening for posttraumatic stress disorder at baseline predicted posttraumatic stress disorder at 3 and 6 months with moderate sensitivity (75 80%) and high specificity (92-95%). Screening for posttraumatic stress disorder at baseline was associated with caregiver anxiety, mindfulness (i.e., ability to be aware of one's thoughts and feelings in the moment), and bond with patient. Furthermore, baseline posttraumatic stress disorder screening was the single most relevant predictor of posttraumatic stress disorder at 3 and 6 months, such that other baseline factors did not significantly improve predictive ability. CONCLUSIONS: Screening neuroscience ICU caregivers for clinically significant posttraumatic stress disorder symptoms during admission is the single most important way to identify the majority of those likely to suffer from chronic posttraumatic stress disorder following discharge. Addressing early posttraumatic stress disorder symptoms and their psychosocial correlates during admission may help prevent chronic posttraumatic stress disorder in these at-risk caregivers. PMID- 29384789 TI - Exploring the Subtleties of Inverse Probability Weighting and Marginal Structural Models. AB - Since being introduced to epidemiology in 2000, marginal structural models have become a commonly used method for causal inference in a wide range of epidemiologic settings. In this brief report, we aim to explore three subtleties of marginal structural models. First, we distinguish marginal structural models from the inverse probability weighting estimator, and we emphasize that marginal structural models are not only for longitudinal exposures. Second, we explore the meaning of the word "marginal" in "marginal structural model." Finally, we show that the specification of a marginal structural model can have important implications for the interpretation of its parameters. Each of these concepts have important implications for the use and understanding of marginal structural models, and thus providing detailed explanations of them may lead to better practices for the field of epidemiology. PMID- 29384790 TI - Exposure to Traffic Emissions and Fine Particulate Matter and Computed Tomography Measures of the Lung and Airways. AB - BACKGROUND: Exposure to ambient air pollution has been associated with lower lung function in adults, but few studies have investigated associations with radiographic lung and airway measures. METHODS: We ascertained lung volume, mass, density, visual emphysema, airway size, and airway wall area by computed tomography (CT) among 2,545 nonsmoking Framingham CT substudy participants. We examined associations of home distance to major road and PM2.5 (2008 average from a spatiotemporal model using satellite data) with these outcomes using linear and logistic regression models adjusted for age, sex, height, weight, census tract median household value and population density, education, pack-years of smoking, household tobacco exposure, cohort, and date. We tested for differential susceptibility by sex, smoking status (former vs. never), and cohort. RESULTS: The mean participant age was 60.1 years (standard deviation 11.9 years). Median PM2.5 level was 9.7 ug/m (interquartile range, 1.6). Living <100 m from a major road was associated with a 108 ml (95% CI = 8, 207) higher lung volume compared with >=400 m away. There was also a log-linear association between proximity to road and higher lung volume. There were no convincing associations of proximity to major road or PM2.5 with the other pulmonary CT measures. In subgroup analyses, road proximity was associated with lower lung density among men and higher odds of emphysema among former smokers. CONCLUSIONS: Living near a major road was associated with higher average lung volume, but otherwise, we found no association between ambient pollution and radiographic measures of emphysema or airway disease. PMID- 29384791 TI - Intake of Sugar-sweetened Beverages and Fecundability in a North American Preconception Cohort. AB - BACKGROUND: Dietary factors, including sugar-sweetened beverages, may have adverse effects on fertility. Sugar-sweetened beverages were associated with poor semen quality in cross-sectional studies, and female soda intake has been associated with lower fecundability in some studies. METHODS: We evaluated the association of female and male sugar-sweetened beverage intake with fecundability among 3,828 women planning pregnancy and 1,045 of their male partners in a North American prospective cohort study. We followed participants until pregnancy or for up to 12 menstrual cycles. Eligible women were aged 21-45 (male partners >=21), attempting conception for <=6 cycles, and not using fertility treatments. Participants completed a comprehensive baseline questionnaire, including questions on sugar-sweetened beverage consumption during the previous 4 weeks. We estimated time-to-pregnancy from follow-up questionnaires completed every 2 months by the female partner. We calculated adjusted fecundability ratios (FR) and 95% confidence intervals (CIs) according to intake of sugar- sweetened beverages using proportional probabilities regression. RESULTS: Both female and male intakes of sugar-sweetened beverages were associated with reduced fecundability (FR = 0.81; 95% CI = 0.70, 0.94 and 0.78; 95% CI = 0.63, 0.95 for >=7 sugar-sweetened beverages per week compared with none, for females and males, respectively). Fecundability was further reduced among those who drank >=7 servings per week of sugar-sweetened sodas (FR = 0.75, 95% CI = 0.59, 0.95 for females and 0.67, 95% CI = 0.51, 0.89 for males). CONCLUSIONS: Sugar-sweetened beverages, particularly sodas and energy drinks, were associated with lower fecundability, but diet soda and fruit juice had little association. PMID- 29384793 TI - Letter to the Editor on the "European Society of Gynaecologic Oncology Quality Indicators for Advanced Ovarian Cancer Surgery" by Querleu et al, Int J Gynecol Cancer 2016;26: 1354-1363. PMID- 29384792 TI - The Effects of Long-term Storage on Commonly Measured Serum Analyte Levels. AB - BACKGROUND: Cohort studies typically bank biospecimens for many years before assay and investigators do not know whether levels of analytes have degraded. METHODS: We collected control samples from 22 nonstudy participants using the same enrollment criteria and specimen collection, processing, and storage protocols as The Sister Study. Serum samples were assayed for 21 analytes at collection and 6 years later. For each sample, the difference between the result at baseline and at 6 years was calculated for each analyte. RESULTS: Some of the analytes experienced a marked decrease in concentration after 6 years of frozen storage in liquid nitrogen vapor, compared with their baseline value. The confidence interval for the mean paired difference excluded 0 for 8 of the 21 analytes tested (aspartate transaminase, total cholesterol, estradiol, glucose, high-density lipoprotein [HDL] cholesterol, luteinizing hormone, protein, and triglycerides). Two analytes, lactate dehydrogenase and sex hormone binding globulin, increased substantially in concentration over time (confidence interval excluded 0). For compounds substantially affected by storage time, the internal laboratory control variance was greater than the estimated mean percent change for HDL cholesterol and luteinizing hormone, indicating that extent of degradation for these analytes did not exceed technical variation. CONCLUSIONS: Despite evidence for systematic changes over long-term storage, correlations between baseline and later measures were high with little relation between size of the correlation and estimated mean difference across time points. QC experiments to assess the impact of long-term storage on anticipated analytes of interest are important in planning cohort studies with banked samples. PMID- 29384794 TI - High rate of acute pancreatitis during the Ramadan fast. AB - BACKGROUND: During the Ramadan fast Muslims celebrate a month of prayer, dawn-to dusk fasting, and nightly feasts. We aimed to assess whether acute pancreatitis (AP) is more common during the Ramadan fast in individuals who celebrate it. PATIENTS AND METHODS: The study was carried out at the emergency department of Rabin Medical Center, Israel. We compared the occurrence of AP in a fasting population and a nonfasting population during the Ramadan versus the rest of the year. RESULTS: Over the 10-year study period, 1167 patients were admitted to the emergency department with AP. Of these, 1069 (91.6%) were nonfasting and 98 (8.4%) were fasting. Of these, 17/98 (17.3%) fasting patients and 95/1069 (8.8%) nonfasting patients were admitted with AP during the Ramadan [relative risk: 1.12; 95% confidence interval (CI): 1.004-1.2; odds ratio (OR): 2.15; 95% CI: 1.23-3.8; P=0.01]. During the Ramadan, the rate of AP out of referrals was 0.1% (17/15 068) in fasting patients versus 0.004% (95/213 913) in nonfasting individuals (OR: 2.54; 95% CI: 1.5-4.25). During the other months of the year, the rate of AP out of referrals was 0.009% (81/86 072) in fasting patients versus 0.008% (974/1 202 405) in nonfasting individuals (OR: 1.16; 95% CI: 0.92-1.45; P<0.001). CONCLUSION: We found a high rate of AP in the fasting population during the Ramadan. Physicians should be aware of this link and suspect it for fasting patients presenting with epigastric pain during the Ramadan fast. PMID- 29384795 TI - Nonalcoholic fatty liver disease: biomarkers as diagnostic tools for liver damage assessment in adult patients from Argentina. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has been increasing constantly and linked to the global obesity epidemic. The NAFLD histologic spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Liver biopsy is the only reliable means to diagnose and stage NASH, but its invasive nature limits its use. Therefore, the prediction of hepatic injury by means of the development of new noninvasive tests represents a growing medical need. Our aim was to evaluate matrix deposition and cell-death markers, which correlate with liver injury in an NAFLD patient cohort. PATIENTS AND METHODS: Liver biopsies and serum from 34 NAFLD adult patients were analyzed. Histological parameters were evaluated. Matrix deposition [hyaluronic acid (HA) and tissue inhibitor of matrix metalloproteinase inhibitor-1 (TIMP-1)] and cell death markers [cytokeratin-18 (M65) and caspase-cleaved cytokeratin-18 (M30)] were measured in serum samples. RESULTS: HA showed an association with fibrosis severity (P=0.03) and M30 with steatosis (P=0.013), inflammation (P=0.004), and fibrosis severity (P=0.04). In contrast, TIMP-1 and M65 showed no association with any histological parameter of liver injury. The evaluation of diagnostic accuracy showed good performance as less invasive markers of significant fibrosis of both HA (area under the receiver operating characteristic curve: 0.928) and M30 (area under the receiver operating characteristic curve: 0.848). CONCLUSION: Biomarkers are essential tools that may provide a quick and accurate diagnosis for patients with life-threatening NAFLD and NASH. HA and M30, together or determined sequentially, have been found to be straightforward tests that may be sufficient to predict significant fibrosis even in a primary care center of an underdeveloped country. PMID- 29384796 TI - Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: a case-control study. AB - BACKGROUND: Direct-acting antivirals (DAAs) therapy against hepatitis C viral (HCV) infection has markedly improved the sustained viral response. However, recent studies have suggested an unsuspected high rate of hepatocellular carcinoma (HCC) recurrence. PATIENTS AND METHODS: A retrospective case-control study was carried out to investigate the impact of DAAs on tumor recurrence in patients with complete response to HCC treatment within our HCV-related cirrhosis cohort. Patients who received [group 1 (G1), n=22] or not [group 2 (G2), n=49] a DAAs therapy were matched 1 : 2 for age, sex, liver function, HCC stage, and treatment. RESULTS: Initial HCC were mostly Barcelona Clinic Liver Cancer stage A (95% G1, 94% G2). Sustained viral response with DAAs was achieved in 86% of patients. After a similar median overall follow-up time with similar radiologic surveillance after HCC treatment, 41% of patients developed radiologic tumor recurrence in G1 versus 35% of patients in G2 (P=0.7904). There was no significant difference in time to progression between the two groups [12 (9-16) months G1 vs. 14 (8-21) months G2, P=0.7688], or Barcelona Clinic Liver Cancer stage at recurrence. However, the interval between HCC treatment and antiviral therapy was significantly different among DAAs patients with recurrence and those without recurrence [7.0 (2.5-9.0) months vs. 36.0 (9.0-58.0) months, P=0.0235, respectively]. CONCLUSION: In our case-control study, HCV therapy with DAAs does not accelerate or prevent early HCC recurrence compared with untreated patients. The rate of recurrence, time to progression, and HCC pattern are similar. Early DAAs treatment (<12 months) after HCC cure should be discouraged considering the HCC recurrence rate during this period. PMID- 29384797 TI - Clarifying the role of C-reactive protein as a bacterial infection predictor in decompensated cirrhosis. AB - INTRODUCTION: Bacterial infections are frequent in cirrhosis and may induce other deleterious complications. Ultrasensitive C-reactive protein (US-CRP), like other acute-phase proteins, is often considered useful in predicting bacterial infection in decompensated cirrhosis. However, US-CRP's reliability remains inconclusive, as inflammation in cirrhosis causes US-CRP synthesis independently of infection. The aim of this study was to clarify US-CRP's role as an infection predictor in decompensated cirrhosis. PATIENTS AND METHODS: This was a prospective single-center study with systematic inclusion of cirrhotic patients admitted because of decompensation. RESULTS: A total of 118 patients were enrolled, of whom 47 (39.8%) had an overt infection, defined by clinical and laboratory/imaging criteria. Within those, 17 had infection confirmed by culture bacterial identification. Escherichia coli was the most frequent isolated bacteria. Seventeen patients had spontaneous bacterial peritonitis, but only four (23.5%) had positive ascitic fluid cultures. US-CRP levels were significantly higher in cases of overt infection and positive culture groups than the no infection group (median: 4.14 and 6.40 vs. 1.11 mg/dl, P<0.0001 for both). When considering both overt infection and positive culture groups, the US-CRP values of area under the curve as an infection predictor were, respectively, 0.824 and 0.870, P<0.0001 for both, with associated cutoff values of 2.40 and 3.92 mg/dl, and sensitivity and specificity of 78.7/74.6 and 82.4/79.2%, respectively. CONCLUSION: The ideal US-CRP infection confirmatory cutoff is probably situated between 2.40 and 3.92 mg/dl. However, as infection is somewhat concealed and hazardous in cirrhotic patients, if not considered with lower US-CRP levels according to specific clinic scenarios, it should be carefully considered, at least, if US-CRP is greater than 2.40 mg/dl (0.5 mg/dl normal upper cutoff). PMID- 29384800 TI - Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy. AB - BACKGROUND: Cardiac abnormalities have been described in patients with Leber hereditary optic neuropathy (LHON). Some are life-threatening because of the risk of ventricular fibrillation and sudden death. The purpose of our study was to better characterize the cardiac abnormalities in a large patient cohort with LHON. METHODS: A retrospective study of the electrocardiogram (EKG) results performed on all patients with LHON evaluated at The Reference Center for Rare Diseases in Ophthalmology, Paris, France, from January 2015 to June 2017. RESULTS: Our series included 73 patients with LHON (9 women/64 men) with a mean age of 30.29 +/- 14.48 years. Although only 1 patient had cardiac complaints, cardiac abnormalities were detected in 17 patients (23.2%): 9 patients had an excitation syndrome, 6 had atrioventricular block, and 2 had repolarization abnormalities. All patients harbored mtDNA point mutations 11778 or 3460. CONCLUSIONS: Cardiac abnormalities occur frequently enough in patients with LHON that a baseline EKG is warranted. However, further studies are needed to determine the true cardiac risk associated with specific LHON mtDNA mutations. PMID- 29384798 TI - Frequency and type of drug-related side effects necessitating treatment discontinuation in the Swiss Inflammatory Bowel Disease Cohort. AB - BACKGROUND AND AIM: Systematic analyses of inflammatory bowel disease (IBD) drug related side effects necessitating treatment cessation in large cohorts of patients with IBD are scarce. We aimed to assess the frequency and type of drug related side effects requiring drug cessation in patients included in the Swiss IBD Cohort. PATIENTS AND METHODS: A retrospective review was performed of data from the Swiss IBD Cohort physician questionnaires documenting a treatment cessation for the following drug categories: aminosalicylates, topical and systemic steroids, thiopurines, methotrexate, tumor necrosis factor-antagonists, and calcineurin inhibitors (tacrolimus, cyclosporine). RESULTS: A total of 3192 patients were analyzed, of whom 1792 (56.1%) had Crohn's disease, 1322 (41.4%) had ulcerative colitis, and 78 (2.5%) had IBD unclassified. Of 3138 patients treated with IBD drugs, 2129 (67.8%) presented with one or several drug-related side effects necessitating drug cessation. We found a significant positive correlation between the number of concomitantly administered IBD drugs and the occurrence of side effects requiring drug cessation (P<0.001). Logistic regression modeling identified Crohn's disease diagnosis [odds ratio (OR)=1.361, P=0.017], presence of extraintestinal manifestations (OR=2.262, P<0.001), IBD related surgery (OR=1.419, P=0.006), and the increasing number of concomitantly used IBD drugs [OR=2.007 (P<0.001) for two concomitantly used IBD drugs; OR=3.225 (P<0.001) for at least three concomitantly used IBD drugs] to be associated significantly with the occurrence of IBD drug-related adverse events that necessitated treatment cessation. CONCLUSION: Physicians should keep in mind that the number of concomitantly administered IBD drugs is the main risk factor for drug-related adverse events necessitating treatment cessation. PMID- 29384801 TI - Posterior Ischemic Optic Neuropathy After Blepharoplasty. PMID- 29384802 TI - Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis. AB - BACKGROUND: The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. METHODS: We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360 degrees ) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. RESULTS: Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 MUm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6 MUm threshold value in a 2 * 2 table analysis with the application of chi tests (P < 0.0001). The 6-MUm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 MUm for identifying unilateral ON in the MS cohort. CONCLUSIONS: An intereye difference of 5-6 MUm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS. PMID- 29384803 TI - Ophthalmologic Approach in Epidermolysis Bullosa: A Cross-Sectional Study With Phenotype-Genotype Correlations. AB - PURPOSE: This study describes ophthalmologic and systemic clinical findings in different subtypes of epidermolysis bullosa (EB) establishing genotype-phenotype correlations. METHODS: A cross-sectional study was conducted in 58 patients with EB together with the Dystrophic Epidermolysis Bullosa Research Association, Chile. Data were stratified by major subtypes such as "simplex epidermolysis bullosa" (EBS), "junctional epidermolysis bullosa" (JEB), "recessive and dominant dystrophic epidermolysis bullosa" and "dominant dystrophic epidermolysis bullosa" (DDEB), and "Kindler syndrome" (KS). The diagnosis was confirmed by skin immunofluorescence mapping and genetic testing. Best-corrected visual acuity, corneal erosions, corneal scarring, symblepharon, blepharitis, ectropion, limbal stem cell deficiency, and esophageal involvement were assessed. Clinical outcome was based on the presence of corneal involvement attributable to EB. RESULTS: The most common ocular manifestations were corneal erosion/scarring and recurrent erosions. Frequencies of the EB subtypes were as follows: 17% EBS, 12% JEB, 16% DDEB, 53% recessive and DDEB, and 2% KS. Patients with EBS and DDEB did not reveal ocular involvement. Patients with recessive dystrophic epidermolysis bullosa (RDEB) were most affected by the disease showing corneal involvement in 16 cases, whereas 2 patients with JEB and the single KS case also showed corneal disease. Before their visit, 24 patients had undergone esophageal dilation, 23 of them with RDEB and 1 with KS. CONCLUSIONS: Although ophthalmic complications are common in EB, the incidence varied with the EB subtype. We also establish the correlation between esophageal and corneal involvement in RDEB. PMID- 29384804 TI - Reduction in Histone H3 Acetylation and Chromatin Remodeling in Corneas of Alloxan-Induced Diabetic Rats. AB - PURPOSE: To evaluate acetylation of histone H3, chromatin remodeling, nuclear size and shape, DNA ploidy, and distribution of nucleolus organizing regions (NORs) in corneal epithelial and stromal cells of diabetic and nondiabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of alloxan. All diabetic rats (n = 20) included in the study had 4 weeks of moderate-to severe hyperglycemia (plasma glucose levels >400 mg/dL). Acetylated histone H3 levels were quantified in corneal tissue using a colorimetric assay. Chromatin remodeling, nuclear sizes (area/perimeter) and shapes (circularity), and DNA ploidies were evaluated from Feulgen-stained tissue sections using video image analysis. Distributions of NORs were studied in tissue sections impregnated with silver ions. Ophthalmic clinical parameters, including corneal sensitivity, were investigated. Twenty nondiabetic rats were used as controls. RESULTS: Acetylation of histone H3 was reduced in the corneas of the diabetic rats. Nuclei in corneal epithelial cells of diabetic rats compacted chromatin, increased in size, modified their shapes, and elevated DNA ploidy. The only nuclear change observed in the corneal stromal cells of diabetic rats was chromatin decompaction. The size of the silver-stained NOR did not differ between the study samples. The corneal sensitivity in diabetic rats was 51.8% lower than that in nondiabetic rats. CONCLUSIONS: The results of this study show that alloxan-induced diabetes altered the histone H3 acetylation pattern and compromised the chromatin supraorganization in corneal tissue/cells. Continued research is needed to understand the clinical and morphofunctional significance of changes in corneal cell nuclei of diabetic individuals. PMID- 29384805 TI - Descemet Stripping Automated Endothelial Keratoplasty for Failed Penetrating Keratoplasty: Influence of the Graft-Host Junction on the Graft Survival Rate. AB - PURPOSE: To investigate the clinical results of Descemet stripping automated endothelial keratoplasty (DSAEK) for failed penetrating keratoplasty (PK) and the influence of the graft-host junction (GHJ) on the graft survival rate. METHODS: Data were retrospectively collected on patient demographics, visual outcomes, complications, and graft survival rate for 17 eyes of 16 patients who underwent DSAEK for failed PK. The graft survival rate was compared between the eyes when divided into a bump group and a well-aligned group according to the shape of the GHJ detected on anterior segment optical coherence tomography. RESULTS: The most common indication for initial PK was bullous keratopathy after glaucoma surgery (35.3%). Seven eyes (41.2%) were classified into the bump group and 10 eyes (58.8%) into the well-aligned group. The mean best-ever documented visual acuity (BDVA) after DSAEK was 0.33 logMAR. Postoperatively, almost 70% of eyes achieved a BDVA that was within 0.2 logMAR of their preoperative BDVA. Graft detachment occurred in 29.4% of eyes and primary graft failure in 17.6%. All primary failures occurred in the bump group. The cumulative graft survival rate was 82.3% at 1 year, 73.2% at 2 years, and 58.6% at 3 years. Graft failure was more likely in eyes in the bump group than in those in the well-aligned group (P = 0.037, Wilcoxon test). CONCLUSIONS: DSAEK for failed PK had a favorable outcome in this study. However, the GHJ should be assessed carefully before performing the procedure. PMID- 29384806 TI - Additional Intrastromal Corneal Ring Segments in Keratoconus. AB - PURPOSE: To evaluate the outcome of additional KeraRing (Mediphacos, Belo Horizonte, Brazil) implantation in patients with keratoconus with previously implanted INTACS (Addition Technology Inc, Fremont, CA) segments. METHODS: The KeraRing was implanted in 5 eyes of 3 patients with keratoconus without removal of previous intrastromal corneal ring segments. Tunnels were created manually. Snellen uncorrected distance visual acuity (UDVA), corrected distance visual acuity, refractive and keratometric values, and higher-order aberrations were recorded before and after KeraRing implantation. RESULTS: UDVA, corrected distance visual acuity, subjective refraction, and keratometric values were improved in 4/5 of cases and remained stable during a median follow-up of 36 months. UDVA improved from 20/200 and 20/100 to 20/100 and 20/40 in the right and left eyes of patient 1, respectively, and from 20/200 to 20/40 in both eyes of patient 2. The reduction in mean keratometric value was 2.1 and 4.4 D in the right and left eyes of patient 1, and 1.4 and 1.9 D in the right and left eyes of patient 2, respectively. In patient 3, UDVA (20/100) and mean keratometric value (52.4) remained unchanged after second intrastromal corneal ring segment implantation. Total higher-order aberrations were improved in all cases. No intraoperative or postoperative complication was observed. However, one of the cases reported glare under scotopic conditions. CONCLUSIONS: KeraRing implantation in properly selected eyes with previously implanted INTACS could enhance final visual and refractive outcomes. PMID- 29384807 TI - An Early Finding of Keratoconus: Increase in Corneal Densitometry. AB - PURPOSE: To investigate the corneal densitometry in subclinical keratoconus with normal elevation and pachymetric parameters. METHODS: Patients with clinical keratoconus in one eye and subclinical keratoconus in the fellow eye were identified. The study group was selected from patients with subclinical keratoconus who showed normal results from topographic and Belin-Ambrosio Enhanced Ectasia Display III (BAD) analysis (Kmean <47.2 diopters, inferior superior asymmetry <1.4 diopters, and KISA% <60%, elevation <5 MUm, PPIaverage <1.06, PPImaximum <1.44, ARTaverage <414 MUm, ARTmaximum <339 MUm, and final D <1.6). The control group was selected from candidates for refractive surgery. The densitometric analyses were performed through the Pentacam HR (Oculus, Germany). RESULTS: The medical records of 3474 patients with keratoconus were examined, and 116 (3.3%) subclinical keratoconus cases were detected. Normal BAD analysis results were obtained from 38 patients (1.1%). The control group also consisted of 38 patients. There were no significant differences between the eyes with subclinical keratoconus and those of the control in corrected distance visual acuity and topographic, topometric, and tomographic parameters (P > 0.05). In all layers of the 0- to 2-mm zone and in the anterior and central layers of the 0- to 6-mm zone, corneal densitometry was significantly higher in the subclinical keratoconus than the control (P < 0.001). In discriminating eyes with subclinical keratoconus from normal, the anterior layer in the 0- to 2-mm zone showed the highest area under the curve (0.883; cutoff: 19.7; sensitivity: 75%; specificity: 90%) in a receiver operating characteristic analysis. CONCLUSIONS: The increase in densitometry in the central zone could be useful in detecting subclinical keratoconus. PMID- 29384808 TI - Regenerative Therapy for Fuchs Endothelial Corneal Dystrophy. AB - PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is an acquired corneal endotheliopathy and is one of the most common indications for corneal transplantation surgery worldwide. Endothelial keratoplasty (EK) is the most popular form of corneal transplantation for FECD. In standard EK surgery, the patient's corneal endothelium and basement membrane [ie, Descemet membrane (DM)] are first removed, followed by transplantation of donor tissue that comprises allogenic corneal endothelial cells, DM, and corneal stroma of variable thickness. We hypothesized that in lieu of EK, transplantation of acellular DM (ie, Descemet membrane transplantation, DMT) may similarly restore anatomical and functional integrity of the corneal endothelium, by stimulating centripetal migration of peripheral host corneal endothelial cells. METHODS: A case report of a first-in-human trial of DMT for treatment of FECD is presented. RESULTS: A patient with FECD was successfully treated with DMT. Her preoperative best corrected Snellen visual acuity (BCVA) was 6/18, central corneal thickness was 603 nm, and central corneal endothelial cell density was unrecordable. By postoperative month 6, her best-corrected Snellen visual acuity had improved to 6/7.5, central corneal thickness was 569 nm, and central corneal endothelial cell density was 889 cells/mm. She remained stable despite complete cessation of all medications including immunosuppressants. No significant postoperative complications have been encountered. CONCLUSIONS: DMT may be effective for treatment of FECD. Achievement of endothelial regeneration without allogenic corneal endothelial cell transplantation and exposure to the attendant risks of graft rejection and chronic immunosuppression represents a significant improvement from the current paradigm of EK. PMID- 29384809 TI - Involvement of Nectin-Afadin in the Adherens Junctions of the Corneal Endothelium. AB - PURPOSE: The cell-cell adhesion molecules, cadherins and nectins, are involved in the formation of adherens junctions. However, involvement of nectins in the corneal endothelium has not yet been established. This study investigated the involvement of nectins in adherens junctions of the corneal endothelium. METHODS: Nectin and cadherin expression in the corneal endothelium was evaluated by real time polymerase chain reaction. Colocalization and direct binding of nectin-1 and N-cadherin to anchoring proteins (afadin and beta-catenin, respectively) were determined by immunostaining and immunoprecipitation. The effect of afadin and N cadherin knockdown on apical junctions was evaluated by immunostaining. RESULTS: Real-time polymerase chain reaction confirmed nectin-1, nectin-2, nectin-3, nectin-4, and afadin expression in the corneal endothelium. Immunofluorescence staining showed colocalization of nectin and afadin at the basal side of the tight junction (where adherens junctions typically locate) and immunoprecipitation confirmed direct binding of nectin to afadin. N-cadherin, P cadherin, VE-cadherin, and OB-cadherin messenger RNAs were expressed in the corneal endothelium. N-cadherin and beta-catenin colocalized at the cell-cell border, where they directly bound and formed a cell-cell adhesion complex. N cadherin knockdown disrupted the normal expression pattern of zonula occludens protein-1 and afadin, but afadin knockdown had no effect on the expression pattern of zonula occludens protein-1 and N-cadherin. CONCLUSIONS: We believe this to be the first report of conservation of the nectin-afadin system in the corneal endothelium and its involvement in the formation of adherens junctions. N cadherin, as a member of the cadherin family, is also essential for the formation and maintenance of cell-cell adhesion mediated by nectins and tight junctions in the corneal endothelium. PMID- 29384810 TI - Effects of Repeated Intravitreal Aflibercept Injection on the Corneal Endothelium in Patients With Age-Related Macular Degeneration: Outcomes From the RE-VIEW Study. AB - PURPOSE: The effects of repeated intravitreal aflibercept injection (IAI) on the corneal endothelium were studied in patients with unilateral neovascular age related macular degeneration. METHODS: RE-VIEW was a phase 4, open-label, single arm, multicenter study. Patients received IAI every 8 weeks after 3 monthly doses. Slit-lamp biomicroscopy was performed at all study visits. The central corneal endothelial health was evaluated by specular microscopy in the treated versus untreated fellow eyes at baseline and weeks 24 and 52. RESULTS: No slit lamp abnormalities were noted in 154 enrolled patients (eyes). Baseline versus 52 week mean (+/-SD) endothelial morphometric values (n = 118) for the treated versus untreated fellow eyes were respectively as follows: endothelial cell density was 2410 +/- 364 versus 2388 +/- 384 cells/mm at baseline and remained unchanged at 2401 +/- 353 versus 2376 +/- 364 cells/mm at 52 weeks (P = 0.87); the coefficient of variation was 33.5 +/- 4.4% versus 34.0 +/- 5.0% at baseline and remained unchanged at 34.2 +/- 4.7% versus 34.1 +/- 4.9% at 52 weeks (P = 0.18); the percentage of hexagonal cells was 59.5 +/- 5.8% versus 59.6 +/- 6.4% at baseline and remained unchanged at 59.5 +/- 6.0% versus 59.5 +/- 5.8% at 52 weeks (P = 0.96). CONCLUSIONS: Repeated IAI for 52 weeks had no apparent corneal endothelial toxicity noted on specular microscopy in patients treated for neovascular age-related macular degeneration. PMID- 29384811 TI - Accuracy of Corneal Thickness by Swept-Source Optical Coherence Tomography and Scheimpflug Camera in Virgin and Treated Fuchs Endothelial Dystrophy. AB - PURPOSE: To assess intraobserver repeatability, intersession reproducibility, and agreement of swept-source Fourier-domain optical coherence tomography (SS-OCT) and the Scheimpflug camera in measuring corneal thickness in virgin and grafted eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: Thirty-six control eyes, 35 FECD eyes, 30 FECD with corneal edema eyes, 25 Descemet stripping automated endothelial keratoplasty (DSAEK) eyes, and 29 Descemet membrane endothelial keratoplasty (DMEK) eyes were included. The apical center, pupillary center, and thinnest corneal thickness were determined in 3 consecutive images and repeated 2 weeks later. Repeatability and reproducibility coefficients, intraclass correlation coefficients, and 95% limits of agreement (LOA) between measurements were calculated. Agreement between devices was assessed using Bland Altman analysis. RESULTS: Corneal thickness measurements were highly reproducible and repeatable with both systems. SS-OCT showed better repeatability in all corneal locations in the normal, FECD, FECD with edema, DSAEK, and DMEK groups (coefficient of variation <=0.60%, <=0.36%, <=0.43%, <=1.09%, and <=0.48%, respectively) than the Scheimpflug (coefficient of variation <=1.15%, <=0.92%, <=1.10%, <=1.25%, and <=1.14%, respectively). Between-session 95% LOA for SS-OCT was less than 3% for all groups except for the FECD with edema group, being almost double using the Scheimpflug camera. Differences between instruments were statistically significant in all groups and locations (P < 0.01) except in the DSAEK group (P <= 0.51); however, SS-OCT underestimated all measurements. CONCLUSIONS: SS-OCT provides better reproducible and repeatable measurements of corneal thickness than those obtained with the Scheimpflug camera in patients with FECD or an endothelial transplant. Variations between examinations higher than the 95% LOA observed in our study should raise awareness of changes in the endothelial function. PMID- 29384812 TI - Descemetorhexis Without Endothelial Keratoplasty (DWEK): Proposal for Nomenclature Standardization. PMID- 29384813 TI - Detection of Near Falls Using Wearable Devices: A Systematic Review. AB - BACKGROUND AND PURPOSE: Falls among older people are a serious health issue. Remote detection of near falls may provide a new way to identify older people at high risk of falling. This could enable exercise and fall prevention programs to target the types of near falls experienced and the situations that cause near falls before fall-related injuries occur. The purpose of this systematic review was to summarize and critically examine the evidence regarding the detection of near falls (slips, trips, stumbles, missteps, incorrect weight transfer, or temporary loss of balance) using wearable devices. METHODS: CINAHL, EMBASE, MEDLINE, Compendex, and Inspec were searched to obtain studies that used a wearable device to detect near falls in young and older people with or without a chronic disease and were published in English. RESULTS: Nine studies met the final inclusion criteria. Wearable sensors used included accelerometers, gyroscopes, and insole force inducers. The waist was the most common location to place a single device. Both high sensitivity (>=85.7%) and specificity (>=90.0%) were reported for near-fall detection during various clinical simulations and improved when multiple devices were worn. Several methodological issues that increased the risk of bias were revealed. Most studies analyzed a single or few near-fall types by younger adults in controlled laboratory environments and did not attempt to distinguish naturally occurring near falls from actual falls or other activities of daily living in older people. CONCLUSIONS: The use of a single lightweight sensor to distinguish between different types of near falls, actual falls, and activities of daily living is a promising low-cost technology and clinical tool for long-term continuous monitoring of older people and clinical populations at risk of falls. However, currently the evidence is limited because studies have largely involved simulated laboratory events in young adults. Future studies should focus on validating near-fall detection in larger cohorts and include data from (i) people at high risk of falling, (ii) activities of daily living, (iii) both near falls and actual falls, and (iv) naturally occurring near falls. PMID- 29384814 TI - The So-Called Aggressive Digital Papillary Adenocarcinoma Is Epithelial Myoepithelial Carcinoma. PMID- 29384815 TI - Reply: Postoperative Patient- and Parent-Reported Outcomes for Children with Congenital Hand Differences: A Systematic Review. PMID- 29384816 TI - BIA-ALCL Incidence: The Variable to be Included in the Denominator. PMID- 29384817 TI - Postoperative Patient- and Parent-Reported Outcomes for Children with Congenital Hand Differences: A Systematic Review. PMID- 29384818 TI - Response to Letter "Radiation Will Always Alter Skin in Breast Cancer Treatment". PMID- 29384819 TI - Medial Row Perforators Are Associated with Higher Rates of Fat Necrosis in Bilateral DIEP Flap Breast Reconstruction. PMID- 29384820 TI - Reply: Treating Breast Conservation Therapy Defects with Brava and Fat Grafting: Technique, Outcomes, and Safety Profile. PMID- 29384821 TI - Treating Breast Conservation Therapy Defects with Brava and Fat Grafting: Technique, Outcomes, and Safety Profile. PMID- 29384822 TI - Smaller Diameter Anastomotic Coupling Devices Have Higher Rates of Venous Thrombosis in Microvascular Free Tissue Transfer. PMID- 29384823 TI - Reply: Smaller Diameter Anastomotic Coupling Devices Have Higher Rates of Venous Thrombosis in Microvascular Free Tissue Transfer. PMID- 29384824 TI - BIA-ALCL: The Importance of Denominators. PMID- 29384826 TI - Childhood Polyarteritis Nodosa Presenting With Symmetric Digital Gangrene and Hyperesthesia. PMID- 29384825 TI - Ophthalmic Manifestations of Allergic Fungal Sinusitis. AB - PURPOSES: To study the ophthalmic manifestations of patients with allergic fungal sinusitis (AFS) and evaluate the importance of early diagnosis and management in preventing the possible future complications of AFS. METHODS: Retrospective chart review of 100 patients with the diagnosis of AFS from a single institution was performed. Age, gender, clinical presentation including ophthalmic and radiological findings, immune status, patterns of sinus involvement, medical and surgical intervention needed, laboratory results, and the course of the disease were evaluated. RESULTS: The mean age at presentation was 19.8 years (range, 10 42 years) with no clear gender predominance (52% of patients were female).The most common sinuses involved were ethmoid and maxillary sinuses. All patients underwent functional endoscopic sinus surgery and received systemic and topical steroids. There were no intervention-related complications. Thirty-four of 100 patients had ophthalmic consequences of AFS. The most common ophthalmic presentation was proptosis (n = 21, 61.7%), followed by epiphora (n = 5, 14.7%), visual loss (n = 4, 11.7%), diplopia (n = 3, 8.8%), and dystopia (n = 1, 2.9%) in addition to 1 patient having ptosis beside proptosis. CT scans of these 34 patients showed that 82.3% had nonhomogenous opacification of sinuses, 52% had erosion of lamina papyracea, 17.6% had intraorbital extension, and 8.8% had intracranial extension. CONCLUSIONS: Ophthalmologists may be the first who encounter these patients which necessitates familiarity with AFS presentations and complications. In cases of sudden visual loss, early intervention may prevent permanent vision loss. Functional endoscopic sinus surgery and postoperative systemic and topical steroids resulted in dramatic improvement of ophthalmic symptoms and signs. PMID- 29384827 TI - Idiopathic Sclerosing Orbital Inflammation in a Relapsing Polychondritis Patient With Impaired Vision. AB - A 55-year-old woman with relapsing polychondritis had progressively enlarged right retro-orbital tumor invading the optic nerve, followed by left retrobulbar infiltrating lesions despite prescription of high-dose corticosteroids and pulse methylprednisolone. Repeated histopathologic analyses showed dense collagen fibers with scanty inflammatory cells, consistent with the diagnosis of idiopathic sclerosing orbital inflammation. This disorder has been recognized as a distinct entity with unique clinical features and coexisting rheumatologic disorders, requiring more focused diagnostic strategies and therapeutic regimens. In summary, we demonstrate a rare ocular manifestation in relapsing polychondritis and emphasize the importance of serial radiological and pathological evaluations in such patients presenting with exophthalmos. PMID- 29384828 TI - Evaluation of Vitamin B12 Deficiency and Associated Factors in Patients With Systemic Sclerosis. AB - BACKGROUND/OBJECTIVE: In patients with systemic sclerosis (SSc) gastrointestinal (GI) involvement, nutritional status and medications may lead to cobalamin (Vit B12) deficiency. We aimed to determine the frequency and the potential causes of Vit B12 deficiency in SSc patients. METHODS: We conducted a cross-sectional analysis of 62 SSc patients in a single center in 1 year period. Medical history and physical examination of patients were reevaluated. Data about organ involvements were obtained from hospital file records. The nutritional status of the patients was assessed with Malnutrition Universal Screening Tool (MUST). Vit B12, homocysteine (except in three patients) and Helicobacter Pylori Immunoglobulin G (H. Pylori IgG) levels were measured in all patients. Vit B12 deficiency was considered as serum Vit B12 level <200 pg/mL or being on Vit B12 replacement therapy. Serum Vit B12 levels of the patients were also grouped as low (<200 pg/mL), borderline (200-300 pg/mL) and normal (>300 pg/mL). Plasma homocysteine levels of the patients were classified as elevated (>9 MUmol/L) and hyperhomocysteinemia (>15 MUmol/L). Mann-Whitney U and Kruskal-Wallis tests were used to compare parameters among the groups. Correlation was tested by Spearman's correlation coefficient. RESULTS: Forty-four (71.0%) patients were defined as Vit B12 deficient; 22 had Vit B12 level <200 pg/mL (four were on Vit B12 replacement therapy) and the remaining 22 had Vit B12 >200 pg/mL and were already on Vit B12 replacement therapy. The percentage of the patients with hyperhomocysteinemia was significantly higher in the group with Vit B12 <200 pg/mL as compared to other groups (P = 0.004) but only 33.3% (7/21) of the patients with Vit B12 <200 pg/mL had hyperhomocysteinemia. There were no statistically significant differences between patients with and without Vit B12 deficiency regarding age, mean disease duration, MUST scores, mean hemoglobin levels, H. Pylori IgG positivity and organ involvements (P > 0.05 for all). CONCLUSIONS: Vit B12 deficiency is frequent in SSc and has multiple causes. All patients should be monitored for Vit B12 deficiency. The homocysteine levels seem unlikely to be helpful for confirmation of Vit B12 deficiency. PMID- 29384829 TI - Oculomotor Nerve Demyelination Secondary to Certolizumab Pegol. PMID- 29384830 TI - Giant Cell Arteritis and Malignancy-More Than Just a Coincidence? PMID- 29384831 TI - A Transactional "Second-Victim" Model-Experiences of Affected Healthcare Professionals in Acute-Somatic Inpatient Settings: A Qualitative Metasynthesis. AB - BACKGROUND: "Second victims" are healthcare professionals traumatized by involvement in significant adverse events. Associated burdens, e.g., guilt, can impair professional performance, thereby endangering patient safety. To date, however, a model of second victims' experiences toward a deeper understanding of qualitative studies is missing. Therefore, we aimed to identify, describe, and interpret these experiences in acute-somatic inpatient settings. METHODS: This qualitative metasynthesis reflects a systematic literature search of PubMed, CINAHL, and PsycINFO, extended by hand searches and expert consultations. Two researchers independently evaluated qualitative studies in German and English, assessing study quality via internationally approved criteria. Results were analyzed inductively and aggregated quantitatively. RESULTS: Based on 19 qualitative studies (explorative-descriptive: n = 13; grounded theory: n = 3; phenomenology: n = 3), a model of second-victim experience was drafted. This depicts a multistage developmental process: in appraising their situation, second victims focus on their involvement in an adverse event, and they become traumatized. To restore their integrity, they attempt to understand the event and to act accordingly; however, their reactions are commonly emotional and issue focused. Outcomes include leaving the profession, surviving, or thriving. This development process is alternately modulated by safety culture and healthcare professionals. CONCLUSIONS: For the first time, this model works systematically from the second-victim perspective based on qualitative studies. Based on our findings, we recommend integrating second victims' experiences into safety culture and root-cause analyses. Our transactional model of second-victim experience provides a foundation for strategies to maintain and improve patient safety. PMID- 29384832 TI - Phenotypic appearances of prostate utilizing PET-MRI and PET-CT with 68Ga-PSMA, radiolabelled choline and 68Ga-DOTATATE. AB - The objective of this study was to highlight the role of multimodality imaging and present the differential diagnosis of abnormal tracer accumulation in the prostate and periprostatic tissue. Our departments have performed molecular imaging of the prostate utilizing PET-CT and PET-MRI with a range of biomarkers including F-FDG, radiolabelled choline, Ga-DOTATATE PET-CT and Ga-PSMA images. We retrospectively reviewed the varying appearances of the prostate gland in different diseases and incidental findings in periprostatic region. The differential diagnosis of pathologies related to prostate and periprostatic tissue on multimodality imaging includes malakoplakia, rhabdomyosarcoma, lymphoma, prostate cancer, neuroendocrine tumours, uchida changes, rectoprostatic fistula, synchronous malignancies, lymphocoele and schwanoma. There exists a wide differential for abnormal tracer accumulation in the prostate gland. As a radiologist and nuclear medicine physician, it is important to be aware of range of prostatic and periprostatic pathologies. PMID- 29384833 TI - A review of paediatric administered radiopharmaceutical activities to determine compliance with prescription guidelines. AB - OBJECTIVE: Attempts are underway to standardize paediatric administered activities, but equally important is knowing the actual activities administered to patients. In this work, paediatric administered activities are reviewed to determine compliance with the institution-prescribed guidelines. PATIENTS AND METHODS: Paediatric administered activities for common studies at our institution, August 2011 to January 2017, have been analysed to determine their deviations from the set guideline tolerance of 10% from prescribed activities. RESULTS: The results for technetium-99m hydroxy diphosphonate (Tc-HDP), technetium-99m mercaptoacetyl triglycine (Tc-MAG3) and technetium-99m dimercaptosuccinic acid (Tc-DMSA), are presented here. Tc-MAG3 mean activities were close to the tolerance guideline at 10.3% SD. For Tc-HDP and Tc-DMSA, the prescribed guidelines were reviewed and reduced in May 2014 and September 2015, respectively. SDs for these studies over the two acquisition periods were different (8.9 and 6.6%, respectively, for Tc-HDP and 11.8 and 14.2%, respectively, for Tc-DMSA).The administered activities (dispensed minus residual activities) to patients depend on prescribed activities and dispensing and injecting techniques. Deviations from the prescribed activities are primarily because of issues related to residual activities, particularly with small activities prescribed in young patients. Small activities in small volumes make residual activities significant. The skill and experience of the nuclear medicine staff are essential in minimizing deviations from prescribed activities. CONCLUSION: It is important to measure residual to accurately determine the administered activities. If precautions are taken with dispensing and injecting techniques, it is possible to administer activities close to 10% of the prescribed activities. The regular review of the administered activities is essential to ensure that patients are not unnecessarily irradiated. PMID- 29384834 TI - Mindsets May Matter in Nursing Education. AB - Nursing education needs innovative and effective teaching models that are easily conveyed and economical. Dweck's mindset model harnesses the predictive power of noncognitive factors such as motivation, perseverance, effort, and academic tenacity to shape the learner's perceptions of intelligence for competency development. All individuals possess perceptions of intelligence; however, the mindset model demonstrates the immense potential associated with endorsement of the growth mindset and student success. PMID- 29384835 TI - Screening and brief intervention to prevent fetal alcohol spectrum disorders. PMID- 29384836 TI - How oral medications affect wound healing. PMID- 29384837 TI - Obituary Prof. Dr. med. D. Sc. h.c. Robert F. Schmidt, Ph.D. PMID- 29384838 TI - Probiotics for Preterm Infants: A Strain-Specific Systematic Review and Network Meta-analysis. AB - OBJECTIVES: Several randomized controlled trials (RCTs) on the use of probiotics to reduce morbidity and mortality in preterm infants have provided inconsistent results. Although meta-analyses that group all of the used strains together are suggesting efficacy, it is not possible to determine the most effective strain that is more relevant to the clinician. We therefore used a network meta-analysis (NMA) approach to identify strains with greatest efficacy. METHODS: A PubMed search identified placebo-controlled or head-to-head RCTs investigating probiotics in preterm infants. From trials that recorded mortality, necrotizing enterocolitis, late-onset sepsis, or time until full enteral feeding as outcomes, data were extracted and Bayesian hierarchical random-effects models were run to construct a NMA. RESULTS: Fifty-one RCTs involving 11,231 preterm infants were included. Most strains or combinations of strains were only studied in one or a few RCTs. Only 3 of 25 studied probiotic treatment combinations showed significant reduction in mortality rates. Seven treatments reduced necrotizing enterocolitis incidence, 2 reduced late-onset sepsis, and 3 reduced time until full enteral feeding. There was no clear overlap of strains, which were effective on multiple outcome domains. CONCLUSIONS: This NMA showed efficacy in reducing mortality and morbidity only in a minority of the studied strains or combinations. This may be due to an inadequate number, or size, of RCTs, or due to a true lack of effect for certain species. Further large and adequately powered RCTs using strains with the greatest apparent efficacy will be needed to more precisely define optimal treatment strategies. PMID- 29384839 TI - Is there any alternative to standard chest compression techniques in infants? A randomized manikin trial of the new "2-thumb-fist" option. AB - BACKGROUND: Pediatric cardiac arrest is a fatal emergent condition that is associated with high mortality, permanent neurological injury, and is a socioeconomic burden at both the individual and national levels. The aim of this study was to test in an infant manikin a new chest compression (CC) technique ("2 thumbs-fist" or nTTT) in comparison with standard 2-finger (TFT) and 2-thumb encircling hands techniques (TTEHT). METHODS: This was prospective, randomized, crossover manikin study. Sixty-three nurses who performed a randomized sequence of 2-minute continuous CC with the 3 techniques in random order. Simulated systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressures (PP, SBP-DBP) in mm Hg were measured. RESULTS: The nTTT resulted in a higher median SBP value (69 [IQR, 63-74] mm Hg) than TTEHT (41.5 [IQR, 39-42] mm Hg), (P < .001) and TFT (26.5 [IQR, 25.5-29] mm Hg), (P <.001). The simulated median value of DBP was 20 (IQR, 19-20) mm Hg with nTTT, 18 (IQR, 17-19) mm Hg with TTEHT and 23.5 (IQR, 22-25.5) mm Hg with TFT. DBP was significantly higher with TFT than with TTEHT (P <.001), as well as with TTEHT than nTTT (P <.001). Median values of simulated MAP were 37 (IQR, 34.5-38) mm Hg with nTTT, 26 (IQR, 25-26) mm Hg with TTEHT and 24.5 (IQR,23.5-26.5) mm Hg with TFT. A statistically significant difference was noticed between nTTT and TFT (P <.001), nTTT and TTEHT (P <.001), and between TTEHT and TFT (P <.001). Sixty-one subjects (96.8%) preferred the nTTT over the 2 standard methods. CONCLUSIONS: The new nTTT technique achieved higher SBP and MAP compared to the standard CC techniques in our infant manikin model. nTTT appears to be a suitable alternative or complementary to the TFT and TTEHT. PMID- 29384840 TI - The relationship between the expression of TN and the efficiency of posterior spinal V osteotomy in patients with traumatic kyphosis. AB - BACKGROUND: This study was conducted with the aim to investigate the relationship between Tetranectin (TN) and efficiency of posterior spinal V osteotomy in patients with traumatic kyphosis. METHODS: Ninety-two patients with traumatic kyphosis admitted in our hospital from February 2014 to June 2016 were included whose serum TN levels were examined by ELISA. Using the mean level of TN as cut off value, patients were classified into TN high level group (group I) and TN low level group (group II). The observation indexes, including operation time, intra operational loss of blood, Cobb angle, postoperative complications and recurrence rate of kyphosis within post-operational 6 months were recorded for comparison. RESULTS: TN level was significantly higher in group I [(6.19 +/- 0.33) MUmol/L] than that in group II [(5.29 +/- 0.34) MUmol/L] (P < .05). There was no significant difference in average age, sex, lesion site and average time from injury to operation between the two groups (all P > 0.05). Compared to group II, operation time in group I was significantly shortened (5.02 +/- 1.15 VS 4.58 +/- 0.53, P = .023), the intra-operational loss of blood decreased (2418.56 +/- 362.06 VS 2235.84 +/- 325.63, P = .013), post-operational Cobb angle decreased (11.10 +/- 1.31 VS 6.93 +/- 1.04, P = .000), and the incidence of postoperative complications (nail-breaking, rod-breaking and looseness) and recurrence rate decreased (18.8% VS 4.5%, P = .036; 10.4% VS 0.0%, P = .028). CONCLUSION: Serum TN level is proved to be related to the efficiency of posterior spinal V osteotomy in patients with traumatic kyphosis, and may serve as a possible indicator for clinical treatment. PMID- 29384841 TI - Independent predictors and lymph node metastasis characteristics of multifocal papillary thyroid cancer. AB - The multifocal papillary thyroid cancer (PTC), with more aggressive and poorer prognosis, is not rare in papillary histotype. Few studies evaluated risk factors and lymph node metastasis in multifocal PTC. The aim of this present study focusing on risk factors and lymph node metastasis characteristics in multifocal PTC was excepted to assist clinical decisions regarding surgery.It was a retrospective study. The 1249 consecutive patients with PTC were reviewed. Of these, 570 patients who met the criteria were selected: 285 with solitary papillary thyroid cancer and 285 with multifocal PTC. The risk factors and lymph node metastasis in multifocal PTC were investigated by univariate and multivariate analysis.Multifocal PTC showed a higher positive rate of capsular invasion, extrathyroidal extension, tumor size >10 mm, pathological T classification, N+ stage, local recurrence, and radioactive iodine ablation (RAI). Capsular invasion (hazard ratio [HR], 1.589; 95% confidence interval [CI],1.352-1.984), advanced pathological T classification (HR, 3.582; 95% CI, 2.184-5.870), and pathological N+ stage (HR, 1.872; 95% CI, 1.278-2.742) were related to increased risk of multifocality and there was a significant increased HR for central neck compartment involvement in male sex (HR, 2.694; 95% CI, 1.740 4.169), advanced pathological T classification (HR, 2.403; 95% CI, 1.479-3.907) and multifocality (HR, 1.988; 95% CI, 1.361-2.906).There is a significant association between capsular invasion, advanced pathological T classification, N+ stage, and multifocal PTC. Total thyroidectomy plus prophylactic bilateral central lymph node dissection should be recommended during surgery due to a stronger predilection for level VI lymph node metastasis in multifocal PTC. PMID- 29384842 TI - Clinical and radiological features of Marchiafava-Bignami disease. AB - Marchiafava-Bignami disease (MBD) is a rare neurological disease usually associated with chronic alcoholism and characterized by demyelination and necrosis. Our aims were to describe the clinicoradiological features and identify factors that may affect the prognosis of patients with MBD.We examined clinical manifestations, laboratory results, and neuroradiological features of 9 patients with MBD. The patients were classified into 2 subgroups (favorable and poor outcome subgroups) based on the Modified Oxford Handicap Scale (MOSH). In addition, we compared the clinical and neuroimaging features between the 2 subgroups.Nine adult male patients (age of onset range 37-62 years, with a mean age of 47.00 +/- 14.50 years) were included in this study. According to MOSH, 4 patients were placed in the poor outcome subgroup (MOHS >= 3), 5 patients were placed in the favorable outcome subgroup (MOHS <= 2). Relatively high score of MAST-C (>=6) (P = .008), extracallosal lesions (P = .048), GCS (P = .026), cerebral lobe impairment (P = .048) was significantly more common in the poor outcome subgroup.Clinical manifestations of MBD are variable and lack specificity. Early diagnosis by relatively specific performance of bisymmetric lesions in corpus callosum of diffusion-weighted imaging (DWI) may affect the prognosis. The prognosis of patients with severe disturbance of consciousness, heavy alcohol consumption, extracallosal lesions, cerebral lobe impairment is probably unfavorable. PMID- 29384843 TI - The expression and significance of microRNA in different stages of colorectal cancer. AB - BACKGROUND: The aim of this study is to compare microRNA expression patterns in different stages of colorectal cancer (CRC) and to discuss the significance of the application of microRNAs in the clinical treatment of CRC. METHODS: The study used gene chip technology to analyze genetic sequences in CRC tissues and surrounding normal tissues at different cancer stages. The bioinformatics profiles of the target genes of the different microRNAs were analyzed to clarify the target gene-related pathways and their functions in the disease. RESULTS: A total of 368 target genes with differential expression, including 275 upregulated and 93 downregulated genes, were screened from CRC patients in different stages of the disease. These microRNAs participated widely in the occurrence and development processes of CRC. The microRNA expression profiles obviously differed in tissues at different CRC stages. CONCLUSION: microRNA regulation of CRC samples can be used as a tool to control the occurrence and development of tumor cells. PMID- 29384844 TI - Modified trapeziectomy with ligament reconstruction tendon interposition for the treatment of advanced thumb carpometacarpal arthritis: A case report. AB - RATIONALE: Thumb carpometacarpal (CMC) arthritis is a common disease. Various procedures have been described for the treatment of advanced thumb CMC arthritis. This essay shows a CMC arthritis case treated by modified trapeziectomy with ligament reconstruction tendon interposition (LRTI). PATIENT CONCERNS: A 53-year old Chinese female complained of pain and swelling at the base of the left thumb for 10 years. Visual analog scale (VAS) for thumb was 7 points, Disabilities of Arm, Shoulder and Hand (DASH) score was 51 points, and Kapandji score was 6 points before surgery. Preoperative range of motion (ROM) for radial abduction and volar abduction were 63 degrees and 62 degrees , respectively. Grip power was 15.3 kg and key-pinch power was 1.8 kg before operation. Preoperative waist flexion power was 20.9 kg. Hand x-ray showed left thumb CMC arthritis in Eaton stage III and the height of the trapezial space was 10 mm. DIAGNOSES: She was diagnosed with left thumb CMC arthritis (Eaton III stage). INTERVENTIONS: The patient underwent modified trapeziectomy with LRTI. After exposing and removing trapezium, and a hole from the dorsal base to the center of the articular surface was drilled. Then we cut the whole flexor carpi radialis and divided it into 2 halves. Afterward, we passed one-half through the hole and tied it to the other part and sutured them. The rest tendon was then tied continuously and sutured. Then we rolled it up into the space where previous trapezium was located. OUTCOMES: Two years after operation, pain and swelling relieved and no recurrence of the clinical symptoms occurred. VAS, DASH, and Kapandji score were 2, 22, 7 points, respectively. ROM for radial abduction and volar abduction were 79 degrees and 78 degrees , respectively. Furthermore, grip power was 22.7 kg and key-pinch power was 3.8 kg. Waist flexion power was 20.0 kg. Hand x-ray showed that the height of the trapezial space was 9.8 mm. LESSONS: Modified trapeziectomy with LRTI in treatment of advanced thumb CMC arthritis had a satisfactory efficacy. This new procedure not only prevents thumb sinking, but also provides enough support for thumb. PMID- 29384845 TI - Chemotherapy in patient with colon cancer after renal transplantation: A case report with literature review. AB - RATIONALE: Experience of pharmacotherapy in posttransplantation colorectal cancer (CRC) patients is inadequate. PATIENT CONCERNS: A Chinese man had right renal transplantation and began immunosuppressive treatment at the age of 31 in 2009. He was diagnosed with colon cancer and underwent anterior resection in 2014. He was diagnosed with metastatic colon carcinoma by abdomen computed tomography (CT) and positron emission tomography-computed tomography in April 2017. DIAGNOSIS: Metastatic colon carcinoma in posttransplantation patient. INTERVENTIONS: Three cycles of FLOFOX (5-fluorouracil and leucovorin and oxaliplatin) chemotherapy were given since April 2017. OUTCOMES: Plasma concentrations of immunosuppressant and kidney function were within normal during the chemotherapy. Abdomen CT revealed the progress of colon cancer at the end of the third course of chemotherapy. LESSONS: A few cases about monochemotherapy of posttransplantation CRC have been reported, whereas experience of doublet chemotherapy was currently unavailable. We shared the experience of FOLFOX in a patient with posttransplantation colon cancer. Neither of incompatibility with immunosuppressant nor serious adverse drug reaction was observed. It provides evidence for the pharmacotherapy of posttransplantation CRC. PMID- 29384847 TI - Identification of key candidate genes and pathways in hepatitis B virus associated acute liver failure by bioinformatical analysis. AB - Hepatitis B virus-associated acute liver failure (HBV-ALF) is a rare but life threatening syndrome that carried a high morbidity and mortality. Our study aimed to explore the possible molecular mechanisms of HBV-ALF by means of bioinformatics analysis. In this study, genes expression microarray datasets of HBV-ALF from Gene Expression Omnibus were collected, and then we identified differentially expressed genes (DEGs) by the limma package in R. After functional enrichment analysis, we constructed the protein-protein interaction (PPI) network by the Search Tool for the Retrieval of Interacting Genes online database and weighted genes coexpression network by the WGCNA package in R. Subsequently, we picked out the hub genes among the DEGs. A total of 423 DEGs with 198 upregulated genes and 225 downregulated genes were identified between HBV-ALF and normal samples. The upregulated genes were mainly enriched in immune response, and the downregulated genes were mainly enriched in complement and coagulation cascades. Orosomucoid 1 (ORM1), orosomucoid 2 (ORM2), plasminogen (PLG), and aldehyde oxidase 1 (AOX1) were picked out as the hub genes that with a high degree in both PPI network and weighted genes coexpression network. The weighted genes coexpression network analysis found out 3 of the 5 modules that upregulated genes enriched in were closely related to immune system. The downregulated genes enriched in only one module, and the genes in this module majorly enriched in the complement and coagulation cascades pathway. In conclusion, 4 genes (ORM1, ORM2, PLG, and AOX1) with immune response and the complement and coagulation cascades pathway may take part in the pathogenesis of HBV-ALF, and these candidate genes and pathways could be therapeutic targets for HBV-ALF. PMID- 29384846 TI - The effects of probiotics on total cholesterol: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Probiotics supplements provide a new nonpharmacological alternative to reduce cardiovascular risk factors. The impact of probiotics on the reduction of total cholesterol (TC) remains controversial. We conducted a meta-analysis to showcase the most updated and comprehensive evaluation of the studies. METHODS: Randomized controlled trials (RCTs) were searched from electronic databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang database dating from January 2007 to January 2017. The curative effects of probiotics on the reduction of TC were assessed using mean difference (MD), as well as their 95% confidence interval (CI). RevMan software (version 5.3) was used to carry out this meta-analysis. RESULTS: Thirty-two RCTs including 1971 patients met the inclusion criteria. Results of this analysis showed that compared with the control group serum TC was significantly reduced in probiotics group [MD = -13.27, 95% CI (-16.74 to 9.80), P < .05]. In addition, specific strains also significantly reduced serum TC, L acidophilus and B lactis [MD = 8.30, 95% CI (-10.44, -6.15), P < .05]; VSL#3 [MD = -11.04, 95% CI (-19.61, 2.48), P < .05]; L plantarum t <= 6 weeks: [MD = -1.56, 95% CI (-6.97, -3.86), P < .05] or t > 6 weeks: [MD = -22.18, 95% CI (-28.73, -15.63), P < .05]. Subgroup analysis indicated that the difference of baseline TC, probiotics forms and intervention duration might have a significant impact on the results. However, strains and doses of probiotics had no significant influence on curative effects. CONCLUSION: Available evidence indicates that probiotics supplements can significantly reduce serum TC. Furthermore, higher baseline TC, longer intervention time, and probiotics in capsules form might contribute to a better curative effect. PMID- 29384848 TI - Economic evaluation of weekends-off antiretroviral therapy for young people in 11 countries. AB - OBJECTIVES: To analyze the cost effectiveness of short-cycle therapy (SCT), where patients take antiretroviral (ARV) drugs 5 consecutive days a week and have 2 days off, as an alternative to continuous ARV therapy for young people infected with human immunodeficiency virus (HIV) and taking efavirenz-based first-line ARV drugs. METHODS: We conduct a hierarchical cost-effectiveness analysis based on data on clinical outcomes and resource use from the BREATHER trial. BREATHER is a randomized trial investigating the effectiveness of SCT and continuous therapy in 199 participants aged 8 to 24 years and taking efavirenz-based first-line ARV drugs in 11 countries worldwide. Alongside nationally representative unit costs/prices, these data were used to estimate costs and quality adjusted life years (QALYs). An incremental cost-effectiveness comparison was performed using a multilevel bivariate regression approach for total costs and QALYs. Further analyses explored cost-effectiveness in low- and middle-income countries with access to low-cost generic ARV drugs and high-income countries purchasing branded ARV drugs, respectively. RESULTS: At 48 weeks, SCT offered significant total cost savings over continuous therapy of US dollar (USD) 41 per patient in countries using generic drugs and USD 4346 per patient in countries using branded ARV drugs, while accruing nonsignificant total health benefits of 0.008 and 0.009 QALYs, respectively. Cost-effectiveness estimates were similar across settings with access to generic ARV drugs but showed significant variation among high income countries where branded ARV drugs are purchased. CONCLUSION: SCT is a cost effective treatment alternative to continuous therapy for young people infected with HIV in countries where viral load monitoring is available. PMID- 29384849 TI - Natural course and outcomes of spontaneous isolated celiac artery dissection according to morphological findings on computed tomography angiography: STROBE compliant article. AB - We aimed to identify natural course and optimal management of spontaneous isolated celiac artery dissection (SICAD) according to morphologic classification determined on computed tomography angiography (CTA), and to investigate the association between symptoms and morphological classification of SICAD.This retrospective observational study included 21 consecutive patients with SICAD from January 2012 to April 2017. Demographic data, clinical features, treatment modalities, follow-up results, and CTA findings including morphologic classification, dissection length, and relative diameter of the true lumen (TLRD) were reviewed. Changes in follow-up CTA were recorded and compared to prior studies to reveal natural course of the disease.The serial changes of SICAD on follow-up CTA according to morphologic classifications were as follows; type I (5/5, no interval change), type IIa (1/1, no interval change), type IIb (1/1, partial remodeling), type IIIa (1/4, complete remodeling; 1/4, partial remodeling; 1/4, no interval change; 1/4, deterioration), type IIIb (4/6, no interval change; 2/6, partial remodeling), and type IV (2/2, no interval change). Thirteen (61.9%) symptomatic and 8 (38.1%) asymptomatic patients were all treated with conservative management with or without antiplatelet and/or anticoagulation therapies. Symptomatic group (SG) more commonly had type IIb, IIIa, IIIb, and IV than asymptomatic group (AG) (SG; 11 patients, AG; 1 patient, P = .002). TLRD in AG was larger than that in SG (SG: 40.5 +/- 24.1%, AG: 61.7 +/- 7.0%, P = .045).SICAD might be treated by conservative management in stable patients irrespective of the morphologic classification except for with type IV (dissecting aneurysm) and extension of celiac branch who may need an early intervention. Types IIb, IIIa, IIIb, and IV are TLRD are associated with patients' symptoms. Further studies on extended natural course of SICAD with a larger number of subjects are needed to draw a strong conclusion. PMID- 29384850 TI - Successful diagnosis and treatment of ingested wooden toothpicks: Two case reports. AB - RATIONALE: Foreign-body ingestion is a common phenomenon and foreign bodies are mostly excreted in stool. Once sharp bodies are ingested without being realized, perforation of intestine is possible and misdiagnosis may be made. We report 2 toothpick ingestion cases that were both diagnosed accurately. PATIENT CONCERNS: We present 2 cases of middle-aged persons who suffered from abdominal pain. They did not realize and provide any information of having the history of swallowing foreign bodies. DIAGNOSES: No serious problem was discovered in the examination and blood test. There were somewhere abnormal in computed tomography (CT) images and ultrasound (US). Then a toothpick was found penetrating the wall of intestine into the adjacent viscera in the laparotomy. INTERVENTIONS: Both patients in the 2 cases were undergone operation to remove the toothpicks. OUTCOMES: The 2 cases' prognoses were good. LESSONS: When accepting patients with abdominal pain, suitable examining means and careful observation should be given to find easily ignored lesions. CT is recommended in the diagnostic process of swallowed foreign mass. When there is a vague place, US can be used for further diagnose. PMID- 29384851 TI - Identifying protein biomarkers in predicting disease severity of dengue virus infection using immune-related protein microarray. AB - Dengue virus is one of the most widespread flaviviruses that re-emerged throughout recent decades. The progression from mild dengue to severe dengue (SD) with the complications such as vascular leakage and hemorrhage increases the fatality rate of dengue. The pathophysiology of SD is not entirely clear. To investigate potential biomarkers that are suggestive of pathogenesis of SD, a small panel of serum samples selected from 1 healthy individual, 2 dengue patients without warning signs (DWS-), 2 dengue patients with warning signs (DWS+), and 5 patients with SD were subjected to a pilot analysis using Sengenics Immunome protein array. The overall fold changes of protein expressions and clustering heat map revealed that PFKFB4, TPM1, PDCL3, and PTPN20A were elevated among patients with SD. Differential expression analysis identified that 29 proteins were differentially elevated greater than 2-fold in SD groups than DWS- and DWS+. From the 29 candidate proteins, pathways enrichment analysis also identified insulin signaling and cytoskeleton pathways were involved in SD, suggesting that the insulin pathway may play a pivotal role in the pathogenesis of SD. PMID- 29384852 TI - Pain correlates with germline mutation in schwannomatosis. AB - Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain.In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale.We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696).We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain. PMID- 29384853 TI - Early detection and integral resection are keys to extend survival in patients suffered from primary angiosarcoma of the spleen: A care-compliant case report and literature review. AB - RATIONALE: Primary angiosarcoma of the spleen (PAS) is a very rare malignant neoplasm that originates from endothelial cells of the splenic blood vessels. Without typical clinical presentations and specific radiological features, PAS is very difficult to be early identified and 1-year mortality is extremely high. Late detection and spleen rupture are considered as the most important risk factors for early metastasis. PATIENT CONCERNS: Without any obvious symptom, a 35 year-old woman was admitted with splenic neoplasm that was accidentally discovered through a routine physical examination. DIAGNOSES: The patient was first diagnosed as lymphoma by laboratory tests and imaging studies, but changed to PAS by histological examinations after the surgery. INTERVENTIONS: After careful preoperational assessment, a laparoscopic-assisted splenectomy was scrutinously performed and the entire spleen was removed without any rupture. OUTCOMES: The postoperative followed-up was uneventful until 3 years later, when she sought medical attention due to persisting back pain. Bone metastasis was consequently identified and the symptom was quickly alleviated after radiation therapy. However, intra-abdominal metastases leading to intestinal obstruction occurred 4.5 years after surgery. Following short palliative treatment, the patient passed away 4 years and 9 months after the operation due to multiple organ failure. LESSONS: PAS is an uncommon and aggressive splenic disease. Once suspected, PAS require prompt and precise surgical procedures to remove the tumor origin. Laparoscopic-assisted splenectomy was technically feasible and therapeutically harmless for PAS treatment compared with open surgery as long as the spleen was removed intact. However, more evaluation of this option will be needed due to limited experience by now. Early discovery, precautious plan, meticulous operation, close follow-up, and comprehensive treatment may significantly prolong the living period of this fatal disease. PMID- 29384854 TI - Uterine artery embolization combined with local infusion of methotrexate and 5- fluorouracil in treating ectopic pregnancy: A CONSORT-compliant article. AB - BACKGROUND: To compare the efficiency and safety of uterine artery embolization (UAE) combined with local infusion of methotrexate (MTX) or MTX and 5 fluorouracil (5-FU) in the treatment of ectopic pregnancy (EP). METHODS: One hundred women with EP were prospectively enrolled from December 2012 to February 2015 and randomly allocated into 2 groups. One group was treated with UAE combined MTX, and the other with UAE combined with MTX and 5-FU. Local MTX was administrated at a dose of 80 to 120 mg, based on the initial beta-human chorionic gonadotropin (beta-HCG) levels, and 5-FU was given intra-arterially at a uniform dose of 0.5 g. RESULTS: Bilateral UAE was successfully performed in all 100 patients, 88 of whom were clinically successfully treated, 45 (91.8%) in the MTX group, and 43 (87.8%) in the MTX + 5-FU group; 89% of the patients achieved normalization of beta-HCG below 70,000 mIU/mL within 14 to 21 days postoperatively. The time to successful beta-HCG resolution was 26.74 +/- 5.57 days for patients receiving MTX + UAE treatment, and 27.57 +/- 5.08 days for those treated with additional 5-FU. Six patients had subsequent intramuscular injections of MTX and 6 had a unilateral salpingectomy after the treatment failure. Mild immediate side effects accounted for 24.5% in the sole MTX and 58.3% in MTX + 5-FU group. CONCLUSION: A combination of UAE and intrauterine infusion of MTX showed comparable efficiency to UAE combined with a local infusion of MTX and 5-FU in treating EP patients with the intention to preserve fertility. PMID- 29384855 TI - Anterior corpectomy and reconstruction using dynamic cervical plate and titanium mesh cage for cervical spondylotic myelopathy: A minimum 5-year follow-up study. AB - Anterior cervical corpectomy and fusion (ACCF) is an effective surgical technique for cervical spondylotic myelopathy (CSM). However, no data exist regarding long term outcomes after ACCF with the dynamic cervical plate for CSM. This study aimed to provide minimum 5-year clinical and radiographic outcomes of anterior corpectomy and reconstruction using dynamic cervical plate and titanium mesh cage (TMC) for CSM.Thirty-five patients who underwent single- or 2-level ACCF with dynamic cervical plate and TMC for the treatment of CSM were retrospectively investigated. The Japanese Orthopedic Association (JOA) score was used to assess the clinical outcome. Radiographic evaluations included TMC subsidence, fusion status, cervical lordosis, segmental angle, and segmental height.Twenty-eight patients underwent single-level and 7 patients underwent 2-level corpectomy with a mean follow-up period of 69.5 months. The average preoperative JOA score was 11.3 +/- 3.0 and improved significantly to 14.2 +/- 2.0 at the last follow-up (P < .001). Both cervical lordosis (P = .013) and segmental angle (P = .001) were significantly increased toward lordosis at the last follow-up. The TMC subsidence rate was 31.4% (n = 11) at the last follow-up. There was no significant difference in JOA recovery rate between subsidence and no subsidence group (P = .43). All patients obtained solid fusion at 1-year follow-up.Anterior corpectomy and reconstruction with dynamic cervical plate and TMC might be an effective method for the treatment of CSM at a minimum 5-year follow-up. It can maintain or restore cervical sagittal alignment. Subsidence of the TMC did not influence the clinical outcome. PMID- 29384856 TI - Use of noncontact infrared thermography to measure temperature in children in a triage room. AB - We compared the accuracy and utility of 3 infrared (IFR) thermographs fitted with axillary digital thermometers used to measure temperature in febrile and afebrile children admitted to an emergency triage room.A total of 184 febrile and 135 afebrile children presenting to a triage room were consecutively evaluated. Axillary temperature was recorded using a digital electronic thermometer. Simultaneously, IFR skin scans were performed on the forehead, the neck (over the carotid artery), and the nape by the same nurse. Fever was defined as an axillary temperature >=37.5 degrees C. The temperature readings at the 4 sites were compared.For all subjects, the median axillary temperature was 37.7 +/- 1.5 degrees C, the IFR forehead temperature was 37 +/- 1.1 degrees C, the IFR neck temperature was 37.6 +/- 1.5 degrees C, and the IFR nape temperature was 37 +/- 1.2 degrees C. A Bland-Altman plot of the differences suggested that all agreements between IFR and axillary measures were poor (the latter measure was considered the standard). The forehead measurements had a sensitivity of 88.6% and a specificity of 60% in patients with temperatures >=36.75 degrees C. The sensitivities of the neck measurement at cut-offs of >=37.35 degrees C and >=36.95 were 95.5% and 78.8% for those aged 2 to 6 years. Thus, 11.4% of febrile subjects were missed when forehead measurements were performed.An IFR scan over the lateral side of neck is a reliable, comfortable, rapid, and noninvasive method for fever screening, particularly in children aged 2 to 6 years, in busy settings such as pediatric triage rooms. PMID- 29384857 TI - Heart rate variability in normal tension glaucoma: A case-control study. AB - Primary vascular dysregulation (PVD) is believed to be a main cause of local vasospasm and impaired autoregulation as a possible contributing factor in the pathogenesis of normal tension glaucoma (NTG). Subjects with PVD respond stronger to psychological stress. Autonomic dysfunction is another reason of instable ocular blood flow and may be studied by means of assessment of heart rate variability (HRV) especially during a hand-cold provocation test (CPT).To compare the shift of HRV parameters in NTG and healthy subjects after a cold provocation test and to assess the relation between structural damage, circulatory parameters and autonomic dysfunction in NTG.HRV was studied using CPT in 78 NTG patients and 60 health control matches. The ocular blood flow was measured using color Doppler imaging (CDI). The 24 hours blood pressure (BP) monitoring was carried out. The cardiovascular fitness assessment was made to all patients before and after CPT. Mean group difference of HRV parameters was compared between NTG and healthy subjects using the Euclidean metric. The mean ocular perfusion pressure (MOPP) was measured. Optic nerve head and retinal nerve fiber layer (RNFL) were evaluated using spectral-domain optic coherence tomography (SD-OCT). The relation between HRV, CDI, and SD-OCT-parameters was assessed.In contrast to healthy subjects, a predominance of the sympathetic activity after the CPT was revealed in the NTG group. The end diastolic velocity (EDV) in central retinal artery (CRA) and short posterior ciliary artery (SPCA) was significantly reduced in NTG compared to healthy eyes. In NTG, the main HRV parameter characterizing the total effect of autonomic blood circulation regulation (SDNN) correlated with MOPP (0.75, P = .035), SPCA EDV (0.93, P < .001), and CRA EDV (0.9, P < .001). The average daily diastolic BP correlated with RNFL (0.67, P = .009).The NTG patients have the disturbance of the autonomic nervous system, which increases in response to stress provocation and is related to ocular blood flow and structural damage. PMID- 29384858 TI - The application of lidocaine to alleviate the discomfort of nasogastric tube insertion: A systematic review and meta-analysis. AB - BACKGROUND: Nasogastric (NG) tube insertion is a common procedure in the clinical setting that causes much discomfort and pain for the patient. Pain control is often suboptimal, as many NG tube insertions are performed without any pain relieving supplements. The aim of this study was to summarize and critically evaluate the evidence from randomized controlled trials (RCTs) on the effect and adverse effects of lidocaine agents in reducing pain and discomfort associated with NG tube insertion. METHODS: Databases from the Cochrane Library, MEDLINE, EMBASE, Airiti Library, PerioPath Index to Taiwan Periodical Literature, and Cumulative Index of Nursing and Allied Health (CINAHL) were searched from inception to April 2017. RCTs focusing on lidocaine before NG tube insertion were appraised. The primary outcome was the visual analog scale (VAS) score. The modified Jadad scale was used for quality assessment. Mean difference (MD) with 95% confidence intervals (95% CIs) and odds ratio (OR) for binary outcomes were assessed by a random effects model. Heterogeneity was determined by using the Cochran Q test and I statistics. Publication bias was analyzed by using a funnel plot analysis. RESULTS: Ten RCTs enrolling 734 patients were included in the meta analysis. Eight of the 10 RCTs reporting VAS scores had sufficient quantitative data to be pooled through meta-analysis. Results revealed a significant reduction in VAS score, with a MD of -26.05 and a CI of -28.21 to -23.89 with moderate heterogeneity (P < .001, I = 56%). There were no significant changes in difficulty of NG tube insertions (MD = -0.30, 95% CI, -1.30 to 0.70, P = .55), number of NG tube insertion attempts (MD = -0.22, 95% CI, -0.98 to 0.53, P = .56), nasal bleeding (OR = 0.62, 95% CI, 0.11-3.41, P = .59), and vomiting (OR = 0.30, 95% CI, 0.07-1.27, P = .10). CONCLUSION: This meta-analysis suggests that applying lidocaine before NG tube insertion can alleviate pain and discomfort by 26% without increasing nasal bleeding or vomiting. PMID- 29384859 TI - Effect of a comprehensive plan for periodontal disease care on oral health related quality of life in patients with periodontal disease in Taiwan. AB - A comprehensive plan for periodontal disease (PD) care in Taiwan provides non surgical and supportive periodontal treatment. The aim of this study was to determine whether the care plan could improve the oral health-related quality of life of patients with PD.This study was conducted by purposive sampling and a quasi-experimental design. Patients with PD were assigned to either comprehensive periodontal treatment (n = 32) or a simple cleaning regimen (n = 32). Their oral health-related quality of life (OHRQoL) was measured using the Taiwanese version of the Brief World Health Organization Quality of Life (WHOQOL-BREF) scale (general QoL) and the Oral Health Impact Profile (OHIP-14) (OHRQoL). Both scales were completed 14, 28, and 90 days after the initial assessment. The extent of PD in the experimental group was determined again at the end of the study.On the 28 item WHOQOL-BREF scale, the scores of the experimental group were higher than those of the control group on 5 items and the environmental domain at 14 days. There was a significant improvement in the experimental group on 2 items at 28 days and at 90 days after periodontal treatment (both P < .05). No difference was found between the 2 groups in score on the OHIP-14; however, there was a significant improvement in the experimental group in total score at 28 and 90 days after periodontal treatment (both P < .05). The number of teeth with probing depth >=5 mm and the percentage of dental plaque were both significantly reduced after the intervention (both P < .001).Patients with a comprehensive plan for PD care showed some improvement in QoL, including in the environmental domain, and on the total score for OHRQoL. Comprehensive periodontal treatment also alleviated periodontal symptoms. PMID- 29384860 TI - Bilateral subthalamic deep brain stimulation initial impact on nonmotor and motor symptoms in Parkinson's disease: An open prospective single institution study. AB - Numerous studies document significant improvement in motor symptoms in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS). However, little is known about the initial effects of STN-DBS on nonmotor domains.Our objective was to elucidate the initial effects of STN-DBS on non-motor and motor symptoms in PD patients in a 4-month follow-up.This open prospective study followed 24 patients with PD who underwent STN-DBS. The patients were examined using dedicated rating scales preoperatively and at 1 and 4 months following STN-DBS to determine initial changes in motor and nonmotor symptoms. Patients at month 1 after STN-DBS had significantly reduced the Parkinson's disease Questionnaire scores (P = .018) and Scales for Outcomes in Parkinson's disease - Autonomic scores (P = .002); these scores had increased at Month 4 after DBS-STN. Nonmotor Symptoms Scale for Parkinson's Disease had improved significantly at Month 1 (P < .001); at Month 4, it remained significantly lower than before stimulation (P = .036). There was no significant difference in The Parkinson's Disease Sleep Scaleat Month 1 and significant improvement at Month 4 (P = .026). There were no significant changes in The Female Sexual Function Index or International Index of Erectile Function. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III scores show significant improvements at Month 1 (P < .001) and at Month 4 (P < .001).STN-DBS in patients with advanced PD clearly improves not only motor symptoms, but also several domains of nonmotor functions, namely sleep, autonomic functions and quality of life quickly following the start of stimulation. PMID- 29384861 TI - Spontaneous cerebrospinal fluid rhinorrhea: A case report and analysis. AB - INTRODUCTION: Spontaneous cerebrospinal fluid leakage is usually caused by developmental abnormalities and is rare, accounting for approximately 5% of the cases of cerebrospinal fluid (CSF) leakage. To the best of our knowledge, clival dysplasia-caused CSF rhinorrhea has never been reported in the neurosurgical field. CONCLUSION: Spontaneous cerebrospinal fluid rhinorrhea is often treated by surgery, and a transsphenoidal approach repair is the main surgical method used, offering the advantages of less trauma, fewer complications, rapid postoperative recovery, and low recurrence rate. PMID- 29384862 TI - Plasma soluble factor following two decades prolonged suppressive antiretroviral therapy in HIV-1-positive males: A cross-sectional study. AB - Acute human immunodeficiency virus (HIV) infection is associated with a marked induction of several pathways that are linked to inflammation and CD4 T-cell depletion. Many of these processes do not fully resolve on short-term combination antiretroviral therapy (cART) (<5 years), despite complete and durable suppression of viremia. The effects of long-term (>15 years) successful antiretroviral therapy (ART) and the linkage between levels of biomarkers remain unclear. Therefore, the present study aims to assess the host plasma proteome in a well-defined clinical material from HIV-1-positive male patients on successful long-term ART (>15 years) and compared them with age-matched healthy controls and treatment-naive male patients with viremia in a cross-sectional manner.Plasma samples were obtained from 3 categories of age-matched HIV-1-positive male patients on long-term successfully (ART, n = 10) with a median (Interquartile range, IQR) of 19 (17-20) years, treatment-naive patients with viremia (VP, n = 14), and HIV-1-negative persons (HC, n = 11). Plasma proteome was analyzed using the proximity extension assay targeting 92 factors. Statistical analyses were performed with GraphPad Prism v7, R-packages, and Qlucore Omics Explorer v3.2. Functional enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG), and interactions of specific molecules were identified using Path Designer integrated into Ingenuity Pathway Analysis (IPA).Group wise comparison identified 53 soluble factors, which differed between the groups (P < .05). Cluster analysis identified 13 discrete soluble factors (CD8A, CRTAM, CXCL13, EGF, CD5, CD40, CXCL9, Gal-1, IL12RB1, KLRD1, PD-1, CASP-8 and TNFRSF9) between the studied groups (adjusted P < .001). The long-term successfully ART-treated individuals clustered and networked with the HC while VPs clustered separately. All of the proinflammatory cytokines and chemokines were normalized back to levels of healthy controls in long-term successfully ART-treated individuals, but not the levels of KLRD1 and PGDFB.sKLRD1 that is involved in the regulation of natural killer cell (NK) mediated cytotoxicity, failed to be restored to the level of HIV-negative individuals despite successful long-term ART. Additional analysis of NK cells along with T-cell subsets can provide insights into the long term effects of ART on the immune system. PMID- 29384863 TI - Myocardial perfusion at rest in uncomplicated type 2 diabetes patients without coronary artery disease evaluated by 320-multidetector computed tomography: A pilot study. AB - Using computed tomography myocardial perfusion imaging (CTP) to investigate resting myocardial perfusion alterations in uncomplicated type 2 diabetes mellitus (T2DM) patients without obstructive coronary artery disease (CAD).A total of 34 participants with 544 myocardial segments were included prospectively: 17 uncomplicated T2DM patients with no significant coronary artery stenosis on coronary computed tomography angiography and 17 healthy controls. Myocardial perfusion was evaluated by transmural perfusion ratio (TPR). Parameters of cardiac structure and function were measured for cardiac comprehensive assessment. Analyses included descriptive statistics and group comparisons.TPR of segments 5, 7, 9, 10 to 14 were significantly reduced in T2DM group compared with controls (P < .05). When 16 myocardial segments were localized into different areas according to the wall orientations, axial levels of left ventricle and coronary artery territories, respectively, TPR of each area in T2DM group were significantly lower than those in the control group (P < .05). No significant differences were found in cardiac anatomy and function analyses between 2 groups.In uncomplicated T2DM patients without obstructive CAD, myocardial perfusion impairments were present and may develop prior to cardiac morphological and functional abnormalities, which can be early detected by CTP. PMID- 29384864 TI - Does spinal fusion to T2, T3, or T4 affects sagittal alignment of the cervical spine in Lenke 1 AIS patients: A retrospective study. AB - : The aim of this stusy was to investigate whether spinal fusion to T2, T3, or T4 affects sagittal alignment of the cervical spine in Lenke 1 adolescent idiopathic scoliosis (AIS) patients.A retrospective study comprised of 64 Lenke 1 AIS patients was performed to assess the radiographic and clinical outcome. According to the upper instrumented vertebrae (UIV) (T2, T3, or T4), the patients were divided into 3 groups. Comparison analyses were performed among these 3 groups of patients as between pre-op, immediate post-op, and final follow-up, as well as between these groups.Between groups, comparison analyses did not detect a statistical difference in cervical lordosis (CL) preoperatively (P = .501), immediately after surgery (P = .795), and at follow-up (P = .510). Immediately after surgery, CL increased significantly in all groups (T2, P = .004, T3, P < .001 and T4, P = .002 respectively). Compared with immediate postoperatively, CL at final follow-up increased in T2 group (P = .037), and T4 group (P = .010). Furthermore, CL at follow-up was significantly correlated with the following parameters: preoperative (coronal plane balance [r = .349, P = .004], pelvic tilt [r = 0.347, P = .004), pelvic incidence [r = 0.261, P = .031], and CL [r = 0.471, P < .001]) immediately postoperative (CL [r = 0.946, P < .001], T1-slope [r = 0.646, P < .001], and thoracic kyphosis [TK] [r = -0.353, P = .003]), and at follow-up (TK [r = -0.342, P = .004], and T1-slope [r = -0.821, P < .001]). However, there was no significant correlation between a selection of UIV and CL at follow-up (r = 0.031, P = .802). Moreover, Scoliosis Research Society (SRS-22) scores between groups were similar preoperatively (P = .242), immediately after surgery (P = .828), and at follow-up (P = .219).In Lenke 1 AIS patients, the selection of UIV mainly affects the coronal plane, especially shoulder balance. Fusion to T2, T3, or T4 did not affect the alignment of the cervical spine, and the SRS-22 score. LEVEL OF EVIDENCE: Level IV. PMID- 29384865 TI - Postoperative outcomes of breast reconstruction after mastectomy: A retrospective study. AB - Breast reconstruction after mastectomy plays an active role in improving the quality-of-life (QoL) and alleviating the psychological trauma of breast cancer patients, and has become an indispensable part of the comprehensive treatment in breast cancer. However, compared with mastectomy alone, breast reconstruction also increase operative complications. The surgical, oncological outcomes, and cosmetic effect of breast reconstruction remains to be evaluated. Data for patients with breast cancer who underwent breast reconstruction after mastectomy from February 2009 to November 2015 in our hospital were retrospectively analyzed, with a median follow-up time of 44 months. The operating time, blood loss, drainage fluid, postoperative complications, postoperative cosmesis, oncological outcomes, and QoL were evaluated and compared between different reconstruction types. A total of 151 women were included. The flap-based group had higher complication rates of marginal necrosis of incision, while the incidence of capsular contracture was higher in immediate implant group. There was no difference in blood loss, drainage fluid, and other postoperative complications. Several independent factors were associated with increased postoperative complications included diabetic, obese, and reconstruction with flap. There was no significant difference in the disease-free survival rate and overall survival rate between different surgical groups. In terms of cosmetic effect, patients in the tissue expander group were more likely to get a satisfactory postoperative breast appearance. QoL outcomes shown that the tissue expander group has better body image and sexual enjoyment, while there was no significant difference for other QoL domains. In conclusion, different methods of breast reconstruction are safe and feasible for patients with breast cancer, tissue expander implantation following delayed implant breast reconstruction is a more effective treatment on cosmetic and QoL outcomes. PMID- 29384866 TI - Association between TNF-alpha-238G/A gene polymorphism and OCD susceptibility: A meta-analysis. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine and has been reported to be associated with the pathogenesis of many autoimmune and inflammatory diseases. TNF-alpha gene is located on a region that has been found to be associated with obsessive-compulsive disorder (OCD). We performed this meta analysis to assess the relationship between susceptibility to OCD and the TNF alpha-238G/A gene polymorphism. METHODS: An extensive search of the available literature on the association between the susceptibility to OCD and the TNF gene polymorphism was conducted by searching PubMed, Web of Knowledge, Embase, Chinese Web of Knowledge, Wanfang, and Chongqing VIP database. The database was searched up to December 2016 and includes language of English and/or Chinese with the keywords of "obsessive-compulsive disorder" or "OCD," polymorphism or variant or mutation, "tumor necrosis factor" or "TNF" or "cytokine." The association between TNF-alpha-238G/A gene polymorphism and the susceptibility of OCD was anticipated by odds ratio (OR) with the corresponding 95% confidence interval (95% CI). RESULTS: Four studies including 435 cases and 1073 controls were incorporated in our meta-analysis. In general, TNF-alpha-238G/A gene polymorphism might lead to a decreased risk of OCD susceptibility (G vs A genotype model: OR = 1.01, 95% CI = 0.37-2.77, P = .981; GG vs AA+AG model: OR = 0.93, 95% CI = 0.37-2.36, P = .879; GG+AG vs AA model: OR = 0.22, 95% CI = 0.06-0.73, P = .014; GG vs AA model: OR = 0.21, 95% CI = 0.06-0.71, P = .012; AG vs AA model: OR = 0.29, 95% CI = 0.07 1.16, P = .081; GG+AA vs AG model: OR = 1.17, 95% CI = 0.55-2.51, P = .683). CONCLUSION: TNF-alpha-238G/A gene polymorphism might lead to a decreased risk of OCD susceptibility. PMID- 29384867 TI - Intravenous lidocaine infusion for pain control after laparoscopic cholecystectomy: A meta-analysis of randomized controlled trials. AB - BACKGROUND: This meta-analysis aimed to assess the efficiency and safety of intravenous infusion of lidocaine for pain management after laparoscopic cholecystectomy (LC). METHODS: A systematic search was performed in PubMed (August 1966-2017), Medline (August 1966-2017), Embase (August 1980-2017), ScienceDirect (August 1985-2017), and the Cochrane Library. Only randomized controlled trials (RCTs) were included. Fixed/random effect model was used according to the heterogeneity tested by I2 statistic. Meta-analysis was performed using Stata.11.0 software. RESULTS: A total of 5 RCTs were retrieved involving 274 patients. The present meta-analysis indicated that there were significant differences between groups in terms of visual analog scale scores at 12hours (weighted mean difference [WMD]=-0.743, 95% CI: -1.246 to -0.240, P = .004), 24hours (WMD=-0.712, 95% CI: -1.239 to -0.184, P = .008), and 48hours (WMD=-0.600, 95% CI: -0.972 to -0.229, P = .002) after LC. Significant differences were found regarding opioid consumption at 12hours (WMD=-3.136, 95% CI: -5.591 to -0.680, P = .012), 24hours (WMD=-4.739, 95% CI: -8.291 to -1.188, P = .009), and 48hours (WMD=-3.408, 95% CI: -5.489 to -1.326, P = .001) after LC. CONCLUSION: Intravenous lidocaine infusion significantly reduced postoperative pain scores and opioid consumption after LC. In addition, there were fewer adverse effects in the lidocaine groups. Higher quality RCTs are still required for further research. PMID- 29384868 TI - Clostridium difficile infection in hospitalized patients with inflammatory bowel disease: Prevalence, risk factors, and prognosis. AB - To evaluate the frequency, possible risk factors, and outcome of Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) patients.There has been an upsurge of CDI in patients with IBD who has been associated with increased morbidity and mortality. Various risk factors have been found to predispose IBD patients to CDI.A retrospective case-control study on IBD patients admitted with exacerbation and tested for CDI at the Tel Aviv Medical Center in 2008 to 2013. Epidemiologic, laboratory, and prognostic data were retrieved from electronic files and compared between patients who tested positive (CDI+) or negative (CDI-) for CDI.CDI was identified in 28 of 311 (7.31%) IBD patients hospitalized with diarrhea. IBD-specific risk factors (univariate analysis) for CDI included: use of systemic steroids therapy (odds ratio [OR] = 3.6, 95% confidence interval [CI] 1.2-10.6) and combinations of >=2 immunomodulator medications (OR = 2.6, 95% CI 1.1-6.3). Additional risk factors for CDI that are common in the general population were hospitalization in the preceding 2 months (OR = 6.0, 95% CI 2.6-14.1), use of antacids (OR = 3.8, 95% CI 1.7-8.4), and high Charlson comorbidity score (OR = 2.5, 95% CI 1.1-5.7). A multivariate analysis confirmed that only hospitalization within the preceding 2 months and use of antacids were significant risk factors for CDI. The prognosis of CDI+ patients was similar to that of CDI- patients.Hospitalized IBD patients with exacerbation treated with antacids or recently hospitalized are at increased risk for CDI and should be tested and empirically treated until confirmation or exclusion of the infection. PMID- 29384869 TI - Vaccination coverage and associated factors for receipt of the 23-valent pneumococcal polysaccharide vaccine in Taiwan: A nation-wide community-based study. AB - Older adults, particularly those with chronic obstructive pulmonary disease, are advised to receive 23-valent pneumococcal polysaccharide vaccine (PPV23). However, the PPV23 vaccination rate in Taiwan and the determinants of receipt remain unclear.We analyzed the data of 1475 community-dwelling older adults aged >=75 years who participated in the Healthy Aging Longitudinal Study in Taiwan. Each participant received assessments of PPV23 status, sociodemographic factors (age, sex, education level, marital status, living alone, and occupation), and health-related factors (chronic diseases, smoking status, alcohol intake, physical activities, cognitive status, and physical performance). PPV23 rate was defined as the number of participants who reported receiving free PPV23 divided by the total number of candidates for free PPV23. Multinomial logistic regression analysis was applied to investigate the sociodemographic and health-related determinants of PPV23 status.A PPV23 vaccination rate of 20.7% (305/1475) was observed. Participants who were female, current smokers, and had a low peak expiratory flow were associated with PPV23 nonreceipt (all P <.05). Of the participants who had a low peak expiratory flow, low education status, and physical inactivity were associated with PPV23 nonreceipt (all P <.05).The PPV23 vaccination rate among adults aged >=75 years was low. Older adults who were women, current smokers, or who had a low PEF were less likely to receive the PPV23. These findings support continual efforts to improve the PPV23 coverage rate in vulnerable populations. PMID- 29384870 TI - Diversity analysis of subgingival microbial bacteria in peri-implantitis in Uygur population. AB - This study is to investigate the subgingival bacterial diversity and community structure in the Uygur subjects with peri-implantitis.Totally 40 cases of gingival crevicular fluid were collected from Uygur subjects and divided into the Control group (healthy implants) and Case group (peri-implantitis), respectively. DNA was extracted, and the sequencing in the 16SrRNA V4-V5 region was conducted on the Illumina Miseq sequencing platform. The 16SrRNA gene clone library was constructed and analyzed.Totally 733,759 valid tags were obtained from these 40 samples. After comparing with the Silva-16S database by the Uparse software, 263 operational taxonomic unit were finally harvested (135 for the Control group and 128 for the Case group). The differential bacteria between these 2 groups at the phylum, class, order, family, and genus levels were Actinobacteria, Actinomycetes, Pasteurellales, Moraxellaceae, and Acinetobacter, respectively. The dominant genera with significantly different distribution between the Control and Case groups included Vibrio, Campylobacter, Granulicatella, Acinetobacter, Micrococcus, and Moraxella. The alpha diverstiy analysis based on the chao diversity index showed that there was significant difference in the microbiological diversity between these 2 groups. Principal coordinates analysis analysis indicated significant differences in the bacterial community structure between these 2 groups. Cluster analysis showed higher abundance of Micrococcus in the Case group, while higher abundance of Prevotella in the Control group.There are significant differences in the diversity of subgingival bacteria between the Uygur subjects with healthy implants and peri-implantitis. Moraxella, Micrococcus, and Acinetobacter might represent dominant bacteria genera causing peri-implantitis in the Uygur population. PMID- 29384871 TI - Salvage radiochemotherapy for lymph node recurrence after radical surgery of esophageal cancer. AB - To evaluate the efficacy of salvage radiochemotherapy (SRC) in patients with recurrent lymph node after radical surgery in esophageal cancer.This study enrolled 58 patients with esophageal squamous cell carcinoma who underwent SRC for lymph node recurrence after radical surgery from August 2011 to November 2015 at our hospital. Survival rates were calculated by the Kaplan-Meier method with the log-rank test. Multivariate analysis was conducted using the Cox model.The overall 1-, 3-, and 5-year survival rates after radical surgery were 94.8%, 53.0%, and 29.6%, respectively. The 1- and 3-year survival rates after SRC were 68.7% and 26.9%, respectively. The major acute toxicities were esophagitis and neutropenia, while most toxicities were grade 1 or 2. There was no unexpected increase in serious adverse events or treatment-related deaths. The results of multivariate analysis showed that time to recurrence (odds ratio [OR]: 0.25, 95% confidence interval [CI]: 0.11-0.53, P = .0004), T stage (OR: 2.75, 95%CI: 1.16 6.49, P = .021), and prophylactic radiotherapy/chemotherapy (PRC, OR: 0.39, 95%CI: 0.16-0.98, P = .045) were determinants of postoperative overall survival, and PRC was the only factor affecting the outcome of SRC (OR: 0.28, 95%CI: 0.12 0.70, P = .006).SRC is an effective treatment for recurrent lymph node after radical surgery of esophageal cancer. PMID- 29384872 TI - The psychological results of 438 patients with persisting GERD symptoms by Symptom Checklist 90-Revised (SCL-90-R) questionnaire. AB - Persisting gastroesophageal reflux disease (GERD) symptoms affect mental state and social activities and mental disorders likewise play a crucial role on GERD symptoms. The aim of this study was to analyze the data of Symptom Checklist by 90-Revised (SCL-90-R) questionnaire in patients with persisting GERD symptom and to explore the impact of psychological factors on them.The patients accepted SCL 90-R questionnaire survey, following endoscopy, high-resolution manometry (HRM) and ambulatory impedance-pH monitoring. Based on these results, we divided patients into different groups. The result of SCL-90-R was also compared by degree of acid reflux, symptoms, symptom duration, and gender.The data from 438 patients were analyzed. All patients were divided into reflux esophagitis (RE) (63, 14.38%); nonerosive gastroesophageal disease (NERD) (106, 24.20%); functional heartburn (FH) (123, 28.08%), and hypersensitive esophagus (HE) (67, 15.29%); depression (DES) (5, 1.14%); hypertensive (10, 3.42%); weak peristalsis (14, 3.20%); achalasia (50, 11.42%). There were significant differences between varied groups judging by DEP, anxiety (ANX), paranoia ideation (PAR), psychoticism (PSY), and global severity index (GSI) domains (all P < .05). The patients with >=2 years symptom duration presented more scores in DEP, ANX, and PSY (all P < .05). Compared to typical symptoms (n = 185), GERD typical plus atypical symptoms (n = 253) had higher scores of somatization (SOM), ANX, PSY and GSI (all P < .05). Women were found to have significantly higher scores than men in all domains (all P < .05).Our results find significant differences between varied patients with different diagnosis in DEP, ANX, PAR, PSY domains, and GSI. Long symptom duration, typical plus atypical symptoms, and female are more risky for psychological disorders. PMID- 29384873 TI - Acute recreational drug toxicity: Comparison of self-reports and results of immunoassay and additional analytical methods in a multicenter European case series. AB - The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity.We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project.Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively.In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives. PMID- 29384874 TI - BMP2 and VEGF165 transfection to bone marrow stromal stem cells regulate osteogenic potential in vitro. AB - An exogenous supply of bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factors 165 (VEGF165) will synergize to promote bone regeneration in vivo. The aim of this study was to confirm the role of VEGF165 on the osteogenesis potential of bone mesenchymal stem cells (BMSCs) transduced by adenovirus vector containing BMP2 gene in vitro.Rabbit BMSCs were isolated and transfected with various adenovirus vectors: Ad-BMP2-VEGF165 (BMP2+VEGF165 group), Ad-BMP2 (BMP2 group), Ad-VEGF165 (VEGF165 group), and Ad-green fluorescent protein (GFP group). The multiplicity of infection was detected by GFP expression. Expression of BMP2 and VEGF165 was detected by Western blot and ELISA, and the osteogenic biological activity of BMP2 and VEGF165 by osteogenic assay. Meanwhile, the osteogenic biological activity of BMP2 and VEGF165 was evaluated by detection of Col I (collagen type I), OC (osteocalcin), and ALP (alkaline phosphatase) activity using OC staining, ALP activity assay, and real time PCR assay.Expression of target genes and proteins reached peak values at 5 days and then gradually declined. The OC staining, ALP activity, and real-time PCR assay of ColI, OC, and ALP were all increased in cells transfected with Ad BMP2-VEGF165, Ad-BMP2, Ad-VEGF165, and Ad-GFP. However, the osteogenic biological activity in cells transfected with Ad-BMP2 was higher compared to cells transfected with other vectors after transfection at 14 and 21 days. We also found that BMP2 +VEGF165 group showed more osteogenic activity effect than the VEGF165 or control group. Furthermore, osteogenic assays in VEGF165 showed that a slightly lower osteogenic effect when compared to controls at 21 days.VEGF165 might be a potent inhibitor of BMSCs differentiation into osteoblasts. The strategies to use BMP2 and VEGF165 in bone regeneration and the molecular mechanism of their interaction require further investigation. PMID- 29384875 TI - Electret filter collects more exhaled albumin than glass condenser: A method comparison based on human study. AB - In recent years, noninvasive diagnosis based on biomarkers in exhaled breath has been extensively studied. The procedure of biomarker collection is a key step. However, the traditional condenser method has low efficacy in collecting nonvolatile compounds especially the protein biomarkers in breath. To solve this deficiency, here we propose an electret filter method.Exhaled breath of 6 volunteers was collected with a glass condenser and an electret filter. The amount of albumin was analyzed. Furthermore, the difference of exhaled albumin between smokers and nonsmokers was evaluated.The electret filter method collected more albumin than the glass condenser method at the same breath volume level (P < .01). Smokers exhaling more albumin than nonsmokers were also observed (P < .01).The electret filter is capable of collecting proteins more effectively than the condenser method. In addition, smokers tend to exhale more albumin than nonsmokers. PMID- 29384876 TI - Predictors of completing a primary health care diabetes prevention intervention programme in people at high risk of type 2 diabetes: Experiences of the DE-PLAN project. AB - It has been shown that real-life implementation studies for the prevention of type 2 diabetes (DM2) performed in different settings and populations can be effective. However, not enough information is available on factors influencing the reach of DM2 prevention programmes. This study examines the predictors of completing an intervention programme targeted at people at high risk of DM2 in Krakow, Poland as part of the DE-PLAN project.A total of 262 middle-aged people, everyday patients of 9 general practitioners' (GP) practices, at high risk of DM2 (Finnish Diabetes Risk Score (FINDRISK) >14) agreed to participate in the lifestyle intervention to prevent DM2. Intervention consisted of 11 lifestyle counseling sessions, organized physical activity sessions followed by motivational phone calls and letters. Measurements were performed at baseline and 1 year after the initiation of the intervention.Seventy percent of the study participants enrolled completed the core curriculum (n = 184), 22% were men. When compared to noncompleters, completers had a healthier baseline diabetes risk profile (P <.05). People who completed the intervention were less frequently employed versus noncompleters (P = .037), less often had hypertension (P = .043), and more frequently consumed vegetables and fruit daily (P = .055).In multiple logistic regression model, employment reduced the likelihood of completing the intervention 2 times (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.25 0.81). Higher glucose 2 hours after glucose load and hypertension were the independent factors decreasing the chance to participate in the intervention (OR 0.79, 95% 0.69-0.92 and OR 0.52, 95% CI 0.27-0.99, respectively). Daily consumption of vegetables and fruits increased the likelihood of completing the intervention (OR 1.86, 95% 1.01-3.41).In conclusion, people with healthier behavior and risk profile are more predisposed to complete diabetes prevention interventions. Male, those who work and those with a worse health profile, are less likely to participate and complete interventions. Targeted strategies are needed in real-life diabetes prevention interventions to improve male participation and to reach those who are working as well as people with a higher risk profile. PMID- 29384877 TI - Acute appendicitis complicated with necrotizing fasciitis in a patient with adult onset Still's disease: A case report. AB - RATIONALE: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, spiking fever, arthralgia/ arthritis, and lymphadenopathy. AOSD sometimes was fatal when it is complicated by macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH). Nonetheless, the literature provides no recommendations for treatment of AOSD patients with severe sepsis. PATIENT CONCERNS: A previously healthy 65-year-old man with history of AOSD was referred to our hospital for persistent right lower quadrant abdominal pain for 2 days. One week later, an abdominal wall abscess and hematoma developed by extravasation from the inferior epigastric vessels, complicated by necrotizing fasciitis of the right thigh and groin region. To our best knowledge, this case was the first reported case of a perforated appendix complicated with necrotizing fasciitis in a patient with AOSD. DIAGNOSES: The patient was diagnosed as acute appendicitis complicated with necrotizing fasciitis and abdominal wall abscess. INTERVENTIONS: This case received intravenous tigecycline injection and daily 10 mg prednisolone initially, and shifted to daily intravenous hydrocortisone 200 mg for suspected MAS or HLH. This patient underwent surgical intervention and debridement for necrotizing fasciitis. OUTCOMES: The patient's symptoms progressed worse rapidly. He died from cytomegalovirus viremia and bacterial necrotizing fasciitis complicated by septic shock. LESSONS: (1) The steroid dose was difficult to titrate when AOSD complicated by sepsis. The differential diagnosis from MAS/HLH with bacterial/viral infection related severe sepsis was difficult but critical for decision making from clinicians and rheumatologists. (2) The conservative treatment with antibiotics for perforated appendix is safe but has a higher failure rate in immunocomprised patients such as systemic lupus erythematosus and AOSD. Early surgical intervention might contribute to better outcome. (3) The abdominal wall abscess can be spread from intra-abdominal lesion through the inferior epigastric vessels which were as weak points of abdominal wall. Imaging examinations contribute to acute diagnosis and help surgeons perform surgical interventions to prevent morbidity and mortality. PMID- 29384878 TI - Extracorporeal shock wave treatment can normalize painful bone marrow edema in knee osteoarthritis: A comparative historical cohort study. AB - Bone marrow edema (BME) represents a reversible but highly painful finding in magnetic resonance imaging (MRI) of patients with knee osteoarthritis. The aim of this retrospective study was to evaluate the efficacy of extracorporeal shock wave treatment (ESWT) on painful BME in osteoarthritis of the knee.This study focuses on people who had early-to-mid stage osteoarthritis with knee pain and MRI findings of BME. Patients who underwent ESWT treatment or prescribed alendronate treatment in our department were analyzed. Knee pain and function were measured using the visual analog scale (VAS) for pain and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), respectively. The degree of BME was measured with MRI scans.A total of 126 patients who received ESWT treatment (Group A, n = 82) or alendronate treatment (Group B, n = 44) were included. All patients were followed up clinically and radiographically for a minimum of 12 months. The mean follow-up was 23.5 months (range, 12-38 months). The VAS and WOMAC score decreased more significantly after treatment in Group A than that in Group B (P <.01) within 3 months. In 6-month MRI follow-ups, there was higher incidence of distinct reduction and complete regression of BME of the affected knee in Group A than that in Group B (P <.01).ESWT is an effective, reliable, and noninvasive treatment in patients with painful BME in osteoarthritis of the knee followed by a rapid normalization of the MRI appearance. It has the potential to shorten the natural course of this disease. PMID- 29384879 TI - Amputation of multiple limbs caused by use of inotropics: Case report, a report of 4 cases. AB - RATIONALE: We present 4 cases of symmetrical peripheral gangrene (SPG) associated with use of inotropic agent to elevate blood pressure. SPG is a relatively rare phenomenon characterized by symmetrical distal ischemic damage that leads to gangrene of 2 or more sites in the absence of large blood vessel obstruction, where vasoconstriction rather than thrombosis is implicated as the underlying pathophysiology. We present 4 SPG cases of the multiple limbs amputation, associated with inevitable use of inotropic agents. PATIENT CONCERNS: Inotropic agents including dopamine and norepinephrine are used frequently in the treatment of hypotension, and its effectiveness in treating shock is firmly established. However, it can be caused peripheral gangrene by prolonged administration of high dose inotropics, inducing the constant contraction of the peripheral blood vessels. DIAGNOSIS: These 4 patients had different clinical histories and background factors, but each experienced sepsis. The level of amputation is determined by the line of demarcation in concert with considerations of the biomechanics of stump stability, weight bearing, and ambulation. INTERVENTIONS: After recovering of general conditions and completion of demarcation, these 4 patients underwent the amputation of multiple limbs.(bilateral amputations of upper extremities or bilateral amputations of lower extremities). OUTCOMES: In each patient, there was no additional amputation caused by extension of SPG, and the rehabilitation with appropriate orthosis was performed. Treatment of underlying disease were continued too. LESSONS: It is important to alert the possibility of amputations, according to the use of inevitable inotropics. We recommended the careful use of the inotropic agents to the physicians in treating septic shock. PMID- 29384880 TI - Risk factors for heart valve calcification in chronic kidney disease. AB - Cardiovascular disease (CVD) is a common cause of death in patients with chronic kidney disease (CKD). Aortic and mitral valve calcification (AVC and MVC, respectively) are critical indicators of CVD and all-cause mortality in CKD patients.We conducted a single center retrospective study of Chinese inpatients with CKD to identify risk factors associated with valve calcification (VC).Of 288 enrolled CKD patients, 22.9% had VC, all of which exhibited AVC, while 21.2% exhibited MVC. The VC group were significantly older than the non-VC group (70.42 +/- 11.83 vs 56.47 +/- 15.00, P < .001), and contained more patients with history of coronary artery disease (12.1% vs 4.5%, P = .025) or stroke (18.2% vs 5.4%, P < .001). Subjective global assessment scoring indicated that more VC patients were mid/severely malnourished. Levels of prealbumin, cholesterol (Ch), triglycerides, low-density lipoprotein (LDL), apolipoprotein E, ejection fraction, and fraction shortening were significantly lower, and blood C reactive protein, IL-6, left ventricular internal end diastole diameter measured in end diastole, and interventricular septum thickness (IVST) levels were significantly higher in the VC group. Bone metabolism did not differ significantly between the 2 groups. Multivariable logistic regression analysis indicated that age, blood Ch, and LDL levels were significantly associated with VC.Advanced age, increased IVST, hypocholesterolemia, and hyper-LDL cholesterolemia were key risk factors for VC in Han patients with CKD. PMID- 29384881 TI - Analysis of anesthesia-controlled operating room time after propofol-based total intravenous anesthesia compared with desflurane anesthesia in functional endoscopic sinus surgery. AB - Anesthesia technique may contribute to the improvement of operation room (OR) efficiency by reducing anesthesia-controlled time. We compared the difference between propofol-based total intravenous anesthesia (TIVA) and desflurane anesthesia (DES) for functional endoscopic sinus surgery (FESS) undergoing general anesthesiaWe performed a retrospective study using data collected in our hospital to compare the anesthesia-controlled time of FESS using either TIVA via target-controlled infusion with propofol/fentanyl or DES/fentanyl-based anesthesia between January 2010 and December 2011. The various time intervals (surgical time, anesthesia time, extubation time, total OR stay time, post anesthesia care unit [PACU] stay time) and the percentage of prolonged extubation were compared between the 2 anesthetic techniques.We included data from 717 patients, with 305 patients receiving TIVA and 412 patients receiving DES. An emergence time >15 minutes is defined as prolonged extubation. The extubation time was faster (8.8 [3.5] vs. 9.6 [4.0] minutes; P = .03), and the percentage of prolonged extubation was lower (7.5% vs. 13.6%, risk difference 6.1%, P < .001) in the TIVA group than in the DES group. However, there was no significant difference between ACT, total OR stay time, and PACU stay time.In our hospital, propofol-based TIVA by target-controlled infusion provide faster emergence and lower chance of prolonged extubation compared with DES anesthesia in FESS. However, the reduction in extubation time may not improve OR efficiency. PMID- 29384882 TI - Tubular microscopes discectomy versus conventional microdiscectomy for treating lumbar disk herniation: Systematic review and meta-analysis. AB - BACKGROUND: The application of tubular microscopes discectomy (TMD) was supposed to have similar or better results than conventional microdiscectomy (CMD). However, this conclusion had not been verified by sufficient evidence. Therefore, the focus of this meta-analysis was to assess the efficiency, safety, and clinical outcome of these 2 surgical procedures for treating lumbar disk herniation (LDH). METHODS: PubMed, Embase, and Cochrane Collaboration Central databases were searched for studies which compared the results of TMD and CMD for the treatment of LDH up to July 2017. Data analysis was conducted using RevMan 5.3. A standardized electronic form of 17 predefined criteria from the Consort statement was used for the quality assessment. RESULTS: Eight randomized controlled trials (RCT) and 2 retrospective studies were included in this review, including 804 patients. The pooled analysis showed that there was no significant difference in operative time (P = .38), blood loss (P = .14), the length of hospital stay (P = .47), the rate of intraoperative complications (P = .79), postoperative complications (P = .16), dural tear (P = .87), the reoperation (P = .20), the short-term back visual analog scale (VAS) scores (P = .76), the long term back VAS scores (P = .64), the short-term leg VAS scores (P = .09), the long term leg VAS scores (P = .35), and the Oswestry disability index (ODI) scores (P = .41). CONCLUSION: The results of this meta-analysis demonstrate that TMD and CMD are both safe and effective surgical procedures which can be recommended for treating LDH. Additionally, the conclusion should be cautiously treated, because it was reached in the context of limited amount of studies and relatively small sample size. Therefore, future studies with good design and more large samples are required to validate this conclusion. PMID- 29384883 TI - Comparison of the clinical effects of zero-profile anchored spacer (ROI-C) and conventional cage-plate construct for the treatment of noncontiguous bilevel of cervical degenerative disc disease (CDDD): A minimum 2-year follow-up. AB - Comparing the clinical and radiographic outcomes in anterior cervical discectomy and fusion (ACDF) using a zero-profile anchored spacer (ROI-C) or a conventional cage-plate construct (CPC) for treating noncontiguous bilevel of cervical degenerative disc disease (CDDD).Overall, 46 patients with 2 noncontiguous segments of CDDD, treated with ACDF from January 2011 to October 2015, were included in this study. ROI-C was used in 22 patients (group A) and CPC in 24 patients (group B). The clinical and radiographic outcomes and complications were compared pre- and postoperatively. All patients were followed up for at least 24 months after surgery.No significant difference was found in fusion rate, cervical curvature, height of fused segment (FSDH), intraoperative blood loss, and Japanese Orthopaedic Association (JOA), and Neck Disability Index (NDI) scores between the 2 groups. Group A had a shorter operation time and significantly lower incidence of dysphagia (3 and 24 months postoperatively) than group B (P < .001 and P < .05, respectively). Moreover, group A had a higher loss of FSDH than group B, but with no difference between the 2 groups (P > .05). Two cages developed subsidence in group A (4.5%) and 2 adjacent levels developed degeneration in group B (2,8%).ACDF with ROI-C device was superior to CPC for noncontiguous bilevel of CDDD because it avoided postoperative dysphagia and required a shorter operation time. Moreover, the clinical outcomes were comparable. Prospective trials with larger samples and longer follow-up are required to confirm the results. PMID- 29384884 TI - Influence of echocardiographic measurements and renal impairments on the prognosis of fulminant myocarditis. AB - Fulminant myocarditis is a severe cardiac emergency that may lead to death if effective cardiopulmonary supports are not provided. This study aimed to evaluate the prognostic predictors in patients with fulminant myocarditis.We retrospectively analyzed the clinical characteristics, complications, laboratory findings, treatments, as well as electrocardiographic and echocardiographic data of 73 consecutive subjects diagnosed with fulminant myocarditis from June 2012 to June 2016. Logistic regression analysis was used to identify the independent predictive factors of nonsurvivor fulminant myocarditis.Ten patients and 63 patients were assigned to the nonsurvivor and survivor fulminant myocarditis groups, respectively. Patients in the nonsurvivor fulminant myocarditis group had higher heart rates; were more likely to develop clinical complications and supraventricular tachycardia (SVT); and had higher serum creatinine (Scr) level, and had higher white blood cell (WBC) counts, and lower abbreviated estimated glomerular filtration rates (eGFR) than the patients in the survivor fulminant myocarditis group. Moreover, we observed larger left atrium dimension (LAd), larger left ventricular end systolic dimensions, and lower left ventricular ejection fraction in the patients from the nonsurvivor fulminant myocarditis group than in those from the other group. A logistic regression model was constructed and demonstrated that eGFR and LAd were 2 independent predictors of mortality in patients with fulminant myocarditis.Higher heart rates, higher incidences of clinical complication, SVT, higher admission levels of Scr and eGFR, higher WBC counts, higher Scr and eGFR at stage of most severe renal damage, and abnormal echocardiographic findings were associated with high risk of mortality in patients with fulminant myocarditis. The major finding was that eGFR and LAd were independent predictors for in-hospital mortality in patients with fulminant myocarditis. PMID- 29384885 TI - Recurrent stroke in a patient of lung cancer without pulmonary mass: A case report. AB - RATIONALE: Repeated occurring stroke in short intervals with hypercoagulability is unusual so in such cases the conventional vascular risk factors might not be the causes of stroke. PATIENT CONCERNS: We have presented a case of 60-year-old male presenting with recurrent stroke due to thrombophilia. DIAGNOSES: Lung cancer was detected by superficial lymph nodes ultrasound and further pathological examination. INTERVENTIONS: The patient suffered a recurrent stroke and he had persistently high level of D-dimer which suggested the diagnosis of thrombophilia, thus, he was treated with low-molecular-weight heparin. Unfortunately, the treatment was not effective for the patient and he died before any other treatments could be administered. OUTCOMES: Despite anticoagulant therapy, the patient suffered multiple episodes of stroke and ultimately died. LESSONS: This case of recurrent stroke with coagulation disorders without evidence of cancer in imaging and blood test is rare. So in a stroke patient, we should consider malignancy or metastasis as a differential diagnosis as it may be the first manifestation of active cancer elsewhere. PMID- 29384886 TI - Validity of the use of a subfascial vessel as the recipient vessel in a second free flap transfer: A retrospective clinical review. AB - Performing a greater number of free flap procedures inevitably results in an increase in the number of cases that experience free flap failure. In cases that require a second free flap after the failure of the first, recipient vessel selection becomes difficult. Furthermore, recipient vessel selection can be complicated if the vessel is deep in the recipient site, or if there is an increased risk of vessel damage during the dissection. Thus, we present our experience where a subfascial vessel beneath the deep fascia was used as a recipient vessel for a second free flap in lower extremity reconstruction due to total or partial first flap failure.Between January 2010 and April 2015, 5 patients underwent second free flap reconstruction using a subfascial vessel as the recipient vessel. The flaps were anastomosed in a perforator-to-perforator manner, using the supermicrosurgery technique. We measured the sizes of the flaps, which varied from 5 * 3 to 15 * 8 cm, and the recipient subfascial vessel diameters.The mean time for the dissection of the recipient perforator was 45 minutes. All the flaps exhibited full survival, although a partial loss of the skin graft at the flap donor site was observed in 1 patient; this defect healed with conservative management.We recommend using a subfascial vessel as the recipient vessel for both first and second free flaps, especially if access to the major vessel is risky or challenging. PMID- 29384887 TI - A rare large cutaneous chondroid syringoma involving a toe: A case report. AB - RATIONALE: Chondroid syringoma (CS) occurs mostly on the face and neck, and rarely occurs in the toe. Malignant CS is invasive, grows quickly, and has a high recurrence rate. The presence of a bilobed CS in 1 toe has never been reported in the literature. PATIENT CONCERNS: A 72-year-old male patient presented with a mass in a third toe of his right foot. The mass had slowly grown in 2 years. He felt mild pain and the mass occupied most of the tip of the toe. DIAGNOSES: Radiographs showed a large soft-tissue mass in the third toe of his right foot without any bone destruction. Ultrasonogram showed 2 partly fused hypoechoic masses within the lesion. The mass was therefore diagnosed as a benign CS. INTERVENTIONS: We amputated the toe with the mass under local anesthesia. The postoperative pathohistological examinations confirmed that the lesion was a bipartite CS exhibiting active cellular proliferation. OUTCOMES: Two years after surgery, there was no tumor recurrence. LESSONS: CS can also present as multiple adjacent masses. Complete surgical resection and long-term follow-up are essential. PMID- 29384889 TI - An approach toward public hospital performance assessment: Retraction. PMID- 29384888 TI - Effectiveness of continuous epidural analgesia on acute herpes zoster and postherpetic neuralgia: A retrospective study. AB - Despite early treatment of herpes zoster (HZ), postherpetic neuralgia (PHN) can persist. This study was designed to compare the therapeutic and pain relief effects of continuous epidural analgesia (CEA) on the chronic phase as well as the acute phase of HZ with standard medical treatment.Medical records of 227 patients with moderate to severe zoster-associated pain that had not responded to standard medications were retrospectively reviewed. Patients received standard treatment alone (medical group) or standard treatment plus concurrent CEA (epidural group). The acute and chronic groups were classified according to a 4 week cut-off with regard to time between the onset of the rash and the first treatment. Four groups were studied: Group A (acute/medical group); Group B (acute/epidural group); Group C (chronic/medical group); and Group D (chronic/epidural group). Pain was assessed using the visual analog scale (VAS) and measured every 2 weeks for 6 months. We compared the pain rating at 6 months after the first treatment with the initial pain rating. Response to treatment was defined as a >=50% reduction in pain severity since the initial visit. Remission was considered complete for patients whose VAS pain score was <=2 for >3 successive visits and who no longer needed medical support.Patients who received a combination of standard treatment plus CEA (Groups B and D) had significantly higher response to treatment (P = .001) than patients receiving standard treatment alone (Groups A and C). The adjusted odds ratio (OR) for response to treatment in the epidural group versus the medical group was 5.17 (95% confidence interval [CI]: 1.75-15.23) in the acute group and 5.37 (95% CI: 1.62-17.79) in the chronic groups. The adjusted OR for complete remission in the epidural group versus the medical group was 3.05 (95% CI: 1.20-7.73) in the acute group and 4.46 (95% CI: 1.20-16.54) in the chronic group.CEA can effectively relieve pain caused by PHN and acute HZ and increase remission rates. Combining CEA with standard medical treatment may offer a clinical advantage in the management of pain caused by PHN as well as acute HZ. PMID- 29384890 TI - Nutrition in Paediatric Inflammatory Bowel Disease: A Position Paper on Behalf of The Porto IBD Group of ESPGHAN. AB - BACKGROUND AND AIMS: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with IBD. We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of paediatric IBD patients. METHODS: A group of 20 experts in paediatric IBD participated in an iterative consensus process including 2 face to-face meetings, following an open call to ESPGHAN Porto, IBD Interest and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a SR of the literature. RESULTS: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment; nutrition as a primary therapy of paediatric IBD; macronutrients needs; trace Elements, minerals and vitamins; probiotics and prebiotics; specific dietary restrictions; dietary compounds and the risk of IBD. CONCLUSIONS: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD. PMID- 29384891 TI - Familial risk for psychiatric disorders in military veterans who have post traumatic stress disorder with psychosis: a retrospective electronic record review. AB - AIMS/OBJECTIVES/BACKGROUND: Post-traumatic stress disorder (PTSD) is a leading cause of morbidity among military veterans, with up to one-in-five individuals with PTSD also having psychotic symptoms. The current study was designed to determine the association between a known family history of psychiatric illness and risk of developing psychosis in patients with PTSD. METHODS: Retrospective medical record review was performed on a cohort study of 414 consecutive individuals admitted to the Veteran Administration in 2014 with a diagnosis of military-related PTSD, but without a prior diagnosis of a psychotic disorder. PTSD with psychotic features was defined as the presence of hallucinations, paranoia, other delusions, thought insertion, withdrawal, broadcasting, and/or dissociative episodes. RESULTS: Overall, 22.9% of individuals with PTSD had psychotic symptoms. Having a first-degree relative with bipolar affective and with anxiety disorders was associated with an increased risk of PTSD with psychosis (odds ratio=2.01, 95% confidence interval: 1.01-4.45 and odds ratio=2.72, 95% confidence interval: 1.16-6.41, respectively). A family history of schizophrenia or depression was not associated with risk of developing psychotic features in patients with PTSD. In veterans with military-related PTSD, a familial vulnerability for bipolar disorder and anxiety disorders was associated with an increased risk of developing PTSD with psychotic features. These are preliminary data, given the limitations of a retrospective record review design. These results await replication in future prospective direct family interview studies. PMID- 29384893 TI - The modified cone reconstruction in the treatment of Ebstein's anomaly: Case reports. AB - RATIONALE: To investigate the early and mid-term clinical outcomes of the modified cone reconstruction in the treatment of Ebstein's anomaly (EA) which provide appropriate surgical treatment for clinical and reduce the incidence of re-operation and valve replacement. PATIENT CONCERNS: Clinical data of 18 consecutive patients with EA in our hospital between May 2008 and August 2015 were analyzed retrospectively. All patients were diagnosed by echocardiography. Among these patients, according to New York Heart Association functional grade, there were 12 patients with grade II cardiac function and 6 patients with grade III. All patients had severe tricuspid regurgitation grade. DIAGNOSES: All patients were diagnosed EA. One case was with acute arterial embolism and amputation of left lower extremity caused by paradoxical embolism of combined secundum atrial septal defect. INTERVENTIONS: The modified cone reconstruction in the treatment of EA of the tricuspid valve uses its own tissues to form not only central bloodstream, but also the coaption between 2 leaflets. For those patients whose anterior leaflet developed poor and smaller, the valve leaflet was widened by using autologous pericardial. For all patients, tricuspid annulus were reinforced by autologous pericardial. One case was combined with double-orifice technique due to postoperative poor closure of the tricuspid valve. OUTCOMES: There were 2 cases with arrhythmia, and they returned to normal after medication. The rest patients recovered smoothly with no death. Review of echocardiography: 1 patient with moderate regurgitation, the rest of patients' leaflets coapted well and had no tricuspid stenosis. All cases were followed up postoperatively for 9 to 38 months, and there were 14 patients with grade I cardiac function and 4 patients with grade II. LESSONS: The early and mid-term clinical outcomes of the modified cone reconstruction in the treatment of EA were which can make leaflets coapt and had a strong antiregurgitation ability, reducing the incidence of re operation, valve replacement, and postoperative mortality. PMID- 29384894 TI - Comparison between CT and MRI in the assessment of pulmonary embolism: A meta analysis. AB - OBJECTIVE: Besides pulmonary arteriography, a number of imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), were adopted in the detection of identifying pulmonary embolism (PE). However, the contrast of sensitivity and specificity in these methods was studied little in a statistical way. To compare the effects of MRI and CT, this study used a series of methods to analyze data in included researches. METHODS: A comprehensive computer search was conducted through internet up to July 2016. The quality assessment was performed by the Quality Assessment Tool for Diagnostic Accuracy Studies, version 2 tool. The diagnostic value of comparison between MRI and CT was evaluated by using the pooled estimate of sensitivity, specificity, and summary receiver operating characteristic (SROC) curve. In addition, sensitivity analysis and bias analysis were applied to ensure the accuracy of the results. RESULTS: Ten studies with 590 cases were involved in the study. Only 2 trials had high risk regarding bias while other trials were supposed to be at low risk of applicability. Heterogeneity existed in analysis of both CT and MRI. The pooled sensitivity of CT was 0.90 (95% CI: 0.85-0.93), pooled specificity was 0.88 (95% CI: 0.77 to 0.95), the pooled sensitivity of MRI was 0.92 (95% CI: 0.89-0.94), and pooled specificity was 0.91 (95% CI: 0.77-0.97). The Q index of sensitivity and specificity for CT and MRI were 71.38, 19.67, 47.14, and 12.35, respectively. The SROC curve area under the curve of CT and MRI were 0.94 (95% CI: 0.91-0.96) and 0.93 (95% CI: 0.91-0.95), respectively. CONCLUSION: This meta-analysis demonstrates that MRI has better sensitivity and specificity in detecting subsegmental artery PE. MRI is a relatively better detection technique for PE. This conclusion is consistent with many published researches. PMID- 29384892 TI - Hemoglobin Levels Across the Pediatric Critical Care Spectrum: A Point Prevalence Study. AB - OBJECTIVES: To determine the prevailing hemoglobin levels in PICU patients, and any potential correlates. DESIGN: Post hoc analysis of prospective multicenter observational data. SETTINGS: Fifty-nine PICUs in seven countries. PATIENTS: PICU patients on four specific days in 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' hemoglobin and other clinical and institutional data. Two thousand three hundred eighty-nine patients with median age of 1.9 years (interquartile range, 0.3-9.8 yr), weight 11.5 kg (interquartile range, 5.4-29.6 kg), and preceding PICU stay of 4.0 days (interquartile range, 1.0-13.0 d). Their median hemoglobin was 11.0 g/dL (interquartile range, 9.6-12.5 g/dL). The prevalence of transfusion in the 24 hours preceding data collection was 14.2%. Neonates had the highest hemoglobin at 13.1 g/dL (interquartile range, 11.2-15.0 g/dL) compared with other age groups (p < 0.001). The percentage of 31.3 of the patients had hemoglobin of greater than or equal to 12 g/dL, and 1.1% had hemoglobin of less than 7 g/dL. Blacks had lower median hemoglobin (10.5; interquartile range, 9.3-12.1 g/dL) compared with whites (median, 11.1; interquartile range, 9.0-12.6; p < 0.001). Patients in Spain and Portugal had the highest median hemoglobin (11.4; interquartile range, 10.0-12.6) compared with other regions outside of the United States (p < 0.001), and the highest proportion (31.3%) of transfused patients compared with all regions (p < 0.001). Patients in cardiac PICUs had higher median hemoglobin than those in mixed PICUs or noncardiac PICUs (12.3, 11.0, and 10.6 g/dL, respectively; p < 0.001). Cyanotic heart disease patients had the highest median hemoglobin (12.6 g/dL; interquartile range, 11.1-14.5). Multivariable regression analysis within diagnosis groups revealed that hemoglobin levels were significantly associated with the geographic location and history of complex cardiac disease in most of the models. In children with cancer, none of the variables tested correlated with patients' hemoglobin levels. CONCLUSIONS: Patients' hemoglobin levels correlated with demographics like age, race, geographic location, and cardiac disease, but none found in cancer patients. Future investigations should account for the effects of these variables. PMID- 29384895 TI - Imaging findings of gastric plexiform fibromyxoma with a cystic change: A case report and review of literature. AB - RATIONALE: Plexiform fibromyxoma (PF) is an extremely rare mesenchymal tumor of the stomach, and its radiological findings have not been well described. Here, we analyzed the imaging features of a case of PF. To our knowledge, this is a rare reported case with a remarkable cystic change in the imaging literature. PATIENT CONCERNS: A previously healthy 50-year-old woman presented with a 1-day history of abdominal pain. Then, she underwent computed tomography (CT) and magnetic resonance imaging (MRI). A cystic-solid well-circumscribed extraluminal mass was located in the posterior wall of the gastric upper body. The solid portion appeared as heterogeneous attenuation/intensity with progressive enhancement while the cystic region had no enhancement. DIAGNOSES: The potential for malignancy could not be excluded. INTERVENTIONS: Laparoscopic partial gastric resection was performed. OUTCOMES: Based on pathological findings, a diagnosis of PF was made. The patient was alive without any recurrence or metastasis of the tumor after 2 years of follow-up. LESSONS: As far as we know, a gastric PF with a remarkable cystic change has never been reported. Additionally, the tumor exhibited a progressive enhancement pattern which is a characteristic radiographic feature in our case. Our report may help increase the awareness of this rare but important new disease entity. PMID- 29384896 TI - A 25-year surveillance of disseminated Bacillus Calmette-Guerin disease treatment in children in Southern Iran. AB - Disseminated Bacillus Calmette-Guerin (BCG) disease is one of the most serious complications of BCG vaccination, mainly among immunocompromised children with high morbidity and mortality.Currently, there is no any consensus with regard to the standard regimen of antituberculosis (anti-TB) agents and duration of treatment in healthy or immunocompromised host in children. The aim of this study is to investigate the effect of various combination treatment strategies for disseminated BCG disease in children.In this cross-sectional study, the outcome of 3 different combination protocols was investigated in 59 patients.All patients were younger than 6 years old. Both possible immunocompetent and proven immunodeficient children were included in a period of 25 years (1991-2014) in a Nemazee referral teaching hospital.The minimum age was 1 month and the maximum was 60 months. The average age of patients was 8 months (8.26 +/- 9.73). Out of 59 cases, 32 (54.2%) were female and 27 (45.8%) were male. Based on the primary work up, 52.5% of cases were classified as definite immunodeficient and 47.5% were classified as possible immunocompetent. Overall mortality rate was 50.8%. Mortality rate of disseminated BCG disease in immunocompetent and immunodeficient children was 28.6% and 71%, respectively. The mortality rate was not statistically different between patients treated with different treatment protocols. These results were not affected by immune status and the type of immunodeficiency.More than 2 anti-TB drugs combination will not change outcome of patient with disseminated BCG disease. PMID- 29384898 TI - Diagnosis and treatment of neoplastic post-transplant lymphoproliferative disorder following hematopoietic stem cell transplant in beta-thalassemia: A pediatric case report. AB - INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is the most common form of lymphoproliferation in childhood and is associated with significant morbidity and mortality. In this report we reviewed the case of a pediatric patient who experienced PTLD after allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-identical sibling. METHODS: The clinical characteristics, diagnosis, and treatment of PTLD after sibling HSCT in a 4-year-old boy with severe beta-thalassemia was retrospectively reviewed. RESULTS: Medical records revealed the patient developed a fever and superficial lymphadenopathy and soft palate enlargement 8 months post-HSCT. Pathologic diagnosis indicated non-Hodgkin lymphoma (B-cell type), which resulted in a reduced dose of immunosuppressant and the initiation of chemotherapy (administered according to the BFM95 protocol for 2 courses; 4 courses of rituximab therapy was also administered). Currently, the patient has been disease free for over 3 years. There are no specific guidelines for the treatment of PTLD. The status of stem cell implantation after transplantation, and graft versus host disease should be evaluated jointly, and rituximab therapy and chemotherapy with BFM-95 may be used for treatment of pediatric PTLD after HSCT. CONCLUSION: The current case represents a unique opportunity to review a pediatric patient with beta-thalassemia. The successful treatment of post transplant non-Hodgkin B lymphoma may help other physicians in the management of similar pediatric cases. PMID- 29384897 TI - Significance of imaging findings in the diagnosis of heterotopic spleen-an intrapancreatic accessory spleen (IPAS): Case report. AB - RATIONALE: Accessory spleen (Heterotopic/Ectopic) or splenunculus has been attributed to the failure of the fusion of splenic primordial buds-derived from dorsal mesentery (mesodermal mesenchymal in origin) during the 5th week of embryonic organogenesis or to an extreme degree of splenic lobulation with pinching off of the spleen tissue. The most common locations for accessory spleens are the hilum of the spleen followed by adjacent to the tail of the pancreas. The patients usually present with no clinical symptoms. PATIENT CONCERNS: A 49-year-old female undergoing a routine medical examination- Abdominal Ultrasound revealed a pancreatic mass. She was admitted into the hospital for 3 days and was put under observation. There are no specific findings during the physical examination or any related abnormalities in the laboratory investigations. DIAGNOSIS: Heterotopic spleen-an intrapancreatic accessory spleen (IPAS). INTERVENTIONS: Noncontrast CT of the abdomen demonstrated a soft tissue mass with a clear boundary in the tail of the pancreas. On contrast examination the arterial phase, it was markedly enhanced, homogenous congruity similar to that of spleen; on magnetic resonance imaging (MRI)-T2WI with fat suppressed sequence, it demonstrated a regular round clear edged mass in the pancreatic tail. On Diffusion Weighted Imaging (DWI), a mass with a clear boundary was observed within the parenchyma of the pancreatic tail. The mass showed a high signal on noncontrast MRI, while on contrast examination, the mass showed a strengthening signal with homogenous enhancement as that of spleen. OUTCOMES: Heterotopic spleen presentation is a very rare asymptomatic clinical condition. During the routine medical examination - it presents mostly as a solitary benign round or oval mass with a clear boundary or as an ectopic focus, either in the pancreatic tail or adjacent to the pancreatic appendage, as an incidental finding. On Contrast CT, it shows as a homogeneously enhanced density- a strengthening mass lesion, in the pancreatic tail, similar to that of spleen. LESSONS: Our case emphasizes the importance of recognizing IPAS radiological characteristics and typical variations in its presentation in an asymptomatic patient that could help the personnel to differentiate it from other mass lesions. Thus, recognizing imaging findings on Plain CT, Contrast CT and MRI plays a key role to form a conclusive diagnosis of an accessory spleen, which has to be clinically associated. So, surgeons should consider IPAS as a differential for which unnecessary resection and an unintended surgical procedure can be avoided. PMID- 29384899 TI - Coinfection of disseminated Talaromyces marneffei and Mycobacteria kansasii in a patient with papillary thyroid cancer: A case report. AB - RATIONALE: Recently, Talaromyces marneffei (T. marneffei) has been reported in human immunodeficiency virus (HIV)-negative patient with underlying diseases, such as oral cancer, colon cancer, haematological malignancies, connective tissue disease, diabetes mellitus, and corticosteroids or immunosuppressive agents. Similar to HIV-positive ones, such patients were observed with CD4 lymphocytopenia. PATIENT CONCERNS: We reported a case of a 45-year-old woman who was diagnosed with disseminated T. marneffei and Mycobacteria kansasii (M. kansasii) with papillary thyroid cancer as the underlying disease. T-cell subsets counts, CD4 T-cell%, CD8 T-cell%, CD4/CD8 ratio, and NK cell% were all turned out to be normal. DIAGNOSES: Based on bronchoalveolar lavage fluid and skin lesions secretion cultures, blood culture, the patient was diagnosed with disseminated T. marneffei and M. kansasii. Pathological examination reported papillary thyroid cancer with cervical lymph node metastasis. INTERVENTIONS: The patient received the combined and longer antifungal therapy and drug regimens for M. kansasii. She had total thyroidectomy with radical neck dissection to treat the papillary thyroid cancer. OUTCOMES: The patient had a favorable outcome for 19 months without recurrence. LESSONS: T. marneffei could infect non-HIV individuals with underlying disease under the condition of normal T-cell counts. The symptoms were lack of specificity and were more likely to be misdiagnosed. Such patients with unidentified T-cell dysfunction or other unidentified primary immunodeficiency disorders may prone to coinfect with other opportunistic pathogens, such as M. kansasii. Compared with HIV-positive ones, they need combined and much longer antifungal therapy. PMID- 29384900 TI - A case report of acute inferior myocardial infarction in a patient with severe hemophilia A after recombinant factor VIII infusion. AB - RATIONALE: The extent of protective effects of hemophilia against thrombotic events such as myocardial infarction (MI) and other acute coronary syndromes remains to be determined, as major risk factors for cardiovascular disease exist despite factor VIII (FVIII) deficiency. We present a case report of a 41-year-old male with severe hemophilia A and several cardiovascular risk factors. PATIENT CONCERNS: This morbidly obese patient developed chest pressure, followed by chest pain and difficulty in breathing shortly after receiving on-demand treatment with intravenous recombinant FVIII (rFVIII) (turoctocog alfa) dosed per body weight. DIAGNOSES: An electrocardiogram revealed a diagnosis of inferior ST-segment elevation MI. INTERVENTIONS: The patient underwent an urgent coronary angiography using a radial artery approach. During the next 12 months, he received dual antiplatelet treatment, acetylsalicylic acid 100 mg, and clopidogrel 75 mg daily. His treatment for severe hemophilia A was changed to plasma-derived FVIII replacement therapy. OUTCOMES: During this 12-month period, he experienced several small bleeds in his elbows. CONCLUSIONS: The temporal relationship between rFVIII infusion and onset of the MI suggests a possible association; however, apart from obesity, the patient also had other major risk factors for arterial thrombosis, such as hypertension and smoking. Furthermore, atherosclerotic disease and underlying atherosclerotic changes could not be excluded with certainty. This case highlights the importance of studies assessing the impact of excess body weight on rFVIII dosing. PMID- 29384901 TI - Acupuncture for idiopathic pulmonary fibrosis: Protocol for a systematic review. AB - BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often suffer from progressive worsening of dyspnea and lung function. Although 2 drugs are now available for IPF treatment, many gaps are still to be filled. Evidences suggest that there may be some beneficial effect of acupuncture on pulmonary diseases. This review aims to systematically determine the efficacy and safety of acupuncture for treating IPF. METHODS: The following 8 databases will be searched from their inception to March 20, 2017: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Data. Randomized controlled trials (RCTs) of acupuncture for IPF without restriction of publication status will be included. Two review authors will independently undertake study selection, extraction of data, and assessment of study quality. Meta-analysis will be conducted after screening of studies if possible. Dichotomous data will be analyzed using odds ratio (OR), and continuous data mean difference (MD). Statistical analysis will be conducted using Review Manager (RevMan) software. RESULTS: This systematic review will provide a detailed summary of the current evidences related to the efficacy and safety of acupuncture in improving breathlessness, exercise limitation, health status impairment of patients with IPF. CONCLUSION: This evidence may be useful to clinicians, patients, and health policy-makers with regard to the use of acupuncture in IPF treatment. ETHICS AND DISSEMINATION: This systematic review will provide up-to-date information on acupuncture for IPF. This review does not require ethical approval and will be disseminated electronically through a peer reviewed publication or conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO 2017:CRD42017059848. PMID- 29384902 TI - Standard versus extralevator abdominoperineal excision and oncologic outcomes for patients with distal rectal cancer: A meta-analysis. AB - BACKGROUND: The role of extralevator abdominoperineal excision (ELAPE) for distal rectal cancer remains controversial, and the procedure is not widely accepted or practiced. METHODS: An electronic search of Medline, EMBASE, Web of Science, and similar databases for articles in English was performed from the inception of the study until October 31, 2017. Two reviewers extracted information and independently assessed the quality of included studies by the methodological index for nonrandomized studies, then data were analyzed with Review Manager 5.3 software and Stata version 12.0 software. RESULTS: Our meta-analysis included 17 studies with 3479 patients, of whom 1915 (55.0%) underwent ELAPE and 1564 (44.0%) underwent abdominoperineal excision (APE). Compared with patients undergoing APE, patients undergoing ELAPE had a significant reduced risk of no more than 3 years local recurrence (LR) (risk ratio [RR] = 0.27, 95% confidence interval [CI] = 0.08-0.94), 3-year mortality (odds ratio [OR] = 0.45, 95% CI = 0.20-0.97), intraoperative bowel perforation (IBP) involvement (RR = 0.48, 95% CI = 0.31 0.74), and circumferential resection margin (CRM) positivity (RR = 0.66, 95% CI = 0.43-1.00) at the threshold level. CONCLUSIONS: The application of ELAPE is more effective in reducing the chance of 3 years LR, mortality, IBP involvement and CRM positivity than conventional APE, and worthy of being widely applied in surgical treatment of the distal rectal cancer. PMID- 29384904 TI - Ectopic immature renal tissue in gubernaculum associated with undescended testis of a 1-year-old child: A case report. AB - RATIONALE: Ectopic immature renal tissue (EIRT) is extremely rare in congenital malformations. Moreover, the fundamental pathogenesis of EIRT is still unclear and controversial. PATIENT CONCERNS: The right scrotum of a 1-year-old man was found empty for a period of 1 month. B-ultrasonography revealed normal bilateral kidneys and a hypoechoic nodule in the right groin. DIAGNOSES: Based on B ultrasonography, surgery and pathological examination, we concluded a case of abnormally located and EIRT in the inguinal canal. INTERVENTIONS: After pathological diagnosis, the patient was not treated with drugs. OUTCOMES: One year after the operation, the patient recovered. LESSONS: EIRT in gubernaculum is extremely rare. Because of the potential risk of malignant transformation, it is necessary to diagnose and treat it early. PMID- 29384903 TI - Outpatient treatment of acute bacterial skin and skin structure infections (ABSSSI) with tedizolid phosphate and linezolid in patients in the United States: Subgroup analysis of 2 randomized phase 3 trials. AB - BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSI) are a frequent cause of hospital admissions in the United States. Safe and effective outpatient treatments may lower ABSSSI-associated health care costs by reducing unnecessary hospital admissions. Using data from 2 phase 3 trials (ESTABLISH-1, NCT01170221; ESTABLISH-2, NCT01421511), this post-hoc analysis explored the efficacy and safety of tedizolid in an outpatient setting. METHODS: Subgroup analysis was performed on US outpatients (defined as patients who were not in hospital at the time of treatment initiation) with ABSSSI caused by presumed or proven gram-positive pathogens. Patients were randomly assigned to receive tedizolid phosphate 200 mg once daily for 6 days (n = 403) or linezolid 600 mg twice daily for 10 days (n = 410). The primary end point was early clinical response (48-72 hours after the start of treatment). Secondary end points included investigator-assessed clinical response at end of therapy (EOT) and post therapy evaluation (PTE; 7-14 days after therapy). Additional assessments included the patient-reported level of pain using a visual analog scale (VAS) and the per-pathogen favorable microbiological response rate at the PTE visit. Compliance with treatment and safety outcomes was also recorded. RESULTS: Early clinical response was similar between treatment groups (tedizolid, 82.4%; linezolid, 79.0%), as was investigator-assessed clinical response at EOT (tedizolid, 87.1%; linezolid, 86.1%) and PTE (tedizolid, 83.1%; linezolid, 83.7%). Mean changes from baseline to days 10 to 13 in VAS scores were identical between treatment groups (tedizolid, -51.9 mm; linezolid, -51.9 mm). Microbiological eradication rates were generally similar in both treatment groups for all key pathogens. Patients in both groups had favorable response at PTE. More tedizolid-treated patients (89.3%) than linezolid-treated patients (77.3%) were compliant with treatment. The most frequently reported drug-related treatment-emergent adverse events were nausea (tedizolid, 10.7%; linezolid, 13.8%), diarrhea (tedizolid, 4.5%; linezolid, 5.9%), and headache (tedizolid, 5.5%; linezolid, 4.4%). Treatment discontinuation rates were low for both treatment groups (tedizolid, 0.7%; linezolid, 1.0%). CONCLUSION: Short-course therapy with tedizolid can successfully treat patients with ABSSSI caused by presumed or proven gram-positive pathogens in an outpatient setting. PMID- 29384905 TI - Central nervous system leukemia in a patient with concurrent nasopharyngeal carcinoma and acute myeloid leukaemia: A case report. AB - RATIONALE: Concurrent case of nasopharyngeal carcinoma (NPC) and acute myeloid leukemia (AML) has not been reported. Here, we report a case of NPC, who was concurrently suffered from AML one mother after the NPC diagnosis. PATIENT CONCERNS: The patient was a 45-year-old male who presented with a mass on his right side neck. DIAGNOSES: The patient was diagnosed with Epstein-Barr virus negative type-2 non-keratinizing carcinoma with clivus involvement and unilateral metastasis to the cervical lymph node. INTERVENTIONS: He was treated with one cycle of cisplatin and 69.76 Gy of concurrent external-beam radiation. OUTCOMES: Three months after completion of chemo-radiotherapy, the patient was diagnosed as acute myeloid leukemia, which achieved complete remission after one course induction chemotherapy. Two months later, however, the patient was diagnosed as central nervous system leukemia. He ultimately died of relapsed leukemia. The overall survival of the patient was 10 months. LESSONS: The co-occurrence of NPC and AML is rare and prognosis is poor. Radiotherapy in NPC can disrupt the blood brain barrier, which may contribute to the pathogenesis of central nervous system leukemia. Early alert and prevention of central nervous system leukemia following radiotherapy in NPC patient is recommended. PMID- 29384906 TI - A rare case report of multiple myeloma presenting with paralytic ileus and type II respiratory failure due to hypercalcemic crisis. AB - RATIONALE: Paralytic ileus is characterized by the signs and symptoms of intestinal obstruction but without any mechanical lesions in the intestinal lumen. Several medical and surgical conditions can lead to this ailment, such as electrolyte disturbances that impair intestinal motility. However, hypercalcemia secondary to multiple myeloma as a major cause of paralytic ileus has rarely been reported. PATIENT CONCERNS: The patient got severe constipation with difficulty in the passage of both gas and feces for 7 days. DIAGNOSES: The patient was diagnosed with a small intestinal obstruction initially and then developed type II respiratory failure. Investigations revealed hypercalcemic crisis, and examination of a bone marrow aspirate was consistent with multiple myeloma. INTERVENTIONS: Conservative treatment was administered for the intestinal obstruction, consisting of food and water deprivation, gastrointestinal decompression, colonic irrigation, intravenous fluid transfusion, anti inflammatory therapy. Invasive respiratory support was provided after type II respiratory failure occurred and salmon calcitonin was used to reduce the blood calcium level. Further therapy was given by the Department of Hematology and Oncology in our hospital after the diagnosis of multiple myeloma. OUTCOMES: Spontaneous respiration and gastrointestinal function were restored after the correction of hypercalcemia. LESSONS: An appropriate diagnostic approach is needed in emergency practice to identify the paralytic ileus and type II respiratory failure caused by hypercalcemia secondary to multiple myeloma. PMID- 29384907 TI - The hepatectomy efficacy of huge hepatocellular carcinoma and its risk factors: A meta analysis. AB - BACKGROUND: There has always been a controversy on the hepatectomy for huge hepatocellular carcinoma (HCC). Therefore, we aim to explore the hepatectomy efficacy of huge HCC and its risk factors. METHODS: A systematic research was performed using PubMed, MedLine, Web of Knowledge, and Cochrane Library from their establishment to August 2017. The major endpoints were overall survival (OS) rate and recurrence-free survival (RFS) rate, and the secondary ones were the morbidity of complications and mortality of hepatectomy. RESULTS: About 13 studies with a total of 7609 patients were included in this meta-analysis. The hepatectomy efficacy of huge HCC was inferior to non-huge HCC both in OS (hazard ratio [HR] = 2.18, 95% confidence interval [CI] = 1.90-2.50, P < .00001; I = 66%, P = .003) and RFS (HR = 1.97, 95% CI = 1.76-2.19, P < .00001; I = 74%, P = .0001). However, the risk difference[RD] of the 1-year, 3-year and 5-year OS tended to be acceptable (RD = -0.05, 95% CI = -0.11-0.00, P = .05; RD = -0.13, 95% CI = -0.21--0.05, P = .002; RD = -0.10, 95% CI = -0.19--0.01, P = .03; respectively). Moreover, there were also no significant differences between huge HCC and non-huge HCC in the morbidity of complication and mortality of hepatectomy (RD = 0.07, 95% CI = -0.09-0.23, P = .38; RD = -0.01, 95% CI = -0.00- 0.03, P = .06; respectively). Related risk factors were measured to explore the differences, and the results showed that the level of alpha fetal protein (AFP) and the margin-positive rate were higher (standard mean difference [SMD] = 0.57, 95% CI = 0.26-0.88, P = .0003; odd radio[OR] = 32.52, 95% CI = 1.02-6.22, P = .04; respectively), the characteristic of huge HCC tended to be worse such as lower clinical or pathological stage, incomplete capsule and incorporate satellite metastases (OR = 2.91, 95% CI = 1.68-5.04, P = .001; OR = 3.99, 95% CI = 3.40-4.67, P < .00001; OR = 2.52, 95% CI = 1.66-3.83, P < .0001; respectively), and the rate of micorvascular invasion (MVI) including portal vein tumor thrombus (PVTT) were higher (OR = 3.36, 95% CI = 1.61-7.02, P = .001; OR = 2.75, 95% CI = 2.29-3.31, P < .00001; respectively) in the huge HCC. CONCLUSION: The hepatectomy efficacy of huge HCC was inferior to non-huge HCC, but its survival benefits and feasibility were confirmed in this meta-analysis. In addition, higher level of AFP, positive margin, lower clinical or pathological stage, incomplete capsule, incorporate satellite metastasis and MVI were significantly correlated with poor OS. PMID- 29384908 TI - Anemia, intractable vomiting, chronic diarrhea, and syndrome of inappropriate antidiuretic secretion: a diagnostic dilemma: Disseminated strongyloidosis in a patient with newly diagnosed HTLV infection-case report and review of literature. AB - RATIONALE: Strongyloidiasis hyperinfection and disseminated disease have high mortality rates due to several complications and early detection of Strongyloides infection is therefore prudent. PATIENT CONCERNS: A 37-year-old male patient came with chronic diarrhea, intractable vomiting and was found to have hyponatremia, and anemia on the initial laboratory tests. DIAGNOSES: Further work up revealed syndrome of inappropriate antidiuretic secretion to be the cause of the hyponatremia in addition to gastrointestinal loses. His hospital course was complicated by persistent hyponatremia and later development of partial small bowel obstruction. INTERVENTIONS: Considering his symptoms we had a suspicion of small bowel pathology for which he underwent an esophagogastroduodenoscopywith biopsies that revealed strongyloidosis as the cause of his symptoms. He was also found to have human T-cell lymphotropic virus infection, likely contributing to the disseminated disease. OUTCOMES: He was started on ivermectin with complete resolution of symptoms and improvement of hyponatremia. LESSONS: It is very important to suspect Strongyloides infection in a patient presenting with syndrome ofinappropriate antidiuretic secretion as hyperinfection and disseminated disease can be life threatening without antihelmintic therapy. PMID- 29384909 TI - Spectral CT in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma: A retrospective study. AB - This study aimed to investigate the value of computed tomographic (CT) spectral imaging in evaluating the effect of transarterial chemoembolization (TACE).The records of 67 patients with hepatocellular carcinoma (HCC) who had undergone dynamic spectral CT before treatment were selected for the study. Iodine concentrations pretreatment in liver parenchyma, the HCC lesion(s), portal vein, and aorta were measured from the decomposition images. The normalized iodine concentrations (NIC) were calculated. All of them underwent plain scan or contrast-enhanced CT post-treatment (approximately 4-6 weeks after TACE).The values of arterial phase normalized iodine concentrations (AP NIC) before TACE correlated with the grades of lipiodol deposition in tumors (r = 0.76, P < .001). However, there was no relationship between normalized iodine concentrations in the portal venous phase (PVP NIC) before TACE and the grade of lipiodol deposition (r = 0.17, P = .17). Values of AP NIC in residual tumors pre-TACE were significantly lower than those in partial lesions with deposition of iodized oil. The threshold AP NIC of 0.18 yielded an AUC of 0.895, 83.33% sensitivity, 81.03% specificity, 83.33% positive predictive value (PPV), and 82.76% negative predictive value, respectively. The survival probability in patients with AP NIC values pre-TACE >= 0.18 was higher than those whose AP NIC values pre-TACE were < 0.18 (P = .028).Spectral CT with quantitative analysis of AP NIC may help to evaluate the utility and predict the therapeutic effect of TACE. Values of AP NIC had high sensitivity and specificity for differentiating partial tumors with lipiodol deposition from those without lipiodol deposition. PMID- 29384910 TI - Ultrasound for postoperative surveillance after mastectomy in patients with breast cancer: A retrospective study. AB - This study aimed to evaluate the clinical usefulness of postoperative surveillance by ultrasound (PSU) in patients after breast cancer surgery.In this retrospective study, 324 patients with breast cancer after mastectomy were included between January 2006 and December 2008. The final-positive lesions (FPL) were diagnosed according to the results of cytopathology, clinical and imaging examinations. The outcome evaluations included the sensitivity (SS), specificity (SC), ultrasound accuracy for FPL (UAFPL), and positive predictive value (PPV) after the mastectomy.A total of 5117 ultrasound examinations were conducted for all those patients to the December 2016. After mastectomy, the SS, SC, UAFPL, and PPV were as follows: mastectomy bed (SS, 100.0%; SC, 99.7%; UAFPL, 99.7%; and PPV, 36.0%), contralateral breast (SS, 100.0%; SC, 99.0%; UAFPL, 99.0%; and PPV, 25.4%), ipsilateral axillary or supraclavicular (SS, 91.7%; SC, 99.4%; UAFPL, 99.4%; and PPV, 25.6%), and contralateral axilla or supraclavicular lymph nodes (SS, 100.0%; SC, 99.9%; UAFPL, 99.9%; and PPV, 33.3%).In summary, we demonstrated that applied PSU can detect the malignant lesions in the breast regional area with high sensitivity, specificity and accuracy. PMID- 29384911 TI - Association between parents' attitudes and behaviors toward children's visual care and myopia risk in school-aged children. AB - The purpose of this survey was to determine the association of parents' attitudes and behaviors toward children's visual care with myopia risk in school-aged children.A total of 894 parents of school-aged children were investigated in primary and middle schools in the central and noncentral urban area in Wuhan through stratified cluster random sampling on July, 2015. We analyzed the association by the generalized linear mixed model.The results indicated that children with parents' high expectations of 1.5 or higher on their vision exhibited a decreased risk of myopia compared with 1.0 and 0.5 or lower (OR = 0.49, 95%CI = 0.36-0.67). Children whose parents only paid attention to their vision in junior and senior school and in primary school had an increased myopia risk than that in preschool (OR = 2.12, 95%CI = 1.01-4.45, and OR = 3.11, 95%CI = 1.28-7.58, respectively). Children whose parents ensured for their sufficient sleep had a decreased myopia risk (OR = 0.45, 95%CI = 0.24-0.85). Compared with children whose parents who never adjusted electronic devices' parameters, the odds ratio of sometimes was 0.49 (95%CI = 0.31-0.79), often 0.53 (95%CI = 0.33 0.85), and always 0.44 (95%CI = 0.26-0.75), respectively.Parents' attitudes and behaviors toward children's visual care are significantly associated with the myopia risk in school-aged children. Consequently, efforts should be made to educate parents on how they protect children's vision and reduce their risk of myopia. PMID- 29384912 TI - Intrahepatic cholestasis of pregnancy or azithromycin-induced intrahepatic cholestasis: A case report. AB - RATIONALE: Azithromycin-induced liver injury has been rarely reported in adult individuals, let alone in a pregnant woman. Here, we describe the clinical features and outcomes of azithromycin-induced liver injury in a pregnant woman. PATIENT CONCERNS: A 30-year-old pregnant woman presented with generalized pruritus and elevated serum bile acid level (123.6 MUmol/L) on day 4 of azithromycin administration. A diagnosis of intrahepatic cholestasis of pregnancy was made, and cesarean section was performed immediately. Interestingly, the alanine aminotransferase level (ALT) reached 211.2 U/L on day 9 after azithromycin administration. DIAGNOSIS: Therefore, drug-induced intrahepatic cholestasis was considered. INTERVENTIONS: (1) Azithromycin withdrawal after the patient hospitalized. (2) Termination of pregnancy by cesarean section was performed inmmediately to protect the fetus. (3) Silymarin capsules and bifendate are used to protect the liver after liver enzymes elevation was discovered. OUTCOMES: The liver enzymes recovered within 4 weeks without any symptoms after treatment with silymarin capsules and bifendate, which helps reduce ALT level and protects the liver from further injury. LESSIONS: A pregnant woman developed azithromycin-induced intrahepatic cholestasis. Physicians should be aware of this side effect of azithromycin, which is widely prescribed. PMID- 29384913 TI - Combing a novel device and negative pressure wound therapy for managing the wound around a colostomy in the open abdomen: A case report. AB - RATIONALE: An open abdomen complicated with small-bowel fistulae becomes a complex wound for local infection, systemic sepsis and persistent soiling irritation by intestinal content. While controlling the fistulae drainage, protecting surrounding skin, healing the wound maybe a challenge. PATIENT CONCERNS: In this paper we described a 68-year-old female was admitted to emergency surgery in general surgery department with severe abdomen pain. Resection part of the injured small bowel, drainage of the intra-abdominal abscess, and fashioning of a colostomy were performed. DIAGNOSES: She failed to improve and ultimately there was tenderness and lot of pus under the skin around the fistulae. The wound started as a 3-cm lesion and progressed to a 6 *13 (78 cm) around the stoma. INTERVENTIONS: In our case we present a novel device for managing colostomy wound combination with negative pressure wound therapy. OUTCOMES: This tube allows for an effective drainage of small-bowel secretion and a safe build-up of granulation tissue. Also it could be a barrier between the bowel suction point and foam. LESSONS: Management of open abdomen wound involves initial dressing changes, antibiotic use and cutaneous closure. When compared with traditional dressing changes, the NPWT offers several advantages including increased granulation tissue formation, reduction in bacterial colonization, decreased of bowel edema and wound size, and enhanced neovascularization. PMID- 29384914 TI - Hepatitis B surface antigen predicts recurrence after radiofrequency ablation in patients with low hepatitis B virus loads. AB - Radiofrequency ablation (RFA) is a first-line option for the treatment of small liver cancers, but the recurrence remains a problem affecting long-term survival. Hepatitis B virus (HBV) activity is associated with the prognosis of hepatocellular carcinoma (HCC). We investigated the significance of hepatitis B surface antigen (HBsAg) in HCC recurrence after curative RFA treatment in HBV related small HCC.We enrolled 404 HBV-related patients with small HCC (<=3 cm) who underwent curative RFA. We used univariate and multivariate analyses to investigate the baseline levels of HBsAg, in addition to other known risk factors for HCC recurrence, for association with HCC tumor recurrence after curative RFA.The overall 1-, 2-, and 3-year recurrence-free survival (RFS) rates were 75%, 50%, and 34%, respectively. The median recurrence-free time was 25 months. The level of HBsAg was an independent risk factor for recurrence in patients with lower HBV-DNA levels. In hepatitis Be antigen (HBeAg)-negative patients, the 1-, 2-, and 3-year RFS rates were 79%, 64%, and 44%, respectively, for that with low HBsAg levels, compared with 73%, 50%, and 37%, respectively, for that with high HBsAg levels (P = .039).HBsAg might serve as a valuable marker to evaluate the risk of HCC recurrence in HBeAg-negative patients with low HBV viral load. PMID- 29384915 TI - Longitudinal extensive transverse myelitis with an abnormal uFLC ratio in a pediatric patient: Case report and literature review. AB - RATIONALE: The serum and urine-free light chain (sFLC/uFLC) ratios of kappa (kappa) to lambda (lambda) serve as biomarkers for plasma cell disorders, especially multiple myeloma. However, to our best knowledge, the ratios have not been appropriately assessed for acute transverse myelitis (ATM). PATIENT CONCERNS: We present a 12-year-old boy who had sudden onset low back pain following paralysis of his 4 extremities and disturbance consciousness. Magnetic resonance imaging (MRI) of the brain and spine indicated diffuse hyperintensity in T2-weighted images from the cervical spinal cord to the conus medullaris. An abnormal serum M-peak and uFLC ratio were detected in acute stage. DIAGNOSES: Based on the image findings, laboratory findings, and physical examination results, the diagnosis of acute transverse myelitis was established. INTERVENTIONS AND OUTCOMES: With the treatment of pulse therapy and 5 courses of plasmapheresis, the patient had improvement in expanded disability status scale (EDSS) score from 9 to 5. Besides, the kappa/lambda ratio was also returned within the normal range. LESSON: The case presented an unusual phenomenon of transient abnormal kappa/lambda ratio combined with an M-peak in the acute course of longitudinally extensive transverse myelitis (LETM), which revealed FLC ratio recovering accompany with the improvement of disease. Further studies are required to identify the association between ATM and monoclonal gammopathy of undetermined significance (MGUS). PMID- 29384916 TI - Tranexamic acid reduces blood loss in intertrochanteric fractures: A meta analysis from randomized controlled trials. AB - BACKGROUND: This meta-analysis aims to assess the efficacy and safety of tranexamic acid for reducing blood loss and transfusion requirements in patients with intertrochanteric fractures. METHODS: We conduct electronic searches of Medline (1966-2017.09), PubMed (1966-2017.09), Embase (1980-2017.09), ScienceDirect (1985-2017.09), and the Cochrane Library. Only randomized controlled trials (RCTs) are included. The quality assessments are performed according to the Cochrane systematic review method. Fixed/random-effect model is used according to the heterogeneity tested by I statistic. Meta-analysis is performed using Stata 11.0 software. RESULTS: A total of 4 RCTs are retrieved involving 514 participants. The present meta-analysis indicated that there were significant differences between groups in terms of total blood loss (weighted mean differences = -131.49, 95% confidence interval (CI): -163.63 to -99.35, P = .00), hemoglobin decline (weighted mean differences = -0.31, 95% CI, -0.44 to 0.19, P = .00), and transfusion rate (risk differences = -1.11, 95% CI, -0.19 to 0.04, P = .00). In addition, no increased risk of adverse effects was identified in both groups. CONCLUSION: Local administration of tranexamic acid is associated with a reduced total blood loss, postoperative hemoglobin decline, and transfusion requirements in patients with intertrochanteric fractures. High quality RCTs are still required for further investigation. PMID- 29384917 TI - Intravitreal bevacizumab associated with photodynamic therapy in a case of polypoidal choroidal vasculopathy associated with choroidal nevus: A case report. AB - RATIONALE: Report the clinical findings and management of a case of polypoidal choroidal vasculopathy associated with choroidal nevus which received combination therapy. PATIENT CONCERNS: Decreased visual acuity in a woman with polypoidal choroidal vasculopathy and choroidal nevus. DIAGNOSES: Polypoidal choroidal vasculopathy and choroidal nevus. INTERVENTIONS: The initial visual acuity was 0.5. After the first treatment with photodynamic therapy, exudation and bleeding appeared around the lesion. After this, the patient received 3 doses of intravitreal bevacizumab. OUTCOMES: After treatment with combination therapy, visual acuity, clinical and imaging findings improved, with no recurrence of exudation and bleeding. LESSONS: Intravitreal bevacizumab as an adjunctive treatment after photodynamic therapy is a good option for patients with polypoidal choroidal vasculopathy associated with choroidal nevus. PMID- 29384918 TI - Low complication rate of sellar reconstruction by artificial dura mater during endoscopic endonasal transsphenoidal surgery. AB - To evaluate effect of sellar reconstruction during pituitary adenoma resection surgery by the endoscopic endonasal transsphenoidal approach using artificial cerebral dura mater patch.This was a retrospective study of 1281 patients who underwent endoscopic transsphenoidal resection for the treatment of pituitary adenomas between December 2006 and May 2014 at the Neurosurgery Department of the People's Liberation Army General Hospital. The patients were classified into 4 grades according to intraoperative cerebrospinal fluid (CSF) leakage site. All patients were followed up for 3 months by telephone and outpatient visits.One thousand seventy three (83.7%) patients underwent sellar reconstruction using artificial dura matter patched outside the sellar region (method A), 106 (8.3%) using artificial dura matter patched inside the sellar region (method B), and 102 (8.0%) using artificial dura matter and a mucosal flap (method C). Method A was used for grade 0-1 leakage, method B for grade 1 to 2 leakage, and method C for grade 2 to 3 leakage. During the 3-month follow-up, postoperative CSF leakage was observed in 7 patients (0.6%): 2 among patients who underwent method B (1.9%) and 5 among those who underwent method C (4.9%). Meningitis was diagnosed in 13 patients (1.0%): 2 among patients who underwent method A (0.2%), 4 among those who underwent method B (3.8%), and 7 among those who underwent method C (6.7%).Compared with other reconstruction methods, sellar reconstruction surgery that only use artificial dura mater as repair material had a low rate of complications. PMID- 29384919 TI - Clinical significance of measuring reticulated platelets in infectious diseases. AB - This study aimed to explore the association between the percentage of reticulated platelets (RP%) and infection, and analyze the value of combined measurement of RP% with other inflammatory indicators in diagnosing infection. A total of 190 patients with signs and symptoms suspicious of infection were included in the infection group, and 70 healthy subjects with comparable percentages of gender and age were included in the control group. Peripheral white blood cell (WBC) count, percentage of neutrophils (N%), platelet count, C-reactive protein (CRP), procalcitonin (PCT), RP%, and axillary temperature were recorded. Dynamic changes in RP% with infection were measured to analyze the association between RP% and infection. The receiver operating characteristic curve was used to evaluate the value of each inflammatory indicator in diagnosing infection and analyze the diagnostic value of the combined adoption of multiple inflammatory indicators. RP% was significantly higher in the infection group than in the noninfection and control groups. The sensitivity and specificity for diagnosing infection were, respectively, 91.78% and 93.18% when RP% and CRP were used in combination, 90.41% and 90.90% when RP% and PCT were used in combination, and 100% and 100% when RP%, CRP, and PCT were used in combination. RP% changed dynamically with the progression of infection and recovered to lower than 5.5% at 2 to 7 days before the body temperature recovered to a normal level. The diagnostic value of RP% was the highest. A combined use with CRP/PCT could improve the sensitivity and specificity in the early diagnosis of infectious diseases. PMID- 29384920 TI - The radiographic parameter risk factors of rapid curve progression in Lenke 5 and 6 adolescent idiopathic scoliosis: A retrospective study. AB - Various parameters related to growth and maturity have been shown to be risk factors for scoliosis curve progression. We previously identified correlations between curve progression and radiographic parameters in clinical practice, but there is a lack of research.The aim of this study was to investigate and identify the radiographic parameters that are risk factors for rapid curve progression in Lenke 5 or 6 adolescent idiopathic scoliosis (AIS).A retrospective review of patients who were prospectively enrolled at the initiation of brace wear and followed through completion of bracing or surgery was performed. The inclusion criteria were as follows: a Lenke type 5 or 6 classification, Risser sign grade 0 or 1 at the initial outpatient examination, a follow-up period of 6 months including a minimum of 4 follow-ups, At each visit, the whole spine x-ray was completed, the following data were measured and collected: angle of the lumbar curve (LC), rotation of the apical vertebra (RAV) in the LC, deviation of the apical vertebra (DAV) in the lumbar curve, clavicle angle, L5 tilt angle (TA), body mass index, flexibility of the LC (FLC), and peak angle velocity (PAV). A binary logistic regression analysis was used to assess the contribution of each variable to PAV onset. The touch types for the determination of the lowest instrumented vertebra (LIV) were compared at both the PAV and final follow up.Thirty-six AIS patients were recruited. The binary logistic regression model indicated that the following variable values significantly contributed to a high risk of PAV occurrence: LC >=30 degrees (OR = 6.153, 95%CI = 1.683-22.488, P = .006), RAV >=III (OR = 15.484, 95%CI = 4.535-52.865, P <.001), DAV >=40 mm (OR = 8.599, 95%CI = 2.483-29.784, P <.001), and TA >=10 degrees (OR = 2.223, 95%CI = 3.094-27.563, P <.001). The touch types for LIV determination changed in 12 of 36 patients, with at least 1 segment added as the LIV between the PAV and the final visit.LC >=30 degrees , RAV >=III, DAV >=40 mm, and L5 TA>=10 degrees were radiographic parameters associated with an increased risk of curve progression in Lenke 5 and 6 AIS. The orthopedic surgery performed at the PAV is the ideal timing, and it will preserve 1 active segment than later surgery.Level of evidence was 4. PMID- 29384921 TI - Three-dimensional-printed upper limb prosthesis for a child with traumatic amputation of right wrist: A case report. AB - RATIONALE: For traumatic upper limb amputees, the prohibitive cost of a custom made prosthesis brings an insufferable financial burden for their families in developing countries. Three-dimensional (3D) printing allows for creating affordable, lightweight, customized, and well-fitting prosthesis, especially for the growing children. PATIENT CONCERNS: We presented a case of an 8-year-old boy, who suffered a traumatic right wrist amputation as result of a mincing machine accident. The patient was immediately sent to the emergency orthopedics department after the accident. DIAGNOSES: He was diagnosed as severed mangled limb crash injury at the level of the right wrist with a Mangled Extremity Severity Score of 8. INTERVENTIONS: A wrist disarticulation was performed and a 3D-printed prosthetic hand was designed and manufactured for this child. A personalized prosthetic rehabilitation training was applied after the prosthesis installation at 6 months postoperatively. The function of the prosthesis was evaluated at 1-month and 3-month follow-up using the Children Amputee Prosthetics Projects (CAPP) score and the University Of New Brunswick Test Of Prosthetic Function for Unilateral Amputees (UNB test). OUTCOMES: The materials cost <20 dollars. The printing took <8 hours and the component assembling was completed within 20 minutes. During the 3-month follow-up, the child's parents were satisfied with the prosthesis and the UNB test showed the significantly improved function of the prosthesis. LESSONS: This novel 3D-printed upper limb prosthesis in a child with the traumatic wrist amputation might serve as a practical and affordable alternative for children in developing countries and those lacking access to health care providers. A personalized prosthetic rehabilitation needs to be undertaken and more clinical studies are warranted to validate the potential superiority of similar 3D-printed prostheses. PMID- 29384922 TI - A case report and literature review of sigmoid volvulus in children. AB - RATIONALE: Sigmoid volvulus (SV) is an exceptionally rare but potentially life threatening condition in children. CHIEF COMPLAINT: Abdominal distention for 1 week. DIAGNOSES: Sigmoid volvulus. PATIENT CONCERNS: We present a case of a 12 year-old boy with mechanical ileus who was finally confirmed to have SV with the combination of abdominal plain film, sonography, and computed tomography (CT) with the finding of mesenteric artery rotation. INTERVENTIONS: Because bowel obstruction was suspected, abdominal plain film, sonography, and CT were performed. The abdominal CT demonstrated whirlpool sign with torsion of the sigmoid vessels. In addition, lower gastrointestinal filling study showed that the contrast medium could only reach the upper descending colon. Therefore, he received laparotomy with mesosigmoidoplasty for detorsion of the sigmoid. OUTCOMES: The postoperative recovery was smooth under empirical antibiotic treatment with cefazolin. A follow-up lower gastrointestinal series on the seventh day of admission showed no obstruction compared with the previous series. He was finally discharged in a stable condition 8 days after admission. LESSONS: SV is a congenital anomaly and an uncommon diagnosis in children. Nevertheless, case series and case reports of SV are becoming more prevalent in the literature. Failure to recognize SV may result in life-threatening complications such as sigmoid gangrene/perforation, peritonitis, sepsis, and death. Thus, if the children have persistent and recurrent abdominal distention, abdominal pain, and vomiting, physicians should consider SV as a "do not miss diagnosis" in the differential diagnosis. PMID- 29384924 TI - Association between KIR gene polymorphisms and type 1 diabetes mellitus (T1DM) susceptibility: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) is a T-cell mediated autoimmune disease with a complex genetic and immunological background. Evidence suggests that killer cell immunoglobulin-like receptor (KIR) genes are associated with T1DM, but the results are inconsistent. Here, we conducted a meta-analysis to comprehensively evaluate the effect of KIR genes on the risk of T1DM. METHODS: The PubMed, Web of Science, the Chinese Biomedical Database, and Chinese National Knowledge Infrastructure databases were systematically searched to select studies on the association between KIR polymorphisms and T1DM. The quality of each study was scoring in term of the Newcastle-Ottawa Scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Subgroup analysis stratified by ethnicity was also conducted. Funnel plot and Egger test were conducted to assess the publication bias. RESULTS: A total of 13 independent case-control studies comprising 2076 T1DM cases and 1967 controls were included in this meta-analysis. We found a negative association between the KIR2DL1 polymorphism and susceptibility to T1DM in the overall population (OR = 0.71, 95%CI = 0.51-0.98, P = .038), but not in ethnic-specific analysis. Additionally, a negative association between the KIR2DS1 polymorphism and susceptibility to T1DM was found in the Asians (OR = 0.76, 95%CI = 0.63-0.92, P = .004), but not in the Caucasians. However, the associations could not withstand Bonferroni correction. Conversely, no association between the other KIRs genes (KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL2, KIR3DL3, and KIR3DS1) and T1DM susceptibility was found in overall and subgroup ethnicity. No publication bias was detected in all comparisons. CONCLUSIONS: In summary, this meta-analysis suggested that the KIR2DL1 and 2DS1 polymorphism might be a potential protective factor for T1DM in the specific ethnicity. Further subtle design studies with more sample size are still needed for a definitive conclusion. PMID- 29384923 TI - Emergency transcatheter arterial embolization for massive gastrointestinal arterial hemorrhage. AB - To evaluate the different arteriographic manifestations of acute arterial massive hemorrhage of the gastrointestinal (GI) tract and the efficacy of emergency transcatheter arterial embolization (ETAE).A total of 88 patients with acute massive GI bleeding who experienced failure of initial endoscopy and/or conservative treatment were referred to our interventional department for acute GI arteriography from January 2007 to June 2015. After locating the source of bleeding, appropriate embolic agents, such as spring coil, hydroxyl methyl acrylic acid gelatin microspheres, polyvinyl alcohol (PVA) particles, etc., were used to embolize the targeted vessels. The angiographic manifestations and the effects of embolization of acute arterial massive hemorrhage of the GI tract were retrospectively analyzed.Of the 88 patients, 54 were diagnosed with arterial hemorrhage of the upper GI tract and 34 with arterial hemorrhage of the lower GI tract. Eighty cases were associated with positive angiography, which showed the following: contrast extravasation (only); gastroduodenal artery stenosis; pseudoaneurysm (only); pseudoaneurysm rupture with contrast extravasation; pseudoaneurysms merged with intestinal artery stenosis; GI angiodysplasia; and tumor vascular bleeding. Eight cases were diagnosed with negative angiography. Seven-two patients underwent successful hemostasis, and a total of 81 arteries were embolized. The technical and clinical success rates (no rebleeding within 30 days) in performing transcatheter embolization on patients with active bleeding were 100% and 84.71%, respectively (72 of 85). Within 30 days, the postoperative rebleeding rate was 15.29% (13/85). Of these rebleeding cases, 2 patients were formerly treated with "blind embolization," 7 underwent interventional embolic retreatment, and 3 had surgical operations. All cases were followed-up for 1 month, and 3 patients died from multiple organ failure. No serious complications such as bowel ischemia necrosis were observed.ETAE is a safe, effective, and minimally invasive treatment; because of the diversified arteriographic manifestations of acute GI hemorrhage, the proper selection of embolic agents and the choice of reasonable embolization method are essential for successful hemostasis. PMID- 29384925 TI - Chart validation of inpatient ICD-9-CM administrative diagnosis codes for ischemic stroke among IGIV users in the Sentinel Distributed Database. AB - The Sentinel Distributed Database (SDD) is a large database of patient-level medical and prescription records, primarily derived from insurance claims and electronic health records, and is sponsored by the U.S. Food and Drug Administration for drug safety assessments. In this chart validation study, we report on the positive predictive value (PPV) of inpatient ICD-9-CM acute ischemic stroke (AIS) administrative diagnosis codes (433.x1, 434.xx, and 436) in the SDD.As part of an assessment of the risk of thromboembolic adverse events following treatment with intravenous immune globulin (IGIV), charts were obtained for 131 potential post-IGIV AIS cases. Charts were abstracted by trained nurses and then adjudicated by stroke experts using pre-specified diagnostic criteria.Case status could be determined for 128 potential AIS cases, of which 34 were confirmed. The PPVs for the inpatient AIS diagnoses recorded in the SDD were 27% overall [95% confidence interval (95% CI): 19-35], 60% (95% CI: 32-84) for principal-position diagnoses, 42% (95% CI: 28-57) for secondary diagnoses, and 6% (95% CI: 2-15) for position-unspecified diagnoses (which in the SDD generally originate from separate physician claims associated with an inpatient stay).Position-unspecified diagnoses were unlikely to represent true AIS cases. PPVs for principal and secondary inpatient diagnosis codes were higher, but still meaningfully lower than estimates from prior chart validation studies. The low PPVs may be specific to the IGIV user study population. Additional research is needed to assess the validity of AIS administrative diagnosis codes in other study populations within the SDD. PMID- 29384926 TI - GLCCI1 rs37973: A potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese asthma patients. AB - Glucocorticoids are the primary anti-inflammatory therapy for asthma, but their effects are characterized by some interindividual variability that might have a genetic basis.We aimed to determine the relationship between pulmonary function change and the variant of the glucocorticoid-induced transcript 1 (GLCCI1) gene in patients with asthma receiving long-term ICS treatment, the association of GLCCI1 genotypes and the level of GLCCI1 expression and cytokines production.A total of 418 patients with asthma, including 25 individuals from 11 families with a history of asthma, were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1 on changes in lung function in response to inhaled glucocorticoids were assessed. The expression levels of GLCCI1 mRNA and cytokines were also measured.The SNP rs37973 in GLCCI1 was independently associated with changes in forced expiratory volume at one second (FEV1) and FEV1%pred. Individuals homozygous for the wild-type allele who had a percent FEV1 change greater than 5% were more common than individuals homozygous for the rare allele. When patients were stratified according to genotype, GLCCI1 expression was enhanced upon administration of low-dose dexamethasone among patients with the rs37973 A allele; however, GG homozygotes required high-dose dexamethasone to achieve enhanced GLCCI1 expression. Furthermore, the levels of some cytokines were significantly reduced after glucocorticoid treatment in individuals with the AA and AG genotypes.The genetic variant rs37973 in GLCCI1 is associated with poorer clinical therapeutic response to inhaled glucocorticoids in a Chinese asthma population. PMID- 29384927 TI - Efficacy and safety of micafungin for the treatment of patients with proven or probable invasive aspergillosis: A non-comparative, multicenter, phase IV, open label study. AB - INTRODUCTION: Few studies have assessed the efficacy and safety of micafungin in patients with proven or probable invasive aspergillosis (IA). This was the aim of the current study, which was conducted in 22 hospitals in China, where micafungin was approved for treatment of IA in 2006. METHODS: This was a non-comparative, phase IV open-label study (NCT02646774). Eligible patient were adults with proven or probable IA. Efficacy endpoints included rates of overall treatment success (primary endpoint) and clinical improvement, fungal clearance, mortality, and the site of Aspergillus infection (all secondary endpoints). Safety endpoints included incidences of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and adverse drug reactions (ADRs). These endpoints were reported descriptively with associated 95% confidence intervals (CI); no hypotheses were tested. RESULTS: The study was discontinued early due to low patient recruitment, which did not allow for the planned sample size to be reached. In total, 68 patients were enrolled: 42 into the full analysis set (for efficacy) and 61 into the safety analysis set. All patients were Han Chinese; the majority were male (n = 26; 61.9%) and <=60 years of age (n = 35; 83.3%). Rates of overall treatment success, clinical improvement, fungal clearance, and mortality were 45.2% (n = 19/42; 95% CI: 29.85-61.33); 59.5% (n = 25/42; 95% CI: 43.28-74.37), 80.0% (n = 4/5; 95% CI: 28.36-99.49), and 7.1% (n = 3/42; 95% CI: 1.50-19.48), respectively. All patients were diagnosed with pulmonary Aspergillus infection. Overall, 155 TEAEs and 8 SAEs were reported by 37 (60.7%) and 7 (11.5%) patients. The most common TEAEs were decreased platelet count and fatigue (both n = 5; 8.2%) and the most common SAEs were intracranial hemorrhage and lung infection (n = 3; 4.9% and n = 2; 3.3%). Eight ADRs (n = 6; 9.8%) were reported but all were completely remitted or remitting during follow-up. CONCLUSIONS: Results suggest that micafungin is efficacious and well-tolerated in patients with proven or probable IA in China. However, these findings should be interpreted with care, due to the small number of patients included in this study. Further comparative trials should be used to confirm the efficacy and safety of micafungin in patients with proven or probable IA. PMID- 29384928 TI - Prostate cancer treated with reduced-volume intensity-modulated radiation therapy: Report on the 5-year outcome of a prospective series. AB - How to define a clinical target volume (CTV) as small as possible for prostate cancer to reduce the dose received by normal organs is an interesting study. We conduct a research to analyze the clinical efficacy of intensity modulated radiotherapy (IMRT) using reduced CTV in the treatment of prostate cancer. From January 2006 to June 2010, 78 patients with prostate cancer were treated with IMRT according to this institutional protocol. Of them, 18 had stage II tumors, 39 had stage III tumors, and 21 had stage IVa tumors. Clinical outcomes included overall survival, biochemical recurrence, recurrence-free survival, and acute and chronic injuries caused by radiotherapy. Risk factors were evaluated using the Cox regression model. As of December 31, 2014, all patients completed radiotherapy as planned. Myelosuppression was mostly grade 1, acute urinary injury was mostly grades 1 and 2, and intestinal injury was mostly grade 1. The 5 year follow-up rate was 91.0%. The overall, progression-free, biochemical recurrence-free, and distant metastasis-free survival rates were 82.1%, 79.4%, 84.6%, and 94.9%, respectively. Tumor volumes defined by small target volumes and Radiation Therapy Oncology Group were 274.21 +/- 92.64 and 600.68 +/- 113.72, respectively, representing a significant difference (P < .05). Age, prostate specific antigen level, eastern cooperative oncology Group score, Gleason score, and volume of CTV were independent risk factors for mortality and disease progression. Our findings indicated that IMRT with reduced CTV have less acute and chronic injuries caused by radiation, particularly grade 3 or higher urinary and intestinal injuries, while ensuring survival benefits and protecting the hematopoietic function. PMID- 29384929 TI - Case report of a bilateral adrenal myelolipoma associated with Cushing disease. AB - RATIONALE: Adrenal myelolipomas are rare benign tumors, composed of a variable mixture of mature adipose tissue and hematopoietic tissue. These tumors are frequently detected incidentally and are usually asymptomatic, and hormonally inactive. PATIENT CONCERNS: During a routine health checkup, a 52-year-old man was found to have a tumor on the bilateral adrenal glands. Abdominal computed tomography revealed a well-defined, heterogeneously enhanced bilateral adrenal mass, suggesting a myelolipoma. DIAGNOSES: The hormonal evaluation revealed adrenocorticotropic hormone (ACTH) dependent Cushing syndrome. INTERVENTIONS: The patient underwent left adrenalectomy, and transsphenoidal resection of a pituitary mass. The final diagnosis was adrenal myelolipoma associated with Cushing disease. OUTCOMES: Growth of right adrenal myelolipoma was detected during the 7-year follow-up. There were enhancing pituitary lesions in repeat magnetic resonance imaging of the sellar region, which implies persistent or recurrent pituitary adenoma. This case reinforces relationship between Cushing disease and adrenal myelolipoma. LESSONS: To the best of our knowledge, this is the first reported pathologically confirmed bilateral adrenal myelolipoma associated with Cushing disease. This report supports the idea that ACTH is associated with the development of adrenal myelolipoma. PMID- 29384930 TI - Multiple cerebral gliomas mimicking central nervous system inflammatory demyelinating diseases: A rare case with review of literature. AB - RATIONALE: Multiple cerebral gliomas (MCGs), usually classified into multifocal and multicentric subtypes, represent major diagnostic challenges as their clinical, radiologic, and pathohistological features are not uniform, often mimicking brain metastatic tumors or central nervous system inflammatory demyelinating diseases (IDD). PATIENT CONCERNS: Here, we report a rare case of MCGs with isolated seizures and 4 lesions in the brain, that was initially misdiagnosed as IDD during treatment. DIAGNOSIS: The pathological diagnosis was astrocytoma, which was classified as a World Health Organization grade II glioma. INTERVENTIONS: The patient was treated with dexamethasone and sodium valproate when he was misdiagnosed as having IDD. After the pathological diagnosis was obtained, he was treated with temozolomide and radiotherapy. OUTCOMES: Three months after the above treatment, the health of the patient had improved; he was asymptomatic, and presented with better radiological manifestations. LESSONS: Diagnostic imaging is valuable in differential diagnosis. Magnetic resonance spectroscopy is a promising technique for the assessment and characterization of lesions, though its role in definitive diagnosis is not yet defined. Brain tissue biopsy remains the golden standard for definitive diagnosis. In China, for various reasons, craniotomy biopsy is not performed routinely in patients with multiple intracranial lesions, and stereotactic cranial biopsy may be a more viable option because of its safety and cost-effectiveness. In summary, this case demonstrates that MCGs need to be included in the differential diagnosis of unknown intracranial multiple lesions. PMID- 29384931 TI - Superior mediastinal typical carcinoid detected by 99mTc-MIBI SPECT/CT imaging: A case report. AB - RATIONALE: This is a rare case of mediastinal typical carcinoid tumor with elevated parathyroid hormone (PTH) and hypercalcemia detected by Tc -methoxy isobutyl-isonitrile(Tc-MIBI) single photon emission computed tomography/computed tomography (SPECT/CT) imaging. PATIENT CONCERNS: A 65-year-old male patient presented with hypercalcemia and elevated PTH. DIAGNOSES: The preoperative diagnosis was ectopic parathyroid adenoma in the right superior mediastinum. INTERVENTIONS: We performed endoscopic removal of the mass in the superior mediastinum. OUTCOMES: Histopathology and immunohistochemistry revealed typical carcinoid. LESSONS: The differential diagnosis of mediastinal tumors with elevated PTH detected by Tc-MIBI dual-phase imaging should include ectopic parathyroid adenoma as well as carcinoid. PMID- 29384932 TI - The relation between blood pressure components and left atrial volume in the context of left ventricular mass index. AB - Left atrial enlargement (LAE) is a risk factor for cardiovascular complications and death. In hypertensive patients, LAE is usually due to left ventricular (LV) hypertrophy and diastolic dysfunction. We aimed to identify factors associated with LAE in patients with increased and normal left ventricular mass index (LVMI) with reference to pulsatile and steady components of blood pressure (BP).The study was carried out as a cross-sectional observation. In a group of inhabitants of suburban area of Cracow, Poland, we measured office, ambulatory and central BP, carotid-femoral pulse wave velocity (PWV), as well as echocardiographic indices and gathered anthropometric data, information on habits and relevant medical history. Further, with division according to sex-stratified dichotomised LVMI, we performed correlation analysis to identify possibly significant relations between measures of left atrial volume and other studied parameters. We also fitted regression models in order to assess the respective value of steady and pulsatile BP components as factors related to measures of left atrial volume.The mean age of 205 patients (136 females-66%) was 53.6 +/- 8.3 years. We found higher values of PWV, office, ambulatory and central BPs in the group of LVMI above median value. This group had also greater left atrial volume index (LAVI), which correlated with LVMI (r = 0.36, P < .001) and ratio of early diastolic mitral peak flow velocity to early diastolic mitral annulus mean velocity in tissue Doppler imaging (E/e') (r = 0.24, P = .04).In the group of LVMI below the median, LAVI correlated with pulsatile and steady BP components. LAVI was independently predicted by mean arterial pressure (MAP) obtained from both ambulatory (MAP24h, beta= 0.15; P = .045) and office measurements (MAPoffice, beta = 0.35; P = .004), but not by pulse pressure.LV mass and function are the main determinants of LAVI. However, in persons with lower LV mass, LAVI depends on the steady component of blood pressure, but not pulsatile one. Increased LAVI reflects early changes in response to systemic blood pressure elevation. PMID- 29384933 TI - Endotracheal intubation under video laryngoscopic guidance during upper gastrointestinal endoscopic surgery in the left lateral position: A randomized controlled trial. AB - BACKGROUND: Patients undergoing upper gastrointestinal endoscopic surgeries are generally placed in the left lateral position and require endotracheal intubation to maintain airway patency. We conducted a prospective, randomized, controlled study to evaluate the feasibility of intubation under video laryngoscopic guidance in the left lateral position during upper gastrointestinal endoscopic surgery. METHODS: We compared the data of patients (n = 120) who underwent intubation under video laryngoscopic guidance in the supine or left lateral position. Patients in Group S (n = 59) were initially placed in the supine position and then shifted to the left lateral position after airway establishment. Patients in Group L (n = 61) were placed in the left decubitus position during both induction and intubation. Laryngoscopic view, intubation time, success rate, hemodynamic changes, adverse effects, and complications of intubation were compared between the groups. RESULTS: The 2 groups showed no difference in terms of time required for intubation (Group L, 23.95 +/- 4.43 seconds and Group S, 23.44 +/- 4.78 seconds; P = .545) and number of intubation attempts. Further, the overall rate of intubation success was 100% in both groups. However, Group S exhibited significant hemodynamic changes during shift of decubitus (P < .001) and severe sore throat (P = .030). The incidences of other adverse effects such as productive cough, dryness of mouth, hoarseness, oral mucosal injury, dental injury, and hypoxia in the 2 groups were comparable. CONCLUSION: We concluded that intubation in the lateral position under video laryngoscopic guidance is safe and feasible performed in the left lateral position and prevents the hemodynamic change and sore throat resulting from change in decubitus. PMID- 29384934 TI - Investigation of an anatomically variant isolated bicuspid pulmonary valve: A case report. AB - INTRODUCTION: We provide a discussion of the anatomical characteristics of the bicuspid pulmonary valve (BPV) in this paper. We performed an autopsy of an isolated BPV found in the heart of a deceased individual. The deceased was a man in his 60s and had no previous history of cardiovascular disease. The heart weighed 260 g and had mild right ventricular hypertrophy. The pulmonary valve had a fish-mouth-like shape that was convex to the pulmonary trunk and both cusps were thickened and hardened. The anterior and left semilunar cusps of the pulmonary valve were fused. Post-stenotic dilatation was noted. CONCLUSIONS: In comparing the present case with previous reports, we found that, in human BPVs, cusps are fused in at least 2 patterns. PMID- 29384935 TI - Internal mammary sentinel lymph node biopsy with modified injection technique: A case report. AB - RATIONALE: In addition to axillary lymph node (ALN), internal mammary lymph node (IMLN) is also the first-echelon drainage nodes reached by metastasising cancer cells from breast cancer, which can provide important prognostic information. PATIENT CONCERNS: In this paper, we will introduce a case of breast cancer patient whose postoperative pathology result showed that she had internal mammary sentinel lymph node (IMSLN) metastases but no axillary sentinel lymph node (ASLN) metastases. DIAGNOSES: She was diagnosed as pT1cN1bM0 breast cancer based on the positive IMSLN but negative ASLN. INTERVENTIONS: She received axillary-sentinel lymph node biopsy (A-SLNB) and internal mammary-sentinel lymph node biopsy (IM SLNB) guided by modified injection technique. In the choice of chemotherapy, she received dose-dense AC * 4 times followed P * 4 times for chemotherapy. As to irradiation therapy, she received irradiation therapy include chest wall, superclavicular region, and internal mammary nodes. OUTCOMES: After performing IM SLNB, the nodal staging of this patient increased (from N0 to N1b). And she received additional chemotherapy and irradiation therapy. LESSONS: With the guidance of modified injection technique, the preoperative visualization rate of IMLN has been improved. IM-SLNB could be a minimally invasive technique for effective evaluation of the status of IMLN to provide information for staging and guide the adjuvant treatment. PMID- 29384937 TI - Acupuncture as a primary and independent treatment for a patient with chronic insomnia: One-year follow-up case report. AB - RATIONALE: Insomnia is a common disease. Till date, no study has reported the long-term (up to 1 year) outcomes of acupuncture as a primary and independent treatment in patients with insomnia. This report aims to present response of patient who was treated by acupuncture. This patient was evaluated with polysomnography. PATIENT CONCERNS: A 40-year-old patient had been diagnosed with insomnia for 2 years and getting worse since 1 month ago. He had undergone depression and anxiety emotion, but refused to take medical treatment for chronic insomnia. DIAGNOSES: In this study, the diagnosis of chronic insomnia was based on the International Classification of Sleep Disorders insomnia. The patient had no obvious differential diagnosis. INTERVENTIONS: Acupuncture treatment was planned for this patient who refused to take medical treatment with chronic insomnia. So the patient received 1 hour of acupuncture treatment for 12 weeks. OUTCOME: Polysomnographic evaluation was performed at baseline and 3 months, and 1 year after acupuncture treatment. He was asked to keep a diary of all his insomnia-related symptoms. All outcome measures substantially improved. Moreover, during the observation period, the patient's sleep quality did not worsen. LESSONS: After acupuncture treatment, improvements of subjective symptoms such as unrefreshing sleep, sleep disturbances, accompanied symptoms (morning headache, fatigue, and mood worsening) were observed. Remarkable improvement was recorded by polysomnographic parameters. The costs of the treatment of insomnia may be reduced, if this therapy was proved useful in future controlled studies. PMID- 29384936 TI - Recurrent Kaposi sarcoma associated with Koebner phenomenon in two HIV seronegative patients: Two case reports and a review of the literature. AB - RATIONALE: Koebner phenomenon is occasionally reported in patients affected by classic Kaposi sarcoma (KS). PATIENT CONCERNS: Here, we report 2 cases of KS associated with Koebner phenomenon and the correlation of human herpesvirus 8 molecular analysis with the clinical outcome. INTERVENTIONS: In the first case, a patient with a history of sporadic cutaneous KS developed a recurrent lesion at the laryngeal tract, the site of a previous nodulectomy. In our second case, immunodeficiency induced by chemotherapy triggered the development of KS and Koebner phenomenon was limited to the skin at the site of safenectomy. LESSONS: Our observations suggest that careful planning of surgical treatment is required in immunocompetent and immunocompromised patients with a medical history of KS. Moreover, mucosal sites (both respiratory and in the gastrointestinal tract) should be considered as potential sites for KS development. PMID- 29384938 TI - A novel iterative modified bicubic interpolation method enables high-contrast and high-resolution image generation for F-18 FDG-PET. AB - Positron emission tomography (PET) has become a useful and important technique in oncology. However, spatial resolution of PET is not high; therefore, small abnormalities can sometimes be overlooked with PET. To address this problem, we devised a novel algorithm, iterative modified bicubic interpolation method (IMBIM). IMBIM generates high resolution and -contrast image. The purpose of this study was to investigate the utility of IMBIM for clinical FDG positron emission tomography/X-ray computed tomography (PET/CT) imaging.We evaluated PET images from 1435 patients with malignant tumor and compared the contrast (uptake ratio of abnormal lesions to background) in high resolution image with the standard bicubic interpolation method (SBIM) and IMBIM. In addition to the contrast analysis, 340 out of 1435 patients were selected for visual evaluation by nuclear medicine physicians to investigate lesion detectability. Abnormal uptakes on the images were categorized as either absolutely abnormal or equivocal finding.The average of contrast with IMBIM was significantly higher than that with SBIM (P < .001). The improvements were prominent with large matrix sizes and small lesions. SBIM images showed abnormalities in 198 of 340 lesions (58.2%), while IMBIM indicated abnormalities in 312 (91.8%). There was statistically significant improvement in lesion detectability with IMBIM (P < .001).In conclusion, IMBIM generates high-resolution images with improved contrast and, therefore, may facilitate more accurate diagnoses in clinical practice. PMID- 29384939 TI - Upregulation of transmembrane 4 L6 family member 1 predicts poor prognosis in invasive breast cancer: A STROBE-compliant article. AB - Transmembrane 4 L6 family member 1 (TM4SF1) belongs to the 4-transmembrane-domain family and functions as an oncogene in multiple human cancers. In this work, we aim to determine TM4SF1 expression and its prognostic impact on patients with invasive breast cancer.Overall, we enrolled 209 invasive breast cancer patients and immunohistochemically examined the expression of TM4SF1 in tumor specimens. The relationship between TM4SF1 expression and clinicopathological parameter and patient survival of breast cancer patients was analyzed.Among the 209 cases, 137 (65.6%) exhibited high expression of TM4SF1. High TM4SF1 expression was significantly associated with advanced histological grade and negative estrogen receptor and progesterone receptor status. Triple-negative breast cancer (TNBC) tumors were more likely to express high levels of TM4SF1 than non-TNBC cases. Patients with high tumoral expression of TM4SF1 had a significantly shorter disease-free survival (DFS; P = .00) and overall survival (OS; P = .01) than those with low expression of TM4SF1. When survival analysis was restricted to the 167 patients (79.9%) receiving adjuvant chemotherapy, TM4SF1 expression was also correlated with poorer DFS and OS (P = .00). In multiple Cox regression analysis TM4SF1 expression remained an independent prognostic indicator for OS and DFS.TM4SF1 is upregulated and serves as an independent poor prognostic indicator in invasive breast cancer. PMID- 29384940 TI - Relationship between obesity and depression in Korean adults: Korea National Health and Nutrition Examination Survey 2014. AB - Previous studies on the relationship between obesity and depression have produced conflicting results. And only a limited number of studies have been conducted in Asians, and few large-scale nationwide studies have been conducted in Korean populations.We investigated the relationship between obesity and depression in Korean adults using data from a population-based sample from the 2014 Korea National Health and Nutritional Examination Survey (KNHANES) by cross-sectional study.In total, 4026 subjects (1692 men, 2334 women) aged 19 to 69 years participated in the 2014 KNHANES. Current depression was defined as a score >=10 on the 9-item Patient Health Questionnaire. Height and weight were measured and the body mass index (BMI) was calculated. The participants were asked to complete questionnaires about socio-demographic factors and disease comorbidities, and health-related behaviors. The chi-squared test and multivariate logistic regression analyses were performed to examine the relationship between obesity and depression.Depression was diagnosed in 5.7% of the study participants (3.9% of men, 7.0% of women). According to body weight status, there was a significant difference in the prevalence of depression (underweight: 16.2%, normal weight: 5.5%, overweight: 4.3%, obese [BMI >=30]: 6.9%). Compared with the normal weight group, the underweight group had a higher adjusted odds ratio (OR) for depression (OR = 3.27, 95% confidence interval [CI]: 1.22, 8.75 in men; OR = 2.00, 95% CI: 1.12, 3.57 in women). Overweight (OR = 0.60, 95% CI: 0.32, 1.13) and obese (OR = 0.62, 95% CI: 0.17, 2.27) men had lower ORs for depression, but this trend was not significant. Compared with normal weight women, obese women had higher adjusted ORs for depression (OR = 1.75, 95% CI: 0.79, 3.88), while overweight women had lower ORs for depression (OR = 0.90, 95% CI: 0.56, 1.45), but these trends were not significant.This study shows differences in the risk of depression depending upon body weight status. Being underweight was correlated with a high risk of developing depression in both men and women, but obesity cannot be ruled out as a risk factor for this condition. PMID- 29384941 TI - Concomitant coronary and pulmonary embolism associated with patent foramen ovale: A case report. AB - RATIONALE: The differential diagnosis of acute chest pain is very important, and can sometimes be challenging. Related diseases share a number of risk factors, and occasionally, 1 condition causes another disease to develop. PATIENT CONCERNS: We described a 59-year-old man who presented to emergency department complaining of chest pain. DIAGNOSES: He was suffered acute myocardial infarction (MI) and pulmonary embolism (PE) simultaneously. INTERVENTIONS: Dual antiplatelet therapy, statin, and low molecular weight heparin were administrated during his stay. The searches for cancers, autoimmune diseases, and hematologic diseases were unremarkable, ruling out a hypercoagulable state. Subsequent ultrasound scan revealed a thrombus in a vein of the lower left extremity. Thus, paradoxical embolism was highly suspected. OUTCOMES: Paradoxical embolism is a rare cause of acute MI, which may have occurred in our patient. This was evidenced by a previously unrecognized patent foramen ovale (PFO) with a right-to-left atrial shunt detected using contrast transesophageal echocardiography. LESSONS: Acute MI complicated with PE is not common in the clinical setting. The fatal condition is difficult to diagnose because of the similar symptoms and confusing causes. Paradoxical embolism can cause this phenomenon, and physicians should be highly vigilant in the search for a PFO in cases of paradoxical embolism. PMID- 29384942 TI - Correlation between resistin gene polymorphism and clinical aspects of lung cancer. AB - Lung cancer is one of the most common cancers and is associated with a poor survival rate in the Chinese Han population. Analysis of genetic variants could lead to improvements in prognosis following lung cancer treatment. Resistin (RETN) is an important mediator of metabolic diseases and tumor progression. In this study, we explored the effects of RETN single nucleotide polymorphisms (SNPs) on the susceptibility and clinicopathological characteristics of patients with lung cancer. Four RETN SNPs (rs7408174, rs1862513, rs3745367, and rs3219175) were analyzed using TaqMan SNP genotyping in 371 patients with lung cancer and 451 cancer-free controls. The results showed that the RETN SNP rs3219175 with AG or at least 1 A allele was associated with a higher risk of lung cancer than wild type (GG) carriers. Moreover, the RETN SNP rs3219175 with AG or AG + AA alleles was associated with a higher risk of distant metastasis than that in patients carrying GG alleles. We also used genotype-tissue expression datasets to compare the correlation of the RETN SNP rs3219175 in lung tissue and whole blood. In conclusion, our study demonstrated, for the first time, that RETN polymorphisms were correlated with lung cancer progression in the Chinese Han population. PMID- 29384943 TI - Single-center, retrospective study of the outcome of laparoscopic inguinal herniorrhaphy in children. AB - Laparoscopic hernia repairs are used increasingly in children.The purpose of this single-center cohort observational research study was to analyze the outcome of children treated surgically for unilateral or bilateral inguinal hernia using laparoscopy.We did a STROBE-compliant retrospective outcome analysis of pediatric, laparoscopic hernia repair. Consecutive laparoscopic herniorrhaphies in 123 children done between March 2, 2010, and March 1, 2014, were included in this analysis. Data analysis was based on reviewing the hospital records and a prospective questionnaire. We evaluated postoperative hernia recurrence rate, occurrence of postoperative complications, duration of postoperative pain medication, and wound cosmesis.We first performed laparoscopic inguinal herniorrhaphy according to the techniques described by Schier et al and Becmeur et al in March 2010. We treated 46 girls and 77 boys with laparoscopically confirmed inguinal hernias, and their ages ranged from 0 to 16 years. Of these, 77 children suffered from unilateral hernias, 30 from unilateral hernias with contralateral patency of the vaginal process, and 16 from indirect bilateral hernias. The median follow-up interval was 38 months (range: 13-58 months). Overall, 8 (6.5%) of these 123 patients experienced a recurrence of the inguinal hernia. Two patients (1.6%) suffered a postoperative infection. Postoperative pain medication was administered by parents for 1 to 3 days in 67 (63.8%) of the 105 families who answered the question, and no pain medication was administered by 5 (4.0%) parents. Wound cosmesis was rated by the parents as invisible or barely visible in 106 (86.2%) of 123 patients and esthetically disturbing in 4 (3.2%) children.Laparoscopic inguinal hernia repair carries a learning curve and is safe and efficient in children thereafter. Further prospective studies are required to evaluate the long-term outcome of laparoscopic inguinal hernia repair in children. PMID- 29384944 TI - Epidemiologic characteristics and outcomes of major trauma patients requiring prolonged mechanical ventilation. AB - The epidemiologic characteristics and outcomes of severe trauma patients requiring prolonged mechanical ventilation (PMV) remain unclear. This retrospective study aims to investigate the outcomes of PMV in this specific group. All patients with major trauma admitted to the respiratory care center (RCC) requiring PMV (duration >=21 days between January 2014 and December 2016) were enrolled. A total of 36343 trauma patients visited our emergency department for management, and 1388 (3.82%) were admitted to the intensive care unit (ICU) after initial resuscitation. After ICU management, 93 major trauma patients required PMV, and were then transferred to the RCC. Their mean age of these 93 patients was 68.6 +/- 18.3 years and 65 patients (70.0%) were older than 65 years. Head/neck trauma (n = 78, 83.9%) were the most common injury, followed by thoracic trauma (n = 30, 32.2%), and extremity trauma (n = 29, 31.2%). Their median injury severity score was 25 (interquartile range [IQR] 16-27). The median length of hospital stay was 50 days (IQR, 39-62). Six patients died of ventilator associated pneumonia for an in-hospital morality rate of 6.5%. In addition, 11 PMV patients became mechanical ventilator-dependent and were transferred to the respiratory care ward for further long-term care. In conclusion, <0.3% of trauma patients required PMV, and their in-hospital mortality rate was only 6.5%. Ventilator-associated pneumonia was the main cause of death and nosocomial infections were common in patients with long-term mechanical ventilator dependence. PMID- 29384945 TI - A retrospective study of optimal surgical management for occult breast carcinoma: Mastectomy or quadrantectomy? AB - The diagnosis and treatment for occult breast carcinoma (OBC) remain controversial because of no detectable primary lesions. We aimed to analyze optimal surgical management for OBC.A total of 26 female patients diagnosed with OBC, which were based on available criteria, were collected at a single clinic center from January 2005 to May 2016. We classified all patients into 4 groups: group A1, mastectomy with axillary lymph node dissection (ALND) + radiotherapy (RT); group A2, mastectomy with ALND; group B1, quadrantectomy with ALND + RT; group B2, quadrantectomy with ALND. Patient characteristics, disease-free survival, and overall survival were compared between groups.There were 14 cases in group A1, 5 cases in group A2, 4 cases in group B1, and 3 cases in group B2. Baseline characteristics were similar among groups. Compared with OBC patients treated with quadrantectomy, the disease-free survival (DFS) and overall survival (OS) rate of those treated with mastectomy had significantly improved (A1 vs. B1, DFS: hazard ratio [HR] 0.018, 95% confidence interval [CI] 0.001-0.241, P = .002; OS: HR 0.002, 95% CI 0.000-0.102, P = .002). Patients treated with radiotherapy had higher local recurrence and OS rate compared with patients treated with no radiotherapy on univariate survival analysis (A1 vs. A2, DFS: HR 0.018, 95% CI 0.001-0.240, P = .002; OS: HR 0.005, 95% CI 0.000-0.170, P = .003).The diagnosis of OBC will need continuous improvement with advances of diagnostic breast imaging. Modified radical mastectomy + RT is still a safe and effective choice. PMID- 29384946 TI - Severe disinhibition due to injuries of neural tracts related to emotion circuit in a patient with traumatic brain injury: A case report. AB - RATIONALE: Approximately 30% of patients with traumatic brain injury (TBI) develop disinhibition, a condition that involves several brain structures, including the amygdala, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Using diffusion tensor tractography (DTT), we report on a patient with severe disinhibition and injuries of the amygdala, OFC, and ACC following TBI. PATIENT CONCERNS: A 27-year-old male patient suffered an in-car accident. DIAGNOSES: Since the onset of the TBI, the patient showed severe disinhibition including violence, as follows: 1) he sometimes attacked therapists and nurses with no provocation, 2) while he was laying on a bed, he shouted and kicked the bed when asked questions, and 3) during therapy with a difficult task, he behaved violently to a therapist. The subscale of disinhibition in Neuropsychiatric Inventory scored three points for severity and for distress. INTERVENTIONS: N/A. OUTCOMES: On 10-month DTT, the connectivity of amygdala to the prefrontal cortex including the medial prefrontal cortex and OFC had decreased in both hemispheres. In the prefronto-thalamic tracts, the orbitofronto-thalamic tractshad narrowed (the right hemisphere), and were non-reconstructed (the left hemisphere). Discontinuations of both anterior cingulums were observed in both hemispheres. LESSONS: Using DTT, concurrent injuries of the amygdala, OFC, and ACC were demonstrated in a patient with severe disinhibition following TBI. Our result suggests the need to assess these neural structures in patients with disinhibition after brain injury. PMID- 29384947 TI - Usefulness of black boundary artifact on opposed-phase imaging from turbo spin echo two-point mDixon MRI for delineation of an arthroscopically confirmed small fracture of the lateral talar dome: A case report. AB - RATIONALE: A nondisplaced chip fracture can be missed on MRI. Opposed-phase imaging from mDixon MRI produces an interesting artifact called black boundary artifact. This artifact can provide better contrast at the fracture line resulting in better depiction of a small chip fracture on MRI. PATIENT CONCERNS: We present a case of small nondisplaced chip fracture at the lateral talar dome that was well delineated only with the aid of a black boundary artifact after using T2-weighted opposed-phase imaging from turbo spin-echo two-point modified Dixon ankle MRI. In other sequences, the lesion demonstrated a focal full thickness cartilage defect, subtle cortical irregularity, or subcortical bone marrow edema but the full delineation of the fracture line was not possible. DIAGNOSES: Opposed-phase imaging from mDixon MRI aided in the diagnosis of lateral talar dome osteochondral fracture (osteochondral lesion), which was confirmed arthroscopically. INTERVENTIONS: The osteochondral fragment was removed by arthroscopy. OUTCOMES: The patient did well with recovery of full range of motion after 2 months. LESSONS: We have identified a black boundary artifact using opposed-phase imaging from mDixon MRI that can aid in detection of small fracture, which can be missed by conventional MRI, by providing a dark linear signal at the fracture line. PMID- 29384948 TI - Treatment with antibodies against primary group A streptococcal peritonitis: A case report and a review of the literature. AB - RATIONALE: Several reports describe severe group A streptococcal (GAS) infections causing septic shock, soft-tissue necrosis, and multiple organ failure known as streptococcal toxic shock syndrome (STSS). However, primary peritonitis with GAS is rare and most of them were undertaken surgical procedure. PATIENT CONCERNS: We herein reported the case of 26-year-old healthy woman with sudden severe abdominal pain and hypotension. Computed tomography (CT) showed that large amount of free fluid in the peritoneal cavity consist with peritonitis, and no free air. DIAGNOSES: Primary peritonitis with GAS. INTERVENTIONS: Proper antibiotic therapy according to blood culture results. OUTCOMES: After antibiotic therapy, the patient recovered well without complications. LESSONS: An appropriate diagnostic approach and prompt antibiotic therapy is essential in GAS primary peritonitis. PMID- 29384949 TI - Compound grafting of residual vascularized fibular head flap to reconstruct contralateral lateral malleolus: A case report. AB - RATIONALE: Serious external ankle injuries caused by high-energy trauma are often associated not only with bone defect but also with a loss of skin and soft tissue that seriously affects ankle function. Therefore, it is particularly important to reconstruct the external ankle. PATIENT CONCERNS: The patient was a 64-year-old man with destructive injury of both lower extremities due to a machine accident. His left ankle and heel bone, along with the soft tissue, were torn off, and the peripheral blood supply and sensation to the toes of the left foot were lost concerns. DIAGNOSES: Complicated lateral malleolus defect. INTERVENTIONS: We used a composite tissueflap taken from thefibular head on the left side to reconstruct the rightfibular lateral malleolus. OUTCOMES: With the help of a prosthesis, the patient regained basic walking function by the 1 year follow-up. LESSONS: Using a combined compositeflap of the vascularizedfibular head to reconstruct the lateral malleolus is a good choice. PMID- 29384950 TI - Usefulness of multiphase computed tomography angiography in a patient with transient ischemic attack in the hyperacute phase: A case report. AB - RATIONALE: Patients with transient ischemic attack (TIA) have the possibility of developing stroke in the future. To prevent recurrent TIA or future stroke, identifying the cause of TIA is important. However, about two-third of patients with TIA have negative findings on diffusion-weighted imaging (DWI).We present a case of TIA, the cause of which was identified using multiphase computed tomography angiography (MCTA) in the hyperacute phase of the disease. PATIENT CONCERNS: The patient was a 57-year-old man who was admitted to the emergency department for right-side weakness persisting for 1 hour. DIAGNOSES: Occlusion of the proximal M3 segment of the left middle cerebral artery territory was found on the initial MCTA. OUTCOMES: The weakness completely resolved at 2 hours after symptom onset, and there was no acute infarction on the initial diffusion weighted magnetic resonance imaging (MRI) on the same day. Follow-up MCTA on the next day showed recanalization of the left M3 segment. Follow-up diffusion weighted MRI showed focal acute infarction in the left middle cerebral artery territory. LESSONS: MCTA could identify distal occlusion of the anterior circulation in patients with cardioembolic TIA in the hyperacute phase with negative DWI findings. PMID- 29384951 TI - Cole-Carpenter syndrome-1 with a de novo heterozygous deletion in the P4HB gene in a Chinese girl: A case report. AB - RATIONALE: Cole-Carpenter syndrome-1 (CLCRP1) is an independent osteogenesis imperfect (OI)-like disorder that manifests as bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. Only 2 types of mutation sites in the P4HB and CRTAP genes have been reported. PATIENT CONCERNS: A 14-month-old Chinese girl presented with prominent ocular proptosis, frontal bossing, craniosynostosis, plump anterior fontanel, growth retardation, osteopenia, and distinctive facial features that were strikingly similar to those in the original 2 cases. DIAGNOSES: Whole-exome sequencing revealed a novel deletion variation in exons 5 to 8 of the P4HB gene, which was found to be heterozygous using fluorogenic quantitative-polymerase chain reaction. LESSONS: This de novo deletion mutation in exons 5 to 8 of the P4HB gene advances our understanding of CLCRP1, expands the mutation spectrum of P4HB, and diversifies the cases reported for this condition. PMID- 29384952 TI - Spontaneous perforation of Meckel diverticulum: A case report. AB - RATIONALE: Meckel diverticulum (MD) is the most common congenital abnormality of the gastrointestinal tract. It is asymptomatic in the majority of patients. Perforation is a rare complication of MD and can be life-threatening. PATIENT CONCERNS: A 20-year-old male patient denying previous systemic disease and complaining of epigastric pain for 5 days came to our emergency department for help. Physical examination showed right lower quadrant tenderness without muscle guarding and rebounding pain. DIAGNOSIS: Blood examination including white blood cell, C reactive protein, liver, and renal function all showed within normal range. Abdominal computed tomography showed suspect MD in the distal ileum and enteritis at the ileum. INTERVENTION: Perforation of MD was found while in surgery, and Meckel diverticulectomy was performed. OUTCOMES: The patient was discharged 7 days after the operation with stable condition. LESSONS: Perforation is an uncommon complication of MD, and the symptom can mimic other acute abdominal conditions such as acute appendicitis while in the emergency space. We should take diagnosis under consideration as a differential diagnosis when we encounter patients whose impression was firstly acute appendicitis. PMID- 29384953 TI - Helicobacter pylori eradication improves the quality of life regardless of the treatment outcome: A multicenter prospective cohort study. AB - Helicobacter pylori (Hp) eradication is recommended for improving the quality of life (QOL) of patients with epigastric symptoms, especially reflux and dyspepsia. However, no reports have investigated the improvement of QOL after the eradication of Hp irrespective of epigastric symptoms. The aim of this study was to investigate the improvement in the QOL after the eradication of Hp irrespective of epigastric symptoms, and evaluate the factors associated with an improved QOL after the eradication of Hp.This prospective cohort study was performed at 15 referral institutions from September 2013 to December 2014. The patients' QOL and epigastric symptoms were evaluated before and after the eradication of Hp using the 8-item Short-Form Health Survey (SF-8) and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease, respectively.One hundred sixty-five of 184 Hp-infected patients underwent Hp eradication treatment. The treatment was successful in 82.4% (136/165) of the cases. One hundred sixty of the 165 Hp-infected patients were eligible for inclusion in the QOL analysis. In the indices of QOL on the SF-8, the scores on both the mental component summary (MCS) and the physical component summary (PCS) were found to have significantly improved after the eradication of Hp. However, the epigastric symptoms before the eradication of Hp were not correlated with either the MCS or PCS. A low QOL value before the eradication of Hp was the factor what was most strongly associated with the improvement in the QOL.The eradication of Hp improved the QOL, regardless of the outcome of the treatment, especially in patients who had an impaired QOL before the eradication. PMID- 29384954 TI - The dose-response association between estimated glomerular filtration rate and prognosis of patients with ST-segment elevation myocardial infarction from rural areas of China's Liaoning province. AB - We aimed to investigate the dose-response associations between chronic kidney disease (CKD), and short and long-term cardiovascular outcomes, to characterize these associations by drawing dose-response curves based on a Chinese rural ST segment elevation myocardial infarction (STEMI) population.In all, 1067 patients with STEMI were consecutively enrolled from 12 secondary hospitals of China's Liaoning province (from June 2009 to June 2010 and January 2015 to December 2015). The follow-up was regularly performed by telephone. Patients were grouped by estimated glomerular filter rate (eGFR): normal, eGFR >=90 mL/min/1.73 m; mild CKD, 60 to 90 mL/min/1.73 m; CKD, <60 mL/min/1.73 m. Adjusted logistic or Cox regression models were employed to compare short and long-term cardiovascular outcomes across different eGFR groups. Dose-response curves were plotted using restricted cubic spline functions.About 18.46% of the STEMI patients had CKD. Patients with CKD were more likely to suffer from other comorbidities, but less likely to receive evidence-based therapies. CKD was independently associated with in-hospital mortality and major adverse cardiac events (MACE) as compared with patients with normal renal function (for in-hospital mortality, adjusted odds ratio [OR] 2.39, 95% confidence interval [CI] 1.18-4.85, P = .02; for in-hospital MACE, adjusted OR 2.01, 95% CI 1.09-3.70, P < .01). Likewise, CKD was significantly associated with long-term mortality as well (CKD vs normal, adjusted hazard ratio 2.55, 95% CI 1.17-5.57, P = .02). The dose-response associations between eGFR, and short and long-term cardiovascular outcomes were found to be linear (all with P values for nonlinear associations >.05).CKD is an independent predictor of worse in-hospital and long-term clinical outcomes. The assessment of eGFR is essential to enable risk stratification, tailored therapy, and early and aggressive management. PMID- 29384955 TI - A rare case report of complications in craniofacial injuries: Cavernous sinus carotid fistula. AB - RATIONALE: Cavernous sinus-carotid fistula (CCF) is a rare complication of craniofacial injuries in patients receiving oral and maxillofacial surgical care. PATIENT CONCERNS: A retrospective review of 15 patients with CCF records was conducted. In addition, we present a rare case of a 32-year-old Chinese woman with CCF receiving oral and maxillofacial surgical care. DIAGNOSES: Digital subtraction angiography (DSA) confirmed a diagnosis of CCF. INTERVENTIONS: Endovascular surgery was performed via the femoral artery under general anesthesia without any complications. OUTCOMES: The postoperative course was uneventful, and the subjective and objective ophthalmic symptoms had resolved. LESSONS: The symptoms of CCF may be delayed for several days or weeks. Thus, maxillofacial surgeons should be aware of this and avoid the untimely repair of facial fractures with potentially disastrous consequences. Interventional neuroradiologic approaches that involve the use of a detachable balloon have made it possible to care for patients with CCF without any complications. PMID- 29384957 TI - The impact of acute coronary syndrome on late drug-eluting stents restenosis: Insights from optical coherence tomography. AB - The aim of the study was to investigate the optical coherence tomography (OCT) identified difference of in-stent restenosis (ISR) tissue characteristics between patients with and without acute coronary syndrome (ACS) at index intervention.The retrospective study included 80 patients with 85 drug-eluting stent (DES) restenosis lesions. Subjects were classified according to clinical presentation at the time of de-novo lesion intervention, namely ACS and non-ACS. OCT was performed at 5 years follow-up. The frequency of malapposition, neointimal characteristics, thrombus, and minimal stent area (MSA) were evaluated.ACS group consisted of 48 (60%) patients. The mean duration from initial intervention to OCT study was 66.15 months. Malapposition was more frequent in the ACS group (25.5% vs 2.9%, P = .006), as well as a higher prevalence of thrombus in the ACS group (21.6% vs 0%, P = .015). MSA of ACS group was significantly less than that of non-ACS group (4.99 +/- 1.80 vs 5.62 +/- 2.08 mm, P = .018). Compared with non ACS group, only MI group was related to smaller MSA (4.37 +/- 1.39 vs 5.62 +/- 2.08 mm, P = .048); The unstable angina (UA) group was not associated with a decreased MSA. The occurrence of neoatherosclerosis tended to be higher in ACS group (60.8% vs 41.2%, P = .076).In DES restenosis, an ACS presentation at initial intervention is associated with a higher incidence of malapposition, thrombus, and smaller MSA. PMID- 29384956 TI - Abnormal glucose regulation in Chinese patients with coronary artery disease: A cross-sectional study. AB - The purpose of this study was to investigate the prevalence of abnormal glucose regulation (AGR) in patients with established coronary artery disease (CAD), and the association of AGR and acute coronary events in Chinese patients.A total of 3441 hospitalized patients with established diagnosis of CAD were recruited from 41 centers in 25 cities of China. Oral glucose tolerance test (OGTT) was performed in 2112 patients without known diabetes. Acute coronary events were recorded for the patients.AGR was detected in 1880 (89%) patients in the OGTT cohort, with 1265 (59.9%) diagnosed with impaired glucose tolerance, 363 (17.2%) diagnosed with diabetes, and 30 (1.4%) diagnosed with isolated impaired fasting glucose. The overall proportion of patients diagnosed with diabetes increased from 30.7% (n = 930) at baseline to 42.6% (n = 1298) following the OGTT analysis. In total 85% (n = 3047) patients in the study was diagnosed with AGR. Multivariate analysis showed that AGR was independently associated with acute coronary events, after adjusting for the traditional risk factors including age, smoking, hypertension, and hyperlipidemia.The prevalence of AGR is increasing in Chinese patients with CAD, as compared with previous report. AGR was independently associated with acute coronary events. Prospective studies are warranted to evaluate the benefit of intervening prediabetes in adult patients with CAD. PMID- 29384958 TI - The intra- and extraluminal appendiceal microbiome in pediatric patients: A comparative study. AB - Intestinal microbiota is involved in metabolic processes and the pathophysiology of various gastrointestinal disorders. We aimed to characterize the microbiome of the appendix in acute pediatric appendicitis comparing extraluminal and intraluminal samples.Between January and June 2015, 29 children (3-17 years, mean age 10.7 +/- 3.4 years, sex M:F = 2.6:1) undergoing laparoscopic appendectomy for acute appendicitis were prospectively included in the study. Samples for bacterial cultures (n = 29) and 16S ribosomal desoxyribonucleic acid (rDNA) sequencing (randomly chosen n = 16/29) were taken intracorporeally from the appendiceal surface before preparation ("extraluminal") and from the appendiceal lumen after removal ("intraluminal"). The degree of inflammation was histologically classified into catarrhal, phlegmonous, and gangrenous appendicitis.Seventeen bacterial species were cultivated in 28 of 29 intraluminal samples and 4 species were cultivated in 2 of 29 extraluminal samples. Using 16S rDNA sequencing, 267 species were detected in intraluminal but none in extraluminal samples. Abundance and diversity of detected species differed significantly between histological groups of acute appendicitis in bacterial cultures (P = .001), but not after 16S rDNA sequencing.The appendiceal microbiome showed a high diversity in acute pediatric appendicitis. The intraluminal microbial composition differed significantly depending on the degree of inflammation. As bacteria were rarely found extraluminally by culture and not at all by sequencing, the inflammation in acute appendicitis may start inside the appendix and spread transmurally. PMID- 29384959 TI - Pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma in an Asian population. AB - Head and neck squamous cell carcinoma (HNSCC) has a high prevalence and is a major cause of cancer deaths in Taiwan. However, there is still no effective salvage therapy that prolongs the life expectancy of patients with recurrent/metastatic (R/M) HNSCC. Immune checkpoint therapy that targets the programmed cell death protein 1 (PD-1) may provide clinical benefit for these patients. We analyzed 22 R/M HNSCC patients who received pembrolizumab, a monoclonal antibody against PD-1, as salvage therapy. Intravenous pembrolizumab was given at a fixed dosage of 100 or 200 mg every 3 weeks. Three patients also received local palliative radiotherapy, but no patients received chemotherapy or targeted drugs. Seventeen patients (77.3%) received at least 3 cycles of pembrolizumab. Based on Response Evaluation Criteria in Solid Tumors criteria (ver. 1.1), 2 patients (9.1%) had complete response, 5 (22.7%) had partial response, and 6 (27.3%) had stable disease, corresponding to a disease control rate of 59.1%. Four patients had confirmed disease progression, 2 of whom had continuous progression over the target lesion after shrinkage of other metastases. One patient developed immune-related pneumonitis that resolved quickly after steroid treatment. Another patient developed itchy skin rashes immediately after administration of pembrolizumab, and this was controlled by an antihistamine. There were no other severe adverse effects. Pembrolizumab is beneficial and well-tolerated for some patients with refractory R/M HNSCC. However, it is important to identify biomarkers to identify the most responsive patients when designing future trials. PMID- 29384961 TI - Two cases of hemolymphangioma in the thoracic spinal canal and spinal epidural space on MRI: The first report in the literature. AB - RATIONALE: Hemolymphangioma is a rare, noninvasive benign tumor of mesenchymal origin resulting from malformation of vascular and lymphatic vessels. The incidence of hemolymphangioma in the spinal canal is low. PATIENT CONCERNS: This report describes 2 patients with a lesion located in the thoracic spinal canal or spinal epidural space, who were misdiagnosed with suspected meningioma or suspected schwannoma, respectively, based on magnetic resonance imaging (MRI). DIAGNOSES: Hemolymphangioma. INTERVENTIONS: The application of a surgery was designed to treat the 2 patients. OUTCOMES: 2 patients stated that symptoms were improved after the operation. LESSONS: This report should raise awareness among clinicians that careful image analysis and consideration of patient history and pathology is required for accurate differential diagnosis of hemolymphangioma in the spinal canal and spinal epidural space. PMID- 29384962 TI - Incidence of major depressive disorder: variation by age and sex in low-income individuals: a population-based 10-year follow-up study: Erratum. PMID- 29384963 TI - Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: A meta-analysis: Erratum. PMID- 29384965 TI - The association of hypernatremia and hypertonic saline irrigation in hepatic hydatid cysts: A case report and retrospective study: Erratum. PMID- 29384964 TI - Effect of different surgical type of coronary artery bypass grafting on kidney injury: A propensity score analysis: Erratum. PMID- 29384960 TI - Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE compliant retrospective observational postauthorization study. AB - The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8 45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain. PMID- 29384966 TI - Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors: Erratum. PMID- 29384967 TI - Clinicopathological factors associated with HER2-positive gastric cancer: A meta analysis: Erratum. PMID- 29384968 TI - A primary gastric synovial sarcoma: a case report and literature review: Erratum. PMID- 29384969 TI - Association of IL-6-174 G/C and IL10-1082 G/A polymorphisms with recurrent aphthous stomatitis risk: A meta-analysis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral disease with unknown etiology. The association between IL-6-174 G/C and IL10-1082 G/A polymorphisms and the risk of RAS remains controversial. Therefore, we conducted this meta-analysis to gain more evidence-based information. METHODS: Four online databases, PubMed, Embase, Web of Science, and Cochrane Library, were searched, and the relevant publications were collected. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association of the IL-6-174 G/C and IL10-1082 G/A polymorphisms with RAS susceptibility. RESULTS: Nine published case-control studies with 779 patients and 1016 controls were collected. The overall analysis proved that the IL10-1082 G/A polymorphism was significantly associated with the risk of RAS in a dominant model (GG + AG vs AA: OR = 1.49, 95% CI = 1.10-2.01, P = .01). A subgroup analysis based on ethnicity revealed significant associations in Asian populations in allelic, heterozygote, and dominant models (G vs A: OR = 1.55, 95% CI = 1.04-2.31, P = .03; AG vs AA: OR = 1.76, 95% CI = 1.16-2.67, P = .01; GG + AG vs AA: OR = 2.04, 95% CI = 1.37 3.03, P = .00). The association in Caucasians and people of mixed ethnicity requires further study. No significant association was detected between the IL-6 174 G/C polymorphism and RAS in any of the genetic models. However, subgroup analysis by ethnicity revealed that the Caucasians were more likely to develop RAS in 4 genetic models (G vs C: OR = 2.36, 95% CI = 1.26-4.41, P = .01; GG vs CC: OR = 7.05, 95% CI = 3.50-14.18, P = .00; GG + CG vs CC: OR = 4.28, 95% CI = 2.17-8.45, P = .00; GG vs CG + CC: OR = 2.59, 95% CI = 1.05-6.41, P = .04). In addition, a significantly decreased risk of RAS susceptibility was found in Asians (CG vs CC: OR = 0.27, 95% CI = 0.07-0.99, P = .049; GG + CG vs CC: OR = 0.27, 95% CI = 0.07-0.98, P = .047). CONCLUSION: Our meta-analysis indicated that the IL10-1082 G/A polymorphism is associated with RAS susceptibility, especially in Asians. In contrast, the IL-6-174 G/C polymorphism does not have a statistically significant association with RAS susceptibility. However, it may play a different role during the development of RAS in different ethnicities. PMID- 29384970 TI - Combination therapy of anabolic and nonbisphosphonates antiresorptive agents for the treatment of osteoporosis: A meta-analysis. AB - BACKGROUND: According to the mechanisms of action, combination therapy of anabolic and antiresorptive agents may produce more effect for the treatment of osteoporosis. However, the combination therapy of anabolic agents and bisphosphonates reports no benefit and even reduced the anabolic effects of anabolic agents. This study aims to assess the effect of combination therapy of anabolic and nonbisphosphonates antiresorptive agents in adults with osteoporosis. METHODS: Medline, EMBASE, and Cochrane Library were searched from January 1, 1980 to November 1, 2017 for randomized controlled trials (RCTs) of adults with osteoporosis treated in combination therapy of anabolic and nonbisphosphonates antiresorptive agents compared with monotherapy of either agent alone. The primary outcome was the incidence of fractures. The secondary outcomes were the bone mineral density (BMD) changes at lumbar spine and total hip. Continuous outcomes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI), while dichotomous outcomes were expressed as risk ratio (RR) and 95% CI. The meta-analysis was performed using a random-effects model. I statistic (I > 50% as a threshold indicates significant heterogeneity) was used to assess the heterogeneity. RESULTS: A total of 10 trials with a total of 1042 patients were included. The pooled results showed that the combination therapy demonstrated a significant advantage over a monotherapy in the BMD improvement at the lumbar spine (SMD 1.18; 95% CI, 0.63 to 1.72; I = 93%) and the total hip (SMD 0.89; 95% CI, 0.48 to 1.29; I = 88%) and further reduce the fracture risk (RR, 0.45; 95%CI, 0.21 to 0.94; I = 0%). CONCLUSIONS: Low-to moderate-quality evidence shows that the combination therapy of anabolic and nonbisphosphonates antiresorptive agents is superior to monotherapy in improving the BMD and reducing the fracture risk. However, further high methodological quality studies are needed to determine the antifracture efficacy, cost effectiveness and safety of this strategy of combination therapy. PMID- 29384971 TI - The side effects and complications of percutaneous iodine-125 seeds implantation under CT-guide for patients with advanced pancreatic cancer. AB - PURPOSE: The present study investigates the side effects and complications of computed tomography (CT)-guided percutaneous iodine-125 (I-125) seeds implantation for advanced pancreatic cancer. METHODS: The clinical data were retrospectively analyzed for patients treated with implantation of I-125 seeds under CT-guide in our hospital from May 2010 to April 2015. The side effects and complications were collected and their possible reasons were analyzed. RESULTS: A total of 78 patients were enrolled. The side effects were categorized as fever in 29 cases (37.18%), abdominal pain in 26 cases (33.33%), nausea and vomiting in 9 cases (11.54%), diarrhea in 5 cases (6.41%), and constipation in 4 cases (5.13%). Complications were composed of pancreatitis in 9 cases (11.54%), infection in 5 cases (6.41%), seed migration in 2 cases (2.56%), intestinal perforation in 1 case (1.28%), and intestinal obstruction in 1 case. The incidence of complication was 23.08% (18/78). The difference in incidence of complication was statistically significant between patients implanted with <=27 seeds and those with >27 seeds (P = .032). CONCLUSION: The side effects and complications frequently occur in implantation of I-125 seeds for patients with advanced pancreatic cancer. More concern should be given to the patients treated by this technique. PMID- 29384972 TI - Long-term low-dose tolvaptan treatment in hospitalized male patients aged >90 years with hyponatremia: Report on safety and effectiveness. AB - The retrospective study aimed at investigating the safety and clinical efficacy of long-term application of tolvaptan in patients >90 years old with hyponatremia. Although tolvaptan has been used to treat hyponatremia, the effect of its long-term use in elderly patients was unknown.Seven patients over 90 with isovolumic or hypervolemic hyponatremia admitted to the PLA Navy General Hospital between October 2011 and October 2013 were enrolled. The patients' serum sodium levels <135 mmol/L persisted for more than 3 months, and oral treatment with tolvaptan lasted for more than 12 months. Tolvaptan dose started from 7.5 mg once daily, with maximum dose no more than 30 mg daily. Clinical and laboratory data of the patients before and after treatment were compared.Serum sodium and chlorine levels increased significantly in the 1st 3 days after treatment (P < .05). All patients' serum sodium levels were above 135 mmol/L 1 month after treatment, and sustained through 1 year after treatment, without extra sodium supplementation. No serious complications were observed.The result indicated a significant improvement in the serum sodium levels and no serious adverse effects after long-term use in very elderly patients. PMID- 29384973 TI - Patient and parent reported outcome measures in cleft lip and palate patients before and after secondary alveolar bone grafting. AB - European and Northern American healthcare authorities increasingly encourage the use of Patient Reported Outcome Measures (PROMs) that complement clinical and laboratory assessments to help holistically evaluate reconstructive outcomes. This is the first study to evaluate PROMs in cleft lip/palate patients who have, or have not, undergone secondary alveolar bone grafting (SABG).A PROMs study was conducted; 40 consecutive consenting cleft lip/palate children between 8 and 14 years old were included. Twenty patients did, and 20 patients did not, have SABG. PROMs scores from children and parents in the 2 groups were compared.Forty patients completed the trial. No significant differences in total score from the Chang Gung Short Form-15 (CGSF-15) were found between children and their parents. Children with SABG reported no more oral-nasal regurgitation than children without SABG, but tended to report more nasal obstruction. There were no statistically significant differences in parent reported outcomes between the 2 groups.Cleft lip/palate patients who underwent SABG reported significantly less nasal regurgitation and more nasal obstruction compared to those patients who did not undergo SABG. PMID- 29384974 TI - Efficacy and safety of tranexamic acid in total hip replacement: A PRISMA compliant meta-analysis of 25 randomized controlled trials. AB - BACKGROUND: Hip osteoarthritis is one of the most prevalent musculoskeletal degenerative diseases in elderly. Total hip arthroplasty (THA) is the most effective surgical treatment for end stage hip osteoarthritis. Tranexamic acid (TA) is a potent drug to reduce surgical blood loss in surgery, therefore, as a potential drug for application in THA. OBJECTIVES: To identify the combined efficacy of TA administration in THA. A meta-analysis including 25 randomized controlled trials was conducted for generating synthesized effects. METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines for reporting systematic reviews and meta analysis. A total of 25 Randomized controlled trials (RCTs) were included for meta-analysis. RESULTS: The pooled results illustrated that total blood loss, intraoperative blood loss, postoperative blood loss, hemoglobin drop, transfusion rate, and average hospital stay were significantly lower than controls (standardized mean difference or odds ratio (OR) (95%CI): -0.87, (-1.13,-0.61), 0.68, (-0.96,-0.39), -1.41, (-2.24,-0.59), -1.11, (-1.63,-0.58), 0.28, (0.20, 0.38), -0.17, (-0.49,0.14), P < .05, respectively). Moreover, TA acts efficiently without increasing risk of thromboembolic events with OR = 1.14, 95%CI = 0.50 2.62, P = .75. Subgroup analysis indicated no statistically significant differences between a higher dose of topical TA (>=2 g or 15 mg/kg) or a lower dose (<2 g or 15 mg/kg). CONCLUSION: The findings indicated that TA is clinically effective and safe in patients receiving total hip arthroplasty. PMID- 29384975 TI - Different characteristics of a single sinonasal inverted papilloma from sequential PET-CT: A case report. AB - RATIONALE: Inverted papilloma (IP) is a benign tumor that should be monitored carefully because it frequently recurs and has the potential to become malignant. PATIENT CONCERNS: We report a case of a 59-year-old woman who presented with a mass which had been found incidentally on positron emission tomography computed tomography (PET CT). DIAGNOSES: Using endoscopy and CT, the preoperative diagnosis was inverted papilloma. PET CT showed a mass with hot uptake in the left ethmoid and frontal sinus (maximum standardized uptake value (SUVmax) = 7.80). INTERVENTIONS: We performed endoscopic sinus surgery (ESS) using 4 mm 0 degrees and 70 degrees endoscopes under general anesthesia. After 15 months of follow-up, remnant masses existed in the left frontal and supraorbital ethmoid cells. In the second PET CT taken at this time, a mass with lower SUV compared to the preoperative PET was observed in the lateral side of the left frontal sinus (SUVmax= 1.71). Revision ESS was performed using the "above and below" technique. OUTCOMES: Two years after initial surgery, follow-up CT showed there was no tumor recurrence in the frontal sinus or supraorbital ethmoid cell. There were no complications such as numbness in the forehead area after the operations. CONCLUSION: If the tumor is located at a site that is difficult to reach with an endoscope alone, it is faster and less painful to choose a more convenient approach for the patientand it can avoid unnecessary cost burden. It should also be noted that the SUV of PET is not a tool to distinguish IP from other inflammatory polyps or cancer. PMID- 29384976 TI - Radiofrequency-induced endometrial ablation for the treatment of postpartum hemorrhage after vaginal delivery: Case report. AB - RATIONALE: Postpartum hemorrhage is a common complication and difficult problem in obstetrics. Radiofrequency-induced endometrial ablation (RFIEA) widely used in abnormal uterine bleeding and achieved good effects. This article will investigate the effect of RFIEA for treatment of postpartum hemorrhage. PATIENTS CONCERNS: A 26-year-old healthy full-term parturient woman presented with postpartum hemorrhage after vaginal delivery for 11 hours, who was ready to emergency surgery (hysterectomy) 7 hours after inserting an intrauterine balloon into uterine cavity. DIAGNOSES: Blood loss after vaginal delivery was more than 500 mL during 11 hours in the full-term parturient woman. INTERVENTION: We applied RFIEA to treatment of postpartum hemorrhage. With the patient in dorsal lithotomy position, we advanced the disposable device according to the instruction and operated the Novasure system in semi-automatic mode. OUTCOMES: There was no obvious endometrial bleeding found with hysteroscopy at the end of surgery. No complications (such as thermal injury to adjacent tissue, uterine perforation, bowel perforation) were observed. LESSONS: It is safe and effective to treat postpartum hemorrhage after vaginal delivery using RFIEA. PMID- 29384977 TI - Improvement of chronic hepatitis B by iron chelation therapy in a patient with iron overload: A case report. AB - RATIONALE: This report describes seroconversion of hepatitis B surface antigen (HBsAg) in a patient with marked iron overload caused by chronic hepatitis B (CHB) after receiving iron chelation therapy and discusses the role of iron chelation therapy in CHB. PATIENT CONCERNS: Increased serum ferritin level for 2 months. DIAGNOSIS: Secondary iron overload and CHB. INTERVENTION: To relieve iron load of the body, the patient underwent regular phlebotomy therapy and deferoxamine (DFO) therapy. During the therapy, serum ferritin and hepatitis B virus (HBV) were monitored and the iron concentration of the liver and heart were followed by T2* of magnetic resonance imaging (MRI) scan. OUTCOMES: Serum ferritin gradually decreased. Approximately 1 year after the therapy, HBsAg turned persistently negative. LESSONS: Iron chelation therapy may attenuate HBV infection. PMID- 29384979 TI - Clinical Characteristics and Risk Factors for Poor Outcome in Infants Less Than 90 Days of Age With Bacterial Meningitis in the United Kingdom and Ireland. AB - BACKGROUND: To describe the clinical characteristics and risk factors associated with poor outcome in infants <90 days of age with bacterial meningitis. METHODS: Prospective, enhanced, national population-based active surveillance for infants <90 days of age with bacterial meningitis in the United Kingdom and Ireland between July 2010 and July 2011. Infants were identified through the British Paediatric Surveillance Unit, laboratory surveillance and meningitis charities. RESULTS: Clinical details was available for 263 of 298 (88%) infants where a bacterium was identified, 184 (70%) were born at term. Fever was reported in 143 (54%), seizures in 73 (28%), bulging fontanelle in 58 (22%), coma in 15 (6%) and neck stiffness in 7 (3%). Twenty-three (9%) died and 56/240 (23%) of the survivors had serious central nervous system complications at discharge. Temperature instability [odds ratio (OR), 2.99; 95% confidence interval (CI): 1.21-7.41], seizures (OR, 7.06; 95% CI: 2.80-17.81), cerebrospinal fluid protein greater than the median concentration (2275 mg/dL; OR, 2.62; 95% CI: 1.13-6.10) and pneumococcal meningitis (OR, 4.83; 95% CI: 1.33-17.58) were independently associated with serious central nervous system complications while prematurity (OR, 5.84; 95% CI: 2.02-16.85), low birthweight (OR, 8.48; 95% CI: 2.60-27.69), coma at presentation (OR, 31.85; 95% CI: 8.46-119.81) and pneumococcal meningitis (OR, 4.62; 95% CI: 1.19-17.91) were independently associated with death. CONCLUSIONS: The classic features of meningitis were uncommon. The presentation in young infants is often nonspecific, and only half of cases presented with fever. A number of clinical and laboratory factors were associated with poor outcomes; further research is required to determine how knowledge of these risk factors might improve clinical management and outcomes. PMID- 29384978 TI - Efficacy and safety of autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia: A study protocol for a multicenter exploratory prospective study (Auto-Ph17 study). AB - INTRODUCTION: The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogeneic hematopoietic cell transplantation (allo-HCT) is a major treatment option, the role of autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reconsidered, especially in patients who achieved early molecular remission. METHODS AND ANALYSIS: This is a multicenter exploratory study for Ph + ALL patients aged between 55 and 70 years who achieved complete molecular remission within 3 cycles of chemotherapy. The target sample size is 5, and the registration period is 2 years. The primary endpoint is Day100- mortality after transplantation, and the secondary endpoints are survival, relapse rate, nonrelapse mortality, and adverse events.This study is divided into 3 phases: peripheral blood stem cell harvest, transplantation, and maintenance. Chemomobilization is performed using a combination of cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (PSL). As a preparative regimen, the LEED regimen is used, which consists of melphalan, CPM, etoposide, and dexamethasone. Twelve cycles of maintenance therapy using a combination of VCR, PSL, and dasatinib are performed.In association with relapse, the minimal residual disease (MRD) of BCR-ABL chimeric gene and T-cell subsets are analyzed both before and after auto-PBSCT. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board of Nagoya University Hospital and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Trial registration number UMIN000026445. PMID- 29384980 TI - Infectious Diseases Consultation Improves Treatment and Decreases Mortality by Enterococcal Bacteremia in Children. AB - BACKGROUND: Enterococci can cause severe infectious diseases (IDs). Delaying appropriate antibiotic therapy for enterococcal bacteremia is associated with increased patient mortality. METHODS: We conducted a retrospective analysis examining the characteristics of children with enterococcal bacteremia at the 2 largest children's hospitals in Japan. We compared outcomes of enterococcal bacteremia patients who received IDs consultation with those who did not. We also evaluated the risk factors for 30-day mortality after onset of enterococcal bacteremia. RESULTS: One hundred fifty-two episodes of enterococcal bacteremia developed in 142 children. The most common pathogen was Enterococcus faecalis (94 episodes, 62%) followed by E. faecium (46 episodes, 30%). An underlying disease was present in 146 (96%) episodes. The most common type of infection was catheter related blood stream infection (90, 59%). ID consultation, provided in 100 of 152 episodes of enterococcal bacteremia, was significantly associated with a higher rate of appropriate empiric therapy (84% versus 56%; P < 0.001) and appropriate definitive therapy (98% versus 73%; P < 0.001), treatment duration >=7 days (97% versus 78%; P < 0.001), and the survival rate during 1 year postonset (P = 0.047). Seventeen children died within 30 days of enterococcal bacteremia onset. In multivariate analysis, those who received definitive therapy with penicillin without glycopeptides were at a statistically lower risk for death within 30 days after onset of enterococcal bacteremia (OR: 0.12; 95% confidence interval: 0.02 0.70; P = 0.02). CONCLUSIONS: ID consultation was associated with a higher rate of appropriate therapy and may decrease mortality because of enterococcal bacteremia in children. PMID- 29384982 TI - TRAUMATIC MACULAR HOLE CLOSURE AND VISUAL IMPROVEMENT AFTER TOPICAL NONSTEROIDAL ANTIINFLAMMATORY DRUG TREATMENT. AB - PURPOSE: To report a case of pediatric traumatic macular hole that closed with visual improvement after treatment with topical ketorolac. METHODS: Retrospective case report. RESULTS: A 15-year-old girl presented with persistent left blurred vision after being hit with a soccer ball 2 months before. Visual acuity was 20/40 with a full-thickness macular hole with cystoid macular edema. After treatment with ketorolac 0.4% four times a day for a month, the hole closed with resolution of the cystoid macular edema but some remaining subretinal fluid. The ketorolac was tapered over the following month, and the subretinal fluid resolved during the subsequent months. At 10 months after initial presentation, patient's vision was 20/20 with a normal foveal contour, no subretinal fluid, and minimal ellipsoid zone disruption. CONCLUSION: Topical nonsteroidal antiinflammatory drug treatment may play a role in the resolution of traumatic macular holes with cystoid macular edema. PMID- 29384981 TI - AUTOSOMAL RECESSIVE BESTROPHINOPATHY: MULTIMODAL IMAGING UPDATE. AB - BACKGROUND: Autosomal recessive bestrophinopathy is part of the diverse spectrum of retinal diseases caused by mutations in the BEST1 gene. METHODS: A case report. RESULTS: We present a case that highlights the classic retinal findings of autosomal recessive bestrophinopathy with an emphasis on modern multimodal imaging. CONCLUSION: We describe modern multimodal imaging in an individual with a BEST1 gene mutation and clinical findings consistent with an autosomal recessive bestrophinopathy. PMID- 29384984 TI - Improving the accuracy of blood pressure measurement: the influence of the European Society of Hypertension International Protocol (ESH-IP) for the validation of blood pressure measuring devices and future perspectives. AB - INTRODUCTION: The European Society of Hypertension (ESH) International Protocol (ESH-IP) for the validation of blood pressure (BP) measuring devices was published in 2002, with the main objective of simplifying the validation procedures, so that more BP monitors would be subjected to independent validation. This article provides an overview of the international impact of the ESH-IP and of the lessons learned from its use, to be able to justify further developments in validation protocols. METHODS: A review of published (PubMed) validation studies from 2002 to 2017 was performed. RESULTS: One hundred and seventy-seven validation studies using the ESH-IP, 59 using the British Hypertension Society protocol, 46 using the Association for the Advancement of Medical Instrumentation (AAMI) standard and 23 using the International Organization for Standardization (ISO) standard were identified. Lists of validated office-clinic, home and ambulatory BP monitors are provided. Of the ESH IP studies, 93% tested oscillometric devices, 80% upper arm, 71% home, 25% office and 7% ambulatory monitors (some had more than one function). CONCLUSION: The original goal of the ESH-IP has been fulfilled in that in the last decade the number of published validation studies has more than doubled. It is now recognized that the provision of accurate devices would be best served by having a universal protocol. An international initiative has been put in place by AAMI, ESH and ISO experts aiming to reach consensus for a universal validation protocol to be accepted worldwide, which will allow a more thorough evaluation of the accuracy and performance of future BP monitors. PMID- 29384985 TI - Retinal vessel narrowing: an early predictor of future arteriosclerosis? PMID- 29384983 TI - A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement. AB - : In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols. PMID- 29384986 TI - Renal infarction management: towards an etiological approach? PMID- 29384987 TI - Hydrogen sulfide, then nitric oxide and vasoprotection. PMID- 29384988 TI - Subclinical target organ damage in primary aldosteronism: resistant to spironolactone therapy? PMID- 29384989 TI - Reply. PMID- 29384990 TI - Mechanisms of salt sensitivity of blood pressure: an unbiased approach to skinning a cat. PMID- 29384991 TI - Reply. PMID- 29384992 TI - Women and Kidney Disease: Reflections on World Kidney Day 2018. AB - : Chronic kidney disease aff ects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus off ering an opportunity to refl ect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Sex diff erences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, off ering an opportunity for diagnosis of kidney disease, but also a state in which acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and on the fetus. Women have diff erent complications on dialysis than men and are more likely to be donors than recipients of kidney transplants.In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29384993 TI - Melatonin prevented spatial deficits and increases in brain asymmetric dimethylarginine in young bile duct ligation rats. AB - Bile duct ligation (BDL) in young rats can cause impaired liver function and cognition deficits. Nitric oxide is implicated in hepatic encephalopathy and is also involved in cognition. In this study, we examined the role of brain asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, in young BDL rats with spatial deficits. Young male Sprague-Dawley rats aged 17 days were assigned to four groups: laparotomy (SHAM), laparotomy plus 5 mg melatonin delivered through a pellet (SHAMM) for 4 weeks, BDL for 4 weeks, and BDL plus 5 mg melatonin delivered through a pellet (BDLM) for 4 weeks. Their spatial memory was assessed using a Morris water-maze task. Plasma and brains were collected for biochemical and ADMA analyses. We found that the BDL group had significantly elevated levels of ADMA in the plasma, the prefrontal cortex, and the dorsal hippocampus, and worse spatial performance than that of the control groups. Melatonin administration prevented an increase in the ADMA levels in the plasma, prefrontal cortex, and dorsal hippocampus, and prevented spatial deficits in BDL rats. In addition, melatonin maintained brain-derived neurotrophic factor in the dorsal hippocampus at a level comparable with controls. We concluded that melatonin is effective in preventing spatial deficits and decreasing ADMA levels in the plasma, prefrontal cortex, and dorsal hippocampus in young BDL rats. Brain ADMA levels might play a role in BDL-induced spatial deficits. PMID- 29384994 TI - Inotropic Therapy for Sepsis. AB - Sepsis, severe sepsis, and septic shock represent a dynamic clinical syndrome involving a systemic inflammatory response, circulatory changes, and end-organ dysfunction from an infection. Early aggressive management to restore perfusion and/or improve hypotension is critical to improving outcomes. Although the basic management principles of early goal-directed therapy for sepsis have not undergone significant changes, there has been a recent shift in recommendations related to the timing and type of inotropic support. The purpose of this article is to review fluid management along with previous and current inotrope recommendations in pediatric sepsis and septic shock. PMID- 29384996 TI - UTILITY OF ULTRA-WIDEFIELD RETINAL IMAGING FOR THE STAGING AND MANAGEMENT OF SICKLE CELL RETINOPATHY. AB - PURPOSE: To determine whether ultra-widefield (UWF) retinal imaging changes the staging or management of sickle cell retinopathy compared with clinical examination. METHODS: Prospective, observational study including patients with sickle cell disease. All patients underwent dilated fundus examination by a fellowship-trained retina specialist, as well as UWF fundus photography (FF) and fluorescein angiography (FA). Sickle retinopathy stage and treatment recommendation per eye were determined after clinical examination, UWF-FF, and UWF-FA, respectively, and differences in retinopathy stage and treatment recommendation were compared. RESULTS: A total of 70 eyes from 35 patients (17 women, 48.6%), mean age 30.4 years, were included. Sickle genotypes included 26 patients with sickle SS (74.3%), 7 SC (20.0%), and 2 beta(+)thalassemia (5.7%). Based on examination, most eyes (42/70; 60.0%) had no visible retinopathy. Based on UWF-FF, about half of the eyes were found to be Goldberg Stage 2 or above (36/70; 51.4%). Based on UWF-FA, nearly all eyes were Goldberg Stage 2 or above (63/70; 90%). However, clinical examination reliably detected neovascularization, and in no case did the addition of UWF imaging change management relative to examination alone. CONCLUSION: Ultra-widefield imaging detects a higher stage of sickle cell retinopathy compared with clinical examination alone, but these differences may not be clinically significant. PMID- 29384997 TI - INNER CHOROIDAL FLOW SIGNAL ATTENUATION IN PACHYCHOROID DISEASE: Optical Coherence Tomography Angiography. AB - PURPOSE: To study zones of reduced inner choroidal flow signal, foci of reduced inner choroidal thickness, and pathologically dilated Haller layer vessels (pachyvessels) in eyes with pachychoroid disease using optical coherence tomography (OCT) and OCT angiography. METHODS: Patients with treatment-naive pachychoroid disease were recruited. All patients prospectively underwent swept source OCT and OCT angiography. Zones of reduced choriocapillaris flow were labeled and enumerated. Areas where reduced flow signal was attributable to masking/artifacts were excluded. Regions of inner choroidal thinning were identified on structural OCT and labeled. Overlap between reduced choriocapillaris flow and structural inner choroidal attenuation was quantified using Jaccard indices. The relationship of reduced flow to pachyvessels was recorded. RESULTS: Twenty-four eyes of 19 patients were identified. All eyes exhibited at least one zone of reduced flow. A total of 146 flow signal attenuation zones were identified. Sixty-two (42%) of 146 zones showed overlap or proximity with structural inner choroidal thinning. The mean Jaccard index per eye was 0.10 (SD = 0.08). Pachyvessels were spatially related to 100 (68%) of 146 zones of flow attenuation. CONCLUSION: Zones of reduced choriocapillaris flow are prevalent in eyes with pachychoroid disease. Approximately 60% of these zones anatomically correlate with pachyvessels. Inner choroidal ischemia seems related to the pathogenesis of pachychoroid diseases. PMID- 29384999 TI - Use of loaded conditioning activities to potentiate middle- and long-distance performance: a narrative review and practical applications. AB - The warm-up is an integral component of a middle- and long-distance athlete's pre performance routine. The use of a loaded conditioning activity (LCA), which elicits a post-activation potentiation (PAP) response to acutely enhance explosive power performance, is well-researched. A similar approach incorporated into the warm-up of a middle- or long-distance athlete potentially provides a novel strategy to augment performance. Mechanisms that underpin a PAP response, relating to acute adjustments within the neuromuscular system, should theoretically improve middle- and long-distance performance via improvements in sub-maximal force-generating ability. Attempts to enhance middle- and long distance related outcomes using a LCA have been used in several recent studies. Results suggest benefits to performance may exist in well-trained middle- and long-distance athletes by including high-intensity resistance training (1-5 repetition maximum) or adding load to the sport skill itself during the latter part of warm-ups. Early stages of performance appear to benefit most, and it is likely that recovery (5-10 min) also plays an important role following a LCA. Future research should consider how priming activity, designed to enhance the V[Combining Dot Above]O2 kinetic response, and a LCA may interact to affect performance, and how different LCA's might benefit various modes and durations of middle- and long-distance exercise. PMID- 29384998 TI - Acute Hypotension After Moderate-Intensity Handgrip Exercise in Hypertensive Elderly People. AB - Souza, LR, Vicente, JB, Melo, GR, Moraes, VC, Olher, RR, Sousa, IC, Peruchi, LH, Neves, RV, Rosa, TS, Ferreira, AP, and Moraes, MR. Acute hypotension after moderate-intensity handgrip exercise in hypertensive elderly people. J Strength Cond Res 32(10): 2971-2977, 2018-Isometric handgrip (IHG) training is effective in reducing blood pressure (BP), but little is known about the occurrence of acute hypotension by postisometric exercise hypotension (PIEH) and the underlying mechanisms. Ten sedentary hypertensive elderly people (7 women and 3 men) individuals, with a mean age of 73.2 +/- 2.2 years and systolic BP (SBP) of 135.1 +/- 6.5, were included; they were hypertensive for 13.2 +/- 3.1 years and were receiving medications. These patients underwent 2 experimental sessions of isometric exercise using a portable hydraulic handgrip dynamometer: (a) sham session with 3% of maximal voluntary isometric contraction (MVIC) and (b) experimental isometric session with 30% MVIC, completing a total of 8 sets of 1 minute contraction and 1-minute rest-pause (overload of work = 51.7 kgf.min). Blood pressure and heart rate were evaluated at rest and 1, 5, 10, 15, 30, 45, and 60 minutes postexercise. Blood lactate (Lac) and salivary nitric oxide (NO) were collected at rest, 0, 30, and 60 minutes postexercise. The SBP presented a reduction as of the tenth minute postexercise to session 30% MVIC (Delta = -14.4 at -18.7 mm Hg, p < 0.05). At 60-minute postexercise, the SBP was 30% lower vs. 3% MVIC (-20.2 mm Hg, p = 0.006). There were no differences for the other cardiovascular parameters and vasoactive substances for both sessions (p > 0.05). These results demonstrated that the IHG exercise with a higher overload of work induced PIEH in hypertensive elderly people, but there was no association with Lac and NO. Therefore, this IHG model with easy execution, quick adherence, short duration, and a portable equipment can be an excellent adjuvant strategy for the control and prevention of hypertension. PMID- 29385000 TI - Effect of Low-Pass Filtering on Isometric Midthigh Pull Kinetics. AB - Dos'Santos, T, Lake, J, Jones, PA, and Comfort, P. Effect of low-pass filtering on isometric midthigh pull kinetics. J Strength Cond Res 32(4): 983-989, 2018-The purpose of this study was to investigate the effect of low-pass filtering on isometric midthigh pull (IMTP) kinetics, including body weight (BW), onset threshold force, time-specific force values (50, 100, 150, and 200 ms), and peak force (PF). Forty IMTP trials from 24 collegiate athletes (age: 21.2 +/- 1.8 years, height: 1.72 +/- 0.09 m, mass: 79.4 +/- 8.2 kg) were analyzed and compared using unfiltered (UF) and low-pass filtered (LPF) (fourth-order Butterworth) with cutoff frequencies of 10 (LPF10) and 100 (LPF100) Hz. Significantly lower (p < 0.001, g = -0.43 to -0.99) onset threshold forces were produced when force data were LPF. This led to significant (p < 0.001, g = 0.05-0.21) underestimations of time-specific force values when LPF10 compared with UF, displaying unacceptable percentage differences (1.2-3.3%) and unacceptable limits of agreement (LOA) ( 25.4 to 100.3 N). Although significantly different (p <= 0.049), trivial (g <= 0.04) and acceptable percentage differences (<=0.8%) and acceptable LOA (-28.0 to 46.2 N) in time-specific force values were observed between UF and LPF100. Statistically significant (p < 0.001), yet trivial (g <= 0.03), and acceptable percentage differences (<=0.7%) and acceptable LOA (-4.7 to 33.9 N) were demonstrated in PF between filtering conditions. No significant differences (p = 1.000) and identical BW values were observed between filtering conditions. Low pass filtering results in underestimations in IMTP kinetics; however, these differences are acceptable between LPF100 and UF but unacceptable between LPF10 and UF (excluding PF). Filtering procedures should be standardized when longitudinally monitoring changes in IMTP force-time characteristics to allow valid comparisons, with analysis of UF data recommended. PMID- 29385001 TI - Upper and Lower Body Power are Strong Predictors for Selection of Male Junior National Volleyball Team Players. AB - The purpose of the present study was to determine whether a battery of anthropometric and lower and upper body strength, speed and power tests predicted selection of young volleyball players for a Junior National Team by expert coaches. Fifty-two male junior volleyball players (14.8+/-0.5 yrs, height: 1.84+/ 0.05 m, body mass: 72.5+/-7.1 kg) took part in a training camp and underwent a selection procedure by expert coaches' of the junior national team. Anthropometric data and fitness tests results were obtained and players were graded on a scale from 0 to 100 on the basis of their performance in a volleyball tournament. Selected players were superior in the majority of measured variables (p<=0.017) and had higher grading scores compared with non-selected players (85.3+/-4.1 vs. 70.5+/-5.6, respectively, p<0.01). The combination of spike jump and reach test (SJR) and 3 kg medicine ball throw velocity (MB3) explained 63.5% of the variance in expert coaches' grading (p<0.001). A multivariate discriminant analysis yielded a significant discriminant function (Wilk's lambda= 0.55, chi= 29.324, p<0.001, eta=0.82). SJR and MB3 were the only variables that contributed to the discriminant function (standardized function coefficients: SJR = 0.68, MB3 = 0.67). Cross-validation results showed that selection was correctly predicted in 14 of the 16 selected players (predictive accuracy: 87.5%) and in 32 of the 36 non-selected players (predictive accuracy: 88.9%). The SJR and MB3 fitness tests can predict a large portion of the variance of expert coaches' grading and successfully discriminate elite young male volleyball players for selection vs. non-selection for a junior national team. This result is very important as performance testing during a selection process may be reduced to only two measurements. PMID- 29385003 TI - Lower Extremity Strength and Recovery Time in Youth Baseball Pitchers: A Pilot Study. AB - The purpose of this study was to investigate the Little League pitching regulations by measuring the change in lower extremity force production after a pitching performance and the subsequent days of rest required for youth baseball pitchers to recover. Bilateral manual muscle testing of the gluteus maximus, hamstrings, gluteus medius, triceps surae, and quadriceps was conducted using a handheld dynamometer. Fifteen healthy, youth baseball pitchers (9.80 +/- 1.08 years) threw a submaximal number of pitches and were tested prior to, immediately after, and for the next four consecutive days. Time in days required per muscle group to return to baseline force production levels were compared to Little League rest guidelines for pitchers. Results indicated that Little League rest requirements did not allow for sufficient recovery of lower extremity strength (p = 0.017). Results suggest that current Little League pitching guidelines provide an inadequate recovery period for youth pitchers, even when pitching a submaximal volume. Little League pitch count regulations and associated rest days may require revisions to avoid having youth athletes pitch while fatigued. PMID- 29385002 TI - Low Second-To-Fourth Digit Ratio Has High Explosive Power? A Prepubertal Study. AB - Hsu, CC, Fong, TH, Chang, HM, Su, B, Chi, CP, Kan, NW, and Hsu, MC. Low second-to fourth digit ratio has high explosive power? A prepubertal study. J Strength Cond Res 32(7): 2091-2095, 2018-A recent study reported that lower limb explosive power had no correlation with the index finger: ring finger (2D:4D) ratio. However, many studies hypothesized that a lower 2D:4D ratio (reflecting a relative higher testosterone exposure) predicts higher physical fitness. The aim of this study was to replicate the study of explosive power and the 2D:4D ratio in a sample of Taiwanese children. A total of 541 Taiwanese prepubertal children (257 girls and 284 boys aged 9-10 years) participated in this study. This study analyzed the relationship between the 2D:4D ratio and explosive power. Explosive power of the lower limbs was assessed using the standing long jump (SLJ) test. The lengths of the second and fourth fingers of the right hand were measured to calculate the 2D:4D ratio. The SLJ length was correlated with the 2D:4D ratios (r = -0.144, p = 0.015) in boys. After controlling for age and the body mass index, this correlation remained significant (r = -0.134, p = 0.024). For girls, 2D:4D ratios were not significantly correlated with SLJ scores. These results indicate that the SLJ distance was negatively correlated with the 2D:4D ratio in boys, but not in girls. These findings might suggest that prenatal testosterone exposure is negatively correlated with the explosive power in men, but not in women. PMID- 29385004 TI - Different Patterns in Muscular Strength and Hypertrophy Adaptations in Untrained Individuals Undergoing Non-Periodized and Periodized Strength Regimens. AB - This study investigated the effects of non-periodized (NP), traditional periodization (TP) and daily undulating (UP) regimens on muscle strength and hypertrophy in untrained individuals. Thirty-three recreationally active males were randomly divided into four groups: NP: n = 8; TP: n = 9; UP: n = 8 and control group (C): n = 8. Experimental groups underwent a 12-week strength training program consisting of two sessions per week. Muscle strength and quadriceps cross-sectional area (QCSA) were assessed at baseline, 6-wk (i.e. mid point) and after 12-wk. All training groups increased squat 1RM from pre to 6-wk mid (NP: 17.02%, TP: 7.7% and UP: 12.9%, p<=0.002) and pre to post 12-wk (NP: 19.5%, TP: 17.9% and UP: 20.4%). TP was the only group that increased squat 1RM from 6-wk mid to 12-wk period (9.4%, p<=0.008). All training groups increased QCSA from pre to 6-wk mid (NP: 5.1%, TP: 4.6% and UP: 5.3%, p<=0.0006) and from pre to post 12-wk (NP: 8.1%, TP: 11.3% and UP: 8.7%). From 6-wk mid to 12-wk period, TP and UP were the only groups that increased QCSA (6.4% and 3.7%, p<=0.02). There were no significant changes for all dependent variables in C group across the time (p>=0.05). In conclusion, our results demonstrated similar training-induced adaptations after 12-wk of NP and periodized regimens. However, our findings suggest that in the latter half of the study (i.e. after the initial 6 weeks), the periodized regimens elicited greater rates of muscular adaptations compared to NP. Strength coaches and practitioners should be aware that periodized regimens might be advantageous at latter stages of training even for untrained individuals. PMID- 29385005 TI - Time Response of Photobiomodulation Therapy on Muscular Fatigue in Humans. AB - The aim of this study was to identify the effects of two different time responses on fatigue of knee extensor. Sixteen male volunteers (26+/-6.0 years 81+/-12 kg, and 181+/-7.4 cm) participated of study. Participants performed the same protocol in five sessions, [control, placebo (placebo applied both 6 hours before and immediately before the test), 6h before + immediately before (PBMT applied both 6 hours before and immediately before the test), 6h before (PBMT applied 6 hours before and placebo applied immediately before the test), and immediately before (placebo applied 6 hours before and PBMT applied immediately before the test)]. PBMT was applied on knee extensor (9 sites; 30 J per site). Maximal isometric voluntary contraction (MIVC) were assessed before and after an isokinetic fatigue (45 flexion-extension concentric at 180 degrees .s), associated with electromyography [root mean square (RMS) and median of frequency (MF)]. For MIVC there was no treatment*time interaction for all variables. Time effect was observed for peak torque (PT), RMS, and MF. While treatment effect was identified for MIVC, which the 6h before + immediately before presented higher PT pre than control (p=0.004) and placebo (p=0.044). The immediately before presented higher PT values than control (p=0.047). Regarding PT post, 6h before + immediately before presented higher values than control (p=0.001) and placebo (p=0.004). PT during MIVC (pre to post) was reduced in 6h before + immediately before treatment (26%) compared to control (33%), placebo (29%), and immediately before (32%). The application of PBMT 6h + immediately before and immediately before exercise protocol is able to reduce the fatigue. PMID- 29385006 TI - Wingate Anaerobic Test Reliability on the Velotron with Ice Hockey Players. AB - This study evaluated the test-retest reliability of the Wingate Anaerobic Test (WAnT) performed on a Velotron electromagnetically-braked cycle ergometer (EE) for power-trained athletes and assessed whether a familiarization trial was necessary to achieve high test-retest reliability. Twenty-one male ice hockey players (age 23.5 +/- 4.7 yrs, mass 86.3 +/- 16.6 kg, height 180.9 +/- 7.4 cm) from a collegiate club team (Club = 10) and a recreational league (Rec = 11) performed three, 30-sec WAnTs within 2 weeks, and with at least 24 hours between visits. Mean power (MP), anaerobic capacity, peak power (PP), anaerobic power, maximum RPM, and fatigue index were assessed. Resistance was 8.5% of the participant's body weight. The effect of time on power output was moderated (p < .001, etap = .24) such that a significant increase was observed after a practice trial, but not between subsequent trials for the Club players; no practice effect was observed among Rec players. Extremely high reliability (ICC1,1) was found between trials after excluding the practice trial (MP = .973, anaerobic capacity = .975, PP = .957, anaerobic power = .890). Club players achieved higher outputs despite no significant differences in body size or age compared to Rec players. Ice hockey players performing the 30-sec WAnT on the Velotron EE had highly reliable data, and using a familiarization trial is recommended to increase reliability and achieve higher power outputs. PMID- 29385007 TI - Alcohol after Resistance Exercise Does not Affect Muscle Power Recovery. AB - The purpose of this study was to investigate the effect of alcohol consumed after heavy eccentric resistance exercise on measures of muscle power. After familiarization and an initial eccentric exercise bout to control for the "repeated-bout effect," ten recreationally resistance-trained men completed two identical heavy eccentric squat bouts (4 sets of 10 repetitions at 110% of concentric 1-repetition maximum) one week apart. Each exercise bout was followed by ingestion of a beverage containing either alcohol (1.09 g ethanol[BULLET OPERATOR]kg fat-free body mass) or no alcohol (placebo; volume of alcohol replaced with water). Vertical jump (VJ) peak power, VJ peak force, VJ jump height, change-of-direction ability (shuttle run), sprint acceleration (sprint test), and muscle soreness were measured before (PRE), 24 hrs after (24H), and 48 hrs after (48H) each eccentric exercise bout. Although the exercise bout resulted in significantly (p < 0.05) decreased VJ peak power at 24H, significantly decreased VJ jump height at 24H, and significantly increased muscle soreness at 24H and 48H, consuming alcohol after the exercise bout did not affect any of the performance outcome measures. When consumed after a non-novel heavy eccentric resistance exercise bout, alcohol did not affect soreness or recovery of muscular power. Practitioners can use this information to advise their athletes with regards to responsible alcohol use after non-novel exercise. Although short-term anaerobic performance does not appear compromised as a result of acute post exercise alcohol ingestion, practitioners and athletes should be aware of potential long-term effects of such alcohol use. PMID- 29385008 TI - Impact of a Community-Based Healthy Lifestyle Program on Individuals With Traumatic Brain Injury. AB - OBJECTIVES: To examine adherence with and effect of an evidence-based healthy lifestyle intervention modified for individuals with traumatic brain injury (TBI). DESIGN: Pre-/postintervention without control. SETTING: Community. PARTICIPANTS: Eighteen individuals with TBI: primarily male (61%), white (67%), with private insurance (50%). Mean age was 45.6 +/- 12.3 years, weight 210 +/- 42.6 lb, and body mass index 31.8 +/- 4.6 (obese category) at baseline. INTERVENTIONS: The primary goal of the Diabetes Prevention Program Group Lifestyle Balance program is 5% to 7% weight loss through increased physical activity and improved dietary behaviors. MAIN OUTCOME MEASURE(S): Adherence (ie, session attendance and self-monitoring of dietary behaviors), physiologic changes (ie, weight loss, blood pressure; waist and arm circumference; and lipid profile), and quality of life (ie, self-reported health, quality of life, and step count). RESULTS: Average participant attendance (85% over 12 months) and self-monitoring (90% over 6 months) were high. Significant decreases were observed in diastolic blood pressure and waist and arm circumference from baseline through 12 months and from baseline to 3 months only for weight and total cholesterol. No significant changes were observed in self-reported health, quality of life, or step count. CONCLUSIONS: Participants demonstrated high adherence with the program, suggesting that individuals with TBI are able to successfully engage in the program and achieve significant weight loss and changes in key physiologic outcomes. PMID- 29385009 TI - Evidence- and Consensus-Based Guidelines for the Management of Communication and Swallowing Disorders Following Pediatric Traumatic Brain Injury. AB - OBJECTIVE: Evidence-based management guidelines for communication and swallowing disorders following pediatric traumatic brain injury (TBI) are scarcely available, potentially resulting in suboptimal outcomes. To improve clinical care of this population, a multidisciplinary guideline development committee was formed to develop evidence-based recommendation (EBR) and consensus-based recommendation (CBR) for the management of speech, language, and swallowing disorders during the first year of recovery. METHODS: A 3-round Delphi survey was completed by the committee to reach agreement (80% consensus) for the CBRs. Systematic review evidence guided development of EBRs, devised using the National Health and Medical Research Council statement form. RESULTS: Altogether, 30 recommendations (5 EBRs and 25 CBRs) were developed to guide management of speech, language, and swallowing disorders, including prediction of these disorders; health team required, optimal timing of assessment; assessment tools; intervention strategies and commencement of treatment; and key information to support parents. CONCLUSION: The developed recommendations provide a basis for the systematic management of communication and swallowing disorders to be refined as new evidence emerges. Key recommendations include screening of children with moderate/severe TBI for these disorders acutely using specified measures. Patients with severe TBI and prolonged ventilation are a particular at-risk group and should be considered for early referral to speech-language pathology to support timely diagnosis and management. No evidence was identified to support an EBR for treatment, highlighting a key area for research. PMID- 29385010 TI - Optimizing Outcome Assessment in Multicenter TBI Trials: Perspectives From TRACK TBI and the TBI Endpoints Development Initiative. AB - Traumatic brain injury (TBI) is a global public health problem that affects the long-term cognitive, physical, and psychological health of patients, while also having a major impact on family and caregivers. In stark contrast to the effective trials that have been conducted in other neurological diseases, nearly 30 studies of interventions employed during acute hospital care for TBI have failed to identify treatments that improve outcome. Many factors may confound the ability to detect true and meaningful treatment effects. One promising area for improving the precision of intervention studies is to optimize the validity of the outcome assessment battery by using well-designed tools and data collection strategies to reduce variability in the outcome data. The Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, conducted at 18 sites across the United States, implemented a multidimensional outcome assessment battery with 22 measures aimed at characterizing TBI outcome up to 1 year postinjury. In parallel, through the TBI Endpoints Development (TED) Initiative, federal agencies and investigators have partnered to identify the most valid, reliable, and sensitive outcome assessments for TBI. Here, we present lessons learned from the TRACK-TBI and TED initiatives aimed at optimizing the validity of outcome assessment in TBI. PMID- 29385011 TI - Early Predictors for Long-Term Functional Outcome After Mild Traumatic Brain Injury in Frail Elderly Patients. AB - OBJECTIVE: To identify the effect of frailty and early postinjury measures on the long-term outcome after mild traumatic brain injury in elderly patients. SETTING: Patients admitted to 3 Dutch hospitals designated as level 1 trauma centers. PARTICIPANTS: The elderly (>=60 years) with mild traumatic brain injury (N = 161). DESIGN: A prospective observational cohort study. MAIN MEASURES: Posttraumatic complaints and the Hospital Anxiety and Depression Scale determined 2 weeks postinjury; the Glasgow Outcome Scale Extended and Groningen frailty indicator determined 1 to 3 years postinjury. RESULTS: A total of 102 nonfrail (63%) and 59 frail elderly (37%) patients, mean age of 70.8 (6.3) years were included. Most patients (54%; 72% nonfrail and 24% frail) recovered completely 1 to 3 years postinjury. Two weeks postinjury, 81% had posttraumatic complaints (83% frail and 80% nonfrail elderly), and 30% showed emotional distress (50% frail and 20% nonfrail). Frailty (odds ratio, 2.1; 95% confidence interval, 1.59 2.77) and presence of early complaints (odds ratio, 1.13; 95% confidence interval, 1.01-1.27) (Nagelkerke R = 46%) were found to predict long-term outcome, whereas age was not a significant predictor. CONCLUSION: The frail elderly had worse long-term outcome, and early complaints were found to be a stronger predictor of unfavorable outcome than age. Understanding the implications of frailty on outcome could help clinicians recognize patients at risk of a poor outcome and allocate care more efficiently. PMID- 29385012 TI - Mortality and Associated Morbidities Following Traumatic Brain Injury in Older Medicare Statin Users. AB - OBJECTIVE: To assess the relationship between posttraumatic brain injury statin use and (1) mortality and (2) the incidence of associated morbidities, including stroke, depression, and Alzheimer's disease and related dementias following injury. SETTING AND PARTICIPANTS: Nested cohort of all Medicare beneficiaries 65 years of age and older who survived a traumatic brain injury (TBI) hospitalization during 2006 through 2010. The final sample comprised 100 515 beneficiaries. DESIGN: Retrospective cohort study of older Medicare beneficiaries. Relative risks (RR) and 95% confidence interval (CI) were obtained using discrete time analysis and generalized estimating equations. MEASURES: The exposure of interest included monthly atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin use. Outcomes of interest included mortality, stroke, depression, and Alzheimer's disease and related dementias. RESULTS: Statin use of any kind was associated with decreased mortality following TBI hospitalization discharge. Any statin use was also associated with a decrease in any stroke (RR, 0.86; 95% confidence intervals (CI), 0.81-0.91), depression (RR, 0.85; 95% CI, 0.79-0.90), and Alzheimer's disease and related dementias (RR, 0.77; 95% CI, 0.73-0.81). CONCLUSION: These findings provide valuable information for clinicians treating older adults with TBI as clinicians can consider, when appropriate, atorvastatin and simvastatin to older adults with TBI in order to decrease mortality and associated morbidities. PMID- 29385013 TI - Investigating the Model of Community-Based Case Management in the New South Wales Brain Injury Rehabilitation Program: A Prospective Multicenter Study. AB - OBJECTIVE: To investigate a model of community-based case management (CM). SETTING: New South Wales (NSW) Brain Injury Rehabilitation Program (BIRP). PARTICIPANTS: All clinicians (N = 72) providing CM within 14 BIRP community rehabilitation teams. DESIGN: A prospective, multicenter study. MAIN MEASURES: A purpose-designed survey. METHODS: Participants from the 12 adult and 2 pediatric services (8 located in metropolitan areas, 6 in rural areas) completed a 3-part survey investigating their organizational context, clinical approach, and CM interventions. Between-groups analyses explored differences among individual services, as well as differences based on age (adult vs pediatric) and location (metropolitan vs rural). RESULTS: All services provided a direct service model of CM. The underlying principles were uniform across services (more direct than indirect service provision; with more client-related than administrative-related tasks; more holistic than service-led in defining client needs; with decision making equally directed by staff and clients; and undertaking a more comprehensive than minimalist range of tasks). CM interventions included the provision of individual support, family support, advocacy, and community development alongside assessment, monitoring, referral, and liaison tasks. There were little differences in practice based on age or location. CONCLUSION: The NSW BIRP has drawn upon the results to produce a model of service for CM. PMID- 29385015 TI - The Effect of Admission Functional Independence on Early Recovery in Pediatric Traumatic and Nontraumatic Brain Injury. AB - OBJECTIVE: To examine functional independence at admission as a predictor of outcomes during an initial inpatient hospitalization for a pediatric brain injury. PARTICIPANTS: A total of 531 pediatric inpatients with traumatic (n = 298) or nontraumatic (n = 233) brain injuries. DESIGN: Retrospective analysis of data extracted from the Uniform Data System for Medical Rehabilitation. MAIN MEASURE: The Functional Independence Measure for Children, a measure of self care, mobility, and cognitive independence. RESULTS: Logistic regression analyses indicated that children with traumatic brain injury showed greater odds of making large functional gains in comparison with children with nontraumatic brain injury. For both groups, children entering rehabilitation with a moderate level of functional independence had the highest probability of making large gains. Children with a nontraumatic brain injury entering treatment with a high level of functioning made greater gains than those entering with low functioning. The opposite trend emerged for children with traumatic injuries. CONCLUSIONS: Level of functioning at admission may be a useful predictor of progress during an inpatient stay for youth with brain injuries. Children with nontraumatic brain injury entering treatment with low functioning are expected to make slower progress during hospitalization. PMID- 29385014 TI - A Latent Content Analysis of Barriers and Supports to Healthcare: Perspectives From Caregivers of Service Members and Veterans With Military-Related Traumatic Brain Injury. AB - OBJECTIVE: To identify barriers and supports that caregivers of individuals with military-related traumatic brain injury (TBI) encounter when navigating the military healthcare system; this information will be used as the foundation of a new patient-reported outcome measure. SETTING: Community. PARTICIPANTS: Forty five caregivers of service members and veterans (SMV) who sustained a medically documented mild, moderate, severe, or penetrating TBI. DESIGN: Latent content analysis. MAIN MEASURES: Nine focus group discussions of barriers and supports to navigating the military healthcare system and community resources. RESULTS: Latent content analysis indicated that caregivers discussed barriers (66%) and supports (34%) to obtaining care within the military healthcare system and the community. Caregivers most frequently discussed SMVs' interactions with healthcare, their own interactions with healthcare, family care, and community organizations. CONCLUSIONS: Caregivers confront numerous challenges while pursuing healthcare services. Although much of the discussion focused on barriers and perceived unmet needs within the military healthcare system, caregivers also recognized supports within the military healthcare system and general community. Increased attention to accessibility and quality of services, as well as reducing financial burden, can lead to improved health-related quality of life for caregivers and their SMVs. PMID- 29385017 TI - Diffusion Imaging Findings in US Service Members With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder. AB - OBJECTIVE: Use diffusion tensor imaging to investigate white matter microstructure attributable to mild TBI (mTBI) and/or posttraumatic stress disorder (PTSD). PARTICIPANTS: Twenty-seven individuals with mTBI only, 16 with PTSD only, 42 with mTBI + PTSD, and 43 service members who sustained orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Clinical diffusion tensor imaging sequence to assess fractional anisotropy, mean, axial, and radial diffusivity within selected regions of interest. RESULTS: Corrected analyses revealed a pattern of lower white matter integrity in the PTSD group for several scalar metrics. Regions affected included primarily right hemisphere areas of the internal capsule. These differences associated with the PTSD only cohort were observed in relation to all 3 comparison groups, while the mTBI + PTSD group did not exhibit any notable pattern of white matter abnormalities. CONCLUSION: Results suggest that lower resolution scan sequences are sensitive to post-acute abnormalities associated with PTSD, particularly in the right hemisphere. In addition, these findings suggest that ongoing PTSD symptoms are associated with differences in white matter diffusion that are more readily detected in a clinical scan sequence than mTBI abnormalities. Future studies are needed to prospectively assess service members prior to onset of injury to verify this pattern of results. PMID- 29385016 TI - Fatigue Is Associated With Global and Regional Thalamic Morphometry in Veterans With a History of Mild Traumatic Brain Injury. AB - OBJECTIVE: Fatigue is a complex, multidimensional phenomenon that commonly occurs following traumatic brain injury (TBI). The thalamus-a structure vulnerable to both primary and secondary injuries in TBI-is thought to play a pivotal role in the manifestation of fatigue. We explored how neuroimaging markers of local and global thalamic morphometry relate to the subjective experience of fatigue post TBI. METHODS: Sixty-three Veterans with a history of mild TBI underwent structural magnetic resonance imaging and completed questionnaires related to fatigue and psychiatric symptoms. FMRIB's Software (FSL) was utilized to obtain whole brain and thalamic volume estimates, as well as to perform regional thalamic morphometry analyses. RESULTS: Independent of age, sex, intracranial volume, posttraumatic stress disorder, and depressive symptoms, greater levels of self-reported fatigue were significantly associated with decreased right (P = .026) and left (P = .046) thalamic volumes. Regional morphometry analyses revealed that fatigue was significantly associated with reductions in the anterior and dorsomedial aspects of the right thalamic body (P < .05). Similar trends were observed for the left thalamic body (P < .10). CONCLUSIONS: Both global and regional thalamic morphometric changes are associated with the subjective experience of fatigue in Veterans with a history of mild TBI. These findings support a theory in which disruption of thalamocorticostriatal circuitry may result in the manifestation of fatigue in individuals with a history of neurotrauma. PMID- 29385018 TI - Quantitative Volumetric Imaging and Clinical Outcome Characterization of Symptomatic Concussion in 10- to 14-Year-Old Adolescent Athletes. AB - OBJECTIVE: Prior work suggests that younger athletes may be more vulnerable to postconcussive syndrome. We investigated measures of clinical outcome and quantitative volumetric imaging in 10- to 14-year-old adolescent athletes to better understand the impact of concussion on this younger population. SETTING: Outpatient clinics. PARTICIPANTS: Ten- to 14-year-old symptomatic pediatric sports concussion patients and typically developing active controls. DESIGN: Prospective, observational multiclinic study. MAIN MEASURES: Demographics, magnetic resonance imaging, clinical assessments (neurocognitive function, postconcussive symptoms, mental health symptoms, quality of life). RESULTS: Neuropsychological performance was comparable between groups while symptoms of mental health were discriminating and comprised the top regression model describing factors related to overall health behavior impairment. Concussion patients had smaller total brain volume as well as total intracranial volume in comparison with controls even though there was no difference on measures of natural development (age, height, weight, education, gender, and handedness). CONCLUSIONS: Findings indicate that 10- to 14-year-old concussion patients symptomatic at 1 month more likely exhibit mental health symptoms impairing health behavior than cognitive dysfunction. There may be a vulnerability for those with smaller brain volumes at the time of the exposure. The study provides new data to support further investigation into risk factors for prolonged symptoms in this younger athlete population. PMID- 29385019 TI - Predicting the Trajectory of Participation After Traumatic Brain Injury: A Longitudinal Analysis. AB - OBJECTIVE: To identify factors that predict trajectories of participation over the first 5 years after moderate to severe traumatic brain injury (TBI). SETTING: TBI Model System Programs. PARTICIPANTS: Community-dwelling individuals with TBI, 16 years of age or older (n = 1947). DESIGN: Secondary analysis of a prospective, nonrandomly sampled, longitudinal data registry. MAIN MEASURES: Participation Assessment with Recombined Tools-Objective (PART-O). RESULTS: Age at injury and FIM Motor score predicted trajectory of participation over the first 5 years after moderate to severe TBI. Older age predicted generally worse participation overall as well as progressively worsening participation over time. Higher FIM Motor raised the predicted participation values, although it reduced the rate of improvement in participation scores over time. FIM Cognitive scores, race, depression, years of education, and living setting did not predict trajectory but did significantly influence participation consistently at all time points. CONCLUSION: The trajectories of participation over the first 5 years after TBI can be predicted by age at injury and FIM Motor scores. These findings may enhance the ability of rehabilitation professionals to identify individuals at risk for poor participation after TBI and develop targeted interventions for optimizing involvement in life activities. PMID- 29385020 TI - Persistent Symptoms and Objectively Measured Balance Performance Among OEF/OIF Veterans With Remote Mild Traumatic Brain Injury. AB - OBJECTIVE: To investigate linear relationships between dizziness, fatigue, and depression and posttraumatic stress disorder (PTSD) and objectively measured balance performance in Veterans with remote mild traumatic brain injury (mTBI). SETTING: Academic laboratory; Veterans Affairs Medical Center. PARTICIPANTS: Thirty Veterans (28 men) who served in Iraq/Afghanistan and whose most recent mTBI was sustained more than 6 months prior to enrollment. DESIGN: Cross sectional, observational trial. MAIN MEASURES: The Computerized Dynamic Posturography-Sensory Organization Test (CDP-SOT) and the Community Balance and Mobility (CB&M) scale measured balance. Dizziness (Dizziness Handicap Inventory), fatigue (Modified Fatigue Impact Scale), depression-related symptoms (Beck Depression Inventory-II), and PTSD-related symptoms (PTSD Checklist 5) were also measured. RESULTS: Objectively measured balance, CDP-SOT composite, was impaired (mean score of 67.9). CDP-SOT scores correlated with dizziness (r = -0.53; P = .002), fatigue (r = -0.38; P = .03), depression (r = -0.55; P = .001), and PTSD symptoms (r = -0.53; P = .002). Dizziness, time since most recent mTBI, and PTSD symptoms and depression combined explained significant variability in CDP-SOT scores (R = 0.46; P = .003), as did fatigue depression and PTSD symptoms (R = 0.33; P = .01). CONCLUSIONS: Impaired balance was identified among the cohort. Findings suggest that dizziness, fatigue, depression and PTSD, and time since most recent mTBI may influence balance performance. Additional research is needed to identify the potentially interrelated natural histories of these co-occurring symptoms. PMID- 29385021 TI - PDE4-Mediated cAMP Signalling. AB - cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart. In the cardiac myocyte, cAMP activates PKA, which phosphorylates a small subset of mostly sarcoplasmic substrate proteins that drive beta-adrenergic enhancement of cardiac function. The phosphorylation of these substrates, many of which are involved in cardiac excitation-contraction coupling, has been shown to be tightly regulated by highly localised pools of individual PDE4 isoforms. The spatial and temporal regulation of cardiac signalling is made possible by the formation of macromolecular "signalosomes", which often include a cAMP effector, such as PKA, its substrate, PDE4 and an anchoring protein such as an AKAP. Studies described in the present review highlight the importance of this relationship for individual cardiac PKA substrates and we provide an overview of how this signalling paradigm is coordinated to promote efficient adrenergic enhancement of cardiac function. The role of PDE4 also extends to the vascular endothelium, where it regulates vascular permeability and barrier function. In this distinct location, PDE4 interacts with adherens junctions to regulate their stability. These highly specific, non-redundant roles for PDE4 isoforms have far reaching therapeutic potential. PDE inhibitors in the clinic have been plagued with problems due to the active site-directed nature of the compounds which concomitantly attenuate PDE activity in all highly localised "signalosomes". PMID- 29385023 TI - Remembering Professor Benito Casu (1927-2016). AB - Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years. PMID- 29385022 TI - A Lateral Flow Strip Based Aptasensor for Detection of Ochratoxin A in Corn Samples. AB - Ochratoxin A (OTA) is a mycotoxin identified as a contaminant in grains and wine throughout the world, and convenient, rapid and sensitive detection methods for OTA have been a long-felt need for food safety monitoring. Herein, we presented a new competitive format based lateral flow strip fluorescent aptasensor for one step determination of OTA in corn samples. Briefly, biotin-cDNA was immobilized on the surface of a nitrocellulose filter on the test line. Without OTA, Cy5 labeled aptamer combined with complementary strands formed a stable double helix. In the presence of OTA, however, the Cy5-aptamer/OTA complexes were generated, and therefore less free aptamer was captured in the test zone, leading to an obvious decrease in fluorescent signals on the test line. The test strip showed an excellent linear relationship in the range from 1 ng.mL-1 to 1000 ng.mL-1 with the LOD of 0.40 ng.mL-1, IC15 value of 3.46 ng.mL-1 and recoveries from 96.4% to 104.67% in spiked corn samples. Thus, the strip sensor developed in this study is an acceptable alternative for rapid detection of the OTA level in grain samples. PMID- 29385025 TI - Looking Forward to the Future of Heparin: New Sources, Developments and Applications. AB - The seven reviews and the eleven articles in this special issue provide an updated survey of recent research and developments in the ever-growing field of heparin, along with low molecular weight heparins (LMWHs) and glycosaminoglycans (GAGs). PMID- 29385026 TI - Effect of Young's Modulus and Surface Roughness on the Inter-Particle Friction of Granular Materials. AB - In the study we experimentally examine the influence of elastic properties and surface morphology on the inter-particle friction of natural soil grains. The experiments are conducted with a custom-built micromechanical apparatus and the database is enhanced by testing engineered-reference grains. Naturally-occurring geological materials are characterized by a wide spectrum of mechanical properties (e.g., Young's modulus) and surface morphology (e.g., roughness), whereas engineered grains have much more consistent characteristics. Comparing to engineered materials, geological materials are found to display more pronounced initial plastic behavior during compression. Under the low normal load range applied in the study, between 1 and 5 N, we found that the frictional force is linearly correlated with the applied normal load, but we acknowledge that the data are found more scattered for natural soil grains, especially for rough and weathered materials which have inconsistent characteristics. The inter-particle coefficient of friction is found to be inversely correlated with the Young's modulus and the surface roughness. These findings are important in geophysical and petroleum engineering contents, since a number of applications, such as landslides and granular flows, hydraulic fracturing using proppants, and weathering process of cliffs, among others, can be simulated using discrete numerical methods. These methods employ contact mechanics properties at the grain scale and the inter-particle friction is one of these critical components. It is stressed in our study that friction is well correlated with the elastic and morphological characteristics of the grains. PMID- 29385024 TI - Use of an Integrated Research-Practice Partnership to Improve Outcomes of a Community-Based Strength-Training Program for Older Adults: Reach and Effect of Lifelong Improvements through Fitness Together (LIFT). AB - Only 17% of older adults meet the recommendations for two days of full body strength training that is associated with improved functional fitness; reduced risk of falls; and reduced morbidity and mortality rates. Community-based interventions are recommended as they provide supportive infrastructure to reach older adults and impact strength training behaviors. Scalability and sustainability of these interventions is directly linked with setting-level buy in. Adapting an intervention through an integrated research-practice partnership may improve individual and setting-level outcomes. The purpose of this study was to evaluate the initial reach and effect of a locally adapted, health educator led strength-training intervention; Lifelong Improvements through Fitness Together (LIFT). LIFT was compared to an evidence-based exercise program, Stay Strong; Stay Healthy (SSSH). Intervention dose and mode were the same for LIFT and SSSH, but LIFT included behavioral change strategies. Older adult functional fitness was assessed before and after the 8-week strength training intervention. Health educators who delivered LIFT and SSSH were able to reach 80 and 33 participants, respectively. Participants in LIFT were able to significantly improve in all functional fitness measures whereas SSSH participants were only able to significantly improve in 5 of the 7 functional fitness measures. In conclusion, this study provides preliminary evidence that the locally adapted program reached more individuals and had improvements in functional fitness. PMID- 29385027 TI - Polymeric Micelle of A3B-Type Lactosome as a Vehicle for Targeting Meningeal Dissemination. AB - Polymeric micelle of the A3B-type lactosome comprising (poly(sarcosine))3-b poly(l-lactic acid) was labeled with 111In. The 111In-labeled A3B-type lactosome was administered to the model mice bearing meningeal dissemination and bone metastasis at mandible. With single-photon emission computed tomography (SPECT) imaging, the meningeal dissemination was identified successfully by 111In-labeled A3B-type lactosome, which was superior to 201TlCl in regard of the imaging contrast. The 111In-labeled A3B-type lactosome was also potential in imaging selectively of bone metastasis at mandible, whilst a nonspecific imaging of the whole bone was obtained by the SPECT imaging using 99mTc-HMDP. The polymeric micelle of the A3B-type lactosome was therefore found to be effective as a vehicle of 111In to be targeted to meningeal dissemination and bone metastasis. PMID- 29385028 TI - The Electronic Properties of O-Doped Pure and Sulfur Vacancy-Defect Monolayer WS2: A First-Principles Study. AB - Based on the density functional theory (DFT), the electronic properties of O doped pure and sulfur vacancy-defect monolayer WS2 are investigated by using the first-principles method. For the O-doped pure monolayer WS2, four sizes (2 * 2 * 1, 3 * 3 * 1, 4 * 4 * 1 and 5 * 5 * 1) of supercell are discussed to probe the effects of O doping concentration on the electronic structure. For the 2 * 2 * 1 supercell with 12.5% O doping concentration, the band gap of O-doped pure WS2 is reduced by 8.9% displaying an indirect band gap. The band gaps in 3 * 3 * 1 and 4 * 4 * 1 supercells are both opened to some extent, respectively, for 5.55% and 3.13% O doping concentrations, while the band gap in 5 * 5 * 1 supercell with 2.0% O doping concentration is quite close to that of the pure monolayer WS2. Then, two typical point defects, including sulfur single-vacancy (VS) and sulfur divacancy (V2S), are introduced to probe the influences of O doping on the electronic properties of WS2 monolayers. The observations from DFT calculations show that O doping can broaden the band gap of monolayer WS2 with VS defect to a certain degree, but weaken the band gap of monolayer WS2 with V2S defect. Doping O element into either pure or sulfur vacancy-defect monolayer WS2 cannot change their band gaps significantly, however, it still can be regarded as a potential method to slightly tune the electronic properties of monolayer WS2. PMID- 29385029 TI - Comparison of Compressive Stress-Relaxation Behavior in Osteoarthritic (ICRS Graded) Human Articular Cartilage. AB - Osteoarthritis (OA) is a common joint disorder found mostly in elderly people. The role of mechanical behavior in the progression of OA is complex and remains unclear. The stress-relaxation behavior of human articular cartilage in clinically defined osteoarthritic stages may have importance in diagnosis and prognosis of OA. In this study we investigated differences in the biomechanical responses among human cartilage of ICRS grades I, II and III using polymer dynamics theory. We collected 24 explants of human articular cartilage (eight each of ICRS grade I, II and III) and acquired stress-relaxation data applying a continuous load on the articular surface of each cartilage explant for 1180 s. We observed a significant decrease in Young's modulus, stress-relaxation time, and stretching exponent in advanced stages of OA (ICRS grade III). The stretch exponential model speculated that significant loss in hyaluronic acid polymer might be the reason for the loss of proteoglycan in advanced OA. This work encourages further biomechanical modelling of osteoarthritic cartilage utilizing these data as input parameters to enhance the fidelity of computational models aimed at revealing how mechanical behaviors play a role in pathogenesis of OA. PMID- 29385030 TI - Classification of Partial Discharge Signals by Combining Adaptive Local Iterative Filtering and Entropy Features. AB - Electromagnetic Interference (EMI) is a technique for capturing Partial Discharge (PD) signals in High-Voltage (HV) power plant apparatus. EMI signals can be non stationary which makes their analysis difficult, particularly for pattern recognition applications. This paper elaborates upon a previously developed software condition-monitoring model for improved EMI events classification based on time-frequency signal decomposition and entropy features. The idea of the proposed method is to map multiple discharge source signals captured by EMI and labelled by experts, including PD, from the time domain to a feature space, which aids in the interpretation of subsequent fault information. Here, instead of using only one permutation entropy measure, a more robust measure, called Dispersion Entropy (DE), is added to the feature vector. Multi-Class Support Vector Machine (MCSVM) methods are utilized for classification of the different discharge sources. Results show an improved classification accuracy compared to previously proposed methods. This yields to a successful development of an expert's knowledge-based intelligent system. Since this method is demonstrated to be successful with real field data, it brings the benefit of possible real-world application for EMI condition monitoring. PMID- 29385031 TI - Near-Patient Sampling to Assist Infection Control-A Case Report and Discussion. AB - Air sampling as an aid to infection control is still in an experimental stage, as there is no consensus about which air samplers and pathogen detection methods should be used, and what thresholds of specific pathogens in specific exposed populations (staff, patients, or visitors) constitutes a true clinical risk. This case report used a button sampler, worn or held by staff or left free-standing in a fixed location, for environmental sampling around a child who was chronically infected by a respiratory adenovirus, to determine whether there was any risk of secondary adenovirus infection to the staff managing the patient. Despite multiple air samples taken on difference days, coinciding with high levels of adenovirus detectable in the child's nasopharyngeal aspirates (NPAs), none of the air samples contained any detectable adenovirus DNA using a clinically validated diagnostic polymerase chain reaction (PCR) assay. Although highly sensitive, in house PCR assays have been developed to detect airborne pathogen RNA/DNA, it is still unclear what level of specific pathogen RNA/DNA constitutes a true clinical risk. In this case, the absence of detectable airborne adenovirus DNA using a conventional diagnostic assay removed the requirement for staff to wear surgical masks and face visors when they entered the child's room. No subsequent staff infections or outbreaks of adenovirus have so far been identified. PMID- 29385032 TI - Disilicate Dental Ceramic Surface Preparation by 1070 nm Fiber Laser: Thermal and Ultrastructural Analysis. AB - Lithium disilicate dental ceramic bonding, realized by using different resins, is strictly dependent on micro-mechanical retention and chemical adhesion. The aim of this in vitro study was to investigate the capability of a 1070 nm fiber laser for their surface treatment. Samples were irradiated by a pulsed fiber laser at 1070 nm with different parameters (peak power of 5, 7.5 and 10 kW, repetition rate (RR) 20 kHz, speed of 10 and 50 mm/s, and total energy density from 1.3 to 27 kW/cm2) and the thermal elevation during the experiment was recorded by a fiber Bragg grating (FBG) temperature sensor. Subsequently, the surface modifications were analyzed by optical microscope, scanning electron microscope (SEM), and energy dispersive X-ray spectroscopy (EDS). With a peak power of 5 kW, RR of 20 kHz, and speed of 50 mm/s, the microscopic observation of the irradiated surface showed increased roughness with small areas of melting and carbonization. EDS analysis revealed that, with these parameters, there are no evident differences between laser-processed samples and controls. Thermal elevation during laser irradiation ranged between 5 degrees C and 9 degrees C. A 1070 nm fiber laser can be considered as a good device to increase the adhesion of lithium disilicate ceramics when optimum parameters are considered. PMID- 29385033 TI - Changes in the Distribution of Cocaine- and Amphetamine-Regulated Transcript Containing Neural Structures in the Human Colon Affected by the Neoplastic Process. AB - The present study analysed changes in the distribution pattern of cocaine- and amphetamine-regulated transcript (CART) in the enteric nervous system (ENS) of the human colon challenged by adenocarcinoma invasion, using the double-labelling immunofluorescence technique. In control specimens, CART immunoreactivity was found in neurons of all studied plexuses, representing 30.1 +/- 4.1%, 12.9 +/- 5.2%, and 4.1 +/- 1.3% of all neurons forming the myenteric plexus (MP), outer submucous plexus (OSP), and inner submucous plexus (ISP), respectively. Tumour growth into the colon wall caused an increase in the relative frequency of CART like immunoreactive (CART-LI) neurons in enteric plexuses located in the vicinity of the infiltrating neoplasm (to 36.1 +/- 6.7%, 32.7 +/- 7.3% and 12.1 +/- 3.8% of all neurons in MP, OSP and ISP, respectively). The density of CART-LI nerves within particular layers of the intestinal wall did not differ between control and adenocarcinoma-affected areas of the human colon. This is the first detailed description of the CART distribution pattern within the ENS during the adenocarcinoma invasion of the human colon wall. The obtained results suggest that CART probably acts as a neuroprotective factor and may be involved in neuronal plasticity evoked by the progression of a neoplastic process. PMID- 29385034 TI - Liver Fat Scores Moderately Reflect Interventional Changes in Liver Fat Content by a Low-Fat Diet but Not by a Low-Carb Diet. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder all over the world, mainly being associated with a sedentary lifestyle, adiposity, and nutrient imbalance. The increasing prevalence of NAFLD accommodates similar developments for type 2 diabetes and diabetes-related comorbidities and complications. Therefore, early detection of NAFLD is an utmost necessity. Potentially helpful tools for the prediction of NAFLD are liver fat indices. The fatty liver index (FLI) and the NAFLD-liver fat score (NAFLD-LFS) have been recently introduced for this aim. However, both indices have been shown to correlate with liver fat status, but there is neither sufficient data on the longitudinal representation of liver fat change, nor proof of a diet-independent correlation between actual liver fat change and change of index values. While few data sets on low-fat diets have been published recently, low-carb diets have not been yet assessed in this context. AIM: We aim to provide such data from a highly effective short-term intervention to reduce liver fat, comparing a low-fat and a low-carb diet in subjects with prediabetes. METHODS: Anthropometric measurements, magnetic resonance (MR)-based intrahepatic lipid (IHL) content, and several serum markers for liver damage have been collected in 140 subjects, completing the diet phase in this trial. Area-under-the-responder-operator-curves (AUROC) calculations as well as cross-sectional and longitudinal Spearman correlations were used. RESULTS: Both FLI and NAFLD-LFS predict liver fat with moderate accuracy at baseline (AUROC 0.775-0.786). These results are supported by correlation analyses. Changes in liver fat, achieved by the dietary intervention, correlate moderately with changes in FLI and NAFLD-LFS in the low-fat diet, but not in the low-carb diet. A correlation analysis between change of actual IHL content and change of single elements of the liver fat indices revealed diet specific moderate to strong correlations between DeltaIHL and changes of measures of obesity, DeltaTG, and DeltaALT (all low-fat, only) and between DeltaIHL and DeltaGGT (low-carb, only). With exception for a stronger decrease of triglycerides (TG) levels in the low-carb diet, there is no statistically significant difference in the effect of the diets on anthropometric or serum based score parameters. CONCLUSION: While liver fat indices have proved useful in the early detection of NAFLD and may serve as a cost-saving substitute for expensive MR measurements in the cross-sectional evaluation of liver status, their capability to represent interventional changes of liver fat content appears to be diet-specific and lacks accuracy. Liver fat reduction by low-fat diets can be monitored with moderate precision, while low-carb diets require different measuring techniques to demonstrate the same dietary effect. PMID- 29385035 TI - Biodiversity within Melissa officinalis: Variability of Bioactive Compounds in a Cultivated Collection. AB - Phytochemical characters were evaluated in a five-year-old lemon balm collection consisting of 15 and 13 subspecies officinalis and altissima accessions, respectively. Stems were lower in essential oil than leaves. First cut leaves (June) gave more oil than those of the second cut (August). Subspecies officinalis plants had leaf oils rich in geranial, neral and citronellal in various proportions in the first cut. However, in the second cut the oils from all accessions appeared very similar with 80-90% geranial plus neral. Leaf oils of subsp. altissima contained sesquiterpenes (beta-caryophyllene, caryophyllene oxide, germacrene D) and also further monoterpenes in the second cut. Leaves had higher rosmarinic acid (RA) contents than stems. More RA was in subsp. officinalis than subsp. altissima leaves. First cut leaves were richer in RA than those from second cut. Total phenolics and antioxidant parameters showed that lemon balm is a valuable source of plant antioxidants. PMID- 29385036 TI - Dietary Patterns Associated with Lower 10-Year Atherosclerotic Cardiovascular Disease Risk among Urban African-American and White Adults Consuming Western Diets. AB - The study's objective was to determine whether variations in the 2013 American College of Cardiology/American Heart Association 10-year risk for atherosclerotic cardiovascular disease (ASCVD) were associated with differences in food consumption and diet quality. Findings from the baseline wave of Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study 2004-2009, revealed participants consumed a Western diet. Diet quality measures, specifically the Healthy Eating Index (HEI)-2010, Dietary Approaches to Stop Hypertension (DASH) diet and the Mean Adequacy Ratio (MAR), based on two 24-h recalls collected during follow-up HANDLS studies from 2009-2013, were used. Reported foods were assigned to 27 groups. In this cross-sectional analysis, the participants (n = 2140) were categorized into tertiles based on their 10-year ASCVD risk. Lower and upper tertiles were used to determine significantly different consumption rates among the food groups. Ten groups were used in hierarchical case clustering to generate four dietary patterns (DPs) based on group energy contribution. The DP with the highest HEI-2010 score included sandwiches along with vegetables and cheese/yogurt. This DP, along with the pizza/sandwiches DP, had significantly higher DASH and MAR scores and a lower 10 year ASCVD risk, compared to the remaining two DPs-meats/sandwiches and sandwiches/bakery products; thus, Western dietary patterns were associated with different levels of ASCVD 10-year risk. PMID- 29385038 TI - Mixtures of Lipophilic Phycotoxins: Exposure Data and Toxicological Assessment. AB - Lipophilic phycotoxins are secondary metabolites produced by phytoplanktonic species. They accumulate in filter-feeding shellfish and can cause human intoxication. Regulatory limits have been set for individual toxins, and the toxicological features are well characterized for some of them. However, phycotoxin contamination is often a co-exposure phenomenon, and toxicological data regarding mixtures effects are very scarce. Moreover, the type and occurrence of phycotoxins can greatly vary from one region to another. This review aims at summarizing the knowledge on (i) multi-toxin occurrence by a comprehensive literature review and (ii) the toxicological assessment of mixture effects. A total of 79 publications was selected for co-exposure evaluation, and 44 of them were suitable for toxin ratio calculations. The main toxin mixtures featured okadaic acid in combination with pectenotoxin-2 or yessotoxin. Only a few toxicity studies dealing with co-exposure were published. In vivo studies did not report particular mixture effects, whereas in vitro studies showed synergistic or antagonistic effects. Based on the combinations that are the most reported, further investigations on mixture effects must be carried out. PMID- 29385037 TI - Cell Penetrating Peptides as Molecular Carriers for Anti-Cancer Agents. AB - Cell membranes with their selective permeability play important functions in the tight control of molecular exchanges between the cytosol and the extracellular environment as the intracellular membranes do within the internal compartments. For this reason the plasma membranes often represent a challenging obstacle to the intracellular delivery of many anti-cancer molecules. The active transport of drugs through such barrier often requires specific carriers able to cross the lipid bilayer. Cell penetrating peptides (CPPs) are generally 5-30 amino acids long which, for their ability to cross cell membranes, are widely used to deliver proteins, plasmid DNA, RNA, oligonucleotides, liposomes and anti-cancer drugs inside the cells. In this review, we describe the several types of CPPs, the chemical modifications to improve their cellular uptake, the different mechanisms to cross cell membranes and their biological properties upon conjugation with specific molecules. Special emphasis has been given to those with promising application in cancer therapy. PMID- 29385041 TI - Microwave-Hydrothermal Treated Grape Peel as an Efficient Biosorbent for Methylene Blue Removal. AB - Biosorption using agricultural wastes has been proven as a low cost and efficient way for wastewater treatment. Herein, grape peel treated by microwave- and conventional-hydrothermal processes was used as low cost biosorbent to remove methylene blue (MB) from aqueous solutions. The adsorption parameters including the initial pH value, dosage of biosorbents, contact time, and initial MB concentration were investigated to find the optimum adsorption conditions. The biosorbent obtained by microwave-hydrothermal treatment only for 3 min at 180 degrees C (microwave-hydrothermal treated grape peel, MGP) showed faster kinetics and higher adsorption capability than that produced by a conventional hydrothermal process (hydrothermal treated grape peel, HGP) with a duration time of 16 h. The maximum adsorption capability of MGP under the optimum conditions (pH = 11, a dosage of 2.50 g/L) as determined with the Langmuir model reached 215.7 mg/g, which was among the best values achieved so far on biosorbents. These results demonstrated that the grape peel treated by a quick microwave hydrothermal process can be a very promising low cost and efficient biosorbent for organic dye removal from aqueous solutions. PMID- 29385039 TI - Glyoxalases in Urological Malignancies. AB - Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide. While advances have been made towards understanding the molecular bases of these diseases, a complete understanding of the pathological mechanisms remains an unmet research goal that is essential for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these malignancies for which no effective therapies are currently being used. Glyoxalases, consisting of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), are enzymes that catalyze the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggests that glyoxalases, especially Glo1, play an important role in the initiation and progression of urological malignancies. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-prostate cancer (PCa) therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis. PMID- 29385040 TI - A Pathological Study of Acute Pulmonary Toxicity Induced by Inhaled Kanto Loam Powder. AB - The frequency and volume of Asian sand dust (ASD) (Kosa) are increasing in Japan, and it has been reported that ASD may cause adverse respiratory effects. The pulmonary toxicity of ASD has been previously analyzed in mice exposed to ASD particles by intratracheal instillation. To study the pulmonary toxicity induced by inhalation of ASD, ICR mice were exposed by inhalation to 50 or 200 mg/m3 Kanto loam powder, which resembles ASD in elemental composition and particle size, for 6 h a day over 1, 3, 6, 9, or 15 consecutive days. Histological examination revealed that Kanto loam powder induced acute inflammation in the whole lung at all the time points examined. The lesions were characterized by infiltration of neutrophils and macrophages. The intensity of the inflammatory changes in the lung and number of neutrophils in both histological lesions and bronchoalveolar lavage fluid (BALF) appeared to increase over time. Immunohistochemical staining showed interleukin (IL)-6- and tumor necrosis factor (TNF)-alpha-positive macrophages and a decrease in laminin positivity in the inflammatory lesions of the lung tissues. Electron microscopy revealed vacuolar degeneration in the alveolar epithelial cells close to the Kanto loam particles. The nitric oxide level in the BALF increased over time. These results suggest that inhaled Kanto loam powder may induce diffuse and acute pulmonary inflammation, which is associated with increased expression of inflammatory cytokines and oxidative stress. PMID- 29385042 TI - Collaborative Indoor Access Point Localization Using Autonomous Mobile Robot Swarm. AB - Localization of access points has become an important research problem due to the wide range of applications it addresses such as dismantling critical security threats caused by rogue access points or optimizing wireless coverage of access points within a service area. Existing proposed solutions have mostly relied on theoretical hypotheses or computer simulation to demonstrate the efficiency of their methods. The techniques that rely on estimating the distance using samples of the received signal strength usually assume prior knowledge of the signal propagation characteristics of the indoor environment in hand and tend to take a relatively large number of uniformly distributed random samples. This paper presents an efficient and practical collaborative approach to detect the location of an access point in an indoor environment without any prior knowledge of the environment. The proposed approach comprises a swarm of wirelessly connected mobile robots that collaboratively and autonomously collect a relatively small number of non-uniformly distributed random samples of the access point's received signal strength. These samples are used to efficiently and accurately estimate the location of the access point. The experimental testing verified that the proposed approach can identify the location of the access point in an accurate and efficient manner. PMID- 29385045 TI - An Improved Method for the Sensitive Detection of Shiga Toxin 2 in Human Serum. AB - Shiga toxins (Stx) released by Stx-producing E. coli (STEC) are virulence factors that are most closely 3associated with hemolytic uremic syndrome (HUS), a life threatening complication of intestinal infections by STEC. Stx have to enter into the circulatory system before they are delivered to target organs and cause damage. The presence of Stx in sera could be a risk indicator for HUS development. However, the detection of Stx, particularly Stx2, has been difficult due to the presence of Stx2-binding components in human serum. Here, we report new ELISA-based methods for the detection of Stx1 and Stx2 in human serum and the effect of guanidinium chloride on enhancing the sensitivity for the detection of Stx2. The recovery rate for Stx2 was 62% when Stx2-spiked serum samples were treated with guanidinium chloride at a concentration of 200 mM, in contrast to 17% without guanidinium chloride treatment. The effectiveness of guanidinium chloride treatment for the detection of Stx2 in human serum was validated using sera from STEC-infected patients. Coimmunoprecipitation results indicated a specific physical interaction between Stx2 and the human serum amyloid P component (HuSAP) in human serum samples. Our in vitro study demonstrated that the inhibition from HuSAP alone for the detection of Stx2 was only 20%, much less than 69.6% from human serum at Stx2 level 10 ng/mL, suggesting that there may be other factors that bind Stx2 in human serum. This study indicates that treatment of serum samples with guanidinium chloride may be useful for the early and sensitive detection of Stx2 in sera of STEC-infected patients, so preventive measures can be adopted in a timely manner. PMID- 29385044 TI - The Influence of Supportive and Ethical Work Environments on Work-Related Accidents, Injuries, and Serious Psychological Distress among Hospital Nurses. AB - The healthcare industry in Japan has experienced many cases of work-related injuries, accidents, and workers' compensation claims because of mental illness. This study examined the influence of supportive and ethical work environments on work-related accidents, injuries, and serious psychological distress among hospital nurses. Self-reported questionnaires were distributed to nurses (n = 1114) from 11 hospitals. Valid responses (n = 822, 93% women, mean age = 38.49 +/ 10.09 years) were used for analyses. The questionnaire included items addressing basic attributes, work and organizational characteristics, social capital and ethical climate at the workplace, psychological distress, and experience of work related accidents or injuries in the last half year. The final model of a multivariate logistic regression analysis revealed that those who work less than 4 h of overtime per week (OR = 0.313), those who work on days off more than once per month (OR = 0.424), and an exclusive workplace climate (OR = 1.314) were significantly associated with work-related accidents or injuries. Additionally, an exclusive workplace climate (OR = 1.696) elevated the risk of serious psychological distress. To prevent work-related compensation cases, which are caused by these variables, strengthening hospitals' occupational health and safety is necessary. PMID- 29385046 TI - Consonant and Vowel Processing in Word Form Segmentation: An Infant ERP Study. AB - Segmentation skill and the preferential processing of consonants (C-bias) develop during the second half of the first year of life and it has been proposed that these facilitate language acquisition. We used Event-related brain potentials (ERPs) to investigate the neural bases of early word form segmentation, and of the early processing of onset consonants, medial vowels, and coda consonants, exploring how differences in these early skills might be related to later language outcomes. Our results with French-learning eight-month-old infants primarily support previous studies that found that the word familiarity effect in segmentation is developing from a positive to a negative polarity at this age. Although as a group infants exhibited an anterior-localized negative effect, inspection of individual results revealed that a majority of infants showed a negative-going response (Negative Responders), while a minority showed a positive going response (Positive Responders). Furthermore, all infants demonstrated sensitivity to onset consonant mispronunciations, while Negative Responders demonstrated a lack of sensitivity to vowel mispronunciations, a developmental pattern similar to previous literature. Responses to coda consonant mispronunciations revealed neither sensitivity nor lack of sensitivity. We found that infants showing a more mature, negative response to newly segmented words compared to control words (evaluating segmentation skill) and mispronunciations (evaluating phonological processing) at test also had greater growth in word production over the second year of life than infants showing a more positive response. These results establish a relationship between early segmentation skills and phonological processing (not modulated by the type of mispronunciation) and later lexical skills. PMID- 29385047 TI - Interface Tailoring Effect for Heusler Based CPP-GMR with an L12-Type Ag3Mg Spacer. AB - Current perpendicular-to-plane (CPP) giant magnetoresistance (GMR) effects are of interest in a possible application of magnetic sensor elements, such as read-head of hard disk drives. To improve the junction performance, the interface tailoring effects were investigated for the Heulser alloy, Co2Fe0.4Mn0.6Si (CFMS), based CPP-GMR junctions with an L 1 2 -Ag3Mg ordered alloy spacer. Ultra-thin Fe or Mg inserts were utilized for the CFMS/Ag3Mg interfaces, and CPP-GMR at low bias current density, J and the J dependence were evaluated for the junctions. Although, at low bias J, MR ratio decreased with increasing the inserts thickness, the device output at high bias J exhibited quite weak dependence on the insert thickness. The output voltages of the order of 4 mV were obtained for the junctions regardless of the insert at an optimal bias J for each. The critical current density J c was evaluated by the shape of MR curves depending on J. J c increased with the insert thicknesses up to 0.45 nm. The enhancement of J c suggests that spin-transfer-torque effect may reduce in the junctions with inserts, which enables a reduction of noise and can be an advantage for device applications. PMID- 29385043 TI - Interplay between ROS and Antioxidants during Ischemia-Reperfusion Injuries in Cardiac and Skeletal Muscle. AB - Ischemia reperfusion (IR), present in myocardial infarction or extremity injuries, is a major clinical issue and leads to substantial tissue damage. Molecular mechanisms underlying IR injury in striated muscles involve the production of reactive oxygen species (ROS). Excessive ROS accumulation results in cellular oxidative stress, mitochondrial dysfunction, and initiation of cell death by activation of the mitochondrial permeability transition pore. Elevated ROS levels can also decrease myofibrillar Ca2+ sensitivity, thereby compromising muscle contractile function. Low levels of ROS can act as signaling molecules involved in the protective pathways of ischemic preconditioning (IPC). By scavenging ROS, antioxidant therapies aim to prevent IR injuries with positive treatment outcomes. Novel therapies such as postconditioning and pharmacological interventions that target IPC pathways hold great potential in attenuating IR injuries. Factors such as aging and diabetes could have a significant impact on the severity of IR injuries. The current paper aims to provide a comprehensive review on the multifaceted roles of ROS in IR injuries, with a focus on cardiac and skeletal muscle, as well as recent advancement in ROS-related therapies. PMID- 29385048 TI - Multi-Response Parameter Interval Sensitivity and Optimization for the Composite Tape Winding Process. AB - The composite tape winding process, which utilizes a tape winding machine and prepreg tapes, provides a promising way to improve the quality of composite products. Nevertheless, the process parameters of composite tape winding have crucial effects on the tensile strength and void content, which are closely related to the performances of the winding products. In this article, two different object values of winding products, including mechanical performance (tensile strength) and a physical property (void content), were respectively calculated. Thereafter, the paper presents an integrated methodology by combining multi-parameter relative sensitivity analysis and single-parameter sensitivity analysis to obtain the optimal intervals of the composite tape winding process. First, the global multi-parameter sensitivity analysis method was applied to investigate the sensitivity of each parameter in the tape winding processing. Then, the local single-parameter sensitivity analysis method was employed to calculate the sensitivity of a single parameter within the corresponding range. Finally, the stability and instability ranges of each parameter were distinguished. Meanwhile, the authors optimized the process parameter ranges and provided comprehensive optimized intervals of the winding parameters. The verification test validated that the optimized intervals of the process parameters were reliable and stable for winding products manufacturing. PMID- 29385049 TI - Metabolomics and Biomarkers for Drug Discovery. AB - Metabolomics and biomarkers are increasingly used in drug discovery and development, and are applied to personalized medicine. Progress in these research areas has increased our understanding of disease pathology and improved therapeutic strategies for many diseases with unmet challenges. Further advances will ultimately result in the development of better drugs and breakthrough therapies, which will benefit millions of patients suffering from chronic and life-threatening diseases worldwide. PMID- 29385051 TI - An Omnidirectional Vision Sensor Based on a Spherical Mirror Catadioptric System. AB - The combination of mirrors and lenses, which defines a catadioptric sensor, is widely used in the computer vision field. The definition of a catadioptric sensors is based on three main features: hardware setup, projection modelling and calibration process. In this paper, a complete description of these aspects is given for an omnidirectional sensor based on a spherical mirror. The projection model of a catadioptric system can be described by the forward projection task (FP, from 3D scene point to 2D pixel coordinates) and backward projection task (BP, from 2D coordinates to 3D direction of the incident light). The forward projection of non-central catadioptric vision systems, typically obtained by using curved mirrors, is usually modelled by using a central approximation and/or by adopting iterative approaches. In this paper, an analytical closed-form solution to compute both forward and backward projection for a non-central catadioptric system with a spherical mirror is presented. In particular, the forward projection is reduced to a 4th order polynomial by determining the reflection point on the mirror surface through the intersection between a sphere and an ellipse. A matrix format of the implemented models, suitable for fast point clouds handling, is also described. A robust calibration procedure is also proposed and applied to calibrate a catadioptric sensor by determining the mirror radius and center with respect to the camera. PMID- 29385050 TI - Sexual Dimorphism in the Selenocysteine Lyase Knockout Mouse. AB - Selenium (Se) is an essential micronutrient known for its antioxidant properties and health benefits, attributed to its presence in selenoproteins as the amino acid, selenocysteine. Selenocysteine lyase (Scly) catalyzes hydrolysis of selenocysteine to selenide and alanine, facilitating re-utilization of Se for de novo selenoprotein synthesis. Previously, it was reported that male Scly-/- mice develop increased body weight and body fat composition, and altered lipid and carbohydrate metabolism, compared to wild type mice. Strikingly, females appeared to present with a less severe phenotype, suggesting the relationship between Scly and energy metabolism may be regulated in a sex-specific manner. Here, we report that while body weight and body fat gain occur in both male and female Scly-/- mice, strikingly, males are susceptible to developing glucose intolerance, whereas female Scly-/- mice are protected. Because Se is critical for male reproduction, we hypothesized that castration would attenuate the metabolic dysfunction observed in male Scly-/- mice by eliminating sequestration of Se in testes. We report that fasting serum insulin levels were significantly reduced in castrated males compared to controls, but islet area was unchanged between groups. Finally, both male and female Scly-/- mice exhibit reduced hypothalamic expression of selenoproteins S, M, and glutathione peroxidase 1. PMID- 29385052 TI - Brillouin Frequency Shift of Fiber Distributed Sensors Extracted from Noisy Signals by Quadratic Fitting. AB - It is a basic task in Brillouin distributed fiber sensors to extract the peak frequency of the scattering spectrum, since the peak frequency shift gives information on the fiber temperature and strain changes. Because of high-level noise, quadratic fitting is often used in the data processing. Formulas of the dependence of the minimum detectable Brillouin frequency shift (BFS) on the signal-to-noise ratio (SNR) and frequency step have been presented in publications, but in different expressions. A detailed deduction of new formulas of BFS variance and its average is given in this paper, showing especially their dependences on the data range used in fitting, including its length and its center respective to the real spectral peak. The theoretical analyses are experimentally verified. It is shown that the center of the data range has a direct impact on the accuracy of the extracted BFS. We propose and demonstrate an iterative fitting method to mitigate such effects and improve the accuracy of BFS measurement. The different expressions of BFS variances presented in previous papers are explained and discussed. PMID- 29385053 TI - Prevalence of Mental Disorders and Addictions among Homeless People in the Greater Paris Area, France. AB - The Samenta study was conducted in 2009 in the Greater Paris area to estimate the prevalence of psychiatric disorders in homeless people. A cross-sectional survey was performed with a three-stage random sample of homeless people (n = 859), including users of day services, emergency shelters, hot meal distribution, long term rehabilitation centres, and social hotels. Information was collected by a lay interviewer, using the Mini International Neuropsychiatric Interview, and completed by a psychologist through an open clinical interview. In the end, a psychiatrist assessed the psychiatric diagnosis according to the International Statistical Classification of Diseases and Related Health Problems (ICD, 10th revision). One third of homeless people in the Paris area had at least one severe psychiatric disorder (SPD): psychotic disorders (13%), anxiety disorders (12%), or severe mood disorders (7%). One in five was alcohol-dependent and 18% were drug users. Homeless women had significantly higher prevalence of anxiety disorders and depression compared to men, who were more likely to suffer from psychotic disorders. Homeless people of French origin were at higher risk of SPD, as well as people who experienced various adverse life events before the age of 18 (running away, sexual violence, parental disputes, and/or addictions) and those who experienced homelessness for the first time before the age of 26. The prevalence rates of the main psychiatric disorders within the homeless population of our study are consistent with those reported in other Western cities. Our results advocate for an improvement in the detection, housing, and care of psychiatric homeless people. PMID- 29385054 TI - A Preliminary Study for Evaluating the Dose-Dependent Effect of d-Allulose for Fat Mass Reduction in Adult Humans: A Randomized, Double-Blind, Placebo Controlled Trial. AB - d-allulose is a rare sugar with zero energy that can be consumed by obese/overweight individuals. Many studies have suggested that zero-calorie d allulose has beneficial effects on obesity-related metabolism in mouse models, but only a few studies have been performed on human subjects. Therefore, we performed a preliminary study with 121 Korean subjects (aged 20-40 years, body mass index >= 23 kg/m2). A randomized controlled trial involving placebo control (sucralose, 0.012 g * 2 times/day), low d-allulose (d-allulose, 4 g * 2 times/day), and high d-allulose (d-allulose, 7 g * 2 times/day) groups was designed. Parameters for body composition, nutrient intake, computed tomography (CT) scan, and plasma lipid profiles were assessed. Body fat percentage and body fat mass were significantly decreased following d-allulose supplementation. The high d-allulose group revealed a significant decrease in not only body mass index (BMI), but also total abdominal and subcutaneous fat areas measured by CT scans compared to the placebo group. There were no significant differences in nutrient intake, plasma lipid profiles, markers of liver and kidney function, and major inflammation markers among groups. These results provide useful information on the dose-dependent effect of d-allulose for overweight/obese adult humans. Based on these results, the efficacy of d-allulose for body fat reduction needs to be validated using dual energy X-ray absorption. PMID- 29385056 TI - Node Location Privacy Protection Based on Differentially Private Grids in Industrial Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) are widely applied in industrial application with the rapid development of Industry 4.0. Combining with centralized cloud platform, the enormous computational power is provided for data analysis, such as strategy control and policy making. However, the data analysis and mining will bring the issue of privacy leakage since sensors will collect varieties of data including sensitive location information of monitored objects. Differential privacy is a novel technique that can prevent compromising single record benefits. Geospatial data can be indexed by a tree structure; however, existing differentially private release methods pay no attention to the concrete analysis about the partition granularity of data domains. Based on the overall analysis of noise error and non uniformity error, this paper proposes a data domain partitioning model, which is more accurate to choose the grid size. A uniform grid release method is put forward based on this model. In order to further reduce the errors, similar cells are merged, and then noise is added into the merged cells. Results show that our method significantly improves the query accuracy compared with other existing methods. PMID- 29385055 TI - Effects of Consuming Preloads with Different Energy Density and Taste Quality on Energy Intake and Postprandial Blood Glucose. AB - Consumption of reduced energy dense foods and drink has the potential to reduce energy intake and postprandial blood glucose concentrations. In addition, the taste quality of a meal (e.g., sweet or savoury) may play a role in satiation and food intake. The objective of this randomised crossover study was to examine whether energy density and taste quality has an impact on energy intake and postprandial blood glucose response. Using a preload design, participants were asked to consume a sweet ("Cheng Teng") or a savoury (broth) preload soup in high energy density (HED; around 0.50 kcal/g; 250 kcal) or low energy density (LED; around 0.12 kcal/g; 50 kcal) in mid-morning and an ad libitum lunch was provided an hour after the preload. Participants recorded their food intake for the rest of the day after they left the study site. Energy compensation and postprandial blood glucose response were measured in 32 healthy lean males (mean age = 28.9 years, mean BMI = 22.1 kg/m2). There was a significant difference in ad libitum lunch intake between treatments (p = 0.012), with higher intake in sweet LED and savoury LED compared to sweet HED and savoury HED. Energy intake at subsequent meals and total daily energy intake did not differ between the four treatments (both p >= 0.214). Consumption of HED preloads resulted in a larger spike in postprandial blood glucose response compared with LED preloads, irrespective of taste quality (p < 0.001). Energy density rather than taste quality plays an important role in energy compensation and postprandial blood glucose response. This suggests that regular consumption of low energy-dense foods has the potential to reduce overall energy intake and to improve glycemic control. PMID- 29385059 TI - Multichannel High Resolution Wide Swath SAR Imaging for Hypersonic Air Vehicle with Curved Trajectory. AB - Synthetic aperture radar (SAR) equipped on the hypersonic air vehicle in near space has many advantages over the conventional airborne SAR. However, its high speed maneuvering characteristics with curved trajectory result in serious range migration, and exacerbate the contradiction between the high resolution and wide swath. To solve this problem, this paper establishes the imaging geometrical model matched with the flight trajectory of the hypersonic platform and the multichannel azimuth sampling model based on the displaced phase center antenna (DPCA) technology. Furthermore, based on the multichannel signal reconstruction theory, a more efficient spectrum reconstruction model using discrete Fourier transform is proposed to obtain the azimuth uniform sampling data. Due to the high complexity of the slant range model, it is difficult to deduce the processing algorithm for SAR imaging. Thus, an approximate range model is derived based on the minimax criterion, and the optimal second-order approximate coefficients of cosine function are obtained using the two-population coevolutionary algorithm. On this basis, aiming at the problem that the traditional Omega-K algorithm cannot compensate the residual phase with the difficulty of Stolt mapping along the range frequency axis, this paper proposes an Exact Transfer Function (ETF) algorithm for SAR imaging, and presents a method of range division to achieve wide swath imaging. Simulation results verify the effectiveness of the ETF imaging algorithm. PMID- 29385057 TI - Dietary Balance Index-07 and the Risk of Anemia in Middle Aged and Elderly People in Southwest China: A Cross Sectional Study. AB - A balanced diet is essential to achieve and maintain good health. In this study, we assessed diet quality of middle aged and elderly people based on Chinese Diet Balance Index-07 (DBI-07) and explored the associations between DBI-07 and anemia. Data analyzed for this study was from the 2010-2012 National Nutrition and Health Survey in Yunnan province, southwest China (n = 738, aged 50-77 years). Dietary recalls over there consecutive days were done in a face-to-face interview. The scores of DBI-07 for each component and three DBI-07 indicators ((Lower Bound Score (LBS), Higher Bound Score (HBS), Diet Quality Distance (DQD)) were calculated according to compliance with the Dietary Guidelines for Chinese residents. Hemoglobin (Hb) concentration was determined using the cyanmethemoglobin method. Univariate and multivariate linear regression models were used to explore the associations between DBI-07 indicators and anemia, as well as scores of DBI-07 components and Hb level. The sample included 336 men and 402 women. Inadequate intakes of vegetables, fruits, dairy, soybean, eggs, fish and excessive intakes of cereals, meat, cooking oil, salt were both common. 91.3% of the participants had moderate or high levels of inadequate food intake, while 37.7% had moderate or high levels of excessive food intake. The mean Hb was 14.2 +/- 1.7 g/dL, with a prevalence of anemia of 13.0%. Subjects with high LBS and DQD were more likely to be anemic (all p < 0.05). After adjustment for potential confounders, there were positive correlations between Hb level and the intakes of vegetables and soybean (betavegetables = 1.04, p < 0.01; betasoybean = 0.82, p = 0.04). In conclusion, dietary imbalance and anemia are common in middle aged and elderly population in southwest China and inadequate intakes of vegetables and soybean may increase the risk of anemia. PMID- 29385058 TI - A Systematic Review of Antiamyloidogenic and Metal-Chelating Peptoids: Two Structural Motifs for the Treatment of Alzheimer's Disease. AB - Alzheimer's disease (AD) is an incurable form of dementia affecting millions of people worldwide and costing billions of dollars in health care-related payments, making the discovery of a cure a top health, societal, and economic priority. Peptide-based drugs and immunotherapies targeting AD-associated beta-amyloid (Abeta) aggregation have been extensively explored; however, their therapeutic potential is limited by unfavorable pharmacokinetic (PK) properties. Peptoids (N substituted glycine oligomers) are a promising class of peptidomimetics with highly tunable secondary structures and enhanced stabilities and membrane permeabilities. In this review, the biological activities, structures, and physicochemical properties for several amyloid-targeting peptoids will be described. In addition, metal-chelating peptoids with the potential to treat AD will be discussed since there are connections between the dysregulation of certain metals and the amyloid pathway. PMID- 29385060 TI - Synthesis of a Cleaved Form of Osteopontin by THP-1 Cells and Its Alteration by Phorbol 12-Myristate 13-Acetate and BCG Infection. AB - The protease-cleaved osteopontin (OPN) was proposed to enhance the migration of memory T cells to granulomas in tuberculosis. Various forms of OPN were identified in human monocytic THP-1 cells stimulated by phorbol 12-myristate 13 acetate (PMA). Antibodies O-17, 10A16 and 34E3, which recognize N-terminus, the C half, and thrombin-cleaved site of OPN, respectively, all detected distinct bands on Western blots following PMA stimulation. Bands corresponding to 18 and 30 kD were detected by antibodies 34E3 and 10A16, indicating that OPN cleavage occurred by endogenous proteases in the PMA-stimulated THP-1 cells. In immune-fluorescence (IF) assay, 34E3 positive signals were detected in intracellular space of non infected and bacillus Calmette-Guerin (BCG)-infected cells; however, 10A16 positive signals were confirmed in extracellular area in PMA-stimulated cells followed by BCG infection. Small amounts of full-length (FL) and thrombin-cleaved (Tr) OPN were detected by ELISA in the supernatants of non-PMA-stimulated cells, and increased levels of all forms, including undefined (Ud) OPN, in PMA stimulated cells. ELISA showed a decrease in OPN synthesis during BCG infection. To our knowledge, this is the first report of OPN cleavage in THP-1 macrophages after PMA stimulation, and of enhanced cleavage induced by BCG infection. PMID- 29385062 TI - A Randomized Double-Blinded, Placebo-Controlled Trial Investigating the Effect of Fish Oil Supplementation on Gene Expression Related to Insulin Action, Blood Lipids, and Inflammation in Gestational Diabetes Mellitus-Fish Oil Supplementation and Gestational Diabetes. AB - Gestational diabetes mellitus (GDM) is a common complication of pregnancy, and it is mostly associated with postpartum diabetes, insulin resistance, and dyslipidemia. Fish oil (omega-3) supplementation has been shown to reduce the risk of different chronic diseases such as cardiovascular disease, type 2 diabetes, and cancers, though the evidence of its impact on gestational diabetes is scarce. Our goal in this study was to determine the effect of fish oil administration on gene expression related to insulin action, blood lipids, and inflammation in women with GDM. Participants with GDM (n = 40), aged 18-40 years, were randomized to take either 1000 mg fish oil capsules, containing 180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid (n = 20), or placebo (n = 20) twice a day for 6 weeks. Gene expression related to insulin, lipids, and inflammation was quantified in peripheral blood mononuclear cells (PBMCs) of GDM women using Reverse Transcription Polymerase Chain Reaction (RT-PCR) method. Results of RT-PCR indicated that omega-3 supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) (P = 0.04) in PBMCs of patients with GDM, compared with the placebo. In addition, gene expression of the low-density lipoprotein receptor (LDLR) (P < 0.001), interleukin-1 (IL-1) (P = 0.007), and tumor necrosis factor alpha (TNF-alpha) (P = 0.01) was downregulated in PBMCs of women with GDM, following omega-3 supplementation. No significant effect of omega-3 supplementation was indicated on gene expression of IL-8 in PBMCs of patients with GDM. Overall, fish oil supplementation for 6 weeks in women with GDM significantly improved gene expression of PPAR-gamma, IL-1, and TNF-alpha, but not gene expression of IL-8. PMID- 29385064 TI - Two-Dimensional Layered Double Hydroxides for Reactions of Methanation and Methane Reforming in C1 Chemistry. AB - CH4 as the paramount ingredient of natural gas plays an eminent role in C1 chemistry. CH4 catalytically converted to syngas is a significant route to transmute methane into high value-added chemicals. Moreover, the CO/CO2 methanation reaction is one of the potent technologies for CO2 valorization and the coal-derived natural gas production process. Due to the high thermal stability and high extent of dispersion of metallic particles, two-dimensional mixed metal oxides through calcined layered double hydroxides (LDHs) precursors are considered as the suitable supports or catalysts for both the reaction of methanation and methane reforming. The LDHs displayed compositional flexibility, small crystal sizes, high surface area and excellent basic properties. In this paper, we review previous works of LDHs applied in the reaction of both methanation and methane reforming, focus on the LDH-derived catalysts, which exhibit better catalytic performance and thermal stability than conventional catalysts prepared by impregnation method and also discuss the anti-coke ability and anti-sintering ability of LDH-derived catalysts. We believe that LDH-derived catalysts are promising materials in the heterogeneous catalytic field and provide new insight for the design of advance LDH-derived catalysts worthy of future research. PMID- 29385063 TI - Anti-Lymphangiogenesis Components from Zoanthid Palythoa tuberculosa. AB - Three new compounds, tuberazines A-C (1-3), and eleven known compounds (4-14) were obtained from the ethanolic extract of Taiwanese zoanthid Palythoa tuberculosa. Compounds 1-4 are rare marine natural products with a pyrazine moiety, and compound 5 is a tricyclic tryptamine derivative isolated from nature for the first time. The structures of all isolated metabolites were determined by analyzing their IR, Mass, NMR, and UV spectrometric data. The absolute configuration of 1 was confirmed by comparing the trend of experimental electronic circular dichroism (ECD) with calculated ECD spectra. The anti lymphangiogenic activities of new compounds were evaluated in human lymphatic endothelial cells (LECs). Of these, new compound 3 displayed the most potent anti lymphangiogenesis property by suppressing cell growth and tube formation of LECs. PMID- 29385061 TI - HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes. AB - SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 uM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency. PMID- 29385065 TI - Breast Milk Lipidome Is Associated with Early Growth Trajectory in Preterm Infants. AB - Human milk is recommended for feeding preterm infants. The current pilot study aims to determine whether breast-milk lipidome had any impact on the early growth pattern of preterm infants fed their own mother's milk. A prospective-monocentric observational birth-cohort was established, enrolling 138 preterm infants, who received their own mother's breast-milk throughout hospital stay. All infants were ranked according to the change in weight Z-score between birth and hospital discharge. Then, we selected infants who experienced "slower" (n = 15, -1.54 +/- 0.42 Z-score) or "faster" (n = 11, -0.48 +/- 0.19 Z-score) growth; as expected, although groups did not differ regarding gestational age, birth weight Z-score was lower in the "faster-growth" group (0.56 +/- 0.72 vs. -1.59 +/- 0.96). Liquid chromatography-mass spectrometry lipidomic signatures combined with multivariate analyses made it possible to identify breast-milk lipid species that allowed clear-cut discrimination between groups. Validation of the selected biomarkers was performed using multidimensional statistical, false-discovery-rate and ROC (Receiver Operating Characteristic) tools. Breast-milk associated with faster growth contained more medium-chain saturated fatty acid and sphingomyelin, dihomo gamma-linolenic acid (DGLA)-containing phosphethanolamine, and less oleic acid containing triglyceride and DGLA-oxylipin. The ability of such biomarkers to predict early-growth was validated in presence of confounding clinical factors but remains to be ascertained in larger cohort studies. PMID- 29385068 TI - Development of Wind Speed Retrieval from Cross-Polarization Chinese Gaofen-3 Synthetic Aperture Radar in Typhoons. AB - The purpose of our work is to determine the feasibility and effectiveness of retrieving sea surface wind speeds from C-band cross-polarization (herein vertical-horizontal, VH) Chinese Gaofen-3 (GF-3) SAR images in typhoons. In this study, we have collected three GF-3 SAR images acquired in Global Observation (GLO) and Wide ScanSAR (WSC) mode during the summer of 2017 from the China Sea, which includes the typhoons Noru, Doksuri and Talim. These images were collocated with wind simulations at 0.12 degrees grids from a numeric model, called the Regional Assimilation and Prediction System-Typhoon model (GRAPES-TYM). Recent research shows that GRAPES-TYM has a good performance for typhoon simulation in the China Sea. Based on the dataset, the dependence of wind speed and of radar incidence angle on normalized radar cross (NRCS) of VH-polarization GF-3 SAR have been investigated, after which an empirical algorithm for wind speed retrieval from VH-polarization GF-3 SAR was tuned. An additional four VH-polarization GF-3 SAR images in three typhoons, Noru, Hato and Talim, were investigated in order to validate the proposed algorithm. SAR-derived winds were compared with measurements from Windsat winds at 0.25 degrees grids with wind speeds up to 40 m/s, showing a 5.5 m/s root mean square error (RMSE) of wind speed and an improved RMSE of 5.1 m/s wind speed was achieved compared with the retrieval results validated against GRAPES-TYM winds. It is concluded that the proposed algorithm is a promising potential technique for strong wind retrieval from cross polarization GF-3 SAR images without encountering a signal saturation problem. PMID- 29385067 TI - Sensing Technologies for Detection of Acetone in Human Breath for Diabetes Diagnosis and Monitoring. AB - The review describes the technologies used in the field of breath analysis to diagnose and monitor diabetes mellitus. Currently the diagnosis and monitoring of blood glucose and ketone bodies that are used in clinical studies involve the use of blood tests. This method entails pricking fingers for a drop of blood and placing a drop on a sensitive area of a strip which is pre-inserted into an electronic reading instrument. Furthermore, it is painful, invasive and expensive, and can be unsafe if proper handling is not undertaken. Human breath analysis offers a non-invasive and rapid method for detecting various volatile organic compounds thatare indicators for different diseases. In patients with diabetes mellitus, the body produces excess amounts of ketones such as acetoacetate, beta-hydroxybutyrate and acetone. Acetone is exhaled during respiration. The production of acetone is a result of the body metabolising fats instead of glucose to produce energy. There are various techniques that are used to analyse exhaled breath including Gas Chromatography Mass Spectrometry (GC-MS), Proton Transfer Reaction Mass Spectrometry (PTR-MS), Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS), laser photoacoustic spectrometry and so on. All these techniques are not portable, therefore this review places emphasis on how nanotechnology, through semiconductor sensing nanomaterials, has the potential to help individuals living with diabetes mellitus monitor their disease with cheap and portable devices. PMID- 29385066 TI - Expansion of Sphingosine Kinase and Sphingosine-1-Phosphate Receptor Function in Normal and Cancer Cells: From Membrane Restructuring to Mediation of Estrogen Signaling and Stem Cell Programming. AB - Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival. Specifically, Estrogen activates S1P receptors (S1PR) and induces growth factor receptor transactivation. SphK, S1P, and S1PR expression are causally associated with endocrine resistance and progression to advanced tumor stages in ER-positive breast cancers in vivo. Recently, the network of SphK/S1PR was shown to promote the development of ER-negative cancers and breast cancer stem cells, as well as stimulating angiogenesis. Novel findings confirm and broaden our knowledge about the cross-talk between sphingolipids and estrogen network in normal and malignant cells. Current S1PRs therapeutic inhibition was indicated as a promising chemotherapy approach in non-responsive and advanced malignancies. Considering that sphingolipid signaling has a prominent role in terminally differentiated cells, the impact should be considered when designing specific SphK/S1PR inhibitors. This study analyzes the dynamic of the transformation of sphingolipid axis during a transition from normal to pathological condition on the level of the whole organism. The sphingolipid-based mediation and facilitation of global effects of estrogen were critically accented as a bridging mechanism that should be explored in cancer prevention. PMID- 29385069 TI - Identification of Novel Hemangioblast Genes in the Early Chick Embryo. AB - During early vertebrate embryogenesis, both hematopoietic and endothelial lineages derive from a common progenitor known as the hemangioblast. Hemangioblasts derive from mesodermal cells that migrate from the posterior primitive streak into the extraembryonic yolk sac. In addition to primitive hematopoietic cells, recent evidence revealed that yolk sac hemangioblasts also give rise to tissue-resident macrophages and to definitive hematopoietic stem/progenitor cells. In our previous work, we used a novel hemangioblast specific reporter to isolate the population of chick yolk sac hemangioblasts and characterize its gene expression profile using microarrays. Here we report the microarray profile analysis and the identification of upregulated genes not yet described in hemangioblasts. These include the solute carrier transporters SLC15A1 and SCL32A1, the cytoskeletal protein RhoGap6, the serine protease CTSG, the transmembrane receptor MRC1, the transcription factors LHX8, CITED4 and PITX1, and the previously uncharacterized gene DIA1R. Expression analysis by in situ hybridization showed that chick DIA1R is expressed not only in yolk sac hemangioblasts but also in particular intraembryonic populations of hemogenic endothelial cells, suggesting a potential role in the hemangioblast-derived hemogenic lineage. Future research into the function of these newly identified genes may reveal novel important regulators of hemangioblast development. PMID- 29385070 TI - Structural Health Monitoring of Railway Transition Zones Using Satellite Radar Data. AB - Transition zones in railway tracks are locations with considerable changes in the rail-supporting structure. Typically, they are located near engineering structures, such as bridges, culverts and tunnels. In such locations, severe differential settlements often occur due to the different material properties and structure behavior. Without timely maintenance, the differential settlement may lead to the damage of track components and loss of passenger's comfort. To ensure the safety of railway operations and reduce the maintenance costs, it is necessary to consecutively monitor the structural health condition of the transition zones in an economical manner and detect the changes at an early stage. However, using the current in situ monitoring of transition zones is hard to achieve this goal, because most in situ techniques (e.g., track-measuring coaches) are labor-consuming and usually not frequently performed (approximately twice a year in the Netherlands). To tackle the limitations of the in situ techniques, a Satellite Synthetic Aperture Radar (InSAR) system is presented in this paper, which provides a potential solution for a consecutive structural health monitoring of transition zones with bi-/tri-weekly data update and mm level precision. To demonstrate the feasibility of the InSAR system for monitoring transition zones, a transition zone is tested. The results show that the differential settlement in the transition zone and the settlement rate can be observed and detected by the InSAR measurements. Moreover, the InSAR results are cross-validated against measurements obtained using a measuring coach and a Digital Image Correlation (DIC) device. The results of the three measuring techniques show a good correlation, which proves the applicability of InSAR for the structural health monitoring of transition zones in railway track. PMID- 29385071 TI - Synthesis and In Vitro Antiproliferative Activity of New 1-Phenyl-3-(4-(pyridin-3 yl)phenyl)urea Scaffold-Based Compounds. AB - A new series of 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea derivatives were synthesized and subjected to in vitro antiproliferative screening against National Cancer Institute (NCI)-60 human cancer cell lines of nine different cancer types. Fourteen compounds 5a-n were synthesized with three different solvent exposure moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure. Substituents with different pi and sigma values were added on the terminal phenyl group. Compounds 5a-e with a 4-hydroxymethylpiperidine moiety showed broad-spectrum antiproliferative activity with higher mean percentage inhibition values over the 60-cell line panel at 10 uM concentration. Compound 5a elicited lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line. Two compounds, 5a and 5d showed promising mean growth inhibitions and thus were further tested at five-dose mode to determine median inhibitory concentration (IC50) values. The data revealed that urea compounds 5a and 5d are the most active derivatives, with significant efficacies and superior potencies than paclitaxel in 21 different cancer cell lines belonging particularly to renal cancer and melanoma cell lines. Moreover, 5a and 5d had superior potencies than gefitinib in 38 and 34 cancer cell lines, respectively, particularly colon cancer, breast cancer and melanoma cell lines. PMID- 29385072 TI - Adverse Selection in Community Based Health Insurance among Informal Workers in Bangladesh: An EQ-5D Assessment. AB - Community-based Health Insurance (CBHI) schemes are recommended for providing financial risk protection to low-income informal workers in Bangladesh. We assessed the problem of adverse selection in a pilot CBHI scheme in this context. In total, 1292 (646 insured and 646 uninsured) respondents were surveyed using the Bengali version of the EuroQuol-5 dimensions (EQ-5D) questionnaire for assessing their health status. The EQ-5D scores were estimated using available regional tariffs. Multiple logistic regression was applied for predicting the association between health status and CBHI scheme enrolment. A higher number of insured reported problems in mobility (7.3%; p = 0.002); self-care (7.1%; p = 0.000) and pain and discomfort (7.7%; p = 0.005) than uninsured. The average EQ 5D score was significantly lower among the insured (0.704) compared to the uninsured (0.749). The regression analysis showed that those who had a problem in mobility (m 1.25-2.17); self-care (OR = 2.29; 95% CI: 1.62-3.25) and pain and discomfort (OR = 1.43; 95% CI: 1.13-1.81) were more likely to join the scheme. Individuals with higher EQ-5D scores (OR = 0.46; 95% CI: 0.31-0.69) were less likely to enroll in the scheme. Given that adverse selection was evident in the pilot CBHI scheme, there should be consideration of this problem when planning scale-up of these kind of schemes. PMID- 29385073 TI - Implementation of Glycan Remodeling to Plant-Made Therapeutic Antibodies. AB - N-glycosylation profoundly affects the biological stability and function of therapeutic proteins, which explains the recent interest in glycoengineering technologies as methods to develop biobetter therapeutics. In current manufacturing processes, N-glycosylation is host-specific and remains difficult to control in a production environment that changes with scale and production batches leading to glycosylation heterogeneity and inconsistency. On the other hand, in vitro chemoenzymatic glycan remodeling has been successful in producing homogeneous pre-defined protein glycoforms, but needs to be combined with a cost effective and scalable production method. An efficient chemoenzymatic glycan remodeling technology using a plant expression system that combines in vivo deglycosylation with an in vitro chemoenzymatic glycosylation is described. Using the monoclonal antibody rituximab as a model therapeutic protein, a uniform Gal2GlcNAc2Man3GlcNAc2 (A2G2) glycoform without alpha-1,6-fucose, plant-specific alpha-1,3-fucose or beta-1,2-xylose residues was produced. When compared with the innovator product Rituxan(r), the plant-made remodeled afucosylated antibody showed similar binding affinity to the CD20 antigen but significantly enhanced cell cytotoxicity in vitro. Using a scalable plant expression system and reducing the in vitro deglycosylation burden creates the potential to eliminate glycan heterogeneity and provide affordable customization of therapeutics' glycosylation for maximal and targeted biological activity. This feature can reduce cost and provide an affordable platform to manufacture biobetter antibodies. PMID- 29385074 TI - Guarana (Paullinia cupana) Stimulates Mitochondrial Biogenesis in Mice Fed High Fat Diet. AB - The aim of this study was to evaluate the effects of guarana on mitochondrial biogenesis in a high-fat diet (HFD)-fed mice. C57BL6J mice were divided in two groups: high-fat diet HFD and high-fat diet + guarana (HFD-GUA). Both groups received HFD and water ad libitum and the HFD-GUA group also received a daily gavage of guarana (1 g/kg weight). Body weight and food intake was measured weekly. Glycemic, triglyceride, and cholesterol levels were determined. VO2 and energy expenditure (EE) were determined by indirect calorimetry. Gene expression was evaluated by real-time PCR and protein content by western blotting. The HFD GUA group presented lower body weight, subcutaneous, retroperitoneal, visceral, and epididyimal adipose tissue depots, and glycemic and triglyceride levels, with no change in food intake and cholesterol levels. Furthermore, the HFD-GUA group presented an increase in VO2 and basal energy expenditure (EE), as well as Pgc1alpha, Creb1, Ampka1, Nrf1, Nrf2, and Sirt1 expression in the muscle and brown adipose tissue. In addition, the HFD-GUA group presented an increase in mtDNA (mitochondrial deoxyribonucleic acid) content in the muscle when compared to the HFD group. Thus, our data showed that guarana leads to an increase in energetic metabolism and stimulates mitochondrial biogenesis, contributing to control of weight gain, even when associated with high-fat diet. PMID- 29385075 TI - Cigarette Smoking Promotes Infection of Cervical Cells by High-Risk Human Papillomaviruses, but not Subsequent E7 Oncoprotein Expression. AB - Persistent cervical infection with high-risk human papillomaviruses (hrHPVs) is a necessary, but not sufficient, condition for the development of cervical cancer. Therefore, there are other co-factors facilitating the hrHPV carcinogenic process, one of which is smoking. To assess the effect of smoking on high-risk (hr) HPV DNA positivity and on the expression of HPV E7 oncoprotein, as a surrogate of persistent hrHPV infection, we used data from women recruited for the PIPAVIR project, which examined the role of E7 protein detection in cervical cancer screening. Women were tested for hrHPV DNA, using Multiplex Genotyping (MPG), and E7 protein, using a novel sandwich ELISA method, and gave information on their smoking habits. Among 1473 women, hrHPV prevalence was 19.1%. The odds ratio (OR) for hrHPV positivity of smokers compared to non-smokers was 1.785 (95% confidence intervals (CI): 1.365-2.332, p < 0.001). The ORs for E7 positivity, concerning hrHPV positive women, ranged from 0.720 to 1.360 depending on the E7 detection assay used, but this was not statistically significant. Smoking increases the probability of hrHPV infection, and smoking intensity is positively associated to this increase. Smoking is not related to an increased probability of E7 protein positivity for hrHPV positive women. PMID- 29385076 TI - Development of a Kalman Filter in the Gauss-Helmert Model for Reliability Analysis in Orientation Determination with Smartphone Sensors. AB - The topic of indoor positioning and indoor navigation by using observations from smartphone sensors is very challenging as the determined trajectories can be subject to significant deviations compared to the route travelled in reality. Especially the calculation of the direction of movement is the critical part of pedestrian positioning approaches such as Pedestrian Dead Reckoning ("PDR"). Due to distinct systematic effects in filtered trajectories, it can be assumed that there are systematic deviations present in the observations from smartphone sensors. This article has two aims: one is to enable the estimation of partial redundancies for each observation as well as for observation groups. Partial redundancies are a measure for the reliability indicating how well systematic deviations can be detected in single observations used in PDR. The second aim is to analyze the behavior of partial redundancy by modifying the stochastic and functional model of the Kalman filter. The equations relating the observations to the orientation are condition equations, which do not exhibit the typical structure of the Gauss-Markov model ("GMM"), wherein the observations are linear and can be formulated as functions of the states. To calculate and analyze the partial redundancy of the observations from smartphone-sensors used in PDR, the system equation and the measurement equation of a Kalman filter as well as the redundancy matrix need to be derived in the Gauss-Helmert model ("GHM"). These derivations are introduced in this article and lead to a novel Kalman filter structure based on condition equations, enabling reliability assessment of each observation. PMID- 29385077 TI - Highly Efficient One-Pot Synthesis of COS-Based Block Copolymers by Using Organic Lewis Pairs. AB - A one-pot synthesis of block copolymer with regioregular poly(monothiocarbonate) block is described via metal-free catalysis. Lewis bases such as guanidine, quaternary onium salts, and Lewis acid triethyl borane (TEB) were equivalently combined and used as the catalysts. By using polyethylene glycol (PEG) as the macromolecular chain transfer agent (CTA), narrow polydispersity block copolymers were obtained from the copolymerization of carbonyl sulfide (COS) and propylene oxide (PO). The block copolymers had a poly(monothiocarbonate) block with perfect alternating degree and regioregularity. Unexpectedly, the addition of CTA to COS/PO copolymerization system could dramatically improve the turnover frequency (TOF) of PO (up to 240 h-1), higher than that of the copolymerization without CTA. In addition, the conversion of CTA could be up to 100% in most cases, as revealed by 1H NMR spectra. Of consequence, the number-average molecular weights (Mns) of the resultant block copolymers could be regulated by varying the feed ratio of CTA to PO. Oxygen-sulfur exchange reaction (O/S ER), which can generate randomly distributed thiocarbonate and carbonate units, was effectively suppressed in all of the cases in the presence of CTA, even at 80 degrees C. This work presents a versatile method for synthesizing sulfur-containing block copolymers through a metal-free route, providing an array of new block copolymers. PMID- 29385078 TI - Terretonin N: A New Meroterpenoid from Nocardiopsis sp. AB - Terretonin N (1), a new highly oxygenated and unique tetracyclic 6 hydroxymeroterpenoid, was isolated together with seven known compounds from the ethyl acetate extract of a solid-state fermented culture of Nocardiopsis sp. Their structures were elucidated by spectroscopic analysis. The structure and absolute configuration of 1 were unambiguously determined by X-ray crystallography. The isolation and taxonomic characterization of Nocardiopsis sp. is reported. The antimicrobial activity and cytotoxicity of the strain extract and compound 1 were studied using different microorganisms and a cervix carcinoma cell line, respectively. PMID- 29385079 TI - Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases. AB - Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs), which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET). We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases. PMID- 29385080 TI - A Systematic Review and Meta-Analysis of the In Vivo Haemodynamic Effects of Delta8-Tetrahydrocannabinol. AB - ?8-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) -19.7 mmHg, p < 0.00001; HR, MD -53.49 bpm, p < 0.00001), conscious animals (BP, MD -12.3 mmHg, p = 0.0007; HR, MD -30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD -61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD -22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered. PMID- 29385082 TI - How Effectively Do People Remember Voice Disordered Speech? An Investigation of the Serial-Position Curve. AB - We examined how well typical adult listeners remember the speech of a person with a voice disorder (relative to that of a person without a voice disorder). Participants (n = 40) listened to two lists of words (one list uttered in a disordered voice and the other list uttered in a normal voice). After each list, participants completed a free recall test, in which they tried to remember as many words as they could. While the total number of words recalled did not differ between the disordered voice condition and the normal voice condition, an investigation of the serial-position curve revealed a difference. In the normal voice condition, a parabolic (i.e., u-shaped) serial-position curve was observed, with a significant primacy effect (i.e., the beginning of the list was remembered better than the middle) and a significant recency effect (i.e., the end of the list was remembered better than the middle). In contrast, in the disordered voice condition, while there was a significant recency effect, no primacy effect was present. Thus, the increased ability to remember the first words uttered by a speaker (relative to subsequent words) may disappear when the speaker has a voice disorder. Explanations and implications of this finding are discussed. PMID- 29385083 TI - Synthesis and Electrochemical Properties of Two-Dimensional RGO/Ti3C2Tx Nanocomposites. AB - MXene is a new type of two-dimensional layered material. Herein, a GO/Ti3C2Tx nanocomposite was prepared by a simple liquid phase method, and the obtained GO/Ti3C2Tx was transformed into RGO/Ti3C2Tx under high temperature with Ar/H2. The prepared samples were characterized using X-ray diffraction (XRD), Raman measurement, scanning electron microscopy (SEM), energy disperse spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). As an electrode material in lithium-ion batteries, the RGO/Ti3C2Tx nanocomposite exhibited an excellent electrochemical performance and an excellent rate performance. Compared to pure Ti3C2Tx, the nanocomposite had a better reversible capacity at different current densities and had no attenuation after 200 cycles, which is one time higher than pure Ti3C2Tx. The improvement in the specific capacity was due to the excellent electrical conductivity and the unique structure of RGO, in which a charge transfer bridge was built among the Ti3C2Tx flakes. Such a bridge shortened the transmission distance of the electrons and ions and effectively controlled the restacking of the laminated materials. PMID- 29385081 TI - Disseminating Metaproteomic Informatics Capabilities and Knowledge Using the Galaxy-P Framework. AB - The impact of microbial communities, also known as the microbiome, on human health and the environment is receiving increased attention. Studying translated gene products (proteins) and comparing metaproteomic profiles may elucidate how microbiomes respond to specific environmental stimuli, and interact with host organisms. Characterizing proteins expressed by a complex microbiome and interpreting their functional signature requires sophisticated informatics tools and workflows tailored to metaproteomics. Additionally, there is a need to disseminate these informatics resources to researchers undertaking metaproteomic studies, who could use them to make new and important discoveries in microbiome research. The Galaxy for proteomics platform (Galaxy-P) offers an open source, web-based bioinformatics platform for disseminating metaproteomics software and workflows. Within this platform, we have developed easily-accessible and documented metaproteomic software tools and workflows aimed at training researchers in their operation and disseminating the tools for more widespread use. The modular workflows encompass the core requirements of metaproteomic informatics: (a) database generation; (b) peptide spectral matching; (c) taxonomic analysis and (d) functional analysis. Much of the software available via the Galaxy-P platform was selected, packaged and deployed through an online metaproteomics "Contribution Fest" undertaken by a unique consortium of expert software developers and users from the metaproteomics research community, who have co-authored this manuscript. These resources are documented on GitHub and freely available through the Galaxy Toolshed, as well as a publicly accessible metaproteomics gateway Galaxy instance. These documented workflows are well suited for the training of novice metaproteomics researchers, through online resources such as the Galaxy Training Network, as well as hands-on training workshops. Here, we describe the metaproteomics tools available within these Galaxy-based resources, as well as the process by which they were selected and implemented in our community-based work. We hope this description will increase access to and utilization of metaproteomics tools, as well as offer a framework for continued community-based development and dissemination of cutting edge metaproteomics software. PMID- 29385084 TI - Viewpoint: A Contributory Role of Shell Ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) for Human Longevity in Okinawa, Japan? AB - The longevity of the population in the Okinawa Islands of Japan has been ascribed to genetic factors and the traditional Okinawa cuisine, which is low in calories and high in plant content. This diet includes shell ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) of the ginger family (Zingiberaceae). Due to its local popularity, Alpinia zerumbet has become the subject of a good deal of study at the University of the Ryukyus in Okinawa. Personal local experience and review of the literature now suggest that culinary shell ginger may contribute to longevity among the population in Okinawa. This is supported by its abundant phytochemical content, with antioxidant and anti-obesity properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain (DDK; 80-410 mg g-1 fresh weight), 5,6-dehydrokawain (DK; <=100 mg g-1), and essential oils, phenols, phenolic acids, and fatty acids (<=150 mg g-1 each). Further, Alpinia zerumbet extends the lifespan in animals by 22.6%. In conclusion, culinary shell ginger may significantly contribute to human longevity in Okinawa. PMID- 29385086 TI - Spiroketones and a Biphenyl Analog from Stems and Leaves of Larrea nitida and Their Inhibitory Activity against IL-6 Production. AB - Bioactivity-guided fractionation for the stems of leaves of Larrea nitida Cav., using interleukin-6 (IL-6) inhibitory assay in human mast cells (HMC-1), led to the isolation of three new compounds with an unprecedented skeleton in nature (1 3) and three known compounds (4-6). Their structures were elucidated through extensive spectroscopic analysis. The three new compounds were elucidated as two new spiroketones, nitidaones A (1), and B (2) and one new biphenyl analog, nitidaol (3). The known compounds were identified as nordihydroguaiaretic acid (4), 7,3',4'-tri-O-methylquercetin (5) and ayanin (6). All the isolates were tested for their inhibitory activity against IL-6 production in HMC-1 cells. Of them, compounds 1, 3-6 showed potent anti-inflammatory activity, with IC50 values of 12.8, 17.5, 14.9, 22.9, and 17.8 uM, respectively. PMID- 29385087 TI - Optimization of the Preparation Conditions of Borneol-Modified Ginkgolide Liposomes by Response Surface Methodology and Study of Their Blood Brain Barrier Permeability. AB - Ginkgolides (GG), containing ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC), are mainly prescribed for ischemic stroke and cerebral infarction. However, the ginkgolides can hardly pass the blood-brain barrier (BBB) into the brain. The purpose of this study was to prepare borneol-modified ginkgolides liposomes (GGB-LPs) to study whether borneol could enhance the transport of ginkgolides across the BBB. The preparation conditions of GGB-LPs were optimized by a response surface-central composite design. Also, pharmacokinetics and biodistribution studies of GGB-LPs were conducted using UPLC-MS. The optimal preparation conditions for GGB-LP were as follows: ratio of lipid to drug (w/w) was 9:1, ratio of phospholipid to cholesterol (w/w) was 7:1, and hydrate volume was 17.5 mL. Under these conditions, the GGB-LP yield was 89.73 +/- 3.45%. With GGB-LPs, borneol significantly promoted the transport of ginkgolide across the BBB. The pharmacokinetic parameters of GGB-LP were significantly improved too, with Tmax of 15 min and a high drug concentration of 3.39 MUg/g in brain. Additionally, the drug targeting index and relative uptake rate of GGB-LP was increased. Borneol-modified ginkgolide liposomes can thus potentially be used to improve the BBB permeability of gingkolide formulations. PMID- 29385085 TI - Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. AB - The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective antioxidant. An intact and functional pineal gland is necessary for preserving optimal human health. Unfortunately, this gland has the highest calcification rate among all organs and tissues of the human body. Pineal calcification jeopardizes melatonin's synthetic capacity and is associated with a variety of neuronal diseases. In the current review, we summarized the potential mechanisms of how this process may occur under pathological conditions or during aging. We hypothesized that pineal calcification is an active process and resembles in some respects of bone formation. The mesenchymal stem cells and melatonin participate in this process. Finally, we suggest that preservation of pineal health can be achieved by retarding its premature calcification or even rejuvenating the calcified gland. PMID- 29385088 TI - Potential Role of Humoral IL-6 Cytokine in Mediating Pro-Inflammatory Endothelial Cell Response in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a multifactorial disease with limited therapeutic options. Numerous intrinsic and extrinsic factors are involved in ALS motor neuron degeneration. One possible effector accelerating motor neuron death in ALS is damage to the blood-Central Nervous System barrier (B-CNS-B), mainly due to endothelial cell (EC) degeneration. Although mechanisms of EC damage in ALS are still unknown, vascular impairment may be initiated by various humoral inflammatory factors and other mediators. Systemic IL-6-mediated inflammation is a possible early extrinsic effector leading to the EC death causing central nervous system (CNS) barrier damage. In this review, we discuss the potential role of humoral factors in triggering EC alterations in ALS. A specific focus was on humoral IL-6 cytokine mediating EC inflammation via the trans-signaling pathway. Our preliminary in vitro studies demonstrated a proof of principle that short term exposure of human bone marrow endothelial cells to plasma from ALS patient leads to cell morphological changes, significantly upregulated IL-6R immunoexpression, and pro-inflammatory cell response. Our in-depth understanding of specific molecular mechanisms of this humoral cytokine in EC degeneration may facilitate an endothelial-IL-6-targeting therapy for restoring cell homeostasis and eventually reestablishing B-CNS-B integrity in ALS. PMID- 29385090 TI - A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87-99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis. AB - In this report, amide-linked cyclic peptide analogues of the 87-99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP87-99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP72-85-induced EAE in Lewis rats. The Lys91 and Pro96 of MBP87-99 are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91-99)[Ala96]MBP87-99, cyclo(87-99)[Ala91,96]MBP87-99 and cyclo(87 99)[Arg91, Ala96]MBP87-99, but not wild-type linear MBP87-99, strongly inhibited MBP72-85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87-99)[Arg91, Ala96]MBP87 99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction. PMID- 29385089 TI - Recent Advances in Treatment of Coronary Artery Disease: Role of Science and Technology. AB - Coronary artery disease (CAD) is one of the most common causes of death worldwide. In the last decade, significant advancements in CAD treatment have been made. The existing treatment is medical, surgical or a combination of both depending on the extent, severity and clinical presentation of CAD. The collaboration between different science disciplines such as biotechnology and tissue engineering has led to the development of novel therapeutic strategies such as stem cells, nanotechnology, robotic surgery and other advancements (3-D printing and drugs). These treatment modalities show promising effects in managing CAD and associated conditions. Research on stem cells focuses on studying the potential for cardiac regeneration, while nanotechnology research investigates nano-drug delivery and percutaneous coronary interventions including stent modifications and coatings. This article aims to provide an update on the literature (in vitro, translational, animal and clinical) related to these novel strategies and to elucidate the rationale behind their potential treatment of CAD. Through the extensive and continued efforts of researchers and clinicians worldwide, these novel strategies hold the promise to be effective alternatives to existing treatment modalities. PMID- 29385092 TI - Influence of PEG Stoichiometry on Structure-Tuned Formation of Self-Assembled Submicron Nickel Particles. AB - Self-assembled submicron nickel particles were successfully synthesized via the one-step surfactant-assisted solvothermal method. The impact of surfactant and reducing agent stoichiometry is investigated in this manuscript. Different morphologies and structures of Ni particles, including flower-like nanoflakes, hydrangea-like structures, chain structures, sphere-like structures, and hollow structures were prepared through different processing conditions with two parameters such as temperature and time. Based on scanning electron microscopy (SEM), X-ray diffraction (XRD), thermal gravimetric analysis (TGA) and vibrating sample magnetometry (VSM), the submicron nickel particles show good saturation magnetization and excellent thermal stabilities with a possible growth mechanism for the variety of the structure-tuned formation. Importantly, the microwave absorption properties of the submicron nickel particles were studied. The lowest reflection loss of Ni-P9/T200/H15 with a thin layer thickness of 1.7 mm can reach -42.6 dB at 17.3 GHz. PMID- 29385091 TI - Exploring Alternative Radiolabeling Strategies for Sialic Acid-Binding Immunoglobulin-Like Lectin 9 Peptide: [68Ga]Ga- and [18F]AlF-NOTA-Siglec-9. AB - Amino acid residues 283-297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates for visualizing inflammation non-invasively using positron emission tomography (PET). Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N''' tetraacetic acid (DOTA)-conjugated Siglec-9 has been evaluated extensively for this purpose. Here, we explored two alternative strategies for radiolabeling Siglec-9 peptide using a 1,4,7-triazacyclononane-triacetic acid (NOTA)-chelator to bind [68Ga]Ga or [18F]AlF. The radioligands were evaluated by in vivo PET imaging and ex vivo gamma-counting of turpentine-induced sterile skin/muscle inflammation in Sprague-Dawley rats. Both tracers showed clear accumulation in the inflamed tissues. The whole-body biodistribution patterns of the tracers were similar. PMID- 29385093 TI - Regulation of Cancer Stem Cell Metabolism by Secreted Frizzled-Related Protein 4 (sFRP4). AB - Tumours contain a small number of treatment-resistant cancer stem cells (CSCs), and it is through these that tumour regrowth originates at secondary sites, thus rendering CSCs an attractive target for treatment. Cancer cells adapt cellular metabolism for aggressive proliferation. Tumour cells use less efficient glycolysis for the production of ATP and increasing tumour mass, instead of oxidative phosphorylation (OXPHOS). CSCs show distinct metabolic shift and, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. Since Wnt signalling promotes glycolysis and tumour growth, we investigated the effect of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on CSC metabolism. We demonstrate that sFRP4 has a prominent role in basal glucose uptake in CSCs derived from breast and prostate tumour cell lines. We show that sFRP4 treatment on CSCs isolated with variable glucose content induces metabolic reprogramming by relocating metabolic flux to glycolysis or OXPHOS. Altogether, sFRP4 treatment compromises cell proliferation and critically affects cell survival mechanisms such as viability, glucose transporters, pyruvate conversion, mammalian target of rapamycin, and induces CSC apoptosis under conditions of variable glucose content. Our findings provide the feasibility of using sFRP4 to inhibit CSC survival in order to induce metabolic reprogramming in vivo. PMID- 29385094 TI - Enhanced Thermostability of Glucose Oxidase through Computer-Aided Molecular Design. AB - Glucose oxidase (GOD, EC.1.1.3.4) specifically catalyzes the reaction of beta-d glucose to gluconic acid and hydrogen peroxide in the presence of oxygen, which has become widely used in the food industry, gluconic acid production and the feed industry. However, the poor thermostability of the current commercial GOD is a key limiting factor preventing its widespread application. In the present study, amino acids closely related to the thermostability of glucose oxidase from Penicillium notatum were predicted with a computer-aided molecular simulation analysis, and mutant libraries were established following a saturation mutagenesis strategy. Two mutants with significantly improved thermostabilities, S100A and D408W, were subsequently obtained. Their protein denaturing temperatures were enhanced by about 4.4 degrees C and 1.2 degrees C, respectively, compared with the wild-type enzyme. Treated at 55 degrees C for 3 h, the residual activities of the mutants were greater than 72%, while that of the wild-type enzyme was only 20%. The half-lives of S100A and D408W were 5.13- and 4.41-fold greater, respectively, than that of the wild-type enzyme at the same temperature. This work provides novel and efficient approaches for enhancing the thermostability of GOD by reducing the protein free unfolding energy or increasing the interaction of amino acids with the coenzyme. PMID- 29385095 TI - Email Reminders Increase the Frequency That Pet Owners Update Their Microchip Information. AB - Stray animals with incorrect microchip details are less likely to be reclaimed, and unclaimed strays are at increased risk of euthanasia. A retrospective cohort study was performed using 394,747 cats and 904,909 dogs registered with Australia's largest microchip database to describe animal characteristics, determine whether annual email reminders increased the frequency that owners updated their information, and to compare frequencies of microchip information updates according to pet and owner characteristics. More than twice as many dogs (70%) than cats (30%) were registered on the database; the most numerous pure breeds were Ragdoll cats and Staffordshire Bull Terrier dogs, and the number of registered animals per capita varied by Australian state or territory. Owners were more likely (p < 0.001) to update their details soon after they were sent a reminder email, compared to immediately before that email, and there were significant (p < 0.001) differences in the frequency of owner updates by state or territory of residence, animal species, animal age, and socioeconomic index of the owner's postcode. This research demonstrates that email reminders increase the probability of owners updating their details on the microchip database, and this could reduce the percentages of stray animals that are unclaimed and subsequently euthanized. PMID- 29385096 TI - Landslide Susceptibility Assessment Using Spatial Multi-Criteria Evaluation Model in Rwanda. AB - Landslides susceptibility assessment has to be conducted to identify prone areas and guide risk management. Landslides in Rwanda are very deadly disasters. The current research aimed to conduct landslide susceptibility assessment by applying Spatial Multi-Criteria Evaluation Model with eight layers of causal factors including: slope, distance to roads, lithology, precipitation, soil texture, soil depth, altitude and land cover. In total, 980 past landslide locations were mapped. The relationship between landslide factors and inventory map was calculated using the Spatial Multi-Criteria Evaluation. The results revealed that susceptibility is spatially distributed countrywide with 42.3% of the region classified from moderate to very high susceptibility, and this is inhabited by 49.3% of the total population. In addition, Provinces with high to very high susceptibility are West, North and South (40.4%, 22.8% and 21.5%, respectively). Subsequently, the Eastern Province becomes the peak under low susceptibility category (87.8%) with no very high susceptibility (0%). Based on these findings, the employed model produced accurate and reliable outcome in terms of susceptibility, since 49.5% of past landslides fell within the very high susceptibility category, which confirms the model's performance. The outcomes of this study will be useful for future initiatives related to landslide risk reduction and management. PMID- 29385098 TI - Synthesis and Biological Evaluations of NO-Donating Oxa- and Aza Pentacycloundecane Derivatives as Potential Neuroprotective Candidates. AB - In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20-39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms. PMID- 29385097 TI - Bioactive Compounds in Functional Meat Products. AB - Meat and meat products are a good source of bioactive compounds with positive effect on human health such as vitamins, minerals, peptides or fatty acids. Growing food consumer awareness and intensified global meat producers competition puts pressure on creating new healthier meat products. In order to meet these expectations, producers use supplements with functional properties for animal diet and as direct additives for meat products. In the presented work seven groups of key functional constituents were chosen: (i) fatty acids; (ii) minerals; (iii) vitamins; (iv) plant antioxidants; (v) dietary fibers; (vi) probiotics and (vii) bioactive peptides. Each of them is discussed in term of their impact on human health as well as some quality attributes of the final products. PMID- 29385100 TI - Auxeticity of Concentric Auxetic-Conventional Foam Rods with High Modulus Interface Adhesive. AB - While the rule of mixture is applicable for addressing the overall Poisson's ratio of a concentrically aligned bi-layered rod under longitudinal loading, the same cannot be said for this rod under torsional loading due to the higher extent of deformation in the rod material further away from the torsional axis. In addition, the use of adhesives for attaching the solid inner rod to the hollow outer rod introduces an intermediate layer, thereby resulting in a tri-layered concentric rod if the adhesive layer is uniformly distributed. This paper investigates the effect of the adhesive properties on the overall auxeticity of a rod consisting of two concentrically aligned cylindrical isotropic foams with Poisson's ratio of opposite signs under torsional loads. An indirect way for obtaining Poisson's ratio of a concentrically tri-layered rod was obtained using a mechanics of materials approach. Results show that the auxeticity of such rods is influenced by the adhesive's stiffness, Poisson's ratio, thickness, and radius from the torsional axis. PMID- 29385099 TI - The Association between Iron and Vitamin D Status in Female Elite Athletes. AB - Vitamin D may influence iron metabolism and erythropoiesis, whereas iron is essential for vitamin D synthesis. We examined whether vitamin D deficiencies (VDD) are associated with reduced iron status and whether progressive iron deficiency (ID) is accompanied by inferior vitamin D status. The study included 219 healthy female (14-34 years old) athletes. VDD was defined as a 25(OH)D concentration < 75 nmol/L. ID was classified based on ferritin, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC) and blood morphology indices. The percentage of ID subjects was higher (32%) in the VDD group than in the 25(OH)D sufficient group (11%) (chi2 = 10.6; p = 0.001). The percentage of VDD subjects was higher (75%) in the ID than in the normal iron status group (48%) (chi2 = 15.6; p = 0.001). The odds ratios (ORs) for VDD increased from 1.75 (95% CI 1.02-2.99; p = 0.040) to 4.6 (95% CI 1.81-11.65; p = 0.001) with progressing iron deficiency. ID was dependent on VDD in both VDD groups (25(OH)D < 75 and < 50 nmol/L). The ID group had a lower 25(OH)D concentration (p = 0.000). The VDD group had lower ferritin (p = 0.043) and iron (p = 0.004) concentrations and higher values of TIBC (p = 0.016) and sTfR (p = 0.001). The current results confirm the association between vitamin D and iron status in female athletes, although it is difficult to assess exactly which of these nutrients exerts a stronger influence over the other. PMID- 29385101 TI - Marine Natural Peptides: Determination of Absolute Configuration Using Liquid Chromatography Methods and Evaluation of Bioactivities. AB - Over the last decades, many naturally occurring peptides have attracted the attention of medicinal chemists due to their promising applicability as pharmaceuticals or as models for drugs used in therapeutics. Marine peptides are chiral molecules comprising different amino acid residues. Therefore, it is essential to establish the configuration of the stereogenic carbon of their amino acid constituents for a total characterization and further synthesis to obtain higher amount of the bioactive marine peptides or as a basis for structural modifications for more potent derivatives. Moreover, it is also a crucial issue taking into account the mechanisms of molecular recognition and the influence of molecular three-dimensionality in this process. In this review, a literature survey covering the report on the determination of absolute configuration of the amino acid residues of diverse marine peptides by chromatographic methodologies is presented. A brief summary of their biological activities was also included emphasizing to the most promising marine peptides. A case study describing an experience of our group was also included. PMID- 29385103 TI - Anticancer Applications of Nanostructured Silica-Based Materials Functionalized with Titanocene Derivatives: Induction of Cell Death Mechanism through TNFR1 Modulation. AB - A series of cytotoxic titanocene derivatives have been immobilized onto nanostructured silica-based materials using two different synthetic routes, namely, (i) a simple grafting protocol via protonolysis of the Ti-Cl bond; and (ii) a tethering method by elimination of ethanol using triethoxysilyl moieties of thiolato ligands attached to titanium. The resulting nanostructured systems have been characterized by different techniques such as XRD, XRF, DR-UV, BET, SEM, and TEM, observing the incorporation of the titanocene derivatives onto the nanostructured silica and slight changes in the textural features of the materials after functionalization with the metallodrugs. A complete biological study has been carried out using the synthesized materials exhibiting moderate cytotoxicity in vitro against three human hepatic carcinoma (HepG2, SK-Hep-1, Hep3B) and three human colon carcinomas (DLD-1, HT-29, COLO320) and very low cytotoxicity against normal cell lines. In addition, the cells' metabolic activity was modified by a 24-h exposure in a dose-dependent manner. Despite not having a significant effect on TNFalpha or the proinflammatory interleukin 1alpha secretion, the materials strongly modulated tumor necrosis factor (TNF) signaling, even at sub-cytotoxic concentrations. This is achieved mainly by upregulation of the TNFR1 receptor production, something which has not previously been observed for these systems. PMID- 29385102 TI - Preventive Effects of Resveratrol on Endocannabinoid System and Synaptic Protein Modifications in Rat Cerebral Cortex Challenged by Bilateral Common Carotid Artery Occlusion and Reperfusion. AB - This study aims to evaluate the putative roles of a single acute dose of resveratrol (RVT) in preventing cerebral oxidative stress induced by bilateral common carotid artery occlusion, followed by reperfusion (BCCAO/R) and to investigate RVT's ability to preserve the neuronal structural integrity. Frontal and temporal-occipital cortices were examined in two groups of adult Wistar rats, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half the rats were gavage-fed with a single dose of RVT (40 mg/per rat in 300 uL of sunflower oil as the vehicle), while the second half received the vehicle alone. In the frontal cortex, RVT pre-treatment prevented the BCCAO/R-induced increase of lipoperoxides, augmented concentrations of palmitoylethanolamide and docosahexaenoic acid, increased relative levels of the cannabinoid receptors type 1 (CB1) and 2 (CB2), and peroxisome-proliferator-activated-receptor (PPAR)-alpha proteins. Increased expression of CB1/CB2 receptors mirrored that of synaptophysin and post-synaptic density-95 protein. No BCCAO/R-induced changes occurred in the temporal-occipital cortex. Collectively, our results demonstrate that, in the frontal cortex, RVT pre-treatment prevents the BCCAO/R-induced oxidative stress and modulates the endocannabinoid and PPAR-alpha systems. The increased expression of synaptic structural proteins further suggests the possible efficacy of RVT as a dietary supplement to preserve the nervous tissue metabolism and control the physiological response to the hypoperfusion/reperfusion challenge. PMID- 29385105 TI - A Rotational Gyroscope with a Water-Film Bearing Based on Magnetic Self-Restoring Effect. AB - Stable rotor levitation is a challenge for rotational gyroscopes (magnetically suspended gyroscopes (MSG) and electrostatically suspended gyroscopes (ESG)) with a ring- or disk-shaped rotor, which restricts further improvement of gyroscope performance. In addition, complicated pick-up circuits and feedback control electronics propose high requirement on fabrication technology. In the proposed gyroscope, a ball-disk shaped rotor is supported by a water-film bearing, formed by centrifugal force to deionized water at the cavity of the lower supporting pillar. Water-film bearing provides stable mechanical support, without the need for complicated electronics and control system for rotor suspension. To decrease sliding friction between the rotor ball and the water-film bearing, a supherhydrophobic surface (SHS) with nano-structures is fabricated on the rotor ball, resulting in a rated spinning speed increase of 12.4% (under the same driving current). Rotor is actuated by the driving scheme of brushless direct current motor (BLDCM). Interaction between the magnetized rotor and the magnetic conducted stator produces a sinusoidal rotor restoring torque, amplitude of which is proportional to the rotor deflection angle inherently. Utilization of this magnetic restoring effect avoids adding of a high amplitude voltage for electrostatic feedback, which may cause air breakdown. Two differential capacitance pairs are utilized to measure input angular speeds at perpendicular directions of the rotor plane. The bias stability of the fabricated gyroscope is as low as 0.5 degrees /h. PMID- 29385104 TI - Amorphous, Smart, and Bioinspired Polyphosphate Nano/Microparticles: A Biomaterial for Regeneration and Repair of Osteo-Articular Impairments In-Situ. AB - Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate (polyP), on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages. In the form of amorphous Ca-polyP nano/microparticles, polyP retains its function to act as both an intra- and extracellular metabolic fuel and a stimulus eliciting morphogenetic signals. The method for synthesis of the nano/microparticles with the polyanionic polyP also allowed the fabrication of hybrid particles with the bisphosphonate zoledronic acid, a drug used in therapy of bone metastases in cancer patients. The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors SOX9 (differentiation towards osteoblasts) and RUNX2 (chondrocyte differentiation). In parallel to this bone anabolic effect, incubation of the femur explants with these particles significantly reduced the expression of the gene encoding the osteoclast bone catabolic enzyme, cathepsin-K, while the expression of the tartrate-resistant acid phosphatase remained unaffected. The gene expression data were supported by the finding of an increased mineralization of the cells in the femur explants in response to the Ca-polyP particles. Finally, we show that the hybrid particles of polyP complexed with zoledronic acid exhibit both the cytotoxic effect of the bisphosphonate and the morphogenetic and mineralization inducing activity of polyP. Our results suggest that the Ca-polyP nano/microparticles are not only a promising scaffold material for repairing long bone osteo-articular damages but can also be applied, as a hybrid with zoledronic acid, as a drug delivery system for treatment of bone metastases. The polyP particles are highlighted as genuine, smart, bioinspired nano/micro biomaterials. PMID- 29385106 TI - Fatal Neurotoxicosis in Dogs Associated with Tychoplanktic, Anatoxin-a Producing Tychonema sp. in Mesotrophic Lake Tegel, Berlin. AB - In May 2017, at least 12 dogs showed signs of acute neurotoxicosis after swimming in or drinking from Lake Tegel, a mesotrophic lake in Berlin, Germany, and several of the affected dogs died shortly afterwards despite intensive veterinary treatment. Cyanobacterial blooms were not visible at the water surface or the shorelines. However, detached and floating water moss (Fontinalis antipyretica) with high amounts of Tychonema sp., a potential anatoxin-a (ATX) producing cyanobacterium, was found near the beaches where the dogs had been swimming and playing. Necropsies of two of the dogs revealed no specific lesions beside the anamnestic neurotoxicosis. ATX was detected in concentrations up to 8700 ug L-1 in the stomach contents, while other (neuro)toxic substances were not found. In the aqueous fraction of Fontinalis/Tychonema clumps sampled after the casualties, ATX was found in concentrations up to 1870 ug L-1. This is the first report of a dense population of Tychonema sp. in stands of Fontinalis resulting in high ATX contents. This case emphasizes the need for further investigation of potentially toxic, non-bloom forming cyanobacteria in less eutrophic water bodies and underlines the novel challenge of developing appropriate surveillance schemes for respective bathing sites. PMID- 29385107 TI - Survey of Candidate Genes for Maize Resistance to Infection by Aspergillus flavus and/or Aflatoxin Contamination. AB - Many projects have identified candidate genes for resistance to aflatoxin accumulation or Aspergillus flavus infection and growth in maize using genetic mapping, genomics, transcriptomics and/or proteomics studies. However, only a small percentage of these candidates have been validated in field conditions, and their relative contribution to resistance, if any, is unknown. This study presents a consolidated list of candidate genes identified in past studies or in house studies, with descriptive data including genetic location, gene annotation, known protein identifiers, and associated pathway information, if known. A candidate gene pipeline to test the phenotypic effect of any maize DNA sequence on aflatoxin accumulation resistance was used in this study to determine any measurable effect on polymorphisms within or linked to the candidate gene sequences, and the results are published here. PMID- 29385108 TI - Protic Ionic Liquids for Lignin Extraction-A Lignin Characterization Study. AB - Protic ionic liquids (PILs) have been established as effective solvents for the selective extraction and recovery of lignin from lignocellulosic biomass. In this study, we utilize extensive analytical techniques to characterize the PIL extracted lignins to (1) expand on the physical/chemical structure, and to (2) develop a better understanding of the mechanism behind the lignin dissolution process. The PIL-lignins were characterized using elemental and FT-IR analyses, alongside molecular weight distribution and chemical modeling via MM2. For the more ionic pyrrolidinium acetate ([Pyrr][Ac]), there is an increase in the fragmentation of lignin, resulting in lignin with a smaller average molecular weight and a more uniform dispersity. This lends better understanding to previous findings indicating that higher ionicity in a PIL leads to increased lignin extraction. PMID- 29385110 TI - Tumor of the Turkish saddle with endocrine disorders as the first manifestation of gastric adenocarcinoma. PMID- 29385109 TI - Development and Validation of a UPLC-MS/MS and UPLC-HR-MS Method for the Determination of Fumonisin B1 and Its Hydrolysed Metabolites and Fumonisin B2 in Broiler Chicken Plasma. AB - A sensitive and specific method for the quantitative determination of Fumonisin B1 (FB1), its partially hydrolysed metabolites pHFB1a+b and hydrolysed metabolite HFB1, and Fumonisin B2 (FB2) in broiler chicken plasma using ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS/MS) was developed. The sample preparation was rapid, straightforward and consisted of a deproteinization and phospholipid removal step using an Oasis(r) OstroTM 96-well plate. Chromatography was performed on an Acquity HSS-T3 column, using 0.3% formic acid and 10 mM ammonium formate in water, and acetonitrile as mobile phases. The MS/MS instrument was operated in the positive electrospray ionization mode and the two multiple reaction monitoring transitions were monitored for each component for quantification and identification, respectively. The method was validated in-house: matrix-matched calibration graphs were prepared and good linearity (r >= 0.99) was achieved over the concentration ranges tested (1-500 ng/mL for FB1 and FB2; 0.86-860 ng/mL for pHFB1a; 0.72-1430 ng/mL for pHFB1b and 2.5-2500 ng/mL for HFB1). Limits of quantification (LOQ) and detection (LOD) in plasma ranged between 0.72 to 2.5 ng/mL and 0.03 to 0.17 ng/mL, respectively. The results for the within-day and between-day precision and accuracy fell within the specified ranges. Moreover, the method was transferred to an UPLC high-resolution mass spectrometry (HR-MS) instrument in order to determine potential metabolites of HFB1, such as N-acyl-HFB1s and phase II metabolites. The method has been successfully applied to investigate the toxicokinetics and biotransformation of HFB1 in broiler chickens. PMID- 29385111 TI - The relationship between hematological parameters and the severity level of chronic obstructive lung disease. AB - INTRODUCTION Chronic obstructive pulmonary disease (COPD) is the most important lung disease leading to disability and even death. Recent studies have shown that the platelet indices are associated with several cardiovascular diseases; however, there is little data on COPD. OBJECTIVES We aimed to explore the relationship between platelet indices, together with the platelet-to lymphocyte ratio (PLR), white blood cell count to mean platelet volume ratio (WMR), and red cell distribution width (RDW) and the severity of COPD. PATIENTS AND METHODS This retrospective study was based on data collected from a total of 153 COPD patients admitted to our outpatient clinic between March 2014 and March 2015. All of the participants underwent pulmonary function tests; FEV1, FVC, and FEV1/FVC were measured. The study population was divided into four according to the severity of COPD as group A (mild), group B (mild to moderate), group C (moderate to severe), and group D (severe). RESULTS A significant increase was found in platelet distribution width (PDW), MPV, plateletcrit, PLR, and RDW while WMR decreased as the COPD severity increases. In the multiple logistic regression analysis, we found that PDW and RDW were independently associated with the presence of severe COPD. ROC curve analysis showed that a PDW>14.85 was associated with severe COPD with 85% sensitivity and 86% specificity while RDW>14.45 was associated with severe COPD with 90% sensitivity and 87% specificity. CONCLUSIONS The PDW and the RDW are independently associated with disease severity, which may indicate hypoxemia, underlying inflammation, and oxidative stress in COPD. PMID- 29385112 TI - Disorders of calcium and phosphate metabolism in patients with significant mitral regurgitation. AB - INTRODUCTION Although there are several known risk factors of cardiovascular diseases (CVDs), the search for new factors continues. In recent years, clinical trials have reported vitamin D and other calcium (Ca) and phosphate (P) metabolism disorders as potential new cardiovascular risk factors, but literature data on this association are limited. OBJECTIVES We aimed to assess the extent of Ca and P metabolism disorders in patients with mitral regurgitation (MR) and potential role of these disorders as risk factors of CVD. PATIENTS AND METHODS We enrolled adult patients with significant MR (vena contracta >3 mm, effective orifice area >0.2 cm2, and MR volume >30 ml/s) hospitalized in our department between July and September 2013. Anthropometric data were collected. Moreover, all patients underwent blood and urine analysis, transthoracic echocardiography, and 6-minute walking test. RESULTS A total of 99 patients were enrolled (median age, 75 years; [Q1-Q3, 66.0-81.5]; women, 35.4%). The median serum Ca level corrected by albumin was 3.22 mmol/l [Q1-Q3, 3.14-3.27]. The mean (SD) serum ionized Ca level corrected by pH was 1.05 (0.08) mmol/l. The median levels of parathyroid hormone (PTH) and 25(OH)D3 were 63.10 pg/ml [Q1-Q3, 40.95-88.55] and 14.80 ng/ml [Q1-Q3, 9.93-20.12], respectively. Patients with a history of heart failure (HF) with reduced ejection fraction (New York Heart Association class IV), shorter distance in the 6-minute walking test, lower left ventricular ejection fraction, and larger left ventricular end-diastolic diameter had significantly higher probability of elevated PTH levels. CONCLUSIONS Disorders of Ca and P metabolism in patients with significant MR are a noteworthy clinical problem. Our study is the first to systematically describe these disorders in patients with CVD. However, larger studies are needed to confirm the significance of our results. PMID- 29385113 TI - Leukotrienes and residual inflammatory risk in coronary artery disease. PMID- 29385114 TI - Long-term management of patients with chronic obstructive pulmonary disease who undergo percutaneous coronary intervention still needs to be dramatically improved. PMID- 29385115 TI - Using simple blood count for the diagnosis of pulmonary embolism in chronic obstructive pulmonary disease exacerbations: are we there yet? PMID- 29385116 TI - Endoscopy ultrasound-guided hepatogastrostomy as an alternative treatment in a patient with cholangiocarcinoma and failure of endoscopic retrograde cholangiopancreatography. PMID- 29385117 TI - T Cell Profile was Altered in Pulmonary Tuberculosis Patients with Type 2 Diabetes. AB - BACKGROUND Studies have suggested that type 2 diabetes (T2D) increases the risk of active pulmonary tuberculosis (TB) infection. T2D might exacerbate TB severity and adversely impact the treatment of TB patients by suppressing the immune response of TB. However, how the immune cell profiles are changed in Chinese TB patients with coincident of T2D compared with TB patients without T2D is still unclear. MATERIAL AND METHODS To explore the immune cell profile alteration in TB patients with T2D, we collected blood samples from 46 TB patients with or without T2D and measured the profiles of T cell subsets. RESULTS We found TB patients with coincident of T2D had higher percentages of Th2 and Th17 cells after TB antigens stimulation, while they had unchanged Th1 cells and decreased CD8+ cytotoxic T cells compared to TB patients without T2D. However, no significant difference in baseline percentages of these T cells subsets was observed. CONCLUSIONS T2D has important impacts on regulating anti-TB immunity by increasing Th2 and Th17 cell differentiation, but reducing the activity of CD8+ T cells. Our study supports the need to perform longitudinal studies to evaluate the roles of immunological interaction between T2D and TB in TB development. PMID- 29385118 TI - Brief interventions to promote behavioral change in primary care settings, a review of their effectiveness for smoking, alcohol and physical inactivity. AB - The brief intervention is a therapeutic strategy suggested to address behavioral changes associated with risk factors for chronic non-communicable diseases and there is ample evidence of its effectiveness. However, this evidence is sustained by various definitions of ?brief intervention?, a fact that makes the clinical application of this strategy difficult. This literature review article aimed to conduct a search for systematic reviews in the Epistemonikos database in order to identify common factors in the definition of ?brief intervention? and summarize some brief intervention strategies frequently used in primary health care. It also seeks to describe their effectiveness, for three risk factors: tobacco, alcohol and physical activity, within this clinical context. PMID- 29385119 TI - Students? scientific production: a proposal to encourage it. AB - The scientific production of medical students in Latin America, is poor and below their potential. The reason for this is the low theoretical and practical knowledge of scientific writing, a low margin for new knowledge generation, a heavy academic and clinical load, and the expected profile of the medical school graduate. In the present short communication, we propose teaching courses in research methodology, scientific writing in English and Spanish, a personalized search for students and mentors with research aptitudes. Also, we propose academic and material stimuli for publishing, rewards for the best papers made by students and the development and support of scientific student journals. Other proposals are the requirement to publish a paper for graduation, and sharing the most outstanding experiences. PMID- 29385121 TI - Does adding interbody fusion to posterolateral fusion increase success in the surgical management of degenerative lumbar spondylolisthesis? AB - INTRODUCTION: Surgical treatment of lumbar degenerative spondylolisthesis usually involves an interbody fusion in addition to a posterolateral fusion. However, the value of this procedure has not been established. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews, including nine primary studies; none of them randomized. We concluded performing interbody fusion in addition to posterolateral fusion during the surgical treatment of lumbar degenerative spondylolisthesis might decrease vertebral body slippage and lead to a slight improvement in quality of life. However, it is associated with higher costs. PMID- 29385122 TI - How to face a patient with benzodiazepine dependence in primary health care? Strategies for withdrawal. AB - Benzodiazepines are widely used in primary health care, and their prolonged use is an important problem given the medical consequences particularly in older adults, such as dependence, cognitive impairment, and risk of falls, among others. Primary care doctors generally have few tools to help with managing withdrawal from benzodiazepines. We conducted a review of the best available evidence on practical strategies to avoid dependence at the time of the initial prescription, and to help the patient with prolonged and probably dependent use. We found ten relevant systematic reviews showing evidence in favor of the use of multifaceted prescription strategies, gradual dose reduction, standardized letters, standardized counseling, pharmacotherapy and cognitive behavioral psychotherapy. For benzodiazepine withdrawal, a simple strategy that can be effective and long-lasting is to inform patients of the need to reduce consumption, giving them in writing the withdrawal guideline, indicating the possible effects of withdrawal and its solution. Given the available evidence, an integrated and step-by-step model is proposed for the management of the benzodiazepine user, from prescription to withdrawal. PMID- 29385123 TI - Rapid autophagic regression of the milk gland during involution is critical for maximizing tsetse viviparous reproductive output. AB - Tsetse flies are important vectors of human and animal trypanosomiasis. Ability to reduce tsetse populations is an effective means of disease control. Lactation is an essential component of tsetse's viviparous reproductive physiology and requires a dramatic increase in the expression and synthesis of milk proteins by the milk gland organ in order to nurture larval growth. In between each gonotrophic cycle, tsetse ceases milk production and milk gland tubules undergo a nearly two-fold reduction in width (involution). In this study, we examined the role autophagy plays during tsetse fly milk gland involution and reproductive output. Autophagy genes show elevated expression in tissues associated with lactation, immediately before or within two hours post-parturition, and decline at 24-48h post-parturition. This expression pattern is inversely correlated with that of the milk gland proteins (lactation-specific protein coding genes) and the autophagy inhibitor fk506-bp1. Increased expression of Drosophila inhibitor of apoptosis 1, diap1, was also observed in the milk gland during involution, when it likely prevents apoptosis of milk gland cells. RNAi-mediated knockdown of autophagy related gene 8a (atg8a) prevented rapid milk gland autophagy during involution, prolonging gestation, and reducing fecundity in the subsequent gonotrophic cycle. The resultant inhibition of autophagy reduced the recovery of stored lipids during the dry (non-lactating) periods by 15-20%. Ecdysone application, similar to levels that occur immediately before birth, induced autophagy, and increased milk gland involution even before abortion. This suggests that the ecdysteroid peak immediately preceding parturition likely triggers milk gland autophagy. Population modeling reveals that a delay in involution would yield a negative population growth rate. This study indicates that milk gland autophagy during involution is critical to restore nutrient reserves and allow efficient transition between pregnancy cycles. Targeting post birth phases of reproduction could be utilized as a novel mechanism to suppress tsetse populations and reduce trypanosomiasis. PMID- 29385124 TI - Coordination of olfactory receptor choice with guidance receptor expression and function in olfactory sensory neurons. AB - Olfactory sensory neurons choose to express a single odorant receptor (OR) from a large gene repertoire and extend axons to reproducible, OR-specific locations within the olfactory bulb. This developmental process produces a topographically organized map of odorant experience in the brain. The axon guidance mechanisms that generate this pattern of connectivity, as well as those that coordinate OR choice and axonal guidance receptor expression, are incompletely understood. We applied the powerful approach of single-cell RNA-seq on newly born olfactory sensory neurons (OSNs) in young zebrafish larvae to address these issues. Expression profiles were generated for 56 individual Olfactory Marker Protein (OMP) positive sensory neurons by single-cell (SC) RNA-seq. We show that just as in mouse OSNs, mature zebrafish OSNs typically express a single predominant OR transcript. Our previous work suggests that OSN targeting is related to the OR clade from which a sensory neuron chooses to express its odorant receptor. We categorized each of the mature cells based on the clade of their predominantly expressed OR. Transcripts expressed at higher levels in each of three clade related categories were identified using Penalized Linear Discriminant Analysis (PLDA). A genome-wide approach was used to identify membrane-associated proteins that are most likely to have guidance-related activity. We found that OSNs that choose to express an OR from a particular clade also express specific subsets of potential axon guidance genes and transcription factors. We validated our identification of candidate axon guidance genes for one clade of OSNs using bulk RNA-seq from a subset of transgene-labeled neurons that project to a single protoglomerulus. The differential expression patterns of selected candidate guidance genes were confirmed using fluorescent in situ hybridization. Most importantly, we observed axonal mistargeting in knockouts of three candidate axonal guidance genes identified in this analysis: nrp1a, nrp1b, and robo2. In each case, targeting errors were detected in the subset of axons that normally express these transcripts at high levels, and not in the axons that express them at low levels. Our findings demonstrate that specific, functional, axonal guidance related genes are expressed in subsets of OSNs that that can be categorized by their patterns of OR expression. PMID- 29385126 TI - Analysis of bacterial genomes from an evolution experiment with horizontal gene transfer shows that recombination can sometimes overwhelm selection. AB - Few experimental studies have examined the role that sexual recombination plays in bacterial evolution, including the effects of horizontal gene transfer on genome structure. To address this limitation, we analyzed genomes from an experiment in which Escherichia coli K-12 Hfr (high frequency recombination) donors were periodically introduced into 12 evolving populations of E. coli B and allowed to conjugate repeatedly over the course of 1000 generations. Previous analyses of the evolved strains from this experiment showed that recombination did not accelerate adaptation, despite increasing genetic variation relative to asexual controls. However, the resolution in that previous work was limited to only a few genetic markers. We sought to clarify and understand these puzzling results by sequencing complete genomes from each population. The effects of recombination were highly variable: one lineage was mostly derived from the donors, while another acquired almost no donor DNA. In most lineages, some regions showed repeated introgression and others almost none. Regions with high introgression tended to be near the donors' origin of transfer sites. To determine whether introgressed alleles imposed a genetic load, we extended the experiment for 200 generations without recombination and sequenced whole population samples. Beneficial alleles in the recipient populations were occasionally driven extinct by maladaptive donor-derived alleles. On balance, our analyses indicate that the plasmid-mediated recombination was sufficiently frequent to drive donor alleles to fixation without providing much, if any, selective advantage. PMID- 29385125 TI - Predicting pathogenicity behavior in Escherichia coli population through a state dependent model and TRS profiling. AB - The Binary State Speciation and Extinction (BiSSE) model is a branching process based model that allows the diversification rates to be controlled by a binary trait. We develop a general approach, based on the BiSSE model, for predicting pathogenicity in bacterial populations from microsatellites profiling data. A comprehensive approach for predicting pathogenicity in E. coli populations is proposed using the state-dependent branching process model combined with microsatellites TRS-PCR profiling. Additionally, we have evaluated the possibility of using the BiSSE model for estimating parameters from genetic data. We analyzed a real dataset (from 251 E. coli strains) and confirmed previous biological observations demonstrating a prevalence of some virulence traits in specific bacterial sub-groups. The method may be used to predict pathogenicity of other bacterial taxa. PMID- 29385127 TI - Inferring sex-specific demographic history from SNP data. AB - The relative female and male contributions to demography are of great importance to better understand the history and dynamics of populations. While earlier studies relied on uniparental markers to investigate sex-specific questions, the increasing amount of sequence data now enables us to take advantage of tens to hundreds of thousands of independent loci from autosomes and the X chromosome. Here, we develop a novel method to estimate effective sex ratios or ESR (defined as the female proportion of the effective population) from allele count data for each branch of a rooted tree topology that summarizes the history of the populations of interest. Our method relies on Kimura's time-dependent diffusion approximation for genetic drift, and is based on a hierarchical Bayesian model to integrate over the allele frequencies along the branches. We show via simulations that parameters are inferred robustly, even under scenarios that violate some of the model assumptions. Analyzing bovine SNP data, we infer a strongly female biased ESR in both dairy and beef cattle, as expected from the underlying breeding scheme. Conversely, we observe a strongly male-biased ESR in early domestication times, consistent with an easier taming and management of cows, and/or introgression from wild auroch males, that would both cause a relative increase in male effective population size. In humans, analyzing a subsample of non-African populations, we find a male-biased ESR in Oceanians that may reflect complex marriage patterns in Aboriginal Australians. Because our approach relies on allele count data, it may be applied on a wide range of species. PMID- 29385129 TI - Correction: Evaluating the sustainability, scalability, and replicability of an STH transmission interruption intervention: The DeWorm3 implementation science protocol. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005988.]. PMID- 29385130 TI - GSimp: A Gibbs sampler based left-censored missing value imputation approach for metabolomics studies. AB - Left-censored missing values commonly exist in targeted metabolomics datasets and can be considered as missing not at random (MNAR). Improper data processing procedures for missing values will cause adverse impacts on subsequent statistical analyses. However, few imputation methods have been developed and applied to the situation of MNAR in the field of metabolomics. Thus, a practical left-censored missing value imputation method is urgently needed. We developed an iterative Gibbs sampler based left-censored missing value imputation approach (GSimp). We compared GSimp with other three imputation methods on two real-world targeted metabolomics datasets and one simulation dataset using our imputation evaluation pipeline. The results show that GSimp outperforms other imputation methods in terms of imputation accuracy, observation distribution, univariate and multivariate analyses, and statistical sensitivity. Additionally, a parallel version of GSimp was developed for dealing with large scale metabolomics datasets. The R code for GSimp, evaluation pipeline, tutorial, real-world and simulated targeted metabolomics datasets are available at: https://github.com/WandeRum/GSimp. PMID- 29385128 TI - High prevalence of S. Stercoralis infection among patients with Chagas disease: A retrospective case-control study. AB - BACKGROUND: We evaluate the association between Trypanosoma cruzi infection and strongyloidiasis in a cohort of Latin American (LA) migrants screened for both infections in a non-endemic setting. METHODOLOGY: Case-control study including LA individuals who were systematically screened for T. cruzi infection and strongyloidiasis between January 2013 and April 2015. Individuals were included as cases if they had a positive serological result for Strongyloides stercoralis. Controls were randomly selected from the cohort of individuals screened for T. cruzi infection that tested negative for S. stercoralis serology. The association between T. cruzi infection and strongyloidiasis was evaluated by logistic regression models. PRINCIPAL FINDINGS: During the study period, 361 individuals were screened for both infections. 52 (14.4%) individuals had a positive serological result for strongyloidiasis (cases) and 104 participants with negative results were randomly selected as controls. 76 (48.7%) indiviuals had a positive serological result for T. cruzi. Factors associated with a positive T. cruzi serology were Bolivian origin (94.7% vs 78.7%; p = 0.003), coming from a rural area (90.8% vs 68.7%; p = 0.001), having lived in an adobe house (88.2% vs 70%; p = 0.006) and a referred contact with triatomine bugs (86.7% vs 63.3%; p = 0.001). There were more patients with a positive S. stercoralis serology among those who were infected with T. cruzi (42.1% vs 25%; p = 0.023). Epidemiological variables were not associated with a positive strongyloidiasis serology. T. cruzi infection was more frequent among those with strongyloidiasis (61.5% vs 42.3%; p = 0.023). In multivariate analysis, T. cruzi infection was associated with a two fold increase in the odds of strongyloidiasis (OR 2.23; 95% CI 1.07-4.64; p = 0.030). CONCLUSIONS: T. cruzi infection was associated with strongyloidiasis in LA migrants attending a tropical diseases unit even after adjusting for epidemiological variables. These findings should encourage physicians in non endemic settings to implement a systematic screening for both infections in LA individuals. PMID- 29385131 TI - Historical perspective: Revisiting the St. Lucia Project, a multi-year comparison trial of schistosomiasis control strategies. PMID- 29385132 TI - Social sensing of floods in the UK. AB - "Social sensing" is a form of crowd-sourcing that involves systematic analysis of digital communications to detect real-world events. Here we consider the use of social sensing for observing natural hazards. In particular, we present a case study that uses data from a popular social media platform (Twitter) to detect and locate flood events in the UK. In order to improve data quality we apply a number of filters (timezone, simple text filters and a naive Bayes 'relevance' filter) to the data. We then use place names in the user profile and message text to infer the location of the tweets. These two steps remove most of the irrelevant tweets and yield orders of magnitude more located tweets than we have by relying on geo-tagged data. We demonstrate that high resolution social sensing of floods is feasible and we can produce high-quality historical and real-time maps of floods using Twitter. PMID- 29385133 TI - Correction: Investigating the case of human nose shape and climate adaptation. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006616.]. PMID- 29385135 TI - Bypassing health facilities for childbirth in the context of the JSY cash transfer program to promote institutional birth: A cross-sectional study from Madhya Pradesh, India. AB - Bypassing health facilities for childbirth can be costly both for women and health systems. There have been some reports on this from Sub-Saharan African and from Nepal but none from India. India has implemented the Janani Suraksha Yojana (JSY), a large national conditional cash transfer program which has successfully increased the number of institutional births in India. This paper aims to study the extent of bypassing the nearest health facility offering intrapartum care in three districts of Madhya Pradesh, India, and to identify individual and facility determinants of bypassing in the context of the JSY program. Our results provide information to support the optimal utilization of facilities at different levels of the healthcare system for childbirth. Data was collected from 96 facilities (74 public) and 720 rural mothers who delivered at these facilities were interviewed. Multilevel logistic regression was used to analyze the data. Facility obstetric care functionality was assessed by the number of emergency obstetric care (EmOC) signal functions performed in the last three months. Thirty eighth percent of the mothers bypassed the nearest public facility for their current delivery. Primiparity, higher education, arriving by hired transport and a longer distance from home to the nearest facility increased the odds of bypassing a public facility for childbirth. The variance partition coefficient showed that 37% of the variation in bypassing the nearest public facility can be attributed to difference between facilities. The number of basic emergency obstetric care signal functions (AOR = 0.59, 95% CI 0.37-0.93), and the availability of free transportation at the nearest facility (AOR = 0.11, 95% CI 0.03-0.31) were protective factors against bypassing. The variation between facilities (MOR = 3.85) was more important than an individual's characteristics to explain bypassing in MP. This multilevel study indicates that in this setting, a focus on increasing the level of emergency obstetric care functionality in public obstetric care facilities will allow more optimal utilization of facilities for childbirth under the JSY program thereby leading to better outcomes for mothers. PMID- 29385134 TI - Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. AB - : The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84 4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]. CONCLUSIONS: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients. PMID- 29385136 TI - Combining Ordinary Kriging with wind directions to identify sources of industrial odors in Portland, Oregon. AB - This study combines Ordinary Kriging, odor monitoring, and wind direction data to demonstrate how these elements can be applied to identify the source of an industrial odor. The specific case study used as an example of how to address this issue was the University Park neighborhood of Portland, Oregon (USA) where residents frequently complain about industrial odors, and suspect the main source to be a nearby Daimler Trucks North America LLC manufacturing plant. We collected 19,665 odor observations plus 105,120 wind measurements, using an automated weather station to measure winds in the area at five-minute intervals, logging continuously from December 2014 through November 2015, while we also measured odors at 19 locations, three times per day, using methods from the American Society of the International Association for Testing and Materials. Our results quantify how winds vary with season and time of day when industrial odors were observed versus when they were not observed, while also mapping spatiotemporal patterns in these odors using Ordinary Kriging. Our analyses show that industrial odors were detected most frequently to the northwest of the Daimler plant, mostly when winds blew from the southeast, suggesting Daimler's facility is a likely source for much of this odor. PMID- 29385138 TI - Correction: Assessing the feasibility of interrupting the transmission of soil transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol. AB - [This corrects the article DOI: 10.1371/journal.pntd.0006166.]. PMID- 29385137 TI - Visual attention mediates the relationship between body satisfaction and susceptibility to the body size adaptation effect. AB - Body size misperception-the belief that one is larger or smaller than reality affects a large and growing segment of the population. Recently, studies have shown that exposure to extreme body stimuli results in a shift in the point of subjective normality, suggesting that visual adaptation may be a mechanism by which body size misperception occurs. Yet, despite being exposed to a similar set of bodies, some individuals within a given geographical area will develop body size misperception and others will not. The reason for these individual difference is currently unknown. One possible explanation stems from the observation that women with lower levels of body satisfaction have been found to pay more attention to images of thin bodies. However, while attention has been shown to enhance visual adaptation effects in low (e.g. rotational and linear motion) and high level stimuli (e.g., facial gender), it is not known whether this effect exists in visual adaptation to body size. Here, we test the hypothesis that there is an indirect effect of body satisfaction on the direction and magnitude of the body fat adaptation effect, mediated via visual attention (i.e., selectively attending to images of thin over fat bodies or vice versa). Significant mediation effects were found in both men and women, suggesting that observers' level of body satisfaction may influence selective visual attention to thin or fat bodies, which in turn influences the magnitude and direction of visual adaptation to body size. This may provide a potential mechanism by which some individuals develop body size misperception-a risk factor for eating disorders, compulsive exercise behaviour and steroid abuse-while others do not. PMID- 29385139 TI - Can simple trachelectomy or conization show comparable survival rate compared with radical trachelectomy in IA1 cervical cancer patients with lymphovascular space invasion who wish to save fertility? A systematic review and guideline recommendation. AB - OBJECTIVE: This study aims to analyze the published literatures on the effect of less radical fertility-preserving procedures, such as conization or simple trachelectomy, on oncological outcomes in IA1 cervical cancer patients with lymphovascular space invasion (LVSI) through a systematic-review. METHODS: The EMBASE and MEDLINE databases and Cochrane Library were searched for published studies reporting the oncological outcomes of conization/simple trachelectomy in these patients, through April 2017. The endpoints were recurrence and mortality rates. Data were presented as per the Meta-analysis Of Observational Studies in Epidemiology checklist. Practice guidelines were generated via the Grading of Recommendation, Assessment, Development and Evaluation system. RESULTS: From 6,755 records, 94 full-texts articles were reviewed for eligibility, and five studies were included in this systematic review. All included studies were nonrandomized studies: two case-control studies comparing conization (n = 14) with hysterectomy (n = 24), and the other three were interrupted time series including conization (n = 20) and simple vaginal trachelectomy (n = 59). During the median follow-up duration of 43 months, no recurrence was reported in both conization and simple trachelectomy groups in IA1 patients with LVSI. From three studies reporting the fertility outcomes, the rates of pregnancy, live birth, preterm delivery, and second-trimester miscarriage were 73% (35/48), 64% (32/50), 10% (5/48), and 6% (3/48), respectively. CONCLUSION: Results suggest that simple trachelectomy or conization could be performed for IA1 cervical cancer patients with LVSI who want to preserve fertility, although these results are only based on a small number of nonrandomized studies (recommendation grade 2 = weak; evidence level D = very low). Further randomized trials with long-term study period are needed to address this issue. PMID- 29385140 TI - Underreporting of deaths in the maternal deaths surveillance system in one region of Morocco. AB - OBJECTIVE: To assess the reliability of maternal deaths surveillance system (MDSS) and to determine the factors that influence its completeness in one region of Morocco. METHODS: We conducted a retrospective survey in "Gharb Chrarda Bni Hssen" region (GCBH) between January the 1st, 2013 and September the 30th, 2014 using multiple sources approach. All deaths of women of reproductive age (WRA) were investigated using certificates with medical cause, medical records and interviews with household members and relatives to ascertain a pregnancy-related or maternal death. An External Expert Committee reviewed the information collected to assign a cause for each death. Our results were compared to those reported in the same period by the MDSS. FINDINGS: Our study identified 690 deaths of WRA and 69 maternal deaths of which 34.8% occurred outside health facilities. The MDSS recorded during the study period 538 deaths of WRA and 29 maternal deaths (including only one outside health facility) representing respectively an underreporting of 22.0% and 58.0%. Late maternal deaths represented 11.4% of all deaths of women with a registered pregnancy within 12 months prior to the death, while the MDSS identified none. The maternal mortality ratio (MMR) was estimated at 103, approximately 2.5 times higher than that reported in the MDSS. CONCLUSION: Our study has shown weaknesses in the current notification system for maternal deaths in the region of GCBH. Therefore, more attention must be given to the regional committees in charge of auditing the cases and defining actions to be implemented to prevent further maternal deaths. PMID- 29385141 TI - Contrasting impacts of competition on ecological and social trait evolution in songbirds. AB - Competition between closely related species has long been viewed as a powerful selective force that drives trait diversification, thereby generating phenotypic diversity over macroevolutionary timescales. However, although the impact of interspecific competition has been documented in a handful of iconic insular radiations, most previous studies have focused on traits involved in resource use, and few have examined the role of competition across large, continental radiations. Thus, the extent to which broad-scale patterns of phenotypic diversity are shaped by competition remain largely unclear, particularly for social traits. Here, we estimate the effect of competition between interacting lineages by applying new phylogenetic models that account for such interactions to an exceptionally complete dataset of resource-use traits and social signaling traits for the entire radiation of tanagers (Aves, Thraupidae), the largest family of songbirds. We find that interspecific competition strongly influences the evolution of traits involved in resource use, with a weaker effect on plumage signals, and very little effect on song. Our results provide compelling evidence that interspecific exploitative competition contributes to ecological trait diversification among coexisting species, even in a large continental radiation. In comparison, signal traits mediating mate choice and social competition seem to diversify under different evolutionary models, including rapid diversification in the allopatric stage of speciation. PMID- 29385142 TI - The auditory cortex hosts network nodes influential for emotion processing: An fMRI study on music-evoked fear and joy. AB - Sound is a potent elicitor of emotions. Auditory core, belt and parabelt regions have anatomical connections to a large array of limbic and paralimbic structures which are involved in the generation of affective activity. However, little is known about the functional role of auditory cortical regions in emotion processing. Using functional magnetic resonance imaging and music stimuli that evoke joy or fear, our study reveals that anterior and posterior regions of auditory association cortex have emotion-characteristic functional connectivity with limbic/paralimbic (insula, cingulate cortex, and striatum), somatosensory, visual, motor-related, and attentional structures. We found that these regions have remarkably high emotion-characteristic eigenvector centrality, revealing that they have influential positions within emotion-processing brain networks with "small-world" properties. By contrast, primary auditory fields showed surprisingly strong emotion-characteristic functional connectivity with intra auditory regions. Our findings demonstrate that the auditory cortex hosts regions that are influential within networks underlying the affective processing of auditory information. We anticipate our results to incite research specifying the role of the auditory cortex-and sensory systems in general-in emotion processing, beyond the traditional view that sensory cortices have merely perceptual functions. PMID- 29385143 TI - Longitudinal microbiome analysis of single donor fecal microbiota transplantation in patients with recurrent Clostridium difficile infection and/or ulcerative colitis. AB - BACKGROUND: Studies of colonoscopic fecal microbiota transplant (FMT) in patients with recurrent CDI, indicate that this is a very effective treatment for preventing further relapses. In order to provide this service at Stony Brook University Hospital, we initiated an open-label prospective study of single colonoscopic FMT among patients with >= 2 recurrences of CDI, with the intention of monitoring microbial composition in the recipient before and after FMT, as compared with their respective donor. We also initiated a concurrent open label prospective trial of single colonoscopic FMT of patients with ulcerative colitis (UC) not responsive to therapy, after obtaining an IND permit (IND 15642). To characterize how FMT alters the fecal microbiota in patients with recurrent Clostridia difficile infections (CDI) and/or UC, we report the results of a pilot microbiome analysis of 11 recipients with a history of 2 or more recurrences of C. difficile infections without inflammatory bowel disease (CDI-only), 3 UC recipients with recurrent C. difficile infections (CDI + UC), and 5 UC recipients without a history of C. difficile infections (UC-only). METHOD: V3V4 Illumina 16S ribosomal RNA (rRNA) gene sequencing was performed on the pre-FMT, 1-week post FMT, and 3-months post-FMT recipient fecal samples along with those collected from the healthy donors. Fitted linear mixed models were used to examine the effects of Group (CDI-only, CDI + UC, UC-only), timing of FMT (Donor, pre-FMT, 1 week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on the diversity and composition of fecal microbiota. Pairwise comparisons were then carried out on the recipient vs. donor and between the pre-FMT, 1-week post-FMT, and 3-months post-FMT recipient samples within each group. RESULTS: Significant effects of FMT on overall microbiota composition (e.g., beta diversity) were observed for the CDI-only and CDI + UC groups. Marked decreases in the relative abundances of the strictly anaerobic Bacteroidetes phylum, and two Firmicutes sub phyla associated with butyrate production (Ruminococcaceae and Lachnospiraceae) were observed between the CDI-only and CDI + UC recipient groups. There were corresponding increases in the microaerophilic Proteobacteria phylum and the Firmicutes/Bacilli group in the CDI-only and CDI + UC recipient groups. At a more granular level, significant effects of FMT were observed for 81 genus-level operational taxonomic units (OTUs) in at least one of the three recipient groups (p<0.00016 with Bonferroni correction). Pairwise comparisons of the estimated pre FMT recipient/donor relative abundance ratios identified 6 Gammaproteobacteria OTUs, including the Escherichia-Shigella genus, and 2 Fusobacteria OTUs with significantly increased relative abundance in the pre-FMT samples of all three recipient groups (FDR < 0.05), however the magnitude of the fold change was much larger in the CDI-only and CDI + UC recipients than in the UC-only recipients. Depletion of butyrate producing OTUs, such as Faecalibacterium, in the CDI-only and CDI + UC recipients, were restored after FMT. CONCLUSION: The results from this pilot study suggest that the microbial imbalances in the CDI + UC recipients more closely resemble those of the CDI-only recipients than the UC-only recipients. PMID- 29385144 TI - T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: An exploratory proof-of-principle study. AB - BACKGROUND: It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer. We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16. METHODS: TCR repertoires of women with HPV16 related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n = 25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n = 51], D [n = 2], J [n = 13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status. RESULTS: TCR repertoire richness was associated with CIN3+ status (P = 0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V gene (TRBV6-7) was significantly associated with CIN3+ status (RA = 0.11%, 0.16%, among cases and controls, respectively, Bonferroni P = 0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90). CONCLUSIONS: Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed. IMPACT: This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection. PMID- 29385145 TI - Pattern dynamics of the reaction-diffusion immune system. AB - In this paper, we will investigate the effect of diffusion, which is ubiquitous in nature, on the immune system using a reaction-diffusion model in order to understand the dynamical behavior of complex patterns and control the dynamics of different patterns. Through control theory and linear stability analysis of local equilibrium, we obtain the optimal condition under which the system loses stability and a Turing pattern occurs. By combining mathematical analysis and numerical simulation, we show the possible patterns and how these patterns evolve. In addition, we establish a bridge between the complex patterns and the biological mechanism using the results from a previous study in Nature Cell Biology. The results in this paper can help us better understand the biological significance of the immune system. PMID- 29385146 TI - Effectiveness of a LED flashlight technique in reducing livestock depredation by lions (Panthera leo) around Nairobi National Park, Kenya. AB - The global lion (Panthera leo) population decline is partly a result of retaliatory killing in response to livestock depredation. Nairobi National Park (NNP) is a small protected area in Kenya surrounded by a human-dominated landscape. Communities around the park use flashlights to deter lions from their livestock bomas. We investigated the response by lions to the installation of a LED flashlight technique during 2007-2016.We interviewed 80 owners of livestock bomas with flashlights (n = 43) and without (n = 37) flashlights in the surroundings of NNP and verified reported attacks on bomas against predation data over10 years. The frequency of attacks on bomas equipped with flashlights was significantly lower compared to bomas without flashlights. We also found that after flashlight installation at livestock bomas, lion attacks took place further away from the park edge, towards areas where bomas without flashlights were still present. With increased numbers of flashlight installations at bomas in recent years, we further noticed a shift from nocturnal to more diurnal predation incidences. Our study shows that the LED flashlight technique is effective in reducing nocturnal livestock predation at bomas by lions. Long term studies on the effects as well as expansion of this technique into other communities around NNP are recommended. PMID- 29385147 TI - Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial. AB - BACKGROUND: The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Delta9 tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex(r)) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants. METHODS: Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time. RESULTS: Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores. CONCLUSIONS: Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence. PMID- 29385148 TI - Low prevalence of HCV infection with predominance of genotype 4 among HIV patients living in Libreville, Gabon. AB - BACKGROUND: Gabon is an endemic area for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) and the risk of co-infection is high. METHOD: Between November 2015 and April 2016, we conducted retrospective study on HCV infection among people living with HIV/AIDS (PLHA). A total of 491 PLHA were included in this study and tested for the presence of HCV infection. HIV viral loads were obtained using the Generic HIV viral Load(r) assay and the CD4+ T cells count was performed using BD FACSCountTM CD4 reagents. HCV screening was performed using the MP Diagnostics HCV ELISA 4.0 kit. HCV genotypes were determined by sequence analysis of NS5B and Core regions. The Mann-Whitney test was used to compare the groups. Chi-2 test and Fisher's Exact Test were used to compare prevalence. RESULTS: HCV seroprevalence was 2.9% (14/491), (95% confidence interval (CI):1.4 4.3%). The percentage of HCV viremic patients, defined by the detection of HCV RNA in plasma, was 57% (8/14), representing 1.6% of the total population. HCV seroprevalence and replicative infection were not statistically differ with gender. The percentage of co-infection increased with age. No correlation with CD4+ T cells count and HIV viral load level was registered in this study. Identified HCV strains were predominantly of genotype 4 (87.5%) including 4k, 4e, 4g, 4p, 4f and 4c subtypes. Only one strain belonged to genotype 2 (subtype 2q). Analysis of the NS5B region did not reveal the presence of resistance-associated substitutions for sofosbuvir. CONCLUSION: A systematic screening of hepatitis C is therefore strongly recommended as well as genotyping of HCV strains in order to adapt treatments for the specific case of people living with HIV/AIDS in Central Africa. PMID- 29385149 TI - Erythropoietin attenuates motor neuron programmed cell death in a burn animal model. AB - Burn-induced neuromuscular dysfunction may contribute to long-term morbidity; therefore, it is imperative to develop novel treatments. The present study investigated whether erythropoietin (EPO) administration attenuates burn-induced motor neuron apoptosis and neuroinflammatory response. To validate our hypothesis, a third-degree hind paw burn rat model was developed by bringing the paw into contact with a metal surface at 75 degrees C for 10 s. A total of 24 male Sprague-Dawley rats were randomly assigned to four groups: Group A, sham control; Group B, burn-induced; Group C, burn + single EPO dose (5000 IU/kg i.p. at D0); and Group D, burn + daily EPO dosage (3000 IU/kg/day i.p. at D0-D6). Two treatment regimens were used to evaluate single versus multiple doses treatment effects. Before sacrifice, blood samples were collected for hematological parameter examination. The histological analyses of microglia activation, iNOS, and COX-2 in the spinal cord ventral horn were performed at week 1 post-burn. In addition, we examined autophagy changes by biomarkers of LC3B and ATG5. The expression of BCL-2, BAX, cleaved caspase-3, phospho-AKT, and mTOR was assessed simultaneously through Western blotting. EPO administration after burn injury attenuated neuroinflammation through various mechanisms, including the reduction of microglia activity as well as iNOS and COX-2 expression in the spinal cord ventral horn. In addition, the expression of phospho-AKT, mTOR and apoptotic indicators, such as BAX, BCL-2, and cleaved caspase-3, was modulated. Furthermore, the activity of burn-induced autophagy in the spinal cord ventral horn characterized by the expression of autophagic biomarkers, LC3B and ATG5, was reduced after EPO administration. The present results indicate that EPO inhibits the AKT-mTOR pathway to attenuate burn-induced motor neuron programmed cell death and microglia activation. EPO can modulate neuroinflammation and programmed cell death and may be a therapeutic candidate for neuroprotection. PMID- 29385151 TI - Examination of China's performance and thematic evolution in quantum cryptography research using quantitative and computational techniques. AB - This study performed two phases of analysis to shed light on the performance and thematic evolution of China's quantum cryptography (QC) research. First, large scale research publication metadata derived from QC research published from 2001 2017 was used to examine the research performance of China relative to that of global peers using established quantitative and qualitative measures. Second, this study identified the thematic evolution of China's QC research using co-word cluster network analysis, a computational science mapping technique. The results from the first phase indicate that over the past 17 years, China's performance has evolved dramatically, placing it in a leading position. Among the most significant findings is the exponential rate at which all of China's performance indicators (i.e., Publication Frequency, citation score, H-index) are growing. China's H-index (a normalized indicator) has surpassed all other countries' over the last several years. The second phase of analysis shows how China's main research focus has shifted among several QC themes, including quantum-key distribution, photon-optical communication, network protocols, and quantum entanglement with an emphasis on applied research. Several themes were observed across time periods (e.g., photons, quantum-key-distribution, secret-messages, quantum-optics, quantum-signatures); some themes disappeared over time (e.g., computer-networks, attack-strategies, bell-state, polarization-state), while others emerged more recently (e.g., quantum-entanglement, decoy-state, unitary operation). Findings from the first phase of analysis provide empirical evidence that China has emerged as the global driving force in QC. Considering China is the premier driving force in global QC research, findings from the second phase of analysis provide an understanding of China's QC research themes, which can provide clarity into how QC technologies might take shape. QC and science and technology policy researchers can also use these findings to trace previous research directions and plan future lines of research. PMID- 29385150 TI - Sleep and biological parameters in professional burnout: A psychophysiological characterization. AB - Professional burnout syndrome has been described in association with insomnia and metabolic, inflammatory and immune correlates. We investigated the interest of exploring biological parameters and sleep disturbances in relation to burnout symptoms among white-collar workers. Fifty-four participants with burnout were compared to 86 healthy control participants in terms of professional rank level, sleep, job strain (Karasek questionnaire), social support, anxiety and depression (HAD scale). Fasting concentrations of glycaemia, glycosylated hemoglobin (HbA1C), total-cholesterol, triglycerides, C-reactive protein (CRP), thyroid stimulating hormone (TSH), 25-hydroxyvitamin D (25[OH]D), and white blood cell (WBC) counts were assessed. Analysis of variance and a forward Stepwise Multiple Logistic Regression were made to identify predictive factors of burnout. Besides reporting more job strain (in particular job control p = 0.02), higher levels of anxiety (p<0.001), and sleep disorders related to insomnia (OR = 21.5, 95%CI = 8.8-52.3), participants with burnout presented higher levels of HbA1C, glycaemia, CRP, lower levels of 25(OH)D, higher number of leukocytes, neutrophils and monocytes (P<0.001 for all) and higher total-cholesterol (P = 0.01). In particular, when HbA1c is > 3.5%, the prevalence of burnout increases from 16.6% to 60.0% (OR = 4.3, 95%CI = 2.8-6.9). Strong significant positive correlation existed between HbA1C and the two dimensions (emotional exhaustion and depersonalization (r = 0.79 and r = 0.71, p<0.01)) of burnout. Models including job strain, job satisfaction, anxiety and insomnia did not predict burnout (p = 0.30 and p = 0.50). However, when HbA1C levels is included, the prediction of burnout became significant (P = 0.03). Our findings demonstrated the interest of sleep and biological parameters, in particular HbA1C levels, in the characterization of professional burnout. PMID- 29385152 TI - Intratumoral heterogeneity characterized by pretreatment PET in non-small cell lung cancer patients predicts progression-free survival on EGFR tyrosine kinase inhibitor. AB - Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell's C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression-free survival (PFS). The highest HR was 6.41 (P<0.01) with co-occurrence (Co) entropy. Increased risk remained present after adjusting for initial stage, performance status (PS), and metabolic volume (MV) (aHR: 4.86, P<0.01). Textural parameters were found to have an incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model of the stage and PS (C-index 0.596 vs. 0.662, P = 0.02, by Co entropy). Heterogeneity textural parameters acquired from pretreatment FDG-PET/CT are highly predictive factors for PFS of EGFR TKI in EGFR mutated NSCLC patients. These parameters are easily applicable to the identification of a subpopulation at increased risk of early EGFR TKI failure. Correlation to genomic alteration should be determined in future studies. PMID- 29385153 TI - Impacts of rising sea temperature on krill increase risks for predators in the Scotia Sea. AB - Climate change is a threat to marine ecosystems and the services they provide, and reducing fishing pressure is one option for mitigating the overall consequences for marine biota. We used a minimally realistic ecosystem model to examine how projected effects of ocean warming on the growth of Antarctic krill, Euphausia superba, might affect populations of krill and dependent predators (whales, penguins, seals, and fish) in the Scotia Sea. We also investigated the potential to mitigate depletion risk for predators by curtailing krill fishing at different points in the 21st century. The projected effects of ocean warming on krill biomass were strongest in the northern Scotia Sea, with a >=40% decline in the mass of individual krill. Projections also suggest a 25% chance that krill biomass will fall below an established depletion threshold (75% of its unimpacted level), with consequent risks for some predator populations, especially penguins. Average penguin abundance declined by up to 30% of its unimpacted level, with up to a 50% chance of falling below the depletion threshold. Simulated krill fishing at currently permitted harvest rates further increased risks for depletion, and stopping fishing offset the increased risks associated with ocean warming in our model to some extent. These results varied by location and species group. Risk reductions at smaller spatial scales also differed from those at the regional level, which suggests that some predator populations may be more vulnerable than others to future changes in krill biomass. However, impacts on predators did not always map directly to those for krill. Our findings indicate the importance of identifying vulnerable marine populations and targeting protection measures at appropriate spatial scales, and the potential for spatially-structured management to avoid aggravating risks associated with rising ocean temperatures. This may help balance tradeoffs among marine ecosystem services in an uncertain future. PMID- 29385154 TI - Effect of maternal age on the risk of preterm birth: A large cohort study. AB - BACKGROUND: Maternal age at pregnancy is increasing worldwide as well as preterm birth. However, the association between prematurity and advanced maternal age remains controversial. OBJECTIVE: To evaluate the impact of maternal age on the occurrence of preterm birth after controlling for multiple known confounders in a large birth cohort. STUDY DESIGN: Retrospective cohort study using data from the QUARISMA study, a large Canadian randomized controlled trial, which collected data from 184,000 births in 32 hospitals. Inclusion criteria were maternal age over 20 years. Exclusion criteria were multiple pregnancy, fetal malformation and intra-uterine fetal death. Five maternal age categories were defined and compared for maternal characteristics, gestational and obstetric complications, and risk factors for prematurity. Risk factors for preterm birth <37 weeks, either spontaneous or iatrogenic, were evaluated for different age groups using multivariate logistic regression. RESULTS: 165,282 births were included in the study. Chronic hypertension, assisted reproduction techniques, pre-gestational diabetes, invasive procedure in pregnancy, gestational diabetes and placenta praevia were linearly associated with increasing maternal age whereas hypertensive disorders of pregnancy followed a "U" shaped distribution according to maternal age. Crude rates of preterm birth before 37 weeks followed a "U" shaped curve with a nadir at 5.7% for the group of 30-34 years. In multivariate analysis, the adjusted odds ratio (aOR) of prematurity stratified by age group followed a "U" shaped distribution with an aOR of 1.08 (95%CI; 1.01-1.15) for 20 24 years, and 1.20 (95% CI; 1.06-1.36) for 40 years and older. Confounders found to have the greatest impact were placenta praevia, hypertensive complications, and maternal medical history. CONCLUSION: Even after adjustment for confounders, advanced maternal age (40 years and over) was associated with preterm birth. A maternal age of 30-34 years was associated with the lowest risk of prematurity. PMID- 29385155 TI - Opinions of general practitioners about psychotherapy and their relationships with mental health professionals in the management of major depression: A qualitative survey. AB - BACKGROUND: French general practitioners (GPs) refer their patients with major depression to psychiatrists or for psychotherapy at particularly low rates. OBJECTIVES: This qualitative study aims to explore general practitioners' (GP) opinions about psychotherapy, their relationships with mental health professionals, their perceptions of their role and that of psychiatrists in treating depression, and the relations between these factors and the GPs' strategies for managing depression. METHODS: In 2011, in-depth interviews based on a semi-structured interview guide were conducted with 32 GPs practicing in southeastern France. Verbatim transcripts were examined by analyzing their thematic content. RESULTS: We identified three profiles of physicians according to their opinions and practices about treatment strategies for depression: pro pharmacological treatment, pro-psychotherapy and those with mixed practices. Most participants considered their relationships with psychiatrists unsatisfactory, would like more and better collaboration with them and shared the same concept of management in general practice. This concept was based both on the values and principles of practice shared by GPs and on their strong differentiation of their management practices from those of psychiatrists. CONCLUSION: Several attitudes and values common to GPs might contribute to their low rate of referrals for psychotherapy in France: strong occupational identity, substantial variations in GPs' attitudes and practices regarding depression treatment strategies, representations sometimes unfavorable toward psychiatrists. Actions to develop a common culture and improve cooperation between GPs and psychiatrists are essential. They include systems of collaborative care and the development of interdisciplinary training common to GPs and psychiatrists practicing in the same area. PMID- 29385156 TI - Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. AB - BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone. METHODS: In total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up. RESULTS: At the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601-0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without. CONCLUSIONS: Patients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy. PMID- 29385157 TI - Pettiness: Conceptualization, measurement and cross-cultural differences. AB - Although pettiness, defined as the tendency to get agitated over trivial matters, is a facet of neuroticism which has negative health implications, no measure exists. The goal of the current study was to develop, and validate a short pettiness scale. In Study 1 (N = 2136), Exploratory Factor Analysis distilled a one-factor model with five items. Convergent validity was established using the Big Five Inventory, DASS, Satisfaction with Life Scale, and Conner-Davidson Resilience Scale. As predicted, pettiness was positively associated with neuroticism, depression, anxiety and stress but negatively related to extraversion, agreeableness, conscientiousness, openness, life satisfaction and resilience. Also, as predicted, pettiness was not significantly related to physical functioning, or blind and constructive patriotism, indicating discriminant validity. Confirmatory Factor Analysis in Study 2 (N = 734) revealed a stable one-factor model of pettiness. In Study 3 (N = 532), the scale, which showed a similar factor structure in the USA and Singapore, also reflected predicted cross-cultural patterns: Pettiness was found to be significantly lower in the United States, a culture categorized as "looser" than in Singapore, a culture classified as "tighter" in terms of Gelfand and colleagues' framework of national tendencies to oppose social deviance. Results suggest that this brief 5 item tool is a reliable and valid measure of pettiness, and its use in health research is encouraged. PMID- 29385158 TI - Identification of high risk areas for avian influenza outbreaks in California using disease distribution models. AB - The coexistence of different types of poultry operations such as free range and backyard flocks, large commercial indoor farms and live bird markets, as well as the presence of many areas where wild and domestic birds co-exist, make California susceptible to avian influenza outbreaks. The 2014-2015 highly pathogenic Avian Influenza (HPAI) outbreaks affecting California and other states in the United States have underscored the need for solutions to protect the US poultry industry against this devastating disease. We applied disease distribution models to predict where Avian influenza is likely to occur and the risk for HPAI outbreaks is highest. We used observations on the presence of Low Pathogenic Avian influenza virus (LPAI) in waterfowl or water samples at 355 locations throughout the state and environmental variables relevant to the disease epidemiology. We used two algorithms, Random Forest and MaxEnt, and two data-sets Presence-Background and Presence-Absence data. The models performed well (AUCc > 0.7 for testing data), particularly those using Presence-Background data (AUCc > 0.85). Spatial predictions were similar between algorithms, but there were large differences between the predictions with Presence-Absence and Presence-Background data. Overall, predictors that contributed most to the models included land cover, distance to coast, and broiler farm density. Models successfully identified several counties as high-to-intermediate risk out of the 8 counties with observed outbreaks during the 2014-2015 HPAI epizootics. This study provides further insights into the spatial epidemiology of AI in California, and the high spatial resolution maps may be useful to guide risk based surveillance and outreach efforts. PMID- 29385159 TI - Antibiotic prophylaxis in orthognathic surgery: A complex systematic review. AB - OBJECTIVE: In orthognathic surgery, antibiotics are prescribed to reduce the risk of postoperative infection. However, there is lack of consensus over the appropriate drug, the dose and duration of administration. The aim of this complex systematic review was to assess the effect of antibiotics on postoperative infections in orthognathic surgery. METHODS: Both systematic reviews and primary studies were assessed. Medline (OVID), The Cochrane Library (Wiley) and EMBASE (embase.com), PubMed (non-indexed articles) and Health Technology Assessment (HTA) publications were searched. The primary studies were assessed using GRADE and the systematic reviews by AMSTAR. RESULTS: Screening of abstracts yielded 6 systematic reviews and 36 primary studies warranting full text scrutiny. In total,14 primary studies were assessed for risk of bias. Assessment of the included systematic reviews identified two studies with a moderate risk of bias, due to inclusion in the meta-analyses of primary studies with a high risk of bias. Quality assessment of the primary studies disclosed one with a moderate risk of bias and one with a low risk. The former compared a single dose of antibiotic with 24 hour prophylaxis using the same antibiotic; the latter compared oral and intravenous administration of antibiotics. Given the limited number of acceptable studies, no statistical analysis was undertaken, as it was unlikely to contribute any relevant information. CONCLUSION: With respect to antibiotic prophylaxis in orthognathic surgery, most of the studies to date have been poorly conducted and reported. Thus scientific uncertainty remains as to the preferred antibiotic and the optimal duration of administration. PMID- 29385160 TI - Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. AB - BACKGROUND: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. HC-070 IN VITRO: To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases. HC-070 IN VIVO: Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms. PMID- 29385162 TI - The balance between apoptosis and autophagy regulates testis regression and recrudescence in the seasonal-breeding South American plains vizcacha, Lagostomus maximus. AB - Mammalian testis undergoes deep changes in their architecture and function during photoregression conditions in seasonal breeders. Particularly, the testicular mechanisms that regulate the transition between the active (functional) and inactive (regression) stage vary between species. The aim of the present study was to analyze the incidence of proliferation, apoptosis and autophagy in the testicular seminiferous ephitelium of a seasonal breeder, Lagostomus maximus, during the annual reproductive cycle. We observed that proliferating spermatogonia increased from the active testis until reaching the maximum peak in the activating testis. During the annual reproductive cycle, the quantity of apoptotic-TUNEL positive spermatogonia and meiotic germ cells was constant and this might be regulated by the members of the BCL2 family. Only in the activating testis, apoptosis of germ cells was almost undetectable. The analysis of the autophagic-related proteins BECN1 and LC3 showed their localization in Leydig cells and the germ cells in the active and activating testis. In the inactive testis, BECN1 and LC3 ceased to be immunolocalized within the seminiferous tubules and the mRNA expression of both regulators decreased. Moreover, the expression of BECN1 and LC3 and also the apoptotic index were up regulated in testicular cultures subjected to nutritional stress. These results suggest a possible interaction between apoptosis and autophagy in the active and activating testis (characterized by high metabolic requirement and nutrient), where autophagy could promote survival over cell death. In the inactive testis, the absence of autophagic-related proteins might explain the massive loss of germ cells, suggesting that autophagy plays new and key role in the alterations of the seminiferous epithelium during photoregression. PMID- 29385161 TI - Can long-term historical data from electronic medical records improve surveillance for epidemics of acute respiratory infections? A systematic evaluation. AB - BACKGROUND: As the deployment of electronic medical records (EMR) expands, so is the availability of long-term datasets that could serve to enhance public health surveillance. We hypothesized that EMR-based surveillance systems that incorporate seasonality and other long-term trends would discover outbreaks of acute respiratory infections (ARI) sooner than systems that only consider the recent past. METHODS: We simulated surveillance systems aimed at discovering modeled influenza outbreaks injected into backgrounds of patients with ARI. Backgrounds of daily case counts were either synthesized or obtained by applying one of three previously validated ARI case-detection algorithms to authentic EMR entries. From the time of outbreak injection, detection statistics were applied daily on paired background+injection and background-only time series. The relationship between the detection delay (the time from injection to the first alarm uniquely found in the background+injection data) and the false-alarm rate (FAR) was determined by systematically varying the statistical alarm threshold. We compared this relationship for outbreak detection methods that utilized either 7 days (early aberrancy reporting system (EARS)) or 2-4 years of past data (seasonal autoregressive integrated moving average (SARIMA) time series modeling). RESULTS: In otherwise identical surveillance systems, SARIMA detected epidemics sooner than EARS at any FAR below 10%. The algorithms used to detect single ARI cases impacted both the feasibility and marginal benefits of SARIMA modeling. Under plausible real-world conditions, SARIMA could reduce detection delay by 5-16 days. It also was more sensitive at detecting the summer wave of the 2009 influenza pandemic. CONCLUSION: Time series modeling of long-term historical EMR data can reduce the time it takes to discover epidemics of ARI. Realistic surveillance simulations may prove invaluable to optimize system design and tuning. PMID- 29385163 TI - Kinetics of calcium binding to dental biofilm bacteria. AB - Dental biofilm bacteria can bind calcium ions and release them during a pH drop, which could decrease the driving force for dental demineralization (i.e. hydroxyapatite dissolution) occurring at reduced pHs. However, the kinetics of this binding and release is not completely understood. Here we validated a method to evaluate the kinetics of calcium binding and release to/from Streptococcus mutans, and estimated the importance of this reservoir as a source of ions. The kinetics of calcium binding was assessed by measuring the amount of bound calcium in S. mutans Ingbrit 1600 pellets treated with PIPES buffer, pH 7.0, containing 1 or 10 mM Ca; for the release kinetics, bacterial pellets previously treated with 1 mM or 10 mM Ca were exposed to the calcium-free or 1 mM Ca PIPES buffer, pH 7.0, for up to 60 min. Binding and release curves were constructed and parameters of kinetics were calculated. Also, calcium release was assessed by exposing pellets previously treated with calcium to a pH 5.0 buffer for 10 min. Calcium binding to bacteria was concentration-dependent and rapid, with maximum binding reached at 5 min. On the other hand, calcium release was slower, and according to the calculations, would never be complete in the groups pretreated with 10 mM Ca. Decreasing pH from 7.0 to 5.0 caused a release of calcium able to increase the surrounding fluid calcium concentration in 2 mM. The results suggest that dental biofilm bacteria may act as a calcium reservoir, rapidly binding ions from surrounding fluids, releasing them slowly at neutral pH and promptly during a pH drop. PMID- 29385164 TI - The specificity of attentional biases by type of gambling: An eye-tracking study. AB - A growing body of research indicates that gamblers develop an attentional bias for gambling-related stimuli. Compared to research on substance use, however, few studies have examined attentional biases in gamblers using eye-gaze tracking, which has many advantages over other measures of attention. In addition, previous studies of attentional biases in gamblers have not directly matched type of gambler with personally-relevant gambling cues. The present study investigated the specificity of attentional biases for individual types of gambling using an eye-gaze tracking paradigm. Three groups of participants (poker players, video lottery terminal/slot machine players, and non-gambling controls) took part in one test session in which they viewed 25 sets of four images (poker, VLTs/slot machines, bingo, and board games). Participants' eye fixations were recorded throughout each 8-second presentation of the four images. The results indicated that, as predicted, the two gambling groups preferentially attended to their primary form of gambling, whereas control participants attended to board games more than gambling images. The findings have clinical implications for the treatment of individuals with gambling disorder. Understanding the importance of personally-salient gambling cues will inform the development of effective attentional bias modification treatments for problem gamblers. PMID- 29385165 TI - A novel expert system for objective masticatory efficiency assessment. AB - Most of the tools and diagnosis models of Masticatory Efficiency (ME) are not well documented or severely limited to simple image processing approaches. This study presents a novel expert system for ME assessment based on automatic recognition of mixture patterns of masticated two-coloured chewing gums using a combination of computational intelligence and image processing techniques. The hypotheses tested were that the proposed system could accurately relate specimens to the number of chewing cycles, and that it could identify differences between the mixture patterns of edentulous individuals prior and after complete denture treatment. This study enrolled 80 fully-dentate adults (41 females and 39 males, 25 +/- 5 years of age) as the reference population; and 40 edentulous adults (21 females and 19 males, 72 +/- 8.9 years of age) for the testing group. The system was calibrated using the features extracted from 400 samples covering 0, 10, 15, and 20 chewing cycles. The calibrated system was used to automatically analyse and classify a set of 160 specimens retrieved from individuals in the testing group in two appointments. The ME was then computed as the predicted number of chewing strokes that a healthy reference individual would need to achieve a similar degree of mixture measured against the real number of cycles applied to the specimen. The trained classifier obtained a Mathews Correlation Coefficient score of 0.97. ME measurements showed almost perfect agreement considering pre- and post-treatment appointments separately (kappa >= 0.95). Wilcoxon signed-rank test showed that a complete denture treatment for edentulous patients elicited a statistically significant increase in the ME measurements (Z = -2.31, p < 0.01). We conclude that the proposed expert system proved able and reliable to accurately identify patterns in mixture and provided useful ME measurements. PMID- 29385167 TI - Foraging plasticity in seabirds: A non-invasive study of the diet of greater crested terns breeding in the Benguela region. AB - Marine predators, such as seabirds, are useful indicators of marine ecosystem functioning. In particular, seabird diet may reflect variability in food-web composition due to natural or human-induced environmental change. Diet monitoring programmes, which sample diet non-invasively, are valuable aids to conservation and management decision-making. We investigated the diet of an increasing population of greater crested terns Thalasseus bergii in the Western Cape, South Africa, during three successive breeding seasons (2013 to 2015), when populations of other seabirds feeding on small pelagic schooling fish in the region were decreasing. Breeding greater crested terns carry prey in their bills, so we used an intensive photo-sampling method to record their diet with little disturbance. We identified 24,607 prey items from at least 47 different families, with 34 new prey species recorded. Fish dominated the diet, constituting 94% of prey by number, followed by cephalopods (3%), crustaceans (2%) and insects (1%). The terns mainly targeted surface-schooling Clupeiformes, with anchovy Engraulis encrasicolus the most abundant prey in all three breeding seasons (65% overall). Prey composition differed significantly between breeding stages and years, with anchovy most abundant at the start of the breeding season, becoming less frequent as the season progressed. The proportion of anchovy in the diet also was influenced by environmental factors; anchovy occurred more frequently with increasing wind speeds and was scarce on foggy days, presumably because terns rely in part on social facilitation to locate anchovy schools. The application of this intensive and non-invasive photo-sampling method revealed an important degree of foraging plasticity for this seabird within a context of locally reduced food availability, suggesting that, unlike species that specialise on a few high-quality prey, opportunistic seabirds may be better able to cope with reductions in the abundance of their preferred prey. PMID- 29385166 TI - Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury. AB - OBJECTIVE: Locomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs' pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury). STUDY DESIGN: Prospective cohort study; pilot trial with small sample size. METHODS: Eight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart. RESULTS: Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants. CONCLUSIONS: These results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03036527. PMID- 29385168 TI - Two way controls of apoptotic regulators consign DmArgonaute-1 a better clasp on it. AB - Argonaute family proteins are well conserved among all organisms. Its role in mitotic cell cycle progression and apoptotic cell elimination is poorly understood. Earlier we have established the contribution of Ago-1 in cell cycle control related to G2/M cyclin in Drosophila. Here we have extended our study in understanding the relationship of Ago-1 in regulating apoptosis during Drosophila development. Apoptosis play a critical role in controlling organ shape and size during development of multi cellular organism. Multifarious regulatory pathways control apoptosis during development among which highly conserved JNK (c-Jun N terminal kinase) pathway play a crucial role. Here we have over expressed Ago-1 in Drosophila eye and brain by employing UAS (upstream activation sequence)-GAL4 system under the expression of eye and brain specific driver. Over expression of Ago-1 resulted in reduced number of ommatidia in the eye and produced smaller size brain in adult and larval Drosophila. A drastic reversal of the phenotype towards normal was observed upon introduction of a single copy of the dominant negative mutation of basket (bsk, Drosophila homolog of JNK) indicating an active and physical involvement of the bsk with Ago-1 in inducing developmental apoptotic process. Further study showed that Ago-1 stimulates phosphorylation of JNK through transforming growth factor-beta activated kinase 1- hemipterous (Tak1 hep) axis of JNK pathway. JNK phosphorylation results in up regulation of pro apoptotic genes head involution defective (hid), grim & reaper (rpr) and induces activation of Drosophila caspases (cysteinyl aspartate proteinases);DRONC (Death regulator Nedd2-like caspase), ICE (alternatively Drice, Death related ICE-like caspase) and DCP1 (Death caspase-1) by inhibiting apoptotic inhibitor protein DIAP1 (Death-associated inhibitor of apoptosis 1). Further, Ago-1 also inhibits miR-14 expression to trigger apoptosis. Our findings propose that Ago-1 acts as a key regulator in controlling cell death, tumor regression and stress response in metazoan providing a constructive bridge between RNAi machinery and cell death. PMID- 29385170 TI - Remoteness influences access to sexual partners and drives patterns of viral sexually transmitted infection prevalence among nomadic pastoralists. AB - Sexually transmitted infections (STIs) comprise a significant portion of the infectious-disease burden among rural people in the Global South. Particular characteristics of ruralness-low-density settlements and poor infrastructure-make healthcare provision difficult, and remoteness, typically a characteristic of ruralness, often compounds the difficultly. Remoteness may also accelerate STI transmission, particularly that of viral STIs, through formation of small, highly connected sexual networks through which pathogens can spread rapidly, especially when partner concurrency is broadly accepted. Herein, we explored the effect of remoteness on herpes simplex virus type-2 (HSV-2) epidemiology among semi-nomadic pastoralists in northwestern (Kaokoveld) Namibia, where, in 2009 we collected HSV 2-specific antibody status, demographic, sexual network, and travel data from 446 subjects (women = 213, men = 233) in a cross-sectional study design. HSV-2 prevalence was high overall in Kaokoveld (>35%), but was heterogeneously distributed across locally defined residential regions: some regions had significantly higher HSV-2 prevalence (39-48%) than others (21-33%). Using log linear models, we asked the following questions: 1) Are sexual contacts among people in high HSV-2-prevalence regions more likely to be homophilous (i.e., from the same region) than those among people from low-prevalence regions? 2) Are high prevalence regions more "functionally" remote, in that people from those regions are more likely to travel within their own region than outside, compared to people from other regions? We found that high-prevalence regions were more sexually homophilous than low-prevalence regions and that those regions also had higher rates of within-region travel than the other regions. These findings indicate that remoteness can create contact structures for accelerated STI transmission among people who are already disproportionately vulnerable to consequences of untreated STIs. PMID- 29385169 TI - Fowlpoxvirus recombinants coding for the CIITA gene increase the expression of endogenous MHC-II and Fowlpox Gag/Pro and Env SIV transgenes. AB - A complete eradication of an HIV infection has never been achieved by vaccination and the search for new immunogens that can induce long-lasting protective responses is ongoing. Avipoxvirus recombinants are host-restricted for replication to avian species and they do not have the undesired side effects induced by vaccinia recombinants. In particular, Fowlpox (FP) recombinants can express transgenes over long periods and can induce protective immunity in mammals, mainly due to CD4-dependent CD8+ T cells. In this context, the class II transactivator (CIITA) has a pivotal role in triggering the adaptive immune response through induction of the expression of class-II major histocompatibility complex molecule (MHC-II), that can present antigens to CD4+ T helper cells. Here, we report on construction of novel FPgp and FPenv recombinants that express the highly immunogenic SIV Gag-pro and Env structural antigens. Several FP-based recombinants, with single or dual genes, were also developed that express CIITA, driven from H6 or SP promoters. These recombinants were used to infect CEF and Vero cells in vitro and determine transgene expression, which was evaluated by real-time PCR and Western blotting. Subcellular localisation of the different proteins was evaluated by confocal microscopy, whereas HLA-DR or MHC-II expression was measured by flow cytometry. Fowlpox recombinants were also used to infect syngeneic T/SA tumour cells, then injected into Balb/c mice to elicit MHC II immune response and define the presentation of the SIV transgene products in the presence or absence of FPCIITA. Antibodies to Env were measured by ELISA. Our data show that the H6 promoter was more efficient than SP to drive CIITA expression and that CIITA can enhance the levels of the gag/pro and env gene products only when infection is performed by FP single recombinants. Also, CIITA expression is higher when carried by FP single recombinants than when combined with FPgp or FPenv constructs and can induce HLA-DR cell surface expression. However, in-vivo experiments did not show any significant increase in the humoral response. As CIITA already proved to elicit immunogenicity by improving antigen presentation, further in-vivo experiments should be performed to increase the immune responses. The use of prime/boost immunisation protocols and the oral administration route of the recombinants may enhance the immunogenicity of Env peptides presented by MHC-II and provide CD4+ T-cell stimulation. PMID- 29385171 TI - Sex differences in circadian food anticipatory activity are not altered by individual manipulations of sex hormones or sex chromosome copy number in mice. AB - Recent studies in mice have demonstrated a sexual dimorphism in circadian entrainment to scheduled feeding. On a time restricted diet, males tend to develop food anticipatory activity (FAA) sooner than females and with a higher amplitude of activity. The underlying cause of this sex difference remains unknown. One study suggests that sex hormones, both androgens and estrogens, modulate food anticipatory activity in mice. Here we present results suggesting that the sex difference in FAA is unrelated to gonadal sex hormones. While a sex difference between males and females in FAA on a timed, calorie restricted diet was observed there were no differences between intact and gonadectomized mice in the onset or magnitude of FAA. To test other sources of the sex difference in circadian entrainment to scheduled feeding, we used sex chromosome copy number mutants, but there was no difference in FAA when comparing XX, XY-, XY-;Sry Tg, and XX;Sry Tg mice, demonstrating that gene dosage of sex chromosomes does not mediate the sex difference in FAA. Next, we masculinized female mice by treating them with 17-beta estradiol during the neonatal period; yet again, we saw no difference in FAA between control and masculinized females. Finally, we observed that there was no longer a sex difference in FAA for older mice, suggesting that the sex difference in FAA is age-dependent. Thus, our study demonstrates that singular manipulations of gonadal hormones, sex chromosomes, or developmental patterning are not able to explain the difference in FAA between young male and female mice. PMID- 29385172 TI - Not in wilderness: African vulture strongholds remain in areas with high human density. AB - Vultures constitute an important functional group in many ecosystems, providing crucial ecosystem services both in natural and humanized environments. These scavengers are facing massive declines worldwide, but in several African countries virtually nothing is known on populations' status and threats, hampering the development of adequate conservation strategies. In Guinea-Bissau, globally important populations of Hooded Necrosyrtes monachus and African white backed vultures Gyps africanus were recently reported. Using the country as a study area, we aim to characterize human-vulture interactions in West Africa applying a multidisciplinary approach. We assessed the status and distribution of vulture populations using data from 1711 km of roadside transects, examined predictors of their distribution, and produced a nationwide population estimate for the Hooded Vulture, using an innovative method based on the relationship between the size of human population in settlements and vulture numbers. We conducted 47 stakeholder interviews to assess perceived roles played by vultures, and to investigate potential anthropogenic threats. Hooded vultures were strongly associated with high human population densities, whereas no relation was found between African white-backed and Ruppell's vultures and any of the tested predictors, which included cattle density, precipitation and Normalized Difference Vegetation Index, among others. We estimate a national population of 43347 Hooded vultures, the largest population reported in the species range. Respondents were generally aware of the services provided by vultures, especially waste and carcass removal, including in urban areas. Hunting for witchcraft and traditional medicine was the most frequently recognised threat, while poisoning was ranked as having the highest impact. We hypothesise that poisoning-related mortality may be affecting African white-backed and Ruppell's vultures' distribution and explain their scarcity in apparently highly suitable habitats. Our results suggest a mutualistic rather than a commensalistic relationship between vultures and humans, with important implications for designing and implementing conservation strategies. PMID- 29385173 TI - Rural versus urban academic hospital mortality following stroke in Canada. AB - INTRODUCTION: Stroke is one of the leading causes of death in Canada. While stroke care has improved dramatically over the last decade, outcomes following stroke among patients treated in rural hospitals have not yet been reported in Canada. OBJECTIVES: To describe variation in 30-day post-stroke in-hospital mortality rates between rural and urban academic hospitals in Canada. We also examined 24/7 in-hospital access to CT scanners and selected services in rural hospitals. MATERIALS AND METHODS: We included Canadian Institute for Health Information (CIHI) data on adjusted 30-day in-hospital mortality following stroke from 2007 to 2011 for all acute care hospitals in Canada excluding Quebec and the Territories. We categorized rural hospitals as those located in rural small towns providing 24/7 emergency physician coverage with inpatient beds. Urban hospitals were academic centres designated as Level 1 or 2 trauma centres. We computed descriptive data on local access to a CT scanner and other services and compared mean 30-day adjusted post-stroke mortality rates for rural and urban hospitals to the overall Canadian rate. RESULTS: A total of 286 rural hospitals (3.4 million emergency department (ED) visits/year) and 24 urban hospitals (1.5 million ED visits/year) met inclusion criteria. From 2007 to 2011, 30-day in-hospital mortality rates following stroke were significantly higher in rural than in urban hospitals and higher than the Canadian average for every year except 2008 (rural average range = 18.26 to 21.04 and urban average range = 14.11 to 16.78). Only 11% of rural hospitals had a CT-scanner, 1% had MRI, 21% had in-hospital ICU, 94% had laboratory and 92% had basic x-ray facilities. CONCLUSION: Rural hospitals in Canada had higher 30-day in-hospital mortality rates following stroke than urban academic hospitals and the Canadian average. Rural hospitals also have very limited local access to CT scanners and ICUs. These rural/urban discrepancies are cause for concern in the context of Canada's universal health care system. PMID- 29385174 TI - Cell type-specific suppression of mechanosensitive genes by audible sound stimulation. AB - Audible sound is a ubiquitous environmental factor in nature that transmits oscillatory compressional pressure through the substances. To investigate the property of the sound as a mechanical stimulus for cells, an experimental system was set up using 94.0 dB sound which transmits approximately 10 mPa pressure to the cultured cells. Based on research on mechanotransduction and ultrasound effects on cells, gene responses to the audible sound stimulation were analyzed by varying several sound parameters: frequency, wave form, composition, and exposure time. Real-time quantitative PCR analyses revealed a distinct suppressive effect for several mechanosensitive and ultrasound-sensitive genes that were triggered by sounds. The effect was clearly observed in a wave form- and pressure level-specific manner, rather than the frequency, and persisted for several hours. At least two mechanisms are likely to be involved in this sound response: transcriptional control and RNA degradation. ST2 stromal cells and C2C12 myoblasts exhibited a robust response, whereas NIH3T3 cells were partially and NB2a neuroblastoma cells were completely insensitive, suggesting a cell type specific response to sound. These findings reveal a cell-level systematic response to audible sound and uncover novel relationships between life and sound. PMID- 29385175 TI - The Glaciozyma antarctica genome reveals an array of systems that provide sustained responses towards temperature variations in a persistently cold habitat. AB - Extremely low temperatures present various challenges to life that include ice formation and effects on metabolic capacity. Psyhcrophilic microorganisms typically have an array of mechanisms to enable survival in cold temperatures. In this study, we sequenced and analysed the genome of a psychrophilic yeast isolated in the Antarctic region, Glaciozyma antarctica. The genome annotation identified 7857 protein coding sequences. From the genome sequence analysis we were able to identify genes that encoded for proteins known to be associated with cold survival, in addition to annotating genes that are unique to G. antarctica. For genes that are known to be involved in cold adaptation such as anti-freeze proteins (AFPs), our gene expression analysis revealed that they were differentially transcribed over time and in response to different temperatures. This indicated the presence of an array of adaptation systems that can respond to a changing but persistent cold environment. We were also able to validate the activity of all the AFPs annotated where the recombinant AFPs demonstrated anti freeze capacity. This work is an important foundation for further collective exploration into psychrophilic microbiology where among other potential, the genes unique to this species may represent a pool of novel mechanisms for cold survival. PMID- 29385176 TI - Somatodendritic surface expression of epitope-tagged and KChIP binding-deficient Kv4.2 channels in hippocampal neurons. AB - Kv4.2 channels mediate a subthreshold-activating somatodendritic A-type current (ISA) in hippocampal neurons. We examined the role of accessory Kv channel interacting protein (KChIP) binding in somatodendritic surface expression and activity-dependent decrease in the availability of Kv4.2 channels. For this purpose we transfected cultured hippocampal neurons with cDNA coding for Kv4.2 wild-type (wt) or KChIP binding-deficient Kv4.2 mutants. All channels were equipped with an externally accessible hemagglutinin (HA)-tag and an EGFP-tag, which was attached to the C-terminal end. Combined analyses of EGFP self fluorescence, surface HA immunostaining and patch-clamp recordings demonstrated similar dendritic trafficking and functional surface expression for Kv4.2[wt]HA,EGFP and the KChIP binding-deficient Kv4.2[A14K]HA,EGFP. Coexpression of exogenous KChIP2 augmented the surface expression of Kv4.2[wt]HA,EGFP but not Kv4.2[A14K]HA,EGFP. Notably, activity-dependent decrease in availability was more pronounced in Kv4.2[wt]HA,EGFP + KChIP2 coexpressing than in Kv4.2[A14K]HA,EGFP + KChIP2 coexpressing neurons. Our results do not support the notion that accessory KChIP binding is a prerequisite for dendritic trafficking and functional surface expression of Kv4.2 channels, however, accessory KChIP binding may play a potential role in Kv4.2 modulation during intrinsic plasticity processes. PMID- 29385177 TI - Increased survival of honeybees in the laboratory after simultaneous exposure to low doses of pesticides and bacteria. AB - Recent studies of honeybees and bumblebees have examined combinatory effects of different stressors, as insect pollinators are naturally exposed to multiple stressors. At the same time the potential influences of simultaneously occurring agricultural agents on insect pollinator health remain largely unknown. Due to different farming methods, and the drift of applied agents and manure, pollinators are most probably exposed to insecticides but also bacteria from organic fertilizers at the same time. We orally exposed honeybee workers to sub lethal doses of the insecticide thiacloprid and two strains of the bacterium Enterococcus faecalis, which can occur in manure from farming animals. Our results show that under laboratory conditions the bees simultaneously exposed to the a bacterium and the pesticide thiacloprid thiacloprid had significant higher survival rates 11 days post exposure than the controls, which surprisingly showed the lowest survival. Bees that were exposed to diet containing thiacloprid showed decreased food intake. General antibacterial activity is increased by the insecticide and the bacteria, resulting in a higher immune response observed in treated individuals compared to control individuals. We thus propose that caloric restriction through behavioural and physiological adaptations may have mediated an improved survival and stress resistance in our tests. However, the decreased food consumption could in long-term also result in possible negative effects at colony level. Our study does not show an additive negative impact of sub-lethal insecticide and bacteria doses, when tested under laboratory conditions. In contrast, we report seemingly beneficial effects of simultaneous exposure of bees to agricultural agents, which might demonstrate a surprising biological capacity for coping with stressors, possibly through hormetic regulation. PMID- 29385178 TI - A high carbohydrate, but not fat or protein meal attenuates postprandial ghrelin, PYY and GLP-1 responses in Chinese men. AB - It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross over study of 9 lean insulin-sensitive (mean+/-SEM HOMA-IR 0.83+/-0.10) and 9 obese insulin-resistant (HOMA-IR 4.34+/-0.41) young (age 21-40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects. PMID- 29385179 TI - Population-based cohort study of the impacts of mild traumatic brain injury in adults four years post-injury. AB - There is increasing evidence that some people can experience persistent symptoms for up to a year following mild TBI. However, few longitudinal studies of mild TBI exist and the longer-term impact remains unclear. The purpose of this study is to determine if there are long-term effects of mild traumatic brain injury (TBI) four-years later. Adults (aged >=16 years) identified as part of a TBI incidence study who experienced a mild-TBI four-years ago (N = 232) were compared to age-sex matched controls (N = 232). Sociodemographic variables, prior TBI and symptoms were assessed at the time of injury. Four years post-injury participants completed the Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index and the Participation Assessment with Recombined Tools. Analysis of covariance was used to compare differences between TBI cases four years post-injury and controls, controlling for prior TBI and depression. A multiple regression model was used to identify the predictors of increased symptoms and reduced participation. The mild-TBI sample experienced significantly increased self-reported cognitive symptoms (F = 19.90, p = <0.01) four years post-injury than controls. There were no differences between the groups for somatic (F = 0.02, p = 0.89) or emotional symptoms (F = 0.31, p = 0.58). Additionally, the mild-TBI group reported significantly poorer community participation across all three domains: productivity (F = 199.07, p = <0.00), social relations (F = 13.93, p = <0.00) and getting out and about (F = 364.69, p = <0.00) compared to controls. A regression model accounting for 41% of the variance in cognitive symptoms in TBI cases revealed a history of TBI, receiving acute medical attention and baseline cognitive symptoms, sleep quality, anxiety and depression were predictive of outcome. The results indicate that whilst somatic and emotional symptoms resolve over time, cognitive symptoms can become persistent and that mild TBI can impact longer-term community participation. Early intervention is needed to reduce the longer-term impact of cognitive symptoms and facilitate participation. PMID- 29385180 TI - Differential determination of perceived stress in medical students and high school graduates due to private and training-related stressors. AB - OBJECTIVE: Numerous studies from diverse contexts have confirmed high stress levels and stress-associated health impairment in medical students. This study aimed to explore the differential association of perceived stress with private and training-related stressors in medical students according to their stage of medical education. METHODS: Participants were high-school graduates who plan to study medicine and students in their first, third, sixth, or ninth semester of medical school or in practical medical training. The self-administered questionnaire included items addressing demographic information, the Perceived Stress Questionnaire, and items addressing potential private and training-related stressors. RESULTS: Results confirmed a substantial burden of perceived stress in students at different stages of their medical education. In particular, 10-28% of students in their third or ninth semesters of medical school showed the highest values for perceived stress. Training-related stressors were most strongly associated with perceived stress, although specific stressors that determined perceived stress varied across different stages of students' medical education. High-school graduates highly interested in pursuing medical education showed specific stressors similar to those of medical students in their third, sixth, or ninth semesters of medical school, as well as stress structures with heights of general stress rates similar to those of medical students at the beginning of practical medical training. CONCLUSIONS: High-school graduates offer new, interesting information about students' fears and needs before they begin medical school. Medical students and high-school graduates need open, comprehensive information about possible stressors at the outset of and during medical education. Programmes geared toward improving resilience behaviour and teaching new, functional coping strategies are recommended. PMID- 29385181 TI - Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy. AB - Hepatitis C virus (HCV) infection has been related to increased risk of development of hepatocellular carcinoma (HCC) while metformin (M) and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S) could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP) and phosphatase and tensin homolog (PTEN) proteins while M inhibited mammalian target of rapamycin (mTOR) and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII) were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma. PMID- 29385183 TI - The structural balance analysis of complex dynamical networks based on nodes' dynamical couplings. AB - The nodes and their connection relationships are the two main bodies for dynamic complex networks. In existing theoretical researches, the phenomena of stabilization and synchronization for complex dynamical networks are generally regarded as the dynamic characteristic behaviors of the nodes, which are mainly caused by coupling effect of connection relationships between nodes. However, the connection relationships between nodes are also one main body of a time-varying dynamic complex network, and thus they may evolve with time and maybe show certain characteristic phenomena. For example, the structural balance in the social networks and the synaptic facilitation in the biological neural networks. Therefore, it is important to investigate theoretically the reasons in dynamics for the occurrence. Especially, from the angle of large-scale systems, how the dynamic behaviors of nodes (such as the individuals, neurons) contribute to the connection relationships is one of worthy research directions. In this paper, according to the structural balance theory of triad proposed by F. Heider, we mainly focus on the connection relationships body, which is regarded as one of the two subsystems (another is the nodes body), and try to find the dynamic mechanism of the structural balance with the internal state behaviors of the nodes. By using the Riccati linear matrix differential equation as the dynamic model of connection relationships subsystem, it is proved under some mathematic conditions that the connection relationships subsystem is asymptotical structural balance via the effects of the coupling roles with the internal state of nodes. Finally, the simulation example is given to show the validity of the method in this paper. PMID- 29385182 TI - Association between temporomandibular disorders, chronic diseases, and ophthalmologic and otolaryngologic disorders in Korean adults: A cross-sectional study. AB - INTRODUCTION: Temporomandibular disorders (TMDs) are common musculoskeletal conditions in the maxillofacial area. Although strong relationships between TMDs and other pain and diseases exist, few studies have comprehensively assessed the association between chronic diseases, ophthalmologic and otolaryngologic disorders and TMD. METHODS: Of 25,534 individuals included in the fifth Korea National Health and Nutrition Examination Survey (2010-2012), 17,575 aged >=20 years who completed survey items on TMD symptoms were included for cross sectional analysis. Logistic regression analysis was performed to assess the association between chronic diseases, ophthalmologic and otolaryngologic disorders and examination findings, and TMD symptoms after adjusting for various confounding variables. RESULTS: Out of 17,575 participants, 2,059 (11.75%) reported experience of >=1 TMD symptom(s). Compared to individuals without chronic disease, those with asthma (odds ratio (OR) 1.46; 95% confidence interval (CI) 1.09-1.96), migraine (1.44; 1.26-1.65), osteoarthritis (1.51; 1.20-1.89), thyroid dysfunction (1.49; 1.13-1.96), and depressive symptoms (1.51; 1.29-1.77) had higher ORs for TMD prevalence. Participants with tinnitus (1.97; 1.70-2.27), hearing difficulties (1.55; 1.29-1.87), dizziness (1.52; 1.27-1.82), rhinitis (1.46; 1.28-1.65), and xerophthalmia (1.82; 1.57-2.12) also displayed higher ORs for TMD prevalence. Patients diagnosed with chronic rhinosinusitis upon otolaryngologic examination exhibited an OR of 1.44 (95% CI 1.11-1.87) for TMD prevalence, while that for individuals with abnormal laryngoscopic results was 0.57 (95% CI 0.36-0.90). CONCLUSIONS: These findings imply that TMDs, chronic diseases, and ophthalmologic and otolaryngologic disorders hold various correlations, suggesting the need for multitarget approaches to effectively address this phenomenon. PMID- 29385184 TI - A short educational intervention diminishes causal illusions and specific paranormal beliefs in undergraduates. AB - Cognitive biases such as causal illusions have been related to paranormal and pseudoscientific beliefs and, thus, pose a real threat to the development of adequate critical thinking abilities. We aimed to reduce causal illusions in undergraduates by means of an educational intervention combining training-in-bias and training-in-rules techniques. First, participants directly experienced situations that tend to induce the Barnum effect and the confirmation bias. Thereafter, these effects were explained and examples of their influence over everyday life were provided. Compared to a control group, participants who received the intervention showed diminished causal illusions in a contingency learning task and a decrease in the precognition dimension of a paranormal belief scale. Overall, results suggest that evidence-based educational interventions like the one presented here could be used to significantly improve critical thinking skills in our students. PMID- 29385185 TI - Association between meibomian gland dysfunction and compliance of topical prostaglandin analogs in patients with normal tension glaucoma. AB - PURPOSE: The aim of this study was to investigate the association between tear film and meibomian gland parameters in patients with normal tension glaucoma (NTG), who underwent topical prostaglandin analog (PGA) monotherapy, and medication compliance. METHODS: Ocular surface disease index (OSDI), Schirmer's test, tear film break-up time (TBUT), keratoepitheliopathy (KEP) score with fluorescein, and meibomian gland parameters were assessed in 45 eyes of 45 patients with NTG (NTG group), who received topical PGA monotherapy for more than 1 year. The results were compared to those of 40 eyes of 40 normal subjects (control group). Medication compliance was assessed by an 8-item Morisky Medication Adherence Scale (MMAS-8). Multiple logistic regression analysis was used to identify the factors associated with medication compliance. RESULTS: There was a significant difference in OSDI (P = 0.043), Schirmer's test (P < 0.001), TBUT (P < 0.001), KEP score (P = 0.015) and all meibomian gland parameters (all P < 0.001) between two groups. When the NTG group was divided into compliant and non-compliant groups based on the scores of MMAS-8, 30 (75%) patients were classified into the compliant group. Multiple logistic regression analysis revealed that the lid margin score (OR, 0.256; 95% CI, 0.072-0.908, P = 0.035), meibum score (OR, 0.144; 95% CI, 0.023-0.915, P = 0.04), and meibo score (OR, 0.344; 95% CI, 0.140-0.845, P = 0.02) were significant factors associated with compliance in patients with NTG. The meibomian gland parameters showed a negative correlation with medication compliance (all P < 0.005). CONCLUSIONS: Malfunction of the meibomian glands can be an important clinical finding associated with compliance of PGA monotherapy in patients with NTG. PMID- 29385187 TI - Exploring unobserved household living conditions in multilevel choice modeling: An application to contraceptive adoption by Indian women. AB - This research analyzes the effect of the poverty-wealth dimension on contraceptive adoption by Indian women when no direct measures of income/expenditures are available to use as covariates. The index-Household Living Conditions (HLC)-is based on household assets and dwelling characteristics and is computed by an item response model simultaneously with the choice model in a new single-step approach. That is, the HLC indicator is treated as a latent covariate measured by a set of items, it depends on a set of concomitant variables, and explains contraceptive choices in a probit regression. Additionally, the model accounts for complex survey design and sample weights in a multilevel framework. Regarding our case study on contraceptive adoption by Indian women, results show that women with better household living conditions tend to adopt contraception more often than their counterparts. This effect is significant after controlling other factors such as education, caste, and religion. The external validation of the indicator shows that it can also be used at aggregate levels of analysis (e.g., county or state) whenever no other indicators of household living conditions are available. PMID- 29385186 TI - Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis. AB - BACKGROUND: Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 MUM BPA decreases basal, but not LH stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models. METHODS: Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 MUM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 MUM BPA (~ 500 MUg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 MUM and 0.038 MUM respectively. Mice grafted with second trimester testes received 0.5 and 50 MUg/kg/day BPA by oral gavage for 5 weeks. RESULTS: With first trimester human testes, using the hFeTA model, 10 MUM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2gamma, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice. CONCLUSIONS: Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures. PMID- 29385189 TI - The use of mosquito nets in fisheries: A global perspective. AB - Free or subsidised mosquito net (MN) distribution has been an increasingly important tool in efforts to combat malaria in recent decades throughout the developing world, making great strides towards eradicating this hugely detrimental disease. However, there has been increasing concern in the natural resource management and healthcare communities over alternative use of MNs, particularly in artisanal fisheries where it has been suggested they pose a threat to sustainability of fish stocks. So far, little evidence has been presented as to the global prevalence and characteristics of MN fishing, limiting global management initiatives and incentives for action across disciplines. We conducted a rapid global assessment of mosquito net fishing (MNF) observations from expert witnesses living and/or working in malarial zones using an internet survey. MNF was found to be a broadly pan-tropical activity, particularly prevalent in sub-Saharan Africa. MNF is conducted using a variety of deployment methods and scales including seine nets, scoop/dip nets, set nets and traps. MNF was witnessed in a broad range of marine and freshwater habitats and was seen to exploit a wide range of taxa, with capture of juvenile fish reported in more than half of responses. Perceived drivers of MNF were closely related to poverty, revealing potentially complex and arguably detrimental livelihood and food security implications which we discuss in light of current literature and management paradigms. The key policies likely to influence future impacts of MNF are in health, regarding net distribution, and natural resource management regarding restrictions on use. We outline critical directions for research and highlight the need for a collaborative, interdisciplinary approach to development of both localised and broad-scale policy. PMID- 29385188 TI - Metabarcoding analysis of eukaryotic microbiota in the gut of HIV-infected patients. AB - Research on the relationship between changes in the gut microbiota and human disease, including AIDS, is a growing field. However, studies on the eukaryotic component of the intestinal microbiota have just begun and have not yet been conducted in HIV-infected patients. Moreover, eukaryotic community profiling is influenced by the use of different methodologies at each step of culture independent techniques. Herein, initially, four DNA extraction protocols were compared to test the efficiency of each method in recovering eukaryotic DNA from fecal samples. Our results revealed that recovering eukaryotic components from fecal samples differs significantly among DNA extraction methods. Subsequently, the composition of the intestinal eukaryotic microbiota was evaluated in HIV infected patients and healthy volunteers through clone sequencing, high throughput sequencing of nuclear ribosomal internal transcribed spacers 1 (ITS1) and 2 (ITS2) amplicons and real-time PCRs. Our results revealed that not only richness (Chao-1 index) and alpha diversity (Shannon diversity) differ between HIV-infected patients and healthy volunteers, depending on the molecular strategy used, but also the global eukaryotic community composition, with little overlapping taxa found between techniques. Moreover, our results based on cloning libraries and ITS1/ITS2 metabarcoding sequencing showed significant differences in fungal composition between HIV-infected patients and healthy volunteers, but without distinct clusters separating the two groups. Malassezia restricta was significantly more prevalent in fecal samples of HIV-infected patients, according to cloning libraries, whereas operational taxonomic units (OTUs) belonging to Candida albicans and Candida tropicalis were significantly more abundant in fecal samples of HIV-infected patients compared to healthy subjects in both ITS subregions. Finally, real-time PCR showed the presence of Microsporidia, Giardia lamblia, Blastocystis and Hymenolepis diminuta in different proportions in fecal samples from HIV patients as compared to healthy individuals. Our work revealed that the use of different sequencing approaches can impact the perceived eukaryotic diversity results of the human gut. We also provide a more comprehensive view of the eukaryotic community in the gut of HIV-infected patients through the complementarity of the different molecular techniques used. Combining these various methodologies may provide a gold standard for a more complete characterization of the eukaryotic microbiome in future studies. PMID- 29385190 TI - The impact of selection bias in randomized multi-arm parallel group clinical trials. AB - The impact of selection bias on the results of clinical trials has been analyzed extensively for trials of two treatments, yet its impact in multi-arm trials is still unknown. In this paper, we investigate selection bias in multi-arm trials by its impact on the type I error probability. We propose two models for selection bias, so-called biasing policies, that both extend the classic guessing strategy by Blackwell and Hodges. We derive the distribution of the F-test statistic under the misspecified outcome model and provide a formula for the type I error probability under selection bias. We apply the presented approach to quantify the influence of selection bias in multi-arm trials with increasing number of treatment groups using a permuted block design for different assumptions and different biasing strategies. Our results confirm previous findings that smaller block sizes lead to a higher proportion of sequences with inflated type I error probability. Astonishingly, our results also show that the proportion of sequences with inflated type I error probability remains constant when the number of treatment groups is increased. Realizing that the impact of selection bias cannot be completely eliminated, we propose a bias adjusted statistical model and show that the power of the statistical test is only slightly deflated for larger block sizes. PMID- 29385191 TI - Effects of arecoline on proliferation of oral squamous cell carcinoma cells by dysregulating c-Myc and miR-22, directly targeting oncostatin M. AB - Arecoline, the major alkaloid of areca nut, is known to induce oral carcinogenesis, however, its mechanism is still needed to elucidate. This study investigated the effects of arecoline on cell viability and cell-cycle progression of oral squamous cell carcinoma (OSCC) cells as well as a relevant cellular gene expression. The results showed that a low concentration of arecoline (0.025 MUg/ml) increased OSCC cell viability, proportion of cells in G2/M phase and cell proliferation. Simultaneously, it induced IL-6, STAT3 and c Myc expression. Interestingly, c-myc promoter activity was also induced by arecoline. MiR-22 expression in arecoline-treated OSCC cells was suppressed and comparable to an upregulated c-Myc expression. In arecoline-treated OSCC cells, oncostatin M (OSM) expression was significantly upregulated and inversely correlated with miR-22 expression. Likewise, OSM expression and its post transcriptional activity were significantly decreased in miR-22-transfected OSCC and 293FT cells. This result demonstrated that miR-22 directly targeted OSM. Interestingly, miR-22 played an important role as a tumor suppresser on suppressing cell proliferation, migration and cell-cycle progression of OSCC cells. This result suggested the effect of arecoline to promote cell proliferation and cell-cycle progression of OSCC cells might be involved in induction of c-Myc expression and reduction of miR-22 resulting in OSM upregulation. PMID- 29385193 TI - Mitochondrial DNA reveals secondary contact in Japanese harbour seals, the southernmost population in the western Pacific. AB - In this study, we used relatively large number of samples (n = 178) and control region of mtDNA (454bp) to clearify the divergence history of Japanese harbour seals (Phoca vitulina stejnegeri) and phylogenetic relationship between the seals in Japan and other countries. Our results suggested that Japanese harbour seals possibly consisted of more than two lineages and secondary contact of populations after a long isolation. Furthermore, one of the lineage was made only by Japanese harbour seals (Group P1). The proportion of Group P1 was the highest at the South West and gradually decreased towards the North East of Hokkaido, Japan. On the other hand, the haplotypes do not belonged to Group P1 showed close relationship to the seals in the North Pacific. Based on the fossil record of harbour seal in Japan and the range of sea ice during the Last Glacial Maximum (LGM), Group P1 might have entered Japan before the LGM and became isolated due to the geographical boundary, and gradually extended its range from the South West towards the North East of Hokkaido after the disappearance of the sea ice, while the seals which are not in Group P1 immigrated into Japan from the North Pacific. PMID- 29385192 TI - Anti-influenza A virus activity of rhein through regulating oxidative stress, TLR4, Akt, MAPK, and NF-kappaB signal pathways. AB - Rhein, an anthraquinone compound existing in many traditional herbal medicines, has anti-inflammatory, antioxidant, antitumor, antiviral, hepatoprotective, and nephroprotective activities, but its anti-influenza A virus (IAV) activity is ambiguous. In the present study, through plaque inhibition assay, time-of addition assay, antioxidant assay, qRT-PCR, ELISA, and western blotting assays, we investigated the anti-IAV effect and mechanism of action of rhein in vitro and in vivo. The results showed that rhein could significantly inhibit IAV adsorption and replication, decrease IAV-induced oxidative stress, activations of TLR4, Akt, p38, JNK MAPK, and NF-kappaB pathways, and production of inflammatory cytokines and matrix metalloproteinases in vitro. Oxidant H2O2 and agonists of TLR4, Akt, p38/JNK and IKK/NF-kappaB could significantly antagonize the inhibitory effects of rhein on IAV-induced cytopathic effect (CPE) and IAV replication. Through an in vivo test in mice, we also found that rhein could significantly improve the survival rate, lung index, pulmonary cytokines, and pulmonary histopathological changes. Rhein also significantly decreased pulmonary viral load at a high dose. In conclusion, rhein can inhibit IAV adsorption and replication, and the mechanism of action to inhibit IAV replication may be due to its ability to suppress IAV-induced oxidative stress and activations of TLR4, Akt, p38, JNK MAPK, and NF-kappaB signal pathways. PMID- 29385195 TI - Anthropogenic marine litter composition in coastal areas may be a predictor of potentially invasive rafting fauna. AB - Anthropogenic plastic pollution is a global problem. In the marine environment, one of its less studied effects is the transport of attached biota, which might lead to introductions of non-native species in new areas or aid in habitat expansions of invasive species. The goal of the present work was to assess if the material composition of beached anthropogenic litter is indicative of the rafting fauna in a coastal area and could thus be used as a simple and cost-efficient tool for risk assessment in the future. Beached anthropogenic litter and attached biota along the 200 km coastline of Asturias, central Bay of Biscay, Spain, were analysed. The macrobiotic community attached to fouled litter items was identified using genetic barcoding combined with visual taxonomic analysis, and compared between hard plastics, foams, other plastics and non-plastic items. On the other hand, the material composition of beached litter was analysed in a standardized area on each beach. From these two datasets, the expected frequency of several rafting taxa was calculated for the coastal area and compared to the actually observed frequencies. The results showed that plastics were the most abundant type of beached litter. Litter accumulation was likely driven by coastal sources (industry, ports) and river/sewage inputs and transported by near-shore currents. Rafting vectors were almost exclusively made up of plastics and could mainly be attributed to fishing activity and leisure/ household. We identified a variety of rafting biota, including species of goose barnacles, acorn barnacles, bivalves, gastropods, polychaetes and bryozoan, and hydrozoan colonies attached to stranded litter. Several of these species were non-native and invasive, such as the giant Pacific oyster (Crassostrea gigas) and the Australian barnacle (Austrominius modestus). The composition of attached fauna varied strongly between litter items of different materials. Plastics, except for foam, had a much more diverse attached community than non-plastic materials. The predicted frequency of several taxa attached to beached litter significantly correlated with the actually observed frequencies. Therefore we suggest that the composition of stranded litter on a beach or an area could allow for predictions about the corresponding attached biotic community, including invasive species. PMID- 29385194 TI - Pre- and post-diagnosis physical activity, television viewing, and mortality among hematologic cancer survivors. AB - PURPOSE: The associations of physical activity and television (TV) viewing with mortality risk among individuals with hematologic malignancies remain unclear. METHODS: We examined the relations of physical activity and TV viewing time before and after diagnosis with mortality among 5182 U.S. adults aged 50-71 years from the NIH-AARP Diet and Health Study cohort who survived a first primary hematologic cancer between 1995-1996 and 2011. RESULTS: For the pre- and post diagnosis analyses, we confirmed 2606 and 613 deaths respectively. In multivariable-adjusted Cox proportional hazard regression models, comparing high (>=4 hrs/wk) versus low (<1 hr/wk) activity levels, pre-diagnosis physical activity was associated with 18%-22% reduced risks of all-cause mortality among all hematologic cancer survivors, and survivors of non-Hodgkin lymphoma, myeloma, and leukemia, respectively. Additional control for BMI had little impact on the results, expect for myeloma survivors, for whom the association was no longer significant. Post-diagnosis physical activity was related to risk reductions in mortality ranging from 36%-47%. The associations for TV viewing did not show a clear pattern. CONCLUSION: Our study suggests that pre- and post-diagnosis physical activity is associated with lower risk of all-cause mortality among hematologic cancer survivors. Further research is required to confirm this observation. PMID- 29385196 TI - Metabolic effect of bodyweight whole-body vibration in a 20-min exercise session: A crossover study using verified vibration stimulus. AB - The ability of whole body vibration (WBV) to increase energy expenditure (EE) has been investigated to some extent in the past using short-term single exercises or sets of single exercises. However, the current practice in WBV training for fitness is based on the execution of multiple exercises during a WBV training session for a period of at least 20 min; nevertheless, very limited and inconsistent data are available on EE during long term WBV training session. This crossover study was designed to demonstrate, in an adequately powered sample of participants, the ability of WBV to increase the metabolic cost of exercise vs. no vibration over the time span of a typical WBV session for fitness (20 min). Twenty-two physically active young males exercised on a vibration platform (three identical sets of six different exercises) using an accelerometer-verified vibration stimulus in both the WBV and no vibration condition. Oxygen consumption was measured with indirect calorimetry and expressed as area under the curve (O2(AUC)). Results showed that, in the overall 20-min training session, WBV increased both the O2(AUC) and the estimated EE vs. no vibration by about 22% and 20%, respectively (P<0.001 for both, partial eta squared [eta2] >=0.35) as well as the metabolic equivalent of task (+5.5%, P = 0.043; eta2 = 0.02) and the rate of perceived exertion (+13%, P<0.001; n2 = 0.16). Results demonstrated that vibration is able to significantly increase the metabolic cost of exercise in a 20-min WBV training session. PMID- 29385198 TI - Vesicular stomatitis forecasting based on Google Trends. AB - BACKGROUND: Vesicular stomatitis (VS) is an important viral disease of livestock. The main feature of VS is irregular blisters that occur on the lips, tongue, oral mucosa, hoof crown and nipple. Humans can also be infected with vesicular stomatitis and develop meningitis. This study analyses 2014 American VS outbreaks in order to accurately predict vesicular stomatitis outbreak trends. METHODS: American VS outbreaks data were collected from OIE. The data for VS keywords were obtained by inputting 24 disease-related keywords into Google Trends. After calculating the Pearson and Spearman correlation coefficients, it was found that there was a relationship between outbreaks and keywords derived from Google Trends. Finally, the predicted model was constructed based on qualitative classification and quantitative regression. RESULTS: For the regression model, the Pearson correlation coefficients between the predicted outbreaks and actual outbreaks are 0.953 and 0.948, respectively. For the qualitative classification model, we constructed five classification predictive models and chose the best classification predictive model as the result. The results showed, SN (sensitivity), SP (specificity) and ACC (prediction accuracy) values of the best classification predictive model are 78.52%,72.5% and 77.14%, respectively. CONCLUSION: This study applied Google search data to construct a qualitative classification model and a quantitative regression model. The results show that the method is effective and that these two models obtain more accurate forecast. PMID- 29385197 TI - Inequalities in global health inequalities research: A 50-year bibliometric analysis (1966-2015). AB - BACKGROUND: Increasing evidence shows that health inequalities exist between and within countries, and emphasis has been placed on strengthening the production and use of the global health inequalities research, so as to improve capacities to act. Yet, a comprehensive overview of this evidence base is still needed, to determine what is known about the global and historical scientific production on health inequalities to date, how is it distributed in terms of country income groups and world regions, how has it changed over time, and what international collaboration dynamics exist. METHODS: A comprehensive bibliometric analysis of the global scientific production on health inequalities, from 1966 to 2015, was conducted using Scopus database. The historical and global evolution of the study of health inequalities was considered, and through joinpoint regression analysis and visualisation network maps, the preceding questions were examined. FINDINGS: 159 countries (via authorship affiliation) contributed to this scientific production, three times as many countries than previously found. Scientific output on health inequalities has exponentially grown over the last five decades, with several marked shift points, and a visible country-income group affiliation gradient in the initiation and consistent publication frequency. Higher income countries, especially Anglo-Saxon and European countries, disproportionately dominate first and co-authorship, and are at the core of the global collaborative research networks, with the Global South on the periphery. However, several country anomalies exist that suggest that the causes of these research inequalities, and potential underlying dependencies, run deeper than simply differences in country income and language. CONCLUSIONS: Whilst the global evidence base has expanded, Global North-South research gaps exist, persist and, in some cases, are widening. Greater understanding of the structural determinants of these research inequalities and national research capacities is needed, to further strengthen the evidence base, and support the long term agenda for global health equity. PMID- 29385199 TI - Target discovery screens using pooled shRNA libraries and next-generation sequencing: A model workflow and analytical algorithm. AB - In the search for novel therapeutic targets, RNA interference screening has become a valuable tool. High-throughput technologies are now broadly accessible but their assay development from baseline remains resource-intensive and challenging. Focusing on this assay development process, we here describe a target discovery screen using pooled shRNA libraries and next-generation sequencing (NGS) deconvolution in a cell line model of Ewing sarcoma. In a strategy designed for comparative and synthetic lethal studies, we screened for targets specific to the A673 Ewing sarcoma cell line. Methods, results and pitfalls are described for the entire multi-step screening procedure, from lentiviral shRNA delivery to bioinformatics analysis, illustrating a complete model workflow. We demonstrate that successful studies are feasible from the first assay performance and independent of specialized screening units. Furthermore, we show that a resource-saving screen depth of 100-fold average shRNA representation can suffice to generate reproducible target hits despite heterogeneity in the derived datasets. Because statistical analysis methods are debatable for such datasets, we created ProFED, an analysis package designed to facilitate descriptive data analysis and hit calling using an aim-oriented profile filtering approach. In its versatile design, this open-source online tool provides fast and easy analysis of shRNA and other count-based datasets to complement other analytical algorithms. PMID- 29385201 TI - Cellulose-dependent expression and antibacterial characteristics of surfactin from Bacillus subtilis HH2 isolated from the giant panda. AB - Surfactin secreted by Bacillus subtilis can confer strong, diverse antipathogenic effects, thereby benefitting the host. Carbon source is an important factor for surfactin production. However, the mechanism that bacteria utilize cellulose, the most abundant substance in the intestines of herbivores, to produce surfactin remains unclear. Here, we used B. subtilis HH2, isolated from the feces of a giant panda, as a model to determine changes in surfactin expression in the presence of different concentrations of cellulose by quantitative polymerase chain reaction and high-performance liquid chromatography. We further investigated the antimicrobial effects of surfactin against three common intestinal pathogens (Escherichia coli, Staphylococcus aureus, and Salmonella enterica) and its resistance to high temperature (60-121 degrees C), pH (1-12), trypsin (100-300 MUg/mL, pH 8), and pepsin (100-300 MUg/mL, pH 2). The results showed that the surfactin expressed lowest in bacteria cultured in the presence of 1% glucose medium as the carbon source, whereas increased in an appropriate cellulose concentration (0.67% glucose and 0.33% cellulose). The surfactin could inhibit E. coli and Staphylococcus aureus, but did not affect efficiently for Salmonella enterica. The antibacterial ability of surfactin did not differ according to temperature (60-100 degrees C), pH (2-11), trypsin (100-300 MUg/mL), and pepsin (100-300 MUg/mL; P > 0.05), but decreased significantly at extreme environments (121 degrees C, pH 1 or 12; P < 0.05) compared with that in the control group (37 degrees C, pH = 7, without any protease). In conclusion, our findings indicated that B. subtilis HH2 could increase surfactin expression in an appropriate cellulose environment and thus provide benefits to improve the intestinal health of herbivores. PMID- 29385200 TI - Preferential use of unmutated immunoglobulin heavy variable region genes in Boxer dogs with chronic lymphocytic leukemia. AB - Human chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease, and immunoglobulin heavy variable region (IGHV) gene mutational status is an important prognostic marker. IGHV mutational status has not been previously examined in canine CLL. We sequenced the IGHV-D-J rearrangements from 55 canine patients with CLL, including 36 non-Boxer and 19 Boxer dogs. The majority of non Boxers (75%) had mutated IGHV genes, whereas the majority of Boxers (79%) had unmutated IGHV genes. IGHV3-41 and IGHV3-67 gene usage was significantly higher in Boxers with CLL compared to non-Boxers. Additionally, 11 Boxers with large B cell lymphoma and the normal IGHV repertoire of six control dogs (three Boxers and three non-Boxers) were sequenced. IGHV3-41 was preferentially used in Boxers with other forms of lymphoma and without lymphoproliferative disease. However, preferential use of unmutated IGHV genes was unique to Boxers with CLL, suggesting Boxers may be a valuable model to investigate unmutated CLL. PMID- 29385202 TI - Historical trends in modifiable indicators of cardiovascular health and self rated health among older adults: Cohort differences over 20 years between the Berlin Aging Study (BASE) and the Berlin Aging Study II (BASE-II). AB - BACKGROUND: The last decades have seen great advances in the understanding, treatment, and prevention of cardiovascular disease (CVD). Although mortality rates due to CVD have declined significantly in the last decades, the burden of CVD is still high, particularly in older adults. This raises the question whether contemporary populations of older adults are experiencing better or worse objective as well as subjective health than earlier-born cohorts. The aim of this study was to examine differences in modifiable indicators of cardiovascular health (CVH), comparing data obtained 20 years apart in the Berlin Aging Study (BASE, 1990-93) and the Berlin Aging Study II (BASE-II, 2009-2014). METHODS: Serial cross-sectional analysis of 242 propensity-score-matched participants of BASE (born 1907-1922) and BASE-II (born 1925-1942). Body mass index (BMI), blood pressure, total cholesterol, glycated hemoglobin (HbA1c), diet, smoking and physical activity were operationalized according to the "Life's simple 7"(LS7) criteria of the American Heart Association. RESULTS: 121 matched pairs were identified based on age, sex, and education. In the later-born BASE-II sample, the mean LS7 score was significantly higher than in the earlier-born sample (7.8+/-1.8 vs. 6.4+/-2.1, p<0.001), indicating better CVH. In detail, diet, physical activity, smoking, cholesterol, and HbA1c were more favorable, whereas blood pressure was significantly higher in individuals from the later-born cohort. BMI did not differ significantly between the two matched samples. Notably, despite better CVH, later-born individuals (BASE-II) reported lower self rated health, presumably because of higher health expectations. CONCLUSIONS: Overall, cardiovascular health was significantly better in the later-born cohort, but several notable exceptions exist. PMID- 29385203 TI - Practice variation and practice guidelines: Attitudes of generalist and specialist physicians, nurse practitioners, and physician assistants. AB - OBJECTIVE: To understand clinicians' beliefs about practice variation and how variation might be reduced. METHODS: We surveyed board-certified physicians (N = 178), nurse practitioners (N = 60), and physician assistants (N = 12) at an academic medical center and two community clinics, representing family medicine, general internal medicine, and cardiology, from February-April 2016. The Internet based questionnaire ascertained clinicians' beliefs regarding practice variation, clinical practice guidelines, and costs. RESULTS: Respondents agreed that practice variation should be reduced (mean [SD] 4.5 [1.1]; 1 = strongly disagree, 6 = strongly agree), but agreed less strongly (4.1 [1.0]) that it can realistically be reduced. They moderately agreed that variation is justified by situational differences (3.9 [1.2]). They strongly agreed (5.2 [0.8]) that clinicians should help reduce healthcare costs, but agreed less strongly (4.4 [1.1]) that reducing practice variation would reduce costs. Nearly all respondents (234/249 [94%]) currently depend on practice guidelines. Clinicians rated differences in clinician style and experience as most influencing practice variation, and inaccessibility of guidelines as least influential. Time to apply standards, and patient decision aids, were rated most likely to help standardize practice. Nurse practitioners and physicians assistants (vs physicians) and less experienced (vs senior) clinicians rated more favorably several factors that might help to standardize practice. Differences by specialty and academic vs community practice were small. CONCLUSIONS: Clinicians believe that practice variation should be reduced, but are less certain that this can be achieved. Accessibility of guidelines is not a significant barrier to practice standardization, whereas more time to apply standards is viewed as potentially helpful. PMID- 29385204 TI - The proteomic response of the reef coral Pocillopora acuta to experimentally elevated temperatures. AB - Although most reef-building corals live near the upper threshold of their thermotolerance, some scleractinians are resilient to temperature increases. For instance, Pocillopora acuta specimens from an upwelling habitat in Southern Taiwan survived a nine-month experimental exposure to 30 degrees C, a temperature hypothesized to induce stress. To gain a greater understanding of the molecular pathways underlying such high-temperature acclimation, the protein profiles of experimental controls incubated at 27 degrees C were compared to those of conspecific P. acuta specimens exposed to 30 degrees C for two, four, or eight weeks, and differentially concentrated proteins (DCPs) were removed from the gels and sequenced with mass spectrometry. Sixty unique DCPs were uncovered across both eukaryotic compartments of the P. acuta-dinoflagellate (genus Symbiodinium) mutualism, and Symbiodinium were more responsive to high temperature at the protein-level than the coral hosts in which they resided at the two-week sampling time. Furthermore, proteins involved in the stress response were more likely to be documented at different cellular concentrations across temperature treatments in Symbiodinium, whereas the temperature-sensitive host coral proteome featured numerous proteins involved in cytoskeletal structure, immunity, and metabolism. These proteome-scale data suggest that the coral host and its intracellular dinoflagellates have differing strategies for acclimating to elevated temperatures. PMID- 29385205 TI - Does adaptation to vertebrate codon usage relate to flavivirus emergence potential? AB - Codon adaptation index (CAI) is a measure of synonymous codon usage biases given a usage reference. Through mutation, selection, and drift, viruses can optimize their replication efficiency and produce more offspring, which could increase the chance of secondary transmission. To evaluate how higher CAI towards the host has been associated with higher viral titers, we explored temporal trends of several historic and extensively sequenced zoonotic flaviviruses and relationships within the genus itself. To showcase evolutionary and epidemiological relationships associated with silent, adaptive synonymous changes of viruses, we used codon usage tables from human housekeeping and antiviral immune genes, as well as tables from arthropod vectors and vertebrate species involved in the flavivirus maintenance cycle. We argue that temporal trends of CAI changes could lead to a better understanding of zoonotic emergences, evolutionary dynamics, and host adaptation. CAI appears to help illustrate historically relevant trends of well characterized viruses, in different viral species and genetic diversity within a single species. CAI can be a useful tool together with in vivo and in vitro kinetics, phylodynamics, and additional functional genomics studies to better understand species trafficking and viral emergence in a new host. PMID- 29385206 TI - Platelet activation and aggregation by the opportunistic pathogen Cutibacterium (Propionibacterium) acnes. AB - Cutibacterium (Propionibacterium) acnes, considered a part of the skin microbiota, is one of the most commonly isolated anaerobic bacteria from medical implants in contact with plasma. However, the precise interaction of C. acnes with blood cells and plasma proteins has not been fully elucidated. Herein, we have investigated the molecular interaction of C. acnes with platelets and plasma proteins. We report that the ability of C. acnes to aggregate platelets is dependent on phylotype, with a significantly lower ability amongst type IB isolates, and the interaction of specific donor-dependent plasma proteins (or concentrations thereof) with C. acnes. Pretreatment of C. acnes with plasma reduces the lag time before aggregation demonstrating that pre-deposition of plasma proteins on C. acnes is an important step in platelet aggregation. Using mass spectrometry we identified several plasma proteins deposited on C. acnes, including IgG, fibrinogen and complement factors. Inhibition of IgG, fibrinogen or complement decreased C. acnes-mediated platelet aggregation, demonstrating the importance of these plasma proteins for aggregation. The interaction of C. acnes and platelets was visualized using fluorescence microscopy, verifying the presence of IgG and fibrinogen as components of the aggregates, and co localization of C. acnes and platelets in the aggregates. Here, we have demonstrated the ability of C. acnes to activate and aggregate platelets in a bacterium and donor-specific fashion, as well as added mechanistic insights into this interaction. PMID- 29385207 TI - Spatiotemporal patterns of the macrofaunal community structure in the East China Sea, off the coast of Zhejiang, China, and the impact of the Kuroshio Branch Current. AB - The Kuroshio Current intrudes in the bottom layer of the East China Sea continental shelf from the northeast of Taiwan via two bottom branches named the Nearshore Kuroshio Branch Current (NKBC, along the 60 m isobath) and the Offshore Kuroshio Branch Current (OKBC, along the 100 m isobath). However, knowledge on the macrofaunal responses to these bottom branches is limited. This study examined the variations in the benthic macrofaunal community in a section of the East China Sea under the influence of the NKBC. Seven sites corresponding to three regions (the west, middle and east region) were sampled using an Agassiz trawl net at a monthly rate from February to November 2015 (except in August). A total of 270 macrofaunal species were collected in this study. Cluster analysis and nMDS ordination revealed three communities: the inshore, Kuroshio and offshore communities, roughly corresponding to the west, middle and east of NKBC route. Significant differences in the species composition (one-way PERMANOVA) and diversity indices (one-way ANOVA) among the regions and communities were observed, while no statistically significant difference among the months was detected. The indicator species also varied among the communities, with Sternaspis scutata and Odontamblyopus rubicundus dominating the inshore community, Camatopsis rubida, Schizaster lacunosus and Craspidaster hesperus dominating the Kuroshio community, and Portunus argentatus, Champsodon snyderi and Coelorinchus multispinulosus dominating the offshore community. Some rare species (e.g., Neobythites sivicola) may indicate the passage of the NKBC better than the indicator species. A redundancy analysis was used to describe the relationship between the macrofaunal species and environmental variables in this study. Water depth and turbidity played important roles in the distribution of the macrofauna. S. scutata and O. rubicundus were associated with high turbidity and shallow depth, while Plesionika izumiae and P. argentatus were associated with low turbidity and deep depth. This study outlines the impact of the NKBC on the distribution patterns of the macrofaunal community of the East China Sea. More studies are needed to understand the detailed interactions between macrofauna and the NKBC in the future. PMID- 29385208 TI - Immunological non-response and low hemoglobin levels are predictors of incident tuberculosis among HIV-infected individuals on Truvada-based therapy in Botswana. AB - BACKGROUND: There is a high burden of tuberculosis (TB) in HIV antiretroviral programmes in Africa. However, few studies have looked at predictors of incident TB while on Truvada-based combination antiretroviral therapy (cART) regimens. METHODS: We estimated TB incidence among individuals enrolled into an observational cohort evaluating the efficacy and tolerability of Truvada-based cART in Gaborone, Botswana between 2008 and 2011. We used Cox proportional hazards regressions to determine predictors of incident TB. RESULTS: Of 300 participants enrolled, 45 (15%) had a diagnosis of TB at baseline. During 428 person-years (py) of follow-up, the incidence rate of TB was 3.04/100py (95% CI, 1.69-5.06), with 60% of the cases occurring within 3 months of ART initiation. Incident cases had low baseline CD4+ T cell counts (153cells/mm3 [Q1, Q3: 82, 242]; p = 0.69) and hemoglobin levels (9.2g/dl [Q1, Q3: 8.5,10.1]; p<0.01). In univariate analysis, low BMI (HR = 0.73; 95% CI 0.58-0.91; p = 0.01) and hemoglobin levels <8 g/dl (HR = 10.84; 95%CI: 2.99-40.06; p<0.01) were risk factors for TB. Time to incident TB diagnosis was significantly reduced in patients with poor immunological recovery (p = 0.04). There was no association between baseline viral load and risk of TB (HR = 1.75; 95%CI: 0.70-4.37). CONCLUSION: Low hemoglobin levels prior to initiation of ART are significant predictors of incident tuberculosis. Therefore, there is potential utility of iron biomarkers to identify patients at risk of TB prior to initiation on ART. Furthermore, additional strategies are required for patients with poor immunological recovery to reduce excess risk of TB while on ART. PMID- 29385209 TI - Integrative analysis of super enhancer SNPs for type 2 diabetes. AB - Clinical studies in type 2 diabetes (T2D) primarily focused on the single nucleotide polymorphisms (SNPs) located in protein-coding regions. Recently, the SNPs located in noncoding regions have also been recognized to play an important role in disease susceptibility. The super enhancer is a cluster of transcriptional enhancers located in noncoding regions. It plays a critical role in cell-type specific gene expression. However, the exact mechanism of the super enhancer SNPs for T2D remains unclear. In this study, we integrated genome-wide association studies (GWASs) and T2D cell/tissue-specific histone modification ChIP-seq data to identify T2D-associated SNPs in super enhancer, followed by comprehensive bioinformatics analyses to further explore the functional importance of these SNPs. We identified several interesting T2D super enhancer SNPs. Interesting, most of them were clustered within the same or neighboring super enhancers. A number of SNPs are involved in chromatin interactive regulation and/or potentially influence the binding affinity of transcription factors. Gene Ontology (GO) analysis showed a significant enrichment in several well-known signaling pathways and regulatory process, e.g. WNT signaling pathway, which plays a key role in T2D metabolism. Our results highlighted the potential functional importance of T2D super enhancer SNPs, which may yield novel insights into the pathogenesis of T2D. PMID- 29385211 TI - Noninvasive measurement of dynamic brain signals using light penetrating the brain. AB - Conventional techniques for the noninvasive measurement of brain activity involve critical limitations in spatial or temporal resolution. Here, we propose the method for noninvasive brain function measurement with high spatiotemporal resolution using optical signals. We verified that diffused near-infrared light penetrating through the upper jaw and into the skull, which we term as optoencephalography (OEG), leads to the detection of dynamic brain signals that vary concurrently with the electrophysiological neural activity. We measured the OEG signals following the stimulation of the median nerve in common marmosets. The OEG signal response was tightly coupled with the electrophysiological response represented by the somatosensory evoked potential (SSEP). The OEG measurement is also shown to offer rather clear discrimination of brain signals. PMID- 29385210 TI - ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells. AB - ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1 expressing cell lines. K562 cells exposed to gradually increasing concentrations of nilotinib (to 2 MUM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced nilotinib IC50 (p<0.001) indicating ABCC6 is likely involved in nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to nilotinib and dasatinib resistance in vitro. With nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy. PMID- 29385214 TI - Ant genera identification using an ensemble of convolutional neural networks. AB - Works requiring taxonomic knowledge face several challenges, such as arduous identification of many taxa and an insufficient number of taxonomists to identify a great deal of collected organisms. Machine learning tools, particularly convolutional neural networks (CNNs), are then welcome to automatically generate high-performance classifiers from available data. Supported by the image datasets available at the largest online database on ant biology, the AntWeb (www.antweb.org), we propose here an ensemble of CNNs to identify ant genera directly from the head, profile and dorsal perspectives of ant images. Transfer learning is also considered to improve the individual performance of the CNN classifiers. The performance achieved by the classifiers is diverse enough to promote a reduction in the overall classification error when they are combined in an ensemble, achieving an accuracy rate of over 80% on top-1 classification and an accuracy of over 90% on top-3 classification. PMID- 29385224 TI - Toward Policy: An Interview With Two Jonas Policy Scholars. PMID- 29385225 TI - Mandating Workplace Violence Training for Nursing Students. PMID- 29385213 TI - The fungal pathogen Magnaporthe oryzae suppresses innate immunity by modulating a host potassium channel. AB - Potassium (K+) is required by plants for growth and development, and also contributes to immunity against pathogens. However, it has not been established whether pathogens modulate host K+ signaling pathways to enhance virulence and subvert host immunity. Here, we show that the effector protein AvrPiz-t from the rice blast pathogen Magnaporthe oryzae targets a K+ channel to subvert plant immunity. AvrPiz-t interacts with the rice plasma-membrane-localized K+ channel protein OsAKT1 and specifically suppresses the OsAKT1-mediated K+ currents. Genetic and phenotypic analyses show that loss of OsAKT1 leads to decreased K+ content and reduced resistance against M. oryzae. Strikingly, AvrPiz-t interferes with the association of OsAKT1 with its upstream regulator, the cytoplasmic kinase OsCIPK23, which also plays a positive role in K+ absorption and resistance to M. oryzae. Furthermore, we show a direct correlation between blast disease resistance and external K+ status in rice plants. Together, our data present a novel mechanism by which a pathogen suppresses plant host immunity by modulating a host K+ channel. PMID- 29385226 TI - Drugs to Treat Hypertension. PMID- 29385212 TI - Recombinant PrPSc shares structural features with brain-derived PrPSc: Insights from limited proteolysis. AB - Very solid evidence suggests that the core of full length PrPSc is a 4-rung beta solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the beta-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133 134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of beta strands, helping us to predict the threading of the beta-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc. PMID- 29385227 TI - Are You Ready for Change? AB - Under the direction of the Journal's new Psychopharmacology Section Editor, a different approach will be taken: psychotropic drugs will be classified based on their neurobiological mechanism of action in the brain. This approach focuses on how the drug acts on brain cells and neurotransmitters involved in the specific symptoms presented by patients. The current article introduces the approach and will help clinicians think about medications as they relate to the neurobiological functions they are trying to correct. [Journal of Psychosocial Nursing and Mental Health Services, 56(2), 11-13.]. PMID- 29385228 TI - Unable to Speak: Selective Mutism in Youth. AB - It is important for psychiatric nurses to be familiar with the clinical presentation and recommended treatment for selective mutism (SM), as it is a childhood anxiety disorder that is not commonly studied. This article provides a brief overview of its diagnostic criteria, prevalence, assessment, and history. Special attention is given to misconceptions regarding the disorder and differentiation of trauma and oppositional disorders. Two vignettes illustrate varied presentations of SM, with and without comorbid social phobia. Empirically supported behavioral and psychopharmacological treatment is outlined, and considerations for nursing are provided. [Journal of Psychosocial Nursing and Mental Health Services, 56(2), 14-18.]. PMID- 29385229 TI - Untitled by Connie English. PMID- 29385230 TI - JPEN Journal Club 33. The Type II Error. PMID- 29385231 TI - Citrus species and hybrids depicted by near- and mid-infrared spectroscopy. AB - BACKGROUND: Citrus trees are among the most cultivated plants in the world, with a high economic impact. The wide sexual compatibility among relatives gave rise to a large number of hybrids that are difficult to discriminate. This work sought to explore the ability of infrared spectroscopy to discriminate among Citrus species and/or hybrids and to contribute to the elucidation of its relatedness. RESULTS: Adult leaves of 18 distinct Citrus plants were included in this work. Near- and mid-infrared (NIR and FTIR) spectra were acquired from leaves after harvesting and a drying period of 1 month. Spectra were modelled by principal component analysis and partial least squares discriminant analysis. Both techniques revealed a high discrimination potential (78.5-95.9%), being the best results achieved with NIR spectroscopy and air-dried leaves (95.9%). CONCLUSION: Infrared spectroscopy was able to successfully discriminate several Citrus species and/or hybrids. Our results contributed also to enhance insights regarding the studied Citrus species and/or hybrids. Despite the benefit of including additional samples, the results herein obtained clearly pointed infrared spectroscopy as a reliable technique for Citrus species and/or hybrid discrimination. (c) 2018 Society of Chemical Industry. PMID- 29385233 TI - Major Need of Foreign Medical Graduate Physicians for Insights into Older Americans. PMID- 29385232 TI - Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study. AB - AIMS: Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione-PEGylated liposomes containing MP (2B3-201). METHODS: The first part was a double-blind, three-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. RESULTS: The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. CONCLUSION: 2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects. PMID- 29385234 TI - Fundamental contradictions among observational and experimental estimates of non trophic species interactions. AB - The difficulty of experimentally quantifying non-trophic species interactions has long troubled ecologists. Increasingly, a new application of the classic "checkerboard distribution" approach is used to infer interactions by examining the pairwise frequency at which species are found to spatially co-occur. However, the link between spatial associations, as estimated from observational co occurrence, and species interactions has not been tested. Here we used nine common statistical methods to estimate associations from surveys of rocky intertidal communities in the Northeast Pacific Ocean. We compared those inferred associations with a new data set of experimentally determined net and direct species interactions. Although association methods generated networks with aggregate structure similar to previously published interaction networks, each method detected a different set of species associations from the same data set. Moreover, although association methods generally performed better than a random model, associations rarely matched empirical net or direct species interactions, with high rates of false positives and true positives, and many false negatives. Our findings cast doubt on studies that equate species co-occurrences to species interactions and highlight a persistent, unanswered question: how do we interpret spatial patterns in communities? We suggest future research directions to unify the observational and experimental study of species interactions, and discuss the need for community standards and best practices in association analysis. PMID- 29385235 TI - Comprehensive geriatric assessment for older people admitted to a surgical service. AB - BACKGROUND: Aging populations are at increased risk of postoperative complications. New methods to provide care for older people recovering from surgery may reduce surgery-related complications. Comprehensive geriatric assessment (CGA) has been shown to improve some outcomes for medical patients, such as enabling them to continue living at home, and has been proposed to have positive impacts for surgical patients. CGA is a coordinated, multidisciplinary collaboration that assesses the medical, psychosocial and functional capabilities and limitations of an older person, with the goal of establishing a treatment plan and long-term follow-up. OBJECTIVES: To assess the effectiveness of CGA interventions compared to standard care on the postoperative outcomes of older people admitted to hospital for surgical care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two clinical trials registers on 13 January 2017. We also searched grey literature for additional citations. SELECTION CRITERIA: Randomized trials of people undergoing surgery aged 65 years and over comparing CGA with usual surgical care and reporting any of our primary (mortality and discharge to an increased level of care) or secondary (length of stay, re-admission, total cost and postoperative complication) outcomes. We excluded studies if the participants did not receive a complete CGA, did not undergo surgery, and if the study recruited participants aged less than 65 years or from a setting other than an acute care hospital. DATA COLLECTION AND ANALYSIS: Two review authors independently screened, assessed risk of bias, extracted data and assessed certainty of evidence from identified articles. We expressed dichotomous treatment effects as risk ratio (RR) with 95% confidence intervals and continuous outcomes as mean difference (MD). MAIN RESULTS: We included eight randomised trials, seven recruited people recovering from a hip fracture (N = 1583) and one elective surgical oncology trial (N = 260), conducted in North America and Europe. For two trials CGA was done pre-operatively and postoperatively for the remaining. Six trials had adequate randomization, five had low risk of performance bias and four had low risk of detection bias. Blinding of participants was not possible. All eight trials had low attrition rates and seven reported all expected outcomes.CGA probably reduces mortality in older people with hip fracture (RR 0.85, 95% CI 0.68 to 1.05; 5 trials, 1316 participants, I2 = 0%; moderate-certainty evidence). The intervention reduces discharge to an increased level of care (RR 0.71, 95% CI 0.55 to 0.92; 5 trials, 941 participants, I2 = 0%; high-certainty evidence).Length of stay was highly heterogeneous, with mean difference between participants allocated to the intervention and the control groups ranging between -12.8 and 8.3 days. CGA probably leads to slightly reduced length of stay (4 trials, 841 participants, moderate-certainty evidence). The intervention probably makes little or no difference in re-admission rates (RR 1.00, 95% CI 0.76 to 1.32; 3 trials, 741 participants, I2 = 37%; moderate-certainty evidence).CGA probably slightly reduces total cost (1 trial, 397 participants, moderate-certainty evidence). The intervention may make little or no difference for major postoperative complications (2 trials, 579 participants, low-certainty evidence) and delirium rates (RR 0.75, 95% CI 0.60 to 0.94, 3 trials, 705 participants, I2 = 0%; low certainty evidence). AUTHORS' CONCLUSIONS: There is evidence that CGA can improve outcomes in people with hip fracture. There are not enough studies to determine when CGA is most effective in relation to surgical intervention or if CGA is effective in surgical patients presenting with conditions other than hip fracture. PMID- 29385236 TI - Strategies to Reduce Catheter-Related Bloodstream Infections in Pediatric Patients Receiving Home Parenteral Nutrition: The Efficacy of Taurolidine-Citrate Prophylactic-Locking. AB - BACKGROUND: Catheter-related bloodstream infections (CRBSIs) remain a major issue in patients who are receiving home parenteral nutrition (HPN). The aim of this interventional study was to assess the impact of a new strategy using taurolidine citrate (T-C) prophylactic locks on the CRBSI rate in children with intestinal failure who are receiving HPN. METHODS: The rate of CRBSIs was monitored every calendar year in a prospective cohort of 195 children with intestinal failure. T C locks were initiated from October 2011 in children with recurring CRBSIs (>=2 episodes per year). RESULTS: In the whole cohort, the median annual CRBSI rate per 1000 catheter days decreased significantly from 2.07 in 2008 to 2010 to 1.23 in 2012 to 2014 (P < .05). T-C locks were used in 40 patients. No adverse events were reported. In taurolidine-treated patients, the CRBSI rate per 1000 catheter days decreased from 4.16 to 0.25 (P < .0001). The cumulative percentage of patients free of CRBSI at 18 months was 92% (95% confidence interval [CI]: 71-98) on T-C lock vs 61% (95% CI: 49-72) in controls (P = .01). In multivariate analysis, factors associated with CRBSI were immune deficiency (adjusted hazard ratio 3.49; 95% CI: 1.01-12.17) and the young age of the parents (adjusted hazard ratio 4.79, 95% CI: 2.16-10.62), whereas T-C locks were protective (adjusted hazard ratio 0.22, 95% CI: 0.06-0.74). CONCLUSION: This study confirms the efficacy of T-C catheter locks in decreasing the incidence of CRBSIs in children with intestinal failure who are receiving HPN. PMID- 29385238 TI - Evaluation of Amazon fruits: chemical and nutritional studies on Borojoa sorbilis. AB - BACKGROUND: Borojoa sorbilis (Ducke) is an Amazonian species with edible fruits that are widely consumed by the local population, but little studied and not yet economically explored. Thus the aim of this study was to describe the chemical composition, volatile compounds, nutritional aspects and antioxidant activity of the fruit pulp and peel of B. sorbilis. RESULTS: Headspace solid-phase microextraction, using polydimethylsiloxane-divinylbenzene (PDMS-DVB) fiber, resulted in the identification of 59 substances in the pulp and peel of B. sorbilis fruits after analysis of the chromatograms obtained by gas chromatography-mass spectrometry using polar and nonpolar columns. Esters were the most abundant. Moisture, lipids, protein, dietary fiber, ash, carbohydrate, total energy value, titratable acid, soluble solids and pH were measured. Protein amount, fat content and antioxidant activity were low in both pulp and peel. Carbohydrate content was 179.2 and 134.9 g kg-1 in pulp and peel, respectively. CONCLUSION: This is the first report on the chemical characteristics, flavor and nutritional aspects of B. sorbilis fruit, which is essential to its economic exploitation. The high energy value associated with the carbohydrate content, plus the low fat content, contribute to a possible use of B. sorbilis fruits as a food supplement. (c) 2018 Society of Chemical Industry. PMID- 29385237 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. AB - Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype. PMID- 29385241 TI - Optimization of breast reconstruction results using TMG flap in 30 cases: Evaluation of several refinements addressing flap design, shaping techniques, and reduction of donor site morbidity. AB - BACKGROUND: The transverse myocutaneous gracilis (TMG) flap is a widely used alternative to abdominal flaps in autologous breast reconstruction. However, secondary procedures for aesthetic refinement are frequently necessary. Herein, we present our experience with an optimized approach in TMG breast reconstruction to enhance aesthetic outcome and to reduce the need for secondary refinements. METHODS: We retrospectively analyzed 37 immediate or delayed reconstructions with TMG flaps in 34 women, performed between 2009 and 2015. Four patients (5 flaps) constituted the conventional group (non-optimized approach). Thirty patients (32 flaps; modified group) underwent an optimized procedure consisting of modified flap harvesting and shaping techniques and methods utilized to reduce denting after rib resection and to diminish donor site morbidity. RESULTS: Statistically significant fewer secondary procedures (0.6 +/- 0.9 versus 4.8 +/- 2.2; P < .001) and fewer trips to the OR (0.4 +/- 0.7 versus 2.3 +/- 1.0 times; P = .001) for aesthetic refinement were needed in the modified group as compared to the conventional group. In the modified group, 4 patients (13.3%) required refinement of the reconstructed breast, 7 patients (23.3%) underwent mastopexy/mammoplasty or lipofilling of the contralateral breast, and 4 patients (13.3%) required refinement of the contralateral thigh. Total flap loss did not occur in any patient. Revision surgery was needed once. CONCLUSIONS: Compared to the conventional group, enhanced aesthetic results with consecutive reduction of secondary refinements could be achieved when using our modified flap harvesting and shaping techniques, as well as our methods for reducing contour deformities after rib resection and for overcoming donor site morbidities. PMID- 29385240 TI - Mindfulness and fear of hypoglycaemia in parents of children with Type 1 diabetes: results from Diabetes MILES Youth - The Netherlands. AB - AIMS: To identify the sociodemographic and clinical correlates of fear of hypoglycaemia among parents of children (aged 4-18 years) with Type 1 diabetes and to examine the relationships between parental fear of hypoglycaemia, mindfulness and mindful parenting. METHODS: Sociodemographic, self-reported clinical and psychological data were extracted from the cross-sectional Diabetes MILES Youth - The Netherlands dataset. Questionnaires included the Hypoglycaemia Fear Survey - Parent Worry (parental fear of hypoglycaemia), the Freiburg Mindfulness Inventory - Short version (mindfulness) and the Interpersonal Mindfulness in Parenting Scale (mindful parenting). RESULTS: A total of 421 parents (359 mothers) participated. Hierarchical linear regression analyses showed that greater parental fear of hypoglycaemia was related to younger parental age, low educational level, non-Dutch nationality, more frequent blood glucose monitoring, and less general mindfulness. Adding mindful parenting to the model negated the previous contribution of general mindfulness. In this model, lower mindful parenting was related to greater parental fear of hypoglycaemia. In particular, parents with an increased ability to be less judgemental of themselves as parents and less reactive to emotions within parenting interactions reported less fear of hypoglycaemia. In total, 21% of the variance in parental fear of hypoglycaemia was explained. CONCLUSION: Parental fear of hypoglycaemia was associated largely with parental characteristics, including non-modifiable sociodemographics (i.e. age, education, nationality) and modifiable psychological factors (i.e. mindful parenting). These findings suggest that it is important to further explore mindfulness-based interventions for parents to reduce fear of hypoglycaemia next to interventions to reduce hypoglycaemia. PMID- 29385239 TI - Faecalibacterium prausnitzii and a Prebiotic Protect Intestinal Health in a Mouse Model of Antibiotic and Clostridium difficile Exposure. AB - BACKGROUND: Clostridium difficile (CD) infection (CDI) increases patient morbidity, mortality and healthcare costs. Antibiotic treatment induces gut dysbiosis and is both a major risk factor for CD colonization and treatment of CDI. Probiotics have been trialed to support commensal gut microbiota and reduce CDI. This study investigated commensal microbe Faecalibacterium prausnitzii (FP) and a prebiotic, both known to yield butyrate and be anti-inflammatory and immunomodulatory, on CD colonization and gut integrity in mice. METHODS: Mice were randomly grouped and supplemented daily with FP, prebiotic, FP + prebiotic, FP/prebiotic supernatant, or saline throughout the entire study. Following treatment with clindamycin for 3 days, mice were exposed to CD. Feces were collected at baseline, the day after antibiotic, and 1, 3, and 5 days after CD exposure and cultured for bacterial overgrowth and CD colonization. On days 1 and 5 after CD exposure, mice were randomly euthanized, and proximal colon was dissected for histological analysis and preparation of RNA for analysis of proinflammatory and anti-inflammatory cytokines. RESULTS: Although all mice exhibited bacterial overgrowth and CD colonization, bacterial burden resolved quicker in the FP + prebiotic group. This was associated with induction and resolution of innate immune responses, anion exchanger, and tight junction protein preservation in proximal colon. CD toxin virulence potential was questionable as expression of CD toxin B receptor was depleted in the FP + prebiotic group. CONCLUSION: Supplementation with anti-inflammatory butyrate supporting commensal bacteria and prebiotic may support innate immune responses and minimize bacterial burden and negative effects during antibiotic and CD exposure. PMID- 29385242 TI - Plasma membrane proteome analysis identifies a role of barley membrane steroid binding protein in root architecture response to salinity. AB - Although the physiological consequences of plant growth under saline conditions have been well described, understanding the core mechanisms conferring plant salt adaptation has only started. We target the root plasma membrane proteomes of two barley varieties, cvs. Steptoe and Morex, with contrasting salinity tolerance. In total, 588 plasma membrane proteins were identified by mass spectrometry, of which 182 were either cultivar or salinity stress responsive. Three candidate proteins with increased abundance in the tolerant cv. Morex were involved either in sterol binding (a GTPase-activating protein for the adenosine diphosphate ribosylation factor [ZIGA2], and a membrane steroid binding protein [MSBP]) or in phospholipid synthesis (phosphoethanolamine methyltransferase [PEAMT]). Overexpression of barley MSBP conferred salinity tolerance to yeast cells, whereas the knock-out of the heterologous AtMSBP1 increased salt sensitivity in Arabidopsis. Atmsbp1 plants showed a reduced number of lateral roots under salinity, and root-tip-specific expression of barley MSBP in Atmsbp1 complemented this phenotype. In barley, an increased abundance of MSBP correlates with reduced root length and lateral root formation as well as increased levels of auxin under salinity being stronger in the tolerant cv. Morex. Hence, we concluded the involvement of MSBP in phytohormone-directed adaptation of root architecture in response to salinity. PMID- 29385243 TI - Arrayed isoelectric focusing using photopatterned multi-domain hydrogels. AB - Isoelectric focusing (IEF) is a powerful separation method, useful for resolving subtle changes in the isoelectric point of unlabeled proteins. While microfluidic IEF has reduced the separation times from hours in traditional benchtop IEF to minutes, the enclosed devices hinder post-separation access to the sample for downstream analysis. The two-layer open IEF device presented here comprises a photopatterned hydrogel lid layer containing the chemistries required for IEF and a thin polyacrylamide bottom layer in which the analytes are separated. The open IEF device produces comparable minimum resolvable difference in isoelectric point and gradient stability to enclosed microfluidic devices while providing post separation sample access by simple removal of the lid layer. Further, using simulations, we determine that the material properties and the length of the separation lanes are the primary factors that affect the electric field magnitude in the separation region. Finally, we demonstrate self-indexed photomasks for alignment-free fabrication of multi-domain hydrogels. We leverage this approach to generate arrayed pH gradients with a total of 80 concurrent separation lanes, which to our knowledge is the first demonstration of multiple IEF separations in series addressed by a single pair of electrodes. PMID- 29385245 TI - Improving Performance Measures With Perioperative Analytics. AB - Perioperative nurses and leadership teams across the country strive to improve outcomes, increase operational efficiency, and achieve performance improvement on key measures in the perioperative department. In today's changing health care environment, which involves increasing pressure to do more with less, it is essential for perioperative leaders to understand analytics and how to use analytics to identify, plan, and implement improvement initiatives that will provide the greatest value. This article examines key performance indicators in the OR, barriers to change, and the strategies and processes that perioperative leaders can use to achieve efficiency and performance improvement goals. It also provides an example of a tactical approach to one of the OR's greatest challenges: measuring and improving block utilization. PMID- 29385244 TI - Malnutrition Identified by Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition Is Associated With More 30-Day Readmissions, Greater Hospital Mortality, and Longer Hospital Stays: A Retrospective Analysis of Nutrition Assessment Data in a Major Medical Center. AB - BACKGROUND: Few studies have compared malnutrition identified by the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition (AND/ASPEN) consensus criteria with clinical outcomes. Our goal was to compare 30 day readmissions (primary outcome), hospital mortality, length of stay (LOS) in survivors, and time to discharge alive (TDA) in all patients assessed as malnourished or not malnourished using these criteria in fiscal year 2015. We hypothesized more frequent admissions, greater mortality, longer LOS, and less likely shorter TDA in the malnourished patients. METHODS: Demographic variables, clinical outcomes, and malnutrition diagnosis for all initial patient admissions were obtained retrospectively from the electronic medical record. Logistic regression was used to compare categorical and Cox proportional hazards for TDA in unadjusted and adjusted (age, sex, race, medical/surgical admission, Charlson Comorbidity Index) models. RESULTS: Of the 3907 patients referred for nutrition assessment, 66.88% met criteria for moderate or severe malnutrition. Malnourished patients were older (61 vs 58 years, P < .0001), and survivors had longer LOS (15 vs 12 days, P = .0067) and were more likely to be readmitted within 30 days (40% vs 23%, P < .0001). In adjusted models, 30-day readmissions (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.82-2.48) and hospital mortality (OR 1.47, 95% CI 1.0-1.99) were increased, and the likelihood of earlier TDA was reduced (hazard ratio [HR] 0.55, 95% CI 0.44-0.77) in those who had >2-day stay. CONCLUSION: The AND/ASPEN criteria identified malnourished patients in a high risk population who had more adverse clinical outcomes. Further studies are needed to determine whether optimal provision of nutrition support can improve these outcomes. PMID- 29385246 TI - Clinical Issues-February 2018: 1.3 www.aornjournal.org/content/cme. PMID- 29385247 TI - The Meaning of Intraoperative Errors: Perioperative Nurse Perspectives. AB - Medical errors involve different health care professionals, are multifaceted, and can occur at the individual practitioner or system level. The conditions for errors vary in the health care environment; some practice areas may be more vulnerable to errors than others. Limited research exists that explores perioperative nursing errors. The purpose of this study was to describe and interpret the experiences of perioperative nurses related to intraoperative errors. We used the hermeneutic phenomenological method. Ten perioperative RNs participated in focus group interviews that we audio-recorded and transcribed. We analyzed data using thematic analysis, and three themes emerged that represent the essence of the experience of nurses involved in intraoperative errors: environment, being human, and moving forward. The findings support efforts to improve quality care and foster a culture of safety in the OR through strategies such as perioperative staff training, interprofessional team building, and controlling environmental factors that are distracting. PMID- 29385248 TI - Guideline Quick View: Venous Thromboembolism. PMID- 29385250 TI - AORN Journal transitions to new publisher in 2018. PMID- 29385249 TI - Embrace Action: Learn, Connect, and Participate at the Annual AORN Conference. PMID- 29385251 TI - Educational Opportunities. PMID- 29385253 TI - Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems. PMID- 29385254 TI - Special Thanks to the 2017 AORN Journal Authors. PMID- 29385255 TI - Corneal transplantation. PMID- 29385257 TI - AORN Global Surgical Conference & Expo 2018 Speaker Interviews. PMID- 29385256 TI - Implementing a Cardiac Skills Orientation and Simulation Program. AB - Patients with cardiac morbidities admitted for cardiac surgical procedures require perioperative nurses with a high level of complex nursing skills. Orienting new cardiac team members takes commitment and perseverance in light of variable staffing levels, high-acuity patient populations, an active cardiac surgical schedule, and the unpredictability of scheduling patients undergoing cardiac transplantation. At an academic medical center in Boston, these issues presented opportunities to orient new staff members to the scrub person role, but hampered efforts to provide active learning opportunities in a safe environment. As a result, facility personnel created a program to increase new staff members' skills, confidence, and proficiency, while also increasing the number of staff members who were proficient at scrubbing complex cardiac procedures. To address the safe learning requirement, personnel designed a simulation program to provide scrubbing experience, decrease orientees' supervision time, and increase staff members' confidence in performing the scrub person role. PMID- 29385258 TI - Building Personal Resilience. PMID- 29385260 TI - Did You Know? PMID- 29385259 TI - Benefits and challenges of remote video auditing in the OR. PMID- 29385261 TI - Applying Hazardous Drug Standards to Antineoplastics Used for Ophthalmology Surgery: 1.8 www.aornjournal.org/content/cme. PMID- 29385262 TI - Evidence appraisal of Bekele A, Makonnen N, Tesfaye L, Taye M. Incidence and patterns of surgical glove perforations: experience from Addis Ababa, Ethiopia. BMC Surg. 2017;17(1):26. https://doi.org/10.1186/s12893-017-0228-8. PMID- 29385263 TI - An Integrative Review on the Effect of Prebiotics, Probiotics, and Synbiotics on Infection After Colorectal Cancer Surgery: 1.7 www.aornjournal.org/content/cme. PMID- 29385264 TI - Getting the (Right) Doctor, Right Away. PMID- 29385265 TI - Forum and House of Delegates Agenda. PMID- 29385267 TI - Surgical Masks and Exposure Protection in the Perioperative Setting. PMID- 29385268 TI - Selective extraction of high-value phenolic compounds from distillation wastewater of basil (Ocimum basilicum L.) by pressurized liquid extraction. AB - During the essential oil steam distillation from aromatic herbs, huge amounts of distillation wastewaters (DWWs) are generated. These by-products represent an exceptionally rich source of phenolic compounds such as rosmarinic acid (RA) and caffeic acid (CA). Herein, the alternative use of dried basil DWWs (dDWWs) to perform a selective extraction of RA and CA by pressurized liquid extraction (PLE) employing bio-based solvent was studied. To select the most suitable solvent for PLE, the theoretical modelling of Hansen solubility parameters (HSP) was carried out. This approach allows reducing the list of candidate to two solvents: ethanol and ethyl lactate. Due to the composition of the sample, mixtures of water with those solvents were also tested. An enriched PLE extract in RA (23.90 +/- 2.06 mg/g extract) with an extraction efficiency of 75.89 +/- 16.03% employing a water-ethanol mixture 25:75 (% v/v) at 50 degrees C was obtained. In the case of CA, a PLE extract with 2.42 +/- 0.04 mg/g extract, having an extraction efficiency of 13.86 +/- 4.96% using ethanol absolute at 50 degrees C was achieved. DWWs are proposed as new promising sources of natural additives and/or functional ingredients for cosmetic, nutraceutical, and food applications. PMID- 29385269 TI - Near-infrared reflectance spectroscopy calibrations for assessment of oil, phenols, glucosinolates and fatty acid content in the intact seeds of oilseed Brassica species. AB - BACKGROUND: Very few near-infrared reflectance spectroscopy (NIRS) calibration models are available for non-destructive estimation of seed quality traits in Brassica juncea. Those that are available also fail to adequately discern variation for oleic acid (C18:1 ), linolenic (C18:3 ) fatty acids, meal glucosinolates and phenols. We report the development of a new NIRS calibration equation that is expected to fill the gaps in the existing NIRS equations. RESULTS: Calibrations were based on the reference values of important quality traits estimated from a purposely selected germplasm set comprising 240 genotypes of B. juncea and 193 of B. napus. We were able to develop optimal NIRS-based calibration models for oil, phenols, glucosinolates, oleic acid, linoleic acid and erucic acid for B. juncea and B. napus. Correlation coefficients (RSQ) of the external validations appeared greater than 0.7 for the majority of traits, such as oil (0.766, 0.865), phenols (0.821, 0.915), glucosinolates (0.951, 0.986), oleic acid (0.814. 0.810), linoleic acid (0.974, 0.781) and erucic acid (0.963, 0.943) for B. juncea and B. napus, respectively. CONCLUSION: The results demonstrate the robust predictive power of the developed calibration models for rapid estimation of many quality traits in intact rapeseed-mustard seeds which will assist plant breeders in effective screening and selection of lines in quality improvement breeding programmes. (c) 2018 Society of Chemical Industry. PMID- 29385270 TI - Cognitive judgement bias is associated with frequency of anticipatory behavior in bottlenose dolphins. AB - Many animals display a suite of increased vigilance and/or activity responses in relation to upcoming events, termed "anticipatory behavior." Anticipatory behavior toward positive events has been suggested as a cross-species measure of affective state as it likely reflects the balance of the reward-sensitivity system: various studies suggest that animals in poorer welfare situations show higher or excessive levels of anticipation for positive events. Another tool for evaluating animals' affective state is cognitive bias testing, and although it has been attempted, a link has not yet been made between cognitive bias and anticipatory behavior levels. Bottlenose dolphins (Tursiops truncatus) in captivity increase the performance of behaviors such as surface-looking and spy hopping in anticipation of training sessions during which food is provided. In this study we measured anticipatory behavior frequency in bottlenose dolphins prior to positive reinforcement training sessions, and assessed whether frequency of anticipatory behavior correlated with their performance on cognitive bias tasks. We found that higher frequencies of anticipatory behavior for training sessions was significantly associated with more pessimistic judgements in cognitive bias tests, supporting previous findings linking higher reward sensitivity with negative affective states. Anticipatory behavior is an easily measured activity and could represent a welfare indicator in dolphins as well as other animals in captive environments. PMID- 29385271 TI - Prescriptive birthweight charts can improve the prediction of adverse outcomes in very preterm infants who are small for gestational age. AB - AIM: We compared three anthropometric charts to determine which provided the best predictions for adverse outcomes in very preterm small for gestational age (SGA) infants to address a lack of consensus on this subject. METHODS: This was a retrospective cohort study of infants born below 32 weeks, who were admitted to two-level three neonatal intensive care units in The Netherlands from 2008 to 2013. The birthweights of 1720 infants were classified as SGA using a conventional, gender-specific birthweight chart, based on births in The Netherlands between 2000 and 2007, a prescriptive, gender-specific birthweight chart, based on the same data but without risk factors for intrauterine growth restriction (IUGR), and a non-gender-specific foetal weight chart derived from American ultrasonographic measurements. RESULTS: The conventional, prescriptive and foetal weight charts classified 126 (7.3%), 494 (28.7%) and 630 (36.6%) infants as SGA. The prescriptive chart, which excluded IUGR, identified 368 SGA infants with significantly increased risks of neonatal mortality and morbidity. The 136 SGA infants just classified by the American foetal weight chart were not at increased risk. CONCLUSION: The prescriptive birthweight chart, which excluded infants with IUGR, was the most effective chart when it came to identifying clinically important risk increases in SGA infants. PMID- 29385272 TI - What does the world think of ankyloglossia? AB - AIM: The diagnosis of tongue-tie (or ankyloglossia) has increased more than 10 fold in some countries. Whether this is a global phenomenon or related to cultural and professional differences is uncertain. METHODS: An online survey in English, Japanese, Chinese and Spanish was disseminated between May and November 2016 via 27 international professional bodies to >30 clinical professions chosen a priori to represent occupations involved in the management of neonatal ankyloglossia. RESULTS: A total of 1721 responses came from nursing (51%), medical (40%), dental (6%) and allied health (4%) clinicians. Nurses (40%) and allied health (34%) professionals were more likely than doctors (8%) to consider ankyloglossia as important for lactation problems, as were western (83%) compared to Asian (52%) clinicians. Referrals to clinicians for ankyloglossia management originated mainly from parents (38%). Interprofessional referrals were not clearly defined. Frenectomies were most likely to be performed by surgeons (65%) and dentists (35%), who were also less likely to be involved in lactation support. Clinicians performing frenectomies were more likely to consider analgesia as important compared to those not performing frenectomies. CONCLUSION: The diagnosis and treatment of ankyloglossia vary considerably around the world and between professions. Efforts to standardise management are required. PMID- 29385273 TI - First report of a hatched, hand-reared, and released African oystercatcher. AB - The African oystercatcher Haematopus moquini is a near-threatened wader that is endemic to southern Africa. In the past, the species suffered a drastic decrease in nesting success due to human disturbance. We present the case report of an African oystercatcher that was hatched, hand-reared, and released in the Western Cape, South Africa. African oystercatchers are semi-altricial birds that tend to be highly sensitive to stress; as a result, strategies to minimize stress and the employment of surrogate parents and pre-release acclimatization are important to ensure post-release survival of hand-reared chicks. Considering the lack of literature on the incubation and hand-rearing of oystercatchers, this case report provides a basis for the development of hand-rearing techniques that might be useful for the protection of this and other threatened wader species. PMID- 29385274 TI - The preterm infant stomach actively degrades milk proteins with increasing breakdown across digestion time. AB - AIM: This study investigated the effect of time post-ingestion on gastric digestion and gastric hormones after feeding preterm infants unfortified and fortified human milk. METHODS: Human milk and infant gastric samples were collected from 14 preterm (23-32 weeks birth gestational age) mother-infant pairs within 7-98 days postnatal age. Gastric samples were collected one, two and three hours after beginning of feeding. Samples were analysed for pH, proteolysis, general protease activity and the concentrations of pepsin, gastrin and gastrin releasing peptide (GRP). One-way ANOVA with repeated measures followed by Tukey's multiple comparisons test was used. RESULTS: Gastric pH was significantly decreased after each hour in the preterm infant stomach from one to three hours postprandial. Proteolysis increased significantly from human milk to gastric contents at one, two and three hours postprandial (by 62, 131% and 181%, p < 0.05). General protease activity increased significantly by 58% from human milk to the gastric contents at two hours postprandial. GRP was present in human milk, whereas gastrin was produced in the infant stomach. CONCLUSION: Although preterm infants may digest human milk proteins to a lesser extent than term infants, we demonstrated that the preterm infant stomach actively degrades milk proteins with increasing breakdown over digestion time. PMID- 29385275 TI - Identification of possible nutritional and stress risk factors in the development of marmoset wasting syndrome. AB - Marmoset wasting syndrome (MWS) describes a series of symptoms in callitrichids that lead to general weakness and a failure to thrive in captive conditions such as zoological institutions. Though the cause of MWS has not been identified, the majority of hypotheses are linked to deficiencies of specific nutrients and increased stress levels. Questionnaires were sent to zoos requesting information on diets and housing of currently living and dead callitrichids before their deaths, as well as their postmortem reports. Risk factors for development and occurrence of MWS include close proximity of predator enclosures and high levels of dietary magnesium and zinc. Variables with effects which may protect against the development of MWS included provision of a nest box, natural trees within enclosure, reduced visibility to visitors, as well as dietary factors such as higher concentrations of potassium and fiber fractions. The protective effects of limited concentrate feeds and increased total dietary fiber may help reduce the risks of developing MWS. The minerals may not have biological implications in MWS per se, however, they may be reflective of diets too high in concentrates and too low in plant matter. Habitat designs that are less naturalistic and those which provide insufficient privacy or hide areas may increase chronic stress for callitrichid species, possibly because of visitor-related stress. Other causes of chronic stress in captive zoo populations should be the topic of further research to reduce occurrence of MWS. PMID- 29385276 TI - Limited association between markers of stress during pregnancy and fetal growth in 'Born into Life', a new prospective birth cohort. AB - AIMS: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birthweight. METHODS: In 2010 2012, we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birthweight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birthweight, respectively, adjusted for gestational age. RESULTS: No significant associations were found between PSS scores or cortisol levels and birthweight. There was a trend towards higher salivary cortisol levels among infants with lower birthweights, and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r = 0.31, p = 0.01), the decline in cortisol levels (r = -0.26, p = 0.03) and evening cortisol levels (r = -0.21, p = 0.09) were negatively correlated with PSS scores. CONCLUSION: Maternal stress during pregnancy was not associated with birthweight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity. PMID- 29385277 TI - Prenatal phthalate exposure was associated with croup in Swedish infants. AB - AIM: This study examined whether prenatal phthalate exposure was associated with lower or upper airway inflammation in infants. METHODS: From 2007 to 2010, we used liquid chromatography-tandem mass spectrometry, adjusted for creatinine, to analyse 14 phthalate metabolites and one phthalate replacement in the urine of 1062 Swedish mothers at a median of 10 weeks of pregnancy. This was used to determine any associations between prenatal phthalate exposure and croup, wheezing or otitis in their offspring until 12 months of age, using logistic regression, adjusted for potential confounders. RESULTS: There were significant associations between phthalate metabolites of butyl-benzyl phthalate (BBzP) and di-ethyl-hexyl phthalate (DEHP) concentrations in maternal prenatal urine and croup in 1062 infants during the first year of life, when adjusted for potential confounders. A dose-response relationship was found between prenatal phthalates exposure and maternal reported croup in the children, with a significant association in boys. There was no clear indication with regard to associations between prenatal phthalate exposure and wheezing or otitis media in the children during the first year of life. CONCLUSION: Our analysis suggests that exposure to BBzP and DEHP phthalates was associated with maternal reports of croup in infants up to 12 months of age. PMID- 29385278 TI - National data showed that delayed sleep in six-year-old children was associated with excessive use of electronic devices at 12 years. AB - AIM: Cross-sectional studies have shown associations between adolescent sleep problems and the use of electronic devices, such as mobile phones, but longitudinal studies remain scarce. We explored any association between delayed bedtimes at six years old and the excessive use of electronic devices at 12 years of age. Texting was a prime focus. METHODS: We analysed 9607 adolescents who owned mobile phones in 2013 using the Japanese Longitudinal Survey of Newborns in the 21st Century, which started in 2001. The outcomes were daily excessive use of a mobile phone, television (TV) and video games. RESULTS: Delayed bedtime at the age of six years was associated with excessive texting at weekends. The adjusted odds ratios and 95% confidence intervals obtained from logistic regression analyses were 1.88 (1.14-3.10) for the 10-11 pm group and 1.98 (1.08-3.63) for the after 11 pm group, compared with the before 9 pm group. Later bedtimes were also associated with increased risks of excessive TV viewing and video game use. CONCLUSION: Our study indicated that six-year-olds who regularly stayed up late at night used electronic devices more frequently, or for longer, at the age of 12. Parents need to be more aware of links between sleep issues and electronic devices. PMID- 29385280 TI - A Three-State System Based on Branched DNA Hybrids. AB - There is a need for materials that respond to chemical or physical stimuli through a change in their structure. While a transition between water-soluble form and solid is not uncommon for DNA-based structures, systems that transition between three different states at room temperature and ambient pressure are rare. Here we report the preparation of branched DNA hybrids with eight oligodeoxycytidylate arms via solution-phase, H-phosphonate-based synthesis. Some hybrids assemble into hydrogels upon lowering the pH, acting as efficient gelators at pH 4-6, but can also transition into a more condensed solid state form upon exposure to divalent cations. Together with the homogeneous solutions that the i-motif-forming compounds give at neutral pH, three-state systems result. Each state has its own color, if chromophores are included in the system. The assembly and gelation properties can be tuned by choosing the chain length of the arms. Their responsive properties make the dC-rich DNA hybrids candidates for smart material applications. PMID- 29385279 TI - Chronic lymphoproliferative disorder of NK-cells: A single-institution review with emphasis on relative utility of multimodality diagnostic tools. AB - BACKGROUND: Chronic lymphoproliferative disorder of NK-cells (CLPD-NK) manifests as a persistent increase (>=2 * 109 /L, for > 6 months) of mature NK-cells in peripheral blood with an indolent clinical course. The disease is rare, and only limited case series have been published. METHODS: We retrospectively studied 11 patients with CLPD-NK diagnosed at our institution between 2005 and 2017. RESULTS: Patients included 7 men and 4 women with a median age of 60 years (range, 25-89 years). Ten patients (91%) had cytopenias. Bone marrow involvement by CLPD-NK ranged from 5-15%. The most commonly detected antigenic aberrancies by low cytometry immunophenotyping were as follows: CD7decreased/dim (30%), CD8uniform+ (36%), CD56-/partial (73%), CD94bright (55%), and KIR restriction (100%). JAK/STAT pathway mutations were detected in 8 of 10 (80%) patients and involved STAT3 (n = 7) and JAK3 (n = 1). The presence of mutations tended to correlate with the occurrence of other cytopenias (anemia/thrombocytopenia) and requirement for treatment. Seven patients received single-agent therapy, with amelioration of symptoms; 4 patients were observed. There were no disease associated deaths or progression to more aggressive disease during the follow-up interval (median, 17 months). CONCLUSIONS: Patients with CLPD-NK have an indolent clinical course and frequent hematologic manifestations that are responsive to single-agent therapy. Mutations in STAT3 are common and portend more pronounced clinical manifestations. PMID- 29385281 TI - Pacifier use in newborns: related to socioeconomic status but not to early feeding performance. AB - AIM: Mothers are often advised not to use pacifiers until breastfeeding has been well-established. This study determined the infant and social factors that were related to pacifier use during the first few days of life and whether it led to alterations in feeding performance. METHODS: We enroled 51 full-term infants and their mothers at Barnes-Jewish Hospital in urban St. Louis, USA, in 2015. Before they were discharged the mothers completed a questionnaire, and infant feeding was assessed using a standardised assessment. RESULTS: There were 24 (47%) infants who used a pacifier during the first few days of life and seven (29%) of these were exclusively breastfed. Pacifier use was less common among mothers who exclusively breastfed (p = 0.04). Pacifier use was more common among mothers whose income was less than 25 000 US dollars (p = 0.02), who were single (p = 0.002) and who did not have a college education (p = 0.03). No associations between pacifier use and feeding performance were observed. CONCLUSION: While lower socioeconomic status was related to pacifier use, feeding performance in the first few days of life was no different between those infants who did and did not use pacifiers after a full-term birth. PMID- 29385282 TI - Single Ion Magnets from 3d to 5f: Developments and Strategies. AB - Single-ion magnets (SIMs), exhibiting slow magnetization relaxation in the absence of the magnetic field, originate from their single spin-carrier centre. In pursuit of high-performance magnetic properties, such as high spin-reversal barrier and high blocking temperature, various metal centres were investigated to establish SIMs, including 3d and 5d transition metal ions, 4f lanthanide ions, and 5f actinide ions, which possess unique zero-field splitting and magnetic properties. Therefore, proper ligand field is of great importance to different types of metals. In the given great breakthroughs since the first SIM, [Pc2 Tb]- (Pc=dianion of phthalocyanine), was reported, strategies of ligand field design have emerged. In this review, the developments of SIMs with different metal centres are summarized, as well as the possible strategies. PMID- 29385283 TI - Consensus should be adapted to the evidence and not vice-versa. PMID- 29385284 TI - Anion Sensing by Fluorescent Expanded Calixpyrroles. AB - Expanded calixpyrrole-type macrocycles, calix[2]benzo[4]pyrroles, bearing fluorescent moieties attached via conjugated vinyl spacers, have been synthesized from the corresponding formyl derivatives through Knoevenagel condensation. The anion-binding properties of the resulting fluorescent macrocycles have been studied by means of NMR, UV/Vis, and fluorescence spectroscopies. Our main focus has been on dicarboxylates matching the size of the binding cavity of the calix[2]benzo[4]pyrrole skeleton. The observed anion-binding properties were compared with those of the regular calix[4]pyrroles bearing identical fluorophores. Surprisingly, the parent calix[4]pyrroles appear to be equally efficient, if not more so, for sensing anions such as dicarboxylates. Affinity constants determined for various anions and dianions show the sensors S1-S5 to be highly cross-reactive. The cross-reactivity of the sensors was utilized in a microchip-based array, which showed perfect (100 %) classification of 18 analytes utilizing only five sensors. Finally, the same array was used to quantitatively analyze dicarboxylates such as oxalate and malonate. The data from the array were subjected to linear regression, allowing the determination of various concentrations of dianions with low error (<2 %). PMID- 29385285 TI - Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation. AB - We describe a case of apparent mineralocorticoid excess (hypertension, hypokalemia, metabolic alkalosis and low plasma renin activity) secondary to itraconazole therapy. Inhibition of 11beta-hydroxysteroid dehydrogenase 2 was demonstrated, and withholding itraconazole led to resolution of adverse effects that did not recur with voriconazole. This report adds to a growing body of evidence linking apparent mineralocorticoid excess with certain triazoles. PMID- 29385286 TI - The fate of ribosomal RNA genes in spontaneous polyploid dogrose hybrids [Rosa L. sect. Caninae (DC.) Ser.] exhibiting non-symmetrical meiosis. AB - Dogroses represent an exceptional system for studying the effects of genome doubling and hybridization: their asymmetrical meiosis enables recombination in bi-parentally inherited chromosomes but prevents it in maternally inherited ones. We employed fluorescent in situ hybridization, genome skimming, amplicon sequencing of genomic and cDNA as well as conventional cloning of nuclear ribosomal DNA in two phylogenetically distinct pentaploid (2n = 5x = 35) species, Rosa canina and Rosa inodora, and their naturally occurring reciprocal hybrids, Rosa dumalis (5x) and Rosa agrestis (5x, 6x). Both progenitor species differed in composition, meiotic behaviour and expression of rDNA loci: R. canina (five 18S and 5-8 5S loci) was dominated by the Canina ribotypes, but R. inodora (four 18S loci and 7-8 5S loci) by the Rubiginosa ribotype. The co-localized 5S/18S loci occurred on either bivalent-forming (R. canina) or univalent-forming (R. inodora) chromosomes. Ribosomal DNA loci were additively inherited; however, the Canina ribotypes were dominantly expressed, even in genotypes with relatively low copy number of these genes. Moreover, we observed rDNA homogenization towards the paternally transmitted Canina ribotype in 6x R. agrestis. The here-observed variation in arrangement and composition of rDNA types between R. canina and R. inodora suggests the involvement of different genomes in bivalent formation. This results supports the hypothesis that the asymmetrical meiosis arose at least twice by independent ancient hybridization events. PMID- 29385287 TI - Photochromic Crystalline Systems Mimicking Bio-Functions. AB - Photoresponsive crystalline systems mimicking bio-functions are prepared using photochromic diarylethenes. Upon UV irradiation of the diarylethene crystal, the photogenerated closed-ring isomers self-aggregate to form needle-shaped crystals on the surface. The rough surface shows the superhydrophobic lotus effect. In addition, the rose-petal effects of wetting, the anti-reflective moth-eye effect, and a double-roughness structure mimicking the surface of a lotus leaf are observed by controlling the heating procedures, UV irradiation processes, and molecular structural modification. By changing the molecular structure, a superhydrophilic surface mimicking a snail shell can be generated. We also find the crystal of a diarylethene derivative that shows a photosalient effect. The effect is observed partly due to the hollow structure of the crystal. It is demonstrated that a photo-response similar to the response of impatiens plant to stimulation is observed by packing small beads in the hollow. These photoresponsive functions are unique, and they demonstrate a macroscopic response by means of microscopic molecular movement induced by light. In the future, such a molecular assembly system will be a promising candidate for fabricating photoresponsive architectures and soft robots. PMID- 29385288 TI - Benefits and risks of intensive blood-pressure lowering in advanced chronic kidney disease. PMID- 29385289 TI - Modulator-Controlled Synthesis of Microporous STA-26, an Interpenetrated 8,3 Connected Zirconium MOF with the the-i Topology, and its Reversible Lattice Shift. AB - A fully interpenetrated 8,3-connected zirconium MOF with the the-i topology type, STA-26 (St Andrews porous material-26), has been prepared using the 4,4',4" (2,4,6-trimethylbenzene-1,3,5-triyl)tribenzoate (TMTB) tritopic linker with formic acid as a modulating agent. In the as-prepared form STA-26 possesses Im3? m symmetry compared with the Pm3? m symmetry of the non-interpenetrated analogue, NU-1200, prepared using benzoic acid as a modulator. Upon removal of residual solvent there is a shift between the interpenetrating lattices and a resultant symmetry change to Cmcm which is fully reversible. This is observed by X-ray diffraction and 13 C MAS NMR is also found to be remarkably sensitive to the structural transition. Furthermore, heating STA-26(Zr) in vacuum dehydroxylates the Zr6 nodes leaving coordinatively unsaturated Zr4+ sites, as shown by IR spectroscopy using CO and CD3 CN as probe molecules. Nitrogen adsorption at 77 K together with grand canonical Monte Carlo simulations confirms a microporous, fully interpenetrated, structure with pore volume 0.53 cm3 g-1 while CO2 adsorption at 196 K reaches 300 cm3 STP g-1 at 1 bar. While the pore volume is smaller than that of its non-interpenetrated mesoporous analogue, interpenetration makes the structure more stable to moisture adsorption and introduces shape selectivity in adsorption. PMID- 29385290 TI - The distress thermometer provides a simple screening tool for selecting distressed childhood cancer survivors. AB - AIM: We investigated the value of the distress thermometer, a one-item screening tool, in childhood cancer survivors. METHODS: The participants were 286 childhood cancer survivors who visited an outpatient clinic at Erasmus MC University-Sophia Children's Hospital, Rotterdam, The Netherlands, for the first time from 2001 to 2008 and completed the distress thermometer and Hospital Anxiety and Depression Scale (HADS). Higher scores reflected more distress. A HADS score >=15 was used as the cut-off point for emotional distress. We calculated the correlation between the HADS and distress thermometer, the relationship between the HADS anxiety and the HADS depression ratings, and the distress score and the sensitivity and specificity for different cut-off scores of the distress thermometer. RESULTS: A moderate correlation was found between the HADS score and the distress thermometer (r: 0.56, p < 0.01, interclass correlation 0.40, p < 0.01). In total, 39% of the variability of distress, as measured by the distress thermometer, could be explained by the HADS anxiety and HADS depression ratings. A cut-off score of at least three on the distress thermometer resulted in a sensitivity of 92% and specificity of 79%. CONCLUSION: The distress thermometer provided a rapid screening tool for identifying distressed childhood cancer survivors who needed further psychological support. PMID- 29385291 TI - Entropically driven Polymeric Enzyme Inhibitors by End-Group directed Conjugation. AB - A new generic concept for polymeric enzyme inhibitors is presented using the example of poly(2-methyl-2-oxazoline) (PMOx) terminated with an iminodiacetate (IDA) function. These polymers are shown to be non-competitive inhibitors for horseradish peroxidase (HRP). Mechanistic investigations revealed that the polymer is directed to the protein by its end group and collapses at the surface in an entropy-driven process as shown by isothermal titration calorimetry. The dissociation constant of the complex was determined as the inhibition constant Ki using HRP kinetic activity measurements. Additional experiments suggest that the polymer does not form a diffusion layer around the protein, but might inhibit by inducing minor conformational changes in the protein. This kind of inhibitor offers new avenues towards designing bioactive compounds. PMID- 29385292 TI - Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing. AB - As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)*0.5 (D)*1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards. PMID- 29385293 TI - Application of Sal classification to parotid gland fine-needle aspiration cytology: 10-year retrospective analysis of 312 patients. AB - BACKGROUND: The accuracy of fine-needle aspiration biopsy (FNAB) is controversial in parotid tumors. We aimed to compare FNAB results with the final histopathological diagnosis and to apply the "Sal classification" to our data and discuss its results and its place in parotid gland cytology. METHODS: The FNAB cytological findings and final histological diagnosis were assessed retrospectively in 2 different scenarios based on the distribution of nondefinitive cytology, and we applied the Sal classification and determined malignancy rate, sensitivity, and specificity for each category. RESULTS: In 2 different scenarios FNAB sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were found to be 81%, 87%, 54.7%, and 96.1%; and 65.3%, 100%, 100%, and 96.1%, respectively. The malignancy rates and sensitivity and specificity were also calculated and discussed for each Sal category. CONCLUSION: We believe that the Sal classification has a great potential to be a useful tool in classification of parotid gland cytology. PMID- 29385294 TI - Outcomes utilizing intensity-modulated radiotherapy in oropharyngeal cancers: Tonsils versus base of tongue. AB - BACKGROUND: The purpose of this study was to present the outcomes of oropharyngeal cancers treated with intensity-modulated radiotherapy (IMRT) especially the differences between tonsillar and base of tongue (BOT) primaries. METHODS: Retrospective analysis of 124 patients with biopsy proven squamous cell carcinomas of the oropharynx, treated with IMRT. RESULTS: Human papillomavirus (HPV) association correlated with improvement in survivals in both tonsillar and BOT primaries. At the 2-year median follow-up, the cumulative incidences of locoregional recurrences were 8% in both the tonsil and BOT groups (P = .76) but the distant metastases were 8% in the tonsil group versus 26% in the BOT group (P = .009). Thirty percent of tonsil primaries has >=N2c neck disease as compared to 54% of BOT. Incidence of distant metastases increases with advanced nodal classification, especially >N2c. CONCLUSION: Even though the locoregional controls are excellent with IMRT and chemotherapy, these patients continue to fail distantly, particularly significant for the BOT group and for nodal stage >N2c. PMID- 29385295 TI - Modified combination of platelet count and neutrophil "to" lymphocyte ratio as a prognostic factor in patients with advanced head and neck cancer. AB - BACKGROUND: We evaluated the prognostic potential of the combination of platelet count and neutrophil to lymphocyte ratio (COP-NLR) in patients with advanced head and neck cancer. METHODS: We proposed a modified COP-NLR scoring system defined as follows: score 0 (platelet count level <300 * 109 /L and NLR <3); score 1 (platelet count level >=300 * 109 /L and NLR <3); and score 2 (NLR >=3). We assessed whether the modified scoring system had better performance as an indicator of prognosis than the existing COP-NLR scoring system (original and 4 group scores). RESULTS: A total of 248 patients were enrolled. The Akaike Information Criterion value with the modified COP-NLR score was the smallest among the 3 models. The 3-year survival rates according to the modified COP-NLR scores of 0, 1, and 2 were 80.6%, 59.9%, and 23.8%, respectively. CONCLUSION: The modified COP-NLR score is a useful prognostic marker in patients with advanced head and neck cancer. PMID- 29385296 TI - Identification and functional study of the endoplasmic reticulum stress sensor IRE1 in Chlamydomonas reinhardtii. AB - In many eukaryotes, endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) via the transmembrane endoribonuclease IRE1 to maintain ER homeostasis. The ER stress response in microalgae has not been studied in detail. Here, we identified Chlamydomonas reinhardtii IRE1 (CrIRE1) and characterized two independent knock-down alleles of this gene. CrIRE1 is similar to IRE1s identified in budding yeast, plants, and humans, in terms of conserved domains, but differs in having the tandem zinc-finger domain at the C terminus. CrIRE1 was highly induced under ER stress conditions, and the expression of a chimeric protein consisting of the luminal N-terminal region of CrIRE1 fused to the cytosolic C-terminal region of yeast Ire1p rescued the yeast ?ire1 mutant. Both allelic ire1 knock-down mutants ire1-1 and ire1-2 were much more sensitive than their parental strain CC-4533 to the ER stress inducers tunicamycin, dithiothreitol and brefeldin A. Treatment with a low concentration of tunicamycin resulted in growth arrest and cytolysis in ire1 mutants, but not in CC-4533 cells. Furthermore, in the mutants, ER stress marker gene expression was reduced, and reactive oxygen species (ROS) marker gene expression was increased. The survival of ire1 mutants treated with tunicamycin improved in the presence of the ROS scavenger glutathione, suggesting that ire1 mutants failed to maintain ROS levels under ER stress. Together, these results indicate that CrIRE1 functions as an important component of the ER stress response in Chlamydomonas, and suggest that the ER stress sensor IRE1 is highly conserved during the evolutionary history. PMID- 29385297 TI - Interplay between cytochrome c and gibberellins during Arabidopsis vegetative development. AB - We studied the effect of reducing the levels of the mitochondrial electron carrier cytochrome c (CYTc) in Arabidopsis thaliana. Plants with CYTc deficiency have delayed growth and development, and reach flowering several days later than the wild-type but with the same number of leaves. CYTc-deficient plants accumulate starch and glucose during the day, and contain lower levels of active gibberellins (GA) and higher levels of DELLA proteins, involved in GA signaling. GA treatment abolishes the developmental delay and reduces glucose accumulation in CYTc-deficient plants, which also show a lower raise in ATP levels in response to glucose. Treatment of wild-type plants with inhibitors of mitochondrial energy production limits plant growth and increases the levels of DELLA proteins, thus mimicking the effects of CYTc deficiency. In addition, an increase in the amount of CYTc decreases DELLA protein levels and expedites growth, and this depends on active GA synthesis. We conclude that CYTc levels impinge on the activity of the GA pathway, most likely through changes in mitochondrial energy production. In this way, hormone-dependent growth would be coupled to the activity of components of the mitochondrial respiratory chain. PMID- 29385298 TI - Head and neck lymphedema management: Evaluation of a therapy program. AB - BACKGROUND: The purpose of this pilot study was to examine a therapeutic intervention for head and neck lymphedema. The 22-week intervention involved therapist-led care and participant self-management. Effectiveness was evaluated using a previously described lymphedema assessment tool, the Assessment of Lymphedema of the Head and Neck (ALOHA) to detect change over the course of the 22 weeks of treatment, and before and after a single treatment session. METHODS: A prospective observational pilot study was conducted with a cohort of 10 participants assessed. Measurements of size (tape measurements) and water content (tissue dielectric constant [TDC]) were used, per the ALOHA protocol. Participants received 13 lymphedema therapy treatments at reducing frequencies over 22 weeks and daily self-management. RESULTS: There was an overall significant reduction in lower neck circumference (F [2.15,19.35] = 7.11; P = .004), upper neck circumference (F [5,45] = 7.27; P < .001) and TDC (F (5,45) = 8.92; P < .001) over time. There were no significant differences over the course of treatment for mean ear-to-ear measurements or before and after a single session of treatment. CONCLUSION: This pilot study found a reduction in head and neck lymphedema over the 22-week lymphedema treatment course. This intervention may be successful in reducing head and neck lymphedema; however, further studies are needed to investigate these findings in a larger sample with the use of a control group to negate improvements from healing over time. PMID- 29385299 TI - Narrow band imaging for head and neck malignancies: Lessons learned from mistakes. AB - BACKGROUND: The accuracy of white light endoscopy in combination with narrow band imaging (WLE + NBI) for diagnosis of squamous cell carcinoma (SCC) does not reach 100%. We evaluated the characteristics of the false-negative and false-positive cases. METHODS: Five hundred thirty lesions of the upper airways were evaluated. The WLE was followed by NBI examination before performing a biopsy. RESULTS: The false-negative lesions (7.36%) were represented by submucosal and non-SCC tumors. Among the 25 non-SCC tumors, 72% did not show any suspicious vascular pattern under NBI. The false-positive lesions (6.04%) were mainly represented by postradiotherapy mucosal changes, ulcers, and infections. Regarding papillomas, NBI accuracy reached 95.32%, although cases with dysplasia were difficult to distinguish from SCC. CONCLUSION: The WLE + NBI improved diagnostic accuracy, but not all lesions were ideally evaluated with current defined patterns. An accurate anamnesis is mandatory, because, in some cases, it may be more relevant than the NBI pattern. PMID- 29385300 TI - Total Synthesis and Stereochemical Revision of Iriomoteolide-2a. AB - Total syntheses of the proposed and correct structures of iriomoteolide-2a, a cytotoxic marine macrolide natural product with an unusual 23-membered macrolactone skeleton, have been accomplished for the first time. The synthesis of the correct structure involves an asymmetric epoxidation/diepoxide cyclization cascade for the construction of the bis(tetrahydrofuran) moiety, a Suzuki-Miyaura coupling for the fragment assembly, and a ring-closing metathesis for the closure of the macrocyclic backbone. In addition, the original stereochemical assignment of iriomoteolide-2a was revised. PMID- 29385301 TI - Long-term terrestrial carbon dynamics in the Midwestern United States during 1850 2015: Roles of land use and cover change and agricultural management. AB - To meet the increasing food and biofuel demand, the Midwestern United States has become one of the most intensively human-disturbed hotspots, characterized by widespread cropland expansion and various management practices. However, the role of human activities in the carbon (C) cycling across managed landscape remains far from certain. In this study, based on state- and national census, field experiments, and model simulation, we comprehensively examined long-term carbon storage change in response to land use and cover change (LUCC) and agricultural management in the Midwest from 1850 to 2015. We also quantified estimation uncertainties related to key parameter values. Model estimation showed LUCC led to a reduction of 1.35 Pg (with a range of 1.3-1.4 Pg) in vegetation C pool of the Midwest, yet agricultural management barely affected vegetation C change. In comparison, LUCC reduced SOC by 4.5 Pg (3.1 to 6.2 Pg), while agricultural management practices increased SOC stock by 0.9 Pg. Moreover, we found 45% of the study area was characterized by continuously decreasing SOC caused by LUCC, and SOC in 13% and 31% of the area was fully and partially recovered, respectively, since 1850. Agricultural management was estimated to increase the area of full recovery and partial recovery by 8.5% and 1.1%. Our results imply that LUCC plays an essential role in regional C balance, and more importantly, sustainable land management can be beneficial for strengthening C sequestration of the agroecosystems in the Midwestern US, which may serve as an important contributor to C sinks in the US. PMID- 29385302 TI - Antimetastatic potentials of salvianolic acid A on oral squamous cell carcinoma by targeting MMP-2 and the c-Raf/MEK/ERK pathway. AB - The metastasis of oral squamous cell carcinoma (OSCC) is one of the most important causes of cancer-related deaths. Thus, various therapeutic strategies have been developed to prevent the metastasis of OSCC. Salvianolic acid A (SAA), a traditional Chinese medicine, has antithrombosis, antiplatelet, anti inflammation, and antitumor activities. Here, we provide molecular evidence indicating that SAA exerts its antimetastatic effects by markedly inhibiting the invasion and migration of oral squamous SCC-9 and SCC-25 cells. SCC-9 and SCC-25 cells were treated with various concentrations of SAA to further investigate the precise involvement of SAA in cancer metastasis. The results of zymography, and Western blotting indicated that SAA treatment may decrease matrix metallopoteinase-2 (MMP-2) expression. SAA also inhibited p-c-Raf, p-MEK1/2, and p-ERK1/2 protein expression. In addition, treating SCC-9 cells with U0126, a MEK specific inhibitor, decreased MMP-2 expression and concomitantly inhibited cell migration. Our findings suggested that SAA inhibits the invasion and migration of OSCC by inhibiting the c-Raf/MEK/ERK pathways that control MMP-2 expression. Our findings provide new insights into the molecular mechanisms that underlie the antimetastatic effect of SAA and are thus valuable for the development of treatment strategies for metastatic OSCC. PMID- 29385303 TI - Effects of excessive fibrin deposit and polylactide adhesion barrier on wound healing in thyroidectomy murine wound model. AB - BACKGROUND: We hypothesize that excessive fibrin formation and inflammation induced by antiadhesive material, SurgiWrap (SW), would have an adverse effect on wound healing. It was evaluated by a thyroidectomy murine wound model. METHODS: Excessive fibrin formation was induced by isthmectomy without hemostasis. Rats were allocated into isthmectomy with SurgiWrap (I+SW+), I+SW-, I-SW+, I-SW-, and isthmectomy after electrocautery for hemostasis (I+C+SW-). The SWs were placed on the superficial and visceral layers for gross and microscopic evaluation. RESULTS: Microscopic examination showed collagen deposition occurred in the I-SW- sham group and at a higher level in I+C+SW-. The collagen deposition decreased in groups without SW with time but increased in groups with SW. Use of SW produced more inflammation and more collagen deposition. The I+SW + group developed the largest area of collagen deposition at 4 weeks and more collagen deposition than the I-SW + group. CONCLUSION: The SW induced more collagen deposition increasing with time. The collagen deposition produced by SW was worsened by excessive fibrin formation and inflammation. PMID- 29385304 TI - Cytochrome-P450-Induced Ordering of Microsomal Membranes Modulates Affinity for Drugs. AB - Although membrane environment is known to boost drug metabolism by mammalian cytochrome P450s, the factors that stabilize the structural folding and enhance protein function are unclear. In this study, we use peptide-based lipid nanodiscs to "trap" the lipid boundaries of microsomal cytochrome P450 2B4. We report the first evidence that CYP2B4 is able to induce the formation of raft domains in a biomimetic compound of the endoplasmic reticulum. NMR experiments were used to identify and quantitatively determine the lipids present in nanodiscs. A combination of biophysical experiments and molecular dynamics simulations revealed a sphingomyelin binding region in CYP2B4. The protein-induced lipid raft formation increased the thermal stability of P450 and dramatically altered ligand binding kinetics of the hydrophilic ligand BHT. These results unveil membrane/protein dynamics that contribute to the delicate mechanism of redox catalysis in lipid membrane. PMID- 29385305 TI - Intraoperative cardiac arrest etiologies in head and neck surgery: A comprehensive review. AB - BACKGROUND: The etiologies of intraoperative cardiac arrest within otolaryngology are not well understood as they are rare events. METHODS: A comprehensive review of the etiologies and corresponding pathophysiologic neural mechanisms of intraoperative cardiac arrest in otolaryngologic surgery are examined. RESULTS: The occurrence of this rare complication has been described in a range of head and neck procedures, including but not limited to suspension laryngoscopy and oncologic resections in the neck, maxilla and thyroid. Three anatomically distinct pathways leading to intraoperative cardiac arrest are described: direct vagal stimulation, the trigeminocardiac reflex and the baroreceptor reflex. All three share the final common pathway of parasympathetic signaling to the sinoatrial node via the cardiac fibers of the vagus nerve. CONCLUSION: With a firm understanding of the mechanistic underpinning of this rare phenomenon, otolaryngologic surgeons can be better prepared for its occurrence. PMID- 29385306 TI - Di(2-ethylhexyl) phthalate (DEHP) influences follicular development in mice between the weaning period and maturity by interfering with ovarian development factors and microRNAs. AB - Although studies have shown that di(2-ethylhexyl) phthalate (DEHP) can disrupt ovarian function, few reports have focused on follicular development in mice between the weaning period and maturity, especially with respect to microRNA (miRNA) expression. In this study, 21-day-old ICR mice were administered DEHP at doses of 0, 100, 400, and 1600 mg/(kg d) for 6 weeks by gavage. After DEHP administration, a significant decrease in the expression of follicle development related factors (including c-kit, kitl, gdf9, and atm) was observed by quantitative real-time PCR (RT-PCR), but no significant difference in the proteins encoded by these genes was observed by Western blot. Bisulfite sequencing suggested that the total methylation percentages of promoter regions of these genes were not notably altered after DEHP exposure. However, RT-PCR revealed a significantly increased expression of ovarian miRNAs (let-7b, miR-17 5p miR-181a, and miR-151), which inhibit follicular granulosa cell proliferation. Overall, this study showed that DEHP administration from weaning to maturity could suppress the mRNA expression of follicular development factors, and this effect was not achieved through changes in the methylation of DNA in CpG islands of development factors. In addition, DEHP was shown to induce miRNAs to inhibit the proliferation of follicular granulosa cells and the anti-apoptosis function of KITL and GDF9 while increasing bax/bcl2 expression to further promote the apoptosis of granulosa cells. PMID- 29385307 TI - Interrupted Baeyer-Villiger Rearrangement: Building A Stereoelectronic Trap for the Criegee Intermediate. AB - The instability of hydroxy peroxyesters, the elusive Criegee intermediates of the Baeyer-Villiger rearrangement, can be alleviated by selective deactivation of the stereoelectronic effects that promote the 1,2-alkyl shift. Stable cyclic Criegee intermediates constrained within a five-membered ring can be prepared by mild reduction of the respective hydroperoxy peroxyesters (beta-hydroperoxy-beta peroxylactones) which were formed in high yields in reaction of beta-ketoesters with BF3 ?Et2 O/H2 O2 . PMID- 29385308 TI - Palladium-Catalyzed Regioselective Aromatic Extension of Internal Alkynes through a Norbornene-Controlled Reaction Sequence. AB - A regioselective aromatic pi-extension reaction of internal alkynes is reported. The proposed method employs three easily available components, namely aryl halides, 2-haloarylcarboxylic acids, and disubstituted acetylenes. The transformation is driven by a controlled reaction sequence of C-H activation, decarboxylation, and annulation to give poly(hetero)aromatic compounds in a site selective fashion. Unlike in previously reported palladium-catalyzed three component annulations, alkyne carbopalladation is the last step of this tandem reaction. PMID- 29385309 TI - Preparative isolation and purification of hainanmurpanin, meranzin, and phebalosin from leaves of Murraya exotica L. using supercritical fluid extraction combined with consecutive high-speed countercurrent chromatography. AB - The objective of this study was to develop a consecutive preparation method for the isolation and purification of hainanmurpanin, meranzin, and phebalosin from leaves of Murraya exotica L. The process involved supercritical fluid extraction with CO2 , solvent extraction, and two-step high-speed countercurrent chromatography. Pressure, temperature, and the volume of entrainer were optimized as 27 MPa, 52 degrees C, and 60 mL by response surface methodology in supercritical fluid extraction with CO2 , and the yield of the crude extracts was 7.91 g from 100 g of leaves. Subsequently, 80% methanol/water was used to extract and condense the three compounds from the crude extracts, and 4.23 g of methanol/water extracts was obtained. Then, a two-step high-speed countercurrent chromatography procedure was developed for the isolation of the three target compounds from methanol/water extracts, including conventional high-speed countercurrent chromatography for further enrichment and consecutive high-speed countercurrent chromatography for purification. The yield of concentrates from high-speed countercurrent chromatography was 2.50 g from 4.23 g of methanol/water extracts. Finally, the consecutive high-speed countercurrent chromatography produced 103.2 mg of hainanmurpanin, 244.7 mg of meranzin, and 255.4 mg of phebalosin with purities up to 97.66, 99.36, and 98.64%, respectively, from 900 mg of high-speed countercurrent chromatography concentrates in one run of three consecutive sample loadings without exchanging a solvent system. PMID- 29385310 TI - Rapid characterization of chemical constituents and metabolites of Qi-Jing-Sheng Bai granule by using UHPLC-Q-TOF-MS. AB - Qi-Jing-Sheng-Bai granule is an effective traditional Chinese medicine formula that has been widely used for the treatment of leukopenia post radiotherapy or chemotherapy. However, its chemical constituents were still unclear, which hindered interpreting bioactive constituents and studying integrative mechanisms. In this study, we developed a three-step strategy to characterize the chemical constituents and metabolites of Qi-Jing-Sheng-Bai by using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. As a result, a total of 143 compounds, including 56 flavonoids, 51 saponins, and 36 other compounds, of which contained six pairs of isomers, were tentatively identified and characterized via reference standards and by comparing mass spectrometry data with literature. After oral administration of 15 g/kg Qi-Jing Sheng-Bai, a number of 42 compounds including 24 prototype compounds and 18 metabolites have been detected in the serum of rats. This work serves as the first reference for Qi-Jing-Sheng-Bai chemical components and metabolites. Moreover, it provided a rapid and valid analytical strategy for characterization of the chemical compounds and metabolites of traditional Chinese medicine formula. PMID- 29385311 TI - Viral eradication and fibrosis resolution in post-liver transplant cholestatic hepatitis C virus. PMID- 29385313 TI - Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial. PMID- 29385314 TI - Diffusion, Ion Pairing and Aggregation in 1-Ethyl-3-Methylimidazolium-Based Ionic Liquids Studied by 1 H and 19 F PFG NMR: Effect of Temperature, Anion and Glucose Dissolution. AB - In this work, using 1 H and 19 F PFG NMR, we probe the effect of temperature, ion size/type and glucose dissolution on the rate of transport in 1-ethyl-3 methylimidazolium ([EMIM]+ )-based ionic liquids by measuring self-diffusion coefficients. Using such data, we are able to establish the degree of ion pairing and quantify the extent of ionic aggregation during diffusion. For the neat 1 ethyl-3-methylimidazolium acetate ([EMIM][OAc]) a strong degree of ion pairing is observed. The substitution of the [OAc]- anion with the bis{(trifluoromethyl)sulfonyl}imide ([TFSI]- ) anion reduces the pairing between the ions, which is attributed to a lower electric charge density on the [TFSI]- anion, hence a weaker electric interaction with the [EMIM]+ cation. The effect of glucose, important for applications of ionic liquids as extracting media, on the strongly paired [EMIM][OAc] sample was also investigated and it is observed that the carbohydrate decreases the degree of ion pairing, which is attributed to the ability of glucose to disrupt inter-ionic interactions by forming hydrogen bonding, particularly with the [OAc]- anion. Calculations of aggregation number from diffusion data show that the [OAc]- anion diffuses as a part of larger aggregates compared to the [EMIM]+ cation. The results and analysis presented here show the usefulness of PFG NMR in studies of ionic liquids, giving new insights into ion pairing and aggregation and the factors affecting these parameters. PMID- 29385312 TI - Toxicity implications for early life stage Japanese medaka (Oryzias latipes) exposed to oxyfluorfen. AB - We investigated the potential toxic effects of Oxyfluorfen (OXY), an herbicide used in agriculture, on the embryo-larval development of Japanese medaka fish (Oryzias latipes). Embryos (1-day postfertilization) and larvae (2-day posthatch) were exposed to OXY (0.5-8 mg/L) for 96 h and evaluated for mortality and hatching on embryos, and the mortality and growth on larvae during depuration. It was observed that the embryo-mortality was inconsistently altered by OXY; only the 2 mg/L group showed significant reduction on embryo survivability. However, larval-mortality was concentration-dependent and OXY exposure induced scoliosis like phenotypic features in the surviving larvae; the calculated LC50 was 5.238 mg/L. Our data further indicated that larval skeleton, both axial and appendicular, was the potential target site of OXY. Skeletal growth in larvae exposed to 2 mg/L was inhibited significantly until 1 week of depuration with regard to the linear lengths of neurocranium, Meckel's cartilage, caudal vertebrae (first 10) in the axial skeletons, and pectoral fin and urostyle in the appendicular skeletons. Moreover, the total protein content remained unaltered by OXY after 96 h exposure; while the RNA concentration was reduced significantly in larvae exposed to 2 mg/L. Expression analysis of several genes by quantitative real-time RT-PCR (RT-qPCR) showed significant upregulation of zic5, a zinc-finger type transcription regulator, at the transcription level. This study indicated that the scoliosis induced by OXY in Japanese medaka larvae was the result of stunted skeletal growth, probably because of deregulation of zinc-finger type transcription regulators, at the genomic level. PMID- 29385315 TI - Foundation for an evidence-informed algorithm for treating pelvic floor mesh complications: a review. AB - : To address evidence gaps on the management of complications related to mesh in pelvic floor surgery, we created an evidence-based algorithm that includes defining evidence gaps. We utilized the Delphi method within a panel of surgeons treating mesh complications to define a treatment strategy. The first round provided a list of clinically based postulates that informed a review expanding postulates to recommendations and included grading of the quality of evidence. A second round informed the final algorithm. While the quality of the available evidence is low, it provides a framework for planning diagnosis and management of mesh-related complications. TWEETABLE ABSTRACT: Removal of mesh must balance resolution of complications with the risk of removal and recurrence of pelvic floor symptoms. PMID- 29385316 TI - Extended endonasal approach versus maxillary swing approach to the parapharyngeal space. AB - BACKGROUND: The nasopharyngeal and parapharyngeal spaces are difficult for surgeons to access. Of the various external routes described, the maxillary swing has emerged as the gold standard because of its simplicity. However, its morbidity has led to the development of less invasive techniques. The purpose of our study was to compare the surgical anatomy of the maxillary swing with that of the endoscopic endonasal approach. METHODS: Each procedure was performed on 10 anatomic specimens. The exposure and the limits obtained were evaluated. A CT scan analysis was performed. RESULTS: The endoscopic endonasal approach extended the limits, offering wider exposure. The endoscopic endonasal approach made possible better visualization of deep structures and precise dissection of the parapharyngeal spaces. However, the maxillary swing provided better access to the oropharynx and could be completed 3 times faster. CONCLUSION: The endoscopic endonasal approach provides excellent exposure, a wide dissection range, and precise definition of anatomic structures, making it an alternative of choice rather than the maxillary swing approach. PMID- 29385317 TI - Design and Synthesis of a BODIPY-Tetrazole Based "Off-On" in-Cell Fluorescence Reporter of Hydrogen Peroxide. AB - BODIPY-linked bithiophene-tetrazoles were designed and synthesized for bioorthogonal photoclick reactions in vitro and in vivo. The reactivity of these tetrazoles toward dimethyl fumarate was found to depend on the BODIPY attachment site, with the meta-linked BODIPY-tetrazole being the most reactive. The resulting pyrazoline cycloadduct showed drastically reduced BODIPY fluorescence. However, BODIPY fluorescence recovered after treatment with hydrogen peroxide. This turn-on effect was attributed to conversion from the pyrazoline to a pyrazole. Finally, we showed that this unique BODIPY-tetrazole off-on fluorescence probe can be used to detect hydrogen peroxide inside HeLa cells. PMID- 29385318 TI - Space-time variability of citrus leprosis as strategic planning for crop management. AB - BACKGROUND: Citrus leprosis is the most important viral disease of citrus. Knowledge of its spatiotemporal structure is fundamental to a representative sampling plan focused on the disease control approach. Such a well-crafted sampling design helps to reduce pesticide use in agriculture to control pests and diseases. RESULTS: Despite the use of acaricides to control citrus leprosis vector (Brevipalpus spp.) populations, the disease has spread rapidly through experimental areas. Citrus leprosis has an aggregate spatial distribution, with high dependence among symptomatic plants. Temporal variation in disease incidence increased among symptomatic plants by 4% per month. CONCLUSIONS: Use of acaricides alone to control the vector of leprosis is insufficient to avoid its incidence in healthy plants. Preliminary investigation into the time and space variation in the incidence of the disease is fundamental to select a sampling plan and determine effective strategies for disease management. (c) 2018 Society of Chemical Industry. PMID- 29385319 TI - Photografted methacrylate-based monolithic columns coated with cellulose tris(3,5 dimethylphenylcarbamate) for chiral separation in CEC. AB - A chiral capillary monolithic column for enantiomer separation in capillary electrochromatography was prepared by coating cellulose tris(3,5 dimethylphenylcarbamate) on porous glycidyl methacrylate-co-ethylene dimethacrylate monolith in capillary format grafted with chains of [2(methacryloyloxy)ethyl] trimethylammonium chloride. The surface modification of the monolith by the photografting of [2(methacryloyloxy)ethyl] trimethylammonium chloride monomer as well as the coating conditions of cellulose tris(3,5 dimethylphenylcarbamate) onto the grafted monolithic scaffold were optimized to obtain a stable and reproducible chiral stationary phase for capillary electrochromatography. The effect of organic modifier (acetonitrile) in aqueous mobile phase for the enantiomer separation by capillary electrochromatography was also investigated. Several pairs of enantiomers including acidic, neutral, and basic analytes were tested and most of them were partially or completely resolved under aqueous mobile phases. The prepared monolithic chiral stationary phases exhibited a good stability, repeatability, and column-to-column reproducibility, with relative standard deviations below 11% in the studied electrochromatographic parameters. PMID- 29385320 TI - A Spin-Active, Electrochromic, Solvent-Free Molecular Liquid Based on Double Decker Lutetium Phthalocyanine Bearing Long Branched Alkyl Chains. AB - Synthesis and characterization of a novel, multifunctional, solvent-free room temperature liquid based on alkylated double-decker lutetium(III) phthalocyanine (Pc2 Lu) are described. Lowering of the melting point and viscosity of intrinsically solid Pc2 Lu compounds has been achieved through the attachment of flexible, bulky, and long branched-alkyl chains, that is, thio-2-octyldodecyl, to the periphery of the Pc2 Lu unit. The embedded Pc2 Lu unit maintains its inherent molecular functions, such as spin-active nature and electrochromic behavior in the liquid state. Comparison of the properties with a solid-like Pc2 Lu derivative, functionalized with shorter alkyl chains, that is, thio-2-ethylhexyl, underlines the importance of the hampering effect on the pi-pi interactions of neighboring Pc2 Lu molecules by bulkier and longer branched-alkyl chains. This study could possibly pave the way for novel multifunctional liquids whose spin activities are associated with their rheological or optoelectronic properties. PMID- 29385321 TI - Electrocatalytic and Photocatalytic Reduction of CO2 to CO by Cobalt(II) Tripodal Complexes: Low Overpotentials, High Efficiency and Selectivity. AB - The reduction of carbon dioxide (CO2 ) has been considered as an approach to mitigate global warming and to provide renewable carbon-based fuels. Rational design of efficient, selective, and inexpensive catalysts with low overpotentials is urgently desired. In this study, four cobalt(II) tripodal complexes are tested as catalysts for CO2 reduction to CO in a MeCN/H2 O (4:1 v/v) solution. The replacement of pyridyl groups in the ligands with less basic quinolinyl groups greatly reduces the required overpotential for CO2 -to-CO conversion down to 200 380 mV. Benefitting from the low overpotentials, a photocatalyst system for CO2 to-CO conversion is successfully constructed, with an maximum turnover number (TON) of 10 650+/-750, a turnover frequency (TOF) of 1150+/-80 h-1 , and almost 100 % selectivity to CO. These outstanding catalytic performances are further elucidated by DFT calculations. PMID- 29385322 TI - SOX10/keratin dual-color immunohistochemistry: An effective first-line test for the workup of epithelioid malignant neoplasms in FNA and small biopsy specimens. AB - BACKGROUND: The characterization of poorly differentiated neoplasms in fine needle aspiration (FNA) and small biopsy specimens usually requires immunohistochemistry (IHC) with a panel of markers. Because of an increasing need to preserve limited diagnostic material for tumor genotyping and a mounting demand for cost containment, the authors investigated the usefulness of dual color IHC with antibodies directed against broad-spectrum keratins and SOX10, a neuroectodermal transcription factor consistently expressed in melanoma, in the workup of epithelioid malignant neoplasms. METHODS: A total of 107 cases of FNA cell blocks (49 cases) and small biopsies (58 cases) were selected, including 34 melanomas, 31 epithelioid/pleomorphic sarcomas, and 42 carcinomas. IHC was performed on all specimens using a peroxidase-based brown chromogen for SOX10 and an alkaline phosphatase-based red chromogen for keratins AE1/AE3. The presence or absence of staining in lesional cells was scored. RESULTS: The majority of tumors demonstrated 1 of 3 distinct patterns: 1) malignant melanomas with nuclear SOX10 (sensitivity of 94% and specificity of 95%); 2) epithelioid/pleomorphic sarcomas negative for both SOX10 and AE1/AE3 (sensitivity of 84% and specificity of 88%); and 3) carcinomas with cytoplasmic AE1/AE3 (sensitivity of 76% and specificity of 98%). In addition, a fourth pattern with cytoplasmic AE1/AE3 and nuclear SOX10 was observed in a subset of carcinomas, most notably triple-negative breast cancers. CONCLUSIONS: SOX10/keratin dual-color IHC appears to be an effective, sensitive, and specific test to distinguish between melanoma, sarcoma, and carcinoma. This approach can identify melanoma, prioritize additional studies, and limit the number of markers needed to workup an epithelioid malignant neoplasm, thereby potentially reducing costs and preserving valuable tissue for ancillary studies with which to guide therapy. Cancer Cytopathol 2018;126:179-89. (c) 2018 American Cancer Society. PMID- 29385323 TI - Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy. AB - Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor alpha (TGF-alpha), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo. Pharmacokinetics, pharmacodynamics, anti-LY antibodies, and change in proteinuria and albuminuria were evaluated. Single and multiple doses of LY administered 3 weeks apart were well tolerated. Pharmacokinetics were nonlinear in healthy subjects and patients with DN, indicating target-mediated drug disposition. Epiregulin level increased in both studies, and TGF-alpha levels increased in the TGAB study, consistent with target engagement; however, LY treatment did not significantly reduce proteinuria or albuminuria in patients with DN. There was no obvious effect of LY on the disease-related biomarkers monocyte chemoattractant protein-1, synaptopodin, or transferrin. Although LY administration resulted in a high frequency of anti-LY antibodies, pharmacokinetics, target engagement, and efficacy were not impacted. PMID- 29385324 TI - Parasites in Forensic Science: a historic perspective AB - Parasites show a great potential to Forensic Science. Forensic Science is the application of any science and methodology to the legal system. The forensic scientist collects and analyses the physical evidence and produce a report of the results to the court. A parasite is an organism that lives at the expense of another and they exist in any ecosystem. Parasites are the cause of many important diseases. The forensic scientists can use the parasites to identify a crime scene, to determine the murder weapon or simply identify an individual. The applications for parasites in the Forensic Science can be many and more studies should be made in Forensic Parasitology. The most important parasites in Forensic Science are helminths specifically schistosomes. Through history there are many cases where schistosomes were described in autopsies and it was related to the cause of death. Here we review the applications of parasites in Forensic Science and its importance to the forensic scientist. PMID- 29385326 TI - Structural Changes as a Function of Thickness in [(SnSe)1+delta]mTiSe2 Heterostructures. AB - Single- and few-layer metal chalcogenide compounds are of significant interest due to structural changes and emergent electronic properties on reducing dimensionality from three to two dimensions. To explore dimensionality effects in SnSe, a series of [(SnSe)1+delta]mTiSe2 intergrowth structures with increasing SnSe layer thickness (m = 1-4) were prepared from designed thin-film precursors. In-plane diffraction patterns indicated that significant structural changes occurred in the basal plane of the SnSe constituent as m is increased. Scanning transmission electron microscopy cross-sectional images of the m = 1 compound indicate long-range coherence between layers, whereas the m >= 2 compounds show extensive rotational disorder between the constituent layers. For m >= 2, the images of the SnSe constituent contain a variety of stacking sequences of SnSe bilayers. Density functional theory calculations suggest that the formation energy is similar for several different SnSe stacking sequences. The compounds show unexpected transport properties as m is increased, including the first p type behavior observed in (MSe)m(TiSe2)n compounds. The resistivity of the m >= 2 compounds is larger than for m = 1, with m = 2 being the largest. At room temperature, the Hall coefficient is positive for m = 1 and negative for m = 2-4. The Hall coefficient of the m = 2 compound changes sign as temperature is decreased. The room-temperature Seebeck coefficient, however, switches from negative to positive at m = 3. These properties are incompatible with single band transport indicating that the compounds are not simple composites. PMID- 29385325 TI - Neuroinvasions caused by parasites AB - Parasitic diseases of the central nervous system are associated with high mortality and morbidity. Many human parasites, such as Toxoplasma gondii, Entamoeba histolytica, Trypanosoma cruzi, Taenia solium, Echinococcus spp., Toxocara canis, T. cati, Angiostrongylus cantonensis, Trichinella spp., during invasion might involve the CNS. Some parasitic infections of the brain are lethal if left untreated (e.g., cerebral malaria - Plasmodium falciparum, primary amoebic meningoencephalitis (PAM) - Naegleria fowleri, baylisascariosis - Baylisascaris procyonis, African sleeping sickness - African trypanosomes). These diseases have diverse vectors or intermediate hosts, modes of transmission and endemic regions or geographic distributions. The neurological, cognitive, and mental health problems caused by above parasites are noted mostly in low-income countries; however, sporadic cases also occur in non-endemic areas because of an increase in international travel and immunosuppression caused by therapy or HIV infection. Thepresence of parasites in the CNS may cause a variety of nerve symptoms, depending on the location and extent of the injury; the most common subjective symptoms include headache, dizziness, and root pain while objective symptoms are epileptic seizures, increased intracranial pressure, sensory disturbances, meningeal syndrome, cerebellar ataxia, and core syndromes. Many early symptoms of CNS invasion are often nonspecific therefore a diagnosis can be difficult. This article presents the epidemiology, pathophysiology and clinical manifestations of selected parasiticneuroinfections. PMID- 29385327 TI - Correlated Chemical and Electrically Active Dopant Analysis in Catalyst-Free Si Doped InAs Nanowires. AB - Direct correlations between dopant incorporation, distribution, and their electrical activity in semiconductor nanowires (NW) are difficult to access and require a combination of advanced nanometrology methods. Here, we present a comprehensive investigation of the chemical and electrically active dopant concentrations in n-type Si-doped InAs NW grown by catalyst-free molecular beam epitaxy using various complementary techniques. N-type carrier concentrations are determined by Seebeck effect measurements and four-terminal NW field-effect transistor characterization and compared with the Si dopant distribution analyzed by local electrode atom probe tomography. With increased dopant supply, a distinct saturation of the free carrier concentration is observed in the mid-1018 cm-3 range. This behavior coincides with the incorporated Si dopant concentrations in the bulk part of the NW, suggesting the absence of compensation effects. Importantly, excess Si dopants with very high concentrations (>1020 cm 3) segregate at the NW sidewall surfaces, which confirms recent first-principles calculations and results in modifications of the surface electronic properties that are sensitively probed by field-effect measurements. These findings are expected to be relevant also for doping studies of other noncatalytic III-V NW systems. PMID- 29385328 TI - Molecular Characterization of Water-Soluble Humic like Substances in Smoke Particles Emitted from Combustion of Biomass Materials and Coal Using Ultrahigh Resolution Electrospray Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - Water-soluble humic like substances (HULIS) in smoke particles emitted from combustion of biomass materials and coal were characterized by ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry. The formulas identified were classified into four main groups: CHO, CHON, CHOS, and CHONS. The average H/C and O/C ratios are 1.13-1.33, 1.01-1.13, 1.26-1.48, 1.09 1.24 and 0.21-0.41, 0.27-0.45, 0.41-0.46, 0.44-0.61 for the CHO, CHON, CHOS, and CHONS groups, respectively. The CHO compound was the predominant component (43% 72%) of the smoke HULIS from biomass burning (BB) and coal combustion, followed by the CHON group for BB-smoke HULIS and the S-containing groups (i.e., CHOS and CHONS) for coal-smoke HULIS. These results indicate that the primary HULIS emitted from biomass burning contain a high abundance of CHON species, which appear to be made up mainly of oxidized nitrogen functional groups such as nitro compounds and/or organonitrates. The coal-smoke HULIS contained more compounds with relatively low molecular weight and high aromaticity index (AImod). They were significantly enriched in S-containing compounds with high double bond equivalent (>=4), and O/S ratios suggest that they are most likely made up of aromatic organosulfates and nitrooxy organosulfates that are usually found in polluted atmospheres. These findings imply that the primary emissions from combustion of biomass and coal fuels are potential sources of water-soluble HULIS in an atmospheric matrix and that coal combustion is an especially important source of sulfate compounds. PMID- 29385329 TI - Effect of Oxidation Process on Complex Refractive Index of Secondary Organic Aerosol Generated from Isoprene. AB - Oxidation of isoprene by hydroxyl radical (OH), ozone (O3), or nitrate radical (NO3) leads to the formation of secondary organic aerosol (SOA) in the atmosphere. This SOA contributes to the radiation balance by scattering and absorbing solar radiation. In this study, the effect of oxidation processes on the wavelength-dependent complex refractive index (RI) of SOA generated from isoprene was examined. Oxidation conditions did not have a large effect on magnitude and wavelength dependence of the real part of the RI. In the case of SOA generated in the presence of sulfur dioxide (SO2), significant light absorption at short visible and ultraviolet wavelengths with the imaginary part of the RI, up to 0.011 at 375 nm, was observed during oxidation with OH. However, smaller and negligible values were observed during oxidation with O3 and NO3, respectively. Moreover, in the absence of SO2, light absorption was not observed regardless of the oxidation process. There was an empirical correlation between the imaginary part of the RI and the average degree of unsaturation of organic molecules. The results obtained herein demonstrate that oxidation processes should be considered for estimating the radiative effect of isoprene-derived SOA. PMID- 29385330 TI - Metal-Tunable Self-Assembly of Hierarchical Structure in Mussel-Inspired Peptide Films. AB - Bottom-up control over structural hierarchy from the nanoscale through the macroscale is a critical aspect of biological materials fabrication and function, which can inspire production of advanced materials. Mussel byssal threads are a prime example of protein-based biofibers in which hierarchical organization of protein building blocks coupled via metal complexation leads to notable mechanical behaviors, such as high toughness and self-healing. Using a natural amino acid sequence from byssal thread proteins, which functions as a pH triggered self-assembly point, we created free-standing peptide films with complex hierarchical organization across multiple length scales that can be controlled by inclusion of metal ions (Zn2+ and Cu2+) during the assembly process. Additionally, analysis of film mechanical performance indicates that metal coordination bestows up to an order of magnitude increase in material stiffness, providing a paradigm for creating tunable polymeric materials with multiscale organizational structure. PMID- 29385331 TI - Controllable Multigeometry Nanoparticles via Cooperative Assembly of Amphiphilic Diblock Copolymer Blends with Asymmetric Architectures. AB - Multigeometry nanoparticles with high complexity in composition and structure have attracted significant attention for enhanced functionality. We assess a simple but versatile strategy to construct hybrid nanoparticles with subdivided geometries through the cooperative assembly of diblock copolymer blends with asymmetric architectures. We report the formation of multicompartmental, vesicular, cylindrical, and spherical structures from pure AB systems. Then, we explore the assemblies of binary AB/AC blends, where the two incompatible, hydrophobic diblock copolymers subdivide into self-assembled local geometries, and the complexity of the obtained morphologies increases. We expand the strategy to ternary AB/AC/AD systems by tuning the effect of phase separation of different hydrophobic domains on the surface or internal region of the nanoparticle. The kinetic control of the coassembly in the initial stage is crucial for controlling the final morphology. The interactions of copolymers with different block lengths and chemistries enable the stabilization of interfaces, rims and ends of subdomains in the hybrid multigeometry nanoparticles. With further exploration of size and shape, the dependence of local geometry on the volume fraction is discussed. We show an efficient approach for controllable multigeometry nanoparticle construction that will be useful for multifunctional and hierarchical nanomaterials. PMID- 29385332 TI - A Nexus Approach for Sustainable Urban Energy-Water-Waste Systems Planning and Operation. AB - Energy, water, and waste systems analyzed at a nexus level are important to move toward more sustainable cities. In this paper, the "resilience.io" platform is developed and applied to emphasize on waste-to-energy pathways, along with the water and energy sectors, aiming to develop waste treatment capacity and energy recovery with the lowest economic and environmental cost. Three categories of waste including wastewater (WW), municipal solid waste (MSW), and agriculture waste are tested as the feedstock for thermochemical treatment via incineration, gasification, or pyrolysis for combined heat and power generation, or biological treatment such as anaerobic digestion (AD) and aerobic treatment. A case study is presented for Ghana in sub-Saharan Africa, considering a combination of waste treatment technologies and infrastructure, depending on local characteristics for supply and demand. The results indicate that the biogas generated from waste treatment turns out to be a promising renewable energy source in the analyzed region, while more distributed energy resources can be integrated. A series of scenarios including the business-as-usual, base case, naturally constrained, policy interventions, and environmental and climate change impacts demonstrate how simulation with optimization models can provide new insights in the design of sustainable value chains, with particular emphasis on whole-system analysis and integration. PMID- 29385333 TI - Development of Activity-Based Chemical Probes for Human Sirtuins. AB - Sirtuins consume stoichiometric amounts of nicotinamide adenine dinucleotide (NAD+) to remove an acetyl group from lysine residues. These enzymes have been implicated in regulating various cellular events and have also been suggested to mediate the beneficial effects of calorie restriction (CR). However, controversies on sirtuin biology also peaked during the past few years because of conflicting results from different research groups. This is partly because these enzymes have been discovered recently and the intricate interaction loops between sirtuins and other proteins make the characterization of them extremely difficult. Current molecular biology and proteomics techniques report protein abundance rather than active sirtuin content. Innovative chemical tools that can directly probe the functional state of sirtuins are desperately needed. We have obtained a set of powerful activity-based chemical probes that are capable of assessing the active content of sirtuins in model systems. These probes consist of a chemical "warhead" that binds to the active site of active enzyme and a handle that can be used for the visualization of these enzymes by fluorescence. In complex native proteome, the probes can selectively "highlight" the active sirtuin components. Furthermore, these probes were also able to probe the dynamic change of sirtuin activity in response to cellular stimuli. These chemical probes and the labeling strategies will provide transformative technology to allow the direct linking of sirtuin activity to distinct physiological processes. They will create new opportunities to investigate how sirtuins provide health benefits in adapting cells to environmental cues and provide critical information to dissect sirtuin regulatory networks. PMID- 29385335 TI - Strain Modulation by van der Waals Coupling in Bilayer Transition Metal Dichalcogenide. AB - Manipulation of lattice strain is emerging as a powerful means to modify the properties of low-dimensional materials. Most approaches rely on external forces to induce strain, and the role of interlayer van der Waals (vdW) coupling in generating strain profiles in homobilayer transition metal dichalcogenide (TMDC) films is rarely considered. Here, by applying atomic-resolution electron microscopy and density functional theory calculations, we observed that a mirror twin boundary (MTB) modifies the interlayer vdW coupling in bilayer TMDC films, leading to the development of local strain for a few nanometers in the vicinity of the MTB. Interestingly, when a single MTB in one layer is "paired" with another MTB in an adjacent layer, interlayer-induced strain is reduced when the MTBs approach each other. Therefore, MTBs are not just 1D discontinuities; they can exert localized 2D strain on the adjacent lattices. PMID- 29385334 TI - New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model. AB - The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series. PMID- 29385336 TI - Enhancing Both Biodegradability and Efficacy of Semiconducting Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy. AB - Theranostic nanoagents are promising for precision medicine. However, biodegradable nanoagents with the ability for photoacoustic (PA) imaging guided photothermal therapy (PTT) are rare. We herein report the development of biodegradable semiconducting polymer nanoparticles (SPNs) with enhanced PA and PTT efficacy for cancer therapy. The design capitalizes on the enzymatically oxidizable nature of vinylene bonds in conjunction with polymer chemistry to synthesize a biodegradable semiconducting polymer (DPPV) and transform it into water-soluble nanoparticles (SPNV). As compared with its counterpart SPN (SPNT), the presence of vinylene bonds within the polymer backbone also endows SPNV with a significantly enhanced mass absorption coefficient (1.3-fold) and photothermal conversion efficacy (2.4-fold). As such, SPNV provides the PA signals and the photothermal maximum temperature higher than SPNT, allowing detection and photothermal ablation of tumors in living mice in a more sensitive and effective way. Our study thus reveals a general molecular design to enhance the biodegradability of optically active polymer nanoparticles while dramatically elevating their imaging and therapeutic capabilities. PMID- 29385337 TI - Differential Dynamics at Glycosidic Linkages of an Oligosaccharide as Revealed by 13C NMR Spin Relaxation and Stochastic Modeling. AB - Among biomolecules, carbohydrates are unique in that not only can linkages be formed through different positions, but the structures may also be branched. The trisaccharide beta-d-Glcp-(1->3)[beta-d-Glcp-(1->2)]-alpha-d-Manp-OMe represents a model of a branched vicinally disubstituted structure. A 13C site-specific isotopologue, with labeling in each of the two terminal glucosyl residues, enabled the acquisition of high-quality 13C NMR relaxation parameters, T1 and T2, and heteronuclear NOE, with standard deviations of <=0.5%. For interpretation of the experimental NMR data, a diffusive chain model was used, in which the dynamics of the glycosidic linkages is coupled to the global reorientation motion of the trisaccharide. Brownian dynamics simulations relying on the potential of mean force at the glycosidic linkages were employed to evaluate spectral densities of the spin probes. Calculated NMR relaxation parameters showed a very good agreement with experimental data, deviating <3%. The resulting dynamics are described by correlation times of 196 and 174 ps for the beta-(1->2)- and beta-(1 >3)-linked glucosyl residues, respectively, i.e., different and linkage dependent. Notably, the devised computational protocol was performed without any fitting of parameters. PMID- 29385338 TI - Reduced Basis Set Dependence in Anharmonic Frequency Calculations Involving Localized Coordinates. AB - Localized normal coordinates are known to be effective in speeding up anharmonic frequency calculations by reducing the complexity of the nuclear Hamiltonian and wave function. Displacing atoms in localized coordinates can also cause relatively small changes in the electronic structure, which can be exploited for further computational efficiency improvements during ab initio electronic structure calculations of the potential energy surface by reducing the electronic basis set dependence. Three different schemes for reducing the basis set dependence have been investigated in this work. These include combining localized coordinate schemes with general mixed basis sets, distance based force-field reductions, and using coordinate specific basis sets. The importance of accurately describing electronic interactions is found to diminish both for multicoordinate terms involving the displacement of remote atoms and when describing the interactions between more remote atoms within specific coordinates. PMID- 29385339 TI - Excited State Dipole Moments in Solution: Comparison between State-Specific and Linear-Response TD-DFT Values. AB - We compare different response schemes for coupling continuum solvation models to time-dependent density functional theory (TD-DFT) for the determination of solvent effects on the excited state dipole moments of solvated molecules. In particular, linear-response (LR) and state-specific (SS) formalisms are compared. Using 20 low-lying electronic excitations, displaying both localized and charge transfer character, this study highlights the importance of applying a SS model not only for the calculation of energies, as previously reported ( J. Chem. Theory Comput. , 2015 , 11 , 5782 , DOI: 10.1021/acs.jctc.5b00679 ), but also for the prediction of excited state properties. Generally, when a range-separated exchange-correlation functional is used, both LR and SS schemes provide very similar dipole moments for local transitions, whereas differences of a few Debye units with respect to LR values are observed for CT transitions. The delicate interplay between the response scheme and the exchange-correlation functional is discussed as well, and we show that using an inadequate functional in a SS framework can yield to dramatic overestimations of the dipole moments. PMID- 29385340 TI - Thermal Population Fluctuations in Two-Dimensional Infrared Spectroscopy Captured with Semiclassical Mechanics. AB - Time-resolved two-dimensional (2D) infrared spectra of the asymmetric stretch mode of solvated CO2 show distinct features corresponding to ground- and excited state thermal populations of the bend modes. The time-dependence of these peaks arises in part from solvent-driven thermal fluctuations in populations of the lower-frequency bend modes through their coupling to the higher-frequency asymmetric stretch. This observation illustrates the capacity of multidimensional vibrational spectroscopy to reveal details of the interactions among vibrational modes in condensed phases. The optimized mean-trajectory (OMT) method is a trajectory-based semiclassical approach to computing the vibrational response functions of multidimensional spectroscopy from a classical Hamiltonian. We perform an OMT calculation of the 2D vibrational spectrum for two coupled anharmonic modes, with the lower-frequency mode undergoing stochastic transitions in energy to mimic solvent-induced fluctuations in quantum populations. The semiclassical calculation reproduces the influence of thermal fluctuations in the low-frequency mode on the 2D spectrum of the high-frequency mode, as in measured spectra of solvated CO2. PMID- 29385341 TI - Understanding Signal and Background in a Thermally Resolved, Single-Branched DNA Assay Using Square Wave Voltammetry. AB - Electrochemical bioanalytical sensors with oligonucleotide transducer molecules have been recently extended for quantifying a wide range of biomolecules, from small drugs to large proteins. Short DNA or RNA strands have gained attention recently due to the existence of circulating oligonucleotides in human blood, yet challenges remain for adequately sensing these targets at electrode surfaces. In this work, we have developed a quantitative electrochemical method which uses target-induced proximity of a single-branched DNA structure to drive hybridization at an electrode surface, with readout by square-wave voltammetry (SWV). Using custom instrumentation, we first show that precise control of temperature can provide both electrochemical signal amplification and background signal depreciation in SWV readout of small oligonucleotides. Next, we thoroughly compared 25 different combinations of binding energies by their signal-to background ratios and differences. These data served as a guide to select the optimal parameters of binding energy, SWV frequency, and assay temperature. Finally, the influence of experimental workflow on the sensitivity and limit of detection (LOD) of the sensor is demonstrated. This study highlights the importance of precisely controlling temperature and SWV frequency in DNA-driven assays on electrode surfaces while also presenting a novel instrumental design for fine-tuning of such systems. PMID- 29385342 TI - Self-Aligned van der Waals Heterojunction Diodes and Transistors. AB - A general self-aligned fabrication scheme is reported here for a diverse class of electronic devices based on van der Waals materials and heterojunctions. In particular, self-alignment enables the fabrication of source-gated transistors in monolayer MoS2 with near-ideal current saturation characteristics and channel lengths down to 135 nm. Furthermore, self-alignment of van der Waals p-n heterojunction diodes achieves complete electrostatic control of both the p-type and n-type constituent semiconductors in a dual-gated geometry, resulting in gate tunable mean and variance of antiambipolar Gaussian characteristics. Through finite-element device simulations, the operating principles of source-gated transistors and dual-gated antiambipolar devices are elucidated, thus providing design rules for additional devices that employ self-aligned geometries. For example, the versatility of this scheme is demonstrated via contact-doped MoS2 homojunction diodes and mixed-dimensional heterojunctions based on organic semiconductors. The scalability of this approach is also shown by fabricating self-aligned short-channel transistors with subdiffraction channel lengths in the range of 150-800 nm using photolithography on large-area MoS2 films grown by chemical vapor deposition. Overall, this self-aligned fabrication method represents an important step toward the scalable integration of van der Waals heterojunction devices into more sophisticated circuits and systems. PMID- 29385343 TI - Two-State Folding Energy Determination Based on Transition Points in Nonequilibrium Single-Molecule Experiments. AB - Many small protein domains or nucleic acid structures undergo two-state unfolding refolding transitions during mechanical stretching using single-molecule techniques. Here, by applying the Jarzynski equality (JE), we analytically express the folding energy of a molecule as a function of the experimentally measured transition points xi* obtained with two typical time-varying mechanical constraints: the force constraints F(t) and the position constraints R(t) of a Hookian spring attached to one end of the molecule. Compared to previous applications of JE based on the integration of accurately measured force extension curves of a tether that typically contains the molecule of interest and handles, our approach just needs to accurately measure a single data point. In the case of the F(t) process, the calculation is handle-independent. The broad applications of the theory are demonstrated by measuring the folding energies of a DNA hairpin, a DNA G-quadruplex, and the titin I27 domain based on transition forces using magnetic tweezers. PMID- 29385344 TI - Design and Synthesis of Open-Chain Hosts Having a Partial Structure of p-tert Butylthiacalixarene. AB - The development of separation materials for hard-to-separate molecular mixtures is highly desired from environmental and economic perspectives. Although the crystal of p-tert-butylthiacalix[4]arene exhibits high guest selectivity in inclusion from a mixture of molecules with similar sizes and shapes, it cannot include molecules larger than its calix cavity. To extend its guest inclusivity, we designed and synthesized an open-chain host, [3,3'-thiobis(5-tert-butyl-2 hydroxybenzene)-1,1'-diyl]diacetic acid (4). The competitive inclusion among toluidine isomers using compound 4 gave inclusion crystals containing the p isomer in 1:1 (host/guest) ratio, with lesser amounts of other isomers and/or solvent molecules. The isomer selectivity varied between 66% and 97% depending on the solvent employed. X-ray analysis of inclusion crystals 4.p-toluidine.MeCN and 4.p-toluidine.(o-toluidine)0.5 revealed that compound 4 includes p-toluidine by forming macrocyclic 2:2 inclusion complex(es) and that its higher-order structure has vacant spaces, in which molecules other than p-toluidine are included. Compound 4 was then transformed into monopropyl ester 5 to fill the vacant spaces with propyl moieties. Compound 5 included p-toluidine with high selectivity (~96%) without the coinclusion of other molecules, regardless of the solvent employed. PMID- 29385345 TI - Thermodynamic Acidity Studies of 6,6'-Dihydroxy-2,2'-bipyridine: A Combined Experimental and Computational Approach. AB - The organic ligand 6,6'-dihydroxy-2,2'-bipyridine (6,6'-dhbp) is frequently used to bind transition metals in order to form catalysts for many organic and inorganic transformations. 6,6'-dhbp exists in two tautomeric forms, the pyridinol tautomer and the amide (lactam) tautomer with each tautomer having two rotational conformers: cis or trans. Only the cis-pyridinol tautomer has the proper configuration to bind transition metals. The pendant OH (or O- groups when deprotonated) in 6,6'-dhbp typically do not bind the metal when forming the metal catalyst but can facilitate the proton transfer steps in the catalysis process. Electronic structure calculations were used to predict the stability of all possible isomers (including conformers and protonation states) in the gas phase and aqueous solution. These results have been compared to experimental data including UV-vis and NMR spectra as a function of pH. The pKa values for the 6,6' dhbp ligand in the -2 to +2 structures were predicted, and these ligands show different behavior in the gas phase versus in aqueous solution. PMID- 29385347 TI - Enhanced Adsorption of p-Arsanilic Acid from Water by Amine-Modified UiO-67 as Examined Using Extended X-ray Absorption Fine Structure, X-ray Photoelectron Spectroscopy, and Density Functional Theory Calculations. AB - p-Arsanilic acid ( p-ASA) is an emerging organoarsenic pollutant comprising both inorganic and organic moieties. For the efficient removal of p-ASA, adsorbents with high adsorption affinity are urgently needed. Herein, amine-modified UiO-67 (UiO-67-NH2) metal-organic frameworks (MOFs) were synthesized, and their adsorption affinities toward p-ASA were 2 times higher than that of the pristine UiO-67. Extended X-ray absorption fine structure (EXAFS), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculation results revealed adsorption through a combination of As-O-Zr coordination, hydrogen bonding, and pi-pi stacking, among which As-O-Zr coordination was the dominant force. Amine groups played a significant role in enhancing the adsorption affinity through strengthening the As-O-Zr coordination and pi-pi stacking, as well as forming new adsorption sites via hydrogen bonding. UiO-67-NH2s could remove p-ASA at low concentrations (<5 mg L-1) in simulated natural and wastewaters to an arsenic level lower than that of the drinking water standard of World Health Organization (WHO) and the surface water standard of China, respectively. This work provided an emerging and promising method to increase the adsorption affinity of MOFs toward pollutants containing both organic and inorganic moieties, via modifying functional groups based on the pollutant structure to achieve synergistic adsorption effect. PMID- 29385346 TI - Via Method for Lithography Free Contact and Preservation of 2D Materials. AB - Atomically thin 2D materials span the common components of electronic circuits as metals, semiconductors, and insulators, and can manifest correlated phases such as superconductivity, charge density waves, and magnetism. An ongoing challenge in the field is to incorporate these 2D materials into multilayer heterostructures with robust electrical contacts while preventing disorder and degradation. In particular, preserving and studying air-sensitive 2D materials has presented a significant challenge since they readily oxidize under atmospheric conditions. We report a new technique for contacting 2D materials, in which metal via contacts are integrated into flakes of insulating hexagonal boron nitride, and then placed onto the desired conducting 2D layer, avoiding direct lithographic patterning onto the 2D conductor. The metal contacts are planar with the bottom surface of the boron nitride and form robust contacts to multiple 2D materials. These structures protect air-sensitive 2D materials for months with no degradation in performance. This via contact technique will provide the capability to produce "atomic printed circuit boards" that can form the basis of more complex multilayer heterostructures. PMID- 29385348 TI - Electrochemically Controlled Cationic Polymerization of Vinyl Ethers. AB - Control of polymer initiation, propagation and termination is important in the development of complex polymer structures and advanced materials. Typically, this has been achieved chemically, electrochemically, photochemically or mechanochemically. Electrochemical control has been demonstrated in radical polymerizations; however, regulation of a cationic polymerization has yet to be achieved. Through the reversible oxidation of a polymer chain end with an electrochemical mediator, temporal control over polymer chain growth in cationic polymerizations was realized. By subjecting a stable organic nitroxyl radical mediator and chain transfer agent to an oxidizing current, control over polymer molecular weight and dispersity is demonstrated and excellent chain end fidelity allows for the synthesis of block copolymers. PMID- 29385350 TI - Airway Basal Cell Reprogramming and Epithelial-Mesenchymal Transition: A Potential Key to Understanding Early Chronic Obstructive Pulmonary Disease. PMID- 29385349 TI - Exploration of Multistate Conformational Dynamics upon Ligand Binding of a Monomeric Enzyme Involved in Pyrophosphoryl Transfer. AB - HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase) is a monomeric protein with 158 residues, which undergoes large-scale conformational changes between apo, open, and holo states responding to ligand binding for its function. It has been explored widely as an excellent target for potential antibacterial drug development. However, little is known about how conformational dynamics between the native states influences the substrate recognition and the functionality of enzymatic catalysis. Here, we report a coarse-grained triple-basin structure based model upon ligand binding to describe such multiple-state system by the molecular dynamics simulation. With our model, we have made theoretical predictions that are in good agreement with the experimental measurements. Our results revealed the intrinsic conformational fluctuations between apo and open states without ligand binding. We found that HPPK can switch to the activated holo state upon the ordered binding of the two ligands (ATP and HP). We uncovered the underlying mechanism by which major induced fit and minor population shift pathways coexist upon ligand binding by quantitative flux analysis. Additionally, we pointed out the structural origin for the conformational changes and identified the key residues as well as contact interactions. We further explored the temperature effect on the conformational distributions and pathway weights. It gave strong support that higher temperatures promote population shift, while the induced fit pathway is always the predominant activation route of the HPPK system. These findings will provide significant insights of the mechanisms of the multistate conformational dynamics of HPPK upon ligand binding. PMID- 29385353 TI - We Miss You, Allen. PMID- 29385351 TI - Reply to Sohal: Airway Basal Cell Reprogramming and Epithelial-Mesenchymal Transition: A Potential Key to Understanding Early Chronic Obstructive Pulmonary Disease. PMID- 29385355 TI - Whose Moral Community? Religiosity, Secularity, and Self-rated Health across Communal Religious Contexts. AB - Scholars have long theorized that religious contexts provide health-promoting social integration and regulation. A growing body of literature has documented associations between individual religiosity and health as well as macro-micro linkages between religious contexts, religious participation, and individual health. Using unique data on individuals and county contexts in the United States, this study offers new insight by using multilevel analysis to examine meso-micro relationships between religion and health. We assess whether and how the relationship between individual religiosity and health depends on communal religious contexts. In highly religious contexts, religious individuals are less likely to have poor health, while nonreligious individuals are markedly more likely to have poor health. In less religious contexts, religious and nonreligious individuals report similar levels of health. Consequently, the health gap between religious and nonreligious individuals is largest in religiously devout contexts, primarily due to the negative effects on nonreligious individuals' health in religious contexts. PMID- 29385356 TI - Internal Affairs: Tenascin-C as a Clinically Relevant, Endogenous Driver of Innate Immunity. AB - To protect against danger, the innate immune system must promptly and accurately sense alarm signals, and mount an appropriate response to restore homeostasis. One endogenous trigger of immunity is tenascin-C, a large hexameric protein of the extracellular matrix. Upregulated upon tissue injury and cellular stress, tenascin-C is expressed during inflammation and tissue remodeling, where it influences cellular behavior by interacting with a multitude of molecular targets, including other matrix components, cell surface proteins, and growth factors. Here, we discuss how these interactions confer upon tenascin-C distinct immunomodulatory capabilities that make this matrix molecule necessary for efficient tissue repair. We also highlight in vivo studies that provide insight into the consequences of misregulated tenascin-C expression on inflammation and fibrosis during a wide range of inflammatory diseases. Finally, we examine how its unique expression pattern and inflammatory actions make tenascin-C a viable target for clinical exploitation in both diagnostic and therapeutic arenas. PMID- 29385357 TI - Differences of energy expenditure while sitting versus standing: A systematic review and meta-analysis. AB - Background Replacing sitting with standing is one of several recommendations to decrease sedentary time and increase the daily energy expenditure, but the difference in energy expenditure between standing versus sitting has been controversial. This systematic review and meta-analysis aimed to determine this difference. Designs and methods We searched Ovid MEDLINE, Ovid Embase Scopus, Web of Science and Google Scholar for observational and experimental studies that compared the energy expenditure of standing versus sitting. We calculated mean differences and 95% confidence intervals using a random effects model. We conducted different predefined subgroup analyses based on characteristics of participants and study design. Results We identified 658 studies and included 46 studies with 1184 participants for the final analysis. The mean difference in energy expenditure between sitting and standing was 0.15 kcal/min (95% confidence interval (CI) 0.12-0.17). The difference among women was 0.1 kcal/min (95% CI 0.0 0.21), and was 0.19 kcal/min (95% CI 0.05-0.33) in men. Observational studies had a lower difference in energy expenditure (0.11 kcal/min, 95% CI 0.08-0.14) compared to randomised trials (0.2 kcal/min, 95% CI 0.12-0.28). By substituting sitting with standing for 6 hours/day, a 65 kg person will expend an additional 54 kcal/day. Assuming no increase in energy intake, this difference in energy expenditure would be translated into the energy content of about 2.5 kg of body fat mass in 1 year. Conclusions The substitution of sitting with standing could be a potential solution for a sedentary lifestyle to prevent weight gain in the long term. Future studies should aim to assess the effectiveness and feasibility of this strategy. PMID- 29385359 TI - Allogeneic Stem-Cell Transplantation - A T-Cell Balancing ACT. PMID- 29385358 TI - Catheter Ablation for Atrial Fibrillation with Heart Failure. AB - BACKGROUND: Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment. METHODS: We randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure. All the patients had New York Heart Association class II, III, or IV heart failure, a left ventricular ejection fraction of 35% or less, and an implanted defibrillator. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure. RESULTS: After a median follow-up of 37.8 months, the primary composite end point occurred in significantly fewer patients in the ablation group than in the medical-therapy group (51 patients [28.5%] vs. 82 patients [44.6%]; hazard ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.87; P=0.007). Significantly fewer patients in the ablation group died from any cause (24 [13.4%] vs. 46 [25.0%]; hazard ratio, 0.53; 95% CI, 0.32 to 0.86; P=0.01), were hospitalized for worsening heart failure (37 [20.7%] vs. 66 [35.9%]; hazard ratio, 0.56; 95% CI, 0.37 to 0.83; P=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; hazard ratio, 0.49; 95% CI, 0.29 to 0.84; P=0.009). CONCLUSIONS: Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy. (Funded by Biotronik; CASTLE-AF ClinicalTrials.gov number, NCT00643188 .). PMID- 29385361 TI - Monogenic Diseases of DNA Repair. PMID- 29385360 TI - The Myth of the Milkmaid. PMID- 29385363 TI - A Disturbing Legacy of Childhood Kidney Disease. PMID- 29385364 TI - History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. AB - BACKGROUND: The long-term risk associated with childhood kidney disease that had not progressed to chronic kidney disease in childhood is unclear. We aimed to estimate the risk of future end-stage renal disease (ESRD) among adolescents who had normal renal function and a history of childhood kidney disease. METHODS: We conducted a nationwide, population-based, historical cohort study of 1,521,501 Israeli adolescents who were examined before compulsory military service in 1967 through 1997; data were linked to the Israeli ESRD registry. Kidney diseases in childhood included congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease; all participants included in the primary analysis had normal renal function and no hypertension in adolescence. Cox proportional-hazards models were used to estimate the hazard ratio for ESRD associated with a history of childhood kidney disease. RESULTS: During 30 years of follow-up, ESRD developed in 2490 persons. A history of any childhood kidney disease was associated with a hazard ratio for ESRD of 4.19 (95% confidence interval [CI], 3.52 to 4.99). The associations between each diagnosis of kidney disease in childhood (congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease) and the risk of ESRD in adulthood were similar in magnitude (multivariable-adjusted hazard ratios of 5.19 [95% CI, 3.41 to 7.90], 4.03 [95% CI, 3.16 to 5.14], and 3.85 [95% CI, 2.77 to 5.36], respectively). A history of kidney disease in childhood was associated with younger age at the onset of ESRD (hazard ratio for ESRD among adults <40 years of age, 10.40 [95% CI, 7.96 to 13.59]). CONCLUSIONS: A history of clinically evident kidney disease in childhood, even if renal function was apparently normal in adolescence, was associated with a significantly increased risk of ESRD, which suggests that kidney injury or structural abnormality in childhood has long-term consequences. PMID- 29385365 TI - Urothelial Carcinoma. PMID- 29385367 TI - Tobacco-Product Use by Adults and Youths in the United States in 2013 and 2014. PMID- 29385366 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. PMID- 29385368 TI - Gene Therapy for Cerebral Adrenoleukodystrophy. PMID- 29385369 TI - Electrocardiographic Changes in Hypothermia. PMID- 29385371 TI - Therapy for Spinal Muscular Atrophy. PMID- 29385372 TI - Tolvaptan in Later-Stage Polycystic Kidney Disease. PMID- 29385370 TI - Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. AB - BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .). PMID- 29385373 TI - Home Sweet Home. PMID- 29385374 TI - Is Pregabalin Ineffective in Acute or Chronic Sciatica? PMID- 29385375 TI - Diuretic Treatment in Heart Failure. PMID- 29385377 TI - Paradigm Shift for Treatment of Atrial Fibrillation in Heart Failure. PMID- 29385376 TI - Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. AB - BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (>=5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .). PMID- 29385378 TI - The Challenging Quest to Improve Rural Health Care. PMID- 29385379 TI - [Erratum to "Pseudo-Bartter syndrome as manifestation of cystic fibrosis with DF508 mutation"]. PMID- 29385380 TI - PreScription: 2017--Some Good Things Happened and Some Others. PMID- 29385381 TI - Certification, Accreditation, and Credentialing for 503A Compounding Pharmacies. AB - The terms certification, accreditation, and credentialing are often used interchangeably when they apply to compounding-pharmacy qualifications, but they are not synonymous. The reasons for obtaining each, the requirements for each, and the benefits of each differ. Achieving such distinctions can negatively or positively affect the status of a pharmacy among peers and prescribers as well as a pharmacy's relationships with third-party payors. Changes in the third-party payor industry evolve constantly and, we suggest, will continue to do so. Compounding pharmacists must be aware of those changes to help ensure success in a highly competitive marketplace. To our knowledge at the time of this writing, there is no certification program for compounding pharmacists, although pharmacy technicians can achieve certification and may be required to do so by the state in which they practice (a topic beyond the scope of this article). For that reason, we primarily address accreditation and credentialing for 503A compounding pharmacies. In this article, the evolution of the third-party payment system for compounds is reviewed; the definitions of certification, accreditation, and credentialing are examined; and the benefits and recognition of obtaining accredited or credentialed status are discussed. Suggestions for selecting an appropriate agency that offers accreditation or credentialing, preparing for and undergoing an onsite survey, responding to findings, and maintaining a pharmacy practice that enables a successful survey outcome are presented. The personal experience of author CK during accreditation and credentialing is discussed, as is the role of a consultant (author BJ) in helping compounders prepare for the survey process. A list of agencies that offer accreditation and credentialing for compounding pharmacies is included for easy reference. PMID- 29385383 TI - The International Academy of Compounding Pharmacists: Government Affairs Lookback on 2017 Accomplishments and Look Ahead at 2018 Initiatives. PMID- 29385382 TI - Pain: Systematic Review of Pharmacy Compounding of Pain Medication. AB - There are limited resources available for pharmacists and doctors to reference proper compounded formulas for pain medications. The systematic review discussed within this article provides the foundation for a searchable database, allowing users to find various compounded formulations. It also provides data about the safety and efficacy of the preparations. Compounding information about several drug classes was reviewed. Those drug classes included, but were not limited to, opioids, non-steroidal anti-inflammatory drugs, central nervous system agents, and anesthetics, with evidence that of the various drugs that could be compounded for pain, anesthetics, non-steroidal anti-inflammatory drugs, and opioids ranked highest within the articles researched. PMID- 29385384 TI - Basics of Compounding: Providing Pharmacy Services to Bariatric Surgery Patients. AB - With the rise in obesity, more individuals are choosing bariatric surgery as a means to successfully lose weight and resolve co-morbidities. These patients need lifelong support from friends, family, and healthcare providers. Pharmacists need to be knowledgeable of the unique needs of these patients in order to provide information and recommendations on drug therapies and supplements. When a patient is wheeled out of the operating room following bariatric surgery, his or her life instantly changes. Like an infant, the patient has to slowly learn how to eat and drink again. Physical activity significantly increases. Taste perception changes. Serious medical problems, such as hypertension, type II diabetes, and hypercholesterolemia completely resolve within a couple of months. The patient has to be disciplined and follow the instructions of the bariatric team and other healthcare providers. Since the patient's gastrointestinal tract has been significantly altered, drug therapies may require some modifications too. Bariatric or weight loss surgery is definitely not the easy way to lose weight, but it is a very powerful tool for the patient. Weight loss, and maintaining that weight loss, is a lifelong journey for the patient that requires support from the bariatric team, healthcare provider(s), co-workers, friends, and family. Pharmacists may also provide support for these patients through counseling about their supplements, medications, and compounding medications to meet their specific needs. PMID- 29385385 TI - Sterile Basics of Compounding: Relationship Between Syringe Size and Dosing Accuracy. AB - The purpose of this study was to investigate the accuracy and reproducibility of a 2-mL volume injection using a 3-mL and 10-mL syringe with pharmacy student compounders. An exercise was designed to assess each student's accuracy in compounding a sterile preparation with the correct 4-mg strength using a 3-mL and 10-mL syringe. The average ondansetron dose when compounded with the 3-mL syringe was 4.03 mg (standard deviation +/- 0.45 mg), which was not statistically significantly different than the intended 4-mg desired dose (P=0.497). The average ondansetron dose when compounded with the 10-mL syringe was 4.18 mg (standard deviation + 0.68 mg), which was statistically significantly different than the intended 4-mg desired dose (P=0.002). Additionally, there also was a statistically significant difference in the average ondansetron dose compounded using a 3-mL syringe (4.03 mg) and a 10-mL syringe (4.18 mg) (P=0.027). The accuracy and reproducibility of the 2-mL desired dose volume decreased as the compounding syringe size increased from 3 mL to 10 mL. PMID- 29385386 TI - Effects of Compounded Stanford Modified Oral Rinse (MucoLox) on the Survival and Migration of Oral Keratinocytes and Fibroblasts: Implications for Wound Healing. AB - Several oral rinses are commercially available to alleviate the symptoms of oral mucositis. Prolonged retention of active pharmaceutical ingredients in the oral cavity is a major problem. In this study, we modified the Stanford oral rinse by including a proprietary mucoadhesive polymer called MucoLox, which we hypothesized would improve active pharmaceutical ingredient mucoadhesion. Characterization of this newly compounded oral rinse showed absence of cytotoxicity in human oral keratinocyte and fibroblast cell lines. The compounded formulation significantly stimulated the migration of these two cell lines in Oris Cell Migration Assay plates, better than the reference commercial product Magic mouthwash. Based on this in vitro study, the new Stanford modified oral rinse with MucoLox is safe and may promote healing of oral mucositis. PMID- 29385387 TI - Stability of an Alcohol-free, Dye-free Hydrocortisone (2 mg/mL) Compounded Oral Suspension. AB - The stability of hydrocortisone in a commercially available dye-free oral vehicle was monitored to establish a beyond-use date for hydrocortisone oral suspension 2 mg/mL. Hydrocortisone oral suspension (2 mg/mL) was prepared from 10-mg tablets in a dye-free oral vehicle (Oral Mix, Medisca) and stored at 4 degrees C and 25 degrees C for 90 days in amber, plastic prescription bottles and oral syringes. The suspendability and dose repeatability of the oral suspension were evaluated. The solubility of hydrocortisone in the dye-free vehicle was determined. Over 90 days, pH and concentration of hydrocortisone in the oral suspension were measured. The stability-indicating nature of a high-pressure liquid chromatographic assay was evaluated in detail. The solubility of hydrocortisone in the dye-free vehicle was 230 mcg/mL at 25 degrees C. This means that about 90% of the drug remains in the solid state where it is less susceptible to degradation. The preparation suspended well to support dose repeatability. The chromatographic assay resolved hydrocortisone from cortisone, excipients in the vehicle, and all degradation products. The assay passed United States Pharmacopeia system suitability tests. Hydrocortisone oral suspension (2 mg/mL) compounded using a dye-free, alcohol-free oral vehicle, Oral Mix, was stable in amber plastic bottles and syringes stored at 4 degrees C and 25 degrees C for 90 days within a 95% confidence interval. PMID- 29385388 TI - Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Palonosetron Hydrochloride Injection and Dexamethasone Sodium Phosphate Injection. AB - Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for selected patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Palonosetron is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL, free base], equivalent to 185 mg of rolapitant hydrochloride) admixed with palonosetron injection 0.25 mg free base in 5 mL (equivalent to 0.28 mg hydrochloride salt) and with either 5 mL (20 mg) or 2.5 mL (10 mg) of dexamethasone sodium phosphate. Admixtures were prepared and stored in VARUBI injectable emulsion ready-to-use glass vials as supplied by the rolapitant manufacturer and in four types of commonly used intravenous administration (tubing) sets. Assessment of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20 degrees C to 25 degrees C) under fluorescent light and under refrigeration (2 degrees C to 8 degrees C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20 degrees C to 25 degrees C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. All samples were physically and chemically compatible throughout the study duration. The pH, turbidity, globule size, and particulate matter of the admixture stayed within narrow and acceptable ranges. VARUBI injectable emulsion admixed with intravenous palonosetron and dexamethasone was chemically and physically stable in the ready-to-use glass vials for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four selected intravenous tubing sets for at least 6 hours at room temperature. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two temperature ranges and time periods studied as measured by high-performance liquid chromatographic analysis. PMID- 29385389 TI - Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Granisetron Hydrochloride. AB - Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine- 3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for select patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Granisetron Hydrochloride Injection USP is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI (rolapitant) injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL], equivalent to 185 mg of rolapitant hydrochloride) admixed with Granisetron Hydrochloride Injection USP (1.0 mg/mL, equivalent to 1.12 mg/mL hydrochloride). Binary admixtures of VARUBI injectable emulsion and Granisetron Hydrochloride Injection USP were prepared and stored in VARUBI ready-to-use glass vials and in four types of commonly used intravenous administration (tubing) sets. Evaluation of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20 degrees C to 25 degrees C) under fluorescent light and under refrigeration (2 degrees C to 8 degrees C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20 degrees C to 25 degrees C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. The pH, turbidity, globule size, and particulate matter of all samples remained within narrow and acceptable ranges at all study time points, indicating that combining the two formulations into a binary admixture is physically and chemically compatible and stable. VARUBI injectable emulsion admixed with Granisetron Hydrochloride Injection USP demonstrated compatibility and stability in a ready-to-use glass vial for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four intravenous tubing sets for at least 6 hours at 20 degrees C to 25 degrees C. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two conditions and time periods studied based on high-performance liquid chromatographic analysis. The levels of impurities stayed below the safety limits set by International Conference on Harmonisation during the study period. PMID- 29385390 TI - Hydrophobic durability characteristics of butterfly wing surface after freezing cycles towards the design of nature inspired anti-icing surfaces. AB - The hydrophobicity and anti-icing performance of the surfaces of some artificial hydrophobic coatings degraded after several icing and de-icing cycles. In this paper, the frost formation on the surfaces of butterfly wings from ten different species was observed, and the contact angles were measured after 0 to 6 frosting/defrosting cycles. The results show that no obvious changes in contact angle for the butterfly wing specimens were not obvious during the frosting/defrosting process. Further, the conclusion was inferred that the topography of the butterfly wing surface forms a special space structure which has a larger space inside that can accommodate more frozen droplets; this behavior prevents destruction of the structure. The findings of this study may provide a basis and new concepts for the design of novel industrially important surfaces to inhibit frost/ice growth, such as durable anti-icing coatings, which may decrease or prevent the socio-economic loss. PMID- 29385394 TI - Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia. AB - Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes. PMID- 29385395 TI - MicroRNA expression pattern differs depending on endometriosis lesion type. AB - MicroRNA (miRNA), noncoding segments of RNA involved in post-transcriptional regulation of protein expression are differentially expressed in eutopic endometrium of women with and without endometriosis compared to endometriotic lesions. However, endometriotic lesion types are known to be biochemically distinct and therefore hypothesized that miRNAs are differentially expressed in endometriomas compared to peritoneal and deep-infiltrating lesions. Therefore, endometrial biopsies and ectopic implants from women (n = 38) undergoing laparoscopic surgery for chronic pelvic pain were collected. Samples of endometriomas, peritoneal or deep-infiltrating lesions were selected from our tissue bank for study participants who exclusively had only one lesion type noted on their surgical report. Quantitative real-time polymerase chain reaction for miR-9, miR-21, miR-424, miR-10a, miR-10b, and miR-204 was performed. miR-204 expression was significantly lower (P = 0.0016) in the eutopic endometrium of women with endometriosis compared to controls. Relative expression of miR-21, miR 424, and miR-10b differed significantly (P < 0.05) across endometriotic lesion types. Finally, all miRNAs isolated from endometriomas, peritoneal and deep infiltrating lesions studied were differentially expressed compared to matched eutopic endometrium samples. We therefore conclude that miRNA expression in the eutopic endometrium from women with endometriosis differs from symptomatic controls. Moreover, miRNA expression pattern is dependent on the endometriotic lesion type studied. We suggest that identification of different miRNA expression patterns for endometriomas, peritoneal and deep-infiltrating lesions could contribute to individualized patient care for women with endometriosis. PMID- 29385396 TI - Isoform-specific requirement for GSK3alpha in sperm for male fertility. AB - Glycogen synthase kinase 3 (GSK3) is a highly conserved protein kinase regulating key cellular functions. Its two isoforms, GSK3alpha and GSK3beta, are encoded by distinct genes. In most tissues the two isoforms are functionally interchangeable, except in the developing embryo where GSK3beta is essential. One functional allele of either of the two isoforms is sufficient to maintain normal tissue functions. Both GSK3 isoforms, present in sperm from several species including human, are suggested to play a role in epididymal initiation of sperm motility. Using genetic approaches, we have tested requirement for each of the two GSK3 isoforms in testis and sperm. Both GSK3 isoforms are expressed at high levels during the onset of spermatogenesis. Conditional knockout of GSK3alpha, but not GSK3beta, in developing testicular germ cells in mice results in male infertility. Mice lacking one allele each of GSK3alpha and GSK3beta are fertile. Despite overlapping expression and localization in differentiating spermatids, GSK3beta does not substitute for GSK3alpha. Loss of GSK3alpha impairs sperm hexokinase activity resulting in low ATP levels. Net adenine nucleotide levels in caudal sperm lacking GSK3alpha resemble immature caput epididymal sperm. Changes in the association of the protein phosphatase PP1gamma2 with its protein interactors occurring during epididymal sperm maturation is impaired in sperm lacking GSK3alpha. The isoform-specific requirement for GSK3alpha is likely due to its specific binding partners in the sperm principal piece. Testis and sperm are unique in their specific requirement of GSK3alpha for normal function and male fertility. PMID- 29385397 TI - Meiosis: the chromosomal foundation of reproduction. AB - Meiosis is the chromosomal foundation of reproduction, with errors in this important process leading to aneuploidy and/or infertility. In this review celebrating the 50th anniversary of the founding of the Society for the Study of Reproduction, the important chromosomal structures and dynamics contributing to genomic integrity across generations are highlighted. Critical unsolved biological problems are identified, and the advances that will lead to their ultimate resolution are predicted. PMID- 29385398 TI - Pilose antler polypeptides ameliorates hypoxic-ischemic encephalopathy by activated neurotrophic factors and SDF1/CXCR4 axis in rats. AB - Hypoxic-ischemic encephalopathy (HIE) is a complex condition which is associated with high mortality and morbidity. However, few promising treatments for HIE exist. In the present study, the central objective was to identify the therapeutic effect of pilose antler polypeptides (PAP) on HIE in rats. Sprague Dawley (SD) rats (14 days old) were used and divided into three groups, including control group, hypoxic-ischemia (HI) group and PAP group. After 21 days of treatment, locomotor activity was improved in PAP-treated rats, brain atrophy was decreased and cerebral edema was mitigated to some extent. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis indicated that PAP administration decreased the expressions of inflammatory cytokines and apoptosis genes in hippocampus compared with HI group. Furthermore, the mRNA expressions of genes related to neurotrophic factors were significantly increased in the hippocampus. In addition, the expressions of oxidative stress markers were all down-regulated after PAP administration. Moreover, PAP up-regulated both the mRNA and protein levels of SDF1 and CXCR4, which may activate the SDF1/CXCR4 axis to moderate brain injury. These results suggest that PAP may be potentially used in the treatment of HIE. PMID- 29385399 TI - Central Blood Pressure Responses to Dietary Sodium and Potassium Interventions. AB - BACKGROUND: To explore how central hemodynamics respond to dietary sodium and potassium interventions, and whether the responses are associated with metabolic traits. METHODS: We conducted a dietary intervention study including a 7-day low sodium (51.3 mmol sodium/day) intervention, a 7-day high-sodium (307.8 mmol sodium/day) intervention, and a 7-day high-sodium with potassium supplementation (60.0 mmol potassium/day) intervention among 99 northern Chinese subjects aged 18 60 years. Five metabolic traits included abdominal obesity, high triglycerides, low HDL cholesterol, raised blood pressure (BP), and high glucose. Central hemodynamics were measured at baseline and during each intervention. RESULTS: Central systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and augmentation index (AIx@75) significantly decreased during low-sodium intervention, increased during high-sodium intervention, and then decreased during potassium supplementation. We observed potential linear trends toward significance of central SBP and PP responses to low-sodium intervention, and significant linear trends of responses to high-sodium intervention as the number of metabolic traits grows. For example, among participants with 0 or 1, 2 or 3, and 4 or 5 metabolic traits, central SBP responses to high-sodium intervention were 8.8 [95% confidence interval (5.8, 11.8)], 9.3 (7.1, 11.6), and 14.0 (11.6, 16.3) mmHg, respectively (P for trend = 0.009). Significant linear trends of central SBP and DBP responses to potassium supplementation were also observed. CONCLUSIONS: Central BP and AIx@75 were lowered by sodium reduction and potassium supplementation, and elevated by sodium-loading. The responses of central BP were pronounced among individuals with metabolic traits clustering. CLINICAL TRIALS REGISTRATION: Trial Number NCT00721721 (The current study is registered on ClinicalTrials.gov; https://clinicaltrials.gov). PMID- 29385400 TI - Octreotide protects against hepatic ischemia/reperfusion injury via HO-1-mediated autophagy. PMID- 29385401 TI - Accurity: accurate tumor purity and ploidy inference from tumor-normal WGS data by jointly modelling somatic copy number alterations and heterozygous germline single-nucleotide-variants. AB - Motivation: Tumor purity and ploidy have a substantial impact on next-gen sequence analyses of tumor samples and may alter the biological and clinical interpretation of results. Despite the existence of several computational methods that are dedicated to estimate tumor purity and/or ploidy from The Cancer Genome Atlas (TCGA) tumor-normal whole-genome-sequencing (WGS) data, an accurate, fast and fully-automated method that works in a wide range of sequencing coverage, level of tumor purity and level of intra-tumor heterogeneity, is still missing. Results: We describe a computational method called Accurity that infers tumor purity, tumor cell ploidy and absolute allelic copy numbers for somatic copy number alterations (SCNAs) from tumor-normal WGS data by jointly modelling SCNAs and heterozygous germline single-nucleotide-variants (HGSNVs). Results from both in silico and real sequencing data demonstrated that Accurity is highly accurate and robust, even in low-purity, high-ploidy and low-coverage settings in which several existing methods perform poorly. Accounting for tumor purity and ploidy, Accurity significantly increased signal/noise gaps between different copy numbers. We are hopeful that Accurity is of clinical use for identifying cancer diagnostic biomarkers. Availability and implementation: Accurity is implemented in C++/Rust, available at http://www.yfish.org/software/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385402 TI - G2S: a web-service for annotating genomic variants on 3D protein structures. AB - Motivation: Accurately mapping and annotating genomic locations on 3D protein structures is a key step in structure-based analysis of genomic variants detected by recent large-scale sequencing efforts. There are several mapping resources currently available, but none of them provides a web API (Application Programming Interface) that supports programmatic access. Results: We present G2S, a real time web API that provides automated mapping of genomic variants on 3D protein structures. G2S can align genomic locations of variants, protein locations, or protein sequences to protein structures and retrieve the mapped residues from structures. G2S API uses REST-inspired design and it can be used by various clients such as web browsers, command terminals, programming languages and other bioinformatics tools for bringing 3D structures into genomic variant analysis. Availability and implementation: The webserver and source codes are freely available at https://g2s.genomenexus.org. Contact: g2s@genomenexus.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385403 TI - TSAPA: identification of tissue-specific alternative polyadenylation sites in plants. AB - Summary: Alternative polyadenylation (APA) is now emerging as a widespread mechanism modulated tissue-specifically, which highlights the need to define tissue-specific poly(A) sites for profiling APA dynamics across tissues. We have developed an R package called TSAPA based on the machine learning model for identifying tissue-specific poly(A) sites in plants. A feature space including more than 200 features was assembled to specifically characterize poly(A) sites in plants. The classification model in TSAPA can be customized by selecting desirable features or classifiers. TSAPA is also capable of predicting tissue specific poly(A) sites in unannotated intergenic regions. TSAPA will be a valuable addition to the community for studying dynamics of APA in plants. Availability and implementation: https://github.com/BMILAB/TSAPA. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385405 TI - Development and validation of Visual Impairment as a Risk for Falls Questionnaire. AB - Purpose: visual impairment is associated with an increased risk of falls, yet eye care professionals are infrequently members of falls prevention clinics. The aim of this preliminary study was to validate a newly created Visual Impairment as a Risk for Falls Questionnaire intended to be used by those professionals not involved in eye care. Methods: about 53 participants with various visual impairments known to be associated with falls and 33 participants with normal sight were contacted within 4 months of a full oculo-visual assessment and were asked the questions from the current questionnaire pertaining to their visual function. A retrospective file review was undertaken and the sensitivity and specificity of participants' responses were calculated compared to the actual vision impairment based on the findings from their visual assessment. Results: the question regarding ability to read was included to identify people with central vision loss, a risk factor for falling. It was found to have sensitivity of 74% and specificity of 87%. Both sensitivity and specificity improved when participants with cognitive impairment were excluded. The question on recognising facial features gave sensitivity of 73% and specificity of 97% for this subgroup. However, questions related to impairments in stereopsis and peripheral fields were not useful. Conclusion: the study demonstrates that several questions of the new questionnaire are useful; however, further testing with a larger population is needed to fully validate the questionnaire for use by health care professionals. PMID- 29385404 TI - TOXsIgN: a cross-species repository for toxicogenomic signatures. AB - Motivation: At the same time that toxicologists express increasing concern about reproducibility in this field, the development of dedicated databases has already smoothed the path toward improving the storage and exchange of raw toxicogenomic data. Nevertheless, none provides access to analyzed and interpreted data as originally reported in scientific publications. Given the increasing demand for access to this information, we developed TOXsIgN, a repository for TOXicogenomic sIgNatures. Results: The TOXsIgN repository provides a flexible environment that facilitates online submission, storage and retrieval of toxicogenomic signatures by the scientific community. It currently hosts 754 projects that describe more than 450 distinct chemicals and their 8491 associated signatures. It also provides users with a working environment containing a powerful search engine as well as bioinformatics/biostatistics modules that enable signature comparisons or enrichment analyses. Availability and implementation: The TOXsIgN repository is freely accessible at http://toxsign.genouest.org. Website implemented in Python, JavaScript and MongoDB, with all major browsers supported. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385406 TI - C-reactive protein is associated with the development of tongue squamous cell carcinoma. AB - C-reactive protein (CRP) acts as a biomarker reflecting different degrees of inflammation. Accumulating reports have suggested that there is a close relationship between CRP and various cancers. However, the influence of CRP on the development of tongue squamous cell carcinoma (TSCC) remains unclear. The purpose of this study was to investigate the role of CRP in TSCC. The results of immunohistochemical staining and statistical analyses showed that CRP expression was associated with TSCC tumor size, lymph node metastasis and pathological differentiation. Cell Counting Kit-8 (CCK-8) assay revealed that CRP could enhance TSCC cell proliferation in a dose- and time-dependent manner. Moreover, with CRP stimulation, proliferating cell nuclear antigen (PCNA) expression patterns presented a notable time-dependent up-regulation. In addition, CRP could enhance the invasion and migration of TSCC cells, as revealed by transwell and wound-healing assays, respectively. Annexin V-FITC/PI staining showed that CRP could protect TSCC cells from starvation- and drug-induced apoptosis. With CRP stimulation, the protein expression levels of phosphorylated protein kinase B (pAkt), phosphorylated mammalian target of rapamycin (pmTOR) and phosphorylated S6 ribosomal protein (pS6) were significantly increased, as demonstrated by western blot analysis. Our data suggest that CRP may play an important role in the development of TSCC. Moreover, the biological effects of CRP on TSCC cells might be related to Akt, mTOR, and S6. PMID- 29385407 TI - Dynamics of DNA methylation reprogramming at the single-cell level in early human embryos. PMID- 29385408 TI - EPS-LASSO: test for high-dimensional regression under extreme phenotype sampling of continuous traits. AB - Motivation: Extreme phenotype sampling (EPS) is a broadly-used design to identify candidate genetic factors contributing to the variation of quantitative traits. By enriching the signals in extreme phenotypic samples, EPS can boost the association power compared to random sampling. Most existing statistical methods for EPS examine the genetic factors individually, despite many quantitative traits have multiple genetic factors underlying their variation. It is desirable to model the joint effects of genetic factors, which may increase the power and identify novel quantitative trait loci under EPS. The joint analysis of genetic data in high-dimensional situations requires specialized techniques, e.g. the least absolute shrinkage and selection operator (LASSO). Although there are extensive research and application related to LASSO, the statistical inference and testing for the sparse model under EPS remain unknown. Results: We propose a novel sparse model (EPS-LASSO) with hypothesis test for high-dimensional regression under EPS based on a decorrelated score function. The comprehensive simulation shows EPS-LASSO outperforms existing methods with stable type I error and FDR control. EPS-LASSO can provide a consistent power for both low- and high dimensional situations compared with the other methods dealing with high dimensional situations. The power of EPS-LASSO is close to other low-dimensional methods when the causal effect sizes are small and is superior when the effects are large. Applying EPS-LASSO to a transcriptome-wide gene expression study for obesity reveals 10 significant body mass index associated genes. Our results indicate that EPS-LASSO is an effective method for EPS data analysis, which can account for correlated predictors. Availability and implementation: The source code is available at https://github.com/xu1912/EPSLASSO. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385409 TI - Osteoarthritis of the hip and knee in former male professional soccer players. AB - Background: Professional soccer (PS) players are at great risk of osteoarthritis (OA) of the knee and hip. Sources of data: Following the PRISMA guidelines, the key words 'osteoarthritis' and 'soccer' or 'football' were matched with 'players' or 'former' or 'retired' and with 'hip' or 'knee' on December 24, 2017 in the following databases: PubMed, Cochrane, Google scholar, Embase and Ovid. Only comparative studies reporting the prevalence rate of OA of both hip and knee joint in former PS athletes (fPSa) and age and sex matched controls were considered. Areas of agreement: In fPSa, the prevalence rate of OA of both hip and knee is significantly higher compared to age and sex matched controls. Areas of controversy: The pathological pathways responsible for the development of OA of the hip and knee in PS athletes (PSa) are still not clearly understood. Growing points: The prevalence rate of clinical OA of the hip was 8.6% in fPSa and 5.6% in controls (odd ratio (OR) = 1.5; 95% CI: 1.06-2.31). The radiographic rate of OA was 21.2% in fPSa and 9.8% in controls (OR = 2.4; 95% CI: 1.66-3.69). A total of 14.6 and 53.7% of fPSa presented clinical and radiographic signs of OA of the knee, respectively, vs 12.9% (OR = 1.16; 95% CI: 0.86-1.55) and 31.9% (OR = 2.47; 95% CI: 2.03-3.00) of controls. Sonographic evidence of OA of the knee was found in 52% of fPSa and 33% of controls (OR = 2.2; 95% CI: 1.24-3.89). Areas timely for developing research: Preventive training programmes should be developed to reduce the number of fPSa presenting early OA. PMID- 29385410 TI - An interview with Dr Linda C. Giudice. PMID- 29385411 TI - Palmitic acid induces ceramide accumulation, mitochondrial protein hyperacetylation, and mitochondrial dysfunction in porcine oocytes. AB - Low oocyte quality is a possible causal factor of obesity-induced infertility. High palmitic acid (PA) concentration in follicular fluid is a crucial feature noted in obese women. This study examined how high PA concentration reduced mitochondrial quality in oocytes and investigated a possible countermeasure against mitochondrial dysfunction. Cumulus cell-oocyte complexes were obtained from the ovaries of gilts, and incubated in medium containing PA (0.5 mM) or vehicle (BSA) for 44 h. Culturing oocytes at high PA concentration induced mitochondrial dysfunction determined by high reactive oxygen species and low ATP content in oocytes. Furthermore, high PA levels increased mitochondrial acetylation levels determined by a high degree of co-localization of TOMM20 and acetylated-lysine. In addition, high PA levels reduced the expression of Sirtuin 3 (SIRT3) and phosphorylated AMP-activated protein kinase (AMPK), while the AMPK activator, AICAR, restored mitochondrial function as well as oocyte ability and reduced the acetylation of mitochondrial protein. Supplementation of culture medium with dorsomorphin dihydrochloride (an AMPK inhibitor) reduced mitochondrial function and increased mitochondrial protein acetylation. Treatment of oocytes with LB100 (an inhibitor of AMPK dephosphorylation) reduced mitochondrial acetylation levels and restored mitochondrial function. Furthermore, high PA levels increased ceramide accumulation in oocytes, and addition of ceramide to the culture medium also induced mitochondrial dysfunction and increased mitochondrial acetylation. This detrimental effect of ceramide was diminished by AICAR treatment of oocytes. Our results indicated that PA induces ceramide accumulation and downregulates the AMPK/SIRT3 pathway causing mitochondrial protein hyperacetylation and dysfunction in oocytes. PMID- 29385412 TI - Leptin resistance during pregnancy is also exerted at the periphery. AB - Pregnancy is a physiological state with a great demand of energy and nutrients in mammals and is characterized by hyperphagia, increase in fat mass, hyperleptinemia, and central resistance to leptin. In order to evaluate whether pregnancy is also a state of leptin resistance at the periphery, we studied the response to leptin in the liver and subcutaneous adipose tissue (SAT). We demonstrated reduced levels of phosphoryalated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated protein kinase B (p-AKT) after intravenous leptin in both tissues in mid-term pregnant rats (G13) and a restored response in late pregnancy (G18). As underlying mechanisms of the peripheral leptin resistance of mid-gestation we found decreased leptin receptor b (LepRb) mRNA levels and increased content of suppressor of cytokine signaling 3 (SOCS3). Furthermore, we demonstrated that in G13 rats the main lipogenic molecules and activity (sterol regulatory element binding transcription protein 1 (SREBP-1) and fatty acid synthase (FAS)) were elevated in the liver and SAT, and the molecules involved in beta-oxidation (peroxisome proliferator activated receptor alpha (PPARalpha) and carnitine palmitoyltransferase 1 (CPT-1)) were reduced, as it happens in early pregnancy. In G18, the opposite pattern is observed. This probably reflects that in G13 the peripheral resistance to the hyperleptinemia might help maintaining the lipogenic metabolism of early pregnancy. In contrast, the recovery of the response to leptin in late pregnancy would favor a catabolic metabolism. Finally, using a pseudogestation model we showed that progesterone and prolactin are not involved in the gestational peripheral leptin resistance. In conclusion, during mid-pregnancy a state of leptin resistance is also exerted at the periphery, and is probably involved in the characteristic lipid regulation of this physiological state. PMID- 29385413 TI - Abdominopelvic and Retroperitoneal Low-Grade Fibromyxoid Sarcoma: A Clinicopathologic Study of 13 Cases. AB - Objectives: Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor often arising in the lower extremities. Only rare examples in the abdominal cavity, pelvis, and retroperitoneum have been reported. Methods: cases of abdominopelvic and retroperitoneal LGFMS were retrieved. MUC4, Actin, ALK, beta-catenin, desmin, DOG1, KIT, S100 protein, and STAT6 testing was performed, and a subset was tested for FUS rearrangement. Results: Sites included intra-abdominal/abdominal wall (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel (two cases), and kidney (one case) (median size, 15 cm; age range, 5-61 years). Tumors harbored spindled cells with mild to moderate atypia, displaying alternating myxoid nodules and hyalinized areas. All cases were positive for MUC4, and five (of five) cases tested harbored FUS rearrangement. Variable positivity for DOG1 (four of 10) and actin (two of 10) was identified. Six tumors recurred, and one patient developed metastasis. Conclusion: LGFMS arising in these central locations exhibits similar clinicopathologic features to its counterpart in the extremities. LGFMS at these sites may show limited immunoreactivity for DOG1 and actin. PMID- 29385415 TI - Reflecting on the Autopsy in the Training of New Residents. PMID- 29385414 TI - Newly Emerging Drugs of Abuse and Their Detection Methods: An ACLPS Critical Review. AB - Objectives: Illicit drug abuse has reached an epidemic level in the United States. Drug overdose has become the leading cause of injury-related deaths since 2008 due to the recent surge of opioid overdose by heroin, controlled prescription drugs, and nonmethadone synthetic opioids. Synthetic designer drugs such as synthetic cathinones ("bath salts") and synthetic cannabinoids ("Spice" and "K2") continue to emerge and attract recreational users. Methods: The emergence of new drugs of abuse poses a steep challenge for clinical toxicology laboratories. Limited information about the emerging drugs and their metabolism, "rebranding" of the illicit drugs, and a lack of Food and Drug Administration approved screening methods for these drugs contribute to this difficulty. Here we review detection methods that can aid in identifying emerging drugs of abuse. Results: One promising approach is the utilization of untargeted drug screening by mass spectrometry. Historically, gas chromatography-mass spectrometry has been the gold standard. Conclusions: Liquid chromatography-tandem mass spectrometry and liquid chromatography-high-resolution mass spectrometry offer improved detection capability of new drugs with simplified sample preparation, making it the new standard. PMID- 29385416 TI - Integrated Analysis of HER2 Copy Number by Cytogenomic Microarray in Breast Cancers With Nonclassical In Situ Hybridization Results. AB - Objectives: To develop and test an integrated approach to human epidermal growth factor receptor 2 (HER2) copy number analysis in breast cancer using in situ hybridization (ISH) and cytogenomic microarray (CMA). Methods: CMA was performed on four clinical breast cancer samples with nonclassical patterns of HER2 ISH results. Integrated analysis was performed by correlating the data from pathology review, ISH, and CMA. Results: Integrated analysis provided a more comprehensive view of the genomic copy number landscape that informed HER2 copy number analysis, but ISH provided essential data in all cases. Conclusions: CMA can be helpful for clarifying HER2 amplification status in breast cancer. However, uncertainties over tumor percentage, clonal heterogeneity, and varying ploidy levels present challenges for genomic methods such as CMA. Accurate interpretation of HER2 copy number by CMA requires correlation with the pathology and ISH data. PMID- 29385417 TI - Crystal-Storing Histiocytosis in Bone Marrow: A Clinicopathologic Study of Eight Cases and Review of the Literature. AB - Objectives: We report the clinicopathologic characteristics of eight cases of crystal-storing histiocytosis (CSH) with bone marrow (BM) involvement (BM-CSH) and review CSH cases published in the English literature. Methods: We queried our pathology database for BM cases with CSH mentioned in the final diagnosis/comments from June 2011 to August 2016. Results: Eight cases of BM-CSH were identified. The underlying diagnoses consisted predominantly of plasma cell disorders (88%) associated with monotypic kappa light chain. In BM aspirates, crystals within histiocytes exhibited a morphologic spectrum including brightly eosinophilic, needle-like, or globule-like. In BM core biopsies, the histiocytes were often in aggregates with intracellular needle-like and/or globular, refractile inclusions. Conclusions: BM-CSH is a rare phenomenon and exhibits a heterogeneous crystalline and histiocytic appearance warranting accurate recognition to avoid misinterpretation of a granulomatous condition or storage disorder. In addition, prompt assessment for an underlying B-cell lymphoma or clonal plasmacytic neoplasm is indicated. PMID- 29385419 TI - Implantation of a novel self-expanding transcatheter heart valve in a highly calcified aortic annulus. PMID- 29385418 TI - DIBS: a repository of disordered binding sites mediating interactions with ordered proteins. AB - Motivation: Intrinsically Disordered Proteins (IDPs) mediate crucial protein protein interactions, most notably in signaling and regulation. As their importance is increasingly recognized, the detailed analyses of specific IDP interactions opened up new opportunities for therapeutic targeting. Yet, large scale information about IDP-mediated interactions in structural and functional details are lacking, hindering the understanding of the mechanisms underlying this distinct binding mode. Results: Here, we present DIBS, the first comprehensive, curated collection of complexes between IDPs and ordered proteins. DIBS not only describes by far the highest number of cases, it also provides the dissociation constants of their interactions, as well as the description of potential post-translational modifications modulating the binding strength and linear motifs involved in the binding. Together with the wide range of structural and functional annotations, DIBS will provide the cornerstone for structural and functional studies of IDP complexes. Availability and implementation: DIBS is freely accessible at http://dibs.enzim.ttk.mta.hu/. The DIBS application is hosted by Apache web server and was implemented in PHP. To enrich querying features and to enhance backend performance a MySQL database was also created. Contact: dosztanyi@caesar.elte.hu or bmeszaros@caesar.elte.hu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29385421 TI - Direct assessment of tricuspid regurgitation by 4D flow cardiovascular magnetic resonance in a patient with Ebstein's anomaly. PMID- 29385422 TI - Sea anemone in the coronary care unit: beauty or the beast? PMID- 29385420 TI - High-Resolution Tissue Mass Spectrometry Imaging Reveals a Refined Functional Anatomy of the Human Adult Adrenal Gland. AB - In the adrenal gland, neuroendocrine cells that synthesize catecholamines and epithelial cells that produce steroid hormones are united beneath a common organ capsule to function as a single stress-responsive organ. The functional anatomy of the steroid hormone-producing adrenal cortex and the catecholamine-producing medulla is ill defined at the level of small molecules. Here, we report a comprehensive high-resolution mass spectrometry imaging (MSI) map of the normal human adrenal gland. A large variety of biomolecules was accessible by matrix assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI, including nucleoside phosphates indicative of oxidative phosphorylation, sterol and steroid metabolites, intermediates of glycolysis and the tricarboxylic acid cycle, lipids, and fatty acids. Statistical clustering analyses yielded a molecularly defined adrenal anatomy of 10 distinct molecular zones including a highly structured corticomedullary interface. By incorporating pathway information, activities of carbohydrate, amino acid, and lipid metabolism as well as endocrine bioactivity were revealed to be highly spatially organized, which could be visualized as different molecularly defined zones. Together, these findings provide a molecular definition of human adult adrenal gland structure beyond classical histological anatomy. PMID- 29385423 TI - Viral Load and Sequence Analysis Reveal the Symptom Severity, Diversity, and Transmission Clusters of Rhinovirus Infections. AB - Background: Rhinovirus (RV) is one of the main viral etiologic agents of acute respiratory illnesses. Despite the heightened disease burden caused by RV, the viral factors that increase the severity of RV infection, the transmission pattern, and seasonality of RV infections remain unclear. Methods: An observational study was conducted among 3935 patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014. Results: The VP4/VP2 gene was genotyped from all 976 RV-positive specimens, where the predominance of RV-A (49%) was observed, followed by RV-C (38%) and RV-B (13%). A significant regression in median nasopharyngeal viral load (VL) (P < .001) was observed, from 883 viral copies/uL at 1-2 days after symptom onset to 312 viral copies/uL at 3-4 days and 158 viral copies/uL at 5-7 days, before declining to 35 viral copies/uL at >=8 days. In comparison with RV-A (median VL, 217 copies/uL) and RV-B (median VL, 275 copies/uL), RV-C-infected subjects produced higher VL (505 copies/uL; P < .001). Importantly, higher RV VL (median, 348 copies/uL) was associated with more severe respiratory symptoms (Total Symptom Severity Score >=17, P = .017). A total of 83 phylogenetic-based transmission clusters were identified in the population. It was observed that the relative humidity was the strongest environmental predictor of RV seasonality in the tropical climate. Conclusions: Our findings underline the role of VL in increasing disease severity attributed to RV-C infection, and unravel the factors that fuel the population transmission dynamics of RV. PMID- 29385424 TI - Are changes in occupational physical activity level compensated by changes in exercise behavior? AB - Background: Physically active occupations with high-energy expenditure may lead to lower motivation to exercise during leisure time, while the reverse can be hypothesized for sedentary occupations. The aim of this study was to investigate the impact of changing occupational activity level on exercise behavior. Methods: Data on occupational physical activity and leisure time exercise were taken from a population-based cohort, with surveys completed in 2010 and 2014. Using data on those employed in both years, two trajectories were analyzed: (i) participants who changed from sedentary to active occupations and (ii) participants who changed from active to sedentary occupations. Exercise was reported in hours per week and changes from 2010 to 2014 were categorized as decreased, increased or stable. Associations were expressed as ORs and 95% CIs adjusting for age, gender and education. Results: Data were available for 12 969 participants (57% women, aged 45 +/- 9 years, 57% highly educated). Relative to participants whose occupational activity was stable, participants who changed to active occupations (n = 549) were more likely to decrease exercise (OR = 1.22, 95% CI = 1.02-1.47) and those who changed to sedentary occupations (n = 373) more likely to increase exercise levels (OR = 1.21, 95% CI = 0.97-1.52). Conclusion: People changing from sedentary to active occupations compensate by exercising less, and those changing from physically active to sedentary occupations seem to compensate by exercising more in their leisure time. When developing and evaluating interventions to reduce occupational sedentary behavior or to promote exercise, mutual influences on physical activity of different contexts should be considered. PMID- 29385425 TI - Corrigendum: Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease. PMID- 29385426 TI - Outcomes of valve-sparing root replacement in acute Type A aortic dissection. AB - OBJECTIVES: To investigate the long-term durability of aortic valves, we reviewed the outcomes of patients who underwent valve-sparing root replacement with acute Type A aortic dissection. METHODS: We included patients who underwent emergent aortic repair for acute Type A aortic dissection at our university hospital between 2000 and 2016. We identified patients who underwent valve-sparing root replacement from the included cohort and assessed their survival and long-term valve durability. RESULTS: We identified 24 of 328 patients who underwent valve sparing root replacement (age: mean +/- SD 49 +/- 11 years; 17 men). All patients underwent reimplantation procedures and 2 had concomitant cusp repairs (central plication). Prolapsed cusps caused by detached commissures in 12 cases were noted and reattached with buttress sutures with or without glue. There was no in hospital mortality. Median follow-up period was 84 months (range 1-202 months) and survival was 100% at 5 and 10 years. Freedom from moderate or greater aortic insufficiency was 82% +/- 10% at 5 years and 65% +/- 13% at 10 years. Freedom from aortic valve reoperation was 83% +/- 9% at 5 years and 69% +/- 12% at 10 years. Valve reoperations were indicated for endocarditis in 1 patient, perforation of the aortic cusp in 1 patient and redetachment of commissures that had been attached with gelatin-resorcinol-formaldehyde glue at the initial operations in 3 patients. CONCLUSIONS: The durability of valve-sparing root replacement in acute aortic dissection was suboptimal. The major cause of late failure was commissure detachment after primary repair with buttress sutures and glue. Gelatin-resorcinol-formaldehyde glue should be avoided for commissural resuspension in patients with acute aortic dissection. PMID- 29385427 TI - Diagnostic Yield of Dysplasia in Polyp-adjacent Biopsies for Patients with Inflammatory Bowel Disease: A Cross-sectional Study. AB - Introduction: Patients with inflammatory bowel disease (IBD) undergoing polypectomy are recommended by current guidelines to have biopsies taken from adjacent mucosa to determine whether there is dysplasia present. With improvements in endoscopic imaging, it is now possible to characterize colonic lesions with higher levels of confidence than previously. We have reviewed the diagnostic yield of polyp-adjacent biopsies in IBD. Materials and Methods: A systematic search of our histopathology database revealed cases in which polyps had been endoscopically resected or biopsied in patients with IBD. Endoscopy reports and medical records were reviewed, and patient demographic and disease specific details were recorded, along with details of polyp characteristics and histopathology outcomes. Results: Three hundred and two polyps were biopsied or resected in 131 patients undergoing 178 colonoscopies. The median polyp size was 4 mm (range 1-45), and the predominant morphology was Paris 0-Is (n = 98, 32%). The histology was tubular adenoma in 76 (25%), tubulovillous adenoma in 14 (5%), hyperplastic in 112 (37%), post-inflammatory in 32 (11%), sessile serrated polyp in 31 (10%), traditional serrated adenoma in 2 (0.7%), flat high-grade dysplasia or cancer in 2 (0.7%) and other in 33 (11%). Dysplasia in adjacent biopsies was detected in 2 patients (0.7%), and was endoscopically visible in both cases. The proportion of endoscopically unsuspected dysplasia was 0/300 (0%, 95% CI 0-1.6%). Conclusion: The diagnostic yield for polyp-adjacent biopsies in patients with IBD is negligible. With high-definition technology and chromoendoscopy, it may no longer be necessary to biopsy endoscopically normal adjacent tissue to detect invisible dysplasia. PMID- 29385428 TI - Decellularized mitral valve in a long-term sheep model. AB - OBJECTIVES: The objective of this study was to evaluate surgical handling, in vivo hemodynamic performance and morphological characteristics of decellularized mitral valves (DMVs) in a long-term sheep model. METHODS: Ovine mitral valves were decellularized using detergents and beta-mercaptoethanol. Orthotopic implantations were performed in 6-month-old sheep (41.3 +/- 1.2 kg, n = 11) without annulus reinforcement. Commercially available stented porcine aortic valves [biological mitral valve (BMV), n = 3] were implanted conventionally and used as controls. Valve function was evaluated by transoesophageal echocardiography and explants were investigated by a routine bright field microscopy and immunofluorescent histology. RESULTS: During implantation, 2 DMVs required cleft closure of the anterior leaflet. All valves were competent on water test and early postoperative transoesophageal echocardiography. Six animals (DMV, n = 4; BMV, n = 2) survived 12 months. Six animals died within the first 4 months due to valve-related complications. At 12 months, transoesophageal echocardiography revealed severe degeneration in all BMVs. Macroscopically, BMV revealed calcification at the commissures and leaflet insertion area. Histological examination showed sporadic cells negative for endothelial nitric oxide synthase, von Willebrand factor and CD45 on their surface. In contrast, DMV showed no calcification or stenosis, and the regurgitation was trivial to moderate in all animals. Fibrotic hardening occurred only along the suture line of the valve annulus, immunostaining revealed collagen IV covering the entire leaflet surface and a repopulation with endothelial cells. CONCLUSIONS: Surgical implantation of DMV is feasible and results in good early graft function. Additional in vivo investigations are required to minimize the procedure-related complications and to increase the reproducibility of surgical implantation. Degenerative profile of allogeneic DMV is superior to commercially available porcine aortic prosthesis. PMID- 29385429 TI - Antithrombotic therapy use and clinical outcomes following thrombo-embolic events in patients with atrial fibrillation: insights from ARISTOTLE. AB - Aims: We investigated baseline characteristics, antithrombotic use, and clinical outcomes of patients with atrial fibrillation (AF) and a thrombo-embolic event in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study to better inform the care of these high-risk patients. Method and results: Thrombo-embolic events were defined as stroke (ischaemic or unknown cause) or systemic embolism (SE). Clinical outcomes were estimated using the Kaplan-Meier method. All-cause mortality and International Society on Thrombosis and Haemostasis (ISTH) major bleeding after events were analysed using a Cox proportional hazards model with time-dependent covariates. Of 18 201 patients in ARISTOTLE, 365 experienced a thrombo-embolic event [337 strokes (ischaemic or unknown cause), 28 SE]; 46 (12.6%) of which were fatal. In the 30 days before and after a thrombo-embolic event, 11% and 37% of patients, respectively, were not taking an oral anticoagulant. During follow-up (median 1.8 years), 22 patients (7.1%/year) had a recurrent stroke, 97 (30.1%/year) died, and 10 (6.7%/year) had major bleeding. Compared with patients without a thrombo embolic event, the short- and long-term adjusted hazards of death in patients with a thrombo-embolic event were high [<=30 days: hazard ratio (HR) 54.3%, 95% confidence interval (95% CI) 41.4-71.3; >30 days: HR 3.5, 95% CI 2.5-4.8; both P < 0.001]. The adjusted hazards of major bleeding were also high short-term (HR 10.37, 95% CI 3.87-27.78; P < 0.001) but not long-term (HR 1.7, 95% CI: 0.77 3.88; P = 0.18). Conclusions: Thrombo-embolic events were rare but associated with high short- and long-term morbidity and mortality. Substantial numbers of patients are not receiving oral anticoagulattherapy before and, despite this risk, after a first thrombo-embolic event. Clinical Trial Registration: ClinicalTrials.gov (NCT00412984). PMID- 29385430 TI - The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study. AB - Background and Aims: Low-dose naltrexone [LDN] is a controversial off-label treatment used by many Crohn's disease [CD] and ulcerative colitis [UC] patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We sought to examine whether initiation of LDN therapy by patients with inflammatory bowel disease [IBD] was followed by changes in dispensing of relevant medication. Methods: We performed a quasi-experimental before-and-after study following a sudden increase in LDN use in the Norwegian population in 2013. IBD patients were identified from among all the patients who had at least one LDN prescription recorded in the Norwegian Prescription Database [NorPD] in 2013. Drug dispensing 2 years before and after the first LDN prescription was compared. Results : We identified 582 IBD patients who had received LDN. Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [ 12%], [ii] intestinal anti-inflammatory agents [-17%], [iii] other immunosuppressants [-29%], [iv] intestinal corticosteroids [-32%] and [v] aminosalicylates [-17%]. In subgroups of identified CD and UC patients, there were significant reductions in the number of users of intestinal corticosteroids [CD: -44%, UC: -53%] and systemic corticosteroids [UC: -24%]. No significant differences in cumulative defined daily doses were observed. Conclusions : Our findings imply that the initiation of LDN in IBD is followed by reduced dispensing of several drugs considered essential in the treatment of CD and UC. PMID- 29385431 TI - Surgery for acute Type I aortic dissection without resection of supra-aortic entry sites leads to unfavourable aortic remodelling. AB - OBJECTIVES: This study aimed to evaluate the impact of remnant re-entries in arch branches on postoperative change in the aortic arch and descending aortic diameters and the rate of major adverse aortic events. METHODS: Between January 2010 and December 2016, 249 patients underwent surgery for acute Type I aortic dissection. Patients who underwent total arch replacement, had Marfan syndrome or had intramural haematoma were excluded. Seventy-two patients with predischarge and follow-up computed tomography scans were enrolled. Patients with and without re-entries in the arch branches after surgery were assigned to the supra-aortic entry (SAE, n = 21) and no supra-aortic entry (n = 51) groups, respectively. Diameters were measured at 7 levels: the innominate artery, left common carotid artery, left subclavian artery, 20 mm distal to the left subclavian artery, pulmonary artery bifurcation, coeliac axis and maximal diameter of the descending thoracic aorta. RESULTS: Growth rates at the levels of the pulmonary artery bifurcation and 20 mm distal to the left subclavian artery were significantly higher in the SAE group than in the no supra-aortic entry group. The rate of freedom from major adverse aortic events (annual growth >5 mm or maximal diameter of the descending thoracic aorta >50 mm) at 5 years was significantly higher in the no supra-aortic entry group than in the SAE group. CONCLUSIONS: Remnant SAE leads to unfavourable aortic remodelling after acute Type I aortic dissection repair. PMID- 29385432 TI - Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. AB - Pulmonary hypertension (PH) is the end result of interaction between pulmonary vascular tone and a complex series of cellular and molecular events termed 'vascular remodelling'. The remodelling process, which can involve the entirety of pulmonary arterial vasculature, almost universally involves medial thickening, driven by increased numbers and hypertrophy of its principal cellular constituent, smooth muscle cells (SMCs). It is noted, however that SMCs comprise heterogeneous populations of cells, which can exhibit markedly different proliferative, inflammatory, and extracellular matrix production changes during remodelling. We further consider that these functional changes in SMCs of different phenotype and their role in PH are dynamic and may undergo significant changes over time (which we will refer to as cellular plasticity); no single property can account for the complexity of the contribution of SMC to pulmonary vascular remodelling. Thus, the approaches used to pharmacologically manipulate PH by targeting the SMC phenotype(s) must take into account processes that underlie dominant phenotypes that drive the disease. We present evidence for time and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed 'SMCs' may arise from many origins, including endothelial cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro inflammatory phenotype by SMC that is essential to the development of PH. We present evidence that metabolic alterations akin to those observed in cancer cells (cytoplasmic and mitochondrial) directly contribute to the phenotype of the SM and SM-like cells involved in PH. Finally, we raise the possibility that SMCs transition from a proliferative to a senescent, pro-inflammatory and metabolically active phenotype over time. PMID- 29385434 TI - Importance of comorbidities in the treatment of primary care patients with heart failure-Baseline results of the observational RECODE-HF Study. AB - Background: Both non-cardiac and cardiac comorbidities are related to the prognosis of chronic heart failure (HF), but so far little is known about the impact of comorbidities on treatment difficulties in routine care. Objectives: To investigate which comorbidities are associated with treatment difficulties in primary care. We hypothesized that somatic comorbidities as well as psychosocial distress are associated with treatment difficulties. Methods: In this baseline analysis of data of the observational RECODE-HF study, HF patients were recruited via primary care practices in two German sites. They received a questionnaire by mail to measure psychosocial distress. Each patient's GP was interviewed by phone regarding the patient's comorbidities and treatment difficulties. Logistic regression analyses controlled for GP cluster effects were calculated to investigate the association between comorbidities/psychosocial distress and treatment difficulties. Results: The 3282 patients of 285 GPs included in the analysis were aged 74.2 (+/-10.1) years and had a mean number of 4.6 (+/-2.4) comorbidities. GPs reported treatment difficulties in 32.5% of the patients. Allergies/drug intolerance [odds ratio (ORs)=2.0], asthma/chronic obstructive pulmonary disease (ORs=1.4), renal insufficiency (ORs=1.3), atherosclerosis/peripheral arterial occlusive disease (ORs=1.3) and cardiac arrhythmias (ORs=1.2) as well as patient-reported psychosocial distress (ORs=1.2), HF severity (ORs=3.7-1.6) and age (ORs=0.98) were associated with treatment difficulties. Conclusion: Five somatic comorbidity groups as well as patient-reported psychosocial distress were significantly associated with a higher risk of GP-reported treatment difficulties. Further efforts to address comorbidities in clinical guidelines could be built on these results. PMID- 29385435 TI - Level of agreement between physician and patient assessment of non-medical health factors. AB - Background: GPs need to consider assorted relevant non-medical factors, such as family or work situations or health insurance coverage, to determine appropriate patient care. If GPs' knowledge of these factors varies according to patients' social position, less advantaged patients might receive poorer care, resulting in the perpetuation of social inequalities in health. Objective: To assess social disparities in GPs' knowledge of non-medical factors relevant to patient care. Methods: Observational survey of GPs who supervise internships in the Paris metropolitan area. Each of the 52 enrolled GPs randomly selected 70 patients from their patient list. Their knowledge of five relevant factors (coverage by publicly funded free health insurance, or by supplementary health insurance, living with a partner, social support and employment status) was analysed as the agreement between the patients' and GPs' answers to matching questions. Occupational, educational and financial disparities were estimated with multilevel models adjusted for age, sex, chronic disease and GP-patient relationship. Results: Agreement varied according to the factor considered from 66% to 91%. The global agreement score (percentage of agreement for all five factors) was 72%. Social disparities and often gradients, disfavouring the less well-off patients, were observed for each factor considered. Social gradients were most marked according to perceived financial situation and for health insurance coverage. Conclusion: GPs must be particularly attentive toward their least advantaged patients, to be aware of the relevant non-medical factors that affect these patients' health and care, and thus provide management adapted to each individual's personal situation. PMID- 29385436 TI - Do patient-reported outcome measures speak for all patient subgroups: is everyone included? PMID- 29385437 TI - International definition of a point-of-care test in family practice: a modified e Delphi procedure. AB - Background: The use of point-of-care tests (POCTs) in family practice is increasing, and the term POCT is often used in medical literature and clinical practice. Yet, no widely supported definition by several professional fields exists. Objective: To reach consensus on an international definition of a POCT in family practice. Methods: We performed a modified international e-Delphi procedure of four rounds among expert panel members from different professional backgrounds-family practitioners, laboratory specialists, policymakers, researchers and manufacturers. Results: Of 27 panel members from seven different countries, 26 participated in all rounds. Most panel members were active in POCT research or policymaking and 70% worked in family medicine. After choosing important components, structuring of answers and feedback, the following definition was chosen as the best or second best definition by 81% of panel members: a point-of-care test in family practice is a test to support clinical decision making, which is performed by a qualified member of the practice staff nearby the patient and on any part of the patient's body or its derivatives, during or very close to the time of consultation, to help the patient and physician to decide upon the best suited approach, and of which the results should be known at the time of the clinical decision making. Conclusion: The definition emerging from this study can inform family practitioners, laboratory specialists, policymakers and manufacturers on the most widely supported and recognized definition and could act as a clear starting point for the organization and execution of professional point-of-care testing in family practice worldwide. PMID- 29385438 TI - Barriers and facilitators among health professionals in primary care to prevention of cardiometabolic diseases: A systematic review. AB - The aim of this study is to identify potential facilitators and barriers for health care professionals to undertake selective prevention of cardiometabolic diseases (CMD) in primary health care. We developed a search string for Medline, Embase, Cinahl and PubMed. We also screened reference lists of relevant articles to retain barriers and facilitators for prevention of CMD. We found 19 qualitative studies, 7 quantitative studies and 2 mixed qualitative and quantitative studies. In terms of five overarching categories, the most frequently reported barriers and facilitators were as follows: Structural (barriers: time restraints, ineffective counselling and interventions, insufficient reimbursement and problems with guidelines; facilitators: feasible and effective counselling and interventions, sufficient assistance and support, adequate referral, and identification of obstacles), Organizational (barriers: general organizational problems, role of practice, insufficient IT support, communication problems within health teams and lack of support services, role of staff, lack of suitable appointment times; facilitators: structured practice, IT support, flexibility of counselling, sufficient logistic/practical support and cooperation with allied health staff/community resources, responsibility to offer and importance of prevention), Professional (barriers: insufficient counselling skills, lack of knowledge and of experience; facilitators: sufficient training, effective in motivating patients), Patient-related factors (barriers: low adherence, causes problems for patients; facilitators: strong GP-patient relationship, appreciation from patients), and Attitudinal (barriers: negative attitudes to prevention; facilitators: positive attitudes of importance of prevention). We identified several frequently reported barriers and facilitators for prevention of CMD, which may be used in designing future implementation and intervention studies. PMID- 29385439 TI - Emergent surgical removal of a migrated left atrial appendage occluder. AB - Occlusion of the left atrial appendage (LAA) in patients with atrial fibrillation has become a standard therapy to prevent thromboembolic complications. We aim to present 3 cases of LAA occluder embolization after percutaneous WATCHMANTM device implantation, which required emergent surgical retrieval. The device was dislocated in the left atrium, introducing LAA perforation and resulting in pericardial effusion and later tamponade in 1 patient who developed multiorgan failure and died 8 days postoperatively. Other patients were successfully operated and discharged. Hence, LAA occluder embolization may occur asymptomatically with immediate/late serious complications, which indicates emergent surgery. PMID- 29385440 TI - 11beta-HSD1 in Human Fetal Membranes as a Potential Therapeutic Target for Preterm Birth. AB - Human parturition is a complex process involving interactions between the myometrium and signals derived from the placenta, fetal membranes, and fetus. Signals originating from fetal membranes are crucial components that trigger parturition, which is clearly illustrated by the labor-initiating consequence of membrane rupture. It has been recognized for a long time that among fetal tissues in late gestation the fetal membranes possess the highest capacity for cortisol regeneration by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). However, the exact role of this unique feature remains a mystery. Accumulating evidence indicates that this extra-adrenal source of cortisol may serve as an upstream signal for critical events in human parturition, including enhanced prostaglandin and estrogen synthesis as well as extracellular matrix remodeling. This may explain why such high capacity for cortisol regeneration develops in human fetal membranes at late gestation. Therefore, inhibition of 11beta-HSD1 may provide a potential therapeutic target for prevention of preterm birth. This review summarizes the current understanding of the functional role of cortisol regeneration by 11beta-HSD1 in human fetal membranes. PMID- 29385441 TI - Anaerobic microbial dehalogenation and its key players in the contaminated Bitterfeld-Wolfen megasite. AB - The megasite Bitterfeld-Wolfen is highly contaminated as a result of accidents and because of dumping of wastes from local chemical industries in the last century. A variety of contaminants including chlorinated ethenes and benzenes, hexachlorohexanes and chlorinated dioxins can still be found in the groundwater and (river) sediments. Investigations of the in situ microbial transformation of organohalides have been performed only over the last two decades at this megasite. In this review, we summarise the research on the activity of anaerobic dehalogenating bacteria at the field site in Bitterfeld-Wolfen, focusing on chlorinated ethenes, monochlorobenzene and chlorinated dioxins. Various methods and concepts were applied including ex situ cultivation and isolation, and in situ analysis of hydrochemical parameters, compound-specific stable isotope analysis of contaminants, 13C-tracer studies and molecular markers. Overall, biotransformation of organohalides is ongoing at the field site and Dehalococcoides mccartyi species play an important role in the detoxification process in the Bitterfeld-Wolfen region. PMID- 29385433 TI - Sexual Dimorphism and the Origins of Human Spinal Health. AB - Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies is on average 10% smaller in healthy newborn girls than in newborn boys, a striking difference that increases during infancy and puberty and is greatest by the time of sexual and skeletal maturity. The smaller CSA of female vertebrae is associated with greater spinal flexibility and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities. This review summarizes the potential endocrine, genetic, and environmental determinants of vertebral cross-sectional growth and current knowledge of the association between the small female vertebrae and greater risk for a broad array of spinal conditions across the lifespan. PMID- 29385442 TI - Comparison of risk factors for, and prevalence of, antibiotic resistance in contaminating and pathogenic urinary Escherichia coli in children in primary care: prospective cohort study. AB - Background: All-cause antibiotic prescribing affects bowel flora antimicrobial susceptibility, and may increase risk of urinary autoinoculation with antibiotic resistant microbes. However, little is known about relative prevalence of, or risk factors for, antimicrobial resistance among potentially pathogenic microbes thought to be contaminating and infecting urine. Methods: Secondary analysis of 824 children under 5 years of age consulting in primary care for an acute illness and their Escherichia coli isolates cultured at >=103 cfu/mL from the Diagnosis of Urinary Tract infection in Young children (DUTY) study. Multivariable logistic regression investigating risk factors for resistance to amoxicillin, co amoxiclav, cefalexin, ciprofloxacin, trimethoprim, nitrofurantoin and cefpodoxime in microbes meeting the laboratory criteria for urinary tract infection: 'pathogens' (>105 cfu/mL, n = 79) and 'contaminants' (103 to 105 cfu/mL, n = 745). Results: Forty-three percent of E. coli were resistant to at least one tested antibiotic, with resistance highest to amoxicillin (49.37% pathogenic versus 37.32% contaminant, P = 0.04), trimethoprim (27.85% versus 16.52%, P = 0.01) and co-amoxiclav (16.46% versus 21.48%, P = 0.30). Multidrug resistance (to >=3 antibiotic groups) was present in 17.07% of pathogens and 30.13% of contaminants (P = 0.04). No isolates were resistant to nitrofurantoin. Recent (0 3 months) exposure to antibiotics was associated with resistance in both pathogens (aOR: 1.10, 95% CI: 1.01-4.39) and contaminants (1.69, 1.09-2.67). Conclusions: Prevalence of resistance (including multidrug) was high, but there was no consistent relationship between isolate pathogen/contamination status and resistance. Recent all-cause antibiotic prescribing increased the probability of antimicrobial resistance in both pathogenic and contaminating urinary E. coli in children in primary care. PMID- 29385444 TI - Oral doxycycline versus intravenous ceftriaxone for treatment of multiple erythema migrans: an open-label alternate-treatment observational trial. AB - Background: Several guidelines advocate the same treatment approaches for both early disseminated Lyme borreliosis, manifested as multiple erythema migrans (EM), and early localized Lyme borreliosis, manifested as solitary EM. Methods: Oral doxycycline (100 mg q12h) was compared on a non-inferiority premise with intravenous ceftriaxone (2 g q24h) for 14 days in 200 adult European patients with multiple EM in an open-label alternate-treatment observational trial performed in a single-centre university hospital. Treatment outcome was assessed at 14 days and at 2, 6 and 12 months post-enrolment. Non-specific symptoms in patients and 192 control subjects without a history of Lyme borreliosis were evaluated and compared. This trial was registered at http://clinicaltrials.gov (identifier NCT01163994). Results: At the 12 month visit, 4/82 (4.9%) multiple EM patients prescribed doxycycline and 6/88 (6.8%) multiple EM patients prescribed ceftriaxone showed incomplete response manifested predominantly as post-Lyme symptoms (1.9% difference, upper limit of 95% CI 5.1%). The upper limit of 95% CI for the difference in proportion of patients with incomplete response between doxycycline and ceftriaxone groups did not exceed the predetermined non inferiority margin of 10%. The frequency of non-specific symptoms in patients was similar to that in controls. Conclusions: The 14 day oral doxycycline was not inferior to the 14 day intravenous ceftriaxone in treatment of adult European patients with early disseminated Lyme borreliosis manifested as multiple EM. The frequency of non-specific symptoms in patients was similar to that in controls without a history of Lyme borreliosis. PMID- 29385443 TI - A tri-serine cluster within the topoisomerase IIalpha-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells. AB - The recQ-like helicase BLM interacts directly with topoisomerase IIalpha to regulate chromosome breakage in human cells. We demonstrate that a phosphosite tri-serine cluster (S577/S579/S580) within the BLM topoisomerase IIalpha interaction region is required for this function. Enzymatic activities of BLM and topoisomerase IIalpha are reciprocally stimulated in vitro by ten-fold for topoisomerase IIalpha decatenation/relaxation activity and three-fold for BLM unwinding of forked DNA duplex substrates. A BLM transgene encoding alanine substitutions of the tri-serine cluster in BLM-/- transfected cells increases micronuclei, DNA double strand breaks and anaphase ultra-fine bridges (UFBs), and decreases cellular co-localization of BLM with topoisomerase IIalpha. In vitro, these substitutions significantly reduce the topoisomerase IIalpha-mediated stimulation of BLM unwinding of forked DNA duplexes. Substitution of the tri serine cluster with aspartic acids to mimic serine phosphorylation reverses these effects in vitro and in vivo. Our findings implicate the modification of this BLM tri-serine cluster in regulating chromosomal stability. PMID- 29385445 TI - Multiple Acquisitions of Pathogen-Derived Francisella Endosymbionts in Soft Ticks. AB - Bacterial endosymbionts of ticks are of interest due to their close evolutionary relationships with tick-vectored pathogens. For instance, whereas many ticks contain Francisella-like endosymbionts (FLEs), others transmit the mammalian pathogen Francisella tularensis. We recently sequenced the genome of an FLE present in the hard tick Amblyomma maculatum (FLE-Am) and showed that it likely evolved from a pathogenic ancestor. In order to expand our understanding of FLEs, in the current study we sequenced the genome of an FLE in the soft tick Ornithodoros moubata and compared it to the genomes of FLE-Am, Francisella persica-an FLE in the soft tick Argus (Persicargas) arboreus, Francisella sp. MA067296-a clinical isolate responsible for an opportunistic human infection, and F. tularensis, the established human pathogen. We determined that FLEs and MA067296 belonged to a sister taxon of mammalian pathogens, and contained inactivated versions of virulence genes present in F. tularensis, indicating that the most recent common ancestor shared by FLEs and F. tularensis was a potential mammalian pathogen. Our analyses also revealed that the two soft ticks (O. moubata and A. arboreus) probably acquired their FLEs separately, suggesting that the virulence attenuation observed in FLEs are not the consequence of a single acquisition event followed by speciation, but probably due to independent transitions of pathogenic francisellae into nonpathogenic FLEs within separate tick lineages. Additionally, we show that FLEs encode intact pathways for the production of several B vitamins and cofactors, denoting that they could function as nutrient-provisioning endosymbionts in ticks. PMID- 29385447 TI - Homeless for the First Time in Later Life: Uncovering More Than One Pathway. AB - Background and Objectives: Increasingly, researchers have recognized the heterogeneity with the growing population of older homeless adults. However, scant research has considered the complex pathways into first-time homelessness from the perspective of older adults themselves. Research Design and Methods: Through in-depth interviews, this constructivist grounded theory study aimed to address this gap by exploring the pathways of 15 adults, aged 50 years and older, into late-life homelessness. Results: Two divergent pathways were revealed: gradual and rapid. Individuals with gradual pathways endured many years of struggle related to poor housing conditions, lack of social support, and social distress. They had reached out for support on several occasions, with little success due to their limited social capital. In contrast, for individuals with rapid moves to homelessness, multiple unanticipated losses threatened their economic and social resources and they were propelled into homelessness with little warning. Despite having access to social networks to help buffer these losses, they preferred homelessness over asking for help and being perceived as dependent. Discussion and Implications: Our study revealed that different pathways into homelessness require divergent strategies of prevention and support. For individuals with gradual moves, strengthening pre-homeless social supports and addressing social distress may have mitigated the eventual loss of housing. For individuals with rapid pathways, homelessness may have been prevented if independence and self-sufficiency were less idealized in our society. PMID- 29385446 TI - A comparison of outcomes between Canada and the United States in patients recovering from hip fracture repair: secondary analysis of the FOCUS trial. AB - Objective: To determine if adjusted mortality, walking ability or return home differed after hip fracture surgery between Canada and the USA. Design: Secondary analysis of the Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial data. Setting: Data were collected from 47 American and Canadian hospitals. Participants: Overall, 2016 subjects with a hip fracture (USA = 1222 (60.6%); Canada = 794 (39.4%)) were randomized to a liberal or restrictive transfusion strategy. Subjects were 50 years and older, with cardiovascular disease and/or risk factors and hemoglobin <100 g/L within 3 days post-surgery. The average age was 82 years and 1527(76%) subjects were females. Intervention: Demographics, health status and health services data were collected up to 60 days post-surgery and mortality to a median of 3 years post surgery. Main outcomes: Mortality, inability to walk and return home. Results: US subjects had higher adjusted mortality than Canadians at 30 days (odds ratio = 1.78; 95% confidence interval: 1.09-2.90), 60 days (1.53; 1.02-2.29) and up to 3 years (hazard ratio = 1.25; 1.07-1.45). There were no differences in adjusted outcomes for walking ability or return home at 30 or 60 days post-surgery. Median hospital length of stay was longer (P < 0.0001) in Canada (9 days; interquartile range: 5-18 days) than the US (3 days; 2-5 days). US subjects (52.9%) were more likely than Canadians (16.8%) to be discharged to nursing homes for rehabilitation (P < 0.001). Conclusions: Adjusted survival favored Canadians post hip fracture while walking ability and return home were not different between countries. The reason(s) for mortality differences warrant further investigation. PMID- 29385448 TI - Comparison of piperacillin exposure in the lungs of critically ill patients and healthy volunteers. AB - Background: Severe infections of the respiratory tracts of critically ill patients are common and associated with excess morbidity and mortality. Piperacillin is commonly used to treat pulmonary infections in critically ill patients. Adequate antibiotic concentration in the epithelial lining fluid (ELF) of the lung is essential for successful treatment of pulmonary infection. Objectives: To compare piperacillin pharmacokinetics/pharmacodynamics in the serum and ELF of healthy volunteers and critically ill patients. Methods: Piperacillin concentrations in the serum and ELF of healthy volunteers and critically ill patients were compared using population methodologies. Results: Median piperacillin exposure was significantly higher in the serum and the ELF of critically ill patients compared with healthy volunteers. The IQR for serum piperacillin exposure in critically ill patients was six times greater than for healthy volunteers. The IQR for piperacillin exposure in the ELF of critically ill patients was four times greater than for healthy volunteers. The median pulmonary piperacillin penetration ratio was 0.31 in healthy volunteers and 0.54 in critically ill patients. Conclusions: Greater variability in serum and ELF piperacillin concentrations is observed in critically ill patients compared with healthy adult subjects and must be considered in the development of dosage regimens. Pulmonary penetration of antimicrobial agents should be studied in critically ill patients, as well as healthy volunteers, during drug development to ensure appropriate dosing of patients with pneumonia. PMID- 29385449 TI - Superior pulmonary arterial flap for the repair of the left coronary artery from the non-facing pulmonary sinus. AB - OBJECTIVES: The anomalous left coronary artery arising from the non-facing pulmonary sinus origin is uncommon but poses a great challenge as its distance precludes direct aortic implantation. We describe an innovative technique for aortic implantation of this anomaly in a 2-month-old infant. METHODS: Using a longitudinal pulmonary arterial flap, coronary tube extension was constructed without pulmonary commissure disturbance. RESULTS: Myocardial recovery after 2 coronary artery system restoration was excellent. CONCLUSIONS: With this approach, coronary transfer using autologous tissue with growth potential is possible. PMID- 29385450 TI - A Systematic Review of Research on Social Networks of Older Adults. AB - Background and Objectives: There has been a substantial interest in life course/life span changes in older adults' social networks and in the relationship between social networks and health and wellbeing. The study embarked on a systematic review to examine the existing knowledgebase on social network in the field of gerontology. Our focus was on studies in which both ego (respondents) and his or her alters (network members) are queried about their social ties. Research Design and Methods: We searched for studies published in English before September, 2017, relied on quantitative methods to obtain data from both ego (60 years of age and older) and alters and provided a quantitative account of the social network properties. We searched the following data sets: APA Psychnet, Pubmed, Sociological abstracts, and Ageline. This was followed by a snowball search of relevant articles using Google Scholar. Titles and abstracts were reviewed and selected articles were extracted independently by two reviewers. Results: A total of 5,519 records were retrieved. Of these, 3,994 records remained after the removal of duplicates. Ten records reporting on five original samples were kept for the systematic review. One study described a social network of community dwelling older adults and the remaining studies described social networks of institutional older adults. Discussion and Implications: The present study points to a lacuna in current understanding of social networks in the field of gerontology. It provides a useful review and possible tools for the design of future studies to address current shortcomings in the field. PMID- 29385451 TI - The development of quality indicators for home care in China. AB - Objectives: To develop a comprehensive system of quality indicators for home care in China. Design: A modified Delphi technique and analytic hierarchy process. Participants: Twenty experts were invited to participate in the Delphi expert consultation. Methods: Experts rated the perceived importance of 92 potential indicators through two rounds of e-mail surveys in November and December 2016. The analytic hierarchy process was used to determine the relative importance of the quality indicators identified through the Delphi expert consultation. Results: The average authoritative coefficient was 0.815 +/- 0.0432 (range: 0.75 0.90). After two rounds of Delphi expert consultation, 77 quality indicators were identified as important in the Chinese home care setting. The mean importance ratings ranged from 4.35 to 4.95 on a 5-point scale, with variation coefficients ranging from 0.04 to 0.15. The percentage of experts giving the maximum possible score on each item ranged from 45% to 95%. In the second round, the Kendall's W coefficients ranged from 0.363 to 0.570. As for relative importance, the weights were 0.198-0.490, 0.029-0.047 and 0.037-0.66 for first-level, secondary-level and third-level quality indicators, respectively, with all consistency ratio values less than 0.1. Conclusion: The absolute and relative importance of 77 indicators identified as potentially valid measures of the quality of Chinese home care was determined. This instrument is the first set of home care quality indicators developed specifically for mainland China, and it should be useful in evaluating and improving the quality of Chinese home care. PMID- 29385452 TI - Are Humor Styles of People With Dementia Linked to Greater Purpose in Life? AB - Objectives: Little is known about humor and purpose in life in people with dementia. Although having a sense of humor is typically associated with positive psychological outcomes, recent evidence suggests that outcomes may vary depending on whether the humor being used is adaptive versus maladaptive. The goal of this study was to determine whether humor styles are predictive of purpose in life in people with dementia. Methods: Questionnaires were verbally administered to people with mild-to-moderate dementia to measure humor styles and purpose in life. Results: Adaptive humor styles were associated with purpose in life whereas maladaptive humor styles were not. Discussion: Having a sense of humor in dementia may be associated with a stronger sense of purpose in life, but it depends on the type of humor used. Results are discussed in the context of understanding the role of humor in the daily lives of people with dementia and implications for care. PMID- 29385453 TI - Individual variation of natural D.melanogaster-associated bacterial communities. AB - Drosophila melanogaster has become an important model organism to study host microbe interaction in the laboratory. However, the natural microbial communities that are associated with D. melanogaster have received less attention. Especially, information on inter-individual variation is still lacking, because most studies so far have used pooled material from several flies. Here, we collected bacterial 16S rRNA gene community profiles from a set of 32 individuals from a single population. We simulated pools from the individual data (i) to assess how well the microbiome of a host population is represented by pools, and (ii) to compare variation of Drosophila microbiomes within and between populations. Taxon richness was increased in simulated pools, suggesting that pools paint a more comprehensive picture of the taxa associated with a host population. Furthermore, microbiome composition varied less between pools than between individuals, indicating that differences even out in pools. Variation in microbiome composition was larger between populations than between simulated pools from a single population, adding to the notion that there are population specific effects on the Drosophila microbiome. Surprisingly, samples from individuals clustered into two groups, suggesting that there are yet unknown factors that affect the composition of natural fly-associated microbial communities and need further research. PMID- 29385454 TI - Assessing functional status after intensive care unit stay: the Barthel Index and the Katz Index. AB - Objective: To assess the functional status of post-ICU patients using the Barthel Index (BI) and the Katz Index (KI) and to assess which is more suitable for this population. Design: Retrospective longitudinal study. Setting: Public tertiary hospital in Sao Paulo (Brazil). Participants: Patients aged >=18 years old, admitted to ICU, who were treated with mechanical ventilation (MV) >= 24 h and were discharged to ward. Exclusion criteria: Inability to answer the BI and the KI; limiting neurological or orthopaedic conditions; ICU stay >=90 days. Patients transferred to or from other hospitals or who died in the wards were not analysed. Intervention: BI and KI were scored pre-ICU and post-ICU and the variation was calculated. Main Outcome Measures: BI and KI scores were compared using analysis based on item response theory (IRT), using degree of difficulty and discriminating items as parameters. Results: Median age was 52 years old, median APACHE II score was 15. Median ICU stay was 11 days and median MV duration was 4 days. BI variation was 44% and KI variation was 55%. In IRT analysis, BI considered a larger number of items with different levels of difficulty. Conclusion: Both the BI and the KI revealed significant deterioration of functional status after ICU discharge. The IRT analysis suggested that the Barthel Index might be a better scale than the Katz Index for the assessment of functional status of patients discharged from ICU, since it presented better discrimination of the ability to carry out the tasks. PMID- 29385455 TI - The Intention to Discuss Advance Care Planning in the Context of Alzheimer's Disease Among Korean Americans. AB - Background and Objectives: Advance care planning (ACP) is crucial for quality end of-life care for patients with Alzheimer's disease. However, limited evidence is available about ACP among ethnic minorities, particularly in the context of Alzheimer's disease. The purpose of this study was to examine intention to discuss ACP for a family member with Alzheimer's disease among Korean Americans. Guided by the theory of planned behavior and prior research, we examined the relationships between acculturation, attitudes, subjective norms, perceived control, and intention to discuss ACP for a family member with Alzheimer's disease. Research Design and Methods: Path analyses were conducted on a cross sectional convenience sample of 261 Korean Americans. Age, gender, education, and knowledge about Alzheimer's disease and ACP were included as covariates. Results: Our descriptive findings showed positive attitudes, strong subjective norms, and a high level of perceived control toward ACP discussion among the participants. The path analyses revealed that attitudes and subjective norms were positively related to intention for ACP discussion. Perceived control was not related to intention for ACP discussion. Among the covariates, greater knowledge about Alzheimer's disease was the only factor shown to be associated with the intention for ACP discussion. Discussion and Implications: To promote ACP among this population, educational interventions designed to address positives attitudes and subjective norms toward ACP are suggested. PMID- 29385457 TI - Cross-sectional study of characteristics of clinical registries in Australia: a resource for clinicians and policy makers. AB - Objectives: To investigate the attributes of Australian clinical quality registries (CQR). Design and setting: Survey of 40 CQRs between September 2015 and April 2016. Participants: CQR lead investigators/project managers. Intervention: None. Main outcome measures: Registry organization, geographical coverage, data quality, management, characteristics, output and outcomes. Results: Of those who responded (34/40; 85.0%), 12 (34.3%) were binational (Australia and New Zealand); 22 (64.7%) were Australian-only registries; and 13 (38.2%) had national coverage. CQRs covered critical care, infection control, cardiovascular diseases, cancer, chronic diseases, procedures and devices, and transplants. Overall, 24/34 CQRs (70.6%) were public sector funded. In total, 14 (41.2%) scored >75% on a composite score developed to assess data quality. Overall, 29/34 (85.3%) produced an annual multi-centred report; only 15/34 (44.1%) produced provider-specific reports. Mortality/survival and quality of life were collected by 82.4 and 32.4% of CQRs, respectively. Most CQRs displayed data in bar/column charts (28/34, 82.4%) and funnel plots (17/34, 50%). Most CQRs adopted an opt-out consent process (n = 17/31; 54.8%). Linear regression indicated that longer duration of CQR was associated with higher data quality (>20 vs 0-5 years coefficient = 4.76, 95% CI: 0.26, 9.26). Opt-in consent was associated with lower data quality (no active consent vs opt-in approval method, coefficient = -5.22, 95% CI: -8.71, -1.72). Six CQRs self-reported having undertaken an economic evaluation of their registry. Conclusion: CQRs varied in geographical coverage; stage of development, approach to recruitment; method and frequency of reporting their output; and data quality assurance. An accreditation system for CQRs would likely assist in recognizing high-quality registries. PMID- 29385456 TI - Dietary supplements during the cold season increase rumen microbial abundance and improve rumen epithelium development in Tibetan sheep. AB - Livestock on the Qinghai-Tibetan Plateau are faced with extreme harsh winters and are often in negative energy balance during this period. Dietary supplementation can improve growth performance of Tibetan sheep and, consequently, we hypothesized that it would also increase microbial abundance and rumen epithelium development. To test this hypothesis, we examined the effect of feed supplementation during the cold season on rumen microbes, fermentation, epithelium development, and absorptive capability in Tibetan sheep. Eighteen 1-yr old ewes (BW = 29.4 +/- 1.79, kg) were offered oat hay ad libitum for 60 d and divided randomly into three groups: 1) no supplement; control group (CON); 2) urea-molasses lick block supplement (BS); and 3) concentrate feed supplement (CS). The ADG of CS ewes (143.3, g/d) was greater (P < 0.05) than BS ewes (87.9, g/d), which was greater (P < 0.05) than CON ewes (44.5, g/d). Serum concentrations of GH, IGF-1, and IGF-2 in the CS and BS groups were greater than in the CON group (P < 0.05). Greater relative abundance of protozoa, Ruminococcus albus, Fibrobacter succinogenes, Streptococcus bovis, and Ruminobacter amylophilus was observed in the CS and BS groups than in the CON group (P < 0.05), and relative abundances of rumen fungi, Butyrivibrio fibrisolvens, and Prevotella ruminicola in the CS group were greater than in the BS and CON groups (P < 0.05). Ruminal total VFA, ammonia, and microbial protein concentrations in the CS and BS groups were greater than in the CON group (P < 0.05), and in the CS group were greater than in the BS group (P < 0.05). Ruminal papillae width and surface area in the CS and BS groups were greater than in the CON group (P < 0.05), while in the CS group were greater than in the BS group (P < 0.05). The mRNA expressions of IGFBP5, NHE1 (sodium/hydrogen antiporter, isoform 1), DRA (downregulated in adenoma), and Na+/K+-ATPase (sodium/potassium ATPase pump) in ruminal epithelium were greater in the CS and BS groups than in the CON group (P < 0.05), and in the CS group was greater than in the BS group (P < 0.05), while NHE3 (sodium/hydrogen antiporter, isoform 3), MCT1 (monocarboxylate transporter 1), and MCT4 (monocarboxylate transporter 4) mRNA expressions in the CS group were greater than in the BS and CON groups (P < 0.05). It was concluded that supplementing Tibetan sheep during the cold season increases rumen microbial abundance and improves fermentation parameters, rumen epithelium development, and absorptive capability. PMID- 29385458 TI - Nutritive value of multienzyme supplemented cold-pressed camelina cake for pigs. AB - Cold-pressed camelina cake (CPCC) is a fibrous co-product of camelina seed pressing and available for livestock feeding. However, information is lacking on the effect of supplementing fiber-degrading enzymes to CPCC-based diets on nutrient utilization by pigs. Experiment 1 determined the effect of multienzyme supplementation on standardized ileal digestibility (SID) of amino acid (AA) and net energy (NE) value of CPCC for pigs. Six ileal-cannulated barrows (average initial body weight [BW] = 36 kg) were fed five diets in 5 * 5 Latin square design with 1 added column to give six replicates per diet. The diets were a corn soybean meal (SBM)-soybean oil-based diet and the basal diet with corn, SBM, and soybean oil replaced by 25% CPCC with or without multienzyme (600 U of xylanase, 75 U of glucanase, 250 U of cellulose, 30 U of mannanase, 350 U of invertase, 2,500 U of protease, and 6,000 U of amylase/kg of diet; Superzyme-CS, 0.5 g/kg) in a 2 * 2 factorial arrangement. The fifth diet was a low-casein cornstarch based diet. The ratio of corn to SBM and soybean oil in the basal diet was identical to the CCPC-containing diets to allow calculation of nutrient digestibility of CPCC by the difference method. On a dry matter (DM) basis, CPCC contained 42% crude protein, 10.5% ether extract, 25.4% neutral detergent fiber (NDF), 2.07% Lys, 0.73% Met, 1.64% Thr, 0.51% Trp, and 22.1 trypsin inhibitor units per milligram, respectively. The SID of Lys, Met, Thr, and Trp for CPCC were 43.5%, 70.7%, 44.8%, and 55.3%, respectively. The digestible energy (DE) and NE values for CPCC were 3,663 and 2,209 kcal/kg of DM, respectively. Multienzyme supplementation did not affect the SID of AA, and DE and NE values for the corn SBM-CPCC-based diet, and for the CPCC. In experiment 2, the effects of multienzyme dosage (0.5 or 50 g/kg of treated feedstuff) on porcine in vitro digestibility of DM (IVDDM) of CPCC was determined. The IVDDM of CPCC was increased (P < 0.001) with an increase in multienzyme dosage. Multienzyme at 0.5 g/kg did not affect IVDDM of CPCC. However, multienzyme at 50 g/kg increased (P < 0.01) IVDDM for CPCC by at least 16%. In conclusion, multienzyme at 0.5 g/kg did not affect SID of AA and NE values, and IVDDM for CPCC. However, multienzyme at 50 g/kg improved IVDDM of CPCC, implying that the efficacy of the multienzyme with regard to improving nutrient digestibility of CPCC in pigs is dosage dependent. PMID- 29385459 TI - Influence of differently processed yeast (Kluyveromyces fragilis) on feed intake and gut physiology in weaned pigs. AB - Two feeding trials were conducted to investigate the effects of hydrolyzed (HY) or non-hydrolyzed (NHY) yeast (Kluyveromyces fragilis) in isoenergetic and isonitrogeneous diets in the postweaning period. In experiment 1, a total of 550 unsexed pigs (6.5 +/- 0.5 kg BW), weaned at 24 +/- 2 d of age, were allocated to five treatment groups, receiving either a control diet (CON) or diets with 1%, 3%, and 5% HY (groups HY1, HY3, and HY5, respectively), or a diet with 3% NHY (group NHY3). In experiment 2, a total of 48 male and female pigs (6.2 +/- 0.3 kg BW, weaned at d 25) were allocated to three dietary groups (n = 8 replicates with two pigs) receiving a control diet (CON) or diets with 1% NHY or 1% HY. Eight animals were sacrificed 2 wk after weaning for histological investigations in the jejunum and colon, determination of apparent ileal digestibility (AID) of CP and ether extract (EE), and electrophysiological measurements in the jejunal tissue after addition of carbachol or l-glutamine using Ussing chambers. In experiment 1, different treatments had no significant effect on pig performance, but diet HY1 tended to increase ADG and G:F in wk 2 after weaning (P < 0.1). In experiment 2, diet HY1 increased feed intake in wk 2 (P < 0.05), whereas NHY yeast had no effect on feed intake. Villus height, villus/crypt ratio in jejunum (P < 0.05), and crypt depth in colon (P < 0.01) were increased in group HY1. Crypt depth in jejunum and small intestinal length were not affected by different treatments. The AID of CP and EE tended to increase in group HY1 (P < 0.1) compared with groups CON and NHY. In the Ussing chamber experiments, no changes in basal electrophysiological parameters were observed, and the reactions of the treatment groups to carbachol and l-glutamine were comparable. ADFI was positively correlated with different parameters of intestinal morphology (villus height, villus/crypt ratio, crypt depth in colon, length of small intestine), AID of CP, EE, and performance. The results suggest that a supplementation of 1% HY based on K. fragilis to pig diets may positively influence ADFI and intestinal morphology in pig in the early postweaning period (d 1 to 14). PMID- 29385460 TI - Weighting genomic and genealogical information for genetic parameter estimation and breeding value prediction in tropical beef cattle. AB - A combined matrix that exploits genealogy together with marker-based information could improve the selection of elite individuals in breeding programs. We present genetic parameters for adaptive and growth traits in beef cattle by exploring linear combinations of pedigree-based (A) and marker-based (G) relationship matrices. We use a data set with 2,111 Brahman (BB) and 2,550 Tropical Composite (TC) cattle with genotypes for 729,068 SNP, and phenotypes for five traits. A weighted relationship matrix (WRM) combining G and A was constructed as WRM = lambdaG + (1 - lambda)A. The weight (lambda) was explored at values from 0.0 to 1.0, at 0.1 intervals. Additionally, four alternative G matrices, in the WRM, were evaluated according to the selection of SNP used to generate them: 1) Gw: all autosomal SNP with minor allele frequency (MAF) > 1%; 2) Gg: autosomal SNP with MAF > 1% and mapped inside to gene coding regions; 3) Gp: autosomal SNP with MAF > 1% and previously reported to have significant pleiotropic effect in these two populations; and 4) Gc: autosomal SNP with MAF > 1% and with significant correlated effects previously reported in both BB and TC populations. In addition, two A matrices were evaluated: 1) A: all relationships between animals were considered after tracing back known ancestors; and 2) Ad: a distorted A matrix where a random 1% of the off-diagonal nonzero values were set to zero to simulate relationship errors. Five independent Ad matrices were explored each with a different random 1% of relationships masked. Criteria for comparing the resulting WRM included estimates of heritability (h2) and cross-validation accuracy (ACC) of genomic estimated breeding values. The choice of WRM had a greater impact on h2 than on ACC estimates. The 1% errors introduced in pedigree relationships generated large distortion in genetic parameters and ACC estimates. However, employing a lambda > 0.7 was an efficient mechanism to compensate for the errors in A. Additionally, although significant (P-value < 0.0001), we found no consistent relationship between the type of SNP used to compute G and h2 or ACC estimates. We devised the optimal value of lambda for maximum h2 and ACC at lambda = 0.7 suggesting a 70% and 30% weighting to genomic and genealogical information, respectively, as an optimal strategy to compensate for pedigree errors, to improve genetic parameters estimates and lead to more accurate selection decisions. PMID- 29385461 TI - Using statistical process control methods to trace small changes in perinatal mortality after a training program in a low-resource setting. AB - Objective: To trace and document smaller changes in perinatal survival over time. Design: Prospective observational study, with retrospective analysis. Setting: Labor ward and operating theater at Haydom Lutheran Hospital in rural north central Tanzania. Participants: All women giving birth and birth attendants. Intervention: Helping Babies Breathe (HBB) simulation training on newborn care and resuscitation and some other efforts to improve perinatal outcome. Main outcome measure: Perinatal survival, including fresh stillbirths and early (24-h) newborn survival. Result: The variable life-adjusted plot and cumulative sum chart revealed a steady improvement in survival over time, after the baseline period. There were some variations throughout the study period, and some of these could be linked to different interventions and events. Conclusion: To our knowledge, this is the first time statistical process control methods have been used to document changes in perinatal mortality over time in a rural Sub-Saharan hospital, showing a steady increase in survival. These methods can be utilized to continuously monitor and describe changes in patient outcomes. PMID- 29385462 TI - Giardia secretome highlights secreted tenascins as a key component of pathogenesis. AB - Background: Giardia is a protozoan parasite of public health relevance that causes gastroenteritis in a wide range of hosts. Two genetically distinct lineages (assemblages A and B) are responsible for the human disease. Although it is clear that differences in virulence occur, the pathogenesis and virulence of Giardia remain poorly understood. Results: The genome of Giardia is believed to contain open reading frames that could encode as many as 6000 proteins. By successfully applying quantitative proteomic analyses to the whole parasite and to the supernatants derived from parasite culture of assemblages A and B, we confirm expression of ~1600 proteins from each assemblage, the vast majority of which are common to both lineages. To look for signature enrichment of secreted proteins, we considered the ratio of proteins in the supernatant compared with the pellet, which defined a small group of enriched proteins, putatively secreted at a steady state by cultured growing trophozoites of both assemblages. This secretome is enriched with proteins annotated to have N-terminal signal peptide. The most abundant secreted proteins include known virulence factors such as cathepsin B cysteine proteases and members of a Giardia superfamily of cysteine rich proteins that comprise variant surface proteins, high-cysteine membrane proteins, and a new class of virulence factors, the Giardia tenascins. We demonstrate that physiological function of human enteric epithelial cells is disrupted by such soluble factors even in the absence of the trophozoites. Conclusions: We are able to propose a straightforward model of Giardia pathogenesis incorporating key roles for the major Giardia-derived soluble mediators. PMID- 29385463 TI - Effects of spray-dried porcine plasma on fecal microbiota in nursery pigs. AB - Spray-dried porcine plasma (SDPP) has been considered as an alternative for in feed antibiotics to improve pig growth performance; however, the effect of SDPP on gut microbiota is unknown. The objective of this study was to evaluate effects of feeding SDPP on fecal microbial communities of nursery pigs. Ninety-six weaned pigs were assigned to 16 pens, which were allotted to two dietary treatments, including the control or the control + SDPP (5% and 2.5% SDPP inclusion in phase 1 and 2, respectively) diet. Fecal samples were collected at d 0, 7, 14, 21, and 28. Multiplex sequencing of V3 region of the 16S rRNA gene was used to characterize the bacterial community structure of fecal samples. Pearson's correlation tests were performed in Calypso to identify bacterial taxa that were either positively or negatively associated with overall growth performance. Feeding SDPP altered microbial structure at family, genus, and operational taxonomic unit (OTU) classifications; however, fecal microbes shifted with time. At the family level, Clostridiaceae increased (P < 0.001) on d 14, but decreased (P < 0.05) on d 28 in SDPP-fed pigs compared with control pigs. Decreased Veillonellaceae (P < 0.05; d 14) and Lachnospiraceae (P = 0.001; overall) were observed in SDPP-fed pigs compared with control pigs. Feeding SDPP increased lactic acid-producing bacteria (Lactobacillus delbrueckii, d 7) and cellulolytic bacteria (Ruminococcus albus, d 7; Clostridium thermocellum, d 7 and 14; and Clostridium saccharoperbutylacetonicum/beijerinckii, d 14; and Megasphaera elsdenii, d 21). On d 28, feeding SDPP decreased (P < 0.05) Clostridium difficile compared with control pigs. In conclusion, feeding SDPP altered fecal microbial communities in nursery pigs. The results of this study may provide information to help explain the positive effects associated with feeding SDPP on nutrient digestibility and gut health of nursery pigs. PMID- 29385464 TI - Influence of feeding thermally peroxidized soybean oil on oxidative status in growing pigs. AB - The objectives of this study were to determine whether feeding thermally processed peroxidized soybean oil (SO) induces markers of oxidative stress and alters antioxidant status in pig tissue, blood, and urine. Fifty-six barrows (25.3 +/- 3.3 kg initial BW) were randomly assigned to dietary treatments containing 10% fresh SO (22.5 degrees C) or thermally processed SO (45 degrees C for 288 h, 90 degrees C for 72 h, or 180 degrees C for 6 h), each with constant air infusion rate of 15 liters/minute. Multiple indices of lipid peroxidation were measured in the SO including peroxide value (2.0, 96, 145, and 4.0 mEq/kg for 22.5, 45, 90, and 180 degrees C processed SO, respectively) and p anisidine value (1.2, 8.4, 261, and 174 for 22.5, 45, 90, and 180 degrees C processed SO, respectively); along with a multitude of aldehydes. Pigs were individually housed and fed ad libitum for 49 d which included a 5 d period in metabolism crates for the collection of urine and serum for measures of oxidative stress. On day 49, pigs were euthanized to determine liver weight and analyze liver-based oxidative stress markers. Oxidative stress markers included serum, urinary, and liver thiobarbituric acid reactive substances (TBARS), and urinary F2-isoprostanes (ISP) as markers of lipid damage; serum and liver protein carbonyls (PC) as a marker of protein damage; and urinary and liver 8-hydroxy-2' deoxyguanosine (8-OH-2dG) as a marker of DNA damage. Superoxide dismutase (SOD), and catalase activity (CAT) were measured in liver, glutathione peroxidase activity (GPx) was measured in serum and liver, and ferric reducing antioxidant power (FRAP) was measured in serum and urine as determinants of antioxidant status. Pigs fed 90 degrees C SO had greater urinary ISP (P = 0.02), while pigs fed the 45 degrees C SO had elevated urinary TBARS (P = 0.02) in comparison to other treatment groups. Pigs fed 45 degrees C and 90 degrees C SO had increased serum PC concentrations (P = 0.01) and pigs fed 90 degrees C SO had greater (P = 0.01) liver concentration of 8-OH-2dG compared to pigs fed the other SO treatments. Furthermore, pigs fed 90 degrees C SO had reduced serum GPx activity in comparison to pigs fed fresh SO (P = 0.01). In addition, pigs fed 180 degrees C SO had increased liver CAT activity (P = 0.01). Liver GPx and SOD or serum and urinary FRAP were not affected by dietary treatment. These results indicate that dietary peroxidized soybean oil induced oxidative stress by increasing serum PC while diminishing serum GPx, increasing urinary ISP and TBARS, and increasing 8 OH-2dG and CAT in liver. PMID- 29385465 TI - Characterization of plasma metabolites at late gestation and lactation in early parity sows on production and post-weaning reproductive performance. AB - Lactation is a very energy demanding period for sows. The current study provides a better understanding of the biochemical response of first- (n = 246) or second parity (n = 127) sows during late gestation through lactation and assesses relationships with piglet production and dam reproductive performance. Plasma samples were collected from first- or second-parity dams at late gestation (110 d gestation [d110G]), d 1 post-farrowing (d1PF), and weaning (WN) then analyzed for various stress and protein metabolism compounds, including; creatine, creatine phosphokinase (CPK) activity, creatinine, urea nitrogen, albumin, and lactate. Litter performance was measured as number of piglets nursed and piglet ADG. Post weaning reproductive performance was assessed by measuring weaning-to-estrus interval (WEI) and subsequent ovulation rate collected at time of harvest. Plasma creatine and CPK activity increased (P < 0.05) between d110G and d1PF. Plasma creatinine decreased (P < 0.05) from d110G through WN in first-parity dams, but remained similar between d110G and d1PF before declining (P < 0.05) at WN in second-parity dams. Plasma urea nitrogen increased (P < 0.05) over the course of the study and was negatively (P < 0.05) associated with piglet ADG at d110G and d1PF and with ovulation rate at d110G (P < 0.05). Similarly, plasma albumin increased (P < 0.05) in first-parity dams over the course of the study, whereas it plateaued (P < 0.05) at d1PF and remained similar (P > 0.10) through WN in second-parity dams. First-parity dams had less (P < 0.05) plasma lactate at d110G than at d1PF or WN. However, second-parity dams had increased (P < 0.05) plasma lactate at d110G and d1PF, then decreased (P < 0.05) levels at WN. Plasma lactate at WN was positively (P < 0.05) associated with WEI in first-parity dams, but negatively (P < 0.05) related to WEI at d1PF in second-parity dams. Plasma lactate levels at all time points were positively (P < 0.05) associated with ovulation rate in second-parity dams. The biochemical profile of these dams differed by parity and merits further investigations into these differences to identify methods to improve physiological response to lactation for improved animal welfare, production, and reproductive performance. PMID- 29385467 TI - Nutritional evaluation and ruminal fermentation patterns of kochia compared with alfalfa and orchardgrass hays and ephedra and cheatgrass compared with orchardgrass hay as alternative arid-land forages for beef cattle in two dual flow continuous culture system experiments. AB - The objective was to evaluate the ruminal fermentation patterns of forage kochia (FK) compared with alfalfa hay (AH) and orchardgrass hay (OH) (Exp. 1), and ephedra (EPH) and immature cheatgrass (CG) compared with OH (Exp. 2), using a dual-flow continuous culture system. Two in vitro experiments were conducted, and in each experiment, treatments were randomly assigned to six dual-flow fermenters (1,223 +/- 21 mL) in a replicated 3 * 3 Latin square design, with three consecutive periods of 10 d each, consisting of 7 d for diet adaptation and 3 d for sample collection. Each fermenter was fed a total of 72 g/d (DM basis) and treatments were as follows: Exp. 1: 1) 100% OH, 2) 100% AH, and 3) 100% dried FK. Exp. 2: 1) 100% OH, 2) 100% dried CG, and 3) 100% dried EPH. On day 8, 9, and 10, samples of solid and liquid effluent from each fermenter were taken for digestibility analysis, and subsamples were collected for NH3-N, VFA, and bacterial N determinations. Data were analyzed using the MIXED procedure of SAS. In Exp. 1, treatments did not affect DM, OM, and NDF digestibilities, total VFA and molar proportions of acetate, propionate, butyrate, and branched-chain VFA. True CP digestibility, ruminal NH3-N concentration, and total N, NH3-N, NAN, and dietary N flows (g/d) were greater (P < 0.05) for FK compared with the other forages. However, treatments did not affect bacterial efficiency. In Exp. 2, DM, OM, and CP digestibilities were greater (P = 0.01) for EPH, and NDF digestibility was greater (P < 0.05) for EPH and CG compared with OH. Ephedra had the highest (P < 0.05) pH and acetate:propionate ratio and the lowest (P < 0.05) total VFA concentration. Total VFA, ruminal NH3-N concentration, and NH3-N flow (g/d) were highest (P < 0.05) for CG. Total N flow and bacterial efficiency were highest (P < 0.05) for OH and CG, while the flows (g/d) of NAN, bacterial N, and dietary N were greater (P < 0.05) for OH compared with the other forages. Results indicate that when compared with AH and OH (Exp. 1), FK has similar ruminal fermentation patterns and may be an adequate alternative for beef cattle producers. Furthermore, when compared with OH (Exp. 2), immature CG may also be an adequate forage alternative. This is especially important for areas in which conventional forages may not grow well such as the U.S. arid-land. However, EPH should not be used as the sole forage due to its poor ruminal fermentation as evidenced by the lowest total VFA concentration and propionate molar proportion. PMID- 29385466 TI - RUMINANT NUTRITION SYMPOSIUM: Effects of postruminal flows of protein and amino acids on small intestinal starch digestion in beef cattle. AB - Many nutritionists adopt feeding strategies designed to increase ruminal starch fermentation because ruminal capacity for starch degradation often exceeds amounts of starch able to be digested in the small intestine of cattle. However, increases in fermentable energy supply are positively correlated with increased instances of metabolic disorders and reductions in DMI, and energy derived by cattle subsequent to fermentation is less than that derived when glucose is intestinally absorbed. Small intestinal starch digestion (SISD) appears to be limited by alpha-glycohydrolase secretions and a precise understanding of digestion of carbohydrates in the small intestine remains equivocal. Interestingly, small intestinal alpha-glycohydrolase secretions are responsive to luminal appearance of milk-specific protein (i.e., casein) in the small intestine of cattle, and SISD is increased by greater postruminal flows of individual AA (i.e., Glu). Greater flows of casein and Glu appear to augment SISD, but by apparently different mechanisms. Greater small intestinal absorption of glucose has been associated with increased omental fat accretion even though SISD can increase NE from starch by more than 42% compared to ruminal starch degradation. Nonetheless, in vitro data suggest that greater glucogenicity of diets can allow for greater intramuscular fat accretion, and if greater small intestinal absorption of glucose does not mitigate hepatic gluconeogenesis then increases in SISD may provide opportunity to increase synthesis of intramuscular fat. If duodenal metabolizable AA flow can be altered to allow for improved SISD in cattle, then diet modification may allow for large improvements in feed efficiency and beef quality. Few data are available on direct effects of increases in SISD in response to greater casein or metabolizable Glu flow. An improved understanding of effects of increased SISD in response to greater postruminal flow of Glu and casein on improvements in NE and fates of luminally assimilated glucose could allow for increased efficiency of energy use from corn and improvements in conversion of corn grain to beef. New knowledge related to effects of greater postruminal flow of Glu and casein on starch utilization by cattle will allow nutritionists to more correctly match dietary nutrients to cattle requirements, thereby allowing large improvements in nutrient utilization and efficiency of gain among cattle fed starch-based diets. PMID- 29385468 TI - The history of adipocyte and adipose tissue research in meat animals. AB - Research in growth and development, accumulation of lean, and fat metabolism in farm animals was gaining attention principally from a carcass perspective by meat scientists and animal nutritionists about a century ago. Under the auspices of the USDA Cooperative State Research Service, State Agricultural Experiment Stations, and the Land Grant University system, researchers from various universities embarked on forming combined regional research projects (across states) with unifying specific aims. In the North Central region, this included states in the upper and lower Mid-West region. For those interested in improving production and eating quality of meats, initially a single multistate committee was formed in the North Central region which was active for many years. However, these efforts were later split into two committees with one addressing lipids and the other muscle biology. Herein we reviewed research of workers in the North Central region in the 1940s and 1950s and to a limited extent in the 2000s on meat animal's lipid metabolism. We further reviewed the history of meat animal carcass composition research and the influence of the Word War II (WWII) period on porcine carcass composition. The development and utilization of adipocyte cellularity research methodology in meat animals was demonstrated. The history of the progression of adipose tissue metabolism research in meat animals was also reviewed. Finally, the history of research on lipid deposition in muscle that ultimately precipitated the expanded marbling and the intramuscular research was delineated. By the 1970s, great interest had emerged on how to curtail excessive fat deposition in meat-producing animals. Thus, for some segments of the animal lipid metabolism community, the focus then shifted to exploring the processes of lipogenesis and lipolysis in farm animals. These efforts morphed into research efforts in fat cell biology and cellularity. Today adipocyte biology is studied by many in the biomedical and agricultural-life sciences communities. In this article, we present a history of this research and notable achievements up to the 1980s. Herein we revisit these research efforts and results that have become an important knowledge base for growth and development, nutrition, and meat science research. PMID- 29385469 TI - Anti-TNF Therapeutic Drug Monitoring in Postoperative Crohn's Disease. AB - Background: Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. Methods: As part of a study of postoperative Crohn's disease management, some patients undergoing resection received prophylactic postoperative adalimumab. In these patients, serum and fecal adalimumab concentration and serum anti-adalimumab antibodies [AAAs] were measured at 6, 12 and 18 months postoperatively. Levels of Crohn's disease activity index [CDAI], C-reactive protein [CRP] and fecal calprotectin [FC] were assessed at 6 and 18 months postoperatively. Body mass index and smoking status were recorded. A colonoscopy was performed at 6 and/or 18 months. Results: Fifty-two patients [32 on monotherapy and 20 on combination therapy with thiopurine] were studied. Adalimumab concentration did not differ significantly between patients in endoscopic remission vs recurrence [Rutgeerts >= i2] [9.98ug/mL vs 8.43 ug/mL, p = 0.387]. Patients on adalimumab monotherapy had a significantly lower adalimumab concentration [7.89 ug/mL] than patients on combination therapy [11.725 ug/mL] [p = 0.001], and were significantly more likely to have measurable AAA [31% vs 17%, p = 0.001]. Adalimumab concentrations were lower in patients with detectable AAA compared with those without [3.59 ug/mL vs 12.0 ug/mL, p < 0.001]. Adalimumab was not detected in fecal samples. Adalimumab serum concentrations were lower in obese patients compared with in non obese patients [p = 0.046]. Conclusion: Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients. PMID- 29385470 TI - Evaluation of conjugated linoleic acid supplementation on markers of joint inflammation and cartilage metabolism in young horses challenged with lipopolysaccharide. AB - Seventeen yearling Quarter Horses were used in a randomized complete block design for a 56-d trial to determine ability of dietary CLA to mitigate joint inflammation and alter cartilage turnover following an inflammatory insult. Horses were blocked by age, sex, and BW, and randomly assigned to dietary treatments consisting of commercial concentrate offered at 1% BW (as-fed) supplemented with either 1% soybean oil (CON; n = 6), 0.5% soybean oil and 0.5% CLA (LOW; n = 5; 55% purity; Lutalin, BASF Corp., Florham Park, NJ), or 1% CLA (HIGH; n = 6) top-dressed daily. Horses were fed individually every 12 h and offered 1% BW (as-fed) coastal bermudagrass (Cynodon dactylon) hay daily. This study was performed in 2 phases: phase I (d 0 to d 41) determined incorporation of CLA into plasma and synovial fluid; phase II (d 42 to d 56) evaluated potential of CLA to mitigate intra-articular inflammation and alter cartilage metabolism. Blood and synovial fluid were collected at 7- and 14-d intervals, respectively, to determine fatty acid concentrations. On d 42, carpal joints within each horse were randomly assigned to receive intra-articular injections of 0.5 ng lipopolysaccharide (LPS) derived from Escherichia coli 055:B5 or sterile lactated Ringer's solution. Synovial fluid samples were obtained at preinjection h 0 and 6, 12, 24, 168, and 336 h postinjection, and analyzed for prostaglandin E2 (PGE2), carboxypeptide of type II collagen (CPII), and collagenase cleavage neopeptide (C2C). Data were analyzed using PROC MIXED procedure of SAS. Horses receiving the CON diet had undetectable levels of CLA for the duration of the study. A quadratic dose response was observed in concentrations of CLA in plasma and synovial fluid (P < 0.01). A negative quadratic dose response was observed for plasma arachidonic acid (20:4) with a reduction in concentration to d 14 in HIGH horses (P = 0.04). Synovial fluid 20:4 tended to decrease in horses receiving the HIGH diet (P = 0.06). Post LPS injection, synovial PGE2 was not affected by dietary treatment (P = 0.15). Synovial C2C was lower in HIGH horses (P = 0.05), and synovial CPII tended to be greater in LOW horses than HIGH and CON horses (P = 0.10). In conclusion, dietary CLA incorporated into plasma and synovial fluid prior to LPS challenge. Dietary CLA did not influence inflammation; however, there was a reduction in cartilage degradation and an increase in cartilage regeneration. PMID- 29385471 TI - Forms of selenium in vitamin-mineral mixes differentially affect serum prolactin concentration and hepatic glutamine synthetase activity of steers grazing endophyte-infected tall fescue. AB - The goal of this study was to test the hypothesis that sodium selenite (ISe), SEL PLEX (OSe), vs. an 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral (VM) mix would differentially affect metabolic parameters and performance of growing steers grazing toxic endophyte-infected tall fescue mixed forage (E+) pasture. Predominately-Angus steers (BW = 183 +/- 34 kg) were randomly selected from herds of fall-calving cows grazing E+ pasture and consuming VM mixes that contained 35 ppm Se as ISe, OSe, and MIX forms. Steers were weaned, depleted of Se for 98 d, and subjected to summer-long common grazing of an E+ pasture (0.51 ppm total ergovaline per ergovalinine; 10.1 ha). Steers were assigned (n = 8 per treatment) to the same Se-form treatments upon which they were raised. Selenium treatments were administered by daily top-dressing 85 g of VM mix onto 0.23 kg soyhulls, using in-pasture Calan gates. The PROC MIXED procedure of SAS was used to assess effect of Se-form treatments on whole blood Se (ng/mL) and serum prolactin (ng/mL) at day 0, 22, 43, 64, and 86, and caudal arterial area (mm2) at day -7, 43, and 86. The effect of Se treatment on ADG (day 86), and liver glutamine synthetase (GS) mRNA, protein, and activity (nmol/mg wet tissue/min) were assessed using the PROC GLM procedure of SAS. Fisher's protected LSD procedure was used to separate treatment means. Whole blood Se increased (P < 0.01) for all treatments from day 0 to 22 and then did not change (P >= 0.17), and was greater (P <= 0.04) for MIX and OSe steers. Serum prolactin decreased (P < 0.01) over time and was greater (P < 0.05) for MIX and OSe steers. Liver GS mRNA content was 66% and 59% greater (P < 0.05) in MIX and OSe steers, respectively, than ISe steers. Liver GS protein content in MIX steers was 94% more (P < 0.01) than ISe steers. Moreover, MIX and OSe steers had 99% and 55% more (P <= 0.01) liver GS activity, respectively, than ISe steers. ADG was not affected (P = 0.36) by Se treatments. We conclude that consumption of 3 mg Se/d as OSe or MIX forms of Se in VM mixes increased 1) whole blood Se content, an indicator of greater whole body Se assimilation; 2) serum prolactin, the reduction of which is a hallmark of fescue toxicosis; and 3) hepatic GS activity, indicating greater hepatic assimilation of acinar ammonia. However, 4) these positive effects on metabolic parameters were not accompanied by increased growth performance. PMID- 29385472 TI - Application of transmission infrared spectroscopy and partial least squares regression to predict immunoglobulin G concentration in dairy and beef cow colostrum. AB - The objective of this study was to explore the potential of transmission infrared (TIR) spectroscopy in combination with partial least squares regression (PLSR) for quantification of dairy and beef cow colostral immunoglobulin G (IgG) concentration and assessment of colostrum quality. A total of 430 colostrum samples were collected from dairy (n = 235) and beef (n = 195) cows and tested by a radial immunodiffusion (RID) assay and TIR spectroscopy. Colostral IgG concentrations obtained by the RID assay were linked to the preprocessed spectra and divided into combined and prediction data sets. Three PLSR calibration models were built: one for the dairy cow colostrum only, the second for beef cow colostrum only, and the third for the merged dairy and beef cow colostrum. The predictive performance of each model was evaluated separately using the independent prediction data set. The Pearson correlation coefficients between IgG concentrations as determined by the TIR-based assay and the RID assay were 0.84 for dairy cow colostrum, 0.88 for beef cow colostrum, and 0.92 for the merged set of dairy and beef cow colostrum. The average of the differences between colostral IgG concentrations obtained by the RID- and TIR-based assays were -3.5, 2.7, and 1.4 g/L for dairy, beef, and merged colostrum samples, respectively. Further, the average relative error of the colostral IgG predicted by the TIR spectroscopy from the RID assay was 5% for dairy cow, 1.2% for beef cow, and 0.8% for the merged data set. The average intra-assay CV% of the IgG concentration predicted by the TIR-based method were 3.2%, 2.5%, and 6.9% for dairy cow, beef cow, and merged data set, respectively.The utility of TIR method for assessment of colostrum quality was evaluated using the entire data set and showed that TIR spectroscopy accurately identified the quality status of 91% of dairy cow colostrum, 95% of beef cow colostrum, and 89% and 93% of the merged dairy and beef cow colostrum samples, respectively. The results showed that TIR spectroscopy demonstrates potential as a simple, rapid, and cost-efficient method for use as an estimate of IgG concentration in dairy and beef cow colostrum samples and assessment of colostrum quality. The results also showed that merging the dairy and beef cow colostrum sample data sets improved the predictive ability of the TIR spectroscopy. PMID- 29385473 TI - Effect of ruminal acidosis and short-term low feed intake on indicators of gastrointestinal barrier function in Holstein steers. AB - The objective of this study was to determine effect of ruminal acidosis (RA) and low feed intake [LFI] on the regional barrier function of the gastrointestinal tract. Twenty-one Holstein steers were fed for ad libitum intake for 5 d (control [CON]), fed at 25% of ad libitum intake for 5 d (LFI), or provided 2 d of ad libitum intake followed by 1-d of feed restriction (25% of ad libitum intake), 1 d where 30% of ad libitum dry matter intake (DMI) was provided as pelleted barley followed by the full allocation (RA) and fed for ad libitum intake the following day. Tissues and digesta from the rumen, omasum, duodenum, jejunum, ileum, cecum, proximal, and distal colon were collected. Permeability was assessed using the mucosal-to-serosal flux of inulin (JMS-inulin) and mannitol (JMS-mannitol). Digesta pH was 0.81, 0.63, and 0.42 pH units less for RA than CON in the rumen, cecum, and proximal colon; while, LFI had pH that was 0.47 and 0.36 pH units greater in the rumen and proximal colon compared to CON. Total ruminal short chain fatty acid (SCFA) concentration were less for LFI (92 mM; P = 0.010) and RA (87 mM; P = 0.007) than CON (172 mM) steers. In the proximal colon, the proportion of butyrate (P = 0.025 and P = 0.022) and isobutyrate (P = 0.019 and P = 0.019) were greater, and acetate (P = 0.028 and P = 0.028) was less for LFI and RA, respectively, when compared to CON steers. Ruminal papillae length, width, perimeter, and surface area were 1.21 mm, 0.78 mm, 3.84 mm, and 11.15 mm2 less for LFI than CON; while, RA decreased papillae width by 0.52 mm relative to CON. The JMS-mannitol was less for LFI steers than CON in the proximal colon (P = 0.041) and in the distal colon (P = 0.015). Increased gene expression for claudin 1, occludin, tight-cell junction protein 1 and 2, and toll-like receptor 4 were detected for LFI relative to CON in the rumen, jejunum, and proximal colon. For RA steers, expression of toll-like receptor 4 in the rumen, and occludin and tight-cell junction protein 1 were greater in the jejunum than CON. An acute RA challenge decreased pH in the rumen and large intestine but did not increase tissue permeability due to increases in the expression of genes related to barrier function within 1 d of the challenge. Steers exposed to LFI for 5 d had reduced ruminal SCFA concentrations, smaller ruminal papillae dimensions, and increased tissue permeability in the proximal and distal colon despite increases for genes related to barrier function and immune function. PMID- 29385474 TI - Effects of heat stress and insulin sensitizers on pig adipose tissue. AB - Heat stress (HS) negatively impacts several swine production variables, including carcass fat quality and quantity. Pigs reared in HS have more adipose tissue than energetically predicted, explainable, in part, by HS-induced hyperinsulinemia. Study objectives were to evaluate insulin's role in altering fat characteristics during HS via feeding insulin-sensitizing compounds. Forty crossbred barrows (113 +/- 9 kg BW) were randomly assigned to one of five environment by diet treatments: 1) thermoneutral (TN) fed ad libitum (TNAL), 2) TN and pair-fed (TNPF), 3) HS fed ad libitum (HSAL), 4) HS fed ad libitum with sterculic oil (SO) supplementation (HSSO; 13 g/d), and 5) HS fed ad libitum with dietary chromium (Cr) supplementation (HSCr; 0.5 mg/d; Kemin Industries, Des Moines, IA). The study consisted of three experimental periods (P). During P0 (2 d), all pigs were exposed to TN conditions (23 +/- 3 degrees C, 68 +/- 10% RH) and fed ad libitum. During P1 (7 d), all pigs received their respective dietary supplements, were maintained in TN conditions, and fed ad libitum. During P2 (21 d), HSAL, HSSO, and HSCr pigs were fed ad libitum and exposed to cyclical HS conditions (28 to 33 degrees C, 58 +/- 10% RH). The TNAL and TNPF pigs remained in TN conditions and were fed ad libitum or pair-fed to their HSAL counterparts. Rectal temperature (TR), respiration rate (RR), and skin temperature (TS) were obtained daily at 0600 and 1800 h. At 1800 h, HS exposed pigs had increased TR, RR, and TS relative to TNAL controls (1.13 degrees C, 48 bpm, and 3.51 degrees C, respectively; P < 0.01). During wk 2 and 3 of P2, HSSO pigs had increased 1800 h TR relative to HSAL and HSCr (~0.40 and ~0.42 degrees C, respectively; P <= 0.05). Heat stress decreased ADFI and ADG compared to TNAL pigs (2.24 vs. 3.28 and 0.63 vs. 1.09 kg/d, respectively; P < 0.01) and neither variable was affected by SO or Cr supplementation. Heat stress increased or tended to increase moisture content of abdominal (7.7 vs. 5.9%; P = 0.07) and inner s.c. (11.4 vs. 9.8%; P < 0.05) adipose depots compared to TNAL controls. Interestingly, TNPF pigs also had increased adipose tissue moisture content and this was most pronounced in the outer s.c. depot (15.0 vs. 12.2%; P < 0.01) compared to TNAL pigs. Heat stress had little or no effect on fatty acid composition of abdominal, inner, and outer s.c. adipose tissue depots. In summary, the negative effects of HS on fat quality do not appear to be fatty acid composition related, but may be explained by increased adipose tissue moisture content. PMID- 29385475 TI - Effects of adding mannan oligosaccharides on digestibility and metabolism of nutrients, ruminal fermentation parameters, immunity, and antioxidant capacity of sheep. AB - The purpose of this study was to investigate the effects of adding mannan oligosaccharides (MOS) on the following parameters in sheep: digestibility and retention rate of nutrients, ruminal fermentation, immunity, and antioxidant capacity. Twelve healthy crossbred wethers (Suffolk ? * Small tail Han-yang ?) with external ruminal fistula and similar body weights (28.04 +/- 2.07 kg) were fed individually four treatments, three repeats of each treatment. The wethers diets were supplemental MOS at 0%, 1.2%, 1.6%, and 2.0%.kg-1 of basal diet (as fed basis). The experiment lasted 17 d, including 10 d of acclimation and 7 d of formal experimentation. The results showed that MOS did not influence the apparent digestibility and retention rate of nutrients, ruminal fermentation, and immunity or concentration of serum nitric oxide and activity of serum nitric oxide synthase (P >= 0.07). However, the apparent digestibility of neutral detergent fiber and acid detergent fiber at MOS supplementation rates of 1.6% and 2.0% both tended to be greater than the control group (P <= 0.103). There was also moderate evidence that MOS might increase the nitrogen retention rate (P = 0.082). MOS increased the antioxidant ability of sheep (P <= 0.018), especially at a dose of 1.6%: an increase in activity of total superoxide dismutase (P = 0.007), glutathione peroxidase (P = 0.018) and total antioxidant capacity (P < 0.001), and a decrease in concentration of malondialdehyde (P < 0.001) were found. The results indicated that in sheep MOS improved fiber digestion, N retention and some antioxidant abilities, but these effects may be too small to improve health and performance. PMID- 29385476 TI - Test of conditions that affect in vitro production of volatile fatty acids and gases. AB - In vitro methods have been developed to measure digestibility, but such methods may not accurately reflect gas production or volatile fatty acid (VFA) profiles. The objective of this study was to determine the effect of different in vitro conditions on VFA and gas production. The experimental design was a 4 * 2 * 2 factorial CRD with four replicates. Treatments were four ratios of medium to rumen fluid by volume (5:95, 25:75, 50:50, and 75:25), two concentrations (w/v) of added timothy hay (0.5% or 1%), with or without added sodium acetate (increased initial concentration by 50 mM). Total volume of medium and rumen fluid was 10 mL per tube. Measurements of gas production and VFA were recorded at 0, 4, 16, 24, and 48 h. Statistical analyses used a mixed model including all fixed effects and interactions with tube as a random effect, and time nested within tube. Total gas production increased (P < 0.001) with higher medium proportion. The final pH increased (P < 0.0001) as medium proportion increased. Medium proportion positively affected (P < 0.05) overall average concentration of both acetate production and propionate production. Higher hay concentration increased (P < 0.0001) total gas produced from 0 to 48 h, increased total acetate production (P < 0.01), propionate production (P < 0.001), and decreased pH between 24 and 48 h (P < 0.0001). Sodium acetate addition increased (P < 0.0001) pH between 24 and 48 h. Acetate:propionate (A:P) concentration decreased over time (P < 0.0001). Initial rumen fluid A:P ratio was 3.7 but average A:P ratio of produced VFA started at 2.2 and increased to 2.50 (SE = +/-0.51). The A:P ratio differed for VFA produced in vitro compared to initial rumen fluid, but no tested treatments were found to change A:P ratio. PMID- 29385477 TI - Excessive backfat of sows at 109 d of gestation induces lipotoxic placental environment and is associated with declining reproductive performance. AB - This study investigated the influence of sow backfat thickness at 109 d of gestation on sow and piglet performance. Data from 846 farrowing multiparous Yorkshire sows with parity from 3 to 5 were collected from a pig breeding farm. Sows were divided into six groups based on backfat thickness (<=16, 17-18, 19-20, 21-22, 23-24, and >=25 mm) at 109 d of gestation. The evaluation of reproductive performance included the litter size, litter weight at birth and at weaning of 21 d, weight of placenta at parturition, placental efficiency, and sow daily feed intake of lactation. Parameters related to plasma lipids and the placental-lipid concentration were measured. Data were analyzed to determine the relationships among backfat thickness, placental lipids, and piglet performance. No differences were observed in the number of piglets born, born alive, after cross-foster, and at weaning among groups (P > 0.05). The litter weight at birth and weaning, piglet birth weight, weaning weight, placental efficiency, and the number and percentage of piglets born with weight of <800 g showed a significantly quadratic effect of the backfat thickness (P < 0.05). During lactation, sow daily feed intake linearly decreased with increased backfat thickness at 109 d of gestation (P < 0.05). Although triglycerides and low-density lipoprotein cholesterol (LDL C) showed no significant difference, cholesterol and high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) concentrations significantly increased (P < 0.05) in both maternal and umbilical cord blood with increased backfat thickness of sow. Placental-lipid concentrations also significantly increased (P < 0.05) with increased backfat thickness. Moreover, backfat thickness and placental-lipid concentration were positively correlated with the number of piglets weighing <800 g (P < 0.01) but negatively correlated with birth weight, litter birth weight, and piglet weaned weight (P < 0.01). In conclusion, backfat thickness of sow at end of gestation correlates with birth and weaning weight of piglets. Placental ectopic lipid accumulation-induced lipotoxicity is likely responsible for such correlation. PMID- 29385478 TI - Impact of Mycoplasma hyopneumoniae and Lawsonia intracellularis on the performance of pigs divergently selected for feed efficiency. AB - Feed efficiency (FE) is a valuable trait, yet how genetic selection for enhanced FE affects other processes such as response to disease is unknown. Disease from endemic respiratory and enteric pathogens such as Mycoplasma hyopneumoniae (Mh) and Lawsonia intracellularis (LI) are common in swine production. Therefore, the aim of this study was to examine if pigs selected for high vs. low FE based on residual feed intake (RFI) respond differently to a dual respiratory and enteric challenge. Pigs selected for low RFI (LRFI, high FE) are considered more FE compared to their high RFI (HRFI, low FE) selected counterparts. Using a 2 * 2 factorial design, 25 littermate pairs from the HRFI and 25 littermate pairs from the LRFI line (barrows, 50 +/- 7 kg BW) were selected, with one pig from each pair assigned to individual pens in either the challenge or the nonchallenge (control) rooms (n = 25 barrows/line/challenge). On days post inoculation (dpi) 0, the challenged pigs were inoculated with LI and Mh (MhLI). Feed intake, BW, fecal swabs, and serum samples were collected and recorded weekly for 42 d. On dpi -2 and 47, 14 littermate pairs (n = 7 barrows/line/challenge) were utilized for initial and final body composition scans using dual-energy X-ray absorptiometry to calculate longitudinal whole body tissue accretion rates for lean, protein, fat, and bone mineral content. Serum antibody levels and fecal shedding of LI were used to confirm infection. Control pigs remained negative by all measures during the 6-wk trial and MhLI inoculated pigs were confirmed positive via serological antibody responses by dpi 14 for LI and Mh. There were no interactions between RFI line and challenge status for any overall performance parameter (P > 0.05). The 6-wk MhLI challenge resulted in a 17% reduction in ADG, a 12% reduction in ADFI, and a 7% reduction in G:F vs. Controls (P < 0.05). In addition, compared to the Control pigs, MhLI challenge reduced lean, protein, and lipid accretion rates by 16% (P < 0.05). Genetic selection for high FE resulted in decreased ADFI and increased G:F (P < 0.01), but did not impact ADG or tissue accretion vs. low FE pigs. Collectively, these results demonstrate that a dual enteric and respiratory pathogen challenge reduced ADG, ADFI, G:F, and tissue accretion in growing pigs. Further, there was no evidence that selection for enhanced FE based on RFI index affects response to disease. PMID- 29385479 TI - Genetic correlations between endo-parasite phenotypes and economically important traits in dairy and beef cattle. AB - Parasitic diseases have economic consequences in cattle production systems. Although breeding for parasite resistance can complement current control practices to reduce the prevalence globally, there is little knowledge of the implications of such a strategy on other performance traits. Records on individual animal antibody responses to Fasciola hepatica, Ostertagia ostertagi, and Neospora caninum were available from cows in 68 dairy herds (study herds); national abattoir data on F. hepatica-damaged livers were also available from dairy and beef cattle. After data edits, 9,271 dairy cows remained in the study herd dataset, whereas 19,542 dairy cows and 68,048 young dairy and beef animals had a record for the presence or absence of F. hepatica-damaged liver in the national dataset. Milk, reproductive, and carcass phenotypes were also available for a proportion of these animals as well as their contemporaries. Linear mixed models were used to estimate variance components of antibody responses to the three parasites; covariance components were estimated between the parasite phenotypes and economically important traits. Heritability of antibody responses to the different parasites, when treated as a continuous trait, ranged from 0.07 (O. ostertagi) to 0.13 (F. hepatica), whereas the coefficient of genetic variation ranged from 4% (O. ostertagi) to 20% (F. hepatica). The antibody response to N. caninum was genetically correlated with the antibody response to both F. hepatica (-0.29) and O. ostertagi (-0.67); a moderately positive genetic correlation existed between the antibody response to F. hepatica and O. ostertagi (0.66). Genetic correlations between the parasite phenotypes and the milk production traits were all close to zero (-0.14 to 0.10), as were the genetic correlations between F. hepatica-damaged livers and the carcass traits of carcass weight, conformation, and fat score evaluated in cows and young animals (0.00 to 0.16). The genetic correlation between F. hepatica-damaged livers in cows and milk somatic cell score was 0.32 (SE = 0.20). Antibody responses to F. hepatica and O. ostertagi had favorable genetic correlations with fertility traits, but conversely, antibody response to N. caninum and F. hepatica-damaged livers were unfavorably genetically correlated with fertility. This study provides the necessary information to undertake national multitrait genetic evaluations for parasite phenotypes. PMID- 29385480 TI - Genotype * prenatal and post-weaning nutritional environment interaction in a composite beef cattle breed using reaction norms and a multi-trait model. AB - Environmental effects have been shown to influence several economically important traits in beef cattle. In this study, genotype * nutritional environment interaction has been evaluated in a composite beef cattle breed (50% Red Angus, 25% Charolais, 25% Tarentaise). Four nutritional environments (marginal restricted [MARG-RES], marginal-control [MARG-CTRL], adequate-restricted [ADEQ RES], and adequate-control [ADEQ-CTRL]) were created based on two levels of winter supplement provided to dams grazing winter range during gestation (MARG and ADEQ) and two levels of input to offspring during post-weaning development (RES and CTRL). Genetic parameters of average daily gain (ADG) during the 140-d post-wean trial, yearling weight (YW), and ultrasound measurement of fat depth (FAT) at the 12th rib and intramuscular fat percentage (IMF) of 3,020 individuals in the four environments were estimated. The heritabilities estimated using a single trait mixed linear model were: ADG: 0.21, 0.23, 0.19 and 0.21; YW: 0.27, 0.33, 0.20 and 0.26; FAT: 0.30, 0.29, 0.29, 0.55; IMF: 0.45, 0.51, 0.33, 0.53 for MARG-RES, ADEQ-RES, MARG-CTRL and ADEQ-CTRL, respectively. The extent of genotype * environment interaction was modeled using two separate methods: reaction norms and multi-trait models. The genetic correlations were estimated using a multi trait model for ADG, YW, FAT and IMF. Growth traits (ADG, YW) and FAT showed correlations less than 0.80 across the four different environments indicating genotype by environment interaction. For example, genetic correlation for ADG between MARG-CTRL and MARG-RES was 0.65 and 0.73 between ADEQ-RES and MARG-RES. In this example, the former genetic correlation corresponds to differences in post-weaning nutritional environment, and the later represents a nutritional difference imposed on dams (i.e., prenatal environment), potentially mediated via fetal programming. The reaction norm model results were in concordance with the multi-trait model, genotype by environment interaction had a higher effect on traits with a lower heritability. PMID- 29385482 TI - The First Case of Trypanosoma cruzi-Associated Retinitis in an Immunocompromised Host Diagnosed With Pan-Organism Polymerase Chain Reaction. AB - We report the first case of Trypanosoma cruzi-associated retinitis diagnosed using 28s ribosomal DNA sequencing. The case highlights the utility of broad range molecular diagnostics for detecting rare and unsuspected ocular pathogens. Ocular involvement in Chagas disease is also discussed. PMID- 29385481 TI - Risk factors associated with animal mortality in pasture-based, seasonal-calving dairy and beef herds. AB - Animal mortality is indicative of animal health and welfare standards, which are of growing concern to the agricultural industry. The objective of the present study was to ascertain risk factors associated with mortality at multiple life stages in pasture-based, seasonal-calving dairy and beef herds. Males and females were stratified into seven life stages based on age (0 to 2 d, 3 to 7 d, 8 to 30 d, 31 to 182 d, 183 to 365 d, 366 to 730 d, and 731 to 1,095 d) whereas females with >=1 calving event were further stratified into five life stages based on cow parity number (1, 2, 3, 4, and 5). Mortality was defined as whether an animal died during each life stage; only animals that either survived the entire duration or died during a life stage were considered. The data, following edits, consisted of 4,404,122 records from 1,358,712 animals. Multivariable logistic regression was used to estimate the logit of the probability of mortality in each life stage separately. The odds of a young animal (i.e., aged <= 1,095 d) dying was generally greater if veterinary assistance was required at their birth relative to no assistance (odds ratio [OR]: 3.10 to 31.85), if the animal was a twin relative to a singleton (OR: 1.46 to 2.31) or if the animal was male relative to female (OR: 1.14 to 6.15). Moreover, the odds of a cow (i.e., females with >=1 calving event) dying were greater when she required veterinary assistance at calving (OR: 2.69 to 7.55) compared with a cow that did not require any assistance, if she produced twin relative to singleton progeny (OR: 1.59 to 2.03) or male relative to female progeny (OR: 1.09 to 1.20). Additionally, the odds of a first or second parity cow dying when she herself had received veterinary assistance at birth were only 0.63 to 0.66 times that of a cow that was provided no assistance at birth. For both young animals and cows, the odds of dying generally increased with herd size, whereas animals residing in expanding herds had lower odds of dying. Results from the present study indicate that the risk factors associated with mortality in pasture-based, seasonal-calving herds are similar to those reported in literature in confinement, nonseasonal-calving herds. Moreover, the present study identifies that these risk factors are similar in both dairy and beef herds, yet the magnitude of the association often differs and also changes with life stage. PMID- 29385483 TI - Genotype by environment interaction for stayability of Red Angus in the United States. AB - Bulls are used across a wide variety of environments through the use of artificial insemination. However, not all bulls rank the same for genetic merit in all environments. Sire selection could be more accurate via improved methods of characterization. The objective of this study was to evaluate the presence of genotype by environment (GxE) interaction for stayability in Red Angus in the United States. Environments were defined as nine regions within the continental United States with similar temperature-humidity indices. Stayability was defined as having a calf at age 4 given that the cow had a calf at age 2. A probit sire model was used to determine the heritability on the underlying scale. The percentage of females that calved at age 2 that also calved at age 4 ranged from 32.9 to 58.5% across regions and was 55.0% for the national data set. The heritability of stayability ranged from 0.10 to 0.57 across regions and was 0.12 for the national data set. Genetic correlations were estimated for stayability between all pairs of regions. An estimate of less than 0.80 indicates GxE at a level for concern. Genetic correlations between regions ranged from 0.32 to 0.87 and were <0.80 for 29 of 36 region pairs. PMID- 29385484 TI - Life cycle efficiency of beef production: IX. Relationship between residual feed intake of heifers and cow efficiency ratios based on harvest, carcass, and wholesale cut weight outputs. AB - Data were collected from 1953 through 1980 from identical and fraternal twin beef and dairy females born in 1953, 1954, 1959, 1964, and 1969, from crossbred females born as singles in 1974, and their progeny. Numbers of dams that weaned at least one calf and were included in the first analysis were 37, 45, and 56 in the 1964, 1969, and 1974 data sets, respectively. Respective numbers of dams that weaned three calves and were included in a second analysis were 6, 8, 8, 22, 33, and 33 in the 1953, 1954, 1959, 1964, 1969, and 1974 experiments. Individual feed consumption was measured at 28-d intervals from the time females were placed on the experiment at 240 d of age until three calves were weaned or the dams had reached 5 yr of age. Residual feed intake (RFI) and residual BW gain (RG) of heifers that subsequently became dams were determined based on ADG and DMI from 240 d of age to first calving. Various measures of cow efficiency were calculated on either a life cycle or actual lifetime basis using ratios of progeny and dam weight outputs to progeny and dam feed inputs. The correlation between RFI and DMI was large and positive (r = 0.67; P < 0.0001), and RG was highly correlated with ADG (r = 0.75; P < 0.0001). Correlations of RFI with cow efficiency ratios that included harvest weight, carcass weight, or weight of trimmed wholesale cuts as measures of output ranged from -0.05 (P > 0.10) to -0.17 (P < 0.10), indicating that heifers with better (i.e., more negative) RFI values tended to become slightly more efficient cows. Correlations of RG with life cycle and actual lifetime cow efficiency ratios ranged from 0.08 (P > 0.10) to 0.23 (P < 0.05), demonstrating that heifers with better (i.e., more positive) values for RG were somewhat more efficient as cows. The correlations were stronger when cow salvage value was included in the measures of cow efficiency. Correlations of DMI and mid-test metabolic BW (MMW) with life cycle cow efficiency ratios that did not include cow salvage value as output ranged from -0.15 (P < 0.10) to -0.22 (P < 0.01). Correlations of DMI and MMW with actual lifetime cow efficiency ratios varied from -0.20 (P < 0.05) to -0.36 (P < 0.001). Therefore, smaller heifers that consumed less feed had superior cow efficiency ratios. Correlations of RFI with carcass grade, backfat thickness, marbling score, and kidney fat of progeny indicated that heifers with superior RFI would tend to produce leaner offspring. PMID- 29385485 TI - Effect of high doses of Natuphos E 5,000 G phytase on growth performance of nursery pigs. AB - A total of 360 pigs (DNA 200 * 400, initially 5.9 +/- 0.1 kg) were used in a 42 d trial to determine the effect of high doses of a recently available phytase source (Natuphos E 5000 G, BASF Corporation, Florham Park, NJ) on nursery pig growth and bone ash. Pigs were randomly allotted to pens at weaning by BW and pens were allotted to one of eight corn-soybean meal-based dietary treatments in a randomized complete block design. There were five pigs per pen and nine pens per treatment. Diets were fed in three phases (d 0 to 7, 7 to 21, and 21 to 42) with formulated total calcium:phosphorus (Ca:P) of 1.07, 1.05, and 0.93, respectively. Treatments included a negative control (NC) with 0.40, 0.30, or 0.25% aP from monocalcium P for Phases 1, 2, and 3 respectively; and NC with either 500, 1,000, 2,000, 3,000, or 4,000 FTU/kg phytase. The last two treatments were a positive control (PC) with 0.55, 0.45, or 0.40% aP from monocalcium P for Phases 1, 2, and 3, respectively, or PC with 2,000 FTU/kg phytase. The NC diet with 500 FTU/kg and PC without added phytase were formulated to be equivalent in available Ca and P. On d 42, one pig per pen was euthanized and the right fibula was removed for bone ash analysis. From d 0 to 42, pigs fed increasing phytase in the NC tended to have increased (quadratic, P = 0.064) ADG and (linear, P = 0.082) ending BW and had improved (quadratic, P = 0.008) G:F. Adding 2,000 FTU/kg phytase to the PC did not influence ADG or ADFI, but tended to improve (P = 0.060) G:F compared with the PC. In addition, percentage bone ash increased as phytase increased in the NC (linear, P < 0.001) or when 2,000 FTU/kg was added to the PC diets (P < 0.001). Pigs fed the PC had increased (P = 0.007) ADFI and tended to have greater (P = 0.099) percentage bone ash than pigs fed NC+500 FTU/kg phytase, but the pigs fed NC+500 FTU/kg phytase had improved (P = 0.032) G:F compared to pigs fed the PC. In summary, increasing concentrations of dietary phytase in a P-deficient diet improved growth and bone ash measurements, and was optimized at 1,000 FTU/kg. There were varied improvements when 2,000 FTU/kg phytase was added in P adequate diets. PMID- 29385486 TI - Influence of feeding thermally peroxidized soybean oil on growth performance, digestibility, and gut integrity in growing pigs. AB - Consumption of highly peroxidized oils has been shown to affect pig performance and oxidative status through the development of compounds which differ according to how oils are thermally processed. The objective of this study was to evaluate the effect of feeding varying degrees of peroxidized soybean oil (SO) on parameters of growth performance; lipid, N, and GE digestibility, gut integrity in growing pigs, and plasma Trp. Fifty-six barrows (25.3 +/- 3.3 kg initial BW) were randomly assigned to one of four diets containing either 10% fresh SO (22.5 degrees C) or thermally processed SO (45 degrees C for 288 h, 90 degrees C for 72 h, or 180 degrees C for 6 h), each with an air infusion of 15 L/min. Peroxide values for the 22.5, 45, 90, and 180 degrees C processed SO were 2.0, 96, 145, and 4.0 mEq/kg, respectively; 2,4-decadienal values for 22.5, 45, 90, and 180 degrees C processed SO were 2.11,5.05, 547.62, and 323.57 mg/kg, respectively; and 4-hydroxynonenal concentrations of 0.05, 1.05, 39.46, and 25.71 mg/kg with increasing SO processing temperature. Pigs were individually housed and fed ad libitum for a 49 d period to determine the effects of SO peroxidation status on growth performance, including a metabolism period for assessing GE and N digestibility, and N retention. In vivo urinary lactulose to mannitol ratio was also assessed to evaluate potential changes in small intestinal integrity. Although there were no differences observed in ADFI (P = 0.19), ADG was decreased in pigs fed 90 degrees C SO diet (P = 0.01), while G:F was increased (P = 0.02) in pigs fed 45 degrees C SO diet compared to the other SO diets. Pigs fed the 90 degrees C processed SO had the lowest (P = 0.01) DE as a percentage of GE, whereas ME as a percentage of DE was lowest (P = 0.05) in pigs fed the 180 degrees C SO and 90 degrees C SO followed by 45 degrees C SO and fresh SO. Ether extract (EE) digestibility was lowest (P = 0.01) in pigs fed 90 degrees C SO followed by pigs fed 180 degrees C SO, 45 degrees C SO, and fresh SO. The percent of N retained was greatest (P = 0.01) in pigs fed fresh SO followed by pigs fed 45 degrees C SO, 180 degrees C SO, and 90 degrees C, respectively. There were no differences observed among SO treatments for urinary lactulose to mannitol ratio (P = 0.60). Pigs fed SO processed at 90 degrees C and 180 degrees C had lower concentrations (P < 0.01) of serum Trp compared to pigs fed the 22.5 degrees C and 45 degrees C SO treatments. The presence of lipid peroxidation products, namely several aldehydes, contained in the 90 degrees C SO diet reduced ADG, GE and EE digestibility, and N balance, but had no impact on gut permeability. PMID- 29385489 TI - A qualitative exploration of stakeholder perceptions of the implementation of place-based working and its potential to reduce health inequality. AB - Background: Local authorities (LAs) have statutory responsibility to reduce health inequalities and improve public health. Place-based approaches may positively influence service provision yet little is known about their implementation and potential for reducing inequality through health and wellbeing improvements. An English LA implemented a place-based working (PBW) pilot in a small geography during austerity measures in the north of England. This involved three strands (early intervention, estate services and community intelligence) which were introduced separately and covered overlapping geographies. Predominantly focusing on early intervention, this qualitative study investigates stakeholders' perceptions of the pilot and its potential to improve health and wellbeing by reducing inequality. Methods: In total, 15 face-to-face qualitative interviews with stakeholders were completed. Thematic analysis produced context, mechanism and outcome configurations in a process adapted from realist evaluation methodology. Results: Stakeholders described PBW as holistic, upstream and cutting across departmental boundaries to engage staff and the community. Collaborative working was considered important and was aided by PBW in our study. Conclusions: PBW has the potential to reduce health inequalities by improving health and wellbeing. LAs deliver services that affect health and wellbeing and PBW may help develop a more coordinated response to improve outcomes and potentially save money. PMID- 29385487 TI - MicroRNA 221 expression in theca and granulosa cells: hormonal regulation and function. AB - Small noncoding RNA molecules (miRNA) regulate protein levels in a post transcriptional manner by partial base pairing to the 3'-UTR of target genes thus mediating degradation or translational repression. Previous studies indicate that numerous miRNA regulate the biosynthesis of intraovarian hormones, and emerging evidence indicates that one of these, miRNA-221 (MIR221), may be a modulator of ovarian function. However, the hormonal control of ovarian MIR221 is not known. The objectives of this study were to investigate the developmental and hormonal regulation of MIR221 expression in granulosa (GC) and theca cell (TC) and its possible role in regulating follicular function. Bovine ovaries were collected from a local abattoir and GC and TC were obtained from small (<6 mm) and large (>=8 mm) follicles. In Exp. 1, GCs of small follicles had 9.7-fold greater (P < 0.001) levels of MIR221 than those of large follicles, and TCs of large follicles had 3.7-fold greater (P < 0.001) levels of MIR221 than those of small follicles. In large follicles, abundance of MIR221 was 66.6-fold greater (P < 0.001) in TCs than in GCs. In small follicles, MIR221 abundance did not differ (P = 0.14) between GC and TCs. In vitro Exp. 2, 3, and 4 revealed that treatment of bovine TCs with various steroids, phytoestrogens, IGF1, forskolin, and dibutyryl cyclic adenosine monophosphate had no effect (P > 0.35) on MIR221 expression, whereas treatment with fibroblast growth factor 9 (FGF9) and FGF2 increased (P < 0.001) TC MIR221 abundance 1.7- to 2.5-fold. In Exp. 5, FGF9 increased (P < 0.05) GC MIR221 abundance by 1.7- and 2.0-fold in small and large follicles, respectively. The role of MIR221 in GC steroidogenesis was investigated in Exp. 6 and it was found that transfection with a MIR221 mimic reduced (P < 0.01) GC estradiol and progesterone production induced by FSH and IGF1, whereas transfection with MIR221 inhibitor had little or no effect. We conclude that thecal MIR221 expression is increased by FGF9 and increased MIR221 may act to inhibit GC steroidogenesis in cattle. PMID- 29385488 TI - Analysis for low-molecular-weight carbohydrates is needed to account for all energy-contributing nutrients in some feed ingredients, but physical characteristics do not predict in vitro digestibility of dry matter. AB - An experiment was conducted to quantify nutrient and fiber fractions of feed ingredients and to determine in vitro apparent ileal digestibility (IVAID) and in vitro apparent total tract digestibility (IVATTD) of DM and OM in each ingredient. Ten ingredients that vary in fiber concentration and composition were used: corn, wheat, soybean meal (SBM), canola meal, distillers dried grains with solubles (DDGS), corn germ meal, copra expellers, sugar beet pulp (SBP), synthetic cellulose (SF), and pectin. Correlations between chemical and physical characteristics of ingredients and IVAID and IVATTD of DM and OM were determined. The physical characteristics measured included bulk density, water-binding capacity (WBC), swelling, and viscosity. The analyzed GE was compared with values for GE calculated from all energy-contributing components. Results indicated that the analyzed chemical composition of most ingredients added to 100% or greater, except for DDGS, SBP, and SF, where nutrients added to only 94.29%, 88.90%, and 96.09%, respectively. The difference between the sum of the calculated GE of the analyzed components and the analyzed GE of the ingredients ranged from -2.25 MJ/kg in DDGS to 1.74 MJ/kg in pectin. No correlation was observed between swelling, WBC, or viscosity and IVAID or IVATTD of DM or OM. The concentration of insoluble dietary fiber (IDF) and total dietary fiber (TDF) was negatively correlated (P < 0.05) with IVAID and IVATTD of DM and OM. There was a tendency for NDF (r = -0.60) and ADF (r = -0.61) to be negatively correlated (P < 0.10) with IVAID of DM. However, no correlation was observed between the concentration of CP, GE, acid-hydrolyzed ether extract, lignin, or soluble dietary fiber and IVAID and IVATTD of DM and OM. The stronger correlations between IDF, TDF, and insoluble non-starch polysaccharides and IVAID and IVATTD of DM and OM than between ADF and NDF and IVAID and IVATTD of DM and OM indicate that the concentration of TDF in feed ingredients is a better predictor of the digestibility of DM and OM than values for NDF and ADF. In conclusion, the calculated GE of some feed ingredients was in agreement with the analyzed GE, which gives confidence that energy-contributing components were accounted for, but for DDGS and SBP, it was not possible to account for all analyzed GE. Concentrations of IDF and TDF, but not the physical characteristics of feed ingredients, may be used to estimate IVAID and IVATTD of DM and OM in feed ingredients. PMID- 29385490 TI - Serum and plasma metabolites associated with postpartum ovulation and pregnancy risks in suckled beef cows subjected to artificial insemination. AB - Two experiments were conducted to determine relationships of blood metabolite concentrations, BW, BCS, and rump fat depth with postpartum ovulation and pregnancy risks, as well as their utility in predicting those outcomes in suckled beef cows. In experiment 1, plasma glucose collected 10 and 3 d before AI of suckled beef cows at seven locations did not differ between cows that had resumed estrous cycles (ovulated) before AI compared with anovulatory cows, whereas plasma glucose 3 d before AI was greater (P < 0.01) in cows that became pregnant compared with nonpregnant cows. Serum beta-hydroxybutyrate (BHB) tended (P = 0.09) to be less in ovulatory cows compared with anovulatory cows 10 d before AI, but was unrelated to pregnancy status. Receiver-operator derived true-positive (sensitivity) and false-positive (1-specificity) risks were determined for plasma glucose and serum BHB as predictors for postpartum ovulation and pregnancy status. Serum BHB 3 d before AI produced true-positive and false-positive risks of 82% and 37%, respectively, when predicting ovulatory status before AI. Serum BHB 10 d before AI produced a true-positive and false-positive risks of 92% and 25%, respectively, when predicting pregnancy status. In experiment 2, blood was collected weekly for 12 wk from multiparous suckled beef cows to assess blood metabolite concentrations in addition to concurrent weekly assessments of BW, BCS, and rump fat. When blood metabolites and physical measures were normalized to parturition reflecting changes occurring during the first 6 wk after calving, we observed reduced (P < 0.05) concentrations of serum BHB and NEFA, and greater (P < 0.05) rump fat and BCS in cows that ovulated before first AI, whereas reduced (P < 0.05) plasma glucose was characteristic of cows that became pregnant. When blood metabolites and physical measures were normalized to the onset of the AI program reflecting changes during 6 wk before AI, ovulatory cows had increased (P < 0.05) BCS and lower (P < 0.05) NEFA from 3 to 6 wk before the onset of the AI program compared with anovulatory cows. With all predictor variables in regression models, some multiple correlation coefficients (R2) exceeded 50% when predicting postpartum ovulatory status, but those for predicting pregnancy risk were less than 25%. Although measures of BCS and BHB during 6 wk after calving were related to postpartum ovulation risk, rump fat, glucose, BCS, and NEFA were associated with cows that were ovulatory and pregnant. PMID- 29385491 TI - Resistance of Seven Cabbage Cultivars to Green Peach Aphid (Hemiptera: Aphididae). AB - The green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae), is an important pest of many crops in the world and a vector of more than 100 plant viruses. It is a major pest of Brassica vegetables such as Chinese cabbage in northern China. Chemical control is extensively used to manage this aphid around the world; however, development of insecticide resistance has been a major obstacle facing growers. Host plant resistance in Chinese cabbage against M. persicae has not been reported yet. In this study, we investigated the resistance categories in seven Chinese cabbage cultivars against M. persicae. The resistance categories of these cultivars included antixenosis, antibiosis, and tolerance related to leaf color and wax content. The cultivar 'Yuanbao' had antibiotic and tolerance effects on the aphid. The rate of intrinsic increase (rm) of M. persicae was lower on Yuanbao compared with the other six cultivars. Yuanbao also had the highest antibiosis against the aphid. The aphid preferred 'Qingan 80', which had the highest wavelength (green) in leaf color. The highest wax content was found in Yuanbao, which had a significantly negative correlation with the preference of M. persicae. The cabbage cultivar Yuanbao was resistant to M. persicae and could be used in the development of integrated pest management (IPM) programs against the aphid in the field. PMID- 29385492 TI - Disparity in utilization and expectation of community-based maternal health care services among women in Myanmar: a cross-sectional study. AB - Background: Aim of this study is to assess women's utilization and expectation of community-based antenatal and delivery care services in Myanmar and determine associated factors for disparity of services received with services women expected to receive. Methods: A cross-sectional survey was conducted among 6 month postpartum women in three townships of Myanmar during May-September 2016. Associated factors for the services with disparity were identified using multinomial logistic regression models. Results: Of 1743 women, the percentages of antenatal care (ANC) attended by a skilled provider, at least four ANC visits, and early ANC were 89, 60 and 36%, respectively. The percentage of non-facility delivery was 65%. Many ANC services received and services expected to receive had lower than 80% coverage. Services with significant disparity included blood hemoglobin and urinary protein testing, and iron supplementation. Low access to ANC, women's socio-economic status, pregnancy and delivery complications, and out of-pocket cost were associated with disparity of these services. Conclusion: Utilization and expectation of community-based ANC services and facility delivery is low in Myanmar. Disparities of the services received with the services women expected to receive were common in ANC. Improving women's expectations on essential services during pregnancy is needed as well as strengthening community participation. PMID- 29385493 TI - Improved overall survival over recent decades in patients with hormone-receptor positive, HER2-negative breast cancer: a single-center retrospective analysis of prognostic factors. AB - Background: Hormone receptor (HR)-positive HER2-negative breast cancer (BC) rates and associated mortality have been increasing among Japanese women. It is unclear whether the prognosis of these patients has improved. Methods: We retrospectively analyzed 1806 Japanese women with operable invasive HR-positive HER2-negative BC, who underwent complete resection at the National Cancer Center Hospital East between July 1992 and December 2010. We investigated whether overall survival (OS) and recurrence-free survival (RFS) had improved by comparing the 4-year periods 1992-96, 1997-2001, 2002-06, and 2007-10. The prognostic factors were evaluated using uni- and multivariate analyses. Results: The number of ER- and PgR-positive cancers had increased over the years (P < 0.001). Tumor sizes and numbers of involved lymph nodes both gradually decreased (P < 0.001 for both). OS and RFS of all patients significantly improved in each of the periods analyzed: 5 year OS was 92.6%, 94.8%, 95.4% and 97.6% (P < 0.001, Log-rank), and 5-year RFS was 82.1%, 82.8%, 88.6% and 94.5% (P < 0.001) in 1992-96, 1997-2001, 2002-06 and 2007-10, respectively. In multivariate analysis, the history of adjuvant AI and that of TAM had positive-correlation with RFS. Conclusions: The prognosis for HR positive HER2-negative BC patients after surgical therapy has improved, resulting in longer OS and RFS across the study periods. These changes could be associated with early detection of tumor and history of hormone therapy. PMID- 29385494 TI - The Transition to Retirement Experiences of Academics in "Higher Education": A Meta-Ethnography. AB - Background and Objectives: There are increasing numbers of older academics working in Higher Education Institutions worldwide. It is essential that academics' retirement experiences are clearly understood as they tend to have different retirement trajectories than other occupational groups. This meta ethnography aims to answer the research question "what are the experiences of academics transitioning to retirement" by identifying and synthesizing qualitative research using a meta-ethnographic approach. Research Design and Methods: A systematic literature search was conducted from January 2000 to September 2016 to identify qualitative studies focusing on academics' experiences of retirement. Two reviewers independently assessed the methodological quality of included papers. Concepts from each study were translated into each other to form theories, which were then combined through a "line-of-argument" synthesis. Results: Twenty papers were included. Five themes were identified: (a) continuing to work in retirement, (b) the impact of the retirement transition on the academics' identity, (c) changing relationships through the retirement transition, (d) experiencing aging processes, and (e) planning for retirement. For most, retirement is characterized by continuing to work in aspects of their role, maintaining associated relationships, with gradual disengagement from academic activities. For another smaller group, the retirement pathway is experienced as an event, with complete detachment from academic activities. Discussion and Implications: The review highlights that academics transitioning to retirement experience varying retirement pathways. Awareness of the benefits of comprehensive retirement planning programs could enable academics to choose a retirement pathway that facilitates a smooth transition to retirement. PMID- 29385495 TI - Influence of previous host plants on the reproductive success of a polyphagous mite pest, Halotydeus destructor (Trombidiformes: Penthaleidae). AB - In the evolution of phytophagous arthropods, adaptation to a single type of host plant is generally assumed to lead to a reduction in fitness on other host plant types, resulting in increasing host specialization. While this process is normally considered to be genetically based, short-term effects acting within one generation (plasticity) or across two generations (cross-generation variation) could also play a role. Here, we test these effects in the redlegged earth mite, Halotydeus destructor (Tucker) (Prostigmata: Penthaleidae), a major agricultural pest of multiple crop plants. Field populations of mites were collected from grasses, legumes, and broad-leaf weeds and placed into enclosures with different plant types. The survival, net reproductive output (Ro), and feeding damage of each mite population were assessed across two generations. The interaction between the origin of mites and plant type had a significant effect on parental survival, Ro, offspring development, and feeding damage. Mites collected from legumes showed higher parental survival on all host types; however, Ro, offspring development and feeding damage were all higher when mites were placed onto the same plant type from which they were collected. These patterns point to the ability of H. destructor to perform well on host plants even in the absence of genetically differentiated host races, but also the likelihood of performance trade-offs when populations are forced to rapidly change hosts within and across sequential generations. PMID- 29385496 TI - The effect of escalating the boost dose for patients with involved resection margin after breast-conserving surgery. AB - Background: This study aims to investigate the impact of boost dose escalation on ipsilateral breast tumor recurrence (IBTR) in breast cancer patients with involved resection margins following breast-conserving surgery. Methods: Between January 1998 and December 2010, 192 patients were treated with a boost dose of over 10 Gy for involved resection margins. We retrospectively analyzed outcomes in 192 patients who underwent whole breast irradiation of 50.4 Gy followed by a median boost dose of 15.0 Gy (range, 12-16 Gy). Boost doses of 12.5 Gy and 15 Gy were delivered to patients with carcinoma in situ and invasive carcinoma, respectively, at the positive margins. We evaluated the impact of the boost dose on the IBTR rate. Results: Median follow-up duration was 6.7 years (0.4-15.6 years). The 5-year cumulative risk of IBTR as a first event was 5.0%. IBTR occurred as a first recurrence in 13 of 192 patients. In-boost-field recurrences were found in 11 patients (85%). Five patients (39%) experienced out-of boost field recurrences, and three experienced both types of recurrences. In multivariate analysis, age (<40 years), pT stage, and positive radial resection margin were prognostic factors for IBTR (P = 0.029, P = 0.024 and P = 0.035, respectively). Conclusions: A median boost dose of 15 Gy might be insufficient in patients younger than 40 years, with tumor size greater than 2 cm, or with involved radial resection margins. On the other hand, in cases of positive superficial or deep margins, dose-escalated boost or re-excision may not be necessary. PMID- 29385497 TI - Geospatial and Climatic Patterns Associated With the Distribution of Sand Fly (Diptera: Psychodidae) Vectors of Leishmaniasis in Pakistan. AB - We provide a comprehensive and updated review on the effects of elevation and climatic factors on distribution of sand fly (Diptera: Psychodidae) vectors of cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) across Pakistan. Our study was undertaken in view of the increasing risk of leishmaniasis, particularly resulting from climatic deviations and political instability in the region. Literature (published and unpublished) on suspected vectors of CL (Phlebotomus sergenti Parrot and Phlebotomus papatasi Scopoli) and VL (Phlebotomus major Yakimoff and Schokhor and Phlebotomus hindustanicus Theodor) was collected, sorted, and utilized in geospatial analysis. P. papatasi and P. sergenti co-occurred in majority of the referenced localities and were generally distributed toward the western and southern parts across a wide range of elevation, whereas P. major and P. hindustanicus were limited to high elevation in cool and humid northern areas of Pakistan. Conversely P. papatasi and P. sergenti exploited diverse ecological settings across the country, being particularly abundant in warm/hot and arid regions. PMID- 29385498 TI - Association between hospital community services and county population health in the USA. AB - Objectives: Little research has utilized population level data to test the association between community health outcomes and (i) hospital-sponsored community services that facilitate access to care and (ii) hospital-sponsored community building services in the USA. Therefore, the purpose of this study was to examine these relationships. Methods: A secondary data analysis of the 2016 County Health Rankings and American Hospital Association databases was conducted via zero-truncated negative Binomial regression. Results: Findings indicate a statistically significant difference between the number of community healthcare access services and community building services with county's rank of health behavior. However, no statistically significant differences were found between the number of community healthcare access services and community building services with county rankings of length of life, quality of life or clinical care. Conclusions: Our findings suggest that quality measures of services may play a more important role in community health improvement and that there is opportunity for hospitals to revamp the way in which community health needs assessments are conducted. Additional federal action is needed to standardize hospital sponsored community health service data reporting so that practitioners, hospital administrators and researchers can more specifically define hospitals' role in public health protection in the USA. PMID- 29385500 TI - Fruit Set and Single Visit Stigma Pollen Deposition by Managed Bumble Bees and Wild Bees in Citrullus lanatus (Cucurbitales: Cucurbitaceae). AB - Pollinators provide essential services for watermelon, Citrullus lanatus (Thunb.; Cucurbitales: Cucurbitaceae). Managed bumble bees, Bombus impatiens (Cresson; Hymenoptera: Apidae), have been shown to be a useful watermelon pollinator in some areas. However, the exact contribution bumble bees make to watermelon pollination and how their contribution compares to that of other bees is unclear. We used large cages (5.4 * 2.5 * 2.4 m) to confine bumble bee hives to watermelon plants and compared fruit set in those cages to cages containing watermelons but no pollinators, and to open areas of field next to cages (allows all pollinators). We also collected data on single visit pollen deposition onto watermelon stigmas by managed bumble bees, honey bees, and wild bees. Overall, more fruit formed within the open cages than in cages of the other two treatment groups. B. impatiens and Melissodes spp. deposited the most pollen onto watermelon stigmas per visit, but all bee species observed visiting watermelon flowers were capable of depositing ample pollen to watermelon stigmas. Although B. impatiens did deposit large quantities of pollen to stigmas, they were not common within the field (i.e., outside the cages) as they were readily drawn to flowering plants outside of the watermelon field. Overall, bumble bees can successfully pollinate watermelon, but may be useful in greenhouses or high tunnels where watermelon flowers have no competition from other flowering plants that could draw bumble bees away from watermelon. PMID- 29385499 TI - A Meta-analysis and Economic Evaluation of Neonicotinoid Seed Treatments and Other Prophylactic Insecticides in Indiana Maize From 2000-2015 With IPM Recommendations. AB - Corn rootworm remains the key pest of maize in the United States. It is managed largely by Bt corn hybrids, along with soil insecticides and neonicotinoid seed treatments (NSTs), the latter of which are applied to virtually all conventionally (non-Bt) produced maize. Frequently, more than one of these pest management approaches is employed at the same time. To determine the utility and relative contributions of these various approaches, a meta-analysis was conducted on plant health and pest damage metrics from 15 yr of insecticide efficacy trials conducted on Indiana maize to compare the pest-protection potential of NSTs to that of other insecticides and Bt hybrids. The probability of recovering the insecticide cost associated with each treatment was also calculated when possible. With the exception of early-season plant health (stand counts), in which the NSTs performed better than all other insecticides, the vast majority of insecticides performed similarly in all plant health metrics, including yield. Furthermore, all tested insecticides (including NSTs) reported a high probability (>80%) of recovering treatment costs. Given the similarity in performance and probability of recovering treatment costs, we suggest NSTs be optional for producers, so that they can be incorporated into an insecticide rotation when managing for corn rootworm, the primary Indiana corn pest. This approach could simultaneously reduce costs to growers, lower the likelihood of nontarget effects, and reduce the risk of pests evolving resistance to the neonicotinoid insecticides. PMID- 29385501 TI - A Microsatellite-Based Analysis of House Infestation With Triatoma Infestans (Hemiptera: Reduviidae) After Insecticide Spraying in the Argentine Chaco. AB - Prevention of vector-borne transmission of Chagas disease mainly relies on residual insecticide spraying. Despite significant success at a regional scale, house infestation with Triatoma infestans (Klug) (Hemiptera: Reduviidae) still persists in the Gran Chaco ecoregion. One key aspect is the identification of the sources of reinfestant triatomines. After detecting fine-scale genetic structure in two rural villages of Pampa del Indio, Argentine Chaco, we tested hypotheses on the putative origins of the triatomines collected at 4, 8, and 12 mo after insecticide house spraying. We genotyped 10 microsatellite loci in 262 baseline and 83 postspraying triatomines from different houses. Genetic variability was similar between baseline and postspraying populations, but 13 low-frequency alleles were not detected at postspraying. FSTs were not significant between insects collected before and after insecticide spraying at the same house in all but one case, and they clustered together in a neighbor-joining tree. A clustering algorithm detected seven genetic groups, four of them mainly composed of baseline and postspraying insects from the same house. Assignment tests suggested multiple putative sources (including the house of collection) for most postspraying insects but excluded a house located more than 9 km from the study area. The origin of three triatomines was attributed to immigration from other unaccounted sources. Our study is compatible with the hypothesis that house reinfestations in the Argentine Chaco are mostly related to residual foci (i.e., survival of insects within the same community), in agreement with field observations, spatial analysis, and morphometric studies previously published. PMID- 29385502 TI - Correcting the linear and nonlinear distortions for atomically resolved STEM spectrum and diffraction imaging. AB - Specimen and stage drift as well as scan distortions can lead to a mismatch between true and desired electron probe positions in scanning transmission electron microscopy (STEM) which can result in both linear and nonlinear distortions in the subsequent experimental images. This problem is intensified in STEM spectrum and diffraction imaging techniques owing to the extended dwell times (pixel exposure time) as compared to conventional STEM imaging. As a consequence, these image distortions become more severe in STEM spectrum/diffraction imaging. This becomes visible as expansion, compression and/or shearing of the crystal lattice, and can even prohibit atomic resolution and thus limits the interpretability of the results. Here, we report a software tool for post-correcting the linear and nonlinear image distortions of atomically resolved 3D spectrum imaging as well as 4D diffraction imaging. This tool improves the interpretability of distorted STEM spectrum/diffraction imaging data. PMID- 29385503 TI - Effects of a live yeast in natural-program finishing feedlot diets on growth performance, digestibility, carcass characteristics, and feeding behavior. AB - Effects of live yeast (Saccharomyces cerevisiae) in steam-flaked corn-based diets fed to natural-program beef cattle on growth performance, total tract apparent digestibility, carcass characteristics, and feeding behavior were evaluated in a randomized block design experiment. Steers (n = 144; 341 +/- 7.03 kg) were blocked by initial BW and assigned randomly to 1 of the 3 treatments (n = 12 pens per treatment with 4 steers per pen). Treatments included the following: 1) control (CTL; no yeast); 2) low yeast (LY; 1.5 g/animal daily [3 * 1010 CFU]); and 3) high yeast (HY; 3.0 g/animal daily [6 * 1010 CFU]). Technologies such as implants, ionophores, and antibiotics were not used, and the steam-flaked corn based finishing diets were fed to provide ad libitum access to feed. Yeast was included in a cottonseed meal-based premix as 1% of the dietary DM. Spot fecal samples (twice daily for 5 consecutive days) and diets were composited by pen and analyzed for acid insoluble ash to estimate apparent total tract digestibility of nutrients. Cattle were slaughtered on days 183 (4 blocks) and 204 (8 blocks). Dry matter intake (P >= 0.29), ADG (P >= 0.17), and G:F (P >= 0.33) did not differ among treatments. The percentage of Premium Choice (P < 0.01) carcasses increased linearly with increasing yeast inclusion in the diet. A quadratic response was observed for total tract apparent digestibility, in which steers fed LY had greater digestibility (P < 0.01) of DM by 5.4%, OM by 4.8%, NDF by 15.2%, ADF by 20.2%, CP by 6.2%, and ether extract (EE) by 2.5% compared with steers fed CTL. Feeding behavior was not affected (P = 0.28) by treatments. Live yeast improved digestibility of DM, OM, CP, EE, and fiber, without changing feeding behavior and growth performance of natural-program steers fed steam-flaked corn-based finishing diets. PMID- 29385504 TI - Synergistic and additive interactions of Serratia marcescens S-JS1 to the chemical insecticides for controlling Nilaparvata lugens (Hemiptera: Delphacidae). AB - The combined use of entomopathogens and chemical agents has been suggested as an alternative strategy to control pest insects. However, the effectiveness of combinations of entomopathogenic bacteria and insecticides against rice planthoppers is largely unknown. Here, we evaluated the separate and combined effects of an entomopathogenic bacterium, Serratia marcescens S-JS1, and spirotetramat or thiamethoxam insecticides against third-instar nymphs of Nilaparvata lugens Stal (Hemiptera: Delphacidae) under laboratory and greenhouse conditions. Under laboratory conditions, the combinations caused higher mortality in the third-instar nymphs of N. lugens and produced a synergistic or additive effect compared with the treatments with either bacterial suspension or insecticide alone. Application of S-JS1 (1 * 109 cfu/ml) in combination with 20 mg/liter spirotetramat resulted in 80.5% of N. lugens nymphal mortality, compared with 52.7% in spirotetramat alone treatments, and interactions resulted in a synergistic responses. Other combination treatments of S-JS1 with either insecticide concentration all exhibited additive interactions. In further greenhouse tests, S-JS1 (1 * 109 cfu/ml) + spirotetramat (20 mg/liter) and S-JS1 (1 * 109 cfu/ml) + thiamethoxam (5 mg/liter) showed additive effects against the nymphs, and were found to be most effective relative to their individual treatments on days 5 and 9. Our results indicate that S. marcescens S-JS1 combined with insecticide may provide a promising new strategy for controlling N. lugens. PMID- 29385506 TI - Erratum: Recovery of Infectious Hepatitis C Virus from Injection Paraphernalia: Implications for Prevention Programs Serving People Who Inject Drugs. PMID- 29385505 TI - Impact evaluation of the routine hepatitis B vaccination program of infants in China. AB - Background: To evaluate the impact of the routine hepatitis B vaccination program of infants in China. Methods: The incidence of new hepatitis B infection and coverage with three doses of the vaccines by age groups and provinces were derived from the National Network Direct Report System of Infectious Disease during 2004-10. Chi square test and Pearson correlation analysis were used to analyze differences in incidence according to vaccination coverage and the relationship between the coverage with three doses and the incidence in different provinces. Results: The incidence of new infection was 8.96/100 000 among children with complete coverage (0-15 years old), which was significantly lower than that with partial or no coverage. Among 0-9-year-old children in 2010, the incidence of new infection was 6.36/100 000, which was significantly lower than 2004. Considering the impact of vaccination on cumulative incidence among 0-5 year-old children, a 2.2-fold greater incidence of new infection was observed in provinces with the lowest to the highest vaccination rate. Conclusion: The impact of the routine hepatitis B vaccination program of infants in China has become more apparent over time. Program implementation and regional disequilibrium should be payed attention to as well as the expanded program. PMID- 29385507 TI - Vitamin D status of female UAE college students and associated risk factors. AB - Objective: Vitamin D deficiency is now recognized as a pandemic with implications for bone health and chronic diseases. The study investigated the vitamin D status and risk factors of subnormal serum vitamin D levels in female college students. Design: Cross-sectional study. Setting: American University of Sharjah, United Arab Emirate. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured for the participating female undergraduate college students using a radioimmunoassay kit. All participants answered a questionnaire that included 30 questions, which covered among others the demographic information, dietary intake, sun exposure and autoimmune diseases. Subjects: Undergraduate college female students (n, 480), aged 18-26 years. Results: Overall, 47.92% had suboptimal serum vitamin D levels. Results indicated that vitamin D deficiency and other health problems are prevalent among female university students. Risk factors included: wearing hijab by 37.5% of the students that might have interfered with the penetration of UVB radiation into the skin, short time sun exposure, use of sunscreens and limited intake of foods rich in vitamin D. Conclusions: Vitamin D deficiency is a problem in female college students due to lifestyle, and avoidance of sun exposure. Poor vitamin D status has been associated with increased risk for development of several autoimmune diseases, and other health conditions. This problem needs to be addressed, where prevention of future health consequences in this young group is still possible. PMID- 29385508 TI - Development, Optimization, and Field Evaluation of the Novel Collapsible Passive Trap for Collection of Mosquitoes. AB - Disease surveillance for mosquito-borne pathogens in remote areas can be challenging. Most traps used to collect mosquitoes either need a source of electricity or are bulky and inflexible, making transportation awkward. To reduce these issues we developed three Collapsible Passive Traps (CPTs) and conducted trials in Cairns, Australia to evaluate the optimal design for a CPT and compared them to traditionally-used traps such as Centers for Disease Control and Prevention (CDC) and Encephalitis Vector Surveillance (EVS) light traps. We found that two of the CPTs collected comparable numbers of mosquitoes and that one of the CPTs outperformed the CDC light trap in collecting Aedes species. Mosquitoes did not have to pass through a fan while entering the CPT, and thus were not damaged and were often alive. Our results suggest that the CPT can be an effective trap for mosquito surveillance, especially in remote areas. PMID- 29385510 TI - The Analysis of Polyploid Genetic Data. AB - Though polyploidy is an important aspect of the evolutionary genetics of both plants and animals, the development of population genetic theory of polyploids has seriously lagged behind that of diploids. This is unfortunate since the analysis of polyploid genetic data-and the interpretation of the results-requires even more scrutiny than with diploid data. This is because of several polyploidy specific complications in segregation and genotyping such as tetrasomy, double reduction, and missing dosage information. Here, we review the theoretical and statistical aspects of the population genetics of polyploids. We discuss several widely used types of inferences, including genetic diversity, Hardy-Weinberg equilibrium, population differentiation, genetic distance, and detecting population structure. For each, we point out how the statistical approach, expected result, and interpretation differ between different ploidy levels. We also discuss for each type of inference what biases may arise from the polyploid specific complications and how these biases can be overcome. From our overview, it is clear that the statistical toolbox that is available for the analysis of genetic data is flexible and still expanding. Modern sequencing techniques will soon be able to overcome some of the current limitations to the analysis of polyploid data, though the techniques are lagging behind those available for diploids. Furthermore, the availability of more data may aggravate the biases that can arise, and increase the risk of false inferences. Therefore, simulations such as we used throughout this review are an important tool to verify the results of analyses of polyploid genetic data. PMID- 29385509 TI - Translational Selection for Speed Is Not Sufficient to Explain Variation in Bacterial Codon Usage Bias. AB - Increasing growth rate across bacteria strengthens selection for faster translation, concomitantly increasing the total number of tRNA genes and codon usage bias (CUB: enrichment of specific synonymous codons in highly expressed genes). Typically, enriched codons are translated by tRNAs with higher gene copy numbers (GCN). A model of tRNA-CUB coevolution based on fast growth-associated selection on translational speed recapitulates these patterns. A key untested implication of the coevolution model is that translational selection should favor higher tRNA GCN for more frequently used amino acids, potentially weakening the effect of growth-associated selection on CUB. Surprisingly, we find that CUB saturates with increasing growth rate across gamma-proteobacteria, even as the number of tRNA genes continues to increase. As predicted, amino acid-specific tRNA GCN is positively correlated with the usage of corresponding amino acids, but there is no correlation between growth rate associated changes in CUB and amino acid usage. Instead, we find that some amino acids-cysteine and those in the NNA/G codon family-show weak CUB that does not increase with growth rate, despite large variation in the corresponding tRNA GCN. We suggest that amino acid specific variation in CUB is not explained by tRNA GCN because GCN does not influence the difference between translation times of synonymous codons as expected. Thus, selection on translational speed alone cannot fully explain quantitative variation in overall or amino acid-specific CUB, suggesting a significant role for other functional constraints and amino acid-specific codon features. PMID- 29385511 TI - Physical activity buffers the negative relationship between multimorbidity, self rated health and life satisfaction. AB - Background: This study aimed to examine the relationship between multimorbidity, self-rated health and life satisfaction, and to test the moderating effect of physical activity on the relationship between multimorbidity, self-rated health and life satisfaction. Methods: This is a cross-sectional study based on data from the European Social Survey 2014. Participants were 25 713 adults (12 830 men), aged 18-64 years old, from 18 European countries and Israel. Self-reported information regarding chronic diseases, health perception, life satisfaction and physical activity was collected through interview. Multimorbidity was defined as the co-occurrence of >= 2 chronic diseases. Linear regression models were used to estimate the effects of multimorbidity, physical activity and the interaction effect of multimorbidity * physical activity on self-rated health and life satisfaction. Results: Multimorbidity was negatively related to self-rated health (d = 0.03) and life satisfaction (d = 0.03). Physical activity was positively related to self-rated health and life satisfaction. There was a significant interaction effect between multimorbidity and physical activity with regard to self-rated health (beta = 0.01, P < 0.001) and life satisfaction (beta = 0.04, P < 0.001). Conclusions: Physical activity buffered the negative relationship between multimorbidity, self-rated health and life satisfaction; contributing to better self-rated health and life satisfaction. PMID- 29385512 TI - Meningococcal vaccination in primary care amongst adolescents in North West England: an ecological study investigating associations with general practice characteristics. AB - Background: In 2015 the meningococcal ACWY (MenACWY) vaccination was introduced amongst adolescents in England following increased incidence and mortality associated with meningococcal group W. Methods: MenACWY vaccination uptake data for 17-18 years old and students delivered in primary care were obtained for 20 National Health Service clinical commissioning groups (CCGs) via the ImmForm vaccination system. Data on general practice characteristics, encompassing demographics and patient satisfaction variables, were extracted from the National General Practice Profiles resource. Univariable analysis of the associations between practice characteristics and vaccination was performed, followed by multivariable negative binomial regression. Results: Data were utilized from 587 general practices, accounting for ~8% of all general practices in England. MenACWY vaccination uptake varied from 20.8% to 46.8% across the CCGs evaluated. Upon multivariable regression, vaccination uptake increased with increasing percentage of patients from ethnic minorities, increasing percentage of patients aged 15-24 years, increasing percentage of patients that would recommend their practice and total Quality and Outcomes Framework achievement for the practice. Conversely, vaccination uptake decreased with increasing deprivation. Conclusions: This study has identified several factors independently associated with MenACWY vaccination in primary care. These findings will enable a targeted approach to improve general practice-level vaccination uptake. PMID- 29385513 TI - The nature and frequency of abdominal symptoms in cancer patients and their associations with time to help-seeking: evidence from a national audit of cancer diagnosis. AB - Background: Raising awareness of possible cancer symptoms is important for timely help-seeking; recent campaigns have focused on symptom groups (such as abdominal symptoms) rather than individual alarm symptoms associated with particular cancer sites. The evidence base supporting such initiatives is still emerging however; understanding the frequency and nature of presenting abdominal symptoms among cancer patients could inform the design and evaluation of public health awareness campaigns. Methods: We examined eight presenting abdominal symptoms (abdominal pain, change in bowel habit, bloating/distension, dyspepsia, rectal bleeding, dysphagia, reflux and nausea/vomiting) among 15 956 patients subsequently diagnosed with cancer in England. We investigated the cancer site case-mix and variation in the patient interval (symptom-onset-to-presentation) by abdominal symptom. Results: Almost a quarter (23%) of cancer patients presented with abdominal symptoms before being diagnosed with one of 27 common and rarer cancers. The patient interval varied substantially by abdominal symptom: median (IQR) intervals ranged from 7 (0-28) days for abdominal pain to 30 (4-73) days for dysphagia. This variation persisted after adjusting for age, sex and ethnicity (P < 0.001). Conclusions: Abdominal symptoms are common at presentation among cancer patients, while time to presentation varies by symptom. The need for awareness campaigns may be greater for symptoms associated with longer intervals to help-seeking. PMID- 29385514 TI - Quantification of the kV X-ray imaging dose during real-time tumor tracking and from three- and four-dimensional cone-beam computed tomography in lung cancer patients using a Monte Carlo simulation. AB - Knowledge of the imaging doses delivered to patients and accurate dosimetry of the radiation to organs from various imaging procedures is becoming increasingly important for clinicians. The purposes of this study were to calculate imaging doses delivered to the organs of lung cancer patients during real-time tumor tracking (RTTT) with three-dimensional (3D), and four-dimensional (4D) cone-beam computed tomography (CBCT), using Monte Carlo techniques to simulate kV X-ray dose distributions delivered using the Vero4DRT. Imaging doses from RTTT, 3D-CBCT and 4D-CBCT were calculated with the planning CT images for nine lung cancer patients who underwent stereotactic body radiotherapy (SBRT) with RTTT. With RTTT, imaging doses from correlation modeling and from monitoring of imaging during beam delivery were calculated. With CBCT, doses from 3D-CBCT and 4D-CBCT were also simulated. The doses covering 2-cc volumes (D2cc) in correlation modeling were up to 9.3 cGy for soft tissues and 48.4 cGy for bone. The values from correlation modeling and monitoring were up to 11.0 cGy for soft tissues and 59.8 cGy for bone. Imaging doses in correlation modeling were larger with RTTT. On a single 4D-CBCT, the skin and bone D2cc values were in the ranges of 7.4-10.5 cGy and 33.5-58.1 cGy, respectively. The D2cc from 4D-CBCT was approximately double that from 3D-CBCT. Clinicians should Figure that the imaging dose increases the cumulative doses to organs. PMID- 29385515 TI - Genuine Smiles by Patients During Marital Interactions are Associated with Better Caregiver Mental Health. AB - Objective: Providing care for a spouse with dementia is associated with an increased risk for poor mental health. To determine whether this vulnerability in caregivers is related to the expression of positive emotion, we examined 57 patients with Alzheimer's disease and behavioral variant frontotemporal dementia and their spouses as they discussed a marital conflict. Method: Facial behavior during the discussion was objectively coded to identify Duchenne (i.e., genuine) smiles and non-Duchenne (i.e., polite) smiles. Caregiver mental health was measured using the Medical Outcomes Survey. Results: Greater expression of Duchenne smiles by patients was associated with better caregiver mental health, even when accounting for covariates (i.e., diagnosis, patient cognitive functioning, and caregiver marital satisfaction). Greater expression of non Duchenne smiles by patients was associated with worse caregiver health, but only when covariates were entered in the model. Expression of Duchenne and non Duchenne smiles by caregivers was not associated with caregiver mental health. Discussion: Patients' expression of Duchenne and non-Duchenne smiles may reveal important aspects of the emotional quality of the patient-caregiver relationship that influence caregiver burden and mental health. PMID- 29385516 TI - Chemical Constituents of Coreopsis lanceolata Stems and Their Antitermitic Activity Against the Subterranean Termite Coptotermes curvignathus. AB - Coreopsis lanceolata is an Asteraceous plant known to contain semiochemicals active against nematodes and leukemic agents. The objective of the study was to discover termite resistant constituents from C. lanceolata stems. Five compounds were isolated from C. lanceolata stems. These compounds were identified as 5 phenyl-2-(1-propynyl)-thiophene (1), 1-phenylhepta-1,3,5-tryne (2), beta sitosterol (3), succinic acid (4), and protocatechuic acid (5), respectively; they were confirmed by spectroscopic analysis. Their antitermitic effects were evaluated with the no-choice feeding test against Coptotermes curvignathus. Of the isolates, 5-phenyl-2-(1-propynyl)-thiophene (1) and 1-phenylhepta-1,3,5-tryne (2) showed strong potent antitermitic activity. Our findings suggested that compounds 1 and 2 isolated from C. lanceolata stems appears to be the active ingredients. PMID- 29385517 TI - Strigolactones: new plant hormones in the spotlight. AB - The development and growth of plants are regulated by interplay of a plethora of complex chemical reactions in which plant hormones play a pivotal role. In recent years, a group of new plant hormones, namely strigolactones (SLs), was discovered and identified. The first SL, strigol, was isolated in 1966, but it took almost 20 years before the details of its structure were fully elucidated. At present, two families of SLs are known, one having the stereochemistry of (+)-strigol and the other that of (-)-orobanchol, the most abundant naturally occurring SL. The most well-known bioproperty of SLs is the germination of seeds of the parasitic weeds Striga and Orobanche. It is evident that SLs are going to play a prominent role in modern molecular botany. In this review, relevant molecular and bioproperties of SLs are discussed. Items of importance are the effect of stereochemistry, structure-activity relationships, design and synthesis of analogues with a simple structure, but with retention of bioactivity, introduction of fluorescent labels into SLs, biosynthetic origin of SLs, mode of action in plants, application in agriculture for the control of parasitic weeds, stimulation of the branching of arbuscular mycorrhizal (AM) fungi, and the control of plant architecture. The future potential of SLs in molecular botany is highlighted. PMID- 29385518 TI - Memory Deficits Precede Increases in Depressive Symptoms in Later Adulthood. AB - Objectives: We examined bidirectional, time-ordered associations between age related changes in depressive symptoms and memory. Method: Data came from 107,599 community-dwelling adults, aged 49-90 years, who participated in the Survey of Health, Ageing, and Retirement in Europe (SHARE). Depressive symptoms were measured with the EURO-D inventory, and memory was evaluated as delayed recall of a 10-word list. Participants were assessed up to five times at 2-year intervals. Dynamic structural equation models were used to estimate longitudinal and time ordered (lead-lag) relations between depressive symptoms and memory performance. Results: Depressive symptoms increased and memory scores decreased across the observed age range, with worsening mostly evident after age 62 years. These long term changes were moderately negatively correlated (r = -.53, p < .001). A time ordered effect emerged such that age-specific memory deficits preceded shorter term increases in depression symptoms. This effect can be translated such that each 1-point decrement on a 10-point memory scale at a given age predicted a 14.5% increased risk for depression two years later. Statistical adjustment for covariates (sex, education, re-test, smoking, and body mass index) had little influence on these associations. Conclusion: In later adulthood, lower memory performance at a given age predicts subsequent 2-year increases in depressive symptoms. PMID- 29385519 TI - Genomic dissection of enhancers uncovers principles of combinatorial regulation and cell type-specific wiring of enhancer-promoter contacts. AB - Genomic binding of transcription factors, like the glucocorticoid receptor (GR), is linked to the regulation of genes. However, as we show here, GR binding is a poor predictor of GR-dependent gene regulation even when taking the 3D organization of the genome into account. To connect GR binding sites to the regulation of genes in the endogenous genomic context, we turned to genome editing. By deleting GR binding sites, individually or in combination, we uncovered how cooperative interactions between binding sites contribute to the regulation of genes. Specifically, for the GR target gene GILZ, we show that the simultaneous presence of a cluster of GR binding sites is required for the activity of an individual enhancer and that the GR-dependent regulation of GILZ depends on multiple GR-bound enhancers. Further, by deleting GR binding sites that are shared between different cell types, we show how cell type-specific genome organization and enhancer-blocking can result in cell type-specific wiring of promoter-enhancer contacts. This rewiring allows an individual GR binding site shared between different cell types to direct the expression of distinct transcripts and thereby contributes to the cell type-specific consequences of glucocorticoid signaling. PMID- 29385520 TI - Zinc injection as a novel castration method in beef bulls: effects on performance, behavior, and testosterone and haptoglobin concentration. AB - Crossbred beef bulls (n = 180) were blocked by initial BW (337 +/- 10.9 kg; six blocks) and assigned randomly to one of three treatments on day 0: 1) INJ; received 1 mL (100 mg Zn) of a Zn solution in each testis, 2) BAN; received blood restrictive rubber band placed around the dorsal aspect of the scrotum, 3) BUL; bulls with testicles remaining intact in a randomized complete block design (three treatment pens per block and 10 cattle per pen). A subset of 54 animals (n = 3 per pen) was fitted with accelerometers on day 0 to quantify behavior variables continuously for 28 d. Testis width and scrotal circumference, and serum haptoglobin (days 0, 1, 3, 5, 7, and 14) and testosterone concentrations (every 28 d until slaughter) were also determined for the subset. During the slaughter process, testes from INJ and BUL were collected to assess final testes weight and for histopathological evaluation. Data were analyzed using a mixed model (alpha = 0.05); pen served as the experimental unit for all dependent variables. Final BW was greater (P < 0.01) for INJ and BUL compared to BAN (672, 686, and 611 kg, respectively; SEM = 4.4). Overall ADG and G:F were greater (P <= 0.03) in INJ and BUL than BAN; whereas, DMI was similar between treatments for the study duration (P = 0.46). Histopathological evaluation (n = 13; INJ = 7; BUL = 6) indicated that INJ testes were degenerative and reproductively nonviable whereas BUL testes were normal. Serum testosterone concentrations on day 168 were similar (P = 0.14) between INJ and BUL whereas after day 14, BAN was nondetectable; however, initial serum testosterone concentrations were similarly low across treatments. Serum haptoglobin concentration was greater (P < 0.01) in INJ than BUL and BAN on days 1, 3, 5, and 7. Scrotal circumference (P = 0.08) and testis width (P = 0.07) on day 168 tended to be greater for BUL than INJ. Motion index (P <= 0.02) and step count (P = 0.04) was greater in BUL and INJ compared to BAN cattle during the 28 d monitoring period. No difference in standing time (P >= 0.85) or lying bouts (P = 0.35) occurred. Zinc injection resulted in sterilization but did not cause complete cessation of testicular function evidenced by testosterone concentrations more similar to BUL than BAN. This resulted in overall increased BW and G:F for INJ vs. BAN, yet the acute phase response was markedly greater directly after Zn injection. Collectively, Zn injection resulted in outcomes more similar to BUL than BAN, implying minimal efficacy of INJ as a castration method in older bulls arriving to the feedlot. PMID- 29385521 TI - Modular discovery of monomeric and dimeric transcription factor binding motifs for large data sets. AB - In some dimeric cases of transcription factor (TF) binding, the specificity of dimeric motifs has been observed to differ notably from what would be expected were the two factors to bind to DNA independently of each other. Current motif discovery methods are unable to learn monomeric and dimeric motifs in modular fashion such that deviations from the expected motif would become explicit and the noise from dimeric occurrences would not corrupt monomeric models. We propose a novel modeling technique and an expectation maximization algorithm, implemented as software tool MODER, for discovering monomeric TF binding motifs and their dimeric combinations. Given training data and seeds for monomeric motifs, the algorithm learns in the same probabilistic framework a mixture model which represents monomeric motifs as standard position-specific probability matrices (PPMs), and dimeric motifs as pairs of monomeric PPMs, with associated orientation and spacing preferences. For dimers the model represents deviations from pure modular model of two independent monomers, thus making co-operative binding effects explicit. MODER can analyze in reasonable time tens of Mbps of training data. We validated the tool on HT-SELEX and ChIP-seq data. Our findings include some TFs whose expected model has palindromic symmetry but the observed model is directional. PMID- 29385522 TI - The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts. AB - Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA. We found that NS5A bound to GU-rich elements in vitro and in cells. Mutation of the NS5A zinc finger abrogated its GU-rich element-binding and mRNA stabilizing activities. Overall, we identified a molecular mechanism whereby HCV manipulates host gene expression by stabilizing host transcripts in a manner that would promote growth and prevent death of virus infected cells, allowing the virus to establish chronic infection and lead to the development of hepatocellular carcinoma. PMID- 29385524 TI - Physical Therapists' Ability to Identify Psychological Factors and Their Self Reported Competence to Manage Chronic Low Back Pain. AB - Background: In the management of chronic low back pain (LBP), identifying and managing more patients who are at high risk and who have psychological barriers to recovery is important yet difficult. Objective: The objective of this study was to test physical therapists' ability to allocate patients into risk stratification groups, test correlations between therapists' assessments of psychological factors and patient questionnaires, and explore relationships between psychological factors and therapists' self-reported competence to manage patients with chronic LBP. Design: This was a pragmatic, observational study. Methods: Patients completed the STarT Back Tool (SBT, for risk stratification), the Four-Dimensional Symptom Questionnaire (distress, depression, anxiety), and the Tampa Scale of Kinesiophobia (kinesiophobia) prior to the intake session. After this session, physical therapists estimated patient prognostic risk using the 3 SBT categories and rated patient psychological factors using a 0-to-10 scale. Finally, therapists reported their self-reported competence to manage the patient. Intraclass and Spearman rank correlations tested correlations between therapists' intuitive assessments and patient questionnaires. A linear-mixed model explored relationships between psychological factors and therapists' self reported competence. Results: Forty-nine patients were managed by 20 therapists. Therapists accurately estimated SBT risk allocation in only 41% of patients. Correlations between therapist perceptions and patient questionnaires were moderate for distress (r = 0.602) and fair for depression (r = 0.304) and anxiety (r = 0.327). There was no correlation for kinesiophobia (r = -0.007). Patient distress was identified as a negative predictor of therapists' self-reported competence. Limitations: This was a cross-sectional study, conducted in only 1 center. Conclusions: Physical therapists were not very accurate at allocating patients into risk stratification groups or identifying psychological factors. Therapists' self-reported competence in managing patients was lowest when patients reported higher distress. PMID- 29385523 TI - TelAP1 links telomere complexes with developmental expression site silencing in African trypanosomes. AB - During its life cycle, Trypanosoma brucei shuttles between a mammalian host and the tsetse fly vector. In the mammalian host, immune evasion of T. brucei bloodstream form (BSF) cells relies on antigenic variation, which includes monoallelic expression and periodic switching of variant surface glycoprotein (VSG) genes. The active VSG is transcribed from only 1 of the 15 subtelomeric expression sites (ESs). During differentiation from BSF to the insect-resident procyclic form (PCF), the active ES is transcriptionally silenced. We used mass spectrometry-based interactomics to determine the composition of telomere protein complexes in T. brucei BSF and PCF stages to learn more about the structure and functions of telomeres in trypanosomes. Our data suggest a different telomere complex composition in the two forms of the parasite. One of the novel telomere associated proteins, TelAP1, forms a complex with telomeric proteins TbTRF, TbRAP1 and TbTIF2 and influences ES silencing kinetics during developmental differentiation. PMID- 29385526 TI - Human C-to-U Coding RNA Editing Is Largely Nonadaptive. AB - C-to-U RNA editing enzymatically converts the base C to U in RNA molecules and could lead to nonsynonymous changes when occurring in coding regions. Hundreds to thousands of coding sites were recently found to be C-to-U edited or editable in humans, but the biological significance of this phenomenon is elusive. Here, we test the prevailing hypothesis that nonsynonymous editing is beneficial because it provides a means for tissue- or time-specific regulation of protein function that may be hard to accomplish by mutations due to pleiotropy. The adaptive hypothesis predicts that the fraction of sites edited and the median proportion of RNA molecules edited (i.e., editing level) are both higher for nonsynonymous than synonymous editing. However, our empirical observations are opposite to these predictions. Furthermore, the frequency of nonsynonymous editing, relative to that of synonymous editing, declines as genes become functionally more important or evolutionarily more constrained, and the nonsynonymous editing level at a site is negatively correlated with the evolutionary conservation of the site. Together, these findings refute the adaptive hypothesis; they instead indicate that the reported C-to-U coding RNA editing is mostly slightly deleterious or neutral, probably resulting from off-target activities of editing enzymes. Along with similar conclusions on the more prevalent A-to-I editing and m6A modification of coding RNAs, our study suggests that, at least in humans, most events of each type of posttranscriptional coding RNA modification likely manifest cellular errors rather than adaptations, demanding a paradigm shift in the research of posttranscriptional modification. PMID- 29385525 TI - The State of Software for Evolutionary Biology. AB - With Next Generation Sequencing data being routinely used, evolutionary biology is transforming into a computational science. Thus, researchers have to rely on a growing number of increasingly complex software. All widely used core tools in the field have grown considerably, in terms of the number of features as well as lines of code and consequently, also with respect to software complexity. A topic that has received little attention is the software engineering quality of widely used core analysis tools. Software developers appear to rarely assess the quality of their code, and this can have potential negative consequences for end-users. To this end, we assessed the code quality of 16 highly cited and compute intensive tools mainly written in C/C++ (e.g., MrBayes, MAFFT, SweepFinder, etc.) and JAVA (BEAST) from the broader area of evolutionary biology that are being routinely used in current data analysis pipelines. Because, the software engineering quality of the tools we analyzed is rather unsatisfying, we provide a list of best practices for improving the quality of existing tools and list techniques that can be deployed for developing reliable, high quality scientific software from scratch. Finally, we also discuss journal as well as science policy and, more importantly, funding issues that need to be addressed for improving software engineering quality as well as ensuring support for developing new and maintaining existing software. Our intention is to raise the awareness of the community regarding software engineering quality issues and to emphasize the substantial lack of funding for scientific software development. PMID- 29385527 TI - Harm Perceptions of Menthol and Nonmenthol Cigarettes Differ by Brand, Race/Ethnicity, and Gender in US Adult Smokers: Results from PATH Wave 1. AB - Introduction: Harm perceptions of menthol cigarettes may contribute to their appeal and use. African-Americans, women, and younger smokers disproportionately use menthol cigarettes, and may misperceive harm of menthol cigarettes. Methods: Data were from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study. Weighted analyses of current adult smokers (18 and older) were used to estimate the correlates of menthol smoking among all cigarette brands and separately for the top three cigarette brands (Newport, Camel, and Marlboro). Adjusted models examined the main effect of menthol smoking on harm perceptions of one's own brand of cigarette and interactions with race/ethnicity, age, and gender. Results: Menthol cigarettes were used by nearly 40% of current smokers, although the prevalence of menthol smoking differed across the top three brands (94% Newport, 46% Camel, and 18% Marlboro). Among menthol smokers, 80% perceived their cigarette as equally harmful, 14% perceived their brand as more harmful, and 7% perceived their brand as less harmful. In adjusted models, menthol smokers were more likely than nonmenthol smokers to misperceive their own brand as more harmful than other brands (compared to no difference in harm). Race and gender emerged as moderators of the association between menthol brand preference and harm perceptions. Conclusions: In adjusted analyses, menthol smokers were more likely than nonmenthol smokers to perceive their brand as more harmful than other brands, with differences by sub-groups who disproportionately use menthol. Implications: Menthol cigarettes have been historically marketed with messages conveying lower harm than other cigarettes. Little is known about how contemporary adult menthol smokers perceive the harm of their usual brand, and potential differences by race, gender, and young adult versus older adult age group. After adjusting for other factors, menthol smokers were more likely than nonmenthol smokers to perceive their cigarette brand as more harmful than other brands. Further, the association between menthol smoking and harm perceptions differed by race and gender, but not by age group (young adult vs. older adult). This type of large-scale study identifies critical links between menthol smoking and harm perceptions among vulnerable smokers that will inform regulatory actions designed to decrease smoking-related harm. PMID- 29385528 TI - Comparison of calculated beta- and gamma-ray doses after the Fukushima accident with data from single-grain luminescence retrospective dosimetry of quartz inclusions in a brick sample. AB - To estimate the beta- and gamma-ray doses in a brick sample taken from Odaka, Minami-Soma City, Fukushima Prefecture, Japan, a Monte Carlo calculation was performed with Particle and Heavy Ion Transport code System (PHITS) code. The calculated results were compared with data obtained by single-grain retrospective luminescence dosimetry of quartz inclusions in the brick sample. The calculated result agreed well with the measured data. The dose increase measured at the brick surface was explained by the beta-ray contribution, and the slight slope in the dose profile deeper in the brick was due to the gamma-ray contribution. The skin dose was estimated from the calculated result as 164 mGy over 3 years at the sampling site. PMID- 29385529 TI - BES1 and BZR1 Redundantly Promote Phloem and Xylem Differentiation. AB - Vascular development is a good model for studying cell differentiation in plants. Two conductive tissues, the xylem and phloem, are derived from common stem cells known as procambial/cambial cells. Glycogen synthase kinase 3 proteins (GSK3s) play crucial roles in maintaining procambial/cambial cells by suppressing their differentiation into xylem or phloem cells. We previously designed an in vitro culture system for analyzing vascular cell differentiation named VISUAL (Vascular cell Induction culture System Using Arabidopsis Leaves). Using this system, we found that the transcription factor BRI1-EMS-SUPPRESSOR 1 (BES1) functions as a downstream target of GSK3s during xylem differentiation. However, the function of BES1 in vascular development remains largely unknown. Here, we found that, in addition to xylem differentiation, BES1 positively regulates phloem differentiation downstream of GSK3s. Transcriptome analysis using VISUAL confirmed that BES1 promotes bi-directional differentiation of procambial cells into xylem and phloem cells. Genetic analysis of loss-of-function mutants newly generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system revealed that BRASSINAZOLE RESISTANT 1 (BZR1), the closest homolog of BES1, functions in vascular development redundantly with BES1. Notably, BZR1 has a weaker impact on vascular cell differentiation than BES1, suggesting that they contribute differentially to this process. In conclusion, our findings indicate that BES1 and BZR1 are key regulators of both xylem and phloem cell differentiation from vascular stem cells. PMID- 29385530 TI - Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells. AB - Transcriptionally non-co-linear (NCL) transcripts can originate from trans splicing (trans-spliced RNA; 'tsRNA') or cis-backsplicing (circular RNA; 'circRNA'). While numerous circRNAs have been detected in various species, tsRNAs remain largely uninvestigated. Here, we utilize integrative transcriptome sequencing of poly(A)- and non-poly(A)-selected RNA-seq data from diverse human cell lines to distinguish between tsRNAs and circRNAs. We identified 24,498 NCL events and found that a considerable proportion (20-35%) of them arise from both tsRNAs and circRNAs, representing extensive alternative trans-splicing and cis backsplicing in human cells. We show that sequence generalities of exon circularization are also observed in tsRNAs. Recapitulation of NCL RNAs further shows that inverted Alu repeats can simultaneously promote the formation of tsRNAs and circRNAs. However, tsRNAs and circRNAs exhibit quite different, or even opposite, expression patterns, in terms of correlation with the expression of their co-linear counterparts, expression breadth/abundance, transcript stability, and subcellular localization preference. These results indicate that tsRNAs and circRNAs may play different regulatory roles and analysis of NCL events should take the joint effects of different NCL-splicing types and joint effects of multiple NCL events into consideration. This study describes the first transcriptome-wide analysis of trans-splicing and cis-backsplicing, expanding our understanding of the complexity of the human transcriptome. PMID- 29385531 TI - Comment on: Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature. PMID- 29385532 TI - Sequence-specific DNA binding activity of the cross-brace zinc finger motif of the piggyBac transposase. AB - The piggyBac transposase (PB) is distinguished by its activity and utility in genome engineering, especially in humans where it has highly promising therapeutic potential. Little is known, however, about the structure-function relationships of the different domains of PB. Here, we demonstrate in vitro and in vivo that its C-terminal Cysteine-Rich Domain (CRD) is essential for DNA breakage, joining and transposition and that it binds to specific DNA sequences in the left and right transposon ends, and to an additional unexpectedly internal site at the left end. Using NMR, we show that the CRD adopts the specific fold of the cross-brace zinc finger protein family. We determine the interaction interfaces between the CRD and its target, the 5'-TGCGT-3'/3'-ACGCA-5' motifs found in the left, left internal and right transposon ends, and use NMR results to propose docking models for the complex, which are consistent with our site directed mutagenesis data. Our results provide support for a model of the PB/DNA interactions in the context of the transpososome, which will be useful for the rational design of PB mutants with increased activity. PMID- 29385533 TI - Sarcoidosis with primary pulmonary cavitation. PMID- 29385534 TI - The C-terminal region of translesion synthesis DNA polymerase eta is partially unstructured and has high conformational flexibility. AB - Eukaryotic DNA polymerase eta catalyzes translesion synthesis of thymine dimers and 8-oxoguanines. It is comprised of a polymerase domain and a C-terminal region, both of which are required for its biological function. The C-terminal region mediates interactions with proliferating cell nuclear antigen (PCNA) and other translesion synthesis proteins such as Rev1. This region contains a ubiquitin-binding/zinc-binding (UBZ) motif and a PCNA-interacting protein (PIP) motif. Currently little structural information is available for this region of polymerase eta. Using a combination of approaches-including genetic complementation assays, X-ray crystallography, Langevin dynamics simulations, and small-angle X-ray scattering-we show that the C-terminal region is partially unstructured and has high conformational flexibility. This implies that the C terminal region acts as a flexible tether linking the polymerase domain to PCNA thereby increasing its local concentration. Such tethering would facilitate the sampling of translesion synthesis polymerases to ensure that the most appropriate one is selected to bypass the lesion. PMID- 29385537 TI - Reply to Truffot et al. PMID- 29385535 TI - RUMINNAT NUTRITION SYMPOSIUM: Tiny but mighty: the role of the rumen microbes in livestock production. AB - The microbes inhabiting the rumen convert low-quality, fibrous, plant material into useable energy for the host ruminant. Consisting of bacteria, protozoa, fungi, archaea, and viruses, the rumen microbiome composes a sophisticated network of symbiosis essential to maintenance, immune function, and overall production efficiency of the host ruminant. Robert Hungate laid the foundation for rumen microbiome research. This area of research has expanded immensely with advances in methodology and technology that have not only improved the ability to describe microbes in taxonomic and density terms but also characterize populations of microbes, their functions, and their interactions with each other and the host. The interplay between the rumen microbiome and the host contributes to variation in many phenotypic traits expressed by the host animal. A better understanding of how the rumen microbiome influences host health and performance may lead to novel strategies and treatments for trait improvement. Furthermore, elucidation of maternal, genetic, and environmental factors that influence rumen microbiome establishment and development may provide novel insights into possible mechanisms for manipulating the rumen microbial composition to enhance long-term host health and performance. The potential for these tiny but mighty rumen microbes to play a role in improving livestock production is appreciated despite being relatively obscure. PMID- 29385538 TI - The impact of menopause on functional status in women with rheumatoid arthritis. AB - Objective: The aim of this study was to investigate the association of menopause with functional status outcomes in women with RA. Methods: Participants were women in a US-wide observational cohort who developed RA before menopause. The HAQ measured functional status. We controlled for confounding variables and used univariate and multivariable generalized estimating equation methods with the sandwich estimator of variance. Best models were selected using the quasi likelihood under the independence model criterion. A sensitivity analysis was performed using linear mixed effects regression models. Results: A total of 8189 women were eligible. Of these, 2005 (24.5%) were pre-menopausal, 611 (7.5%) transitioned through menopause during the study, and 5573 (68.1%) were post menopausal. Within each respective group, the mean (s.d.) ages were 39.7 (7.8), 50.7 (3.4) and 62.3 (9.3) years. Our results showed that women who were pre menopausal had less functional decline as measured by the HAQ compared with women who were post-menopausal; these results were robust and strong even after adjustment for other significant factors. The ever-use of hormonal replacement therapy, ever having a pregnancy, and longer length of reproductive life were associated with less functional decline. After menopause, the trajectory of functional decline worsened and accelerated in women with RA. Conclusion: The results suggest that menopausal status is associated with functional decline in women with RA. Furthermore, menopause is associated with a worsening progression of functional decline. These data indicate that menopause has a significant impact on the level and rate of functional decline in women with RA. PMID- 29385539 TI - Foxg1 Overexpression in Neocortical Pyramids Stimulates Dendrite Elongation Via Hes1 and pCreb1 Upregulation. AB - The architecture of neocortical projection neurons is subject of a complex gene control. Here we demonstrated that Foxg1, a transcription factor gene which patterns the early rostral brain and sets the pace of telencephalic neuronogenesis, specifically stimulates dendrite elongation. This phenomenon occurs in vivo like in vitro, and it is detectable even upon moderate changes of Foxg1 expression levels. We found that Foxg1 acts by stimulating Hes1, which in turn upregulates pCreb1, a well-known pro-dendritogenic effector, and downregulates Syt and Ndr1, namely two established antagonizers of dendrite elongation. Moreover, Foxg1-driven pCreb1 upregulation requires PKA and AKT, and correlates with reduced PP1 and PP2A phosphatase activity. These findings contribute to clarify normal neurodevelopmental and activity-related regulation of neuritogenesis. They further suggest that an abnormal sizing of the dendritic tree of neocortical projection neurons may occur in West and Rett syndrome patients with anomalous FOXG1 allele dosages and contribute to their neurolopathological profiles. PMID- 29385540 TI - Measurement of Human Immunodeficiency Virus p24 Antigen in Human Cerebrospinal Fluid With Digital Enzyme-Linked Immunosorbent Assay and Association With Decreased Neuropsychological Performance. AB - New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance. PMID- 29385536 TI - Pumilio directs deadenylation-associated translational repression of the cyclin dependent kinase 1 activator RGC-32. AB - Response gene to complement-32 (RGC-32) activates cyclin-dependent kinase 1, regulates the cell cycle and is deregulated in many human tumours. We previously showed that RGC-32 expression is upregulated by the cancer-associated Epstein Barr virus (EBV) in latently infected B cells through the relief of translational repression. We now show that EBV infection of naive primary B cells also induces RGC-32 protein translation. In EBV-immortalised cell lines, we found that RGC-32 depletion resulted in cell death, indicating a key role in B cell survival. Studying RGC-32 translational control in EBV-infected cells, we found that the RGC-32 3'untranslated region (3'UTR) mediates translational repression. Repression was dependent on a single Pumilio binding element (PBE) adjacent to the polyadenylation signal. Mutation of this PBE did not affect mRNA cleavage, but resulted in increased polyA tail length. Consistent with Pumilio-dependent recruitment of deadenylases, we found that depletion of Pumilio in EBV-infected cells increased RGC-32 protein expression and polyA tail length. The extent of Pumilio binding to the endogenous RGC-32 mRNA in EBV-infected cell lines also correlated with RGC-32 protein expression. Our data demonstrate the importance of RGC-32 for the survival of EBV-immortalised B cells and identify Pumilio as a key regulator of RGC-32 translation. PMID- 29385541 TI - New models to study vascular mural cell embryonic origin: implications in vascular diseases. AB - A key question in vascular biology is how the diversity of origin of vascular mural cells, namely smooth muscle cells (SMCs) and pericytes influences vessel properties, in particular the regional propensity to vascular diseases. This review therefore first describes the role and regulation of mural cells during vascular formation, with a focus on embryonic origin. We then consider the evidence that connects heterogeneities in SMC and pericyte origins with disease. Since this idea has major implications for understanding and modelling human disease, then there is a pressing need for new model systems to investigate mural cell development and the consequences of heterogeneity. Recent advances arising from in vitro strategies for deriving mural cells from human pluripotent stem cells as well as from the zebrafish model will be discussed and the medical relevance of these discoveries will be highlighted. PMID- 29385542 TI - The association between the patient and the physician genders and the likelihood of intensive care unit admission in hospital with restricted ICU bed capacity. AB - Background: Despite the evidence that the patient gender is an important component in the intensive care unit (ICU) admission decision, the role of physician gender and the interaction between the two remain unclear. Objective: To investigate the association of both the patient and the physician gender with ICU admission rate of critically ill emergency department (ED) medical patients in a hospital with restricted ICU bed capacity operates with 'closed door' policy. Methods: A retrospective population-based cohort analysis. We included patients above 18 admitted to an ED resuscitation room (RR) of a tertiary hospital during 2011-12. Data on medical, laboratory and clinical characteristics were obtained. We used an adjusted multivariable logistic regression to analyze the association between both the patient and the physician gender to the ICU admission decision. Results: We included 831 RR admissions, 388 (46.7%) were female patients and 188 (22.6%) were treated by a female physicians. In adjusted multivariable analysis (adjusted for age, diabetes, mode of hospital transportation, first pH and patients who were treated with definitive airway and vasso-pressors in the RR), female-female combination (patient-physician, respectively) showed the lowest likelihood to be admitted to ICU (adjusted OR: 0.21; 95% CI: 0.09-0.51) compared to male-male combination, in addition to a smaller decrease among female-male (adjusted OR: 0.53; 95% CI: 0.32-0.86) and male-female (adjusted OR: 0.43; 95% CI: 0.21-0.89) combinations. Conclusion: We demonstrated the existence of the possible gender bias where female gender of the patient and treating physician diminish the likelihood of the restricted health resource use. PMID- 29385544 TI - Inhibition of Voriconazole Metabolism by Meropenem: A Role for Inflammation? PMID- 29385545 TI - Comment on: Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature: reply. PMID- 29385546 TI - Development of novel metabolite-responsive transcription factors via transposon mediated protein fusion. AB - Naturally evolved metabolite-responsive biosensors enable applications in metabolic engineering, ranging from screening large genetic libraries to dynamically regulating biosynthetic pathways. However, there are many metabolites for which a natural biosensor does not exist. To address this need, we developed a general method for converting metabolite-binding proteins into metabolite responsive transcription factors-Biosensor Engineering by Random Domain Insertion (BERDI). This approach takes advantage of an in vitro transposon insertion reaction to generate all possible insertions of a DNA-binding domain into a metabolite-binding protein, followed by fluorescence activated cell sorting to isolate functional biosensors. To develop and evaluate the BERDI method, we generated a library of candidate biosensors in which a zinc finger DNA-binding domain was inserted into maltose binding protein, which served as a model well studied metabolite-binding protein. Library diversity was characterized by several methods, a selection scheme was deployed, and ultimately several distinct and functional maltose-responsive transcriptional biosensors were identified. We hypothesize that the BERDI method comprises a generalizable strategy that may ultimately be applied to convert a wide range of metabolite-binding proteins into novel biosensors for applications in metabolic engineering and synthetic biology. PMID- 29385548 TI - Molecular responses to dehydration and desiccation in desiccation-tolerant angiosperm plants. AB - Due to the ability to tolerate extreme dehydration, desiccation-tolerant plants have been widely investigated to find potential approaches for improving water use efficiency or developing new crop varieties. The studies of desiccation tolerant plants have identified sugar accumulation, specific protein synthesis, cell structure changes, and increased anti-oxidative reactions as part of the mechanisms of desiccation tolerance. However, plants respond differently according to the severity of water loss, and the process of water loss affects desiccation tolerance. A detailed analysis within the dehydration process is important for understanding the process of desiccation tolerance. This review defines dehydration and desiccation, finds the boundary for the relative water content between dehydration and desiccation, compares the molecular responses to dehydration and desiccation, compares signaling differences between dehydration and desiccation, and finally summarizes the strategies launched in desiccation tolerant plants for dehydration and desiccation, respectively. The roles of abscisic acid (ABA) and reactive oxygen species (ROS) in sensing and signaling during dehydration are discussed. We outline how this knowledge can be exploited to generate drought-tolerant crop plants. PMID- 29385549 TI - The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention. AB - Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition. PMID- 29385547 TI - Improving adoption and acceptability of digital health interventions for HIV disease management: a qualitative study. AB - Disease management remains a challenge for many people living with HIV (PLWH). Digital health interventions (DHIs) may assist with overcoming these challenges and reducing burdens on clinical staff; however, there is limited data regarding methods to improve uptake and acceptability of DHIs among PLWH. This qualitative study aimed to assess patient and provider perspectives on the use of DHIs and strategies to promote uptake among PLWH. Eight focus groups with patients (k = 5 groups; n = 24) and providers (k = 3 groups; n = 12) were conducted May through October of 2014. Focus groups (~90 min) followed a semi-structured interview guide. Data were analyzed using thematic analysis on three main themes: (a) perspectives towards the adoption and use of DHIs for HIV management; (b) perceptions of barriers and facilitators to patient usage; and (c) preferences regarding content, structure, and delivery. Analyses highlighted barriers and facilitators to DHI adoption. Patients and providers agreed that DHIs feel "impersonal" and "lack empathy," may be more effective for certain subpopulations, should be administered in the clinic setting, and should use multimodal delivery methods. Emergent themes among the providers included development of DHIs for providers as the target market and the need for culturally adapted DHIs for patient subpopulations. DHIs have potential to improve HIV management and health outcomes. DHIs should be developed in conjunction with anticipated consumers, including patients, providers, and other key stakeholders. DHIs tailored for specific HIV subpopulations are needed. Future studies should evaluate dissemination methods and marketing strategies to promote uptake. PMID- 29385543 TI - Smooth muscle cell fate and plasticity in atherosclerosis. AB - Current knowledge suggests that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer. During this process, SMCs undergo complex structural and functional changes giving rise to a broad spectrum of phenotypes. Classically, intimal SMCs are described as dedifferentiated/synthetic SMCs, a phenotype characterized by reduced expression of contractile proteins. Intimal SMCs are considered to have a beneficial role by contributing to the fibrous cap and thereby stabilizing atherosclerotic plaque. However, intimal SMCs can lose their properties to such an extent that they become hard to identify, contribute significantly to the foam cell population, and acquire inflammatory-like cell features. This review highlights mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligoclonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs in this disease. PMID- 29385550 TI - Reducing informal caregiver burden in cancer: evidence-based programs in practice. AB - Caring for people with cancer can be a burdensome and emotionally straining experience. Without adequate psychosocial support, distressed caregivers are at risk for psychiatric and medical morbidity, which can adversely affect patient outcomes. Although there is a tremendous need to provide effective and timely supportive care services for cancer caregivers, few community or clinically based services exist and the needs of these essential caregivers are profoundly underserved. This article describes three existing evidence-based programs and tools that address the needs of family caregivers of cancer patients: (a) the FOCUS Program, tested for efficacy in prior randomized clinical trials and implemented in community settings by agency staff; (b) the Program for the Study of Cancer Caregivers at Memorial Sloan Kettering Cancer Center (MSKCC), which addresses the needs of caregivers in a large health care system; and (c) CancerSupportSource(r)-Caregiver, an online platform for distress screening and referral developed by the Cancer Support Community to assess and address caregivers' needs. We also describe next steps related to broader dissemination for practitioners considering how best to support cancer caregivers now and in the future. Although each evidence-based program or tool represents a unique approach to supporting caregivers, together these approaches allow for a greater likelihood of meeting caregiver needs across a variety of contexts. Collaboration within and across organizations allowed for the development and effective implementation of each of the described initiatives. PMID- 29385551 TI - Society of Behavioral Medicine (SBM) position statement: improving access to psychosocial care for individuals with persistent pain: supporting the National Pain Strategy's call for interdisciplinary pain care. AB - Policy makers have articulated a need for clear, evidence-based guidance to help inform pain policy. Persistent pain is common, expensive, and debilitating, and requires comprehensive assessment and treatment planning. Recently released opioid prescribing guidelines by the CDC (2016) emphasize the importance of using nonopioid therapies before considering opioid treatment for those without a malignant illness. The National Pain Strategy (2016) underscores the importance of comprehensive, interdisciplinary pain care. Unfortunately, despite persuasive evidence supporting the efficacy of psychosocial approaches, these interventions are inaccessible to the majority of Americans. Psychosocial approaches to pain management should be available for all individuals with persistent pain and in all health care settings and contexts as part of the comprehensive, interdisciplinary approach to pain care as outlined in the National Pain Strategy. To achieve this, we must prioritize reimbursement of evidence-based psychosocial approaches for pain assessment and management and improve provider training and competencies to implement these approaches. PMID- 29385553 TI - BIOnIC: a classification system to effectively incorporate mobile applications in the psychiatric treatment of children and adolescents. PMID- 29385554 TI - Effect of Polygonum persicaria (Polygonales: Polygonaceae) Extracted Agglutinin on Life Table and Antioxidant Responses in Helicoverpa armigera (Lepidoptera: Noctuidae) Larvae. AB - Plant lectins could reduce insect populations by imposing imbalances in biology and physiology. Here, an agglutinin was extracted from Polygonum persicaria L. (PPA; Polygonales: Polygonaceae) and its effects were investigated on life table parameters and antioxidant system of Helicoverpa armigera Hubner (Lepidoptera: Noctuidae). PPA significantly changed demographic parameters showing adverse effects on age-stage survival rate (Sxj), age-specific survival rate (lx), age specific fecundity rate (mx), age stage specific fecundity (fxj), and life expectancy (exj). Also, life table parameters including net reproduction rate (R0) (Offspring/female), intrinsic rate of population increase (rm) (days-1), finite rate of increase (lambda) (days-1), gross reproduction rate (GRR) (Offspring/female) significantly decreased in the PPA-treated H. armigera compared to control except for mean generation time (T) (days). Activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CA), peroxidase (POX), glutathione S-transferase (GST) and glucose 6-phosphate dehydrogenase (GPDH) increased statistically in the PPA-treated larvae compared to control while no significant difference was observed in the activity of ascorbate peroxidase (APOX) activity. Moreover, ratio of RSSR/RSH and concentration of malondialdehyde (MDA) were found to be statistically higher in PPA-treated larvae than control. The current results clearly showed that PPA not only had a negative impact on demography of H. armigera but also induced antioxidant raise by releasing free radicals. These released radicals, together with impaired digestion and absorption observed in our previous report, could be considered as a reason for reducing biological fitness of H. armigera. PMID- 29385552 TI - Bayesian Divergence-Time Estimation with Genome-Wide Single-Nucleotide Polymorphism Data of Sea Catfishes (Ariidae) Supports Miocene Closure of the Panamanian Isthmus. AB - The closure of the Isthmus of Panama has long been considered to be one of the best defined biogeographic calibration points for molecular divergence-time estimation. However, geological and biological evidence has recently cast doubt on the presumed timing of the initial isthmus closure around 3 Ma but has instead suggested the existence of temporary land bridges as early as the Middle or Late Miocene. The biological evidence supporting these earlier land bridges was based either on only few molecular markers or on concatenation of genome-wide sequence data, an approach that is known to result in potentially misleading branch lengths and divergence times, which could compromise the reliability of this evidence. To allow divergence-time estimation with genomic data using the more appropriate multispecies coalescent (MSC) model, we here develop a new method combining the single-nucleotide polymorphism-based Bayesian species-tree inference of the software SNAPP with a molecular clock model that can be calibrated with fossil or biogeographic constraints. We validate our approach with simulations and use our method to reanalyze genomic data of Neotropical army ants (Dorylinae) that previously supported divergence times of Central and South American populations before the isthmus closure around 3 Ma. Our reanalysis with the MSC model shifts all of these divergence times to ages younger than 3 Ma, suggesting that the older estimates supporting the earlier existence of temporary land bridges were artifacts resulting at least partially from the use of concatenation. We then apply our method to a new restriction-site associated DNA sequencing data set of Neotropical sea catfishes (Ariidae) and calibrate their species tree with extensive information from the fossil record. We identify a series of divergences between groups of Caribbean and Pacific sea catfishes around 10 Ma, indicating that processes related to the emergence of the isthmus led to vicariant speciation already in the Late Miocene, millions of years before the final isthmus closure. PMID- 29385555 TI - Feasibility of a support person intervention to promote smoking cessation treatment use among smokers with mental illness. AB - Social support may be an effective strategy to increase engagement in cessation treatment for smokers with mental illness. The purpose of this pilot study was to assess the feasibility of a support person intervention linking smokers with mental illness to an online smoking cessation decision aid. We conducted a 12 week pilot study of a one-session telephone coaching intervention ("Care2Quit") to train nonsmoking family members and friends (i.e., support persons) to promote the use of an online cessation decision aid by smokers with mental illness. The primary aim of the study was to assess the feasibility of the support person intervention by examining recruitment, retention, adherence, and participant satisfaction. A secondary aim was to explore changes in the hypothesized mechanism underlying the intervention effect (i.e., cessation support provided) and primary outcome (i.e., smoker use of online cessation decision aid). Seventeen support persons enrolled, of which 94% (n = 16) completed the telephone coaching intervention. Eighty-eight percent of support persons rated the intervention as highly acceptable. Self-reported cessation supportive behaviors by the support person increased significantly by 6 weeks post intervention. Forty one percent of smokers (n = 7) linked to support persons used the online cessation decision aid by 12 weeks following the support person's telephone coaching session. Preliminary results from this study demonstrate the feasibility of a support person intervention to promote the use of smoking cessation treatment among smokers with mental illness. Future research to evaluate the efficacy of the Care2Quit support partner intervention is warranted. PMID- 29385556 TI - Inference of Adaptive Shifts for Multivariate Correlated Traits. AB - To study the evolution of several quantitative traits, the classical phylogenetic comparative framework consists of a multivariate random process running along the branches of a phylogenetic tree. The Ornstein-Uhlenbeck (OU) process is sometimes preferred to the simple Brownian motion (BM) as it models stabilizing selection toward an optimum. The optimum for each trait is likely to be changing over the long periods of time spanned by large modern phylogenies. Our goal is to automatically detect the position of these shifts on a phylogenetic tree, while accounting for correlations between traits, which might exist because of structural or evolutionary constraints. We show that, in the presence of shifts, phylogenetic Principal Component Analysis fails to decorrelate traits efficiently, so that any method aiming at finding shifts needs to deal with correlation simultaneously. We introduce here a simplification of the full multivariate OU model, named scalar OU, which allows for noncausal correlations and is still computationally tractable. We extend the equivalence between the OU and a BM on a rescaled tree to our multivariate framework. We describe an Expectation-Maximization (EM) algorithm that allows for a maximum likelihood estimation of the shift positions, associated with a new model selection criterion, accounting for the identifiability issues for the shift localization on the tree. The method, freely available as an R-package (PhylogeneticEM) is fast, and can deal with missing values. We demonstrate its efficiency and accuracy compared to another state-of-the-art method ($?ell$1ou) on a wide range of simulated scenarios and use this new framework to reanalyze recently gathered data sets on New World Monkeys and Anolis lizards. PMID- 29385557 TI - Implementation contextual factors related to youth advocacy for healthy eating and active living. AB - Healthy eating and active living are critical to youth health and development. Youth advocacy can improve health-related behaviors and environments by empowering youth to act as change agents in their community. This mixed-method study examined implementation contextual factors in relation to implementation success in high school youth advocacy projects targeting healthy eating and active living. Semi-structured interviews were conducted with key informants from each of the 21 participating youth groups. Interviews gathered information on implementation processes, barriers and facilitators, and Implementation Outcomes (Progress, Penetration, Health Impact, Sustainability, and an overall Implementation Success Composite). Interview responses were coded using the Consolidated Framework for Implementation Research (CFIR). Each identified construct was rated for its impact on implementation and ratings were tested for their association with the Implementation Outcomes. Cosmopolitanism (leveraging connections within the community; rated in 20 groups) and Internal Intervention Source (rated in 9 groups) showed consistent moderate/large associations with the Implementation Outcomes and Implementation Success Composite. Other moderate/large associations were outcome specific, with Student Group Leader Engagement, External Change Agents, and Student and Community Needs and Resources also being associated with the Implementation Success Composite. Implementation contextual factors, particularly community-connectedness, group functioning, and internal project idea development are important factors for implementing youth advocacy projects that will reach large numbers of people and be likely to lead to sustained health improvements. Implementation strategies that target these factors need to be developed and tested in partnership with community organizations to maximize success of youth advocacy efforts. PMID- 29385558 TI - Accounting for Calibration Uncertainty: Bayesian Molecular Dating as a "Doubly Intractable" Problem. AB - This study introduces a new Bayesian technique for molecular dating that explicitly accommodates for uncertainty in the phylogenetic position of calibrated nodes derived from the analysis of fossil data. The proposed approach thus defines an adequate framework for incorporating expert knowledge and/or prior information about the way fossils were collected in the inference of node ages. Although it belongs to the class of "node-dating" approaches, this method shares interesting properties with "tip-dating" techniques. Yet, it alleviates some of the computational and modeling difficulties that hamper tip-dating approaches. The influence of fossil data on the probabilistic distribution of trees is the crux of the matter considered here. More specifically, among all the phylogenies that a tree model (e.g., the birth-death process) generates, only a fraction of them "agree" with the fossil data. Bayesian inference under the new model requires taking this fraction into account. However, evaluating this quantity is difficult in practice. A generic solution to this issue is presented here. The proposed approach relies on a recent statistical technique, the so called exchange algorithm, dedicated to drawing samples from "doubly intractable" distributions. A small example illustrates the problem of interest and the impact of uncertainty in the placement of calibration constraints in the phylogeny given fossil data. An analysis of land plant sequences and multiple fossils further highlights the pertinence of the proposed approach. PMID- 29385559 TI - Effectiveness of an evidence-based HIV prevention intervention when implemented by frontline providers. AB - Carefully conducted randomized trials have established that sexual behavior change interventions can significantly reduce intervention participants' risk of acquiring HIV. Establishing the effectiveness of these evidence-based interventions when implemented by frontline HIV prevention service providers is increasingly important in order to achieve maximum public health impact. This study sought to assess the effectiveness of an evidence-based intervention when implemented by frontline HIV prevention service providers. We evaluated Sisters Informing Sisters on Topics about AIDS (SISTA), an HIV prevention intervention for heterosexual African American women, as implemented by four AIDS service organizations. Women enrolled in HIV counseling, testing, and referral (CTR) at each agency served as contemporaneous controls. Measures included self-reported number of occasions of unprotected vaginal intercourse and number of vaginal sex partners in the previous 90 days. 1,262 participants completed baseline and follow-up assessments across both conditions (SISTA = 537 [57%]; CTR = 725 [62%]). In the full sample of HIV-negative women, CTR participants' odds of having had unprotected sex decreased over time by 38% while SISTA participants' odds of having had unprotected sex did not change. Similar results were found among only those participants who had sex at baseline. Hypothesized interaction effects indicating positive changes in sexual risks over time for SISTA participants were not observed. PMID- 29385560 TI - Trapped crystals in synovial fluid: neutrophil extracellular traps from bench to bedside. PMID- 29385561 TI - SBM recommends policy support to reduce smoking disparities for sexual and gender minorities. AB - The Society of Behavioral Medicine supports the inclusion of gender and sexual minorities in all local, state, and national tobacco prevention and control activities. These activities include surveillance of tobacco use and cessation activities, targeted outreach and awareness campaigns, increasing access to culturally appropriate tobacco use dependence treatments, and restricting disproportionate marketing to lesbian, gay, bisexual, and transgender communities by the tobacco industry, especially for mentholated tobacco products. PMID- 29385562 TI - Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. AB - Anthracyclines, such as doxorubicin, are highly efficient chemotherapeutic agents against a variety of cancers. However, anthracyclines are also among the most cardiotoxic therapeutic drugs presently on the market. Chemotherapeutic-induced cardiomyopathy is one of the leading causes of disease and mortality in cancer survivors. The exact mechanisms responsible for doxorubicin-induced cardiomyopathy are not completely known, but the fact that the cardiotoxicity is dose-dependent and that there is a variation in time-to-onset of toxicity, and gender- and age differences suggests that several mechanisms may be involved. In this study, we investigated doxorubicin-induced cardiotoxicity in human pluripotent stem cell-derived cardiomyocytes using proteomics. In addition, different sources of omics data (protein, mRNA, and microRNA) from the same experimental setup were further combined and analyzed using newly developed methods to identify differential expression in data of various origin and types. Subsequently, the results were integrated in order to generate a combined visualization of the findings. In our experimental model system, we exposed cardiomyocytes derived from human pluripotent stem cells to doxorubicin for up to 2 days, followed by a wash-out period of additionally 12 days. Besides an effect on the cell morphology and cardiomyocyte functionality, the data show a strong effect of doxorubicin on all molecular levels investigated. Differential expression patterns that show a linkage between the proteome, transcriptome, and the regulatory microRNA network, were identified. These findings help to increase the understanding of the mechanisms behind anthracycline-induced cardiotoxicity and suggest putative biomarkers for this condition. PMID- 29385564 TI - A framework for examining the function of digital health technologies for weight management. AB - Research is rapidly extending its focus to develop and evaluate weight management interventions that incorporate eHealth technologies. Comparative effectiveness of eHealth interventions is partly limited by the extensive heterogeneity in intervention design, variation in use of eHealth tools, and expanding development of novel tools to promote weight management. We closely examined, characterized, and categorized the use and function of eHealth tools across a wide range of eHealth interventions for weight management in order to first create a novel schematic framework for eHealth interventions and, second, to evaluate eHealth interventions using this framework. We examined 49 randomized controlled trials from two systematic reviews evaluating the effectiveness of eHealth interventions for weight loss. Further characterization of each intervention identified common use and function of eHealth tools represented within interventions and thus important to include in the proposed framework. This resulted in six descriptive domains. We then categorized each eHealth intervention within the context of the newly developed framework. Last, we examined efficacious interventions in the context of the framework. Twenty-five randomized controlled trials reported significantly more weight loss between the intervention group utilizing eHealth, compared to a non-eHealth control intervention and/or within an eHealth intervention group. Of these 25 interventions, 15 (60%) used automated feedback (Domain 1), 13 (52%) used non-eHealth tailored feedback by a health care provider (Domain 5), and 8 (32%) used tailored feedback from a health care professional through an electronic channel (Domain 2). The proposed schematic framework offers an alternative and novel approach for comparing across interventions and informing the development and evaluation of eHealth interventions. PMID- 29385565 TI - Perception of sexual ramification among women toward male doctors in today's Indian society. AB - The objective of the study was to assess the perception of women patients toward attitude of health professionals who have undergone physical examination.A descriptive cross-sectional study was conducted among 1,257 women. A self administered structured questionnaire comprising of 16 questions was designed to assess perception of patients toward attitude of health professionals.Mean perception scores of the study population were 19.79 +/- 1.78. Women in the age group of 29-38 years had a greater perception (20.34 +/- 1.54) that they had been a subject or could be a subject to sexual exploitation by a doctor. Graduate and above group participants had a greater perception (19.54 +/- 1.86) when compared to primary and secondary education level (19.52 +/- 1.85, 18.35 +/- 1.5). Data were analyzed using ANOVA.Women had mixed perception of sexual gratification toward male doctors. It is necessary to educate the doctors regarding the respect, dignity, and values for female patients, which could reduce occupational defamation. PMID- 29385563 TI - Phenotypic and Genetic Structure Support Gene Flow Generating Gene Tree Discordances in an Amazonian Floodplain Endemic Species. AB - Before populations become independent evolutionary lineages, the effects of micro evolutionary processes tend to generate complex scenarios of diversification that may affect phylogenetic reconstruction. Not accounting for gene flow in species tree estimates can directly impact topology, effective population sizes and branch lengths, and the resulting estimation errors are still poorly understood in wild populations. In this study, we used an integrative approach, including sequence capture of ultra-conserved elements (UCEs), mtDNA Sanger sequencing and morphological data to investigate species limits and phylogenetic relationships in face of gene flow in an Amazonian endemic species (Myrmoborus lugubris: Aves). We used commonly implemented species tree and model-based approaches to understand the potential effects of gene flow in phylogenetic reconstructions. The genetic structure observed was congruent with the four recognized subspecies of M. lugubris. Morphological and UCEs data supported the presence of a wide hybrid zone between M. l. femininus from the Madeira river and M. l. lugubris from the Middle and lower Amazon river, which were recovered as sister taxa by species tree methods. When fitting gene flow into simulated demographic models with different topologies, the best-fit model indicated these two taxa as non sister lineages, a finding that is in agreement with the results of mitochondrial and morphological analyses. Our results demonstrated that failing to account for gene flow when estimating phylogenies at shallow divergence levels can generate topological uncertainty, which can nevertheless be statistically well supported, and that model testing approaches using simulated data can be useful tools to test alternative phylogenetic hypotheses. PMID- 29385566 TI - Building the infrastructure to accelerate evidence-generating mobile and wireless health research: National Institutes of Health and National Science Foundation perspectives. PMID- 29385568 TI - rRNA adenine methylation requires T07A9.8 gene as rram-1 in Caenorhabditis elegans. AB - RNAs are post-transcriptionally modified in all kingdoms of life. Of these modifications, base methylations are highly conserved in eukaryote ribosomal RNA (rRNA). Recently, rRNA processing protein 8 (Rrp8) and nucleomethylin (NML) were identified as factors of N1-methyladenosine (m1A) modification in yeast 25 S and mammalian 28 S rRNA, respectively. However, m1A modification of rRNA is still poorly understood in Caenorhabditis elegans (C. elegans). Here, using the liquid chromatography/tandem mass spectrometry analysis and RNA immunoprecipitation assay, we have identified that the m1A modification is located around position 674 (A674) of 26 S rRNA in C. elegans. Furthermore, quantitative PCR-based analysis revealed that T07A9.8, a C. elegans homolog of yeast Rrp8 and human NML, is responsible for m1A modification at A674 of 26 S rRNA. This m1A modification site in C. elegans corresponds to those in yeast 25 S rRNA and human 28 S rRNA. Intriguingly, T07A9.8 is not associated with pre-rRNA transcription under normal nutrient conditions. Since the m1A modification of 26 S rRNA requires T07A9.8 in C. elegans, we designated the gene as rRNA adenine methyltransferase-1 (rram-1). PMID- 29385569 TI - Dronedarone-Induced Cardiac Mitochondrial Dysfunction and Its Mitigation by Epoxyeicosatrienoic Acids. AB - Dronedarone and amiodarone are structurally similar antiarrhythmic drugs. Dronedarone worsens cardiac adverse effects with unknown causes while amiodarone has no cardiac adversity. Dronedarone induces preclinical mitochondrial toxicity in rat liver and exhibits clinical hepatotoxicity. Here, we further investigated the relative potential of the antiarrhythmic drugs in causing mitochondrial injury in cardiomyocytes. Differentiated rat H9c2 cardiomyocytes were treated with dronedarone, amiodarone, and their respective metabolites namely N desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA). Intracellular ATP content, mitochondrial membrane potential (Deltapsim), and inhibition of carnitine palmitoyltransferase I (CPT1) activity and arachidonic acid (AA) metabolism were measured in H9c2 cells. Inhibition of electron transport chain (ETC) activities and uncoupling of ETC were further studied in isolated rat heart mitochondria. Dronedarone, amiodarone, NDBD and NDEA decreased intracellular ATP content significantly (IC50 = 0.49, 1.84, 1.07, and 0.63 uM, respectively) and dissipated Deltapsim potently (IC50 = 0.5, 2.94, 12.8, and 7.38 uM, respectively). Dronedarone, NDBD, and NDEA weakly inhibited CPT1 activity while amiodarone (IC50 > 100 uM) yielded negligible inhibition. Only dronedarone inhibited AA metabolism to its regioisomeric epoxyeicosatrienoic acids (EETs) consistently and potently. NADH-supplemented ETC activity was inhibited by dronedarone, amiodarone, NDBD and NDEA (IC50 = 3.07, 5.24, 11.94, and 16.16 uM, respectively). Cytotoxicity, ATP decrease and Deltapsim disruption were ameliorated via exogenous pre-treatment of H9c2 cells with 11, 12-EET and 14, 15 EET. Our study confirmed that dronedarone causes mitochondrial injury in cardiomyocytes by perturbing Deltapsim, inhibiting mitochondrial complex I, uncoupling ETC and dysregulating AA-EET metabolism. We postulate that cardiac mitochondrial injury is one potential contributing factor to dronedarone-induced cardiac failure exacerbation. PMID- 29385570 TI - OK, thanks! A new mutualism between Chlamydomonas and methylobacteria facilitates growth on amino acids and peptides. AB - Nitrogen is a key nutrient for land plants and phytoplankton in terrestrial and aquatic ecosystems. The model alga Chlamydomonas reinhardtii can grow efficiently on several inorganic nitrogen sources (e.g. ammonium, nitrate, nitrite) as well as many amino acids. In this study, we show that Chlamydomonas is unable to use proline, hydroxyproline and peptides that contain these amino acids. However, we discovered that algal growth on these substrates is supported in association with Methylobacterium spp., and that a mutualistic carbon-nitrogen metabolic exchange between Chlamydomonas and Methylobacterium spp. is established. Specifically, the mineralization of these amino acids and peptides by Methylobacterium spp. produces ammonium that can be assimilated by Chlamydomonas, and CO2 photosynthetically fixed by Chlamydomonas yields glycerol that can be assimilated by Methylobacterium. As Chlamydomonas is an algal ancestor to land plants and Methylobacterium is a plant growth-promoting bacterium, this new model of mutualism may facilitate insights into the ecology and evolution of plant bacterial interactions and design principles of synthetic ecology. PMID- 29385571 TI - The solute transport profile of two Aza-guanine transporters from the Honey bee pathogen Paenibacillus larvae. AB - Two nucleobase transporters encoded in the genome of the Honey bee bacterial pathogen Paenibacillus larvae belong to the azaguanine-like transporters and are referred to as PlAzg1 and PlAzg2. PlAzg1 and 2 display significant amino acid sequence similarity, and share predicted secondary structures and functional sequence motifs with two Escherichia coli nucleobase cation symporter 2 (NCS2) members: adenine permease (EcAdeP) and guanine-hypoxanthine permease EcGhxP. However, similarity does not define function. Heterologous complementation and functional analysis using nucleobase transporter-deficient Saccharomyces cerevisiae strains revealed that PlAzg1 transports adenine, hypoxanthine, xanthine and uracil, while PlAzg2 transports adenine, guanine, hypoxanthine, xanthine, cytosine and uracil. Both PlAzg1 and 2 display high affinity for adenine with Km of 2.95 +/- 0.22 and 1.92 +/- 0.22 MUM, respectively. These broad nucleobase transport profiles are in stark contrast to the narrow transport range observed for EcAdeP (adenine) and EcGhxP (guanine and hypoxanthine). PlAzg1 and 2 are similar to eukaryotic Azg-like transporters in that they share a broad solute transport profile, particularly the fungal Aspergillus nidulans AzgA (that transports adenine, guanine and hypoxanthine) and plant AzgA transporters from Arabidopsis thaliana and Zea mays (that collectively move adenine, guanine, hypoxanthine, xanthine, cytosine and uracil). PMID- 29385567 TI - Elucidating the Small Regulatory RNA Repertoire of the Sea Anemone Anemonia viridis Based on Whole Genome and Small RNA Sequencing. AB - Cnidarians harbor a variety of small regulatory RNAs that include microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), but detailed information is limited. Here, we report the identification and expression of novel miRNAs and putative piRNAs, as well as their genomic loci, in the symbiotic sea anemone Anemonia viridis. We generated a draft assembly of the A. viridis genome with putative size of 313 Mb that appeared to be composed of about 36% repeats, including known transposable elements. We detected approximately equal fractions of DNA transposons and retrotransposons. Deep sequencing of small RNA libraries constructed from A. viridis adults sampled at a natural CO2 gradient off Vulcano Island, Italy, identified 70 distinct miRNAs. Eight were homologous to previously reported miRNAs in cnidarians, whereas 62 appeared novel. Nine miRNAs were recognized as differentially expressed along the natural seawater pH gradient. We found a highly abundant and diverse population of piRNAs, with a substantial fraction showing ping-pong signatures. We identified nearly 22% putative piRNAs potentially targeting transposable elements within the A. viridis genome. The A. viridis genome appeared similar in size to that of other hexacorals with a very high divergence of transposable elements resembling that of the sea anemone genus Exaiptasia. The genome encodes and expresses a high number of small regulatory RNAs, which include novel miRNAs and piRNAs. Differentially expressed small RNAs along the seawater pH gradient indicated regulatory gene responses to environmental stressors. PMID- 29385572 TI - Illumina Library Preparation for Sequencing the GC-Rich Fraction of Heterogeneous Genomic DNA. AB - Standard Illumina libraries are biased toward sequences of intermediate GC content. This results in an underrepresentation of GC-rich regions in sequencing projects of genomes with heterogeneous base composition, such as mammals and birds. We developed a simple, cost-effective protocol to enrich sheared genomic DNA in its GC-rich fraction by subtracting AT-rich DNA. This was achieved by heating DNA up to 90 degrees C before applying Illumina library preparation. We tested the new approach on chicken DNA and found that heated DNA increased average coverage in the GC-richest chromosomes by a factor up to six. Using a Taq polymerase supposedly appropriate for PCR amplification of GC-rich sequences had a much weaker effect. Our protocol should greatly facilitate sequencing and resequencing of the GC-richest regions of heterogeneous genomes, in combination with standard short-read and long-read technologies. PMID- 29385574 TI - Activity and expression of Candida glabrata vacuolar proteases in autophagy-like conditions. AB - Candida glabrata is an emerging opportunistic pathogen that has intrinsic resistance to azoles. During infection or while living as a commensal, it encounters nutritional stresses such as deficiency of carbon or nitrogen sources. Herein, we investigate the expression and activity of PrA, Ape1, Ape3 and CpY vacuolar proteases during these stressful nutrimental conditions. Our findings demonstrate a differential activity profile depending on the addition or lack of carbon, nitrogen or both. Of the four proteases tested, PrA and Ape3 showed a higher activity in the absence of nitrogen. Steady-state RNA levels for all the proteases were also differentially expressed although not always correlated with its activity, suggesting multiple levels of regulation. Microscopy observations of C. glabrata cells subjected to the different conditions showed an increase in the vacuolar volume. Moreover, the presence of ATG8-PE and an increased expression of ATG8 were observed in the yeast under the tested conditions suggesting that C. glabrata is in autophagy stage. Taken together, our results showed that PrA, Ape1, Ape3 and CpY have varying activities and expression depending on whether nitrogen or carbon is added to the media, and that these vacuolar proteases might have a role in the autophagy process. PMID- 29385573 TI - Challenges Associated With Applying Physiologically Based Pharmacokinetic Modeling for Public Health Decision-Making. AB - The development and application of physiologically based pharmacokinetic (PBPK) models in chemical toxicology have grown steadily since their emergence in the 1980s. However, critical evaluation of PBPK models to support public health decision-making across federal agencies has thus far occurred for only a few environmental chemicals. In order to encourage decision-makers to embrace the critical role of PBPK modeling in risk assessment, several important challenges require immediate attention from the modeling community. The objective of this contemporary review is to highlight 3 of these challenges, including: (1) difficulties in recruiting peer reviewers with appropriate modeling expertise and experience; (2) lack of confidence in PBPK models for which no tissue/plasma concentration data exist for model evaluation; and (3) lack of transferability across modeling platforms. Several recommendations for addressing these 3 issues are provided to initiate dialog among members of the PBPK modeling community, as these issues must be overcome for the field of PBPK modeling to advance and for PBPK models to be more routinely applied in support of public health decision making. PMID- 29385575 TI - Osmotolerance of Dekkera bruxellensis and the role of two Stl glycerol-proton symporters. AB - Dekkera bruxellensis is important for lambic beer fermentation but is considered a spoilage yeast in wine fermentation. We compared two D. bruxellensis strains isolated from wine and found that they differ in some basic properties, including osmotolerance. The genomes of both strains contain two highly similar copies of genes encoding putative glycerol-proton symporters from the STL family that are important for yeast osmotolerance. Cloning of the two DbSTL genes and their expression in suitable osmosensitive Saccharomyces cerevisiae mutants revealed that both identified genes encode functional glycerol uptake systems, but only DbStl2 has the capacity to improve the osmotolerance of S. cerevisiae cells. PMID- 29385577 TI - Interprofessional case conference: impact on learner outcomes. AB - Transition to interprofessional team-based care is a quickly progressing healthcare model and requires changes in medical training approaches. The Department of Veteran Affairs (VA) has taken a lead role in creating such training experiences, one of which is the establishment of multiple Centers of Excellence in Primary Care Education (CoEPCE). These sites are tasked with developing teaching innovations to better facilitate interprofessional team-based care. The patient-aligned care team interprofessional care update (PACT-ICU) is an interprofessional workplace learning activity with the goals of simultaneously addressing educational and patient care needs. Participants of the PACT-ICU included trainees and faculty of a variety of medical disciplines (e.g., internal medicine, psychology, and pharmacy) involved in a training primary care clinic. Two medically complex patients were presented at each PACT-ICU conference with the purpose of creating a plan of care that maintained an interprofessional team based approach. Following implementation of the PACT-ICU conference intervention, two primary outcomes were assessed. First, self-assessment of PACT-ICU attendee learner outcomes was measured using a brief questionnaire surveying knowledge gain as it related to increase in knowledge of other professions' capabilities, roles, and responsibilities. Secondly, trainee provider behavior change was evaluated by measuring number of "within PACT" consults before and after participating in PACT-ICU. There was a significant positive change in self assessed knowledge along with an indication of trainee behavioral change, as measured by electronic medical record consult patterns. This study demonstrates that interprofessional case conferences involving trainees and staff from multiple professions can increase awareness of other professions roles in patient care as well as facilitate interprofessional collaboration. PMID- 29385576 TI - Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure. AB - The role of environmental stressors, particularly exposure to air pollution, in the development of neurodegenerative disease remains underappreciated. We examined the neurological effects of acute ozone (O3) exposure in aged mice, where increased blood-brain barrier (BBB) permeability may confer vulnerability to neuroinflammatory outcomes. C57BL/6 male mice, aged 8-10 weeks or 12-18 months were exposed to either filtered air or 1.0 ppm O3 for 4 h; animals received a single IP injection of sodium fluorescein (FSCN) 20 h postexposure. One-hour post FSCN injection, animals were transcardially perfused for immunohistochemical analysis of BBB permeability. beta-amyloid protein expression was assessed via ELISA. Flow cytometric characterization of infiltrating immune cells, including neutrophils, macrophages, and microglia populations was performed 20 h post-O3 exposure. Flow cytometry analysis of brains revealed increased microglia "activation" and presentation of CD11b, F4/80, and MHCII in aged animals relative to younger ones; these age-induced differences were potentiated by acute O3 exposure. Cortical and limbic regions in aged brains had increased reactive microgliosis and beta-amyloid protein expression after O3 insult. The aged cerebellum was particularly vulnerable to acute O3 exposure with increased populations of infiltrating neutrophils, peripheral macrophages/monocytes, and Ly6C+ inflammatory monocytes after insult, which were not significantly increased in the young cerebellum. O3 exposure increased the penetration of FSCN beyond the BBB, the infiltration of peripheral immune cells, and reactive gliosis of microglia. Thus, the aged BBB is vulnerable to insult and becomes highly penetrable in response to O3 exposure, leading to greater neuroinflammatory outcomes. PMID- 29385578 TI - Factors influencing the impact of pharmacogenomic prescribing on adherence to nicotine replacement therapy: A qualitative study of participants from a randomized controlled trial. AB - Pharmacogenomics may improve health outcomes in two ways: by more precise and therefore more effective prescribing, tailored to genotype, and by increasing perceived effectiveness of treatments and so motivation for adherence. Little is known about patients' experiences of, and reactions to, receiving pharmacogenomically tailored treatments. The aim of this study was to explore the impact of pharmacogenomic prescribing of nicotine replacement therapy (NRT) on smokers' initial expectations of quit success, adherence, and perceived important differences from previous quit attempts. Semi-structured interviews were conducted with 40 smokers, purposively sampled from the Personalized Extra Treatment (PET) trial (ISRCTN 14352545). Together with NRT patches, participants were prescribed doses of oral NRT based on either mu-opioid receptor (OPRM1) genotype or nicotine dependence questionnaire score (phenotype). Data were analyzed using framework analysis, comparing views of participants in the two trial arms. Although most participants understood the basis for their prescribed NRT dose, it little influenced their views. The salient features of this quit attempt were the individualized behavioral support and combined NRT, not pharmacogenomic tailoring. Participants' initial expectations of success were mostly based on prior experiences of quitting. They attributed taking medication to nurse advice to do so, and attributed reducing or stopping it to side effects, forgetfulness, or practical difficulties. Intentional nonadherence appeared very rare. Pharmacogenomic NRT prescribing was not especially remarkable to participants and did not seem to influence adherence. Where services already tailor prescriptions to phenotype and provide individualized behavioral support for treatment adherence, pharmacogenomic prescribing may have limited additional benefit. PMID- 29385579 TI - The impact of raw DNA availability and corresponding online interpretation services: A mixed-methods study. AB - Consumer access to third-party services to interpret raw DNA has raised concerns about downstream healthcare implications. This mixed-methods study set out to examine the extent to which genetic counselors have been contacted by consumers of third-party services and describe counselors' experiences with these "consumer" patients. Counselor views on the quality of information provided to consumers were also examined. Eighty-five genetic counselors completed an online survey, of which 22 completed in-depth telephone interviews. Survey and interview data were analyzed and combined using triangulation techniques. Over half (53%) of the survey respondents indicated they had been contacted by a patient following the use of a third-party raw DNA interpretation service. Among counselors contacted, 72% saw at least one patient. Counselors reported challenges unique to this patient population including overemphasis by patients on the validity of the data and patient resistance to information provided by the counselor. Preparation time burden and counselor inexperience and discomfort counseling these patients were additional challenges. Counselors expressed concern about the quality of the raw data and the clarity and usefulness of interpretation reports. Genetic counselors' experiences with consumer's use of third-party DNA interpretation services provide insight on the opportunities and challenges with the availability of raw DNA directly to consumers. Efforts to better support both consumers and genetic service providers are needed to maximize the effective translation of genome-based knowledge for population health. PMID- 29385581 TI - Genetic test reporting of CDKN2A provides informational and motivational benefits for managing melanoma risk. AB - A CDKN2A/p16 mutation confers 28%-67% lifetime melanoma risk, a risk that may be moderated by ultraviolet radiation exposure. The aim of this study was to test whether melanoma genetic counseling and test disclosure conferred unique informational, motivational, or emotional benefits compared to family history based counseling. Participants included were 114 unaffected members of melanoma prone families, ages 16-69, 51.8% men, 65.8% with minor children or grandchildren. Carriers (n = 28) and noncarriers (n = 41) from families with a CDKN2A mutation were compared to no-test controls (n = 45) from melanoma-prone families without an identifiable CDKN2A mutation. All participants received equivalent counseling about melanoma risk and management; only CDKN2A participants received genetic test results. Using newly developed inventories, participants rated perceived costs and benefits for managing their own and their children's or grandchildren's melanoma risk 1 month and 1 year after counseling. Propensity scores controlled for baseline family differences. Compared to no-test controls, participants who received test results (carriers and noncarriers) reported feeling significantly more informed and prepared to manage their risk, and carriers reported greater motivation to reduce sun exposure. All groups reported low negative emotions about melanoma risk. Parents reported high levels of preparedness to manage children's risk regardless of group. Carrier parents reported greater (but moderate) worry about their children's risk than no-test control parents. Women, older, and more educated respondents reported greater informational and motivational benefits regardless of group. Genetic test results were perceived as more informative and motivating for personal sun protection efforts than equivalent counseling based on family history alone. PMID- 29385580 TI - Patient communication of cancer genetic test results in a diverse population. AB - Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds. PMID- 29385582 TI - Heart disease risk information, encouragement, and physical activity among Mexican-origin couples: Self- or spouse-driven change? AB - Family health history is an accessible, clinically-recommended genomic tool that improves health risk evaluation. It captures both genetic and modifiable risk factors that cluster within families. Thus, families represent a salient context for family health history-based interventions that motivate engagement in risk reducing behaviors. While previous research has explored how individuals respond to their personal risk information, we extend this inquiry to consider how individuals respond to their spouse's risk information among a sample of Mexican Americans. One hundred and sixty spouse-dyads within Mexican-heritage households received a pedigree or a pedigree and personalized risk assessments, with or without behavioral recommendations. Analyses of Covariance (ANCOVAs) were conducted to assess the relationship between risk feedback, both personal and spouse, and self-reported physical activity levels at 3-month and 10-month assessments, controlling for baseline levels. The effect of being identified as an encourager of spouse's healthy weight was also evaluated. Personal feedback had no effect on participants' physical activity at either 3- or 10-month assessments. However, husbands' risk information was associated with wives' physical activity levels at 3-month assessment, with women whose husbands received both increased risk feedback and behavioral recommendations engaging in significantly higher physical activity levels than all other women. At 10-month follow-up, physical activity levels for both husbands and wives differed depending on whether they encouraged their spouse's healthy weight. Spousal risk information may be a stronger source of motivation to improve physical activity patterns than personal risk information, particularly for women. Interventions that activate interpersonal encouragement among spouses may more successfully extend intervention effects. PMID- 29385583 TI - Preferences for learning different types of genome sequencing results among young breast cancer patients: Role of psychological and clinical factors. AB - The growing importance of genome sequencing means that patients will increasingly face decisions regarding what results they would like to learn. The present study examined psychological and clinical factors that might affect these preferences. 1,080 women diagnosed with breast cancer at age 40 or younger completed an online survey. We assessed their interest in learning various types of genome sequencing results: risk of preventable disease or unpreventable disease, cancer treatment response, uncertain meaning, risk to relatives' health, and ancestry/physical traits. Multivariable logistic regression was used to examine whether being "very" interested in each result type was associated with clinical factors: BRCA1/2 mutation status, prior genetic testing, family history of breast cancer, and psychological factors: cancer recurrence worry, genetic risk worry, future orientation, health information orientation, and genome sequencing knowledge. The proportion of respondents who were very interested in learning each type of result ranged from 16% to 77%. In all multivariable models, those who were very interested in learning a result type had significantly higher knowledge about sequencing benefits, greater genetic risks worry, and stronger health information orientation compared to those with less interest (p-values < .05). Our findings indicate that high interest in return of various types of genome sequencing results was more closely related to psychological factors. Shared decision-making approaches that increase knowledge about genome sequencing and incorporate patient preferences for health information and learning about genetic risks may help support patients' informed choices about learning different types of sequencing results. PMID- 29385585 TI - Shared decision making: Implications for return of results from whole-exome and whole-genome sequencing. AB - In this issue, Kaphingst and colleagues report on young breast cancer patient's preferences for learning about various results from genomic sequencing. In our commentary, we discuss the results in light of the burgeoning clinical use of whole-exome and whole-genome sequencing (WES/WGS). In particular, we consider findings in the context of a Shared Decision Making approach to return of results. We also identify additional important factors to consider that may influence patient preferences that were largely absent from the paper by Kaphingst and colleagues, including cultural context, costs of testing, and provider factors. PMID- 29385584 TI - Parental attitudes and expectations towards receiving genomic test results in healthy children. AB - Little evidence is available to guide returning genomic results in children without medical indication for sequencing. Professional guidelines for returning information on adult-onset conditions are conflicting. The goal of this study was to provide preliminary information on parental attitudes and expectations about returning medically actionable genomic results in children who have been sequenced as part of a population biobank.Four focus groups of parents with a child enrolled in a population biobank were conducted. A deliberative engagement format included education about professional guidelines and ethical issues around returning results to children. Parents were presented two scenarios where their healthy child has a pathogenic variant for: (a) a medically actionable childhood condition; (b) a hereditary cancer syndrome with no medical management until adulthood. Thematic analysis was conducted on verbatim transcripts. Regardless of the scenario, parents stated that the genomic information was important, was like other unexpected medical information, and disclosure should be tailored to the child's age and result. Parents wanted the results in their child's medical record. Reasons for learning adult-onset results in their healthy children included to prepare their child for necessary medical action in adulthood. Parents also provided suggestions for program design. This preliminary evidence suggests that parents desire genomic results and expect to use this information to protect their child's health. More empirical research on psychosocial adjustment to such information with continued engagement of parents and children is needed to further inform how to best support families in the communication and use of genomic information. PMID- 29385586 TI - Translation research to apply genomics to improve health promotion: Is it worth the investment? PMID- 29385587 TI - Social and behavioral science priorities for genomic translation. AB - This commentary highlights the essential role of the social and behavioral sciences for genomic translation, and discusses some priority research areas in this regard. The first area encompasses genetics of behavioral, social, and neurocognitive factors, and how integration of these relationships might impact the development of treatments and interventions. The second area includes the contributions that social and behavioral sciences make toward the informed translation of genomic developments. Further, there is a need for behavioral and social sciences to inform biomedical research for effective implementation. The third area speaks to the need for increased outreach and education efforts to improve the public's genomic literacy such that individuals and communities can make informed health-related and societal (e.g., in legal or consumer settings) decisions. Finally, there is a need to prioritize representation of diverse communities in genomics research and equity of access to genomic technologies. Examples from National Institutes of Health-based intramural and extramural research programs and initiatives are used to discuss these points. PMID- 29385588 TI - A comparison of views regarding the use of de-identified data. AB - Data sharing of large genomic databases and biorepositories provides researchers adequately powered samples to advance the goals of precision medicine. Data sharing may also introduce, however, participant privacy concerns including possible reidentification. This study compares views of research participants, genetic researchers, and institutional review board (IRB) professionals regarding concerns about the use of de-identified data. An online survey was completed by cancer patients, their relatives, and controls from the Northwest Cancer Genetics Registry (n = 450) querying views about potential harms with the use of de identified data. This was compared to our previous online national survey of human genetic researchers (n = 351) and IRB professionals (n = 208). Researchers were less likely to feel that participants would be personally identified or harmed from a study involving de-identified data or feel that a federal agency might compel researchers to disclose information about research participants. Compared to genetic researchers, IRB professionals and participants were significantly more likely to express that personal identification or harm was likely or that researchers might be forced to disclose information by a federal agency. An understanding of the differences in views regarding possible harm from the use of de-identified data between these three important stakeholder groups is necessary to move forward with genomic research. PMID- 29385589 TI - The research participant perspective related to the conduct of genomic cohort studies: A systematic review of the quantitative literature. AB - Observational genome-wide association studies require large sample sizes. Evaluating the interplay between genomic, environmental, and lifestyle factors can require even larger sample sizes. The All of Us Research Program will recruit 1 million participants to facilitate research on genomic, environmental, and lifestyle factors. Integrating participant preferences into the research process is a new paradigm and a necessary component of the All of Us Research Program. The purpose of the study is to summarize quantitative studies of participant preferences related to participation in observational genomic research studies, starting with consent through return of results. Integrating this information into the conduct of genomic studies may benefit participants, and improve participant satisfaction, recruitment, and retention. We conducted a systematic review of the literature regarding participant views related to reconsent and broad consent, use of de-identified data, contribution of data to a biorepository, risk of identification, return of individual genetic results, and motivation for participation in genomic studies. Twenty-three articles met our inclusion and exclusion criteria. Study results found that most participants support broad consent; however, significant differences related to reconsent preferences have been shown by gender and age. Most participants support the return of individual genomic results and do not feel it is necessary to maintain a link to their de-identified data. Reasons given for joining research studies varied by population source. These findings, in addition to the knowledge that participants are more accepting of broad informed consent methods when the rationale is explained, can assist in developing guidelines for future observational genomic research. PMID- 29385590 TI - Effect of co-payment on behavioral response to consumer genomic testing. AB - Existing research in consumer behavior suggests that perceptions and usage of a product post-purchase depends, in part, on how the product was marketed, including price paid. In the current study, we examine the effect of providing an out-of-pocket co-payment for consumer genomic testing (CGT) on consumer post purchase behavior using both correlational field evidence and a hypothetical online experiment. Participants were enrolled in a longitudinal cohort study of the impact of CGT and completed behavioral assessments before and after receipt of CGT results. Most participants provided a co-payment for the test (N = 1668), while others (N = 369) received fully subsidized testing. The two groups were compared regarding changes in health behaviors and post-test use of health care resources. Participants who paid were more likely to share results with their physician (p = .012) and obtain follow-up health screenings (p = .005) relative to those who received fully subsidized testing. A follow-up online experiment in which participants (N = 303) were randomized to a "fully-subsidized" versus "co payment" condition found that simulating provision of a co-payment significantly increased intentions to seek follow-up screening tests (p = .050) and perceptions of the test results as more trustworthy (p = .02). Provision of an out-of-pocket co-payment for CGT may influence consumer's post-purchase behavior consistent with a price placebo effect. Cognitive dissonance or sunk cost may help explain the increase in screening propensity among paying consumers. Such individuals may obtain follow-up screenings to validate their initial decision to expend personal resources to obtain CGT. PMID- 29385591 TI - Toward the implementation of genomic applications for smoking cessation and smoking-related diseases. AB - The incorporation of genomic information into routine care settings is a burgeoning area for investigation in behavioral medicine. The past decade has witnessed rapid advancements in knowledge of genetic biomarkers associated with smoking behaviors and tobacco-related morbidity and mortality, providing the basis for promising genomic applications in clinical and community settings. We assessed the current state of readiness for implementing genomic applications involving variation in the alpha5 nicotinic cholinergic receptor subunit gene CHRNA5 and smoking outcomes (behaviors and related diseases) using a process that could be translatable to a wide range of genomic applications in behavioral medicine. We reviewed the scientific literature involving CHRNA5 genetic variation and smoking cessation, and then summarized and synthesized a chain of evidence according to analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications (ACCE), a well-established set of criteria used to evaluate genomic applications. Our review identified at least three specific genomic applications for which implementation may be considered, including the use of CHRNA5 genetic test results for informing disease risk, optimizing smoking cessation treatment, and motivating smoking behavior change. For these genomic applications, we rated analytic validity as convincing, clinical validity as adequate, and clinical utility and ethical, legal, and social implications as inadequate. For clinical genomic applications involving CHRNA5 variation and smoking outcomes, research efforts now need to focus on establishing clinical utility. This approach is compatible with pre implementation research, which is also needed to accelerate translation, improve innovation design, and understand and refine system processes involved in implementation. This study informs the readiness to incorporate smoking-related genomic applications in real-world settings and facilitates cross-disciplinary collaboration to accelerate the integration of evidence-based genomics in behavioral medicine. PMID- 29385593 TI - Introduction to the Special Issue on Clinical and Public Health Genomics: Opportunities for translational behavioral medicine research, practice, and policy. PMID- 29385592 TI - Communication of cancer-related genetic and genomic information: A landscape analysis of reviews. AB - Cancer-related genetic and genomic testing (CGT) is changing cancer care by personalizing care options, leading to an era of precision medicine. Advances in and increased use of CGT add complexity to clinical communication. This landscape analysis assessed published reviews of communication issues related to CGT and discusses implications for practice and behavioral research. A comprehensive electronic literature search was conducted of peer-reviewed literature reviews on studies related to CGT communication published between January 2010 and January 2017, resulting in a final sample of 24 reviews. Reviews were categorized, with overlaps, into four domains across the genetic testing communication continuum. Reviews on CGT-related knowledge, attitudes, and perceptions (n = 8) found that despite substantial public interest, their knowledge and awareness remains low. Providers also reported insufficient knowledge and overall caution, particularly regarding direct-to-consumer (DTC) genetic testing. Reviews of decision-making about CGT and test uptake (n = 8) identified individual, interpersonal, and systems-level barriers to uptake. Reviews of patient-provider CGT communication (n = 8) revealed limited communication and little empirical research on outcomes of communication or efforts at improving clinical and family communication. There were mixed findings in reviews (n = 15) on the psychological and behavioral impact of CGT, and DTC testing particularly had little effect on behaviors. Taken together, there is very little extant research in CGT in minority and underserved communities. In order for scientific advances in CGT to translate into equitable, patient-centered care, behavioral research, including health literacy and communication, plays critical roles. PMID- 29385594 TI - 7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia. AB - Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia. PMID- 29385596 TI - Optimized Methods to Explore the Mechanistic and Biomarker Potential of Hepatocyte-Derived Exosomes in Drug-Induced Liver Injury. AB - Recent evidence supports that alterations in hepatocyte-derived exosomes (HDE) may play a role in the pathogenesis of drug-induced liver injury (DILI). HDE based biomarkers also hold promise to improve the sensitivity of existing in vitro assays for predicting DILI liability. Primary human hepatocytes (PHH) provide a physiologically relevant in vitro model to explore the mechanistic and biomarker potential of HDE in DILI. However, optimal methods to study exosomes in this culture system have not been defined. Here we use HepG2 and HepaRG cells along with PHH to optimize methods for in vitro HDE research. We compared the quantity and purity of HDE enriched from HepG2 cell culture medium by 3 widely used methods: ultracentrifugation (UC), OptiPrep density gradient ultracentrifugation (ODG), and ExoQuick (EQ)-a commercially available exosome precipitation reagent. Although EQ resulted in the highest number of particles, UC resulted in more exosomes as indicated by the relative abundance of exosomal CD63 to cellular prohibitin-1 as well as the comparative absence of contaminating extravesicular material. To determine culture conditions that best supported exosome release, we also assessed the effect of Matrigel matrix overlay at concentrations ranging from 0 to 0.25 mg/ml in HepaRG cells and compared exosome release from fresh and cryopreserved PHH from same donor. Sandwich culture did not impair exosome release, and freshly prepared PHH yielded a higher number of HDE overall. Taken together, our data support the use of UC-based enrichment from fresh preparations of sandwich-cultured PHH for future studies of HDE in DILI. PMID- 29385595 TI - Interference with Clp protease impairs carotenoid accumulation during tomato fruit ripening. AB - Profound metabolic and structural changes are required for fleshy green fruits to ripen and become colorful and tasty. In tomato (Solanum lycopersicum), fruit ripening involves the differentiation of chromoplasts, specialized plastids that accumulate carotenoid pigments such as beta-carotene (pro-vitamin A) and lycopene. Here, we explored the role of the plastidial Clp protease in chromoplast development and carotenoid accumulation. Ripening-specific silencing of one of the subunits of the Clp proteolytic complex resulted in beta-carotene enriched fruits that appeared orange instead of red when ripe. Clp-defective fruit displayed aberrant chromoplasts and up-regulated expression of nuclear genes encoding the tomato homologs of Orange (OR) and ClpB3 chaperones, most probably to deal with misfolded and aggregated proteins that could not be degraded by the Clp protease. ClpB3 and OR chaperones protect the carotenoid biosynthetic enzymes deoxyxylulose 5-phosphate synthase and phytoene synthase, respectively, from degradation, whereas OR chaperones additionally promote chromoplast differentiation by preventing the degradation of carotenoids such as beta-carotene. We conclude that the Clp protease contributes to the differentiation of chloroplasts into chromoplasts during tomato fruit ripening, acting in co-ordination with specific chaperones that alleviate protein folding stress, promote enzyme stability and accumulation, and prevent carotenoid degradation. PMID- 29385597 TI - OsNRT2.4 encodes a dual-affinity nitrate transporter and functions in nitrate regulated root growth and nitrate distribution in rice. AB - Plant NRT2 nitrate transporters commonly require a partner protein, NAR2, for transporting nitrate at low concentrations, but their role in plants is not well understood. In this study, we characterized the gene for one of these transporters in the rice genome, OsNRT2.4, in terms of its activity and roles in rice grown in environments with different N supply. In Xenopus oocytes, OsNRT2.4 alone without OsNAR2 co-expression facilitated nitrate uptake showing biphasic kinetics at a wide concentration range, with high- and low-affinity KM values of 0.15 and 4 mM, respectively. OsNRT2.4 did not have nitrate efflux or IAA influx activity. In rice roots, OsNRT2.4 was expressed mainly in the base of lateral root primordia. Knockout of OsNRT2.4 decreased lateral root number and length, and the total N uptake per plant at both 0.25 and 2.5 mM NO3- levels. In the shoots, OsNRT2.4 was expressed mainly in vascular tissues, and its knockout decreased the growth and NO3--N distribution. Knockout of OsNRT2.4, however, did not affect rice growth and N uptake under conditions without N or with only NH4+ supply. We conclude that OsNRT2.4 functions as a dual-affinity nitrate transporter and is required for nitrate-regulated root and shoot growth of rice. PMID- 29385598 TI - Effect of increasing the level of alfalfa hay in finishing beef heifer diets on intake, sorting, and feeding behavior. AB - Eight rumen cannulated Simmental heifers (BW = 281.4 +/- 7.28 kg) were randomly assigned to one of four experimental treatments in a 4 * 4 replicated Latin square design to ascertain the effects of increasing levels of alfalfa hay on intake, sorting, and feeding behavior in comparison to barley straw as forage source. Treatments tested were four total mixed rations with: 1) 10% barley straw (10BS) with 7.0% NDF from forage, 2) 13% alfalfa hay (13AH) and less NDF from forage (5.7%) than 10BS, 3) 16% alfalfa hay (16AH) and the same NDF from forage (7.0%) as 10BS, and 4) 19% alfalfa hay (19AH) and more NDF from forage (8.3%) than 10BS. Each experimental period consisted of 3 wk for adaptation and 1 wk for sampling. Increasing the proportion of alfalfa hay in the diet linearly increased (P < 0.05) total DMI, CP intake, water consumption, intake of long, medium and fine particle size, extent of sorting of fine particle size, and time spent rumination, but linearly decreased (P < 0.05) extent of sorting of short particle size. Intake of DM was higher in heifers fed 16AH and 19AH than in heifers fed 10BS (P < 0.001). Intake of NDF and physically effective NDF (peNDF) was greater in 13AH, 16AH, and 19AH than in 10BS (P < 0.01). The DMI of medium and short particle size was greater in 13AH, 16AH, and 19AH than in 10BS (P < 0.05), whereas DMI of long particle size was greater in 16AH and 19AH compared to 10BS (P < 0.001). Heifers fed 13AH, 16AH, and 19AH diets sorted against fine particle size and sorted for or tended to sort for short, medium, and long particle sizes. Meal length was greater in heifers fed 16AH and 19AH than 10BS (P < 0.05). Time spent eating was not affected by diet but time spent ruminating was greater in heifers fed 19AH than in 10BS (P < 0.05). Results indicate that the inclusion of alfalfa hay at 19% of incorporation caused an increase in DM, NDF, and peNDF intake, in comparison to the 10BS diet. In the same way, intake of long, medium, and short particle size was greater in this diet. Moreover, heifers fed 19AH sorted for medium particle size and tended to sort for long and short particles size, and against fine particle size. Sorting behavior and meal length increased in the 19AH diet, which leads us to think that sorting feed ingredients requires time and therefore lengthens the meal. Time spent ruminating was greater in heifers fed 19AH, thus reducing the risk of ruminal acidosis when animals are fed high concentrate diets. PMID- 29385599 TI - Response of lactating dairy cows with or without purulent vaginal discharge to gonadotropin-releasing hormone and prostaglandin F2alpha. AB - Purulent vaginal discharge (PVD) is a common uterine disease in dairy cattle that has negative effects on reproductive performance. Reproductive management programs that synchronize ovulation use gonadotropin-releasing hormone (GnRH) to induce ovulation and prostaglandin F2alpha (PGF2alpha) to induce luteolysis. The objectives of this study were to evaluate ovarian response to treatment with GnRH and the odds of bearing a corpus luteum or being inseminated in dairy cows with or without PVD. Another objective was to determine the hazard of insemination after administration of PGF2alpha in dairy cows with or without PVD. Primiparous (n = 291) and multiparous (n = 402) cows were evaluated for PVD using a Metricheck device at 46 +/- 3 and 35 +/- 3 days in milk (DIM) (study day 0), respectively. On study day 14, primiparous (n = 107) and multiparous (n = 197) cows were treated with GnRH and subsequent ovulation was recorded. Primiparous (n = 178) and multiparous (n = 368) cows not inseminated by study day 21 were administered PGF2alpha and response to PGF2alpha treatment was determined by detection of estrus. Furthermore, cows were categorized by the presence of a CL or being inseminated by study days 14, 21, and 35. Overall prevalence of PVD was 28.5% and 13.4% for primiparous and multiparous cows, respectively. Projected 305 d milk yield was less (P < 0.01) in PVD+ multiparous cows compared with PVD- multiparous cows, however, no (P = 0.26) difference was detected between primiparous PVD+ and PVD- cows. Ovulatory response to GnRH treatment was 51.8% and 47.8% for primiparous and multiparous cows, respectively. Primiparous PVD- cows tended (P = 0.06) to be less likely to ovulate to GnRH than primiparous PVD+ cows, whereas multiparous PVD+ cows were less (P = 0.04) likely to ovulate to GnRH than PVD- multiparous cows. The odds of bearing a corpus luteum or being inseminated by study days 14, 21, or 35 was not associated with PVD in primiparous cows. In contrast, the odds of bearing a corpus luteum or being inseminated by study days 14 and 21 was (P <= 0.03) associated with PVD in multiparous cows, but not (P = 0.11) on study day 35. Hazard of insemination after PGF2alpha was not (P >= 0.38) associated with PVD in primiparous or multiparous cows. Purulent vaginal discharge is associated with response to treatment with GnRH in dairy cattle. Purulent vaginal discharge might negatively affect reproductive management programs that use GnRH to induce ovulation. PMID- 29385600 TI - Effects of gradual reduction in frequency of energy supplementation on growth and immunity of beef steers. AB - This study evaluated the effects of gradual reduction in frequency of energy supplementation following vaccination on growth and measurements of innate and humoral immunity of beef steers. At 14-d postweaning (d 0), Angus steers (n = 42; 200 +/- 5 kg of BW; 175 +/- 4 d of age) were stratified by BW and age, and randomly assigned into 1 of 14 drylot pens (three steers/pen). From d 0 to 42, steers were provided ad libitum ground tall fescue hay (57% TDN, 13% CP of DM basis) and supplemented with concentrate at 1% of BW (50:50 soybean hulls and corn gluten feed; 71% TDN, 15% CP of DM basis). Treatments were randomly assigned to pens, and consisted of similar weekly concentrate DM supplementation (1% of BW multiplied by 7 d) that was divided and offered daily from d 0 to 42 (7X; 4 pens), 3 times weekly from d 0 to 42 (3X; Monday, Wednesday, and Friday; 5 pens), or daily from d 0 to 15 and then 3 times weekly from d 16 to 42 (7-3X; 5 pens). Steers were vaccinated against infectious bovine rhinotracheitis (IBR), bovine viral diarrhea virus (BVDV), parainfluenza-3 (PI-3), Mannheimia haemolytica, and Clostridium on d 0 and 15. Individual shrunk BW was collected on d 0 and 42, following 12 h of feed and water withdrawal. Blood samples were collected via jugular venipuncture 4 h after concentrate supplementation on d 0, 1, 2, 3, 7, 15, 16, 17, 18, 22, and 42. Mean BW, ADG, G:F, hay DMI, and total DMI over the 42 d period did not differ among treatments (P >= 0.26). Plasma concentrations of cortisol and mean serum BVDV-1a titers also did not differ among treatments (P >= 0.35), but overall plasma haptoglobin concentrations were greater for 3X vs. 7-3X and 7X steers (P <= 0.05; 0.44, 0.37, and 0.33 +/- 0.026 mg/mL, respectively). Also, 3X steers had less mean serum IBR titers (P <= 0.05; 0.29 vs. 0.88 and 0.79 +/- 0.179 log2, respectively) and less seroconversion to PI-3 virus on d 15 than 7-3X and 7X steers (P <= 0.05; 36.0 vs. 76.6 and 57.8 +/- 8.24%, respectively). In summary, a gradual reduction in frequency of energy supplementation during a 42-d preconditioning period did not negatively impact growth, but alleviated indices of inflammation and prevented reductions in vaccine response against BVDV 1a and PI-3 viruses compared to steers offered concentrate 3 times weekly during the entire study. PMID- 29385601 TI - Feed preference of weaned pigs fed diets containing soybean meal, Brassica napus canola meal, or Brassica juncea canola meal. AB - Brassica napus and Brassica juncea canola meal (CM) may replace soybean meal (SBM) in pig diets, but differ in fiber, glucosinolates content and profile. Preference of weaned pigs provided double-choice selections to diets containing 20% SBM, B. napus CM, or B. juncea CM was evaluated in two studies. In experiment 1, 216 pigs (9.4 +/- 1.6 kg initial BW) were housed in 27 pens of 8 pigs (four gilts and four barrows). In experiment 2, 144 pigs (8.9 +/- 1.1 kg) were housed in 36 pens of 4 pigs (two gilts and two barrows). Pigs were offered three dietary choices: B. napus CM with SBM as reference (B. napus CM [SBM]), B. juncea CM with SBM as reference (B. juncea CM [SBM]), and B. juncea CM with B. napus CM as reference (B. juncea CM [B. napus CM]) in a replicated 3 * 3 Latin square. Diets were formulated to provide 2.4 Mcal NE/kg and 4.5 g standardized ileal digestible Lys/Mcal NE and were balanced using canola oil and crystalline AA. Each pair of diets was offered in two self-feeders per pen as mash (experiment 1) or pellets (experiment 2) during three test-periods of 4-d, followed by a 3-d non-test period when a common diet was offered in both feeders. Feeders with different diets were rotated daily among pens during preference periods for both experiments, and feeder positions (right or left) were switched daily in experiment 2. Prior to the study and between periods, pigs were fed non-test diets containing SBM (experiment 1) or without test feedstuffs (experiment 2). Overall in both experiments, pigs preferred (P < 0.001) SBM over B. napus and B. juncea CM diets, and preferred (P < 0.001) B. napus over B. juncea CM diet. Dietary choice did not affect (P > 0.05) growth performance in both experiments, except for greater G:F (P < 0.05) for pigs fed the B. juncea CM [B. napus CM] diets than pigs fed the B. napus CM [SBM] or B. juncea CM [SBM] diets in experiment 1. In conclusion, weaned pigs preferred SBM over CM diets when given a choice, and preferred B. napus over the B. juncea diet that contained more total glucosinolates especially gluconapin. Weaned pigs fed the B. juncea CM [B. napus CM] diets in the double-choice selection did not reduce feed intake, weight gain, and G:F compared to pigs fed the B. napus CM [SBM] or B. juncea CM [SBM] diets. PMID- 29385602 TI - Consistency of feed efficiency ranking and mechanisms associated with inter animal variation among growing calves. AB - This study investigated the possible mechanisms for explaining interanimal variation in efficiency of feed utilization in intact male Holstein calves. Additionally, we examined whether the feed efficiency (FE) ranking of calves (n = 26) changed due to age and/or diet quality. Calves were evaluated during three periods (P1, P2, and P3) while fed a high-quality diet (calculated mobilizable energy [ME] of 11.8 MJ/kg DM) during P1 and P3, and a low-quality diet (calculated ME of 7.7 MJ/kg DM) during P2. The study periods were 84, 119, and 127 d, respectively. Initial ages of the calves in P1, P2, and P3 were 7, 11, and 15 mo, respectively, and initial body weight (BW) were 245, 367, and 458 kg, respectively. Individual dry matter intake (DMI), average daily gain (ADG), diet digestibility, and heat production (HP) were measured in all periods. The measured FE indexes were: residual feed intake (RFI), the gain-to-feed ratio (G:F), residual gain (RG), residual gain and intake (RIG), the ratio of HP-to-ME intake (HP/MEI), and residual heat production (RHP). For statistical analysis, animals' performance data in each period, were ranked by RFI, and categorized into high-, medium-, and low-RFI groups (H-RFI, M-RFI, and L-RFI). RFI was not correlated with in vivo digestibility, age, BW, BCS, or ADG in all three periods. The L-RFI group had lowest DMI, MEI, HP, retained energy (RE), and RE/ADG. Chemical analysis of the longissimus dorsi muscle shows that the L-RFI group had a higher percentage of protein and a lower percentage of fat compared to the H RFI group. We suggested that the main mechanism separating L- from H-RFI calves is the protein-to-fat ratio in the deposited tissues. When efficiency was related to kg/day (DMI and ADG) and not to daily retained energy, the selected efficient L-RFI calves deposited more protein and less fat per daily gain than less efficient H-RFI calves. However, when the significant greater heat increment and maintenance energy requirement of protein compared to fat deposition in tissue were considered, we could not exclude the hypothesis that variation in efficiency is partly explained by efficient energy utilization. The ranking classification of calves to groups according to their RFI efficiency was independent of diet quality and age. PMID- 29385604 TI - MRI Indices of Cortical Development in Young People With Psychotic Experiences: Influence of Genetic Risk and Persistence of Symptoms. AB - Background: Psychotic experiences (PEs) are considered part of an extended psychosis phenotype and are associated with an elevated risk of developing a psychotic disorder. Risk of transition increases with persistence of PEs, and this is thought to be modulated by genetic and environmental factors. However, it is unclear if persistence is associated with progressive schizophrenia-like changes in neuroanatomy. Methods: We examined cortical morphometry using MRI in 247 young adults, from a population-based cohort, assessed for the presence of PEs at ages 18 and 20. We then incorporated a polygenic risk score for schizophrenia (PRS) to elucidate the effects of high genetic risk. Finally, we used atlas-based tractography data to examine the underlying white matter. Results: Individuals with persisting PEs showed reductions in gyrification (local gyrification index: lGI) in the left temporal gyrus as well as atypical associations with brain volume (TBV) in the left occipital and right prefrontal gyri. No main effect was found for the PRS, but interaction effects with PEs were identified in the orbitofrontal, parietal, and temporal regions. Examination of underlying white matter did not provide strong evidence of further disturbances. Conclusions: Disturbances in lGI were similar to schizophrenia but findings were mostly limited to those with persistent PEs. These could reflect subtle changes that worsen with impending psychosis or reflect an early vulnerability associated with the persistence of PEs. The lack of clear differences in underlying white matter suggests our findings reflect early disturbances in cortical expansion rather than progressive changes in brain structure. PMID- 29385603 TI - Effects of mono-component xylanase supplementation on nutrient digestibility and performance of lactating sows fed a coarsely ground diet. AB - The objective of the current study was to investigate the effect of supplementing a mono-component xylanase to a coarsely ground lactation diet (feed fraction particle size above 2 mm was more than 17%) based on wheat, barley, and soybean meal on nutrient digestibility and performance of lactating sows. A total of 30 cross-bred (Danish Landrace * Yorkshire) multiparous sows (parity 2 to 5) were used. Sows were fed a standard gestation diet from mating until day 108 of gestation, and then stratified for BW (295.4 +/- 26.1 kg average BW) and parity to receive one of two dietary treatments (n = 15 per treatment), a lactation diet without (control diet) or with supplemented enzyme (enzyme diet). The enzyme applied was a mono-component xylanase dosed at 200 enzyme unit (FXU) per kg of feed, which corresponds to 200 g per ton of feed. The diets were fed until weaning at day 28 of lactation. On day 2 of lactation, litter size of each sow was adjusted to 14 piglets within treatment. Reproductive performance of the sows, growth of the piglets, yield and composition of sow milk, plasma metabolites and apparent total tract digestibility (ATTD) of nutrients were measured. Supplementation of xylanase had no effect (P > 0.05) on total born and live born piglets or stillbirth rate (%) at parturition. Initial parameters on day 2 of lactation including sow BW and back fat thickness, litter size, piglet weight, and litter weight were similar (P > 0.05) between treatments. Piglet weight gain, litter weight gain, litter size, and daily milk yield did not differ (P > 0.05) between treatments. The ADFI was increased by 4.5% (P < 0.01), and BW loss during the whole lactation was reduced from -13.6 to -5.2 kg (P = 0.04) with xylanase addition when compared to control sows. The ATTD of GE (83.9 vs. 82.9, P < 0.01), DM (84.2 vs. 83.4, P < 0.01), N (83.4 vs. 81.7, P = 0.02), OM (86.5 vs. 85.7, P < 0.01) and total nonstarch polysaccharides (NSP; 59.4 vs. 56.7, P = 0.02) were all increased by xylanase supplementation. Milk composition and plasma metabolites were not affected (P > 0.05), except that plasma triglycerides content was increased by xylanase addition (0.23 vs. 0.20 mM, P = 0.04). In conclusion, supplementing a mono-component xylanase to a coarsely ground lactating diet based on wheat, barley, and soybean meal improved sow feed intake and nutrient digestibility, thereby reducing sow BW loss throughout lactation, whereas milk yield and piglet performance were not affected. PMID- 29385606 TI - Rare Variants in Tissue Inhibitor of Metalloproteinase 2 as a Risk Factor for Schizophrenia: Evidence From Familial and Cohort Analysis. AB - Candidate gene and genome-wide association study based common risk variant identification is being complemented by whole exome sequencing (WES)/whole genome sequencing based rare variant discovery in elucidation of genetic landscape of schizophrenia (SZ), a common neuropsychiatric disorder. WES findings of de novo mutations in case-parent trios have further implied genetic etiology, but do not explain the high genetic risk in general populations. Conversely, WES in multiplex families may be an insightful strategy for the identification of highly penetrant rare variants in SZ and possibly enhance our understanding of disease biology. In this study, we analyzed a 5-generation Indian family with multiple members affected with SZ by WES. We identified a rare heterozygous missense variant (NM_003255: c.506C>T; p.Pro169Leu; MAF = 0.0001) in Tissue Inhibitor of Metalloproteinase 2 (TIMP2, 17q25.3) segregating with all 6 affected individuals but not with unaffected members. Linkage analysis indicated a maximum logarithm of the odds score of 1.8, theta = 0 at this locus. The variant was predicted to be damaging by various in silico tools and also disrupt the structural integrity by molecular dynamics simulations. WES based screening of an independent SZ cohort (n = 370) identified 4 additional rare missense variants (p.Leu20Met, p.Ala26Ser, p.Lys48Arg and p. Ile217Leu) and a splice variant rs540397728 (NM_003255:c.232-5T>C), also predicted to be damaging, increasing the likelihood of contribution of this gene to SZ risk. Extensive biochemical and knockout mouse studies suggesting involvement of TIMP2 in neurodevelopmental and behavioral deficits, together with genetic evidence for TIMP2 conferring SZ risk from this study may have possible implications for new therapeutics. PMID- 29385605 TI - Effect of level of soluble fiber and n-6/n-3 fatty acid ratio on performance of rabbit does and their litters. AB - The aim of this work was to study whether the dietary supplementation with soluble fiber (SF) and the reduction of the n-6/n-3 fatty acid ratio or the combination of both influences the survival, body and milk composition, and reproductive performance of rabbit does during the first four parturitions. Four diets in a 2 * 2 factorial arrangement were used with two levels of SF (7.8 vs. 13.0, on dry matter [DM] basis; high soluble fiber [HSF] and low soluble fiber [LSF]) and two different n-6/n-3 fatty acid ratios (13.4/1 vs. 3.5/1). Nulliparous does (24/diet) were inseminated 11 d after parturition. Body chemical composition and energy content of rabbit does and their performance, litter growth, and milk production were measured between birth and weaning (25 d) along four parturitions, and milk composition and fecal digestibility were also recorded. The proportion of total removed does decreased in HSF respect to LSF groups (22.9 vs. 50.0%; P = 0.005), and it tended to decrease in LSF groups when the n-6/n-3 ratio increased and in HSF groups when the n-6/n-3 ratio decreased (P = 0.059). The increase of the level of SF reduced the digestible crude protein (CP)/digestible energy ratio (by 4%; P < 0.001) and improved the digestibility of all fibrous fractions (P < 0.001). The reduction of the n-6/n-3 ratio reduced the total dietary fiber digestibility in rabbit does fed LSF diets, but it had no effect in those fed HSF diets (P = 0.043). Treatments had no effect on average daily feed intake among parturitions (P = 0.16), but the digestible CP intake among parturitions was lower in HSF than in LSF groups (P = 0.003). Treatments had no effect on the total number of kits born, litter or average kit weight at birth, or litter size at weaning, fertility, feed efficiency, total milk production, and body chemical composition and energy content of rabbit does (P >= 0.29). The average weight of kits at weaning of LSF_Hn-6/n-3 and HSF_Ln-6/n-3 groups decreased by 6% compared with those from the other two groups (P = 0.030). The reduction of the dietary n-6/n-3 ratio increased the milk fat content by 12% with no effect on protein and DM content (P = 0.031). The proportion of milk odd fatty acids and saturated fatty acid increased in rabbit does fed the HSF diets compared with those fed LSF diets (P <= 0.037) with no effect of the n-6/n-3 fatty acid ratio. In conclusion, SF reduced the replacement rate of rabbit does with no effect of the n-6/n-3 ratio, while both dietary factors modified milk composition and fatty acid profile with minor influence on litter productivity. PMID- 29385607 TI - Genetic parameter estimates and targeted association analyses of growth, carcass, and meat quality traits in German Merinoland and Merinoland-cross lambs. AB - In this study, genetic parameters of nine growth, carcass, and meat quality (MQ) traits were estimated, and targeted association studies were conducted using mixed models. Phenotypic information was collected on 1,599 lambs, including both purebred Merinoland (ML) animals and five different F1 crosses. The F1 lambs were produced by mating rams of the meat-type breeds Charollais, Ile de France, German Blackheaded Mutton (Deutsches Schwarzkopfiges Fleischschaf), Suffolk, and Texel with ML ewes. Between four and six sires were used per sire breed. In total, 29 sires and 298 purebred ML sheep were genotyped with the Illumina OvineSNP50 BeadChip. All F1 individuals were genotyped for 289 SNPs located on the chromosomes 1, 2, 3, 18, and 21. These SNPs were used to impute SNPs on five chromosomes of the Illumina Ovine chip in the F1 individuals. Several Bonferroni corrected significant associations were identified for shoulder width. A number of additional significant associations were found for other traits. Genetic parameters were estimated and single-marker association analyses were performed with breed-specific effects. Moderate heritability estimates were found for average daily gain (0.23), kidney fat weight (0.19), carcass length (0.15), shoulder width (0.33), subcutaneous fat thickness (0.22), and cutlet area (0.36). While heritability for cooking loss was found to be low (0.07), shear force (0.17) and dressing percentage (0.20) showed moderate heritability, and thus might be candidate traits to be included in the selection index in the population. In general, low phenotypic and low or moderate genetic correlations were detected between the traits. PMID- 29385608 TI - Preweaning injections of bovine ST enhanced reproductive performance of Bos indicus-influenced replacement beef heifers. AB - A 3 yr study evaluated the effects of three preweaning injections of bovine ST, administered 14 d apart, on growth and reproductive performance of Bos indicus influenced beef heifers. On d 0 of each year, suckling Angus * Brangus heifers (n = 15 heifers/treatment/yr) were stratified by BW (147 +/- 20 kg) and age (134 +/- 11 d) and randomly assigned to receive an s.c. injection of saline (SAL; 5 mL; 0.9% NaCl) or 250 mg of sometribove zinc (BST; Posilac, Elanco, Greenfield, IN) on d 0, 14, and 28. Heifers and respective dams were managed as a single group on bahiagrass (Paspalum notatum) pastures from d 0 until weaning (d 127). From d 127 to 346, heifers were grouped by treatment, allocated to bahiagrass pastures (1 pasture/treatment/yr) and fed a molasses-based supplement (2.9 kg/heifer daily; DM basis) until d 346. Blood samples were collected on d 0, 14, 28, 42, and then every 9-10 d from d 179 to 346. In yr 3, liver biopsy samples were collected on d 0, 42, and 263. Heifers were exposed to mature Angus bulls from d 263 to 346. Growth performance and physiological parameters were analyzed using the MIXED procedure, whereas reproductive variables were analyzed using the GLIMMIX procedure of SAS. Effects of treatment * year and treatment * year * time were not detected for any variable measured in this study (P >= 0.14), except for calving percentage (P = 0.03). Heifers assigned to BST injections had greater overall plasma concentrations of IGF-1 and ADG from d 0 to 42 (P <= 0.05), less ADG from d 42 to 127 (P = 0.04), but had similar BW at weaning and postweaning ADG (P >= 0.25) compared to SAL heifers. Heifers assigned to BST tended to achieve puberty 26 d earlier (P = 0.10), had greater percentage of pubertal heifers on d 244, 263, 284, and 296 (P <= 0.04), tended to have greater overall pregnancy percentage (P = 0.10), and had greater (P <= 0.05) calving percentages in yr 1 and 2 (but not yr 3; P = 0.68) compared to SAL heifers. Liver mRNA expression of GHR-1B and IGF-1 on d 0 and 42 did not differ between treatments (P >= 0.15), but was greater for BST vs. SAL heifers on d 263 (P <= 0.02). Hence, administering three injections containing 250 mg of sometribove zinc at 14 d intervals before weaning (between 135 and 163 d of age) induced long-term impacts on liver gene expression and may be a feasible management practice to enhance puberty and pregnancy attainment in B. indicus-influenced replacement beef heifers. PMID- 29385609 TI - Dietary protein reduction on microbial protein, amino acid digestibility, and body retention in beef cattle: 2. Amino acid intestinal absorption and their efficiency for whole-body deposition. AB - The objective of this study was to determine the apparent and true intestinal digestibility of total and individual AA, and to estimate the efficiency of whole body AA retention from individual and total absorbed AA. Four Nellore animals (241.3 kg initial BW) and four crossbred Angus * Nellore (263.4 kg initial BW) cannulated in rumen and ileum were randomly allocated in two 4 * 4 Latin squares. The experiment lasted four 17 d periods, with 10 d for adaptation to diets and another 7 d for data collection. The diets consisted of increasing CP levels: 100, 120, or 140 g/kg of DM offered ad libitum, and restricted intake diet with 120 g CP/kg DM (experiment 1). In experiment 2, forty-four bulls (22 Nellore and 22 crossbred F1 Angus * Nellore) with 8 months and initial shrunk BW 215.0 +/- 15.0 kg (Nellore = 208.0 +/- 12.78 kg; Angus * Nellore = 221.9 +/- 14.16 kg) were used. Eight of those animals were slaughtered at the beginning of the experiment. The remaining 36 bulls were allocated in a completely randomized design with six replicates, in a 2 (genetic groups) * 3 (CP contents) factorial scheme. The amount of essential AA (EAA) and nonessential AA (NEAA) reaching the small intestine increased linearly (P < 0.05) in response to CP content. The apparent digestibility of EAA was not affected (P > 0.05) by CP content, with exception for histidine (P = 0.07, linear effect), leucine (P = 0.01, linear effect), and methionine (P = 0.05, linear effect). Differences existed among AA when compared the apparent digestibility of NEAA. The apparent digestibility of alanine (P = 0.05), aspartic acid (P = 0.07), glutamic acid (P = 0.02), glycine (P = 0.05), proline (P = 0.02), and serine (P = 0.04) responded quadratically to CP content increase. However, the apparent digestibility of cystine and tyrosine was not affected (P > 0.05) by increasing dietary CP. The true intestinal digestibilities of total, essential, nonessential AA, lysine, and methionine were 75.0%, 77.0%, 74.0%, 77.0%, and 86%, respectively. The true intestinal digestibility of total microbial AA was 80%. The efficiency of utilization of total AA for whole-body protein deposition was 40%. The efficiency of utilization of lysine and methionine was 37% and 58%, respectively. It was concluded that the AA flow to the omasum increases in response to dietary CP content. In addition, there are differences among AA in the efficiency that they are used by beef cattle. PMID- 29385610 TI - Substituting ground woody plants for cottonseed hulls in lamb feedlot diets: carcass characteristics, adipose tissue fatty acid composition, and sensory panel traits. AB - Effects of using ground woody plants in Rambouillet wether lamb (n = 48) feedlot diets on carcass characteristics, adipose tissue fatty acid composition, and sensory panel traits were evaluated. In a randomized design study with two feeding periods (period 1 = fed a 70% concentrate diet from days 0 to 27; period 2 = fed an 86% concentrate diet from days 28 to 57), lambs were individually fed six diets that differed only by roughage source (n = 8 animals/treatment; initial BW = 32.9 +/- 3.2 kg): cottonseed hulls (CSH; control) or ground wood consisting of either redberry (RED), blueberry (BLUE), one-seed (ONE), or eastern red cedar (ERC) Juniperus spp., or Prosopis glandulosa (MESQ). After 57 d, the lambs were humanely harvested and after chilling (2 +/- 1 oC) 24 h, carcasses were evaluated for carcass traits. At 48 h postmortem, the longissimus thoracis (LT) was removed from the left side of the carcass, and after freezing for no more than 3 mo, were thawed for 24 h, cooked, and evaluated by a trained sensory panel. Additionally, volatile aroma chemicals on the LT were determined by gas chromatograph/mass spectrometer/olfactory (GC/MS/OF, respectively) analyses. Lamb HCW was greater (P = 0.01) for lambs fed CSH compared with all other diets, but lambs had similar (P > 0.08) LM area, back fat thickness, leg circumference, and body wall. Neither adipose tissue fatty acid composition (P > 0.08) nor trained sensory panel evaluation (P > 0.18) was affected by finishing diet roughage source. Of the 81 volatile aroma compounds found in the grilled lamb chops, only seven were affected (P < 0.05) by dietary roughage source and included 1-pentanol (a sweet, pleasant aroma), heptenal (a fishy aroma), pentanal (fermented, bready aroma description), 1-(1H-pyrol-2yl)-ethanone (caramel-like), 2-heptanone (cheesy, banana, fruity aromatic), 6,7-dodecanedione (unknown aroma), and butanoic acid (a sweaty, rancid aroma). The addition of any of four species of juniper or mesquite may be substituted for CSH without negatively affecting carcass fat and muscling, fatty acid, or sensory traits. PMID- 29385611 TI - BIG DATA ANALYTICS AND PRECISION ANIMAL AGRICULTURE SYMPOSIUM: Machine learning and data mining advance predictive big data analysis in precision animal agriculture. AB - Precision animal agriculture is poised to rise to prominence in the livestock enterprise in the domains of management, production, welfare, sustainability, health surveillance, and environmental footprint. Considerable progress has been made in the use of tools to routinely monitor and collect information from animals and farms in a less laborious manner than before. These efforts have enabled the animal sciences to embark on information technology-driven discoveries to improve animal agriculture. However, the growing amount and complexity of data generated by fully automated, high-throughput data recording or phenotyping platforms, including digital images, sensor and sound data, unmanned systems, and information obtained from real-time noninvasive computer vision, pose challenges to the successful implementation of precision animal agriculture. The emerging fields of machine learning and data mining are expected to be instrumental in helping meet the daunting challenges facing global agriculture. Yet, their impact and potential in "big data" analysis have not been adequately appreciated in the animal science community, where this recognition has remained only fragmentary. To address such knowledge gaps, this article outlines a framework for machine learning and data mining and offers a glimpse into how they can be applied to solve pressing problems in animal sciences. PMID- 29385612 TI - Potato late blight field resistance from QTL dPI09c is conferred by the NB-LRR gene R8. AB - Following the often short-lived protection that major nucleotide binding, leucine rich-repeat (NB-LRR) resistance genes offer against the potato pathogen Phytophthora infestans, field resistance was thought to provide a more durable alternative to prevent late blight disease. We previously identified the QTL dPI09c on potato chromosome 9 as a more durable field resistance source against late blight. Here, the resistance QTL was fine-mapped to a 186 kb region. The interval corresponds to a larger, 389 kb, genomic region in the potato reference genome of Solanum tuberosum Group Phureja doubled monoploid clone DM1-3 (DM) and from which functional NB-LRRs R8, R9a, Rpi-moc1, and Rpi_vnt1 have arisen independently in wild species. dRenSeq analysis of parental clones alongside resistant and susceptible bulks of the segregating population B3C1HP showed full sequence representation of R8. This was independently validated using long-range PCR and screening of a bespoke bacterial artificial chromosome library. The latter enabled a comparative analysis of the sequence variation in this locus in diverse Solanaceae. We reveal for the first time that broad spectrum and durable field resistance against P. infestans is conferred by the NB-LRR gene R8, which is thought to provide narrow spectrum race-specific resistance. PMID- 29385613 TI - Prophylactic and therapeutic interventions for bleeding in dengue: a systematic review. AB - The global incidence of dengue has increased sevenfold between 1990 and 2013. Despite a low case fatality rate (<1%), during epidemics, due to the large number of people affected, overall mortality rates can be significant. The risk of clinically significant bleeding in dengue is unpredictable and often contributes to an adverse outcome. This systematic review focuses on the evidence for prophylactic and therapeutic interventions for bleeding in dengue infection. PubMed, CINAHL, Cochrane Library, Embase and Google Scholar were searched for randomized, quasi-randomized and non-randomized, prospective or retrospective studies that had a control group alongside an intervention aimed at stopping or preventing bleeding in dengue infection. Eleven studies that included 1904 patients in 12 study arms were eligible. These assessed the role of platelet transfusion [two randomized controlled trials (RCTs) and three non-randomized studies], plasma transfusion (one RCT), recombinant activated factor VII (one RCT), anti-D globulin (two RCTs), immunoglobulin (one RCT) and interleukin 11 (one RCT) as prevention or treatment for bleeding. Due to significant heterogeneity in study design and outcome reporting, a meta-analysis was not performed. Currently there is no evidence that any of the above interventions would have a beneficial effect in preventing or treating clinically significant bleeding in dengue. PMID- 29385615 TI - Orange: a target gene for regulating carotenoid homeostasis and increasing plant tolerance to environmental stress in marginal lands. AB - Carotenoids play essential roles in various light-harvesting processes in plants and help protect the photosynthetic machinery from photo-oxidative damage. Orange genes, which play a role in carotenoid accumulation, have recently been isolated from several plant species, and their functions have been intensively investigated. The Orange gene (IbOr) of sweet potato [Ipomoea batatas (L.) Lam] helps maintain carotenoid homeostasis to improve plant tolerance to environmental stress. IbOr, a protein with strong holdase chaperone activity, directly interacts with phytoene synthase, a key enzyme involved in carotenoid biosynthesis, in plants under stress conditions, resulting in increased carotenoid accumulation and abiotic stress tolerance. In addition, IbOr interacts with the oxygen-evolving enhancer protein 2-1, a member of a protein complex in photosystem II that is denatured under heat stress. Transgenic sweet potato plants overexpressing IbOr showed enhanced tolerance to high temperatures (47 degrees C). These findings indicate that IbOr protects plants from environmental stress not only by controlling carotenoid biosynthesis, but also by directly stabilizing photosystem II. In this review, we discuss the functions of IbOr and Or proteins in other plant species and their possible biotechnological applications for molecular breeding for sustainable development on marginal lands. PMID- 29385614 TI - Induction of autophagy and interleukin 6 secretion in bystander cells: metabolic cooperation for radiation-induced rescue effect? AB - We hypothesized that radiation-induced rescue effect (RIRE) shared similar mechanisms with 'metabolic cooperation', in which nutrient-deprived cancer cells prompted normal cells to provide nutrients. Our data demonstrated that X-ray irradiation induced autophagy in HeLa cells, which could last at least 18 h, and proved that the irradiated cells (IRCs) resorted to breaking down their own intracellular components to supply the molecules required for cell-repair enhancement (e.g. to activate the NF-kappaB pathway) in the absence of support from bystander unirradiated cells (UICs). Furthermore, autophagy accumulation in IRCs was significantly reduced when they were partnered with UICs, and more so with UICs with pre-induced autophagy before partnering (through starvation using Earle's Balanced Salt Solution), which showed that the autophagy induced in UICs supported the IRCs. Our results also showed that interleukin 6 (IL-6) was secreted by bystander UICs, particularly the UICs with pre-induced autophagy, when they were cultured in the medium having previously conditioned irradiated HeLa cells. It was established that autophagy could activate the signal transducer and activator of transcription 3 (STAT3) that was required for the IL 6 production in the autophagy process. Taken together, the metabolic cooperation of RIRE was likely initiated by the bystander factors released from IRCs, which induced autophagy and activated STAT3 to produce IL-6 in bystander UICs, and was finally manifested in the activation of the NF-kappaB pathway in IRCs by the IL-6 secreted by the UICs. PMID- 29385616 TI - Distinct gibberellin functions during and after grapevine bud dormancy release. AB - The molecular mechanism regulating dormancy release in grapevine buds is as yet unclear. It has been hypothesized that (i) abscisic acid (ABA) represses bud meristem activity; (ii) perturbation of respiration induces an interplay between ethylene and ABA metabolism, which leads to removal of repression; and (iii) gibberellin (GA)-mediated growth is resumed. The first two hypothesis have been formally supported. The current study examines the third hypothesis regarding the potential involvement of GA in dormancy release. We found that during natural dormancy induction, levels of VvGA3ox, VvGA20ox, and VvGASA2 transcripts and of GA1 were decreased. However, during dormancy release, expression of these genes was enhanced, accompanied by decreased expression of the bud-expressed GA deactivating VvGA2ox. Despite indications for its positive role during natural dormancy release, GA application had inhibitory effects on bud break. Hydrogen cyanamide up-regulated VvGA2ox and down-regulated VvGA3ox and VvGA20ox expression, reduced GA1 levels, and partially rescued the negative effect of GA. GA had an inhibitory effect only when applied simultaneously with bud-forcing initiation. Given these results, we hypothesize that during initial activation of the dormant bud meristem, the level of GA must be restricted, but after meristem activation an increase in its level serves to enhance primordia regrowth. PMID- 29385617 TI - The GARP/MYB-related grape transcription factor AQUILO improves cold tolerance and promotes the accumulation of raffinose family oligosaccharides. AB - Grapevine (Vitis vinifera L.) is a widely cultivated fruit crop whose growth and productivity are greatly affected by low temperatures. On the other hand, wild Vitis species represent valuable genetic resources of natural stress tolerance. We have isolated and characterized a MYB-like gene encoding a putative GARP-type transcription factor from Amur grape (V. amurensis) designated as VaAQUILO. AQUILO (AQ) is induced by cold in both V. amurensis and V. vinifera, and its overexpression results in significantly improved tolerance to cold both in transgenic Arabidopsis and in Amur grape calli. In Arabidopsis, the ectopic expression of VaAQ increased antioxidant enzyme activities and up-regulated reactive oxygen species- (ROS) scavenging-related genes. Comparative mRNA sequencing profiling of 35S:VaAQ Arabidopsis plants suggests that this transcription factor is related to phosphate homeostasis like their Arabidopsis closest homologues: AtHRS1 and AtHHO2. However, when a cold stress is imposed, AQ is tightly associated with the cold-responsive pathway and with the raffinose family oligosaccharides (RFOs), as observed by the up-regulation of galactinol synthase (GoLS) and raffinose synthase genes. Gene co-expression network (GCN) and cis-regulatory element (CRE) analyses in grapevine indicated AQ as potentially regulating VvGoLS genes. Increased RFO content was confirmed in both transgenic Arabidopsis and Amur grape calli overexpressing VaAQ. Taken together, our results imply that AQ improves cold tolerance through promoting the accumulation of osmoprotectants. PMID- 29385619 TI - The "Healing Healer"? A Psychologist's Personal Narrative of Psychosis and Early Intervention. PMID- 29385618 TI - Radiomics and radiogenomics for precision radiotherapy. AB - Imaging plays an important role in the diagnosis and staging of cancer, as well as in radiation treatment planning and evaluation of therapeutic response. Recently, there has been significant interest in extracting quantitative information from clinical standard-of-care images, i.e. radiomics, in order to provide a more comprehensive characterization of image phenotypes of the tumor. A number of studies have demonstrated that a deeper radiomic analysis can reveal novel image features that could provide useful diagnostic, prognostic or predictive information, improving upon currently used imaging metrics such as tumor size and volume. Furthermore, these imaging-derived phenotypes can be linked with genomic data, i.e. radiogenomics, in order to understand their biological underpinnings or further improve the prediction accuracy of clinical outcomes. In this article, we will provide an overview of radiomics and radiogenomics, including their rationale, technical and clinical aspects. We will also present some examples of the current results and some emerging paradigms in radiomics and radiogenomics for clinical oncology, with a focus on potential applications in radiotherapy. Finally, we will highlight the challenges in the field and suggest possible future directions in radiomics to maximize its potential impact on precision radiotherapy. PMID- 29385620 TI - CHARACTERIZATION OF 27 MEV PROTON BEAM GENERATED BY TOP-IMPLART LINEAR ACCELERATOR. AB - The first proton linear accelerator for tumor therapy based on an actively scanned beam up to the energy of 150 MeV, is under development and construction by ENEA-Frascati, ISS and IFO, under the Italian TOP-IMPLART project. Protons up to the energy of 7 MeV are generated by a customized commercial injector operating at 425 MHz; currently three accelerating modules allow proton delivery with energy up to 27 MeV. Beam homogeneity and reproducibility were studied using a 2D ionizing chamber, EBT3 films, a silicon diode, MOSFETs, LiF crystals and alanine dosimetry systems. Measurements were taken in air with the detectors at ~1 m from the beam line exit window. The maximum energy impinging on the detectors surface was 24.1 MeV, an energy suitable for radiobiological studies. Results showed beam reproducibility within 5% and homogeneity within 4%, on a circular surface of 16 mm in diameter. PMID- 29385623 TI - INTERNATIONAL COMPARISON EXERCISE ON NEUTRON SPECTRA UNFOLDING IN BONNER SPHERES SPECTROMETRY: PROBLEM DESCRIPTION AND PRELIMINARY ANALYSIS. AB - This article describes the purpose, the proposed problems and the reference solutions of an international comparison on neutron spectra unfolding in Bonner spheres spectrometry, organised within the activities of EURADOS working group 6: computational dosimetry. The exercise considered four realistic situations: a medical accelerator, a workplace field, an irradiation room and a skyshine scenario. Although a detailed analysis of the submitted solutions is under preparation, the preliminary discussion of some physical aspects of the problem, e.g. the changes in the unfolding results due to the perturbation of the neutron field by the Bonner spheres, is presented. PMID- 29385621 TI - Outgroup emotion processing in the vACC is modulated by childhood trauma and CACNA1C risk variant. AB - A high frequency of outgroup contact-as experienced by urban dwellers and migrants-possibly increases schizophrenia risk. This risk might be further amplified by genetic and environmental risk factors, such as the A-allele of rs1006737 within the calcium voltage-gated channel subunit alpha1 C gene and childhood interpersonal trauma (CIT). Both have been related to ventral anterior cingulate cortex (vACC) functioning. We investigated vACC functioning, during ingroup and outgroup emotion perception in relation to rs1006737 and CIT. Group membership was manipulated through a minimal group paradigm. Thus, in our functional magnetic resonance imaging study, a group of healthy Caucasian participants (n = 178) viewed video-recorded facial emotions (happy vs angry) of actors artificially assigned to represent the ingroup or the outgroup. Rs1006737 and CIT were related to brain activation for group and emotion specific processing. The group-emotion interaction in the vACC showed reduced sensitivity to emotional valence for outgroup member processing. Specifically for the angry outgroup condition, we found a gene by environment interaction in vACC activity. We speculate that the increased schizophrenia risk in migrants and urban dwellers could therefore be facilitated via this pathophysiological pathway. PMID- 29385624 TI - Comparative Genotoxicity of TEMPO and 3 of Its Derivatives in Mouse Lymphoma Cells. AB - TEMPO (2, 2, 6, 6-tetramethylphiperidine-1-oxyl) and its derivatives are stable free radical nitroxides widely used in the field of chemistry, biology, and pharmacology. TEMPO was previously found to be mutagenic and to induce micronuclei in mammalian cells. In this study, we investigated and quantified the genotoxicity of 4 structurally similar nitroxides, TEMPO and 3 of its derivatives (4-hydroxy-TEMPO, 4-oxo-TEMPO, and 4-methoxy-TEMPO), using the mouse lymphoma assay (MLA) and Comet assay in L5178Y Tk+/- cells. The results showed that all tested nitroxides were cytotoxic and mutagenic in the MLA, both in the presence and absence of S9, with metabolic activation significantly enhancing the cytotoxicity and/or mutagenicity. In addition, the 4 nitroxides caused DNA-strand breakage. The mutagenicity and DNA damaging dose-responses of the test articles were compared using the PROAST benchmark dose software package. The potency ranking of the 4 nitroxides for mutagenicity was different from the ranking of the DNA damaging effects. The mode of action analysis by a multi-endpoint DNA damage pathway assay classified all 4 nitroxides as clastogens. In addition, the majority of the induced Tk mutants showed loss of heterozygosity at the Tk and D11Mit42 loci (ie, chromosome damage <31 Mbp). These results suggest that TEMPO and its 3 derivatives are cytotoxic and mutagenic in mouse lymphoma cells through a mechanism that involves strand breakage and large alterations to DNA. The potency rankings indicate that the different TEMPO derivatives vary in their mutagenic and DNA damaging potential. PMID- 29385625 TI - Should I Stay or Should I Go? FMRI Study of Response Inhibition in Early Illness Schizophrenia and Risk for Psychosis. AB - Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI. PMID- 29385626 TI - Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study. AB - Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function. PMID- 29385627 TI - Mechanisms Underlying Aluminum Neurotoxicity Related to 14-3-3zeta Protein. AB - Studies have shown that aluminum (Al) is associated with Alzheimer's disease (AD) causality, however, the mechanism underlying this link remains unclear. To investigate the Al neurotoxicity, the high Al-affinity protein from pig hippocampus was screened by native gel electrophoresis and Al3+ plus 8 hydroxyquinoline (8-HQ) staining. The protein with high Al3+ affinity was identified to be 14-3-3zeta, which was then used for raising antibodies. By 8-HQ staining and immunocytochemical localization, we found that the co-location of Al3+ and 14-3-3zeta increased markedly in the Al-exposed rat hippocampus tissue and the cultured rat primary hippocampal neuronal cells. By immune analysis with antibodies against tau, we found that tau accumulation mainly located in the neurons of cornu amonis 3 and dentate gyrus of the rat hippocampus. Total free tau in hippocampus tissue and in neuronal cells increased 26.0% and 20.2%, respectively after Al-exposure. By immunofluorescent staining, we found that the levels of tau and 14-3-3zeta co-location declined 15.9% or 12.1% in the hippocampus tissue or in neuronal cells after Al exposure. These findings indicated that 14-3-3zeta combing with tau can prevent the over phosphorylation of tau and can be disturbed by Al exposure due to Al3+ binding to 14-3-3zeta, which could account for the mechanisms underlying Al neurotoxicity related to AD. PMID- 29385622 TI - Functional connectivity pattern underlies individual differences in independent self-construal. AB - Independent vs interdependent self-construal is a concept that reflects how people perceive the relationship between self and other people, which has been extensively examined across disciplines. However, little evidence on the whole brain functional connectivity (FC) pattern of independent vs interdependent self construal has been reported. Here, in a sample of 51 healthy participants, we used resting-state functional magnetic resonance imaging and voxel-based FC analysis (i.e. FC strength and seed-based FC) by measuring the temporal correlation of blood oxygen level-dependent signals between spatially separate brain regions to investigate the neural mechanism of independent vs interdependent self-construal. First, we found that FC strength of bilateral posterior cingulate cortex and precuneus, and left inferior frontal gyrus were positively correlated with the independent vs interdependent score. Seed-based FC analysis with these three regions as seeds revealed that, FC within default mode network and executive control network was positively correlated with the independent vs interdependent score. Negative correlation with independent vs interdependent score was shown in the connections between default mode network and executive control regions. Taking together, our results provide a comprehensive FC architecture of the independent vs interdependent self-construal and advance the understanding of the interplay between culture, mind and brain. PMID- 29385629 TI - Exposure to DBP and High Iodine Aggravates Autoimmune Thyroid Disease Through Increasing the Levels of IL-17 and Thyroid-Binding Globulin in Wistar Rats. AB - Autoimmune thyroid disease (AITD) is the most common autoimmune disease that causes hypothyroidism. High iodine is a well-known factor that can induce thyroid disorders, including Hashimoto's thyroiditis, one of the main types of AITD. Recent epidemiological studies have indicated that phthalates, especially di-n butyl phthalate (DBP) may induce thyroid disease. In this study, we aim to determine the effects and underlying mechanisms of high iodine and/or DBP exposure on AITD. Female Wistar rats were modeled with thyroglobulin and exposed to high iodine and/or DBP. We investigated histopathological changes in the thyroid and measured thyroid hormone levels in serum to assess thyroid function. In the thyroid and liver, we detected oxidative stress, proinflammatory factors (IL-1beta, IL-6, and IL-17) and the activation of activator protein 1 (AP-1), a transcription factor that is related to the synthesis of the thyroxine-binding globulin (TBG) and the activation of Th17. After blocking AP-1 with SP600125, we detected TBG and the Th17 related cytokines (IL-6 and IL-17). The data showed that thyroid damage and the alteration of thyroid hormones were greater when the rats were exposed to both high iodine and DBP. Coexposure to DBP and high iodine enhanced the activation of AP-1 in the liver and thyroid, and induced an increase in the levels of TBG in serum and IL-17 in the thyroid. Blocking AP-1 activation prevented the increase of TBG and IL-17. The results indicate that high iodine and/or DBP exposure exacerbated AITD through altering TBG levels in serum and aggravating IL-17 in the thyroid. PMID- 29385628 TI - Evaluating In Vitro-In Vivo Extrapolation of Toxicokinetics. AB - Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo TK data available to benchmark these methods are from pharmaceuticals. Here we report on new, in vivo rat TK experiments for 26 non pharmaceutical chemicals with environmental relevance. Both intravenous and oral dosing were used to calculate bioavailability. These chemicals, and an additional 19 chemicals (including some pharmaceuticals) from previously published in vivo rat studies, were systematically analyzed to estimate in vivo TK parameters (e.g., volume of distribution [Vd], elimination rate). For each of the chemicals, rat-specific HTTK data were available and key TK predictions were examined: oral bioavailability, clearance, Vd, and uncertainty. For the non-pharmaceutical chemicals, predictions for bioavailability were not effective. While no pharmaceutical was absorbed at less than 10%, the fraction bioavailable for non pharmaceutical chemicals was as low as 0.3%. Total clearance was generally more under-estimated for nonpharmaceuticals and Vd methods calibrated to pharmaceuticals may not be appropriate for other chemicals. However, the steady state, peak, and time-integrated plasma concentrations of nonpharmaceuticals were predicted with reasonable accuracy. The plasma concentration predictions improved when experimental measurements of bioavailability were incorporated. In summary, HTTK and IVIVE methods are adequately robust to be applied to high throughput in vitro toxicity screening data of environmentally relevant chemicals for prioritizing based on human health risks. PMID- 29385631 TI - New perspectives for the action of steroids in the brain. PMID- 29385630 TI - Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure. AB - Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = -0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance. PMID- 29385632 TI - Immediate and delayed loading of fixed dental prostheses supported by single or two splinted implants: A histomorphometric study in dogs. AB - To evaluate presumptive differences in osseointegration at implants supporting crowns that are physiologically loaded either immediately or 3 months after installation. All premolars and first molars were extracted bilaterally in six dogs. After 3 months of healing, three implants were installed on the premolar region and two in the molar region in one side of the mandible. Likewise, after another 3 months, five implants were installed in the contralateral side, and impressions were taken bilaterally. Within 48 hours, two single crowns were screwed bilaterally onto two implants in the premolar region, and two splinted crowns reproducing the shape of the first molar were screwed bilaterally onto the implants in the molar region. The mesial implants were used as no-loaded controls. Sacrifices were performed after 3 months, and histological analyses were performed. At the premolar sites, mineralised bone-to-implant contact (MBIC%) was 78.0 +/- 4.0% and 70.9 +/- 7.9% at the delayed and immediately loaded sites, respectively. This difference was statistically significant. At the control implants, MBIC% was 61.4 +/- 14.7% and 63.1 +/- 13.1% at the delayed and the immediately loaded sites, respectively. At the molar sites, MBIC% was 79.2 +/ 10.9% and 61.1 +/- 10.3% at the delayed and immediately loaded sites, respectively. Applying a delayed loading to fixed dental prostheses supported by single or two splinted implants yielded higher proportions of bone-to-implant contact (osseointegration) compared to immediately loaded implants. Moreover, both types of loading protocols yielded a higher rate of osseointegration compared to unloaded implant sites after 3 months following implant installation. PMID- 29385633 TI - Higher level of GGT during mid-pregnancy is associated with increased risk of gestational diabetes mellitus. AB - OBJECTIVE: This study was to explore the link between gamma-glutamyl transferase (GGT), alanine transaminase (ALT) and aspartate transaminase (AST) levels during early-middle pregnancy and subsequent risk of gestational diabetes mellitus (GDM). METHODS: In a prospective cohort study, pregnant women enrolled prior to 16 weeks of gestation were followed up until delivery. GGT, AST and ALT levels were tested during weeks 14-18 of gestation and oral glucose tolerance test was conducted during 24-28 weeks to screen GDM. RESULTS: The GDM rate was 8.1% (122/1512). Mean GGT level was higher in GDM than non-GDM women (18.7 +/- 13.0 vs 14.5 +/- 7.0, P < .001). The higher GGT level was 26.9~74.0 U/L, which was significantly associated with increased risk of GDM. The adjusted RR (95% CI) comparing higher GGT level versus lower was 5.40 (3.36-8.68). No significant correlation was found between ALT or AST levels and the risk of GDM. CONCLUSIONS: The results suggest that pregnant women with higher serum GGT during early-middle pregnancy have higher risk of developing GDM. A GGT level >26.9 U/L may indicate an increased risk of developing GDM later and should be further concerned. PMID- 29385634 TI - Unraveling lipid metabolism in maize with time-resolved multi-omics data. AB - Maize is the cereal crop with the highest production worldwide, and its oil is a key energy resource. Improving the quantity and quality of maize oil requires a better understanding of lipid metabolism. To predict the function of maize genes involved in lipid biosynthesis, we assembled transcriptomic and lipidomic data sets from leaves of B73 and the high-oil line By804 in two distinct time-series experiments. The integrative analysis based on high-dimensional regularized regression yielded lipid-transcript associations indirectly validated by Gene Ontology and promoter motif enrichment analyses. The co-localization of lipid transcript associations using the genetic mapping of lipid traits in leaves and seedlings of a B73 * By804 recombinant inbred line population uncovered 323 genes involved in the metabolism of phospholipids, galactolipids, sulfolipids and glycerolipids. The resulting association network further supported the involvement of 50 gene candidates in modulating levels of representatives from multiple acyl-lipid classes. Therefore, the proposed approach provides high confidence candidates for experimental testing in maize and model plant species. PMID- 29385635 TI - Deciphering genetic factors that determine melon fruit-quality traits using RNA Seq-based high-resolution QTL and eQTL mapping. AB - Combined quantitative trait loci (QTL) and expression-QTL (eQTL) mapping analysis was performed to identify genetic factors affecting melon (Cucumis melo) fruit quality, by linking genotypic, metabolic and transcriptomic data from a melon recombinant inbred line (RIL) population. RNA sequencing (RNA-Seq) of fruit from 96 RILs yielded a highly saturated collection of > 58 000 single-nucleotide polymorphisms, identifying 6636 recombination events that separated the genome into 3663 genomic bins. Bin-based QTL analysis of 79 RILs and 129 fruit-quality traits affecting taste, aroma and color resulted in the mapping of 241 QTL. Thiol acyltransferase (CmThAT1) gene was identified within the QTL interval of its product, S-methyl-thioacetate, a key component of melon fruit aroma. Metabolic activity of CmThAT1-encoded protein was validated in bacteria and in vitro. QTL analysis of flesh color intensity identified a candidate white-flesh gene (CmPPR1), one of two major loci determining fruit flesh color in melon. CmPPR1 encodes a member of the pentatricopeptide protein family, involved in processing of RNA in plastids, where carotenoid and chlorophyll pigments accumulate. Network analysis of > 12 000 eQTL mapped for > 8000 differentially expressed fruit genes supported the role of CmPPR1 in determining the expression level of plastid targeted genes. We highlight the potential of RNA-Seq-based QTL analysis of small to moderate size, advanced RIL populations for precise marker-assisted breeding and gene discovery. We provide the following resources: a RIL population genotyped with a unique set of SNP markers, confined genomic segments that harbor QTL governing 129 traits and a saturated set of melon eQTLs. PMID- 29385637 TI - Validation of contralateral premolars as the substrate for endodontic comparison studies. AB - AIM: To use micro-CT technology and metrology software to validate the use of contralateral premolars as samples in endodontic comparison studies by comparing them before and after canal instrumentation with one instrumentation system. Furthermore, to determine whether contralateral premolar roots (CPRs) will yield non-significantly different outcomes regarding shaping ability (volume), degree of twisting and three-dimensional shape changes. The null-hypothesis (H0 ) is that there are no differences between the CPRs pre- or post-instrumentation. METHODOLOGY: Twenty-eight extracted human contralateral premolars (n = 44 contralateral roots) from 12 donor patients were scanned with microcomputed tomography before and after instrumentation. Root canal lengths (RCLs) were measured visually using a dental-operating microscope, electronic apex locator and micro-CT scans. Data were analysed statistically for differences between pre- and post-instrumentation. RESULTS: Instrumentation increased the volume of the canals significantly (P < 0.05). Degree of twisting for a majority (83%) of the contralateral roots pairs did not change significantly (P > 0.05). There was no significant difference (P > 0.05) in the shape deviation analysis between contralateral pairs. There was no significant difference (P > 0.05) for RCL between the contralateral pairs for any of the three endometric methods. CONCLUSION: Contralateral premolar root canals were associated with similar changes in terms of volume, three-dimensional shape and degree of twisting from pre- to post-instrumentation. There was no difference between the CPR pairs pre- and post-instrumentation, and the study validates contralateral premolars as samples for root canal comparison studies. The null-hypothesis (H0 ) could not be rejected. PMID- 29385636 TI - Body length and occipitofrontal circumference may be good indicators of neurodevelopment in very low birthweight infants - secondary publication. AB - AIM: The aim of this study was to predict the neurological prognosis of very low birthweight (VLBW) infants. We examined the relationship between nutritional status, brain volume measured by magnetic resonance imaging (MRI) and anthropometric measurements of VLBW infants at term-equivalent age (TEA). METHODS: We evaluated 27 VLBW infants, born at Showa University Hospital in Japan between April 2012 and August 2013, who underwent brain MRI at TEA. Based on their clinical data, we analysed their protein and energy intake. RESULTS: Median values for the 27 VLBW infants were as follows: gestational age, 29.7 weeks; birthweight 1117 g; protein intake 2.7 g/kg/day and energy intake 97.9 kcal/kg/day. At TEA, the standard deviation scores (SDSs) of body weight, body length and the occipitofrontal circumference (OFC) were -0.8, -1.4 and 0.7, respectively. Multiple regression analysis revealed that the SDSs of body length and the OFC at TEA were significant determinants of white matter volume, but that the SDS of body weight at TEA was not. CONCLUSION: Our findings suggest that the SDSs of body length and the OFC at TEA may be better indicators than body weight for predicting the development of the central nervous system in VLBW infants receiving nutritional management. PMID- 29385638 TI - Procalcitonin and C-reactive protein may help to detect invasive bacterial infections in children who have fever without source. AB - AIM: This study evaluated the epidemiology and performance of biomarkers for identifying bacterial infections in children who presented with fever without source. METHODS: We conducted a prospective cohort study in the paediatric department at the University Hospital of Nantes, France, in 2016. Children older than six days and younger than five years of age were included. RESULTS: A total of 1060 children (52.2% male) with fever without source were admitted, and the median age was 17 months (interquartile range: 6.6-24.3 months). Severe bacterial infections were diagnosed in 127 (11.9%) children and invasive bacterial infections in 11 (1.0%) children: four (0.3%) with bacterial meningitis and seven (0.6%) with bacteraemia. A further 114 (10.7%) had urinary tract infections. We explored the area under the receiver-operating characteristic curves for identifying invasive bacterial infections. The curves for procalcitonin and C reactive protein assays were better than those for the absolute neutrophil counts and the white blood cell counts. CONCLUSION: This study found that there was a low prevalence of invasive bacterial infections in children who presented with fever without source. It also showed that procalcitonin and C-reactive protein may help to detect invasive bacterial infections in children who have fever without source. PMID- 29385639 TI - Cyclic fatigue resistances of several nickel-titanium glide path rotary and reciprocating instruments at body temperature. AB - AIM: To compare the cyclic fatigue resistance of the One G, ProGlider, HyFlex EDM and R-Pilot glide path NiTi files at body temperature. METHODOLOGY: Twenty One G (size 14, .03 taper), 20 ProGlider (size 16, .02 taper), 20 HyFlex EDM (size 10, .05 taper) and 20 R-Pilot (size 12.5, .04 taper) instruments were operated in rotation at 300 rpm (One G, ProGlider and HyFlex) or in reciprocation (R-Pilot) at 35 degrees C in artificial canals that were manufactured by reproducing the size and taper of the instrument until fracture occurred. The time to fracture was recorded in seconds using a digital chronometer, and the length of the fractured fragments was registered. Mean data were analysed statistically using the Kruskal-Wallis test and post hoc Tukey tests via SPSS 21.0 software. The statistical significance level was set at 5%. RESULTS: The cyclic fatigue resistance of the R-Pilot files was significantly greater than the other instruments, and the One G was significantly lower (P < 0.05). There was no difference between the HyFlex EDM and the ProGlider (P > 0.05). No significant difference (P > 0.05) was evident in the mean length of the fractured fragments of the various instruments. CONCLUSIONS: The cyclic fatigue resistance of the R Pilot reciprocating glide path file was significantly greater than that of the rotary HyFlex EDM, ProGlider and One G glide path files. PMID- 29385640 TI - Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects. AB - AIM: Hyperinsulinaemic hypoglycaemia (HH) is a very common cause of hypoglycaemia in small for gestational age (SGA) neonates. We compared using early oral diazoxide or a placebo for this patient group. METHODS: This was a randomised, double-blind, placebo-controlled trial that focused on SGA neonates born at at least 32 weeks of gestation with HH during the first five days of life. Neonates with severe perinatal asphyxia, sepsis or contraindications for oral feeds were excluded. The primary outcome was the hours taken to achieve hypoglycaemic control, with a glucose infusion rate of <=4 mg/kg/min. The secondary outcomes were the duration of intravenous fluids, sepsis episodes, time to achieve full feeds and mortality. RESULTS: We screened 490 neonates and 30 neonates were eligible for randomisation and completed the trial. Half received diazoxide and half received a placebo. The median time to achieve hypoglycaemia control (40 vs 71.5 hours, p = 0.015), the total duration of intravenous fluids (114 vs 164 hours, p = 0.04) and time to achieve full feeds (74 vs 124 hours, p = 0.02) were significantly lower in the diazoxide group, with no adverse effects attributed to the drug. CONCLUSION: Using oral diazoxide for SGA neonates with HH provided early hypoglycaemic control with no apparent adverse effects. PMID- 29385643 TI - Cross-sectional association between oral health and retinal microcirculation. AB - AIM: To investigate the relation between oral health status and microcirculation, we analysed the association between periodontitis and number of teeth with retinal vessel diameters in a population-based study. METHODS: We analysed data from the Study of Health in Pomerania-TREND (SHIP-TREND). All subjects (3,183 for number of teeth, 3,013 for mean probing depth and 2,894 for mean attachment level) underwent nonmydriatic funduscopy and dental examination. We measured central retinal arteriolar (CRAE), venular (CRVE) vessel diameters and calculated arterio-venous ratio (AVR) from static vessel analysis (SVA). Periodontal status was assessed using the case definition of the Center for Disease Control and Prevention/American Academy of Periodontology (CDC/AAP). Data were analysed by linear (CRAE, CRVE, AVR) and logistic regression (AVR < 0.8) adjusted for age, sex, smoking status, alcohol consumption, body mass index, systolic blood pressure, hsCRP and type-2-diabetes mellitus. RESULTS: Only in men, significant associations were found between periodontal and retinal conditions. Severe periodontitis [beta = -0.0120 (-0.0218; -0.0007 95%-CI)] and mean probing depth [beta = -0.0054 (-0.0105; -0.0002 95%-CI)] were inversely associated with AVR; severe periodontitis [beta = 3.80 (0.61; 6.98 95%-CI)], mean probing depth [beta = 1.86 (0.23; 3.49 95%-CI)] and mean attachment level [beta = 1.31 (0.34; 2.27 95%-CI)] with CRVE and mean attachment level with CRAE [beta = 0.91 (0.14; 1.69 95%-CI)]. CONCLUSIONS: Our results point towards an association between periodontal conditions and AVR in men. Periodontitis may impact microvascular endothelium function. Improving oral health to reduce periodontitis might lead to reduced risk for other age-related diseases. PMID- 29385642 TI - Frozen elephant trunk technique for Kommerell's diverticulum with right-sided aortic arch and aberrant left subclavian artery. PMID- 29385641 TI - Cellular distribution of secretory pathway markers in the haploid synergid cells of Arabidopsis thaliana. AB - In flowering plants, cell-cell communication plays a key role in reproductive success, as both pollination and fertilization require pathways that regulate interactions between many different cell types. Some of the most critical of these interactions are those between the pollen tube (PT) and the embryo sac, which ensure the delivery of sperm cells required for double fertilization. Synergid cells function to attract the PT through secretion of small peptides and in PT reception via membrane-bound proteins associated with the endomembrane system and the cell surface. While many synergid-expressed components regulating PT attraction and reception have been identified, few tools exist to study the localization of membrane-bound proteins and the components of the endomembrane system in this cell type. In this study, we describe the localization and distribution of seven fluorescent markers that labelled components of the secretory pathway in synergid cells of Arabidopsis thaliana. These markers were used in co-localization experiments to investigate the subcellular distribution of the two PT reception components LORELEI, a GPI-anchored surface protein, and NORTIA, a MILDEW RESISTANCE LOCUS O protein, both found within the endomembrane system of the synergid cell. These secretory markers are useful tools for both reproductive and cell biologists, enabling the analysis of membrane-associated trafficking within a haploid cell actively involved in polar transport. PMID- 29385644 TI - Evaluating periodontal disease misclassification mechanisms under partial-mouth recording protocols. AB - AIM: To evaluate the assumptions underlying the use of partial-mouth recording (PMR) protocols and the associated mechanisms of potential misclassification of periodontal disease. METHODS: Using data from 640 participants in the VA Dental Longitudinal Study, we compared tooth-specific and site-specific clinical measures and calculated sensitivity and specificity of different PMR protocols by applying the Centers for Disease Control and Prevention in collaboration with the American Academy of Periodontology definitions for periodontitis as the full mouth reference standard. Additionally, we evaluated alternative case definitions for PMR protocols that accounted for the reduction in numbers of teeth under observation. RESULTS: In this cohort, periodontitis presented as a generalized condition in that measures of clinical severity did not differ meaningfully according to site measured, oral quadrant or jaw. Sensitivity of disease classification under PMR protocols was a function of the number of teeth and sites under observation and the case definition applied. Sensitivity increased when case definitions were modified to account for the smaller number of teeth under observation with PMR protocols. However, specificity was reduced. CONCLUSIONS: Misclassification of periodontal disease by PMR protocols is not random, even if sites under observation are randomly selected. PMR protocols can be selected/modified to maximize sensitivity, but they do so at the expense of bias in mean measures of severity. PMID- 29385645 TI - Aggregatibacter actinomycetemcomitans serotypes associate with periodontal and coronary artery disease status. AB - AIM: We investigated the association between the Aggregatibacter actinomycetemcomitans serotypes, periodontal status and coronary artery disease (CAD). MATERIALS AND METHODS: The study population included 497 patients who underwent coronary angiography, and clinical oral examination. Quantitative polymerase chain reaction assays were designed to identify the serotypes from saliva samples. RESULTS: Aggregatibacter actinomycetemcomitans serotype frequencies were as follows: serotype "c" 35.7%, "b" 28.6%, "a" 26.2%, "e" 7.1%, "d" 2.4% and "f" 0%. The subjects with a detectable serotype had less teeth and higher bleeding on probing than those with no serotype. Serotypes "b" and "c" associated with periodontal probing depths and periodontal inflammatory burden. The saliva and subgingival bacterium quantities and serum antibody levels against A. actinomycetemcomitans were highest in patients harbouring serotype "c." Serotypes "b" and "c" were most frequent (59.3%) in patients with CAD (p = .040), and they associated with the risk of stable CAD with an odds ratio of 2.67 (95% confidence interval 1.06-7.44). Also, the severity of CAD (p = .018) associated with serotypes "b" and "c." CONCLUSIONS: Aggregatibacter actinomycetemcomitans serotypes "b" and "c" associate with both periodontal and CAD status. Detectable serotypes associate with the quantity and the serology of the bacterium emphasizing both local and systemic effect of the A. actinomycetemcomitans serotypes. PMID- 29385646 TI - Retrospective observational study indicates that the paediatric assessment triangle may suggest the severity of Kawasaki disease. AB - AIM: We examined whether the paediatric assessment triangle (PAT) could predict the severity of Kawasaki disease. METHODS: We enroled patients diagnosed with Kawasaki disease between July 2012 and June 2016 at the emergency department of Tokyo Metropolitan Children's Medical Center in Tokyo, Japan. Triage nurses assigned participants to unstable or stable PAT groups. We compared the incidence of coronary artery aneurysms (CAA), the Kobayashi score, which measures resistance to intravenous immunoglobulin treatment, and the incidence of initial treatment resistance. RESULTS: Of the 420 participants, who were aged 0-145 months with a mean age of 31.2 +/- 23.9 months, 66 (16%) were assigned to the unstable PAT group. The incidence of CAA was similar between the two groups. The percentage of unstable PAT group participants with a Kobayashi score of at least five points (39 versus 18%, p < 0.001) and initial treatment resistance (25 versus 15%, p = 0.047) were significantly higher than in the stable PAT group. Unstable PAT was an independent risk factor for initial treatment resistance (odds ratio 2.02, 95% confidence interval 1.05-3.90, p = 0.035). CONCLUSION: An unstable PAT was able to predict the severity of Kawasaki disease when measured by a higher rate of initial treatment resistance. PMID- 29385647 TI - Purification and characterization of Arabidopsis thaliana oligosaccharyltransferase complexes from the native host: a protein super expression system for structural studies. AB - The oligosaccharyltransferase (OT) complex catalyzes N-glycosylation of nascent secretory polypeptides in the lumen of the endoplasmic reticulum. Despite their importance, little is known about the structure and function of plant OT complexes, mainly due to lack of efficient recombinant protein production systems suitable for studies on large plant protein complexes. Here, we purified Arabidopsis OT complexes using the tandem affinity-tagged OT subunit STAUROSPORINE AND TEMPERATURE SENSITIVE3a (STT3a) expressed by an Arabidopsis protein super-expression platform. Mass-spectrometry analysis of the purified complexes identified three essential OT subunits, OLIGOSACCHARYLTRANSFERASE1 (OST1), HAPLESS6 (HAP6), DEFECTIVE GLYCOSYLATION1 (DGL1), and a number of ribosomal subunits. Transmission-electron microscopy showed that STT3a becomes incorporated into OT-ribosome super-complexes formed in vivo, demonstrating that this expression/purification platform is suitable for analysis of large protein complexes. Pairwise in planta interaction analyses of individual OT subunits demonstrated that all subunits identified in animal OT complexes are conserved in Arabidopsis and physically interact with STT3a. Genetic analysis of newly established OT subunit mutants for OST1 and DEFENDER AGAINST APOTOTIC DEATH (DAD) family genes revealed that OST1 and DAD1/2 subunits are essential for the plant life cycle. However, mutations in these individual isoforms produced much milder growth/underglycosylation phenotypes than previously reported for mutations in DGL1, OST3/6 and STT3a. PMID- 29385648 TI - Specific substitutions of light-harvesting complex I proteins associated with photosystem I are required for supercomplex formation with chloroplast NADH dehydrogenase-like complex. AB - In Arabidopsis, the chloroplast NADH-dehydrogenase-like (NDH) complex is sandwiched between two copies of photosystem I (PSI) supercomplex, consisting of a PSI core and four light-harvesting complex I (LHCI) proteins (PSI-LHCI) to form the NDH-PSI supercomplex. Two minor LHCI proteins, Lhca5 and Lhca6, contribute to the interaction of each PSI-LHCI copy with the NDH complex. Here, large-pore blue native gel electrophoresis revealed that, in addition to this complex, there were at least two types of higher-order association of more LHCI copies with the NDH complex. In single-particle images, this higher-order association of PSI-LHCI preferentially occurs at the left side of the NDH complex when viewed from the stromal side, placing subcomplex A at the top (Yadav et al., Biochim. Biophys. Acta - Bioenerg., 1858, 2017, 12). The association was impaired in the lhca6 mutant but not in the lhca5 mutant, suggesting that the left copy of PSI-LHCI was linked to the NDH complex via Lhca6. From an analysis of subunit compositions of the NDH-PSI supercomplex in lhca5 and lhca6 mutants, we propose that Lhca6 substitutes for Lhca2 in the left copy of PSI-LHCI, whereas Lhca5 substitutes for Lhca4 in the right copy. In the lhca2 mutant, Lhca3 was specifically stabilized in the NDH-PSI supercomplex through heterodimer formation with Lhca6. In the left copy of PSI-LHCI, subcomplex B, Lhca6 and NdhD likely formed the core of the supercomplex interaction. In contrast, a larger protein complex, including at least subcomplexes B and L and NdhB, was needed to form the contact site with Lhca5 in the right copy of PSI-LHCI. PMID- 29385649 TI - Left atrial thrombi following tranexamic acid in a bleeding trauma patient-A word of caution. AB - We describe the case of a bleeding trauma patient who received tranexamic acid (TXA) during air transport who subsequently developed multiple intra-cardiac thrombi. The administration of TXA during transport may be associated with this unusual presentation. PMID- 29385650 TI - The distinct functions of two classical arabinogalactan proteins BcMF8 and BcMF18 during pollen wall development in Brassica campestris. AB - Arabinogalactan proteins (AGPs) are extensively glycosylated hydroxyproline-rich glycoproteins ubiquitous in all plant tissues and cells. AtAGP6 and AtAGP11, the only two functionally known pollen-specific classical AGP encoding genes in Arabidopsis, are reported to have redundant functions in microspore development. BcMF18 and BcMF8 isolated from Brassica campestris are the orthologues of AtAGP6 and AtAGP11, respectively. In contrast to the functional redundancy of AtAGP6 and AtAGP11, single-gene disruption of BcMF8 led to deformed pollen grains with abnormal intine development and ectopic aperture formation in B. campestris. Here, we further explored the action of BcMF18 and its relationship with BcMF8. BcMF18 was specifically expressed in pollen during the late stages of microspore development. Antisense RNA transgenic lines with BcMF18 reduction resulted in aberrant pollen grains with abnormal cellulose distribution, lacking intine, cytoplasm and nuclei. Transgenic plants with repressive expression of both BcMF8 and BcMF18 showed a hybrid phenotype, expressing a mixture of the phenotypes of the single gene knockdown plant lines. In addition, we identified functional diversity between BcMF18/BcMF8 and AtAGP6/AtAGP11, mainly reflected by the specific contribution of BcMF18 and BcMF8 to pollen wall formation. These results suggest that, unlike the orthologous genes AtAGP6 and AtAGP11 in Arabidopsis, BcMF18 and BcMF8 are both integral to pollen biogenesis in B. campestris, acting through independent pathways during microspore development. PMID- 29385651 TI - Atlantic salmon Salmo salar in the chalk streams of England are genetically unique. AB - Recent research has identified genetic groups of Atlantic salmon Salmo salar that show association with geological and environmental boundaries. This study focuses on one particular subgroup of the species inhabiting the chalk streams of southern England, U.K. These fish are genetically distinct from other British and European S. salar populations and have previously demonstrated markedly low admixture with populations in neighbouring regions. The genetic population structure of S. salar occupying five chalk streams was explored using 16 microsatellite loci. The analysis provides evidence of the genetic distinctiveness of chalk-stream S. salar in southern England, in comparison with populations from non-chalk regions elsewhere in western Europe. Little genetic differentiation exists between the chalk-stream populations and a pattern of isolation by distance was evident. Furthermore, evidence of temporal stability of S. salar populations across the five chalk streams was found. This work provides new insights into the temporal stability and lack of genetic population sub structuring within a unique component of the species' range of S. salar. PMID- 29385652 TI - Detecting the genomic signal of polygenic adaptation and the role of epistasis in evolution. AB - Over the last decade, the genomic revolution has offered the possibility to generate tremendous amounts of data that contain valuable information on the genetic basis of phenotypic traits, such as those linked to human diseases or those that allow for species to adapt to a changing environment. Most ecologically relevant traits are controlled by a large number of genes with small individual effects on trait variation, but that are connected with one another through complex developmental, metabolic and biochemical networks. As a result, it has recently been suggested that most adaptation events in natural populations are reached via correlated changes at multiple genes at a time, for which the name polygenic adaptation has been coined. The current challenge is to develop methods to extract the relevant information from genomic data to detect the signature of polygenic evolutionary change. The symposium entitled "Detecting the Genomic Signal of Polygenic Adaptation and the Role of Epistasis in Evolution" held in 2017 at the University of Zurich aimed at reviewing our current state of knowledge. In this review, we use the talks of the invited speakers to summarize some of the most recent developments in this field. PMID- 29385653 TI - Technical Note: Automated quantitative analysis of planar scintigraphic resolution with the ACR SPECT phantom. AB - PURPOSE: Evaluating gamma camera image quality is a routine task required for annual physics surveys and laboratory accreditation. A common method is visual assessment of a planar view of the American College of Radiology (ACR) phantom, for which a satisfactory result is to resolve 7.9 mm diameter cold rods with high contrast. The objective was to investigate an automated quantitative measure of planar image quality for more precise evaluation of gamma camera performance. METHODS: Planar images were automatically co-registered to a template of the phantom's cold rod pattern. Contrast-to-noise ratio (CNR) was measured for each cold rods sector by automatic placement of regions of interests on each rod and on each gap between rods. A quadratic fit to CNR vs. rod diameter yielded the Minimum Detectable Rod Diameter (MDRD) corresponding to a CNR threshold of 4. This methodology was applied to planar images acquired on a variety of gamma cameras according to ACR guidelines and also to planar images generated by Monte Carlo simulation. RESULTS: The automated MDRD analysis had reproducibility of 0.1 mm in repeat phantom scans with random repositioning between scans. The MDRD was 5.8 mm for modern fully digital gamma cameras and 6.2 mm for an older analog gamma camera, whereas visual assessment was identical for all cameras. Simulated Monte Carlo images had MDRD of 5.6 mm using the following parameters: 3.5 mm FWHM intrinsic detector resolution, LEHR collimators, 9.0% FWHM energy resolution, and 15% energy window. Further simulations revealed that collimator design and detector resolution have a substantial impact on MDRD but that energy window width and energy resolution have a minor or negligible impact. The small difference between the Monte Carlo simulations and the modern fully digital gamma cameras was attributed to nonlinearities associated with event positioning and depth-of-interaction effects, which were not modeled in the simulations. CONCLUSIONS: Automated MDRD analysis of planar phantom images is a robust technique that provides more precise and meaningful evaluation of camera performance than visual assessment. MDRD is a suitable measure for quality assurance and for annual physics surveys of gamma cameras. PMID- 29385654 TI - Cross-sectional and prospective associations of meeting 24-h movement guidelines with overweight and obesity in preschool children. AB - BACKGROUND: Cross-sectional studies report that meeting the newly developed 24-h movement guidelines (>=60 min moderate to vigorous physical activity (MVPA), <=120 min screen time and 9-11 h sleep duration) are associated with lower adiposity indicators in children. However, prospective data are absent. METHODS: The study sample consisted of 830 children from the PRIMROSE study with GT3X+ accelerometer measured physical activity and parent reported screen time and sleep duration at age 4 years and objectively measured anthropometrics at age 4 and 5 years. The main outcome variables were weight status, body mass index (BMI) and BMI z-score at ages 4 and 5 years. Exposure variables were defined as meeting vs. not meeting the 24-h movement guidelines and combinations of these recommendations. RESULTS: On average, 18.4% of the total study sample met the combination of MVPA, sleep duration and screen time recommendations. In isolation, the MVPA, screen time and sleep guidelines were met by 31%, 63% and 98% of the total study sample, respectively. Adherence to any single recommendation, or any combination of recommendations at age 4 years, was not associated with being overweight or obese nor with BMI and BMI z-score at age 4 or 5 years. CONCLUSIONS: In contrast to previous cross-sectional studies, neither individual movement behaviours nor combinations of behaviours at age 4 years was associated with overweight or obesity, BMI or BMI z-score at age 4 or 5 years. More prospective data are needed before effects on weight status from meeting the 24-h movement guidelines are elucidated. PMID- 29385655 TI - Implementation of a Novel Algorithm to Decrease Unnecessary Hospitalizations in Patients Presenting to a Community Emergency Department With Atrial Fibrillation. AB - OBJECTIVES: Atrial fibrillation (AFib) is the most common dysrhythmia in the United States. Patients seen in the emergency department (ED) in rapid AFib are often started on intravenous rate-controlling agents and admitted for several days. Although underlying and triggering illnesses must be addressed, AFib, intrinsically, is rarely life-threatening and can often be safely managed in an outpatient setting. At our academic community hospital, we implemented an algorithm to decrease hospital admissions for individuals presenting with a primary diagnosis of AFib. We focused on lenient oral rate control and discharge home. Our study evaluates outcomes after implementation of this algorithm. METHODS: Study design is a retrospective cohort analysis pre- and postimplementation of the algorithm. The primary outcome was hospital admissions. Secondary outcomes were 3- and 30-day ED visits and any associated hospital admissions. These outcomes were compared before (March 2013-February 2014) and after (March 2015-February 2016) implementation. Chi-square tests and logistic regressions were run to test for significant changes in the three outcome variables. RESULTS: A total of 1,108 individuals met inclusion criteria with 586 patients in the preimplementation group and 522 in the postimplementation group. Cohorts were broadly comparable in terms of demographics and health histories. Admissions for persons presenting with AFib after implementation decreased significantly (80.4% pre vs. 67.4% post, adjusted odds ratio [OR] = 3.4, p < 0.001). Despite this difference there was no change in ED return rates within 3 or 30 days (adjusted ORs = 0.93 and 0.89, p = 0.91 and 0.73, respectively). CONCLUSIONS: Implementation of a novel algorithm to identify and treat low-risk patients with AFib can significantly decrease the rate of hospital admissions without increased ED returns. This simple algorithm could be adopted by other community hospitals and help lower costs. PMID- 29385656 TI - T-type calcium channels drive migration/invasion in BRAFV600E melanoma cells through Snail1. AB - Melanoma is a malignant tumor derived from melanocytes. Once disseminated, it is usually highly resistant to chemotherapy and is associated with poor prognosis. We have recently reported that T-type calcium channels (TTCCs) are overexpressed in melanoma cells and play an important role in melanoma progression. Importantly, TTCC pharmacological blockers reduce proliferation and deregulate autophagy leading to apoptosis. Here, we analyze the role of autophagy during migration/invasion of melanoma cells. TTCC Cav3.1 and LC3-II proteins are highly expressed in BRAFV600E compared with NRAS mutant melanomas, both in cell lines and biopsies. Chloroquine, pharmacological blockade, or gene silencing of TTCCs inhibit the autophagic flux and impair the migration and invasion capabilities, specifically in BRAFV600E melanoma cells. Snail1 plays an important role in motility and invasion of melanoma cells. We show that Snail1 is strongly expressed in BRAFV600E melanoma cells and patient biopsies, and its expression decreases when autophagy is blocked. These results demonstrate a role of Snail1 during BRAFV600E melanoma progression and strongly suggest that targeting macroautophagy and, particularly TTCCs, might be a good therapeutic strategy to inhibit metastasis of the most common melanoma type (BRAFV600E). PMID- 29385658 TI - The role of glucocerebrosidase in Parkinson disease pathogenesis. AB - GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of alpha synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of alpha-synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of alpha synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD. PMID- 29385657 TI - In silico analysis of structural modifications in and around the integrin alphaIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia. AB - BACKGROUND: Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the alphaIIbbeta3 integrin in platelet aggregation. Stable bent alphaIIbbeta3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The alphaIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the alphaIIb genu define GT phenotype. METHODS: Sanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT-causing missense mutations extending from the lower part of the beta-propeller, and through the thigh and upper calf-1 domains. RESULTS: A homozygous c.1772A>C transversion in exon 18 of ITGA2B coding for a p.Asp591Ala substitution in an interconnecting loop of the lower thigh domain of alphaIIb in a patient with platelets lacking alphaIIbbeta3 led us to extend our in silico modeling to all 16 published disease-causing missense variants potentially affecting the alphaIIb genu. Modifications of structuring H-bonding were the major cause in the thigh domain although one mutation gave mRNA decay. In contrast, short-range changes induced in calf-1 appeared minor suggesting long-range effects. All result in severe to total loss of alphaIIbbeta3 in platelets. The absence of mutations within a key Ca2+-binding loop in the genu led us to scan public databases; three potential single allele variants giving major structural changes were identiffied suggesting that this key region is not protected from genetic variation. CONCLUSIONS: It appears that the alphaIIb genu is the object of stringent quality control to prevent platelets from circulating with activated and extended integrin. PMID- 29385660 TI - Protection of Radiation-Induced DNA Damage by Functional Cosmeceutical Poly-Gamma Glutamate. AB - This study compared the radioprotective effects of high-molecular-weight poly gamma-glutamate (gamma-PGA, average molecular mass 3,000 kDa) and a reduced form of glutathione (GSH, a known radioprotector) on calf thymus DNA damage. The radiation-induced DNA damage was measured on the basis of the decreased fluorescence intensity after binding the DNA with ethidium bromide. All the experiments used 60Co gamma radiation at 1,252 Gy, representing 50% DNA damage. When increasing the concentration of gamma-PGA from 0.33 to 1.65 MUM, the DNA protection from radiation-induced damage also increased, with a maximum of 87% protection. Meanwhile, the maximal DNA protection when increasing the concentration of GSH was only 70%. Therefore, gamma-PGA exhibited significant radioprotective effects against gamma irradiation. PMID- 29385661 TI - Conessine treatment reduces dexamethasone-induced muscle atrophy by regulating MuRF1 and atrogin-1 expression. AB - Conessine, a steroidal alkaloid, is a potent histamine H3 antagonist with anti malarial activity. We recently reported that conessine treatment interferes with H2O2-induced cell death by regulating autophagy. However, the cellular signaling pathways involved in conessine treatment are not fully understood. Here, we report that conessine reduces muscle atrophy by interfering with the expression of atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Promoter reporter assay revealed that conessine treatment inhibits FoxO3a-dependent transcription, NF-kappaB-dependent transcription and p53-dependent transcription. We also showed that conessine treatment reduced dexamethasone-induced expression of MuRF1 and atrogin-1 by the quantitative RT-PCR and Western blot. Finally, we demonstrated that conessine treatment reduced dexamethasone-induced muscle atrophy using differentiated C2C12 cells. These results collectively suggest that conessine is potentially useful in the treatment of muscle atrophy. PMID- 29385659 TI - In-hospital worsening heart failure: a clinically relevant endpoint? AB - Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In-hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information. Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in-hospital WHF. In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in-hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes. PMID- 29385663 TI - Synthesis of aesculetin and aesculin glycosides using engineered Escherichia coli expressing Neisseria polysaccharea amylosucrase. AB - Because glycosylation of aesculetin and its 6-glucoside, aesculin, enhances their biological activities and physicochemical properties, whole-cell biotransformation and enzymatic synthesis methodologies using Neisseria polysaccharea amylosucrase were compared to determine the optimal production method for glycoside derivatives. High performance liquid chromatography analysis of reaction products revealed two glycosylated products (AGG1 and AGG2) when aesculin was used as an acceptor and three products (AG1, AG2, and AG3) when using aesculetin. The whole-cell biotransformation production yields of the major transfer products for each acceptor (AGG1 and AG1) were 85% and 25%, respectively, compared to 68% and 14% for enzymatic synthesis. These results indicate that whole-cell biotransformation is more efficient than enzymatic synthesis for the production of glycoside derivatives. PMID- 29385662 TI - A New Method of Producing a Natural Antibacterial Peptide by Encapsulated Probiotics Internalized with Inulin Nanoparticles as Prebiotics. AB - Synbiotics are a combination of probiotics and prebiotics, which lead to synergistic benefits in host welfare. Probiotics have been used as an alternative to antibiotics. Among the probiotics, Pediococcus acidilactici (PA) has shown excellent antimicrobial activity against Salmonella Gallinarum (SG) as a major poultry pathogen and has improved the production performances of animals. Inulin is widely used as a prebiotic for the improvement of animal health and growth. The main aim of this study is to investigate the effect of the antimicrobial activity of inulin nanoparticles (INs)-internalized PA encapsulated into alginate/chitosan/alginate (ACA) microcapsules (MCs) in future in vivo application. The prepared phthalyl INs (PINs) were characterized by DLS and FE SEM. The contents of phthal groups in phthalyl inulin were estimated by 1H-NMR measurement as 25.1 mol.-%. The sizes of the PINs measured by DLS were approximately 203 nm. Internalization into PA was confirmed by confocal microscopy and flow cytometry. Antimicrobial activity of PIN-internalized probiotics encapsulated into ACA MCs was measured by co-culture antimicrobial assays on SG. PIN-internalized probiotics had a higher antimicrobial ability than that of ACA MCs loaded with PA/inulin or PA. Interestingly, when PINs were treated with PA and encapsulated into ACA MCs, as a natural antimicrobial peptide, pediocin was produced much more in the culture medium compared with other groups inulin-loaded ACA MCs and PA-encapsulated into ACA MCs. PMID- 29385664 TI - Hydroxylation of Resveratrol with DoxA In Vitro: An Enzyme with the Potential for the Bioconversion of a Bioactive Stilbene. AB - The late-stage doxorubicin biosynthesis pathway acting enzyme (DoxA) from Streptomyces peucetius CYP129A2 exhibited substrate promiscuity towards the stilbene group of compounds such as resveratrol. DoxA along with two accessory enzymes ferrdoxin reductase and ferredoxin from spinach hydroxylated resveratrol at the 3'-position in vitro to produce piceatannol. The product was identified by HPLC-PDA and high-resolution HR-qTOF-ESI/MS analyses in positive mode. The ESI/MS fragments resembled the hydroxylated product of resveratrol. PMID- 29385665 TI - Improving the Microbial Safety of Fresh-Cut Endive with a Combined Treatment of Cinnamon Leaf Oil Emulsion Containing Cationic Surfactants and Ultrasound. AB - Endive is widely consumed in a fresh-cut form owing to its rich nutritional content. However, fresh-cut vegetables are susceptible to contamination by pathogenic bacteria. This study investigated the antibacterial activities of the combined treatment of cinnamon leaf oil emulsion containing cetylpyridinium chloride or benzalkonium chloride (CLC and CLB, respectively) as a cationic surfactant and ultrasound (US) against Listeria monocytogenes and Escherichia coli O157:H7 on endive. The combined treatment of CLC or CLB with US reduced the population of L. monocytogenes by 1.58 and 1.47 log colony forming units (CFU)/g, respectively, and that of E. coli O157:H7 by 1.60 and 1.46 log CFU/g, respectively, as compared with water washing treatment. The reduction levels of both pathogens were higher than those observed with 0.2 mg/ml sodium hypochlorite. In addition, the combined treatment showed no effect on the quality of the fresh-cut endive (FCE). In particular, the degree of browning in FCE was less for the treatment group than for the control and water washing treatment groups. Thus, cationic surfactant-based cinnamon leaf oil emulsions combined with US may be an effective washing treatment for the microbial safety of FCE. PMID- 29385666 TI - Characterization of a Multimodular Endo-beta-1,4-Glucanase (Cel9K) from Paenibacillus sp. X4 with a Potential Additive for Saccharification. AB - An endo-beta-1,4-glucanase gene, cel9K, was cloned using the shot-gun method from Paenibacillus sp. X4, which was isolated from alpine soil. The gene was 2,994 bp in length, encoding a protein of 997 amino acid residues with a predicted signal peptide composed of 32 amino acid residues. Cel9K was a multimodular enzyme, and the molecular mass and theoretical pI of the mature Cel9K were 103.5 kDa and 4.81, respectively. Cel9K contains the GGxxDAGD, PHHR, GAxxGG, YxDDI, and EVxxDYN motifs found in most glycoside hydrolase family 9 (GH9). The protein sequence showed the highest similarity (88%) with the cellulase of Bacillus sp. BP23 in comparison to the enzymes with reported properties. The enzyme was purified by chromatography using HiTrap Q, CHT-II, and HiTrap Butyl HP. Using SDS PAGE/activity staining, the molecular mass of Cel9K was estimated to be 93 kDa, which is a truncated form produced by the proteolytic cleavage of its C-terminus. Cel9K was optimally active at pH 5.5 and 50 degrees C and showed a half-life of 59.2 min at 50 degrees C. The CMCase activity was increased to more than 150% in the presence of 2 mM Na+, K+, and Ba2+, but decreased significantly to less than 50% by Mn2+ and Co2+. The addition of Cel9K to a commercial enzyme set (Celluclast 1.5L + Novozym 188) increased the saccharification of the pretreated reed and rice straw powders by 30.4 and 15.9%, respectively. The results suggest that Cel9K can be used to enhance the enzymatic conversion of lignocellulosic biomass to reducing sugars as an additive. PMID- 29385667 TI - Hanseniaspora thailandica BC9 beta-Glucosidase for the Production of beta-D-Hexyl Glucoside. AB - For biotechnological production of high-valued beta-D-hexyl glucoside, the catalytic properties of Hanseniaspora thailandica BC9 beta-glucosidase purified from the periplasmic fraction were studied, and the transglycosylation activity for the production of beta-D-hexyl glucoside was optimized. The constitutive BC9 beta-glucosidase exhibited maximum specific activity at pH 6.0 and 40oC, and the activity of BC9 beta-glucosidase was not significantly inhibited by various metal ions. BC9 beta-glucosidase did not show a significant activity of cellobiose hydrolysis, but the activity was rather enhanced in the presence of sucrose and medium-chain alcohols. BC9 beta-glucosidase exhibited enhanced production of beta D-hexyl glucoside in the presence of DMSO, and 62% of beta-D-hexyl glucoside conversion was recorded in 4 h in the presence of 5% 1-hexanol and 15% DMSO. PMID- 29385668 TI - Crystal Structure and Biochemical Characterization of Xylose Isomerase from Piromyces sp. E2. AB - Biofuel production using lignocellulosic biomass is gaining attention because it can be substituted for fossil fuels without competing with edible resources. However, because Saccharomyces cerevisiae does not have a D-xylose metabolic pathway, oxidoreductase or isomerase pathways must be introduced to utilize D xylose from lignocellulosic biomass in S. cerevisiae. To elucidate the biochemical properties of xylose isomerase (XI) from Piromyces sp. E2 (PsXI), we determine its crystal structure in complex with substrate mimic glycerol. An amino acid sequence comparison with other reported XIs and the relative activity measurements using five kinds of divalent metal ions confirmed that PsXI belongs to class II XI. Moreover kinetic analysis of PsXI was also performed using Mn2+, the preferred divalent metal ion for PsXI. In addition, the substrate-binding mode of PsXI could be predicted with the substrate mimic glycerol bound to the active site. These studies may provide structural information to enhance D-xylose utilization for biofuel production. PMID- 29385669 TI - Immobilization of Xylanase Using a Protein-Inorganic Hybrid System. AB - In this study, the immobilization of xylanase using a protein-inorganic hybrid nanoflower system was assessed to improve the enzyme properties. The synthesis of hybrid xylanase nanoflowers was very effective at 4 degrees C for 72 h, using 0.25 mg/ml protein, and efficient immobilization of xylanase was observed, with a maximum encapsulation yield and relative activity of 78.5% and 148%, respectively. Immobilized xylanase showed high residual activity at broad pH and temperature ranges. Using birchwood xylan as a substrate, the Vmax and Km values of xylanase nanoflowers were 1.60 mg/ml and 455 MUmol/min/mg protein, compared with 1.42 mg/ml and 300 MUmol/min/mg protein, respectively, for the free enzyme. After 5 and 10 cycles of reuse, the xylanase nanoflowers retained 87.5% and 75.8% residual activity, respectively. These results demonstrate that xylanase immobilization using a protein-inorganic hybrid nanoflower system is an effective approach for its potential biotechnological applications. PMID- 29385670 TI - PPARalpha-Target Gene Expression Requires TIS21/BTG2 Gene in Liver of the C57BL/6 Mice under Fasting Condition. AB - The TIS21/BTG2/PC3 gene belongs to the antiproliferative gene (APRO) family and exhibits tumor suppressive activity. However, here we report that TIS21 controls lipid metabolism, rather than cell proliferation, under fasting condition. Using microarray analysis, whole gene expression changes were investigated in liver of TIS21 knockout (TIS21-KO) mice after 20 h fasting and compared with wild type (WT). Peroxisome proliferator-activated receptor alpha (PPARalpha) target gene expression was almost absent in contrast to increased lipid synthesis in the TIS21-KO mice compared to WT mice. Immunohistochemistry with hematoxylin and eosin staining revealed that lipid deposition was focal in the TIS21-KO liver as opposed to the diffuse and homogeneous pattern in the WT liver after 24 h starvation. In addition, cathepsin E expression was over 10 times higher in the TIS21-KO liver than that in the WT, as opposed to the significant reduction of thioltransferase in both adult and fetal livers. At present, we cannot account for the role of cathepsin E. However, downregulation of glutaredoxin 2 thioltransferase expression might affect hypoxic damage in the TIS21-KO liver. We suggest that the TIS21/BTG2 gene might be essential to maintain energy metabolism and reducing power in the liver under fasting condition. PMID- 29385671 TI - Overexpression of microRNA-612 Restrains the Growth, Invasion, and Tumorigenesis of Melanoma Cells by Targeting Espin. AB - microRNA (miR)-612 shows anticancer activity in several types of cancers, yet its function in melanoma is still unclear. This study was undertaken to investigate the expression of miR-612 and its biological relevance in melanoma cell growth, invasion, and tumorigenesis. The expression and prognostic significance of miR 612 in melanoma were examined. The effects of miR-612 overexpression on cell proliferation, colony formation, tumorigenesis, and invasion were determined. Rescue experiments were conducted to identify the functional target gene(s) of miR-612. miR-612 was significantly downregulated in melanoma tissues compared to adjacent normal tissues. Low miR-612 expression was significantly associated with melanoma thickness, lymph node metastasis, and shorter overall, and disease-free survival of patients. Overexpression of miR-612 significantly decreased cell proliferation, colony formation, and invasion of SK-MEL-28 and A375 melanoma cells. In vivo tumorigenic studies confirmed that miR-612 overexpression retarded the growth of A375 xenograft tumors, which was coupled with a decline in the percentage of Ki-67-positive proliferating cells. Mechanistically, miR-612 targeted Espin in melanoma cells. Overexpression of Espin counteracted the suppressive effects of miR-612 on melanoma cell proliferation, invasion, and tumorigenesis. A significant inverse correlation (r = -0.376, P = 0.018) was observed between miR-612 and Espin protein expression in melanoma tissues. In addition, overexpression of miR-612 and knockdown of Espin significantly increased the sensitivity of melanoma cells to doxorubicin. Collectively, miR-612 suppresses the aggressive phenotype of melanoma cells through downregulation of Espin. Delivery of miR-612 may represent a novel therapeutic strategy against melanoma. PMID- 29385672 TI - CBP7 Interferes with the Multicellular Development of Dictyostelium Cells by Inhibiting Chemoattractant-Mediated Cell Aggregation. AB - Calcium ions are involved in the regulation of diverse cellular processes. Fourteen genes encoding calcium binding proteins have been identified in Dictyostelium. CBP7, one of the 14 CBPs, is composed of 169 amino acids and contains four EF-hand motifs. Here, we investigated the roles of CBP7 in the development and cell migration of Dictyostelium cells and found that high levels of CBP7 exerted a negative effect on cells aggregation during development, possibly by inhibiting chemoattractant-directed cell migration. While cells lacking CBP7 exhibited normal development and chemotaxis similar that of wild type cells, CBP7 overexpressing cells completely lost their chemotactic abilities to move toward increasing cAMP concentrations. This resulted in inhibition of cellular aggregation, a process required for forming multicellular organisms during development. Low levels of cytosolic free calcium were observed in CBP7 overexpressing cells, which was likely the underlying cause of their lack of chemotaxis. Our results demonstrate that CBP7 plays an important role in cell spreading and cell-substrate adhesion. cbp7 null cells showed decreased cell size and cell-substrate adhesion. The present study contributes to further understanding the role of calcium signaling in regulation of cell migration and development. PMID- 29385673 TI - Post-Translational Regulation of the RSF1 Chromatin Remodeler under DNA Damage. AB - Chromatin remodeling factors are involved in many cellular processes such as transcription, replication, and DNA damage response by regulating chromatin structure. As one of chromatin remodeling factors, remodeling and spacing factor 1 (RSF1) is recruited at double strand break (DSB) sites and regulates ataxia telangiectasia mutated (ATM) -dependent checkpoint pathway upon DNA damage for the efficient repair. RSF1 is overexpressed in a variety of cancers, but regulation of RSF1 levels remains largely unknown. Here, we showed that protein levels of RSF1 chromatin remodeler are temporally upregulated in response to different DNA damage agents without changing the RSF1 mRNA level. In the absence of SNF2h, a binding partner of RSF1, the RSF1 protein level was significantly diminished. Intriguingly, the level of RSF1-3SA mutant lacking ATM-mediated phosphorylation sites significantly increased, and upregulation of RSF1 levels under DNA damage was not observed in cells overexpressing ATM kinase. Furthermore, failure in the regulation of RSF1 level caused a significant reduction in DNA repair, whereas reconstitution of RSF1, but not of RSF1-3SA mutants, restored DSB repair. Our findings reveal that temporal regulation of RSF1 levels at its post-translational modification by SNF2h and ATM is essential for efficient DNA repair. PMID- 29385674 TI - Generation of Isthmic Organizer-Like Cells from Human Embryonic Stem Cells. AB - The objective of this study was to induce the production of isthmic organizer (IsO)-like cells capable of secreting fibroblast growth factor (FGF) 8 and WNT1 from human embryonic stem cells (ESCs). The precise modulation of canonical Wnt signaling was achieved in the presence of the small molecule CHIR99021 (0.6 MUM) during the neural induction of human ESCs, resulting in the differentiation of these cells into IsO-like cells having a midbrain-hindbrain border (MHB) fate in a manner that recapitulated their developmental course in vivo. Resultant cells showed upregulated expression levels of FGF8 and WNT1. The addition of exogenous FGF8 further increased WNT1 expression by 2.6 fold. Gene ontology following microarray analysis confirmed that IsO-like cells enriched the expression of MHB related genes by 40 fold compared to control cells. Lysates and conditioned media of IsO-like cells contained functional FGF8 and WNT1 proteins that could induce MHB-related genes in differentiating ESCs. The method for generating functional IsO-like cells described in this study could be used to study human central nervous system development and congenital malformations of the midbrain and hindbrain. PMID- 29385675 TI - Curcumin Analog CH-5 Suppresses the Proliferation, Migration, and Invasion of the Human Gastric Cancer Cell Line HGC-27. AB - Gastric cancer is one of the most frequent malignant tumors in the world. The majority of patients are diagnosed with metastatic gastric cancer, which has a low survival rate. These data reinforce the importance of studying the anticancer activity of new molecules with the potential to suppress gastric cancer metastasis. Curcumin is a well-studied compound that has demonstrated anti metastatic effects. Here we investigated if CH-5, a curcumin derivative compound, has anti-metastatic properties in the human gastric cancer cell line HGC-27. Firstly, we found that CH-5 decreased viability and induced apoptosis in HGC-27 cells in a dose-dependent manner. Additionally, CH-5 suppressed the migration and invasion of HGC-27 cells by downregulating the expression and collagenase activity of matrix metalloproteinase 2 in a dose-dependent manner. In conclusion, CH-5 showed anticancer activities, including the induction of apoptosis, and the suppression of migration and invasion in HGC-27 cells, suggesting that CH-5 can be a lead molecule for the development of anti-metastatic drugs for gastric cancer therapy. PMID- 29385677 TI - Announcing the 2018 Toxics Travel Award for Post-Doctoral Fellows. AB - This year we enjoyed a large number of very highly meritorious applications for our annual Toxics Travel Award. PMID- 29385676 TI - Naturally Occurring Canine Melanoma as a Predictive Comparative Oncology Model for Human Mucosal and Other Triple Wild-Type Melanomas. AB - Melanoma remains mostly an untreatable fatal disease despite advances in decoding cancer genomics and developing new therapeutic modalities. Progress in patient care would benefit from additional predictive models germane for human disease mechanisms, tumor heterogeneity, and therapeutic responses. Toward this aim, this review documents comparative aspects of human and naturally occurring canine melanomas. Clinical presentation, pathology, therapies, and genetic alterations are highlighted in the context of current basic and translational research in comparative oncology. Somewhat distinct from sun exposure-related human cutaneous melanomas, there is growing evidence that a variety of gene copy number alterations and protein structure/function mutations play roles in canine melanomas, in circumstances more analogous to human mucosal melanomas and to some extent other melanomas with murine sarcoma viral oncogene homolog B (BRAF), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), and neurofibromin 1 tumor suppressor NF1 triple wild-type genotype. Gaps in canine genome annotation, as well as an insufficient number and depth of sequences covered, remain considerable barriers to progress and should be collectively addressed. Preclinical approaches can be designed to include canine clinical trials addressing immune modulation as well as combined-targeted inhibition of Rat Sarcoma Superfamily/Mitogen-activated protein kinase (RAS/MAPK) and/or Phosphatidylinositol-3-Kinase/Protein Kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal transduction, pathways frequently activated in both human and canine melanomas. Future investment should be aimed towards improving understanding of canine melanoma as a predictive preclinical surrogate for human melanoma and for mutually benefiting these uniquely co-dependent species. PMID- 29385678 TI - Efficient OLEDs Fabricated by Solution Process Based on Carbazole and Thienopyrrolediones Derivatives. AB - Four low molecular weight compounds-three of them new, two of them with carbazole (Cz) as functional group and the other two with thienopyrroledione (TPD) group were used as emitting materials in organic light emitting diodes (OLEDs). Devices were fabricated with the configuration ITO/PEDOT:PSS/emitting material/LiF/Al. The hole injector layer (HIL) and the emitting sheet were deposited by spin coating; LiF and Al were thermally evaporated. OLEDs based on carbazole derivatives show luminances up to 4130 cd/m2, large current efficiencies about 20 cd/A and, cautiously, a very impressive External Quantum Efficiency (EQE) up to 9.5%, with electroluminescence peaks located around 490 nm (greenish blue region). Whereas, devices manufactured with TPD derivatives, present luminance up to 1729 cd/m2, current efficiencies about 4.5 cd/A and EQE of 1.5%. These results are very competitive regarding previous reported materials/devices. PMID- 29385680 TI - Radiation and Anti-Cancer Vaccines: A Winning Combination. AB - The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future. PMID- 29385679 TI - The Molecular Mechanisms of Plant-Derived Compounds Targeting Brain Cancer. AB - Glioblastoma multiforme (GBM) is one of the most aggressive and malignant forms of brain tumors. Despite recent advances in operative and postoperative treatments, it is almost impossible to perform complete resection of these tumors owing to their invasive and diffuse nature. Several natural plant-derived products, however, have been demonstrated to have promising therapeutic effects, such that they may serve as resources for anticancer drug discovery. The therapeutic effects of one such plant product, n-butylidenephthalide (BP), are wide-ranging in nature, including impacts on cancer cell apoptosis, cell cycle arrest, and cancer cell senescence. The compound also exhibits a relatively high level of penetration through the blood-brain barrier (BBB). Taken together, its actions have been shown to have anti-proliferative, anti-chemoresistance, anti invasion, anti-migration, and anti-dissemination effects against GBM. In addition, a local drug delivery system for the subcutaneous and intracranial implantation of BP wafers that significantly reduce tumor size in xenograft models, as well as orthotopic and spontaneous brain tumors in animal models, has been developed. Isochaihulactone (ICL), another kind of plant product, possesses a broad spectrum of pharmacological activities, including impacts on cancer cell apoptosis and cell cycle arrest, as well as anti-proliferative and anti chemoresistance effects. Furthermore, these actions have been specifically shown to have cancer-fighting effects on GBM. In short, the results of various studies reviewed herein have provided substantial evidence indicating that BP and ICH are promising novel anticancer compounds with good potential for clinical applications. PMID- 29385681 TI - Comparative Transcriptome Analyses Uncover Key Candidate Genes Mediating Flight Capacity in Bactrocera dorsalis (Hendel) and Bactrocera correcta (Bezzi) (Diptera: Tephritidae). AB - Flight capacity is important for invasive pests during entry, establishment and spreading. Both Bactroceradorsalis Hendel and Bactroceracorrecta Bezzi are invasive fruit flies but their flight capacities differ. Here, a tethered flight mill test demonstrated that B. dorsalis exhibits a greater flight capacity than B. correcta. RNA-Seq was used to determine the transcriptomic differences associated with the flight capacity of two Bactrocera species. Transcriptome data showed that 6392 unigenes were differentially expressed between the two species in the larval stage, whereas in the adult stage, 4104 differentially expressed genes (DEGs) were identified in females, and 3445 DEGs were observed in males. The flight capacity appeared to be correlated with changes in the transcriptional levels of genes involved in wing formation, flight muscle structure, energy metabolism, and hormonal control. Using RNA interference (RNAi) to verify the function of one DEG, the epidermal growth factor receptor (EGFR), we confirmed the role of this gene in regulating wing development, and thereby flight capacity, in both species. This work reveals the flight mechanism of fruit flies and provides insight into fundamental transcriptomics for further studies on the flight performance of insects. PMID- 29385682 TI - Serum Antioxidant Associations with Metabolic Characteristics in Metabolically Healthy and Unhealthy Adolescents with Severe Obesity: An Observational Study. AB - Considering the inadequacy of some antioxidant nutrients in severely obese adolescents, this study aimed to assess the relationship between antioxidant micronutrients status and metabolic syndrome components in metabolically healthy obesity (MHO) and unhealthy obesity (MUO). We performed an observational study in severely obese adolescents (body mass index > 99th percentile) and they were classified into MHO or MUO, according to the criteria adapted for adolescents. Anthropometric, biochemical, and clinical variables were analyzed to characterize the sample of adolescents. The serum antioxidant nutrients assessed were retinol, beta-carotene, Vitamin E, Vitamin C, zinc and selenium. A total of 60 adolescents aged 17.31 +/- 1.34 years were enrolled. MHO was identified in 23.3% of adolescents. The MHO group showed lower frequency of non-alcoholic fatty liver disease (14.3% vs. 78.3%, p < 0.001) when compared to MUO. A correlation was found between retinol and beta-carotene concentrations with glycemia (r = -0.372; p = 0.011 and r = -0.314; p = 0.034, respectively) and between Vitamin E with waist circumference (r = -0.306; p = 0.038) in the MUO group. The current study shows that some antioxidant nutrients status, specifically retinol, beta carotene, and Vitamin E, are negatively associated with metabolic alterations in MUO. Further studies are necessary to determine the existing differences in the serum antioxidant profile of metabolically healthy and unhealthy obese adolescents. PMID- 29385683 TI - Preliminary Characterization, Antioxidant and Hepatoprotective Activities of Polysaccharides from Taishan Pinus massoniana Pollen. AB - The objectives of the present study were to characterize the chemical composition, antioxidant activity and hepatoprotective effect of the polysaccharides from Taishan Pinus massoniana pollen (TPPPS). HPLC analysis showed that TPPPS was an acidic heteropolysaccharide with glucose and arabinose as the main component monosaccharides (79.6%, molar percentage). Fourier transform-infrared spectroscopy (FT-IR) analysis indicated that the spectra of TPPPS displayed infrared absorption peaks characteristic of polysaccharides. In in vitro assays TPPPS exhibited different degrees of dose-dependent antioxidant activities , and this was further verified by suppression of CCl4-induced oxidative stress in the liver with three tested doses of TPPPS (100, 200, and 400 mg/kg bw) in rats. Pretreatment with TPPPS significantly decreased the levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT), alkaline phosphatase (ALP), lactic dehydrogenase (LDH) and malondialdehyde (MDA) against CCl4 injuries, and elevated the activities of superoxide dismutase (SOD) as well as glutathione peroxidase (GSH-Px). Histopathological observation further confirmed that TPPPS could protect the liver tissues from CCl4-induced histological alternation. These results suggest that TPPPS has strong antioxidant activities and significant protective effect against acute hepatotoxicity induced by CCl4. The hepatoprotective effect may partly be related to its free radical scavenging effect, increasing antioxidant activity and inhibiting lipid peroxidation. PMID- 29385684 TI - Managing Early Childhood Caries for Young Children in China. AB - The latest national survey found that 70% of 5-year-old children in China had dental caries. The prevalence of early childhood caries (ECC) may not only be attributed to poor oral hygiene and unhealthy diet, but also to limited access to and availability of dental care. The prevailing preventive measures adopted by industrialised countries for ECC management are neither practical nor affordable in China. Hence, an alternative approach to ECC management is necessary. Atraumatic restorative treatment (ART) has been advocated because the simple and short operative time renders ART affordable. However, the success rate of ART in restoring anterior primary teeth is unfavourable. Although there is no water fluoridation in China, topical fluorides may be used to manage ECC. Tooth brushing with fluoride toothpaste is effective for caries control, but not all toothpastes in China are fluoridated. Professionally applied fluorides such as sodium fluoride varnish can be a cost-effective treatment for managing the high prevalence of ECC in China. Silver diamine fluoride (SDF) at 38% is suggested to be effective in arresting ECC in China. It can be a simple, non-invasive and low cost treatment. However, it stains caries black. Children and their parents must be well informed before SDF treatment. PMID- 29385686 TI - New Antibacterial Phenone Derivatives Asperphenone A-C from Mangrove-Derived Fungus Aspergillus sp. YHZ-1. AB - Marine fungi are a promising source of novel bioactive natural products with diverse structure. In our search for new bioactive natural products from marine fungi, three new phenone derivatives, asperphenone A-C (1-3), have been isolated from the ethyl acetate extract of the fermentation broth of the mangrove-derived fungus, Aspergillus sp. YHZ-1. The chemical structures of these natural products were elucidated on the basis of mass spectrometry, one- and two-dimensional NMR spectroscopic analysis and asperphenone A and B were confirmed by single-crystal X-ray crystallography. Compounds 1 and 2 exhibited weak antibacterial activity against four Gram-positive bacteria, Staphylococcus aureus CMCC(B) 26003, Streptococcus pyogenes ATCC19615, Bacillus subtilis CICC 10283 and Micrococcus luteus, with the MIC values higher than 32.0 uM. PMID- 29385687 TI - Assessing the Knowledge, Attitudes and Behaviors of Human and Animal Health Students towards Antibiotic Use and Resistance: A Pilot Cross-Sectional Study in the UK. AB - The Global Action Plan on Antimicrobial Resistance highlights the importance of training all healthcare professionals. No study has assessed patterns of students' knowledge, attitudes and practices concerning antibiotic use simultaneously across different healthcare course types. We conducted a cross sectional multi-center survey among UK students. The survey was advertised through local survey coordinators at 25 universities. The online survey was accessible from 10th October to 17th November 2016 (before European Antibiotic Awareness Day). A total of 255 students from 25 universities participated, including students on medicine, pharmacy, nursing, physician associate, dentistry and veterinary medicine courses. Antibiotic resistance was considered to be a more important global challenge than climate change, obesity or food security (p < 0.001). Most students (95%) believed that antibiotic resistance will be a problem for their future practice, but fewer (69%) thought that the antibiotics they will prescribe, administer or dispense will contribute to the problem. A fifth of students felt they had sufficient knowledge of antibiotic use for their future work. Our exploratory study suggests that UK human and animal healthcare students are aware of the importance of antibiotic resistance, but many still have certain misconceptions. Campaigns and improved educational efforts applying behavioral insights methodology could address these. PMID- 29385685 TI - MiR200 and miR302: Two Big Families Influencing Stem Cell Behavior. AB - In this review, we described different factors that modulate pluripotency in stem cells, in particular we aimed at following the steps of two large families of miRNAs: the miR-200 family and the miR-302 family. We analyzed some factors tuning stem cells behavior as TGF-beta, which plays a pivotal role in pluripotency inhibition together with specific miRNAs, reactive oxygen species (ROS), but also hypoxia, and physical stimuli, such as ad hoc conveyed electromagnetic fields. TGF-beta plays a crucial role in the suppression of pluripotency thus influencing the achievement of a specific phenotype. ROS concentration can modulate TGF-beta activation that in turns down regulates miR 200 and miR-302. These two miRNAs are usually requested to maintain pluripotency, while they are down-regulated during the acquirement of a specific cellular phenotype. Moreover, also physical stimuli, such as extremely-low frequency electromagnetic fields or high-frequency electromagnetic fields conveyed with a radioelectric asymmetric conveyer (REAC), and hypoxia can deeply influence stem cell behavior by inducing the appearance of specific phenotypes, as well as a direct reprogramming of somatic cells. Unraveling the molecular mechanisms underlying the complex interplay between externally applied stimuli and epigenetic events could disclose novel target molecules to commit stem cell fate. PMID- 29385688 TI - Small Molecules in Rare Tumors: Emerging Role of MicroRNAs in GIST. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs have very different clinical phenotypes and underlying molecular characteristics that are not yet completely understood. microRNAs (miRNAs) have been shown to participate in carcinogenesis pathways through post-transcriptional regulation of gene expression in different tumors. Over the last years emerging evidence has highlighted the role of miRNAs in GISTs. This review provides an overview of original research papers that analyze miRNA deregulation patterns, functional role, diagnostic, therapeutic and prognostic implications in GIST as well as provides directions for further research in the field. PMID- 29385690 TI - Molecular Research on Emerging Viruses: Evolution, Diagnostics, Pathogenesis, and Therapeutics. AB - Viruses are increasingly recognized as emerging infectious disease agents in both humans and animals.[...]. PMID- 29385689 TI - Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene. AB - Combining virus-enhanced immunogenicity with direct delivery of immunomodulatory molecules would represent a novel treatment modality for melanoma, and would require development of new viral vectors capable of targeting melanoma cells preferentially. Here we explore the use of rodent protoparvoviruses targeting cells of the murine melanoma model B16F10. An uncloned stock of mouse parvovirus 1 (MPV1) showed some efficacy, which was substantially enhanced following serial passage in the target cell. Molecular cloning of the genes of both starter and selected virus pools revealed considerable sequence diversity. Chimera analysis mapped the majority of the improved infectivity to the product of the major coat protein gene, VP2, in which linked blocks of amino acid changes and one or other of two apparently spontaneous mutations were selected. Intragenic chimeras showed that these represented separable components, both contributing to enhanced infection. Comparison of biochemical parameters of infection by clonal viruses indicated that the enhancement due to changes in VP2 operates after the virus has bound to the cell surface and penetrated into the cell. Construction of an in silico homology model for MPV1 allowed placement of these changes within the capsid shell, and revealed aspects of the capsid involved in infection initiation that had not been previously recognized. PMID- 29385691 TI - Total and Free Sugar Content of Pre-Packaged Foods and Non-Alcoholic Beverages in Slovenia. AB - Scientific evidence of the association between free sugar consumption and several adverse health effects has led many public health institutions to take measures to limit the intake of added or free sugar. Monitoring the efficiency of such policies and the amount of free sugar consumed requires precise knowledge of free sugar content in different food products. To meet this need, our cross-sectional study aimed at assessing free sugar content for 10,674 pre-packaged food items available from major Slovenian food stores during data collection in 2015. Together, 52.6% of all analyzed products contained free sugar, which accounted for an average of 57.5% of the total sugar content. Food categories with the highest median free sugar content were: honey and syrups (78.0 g/100 g), jellies (62.9 g/100 g), chocolate and sweets (44.6 g/100 g), jam and spreads (35.9 g/100 g), and cereal bars (23.8 g/100 g). Using year-round sales data provided by the retailers, the data showed that chocolate, sweets, and soft drinks alone accounted for more than 50% of all free sugar sold on the Slovenian market. The results of this study can be used to prepare more targeted interventions and efficient dietary recommendations. PMID- 29385692 TI - An Inhalable Powder Formulation Based on Micro- and Nanoparticles Containing 5 Fluorouracil for the Treatment of Metastatic Melanoma. AB - Melanoma is the most aggressive and lethal type of skin cancer, with a poor prognosis because of the potential for metastatic spread. The aim was to develop innovative powder formulations for the treatment of metastatic melanoma based on micro- and nanocarriers containing 5-fluorouracil (5FU) for pulmonary administration, aiming at local and systemic action. Therefore, two innovative inhalable powder formulations were produced by spray-drying using chondroitin sulfate as a structuring polymer: (a) 5FU nanoparticles obtained by piezoelectric atomization (5FU-NS) and (b) 5FU microparticles of the mucoadhesive agent MethocelTM F4M for sustained release produced by conventional spray drying (5FU MS). The physicochemical and aerodynamic were evaluated in vitro for both systems, proving to be attractive for pulmonary delivery. The theoretical aerodynamic diameters obtained were 0.322 +/- 0.07 um (5FU-NS) and 1.138 +/- 0.54 um (5FU-MS). The fraction of respirable particles (FR%) were 76.84 +/- 0.07% (5FU NS) and 55.01 +/- 2.91% (5FU-MS). The in vitro mucoadhesive properties exhibited significant adhesion efficiency in the presence of MethocelTM F4M. 5FU-MS and 5FU NS were tested for their cytotoxic action on melanoma cancer cells (A2058 and A375) and both showed a cytotoxic effect similar to 5FU pure at concentrations of 4.3 and 1.7-fold lower, respectively. PMID- 29385693 TI - Three-Dimensional Resistive Metamaterial Absorber Loaded with Metallic Resonators for the Enhancement of Lower-Frequency Absorption. AB - Resistive patch array incorporating with metallic backplane provided an effective way to achieve broadband metamaterial absorbers (MAs) in microwave frequency, and the outstanding construction contributed more flexible and diversified broadband absorption. In this paper, we attempted to load metallic resonators (MRs) to three-dimensional resistive MA to further enhance the lower-frequency absorption performance. Simulation showed that the partial absorption peak was separated to the lower frequency, while the rest of broadband absorption was unaffected. Meanwhile, after combining multi-unit of the proposed MAs, the stair-stepping broadband absorption was also achieved. Finally, three samples were fabricated. The agreements between simulations and experimental results demonstrated that resistive MA loaded with MRs provided an effective way for further enhancement of lower-frequency absorption with almost no change of the absorbing structure and lightweight characteristic. Thus, it was worthy to expect a wide range of applications to emerge inspired from the proposed attempt. PMID- 29385694 TI - Glucose Sensing Using Capacitive Biosensor Based on Polyvinylidene Fluoride Thin Film. AB - A polyvinylidene fluoride (PVDF) film-based capacitive biosensor was developed for glucose sensing. This device consists of a PVDF film sandwiched between two electrodes. A capacitive biosensor measures the dielectric properties of the dielectric layers at the interface between the electrolyte and the electrode. A glucose oxidase (GOx) enzyme was immobilized onto the electrode to oxidize glucose. In practice, the biochemical reaction of glucose with the GOx enzyme generates free electron carriers. Consequently, the potential difference between the electrodes is increased, resulting in a measurable voltage output of the biosensor. The device was tested for various glucose concentrations in the range of 0.013 to 5.85 M, and various GOx enzyme concentrations between 4882.8 and 2.5 million units/L. We found that the sensor output increased with increasing glucose concentration up to 5.85 M. These results indicate that the PVDF film based capacitive biosensors can be properly applied to glucose sensing and provide opportunities for the low-cost fabrication of glucose-based biosensors based on PVDF materials. PMID- 29385695 TI - Members of Glycosyl-Hydrolase Family 17 of A. fumigatus Differentially Affect Morphogenesis. AB - Cell wall biosynthesis and remodeling are essential for fungal growth and development. In the fungal pathogen Aspergillus fumigatus, the beta(1,3)glucan is the major cell wall polysaccharide. This polymer is synthesized at the plasma membrane by a transmembrane complex, then released into the parietal space to be remodeled by enzymes, and finally incorporated into the pre-existing cell wall. In the Glycosyl-Hydrolases family 17 (GH17) of A. fumigatus, two beta(1,3)glucanosyltransferases, Bgt1p and Bgt2p, have been previously characterized. Disruption of BGT1 and BGT2 did not result in a phenotype, but sequence comparison and hydrophobic cluster analysis showed that three other genes in A. fumigatus belong to the GH17 family, SCW4, SCW11, and BGT3. In constrast to Deltabgt1bgt2 mutants, single and multiple deletion of SCW4, SCW11, and BGT3 showed a decrease in conidiation associated with a higher conidial mortality and an abnormal conidial shape. Moreover, mycelium was also affected with a slower growth, stronger sensitivity to cell wall disturbing agents, and altered cell wall composition. Finally, the synthetic interactions between Bgt1p, Bgt2p, and the three other members, which support a functional cooperation in cell-wall assembly, were analyzed. Our data suggest that Scw4p, Scw11p, and Bgt3p are essential for cell wall integrity and might have antagonistic and distinct functions to Bgt1p and Bgt2p. PMID- 29385697 TI - Contractile Response of Bovine Lateral Saphenous Vein to Ergotamine Tartrate Exposed to Different Concentrations of Molecularly Imprinted Polymer. AB - Ergot alkaloids, in their active isomeric form, affect animal health and performance, and adsorbents are used to mitigate toxicities by reducing bioavailability. Adsorbents with high specificity (molecularly imprinted polymers: MIP) adsorb ergot alkaloids in vitro, but require evaluation for biological implications. Using ex vivo myography, synthetic polymers were evaluated for effects on the bioactivity of ergotamine tartrate (ETA). Polymers were first evaluated using isotherms. Lateral saphenous veins were collected from 17 steers for four independent studies: dose response of ETA, adsorbent dose response, validation of pre-myograph incubation conditions and MIP/ non molecularly imprinted polymer (NIP) comparison. Norepinephrine normalized percent contractile response to increasing ETA exhibited a sigmoidal dose response (max: 88.47 and log of the effective molar concentration (EC50) (-log [ETA]) of 6.66 +/ 0.17 M). Although sample preparation time affected contractile response (p < 0.001), pre-myograph incubation temperature (39 vs. 21 degrees C, 1 h) had no effect (p > 0.05). Isothermal adsorption showed a maximum adsorption of 3.27E-008 moles.mg-1 and affinity between 0.51 and 0.57 mg (R2: 0.83-0.92) for both polymers, with no significant difference between polymers (p > 0.05). No significant differences in maximum inhibitory (p = 0.96) and IC50 responses (p = 0.163) between MIP and NIP were noticed. Normalized percent contraction could be predicted from the in vitro adsorption data (R2 = 0.87, p < 0.01), for both polymers. These studies indicate that synthetic polymers are potentially effective adsorbents to mitigate ergot toxicity caused by ergot alkaloids, with little evidence of significant differences between MIP and NIP in aqueous media. PMID- 29385696 TI - CRISPR-Cas9 Genetic Analysis of Virus-Host Interactions. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) has greatly expanded the ability to genetically probe virus-host interactions. CRISPR systems enable focused or systematic, genomewide studies of nearly all aspects of a virus lifecycle. Combined with its relative ease of use and high reproducibility, CRISPR is becoming an essential tool in studies of the host factors important for viral pathogenesis. Here, we review the use of CRISPR-Cas9 for the loss-of function analysis of host dependency factors. We focus on the use of CRISPR pooled screens for the systematic identification of host dependency factors, particularly in Epstein-Barr virus-transformed B cells. We also discuss the use of CRISPR interference (CRISPRi) and gain-of-function CRISPR activation (CRISPRa) approaches to probe virus-host interactions. Finally, we comment on the future directions enabled by combinatorial CRISPR screens. PMID- 29385698 TI - Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and beta-Cyclodextrins. AB - Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with beta cyclodextrin (betaCD) and its derivatives, heptakis-(2,6-di-O-methyl)-beta cyclodextrin (2,6-DMbetaCD) and (2-hydroxypropyl)-beta-cyclodextrin (HPbetaCD). The AL-type diagram of the phase solubility studies of PNS exhibited the formed inclusion complexes with the 1:1 molar ratio. Inclusion complexes were prepared by the freeze-drying method and were characterized by differential scanning calorimetry (DSC). Two-dimensional nuclear magnetic resonance (2D-NMR) and steered molecular dynamics (SMD) simulation revealed two different binding modes of PNS, i.e., its phenyl- (P-PNS) and chromone- (C-PNS) rings preferably inserted into the cavity of betaCD derivatives whilst only one orientation of PNS, where the C-PNS ring is inside the cavity, was detected in the case of the parental betaCD. All PNS/betaCDs complexes had a higher dissolution rate than free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against MCF-7 and HeLa cancer cell lines in vitro. PMID- 29385699 TI - Vortex Lattice Instabilities in YBa2Cu3O7-x Nanowires. AB - High-resolution focused ion beam lithography has been used to fabricate YBa2Cu3O7 x (YBCO) wires with nanometric lateral dimensions. In the present work, we investigate Flux-flow instabilities in nanowires of different widths, showing sudden voltage switching jumps from the superconducting to the normal state. We present an extensive study on the temperature and field dependence of the switching characteristics which reveal that voltage jumps become less abrupt as the temperature increases, and disappear at the vortex-liquid state. On the contrary, the current distribution at the critical point becomes narrower at high temperatures. Sharp voltage switchings very close to the critical current density can be obtained by reducing the width of the nanowires, making them very appealing for practical applications. PMID- 29385700 TI - What is the Best Configuration of Wearable Sensors to Measure Spatiotemporal Gait Parameters in Children with Cerebral Palsy? AB - Wearable inertial devices have recently been used to evaluate spatiotemporal parameters of gait in daily life situations. Given the heterogeneity of gait patterns in children with cerebral palsy (CP), the sensor placement and analysis algorithm may influence the validity of the results. This study aimed at comparing the spatiotemporal measurement performances of three wearable configurations defined by different sensor positioning on the lower limbs: (1) shanks and thighs, (2) shanks, and (3) feet. The three configurations were selected based on their potential to be used in daily life for children with CP and typically developing (TD) controls. For each configuration, dedicated gait analysis algorithms were used to detect gait events and compute spatiotemporal parameters. Fifteen children with CP and 11 TD controls were included. Accuracy, precision, and agreement of the three configurations were determined in comparison with an optoelectronic system as a reference. The three configurations were comparable for the evaluation of TD children and children with a low level of disability (CP-GMFCS I) whereas the shank-and-thigh-based configuration was more robust regarding children with a higher level of disability (CP-GMFCS II III). PMID- 29385701 TI - Prevalence of Vitamin D Deficiency Varies Widely by Season in Canadian Children and Adolescents with Sickle Cell Disease. AB - Sickle cell disease (SCD) is an inherited disorder caused by a variant (rs334) in the beta-globin gene encoding hemoglobin. Individuals with SCD are thought to be at risk of vitamin D deficiency. Our aim was to assess serum 25-hydroxyvitamin D (25OHD) concentrations, estimate deficiency prevalence, and investigate factors associated with 25OHD concentrations in children and adolescents with SCD attending BC Children's Hospital in Vancouver, Canada. We conducted a retrospective chart review of SCD patients (2-19 y) from 2012 to 2017. Data were available for n = 45 patients with n = 142 25OHD measurements assessed using a EUROIMMUN analyzer (EUROIMMUN Medizinische Labordiagnostika AG, Lubeck, Germany). Additional data were recorded, including age, sex, and season of blood collection. Linear regression was used to measure associations between 25OHD concentration and predictor variables. Overall, mean +/- SD 25OHD concentration was 79 +/- 36 nmol/L; prevalence of low 25OHD concentrations (<30, <40, and <75 nmol/L) was 5%, 17% and 50%, respectively. Mean 25OHD concentrations measured during Jul-Sep were higher (28 (95% confidence interval CI: 16-40) nmol/L higher, P < 0.001) compared to Jan-Mar. Vitamin D deficiency rates varied widely by season: Based on 25OHD <30 nmol/L, prevalence was 0% in Oct-Dec and 6% in Jan Mar; based on <40 nmol/L, prevalence was 0% in Oct-Dec and 26% in Jan-Mar. PMID- 29385703 TI - CERA Attenuates Kidney Fibrogenesis in the db/db Mouse by Influencing the Renal Myofibroblast Generation. AB - Tubulointerstitial fibrosis (TIF) is a pivotal pathophysiological process in patients with diabetic nephropathy (DN). Multiple profibrotic factors and cell types, including transforming growth factor beta 1 (TGF-beta1) and interstitial myofibroblasts, respectively, are responsible for the accumulation of extracellular matrix in the kidney. Matrix-producing myofibroblasts can originate from different sources and different mechanisms are involved in the activation process of the myofibroblasts in the fibrotic kidney. In this study, 16-week-old db/db mice, a model for type 2 DN, were treated for two weeks with continuous erythropoietin receptor activator (CERA), a synthetic erythropoietin variant with possible non-hematopoietic, tissue-protective effects. Non-diabetic and diabetic mice treated with placebo were used as controls. The effects of CERA on tubulointerstitial fibrosis (TIF) as well as on the generation of the matrix producing myofibroblasts were evaluated by morphological, immunohistochemical, and molecular biological methods. The placebo-treated diabetic mice showed significant signs of beginning renal TIF (shown by picrosirius red staining; increased connective tissue growth factor (CTGF), fibronectin and collagen I deposition; upregulated KIM1 expression) together with an increased number of interstitial myofibroblasts (shown by different mesenchymal markers), while kidneys from diabetic mice treated with CERA revealed less TIF and fewer myofibroblasts. The mechanisms, in which CERA acts as an anti-fibrotic agent/drug, seem to be multifaceted: first, CERA inhibits the generation of matrix-producing myofibroblasts and second, CERA increases the ability for tissue repair. Many of these CERA effects can be explained by the finding that CERA inhibits the renal expression of the cytokine TGF-beta1. PMID- 29385705 TI - Analysis of 3D Scan Measurement Distribution with Application to a Multi-Beam Lidar on a Rotating Platform. AB - Multi-beam lidar (MBL) rangefinders are becoming increasingly compact, light, and accessible 3D sensors, but they offer limited vertical resolution and field of view. The addition of a degree-of-freedom to build a rotating multi-beam lidar (RMBL) has the potential to become a common solution for affordable rapid full-3D high resolution scans. However, the overlapping of multiple-beams caused by rotation yields scanning patterns that are more complex than in rotating single beam lidar (RSBL). In this paper, we propose a simulation-based methodology to analyze 3D scanning patterns which is applied to investigate the scan measurement distribution produced by the RMBL configuration. With this purpose, novel contributions include: (i) the adaption of a recent spherical reformulation of Ripley's K function to assess 3D sensor data distribution on a hollow sphere simulation; (ii) a comparison, both qualitative and quantitative, between scan patterns produced by an ideal RMBL based on a Velodyne VLP-16 (Puck) and those of other 3D scan alternatives (i.e., rotating 2D lidar and MBL); and (iii) a new RMBL implementation consisting of a portable tilting platform for VLP-16 scanners, which is presented as a case study for measurement distribution analysis as well as for the discussion of actual scans from representative environments. Results indicate that despite the particular sampling patterns given by a RMBL, its homogeneity even improves that of an equivalent RSBL. PMID- 29385702 TI - Altered Circadian Timing System-Mediated Non-Dipping Pattern of Blood Pressure and Associated Cardiovascular Disorders in Metabolic and Kidney Diseases. AB - The morning surge in blood pressure (BP) coincides with increased cardiovascular (CV) events. This strongly suggests that an altered circadian rhythm of BP plays a crucial role in the development of CV disease (CVD). A disrupted circadian rhythm of BP, such as the non-dipping type of hypertension (i.e., absence of nocturnal BP decline), is frequently observed in metabolic disorders and chronic kidney disease (CKD). The circadian timing system, controlled by the central clock in the suprachiasmatic nucleus of the hypothalamus and/or by peripheral clocks in the heart, vasculature, and kidneys, modulates the 24 h oscillation of BP. However, little information is available regarding the molecular and cellular mechanisms of an altered circadian timing system-mediated disrupted dipping pattern of BP in metabolic disorders and CKD that can lead to the development of CV events. A more thorough understanding of this pathogenesis could provide novel therapeutic strategies for the management of CVD. This short review will address our and others' recent findings on the molecular mechanisms that may affect the dipping pattern of BP in metabolic dysfunction and kidney disease and its association with CV disorders. PMID- 29385704 TI - Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only finding related to their function is the genetically conserved YSK2 motif present in plant dehydrins. These proteins were shown to be IDPs with the YSK2 motif serving as a core region for the dehydrins' cryoprotective activity. Here we examined the cryoprotective activity of randomly selected IDPs toward the model enzyme lactate dehydrogenase (LDH). All five IDPs that were examined were in the range of 35-45 amino acid residues in length and were equally potent at a concentration of 50 MUg/mL, whereas folded proteins, the PSD-95/Dlg/ZO-1 (PDZ) domain, and lysozymes had no potency. We further examined their cryoprotective activity toward glutathione S transferase as an example of the other enzyme, and toward enhanced green fluorescent protein as a non-enzyme protein example. We further examined the lyophilization protective activity of the peptides toward LDH, which revealed that some IDPs showed a higher activity than that of bovine serum albumin (BSA). Based on these observations, we propose that cryoprotection is a general feature of IDPs. Our findings may become a clue to various industrial applications of IDPs in the future. PMID- 29385706 TI - Transparent Glass-Ceramics Produced by Sol-Gel: A Suitable Alternative for Photonic Materials. AB - Transparent glass-ceramics have shown interesting optical properties for several photonic applications. In particular, compositions based on oxide glass matrices with fluoride crystals embedded inside, known as oxyfluoride glass-ceramics, have gained increasing interest in the last few decades. Melt-quenching is still the most used method to prepare these materials but sol-gel has been indicated as a suitable alternative. Many papers have been published since the end of the 1990s, when these materials were prepared by sol-gel for the first time, thus a review of the achievements obtained so far is necessary. In the first part of this paper, a review of transparent sol-gel glass-ceramics is made focusing mainly on oxyfluoride compositions. Many interesting optical results have been obtained but very little innovation of synthesis and processing is found with respect to pioneering papers published 20 years ago. In the second part we describe the improvements in synthesis and processing obtained by the authors during the last five years. The main achievements are the preparation of oxyfluoride glass ceramics with a much higher fluoride crystal fraction, at least double that reported up to now, and the first synthesis of NaGdF4 glass-ceramics. Moreover, a new SiO2 precursor was introduced in the synthesis, allowing for a reduction in the treatment temperature and favoring hydroxyl group removal. Interesting optical properties demonstrated the incorporation of dopant ions in the fluoride crystals, thus obtaining crystal-like spectra along with higher efficiencies with respect to xerogels, and hence demonstrating that these materials are a suitable alternative for photonic applications. PMID- 29385707 TI - Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role. AB - The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting information about the role of the estrogen receptor alpha (ERalpha), progesterone receptor (PgR) and androgen receptor (AR) has been described and in most cases the use of sex hormone antagonists is not contemplated in clinical practice. In this study, we analyzed a panel of sex hormone receptors that have not been widely investigated in SGTs-ERalpha, PgR, AR, but also ERbeta and GPR30-to define their expression pattern and their prognostic and predictive value in a case series of 69 benign and malignant SGTs. We showed the aberrant expression of AR in mucoepidermoid and oncocytic carcinoma, a strong relation between cytoplasmic ERbeta expression and tumor grade, and a strong correlation between nuclear GPR30 expression and disease-free survival (DFS) of SGT patients. PMID- 29385708 TI - Differential Glycosylation and Modulation of Camel and Human HSP Isoforms in Response to Thermal and Hypoxic Stresses. AB - Increased expression of heat shock proteins (HSPs) following heat stress or other stress conditions is a common physiological response in almost all living organisms. Modification of cytosolic proteins including HSPs by O-GlcNAc has been shown to enhance their capabilities for counteracting lethal levels of cellular stress. Since HSPs are key players in stress resistance and protein homeostasis, we aimed to analyze their forms at the cellular and molecular level using camel and human HSPs as models for efficient and moderate thermotolerant mammals, respectively. In this study, we cloned the cDNA encoding two inducible HSP members, HSPA6 and CRYAB from both camel (Camelus dromedarius) and human in a Myc tagged mammalian expression vector. Expression of these chaperones in COS-1 cells revealed protein bands of approximately 25-kDa for both camel and human CRYAB and 70-kDa for camel HSPA6 and its human homologue. While localization and trafficking of the camel and human HSPs revealed similar cytosolic localization, we could demonstrate altered glycan structure between camel and human HSPA6. Interestingly, the glycoform of camel HSPA6 was rapidly formed and stabilized under normal and stress culture conditions whereas human HSPA6 reacted differently under similar thermal and hypoxic stress conditions. Our data suggest that efficient glycosylation of camel HSPA6 is among the mechanisms that provide camelids with a superior capability for alleviating stressful environmental circumstances. PMID- 29385709 TI - Polyphenolic Characterization and Antioxidant Activity of Malus domestica and Prunus domestica Cultivars from Costa Rica. AB - The phenolic composition of skin and flesh from Malus domestica apples (Anna cultivar) and Prunus domestica plums (satsuma cultivar) commercial cultivars in Costa Rica, was studied using Ultra Performance Liquid Chromatography coupled with High Resolution Mass Spectrometry (UPLC-DAD-ESI-MS) on enriched-phenolic extracts, with particular emphasis in proanthocyanidin and flavonoids characterization. A total of 52 compounds were identified, including 21 proanthocyanidins ([(+)-catechin and (-)-epicatechin]) flavan-3-ols monomers, five procyanidin B-type dimers and two procyanidin A-type dimers, five procyanidin B-type trimers and two procyanidin A-type trimers, as well as one procyanidin B-type tetramer, two procyanidin B-type pentamers, and two flavan-3 ol gallates); 15 flavonoids (kaempferol, quercetin and naringenin derivatives); nine phenolic acids (protochatechuic, caffeoylquinic, and hydroxycinnamic acid derivatives); five hydroxychalcones (phloretin and 3-hydroxyphloretin derivatives); and two isoprenoid glycosides (vomifoliol derivatives). These findings constitute the first report of such a high number and diversity of compounds in skins of one single plum cultivar and of the presence of proanthocyanidin pentamers in apple skins. Also, it is the first time that such a large number of glycosylated flavonoids and proanthocyanidins are reported in skins and flesh of a single plum cultivar. In addition, total phenolic content (TPC) was measured with high values observed for all samples, especially for fruits skins with a TPC of 619.6 and 640.3 mg gallic acid equivalents/g extract respectively for apple and plum. Antioxidant potential using 2,2-diphenyl-1 picrylhidrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) methods were evaluated, with results showing also high values for all samples, especially again for fruit skins with IC50 of 4.54 and 5.19 ug/mL (DPPH) and 16.8 and 14.6 mmol TE/g (ORAC) respectively for apple and plum, indicating the potential value of these extracts. Significant negative correlation was found for both apple and plum samples between TPC and DPPH antioxidant values, especially for plum fruits (R = -0.981, p < 0.05) as well as significant positive correlation between TPC and ORAC, also especially for plum fruits (R = 0.993, p < 0.05) and between both, DPPH and ORAC antioxidant methods (R = 0.994, p < 0.05). PMID- 29385711 TI - Predicting Observable Quantities of Self-Assembled Metamaterials from the T Matrix of Its Constituting Meta-Atom. AB - Self-assembled metamaterials attract considerable interest as they promise to make isotropic bulk metamaterials available at low costs. The optical response of self-assembled metamaterials is derived predominantly from the response of its individual constituents, i.e., the meta-atoms. Beyond effective properties, primary experimentally observable quantities, such as specific cross-sections, are at the focus of interest as they are frequently considered when exploiting metamaterials in specific applications. This posses the challenge of predicting these observable quantities for a diluted ensemble of randomly oriented meta atoms. Thus far, this has been achieved by either averaging the optical response of the meta-atom across all possible incident fields or by restricting the consideration to only an electric and magnetic dipolar response. This, however, is either time-consuming or imposes an unnecessary limitation. Here, we solve this problem by deriving and presenting explicit expressions for experimentally observable quantities of metamaterials made from randomly arranged and oriented meta-atoms characterized by their T-matrix. PMID- 29385710 TI - A Review of the Catalytic Mechanism of Human Manganese Superoxide Dismutase. AB - Superoxide dismutases (SODs) are necessary antioxidant enzymes that protect cells from reactive oxygen species (ROS). Decreased levels of SODs or mutations that affect their catalytic activity have serious phenotypic consequences. SODs perform their bio-protective role by converting superoxide into oxygen and hydrogen peroxide by cyclic oxidation and reduction reactions with the active site metal. Mutations of SODs can cause cancer of the lung, colon, and lymphatic system, as well as neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis. While SODs have proven to be of significant biological importance since their discovery in 1968, the mechanistic nature of their catalytic function remains elusive. Extensive investigations with a multitude of approaches have tried to unveil the catalytic workings of SODs, but experimental limitations have impeded direct observations of the mechanism. Here, we focus on human MnSOD, the most significant enzyme in protecting against ROS in the human body. Human MnSOD resides in the mitochondrial matrix, the location of up to 90% of cellular ROS generation. We review the current knowledge of the MnSOD enzymatic mechanism and ongoing studies into solving the remaining mysteries. PMID- 29385714 TI - Do Working Conditions of Patients in Psychotherapeutic Consultation in the Workplace Differ from Those in Outpatient Care? Results from an Observational Study. AB - In previous studies, it was found that patients treated at a psychosomatic outpatient clinic (PSOC) for common mental disorders showed more severe symptoms than those who used a psychotherapeutic consultation service at the workplace (PSIW). This study examines whether the higher symptom severity of the PSOC patients in comparison to their PSIW counterparts is also related to higher levels of occupational stress as measured by the demand-control-support model (DCS). N = 253 participants (PSIW n = 100; PSOC n = 153) provided self-reported data on demands, decision latitude, social support, and health before consultation. The association between mental health care setting, symptom level and demands, decision latitude, and social support was assessed by means of a path model. Results of the path model indicated that the higher level of depression in PSOC patients was related to higher levels of demands and lower levels of social support. Demands and social support were found to be indirectly associated with treatment setting. No interaction effect between demands, decision latitude, social support, and depression was found. Results of this study reveal that the working conditions influenced the pathway to care process via symptom severity. PMID- 29385713 TI - Nanobody Based Dual Specific CARs. AB - Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity. PMID- 29385712 TI - Colorectal Cancer and Alcohol Consumption-Populations to Molecules. AB - Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and rising habit of modern society, is one of the major risk factors for development of CRC. Here, we will summarize the evidence linking alcohol with colon carcinogenesis and possible underlying mechanisms. Some epidemiologic studies suggest that even moderate drinking increases the CRC risk. Metabolism of alcohol involves ethanol conversion to its metabolites that could exert carcinogenic effects in the colon. Production of ethanol metabolites can be affected by the colon microbiota, another recently recognized mediating factor to colon carcinogenesis. The generation of acetaldehyde and alcohol's other metabolites leads to activation of cancer promoting cascades, such as DNA-adduct formation, oxidative stress and lipid peroxidation, epigenetic alterations, epithelial barrier dysfunction, and immune modulatory effects. Not only does alcohol induce its toxic effect through carcinogenic metabolites, but alcoholics themselves are predisposed to a poor diet, low in folate and fiber, and circadian disruption, which could further augment alcohol-induced colon carcinogenesis. PMID- 29385715 TI - Different Achilles Tendon Pathologies Show Distinct Histological and Molecular Characteristics. AB - Reasons for the development of chronic tendon pathologies are still under debate and more basic knowledge is needed about the different diseases. The aim of the present study was therefore to characterize different acute and chronic Achilles tendon disorders. Achilles tendon samples from patients with chronic tendinopathy (n = 7), chronic ruptures (n = 6), acute ruptures (n = 13), and intact tendons (n = 4) were analyzed. The histological score investigating pathological changes was significantly increased in tendinopathy and chronic ruptures compared to acute ruptures. Inflammatory infiltration was detected by immunohistochemistry in all tendon pathology groups, but was significantly lower in tendinopathy compared to chronic ruptures. Quantitative real-time PCR (qRT-PCR) analysis revealed significantly altered expression of genes related to collagens and matrix modeling/remodeling (matrix metalloproteinases, tissue inhibitors of metalloproteinases) in tendinopathy and chronic ruptures compared to intact tendons and/or acute ruptures. In all three tendon pathology groups markers of inflammation (interleukin (IL) 1beta, tumor necrosis factor alpha, IL6, IL10, IL33, soluble ST2, transforming growth factor beta1, cyclooxygenase 2), inflammatory cells (cluster of differentaition (CD) 3, CD68, CD80, CD206), fat metabolism (fatty acid binding protein 4, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, adiponectin), and innervation (protein gene product 9.5, growth associated protein 43, macrophage migration inhibitory factor) were detectable, but only in acute ruptures significantly regulated compared to intact tendons. The study gives an insight into structural and molecular changes of pathological processes in tendons and might be used to identify targets for future therapy of tendon pathologies. PMID- 29385716 TI - Virus Infection Triggers MAVS Polymers of Distinct Molecular Weight. AB - The mitochondrial antiviral signaling (MAVS) adaptor protein is a central signaling hub required for cells to mount an antiviral response following virus sensing by retinoic acid-inducible gene I (RIG-I)-like receptors. MAVS localizes in the membrane of mitochondria and peroxisomes and in mitochondrial-associated endoplasmic reticulum membranes. Structural and functional studies have revealed that MAVS activity relies on the formation of functional high molecular weight prion-like aggregates. The formation of protein aggregates typically relies on a dynamic transition between oligomerization and aggregation states. The existence of intermediate state(s) of MAVS polymers, other than aggregates, has not yet been documented. Here, we used a combination of non-reducing SDS-PAGE and semi denaturing detergent agarose gel electrophoresis (SDD-AGE) to resolve whole cell extract preparations to distinguish MAVS polymerization states. While SDD-AGE analysis of whole cell extracts revealed the formation of previously described high molecular weight prion-like aggregates upon constitutively active RIG-I ectopic expression and virus infection, non-reducing SDS-PAGE allowed us to demonstrate the induction of lower molecular weight oligomers. Cleavage of MAVS using the NS3/4A protease revealed that anchoring to intracellular membranes is required for the appropriate polymerization into active high molecular weight aggregates. Altogether, our data suggest that RIG-I-dependent MAVS activation involves the coexistence of MAVS polymers with distinct molecular weights. PMID- 29385718 TI - The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis. AB - The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called "Brother of Regulator of Imprinted Sites" (BORIS) or "CTCF-like" (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint. PMID- 29385717 TI - RhoB: Team Oncogene or Team Tumor Suppressor? AB - Although Rho GTPases RhoA, RhoB, and RhoC share more than 85% amino acid sequence identity, they play very distinct roles in tumor progression. RhoA and RhoC have been suggested in many studies to contribute positively to tumor development, but the role of RhoB in cancer remains elusive. RhoB contains a unique C-terminal region that undergoes specific post-translational modifications affecting its localization and function. In contrast to RhoA and RhoC, RhoB not only localizes at the plasma membrane, but also on endosomes, multivesicular bodies and has even been identified in the nucleus. These unique features are what contribute to the diversity and potentially opposing functions of RhoB in the tumor microenvironment. Here, we discuss the dualistic role that RhoB plays as both an oncogene and tumor suppressor in the context of cancer development and progression. PMID- 29385719 TI - A Flexible Multiring Concentric Electrode for Non-Invasive Identification of Intestinal Slow Waves. AB - Developing new types of optimized electrodes for specific biomedical applications can substantially improve the quality of the sensed signals. Concentric ring electrodes have been shown to provide enhanced spatial resolution to that of conventional disc electrodes. A sensor with different electrode sizes and configurations (monopolar, bipolar, etc.) that provides simultaneous records would be very helpful for studying the best signal-sensing arrangement. A 5-pole electrode with an inner disc and four concentric rings of different sizes was developed and tested on surface intestinal myoelectrical recordings from healthy humans. For good adaptation to a curved body surface, the electrode was screen printed onto a flexible polyester substrate. To facilitate clinical use, it is self-adhesive, incorporates a single connector and can perform dry or wet (with gel) recordings. The results show it to be a versatile electrode that can evaluate the optimal configuration for the identification of the intestinal slow wave and reject undesired interference. A bipolar concentric record with an outer ring diameter of 30 mm, a foam-free adhesive material, and electrolytic gel gave the best results. PMID- 29385720 TI - Regulatory Role of MicroRNAs in Muscle Atrophy during Exercise Intervention. AB - Skeletal muscle comprising approximately 40% of body weight is highly important for locomotion and metabolic homeostasis. The growth and regeneration of skeletal muscle are highly organized processes; thus, it is not surprising to reveal certain complexity during these regulatory processes. Recently, a large number of evidence indicate that microRNAs can result in obvious impacts on growth, regeneration and metabolism of skeletal muscle. In this review, recent research achievements of microRNAs in regulating myogenesis, atrophy and aging during exercise intervention are discussed, which will provide the guidance for developing potential applications of microRNAs in health promotion and rehabilitation of sports injuries. PMID- 29385722 TI - Automatic Coregistration Algorithm to Remove Canopy Shaded Pixels in UAV-Borne Thermal Images to Improve the Estimation of Crop Water Stress Index of a Drip Irrigated Cabernet Sauvignon Vineyard. AB - Water stress caused by water scarcity has a negative impact on the wine industry. Several strategies have been implemented for optimizing water application in vineyards. In this regard, midday stem water potential (SWP) and thermal infrared (TIR) imaging for crop water stress index (CWSI) have been used to assess plant water stress on a vine-by-vine basis without considering the spatial variability. Unmanned Aerial Vehicle (UAV)-borne TIR images are used to assess the canopy temperature variability within vineyards that can be related to the vine water status. Nevertheless, when aerial TIR images are captured over canopy, internal shadow canopy pixels cannot be detected, leading to mixed information that negatively impacts the relationship between CWSI and SWP. This study proposes a methodology for automatic coregistration of thermal and multispectral images (ranging between 490 and 900 nm) obtained from a UAV to remove shadow canopy pixels using a modified scale invariant feature transformation (SIFT) computer vision algorithm and Kmeans++ clustering. Our results indicate that our proposed methodology improves the relationship between CWSI and SWP when shadow canopy pixels are removed from a drip-irrigated Cabernet Sauvignon vineyard. In particular, the coefficient of determination (R2) increased from 0.64 to 0.77. In addition, values of the root mean square error (RMSE) and standard error (SE) decreased from 0.2 to 0.1 MPa and 0.24 to 0.16 MPa, respectively. Finally, this study shows that the negative effect of shadow canopy pixels was higher in those vines with water stress compared with well-watered vines. PMID- 29385721 TI - Database Analysis of Depression and Anxiety in a Community Sample-Response to a Micronutrient Intervention. AB - BACKGROUND: Depression and anxiety are common mental health concerns worldwide. Broad-spectrum multi-vitamin/mineral approaches have been found to alleviate a number of psychiatric symptoms. We investigated the effects of a nutrient intervention program, which includes optimizing vitamin D levels, on depression and anxiety outcomes from community-based program. METHODS: We evaluated self reported health measures of depression and anxiety collected as part of a community-based program focused on optimizing overall health through nutritional supplementation, education and lifestyle advice. RESULTS: Data were collected from 16,020 participants, with measures including European Quality of Life Five Dimensions (EQ-5D) and Targeted Symptoms List (TSL) providing self-reported depression and anxiety. More than 56% of participants were identified as having elevated levels of depression and anxiety at baseline as reported on the EQ-5D. After one year in the program, 49.2% (n = 7878) of participants who reported any level of depression or anxiety at baseline reported improvement at follow-up. Of those who reported severe/extreme depression at baseline (n = 829), 97.2% reported improvement after one year. Regression analyses revealed a significant association of improvement in depression and anxiety with higher vitamin D status (>100 nmol/L) and more strenuous physical activity. CONCLUSION: Overall, people from the general population who suffer from mood and anxiety problems may benefit from improved nutritional status achieved with nutritional supplements. PMID- 29385723 TI - Alginic Acid-Aided Dispersion of Carbon Nanotubes, Graphene, and Boron Nitride Nanomaterials for Microbial Toxicity Testing. AB - Robust evaluation of potential environmental and health risks of carbonaceous and boron nitride nanomaterials (NMs) is imperative. However, significant agglomeration of pristine carbonaceous and boron nitride NMs due to strong van der Waals forces renders them not suitable for direct toxicity testing in aqueous media. Here, the natural polysaccharide alginic acid (AA) was used as a nontoxic, environmentally relevant dispersant with defined composition to disperse seven types of carbonaceous and boron nitride NMs, including multiwall carbon nanotubes, graphene, boron nitride nanotubes, and hexagonal boron nitride flakes, with various physicochemical characteristics. AA's biocompatibility was confirmed by examining AA effects on viability and growth of two model microorganisms (the protozoan Tetrahymena thermophila and the bacterium Pseudomonas aeruginosa). Using 400 mg.L-1 AA, comparably stable NM (200 mg.L-1) stock dispersions were obtained by 30-min probe ultrasonication. AA non-covalently interacted with NM surfaces and improved the dispersibility of NMs in water. The dispersion stability varied with NM morphology and size rather than chemistry. The optimized dispersion protocol established here can facilitate preparing homogeneous NM dispersions for reliable exposures during microbial toxicity testing, contributing to improved reproducibility of toxicity results. PMID- 29385724 TI - A Liquid-Surface-Based Three-Axis Inclination Sensor for Measurement of Stage Tilt Motions. AB - In this paper a new concept of a liquid-surface-based three-axis inclination sensor for evaluation of angular error motion of a precision linear slide, which is often used in the field of precision engineering such as ultra-precision machine tools, coordinate measuring machines (CMMs) and so on, is proposed. In the liquid-surface-based three-axis inclination sensor, a reference float mounting a line scale grating having periodic line grating structures is made to float over a liquid surface, while its three-axis angular motion is measured by using an optical sensor head based on the three-axis laser autocollimation capable of measuring three-axis angular motion of the scale grating. As the first step of research, in this paper, theoretical analysis on the angular motion of the reference float about each axis has been carried out based on simplified kinematic models to evaluate the possibility of realizing the proposed concept of a three-axis inclination sensor. In addition, based on the theoretical analyses results, a prototype three-axis inclination sensor has been designed and developed. Through some basic experiments with the prototype, the possibility of simultaneous three-axis inclination measurement by the proposed concept has been verified. PMID- 29385726 TI - Compact Surface Plasmon Resonance System with Au/Si Schottky Barrier. AB - Ethanol concentration was quantified by the use of a compact surface plasmon resonance (SPR) system, which electrically detects hot electrons via a Schottky barrier. Although it is well known that SPR can be used as bio/chemical sensors, implementation is not necessarily practical, due to the size and cost impediments associated with a system with variable wavelength or angle of incidence. However, scanning capability is not a prerequisite if the objective is to use SPR in a sensor. It is possible to build a small, inexpensive SPR sensor if the optics have no moving parts and a Schottky barrier is used for electrical current detection in place of a photodetector. This article reports on the design and performance of such a novel SPR sensor, and its application for quantifying ethanol concentration. As the concentration of ethanol is increased, the change in the angle dependence of the SPR current is observed. This change can be understood as a superposition of contributions of SPR coupled with the +3rd- and 3rd-order diffraction. Moreover, real-time monitoring of ethanol concentration was demonstrated using the proposed SPR system. PMID- 29385725 TI - Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models. AB - Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. PMID- 29385728 TI - The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization. AB - Some novel anthranilate diamides derivatives 4a-e, 6a-c and 9a-d were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, 1H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out. PMID- 29385727 TI - Electrospinning of Chitosan-Based Solutions for Tissue Engineering and Regenerative Medicine. AB - Electrospinning has been used for decades to generate nano-fibres via an electrically charged jet of polymer solution. This process is established on a spinning technique, using electrostatic forces to produce fine fibres from polymer solutions. Amongst, the electrospinning of available biopolymers (silk, cellulose, collagen, gelatine and hyaluronic acid), chitosan (CH) has shown a favourable outcome for tissue regeneration applications. The aim of the current review is to assess the current literature about electrospinning chitosan and its composite formulations for creating fibres in combination with other natural polymers to be employed in tissue engineering. In addition, various polymers blended with chitosan for electrospinning have been discussed in terms of their potential biomedical applications. The review shows that evidence exists in support of the favourable properties and biocompatibility of chitosan electrospun composite biomaterials for a range of applications. However, further research and in vivo studies are required to translate these materials from the laboratory to clinical applications. PMID- 29385729 TI - Antioxidative and Anti-Melanogenic Activities of Bamboo Stems (Phyllostachys nigra variety henosis) via PKA/CREB-Mediated MITF Downregulation in B16F10 Melanoma Cells. AB - Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. The anti-melanogenic and antioxidative activities of the EtOAc fraction (PN3) of a P. nigra stem extract were investigated in a cell-free system and in B16F10 melanoma cells. PN3 consisted of a mixture of flavonoids, such as catechin, chlorogenic acid, caffeic acid, and p coumaric acid. The antioxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)), and hydroxyl radical scavenging) was evaluated, as well as the inhibition of reactive oxygen species (ROS) produced by the Fenton reaction. PN3 showed in vitro tyrosinase inhibition activity with the half maximal inbihitory concentration (IC50) values of 240 MUg/mL, and in vivo cytotoxic concentration ranges > 100 MUg/mL. The protein expression levels and mRNA transcription levels of TYR, TRP-1, and MITF were decreased in a dose-dependent manner by the treatment with PN3. PN3 interfered with the phosphorylation of intracellular protein kinase A (PKA)/cAMP response element-binding protein (CREB), demonstrating potent anti-melanogenic effects. PN3 could inhibit PKA/CREB and the subsequent degradation of microphthalmia-associated transcription factor (MITF), resulting in the suppression of melanogenic enzymes and melanin production, probably because of the presence of flavonoid compounds. These properties make it a candidate as an additive to whitening cosmetics. PMID- 29385730 TI - Evaluation of Optimized Tube-Gel Methods of Sample Preparation for Large-Scale Plant Proteomics. AB - The so-called tube-gel method is a sample preparation protocol allowing for management of SDS for protein solubilization through in-gel protein trapping. Because of its simplicity, we assumed that once miniaturized, this method could become a standard for large scale experiments. We evaluated the performances of two variants of the miniaturized version of the tube-gel method based on different solubilization buffers (Tris-SDS or urea-SDS). To this end, we compared them to two other digestion methods: (i) liquid digestion after protein solubilization in the absence of SDS (liquid method) and (ii) filter-aided sample preparation (FASP). As large-scale experiments may require long term gel storage, we also examined to which extent gel aging affected the results of the proteomics analysis. We showed that both tube-gel and FASP methods extracted membrane proteins better than the liquid method, while the latter allowed the identification and quantification of a greater number of proteins. All methods were equivalent regarding quantitative stability. However, important differences were observed regarding post-translational modifications. In particular, methionine oxidation was higher with the tube-gel method than with the other methods. Based on these results, and considering time, simplicity, and cost aspects, we conclude that the miniaturized tube-gel method is suitable for sample preparation in the context of large-scale experiments. PMID- 29385731 TI - Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives. AB - Benzodiazepines are some of the most commonly prescribed medications in the world. These sedative-hypnotics can provide rapid relief for symptoms like anxiety and insomnia, but are also linked to a variety of adverse effects (whether used long-term, short-term, or as needed). Many patients take benzodiazepines long-term without ever receiving evidence-based first-line treatments (e.g., psychotherapy, relaxation techniques, sleep hygiene education, serotonergic agents). This review discusses the risks and benefits of, and alternatives to benzodiazepines. We discuss evidence-based indications and contraindications, and the theoretical biopsychosocial bases for effectiveness, ineffectiveness and harm. Potential adverse effects and drug-drug interactions are summarized. Finally, both fast-acting/acute and delayed-action/chronic alternative treatments for anxiety and/or insomnia are discussed. Response to treatment-whether benzodiazepines, other pharmacological agents, or psychotherapy should be determined based on functional recovery and not merely sedation. PMID- 29385732 TI - Biomarkers for Detecting Mitochondrial Disorders. AB - (1) Objectives: Mitochondrial disorders (MIDs) are a genetically and phenotypically heterogeneous group of slowly or rapidly progressive disorders with onset from birth to senescence. Because of their variegated clinical presentation, MIDs are difficult to diagnose and are frequently missed in their early and late stages. This is why there is a need to provide biomarkers, which can be easily obtained in the case of suspecting a MID to initiate the further diagnostic work-up. (2) Methods: Literature review. (3) Results: Biomarkers for diagnostic purposes are used to confirm a suspected diagnosis and to facilitate and speed up the diagnostic work-up. For diagnosing MIDs, a number of dry and wet biomarkers have been proposed. Dry biomarkers for MIDs include the history and clinical neurological exam and structural and functional imaging studies of the brain, muscle, or myocardium by ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), MR-spectroscopy (MRS), positron emission tomography (PET), or functional MRI. Wet biomarkers from blood, urine, saliva, or cerebrospinal fluid (CSF) for diagnosing MIDs include lactate, creatine-kinase, pyruvate, organic acids, amino acids, carnitines, oxidative stress markers, and circulating cytokines. The role of microRNAs, cutaneous respirometry, biopsy, exercise tests, and small molecule reporters as possible biomarkers is unsolved. (4) Conclusions: The disadvantages of most putative biomarkers for MIDs are that they hardly meet the criteria for being acceptable as a biomarker (missing longitudinal studies, not validated, not easily feasible, not cheap, not ubiquitously available) and that not all MIDs manifest in the brain, muscle, or myocardium. There is currently a lack of validated biomarkers for diagnosing MIDs. PMID- 29385733 TI - Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. AB - Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the NR2E3 gene. However, rare mutations in the NRL gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive NRL (arNRL) mutations. Three Moroccan patients of two different families with arNRL mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the NRL gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The arNRL mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by NR2E3 mutations, and rarely by NRL mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with NR2E3-associated ESCS, confirming previous reports of NRL as a second gene to cause ESCS. PMID- 29385734 TI - Single Nucleotide Polymorphisms in Taste Receptor Genes Are Associated with Snacking Patterns of Preschool-Aged Children in the Guelph Family Health Study: A Pilot Study. AB - Snacking is an integral component of eating habits in young children that is often overlooked in nutrition research. While snacking is a substantial source of calories in preschoolers' diets, there is limited knowledge about the factors that drive snacking patterns. The genetics of taste may help to better understand the snacking patterns of children. The rs1761667 single nucleotide polymorphism (SNP) in the CD36 gene has been linked to fat taste sensitivity, the rs35874116 SNP in the TAS1R2 gene has been related to sweet taste preference, and the rs713598 SNP in the TAS2R38 gene has been associated with aversion to bitter, green leafy vegetables. This study seeks to determine the cross-sectional associations between three taste receptor SNPs and snacking patterns among preschoolers in the Guelph Family Health Study. Preschoolers' snack quality, quantity, and frequency were assessed using three-day food records and saliva was collected for SNP genotyping (n = 47). Children with the TT genotype in TAS1R2 consumed snacks with significantly more calories from sugar, and these snacks were consumed mostly in the evening. Total energy density of snacks was highest in the CC and CG genotypes compared to the GG genotype in TAS2R38, and also greater in the AA genotype in CD36 compared to G allele carriers, however this difference was not individually attributable to energy from fat, carbohydrates, sugar, or protein. Genetic variation in taste receptors may influence snacking patterns of preschoolers. PMID- 29385736 TI - Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors. AB - Resistance to aminoglycoside antibiotics has had a profound impact on clinical practice. Despite their powerful bactericidal activity, aminoglycosides were one of the first groups of antibiotics to meet the challenge of resistance. The most prevalent source of clinically relevant resistance against these therapeutics is conferred by the enzymatic modification of the antibiotic. Therefore, a deeper knowledge of the aminoglycoside-modifying enzymes and their interactions with the antibiotics and solvent is of paramount importance in order to facilitate the design of more effective and potent inhibitors and/or novel semisynthetic aminoglycosides that are not susceptible to modifying enzymes. PMID- 29385738 TI - Chloro-1,4-dimethyl-9H-carbazole Derivatives Displaying Anti-HIV Activity. AB - BACKGROUND: Despite the progress achieved by anti-retroviral drug research in the last decades, the discovery of novel compounds endowed with selective antiviral activity and reduced side effects is still a necessity. At present, the most urgent requirement includes the improvement of HIV (Human Immunodeficiency Virus) prevention and sexual transmission and the development of new drugs to treat the chronic lifelong infection. METHODS: Six chloro-1,4-dimethyl-9H-carbazoles (2a,b 4a,b) have been prepared following opportunely modified known chemical procedures and tested in luciferase and Escherichia coli beta-galactosidase expressing CD4+, CXCR4+, CCR5+ TZM-bl cells. RESULTS AND CONCLUSION: a preliminary biological investigation on the synthesized small series of chloro-1,4-dimethyl-9H carbazoles has been carried out. Among all tested compounds, a nitro-derivative (3b) showed the most interesting profile representing a suitable lead for the development of novel anti-HIV drugs. PMID- 29385740 TI - Effects of Combining Medication and Pivotal Response Treatment on Aberrant Behavior in Children with Autism Spectrum Disorder. AB - Abstract: The purpose of this study was to investigate the effects of combined risperidone (RIS) and pivotal response treatment (PRT) on children with autism spectrum disorder (ASD). A total of 34 children diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) (mean age of 12.36 years) were randomly assigned to either of two groups; the first group (n = 17) received combined PRT-RIS while the second group (n = 17) received RIS only. Behavioral problems were evaluated with the Aberrant Behavior Checklist (ABC), whereas global improvement (GI) was measured with the Clinical Global Impressions (CGI). Assessment of ABC was performed before intervention, after intervention (12 weeks), and following 3 months of the intervention (follow up). Total ABC scores were seen to decrease in both groups after 3 months, as compared with the scores prior to the interventions. Also, in both groups, mean scores of behavioral problems after the intervention were not significantly different from those prior to the intervention, in all subscales but the inappropriate speech (p < 0.001). However, both groups showed significant differences in mean scores of ABC subscales in both of the post-intervention evaluation stages. It was concluded that the combination of behavioral and drug interventions can further improve behavioral problems, ultimately improving patient's communication and social skills. PMID- 29385735 TI - Peptides as Potential Therapeutics for Alzheimer's Disease. AB - Intracellular synthesis, folding, trafficking and degradation of proteins are controlled and integrated by proteostasis. The frequency of protein misfolding disorders in the human population, e.g., in Alzheimer's disease (AD), is increasing due to the aging population. AD treatment options are limited to symptomatic interventions that at best slow-down disease progression. The key biochemical change in AD is the excessive accumulation of per-se non-toxic and soluble amyloid peptides (Abeta(1-37/44), in the intracellular and extracellular space, that alters proteostasis and triggers Abeta modification (e.g., by reactive oxygen species (ROS)) into toxic intermediate, misfolded soluble Abeta peptides, Abeta dimers and Abeta oligomers. The toxic intermediate Abeta products aggregate into progressively less toxic and less soluble protofibrils, fibrils and senile plaques. This review focuses on peptides that inhibit toxic Abeta oligomerization, Abeta aggregation into fibrils, or stabilize Abeta peptides in non-toxic oligomers, and discusses their potential for AD treatment. PMID- 29385739 TI - Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer. AB - Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune oncology were addressed. PMID- 29385737 TI - PTEN Inhibition in Human Disease Therapy. AB - The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing. In these conditions, inhibition of PTEN catalysis is being explored as a potentially beneficial therapeutic intervention. Here, an overview of human diseases and conditions in which PTEN inhibition could be beneficial is presented, together with an update on the current status of specific small molecule inhibitors of PTEN enzymatic activity, their use in experimental models, and their limitations as research or therapeutic drugs. PMID- 29385741 TI - Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation. AB - Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-alpha (Wy14643) and -gamma (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-alpha/beta/gamma blocked the activation of VDR. PPAR-beta (linoleic acid) reversed the inhibition of NO release, whereas PPAR-gamma (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress. PMID- 29385742 TI - Validation of the Brazilian Healthy Eating Index-Revised Using Biomarkers in Children and Adolescents. AB - The Brazilian Healthy Eating Index-Revised (BHEI-R) can be used to determine overall dietary patterns. We assessed the BHEI-R scores in children and adolescents, aged from 9 to 13 years old, and associated its component scores with biomarkers of health and dietary exposure. Three 24-h recalls were used to generate BHEI-R. Biomarkers were analyzed in plasma and red blood cells. Correlation tests, agreement, and covariance analyses were used to associate BHEI R components with biomarkers. Data from 167 subjects were used. The strongest correlations were between fruits, vegetables and legumes with omega-6 and omega-3 fatty acids, and beta-carotene intakes. Milk and dairy correlated with plasma retinol and pyridoxine. All components rich in vegetable and animal protein sources correlated with plasma creatine. Total BHEI-R scores were positively associated with intakes of omega-6, omega-3, fiber and vitamin C, and inversely associated with energy and saturated fat intakes of individuals. Plasma beta carotene and riboflavin biomarkers were positively associated with total BHEI-R. An inadequate food consumption pattern was captured by both biomarkers of health and dietary exposure. BHEI-R was validated for the above dietary components and can be associated with metabolomics and nutritional epidemiological data in future pediatric studies. PMID- 29385745 TI - Simulation and Analysis of Mechanical Properties of Silica Aerogels: From Rationalization to Prediction. AB - Silica aerogels are highly porous 3D nanostructures and have exhibited excellent physio-chemical properties. Although silica aerogels have broad potential in many fields, the poor mechanical properties greatly limit further applications. In this study, we have applied the finite volume method (FVM) method to calculate the mechanical properties of silica aerogels with different geometric properties such as particle size, pore size, ligament diameter, etc. The FVM simulation results show that a power law correlation existing between relative density and mechanical properties (elastic modulus and yield stress) of silica aerogels, which are consistent with experimental and literature studies. In addition, depending on the relative densities, different strategies are proposed in order to synthesize silica aerogels with better mechanical performance by adjusting the distribution of pore size and ligament diameter of aerogels. Finally, the results suggest that it is possible to synthesize silica aerogels with ultra-low density as well as high strength and stiffness as long as the textural features are well controlled. It is believed that the FVM simulation methodology could be a valuable tool to study mechanical performance of silica aerogel based materials in the future. PMID- 29385744 TI - The PUF Protein Family: Overview on PUF RNA Targets, Biological Functions, and Post Transcriptional Regulation. AB - Post-transcriptional regulation of gene expression plays a crucial role in many processes. In cells, it is mediated by diverse RNA-binding proteins. These proteins can influence mRNA stability, translation, and localization. The PUF protein family (Pumilio and FBF) is composed of RNA-binding proteins highly conserved among most eukaryotic organisms. Previous investigations indicated that they could be involved in many processes by binding corresponding motifs in the 3'UTR or by interacting with other proteins. To date, most of the investigations on PUF proteins have been focused on Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae, while only a few have been conducted on Arabidopsis thaliana. The present article provides an overview of the PUF protein family. It addresses their RNA-binding motifs, biological functions, and post-transcriptional control mechanisms in Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, and Arabidopsis thaliana. These items of knowledge open onto new investigations into the relevance of PUF proteins in specific plant developmental processes. PMID- 29385743 TI - Natural Anti-Estrogen Receptor Alpha Antibodies Able to Induce Estrogenic Responses in Breast Cancer Cells: Hypotheses Concerning Their Mechanisms of Action and Emergence. AB - The detection of human anti-estrogen receptor alpha antibodies (ERalphaABs) inducing estrogenic responses in MCF-7 mammary tumor cells suggests their implication in breast cancer emergence and/or evolution. A recent report revealing a correlation between the titer of such antibodies in sera from patients suffering from this disease and the percentage of proliferative cells in samples taken from their tumors supports this concept. Complementary evidence of the ability of ERalphaABs to interact with an epitope localized within the estradiol-binding core of ERalpha also argues in its favor. This epitope is indeed inserted in a regulatory platform implicated in ERalpha-initiated signal transduction pathways and transcriptions. According to some experimental observations, two auto-immune reactions may already be advocated to explain the emergence of ERalphaABs: one involving probably the idiotypic network to produce antibodies acting as estrogenic secretions and the other based on antibodies able to abrogate the action of a natural ERalpha inhibitor or to prevent the competitive inhibitory potency of released receptor degradation products able to entrap circulating estrogens and co-activators. All of this information, the aspect of which is mainly fundamental, may open new ways in the current tendency to combine immunological and endocrine approaches for the management of breast cancer. PMID- 29385746 TI - The Effect of Methyl-beta-cyclodextrin on Apoptosis, Proliferative Activity, and Oxidative Stress in Adipose-Derived Mesenchymal Stromal Cells of Horses Suffering from Metabolic Syndrome (EMS). AB - Methyl-beta-cyclodextrin (MbetaCD) is a cyclic oligosaccharide, commonly used as a pharmacological agent to deplete membrane cholesterol. In this study, we examined the effect of MbetaCD on adipose-derived mesenchymal stromal cells (ASCs) isolated form healthy horses (ASCCTRL) and from horses suffering from metabolic syndrome (ASCEMS). We investigated the changes in the mRNA levels of the glucose transporter 4 (GLUT4) and found that MbetaCD application may lead to a significant improvement in glucose transport in ASCEMS. We also showed that MbetaCD treatment affected GLUT4 upregulation in an insulin-independent manner via an NO-dependent signaling pathway. Furthermore, the analysis of superoxide dismutase activity (SOD) and reactive oxygen species (ROS) levels showed that MbetaCD treatment was associated with an increased antioxidant capacity in ASCEMS. Moreover, we indicated that methyl-beta-cyclodextrin treatment did not cause a dysfunction of the endoplasmic reticulum and lysosomes. Thereby, we propose the possibility of improving the functionality of ASCEMS by increasing their metabolic stability. PMID- 29385748 TI - Prototyping a Web-of-Energy Architecture for Smart Integration of Sensor Networks in Smart Grids Domain. AB - Sensor networks and the Internet of Things have driven the evolution of traditional electric power distribution networks towards a new paradigm referred to as Smart Grid. However, the different elements that compose the Information and Communication Technologies (ICTs) layer of a Smart Grid are usually conceived as isolated systems that typically result in rigid hardware architectures which are hard to interoperate, manage, and to adapt to new situations. If the Smart Grid paradigm has to be presented as a solution to the demand for distributed and intelligent energy management system, it is necessary to deploy innovative IT infrastructures to support these smart functions. One of the main issues of Smart Grids is the heterogeneity of communication protocols used by the smart sensor devices that integrate them. The use of the concept of the Web of Things is proposed in this work to tackle this problem. More specifically, the implementation of a Smart Grid's Web of Things, coined as the Web of Energy is introduced. The purpose of this paper is to propose the usage of Web of Energy by means of the Actor Model paradigm to address the latent deployment and management limitations of Smart Grids. Smart Grid designers can use the Actor Model as a design model for an infrastructure that supports the intelligent functions demanded and is capable of grouping and converting the heterogeneity of traditional infrastructures into the homogeneity feature of the Web of Things. Conducted experimentations endorse the feasibility of this solution and encourage practitioners to point their efforts in this direction. PMID- 29385747 TI - Hydrophilicity, Viscoelastic, and Physicochemical Properties Variations in Dental Bone Grafting Substitutes. AB - The indication-oriented Dental Bone Graft Substitutes (DBGS) selection, the correct bone defects classification, and appropriate treatment planning are very crucial for obtaining successful clinical results. However, hydrophilic, viscoelastic, and physicochemical properties' influence on the DBGS regenerative potential has poorly been studied. For that reason, we investigated the dimensional changes and molecular mobility by Dynamic Mechanical Analysis (DMA) of xenograft (cerabone(r)), synthetic (maxresorb(r)), and allograft (maxgraft(r), Puros(r)) blocks in a wet and dry state. While no significant differences could be seen in dry state, cerabone(r) and maxresorb(r) blocks showed a slight height decrease in wet state, whereas both maxgraft(r) and Puros(r) had an almost identical height increase. In addition, cerabone(r) and maxresorb(r) blocks remained highly rigid and their damping behaviour was not influenced by the water. On the other hand, both maxgraft(r) and Puros(r) had a strong increase in their molecular mobility with different damping behaviour profiles during the wet state. A high-speed microscopical imaging system was used to analyze the hydrophilicity in several naturally derived (cerabone(r), Bio-Oss(r), NuOss(r), SIC(r) nature graft) and synthetic DBGS granules (maxresorb(r), BoneCeramic(r), NanoBone(r), Ceros(r)). The highest level of hydrophilicity was detected in cerabone(r) and maxresorb(r), while Bio-Oss(r) and BoneCeramic(r) had the lowest level of hydrophilicity among both naturally derived and synthetic DBGS groups. Deviations among the DBGS were also addressed via physicochemical differences recorded by Micro Computed Tomography, Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, X-ray powder Diffractometry, and Thermogravimetric Analysis. Such DBGS variations could influence the volume stability at the grafting site, handling as well as the speed of vascularization and bone regeneration. Therefore, this study initiates a new insight into the DBGS differences and their importance for successful clinical results. PMID- 29385749 TI - A Brief Review of Facial Emotion Recognition Based on Visual Information. AB - Facial emotion recognition (FER) is an important topic in the fields of computer vision and artificial intelligence owing to its significant academic and commercial potential. Although FER can be conducted using multiple sensors, this review focuses on studies that exclusively use facial images, because visual expressions are one of the main information channels in interpersonal communication. This paper provides a brief review of researches in the field of FER conducted over the past decades. First, conventional FER approaches are described along with a summary of the representative categories of FER systems and their main algorithms. Deep-learning-based FER approaches using deep networks enabling "end-to-end" learning are then presented. This review also focuses on an up-to-date hybrid deep-learning approach combining a convolutional neural network (CNN) for the spatial features of an individual frame and long short-term memory (LSTM) for temporal features of consecutive frames. In the later part of this paper, a brief review of publicly available evaluation metrics is given, and a comparison with benchmark results, which are a standard for a quantitative comparison of FER researches, is described. This review can serve as a brief guidebook to newcomers in the field of FER, providing basic knowledge and a general understanding of the latest state-of-the-art studies, as well as to experienced researchers looking for productive directions for future work. PMID- 29385750 TI - Design and Evaluation of a Pervasive Coaching and Gamification Platform for Young Diabetes Patients. AB - Self monitoring, personal goal-setting and coaching, education and social support are strategies to help patients with chronic conditions in their daily care. Various tools have been developed, e.g., mobile digital coaching systems connected with wearable sensors, serious games and patient web portals to personal health records, that aim to support patients with chronic conditions and their caregivers in realizing the ideal of self-management. We describe a platform that integrates these tools to support young patients in diabetes self management through educational game playing, monitoring and motivational feedback. We describe the design of the platform referring to principles from healthcare, persuasive system design and serious game design. The virtual coach is a game guide that can also provide personalized feedback about the user's daily care related activities which have value for making progress in the game world. User evaluations with patients under pediatric supervision revealed that the use of mobile technology in combination with web-based elements is feasible but some assumptions made about how users would connect to the platform were not satisfied in reality, resulting in less than optimal user experiences. We discuss challenges with suggestions for further development of integrated pervasive coaching and gamification platforms in medical practice. PMID- 29385751 TI - Polarimetric Calibration and Quality Assessment of the GF-3 Satellite Images. AB - The GaoFen-3 (GF-3) satellite is the first fully polarimetric synthetic aperture radar (SAR) satellite designed for civil use in China. The satellite operates in the C-band and has 12 imaging modes for various applications. Three fully polarimetric SAR (PolSAR) imaging modes are provided with a resolution of up to 8 m. Although polarimetric calibration (PolCAL) of the SAR system is periodically undertaken, there is still some residual distortion in the images. In order to assess the polarimetric accuracy of this satellite and improve the image quality, we analyzed the polarimetric distortion errors and performed a PolCAL experiment based on scattering properties and corner reflectors. The experiment indicates that the GF-3 images can meet the satellite's polarimetric accuracy requirements, i.e., a channel imbalance of 0.5 dB in amplitude and +/-10 degrees in phase and a crosstalk accuracy of -35 dB. However, some images still contain residual polarimetric distortion. The experiment also shows that the residual errors of the GF-3 standard images can be diminished after further PolCAL, with a channel imbalance of 0.26 dB in amplitude and +/-0.2 degrees in phase and a crosstalk accuracy of -42 dB. PMID- 29385752 TI - Wireless Networks under a Backoff Attack: A Game Theoretical Perspective. AB - We study a wireless sensor network using CSMA/CA in the MAC layer under a backoff attack: some of the sensors of the network are malicious and deviate from the defined contention mechanism. We use Bianchi's network model to study the impact of the malicious sensors on the total network throughput, showing that it causes the throughput to be unfairly distributed among sensors. We model this conflict using game theory tools, where each sensor is a player. We obtain analytical solutions and propose an algorithm, based on Regret Matching, to learn the equilibrium of the game with an arbitrary number of players. Our approach is validated via simulations, showing that our theoretical predictions adjust to reality. PMID- 29385753 TI - A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine. AB - In recent years, enterovirus D68 (EVD68) has been reported increasingly to be associated with severe respiratory tract infections and acute flaccid myelitis (AFM) in children all over the world. Yet, no effective vaccines or antiviral drugs are currently available for EVD68. Although several experimental animal models have been developed, immunogenicity and protective efficacy of inactivated EVD68 vaccines has not been fully evaluated. To promote the development of vaccines, we established an Institute of Cancer Research (ICR) suckling mouse model of EVD68 infection in this study. The results showed that ICR neonatal mice up to about nine days of age were susceptible to infection with EVD68 clinical strain US/MO/14-18947 by intraperitoneal injection. The infected mice exhibited progressive limb paralysis prior to death and the mortality of mice was age- and virus dose-dependent. Tissue viral load analysis showed that limb muscle and spinal cord were the major sites of viral replication. Moreover, histopathologic examination revealed the severe necrosis of the limb and juxtaspinal muscles, suggesting that US/MO/14-18947 has a strong tropism toward muscle tissues. Additionally, beta-propiolactone-inactivated EVD68 vaccine showed high purity and quality and induced robust EVD68-specific neutralizing antibody responses in adult mice. Importantly, results from both antisera transfer and maternal immunization experiments clearly showed that inactivated EVD68 vaccine was able to protect against lethal viral infection in the mouse model. In short, these results demonstrate the successful establishment of the mouse model of EVD68 infection for evaluating candidate vaccines against EVD68 and also provide important information for the development of inactivated virus-based EVD68 vaccines. PMID- 29385754 TI - 2-(2-Phenylethyl)-4H-chromen-4-one Derivatives from the Resinous Wood of Aquilaria sinensis with Anti-Inflammatory Effects in LPS-Induced Macrophages. AB - The resinous wood of Aquilaria sinensis, known as agarwood (Chen Xiang in Chinese), is traditionally used for the treatment of abdominal pain, vomiting, circulatory disorders, and dyspnea. Four new 2-(2-phenylethyl)-4H-chromen-4-one derivatives, namely 7-methoxy-2-[2-(4'-hydroxy-phenyl)ethyl]chromone (1), 7 hydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (2), 5,6-dihydroxy- 2-[2-(3' hydroxy-4'-methoxyphenyl)ethyl]chromone (3), and 6-hydroxy-5-methoxy-2-(2-phenyl ethyl)chromone (4), have been isolated from the resinous wood of A. sinensis, together with nine known compounds. The structures of these compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, neopetasan, 7-methoxy-2-(2-phenylethyl)-chromone, 6,7-dimethoxy-2-(2 phenylethyl)chromone, and 6,7-dimethoxy-2-[2-(4'-methoxy-phenyl)ethyl]chromone inhibited NF-kappaB activation in LPS-stimulated RAW 264.7 macrophages with relative luciferase activity values of 0.55 +/- 0.09, 0.54 +/- 0.03, 0.31 +/- 0.05, and 0.38 +/- 0.14, respectively, versus that of vehicle control (1.03 +/- 0.02). In addition, 5,6-dihydroxy-2-[2-(3'-hydroxy-4' methoxyphenyl)ethyl]chromone, 7-methoxy-2-(2-phenylethyl)chromone, 7-dimethoxy-2 (2-phenylethyl)chromone, and 6,7-dimethoxy-2-[2-(4'-methoxyphenyl)ethyl]chromone could suppress LPS-induced NO production in RAW 264.7 cells and did not induce cytotoxicity against RAW 264.7 cells after 24-h treatment. PMID- 29385756 TI - Mechanical Properties Optimization of Poly-Ether-Ether-Ketone via Fused Deposition Modeling. AB - Compared to the common selective laser sintering (SLS) manufacturing method, fused deposition modeling (FDM) seems to be an economical and efficient three dimensional (3D) printing method for high temperature polymer materials in medical applications. In this work, a customized FDM system was developed for polyether-ether-ketone (PEEK) materials printing. The effects of printing speed, layer thickness, printing temperature and filling ratio on tensile properties were analyzed by the orthogonal test of four factors and three levels. Optimal tensile properties of the PEEK specimens were observed at a printing speed of 60 mm/s, layer thickness of 0.2 mm, temperature of 370 degrees C and filling ratio of 40%. Furthermore, the impact and bending tests were conducted under optimized conditions and the results demonstrated that the printed PEEK specimens have appropriate mechanical properties. PMID- 29385757 TI - In-Hospital Palliative Care: Should We Need to Reconsider What Role Hospitals Should Have in Patients with End-Stage Disease or Advanced Cancer? AB - Traditionally, palliative care (PC) systems focused on the needs of advanced cancer patients, but most patients needing PC have end-stage organ diseases. Similarly, PC models focus on the needs of patients in hospices or at home; however, in most cases PC is provided in acute hospitals. Indeed, the symptom burden that these patients experience in the last year of life frequently forces them to seek care in emergency departments. The majority of them are admitted to the hospital and many die. This issue poses important concerns. Despite the efforts of attending healthcare professionals, in-hospital patients do not receive optimal care near the end-of-life. Also, evidence is emerging that delay in identifying patients needing PC have a detrimental impact on their quality of life (QoL). Therefore, there is an urgent need to identify, early and properly, these patients among those hospitalized. Several trials reported the efficacy of PC in improving the QoL in these patients. Each hospital should ensure that a multidisciplinary PC team is available to support attending physicians to achieve the best QoL for both PC patients and their families. This review discusses the role and the impact of in-hospital PC in patients with end-stage disease or advanced cancer. PMID- 29385755 TI - Liposomes: Clinical Applications and Potential for Image-Guided Drug Delivery. AB - Liposomes have been extensively studied and are used in the treatment of several diseases. Liposomes improve the therapeutic efficacy by enhancing drug absorption while avoiding or minimizing rapid degradation and side effects, prolonging the biological half-life and reducing toxicity. The unique feature of liposomes is that they are biocompatible and biodegradable lipids, and are inert and non immunogenic. Liposomes can compartmentalize and solubilize both hydrophilic and hydrophobic materials. All these properties of liposomes and their flexibility for surface modification to add targeting moieties make liposomes more attractive candidates for use as drug delivery vehicles. There are many novel liposomal formulations that are in various stages of development, to enhance therapeutic effectiveness of new and established drugs that are in preclinical and clinical trials. Recent developments in multimodality imaging to better diagnose disease and monitor treatments embarked on using liposomes as diagnostic tool. Conjugating liposomes with different labeling probes enables precise localization of these liposomal formulations using various modalities such as PET, SPECT, and MRI. In this review, we will briefly review the clinical applications of liposomal formulation and their potential imaging properties. PMID- 29385758 TI - Process Evaluation and Costing of a Multifaceted Population-Wide Intervention to Reduce Salt Consumption in Fiji. AB - This paper reports the process evaluation and costing of a national salt reduction intervention in Fiji. The population-wide intervention included engaging food industry to reduce salt in foods, strategic health communication and a hospital program. The evaluation showed a 1.4 g/day drop in salt intake from the 11.7 g/day at baseline; however, this was not statistically significant. To better understand intervention implementation, we collated data to assess intervention fidelity, reach, context and costs. Government and management changes affected intervention implementation, meaning fidelity was relatively low. There was no active mechanism for ensuring food companies adhered to the voluntary salt reduction targets. Communication activities had wide reach but most activities were one-off, meaning the overall dose was low and impact on behavior limited. Intervention costs were moderate (FJD $277,410 or $0.31 per person) but the strategy relied on multi-sector action which was not fully operationalised. The cyclone also delayed monitoring and likely impacted the results. However, 73% of people surveyed had heard about the campaign and salt reduction policies have been mainstreamed into government programs. Longer-term monitoring of salt intake is planned through future surveys and lessons from this process evaluation will be used to inform future strategies in the Pacific Islands and globally. PMID- 29385759 TI - Heavily Boron-Doped Silicon Layer for the Fabrication of Nanoscale Thermoelectric Devices. AB - Heavily boron-doped silicon layers and boron etch-stop techniques have been widely used in the fabrication of microelectromechanical systems (MEMS). This paper provides an introduction to the fabrication process of nanoscale silicon thermoelectric devices. Low-dimensional structures such as silicon nanowire (SiNW) have been considered as a promising alternative for thermoelectric applications in order to achieve a higher thermoelectric figure of merit (ZT) than bulk silicon. Here, heavily boron-doped silicon layers and boron etch-stop processes for the fabrication of suspended SiNWs will be discussed in detail, including boron diffusion, electron beam lithography, inductively coupled plasma (ICP) etching and tetramethylammonium hydroxide (TMAH) etch-stop processes. A 7 MUm long nanowire structure with a height of 280 nm and a width of 55 nm was achieved, indicating that the proposed technique is useful for nanoscale fabrication. Furthermore, a SiNW thermoelectric device has also been demonstrated, and its performance shows an obvious reduction in thermal conductivity. PMID- 29385760 TI - Red Blood Cell Transfusion Need for Elective Primary Posterior Lumbar Fusion in A High-Volume Center for Spine Surgery. AB - (1) Background: This study evaluated the perioperative red blood cell (RBC) transfusion need and determined predictors for transfusion in patients undergoing elective primary lumbar posterior spine fusion in a high-volume center for spine surgery. (2) Methods: Data from all patients undergoing spine surgery between 1 January 2014 and 31 December 2016 were reviewed. Patients' demographics and comorbidities, perioperative laboratory results, and operative time were analyzed in relation to RBC transfusion. Multivariate logistic regression analysis was performed to identify the predictors of transfusion. (3) Results: A total of 874 elective surgeries for primary spine fusion were performed over the three years. Only 54 cases (6%) required RBC transfusion. Compared to the non-transfused patients, transfused patients were mainly female (p = 0.0008), significantly older, with a higher ASA grade (p = 0.0002), and with lower pre-surgery hemoglobin (HB) level and hematocrit (p < 0.0001). In the multivariate logistic regression, a lower pre-surgery HB (OR (95% CI) 2.84 (2.11-3.82)), a higher ASA class (1.77 (1.03-3.05)) and a longer operative time (1.02 (1.01-1.02)) were independently associated with RBC transfusion. (4) Conclusions: In the instance of elective surgery for primary posterior lumbar fusion in a high-volume center for spine surgery, the need for RBC transfusion is low. Factors anticipating transfusion should be taken into consideration in the patient's pre-surgery preparation. PMID- 29385761 TI - Catalytic Activity of Silicon Nanowires Decorated with Gold and Copper Nanoparticles Deposited by Pulsed Laser Ablation. AB - Silicon nanowires (SiNWs) decorated by pulsed laser ablation with gold or copper nanoparticles (labeled as AuNPs@SiNWs and CuNPs@SiNWs) were investigated for their catalytic properties. Results demonstrated high catalytic performances in the Caryl-N couplings and subsequent carbonylations for gold and copper catalysts, respectively, that have no precedents in the literature. The excellent activity, attested by the very high turn over number (TON) values, was due both to the uniform coverage along the NW length and to the absence of the chemical shell surrounding the metal nanoparticles (MeNPs). A high recyclability was also observed and can be ascribed to the strong covalent interaction at the Me-Si interface by virtue of metal "silicides" formation. PMID- 29385762 TI - Incidence and Determinants of Health Care-Associated Blood Stream Infection at a Neonatal Intensive Care Unit in Ujjain, India: A Prospective Cohort Study. AB - Very little is known about laboratory-confirmed blood stream infections (LCBIs) in neonatal intensive care units (NICUs) in resource-limited settings. The aim of this cohort study was to determine the incidence, risk factors, and causative agents of LCBIs in a level-2 NICU in India. The diagnosis of LCBIs was established using the Centre for Disease Control, USA criteria. A predesigned questionnaire containing risk factors associated with LCBIs was filled-in. A total of 150 neonates (43% preterm) were included in the study. The overall incidence of LCBIs was 31%. The independent risk factors for LCBIs were: preterm neonates (relative risk (RR) 2.23), duration of NICU stay more than 14 days (RR 1.75), chorioamnionitis in the mother (RR 3.18), premature rupture of membrane in mothers (RR 2.32), neonate born through meconium-stained amniotic fluid (RR 2.32), malpresentation (RR 3.05), endotracheal intubation (RR 3.41), umbilical catheterization (RR 4.18), and ventilator-associated pneumonia (RR 3.17). The initiation of minimal enteral nutrition was protective from LCBIs (RR 0.22). The predominant causative organisms were gram-negative pathogens (58%). The results of the present study can be used to design and implement antibiotic stewardship policy and introduce interventions to reduce LCBIs in resource-limited settings. PMID- 29385763 TI - Enzymatic Synthesis of Amino Acids Endcapped Polycaprolactone: A Green Route Towards Functional Polyesters. AB - epsilon-caprolactone (CL) has been enzymatically polymerized using alpha-amino acids based on sulfur (methionine and cysteine) as (co-)initiators and immobilized lipase B of Candida antarctica (CALB) as biocatalyst. In-depth characterizations allowed determining the corresponding involved mechanisms and the polymers thermal properties. Two synthetic strategies were tested, a first one with direct polymerization of CL with the native amino acids and a second one involving the use of an amino acid with protected functional groups. The first route showed that mainly polycaprolactone (PCL) homopolymer could be obtained and highlighted the lack of reactivity of the unmodified amino acids due to poor solubility and affinity with the lipase active site. The second strategy based on protected cysteine showed higher monomer conversion, with the amino acids acting as (co-)initiators, but their insertion along the PCL chains remained limited to chain endcapping. These results thus showed the possibility to synthesize enzymatically polycaprolactone-based chains bearing amino acids units. Such cysteine endcapped PCL materials could then find application in the biomedical field. Indeed, subsequent functionalization of these polyesters with drugs or bioactive molecules can be obtained, by derivatization of the amino acids, after removal of the protecting group. PMID- 29385764 TI - Structural and Functional Basis of the Fidelity of Nucleotide Selection by Flavivirus RNA-Dependent RNA Polymerases. AB - Viral RNA-dependent RNA polymerases (RdRps) play a central role not only in viral replication, but also in the genetic evolution of viral RNAs. After binding to an RNA template and selecting 5'-triphosphate ribonucleosides, viral RdRps synthesize an RNA copy according to Watson-Crick base-pairing rules. The copy process sometimes deviates from both the base-pairing rules specified by the template and the natural ribose selectivity and, thus, the process is error-prone due to the intrinsic (in)fidelity of viral RdRps. These enzymes share a number of conserved amino-acid sequence strings, called motifs A-G, which can be defined from a structural and functional point-of-view. A co-relation is gradually emerging between mutations in these motifs and viral genome evolution or observed mutation rates. Here, we review our current knowledge on these motifs and their role on the structural and mechanistic basis of the fidelity of nucleotide selection and RNA synthesis by Flavivirus RdRps. PMID- 29385766 TI - Benzodiazepines II: Waking Up on Sedatives: Providing Optimal Care When Inheriting Benzodiazepine Prescriptions in Transfer Patients. AB - This review discusses risks, benefits, and alternatives in patients already taking benzodiazepines when care transfers to a new clinician. Prescribers have the decision-sometimes mutually agreed-upon and sometimes unilateral-to continue, discontinue, or change treatment. This decision should be made based on evidence based indications (conditions and timeframes), comorbidities, potential drug-drug interactions, and evidence of adverse effects, misuse, abuse, dependence, or diversion. We discuss management tools involved in continuation (e.g., monitoring symptoms, laboratory testing, prescribing contracts, state prescription databases, stages of change) and discontinuation (e.g., tapering, psychotherapeutic interventions, education, handouts, reassurance, medications to assist with discontinuation, and alternative treatments). PMID- 29385765 TI - Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine. AB - Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine. PMID- 29385768 TI - Evaluation of Colorectal Cancer Incidence Trends in the United States (2000 2014). AB - Colorectal cancer (CRC) incidence rates have declined in recent years for people of all races/ethnicities; however, the extent to which the decrease varies annually by demographic and disease-related characteristics is largely unknown. This study examines trends and annual percent change (APC) in the incidence among persons diagnosed with CRC in the United States of America from 2000-2014. The data obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program were analyzed, and all persons (N = 577,708) with malignant CRC recorded in the SEER 18 database from 2000 to 2014 were characterized according to sex, race, age at diagnosis, disease site and stage. Incidence rates and APC were calculated for the entire study period. Overall, the incidence rate of CRC decreased from 54.5 in 2000 to 38.6 per 100,000 in 2014, with APC = -2.66 (p < 0.0001). Decline in rates was most profound between 2008 and 2011 from 46.0 to 40.7 per 100,000 (APC = -4.04; p < 0.0001). Rates were higher for males (vs. females; rate ratio (RR) = 1.33) and for blacks (vs. whites; RR = 1.23). Proximal colon cancers at the localized stage were the predominant cancers. An increase in rate was observed among people younger than 50 years (6.6 per 100,000, APC= 1.5). The annual rate of CRC has decreased over time. However, the development and implementation of interventions that further reduce the disparities among demographic and disease-related subgroups are warranted. PMID- 29385767 TI - Moonlighting with WDR5: A Cellular Multitasker. AB - WDR5 is a highly conserved WD40 repeat-containing protein that is essential for proper regulation of multiple cellular processes. WDR5 is best characterized as a core scaffolding component of histone methyltransferase complexes, but emerging evidence demonstrates that it does much more, ranging from expanded functions in the nucleus through to controlling the integrity of cell division. The purpose of this review is to describe the current molecular understandings of WDR5, discuss how it participates in diverse cellular processes, and highlight drug discovery efforts around WDR5 that may form the basis of new anti-cancer therapies. PMID- 29385769 TI - The GReat-ChildTM Trial: A Quasi-Experimental Intervention on Whole Grains with Healthy Balanced Diet to Manage Childhood Obesity in Kuala Lumpur, Malaysia. AB - Background: The GReat-Child Trial was a quasi-experimental intervention that has emphasized whole grain as a strategy to manage childhood obesity. Methods: Two schools in Kuala Lumpur with similar demographic characteristics were assigned as intervention (IG) and control (CG). Eligibility criteria were overweight/obese children aged 9 to 11 years who had no serious co-morbidity. Children who reported consuming wholegrain foods in their 3-day diet-recall during screening were excluded. A total of 63 children (31 IG; 32 CG) completed the entire intervention program. The IG children underwent six 30-min nutrition education lessons and had school delivery of wholegrain food on a daily basis over a 12 week period. Parents of IG children attended 1-h individual diet counseling. Anthropometric outcomes including BMI-for-age z-score (BAZ), body fat percentage and waist circumference were measured at baseline [T0], post-intervention [T1] (3rd month) and follow-up [T2] (9th month). Results: IG showed significantly lower BAZ (weighted difference: -0.12; 95% CI: -0.21, -0.03; p = 0.009), body fat percentage (weighted difference: -2.6%; 95% CI: -3.7, -1.5; p < 0.001) and waist circumference (weighted difference: -2.4 cm; 95% CI: -3.8, -1.0; p = 0.001) compared to CG. IG reported significantly lower body fat percentage (weighted difference: -3.4%; 95% CI: 1.8, 5.0; p < 0.001) and waist circumference (weighted difference: -2.1 cm; 95% CI: -3.7, -0.5; p = 0.014) at T1 compared to T0. Conclusions: The GReat-Child Trial made a positive impact in managing childhood obesity. It can be incorporated into childhood obesity intervention programs that are being implemented by the policy makers. PMID- 29385771 TI - Factors Associated with Pregnancy among Married Adolescents in Nepal: Secondary Analysis of the National Demographic and Health Surveys from 2001 to 2011. AB - Pregnancy-related morbidity and mortality are much more prevalent among adolescents than adults, particularly in low-income settings. Little is known about risk factors for pregnancy among adolescents in Nepal, but setting-specific evidence is needed to inform interventions. This study aimed to describe the prevalence, and identify factors associated with pregnancy among adolescents in Nepal between 2001 and 2011. Secondary analyses of Nepal Demographic Health Surveys (NDHS) data from 2001, 2006, and 2011 were completed. The outcome was any pregnancy or birth among married adolescents; prevalence was calculated for each survey year. Although the rate of marriage among adolescent women in Nepal decreased significantly from 2001 to 2011, prevalence of pregnancy and birth among married adolescent women in Nepal remains high (average 56%) in Nepal, and increased significantly between 2001 and 2011. Regression analyses of this outcome indicate higher risk was associated with living in the least resourced region, early sexual debut, and older husband. Despite national efforts to reduce pregnancies among married adolescent women in Nepal, prevalence remains high. Integrated, cross-sectoral prevention efforts are required. Poverty reduction and infrastructure improvements may lead to lower rates of adolescent pregnancy. PMID- 29385770 TI - The Effect of the eHealth Intervention 'MyPlan 1.0' on Physical Activity in Adults Who Visit General Practice: A Quasi-Experimental Trial. AB - Physical inactivity is one of the major risk factors for poor health in the world. Therefore, effective interventions that promote physical activity are needed. Hence, we developed an eHealth intervention for adults, i.e., 'MyPlan 1.0', which includes self-regulation techniques for behaviour change. This study examined the effect of 'MyPlan 1.0' on physical activity (PA) levels in general practice. 615 adults (>=18 years) were recruited in 19 Flemish general practices, for the intervention group (n = 328) or for the wait-list control group (n = 183). Participants in the intervention group received the web-based intervention 'MyPlan 1.0' and were prompted to discuss their personal advice/action plan with their general practitioner. Participants in the wait-list control group only received general advice from the website. Self-reported physical activity was assessed with the International Physical Activity Questionnaire (IPAQ) at baseline and after one month. A three-level (general practice, adults, time) regression analysis was conducted in MLwiN. Significant intervention effects were found for total PA and moderate to vigorous PA with an increase for the intervention group compared to a decrease in the control condition. However, there was a high dropout rate in the intervention group (76%) and the wait-list control group (57%). Our self-regulation intervention was effective in increasing physical activity levels in adults. Future studies should consider strategies to prevent the large dropout from participants. PMID- 29385772 TI - Ventilation Positive Pressure Intervention Effect on Indoor Air Quality in a School Building with Moisture Problems. AB - This case study investigates the effects of ventilation intervention on measured and perceived indoor air quality (IAQ) in a repaired school where occupants reported IAQ problems. Occupants' symptoms were suspected to be related to the impurities leaked indoors through the building envelope. The study's aim was to determine whether a positive pressure of 5-7 Pa prevents the infiltration of harmful chemical and microbiological agents from structures, thus decreasing symptoms and discomfort. Ventilation intervention was conducted in a building section comprising 12 classrooms and was completed with IAQ measurements and occupants' questionnaires. After intervention, the concentration of total volatile organic compounds (TVOC) and fine particulate matter (PM2.5) decreased, and occupants' negative perceptions became more moderate compared to those for other parts of the building. The indoor mycobiota differed in species composition from the outdoor mycobiota, and changed remarkably with the intervention, indicating that some species may have emanated from an indoor source before the intervention. PMID- 29385773 TI - Association between Social Activities and Cognitive Function among the Elderly in China: A Cross-Sectional Study. AB - Participation in social activities is one of important factors for older adults' health. The present study aims to examine the cross-sectional association between social activities and cognitive function among Chinese elderly. A total of 8966 individuals aged 60 and older from the 2015 China Health and Retirement Longitudinal Study were obtained for this study. Telephone interviews of cognitive status, episodic memory, and visuospatial abilities were assessed by questionnaire. We used the sum of all three of the above measures to represent the respondent's cognitive status as a whole. Types and frequencies of participation in social groups were used to measure social activities. Multiple linear regression analysis was used to explore the relationship between social activities and cognitive function. After adjustment for demographics, smoking, drinking, depression, hypertension, diabetes, basic activities of daily living, instrumental activities of daily living, and self-rated health, multiple linear regression analysis revealed that interaction with friends, participating in hobby groups, and sports groups were associated with better cognitive function among both men and women (p < 0.05); doing volunteer work was associated with better cognitive function among women but not among men (p < 0.05). These findings suggest that there is a cross-sectional association between participation in social activities and cognitive function among Chinese elderly. Longitudinal studies are needed to examine the effects of social activities on cognitive function. PMID- 29385774 TI - An Advanced Bio-Inspired PhotoPlethysmoGraphy (PPG) and ECG Pattern Recognition System for Medical Assessment. AB - Physiological signals are widely used to perform medical assessment for monitoring an extensive range of pathologies, usually related to cardio-vascular diseases. Among these, both PhotoPlethysmoGraphy (PPG) and Electrocardiography (ECG) signals are those more employed. PPG signals are an emerging non-invasive measurement technique used to study blood volume pulsations through the detection and analysis of the back-scattered optical radiation coming from the skin. ECG is the process of recording the electrical activity of the heart over a period of time using electrodes placed on the skin. In the present paper we propose a physiological ECG/PPG "combo" pipeline using an innovative bio-inspired nonlinear system based on a reaction-diffusion mathematical model, implemented by means of the Cellular Neural Network (CNN) methodology, to filter PPG signal by assigning a recognition score to the waveforms in the time series. The resulting "clean" PPG signal exempts from distortion and artifacts is used to validate for diagnostic purpose an EGC signal simultaneously detected for a same patient. The multisite combo PPG-ECG system proposed in this work overpasses the limitations of the state of the art in this field providing a reliable system for assessing the above-mentioned physiological parameters and their monitoring over time for robust medical assessment. The proposed system has been validated and the results confirmed the robustness of the proposed approach. PMID- 29385776 TI - Determining Exposure Factors of Anti-Fogging, Dye, Disinfectant, Repellent, and Preservative Products in Korea. AB - Reliable exposure factors are essential to determine health risks posed by chemicals in consumer products. We analyzed five risk-concerned product categories (anti-fogging, dye, disinfectant, repellent, and preservative products) for 13 products (three car anti-fogging products, a lens anti-fogging product, two car dye products, two drain disinfectants, an air conditioner disinfectant, a chlorine-based disinfectant, a fabric repellent, an insect repellent for food, and a wood preservative) considered to be of high risk in order to determine exposure factors via web surveys and estimation of amount of product. Among the 3000 participants (1482 (49%) men) aged >=19 years, drain disinfectants were used most frequently (38.2%); the rate of usage of the other products ranged between 1.1-24.0%. The usage rates for the consumer products differed by sex, age, income, and education. Some consumer products such as car and lens anti-fogging products, chlorine-based disinfectants, fabric repellents, and drain disinfectants were regularly used more than once a month, while car dye products, air conditioner disinfectants, insect repellents for food, and wood preservatives were not regularly used owing to the specific product purposes and seasonal needs. Our results could be used for managing or controlling chemical substances in consumer products and conducting accurate exposure assessments. PMID- 29385775 TI - Substrate Recognition and Specificity of Chitin Deacetylases and Related Family 4 Carbohydrate Esterases. AB - Carbohydrate esterases family 4 (CE4 enzymes) includes chitin and peptidoglycan deacetylases, acetylxylan esterases, and poly-N-acetylglucosamine deacetylases that act on structural polysaccharides, altering their physicochemical properties, and participating in diverse biological functions. Chitin and peptidoglycan deacetylases are not only involved in cell wall morphogenesis and remodeling in fungi and bacteria, but they are also used by pathogenic microorganisms to evade host defense mechanisms. Likewise, biofilm formation in bacteria requires partial deacetylation of extracellular polysaccharides mediated by poly-N-acetylglucosamine deacetylases. Such biological functions make these enzymes attractive targets for drug design against pathogenic fungi and bacteria. On the other side, acetylxylan esterases deacetylate plant cell wall complex xylans to make them accessible to hydrolases, making them attractive biocatalysts for biomass utilization. CE4 family members are metal-dependent hydrolases. They are highly specific for their particular substrates, and show diverse modes of action, exhibiting either processive, multiple attack, or patterned deacetylation mechanisms. However, the determinants of substrate specificity remain poorly understood. Here, we review the current knowledge on the structure, activity, and specificity of CE4 enzymes, focusing on chitin deacetylases and related enzymes active on N-acetylglucosamine-containing oligo and polysaccharides. PMID- 29385777 TI - Robotic-Assisted Percutaneous Coronary Intervention: Rationale, Implementation, Case Selection and Limitations of Current Technology. AB - Interventional cardiologists have witnessed an explosive growth in the field. A wide array of percutaneous procedures allow us to treat numerous cardiac conditions less invasively. However, the way we work has changed very little over the past decades. We continue to stand at the tableside for prolonged periods of time, exposing ourselves to the very real risks of radiation exposure as well as to the associated orthopedic injuries from radiation protection. The precision of our procedures is limited by the distance from the fluoroscopic images and, furthermore, patients are potentially at risk from operator fatigue caused by a physician standing at the table for prolonged periods while wearing cumbersome radiation protection gear. Robotic-assisted coronary intervention removes the operator from the radiation field and has been shown to markedly reduce operator exposure as well as allow for more precise positioning of balloons and stents. This technology holds great promise for making interventional procedures safer and more comfortable for the operators as well as reducing fatigue, potentially improving patient outcomes. Currently, we are in an 'early adopter' phase of this technology and this paper reviews the rationale, methodology, optimal case selection, and limitations of robotic-assisted coronary intervention. PMID- 29385778 TI - Patient Satisfaction with Pre-Hospital Emergency Services. A Qualitative Study Comparing Professionals' and Patients' Views. AB - Objective: To describe patient satisfaction with pre-hospital emergency knowledge and determine if patients and professionals share a common vision on the satisfaction predictors. Methods: A qualitative study was conducted in two phases. First, a systematic review following the PRISMA protocol was carried out searching publications between January 2000 and July 2016 in Medline, Scopus, and Cochrane. Second, three focus groups involving professionals (advisers and healthcare providers) and a total of 79 semi-structured interviews involving patients were conducted to obtain information about what dimensions of care were a priority for patients. Results: Thirty-three relevant studies were identified, with a majority conducted in Europe using questionnaires. They pointed out a very high level of satisfaction of callers and patients. Delay with the assistance and the ability for resolution of the case are the elements that overlap in fostering satisfaction. The published studies reviewed with satisfaction neither the overall care process nor related the measurement of the real time in responding to an emergency. The patients and professionals concurred in their assessments about the most relevant elements for patient satisfaction, although safety was not a predictive factor for patients. Response capacity and perceived capacity for resolving the situation were crucial factors for satisfaction. Conclusions: Published studies have assessed similar dimensions of satisfaction and have shown high patient satisfaction. Expanded services resolving a wide number of issues that can concern citizens are also positively assessed. Delays and resolution capacity are crucial for satisfaction. Furthermore, despite the fact that few explanations may be given due to a lack of face-to-face attention, finding the patient's location, taking into account the caller's emotional needs, and maintaining phone contact until the emergency services arrive are high predictors of satisfaction. PMID- 29385779 TI - Effectiveness of a Lifestyle Intervention on Social Support, Self-Efficacy, and Physical Activity among Older Adults: Evaluation of Texercise Select. AB - Despite the well-recognized benefits of physical activity across the life course, older adults are more inactive than other age groups. The current study examines the effects of Texercise Select participation on self-reported sedentary, light, moderate, and vigorous physical activity. Secondarily, this study examined intervention effects on two potential facilitators of physical activity: (1) self efficacy for being more physically active and (2) social support received for physical activity. This study used a non-equivalent group design with self reported surveys administered at baseline, three-month (immediate post for cases) and six-month follow-ups for the intervention (n = 163) and a comparison group (n = 267). Multivariable mixed model analyses were conducted controlling for age, sex, race, ethnicity, education, comorbid conditions, and site. Among the intervention group, the program had significant immediate effects on most primary outcomes (p < 0.05) at three months. Furthermore, significant improvements were observed for all physical activity intensity levels at six months (p < 0.05). The reduction in sedentary behavior and increases in all physical activity intensity levels were significantly greater from baseline to three-month and baseline to six-month follow-ups among intervention group participants relative to those in the comparison group. This study confirms the effectiveness of Texercise Select to reduce sedentary behavior and improve physicality, supporting the intervention's robustness as a scalable and sustainable evidence-based program. It also counters negative stereotypes that older adults are not interested in attending multi-modal lifestyle intervention programs nor able to make health behavior changes that can improve health and overall functioning. PMID- 29385781 TI - The External Performance Appraisal of China Energy Regulation: An Empirical Study Using a TOPSIS Method Based on Entropy Weight and Mahalanobis Distance. AB - In China's industrialization process, the effective regulation of energy and environment can promote the positive externality of energy consumption while reducing negative externality, which is an important means for realizing the sustainable development of an economic society. The study puts forward an improved technique for order preference by similarity to an ideal solution based on entropy weight and Mahalanobis distance (briefly referred as E-M-TOPSIS). The performance of the approach was verified to be satisfactory. By separately using traditional and improved TOPSIS methods, the study carried out the empirical appraisals on the external performance of China's energy regulation during 1999~2015. The results show that the correlation between the performance indexes causes the significant difference between the appraisal results of E-M-TOPSIS and traditional TOPSIS. The E-M-TOPSIS takes the correlation between indexes into account and generally softens the closeness degree compared with traditional TOPSIS. Moreover, it makes the relative closeness degree fluctuate within a small amplitude. The results conform to the practical condition of China's energy regulation and therefore the E-M-TOPSIS is favorably applicable for the external performance appraisal of energy regulation. Additionally, the external economic performance and social responsibility performance (including environmental and energy safety performances) based on the E-M-TOPSIS exhibit significantly different fluctuation trends. The external economic performance dramatically fluctuates with a larger fluctuation amplitude, while the social responsibility performance exhibits a relatively stable interval fluctuation. This indicates that compared to the social responsibility performance, the fluctuation of external economic performance is more sensitive to energy regulation. PMID- 29385780 TI - Patterns of Signs That Telephone Crisis Support Workers Associate with Suicide Risk in Telephone Crisis Line Callers. AB - Signs of suicide are commonly used in suicide intervention training to assist the identification of those at imminent risk for suicide. Signs of suicide may be particularly important to telephone crisis-line workers (TCWs), who have little background information to identify the presence of suicidality if the caller is unable or unwilling to express suicidal intent. Although signs of suicide are argued to be only meaningful as a pattern, there is a paucity of research that has examined whether TCWs use patterns of signs to decide whether a caller might be suicidal, and whether these are influenced by caller characteristics such as gender. The current study explored both possibilities. Data were collected using an online self-report survey in a Australian sample of 137 TCWs. Exploratory factor analysis uncovered three patterns of suicide signs that TCWs may use to identify if a caller might be at risk for suicide (mood, hopelessness, and anger), which were qualitatively different for male and female callers. These findings suggest that TCWs may recognise specific patterns of signs to identify suicide risk, which appear to be influenced to some extent by the callers' inferred gender. Implications for the training of telephone crisis workers and others including mental-health and medical professionals, as well as and future research in suicide prevention are discussed. PMID- 29385782 TI - Animal Model of Interstitial Cystitis/Bladder Pain Syndrome. PMID- 29385783 TI - The Therapeutic Effect of Human Embryonic Stem Cell-Derived Multipotent Mesenchymal Stem Cells on Chemical-Induced Cystitis in Rats. AB - PURPOSE: To evaluate the therapeutic effect of human embryonic stem cell (hESC) derived multipotent mesenchymal stem cells (M-MSCs) on ketamine-induced cystitis (KC) in rats. METHODS: To induce KC, 10-week-old female rats were injected with 25-mg/kg ketamine hydrochloride twice weekly for 12 weeks. In the sham group, phosphate buffered saline (PBS) was injected instead of ketamine. One week after the final injection of ketamine, the indicated doses (0.25, 0.5, and 1*106 cells) of M-MSCs (KC+M-MSC group) or PBS vehicle (KC group) were directly injected into the bladder wall. One week after M-MSC injection, the therapeutic outcomes were evaluated via cystometry, histological analyses, and measurement of gene expression. Next, we compared the efficacy of M-MSCs at a low dose (1*105 cells) to that of an identical dose of adult bone marrow (BM)-derived MSCs. RESULTS: Rats in the KC group exhibited increased voiding frequency and reduced bladder capacity compared to rats of the sham group. However, these parameters recovered after transplantation of M-MSCs at all doses tested. KC bladders exhibited markedly increased mast cell infiltration, apoptosis, and tissue fibrosis. Administration of M-MSCs significantly reversed these characteristic histological alterations. Gene expression analyses indicated that several genes associated with tissue fibrosis were markedly upregulated in KC bladders. However the expression of these genes was significantly suppressed by the administration of M MSCs. Importantly, M-MSCs ameliorated bladder deterioration in KC rats after injection of a low dose (1*105) of cells, at which point BM-derived MSCs did not substantially improve bladder function. CONCLUSIONS: This study demonstrates for the first time the therapeutic efficacy of hESC-derived M-MSCs on KC in rats. M MSCs restored bladder function more effectively than did BM-derived MSCs, protecting against abnormal changes including mast cell infiltration, apoptosis and fibrotic damage. PMID- 29385785 TI - Urothelial Dysfunction and Chronic Inflammation are Associated With Increased Bladder Sensation in Patients With Chronic Renal Insufficiency. AB - PURPOSE: Chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients usually have lower urinary tract symptoms, such as frequency and urgency. Additionally, they frequently suffer from urinary tract infections. This study investigated dysfunction and chronic inflammation of the bladder urothelium in ESRD/CKD patients. METHODS: This study enrolled 27 patients with CKD (n=13) or ESRD (n=14) for urodynamic studies and bladder biopsies. Patients presented with detrusor underactivity (DU; n=8) or bladder oversensitivity (BO; n=19). Bladder biopsies were performed in these patients and in 20 controls. The bladder mucosa was examined for E-cadherin and zonula occludens-1 (ZO-1) expression, activated mast cell count (through tryptase staining), and urothelial apoptosis (through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling [TUNEL]). The urodynamic parameters were also compared with variables regarding urothelial dysfunction. RESULTS: The bladder mucosa samples of ESRD and CKD patients revealed significantly higher mast cell counts, more urothelial apoptosis, and lower levels of ZO-1 expression than the control samples. E cadherin expression was significantly reduced in ESRD/CKD patients with DU, but not in ESRD/CKD patients with BO. Increased mast cell and apoptotic cell counts were also associated with ESRD/CKD with BO. Less expression of ZO-1 and E cadherin was significantly associated with increased bladder sensation and a small bladder capacity. CONCLUSIONS: Bladder urothelial dysfunction and chronic inflammation were present to a noteworthy extent in patients with ESRD or CKD. Increased inflammation and defective barrier function were more notable in ESRD/CKD bladders with BO than in those with DU. The clinical characteristics of these patients may involve urothelial pathophysiology. PMID- 29385784 TI - Laparoscopic Approach for Intravesical Surgery Using Pneumovesicum in Urology: Literature Review. AB - Minimally invasive laparoscopic surgical procedures are increasingly being used in the management of various urological diseases. In particular, the laparoscopic approach for intravesical surgery using pneumovesicum (LPV) is a minimally invasive alternative with potential advantages including decreased morbidity, shorter hospital stays, and improved cosmesis. We review the applications of LPV in urology, summarize data for different surgical approaches, and provide an overview of patient management, as well as other considerations. This narrative review focused primarily on articles indexed in PubMed, Google Scholar, Scopus, and Embase databases. No formal search strategy was used, and no meta-analysis of data was performed. PMID- 29385786 TI - Expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and the GDNF Family Receptor Alpha Subunit 1 in the Paravaginal Ganglia of Nulliparous and Primiparous Rabbits. AB - PURPOSE: To evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) and its receptor, GDNF family receptor alpha subunit 1 (GFRalpha-1) in the pelvic (middle third) vagina and, particularly, in the paravaginal ganglia of nulliparous and primiparous rabbits. METHODS: Chinchilla-breed female rabbits were used. Primiparas were killed on postpartum day 3 and nulliparas upon reaching a similar age. The vaginal tracts were processed for histological analyses or frozen for Western blot assays. We measured the ganglionic area, the Abercrombie-corrected number of paravaginal neurons, the cross-sectional area of the neuronal somata, and the number of satellite glial cells (SGCs) per neuron. The relative expression of both GDNF and GFRalpha-1 were assessed by Western blotting, and the immunostaining was semiquantitated. Unpaired two-tailed Student t -test or Wilcoxon test was used to identify statistically significant differences (P<=0.05) between the groups. RESULTS: Our findings demonstrated that the ganglionic area, neuronal soma size, Abercrombie-corrected number of neurons, and number of SGCs per neuron were similar in nulliparas and primiparas. The relative expression of both GDNF and GFRalpha-1 was similar. Immunostaining for both GDNF and GFRalpha-1 was observed in several vaginal layers, and no differences were detected regarding GDNF and GFRalpha-1 immunostaining between the 2 groups. In the paravaginal ganglia, the expression of GDNF was increased in neurons, while that of GFRalpha-1 was augmented in the SGCs of primiparous rabbits. CONCLUSIONS: The present findings suggest an ongoing regenerative process related to the recovery of neuronal soma size in the paravaginal ganglia, in which GDNF and GFRalpha-1 could be involved in cross-talk between neurons and SGCs. PMID- 29385787 TI - Differences in Urodynamic Parameters According to the Presence of a Hunner Lesion in Women With Interstitial Cystitis/Bladder Pain Syndrome. AB - PURPOSE: Differences in the severity of subjective symptoms have been noted depending on whether a Hunner lesion is present in women with interstitial cystitis/bladder pain syndrome (IC/BPS). In this study, we aimed to identify differences in objective urodynamic parameters in women with IC/BPS according to the presence of a Hunner lesion. METHODS: This cross-sectional study included a total of 55 patients with IC/BPS. IC/BPS and the presence of a Hunner lesion on cystoscopy were diagnosed according to American Urological Association guidelines. The patients were categorized into a Hunner IC/BPS group and a non Hunner IC/BPS group according to the presence of a Hunner lesion on cystoscopy. At the initial visit, a medical history was taken from all patients with IC/BPS, and they underwent symptom assessment using a 3-day voiding diary and laboratory tests. A urodynamic study was then performed before any treatment was performed. Baseline characteristics and urodynamic parameters were compared between the 2 groups. RESULTS: Of the 55 patients, 23 (41.8%) had a Hunner lesion on cystoscopy. As documented in the voiding diaries, the Hunner IC/BPS group had more frequent voids and a smaller maximal voided volume (P=0.045, P<0.001, respectively). Regarding urodynamic parameters, the mean volume at the first desire to void, normal desire to void, strong desire to void (SDV), and maximum cystometric bladder capacity (MBC) was significantly lower in the Hunner IC/BPS group (P=0.001, P=0.004, P<0.001, and P<0.001, respectively). On receiver operating characteristic curve analysis, patients with an SDV<=210 mL (area under the curve [AUC]=0.838, P<0.001) and an MBC<=234 mL (AUC=0.857, P<0.001) were likely to be in the Hunner IC/BPS group. CONCLUSIONS: The differences in patients' subjective symptoms between the Hunner IC/BPS and non-Hunner IC/BPS groups were confirmed to correspond to differences in objective urodynamic parameters. PMID- 29385788 TI - Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome. AB - The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains elusive and may involve multiple causes. To better understand its pathophysiology, many efforts have been made to create IC/BPS models. Most existing models of IC/BPS strive to recreate bladder-related features by applying noxious intravesical or systemic stimuli to healthy animals. These models are useful to help understand various mechanisms; however, they are limited to demonstrating how the bladder and nervous system respond to noxious stimuli, and are not representative of the complex interactions and pathophysiology of IC/BPS. To study the various factors that may be relevant for IC/BPS, at least 3 different types of animal models are commonly used: (1) bladder-centric models, (2) models with complex mechanisms, and (3) psychological and physical stressors/natural disease models. It is obvious that all aspects of the human disease cannot be mimicked by a single model. It may be the case that several models, each contributing to a piece of the puzzle, are required to recreate a reasonable picture of the pathophysiology and time course of the disease(s) diagnosed as IC/BPS, and thus to identify reasonable targets for treatment. PMID- 29385789 TI - Overview of the Minireviews on Autophagy. PMID- 29385790 TI - Recurrent varices after surgery: a clinical and color-Doppler ultrasound scan analysis. AB - BACKGROUND: To evaluate clinical pictures, symptoms and etiology of recurrent varices after surgery (REVAS) through a clinical and color-Doppler-ultrasound scan (CDUS) analysis. METHODS: During a three-year period, data about 9043 consecutive outpatients were collected. Among these, 160 patients (1.8%) were affected by REVAS. Data about risk factors, types of primary vein surgery, symptoms, clinical and CDUS characteristics were analyzed using the Clinical, Etiology, Anatomy and Pathophysiology (CEAP), Stonebridge and Perrin classifications in order to evaluate clinical and anatomical varices patterns. RESULTS: Family history for chronic venous disease (90%), sedentary lifestyle (61.9%) and obesity (11.9%) were the most representative risk factors. REVAS symptoms were rather heterogeneous, although only 10% of cases was fully asymptomatic. CEAP classification showed a prevalence of C2 and C3 class (56.3% and 35% respectively). About half of inguinal REVAS was connected from a great saphenous vein residual stump (Stonebridge type 1). Lower limb perforating veins resulted associated to REVAS in 43.8% of cases. CONCLUSIONS: REVAS remain a major and still unsolved problem in patients following varicose veins surgery. Their clinical pictures and symptoms are heterogeneous and require a watchful analysis in order to identify both etiology and natural history. PMID- 29385791 TI - The influence of patients' nutritional status on the prevalence, course and treatment outcomes of lower limb ischemia: an overview of current evidence. AB - INTRODUCTION: The association of lower limb ischemia (LLI) with disturbances in nutritional status, in respect to over- or undernutrition, is still uncertain. The aim of this study was to present the current state of knowledge on this issue. EVIDENCE ACQUISITION: Systematic review of papers published between 2006 and 2018. EVIDENCE SYNTHESIS: The literature shows inconclusive evidence regarding the impact of nutritional status on the risk, course, prognosis and outcomes of conservative and invasive treatment of LLI. The majority of publications available demonstrate greater LLI prevalence in overweight and obese patients, a worse prognosis both in malnourished and severely obese patients, poorer outcomes of invasive treatment in underweight patients, and better results for endovascular and surgical treatment in patients with overweight and class I obesity, although without such a relationship for conservative therapy. Possible explanations linking nutritional status and LLI seem to be: the endocrine, paracrine, and autocrine activity of adipose tissue, a decrease in physical activity, and the effect of diet-dependent comorbidities, e.g. diabetes mellitus, hypertension and dyslipidemia. CONCLUSIONS: There is a growing body of evidence concerning an association between LLI and patients' nutritional status. A so called "obesity paradox" or "BMI paradox" seems to exist among patients with LLI and mainly concerns outcomes of endovascular and surgical treatment. However, further studies are needed to evaluate the clinical importance of body composition, the distribution and endocrine activity of adipose tissue, and the effect of weight reduction and/or nutritional support in the LLI patient group. PMID- 29385792 TI - Efficacy of micronized purified flavonoid fraction (Daflon(r)) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo controlled trials. AB - INTRODUCTION: The use of a venoactive drug is considered an important component of medical treatment of chronic venous disease (CVD), although the efficacy of certain venoactive drugs (VADs) on one or more individual leg symptoms or signs may have not been extensively studied to justify a strong recommendation in guidelines on CVD. The aim of this systematic review and meta-analysis was to study the effectiveness of the micronized purified flavonoid fraction (MPFF, Daflon(r)) across the spectrum of defined venous symptoms, signs, quality of life (QoL) and treatment assessment by the physician. EVIDENCE ACQUISITION: On September 9, 2017, a systematic review of the databases MEDLINE, Scopus and Cochrane Central was performed, supplemented by hand searching, to identify randomized double-blind placebo-controlled trials on MPFF in patients with CVD. EVIDENCE SYNTHESIS: The main outcome measures were the individual and global symptoms, leg edema and redness, skin changes, QoL and evaluation of the overall effectiveness of the treatment by the physician. The effectiveness of MPFF compared with placebo was expressed as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI). Trial quality of evidence was graded using the GRADE system. RESULTS: We identified 7 trials, mostly with low risk of bias, involving 1,692 patients. On qualitative analysis, MPFF significantly improved nine defined leg symptoms, including pain, heaviness, feeling of swelling, cramps, paresthesia, burning sensation, and pruritus (itching), but also functional discomfort compared with placebo, leg redness, skin changes and QoL. On quantitative analysis, MPFF compared with placebo, assessed as a categorical variable, reduced leg pain (RR 0.53, P=0.0001, NNT=4.2), heaviness (RR 0.35, P<0.00001, NNT=2.0), feeling of swelling (RR 0.39, P<0.00001, NNT=3.1), cramps (RR 0.51, P=0.02, NNT=4.8), paresthesia (RR 0.45, P=0.03, NNT=3.5), and functional discomfort (RR 0.41, P=0.0004, NNT=3.0). Similarly, MPFF compared with placebo, assessed as a continuous variable reduced pain (SMD -0.25, 95% CI -0.38 to -0.11), heaviness (SMD -0.80, 95% CI -1.05 to 0.54), feeling of swelling (SMD -0.99, 95% CI -1.25 to -0.73), burning sensation (SMD -0.46, 95% CI -0.78 to -0.14), cramps (SMD -0.46, 95% CI -0.78 to -0.14), and functional discomfort (SMD -0.87, 95% CI -1.13 to -0.61). Regarding objective assessments of leg edema, the use of MPFF compared with placebo reduced ankle circumference (SMD -0.59, 95% CI -1.15 to -0.02), and leg redness (SMD -0.32, 95% CI -0.56 to -0.07, RR 0.50, P=0.03, NNT=3.6), improved skin changes (RR 0.18, P=0.0003, NNT=1.6) and quality of life (SMD -0.21, 95% CI -0.37 to -0.04) and was associated with clinical improvement as assessed by the physician (RR 0.28, P<0.00001, NNT=2.5). Heterogeneity was mostly minimal. The existing evidence where sufficient was mostly of high quality. CONCLUSIONS: Based on high quality evidence, MPFF is highly effective in improving leg symptoms, edema and quality of life in patients with CVD. PMID- 29385793 TI - Effect of Binding Components in Complex Sample Matrices on Recovery in Direct Immersion Solid-Phase Microextraction: Friends or Foe? AB - The development of matrix compatible coatings for solid-phase microextraction (SPME) has enabled direct extraction of analytes from complex sample matrices. The direct immersion (DI) mode of SPME when utilized in conjunction with such extraction phases facilitates extraction of a wide range of analytes from complex matrices without the incurrence of fouling or coating saturation. In this work, mathematical models and computational simulations were employed to investigate the effect of binding components present in complex samples on the recovery of small molecules varying in logP for extractions carried out using the direct immersion approach. The presented findings corroborate that the studied approach indeed enables the extraction of both polar and nonpolar analytes from complex matrices, provided a suitable sorbent is employed. Further results indicated that, in certain cases, the kinetics of extraction of a given analyte in its free form might be dependent on the desorption kinetics of their bound form from matrix components, which might lower total recoveries of analytes with high affinity for the matrix. However, the binding of analytes to matrix components also enables SPME to extract a balanced quantity of different logP analytes, facilitated by multiphase equilibria, with a single extraction device. PMID- 29385794 TI - CuO Nanoparticle Dissolution and Toxicity to Wheat ( Triticum aestivum) in Rhizosphere Soil. AB - It has been suggested, but not previously measured, that dissolution kinetics of soluble nanoparticles such as CuO nanoparticles (NPs) in soil affect their phytotoxicity. An added complexity is that such dissolution is also affected by the presence of plant roots. Here, we measured the rate of dissolution of CuO NPs in bulk soil, and in soil in which wheat plants ( Triticum aestivum) were grown under two soil NP dosing conditions: (a) freshly added CuO NPs (500 mg Cu/kg soil) and (b) CuO NPs aged for 28 d before planting. At the end of the plant growth period (14 d), available Cu was measured in three different soil compartments: bulk (not associated with roots), loosely attached to roots, and rhizosphere (soil firmly attached to roots). The labile Cu fraction increased from 17 mg/kg to 223 mg/kg in fresh treatments and from 283 mg/kg to 305 mg/kg in aged treatments over the growth period due to dissolution. Aging CuO NPs increased the toxicity to Triticum aestivum (reduction in root maximal length). The presence of roots in the soil had opposite and somewhat compensatory effects on NP dissolution, as measured in rhizosphere soil. pH increased 0.4 pH units for fresh NP treatments and 0.6 pH units for aged NPs. This lowered CuO NP dissolution in rhizosphere soil. Exudates from T. aestivum roots also increased soluble Cu in pore water. CaCl2 extractable Cu concentrations increaed in rhizosphere soil compared to bulk soil, from 1.8 mg/kg to 6.2 mg/kg in fresh treatment and from 3.4 mg/kg to 5.4 mg/kg in aged treatments. Our study correlated CuO NP dissolution and the resulting Cu ion exposure profile to phytotoxicity, and showed that plant-induced changes in rhizosphere conditions should be considered when measuring the dissolution of CuO NPs near roots. PMID- 29385796 TI - Influence of Solvent on the Drug-Loading Process of Amphiphilic Nanogel Star Polymers. AB - We present an all-atom molecular dynamics study of the effect of a range of organic solvents (dichloromethane, diethyl ether, toluene, methanol, dimethyl sulfoxide, and tetrahydrofuran) on the conformations of a nanogel star polymeric nanoparticle with solvophobic and solvophilic structural elements. These nanoparticles are of particular interest for drug delivery applications. As drug loading generally takes place in an organic solvent, this work serves to provide insight into the factors controlling the early steps of that process. Our work suggests that nanoparticle conformational structure is highly sensitive to the choice of solvent, providing avenues for further study as well as predictions for both computational and experimental explorations of the drug-loading process. Our findings suggest that when used in the drug-loading process, dichloromethane, tetrahydrofuran, and toluene allow for a more extensive and increased drug loading into the interior of nanogel star polymers of the composition studied here. In contrast, methanol is more likely to support shallow or surface loading and, consequently, faster drug release rates. Finally, diethyl ether should not work in a formulation process since none of the regions of the nanogel star polymer appear to be sufficiently solvated by it. PMID- 29385795 TI - Pharmacometabonomics Analysis Reveals Serum Formate and Acetate Potentially Associated with Varying Response to Gemcitabine-Carboplatin Chemotherapy in Metastatic Breast Cancer Patients. AB - Gemcitabine-carboplatin (GC) chemotherapy was efficacious in metastatic breast cancer (MBC) patients probably resistant to anthracyclines and taxanes, but showed significant interindividual variation in treatment responses. Early prediction of response to treatment is clinically relevant to identify patients who will achieve clinical benefit. In this study, nuclear magnetic resonance (NMR) based pharmacometabonomics was used to noninvasively predict the response to GC chemotherapy of 29 MBC patients with prior exposure to both anthracyclines and taxanes from a phase II study. Formate and acetate levels in the baseline serum collected prior to GC chemotherapy were identified as potential predictive markers to select patients who will achieve clinical benefit and to identify those who should not be treated with the therapy to avoid futile treatment. The significantly lower baseline levels of serum formate and acetate in patients with resistant disease may reflect the higher demand of them as alternate/additional nutritional sources to fuel the accelerated proliferation of breast cancer cells that are biologically more aggressive or resistant to therapy. The results suggest that pharmacometabonomics can be a potential useful tool for predicting chemotherapy response in the context of precision medicine. Prospective studies with larger patient cohorts are required for validation of the findings. PMID- 29385797 TI - In Vitro Bioavailability, Cellular Antioxidant Activity, and Cytotoxicity of beta Carotene-Loaded Emulsions Stabilized by Catechin-Egg White Protein Conjugates. AB - Previously, it was shown that catechin-egg white protein (CT-EWP) conjugates were effective antioxidant emulsifiers that could form and stabilize emulsions, and also inhibit the degradation of encapsulated carotenoids. The objective of the current study was to evaluate the impact of conjugation on the in vitro bioavailability, cellular antioxidant activity, and cytotoxicity of beta-carotene loaded emulsions. Lipid droplets coated with EWP or with CT-EWP conjugates exhibited quite similar behavior when they were passed through a simulated gastrointestinal tract. The beta-carotene encapsulated in emulsions stabilized by CT-EWP conjugates exhibited a higher overall in vitro bioavailability, which was attributed to a greater stability of the carotenoids to chemical transformation. The emulsions stabilized by CT-EWP conjugates also exhibited greater ability in inhibiting oxidation in a cell-based assay (dichlorofluorescein diacetate). Cytotoxicity analysis suggested that beta-carotene emulsions stabilized by CT-EWP conjugates only exhibited a slight cytotoxicity when used at high concentrations. These results suggest that CT-EWP conjugates can be used to formulate emulsion based delivery systems for chemically labile hydrophobic bioactives with enhanced antioxidant activity and bioavailability. PMID- 29385798 TI - Terbium Functionalized Micelle Nanoprobe for Ratiometric Fluorescence Detection of Anthrax Spore Biomarker. AB - Rapid, sensitive, and selective quantitative detection of pyridine dicarboxylic acid (DPA) as biomarker of anthrax spores is in great demand since anthrax spores are highly lethal to human beings and animals and also potential biological warfare agents. Herein, we prepared a ratiometric fluorescence lanthanide functionalized micelle nanoprobe by "one-pot" self-assembly, with an amphiphilic ligand containing beta-diketone derivative which can "immobilize" terbium ions through the coordination interaction and a fluorophore as fluorescence reference (FR). The detection strategy was ascribed to Tb3+ ions in lanthanide functionalized micelle, which can be sensitized to emit the intrinsic luminescence upon addition of DPA due to the presence of energy transfer when DPA chromophore coordinated with Tb3+ ion. The fluorescence intensity of FR remained essentially constant, leading to ratiometric fluorescence response toward DPA. The results demonstrate that the terbium functionalized micelle was able to sensitively detect DPA with a linear relation in the range of 0 MUM to 7.0 MUM in aqueous solution, which also showed remarkable selectivity to DPA over other aromatic ligands. Our work paves a new way in the design of ratiometric fluorescence lanthanide functionalized micelle nanoprobes which can be promising for selective and sensitive detection of bacterial spores or biomolecules. PMID- 29385799 TI - Interface Engineering of Earth-Abundant Transition Metals Using Boron Nitride for Selective Electroreduction of CO2. AB - Two-dimensional atomically thin hexagonal boron nitride (h-BN) monolayers have attracted considerable research interest. Given the tremendous progress in the synthesis of h-BN monolayers on transition metals and their potential as electrocatalysts, we investigate the electrocatalytic activities of h-BN/Ni, h BN/Co, and h-BN/Cu interfaces for CO2 reduction by the first-principles density functional theory. We find that with the h-BN monolayer on the metal, electrons transfer from the metal to the interface and accumulate under the B atoms. By calculating the binding energies of three key intermediates (H, HCOO, and COOH) for hydrogen evolution and CO2 reduction, we find that H binding on the metal can be significantly weakened by the h-BN monolayer, preventing the hydrogen evolution reaction (HER). However, the binding strength of HCOO is strong on both the metal and h-BN/metal, especially for Ni and Co, promoting the CO2 reduction channel. On the basis of the free-energy diagrams, we predict that h-BN/Ni and h BN/Co will have very good electrocatalytic activities for CO2 reduction to HCOOH, while the competitive HER channel is filtered out by the surface h-BN monolayer. Our study opens a new way for selective electroreduction of CO2 via the interface engineering of the h-BN/metal system. PMID- 29385800 TI - Isotropic-Nematic Transition and Demixing Behavior in Binary Mixtures of Hard Spheres and Hard Spherocylinders Confined in a Disordered Porous Medium: Scaled Particle Theory. AB - We develop the scaled particle theory to describe the thermodynamic properties and orientation ordering of a binary mixture of hard spheres (HS) and hard spherocylinders (HSC) confined in a disordered porous medium. Using this theory, the analytical expressions of the free energy, the pressure, and the chemical potentials of HS and HSC have been derived. The improvement of obtained results is considered by introducing the Carnahan-Starling-like and Parsons-Lee-like corrections. Phase diagrams for the isotropic-nematic transition are calculated from the bifurcation analysis of the integral equation for the orientation singlet distribution function and from the conditions of thermodynamic equilibrium. Both the approaches correctly predict the isotropic-nematic transition at low concentrations of hard spheres. However, the thermodynamic approach provides more accurate results and is able to describe the demixing phenomena in the isotropic and nematic phases. The effects of porous medium on the isotropic-nematic phase transition and demixing behavior in a binary HS/HSC mixture are discussed. PMID- 29385801 TI - Profiling of Sialylated Oligosaccharides in Mammalian Milk Using Online Solid Phase Extraction-Hydrophilic Interaction Chromatography Coupled with Negative-Ion Electrospray Mass Spectrometry. AB - Sialylated oligosaccharides are important components in mammalian milk. They play a key role in the health and growth of infants by helping to shape up infant's gastrointestinal microbiota and defense against infection by various pathogenic agents. A detailed knowledge of the structures, compositions, and quantities of the sialylated milk oligosaccharides (SMOs) is a prerequisite for understanding their biological roles. However, because of the presence of very large amounts of lactose and neutral oligosaccharides, accurate analysis of SMOs is difficult. A pretreatment step is required to remove lactose and neutral oligosaccharides but conventional off-line pretreatment methods are time-consuming and of poor reproducibility. In this presentation, we linked solid-phase extraction (SPE) with hydrophilic interaction chromatography (HILIC) followed by mass spectrometry (MS) identification for the analysis of SMOs. A SPE column with electrostatic repulsion function was used for removal of lactose and neutral oligosaccharides, a HILIC analytical column for separation of the SMOs, and negative-ion electrospray ionization tandem MS was used for their identification and sequencing. The success of the established online SPE-HILIC-MS method was demonstrated by profiling of SMOs in human to investigate detailed SMO changes during lactation period and in animals to compare the difference in SMO contents among the different species. PMID- 29385802 TI - Nitric Oxide-Delivering High-Density Lipoprotein-like Nanoparticles as a Biomimetic Nanotherapy for Vascular Diseases. AB - Disorders of blood vessels cause a range of severe health problems. As a powerful vasodilator and cellular second messenger, nitric oxide (NO) is known to have beneficial vascular functions. However, NO typically has a short half-life and is not specifically targeted. On the other hand, high-density lipoproteins (HDLs) are targeted natural nanoparticles (NPs) that transport cholesterol in the systemic circulation and whose protective effects in vascular homeostasis overlap with those of NO. Evolving the AuNP-templated HDL-like nanoparticles (HDL NPs), a platform of bioinspired HDL, we set up a targeted biomimetic nanotherapy for vascular disease that combines the functions of NO and HDL. A synthetic S nitrosylated (SNO) phospholipid (1,2-dipalmitoyl-sn-glycero-3 phosphonitrosothioethanol) was synthesized and assembled with S-containing phospholipids and the principal protein of HDL, apolipoprotein A-I, to construct NO-delivering HDL-like particles (SNO HDL NPs). SNO HDL NPs self-assemble under mild conditions similar to natural processes, avoiding the complex postassembly modification needed for most synthetic NO-release nanoparticles. In vitro data demonstrate that the SNO HDL NPs merge the functional properties of NO and HDL into a targeted nanocarrier. Also, SNO HDL NPs were demonstrated to reduce ischemia/reperfusion injury in vivo in a mouse kidney transplant model and atherosclerotic plaque burden in a mouse model of atherosclerosis. Thus, the synthesis of SNO HDL NPs provides not only a bioinspired nanotherapy for vascular disease but also a foundation to construct diversified multifunctional platforms based on HDL NPs in the future. PMID- 29385803 TI - Gate-Induced Interfacial Superconductivity in 1T-SnSe2. AB - Layered metal chalcogenide materials provide a versatile platform to investigate emergent phenomena and two-dimensional (2D) superconductivity at/near the atomically thin limit. In particular, gate-induced interfacial superconductivity realized by the use of an electric-double-layer transistor (EDLT) has greatly extended the capability to electrically induce superconductivity in oxides, nitrides, and transition metal chalcogenides and enable one to explore new physics, such as the Ising pairing mechanism. Exploiting gate-induced superconductivity in various materials can provide us with additional platforms to understand emergent interfacial superconductivity. Here, we report the discovery of gate-induced 2D superconductivity in layered 1T-SnSe2, a typical member of the main-group metal dichalcogenide (MDC) family, using an EDLT gating geometry. A superconducting transition temperature Tc ~ 3.9 K was demonstrated at the EDL interface. The 2D nature of the superconductivity therein was further confirmed based on (1) a 2D Tinkham description of the angle-dependent upper critical field Bc2, (2) the existence of a quantum creep state as well as a large ratio of the coherence length to the thickness of superconductivity. Interestingly, the in-plane Bc2 approaching zero temperature was found to be 2-3 times higher than the Pauli limit, which might be related to an electric field modulated spin-orbit interaction. Such results provide a new perspective to expand the material matrix available for gate-induced 2D superconductivity and the fundamental understanding of interfacial superconductivity. PMID- 29385805 TI - Spotlights: Volume 9, Issue 3. PMID- 29385804 TI - Electrothermally Tunable Graphene Resonators Operating at Very High Temperature up to 1200 K. AB - The unique negative thermal expansion coefficient and remarkable thermal stability of graphene make it an ideal candidate for nanoelectromechanical systems (NEMS) with electrothermal tuning. We report on the first experimental demonstration of electrothermally tuned single- and few-layer graphene NEMS resonators operating in the high frequency (HF) and very high frequency (VHF) bands. In single-, bi-, and trilayer (1L, 2L, and 3L) graphene resonators with carefully controlled Joule heating, we have demonstrated remarkably broad frequency tuning up to Delta f/ f0 ~ 310%. Simultaneously, device temperature variations imposed by Joule heating are monitored using Raman spectroscopy; we find that the device temperature increases from 300 K up to 1200 K, which is the highest operating temperature known to date for electromechanical resonators. Using the measured frequency and temperature variations, we further extract both thermal expansion coefficients and thermal conductivities of these devices. Comparison with graphene electrostatic gate tuning indicates that electrothermal tuning is more efficient. The results clearly suggest that the unique negative thermal expansion coefficient of graphene and its excellent tolerance to very high temperature can be exploited for engineering highly tunable and robust graphene transducers for harsh and extreme environments. PMID- 29385806 TI - Machine Learning. PMID- 29385808 TI - Machine Learning. PMID- 29385807 TI - Machine Learning. PMID- 29385810 TI - Session Viewpoints on the 2017 Dynamics of Molecular Collisions Conference. PMID- 29385809 TI - Keiji Morokuma. PMID- 29385811 TI - Applying Strengths Model principles to build a rural community-based mental health support service and achieve recovery outcomes. AB - INTRODUCTION: The Personal Helpers and Mentors (PHaMs) service is a non-clinical, community-based Australian Government initiative aimed at increasing opportunities for recovery for people whose lives are severely affected by mental illness. Using a strengths-based recovery model, PHaMs caseworkers support and mentor people 'at risk of falling through the gaps' between state funded clinical treatment services and federally funded social services (such as supported housing, education and employment). While there is evidence that PHaMs realises its aim in metropolitan areas, little is known about how services are developed and function in low resource rural settings and what outcomes are achieved. These questions were addressed in a case study of a PHaMs service in a rural town in the state of New South Wales, Australia. METHODS: Data were collected from two sources: local service documents prepared for staff orientation and operational purposes, and records and reports of service participants?' performance and achievements. Participants?' gains in wellbeing, recovery goals, and the target outcome areas of increased access to services, increased personal capacity and self-reliance, and increased community participation, were gathered from self-reports. The Role Functioning Scale was used as a measure of caseworker ratings of participants?' adaptive functioning. The qualitative data were examined for semantic content and underlying themes. The quantitative analyses involved repeated measures and between-groups comparisons of uncontrolled pre-test–post-test and retrospective pre-test data. RESULTS: From commencement of the service in October 2009 to June 2014, an estimated 31% of the people living with severe mental illness in the local government area had accessed the PHaMs service (N=126; mean age 31.9 years; 42% male, 27% Aboriginal). The document analysis revealed that despite a lack of detail on how a PHaMs service should be developed or delivered, by focusing on the goal of client recovery, and taking a strengths-based rather than a deficit approach to the human and other resources that were available, the PHaMs service was established and is maintained by applying Strengths Model principles and being committed to teamwork and interagency respect. Caseworker ratings of participants who had completed an Individual Recovery Plan indicated significant gains in adaptive functioning, including improvements in physical health and wellbeing, management of symptoms, accommodation, vocational skills development and increased community involvement. CONCLUSIONS: Strengths-based recovery services offered by a rural PHaMs service can assist Australians with severe mental illness to achieve meaningful gains towards recovery. Furthermore, a Strengths Model approach to service development and operations – one that recognises individual abilities and prizes interpersonal relationships and teamwork – can maximise the potential of local human and other resources, and serve as a solution to resolving apparent service gaps and perceived deficits in rural and regional areas. PMID- 29385812 TI - Mini Versus Standard Percutaneous Nephrolithotomy: The Impact of Sheath Size on Intrarenal Pelvic Pressure and Infectious Complications in a Porcine Model. AB - OBJECTIVE: To determine how sheath and endoscope size affect intrarenal pelvic pressures and risk of postoperative infectious complications comparing "Mini" vs "Standard" percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: Uropathogenic Escherichia coli were grown and 109 of them were instilled into the porcine renal pelvis through retrograde access for 1 hour. Percutaneous access utilized a 14/16F 20 cm ureteral access sheath for the Mini arm and a 30F sheath for the Standard arm. Nephroscopy was simulated utilizing either an 8/9.8F semirigid ureteroscope or 26F nephroscope for 1 hour while intrarenal pelvic pressure was continuously monitored. Blood and tissue cultures of kidney, liver, and spleen biopsies were plated and incubated and positive cultures were confirmed with polymerase chain reaction. RESULTS: Intrapelvic pressures were higher in the Mini group, 18.76 +/- 5.82 mm Hg vs 13.56 +/- 5.82 mm Hg (p < 0.0001). Time spent above 30 mm Hg was greater in the Mini arm, 117.0 seconds vs 66.1 seconds (p = 0.0452). All pigs had positive kidney tissue cultures whereas spleen cultures were positive in 100% and 60% of pigs in the Mini and Standard arms, respectively (p = 0.0253); 90% and 30% had positive liver tissue culture in the Mini and Standard arms, respectively (p = 0.0062). Blood cultures were positive in 30% of pigs in the Mini arm compared with none in the Standard arm (p = 0.0603). CONCLUSION: Mini-PCNL was associated with higher intrarenal pressures and higher risk of end organ bacterial seeding in the setting of an infected collecting system. This suggests a higher potential for infectious complications in a clinical setting. PMID- 29385813 TI - The Role of Musk in Relieving the Neurodegenerative Changes Induced After Exposure to Chronic Stress. AB - OBJECTIVE: This study aimed to evaluate the effect induced by musk on Alzheimer's disease-such as neurodegenerative changes in mice exposed to chronic unpredictable mild stress (CUMS). MATERIAL AND METHODS: Forty male Swiss albino mice were divided into 4 groups (n = 10); control, CUMS, CUMS + fluoxetine, CUMS + musk. At the end of the experiment, behavior of the mice was assessed. Serum corticosterone level, hippocampal protein level of the glucocorticoid receptors, and brain-derived neurotropic factor were also assessed. Hippocampus was histopathologically examined. RESULTS: Musk improved depressive status induced after exposure to CUMS as evidenced by the forced swimming and open field tests and improved the short-term memory as evidenced by the elevated plus maze test. Musk reduced both corticosterone levels and the hippocampal neurodegenerative changes observed after exposure to CUMS. These improvements were comparable to those induced by fluoxetine. CONCLUSION: Musk alleviated the memory impairment and neurodegenerative changes induced after exposure to the chronic stress. PMID- 29385814 TI - Addition of Sodium Bicarbonate to Irrigation Solution May Assist in Dissolution of Uric Acid Fragments During Ureteroscopy. AB - INTRODUCTION: We hypothesized that adding sodium bicarbonate (bicarb) to normal saline (NS) irrigation during ureteroscopy in patients with uric acid (UA) nephrolithiasis may assist in dissolving small stone fragments produced during laser lithotripsy. In vitro testing was performed to determine whether dissolution of UA fragments could be accomplished within 1 hour. MATERIALS AND METHODS: In total 100% UA renal calculi were fragmented, filtered, and separated by size. Fragment sizes were <0.5 mm and 0.5 to 1 mm. Similar amounts of stone material were agitated in solution at room temperature. Four solutions were tested (NS, NS +1 ampule bicarb/L, NS +2, NS +3). Both groups were filtered to remove solutions after fixed periods. Filtered specimens were dried and weighed. Fragment dissolution rates were calculated as percent removed per hour. Additional testing was performed to determine whether increasing the temperature of solution affected dissolution rates. RESULTS: For fragments <0.5 mm, adding 2 or 3 bicarb ampules/L NS produced a dissolution rate averaging 91% +/- 29% per hour. This rate averaged 226% faster than NS alone. With fragments 0.5 to 1 mm, addition of 2 or 3 bicarb ampules/L NS yielded a dissolution rate averaging 22% +/- 7% per hour, which was nearly five times higher than NS alone. There was a trend for an increase in mean dissolution rate with higher temperature but this increase was not significant (p = 0.30). CONCLUSIONS: The addition of bicarbonate to NS more than doubles the dissolution rate of UA stone fragments and fragments less than 0.5 mm can be completely dissolved within 1 hour. Addition of bicarb to NS irrigation is a simple and inexpensive approach that may assist in the dissolution of UA fragments produced during ureteroscopic laser lithotripsy. Further studies are needed to determine whether a clinical benefit exists. PMID- 29385815 TI - Culturally-tailored interventions for chronic disease self-management among Chinese Americans: a systematic review. AB - OBJECTIVES: Literature review evaluating the effectiveness and cultural surface and deep structures of interventions designed to improve Chinese Americans' chronic disease self-management. METHOD: PubMed, PsycINFO, CINAHL, and Health Source databases were searched for research conducted from 1990 to 2016 on self management interventions for Chinese Americans with chronic disease. RESULTS: Ten articles comprised eight interventions, which each addressed a dimension of cultural surface structure, all providing linguistically appropriate messages delivered via bilingual staff. Five interventions also addressed cultural deep structure dimensions by providing culturally congruent counsellors or educators, or incorporating Chinese cultural values and social customs. Six interventions resulted in significant improvements in major outcome variables. Participants also reported high satisfaction and retention rates were high. CONCLUSION: Culturally-tailored interventions that incorporate surface and deep structural elements of culture are sensitive and generally effective for Chinese Americans to improve access to health care, disease awareness, social environment, and participants' ability to practice self-management skills. PMID- 29385816 TI - The Time Has Come to Report Stone Burden in Terms of Volume Instead of Largest Diameter. PMID- 29385818 TI - Court rulings involving individuals with dementia in Israel: A qualitative perspective. AB - Background Individuals with dementia may appear before the courts in different roles. Despite the growing interest in the rights of older persons with dementia, relatively little empirical data exist regarding their actual interactions and experiences in court. Methods This study used a qualitative, textual analysis methodology. A total of 281 Israeli legal court cases, which addressed issues relating to dementia, were analyzed. Results Four key themes were found in the legal texts: (1) The legal construction of dementia and its relationships to old age; (2) The importance of procedural justice; (3) The implications and outcomes of the legal process; and (4) The legal implications to the society as a whole. Conclusions The legal narratives, which surround legal cases that deal with dementia in Israel, reveal an internal tension between stigmatic and anti stigmatic narratives. This complex reality raises the need for further research and for a clearer judicial policy. PMID- 29385819 TI - Caregivers' interactions with health care services - Mediator of stress or added strain? Experiences and perceptions of informal caregivers of people with dementia - A qualitative study. AB - Background There are an estimated 46.8 million people worldwide living with dementia in 2015, being cared for usually by family members or friends (informal caregivers). The challenges faced by informal caregivers often lead to increased levels of stress, burden and risk of care-recipient institutionalisation. Aim The overarching aim of this study was to explore the experiences and perceptions of informal caregivers of people with dementia when interacting with the health care system, and whether the support received acted as a mediator of caregiver stress. The secondary aim was to investigate healthcare professionals' views and current practice regarding people with dementia and their interactions with informal caregivers. Method We employed a qualitative research design, using focus groups and one face-to-face interview with a purposive sample of informal caregivers and healthcare professionals in Lincolnshire, UK. Data were collected between March and July 2015. We used the stress-process model of stress in caregivers as a theoretical framework. Results We interviewed 18 caregivers and 17 healthcare professionals. Five themes, mapped to the stress-process in caregivers' model, captured the main challenges faced by caregivers and the type of support they wanted from health care services. Primary stressors included the challenge of diagnosing dementia; caregivers' needs and expectations of an in-depth knowledge and understanding of dementia from healthcare professionals; and need for carer education. Secondary role strain included lack of support and mismatch of communication and expectations. Caregiver involvement in monitoring care and disease was a potential mediator tool. Conclusions Fragmentation of dementia care services, lack of training for healthcare professionals and the dearth of information for caregivers means health care services are only partially fulfilling a support role. In turn, lack of support may be intensifying caregiver stress leading to worsening in their health and well-being; thus, potentially increasing the risk of institutionalisation of their care-recipient. PMID- 29385820 TI - Characteristics of psychiatric emergency department use among privately insured adolescents with autism spectrum disorder. AB - This study examined differences in the rates of psychiatric-related emergency department visits among adolescents with autism spectrum disorder, adolescents with attention deficit hyperactivity disorder, and adolescents without autism spectrum disorder or attention deficit hyperactivity disorder. Additional outcomes included emergency department recidivism, probability of psychiatric hospitalization after the emergency department visit, and receipt of outpatient mental health services before and after the emergency department visit. Data came from privately insured adolescents, aged 12-17 years, with autism spectrum disorder (N = 46,323), attention deficit hyperactivity disorder (N = 408,066), and neither diagnosis (N = 2,330,332), enrolled in the 2010-2013 MarketScan Commercial Claims Database. Adolescents with autism spectrum disorder had an increased rate of psychiatric emergency department visits compared to adolescents with attention deficit hyperactivity disorder (IRR = 2.0, 95% confidence interval: 1.9, 2.1) and adolescents with neither diagnosis (IRR = 9.9, 95% confidence interval: 9.4, 10.4). Compared to the other groups, adolescents with autism spectrum disorder also had an increased probability of emergency department recidivism, psychiatric hospitalization after the emergency department visit, and receipt of outpatient care before and after the visit (all p < 0.001). Further research is required to understand whether these findings extend to youth with other neurodevelopmental disorders, particularly those who are publicly insured. PMID- 29385821 TI - Reflections of patients and therapists on a multidisciplinary rehabilitation programme for persons with brachial plexus injuries. AB - PURPOSE: There is lack of knowledge, evidence, and guidelines for rehabilitation interventions for persons with neuralgic amyotrophy (NA) or brachial plexus pathology. A first pilot study, evaluating the effect of an integrated rehabilitation programme, showed improvements in activity and participation levels. AIM: To gain insight, from the perspective of patients and therapists, into the critical ingredients of the programme, that contributed to improvements in activity and participation. MATERIALS AND METHODS: A qualitative study using semi-structured interviews with eight patients and five therapists (three occupational therapists and two physical therapists). Participants were asked to identify and describe factors regarding the rehabilitation that they perceived as positive and aspects of the programme that could be improved. Data were analysed using a constant comparative approach. RESULTS: Patients reported (1) Time to diagnose: "Finally I'm in the right place;" (2) Awareness: "They gave me a mirror;" (3) Partnership: "There was real contact with the therapists; we made decisions together;" (4) Close collaboration: "Overlapping scopes of practice; doing the same from a different perspective;" and finally (5) Self-management: "Now I can do it myself." Therapists reported (1) "Patients knowledge and understanding is critical to success;" (2) "Activate problem solving and decision making;" (3) "Personalize your therapy; it's more than just giving exercises and information;" (4) "Constant consultation within the team; consistency in messages and approach;" and (5)" Ultimately the patient is in charge." CONCLUSIONS: The critical ingredients, correspond well with each other and include a person centred approach, education, support in problem solving and decision making and an integrated team approach. These ingredients provided the patients with confidence to take responsibility to manage their everyday lives, the ultimate goal of the programme. Implications for rehabilitation Both patients and therapists believe that the ability to self-manage and take control should be the outcome of high quality integrated rehabilitation programmes for patients with neuralgic amyotrophy and/or other brachial plexus injuries. A person-centred, collaborative, and integrated team approach, among all members of the team, are critical components of care delivery in personalised interventions. Critical programme ingredients are knowledge and education of both the patient and therapists; partnership between patient-therapist and within the team; patient activation and self-reflection; and personalised care. Patients recommend more options for personalisation of the intensity and duration of rehabilitation, the possibility to consult a psychologist and peer support within a group setting. PMID- 29385822 TI - HeartBeat. PMID- 29385823 TI - Optimizing the Pharmacologic Treatment of Individuals With First-Episode Psychosis. PMID- 29385825 TI - The Impact of Underpowered Studies on Clinical Trial Results. PMID- 29385826 TI - The "Loss of Pride" Syndrome in Yazidi Refugees. PMID- 29385827 TI - Pharmacogenetic Tests in Psychiatry. PMID- 29385828 TI - Prolonged Postconcussive Symptoms. PMID- 29385829 TI - Growing Up: Evolving Concepts of Adult Attention Deficit Hyperactivity Disorder. PMID- 29385830 TI - Antisuicidal Effects of Ketamine: A Promising First Step. PMID- 29385831 TI - The Importance of Adequately Powered Clinical Studies: Response to Khan et al. PMID- 29385833 TI - Why Apathy in Alzheimer's Matters. PMID- 29385834 TI - Association Between Frailty and HIV-Associated Neurodegenerative Disorders Among Older Adults Living with HIV. AB - The population of aging adults living with human immunodeficiency virus (HIV) is growing worldwide and evidence suggests that frailty occurs prematurely among them. In turn, frailty has been associated with cognitive decline. It is unknown, however, if people with both frailty and HIV infection have a higher risk of cognitive impairment compared with nonfrail HIV-infected persons. Therefore, the main objective of this study was to determine the association between the phenotype of frailty and HIV-associated neurocognitive disorders (HAND) among adults aged 50 years or older living with HIV/AIDS. A cross-sectional study was conducted on 206 adults living with HIV receiving care in a university-affiliated tertiary care hospital in Mexico City. Frailty was defined as per the Fried criteria. The presence of HAND was established according to the Antinori criteria: HIV-associated asymptomatic neurocognitive impairment (ANI), HIV associated mild neurocognitive disorder (MND), or cognitively nonimpaired. Multinomial logistic regression models were used to test the independent association between frailty and HAND adjusting for potential confounders. Mean age of participants was 60.5 +/- 6.3 years and 84.9% were male. Prevalence of HAND and frailty phenotype was 66.0% and 2.9%, respectively. The unadjusted analysis showed that both prefrail and frail statuses were associated with MND but not with ANI. However, after adjustment, the association with MND remained significant only among prefrail participants and no longer for frail persons (risk ratio [RR] = 5.7, 95% confidence intervals [CI] 1.09-29.82; p = .039 and RR = 18.3, 95% CI 0.93-362.6; p = .056, respectively). Prefrailty is associated with symptomatic neurocognitive disorders in older adults living with HIV. The spectrum of the frailty phenotype in this already vulnerable population should serve as an indicator of concomitant cognitive decline. PMID- 29385835 TI - Social capital, social relationships and adults with acquired visual impairment: a nigerian perspective. AB - PURPOSE: This study investigates the social capital implications of vision loss among working-age adults in Nigeria. The study explores the challenges of acquiring and maintaining social relationships post-vision loss, and investigates the extent to which visual rehabilitation services support social goals. METHOD: A qualitative study using a phenomenological approach was undertaken. Eight adults (18-59 years) were recruited from disability service organizations in Nigeria. Telephone interviews were recorded and transcribed, and thematic content analysis was used to analyze the data gathered in this study. RESULTS: Three broad themes were developed from participants' accounts of their experiences: (1) changes to relationships with friends and others; (2) finding strength in family relationships; and (3) rehabilitation and the confidence to interact. The findings indicate that the relationship between participants and their family members improved post vision impairment, enhancing bonding social capital. However, participants experienced reduced bridging and linking social capital due to diminished or broken relationships with managers, coworkers, friends, and others in the community. CONCLUSIONS: As social connectedness and relationships are highly valued in Nigeria's diverse society, we suggest that adults with visual impairment would significantly benefit from visual rehabilitation services placing greater emphasis on addressing the social goals of participants. Implications for Rehabilitation Visual impairment in working-age adults can strengthen family relationships (homogenous groups), creating bonding capital that is associated with access to important resources including emotional and moral support, and some financial and material resources. Visual impairment can negatively impact relationships with managers, coworkers, and others in the community (heterogeneous groups), resulting in diminished bridging and linking capital. Visual impairment can reduce access to resources such as an income, social status, and reduces participation in the wider community. Visual Rehabilitation Services could significantly benefit participants by placing greater emphasis on social goals, such as building and maintaining social networks, particularly with diverse (heterogeneous groups), which are valued in Nigeria's diverse cultural climate. PMID- 29385836 TI - Differential associations of functional and cognitive health outcomes with pre frailty and frailty states in community-dwelling older adults. AB - : This study examined associations of pre-frailty and frailty states with cognitive and functional health outcomes among community-residing older adults ( N = 457) in the Bronx, New York. RESULTS: older adults who met criteria for frailty demonstrated poorer performance in attention, verbal memory, and overall global cognitive functioning compared to healthy controls. Moreover, pre-frail and frail older adults had significantly worse health outcomes including greater perceived difficulty with lower and upper extremity functioning and perceived limitations in completing daily activities, suggesting the need for targeted interventions in the community that may ameliorate age-related health decline. PMID- 29385837 TI - Verification of a proteomic biomarker panel to diagnose minor stroke and transient ischaemic attack: phase 1 of SpecTRA, a large scale translational study. AB - OBJECTIVE: To derive a plasma biomarker protein panel from a list of 141 candidate proteins which can differentiate transient ischaemic attack (TIA)/minor stroke from non-cerebrovascular (mimic) conditions in emergency department (ED) settings. DESIGN: Prospective clinical study (#NCT03050099) with up to three timed blood draws no more than 36 h following symptom onset. Plasma samples analysed by multiple reaction monitoring-mass spectrometry (MRM-MS). PARTICIPANTS: Totally 545 participants suspected of TIA enrolled in the EDs of two urban medical centres. OUTCOMES: 90-day, neurologist-adjudicated diagnosis of TIA informed by clinical and radiological investigations. RESULTS: The final protein panel consists of 16 proteins whose patterns show differential abundance between TIA and mimic patients. Nine of the proteins were significant univariate predictors of TIA [odds ratio (95% confidence interval)]: L-selectin [0.726 (0.596-0.883)]; Insulin-like growth factor-binding protein 3 [0.727 (0.594 0.889)]; Coagulation factor X [0.740 (0.603-0.908)]; Serum paraoxonase/lactonase 3 [0.763 (0.630-0.924)]; Thrombospondin-1 [1.313 (1.081-1.595)]; Hyaluronan binding protein 2 [0.776 (0.637-0.945)]; Heparin cofactor 2 [0.775 (0.634 0.947)]; Apolipoprotein B-100 [1.249 (1.037-1.503)]; and von Willebrand factor [1.256 (1.034-1.527)]. The scientific plausibility of the panel proteins is discussed. CONCLUSIONS: Our panel has the potential to assist ED physicians in distinguishing TIA from mimic patients. PMID- 29385838 TI - Oxidoreductases for the remediation of organic pollutants in water - a critical review. AB - Water contamination by various recalcitrant organic aromatic compounds is an emerging environmental issue that is increasingly attracting the attention of environmental scientists. A great majority of these recalcitrant pollutants are industrial wastes, textile dyes, pharmaceuticals, hormones, and personal care products that are discharged into wastewater. Not surprisingly, various chemical, physical, and biological strategies have been proposed and developed to remove and/or degrade these pollutants from contaminated water bodies. Biological approaches, specifically using oxidoreductase enzymes (such as peroxidases and laccases) for pollutant degradation are a relatively new and a promising research area that has potential advantages over other methods due to their higher efficiency and the ease of handling. This review focuses on the application of different classes of oxidoreductase enzymes to degrade various classes of organic pollutants. In addition to classifying these enzymes based on structural differences, the major factors that can affect their remediation ability, such as the class of peroxidases employed, pH, molecular structure of the pollutant, temperature, and the presence of redox mediators are also examined and discussed. Interestingly, a literature survey combined with our unpublished data suggests that "peroxidases" are a very heterogeneous and diverse family of enzymes and have different pH profiles, temperature optima, thermal stabilities, requirements for redox mediators, and substrate specificities as well as varying detoxification abilities. Additionally, remediation of real-life polluted samples by oxidoreductases is also highlighted as well as a critical look at current challenges and future perspectives. PMID- 29385839 TI - Examining sensory ability, feature matching and assessment-based adaptation for a brain-computer interface using the steady-state visually evoked potential. AB - PURPOSE: We investigated how overt visual attention and oculomotor control influence successful use of a visual feedback brain-computer interface (BCI) for accessing augmentative and alternative communication (AAC) devices in a heterogeneous population of individuals with profound neuromotor impairments. BCIs are often tested within a single patient population limiting generalization of results. This study focuses on examining individual sensory abilities with an eye toward possible interface adaptations to improve device performance. METHODS: Five individuals with a range of neuromotor disorders participated in four-choice BCI control task involving the steady state visually evoked potential. The BCI graphical interface was designed to simulate a commercial AAC device to examine whether an integrated device could be used successfully by individuals with neuromotor impairment. RESULTS: All participants were able to interact with the BCI and highest performance was found for participants able to employ an overt visual attention strategy. For participants with visual deficits to due to impaired oculomotor control, effective performance increased after accounting for mismatches between the graphical layout and participant visual capabilities. CONCLUSION: As BCIs are translated from research environments to clinical applications, the assessment of BCI-related skills will help facilitate proper device selection and provide individuals who use BCI the greatest likelihood of immediate and long term communicative success. Overall, our results indicate that adaptations can be an effective strategy to reduce barriers and increase access to BCI technology. These efforts should be directed by comprehensive assessments for matching individuals to the most appropriate device to support their complex communication needs. Implications for Rehabilitation Brain computer interfaces using the steady state visually evoked potential can be integrated with an augmentative and alternative communication device to provide access to language and literacy for individuals with neuromotor impairment. Comprehensive assessments are needed to fully understand the sensory, motor, and cognitive abilities of individuals who may use brain-computer interfaces for proper feature matching as selection of the most appropriate device including optimization device layouts and control paradigms. Oculomotor impairments negatively impact brain-computer interfaces that use the steady state visually evoked potential, but modifications to place interface stimuli and communication items in the intact visual field can improve successful outcomes. PMID- 29385840 TI - The efficacy of virtual reality assisted versus traditional rehabilitation intervention on individuals with functional ankle instability: a pilot randomized controlled trial. AB - PURPOSE: Virtual reality (VR) training, a virtual environment commonly generated by computer systems, may enhance the therapeutic efficacy of functional rehabilitation programmes. The aim of this study was to investigate the efficacy of a VR assisted intervention (VRAI) versus traditional rehabilitation intervention (TRI) on functional ankle instability (FAI). METHODS: A single-blind randomized controlled study was conducted with 10 subjects for each group. The VRAI was conducted with the Nintendo Wii Fit Plus, whilst the TRI was conducted with a series of exercises with theraband. The muscle strength change of the two groups and the difference between pre and post interventions for each group were compared. RESULTS: The VRAI group had less improvement in the muscle strength of all ankle motions than did the TRI group (p > .05). The VRAI group had a greater improvement in muscle strength of plantar flexion than other motions, whilst the TRI group had an improvement in muscle strength of all ankle motions (p < .05). CONCLUSIONS: The effects of VR training for the condition of FAI were not comparable to conventional training. However, VR training may be added to the conventional training programme as an optional for the condition of FAI. Implications for Rehabilitation Functional ankle instability (FAI) is subjective feelings of ankle instability resulting from proprioceptive and neuromuscular deficits in which individuals may experience "giving way" condition of the ankle. Therapeutic applications of virtual reality (VR) may be comparable to traditional rehabilitation interventions (TRI) in the rehabilitation of individuals with FAI. However, there is no definitive evidence for the issue. Integrating low-cost VR into functional rehabilitation programme can provide insight into an issue of whether it can be replaced with traditional therapeutic approaches. Although, the efficacy of VR application on strengthening muscles is unable to compare to traditional strengthening programmes, it may be considered an optional treatment based on the proprioceptive improvements. PMID- 29385841 TI - Ectopic adrenal rest cells of the fallopian tube: a case report and review of the literature. PMID- 29385842 TI - Long-term use of the JACO robotic arm: a case series. AB - PURPOSE: Past research with JACO has principally focused on the short-term impacts on new users. Therefore, this study aims to document the long-term impacts of this assistive device on users and their family caregivers following prolonged use. METHODS: Users' characteristics, caregivers' characteristics and expenses related to JACO were documented with questionnaires designed for this study. Upper extremity performance was measured with an adaptation of an upper extremity performance test, the TEMPA, and accomplishment of life habits was documented in an interview based on the LIFE-H questionnaire. Satisfaction with JACO and psychosocial impacts of its use were measured with validated questionnaires, namely the QUEST and the PIADS-10. Impacts of JACO on family caregivers were documented with a validated questionnaire, the CATOM. Descriptive statistics were used to report the results. RESULTS: Seven users and five caregivers were recruited. One user had expenses related to JACO in the past two months. Users had a better upper extremity performance with JACO than without it and they used their robotic arm to accomplish certain life habits. Most users were satisfied with JACO and the psychosocial impacts were positive. Impacts on family caregivers were slight. CONCLUSIONS: JACO increased performance in manipulation and facilitated the accomplishment of certain life habits. Users' increased participation in their life habits may slightly decrease the amount of caregiver assistance required. Future studies are needed to clarify its economic potential, its impact on caregivers' burden, including paid caregivers, and the variability in the tasks performed using JACO. Implications for Rehabilitation The use of JACO may have positive impacts on its users in terms of upper extremity performance, accomplishment of life habits, satisfaction with the device and psychosocial impacts. More research is needed to quantify more accurately the economic potential of the long-term use of JACO, to explore the factors related to the variability in the tasks performed using JACO, and to clarify the impact of JACO on caregivers' burden, including paid caregivers. PMID- 29385843 TI - Idiopathic intracranial hypertension and bariatric surgery: a literature review and a presentation of two cases. AB - OBJECTIVE: There is paucity of data concerning the impact of bariatric surgery on idiopathic intracranial hypertension (IIH). We therefore present the clinical course of two cases that were managed at our centre, which is a regional referral centre for bariatric surgery and present a literature review of patients with IIH who underwent bariatric surgery for the treatment of obesity. METHOD: Two patients were referred for bariatric surgery who were both morbidly obese and were diagnosed with IIH. One patient underwent bariatric surgery; the other patient's weight was managed conservatively. We followed up both patients for 2 years. PubMed was searched for published studies of patients with IIH undergoing bariatric surgery. RESULTS: The patient that underwent weight loss surgery achieved sustained weight loss from 108kg to 87kg and gross resolution of their symptoms. The patient whose weight was managed conservatively lost weight initially and then put the weight back on. Her IIH symptoms persisted despite CSF shunt therapy. The literature review identified 12 original studies, containing 51 patients. Weight loss after bariatric surgery was reported for 84% of patients and improvement or resolution of IIH symptoms was reported for 84% of patients. CONCLUSION: In light of the literature review and our experience, bariatric surgery appears to be a potential treatment option for IIH alongside the comorbidities associated with obesity. However, more robust studies are needed. PMID- 29385844 TI - Response to "Clinical implications of assay-specific differences in f calprotectin when monitoring inflammatory bowel disease activity over time". PMID- 29385845 TI - Reliability and responsiveness of the Self-Efficacy in Assessing, Training and Spotting wheelchair skills (SEATS) outcome measure. AB - OBJECTIVES: The aim of this study was to evaluate the internal consistency, test retest reliability and responsiveness of the Self-Efficacy in Assessing, Training and Spotting manual wheelchair skills (SEATS-M) and Self-Efficacy in Assessing, Training and Spotting power wheelchair skills (SEATS-P). METHODS: A 2-week test retest design was used with a convenience sample of occupational and physical therapists who worked at a provincial rehabilitation centre (inpatient and outpatient services). Sixteen participants completed the SEATS-M and 18 participants completed the SEATS-P. RESULTS: For the SEATS-M assessment, training, spotting and documentation sections, Cronbach's alpha coefficients ranged from 0.90 to 0.97, the 2-week intraclass correlation coefficients (ICC1,1) ranged from 0.81 to 0.95, the standard error of measurements (SEM) ranged from 5.06 to 8.70 and the smallest real differences (SRD) ranged from 6.24 to 8.18. For the SEATS-P assessment, training, spotting and documentation sections, Cronbach's alpha coefficients ranged from 0.83 to 0.92, the ICCs ranged from 0.72 to 0.86, the SEMs ranged from 4.54 to 8.91 and the SRDs ranged from 5.90 to 8.27. CONCLUSIONS: There is preliminary evidence that both the SEATS-M and the SEATS-P have high internal consistency, good test-retest reliability and support for responsiveness. These tools can be used in evaluating clinician self-efficacy with assessing, training, spotting and documenting wheelchair skills included on the Wheelchair Skills Test. Implications for Rehabilitation There is preliminary evidence that the SEATS-M and SEATS-P are reliable and responsive outcome measures that can be used to evaluate the self-efficacy of clinicians to administer the Wheelchair Skills Program. Measurement of clinicians' self efficacy in this area of practice may enable an enhanced understanding of the areas in which clinicians lack self-efficacy, thereby informing the development of improved knowledge translation interventions. PMID- 29385846 TI - Unraveling uncultivable pesticide degraders via stable isotope probing (SIP). AB - Uncultivable microorganisms account for over 99% of all species on earth, playing essential roles in ecological processes such as carbon/nitrogen cycle and chemical mineralization. Their functions remain unclear in ecosystems and natural habitats, requiring cutting-edge biotechnologies for a deeper understanding. Stable isotope probing (SIP) incorporates isotope-labeled elements, e.g. 13 C, 18 O or 15 N, into the cellular components of active microorganisms, serving as a powerful tool to link phylogenetic identities to their ecological functions in situ. Pesticides raise increasing attention for their persistence in the environment, leading to severe damage and risks to the ecosystem and human health. Cultivation and metagenomics help to identify either cultivable pesticide degraders or potential pesticide metabolisms within microbial communities, from various environmental media including the soil, groundwater, activated sludge, plant rhizosphere, etc. However, the application of SIP in characterizing pesticide degraders is limited, leaving considerable space in understanding the natural pesticide mineralization process. In this review, we try to comprehensively summarize the fundamental principles, successful cases and technical protocols of SIP in unraveling functional-yet-uncultivable pesticide degraders, by raising its shining lights and shadows. Particularly, this study provides deeper insights into various feasible isotope-labeled substrates in SIP studies, including pesticides, pesticide metabolites, and similar compounds. Coupled with other techniques, such as next-generation sequencing, nanoscale secondary ion mass spectrometry (NanoSIMS), single cell genomics, magnetic nanoparticle-mediated isolation (MMI) and compound-specific isotope analysis (CSIA), SIP will significantly broaden our understanding of pesticide biodegradation process in situ. PMID- 29385847 TI - Comparing the effectiveness of two app-based number lines to teach price comparison to students with autism spectrum disorders. AB - PURPOSE: A number line consisting of Arabic numerals is a commonly used instructional tool for teaching price comparison. However, typical number lines lack concrete visual cues, which may benefit students with autism spectrum disorders (ASD) who have not yet mastered the representation of Arabic numerals. METHOD: This study investigated the effects of additional visual cues (i.e., dots) by comparing two types of app-based number line conditions: number lines with and without dots. A single-subject, alternating treatment design study was employed across five secondary students with ASD. RESULTS: Both number line conditions were effective for four of the students in assisting them to select cheaper items and complete task analysis steps. The number line with dots was effective or slightly more effective in selecting smaller numbers for three of the students. CONCLUSIONS: The findings of this study support the literature on the use of number lines as an effective tool to assist students in price comparison. The benefits of adding concrete visual cues and other teaching strategies (e.g., the holistic and decomposition models) were discussed. Implications for Rehabilitation This study investigated the effectiveness of concrete visual cues, such as dots, on a number line app for teaching students with ASD who had not yet developed the association of quantities with the numerals. We found that incorporation of a hybrid number comparison model - first holistic (for whole numbers) and then decomposition (for numbers after the decimal point) - is effective when teaching students how to compare prices with an uneven number of digits. This study provides an alternative for special education teachers to schedule practice, such as the use of simulated settings to achieve mastery, then transitioning to community-based settings to test skill generalization. PMID- 29385848 TI - Exposure to stressful events during a peacekeeping mission may have a price: The impact on trait of negative and positive affect and mental health. AB - We evaluated the participants' negative affect, positive affect, post-traumatic stress disorder, and depression symptoms before and after a peacekeeping mission. Depression symptoms and positive affect after mission were significantly associated with exposure to stressful events during the mission, controlled by the respective characteristics before mission. Negative affect and post-traumatic stress disorder symptoms after mission had a tendency to be associated with exposure to stressful events during the mission, controlled by the respective characteristics before mission. In conclusion, even in healthy and physically active male peacekeepers, those more exposed to stressful events could be more vulnerable to present negative outcomes. PMID- 29385849 TI - Development of paracetamol-caffeine co-crystals to improve compressional, formulation and in vivo performance. AB - Paracetamol, a frequently used antipyretic and analgesic drug, has poor compression moldability owing to its low plasticity. In this study, new co crystals of paracetamol (PCM) with caffeine (as a co-former) were prepared and delineated. Co-crystals exhibited improved compaction and mechanical behavior. A screening study was performed by utilizing a number of methods namely dry grinding, liquid assisted grinding (LAG), solvent evaporation (SE), and anti solvent addition using various weight ratios of starting materials. LAG and SE were found successful in the screening study. Powders at 1:1 and 2:1 weight ratio of PCM/CAF by LAG and SE, respectively, resulted in the formation of co-crystals. Samples were characterized by PXRD, DSC, and ATR-FTIR techniques. Compressional properties of PCM and developed co-crystals were analyzed by in-die heckle model. Mean yield pressure (Py), an inverse measure of plasticity, obtained from the heckle plots decreased significantly (p < .05) for co-crystals than pure drug. Intrinsic dissolution profile of co-crystals showed up to 2.84-fold faster dissolution than PCM and physical mixtures in phosphate buffer pH 6.8 at 37 degrees C. In addition, co-crystals formulated into tablets by direct compression method showed better mechanical properties like hardness and tensile strength. In vitro dissolution studies on tablets also showed enhanced dissolution profiles (~90-97%) in comparison to the tablets of PCM prepared by direct compression (~55%) and wet granulation (~85%) methods. In a single dose sheep model study, co crystals showed up to twofold increase in AUC and Cmax. A significant (p < .05) decrease in clearance as compared to pure drug was also recorded. In conclusion, new co-crystals of PCM were successfully prepared with improved tabletability in vitro and in vivo profile. Enhancement in AUC and Cmax of PCM by co crystallization might suggest the dose reduction and avoidance of side effects. PMID- 29385850 TI - Human Papilloma Virus (HPV) self-sampling: do women accept it? AB - This study aims to determine the acceptability of Human Papilloma Virus (HPV) self-sampling and the factors associated with willingness to buy HPV self sampling kit in the future. A total of 164 women aged 28-60 years old from Obstetrics & Gynaecology clinics at a teaching hospital performed HPV self sampling using the Digene HC2 DNA collection kit. After samples were taken, the participants were given self-administered questionnaires. The majority of the participants were Malay (93.9%), had attained tertiary education (65.2%) and were employed (70.1%). The acceptability was good. More than half of the participants felt that self-sampling was easy. Only 1.2% felt that the procedure was difficult to perform. Most reported no pain at all during the procedure (66.9%). The commonest concern was getting a good sample (90.1%). A number of Pap smears were found to be significantly associated with the willingness to buy the HPV self sampling kit. HPV self-sampling has the potential to be included in the cervical cancer screening programme. Impact Statement What is already known on this subject: HPV self-sampling is acceptable in some developed and developing countries. It is acceptable because it was easy to perform with very minimal pain or discomfort. Studies on the acceptance of self-screening are needed to plan a policy on self-sampling in the future. What the results of this study add: Our study adds new findings to the body of knowledge on self-sampling in the local population. We found that more women are willing to do the self-sampling at the clinic rather than at home. Although more than 90% expressed willingness to do self-sampling in the future, only 70% of them were willing to purchase the kit. Cost is a potential barrier to women who have the interest to perform the self sampling. Given the global economic challenges, cost is inevitably an important predictor that we have to consider. What the implications are of these findings for clinical practice and/or further research: Future research should examine women from the rural areas and those who are resilient to Pap smear screening. In clinical practice, clinicians should acknowledge that cost is a potential barrier for women who are willing to do self-sampling. Self-sampling could be an option for women with no financial constraint to buy the kit. However, clinicians should counsel women so that they can make an informed choice in determining their screening method. PMID- 29385851 TI - Transcranial magnetic stimulation as an antioxidant. AB - In the last decades, different transcranial magnetic stimulation protocols have been developed as a therapeutic tool against neurodegenerative and psychiatric diseases, although the biochemical, molecular and cellular mechanisms underlying these effects are not well known. Recent data show that those magnetic stimulation protocols showing beneficial effects could trigger an anti-oxidant action that would favour, at least partially, their therapeutic effect. We have aimed to review the molecular effects related to oxidative damage induced by this therapeutic strategy, as well as from them addressing a broader definition of the anti-oxidant concept. PMID- 29385852 TI - Clinical Trial of MGMT(P140K) Gene Therapy in the Treatment of Pediatric Patients with Brain Tumors. AB - Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit. In a trial of this strategy in adult glioma patients, significant engraftment of gene-modified HSCs expressing a mutant of the DNA repair protein O6-methyl-guanine-methyl-transferase (MGMT(P140K)) showed potential in conferring drug resistance against the combined effect of O6-benzylguanine (O6BG)/temozolomide (TMZ) chemotherapy. The aim was to test the safety and feasibility of this approach in children with poor prognosis brain tumors. In this Phase I trial, seven patients received gene-modified HSC following myelo suppressive conditioning, but with only transient low-level engraftment of MGMT(P140K) gene-modified cells detectable in four patients. All patients received O6BG/TMZ chemotherapy following infusion of gene-modified cells, with five patients eligible for chemotherapy dose escalation, though in the absence of demonstrable transgene-mediated chemoprotection. Since all gene-modified cell products met the criteria for release and assays for engraftment potential met expected outcome measures, inadequate cell dose, conditioning chemotherapy, and/or underlying bone-marrow function may have contributed to the lack of sustained engraftment of gene-modified cells. We were able to demonstrate safe conduct of a technically complex Phase I study encompassing manufacture of the gene therapy vector, genetically modified cells, and a drug product specifically for the trial in compliance with both local and national regulatory requirements. PMID- 29385853 TI - Molecular properties and immunomodulatory activities of a water-soluble heteropolysaccharide isolated from Plantago asiatica L. leaves. AB - This study aims at investigating physical-chemical properties of a water-soluble heteropolysaccharide from Plnatago asiatica L. leaves, and its immunomodulatory effects on macrophages RAW264.7 cells. Hot water-extracted crude polysaccharide from the plant leaves (PLLCP) was fractionated into four fractions by DEAE Sepharose Fast Flow eluted with 0.1-0.5 M NaCl solutions. The most abundant fraction (0.3 M NaCl elution), designated PLLP-2, was identified as a heteropolysaccharide with an average molecular weight (Mw) of 3.54 * 104 and composed mainly of Gal (34.4%), GalA (36.5%), Ara (10.1%) and Rha (8.4%). PLLP-2 was an acidic polysaccharide exhibiting inflaky curly aggregation with smooth surface. PLLCP and its main subfraction PLLP-2 displayed immunomodulatory activities by stimulating the production of pro-inflammatory cytokines, including TNF-alpha and IL-1beta in macrophage RAW264.7 cells. These results indicate that the main polysaccharide fraction purified from P. asiatica L. leaves is probably pectin, and have potential immunomodulatory function. PMID- 29385854 TI - HealthyhornsTXT: A Text-Messaging Program to Promote College Student Health and Wellness. AB - OBJECTIVE: Text-messaging interventions positively affect health behaviors, but their use on college campuses has been limited. Text messaging serves as a relatively affordable way to communicate with large audiences and is one of the preferred modes of communication for young adults. This study examined the feasibility and acceptability of a campus-wide, health text-messaging program. PARTICIPANTS: The subscriber pool consisted of approximately 6,000 undergraduate students from a large, southern university. From that pool, 1,095 participants (64% female; 41% White) completed a posttest survey. METHOD: Text messages covered a range of health topics and information about campus resources. Research was conducted from August through December 2015. Process data were collected throughout the semester; participants' attitudes were assessed via an online survey at the program's conclusion. RESULTS: Students demonstrated engagement with the messages throughout the semester as evidenced by replies to text-back keywords and clicks on website links embedded within messages. Messages about sleep, stress management, and hydration were considered most relevant. The majority of participants (61%) reported increased awareness regarding their health. CONCLUSIONS: Text-messaging interventions are a feasible strategy to improve college student health. PMID- 29385855 TI - Assessing and Mobilizing Faith Organizations to Implement Childhood Obesity Prevention Advocacy Strategies. AB - Childhood obesity remains a public health problem requiring mobilization across diverse social and political sectors. The faith-based sector can contribute to obesity prevention advocacy when existing resources are supported and leveraged. This article describes an advocacy resource assessment conducted in six Chicago faith organizations. Key administrators and congregation members were surveyed to identify organizational resources that could be mobilized for childhood obesity prevention advocacy. Survey data were analyzed using SPSS and Excel. Descriptive statistics were calculated for each organization and for all combined. Organizational resources for advocacy were identified, with varying degrees of resources within organizations. Congregation members and faith leaders expressed interest in advocacy training and activities but acknowledged competing organizational priorities. Participating organizations received a stipend to pursue recommended action items based on their assessment. Faith organizations have unique resources and human capital and can be key partners in childhood obesity prevention. Conducting an assessment prior to planning interventions and advocacy approaches can strengthen partnerships, leverage assets among partners, and ensure efforts are relevant and beneficial for faith organizations. It may also be strategic to incorporate funding in grant budgets in order to empower faith organizations to act on findings from the assessment process. PMID- 29385856 TI - Bilateral remote cerebellar hemorrhage following surgical clipping a ruptured supratentorial aneurysm. AB - Remote cerebellar hemorrhage (RCH) is a rare and severe complication after supratentorial surgery, with various risk factors and mechanisms remaining uncertain. Herein, we report a 64-year-old female patient suffered bilateral RCH following surgical clipping a ruptured aneurysm of internal carotid artery bifurcation. RCH is considered as venous in origin, and is likely the result of intra-operative or post-operative loss of CSF. Thus, appropriate control and close monitor the intra-operative and post-operative loss of CSF is of great importance for preventing the occurrence of RCH. PMID- 29385857 TI - Fatty acids from oleaginous yeasts and yeast-like fungi and their potential applications. AB - PURPOSE: Oleaginous yeasts, fatty acids biosynthesis and regulation in the oleaginous yeasts and the fatty acids from the oleaginous yeasts and their applications are reviewed in this article. RESULTS: Oleaginous yeasts such as Rhodosporidium toruloides, Yarrowia lipolytica, Rhodotorula mucilaginosa, and Aureobasidium melanogenum, which can accumulate over 50% lipid of their cell dry weight, have many advantages over other oleaginous microorganisms. The fatty acids from the oleaginous yeasts have many potential applications. Many oleaginous yeasts have now been genetically modified to over-produce fatty acids and their derivatives. The most important features of the oleaginous yeasts are that they have special enzymatic systems for enhanced biosynthesis and regulation of fatty acids in their lipid particles. Recently, some oleaginous yeasts such as R. toruloides have been found to have a unique fatty acids synthetase and other oleaginous yeasts such as A. melanogenum have a unique highly reducing polyketide synthase (HR-PKS) involved in the biosynthesis of hydroxyl fatty acids. CONCLUSIONS: It is necessary to further enhance lipid biosynthesis using metabolic engineering and explore new applications of fatty acids in biotechnology. PMID- 29385858 TI - Spontaneous umbilical artery haematoma diagnosed in the third trimester: a case report. AB - Spontaneous haematoma of the umbilical cord is a rare, unpreventable maternal event. The complications of this anomaly are an uneventful pregnancy, foetal distress or even an intrauterine foetal death. Umbilical cord haematoma usually results from the rupture of the umbilical vein, rarely of the umbilical arteries. We present the case of spontaneous umbilical cord haematoma diagnosed antenatally with ultrasonography, with the baby being successfully delivered by caesarean section. PMID- 29385859 TI - The NLRP3 rs10754558 polymorphism is a risk factor for preeclampsia in a Chinese Han population. AB - OBJECTIVE: Previous studies have indicated that the nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is activated by monosodium urate in the trophoblast of preeclampsia (PE) patients, leading to augmented placental IL-1beta levels. Thus, the purpose of our study was to investigate the association between NLRP3 polymorphisms, rs10754558 and rs2027432, and PE in Chinese Han population. METHODS: The NLRP3 polymorphisms, rs10754558 and rs2027432, were genotyped by real-time PCR in 1024 PE patients and 1194 control subjects. A chi2 test was used to compare the genetic distribution between the two groups, and an analysis of variance was used to conduct the genotype-phenotype analysis. RESULTS: We demonstrated a significant difference in genotypic frequency of the rs10754558 (chi2 = 9.97, p = .007) in NLRP3 between PE patients and controls. Additionally, there was a significant difference between cases and controls in the dominant model of G allele (chi2 = 7.70, p = .006, odds ratio =0.77, 95%confidence interval 0.64-0.93). What's more, the genotypes distributions of rs10754558 were found to be associated with both the severe and late onset PE. (chi2 = 8.53 p = .01, chi2 = 9.24, p = .01.) However, no significant statistic differences were found in the genotypic distributions and allelic frequencies for rs2027432 between two groups (for genotypic distribution, chi2 = 0.17, p = .92; for allelic frequency, chi2 = 2.26, p = .13, odds ratio =0.90, 95% confidence interval 0.79-1.03). CONCLUSIONS: Our results reveal that NLRP3 may be involved in the development of PE in a Chinese Han population. However, further validation of the associations of other NLRP3 SNPs with PE in other populations is required. PMID- 29385860 TI - Serum miRNAs in women affected by hyperandrogenic polycystic ovary syndrome: the potential role of miR-155 as a biomarker for monitoring the estroprogestinic treatment. AB - MicroRNAs can be used as very efficient circulating biomarkers. The role of microRNAs in polycystic ovary syndrome (PCOS) and the effects of antiandrogen therapy on microRNA expression is still not fully understood. A panel of serum microRNAs were retrotranscribed via looped reverse primer transcription specific for each miRNA and quantified via probe specific RT-PCR in 16 Caucasian hyperandrogenic PCOS women selected according to the Rotterdam criteria and in a subset of seven patients after four months of sequential reverse antiandrogenic therapy. All women recruited underwent an oral glucose tolerance test (OGTT) and a baseline total cholesterol, high density lipoproteins cholesterol, triglycerides, AST and ALT dosage. In the follicular phase women were evaluated for total testosterone, Delta4-androstenedione, DHEAS, 17OHpg, FSH, LH, and 17 beta-E2. The AUC2hglucose, ISI Matsuda, oral disposition index (DIo) and visceral adipose index (VAI) were also calculated. We suggest that miR-155 might have a role as biomarker in hyperandrogenic PCOS patients to monitor the effect of antiandrogen therapy. PMID- 29385861 TI - Admission volume is associated with mortality of neonatal respiratory failure in emerging neonatal intensive care units. AB - OBJECTIVE: The aim of this survey was to explore the relationship between admission volume and mortality of neonates with hypoxemic respiratory failure (NRF) in emerging neonatal intensive care units (NICUs). METHODS: NRF from 55 NICUs were retrospectively included with death risk as the major outcome. Perinatal comorbidities, underlying disease severity, respiratory support, facility utilization, and economic burden in the early postnatal period were compared among five NICU admission volume categories defined by NRF incidence, with score for neonatal acute physiology perinatal extension II (SNAPPE-II) also assessed as initial severity. RESULTS: Compared to NICUs with NRF < 50 cases/year, NRF incidence, NRF/NICU, NRF/NICU admissions, and magnitude of ventilator use were several times higher, and mortality rates 20-50% lower, in NICUs of 150-199 and >=200 cases/year (p < .01), even after adjustment with SNAPPE-II in stratified ranges. Median SNAPPE-II values, which correlated with the death rate of NRF (r = .282, p < .001), were lower in NICUs of 150-199 and >=200 than in <50, 50-99, and 100-149 categories (13 versus 18, p < .01). NRF mortalities were not correlated with the proportion of very low birth weight patients in each category. CONCLUSIONS: Neonates in NICUs with smaller NRF admission volume and decreased magnitude of ventilator use had a higher risk of death as assessed by SNAPPE-II, which should be targeted in the quality improvement of newly established, resource-limited NICUs. PMID- 29385862 TI - Analysis of serum IL-38 in juvenile-onset systemic lupus erythematosus. PMID- 29385863 TI - Preoperative predictors that impact the survival and outcome of patients undergoing secondary cytoreduction for ovarian cancer. AB - This study aimed to examine the factors affecting feasibility of optimal and complete secondary cytoreductive surgery (SCRS) and to characterise the prognostic factors that correlate with improved survival in patients who underwent SCRS. This is a retrospective single-institutional cohort study of patients who underwent SCRS for recurrent epithelial ovarian cancer (EOC). One hundred and forty-eight patients met inclusion criteria. Platinum sensitivity was associated with complete cytoreduction at SCRS. Factors associated with suboptimal cytoreduction (SOC) were age >55 years, serous histology, largest tumour implant size >4 cm, and SOC at primary surgery. Overall survival analysis showed significantly longer survival with complete cytoreduction compared to optimal and SOC. Surgical outcome of SCRS was an independent predictor of survival regardless of the outcome of primary cytoreduction. Location of the largest implant, DFI and timing of chemotherapy also impact on survival. PMID- 29385864 TI - Effects of implementing time-variable postgraduate training programmes on the organization of teaching hospital departments. AB - INTRODUCTION: As competency-based education has gained currency in postgraduate medical education, it is acknowledged that trainees, having individual learning curves, acquire the desired competencies at different paces. To accommodate their different learning needs, time-variable curricula have been introduced making training no longer time-bound. This paradigm has many consequences and will, predictably, impact the organization of teaching hospitals. The purpose of this study was to determine the effects of time-variable postgraduate education on the organization of teaching hospital departments. METHODS: We undertook exploratory case studies into the effects of time-variable training on teaching departments' organization. We held semi-structured interviews with clinical teachers and managers from various hospital departments. RESULTS: The analysis yielded six effects: (1) time-variable training requires flexible and individual planning, (2) learners must be active and engaged, (3) accelerated learning sometimes comes at the expense of clinical expertise, (4) fast-track training for gifted learners jeopardizes the continuity of care, (5) time-variable training demands more of supervisors, and hence, they need protected time for supervision, and (6) hospital boards should support time-variable training. CONCLUSIONS: Implementing time-variable education affects various levels within healthcare organizations, including stakeholders not directly involved in medical education. These effects must be considered when implementing time-variable curricula. PMID- 29385866 TI - Lentigo vaginae (vaginal melanosis). PMID- 29385865 TI - Three-dimensional limb lengthening after total knee arthroplasty in a simulation study. AB - OBJECTIVES: Limb lengthening after total knee arthroplasty (TKA) has been reported in some cases, all of which were evaluated using two-dimensional images. To our knowledge, no case has been evaluated using three-dimensional (3D) images. We investigated 3D limb lengthening after TKA. METHODS: We simulated 100 varus knees using 3D templating software. Virtual TKA was performed to maintain the original joint line by conducting a measured-resection technique. We examined the relationships of 3D distance between the femoral head center and ankle center before and after TKA, degree of hip-knee-ankle angle (HKA) improvement, and degree of flexion contracture angle improvement. RESULTS: All cases showed limb lengthening (average, 9.4 +/- 6.0 mm). The coefficients of correlation with limb lengthening and the degree of HKA improvement and the degree of flexion contracture angle improvement were good (0.730 and 0.751, respectively). The correlation between the degree of total improvement (the degree of HKA improvement + the degree of flexion contracture angle improvement) and limb lengthening was strong (r = 0.896). CONCLUSION: The expected limb lengthening when performing measured-resection TKA is expressed as 0.58 * (the degree of HKA improvement + the degree of flexion contracture angle improvement) mm and is a useful index. PMID- 29385867 TI - Combination Therapy with Tenofovir Disoproxil Fumarate/Emtricitabine/Elvitegravir/Cobicistat Plus Darunavir Once Daily in Antiretroviral-Naive and Treatment-Experienced Patients: A Retrospective Review. AB - BACKGROUND: Patients with drug-resistant HIV often require complex antiretroviral regimens. However, combining fixed-dose combination tablets such as tenofovir disoproxil-fumarate, emtricitabine, and cobicistat-boosted elvitegravir (TDF/FTC/EVG/cobi) with darunavir (DRV) can provide a simple, once-daily (QD), 2 tablet regimen for patients with drug-resistant HIV. Primary objective was to determine the percentage of patients with HIV-1 RNA <40 copies/mL at 48 weeks. METHODS: We performed a retrospective chart review of patients initiated on TDF/FTC/EVG/cobi plus DRV. RESULTS: Among the 21 included patients, prior resistance showed a median of 2 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase mutation, and 1 protease inhibitor mutation. At week 48, 14 (67%) patients achieved HIV-1 RNA <40 copies/mL, 1 patient experienced viral rebound, and 6 (29%) had missing data or discontinued therapy. No patient discontinued for adverse events. CONCLUSION: According to this observational study, QD TDF/FTC/EVG/cobi plus DRV is considered safe, well tolerated, and generally effective in suppressing HIV drug-resistant virus. PMID- 29385868 TI - The non-monotypic status of the neotropical fish genus Hemiodontichthys (Siluriformes, Loricariidae) evidenced by genetic approaches. AB - The combination of cytogenetic and molecular data with those traditionally obtained in areas like systematics and taxonomy created interesting perspectives for the analysis of natural populations under different aspects. In this context, this study aimed to evaluate the genetic differentiation among populations of the genus Hemiodontichthys Bleeker, 1862, through combined genetic techniques and included the analysis of populations sampled in the Araguaia River, Guama River, Madeira River and two populations from the Purus River. Hemiodontichthys samples from the two localities in Purus River were also karyotyped in order to address the degree of chromosomal variation between populations. Through GMYC analysis of the COI tree, the patterns of genetic variation among local populations revealed to be higher than the ones found among distinct species from other genera of the subfamily Loricariinae, suggesting the existence of probable four cryptic species in this genus. The possible existence of a species complex in the genus is corroborated by the different cytogenetic patterns between Hemiodontichthys sp. 1 and sp. 2, revealing the necessity of a deep taxonomic review of the group. PMID- 29385869 TI - The use of ultrasound as an adjunct to peripheral venous cannulation by junior doctors in clinical practice. AB - PURPOSE: There is little consensus on the role of training in bedside ultrasound skills for medical students or junior doctors early in their careers. METHODS: We trained 20 Foundation Year 1 doctors in the use of ultrasound as an adjunct to peripheral venous cannulation and following an assessment of competence gave them access to an ultrasound machine to assist with difficult cannulations in their clinical practice. Self-reported confidence and competence were assessed using pre- and post-training questionnaires, with competence objectively assessed immediately post-training and at one and three months follow up. Clinical use of ultrasound was studied over three months. RESULTS: Improvements in self-reported confidence and competence were observed post-training and retained at three months. 85% (17/20) of participants were objectively assessed as competent immediately post-training, with retention of competence demonstrated in 80% (16/20) and 75% (15/20) at one and three months, respectively. There were 33 separate uses of ultrasound during the three month study period with a 73% (24/33) success rate and no adverse incidents. CONCLUSIONS: We suggest that doctors in their first post-graduate year can be trained in the use of ultrasound as an adjunct to peripheral venous cannulation, retain the skill over time and use it safely in their clinical practice. PMID- 29385870 TI - Predicting Psychosocial Maladjustment in Emerging Adulthood From High School Experiences of Peer Victimization. AB - The aim of the present study was to compare recollections of sexual, physical, verbal, social, and cyber peer victimization experienced in high school in terms of depressed affect, self-esteem, and loneliness experienced in university. In all, 247 university students (70 males and 177 females; M = 20.62, SD = 2.54) completed online measures assessing retrospective accounts of their experiences of different forms of peer victimization during high school (i.e., sexual, physical, verbal, social, and cyber) and their current psychosocial adjustment (i.e., self-esteem, depressed affect, and loneliness). Three separate hierarchical multiple regressions were conducted to determine whether different indices of negative psychosocial adjustment are more strongly predicted by experiencing sexual or nonsexual forms of peer victimization. Although many university students recalled experiencing sexual peer victimization in high school at least once at an even higher percentage than verbal and social forms of peer victimization, the results of the present study suggest that social peer victimization in high school predicts higher levels of depressed affect and loneliness in university students than sexual peer victimization experienced in high school. Surprisingly, the young adults reporting higher levels of cyber peer victimization in high school were less lonely in university. Although the hypothesized relationships between each form of peer victimization and specific indices of psychosocial functioning were not consistently supported, these findings suggest that the form of peer victimization matters and may be differentially associated with well-being in emerging adulthood. It is important that future research explores how individual characteristics may further predict varied experiences of peer victimization and the long-term impact of those experiences. PMID- 29385871 TI - The association between maternal serum first trimester free betahCG, second trimester intact hCG levels and foetal growth restriction and preeclampsia. AB - The purpose of this study was to analyse the association between free beta hCG (fbetahCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fbetahCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fbetahCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fbetahCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fbetahCG (>3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fbetahCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fbetahCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fbetahCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fbetahCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fbetahCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as >3.00 MoM; additional studies are needed to explore the association between increased first trimester fbetahCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester. PMID- 29385872 TI - Mitochondrial diversity and phylogeography of Acrossocheilus paradoxus (Teleostei: Cyprinidae). AB - Mitochondrial DNA cytochrome b sequences (1141 bp) in 229 specimens of Acrossocheilus paradoxus from 26 populations were identified as four lineages. The pairwise genetic distances among these four lineages ranged from 1.57 to 2.37% (mean= 2.00%). Statistical dispersal-vicariance analysis suggests that the ancestral populations were distributed over mainland China and Northern and Western Taiwan. Approximate Bayesian computation approaches show that the three lineages in Taiwan originated from the lineage in mainland China through three colonization routes during two glaciations. The results indicated that during the glaciation and inter-glacial periods, the Taiwan Strait was exposed and sank, which contributed to the dispersion and differentiation of populations. Furthermore, the populations of A. paradoxus colonized Taiwan through a land bridge to the north of the Formosa Bank, and the Miaoli Plateau in Taiwan was an important barrier that limited gene exchange between populations on both the sides. PMID- 29385873 TI - Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus. AB - OBJECTIVES: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). METHODS: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132. RESULTS: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs. CONCLUSION: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE. PMID- 29385874 TI - Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment. AB - OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL) 4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-alpha concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD. PMID- 29385875 TI - Complete mitogenomes from Kurdistani sheep: abundant centromeric nuclear copies representing diverse ancestors. AB - The geographical centre of domestication and species diversity for sheep (Ovis aries) lies around the Kurdistan region of Northern Iraq, within the 'Fertile Crescent'. From whole genome sequence reads, we assembled the mitochondrial genomes (mtDNA or mitogenome) of five animals of the two main Kurdistani sheep breeds Hamdani and Karadi and found they fitted into known sheep haplogroups (or matrilineages), with some SNPs. Haplotyping 31 animals showed presence of the main Asian (hpgA) and European (hpgB) haplogroups, as well as the rarer Anatolian haplogroup hpgC. From the sequence reads, near-complete genomes of mitochondria from wild sheep species (or subspecies), and even many sequences similar to goat (Capra) mitochondria, could be extracted. Analysis suggested that these polymorphic reads were nuclear mitochondrial DNA segments (numts). In situ hybridization with seven regions of mitochondria chosen from across the whole genome showed strong hybridization to the centromeric regions of all autosomal sheep chromosomes, but not the Y. Centromeres of the three submetacentric pairs and the X chromosomes showed fewer copies of numts, with varying abundance of different mitochondrial regions. Some mitochondrial-nuclear transfer presumably occurred before species divergence within the genus, and there has been further introgression of sheep mitochondrial sequences more recently. This high abundance of nuclear mitochondrial sequences is not reflected in the whole nuclear genome assemblies, and the accumulation near major satellite sequences at centromeres was unexpected. Mitochondrial variants including SNPs, numts and heteroplasmy must be rigorously validated to interpret correctly mitochondrial phylogenies and SNPs. PMID- 29385876 TI - Antiphospholipid syndrome, "the best prophet of the future". AB - The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of venous and arterial thromboses, often multiple, and obstetric related adverse events in the presence of antiphospholipid antibodies (aPL). APS, first described in 1983, as thrombosis, abortion and cerebral disease, is nowadays recognised as a systemic disease with a wide constellation of clinical manifestations related to acute and chronic vascular lesions. The presence of aPL is the serological hallmark of APS representing a heterogeneous population of autoantibodies with many antigenic specificities directed to phospholipid-binding proteins, either alone or in combination with phospholipids. Many assays have been developed for aPL detection. Particularly, anticardiolipin antibodies, anti beta2-glycoprotein I antibodies and lupus anticoagulant are essential tools for APS diagnosis. The cumulative evidence indicates that aPL are pathogenic autoantibodies binding to target cells and promoting thrombosis and pregnancy complications through a wide range of pathological mechanisms not yet fully understood. Finally, the recognition of the important role of aPL to assess the individual risk of thrombosis or pregnancy complications has expanded the concept of aPL, and currently aPL profile is regarded as a major risk factor for clinical thrombotic events. PMID- 29385878 TI - Nationwide population-based study on the use of novel antiandrogens in men with prostate cancer in Sweden. AB - OBJECTIVES: The aim of this study was to examine the use of abiraterone and enzalutamide, two oral novel antiandrogens (NOVAs), in men with prostate cancer (PCa) in Sweden. MATERIALS AND METHODS: This cross-sectional study investigated filled prescriptions for NOVAs recorded in the Swedish Prescribed Drug Register between July 2015 and April 2016. Associations between age, comorbidity, educational level, marital status and county of residence and filled prescriptions were analyzed in the National Prostate Cancer Register (NPCR) and other health population-based registers, using multivariable logistic regression. RESULTS: Of 91,209 men, 1650 (2%) had at least one prescription filled for NOVAs, of whom 1350 (82%) had high-risk or metastatic PCa at diagnosis.. Of 1914 men with M1 disease and a high probability of castration-resistant prostate cancer (CRPC), 22% had a prescription for NOVAs at a median 3 years after the date of diagnosis. At multivariable logistic regression analysis,, the likelihood of NOVA use was lower in older men [age >80 vs <70 years: odds ratio (OR) 0.23, 95% confidence interval (CI) 0.15-0.35] and in men with lower educational level (high vs low education: OR 1.64, 95% CI 1.23-2.20). There was up to a five-fold difference in the use of NOVAs between county councils. CONCLUSIONS: Less than one-third of potentially eligible men with CRPC received NOVAs in 2015-2016. There were large differences in use according to age and region of residence, indicating that efforts are needed to improve equal access to novel cancer drugs. PMID- 29385877 TI - Psychiatric disorders in patients with intractable dizziness in the department of otolaryngology. AB - OBJECTIVE: Vertigo and dizziness are often not fully explained by organic illnesses, but instead may be related to psychiatric disorders. It is important to determine the types of psychiatric comorbidities that are frequent in cases of intractable dizziness. METHOD: The study subjects were 90 patients who had experienced intractable dizziness for more than three months and were referred to a psychiatrist when their symptoms could not be fully explained based on their physical illness. The patients' final diagnosis and questionnaire (DHI,SDS and STAI) scores were evaluated. RESULTS: Seventy percent (63/90) of patients with intractable dizziness had been diagnosed as having psychiatric conditions by the study psychiatrists. The most common diagnosis was unspecified depressive disorder. CONCLUSIONS: Psychiatric comorbidities seem to be more prevalent in certain subgroups of organic dizziness. We found a higher rate of depressive disorders in the sequelae of sudden deafness and migraine-related dizziness. PMID- 29385879 TI - 'Learning together': sharing international experience on new models of primary care. PMID- 29385880 TI - The effect of antioxidants on angiogenesis in uterine transplantation. AB - The aim of this study was to investigate the effect of antioxidants on angiogenesis in uterine transplantation. We used 24 female rats equally divided into four groups: Group 1 had the uterus stored in HTK (Histidine-Tryptophan Ketoglutarate) solution at 4 degrees C cold storage for 4 h. Group 2 had the uterine tissue stored in HTK solution combined with acetyl L-carnitine (10-8 M) for 4 h at +4 degrees C. The same procedures with Group 1 and 2 were repeated for 24 h for Groups 3 and 4, respectively. Histological investigation and immunohistochemical analysis were performed. Histological findings showed that storing donor uterus in HTK solution at +4 degrees C for 24 h results in histological alteration in uterus. We also found that immunoreactivity of VEGFR-2 in all layers of rat uterus in Group 2 was lower than that in Group 1, and the expression of the uterus in Group 4 was lower than that in Group 3. We concluded that antioxidant acetyl L-carnitine, which was added to the organ preservation solution HTK, had prevented the formation of free radicals, and thus protected the uterus that was stored in short and long cold storage periods. Impact statement What is already known on this subject? Ischemia-reperfusion is a complex pathophysiological process involve in hypoxia and/or reoxygenation, ionic imbalance-induced oedema and acidosis, oxidative stress, mitochondrial uncoupling, coagulation and endothelium activation. The composition of preservation solutions must be adapted to the severity of ischaemia-reperfusion injuries to reduce cellular damage and inflammation and preserve graft functionality and integrity, thus improving short-term and long-term graft outcome. Clinicians use three types of composition of solution for static cold preservation: intracellular, intermediate and extracellular. HTK will be used frequently, especially with the consideration of lower price and more easy handling aspects. L-carnitine acts as an antioxidant, protects against free radicals and prevents mitochondrial damage. VEGFR-2 plays an important role in angiogenesis, chemotaxis, proliferation and migration of endothelial cells. What this study adds? In this study, we investigate the effect of antioxidants on angiogenesis in uterus transplantation. Our results showed that antioxidant acetyl L-carnitine that added to the organ preservation solution HTK, has prevented the formation of free radicals, thus protect the uterus that was stored in short and long cold storage periods. What the implications are for future studies? Therefore, we will contribute to the literature with the results of this study. PMID- 29385881 TI - Effective Governance and Hospital Boards Revisited: Reflections on 25 Years of Research. AB - This study reviews and synthesizes empirical research literature focusing on the relationship between boards of directors and organizational effectiveness of U.S. hospitals. The study examines literature published in scholarly journals during the period of 1991-2017. Fifty-one empirical articles were identified that met the study's inclusion criteria. A framework from the corporate governance and nonprofit governance literature is used to classify the articles according to level of analysis (individual actors, governing bodies, organizations, and networks, alliances and multiorganizational initiatives) and focus of research (formal structure and behavioral dynamics-including informal structures and processes). Results are discussed, emerging trends are identified, and recommendations are made for future research. PMID- 29385882 TI - RETRACTED: Cost-utility analysis of trastuzumab combined with Docetaxel for patients with HER-2 positive metastatic breast cancer - real world claim data. PMID- 29385883 TI - Successful use of cytarabine and bendamustine in a patient with mantle cell lymphoma and acute renal failure using intermittent hemodialysis: A case report. AB - Mantle cell lymphoma is a mature B-cell non-Hodgkin lymphoma characterized by the hallmark (11;14) chromosomal translocation, which often presents with lymphadenopathy and extra-nodal involvement. Young, fit patients are generally treated with chemotherapy approaches that incorporate high-dose cytarabine (e.g. the Nordic regimen) followed by autologous hematopoietic cell transplantation. Because of the significant activity of cytarabine in mantle cell lymphoma, increasingly, high- and intermediate-dose cytarabine are being used in the treatment of elderly mantle cell lymphoma patients. In practice, many patients present with significant organ dysfunction and there is limited data on the use of high- to intermediate-dose cytarabine and bendamustine in this setting. Here, we report a case of a critically ill, elderly patient with mantle cell lymphoma and concomitant acute kidney injury and oliguria who was successfully treated with a cycle of cytarabine (Ara-C) and bendamustine accompanied by intermittent hemodialysis. PMID- 29385885 TI - LRRK2 Phosphorylation: Behind the Scenes. AB - Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are known today as the most common genetic cause of Parkinson's disease (PD). LRRK2 is a large protein that is hypothesized to regulate other proteins as a scaffold in downstream signaling pathways. This is supported by the multiple domain composition of LRRK2 with several protein-protein interaction domains combined with kinase and GTPase activity. LRRK2 is highly phosphorylated at sites that are strictly controlled by upstream regulators, including its own kinase domain. In cultured cells, most pathogenic mutants display increased autophosphorylation at S1292, but decreased phosphorylation at sites controlled by other kinases. We only begin to understand how LRRK2 phosphorylation is regulated and how this impacts its physiological and pathological function. Intriguingly, LRRK2 kinase inhibition, currently one of the most prevailing disease-modifying therapeutic strategies for PD, induces LRRK2 dephosphorylation at sites that are also dephosphorylated in pathogenic variants. In addition, LRRK2 kinase inhibition can induce LRRK2 protein degradation, which might be related to the observed inhibitor-induced adverse effects on the lung in rodents and non-human primates, as it resembles the lung pathology in LRRK2 knock-out animals. In this review, we will provide an overview of how LRRK2 phosphorylation is regulated and how this complex regulation relates to several molecular and cellular features of LRRK2. PMID- 29385884 TI - Effects of triptolide on pharmacokinetics of amlodipine in rats by using LC MS/MS. AB - CONTEXT: Triptolide and amlodipine are often simultaneously used for reducing urine protein excretion after renal transplantation in China clinics. OBJECTIVE: This study investigated the effects of triptolide on the pharmacokinetics of amlodipine in male Sprague-Dawley rats. MATERIALS AND METHODS: The pharmacokinetics of amlodipine (1 mg/kg) with or without triptolide pre-treatment (2 mg/kg/day for seven days) were investigated using a sensitive and reliable LC MS/MS method. Additionally, the inhibitory effects of triptolide on the metabolic stability of amlodipine were investigated using rat liver microsome incubation systems. RESULTS: The results indicated that when the rats were pre-treated with triptolide, the Cmax of amlodipine increased from 13.78 +/- 3.57 to 19.96 +/- 4.56 ng/mL (p < 0.05), the Tmax increased from 4.04 +/- 1.15 to 5.89 +/- 1.64 h (p < 0.05), and the AUC0-t increased by approximately 104% (p < 0.05), which suggested that the pharmacokinetic behaviour of amlodipine was affected after oral co-administration of triptolide. Additionally, the metabolic half-life was prolonged from 22.5 +/- 4.26 to 36.8 +/- 6.37 min (p < 0.05) with the pre treatment of triptolide. CONCLUSIONS: In conclusion, these results indicated that triptolide could affect the pharmacokinetics of amlodipine, possibly by inhibiting the metabolism of amlodipine in rat liver when they are co administered. PMID- 29385886 TI - During stress, heart rate variability moderates the impact of childhood adversity in women with breast cancer. AB - Childhood adversity has long-lasting neuro-biological effects that can manifest as exaggerated stress responsivity to environmental challenge. These manifestations include a dysregulated hypothalamic-pituitary-adrenocortical (HPA) axis as well as increased levels of inflammatory mediators in response to stress. In this investigation, vagal parasympathetic activity was assessed for its capacity to moderate the relationship between childhood adversity and stress responsivity (cortisol and inflammation) during an acute laboratory challenge (Trier Social Stress Test-TSST). Thirty women recently diagnosed with breast cancer underwent the TSST during which their heart rate was recorded and saliva samples collected for measurement of cortisol and the proinflammatory cytokine, IL-6. Vagal activity during the TSST was calculated as the high-frequency (HF) component of heart rate variability (HRV). Vagal activity during the TSST moderated the effect of childhood adversity on both the cortisol and the IL-6 response. Women who had lower vagal stress-reactivity during the TSST and reported greater childhood adversity showed a larger rise in cortisol and IL-6 when compared to women with lower childhood adversity. The findings demonstrate that women with exposure to childhood adversity and low vagal stress-reactivity (reduced parasympathetic activity) exhibit an elevated stress response characterized by greater cortisol and proinflammatory cytokine release. Inflammatory burden and HPA dysregulation subsequent to stress may impair cancer control. PMID- 29385887 TI - Short-term inhalation study of graphene oxide nanoplates. AB - Graphene oxides possess unique physicochemical properties with important potential applications in electronics, pharmaceuticals, and medicine. However, the toxicity following inhalation exposure to graphene oxide has not yet been clarified. Therefore, this study conducted a short-term graphene oxide inhalation toxicity analysis using a nose-only inhalation exposure system and male Sprague Dawley rats. A total of four groups (15 rats per group) were exposed: (1) control (fresh air), (2) low concentration (0.76 +/- 0.16 mg/m3), (3) moderate concentration (2.60 +/- 0.19 mg/m3), and (4) high concentration (9.78 +/- 0.29 mg/m3). The rats were exposed to graphene oxide for 6 h/day for 5 days, followed by recovery for 1, 3, and 21 days. No significant body or organ weight changes were noted after the short-term exposure or during the recovery period. Similarly, no significant systemic effects of toxicological importance were noted in the hematological assays, bronchoalveolar lavage fluid (BAL) inflammatory markers, BAL fluid cytokines, or blood biochemical assays following the graphene oxide exposure or during the post-exposure observation period. Moreover, no significant differences were observed in the BAL cell differentials, such as lymphocytes, macrophages, or polymorphonuclear cells. Graphene oxide-ingested alveolar macrophages as a spontaneous clearance reaction were observed in the lungs of all the concentration groups from post 1 day to post 21 days. Histopathological examination of the liver and kidneys did not reveal any significant test-article-relevant histopathological lesions. Importantly, similar to previously reported graphene inhalation data, this short-term nose-only inhalation study found only minimal or unnoticeable graphene oxide toxicity in the lungs and other organs. PMID- 29385889 TI - Enhanced Recovery After Surgery program with dexamethasone administration for major head and neck surgery with free tissue transfer reconstruction: initial institutional experience. AB - OBJECTIVES: Enhanced Recovery After Surgery (ERAS) protocols promote recovery after various invasive surgeries. Likewise, preoperative glucocorticoid administration can reduce complications after some surgeries. However, the effects of ERAS protocols and glucocorticoid administration in patients undergoing major surgery for head and neck cancer have not been well described. The aim of this study was to evaluate the effect of an ERAS protocol with preoperative glucocorticoid administration in major surgery for head and neck cancer. METHODS: This retrospective study included 28 patients who underwent major head and neck surgery with free tissue transfer reconstruction at our institution from September 2016 to May 2017, after implementation of an ERAS protocol with preoperative glucocorticoid administration. Outcomes in that group were compared with those in a control group that underwent surgery from January 2015 to September 2016, before implementation of the protocol. RESULTS: Analysis revealed significantly less body weight fluctuation, lower C-reactive protein levels, higher albumin levels, and lower body temperature in the ERAS group than in the control group postoperatively. CONCLUSIONS: Patients undergoing major surgery for head and neck cancer who were treated with the ERAS protocol and preoperative glucocorticoid administration had evidence of better hemodynamic stability and less inflammatory response than control patients. PMID- 29385888 TI - Andrographolide relieved pathological pain generated by spared nerve injury model in mice. AB - CONTEXT: Andrographolide (Andro), found in large quantities in Andrographis paniculata Nees (Acanthaceae), is anti-inflammatory, especially in the central nervous system (CNS) glia. OBJECTIVE: The objective of this study is to test Andro's ability to reduce allodynia in a spared nerve injury model. MATERIAL AND METHODS: Male 30 g BalbC mice were divided into four groups: (1) Sham-operated control (Sham-group); (2) nerve injured and treated with saline (Saline-group); (3) nerve injured and treated with Andro (Andro-group); (4) nerve injured and treated with non-steroidal anti-inflammatory drugs (NSAIDS) (NSAIDS-group). Andro or NSAIDS (diclofenac salt) were injected intraperitoneally at 5 mg/kg body weight daily. Mechanical allodynia was assessed by von Frey tests at 3, 7, and 14 d. For immunohistochemical analysis, samples were collected at 7 d. RESULTS: The threshold for inducing allodynia increased and the response percentage reduced in the Andro-group when compared with the Saline-group, as well as when compared with NSAIDS groups throughout 3-14 d. The ratio of threshold for OP-Andro/OP saline and for OP-Andro/OP-NSAIDS groups was 20.42 and 11.67 at 14 d, respectively. The ratio of response percentage for OP-Andro/OP-saline and for OP Andro/OP-NSAIDS was 0.32 and 0.39 at 14 d, respectively. Interleukin-1 (IL-1) immunostaining in the spinal cord was reduced in the Andro-group. Astrocytic activities were not significantly reduced in the Andro-group compared with the Saline-group at 7 d post-operation (PO) Conclusions: Andro reduced mechanical allodynia more than NSAIDS at the same concentration, and the observed behaviour was associated with a reduction in inflammatory cytokine produced in the spinal cord. PMID- 29385891 TI - Biosynthesis of silver nanoparticles using Sida acuta extract for antimicrobial actions and corrosion inhibition potential. AB - Nanotechnology exhibits a multidisciplinary area and gained interests for researchers. Nanoparticles produced via physical and chemical methods affects ecosystem drastically. Green synthesis is the charming technique that is inexpensive and safe for the environment. This study aimed to explore the antibacterial actions of as-synthesized silver nanoparticles (Ag-NPs) against Escherichia coli, Staphylococcus aureus and Streptococcus faecalis. Also, the anti-corrosion actions confirmed that the Ag-NPs proved as good inhibitors. In this way, Ag-NPs were prepared via biosynthesis technique by consuming the ground leaves and stem of 'Sida acuta' as a capping agent. The Ag-NPs were formed by irradiation of the aqueous solution of silver nitrate (AgNO3) with extract of S. acuta stem and leaves. The as-synthesized reaction mixture of Ag-NPs was found to exhibit an absorbance band at 446-447 nm, by an UV/VIS spectrophotometer, which is a characteristic of Ag-NPs due to the surface plasmon resonance absorption band. The X-ray diffraction and transmission electron microscopy (TEM) were used for the confirmation of Ag-NPs' variety dimension, morphology and dispersion. The infrared spectra confirmed the bio-fabrication of the Ag-NPs displayed the existence of conceivable functional groups responsible for the bio-reduction and capping. The antimicrobial actions were measured and the zone of inhibition was compared with standard antibiotics. PMID- 29385892 TI - Comparative toxicity of three differently shaped carbon nanomaterials on Daphnia magna: does a shape effect exist? AB - The acute toxicity of three differently shaped carbon nanomaterials (CNMs) was studied on Daphnia magna, comparing the induced effects and looking for the toxic mechanisms. We used carbon nano-powder (CNP), with almost spherical primary particle morphology, multi-walled carbon nanotubes (CNTs), tubes of multi graphitic sheets, and cubic-shaped carbon nanoparticles (CNCs), for which no ecotoxicological data are available so far. Daphnids were exposed to six suspensions (1, 2, 5, 10, 20 and 50 mg L-1) of each CNM, and then microscopically analyzed. Ultrastructural analyses evidenced cellular uptake of nanoparticle in CNP and CNT exposed groups, but not in samples exposed to CNCs. Despite this difference, very similar effects were observed in tissues exposed to the three used CNMs: empty spaces between cells, cell detachment from the basal lamina, many lamellar bodies and autophagy vacuoles. These pathological figures were qualitatively similar among the three groups, but they differed in frequency and severity. CNCs caused the most severe effects, such as partial or complete dissolution of the brush border and thinning of the digestive epithelium. Being the cubic shape not allowed to be internalized into cells, but more effective than others in determining physical damages, we can conclude that shape is an important factor for driving nanoparticle uptake by cells and for determining the acute toxicological endpoints. Shape also plays a key role in determining the kind and the severity of pathologies, which are linked to the physical interactions of CNMs with the exposed tissues. PMID- 29385890 TI - Unique Sensory and Motor Behavior in Thy1-GFP-M Mice before and after Spinal Cord Injury. AB - Sensorimotor recovery after spinal cord injury (SCI) is of utmost importance to injured individuals and will rely on improved understanding of SCI pathology and recovery. Novel transgenic mouse lines facilitate discovery, but must be understood to be effective. The purpose of this study was to characterize the sensory and motor behavior of a common transgenic mouse line (Thy1-GFP-M) before and after SCI. Thy1-GFP-M positive (TG+) mice and their transgene negative littermates (TG-) were acquired from two sources (in-house colony, n = 32, Jackson Laboratories, n = 4). C57BL/6J wild-type (WT) mice (Jackson Laboratories, n = 10) were strain controls. Moderate-severe T9 contusion (SCI) or transection (TX) occurred in TG+ (SCI, n = 25, TX, n = 5), TG- (SCI, n = 5), and WT (SCI, n = 10) mice. To determine responsiveness to rehabilitation, a cohort of TG+ mice with SCI (n = 4) had flat treadmill (TM) training 42-49 days post-injury (dpi). To characterize recovery, we performed Basso Mouse Scale, Grid Walk, von Frey Hair, and Plantar Heat Testing before and out to day 42 post-SCI. Open field locomotion was significantly better in the Thy1 SCI groups (TG+ and TG-) compared with WT by 7 dpi (p < 0.01) and was maintained through 42 dpi (p < 0.01). These unexpected locomotor gains were not apparent during grid walking, indicating severe impairment of precise motor control. Thy1 derived mice were hypersensitive to mechanical stimuli at baseline (p < 0.05). After SCI, mechanical hyposensitivity emerged in Thy1 derived groups (p < 0.001), while thermal hyperalgesia occurred in all groups (p < 0.001). Importantly, consistent findings across TG+ and TG- groups suggest that the effects are mediated by the genetic background rather than transgene manipulation itself. Surprisingly, TM training restored mechanical and thermal sensation to baseline levels in TG+ mice with SCI. This behavioral profile and responsiveness to chronic training will be important to consider when choosing models to study the mechanisms underlying sensorimotor recovery after SCI. PMID- 29385895 TI - Resting-State Alpha-Band Oscillations in Migraine. AB - Migraine groups show differences in motion perception compared with controls, when tested in between migraine attacks (interictally). This is thought to be due to an increased susceptibility to stimulus degradation (multiplicative internal noise). Fluctuations in alpha-band oscillations are thought to regulate visual perception, and so differences could provide a mechanism for the increased multiplicative noise seen in migraine. The aim of this article was to characterise resting-state alpha-band oscillations (between 8 and 12 Hz) in the visual areas of the brain in migraine and control groups. Alpha-band activity in the resting state (with eyes closed) was recorded before and after a visual psychophysics task to estimate equivalent noise, specifically a contrast detection task. The lower alpha-band (8 to 10 Hz) resting-state alpha-band power was increased in the migraine compared with the control group, which may provide a mechanism for increased multiplicative noise. In agreement with previous research, there were no differences found in the additive (baseline) internal noise, estimated using an equivalent noise task in the same observers. As fluctuations in alpha-band oscillations control the timing of perceptual processing, increased lower alpha-band (8 to 10 Hz) power could explain the behavioural differences in migraine compared with control groups, particularly on tasks relying on temporal integration. PMID- 29385896 TI - Dr Stian Erichsen. PMID- 29385894 TI - Role of immune-checkpoint inhibitors in lung cancer. AB - Immune checkpoint inhibitors, mainly drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways, represent a remarkable advance in lung cancer treatment. Immune checkpoint inhibitors targeting PD-1 and PD-L1 are approved for the treatment of patients with non-small-cell lung cancer, with impressive clinical activity and durable responses in some patients. This review will summarize the mechanism of action of these drugs, the clinical development of these agents and the current role of these agents in the management of patients with lung cancer. In addition, the review will discuss the role of predictive biomarkers for optimal patient selection for immunotherapy and management of autoimmune side effects of these agents. PMID- 29385893 TI - Population modification of Anopheline species to control malaria transmission. AB - Vector control strategies based on population modification of Anopheline mosquitoes may have a significant role in the malaria eradication agenda. They could consolidate elimination gains by providing barriers to the reintroduction of parasites and competent vectors, and allow resources to be allocated to new control sites while maintaining treated areas free of malaria. Synthetic biological approaches are being used to generate transgenic mosquitoes for population modification. Proofs-of-principle exist for mosquito transgenesis, the construction of anti-parasite effector genes and gene-drive systems for rapidly introgressing beneficial genes into wild populations. Key challenges now are to develop field-ready strains of mosquitoes that incorporate features that maximize safety and efficacy, and specify pathways from discovery to development. We propose three pathways and a framework for target product profiles that maximize safety and efficacy while meeting the demands of the complexity of malaria transmission, and the regulatory and social diversity of potential end-users and stakeholders. PMID- 29385897 TI - Revised taxonomy and nomenclature of rodent Pasteurellaceae: Implications for monitoring. AB - Pasteurellosis is a well-recognized disease with similar pathology in all laboratory rodent species. Pasteurella pneumotropica is the most frequently mentioned member of the Pasteurellaceae isolated from mice and rats. Numerous other Pasteurellaceae taxa have been obtained from mice, rats, and other rodent species. Recently, rodent Pasteurellaceae have been submitted to comprehensive genetic and phenotypic (polyphasic) taxonomic studies. As a result they are now classed within six validly published new genera, namely Cricetibacter, Mesocricetibacter, Mannheimia, Muribacter, Necropsobacter, and Rodentibacter. All previously used names such as P. pneumotropica have become obsolete. The new classification forms a firm basis for the correct phenotypic identification of Pasteurellaceae from laboratory animals and for the selection of strains for pathogenicity studies. Consequences of taxonomic changes notably involve molecular methods used for the detection of Pasteurellaceae infection in laboratory animal colonies. Testing may be done using primer sets that detect all Pasteurellaceae taxa or sets developed to detect host-specific members of the family. PMID- 29385898 TI - Evaluation of ureteral lesions in ureterorenoscopy: impact of access sheath use. AB - OBJECTIVE: The aim of this study was to evaluate the incidence of ureteral lesions in retrograde intrarenal surgery (RIRS) with and without the use of a 10/12 Fr ureteral access sheath (UAS). A further objective was to search for preoperative factors that could influence the risk of ureteral damage. MATERIALS AND METHODS: Data were collected from a clinical database on 180 consecutive adult patients undergoing RIRS for kidney stones with or without a 10/12 Fr UAS. The primary outcome measure was ureteral lesions endoscopically identified at the end of surgery using the Post-Ureteroscopic Lesion Scale (PULS) classification system. RESULTS: The use of 10/12 Fr UASs resulted in less severe lesions than reported previously with larger diameter UASs. There was a higher risk of superficial lesions in the UAS group, with a calculated crude odds ratio (OR) of 1.84 [95% confidence interval (CI) 1.00-3.37]. When adjusting for age and gender, the OR was 1.68 (95% CI 0.90-3.13; p = 0.10) and thus was not significant. The only factor that remained significant was age (OR =1.02/year, 95% CI 1.00-1.04). CONCLUSION: There was a trend towards a higher risk of ureteral lesions in RIRS with a 10/12 Fr UAS compared with an endoscope alone, but when adjusting for age and gender the incidence of ureteral lesions was comparable between RIRS with and without the use of a 10/12 Fr UAS. PMID- 29385900 TI - Looking to the future of nasal drug delivery - an interview with Per Gisle Djupesland. AB - Per G Djupesland, MD, PhD speaks to Hannah Makin, Commissioning Editor: Dr Djupesland is the inventor of OptiNose(r)'s patented, bi-directional nasal drug delivery technology and is a Co-Founder of OptiNose AS. Dr. Djupesland is a lead inventor on all 38 OptiNose patent families/patent applications, and serves as Chief Scientific Officer of OptiNose AS, with primary responsibility for device discovery and early development efforts. These early development efforts include identifying new product opportunities that use bi-directional technology, advancing the design of devices using the bi-directional technology to treat a variety of medical conditions and conducting Phase I and IIa trials with new 'nose-to-brain' applications for the technology. Dr Djupesland is an otolaryngologist (ENT) with a specialization in rhinology and more than 25 years of clinical experience. Among other positions prior to OptiNose, he served as a Clinical Research Fellow at the Hospital for Sick Children and Toronto General in Toronto, Canada, primarily studying the role of nitric oxide in the upper airways. Dr Djupesland has authored more than 60 peer reviewed articles in international medical journals and has lectured at numerous international scientific conferences. He earned medical and doctorate degrees in the field of nasal physiology and aerodynamics from the University of Oslo. PMID- 29385899 TI - Insulin-like growth factor-1 (IGF1) in systemic lupus erythematosus: relation to disease activity, organ damage and immunological findings. AB - Background Insulin growth factor-1 (IGF1) activates cell proliferation pathways and inhibits apoptosis. IGF1 is involved in tumour growth and required for T-cell independent activation of B cells. Activated B cells and autoantibody production are a hallmark of systemic lupus erythematosus (SLE). To investigate the possible role of IGF1 in SLE, we studied IGF1 across clinical characteristics, immunological biomarkers, disease activity and organ damage in SLE patients. Method In a cross-sectional study, we collected clinical characteristics, medication, disease activity (SLEDAI-2K) and organ damage (SDI) for 94 SLE patients. Autoantibodies and cytokines were measured by ELISA, and levels of IGF1 and IGF binding protein 3 (IGFBP3) by chemiluminescence. Free IGF1 was estimated by the IGF1:IGFBP3 ratio. Healthy controls served as a comparator group. Results There was a significant age-related decline in IGF1, IGFBP3 and free IGF1 (IGF1:IGFBP3 ratio) that was similar in SLE patients and controls with very few outliers. Free IGF1 was inversely related to blood pressure (Rs -0.327, p < 0.01) and HbA1c (Rs -0.31, p < 0.01). Free IGF1 was higher in disease-modifying antirheumatic drug-treated patients ( p < 0.01), but there was no significant association between the IGF1 axis and autoantibody profiles, cytokine levels or SLEDAI-2K or SDI categories. IGF1 correlated inversely with BAFF level and B, natural killer and CD8 + cell counts. Conclusion Free IGF1 levels in SLE patients declined appropriately with age. IGF1 levels were not associated with disease activity, severity or autoantibody levels in SLE. Free IGF1 had positive metabolic effects in SLE and may play an indirect role in dampening the cellular immune response by downregulating B- and T-cell activity. PMID- 29385901 TI - OPAT: proof of concept in a peripheral Belgian hospital after review of the literature. AB - Since its introduction in the 1970s in the United States, outpatient parenteral antibiotic/antimicrobial therapy (OPAT) has been adopted internationally for long term intravenous (IV) treatment of stable infectious diseases. The aim is to provide a safe and successful completion of IV antimicrobial treatment at the ambulatory care center or at home without complications and costs associated with hospitalization. OPAT implementation has been accelerated by progress in vascular access devices, newly available antibiotics, the emphasis on cost-savings, as well as an improved patient comfort and a reduced incidence of health care associated infections with a similar outcome. OPAT utilization is supported by an extensive published experience and guidelines of the British Society of Antimicrobial Chemotherapy and the Infectious Diseases Society of America for adults as well as for children. Despite these recommendations and its widespread adoption, in Belgium OPAT is only fully reimbursed and established for cystic fibrosis patients. Possible explanations for this unpopularity include physician unfamiliarity and a lack of uniform funding arrangements with higher costs for the patient. This article aims to briefly review benefits, risks, indications, financial impact for supporting OPAT in a non-university hospital as standard of care. Our experience with OPAT at the ambulatory care center of our hospital and its subsequent recent introduction in the home setting is discussed. PMID- 29385902 TI - Understanding the meaning of youth sexual and reproductive well-being in Fiji. AB - Well-being is a term commonly used in discussions of sexuality, reproduction and sexual health, yet the meaning of the term is elusive and often disregarded. As an example, the 'well-being' component of sexual and reproductive health and well being is often not explicitly addressed in research, policy and programme development. The goal of this paper is to explore the meanings of sexual and reproductive well-being among young people in Fiji and their implications. Fourteen focus group discussions with young people aged 15 to 19 years and 40 key informant interviews were held in four Fijian settings. We found both different and shared meanings of sexual and reproductive well-being and suggest areas in which it can be strengthened in Fiji. PMID- 29385903 TI - The changing relationship between unemployment and total fertility. AB - The aim of this paper is to investigate whether there has been a fundamental change in the relationship between economic conditions and fertility. We use panel data methods to study the short-term changes in total fertility and the unemployment rate in a range of Organisation for Economic Co-operation and Development (OECD) countries from 1957 to 2014. We find that although fertility was counter-cyclical before 1970, with good economic times being associated with lower fertility, since then it has become pro-cyclical, with good economic times being associated with higher fertility. PMID- 29385905 TI - Relevance of the listener's motor system in recalling phrases enacted by the speaker. AB - Memory for series of action phrases improves in listeners when speakers accompany each phrase with congruent gestures compared to when speakers stay still. Studies reveal that the listeners' motor system, at encoding, plays a crucial role in this enactment effect. We present two experiments on gesture observation, which explored the role of the listeners' motor system at recall. The participants listened to the phrases uttered by a speaker in two conditions in each experiment. In the gesture condition, the speaker uttered the phrases with accompanying congruent gestures, and in the no-gesture condition, the speaker stayed still while uttering the phrases. The participants were then invited, in both conditions of the experiments, to perform a motor task while recalling the phrases proffered by the speaker. The results revealed that the advantage of observing gestures on memory disappears if the listeners move at recall arms and hands (same motor effectors moved by the speaker, Experiment 1a), but not when the listeners move legs and feet (different motor effectors from those moved by the speaker, Experiment 1b). The results suggest that the listeners' motor system is involved not only during the encoding of action phrases uttered by a speaker but also when recalling these phrases during retrieval. PMID- 29385904 TI - Effects of weightlifting exercise, traditional resistance and plyometric training on countermovement jump performance: a meta-analysis. AB - Jump performance is considered an important factor in many sports. Thus, strategies such as weightlifting (WL) exercises, traditional resistance training (TRT) and plyometric training (PT) are effective at improving jump performance. However, it is not entirely clear which of these strategies can enable greater improvements on jump height. Thus, the purpose of the meta-analysis was to compare the improvements on countermovement jump (CMJ) performance between training methods which focus on WL exercises, TRT, and PT. Seven studies were included, of which one study performed both comparison. Therefore, four studies comparing WL exercises vs. TRT (total n = 78) and four studies comparing WL exercises vs. PT (total n = 76). The results showed greater improvements on CMJ performance for WL exercises compared to TRT (ESdiff: 0.72 +/- 0.23; 95%CI: 0.26, 1.19; P = 0.002; Delta % = 7.5 and 2.1, respectively). The comparison between WL exercises vs. PT revealed no significant difference between protocols (ESdiff: 0.15 +/- 0.23; 95%CI: -0.30, 0.60; P = 0.518; Delta % = 8.8 and 8.1, respectively). In conclusion, WL exercises are superior to promote positive changes on CMJ performance compared to TRT; however, WL exercises and PT are equally effective at improving CMJ performance. PMID- 29385906 TI - Process and impact evaluation of a community gender equality intervention with young men in Rajasthan, India. AB - This paper reports on the results of a process and impact evaluation to assess the effects of a project aiming to engage men in changing gender stereotypes and improving health outcomes for women in villages in Rajasthan, India. We conducted seven focus group discussions with participants in the programme and six in-depth interviews with intervention group leaders. We also conducted 137 pre- and 70 post-intervention surveys to assess participant and community knowledge, attitudes and behaviours surrounding gender, violence and sexuality. We used thematic analysis to identify process and impact themes, and hierarchical mixed linear regression for the primary outcome analysis of survey responses. Post intervention, significant changes in knowledge and attitudes regarding gender, sexuality and violence were made on the individual level by participants, as well as in the community. Moderate behavioural changes were seen in individuals and in the community. Study findings offer a strong model for prevention programmes working with young men to create a community effect in encouraging gender equality in social norms. PMID- 29385907 TI - Analysis of synovial fluid visfatin level in temporomandibular joint disorders. AB - BACKGROUND: Biochemical analysis of synovial fluid (SF) is an important means of understanding the pathogenesis of temporomandibular disorder (TMD) and confirming diagnoses made using traditional methods. OBJECTIVE: The aim of this study was to determine whether or not SF visfatin levels can serve as a biochemical marker in the diagnosis of TMD. METHOD: Sixty samples of SF were obtained from 60 patients with internal derangement (ID) or osteoarthritis (OA). Visfatin in the SF was examined by enzyme-linked immunosorbent assay (ELISA). RESULT: Visfatin levels showed positive correlations with TMD pain and ID stage and a negative correlation with maximum mouth opening. In addition, Visfatin levels in joints with OA changes in the condyle were significantly higher in comparison to joints with no OA changes. CONCLUSION: Within the limitations of this study, it can be concluded that visfatin may play a role in the pathogenesis of TMD. PMID- 29385908 TI - The calm before the storm: clinical observations of Middle East respiratory syndrome (MERS) patients. AB - BACKGROUND: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection emerged in 2012. The majority of cases occurred in the Kingdom of Saudi Arabia and the disease carries a high case fatality rate. METHODS: We present three MERS CoV cases and highlight the salient clinical features and laboratory, and radiographic characteristics. RESULTS: Although all nasopharyngeal samples were negative, MERS CoV infection was confirmed by reverse transcription-polymerase chain reaction of the E gene (UpE) and open reading frame (ORF1b) on sputum samples. The Ct value of the ORF1 gene was 24.8-29.11. One patient had been on immune suppressive agent and two patients had diabetes mellitus. The average length of hospital stay was 10.6 days. Two patients received ribavirin and IFN a2b in addition to supportive management. The clinical course for these patients started with a febrile period lasting five days, a reduction in fever was coinciding with increased respiratory rate and oxygen requirements. All patients were discharged home. None of the 50 contacts tested positive for MERS-CoV. CONCLUSION: Resolution of the fever was accompanied by an increase in oxygen requirements and respiratory rate also lasting several days. This was followed by resolution of all symptoms and return to normal. PMID- 29385909 TI - Wu-Tou Decoction Inhibits Angiogenesis in Experimental Arthritis by Targeting VEGFR2 Signaling Pathway. AB - Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been extensively used for the treatment of rheumatoid arthritis (RA). Previous reports indicate that WTD possesses anti-inflammatory and antinociceptive activities, and inhibits the development of arthritic joints and disease severity of collagen-induced arthritis (CIA) or adjuvant-induced rats; however, its action on angiogenesis of RA has not been clarified. This study aims to determine the anti-angiogenic activity of WTD in CIA rats and in various angiogenesis models. Our data showed that WTD (0.95, 1.9, and 3.8 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA rats. It also inhibited in vivo angiogenesis in chick embryo and VEGF165-induced microvessel sprout formation ex vivo. Meanwhile, WTD suppressed VEGF165-/MH7A induced migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, WTD significantly reduced the expression of angiogenic activators, including vascular endothelial growth factor (VEGF), VEGFR2, interleukin (IL)-1beta, IL-17, transforming growth factor-beta, platelet derived growth factor, placenta growth factor, angiopoietin (Ang) I and Ang II in synovium of CIA rats, and/or in HUVECs. More interestingly, WTD blocked the autophosphorylation of VEGF165-induced VEGFR2 and consequently downregulated the signaling pathways of activated AKT, ERK1/2, JNK, and p38 in VEGF165-induced HUVECs. These findings suggest for the first time that WTD possesses the anti angiogenic effect in RA in vivo, ex vivo, and in vitro by interrupting the targeting of VEGFR2 activation. PMID- 29385910 TI - Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis. AB - The aim of this study was to evaluate mannose-anchored thiolated chitosan (MTC) based nanocarriers (NCs) for enhanced permeability, improved oral bioavailability and anti-parasitic potential of amphotericin B (AmB). Transgenic Leishmania donovani parasites expressing red fluorescent protein DsRed2 and imaging-flow cytometry was used to investigate parasitic burdens inside bone marrow-derived macrophages ex vivo. Cytokine estimation revealed that MTC nanocarriers activated the macrophages to impart an explicit immune response by higher production of TNF alpha and IL-12 as compared to control. Cells treated with MTC NCs showed a significantly higher magnitude of nitrite and propidium iodide (PI) fluorescence intensity in contrast to cells treated with AmB. Concerning to apparent permeability coefficient (Papp) results, the MTC NCs formulation displayed more specific permeation across the Caco-2 cell monolayer as compared to AmB. The half life of MTC NCs was about 3.3-fold persistent than oral AmB used as positive control. Also, t oral bioavailability of AmB was increased to 6.4-fold for MTC NCs compared to AmB for positive control. Acute oral evaluation indicated that MTC NCs were significantly less toxic compared to the AmB. Based on these findings, MTC NCs seems to be promising for significant oral absorption and improved oral bioavailability of AmB in leishmaniasis chemotherapy. PMID- 29385911 TI - Cultural and communicative memories: contrasting Argentina's 1976 coup d'etat and the 2001 economic-political-social crisis. AB - Studies on collective memory have recently addressed the distinction between cultural and communicative memory as a way to understand how the source of a memory affects its structure or form. When a groups' memory is mediated by memorials, documentaries or any other cultural artifacts, collective memory is shaped by cultural memory. When it is based mostly in communication with other people, its source is communicative memory. We address this distinction by studying two recent events in Argentinean history: the 2001 economic-political social crisis (communicative memory) and the 1976 coup (cultural memory). We also examine the political ideology and the type of memory involved in collective memory. The memory of the studied events may occur during the lifetime of the rememberer (Lived Memory) or refer to distant events (Distant Memory). 100 participants responded to a Free Recall task about the events of 2001 in Argentina. Narrative analysis allowed comparing these recalls with our 1976 study. Results show: 1) Cultural memories are more contextualised, more impersonal and less affective. 2) Communicative memories are more personal and affective. Study shows how collective memory form changes when it has a different prevalent source. PMID- 29385913 TI - Erratum. Initial experience with a robotically operated video optical telescopic microscope in cranial neurosurgery: feasibility, safety, and clinical applications. PMID- 29385912 TI - Editorial. Tremor, thalamotomy, and cognition. PMID- 29385914 TI - Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy for tremor: technical note. AB - Although the use of focused ultrasound (FUS) in neurosurgery dates to the 1950s, its clinical utility was limited by the need for a craniotomy to create an acoustic window. Recent technological advances have enabled efficient transcranial delivery of US. Moreover, US is now coupled with MRI to ensure precise energy delivery and monitoring. Thus, MRI-guided transcranial FUS lesioning is now being investigated for myriad neurological and psychiatric disorders. Among the first transcranial FUS treatments is thalamotomy for the treatment of various tremors. The authors provide a technical overview of FUS thalamotomy for tremor as well as important lessons learned during their experience with this emerging technology. PMID- 29385915 TI - Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters. AB - OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future. PMID- 29385916 TI - Introduction. Focused ultrasound. PMID- 29385917 TI - A meta-analysis of outcomes and complications of magnetic resonance-guided focused ultrasound in the treatment of essential tremor. AB - OBJECTIVE Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel technique that uses high-intensity focused ultrasound to achieve target ablation. Like a lens focusing the sun's rays, the ultrasound waves are focused to generate heat. This therapy combines the noninvasiveness of Gamma Knife thalamotomy and the real-time ablation of deep brain stimulation with acceptable complication rates. The aim of this study was to analyze the overall outcomes and complications of MRgFUS in the treatment of essential tremor (ET). METHODS A meta analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was made by searching PubMed, Cochrane library database, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Patients with the diagnosis of ET who were treated with MRgFUS were included in the study. The change in the Clinical Rating Scale for Tremor (CRST) score after treatment was analyzed. The improvement in disability was assessed with the Quality of Life in Essential Tremor Questionnaire (QUEST) score. The pooled data were analyzed by the DerSimonian Laird random-effects model. Tests for bias and heterogeneity were performed. RESULTS Nine studies with 160 patients who had ET were included in the meta analysis. The ventral intermediate nucleus was the target in 8 of the studies. The cerebellothalamic tract was targeted in 1 study. There was 1 randomized controlled trial, 6 studies were retrospective, and 2 were prospective. The mean number of sonications given in various studies ranged from 11 +/- 3.2 to 22.5 +/- 7.5 (mean +/- SD). The maximum delivered energy ranged from 10,320 +/- 4537 to 14,497 +/- 6695 Joules. The mean of peak temperature reached ranged from 53 degrees C +/- 2.3 degrees C to 62.0 degrees C +/- 2.5 degrees C. On meta-analysis with the random-effects model, the pooled percentage improvements in the CRST Total, CRST Part A, CRST Part C, and QUEST scores were 62.2%, 62.4%, 69.1%, and 46.5%, respectively. Dizziness was the most common in-procedure complication, occurring in 45.5%, followed by nausea and vomiting in 26.85% (pooled percentage). At 3 months, ataxia was the most common complication, occurring in 32.8%, followed by paresthesias in 25.1% of the patients. At 12 months posttreatment, the ataxia had significantly recovered and paresthesias became the most common persisting complication, at 15.3%. CONCLUSIONS The MRgFUS therapy for ET significantly improves the CRST scores and improves the quality of life in patients with ET, with an acceptable complication rate. Therapy with MRgFUS is a promising frontier in functional neurosurgery. PMID- 29385918 TI - Magnetic resonance-guided, high-intensity focused ultrasound sonolysis: potential applications for stroke. AB - Stroke is one of the leading causes of death worldwide and a significant source of long-term morbidity. Unfortunately, a substantial number of stroke patients either are ineligible or do not significantly benefit from contemporary medical and interventional therapies. To address this void, investigators recently made technological advances to render transcranial MR-guided, high-intensity focused ultrasound (MRg-HIFU) sonolysis a potential therapeutic option for both acute ischemic stroke (AIS)-as an alternative for patients with emergent large-vessel occlusion (ELVO) who are ineligible for endovascular mechanical thrombectomy (EMT) or as salvage therapy for patients in whom EMT fails-and intracerebral hemorrhage (ICH)-as a neoadjuvant means of clot lysis prior to surgical evacuation. Herein, the authors review the technological principles behind MRg HIFU sonolysis, its results in in vitro and in vivo stroke models, and its potential clinical applications. As a noninvasive transcranial technique that affords rapid clot lysis, MRg-HIFU thrombolysis may develop into a therapeutic option for patients with AIS or ICH. However, additional studies of transcranial MRg-HIFU are necessary to ascertain the merit of this treatment approach for thrombolysis in both AIS and ICH, as well as its technical limitations and risks. PMID- 29385919 TI - Focused ultrasound in neurosurgery: a historical perspective. AB - Focused ultrasound (FUS) has been under investigation for neurosurgical applications since the 1940s. Early experiments demonstrated ultrasound as an effective tool for the creation of intracranial lesions; however, they were limited by the need for craniotomy to avoid trajectory damage and wave distortion by the skull, and they also lacked effective techniques for monitoring. Since then, the development and hemispheric distribution of phased arrays has resolved the issue of the skull and allowed for a completely transcranial procedure. Similarly, advances in MR technology have allowed for the real-time guidance of FUS procedures using MR thermometry. MR-guided FUS (MRgFUS) has primarily been investigated for its thermal lesioning capabilities and was recently approved for use in essential tremor. In this capacity, the use of MRgFUS is being investigated for other ablative indications in functional neurosurgery and neurooncology. Other applications of MRgFUS that are under active investigation include opening of the blood-brain barrier to facilitate delivery of therapeutic agents, neuromodulation, and thrombolysis. These recent advances suggest a promising future for MRgFUS as a viable and noninvasive neurosurgical tool, with strong potential for yet-unrealized applications. PMID- 29385920 TI - A minimally invasive catheter-based ultrasound technology for therapeutic interventions in brain: initial preclinical studies. AB - OBJECTIVE Minimally invasive procedures may allow surgeons to avoid conventional open surgical procedures for certain neurological disorders. This paper describes the iterative process for development of a catheter-based ultrasound thermal therapy applicator. METHODS Using an ultrasound applicator with an array of longitudinally stacked and angularly sectored tubular transducers within a catheter, the authors conducted experimental studies in porcine liver, in vivo and ex vivo, in order to characterize the device performance and lesion patterns. In addition, they applied the technique in a rodent model of Parkinson's disease to investigate the feasibility of its application in brain. RESULTS Thermal lesions with multiple shapes and sizes were readily achieved in porcine liver. The feasibility of catheter-based focused ultrasound in the treatment of brain conditions was demonstrated in a rodent model of Parkinson's disease. CONCLUSIONS The authors show proof of principle of a catheter-based ultrasound system that can create lesions with concurrent thermode-based measurements. PMID- 29385921 TI - Volumetric analysis of magnetic resonance-guided focused ultrasound thalamotomy lesions. AB - OBJECTIVE Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy was recently approved for use in the treatment of medication-refractory essential tremor (ET). Previous work has described lesion appearance and volume on MRI up to 6 months after treatment. Here, the authors report on the volumetric segmentation of the thalamotomy lesion and associated edema in the immediate postoperative period and 1 year following treatment, and relate these radiographic characteristics with clinical outcome. METHODS Seven patients with medication-refractory ET underwent MRgFUS thalamotomy at Brigham and Women's Hospital and were monitored clinically for 1 year posttreatment. Treatment effect was measured using the Clinical Rating Scale for Tremor (CRST). MRI was performed immediately postoperatively, 24 hours posttreatment, and at 1 year. Lesion location and the volumes of the necrotic core (zone I) and surrounding edema (cytotoxic, zone II; vasogenic, zone III) were measured on thin-slice T2-weighted images using Slicer 3D software. RESULTS Patients had significant improvement in overall CRST scores (baseline 51.4 +/- 10.8 to 24.9 +/- 11.0 at 1 year, p = 0.001). The most common adverse events (AEs) in the 1-month posttreatment period were transient gait disturbance (6 patients) and paresthesia (3 patients). The center of zone I immediately posttreatment was 5.61 +/- 0.9 mm anterior to the posterior commissure, 14.6 +/- 0.8 mm lateral to midline, and 11.0 +/- 0.5 mm lateral to the border of the third ventricle on the anterior commissure-posterior commissure plane. Zone I, II, and III volumes immediately posttreatment were 0.01 +/- 0.01, 0.05 +/- 0.02, and 0.33 +/- 0.21 cm3, respectively. These volumes increased significantly over the first 24 hours following surgery. The edema did not spread evenly, with more notable expansion in the superoinferior and lateral directions. The spread of edema inferiorly was associated with the incidence of gait disturbance. At 1 year, the remaining lesion location and size were comparable to those of zone I immediately posttreatment. Zone volumes were not associated with clinical efficacy in a statistically significant way. CONCLUSIONS MRgFUS thalamotomy demonstrates sustained clinical efficacy at 1 year for the treatment of medication-refractory ET. This technology can create accurate, predictable, and small-volume lesions that are stable over time. Instances of AEs are transient and are associated with the pattern of perilesional edema expansion. Additional analysis of a larger MRgFUS thalamotomy cohort could provide more information to maximize clinical effect and reduce the rate of long lasting AEs. PMID- 29385922 TI - A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy. AB - Magnetic resonance-guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain. PMID- 29385923 TI - High-intensity focused ultrasound: past, present, and future in neurosurgery. AB - Since Lynn and colleagues first described the use of focused ultrasound (FUS) waves for intracranial ablation in 1942, many strides have been made toward the treatment of several brain pathologies using this novel technology. In the modern era of minimal invasiveness, high-intensity focused ultrasound (HIFU) promises therapeutic utility for multiple neurosurgical applications, including treatment of tumors, stroke, epilepsy, and functional disorders. Although the use of HIFU as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists, neurologists, or even neurosurgeons are familiar with it. In this extensive review, the authors intend to shed light on the current use of HIFU in different neurosurgical avenues and its mechanism of action, as well as provide an update on the outcome of various trials and advances expected from various preclinical studies in the near future. Although the initial technical challenges have been overcome and the technology has been improved, only very few clinical trials have thus far been carried out. The number of clinical trials related to neurological disorders is expected to increase in the coming years, as this novel therapeutic device appears to have a substantial expansive potential. There is great opportunity to expand the use of HIFU across various medical and surgical disciplines for the treatment of different pathologies. As this technology gains recognition, it will open the door for further research opportunities and innovation. PMID- 29385925 TI - Predicting lesion size during focused ultrasound thalamotomy: a review of 63 lesions over 3 clinical trials. AB - OBJECTIVE The goal of this study was to improve the predictability of lesion size during focused ultrasound (FUS) thalamotomy procedures. METHODS Treatment profiles and T2-weighted MRI (T2 MRI) studies obtained in 63 patients who participated in 3 clinical trials of FUS thalamotomy from February 2011 to March 2015 were reviewed retrospectively. Four damage estimate models were compared with lesion sizes measured on postprocedural T2 MRI. Models were based on 54 degrees C * 3 seconds, 240 cumulative equivalent minutes at 43 degrees C, and simple thermal threshold analysis, which recorded the maximum diameter that reached a temperature of at least 51 degrees C and 54 degrees C. Energy requirements per degrees C thermal rise above 37 degrees C were also recorded. RESULTS Lesion diameters from T2 MRI correlated poorly from the day of the procedure to day 1 postprocedure (mean increase 78% [SD 79%]). There was more predictability of lesion size from day 1 to day 30, with a mean reduction in lesion diameter of 11% (SD 24%). Of the 4 models tested, the most correlative model to day 1 findings on T2 MRI was a 51 degrees C threshold. The authors observed an increase in the energy requirement for each subsequent treatment sonication, with the largest percentage increase from treatment sonication 1 to treatment sonication 2 (mean increase 20% in energy required per degrees C increase in temperature above 37 degrees C). CONCLUSIONS At the margins, 51 degrees C temperature threshold diameters correlated best to lesion diameters measured at day 1 with T2 MRI. The lesion size from T2 MRI decreases from day 1 to day 30 in a predictable manner, much more so than from the day of the procedure to day 1 postprocedure. Energy requirements per degrees C rise above 37 degrees C continuously increase with each successive sonication. PMID- 29385924 TI - Neuromodulation with transcranial focused ultrasound. AB - The understanding of brain function and the capacity to treat neurological and psychiatric disorders rest on the ability to intervene in neuronal activity in specific brain circuits. Current methods of neuromodulation incur a tradeoff between spatial focus and the level of invasiveness. Transcranial focused ultrasound (FUS) is emerging as a neuromodulation approach that combines noninvasiveness with focus that can be relatively sharp even in regions deep in the brain. This may enable studies of the causal role of specific brain regions in specific behaviors and behavioral disorders. In addition to causal brain mapping, the spatial focus of FUS opens new avenues for treatments of neurological and psychiatric conditions. This review introduces existing and emerging FUS applications in neuromodulation, discusses the mechanisms of FUS effects on cellular excitability, considers the effects of specific stimulation parameters, and lays out the directions for future work. PMID- 29385926 TI - Magnetic resonance-guided interstitial high-intensity focused ultrasound for brain tumor ablation. AB - Currently, treatment of brain tumors is limited to resection, chemotherapy, and radiotherapy. Thermal ablation has been recently explored. High-intensity focused ultrasound (HIFU) is being explored as an alternative. Specifically, the authors propose delivering HIFU internally to the tumor with an MRI-guided robotic assistant (MRgRA). The advantage of the authors' interstitial device over external MRI-guided HIFU (MRgHIFU) is that it allows for conformal, precise ablation and concurrent tissue sampling. The authors describe their workflow for MRgRA HIFU delivery. PMID- 29385927 TI - Preliminary experience with a transcranial magnetic resonance-guided focused ultrasound surgery system integrated with a 1.5-T MRI unit in a series of patients with essential tremor and Parkinson's disease. AB - OBJECTIVE Transcranial magnetic resonance-guided focused ultrasound surgery (tcMRgFUS) is one of the emerging noninvasive technologies for the treatment of neurological disorders such as essential tremor (ET), idiopathic asymmetrical tremor-dominant Parkinson's disease (PD), and neuropathic pain. In this clinical series the authors present the preliminary results achieved with the world's first tcMRgFUS system integrated with a 1.5-T MRI unit. METHODS The authors describe the results of tcMRgFUS in a sample of patients with ET and with PD who underwent the procedure during the period from January 2015 to September 2017. A monolateral ventralis intermedius nucleus (VIM) thalamic ablation was performed in both ET and PD patients. In all the tcMRgFUS treatments, a 1.5-T MRI scanner was used for both planning and monitoring the procedure. RESULTS During the study period, a total of 26 patients underwent tcMRgFUS thalamic ablation for different movement disorders. Among these patients, 18 were diagnosed with ET and 4 were affected by PD. All patients with PD were treated using tcMRgFUS thalamic ablation and all completed the procedure. Among the 18 patients with ET, 13 successfully underwent tcMRgFUS, 4 aborted the procedure during ultrasound delivery, and 1 did not undergo the tcMRgFUS procedure after stereotactic frame placement. Two patients with ET were not included in the results because of the short follow-up duration at the time of this study. A monolateral VIM thalamic ablation in both ET and PD patients was performed. All the enrolled patients were evaluated before the treatment and 2 days after, with a clinical control of the treatment effectiveness using the graphic items of the Fahn-Tolosa-Marin tremor rating scale. A global reevaluation was performed 3 months (17/22 patients) and 6 months (11/22 patients) after the treatment; the reevaluation consisted of clinical questionnaires, neurological tests, and video recordings of the tests. All the ET and PD treated patients who completed the procedure showed an immediate amelioration of tremor severity, with no intra- or posttreatment severe permanent side effects. CONCLUSIONS Although this study reports on a small number of patients with a short follow-up duration, the tcMRgFUS procedure using a 1.5-T MRI unit resulted in a safe and effective treatment option for motor symptoms in patients with ET and PD. To the best of the authors' knowledge, this is the first clinical series in which thalamotomy was performed using tcMRgFUS integrated with a 1.5-T magnet. PMID- 29385928 TI - Effects on cognition and quality of life with unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor. AB - OBJECTIVE Although neurosurgical procedures are effective treatments for controlling involuntary tremor in patients with essential tremor (ET), they can cause cognitive decline, which can affect quality of life (QOL). The purpose of this study is to assess the changes in the neuropsychological profile and QOL of patients following MR-guided focused ultrasound (MRgFUS) thalamotomy for ET. METHODS The authors prospectively analyzed 20 patients with ET who underwent unilateral MRgFUS thalamotomy at their institute in the period from March 2012 to September 2014. Patients were regularly evaluated with the Clinical Rating Scale for Tremor (CRST), neuroimaging, and cognition and QOL measures. The Seoul Neuropsychological Screening Battery was used to assess cognitive function, and the Quality of Life in Essential Tremor Questionnaire (QUEST) was used to evaluate the postoperative change in QOL. RESULTS The total CRST score improved by 67.3% (from 44.75 +/- 9.57 to 14.65 +/- 9.19, p < 0.001) at 1 year following MRgFUS thalamotomy. Mean tremor scores improved by 68% in the hand contralateral to the thalamotomy, but there was no significant improvement in the ipsilateral hand. Although minimal cognitive decline was observed without statistical significance, memory function was much improved (p = 0.031). The total QUEST score also showed the same trend of improving (64.16 +/- 17.75 vs 27.38 +/- 13.96, p < 0.001). CONCLUSIONS The authors report that MRgFUS thalamotomy had beneficial effects in terms of not only tremor control but also safety for cognitive function and QOL. Acceptable postoperative changes in cognition and much-improved QOL positively support the clinical significance of MRgFUS thalamotomy as a new, favorable surgical treatment in patients with ET. PMID- 29385929 TI - Extensive mitochondrial heteroplasmy in the neotropical ants of the Ectatomma ruidum complex (Formicidae: Ectatomminae). AB - We assembled mitogenomes from 21 ant workers assigned to four morphospecies (E. ruidum spp. 1-4) and putative hybrids of the Ectatomma ruidum complex (E. ruidum spp. 2x3), and to E. tuberculatum using NGS data. Mitogenomes from specimens of E. ruidum spp. 3, 4 and 2 * 3 had a high proportion of polymorphic sites. We investigated whether polymorphisms in mitogenomes are due to nuclear mt paralogues (numts) or due to the presence of more than one mitogenome within an individual (heteroplasmy). We did not find loss of function signals in polymorphic protein-coding genes, and observed strong evidence for purifying selection in two haplotype-phased genes, which indicate the presence of two functional mitochondrial genomes coexisting within individuals instead of numts. Heteroplasmy due to hybrid paternal leakage is not supported by phylogenetic analyses. Our results reveal the presence of a fast-evolving secondary mitochondrial lineage of uncertain origin in the E. ruidum complex. PMID- 29385931 TI - Neuropsychiatry of Traumatic Brain Injury: A 30-Year Perspective. PMID- 29385930 TI - Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems. AB - An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users. PMID- 29385932 TI - The Habenula's Role in Adaptive Behaviors: Contributions From Neuroimaging. PMID- 29385933 TI - Gestational impaired glucose tolerance (GIGT)-induced suppression of fetal thyroid secretion: effect on fetal outcome. AB - INTRODUCTION: Gestational impaired glucose tolerance (GIGT) is a milder form of gestational diabetes mellitus (GDM), which is often poorly managed. Although, GDM is known to be associated with increased incidence of thyroid dysfunction, no study has been done to study the effect of GIGT on thyroid status and its effect on fetal outcome. Here, we carried out a study to assess thyroid function and glycemic status in both maternal and cord blood of the subjects with GIGT, and to find their association with the fetal outcome. MATERIALS AND METHODS: Women who came to the hospital for safe confinement during 37-40th weeks of gestation were recruited in the study. Based on the 2 hours post prandial blood glucose levels with 75 grams OGTT, done at 24-28 weeks of gestation, all the subjects were stratified into two groups: (1) Cases or GIGT group - women with blood glucose levels between 120 and 140 mg/dl and (2) Controls - women with blood glucose levels of less than 120 mg/dl. Three milliliters of venous blood was collected from mothers and 3 ml of cord blood was collected during delivery. New-borns were assessed for birth weight, head circumference, abdominal circumference, thigh circumference, and crown-heel length. Glycated hemoglobin was carried out using immunoturbidimetry (DiaSys Diagnostic Systems GmbH, Holzheim, Germany) and fructosamine was estimated using dye binding method (Biosystems, Spain). Estimation of total T3 (TT3), free T3 (FT3), total T4 (TT4), free T4 (FT4), and TSH was done by chemiluminescence in Siemens Advia Centaur CP using competitive immunoassay. RESULTS: Although within the normal reference range, GIGT mothers had higher concentration of free and total T4 than controls. Cord fructosamine levels were significantly higher in babies of GIGT mothers than controls, indicating the reflection of maternal hyperglycemia. There was a positive correlation between the maternal glycated hemoglobin and cord blood fructosamine in the GIGT group. Statistically significant lower levels of total T3 and T4 with high TSH levels were found in babies with GIGT mothers, indicating the suppressive effect of maternal hyperglycemia on fetal thyroid function. Birth weight, head circumference, and thigh circumference were significantly higher in babies born to mothers with GIGT, which may be a combined effect of maternal hyperglycemia and fetal thyroid suppression. CONCLUSIONS: Maternal hyperglycemia, even in milder form of GIGT may cause suppression of fetal thyroid function. Both these factors may predispose to change in fetal anthropometry, leading to a large baby. Therefore, it is recommended to evaluate maternal and cord thyroid function for timely management strategies. PMID- 29385934 TI - A case of prolonged hyperemesis resulting in hepatorenal failure, foetal distress and neonatal mortality. AB - Hyperemesis gravidarum is defined as a condition emerging during pregnancy, is prominent with severe nausea and vomiting, a water-electrolyte imbalance and liver-kidney function disorder and causes more than 5% loss of body weight. In cases of severe hyperemesis gravidarum, maternal morbidities such as water electrolyte imbalance, hepatorenal failure, Wernicke's encephalopathy, splenic avulsion, oesophageal rupture, pneumothorax have been reported. We present a case of hyperemesis gravidarum, which continued until the third trimester and developed secondary hepatorenal failure, a water-electrolyte imbalance, intrauterine growth restriction, anhydramnios, foetal distress and neonatal mortality. PMID- 29385935 TI - Calf and colostrum management practices on New Zealand dairy farms and their associations with concentrations of total protein in calf serum. AB - AIMS: To gather information on management practices and farmer attitudes to management of cows and calves during the immediate post-partum period on dairy farms in New Zealand, and to assess these practices for associations with concentrations of total protein (TP) in serum of calves 1-8 days-old. METHOD: Between July and September 2015 blood samples were collected from calves aged between 24 hours and 7 days, from dairy farms (n=105) in nine areas in New Zealand, on three occasions throughout the calving period. Concentrations of TP were determined in all serum samples. At each visit technicians collected 1 L of the pooled colostrum that was intended for feeding to newborn calves that day. These samples were assessed for Brix, coliform and total bacterial counts. After the last sampling visit, the calf rearer or farm manager were asked to complete a questionnaire describing calf and colostrum management practices on the farm. Potential farm-level variables associated with concentrations of TP in serum of sampled calves were identified using univariable and multivariable linear mixed models. RESULTS: Mean concentration of TP in serum of calves across all farms was 59.8 (95% CI=59.4-60.2) g/L, and was associated with region and herd size in the final multivariable model. Concentrations of TP were lower in calves from farms in Otago (56.2 (95% CI=53.4-58.9) g/L) and Southland (56.9 (95% CI=54.1-59.7) g/L) compared to calves on farms in the Far North (62.6 (95% CI=59.8-65.3) g/L), and were lower in calves from farms with a herd size >600 (58.3 (95% CI=56.7 59.8) g/L) than <=600 (61.3 (95% CI=60.1-62.5) g/L) cows. After accounting for fixed effects, farm accounted for only 8.4% of the unexplained variation. There was no association between any of the measures of colostrum quality and concentrations of TP in serum (p>0.2). CONCLUSION AND CLINICAL RELEVANCE: Very few herd-level variables were associated with concentrations of TP in serum. Risk factors that have been shown to be of importance in previous studies outside New Zealand were not identified as important in the current study. It is possible that, in the situation where calves are kept at pasture with their dams for prolonged periods, variables which influence how well a cow can feed its calf in the first 12-24 hours have a larger influence on concentrations of TP in serum than the collection and management of calves once they reach the rearing shed. PMID- 29385936 TI - Hippocrates the otolaryngologist: an epidemiological analysis of ear-throat-nose diseases in the Corpus Hippocraticum. AB - INTRODUCTION: Hippocrates, a Greek physician during the fifth century BC., is often considered the father of medicine. The Corpus Hippocraticum comprising of 58 volumes was attributed to him alone for a long time. Nowadays, it is considered that several authors contributed to its creation between 450 and 150 BC., so over a period of 300 years. The objective of our study was to develop a nosological classification of all passages treating head and neck diseases. MATERIAL AND METHODS: We read and analyzed all volumes of the Corpus Hippocraticum in French translation and extracted all passages dealing with oto rhino-laryngological and maxillo-facial conditions (n = 65). We classified all pathologies into five distinctive nosological groups: traumatic, infectious, malformation, cancerous and inflammatory Results: Traumatic diseases represented 36.9% (n = 24), infectious 52.3% (n= 34), malformation 0% (n = 0), cancerous 11.5% (n = 1) and inflammatory 9.3% (n= 6). These results represent the living conditions of this era, during which diseases were mostly of infectious or traumatic nature (wars, physical labor and recreational sporting activity, living together on close quarters, etc.). CONCLUSION: The meticulously detailed observations of the corpus give us a precious insight into the early perception of diseases, their progression and early attempts of treatment. PMID- 29385938 TI - Medical students and intimate examinations: What affects whether a woman will consent? AB - OBJECTIVE: Undergraduate medical students often struggle to gain satisfactory competence levels in intimate examination. What factors increase the likelihood of a woman allowing a student to perform an intimate examination? METHODS: Questionnaires were given to women attending a tertiary gynecology hospital. Women were asked a series of questions about what would influence their decision to agree to be examined by a student. Demographic data and data on previous gynaecological history and preferences on any student who might see them in clinic. We asked women to indicate their willingness to agree to vaginal examination (but not to undergo the examination). RESULTS: Age, parity or civil status or the source of the request did not affect willingness to have a vaginal examination. The woman's hypothetical agreement was positively affected by the student's gender (female) and age (preferring older students); positively affected by an informal/relaxed manner and smart presentation, and positively by whether the woman had experienced gynecology clinics before. An association existed between being willing to be examined and whether the student had engaged with the woman by finding out what her presenting complaint was. CONCLUSIONS: Women's willingness to agree to vaginal examination is influenced by several student-related factors, some modifiable. PMID- 29385937 TI - Commentary: Polymerization and Its Similarity With Building Solid Evidence. PMID- 29385939 TI - Benign Chondromyxoid Fibroma of the Iliac Crest. AB - A 23-year-old woman initiated a running program and after 2 months began experiencing right hip joint pain and sharp pain at the iliac crest. Following evaluation by her primary care physician, she was referred to a physical therapist. Eighteen months later, the patient had developed a bony prominence at the iliac crest that was painful to touch. She returned to see her primary care physician. Radiographs of the right hip and pelvis were completed and showed a lytic lesion that warranted additional imaging. Computed tomography and magnetic resonance imaging precontrast and postcontrast were performed, and the patient was referred to an orthopaedic oncologist. Conclusive laboratory testing determined that the tumor was a chondromyxoid fibroma J Orthop Sports Phys Ther 2018;48(2):122. doi:10.2519/jospt.2018.7551. PMID- 29385940 TI - Knee Pain and Mobility Impairments: Meniscal and Articular Cartilage Lesions Revision 2018. AB - The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to meniscus and articular cartilage lesions. J Orthop Sports Phys Ther. 2018;48(2):A1-A50. doi:10.2519/jospt.2018.0301. PMID- 29385941 TI - Tarlov Cysts in a Woman With Lumbar Pain. AB - A 25-year-old woman presented to her primary care physician with thoracic spine pain; two weeks later, she returned to her primary care physician with lumbar spine pain that limited exercise and sitting for 30 minutes or less. The patient was referred to physical therapy for examination, then referred back to her primary care physician after complaints raised concern for a mass or other source of neurologic compression. Magnetic resonance imaging was performed and revealed 4 sacral perineural (Tarlov) cysts. J Orthop Sports Phys Ther 2018;48(2):121. doi:10.2519/jospt.2018.7644. PMID- 29385942 TI - Optimizing Recovery After Knee Meniscal or Cartilage Injury: Guidelines Help Deliver Quality Care. AB - An injury to your knee meniscus or joint cartilage can happen when you move suddenly or repeatedly move the wrong way. If you have such an injury, you may feel knee pain and have limited motion. Physical therapists can ensure that you and others with these injuries receive quality care to optimize recovery. The goal of revised clinical practice guidelines published in the February 2018 issue of the JOSPT is to make recommendations based on best practices from recent published literature for the evaluation, diagnosis, treatment, and determination of patient readiness to return to activities following knee meniscus or joint cartilage injury. Based on scientific research, these guidelines summarize the treatment options currently available. J Orthop Sports Phys Ther 2018;48(2):125. doi:10.2519/jospt.2018.0504. PMID- 29385943 TI - Entrapment Neuropathies: Challenging Common Beliefs With Novel Evidence. AB - Entrapment neuropathies are the most prevalent type of peripheral neuropathy and often a challenge to diagnose and treat. To a large extent, our current knowledge is based on empirical concepts and early (often biomechanical) studies. This Viewpoint will challenge some of the current beliefs with recent advances in both basic and clinical neurosciences. J Orthop Sports Phys Ther 2018;48(2):58-62. doi:10.2519/jospt.2018.0603. PMID- 29385944 TI - Knee Pain and Mobility Impairments: Meniscal and Articular Cartilage Lesions Revision 2018: Using the Evidence to Guide Physical Therapist Practice. AB - Meniscus and articular cartilage lesions are common knee injuries. The resulting knee pain and mobility impairments can be improved by physical therapists during nonoperative and operative management. Recommendations from clinical practice guidelines (CPGs) such as this revision, titled "Knee Pain and Mobility Impairments: Meniscal and Articular Cartilage Lesions," published in the February 2018 issue of JOSPT, can help physical therapists engage in evidence-informed practice and reduce unnecessary clinical variation. J Orthop Sports Phys Ther 2018;48(2):123-124. doi:10.2519/jospt.2018.0503. PMID- 29385945 TI - Low Back Pain: What Have Clinical Guidelines Ever Done for Us? AB - The burden that low back pain (LBP) presents to sufferers and society is well established. This ubiquitous condition is served by a complex global clinical marketplace offering a wide range of assessment alternatives and accompanying interventions. Yet, while the costs of care are rising, the global burden does not appear to be diminishing. Considerable effort internationally has gone into developing CPGs for LBP. The authors highlight the similarities and differences between existing CPGs for LBP, as well as strengths, weaknesses, and opportunities for improvement in the implementation of guidelines generally. J Orthop Sports Phys Ther 2018;48(2):54-57. doi:10.2519/jospt.2018.0602. PMID- 29385946 TI - The Impact of Annual Audiograms on Employee's Habits and Awareness Regarding Hearing Protection and Noise Induced Hearing Loss, On and Off the Job. AB - Noise-induced hearing loss occurs among workers across a wide spectrum of industries. The purpose of this study was to investigate whether annual hearing testing contributed to a change in employees' habits and awareness and aimed to evaluate the use of hearing protection at work and at home. Employees enrolled in a university's hearing conservation program (HCP) were anonymously surveyed regarding their hearing protection habits and awareness of noise exposures on and off the job using a Likert-type scale. Approximately half were "very much" concerned about hearing loss over time. Evidence supports that annual testing, part of the workplace HCP, also led over half of participants to change their habits at work and at home. Awareness of noise exposures increased both at home and at work with annual testing. Overall, the HCP in this particular setting was associated with improved on-the-job and home hearing protection use. PMID- 29385947 TI - On medical treatment for ureteral stone expulsion. AB - There is evidence that alpha-adrenoceptor (alpha-AR) antagonists facilitate the passage of ureteric stones, but the mechanism behind this effect has not been established. If one accepts that it is the friction between a ureteral stone and the mucosa that hampers the passage of the stone, and that the passage traumatizes the mucosa, the aim of treatment must be to reduce this friction. Elevated pressure above an obstructing stone results in an increase in tension in the wall of the upper urinary tract, including the tension at stone level, which causes an increase in friction and ureteric colic. Reducing pressure, by low but adequate fluid intake, non-steroidal anti-inflammatory drugs (NSAIDs), or alpha AR antagonists that reduce the friction and give pain relief, seems to be rational. When the stone is pressed downwards by a high pressure the mucosa forms a bar ahead of the stone. These factors reduce the ureteral lumen and hamper the passage of both urine and the stone. The swelling can be reduced by NSAIDs. Filling of the ureter ahead of the stone reduces the friction between the stone and the ureteral mucosa. Evacuation of the urine ahead of the stone by effective peristaltic activity increases this friction. alpha-AR antagonists that reduce peristalsis may therefore be used to reduce the friction and consequently allow the stones to pass more often and earlier. For very early stone expulsion, a combination of NSAIDs and alpha-AR antagonists may be useful. There is no evidence that spasm influences the passage of ureteral stones. PMID- 29385948 TI - The narrow vesicourethral angle measured on postoperative cystography can predict urinary incontinence after robot-assisted laparoscopic radical prostatectomy. AB - OBJECTIVE: Radical prostatectomy is associated with complications including urinary incontinence. A significant association between specific features of the vesicourethral anastomosis and urinary incontinence after radical prostatectomy has been demonstrated. The aim of this study was to identify the most useful predictor of postoperative urinary incontinence after robot-assisted laparoscopic radical prostatectomy (RALP) according to the features of the vesicourethral anastomosis as determined by postoperative cystography. MATERIALS AND METHODS: The final study cohort consisted of 150 patients. Postoperative cystography was performed within 1 week after RALP. The ratio between the longitudinal and horizontal lengths (L/H) of the bladder, the position of the urethrovesical junction (UVJ) and the bladder neck angle as seen on the cystogram were evaluated. Postoperative continence status was evaluated by a 1 h pad test 1 day after catheter removal and by the use of safety pads, retrieved retrospectively from patient records. The association between these variables and urinary incontinence was then analyzed. All patients were followed for at least 1 year postoperatively. RESULTS: The continence rates on the 1 h pad test and 1 month and 1 year after RALP were 31.3%, 56% and 93.3%, respectively. In multivariate analyses, urinary incontinence was significantly associated with nerve sparing, L/H and the vesical angle as determined on the 1 h pad test, but only with the vesical angle at 1 month and 1 year postoperatively. CONCLUSION: A narrow vesical angle measured on cystography is a useful predictor of postoperative urinary incontinence after RALP. PMID- 29385949 TI - Partnering With Black Churches to Increase Access to Care. PMID- 29385950 TI - How can interventions increase motivation for physical activity? A systematic review and meta-analysis. AB - Motivation is a proximal determinant of behaviour, and increasing motivation is central to most health behaviour change interventions. This systematic review and meta-analysis sought to identify features of physical activity interventions associated with favourable changes in three prominent motivational constructs: intention, stage of change and autonomous motivation. A systematic literature search identified 89 intervention studies (k = 200; N = 19,212) which assessed changes in these motivational constructs for physical activity. Intervention descriptions were coded for potential moderators, including behaviour change techniques (BCTs), modes of delivery and theory use. Random effects comparative subgroup analyses identified 18 BCTs and 10 modes of delivery independently associated with changes in at least one motivational outcome (effect sizes ranged from d = 0.12 to d = 0.74). Interventions delivered face-to-face or in gym settings, or which included the BCTs 'behavioural goal setting', 'self-monitoring (behaviour)' or 'behavioural practice/rehearsal', or which combined self monitoring (behaviour) with any other BCT derived from control theory, were all associated with beneficial changes in multiple motivational constructs (effect sizes ranged from d = 0.12 to d = 0.46). Meta-regression analyses indicated that increases in intention and stage of change, but not autonomous motivation, were significantly related to increases in physical activity. The intervention characteristics associated with changes in motivation seemed to form clusters related to behavioural experience and self-regulation, which have previously been linked to changes in physical activity behaviour. These BCTs and modes of delivery merit further systematic study, and can be used as a foundation for improving interventions targeting increases in motivation for physical activity. PMID- 29385951 TI - Integration of two-stage nanofiltration with arsenic and calcium intermediate chemical precipitation for gold mining effluent treatment. AB - The aim of this study was to evaluate an innovative treatment route for gold mining effluents rich in calcium, arsenic, and sulfate. This treatment route comprised two nanofiltration (NF) stages and a two-step intermediate precipitation. Arsenic and iron coprecipitation (first step) and calcium carbonate precipitation (second step) were assessed aiming to treat the first stage NF concentrate and increase the permeate recovery rate in a second-stage NF. The pH, the molar ratio of Fe/As (first step), and the molar ratio of CO3/Ca (second step) were optimized by using rotational central composite design. Under optimal conditions, the arsenic removal was 99.8% (at pH = 7.0 and Fe/As = 4.0), and the calcium removal was 99.5% (at pH 11.5 and CO3/Ca = 3.5). The supernatant of Ca precipitation had very basic pH and had to be acidified before the second stage NF. The pH 8.5 proved to be the best one regarding retention efficiency and flux. The flux decay of the second-stage NF was attributed to both osmotic pressure increase and reversible fouling resistance. It was concluded that the proposed treatment system is efficient for the treatment of gold-mining wastewater, ensuring higher production of treated effluent and an easy disposable of the final concentrate. PMID- 29385952 TI - Peer-Led Self-Management of General Medical Conditions for Patients With Serious Mental Illnesses: A Randomized Trial. AB - OBJECTIVE: Individuals with serious mental illnesses have high rates of general medical comorbidity and challenges in managing these conditions. A growing workforce of certified peer specialists is available to help these individuals more effectively manage their health and health care. However, few studies have examined the effectiveness of peer-led programs for self-management of general medical conditions for this population. METHODS: This randomized study enrolled 400 participants with a serious mental illness and one or more chronic general medical conditions across three community mental health clinics. Participants were randomly assigned to the Health and Recovery Peer (HARP) program, a self management program for general medical conditions led by certified peer specialists (N=198), or to usual care (N=202). Assessments were conducted at baseline and three and six months. RESULTS: At six months, participants in the intervention group demonstrated a significant differential improvement in the primary study outcome, health-related quality of life. Specifically, compared with the usual care group, intervention participants had greater improvement in the Short-Form Health Survey physical component summary (an increase of 2.7 versus 1.4 points, p=.046) and mental component summary (4.6 versus 2.5 points, p=.039). Significantly greater six-month improvements in mental health recovery were seen for the intervention group (p=.02), but no other between-group differences in secondary outcome measures were significant. CONCLUSIONS: The HARP program was associated with improved physical health- and mental health-related quality of life among individuals with serious mental illness and comorbid general medical conditions, suggesting the potential benefits of more widespread dissemination of peer-led disease self-management in this population. PMID- 29385953 TI - Behavioral Health Treatment Patterns Among Employer-Insured Adults in Same- and Different-Gender Marriages and Domestic Partnerships. AB - OBJECTIVE: This study examined specialty behavioral health treatment patterns among employer-insured adults in same- and different-gender domestic partnerships and marriages. METHODS: The study used behavioral health service claims (2008 2013) from Optum to estimate gender-stratified penetration rates of behavioral health service use by couple type and partnership status among partnered adults ages 18-64 (N=12,727,292 person-years) and levels of use among those with any use (conditional analyses). Least-squares, logistic, and zero-truncated negative binomial regression analyses adjusted for age, employer and plan characteristics, and provider supply and for sociodemographic factors in sensitivity analyses. Generalized estimating equations were used to address within-group correlation of adults clustered in employer groups. RESULTS: Both women and men in same-gender marriages or domestic partnerships had higher rates of behavioral health service use, particularly diagnostic evaluation, individual psychotherapy, and medication management, and those in treatment had, on average, more psychotherapy visits than those in different-gender marriages. Behavioral health treatment patterns were similar between women in same-gender domestic partnerships and same-gender marriages, but they diverged between men in same-gender domestic partnerships and same-gender marriages. Moderation analysis results indicated that adults with same-gender partners living in states with fewer legal protections for lesbian, gay, bisexual, and transgender persons were less likely than adults with same gender partners in LGBT-friendly states to receive behavioral health treatment. Sensitivity analyses did not affect findings. CONCLUSIONS: Behavioral health treatment patterns varied by couple type, partnership status, and gender. Results highlight the importance of increasing service acceptability and delivering inclusive, culturally relevant behavioral health treatment for lesbian, gay, and bisexual persons. PMID- 29385954 TI - Identifying Recipients of Electroconvulsive Therapy: Data From Privately Insured Americans. AB - OBJECTIVE: Despite the effectiveness of electroconvulsive therapy (ECT), limited epidemiologic research has been conducted to identify rates of ECT use and characteristics of patients who receive ECT. Sociodemographic and clinical characteristics associated with ECT use were examined among patients with mood disorders in the MarketScan commercial insurance claims database. METHODS: Among individuals with major depressive disorder or bipolar disorder, sociodemographic and clinical characteristics of those who received ECT and those who did not were compared by using bivariate effect size comparisons and multivariate logistic regression. RESULTS: Among unique individuals in the 2014 MarketScan database (N=47,258,528), the ECT utilization rate was 5.56 ECT patients per 100,000 in the population. Of the 969,277 patients with a mood disorder, 2,471 (.25%) received ECT. Those who received ECT had substantially higher rates of additional comorbid psychiatric disorders (risk ratio [RR]=5.70 for any additional psychiatric disorder), numbers of prescription fills for any psychotropic medication (Cohen's d=.77), rates of any substance use disorder (RR=1.97), and total outpatient psychotherapy visits (Cohen's d=.49). The proportion of patients with a mood disorder who received ECT in the West (.19%) was substantially lower than in other U.S. regions (.28%). This difference was almost entirely accounted for by one western state comprising 59.1% of patients in that region. CONCLUSIONS: Use of ECT is exceptionally uncommon and limited to patients with extensive multimorbidity and high levels of service use. ECT utilization is most limited in areas of the country where regulatory restrictions are greatest. PMID- 29385956 TI - Racial, Ethnic, and Gender Disparities in Health Care Access and Use Among U.S. Adults With Serious Psychological Distress. AB - OBJECTIVE: This study compared health care access and utilization among adults with serious psychological distress by race-ethnicity and gender in years surrounding implementation of the Affordable Care Act. METHODS: Data for adults ages 18 to 64 with serious psychological distress in the 2006-2015 National Health Interview Survey (N=8,940) were analyzed by race-ethnicity and gender on access and utilization indicators: health insurance coverage, insufficient money to buy medications, delay in health care, insufficient money for health care, visited a doctor more than ten times in the past 12 months, change in place of health care, change in place of health care because of insurance, saw a mental health provider in the past 12 months, and insufficient money for mental health care. RESULTS: The proportions of white and black adults with serious psychological distress were largest in the South, the region with the largest proportion of persons with serious psychological distress and no health coverage. Multivariate models that adjusted for health coverage, sociodemographic characteristics, health conditions, region, and year indicated that whites were more likely than blacks to report insufficient money for medications and mental health care and delays in care. A greater proportion of whites used private coverage, compared with blacks and Hispanics, and blacks were more likely than all other racial-ethnic groups to have Medicaid. CONCLUSIONS: More research is needed on health care utilization among adults with serious psychological distress. In this group, whites and those with private coverage reported poor utilization, compared with other racial-ethnic groups and those with Medicaid, respectively. PMID- 29385957 TI - Psychiatry's Role in Improving the Physical Health of Patients With Serious Mental Illness: A Report From the American Psychiatric Association. AB - The American Psychiatric Association Integrated Care Workgroup recently convened an expert panel charged with addressing the role of psychiatry in improving the physical health of persons with serious mental illness. The group reviewed the peer-reviewed and gray literature and developed a set of recommendations grounded in this review. This column summarizes the panel's primary findings and recommendations to key stakeholders, including clinicians, health care organizations, researchers, and policy makers. PMID- 29385955 TI - Psychiatric Case Review and Treatment Intensification in Collaborative Care Management for Depression in Primary Care. AB - OBJECTIVE: This study examined whether psychiatric case review was associated with depression medication modification in a large implementation program of collaborative care for depression in safety-net primary care clinics. METHODS: Registry data were examined from an implementation of the collaborative care model in Washington State. A total of 14,960 adults from 178 primary care clinics who initiated care between January 1, 2008, and September 30, 2014, and who had a baseline Patient Health Questionnaire-9 (PHQ-9) score of 10 or higher were included. Rates of psychiatric case reviews and receipt of new depression medications were extracted from the registry for all patients and for a subset of patients who did not improve by eight weeks of treatment (did not achieve a PHQ-9 score of less than 10 or a reduction in PHQ-9 score of 50% or more, compared with baseline). RESULTS: One-half of patients received a new depression medication. Psychiatric case review in any given month was associated with a doubling of the probability of receiving a new medication in the following month. Among patients who did not improve by eight weeks of treatment, a psychiatric case review during weeks 8-12 was associated with a higher rate of receipt of new medications during weeks 8-16 or weeks 8-20. CONCLUSIONS: In a collaborative care program, psychiatric case review was associated with higher rates of subsequent receipt of a new depression medication. This finding supports the importance of psychiatric case review in reducing clinical inertia in collaborative care treatment of depression. PMID- 29385958 TI - Mental Health Providers' Attitudes About Criminal Justice-Involved Clients With Serious Mental Illness. AB - OBJECTIVE: Community mental health providers' attitudes toward criminal justice involved clients with serious mental illness were examined. METHODS: A total of 627 Maryland psychiatric rehabilitation program providers responded to a survey (83% response rate). Measures assessed providers' experience with, positive regard for, and perceptions of similarity, with their clients with serious mental illness. Chi-square tests were used to compare providers' attitudes toward clients with and without criminal justice involvement. RESULTS: Providers reported lower regard for criminal justice-involved clients than for clients without such involvement. Providers were less likely to report having a great deal of respect for clients with (79%) versus without (95%) criminal justice involvement. On all items that measured providers' perceived similarity with their clients, less than 50% of providers rated themselves as similar, regardless of clients' criminal justice status. CONCLUSIONS: Future research should explore how providers' attitudes toward criminal justice-involved clients influence service delivery for this group. PMID- 29385959 TI - Reducing Frequent Utilization of Psychiatric Emergency Services Among Veterans While Maintaining Quality of Care. AB - OBJECTIVE: Use of psychiatric emergency services in emergency departments (EDs) and inpatient psychiatry units contributes substantially to the cost of mental health care. Among patients who utilize psychiatric emergency services, a small percentage ("high utilizers") contributes a disproportionate share of the total cost, yet little is known about the context of care for these patients. This study employed qualitative methods to identify barriers to and facilitators of reducing use of psychiatric emergency services among high utilizers. METHODS: Semistructured phone interviews were conducted with 31 directors of mental health services and providers of psychiatric emergency services across 22 Veterans Health Administration medical centers. The Consolidated Framework for Implementation Research was used to guide the interviews to evaluate the context of care for high utilizers. Thematic coding was used to identify barriers to and facilitators of reducing utilization. RESULTS: Barriers emerged at the patient level (for example, treatment nonadherence and transiency), provider level (for example, stigma toward high utilizers and lack of expertise and training in the management of psychiatric issues among ED staff), and system level (for example, lack of specialized services to address short- and long-term care needs). Facilitators included recovery-oriented care; interdisciplinary care coordination and case management, with emphasis on the role of psychiatric social workers; and predictive analytics to flag high utilizers. CONCLUSIONS: The findings lay the groundwork for the design of novel approaches to care for high utilizers of psychiatric emergency services while limiting provider burnout, managing costs, and optimizing treatment outcomes. PMID- 29385960 TI - Understanding Mental Illness Stigma Toward Persons With Multiple Stigmatized Conditions: Implications of Intersectionality Theory. AB - People with mental illness are often members of multiple stigmatized social groups. Therefore, experienced disadvantage might not be determined solely by mental illness stigma. Nevertheless, most available research does not consider the effects and implications of membership in multiple stigmatized social groups among people with mental illness. Reflecting on intersectionality theory, the authors discuss two intersectional effects determining disadvantage among people with mental illness who are members of multiple stigmatized social groups, namely double disadvantage and prominence. To be effective, interventions to reduce disadvantage experienced by people with mental illness need to be flexible and targeted rather than universal in order to address the implications of intersectionality. Whereas education-based approaches usually assume homogeneity and use universal strategies, contact-based interventions consider diversity among people with mental illness. PMID- 29385961 TI - National Estimates of Recovery-Remission From Serious Mental Illness. AB - OBJECTIVE: A broad range of estimates of recovery among previously institutionalized persons has been reported, but no current, community-based national estimate of recovery from serious mental illness exists. This study reports recovery rate results, based on a remission definition, and explores related demographic factors. METHODS: A national, geographically stratified, and random cross-sectional survey conducted from September 2014 to December 2015 resulted in responses from more than 41,000 individuals. Lifetime prevalence of serious mental illness was assessed by asking about receipt of a diagnosis (major depression, bipolar disorder, manic depression, and schizophrenia or schizoaffective disorder) and hospitalization and impairment associated with the diagnosis. Recovery was determined by asking about impairments over the past 12 months. RESULTS: Almost 17% reported receiving one of the diagnoses in their lifetime, 6% had a lifetime rate of a serious mental illness, and nearly 4% continued to experience interference associated with serious mental illness. One third of those with a lifetime serious mental illness reported having been in remission for at least the past 12 months. Recovery rates were low until age 32 and then progressively increased. CONCLUSIONS: Lifetime estimates of diagnosed illness and current prevalence of serious mental illness are consistent with previous research. Results indicate that recovery is possible and is associated with age. Further research is needed to understand factors that promote recovery, and sustained evaluation efforts using similar parsimonious approaches may be useful in conducting timely assessments of national and local mental health policies. PMID- 29385962 TI - Tissue engineering; strategies, tissues, and biomaterials. AB - Current tissue regenerative strategies rely mainly on tissue repair by transplantation of the synthetic/natural implants. However, limitations of the existing strategies have increased the demand for tissue engineering approaches. Appropriate cell source, effective cell modification, and proper supportive matrices are three bases of tissue engineering. Selection of appropriate methods for cell stimulation, scaffold synthesis, and tissue transplantation play a definitive role in successful tissue engineering. Although the variety of the players are available, but proper combination and functional synergism determine the practical efficacy. Hence, in this review, a comprehensive view of tissue engineering and its different aspects are investigated. PMID- 29385963 TI - Accuracy, intra- and inter-unit reliability, and comparison between GPS and UWB based position-tracking systems used for time-motion analyses in soccer. AB - There is interest in the accuracy and inter-unit reliability of position-tracking systems to monitor players. Research into this technology, although relatively recent, has grown exponentially in the last years, and it is difficult to find professional team sport that does not use Global Positioning System (GPS) technology at least. The aim of this study is to know the accuracy of both GPS based and Ultra Wide Band (UWB)-based systems on a soccer field and their inter- and intra-unit reliability. A secondary aim is to compare them for practical applications in sport science. Following institutional ethical approval and familiarization, 10 healthy and well-trained former soccer players (20 +/- 1.6 years, 1.76 +/- 0.08 cm, and 69.5 +/- 9.8 kg) performed three course tests: (i) linear course, (ii) circular course, and (iii) a zig-zag course, all using UWB and GPS technologies. The average speed and distance covered were compared with timing gates and the real distance as references. The UWB technology showed better accuracy (bias: 0.57-5.85%), test-retest reliability (%TEM: 1.19), and inter-unit reliability (bias: 0.18) in determining distance covered than the GPS technology (bias: 0.69-6.05%; %TEM: 1.47; bias: 0.25) overall. Also, UWB showed better results (bias: 0.09; ICC: 0.979; bias: 0.01) for mean velocity measurement than GPS (bias: 0.18; ICC: 0.951; bias: 0.03). PMID- 29385964 TI - A patient post hoc perspective on advantages and disadvantages of blended cognitive behaviour therapy for depression: A qualitative content analysis. AB - BACKGROUND: Blended cognitive behavioural therapy (bCBT), which combines face-to face (FtF), and internet-based cognitive behavioural therapy (iCBT), may be a particularly promising approach, but little is known about the effectiveness and patients' subjective evaluations of the bCBT format. The aim of this qualitative study is to explore perceived advantages and disadvantages of bCBT from the patients' perspective in specialized mental health care. METHODS: Semi-structured interviews were conducted with 15 patients suffering from major depression who underwent treatment in a bCBT format. The interview data were processed by means of a qualitative content analysis. RESULTS: The content analysis generated 18 advantages and 15 disadvantages which were grouped into 6 main topics. In general, bCBT was perceived as purposive and effective for treating depression. The patients perceived the combined treatment as complementary and emphasized the advantage of the constant availability of the online programme. Furthermore, a segment analysis revealed that patients reported different advantages and disadvantages of bCBT as a function of the severity of their depressive episode. CONCLUSION: The findings of the present study reveal advantages and disadvantages of bCBT, which should be taken into account in the further implementation of this new treatment format. PMID- 29385966 TI - Australia urgently needs a quality improvement approach to emergency laparotomy. PMID- 29385965 TI - Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment. PMID- 29385967 TI - A self-management support program for older Australians with multiple chronic conditions: a randomised controlled trial. AB - OBJECTIVE: To determine whether a clinician-led chronic disease self-management support (CDSMS) program improves the overall self-rated health level of older Australians with multiple chronic health conditions. DESIGN: Randomised controlled trial: participants were allocated to a clinician-led CDSMS group (including client-centred goal setting and the development of individualised care plans) or to a control group in which they received positive attention only. SETTING AND PARTICIPANTS: Patients aged 60 years or more with at least two chronic conditions, recruited between September 2009 and June 2010 from five general practices in Adelaide. MAIN OUTCOME MEASURES: The primary outcome was self-rated health. Secondary outcome measures related to health status (fatigue, pain, health distress, energy, depression, illness intrusiveness), health behaviour (exercise, medication adherence), and health service utilisation. RESULTS: 254 participants were randomised to the CDSMS and control groups, of whom 231 (117 control and 114 CDSMS participants) completed the 6-month programs and provided complete outcomes data (91%). An intention-to-treat analysis found that CDSMS participants were more likely than control participants to report improved self-rated health at 6 months (odds ratio, 2.50; 95% confidence interval, 1.13-5.50; P = 0.023). Between-group differences for secondary outcomes were not statistically significant. CONCLUSION: CDSMS may benefit some older people with multiple chronic conditions to a greater extent than positive attention and health education. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000726257. PMID- 29385968 TI - Salt consumption by Australian adults: a systematic review and meta-analysis. AB - OBJECTIVE: Salt reduction is a public health priority because it is a leading contributor to the global burden of disease. As in Australia there is uncertainty about the current level of salt intake, we sought to estimate current levels. STUDY DESIGN: Random effects meta-analysis of data from 31 published studies and one unpublished dataset that reported salt or sodium consumption by Australian adults on the basis of 24-hour urine collections or dietary questionnaires. DATA SOURCES: MEDLINE (via Ovid) and EMBASE (to August 2016). DATA SYNTHESIS: Thirty one published studies and one unpublished dataset (1989-2015; 16 836 individuals) were identified. The mean weighted salt consumption estimated from 24-hour urine collections was 8.70 g/day (95% CI, 8.39-9.02 g/day); after adjusting for non urinary salt excretion, the best estimate of salt intake in Australia is 9.6 g/day. The mean weighted intake was 10.1 g/day (95% CI, 9.68-10.5 g/day) for men and 7.34 g/day (95% CI, 6.98-7.70 g/day) for women. Mean weighted consumption was 6.49 g/day (95% CI, 5.94-7.03 g/day) when measured with diet diaries, 6.76 g/day (95% CI, 5.48-8.05 g/day) when assessed with food frequency questionnaires, and 6.73 g/day (95% CI, 6.34-7.11) when assessed by dietary recall. Salt intake had not decreased between 1989 and 2015 (R2 = -0.02; P = 0.36). CONCLUSION: Salt intake in Australian adults exceeds the WHO-recommended maximum of 5 g/day and does not appear to be declining. Measuring salt intake with methods based on self-reporting can substantially underestimate consumption. The data highlight the need for ongoing action to reduce salt consumption in Australia and robust monitoring of population salt intake. PMID- 29385970 TI - Disease prestige and the hierarchy of suffering. PMID- 29385972 TI - Gas gangrene of the eye: endogenous Clostridium perfringens endophthalmitis. PMID- 29385971 TI - Standard deviation and standard error: interpretation, usage and reporting. PMID- 29385973 TI - A novel approach to managing mental health in general practice. PMID- 29385974 TI - Self-management support for patients with chronic disease: potential and questions. PMID- 29385975 TI - Tongue-tie and frenotomy: what evidence do we have and what do we need? PMID- 29385976 TI - Frenotomy for tongue-tie in Australian children, 2006-2016: an increasing problem. PMID- 29385977 TI - Abnormal uterine bleeding: managing endometrial dysfunction and leiomyomas. AB - Abnormal uterine bleeding refers to any change in the regularity, frequency, heaviness or length of menstruation. There are several potential causes for bleeding disturbance, the two most common being primary endometrial dysfunction and fibroids. Management of abnormal uterine bleeding involves both medical and surgical options and will largely depend on a patient's fertility plans. The use of levonorgestrel-releasing intrauterine devices for heavy menstrual bleeding is increasing in Australia, and they are considered first-line medical management for women accepting of hormonal therapies. Tranexamic acid, non-steroidal anti inflammatory drugs, the combined oral contraceptive pill and oral progestins offer alternatives. Hysterectomy offers a definitive surgical approach to abnormal uterine bleeding and is associated with high levels of patient satisfaction. Women wishing to preserve their fertility, or avoid hysterectomy, may be offered myomectomy. Submucosal fibroids should be removed via hysteroscopy in symptomatic or infertile patients. Intramural and subserosal fibroids may be removed via an open or laparoscopic approach. There are several minimally invasive options, including uterine artery embolisation, magnetic resonance guided focused ultrasound and endometrial ablation, but patients should be aware that there is insufficient evidence to ensure fertility preservation with these procedures and further research is needed. Areas for additional research include cost-effectiveness of treatments and quality of life comparisons between management options using patient reported outcome measures to evaluate patient satisfaction. PMID- 29385978 TI - Burnout in intensive care. PMID- 29385979 TI - Emerging infectious disease agents and blood safety in Australia: spotlight on Zika virus. PMID- 29385980 TI - Adherence to diabetic eye examination guidelines in Australia: the National Eye Health Survey. PMID- 29385981 TI - Learning from the greats. PMID- 29385983 TI - Germline contamination and leakage in whole genome somatic single nucleotide variant detection. AB - BACKGROUND: The clinical sequencing of cancer genomes to personalize therapy is becoming routine across the world. However, concerns over patient re identification from these data lead to questions about how tightly access should be controlled. It is not thought to be possible to re-identify patients from somatic variant data. However, somatic variant detection pipelines can mistakenly identify germline variants as somatic ones, a process called "germline leakage". The rate of germline leakage across different somatic variant detection pipelines is not well-understood, and it is uncertain whether or not somatic variant calls should be considered re-identifiable. To fill this gap, we quantified germline leakage across 259 sets of whole-genome somatic single nucleotide variant (SNVs) predictions made by 21 teams as part of the ICGC-TCGA DREAM Somatic Mutation Calling Challenge. RESULTS: The median somatic SNV prediction set contained 4325 somatic SNVs and leaked one germline polymorphism. The level of germline leakage was inversely correlated with somatic SNV prediction accuracy and positively correlated with the amount of infiltrating normal cells. The specific germline variants leaked differed by tumour and algorithm. To aid in quantitation and correction of leakage, we created a tool, called GermlineFilter, for use in public-facing somatic SNV databases. CONCLUSIONS: The potential for patient re identification from leaked germline variants in somatic SNV predictions has led to divergent open data access policies, based on different assessments of the risks. Indeed, a single, well-publicized re-identification event could reshape public perceptions of the values of genomic data sharing. We find that modern somatic SNV prediction pipelines have low germline-leakage rates, which can be further reduced, especially for cloud-sharing, using pre-filtering software. PMID- 29385984 TI - Effects of low-intensity bodyweight training with slow movement on motor function in frail elderly patients: a prospective observational study. AB - BACKGROUND: Slow-motion training, an exercise marked by extremely slow movements, yields a training effect like that of a highly intense training, even when the applied load is small. This study evaluated the effects of low-intensity bodyweight training with slow movement on motor function in frail, elderly patients. METHODS: Ninety-seven elderly men and women aged 65 years or older, whose level of nursing care was classified as either support required (1 and 2) or long-term care required (care level 1 and 2), volunteered to participate. Two facilities were used. Participants in the first facility used low-intensity bodyweight training with slow movement (the LST group, n = 65), and participants in another facility used machine training (the control group, n = 31). Exercises were conducted for 3 months, once or twice a week, depending on the required level of nursing care. Changes in motor function were examined. RESULTS: Post exercise measurements showed significant improvements from the pre-exercise levels after 3 months, based on the results of the Timed Up and Go test (p = 0.0263) and chair-stand test (p = 0.0016) in the low-intensity exercise with slow movement and tonic force generation (LST) group. Although the ability to stand on one leg with eyes open tended to improve, no significant change was found (p = 0.0964). CONCLUSIONS: We confirmed that carrying out LST bodyweight training for 3 months led to improvements in ambulatory function and lower-limb muscle strength. In this way, it is possible that LST training performed by holding a bar or by staying seated on a chair contributes to improved motor function in elderly patients within a short time. TRIAL REGISTRATION: UMIN000030853 . Registered 17 January 2018. (retrospectively registered). PMID- 29385985 TI - Resilience and burden in caregivers of older adults: moderating and mediating effects of perceived social support. AB - BACKGROUND: The burden of caring for an older adult can be a form of stress and influence caregivers' daily lives and health. Previous studies have reported that resilience and social support play an important role in reducing physical and psychological burden in caregivers. Thus, the present study aimed to examine whether perceived social support served as a possible protective factor of burden among caregivers of older adults in Singapore using moderation and mediation effects' models. METHODS: We conducted a cross-sectional study with 285 caregivers providing care to older adults aged 60 years and above who were diagnosed with physical and/or mental illness in Singapore. The Connor-Davidson Resilience Scale (CD-RISC) was used to measure resilience and burden was measured by the Zarit Burden Interview (ZBI). The Multidimensional Scale of Perceived Social Support (MSPSS) was used to measure perceived social support. Hayes' PROCESS macro was used to test moderation and mediation effects of perceived social support in the relationship between resilience and burden after controlling for sociodemographic variables. Indirect effects were tested using bootstrapped confidence intervals (CI). RESULTS: The mean scores observed were CD RISC: 70.8/100 (SD = 15.1), MSPSS: 62.2/84 (SD = 12.2), and ZBI: 23.2/88 (SD = 16.0) respectively. While perceived social support served as a full mediator between resilience and caregiver burden (beta = - 0.14, 95% CI -0.224 to - 0.072, p < 0.05), it did not show a significant moderating effect. CONCLUSIONS: Perceived social support mediates the association between resilience and caregiver burden among caregivers of older adults in Singapore. It is crucial for healthcare professionals, particularly those who interact and deliver services to assist caregivers, to promote and identify supportive family and friends' network that may help to address caregiver burden. PMID- 29385987 TI - An elevated expression of serum exosomal microRNA-191, - 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker. AB - BACKGROUND: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. METHODS: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TCTM. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. RESULTS: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5 20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). CONCLUSIONS: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs). PMID- 29385986 TI - Transcriptome profiling of lentil (Lens culinaris) through the first 24 hours of Ascochyta lentis infection reveals key defence response genes. AB - BACKGROUND: Ascochyta blight, caused by the fungus Ascochyta lentis, is one of the most destructive lentil diseases worldwide, resulting in over $16 million AUD annual loss in Australia alone. The use of resistant cultivars is currently considered the most effective and environmentally sustainable strategy to control this disease. However, little is known about the genes and molecular mechanisms underlying lentil resistance against A. lentis. RESULTS: To uncover the genetic basis of lentil resistance to A. lentis, differentially expressed genes were profiled in lentil plants during the early stages of A. lentis infection. The resistant 'ILL7537' and susceptible 'ILL6002' lentil genotypes were examined at 2, 6, and 24 h post inoculation utilising high throughput RNA-Sequencing. Genotype and time-dependent differential expression analysis identified genes which play key roles in several functions of the defence response: fungal elicitors recognition and early signalling; structural response; biochemical response; transcription regulators; hypersensitive reaction and cell death; and systemic acquired resistance. Overall, the resistant genotype displayed an earlier and faster detection and signalling response to the A. lentis infection and demonstrated higher expression levels of structural defence-related genes. CONCLUSIONS: This study presents a first-time defence-related transcriptome of lentil to A. lentis, including a comprehensive characterisation of the molecular mechanism through which defence against A. lentis is induced in the resistant lentil genotype. PMID- 29385988 TI - A patient and family data domain collection framework for identifying disparities in pediatrics: results from the pediatric health equity collaborative. AB - BACKGROUND: By 2020, the child population is projected to have more racial and ethnic minorities make up the majority of the populations and health care organizations will need to have a system in place that collects accurate and reliable demographic data in order to monitor disparities. The goals of this group were to establish sample practices, approaches and lessons learned with regard to race, ethnicity, language, and other demographic data collection in pediatric care setting. METHODS: A panel of 16 research and clinical professional experts working in 10 pediatric care delivery systems in the US and Canada convened twice in person for 3-day consensus development meetings and met multiple times via conference calls over a two year period. Current evidence on adult demographic data collection was systematically reviewed and unique aspects of data collection in the pediatric setting were outlined. Human centered design methods were utilized to facilitate theme development, facilitate constructive and innovative discussion, and generate consensus. RESULTS: Group consensus determined six final data collection domains: 1) caregivers, 2) race and ethnicity, 3) language, 4) sexual orientation and gender identity, 5) disability, and 6) social determinants of health. For each domain, the group defined the domain, established a rational for collection, identified the unique challenges for data collection in a pediatric setting, and developed sample practices which are based on the experience of the members as a starting point to allow for customization unique to each health care organization. Several unique challenges in the pediatric setting across all domains include: data collection on caregivers, determining an age at which it is appropriate to collect data from the patient, collecting and updating data at multiple points across the lifespan, the limits of the electronic health record, and determining the purpose of the data collection before implementation. CONCLUSIONS: There is no single approach that will work for all organizations when collecting race, ethnicity, language and other social determinants of health data. Each organization will need to tailor their data collection based on the population they serve, the financial resources available, and the capacity of the electronic health record. PMID- 29385989 TI - Influence of new societal factors on neovascular age-related macular degeneration outcomes. AB - BACKGROUND: To assess the impact of unstudied societal factors for neovascular age-related macular degeneration (nAMD) on functional outcomes after anti-VEGFs. METHODS: Charts of 94 nAMD patients treated in the Monticelli-Paradis Centre, Marseille, France, were reviewed. Phone interviews were conducted to assess societal factors, including transportation, living status, daily reading and social security scheme (SSS). Primary outcome was the impact of family support and disease burden on functional improvement in nAMD. RESULTS: Between baseline and month 24 (M24), 42.4% of the variability in best-corrected visual acuity (BCVA) was explained by the cumulative effect of the following societal factors: intermittent out-patient follow-up, marital status, daily reading, transportation type, commuting time. No isolated societal factor significantly correlated with ETDRS BCVA severity at M24. A trend to correlation was observed between the EDTRS score at M24 and the SSS (P = 0.076), economic burden (P = 0.075), time between diagnosis and treatment initiation (P = 0.070). A significant correlation was found for the disease burdensome on the patient (P = 0.034) and low vision rehabilitation (P = 0.014). CONCLUSIONS: Societal factors could influence functional outcomes in nAMD patients treated with anti-VEGFs. They could contribute to the healing process or sustain disease progression. PMID- 29385990 TI - Urox containing concentrated extracts of Crataeva nurvala stem bark, Equisetum arvense stem and Lindera aggregata root, in the treatment of symptoms of overactive bladder and urinary incontinence: a phase 2, randomised, double-blind placebo controlled trial. AB - BACKGROUND: Storage lower urinary tract symptoms (LUTS) including overactive bladder (OAB) and urinary incontinence (UI) affect millions of people worldwide, significantly impacting quality of life. Plant based medicines have been documented both empirically and in emerging scientific research to have varying benefits in reducing bladder symptoms. We assessed the efficacy of Urox(r), a proprietary combination of phytomedicine extracts including, CratevoxTM (Crataeva nurvala) stem bark, Equisetem arvense stem and Lindera aggregata root, in reducing symptoms of OAB and UI. METHODS: Efficacy of the herbal combination on a variety of bladder symptoms compared to an identical placebo, were documented in a randomised, double-blind, placebo controlled trial conducted at two primary care centres. Data were collected at baseline, 2, 4 and 8 weeks, with the primary outcome being self-reported urinary frequency. Statistical analysis included mixed effects ordered logistic regression with post hoc Holm's test to account for repeated measures, and included an intention-to-treat analysis. RESULTS: One hundred and fifty participants (59% female, aged; mean +/- SD; 63.5 +/- 13.1 years) took part in the study. At week 8, urinary day frequency was significantly lower (OR 0.01; 95%CI 0.01 to 0.02; p < 0.001) in response to treatment (mean +/- SD; 7.69 +/- 2.15/day) compared to placebo (10.95 +/- 2.47/day). Similarly, episodes of nocturia were significantly fewer (OR 0.03; 95%CI 0.02 to 0.05) after 8 weeks of treatment (2.16 +/- 1.49/night) versus placebo (3.14 +/- 1.36/night). Symptoms of urgency (OR 0.02; 95%CI 0.01 to 0.03), and total incontinence (OR 0.03; 95% CI 0.01 to 0.06) were also lower (all p < 0.01) in the treatment group. Significant improvements in quality of life were reported after treatment in comparison to placebo. No significant side effects were observed resulting in withdrawal from treatment. CONCLUSIONS: The outcome of this study demonstrated both statistical significance and clinical relevance in reducing symptoms of OAB, urinary frequency and/or urgency and incontinence. The demonstrated viability of the herbal combination to serve as an effective treatment, with minimal side effects, warrants further longer term research and consideration by clinicians. TRIAL REGISTRATION: NCT02396160 (registered on 17 March 2015 - before any statistical analyses commenced). PMID- 29385991 TI - Validity of St Gallen risk categories in prognostication of breast cancer patients in Southern Sri Lanka. AB - BACKGROUND: Although, there are many developments in the field of management, breast cancer is still the commonest cause of cancer related deaths in women in Sri Lanka. This emphasizes the need for validation of treatment protocols that are used in Sri Lanka for managing breast cancers. There are no published papers on treatment and survival of breast cancer patients in Sri Lanka. Hence this study was designed to determine the validity of St Gallen risk categories based on the survival outcomes of breast cancer patients in Southern Sri Lanka. METHOD: This retro-prospective study included all female breast cancer patients who had sought the immunohistochemistry services of our unit from May 2006 to December 2012. Patients who had neo-adjuvant chemotherapy were excluded. Patients were stratified according to the St Gallen risk categories; low-risk (LR), intermediate-risk (IR) and high-risk (HR), which is used in deciding on the adjuvant treatment. IR category was subdivided based on presence/absence of 1-3 positive-nodes (absent-IR1, present-IR2) and HR on the number of positive-nodes(1 3 lymph nodes;HR1,> 3 lymph nodes;HR2). Kaplan-Meier and Cox-regression models were used in the survival analysis. RESULTS: This study included 713breast cancer patients (LR-2%, IR1-45%, IR2-10%, HR1-13%, HR2-30%). Five year breast cancer specific survival (BCSS)wasLR-100%, IR-91%, HR-66% and the recurrence free survival (RFS) was LR-85%, IR-84%, HR-65%. BCSS and RFS curves were significantly different between the three risk categories (p < 0.001). No survival difference was evident between the IR1 and IR2 (BCSS-p = 0.232, RFS-p = 0.118). HR1 and HR2 had a distinctly different BCSS (p = 0.033) with no difference in RFS (p = 0.190). CONCLUSION: This study validates the St Gallen risk categorization of female breast cancer patients in our setting. However, the HR includes two subsets of patients with a distinct difference in BCSS. PMID- 29385992 TI - Symptoms and diagnostic criteria of acquired Megacolon - a systematic literature review. AB - BACKGROUND: Acquired Megacolon (AMC) is a condition involving persistent dilatation and lengthening of the colon in the absence of organic disease. Diagnosis depends on subjective radiological, endoscopic or surgical findings in the context of a suggestive clinical presentation. This review sets out to investigate diagnostic criteria of AMC. METHODS: The literature was searched using the databases - PubMed, Medline via OvidSP, ClinicalKey, Informit and the Cochrane Library. Primary studies, published in English, with more than three patients were critically appraised based on study design, methodology and sample size. Exclusion criteria were studies with the following features: post operative; megarectum-predominant; paediatric; organic megacolon; non-human; and failure to exclude organic causes. RESULTS: A review of 23 articles found constipation, abdominal pain, distension and gas distress were predominant symptoms. All ages and both sexes were affected, however, symptoms varied with age. Changes in anorectal manometry, histology and colonic transit are consistently reported. Studies involved varying patient numbers, demographics and data acquisition methods. CONCLUSIONS: Outcome data investigating the diagnosis of AMC must be interpreted in light of the limitations of the low-level evidence studies published to date. Proposed diagnostic criteria include: (1) the exclusion of organic disease; (2) a radiological sigmoid diameter of ~ 10 cm; (3) and constipation, distension, abdominal pain and/or gas distress. A proportion of patients with AMC may be currently misdiagnosed as having functional gastrointestinal disorders. Our conclusions are inevitably tentative, but will hopefully stimulate further research on this enigmatic condition. PMID- 29385993 TI - A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites. AB - BACKGROUND: Ramucirumab has recently proved to be effective for advanced or recurrent gastric cancer (AGC). Ascites and peritoneal metastasis are among the most common complications of AGC. However, there are few data on the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites. The purpose of this retrospective study was to evaluate the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites. METHODS: We retrospectively evaluated the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites in comparison with patients without ascites in a single institution from June 2015 to May 2016. The median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and differences evaluated using the Log-lank test. The differences in baseline characteristics and response rates of each ascites group were calculated for homogeneity by chi-square tests and for trends by Fisher's exact test. RESULTS: Eighty-three patients were analyzed in this study. Ascites was detected in 40 patients, 26 patients (31%) had small to moderate ascites and 14 (17%) had massive ascites. The proportion of patients who started with a reduced dose of paclitaxel was higher for patients with massive ascites than others. The frequencies of any grade 3 or 4 hematological toxicity were 51% in patients without ascites, 77% in patients with small to moderate ascites, and 71% in patients with massive ascites. The frequencies of common ramucirumab-related adverse events were also not significantly different among ascites groups, however one patient had a tumor hemorrhage, and one patient had a gastrointestinal perforation. PFS and OS were shorter in patients with massive ascites than in patients with small or moderate ascites or patients without ascites. CONCLUSIONS: The use of paclitaxel and ramucirumab in patients with AGC with large amounts of ascites was tolerable with adequate dose modification. However, we should pay attention to the risks of ramucirumab-related toxicity in patients with bleeding tumors or intestinal stenosis. PMID- 29385994 TI - Effect of neoadjuvant chemotherapy in patients with gastric cancer: a PRISMA compliant systematic review and meta-analysis. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) is extensively used in the treatment of patients with gastric cancer (GC), particularly in high risk, advanced gastric cancer. Previous trials testing the efficacy of NAC have reported inconsistent results. METHODS: This study compares the combined use of NAC and surgery with surgery alone for GC by using a meta-analytic approach. We performed an electronic search of PubMed, EmBase, and the Cochrane Library to identify randomized controlled trials (RCTs) on NAC published before Oct 2015. The primary outcome of the studies was data on survival rates for patients with GC. The summary results were pooled using the random-effects model. We included 12 prospective RCTs reporting data on 1538 GC patients. RESULTS: Patients who received NAC were associated with significant improvement of OS (P = 0.001) and PFS (P < 0.001). Furthermore, NAC therapy significantly increased the incidence of 1-year survival rate (SR) (P = 0.020), 3-year SR (P = 0.011), and 4-year SR (P = 0.001). Similarly, NAC therapy was associated with a lower incidence of 1-year (P < 0.001), 2-year (P < 0.001), 3-year (P < 0.001), 4-year (P = 0.001), and 5 year recurrence rate (P = 0.002). Conversely, patients who received NAC also experienced a significantly increased risk of lymphocytopenia (P = 0.003), and hemoglobinopathy (P = 0.021). CONCLUSIONS: The findings of this study suggested that NAC is associated with significant improvement in the outcomes of survival and disease progression for GC patients while also increasing some toxicity. PMID- 29385995 TI - Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer. AB - BACKGROUND: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. METHODS: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. RESULTS: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. CONCLUSIONS: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione. PMID- 29385996 TI - The association between cold hypersensitivity in the hands and feet and chronic disease: results of a multicentre study. AB - BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a common symptom in Korea and patients with CHHF complain of coldness in the hands and feet in an environment that is not considered cold by unaffected people. In traditional East Asian medicine, CHHF is believed to be accompanied by various diseases and symptoms, and is considered a symptom that needs active treatment. CHHF is used for pattern identification in the cold pattern, yang deficiency, and constitution. This study aimed to examine the differences in frequencies of chronic diseases with respect to the presence of CHHF. METHODS: Disease history, CHHF, body measurements, and blood test survey data from 6149 patients collected by 25 medical institutes in Korea were obtained from the Korean Medicine Data Center. The participants were divided into CHHF (n = 1909) and non-CHHF groups (n = 3017) according to the CHHF survey. The differences in frequencies of 18 diseases were analysed using chi-square tests, and the odds ratios (ORs) for each disease according to CHHF status were examined via logistic regression with adjustment for age, sex, and body mass index (BMI). RESULTS: Based on chi-square test results, the CHHF group showed a higher frequency of the following diseases: anaemia, hypotension, chronic gastritis, reflux oesophagitis, chronic rhinitis, dysmenorrhoea, and gastroduodenal ulcer. Diseases found in lower frequencies were as follows: hypertension, diabetes mellitus, impaired fasting glucose, dyslipidaemia, stroke, fatty liver, and angina pectoris. In addition, from the logistic regression with adjustment for age, sex, and BMI, the CHHF group showed a lower OR in diabetes mellitus and dyslipidaemia than the non-CHHF group, but a higher OR in degenerative arthritis, chronic gastritis, gastroduodenal ulcer, reflux oesophagitis, and chronic rhinitis. CONCLUSIONS: This study showed that CHHF is associated with chronic disease. Further large-scale prospective studies are needed to validate these associations. PMID- 29385997 TI - Proteinuric kidney disease in children at Queen Elizabeth Central Hospital, Malawi. AB - BACKGROUND: There is a paucity of data on paediatric kidney disease in developing countries such as Malawi. Descriptive research on kidney disease is essential to improving patient outcomes. METHODS: We conducted a cross-sectional study at a tertiary hospital in Malawi from 2012 to 2013. Children under 14 years with proteinuric kidney disease were enrolled from paediatric wards and outpatient clinics at Queen Elizabeth Central Hospital (QECH). Demographic, clinical and laboratory data were collected from patients at enrolment and at 3 months review at which point clinical status and disease outcome were ascertained. RESULTS: Thirty-four (22 male) patients were studied, mean age 8.54 (SD = 3.62 years). Glomerular disease (n = 25, 68%) was the most common presumed renal lesion at presentation. Nephritic syndrome (10) was characterised by a lower baseline complement C3 than nephrotic syndrome (p = 0.0027). Seven (47%) cases of nephrotic syndrome achieved complete remission. Eight (80%) cases of nephritic syndrome improved with supportive therapy. Nineteen (56%) patients presented with clinically significant renal damage with eGFR< 60 ml/min/1.73m2. Six patients presented in chronic kidney disease (CKD) stage 5 of unclear aetiology, five (83%) died. Three (9%) patients had impaired kidney function and obstructive uropathy demonstrated on ultrasound, two recovered after surgery and one died. Eight (24%) patients had acute kidney injury (AKI) due to primary kidney disease, three of these patients progressed to CKD stage G3a. Seven (21%) patients were lost to follow up. CONCLUSION: Kidney disease is a significant cause of mortality and morbidity in children at QECH. Less than half of Nephrotic syndrome cases achieved complete remission. Mortality is highest in children with CKD of unclear cause. Some patients with AKI secondary to primary renal disease progressed to CKD. Understanding the aetiology of paediatric kidney disease and improving patient outcomes by developing enhanced diagnostic and clinical services are priorities at QECH and within Malawi. PMID- 29385998 TI - Heart rate in patients with reduced ejection fraction: relationship between single time point measurement and mean heart rate on prolonged implantable cardioverter defibrillator monitoring. AB - BACKGROUND: Heart rate (HR) is a prognostic marker that is increasingly used as a therapeutic target in patients with cardiovascular disease. The association between resting and mean HR remains unclear. We therefore set out to determine the relationship between resting HR on the electrocardiogram (ECG) obtained at a single time point, and mean HR on implantable cardioverter defibrillator (ICD) interrogation amongst patients with a reduced left ventricular ejection fraction (LVEF). METHODS: Prospective ICD data were obtained from 54 patients with LVEF < 40%. Mean HR determined using the ICD HR histograms was compared with resting HR measured on the ECG performed in the clinic. RESULTS: Average resting and ICD mean HRs were 67.9 +/- 10.1 and 67.8 +/- 9.6 bpm respectively. There was good correlation in the overall cohort (r = 0.79), in those with resting ECG HRs <= 70 bpm (r = 0.62), and amongst the 27 patients on intermediate-to-high dose beta blockers (r = 0.91). However, Bland-Altman analysis demonstrated wide limits of agreement in the overall cohort (- 12.5, 12.7 bpm), at resting HRs <= 70 bpm (- 12.7, 9.8 bpm), and on intermediate-to-high dose beta-blockers (- 8.9, 7.4 bpm). Moreover, resting HR did not predict the 10-bpm interval where the most time was spent. CONCLUSIONS: While resting HR correlated with mean HR in patients with reduced LVEF, and in important subgroups, the limits of agreement were unacceptably wide raising concern over the use of single time point resting HR as a therapeutic target. PMID- 29385999 TI - A statewide investigation of geographic lung cancer incidence patterns and radon exposure in a low-smoking population. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Utah despite having the nation's lowest smoking rate. Radon exposure and differences in lung cancer incidence between nonmetropolitan and metropolitan areas may explain this phenomenon. We compared smoking-adjusted lung cancer incidence rates between nonmetropolitan and metropolitan counties by predicted indoor radon level, sex, and cancer stage. We also compared lung cancer incidence by county classification between Utah and all SEER sites. METHODS: SEER*Stat provided annual age-adjusted rates per 100,000 from 1991 to 2010 for each Utah county and all other SEER sites. County classification, stage, and sex were obtained from SEER*Stat. Smoking was obtained from Environmental Public Health Tracking estimates by Ortega et al. EPA provided low (< 2 pCi/L), moderate (2-4 pCi/L), and high (> 4 pCi/L) indoor radon levels for each county. Poisson models calculated overall, cancer stage, and sex-specific rates and p-values for smoking adjusted and unadjusted models. LOESS smoothed trend lines compared incidence rates between Utah and all SEER sites by county classification. RESULTS: All metropolitan counties had moderate radon levels; 12 (63%) of the 19 nonmetropolitan counties had moderate predicted radon levels and 7 (37%) had high predicted radon levels. Lung cancer incidence rates were higher in nonmetropolitan counties than metropolitan counties (34.8 vs 29.7 per 100,000, respectively). Incidence of distant stage cancers was significantly higher in nonmetropolitan counties after controlling for smoking (16.7 vs 15.4, p = 0.02*). Incidence rates in metropolitan, moderate radon and nonmetropolitan, moderate radon counties were similar. Nonmetropolitan, high radon counties had a significantly higher incidence of lung cancer compared to nonmetropolitan, moderate radon counties after adjustment for smoking (41.7 vs 29.2, p < 0.0001*). Lung cancer incidence patterns in Utah were opposite of metropolitan/nonmetropolitan trends in other SEER sites. CONCLUSION: Lung cancer incidence and distant stage incidence rates were consistently higher in nonmetropolitan Utah counties than metropolitan counties, suggesting that limited access to preventative screenings may play a role in this disparity. Smoking adjusted incidence rates in nonmetropolitan, high radon counties were significantly higher than moderate radon counties, suggesting that radon was also major contributor to lung cancer in these regions. National studies should account for geographic and environmental factors when examining nonmetropolitan/metropolitan differences in lung cancer. PMID- 29386000 TI - Comparative efficacy of Chinese herbal injections for treating chronic heart failure: a network meta-analysis. AB - BACKGROUND: On account of deterioration of chronic heart failure (CHF) and extensive exploration of Chinese herbal injections (CHIs), we performed a network meta-analysis to investigate the efficacy of CHIs (Huangqi injection, Shenfu injection, Shengmai injection, Shenmai injection, Shenqi Fuzheng injection, Yiqifumai injection) on the basis of western medicine (WM) treatment in CHF. METHODS: Literature search was conducted in Embase, the Cochrane Library, Pubmed, Chinese Biological Medicine Database, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database from inception to June 12nd 2017, and study selection was abided by a prior eligible criteria. RESULTS: Ultimately, a total of 113 randomized controlled trials (RCTs) were enrolled. The clinical data of the effective clinical rate, left ventricular ejection fraction, cardiac output and others outcomes was estimated by Stata software and Winbugs software. Risk of bias was assessed by Cochrane Collaboration's tools. Integrating the each outcome's results, a combination of Shengmai injection/Shenmai injection and WM obtain a first rank in most outcomes, particularly primary outcomes. CONCLUSIONS: In conclusion, on the basis of WM, Shengmai injection or Shenmai injection may be a perforable treatment in CHF. In terms of insufficient of this study, more high quality RCTs needed to implement to support our conclusions. PMID- 29386001 TI - Evaluating the impact of DREAMS on HIV incidence among young women who sell sex: protocol for a non-randomised study in Zimbabwe. AB - BACKGROUND: "Determined, Resilient, AIDS-free, Mentored and Safe" (DREAMS) is a package of biomedical, social and economic interventions offered to adolescent girls and young women aged 10-24 years with the aim of reducing HIV incidence. In four of the six DREAMS districts in Zimbabwe, DREAMS includes an offer of oral pre-exposure prophylaxis (DREAMS+PrEP), alongside interventions to support demand and adherence, to women aged 18-24 who are at highest risk of HIV infection, including young women who sell sex (YWSS). This evaluation study addresses the question: does the delivery of DREAMS+PrEP through various providers reduce HIV incidence among YWSS Zimbabwe? We describe our approach to designing a rigorous study to assess whether DREAMS+PrEP had an impact on HIV incidence. METHODS: The study design needed to account for the fact that: 1) DREAMS+PrEP was non-randomly allocated; 2) there is no sampling frame for the target population for the evaluation; 3) there are a small number of DREAMS districts (N = 6), and 4) DREAMS+PrEP is being implemented by various providers. The study will use a cohort analysis approach to compare HIV incidence among YWSS in two DREAMS+PrEP districts to HIV incidence among YWSS in non-DREAMS comparison sites. YWSS will be referred to services and recruited into the cohort through a network-based (respondent-driven) recruitment strategy, and followed-up 12- and 24-months after enrolment. Women will be asked to complete a questionnaire and offered HIV testing. Additional complications of this study include identifying comparable populations of YWSS in the DREAMS+PrEP and non-DREAMS comparison sites, and retention of YWSS over the 24-month period. The primary outcome is HIV incidence among YWSS HIV-negative at study enrolment measured by repeat, rapid HIV testing over 24-months. Inference will be based on plausibility that DREAMS+PrEP had an impact on HIV incidence. A process evaluation will be conducted to understand intervention implementation, and document any contextual factors determining the success or failure of intervention delivery. DISCUSSION: HIV prevention products of known efficacy are available. Innovative studies are needed to provide evidence of how to optimise product use through combination interventions to achieve population impact within different contexts. We describe the design of such a study. PMID- 29386002 TI - Extended left hepatectomy for intrahepatic cholangiocarcinoma: hepatic vein reconstruction with in-situ hypothermic perfusion and extracorporeal membrane oxygenation. AB - BACKGROUND: Liver resection for intrahepatic cholangiocarcinoma (ICC) with invasion of the inferior vena cava (IVC) and hepatic veins (HV) is a challenging procedure. CASE PRESENTATION: We report a case of a 63-year-old woman with a 6 cm, centrally located liver mass. Her biochemistry results were normal except for a Ca19-9 level of 1199 U/ml. The liver biopsy was consistent with ICC and 60% macrosteatosis. Abdominal CT scans revealed a large central mass invading the left HV, middle HV and right HV, infringing on their junction with the vena cava. An operation was planned using a 3-dimensional (3D) computer simulation model using dedicated software. We also describe a novel veno-portal-venous extracorporeal membrane oxygenation (VPV-ECMO) support with in-situ hypothermic perfusion (IHP) during this procedure. We aimed to perform an extended left hepatectomy and reconstruct 3 right HV orifices with an interposition jump graft to the IVC with total vascular exclusion (TVE) and IHP A supplemental video describing the preoperative planning, the operative procedure with the postoperative follow-up in detail is presented. After the patient was discharged, she developed a hepatic venous outflow obstruction 3 months postoperatively, which was effectively managed with hepatic venous stenting by interventional radiology. She is currently symptom free and without tumour recurrence at the 1 year follow-up. CONCLUSIONS: This report demonstrates that extended left hepatectomy for IHC with IHP and VPV-ECMO is safe and feasible under the supervision of a highly experienced team. PMID- 29386003 TI - Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene. AB - BACKGROUND: Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML. CASE PRESENTATION: We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X chromosome inactivation assay. CONCLUSIONS: We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases. PMID- 29386004 TI - Pretreatment quality of life as a predictor of survival for patients with nasopharyngeal carcinoma treated with IMRT. AB - BACKGROUND: To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. METHODS: We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. RESULTS: Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003, < 0.0001, and 0.031, respectively. In multivariate analysis, pretreatment cognitive functioning of QLQ C30 was significantly associated with LRFS, with HR of 0.971(95%CI 0.951-0.990), P = 0.004. Among scales of QLQ-H&N35 for multivariate analysis, pretreatment teeth (P = 0.026) and felt ill (P = 0.012) was significantly associated with PFS, with HR of 0.984 (95%CI 0.971-.998) and 1.004 (95%CI 1.001-1.007), respectively. Felt ill of QLQ-H&N35 was significantly associated with DMFS, with HR of 1.004(95%CI 1.000-1.007), P = 0.043. There is no QoL scale significantly associated with OS after multivariate analysis. CONCLUSIONS: In conclusion, our analysis confirms that pretreatment teeth and felt ill was significantly associated with PFS in NPC patients treated with IMRT. In addition, the posttreatment EBV DNA was significantly associated with OS. PMID- 29386005 TI - Attitudes and knowledge about direct and indirect risks among conventional and complementary health care providers in cancer care. AB - BACKGROUND: Many complementary therapies offer benefits for patients with cancer. Others may be risky for patients due to negative interactions with conventional treatment and adverse effects. Therefore, cancer patients need guidance from health care providers to assess complementary modalities appropriately to receive benefits and avoid harm. METHOD: In a self-administered questionnaire-based cross sectional study, we compared knowledge and attitudes of health care providers with no training in complementary modalities to that of health care providers with training in complementary modalities about the risks for patients who combine complementary modalities with conventional treatment in cancer care. The analysis was based on responses from 466 participants. RESULTS: The attitudes and knowledge about direct risk followed provider specialty. Ninety-four percent of the medical doctors, 93% of the nurses, and 87% of the providers with dual training, but 70% of the complementary therapists, believed that complementary modalities can cause adverse effects (p < 0.001). The majority of the medical doctors and nurses believed that it is risky to combine complementary and conventional cancer treatments (78% and 93%, respectively), compared to 58% of the providers with dual training and 43% of the complementary therapists (p < 0.001). Eighty-nine percent of the medical doctors and nurses believed that complementary modalities should be subjected to more scientific testing before being accepted by conventional health care providers, in contrast to 56% of the dually trained and 57% of the complementary therapists (p < 0.001). The majority of the medical doctors (61%) and nurses (55%) would have neither discouraged nor encouraged the use of complementary modalities if patients asked them for advice. Moreover, less than 1% of the complementary therapists would have discouraged the use of conventional cancer treatments. The study participants believed that the most important factor to recommend a complementary cancer modality to patients is evidence for safety. CONCLUSION: The health care providers in this study believed that complementary modalities are associated with direct risk and can cause adverse effects, and that it is risky to combine conventional and complementary treatments due to potential harmful interactions. PMID- 29386007 TI - Cost-effectiveness of comprehensive geriatric assessment at an ambulatory geriatric unit based on the AGe-FIT trial. AB - BACKGROUND: Older people with multi-morbidity are increasingly challenging for today's healthcare, and novel, cost-effective healthcare solutions are needed. The aim of this study was to assess the cost-effectiveness of comprehensive geriatric assessment (CGA) at an ambulatory geriatric unit for people >=75 years with multi-morbidity. METHOD: The primary outcome was the incremental cost effectiveness ratio (ICER) comparing costs and quality-adjusted life years (QALYs) of a CGA strategy with usual care in a Swedish setting. Outcomes were estimated over a lifelong time horizon using decision-analytic modelling based on data from the randomized AGe-FIT trial. The analysis employed a public health care sector perspective. Costs and QALYs were discounted by 3% per annum and are reported in 2016 euros. RESULTS: Compared with usual care CGA was associated with a per patient mean incremental cost of approximately 25,000 EUR and a gain of 0.54 QALYs resulting in an ICER of 46,000 EUR. The incremental costs were primarily caused by intervention costs and costs associated with increased survival, whereas the gain in QALYs was primarily a consequence of the fact that patients in the CGA group lived longer. CONCLUSION: CGA in an ambulatory setting for older people with multi-morbidity results in a cost per QALY of 46,000 EUR compared with usual care, a figure generally considered reasonable in a Swedish healthcare context. A rather simple reorganisation of care for older people with multi-morbidity may therefore cost effectively contribute to meet the needs of this complex patient population. TRIAL REGISTRATION: The trial was retrospectively registered in clinicaltrial.gov, NCT01446757 . September, 2011. PMID- 29386006 TI - The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis. AB - BACKGROUND: Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. METHODS: The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (>= 1 of 3 AIs positive) and MRZR-2 (>= 2 of 3 AIs positive), were applied. RESULTS: There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR 1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each). CONCLUSIONS: Considering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND. PMID- 29386008 TI - Timely initiation of complementary feeding to children aged 6-23 months in rural Soro district of Southwest Ethiopia: a cross-sectional study. AB - BACKGROUND: Poor complementary feeding practice to infants is one of risk factors for child undernutrition in Ethiopia. This would vary across the culturally and socioeconomically diverse settings in this country. Thus, this study was aimed to determine the proportion of timely initiated complementary feeding practice of women to their children aged 6-23 months in rural Soro district in Southwest Ethiopia. METHODS: A community based crossectional survey was conducted in Soro district from August to September in 2015. Randomly selected 543 women having children aged 6-23 months were the final sampling units for this study. First, local administrative units (kebeles) of residents were randomly selected from such lists in the district. Secondly, the sample size was proportionally allocated to each selected kebele by population sizes. Individual households were selected by systematic random technique. Data was collected by using a structured questionnaire through face to face interview. Descriptive statistics was done for univariate results, and we applied bivariate logistic regression to look for crude association, and multivariate logistic regression to model predictors with effect measures and 95% confidence intervals (CI). Statistical significance was decaled at P < 0.05. RESULTS: The proportion of timely initiated complementary feeding was 34.3% at 95%CI: (30.31, 38.29) in this study. Secondary and above education levels of respondents (AOR = 2.25 95%CI: 1.17, 4.30) and husbands (AOR = 2.33 at 95% CI: 1.06, 5.14), and maternal Postnatal Care visits (AOR = 1.94 at 95% CI: 1.19, 3.16) were found independent predictors for timely initiated complementary feeding practice in this study. CONCLUSIONS: Timely complementary feeding practice in the study area was low compared to the standard recommends for it. Education in general and equipping child bearing women with specific messages on Infant and Child Feeding Practices may improve infant and child feeding practice in the area. Optimizing utilization of Postnatal Care by post partum women and including specific advices on complementary feeding are recommended. PMID- 29386009 TI - Screening for immune-potentiating antigens from hepatocellular carcinoma patients after radiofrequency ablation by serum proteomic analysis. AB - BACKGROUND: Radiofrequency ablation (RFA) can not only effectively kill hepatocellular carcinoma (HCC) tumour cells but also release tumour antigens that can provoke an immune response. However, there is no consensus regarding which antigens could constitutively be generated after RFA and could potentiate the immune response. The aim of this study was to identify these immune-potentiating antigens. METHODS: We performed two-dimensional electrophoresis (2-DE) and MALDI TOF-MS/MS analyses on serum obtained before and after RFA from 5 HCC patients. Further validation for selected proteins was performed utilizing ELISA analysis on another 52 HCC patients. Disease-free survival (DFS) analysis according to the differential expression of the interested protein before and after RFA was performed. RESULTS: Twelve decreased and 6 increased proteins after RFA were identified by MS. Three proteins, including clusterin, Ficolin-3, and serum retinol binding protein-4, were further verified by ELISA on the 52 HCC patients. Only Ficolin-3 proved to be significantly changed after RFA. The 52 patients were divided into two groups according to the expression of Ficolin-3 before and after RFA. The 1-, 2- and 3-year DFS rates were 59.1%, 31.8%, and 22.7%, respectively, for patients in the low Ficolin-3 group (22 patients) and 73.3%, 60.0%, and 50.0%, respectively, for patients in the high Ficolin-3 group (30 patients) (P = 0.038). CONCLUSIONS: In conclusion, Ficolin-3 was overexpressed in the serum of most HCC patients after RFA. Ficolin-3 might be a biomarker for RFA treatment efficacy and a potential target for HCC immunotherapy. PMID- 29386010 TI - Leveraging healthcare utilization to explore outcomes from musculoskeletal disorders: methodology for defining relevant variables from a health services data repository. AB - BACKGROUND: Large healthcare databases, with their ability to collect many variables from daily medical practice, greatly enable health services research. These longitudinal databases provide large cohorts and longitudinal time frames, allowing for highly pragmatic assessment of healthcare delivery. The purpose of this paper is to discuss the methodology related to the use of the United States Military Health System Data Repository (MDR) for longitudinal assessment of musculoskeletal clinical outcomes, as well as address challenges of using this data for outcomes research. METHODS: The Military Health System manages care for approximately 10 million beneficiaries worldwide. Multiple data sources pour into the MDR from multiple levels of care (inpatient, outpatient, military or civilian facility, combat theater, etc.) at the individual patient level. To provide meaningful and descriptive coding for longitudinal analysis, specific coding for timing and type of care, procedures, medications, and provider type must be performed. Assumptions often made in clinical trials do not apply to these cohorts, requiring additional steps in data preparation to reduce risk of bias. The MDR has a robust system in place to validate the quality and accuracy of its data, reducing risk of analytic error. Details for making this data suitable for analysis of longitudinal orthopaedic outcomes are provided. RESULTS: Although some limitations exist, proper preparation and understanding of the data can limit bias, and allow for robust and meaningful analyses. There is the potential for strong precision, as well as the ability to collect a wide range of variables in very large groups of patients otherwise not captured in traditional clinical trials. This approach contributes to the improved understanding of the accessibility, quality, and cost of care for those with orthopaedic conditions. CONCLUSION: The MDR provides a robust pool of longitudinal healthcare data at the person-level. The benefits of using the MDR database appear to outweigh the limitations. PMID- 29386011 TI - Two rare cases of synchronous and metachronous colonic metastases in patients with advanced gastric cancer. AB - BACKGROUND: Patients with advanced gastric cancer (GC) may ultimately die because GC mostly leads to synchronous or metachronous metastasis. However, colonic metastasis of GC is extremely rare. According to a PubMed search of papers published from May 1968 to March 2017, only 21 patients with GC (10 patients from 10 case reports and 11 patients from a retrospective study) have been found to have colonic metastasis. In this report, we present two cases of synchronous and metachronous colonic metastases of advanced GC. CASE PRESENTATION: Two patients with advanced GC received a diagnosis of colonic metastasis based on colonoscopic findings and computed tomography images, and the diagnosis was confirmed through pathological immunohistochemical analysis. Herein, we describe the management and outcomes of these metastases. CONCLUSIONS: Submucosal swelling and segmental bowel wall thickening observed through colonoscopy in patients with advanced GC might indicate colonic metastasis. PMID- 29386012 TI - Applying social innovation theory to examine how community co-designed health services develop: using a case study approach and mixed methods. AB - BACKGROUND: Citizen participation in health service co-production is increasingly enacted. A reason for engaging community members is to co-design services that are locally-appropriate and harness local assets. To date, much literature examines processes of involving participants, with little consideration of innovative services are designed, how innovations emerge, develop and whether they sustain or diffuse. This paper addresses this gap by examining co-designed initiatives through the lens of social innovation - a conceptualisation more attuned to analysing grassroots innovation than common health services research approaches considering top-down, technical innovations. This paper considers whether social innovation is a useful frame for examining co-designed services. METHODS: Eighty-eight volunteer community-based participants from six rural Australian communities were engaged using the same, tested co-design framework for a 12-month design and then 12-month implementation phase, in 24 workshops (2014-16). Mixed, qualitative data were collected and used to formulate five case studies of community co-designed innovations. A social innovation theory, derived from literature, was applied as an analytical frame to examine co-design cases at 3 stages: innovation growth, development and sustainability/diffusion. RESULTS: Social innovation theory was found relevant in examining and understanding what occurred at each stage of innovation development. Innovations themselves were all adaptations of existing ideas. They emerged due to local participants combining knowledge from local context, own experiences and exemplars. External facilitation brought resources together. The project provided a protective niche in which pilot innovations developed, but they needed support from managers and/or policymakers to be implemented; and to be compatible with existing health system practices. For innovations to move to sustainability/diffusion required political relationships. Challenging existing practice without these was problematical. CONCLUSIONS: Social innovation provides a useful lens to understand the grassroots innovation process implied in community participation in service co-design. It helps to show problems in co-design processes and highlights the need for strong partnerships and advocacy beyond the immediate community for new ideas to thrive. Regional commissioning organisations are intended to diffuse useful, co-designed service innovations. Efforts are required to develop an innovation system to realise the potential of community involvement in co-design. PMID- 29386013 TI - Effect of neoadjuvant chemotherapy and its correlation with HPV status, EGFR, Her 2-neu, and GADD45 expression in oral squamous cell carcinoma. AB - BACKGROUND: Head and neck cancers are the commonest cancer in Southeast Asia. Despite being a surface cancer, it is associated with significant morbidity as despite early detection by the patients they often report for treatment late and hence are associated with poor prognosis. The role of neoadjuvant chemotherapy in head and neck cancer is still under evaluation; there is a large subgroup of population that does not respond to chemotherapy, and hence, most studies have failed to show any survival benefit. This study evaluated the role of neoadjuvant therapy with docetaxel and carboplatin in patients with oral cancer and correlated the response to human papilloma virus, EGFR1, EGFR2, and GADD45 expression. METHODS: A total of 24 locally advanced, non-metastatic oral cancer patients were included in the study. Tumor biopsies were taken prior to the start of neoadjuvant therapy for expression of EGFR, Her-2-Neu, and GADD45 by immunohistochemistry and for HPV by PCR. The response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria after three cycles of chemotherapy. Statistical analysis was performed using correlation and Kaplan Meier analysis; the difference in survival was calculated with log rank test. RESULTS: A total of 21 male and 3 female with a mean age of 53.12 years were enrolled. Sixty-five percent of these received three cycles of chemotherapy. Five patients were positive for HPV 16 and none for HPV 18. Twenty-two of 24 patients showed GADD45 expression, 3 showed expression of Her-2-Neu while all 24 showed expression for EGFR1 protein. Two-year overall survival was 81%; GADD45 expressions were found to significantly affect the overall and disease-free survival, while any of the other protein expression studied and HPV status was not significant. CONCLUSION: The result of the present study shows significant downgrading of the oral cancers with neoadjuvant chemotherapy suggesting its utility in borderline operable cases. However, the response of chemotherapy does not appear to be related to the expression of EGFR, Her-2-Neu, and GADD45 protein or presence of HPV. Bone involvement, perineural invasion, and GADD45 expression significantly predict OS and DFS. All patients who did not express Gadd45 died before 2 years. Study with more subjects and longer follow-up should be carried out to elucidate this relation further. PMID- 29386014 TI - Longitudinal autoantibody responses against tumor-associated antigens decrease in breast cancer patients according to treatment modality. AB - BACKGROUND: Metastatic breast cancer (BCa) is most often diagnosed months after completion of treatment of the primary tumor when a patient reports physical symptoms. Besides a physical examination, no other alternative recurrence screening method is recommended for routine follow-up care. Detection of autoantibodies against tumor-associated antigens (TAAs) has demonstrated promise for distinguishing healthy women from patients diagnosed with primary BCa. However, it is unknown what changes occur to patient autoantibody levels during and after treatment. METHODS: Three serial blood draws were collected from 200 BCa patients: before treatment, 6 and 12 months after surgery. Patients were categorized according to treatment regimen, including surgery, chemotherapy, radiation, trastuzumab and hormonal therapies. The longitudinal samples were assayed for autoantibody responses against 32 conformation-carrying TAAs using a Luminex multiplex bead assay. RESULTS: The treatment modality groups that had the greatest decrease in autoantibody response levels were radiation + hormonal therapy; radiation + chemotherapy; and radiation + hormonal therapy + chemotherapy. For these three treatment groups, autoantibody responses against 9 TAAs (A1AT, ANGPTL4, CAPC, CST2, DKK1, GFRA1, GRN, LGALS3 and LRP10) were significantly reduced at 12 months after surgery compared to before treatment. One TAA, GRP78, had a significantly increased autoantibody response after 12 months. CONCLUSIONS: Single treatment regimens alone did not significantly alter autoantibodies levels against the studied TAAs. Radiation treatment was the common denominator of the three most affected groups for significant changes in autoantibody response levels. PMID- 29386015 TI - Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR 224 and regulating p21, PTEN expression. AB - BACKGROUND: Circ-ITCH is a circRNA generated from several exons of itchy E3 ubiquitin protein ligase (ITCH) and tumor suppressor served as a sponge for certain miRNAs targeting their parental transcripts of ITCH. However, the role of circ-ITCH in bladder cancer (BCa) was not reported. In the present study, we investigated the role of circ-ITCH in BCa. METHODS: Quantitative real-time PCR was used to detect the expression of circ-ITCH and survival analysis was adopted to explore the association between circ-ITCH expression and the prognosis of BCa. BCa cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion, cell cycle and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effect of circ-ITCH in BCa. Biotin-coupled probe pull down assay, Biotin-coupled miRNA capture, Fluorescence in situ hybridization and Luciferase reporter assay were conducted to confirm the relationship between the circ-ITCH and the microRNA. RESULTS: In the present study, we found that circ-ITCH, is down-regulated in BCa tissues and cell lines. BCa patients with low circ-ITCH expression had shortened survival. Enforced- expression of circ-ITCH inhibited cells proliferation, migration, invasion and metastasis both in vitro and in vivo. Mechanistically, we demonstrated that circ-ITCH up-regulates the expression of miR-17 and miR-224 target gene p21 and PTEN through 'sponging' miR-17 and miR-224, which suppressed the aggressive biological behaviors of BCa. CONCLUSIONS: circ-ITCH acts as a tumor suppressor by a novel circ-ITCH/miR-17, miR-224/p21, PTEN axis, which may provide a potential biomarker and therapeutic target for the management of BCa. PMID- 29386016 TI - Phytochemical investigation and antimicrobial appraisal of Parrotiopsis jacquemontiana (Decne) Rehder. AB - BACKGROUND: Parrotiopsis jacquemontiana (Decne) Rehder. is locally used for skin infections and in wound healing. In this study we have evaluated methanol extract of its leaves and derived fractions against the clinical multi-drug resistant bacterial strains. METHODS: P. jacquemontiana leaves powder extracted with 95% methanol (PJM) and fractionated in escalating polarity of solvents; n-hexane (PJH), chloroform (PJC), ethyl acetate (PJE), n-butanol (PJB) and the remaining as aqueous fraction (PJA). Clinical as well as environmental 19 bacterial strains and 8 fungal strains were screened for minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentration (MBC/MFC). Preliminary phytochemical investigation for various phytochemical classes was also carried out. RESULTS: PJM contained the coumarins, phenols, flavonoids, tannins, alkaloids, glycosides, saponins, sterols, phlobatannins, steroids, phytosterols, triterpenoids, acids, quinones, proteins, vitamin C, betacyanins, oils and resins while anthraquinones, phytosteroids, carbohydrates and anthocyanins were not detected. Disc diffusion assay (1 mg/disc) indicated the sensitivity of all the MDR strains of bacteria with PJM, PJE and PJB, while no inhibition was recorded with PJA. PJH and PJC inhibited the growth of all the strains of Staphylococcus aureus, Pseudomonas aeruginosa and Coagulase negative staphylococci used in this study. Maximum zone of inhibition (35.5 +/- 1.32 mm) was obtained with PJM against Staphylococcus lugdenesis MDR (6197). Comparatively lower MIC (8-64 MUg/ml) and MBC (32-256 MUg/ml) values were recorded for PJM and PJE. In case of fungal strains only PJM, PJE and PJB markedly inhibited the growth and lower MIC (8-128 MUg/ml) and MFC (32-512 MUg/ml) values were determined for PJM and PJE. CONCLUSION: The remarkable inhibition of various bacterial and fungal strains at low doses of the extract/fractions suggested the strong antibacterial, antifungal and anti-candidal potential of P. jacquemontiana leaves. PMID- 29386017 TI - A review of influenza detection and prediction through social networking sites. AB - Early prediction of seasonal epidemics such as influenza may reduce their impact in daily lives. Nowadays, the web can be used for surveillance of diseases. Search engines and social networking sites can be used to track trends of different diseases seven to ten days faster than government agencies such as Center of Disease Control and Prevention (CDC). CDC uses the Illness-Like Influenza Surveillance Network (ILINet), which is a program used to monitor Influenza-Like Illness (ILI) sent by thousands of health care providers in order to detect influenza outbreaks. It is a reliable tool, however, it is slow and expensive. For that reason, many studies aim to develop methods that do real time analysis to track ILI using social networking sites. Social media data such as Twitter can be used to predict the spread of flu in the population and can help in getting early warnings. Today, social networking sites (SNS) are used widely by many people to share thoughts and even health status. Therefore, SNS provides an efficient resource for disease surveillance and a good way to communicate to prevent disease outbreaks. The goal of this study is to review existing alternative solutions that track flu outbreak in real time using social networking sites and web blogs. Many studies have shown that social networking sites can be used to conduct real time analysis for better predictions. PMID- 29386019 TI - Anatomical axes of the proximal and distal halves of the femur in a normally aligned healthy population: implications for surgery. AB - BACKGROUND: The anatomical axis of the femur is crucial for determining the correct alignment in corrective osteotomies of the knee, total knee arthroplasty (TKA), and retrograde and antegrade femoral intramedullary nailing (IMN). The aim of this study was to propose the concept of different anatomical axes for the proximal and distal parts of the femur; compare these axes in normally aligned subjects and also to propose the clinical application of these axes. METHODS: In this cross-sectional study, the horizontal distances between the anatomical axis of the proximal and distal halves of the femur and the center of the intercondylar notch were measured in 100 normally aligned femurs using standard full length alignment view X-rays. RESULTS: The average age was 34.44 +/- 11.14 years. The average distance from the proximal anatomical axis to the center of the intercondylar notch was 6.68 +/- 5.23 mm. The proximal anatomical axis of femur passed lateral to the center of the intercondylar notch in 12 cases (12%), medial in 84 cases (84%) and exactly central in 4 cases (4%). The average distance from the distal anatomical axis to the center of the intercondylar notch was 3.63 +/- 2.09 mm. The distal anatomical axis of the femur passed medially to the center of the intercondylar notch in 82 cases (82%) and exactly central in 18 cases (18%). There was a significant difference between the anatomical axis of the proximal and distal parts of the femur in reference to the center of intercondylar notch (P value < 0.05), supporting the hypothesis that anatomical axes of the proximal and distal halves of the femur are different in the coronal plane. CONCLUSIONS: While surgeons are aware that the anatomical axis of the distal part of the femur is different than the anatomical axis of the proximal part in patients with femoral deformities, we have shown that these axes are also different in the normally aligned healthy people due to the anatomy of the femur in coronal plane. Also the normal ranges provided here can be used as a reference for the alignment guide entry point in TKA and antegrade and retrograde intramedullary femoral nailing. PMID- 29386018 TI - Targeting Gas6/TAM in cancer cells and tumor microenvironment. AB - Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer. PMID- 29386021 TI - A coordinate deregulation of microRNAs expressed in mucosa adjacent to tumor predicts relapse after resection in localized colon cancer. AB - Up to 20% of colorectal cancer (CRC) node-negative patients develop loco-regional or distant recurrences within 5 years from surgery. No predictive biomarker able to identify the node-negative subjects at high risk of relapse after curative treatment is presently available.Forty-eight localized (i.e. stage I-II) colon cancer patients who underwent radical tumor resection were considered. The expression of five miRNAs, involved in CRC progression, was investigated by qRT PCR in both tumor tissue and matched normal colon mucosa.Interestingly, we found that the coordinate deregulation of four miRNAs (i.e. miR-18a, miR-21, miR-182 and miR-183), evaluated in the normal mucosa adjacent to tumor, is predictive of relapse within 55 months from curative surgery.Our results, if confirmed in independent studies, may help to identify high-risk patients who could benefit most from adjuvant therapy. Moreover, this work highlights the importance of extending the search for tissue biomarkers also to the tumor-adjacent mucosa. PMID- 29386020 TI - Acting on audit & feedback: a qualitative instrumental case study in mental health services in Norway. AB - BACKGROUND: The National Guideline for Assessment, Treatment and Social Rehabilitation of Persons with Concurrent Substance Use and Mental Health Disorders, launched in 2012, is to be implemented in mental health services in Norway. Audit and feedback (A&F) is commonly used as the starting point of an implementation process. It aims to measure the research-practice gap, but its effect varies greatly. Less is known of how audit and feedback is used in natural settings. The aim of this study was to describe and investigate what is discussed and thematised when Quality Improvement (QI) teams in a District Psychiatric Centre (DPC) work to complete an action form as part of an A&F cycle in 2014. METHODS: This was an instrumental multiple case study involving four units in a DPC in Norway. We used open non-participant observation of QI team meetings in their natural setting, a total of seven teams and eleven meetings. RESULTS: The discussions provided health professionals with insight into their own and their colleagues' practices. They revealed insufficient knowledge of substance-related disorders and experienced unclear role expectations. We found differences in how professional groups sought answers to questions of clinical practice and that they were concerned about whether new tasks fitted in with their routine ways of working. CONCLUSION: Acting on A&F provided an opportunity to discuss practice in general, enhancing awareness of good practice. There was a general need for arenas to relate to practice and QI team meetings after A&F may well be a suitable arena for this. Self-assessment audits seem valuable, particular in areas where no benchmarked data exists, and there is a demand for implementation of new guidelines that might change routines and develop new roles. QI teams could benefit from having a unit leader present at meetings. Nurses and social educators and others turn to psychiatrists or psychologists for answers to clinical and organisational questions beyond guidelines, and show less confidence or routine in seeking research-based information. There is a general need to emphasise training in evidence-based practice and information seeking behaviour for all professional groups. PMID- 29386022 TI - Thromboelastometric assessment of hemostasis following hydroxyethyl starch (130/0.4) administration as a constant rate infusion in hypoalbuminemic dogs. AB - BACKGROUND: The primary aim was to evaluate by means of thromboelastometry (ROTEM) the effects of hydroxyethyl starch (HES) 130/0.4 administered as a constant rate infusion (CRI) on hemostasis in hypoalbuminemic dogs. The second aim was to use ROTEM analysis to detect whether all hypoalbuminemic dogs of our population were hypercoagulable. RESULTS: The study sample was 20 hypoalbuminemic dogs (albumin < 2 g/dl) with normal perfusion parameters and requiring intravenous fluid therapy. In order to support plasma colloid osmotic pressure, in addition to crystalloid, HES 130/0.4 was administered as a constant rate infusion at 1 ml/kg/h (group 1, n = 11) or 2 ml/kg/h for 24 h (group 2, n = 9). Blood samples were collected at baseline (T0) and 24 h postinfusion (T1); coagulation was assessed by standard coagulation profile (prothrombin time, activated partial thromboplastin time, and fibrinogen), and ROTEM analysis (in TEM(r), ex-TEM(r) and fib- TEM(r) profile). No statistically significant differences in ROTEM values in group 1 were observed (P > 0.05), whereas in group 2 statistically significant differences (P < 0.05) were found at T1 in the in TEM(r) profile [decrease in clot formation time (P = 0.04) and increase in alpha angle (P = 0.02)] and in the ex-TEM(r) profile [increase in maximum clot firmness (P = 0.008) and alpha angle (P = 0.01)]; no changes were identified in the fib TEM(r) profile. In both groups, a statistically significant decrease (P = 0.007) in hematocrit was noted, whereas no statistically significant differences in platelet count and standard coagulation profile were found. In group 2, a statistically significant increase in TS values (P = 0.03) was noted at T1. ROTEM tracings indicating a hypercoagulable state were observed in 7/20 dogs at T0 (5/11 in group 1 and 2/9 in the group 2). CONCLUSION: Our findings suggest that HES 130/0.4 administered as CRI does not cause hypocoagulability in hypoalbuminemic dogs. A trend toward hypercoagulability, probably related to the underlying diseases, was observed in group 2 at T1. Although all dogs were hyoalbuminemic, only 7/20 were hypercoagulable at T0, confirming the lack of correlation between albumin level and prothrombotic state. PMID- 29386023 TI - Public health opportunities and challenges in the provision of partner notification services: the New England experience. AB - BACKGROUND: Partner notification services (PNS) are recommended by the Centers for Disease Control and Prevention as a public health intervention for addressing the spread of HIV and other sexually transmitted diseases (STDs). Barriers and facilitators to the partner notification process from a public health perspective have not been well described. METHODS: In 2015, a coalition of New England public health STD directors and investigators formed to address the increasing STD prevalence across the region (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont) and to promote communication between state STD programs. To evaluate barriers and facilitators of PNS programs, a survey was administered to representatives from each state to describe PNS processes and approaches. RESULTS: Of the six PNS programs, Connecticut, Maine, Massachusetts, Vermont, and New Hampshire had combined HIV and STD PNS programs; Rhode Island's programs were integrated but employed separate disease intervention specialists (DIS). All states performed PNS for HIV and syphilis. Maine, New Hampshire and Vermont performed services for all gonorrhea cases. Rhode Island, Connecticut, and Massachusetts performed limited partner notification for gonorrhea due to lack of resources. None of the six states routinely provided services for chlamydia, though Maine and Vermont did so for high-priority populations such as HIV co-infected or pregnant individuals. Across all programs, clients received risk reduction counseling and general STD education as a component of PNS, in addition to referrals for HIV/STD care at locations ranging from Planned Parenthood to community- or hospital-based clinics. Notable barriers to successful partner notification across all states included anonymous partners and index cases who did not feel comfortable sharing partners' names with DIS. Other common barriers included insufficient staff, inability of DIS to identify and contact partners, and index cases declining to speak with DIS staff. CONCLUSIONS: In New England, state health departments use different strategies to implement PNS programs and referral to STD care. Despite this, similar challenges exist across settings, including difficulty with anonymous partners and limited state resources. PMID- 29386024 TI - A review of characteristics and outcomes of Australia's undergraduate medical education rural immersion programs. AB - BACKGROUND: A key strategy for increasing the supply of rural doctors is rurally located medical education. In 2000, Australia introduced a national policy to increase rural immersion for undergraduate medical students. This study aims to describe the characteristics and outcomes of the rural immersion programs that were implemented in Australian medical schools. METHODS: Information about 19 immersion programs was sourced in 2016 via the grey and published literature. A scoping review of the published peer-reviewed studies via Ovid MEDLINE and Informit (2000-2016) and direct journal searching included studies that focused on outcomes of undergraduate rural immersion in Australian medical schools from 2000 to 2016. RESULTS: Programs varied widely by selection criteria and program design, offering between 1- and 6-year immersion. Based on 26 studies from 10 medical schools, rural immersion was positively associated with rural practice in the first postgraduate year (internship) and early career (first 10 years post qualifying). Having a rural background increased the effects of rural immersion. Evidence suggested that longer duration of immersion also increases the uptake of rural work, including by metropolitan-background students, though overall there was limited evidence about the influence of different program designs. Most evidence was based on relatively weak, predominantly cross-sectional research designs and single-institution studies. Many had flaws including small sample sizes, studying internship outcomes only, inadequately controlling for confounding variables, not using metropolitan-trained controls and providing limited justification as to the postgraduate stage at which rural practice outcomes were measured. CONCLUSIONS: Australia's immersion programs are moderately associated with an increased rural supply of early career doctors although metropolitan-trained students contribute equal numbers to overall rural workforce capacity. More research is needed about the influence of student interest in rural practice and the duration and setting of immersion on rural work uptake and working more remotely. Research needs to be more nationally balanced and scaled-up to inform national policy development. Critically, the quality of research could be strengthened through longer-term follow-up studies, adjusting for known confounders, accounting for postgraduate stages and using appropriate controls to test the relative effects of student characteristics and program designs. PMID- 29386025 TI - miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis. AB - BACKGROUND: Chemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling. METHODS: miRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway. RESULTS: CXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3' UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR 23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naive mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice. CONCLUSIONS: miR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity. PMID- 29386026 TI - A qualitative study of health care providers' perceptions and experiences of working together to care for children with medical complexity (CMC). AB - BACKGROUND: Children with medical complexity (CMC) have a wide range of long term health problems and disabilities that have an adverse impact on their quality of life. They have high levels of family identified health care needs and health care utilisation. There is no Australian literature on the experiences of health care providers working in the Australian tertiary, secondary and primary health care system, whilst managing CMC. This information is essential to inform the design of integrated health care systems for these children. We address this knowledge gap by exploring the perceptions and experiences of health care providers on the provision of health care for CMC aged 0 to 18 years. METHOD: A qualitative research study was undertaken. Stakeholder forums, group and individual in depth interviews were undertaken using a semi-structured interview guide. The stakeholder forums were audio recorded and transcribed verbatim. Field notes of the stakeholder forums, group and individual interviews were taken. Inductive thematic analysis was undertaken to identify key themes. RESULTS: One hundred and three providers took part in the stakeholder forums and interviews across 3 local health districts, a tertiary paediatric hospital network, and primary health care organisations. Providers expressed concern regarding family capacity to negotiate the system, which was impacted by the medical complexity of the children and psychosocial complexity of their families. Lack of health care provider capacity in terms of their skills, time and availability to manage CMC was also a key problem. These issues occurred within a health system that had impaired capacity in terms of fragmentation of care and limited communication among health care providers. CONCLUSION: When designing integrated care models for CMC, it is essential to understand and address the challenges experienced by their health care providers. This requires adequate training of providers, additional resources and time for coordination of care, improved systems of communication among services, with timely access to key information for parents and providers. PMID- 29386027 TI - The effect of informal caregiver support on utilization of acute health services among home care clients: a prospective observational study. AB - BACKGROUND: Emergency department visits and hospitalizations (EDVH) place a large burden on patients and the health care system. The presence of informal caregivers may be beneficial for reducing EDVH among patients with specific diagnoses. Our objective was to determine whether the presence of an informal caregiver was associated with the occurrence of an EDVH among clients 50 years of age or older. METHODS: Using a database accessed through the Toronto Central Community Care Access Centre (CCAC), we identified 479 adults over 50 years of age who received home care in Toronto, Canada. Exposure variables were extracted from the interRAI health assessment form completed at the time of admission to the CCAC. EDVH data were linked to provincial records through the CCAC database. Data on emergency room visits were included for up to 6 months after time of admission to home care. Multiple logistic regression analysis was used to identify factors associated with the occurrence of an EDVH. RESULTS: Approximately half of all clients had an EDVH within 180 days of admission to CCAC home care. No significant association was found between the presence of an informal caregiver and the occurrence of an EDVH. Significant factors associated with an EDVH included: Participants having a poor perception of their health (adjusted OR = 1.68, 95% CI: 1.11-2.56), severe cardiac disorders (adjusted OR = 1.54, 95% CI: 1.04-2.29), and pulmonary diseases (adjusted OR = 1.99, 95% CI: 1.16-3.47). CONCLUSIONS: The presence of an informal caregiver was not significantly associated with the occurrence of an EDVH. Future research should examine the potential associations between length of hospital stay or quality of life and the presence of an informal caregiver. In general, our work contributes to a growing body of literature that is increasingly concerned with the health of our aging population, and more specifically, health service use by elderly patients, which may have implications for health care providers. PMID- 29386028 TI - Pulmonary exposure to carbonaceous nanomaterials and sperm quality. AB - BACKGROUND: Semen quality parameters are potentially affected by nanomaterials in several ways: Inhaled nanosized particles are potent inducers of pulmonary inflammation, leading to the release of inflammatory mediators. Small amounts of particles may translocate from the lungs into the lung capillaries, enter the systemic circulation and ultimately reach the testes. Both the inflammatory response and the particles may induce oxidative stress which can directly affect spermatogenesis. Furthermore, spermatogenesis may be indirectly affected by changes in the hormonal milieu as systemic inflammation is a potential modulator of endocrine function. The aim of this study was to investigate the effects of pulmonary exposure to carbonaceous nanomaterials on sperm quality parameters in an experimental mouse model. METHODS: Effects on sperm quality after pulmonary inflammation induced by carbonaceous nanomaterials were investigated by intratracheally instilling sexually mature male NMRI mice with four different carbonaceous nanomaterials dispersed in nanopure water: graphene oxide (18 MUg/mouse/i.t.), Flammruss 101, Printex 90 and SRM1650b (0.1 mg/mouse/i.t. each) weekly for seven consecutive weeks. Pulmonary inflammation was determined by differential cell count in bronchoalveolar lavage fluid. Epididymal sperm concentration and motility were measured by computer-assisted sperm analysis. Epididymal sperm viability and morphological abnormalities were assessed manually using Hoechst 33,342/PI flourescent and Spermac staining, respectively. Epididymal sperm were assessed with regard to sperm DNA integrity (damage). Daily sperm production was measured in the testis, and testosterone levels were measured in blood plasma by ELISA. RESULTS: Neutrophil numbers in the bronchoalveolar fluid showed sustained inflammatory response in the nanoparticle exposed groups one week after the last instillation. No significant changes in epididymal sperm parameters, daily sperm production or plasma testosterone levels were found. CONCLUSION: Despite the sustained pulmonary inflammatory response, an eight week exposure to graphene oxide, Flammruss 101, Printex 90 and the diesel particle SRM1650b in the present study did not appear to affect semen parameters, daily sperm production or testosterone concentration in male NMRI mice. PMID- 29386029 TI - Effects of dietary supplementation with oridonin on the growth performance, relative organ weight, lymphocyte proliferation, and cytokine concentration in broiler chickens. AB - BACKGROUND: The present study was conducted to investigate the effects of oridonin (ORI) on growth performance, relative organ weight, lymphocyte proliferation, phagocytic function of neutrophils, and cytokine concentration in broiler chickens. A total of 240 one-day-old Arbor Acres male broilers were randomly assigned to four treatments with six replicate pens of 10 broiler chickens per pen. Broiler chickens were fed diets based on four levels of dietary ORI (0, 50, 80 and 100 mg/kg) for a 42-d feeding trial. The experimental diets were fed in three phases: 1 to 14 d, 15 to 28 d and 29 to 42 d. RESULTS: The results indicated that ORI has no influence on the growth performance (P > 0.05). However, ORI increased the relative weights of spleen and bursa, the number of proliferation peripheral blood T and B lymphocytes, the phagocytic rate of neutrophils, as well as the Interleukin-2 (IL-2), Interleukin-4 (IL-4) and tumor necrosis factor-a (TNF-a) serum concentrations in serum in broilers at days 14, 28 and 42 (P < 0.05). CONCLUSIONS: In conclusion, ORI can enhance immune function and resistance to disease in broiler chickens by stimulating T and B lymphocyte formation, division, and proliferation, as well as the modulation of Th1/Th2 cytokine secretion profiles. PMID- 29386030 TI - "I've made this my lifestyle now": a prospective qualitative study of motivation for lifestyle change among people with newly diagnosed type two diabetes mellitus. AB - BACKGROUND: Diagnosis with Type 2 Diabetes is an opportunity for individuals to change their physical activity and dietary behaviours. Diabetes treatment guidelines recommend theory-based, patient-centred care and advocate the provision of support for patient motivation but the motivational experiences of people newly diagnosed with diabetes have not been well studied. Framed in self determination theory, this study aimed to qualitatively explore how this patient group articulate and experience different types of motivation when attempting lifestyle change. METHODS: A secondary analysis of semi-structured interview data collected with 30 (n female = 18, n male = 12) adults who had been newly diagnosed with type two diabetes and were participants in the Early ACTID trial was undertaken. Deductive directed content analysis was performed using NVivo V10 and researcher triangulation to identify and describe patient experiences and narratives that reflected the motivation types outlined in self-determination theory and if/how these changed over time. RESULTS: The findings revealed the diversity in motivation quality both between and within individuals over time and that patients with newly-diagnosed diabetes have multifaceted often competing motivations for lifestyle behaviour change. Applying self-determination theory, we identified that many participants reported relatively dominant controlled motivation to comply with lifestyle recommendations, avoid their non-compliance being "found out" or supress guilt following lapses in behaviour change attempts. Such narratives were accompanied by experiences of frustrating slow behaviour change progress. More autonomous motivation was expressed as something often achieved over time and reflected goals to improve health, quality of life or family time. Motivational internalisation was evident and some participants had integrated their behaviour change to a new way of life which they found resilient to common barriers. CONCLUSIONS: Motivation for lifestyle change following diagnosis with type two diabetes is complex and can be relatively low in self determination. To achieve the patient empowerment aspirations of current national health care plans, intervention developers, and clinicians would do well to consider the quality not just quantity of their patients' motivation. TRIAL REGISTRATION: ISRCTN ISRCTN92162869 . Retrospectively registered. PMID- 29386031 TI - Psychometric properties of the German version of Observer OPTION5. AB - BACKGROUND: In order to conduct studies on shared decision-making (SDM) and to implement SDM in routine practice, psychometrically tested measures are needed. The development of the short 5-item version of the OPTION scale (Observer OPTION5) allows to assess SDM from an observer perspective. Observer OPTION5 is so far only available in English and Dutch. The aim of this study was to translate the Observer OPTION5 rating scale into German and to test its psychometric properties. METHODS: The German Observer OPTION5 was tested in a secondary data analysis of audio-recordings of patient-physician-consultations (N = 79) in German primary care practices. Demographic data were analysed using descriptive statistics. To assess inter- and intra-rater reliability, intraclass correlation coefficients (ICCs) were calculated. For assessing concurrent validity, a correlation (Spearman's Rho) of the sum score of Observer OPTION5 and Observer OPTION12 was calculated. RESULTS: The consultations dealt with decisions regarding type 2 diabetes (N = 31), chronic back pain (N = 23), depression (N = 20), and other diseases (N = 5). Analysis of inter-rater reliability yielded an ICC of 0.82 for the sum score; across the five single items ICCs ranged between 0.45 and 0.77. For the intra-rater reliability an ICC of 0.83 was observed for the total score; across the five single items ICCs ranged between 0.45 and 0.86. The Observer OPTION5 had a mean total score of 11.84 (SD = 11.92) and the Observer OPTION12 had a mean total score of 10.3 (SD = 7.9), both on a potential range of 0 to 100. The correlation between the total scores of Observer OPTION5 and Observer OPTION12 was r = 0.47 (p = 0.01). CONCLUSIONS: The results regarding inter- and intra-rater reliability were excellent on the total score level. Observer OPTION5 showed moderate concurrent validity using Observer OPTON12. The results are generally comparable to the results of the original English version of Observer OPTION5. The German version of Observer OPTION5 can be used in research and evaluation of clinical practice. Nevertheless, further testing is adviced. PMID- 29386032 TI - Recruiting families for an intervention study to prevent second-hand smoke exposure in children. AB - BACKGROUND: We evaluated the effectiveness of different recruitment strategies used in a study aimed at eliminating/reducing second-hand smoke (SHS) exposure in Dutch children 0-13 years of age with a high risk of asthma. METHODS: The different strategies include: 1) questionnaires distributed via home addresses, physicians or schools of the children; 2) cohorts from other paediatric studies; 3) physicians working in the paediatric field (family physicians, paediatricians and Youth Health Care (YHC) physicians); and 4) advertisements in a local newsletter, at child-care facilities, and day-care centres. RESULTS: More than 42,782 families were approached to take part in the screening of which 3663 could be assessed for eligibility. Of these responders, 196 families met the inclusion criteria for the study. However, only 58 (one third) could be randomised in the trial, mainly because of no interest or time of the parents. The results showed that recruiting families who expose their children to SHS exposure is very challenging, which may be explained by lack of 'recognition' or awareness that SHS occurs in homes. The presence of asthma in the family, respiratory symptoms in the children, and even incentives did not increase parental motivation for participation in the study. CONCLUSIONS: The recruitment process for an intervention program addressing SHS exposure in children was considerably more challenging and time consuming than anticipated. Barriers at both a parents level and a doctor's level can be discriminated. PMID- 29386033 TI - Clinical comparison of unilateral biportal endoscopic technique versus open microdiscectomy for single-level lumbar discectomy: a multicenter, retrospective analysis. AB - BACKGROUND: The unilateral biportal endoscopic (UBE) technique is a minimally invasive procedure for spinal surgery, while open microscopic discectomy is the most common surgical treatment for ruptured or herniated discs of the lumbar spine. A new endoscopic technique that uses a UBE approach has been applied to conventional arthroscopic systems for the treatment of spinal disease. In this study, we aimed to compare and evaluate the perioperative parameters and clinical outcomes, including recovery from surgery, pain and life quality modification, patient's satisfaction, and complications, between UBE and open lumbar microdiscectomy (OLM) for single-level discectomy procedures. METHODS: This study included 141 patients with degenerative disc disease requiring discectomy at a single level from L2-L3 to L5-S1. A total of 60 and 81 patients underwent UBE and OLM, respectively. Analysis was based on comparison of perioperative metrics, operation time (OT); estimated blood loss (EBL); length of hospital stay (HS); clinical outcomes, including assessment using the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI); patient satisfaction (the MacNab score); and the incidence of reoperation and complications. RESULTS: The study cohort was 56.7% women, and the mean patient age was 50.98 +/- 18.23 years. The mean VAS (the back and leg), MacNab score, and ODI improved significantly from the preoperative period to the last follow-up (12.92 +/- 3.92) in both groups (p < 0.001). One week after operation, the back VAS score in the UBE group showed significantly more improvement than that in the OLM group. However, the 1-week, 3-month, and 12 month VAS (the back and leg), ODI improvement, modified MacNab score, and OT were not significantly different between the two groups. In the UBE group, EBL (34.67 +/- 16.92) was smaller and HS (2.77 +/- 1.2) was shorter than that of the OLM group (140.05 +/- 57.8, 6.37 +/- 1.39). However, OT (70.15 +/- 22.0) was longer in the UBE group than in the OLM group (60.38 +/- 15.5), and the difference was statistically significant. Meanwhile, the differences in the rate of surgical conversion and complications between the two groups were not statistically significant. CONCLUSIONS: The UBE for single-level discectomy yielded similar clinical outcomes to OLM, including pain control, functional disability, and patient satisfaction, but incurred minimal EBL, HS, and postoperative back pain. TRIAL REGISTRATION: Not applicable. PMID- 29386034 TI - Integrating community-based health promotion programs and primary care: a mixed methods analysis of feasibility. AB - BACKGROUND: Implementation of evidence-based programs (EBPs) for disease self management and prevention is a policy priority. It is challenging to implement EBPs offered in community settings and to integrate them with healthcare. We sought to understand, categorize, and richly describe key challenges and opportunities related to integrating EBPs into routine primary care practice in the United States. METHODS: As part of a parent, participatory action research project, we conducted a mixed methods evaluation guided by the PRECEDE implementation planning model in an 11-county region of Southeast Minnesota. Our community-partnered research team interviewed and surveyed 15 and 190 primary care clinicians and 15 and 88 non-clinician stakeholders, respectively. We coded interviews according to pre-defined PRECEDE factors and by participant type and searched for emerging themes. We then categorized survey items-before looking at participant responses-according to their ability to generate further evidence supporting the PRECEDE factors and emerging themes. We statistically summarized data within and across responder groups. When consistent, we merged these with qualitative insight. RESULTS: The themes we found, "Two Systems, Two Worlds," "Not My Job," and "Seeing is Believing," highlighted the disparate nature of prescribed activities that different stakeholders do to contribute to health. For instance, primary care clinicians felt pressured to focus on activities of diagnosis and treatment and did not imagine ways in which EBPs could contribute to either. Quantitative analyses supported aspects of all three themes, highlighting clinicians' limited trust in community-placed activities, and the need for tailored education and system and policy-level changes to support their integration with primary care. CONCLUSIONS: Primary care and community-based programs exist in disconnected worlds. Without urgent and intentional efforts to bridge well-care and sick-care, interventions that support people's efforts to be and stay well in their communities will remain outside of-if not at odds with healthcare. PMID- 29386035 TI - The degree of peri-implant osteolysis induced by PEEK, CoCrMo, and HXLPE wear particles: a study based on a porous Ti6Al4V implant in a rabbit model. AB - BACKGROUND: Polyether-ether-ketone (PEEK), cobalt-chromium-molybdenum (CoCrMo), and highly cross-linked polyethylene (HXLPE) are biomaterials used in orthopedic implants; their wear particles are considered to induce peri-implant osteolysis. We examined whether different particle types induce the same degree of peri implant osteolysis. METHODS: Forty female rabbits were randomly divided into four groups-the control group (n = 10), which received implantation operation and sham operation at 1 month postoperation; three experimental groups (n = 10 in each group), which received implantation operation along with administration of 0.1 mL of particle suspension (approximately 1.0 * 108 PEEK, CoCrMo, or HXLPE wear particles) into the knee joint at 1 month postoperation. All rabbits were sacrificed at 2 months postoperation. The synovium was removed and histologically assessed. The distal femurs with the implants were analyzed via micro-computed tomography (CT) and hard tissue biopsy. RESULTS: The average size of almost 90% of the particles was < 5 MUm, indicating no significant difference in the three particle types. IL-1beta, IL-8, TNFalpha, RANKL, and MCP-1 expression in PEEK and CoCrMo groups was high, while that in the HXLPE group was low. The bone density (BD) and bone volume/total volume (BV/TV) of the porous structures (part of the implants in all groups) in experimental groups did not decrease markedly (p > 0.05), while BD in the peripheral regions in experimental groups decreased markedly compared to control groups (p < 0.05). BV/TV in the peripheral regions was significantly decreased in PEEK and CoCrMo groups when compared to control group (p < 0.05), while no significant difference was noted between HXLPE and control groups (p > 0.05). The changes in BV observed in the hard tissue sections were consistent with those noted in the micro-CT findings. CONCLUSION: PEEK, CoCrMo, and HXLPE wear particles (approximately having the same size and doses) induce peri-implant osteolysis to a different degree: HXLPE particles induce peri implant osteolysis to a mild degree, while PEEK and CoCrMo particles caused significant peri-implant osteolysis. In case of a porous implant, osteolysis occurred primarily in the peripheral region, rather than in the porous structures. Our findings would be helpful for implant designers to choose friction pairs in orthopedic components. PMID- 29386036 TI - A novel role of ER stress signal transducer ATF6 in regulating enterovirus A71 viral protein stability. AB - BACKGROUND: Due to limited coding capacity of viral genome, enterovirus A71 (EV A71) co-opts host nuclear proteins for its replication. Upon ER stress, the ER localized 90 kDa activating transcription factor 6 (p90ATF6) is proteolytically cleaved to produce the transcriptionally active amino-terminal 50 kDa (p50ATF6) product where it enters the nucleus to activate a subset of unfolded protein response and ER-associated degradation (also known as ERAD) genes. During EV-A71 infection, however, this p50ATF6 product was not detected in the nucleus, and its downstream target genes were not activated. METHODS: We examined the role of ATF6 during EV-A71 infection, including its cleavage process and its role in viral life cycle by silencing or overexpressing ATF6. RESULTS: We showed that a potential cleavage in the middle of p90ATF6 produced an amino-terminal ~ 45 kDa fragment in a viral protease-independent but EV-A71-dependent manner. The disappearance of ATF6 was not restricted to a specific strain of EV-A71 or cell type, and was not simply caused by picornavirus-mediated global translational shutoff. This cleavage of ATF6, which was most likely mediated by the host response, was nevertheless independent of both cellular caspases and XBP1 associated proteasomes. The silencing of ATF6 expression by small interfering RNA suppressed viral titers due to reduced viral protein stability. This effect was markedly restored by the ectopic expression of p90ATF6. CONCLUSION: Our findings indicate that ATF6 plays a distinct role in viral protein stability and that the host uses different cleavage strategies, rather than conventional cleavage by generating p50ATF6, to combat viral infection. PMID- 29386038 TI - Correction to: A multiplex marker set for microsatellite typing and sexing of sooty terns Onychoprion fuscatus. AB - Following publication of the original article [1], one of the authors reported that his name was listed incorrectly, and that he would like his name to appear as S. James Reynolds instead of Silas James Reynolds. The latter format would confuse citations as all his previous publications are in the former format. PMID- 29386037 TI - Long non-coding RNA XLOC_000647 suppresses progression of pancreatic cancer and decreases epithelial-mesenchymal transition-induced cell invasion by down regulating NLRP3. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) play an important role in the development and progression of various tumors, including pancreatic cancer (PC). Recent studies have shown that lncRNAs can 'act in cis' to regulate the expression of its neighboring genes. Previously, we used lncRNAs microarray to identify a novel lncRNA termed XLOC_000647 that was down-regulated in PC tissues. However, the expression and function of XLOC_000647 in PC remain unclear. METHODS: The expression of XLOC_000647 and NLRP3 in PC specimens and cell lines were detected by quantitative real-time PCR. Transwell assays were used to determine migration and invasion of PC cells. Western blot was carried out for detection of epithelial-mesenchymal transition (EMT) markers in PC cells. The effect of XLOC_000647 on PC cells was assessed in vitro and in vivo. The function of NOD-like receptor family pyrin domain-containing 3 (NLRP3) in PC was investigated in vitro. In addition, the regulation of NLRP3 by XLOC_000647 in PC was examined in vitro. RESULTS: Here, XLOC_000647 expression was down-regulated in PC tissues and cell lines. The expression level of XLOC_000647 was significantly correlated to tumor stage, lymph node metastasis, and overall survival. Overexpression of XLOC_000647 attenuated cell proliferation, invasion, and EMT in vitro and impaired tumor growth in vivo. Further, a significantly negative correlation was observed between XLOC_000647 levels and its genomic nearby gene NLRP3 in vitro and in vivo. Moreover, XLOC_000647 decreased NLRP3 by inhibiting its promoter activity. Knockdown of NLRP3 decreased proliferation of cancer cells, invasion, and EMT in vitro. Importantly, after XLOC_000647 was overexpressed, the corresponding phenotypes of cells invasion and EMT were reversed by overexpression of NLRP3. CONCLUSIONS: Together, these results indicate that XLOC_000647 functions as a novel tumor suppressor of lncRNA and acts as an important regulator of NLRP3, inhibiting cell proliferation, invasion, and EMT in PC. PMID- 29386040 TI - Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR. AB - BACKGROUND: It has been suggested that ultra-rare diseases should be recognized as distinct from more prevalent rare diseases, but how drugs developed to treat ultra-rare diseases (DURDs) might be distinguished from drugs for 'other' rare diseases (DORDs) is not clear. We compared the characteristics of DURDs to DORDs from a health technology assessment (HTA) perspective in submissions made to the CADTH Common Drug Review. We defined a DURD as a drug used to treat a disease with a prevalence <= 1 patient per 100,000 people, a DORD as a drug used to treat a disease with a prevalence > 1 and <= 50 patients per 100,000 people. We assessed differences in the level and quantity of evidence supporting each HTA submission, the molecular basis of treatment agents, annual treatment cost per patient, type of reimbursement recommendation made by CADTH, and reasons for negative recommendations. RESULTS: We analyzed 14 DURD and 46 DORD submissions made between 2004 and 2016. Compared to DORDs, DURDs were more likely to be biologic drugs (OR = 6.06, 95%CI 1.25 to 38.58), to have been studied in uncontrolled clinical trials (OR = 23.11, 95%CI 2.23 to 1207.19), and to have a higher annual treatment cost per patient (median difference = CAN$243,787.75, 95%CI CAN$83,396 to CAN$329,050). Also, submissions for DURDs were associated with a less robust evidence base versus DORDs, as DURD submissions were less likely to include data from at least one double-blinded randomized controlled trial (OR = 0.13, 95%CI 0.02 to 0.70) and have smaller patient cohorts in clinical trials (median difference = -108, 95%CI -234 to -50). Furthermore, DURDs are less likely to receive a positive reimbursement recommendation (OR = 0.22, 95%CI 0.05 to 0.91), and low level of evidence was the major contributor for a negative recommendation. CONCLUSIONS: The results suggest that DURDs could be viewed as distinct category from an HTA perspective. Applying the same HTA decision-making framework to DURDs and DORDs might have contributed the higher rate of negative reimbursement recommendations made for DURDs. Recognition of DURDs as a distinct subgroup of DRDs by explicitly defining DURDs based on objective criteria may facilitate the implementation of HTA assessment process that accounts for the issues associated with DURD. PMID- 29386039 TI - Posterior reversible encephalopathy syndrome secondary to asymptomatic poststreptococcal glomerulonephritis in a child with sickle cell anemia: a case report. AB - BACKGROUND: Posterior reversible encephalopathy syndrome is a neurotoxic condition that occurs as a result of the failure of posterior circulatory autoregulation in response to acute changes in blood pressure. Overperfusion with resultant disruption of the blood-brain barrier results in vasogenic edema, but not infarction. Posterior reversible encephalopathy syndrome can be the presenting feature of postinfectious glomerulonephritis, which has been reported in approximately 5% of hospitalized children, and it has been reported in very few cases of adult patients with sickle cell anemia. We report a very rare case of posterior reversible encephalopathy syndrome that occurred in a child with sickle cell anemia. This presentation should be differentiated from other neurologic manifestations that occur in patients with sickle cell anemia, because management is totally different. CASE PRESENTATION: We report what is to our knowledge the first reported case of a 9-year-old Saudi girl with sickle cell anemia who developed posterior reversible encephalopathy syndrome secondary to asymptomatic poststreptococcal glomerulonephritis. This occurred after full recovery from acute chest syndrome and severe vaso-occlusive crisis. CONCLUSIONS: The purpose of this report is to emphasize that all efforts should be made to explore the causes of different neurologic manifestations that occur in patients with sickle cell anemia, because this will require different pathways of management. PMID- 29386041 TI - Mesenchymal stem cells in the osteosarcoma microenvironment: their biological properties, influence on tumor growth, and therapeutic implications. AB - During tumorigenesis and development, participation of the tumor microenvironment is not negligible. As an important component in the tumor microenvironment, mesenchymal stem cells (MSCs) have been corroborated to mediate proliferation, metastasis, and drug resistance in many cancers, including osteosarcoma. What's more, because of tumor site tropism, MSCs can be engineered to be loaded with therapeutic agents so that drugs can be precisely delivered to tumor lesions. In this review, we mainly discuss recent advances concerning the functions of MSCs in osteosarcoma and their possible clinical applications in the future. PMID- 29386042 TI - Assessment of risky sexual behavior and practice among Aksum University students, Shire Campus, Shire Town, Tigray, Ethiopia, 2017. AB - OBJECTIVE: Having sex at early age, having multiple sexual partners, having sex while under the influence of alcohol or drugs and unprotected sexual behaviors are the common characteristics of risky sexual behavior which increases risk of individuals to sexuality and reproductive health problems. Risky sexual behavior is the most common problem in adolescents and young adults which may expose individuals for permanent social, economical, psychological and physical problem. So that this study focus on assessment of risk sexual behavior using institution based cross-sectional study design on 287 randomly selected subjects among Aksum University students. RESULTS: Almost 60% students reported to have ever had sexual activity. Of which 86 (83.5%) and 112 (64.4%) reported having inconsistent condom use and multiple sexual partners respectively. Even though more than half of first sexual intercourse (61.5%) starts due to their desire but still peer pressure and alcohol have significant effect. Similarly the study indicated that a significant segment of students have risk sexual behaviors which increase individuals' risk of acquiring HIV/AIDS. Unless appropriate age and institutional targeted interventions exist, certain behaviors can place the university students at greater risk of HIV infection and sexually transmitted disease. PMID- 29386043 TI - Predictive factors of late cholangitis in patients undergoing pancreaticoduodenectomy. AB - BACKGROUND: Because the survival rate for patients experiencing late complications after pancreaticoduodenectomy (PD) is increasing, late complications should receive as much attention as early complications do. METHODS: Between April 2007 and August 2016, 133 patients underwent PD at our institution. We analyzed their cases to determine the predictors of late cholangitis after PD. RESULTS: Of the 133 patients, 28 (21.1%) were diagnosed with postoperative cholangitis. A multivariate analysis showed that abnormal postoperative values of alkaline phosphatase were independently associated with postoperative cholangitis (odds ratio, 3.81; 95% confidence interval, 1.519 9.553; P = 0.004). The optimal cut-off value for postoperative alkaline phosphatase calculated from the receiver operating characteristic curve was 410 IU/L (sensitivity, 76.2%; specificity, 67.9%; area under the curve, 0.73). A univariate analysis to identify risk factors showed that pneumobilia was significantly related to a postoperative alkaline phosphatase value >= 410 IU/L (P = 0.041). CONCLUSION: This study suggests that an alkaline phosphatase level >= 410 IU/L is a predictor of late postoperative cholangitis. In addition, pneumobilia is also related to the postoperative alkaline phosphatase level. Therefore, alkaline phosphatase levels should be carefully monitored in patients with postoperative pneumobilia in the late postoperative course. PMID- 29386044 TI - Integrin-beta5, a miR-185-targeted gene, promotes hepatocellular carcinoma tumorigenesis by regulating beta-catenin stability. AB - BACKGROUND: The tumour microenvironment is essential for cancer progress and metastasis. Integrin-beta5 (ITGB5), a member of the integrin family, has been implicated to mediate the interactions of cells with the extracellular matrix (ECM) and promote tumorigenesis in several malignancies. However, the role of ITGB5 in hepatocellular carcinoma (HCC) is still unknown. METHODS: The biological function of ITGB5 in HCC was investigated using migration, colony formation assays. The potential molecular mechanism of ITGB5 in regulating HCC tumorigenesis and beta-catenin stabilization was investigated by western blotting, co-immunoprecipitation and ubiquitination assays. The expression level of ITGB5 mediated by miR-185 was confirmed by bioinformatic analysis, luciferase assay. The clinical significance of ITGB5 was based on human tissue microarray (TMA) analysis. RESULTS: Here, we found that the expression of ITGB5 is increased in HCC tissues. Elevated ITGB5 markedly facilitates HCC cell migration and tumorigenesis in vitro and in vivo. Further mechanistic studies revealed that ITGB5, as a partner of beta-catenin, directly interacts with beta-catenin and inhibits its degradation, thus leading to WNT/beta-catenin activity. Subsequently, we also found that ITGB5 is a direct targeted gene of miR-185. The downregulation of miR-185 in HCC cells promotes an increase in ITGB5. An additional increase of ITGB5 is associated with beta-catenin upregulation and a miR-185 decrease in HCC tissues. CONCLUSIONS: Our data reveal that the miR-185 ITGB5-beta-catenin pathway plays an important role in HCC tumorigenesis, and ITGB5 may be a promising specific target for HCC therapy. PMID- 29386045 TI - Mesenchymal stem cell-based therapy for radiation-induced lung injury. AB - Since radiotherapy is widely used in managing thoracic tumors, physicians have begun to realize that radiation-induced lung injury (RILI) seriously limits the effects of radiotherapy. Unfortunately, there are still no effective methods for controlling RILI. Over the last few decades numerous studies have reported the beneficial effects of mesenchymal stem cells (MSCs) on tissue repair and regeneration. MSCs can not only differentiate into lung alveolar epithelial cells and secrete anti-inflammatory factors, but they also deliver some vehicles for gene therapy in repairing the injured lung, which provides new ideas for managing RILI. Thus, many scientists have attempted to manage RILI using MSC-based therapy. However, as a novel therapy MSCs still face various limitations. Herein, we shed light on the current understanding of MSC-based therapy for RILI, including the feasibility, molecular mechanisms, animal studies, and clinical research of MSC-based therapy for RILI. We also present an overview of RILI and MSCs. PMID- 29386046 TI - Factors associated with timing of umbilical cord clamping in tertiary hospital of Nepal. AB - OBJECTIVE: Delayed umbilical cord clamping (DCC) (>= 60 s) is recognized to improve iron status and neurodevelopment compared to early umbilical cord clamping. The aim of this study is to identify current umbilical cord clamping practice and factors determining the timing of clamping in a low-resource setting where prevalence of anemia in infants is high. RESULTS: A cross-sectional study design including 128 observations of clinical practice in a tertiary-level maternity hospital in Kathmandu, Nepal. Overall 48% of infants received DCC. The mean and median cord clamping times were 61 +/- 33 and 57 (38-79) s, respectively. Univariate analysis showed that infants born during the night shift were five times more likely to receive DCC (OR 5.6, 95% CI 1.4-38.0). Additionally, infants born after an obstetric complication were 2.5 times more likely to receive DCC (OR 2.5, 95% CI 1.2-5.3), and babies requiring ventilation had a 65% lower likelihood of receiving DCC (OR 0.35, 95% CI 0.13-0.88). Despite the existence of standard protocols for cord clamping and its proven benefit, the lack of uniformity in the timing of cord clamping reveals poor translation of clinical guidelines into clinical practice. Clinical trial registration ISRCTN97846009. PMID- 29386047 TI - Histopathological and immunohistochemical characterisation of hepatic granulomas in Leishmania donovani-infected BALB/c mice: a time-course study. AB - BACKGROUND: Visceral leishmaniasis (VL) is a neglected tropical disease (NTD), caused by the intracellular protozoan parasites Leishmania donovani and Leishmania infantum. Symptomatic VL is considered fatal when left untreated. At present, there is no effective vaccine licensed for human use and available chemotherapies have limitations. Understanding the local immune mechanisms required for the control of infection is a key factor for developing effective vaccines and therapeutics. METHODS: We have investigated the development of the typical granulomatous lesions in the liver in experimental VL over time, together with the local immune responses. BALB/c mice were infected intravenously with a dose of 2 * 107 L. donovani amastigotes (MHOM/ET/67/HU3) and sacrificed at 15, 35 and 63 days post-infection (dpi). Histopathology and immunohistochemical techniques were used for the detection of Leishmania antigen, selected cell types including B and T lymphocytes, macrophages and neutrophils (CD45R-B220+, CD3+, F4/80+ and Ly-6G+) and iNOS. RESULTS: Granulomatous lesions were identified as early as 15 dpi in the livers of all infected animals. Three categories were used to classify liver granulomas (immature, mature and clear). Clear granulomas were exclusively detected from 35 dpi onwards. Kupffer cells (F4/80+) were predominant in immature granulomas, regardless of the dpi. Nonetheless, the highest expression was found 63 dpi. Positive staining for iNOS was mainly observed in the cytoplasm of fused Kupffer cells and the highest expression observed at 35 dpi. T cells (CD3+) and B cells (CD45R-B220+) were predominant in more advanced granuloma stages, probably related to the establishment of acquired immunity. Neutrophils (Ly-6G+) were predominantly observed in mature granulomas with the highest expression at 15 dpi. Neutrophils were lower in numbers compared to other cell types, particularly at later time points. CONCLUSIONS: Our results reflect the role of macrophages during the early stage of infection and the establishment of a lymphocytic response to control the infection in more advanced stages. PMID- 29386048 TI - Variation of poorly ventilated lung units (silent spaces) measured by electrical impedance tomography to dynamically assess recruitment. AB - BACKGROUND: Assessing alveolar recruitment at different positive end-expiratory pressure (PEEP) levels is a major clinical and research interest because protective ventilation implies opening the lung without inducing overdistention. The pressure-volume (P-V) curve is a validated method of assessing recruitment but reflects global characteristics, and changes at the regional level may remain undetected. The aim of the present study was to compare, in intubated patients with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS), lung recruitment measured by P-V curve analysis, with dynamic changes in poorly ventilated units of the dorsal lung (dependent silent spaces [DSSs]) assessed by electrical impedance tomography (EIT). We hypothesized that DSSs might represent a dynamic bedside measure of recruitment. METHODS: We carried out a prospective interventional study of 14 patients with AHRF and ARDS admitted to the intensive care unit undergoing mechanical ventilation. Each patient underwent an incremental/decremental PEEP trial that included five consecutive phases: PEEP 5 and 10 cmH2O, recruitment maneuver + PEEP 15 cmH2O, then PEEP 10 and 5 cmH2O again. We measured, at the end of each phase, recruitment from previous PEEP using the P-V curve method, and changes in DSS were continuously monitored by EIT. RESULTS: PEEP changes induced alveolar recruitment as assessed by the P-V curve method and changes in the amount of DSS (p < 0.001). Recruited volume measured by the P-V curves significantly correlated with the change in DSS (rs = 0.734, p < 0.001). Regional compliance of the dependent lung increased significantly with rising PEEP (median PEEP 5 cmH2O = 11.9 [IQR 10.4-16.7] ml/cmH2O, PEEP 15 cmH2O = 19.1 [14.2-21.3] ml/cmH2O; p < 0.001), whereas regional compliance of the nondependent lung decreased from PEEP 5 cmH2O to PEEP 15 cmH2O (PEEP 5 cmH2O = 25.3 [21.3-30.4] ml/cmH2O, PEEP 15 cmH2O = 20.0 [16.6-22.8] ml/cmH2O; p <0.001). By increasing the PEEP level, the center of ventilation moved toward the dependent lung, returning to the nondependent lung during the decremental PEEP steps. CONCLUSIONS: The variation of DSSs dynamically measured by EIT correlates well with lung recruitment measured using the P-V curve technique. EIT might provide useful information to titrate personalized PEEP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02907840 . Registered on 20 September 2016. PMID- 29386049 TI - An open-label proof-of-concept study of intrathecal autologous bone marrow mononuclear cell transplantation in intellectual disability. AB - BACKGROUND: The underlying pathophysiology in intellectual disability (ID) involves abnormalities in dendritic branching and connectivity of the neuronal network. This limits the ability of the brain to process information. Conceptually, cellular therapy through its neurorestorative and neuroregenerative properties can counteract these pathogenetic mechanisms and improve neuronal connectivity. This improved networking should exhibit as clinical efficacy in patients with ID. METHODS: To assess the safety and efficacy of cellular therapy in patients with ID, we conducted an open-label proof-of-concept study from October 2011 to December 2015. Patients were divided into two groups: intervention group (n = 29) and rehabilitation group (n = 29). The intervention group underwent cellular transplantation consisting of intrathecal administration of autologous bone marrow mononuclear cells and standard neurorehabilitation. The rehabilitation group underwent only standard neurorehabilitation. The results of the symptomatic outcomes were compared between the two groups. In the intervention group analysis, the outcome measures used were the intelligence quotient (IQ) and the Wee Functional Independence Measure (Wee-FIM). To compare the pre-intervention and post-intervention results, statistical analysis was done using Wilcoxon's matched-pairs test for Wee-FIM scores and McNemar's test for symptomatic improvements and IQ. The effect of age and severity of the disorder were assessed for their impact on the outcome of intervention. Positron emission tomography-computed tomography (PET-CT) brain scan was used as a monitoring tool to study effects of the intervention. Adverse events were monitored for the safety of cellular therapy. RESULTS: On symptomatic analysis, greater improvements were seen in the intervention group as compared to the rehabilitation group. In the intervention group, the symptomatic improvements, IQ and Wee-FIM were statistically significant. A significantly better outcome of the intervention was found in the paediatric age group (<18 years) and patients with milder severity of ID. Repeat PET-CT scan in three patients of the intervention group showed improved metabolism in the frontal, parietal cortex, thalamus, mesial temporal structures and cerebellum. No major adverse events were witnessed. CONCLUSIONS: Cellular transplantation with neurorehabilitation is safe and effective for the treatment of underlying brain deficits in ID. TRIAL REGISTRATION: ClinicalTrials.gov NCT02245724. Registered 12 September 2014. PMID- 29386050 TI - Curcumin-mediated bone marrow mesenchymal stem cell sheets create a favorable immune microenvironment for adult full-thickness cutaneous wound healing. AB - BACKGROUND: Adult full-thickness cutaneous wound repair suffers from an imbalanced immune response, leading to nonfunctional reconstructed tissue and fibrosis. Although various treatments have been reported, the immune-mediated tissue regeneration driven by biomaterial offers an attractive regenerative strategy for damaged tissue repair. METHODS: In this research, we investigated a specific bone marrow-derived mesenchymal stem cell (BMSC) sheet that was induced by the Traditional Chinese Medicine curcumin (CS-C) and its immunomodulatory effects on wound repair. Comparisons were made with the BMSC sheet induced without curcumin (CS-N) and control (saline). RESULTS: In vitro cultured BMSC sheets (CS-C) showed that curcumin promoted the proliferation of BMSCs and modified the features of produced extracellular matrix (ECM) secreted by BMSCs, especially the contents of ECM structural proteins such as fibronectin (FN) and collagen I and III, as well as the ratio of collagen III/I. Two-photon fluorescence (TPF) and second-harmonic generation (SHG) imaging of mouse implantation revealed superior engraftment of BMSCs, maintained for 35 days in the CS-C group. Most importantly, CS-C created a favorable immune microenvironment. The chemokine stromal cell-derived factor 1 (SDF1) was abundantly produced by CS-C, thus facilitating a mass migration of leukocytes from which significantly increased expression of signature TH1 cells (interferon gamma) and M1 macrophages (tumor necrosis factor alpha) genes were confirmed at 7 days post-operation. The number of TH1 cells and associated pro-inflammatory M1 macrophages subsequently decreased sharply after 14 days post-operation, suggesting a rapid type I immune regression. Furthermore, the CS-C group showed an increased trend towards M2 macrophage polarization in the early phase. CS-C led to an epidermal thickness and collagen deposition that was closer to that of normal skin. CONCLUSIONS: Curcumin has a good regulatory effect on BMSCs and this promising CS-C biomaterial creates a pro-regenerative immune microenvironment for cutaneous wound healing. PMID- 29386052 TI - Correction to: An exotic abscess within the United Kingdom from The Gambia: a case report. AB - CORRECTION: In the publication of this article [1], there is an error in an authors name.The error: 'Estelle Hong How' Should instead read: 'Estelle How Hong'This has now been included in this erratum. PMID- 29386051 TI - The proBAM and proBed standard formats: enabling a seamless integration of genomics and proteomics data. AB - On behalf of The Human Proteome Organization (HUPO) Proteomics Standards Initiative, we introduce here two novel standard data formats, proBAM and proBed, that have been developed to address the current challenges of integrating mass spectrometry-based proteomics data with genomics and transcriptomics information in proteogenomics studies. proBAM and proBed are adaptations of the well-defined, widely used file formats SAM/BAM and BED, respectively, and both have been extended to meet the specific requirements entailed by proteomics data. Therefore, existing popular genomics tools such as SAMtools and Bedtools, and several widely used genome browsers, can already be used to manipulate and visualize these formats "out-of-the-box." We also highlight that a number of specific additional software tools, properly supporting the proteomics information available in these formats, are now available providing functionalities such as file generation, file conversion, and data analysis. All the related documentation, including the detailed file format specifications and example files, are accessible at http://www.psidev.info/probam and at http://www.psidev.info/probed . PMID- 29386053 TI - Routine versus on demand removal of the syndesmotic screw; a protocol for an international randomised controlled trial (RODEO-trial). AB - BACKGROUND: Syndesmotic injuries are common and their incidence is rising. In case of surgical fixation of the syndesmosis a metal syndesmotic screw is used most often. It is however unclear whether this screw needs to be removed routinely after the syndesmosis has healed. Traditionally the screw is removed after six to 12 weeks as it is thought to hamper ankle functional and to be a source of pain. Some studies however suggest this is only the case in a minority of patients. We therefore aim to investigate the effect of retaining the syndesmotic screw on functional outcome. DESIGN: This is a pragmatic international multicentre randomised controlled trial in patients with an acute syndesmotic injury for which a metallic syndesmotic screw was placed. Patients will be randomised to either routine removal of the syndesmotic screw or removal on demand. Primary outcome is functional recovery at 12 months measured with the Olerud-Molander Score. Secondary outcomes are quality of life, pain and costs. In total 194 patients will be needed to demonstrate non-inferiority between the two interventions at 80% power and a significance level of 0.025 including 15% loss to follow-up. DISCUSSION: If removal on demand of the syndesmotic screw is non inferior to routine removal in terms of functional outcome, this will offer a strong argument to adopt this as standard practice of care. This means that patients will not have to undergo a secondary procedure, leading to less complications and subsequent lower costs. TRIAL REGISTRATION: This study was registered at the Netherlands Trial Register (NTR5965), Clinicaltrials.gov ( NCT02896998 ) on July 15th 2016. PMID- 29386055 TI - Focus on African diversity confirms complexity of skin pigmentation genetics. AB - Renewed focus on African populations confirms the complexity of skin pigmentation genetics, and suggests future directions for pigmentation research. PMID- 29386054 TI - Myoblast fusion confusion: the resolution begins. AB - The fusion of muscle precursor cells is a required event for proper skeletal muscle development and regeneration. Numerous proteins have been implicated to function in myoblast fusion; however, the majority are expressed in diverse tissues and regulate numerous cellular processes. How myoblast fusion is triggered and coordinated in a muscle-specific manner has remained a mystery for decades. Through the discovery of two muscle-specific fusion proteins, Myomaker and Myomerger-Minion, we are now primed to make significant advances in our knowledge of myoblast fusion. This article reviews the latest findings regarding the biology of Myomaker and Minion-Myomerger, places these findings in the context of known pathways in mammalian myoblast fusion, and highlights areas that require further investigation. As our understanding of myoblast fusion matures so does our potential ability to manipulate cell fusion for therapeutic purposes. PMID- 29386056 TI - Simple motion correction strategy reduces respiratory-induced motion artifacts for k-t accelerated and compressed-sensing cardiovascular magnetic resonance perfusion imaging. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) stress perfusion imaging provides important diagnostic and prognostic information in coronary artery disease (CAD). Current clinical sequences have limited temporal and/or spatial resolution, and incomplete heart coverage. Techniques such as k-t principal component analysis (PCA) or k-t sparcity and low rank structure (SLR), which rely on the high degree of spatiotemporal correlation in first-pass perfusion data, can significantly accelerate image acquisition mitigating these problems. However, in the presence of respiratory motion, these techniques can suffer from significant degradation of image quality. A number of techniques based on non rigid registration have been developed. However, to first approximation, breathing motion predominantly results in rigid motion of the heart. To this end, a simple robust motion correction strategy is proposed for k-t accelerated and compressed sensing (CS) perfusion imaging. METHODS: A simple respiratory motion compensation (MC) strategy for k-t accelerated and compressed-sensing CMR perfusion imaging to selectively correct respiratory motion of the heart was implemented based on linear k-space phase shifts derived from rigid motion registration of a region-of-interest (ROI) encompassing the heart. A variable density Poisson disk acquisition strategy was used to minimize coherent aliasing in the presence of respiratory motion, and images were reconstructed using k-t PCA and k-t SLR with or without motion correction. The strategy was evaluated in a CMR-extended cardiac torso digital (XCAT) phantom and in prospectively acquired first-pass perfusion studies in 12 subjects undergoing clinically ordered CMR studies. Phantom studies were assessed using the Structural Similarity Index (SSIM) and Root Mean Square Error (RMSE). In patient studies, image quality was scored in a blinded fashion by two experienced cardiologists. RESULTS: In the phantom experiments, images reconstructed with the MC strategy had higher SSIM (p < 0.01) and lower RMSE (p < 0.01) in the presence of respiratory motion. For patient studies, the MC strategy improved k-t PCA and k-t SLR reconstruction image quality (p < 0.01). The performance of k-t SLR without motion correction demonstrated improved image quality as compared to k-t PCA in the setting of respiratory motion (p < 0.01), while with motion correction there is a trend of better performance in k-t SLR as compared with motion corrected k-t PCA. CONCLUSIONS: Our simple and robust rigid motion compensation strategy greatly reduces motion artifacts and improves image quality for standard k-t PCA and k-t SLR techniques in setting of respiratory motion due to imperfect breath-holding. PMID- 29386057 TI - Delivery of VEGFA in bone marrow stromal cells seeded in copolymer scaffold enhances angiogenesis, but is inadequate for osteogenesis as compared with the dual delivery of VEGFA and BMP2 in a subcutaneous mouse model. AB - BACKGROUND: In bone tissue engineering (BTE), extensive research into vascular endothelial growth factor A (VEGFA)-mediated angiogenesis has yielded inconsistent results. The aim of this study was to investigate the influence on angio- and osteogenesis of adenoviral-mediated delivery of VEGFA alone or in combination with bone morphogenetic protein 2 (BMP2) in bone marrow stromal cells (BMSC) seeded onto a recently developed poly(LLA-co-CL) scaffold. METHODS: Human BMSC were engineered to express VEGFA alone or in combination with BMP2 and seeded onto poly(LLA-co-CL) scaffolds. Changes in angiogenic and osteogenic gene and protein levels were examined by quantitative reverse-transcription polymerase chain reaction (RT-PCR), PCR array, and alkaline phosphatase assay. An in vivo subcutaneous mouse model was used to investigate the effect on angio- and osteogenesis of VEGFA alone or in combination with BMP2, using microcomputed tomography (MUCT), histology, immunohistochemistry, and immunofluorescence. RESULTS: Combined delivery of a lower ratio (1:3) of VEGFA and BMP2 (ad-BMP2 + VEGFA) led to upregulation of osteogenic and angiogenic genes in vitro at 3 and 14 days, compared with mono-delivery of VEGFA (ad-VEGFA) and other controls. In vivo, in a subcutaneous mouse model, both ad-VEGFA and ad-BMP2 + VEGFA scaffold explants exhibited increased angiogenesis at 2 weeks. Enhanced angiogenesis was largely related to the recruitment and differentiation of mouse progenitor cells to the endothelial lineage and, to a lesser extent, to endothelial differentiation of the implanted BMSC. MUCT and histological analyses revealed enhanced de novo bone formation only in the ad-BMP2 + VEGFA group, corresponding at the molecular level to the upregulation of genes related to osteogenesis, such as ALPL, RUNX2, and SPP1. CONCLUSIONS: Although BMSC expressing VEGFA alone or in combination with BMP2 significantly induced angiogenesis, VEGFA alone failed to demonstrate osteogenic activity both in vitro and in vivo. These results not only call into question the use of VEGFA alone in bone regeneration, but also highlight the importance in BTE of appropriately formulated combined delivery of VEGFA and BMP2. PMID- 29386058 TI - Teaching pain recognition through art: the Ramsay-Caravaggio sedation scale. AB - BACKGROUND: Clinical observation is a key component of medical ability, enabling immediate evaluation of the patient's emotional state and contributing to a clinical clue that leads to final decision making. In medical schools, the art of learning to look can be taught using medical humanities and especially visual arts. By presenting a Ramsay sedation score (RSS) integrated with Caravaggio's paintings during a procedural sedation conference for pediatric residents, we want to test the effectiveness of this approach to improve the quality of learning. METHODS: In this preliminary study, we presented videos showing sedated pediatric patients in the setting of a procedural sedation lesson to two randomized groups of residents, one attending a lesson on RSS explained through the masterpieces of Caravaggio, the other without artistic support. A week later we tested their learning with ten multi-choice questions focused on theoretical questions about sedation monitoring and ten more questions focused on recognizing the appropriate RSS viewing the videos. The primary outcome was the comparison of the total number of RSS layers properly recognized in both groups. We also evaluated the appreciation of the residents of the use of works of art integrated with the lesson. RESULTS: Eleven students were randomized to each group. Two residents in the standard lesson did not attend the test. The percentage of correct answers on the theoretical part was similar, 82% in the art group and 89% in the other (p > 0.05). No difference was found in the video recognition part of the RSS recognition test. Residents exposed to paintings shown great appreciation for the integration of the lesson with the Caravaggio's masterpieces. CONCLUSIONS: Adding artwork to a standard medical conference does not improve the performance of student tests, although this approach has been greatly appreciated by residents. PMID- 29386059 TI - MicroRNA-150 enhances radiosensitivity by inhibiting the AKT pathway in NK/T cell lymphoma. AB - BACKGROUND: Radioresistance is a major challenge during the treatment of NK/T cell lymphoma. This study aimed to investigate the potential role of MicroRNA-150 (miR-150) in increase the sensitivities of NK/T cell lymphoma to ionizing radiation. RESULTS: In this study, we found that miR-150 was significantly decreased in NK/T cell lymphoma tissues and cell lines. Low expression of miR-150 was positively associated with therapeutic resistance in 36 NK/T cell lymphoma cases. Our further in vitro and in vivo studies illustrated that overexpression of miR-150 substantially enhanced the sensitivity of NK/T cell lymphoma cells to ionizing radiation treatment. Furthermore, luciferase reporter assays in NK/T cell lymphoma cells transfected with the AKT2 or AKT3 three prime untranslated region reporter constructs established AKT2 and AKT3 as direct targets of miR 150. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit Akt to verify miR-150 increase NK/T cell lymphoma cell radiorsensitivity through suppress the PI3K/AKT/mTOR pathway. CONCLUSIONS: Taken together, this study demonstrates that miR-150 might serve as a potential therapeutic sensitizer through inhibition of the AKT pathway in NK/T cell lymphoma treatment. PMID- 29386060 TI - Synergistic mechanism of Ag+-Zn2+ in anti-bacterial activity against Enterococcus faecalis and its application against dentin infection. AB - BACKGROUND: Ag+ and Zn2+ have already been used in combinations to obtain both enhanced antibacterial effect and low cytotoxicity. Despite this, it is still unclear how the Zn2+ co-works with Ag+ in the synergistic antibacterial activity. The main purposes of this study were to investigate the co-work pattern and optimum ratio between Ag+ and Zn2+ in their synergistic antibacterial activity against E. faecalis, the possible mechanisms behind this synergy and the primary application of optimum Ag+-Zn2+ co-work pattern against the E. faecalis biofilm on dentin. A serial of Ag+-Zn2+ atomic combination ratios were tested on both planktonic and biofilm-resident E. faecalis on dentin, their antibacterial efficiency was calculated and optimum ratio determined. And the cytotoxicity of various Ag+-Zn2+ atomic ratios was tested on MC3T3-E1 Cells. The role of Zn2+ in Ag+-Zn2+co-work was evaluated using a Zn2+ pretreatment study and membrane potential-permeability measurement. RESULTS: The results showed that the synergistically promoted antibacterial effect of Ag+-Zn2+ combinations was Zn2+ amount-dependent with the 1:9 and 1:12 Ag+-Zn2+ atomic ratios showing the most powerful ability against both planktonic and biofilm-resident E. faecalis. This co-work could likely be attributed to the depolarization of E. faecalis cell membrane by the addition of Zn2+. The cytotoxicity of the Ag+-Zn2+ atomic ratios of 1:9 and 1:12 was much lower than 2% chlorhexidine. CONCLUSIONS: The Ag+-Zn2+ atomic ratios of 1:9 and 1:12 demonstrated similar strong ability against E. faecalis biofilm on dentin but much lower cytotoxicity than 2% chlorhexidine. New medications containing optimum Ag+-Zn2+ atomic ratios higher than 1:6, such as 1:9 or 1:12, could be developed against E. faecalis infection in root canals of teeth or any other parts of human body. PMID- 29386061 TI - Dihydroisotanshinone I combined with radiation inhibits the migration ability of prostate cancer cells through DNA damage and CCL2 pathway. AB - BACKGROUND: Radiotherapy plays an important role in the treatment of prostate cancer. Despite that sophisticated techniques of radiotherapy and radiation combined with chemotherapy were applied to the patients, some tumors may recur. Therefore, the study investigated the effect of dihydroisotanshinone I (DT) and the combination treatment of 5 MUM DT and 5Gy irradiation (IR) against the migration ability of prostate cancer cells. METHODS: DT and the combination treatment were studied for its biological activity against migration ability of prostate cancer cells with transwell migration assay. Subsequently, we tried to explore the underlying mechanism with ELISA, flow cytometry and Western's blotting assay. RESULTS: The results showed that DT and the combination treatment substantially inhibited the migration ability of prostate cancer cells. DT and the combined treatment can decrease the ability of macrophages to recruit prostate cancer cells. Mechanistically, DT and the combination treatment reduced the secretion of chemokine (C-C Motif) Ligand 2 (CCL2) from prostate cancer cells. We also found that DT treatment induced the cell cycle of prostate cancer cells entering S phase and increased the protein expression of DNA damage response proteins (rH2AX and phosphorylated ataxia telangiectasia-mutated [ATM]) in DU145 cells and PC-3 cells. CONCLUSIONS: DT displays radiosensitization and antimigration effects in prostate cancer cells by inducing DNA damage and inhibiting CCL2 secretion. We suggest that DT can be used as a novel antimetastatic cancer drug or radiosensitizer in the armamentarium of prostate cancer management. PMID- 29386062 TI - An OTU deubiquitinating enzyme in Eimeria tenella interacts with Eimeria tenella virus RDRP. AB - BACKGROUND: Chicken coccidiosis, a disease caused by seven species of Eimeria (Apicomplexa: Coccidia), inflicts severe economic losses on the poultry industry. Eimeria tenella is the one of the most virulent species pathogenic to chickens. Many parasitic protozoans are parasitised by double-stranded (ds) RNA viruses, and the influence of protozoan viruses on parasitic protozoans has been extensively reported. E. tenella RNA virus 1 (Etv) was identified in E. tenella, and the complete genome sequence of Etv was analysed. Here, we screened Etv-RNA dependent RNA polymerase (RDRP)-interacting host protein E. tenella ovarian tumour (OTU) protein-like cysteine protease (Et-OTU) using a yeast two-hybrid system with pGBKT7-RDRP plasmid serving as bait. A previous study demonstrated that Et-OTU could regulate the telomerase activity of E. tenella, indicating that Et-OTU affects E. tenella proliferation. However, whether Etv-RDRP affects the molecular biological characteristics of E. tenella by interacting with OTU remains unclear. RESULTS: We obtained seven positive clones from the initial screen, and six of the seven preys were identified as false-positives. Finally, we identified an RDRP-associated protein predicted to be an E. tenella OTU protein. A alpha-galactosidase assay showed that the bait vector did not activate the GAL4 reporter gene, indicating no autoactivation activity from the RDRP bait fusion. Pull-down and co-immunoprecipitation assays verified the interaction between Et-OTU and Etv-RDRP both intracellularly and extracellularly. Additionally, Et-OTU was able to deconjugate K48- and K6-linked di-ubiquitin (di Ub) chains in vitro but not K63-, K11-, K29-, or K33-linked di-Ub chains. The C239A and H351A mutations eliminated the deubiquitinase (DUB) activity of Et-OTU, whereas the D236A mutation did not. Additionally, when combined with RDRP, the DUB activity of Et-OTU towards K48- and K6-linked chains was significantly enhanced. CONCLUSION: Etv-RDRP interacts with Et-OTU both intracellularly and extracellularly. Etv-RDRP enhances the hydrolysis of Et-OTU to K6- or K48-linked ubiquitin chains. This study lays the foundation for further research on the relationship between E. tenella and Etv. PMID- 29386063 TI - Synaptic dysfunction in complex psychiatric disorders: from genetics to mechanisms. AB - Breakthroughs on many fronts have provided strong evidence to support synaptic dysfunction as a causal factor for neuropsychiatric diseases. Genetic studies have identified variants implicated in novel biological and synaptic pathways, and animal and patient-derived induced pluripotent stem cell-based models have allowed mechanistic investigations of synaptic dysfunction in pathological processes. PMID- 29386064 TI - The growth and evolution of cardiovascular magnetic resonance: a 20-year history of the Society for Cardiovascular Magnetic Resonance (SCMR) annual scientific sessions. AB - BACKGROUND AND PURPOSE: The purpose of this work is to summarize cardiovascular magnetic resonance (CMR) research trends and highlights presented at the annual Society for Cardiovascular Magnetic Resonance (SCMR) scientific sessions over the past 20 years. METHODS: Scientific programs from all SCMR Annual Scientific Sessions from 1998 to 2017 were obtained. SCMR Headquarters also provided data for the number and the country of origin of attendees and the number of accepted abstracts according to type. Data analysis included text analysis (key word extraction) and visualization by 'word clouds' representing the most frequently used words in session titles for 5-year intervals. In addition, session titles were sorted into 17 major subject categories to further evaluate research and clinical CMR trends over time. RESULTS: Analysis of SCMR annual scientific sessions locations, attendance, and number of accepted abstracts demonstrated substantial growth of CMR research and clinical applications. As an international field of study, significant growth of CMR was documented by a strong increase in SCMR scientific session attendance (> 500%, 270 to 1406 from 1998 to 2017, number of accepted abstracts (> 700%, 98 to 701 from 1998 to 2018) and number of international participants (42-415% increase for participants from Asia, Central and South America, Middle East and Africa in 2004-2017). 'Word clouds' based evaluation of research trends illustrated a shift from early focus on 'MRI technique feasibility' to new established techniques (e.g. late gadolinium enhancement) and their clinical applications and translation (key words 'patient', 'disease') and more recently novel techniques and quantitative CMR imaging (key words 'mapping', 'T1', 'flow', 'function'). Nearly every topic category demonstrated an increase in the number of sessions over the 20-year period with 'Clinical Practice' leading all categories. Our analysis identified three growth areas 'Congenital', 'Clinical Practice', and 'Structure/function/flow'. CONCLUSION: The analysis of the SCMR historical archives demonstrates a healthy and internationally active field of study which continues to undergo substantial growth and expansion into new and emerging CMR topics and clinical application areas. PMID- 29386065 TI - Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 * Tg-AD mice. AB - BACKGROUND: Accumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p Tau) seeds with the host neuron protein. Thus, clearance of Tau seeds by immunization with Tau antibodies could provide a potential therapeutic opportunity to block the spread of the pathology in Alzheimer's disease (AD) and other tauopathies. We report prevention of the seeding and spread of tau pathology with mouse monoclonal antibody 43D against the N-terminal projection domain of Tau (Tau 6-18) in triple-transgenic AD (3 * Tg-AD) mice. METHODS: Female 11- to 12-month-old 3 * Tg-AD mice were intravenously immunized weekly for 6 weeks with 15 MUg/injection of mouse monoclonal antibody 43D or with mouse immunoglobulin G as a control. AD p-Tau isolated from a frozen autopsied AD brain was unilaterally injected into the right hippocampus on the day of the second dose of immunization. Tau pathology and its effect on Abeta pathology were assessed by immunohistochemical staining. RESULTS: We found that the injection of AD p-Tau into the hippocampus of 11- to 12-month-old 3 * Tg-AD mice time dependently induced Tau aggregation in the hippocampus and promoted the spread of Tau pathology to the contralateral hippocampus. Tau pathology was observed as early as 6 weeks after AD p-Tau injection. Tau pathology templated by AD p-Tau was thioflavin-S-positive and was about two-fold greater than that seen in naive 18-month-old 3 * Tg-AD mice; Tau pathology in the latter was thioflavin-S negative. Immunization with Tau antibody 43D dramatically blocked AD p-Tau seeding in the ipsilateral hippocampus and inhibited its propagation to the contralateral side in 3 * Tg-AD mice. Furthermore, AD p-Tau injection enhanced the amyloid plaque load in the ipsilateral side, and immunization with 43D showed a tendency to attenuate it. CONCLUSIONS: These findings indicate that AD p-Tau injected 3 * Tg-AD mice represent a practical model to study the seeding and spread of Tau pathology, their effect on Abeta pathology, and the effect of Tau immunotherapy on both Tau and Abeta pathologies. Immunization with Tau antibody 43D to Tau 6-18 can prevent the seeding and spread of Tau pathology, making it a potential therapeutic treatment for AD and related tauopathies. PMID- 29386066 TI - Carcinoid heart disease revealed by cyanosis with both right and left valvular involvement: a case report. AB - BACKGROUND: Carcinoid heart disease is a frequent complication of carcinoid syndrome. It is related to the release by the carcinoid tumor and/or its metastases of bioactive substances such as serotonin. It is characterized by right-sided valvular involvement and can lead to right-sided heart failure. It is a prognostic factor of carcinoid syndrome. CASE PRESENTATION: We report the case of a 53-year-old African woman with an endocrine tumor of her small intestine complicated by carcinoid heart disease, revealed by right-sided heart failure. The diagnosis was confirmed by transthoracic echocardiography, which showed a severe tricuspid regurgitation with a patent foramen ovale, and by increased serum chromogranin A and urinary 5-hydroxyindoleacetic acid. Initially she was treated with medical therapy (furosemide and injection of somatostatin). Afterwards she was proposed for surgery. The evolution of her treatment was good. CONCLUSIONS: Carcinoid syndrome is complicated in 60% of the cases of a heart disease, and is responsible for an important morbidity and mortality. The prognosis of patients with carcinoid heart disease has improved in recent years through somatostatin analogues and the cardiac surgery. PMID- 29386067 TI - Antibiotic susceptibilities of indicator bacteria Escherichia coli and Enterococci spp. isolated from ducks in Morogoro Municipality, Tanzania. AB - OBJECTIVE: To estimate the prevalence of antibiotic resistance in indicator bacteria Escherichia coli and Enterococci isolated from duck faeces in Morogoro Municipality, Tanzania. RESULTS: Escherichia coli and Enterococcus isolation rates from ducks faeces were 91 and 100% respectively. The prevalence of antibiotic resistance of E. coli and Enterococcus was 70.3 and 42%, respectively. E. coli resistant to four antibiotics were 28 (30.8%) and showed high resistance to ampicillin (81.3), tetracycline (75.8) and trimethoprim-sulphamethoxine (62.3). Multiple antibiotic resistance of Enterococcus were more than 65%. High resistance rates shown by Enterococcus were observed in rifampin (62%), ampicillin (62%) and tetracycline (42%). Almost all farmers (92.3%) left their ducks to scavenge for food around their houses. Antibiotics used in animal treatments were oxytetracyclines, sulfonamides, penicillin dihydrostreptomycin while in humans were tetracycline, ampicillin, and amoxicillin. PMID- 29386068 TI - Effects of hPMSCs on granulosa cell apoptosis and AMH expression and their role in the restoration of ovary function in premature ovarian failure mice. AB - BACKGROUND: This study was performed to determine the effects of human placenta mesenchymal stem cell (hPMSC) transplantation on granulosa cell apoptosis and anti-Mullerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression in autoimmune drug-induced premature ovarian failure (POF) mice. The aim of this research is to investigate the mechanisms of hPMSCs on ovarian reserve capacity. METHODS: The POF mice model was established by injection of zona pellucida 3 peptide (pZP3). hPMSC transplantation was conducted by intravenous injection into mice following pZP3 treatment. The follicle number was examined by histopathology. The serum levels of FSH, LH, E2, AMH and anti-zona pellucida antibody (AzpAb) were measured by enzyme-linked immunosorbent assay. AMH and FSHR expression in the ovary was analyzed by immunohistochemistry and western blot analysis. Granulosa cell apoptosis of the ovaries was examined by In Situ Cell Death Detection Kit. Granulosa cells were isolated and treated with SiAmh interference and hPMSC supernatant to observe the effects of AMH expression on granulosa cell apoptosis in vitro. RESULTS: The results showed that hPMSC transplantation can significantly recover the estrus cycle in the POF group. Morphological staining showed that the basal follicles and sinus follicles after hPMSC transplantation were higher in POF mice than in those without treatment, and the follicle number was significantly decreased with atresia. The serum levels of FSH, LH and AzpAb in the hPMSC transplantation group were reduced considerably, but the E2 and AMH levels were significantly increased. After hPMSC transplantation, the AMH and FSHR expression in ovarian tissue was significantly higher than in the POF group as determined by immunochemistry and western blot analysis. The FSHR expression was shown in granulosa cells only, and FSHR expression increases with AMH expressed in the ovary; granulosa cell apoptosis was decreased following hPMSC transplantation. The same results were observed from the in-vitro study. CONCLUSIONS: hPMSC transplantation can significantly improve the serum levels of high gonadotropin and low estrogen of POF mice, promote follicular development, inhibit excessive follicular atresia and granulosa cell apoptosis, and improve the ovarian reserve capacity. The mechanism may be achieved by increasing the expression of AMH and FSHR in ovaries. PMID- 29386071 TI - Organisational barriers to the facilitation of overseas volunteering and training placements in the NHS. AB - BACKGROUND: Undertaking a period of voluntary work or a professional placement overseas has long been a feature of medical training in the UK. There are now a number of high profile National Health Service (NHS) initiatives aimed at increasing access to such opportunities for staff at all levels. We present findings from a qualitative study involving a range of NHS staff and other stakeholders which explored barriers to participation in these activities. METHODS: A grounded theory methodology was drawn upon to conduct thematic based analysis. Our data included in-depth, semi-structured interviews with a range of returned volunteers, non-volunteers and other stakeholders (n = 51) who were, or had been, employed by the NHS. RESULTS: There are significant barriers to placement and volunteering activity stemming from structural and organisational shortcomings within the NHS. Difficulties in filling clinical roles has a significant impact on the ability of staff to plan and undertake independent placements. There is currently no clearly defined pathway within the NHS by which the majority of grades can apply for, or organise, a period of overseas voluntary or professional placement activity. There were divergent views on the relevance and usefulness of overseas professional placements. CONCLUSIONS: We argue that in the context of current UK policy initiatives aimed at facilitating overseas volunteer and professional placement activity, urgent attention needs to be given to the structural and organisational framework within which such initiatives will be required to work. PMID- 29386070 TI - Down selecting adjuvanted vaccine formulations: a comparative method for harmonized evaluation. AB - BACKGROUND: The need for rapid and accurate comparison of panels of adjuvanted vaccine formulations and subsequent rational down selection, presents several challenges for modern vaccine development. Here we describe a method which may enable vaccine and adjuvant developers to compare antigen/adjuvant combinations in a harmonized fashion. Three reference antigens: Plasmodium falciparum apical membrane antigen 1 (AMA1), hepatitis B virus surface antigen (HBsAg), and Mycobacterium tuberculosis antigen 85A (Ag85A), were selected as model antigens and were each formulated with three adjuvants: aluminium oxyhydroxide, squalene in-water emulsion, and a liposome formulation mixed with the purified saponin fraction QS21. RESULTS: The nine antigen/adjuvant formulations were assessed for stability and immunogenicity in mice in order to provide benchmarks against which other formulations could be compared, in order to assist subsequent down selection of adjuvanted vaccines. Furthermore, mouse cellular immune responses were analyzed by measuring IFN-gamma and IL-5 production in splenocytes by ELISPOT, and humoral responses were determined by antigen-specific ELISA, where levels of total IgG, IgG1, IgG2b and IgG2c in serum samples were determined. CONCLUSIONS: The reference antigens and adjuvants described in this study, which span a spectrum of immune responses, are of potential use as tools to act as points of reference in vaccine development studies. The harmonized methodology described herein may be used as a tool for adjuvant/antigen comparison studies. PMID- 29386069 TI - Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions. AB - A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies. Combination therapies of classic chemotherapeutic drugs and novel agents or novel therapeutic combinations might bring hope to the dismal prognosis for PDAC patients. PMID- 29386075 TI - (New) political interfaces in the life sciences. PMID- 29386074 TI - Helminth community from Azara's grass mouse (Akodon azarae) in three habitats with different land use in farming systems of Argentina. AB - In the Pampa region of Argentina, farming activities have been performed since the beginning of the 20th century, but in the 1990s, land-use patterns rapidly changed towards intensive agriculture and poultry breeding. This study compares the helminth community of Akodon azarae (Rodentia) among three habitats with different land use in pampean agroecosystems: poultry farms, mono-cultivated fields and abandoned fields (not used for 35 years), under the prediction that there will be greater helminth richness and diversity in mice from abandoned fields compared to those from the other habitats. Nevertheless, the highest abundance of A. azarae occurred on poultry farms, the habitat most disturbed by human activity, while cultivated fields showed the lowest. Helminth richness and diversity were significantly higher on poultry farms than in the other habitats, due to the presence of Trichuris laevitestis, Protospirura numidica criceticola and cysts of Taenia taeniaeformis. We suggest that the helminth fauna of A. azarae can survive on poultry farms despite disturbance from farming activities, because rodents can move and get shelter within farm perimeter fences, where dense and high vegetation grows. This farm area could offer good conditions for geohelminth development, while chicken sheds could attract insects that are intermediate hosts of helminths with indirect life cycles. On the contrary, agrochemicals applied in cultivated fields would negatively influence helminth diversity and composition, by decreasing host populations (arthropods and rodents) and affecting free larval stages of geohelminths. PMID- 29386073 TI - Personalized and yet standardized: An informed approach to the integration of bereavement care in pediatric oncology settings. AB - OBJECTIVE: The death of a child has been associated with adverse parental outcomes, including a heightened risk for psychological distress, poor physical health, loss of employment income, and diminished psychosocial well-being. Psychosocial standards of care for centers serving pediatric cancer patients recommend maintaining at least one meaningful contact between the healthcare team and bereaved parents to identify families at risk for negative psychosocial sequelae and to provide resources for bereavement support. This study assessed how this standard is being implemented in current healthcare and palliative care practices, as well as barriers to its implementation. METHOD: Experts in the field of pediatric palliative care and oncology created a survey that was posted with review and permission on four listservs. The survey inquired about pediatric palliative and bereavement program characteristics, as well as challenges and barriers to implementation of the published standards of care. Result The majority of participants (N = 100) self-reported as palliative care physicians (51%), followed by oncologists (19%). Although 59% of staff reported that their center often or always deliver bereavement care after a child's death, approximately two-thirds reported having no policy for the oncology team to routinely assess bereavement needs. Inconsistent types of bereavement services and varying duration of care was common. Twenty-eight percent of participants indicated that their center has no systematic contact with bereaved families after the child's death. Among centers where contacts are made, the person who calls the bereaved parent is unknown to the family in 30% of cases. Few centers (5%) use a bereavement screening or assessment tool. Significance of results Lack of routine assessment of bereavement needs, inconsistent duration of bereavement care, and tremendous variability in bereavement services suggest more work is needed to promote standardized, policy-driven bereavement care. The data shed light on multiple areas and opportunities for improvement. PMID- 29386072 TI - Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. AB - Natural killer/T-cell lymphoma (NKTCL) is a rare subtype of non-Hodgkin lymphoma that is associated with a poor outcome. Currently, the treatment needs of NKTCL remain unmet, and efforts to further improve treatment are urgently needed. Herein, seven patients with NKTCL who failed to respond to various types of chemotherapies were treated with the anti-programmed death 1 (anti-PD-1) antibody pembrolizumab at 100 mg every 3 weeks. After a median of four cycles of treatment (range 2-18), four out of seven patients responded (two complete response, two partial response, overall response rate 57%). Expression of PD1-ligand available was 50, 20, 30, 70, and 30% of five patients respectively. It is negative in one patient and not tested in one patient. Adverse events, which mostly ranged from grade I to grade III, were tolerable and could be safely handled, although immune related pneumonitis was notable. Overall, PD-1 blockade with pembrolizumab represents a favorable strategy for the treatment of refractory/relapsed NKTCL. PMID- 29386076 TI - Outbreak of Legionnaires' disease associated with cooling towers at a California state prison, 2015. AB - A large outbreak of Legionnaires' disease occurred at a California state prison in August 2015. We conducted environmental and epidemiological investigations to identify the most likely source of exposure and characterise morbidity. Sixty four inmates had probable Legionnaires' disease; 14 had laboratory-confirmed legionellosis. Thirteen (17%) inmates were hospitalised; there were no deaths. Ill inmates were more likely to be ?65 years old (P < 0.01), have the chronic obstructive pulmonary disease (P < 0.01), diabetes mellitus (P = 0.02), hepatitis C infection (P < 0.01), or end-stage liver disease (P < 0.01). The case-patients were in ten housing units throughout the prison grounds. All either resided in or were near the central clinical building (for appointments or yard time) during their incubation periods. Legionella pneumophila serogroup 1 was cultured from three cooling towers on top of the central medical clinic (range, 880-1200 cfu/ml). An inadequate water management program, dense biofilm within the cooling towers, and high ambient temperatures preceding the outbreak created an ideal environment for Legionella sp. proliferation. All state prisons were directed to develop local operating procedures for maintaining their cooling towers and the state health department added a review of the maintenance plans to their environmental inspection protocol. PMID- 29386077 TI - Dissociation of Spinothalamic Modalities Following Anterolateral Cordotomy. PMID- 29386078 TI - Current levels of gonorrhoea screening in MSM in Belgium may have little effect on prevalence: a modelling study. AB - There is considerable uncertainty as to the effectiveness of Neisseria gonorrhoeae (NG) screening in men who have sex with men. It is important to ensure that screening has benefits that outweigh the risks of increased antibiotics resistance. We develop a mathematical model to estimate the effectiveness of screening on prevalence. Separable Temporal Exponential family Random Graph Models are used to model the sexual relationships network, both with main and casual partners. Next, the transmission of Gonorrhoea is simulated on this network. The models are implemented using the R package 'statnet', which we adapted among other things to incorporate infection status at the pharynx, urethra and rectum separately and to distinguish between anal sex, oral sex and rimming. The different screening programmes compared are no screening, 3.5% of the population screened, 32% screened and 50% screened. The model simulates day by-day evolution for 10 years of a population of 10 000. If half of the population would be screened, the prevalence in the pharynx decreases from 11.9% to 10.2%. We conclude that the limited impact of screening on NG prevalence may not outweigh the increased risk of antibiotic resistance. PMID- 29386079 TI - Parental perspectives on hand, foot, and mouth disease among children in Hong Kong: a longitudinal study. AB - Hand, foot, and mouth disease (HFMD), usually a self-limiting illness for young children, could cause a significant burden for parents because it can take up to 1-2 weeks for a sick child to recover. We conducted a two-wave longitudinal study over one summer peak season (May-July 2014) of HFMD to examine parents' HFMD related risk perceptions and protective responses. In total, 618 parents with at least one child aged ?12 years, recruited using randomly-dialled household telephone calls completed the baseline survey interview, 452 of whom subsequently completed the follow-up survey. Around two-thirds of participants perceived the chance of their child being infected by HFMD was 'zero/very small/small' but the likelihood of being hospitalized once infected was 'somewhat likely/likely/very likely'. At follow-up, 82% reported washing child's hands frequently (Hygiene), 16% would keep their child away from school if HFMD cases were identified in school (Distancing) and 23% were 'very likely/certainly' to take the child for HFMD vaccination if available (Vaccination). Anticipated regret was consistently the strongest predictor for Hygiene (OR 3.34), and intention of Distancing (OR 2.58) and Vaccination (OR 3.16). Interventions focusing on anticipated regret may be effective to promote protective behaviour against HFMD among parents for their children. PMID- 29386080 TI - DO BIOMARKERS VARY BY SOCIAL CLASS, EDUCATION AND REGION AND IS MIGRATION IMPORTANT? EVIDENCE FROM A COHORT OF BRITISH ADULTS. AB - The aim of this study was to test whether Body Mass Index (BMI), waist circumference, systolic and diastolic blood pressure, Forced Expiratory Volume (FEV1) and Peak Expiratory Flow (PEF) vary in relation to social class at birth and adulthood, educational level and region of residence, and also with inter generational social, educational and regional mobility/migration. The study used 5702 adults (2894 males and 2718 females) from the longitudinal British National Child Development Study (all children born in England, Scotland and Wales during the first week in March 1958 with follow-up throughout childhood and adulthood, most recently at 55 years of age). In both sexes BMI and waist circumference tended to increase from social classes I+II to IV+V and higher social class was associated with higher mean FEV1 and PEF. Better-educated adults tended to have lower BMI and waist circumference, and higher mean FEV1 and PEF. Women from Wales had the highest mean BMI and waist circumference but the lowest mean PEF, while women in Scotland had the highest mean systolic blood pressure and the lowest mean FEV1. For men only, FEV1 and PEF showed regional variation and the lowest mean FEV1 was in Wales and the lowest PEF in Yorkshire & Humberside. Inter generational social mobility was not found to be associated with any of the biomarkers, while educational mobility was related only to FEV1 and PEF. In both sexes, in unadjusted regression analysis regional migrant cohort members tended to have a lower mean BMI than sedentes. Regional male migrants also tended to have a lower waist circumference and a higher FEV1 and PEF than sedentes. PMID- 29386081 TI - Chinese women's experiences, emotions and expectations of breast-feeding in public: a qualitative study. AB - OBJECTIVE: To explore Chinese mothers' experiences, emotions and expectations of breast-feeding in public places. DESIGN: Exploratory qualitative study. Purposive sampling was used to recruit participants and face-to-face interviews were conducted. Themes were identified by content analysis. SETTING: Two different geographical communities in Wuhan, Hubei Province, central China, March-May 2016. SUBJECTS: A total of twenty-seven mothers aged 23-33 years, who had one child under 3 years of age and had experience of breast-feeding in public places. RESULTS: Seven themes emerged from the interviews: struggling to balance infant's needs and personal feelings; embarrassed or natural emotion regarding breast feeding in public places; effect of cultural and social norms; internalized concerns going beyond actual social reaction; measures to make breast-feeding in public places easier; desire for more public facilities; and expecting emotional support from society members. CONCLUSIONS: More positive social support, favourable policies and necessary facilities were desired to enable mothers to breast-feed in an appropriate public location. Women expected increased public acceptance of breast-feeding practices and support from government health officials to ensure women's success in breast-feeding in public settings. PMID- 29386082 TI - What's the fuss about? Parent presentations of fussy eating to a parenting support helpline. AB - OBJECTIVE: To characterise parent presentations of fussy eating and mealtime interactions at a point of crisis, through analyses of real-time recordings of calls to a parenting helpline. DESIGN: Qualitative analysis included an inductive thematic approach to examine clinical parent presentations of fussy eating and derive underlying themes relating to mealtime interactions. SETTING: Calls made to the Child Health Line regarding feeding concerns were recorded and transcribed verbatim. SUBJECTS: From a corpus of 723 calls made during a 4-week period in 2009, twelve were from parents of children aged 6-48 months. RESULTS: Parents of infants (<=12 months, n 6) presented feeding concerns as learning challenges in the process of transitioning from a milk-based to a solid-based diet, while parents of toddlers (13-48 months, n 6) presented emotional accounts of feeding as an intractable problem. Parents presented their child's eating behaviour as a battle (conflict), in which their children's agency over limited intake and variety of foods (child control) was constructed as 'bad' or 'wrong'. Escalating parent anxiety (parent concern) had evoked parent non-responsive feeding practices or provision of foods the child preferred. CONCLUSIONS: Real-time descriptions of young children's fussy eating at a time of crisis that initiated parents' call for help have captured the highly charged emotional underpinnings of mealtime interactions associated with fussy eating. Importantly, they show the child's emerging assertion of food autonomy can escalate parents' emotional distress that, in the short term, initiates non-responsive feeding practices. The current study identifies the importance of educational and emotional support for parents across the period of introducing solids. PMID- 29386083 TI - Molecular data confirm the taxonomic position of Hymenolepis erinacei (Cyclophyllidea: Hymenolepididae) and host switching, with notes on cestodes of Palaearctic hedgehogs (Erinaceidae). AB - The cestode Hymenolepis erinacei is regarded as a widely distributed parasite in European hedgehogs of the genus Erinaceus, although the taxonomic position of this hymenolepidid has been debated for a considerable period of time. We present the first molecular data for this cestode, including partial DNA sequences of mitochondrial 16S and nuclear 28S ribosomal genes. Molecular phylogenetic analysis clusters H. erinacei in one clade together with representatives of the genus Hymenolepis from rodents. Characteristic morphological features, including the oval embryophore without filaments and shape of the embryonic hooks of H. erinacei are described. Features of these cestode eggs are proposed as a basis for non-invasive detection of parasitic infections in small mammal populations. The present study explores phylogenetic relationships within the genus Hymenolepis and the host switching related to H. erinacei. Cases of host switching in other genera of the family Hymenolepididae are reviewed. A short critical review of cestodes parasitizing hedgehogs in the Palaearctic is presented. PMID- 29386084 TI - Association analysis of rare and common variants with multiple traits based on variable reduction method. AB - Pleiotropy, the effect of one variant on multiple traits, is widespread in complex diseases. Joint analysis of multiple traits can improve statistical power to detect genetic variants and uncover the underlying genetic mechanism. Currently, a large number of existing methods target one common variant or only rare variants. Increasing evidence shows that complex diseases are caused by common and rare variants. Here we propose a region-based method to test both rare and common variant associated multiple traits based on variable reduction method (abbreviated as MULVR). However, in the presence of noise traits, the MULVR method may lose power, so we propose the MULVR-O method, which jointly analyses the optimal number of traits associated with genetic variants by the MULVR method, to guard against the effect of noise traits. Extensive simulation studies show that our proposed method (MULVR-O) is applied to not only multiple quantitative traits but also qualitative traits, and is more powerful than several other comparison methods in most scenarios. An application to the two genes (SHBG and CHRM3) and two phenotypes (systolic blood pressure and diastolic blood pressure) from the GAW19 dataset illustrates that our proposed methods (MULVR and MULVR-O) are feasible and efficient as a region-based method. PMID- 29386085 TI - DNA methylation is not involved in dietary restriction induced lifespan extension in adult Drosophila. AB - Dietary restriction (DR) is widely regarded as a viable intervention to extend lifespan and healthspan in diverse organisms. The precise molecular regulatory mechanisms are largely unknown. Epigenetic modifications are not stable upon DR and also keep changing with age. Here, we employed whole genome bisulfite sequencing to determine the DNA methylation changes upon DR in adult Drosophila. Our results indicate that although a low level of DNA methylation exists in the adult Drosophila genome, there is no significant difference in DNA methylation levels upon DR when compared to unrestricted flies. This suggests that other epigenetic components such as histone modifications might be altered by DR. PMID- 29386086 TI - Up-regulation of miR-324-5p inhibits proliferation and invasion of colorectal cancer cells by targeting ELAVL1. AB - Colorectal cancer (CRC) is a common clinical cancer, which remains incurable in most cases. MiRNAs are reported to playa part in development of various tumors. In the present study, we found that miR-324-5p was down-regulated in colorectal cancer cells while ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-Like Protein 1 (ELAVL1) showed a higher expression. MiR-324-5p transfection significantly inhibited the proliferation as well as invasion in both SW620 and SW480 cells. MiR-324-5p mimics transfection markedly decreased the expression of ELAVL1. Luciferase reporter gene assay confirmed that ELAVL1 is a direct target of miR-324-5p. Furthermore, cancer invasion factors uPA, uPAR and MMP-9 were found to drop significantly in miR-324-5p transfected groups. To conclude, our findings indicate that miR-324-5p may play a suppressive role in colorectal cell viability and invasion, at least in part, through directly targeting ELAVL1. Therefore, miR-234-5p might function as a promising candidate for CRC treatment and deserves deeper research. PMID- 29386087 TI - miR-135a Confers Resistance to Gefitinib in Non-Small Cell Lung Cancer Cells by Upregulation of RAC1. AB - The EGFR tyrosine kinase inhibitor gefitinib is used in therapy for non-small cell lung cancer (NSCLC). However, the therapeutic efficacy of gefitinib is known to be impeded by mutations of EGFR. The aim of the present study was to reveal the role of miR-135a in gefitinib resistance of NSCLC cells. Human NSCLC cell lines, NCI-H1650 and NCI-H1975, were transfected with miR-135a mimic/inhibitor or miR-135a inhibitor plus pEX-RAC1 (a RAC1-expressing vector). The effects of miR 135a and RAC1 expression on cell viability, apoptosis, migration, and invasion were then detected. The transfected cells were exposed to 0-20 MUM gefitinib, and cell viability was then detected at 48 h posttreatment. Western blot analysis was performed to detect the expression changes of main factors in the PI3K/AKT pathway. miR-135a overexpression promoted viability, migration, and invasion, but inhibited apoptosis of NCI-H1650 and NCI-H1975 cells. Cell viability was significantly reduced by gefitinib, and the LC50 values of gefitinib in NCI-H1650 and NCI-H1795 cells were 0.845 and 0.667 MUM, respectively. miR-135a overexpression could increase cell viability even under high concentrations of gefitinib. Rac1 was not predicted as a target of miR-135a, while miR-135a could upregulate the expression of RAC1. miR-135a promoted cell growth and metastasis and activated the PI3K/AKT signaling pathway via a RAC1-dependent manner. To conclude, this study demonstrated that miR-135a confers NSCLC cell resistance to gefitinib via upregulation of RAC1. Therapies designed to downregulate miR-135a may help NSCLC patients to overcome gefitinib resistance. PMID- 29386089 TI - Long Noncoding RNA GAS5 Promotes Proliferation, Migration, and Invasion by Regulation of miR-301a in Esophageal Cancer. AB - Long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) has been revealed to be associated with the progression of various cancers. However, the biological roles of GAS5 in esophageal cancer (EC) remain unclear. We aimed to thoroughly explore the functions of GAS5 in EC. The results showed that GAS5 expression was increased in EC cells (ECA109, TE-1, TE-3, and EC9706) compared to SHEE cells. Knockdown of GAS5 decreased cell viability, migration, and invasion and induced apoptosis in EC9706 cells. Moreover, miR-301a appeared to be directly sponged by GAS5, and miR-301a suppression obviously alleviated the protumor effects of GAS5. Furthermore, miR-301a positively regulated CXCR4 expression, and overexpression of CXCR4 induced apoptosis and abolished the promoting effect of miR-301a inhibition on cell viability, migration, and invasion. Besides, miR-301a blocked Wnt/beta-catenin and NF-kappaB signaling pathways by regulation of CXCR4. Our results indicated that GAS5 promoted proliferation and metastasis and inhibited apoptosis by regulation of miR-301a in EC. These data contributed to our understanding of the mechanisms of miRNA-lncRNA interaction and provides a novel therapeutic strategy for EC. PMID- 29386090 TI - MicroRNA-18a targets IRF2 and CBX7 to promote cell proliferation in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are a family of non-coding RNAs with ~22nt in length that played important roles in the tumor initiation and progression processes. The aberrant expression status of miR-18a has been reported in hepatocellular carcinoma (HCC). However, the biological role and the underlying mechanism of miR 18a in HCC progression still to be elucidated. In this study, we examined the expression level of miR-18a in HCC cell lines using quantitative real-time PCR method. We showed that miR-18a expression in human HCC cell lines was elevated compared with in normal liver cell line. Meanwhile, force miR-18a expression by miR-18a mimic in HCC cell lines promoted cell proliferation and migration, while inhibit miR-18a expression by miR-18a inhibitor caused the opposite effects. Using the bioinformatic analysesmethods, we found the 3'-untranlated regions (3' UTR) of Interferon regulatory factor 2 (IRF2) and Chromobox protein homolog 7 (CBX7) contain putative binding sequence for miR-18a. Further luciferase assay validated that both IRF2 and CBX7were the direct targets of miR-18a in HCC. Moreover, we revealed that depletion of the expression of IRF2 and CBX7 has the similar effects as miR-18a overexpression on HCC cell lines. Our results illustrated that miR-18a plays a positive role in HCCprogression process by stimulating cell proliferation and migration partly through regulating IRF2 and CBX7. PMID- 29386088 TI - Phosphoglycerate Mutase 1 (PGAM1) Promotes Pancreatic Ductal Adenocarcinoma (PDAC) Metastasis by Acting as a Novel Downstream Target of the PI3K/Akt/mTOR Pathway. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors known, with an overall 5-year survival rate of less than 6% due to early local invasion and distant metastasis. Exploring suitable therapeutic targets associated with invasion and metastasis is required for improving the prognosis of PDAC. In this study, we investigated the role of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) in PDAC. PGAM1 expression was examined in tissue samples of 54 PDAC patients using immunohistochemistry, and the correlation between clinicopathological expression and PGAM1 expression was determined. A survival curve was generated using the Kaplan-Meier method. After silencing PGAM1 by siRNA in pancreatic cancer cell lines Aspc-1 and Panc-1, the changes in proliferation, migration, and invasion, and signal pathways were determined. In this study, the expression of PGAM1 was found positively related to poor differentiation, metastasis, advanced clinical stage, and poor survival rate. Silencing PGAM1 decreased the proliferation of Aspc-1 and Panc-1 cells with an S phase arrest, but without influencing cell apoptosis. Migration and invasion also decreased significantly, independent of proliferation. PGAM1 was also found to promote EMT of PDAC cell lines by regulating the Wnt/beta-catenin pathway. PGAM1 itself was modulated by the PI3K/Akt/mTOR pathway as a novel downstream target and has a positive mutual regulation with HIF-1alpha. This study indicates that PGAM1 is closely associated with clinical metastasis and poor prognosis of PDAC. PGAM1 is considered as a potential therapeutic target in PDAC metastasis. PMID- 29386091 TI - Matrine Inhibits Neuroblastoma Cell Proliferation and Migration by Enhancing Tribbles 3 Expression. AB - Neuroblastoma is a major contributor of cancer-specific mortality. Although remarkable enhancement has been achieved in the treatment of neuroblastoma in patients with early stage disease, limited progress has been made in the treatment of patients with high-risk neuroblastoma. Thus, innovative approaches are required to achieve further improvements in neuroblastoma patient survival outcomes. The major alkaloid obtained from Sophora flavescens Ait, matrine, has been shown to counteract malignancy in various kinds of cancers. In the current study, we evaluated the effects of matrine on the migration and proliferation of neuroblastoma cells. Cell cycle analysis coupled with Transwell and wound healing experiments showed that matrine triggers G2/M cell cycle arrest and suppresses neuroblastoma migration. This effect of matrine is due to upregulation of TRB3 expression followed by inhibition of the PI3K/AKT activation. Consistent with the in vitro data, growth of xenograft cancer was also suppressed by matrine. Our results indicate that matrine inhibits neuroblastoma cell proliferation and migration by enhancing TRB3 expression, suggesting that matrine may serve as a promising agent for the treatment of neuroblastoma. PMID- 29386092 TI - miR-522-3p Promotes Tumorigenesis in Human Colorectal Cancer via Targeting Bloom Syndrome Protein. AB - miR-522-3p is known to degrade bloom syndrome protein (BLM) and enhance expression of other proto-oncogenes, leading to tumorigenesis. This study aimed to investigate the molecular mechanisms of miR-522-3p in human colorectal cancer (CRC) cells. Expressions of miR-522-3p in CRC and adjacent tissues, as well as in normal human colon epithelial cell line (FHC) and five CRC cell lines, were detected. Human CRC cell lines, HCT-116 and HT29, were transfected with miR-522 3p mimic, inhibitor, or scrambled controls. Then cell viability, apoptosis, cell cycle progression, and the expressions of c-myc, cyclin E, CDK2, and BLM were assessed. It was found that miR-522-3p was highly expressed in CRC tissues when compared to adjacent nontumor tissues and was highly expressed in CRC cell lines when compared to FHC cells. miR-522-3p overexpression promoted cell viability, reduced apoptotic cell rate, arrested more cells in the S phase, and upregulated c-myc, cyclin E, and CDK2 expression. BLM was a target gene of miR-522-3p, and miR-522-3p suppression did not exert antiproliferative and proapoptotic activities when BLM was silenced. These findings demonstrate that miR-522-3p upregulation negatively regulates the expression of BLM, with upregulation of c myc, CDK2, and cyclin E, and thereby promoting the proliferation of human CRC cells. PMID- 29386094 TI - Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 2017. AB - Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination. PMID- 29386093 TI - Incidence and seasonality of respiratory syncytial virus hospitalisations in young children in Denmark, 2010 to 2015. AB - For future decisions on respiratory syncytial virus (RSV)-vaccination strategies and implementation into national immunisation-programmes, we used national registry data (hospitalisation, microbiology and vital statistics) to determine the age-specific incidence and direct medical costs of annual RSV-associated admissions in children < 5 years-old for the period of 2010-2015. We identified ca 2,500 RSV-associated hospitalisations annually amounting to total direct medical-costs of ca EUR 4.1 million per year. The incidence of RSV-associated hospitalisations peaked in infants 1-2 months of age followed by infants 2-3 months of age, and infants < 1 month of age, respectively. Infant boys were at higher risk of severe RSV infection as compared to infant girls: male-to-female ratio peaked with 1.4 at four months of age and gradually levelled out with increasing age to 1.0 at 4 years of age. Five RSV-associated deaths were identified. Our findings demonstrate that in a western country as Denmark, RSV constitutes a considerable burden on childhood health. Furthermore, the best approach to reduce the high incidence of RSV-associated hospitalisations in young infants < 3 months of age may be maternal vaccination due to general challenges in achieving sufficient and protective immune responses in young infants. PMID- 29386096 TI - Cost analysis of an integrated aged care program for residential aged care facilities. AB - Objective To compare annual costs of an intervention for acutely unwell older residents in residential age care facilities (RACFs) with usual care. The intervention, the Aged Care Emergency (ACE) program, includes telephone clinical support aimed to reduce avoidable emergency department (ED) presentations by RACF residents.Methods This costing of the ACE intervention examines the perspective of service providers: RACFs, Hunter Medicare Local, the Ambulance Service of New South Wales, and EDs in the Hunter New England Local Health District. ACE was implemented in 69 RACFs in the Hunter region of NSW, Australia. Analysis used 14 weeks of ACE and ED service data (June-September 2014). The main outcome measure was the net cost and saving from ACE compared with usual care. It is based on the opportunity cost of implementing ACE and the opportunity savings of ED presentations avoided.Results Our analysis estimated that 981 avoided ED presentations could be attributed to ACE annually. Compared with usual care, ACE saved an estimated A$921214.Conclusions The ACE service supported a reduction in avoidable ED presentations and ambulance transfers among RACF residents. It generated a cost saving to health service providers, allowing reallocation of healthcare resources.What is known about the topic? Residents from RACFs are at risk of further deterioration when admitted to hospital, with high rates of delirium, falls, and medication errors. For this cohort, some conditions can be managed in the RACF without hospital transfer. By addressing avoidable presentations to EDs there is an opportunity to improve ED efficiency as well as providing care that is consistent with the resident's goals of care. RACFs generate some avoidable ED presentations for residents who may be more appropriately treated in situ.What does this paper add? Telephone triaging with nursing support and training is a means by which ED presentations from RACFs can be reduced. One of the consequences of this intervention is 'cost avoided', largely through savings on ambulance costs.What are the implications for practitioners? Unnecessary transfer from RACFs to ED can be avoided through a multicomponent program that includes telephone support with cost-saving implications for EDs and ambulance services. PMID- 29386095 TI - The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) - what is the evidence for causation? AB - BackgroundEnterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. In recent years, there has been evidence of an increase in EV-D68 infections globally. Large outbreaks of EV-D68, with thousands of cases, occurred in the United States, Canada and Europe in 2014. The outbreaks were associated temporally and geographically with an increase in clusters of acute flaccid myelitis (AFM).?Aims: We aimed to evaluate a causal association between EV-D68 and AFM. ?Methods: Using data from the published and grey literature, we applied the Bradford Hill criteria, a set of nine principles applied to examine causality, to evaluate the relationship between EV-D68 and AFM. Based on available evidence, we defined the Bradford Hill Criteria as being not met, or met minimally, partially or fully. ?Results: Available evidence applied to EV-D68 and AFM showed that six of the Bradford Hill criteria were fully met and two were partially met. The criterion of biological gradient was minimally met. The incidence of EV-D68 infections is increasing world-wide. Phylogenetic epidemiology showed diversification from the original Fermon and Rhyne strains since the year 2000, with evolution of a genetically distinct outbreak strain, clade B1. Clade B1, but not older strains, is associated with AFM and is neuropathic in animal models. ?Conclusion: While more research is needed on dose-response relationship, application of the Bradford Hill criteria supported a causal relationship between EV-D68 and AFM. PMID- 29386097 TI - Comparison of specialist and generalist care. AB - Objective The choice of whether to admit under a specialist or a generalist unit is often made with neither clear rationale nor understanding of its consequences. The present study compared the characteristics and outcomes of patients admitted with community-acquired pneumonia to either a general medicine or respiratory unit.Methods This study was a retrospective cross-sectional study using data from public hospitals in Adelaide, South Australia. Over 5 years there were 9775 overnight, unplanned appropriate adult admissions. Patient length of hospital stay, in-patient mortality rate and 30-day unplanned readmission rate were calculated, with and without adjustment for patient age and comorbidity burden.Results Over 80% of these patients were cared for by a general medicine unit rather than a specialist unit. Patients admitted to a general medicine unit were, on average, 4 years older than those admitted to a respiratory unit. Comorbidity burdens were similar between units at the same hospital. Length of in patient stay was >1 day shorter for those admitted to a general medicine unit, without significant compromise in mortality or readmission rates. Between each hospital, general medicine units showed a range of mortality rates and length of hospital stay, for which there was no obvious explanation.Conclusions Compared with speciality care, general medicine units can safely and efficiently care for patients presenting to hospital with community-acquired pneumonia.What is known about the topic? Within the narrow range of any specific disease, generalist medical services are often cited as inferior in performance compared with a speciality service. This has implications for hospital resourcing, including both staffing and ward allocation.What does this paper add? This paper demonstrates that most patients admitted with a principal diagnosis of community-acquired pneumonia were admitted to a generalist unit and did not apparently fare worse than patients admitted to a specialist service; patients admitted to a generalist unit spent less time in hospital and there was no difference in mortality or readmission rate compared with patients admitted to a specialist service.What are the implications for practitioners? The provision of generalist services at urban hospitals in Australia provides a safe alternative admission option for patients presenting with pneumonia, and possibly for other common acute medical conditions. PMID- 29386098 TI - Production and characterization of novel hydrocarbon degrading enzymes from Alcanivorax borkumensis. AB - This study investigates the production of alkane hydroxylase, lipase and esterase by the marine hydrocarbon degrading bacteria Alcanivorax borkumensis. The focus of this study is the remediation of petroleum hydrocarbons, hexane, hexadecane and motor oil as model substrates. A. borkumensis showed an incremental growth on these substrates with a high cell count. Growth on motor oil showed highest alkane hydroxylase and lipase production of 2.62 U/ml and 71 U/ml, respectively, while growth on hexadecane showed the highest esterase production of 57.5 U/ml. The percentage of hexane, hexadecane, and motor oil degradation during A. borkumensis growth after 72 h, was around 80%, 81.5% and 75%, respectively. Zymogram showed two different bands with a molecular weight of approx. 52 and 40 kDa, respectively with lipase and esterase activity. Alkane hydroxylase reached optimum activity at pH 8.0 and 70 +/- 1 degrees C for hexane and hexadecane and 75 +/- 1 degrees C for motor oil. Lipase and esterase showed optimum activity at 35 +/- 1 degrees C and 40 +/- 1 degrees C, respectively and pH 7.0. The crude enzymes showed higher stability in a wide range of pH, but they were not thermostable at higher temperatures. PMID- 29386099 TI - DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans. AB - Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis. PMID- 29386100 TI - Terminal Nerve GnRH3 Neurons Mediate Slow Avoidance of Carbon Dioxide in Larval Zebrafish. AB - Escape responses to threatening stimuli are vital for survival in all animal species. Larval zebrafish display fast escape responses when exposed to tactile, acoustic, and visual stimuli. However, their behavioral responses to chemosensory stimuli remain unknown. In this study, we found that carbon dioxide (CO2) induced a slow avoidance response, which was distinct from the touch-evoked fast escape response. We identified the gonadotropin-releasing hormone 3-expressing terminal nerve as the CO2 sensor in the nose. Wide-field calcium imaging revealed downstream CO2-activated ensembles of neurons along three distinct neural pathways, olfactory, trigeminal, and habenulo-interpeduncular, further reaching the reticulospinal neurons in the hindbrain. Ablation of the nose, terminal nerve, or trigeminal ganglion resulted in a dramatic decrease in CO2-evoked avoidance responses. These findings demonstrate that the terminal nerve trigeminal system plays a pivotal role in triggering a slow chemosensory avoidance behavior in the larval zebrafish. PMID- 29386101 TI - Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus. AB - Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young versus aged mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age. PMID- 29386102 TI - The N Terminus of the OB Domain of Telomere Protein TPP1 Is Critical for Telomerase Action. AB - Telomerase recruitment to telomeres and enzymatic processivity are mediated by TPP1, an essential component of telomere integrity and telomerase function. A surface on the OB domain of TPP1 called the TEL patch is critical for TPP1's telomerase-associated functions. Here, we identify a separate region in the N terminus of the OB domain (termed NOB) of TPP1 that, like the TEL patch, is essential for telomerase repeat addition processivity in vitro as well as telomerase recruitment to telomeres and telomere lengthening in cells. Although well-conserved among most mammalian TPP1 homologs, the NOB region in mice is distinct. Swapping the sequence of human NOB into mouse TPP1 allows it to stimulate human telomerase, qualifying NOB as an important determinant of species specificity for TPP1-telomerase interaction. Our studies show that TPP1 NOB is critical for telomerase function and demonstrate that the telomerase interaction surface on TPP1 is more elaborate than previously appreciated. PMID- 29386103 TI - The C-Domain of the NAC Transcription Factor ANAC019 Is Necessary for pH-Tuned DNA Binding through a Histidine Switch in the N-Domain. AB - The affinity of transcription factors (TFs) for their target DNA is a critical determinant of gene expression. Whether the DNA-binding domain (DBD) of TFs alone can regulate binding affinity to DNA is an important question for identifying the design principle of TFs. We studied ANAC019, a member of the NAC TF family of proteins in Arabidopsis, and found a well-conserved histidine switch located in its DBD, which regulates both homodimerization and transcriptional control of the TF through H135 protonation. We found that the removal of a C-terminal intrinsically disordered region (IDR) in the TF abolished the pH-dependent binding of the N-terminal DBD to DNA. We propose a mechanism in which long-range electrostatic interactions between DNA and the negatively charged C-terminal IDR turns on the pH dependency of the DNA-binding affinity of the N-terminal DBD. PMID- 29386104 TI - Super-Resolution Microscopy Reveals the Native Ultrastructure of the Erythrocyte Cytoskeleton. AB - The erythrocyte cytoskeleton is a textbook prototype for the submembrane cytoskeleton of metazoan cells. While early experiments suggest a triangular network of actin-based junctional complexes connected by ~200-nm-long spectrin tetramers, later studies indicate much smaller junction-to-junction distances in the range of 25-60 nm. Through super-resolution microscopy, we resolve the native ultrastructure of the cytoskeleton of membrane-preserved erythrocytes for the N and C termini of beta-spectrin, F-actin, protein 4.1, tropomodulin, and adducin. This allows us to determine an ~80-nm junction-to-junction distance, a length consistent with relaxed spectrin tetramers and theories based on spectrin abundance. Through two-color data, we further show that the cytoskeleton meshwork often contains nanoscale voids where the cell membrane remains intact and that actin filaments and capping proteins localize to a subset of, but not all, junctional complexes. Together, our results call for a reassessment of the structure and function of the submembrane cytoskeleton. PMID- 29386105 TI - Active Ebola Virus Replication and Heterogeneous Evolutionary Rates in EVD Survivors. AB - Following cessation of continuous Ebola virus (EBOV) transmission within Western Africa, sporadic EBOV disease (EVD) cases continued to re-emerge beyond the viral incubation period. Epidemiological and genomic evidence strongly suggests that this represented transmission from EVD survivors. To investigate whether persistent infections are characterized by ongoing viral replication, we sequenced EBOV from the semen of nine EVD survivors and a subset of corresponding acute specimens. EBOV evolutionary rates during persistence were either similar to or reduced relative to acute infection rates. Active EBOV replication/transcription continued during convalescence, but decreased over time, consistent with viral persistence rather than viral latency. Patterns of genetic divergence suggest a moderate relaxation of selective constraints within the sGP carboxy-terminal tail during persistent infections, but do not support widespread diversifying selection. Altogether, our data illustrate that EBOV persistence in semen, urine, and aqueous humor is not a quiescent or latent infection. PMID- 29386106 TI - Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis. AB - Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis from Gpr161 deletion was cilium dependent, unlike normal development. Low GPR161 expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis. PMID- 29386107 TI - Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer. AB - Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC. PMID- 29386108 TI - Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes. AB - Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. PMID- 29386109 TI - A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis. AB - Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction. Subsequent validation experiments showed that targeted inactivation of the Pi4ka catalytic domain or reduction in mRNA expression inhibited myeloid and erythroid cell differentiation in vitro and promoted anemia in vivo through a mechanism involving deregulation of AKT, MAPK, SRC, and JAK-STAT signaling. Finally, we provide evidence linking PI4KAP2, previously considered a pseudogene, to human myeloid and erythroid leukemia. PMID- 29386110 TI - Temporal Control of Metabolic Amplitude by Nocturnin. AB - The timing of food intake and nutrient utilization is critical to health and regulated partly by the circadian clock. Increased amplitude of circadian oscillations and metabolic output has been found to improve health in diabetic and obesity mouse models. Here, we report a function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct-/-) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct-/- mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways, and loss of this activity results in increased metabolic flux and reduced obesity. PMID- 29386111 TI - Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells. AB - Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies. PMID- 29386112 TI - TRAF6 Mediates Basal Activation of NF-kappaB Necessary for Hematopoietic Stem Cell Homeostasis. AB - Basal nuclear factor kappaB (NF-kappaB) activation is required for hematopoietic stem cell (HSC) homeostasis in the absence of inflammation; however, the upstream mediators of basal NF-kappaB signaling are less well understood. Here, we describe TRAF6 as an essential regulator of HSC homeostasis through basal activation of NF-kappaB. Hematopoietic-specific deletion of Traf6 resulted in impaired HSC self-renewal and fitness. Gene expression, RNA splicing, and molecular analyses of Traf6-deficient hematopoietic stem/progenitor cells (HSPCs) revealed changes in adaptive immune signaling, innate immune signaling, and NF kappaB signaling, indicating that signaling via TRAF6 in the absence of cytokine stimulation and/or infection is required for HSC function. In addition, we established that loss of IkappaB kinase beta (IKKbeta)-mediated NF-kappaB activation is responsible for the major hematopoietic defects observed in Traf6 deficient HSPC as deletion of IKKbeta similarly resulted in impaired HSC self renewal and fitness. Taken together, TRAF6 is required for HSC homeostasis by maintaining a minimal threshold level of IKKbeta/NF-kappaB signaling. PMID- 29386113 TI - Reciprocal TCR-CD3 and CD4 Engagement of a Nucleating pMHCII Stabilizes a Functional Receptor Macrocomplex. AB - CD4+ T cells convert the time that T cell receptors (TCRs) interact with peptides embedded within class II major histocompatibility complex molecules (pMHCII) into signals that direct cell-fate decisions. In principle, TCRs relay information to intracellular signaling motifs of the associated CD3 subunits, while CD4 recruits the kinase Lck to those motifs upon coincident detection of pMHCII. But the mechanics by which this occurs remain enigmatic. In one model, the TCR and CD4 bind pMHCII independently, while in another, CD4 interacts with a composite surface formed by the TCR-CD3 complex bound to pMHCII. Here, we report that the duration of TCR-pMHCII interactions impact CD4 binding to MHCII. In turn, CD4 increases TCR confinement to pMHCII via reciprocal interactions involving membrane distal and proximal CD4 ectodomains. The data suggest that a precisely assembled macrocomplex functions to reliably convert TCR-pMHCII confinement into reproducible signals that orchestrate adaptive immunity. PMID- 29386114 TI - Age-Associated Decline in Thymic B Cell Expression of Aire and Aire-Dependent Self-Antigens. AB - Although autoimmune disorders are a significant source of morbidity and mortality in older individuals, the mechanisms governing age-associated increases in susceptibility remain incompletely understood. Central T cell tolerance is mediated through presentation of self-antigens by cells constituting the thymic microenvironment, including epithelial cells, dendritic cells, and B cells. Medullary thymic epithelial cells (mTECs) and B cells express distinct cohorts of self-antigens, including tissue-restricted self-antigens (TRAs), such that developing T cells are tolerized to antigens from peripheral tissues. We find that expression of the TRA transcriptional regulator Aire, as well as Aire dependent genes, declines with age in thymic B cells in mice and humans and that cell-intrinsic and cell-extrinsic mechanisms contribute to the diminished capacity of peripheral B cells to express Aire within the thymus. Our findings indicate that aging may diminish the ability of thymic B cells to tolerize T cells, revealing a potential mechanistic link between aging and autoimmunity. PMID- 29386115 TI - CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology. AB - The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1beta and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1beta and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRgamma-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs. PMID- 29386118 TI - Balance Control Mediated by Vestibular Circuits Directing Limb Extension or Antagonist Muscle Co-activation. AB - Maintaining balance after an external perturbation requires modification of ongoing motor plans and the selection of contextually appropriate muscle activation patterns that respect body and limb position. We have used the vestibular system to generate sensory-evoked transitions in motor programming. In the face of a rapid balance perturbation, the lateral vestibular nucleus (LVN) generates exclusive extensor muscle activation and selective early extension of the hindlimb, followed by the co-activation of extensor and flexor muscle groups. The temporal separation in EMG response to balance perturbation reflects two distinct cell types within the LVN that generate different phases of this motor program. Initially, an LVNextensor population directs an extension movement that reflects connections with extensor, but not flexor, motor neurons. A distinct LVNco-activation population initiates muscle co-activation via the pontine reticular nucleus. Thus, distinct circuits within the LVN generate different elements of a motor program involved in the maintenance of balance. PMID- 29386116 TI - Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling. AB - Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type. PMID- 29386117 TI - Stellate Cells in the Medial Entorhinal Cortex Are Required for Spatial Learning. AB - Spatial learning requires estimates of location that may be obtained by path integration or from positional cues. Grid and other spatial firing patterns of neurons in the superficial medial entorhinal cortex (MEC) suggest roles in behavioral estimation of location. However, distinguishing the contributions of path integration and cue-based signals to spatial behaviors is challenging, and the roles of identified MEC neurons are unclear. We use virtual reality to dissociate linear path integration from other strategies for behavioral estimation of location. We find that mice learn to path integrate using motor related self-motion signals, with accuracy that decreases steeply as a function of distance. We show that inactivation of stellate cells in superficial MEC impairs spatial learning in virtual reality and in a real world object location recognition task. Our results quantify contributions of path integration to behavior and corroborate key predictions of models in which stellate cells contribute to location estimation. PMID- 29386119 TI - IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cavbeta3. AB - Voltage-gated calcium channels (Cavs) are major Ca2+ entry pathways in excitable cells. Their beta subunits facilitate membrane trafficking of the channel's ion conducting alpha1 pore and modulate its gating properties. We report that one beta subunit, beta3, reduces Ca2+ release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP3) formation. This effect requires the SH3-HOOK domain of Cavbeta3, includes physical beta3/IP3 receptor interaction, and prevails when agonist-induced IP3 formation is bypassed by photolysis of caged IP3. In agreement with beta3 acting as a brake on Ca2+ release, fibroblast migration is enhanced in vitro, and in vivo, closure of skin wounds is accelerated in the absence of beta3. To mediate specific physiological responses and to prevent Ca2+ toxicity, cytoplasmic Ca2+ signals must be tightly controlled. The described function of beta3, unrelated to its function as a Cav subunit, adds to this tight control. PMID- 29386120 TI - PHB3 Maintains Root Stem Cell Niche Identity through ROS-Responsive AP2/ERF Transcription Factors in Arabidopsis. AB - The root stem cell niche, which is composed of four mitotically inactive quiescent center (QC) cells and the surrounding actively divided stem cells in Arabidopsis, is critical for growth and root development. Here, we demonstrate that the Arabidopsis prohibitin protein PHB3 is required for the maintenance of root stem cell niche identity by both inhibiting proliferative processes in the QC and stimulating cell division in the proximal meristem (PM). PHB3 coordinates cell division and differentiation in the root apical meristem by restricting the spatial expression of ethylene response factor (ERF) transcription factors 115, 114, and 109. ERF115, ERF114, and ERF109 mediate ROS signaling, in a PLT independent manner, to control root stem cell niche maintenance and root growth through phytosulfokine (PSK) peptide hormones in Arabidopsis. PMID- 29386121 TI - A Global Interactome Map of the Dengue Virus NS1 Identifies Virus Restriction and Dependency Host Factors. PMID- 29386122 TI - Comprehensive analysis of the lysine acetylome and its potential regulatory roles in the virulence of Streptococcus pneumoniae. AB - : Protein lysine acetylation is a well-known modification with vital regulatory roles in various biological processes. Currently, the acetylated proteome in Streptococcus pneumoniae (S. pneumoniae) is not yet clear. Combining immune affinity enrichment with mass spectrometry-based proteomics, we identified the first lysine acetylome of S. pneumoniae. In total, 653 lysine acetylated sites on 392 proteins were identified, which are involved in diverse important biological pathways, including gene expression and central metabolism. S. pneumoniae has a relatively high acetylation level, implying its prominent and diverse roles in the regulation of biological processes. In the acetylome of S. pneumoniae, the most frequently occurring motifs of acetylation are KacK, KacR, KacxK, KacxxK and KacH. Compared with the reported acetylation motifs in various bacterial species, the motif unique to S. pneumoniae is KacT, indicating that species-specific characteristics, regulations and molecular mechanisms of acetylation may exist in this bacterium. Notably, many proteins directly or indirectly contributing to virulence are prevalently acetylated, suggesting that acetylation may coordinate bacterial virulence. This work presented here provides the first system-wide analysis of lysine acetylation in Streptococcus species, which may facilitate a deeper understanding on the regulatory roles of acetylation in the bacteria. BIOLOGICAL SIGNIFICANCE: S. pneumoniae causes a series of serious human diseases. Protein acetylation regulates many important biological pathways in bacteria. In this study, the first lysine acetylome of S. pneumoniae was identified and comprehensively analyzed with bioinformatics methods. One unique acetylated motif (KacT) was identified, suggesting that specific characteristics of lysine acetylation reaction may exist in S. pneumoniae. Besides, our data suggest that lysine acetylation closely regulates bacterial virulence. Further study focusing on the biological functions of these acetylproteins may provide important clues for the therapy of S. pneumoniae infection. PMID- 29386124 TI - The E3 Ubiquitin Ligase HectD1 Suppresses EMT and Metastasis by Targeting the +TIP ACF7 for Degradation. AB - Cancer cells exploit the epithelial-to-mesenchymal transition (EMT) program to become metastatic. Cytoskeletal regulators are required in mesenchymal cells where they promote EMT and EMT-induced migration. In a search for regulators of metastasis, we conducted shRNA screens targeting the microtubule plus-end tracking proteins (+TIPs). We show that the +TIP ACF7 is essential both for the maintenance of the EMT program and to promote migration. We find that the E3 ubiquitin ligase HectD1 promotes ACF7-proteasome-mediated degradation. Depletion of HectD1 stabilized ACF7, and this enhanced EMT and migration. Decreased HectD1 expression increased metastases in mouse models and conferred increased resistance to the cytotoxic drug cisplatin. A retrospective analysis of biopsies from breast cancer patients also reveals a correlation between higher ACF7 or lower HectD1 expression with poor clinical outcomes. Together, these results suggest that the control of ACF7 levels by HectD1 modulates EMT and the efficiency of metastasis. PMID- 29386123 TI - Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation. AB - Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior. PMID- 29386125 TI - BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation. AB - The controlled release of RNA polymerase II (RNAPII) from promoter-proximal pausing (PPP) sites is critical for transcription elongation in metazoans. We show that the human tumor suppressor BRCA2 interacts with RNAPII to regulate PPP release, thereby preventing unscheduled RNA-DNA hybrids (R-loops) implicated in genomic instability and carcinogenesis. BRCA2 inactivation by depletion or cancer causing mutations instigates RNAPII accumulation and R-loop accrual at PPP sites in actively transcribed genes, accompanied by gammaH2AX formation marking DNA breakage, which is reduced by ERCC4 endonuclease depletion. BRCA2 inactivation decreases RNAPII-associated factor 1 (PAF1) recruitment (which normally promotes RNAPII release) and diminishes H2B Lys120 ubiquitination, impeding nascent RNA synthesis. PAF1 depletion phenocopies, while its overexpression ameliorates, R loop accumulation after BRCA2 inactivation. Thus, an unrecognized role for BRCA2 in the transition from promoter-proximal pausing to productive elongation via augmented PAF1 recruitment to RNAPII is subverted by disease-causing mutations, provoking R-loop-mediated DNA breakage in BRCA2-deficient cells. PMID- 29386126 TI - Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes. AB - Variants in the phospholipase D3 (PLD3) gene have genetically been linked to late onset Alzheimer's disease. We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery. PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination. In multivesicular endosomes, PLD3 is subjected to proteolytic cleavage, yielding a stable glycosylated luminal polypeptide and a rapidly degraded N-terminal membrane-bound fragment. This pathway closely resembles the delivery route of carboxypeptidase S to the yeast vacuole. Our experiments reveal a biosynthetic route of PLD3 involving proteolytic processing and ESCRT-dependent sorting for its delivery to lysosomes in mammalian cells. PMID- 29386127 TI - The Biological Role of the zeta Subunit as Unidirectional Inhibitor of the F1FO ATPase of Paracoccus denitrificans. AB - The biological roles of the three natural F1FO-ATPase inhibitors, epsilon, zeta, and IF1, on cell physiology remain controversial. The zeta subunit is a useful model for deletion studies since it mimics mitochondrial IF1, but in the F1FO ATPase of Paracoccus denitrificans (PdF1FO), it is a monogenic and supernumerary subunit. Here, we constructed a P. denitrificans 1222 derivative (PdDeltazeta) with a deleted zeta gene to determine its role in cell growth and bioenergetics. The results show that the lack of zeta in vivo strongly restricts respiratory P. denitrificans growth, and this is restored by complementation in trans with an exogenous zeta gene. Removal of zeta increased the coupled PdF1FO-ATPase activity without affecting the PdF1FO-ATP synthase turnover, and the latter was not affected at all by zeta reconstitution in vitro. Therefore, zeta works as a unidirectional pawl-ratchet inhibitor of the PdF1FO-ATPase nanomotor favoring the ATP synthase turnover to improve respiratory cell growth and bioenergetics. PMID- 29386128 TI - Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity. AB - Caloric restriction (CR) is standard lifestyle therapy in obesity management. CR induced weight loss improves the metabolic profile of individuals with obesity. In mice, occurrence of beige fat cells in white fat depots favors a metabolically healthy phenotype, and CR promotes browning of white adipose tissue (WAT). Here, human subcutaneous abdominal WAT samples were analyzed in 289 individuals with obesity following a two-phase dietary intervention consisting of an 8 week very low calorie diet and a 6-month weight-maintenance phase. Before the intervention, we show sex differences and seasonal variation, with higher expression of brown and beige markers in women with obesity and during winter, respectively. The very low calorie diet resulted in decreased browning of subcutaneous abdominal WAT. During the whole dietary intervention, evolution of body fat and insulin resistance was independent of changes in brown and beige fat markers. These data suggest that diet-induced effects on body fat and insulin resistance are independent of subcutaneous abdominal WAT browning in people with obesity. PMID- 29386129 TI - Systematic Profiling of Histone Readers in Arabidopsis thaliana. AB - Histone post-translational modifications (PTMs) and their recognition by histone readers exert crucial functions in eukaryotes. Despite extensive studies, conservation and diversity of histone PTM regulation between animals and plants remain less explored because of a lack of systematic knowledge of histone readers in plants. Based on a high-throughput surface plasmon resonance imaging (SPRi) platform, we report the lab-on-chip profiling of interactions between 204 putative reader domains and 11 types of histone peptides in Arabidopsis thaliana. Eleven reader hits were then chosen for histone combinatorial readout pattern profiling. Systematic analysis of histone PTM recognition in Arabidopsis thaliana reveals that plant and human histone readers share conservation in domain types and recognition mechanisms. The differences in particular histone mark recognition by transcription regulator EML1 and DNA damage repair factor MSH6 indicate plant-specific histone PTMs function in Arabidopsis thaliana acquired during evolution. PMID- 29386130 TI - Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model. PMID- 29386131 TI - A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef. AB - We recently identified the multipass transmembrane protein SERINC5 as an antiviral protein that can potently inhibit HIV-1 infectivity and is counteracted by HIV-1 Nef. We now report that the anti-HIV-1 activity, but not the sensitivity to Nef, is conserved among vertebrate SERINC5 proteins. However, a Nef-resistant SERINC5 became Nef sensitive when its intracellular loop 4 (ICL4) was replaced by that of Nef-sensitive human SERINC5. Conversely, human SERINC5 became resistant to Nef when its ICL4 was replaced by that of a Nef-resistant SERINC5. In general, ICL4 regions from SERINCs that exhibited resistance to a given Nef conferred resistance to the same Nef when transferred to a sensitive SERINC, and vice versa. Our results establish that human SERINC5 can be modified to restrict HIV-1 infectivity even in the presence of Nef. PMID- 29386132 TI - Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion. AB - Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of beta-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic beta-islet cell progenitors, as well as the proliferation of insulin secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action. PMID- 29386134 TI - Synapse Elimination Triggered by BMP4 Exocytosis and Presynaptic BMP Receptor Activation. AB - In vitro screening of signaling molecules involved in neural circuit formation has identified a large number of synaptogenic proteins. However, factors that drive synapse elimination remain elusive. Here, we report that bone morphogenetic protein 4 (BMP4) released from axons has the ability to eliminate synapses. We found fast axonal transport of BMP4 in dense-core vesicles, its exocytosis, and subsequent cell surface clustering via type I BMP receptors near synapses. BMP4 overexpression or knockout in culture reduced or increased presynaptic structures, respectively. The destabilizing effect of surface BMP4 clusters was limited to nearby synapses. In vivo knockout of BMP4 and subsequent two-photon imaging of synapse dynamics confirmed its critical role in maintaining an appropriate density of presynaptic components along the axon. These results suggest an essential role for perisynaptic clustering of BMP4 during development in the construction of functional neuronal circuits. PMID- 29386133 TI - Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala. AB - The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing. PMID- 29386135 TI - Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease. AB - Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson's disease (PD). Therapies based on PQ's presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor. PMID- 29386136 TI - Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates. AB - Dopamine (DA) loss in Parkinson's disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the "on" state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy. PMID- 29386137 TI - Energy Scarcity Promotes a Brain-wide Sleep State Modulated by Insulin Signaling in C. elegans. AB - Neural information processing entails a high energetic cost, but its maintenance is crucial for animal survival. However, the brain's energy conservation strategies are incompletely understood. Employing functional brain-wide imaging and quantitative behavioral assays, we describe a neuronal strategy in Caenorhabditis elegans that balances energy availability and expenditure. Upon acute food deprivation, animals exhibit a transiently elevated state of arousal, indicated by foraging behaviors and increased responsiveness to food-related cues. In contrast, long-term starvation suppresses these behaviors and biases animals to intermittent sleep episodes. Brain-wide neuronal population dynamics, which are likely energetically costly but important for behavior, are robust to starvation while animals are awake. However, during starvation-induced sleep, brain dynamics are systemically downregulated. Neuromodulation via insulin-like signaling is required to transiently maintain the animals' arousal state upon acute food deprivation. Our data suggest that the regulation of sleep and wakefulness supports optimal energy allocation. PMID- 29386138 TI - Ceramide Synthase Schlank Is a Transcriptional Regulator Adapting Gene Expression to Energy Requirements. AB - Maintenance of metabolic homeostasis requires adaption of gene regulation to the cellular energy state via transcriptional regulators. Here, we identify a role of ceramide synthase (CerS) Schlank, a multiple transmembrane protein containing a catalytic lag1p motif and a homeodomain, which is poorly studied in CerSs, as a transcriptional regulator. ChIP experiments show that it binds promoter regions of lipases lipase3 and magro via its homeodomain. Mutation of nuclear localization site 2 (NLS2) within the homeodomain leads to loss of DNA binding and deregulated gene expression, and NLS2 mutants can no longer adjust the transcriptional response to changing lipid levels. This mechanism is conserved in mammalian CerS2 and emphasizes the importance of the CerS protein rather than ceramide synthesis. This study demonstrates a double role of CerS Schlank as an enzyme and a transcriptional regulator, sensing lipid levels and transducing the information to the level of gene expression. PMID- 29386140 TI - Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular Subventricular Zone. AB - Neurogenesis continues in the ventricular-subventricular zone (V-SVZ) of the adult forebrain from quiescent neural stem cells (NSCs). V-SVZ NSCs are a reservoir for new olfactory bulb (OB) neurons that migrate through the rostral migratory stream (RMS). To generate neurons, V-SVZ NSCs need to activate and enter the cell cycle. The mechanisms underlying NSC transition from quiescence to activity are poorly understood. We show that Notch2, but not Notch1, signaling conveys quiescence to V-SVZ NSCs by repressing cell-cycle-related genes and neurogenesis. Loss of Notch2 activates quiescent NSCs, which proliferate and generate new neurons of the OB lineage. Notch2 deficiency results in accelerated V-SVZ NSC exhaustion and an aging-like phenotype. Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj-mediated canonical Notch signaling; thus, Notch2 functions are not compensated in NSCs, and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ. PMID- 29386139 TI - The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse. AB - T lymphocyte cytotoxicity relies on a synaptic ring of lymphocyte function associated antigen 1 (LFA-1), which permits polarized delivery of lytic granules. How LFA-1 organization is controlled by underlying actin cytoskeleton dynamics is poorly understood. Here, we explored the contribution of the actin cytoskeleton regulator WASP to the topography of LFA-1 using a combination of microscopy modalities. We uncover that the reduced cytotoxicity of Wiskott-Aldrich syndrome patient-derived CD8+ T lymphocytes lacking WASP is associated with reduced LFA-1 activation, unstable synapse, and delayed lethal hit. At the nanometric scale, WASP constrains high-affinity LFA-1 into dense nanoclusters located in actin meshwork interstices. At the cellular scale, WASP is required for the assembly of a radial belt composed of hundreds of LFA-1 nanoclusters and for lytic granule docking within this belt. Our study unravels the nanoscale topography of LFA-1 at the lytic synapse and identifies WASP as a molecule controlling individual LFA-1 cluster density and LFA-1 nanocluster belt integrity. PMID- 29386141 TI - Analysis of bluetongue serotype 3 spread in Tunisia and discovery of a novel strain related to the bluetongue virus isolated from a commercial sheep pox vaccine. AB - Bluetongue (BT), is one of the OIE-listed major diseases of ruminants. Following the official report of BT virus serotype 3 (BTV-3) in a sheep in Cap Bon (Tunisia), blood and serum samples of ruminants were collected from some areas of Tunisia to further investigate the presence of this virus in the country. A quantitative real time RT-PCR has been first developed for the detection and quantitation of BTV-3 RNA from field specimens. Out of 62 collected blood samples, 23 were shown to be positive for BTV-3 RNA. Isolation on cell cultures was also possible from six samples. Genome sequencing revealed the circulation of two unrelated western strains of BTV-3, one circulating in Cap Bon and neighboring areas, and the other circulating nearby the border with Libya. The presence of a putative novel BTV serotype (BTV-Y TUN2017) in sheep introduced from Libya to Tunisia, genomically related to the BTV strain contaminating a commercially-available sheep pox vaccine and to BTV-26, has been also demonstrated. This finding highlights the pressing need for a prompt production and release of a novel inactivated BTV-3 vaccine to be used in case of emergence or proactively in the areas of Southern Europe at major risk of BTV introduction. The assessment of a novel vaccine will certainly exalt the role and importance of surveillance activities and collaboration with Northern African countries. PMID- 29386142 TI - Oncocytic tumors are marked by enhanced mitochondrial content and mtDNA mutations of complex I in Chinese patients. AB - Oncocytic tumors are composed of oncocytes characterized by acidophilic granular and reticular cytoplasm. Such features have been attributed to the distinctive aggregation of abnormal mitochondria. Sporadic mitochondrial DNA (mtDNA) mutations, particularly those in complex I subunit genes, have been identified as one of the most noticeable alterations. We reviewed 11,051 cases of patients with thyroid tumors who visited the First Affiliated Hospital of Wenzhou Medical University from January 2011 to August 2017, and we were able to identify 123 cases as oncocytic tumors. We found that older people are at higher risk (P < 0.001) for oncocytic tumors. We confirmed an increased mitochondrial mass in representative samples. Furthermore, a comprehensive analysis of the mitochondrial genomes in patients with oncocytomas revealed 1) haplogroups D5 and A exhibit increased risk of oncocytomas; 2) 60% of mtDNA mutations are in genes encoding respiratory complex subunits while 8% occur in rRNA and 4% in tRNA regions; 3) among mutations in coding regions, 50% are in Complex I genes, including most of the disruptive mutations; 4) 64% of mtDNA mutations are heteroplasmic. Our studies imply a tumorigenesis mechanism for oncocytomas involving mitochondrial alterations mediated by genome instability and modified by mitochondrial haplogroups. PMID- 29386143 TI - Un diagnostic de borreliose sur frottis sanguin. PMID- 29386144 TI - Critical care testing: SFBC recommendations in 2018. AB - The SFBC Working Group on critical care testing describes in this paper the SFBC recommendations for the determination of maximal turnaround times (TAT) for laboratory medicine examination in emergency conditions. The table presented in a previous paper was updated, taken into account the clinical situations, as well as the emergency response capabilities of the medical laboratory. These new French recommendations must to be based to each local situation in a clinical biological context between the physicians and the specialist in Lab Medicine. PMID- 29386145 TI - 2018 should be a very good year for SFBC, the year of a renewal. PMID- 29386146 TI - Positivity of antineutrophil cytoplasmic antibodies in children: prevalence and etiologies. AB - In adults, anti-neutrophil cytoplasmic antibodies (ANCA) are considered as serological markers of several diseases, especially vasculitis and glomerulonephritis. Since ANCA are rarely positive in children, few data about the clinical relevance of these auto-antibodies in pediatric population have been reported. Therefore, our study aims to describe the spectrum of disorders associated with positive ANCA in Tunisian children. This study had been carried out over a period of 12 years and a half. All patients under the age of 15 for whom ANCA screening was performed in our laboratory were included. Clinical data were collected retrospectively. Indirect immunofluorescence (IFI) technique for ANCA detection was performed using PNN smears fixed with ethanol, formalin and, if necessary, methanol. Positive results were tested using immunodot to characterize the antigenic targets (myeloperoxydase (MPO) and proteinase 3 (PR3)). Our results showed that 410/5,990 (6.8%) laboratory requests for ANCA screening were for children. Forty (9.7%) requests were positive (24 children). Clinical data were available for 19 patients only. Sex-ratio (F/M) was 1.25. The mean age was 9 years and a half (3-15 years). The most frequent IIF patterns were x-ANCA (n=12) and p-ANCA (n=7). In our patients, the most frequent conditions associated to ANCA were treatment with benzylthiouracil for hypothyroidism (n=6), inflammatory bowel disease (n=4) and hemolytic anemia (n=4). In conclusion, the positivity of ANCA in children seems to be a rare event. Associated conditions include clinical disorders specific to the pediatric population. Treatment with benzylthiouracil is an etiology to be taken into consideration. PMID- 29386147 TI - Editor-in-chief of the Annales de Biologie Clinique (Paris) for 10 years: thanks for your confidence! PMID- 29386148 TI - Diversity and antimicrobial activities of Streptomyces isolates from Fetzara Lake, north eastern Algeria. AB - A total of 125 Streptomyces strains were isolated from an Algerian wetland (Fetzara Lake) and characterized by growth on different culture media. Phylogenetic analyses were carried out by 16S rRNA sequence comparison after PCR amplification using universal primers. Antibacterial bioassays performed by the agar diffusion method enabled us to retain 33 Streptomyces isolates for their activity against two Gram-positive bacteria (Bacillus subtilis and Micrococcus luteus) and one Gram-negative bacteria (Escherichia coli). Among them, six isolates inhibited all three indicator strains. Antibacterial compounds were then extracted from the solid culture media with ethanol and ethyl acetate as organic solvents. The minimal inhibitory concentration (% v/v) of the extracts was evaluated by a standardized broth dilution method against different clinical resistant bacterial isolates and Candida albicans. The most active crude extracts were selected for further characterization by chromatographic analysis (RP-HPLC). PMID- 29386149 TI - Gisele Le Moel. PMID- 29386150 TI - Zein based magnesium oxide nanoparticles: Assessment of antimicrobial activity for dental implications. AB - MgO nanoparticles have been recently discovered as an antibacterial, however, they limited by property degradation due to agglomeration. The addition of a coating agent, such as a zein polymer, is effective in preventing agglomeration without affecting nanosized properties. The aim of this study was to assess the antimicrobial property of MgO nanoparticles when coated with a zein polymer against several oral bacteria and fungi. This was done by utilizing various assessment techniques. The ultimate aim is to use these nanoparticles in dental preparations. The antimicrobial activity of zein-coated MgO nanoparticles at different concentrations of 0.5, 1 and 2% were tested against four different microorganisms: Staphylococcus aureus, Streptococcus mutans and Enterococcus faecalis (gram positive bacteria), and Candida albicans (as oral fungus). Two different techniques were utilized: the Kirby-Bauer test, and a modified direct contact test. The results indicated that the antibacterial effect of 1% or 2% zein-coated MgO nanowires were statistically significant (p<0.05) against the four organisms studied: S. mutans, S. aureus, E. faecalis and C. albicans. Zein coated MgO nanoparticles are a new human friendly and potent antimicrobial agent that can be incorporated in the formulation of a variety of new dental materials and products that should provide improvements in dental care and oral health. PMID- 29386151 TI - Biosurfactants production potential of native strains of Bacillus cereus and their antimicrobial, cytotoxic and antioxidant activities. AB - Present study was designed to evaluate the biosurfactant production potential by native strains of Bacillus cereus as well as determine their antimicrobial and antioxidant activities. The strains isolated from garden soil were characterized as B. cereus MMIC 1, MMIC 2 and MMIC 3. Biosurfactants were extracted as grey white precipitates. Optimum conditions for biosurfactant production were 37 degrees C, the 7th day of incubation, 0.5% NaCl, pH 7.0. Moreover, corn steep liquor was the best carbon source. Biuret test, Thin Layer Chromatography (TLC), agar double diffusion and Fourier Transform Infrared Spectroscopy (FTIR) characterized the biosurfactants as cationic lipopeptides. Biosurfactants exhibited significant antibacterial and antifungal activity against S. aureus, E. coli, P. aeruginosa, K. pneumoniae, A. niger and C. albicans at 30 mg/ml. Moreover, they also possessed antiviral activity against NDV at 10 mg/ml. Cytotoxicity assay in BHK-21 cell lines revealed 63% cell survival at 10 mg/ml of biosurfactants and thus considered as safe. They also showed very good antioxidant activity by ferric-reducing activity and DPPH scavenging activity at 2 mg/ml. Consequently, the study offers an insight for the exploration of new bioactive molecules from the soil. It was concluded that lipopeptide biosurfactants produced from native strains of B. cereus may be recommended as safe antimicrobial, emulsifier and antioxidant agent. PMID- 29386152 TI - Neurite outgrowth properties of Calotropis procera: In search for a neuroprotectant. AB - In view of the well-documented medicinal properties of Calotropis procera (CP), the present study was designed to evaluate the neuroprotective effect of the extract. We have prepared a methanolic extract of Calotropis procera and screen varying concentration of CP (20, 30, 40, 50 and 70MUg/ml) for the stimulatory potency on neurite outgrowth. The stimulatory effect of CP on neurite outgrowth was assessed in primary hippocampal neurons. Neurite lengths were measured using optika provison analysis software. Neuritogenesis was further analyzed by immunostaining by using specific neuronal marker beta III-tubulin. The data show that neurite outgrowth from hippocampal neurons were significantly enhanced in the presence of CP (40MUg/ml). The most stimulatory neurite outgrowth effects were appeared after 48hrs incubation of neurons with CP (40MUg/ml). These data confirm that CP extract could promote invitro hippocampal neurite outgrowth in a dose-dependent manner. Our results indicate that CP can be used as a healthy dietary supplement for the cognitive functions of the brain. PMID- 29386153 TI - Effect of the serum of rats treated with Suo Quan pill on embryonic stem cells. AB - Suo Quan pill(SQP), a well-known and classical traditional Chinese medicine compound, consists of three traditional Chinese medicine: Alpinia oxyphylla Miq., Lindera aggregata (Sims) Kosterm., Dioscorea opposite. Its effect was summarized as supplementing kidney-yang and shrinkaging urination. This study evaluated the effects of the serum of rats treated with Suo Quan pill on embryonic stem cells(ES cells). Cell proliferation was detected by MTT assay. Cell cycle and apoptosis of ES cells were evaluated with flow cytometry. Nanog mRNA expression was verified by fluorescence quantitative PCR and Nanog protein in ES cells was determined by Western blot. The serum of SQP-treated rats not only promoted ES cells proliferation and Nanog expression in ES cells, but also inhibited H202 stimulated cell apoptosis. Furthermore, the serum of rats containing SQP affected the cell cycle distribution of ES cells, reducing the percentage of cells in G0/G1phase and increasing the percentage of cells in G2/M phase, increasing the proliferation index of ES cells. These results illustrate that the enhanced effect of SQP on ES cells proliferation is in part due to the increased expression of Nanog in ES cells, the accelerated cell cycle period and the inhibited apoptosis of ES cells. PMID- 29386154 TI - Assesment of predictor variables and clinical consequences associated with surgical site infection in tertiary care setting, Karachi, Pakistan. AB - Among the well-known Health care-associated infections (HAIs), surgical site infections (SSIs) contribute to considerable high mortality and morbidity rate, substantial prolongation in hospitalization period and extra expenses in terms of treatment cost. This study was aimed to evaluate the predictive variables associated with surgical site infections, and their clinical consequences. This was a prospective, cross sectional study conducted in the surgical department of tertiary care setting in Karachi, Pakistan. Each patient was followed up from the time of admission until time of the discharge postoperatively for 30 days. A total of 554 surgical procedures were performed and 81 SSIs were identified. The predictor variable/risk factors significantly associated with the presence of SSI were age, gender, BMI, ASA score, co-morbid condition, surgical wound class, emergency surgeries, duration of surgery, type of anesthesia, prosthetic implant, pre operative length of stay and pre operative blood transfusion. Outcomes of such studies may be utilized in the design of a multi factorial practice to get better patient's safety and clinical outcomes. PMID- 29386155 TI - Therapeutic effect of alkaloids and glycosides of colocynth seeds on liver injury, associated with metabolic syndrome in wistar rats, subject to nutritional stress. AB - The Citrullus colocynthis, commonly called colocynth, is known because of its purgative effects and whose seeds are commonly used as certain diseases treatment, namely liver diseases, in the Mediterranean countries traditional medicine. This study aims to analyze the effect of two colocynth extracts " glycosides " and " alkaloids " on metabolic and histological disorders associated with liver function in Wistar rats (Rattus norvegicus). This pathology is due to an enriched oil palm diet. For this purpose, Wistar male rats n = 18, weighing between 130g and 150g, are divided into two lots. A control group (C) n = 6, receives a standard laboratory diet ; an experimental group (E) n = 12, receives a standard laboratory diet supplemented with palm oil. After seven months of experimentation, 8 experimental rats were sacrificed for the morphological study and the remaining 12 rats undergo a colocynth treatment (Tr) for eight weeks. They are subdivided into: The first six experimental rats receive a 70mg/kg single intraperitoneal injection of ethanol extract of cucurbitacin glycosides (Glc). The second lot receives a 70mg/kg single intraperitoneal injection of total alkaloids extract (Alc). The animals of (E) group showed hyperglycemia, hyperinsulinemia, hyperlipemia, dyslipoproteinemia, a significant increase of the enzymatic activity of transaminase (AST and ALT) and alkaline phosphatase (ALP). Histological examination of the liver gland shows major damages Non-alcoholic steatohepatitis [NASH]. Treatment with colocynth glycosides and alkaloids reveals a significant improvement at different levels in plasma as well as in tissue. Treatment with colocynth glycosides and alkaloids shows a hypoglycemic effect, lipid-lowering a well as a hepato-protective effect. PMID- 29386156 TI - A randomized, control and comparative study of polyherbal formulation use for Malaria (Plasmodium falciparum). AB - Plasmodium falciparum is the most well-known reason for extreme and life debilitating malaria. Falciparum malaria causes more than 1 million deaths annually. Malaria remains a noteworthy reason for major morbidity and mortality in the tropics, with Plasmodium falciparum accountable for the mainstream of the disease weight and Plasmodium vivax being the geologically greatest broadly dispersed cause of malaria. The controlling of severe malaria comprises quick direction of suitable parenteral anti-malarial agents and initial acknowledgement and treatment of the complications. This clinical trial was piloted in 100 patients, in which 50 received the test drug (Malarina) and 50 received the control drug (Quinine Bisulphate). The age range of patients was 12 years to above 50 years. The sample paired t-test was applied to evaluate the significant level. Malarina was very effective in treating malaria sign and symptoms. The new treatment Malarina was safe and well tolerated in all patients. PMID- 29386157 TI - Vitex negundo induces an anticonvulsant effect by inhibiting voltage gated sodium channels in murine Neuro 2A cell line. AB - Vitex negundo (Vn) extract is famous for the treatment of neurological diseases such as migraine and epilepsy. These neurological diseases have been associated with abnormally increased influx of sodium ions into the neurons. Drugs that inhibit voltage gated sodium channels can be used as potent anti-epileptics. Till now, the effects of Vn on sodium channels have not been investigated. Therefore, we have investigated the effects of methalonic fraction of Vn extract in Murine Neuro 2A cell line. Cells were cultured in a defined medium with or without the Vn extract (100 MUg/ml). Sodium currents were recorded using whole-cell patch clamp method. The data show that methanolic extract of Vn inhibited sodium currents in a dose dependent manner (IC50 =161MUg/ml). Vn (100 MUg/ml) shifted the steady-state inactivation curve to the left or towards the hyper polarization state. However, Vn did not show any effects on outward rectifying potassium currents. Moreover, Vn (100 MUg/ml) significantly reduced the sustained repetitive (48+/-4.8%, P<0.01) firing from neonatal hippocampal neurons at 12 DIV. Hence, our data suggested that inhibition of sodium channels by Vn may exert pharmacological effects in reducing pain and convulsions. PMID- 29386158 TI - Albendazole in the treatment of Hymenolepiasis in school children. AB - Hymenolepiasis is a helminthic and occasionally fatal disease of human imposing heavy economic losses to human society. Present study was aimed to diagnose the school children for the prevalence and control of Hymenolepiasis. A school based cross-sectional analysis of stool samples collected from 188 children aged 06-15 years was carried out (February to June 2016). Two stool samples were collected from each student before diagnosing and after treatment. The samples were fixed in 10% formalin and observed under the light microscope using the methods of direct smear in Lugol's solution, normal saline and flotation techniques. On the basis of drugs accessibility all the H. nana infected children were divided in to 2- groups. Children in group A were treated with albendazole (bendazol) 400mg once orally, group B was treated with albendazole (zentel) 200mg orally. Eggs per gram of faeces were counted in each group before and after treatment. Of the 188 children, current study reveals only 6.08% (n=18/296) infection with H.nana and 10.5% (n=16/151) were diagnosed with co infections. The % efficacy of albendazole (Zentel) and albendazole (bendazol) against Hymenolepis nana infection was reported as 83% and 75% respectively. Present study was concluded that albendazole (zentel) is the drug of choice for the treatment of hymenolepiasis in children. PMID- 29386159 TI - Bioanalytical method development and validation for quantification of morachalcone A in rabbit plasma using high performance liquid chromatography. AB - Artocarpus champeden (A. champeden) ethanol extract has been reported as antimalarial activity and prospective to be developed as phytomedicine products. The active marker compound was identical with known prenylated chalcone compound, Morachalcone A. To further develop phytomedicine products from A. champeden especially in aspects of bioavailability and pharmacokinetic, a valid, selective and sensitive analytical method becomes important to determine morachalcone A in plasma. The aim of study was to develop and validate selectivity and sensitivity of High Performance Liquid Chromatography (HPLC) method to determine morachalcone A in rabbit plasma. This method was used a RP-18 Column (250 x 4.6 mm i.d, 5 um), under isocratic elution and acetonitrile:water (50:50 v/v) was used as mobile phase with flow rate of 1.0ml/min. Detection was carried out at 368 nm, 4 hydroxychalcone and methanol were used as internal standard and precipitant. Results showed that this HPLC method was selective with good linearity in range of 3096.774 to 154.839ng/ml. LOD and LLOQ were 89.384 and 154.839ng/ml, respectively. The mean %different was found between 2.79 to 14.33%. Intra and inter-day precision were <=15% and recovery from this extraction method of morachalcone A and Internal Standard were 80-120%. PMID- 29386160 TI - Preventive effect of Xanthoria parietina polyphenols on the complications of diabetes in white rat. AB - Polyphenols have shown antioxidant activity and an ability to prevent the toxic effects of oxidative stress in diabetes. The objective of this study was to evaluate the hypoglycemic and antioxidant effect of the methanolic extract of Xanthoria parietina on rats diabetes induced by streptozotocin (40 mg/g). The results obtained show that streptozotocin induces diabetes in the animal characterized by hyperglycemia, elevation of oxidative stress markers and a decrease of enzymatic and non-enzymatic antioxidant defense system. However, the methanolic extract results in a marked improvement in the antioxidant state in the liver. Indeed our results show a decrease in the malonyldialdehyde concentration of 25.91% and an increase in the reduced glutathione rate of 23.62%, an increase in the superoxide dismutase activity of 23.53% and catalase activity of 49.10%. The effect of the polyphenolic extract on the blood glucose level is tested on rats rendered hyperglycemic. The feeding with the extract showed a significant hypoglycaemic effect during 120 minutes of treatment. In conclusion, the present study suggests that Xanthoria parietina has a beneficial effect on the control of blood glucose, lipid profile and oxidative status, activating antioxidant enzymes and decreasing lipid peroxidation in the liver. Such treatments may help reduce the development of complications associated with diabetes. PMID- 29386161 TI - Saudi plants as a source of potential beta-lactamase inhibitors. AB - This study was performed to assess the potential beta-lactamase inhibitory properties of nineteen crude Saudi plant extracts belonging to eight families against extended spectrum beta-lactamase (ESbetaL) strains of Klebsiella pneumoniae and other medically important pathogens. A total of 276 microbial isolates of pathogenic bacteria were used in this study; only 15 of them showed decreased sensitivity to one or several of ceftazidime, aztreonam, cefotaxime or ceftriaxone, which are deemed to be possible producers of ESbetaL. Antibacterial activities of plant extracts were carried out against ESbetaL positive isolates by the disc diffusion method. The potential ESbetaL suppressing activities of plant extracts and prepared fractions, (chloroform and methanol), with or without antibiotic were studied by disc diffusion method. Results revealed that selected plant extracts showed no antibacterial activity against tested strains; meanwhile, only Echinops viscosus, Pulicaria arabica, Tephrosia nubica, Chrozophora oblongifolia, and Clutia myricoides showed pronounced ESbetaL inhibitory activities. The extracts were quantified for phenolic compounds and their antioxidant properties. Bio-guided fractionation of the active extracts revealed that the chloroform fraction of C. myricoides possess a promising ESbetaL inhibitory activity. The separation and the structural elucidation of the active compounds from C. myricoides will offer beneficial leads for developing beta-lactamase inhibitors. PMID- 29386162 TI - Metabolomic profiling of the effects of Curcumae rhizoma and Sparganii rhizome on stress-led blood stasis. AB - Blood stasis (BS) is a complex syndrome with blood flow retardation or cessation. The Traditional Chinese Medicine, Curcumae rhizome (CR) and Sparganii rhizome (SR), showed promising effects on this disease, and especially effective when used in combination. However, the detailed influence of the TCMs on the BSS disturbed metabolic pathways was still unclear. In this study, a BS model was constructed in SD rat and the TCMs were used individually or in combination to assess the effects. As a result, combination of CR and SR led to the improvement in hemorheology parameters of up to 80% in the BS model. Further analyzing using metabolomics showed several metabolic pathways, including center carbon metabolism, amino acid metabolism, etc., recovered to the normal levels after treatment. Informatively, tyrosine and thymidine exhibited potential importance in the BSS and its treatment process. From these results, the metabolic profiles of BS and the SR-CR treatment were provided, which may helpful for better understanding the BSS mechanism and the development of more effective therapies. PMID- 29386163 TI - Neuroprotective capabilities of Vitex negundo in primary hippocampal neurons. AB - Vitex negundu (Vn) is a well-known aromatic shrub commonly used as a traditional folk medicine famous for its potential pharmacological and biological activities. Several chemical compounds are extracted and identified from the different parts of the Vn such as leaves, root, seeds and flowers. Number of researches reported the herb as antimicrobial, anti-androgenic, anti-osteoporotic, and anti-tumour, anti-cancer, anti-inflammatory, anti-oxidant, anti-hyperglycemic and hepatoprotective. The effects of Vn on neurite outgrowth have not been identified till now. Therefore present study was designed to investigate the neurite outgrowth effects of Vn extract in hippocampal neurons. Neurons from P0 mice were isolated and cultured in defined medium containing the different concentrations of Vn (20, 30, 40, 50, 100, 150 and 200 MUg/ml) for 48 hrs. The presence of the neurites was confirmed by using betaIII-tubulin antibody which specifically labels only the neurites. Morphometric analysis was done by using Optika Pro Vision software. The data show that Vn at 30 and 40 MUg/ml significantly increased the mean average length of the longest neurite whereas at 150 and 200 MUg/ml it significantly decreased the mean average length of the 10 longest neurite in hippocampal neurons. Nevertheless Vn did not show any significant effects on the sum of all the neurite lengths at any concentrations tested. Taken together the result shows that methanolic extract of Vn has potential to produce long neurites at 30 and 40 MUg/ml and therefore can be act as a neuroprotective agent in the future drug development. PMID- 29386164 TI - Formulation and evaluation of diclofenac controlled release matrix tablets made of HPMC and Poloxamer 188 polymer: An assessment on mechanism of drug release. AB - In this study, hydrophilic hydroxypropyl methylcellulose matrices with various concentrations of Poloxamer 188 were used in the development of oral controlled release tablets containing diclofenac sodium. Four formulations of hydrophilic matrix tablets containing 16.7% w/w HPMC and 0, 6.7, 16.7 and 25.0% w/w Poloxamer 188, respectively, were developed. Tablets were prepared by direct compression and characterized for diameter, hardness, thickness, weight and uniformity of content. The influence of various blends of hydroxypropyl methylcellulose and Poloxamer 188 on the in vitro dissolution profile and mechanism of drug release of was investigated. In the four formulations, the rate of drug release decreased with increasing the concentration of Poloxamer 188 at the initial dissolution stages due to the increase in the apparent viscosity of the gel diffusion layer. However, in the late dissolution stages, the rate of drug release increased with increasing Poloxamer 188 concentration due to the increase in wettability and dissolution of the matrix. The kinetic of drug release from the tablets followed non-Fickian mechanism, as predicted by Korsmeyer-Peppas model, which involves diffusion through the gel layer and erosion of the matrix system. PMID- 29386165 TI - Spectrophotometric method development and validation for determination of chlorpheniramine maleate in bulk and controlled release tablets. AB - Spectrophotometric technique is considered to be the simplest and operator friendly among other available analytical methods for pharmaceutical analysis. The objective of the study was to develop a precise, accurate and rapid UV spectrophotometric method for the estimation of chlorpheniramine maleate (CPM) in pure and solid pharmaceutical formulation. Drug absorption was measured in various solvent systems including 0.1N HCl (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and distil water (pH 7.0). Method validation was performed as per official guidelines of ICH, 2005. High drug absorption was observed in 0.1N HCl medium with lambdamax of 261nm. The drug showed the good linearity from 20 to 60MUg/mL solution concentration with the correlation coefficient linear regression equation Y= 0.1853 X + 0.1098 presenting R2 value of 0.9998. The method accuracy was evaluated by the percent drug recovery, presents more than 99% drug recovery at three different levels assessed. The % RSD value <1 was computed for inter and intraday analysis indicating the high accuracy and precision of the developed technique. The developed method is robust because it shows no any significant variation in with minute changes. The LOD and LOQ values were assessed to be 2.2MUg/mL and 6.6MUg/mL respectively. The investigated method proved its sensitivity, precision and accuracy hence could be successfully used to estimate the CPM content in bulk and pharmaceutical matrix tablets. PMID- 29386166 TI - [Feline leukemia virus infection: importance and current situation in Switzerland]. AB - INTRODUCTION: Feline leukemia virus (FeLV) leads to fatal disease in cats with progressive infection. The aim of this study was to determine the importance of FeLV infection in Switzerland and make a comparison with previous studies. Of 881 blood samples taken from cats living in Switzerland (minimum of 20 samples per Canton), 47 samples were provirus-positive (5.3%; 95% confidence interval (CI) 3.9-7.0%) and 18 samples were antigen-positive (2%; 95% CI 1.2-3.2%). Together with data previously collected in similar studies, these findings demonstrated a decrease in prevalence between 1997 and 2003 followed by a relative constant low prevalence thereafter. Young cats (=2 years) were more frequently infected than older cats, but FeLV-positive cats were up to 15 (antigen-positive) and 19 (provirus-positive) years old. Sexually intact cats were more frequently viremic than neutered cats; purebred cats were somewhat less frequently FeLV-positive than non-purebred cats. In a second study, in which 300 saliva samples were analyzed, samples from 5 cats were FeLV-RNA positive (1.7%; 95% CI, 0.5-3.8%), although one young feral cat had been falsely assumed to be FeLV-negative based on a point-of-care test. Of the 300 cats, only 50% were FeLV tested or vaccinated, although 90% of the cats were at risk of exposure to FeLV. Testing and vaccination of all cats with exposure risk may help further decrease the prevalence of FeLV infection. Moreover, characteristics of FeLV tests should be considered, such as the risk of false negative results in the early phase of infection when performing antigen testing. PMID- 29386167 TI - [Correlation of a lameness scoring system and claw lesion]. AB - INTRODUCTION: The aim of this study was to investigate the relationship between lameness scoring and clinical findings. The lameness scoring and a gait assessment took place during drying off, the first week after calving and two months after calving in 29 lame and 27 free of lameness cows. In between the farmer scored the lamness. Most of the lameness occurred in the hind limbs and were most frequently caused by dermatitis digitalis, Mortellaro, Limax, and Rusterholz sole ulcer. The mean duration of lameness after treatment was 26 days (median 16 days) and was significantly longer in case of horn lesions than in skin lesions (including interdigital dermatitis). Lameness- free control animals were often affected by heel horn erosion and digital dermatitis. It was shown that the sensitivity of lameness (lameness is caused by a certain aetiology) for a certain cause of lameness (dermatitis interdigitalis, doble sole, purulent hollow wall, Limax, digital dermatitis, Rusterholz sole ulcer and sole contusion) increases along with the threshold (degree of lameness) but that the specificity (no lameness is not related to a certain aetiology) remained constant at the same time. The highest sensitivity was achieved in injuries, followed by interdigital hyperplasia. The receiver operating curve (ROC) showed that lameness was the best selecting symptom in white line lesions followed by claw injury. The positive predictive values varied between 38.8% in white line lesions and 0% in Rusterholz's sole ulcer. The negative predictive values varied between 99.1% in interdigital dermatitis and 82.3% in interdigital dermatitis. The ROC analysis shows which lameness is more related to a certain claw disease. The results demonstrate, that a lameness score cannot be linked to a certain claw disease. PMID- 29386168 TI - [Effects of lameness at the time of drying off on the lactation and fertility performance of the following lactation]. AB - INTRODUCTION: The aim of the study was to clarify how lameness and its severity in dairy cows at the time of drying off will affect the milk performance and fertility in the following lactation when treated appropriately at the time of drying off. The lameness scoring and a gait assessment took place during drying off, in the 1st week after calving, as well as 2 months after calving. Each lame cow was compared with a non-lame control cow from the same farm. The milk and fertility data of the following lactation were compared with those of the previous lactation. Most of the lameness occurred in the hind limbs and was most frequently due to digital dermatitis (Mortellaro), limax, and Rusterholz sole ulcer. The mean lameness duration after treatment was 26 days (median 16 days) and was significantly longer in case of horn lesions than in skin lesions. Recurrences most often occured in the interdigital cleft region. Lameness- free control animals were often affected by heel horn erosion and digital dermatitis. In the present study, a lameness treated at the time of dry off did not have a negative effect on fertility, but on milk yield and milk fat. Treatment could not eliminate these negative effects. However, it can be hypothesized that the negative effects on these and other parameters would have been even greater than without adequate treatment. PMID- 29386169 TI - Effects of a reduced dose of injected iron on health, iron status and growth of suckling piglets with access to iron enriched soil. AB - INTRODUCTION: The effects of the recommended dose of 200 mg iron and of half that dose injected on the first day of life on health, iron status and performance during the 4 week suckling period were studied in 2'123 piglets. All piglets received creep feed and soil which was supplemented with 14 g iron per kg. Neither mortality nor the prevalence of arthritis, meningitis and foot abscess (each disease affecting about 1% of the piglets) differed between the two groups. The low dose of 100 mg iron decreased blood haemoglobin concentration at weaning (110 +/- 19 vs.120 +/- 15 g/l), but did not affect growth rate. PMID- 29386171 TI - A Wearable Sensor-Based Exercise Biofeedback System: Mixed Methods Evaluation of Formulift. AB - BACKGROUND: Formulift is a newly developed mobile health (mHealth) app that connects to a single inertial measurement unit (IMU) worn on the left thigh. The IMU captures users' movements as they exercise, and the app analyzes the data to count repetitions in real time and classify users' exercise technique. The app also offers feedback and guidance to users on exercising safely and effectively. OBJECTIVE: The aim of this study was to assess the Formulift system with three different and realistic types of potential users (beginner gym-goers, experienced gym-goers, and qualified strength and conditioning [S&C] coaches) under a number of categories: (1) usability, (2) functionality, (3) the perceived impact of the system, and (4) the subjective quality of the system. It was also desired to discover suggestions for future improvements to the system. METHODS: A total of 15 healthy volunteers participated (12 males; 3 females; age: 23.8 years [SD 1.80]; height: 1.79 m [SD 0.07], body mass: 78.4 kg [SD 9.6]). Five participants were beginner gym-goers, 5 were experienced gym-goers, and 5 were qualified and practicing S&C coaches. IMU data were first collected from each participant to create individualized exercise classifiers for them. They then completed a number of nonexercise-related tasks with the app. Following this, a workout was completed using the system, involving squats, deadlifts, lunges, and single-leg squats. Participants were then interviewed about their user experience and completed the System Usability Scale (SUS) and the user version of the Mobile Application Rating Scale (uMARS). Thematic analysis was completed on all interview transcripts, and survey results were analyzed. RESULTS: Qualitative and quantitative analysis found the system has "good" to "excellent" usability. The system achieved a mean (SD) SUS usability score of 79.2 (8.8). Functionality was also deemed to be good, with many users reporting positively on the systems repetition counting, technique classification, and feedback. A number of bugs were found, and other suggested changes to the system were also made. The overall subjective quality of the app was good, with a median star rating of 4 out of 5 (interquartile range, IQR: 3-5). Participants also reported that the system would aid their technique, provide motivation, reassure them, and help them avoid injury. CONCLUSIONS: This study demonstrated an overall positive evaluation of Formulift in the categories of usability, functionality, perceived impact, and subjective quality. Users also suggested a number of changes for future iterations of the system. These findings are the first of their kind and show great promise for wearable sensor-based exercise biofeedback systems. PMID- 29386170 TI - A Social Media-Based Acute Alcohol Consumption Behavior (NekNomination): Case Series in Italian Emergency Departments. AB - BACKGROUND: NekNomination, also known as NekNominate, Neck and Nominate, or Neck Nomination, is a social network-based drinking game which is thought to have originated in Australia and spread all over the world between 2013 and 2014. Individuals record videos of themselves while rapidly drinking excessive quantities of alcoholic drinks (necking) and then nominate friends to outdo them within 24 hours; the videos are then posted on social media such as Facebook or YouTube. The consequences of this drinking game have been very dangerous; at least 5 people under age 30 years have died after drinking deadly cocktails, and many others have suffered from alcohol intoxication. OBJECTIVE: The goal of the research is to evaluate data about clinically important acute alcohol intoxication among teenagers and young adults and inform and educate the general public, especially parents, teachers, and health workers, about the spreading craze of dangerous Internet-related behavior among today's teenagers and young people up to the age of 23 years. METHODS: Patients aged 15 to 23 years with acute alcohol intoxication who came to the emergency department (ED) of 2 major hospitals in Italy from January 1, 2011, to June 30, 2014, were included in this study. Data were retrieved from prehospital and intrahospital medical records and included personal information, methods of intoxication, triage color code, date and time of access to the ED, any relevant signs and symptoms, blood alcohol concentration, and diagnosis at discharge. RESULTS: A total of 450 young patients (male 277/450, 61.5%, female 173/450, 38.5%; age 15 to 16 years 15/450, 3.3%, age 17 to 18 years 184/450, 40.9%, age 19 to 23 years 251/450, 55.8%) were recruited. The causes of intoxication were happy hour, binge drinking, NekNominate, eyeballing, other alcoholic games, or a mix of them. Happy hour was found to be more common among the older patients, whereas NekNominate accounted for almost half of the youngest group of hospitalizations. Eyeballing occurred in 1.6% (7/450) of cases; binge drinking and other alcoholic games caused 23.3% (105/450) and 23.8% (107/450) of hospitalizations, respectively. On admission, 44.2% (199/450) of patients were assigned a red or yellow color code requiring immediate medical attention; about 14% of them required additional medical assistance (after being in the ED) or hospitalization, some in semi-intensive care units. CONCLUSIONS: Our study shows that the increased numbers of hospitalizations due to alcohol intoxication in the adolescent age group, as a consequence of NekNominate or other drinking games, is alarming and represents a serious public health issue. The potential markers of improper use of social networks must be clearly identified, including categories at risk of alcohol abuse, in order to develop intervention and prevention strategies in terms of education and awareness, which may help in averting potentially fatal episodes. PMID- 29386173 TI - Web-Delivered Cognitive Behavioral Therapy for Distressed Cancer Patients: Randomized Controlled Trial. AB - BACKGROUND: Web-based interventions present a potentially cost-effective approach to supporting self-management for cancer patients; however, further evidence for acceptability and effectiveness is needed. OBJECTIVE: The goal of our research was to assess the effectiveness of an individualized Web-based cognitive behavioral therapy (CBT) intervention on improving psychological and quality of life outcomes in cancer patients with elevated psychological distress. METHODS: A total of 163 distressed cancer patients (111 female, 68.1%) were recruited through the Queensland Cancer Registry and the Cancer Council Queensland Cancer Helpline and randomly assigned to either a Web-based tailored CBT intervention (CancerCope) (79/163) or a static patient education website (84/163). At baseline and 8-week follow-up we assessed primary outcomes of psychological and cancer specific distress and unmet psychological supportive care needs and secondary outcomes of positive adjustment and quality of life. RESULTS: Intention-to-treat analyses showed no evidence of a statistically significant intervention effect on primary or secondary outcomes. However, per-protocol analyses found a greater decrease for the CancerCope group in psychological distress (P=.04), cancer specific distress (P=.02), and unmet psychological care needs (P=.03) from baseline to 8 weeks compared with the patient education group. Younger patients were more likely to complete the CancerCope intervention. CONCLUSIONS: This online CBT intervention was associated with greater decreases in distress for those patients who more closely adhered to the program. Given the low costs and high accessibility of this intervention approach, even if only effective for subgroups of patients, the potential impact may be substantial. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613001026718; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364768&isReview= rue (Archived by WebCite at http://www.webcitation.org/6uPvpcovl). PMID- 29386172 TI - Remote Collaborative Depression Care Program for Adolescents in Araucania Region, Chile: Randomized Controlled Trial. AB - BACKGROUND: Despite evidence on efficacious interventions, a great proportion of depressed adolescents do not receive evidence-based treatment and have no access to specialized mental health care. Remote collaborative depression care (RCDC) may help to reduce the gap between needs and specialized mental health services. OBJECTIVE: The objective of this study was to assess the feasibility, acceptability, and effectiveness of an RCDC intervention for adolescents with major depressive disorder (MDD) living in the Araucania Region, Chile. METHODS: A cluster randomized, assessor-blind trial was carried out at 16 primary care centers in the Araucania Region, Chile. Before randomization, all participating primary care teams were trained in clinical guidelines for the treatment of adolescent depression. Adolescents (N=143; 13-19 years) with MDD were recruited. The intervention group (RCDC, N=65) received a 3-month RCDC treatment that included continuous remote supervision by psychiatrists located in Santiago, Chile's capital city, through shared electronic health records (SEHR) and phone patient monitoring. The control group (enhanced usual care or EUC; N=78) received EUC by clinicians who were encouraged to follow clinical guidelines. Recruitment and response rates and the use of the SEHR system were registered; patient adherence and satisfaction with the treatment and clinician satisfaction with RCDC were assessed at 12-week follow-up; and depressive symptoms and health related quality of life (HRQoL) were evaluated at baseline and 12-weeks follow up. RESULTS: More than 60.3% (143/237) of the original estimated sample size was recruited, and a response rate of 90.9% (130/143) was achieved at 12-week follow up. A mean (SD) of 3.5 (4.0) messages per patient were written on the SEHR system by primary care teams. A third of the patients showed an optimal adherence to psychopharmacological treatment, and adolescents in the RCDC intervention group were more satisfied with psychological assistance than those in EUC group. Primary care clinicians were satisfied with the RCDC intervention, valuing its usefulness. There were no significant differences in depressive symptoms or HRQoL between groups. Satisfaction with psychological care, in both groups, was related to a significant change in depressive symptomatology at 12-weeks follow-up (beta= 4.3, 95% CI -7.2 to -1.3). CONCLUSIONS: This is the first trial of its kind in Latin America that includes adolescents from vulnerable backgrounds, with an intervention that proved to be feasible and well accepted by both patients and primary care clinicians. Design and implementation issues may explain similar effectiveness across arms. The effectiveness of the intervention seems to be comparable with an already nationwide established treatment program that proved to be highly efficacious under controlled conditions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01860443; https://clinicaltrials.gov/ct2/show/NCT01860443 (Archived by WebCite at http://www.webcitation.org/6wafMKlTY). PMID- 29386174 TI - mHealth Intervention Promoting Cardiovascular Health Among African-Americans: Recruitment and Baseline Characteristics of a Pilot Study. AB - BACKGROUND: Mobile health (mHealth) interventions are promising avenues to promote cardiovascular (CV) health among African-Americans (AAs) and culturally tailored technology-based interventions are emerging for this population. OBJECTIVE: The objectives of this study were to use a community-based participatory research (CBPR) approach to recruit AAs into a pilot intervention study of an innovative mHealth CV health promotion program and to characterize technology use patterns and eHealth literacy (EHL). METHODS: Community partners from five predominately AA churches in southeast Minnesota collaborated with our academic institution to recruit AA congregants into the pilot study. Field notes as well as communications between the study team and community partners were used to design the recruitment strategy and its implementation with a goal of enrolling 50 participants. At its core, the recruitment strategy included community kickoff events to detail the state-of-the-art nature of the mHealth intervention components, the utility of CV health assessments (physical examination, laboratory studies and surveys) and the participants' role in advancing our understanding of the efficacy of mHealth interventions among racial/ethnic minority groups. Detailed recruitment data were documented throughout the study. A self-administered, electronic survey measured sociodemographics, technology use and EHL (eHEALS scale). RESULTS: A total of 50 participants (70% women) from five AA churches were recruited over a one-month period. The majority (>90%) of participants reported using some form of mobile technology with all utilizing these technologies within their homes. Greater than half (60% [30/50]) reported being "very comfortable" with mobile technologies. Overall, participants had high EHL (84.8% [39/46] with eHEALS score >=26) with no differences by sex. CONCLUSIONS: This study illustrates the feasibility and success of a CBPR approach in recruiting AAs into mHealth intervention research and contributes to the growing body of evidence that AAs have high EHL, are high users of mobile technologies, and thus are likely to be receptive to mHealth interventions. PMID- 29386175 TI - The Effectiveness and Cost-Effectiveness of Web-Based and Home-Based Postnatal Psychoeducational Interventions for First-Time Mothers: Randomized Controlled Trial Protocol. AB - BACKGROUND: In addition to recuperating from the physical and emotional demands of childbirth, first-time mothers are met with demands of adapting to their social roles while picking up new skills to take care of their newborn. Mothers may not feel adequately prepared for parenthood if they are situated in an unsupported environment. Postnatal psychoeducational interventions have been shown to be useful and can offer a cost-effective solution for improving maternal outcomes. OBJECTIVE: The objective of this study was to examine the effectiveness and cost-effectiveness of Web-based and home-based postnatal psychoeducational programs for first-time mothers on maternal outcomes. METHODS: A randomized controlled three-group pre- and posttests experimental design is proposed. This study plans to recruit 204 first-time mothers on their day of discharge from a public tertiary hospital in Singapore. Eligible first-time mothers will be randomly allocated to either a Web-based psychoeducation group, a home-based psychoeducation group, or a control group receiving standard care. The outcomes include maternal parental self-efficacy, social support, psychological well-being (anxiety and postnatal depression), and cost evaluation. Data will be collected at baseline, 1 month, 3 months, and 6 months post-delivery. RESULTS: The recruitment (n=204) commenced in October 2016 and was completed in February 2017, with 68 mothers in each group. The 6-month follow-up data collection was completed in August 2017. CONCLUSIONS: This study may identify an effective and cost-effective Web-based postnatal psychoeducational program to improve first time mothers' health outcomes. The provision of a widely-accessed Web-based postnatal psychoeducational program will eventually lead to more positive postnatal experiences for first-time mothers and positively influence their future birth plans. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 45202278; http://www.isrctn.com/ISRCTN45202278 (Archived by WebCite at http://www.webcitation.org/6whx0pQ2F). PMID- 29386177 TI - Tim Spector: Go with your gut. PMID- 29386176 TI - The Effects of Social Presence on Adherence-Focused Guidance in Problematic Cannabis Users: Protocol for the CANreduce 2.0 Randomized Controlled Trial. AB - BACKGROUND: In European countries, including Switzerland, cannabis is the most commonly used illicit drug. Offering a Web-based self-help tool could potentially reach users who otherwise would not seek traditional help. However, such Web based self-help tools often suffer from low adherence. OBJECTIVE: Through adherence-focused guidance enhancements, the aim of this study was to increase adherence in cannabis users entering a Web-based self-help tool to reduce their cannabis use and, in this way, augment its effectiveness. METHODS: This paper presents the protocol for a three-arm randomized controlled trial (RCT) to compare the effectiveness of (1) an adherence-focused, guidance-enhanced, Web based self-help intervention with social presence; (2) an adherence-focused, guidance-enhanced, Web-based self-help intervention without social presence; and (3) a treatment-as-usual at reducing cannabis use in problematic users. The two active interventions, each spanning 6 weeks, consist of modules designed to reduce cannabis use and attenuate common mental disorder (CMD) symptoms, including depression, anxiety, and stress-related disorder symptoms based on the approaches of motivational interviewing and cognitive behavioral therapy. With a target sample size of 528, data will be collected at baseline, 6 weeks, and 3 months after baseline. The primary outcome measurement will be the number of days of cannabis use on the preceding 7 days. Secondary outcomes will include the quantity of cannabis used in standardized cannabis joints, the severity of cannabis dependence, changes in CMD symptoms, and adherence to the program. Data analysis will follow the intention-to-treat principle and employ (generalized) linear mixed models. RESULTS: The project commenced in August 2016; recruitment is anticipated to end by December 2018. First results are expected to be submitted for publication in summer 2019. CONCLUSIONS: This study will provide detailed insights on if and how the effectiveness of a Web-based self-help intervention aiming to reduce cannabis use in frequent cannabis users can be improved by theory-driven, adherence-focused guidance enhancement. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Registry: ISRCTN11086185; http://www.isrctn.com/ISRCTN11086185 (Archived by WebCite at http://www.webcitation.org/6wspbuQ1M). PMID- 29386178 TI - Turkish medical leaders are arrested after protesting against Syria incursion. PMID- 29386179 TI - Experts urge addition of folic acid to flour to halt "avoidable tragedy" of birth defects. PMID- 29386180 TI - Cross-sectional epidemiology of hearing loss in Australian children aged 11-12 years old and 25-year secular trends. AB - OBJECTIVE: In a national study of Australian children aged 11-12 years old, we examined the (1) prevalence and characteristics of hearing loss, (2) its demographic risk factors and (3) evidence for secular increases since 1990. METHODS: This is a cross-sectional CheckPoint wave within the Longitudinal Study of Australian Children. 1485 children (49.8% retention; 49.7% boys) underwent air conduction audiometry. Aim 1: hearing loss (>=16 decibels hearing level (dB HL)) was defined in four ways to enable prior/future comparisons: high Fletcher Index (mean of 1, 2 and 4 kHz; primary outcome relevant to speech perception), four frequency (1, 2, 4 and 8 kHz), lower frequency (1 and 2 kHz) and higher frequency (4 and 8 kHz); aim 2: logistic regression of hearing loss by age, gender and disadvantage index; and aim 3: P for trend examining CheckPoint and reported prevalence in studies arranged by date since 1990. RESULTS: For high Fletcher Index, the prevalence of bilateral and unilateral hearing loss >=16 dB HL was 9.3% and 13.3%, respectively. Slight losses (16-25 dB HL) were more prevalent than mild or greater (>=26 dB HL) losses (bilateral 8.5% vs 0.8%; unilateral 12.5% vs 0.9%), and lower frequency more prevalent than higher frequency losses (bilateral 11.0% vs 6.9%; unilateral 15.4% vs 11.5%). Demographic characteristics did not convincingly predict hearing loss. Prevalence of bilateral/unilateral lower and higher frequency losses >=16 dB HL has risen since 1990 (all P for trend <0.001). CONCLUSIONS AND RELEVANCE: Childhood hearing loss is prevalent and has risen since 1990. Future research should investigate the causes, course and impact of these changes. PMID- 29386182 TI - Migraine and risk of cardiovascular disease. PMID- 29386181 TI - Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. AB - OBJECTIVE: To examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort. DESIGN: Nationwide, population based cohort study. SETTING: All Danish hospitals and hospital outpatient clinics from 1995 to 2013. PARTICIPANTS: 51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year. MAIN OUTCOME MEASURES: Comorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis. RESULTS: Higher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 v 17 for myocardial infarction, 45 v 25 for ischaemic stroke, 11 v 6 for haemorrhagic stroke, 13 v 11 for peripheral artery disease, 27 v 18 for venous thromboembolism, 47 v 34 for atrial fibrillation or atrial flutter, and 19 v 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking. CONCLUSIONS: Migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases. PMID- 29386183 TI - Follow-up patterns and associated risk factors after paediatric cataract surgery: observation over a 5-year period. AB - PURPOSE: To study the pattern of compliance to follow-up of children less than 5 years of age undergoing surgery for congenital and developmental cataract over a period of 5 years. METHODS: It is a retrospective study of children less than 5 years of age undergoing cataract surgery between January and December 2010 for congenital or developmental cataract and followed up until 31 December 2015. Age, sex, distance from hospital and urban or rural habitat, delay in presentation, socioeconomic status, laterality, morphology and type of cataract, implantation of intraocular lens and interventions done were noted. Compliance to follow-up at postoperative 1 week, 1 month, 3 months, 6 months, 1 year and then once a year until 5 years were recorded. RESULTS: 169 patients were included in the study. The median follow-up was 22 months. Median age at surgery was 10 months and had a negative correlation with total follow-up. Male-to-female ratio was 1.82. Logarithmic curve of follow-up was noticed with 85%, 61%, 55%, 52%, 39% and 28% patients attending 1 month, 3 months, 6 months, 1 year, 3 years and 5 years of follow-up, respectively. Low socioeconomic group had poor follow-up compared with higher socioeconomic group (P=0.009), but the curve of follow-up was similar in both groups; multiple interventions group had better follow-up (P<0.0001). CONCLUSION: Curve of loss to follow-up is logarithmic in children undergoing paediatric cataract surgery. Age at surgery and low economic status are the most important factors associated with poor follow-up. PMID- 29386184 TI - LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response. AB - Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein alpha-subunit Galphai2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1alpha. HIF1alpha in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1alpha-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923-34. (c)2018 AACR. PMID- 29386185 TI - TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3. AB - Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792-804. (c)2018 AACR. PMID- 29386186 TI - NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses. AB - Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses. In this study, we investigated the role of CDK8 in NK-cell function in vivo using mice with conditional ablation of CDK8 in NKp46+ cells (Cdk8fl/flNcr1Cre). Regardless of CDK8 expression, NK cells develop and mature normally in bone marrow and spleen. However, CDK8 deletion increased expression of the lytic molecule perforin, which correlated with enhanced NK-cell cytotoxicity in vitro This translates into improved NK cell-mediated tumor surveillance in vivo in three independent models: B16F10 melanoma, v-abl+ lymphoma, and a slowly developing oncogene-driven leukemia. Our results thereby define a suppressive effect of CDK8 on NK-cell activity. Therapies that target CDK8 in cancer patients may enhance NK-cell responses against tumor cells. Cancer Immunol Res; 6(4); 458-66. (c)2018 AACR. PMID- 29386187 TI - Enhanced Redox State and Efficiency of Glucose Oxidation With miR Based Suppression of Maladaptive NADPH-Dependent Malic Enzyme 1 Expression in Hypertrophied Hearts. AB - RATIONALE: Metabolic remodeling in hypertrophic hearts includes inefficient glucose oxidation via increased anaplerosis fueled by pyruvate carboxylation. Pyruvate carboxylation to malate through elevated ME1 (malic enzyme 1) consumes NADPH necessary for reduction of glutathione and maintenance of intracellular redox state. OBJECTIVE: To elucidate upregulated ME1 as a potential maladaptive mechanism for inefficient glucose oxidation and compromised redox state in hypertrophied hearts. METHODS AND RESULTS: ME1 expression was selectively inhibited, in vivo, via non-native miR-ME1 (miRNA specific to ME1) in pressure overloaded rat hearts. Rats subjected to transverse aortic constriction (TAC) or Sham surgery received either miR-ME1 or PBS. Effects of ME1 suppression on anaplerosis and reduced glutathione (GSH) content were studied in isolated hearts supplied 13C-enriched substrate: palmitate, glucose, and lactate. Human myocardium collected from failing and nonfailing hearts during surgery enabled RT qPCR confirmation of elevated ME1 gene expression in clinical heart failure versus nonfailing human hearts (P<0.04). TAC induced elevated ME1 content, but ME1 was lowered in hearts infused with miR-ME1 versus PBS. Although Sham miR-ME1 hearts showed no further reduction of inherently low anaplerosis in normal heart, miR-ME1 reduced anaplerosis in TAC to baseline: TAC miR-ME1=0.034+/-0.004; TAC PBS=0.081+/-0.005 (P<0.01). Countering elevated anaplerosis in TAC shifted pyruvate toward oxidation in the tricarboxylic acid cycle. Importantly, via the link to NADPH consumption by pyruvate carboxylation, ME1 suppression in TAC restored GSH content, reduced lactate production, and ultimately improved contractility. CONCLUSIONS: A maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied rat hearts, which is also elevated in failing human hearts, reduced pyruvate carboxylation thereby normalizing anaplerosis, restoring GSH content, and reducing lactate accumulation. Reducing ME1 induced favorable metabolic shifts for carbohydrate oxidation, improving intracellular redox state and enhanced cardiac performance in pathological hypertrophy. PMID- 29386188 TI - Patient-Specific Computer Simulation to Elucidate the Role of Contact Pressure in the Development of New Conduction Abnormalities After Catheter-Based Implantation of a Self-Expanding Aortic Valve. AB - BACKGROUND: The extent to which pressure generated by the valve on the aortic root plays a role in the genesis of conduction abnormalities after transcatheter aortic valve replacement (TAVR) is unknown. This study elucidates the role of contact pressure and contact pressure area in the development of conduction abnormalities after TAVR using patient-specific computer simulations. METHODS AND RESULTS: Finite-element computer simulations were performed to simulate TAVR of 112 patients who had undergone TAVR with the self-expanding CoreValve/Evolut R valve. On the basis of preoperative multi-slice computed tomography, a patient specific region of the aortic root containing the atrioventricular conduction system was determined by identifying the membranous septum. Contact pressure and contact pressure index (percentage of area subjected to pressure) were quantified and compared in patients with and without new conduction abnormalities. Sixty-two patients (55%) developed a new left bundle branch block or a high-degree atrioventricular block after TAVR. Maximum contact pressure and contact pressure index (median [interquartile range]) were significantly higher in patients with compared with those without new conduction abnormalities (0.51 MPa [0.43-0.70 MPa] and 33% [22%-44%], respectively, versus 0.29 MPa [0.06-0.50 MPa] and 12% [1% 28%]). By multivariable regression analysis, only maximum contact pressure (odds ratio, 1.35; confidence interval, 1.1-1.7; P=0.01) and contact pressure index (odds ratio, 1.52; confidence interval, 1.1-2.1; P=0.01) were identified as independent predictors for conduction abnormalities, but not implantation depth. CONCLUSIONS: Patient-specific computer simulations revealed that maximum contact pressure and contact pressure index are both associated with new conduction abnormalities after CoreValve/Evolut R implantation and can predict which patient will have conduction abnormalities. PMID- 29386189 TI - Letter by Smilowitz Regarding Article, "Three-Vessel Assessment of Coronary Microvascular Dysfunction in Patients With Clinical Suspicion of Ischemia: Prospective Observational Study With the Index of Microcirculatory Resistance". PMID- 29386190 TI - Response by Kobayashi et al to Letter Regarding Article, "Three-Vessel Assessment of Coronary Microvascular Dysfunction in Patients with Clinical Suspicion of Ischemia: Prospective Observation Study With the Index of Microcirculatory Resistance". PMID- 29386191 TI - Retraction for Anderson et al., "Assembly of Minicellulosomes on the Surface of Bacillus subtilis". PMID- 29386192 TI - Cancer risk associated with chronic diseases and disease markers: prospective cohort study. AB - OBJECTIVES: To assess the independent and joint associations of major chronic diseases and disease markers with cancer risk and to explore the benefit of physical activity in reducing the cancer risk associated with chronic diseases and disease markers. DESIGN: Prospective cohort study. SETTING: Standard medical screening program in Taiwan. PARTICIPANTS: 405 878 participants, for whom cardiovascular disease markers (blood pressure, total cholesterol, and heart rate), diabetes, chronic kidney disease markers (proteinuria and glomerular filtration rate), pulmonary disease, and gouty arthritis marker (uric acid) were measured or diagnosed according to standard methods, were followed for an average of 8.7 years. MAIN OUTCOME MEASURES: Cancer incidence and cancer mortality. RESULTS: A statistically significantly increased risk of incident cancer was observed for the eight diseases and markers individually (except blood pressure and pulmonary disease), with adjusted hazard ratios ranging from 1.07 to 1.44. All eight diseases and markers were statistically significantly associated with risk of cancer death, with adjusted hazard ratios ranging from 1.12 to 1.70. Chronic disease risk scores summarizing the eight diseases and markers were positively associated with cancer risk in a dose-response manner, with the highest scores associated with a 2.21-fold (95% confidence interval 1.77-fold to 2.75-fold) and 4.00-fold (2.84-fold to 5.63-fold) higher cancer incidence and cancer mortality, respectively. High chronic disease risk scores were associated with substantial years of life lost, and the highest scores were associated with 13.3 years of life lost in men and 15.9 years of life lost in women. The population attributable fractions of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors combined (cancer incidence: 20.5% v 24.8%; cancer mortality: 38.9% v 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was attenuated by 48% for cancer incidence and 27% for cancer mortality. CONCLUSIONS: Chronic disease is an overlooked risk factor for cancer, as important as five major lifestyle factors combined. In this study, chronic diseases contributed to more than one fifth of the risk for incident cancer and more than one third of the risk for cancer death. Physical activity is associated with a nearly 40% reduction in the cancer risk associated with chronic diseases. PMID- 29386194 TI - Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kdelta inhibitors and VIP antagonists. AB - Adoptive therapy with ex vivo-expanded genetically modified antigen-specific T cells can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. Lower rates of ex vivo expansion and clinical response using anti-CD19 chimeric antigen receptor (CAR) T cells have been seen in heavily pretreated lymphoma patients compared with B-cell acute lymphoblastic leukemia patients and motivate the development of novel strategies to enhance ex vivo T cell expansion and their persistence in vivo. We demonstrate that inhibition of phosphatidylinositol 3-kinase delta (PI3Kdelta) and antagonism of vasoactive intestinal peptide (VIP) signaling partially inhibits the terminal differentiation of T cells during anti-CD3/CD28 bead-mediated expansion (mean, 54.4% CD27+CD28+ T cells vs 27.4% in control cultures; P < .05). This strategy results in a mean of 83.7% more T cells cultured from lymphoma patients in the presence of PI3Kdelta and VIP antagonists, increased survival of human T cells from a lymphoma patient in a murine xenograft model, enhanced cytotoxic activity of antigen-specific human CAR T cells and murine T cells against lymphoma, and increased transduction and expansion of anti-CD5 human CAR T cells. PI3Kdelta and VIP antagonist-expanded T cells from lymphoma patients show reduced terminal differentiation, enhanced polyfunctional cytokine expression, and preservation of costimulatory molecule expression. Taken together, synergistic blockade of these pathways is an attractive strategy to enhance the expansion and functional capacity of ex vivo-expanded cancer-specific T cells. PMID- 29386193 TI - BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor. AB - Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 371. PMID- 29386195 TI - Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. AB - A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. We previously reported a pilot study of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia (AML) patients. We have now conducted a phase 2 study investigating this vaccine in adults with AML in first complete remission (CR1). Patients received 6 vaccinations administered over 10 weeks with the potential to receive 6 additional monthly doses if they remained in CR1. Immune responses (IRs) were evaluated after the 6th and 12th vaccinations by CD4+ T-cell proliferation, CD8+ T-cell interferon-gamma secretion (enzyme-linked immunospot), or the CD8-relevant WT1 peptide major histocompatibility complex tetramer assay (HLA-A*02 patients only). Twenty-two patients (7 males; median age, 64 years) were treated. Fourteen patients (64%) completed >=6 vaccinations, and 9 (41%) received all 12 vaccine doses. Fifteen patients (68%) relapsed, and 10 (46%) died. The vaccine was well tolerated, with the most common toxicities being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%). Median disease-free survival from CR1 was 16.9 months, whereas the overall survival from diagnosis has not yet been reached but is estimated to be >=67.6 months. Nine of 14 tested patients (64%) had an IR in >=1 assay (CD4 or CD8). These results indicated that the WT1 vaccine was well tolerated, stimulated a specific IR, and was associated with survival in excess of 5 years in this cohort of patients. This trial was registered at www.clinicaltrials.gov as #NCT01266083. PMID- 29386196 TI - A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL. AB - In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737. PMID- 29386197 TI - Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis. AB - Growth differentiation factor-15 (GDF-15) improves prognostication in patients with cardiovascular disorders in addition to conventional cardiac markers (N terminal pro B-type natriuretic peptide [NT-proBNP], troponins [Tns]) and has shown prognostic value in patients with renal diseases. In patients with light chain (AL) amyloidosis, cardiac involvement is the major determinant of prognosis, and cardiac markers define prognosis, whereas biomarkers of renal involvement stratify renal risk. We explored the prognostic importance of serum level of GDF-15 in patients with AL amyloidosis in 2 independent cohorts. The prognostic value of GDF-15 level was initially evaluated in a cohort of 107 consecutive previously untreated patients with AL amyloidosis from Athens, Greece, and was then validated in a second cohort of 202 consecutive previously untreated patients from Pavia, Italy. High GDF-15 level was associated with a higher risk of early death and poor overall survival independently of NT-proBNP and high-sensitivity TnT (hsTnT) or hsTnI levels. At the 6-month landmark, reduction of GDF-15 level >=25% was associated with improved outcome. GDF-15 level >=4000 pg/mL was associated with a high risk of progression to dialysis, independently of renal risk defined by estimated glomerular filtration rate and proteinuria, in both cohorts; failure to reduce GDF-15 below this level was associated with increased risk at either the 3- or 6-month landmark, independently of the established renal response or progression criteria. In conclusion, GDF-15 has prognostic implications for different outcomes in patients with AL and adds prognostic information independent of that provided by cardiac and renal risk biomarkers. PMID- 29386198 TI - Effect of nonpermissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T-cell depletion. AB - We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression. PMID- 29386199 TI - David Oliver: Should NHS doctors work in unsafe conditions? PMID- 29386200 TI - Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. PMID- 29386201 TI - CD301b/MGL2+ Mononuclear Phagocytes Orchestrate Autoimmune Cardiac Valve Inflammation and Fibrosis. AB - BACKGROUND: Valvular heart disease is common and affects the mitral valve (MV) most frequently. Despite the prevalence of MV disease (MVD), the cellular and molecular pathways that initiate and perpetuate it are not well understood. METHODS: K/B.g7 T-cell receptor transgenic mice spontaneously develop systemic autoantibody-associated autoimmunity, leading to fully penetrant fibroinflammatory MVD and arthritis. We used multiparameter flow cytometry, intracellular cytokine staining, and immunofluorescent staining to characterize the cells in inflamed K/B.g7 MVs. We used genetic approaches to study the contribution of mononuclear phagocytes (MNPs) to MVD in this model. Specifically, we generated K/B.g7 mice in which either CX3CR1 or CD301b/macrophage galactose N acetylgalactosamine-specific lectin 2 (MGL2)-expressing MNPs were ablated. Using K/B.g7 mice expressing Cx3Cr1-Cre, we conditionally deleted critical inflammatory molecules from MNPs, including the Fc-receptor signal-transducing tyrosine kinase Syk and the cell adhesion molecule very late antigen-4. We performed complementary studies using monoclonal antibodies to block key inflammatory molecules. We generated bone marrow chimeric mice to define the origin of the inflammatory cells present in the MV and to determine which valve cells respond to the proinflammatory cytokine tumor necrosis factor (TNF). Finally, we examined specimens from patients with rheumatic heart disease to correlate our findings to human pathology. RESULTS: MNPs comprised the vast majority of MV-infiltrating cells; these MNPs expressed CX3CR1 and CD301b/MGL2. Analogous cells were present in human rheumatic heart disease valves. K/B.g7 mice lacking CX3CR1 or in which CD301b/MGL2-expressing MNPs were ablated were protected from MVD. The valve infiltrating CD301b/MGL2+ MNPs expressed tissue-reparative molecules including arginase-1 and resistin-like molecule alpha. These MNPs also expressed the proinflammatory cytokines TNF and interleukin-6, and antibody blockade of these cytokines prevented MVD. Deleting Syk from CX3CR1-expressing MNPs reduced their TNF and interleukin-6 production and also prevented MVD. TNF acted through TNF receptor-1 expressed on valve-resident cells to increase the expression of vascular cell adhesion molecule-1. Conditionally deleting the vascular cell adhesion molecule-1 ligand very late antigen-4 from CX3CR1-expressing MNPs prevented MVD. CONCLUSIONS: CD301b/MGL2+ MNPs are key drivers of autoimmune MVD in K/B.g7 mice and are also present in human rheumatic heart disease. We define key inflammatory molecules that drive MVD in this model, including Syk, TNF, interleukin-6, very late antigen-4, and vascular cell adhesion molecule-1. PMID- 29386202 TI - Six-Year Changes in Physical Activity and the Risk of Incident Heart Failure: ARIC Study. AB - BACKGROUND: Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown. METHODS: We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987 1989) and third ARIC visits and HF risk. RESULTS: During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ~30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96). CONCLUSIONS: Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF. PMID- 29386203 TI - Single-Cell Sequencing of the Healthy and Diseased Heart Reveals Cytoskeleton Associated Protein 4 as a New Modulator of Fibroblasts Activation. AB - BACKGROUND: Genome-wide transcriptome analysis has greatly advanced our understanding of the regulatory networks underlying basic cardiac biology and mechanisms driving disease. However, so far, the resolution of studying gene expression patterns in the adult heart has been limited to the level of extracts from whole tissues. The use of tissue homogenates inherently causes the loss of any information on cellular origin or cell type-specific changes in gene expression. Recent developments in RNA amplification strategies provide a unique opportunity to use small amounts of input RNA for genome-wide sequencing of single cells. METHODS: Here, we present a method to obtain high-quality RNA from digested cardiac tissue from adult mice for automated single-cell sequencing of both the healthy and diseased heart. RESULTS: After optimization, we were able to perform single-cell sequencing on adult cardiac tissue under both homeostatic conditions and after ischemic injury. Clustering analysis based on differential gene expression unveiled known and novel markers of all main cardiac cell types. Based on differential gene expression, we could identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cell subpopulations. As such, we identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlates with known myofibroblast markers in both mouse and human cardiac tissue. Cytoskeleton associated protein 4 inhibition in activated fibroblasts treated with transforming growth factor beta triggered a greater increase in the expression of genes related to activated fibroblasts compared with control, suggesting a role of cytoskeleton-associated protein 4 in modulating fibroblast activation in the injured heart. CONCLUSIONS: Single-cell sequencing on both the healthy and diseased adult heart allows us to study transcriptomic differences between cardiac cells, as well as cell type-specific changes in gene expression during cardiac disease. This new approach provides a wealth of novel insights into molecular changes that underlie the cellular processes relevant for cardiac biology and pathophysiology. Applying this technology could lead to the discovery of new therapeutic targets relevant for heart disease. PMID- 29386204 TI - Hospital Variation in Adherence Rates to Secondary Prevention Medications and the Implications on Quality. AB - BACKGROUND: Medication adherence is important to improve the long-term outcomes after acute myocardial infarction (MI). We hypothesized that there is significant variation among US hospitals in terms of medication adherence after MI, and that patients treated at hospitals with higher medication adherence after MI will have better long-term cardiovascular outcomes. METHODS: We identified 19 704 Medicare patients discharged after acute MI from 347 US hospitals participating in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines) from January 2, 2007, to October 1, 2010. Using linked Medicare Part D prescription filling data, medication adherence was defined as proportion of days covered >80% within 90 days after discharge. Cox proportional hazards modeling was used to compare 2-year major adverse cardiovascular events among hospitals with high, moderate, and low 90-day medication adherence. RESULTS: By 90 days after MI, overall rates of adherence to medications prescribed at discharge were 68% for beta-blockers, 63% for statins, 64% for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 72% for thienopyridines. Adherence to these medications up to 90 days varied significantly among hospitals: beta-blockers (proportion of days covered >80%; 59% to 75%), statins (55% to 69%), thienopyridines (64% to 77%), and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (57% to 69%). Compared with hospitals in the lowest quartile of 90-day composite medication adherence, hospitals with the highest adherence had lower unadjusted and adjusted 2-year major adverse cardiovascular event risk (27.5% versus 35.3%; adjusted hazard ratio, 0.88; 95% confidence interval, 0.80-0.96). High-adherence hospitals also had lower adjusted rates of death or readmission (hazard ratio, 0.90; 95% confidence interval, 0.85-0.96), whereas there was no difference in mortality after adjustment. CONCLUSIONS: Use of secondary prevention medications after discharge varies significantly among US hospitals and is inversely associated with 2-year outcomes. Hospitals may improve medication adherence after discharge and patient outcomes through better coordination of care between inpatient and outpatient settings. PMID- 29386206 TI - Targeting Germinal Matrix Hemorrhage-Induced Overexpression of Sodium-Coupled Bicarbonate Exchanger Reduces Posthemorrhagic Hydrocephalus Formation in Neonatal Rats. AB - BACKGROUND: Germinal matrix hemorrhage (GMH) is a leading cause of mortality and lifelong morbidity in preterm infants. Posthemorrhagic hydrocephalus (PHH) is a common complication of GMH. A sodium-coupled bicarbonate exchanger (NCBE) encoded by solute carrier family 4 member 10 gene is expressed on the choroid plexus basolateral membrane and may play a role in cerebrospinal fluid production and the development of PHH. Following GMH, iron degraded from hemoglobin has been linked to PHH. Choroid plexus epithelial cells also contain iron-responsive element-binding proteins (IRPs), IRP1, and IRP2 that bind to mRNA iron-responsive elements. The present study aims to resolve the following issues: (1) whether the expression of NCBE is regulated by IRPs; (2) whether NCBE regulates the formation of GMH-induced hydrocephalus; and (3) whether inhibition of NCBE reduces PHH development. METHODS AND RESULTS: GMH model was established in P7 rat pups by injecting bacterial collagenase into the right ganglionic eminence. Another group received iron trichloride injections instead of collagenase. Deferoxamine was administered intraperitoneally for 3 consecutive days after GMH/iron trichloride. Solute carrier family 4 member 10 small interfering RNA or scrambled small interfering RNA was administered by intracerebroventricular injection 24 hours before GMH and followed with an injection every 7 days over 21 days. NCBE expression increased while IRP2 expression decreased after GMH/iron trichloride. Deferoxamine ameliorated both the GMH-induced and iron trichloride-induced decrease of IRP2 and decreased NCBE expressions. Deferoxamine and solute carrier family 4 member 10 small interfering RNA improved cognitive and motor functions at 21 to 28 days post GMH and reduced cerebrospinal fluid production as well as the degree of hydrocephalus at 28 days after GMH. CONCLUSIONS: Targeting iron induced overexpression of NCBE may be a translatable therapeutic strategy for the treatment of PHH following GMH. PMID- 29386207 TI - Absence of July Phenomenon in Acute Ischemic Stroke Care Quality and Outcomes. AB - BACKGROUND: Lower care quality and an increase in adverse outcomes as a result of new medical trainees is a concept well rooted in popular belief, termed the "July phenomenon." Whether this phenomenon occurs in acute ischemic stroke has not been well studied. METHODS AND RESULTS: We analyzed data from patients admitted with ischemic stroke in 1625 hospitals participating in the Get With The Guidelines Stroke program for the 5-year period between January 2009 and December 2013. We compared acute stroke treatment processes and in-hospitals outcomes among the 4 quarters (first quarter: July-September, last quarter: April-June) of the academic year. Multivariable logistic regression models were used to evaluate the relationship between academic year transition and processes measures. A total of 967 891 patients were included in the study. There was a statistically significant, but modest (<4 minutes or 5 percentage points) difference in distribution of or quality and clinical metrics including door-to-computerized tomography time, door-to-needle time, the proportion of patients with symptomatic intracranial hemorrhage within 36 hours of admission, and the proportion of patients who received defect-free care in stroke performance measures among academic year quarters (P<0.0001). In multivariable analyses, there was no evidence that quarter 1 of the academic year was associated with lower quality of care or worse in-hospital outcomes in teaching and nonteaching hospitals. CONCLUSIONS: We found no evidence of the "July phenomenon" in patients with acute ischemic stroke among hospitals participating in the Get With The Guidelines Stroke program. PMID- 29386208 TI - Observation Versus Inpatient Stay for Heart Failure: Is It Semantics? PMID- 29386205 TI - Liver X Receptor-Binding DNA Motif Associated With Atherosclerosis-Specific DNA Methylation Profiles of Alu Elements and Neighboring CpG Islands. AB - BACKGROUND: The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription. METHODS AND RESULTS: We sought to functionally characterize the DMM. We showed that the DMM overlaps with the RNA polymerase III-binding B box of Alu short interspersed nuclear elements and contains a DR2 nuclear receptor response element. Pointing to a possible functional role for an Alu DMM, CGIs proximal (<100 bp) to near-intact DMM harboring Alu are significantly less methylated relative to CGIs proximal to degenerate DMM-harboring Alu or to DMM-devoid mammalian-wide interspersed repeat short interspersed nuclear elements in human arteries. As for DMM-binding factors, LXRB (liver X receptor beta) binds the DMM in a DR2-dependent fashion, and LXR (liver X receptor) agonists induce significant hypermethylation of the bulk of Alu in THP-1 cells. Furthermore, we describe 3 intergenic long noncoding RNAs that harbor a DMM, are under transcriptional control by LXR agonists, and are differentially expressed between normal and atherosclerotic human aortas. Notably, CGIs adjacent to those long noncoding RNAs tend to be hypomethylated in symptomatic relative to stable human atheromas. CONCLUSIONS: Collectively, the data suggest that a DMM is associated with 2 distinct methylation states: relatively low methylation of in cis CGIs and Alu element hypermethylation. Based on the known atheroprotective role of LXRs, we propose that LXR agonist-induced Alu hypermethylation, a landmark of atherosclerosis, is a compensatory rather than proatherogenic response. PMID- 29386209 TI - When a wound is the harbinger of a serious underlying systemic illness. AB - A 55-year-old woman presented with progressive enlarging and painful non-healing ulcers on her bilateral lower extremities; biopsy was consistent with pyoderma gangrenosum. Workup for an underlying illness revealed a cavitary lung nodule and an ulcerating mass in the anal canal. Patient did not have any respiratory or gastrointestinal symptoms. Differential diagnosis included inflammatory bowel disease, rectal carcinoma or infection such as tuberculosis, fungal process. Histopathology did not reveal any malignancy, inflammatory bowel disease or infection. Serological studies were positive for perinuclear antineutrophil antibodies specific to proteinase-3 antigen, and the patient was ultimately diagnosed with granulomatosis with polyangiitis. Intravenous pulse dose steroids were initiated followed by monthly pulse cyclophosphamide for 6 months, resulting in rapid and significant improvement of the wounds. PMID- 29386210 TI - Two patients with localised hyperhidrosis of the hand based on functional and structural abnormalities of sweat glands. AB - A 14-year-old girl and a 30-year-old woman presented with localised hyperhidrosis on the dorsal hand and wrist, respectively, provoked by different stimuli such as physical activity and minor trauma to the skin. The skin was seemingly normal in both patients where an iodine-starch test revealed a well-demarcated area of hyperhidrosis. Following histopathological examination, the diagnosis was unilateral localised hyperhidrosis in both cases; one with normal histology and one with a nevus sudoriferous. Both patients were successfully treated with botulinum toxin type A. The 30-year-old woman additionally used low-dose propantheline bromide periodically and experienced long-term remission on this therapy. Hyperhidrosis may embarrass and interfere with patients' school and careers, and it is therefore important to tailor an effective individual treatment. PMID- 29386212 TI - Effective uric acid reduction with probenecid and febuxostat in a patient with chronic kidney disease. AB - A 33-year-old male with poorly controlled chronic tophaceous gout and chronic kidney disease (CKD) with estimated glomerular filtration rate (GFR) of 37 cc/min. His uric acid was 11 mg/dL despite maximal dosing of febuxostat. He had previously failed pegloticase infusions as well. This patient had a reduction in his uric acid level to less than 6 mg/dL following addition of probenecid to his febuxostat regimen. Most guidelines recommend against utilisation of probenecid therapy in patients with GFR <50, but there is no obvious contraindication to its use, provided renal calculi do not develop. Our case illustrates the synergistic effect probenecid can add to maximal xanthine oxidase inhibitor therapy for patients with refractory hyperuricaemia in a patient with CKD stage IIIb. With the approval of a new uricosuric medication, lesinurad, probenecid may remain a suitable alternative for patients with financial limitations to achieve target uric acid levels. PMID- 29386211 TI - Neurofibromatosis type 1: a case highlighting pulmonary and other rare clinical manifestations. AB - Neurofibromatosis type 1 (NF1)-related lung disease is a rare but increasingly recognised, high morbidity associated feature of the condition. We present a 48 year-old male patient with NF1, who was initially admitted for a subarachnoid haemorrhage requiring aneurysmal coil embolisation. During his recovery, he developed a left-sided pneumothorax requiring chest tube placement followed by concerns for re-expansion pulmonary oedema requiring intubation. Subsequently, the patient also developed a right-sided pneumothorax requiring additional chest tube placement but did not develop right-sided pulmonary oedema. During his hospitalisation, the patient also exemplified other important NF1-related pathophysiology including pheochromocytoma, cerebrovascular abnormalities and cardiovascular manifestations. Due to his multiple comorbidities and poor prognosis, we held a goals of care discussion with the patient's mother, and with her agreement, the patient underwent compassionate withdrawal of artificial life support. PMID- 29386213 TI - Cisplatin-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) with life-threatening hyponatraemia. AB - We present a case of cisplatin-induced syndrome of inappropriate antidiuretic hormone (SIADH) in a patient with metastatic recurrent urothelial carcinoma. Cisplatin-induced SIADH is an uncommon but potentially life-threatening toxicity. Pharmacogenetic characteristics may result in different toxicity profiles in different populations. With such widespread use of cisplatin in a diverse range of cancers, prompt recognition is crucial to detect and prevent severe neurological sequelae. PMID- 29386214 TI - Antenatal chemotherapy in a case of diffuse large B-cell lymphoma. AB - A 28-year-old pregnant woman in the sixth month of gestation presented with complaints of altered bowel habit for a month, on examination found to have generalised lymphadenopathy, pedal oedema and locally infiltrating ano-rectal growth. Rectal growth biopsy was reported as high-grade B-cell lymphoma. After a discussion in a multidisciplinary panel consisting of haemato-oncologists, obstetricians and physicians, she was planned to receive antenatal chemotherapy. She delivered a live baby of 1.86 kg at 36 weeks of gestational age by normal vaginal delivery. After 6 cycles of chemotherapy she had complete regression of the disease. PMID- 29386215 TI - Tension pneumoperitoneum. AB - A 35-year-old man stopped breathing after injecting a large dose of heroin. He subsequently received cardiopulmonary resuscitation from friends. He arrived to accident and emergency department with Glasgow Coma Scale of 13. On examination, he had distended and tense abdomen. CT Thorax, Abdomen, and Pelvis confirmed massive tension pneumoperitoneum. A 14 Fr intravenous cannula was inserted through the umbilicus to relieve the intra-abdominal pressure. An emergency laparotomy showed petechia along the anterior gastric wall, haematoma of lesser omentum but showed no evidence of gastrointestinal perforation or organ injury. Air leak test performed by insufflating air into the stomach via nasogastric tube and abdomen filled with normal saline showed no leak. On-table oesophagogastroduodenoscopy showed mild oesophagitis and petechia of cardiac gastric mucosa. He was treated with intravenous antibiotics and discharged on the fifth postoperative day with adequate analgesia. PMID- 29386216 TI - High-dose steroids as a therapeutic option in the management of spur cell haemolytic anaemia. AB - Spur cell haemolytic anaemia (SCA) is a form of anaemia that can be seen in patients with severely impaired liver function or advanced cirrhosis. It is associated with high mortality. The treatment options for SCA secondary to cirrhosis are limited. Our patient is a middle-aged man who developed SCA and was not a candidate for liver transplantation or splenectomy. High-dose steroids helped ameliorate haemolysis and improve anaemia and general condition of our patient. PMID- 29386217 TI - Antitumor T-cell Reconditioning: Improving Metabolic Fitness for Optimal Cancer Immunotherapy. AB - With the rapid rise of immunotherapy for cancer treatment, attention has focused on gaining a better understanding of T-cell biology in the tumor microenvironment. Elucidating the factors underlying changes in their function will allow for the development of new therapeutic strategies that could expand the patient population benefiting from immunotherapy, as well as circumvent therapy resistance. Cancers go beyond avoiding immune recognition and inducing T cell dysfunction through coinhibitory molecules. Recent work has demonstrated that the tumor microenvironment elicits metabolic changes in T cells that dampen their ability to respond and that manipulating these metabolic changes can strengthen an antitumor immune response. Here we review the metabolic status of various types of T cells, the energetic state of the tumor microenvironment, and proposed modalities for improvement of immunotherapy through metabolic remodeling. Clin Cancer Res; 24(11); 2473-81. (c)2018 AACR. PMID- 29386218 TI - Long Noncoding RNA LINC01234 Functions as a Competing Endogenous RNA to Regulate CBFB Expression by Sponging miR-204-5p in Gastric Cancer. AB - Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer.Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings.Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor beta (CBFB).Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234-miR-204-5p-CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002-14. (c)2018 AACR. PMID- 29386219 TI - A Combination of SAHA and Quinacrine Is Effective in Inducing Cancer Cell Death in Upper Gastrointestinal Cancers. AB - Purpose: We aimed to investigate the therapeutic efficacy of single agent and the combination of quinacrine and suberoylanilide hydroxamic acid (SAHA) in wt- and mut-p53 upper gastrointestinal cancer (UGC) cell models.Experimental Design: ATP Glo, clonogenic cell survival, Annexin V, comet, DNA double-strand breaks (DSBs), qPCR, and Western blot analysis assays were utilized.Results: Using clonogenic cell survival, ATP-Glo cell viability, Annexin V, and sub-G0 population analysis, we demonstrated that a combination of quinacrine and SAHA significantly decreased colony formation and increased cancer cell death (range, 4-20 fold) in six UGC cell models, as compared with single-agent treatments, irrespective of the p53 status (P < 0.01). The combination of quinacrine and SAHA induced high levels of DSB DNA damage (>20-fold, P < 0.01). Western blot analysis showed activation of caspases-3, 9, and gamma-H2AX in all cell models. Of note, although quinacrine treatment induced expression of wt-p53 protein, the combination of quinacrine and SAHA substantially decreased the levels of both wt-P53 and mut-P53. Furthermore, cell models that were resistant to cisplatin (CDDP) or gefitinib treatments were sensitive to this combination. Tumor xenograft data confirmed that a combination of quinacrine and SAHA is more effective than a single-agent treatment in abrogating tumor growth in vivo (P < 0.01).Conclusions: Our novel findings show that the combination of quinacrine and SAHA promotes DNA damage and is effective in inducing cancer cell death, irrespective of p53 status and resistance to CDDP or gefitinib in UGC models. Clin Cancer Res; 24(8); 1905-16. (c)2018 AACR. PMID- 29386220 TI - Metastasis Seeding Cells: Lone Invaders or Mass Migrators? AB - Lymph node metastases are among the best predictors of recurrence and of cancer related death in early-stage colorectal cancers. Yet, despite their clinical and biological relevance, it remains elusive how lymph node metastases develop and whether metastatic seeding is a major bottleneck that restrains genetic heterogeneity of metastatic disease. Clin Cancer Res; 24(9); 2032-4. (c)2018 AACRSee related article by Ulintz et al., p. 2214. PMID- 29386221 TI - Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer. AB - Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivoConclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. (c)2018 AACR. PMID- 29386223 TI - Is the provision of paediatric oral liquid unlicensed medicines safe? PMID- 29386222 TI - Is palliative care support associated with better quality end-of-life care indicators for patients with advanced cancer? A retrospective cohort study. AB - OBJECTIVES: This study aimed to establish the association between timing and provision of palliative care (PC) and quality of end-of-life care indicators in a population of patients dying of cancer. SETTING: This study uses linked cancer patient data from the National Cancer Registry, the electronic medical record system used in primary care (SystmOne) and the electronic medical record system used within a specialist regional cancer centre. The population resided in a single city in Northern England. PARTICIPANTS: Retrospective data from 2479 adult cancer decedents who died between January 2010 and February 2012 were registered with a primary care provider using the SystmOne electronic health record system, and cancer was certified as a cause of death, were included in the study. RESULTS: Linkage yielded data on 2479 cancer decedents, with 64.5% who received at least one PC event. Decedents who received PC were significantly more likely to die in a hospice (39.4% vs 14.5%, P<0.005) and less likely to die in hospital (23.3% vs 40.1%, P<0.05), and were more likely to receive an opioid (53% vs 25.2%, P<0.001). PC initiated more than 2 weeks before death was associated with avoiding a hospital death (>=2 weeks, P<0.001), more than 4 weeks before death was associated with avoiding emergency hospital admissions and increased access to an opioid (>=4 weeks, P<0.001), and more than 33 weeks before death was associated with avoiding late chemotherapy (>=33 weeks, no chemotherapy P=0.019, chemotherapy over 4 weeks P=0.007). CONCLUSION: For decedents with advanced cancer, access to PC and longer duration of PC were significantly associated with better end-of-life quality indicators. PMID- 29386224 TI - Intricate but tight coupling of spiracular activity and abdominal ventilation during locust discontinuous gas exchange cycles. AB - Discontinuous gas exchange (DGE) is the best studied among insect gas exchange patterns. DGE cycles comprise three phases, which are defined by their spiracular state: closed, flutter and open. However, spiracle status has rarely been monitored directly; rather, it is often assumed based on CO2 emission traces. In this study, we directly recorded electromyogram (EMG) signals from the closer muscle of the second thoracic spiracle and from abdominal ventilation muscles in a fully intact locust during DGE. Muscular activity was monitored simultaneously with CO2 emission, under normoxia and under various experimental oxic conditions. Our findings indicate that locust DGE does not correspond well with the commonly described three-phase cycle. We describe unique DGE-related ventilation motor patterns, coupled to spiracular activity. During the open phase, when CO2 emission rate is highest, the thoracic spiracles do not remain open; rather, they open and close rapidly. This fast spiracle activity coincides with in-phase abdominal ventilation, while alternating with the abdominal spiracle and thus facilitating a unidirectional air flow along the main trachea. A change in the frequency of rhythmic ventilation during the open phase suggests modulation by intra-tracheal CO2 levels. A second, slow ventilatory movement pattern probably serves to facilitate gas diffusion during spiracle closure. Two flutter-like patterns are described in association with the different types of ventilatory activity. We offer a modified mechanistic model for DGE in actively ventilating insects, incorporating ventilatory behavior and changes in spiracle state. PMID- 29386225 TI - PDGF-BB Carried by Endothelial Cell-Derived Extracellular Vesicles Reduces Vascular Smooth Muscle Cell Apoptosis in Diabetes. AB - Endothelial cell-derived extracellular vesicles (CD31EVs) constitute a new entity for therapeutic/prognostic purposes. The roles of CD31EVs as mediators of vascular smooth muscle cell (VSMC) dysfunction in type 2 diabetes (T2D) are investigated herein. We demonstrated that, unlike serum-derived extracellular vesicles in individuals without diabetes, those in individuals with diabetes (D CD31EVs) boosted apoptosis resistance of VSMCs cultured in hyperglycemic condition. Biochemical analysis revealed that this effect relies on changes in the balance between antiapoptotic and proapoptotic signals: increase of bcl-2 and decrease of bak/bax. D CD31EV cargo analysis demonstrated that D CD31EVs are enriched in membrane-bound platelet-derived growth factor-BB (mbPDGF-BB). Thus, we postulated that mbPDGF-BB transfer by D CD31EVs could account for VSMC resistance to apoptosis. By depleting CD31EVs of platelet-derived growth factor BB (PDGF-BB) or blocking the PDGF receptor beta on VSMCs, we demonstrated that mbPDGF-BB contributes to D CD31EV-mediated bak/bax and bcl-2 levels. Moreover, we found that bak expression is under the control of PDGF-BB-mediated microRNA (miR) 296-5p expression. In fact, while PDGF-BB treatment recapitulated D CD31EV mediated antiapoptotic program and VSMC resistance to apoptosis, PDGF-BB-depleted CD31EVs failed. D CD31EVs also increased VSMC migration and recruitment to neovessels by means of PDGF-BB. Finally, we found that VSMCs, from human atherosclerotic arteries of individuals with T2D, express low bak/bax and high bcl-2 and miR-296-5p levels. This study identifies the mbPDGF-BB in D CD31EVs as a relevant mediator of diabetes-associated VSMC resistance to apoptosis. PMID- 29386226 TI - Stac3 enhances expression of human CaV1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels. AB - Mutations of CaV1.1, the pore-forming subunit of the L-type Ca2+ channel in skeletal muscle, are an established cause of hypokalemic periodic paralysis (HypoPP). However, functional assessment of HypoPP mutant channels has been hampered by difficulties in achieving sufficient plasma membrane expression in cells that are not of muscle origin. In this study, we show that coexpression of Stac3 dramatically increases the expression of human CaV1.1 (plus alpha2-delta1b and beta1a subunits) at the plasma membrane of Xenopus laevis oocytes. In voltage clamp studies with the cut-open oocyte clamp, we observe ionic currents on the order of 1 MUA and gating charge displacements of ~0.5-1 nC. Importantly, this high expression level is sufficient to ascertain whether HypoPP mutant channels are leaky because of missense mutations at arginine residues in S4 segments of the voltage sensor domains. We show that R528H and R528G in S4 of domain II both support gating pore currents, but unlike other R/H HypoPP mutations, R528H does not conduct protons. Stac3-enhanced membrane expression of CaV1.1 in oocytes increases the throughput for functional studies of disease-associated mutations and is a new platform for investigating the voltage-dependent properties of CaV1.1 without the complexity of the transverse tubule network in skeletal muscle. PMID- 29386227 TI - Role of 11beta-HSD type 1 in abnormal HPA axis activity during immune-mediated arthritis. AB - Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme. 11beta-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11beta-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11beta-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11beta-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11beta-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis. PMID- 29386228 TI - Disorders of sex development: a study of 194 cases. AB - OBJECTIVE: To study the clinical profile and the management of patients with disorders of sex development (DSD). DESIGN AND SETTING: Retrospective study from a tertiary care hospital of North India. METHODS AND PATIENTS: One hundred ninety four patients of DSD registered in the Endocrine clinic of Postgraduate Institute of Medical Education and Research, Chandigarh between 1995 and 2014 were included. RESULTS: One hundred and two patients (52.5%) had 46,XY DSD and seventy four patients (38.1%) had 46,XX DSD. Sex chromosome DSD was identified in seven (3.6%) patients. Of 102 patients with 46,XY DSD, 32 (31.4%) had androgen insensitivity syndrome and 26 (25.5%) had androgen biosynthetic defect. Of the 74 patients with 46,XX DSD, 52 (70.27%) had congenital adrenal hyperplasia (CAH) and eight (10.8%) had ovotesticular DSD. Five patients with sex chromosome DSD had mixed gonadal dysgenesis. Excluding CAH, majority of the patients (90%) presented in the post-pubertal period. One-fourth of the patients with simple virilising CAH were reared as males because of strong male gender identity and behaviour and firm insistence by the parents. Corrective surgeries were performed in twenty patients (20%) of 46,XY DSD without hormonal evaluation prior to the presentation. CONCLUSION: Congenital adrenal hyperplasia is the most common DSD in the present series. Most common XY DSD is androgen insensitivity syndrome, while CAH is the most common XX DSD. Delayed diagnosis is a common feature, and corrective surgeries are performed without seeking a definite diagnosis. PMID- 29386230 TI - Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course. AB - The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same RET proto-oncogene mutation carriers but also among sporadic MTC patients with no RET germinal mutations, which suggests the involvement of additional modulators of the disease. However, genetic factors responsible for this heterogeneity of the MTC clinical course still remain unknown. The aim of this study was to determine if polymorphic variants or specific haplotypes of the RET gene may modify the MTC clinical course. We genotyped the following loci: c.73+9277T>C, c.135G>A, c.1296A>G, c.2071G>A, c.2307T>C, c.2508C>T and c.2712C>G in 142 MTC patients and controls. We demonstrated considerable differences in the genotypes distribution within c.73+9277T>C, c.135G>A and c.2307T>C loci Our results show that the c.73+9277T variant associated with a decreased activity of the MCS+9.7 RET enhancer is rare in hereditary MTC patients with primary hyperparathyroidism, and thus, may influence the MTC clinical picture. The decreased activity of the RET promoter enhancer reduces RET expression level and may counterbalance the activating mutation in this gene. Frequent co-occurrence of the c.73+9277T allele with p.E768D, p.Y791F, p.V804M or p.R844Q RET mutations may be associated with their attenuation and milder clinical picture of the disease. Haplotypes analysis showed that C-G-A-G-T-(C)-C (c.73+9277T>C - c.135G>A - c.1296A>G - c.2071G>A - c.2307T>G - (c.2508C>T) - c.2712C>G) alleles combination predisposes to pheochromocytomas and primary hyperparathyroidism. We consider that RET haplotypes defining may become an auxiliary diagnostic tool in MTC patients. PMID- 29386229 TI - The comprehensive impact on human body induced by resolution of growth hormone excess. AB - CONTEXT: Chronic excess of growth hormone (GH) often leads to systemic complications. The reversibility of these complications after GH resolution is not fully understood. OBJECTIVE: To investigate when and to what extent will the comorbidities be ameliorated. DESIGN: We conducted a prospective study comprising 24 patients with acromegaly, who achieved remission after transsphenoidal surgery. The dynamic changes of endocrine, cardiovascular, respiratory, sleep, bone and morphology parameters were evaluated at enrollment and 1 week, 1 month, 3 months, 6 months and 12 months after surgery. RESULTS: Random GH dropped by 98.4% at the first day postoperatively. IGF-I index dropped by 50% and 64% at 1 week and 1 month respectively and remained unchanged onwards. Glucose metabolism improved significantly at 1 week and stabilized at 1 month. Testosterone in male patients recovered to normal range since 1 month. Systolic blood pressures dropped markedly at 3 months while diastolic blood pressures fell mildly at later visits. Abnormal lung function showed no improvement. The decrease of bone formation and resorption markers occurred at 1 week and 3 months, respectively. At 1 month, the tongue area declined while the airway volume increased significantly, accompanied with improved obstructive sleep apnea syndrome. Extremities, lips and nasal ala became smaller since 1 week. Liver, kidney and spleen volumes declined by 6.4, 15.9, 9.2%, respectively at 1 month. The volumes of pancreas and adrenal showed no change. CONCLUSIONS: The rapid resolution of excessive GH led to the reversible changes of systemic comorbidities in a time dependent and organ-specific manner. PMID- 29386231 TI - Atypical chemokine receptor 4 shapes activated B cell fate. AB - Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate. PMID- 29386232 TI - Interindividual Regulation of the Breast Cancer Resistance Protein/ABCG2 Transporter in Term Human Placentas. AB - The breast cancer resistance protein (BCRP/ABCG2) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. In this study, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex-branched DNA analysis. BCRP expression and ABCG2 genotypes were determined using Western blot and Fluidigm Biomark genetic analysis, respectively. Placentas were obtained from a racially and ethnically diverse population, including Caucasian (33%), African American (14%), Asian (14%), Hispanic (15%), and mixed (16%) backgrounds, as well as unknown origins (7%). Between placentas, BCRP mRNA and protein varied up to 47-fold and 14-fold, respectively. In particular, BCRP mRNA correlated significantly with known transcription factor mRNAs, including nuclear factor erythroid 2-related factor 2 and aryl hydrocarbon receptor. Somewhat surprisingly, single-nucleotide polymorphisms (SNPs) in the ABCG2 noncoding regions were not associated with variation in placental BCRP mRNA or protein. Instead, the coding region polymorphism (C421A/Q141K) corresponded with 40%-50% lower BCRP protein in 421C/A and 421A/A placentas compared with wild types (421C/C). Although BCRP protein and mRNA expression weakly correlated (r = 0.25, P = 0.040), this relationship was absent in individuals expressing the C421A variant allele. Study results contribute to our understanding of the interindividual regulation of BCRP expression in term placentas and may help to identify infants at risk for increased fetal exposure to chemicals due to low expression of this efflux protein. PMID- 29386233 TI - LC-MS Differential Analysis for Fast and Sensitive Determination of Biotransformation of Therapeutic Proteins. AB - Therapeutic biologics have become a fast-growing segment within the pharmaceutical industry during the past 3 decades. Although the metabolism of biologics is more predictable than small molecule drugs, biotransformation can significantly affect the activity of biologics. Unfortunately, there are only a limited number of published studies on the biotransformation of biologics, most of which are focused on one or a few types of modifications. In this study, an untargeted LC-MS-based differential analysis approach was developed to rapidly and precisely determine the universal biotransformation profile of biologics with the assistance of bioinformatic tools. A human monoclonal antibody (mAb) was treated with t-butyl hydroperoxide and compared with control mAb using a bottom up proteomics approach. Thirty-seven types of post-translational modifications were identified, and 38 peptides were significantly changed. Moreover, although all modifications were screened and detected, only the ones related to the treatment process were revealed by differential analysis. Other modifications that coexist in both groups were filtered out. This novel analytical strategy can be effectively applied to study biotransformation-mediated protein modifications, which will streamline the process of biologic drug discovery and development. PMID- 29386237 TI - The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. AB - It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the Ar gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50-80% lower than wild-type (WT) and 75-90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function. PMID- 29386238 TI - Authors' Response. PMID- 29386236 TI - The Ewing Sarcoma Secretome and Its Response to Activation of Wnt/beta-catenin Signaling. AB - Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta-catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells up-regulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression. PMID- 29386239 TI - Fulminant Nocardiosis Due to a Multidrug-Resistant Isolate in a 12-Year-Old Immunocompetent Child. AB - Nocardiosis is a rare cause of infection that usually affects immunocompromised adult patients and might not be recognized by pediatricians. We report a fatal case of disseminated nocardiosis in a previously healthy child initially admitted for an abdominal mass with suspicion of a renal malignant tumor. The patient, originating from Mali without any medical history, displayed abdominal pain with progressive altered general status. Laboratory and imaging findings revealed lymphocytic meningitis and disseminated abscesses in the brain and the cerebellum and a large number of cystic lesions of the kidney. Despite being administered wide-spectrum antibiotics and antituberculous and antifungal therapies with an external ventricular drainage for intracranial hypertension, the patient died 6 days after his admission. Nocardia spp was cultured from a renal biopsy and the cerebrospinal fluid. Species identification and antibiotic susceptibility were obtained later, revealing a multidrug-resistant isolate of the Nocardia elegans/aobensis/africana complex. This case reveals the difficulties of diagnosing nocardiosis, in particular in children not known to be immunocompromised, because we face multiple differential diagnoses and the importance of treating nocardiosis appropriately because of intrinsic resistance issues. PMID- 29386234 TI - Practice Guidelines for Clinical Microbiology Laboratories: Mycobacteria. AB - Mycobacteria are the causative organisms for diseases such as tuberculosis (TB), leprosy, Buruli ulcer, and pulmonary nontuberculous mycobacterial disease, to name the most important ones. In 2015, globally, almost 10 million people developed TB, and almost half a million patients suffered from its multidrug resistant form. In 2016, a total of 9,287 new TB cases were reported in the United States. In 2015, there were 174,608 new case of leprosy worldwide. India, Brazil, and Indonesia reported the most leprosy cases. In 2015, the World Health Organization reported 2,037 new cases of Buruli ulcer, with most cases being reported in Africa. Pulmonary nontuberculous mycobacterial disease is an emerging public health challenge. The U.S. National Institutes of Health reported an increase from 20 to 47 cases/100,000 persons (or 8.2% per year) of pulmonary nontuberculous mycobacterial disease among adults aged 65 years or older throughout the United States, with 181,037 national annual cases estimated in 2014. This review describes contemporary methods for the laboratory diagnosis of mycobacterial diseases. Furthermore, the review considers the ever-changing health care delivery system and stresses the laboratory's need to adjust and embrace molecular technologies to provide shorter turnaround times and a higher quality of care for the patients who we serve. PMID- 29386240 TI - These Findings Are Not Consistent With National Data. PMID- 29386241 TI - Kassa H, Moon RY, Colvin JD. Risk Factors for Sleep-Related Infant Deaths in In Home and Out-of-Home Settings. Pediatrics. 2016;138(5):e20161124. PMID- 29386242 TI - Breuner CC, Levine DA; AAP Committee on Adolescence. Adolescent and Young Adult Tattooing, Piercing, and Scarification. Pediatrics. 2017;140(4):e20171962. PMID- 29386243 TI - Boppana SB, Fowler KB. Insight Into Long-term Neurodevelopmental Outcomes in Asymptomatic Congenital CMV Infection. Pediatrics. 2017;140(5):e20172526. PMID- 29386235 TI - An Update on Host-Pathogen Interplay and Modulation of Immune Responses during Orientia tsutsugamushi Infection. AB - The obligate intracellular bacterium Orientia tsutsugamushi is the causative agent of scrub typhus in humans, a serious mite-borne disease present in a widespread area of endemicity, which affects an estimated 1 million people every year. This disease may exhibit a broad range of presentations, ranging from asymptomatic to fatal conditions, with the latter being due to disseminated endothelial infection and organ injury. Unique characteristics of the biology and host-pathogen interactions of O. tsutsugamushi, including the high antigenic diversity among strains and the highly variable, short-lived memory responses developed by the host, underlie difficulties faced in the pursuit of an effective vaccine, which is an imperative need. Other factors that have hindered scientific progress relative to the infectious mechanisms of and the immune response triggered by this bacterium in vertebrate hosts include the limited number of mechanistic studies performed on animal models and the lack of genetic tools currently available for this pathogen. However, recent advances in animal model development are promising to improve our understanding of host-pathogen interactions. Here, we comprehensively discuss the recent advances in and future perspectives on host-pathogen interactions and the modulation of immune responses related to this reemerging disease, highlighting the role of animal models. PMID- 29386245 TI - Genome and epigenome engineering CRISPR toolkit for in vivo modulation of cis regulatory interactions and gene expression in the chicken embryo. AB - CRISPR/Cas9 genome engineering has revolutionised all aspects of biological research, with epigenome engineering transforming gene regulation studies. Here, we present an optimised, adaptable toolkit enabling genome and epigenome engineering in the chicken embryo, and demonstrate its utility by probing gene regulatory interactions mediated by neural crest enhancers. First, we optimise novel efficient guide-RNA mini expression vectors utilising chick U6 promoters, provide a strategy for rapid somatic gene knockout and establish a protocol for evaluation of mutational penetrance by targeted next-generation sequencing. We show that CRISPR/Cas9-mediated disruption of transcription factors causes a reduction in their cognate enhancer-driven reporter activity. Next, we assess endogenous enhancer function using both enhancer deletion and nuclease-deficient Cas9 (dCas9) effector fusions to modulate enhancer chromatin landscape, thus providing the first report of epigenome engineering in a developing embryo. Finally, we use the synergistic activation mediator (SAM) system to activate an endogenous target promoter. The novel genome and epigenome engineering toolkit developed here enables manipulation of endogenous gene expression and enhancer activity in chicken embryos, facilitating high-resolution analysis of gene regulatory interactions in vivo. PMID- 29386247 TI - The role of the AR/ER ratio in ER-positive breast cancer patients. AB - The significance of androgen receptor (AR) in breast cancer (BC) management is not fully defined, and it is still ambiguous how the level of AR expression influences oestrogen receptor-positive (ER+) tumours. The aim of the present study was to analyse the prognostic impact of AR/ER ratio, evaluated by immunohistochemistry (IHC), correlating this value with clinical, pathological and molecular characteristics. We retrospectively selected a cohort of 402 ER+BC patients. On each tumour, IHC analyses for AR, ER, PgR, HER2 and Ki67 were performed and AR+ cases were used to calculate the AR/ER value. A cut-off of >=2 was selected using receiver-operating characteristic (ROC) curve analyses. RNA from 19 cases with AR/ER>=2 was extracted and used for Prosigna-PAM50 assays. Tumours with AR/ER>=2 (6%) showed more frequent metastatic lymph nodes, larger size, higher histological grade and lower PgR levels than cases with AR/ER<2. Multivariate analysis confirmed that patients with AR/ER>=2 had worse disease free interval (DFI) and disease-specific survival (DSS) (hazard ratios (HR) = 4.96 for DFI and HR = 8.69 for DSS, both P <= 0.004). According to the Prosigna PAM50 assay, 63% (12/19) of these cases resulted in intermediate or high risk of recurrence categories. Additionally, although all samples were positive for ER assessed by IHC, the molecular test assigned 47.4% (9/19) of BCs to intrinsic non luminal subtypes. In conclusion, the AR/ER ratio >=2 identifies a subgroup of patients with aggressive biological features and may represent an additional independent marker of worse BC prognosis. Moreover, the Prosigna-PAM50 results indicate that a significant number of cases with AR/ER>=2 could be non-luminal tumours. PMID- 29386246 TI - beta-Catenin signaling is essential for mammalian larynx recanalization and the establishment of vocal fold progenitor cells. AB - Congenital laryngeal webs result from failure of vocal fold separation during development in utero Infants present with life-threatening respiratory problems at birth, and extensive lifelong difficulties in breathing and voicing. The molecular mechanisms that instruct vocal fold formation are rarely studied. Here, we show, for the first time, that conditional inactivation of the gene encoding beta-catenin in the primitive laryngopharyngeal epithelium leads to failure in separation of the vocal folds, which approximates the gross phenotype of laryngeal webbing. These defects can be traced to a series of morphogenesis defects, including delayed fusion of the epithelial lamina and formation of the laryngeal cecum, failed separation of the larynx and esophagus with reduced and disorganized cartilages and muscles. Parallel to these morphogenesis defects, inactivation of beta-catenin disrupts stratification of epithelial cells and establishment of p63+ basal progenitors. These findings provide the first line of evidence that links beta-catenin function to the cell proliferation and progenitor establishment during larynx and vocal fold development. PMID- 29386244 TI - In vivo imaging of emerging endocrine cells reveals a requirement for PI3K regulated motility in pancreatic islet morphogenesis. AB - The three-dimensional architecture of the pancreatic islet is integral to beta cell function, but the process of islet formation remains poorly understood due to the difficulties of imaging internal organs with cellular resolution. Within transparent zebrafish larvae, the developing pancreas is relatively superficial and thus amenable to live imaging approaches. We performed in vivo time-lapse and longitudinal imaging studies to follow islet development, visualizing both naturally occurring islet cells and cells arising with an accelerated timecourse following an induction approach. These studies revealed previously unappreciated fine dynamic protrusions projecting between neighboring and distant endocrine cells. Using pharmacological compound and toxin interference approaches, and single-cell analysis of morphology and cell dynamics, we determined that endocrine cell motility is regulated by phosphoinositide 3-kinase (PI3K) and G protein-coupled receptor (GPCR) signaling. Linking cell dynamics to islet formation, perturbation of protrusion formation disrupted endocrine cell coalescence, and correlated with decreased islet cell differentiation. These studies identified novel cell behaviors contributing to islet morphogenesis, and suggest a model in which dynamic exploratory filopodia establish cell-cell contacts that subsequently promote cell clustering. PMID- 29386248 TI - Trends in Hospital Admission for Diabetic Ketoacidosis in Adults With Type 1 and Type 2 Diabetes in England, 1998-2013: A Retrospective Cohort Study. AB - OBJECTIVE: This study determined trends in hospital admission for diabetic ketoacidosis (DKA) in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) from 1998 to 2013 in England. RESEARCH DESIGN AND METHODS: The study population included 23,246 adults with T1DM and 241,441 adults with T2DM from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). All hospital admissions for DKA as the primary diagnosis from 1998 to 2013 were identified. Trends in hospital admission for DKA in incidence, length of hospital stay, 30-day all-cause readmission rate, and 30 day and 1-year all-cause mortality rates were determined using joinpoint regression, negative binomial regression, and logistic regression models. RESULTS: For T1DM, the incidence of hospital admission for DKA increased between 1998 and 2007 and remained static until 2013. The incidence in 2013 was higher than that in 1998 (incidence rate ratio 1.53 [95% CI 1.09-2.16]). For T2DM, the incidence increased 4.24% (2.82-5.69) annually between 1998 and 2013. The length of hospital stay decreased over time for both diabetes types (P <= 0.0004). Adults with T1DM were more likely to be discharged within 2 days compared with adults with T2DM (odds ratio [OR] 1.28 [1.07-1.53]). The 30-day readmission rate was higher in T1DM than in T2DM (OR 1.61 [1.04-2.50]) but remained unchanged for both diabetes types over time. Trends in 30-day and 1-year all-cause mortality rates were also stable, with no difference by diabetes type. CONCLUSIONS: In the previous two decades in England, hospitalization for DKA increased in adults with T1DM and in those with T2DM, and associated health care performance did not improve except decreased length of hospital stay. PMID- 29386249 TI - Precision Medicine in Type 2 Diabetes: Clinical Markers of Insulin Resistance Are Associated With Altered Short- and Long-term Glycemic Response to DPP-4 Inhibitor Therapy. AB - OBJECTIVE: A precision approach to type 2 diabetes therapy would aim to target treatment according to patient characteristics. We examined if measures of insulin resistance and secretion were associated with glycemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy. RESEARCH DESIGN AND METHODS: We evaluated whether markers of insulin resistance and insulin secretion were associated with 6-month glycemic response in a prospective study of noninsulin treated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents [PRIBA] study; n = 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink [CPRD]; n = 23,001). In CPRD, we evaluated associations between baseline markers and 3-year durability of response. To test the specificity of findings, we repeated analyses for glucagon-like peptide 1 (GLP-1) receptor agonists (PRIBA, n = 339; CPRD, n = 4,464). RESULTS: In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [P = 0.03], HOMA2 insulin resistance [P = 0.01], and triglycerides [P < 0.01]) were associated with reduced 6-month HbA1c response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA1c response (both P < 0.01). A subgroup defined by obesity (BMI >=30 kg/m2) and high triglycerides (>=2.3 mmol/L) had reduced 6 month response in both data sets (PRIBA HbA1c reduction 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and normal triglycerides]; P = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; P < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists. CONCLUSIONS: Markers of higher insulin resistance are consistently associated with reduced glycemic response to DPP-4 inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP-4 inhibitor therapy. PMID- 29386251 TI - Use of radiography in small animal practice in the UK and Republic of Ireland in 2013. AB - Radiography is an essential diagnostic tool in small animal practice. A major transition is currently underway from film screen to digital systems. However, there is limited published research detailing the use of radiography in practices in the UK and Republic of Ireland (ROI). The study aimed to describe the uptake of digital radiographic systems, wider aspects of radiographic practice and use of other diagnostic imaging techniques in the UK and ROI. This is a cross sectional study using paper and online questionnaires. Veterinary surgeons, veterinary nurses and veterinary radiographers working in small animal practice in the UK and ROI were eligible to participate in the survey. Seventy-five per cent of respondents worked in practices using digital radiography systems. Cost appeared to be the largest barrier to digital conversion. Chemical restraint was used on 86 per cent of cases; however, 3 per cent of cases were reported to be restrained by hand. Thirty-one per cent of respondents had not received specific training in radiation safety. Ultrasonography is reportedly now widely utilised on a regular basis. These results provide useful information on the use of radiography and additional diagnostic imaging techniques in the UK. These results should be used to indicate future training requirements, particularly to improve radiation safety. PMID- 29386250 TI - Differential Association of Microvascular Attributions With Cardiovascular Disease in Patients With Long Duration of Type 1 Diabetes. AB - OBJECTIVE: Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland. RESEARCH DESIGN AND METHODS: This cross-sectional study characterized U.S. residents (n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort (n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression. RESULTS: CVD prevalence in the Medalists with CKD and without PDR (+CKD/-PDR) (n = 30) and CVD prevalence in the -CKD/+PDR group (n = 339) were half the prevalence in the +CKD/+PDR group (n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08-0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/-PDR group (n = 21) compared with the +CKD/+PDR group (n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed. CONCLUSIONS: Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist. PMID- 29386253 TI - Deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson's disease: a randomised blinded evaluation. AB - BACKGROUND: Several open-label studies have shown good effect of deep brain stimulation (DBS) in the caudal zona incerta (cZi) on tremor, including parkinsonian tremor, and in some cases also a benefit on akinesia and axial symptoms. The aim of this study was to evaluate objectively the effect of cZi DBS in patients with Parkinson's disease (PD). METHOD: 25 patients with PD were randomised to either cZi DBS or best medical treatment. The primary outcomes were differences between the groups in the motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS-III) rated single-blindly at 6 months and differences in the Parkinson's Disease Questionnaire 39 items (PDQ-39). 19 patients, 10 in the medical arm and 9 in the DBS arm, fulfilled the study. RESULTS: The DBS group had 41% better UPDRS-III scores off-medication on-stimulation compared with baseline, whereas the scores of the non-surgical patients off-medication were unchanged. In the on-medication condition, there were no differences between the groups, neither at baseline nor at 6 months. Subitems of the UPDRS-III showed a robust effect of cZi DBS on tremor. The PDQ-39 domains 'stigma' and 'ADL' improved only in the DBS group. The PDQ-39 summary index improved in both groups. CONCLUSION: This is the first randomised blinded evaluation of cZi DBS showing its efficacy on PD symptoms. The most striking effect was on tremor; however, the doses of dopaminergic medications could not be decreased. cZi DBS in PD may be an addition to existing established targets, enabling tailoring the surgery to the needs of the individual patient. PMID- 29386254 TI - Inflammation-Sensitive Myosin-X Functionally Supports Leukocyte Extravasation by Cdc42-Mediated ICAM-1-Rich Endothelial Filopodia Formation. AB - Leukocyte transendothelial migration is key to inflammation. Leukocytes first start rolling over the inflamed endothelium, followed by firmly adhering to it. Under inflammatory conditions, endothelial cells express small finger-like protrusions that stick out into the lumen. The function and regulation of these structures are unclear. We present evidence that these ICAM-1- and F-actin-rich endothelial finger-like protrusions are filopodia and function as adhesive structures for leukocytes to transit from rolling to crawling but are dispensable for diapedesis. Mechanistically, these structures require the motor function of myosin-X, activity of the small GTPase Cdc42, and p21-activated kinase 4. Moreover, myosin-X expression is under control of TNF-alpha-mediated c-Jun N terminal kinase activity and is upregulated in human atherosclerotic regions. To our knowledge, this is the first study to identify that regulation of endothelial filopodia is crucial for leukocyte extravasation, in particular for the initiation of leukocyte adhesion under flow conditions. PMID- 29386252 TI - Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. AB - BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers. PMID- 29386255 TI - HPV18 Persistence Impairs Basal and DNA Ligand-Mediated IFN-beta and IFN-lambda1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling. AB - Although it is clear that high-risk human papillomaviruses (HPVs) can selectively infect keratinocytes and persist in the host, it still remains to be unequivocally determined whether they can escape antiviral innate immunity by interfering with pattern recognition receptor (PRR) signaling. In this study, we have assessed the innate immune response in monolayer and organotypic raft cultures of NIKS cells harboring multiple copies of episomal HPV18 (NIKSmcHPV18), which fully recapitulates the persistent state of infection. We show for the first time, to our knowledge, that NIKSmcHPV18, as well as HeLa cells (a cervical carcinoma-derived cell line harboring integrated HPV18 DNA), display marked downregulation of several PRRs, as well as other PRR downstream effectors, such as the adaptor protein stimulator of IFN genes and the transcription factors IRF1 and 7. Importantly, we provide evidence that downregulation of stimulator of IFN genes, cyclic GMP-AMP synthase, and retinoic acid-inducible gene I mRNA levels occurs at the transcriptional level through a novel epigenetic silencing mechanism, as documented by the accumulation of repressive heterochromatin markers seen at the promoter region of these genes. Furthermore, stimulation of NIKSmcHPV18 cells with salmon sperm DNA or poly(deoxyadenylic-deoxythymidylic) acid, two potent inducers of PRR signaling, only partially restored PRR protein expression. Accordingly, the production of IFN-beta and IFN-lambda1 was significantly reduced in comparison with the parental NIKS cells, indicating that HPV18 exerts its immunosuppressive activity through downregulation of PRR signaling. Altogether, our findings indicate that high-risk human papillomaviruses have evolved broad-spectrum mechanisms that allow simultaneous depletion of multiple effectors of the innate immunity network, thereby creating an unreactive cellular milieu suitable for viral persistence. PMID- 29386256 TI - Phospholipase D in TCR-Mediated Signaling and T Cell Activation. AB - Phospholipase D (PLD) is an enzyme that catalyzes the hydrolysis of phosphatidylcholine, the major phospholipid in the plasma membrane, to generate an important signaling lipid, phosphatidic acid. Phosphatidic acid is a second messenger that regulates vesicular trafficking, cytoskeletal reorganization, and cell signaling in immune cells and other cell types. Published studies, using pharmacological inhibitors or protein overexpression, indicate that PLD plays a positive role in TCR-mediated signaling and cell activation. In this study, we used mice deficient in PLD1, PLD2, or both to assess the function of these enzymes in T cells. Our data showed that PLD1 deficiency impaired TCR-mediated signaling, T cell expansion, and effector function during immune responses against Listeria monocytogenes; however, PLD2 deficiency had a minimal impact on T cells. Biochemical analysis indicated that PLD1 deficiency affected Akt and PKCtheta activation. In addition, it impaired TCR downregulation and the secondary T cell response. Together, our results suggested that PLD1 plays an important role in T cell activation. PMID- 29386257 TI - GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis. AB - At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food Ags. The molecular mechanisms underlying this phenomenon remain poorly understood. In this study, we report that signaling by GPR81, a receptor for lactate, in colonic dendritic cells and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of proinflammatory cytokines (IL-6, IL-1beta, and TNF-alpha) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation. PMID- 29386259 TI - Dynamic Interactions between Top-Down Expectations and Conscious Awareness. AB - It is well known that top-down expectations affect perceptual processes. Yet, remarkably little is known about the relationship between expectations and conscious awareness. We address three crucial outstanding questions: (1) how do expectations affect the likelihood of conscious stimulus perception?; (2) does the brain register violations of expectations nonconsciously?; and (3) do expectations need to be conscious to influence perceptual decisions? Using human participants, we performed three experiments in which we manipulated stimulus predictability within the attentional blink paradigm, while combining visual psychophysics with electrophysiological recordings. We found that valid stimulus expectations increase the likelihood of conscious access of stimuli. Furthermore, our findings suggest a clear dissociation in the interaction between expectations and consciousness: conscious awareness seems crucial for the implementation of top-down expectations, but not for the generation of bottom-up stimulus-evoked prediction errors. These results constrain and update influential theories about the role of consciousness in the predictive brain.SIGNIFICANCE STATEMENT While the relationship between expectations and conscious awareness plays a major role in many prediction-based theories of brain functioning, thus far few empirical studies have examined this relationship. Here, we address this gap in knowledge in a set of three experiments. Our results suggest that the effect of expectations on conscious awareness varies between different steps of the hierarchy of predictive processing. While the active use of top-down expectations for perceptual decisions requires conscious awareness, prediction errors can be triggered outside of conscious awareness. These results constrain and update influential theories about the role of consciousness in the predictive brain. PMID- 29386258 TI - Endoplasmic Reticulum Stress Contributes to the Loss of Newborn Hippocampal Neurons after Traumatic Brain Injury. AB - Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK eIF2alpha pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies.SIGNIFICANCE STATEMENT The hippocampus, a structure in the temporal lobe, is critical for learning and memory. The hippocampus is one of only two areas in which neurons are generated in the adult brain. These newborn neurons are required for certain types of memory, and are particularly vulnerable to traumatic brain injury (TBI). However, the mechanism(s) that causes the loss of these cells after TBI is poorly understood. We show that endoplasmic reticulum (ER) stress pathways are activated in newborn neurons after TBI, and that manipulation of the CHOP cascade improves newborn neuron survival and cognitive outcome. These results suggest that treatments that prevent/resolve ER stress may be beneficial in treating TBI-triggered memory dysfunction. PMID- 29386260 TI - Neurons in primate entorhinal cortex represent gaze position in multiple spatial reference frames. AB - Primates predominantly rely on vision to gather information from the environment, and neurons representing visual space and gaze position are found in many brain areas. Within the medial temporal lobe, a brain region critical for memory, neurons in the entorhinal cortex of macaque monkeys exhibit spatial selectivity for gaze position. Specifically, the firing rate of single neurons reflects fixation location within a visual image (Killian et al., 2012). In the rodents, entorhinal cells such as grid cells, border cells, and head direction cells show spatial representations aligned to visual environmental features instead of the body (Hafting et al., 2005, Solstad et al. 2008, Sargolini et al., 2006, Diehl et al., 2017). However, it is not known whether similar allocentric representations exist in primate entorhinal cortex. Here, we recorded neural activity in the entorhinal cortex in two male rhesus monkeys during a naturalistic, free-viewing task. Our data reveal that a majority of entorhinal neurons represent gaze position, and that simultaneously recorded neurons represent gaze position relative to distinct spatial reference frames, with some neurons aligned to the visual image and others aligned to the monkey's head position. Our results also show that entorhinal neural activity can be used to predict gaze position with a high degree of accuracy. These findings demonstrate that visuospatial representation is a fundamental property of entorhinal neurons in primates, and suggest that entorhinal cortex may support relational memory and motor planning by coding attentional locus in distinct, behaviorally relevant frames of reference.SIGNIFICANCE STATEMENTThe entorhinal cortex, a brain area important for memory, shows striking spatial activity in rodents through grid cells, border cells, head direction cells, and nongrid spatial cells. The majority of entorhinal neurons signal the location of a rodent relative to visual environmental cues, representing the location of the animal relative to space in the world instead of the body. Recently, our laboratory found that entorhinal neurons can signal location of gaze while a monkey visually explores images. Here, we report that spatial entorhinal neurons are widespread in the monkey, and these neurons are capable of showing a world-based spatial reference frame locked to the bounds of explored images. These results help connect the extensive findings in rodents to the primate. PMID- 29386261 TI - Timescales of Intrinsic BOLD Signal Dynamics and Functional Connectivity in Pharmacologic and Neuropathologic States of Unconsciousness. AB - Environmental events are processed on multiple timescales via hierarchical organization of temporal receptive windows (TRWs) in the brain. The dependence of neural timescales and TRWs on altered states of consciousness is unclear. States of reduced consciousness are marked by a shift toward slowing of neural dynamics (<1 Hz) in EEG/ECoG signals. We hypothesize that such prolongation of intrinsic timescales are also seen in blood-oxygen-level-dependent (BOLD) signals. To test this hypothesis, we measured the timescales of intrinsic BOLD signals using mean frequency (MF) and temporal autocorrelation (AC) in healthy volunteers (n = 23; male/female 14/9) during graded sedation with propofol. We further examined the relationship between the intrinsic timescales (local/voxel level) and its regional connectivity (across neighboring voxels; regional homogeneity, ReHo), global (whole-brain level) functional connectivity (GFC), and topographical similarity (Topo). Additional results were obtained from patients undergoing deep general anesthesia (n = 12; male/female: 5/7) and in patients with disorders of consciousness (DOC) (n = 21; male/female: 14/7). We found that MF, AC, and ReHo increased, whereas GFC and Topo decreased, during propofol sedation. The local alterations occur before changes of distant connectivity. Conversely, all of these parameters decreased in deep anesthesia and in patients with DOC. We conclude that propofol synchronizes local neuronal interactions and prolongs the timescales of intrinsic BOLD signals. These effects may impede communication among distant brain regions. Furthermore, the intrinsic timescales exhibit distinct dynamic signatures in sedation, deep anesthesia, and DOC. These results improve our understanding of the neural mechanisms of unconsciousness in pharmacologic and neuropathologic states.SIGNIFICANCE STATEMENT Information processing in the brain occurs through a hierarchy of temporal receptive windows (TRWs) in multiple timescales. Anesthetic drugs induce a reversible suppression of consciousness and thus offer a unique opportunity to investigate the state dependence of neural timescales. Here, we demonstrate for the first time that sedation with propofol is accompanied by the prolongation of the timescales of intrinsic BOLD signals presumably reflecting enlarged TRWs. We show that this is accomplished by an increase of local and regional signal synchronization, effects that may disrupt information exchange among distant brain regions. Furthermore, we show that the timescales of intrinsic BOLD signals exhibit distinct dynamic signatures in sedation, deep anesthesia, and disorders of consciousness. PMID- 29386262 TI - Evaluation of the Accelerate Pheno System: Results from Two Academic Medical Centers. AB - Rapid diagnostic tests are needed to improve patient care and to combat the problem of antimicrobial resistance. The Accelerate Pheno system (Accelerate Diagnostics, Tucson, AZ) is a new diagnostic device that can provide rapid bacterial identification and antimicrobial susceptibility test (AST) results directly from a positive blood culture. The device was compared to the standard of care at two academic medical centers. There were 298 blood cultures included in the study, and the Accelerate Pheno system provided a definitive identification result in 218 instances (73.2%). The Accelerate Pheno system provided a definitive and correct result for 173 runs (58.1%). The Accelerate Pheno system demonstrated an overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 94.7%, 98.9%, 83.7%, and 99.7%, respectively. An AST result was available for analysis in 146 instances. The overall category agreement was 94.1% with 12 very major errors, 5 major errors, and 55 minor errors. After a discrepancy analysis, there were 5 very major errors and 4 major errors. The Accelerate Pheno system provided an identification result in 1.4 h and an AST result in 6.6 h; the identification and AST results were 41.5 h and 48.4 h faster than those with the standard of care, respectively. This study demonstrated that the Accelerate Pheno system is able to provide fast and accurate organism identification and AST data. A limitation is the frequency with which cultures required the use of alternative identification and AST methods. PMID- 29386263 TI - Simultaneous Immunodetection of Anthrax, Plague, and Tularemia from Blood Cultures by Use of Multiplexed Suspension Arrays. AB - Multiplexed detection technologies are becoming increasingly important given the possibility of bioterrorism attacks, for which the range of suspected pathogens can vary considerably. In this work, we describe the use of Luminex MagPlex magnetic microspheres for the construction of two multiplexed diagnostic suspension arrays, enabling antibody-based detection of bacterial pathogens and their related disease biomarkers directly from blood cultures. The first 4-plex diagnostic array enabled the detection of both anthrax and plague infections using soluble disease biomarkers, including protective antigen (PA) and anthrax capsular antigen for anthrax detection and the capsular F1 and LcrV antigens for plague detection. The limits of detection (LODs) ranged between 0.5 and 5 ng/ml for the different antigens. The second 2-plex diagnostic array facilitated the detection of Yersinia pestis (LOD of 1 * 106 CFU/ml) and Francisella tularensis (LOD of 1 * 104 CFU/ml) from blood cultures. Inoculated, propagated blood cultures were processed (15 to 20 min) via 2 possible methodologies (Vacutainer or a simple centrifugation step), allowing the direct detection of bacteria in each sample, and the entire assay could be performed in 90 min. While detection of bacteria and soluble markers from blood cultures using PCR Luminex suspension arrays has been widely described, to our knowledge, this study is the first to demonstrate the utility of the Luminex system for the immunodetection of both bacteria and soluble markers directly from blood cultures. Targeting both the bacterial pathogens as well as two different disease biomarkers for each infection, we demonstrated the benefit of the multiplexed developed assays for enhanced, reliable detection. The presented arrays could easily be expanded to include antibodies for the detection of other pathogens of interest in hospitals or labs, demonstrating the applicability of this technology for the accurate detection and confirmation of a wide range of potential select agents. PMID- 29386264 TI - Diagnostic Testing for Zika Virus: a Postoutbreak Update. AB - Since the emergence and dissemination of Zika virus (ZIKV) in late 2015, our understanding of the biology, transmission, clinical disease, and potential sequelae associated with infection has markedly expanded. Over the past 2 years, the number of diagnostic assays for ZIKV has increased from none in 2015 to 5 serological assays and 14 molecular assays in 2017, all with emergency use authorization granted through the U.S. Food and Drug Administration. Here we provide an update on ZIKV, addressing what we have collectively learned since the outbreak began, including a summary of currently available diagnostic assays for this virus. PMID- 29386265 TI - Rapid Increase in Prevalence of Carbapenem-Resistant Enterobacteriaceae (CRE) and Emergence of Colistin Resistance Gene mcr-1 in CRE in a Hospital in Henan, China. AB - The global spread of carbapenem-resistant Enterobacteriaceae (CRE) is one of the most severe threats to human health in a clinical setting. The recent emergence of plasmid-mediated colistin resistance gene mcr-1 among CRE strains greatly compromises the use of colistin as a last resort for the treatment of infections caused by CRE. This study aimed to understand the current epidemiological trends and characteristics of CRE from a large hospital in Henan, the most populous province in China. From 2014 to 2016, a total of 7,249 Enterobacteriaceae isolates were collected from clinical samples, among which 18.1% (1,311/7,249) were carbapenem resistant. Carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Escherichia coli were the two most common CRE species, with Klebsiella pneumoniae carbapenemases (KPC) and New Delhi metallo-beta-lactamases (NDM), respectively, responsible for the carbapenem resistance of the two species. Notably, >57.0% (n = 589) of the K. pneumoniae isolates from the intensive care unit were carbapenem resistant. Furthermore, blaNDM-5 and mcr-1 were found to coexist in one E. coli isolate, which exhibited resistance to almost all tested antibiotics. Overall, we observed a significant increase in the prevalence of CRE isolates during the study period and suggest that carbapenems may no longer be considered to be an effective treatment for infections caused by K. pneumoniae in the studied hospital. PMID- 29386267 TI - Erratum. PMID- 29386266 TI - Performance of the Xpert HIV-1 Viral Load Assay: a Systematic Review and Meta analysis. AB - Viral load (VL) is the preferred treatment-monitoring approach for HIV-positive patients. However, more rapid, near-patient, and low-complexity assays are needed to scale up VL testing. The Xpert HIV-1 VL assay (Cepheid, Sunnyvale, CA) is a new, automated molecular test, and it can leverage the GeneXpert systems that are being used widely for tuberculosis diagnosis. We systematically reviewed the evidence on the performance of this new tool in comparison to established reference standards. A total of 12 articles (13 studies) in which HIV patient VLs were compared between Xpert HIV VL assay and a reference standard VL assay were identified. Study quality was generally high, but substantial variability was observed in the number and type of agreement measures reported. Correlation coefficients between Xpert and reference assays were high, with a pooled Pearson correlation (n = 8) of 0.94 (95% confidence interval [CI], 0.89, 0.97) and Spearman correlation (n = 3) of 0.96 (95% CI, 0.86, 0.99). Bland-Altman metrics (n = 11) all were within 0.35 log copies/ml of perfect agreement. Overall, Xpert HIV-1 VL performed well compared to current reference tests. The minimal training and infrastructure requirements for the Xpert HIV-1 VL assay make it attractive for use in resource-constrained settings, where point-of-care VL testing is most needed. PMID- 29386269 TI - Dispatches from the editor: how should we reward those that peer review for our military journal? PMID- 29386270 TI - Finding fibrillin in cerebral artery dissection. PMID- 29386271 TI - Dementia and motor vehicle crash hospitalizations: Role of physician reporting laws. AB - OBJECTIVE: To determine the effect of physician reporting laws and state licensing requirements on crash hospitalizations among drivers with dementia. METHODS: A study of drivers hospitalized because of vehicle crashes, identified from the State Inpatient Databases of the Agency for Healthcare Research and Quality. Multivariable logistic regression was used to examine the effect of mandatory physician reporting of at-risk drivers and state licensing requirement on the prevalence of dementia among hospitalized drivers. RESULTS: Physician reporting laws, mandated or legally protected, were not associated with a lower likelihood of dementia among crash hospitalized drivers. Hospitalized drivers aged 60 to 69 years in states with in-person renewal laws were 37% to 38% less likely to have dementia than drivers in other states and 23% to 28% less likely in states with vision testing at in-person renewal. Road testing was associated with lower dementia prevalence among hospitalized drivers aged 80 years and older. CONCLUSION: Vision testing at in-person renewal and in-person renewal requirements were significantly related with a lower prevalence of dementia in hospitalized older adults among drivers aged 60 to 69 years. Road testing was significantly associated with a lower proportion of dementia among hospitalized drivers aged 80 years and older. Mandatory physician driver reporting laws lacked any independent association with prevalence of dementia among hospitalized drivers. PMID- 29386272 TI - Pediatric epilepsy surgery: Toward increased utilization and reduced invasiveness. PMID- 29386273 TI - FLAIR vascular hyperintensities predict early ischemic recurrence in TIA. AB - OBJECTIVE: To evaluate the relationship between fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) and early ischemic lesion recurrence (follow-up diffusion-weighted imaging [FU-DWI] [+]) in patients with lesion-negative TIA. METHODS: We recruited consecutive patients with lesion negative TIA within 24 hours of symptom onset, who underwent follow-up MRI during the acute period. FVH was defined as a focal or serpentine high signal intensity on FLAIR images. Other potential confounders were adjusted to evaluate the relationship between FVH and FU-DWI (+). Furthermore, to compare clinical outcomes between the FU-DWI (+) and FU-DWI (-) groups, we assessed 1-year recurrent ischemic stroke or TIA. RESULTS: Among 392 patients with lesion negative TIA, 82 patients had FU-DWI (+) on the follow-up MRI. In the multivariate analysis, FVH remained an independent predictor of FU-DWI (+) (adjusted odds ratio [aOR] = 4.77, 95% confidence interval [CI] 2.45-9.29, p < 0.001). The time to initial MRI (aOR = 0.49, 95% CI = 0.33-0.70, p < 0.001) and intracranial atherosclerosis (aOR = 2.07, 95% CI = 1.10-3.92, p = 0.025) were also associated with FU-DWI (+), independent of FVH. In clinical outcomes, the FU DWI (+) group showed more frequent 1-year recurrent ischemic stroke events than the FU-DWI (-) group (10.7% vs 3.1%, respectively, p = 0.007). CONCLUSIONS: FVH is associated with FU-DWI (+) in patients with lesion-negative TIA. As FU-DWI (+) frequently occurs during the acute period and has a subsequent worse outcome after discharge, additional radiologic or clinical markers for it are necessary. PMID- 29386274 TI - Efficacy of Balance and Eye-Movement Exercises for Persons With Multiple Sclerosis (BEEMS). AB - OBJECTIVE: To determine whether a multifaceted vestibular-related rehabilitation program (Balance and Eye-Movement Exercises for Persons with Multiple Sclerosis; BEEMS) improves balance in persons with MS and whether there are differences in outcomes based on brainstem/cerebellar lesion involvement. METHODS: A 2-arm, examiner-blinded, stratified (involvement vs no involvement of brainstem/cerebellar structures), randomized controlled trial was implemented. Eighty-eight participants were allocated to BEEMS or no treatment control. Computerized Dynamic Posturography-Sensory Organization Test (CDP-SOT) measured balance control. The Dizziness Handicap Inventory (DHI), Modified Fatigue Impact Scale (MFIS), and Short Form-36 Health Status Questionnaire (SF-36) were also administered. Linear mixed models were used to investigate the primary and secondary aims. RESULTS: From baseline to 6 weeks, BEEMS participants experienced greater improvements compared to control participants in CDP-SOT composite (model estimated difference in change 4.9, 95% confidence interval 1.39-8.38, p = 0.006), DHI total (-13.5, -17.7 to -7.25, p < 0.0001), MFIS total (-11.4, -15.7 to -7.0, p < 0.0001), SF-36 Mental (5.6, 2.43-8.71, p = 0.0006), and SF-36 Physical (3.5, 1.12-5.81, p = 0.004) scores and from baseline to 14 weeks in CDP SOT composite (8.3, 4.73-11.9, p < 0.0001), DHI total (-13.9, -19.3 to -8.62, p < 0.0001), MFIS total (-12.3, -16.7 to -7.79, p < 0.0001), SF-36 Mental (3.9, 0.70 7.16, p = 0.02), and SF-36 Physical (3.2, 0.79-5.62, p = 0.01) scores. From baseline to 6 weeks, BEEMS participants with brainstem/cerebellar lesion involvement experienced greater improvements compared to those without in CDP-SOT composite (5.26, 0.34-10.2, p = 0.04) and MFIS total (-7.6, -14.0 to -1.33, p = 0.02) scores. CONCLUSION: BEEMS improved multiple outcomes regardless of whether brainstem/cerebellar lesions were present, supporting the generalizability of BEEMS for ambulatory people with MS who have at least minimally impaired balance and fatigue. CLINICAL TRIALSGOV IDENTIFIER: NCT01698086. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that BEEMS training improves dynamic posturography-based balance, dizziness, fatigue, and quality of life in persons with MS. PMID- 29386275 TI - Risk for injuries and accidents in epilepsy: A prospective population-based cohort study. AB - OBJECTIVE: To study the risk for injuries/accidents in people with newly diagnosed epileptic seizures in relation to comorbidities. METHODS: Between September 1, 2001, and August 31, 2008, individuals in northern Stockholm with incident unprovoked seizures (epilepsy; n = 2,130) were included in a registry. For every epilepsy patient, 8 individuals matched for sex and inclusion year (n = 16,992) were randomly selected as references from the population of the catchment area. Occurrence of injuries/accidents was monitored through the national patient and cause of death registers until December 31, 2013. These registers also provided information on comorbidities (e.g., brain tumor, stroke, psychiatric disease, diabetes mellitus). RESULTS: Injury/accident was demonstrated in 1,033 epilepsy cases and 6,202 references (hazard ratio [HR] 1.71, 95% confidence interval 1.60-1.83). The excess risk was seen mainly during the first 2 years after diagnosis. Sex and educational status had no significant effect on HR. The risk was normal in children but increased in adults. Highest HR was seen for drowning, poisoning, adverse effect of medication, and severe traumatic brain injury. Compared to references without comorbidities, HR was 1.17 (1.07-1.28) in epilepsy without comorbidities, 4.52 (4.18-4.88) in references with comorbidities, and 7.15 (6.49-7.87) in epilepsy with comorbidities. CONCLUSION: Presence of comorbidities should be considered when counseling patients with newly diagnosed epilepsy concerning risk for injuries/accidents. Early information is important, as the risk is highest during the first 2 years following seizure onset. PMID- 29386277 TI - Trends in intracranial monitoring for pediatric medically intractable epilepsy: 2000-2012. AB - OBJECTIVE: To retrospectively examine nationwide trends in intracranial monitoring (ICM) for pediatric medically intractable epilepsy (MIE) from 2000 to 2012. METHODS: The Healthcare Cost and Utilization Project Kids' Inpatient Database was analyzed to identify admissions with ICD-9-CM codes corresponding to MIE and ICM from 2000 to 2012, inclusive. Associations between independent variables and outcomes were tested using chi2 test or Fisher exact test. A multivariate logistic regression analysis of variables associated with ICM was completed using stepwise selection. The Cochran-Armitage test was used to test for trend of a variable over the study period. RESULTS: The number of ICM procedures increased over the study period; however, secondary to large increases in the number of MIE admissions, the rate of ICM declined from 5.39% in 2000 to 2.56% in 2012 (p < 0.001). Despite this decline, ICM increasingly resulted in resective epilepsy procedures. In 2000, only 45.18% of ICM cases led to resective epilepsy surgery, which increased to 75.83% by 2012 (p < 0.001). ICM complication rates were comparable to, if not lower than, standard resective surgery. Disparities in access to ICM exist, with African American individuals and those with Medicaid significantly less likely to undergo ICM. CONCLUSION: In this nationwide characterization of pediatric ICM trends, we identified a slight, significant downward trend in the rate of utilization of ICM for MIE. This was secondary to substantial increases in the number of hospital admissions for MIE. Reasons for this large increase and why it has not led to increased rates of ICM warrant further investigation. PMID- 29386276 TI - An interdisciplinary response to contemporary concerns about brain death determination. AB - In response to a number of recent lawsuits related to brain death determination, the American Academy of Neurology Ethics, Law, and Humanities Committee convened a multisociety quality improvement summit in October 2016 to address, and potentially correct, aspects of brain death determination within the purview of medical practice that may have contributed to these lawsuits. This article, which has been endorsed by multiple societies that are stakeholders in brain death determination, summarizes the discussion at this summit, wherein we (1) reaffirmed the validity of determination of death by neurologic criteria and the use of the American Academy of Neurology practice guideline to determine brain death in adults; (2) discussed the development of systems to ensure that brain death determination is consistent and accurate; (3) reviewed strategies to respond to objections to determination of death by neurologic criteria; and (4) outlined goals to improve public trust in brain death determination. PMID- 29386278 TI - An intervention to improve balance in persons with multiple sclerosis. PMID- 29386279 TI - Prescription of antihypertensive medication at discharge influences survival following stroke. AB - OBJECTIVE: To investigate the risk of death from cardiovascular disease between patients who were and were not prescribed antihypertensive medication following stroke or TIA. METHODS: This was a large cohort study using routinely collected prospective data from the Australian Stroke Clinical Registry. Patients registered between 2009 and 2013 who were discharged to the community or rehabilitation were included. Cases were linked to the National Death Index to determine the date and cause of death. Propensity score matching with stratification was utilized to compare between similar subgroups of patients. Multivariable competing risks regression, with noncardiovascular death as a competing risk, was conducted to investigate the association between the prescription of antihypertensive medications and cardiovascular death at 180 days after admission. RESULTS: Among 12,198 patients from 40 hospitals, 70% were prescribed antihypertensive medications. Patients who were older, were treated in a stroke unit, and had better socioeconomic position were more often discharged from hospital with an antihypertensive medication. Including only patients within propensity score quintiles with acceptable levels of balance in covariates between groups (n = 8,786), prescription of antihypertensive medications was associated with a 23% greater reduction in the subhazard of cardiovascular death compared to those who were not prescribed these agents (subhazard ratio 0.77; 95% confidence interval 0.61 to 0.97). CONCLUSIONS: People who are prescribed antihypertensive medications at discharge from hospital after a stroke or TIA demonstrate better cardiovascular and all-cause survival outcomes than those not prescribed these agents. PMID- 29386280 TI - Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta analysis. AB - OBJECTIVE: To perform a meta-analysis of 4 core CSF biomarkers (beta-amyloid [Abeta]42, Abeta40, total tau [t-tau], and phosphorylated tau [p-tau]) to assess which of these are most altered in sporadic cerebral amyloid angiopathy (CAA). METHODS: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting amyloid precursor protein metabolism (Abeta42, Abeta40), neurodegeneration (t-tau), and tangle pathology (p-tau) in symptomatic sporadic CAA cohorts vs controls and patients with Alzheimer disease (AD). Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations: (1) in patients with CAA vs healthy controls and (2) in patients with CAA vs patients with AD. RoM >1 indicates higher biomarker concentration in patients with CAA vs comparison population and RoM <1 indicates higher concentration in comparison groups. RESULTS: Three studies met inclusion criteria. These comprised 5 CAA patient cohorts (n = 59 patients) vs healthy controls (n = 94 cases) and AD cohorts (n = 158). Three core biomarkers differentiated CAA from controls: CSF Abeta42 (RoM 0.49, 95% confidence interval [CI] 0.38-0.64, p < 0.003), Abeta40 (RoM 0.70, 95% CI 0.63 0.78, p < 0.0001), and t-tau (RoM 1.54, 95% CI 1.15-2.07, p = 0.004); p-tau was marginal (RoM 1.24, 95% CI 0.99-1.54, p = 0.062). Differentiation between CAA and AD was strong for CSF Abeta40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001), but not Abeta42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For t-tau and p-tau, average CSF ratios in patients with CAA vs patients with AD were 0.63 (95% CI 0.54-0.74, p < 0.0001) and 0.60 (95% CI 0.50-0.71, p < 0.0001), respectively. CONCLUSION: Specific CSF patterns of Abeta42, Abeta40, t-tau, and p-tau might serve as molecular biomarkers of CAA, but analyses in larger CAA cohorts are needed. PMID- 29386281 TI - The value of plasma fibrillin-1 level in patients with spontaneous cerebral artery dissection. AB - OBJECTIVE: To explore the value of plasma fibrillin-1 levels in patients with spontaneous cerebral artery dissection (sCeAD). METHODS: A single-center prospective cohort of 99 consecutive patients with sCeAD between February 2013 and December 2015 were age and sex matched with 115 patients with non-sCeAD ischemic stroke and 20 healthy participants undergoing routine physical examination. The plasma fibrillin-1 level was measured with ELISA and compared among the 3 groups. The associations of fibrillin-1 with site, acuity, and severity of dissection, as well as clinical and radiographic prognosis of patients, were analyzed. RESULTS: One hundred nine plasma samples from 99 patients with sCeAD, 115 from disease control patients, and 20 from healthy participants were collected. The plasma fibrillin-1 level of the dissection group (mean 85.56 ng/mL [95% confidence interval 81.53-89.59]) was higher than that of non-sCeAD ischemic stroke group (77.13 ng/mL [73.64-80.63], p = 0.015) or healthy controls (73.04 ng/mL [65.94-80.13], p = 0.029). Such differences were most prominent in the acute stage (97.64 ng/mL [91.64-103.64], 74.39 ng/mL [68.95 79.84], and 73.04 ng/mL [65.95-80.13], respectively). A cutoff value of 88.455 ng/mL was determined to differentiate acute dissection from nondissection stroke with a sensitivity of 0.778 and a specificity of 0.800. Higher fibrillin-1 level was detected in patients with more severe dissection radiographically (p < 0.001), while patients with lower fibrillin-1 concentration at baseline achieved better morphologic recovery on follow-up imaging tests (p = 0.003). CONCLUSION: Plasma fibrillin-1 is a promising biomarker for aiding the diagnosis of acute sCeAD and may have potential value in lesion severity grading and radiographic prognosis prediction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with sCeAD have significantly higher levels of plasma fibrillin-1 than patients with ischemic stroke attributable to a cause other than sCeAD. PMID- 29386282 TI - Characterization of Equine Infectious Anemia Virus Long Terminal Repeat Quasispecies In Vitro and In Vivo. AB - The equine infectious anemia virus (EIAV) attenuated vaccine was developed by long-term passaging of a field-isolated virulent strain in cross-species hosts, followed by successive cultivation in cells in vitro To explore the molecular mechanism underlying the evolution of the EIAV attenuated vaccine, a systematic study focusing on long-terminal-repeat (LTR) variation in numerous virus strains ranging from virulent EIAV to attenuated EIAV was performed over time both in vitro and in vivo Two hypervariable regions were identified within the U3 region in the enhancer region (EHR) and the negative regulatory element (NRE) and within the R region in the transcription start site (TSS) and the Tat-activating region (TAR). Among these sites, variation in the U3 region resulted in the formation of additional transcription factor binding sites; this variation of the in vitro adapted strains was consistent with the loss of pathogenicity. Notably, the same LTR variation pattern was observed both in vitro and in vivo Generally, the LTR variation in both the attenuated virus and the virulent strain fluctuated over time in vivo Interestingly, the attenuated-virus-specific LTR variation was also detected in horses infected with the virulent strain, supporting the hypothesis that the evolution of an attenuated virus might have involved branching from EIAV quasispecies. This hypothesis was verified by phylogenetic analysis. The present systematic study examining the molecular evolution of attenuated EIAV from EIAV quasispecies may provide an informative model reflecting the evolution of similar lentiviruses.IMPORTANCE The attenuated EIAV vaccine was the first lentiviral vaccine used to successfully control for equine infectious anemia in China. This vaccine provides an important reference for studying the relationship between EIAV gene variation and changes in biological characteristics. Importantly, the vaccine provides a model for the investigation of lentiviral quasispecies evolution. This study followed the "natural" development of the attenuated EIAV vaccine by use of a systematic analysis of LTR evolution in vitro and in vivo The results revealed that the increase in LTR variation with passaging was accompanied by a decrease in virulence, which indicated that LTR variability might parallel the attenuation of virulence. Interestingly, the attenuated-virus specific LTR variation was also detected in virulent-strain-infected horses, a finding consistent with those of previous investigations of gp90 and S2 evolution. Therefore, we present a hypothesis that the evolution of the attenuated virus may involve branching from EIAV quasispecies present in vivo. PMID- 29386283 TI - Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells. AB - Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3' untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis.IMPORTANCE KS lesions consist of endothelial cells latently infected with KSHV. Cells that make up these lesions express KSHV miRNAs. Identification of the targets of KSHV miRNAs will help us understand their role in viral oncogenesis. The cross-linking and sequencing of hybrids (CLASH) protocol is a method for unambiguously identifying miRNA targetomes. We developed a streamlined version of CLASH, called quick CLASH (qCLASH). qCLASH requires a lower initial input of cells than for its parent protocol. Additionally, a new fast-growing KSHV-negative endothelial cell line, named TIVE EX-LTC cells, was established. qCLASH was performed on TIVE-EX-LTC cells latently infected with wild-type (WT) KSHV or a mutant virus lacking miR-K12-11/11*. A number of novel targets of KSHV miRNAs were identified, including targets of miR K12-11, the ortholog of the cellular oncogenic miRNA (oncomiR) miR-155. Many of the miRNA targets were involved in processes related to oncogenesis, such as glycolysis, apoptosis, and cell cycle control. PMID- 29386284 TI - Dehydration of Prions on Environmentally Relevant Surfaces Protects Them from Inactivation by Freezing and Thawing. AB - Chronic wasting disease (CWD) is an emerging prion disease in North America. Recent identification of CWD in wild cervids from Norway raises the concern of the spread of CWD in Europe. CWD infectivity can enter the environment through live animal excreta and carcasses where it can bind to soil. Well-characterized hamster prion strains and CWD field isolates in unadsorbed or soil-adsorbed forms that were either hydrated or dehydrated were subjected to repeated rounds of freezing and thawing. We found that 500 cycles of repeated freezing and thawing of hydrated samples significantly decreased the abundance of PrPSc and reduced protein misfolding cyclic amplification (PMCA) seeding activity that could be rescued by binding to soil. Importantly, dehydration prior to freezing and thawing treatment largely protected PrPSc from degradation, and the samples maintained PMCA seeding activity. We hypothesize that redistribution of water molecules during the freezing and thawing process alters the stability of PrPSc aggregates. Overall, these results have significant implications for the assessment of prion persistence in the environment.IMPORTANCE Prions excreted into the environment by infected animals, such as elk and deer infected with chronic wasting disease, persist for years and thus facilitate horizontal transmission of the disease. Understanding the fate of prions in the environment is essential to control prion disease transmission. The significance of our study is that it provides information on the possibility of prion degradation and inactivation under natural weathering processes. This information is significant for remediation of prion-contaminated environments and development of prion disease control strategies. PMID- 29386285 TI - Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions. AB - The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41 and is among the broadest known neutralizing antibodies against HIV 1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing the charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface patches, the neutralization potency of the antibody may be enhanced. We found that an increased positive charge at this paratope surface strengthened an electrostatic interaction between the antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 antibody did not gain any apparent polyreactivity and neutralized virus with a significantly greater potency. Binding analyses indicated that the optimized 10E8 antibody bound with a higher affinity to the epitope peptide anchored in lipid bilayers and to Env spikes on virions. Overall, our data provide a proof of principle for the rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect the potency of the first-generation anti-MPER antibody 4E10 shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1.IMPORTANCE The broadly neutralizing antibody 10E8 blocks infection by nearly all HIV-1 isolates, a capacity which vaccine design seeks to reproduce. Engineered versions of this antibody also represent a promising treatment for HIV infection by passive immunization. Understanding its mechanism of action is therefore important to help in developing effective vaccines and biologics to combat HIV/AIDS. 10E8 engages its helical MPER epitope where the base of the envelope spike submerges into the viral membrane. To enable this interaction, this antibody evolved an unusual property: the ability to interact with the membrane surface. Here, we provide evidence that 10E8 can be made more effective by enhancing its interactions with membranes. Our findings strengthen the idea that to elicit antibodies similar to 10E8, vaccines must reproduce the membrane environment where these antibodies perform their function. PMID- 29386286 TI - Modifications to the Foot-and-Mouth Disease Virus 2A Peptide: Influence on Polyprotein Processing and Virus Replication. AB - Foot-and-mouth disease virus (FMDV) has a positive-sense single-stranded RNA (ssRNA) genome that includes a single, large open reading frame encoding a polyprotein. The cotranslational "cleavage" of this polyprotein at the 2A/2B junction is mediated by the 2A peptide (18 residues in length) using a nonproteolytic mechanism termed "ribosome skipping" or "StopGo." Multiple variants of the 2A polypeptide with this property among the picornaviruses share a conserved C-terminal motif [D(V/I)E(S/T)NPG?P]. The impact of 2A modifications within this motif on FMDV protein synthesis, polyprotein processing, and virus viability were investigated. Amino acid substitutions are tolerated at residues E14, S15, and N16 within the 2A sequences of infectious FMDVs despite their reported "cleavage" efficiencies at the 2A/2B junction of only ca. 30 to 50% compared to that of the wild type (wt). In contrast, no viruses containing substitutions at residue P17, G18, or P19, which displayed little or no "cleavage" activity in vitro, were rescued, but wt revertants were obtained. The 2A substitutions impaired the replication of an FMDV replicon. Using transient expression assays, it was shown that certain amino acid substitutions at residues E14, S15, N16, and P19 resulted in partial "cleavage" of a protease-free polyprotein, indicating that these specific residues are not essential for cotranslational "cleavage." Immunofluorescence studies, using full-length FMDV RNA transcripts encoding mutant 2A peptides, indicated that the 2A peptide remained attached to adjacent proteins, presumably 2B. These results show that efficient "cleavage" at the 2A/2B junction is required for optimal virus replication. However, maximal StopGo activity does not appear to be essential for the viability of FMDV.IMPORTANCE Foot-and-mouth disease virus (FMDV) causes one of the most economically important diseases of farm animals. Cotranslational "cleavage" of the FMDV polyprotein precursor at the 2A/2B junction, termed StopGo, is mediated by the short 2A peptide through a nonproteolytic mechanism which leads to release of the nascent protein and continued translation of the downstream sequence. Improved understanding of this process will not only give a better insight into how this peptide influences the FMDV replication cycle but may also assist the application of this sequence in biotechnology for the production of multiple proteins from a single mRNA. Our data show that single amino acid substitutions in the 2A peptide can have a major influence on viral protein synthesis, virus viability, and polyprotein processing. They also indicate that efficient "cleavage" at the 2A/2B junction is required for optimal virus replication. However, maximal StopGo activity is not essential for the viability of FMDV. PMID- 29386287 TI - Respiratory Syncytial Virus Replication Is Promoted by Autophagy-Mediated Inhibition of Apoptosis. AB - Respiratory syncytial virus (RSV) is the main cause of acute lower respiratory tract infection (ALRI) in children worldwide. Virus-host interactions affect the progression and prognosis of the infection. Autophagy plays important roles in virus-host interactions. Respiratory epithelial cells serve as the front line of host defense during RSV infection, However, it is still unclear how they interact with RSV. In this study, we found that RSV induced autophagy that favored RSV replication and exacerbated lung pathology in vivo Mechanistically, RSV induced complete autophagy flux through reactive oxygen species (ROS) generation and activation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK-MTOR) signaling pathway in HEp-2 cells. Furthermore, we evaluated the functions of autophagy in RSV replication and found that RSV replication was increased in HEp-2 cells treated with rapamycin but decreased remarkably in cells treated with 3-methylademine (3-MA) or wortmannin. Knockdown key molecules in the autophagy pathway with short hairpinp RNA (shRNA) against autophagy-related gene 5 (ATG5), autophagy-related gene 7 (ATG7), or BECN1/Beclin 1 or treatment with ROS scavenger N-acetyl-l-cysteine (NAC) and AMPK inhibitor (compound C) suppressed RSV replication. 3-MA or shATG5/BECN1 significantly decreased cell viability and increased cell apoptosis at 48 hours postinfection (hpi). Blocking apoptosis with Z-VAD-FMK partially restored virus replication at 48 hpi. Those results provide strong evidence that autophagy may function as a proviral mechanism in a cell-intrinsic manner during RSV infection.IMPORTANCE An understanding of the mechanisms that respiratory syncytial virus utilizes to interact with respiratory epithelial cells is critical to the development of novel antiviral strategies. In this study, we found that RSV induces autophagy through a ROS-AMPK signaling axis, which in turn promotes viral infection. Autophagy favors RSV replication through blocking cell apoptosis at 48 hpi. Mechanistically, RSV induces mitophagy, which maintains mitochondrial homeostasis and therefore decreases cytochrome c release and apoptosis induction. This study provides a novel insight into this virus-host interaction, which may help to exploit new antiviral treatments targeting autophagy processes. PMID- 29386289 TI - Immunization of Pigs by DNA Prime and Recombinant Vaccinia Virus Boost To Identify and Rank African Swine Fever Virus Immunogenic and Protective Proteins. AB - African swine fever virus (ASFV) causes an acute hemorrhagic fever in domestic pigs, with high socioeconomic impact. No vaccine is available, limiting options for control. Although live attenuated ASFV can induce up to 100% protection against lethal challenge, little is known of the antigens which induce this protective response. To identify additional ASFV immunogenic and potentially protective antigens, we cloned 47 viral genes in individual plasmids for gene vaccination and in recombinant vaccinia viruses. These antigens were selected to include proteins with different functions and timing of expression. Pools of up to 22 antigens were delivered by DNA prime and recombinant vaccinia virus boost to groups of pigs. Responses of immune lymphocytes from pigs to individual recombinant proteins and to ASFV were measured by interferon gamma enzyme-linked immunosorbent spot (ELISpot) assays to identify a subset of the antigens that consistently induced the highest responses. All 47 antigens were then delivered to pigs by DNA prime and recombinant vaccinia virus boost, and pigs were challenged with a lethal dose of ASFV isolate Georgia 2007/1. Although pigs developed clinical and pathological signs consistent with acute ASFV, viral genome levels were significantly reduced in blood and several lymph tissues in those pigs immunized with vectors expressing ASFV antigens compared with the levels in control pigs.IMPORTANCE The lack of a vaccine limits the options to control African swine fever. Advances have been made in the development of genetically modified live attenuated ASFV that can induce protection against challenge. However, there may be safety issues relating to the use of these in the field. There is little information about ASFV antigens that can induce a protective immune response against challenge. We carried out a large screen of 30% of ASFV antigens by delivering individual genes in different pools to pigs by DNA immunization prime and recombinant vaccinia virus boost. The responses in immunized pigs to these individual antigens were compared to identify the most immunogenic. Lethal challenge of pigs immunized with a pool of antigens resulted in reduced levels of virus in blood and lymph tissues compared to those in pigs immunized with control vectors. Novel immunogenic ASFV proteins have been identified for further testing as vaccine candidates. PMID- 29386288 TI - HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees. AB - Induction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier 2 neutralization phenotype. Unique antigenicity was determined by nonredundancy (Spearman correlation), and antigens were clustered using partitioning around medoids (PAM) to identify antigen diversity. Cross-validation demonstrated that the PAM method was better than selection by reactivity and random selection. Analysis of vaccine elicited V1V2 binding antibody in longitudinal samples from the RV144 clinical trial revealed the striking heterogeneity among individual vaccinees in maintaining durable responses. These data support the idea that a major goal for vaccine development is to improve antibody levels, breadth, and durability at the population level. Elucidating the level and durability of vaccine-elicited binding antibody breadth needed for protection is critical for the development of a globally efficacious HIV vaccine.IMPORTANCE The path toward an efficacious HIV 1 vaccine will require characterization of vaccine-induced immunity that can recognize and target the highly genetically diverse virus envelope glycoproteins. Antibodies that target the envelope glycoproteins, including diverse sequences within the first and second hypervariable regions (V1V2) of gp120, were identified as correlates of risk for the one partially efficacious HIV-1 vaccine. To build upon this discovery, we experimentally and computationally evaluated humoral responses to define envelope glycoproteins representative of the antigenic diversity of HIV globally. These diverse envelope antigens distinguished binding antibody breadth and durability among vaccine candidates, thus providing insights for advancing the most promising HIV-1 vaccine candidates. PMID- 29386290 TI - alpha4beta7+ CD4+ Effector/Effector Memory T Cells Differentiate into Productively and Latently Infected Central Memory T Cells by Transforming Growth Factor beta1 during HIV-1 Infection. AB - HIV-1 transmission occurs mainly through mucosal tissues. During mucosal transmission, HIV-1 preferentially infects alpha4beta7+ gut-homing CCR7- CD4+ effector/effector memory T cells (TEM) and results in massive depletion of these cells and other subsets of TEM in gut-associated lymphoid tissues. However, besides being eliminated by HIV-1, the role of TEM during the early stage of infection remains inconclusive. Here, using in vitro-induced alpha4beta7+ gut homing TEM (alpha4beta7+ TEM), we found that alpha4beta7+ TEM differentiated into CCR7+ CD4+ central memory T cells (TCM). This differentiation was HIV-1 independent but was inhibited by SB431542, a specific transforming growth factor beta (TGF-beta) receptor I kinase inhibitor. Consistently, TEM-to-TCM differentiation was observed in alpha4beta7+ TEM stimulated with TGF-beta1 (TGF beta). The TCM properties of the TGF-beta-induced TEM-derived TCM (alpha4beta7+ TCM) were confirmed by their enhanced CCL19 chemotaxis and the downregulation of surface CCR7 upon T cell activation in vitro Importantly, the effect of TGF-beta on TCM differentiation also held in TEM directly isolated from peripheral blood. To investigate the significance of the TGF-beta-dependent TEM-to-TCM differentiation in HIV/AIDS pathogenesis, we observed that both productively and latently infected alpha4beta7+ TCM could differentiate from alpha4beta7+ TEM in the presence of TGF-beta during HIV-1 infection. Collectively, this study not only provides a new insight for the plasticity of TEM but also suggests that the TGF-beta-dependent TEM-to-TCM differentiation is a previously unrecognized mechanism for the formation of latently infected TCM after HIV-1 infection.IMPORTANCE HIV-1 is the causative agent of HIV/AIDS, which has led to millions of deaths in the past 30 years. Although the implementation of highly active antiretroviral therapy has remarkably reduced the HIV-1-related morbidity and mortality, HIV-1 is not eradicated in treated patients due to the presence of latent reservoirs. Besides, the pathogenesis in CD4 T cells early after infection still remains elusive. Immediately after HIV-1 mucosal infection, CD4 T cells are preferentially infected and depleted. However, in addition to being depleted, the other roles of the CD4 T cells, especially the effector/effector memory T cells (TEM), in disease progression are not completely understood. The significance of this study is in revealing a novel mechanism for the formation of latently HIV-1 infected central memory CD4 T cells, a major latent reservoir from CD4 TEM after infection. Our findings suggest previously unrecognized roles of CD4 TEM in HIV-1 pathogenesis. PMID- 29386291 TI - NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination. AB - The inflammasome represents a molecular platform for innate immune regulation and controls proinflammatory cytokine production. The NLRP3 inflammasome is comprised of NLRP3, ASC, and procaspase-1. When the NLRP3 inflammasome is activated, it causes ASC speck formation and caspase-1 activation, resulting in the maturation of interleukin-1beta (IL-1beta). The NLRP3 inflammasome is regulated at multiple levels, with one level being posttranslational modification. Interestingly, ubiquitination of ASC has been reported to be indispensable for the activation of the NLRP3 inflammasome. Influenza A virus (IAV) infection induces NLRP3 inflammasome-dependent IL-1beta secretion, which contributes to the host antiviral defense. However, IAVs have evolved multiple antagonizing mechanisms, one of which is executed by viral NS1 protein to suppress the NLRP3 inflammasome. In this study, we compared IL-1beta production in porcine alveolar macrophages in response to IAV infection and found that the 2009 pandemic H1N1 induced less IL 1beta than swine influenza viruses (SIVs). Further study revealed that the NS1 C terminus of pandemic H1N1 but not that of SIV was able to significantly inhibit NLRP3 inflammasome-mediated IL-1beta production. This inhibitory function was attributed to impaired ASC speck formation and suppression of ASC ubiquitination. Moreover, we identified two target lysine residues, K110 and K140, which are essential for both porcine ASC ubiquitination and NLRP3 inflammasome-mediated IL 1beta production. These results revealed a novel mechanism by which the NS1 protein of the 2009 pandemic H1N1 suppresses NLRP3 inflammasome activation.IMPORTANCE Influenza A virus (IAV) infection activates the NLRP3 inflammasome, resulting in the production of IL-1beta, which contributes to the host innate immune response. ASC, an adaptor protein of NLRP3, forms specks that are critical for inflammasome activation. Here, we report that the NS1 C terminus of the 2009 pandemic H1N1 has functions to suppress porcine IL-1beta production by inhibiting ASC speck formation and ASC ubiquitination. Furthermore, the ubiquitination sites on porcine ASC were identified. The information gained here may contribute to an in-depth understanding of porcine inflammasome activation and regulation in response to different IAVs, helping to further enhance our knowledge of innate immune responses to influenza virus infection in pigs. PMID- 29386292 TI - Porcine Epidemic Diarrhea Virus-Induced Epidermal Growth Factor Receptor Activation Impairs the Antiviral Activity of Type I Interferon. AB - Porcine epidemic diarrhea virus (PEDV) causes acute and devastating enteric disease in suckling piglets and results in huge economic losses in the pig industry worldwide. To establish productive infection, viruses must first circumvent the host innate immune response. In this study, we found that PEDV infection stimulated epidermal growth factor receptor (EGFR) activation, which has been linked to not only anticancer therapeutics, but also antiviral signaling. Therefore, we determined whether EGFR activation affected PEDV infection by using an activator or overexpression assay. The data showed that EGFR activation enhanced virus replication in both cases. We also found that specific inhibition of EGFR by either inhibitors or small interfering RNA (siRNA) led to a decrease in virus yields. Further analysis revealed that inhibition of EGFR produced augmentation of type I interferon genes. We next observed that the EGFR downstream cascade STAT3 was also activated upon PEDV infection. Similar to the case of EGFR, specific inhibition of STAT3 by either inhibitor or siRNA increased the antiviral activity of interferon and resulted in decreased PEDV RNA levels, and vice versa. The data on STAT3 depletion in combination with EGFR activation suggest that the attenuation of antiviral activity by EGFR activation requires activation of the STAT3 signaling pathway. Taken together, these data demonstrate that PEDV-induced EGFR activation serves as a negative regulator of the type I interferon response and provides a novel therapeutic target for virus infection.IMPORTANCE EGFR is a transmembrane tyrosine receptor that mediates various cellular events, as well as several types of human cancers. In this study, we investigated for the first time the role of EGFR in PEDV infection. We observed that PEDV infection induced EGFR activation. The role of EGFR activation is to impair the antiviral activity of type I interferon, which requires the involvement of the EGFR downstream signaling cascade STAT3. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response, which might serve as a therapeutic target against virus infection. PMID- 29386293 TI - Conserved Surface Residues on the Feline Calicivirus Capsid Are Essential for Interaction with Its Receptor Feline Junctional Adhesion Molecule A (fJAM-A). AB - Host cell surface receptors are required for attachment, binding, entry, and infection by nonenveloped viruses. Receptor binding can induce conformational changes in the viral capsid and/or the receptor that couple binding with downstream events in the virus life cycle (intracellular signaling, endocytosis and trafficking, and membrane penetration). Virus-receptor interactions also influence viral spread and pathogenicity. The interaction between feline calicivirus (FCV) and its receptor, feline junctional adhesion molecule A (fJAM A), on host cells is required for infection and induces irreversible, inactivating conformational changes in the capsid of some viral strains. Cryoelectron microscopy (cryo-EM) structures of FCV bound to fJAM-A showed several possible virus-receptor interactions. However, the specific residues on the viral capsid required for binding are not known. Capsid residues that may be involved in postbinding events have been implicated by isolation of soluble receptor-resistant (srr) mutants in which changes in the capsid protein sequence change the capacity of such srr mutants to be inactivated upon incubation with soluble fJAM-A. To clarify which residues on the surface of FCV are required for its interaction with fJAM-A and to potentially identify residues required for postreceptor binding events, we used the existing atomic-resolution structures of FCV and the FCV-fJAM-A cryo-EM structures to select 14 capsid residues for mutation and preparation of recombinant viral capsids. Using this approach, we identified residues on the FCV capsid that are required for fJAM-A binding and other residues that are not required for binding but are required for infection that are likely important for subsequent postbinding events.IMPORTANCE Feline calicivirus (FCV) is a common cause of mild upper respiratory disease in cats. Some FCV isolates can cause virulent systemic disease. The genetic determinants of virulence for FCV are unknown. We previously found that virulent FCV isolates have faster in vitro growth kinetics than less virulent isolates. Differences in viral growth in vitro may correlate with differences in virulence. Here, we investigated the roles of specific FCV capsid residues on the receptor-virus interaction and viral growth in vitro We show that the capsid protein genes of the virulent FCV-5 isolate determine its faster in vitro growth kinetics compared to those of the nonvirulent FCV-Urbana infectious clone. We also identified residues on the capsid VP1 protein that are important for receptor binding or for steps subsequent to receptor binding. Our data provide further insight into the specific molecular interactions between fJAM-A and the FCV capsid that regulate binding and infectious entry. PMID- 29386294 TI - The non-motor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation. AB - Mitotic spindle assembly and organization require forces generated by motor proteins. The activity of these motors is regulated by non-motor adaptor proteins. However, there are limited studies reporting the functional importance of adaptors on the balance of motor forces and the promotion of faithful and timely cell division. Here, we show that genomic deletion or siRNA silencing of the non-motor adaptor Hmmr/HMMR disturbs spindle microtubule organization and bipolar chromosome-kinetochore attachments with a consequent elevated occurrence of aneuploidy. Rescue experiments show a conserved motif in HMMR is required to generate inter-kinetochore tension and promote anaphase entry. This motif bears high homology with the kinesin Kif15 and is known to interact with TPX2, a spindle assembly factor. We find that HMMR is required to dampen kinesin Eg5 mediated forces through localizing TPX2 and promoting the formation of inhibitory TPX2-Eg5 complexes. In HMMR-silenced cells, K-fiber stability is reduced while the frequency of unattached chromosomes and the time needed for chromosome segregation are both increased. These defects can be alleviated in HMMR-silenced cells with chemical inhibition of Eg5, but not through the silencing of Kif15. Together, our findings indicate that HMMR balances Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation. PMID- 29386295 TI - Dynamics of human telomerase recruitment depend on template- telomere base pairing. AB - The reverse transcriptase telomerase adds telomeric repeats to chromosome ends to counteract telomere shortening and thereby assures genomic stability in dividing human cells. Key parameters in telomere homeostasis are the frequency with which telomerase engages the chromosome end and the number of telomeric repeats it adds during each association event. To study telomere elongation in vivo we have established a live-cell imaging assay to track individual telomerase RNPs in CRISPR-edited HeLa cells. Using this assay and the drug imetelstat, which is a competitive inhibitor of telomeric DNA binding, we demonstrate that stable association of telomerase with the single-stranded overhang of the chromosome end requires telomerase-DNA base pairing. Furthermore, we show that telomerase processivity contributes to telomere elongation in vivo Together, these findings provide new insight into the dynamics of telomerase recruitment and the importance of processivity in maintaining telomere length in human cancer cells. PMID- 29386296 TI - Respiratory Chain Supercomplexes associate with the Cysteine Desulfurase Complex of the Iron-Sulfur Cluster Assembly Machinery. AB - Mitochondria are the powerhouses of eukaryotic cells. The activity of the respiratory chain complexes generates a proton gradient across the inner membrane, which is used by the F1FO-ATP synthase to produce ATP for cellular metabolism. In baker's yeast Saccharomyces cerevisiae the cytochrome bc1 complex (complex III) and cytochrome c oxidase (complex IV) associate in respiratory chain supercomplexes. Iron-sulfur clusters (ISC) form reactive centers of respiratory chain complexes. The assembly of ISC occurs in the mitochondrial matrix and is essential for cell viability. The cysteine desulfurase Nfs1 provides sulfur for ISC assembly and forms with partner proteins the ISC biogenesis desulfurase complex (ISD complex). Here, we report an unexpected interaction of the active ISD complex with the cytochrome bc1 complex and cytochrome c oxidase. The individual deletion of complex III or complex IV blocks the association of the ISD complex with respiratory chain components. We conclude that the ISD complex binds selectively to respiratory chain supercomplexes. We propose that this molecular link contributes to coordination of iron-sulfur cluster formation with respiratory activity. PMID- 29386297 TI - Dynein-pulling forces counteract lamin-mediated nuclear stability during nuclear envelope repair. AB - Recent work done exclusively in tissue culture cells revealed that the nuclear envelope (NE) ruptures and repairs in interphase. The duration of NE ruptures depends on lamins, however the underlying mechanisms and relevance to in vivo events is not known. Here, we use the C. elegans zygote to analyze lamin's role in NE rupture and repair in vivo Transient NE ruptures and subsequent NE collapse are induced by weaknesses in the nuclear lamina caused by expression of an engineered hypomorphic C. elegans lamin allele. Dynein-generated forces that position nuclei enhance the severity of transient NE ruptures and cause NE collapse. Reduction of dynein forces allows the weakened lamin network, but not lamin-deficient nuclei, to restrict nucleo-cytoplasmic mixing and support stable NE recovery. Surprisingly, the high incidence of transient NE ruptures does not contribute to embryonic lethality, which is instead correlated with stochastic chromosome scattering resulting from premature NE collapse, suggesting that C. elegans tolerate transient losses of NE compartmentalization during early embryogenesis. In sum, we demonstrate that lamin counteracts dynein forces and supports stable NE repair to prevent catastrophic loss of the nuclear permeability barrier, and thus provide the first mechanistic analysis of NE ruptures in an organismal context. PMID- 29386299 TI - Donor intravascular monocyte trafficking: a potential therapeutic target for primary graft dysfunction following lung transplantation? PMID- 29386300 TI - In Vivo Analysis of a Gain-of-Function Mutation Confirms Unc18/Munc18's Role in Priming. PMID- 29386298 TI - Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations. AB - BACKGROUND: Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. OBJECTIVE: To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. METHODS: We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. RESULTS: The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis. CONCLUSIONS: Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. TRIAL REGISTRATION NUMBER: Results, NCT01360398. PMID- 29386301 TI - Phosphorylation Switch of Orco Shapes the Sense of Smell in Insects. PMID- 29386302 TI - Does Routine Bioimpedance-Guided Fluid Management Provide Additional Benefit to Non-Anuric Peritoneal Dialysis Patients? Results from COMPASS Clinical Trial. AB - INTRODUCTION: In peritoneal dialysis (PD) patients, volume overload is related to cardiac dysfunction and mortality, while intravascular volume depletion is associated with a rapid decline in the residual renal function (RRF). This study sought to determine the clinical usefulness of bioimpedance spectroscopy (BIS) guided fluid management for preserving RRF and cardiac function in PD patients. SUBJECTS AND METHODS: This is a multicenter, prospective, open-label study that was conducted over a 1-year period (NCT01887262). Non-anuric (urine volume > 500 mL/day) subjects on PD were enrolled. Subjects in the control group received fluid management based on the clinical information alone. Those in the BIS group received BIS-guided fluid management along with clinical information. RESULTS: The subjects (N = 137, mean age 51.3 +/- 12.8 years, 54% male) were randomly assigned to the BIS group (n = 67) or to the control group (n = 70). There were no significant differences between the 2 groups with regard to age, sex ratio, cause of kidney failure, duration of PD, baseline comorbidity, RRF, PD method, or peritoneal transport type. At baseline, the 2 groups were not different in terms of RRF (glomerular filtration rate [GFR], 5.1 +/- 2.9 vs 5.5 +/- 3.7 mL/min/1.73 m2). After follow-up, changes in the GFR between the 2 groups were not different (-1.5 +/- 2.4 vs -1.3 +/- 2.6 mL/min/1.73 m2, p = 0.593). Over the 1-year study period, both groups maintained stability of various fluid status parameters. Between the 2 groups, there were no differences in the net change of various fluid status parameters such as overhydration (OH) and extracellular water/total body water (ECW/TBW). A net change in ECW over 1 year was slightly but significantly higher in the control group (net increase, 0.57 +/- 1.27 vs 0.05 +/ 1.63 L, p = 0.047). However, this difference was not translated into an improvement in RRF in the BIS group. There were no differences in echocardiographic parameters or arterial stiffness at the end of follow-up. CONCLUSION: Routine BIS-guided fluid management in non-anuric PD patients did not provide additional benefit in volume control, RRF preservation, or cardiovascular (CV) parameters. However, our study cannot be generalized to the whole PD population. Further research is warranted in order to investigate the subpopulation of PD patients who may benefit from routine BIS-guided fluid management. PMID- 29386303 TI - Randomized Controlled Trial Comparing Open Versus Laparoscopic Placement of a Peritoneal Dialysis Catheter and Outcomes: The CAPD I Trial. AB - OBJECTIVE: To determine the best operation technique, open versus laparoscopic, for insertion of a peritoneal dialysis (PD) catheter with regard to clinical success. Clinical success was defined as an adequate function of the catheter 2 - 4 weeks after insertion. METHODS: All patients with end-stage renal disease who were suitable for PD and gave informed consent were randomized for either open surgery or laparoscopic surgery. A previous laparotomy was not considered an exclusion criterion. Laparoscopic placement had the advantage of pre-peritoneal tunneling, the possibility for adhesiolysis, and placement of the catheter under direct vision. Catheter fixation techniques, omentopexy, or other adjunct procedures were not performed. Other measured parameters were in-hospital morbidity and mortality and post-operative infections. RESULTS: Between 2010 and 2016, 95 patients were randomized to this study protocol. After exclusion of 5 patients for various reasons, 44 patients received an open procedure and 46 patients a laparoscopic procedure. Gender, age, body mass index (BMI), hypertension, current hemodialysis, severe heart failure, and previous an abdominal operation were not significantly different between the groups. However, in the open surgery group, fewer patients had a previous median laparotomy compared with the laparoscopic group (6 vs 16 patients; p = 0.027). There was no statistically significant difference in mean operation time (36 +/- 24 vs 38 +/- 15 minutes) and hospital stay (2.1 +/- 2.7 vs 3.1 +/- 7.3 days) between the groups. In the open surgery group 77% of the patients had an adequate functioning catheter 2 - 4 weeks after insertion compared with 70% of patients in the laparoscopic group (p = not significant [NS]). In the open surgery group there was 1 post-operative death (2%) compared with none in the laparoscopic group (p = NS). The morbidity in both groups was low and not significantly different. In the open surgery group, 2 patients had an exit-site infection and 1 patient had a paramedian wound infection. In the laparoscopic group, 1 patient had a transient cardiac event, 1 patient had intraabdominal bleeding requiring reoperation, and 1 patient had fluid leakage that could be managed conservatively. The survival curve demonstrated a good long-term function of PD. CONCLUSION: This randomized controlled trial (RCT) comparing open vs laparoscopic placement of PD catheters demonstrates equal clinical success rates between the 2 techniques. Advanced laparoscopic techniques such as catheter fixation techniques and omentopexy might further improve clinical outcome. PMID- 29386305 TI - Single Daily Icodextrin Exchange as Initial and Solitary Therapy. AB - BACKGROUND: Incremental dialysis utilizes gradually increasing dialysis doses in response to declines in residual kidney function, and it is the preferred renal replacement therapy for patients who have just transitioned to end-stage renal disease (ESRD). Incremental peritoneal dialysis (PD) may impose fewer restrictions on patients' lifestyle, help attenuate lifetime peritoneal and systemic exposure to glucose and its degradation products, and minimize connections that could compromise the sterile fluid path. In this study, we utilized a 3-pore kinetic model to assess fluid and solute removal during single daily icodextrin treatments for patients with varying glomerular filtration rates (GFR). METHODS: Single icodextrin exchanges of 8 to 16 hours using 2- and 2.5-L bag volumes were simulated for different patient transport types (i.e., high to low) to predict daily peritoneal ultrafiltration (UF), daily peritoneal sodium removal, and weekly total (peritoneal + residual kidney) Kt/V (Kt/VTotal) for patients with residual renal GFRs ranging from 0 to 15 mL/min/1.73 m2. RESULTS: Daily peritoneal UF varied from 359 to 607 mL, and daily peritoneal Na removal varied from 52 to 87 mEq depending on length of icodextrin exchange and bag volume. Both were effectively independent of patient transport type. All but very large patients (total body water [TBW] > 60 L) were predicted to achieve adequate dialysis (Kt/VTotal >= 1.7) with a GFR of 10 mL/min/1.73 m2, and small patients (TBW: 30 L) were predicted to achieve adequate dialysis with a GFR of 6 mL/min/1.73 m2. CONCLUSIONS: A single daily icodextrin exchange can be tailored to augment urea, UF, and Na removal in patients with sufficient residual kidney function (RKF). A solitary icodextrin exchange may therefore be reasonable initial therapy for some incident ESRD patients. PMID- 29386304 TI - Abdominal Aortic Calcifications Predict Survival in Peritoneal Dialysis Patients. AB - BACKGROUND: Peripheral arterial disease and vascular calcifications contribute significantly to the outcome of dialysis patients. The aim of this study was to evaluate the prognostic role of severity of abdominal aortic calcifications and peripheral arterial disease on outcome of peritoneal dialysis (PD) patients using methods easily available in everyday clinical practice. METHODS: We enrolled 249 PD patients (mean age 61 years, 67% male) in this prospective, observational, multicenter study from 2009 to 2013. The abdominal aortic calcification score (AACS) was assessed using lateral lumbar X ray, and the ankle-brachial index (ABI) using a Doppler device. RESULTS: The median AACS was 11 (range 0 - 24). In 58% of the patients, all 4 segments of the abdominal aorta showed deposits, while 19% of patients had no visible deposits (AACS 0). Ankle-brachial index was normal in 49%, low (< 0.9) in 17%, and high (> 1.3) in 34% of patients. Altogether 91 patients (37%) died during the median follow-up of 46 months. Only 2 patients (5%) with AACS 0 died compared with 50% of the patients with AACS >= 7 (p < 0.001). The adjusted hazard ratio for all-cause mortality was 4.85 (95% confidence interval [CI] 1.94 - 24.46) for aortic calcification (AACS >= 7), 2.14 for diabetes (yes/no), 0.93 for albumin (per 1 g/L), and 1.04 for age (per year). A low or high ABI were not independently associated with mortality. CONCLUSIONS: Severe aortic calcification was a strong predictor of all-cause mortality in PD patients. The evaluation of aortic calcifications by lateral X ray is a simple method that allows the identification of high-risk patients. PMID- 29386307 TI - A Retrospective Analysis of Etiology and Outcomes of Refractory CAPD Peritonitis in a Tertiary Care Center from North India. AB - BACKGROUND: Refractory peritonitis is defined as failure of clearance of peritoneal fluid despite 5 days of appropriate antibiotic therapy. Catheter removal decreases morbidity and mortality. Data on the outcomes of refractory peritonitis and of reinitiation of peritoneal dialysis (PD) in this group of patients are sparse. The present study analyzed etiology, outcomes, and prognostic factors of refractory peritonitis as well as survival of the reinitiation of the technique. METHODS: This was a single-center retrospective study that included 90 patients of refractory continuous ambulatory PD (CAPD) peritonitis at a tertiary care center in North India. We collected information regarding symptomatology, causes, prognostic factors, and outcomes of refractory peritonitis. RESULTS: Ninety patients suffered 93 episodes of refractory peritonitis. Fungal peritonitis was the most common cause of refractory peritonitis. Twenty nine (31%) episodes were culture-negative. We observed no difference between culture-positive and culture-negative peritonitis. Out of 90 patients, 54 (60%) recovered while 36 (40%) died. Septic shock at presentation alone was significantly associated with mortality in our study. The immediate mortality of refractory peritonitis is high. Even in patients who were shifted to permanent hemodialysis, 33% died in the first 3 months. Mean duration of technique survival after reinitiation was 23 months (1 - 85 months). Among the 12 patients who were reinitiated on CAPD, 5 patients had technique failure due to refractory peritonitis or ultrafiltration (UF) failure. CONCLUSION: Refractory peritonitis is associated with significant morbidity and mortality despite catheter removal. Reinitiation is confounded by residual infection, which is a concern for poor technique survival, and high immediate mortality. PMID- 29386306 TI - Brachial-Ankle Pulse Wave Velocity Could Be a Predictor of Mortality in Patients on Peritoneal Dialysis. AB - BACKGROUND AND OBJECTIVE: Elevated pulse wave velocity (PWV) has been associated with higher mortality in the general population, chronic kidney disease (CKD) patients, and hemodialysis patients. However, in peritoneal dialysis (PD) patients, this association has received little attention. The aim of this study was to evaluate the association between baseline brachial-ankle PWV (baPWV) levels and total mortality in PD patients. METHODS: In this single-center retrospective cohort study, 254 incident PD patients with baseline baPWV were followed up from 1 January 2013 to 31 July 2016. Collected baseline data included demographic characteristics and clinical and laboratory measurements. The association of baseline baPWV levels with total mortality was assessed using multivariable-adjusted Cox models. RESULTS: Of 254 patients, mean age was 61.4 (+/-15.3) years, 61.4% of patients were men, and 22.4% of patients were diabetic. The mean baseline baPWV level was 17.6 (+/-5.84) m/s. During a mean 31.5 (+/ 20.8) month follow-up period, 45 patients died, of which 13 deaths were caused by cardiovascular disease. After adjusting for sex, age, blood pressure (BP), body mass index (BMI), and hemoglobin, as well as serum albumin, calcium, phosphorus, intact parathyroid hormone (iPTH), uric acid, and medication use, the highest baPWV tertile was significantly associated with a hazard ratio (HR) for total mortality of 2.97 (95% confidence interval [CI], 1.23 - 7.16; p = 0.02). Each 1 m/s higher baseline baPWV level was associated with a 7% (95% CI, 1.03 - 1.12; p = 0.001) higher risk of total mortality. In sensitivity analyses, individuals with baPWV > 21.0 m/s had the highest adjusted risk for total death (HR, 3.22; 95% CI, 1.71 - 6.08; p < 0.001). CONCLUSION: Higher baseline baPWV levels at the commencement of PD were independently associated with total mortality, which suggests that clinicians could use baPWV as a predictor of higher risk of mortality in PD patients. PMID- 29386308 TI - Effects of Oral Paricalcitol and Calcitriol Treatment on Peritoneal Membrane Characteristics of Peritoneal Dialysis Patients - A Pilot Study. AB - BACKGROUND: Long-term peritoneal dialysis (PD) is frequently complicated by technique failure preceded by peritoneal remodeling. Vitamin D has potent immunomodulatory characteristics: anti-inflammatory, anti-angiogenic, anti fibrotic properties, and influences on the macrophage phenotype. Little is known about the relation between pleiotropic effects attributed to vitamin D3 and the peritoneal membrane and what is the most appropriate vitamin D sterol in prevention of peritoneal remodeling in PD patients. Animal studies have suggested that paricalcitol has advantageous effects: decrease in plasma markers of inflammation, less peritoneal fibrosis, less pronounced PD-induced omental angiogenesis, and prevention of loss of ultrafiltration. We investigated whether paricalcitol is advantageous over calcitriol in PD patients. METHOD: A multicenter open-label 1:1 randomized non-blinded clinical pilot study enrolled prevalent continous ambulatory PD (CAPD) patients for a period of 6 months comparing paricalcitol with calcitriol. All patients were treated with biocompatible PD fluids. The primary endpoint was peritoneal transport parameters, exploratory endpoints were biomarkers of peritoneal damage and cell analysis (including M1/M2 macrophages), and safety endpoints were metabolic parameters. RESULTS: Twenty-seven patients were included. Fourteen were randomized to treatment with paricalcitol. There was no difference in peritoneal transport parameters between the groups. We found similar Kt/V, D/P creatinine, D/D0 glucose, ultrafiltration, residual renal function and 24-h urine volume during the study. There was no difference in biomarker concentrations in peritoneal effluents, and no difference in leucocyte differentiation or mesothelial cells between the groups at any time point. Parathyroid hormone (PTH) levels decreased after administration of calcitriol after 12 and 24 weeks compared with baseline (p = 0.001; p = 0.025). Parathyroid hormone levels in the paricalcitol group did not change significantly. CONCLUSION: In this pilot study we investigated the effect of active vitamin D in PD patients. We found no specific benefit of active vitamin D3 in vitamin D3-sufficient PD patients. Additional studies in preferably incident patients, with an adequate PTH suppression in the intervention groups and during a longer period, are required to test the beneficial effects of active vitamin D3 over no treatment and to investigate whether in 25(OH)D3-deficient PD patients the type of active vitamin D3 matters. PMID- 29386309 TI - Increased Serum Lactate in Peritoneal Dialysis Patients Presenting with Intercurrent Illness. AB - BACKGROUND: Lactate is the most commonly used buffer in peritoneal dialysis (PD) solutions. While previous studies have shown that serum lactate is normal in stable PD patients, the purpose of our study was to evaluate whether abnormal lactate values are more common in PD patients presenting to the emergency department (ED) and have the same significance as in the general population. METHODS: This observational cohort study assessed the prevalence of elevated serum lactate in PD patients presenting to the ED and evaluated clinical factors associated with an abnormal lactate value. RESULTS: We studied 172 patient visits in 89 PD patients to the ED at a major academic center between January 1, 2015, and December 31, 2015. An initial venous blood lactate value was performed in 91 visits (53%) and was found to be elevated (> 2 mmol/L) in 26 cases (29%). While an abnormal lactate was associated with signs of hemodynamic compromise such as intensive care unit (ICU) admission (26.9% vs 10.8%, p = 0.05) and tachycardia (46.2% vs 9.2%, p < 0.01), in half of the cases with elevated lactate, there was no evidence of hemodynamic instability at initial presentation. Moreover, an abnormal lactate value was also associated with a greater likelihood of undergoing an abdominal computed tomography (CT) scan (46.2% vs 18.5%, p < 0.01), but bowel ischemia was present in only 1 case. CONCLUSION: An abnormal lactate value is often seen in PD patients presenting to the ED, even in the absence of signs of hemodynamic instability, and very rarely indicates bowel ischemia. We postulate that in the setting of an acute intercurrent illness, there is a transient disruption in the metabolism of lactate absorbed from the PD fluid. This novel observation suggests that elevated serum lactate in the sick PD patient does not necessarily indicate tissue hypoperfusion or gut ischemia and may obviate unnecessary investigations. PMID- 29386310 TI - Comprehensive Approach to Peritoneal Dialysis-Related Peritonitis by Enteric Microorganisms. Comparison Between Single Organism and Polymicrobial Infections. AB - BACKGROUND: Peritoneal infections of enteric origin (EntP) have been classically investigated using partial strategies, focused on particular subgroups of microorganisms. A more comprehensive approach may facilitate the definition of the nomenclature and clinical presentation of these infections. OBJECTIVES: To investigate the clinical presentation and outcomes of a full spectrum of EntP, with a particular interest in the comparison between single-organism and polymicrobial infections. METHOD: Following an observational design, we investigated 165 single-organism and 83 polymicrobial peritonitis episodes with isolation of at least 1 enteric bacteria (Enterobacteriaceae, Enterococcus spp. and/or intestinal anaerobics). We compared the risk of treatment failure for these 2 types of infection and explored the significance of the isolation of specific microorganisms and of their antibacterial susceptibility patterns. RESULTS: Polymicrobial EntP was associated with higher rates of hospitalization, more changes to initial antibiotic therapy, more surgical explorations, and higher mortality and treatment failure rates than monobacterial EntP. However, stratified and multivariate analyses revealed that the burden of these differences rested on the isolation of intestinal anaerobics (odds ratio [OR] 12.05, 95% confidence interval [CI] 2.53-31.09, p < 0.001) and/or Enterococcus faecium (OR 3.37, 95% CI 1.02-11.30, p = 0.046), while other polymicrobial infections were more comparable with single-organism peritonitis, except for even higher mortality rates in the former group. Lower antibiotic susceptibility of the isolations (OR 1.18, 95% CI 0.51-2.70, p = 0.70) did not perform as a predictor of treatment failure. CONCLUSION: A comprehensive approach to peritoneal infections by intestinal microorganisms may provide a focused perspective of the clinical presentation and outcomes of these complications of peritoneal dialysis. PMID- 29386311 TI - Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG). AB - BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1 16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy. PMID- 29386314 TI - The Power to Choose. PMID- 29386313 TI - Benefit-Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib. AB - : On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo-controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28-day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50-0.79, p < .0001) with an estimated median OS of 10.6 months in the regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression-free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52-60] (HR = 0.46; 95% CI, 0.37-0.56, p < .0001) was also demonstrated; the estimated median PFS was 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar-plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit to-risk evaluation led to approval for treatment of patients with advanced HCC. IMPLICATIONS FOR PRACTICE: Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients. PMID- 29386315 TI - NHS must stop sharing confidential patient data with Home Office, say MPs. PMID- 29386312 TI - Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma. AB - : Gynecologic carcinosarcomas, previously known as malignant mixed Mullerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase E (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. KEY POINTS: Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase E (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors. PMID- 29386316 TI - Avoiding blame and liability is vital to learning from errors and engineering a safer NHS. PMID- 29386317 TI - Mental health workforce will suffer under Brexit, providers warn. PMID- 29386318 TI - Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study. PMID- 29386319 TI - Margaret McCartney: Doctors and families must be able to work together for safer care. PMID- 29386320 TI - Off-label drugs directly compete with licensed drugs for same use, rules European court. PMID- 29386321 TI - US's $2bn annual spend on dry eye disease "brings tears to your eyes," say critics. PMID- 29386322 TI - Government will give equal weight to mental health in 1.6 million disability benefit reviews. PMID- 29386323 TI - Sixty seconds on . . . the Presidents Club. PMID- 29386324 TI - Moving to accountable care in the NHS. PMID- 29386325 TI - Socioeconomic deprivation and mode-specific outcomes in patients with chronic heart failure. AB - OBJECTIVE: To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF). METHODS: We prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) <=45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year). RESULTS: A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005). CONCLUSIONS: Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non cardiovascular events. PMID- 29386326 TI - Practical guide for the comparison of two next-generation sequencing systems for solid tumour analysis in a universal healthcare system. AB - AIMS: Although there have been excellent reports in the literature of validating next-generation sequencing, comparisons between two systems are not often published due to cost and time. We set out to establish that targetable mutations could be reliably detected with different gene panels and different chemistries using a common bioinformatics pipeline for meaningful comparisons to be made. METHODS: After running selected formalin-fixed, paraffin-embedded samples through QPCR, Sanger sequencing and the 50 gene hotspot v2 panel from Life Technologies to determine standard-of-care variants, we compared the Oncomine panel from Life Technologies performed on a Personal Genome Machine (PGM) and the eight-gene actionable panel from Qiagen performed on a MiSeq platform. We used a common bioinformatics program following the creation of respective VCF files. RESULTS: Both panels were accurate to above 90%, the actionable panel workflow was easier to perform but the lowest effective starting DNA load was obtained on the Oncomine workflow at 4 ng. Such minimal DNA can help with samples where there is limited material such as those for lung cancer molecular studies. We also discuss gene panel content and propose that increasing the gene profile of a panel will not benefit clinical laboratories where standard-of-care testing is all that is required. CONCLUSIONS: Once recognised, it may be cost-effective for such laboratories to begin validation with an appropriate bioinformatics pipeline for targeted multigene hotspot molecular testing. PMID- 29386327 TI - Positive Influence of Behavior Change Communication on Knowledge, Attitudes, and Practices for Visceral Leishmaniasis/Kala-azar in India. AB - BACKGROUND: Visceral leishmaniasis (VL) is endemic to 54 districts in 4 states of India. Poor awareness of the disease and inappropriate health-seeking behavior are major challenges to eliminating the disease. Between February 2016 and March 2017, we implemented a behavior change communication (BCC) intervention in 33 districts of Bihar, 4 districts of Jharkhand, and 3 districts of West Bengal using a mix of channels, including group and interpersonal communication, to improve knowledge, attitudes, and practices of communities, frontline health workers, and opinion leaders. We conducted an impact assessment in October 2016, after the second indoor residual spraying (IRS) round, in Bihar and Jharkhand to evaluate the effect of the BCC intervention. METHODS: Villages in 10 districts of Bihar and 4 districts in Jharkhand were selected for inclusion in the assessment. Selected villages were categorized as either intervention or control based on where project activities were conducted. Households were randomly selected proportional to caste composition, and interviewers surveyed the head of the household on whether the house was sprayed during the last IRS round and on knowledge, attitudes, and practices related to VL. We interviewed 700 households in intervention villages and 350 households in control villages and conducted correlation analysis to explore the association between IRS refusal and socioeconomic variables, and tested for association between IRS refusal and exposure to BCC activities. Odds ratios (ORs) were calculated. RESULTS: We reached an estimated 3.3 million contacts in Bihar and Jharkhand through the intervention's BCC activities. IRS refusal rates were significantly lower in intervention households than control households (mean=7.95% vs. 24.45%, respectively; OR, 0.27; 95% confidence interval [CI], 0.11 to 0.62; P<.001). Households in intervention villages were more aware than those in control villages that VL is spread by sand flies (68.4% vs. 7.4%, respectively; P<.001) and of IRS as an effective control measure (82.3% vs. 41.7%, respectively; P<.001). A greater percentage of households in intervention villages than control villages indicated they would encourage a patient to go to primary health centers for diagnosis and treatment of VL (77.0% vs. 39.4%, respectively) and to encourage others to accept IRS (78.6% vs. 44.6%, respectively; P<.001). CONCLUSION: Households that were exposed to community-based BCC activities largely using group and interpersonal communication had better knowledge, attitudes, and practices related to VL, including acceptance of IRS as a preventive measure, than households not exposed. BCC activities are thus an important component of VL elimination strategies. PMID- 29386328 TI - The Big Bang of tissue growth: Apical cell constriction turns into tissue expansion. AB - How tissue growth is regulated during development and cancer is a fundamental question in biology. In this issue, Tsoumpekos et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201705104) and Forest et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201705107) identify Big bang (Bbg) as an important growth regulator of the Drosophila melanogaster wing imaginal disc. PMID- 29386329 TI - Correction: Specialized ribosomes and specific ribosomal protein paralogs control translation of mitochondrial proteins. PMID- 29386330 TI - SAM68 is required for regulation of Pumilio by the NORAD long noncoding RNA. AB - The number of known long noncoding RNA (lncRNA) functions is rapidly growing, but how those functions are encoded in their sequence and structure remains poorly understood. NORAD (noncoding RNA activated by DNA damage) is a recently characterized, abundant, and highly conserved lncRNA that is required for proper mitotic divisions in human cells. NORAD acts in the cytoplasm and antagonizes repressors from the Pumilio family that bind at least 17 sites spread through 12 repetitive units in NORAD sequence. Here we study conserved sequences in NORAD repeats, identify additional interacting partners, and characterize the interaction between NORAD and the RNA-binding protein SAM68 (KHDRBS1), which is required for NORAD function in antagonizing Pumilio. These interactions provide a paradigm for how repeated elements in a lncRNA facilitate function. PMID- 29386331 TI - Unexpected conformational variations of the human centromeric chromatin complex. AB - We combined classical salt fractionation with chromatin immunoprecipitation to recover human centromeric chromatin under native conditions. We found that >85% of the total centromeric chromatin is insoluble under conditions typically used for native chromatin extraction. To map both soluble and insoluble chromatin in situ, we combined CUT&RUN (cleavage under targets and release using nuclease), a targeted nuclease method, with salt fractionation. Using this approach, we observed unexpected structural and conformational variations of centromere protein A (CENP-A)-containing complexes on different alpha-satellite dimeric units within highly homogenous arrays. Our results suggest that slight alpha satellite sequence differences control the structure and occupancy of the associated centromeric chromatin complex. PMID- 29386332 TI - Kynurenic acid accumulation underlies learning and memory impairment associated with aging. AB - A general feature of animal aging is decline in learning and memory. Here we show that in Caenorhabditis elegans, a significant portion of this decline is due to accumulation of kynurenic acid (KYNA), an endogenous antagonist of neural N methyl-D-aspartate receptors (NMDARs). We show that activation of a specific pair of interneurons either through genetic means or by depletion of KYNA significantly improves learning capacity in aged animals even when the intervention is applied in aging animals. KYNA depletion also improves memory. We show that insulin signaling is one factor in KYNA accumulation. PMID- 29386334 TI - Duchenne muscular dystrophy: genome editing gives new hope for treatment. AB - Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal and cardiac muscles, representing one of the most common recessive fatal inherited genetic diseases with 1:3500-1:5000 in yearly incidence. It is caused by mutations in the DMD gene that encodes the membrane-associated dystrophin protein. Over the years, many have been the approaches to management of DMD, but despite all efforts, no effective treatment has yet been discovered. Hope for the development of potential therapeutics has followed the recent advances in genome editing and gene therapy. This review gives an overview to DMD and summarises current lines of evidence with regard to treatment and disease management alongside the appropriate considerations. PMID- 29386335 TI - Effects of continuous positive airway pressure therapy on left ventricular diastolic function: a randomised, sham-controlled clinical trial. AB - Continuous positive airway pressure (CPAP) therapy may decrease left ventricular (LV) loads and improve myocardial oxygenation. In this study, we investigated the effect of CPAP on LV diastolic function compared with sham treatment in patients with severe obstructive sleep apnoea (OSA).This 3-month prospective single-centre randomised sham-controlled trial analysed 52 patients with severe OSA. Patients were randomly assigned (1:1) to receive either CPAP or sham treatment for 3 months. The main investigator and patients were masked to the trial randomisation. The primary end-point was change of early diastolic mitral annular (e') velocity over the 3-month period. Secondary end-points were pulse wave velocity (PWV), 24-h ambulatory blood pressure (BP) and variables of ventricular vascular coupling at 3 months.After 3 months of follow-up, CPAP treatment significantly increased the e' velocity, and was greater than the sham treatment (0.65+/-1.70 versus -0.61+/-1.85 cm.s-1, p=0.014). The PWV, 24-h mean diastolic BP, night-time diastolic BP, arterial elastance index and ventricular-vascular coupling index after 3 months of follow-up decreased significantly in the CPAP group.In patients with severe OSA, CPAP treatment for 3 months improved LV diastolic function more than sham treatment, and was accompanied by improvements in arterial stiffness and ventricular-vascular coupling. PMID- 29386333 TI - Molecular barcoding of viral vectors enables mapping and optimization of mRNA trans-splicing. AB - Genome editing has proven to be highly potent in the generation of functional gene knockouts in dividing cells. In the CNS however, efficient technologies to repair sequences are yet to materialize. Reprogramming on the mRNA level is an attractive alternative as it provides means to perform in situ editing of coding sequences without nuclease dependency. Furthermore, de novo sequences can be inserted without the requirement of homologous recombination. Such reprogramming would enable efficient editing in quiescent cells (e.g., neurons) with an attractive safety profile for translational therapies. In this study, we applied a novel molecular-barcoded screening assay to investigate RNA trans-splicing in mammalian neurons. Through three alternative screening systems in cell culture and in vivo, we demonstrate that factors determining trans-splicing are reproducible regardless of the screening system. With this screening, we have located the most permissive trans-splicing sequences targeting an intron in the Synapsin I gene. Using viral vectors, we were able to splice full-length fluorophores into the mRNA while retaining very low off-target expression. Furthermore, this approach also showed evidence of functionality in the mouse striatum. However, in its current form, the trans-splicing events are stochastic and the overall activity lower than would be required for therapies targeting loss-of-function mutations. Nevertheless, the herein described barcode-based screening assay provides a unique possibility to screen and map large libraries in single animals or cell assays with very high precision. PMID- 29386336 TI - The independent contribution of Pseudomonas aeruginosa infection to long-term clinical outcomes in bronchiectasis. AB - Pseudomonas aeruginosa is responsible for chronic infection in many bronchiectasis patients but it is not known whether it is associated with worse clinical outcomes independent of the underlying severity of disease.This study analysed data from 2596 bronchiectasis patients included from 10 different bronchiectasis clinical centres across Europe and Israel, with a 5-year follow-up period. Prevalence of P. aeruginosa chronic infection and its independent impact on exacerbations, hospitalisations, quality of life and mortality was assessed.The prevalence of P. aeruginosa chronic infection was 15.0% (n=389). P. aeruginosa was associated with a higher mortality in a univariate analysis (hazard ratio (HR) 2.02; 95% (confidence interval) CI 1.53-2.66; p<0.0001) but an independent impact on mortality was not found in a multivariate analysis (HR 0.98; 95% CI 0.70-1.36; p=0.89). P. aeruginosa was independently associated with increased mortality only in patients with frequent exacerbations (two or more per year) (HR 2.03; 95% CI 1.36-3.03; p=0.001). An independent association with worse quality of life of 7.46 points (95% CI 2.93-12.00; p=0.001) was found in a multivariable linear regression. P. aeruginosa was therefore found to be independently associated with exacerbation frequency, hospital admissions and worse quality of life. Mortality was increased in patients with P. aeruginosa particularly in the presence of frequent exacerbations. PMID- 29386337 TI - Mindfulness-based cognitive therapy in COPD: a cluster randomised controlled trial. AB - A considerable proportion of patients with chronic obstructive pulmonary disease (COPD) entering pulmonary rehabilitation (PR) report psychological distress, which is often accompanied by poor physical health status. Mindfulness-based cognitive therapy (MBCT) has been shown to improve psychological and physical outcomes in other chronic diseases. We therefore evaluated the efficacy of MBCT as an add-on to a standard PR programme in COPD.COPD patients eligible for PR were cluster randomised to receive either an 8-week, group-based MBCT programme as an add-on to an 8-week PR programme (n=39), or PR alone (n=45). The primary outcomes of psychological distress and physical health status impairment were measured with the Hospital Anxiety and Depression Scale (HADS) and the COPD Assessment Test (CAT) before randomisation (T1), mid- (T2) and post-intervention (T3), and at 3 (T4) and 6 (T5) months' follow-up .A statistically significant time*arm effect was found for the HADS (Cohen's d=0.62, 95% CIs (d)=0.18-1.06, p=0.010). The treatment effect on the CAT failed to reach statistical significance (d=0.42, 95% CIs (d)=-0.06-0.90, p=0.061).MBCT showed a statistically significant and durable effect on psychological distress, indicating that MBCT may be an efficacious add-on to standard PR programmes in COPD. PMID- 29386338 TI - Inhaled corticosteroids and increased microbial load in COPD: potential role of epithelial adhesion molecules. PMID- 29386340 TI - Pseudomonas aeruginosa infection and exacerbations in bronchiectasis: more questions than answers. PMID- 29386339 TI - Physical activity to improve health: do not forget that the lungs benefit too. PMID- 29386341 TI - The scale of the problem of obstructive lung disease in Africa becomes clearer, but where are the solutions? PMID- 29386342 TI - "Global strategy for asthma management and prevention: GINA executive summary." E.D. Bateman, S.S. Hurd, P.J. Barnes, J. Bousquet, J.M. Drazen, J.M. FitzGerald, P. Gibson, K. Ohta, P. O'Byrne, S.E. Pedersen, E. Pizzichini, S.D. Sullivan, S.E. Wenzel and H.J. Zar. Eur Respir J 2008; 31: 143-178. PMID- 29386343 TI - Prevalence, risk factors and clinical correlates of COPD in a rural setting in Tanzania. AB - Chronic obstructive pulmonary disease (COPD) causes substantial burden of disease in developed countries, but there are limited data from Africa. We aimed to estimate the prevalence of COPD in Tanzania and identify the risk factors associated with it.This was a cross-sectional descriptive survey involving adults aged >=35 years. We collected data on symptoms and risk factors using the Burden of Obstructive Lung Diseases questionnaire. Spirometry was performed and COPD diagnosed based on post-bronchodilator forced expiratory volume in 1 s/forced vital capacity <70%. We also measured indoor and outdoor carbon monoxide (CO) levels.A total of 869 participants (49.1% females) completed the questionnaires. Of these, 57.1% completed post-bronchodilator spirometry. Of the 25.2% ever smokers, only 5.4% were current smokers. COPD prevalence was estimated at 17.5% (21.7% in males and 12.9% in females). COPD was associated with a history of cough, phlegm production and wheezing. 51.7% of COPD patients reported cough and 85% had mild to moderate airway limitation. Females had a higher rate of exacerbation. Pulmonary tuberculosis (TB) was reported in 10% of patients. Only 1.7% of patients who were diagnosed as COPD had ever received any medication, with only one female COPD patient having received an inhaler. 99.5% of the population used biomass fuels for cooking. The majority of households had CO levels up to 20 ppm.The prevalence of COPD in Tanzania is high, with a peak at a relatively young age and a preponderance in males. A history of TB, cigarette smoking and male sex are important risk factors. Indoor air pollution coupled with use of biomass fuel for cooking and heating may be an important risk factor for developing COPD in rural Tanzania. However, these factors need to be studied further. PMID- 29386344 TI - Synergistic role of HSP90alpha and HSP90beta to promote myofibroblast persistence in lung fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90alpha and HSP90beta, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90alpha in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90alpha and HSP90beta was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-beta1.We demonstrate that circulating HSP90alpha is upregulated in IPF patients in correlation with disease severity. The release of HSP90alpha is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90alpha signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90beta stabilises LRP1, thus amplifying HSP90alpha extracellular action.We believe that the specific inhibition of extracellular HSP90alpha is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF. PMID- 29386345 TI - Social deprivation and prognosis in Scottish patients with pulmonary arterial hypertension. AB - Several demographic and clinical factors have prognostic significance in idiopathic pulmonary arterial hypertension (IPAH). Studies in China and the USA have suggested an association between low socioeconomic status and reduced survival. The impact of social deprivation on IPAH survival in the UK is not known.280 patients with IPAH and hereditary PAH (HPAH) attending the Scottish Pulmonary Vascular Unit (Glasgow, UK) were assigned to social deprivation quintiles using the Scottish Index of Multiple Deprivation database. The association between survival and social deprivation quintile was assessed using Cox proportional hazards regression analysis.The distribution of IPAH/HPAH patients was more socially deprived than would be expected based on Scottish citizenry as a whole (Chi-squared 16.16, p=0.003), suggesting referral and access to care is not impeded by socioeconomic status. Univariate analysis demonstrated no significant association between social deprivation and survival (p=0.81), and this association failed to reach significance with inclusion of time, sex and age as covariates in the model (p=0.23). There were no statistically significant correlations between social deprivation and baseline clinical variables of prognostic importance except for age, sex and quality of life.Social deprivation is not a significant referral barrier or prognostic factor for IPAH and HPAH in Scotland. PMID- 29386346 TI - Role of a prolonged inpatient admission when evaluating children with problematic severe asthma. PMID- 29386347 TI - Does physical fitness enhance lung function in children and young adults? AB - Although physical activity is important for lung health, it is unclear whether physical fitness influences lung function. We investigated associations between lung function and fitness in two population-based cohort studies of children and young adults.Aerobic fitness was measured using a maximal cycle ergometer test at ages 9, 15, 21 and 29 years in Odense, Denmark and using a submaximal cycle test at ages 15, 26, 32 and 38 years in Dunedin, New Zealand.Aerobic fitness was positively associated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in cross-sectional analyses at all ages in both cohorts, independently of height, weight, sex, asthma and smoking. Each standard deviation difference in fitness was associated with 2-3% predicted higher values of FEV1 and FVC. Improvements in fitness during childhood and adolescence were associated with growth in lung volumes in longitudinal analyses. These associations tended to be stronger in males than females. No longitudinal associations were found after peak adult lung function had been attained. Fitness was not significantly associated with FEV1/FVC ratios.Aerobic fitness is positively associated with lung volumes. Improving fitness during childhood and adolescence is associated with greater adult lung volumes, but not with airway calibre. PMID- 29386348 TI - First trimester fetal size and prescribed asthma medication at 15 years of age. AB - There is increasing evidence that antenatal factors predispose to childhood asthma. We tested the hypothesis that reduced first trimester fetal size is associated with increased risk for asthma at 15 years of age.Fetal size in the first and second trimester was ascertained by ultrasound scan. The primary outcome of being dispensed one or more asthma medications by the family doctor in the year before the 15th birthday was determined from routinely acquired dispensing data.Dispensing data were available for 1699 (88% of the original cohort) participants at 15 years of age and questionnaire data for 750 (39%). Each reduction in z-score for first trimester size was associated with increased odds for dispensed asthma medication at 15 years of age (OR 1.26, 95% CI 1.03 1.54) and self-reported use of asthma medications (OR 1.55, 95% CI 1.16-2.08). Overall, first and second trimester size and forced expiratory volume in 1 s at ages 5, 10 and 15 years were reduced for those dispensed asthma medications compared with those not dispensed asthma medications (p=0.003).Antenatal factors that are active by the first trimester may contribute to respiratory well-being throughout childhood. Dropout from a birth cohort study can overestimate of the magnitude of any true association. PMID- 29386349 TI - Airway infection, systemic inflammation and lung clearance index in children and adults with cystic fibrosis. PMID- 29386350 TI - A Universal Standard for the Validation of Blood Pressure Measuring Devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement. AB - In the past 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers, and manufacturers, would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by the AAMI, ESH, and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH, and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols. PMID- 29386351 TI - Engineering a potent inhibitor of matriptase from the natural hepatocyte growth factor activator inhibitor type-1 (HAI-1) protein. AB - Dysregulated matriptase activity has been established as a key contributor to cancer progression through its activation of growth factors, including the hepatocyte growth factor (HGF). Despite its critical role and prevalence in many human cancers, limitations to developing an effective matriptase inhibitor include weak binding affinity, poor selectivity, and short circulating half-life. We applied rational and combinatorial approaches to engineer a potent inhibitor based on the hepatocyte growth factor activator inhibitor type-1 (HAI-1), a natural matriptase inhibitor. The first Kunitz domain (KD1) of HAI-1 has been well established as a minimal matriptase-binding and inhibition domain, whereas the second Kunitz domain (KD2) is inactive and involved in negative regulation. Here, we replaced the inactive KD2 domain of HAI-1 with an engineered chimeric variant of KD2/KD1 domains and fused the resulting construct to an antibody Fc domain to increase valency and circulating serum half-life. The final protein variant contains four stoichiometric binding sites that we showed were needed to effectively inhibit matriptase with a Ki of 70 +/- 5 pm, an increase of 120-fold compared with the natural HAI-1 inhibitor, to our knowledge making it one of the most potent matriptase inhibitors identified to date. Furthermore, the engineered inhibitor demonstrates a protease selectivity profile similar to that of wildtype KD1 but distinct from that of HAI-1. It also inhibits activation of the natural pro-HGF substrate and matriptase expressed on cancer cells with at least an order of magnitude greater efficacy than KD1. PMID- 29386352 TI - Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response. AB - Although stop codon readthrough is used extensively by viruses to expand their gene expression, verified instances of mammalian readthrough have only recently been uncovered by systems biology and comparative genomics approaches. Previously, our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates. Extending on the identification of this readthrough motif, we here investigated stop codon readthrough, using tissue culture reporter assays, for all previously untested human genes containing UGA_CUAG. The readthrough efficiency of the annotated stop codon for the sequence encoding vitamin D receptor (VDR) was 6.7%. It was the highest of those tested but all showed notable levels of readthrough. The VDR is a member of the nuclear receptor superfamily of ligand-inducible transcription factors, and it binds its major ligand, calcitriol, via its C-terminal ligand-binding domain. Readthrough of the annotated VDR mRNA results in a 67 amino acid-long C-terminal extension that generates a VDR proteoform named VDRx. VDRx may form homodimers and heterodimers with VDR but, compared with VDR, VDRx displayed a reduced transcriptional response to calcitriol even in the presence of its partner retinoid X receptor. PMID- 29386353 TI - The Candida albicans ENO1 gene encodes a transglutaminase involved in growth, cell division, morphogenesis, and osmotic protection. AB - Candida albicans is an opportunistic fungus that is part of the normal microflora commonly found in the human digestive tract and the normal mucosa or skin of healthy individuals. However, in immunocompromised individuals, it becomes a serious health concern and a threat to their lives and is ranked as the leading fungal infection in humans worldwide. As existing treatments for this infection are non-specific or under threat of developing resistance, there is a dire necessity to find new targets for designing specific drugs to defeat this fungus. Some authors reported the presence of the transglutaminase activity in Candida and Saccharomyces, but its identity remains unknown. We report here the phenotypic effects produced by the inhibition of transglutaminase enzymatic activity with cystamine, including growth inhibition of yeast cells, induction of autophagy in response to damage caused by cystamine, alteration of the normal yeast division pattern, changes in cell wall, and inhibition of the yeast-to mycelium transition. The latter phenomenon was also observed in the C. albicans ATCC 26555 strain. Growth inhibition by cystamine was also determined in other Candida strains, demonstrating the importance of transglutaminase in these species. Finally, we identified enolase 1 as the cell wall protein responsible for TGase activity. After studying the inhibition of enzymatic activities with anti-CaEno1 antibodies and through bioinformatics studies, we suggest that the enolase and transglutaminase catalytic sites are localized in different domains of the protein. The aforementioned data indicate that TGase/Eno1 is a putative target for designing new drugs to control C. albicans infection. PMID- 29386354 TI - Antagonism between the transcription factors NANOG and OTX2 specifies rostral or caudal cell fate during neural patterning transition. AB - During neurogenesis, neural patterning is a critical step during which neural progenitor cells differentiate into neurons with distinct functions. However, the molecular determinants that regulate neural patterning remain poorly understood. Here we optimized the "dual SMAD inhibition" method to specifically promote differentiation of human pluripotent stem cells (hPSCs) into forebrain and hindbrain neural progenitor cells along the rostral-caudal axis. We report that neural patterning determination occurs at the very early stage in this differentiation. Undifferentiated hPSCs expressed basal levels of the transcription factor orthodenticle homeobox 2 (OTX2) that dominantly drove hPSCs into the "default" rostral fate at the beginning of differentiation. Inhibition of glycogen synthase kinase 3beta (GSK3beta) through CHIR99021 application sustained transient expression of the transcription factor NANOG at early differentiation stages through Wnt signaling. Wnt signaling and NANOG antagonized OTX2 and, in the later stages of differentiation, switched the default rostral cell fate to the caudal one. Our findings have uncovered a mutual antagonism between NANOG and OTX2 underlying cell fate decisions during neural patterning, critical for the regulation of early neural development in humans. PMID- 29386355 TI - The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization. AB - PRKR-like endoplasmic reticulum kinase (PERK) is one of the major sensor proteins that detect protein folding imbalances during endoplasmic reticulum (ER) stress. However, it remains unclear how ER stress activates PERK to initiate a downstream unfolded protein response (UPR). Here, we found that PERK's luminal domain can recognize and selectively interact with misfolded proteins but not with native proteins. Screening a phage-display library, we identified a peptide substrate, P16, of the PERK luminal domain and confirmed that P16 efficiently competes with misfolded proteins for binding this domain. To unravel the mechanism by which the PERK luminal domain interacts with misfolded proteins, we determined the crystal structure of the bovine PERK luminal domain complexed with P16 to 2.8-A resolution. The structure revealed that PERK's luminal domain binds the peptide through a conserved hydrophobic groove. Substitutions within hydrophobic regions of the PERK luminal domain abolished the binding between PERK and misfolded proteins. We also noted that peptide binding results in major conformational changes in the PERK luminal domain that may favor PERK oligomerization. The structure of the PERK luminal domain-P16 complex suggested stacking of the luminal domain that leads to PERK oligomerization and activation via autophosphorylation after ligand binding. Collectively, our structural and biochemical results strongly support a ligand-driven model in which the PERK luminal domain interacts directly with misfolded proteins to induce PERK oligomerization and activation, resulting in ER stress signaling and the UPR. PMID- 29386356 TI - Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity. AB - Recovery after stroke, a major cause of adult disability, is often unpredictable and incomplete. Behavioral recovery is associated with functional reorganization (remapping) in perilesional regions, suggesting that promoting this process might be an effective strategy to enhance recovery. However, the molecular mechanisms underlying remapping after brain injury and the consequences of its modulation are poorly understood. Focal sensory loss or deprivation has been shown to induce remapping in the corresponding brain areas through activity-regulated cytoskeleton-associated protein (Arc)-mediated synaptic plasticity. We show that targeted sensory deprivation via whisker trimming in mice after induction of ischemic stroke in the somatosensory cortex representing forepaw accelerates remapping into the whisker barrel cortex and improves sensorimotor recovery. These improvements persisted even after focal sensory deprivation ended (whiskers allowed to regrow). Mice deficient in Arc, a gene critical for activity-dependent synaptic plasticity, failed to remap or recover sensorimotor function. These results indicate that post-stroke remapping occurs through Arc-mediated synaptic plasticity and is required for behavioral recovery. Furthermore, our findings suggest that enhancing perilesional cortical plasticity via focal sensory deprivation improves recovery after ischemic stroke in mice. PMID- 29386357 TI - Eradication of spontaneous malignancy by local immunotherapy. AB - It has recently become apparent that the immune system can cure cancer. In some of these strategies, the antigen targets are preidentified and therapies are custom-made against these targets. In others, antibodies are used to remove the brakes of the immune system, allowing preexisting T cells to attack cancer cells. We have used another noncustomized approach called in situ vaccination. Immunoenhancing agents are injected locally into one site of tumor, thereby triggering a T cell immune response locally that then attacks cancer throughout the body. We have used a screening strategy in which the same syngeneic tumor is implanted at two separate sites in the body. One tumor is then injected with the test agents, and the resulting immune response is detected by the regression of the distant, untreated tumor. Using this assay, the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG)-a Toll-like receptor 9 (TLR9) ligand-and anti-OX40 antibody provided the most impressive results. TLRs are components of the innate immune system that recognize molecular patterns on pathogens. Low doses of CpG injected into a tumor induce the expression of OX40 on CD4+ T cells in the microenvironment in mouse or human tumors. An agonistic anti-OX40 antibody can then trigger a T cell immune response, which is specific to the antigens of the injected tumor. Remarkably, this combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers. PMID- 29386358 TI - Tissue-resident mesenchymal stromal cells: Implications for tissue-specific antifibrotic therapies. AB - Recent scientific findings support the notion that fibrosis is driven by tissue specific cellular and molecular mechanisms. Analysis of seemingly equivalent mesenchymal stromal cell (MSC) populations residing in different organs revealed unique properties and lineage capabilities that vary from one anatomical location to another. We review recently characterized tissue-resident MSC populations with a prominent role in fibrosis and highlight therapeutically relevant molecular pathways regulating their activity in chronic disease. PMID- 29386360 TI - Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma. AB - High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse EMU-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL. PMID- 29386359 TI - Zika virus-related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice. AB - Although Zika virus (ZIKV) infection in pregnant women can cause placental damage, intrauterine growth restriction, microcephaly, and fetal demise, these disease manifestations only became apparent in the context of a large epidemic in the Americas. We hypothesized that ZIKV is not unique among arboviruses in its ability to cause congenital infection. To evaluate this, we tested the capacity of four emerging arboviruses [West Nile virus (WNV), Powassan virus (POWV), chikungunya virus (CHIKV), and Mayaro virus (MAYV)] from related (flavivirus) and unrelated (alphavirus) genera to infect the placenta and fetus in immunocompetent, wild-type mice. Although all four viruses caused placental infection, only infection with the neurotropic flaviviruses (WNV and POWV) resulted in fetal demise. WNV and POWV also replicated efficiently in second trimester human maternal (decidua) and fetal (chorionic villi and fetal membrane) explants, whereas CHIKV and MAYV replicated less efficiently. In mice, RNA in situ hybridization and histopathological analysis revealed that WNV infected the placenta and fetal central nervous system, causing injury to the developing brain. In comparison, CHIKV and MAYV did not cause substantive placental or fetal damage despite evidence of vertical transmission. On the basis of the susceptibility of human maternal and fetal tissue explants and pathogenesis experiments in immunocompetent mice, other emerging neurotropic flaviviruses may share with ZIKV the capacity for transplacental transmission, as well as subsequent infection and injury to the developing fetus. PMID- 29386361 TI - An eutherian intronic sequence gave rise to a major satellite DNA in Platyrrhini. AB - Satellite DNAs (satDNAs) are major components of eukaryote genomes. However, because of their quick divergence, the evolutionary origin of a given satDNA family can rarely be determined. Herein we took advantage of available primate sequenced genomes to determine the origin of the CapA satDNA (approx. 1500 bp long monomers), first described in the tufted capuchin monkey Sapajus apella We show that CapA is an abundant satDNA in Platyrrhini, whereas in the genomes of most eutherian mammals, including humans, this sequence is present only as a single copy located within a large intron of the NOS1AP (nitric oxide synthase 1 adaptor protein) gene. Our data suggest that this intronic CapA-like sequence gave rise to the CapA satDNA and we discuss possible mechanisms implicated in this event. This is the first report to our knowledge of a single copy intronic sequence giving origin to a satDNA that reaches up to 100 000 copies in some genomes. PMID- 29386362 TI - Understanding heterogeneities in mosquito-bite exposure and infection distributions for the elimination of lymphatic filariasis. AB - It is well known that individuals in the same community can be exposed to a highly variable number of mosquito bites. This heterogeneity in bite exposure has consequences for the control of vector-borne diseases because a few people may be contributing significantly to transmission. However, very few studies measure sources of heterogeneity in a way which is relevant to decision-making. We investigate the relationship between two classic measures of heterogeneity, spatial and individual, within the context of lymphatic filariasis, a parasitic mosquito-borne disease. Using infection and mosquito-bite data for five villages in Papua New Guinea, we measure biting characteristics to model what impact bed nets have had on control of the disease. We combine this analysis with geospatial modelling to understand the spatial relationship between disease indicators and nightly mosquito bites. We found a weak association between biting and infection heterogeneity within villages. The introduction of bed-nets increased biting heterogeneity, but the reduction in mean biting more than compensated for this, by reducing prevalence closer to elimination thresholds. Nightly biting was explained by a spatial heterogeneity model, while parasite load was better explained by an individual heterogeneity model. Spatial and individual heterogeneity are qualitatively different with profoundly different policy implications. PMID- 29386363 TI - Priority effects are weakened by a short, but not long, history of sympatric evolution. AB - Priority effects, or the effects of species arrival history on local species abundances, have been documented in a range of taxa. However, factors determining the extent to which priority effects affect community assembly remain unclear. Using laboratory populations of the bacterium Pseudomonas fluorescens, we examined whether shared evolutionary history affected the strength of priority effects. We hypothesized that sympatric evolution of populations belonging to the same guild would lead to niche differentiation, resulting in phenotypic complementarity that weakens priority effects. Consistent with this hypothesis, we found that priority effects tended to be weaker in sympatrically evolved pairs of immigrating populations than in allopatrically evolved pairs. Furthermore, priority effects were weaker under higher phenotypic complementarity. However, these patterns were observed only in populations with a relatively short history of sympatric evolution, and disappeared when populations had evolved together for a long time. Together, our results suggest that the evolutionary history of organismal traits may dictate the strength of priority effects and, consequently, the extent of historical contingency in the assembly of ecological communities. PMID- 29386364 TI - Imitation of novel conspecific and human speech sounds in the killer whale (Orcinus orca). AB - Vocal imitation is a hallmark of human spoken language, which, along with other advanced cognitive skills, has fuelled the evolution of human culture. Comparative evidence has revealed that although the ability to copy sounds from conspecifics is mostly uniquely human among primates, a few distantly related taxa of birds and mammals have also independently evolved this capacity. Remarkably, field observations of killer whales have documented the existence of group-differentiated vocal dialects that are often referred to as traditions or cultures and are hypothesized to be acquired non-genetically. Here we use a do-as I-do paradigm to study the abilities of a killer whale to imitate novel sounds uttered by conspecific (vocal imitative learning) and human models (vocal mimicry). We found that the subject made recognizable copies of all familiar and novel conspecific and human sounds tested and did so relatively quickly (most during the first 10 trials and three in the first attempt). Our results lend support to the hypothesis that the vocal variants observed in natural populations of this species can be socially learned by imitation. The capacity for vocal imitation shown in this study may scaffold the natural vocal traditions of killer whales in the wild. PMID- 29386365 TI - Low intensity blood parasite infections do not reduce the aerobic performance of migratory birds. AB - Blood parasites (Haemosporidia) are thought to impair the flight performance of infected animals, and therefore, infected birds are expected to differ from their non-infected counterparts in migratory capacity. Since haemosporidians invade host erythrocytes, it is commonly assumed that infected individuals will have compromised aerobic capacity, but this has not been examined in free-living birds. We tested if haemosporidian infections affect aerobic performance by examining metabolic rates and exercise endurance in migratory great reed warblers (Acrocephalus arundinaceus) experimentally treated with Plasmodium relictum pGRW04 and in naturally infected wild birds over consecutive life-history stages. We found no effect of acute or chronic infections on resting metabolic rate, maximum metabolic rate or exercise endurance in either experimentally treated or free-living birds. Oxygen consumption rates during rest and while undergoing maximum exercise as well as exercise endurance increased from breeding to migration stages in both infected and non-infected birds. Importantly, phenotypic changes associated with preparation for migration were similarly unaffected by parasitaemia. Consequently, migratory birds experiencing parasitaemia levels typical of chronic infection do not differ in migratory capacity from their uninfected counterparts. Thus, if infected hosts differ from uninfected conspecifics in migration phenology, other mechanisms besides aerobic capacity should be considered. PMID- 29386366 TI - Evolutionary conserved neural signature of early life stress affects animal social competence. AB - In vertebrates, the early social environment can persistently influence behaviour and social competence later in life. However, the molecular mechanisms underlying variation in animal social competence are largely unknown. In rats, high-quality maternal care causes an upregulation of hippocampal glucocorticoid receptors (gr) and reduces offspring stress responsiveness. This identifies gr regulation as a candidate mechanism for maintaining variation in animal social competence. We tested this hypothesis in a highly social cichlid fish, Neolamprologus pulcher, reared with or without caring parents. We find that the molecular pathway translating early social experience into later-life alterations of the stress axis is homologous across vertebrates: fish reared with parents expressed the glucocorticoid receptor gr1 more in the telencephalon. Furthermore, expression levels of the transcription factor egr-1 (early growth response 1) were associated with gr1 expression in the telencephalon and hypothalamus. When blocking glucocorticoid receptors (GR) with an antagonist, mifepristone (RU486), parent-reared individuals showed more socially appropriate, submissive behaviour when intruding on a larger conspecific's territory. Remarkably, mifepristone treated fish were less attacked by territory owners and had a higher likelihood of territory takeover. Our results indicate that early social-environment effects on stress axis programming are mediated by an evolutionary conserved molecular pathway, which is causally involved in environmentally induced variation of animal social competence. PMID- 29386367 TI - Reinterpretation of a previously described Jehol bird clarifies early trophic evolution in the Ornithuromorpha. AB - STM35-3 from the Yixian Formation is the only Early Cretaceous ornithuromorph preserving direct evidence of granivory. The crop contains numerous seeds and the preservation of gastroliths presumably within the ventriculus indicates this diet was paired with the presence of a gastric mill as in living granivorous birds. STM35-3 was originally referred to Hongshanornis longicresta, member of a diverse clade of small, basal ornithuromorphs with elongate hindlimbs known as the Hongshanornithidae. Hindlimb proportions suggest that hongshanornithids were wading birds, an ecological inference somewhat in conflict with direct evidence suggesting Hongshanornis fed on seeds. However, close inspection of STM35-3 reveals that the specimen represents a new species not closely related to hongshanornithids, distinguished by large forelimbs that exceed the length of the hindlimbs, robust and narrow coracoids, and a delicate edentulous rostrum. By contrast, all hongshanornithids have hindlimbs that far exceed the length of the forelimbs, coracoids with wide sternal margins, and small teeth throughout the upper and lower jaws. Reinterpretation of this new taxon, Eogranivora edentulata gen. et sp. nov, helps to clarify trophic driven patterns of tooth loss within the Ornithuromorpha. Apparent loss of the hallux may represent the first such occurrence in a Mesozoic bird and suggests a highly terrestrial lifestyle. PMID- 29386368 TI - Equilibrium dynamics of European pre-industrial populations: the evidence of carrying capacity in human agricultural societies. AB - Human populations tend to grow steadily, because of the ability of people to make innovations, and thus overcome and extend the limits imposed by natural resources. It is therefore questionable whether traditional concepts of population ecology, including environmental carrying capacity, can be applied to human societies. The existence of carrying capacity cannot be simply inferred from population time-series, but it can be indicated by the tendency of populations to return to a previous state after a disturbance. So far only indirect evidence at a coarse-grained scale has indicated the historical existence of human carrying capacity. We analysed unique historical population data on 88 settlements before and after the Thirty Years War (1618-1648), one the longest and most destructive conflicts in European history, which reduced the population of Central Europe by 30-50%. The recovery rate of individual settlements after the war was positively correlated with the extent of the disturbance, so that the population size of the settlements after a period of regeneration was similar to the pre-war situation, indicating an equilibrium population size (i.e. carrying capacity). The carrying capacity of individual settlements was positively determined mostly by the fertility of the soil and the area of the cadastre, and negatively by the number of other settlements in the surroundings. Pre-industrial human population sizes were thus probably controlled by negative density dependence mediated by soil fertility, which could not increase due to limited agricultural technologies. PMID- 29386369 TI - Redirected aggression as a conflict management tactic in the social cichlid fish Julidochromis regani. AB - Conflict management consists of social behaviours that reduce the costs of conflict among group members. Redirected aggression-that is, when a recently attacked individual attacks a third party immediately after the original aggression-is considered a conflict management tactic, as it may reduce the victim's probability of being the object of further aggression. Redirected aggression has been reported in many vertebrates, but few quantitative studies have been conducted on this behaviour in fishes. We examined the function of redirected aggression in Julidochromis regani, a social cichlid fish. Behavioural experiments showed that redirected aggression functioned to divert the original aggressor's attention towards a third party and to pre-empt an attack towards the victim by the third-party individual, specifically among females. We found, however, that redirected aggression did not delay the recurrence of aggression by the original aggressor. These results suggest that a primary function of redirected aggression is to maintain the dominance of its actor against a subordinate occupying an adjacent rank. This study provides, to our knowledge, the first evidence that redirected aggression functions to manage conflict in social fish. PMID- 29386371 TI - Knowledge of childhood burn risks and burn first aid: Cool Runnings. AB - AIM: The high incidence of hot beverage scalds among young children has not changed in the past 15 years, but preventive campaigns have been scarce. A novel approach was used to engage mothers of young children in an app-based hot beverage scald prevention campaign 'Cool Runnings'. This paper provides baseline data for this randomised controlled trial (RCT). METHOD: Queensland-based mothers aged 18+ years with at least one child aged 5-12 months were recruited via social media to Cool Runnings, which is a two-group, parallel, single-blinded RCT. RESULTS: In total, 498 participants from across Queensland completed the baseline questionnaire. The most common source of burn first aid information was the internet (79%). One-third (33%) correctly identified hot beverage scalds as the leading cause of childhood burns, 43% knew the age group most at risk. While 94% reported they would cool a burn with water, only 10% reported the recommended 20min duration. After adjusting for all relevant variables, there were two independent predictors of adequate burn first aid knowledge: first aid training in the past year (OR=3.32; 95% CI 1.8 to 6.1) and smoking status (OR=0.17; 95% CI 0.04 to 0.7). CONCLUSION: In this study, mothers of young children were largely unaware how frequently hot beverage scalds occur and the age group most susceptible to them. Inadequate burn first aid knowledge is prevalent across mothers of young children; there is an urgent and compelling need to improve burn first aid knowledge in this group. Given the high incidence of hot beverages scalds in children aged 6-24 months, it is important to target future burn prevention/first aid campaigns at parents of young children. TRIAL REGISTRATION NUMBER: ACTRN12616000019404; Pre-results. PMID- 29386370 TI - School is out on noisy reefs: the effect of boat noise on predator learning and survival of juvenile coral reef fishes. AB - Noise produced by anthropogenic activities is increasing in many marine ecosystems. We investigated the effect of playback of boat noise on fish cognition. We focused on noise from small motorboats, since its occurrence can dominate soundscapes in coastal communities, the number of noise-producing vessels is increasing rapidly and their proximity to marine life has the potential to cause deleterious effects. Cognition-or the ability of individuals to learn and remember information-is crucial, given that most species rely on learning to achieve fitness-promoting tasks, such as finding food, choosing mates and recognizing predators. The caveat with cognition is its latent effect: the individual that fails to learn an important piece of information will live normally until the moment where it needs the information to make a fitness related decision. Such latent effects can easily be overlooked by traditional risk assessment methods. Here, we conducted three experiments to assess the effect of boat noise playbacks on the ability of fish to learn to recognize predation threats, using a common, conserved learning paradigm. We found that fish that were trained to recognize a novel predator while being exposed to 'reef + boat noise' playbacks failed to subsequently respond to the predator, while their 'reef noise' counterparts responded appropriately. We repeated the training, giving the fish three opportunities to learn three common reef predators, and released the fish in the wild. Those trained in the presence of 'reef + boat noise' playbacks survived 40% less than the 'reef noise' controls over our 72 h monitoring period, a performance equal to that of predator-naive fish. Our last experiment indicated that these results were likely due to failed learning, as opposed to stress effects from the sound exposure. Neither playbacks nor real boat noise affected survival in the absence of predator training. Our results indicate that boat noise has the potential to cause latent effects on learning long after the stressor has gone. PMID- 29386372 TI - Supplemental surveillance: a review of 2015 and 2016 agricultural injury data from news reports on AgInjuryNews.org. AB - BACKGROUND: Agriculture, forestry, fishing and hunting industry is the most hazardous occupational sector in the USA. Even with this level of occupational risk, several national and state-level occupational injury surveillance programmes have been eliminated, leaving regional efforts to analyse multiple sources and compile data on agricultural injuries and fatalities. No up-to-date centralised national database for agricultural injuries/fatalities in the USA currently exists. OBJECTIVE: Using the public data on AgInjuryNews.org, this study considered a wide range of variables to examine fatalities and injuries of the industry in 2015 and 2016. The results reported in this paper sought to explore and understand common data elements of US news reports. METHODS: As of 5 April 2017, more than 3000 articles across 36 years were contained in the dataset. We selected 2 years to review, 2015 and 2016, which represented the most complete years to date; 2015 was the first year in which systematic collection was initiated by the AgInjuryNews.org team. Data were coded based on the Occupational Injury and Illness Classification System source and event/exposure types. RESULTS: A total of 1345 victims were involved in 1044 incidents. Leading sources of injuries were vehicles and machinery, and the most common event/exposure type was transportation. CONCLUSIONS: This study demonstrated that data from AgInjuryNew.org is consistent with previous literature, and it can supply up-to-date data as an open-source surveillance supplement, disseminated for health and safety stakeholders. PMID- 29386373 TI - Allogeneic stem cell transplantation for FLT3 mutated acute myeloid leukemia in first complete remission: does age really matter? PMID- 29386374 TI - Large granular lymphocyte cells and immune dysregulation diseases - the chicken or the egg? PMID- 29386375 TI - Hemophilia A: different phenotypes may be explained by multiple and variable effects of the causative mutation in the F8 gene. PMID- 29386376 TI - Remembering Professor Felice Gavosto (February 16, 1921 - December 11, 2017). PMID- 29386378 TI - Ovarian angiogenesis in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most prevalent endocrine pathology among women in reproductive age. Its main symptoms are oligo or amenorrhea, hyperandrogenism and the presence of ovarian cysts. It is also associated with infertility, obesity and insulin resistance. Mainly due to its heterogeneity, PCOS treatments are directed to manage its symptoms and to prevent associated diseases. The correct formation and regression of blood vessels during each ovarian cycle is indispensable for proper follicular development, ovulation and corpus luteum formation. The importance of these processes opened a new and promising field: ovarian angiogenesis. Vascular alterations characterize numerous pathologies, either with increased, decreased or abnormal angiogenesis. In the last years, several anomalies of ovarian angiogenesis have been described in women with PCOS. Therefore, it has been suggested that these alterations may be associated with the decreased - or lack of - ovulation rates and for the formation of cysts in the PCOS ovaries. Restoration of a proper vessel formation in the ovaries may lead to improved follicular development and ovulation in these patients. In the present review, we attempt to summarize the alterations in ovarian angiogenesis that have been described in women with PCOS. We also discuss the therapeutic approaches aimed to correct these alterations and their beneficial effects on the treatment of infertility in PCOS. PMID- 29386377 TI - Molecular control of stomatal development. AB - Plants have evolved developmental plasticity which allows the up- or down regulation of photosynthetic and water loss capacities as new leaves emerge. This developmental plasticity enables plants to maximise fitness and to survive under differing environments. Stomata play a pivotal role in this adaptive process. These microscopic pores in the epidermis of leaves control gas exchange between the plant and its surrounding environment. Stomatal development involves regulated cell fate decisions that ensure optimal stomatal density and spacing, enabling efficient gas exchange. The cellular patterning process is regulated by a complex signalling pathway involving extracellular ligand-receptor interactions, which, in turn, modulate the activity of three master transcription factors essential for the formation of stomata. Here, we review the current understanding of the biochemical interactions between the epidermal patterning factor ligands and the ERECTA family of leucine-rich repeat receptor kinases. We discuss how this leads to activation of a kinase cascade, regulation of the bHLH transcription factor SPEECHLESS and its relatives, and ultimately alters stomatal production. PMID- 29386379 TI - Resolving single-actin filaments within the contractile ring of fission yeast. PMID- 29386380 TI - Light-enabled reversible self-assembly and tunable optical properties of stable hairy nanoparticles. AB - The ability to dynamically organize functional nanoparticles (NPs) via the use of environmental triggers (temperature, pH, light, or solvent polarity) opens up important perspectives for rapid and convenient construction of a rich variety of complex assemblies and materials with new structures and functionalities. Here, we report an unconventional strategy for crafting stable hairy NPs with light enabled reversible and reliable self-assembly and tunable optical properties. Central to our strategy is to judiciously design amphiphilic star-like diblock copolymers comprising inner hydrophilic blocks and outer hydrophobic photoresponsive blocks as nanoreactors to direct the synthesis of monodisperse plasmonic NPs intimately and permanently capped with photoresponsive polymers. The size and shape of hairy NPs can be precisely tailored by modulating the length of inner hydrophilic block of star-like diblock copolymers. The perpetual anchoring of photoresponsive polymers on the NP surface renders the attractive feature of self-assembly and disassembly of NPs on demand using light of different wavelengths, as revealed by tunable surface plasmon resonance absorption of NPs and the reversible transformation of NPs between their dispersed and aggregated states. The dye encapsulation/release studies manifested that such photoresponsive NPs may be exploited as smart guest molecule nanocarriers. By extension, the star-like block copolymer strategy enables the crafting of a family of stable stimuli-responsive NPs (e.g., temperature- or pH sensitive polymer-capped magnetic, ferroelectric, upconversion, or semiconducting NPs) and their assemblies for fundamental research in self-assembly and crystallization kinetics of NPs as well as potential applications in optics, optoelectronics, magnetic technologies, sensory materials and devices, catalysis, nanotechnology, and biotechnology. PMID- 29386382 TI - Adaptive value of novel MHC immune gene variants. PMID- 29386381 TI - Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. AB - There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcgamma receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by alphaIIbbeta3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC driven diseases. PMID- 29386383 TI - Conceptualizing degrees of theory of mind. PMID- 29386384 TI - DJ-1 deficiency impairs synaptic vesicle endocytosis and reavailability at nerve terminals. AB - Mutations in DJ-1 (PARK7) are a known cause of early-onset autosomal recessive Parkinson's disease (PD). Accumulating evidence indicates that abnormalities of synaptic vesicle trafficking underlie the pathophysiological mechanism of PD. In the present study, we explored whether DJ-1 is involved in CNS synaptic function. DJ-1 deficiency impaired synaptic vesicle endocytosis and reavailability without inducing structural alterations in synapses. Familial mutants of DJ-1 (M26I, E64D, and L166P) were unable to rescue defective endocytosis of synaptic vesicles, whereas WT DJ-1 expression completely restored endocytic function in DJ 1 KO neurons. The defective synaptic endocytosis shown in DJ-1 KO neurons may be attributable to alterations in membrane cholesterol level. Thus, DJ-1 appears essential for synaptic vesicle endocytosis and reavailability, and impairment of this function by familial mutants of DJ-1 may be related to the pathogenesis of PD. PMID- 29386385 TI - Tobacco smoking, E-cigarettes, and nicotine harm. PMID- 29386386 TI - De novo mutation in RING1 with epigenetic effects on neurodevelopment. AB - RING1 is an E3-ubiquitin ligase that is involved in epigenetic control of transcription during development. It is a component of the polycomb repressive complex 1, and its role in that complex is to ubiquitylate histone H2A. In a 13 year-old girl with syndromic neurodevelopmental disabilities, we identified a de novo mutation, RING1 p.R95Q, which alters a conserved arginine residue in the catalytic RING domain. In vitro assays demonstrated that the mutant RING1 retains capacity to catalyze ubiquitin chain formation, but is defective in its ability to ubiquitylate histone H2A in nucleosomes. Consistent with this in vitro effect, cells of the patient showed decreased monoubiquitylation of histone H2A. We modeled the mutant RING1 in Caenorhabditis elegans by editing the comparable amino acid change into spat-3, the suggested RING1 ortholog. Animals with either the missense mutation or complete knockout of spat-3 were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Relevant to our patient, animals heterozygous for either the missense or knockout allele also showed neuronal defects. Our results support three conclusions: mutation of RING1 is the likely cause of a human neurodevelopmental syndrome, mutation of RING1 can disrupt histone H2A ubiquitylation without disrupting RING1 catalytic activity, and the comparable mutation in C. elegans spat-3 both recapitulates the effects on histone H2A ubiquitylation and leads to neurodevelopmental abnormalities. This role for RING1 adds to our understanding of the importance of aberrant epigenetic effects as causes of human neurodevelopmental disorders. PMID- 29386388 TI - Multidimensional photon correlation spectroscopy of cavity polaritons. AB - The strong coupling of atoms and molecules to radiation field modes in optical cavities creates dressed matter/field states known as polaritons with controllable dynamical and energy transfer properties. We propose a multidimensional optical spectroscopy technique for monitoring polariton dynamics. The response of a two-level atom to the time-dependent coupling to a single-cavity mode is monitored through time-and-frequency-resolved single-photon coincidence measurements of spontaneous emission. Polariton population and coherence dynamics and its variation with cavity photon number and controlled by gating parameters are predicted by solving the Jaynes-Cummings model. PMID- 29386389 TI - Mechanism of inhibition of retromer transport by the bacterial effector RidL. AB - Retrograde vesicle trafficking pathways are responsible for returning membrane associated components from endosomes to the Golgi apparatus and the endoplasmic reticulum (ER), and they are critical for maintaining organelle identity, lipid homeostasis, and many other cellular functions. The retrograde transport pathway has emerged as an important target for intravacuolar bacterial pathogens. The opportunistic pathogen Legionella pneumophila exploits both the secretory and recycling branches of the vesicle transport pathway for intracellular bacterial proliferation. Its Dot/Icm effector RidL inhibits the activity of the retromer by directly engaging retromer components. However, the mechanism underlying such inhibition remains unknown. Here we present the crystal structure of RidL in complex with VPS29, a subunit of the retromer. Our results demonstrate that RidL binds to a highly conserved hydrophobic pocket of VPS29. This interaction is critical for endosomal recruitment of RidL and for its inhibitory effects. RidL inhibits retromer activity by direct competition, in which it occupies the VPS29 binding site of the essential retromer regulator TBC1d5. The mechanism of retromer inhibition by RidL reveals a hotspot on VPS29 critical for recognition by its regulators that is also exploited by pathogens, and provides a structural basis for the development of small molecule inhibitors against the retromer. PMID- 29386390 TI - Family with sequence similarity 13, member A modulates adipocyte insulin signaling and preserves systemic metabolic homeostasis. AB - Adipose tissue dysfunction is causally implicated in the impaired metabolic homeostasis associated with obesity; however, detailed mechanisms underlying dysregulated adipocyte functions in obesity remain to be elucidated. Here we searched for genes that provide a previously unknown mechanism in adipocyte metabolic functions and identified family with sequence similarity 13, member A (Fam13a) as a factor that modifies insulin signal cascade in adipocytes. Fam13a was highly expressed in adipose tissue, predominantly in mature adipocytes, and its expression was substantially reduced in adipose tissues of obese compared with lean mice. We revealed that Fam13a accentuated insulin signaling by recruiting protein phosphatase 2A with insulin receptor substrate 1 (IRS1), leading to protection of IRS1 from proteasomal degradation. We further demonstrated that genetic loss of Fam13a exacerbated obesity-related metabolic disorders, while targeted activation of Fam13a in adipocytes ameliorated it in association with altered adipose tissue insulin sensitivity in mice. Our data unveiled a previously unknown mechanism in the regulation of adipocyte insulin signaling by Fam13a and identified its significant role in systemic metabolic homeostasis, shedding light on Fam13a as a pharmacotherapeutic target to treat obesity-related metabolic disorders. PMID- 29386391 TI - Arabidopsis mRNA decay landscape arises from specialized RNA decay substrates, decapping-mediated feedback, and redundancy. AB - The decay of mRNA plays a vital role in modulating mRNA abundance, which, in turn, influences cellular and organismal processes. In plants and metazoans, three distinct pathways carry out the decay of most cytoplasmic mRNAs: The mRNA decapping complex, which requires the scaffold protein VARICOSE (VCS), removes a protective 5' cap, allowing for 5' to 3' decay via EXORIBONUCLEASE4 (XRN4, XRN1 in metazoans and yeast), and both the exosome and SUPPRESSOR OF VCS (SOV)/DIS3L2 degrade RNAs in the 3' to 5' direction. However, the unique biological contributions of these three pathways, and whether they degrade specialized sets of transcripts, are unknown. In Arabidopsis, the participation of SOV in RNA homeostasis is also unclear, because Arabidopsis sov mutants have a normal phenotype. We carried out mRNA decay analyses in wild-type, sov, vcs, and vcs sov seedlings, and used a mathematical modeling approach to determine decay rates and quantify gene-specific contributions of VCS and SOV to decay. This analysis revealed that VCS (decapping) contributes to decay of 68% of the transcriptome, and, while it initiates degradation of mRNAs with a wide range of decay rates, it especially contributes to decay of short-lived RNAs. Only a few RNAs were clear SOV substrates in that they decayed more slowly in sov mutants. However, 4,506 RNAs showed VCS-dependent feedback in sov that modulated decay rates, and, by inference, transcription, to maintain RNA abundances, suggesting that these RNAs might also be SOV substrates. This feedback was shown to be independent of siRNA activity. PMID- 29386392 TI - Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. AB - Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and alpha-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2 induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2. PMID- 29386393 TI - Identification of Wiskott-Aldrich syndrome protein (WASP) binding sites on the branched actin filament nucleator Arp2/3 complex. AB - Arp2/3 complex nucleates branched actin filaments important for cellular motility and endocytosis. WASP family proteins are Arp2/3 complex activators that play multiple roles in branching nucleation, but little is known about the structural bases of these WASP functions, owing to an incomplete understanding of how WASP binds Arp2/3 complex. Recent data show WASP binds two sites, and biochemical and structural studies led to models in which the WASP C segment engages the barbed ends of the Arp3 and Arp2 subunits while the WASP A segment binds the back side of the complex on Arp3. However, electron microscopy reconstructions showed density for WASP inconsistent with these models on the opposite (front) side of Arp2/3 complex. Here we use chemical cross-linking and mass spectrometry (XL-MS) along with computational docking and structure-based mutational analysis to map the two WASP binding sites on the complex. Our data corroborate the barbed end and back side binding models and show one WASP binding site on Arp3, on the back side of the complex, and a second site on the bottom of the complex, spanning Arp2 and ARPC1. The XL-MS-identified cross-links rule out the front side binding model and show that the A segment of WASP binds along the bottom side of the ARPC1 subunit, instead of at the Arp2/ARPC1 interface, as suggested by FRET experiments. The identified binding sites support the Arp3 tail release model to explain WASP-mediated activating conformational changes in Arp2/3 complex and provide insight into the roles of WASP in branching nucleation. PMID- 29386394 TI - Endocrine regulation of airway clearance in Drosophila. AB - Fluid clearance from the respiratory system during developmental transitions is critically important for achieving optimal gas exchange in animals. During insect development from embryo to adult, airway clearance occurs episodically each time the molt is completed by performance of the ecdysis sequence, coordinated by a peptide-signaling cascade initiated by ecdysis-triggering hormone (ETH). We find that the neuropeptide Kinin (also known as Drosokinin or Leukokinin) is required for normal respiratory fluid clearance or "tracheal air-filling" in Drosophila larvae. Disruption of Kinin signaling leads to defective air-filling during all larval stages. Such defects are observed upon ablation or electrical silencing of Kinin neurons, as well as RNA silencing of the Kinin gene or the ETH receptor in Kinin neurons, indicating that ETH targets Kinin neurons to promote tracheal air filling. A Kinin receptor mutant fly line (Lkrf02594 ) also exhibits tracheal air filling defects in all larval stages. Targeted Kinin receptor silencing in tracheal epithelial cells using breathless or pickpocket (ppk) drivers compromises tracheal air-filling. On the other hand, promotion of Kinin signaling in vivo through peptide injection or Kinin neuron activation through Drosophila TrpA1 (dTrpA1) expression induces premature tracheal collapse and air-filling. Moreover, direct exposure of tracheal epithelial cells in vitro to Kinin leads to calcium mobilization in tracheal epithelial cells. Our findings strongly implicate the neuropeptide Kinin as an important regulator of airway clearance via intracellular calcium mobilization in tracheal epithelial cells of Drosophila. PMID- 29386387 TI - Statistical tests and identifiability conditions for pooling and analyzing multisite datasets. AB - When sample sizes are small, the ability to identify weak (but scientifically interesting) associations between a set of predictors and a response may be enhanced by pooling existing datasets. However, variations in acquisition methods and the distribution of participants or observations between datasets, especially due to the distributional shifts in some predictors, may obfuscate real effects when datasets are combined. We present a rigorous statistical treatment of this problem and identify conditions where we can correct the distributional shift. We also provide an algorithm for the situation where the correction is identifiable. We analyze various properties of the framework for testing model fit, constructing confidence intervals, and evaluating consistency characteristics. Our technical development is motivated by Alzheimer's disease (AD) studies, and we present empirical results showing that our framework enables harmonizing of protein biomarkers, even when the assays across sites differ. Our contribution may, in part, mitigate a bottleneck that researchers face in clinical research when pooling smaller sized datasets and may offer benefits when the subjects of interest are difficult to recruit or when resources prohibit large single-site studies. PMID- 29386395 TI - Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. AB - Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+ T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (~14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer. PMID- 29386396 TI - Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. AB - Derivation of human hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) offers considerable promise for cell therapy, disease modeling, and drug screening. However, efficient derivation of functional iPSC-derived HSCs with in vivo engraftability and multilineage potential remains challenging. Here, we demonstrate a tractable approach for respecifying iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells (HSPCs) through transient expression of a single transcription factor, MLL-AF4 These induced HSPCs (iHSPCs) derived from iPSCs are able to fully reconstitute the human hematopoietic system in the recipient mice without myeloid bias. iHSPCs are long term engraftable, but they are also prone to leukemic transformation during the long-term engraftment period. On the contrary, primary HSPCs with the same induction sustain the long-term engraftment without leukemic transformation. These findings demonstrate the feasibility of activating the HSC network in human iPSC-derived blood cells through expression of a single factor and suggest iHSPCs are more genomically instable than primary HSPCs, which merits further attention. PMID- 29386398 TI - A novel framework for evaluating the performance of codon usage bias metrics. AB - The unequal utilization of synonymous codons affects numerous cellular processes including translation rates, protein folding and mRNA degradation. In order to understand the biological impact of variable codon usage bias (CUB) between genes and genomes, it is crucial to be able to accurately measure CUB for a given sequence. A large number of metrics have been developed for this purpose, but there is currently no way of systematically testing the accuracy of individual metrics or knowing whether metrics provide consistent results. This lack of standardization can result in false-positive and false-negative findings if underpowered or inaccurate metrics are applied as tools for discovery. Here, we show that the choice of CUB metric impacts both the significance and measured effect sizes in numerous empirical datasets, raising questions about the generality of findings in published research. To bring about standardization, we developed a novel method to create synthetic protein-coding DNA sequences according to different models of codon usage. We use these benchmark sequences to identify the most accurate and robust metrics with regard to sequence length, GC content and amino acid heterogeneity. Finally, we show how our benchmark can aid the development of new metrics by providing feedback on its performance compared to the state of the art. PMID- 29386397 TI - Entorhinal fast-spiking speed cells project to the hippocampus. AB - The mammalian positioning system contains a variety of functionally specialized cells in the medial entorhinal cortex (MEC) and the hippocampus. In order for cells in these systems to dynamically update representations in a way that reflects ongoing movement in the environment, they must be able to read out the current speed of the animal. Speed is encoded by speed-responsive cells in both MEC and hippocampus, but the relationship between the two populations has not been determined. We show here that many entorhinal speed cells are fast-spiking putative GABAergic neurons. Using retrograde viral labeling from the hippocampus, we find that a subset of these fast-spiking MEC speed cells project directly to hippocampal areas. This projection contains parvalbumin (PV) but not somatostatin (SOM)-immunopositive cells. The data point to PV-expressing GABAergic projection neurons in MEC as a source for widespread speed modulation and temporal synchronization in entorhinal-hippocampal circuits for place representation. PMID- 29386399 TI - A discrete fibre dispersion method for excluding fibres under compression in the modelling of fibrous tissues. AB - Recently, micro-sphere-based methods derived from the angular integration approach have been used for excluding fibres under compression in the modelling of soft biological tissues. However, recent studies have revealed that many of the widely used numerical integration schemes over the unit sphere are inaccurate for large deformation problems even without excluding fibres under compression. Thus, in this study, we propose a discrete fibre dispersion model based on a systematic method for discretizing a unit hemisphere into a finite number of elementary areas, such as spherical triangles. Over each elementary area, we define a representative fibre direction and a discrete fibre density. Then, the strain energy of all the fibres distributed over each elementary area is approximated based on the deformation of the representative fibre direction weighted by the corresponding discrete fibre density. A summation of fibre contributions over all elementary areas then yields the resultant fibre strain energy. This treatment allows us to exclude fibres under compression in a discrete manner by evaluating the tension-compression status of the representative fibre directions only. We have implemented this model in a finite element programme and illustrate it with three representative examples, including simple tension and simple shear of a unit cube, and non-homogeneous uniaxial extension of a rectangular strip. The results of all three examples are consistent and accurate compared with the previously developed continuous fibre dispersion model, and that is achieved with a substantial reduction of computational cost. PMID- 29386400 TI - Saturation limits the contribution of acceleration feedback to balancing against reaction delay. AB - A nonlinear model for human balancing subjected to a saturated delayed proportional-derivative-acceleration (PDA) feedback is analysed. Compared to the proportional-derivative (PD) controller, it is confirmed that the PDA controller improves local stability even for large feedback delays. However, it is shown that the saturated PDA controller typically introduces subcritical Hopf bifurcation into the system, which can also lead to falling for large enough perturbations. The subcriticality becomes stronger as the acceleration feedback gain increases or the saturation torque limit decreases. These explain some features of human balancing failure related to the increased reaction delay of inactive elderly people. PMID- 29386401 TI - Efficient analysis of stochastic gene dynamics in the non-adiabatic regime using piecewise deterministic Markov processes. AB - Single-cell experiments show that gene expression is stochastic and bursty, a feature that can emerge from slow switching between promoter states with different activities. In addition to slow chromatin and/or DNA looping dynamics, one source of long-lived promoter states is the slow binding and unbinding kinetics of transcription factors to promoters, i.e. the non-adiabatic binding regime. Here, we introduce a simple analytical framework, known as a piecewise deterministic Markov process (PDMP), that accurately describes the stochastic dynamics of gene expression in the non-adiabatic regime. We illustrate the utility of the PDMP on a non-trivial dynamical system by analysing the properties of a titration-based oscillator in the non-adiabatic limit. We first show how to transform the underlying chemical master equation into a PDMP where the slow transitions between promoter states are stochastic, but whose rates depend upon the faster deterministic dynamics of the transcription factors regulated by these promoters. We show that the PDMP accurately describes the observed periods of stochastic cycles in activator and repressor-based titration oscillators. We then generalize our PDMP analysis to more complicated versions of titration-based oscillators to explain how multiple binding sites lengthen the period and improve coherence. Last, we show how noise-induced oscillation previously observed in a titration-based oscillator arises from non-adiabatic and discrete binding events at the promoter site. PMID- 29386402 TI - Mechanical power curve measured in the wake of pied flycatchers indicates modulation of parasite power across flight speeds. AB - How aerodynamic power required for animal flight varies with flight speed determines optimal speeds during foraging and migratory flight. Despite its relevance, aerodynamic power provides an elusive quantity to measure directly in animal flight. Here, we determine the aerodynamic power from wake velocity fields, measured using tomographical particle image velocimetry, of pied flycatchers flying freely in a wind tunnel. We find a shallow U-shaped power curve, which is flatter than expected by theory. Based on how the birds vary body angle with speed, we speculate that the shallow curve results from increased body drag coefficient and body frontal area at lower flight speeds. Including modulation of body drag in the model results in a more reasonable fit with data than the traditional model. From the wake structure, we also find a single starting vortex generated from the two wings during the downstroke across flight speeds (1-9 m s-1). This is accomplished by the arm wings interacting at the beginning of the downstroke, generating a unified starting vortex above the body of the bird. We interpret this as a mechanism resulting in a rather uniform downwash and low induced power, which can help explain the higher aerodynamic performance in birds compared with bats. PMID- 29386404 TI - New Year's revolution. PMID- 29386403 TI - Hydrodynamics govern the pre-fusion docking time of synaptic vesicles. AB - Synaptic vesicle fusion is a crucial step in the neurotransmission process. Neurotransmitter-filled vesicles are pre-docked at the synapse by the mediation of ribbon structures and SNARE proteins at the ribbon synapses. An electrical impulse triggers the fusion process of pre-docked vesicles, leading to the formation of a fusion pore and subsequently resulting in the release of neurotransmitter into the synaptic cleft. In this study, a continuum model of lipid membrane along with lubrication theory is used to determine the traverse time of the synaptic vesicle under the influence of hydrodynamic forces. We find that the traverse time is strongly dependent on how fast the driving force decays or grows with closure of the gap between the vesicle and the plasma membrane. If the correct behaviour is chosen, the traverse time obtained is of the order of a few hundred milliseconds and lies within the experimentally obtained value of approximately 250 ms (Zenisek D, Steyer JA, Almers W. 2000 Nature406, 849-854 (doi:10.1038/35022500)). We hypothesize that there are two different force behaviours, which complies with the experimental findings of pre-fusion docking of synaptic vesicles at the ribbon synapses. The common theme in the proposed force models is that the driving force has to very rapidly increase or decrease with the amount of clamping. PMID- 29386405 TI - The Pseudomonas aeruginosa ExoY phenotype of high-copy-number recombinants is not detectable in natural isolates. AB - The nucleotidyl cyclase ExoY is an effector protein of the type III secretion system of Pseudomonas aeruginosa We compared the cyclic nucleotide production and lung disease phenotypes caused by the ExoY-overexpressing strain PA103DeltaexoUexoT::Tc pUCPexoY, its vector control strain PA103DeltaexoUexoT::Tc pUCP18, its loss-of-function control PA103DeltaexoUexoT::Tc pUCPexoY K81M and natural ExoY-positive and ExoY-negative isolates in a murine acute airway infection model. Only the P. aeruginosa carrier of the exoY-plasmid produced high levels of cUMP and caused the most severe course of infection. The pathology ascribed to ExoY from studies using the high-copy-number plasmid on mammalian cells in vitro and in vivo was not observed with natural P. aeruginosa isolates. This indicates that the role of ExoY during infection with real-life P. aeruginosa still needs to be resolved. PMID- 29386407 TI - Harnessing functional segregation across brain rhythms as a means to detect EEG oscillatory multiplexing during music listening. AB - OBJECTIVE: Music, being a multifaceted stimulus evolving at multiple timescales, modulates brain function in a manifold way that encompasses not only the distinct stages of auditory perception, but also higher cognitive processes like memory and appraisal. Network theory is apparently a promising approach to describe the functional reorganization of brain oscillatory dynamics during music listening. However, the music induced changes have so far been examined within the functional boundaries of isolated brain rhythms. APPROACH: Using naturalistic music, we detected the functional segregation patterns associated with different cortical rhythms, as these were reflected in the surface electroencephalography (EEG) measurements. The emerged structure was compared across frequency bands to quantify the interplay among rhythms. It was also contrasted against the structure from the rest and noise listening conditions to reveal the specific components stemming from music listening. Our methodology includes an efficient graph-partitioning algorithm, which is further utilized for mining prototypical modular patterns, and a novel algorithmic procedure for identifying 'switching nodes' (i.e. recording sites) that consistently change module during music listening. MAIN RESULTS: Our results suggest the multiplex character of the music induced functional reorganization and particularly indicate the dependence between the networks reconstructed from the delta and beta H rhythms. This dependence is further justified within the framework of nested neural oscillations and fits perfectly within the context of recently introduced cortical entrainment to music. SIGNIFICANCE: Complying with the contemporary trends towards a multi-scale examination of the brain network organization, our approach specifies the form of neural coordination among rhythms during music listening. Considering its computational efficiency, and in conjunction with the flexibility of in situ electroencephalography, it may lead to novel assistive tools for real-life applications. PMID- 29386408 TI - Transcutaneous spinal direct current stimulation of the lumbar and sacral spinal cord: a modelling study. AB - OBJECTIVE: Our aim was to perform a computational study of the electric field (E field) generated by transcutaneous spinal direct current stimulation (tsDCS) applied over the thoracic, lumbar and sacral spinal cord, in order to assess possible neuromodulatory effects on spinal cord circuitry related with lower limb functions. APPROACH: A realistic volume conductor model of the human body consisting of 14 tissues was obtained from available databases. Rubber pad electrodes with a metallic connector and a conductive gel layer were modelled. The finite element (FE) method was used to calculate the E-field when a current of 2.5 mA was passed between two electrodes. The main characteristics of the E field distributions in the spinal grey matter (spinal-GM) and spinal white matter (spinal-WM) were compared for seven montages, with the anode placed either over T10, T8 or L2 spinous processes (s.p.), and the cathode placed over right deltoid (rD), umbilicus (U) and right iliac crest (rIC) areas or T8 s.p. Anisotropic conductivity of spinal-WM and of a group of dorsal muscles near the vertebral column was considered. MAIN RESULTS: The average E-field magnitude was predicted to be above 0.15 V m-1 in spinal cord regions located between the electrodes. L2 T8 and T8-rIC montages resulted in the highest E-field magnitudes in lumbar and sacral spinal segments (>0.30 V m-1). E-field longitudinal component is 3 to 6 times higher than the ventral-dorsal and right-left components in both the spinal GM and WM. Anatomical features such as CSF narrowing due to vertebrae bony edges or disks intrusions in the spinal canal correlate with local maxima positions. SIGNIFICANCE: Computational modelling studies can provide detailed information regarding the electric field in the spinal cord during tsDCS. They are important to guide the design of clinical tsDCS protocols that optimize stimulation of application-specific spinal targets. PMID- 29386406 TI - Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle. AB - Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with alpha1-adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP3) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP induced IP3 production. aVP stimulation resulted in beta-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit beta-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced beta arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity. PMID- 29386409 TI - Enhancement of wound healing efficiency mediated by artificial dermis functionalized with EGF or NRG1. AB - The use of artificial dermis as a skin substitute is a field of active study, as acellular dermal matrices from cadavers are susceptible to infection owing to their human origin. One such alternative dermal replacement scaffold, INSUREGRAF(r), is derived primarily from extracellular matrix proteins such as collagen and elastin and has been clinically used to treat severe skin wounds such as burns. This scaffold has proven to be useful to minimize wound contraction and scar formation owing to its biocompatibility, interconnected pore structure, sufficient biodegradability, and suitable mechanical properties. However, INSUREGRAF(r) does not provide scar-free wound healing in cases of severe skin damage such as full-thickness (FT) excision. Considering that the efficient recruitment of fibroblasts and keratinocytes into a wound site represents a critical step in the regeneration of damaged skin, we attempted to enhance the efficiency for wound healing by fabricating growth factor functionalized INSUREGRAF(r). In particular, we utilized epidermal growth factor (EGF) and an EGF family member, neuregulin-1 (NRG1), not previously studied in the context of wound healing, whose cellular role is to promote proliferation and migration in fibroblasts and keratinocytes. Both artificial dermis-growth factor combinations led to efficient recruitment of fibroblasts and keratinocytes into a wound site during the early steps of skin regeneration. Notably, EGF- or NRG1 functionalized INSUREGRAF(r) induced rapid proliferation of skin cells in an ERK pathway-dependent manner and exhibited efficient wound healing in a Sprague Dawley rat FT excision and grafting model. These results provide the foundation for expanding the use of growth factor-functionalized INSUREGRAF(r) to clinical application in cases of severe skin injury. PMID- 29386410 TI - Success in Publishing: Selecting an Appropriate Journal and Braving the Peer review Process. PMID- 29386412 TI - Strengthen mental health services for universal health coverage in India. PMID- 29386411 TI - Vitamin D in diabetic nephropathy. PMID- 29386413 TI - Effect of Vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: A randomized, double-blind clinical trial. AB - BACKGROUND: Despite different management strategies, progression of proteinuria occurs in a sizable category of patients with diabetic nephropathy (DN). Increase in serum renin levels induced by the renin-angiotensin system (RAS) may contribute to this. Vitamin D therapy is found to have an inhibitory effect on the RAS. We aimed to study the effects of Vitamin D therapy on renal functions of patients with DN. METHODS: This was a double-blind, randomized, placebo controlled study. Patients with DN (urinary albumin [UA] >30 mg/g of creatinine) whose estimated glomerular filtration rate (eGFR) was more than 30 mL/min were selected and their plasma renin, parathyroid hormone, serum Vitamin D, serum calcium, serum creatinine, fasting blood sugar were done as baseline measurements. Subjects were randomized into two groups and treatment group was given Vitamin D, 50000 IU (0.25 ml) intramuscularly (IM) monthly for 6 months; control group received distilled water IM. Investigations were repeated after 6 months of therapy. RESULTS: Of 155 patients invited, 85 were randomly assigned to two groups. After 6 months, mean reduction of UA to creatinine ratio in the treatment and control group was 51.8 mg/g (95% confidence interval [CI]; 66.1- 37.5, P <= 0.001); 22.4 mg/g (95% CI; -45.7-0.8, P = 0.06), respectively (between group difference P = 0.001). Significant increase in the eGFR observed in the treatment group while eGFR remained unchanged in the control group (P = 0.03 for the between-group difference). Mean reduction in plasma renin in treatment group and control group was 5.85 pg/mL (95% CI; -6.7--4.6) (P < 0.001) and 0.95 pg/mL (95% CI; -1.4--0.14, P = 0.02), respectively. CONCLUSIONS: Vitamin D 50000 IU given IM monthly for 6 months reduces urine albumin, serum creatinine, and renin levels in patients with DN. PMID- 29386414 TI - Epidemiology of mental disability using Indian Disability Evaluation Assessment Scale among general population in an urban area of Puducherry, India. AB - BACKGROUND: There is paucity of information on epidemiology of mental disability in India. OBJECTIVE: The objective of this study was to assess mental disability, and to study the association between sociodemographic and comorbid chronic conditions with mental disability. MATERIALS AND METHODS: This community-based cross-sectional study was conducted among >=5 years age group in an urban area attached to a Tertiary Care Medical Institute in Puducherry, India. Mental disability was assessed using Indian Disability Evaluation and Assessment Scale. Chronic morbid conditions and other associated factors were collected using pretested questionnaire. STATISTICAL ANALYSIS: Univariate and multiple logistic regression analysis. RESULTS: About 2537 subjects were covered with a response rate of 94.1%. Overall, the prevalence of mental disability was found to be 7.1% (181/2537). Among them, majority had mild mental disability (151, 83.4%), followed by moderate (21, 11.6%), severe (8, 4.4%), and profound (1, 0.6%) mental disability. Univariate analysis showed that age group status, marital status, education level, occupation, family type, religion, hypertension, joint pain, backache, current smoking, current alcohol use, and conflicts were associated with mental disability (P < 0.05). Multiple logistic regression analysis showed that male gender (adjusted odds ratio [AOR] =2.064), widowed status (AOR = 27.022), separated/divorced status (AOR = 16.674), currently married status (AOR = 18.487), being illiterate (AOR = 4.352), having 1st-10th standard education (AOR = 2.531), being in an unskilled (AOR = 0.287) or semiskilled/skilled occupation (AOR = 0.025), belonging to a nuclear family (AOR = 1.816), and absence of family conflicts (AOR = 0.259) were significantly associated with mental disability compared to their counterparts. CONCLUSION: Mental disability is more common in this area. Males, lesser education level, skilled or unskilled occupation, nuclear family, and conflicts were associated with mental disability after adjusting other variables. Multicentric cross-sectional analytical studies will explore the mental disability burden and its associated factors at regional or country level. PMID- 29386415 TI - Multicentric study on prevalence and risk factors for hypertension and diabetes in tribal communities in Western and Northern Maharashtra. AB - BACKGROUND AND OBJECTIVES: Although a number of studies have been conducted on the prevalence of hypertension (HTN) and diabetes on tribal populations in different parts of India, comparative tribe-specific information is very meager. The main objective of this study is to generate tribe-specific information on the noncommunicable disorders (NCDs) and associated risk factors in scheduled tribes (STs) in Coastal and Western Maharashtra. METHODS: The study was conducted on 1864 (females 960) adults (>=18 years) of both sexes in four dominant tribes in the region, namely, Bhils (748), Katkaris (560), Kokana (352), and Thakars (204), using the protocols approved by the Institutional Review Board. The study areas were geographically separated by large distances (250-500 km apart). Prevalence of overweight, diabetes, HTN, and hypercholesterolemia was measured using standard field-based techniques described in our earlier publication. RESULTS: All STs in this study are grossly underweight; the Katkaris are worst affected. The prevalence of obesity (body mass index >=30 kg/m2), HTN (blood pressure >=140 mmHg), diabetes (capillary blood glucose >126 mg/dl), and hypercholesterolemia (cholesterol >=200 mg/dl) was 0.9%, 11.7%, 6.7%, and 0.6% respectively. There are no statistically significant inter-tribal differences in the prevalence of these parameters. Age and obesity appeared to be the most dominant risk factors for HTN. However, there is no clear-cut picture about the influence of risk factors on diabetes or hypercholesterolemia. INTERPRETATION AND CONCLUSION: The prevalence of NCDs is still very low in STs, probably due to near absence of the risk factors such as obesity, sedentary lifestyle, and hyperlipidemia. STs are highly endogamous, and the study areas are separated by large distances ruling out intermingling of tribes. Yet, there is no consistent inter-tribal prevalence pattern for NCDs. Although the sample size is small, the results support the view that environmental factors are likely to be more important than host genetics in the causation of NCDs. PMID- 29386416 TI - Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a novel mutation. AB - Childhood cerebral X-linked adrenoleukodystrophy (XALD) typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnostic clue is the characteristic neuroinflammatory parieto-occipital white matter lesions on magnetic resonance imaging. This study reports a 5-year 10-month old boy presenting with generalized skin hyperpigmentation since 3 years of age. Over the past 9 months, he had developed right-sided hemiparesis and speech and behavioral abnormalities, which had progressed over 5 months to bilateral hemiparesis. Retrospective analyses of serial brain magnetic resonance images revealed an unusual pattern of lesions involving the internal capsules, corticospinal tracts in the midbrain and brainstem, and cerebellar white matter. The clinical diagnosis of childhood cerebral adrenoleukodystrophy was confirmed by elevated basal levels of adrenocorticotropin hormone and plasma very long chain fatty acid levels. Additionally, sequencing of the ABCD1 gene revealed a novel mutation. The only specific palliative therapy that could be offered after diagnosis was dietary intervention. The patient died within 16 months of onset of neurological symptoms. Awareness that childhood cerebral XALD can present with atypical neuroimaging patterns early in its course may aid diagnosis at a stage when definitive treatment can be attempted and timely genetic counseling be offered to the family. PMID- 29386417 TI - Ocular surface leproma. PMID- 29386418 TI - Cinema-like sensory phenomena in a migraine patient on topiramate. PMID- 29386419 TI - Powdered gloves: Time to bid adieu. PMID- 29386420 TI - Reply to Letter to Editor regarding the article, "Powdered gloves: Time to bid adieu". PMID- 29386421 TI - Clinical Characteristics of Nonobese Patients with Acute Coronary Syndrome and Increased Epicardial Fat Volume. AB - AIM: Increased epicardial fat volume (EFV) is an independent risk factor for acute coronary syndrome (ACS). Although EFV increases with body mass index (BMI), some ACS patients have an increased EFV but normal BMI. We here investigated the clinical characteristics of nonobese ACS patients with an increased EFV. METHODS: A total of 197 Japanese patients hospitalized for ACS was evaluated for EFV, abdominal visceral fat area (VFA), and lipid and glucose profiles. Control subjects comprised 141 individuals who were suspected of having ACS but whose coronary computed tomography findings were normal. RESULTS: EFV was increased in ACS patients compared with control subjects (120+/-47 versus 95+/-45 mL, P<0.01). ACS patients were divided into four groups based on average EFV (120 mL) and a BMI obesity cutoff of 25 kg/m2. For the 30 nonobese ACS patients with an above average EFV, EFV was positively correlated with VFA (r=0.23, P=0.031). These individuals were significantly older (74+/-10 years) and tended to have a higher homeostasis model assessment-insulin resistance value (5.5+/-3.8) compared with other ACS patients. Among nonobese study subjects, EFV was independently associated with ACS (odds ratio=2.01, P=0.021) and correlated with abdominal circumference (r=0.26, P=0.017). CONCLUSION: Nonobese ACS patients with an increased EFV were elderly and tended to manifest insulin resistance. Measurement of EFV may prove informative for evaluation of ACS risk among elderly nonobese individuals with an increased abdominal girth. PMID- 29386422 TI - [Quality Evaluation of Saposhnikoviae Radix (Differences between Wild-type and Cultivated Products)]. AB - Saposhnikoviae Radix ("Boufu") is an important crude drug used in Kampo formulation. It is extracted from wild-type plants. However, recently, extraction has become difficult because of a decrease in wild-type plants. Therefore, cultivated plants account for the majority of the market, from which the crude drug is extracted. However, the cultivation techniques used are not sufficient to obtain the desirable extracts. In this study, we compared the contents of the extract and the quantitative values of characteristic constituents obtained from wild-type and cultivated plants, and found a remarkable difference. Therefore, it is considered that these indicators play an important role in the establishment of better cultivation technology. PMID- 29386423 TI - Risk factors for musculoskeletal disorders in manual harvesting farmers of Rajasthan. AB - Manual harvesting is a physically demanding occupation with several work-related issues in which musculoskeletal disorders (MSDs) happen most commonly. The risk factors for MSDs among manual harvesting farmers are not investigated properly in low and low-middle-income nations. Therefore, a study among 140 farmers of Rajasthan, India was carried out through the usage of Nordic Musculoskeletal Questionnaire and the Rapid Upper Limb Assessment (RULA) technique to identify ergonomic risks. chi2 analysis was used to find the relationship between the MSDs and various factors. Also, logistic regression methodology was applied to get the most influencing factor for MSDs in different body regions. The lower-back, fingers, shoulders and wrists/hands were the body parts in which more than 50% workers reported MSDs. MSDs in one or more body regions were found to be associated with age, daily working in farms, farming experience, gender, hand dominance and perceived work fatigue. The age was majorly associated with MSDs in all body regions except the shoulder and neck as per the outcome of logistic regression. The outcome of RULA grand score had been found higher than or equal to 5 in 92% of the farmers which give directions for further research and changes. PMID- 29386424 TI - Phosphodiesterase 9 (PDE9) regulates bovine tracheal smooth muscle relaxation. AB - The present study was designed to clarify phosphodiesterase 9 (PDE9) expression in bovine tracheal smooth muscle tissue, and to elucidate that PDE9 may contribute to the regulation of airway relaxation. PDE9 mRNA expression was detected in bovine tracheal smooth muscle. Sodium nitroprusside (an NO donor) and BAY 73-6691 (a selective PDE9 inhibitor) reduced high K+- and carbachol-induced contraction. BAY 73-6691 relaxed tracheal tissue on the same level with vardenafil (a selective PDE5 inhibitor). These results support our hypothesis that PDE9 plays functional role in the tracheal smooth muscle relaxation. PDE9 inhibitors are expected to be a novel target of the add-on treatment of airway hyperresponsiveness. PMID- 29386425 TI - Molecular Characterization of the Bacterial Community in Biofilms for Degradation of Poly(3-Hydroxybutyrate-co-3-Hydroxyhexanoate) Films in Seawater. AB - Microplastics are fragmented pieces of plastic in marine environments, and have become a serious environmental issue. However, the dynamics of the biodegradation of plastic in marine environments have not yet been elucidated in detail. Polyhydroxyalkanoates (PHAs) are biodegradable polymers that are synthesized by a wide range of microorganisms. One of the PHA derivatives, poly(3-hydroxybutyrate co-3-hydroxyhexanoate) (PHBH) has flexible material properties and a low melting temperature. After an incubation in seawater samples, a significant amount of biofilms were observed on the surfaces of PHBH films, and some PHBH films were mostly or partially degraded. In the biofilms that formed on the surfaces of unbroken PHBH films, the most dominant operational taxonomic units (OTUs) showed high similarity with the genus Glaciecola in the family Alteromonadaceae. On the other hand, the dominant OTUs in the biofilms that formed on the surfaces of broken PHBH films were assigned to the families Rhodobacteraceae, Rhodospirillaceae, and Oceanospirillaceae, and the genus Glaciecola mostly disappeared. The bacterial community in the biofilms on PHBH films was assumed to have dynamically changed according to the progression of degradation. Approximately 50 colonies were isolated from the biofilm samples that formed on the PHBH films and their PHBH-degrading activities were assessed. Two out of three PHBH-degrading isolates showed high similarities to Glaciecola lipolytica and Aestuariibacter halophilus in the family Alteromonadaceae. These results suggest that bacterial strains belonging to the family Alteromonadaceae function as the principal PHBH-degrading bacteria in these biofilms. PMID- 29386426 TI - [Factors Related to Presenteeism in Young and Middle-aged Nurses]. AB - OBJECTIVE: Presenteeism is considered to be not only a work-related stressor but also a factor involved in the development of workaholism and error proneness, which is often described as careless. Additionally, increasing health issues arising from aging suggest the possibility that presenteeism in middle-aged nurses is different than that in young ones. Therefore, the present study aimed to identify and tease apart factors involved in presenteeism among young and middle-aged nurses. METHODS: An anonymous self-administered questionnaire survey was conducted among 2,006 nurses working at 10 hospitals. In total, 761 nurses aged <40 years and 536 nurses aged >=40 years were enrolled in this study. Work Impairment Scores (WIS) on the Japanese version of the Stanford Presenteeism Scale were measured for presenteeism. Job stressors, workaholism, and error proneness were measured for related factors. Multiple regression analysis was conducted after determining the WIS as the dependent variable and related factors as independent variables. RESULTS: Overall, 70.8% of the young nurses reported health problems compared to 82.5% of the middle-aged nurses. However, WIS in young nurses was significantly higher than that in middle-aged ones (p < 0.001). WIS in young nurses showed a significant relationship with the degree of stressors, "difficulty of work" (beta = 0.28, p < 0.001) and tendency to "work excessively" (beta = 0.18, p < 0.001), which is a subscale of workaholism, error proneness of "action slips" (beta = 0.14, p < 0.01) and "cognitive narrowing" (beta = 0.11, p < 0.05). Conversely, WIS in middle-aged nurses showed a significant relationship with "cognitive narrowing" (beta = 0.29, p < 0.001) and to "work excessively" (beta = 0.17, p < 0.001), the degree of stressors on "difficulty of work" (beta = 0.12, p < 0.05) and "lack of communication" (beta = 0.13, p < 0.01). CONCLUSION: It was clarified that the increased health problems of middle-aged nurses does not necessarily lower their working capacity. Also, compared to young nurses, the degree of failing tendency, rather than the degree of job stressors, was more related to presenteeism for middle-aged nurses. It can be considered that middle-aged nurses simply realize that their working ability is hindered because of incidents resulting from attention narrowing. As fatigue and state of tension tend to cause narrowing of attention, it may be necessary to reduce such risks and adjust work environments so mistakes can be avoided. PMID- 29386427 TI - [The Immunosuppressive Function of Myeloid-derived Suppressor Cells Is Regulated by the HMGB1-TLR4 Axis]. AB - Myeloid-derived suppressor cells (MDSCs) accumulate under pathological conditions, including cancer and chronic inflammation, and they suppress various immune responses such as T cell proliferation. Although several inflammatory signals enhance the differentiation and/or function of MDSCs, it is not clear which factors regulate their differentiation and immunosuppressive function. It has been highlighted that damage-associated molecular patterns (DAMPs) play important roles in the induction of inflammation. One of the DAMPs, the high mobility group box 1 (HMGB1), is released from necrotic cells and secreted by macrophages. It has been shown that HMGB1 level is elevated in tumors and tumor bearing hosts. It has also been reported that HMGB1 transduces intracellular signaling via several receptors, including the receptor for advanced glycation end-products (RAGE) and the toll-like receptor (TLR)4, both of which enhance the differentiation and/or function of MDSCs. However, the effects of HMGB1 on MDSCs remain unclear. In the present study, we examined the effect of HMGB1 on in vitro MDSC differentiation and immunosuppressive functions. Since murine bone marrow (BM) cells can differentiate into MDSCs upon granulocyte-macrophage colony stimulating factor (GM-CSF) stimulation for 4 d in vitro, we cultured murine BM cells in the presence of HMGB1 and GM-CSF. The results demonstrated that HMGB1 enhanced the suppressive activity of in vitro MDSCs, depending on TLR4, whereas lipopolysaccharide (LPS), one of the TLR4 ligands, interfered with this differentiation and immunosuppressive activity of in vitro MDSCs, depending on TLR4. Our findings thus suggest that the HMGB1-TLR4 axis enhances the immunosuppressive function of MDSCs. PMID- 29386428 TI - [Role of Pharmacy in the Promotion of Drug Safety in Pharmacotherapy]. PMID- 29386429 TI - [Pathogenic Mechanism and Diagnostic Testing for Drug Allergies]. AB - Three stages of the pathogenic mechanism of drug allergies can be considered: antigen formation, immune reaction and inflammation/disorder reaction. Drugs are thought to form 4 types of antigens: drug only, polymers, drug-carrier conjugates, and metabolite-carrier complexes. Antigens are recognized by B cell receptors and T cell receptors. Helper T cells (Th) are differentiated into four subsets, namely, Th1, Th2, Th17 and regulatory T cells (Treg). Th1 produces interleukin (IL)-2 and interferon (IFN)-gamma, and activates macrophages and cytotoxic T cells (Tc). Macrophages induce type IV allergies, and Tc lead to serious type IV allergies. On the other hand, Th2 produces IL-4, IL-5, and IL-6, etc., and activates B cells. B cells produce IgE antibodies, and the IgE antibody affects mast cells and induces type I allergies. Activated eosinophil leads to the chronic state of type I allergy. Diagnostic testing for allergenic drugs is necessary for patients with drug allergies. Because in vivo diagnostic tests for allergenic drugs are associated with a risk and burden to the patient, in vitro allergy tests are recommended to identify allergenic drugs. In allergy tests performed in vitro, cytological tests are more effective than serological tests, and the leukocyte migration test (LMT) presently has the highest efficacy. An LMT chamber is better than LMT-agarose in terms of usability and sensitivity, and it can detect about 80% of allergenic drugs. PMID- 29386430 TI - [Development of "Patient Friendly Formulations" to Counter the Side Effects of Cancer Chemotherapy]. AB - Anticancer drug-induced stomatitis develops in 30% to 40% of cancer patients undergoing chemotherapy. However, medications for this condition are not commercially available in Japan. The "hospital formulation" is a customized medicine which hospital pharmacists prepare when doctors cannot carry out the medical therapy most suitable for a patient using commercial medicines. However, as the duties of pharmacists increase, use of the "hospital fomulation" decreases. Therefore, development of "hospital fomulations" based on individual evidence has a limit. Irsogladine maleate (IM) is a drug with gastric mucosal protective properties. IM increases intracellular cAMP levels in the gastric mucosa and activates communication between cells. It has been reported that the oral administration of IM reduces the incidence of 5-FU-based chemotherapy induced stomatitis. However, there have been no reports on the effect of the direct use of IM in treating stomatitis. Therefore, we studied the development of an IM oral spray for stomatitis treatment, and obtained evidence of a direct effect in an animal experiment using a stomatitis model. Next, rebamipide mouthwash was administered to patients who had stomatitis caused by cancer chemotherapy. The total scores were classified into Grades 0 to 4 and evaluated as a stomatitis evaluation score (SES). When comparing SES and changes in the stomatitis area in patients, gradual reductions in the extent of stomatitis were observed, even during the period when SES did not change. Having patients fill in an observation chart was effective for grasping changes in symptoms in outpatients. PMID- 29386431 TI - [Safe Use of Recent New Drugs-Current Status and Challenges]. AB - In Japan and overseas, Chugai Pharmaceutical Company handles numerous biopharmaceuticals, molecular targeted therapies and other pharmaceuticals with innovative modes of action. Expert safety evaluation is essential for promoting the appropriate use of these pharmaceuticals around the world and in gaining acceptance from patients and healthcare professionals (HCPs), while speedy decision-making is crucial for the timely collection and provision of safety information and thus ensuring safety. In 2015, we collected safety information on more than 180000 cases and evaluated it from a medical standpoint. We have established a system for recording the collected information in a global database, and are conducting signal detection of adverse drug reactions using this database. With this system, we promptly disclose information to regulatory authorities in Japan, the US, Europe and Asia. We have in-house medical doctors with abundant clinical experience who conduct expert safety evaluations. Many innovative drugs, such as anticancer drugs or biopharmaceuticals, require wider ranging, more rigorous management, including the provision of appropriate safety information to HCPs, management of distribution through wholesalers and dispensing pharmacies, and confirmation of conditions of use, in addition to all case registration surveillance. With progress in the development of individualized medicine and drugs with new modes of action, in order for HCPs to understand the characteristics of these new drugs and use them appropriately, pharmacists and pharmaceutical companies should cooperate in promoting their appropriate use in the spirit of 'All Pharmacists for Patients'. PMID- 29386432 TI - [Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases]. AB - Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning. PMID- 29386433 TI - [Stereocontrolled Total Synthesis of Biologically Active Natural Products]. AB - This review article describes the total syntheses of englerin A, ophiodilactones A and B, marinomycin A, N-methylwelwitindolinone C isothiocyanate, tirandamycins A-D, and tirandalydigin, which possess intriguing biological activities and challenging structures with characteristic ring systems. The focus is on the synthetic methodologies that lead to the highly stereocontrolled assembly of these natural products. PMID- 29386434 TI - [From a Ph.D. Thesis: Understanding the Past, Predicting the Future]. AB - Posey et al. have reported multiple molecular diagnoses in 4.5% of cases (101/2076) in which whole-exome sequencing was informative. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. My research projects at the Niigata University of Pharmacy have investigated underlying mechanisms involved in human disease, including fatty acid metabolism, diabetic cardiomyopathy, atopic dermatitis, colitis, hepatitis, etc. Three students from abroad graduated this year from the Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences. These students reported on treatments for heart disease, non-alcoholic steatohepatitis and atopic dermatitis, as well as the underlying mechanisms involved in each. The titles of these reports are "Study of the role of cardiac 14-3-3eta protein in cardiac inflammation and adverse cardiac remodeling during heart failure in mice", "Non-alcoholic steatohepatitis: onset of mechanisms under diabetic background and treatment strategies" and "The role of HMGB1 and its cascade signaling pathway in atopic dermatitis". It can be concluded from these three theses that oxidative stress and inflammation are among the principal mechanisms underlying these diseases. PMID- 29386435 TI - [Modification of the Insulin Pen Assistive Device to Improve the Usability and Its Evaluation]. AB - In this study, we prepared 4 assistive devices (A-D) for Miriopen(r) to improve the "ease of holding" and "ease of pushing" and compared their usability with that of a device provided by the pharmaceutical company (S). Fifty-five healthy volunteers in their 20s performed the self-injection maneuver using all 5 assistive devices and ranked them regarding 3 items, i.e., the "ease of holding", "ease of pushing", and "overall ease of administration". In all evaluation items, C was ranked first by the largest number of subjects, and the ranking by the subjects was shown by Kendall's coefficient of concordance to be consistent. In addition, comparison of the distance scale calculated from the ordinal scale showed significantly higher ranks of C and D compared with A, B, and S in all evaluation items. No significant difference was noted between C and D. Since C and D had shapes with concavities and convexities that fit the index, middle, and ring fingers (2nd-4th fingers), the fingers are considered to be better stabilized during the injection maneuver with consequent high ratings. Moreover, the 4 assistive devices prepared in this study were rated to be equal to or higher than S. PMID- 29386436 TI - [Analysis of Time-to-onset of Interstitial Lung Disease after the Administration of Small Molecule Molecularly-targeted Drugs]. AB - The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD. PMID- 29386437 TI - [Comparative Study of the Efficacy and Safety of Caffeine and Aminophylline for the Treatment of Apnea in Preterm Infants]. AB - Methylxanthine is widely administered for the treatment of apnea of prematurity in many countries, and previous reports have clearly established that caffeine is effective for the treatment of apnea of prematurity. In Japan, caffeine has been available since December 2014. Thus, we compared the efficacy and safety of caffeine with that of aminophylline in our hospital. There was no significant difference between the caffeine group and aminophylline group regarding the characteristics of the study patients. The mean efficacy rate from day 1 to day 10 was 89.5% in the caffeine group, and 81.9% in the aminophylline group, although the rate of improvement in apnea episodes each day from day 1 to day 10 was not significantly different between the two groups. On the other hand, the adverse event rates in the caffeine group and the aminophylline group were 70.6% and 75.0%, respectively. No significant difference was observed in the adverse event rates between the two groups. Moreover, suspected abdominal distension due to the drug administration was more frequently observed with the aminophylline group. Our findings indicate that caffeine is as effective as aminophylline, while it is superior to aminophylline regarding its overall safety. PMID- 29386438 TI - [The Present Implementation Status and Problems of Vital-signs Measurement by Community Pharmacists in Home Medical Care in Osaka]. AB - While the community-based integrated care systems are in the process of being structured currently, more and more community pharmacists want to learn physical assessment skills. However, no large-scale survey focusing on present implementation status and problems of physical assessment by community pharmacists has been conducted yet. Osaka has the 2nd highest number of community pharmacies in Japan now, and the population aged >=65 years will be expected to become the 3rd highest in 2025. Thus, Osaka can become a national leading model case for community pharmacists' activity in future home medical care. Therefore, this study aimed to reveal the present implementation status and problems of physical assessment by community pharmacists in Osaka, especially focusing on vital-signs. The questionnaires were sent to all the 3571 insurance pharmacies belonging to the Osaka Pharmaceutical Association and 871 pharmacies responded. Many pharmacists recognized the necessity for vital-signs measurement by pharmacists in home medical care (81.5% of pharmacies that offered home medical care and 75.4% of pharmacies that did not offer one). However, the proportion of pharmacies that conduct vital-signs measurement in home medical care was 18.7%, therefore, it was suggested that the present problem is "many pharmacists cannot conduct vital-signs measurement, although they think it should be conducted". Moreover, the most common reason for not measuring vital-signs was the lack of instruments, such as stethoscopes and sphygmomanometer (43.2%). This is the latest report with a large-scale sample, thus, it can serve as valuable knowledge in considering what pharmacists do for the future. PMID- 29386439 TI - [Survey of Description on Package Inserts of OTC Drugs]. AB - The "self-medication tax deduction" system began in Japan in January 2017, allowing people to encourage the use of OTC drugs. Package inserts contain important information for consumers regarding their use. In this study, we first checked whether the items, as required in the notifications of the Japanese Ministry of Health, Labour and Welfare, are described in the package inserts of cold remedies and analgesic antipyretics in OTC drugs. The descriptions of almost all packages checked in this study were based on the notifications, but those of a small number of them were not. Next, we examined the description of the items, unrequired in the notification, but worthy for proper use of drugs; e.g., the description of prohibition for use by "patients with severe hypertension" in case of ibuprofen-containing products, and the description was found in only seven of 180 products. Manufactures should make package inserts along with notifications, including the description for proper use of drugs. PMID- 29386440 TI - [Multiple Chemical Sensitivity (MCS): History, Epidemiology and Mechanism]. AB - Multiple chemical sensitivity (MCS), also known as idiopathic environmental intolerance, has been described as a chronic acquired disorder characterized by nonspecific symptoms in multiple organ systems and is associated with exposure to low-level chemicals. The name was established by Cullen, in 1987, although the name and diagnostic criteria are still under debate even now. A number of hypotheses concering the etiology and pathogenesis of MCS have been proposed, including impairmens of neurological, immunological and psychological systems. However, research on the possible mechanisms underlying MCS is far from complete. The name and diagnostic criteria of its history as well as theoretical and experimental mechanisms underlying MCS are reviewed here. PMID- 29386441 TI - [Preface]. PMID- 29386442 TI - [Hygiene in Sleep: Problems of Sleeping Habits in Shift Workers]. AB - Since World War II, Japan has achieved remarkable economic development and has become an advanced country. Particularly in the industrial field, a production system has been developed to reduce the loss of machining time by adopting a shiftwork in factories operating 24 hours a day, which contributes to the improvement of productivity. Nowadays, this shiftwork practice has spread from the industrial field to other businesses such as 24-hour entertainment facilities and convenience stores, which lead to sleep deprivation in Japanese society. Even at home, certain conditions adversely affect sleeping habits. We are concerned about the risks of physical and mental health, impairments posed by the use of tablets, PCs, smartphones, and other devices so popular in today's Japan, as they delay sleep. It is urgent to improve poor sleeping habits because their outcomes such as sleep disorders and deprivation may also lead to traffic and industrial accidents. PMID- 29386443 TI - [Electromyography Analysis of Rapid Eye Movement Sleep Behavior Disorder]. AB - Polysomnography (PSG), which records physiological phenomena including brain waves, breathing status, and muscle tonus, is useful for the diagnosis of sleep disorders as a gold standard. However, measurement and analysis are complex for several specific sleep disorders, such as rapid eye movement (REM) sleep behavior disorder (RBD). Usually, brain waves during REM sleep indicate an awakening pattern under relaxed conditions of skeletal and antigravity muscles. However, these muscles are activated during REM sleep when patients suffer from RBD. These activated muscle movements during REM, so-called REM without atonia (RWA) recorded by PSG, may be related to a neurodegenerative disease such as Parkinson's disease. Thus, careful analysis of RWA is significant not only physically, but also clinically. Commonly, manual viewing measurement analysis of RWA is time-consuming. Therefore, quantitative studies on RWA are rarely reported. A software program, developed from Microsoft Office Excel(r), was used to semiautomatically analyze the RWA ratio extracted from PSG to compare with manual viewing measurement analysis. In addition, a quantitative muscle tonus study was carried out to evaluate the effect of medication on RBD patients. Using this new software program, we were able to analyze RWA on the same cases in approximately 15 min as compared with 60 min in the manual viewing measurement analysis. This software program can not only quantify RWA easily but also identify RWA waves for either phasic or tonic bursts. We consider that this software program will support physicians and scientists in their future research on RBD. We are planning to offer this software program for free to physicians and scientists. PMID- 29386444 TI - [Study of Equilibrium Control System during a Lowering at Arousal Level]. AB - OBJECTIVES: Contingent negative variation (CNV) is an event-related potential proportional to vigilance degree. A CNV graph shows an inverted U-shape, and this bioreaction disappears after falling below a threshold of vigilance degree. Previous studies have shown that the event-related potential gained with time decreases with sleep deprivation, and a decrease in the vigilance degree has been confirmed using Flicker values (FV) and the Stanford Sleepiness Scale (SSS) score. The minimum integrated value was recorded 24 h after the onset of sleep deprivation. In a present study, we used 36-h sleep deprivation. The FVs, SSS scores, and stabilograms were obtained every 90 min for 52 h, except for the 12 h of sleep. We herein examine whether the biocontrol system is changed by sleep deprivation. RESULTS: The time sequences in FV and SSS score showed that the degree of vigilance markedly decreased 22.5 h after the onset of this experiment, which supported CNV disappearance with sleep deprivation. The sway value with subjects' eyes closed was greatest 22.5 h after the onset of this experiment. Furthermore, there were no significant differences between the sway value during the above-mentioned sleep deprivation and that after 12 h of sleep. We considered that the equilibrium function and vigilance after 36-h sleep deprivation did not recover markedly well with sleep of sufficient duration. That is, the biocontrol process in the subconscious still proceeds after awakening. CONCLUSIONS: In this study, we focused on bioprocessing, especially the equilibrium function, during sleep deprivation and investigated the relationship between the equilibrium function and sleep deprivation. We obtained evidence supporting CNV disappearance after sleep deprivation for 36 h. The equilibrium control system without CNV was compared with that with CNV. PMID- 29386445 TI - [Effect of Reading a Book on a Tablet Computer on Cerebral Blood Flow in the Prefrontal Cortex]. AB - OBJECTIVES: By measuring cerebral blood flow in the prefrontal cortex, we aimed to determine how reading a book on a tablet computer affects sleep. METHODS: Seven students (7 men age range, 21-32 years) participated in this study. In a controlled illuminance environment, the subjects read a novel in printed form or on a tablet computer from any distance. As the subjects were reading, the cerebral blood flow in their prefrontal cortex was measured by near-infrared spectroscopy. The study protocol was as follows. 1) Subjects mentally counted a sequence of numbers for 30 s as a pretest to standardized thinking and then 2) read the novel for 10 min, using the printed book or tablet computer. In step 2), the use of the book or tablet computer was in a random sequence. Subjects rested between the two tasks. RESULTS: Significantly increased brain activity (increase in regional cerebral blood flow) was observed following reading a novel on a tablet computer compared with that after reading a printed book. Furthermore, the region around Broca's area was more active when reading on a tablet computer than when reading a printed book. CONCLUSIONS: Considering the results of this study and previous studies on physiological characteristics during nonrapid eye movement sleep, we concluded that reading a book on a tablet computer before the onset of sleep leads to the potential inhibition of sound sleep through mechanisms other than the suppression of melatonin secretion. PMID- 29386446 TI - [Topics on Child Development in Pediatrics]. AB - Over the past few decades, advances in neonatal medicine have increased survival rates among very-low-birth-weight (VLBW) babies. Despite improvements in short term outcomes, there is increasing concern about the probability of mild cognitive dysfunction in this population. Our analysis of VLBW babies born in our hospital revealed that the incidence of mild developmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactive disorder (ADHD) at the age of 3 years is 7.2%, which is markedly higher than the 2.8% incidence of ASD in the general population. Because problems related to ASD or ADHD tend to become more prominent as children grow up, the ages at diagnosis of developmental disorders are generally 6 years or above. Thus, in our follow up study of VLBW babies at age 6, the incidence of these developmental disorders had risen to 30%. These patients are apparently obstinate and difficult to train, causing parental problems with child care. It is important to support these children and help them establish good relationships with their parents. Given these problems, it is necessary to follow up VLBW children in the longterm, at least until they are elementary school students. PMID- 29386447 TI - [Underlying Mechanisms of Methamphetamine-Induced Self-Injurious Behavior and Lethal Effects in Mice]. AB - Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug abuse-induced acute toxicity. PMID- 29386448 TI - [Some Attentional Points in the Clinical Aspects of Trauma Care]. AB - Almost all patients requiring care for a combination of sexual, physiological, and psychological trauma, suffer from psychological or mental illness. Mental symptoms are well known to be associated with the violence very well and assailants have a violence dependency but it is not a well known mental disease. Changing of roles between being an assailant and being a victim is observed in half of the patients. In patients with trauma, hyperarousal and apathy appears simultaneously, and avoidance symptoms, intrusion symptoms, and crashed sleep, dissociation are also recognized. In addition, symptoms of orality are observed in patients requiring trauma care. However, hyperarousal, disturbance of sleep, and suicidal ideation improve quickly and the symptoms of a pair of a mother child pair are well correlated. In organic non-temporary hyper psychogenic diseases (physiological diseases and surgery, and so on), non-organic psychogenic diseases (psychiatric diseases), and diseases on the border line between organic and non-organic diseases (psychosomatic diseases and may be unknown to non medical professionals knowledge of such characteristic symptoms) is important information for health and medical care in the regional comprehensive care setting. PMID- 29386449 TI - [Ego-state Therapy: Psychotherapy for Multiple Personality Disorders]. AB - The author describes ego-state therapy. This psychotherapy is used for treating multiple personality disorders. The author mentions the theoretical background of this method, and practical points. Initially, ego-state therapy was developed as a type of hypnotherapy, but it evolved as a safe therapeutic method in combination with trauma processing therapies. The author presents a case study, and discusses the clinical significance of this treatment. PMID- 29386450 TI - [Approach to the Development of Mind and Persona]. AB - OBJECTIVES: To access medical specialists by health specialists working in the regional health field, the possibility of utilizing the voice approach for dissociative identity disorder (DID) patients as a health assessment for medical access (HAMA) was investigated. The first step is to investigate whether the plural personae in a single DID patient can be discriminated by voice analysis. METHODS: Voices of DID patients including these with different personae were extracted from YouTube and were analysed using the software PRAAT with basic frequency, oral factors, chin factors and tongue factors. In addition, RAKUGO story teller voices made artificially and dramatically were analysed in the same manner. Quantitive and qualitative analysis method were carried out and nested logistic regression and a nested generalized linear model was developed. RESULTS: The voice from different personae in one DID patient could be visually and easily distinquished using basic frequency curve, cluster analysis and factor analysis. In the canonical analysis, only Roy's maximum root was <0.01. In the nested generalized linear model, the model using a standard deviation (SD) indicator fit best and some other possibilities are shown here. CONCLUSIONS: In DID patients, the short transition time among plural personae could guide to the risky situation such as suicide. So if the voice approach can show the time threshold of changes between the different personae, it would be useful as an Access Assessment in the form of a simple HAMA. PMID- 29386452 TI - [Academic Research Strategy against an Aging Society with Fewer Children]. PMID- 29386451 TI - [Recent Trends of Trace Element Studies in Clinical Medicine in Japan]. AB - The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed breast milk with low zinc concentration, individuals administered chelating medicines, athletes and patients with diabetes mellitus, hepatic cirrhosis or nephrosis syndrome. Menkes disease is associated with severe copper deficiency, and there is no effective treatment. Deficiencies of selenium and iodine are observed in patients who receive special formulas of milk and enteral formula with low selenium and iodine concentrations, respectively. In contrast, neonatal transient hypothyroidism due to excess intake of iodine in pregnant women has also reported in Japan. It is expected that collaborative studies by researchers and clinicians will contribute to clarify the detail mechanism, diagnosis and treatment of these abnormalities. PMID- 29386453 TI - [Nutritional Status of Japanese Women of Childbearing Age and the Ideal Weight Range for Pregnancy]. AB - According to the recent 2015 Nutrition Survey, the prevalence of being underweight (Body Mass Index, BMI <18.5 kg/m2) among women in their 20s is 22.3%. Women of childbearing age tend to have a lower intake of protein and their total energy intake is lower than the requirements established by the 2015 Dietary Reference Intakes for Japanese. There is a growing body of evidence showing that underweight women tend to bear small babies and that these babies have an increased risk of diabetes or cancer in their adulthood. In order to prevent Japanese women from bearing small babies, the literature has suggested that women of childbearing age should be encouraged to remain at a normal weight before pregnancy. For optimal weight gain during pregnancy, existing guidelines recommend different ranges of weight gain based on prepregnancy BMI. Owing to the absence of official GWG recommendations in Asian countries, including China and Taiwan, the US Institute of Medicine (IOM) guidelines are generally followed. However, Asian women are smaller and experience lower weight gains; therefore, excessive weight gain may lead to harmful events including macrosomia, preterm birth, preeclampsia, gestational diabetes, pregnancy-induced hypertension, and short- and long-term postpartum weight retention. Thus, an accurate GWG range should be determined for Asian women. We introduce one epidemiological study in which the optimal weight gain range was investigated by analyzing receiver operating characteristic curves together with potential research ideas in this field with the aim of encouraging young researchers to solve this public health problem affecting mothers and children. PMID- 29386454 TI - [Importance of an Aldehyde Dehydrogenase 2 Polymorphism in Preventive Medicine]. AB - Unlike genetic alterations in other aldehyde dehydrogenase (ALDH) isozymes, a defective ALDH2 polymorphism (rs671), which is carried by almost half of East Asians, does not show a clear phenotype such as a shortened life span. However, impacts of a defective ALDH2 allele, ALDH2*2, on various disease risks have been reported. As ALDH2 is responsible for the detoxification of endogenous aldehydes, a negative effect of this polymorphism is predicted, but bidirectional effects have been actually observed and the mechanisms underlying such influences are often complex. One reason for this complexity may be the existence of compensatory aldehyde detoxification systems and the secondary effects of these systems. There are many issues to be addressed with regard to the ALDH2 polymorphism in the field of preventive medicine, including the following concerns. First, ALDH2 in the fetal stage plays a role in aldehyde detoxification; therefore, prenatal health effects of environmental aldehyde exposure are of concern for ALDH2*2-carrying fetuses. Second, ALDH2*2 carriers are at high risk of drinking-related cancers. However, their drinking habits result in less worsening of physiological findings, such as energy metabolism index and liver functions, compared with non-ALDH2*2 carriers, and therefore opportunities to detect excessive drinking can be lost. Third, personalized medicine such as personalized prescriptions for ALDH2*2 carriers will be required in the clinical setting, and accumulation of evidence is awaited. Lastly, since the ALDH2 polymorphism is not considered in workers' limits of exposure to aldehydes and their precursors, efforts to lower exposure levels beyond legal standards are required. PMID- 29386456 TI - [Editor's Note]. PMID- 29386455 TI - [An Investigation of Factors Associated with Emotional Exhaustion among Hospital Nurses: Adherence to "Maternal Affection" and Agreement with Stereotypical Gender Roles]. AB - OBJECTIVE: To investigate factors including adherence to "maternal affection" and stereotypical gender roles associated with emotional exhaustion among hospital nurses. METHOD: In 2014, among 2,690 workers recruited for this study, 891 participated with written informed consent. Of these, we investigated 464 hospital nurses. Adherence to maternal affection and emotional exhaustion were measured using valid and reliable scales developed by Egami (2005, 12 items) and Kubo (1992, 5 items), respectively. Stereotypical gender role was measured by asking "how much do you agree with the idea that women should stay home and men should work?". Workfamily conflict was measured in terms of the discrepancy in priority in life (i.e., a work or a private life) between the participant's ideal and the real world. RESULT: The majority of our participants were women (86%), aged 39 or younger (80%), and single (70%). About one-quarter had workfamily conflict (26%) and agreed with the stereotypical gender role (28%). The mean scores of emotional exhaustion and adherence to maternal affection were 17.2 (out of 25) and 30.8 (out of 48), respectively. A stepwise multivariable model showed that being a woman (p=0.028), being young (p=0.022), being single (p=0.007), and having workfamily conflict (p<0.001) were more likely to increase emotional exhaustion after adjusting for household income. Adherence to maternal affection and stereotypical gender role were not significantly associated with emotional exhaustion. CONCLUSION: This study demonstrated that adherence to "maternal affection" and stereotypical gender roles were not associated with psychological burnout. Special attention should be paid to hospital nurses who are women, young, or single, or who have workfamily conflict. PMID- 29386457 TI - Giant Cell Tumors of the Bone: Changes in Image Features after Denosumab Administration. AB - PURPOSE: To assess the clinical importance in the feature change in giant cell tumors of the bone (GCTB) after denosumab treatment, detected by MRI. METHODS: In 12 patients, MRI and CT of GCTB obtained before and after the treatment retrospectively compared. The tumor size, the signal intensity (SI) ratio between the solid part of the GCTB and muscle, cystic part size, gadolinium enhancement and apparent diffusion coefficient (ADC) value were measured on MRI. The bone formation in the tumor was observed on CT and X-ray. RESULTS: The mean number of denosumab injections was 19 +/- 10. The follow-up period was up to 2 years. One case showed partial remission, while the other 11 cases were stable. A mean SI ratio on T2-weighted image statistically significantly decreased from 3.9 to 1.9 after the treatment. A cystic component in the tumor was observed in five cases before the treatment, and the diameter of the cystic part decreased after the treatment in 80% of cases (4/5). All the tumors showed contrast enhancement on T1 weighted image pre- and post-treatment (11/11). The averaged ADC values were 1.52 * 10-3 mm2/s before and 1.44 * 10-3 mm2/s after the treatment (P = 0.63). Bone formation in the tumor was observed in 58% of cases (7/12). CONCLUSION: The decrease of SI ratio on T2-weighted image, shrinkage of cystic part and bone formation should be regarded as the effectiveness of denosumab treatment despite of no substantial change in the tumor size. PMID- 29386458 TI - Quantitative T2 Mapping of Knee Cartilage: Comparison between the Synthetic MR Imaging and the CPMG Sequence. AB - The purpose was to evaluate the feasibility of quantitative MRI T2 mapping based on the quantitative MRI (QRAPMASTER) sequence for the quantitative assessment of knee cartilage. The T2 values from the phantom study showed excellent correlation between the two techniques (r2 = 0.998). The cartilage T2 values exhibited strong correlations (r2 = 0.867-0.982). Quantitative MRI (qMRI) T2 mapping can be used as an alternative to multi-echo T2 mapping, with relatively short scan time. PMID- 29386459 TI - Synthetic Studies on Heteropolycyclic Natural Products: Development of Divergent Strategy. AB - The divergent total syntheses of three types of heteropolycyclic natural products, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. A strategy involving a late-stage pluripotent common synthetic intermediate prepared via original and innovative transformations was employed. A brief description of the philosophy and criteria for choosing the synthetic targets and common synthetic precursors, as well as details regarding the development of the overall synthetic schemes from a common intermediate are discussed. PMID- 29386460 TI - Foreword. PMID- 29386461 TI - Chemical Ligation Reactions of Oligonucleotides for Biological and Medicinal Applications. AB - Chemical ligation of oligonucleotides (ONs) is the key reaction for various ON based technologies. We have tried to solve the problems of RNA interference (RNAi) technology by applying ON chemical ligation to RNAi. We designed a new RNAi system, called intracellular buildup RNAi (IBR-RNAi), where the RNA fragments are built up into active small-interference RNA (siRNA) in cells through a chemical ligation reaction. Using the phosphorothioate and iodoacetyl groups as reactive functional groups for the ligation, we achieved RNAi effects without inducing immune responses. Additionally, we developed a new chemical ligation for IBR-RNAi, which affords a more native-like structure in the ligated product. The new ligation method should be useful not only for IBR-RNAi but also for the chemical synthesis of biofunctional ONs. PMID- 29386462 TI - Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics. AB - Muraymycins, isolated from a culture broth of Streptomyces sp., are members of a class of naturally occurring nucleoside antibiotics. They are strong inhibitors of the phospho-MurNAc-pentapeptide translocase (MraY), which is responsible for the peptidoglycan biosynthesis. Since MraY is an essential enzyme among bacteria, muraymycins are expected to be a novel antibacterial agent. In this review, our efforts to synthesize muraymycin D2, simplify the chemical structure, improve antibacterial spectrum, and solve the X-ray crystal structure of the muraymycin D2/MraY complex are described. PMID- 29386463 TI - Unnatural Base Pairs for Synthetic Biology. AB - In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology. Prior to introducing our research results, we present investigations by four outstanding groups in the field. Their research results demonstrate the importance of shape complementarity and stacking ability as well as hydrogen bonding (H-bonding) patterns for unnatural base pairs. On the basis of this research background, we developed unnatural base pairs consisting of imidazo[5',4':4.5]pyrido[2,3-d]pyrimidines and 1,8-naphthyridines, i.e., Im : Na pairs. Since Im bases are recognized as ring-expanded purines and Na bases are recognized as ring-expanded pyrimidines, Im : Na pairs are expected to satisfy the criteria of shape complementarity and enhanced stacking ability. In addition, these pairs have four non-canonical H-bonds. Because of these preferable properties, ImNN : NaOO, one of the Im : Na pairs, is recognized as a complementary base pair in not only single nucleotide insertion, but also the PCR. PMID- 29386464 TI - Synthesis of 4'-Thionucleosides as Antitumor and Antiviral Agents. AB - Many attempts have been made to synthesize structurally novel nucleoside derivatives in order to identify effective compounds for the treatment of tumors and virus-caused disease. At our laboratories, as part of our efforts to synthesize 4'-thionucleosides, we have identified and characterized biologically active nucleosides. During the course of our synthetic study, we developed the Pummerer-type thioglycosylation reaction. As a result, we synthesized a potent antineoplastic nucleoside, 1-(2-deoxy-2-fluoro-beta-D-4-thio-arabino furanosyl)cytosine (4'-thioFAC), and several novel 4'-thionucleosides that possess antiherpes virus activities. PMID- 29386465 TI - Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines. AB - In recent years, nucleic acid-based drug therapeutics have gained considerable attention for their potential in the treatment of various diseases. However, their therapeutic value is greatly hindered by the challenge of delivering them into cells. One possible strategy to improve cellular uptake is the use of "prodrug-type oligonucleotide medicine" in which negatively charged phosphodiester moieties are masked by bio-labile protecting groups. In this review, we describe our recent studies related to bio-labile protecting groups for phosphodiester moieties in the development of prodrug-type oligonucleotide medicines. PMID- 29386466 TI - Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP Ribose, a Ca2+-Mobilizing Second Messenger. AB - Cyclic ADP-ribose (cADPR), a general mediator involved in Ca2+ signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxy groups of the riboses are linked by a pyrophosphate unit. This review focuses on chemical synthetic studies of cADPR analogues of biological importance. Although cADPR analogues can be synthesized by enzymatic and chemo-enzymatic methods using ADP-ribosyl cyclase, the analogues obtained by these methods are limited due to the substrate specificity of the enzymes. Consequently, chemical synthetic methods providing a greater variety of cADPR analogues are required. Although early chemical synthetic studies demonstrated that construction of the large 18-membered ring structure is difficult, the construction was achieved using the phenylthiophosphate-type substrates by treating with AgNO3 or I2. This is now a general method for synthesizing these types of biologically important cyclic nucleotides. Using this method as the key step, the chemically and biologically stable cADPR mimic, cADP-carbocyclic-ribose (cADPcR) and -4-thioribose (cADPtR), were synthesized. PMID- 29386468 TI - Simulation Study on Complex Conformations of Abeta42 Peptides on a GM1 Ganglioside-Containing Lipid Membrane. AB - Aggregation and complex formation of amyloid beta (Abeta) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Abeta42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Abetas due to adhesion on the membrane and subsequent molecular interactions among the Abetas were monitored. It was suggested from results of the two 1.0 us simulation trials that stable complexes of Abeta peptides were not rapidly generated but that a steady binding of two Abetas was gradually formed. Observation of two Abetas that will be a complex with steady binding revealed that one Abeta was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side chains of Arg5 and Lys28 working as anchors to hold the Abeta helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Abeta can search for an energetically favorable binding position on the first one. A parallel beta-sheet structure was formed between the C-terminal sides of the two Abetas. Ala30 was critically important to lead the stable beta-sheet conformation at the C-terminal hydrophobic domains of Abetas. In the N-terminal sides, helix structures were kept in both Abetas. PMID- 29386467 TI - Alkaloids from Stephania venosa as Chemo-Sensitizers in SKOV3 Ovarian Cancer Cells via Akt/NF-kappaB Signaling. AB - Crebanine (CN), tetrahydropalmatine (THP), O-methylbulbocapnine (OMBC) and N methyl tetrahydropalmatine (NMTHP) are isoquinoline derived natural alkaloids isolated from tubers of Stephania venosa. We investigated chemo-sensitizing effects of these alkaloids in ovarian cancer cells and evaluated underlying molecular mechanisms involved in chemo-sensitivity. Detection of cell apoptosis was evaluated by using flow cytometry. Cell viability was analyzed using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Chou-Talalay median effect principle was used to evaluate potential drug interactions. Protein analyses were performed on ovarian carcinoma cells using Western blotting upon treatment with anticancer drug and alkaloids. Aporphine alkaloids, such as CN and OMBC, enhanced cisplatin sensitivity in intrinsic cisplatin resistant SKOV3 cells, but not in cisplatin sensitive A2780 cells. Protoberberine alkaloids, such as THP and NMTHP, had no synergistic effect on cisplatin sensitivity in either cell line. Chemo-sensitizing effects of CN and OMBC in SKOV3 cells were mediated via activating apoptosis-induced cell death through caspase-3, -8 and cleaved poly ADP-ribose polymerase (PARP) and via inhibiting anti-apopotic and survival protein expression, such as Bcl-xL, Baculoviral IAP repeat-containing protein 3 (cIAP-2), survivin and interleukin (IL) -6. Cisplatin stimulated protein kinase B (Akt) and nuclear factor-kappaB (NF-kappaB) signaling pathways, but not mitogen activated protein kinase (MAPK), activator protein 1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) in SKOV3 cells. Akt/NF-kappaB signaling was blocked by CN and OMBC leading to increased sensitization to cisplatin. These findings demonstrate that CN and OMBC sensitizes SKOV3 cells to cisplatin via inhibition of Akt/NF-kappaB signaling and the down regulation of NF-kappaB mediated gene products. Our results suggest that alkaloids obtained from S. venosa could be used as chemo-sensitizers in ovarian cancer to sensitize and minimize the dose related toxicity of platinum-based chemotherapeutic drugs. PMID- 29386469 TI - Total Synthesis of Carbazomycins A and B. AB - Total syntheses of carbazomycins A and B were demonstrated using a ytterbium catalyzed Diels-Alder reaction with (silyloxyvinyl)indole as a diene. The densely substituted benzene ring of the target compound was successfully constructed by functionalization of a hydrocarbazolone intermediate and subsequent aromatization using N-bromosuccinimide. PMID- 29386470 TI - Formation of 8-S-L-Cysteinyladenosine from 8-Bromoadenosine and Cysteine. AB - When 8-bromoadenosine was incubated with cysteine at pH 7.2 and 37 degrees C, an exclusive product was generated. This product was identified as a cysteine substitution derivative of adenosine at the 8 position, 8-S-L-cysteinyladenosine. The reaction accelerated as pH increased from mildly acidic to basic conditions. The isolated cysteine adduct of adenosine decreased with a half-life of 15 h at pH 7.2 and 37 degrees C. Similar results were obtained for the incubation of 8 bromo-2'-deoxyadenosine and 8-bromoadenosine 3',5'-cyclic monophosphate with cysteine. These results suggest that 8-bromoadenine in nucleotides, RNA, and DNA can react with thiols, resulting in adducts under physiological conditions. PMID- 29386471 TI - The synthesis, modification, and application of nanosilica in polymethyl methacrylate denture base. AB - This study aimed to investigate amount of gamma methacryloxypropyltrimethoxysilane (MPS) silanized on experimental nanosilica particles (NPs), amount of NP and amount of MPS silanized NP on flexural strength (FS), flexural modulus (FM), and fracture toughness (FT) of NP reinforced polymethyl methacrylate (PMMA). The chemisorbed amount of MPS was determined using elemental analysis. Six groups (n=8) were prepared with chemisorbed amount and mixed with PMMA-monomer to make 0.25, 0.5, 1, 5, 10 and 15% (w/w) of NP reinforced PMMA. PMMA without NP served as control. Seven groups (n=8) were prepared with 1% of NP silanized with 0, 0.061, 0.123, 0.246, 0.493, 0.987, and 1.974 gMPS/gsilica and mixed with PMMA-monomer to make NP reinforced PMMA. FS, FM, and FT were determined using 3-point bending test. One-way ANOVA and multiple comparisons showed that 0.246 gMPS/gsilica of 1% amount of silanized NP group was significantly highest in FS, FM, and FT compared to the others (p<0.05). PMID- 29386472 TI - Assessment of the Quality of Breast MR Imaging Using the Modified Dixon Method and Frequency-Selective Fat Suppression: A Phantom Study. AB - To obtain objective and concrete data by physically assessing the quality of breast magnetic resonance images based on the fat-suppression effect by the modified Dixon method (mDixon) and frequency-selective fat suppression (e-Thrive) using an original lipid-content breast phantom that could easily reveal the influence of non-uniform fat suppression in breast magnetic resonance imaging. The fat-suppression uniformity was approximately seven times superior when using mDixon compared with when using e-Thrive. mDixon appears to have a significant advantage. PMID- 29386473 TI - Direct Repair of Localized Aortic Dissection with Critical Malperfusion of the Left Main Trunk. AB - BACKGROUND: Localized aortic dissection on the left coronary cusp with critical malperfusion of the left main trunk (LMT) is rare and carries a high risk of death. CASE PRESENTATION: We report a case of a 48-year-old patient who developed localized aortic dissection of the left coronary cusp complicated by critical malperfusion of the LMT of the coronary artery. After percutaneous coronary intervention (PCI) for the LMT, a Koster-Collins-like direct repair of the localized aortic dissection was carried out by closure of the false channel using BioGlue (CyroLife, Inc., Kennesaw, GA, USA) with the reinforcement of double Teflon felt strips. CONCLUSION: The aortic repair using a modified Koster-Collins technique was successful. PMID- 29386474 TI - Long-Term Clinical Outcomes Survey of Bone Marrow-Derived Cell Therapy in Critical Limb Ischemia in Japan. AB - BACKGROUND: The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan.Methods and Results:The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10 year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV. CONCLUSIONS: Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV. PMID- 29386475 TI - Ability of B-Type Natriuretic Peptide Testing to Predict Cardioembolic Stroke in the General Population - Comparisons With C-Reactive Protein and Urinary Albumin. AB - BACKGROUND: The ability of cardiovascular biomarkers to predict the incidence of stroke subtypes remains ill-defined in the general population.Methods and Results:The blood levels of B-type natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) and urinary albumin corrected by urinary creatinine (UACR) were determined in a general population (n=13,575). The ability to predict the incidence of ischemic stroke subtypes (lacunar, atherothrombotic, cardioembolic) for each biomarker was assessed based on the area under the receiver-operating characteristic curve (AUC-ROC) and using Cox proportional hazard modeling. The predictive abilities of UACR and hs-CRP for any subtype of ischemic event were found to be suboptimal. However, the ability of BNP to predict the incidence of cardioembolic stroke was excellent (AUC-ROC=0.81). When BNP was added to established stroke risk factors, the ability to predict cardioembolic stroke in terms of the AUC-ROC significantly improved (4-year follow-up, P=0.018; 8-year follow-up, P=0.009). Furthermore, when BNP was added to the JPHC score, the ability to predict cardioembolic stroke was significantly improved (net reclassification improvement=0.968, P<0.0001: integrated discrimination improvement=0.039, P<0.05). CONCLUSIONS: In the general population, plasma BNP was an excellent biomarker for predicting the incidence of cardioembolic stroke when used alone or in combination with established stroke risk factors. PMID- 29386476 TI - The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities. AB - The discovery of the chimeric tyrosine kinase breakpoint cluster region kinase Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3 hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC50 value of 9.3 uM. In contrast, the IC50 against normal peripheral blood mononuclear cells was 276.0 uM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC50=8.7 uM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. PMID- 29386477 TI - Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Phi) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Phi and clinical efficacy. Furthermore, using Phi as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Phi (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Phi. It was also revealed that the Phi value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors. PMID- 29386478 TI - The Role of Interleukin-19 in Contact Hypersensitivity. AB - Interleukin (IL)-19 is a member of the IL-10 family of interleukins and is an immuno-modulatory cytokine produced by the main macrophages. The gastrointestinal tissues of IL-19 knockout mice show exacerbated experimental colitis mediated by the innate immune system and T cells. There is an increasing focus on the interaction and relationship of IL-19 with the function of T cells. Contact hypersensitivity (CHS) is T cell-mediated cutaneous inflammation. Therefore, we asked whether IL-19 causes CHS. We investigated the immunological role of IL-19 in CHS induced by 1-fluoro-2,4-dinitrofluorobenzene as a hapten. IL-19 was highly expressed in skin exposed to the hapten, and ear swelling was increased in IL-19 knockout mice. The exacerbation of the CHS response in IL-19 knockout mice correlated with increased levels of IL-17 and IL-6, but no alterations were noted in the production of interferon (IFN)gamma and IL-4 in the T cells of the lymph nodes. In addition to the effect on T cell response, IL-19 knockout mice increased production of inflammatory cytokines. These results show that IL-19 suppressed hapten-dependent skin inflammation in the elicitation phase of CHS. PMID- 29386479 TI - Peyer's Patches as a Portal for DNA Delivery by Lactococcus lactis in Vivo. AB - Application of food-grade Lactococcus lactis (L. lactis) as a safe delivery tool for DNA vaccines and therapeutic proteins has been well investigated. Although some studies showed that eukaryotic expression plasmids were transferred from L. lactis to enterocytes, the precise mechanism of the DNA transfer remains unknown. In this study, we generated an invasive L. lactis strain that expresses "murinized" Internalin A, an invasin of intracellular bacteria Listeria monocytogenes with two amino acid alterations for invasion into murine cells, and confirmed that this L. lactis strain delivered DNA in an invasin-dependent manner into a monolayer of epithelial cells polarized to mimic the gastrointestinal tract environment. Although invasive L. lactis inoculated orally can deliver DNA into enterocytes in the gastrointestinal tract of mice, the efficiency of DNA transfer was similar to that of non-invasive L. lactis strain, suggesting that the in vivo DNA transfer from L. lactis occurs invasin-independently. A ligated intestinal loop assay, a method for a short-term culturing of the whole intestine filled with materials to evaluate the interaction of the materials with intestinal cells, demonstrated that both non-invasive and invasive L. lactis strains were present in the Peyer's patches of the small intestine. On the other hand, few L. lactis was detected in the non-Peyer's patch epithelial region. Thus, our observations lead us to speculate that DNA transfer from L. lactis occurs predominantly in the Peyer's patches in an invasin-independent manner. PMID- 29386480 TI - Antimicrobial Activity of the Phenolic Compounds of Prunus mume against Enterobacteria. AB - Mume fruit, the Japanese apricot (Prunus mume SIEB. et ZUCC.), is popular in Japan and is mostly consumed in the pickled form called umeboshi. This fruit is known to have anti-microbial properties, but the principal constituents responsible for the antimicrobial properties have not yet been elucidated. We investigated the antimicrobial activities of the phenolic compounds in P. mume against enterobacteria. In this study, growth inhibitory activities were measured as an index of the antibacterial activities. The phenolic compounds were prepared from a byproduct of umeboshi called umesu or umezu (often translated as "mume vinegar"). Umesu or umezu phenolics (UP) contain approximately 20% phenolic compounds with p-coumaric acid as a standard and do not contain citric acid. We observed the inhibitory effects of UP against the growth of some enterobacteria, at a relatively high concentration (1250-5000 ug/mL). Alkali hydrolysates of UP (AHUP) exhibited similar antibacterial activities, but at much lower concentrations of 37.5-300 ug/mL. Since AHUP comprises hydroxycinnamic acids such as caffeic acid, p-coumaric acid, and ferulic acid, the antibacterial activities of each of these acids were examined. Our study shows that the phenolic compounds in P. mume other than citric acid contribute to its antimicrobial activity against enterobacteria in the digestive tract. PMID- 29386482 TI - Assessment of Anticancer Drug Effects on Pancreatic Cancer Cells under Glucose Depleted Conditions Using Intracellular and Extracellular Amino Acid Metabolomics. AB - Previously, we developed a method to evaluate states of cells treated with anticancer drugs via the comprehensive analysis of amino acids, termed amino acid metabolomics. In the present study, we evaluated the effects of the anticancer drugs, gemcitabine hydrochloride and pyrvinium pamoate, on the proliferation of a pancreatic cancer cell line (PANC-1) under hypoglycemic conditions using amino acid metabolomics. Intracellular and extracellular amino acid profiles of PANC-1 were determined by hydrophilic interaction chromatography-tandem mass spectrometry with simple pretreatment. Changes to the drugs' anticancer effects resulting from glucose starvation conditions were presented in score plots obtained from principal component analyses. In particular, the analysis of intracellular amino acids was found to be the superior approach because the results allowed a clearer assessment of the cell state. Further, orthogonal partial least squares discriminant analysis was performed to search for amino acid candidates that discriminate with anticancer drug-treated PANC-1 cells. We identified several amino acids that might be able to distinguish the drug-treated group from the control group. These results might provide a better understanding of the mechanisms underlying cell responses such as drug resistance or austerity. The present study is the first to evaluate the efficacy of anticancer drugs under glucose starvation based on the analysis of the variation of extracellular and intracellular amino acid profiles in vitro. PMID- 29386481 TI - Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats. AB - Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST. PMID- 29386483 TI - Exploration of the Key Factors for Optimizing the in Vivo Oral Delivery of Insulin by Using a Noncovalent Strategy with Cell-Penetrating Peptides. AB - This present study aimed to determine the optimal oral insulin delivery conditions that would maximize the utility of cell-penetrating peptides (CPPs) by using a noncovalent strategy. We first compared the effectiveness of two potential CPPs, penetratin and its analog PenetraMax, as absorption enhancers for insulin. The combined effect was evaluated under in vivo oral administration conditions. Both D-forms of CPPs were highly effective for increasing the oral absorption of insulin, and D-PenetraMax showed a more rapid onset of absorption enhancement effects compared with those of D-penetratin. However, synergistic absorption enhancement effects after combination treatment were not observed. Next, we tried a theoretical approach to establish optimized oral insulin delivery conditions. A surface plasmon resonance (SPR)-based analysis demonstrated that binding between insulin and penetratin (2 mM) might be saturated at 100-500 uM penetratin, while the bound concentration of penetratin could increase in accordance with an increased concentration of mixed insulin. To test this hypothesis, we investigated the effectiveness of different insulin doses in the gastric pH-neutralized mice. The results showed that the dissociation of noncovalent complexes of insulin and CPPs at the low gastric pH was prevented in these mice. Our findings clearly suggested that a noncovalent strategy with CPPs represents an effective approach for the L-form of CPP to increase the concentration of CPP-bound insulin to attain greater absorption of insulin, although this approach may not be appropriate for the D-form of CPP. Our findings will contribute to the development of oral dosage forms of insulin for noncovalent strategies involving CPP. PMID- 29386484 TI - Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias. AB - Ephedrine alkaloids-free Ephedra Herb extract (EFE) has been developed to eliminate the adverse effects caused by ephedrine alkaloid-induced sympathetic hyperactivation. Previously, we reported that EFE possesses analgesic, anti influenza, and cancer metastatic inhibitory effects at comparable levels to that of Ephedra Herb extract (EHE). However, it has not yet been demonstrated that EFE is free from the known side effects of EHE, such as excitation, insomnia, and arrhythmias. In this study, the incidence of these adverse effects was compared between mice administered EHE and those administered EFE. Increased locomotor activity in an open-field test, reduced immobility times in a forced swim test, and reduced sleep times in a pentobarbital-induced sleep test were observed in EHE-treated mice, when compared to the corresponding values in vehicle-treated mice. In contrast, EFE had no obvious effects in these tests. In electrocardiograms, atrial fibrillation (i.e., irregular heart rhythm, absence of P waves, and appearance of f waves) was observed in the EHE-treated mice. It was suggested that this atrial fibrillation was induced by stimulation of adrenaline beta1 receptors, but not by hypokalemia. However, EFE did not affect cardiac electrophysiology. These results suggest that the abovementioned side effects are caused by ephedrine alkaloids in EHE, and that EFE is free from these adverse effects, such as excitation, insomnia, and arrhythmias. Thus, EFE is a promising new botanical drug with few adverse effects. PMID- 29386485 TI - Juniperus chinensis Fruits Attenuate Oxazolone- and 2,4-Dinitrochlorobenzene Induced Atopic Dermatitis Symptoms in Mice. AB - Juniperus chinensis, commonly Chinese juniper, has been used for treating inflammatory diseases. This study aimed to investigate anti-atopic dermatitis (AD) effects of standardized J. chinensis fruits extract on murine oxazolone- and 2,4-dinitrochlorobenzene (DNCB)-induced models of AD. Ear swelling, epidermis thickening, and eosinophils infiltration in the oxazolone-mediated dermatitis of BALB/c mice were significantly reduced upon topical application of J. chinensis fruits 95% EtOH extract (JCE). Besides, transdermal administration of JCE to SKH 1 hairless mice inhibited the development of DNCB-induced AD-like skin lesions by suppressing transepidermal water loss and improving skin hydration. Decreased total serum immunoglobulin E (IgE) and interleukin (IL)-4 levels could be observed in atopic dorsal skin samples of JCE-treated group. According to the phytochemical analysis, JCE was found to contain isoscutellarein-7-O-beta-D xyloside, cupressuflavone, and amentoflavone as main compounds. Therapeutic attempts with the J. chinensis fruits might be useful in the treatment of AD and related skin inflammatory diseases. PMID- 29386486 TI - Potential Interference of Oil Vehicles on Genital Tubercle Development during the Fetal Period in ICR Mice. AB - Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development. PMID- 29386487 TI - Methylglyoxal Impairs beta2-Adrenoceptor-Mediated Vasodilatory Mechanisms in Rat Retinal Arterioles. AB - Methylglyoxal, a highly reactive dicarbonyl compound, is formed as a by-product of glycolysis and plays an important role in the pathogenesis of diabetic complications, including diabetic retinopathy. However, it remains to be determined how methylglyoxal affects the regulatory mechanisms of retinal blood flow. In this study, we examined the effects of methylglyoxal on beta2 adrenoceptor-mediated vasodilatory mechanisms in rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of methylglyoxal significantly diminished the vasodilation of retinal arterioles induced by the beta2-adrenoceptor agonist salbutamol. The vasodilator effect of BMS-191011, a large-conductance Ca2+-activated K+ (BKCa) channel opener, on retinal arterioles was also attenuated by methylglyoxal. In contrast, methylglyoxal had no significant effect on retinal vasodilator response to forskolin. Methylglyoxal attenuated retinal vasodilator response to salbutamol under blockade of BKCa channels with iberiotoxin, an inhibitor of the channels. These results suggest that methylglyoxal attenuates beta2-adrenoceptor-mediated retinal vasodilation by impairing the coupling of the beta2-adrenoceptor to the guanine nucleotide binding protein (Gs protein) and the function of the BKCa channel. Increased methylglyoxal in the eyes may contribute to the impairment of regulatory mechanisms of retinal blood flow in patients with diabetic retinopathy. PMID- 29386489 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 29386488 TI - Effects of Red Wine Vinegar Beverage on the Colonic Tissue of Rodents: Biochemical, Functional and Pharmacological Analyses. AB - A beverage made of red wine vinegar and grape juice (Yamanashi-no-megumiTM) was developed as a supplemental fluid containing polyphenols, which has been clinically shown to enhance the colonic transit. In this study, we assessed the mechanism of its prokinetic action by analyzing the effects on both the colonic phosphodiesterase activity of rats (n=4) and the isolated colonic strip preparation of guinea pigs (n=4). The 7% (v/v) solution of the beverage significantly decreased the phosphodiesterase activity by 9% (n=4). The beverage in concentrations of 0.7, 2.1 and 7% (v/v) relaxed the colonic strips pre contracted by 1 umol/L of carbachol in a concentration-related manner with 50, 58 and 79%, each response of which was diminished to 11, 19 and 46%, respectively in the presence of 100 umol/L of L-nitro-arginine methyl ester. These results obtained by biochemical, functional and pharmacological analyses suggest that the beverage could relax the colon through both cAMP-associated and nitric oxide dependent pathways, which may partly explain clinically observed prokinetic effect of the beverage. PMID- 29386490 TI - Guidelines for personal exposure monitoring of chemicals: Part IV. AB - This Document, "Guidelines for personal exposure monitoring of chemicals" ("this Guideline"), has been prepared by "The Committee for Personal Exposure Monitoring" ("the Committee") of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a "practical guideline" for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 "Appendices" are provided in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an "expert-centered basic method to reasonably proceed with the assessment and management of risk at workplaces." It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan. PMID- 29386491 TI - [A case of severe obstructive sleep apnea mimicking REM sleep behavior disorder]. AB - The rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream-enacting behaviors related to the loss of the normal generalized skeletal muscle atonia during REM sleep, and shows REM sleep without atonia (RWA) during polysomnography (PSG). Patients with idiopathic RBD have been known to have a siginificantly increased risk of developing one of the alpha synucleiopathies later in life, therefore the diagnosis of RBD is very important and must be dealt with carefully. A 51-year-old man was identified presenting dream-enacting behaviors and unpleasant dreams suggesting the diagnosis of RBD, in addition to snoring and excessive daytime sleepiness. Attended video-PSG excluded RBD showing REM sleep with atonia and without increased phasic EMG activity, and diagnosed with severe obstructive sleep apnea (OSA) with an apnea hypopnea index of 30.1 demonstrating that the reported abnormal sleep behaviors occurred only during respiratory event-induced arousals. Continuous positive airway pressure therapy eliminated the abnormal behaviors, unpleasant dreams, snoring and daytime hypersomnolence. This case shows that severe OSA mimic the symptoms of RBD and that attended video-PSG is necessary to establish the diagnosis of RBD, and identify or exclude other causes of dream-enacting behaviors. PMID- 29386492 TI - [A case of neurolymphomatosis that was diagnosed by acoustic nerve biopsy]. AB - A 58-year-old female was admitted to our hospital because of recurrent multiple cranial neuropathy (right facial palsy followed by involvement of the left trigeminal, facial, acoustic, pharyngeal, and vagal nerves and the right abducens nerve). Brain MRI showed gadolinium enhancement of the right abducens, bilateral facial/acoustic, and left pharyngeal/vagal nerves, and 18F-Fluorodeoxyglucose (FDG)-positron emission tomography revealed abnormal FDG uptake in the right facial, acoustic, pharyngeal, and vagal nerves and the left cervical lymph nodes. Blood and biochemical analyses did not show any abnormalities, including in the patient's lactate dehydrogenase and soluble interleukin-2 receptor (sIL2R) levels. A cerebrospinal fluid (CSF) examination showed gradual increases in the patient's cell counts and protein, beta2-microglobulin, and sIL2R levels, but no malignant cells were detected. A thorough investigation involving repeated CSF examinations, whole-body computed tomography, bone marrow aspiration, random skin biopsies, and cervical lymph node aspiration biopsy examinations did not result in any definitive conclusions. Steroid therapy was ineffective, and the patient developed deafness in her left ear. Therefore, we performed a biopsy examination of the left acoustic nerve, which resulted in the patient being diagnosed with diffuse large B-cell lymphoma. High-dose MTX following the intrathecal administration of MTX, cytarabine, and prednisolone partially improved her symptoms, but she died after several episodes of clinical recurrence. Acoustic nerve biopsy may help diagnose neurolymphomatosis in carefully selected cases. PMID- 29386493 TI - [A case of Wernicke encephalopathy with hypoacusia and MR high intensity of the inferior colliculi that normalized after thiamine administration]. AB - A 61-year-old man was admitted to our institution with progressive hypoacusia, double vision, and lightheadedness. Neurological examination on day 6 of his illness showed severe hypoacusia, mild confusion, ocular motility disorder, truncal ataxia and absence of a deep tendon reflex. MRI fluid-attenuated inversion recovery imaging revealed symmetrical high intensities in the tectum of the midbrain, involving the bilateral inferior colliculi and the bilateral medial thalami, which suggested Wernicke encephalopathy (WE). Thiamine was administered immediately after completion of the MRI, and the patients' hearing and other abnormal neurologic signs improved rapidly within a few days, except for the absence of the deep tendon reflex. Whole blood examination at admission revealed very low levels of vitamin B1. The patient was discharged on day 19, and MRI on day 39 showed the disappearance of the abnormal high intensities involving the bilateral inferior colliculi. The present case indicates that hypoacusia and abnormal MRI signal due to WE might be normalized by administration of thiamine a few days after the onset of symptoms. PMID- 29386494 TI - [A case of chronic progressive neuro-Behcet's disease with cerebellar ataxia and bulbar palsy preceding mucocutaneo-ocular symptoms]. AB - A 77-year-old man with a history of cigarette smoking had suffered from vertigo and depression repeatedly for twelve years. He gradually developed bradykinesia in the past half decade and fell down 3 times in the last half year. On admission, he presented with cerebellar ataxia and bulbar symptoms. Brain MRI showed atrophy in the cerebellum and brainstem. 123I-IMP SPECT showed hypoperfusion bilaterally in the cerebellum. Blood examinations showed various elevated inflammatory values and positive for HLA-B51. Cerebrospinal fluid (CSF) revealed aseptic meningitis and increased IL-6 levels. Therefore, we strongly suspected that he had chronic progressive neuro-Behcet's disease (CPNBD), clinically. Systemic mucocutaneous symptoms appeared 1 month after starting treatments. Pathological findings of his skin biopsy were consistent with Behcet's disease. It should be kept in mind that both positive HLA-B51 and increased CSF IL-6 levels have the possibility of containing important clues in the diagnosis of CPNBD. PMID- 29386495 TI - [Retinal vasculopathy with cerebral leukoencephalopathy carrying TREX1 mutation diagnosed by the intracranial calcification: a case report]. AB - A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c.703_704insG (p.Val235GlyfsX6), thereby we diagnosed her as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RVCL is an autosomal dominant condition caused by C-terminal frame-shift mutation in TREX1. TREX1 protein is a major 3' to 5' DNA exonuclease, which are important in DNA repair. While TREX1 mutations identified in Aicardi-Goutieres syndrome patients lead to a reduction of enzyme activity, it is suggested that mutations in RVCL alter an intracellular location of TREX1 protein. There are no treatments based evidences in RVCL. We administered cilostazol to protect endothelial function, and her brain lesions and renal function have not become worse for 10 months after. It is necessary to consider RVCL associated with TREX1 mutation if a patient has retinal lesions, white matter lesions accompanied with calcifications, and multiple organ dysfunction. PMID- 29386496 TI - [A case of chronic inflammatory demyelinating polyradiculoneuropathy presenting recurrent attacks associated with pregnancies]. AB - At 37 years of age, the patient initially presented with symptoms of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) during her 1st pregnancy. She was treated with intravenous immunoglobulin (IVIg), and showed favorable recovery, becoming almost asymptomatic by the age of 38. At 39 years of age, during her puerperal period of her second pregnancy, she developed symmetrical muscle weakness and sensory disturbance of the upper and lower limbs. Nerve conduction studies revealed diffuse demyelination of peripheral nerves, and she was diagnosed with recurrence of CIDP. Once again, she showed remarkable improvement after IVIg therapy, and she has remained asymptomatic without the induction of preventative therapies. Recurrence of CIDP triggered in accordance with multiple pregnancies is extremely rare, and its clinical and electrophysiological features are presented in this report. PMID- 29386497 TI - [A case of acute leukoencephalopathy induced by a combination of 5-fluorouracil and metronidazole]. AB - We describe a 66-year-old woman who received folinic acid, leucovorin, fluorouracil and oxaliplatin for advanced rectal carcinoma. These drugs were initiated on day 1, and a pelvic abscess was identified on day 7. Piperacillin tazobactam was initially administered, but was changed to ceftriaxone and metronidazole on day 14 on the basis of antimicrobial susceptibility testing. On the following day, the patient reported blindness, and MRI of the brain showed signal abnormalities in the splenium of the corpus callosum on DWI, suggestive of metronidazole encephalopathy. Although the total body exposure was 2 g, metronidazole was discontinued. The patient developed coma a few days later, and MRI of the brain on day 26 showed high signal intensity extensively involving the white matter in the cerebrum as well as the brainstem and cerebellum. She died 37 days after the initial administration of the chemotherapy. Pathological studies demonstrated decreased staining intensity in the myelin sheath and multiple vacuolar alterations, consistent with toxicity induced by metronidazole and fluorouracil. Care should be taken when administering a combination of these drugs, even if the total body exposure to each drug is limited. PMID- 29386498 TI - [A retrospective study of the effects of 3,4-diaminopyridine treatment in Lambert Eaton myasthenic syndrome]. AB - In this independent clinical study, we analyzed retrospectively the clinical features of 9 cases (6 male and 3 female) of Lambert-Eaton myasthenic syndrome that were administered 3,4-diaminopyridine (3,4-DAP). Four cases showed no cancer and 5 cases had small cell lung carcinoma. Seven cases were positive for anti voltage-gated calcium channel antibodies. Activities of daily living (ADL) were improved by 3,4-DAP in 8 cases that showed mainly weakness of the extremities, but did not improve ADL in 1 case with cerebellar ataxia of paraneoplastic cerebellar degeneration (PCD). Seven cases showed autonomic symptoms, and 6 cases were improved with 3,4-DAP. The maintenance dose varied widely among individuals, with a single dose ranging from 10 to 40 mg. Each patient was prescribed a maintenance dose 3 to 7 times a day. The daily dosage ranged from 36 to 100 mg. Two cases showed adverse effects to the treatment. Of those 2 cases, 1 case treated at 45 mg/day discontinued treatment, but another case treated at 100 mg/day reduced the dosage and continued treatment. The administration period was 1 to 149 months. Three cases have continued 3,4-DAP for more than 10 years. Four cases have discontinued 3,4-DAP, with 2 cases discontinuing due to death, 1 case discontinuing due to progression of cancer, and 1 case discontinuing due to an adverse reaction. Our results suggest that 3,4-DAP treatment is effective for weakness and autonomic symptoms, but may be ineffective for ataxia of PCD. Treatment with 3,4-DAP can be tolerated for a long period, but the optimal dosage varies widely among individuals. PMID- 29386499 TI - [A case of Lyme neuroborreliosis without erythema migrans]. AB - A 56-year-old man was sustained ticks at the left axilla and flank. He did not have a rash. About 3 months after the tick bites, he developed back pain, right leg weakness, right abducens nerve palsy, and left facial palsy. Western blot analysis for serum IgM and IgG antibodies against Borrelia were positive. We diagnosed Lyme borreliosis. The patient was treated with antibiotics and steroids, and the symptoms improved. Our findings demonstrate that, even if erythema migrans is not obvious, neuroborreliosis should be considered when neurological signs, such as multiple cranial nerve palsies, are present. PMID- 29386500 TI - Non Uremic Calciphylaxis Post Liver Transplantation: A Case Report and Literature Review of an Unusual Presentation of a Rare Disease. AB - BACKGROUND Calciphylaxis results from abnormal calcification of small to medium sized vessels, resulting in painful ischemic necrosis of the surrounding tissues. It is most commonly seen in patients with end stage renal disease on dialysis, but has also been reported in patients with preserved renal function. CASE REPORT We report a case of non uremic calciphylaxis in a 65-year-old female who presented with painful skin lesions and ulcerations involving both thighs one month after receiving a liver transplantation. She was treated with sodium thiosulfate along with wound care and hyperbaric oxygen with complete resolution of the lesions, but with residual scarring. CONCLUSIONS Non uremic calciphylaxis is a rare phenomenon that is poorly understood. It should be in the differential of unexplained skin lesions even in the absence of renal insufficiency. Sodium thiosulfate plays a role in treatment, but wound care remains the main focus of treatment. PMID- 29386501 TI - Emodin, A Chinese Herbal Medicine, Inhibits Reoxygenation-Induced Injury in Cultured Human Aortic Endothelial Cells by Regulating the Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) and Endothelial Nitric Oxide Synthase (eNOS) Signaling Pathway. AB - BACKGROUND Ischemia-reperfusion injury is associated with vascular dysfunction. The aim of this study was to investigate the role of emodin, a Chinese herbal medicine, in hypoxia-reoxygenation injury in cultured human aortic endothelial cells (HAECs) and its effects on the expression of the peroxisome proliferator activated receptor-gamma (PPAR-gamma) and endothelial nitric oxide synthase (eNOS) signaling pathway. MATERIAL AND METHODS An in vitro hypoxia-reoxygenation model used cultured human aortic endothelial cells (HAECs). A colorimetric method evaluated the activity of peroxisome proliferator-activated receptor-gamma (PPAR gamma). Phosphorylation of PPAR-gamma and endothelial nitric oxide synthase (eNOS) were measured by Western blotting. Expression of inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 were evaluated by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Nitric oxide (NO) production was detected by diaminofluorescein-FM diacetate (DAF-FM DA) fluorescence. Immunoprecipitation was used to evaluate the molecular coupling of heat shock protein (HSP)90 and eNOS. RESULTS Hypoxia-reoxygenation injury of HAECs reduced the activity and phosphorylation of PPAR-gamma, and eNOS, NO production, and HSP90/eNOS molecular coupling in a time-dependent manner. Hypoxia reoxygenation increased the levels of inflammatory cytokines TNF-alpha, IL-6, and IL-8 in a time-dependent manner. Emodin treatment recovered PPAR-gamma activity and phosphorylation, eNOS phosphorylation, and HSP90/eNOS coupling in HAECS in a concentration-dependent manner, which was reversed by the PPAR-gamma inhibitor GW9662, and the eNOS inhibitor, L-NAME. The recovery of HSP90/eNOS coupling by emodin was impaired by GW9662 treatment. CONCLUSIONS An in vitro hypoxia reoxygenation (ischemia-reperfusion injury) model of induction of endothelial cell inflammatory mediators showed that emodin recovered the PPAR-gamma and eNOS pathway activity. PMID- 29386502 TI - Integrated circuits based on conjugated polymer monolayer. AB - It is still a great challenge to fabricate conjugated polymer monolayer field effect transistors (PoM-FETs) due to intricate crystallization and film formation of conjugated polymers. Here we demonstrate PoM-FETs based on a single monolayer of a conjugated polymer. The resulting PoM-FETs are highly reproducible and exhibit charge carrier mobilities reaching 3 cm2 V-1 s-1. The high performance is attributed to the strong interactions of the polymer chains present already in solution leading to pronounced edge-on packing and well-defined microstructure in the monolayer. The high reproducibility enables the integration of discrete unipolar PoM-FETs into inverters and ring oscillators. Real logic functionality has been demonstrated by constructing a 15-bit code generator in which hundreds of self-assembled PoM-FETs are addressed simultaneously. Our results provide the state-of-the-art example of integrated circuits based on a conjugated polymer monolayer, opening prospective pathways for bottom-up organic electronics. PMID- 29386503 TI - Publisher Correction: Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA). AB - The originally published version of this Article contained an error in Equation 30, which was inadvertently introduced during the production process. This has now been corrected in the PDF and HTML versions of the Article. PMID- 29386505 TI - Improved security bound for the round-robin-differential-phase-shift quantum key distribution. AB - The round-robin-differential-phase-shift (RRDPS) quantum key distribution (QKD) protocol has attracted intensive study due to its distinct security characteristics; e.g., information leakage is bounded without learning the error rate of key bits. Nevertheless, its practicality and performance are still not satisfactory. Here, by observing the phase randomization of the encoding states and its connection with eavesdropper's attack, we develop an improved bound on information leakage. Interestingly, our theory is especially useful for implementations with short trains of pulses, and running without monitoring signal disturbance is still available. As a result, the practicality and performance of RRDPS are improved. Furthermore, we realize a proof-of-principle experiment with up to 140 km of fiber, which has been the longest achievable distance of RRDPS until now, whereas the original theory predicted that no secret key could be generated in our experiment. Our results will help in bringing practical RRDPS closer to practical implementations. PMID- 29386504 TI - Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. AB - Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hexon symmetry and gain avidity. The shield reduces virion clearance in the liver. When the shielded particles are equipped with adaptor proteins, the virions deliver their payload genes into human cancer cells expressing HER2 or EGFR. The combination of shield and adapter also increases viral gene delivery to xenografted tumors in vivo, reduces liver off-targeting and immune neutralization. Our study highlights the power of protein engineering for viral vectors overcoming the challenges of local and systemic viral gene therapies. PMID- 29386506 TI - Author Correction: Conventional CD4+ T cells present bacterial antigens to induce cytotoxic and memory CD8+ T cell responses. AB - The original version of this Article contained an error in the spelling of the author Jose Maria Gonzalez-Granado, which was incorrectly given as Jose Maria Gozalez-Granado. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29386507 TI - Practical device-independent quantum cryptography via entropy accumulation. AB - Device-independent cryptography goes beyond conventional quantum cryptography by providing security that holds independently of the quality of the underlying physical devices. Device-independent protocols are based on the quantum phenomena of non-locality and the violation of Bell inequalities. This high level of security could so far only be established under conditions which are not achievable experimentally. Here we present a property of entropy, termed "entropy accumulation", which asserts that the total amount of entropy of a large system is the sum of its parts. We use this property to prove the security of cryptographic protocols, including device-independent quantum key distribution, while achieving essentially optimal parameters. Recent experimental progress, which enabled loophole-free Bell tests, suggests that the achieved parameters are technologically accessible. Our work hence provides the theoretical groundwork for experimental demonstrations of device-independent cryptography. PMID- 29386509 TI - Platinum-bearing chromite layers are caused by pressure reduction during magma ascent. AB - Platinum-bearing chromitites in mafic-ultramafic intrusions such as the Bushveld Complex are key repositories of strategically important metals for human society. Basaltic melts saturated in chromite alone are crucial to their generation, but the origin of such melts is controversial. One concept holds that they are produced by processes operating within the magma chamber, whereas another argues that melts entering the chamber were already saturated in chromite. Here we address the problem by examining the pressure-related changes in the topology of a Mg2SiO4-CaAl2Si2O8-SiO2-MgCr2O4 quaternary system and by thermodynamic modelling of crystallisation sequences of basaltic melts at 1-10 kbar pressures. We show that basaltic melts located adjacent to a so-called chromite topological trough in deep-seated reservoirs become saturated in chromite alone upon their ascent towards the Earth's surface and subsequent cooling in shallow-level chambers. Large volumes of these chromite-only-saturated melts replenishing these chambers are responsible for monomineralic layers of massive chromitites with associated platinum-group elements. PMID- 29386508 TI - Anderson light localization in biological nanostructures of native silk. AB - Light in biological media is known as freely diffusing because interference is negligible. Here, we show Anderson light localization in quasi-two-dimensional protein nanostructures produced by silkworms (Bombyx mori). For transmission channels in native silk, the light flux is governed by a few localized modes. Relative spatial fluctuations in transmission quantities are proximal to the Anderson regime. The sizes of passive cavities (smaller than a single fibre) and the statistics of modes (decomposed from excitation at the gain-loss equilibrium) differentiate silk from other diffusive structures sharing microscopic morphological similarity. Because the strong reflectivity from Anderson localization is combined with the high emissivity of the biomolecules in infra red radiation, silk radiates heat more than it absorbs for passive cooling. This collective evidence explains how a silkworm designs a nanoarchitectured optical window of resonant tunnelling in the physically closed structures, while suppressing most of transmission in the visible spectrum and emitting thermal radiation. PMID- 29386510 TI - Continental shelves as a variable but increasing global sink for atmospheric carbon dioxide. AB - It has been speculated that the partial pressure of carbon dioxide (pCO2) in shelf waters may lag the rise in atmospheric CO2. Here, we show that this is the case across many shelf regions, implying a tendency for enhanced shelf uptake of atmospheric CO2. This result is based on analysis of long-term trends in the air sea pCO2 gradient (DeltapCO2) using a global surface ocean pCO2 database spanning a period of up to 35 years. Using wintertime data only, we find that DeltapCO2 increased in 653 of the 825 0.5 degrees cells for which a trend could be calculated, with 325 of these cells showing a significant increase in excess of +0.5 MUatm yr-1 (p < 0.05). Although noisier, the deseasonalized annual data suggest similar results. If this were a global trend, it would support the idea that shelves might have switched from a source to a sink of CO2 during the last century. PMID- 29386511 TI - Joint coding of shape and blur in area V4. AB - Edge blur, a prevalent feature of natural images, is believed to facilitate multiple visual processes including segmentation and depth perception. Furthermore, image descriptions that explicitly combine blur and shape information provide complete representations of naturalistic scenes. Here we report the first demonstration of blur encoding in primate visual cortex: neurons in macaque V4 exhibit tuning for both object shape and boundary blur, with observed blur tuning not explained by potential confounds including stimulus size, intensity, or curvature. A descriptive model wherein blur selectivity is cast as a distinct neural process that modulates the gain of shape-selective V4 neurons explains observed data, supporting the hypothesis that shape and blur are fundamental features of a sufficient neural code for natural image representation in V4. PMID- 29386512 TI - Liquid crystal elastomer coatings with programmed response of surface profile. AB - Stimuli-responsive liquid crystal elastomers with molecular orientation coupled to rubber-like elasticity show a great potential as elements in soft robotics, sensing, and transport systems. The orientational order defines their mechanical response to external stimuli, such as thermally activated muscle-like contraction. Here we demonstrate a dynamic thermal control of the surface topography of an elastomer prepared as a coating with a pattern of in-plane molecular orientation. The inscribed pattern determines whether the coating develops elevations, depressions, or in-plane deformations when the temperature changes. The deterministic dependence of the out-of-plane dynamic profile on the in-plane orientation is explained by activation forces. These forces are caused by stretching-contraction of the polymer networks and by spatially varying molecular orientation. The activation force concept brings the responsive liquid crystal elastomers into the domain of active matter. The demonstrated relationship can be used to design coatings with functionalities that mimic biological tissues such as skin. PMID- 29386513 TI - Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. AB - Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1 dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth. PMID- 29386515 TI - Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial. AB - We compared the efficacy and safety of infliximab with intravenous immunoglobulin (IVIG), a standard therapy, in a phase 3 trial (NCT01596335) for Japanese patients with Kawasaki disease (KD) showing persistent fever after initial IVIG. Patients with initial IVIG-refractory KD, aged 1-10 years, received a single dose of IV infliximab 5 mg/kg or IV polyethylene glycol-treated human immunoglobulin (VGIH) 2 g/kg on day 0. Primary outcome was defervescence rate within 48 h after the start of treatment. Safety was evaluated through day 56. Overall, 31 patients were randomized (infliximab, n = 16; VGIH, n = 15); 31.3% and 60.0% patients discontinued due to worsening KD. Defervescence rate within 48 h was greater with infliximab (76.7%) than VGIH (37.0%) (p = 0.023), and defervescence was achieved earlier with infliximab (p = 0.0072). Coronary artery lesions occurred in 1 (6.3%) and 3 (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No serious adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48 h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD. PMID- 29386514 TI - Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation. AB - The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype. PMID- 29386516 TI - The effect of PU.1 knockdown on gene expression and function of mast cells. AB - PU.1 is a hematopoietic cell-specific transcription factor. In the current study, we investigated the role of PU.1 in the gene expression and the function of mouse mast cells (MCs) in vitro and in vivo. When PU.1 siRNA was introduced into bone marrow-derived MCs (BMMCs), IgE-mediated activation was reduced, and the Syk and FcepsilonRIbeta mRNA levels were significantly decreased. As the regulatory mechanism of the Syk gene is largely unknown, we performed promoter analysis and found that PU.1 transactivated the Syk promoter through direct binding to a cis element in the 5'-untranslated region. The involvement of PU.1 in the Syk promoter was also observed in mouse dendritic cells and human MCs, suggesting that the relationship between PU.1 and Syk is common in mammals and in hematopoietic lineages. When antigen was administrated intravenously after the transfusion of siRNA-transfected BMMCs in the mouse footpad, the footpad thickening was significantly suppressed by PU.1 knockdown. Finally, administration of the immunomodulator pomalidomide suppressed passive systemic anaphylaxis of mice. Taken together, these results indicate that PU.1 knockdown might be an efficacious strategy for the prevention of MC-mediated allergic diseases. PMID- 29386517 TI - Differences in the mechanical unfolding pathways of apo- and copper-bound azurins. AB - Metalloproteins carry out diverse biological functions including metal transport, electron transfer, and catalysis. At present, the influence of metal cofactors on metalloprotein stability is not well understood. Here, we report the mechanical stability and unfolding pathway of azurin, a cupredoxin family protein with beta barrel topology and type I copper-binding centre. Single-molecule force spectroscopy (SMFS) experiments reveal 2-state and 3-state unfolding pathways for apo-azurin. The intermediate in the 3-state pathway occurs at an unfolding contour length of 7.5 nm from the native state. Steered molecular dynamics (SMD) simulations show that apo-azurin unfolds via a first transition state (TS) where beta2Beta-beta8 and beta7-beta8 strand pairs rupture to form the intermediate, which subsequently unfolds by the collective rupture of remaining strands. SMFS experiments on holo-azurin exhibit an additional 4-state pathway besides the 2 state and 3-state pathways. The unfolding contour length leading to the first intermediate is 6.7 nm suggesting a sequestration of ~1 nm polypeptide chain length by the copper. SMD simulations reveal atomistic details of the copper sequestration and predict a combined beta4-beta7 pair and copper coordination sphere rupture to create the third TS in the 4-state pathway. Our systematic studies provide detailed mechanistic insights on modulation of protein mechanical properties by metal-cofactors. PMID- 29386518 TI - In vivo photoacoustic monitoring using 700-nm region Raman source for targeting Prussian blue nanoparticles in mouse tumor model. AB - Photoacoustic imaging (PAI) is a noninvasive imaging tool to visualize optical absorbing contrast agents. Due to high ultrasonic resolution and superior optical sensitivity, PAI can be used to monitor nanoparticle-mediated cancer therapy. The current study synthesized Food and Drug Administration-approved Prussian blue (PB) in the form of nanoparticles (NPs) with the peak absorption at 712 nm for photoacoustically imaging tumor-bearing mouse models. To monitor PB NPs from the background tissue in vivo, we also developed a new 700-nm-region stimulated Raman scattering (SRS) source (pulse energy up to 200 nJ and repetition rate up to 50 kHz) and implemented optical-resolution photoacoustic microscopy (OR-PAM). The SRS-assisted OR-PAM system was able to monitor PB NPs in the tumor model with micrometer resolution. Due to strong light absorption at 712 nm, the developed SRS light yielded a two-fold higher contrast from PB NPs, in comparison with a 532-nm pumping source. The proposed laser source involved cost-effective and simple system implementation along with high compatibility with the fiber-based OR-PAM system. The study highlights the OR-PAM system in conjunction with the tunable-color SRS light source as a feasible tool to assist NP-mediated cancer therapy. PMID- 29386519 TI - A diverse mammal-dominated, footprint assemblage from wetland deposits in the Lower Cretaceous of Maryland. AB - A newly discovered assemblage of predominantly small tracks from the Cretaceous Patuxent Formation at NASA's Goddard Space Flight Center, Maryland, reveals one of the highest track densities and diversities ever reported (~70 tracks, representing at least eight morphotypes from an area of only ~2 m2). The assemblage is dominated by small mammal tracks including the new ichnotxon Sederipes goddardensis, indicating sitting postures. Small crow-sized theropod trackways, the first from this unit, indicate social trackmakers and suggest slow paced foraging behavior. Tracks of pterosaurs, and other small vertebrates suggest activity on an organic-rich substrate. Large well-preserved sauropod and nodosaurs tracks indicate the presence of large dinosaurs. The Patuxent Formation together with the recently reported Angolan assemblage comprise the world's two largest Mesozoic mammal footprint assemblages. The high density of footprint registration at the NASA site indicates special preservational and taphonomic conditions. These include early, penecontemporaneous deposition of siderite in organic rich, reducing wetland settings where even the flesh of body fossils can be mummified. Thus, the track-rich ironstone substrates of the Patuxent Formation, appear to preserve a unique vertebrate ichnofacies, with associated, exceptionally-preserved body fossil remains for which there are currently no other similar examples preserved in the fossil record. PMID- 29386520 TI - Angiogenesis and evading immune destruction are the main related transcriptomic characteristics to the invasive process of oral tongue cancer. AB - Metastasis of head and neck tumors is responsible for a high mortality rate. Understanding its biochemistry may allow insights into tumorigenesis. To that end we carried out RNA-Seq analyses of 5 SCC9 derived oral cancer cell lines displaying increased invasive potential. Differentially expressed genes (DEGs) were annotated based on p-values and false discovery rate (q-values). All 292 KEGG pathways related to the human genome were compared in order to pinpoint the absolute and relative contributions to the invasive process considering the 8 hallmarks of cancer plus 2 new defined categories, as well as we made with our transcriptomic data. In terms of absolute contribution, the highest correlations were associated to the categories of evading immune destruction and energy metabolism and for relative contributions, angiogenesis and evading immune destruction. DEGs were distributed into each one of all possible modes of regulation, regarding up, down and continuum expression, along the 3 stages of metastatic progression. For p-values twenty-six genes were consistently present along the tumoral progression and 4 for q-values. Among the DEGs, we found 2 novel potentially informative metastatic markers: PIGG and SLC8B1. Furthermore, interactome analysis showed that MYH14, ANGPTL4, PPARD and ENPP1 are amenable to pharmacological interventions. PMID- 29386521 TI - Human migration and the spread of malaria parasites to the New World. AB - We examined the mitogenomes of a large global collection of human malaria parasites to explore how and when Plasmodium falciparum and P. vivax entered the Americas. We found evidence of a significant contribution of African and South Asian lineages to present-day New World malaria parasites with additional P. vivax lineages appearing to originate from Melanesia that were putatively carried by the Australasian peoples who contributed genes to Native Americans. Importantly, mitochondrial lineages of the P. vivax-like species P. simium are shared by platyrrhine monkeys and humans in the Atlantic Forest ecosystem, but not across the Amazon, which most likely resulted from one or a few recent human to-monkey transfers. While enslaved Africans were likely the main carriers of P. falciparum mitochondrial lineages into the Americas after the conquest, additional parasites carried by Australasian peoples in pre-Columbian times may have contributed to the extensive diversity of extant local populations of P. vivax. PMID- 29386522 TI - DNA-assisted swarm control in a biomolecular motor system. AB - In nature, swarming behavior has evolved repeatedly among motile organisms because it confers a variety of beneficial emergent properties. These include improved information gathering, protection from predators, and resource utilization. Some organisms, e.g., locusts, switch between solitary and swarm behavior in response to external stimuli. Aspects of swarming behavior have been demonstrated for motile supramolecular systems composed of biomolecular motors and cytoskeletal filaments, where cross-linkers induce large scale organization. The capabilities of such supramolecular systems may be further extended if the swarming behavior can be programmed and controlled. Here, we demonstrate that the swarming of DNA-functionalized microtubules (MTs) propelled by surface-adhered kinesin motors can be programmed and reversibly regulated by DNA signals. Emergent swarm behavior, such as translational and circular motion, can be selected by tuning the MT stiffness. Photoresponsive DNA containing azobenzene groups enables switching between solitary and swarm behavior in response to stimulation with visible or ultraviolet light. PMID- 29386523 TI - TT(N)mGCCTC inhibits archaeal family B DNA polymerases. AB - The proofreading activity of the archaeal family B DNA polymerases enables PCR with high fidelity. However, thermostable proofreading DNA polymerases occasionally failed to amplify target fragment that could be amplified by Taq DNA polymerase. We have previously showed that G-rich sequences, which form G quadruplex, can bind to and inhibit proofreading DNA polymerases. Here we showed that single-stranded oligonucleotides containing sequences of TT(N)mGCCTC can bind and inhibit archaeal family B DNA polymerases but not Taq DNA polymerase. It is very likely that TT(N)mGCCTC inhibits thermostable DNA polymerases during PCR in a single-stranded form. To the best of our knowledge, this is the first example of DNA sequence that could inhibit DNA polymerase in its single-stranded form. PMID- 29386524 TI - Work Function Variations in Twisted Graphene Layers. AB - By combining optical imaging, Raman spectroscopy, kelvin probe force microscopy (KFPM), and photoemission electron microscopy (PEEM), we show that graphene's layer orientation, as well as layer thickness, measurably changes the surface potential (Phi). Detailed mapping of variable-thickness, rotationally-faulted graphene films allows us to correlate Phi with specific morphological features. Using KPFM and PEEM we measure DeltaPhi up to 39 mV for layers with different twist angles, while DeltaPhi ranges from 36-129 mV for different layer thicknesses. The surface potential between different twist angles or layer thicknesses is measured at the KPFM instrument resolution of <= 200 nm. The PEEM measured work function of 4.4 eV for graphene is consistent with doping levels on the order of 1012cm-2. We find that Phi scales linearly with Raman G-peak wavenumber shift (slope = 22.2 mV/cm-1) for all layers and twist angles, which is consistent with doping-dependent changes to graphene's Fermi energy in the 'high' doping limit. Our results here emphasize that layer orientation is equally important as layer thickness when designing multilayer two-dimensional systems where surface potential is considered. PMID- 29386525 TI - Nonlinear mixed-modelling discriminates the effect of chemicals and their mixtures on zebrafish behavior. AB - Zebrafish (Danio rerio) early-life stage behavior has the potential for high throughput screening of neurotoxic environmental contaminants. However, zebrafish embryo and larval behavioral assessments typically utilize linear analyses of mean activity that may not capture the complexity of the behavioral response. Here we tested the hypothesis that nonlinear mixed-modelling of zebrafish embryo and larval behavior provides a better assessment of the impact of chemicals and their mixtures. We demonstrate that zebrafish embryo photomotor responses (PMRs) and larval light/dark locomotor activities can be fit by asymmetric Lorentzian and Ricker-beta functions, respectively, which estimate the magnitude of activity (e.g., maximum and total activities) and temporal aspects (e.g., duration of the responses and its excitatory periods) characterizing early life-stage zebrafish behavior. We exposed zebrafish embryos and larvae to neuroactive chemicals, including isoproterenol, serotonin, and ethanol, as well as their mixtures, to assess the feasibility of using the nonlinear mixed-modelling to assess behavioral modulation. Exposure to chemicals led to distinct effects on specific behavioral characteristics, and interactive effects on temporal characteristics of the behavioral response that were overlooked by the linear analyses of mean activity. Overall, nonlinear mixed-modelling is a more comprehensive approach for screening the impact of chemicals and chemical mixtures on zebrafish behavior. PMID- 29386526 TI - Monitoring cotton root rot by synthetic Sentinel-2 NDVI time series using improved spatial and temporal data fusion. AB - To better understand the progression of cotton root rot within the season, time series monitoring is required. In this study, an improved spatial and temporal data fusion approach (ISTDFA) was employed to combine 250-m Moderate Resolution Imaging Spectroradiometer (MODIS) Normalized Different Vegetation Index (NDVI) and 10-m Sentinetl-2 NDVI data to generate a synthetic Sentinel-2 NDVI time series for monitoring this disease. Then, the phenology of healthy cotton and infected cotton was modeled using a logistic model. Finally, several phenology parameters, including the onset day of greenness minimum (OGM), growing season length (GLS), onset of greenness increase (OGI), max NDVI value, and integral area of the phenology curve, were calculated. The results showed that ISTDFA could be used to combine time series MODIS and Sentinel-2 NDVI data with a correlation coefficient of 0.893. The logistic model could describe the phenology curves with R-squared values from 0.791 to 0.969. Moreover, the phenology curve of infected cotton showed a significant difference from that of healthy cotton. The max NDVI value, OGM, GSL and the integral area of the phenology curve for infected cotton were reduced by 0.045, 30 days, 22 days, and 18.54%, respectively, compared with those for healthy cotton. PMID- 29386527 TI - Transcriptomic responses to biotic stresses in Malus x domestica: a meta-analysis study. AB - RNA-Seq analysis is a strong tool to gain insight into the molecular responses to biotic stresses in plants. The objective of this work is to identify specific and common molecular responses between different transcriptomic data related to fungi, virus and bacteria attacks in Malus x domestica. We analyzed seven transcriptomic datasets in Malus x domestica divided in responses to fungal pathogens, virus (Apple Stem Grooving Virus) and bacteria (Erwinia amylovora). Data were dissected using an integrated approach of pathway- and gene- set enrichment analysis, Mapman visualization tool, gene ontology analysis and inferred protein-protein interaction network. Our meta-analysis revealed that the bacterial infection enhanced specifically genes involved in sugar alcohol metabolism. Brassinosteroids were upregulated by fungal pathogens while ethylene was highly affected by Erwinia amylovora. Gibberellins and jasmonates were strongly repressed by fungal and viral infections. The protein-protein interaction network highlighted the role of WRKYs in responses to the studied pathogens. In summary, our meta-analysis provides a better understanding of the Malus X domestica transcriptome responses to different biotic stress conditions; we anticipate that these insights will assist in the development of genetic resistance and acute therapeutic strategies. This work would be an example for next meta-analysis works aiming at identifying specific common molecular features linked with biotic stress responses in other specialty crops. PMID- 29386528 TI - Construction of two whole genome radiation hybrid panels for dromedary (Camelus dromedarius): 5000RAD and 15000RAD. AB - The availability of genomic resources including linkage information for camelids has been very limited. Here, we describe the construction of a set of two radiation hybrid (RH) panels (5000RAD and 15000RAD) for the dromedary (Camelus dromedarius) as a permanent genetic resource for camel genome researchers worldwide. For the 5000RAD panel, a total of 245 female camel-hamster radiation hybrid clones were collected, of which 186 were screened with 44 custom designed marker loci distributed throughout camel genome. The overall mean retention frequency (RF) of the final set of 93 hybrids was 47.7%. For the 15000RAD panel, 238 male dromedary-hamster radiation hybrid clones were collected, of which 93 were tested using 44 PCR markers. The final set of 90 clones had a mean RF of 39.9%. This 15000RAD panel is an important high-resolution complement to the main 5000RAD panel and an indispensable tool for resolving complex genomic regions. This valuable genetic resource of dromedary RH panels is expected to be instrumental for constructing a high resolution camel genome map. Construction of the set of RH panels is essential step toward chromosome level reference quality genome assembly that is critical for advancing camelid genomics and the development of custom genomic tools. PMID- 29386529 TI - Serendipitous Discovery of a Guanine-rich DNA Molecule with a Highly Stable Structure in Urea. AB - We have made an accidental discovery of an unusual, single-stranded, guanine-rich DNA molecule that is capable of adopting a folded structure in 7 M urea (7MU) known to denature nucleic acid structures. The folding of this molecule requires Na+ and Mg2+ and the folded structure remains stable when subjected to denaturing (7MU) polyacrylamide gel electrophoresis. Results from sequence mutagenesis, DNA methylation, and circular dichroism spectroscopy studies suggest that this molecule adopts an intramolecular guanine-quadruplex structure with 5 layers of guanine tetrads. Our finding indicates that DNA has the ability to create extremely stable structural folds despite its limited chemical repertoire, making it possible to develop DNA-based systems for unconventional applications. PMID- 29386530 TI - Identification of valid reference genes for mRNA and microRNA normalisation in prostate cancer cell lines. AB - RT-qPCR offers high sensitivity, for accurate interpretations of qPCR results however, normalisation using suitable reference genes is fundamental. Androgens can regulate transcriptional expression including reference gene expression in prostate cancer. In this study, we evaluated ten mRNA and six non-protein coding RNA reference genes in five prostate cell lines under varied dihydrotestosterone (DHT) treatments. We validated the effects of DHT-treatments using media containing charcoal-stripped serum prior to DHT stimulation on the test samples by Western blot experiments. Reference gene expression stability was analysed using three programs (geNorm, NormFinder and BestKeeper), and the recommended comprehensive ranking is provided. Our results reveal that ACTB and GAPDH, and miR-16 and miR-1228-3p are the most suitable mRNA and miRNA reference genes across all cell lines, respectively. Considering prostate cancer cell types, ACTB/GAPDH and ACTB/HPRT1 are the most suitable reference gene combinations for mRNA analysis, and miR-16/miR-1228-3p and RNU6-2/RNU43 for miRNA analysis in AR+, and AR- and normal cell lines, respectively. Comparison of relative target gene (PCA3 and miR-141) expression reveals different patterns depending on reference genes used for normalisation. To our knowledge, this is the first report on validation of reference genes under different DHT treatments in prostate cancer cells. This study provides insights for discovery of reliable DHT-regulated genes in prostate cells. PMID- 29386531 TI - Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling. AB - Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants. PMID- 29386532 TI - CT pulmonary angiography in patients with acute or chronic renal insufficiency: Evaluation of a low dose contrast material protocol. AB - Adverse effects of intravenous contrast media (CM) in patients with renal risk factors and acute kidney injury are still controversially discussed. The aim of this study was to investigate whether dual-energy (DE) pulmonary CT angiography (CTPA) in combination with a noise optimized virtual monoenergetic imaging algorithm allows for a reduction of CM. This IRB-approved study comprised 150 patients with suspected pulmonary embolism (78 male; mean age 65 +/- 17years). 50 patients with acute/chronic renal failure were examined on a 3rd generation dual source CT with an optimized DE CTPA protocol and a low CM injection protocol (5.4 g iodine). 100 further patients were either examined with a standard CTPA protocol or a standard DE CTPA (32 g iodine). For the DE CTPA virtual monoenergetic spectral datasets (40-100 keV) were reconstructed. Main pulmonary arteries at 50 keV and peripheral pulmonary arteries at 40 keV datasets provided the highest contrast-to-noise-ratio (CNR) for both the standard DE CTPA and the optimized protocol, with significantly higher CNR values for the standard DE CTPA protocol (p < 0.05). No pulmonary embolism was missed on the optimized CM protocol. DE CTPA utilizing image reconstruction at 40/50 keV allowed for a reduction of 84% in iodine load while maintaining CNR, which is especially important in patients with acute/chronic renal failure. PMID- 29386533 TI - Lectin-mediated protocell crosslinking to mimic cell-cell junctions and adhesion. AB - Cell adhesion is a crucial feature of all multicellular organisms, as it allows cells to organise themselves into tissues to carry out specific functions. Here, we present a mimetic approach that uses multivalent lectins with opposing binding sites to crosslink glycan-functionalised giant unilamellar vesicles. The crosslinking process drives the progression from contact puncta into elongated protocellular junctions, which form the vesicles into polygonal clusters resembling tissues. Due to their carbohydrate specificity, different lectins can be engaged in parallel with both natural and synthetic glycoconjugates to generate complex interfaces with distinct lectin domains. In addition, the formation of protocellular junctions can be combined with adhesion to a functionalised support by other ligand-receptor interactions to render increased stability against fluid flow. Furthermore, we consider that adhesion is a complex process of attraction and repulsion by doping the vesicles with a PEG-modified lipid, and demonstrate a dose-dependent decrease of lectin binding and formation of protocellular junctions. We suggest that the engineering of prototissues through lectin-glycan interactions is an important step towards synthetic minimal tissues and in designing artificial systems to reconstruct the fundamental functions of biology. PMID- 29386534 TI - Electrostatic Variation of Haemagglutinin as a Hallmark of the Evolution of Avian Influenza Viruses. AB - Avian influenza virus is a zoonotic agent that significantly impacts public health and the poultry industry. Monitoring viral evolution and spread is crucial for surveillance and tracing programmes, which are currently based on serological or DNA sequencing-phylogenetics analysis. However, virus-host interactions, antigenic drift and spreading of viral clades strongly depend on variation in the surface features of capsid proteins. We report here that in silico comparative structural analysis of haemagglutinin can reveal relevant evolutionary fingerprints, particularly when integrated with sequence-based analyses. Phylogenetic analyses of H9 viral strains from wild birds and poultry, performed with different methods, reliably led to clustering of viruses into five main groups. Subsequent comparison of structural features showed congruence between such clustering and surface electrostatic fingerprints. These latter fingerprints relate group-specific variations in electrostatic charges and isocontours to well known haemagglutinin sites involved in the modulation of immune escape and host specificity. This work suggests that the integration of structural and sequence comparisons may enhance investigations of trends and relevant mechanisms in viral evolution. PMID- 29386535 TI - Comparative analyses of co-evolving host-parasite associations reveal unique gene expression patterns underlying slavemaker raiding and host defensive phenotypes. AB - The transition to parasitism is a drastic shift in lifestyle, involving rapid changes in gene structure, function, and expression. After the establishment of antagonistic relationships, parasites and hosts co-evolve through reciprocal adaptations, often resulting in evolutionary arms-races. Repeated evolution of social parasitism and slavery among Temnothorax ants allows us to examine those gene expression patterns that characterize slavemaker raiding and reciprocal host defensive phenotypes. Previous behavioural studies have established that raiding strategies between Temnothorax slavemakers diverge, while host defense portfolios shift similarly under parasite pressure. We are the first to confirm this at the molecular level, revealing that slavemaking species exhibit a wider variety of genes with species-specific patterns of expression within their raiding phenotypes, whereas expression similarity is commonly found during the non raiding phenotype. Host species response to slavemaker aggression, however, is indicated by strong changes in the expression of a relatively few number genes. Additionally, the expression of individual genes such as Acyl-CoA-Delta(11) desaturase and Trypsin-7 is strongly associated with the raiding phenotype of all three slavemaking species. Here, we provide novel insight into the gene expression patterns associated with raiding and nest defense behavior in Temnothorax ants, suggesting lineage-specific evolutionary patterns among both slavemakers and hosts. PMID- 29386536 TI - Additive manufacturing of magnetic shielding and ultra-high vacuum flange for cold atom sensors. AB - Recent advances in the understanding and control of quantum technologies, such as those based on cold atoms, have resulted in devices with extraordinary metrological performance. To realise this potential outside of a lab environment the size, weight and power consumption need to be reduced. Here we demonstrate the use of laser powder bed fusion, an additive manufacturing technique, as a production technique relevant to the manufacture of quantum sensors. As a demonstration we have constructed two key components using additive manufacturing, namely magnetic shielding and vacuum chambers. The initial prototypes for magnetic shields show shielding factors within a factor of 3 of conventional approaches. The vacuum demonstrator device shows that 3D-printed titanium structures are suitable for use as vacuum chambers, with the test system reaching base pressures of 5 +/- 0.5 * 10-10 mbar. These demonstrations show considerable promise for the use of additive manufacturing for cold atom based quantum technologies, in future enabling improved integrated structures, allowing for the reduction in size, weight and assembly complexity. PMID- 29386537 TI - Metallic phase in stoichiometric CeOBiS2 revealed by space-resolved ARPES. AB - Recently CeOBiS2 system without any fluorine doping is found to show superconductivity posing question on its origin. Using space resolved ARPES we have found a metallic phase embedded in the morphological defects and at the sample edges of stoichiometric CeOBiS2. While bulk of the sample is semiconducting, the embedded metallic phase is characterized by the usual electron pocket at X point, similar to the Fermi surface of doped BiS2-based superconductors. Typical size of the observed metallic domain is larger than the superconducting correlation length of the system suggesting that the observed superconductivity in undoped CeOBiS2 might be due to this embedded metallic phase at the defects. The results also suggest a possible way to develop new systems by manipulation of the defects in these chalcogenides with structural instability. PMID- 29386538 TI - A comparative Study of Aptasensor Vs Immunosensor for Label-Free PSA Cancer Detection on GQDs-AuNRs Modified Screen-Printed Electrodes. AB - Label-free and sensitive detection of PSA (Prostate Specific Antigen) is still a big challenge in the arena of prostate cancer diagnosis in males. We present a comparative study for label-free PSA aptasensor and PSA immunosensor for the PSA specific monoclonal antibody, based on graphene quantum dots-gold nanorods (GQDs AuNRs) modified screen-printed electrodes. GQDs-AuNRs composite has been synthesized and used as an electro-active material, which shows fast electron transfer and catalytic property. Aptamer or anti-PSA has immobilized onto the surface of modified screen printed electrodes. Three techniques are used simultaneously, viz. cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedence spectroscopy (EIS) to investigate the analytical performance of both PSA aptasensor and PSA immunosensor with its corresponding PSA antigen. Under optimum conditions, both sensors show comparable results with an almost same limit of detection (LOD) of 0.14 ng mL-1. The results developed with aptasensor and anti-PSA is also checked through the detection of PSA in real samples with acceptable results. Our study suggests some advantages of aptasensor in terms of better stability, simplicity and cost effectiveness. Further our present work shows enormous potential of our developed sensors for real application using voltammetric and EIS techniques simultaneous to get reliable detection of the disease. PMID- 29386539 TI - MET or NRAS amplification is an acquired resistance mechanism to the third generation EGFR inhibitor naquotinib. AB - As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib resistant cells, two of which were derived from EGFR-TKI-naive cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors. PMID- 29386540 TI - Proposed mechanism of HCP -> FCC phase transition in titianium through first principles calculation and experiments. AB - By means of first principles calculation and experiments, a detailed mechanism is proposed to include the stages of slip, adjustment, and expansion for the HCP -> FCC phase transformation with the prismatic relation of [Formula: see text] and [Formula: see text] in titanium. It is revealed that the formation of four FCC layers is preferable after the slip of Shockley partial dislocations of 1/6 [Formula: see text] on [Formula: see text] planes, and that the adjustment of interplanar spacing and the volume expansion are energetically favorable and could happen spontaneously without any energy barrier. It is also found that the transformed FCC lattice first follows the c/a ratio (1.583) of HCP and then becomes an ideal FCC structure (c/a = ?2). The proposed mechanism could not only provide a deep understanding to the process of HCP -> FCC prismatic transformation in titanium, but also clarify the controversy regarding volume expansion of HCP-FCC phase transition of titanium in the literature. PMID- 29386541 TI - Genome-wide associations identify novel candidate loci associated with genetic susceptibility to tuberculosis in wild boar. AB - Tuberculosis (TB) affects a wide range of host species worldwide. Understanding host-pathogen co-evolution remains a global challenge owing to complex interactions among host genetic factors, pathogen traits and environmental conditions. We used an endemic wild boar population that had undergone a huge increase in Mycobacterium bovis infection prevalence, from 45% in 2002/06 to 83% in 2009/12, to understand the effects of host genetics on host TB outcomes and disease dynamics. Host genomic variation was characterized using a high-density single nucleotide polymorphism (SNP) array, while host TB phenotype was assessed using both gross pathology and mycobacterial culture. Two complementary genome wide association (GWAS) analyses were conducted: (i) infected-uninfected; and (ii) 2002/06-2009/12. The SNPs with the highest allelic frequency differences between time-periods and TB outcomes were identified and validated in a large dataset. In addition, we quantified the expression levels of some of their closest genes. These analyses highlighted various SNPs (i.e. rs81465339, rs81394585, rs81423166) and some of the closest genes (i.e. LOC102164072, BDNF/NT 3, NTRK2, CDH8, IGSF21) as candidates for host genetic susceptibility. In addition to TB-driven selection, our findings outline the putative role of demographic events in shaping genomic variation in natural populations and how population crashes and drift may impact host genetic susceptibility to TB over time. PMID- 29386543 TI - A comparative study of low energy radiation response of AlAs, GaAs and GaAs/AlAs superlattice and the damage effects on their electronic structures. AB - In this study, the low energy radiation responses of AlAs, GaAs and GaAs/AlAs superlattice are simulated and the radiation damage effects on their electronic structures are investigated. It is found that the threshold displacement energies for AlAs are generally larger than those for GaAs, i.e., the atoms in AlAs are more difficult to be displaced than those in GaAs under radiation environment. As for GaAs/AlAs superlattice, the Ga and Al atoms are more susceptible to the radiation than those in the bulk AlAs and GaAs, whereas the As atoms need comparable or much larger energies to be displaced than those in the bulk states. The created defects are generally Frenkel pairs, and a few antisite defects are also created in the superlattice structure. The created defects are found to have profound effects on the electronic properties of GaAs/AlAs superlattice, in which charge transfer, redistribution and even accumulation take place, and band gap narrowing and even metallicity are induced in some cases. This study shows that it is necessary to enhance the radiation tolerance of GaAs/AlAs superlattice to improve their performance under irradiation. PMID- 29386542 TI - Development and validation of risk prediction models for cardiovascular mortality in Chinese people initialising peritoneal dialysis: a cohort study. AB - Cardiovascular disease is the leading cause of death among patients receiving peritoneal dialysis. We aimed to develop and validate a risk prediction model for cardiovascular death within 2 years after the initiation of peritoneal dialysis (PD). A cohort including all patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2014. Multivariate logistic regression analysis was used to develop the risk prediction model. The HPDR data was randomly divided into two cohorts with 60% (1,835 patients) for model derivation, and 40% (1,219 patients) for model validation. The absolute rate of cardiovascular mortality was 14.2% and 14.4 in the derivation and validation cohort, respectively. Age, body mass index, blood pressure, serum lipids, fasting glucose, sodium, albumin, total protein, and phosphorus were the strongest predictors of cardiovascular mortality in the final model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with good calibration of observed and predicted risks. The new prediction model that has been developed and validated with clinical measurements that are available at the point of initiation of PD and could serve as a tool to screen for patients at high risk of cardiovascular death and tailor more intensive cardio-protective care. PMID- 29386544 TI - Identification of molecular pathways and candidate genes associated with cocks' comb size trait by genome-wide transcriptome analysis. AB - The comb of the male is an important secondary sexual characteristic. Although quantitative trait loci (QTLs) related to comb size have been identified, molecular mechanisms underlying this trait remain mostly unknown. In this study, RNA sequencing (RNA-seq) was employed to compare whole transcriptomic differences between two groups of Partridge Shank chickens that are divergent in comb sizes. A total of 563 differentially expressed genes (DEGs) were identified, including 277 up-regulated and 286 down-regulated DEGs. According to the animal QTL database, eight DEGs including BMP2 and CHADL matching the reported QTLs were associated with the comb size. Functional annotation analysis revealed that DEGs were involved in cell communication and calcium signaling. Protein-protein interaction network analysis showed that STK32A, PIK3R1, EDN1, HSPA5, and HSPA8 have an impact on comb growth. Moreover, potential alternative splicing events and single nucleotide polymorphisms were also identified. Our data provide a source for identifying genes and pathways with functions critical to comb size and accelerate studies involving molecular mechanisms of this sexual ornament. PMID- 29386545 TI - Hemojuvelin Predicts Acute Kidney Injury and Poor Outcomes Following Cardiac Surgery. AB - Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary HJV, neutrophil gelatinase associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement [NRI] = 0.598; p < 0.001). PMID- 29386546 TI - Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells. AB - Prostate cancer stem-like cells (PCSCs) are not only enriched in the CD44+PSA-/lo subpopulation but also employ androgen-independent signaling mechanisms for survival. CD44+ PCSCs defy androgen deprivation, resist chemo- and radiotherapy and are highly tumorigenic. Human prostate tissue microarray (TMA) staining revealed an increased membranous staining of CD44 in the luminal compartment in higher grade G7-G9 tumors versus staining of the basal layer in benign hyperplasia. To uncover tyrosine kinase/s critical for the survival of the CD44+PSA-/lo subpopulation, we performed an unbiased screen targeting 87 tyrosine kinases with gene specific siRNAs. Among a subset of tyrosine kinases crucial for PCSC survival, was a non-receptor tyrosine kinase, ACK1/TNK2, a critical regulator of castration resistant prostate cancer (CRPC) growth. Consistently, activated ACK1 as measured by phosphorylation at Tyr284 was significant in the CD44+PSA-/lo population. Conversely, pharmacological inhibition by ACK1 inhibitor, (R)-9bMS mitigated CD44+PSA-/lo sphere formation, overcame resistance to radiation-induced cell death, induced significant apoptosis in PCSCs and inhibited CD44+PSA-/lo xenograft tumor growth in castrated mice suggesting dependency of PCSCs on ACK1 for survival. Thus, blockade of ACK1/TNK2 could be a new therapeutic modality to target recalcitrant PCSCs. PMID- 29386547 TI - The preference choices of Conopomorpha sinensis Bradley (Lepidoptera: Gracilariidae) for litchi based on its host surface characteristics and volatiles. AB - Conopomorpha sinensis Bradley is a host-specific pest of Litchi chinensis and Euphoria longan. Here, we demonstrated that C. sinensis has evolved special physical and chemical mechanisms for host plant location that enable it to survive and reproduce. Females favored laying their eggs on the convex surface of litchi fruit that had particular volatile characteristics. Experiments using a H type olfactometer showed that female C. sinensis were attracted to litchi flowers, tender shoots, immature fruits, and mature fruits, with the highest attraction rate to mature fruits (74.67 +/- 2.31%). There were no significant differences in the attraction of male C. sinensis to different litchi tissues. Further oviposition preference tests using the pericarp, pulp, and seeds of mature litchi fruits revealed that female C. sinensis prefer to lay their eggs on the pericarp. Litchi volatiles were found to be important in attracting C. sinensis to fruits for oviposition. Analysis of volatiles from different litchi tissues by HS-SPME-GC-MS revealed 31 similar volatiles, some of which may be important in the oviposition preference choices of C. sinensis on litchi fruit. PMID- 29386548 TI - Tracking natural and anthropogenic Pb exposure to its geological source. AB - Human Pb exposure comes from two sources: (i) natural uptake through ingestion of soils and typified by populations that predate mining activity and (ii) anthropogenic exposure caused by the exposure to Pb derived from ore deposits. Currently, the measured concentration of Pb within a sample is used to discriminate between these two exposure routes, with the upper limit for natural exposure in skeletal studies given as 0.5 or 0.7 mg/kg in enamel and 0.5/0.7 MUg/dL in blood. This threshold approach to categorising Pb exposure does not distinguish between the geological origins of the exposure types. However, Pb isotopes potentially provide a more definitive means of discriminating between sources. Whereas Pb from soil displays a crustal average 238U/204Pb (MU) value of c 9.7, Pb from ore displays a much wider range of evolution pathways. These characteristics are transferred into tooth enamel, making it possible to characterize human Pb exposure in terms of the primary source of ingested Pb and to relate mining activity to geotectonic domains. We surmise that this ability to discriminate between silicate and sulphide Pb exposure will lead to a better understanding of the evolution of early human mining activity and development of exposure models through the Anthropocene. PMID- 29386549 TI - Comparison of a PCR assay using novel selective primers with current methods in terms of ABO blood phenotyping in rhesus macaques. AB - Nonhuman primates are important animal models in transplantation. To prevent fatal transplantation-induced immune responses, it is necessary to accurately phenotype the monkey ABH antigens, which are the same as those in humans but (unlike in humans) are not expressed on red blood cells (RBCs). We compared the ability of two established ABO-typing methods, namely, serological testing and immunohistochemistry (IHC), and our novel polymerase chain reaction (PCR)-based assay to type 66 rhesus monkeys. The serological test assessed the ability of monkey sera to hemagglutinate human RBCs. The IHC assay measured the binding of murine anti-A and anti-B antibodies to monkey buccal mucosa cells. The whole blood-based PCR assay involved selective primers that were derived from the exon 7 sequences of A+, B+, and O+ monkeys. IHC and PCR unequivocally yielded the same types in all monkeys. Serological testing yielded inconsistent types in seven (10.6%). FACS analysis with monkey sera preabsorbed with O+ RBCs showed that the incorrect serological results related to nonspecific or xenoreactive binding of the human RBCs. Unlike previous PCR-based assay, our algorithm directly detected O+ monkeys and A and B homozygotes and heterozygotes. Given the logistical limitations of IHC, this PCR assay may be useful for typing rhesus monkeys. PMID- 29386550 TI - Predator arrival elicits differential dispersal, change in age structure and reproductive performance in a prey population. AB - Predators are an important ecological and evolutionary force shaping prey population dynamics. Ecologists have extensively assessed the lethal effects of invasive predators on prey populations. However, the role of non-lethal effects, such as physiological stress or behavioural responses like dispersal, has been comparatively overlooked and their potential population effects remain obscure. Over the last 23 years, we developed a mark-recapture program for the Audouin's gull and an intensive carnivore monitoring program to assess how the appearance and invasion of the study site by carnivores affects population dynamics. We evaluate changes in turnover of discrete breeding patches within the colony, age structure and breeding performance. Once carnivores entered the colony, the number of occupied patches increased, indicating a higher patch turnover. Breeders responded by moving to areas less accessible to carnivores. More importantly, the presence of carnivores caused differential (and density independent) breeding dispersal: experienced, better-performing breeders were more likely to leave the colony than younger breeders. This differential dispersal modified the age structure and reduced the reproductive performance of the population. Our results confirm the importance experience in the study of populations. The role of differential dispersal for animal population dynamics might be more important than previously thought, especially under scenarios of global change. PMID- 29386551 TI - Cone degeneration is triggered by the absence of USH1 proteins but prevented by antioxidant treatments. AB - Usher syndrome type 1 (USH1) is a major cause of inherited deafness and blindness in humans. The eye disorder is often referred to as retinitis pigmentosa, which is characterized by a secondary cone degeneration following the rod loss. The development of treatments to prevent retinal degeneration has been hampered by the lack of clear evidence for retinal degeneration in mutant mice deficient for the Ush1 genes, which instead faithfully mimic the hearing deficit. We show that, under normal housing conditions, Ush1g-/- and Ush1c-/- albino mice have dysfunctional cone photoreceptors whereas pigmented knockout animals have normal photoreceptors. The key involvement of oxidative stress in photoreceptor apoptosis and the ensued retinal gliosis were further confirmed by their prevention when the mutant mice are reared under darkness and/or supplemented with antioxidants. The primary degeneration of cone photoreceptors contrasts with the typical forms of retinitis pigmentosa. Altogether, we propose that oxidative stress probably accounts for the high clinical heterogeneity among USH1 siblings, which also unveils potential targets for blindness prevention. PMID- 29386552 TI - Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-kappaB pathway. AB - We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-kappaB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-kappaB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-kappaB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS. PMID- 29386553 TI - Oxidative C-H activation of amines using protuberant lychee-like goethite. AB - Goethite with protuberant lychee morphology has been synthesized that accomplishes C-H activation of N-methylanilines to generate alpha-aminonitriles; the catalyst takes oxygen from air and uses it as a co-oxidant in the process. PMID- 29386554 TI - Field-controllable Spin-Hall Effect of Light in Optical Crystals: A Conoscopic Mueller Matrix Analysis. AB - Electric-field applied perpendicular to the direction of propagation of paraxial beam through an optical crystal dynamically modifies the spin-orbit interaction (SOI), leading to the demonstration of controllable spin-Hall effect of light (SHEL). The electro- and piezo-optic effects of the crystal modifies the radially symmetric spatial variation in the fast-axis orientation of the crystal, resulting in a complex pattern with different topologies due to the symmetry breaking effect of the applied field. This introduces spatially-varying Pancharatnam-Berry type geometric phase on to the paraxial beam of light, leading to the observation of SHEL in addition to the spin-to-vortex conversion. A wave vector resolved conoscopic Mueller matrix measurement and analysis provides a first glimpse of the SHEL in the biaxial crystal, identified via the appearance of weak circular birefringence. The emergence of field-controllable fast-axis orientation of the crystal and the resulting SHEL provides a new degree of freedom for affecting and controlling the spin and orbital angular momentum of photons to unravel the rich underlying physics of optical crystals and aid in the development of active photonic spin-Hall devices. PMID- 29386555 TI - Micro 3D Printing of a Temperature-Responsive Hydrogel Using Projection Micro Stereolithography. AB - Stimuli-responsive hydrogels exhibiting physical or chemical changes in response to environmental conditions have attracted growing attention for the past few decades. Poly(N-isopropylacrylamide) (PNIPAAm), a temperature responsive hydrogel, has been extensively studied in various fields of science and engineering. However, manufacturing of PNIPAAm has been heavily relying on conventional methods such as molding and lithography techniques that are inherently limited to a two-dimensional (2D) space. Here we report the three dimensional (3D) printing of PNIPAAm using a high-resolution digital additive manufacturing technique, projection micro-stereolithography (PMUSL). Control of the temperature dependent deformation of 3D printed PNIPAAm is achieved by controlling manufacturing process parameters as well as polymer resin composition. Also demonstrated is a sequential deformation of a 3D printed PNIPAAm structure by selective incorporation of ionic monomer that shifts the swelling transition temperature of PNIPAAm. This fast, high resolution, and scalable 3D printing method for stimuli-responsive hydrogels may enable many new applications in diverse areas, including flexible sensors and actuators, bio medical devices, and tissue engineering. PMID- 29386556 TI - Recombinant Mtb9.8 of Mycobacterium bovis stimulates TNF-alpha and IL-1beta secretion by RAW264.7 macrophages through activation of NF-kappaB pathway via TLR2. AB - The Mtb9.8 antigenic protein of Mycobacterium bovis/Mycobacterium tuberculosis has been identified as a target of the T-cell response. However, the interaction of Mtb9.8 with Toll-like receptors (TLRs) and the relevant signaling pathways have not been fully clarified. In this study, recombinant Mtb9.8 (rMtb9.8) derived from M. bovis-stimulated RAW264.7 cells initiated the secretion of TNF alpha and IL-1beta in a dose-dependent manner. Blocking assays show that TLR2 neutralizing antibody decreases the production of TNF-alpha and IL-1beta. Moreover, NF-kappaB activation is associated with TNF-alpha and IL-1beta production by rMtb9.8 stimulation, and rMtb9.8 stimulation also induces the phosphorylation of NF-kappaB p65 at Ser536 and its rapid nuclear translocation in RAW264.7 cells. Furthermore, NF-kappaB luciferase activity is rapidly activated in response to rMtb9.8 in RAW264.7 cells and is also significantly increased in rMtb9.8-induced HEK293-TLR2. However, these activations were abrogated in cells with a dominant-negative mutation of NF-kappaB p65 and by treatment with anti TLR2 antibody. We also find that rMtb9.8 induces the activation of IRF-1. These findings indicate that M. bovis-derived rMtb9.8 activates the NF-kappaB pathway via TLR2 in RAW264.7 cells. In particular, it phosphorylates NF-kappaB p65 at Ser536 and induces nuclear translocation, thereby leading to the production of TNF-alpha and IL-1beta, which correlates with the induction of IRF-1. PMID- 29386557 TI - Spatial memory is as important as weapon and body size for territorial ownership in a lekking hummingbird. AB - Advanced cognitive abilities have long been hypothesized to be important in mating. Yet, most work on sexual selection has focused on morphological traits and its relevance for cognitive evolution is poorly understood. We studied the spatial memory of lekking long-billed hermits (Phaethornis longirostris) and evaluated its role in lek territory ownership, the magnitude of its effect compared to phenotypic traits expected to influence sexual selection, and whether its variation is indicated in the structure of mating vocal signal. Spatial memory (the ability to recall the position of a rewarding feeder) was compared between "territorial" and "floater" males. Interestingly, although spatial memory and body size both positively affected the probability of lek territory ownership, our results suggest a stronger effect of spatial memory. Bill tip length (used as weapon in agonistic interactions) also showed a positive but smaller effect. Load lifting during vertical flight, a measure of physical performance relevant to agonistic interactions, had no effect on territory ownership. Finally, both body size and spatial memory were indicated in the structure of male song: body size negatively correlated with song lowest frequency, while spatial memory positively predicted song consistency. Together, our findings lend support for cognition as a sexual selection target. PMID- 29386558 TI - Lithosphere strain rate and stress field orientations near the Alpine arc in Switzerland. AB - In this study we test whether principal components of the strain rate and stress tensors align within Switzerland. We find that 1) Helvetic Nappes line (HNL) is the relevant tectonic boundary to define different domains of crustal stress/surface strain rates orientations and 2) orientations of T- axes (of moment tensor solutions) and long-term asthenosphere cumulative finite strain (from SKS shear wave splitting) are consistent at the scale of the Alpine arc in Switzerland. At a more local scale, we find that seismic activity and surface deformation are in agreement but in three regions (Basel, Swiss Jura and Ticino); possibly because of the low levels of deformation and/or seismicity. In the Basel area, deep seismicity exists while surface deformation is absent. In the Ticino and the Swiss Jura, where seismic activity is close to absent, surface deformation is detected at a level of ~2 10-8/yr (~6.3 10-16/s). PMID- 29386559 TI - Adrenergic hormones induce extrapituitary prolactin gene expression in leukocytes potential implications in obesity. AB - The pituitary hormone prolactin (PRL), originally described for its role in lactation, has been implemented in over 300 functions and is produced by multiple cell types outside of the pituitary. Monocyte/macrophages in particular show robust expression of extra-pituitary prolactin (ePRL). While ePRL protein is identical to pituitary PRL and translated from the same gene, tissues outside the pituitary engage an alternative promoter to regulate expression. Many of the factors regulating this expression, however, remain unknown. Here we show that the adrenergic hormones epinephrine and norepinephrine induce PRL expression in the human monocytic cell line THP-1 at physiological concentrations. Furthermore, our experiments show the polarization state of differentiated macrophages can influence their response in vitro, with inflammatory M1 macrophages-common in obese adipose-showing the highest levels of PRL expression compared to other macrophage types. Adrenergic hormones have a clearly defined role in adipocyte lipid metabolism, stimulating lipolysis through hormone sensitive lipase (HSL) induction. Meanwhile, PRL has been shown to stimulate lipogenesis. This highlights ePRL production as a possible factor in obesity. The overall balance of these two signals could play a critical role in determining overall lipid turnover/accumulation in adipose depots where large numbers of adipose tissue macrophages (ATMs) reside. PMID- 29386560 TI - High-throughput sequencing analysis revealed the regulation patterns of small RNAs on the development of A. comosus var. bracteatus leaves. AB - Studies of the molecular mechanisms involved in the formation of the albino leaf cells are important for understanding the development of chimera leaves in Ananas comosus var. bracteatus. In this study, we identified a total of 163 novel miRNAs involved in the development of complete white (CWh) and complete green (CGr) leaves using high-throughput sequencing method. The potential miRNA target genes were predicted and annotated using the NR, Swiss-Prot, GO, COG, KEGG, KOG and Pfam databases. The main biological processes regulated by miRNAs were revealed. The miRNAs which potentially play important roles in the development of the leaves and the albino of the CWh leaf cells were selected and their expression patterns were analyzed. The expression levels of nine miRNAs and their potential target genes were studied using qRT-PCR. These results will help to elucidate the functional and regulatory roles of miRNAs in the formation of the albino cells and the development of the leaves of A. comosus var. bracteatus. These data may also be helpful as a resource for studies of small RNA in other leaf color chimeric plant species. PMID- 29386561 TI - Hidden geometries in networks arising from cooperative self-assembly. AB - Multilevel self-assembly involving small structured groups of nano-particles provides new routes to development of functional materials with a sophisticated architecture. Apart from the inter-particle forces, the geometrical shapes and compatibility of the building blocks are decisive factors. Therefore, a comprehensive understanding of these processes is essential for the design of assemblies of desired properties. Here, we introduce a computational model for cooperative self-assembly with the simultaneous attachment of structured groups of particles, which can be described by simplexes (connected pairs, triangles, tetrahedrons and higher order cliques) to a growing network. The model incorporates geometric rules that provide suitable nesting spaces for the new group and the chemical affinity of the system to accept excess particles. For varying chemical affinity, we grow different classes of assemblies by binding the cliques of distributed sizes. Furthermore, we characterize the emergent structures by metrics of graph theory and algebraic topology of graphs, and 4 point test for the intrinsic hyperbolicity of the networks. Our results show that higher Q-connectedness of the appearing simplicial complexes can arise due to only geometric factors and that it can be efficiently modulated by changing the chemical potential and the polydispersity of the binding simplexes. PMID- 29386562 TI - Polarization-maintaining reflection-mode THz time-domain spectroscopy of a polyimide based ultra-thin narrow-band metamaterial absorber. AB - This paper reports the design, the microfabrication and the experimental characterization of an ultra-thin narrow-band metamaterial absorber at terahertz frequencies. The metamaterial device is composed of a highly flexible polyimide spacer included between a top electric ring resonator with a four-fold rotational symmetry and a bottom ground plane that avoids misalignment problems. Its performance has been experimentally demonstrated by a custom polarization maintaining reflection-mode terahertz time-domain spectroscopy system properly designed in order to reach a collimated configuration of the terahertz beam. The dependence of the spectral characteristics of this metamaterial absorber has been evaluated on the azimuthal angle under oblique incidence. The obtained absorbance levels are comprised between 67% and 74% at 1.092 THz and the polarization insensitivity has been verified in transverse electric polarization. This offers potential prospects in terahertz imaging, in terahertz stealth technology, in substance identification, and in non-planar applications. The proposed compact experimental set-up can be applied to investigate arbitrary polarization sensitive terahertz devices under oblique incidence, allowing for a wide reproducibility of the measurements. PMID- 29386563 TI - Characterization of soil nematode communities in three cropping systems through morphological and DNA metabarcoding approaches. AB - We used complementary morphological and DNA metabarcoding approaches to characterize soil nematode communities in three cropping systems, conventional till (CT), no-till (NT) and organic (ORG), from a long-term field experiment. We hypothesized that organic inputs to the ORG system would promote a more abundant nematode community, and that the NT system would show a more structured trophic system (higher Bongers MI) than CT due to decreased soil disturbance. The abundance of Tylenchidae and Cephalobidae both showed positive correlations to soil organic carbon and nitrogen, which were highest in the ORG system. The density of omnivore-predator and bacterial-feeding nematodes was reduced in NT soils compared to CT, while some plant-parasitic taxa increased. NT soils had similar Bongers MI values to CT, suggesting they contained nematode communities associated with soils experiencing comparable levels of disturbance. Metabarcoding revealed within-family differences in nematode diversity. Shannon and Simpson's index values for the Tylenchidae and Rhabditidae were higher in the ORG system than CT. Compared to morphological analysis, metabarcoding over- or underestimated the prevalence of several nematode families and detected some families not observed based on morphology. Discrepancies between the techniques require further investigation to establish the accuracy of metabarcoding for characterization of soil nematode communities. PMID- 29386564 TI - Nonlinear Absorption Response Correlated to Embedded Ag Nanoparticles in BGO Single Crystal: From Two-Photon to Three-Photon Absorption. AB - We report on the embedded silver (Ag) nanoparticles fabricated by Ag+ ion implantation into the Bi4Ge3O12 (BGO) crystal. Localized surface plasmon resonance (LSPR) phenomenon has been observed by linear optical absorption spectrum, which is accordance with the expectation based on Mie theory calculation. Further proofs are given by SRIM, TEM and SAED analysis, which explain the slight difference between experiment and calculation. Based on the z scan system, it is found that the nonlinear optical response is converted from two-photon absorption to three-photon absorption under the 515 nm femtosecond pulse excitation within the LSPR band. The nonlinear absorption coefficient is measured to be ~3.1 * 10-9 cm/W (two-photon absorption coefficient) and ~8.9 * 10 14cm3/W2 (three-photon absorption coefficient) for pure BGO crystal and the sample embedded with Ag nanoparticles (Ag:BGO), respectively. Finally, we have proposed a model to explain the asymmetric nonlinear transmittance, which is in good agreement with the experimental results. PMID- 29386565 TI - DNA Barcode Authentication and Library Development for the Wood of Six Commercial Pterocarpus Species: the Critical Role of Xylarium Specimens. AB - DNA barcoding has been proposed as a useful tool for forensic wood identification and development of a reliable DNA reference library is an essential first step. Xylaria (wood collections) are potentially enormous data repositories if DNA information could be extracted from wood specimens. In this study, 31 xylarium wood specimens and 8 leaf specimens of six important commercial species of Pterocarpus were selected to investigate the reliability of DNA barcodes for authentication at the species level and to determine the feasibility of building wood DNA barcode reference libraries from xylarium specimens. Four DNA barcodes (ITS2, matK, ndhF-rpl32 and rbcL) and their combination were tested to evaluate their discrimination ability for Pterocarpus species with both TaxonDNA and tree based analytical methods. The results indicated that the combination barcode of matK + ndhF-rpl32 + ITS2 yielded the best discrimination for the Pterocarpus species studied. The mini-barcode ndhF-rpl32 (167-173 bps) performed well distinguishing P. santalinus from its wood anatomically inseparable species P. tinctorius. Results from this study verified not only the feasibility of building DNA barcode libraries using xylarium wood specimens, but the importance of using wood rather than leaves as the source tissue, when wood is the botanical material to be identified. PMID- 29386566 TI - Innovatively Continuous Mass Production Couette-taylor Flow: Pure Inorganic Green Emitting Cs4PbBr6 Perovskite Microcrystal for display technology. AB - We report for the first time the mass production of Cs4PbBr6 perovskite microcrystal with a Couette-Taylor flow reactor in order to enhance the efficiency of the synthesis reaction. We obtained a pure Cs4PbBr6 perovskite solid within 3 hrs that then realized a high photoluminescence quantum yield (PLQY) of 46%. Furthermore, the Cs4PbBr6 perovskite microcrystal is applied with red emitting K2SiF6 phosphor on a blue-emitting InGaN chip, achieving a high performance luminescence characteristics of 9.79 lm/W, external quantum efficiency (EQE) of 2.9%, and correlated color temperature (CCT) of 2976 K; therefore, this perovskite is expected to be a promising candidate material for applications in optoelectronic devices. PMID- 29386567 TI - MGAT1 and Complex N-Glycans Regulate ERK Signaling During Spermatogenesis. AB - Mechanisms that regulate spermatogenesis in mice are important to define as they often apply to fertility in man. We previously showed that conditional deletion of the mouse Mgat1 gene (Mgat1 cKO) in spermatogonia causes a germ-cell autonomous defect leading to infertility. MGAT1 is the N acetylglucosaminyltransferase (GlcNAcT-I) that initiates the synthesis of complex N-glycans. Mechanistic bases of MGAT1 loss were investigated in germ cells from 22- and 23-day males, before any changes in germ cell morphology were apparent. Gene expression changes induced by deletion of Mgat1 were determined using the Affymetrix gene chip Mouse Mogene 2.0 ST array, and relationships were investigated by bioinformatics including Gene Ontology (GO), Ingenuity Pathway Analysis (IPA), and Gene Set Enrichment Analysis (GSEA). The loss of complex N glycans promoted the premature up-regulation of genes normally expressed later in spermatogenesis and spermiogenesis, and IPA and GSEA implicated ERK signaling. EGFR and PDGFRA transcripts and ERK1/2 signaling were reduced in 22-day Mgat1 cKO germ cells. Basigin, a germ cell target of MGAT1, activated ERK1/2 in CHO cells, but not in a Lec1 CHO mutant that lacks MGAT1 and complex N-glycans. Thus, MGAT1 is required to regulate ERK1/2 signaling during spermatogenesis, potentially via different mechanisms. PMID- 29386568 TI - Secretory factors from OP9 stromal cells delay differentiation and increase the expansion potential of adult erythroid cells in vitro. AB - Development of in vitro culture systems for the generation of red blood cells is a goal of scientists globally with the aim of producing clinical grade products for transfusion. Although mature reticulocytes can be efficiently generated by such systems, the numbers produced fall short of that required for therapeutics, due to limited proliferative capacity of the erythroblasts. To overcome this hurdle, approaches are required to increase the expansion potential of such culture systems. The OP9 mouse stromal cell line is known to promote haematopoietic differentiation of pluripotent stem cells, however an effect of OP9 cells on erythropoiesis has not been explored. In this study, we show not only OP9 co-culture, but factors secreted by OP9 cells in isolation increase the proliferative potential of adult erythroid cells by delaying differentiation and hence maintaining self-renewing cells for an extended duration. The number of reticulocytes obtained was increased by approximately 3.5-fold, bringing it closer to that required for a therapeutic product. To identify the factors responsible, we analysed the OP9 cell secretome using comparative proteomics, identifying 18 candidate proteins. These data reveal the potential to increase erythroid cell numbers from in vitro culture systems without the need for genetic manipulation or co-culture. PMID- 29386569 TI - Yellow coloured mats from lava tubes of La Palma (Canary Islands, Spain) are dominated by metabolically active Actinobacteria. AB - Microbial diversity in lava tubes from Canary Islands (Spain) has never been explored thus far offering a unique opportunity to study subsurface microbiology. Abundant yellow coloured mats developing on coralloid speleothems in a lava tube from La Palma Islands were studied by next-generation sequencing and DNA/RNA clone library analyses for investigating both total and metabolically active bacteria. In addition, morphological and mineralogical characterization was performed by field emission scanning electron microscopy (FESEM), micro-computed tomography, X-ray diffraction and infrared spectroscopy to contextualize sequence data. This approach showed that the coralloid speleothems consist of banded siliceous stalactites composed of opal-A and hydrated halloysite. Analytical pyrolysis was also conducted to infer the possible origin of cave wall pigmentation, revealing that lignin degradation compounds can contribute to speleothem colour. Our RNA-based study showed for the first time that members of the phylum Actinobacteria, with 55% of the clones belonging to Euzebyales order, were metabolically active components of yellow mats. In contrast, the DNA clone library revealed that around 45% of clones were affiliated to Proteobacteria. Composition of microbial phyla obtained by NGS reinforced the DNA clone library data at the phylum level, in which Proteobacteria was the most abundant phylum followed by Actinobacteria. PMID- 29386570 TI - Endogenous emotion generation ability is associated with the capacity to form multimodal internal representations. AB - Training the capacity to self-generate emotions can be a potent "vaccine" against negative stressors and be an effective intervention for affective psychopathology. However, due to a lack of knowledge about sources of individual differences in generation abilities, it is unclear how to optimally design such interventions. We investigated one potential source of variation, namely preference for using different information modalities (Visual Imagery, Auditory Imagery, Bodily Interoception, and Semantic Analysis). A representative sample of 293 participants self-induced positive and negative emotional states, freely choosing to use these modalities singly or in combination. No evidence was found for modality usage being associated with differential efficacy at generating of positive or negative emotion. Rather, usage of all modalities (except Auditory Imagery) predicted success at generation of both positive and negative emotional states. Increasing age predicted capacity to generate, especially negative, emotions. While no specific combinations of modalities were superior, the overall degree to which participants adopted multimodal implementations did predict generation efficacy. These findings inform interventions aimed at improving emotional self-generation, suggesting these must be mindful of individual differences in generation abilities and implementation tendencies, and that they should focus on enhancing the capacity to use multiple modalities. PMID- 29386571 TI - Pulmonary fibrosis in vivo displays increased p21 expression reduced by 5-HT2B receptor antagonists in vitro - a potential pathway affecting proliferation. AB - Serotonin (5-hydroxytryptamine) has repeatedly been associated with the development of fibrotic disorders such as pulmonary fibrosis. By blocking the binding of 5-HT to 5-HT2B receptors with receptor antagonists, several pro fibrotic mechanisms can be inhibited. Bleomycin-induced pulmonary fibrosis is a model used to evaluate pathological mechanisms and pharmacological interventions. Previously we have shown attenuated fibrosis in systemic bleomycin-treated mice following treatment with two 5-HT2B receptor antagonists (EXT5 and EXT9). Our aim is to further identify cellular effects and signaling pathways associated with the anti-fibrotic effects of EXT5/9. Gene expressions in lung tissues from systemic bleomycin-treated mice were examined, revealing significant increased expression of Cdkn1alpha (a gene coding for p21), particularly in distal regions of the lung. In vitro studies in human lung fibroblasts revealed increased levels of p21 (p = 0.0032) and pAkt (p = 0.12) following treatment with 5-HT (10 uM). The induction of p21 and pAkt appears to be regulated by 5-HT2B receptors, with diminished protein levels following EXT9-treatment (p21 p = 0.0024, pAkt p = 0.15). Additionally, 5-HT induced fibroblast proliferation, an event significantly reduced by EXT5 (10 uM) and EXT9 (10 uM). In conclusion, our results suggest that 5-HT2B receptor antagonism attenuates pulmonary fibrosis in part by anti-proliferative effects, associated with inhibited pAkt/p21 signaling pathway. PMID- 29386572 TI - Correction: Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan. AB - Correction to: Journal of Human Genetics advance online publication, 08 November 2017; https://doi.org/10.1038/s10038-017-0355-1. PMID- 29386573 TI - Circadian coordination of ATP release in the urothelium via connexin43 hemichannels. AB - Day-night changes in the storage capacity of the urinary bladder are indispensable for sound sleep. Connexin 43 (Cx43), a major gap junction protein, forms hemichannels as a pathway of ATP in other cell types, and the urinary bladder utilizes ATP as a mechanotransduction signals to modulate its capacity. Here, we demonstrate that the circadian clock of the urothelium regulates diurnal ATP release through Cx43 hemichannels. Cx43 was expressed in human and mouse urothelium, and clock genes oscillated in the mouse urothelium accompanied by daily cycles in the expression of Cx43 and extracellular ATP release into the bladder lumen. Equivalent chronological changes in Cx43 and ATP were observed in immortalized human urothelial cells, but these diurnal changes were lost in both arrhythmic Bmal1-knockout mice and in BMAL1-knockdown urothelial cells. ATP release was increased by Cx43 overexpression and was decreased in Cx43 knockdown or in the presence of a selective Cx43 hemichannel blocker, which indicated that Cx43 hemichannels are considered part of the components regulating ATP release in the urothelium. Thus, a functional circadian rhythm exists in the urothelium, and coordinates Cx43 expression and function as hemichannels that provide a direct pathway of ATP release for mechanotransduction and signalling in the urothelium. PMID- 29386574 TI - Development of an Immune-Pathology Informed Radiomics Model for Non-Small Cell Lung Cancer. AB - With increasing use of immunotherapy agents, pretreatment strategies for identifying responders and non-responders is useful for appropriate treatment assignment. We hypothesize that the local immune micro-environment of NSCLC is associated with patient outcomes and that these local immune features exhibit distinct radiologic characteristics discernible by quantitative imaging metrics. We assembled two cohorts of NSCLC patients treated with definitive surgical resection and extracted quantitative parameters from pretreatment CT imaging. The excised primary tumors were then quantified for percent tumor PDL1 expression and density of tumor-infiltrating lymphocyte (via CD3 count) utilizing immunohistochemistry and automated cell counting. Associating these pretreatment radiomics parameters with tumor immune parameters, we developed an immune pathology-informed model (IPIM) that separated patients into 4 clusters (designated A-D) utilizing 4 radiomics features. The IPIM designation was significantly associated with overall survival in both training (5 year OS: 61%, 41%, 50%, and 91%, for clusters A-D, respectively, P = 0.04) and validation (5 year OS: 55%, 72%, 75%, and 86%, for clusters A-D, respectively, P = 0.002) cohorts and immune pathology (all P < 0.05). Specifically, we identified a favorable outcome group characterized by low CT intensity and high heterogeneity that exhibited low PDL1 and high CD3 infiltration, suggestive of a favorable immune activated state. We have developed a NSCLC radiomics signature based on the immune micro-environment and patient outcomes. This manuscript demonstrates model creation and validation in independent cohorts. PMID- 29386576 TI - Analogies of the classical Euler top with a rotor to spin squeezing and quantum phase transitions in a generalized Lipkin-Meshkov-Glick model. AB - We show that the classical model of Euler top (freely rotating, generally asymmetric rigid body), possibly supplemented with a rotor, corresponds to a generalized Lipkin-Meshkov-Glick (LMG) model describing phenomena of various branches of quantum physics. Classical effects such as free precession of a symmetric top, Feynman's wobbling plate, tennis-racket instability and the Dzhanibekov effect, attitude control of satellites by momentum wheels, or twisting somersault dynamics, have their counterparts in quantum effects that include spin squeezing by one-axis twisting and two-axis countertwisting, transitions between the Josephson and Rabi regimes of a Bose-Einstein condensate in a double-well potential, and other quantum critical phenomena. The parallels enable us to expand the range of explored quantum phase transitions in the generalized LMG model, as well as to present a classical analogy of the recently proposed LMG Floquet time crystal. PMID- 29386575 TI - The role of local-geometrical-orders on the growth of dynamic-length-scales in glass-forming liquids. AB - The precise nature of complex structural relaxation as well as an explanation for the precipitous growth of relaxation time in cooling glass-forming liquids are essential to the understanding of vitrification of liquids. The dramatic increase of relaxation time is believed to be caused by the growth of one or more correlation lengths, which has received much attention recently. Here, we report a direct link between the growth of a specific local-geometrical-order and an increase of dynamic-length-scale as the atomic dynamics in metallic glass-forming liquids slow down. Although several types of local geometrical-orders are present in these metallic liquids, the growth of icosahedral ordering is found to be directly related to the increase of the dynamic-length-scale. This finding suggests an intriguing scenario that the transient icosahedral connectivity could be the origin of the dynamic-length-scale in metallic glass-forming liquids. PMID- 29386577 TI - Quartz-based flat-crystal resonant inelastic x-ray scattering spectrometer with sub-10 meV energy resolution. AB - Continued improvement of the energy resolution of resonant inelastic x-ray scattering (RIXS) spectrometers is crucial for fulfilling the potential of this technique in the study of electron dynamics in materials of fundamental and technological importance. In particular, RIXS is the only alternative tool to inelastic neutron scattering capable of providing fully momentum resolved information on dynamic spin structures of magnetic materials, but is limited to systems whose magnetic excitation energy scales are comparable to the energy resolution. The state-of-the-art spherical diced crystal analyzer optics provides energy resolution as good as 25 meV but has already reached its theoretical limit. Here, we demonstrate a novel sub-10 meV RIXS spectrometer based on flat crystal optics at the Ir-L3 absorption edge (11.215 keV) that achieves an analyzer energy resolution of 3.9 meV, very close to the theoretical value of 3.7 meV. In addition, the new spectrometer allows efficient polarization analysis without loss of energy resolution. The performance of the instrument is demonstrated using longitudinal acoustical and optical phonons in diamond, and magnon in Sr3Ir2O7. The novel sub-10 meV RIXS spectrometer thus provides a window into magnetic materials with small energy scales. PMID- 29386579 TI - Plastid super-barcodes as a tool for species discrimination in feather grasses (Poaceae: Stipa). AB - Present study was designed to verify which or if any of plastome loci is a hotspot region for mutations and hence might be useful for molecular species identification in feather grasses. 21 newly sequenced complete plastid genomes representing 19 taxa from the genus of Stipa were analyzed in search of the most variable and the most discriminative loci within Stipa. The results showed that the problem with selecting a good barcode locus for feather grasses lies in the very low level of genetic diversity within its plastome. None of the single chloroplast loci is polymorphic enough to play a role of a barcode or a phylogenetic marker for Stipa. The biggest number of taxa was successfully identified by the analysis of 600 bp long DNA fragment comprising a part of rbcL gene, the complete rbcL-rpl23 spacer and a part of rpl23 gene. The effectiveness of multi-locus barcode composed of six best-performing loci for Stipa (ndhH, rpl23, ndhF-rpl32, rpl32-ccsA, psbK-psbI and petA-psbJ) didn't reach 70% of analyzed taxa. The analysis of complete plastome sequences as a super-barcode for Stipa although much more effective, still didn't allow for discrimination of all the analyzed taxa of feather grasses. PMID- 29386581 TI - Hydrogen storage of Li4&B36 cluster. AB - The Saturn-like charge-transfer complex Li4&B36, which was recently predicted with extensive first-principles theory calculations, were studied as a candidate for hydrogen storage material in the present work. The bonding characters of Li B, B-B and Li-H2 bonds were revealed by the quantum theory of atoms in molecules (QTAIM). Each Li atom in Li4&B36 cluster can bind six H2 molecules at most, which results into the gravimetric density of 10.4%. The adsorption energies of H2 molecules on Li4&B36 cluster are predicted in the range of 0.08-0.14 eV at the wB97x level of theory. PMID- 29386580 TI - IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells. AB - X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap-/- regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap-/- Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap-/- Treg cells. In addition, Xiap-/- Treg cells are prone to IFN-gamma secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap-/- mice. Notably, inflammation-induced reprogramming of Xiap-/- Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL 6R and Xiap-/- Treg cells confers survival to inflammatory infection in Xiap-/- mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP. PMID- 29386578 TI - A model species for agricultural pest genomics: the genome of the Colorado potato beetle, Leptinotarsa decemlineata (Coleoptera: Chrysomelidae). AB - The Colorado potato beetle is one of the most challenging agricultural pests to manage. It has shown a spectacular ability to adapt to a variety of solanaceaeous plants and variable climates during its global invasion, and, notably, to rapidly evolve insecticide resistance. To examine evidence of rapid evolutionary change, and to understand the genetic basis of herbivory and insecticide resistance, we tested for structural and functional genomic changes relative to other arthropod species using genome sequencing, transcriptomics, and community annotation. Two factors that might facilitate rapid evolutionary change include transposable elements, which comprise at least 17% of the genome and are rapidly evolving compared to other Coleoptera, and high levels of nucleotide diversity in rapidly growing pest populations. Adaptations to plant feeding are evident in gene expansions and differential expression of digestive enzymes in gut tissues, as well as expansions of gustatory receptors for bitter tasting. Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles. Finally, duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA. The L. decemlineata genome provides opportunities to investigate a broad range of phenotypes and to develop sustainable methods to control this widely successful pest. PMID- 29386582 TI - Spinal cholinergic interneurons differentially control motoneuron excitability and alter the locomotor network operational range. AB - While cholinergic neuromodulation is important for locomotor circuit operation, the specific neuronal mechanisms that acetylcholine employs to regulate and fine tune the speed of locomotion are largely unknown. Here, we show that cholinergic interneurons are present in the zebrafish spinal cord and differentially control the excitability of distinct classes of motoneurons (slow, intermediate and fast) in a muscarinic dependent manner. Moreover, we reveal that m2-type muscarinic acetylcholine receptors (mAChRs) are present in fast and intermediate motoneurons, but not in the slow motoneurons, and that their activation decreases neuronal firing. We also reveal a strong correlation between the muscarinic receptor configuration on motoneurons and the ability of the animals to locomote at different speeds, which might serve as a plasticity mechanism to alter the operational range of the locomotor networks. These unexpected findings provide new insights into the functional flexibility of motoneurons and how they execute locomotion at different speeds. PMID- 29386583 TI - Covert lie detection using keyboard dynamics. AB - Identifying the true identity of a subject in the absence of external verification criteria (documents, DNA, fingerprints, etc.) is an unresolved issue. Here, we report an experiment on the verification of fake identities, identified by means of their specific keystroke dynamics as analysed in their written response using a computer keyboard. Results indicate that keystroke analysis can distinguish liars from truth tellers with a high degree of accuracy around 95% - thanks to the use of unexpected questions that efficiently facilitate the emergence of deception clues. PMID- 29386584 TI - Protein corona of airborne nanoscale PM2.5 induces aberrant proliferation of human lung fibroblasts based on a 3D organotypic culture. AB - Exposure to PM2.5 has become one of the most important factors affecting public health in the world. Both clinical and research studies have suggested that PM2.5 inhalation is associated with impaired lung function. In this study, material characterization identified the existence of nanoscale particulate matter (NPM) in airborne PM2.5 samples. When coming into contact with protein-rich fluids, the NPM becomes covered by a protein layer that forms a "protein corona". Based on a 3D organotypic cell culture, the protein corona was shown to mitigate NPM cytotoxicity and further stimulate the proliferation of human lung fibroblasts (HLFs). ROS-activated alpha-smooth muscle actin (alpha-SMA) is considered to be one of the proliferation pathways. In this research, 3D cell cultures exhibited more tissue-like properties compared with the growth in 2D models. Animal models have been widely used in toxicological research. However, species differences make it impossible to directly translate discoveries from animals to humans. In this research, the 3D HLF model could partly simulate the biological responses of NPM-protein corona-induced aberrant HLF proliferation in the human lung. Our 3D cellular results provide auxiliary support for an animal model in research on PM2.5-induced impaired lung function, particularly in lung fibrosis. PMID- 29386585 TI - LLO-mediated Cell Resealing System for Analyzing Intracellular Activity of Membrane-impermeable Biopharmaceuticals of Mid-sized Molecular Weight. AB - Cell-based assays have become increasingly important in the preclinical studies for biopharmaceutical products such as specialty peptides, which are of interest owing to their high substrate specificity. However, many of the latter are membrane impermeable and must be physically introduced into cells to evaluate their intracellular activities. We previously developed a "cell-resealing technique" that exploited the temperature-dependent pore-forming activity of the streptococcal toxin, streptolysin O (SLO), that enabled us to introduce various molecules into cells for evaluation of their intracellular activities. In this study, we report a new cell resealing method, the listeriolysin O (LLO)-mediated resealing method, to deliver mid-sized, membrane-impermeable biopharmaceuticals into cells. We found that LLO-type resealing required no exogenous cytosol to repair the injured cell membrane and allowed the specific entry of mid-sized molecules into cells. We use this method to introduce either a membrane impermeable, small compound (8-OH-cAMP) or specialty peptide (Akt-in), and demonstrated PKA activation or Akt inhibition, respectively. Collectively, the LLO-type resealing method is a user-friendly and reproducible intracellular delivery system for mid-sized membrane-impermeable molecules into cells and for evaluating their intracellular activities. PMID- 29386587 TI - Mycorrhiza stimulates root-hair growth and IAA synthesis and transport in trifoliate orange under drought stress. AB - Root-hair growth and development regulated by soil microbes is associated with auxin. In this background, we hypothesized that mycorrhizal fungal inoculation induces greater root-hair growth through stimulated auxin synthesis and transport under water stress conditions. Trifoliate orange (Poncirus trifoliata) was inoculated with an arbuscular mycorrhizal (AM) fungus (Funneliformis mosseae) under well-watered (WW) and drought stress (DS) for 9 weeks. Compared with non-AM seedlings, AM seedlings displayed significantly higher density, length, and diameter of root hairs and root indoleacetic acid (IAA) level, whereas lower total root IAA efflux, regardless of soil moisture status. Root PtYUC3 and PtYUC8 involved in IAA biosynthesis were up-regulated by mycorrhization under WW and DS, whereas AM-modulated expression in PtTAA1, PtTAR2, PtYUC4, and PtYUC6 depended on status of soil moisture. Mycorrhizal inoculation down-regulated the transcript level of root auxin efflux carriers like PtPIN1 and PtPIN3, whereas significantly up-regulated the expression of root auxin-species influx carriers like PtABCB19 and PtLAX2 under DS. These results indicated that AMF-stimulated greater root hair growth of trifoliate orange under DS that is independent on AMF species is related with mycorrhiza-modulated auxin synthesis and transport, which benefits the host plant to enhance drought tolerance. PMID- 29386586 TI - Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic beta cell line, INS-1 cells. AB - Thyroid stimulating hormone (TSH) stimulates the secretion of thyroid hormones by binding the TSH receptor (TSHR). TSHR is well-known to be expressed in thyroid tissue, excepting it, TSHR has also been expressed in many other tissues. In this study, we have examined the expression of TSHR in rat pancreatic islets and evaluated the role of TSH in regulating pancreas-specific gene expression. TSHR was confirmed to be expressed in rodent pancreatic islets and its cell line, INS 1 cells. TSH directly affected the glucose uptake in INS cells by up-regulating the expression of GLUT2, and furthermore this process was blocked by SB203580, the specific inhibitor of the p38 MAPK signaling pathway. Similarly, TSH stimulated GLUT2 promoter activity, while both a dominant-negative p38MAPK alpha isoform (p38MAPK alpha-DN) and the specific inhibitor for p38MAPK alpha abolished the stimulatory effect of TSH on GLUT2 promoter activity. Finally, INS-1 cells treated with TSH showed increased protein level of glucokinase and enhanced glucose-stimulated insulin secretion. Together, these results confirm that TSHR is expressed in INS-1 cells and rat pancreatic islets, and suggest that activation of the p38MAPK alpha might be required for TSH-induced GLUT2 gene transcription in pancreatic beta cells. PMID- 29386589 TI - Black silicon significantly enhances phosphorus diffusion gettering. AB - Black silicon (b-Si) is currently being adopted by several fields of technology, and its potential has already been demonstrated in various applications. We show here that the increased surface area of b-Si, which has generally been considered as a drawback e.g. in applications that require efficient surface passivation, can be used as an advantage: it enhances gettering of deleterious metal impurities. We demonstrate experimentally that interstitial iron concentration in intentionally contaminated silicon wafers reduces from 1.7 * 1013 cm-3 to less than 1010 cm-3 via b-Si gettering coupled with phosphorus diffusion from a POCl3 source. Simultaneously, the minority carrier lifetime increases from less than 2 MUs of a contaminated wafer to more than 1.5 ms. A series of different low temperature anneals suggests segregation into the phosphorus-doped layer to be the main gettering mechanism, a notion which paves the way of adopting these results into predictive process simulators. This conclusion is supported by simulations which show that the b-Si needles are entirely heavily-doped with phosphorus after a typical POCl3 diffusion process, promoting iron segregation. Potential benefits of enhanced gettering by b-Si include the possibility to use lower quality silicon in high-efficiency photovoltaic devices. PMID- 29386588 TI - Social status shapes the bacterial and fungal gut communities of the honey bee. AB - Despite the fungal abundance in honey and bee bread, little is known about the fungal gut community of the honey bee and its effect on host fitness. Using pyrosequencing of the 16S rRNA gene and ITS2 region amplicons, we analysed the bacterial and fungal gut communities of the honey bee as affected by the host social status. Both communities were significantly affected by the host social status. The bacterial gut community was similar to those characterised in previous studies. The fungal gut communities of most worker bees were highly dominated by Saccharomyces but foraging bees and queens were colonised by diverse fungal species and Zygosaccharomyces, respectively. The high fungal density and positive correlation between Saccharomyces species and Lactobacillus species, known yeast antagonists, were only observed in the nurse bee; this suggested that the conflict between Saccharomyces and Lactobacillus was compromised by the metabolism of the host and/or other gut microbes. PICRUSt analysis revealed significant differences in enriched gene clusters of the bacterial gut communities of the nurse and foraging bees, suggesting that different host social status might induce changes in the gut microbiota, and, that consequently, gut microbial community shifts to adapt to the gut environment. PMID- 29386590 TI - Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound. AB - Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use. PMID- 29386591 TI - Interactive Holographic Display Based on Finger Gestures. AB - In this paper, we demonstrate an interactive, finger-sensitive system which enables an observer to intuitively handle electro-holographic images in real time. In this system, a motion sensor detects finger gestures (swiping and pinching) and translates them into the rotation and enlargement/reduction of the holographic image, respectively. By parallelising the hologram calculation using a graphics processing unit, we realised the interactive handling of the holographic image in real time. In a demonstration of the system, we used a Leap Motion sensor and a phase modulation-type spatial light modulator with 1,920 * 1,080 pixels and a pixel pitch of 8.0 um * 8.0 um. The constructed interactive finger-sensitive system was able to rotate a holographic image composed of 4,096 point light sources using a swiping gesture and enlarge or reduce it using a pinching gesture in real time. The average calculation speed was 27.6 ms per hologram. Finally, we extended the constructed system to a full-colour reconstruction system that generates a more realistic three-dimensional image. The extended system successfully allowed the handling of a full-colour holographic image composed of 1,709 point light sources with a calculation speed of 22.6 ms per hologram. PMID- 29386593 TI - Autoinflammatory diseases: Free IL-18 causes macrophage activation syndrome. PMID- 29386592 TI - A New Optical Method for Suppressing Radial Magnetic Error in a Depolarized Interference Fiber Optic Gyroscope. AB - Based on the theory of the radial magnetic error (RME) in depolarized interference fiber optic gyroscopes (D-IFOGs) under magnetic field, a new optical method is proposed to decrease the RME by adding a suppressing section fiber (SSF) in D-IFOGs. A related theoretical model is established, and the solutions of the parameters of the SSF are obtained with numerical calculations. Then the results of the suppressed RME are simulated. An experimental system is set up to verify the theory and simulation, and the experimental results prove that the RME can be suppressed effectively with a SSF added in the D-IFOG. The magnitude of the RME can be reduced to one-tenth of the original. PMID- 29386594 TI - Lyme arthritis: Bystander-activated T cells contribute to Lyme arthritis. PMID- 29386595 TI - Autoimmunity: Glycoengineering has therapeutic potential. PMID- 29386596 TI - Fracture and damage localization in volcanic edifice rocks from El Hierro, Stromboli and Tenerife. AB - We present elastic wave velocity and strength data from a suite of three volcanic rocks taken from the volcanic edifices of El Hierro and Tenerife (Canary Islands, Spain), and Stromboli (Aeolian Islands, Italy). These rocks span a range of porosity and are taken from volcanoes that suffer from edifice instability. We measure elastic wave velocities at known incident angles to the generated through going fault as a function of imposed strain, and examine the effect of the damage zone on P-wave velocity. Such data are important as field measurements of elastic wave tomography are key tools for understanding volcanic regions, yet hidden fractures are likely to have a significant effect on elastic wave velocity. We then use elastic wave velocity evolution to calculate concomitant crack density evolution which ranges from 0 to 0.17: highest values were correlated to the damage zone in rocks with the highest initial porosity. PMID- 29386599 TI - Neurodegenerative diseases: Inflammasome protein seeds plaques in Alzheimer disease. PMID- 29386598 TI - Directing lateral growth of lithium dendrites in micro-compartmented anode arrays for safe lithium metal batteries. AB - Uncontrolled growth of lithium dendrites during cycling has remained a challenging issue for lithium metal batteries. Thus far, various approaches have been proposed to delay or suppress dendrite growth, yet little attention has been paid to the solutions that can make batteries keep working when lithium dendrites are already extensively present. Here we develop an industry-adoptable technology to laterally direct the growth of lithium dendrites, where all dendrites are retained inside the compartmented copper current collector in a given limited cycling capacity. This featured electrode layout renders superior cycling stability (e.g., smoothly running for over 150 cycles at 0.5 mA cm-2). Numerical simulations indicate that reduced dendritic stress and damage to the separator are achieved when the battery is abusively running over the ceiling capacity to generate protrusions. This study may contribute to a deeper comprehension of metal dendrites and provide a significant step towards ultimate safe batteries. PMID- 29386600 TI - Inflammation: Microbiome manipulation ameliorates colitis. PMID- 29386597 TI - New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia. AB - Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH. PMID- 29386601 TI - Gene therapy: CRISPR therapies - making the grade not the cut. PMID- 29386603 TI - Pfizer exits neuroscience. PMID- 29386602 TI - 2017 FDA drug approvals. AB - This corrects the article DOI: 10.1038/nrd.2018.4. PMID- 29386604 TI - EMA recommended 35 new drugs in 2017. PMID- 29386605 TI - Regenerative medicine: Cholesterol clearance restores remyelination. PMID- 29386606 TI - Gene therapy: Reprogramming alpha-cells reverses diabetes. PMID- 29386607 TI - Pharmacogenomics: Know your GPCR mutations (and target them right). PMID- 29386608 TI - Top product sales forecasts for 2018. PMID- 29386609 TI - Immunotherapy: Oncolytic virotherapy enables checkpoint blockade. PMID- 29386611 TI - Cancer: Anticancer effects of alcohol abuse drug. PMID- 29386610 TI - Biopharma deal-making in 2017. PMID- 29386612 TI - Cell biology of the neuron: ARC goes viral. PMID- 29386613 TI - Neural development: 'Enhancing' human cognition. PMID- 29386614 TI - Spatial processing: An 'other' kind of place cell. PMID- 29386615 TI - Corneal sensitivity and subjective complaints of ocular pain in patients with fibromyalgia. AB - PurposeFibromyalgia (FM) is a chronic pain disorder associated with pain and hypersensitivity in various parts of the body. The aim of this study was to understand whether changes in corneal sensitivity were associated with the subjective complaints of these patients.Patients and methodsIn this study, we included 36 patients with FM (30 female, 6 male, mean age: 46.7+/-9.2 years) and 39 healthy control subjects (33 females, 6 males, mean age: 44.3+/-7.6 years). We performed a detailed ophthalmological examination, measured tear film breakup time (TBUT), and performed Schirmer I test without anesthetic (SIT). Only patients that did not have any eye disease were included in this study. Subjective complaints of the patients were evaluated with ocular surface disease index (OSDI) scores and the corneal sensation was evaluated with Cochet-Bonnet esthesiometer.ResultsThere was no significant difference between the groups for age, sex, and visual acuity. Both SIT (16.1 mm vs 15.3 mm, P=0.36) and TBUT results (17.8 s vs 18.8 s, P=0.40) were similar in FM group and the controls subjects. However, corneal sensations in central (60.0 mm vs 55.0 mm, P=0.03), superior (57.5 mm vs 50.0 mm, P=0.005), and inferior (53.89 mm vs 46.03 mm, P<0.001) regions were significantly increased in FM patients. There was a significant positive correlation between corneal sensation and OSDI scores.ConclusionIn this study, we have demonstrated that the patients with FM have increased corneal sensitivity and have related ocular surface complaints similar to dry eye disease in the absence of it. PMID- 29386616 TI - Bruch's membrane opening-based optical coherence tomography of the optic nerve head: a useful diagnostic tool to detect glaucoma in macrodiscs. AB - PurposeTo compare Bruch's membrane opening (BMO)-based spectral domain optical coherence tomography (SD-OCT) and margin based confocal scanning laser tomography (CSLT) of the optic nerve head (ONH) to visual field function in large optic discs (macrodiscs) and to assess performance for glaucoma detection.MethodsIn a case-control, cross-sectional study, 125 eyes of 125 patients with disc size >2.45 mm2, thereof 44 glaucoma and 11 ocular hypertension (OHT) patients and 70 healthy controls underwent SD-OCT and CSLT examination, visual field testing and clinical evaluation. Mean outcome measures BMO-based minimum rim width (BMO-MRW), retinal nerve fiber layer thickness (RNFLT) in SD-OCT, and rim area measured in CSLT were compared and correlated to visual field function.ResultsAll participants had a mean disc area of 2.91+/-0.38 mm2 in CSLT and a BMO area of 2.45+/-0.39 mm2 (r=0.76;P<0.001). In glaucoma patients, visual field mean deviation was -10.0+/-6.1 dB. Global BMO-MRW correlated better to visual field function (Spearman's Rho (rho)=0.71; P<0.001) than RNFLT (rho=0.52;P<0.001) and CSLT rim area (rho=0.63; P<0.001). BMO-MRW was significantly decreased with higher visual field loss (P<0.001). In ROC analysis, diagnostic power to differentiate glaucoma patients and healthy controls was highest for BMO-MRW (Area under curve, AUC=0.96; sensitivity at 95% specificity=82%). Rim area in CSLT (AUC=0.91; sensitivity=61.0%; P=0.04) and RNFLT (AUC=0.89; sensitivity=61%; P=0.01) were significantly less powerful.ConclusionsIn macrodiscs, BMO-MRW has the best diagnostic power to discriminate glaucoma patients from normal controls compared to RNFLT and rim area in CSLT. Additionally, BMO-MRW seems to reflect the structure-function relationship better than the other two parameters. PMID- 29386617 TI - Microbial keratitis in corneal grafts: predisposing factors and outcomes. AB - PurposeTo identify the nature of microbial keratitis in corneal grafts and the clinical outcomes at a tertiary hospital in the United Kingdom.Patients and methodsA retrospective case series of microbial keratitis in corneal grafts at the Royal Victoria Infirmary, Newcastle upon Tyne over a 17-year period (1997 2014).ResultsA total of 759 consecutive corneal grafts were identified from the Cornea Transplantation database. Of these, 59 episodes of microbial keratitis occurred in 41 eyes of 41 patients (5.4%; 19 male, 46.3%). Median patient age was 73 years (SD=19.4 years). The most common indication for corneal transplantation was bullous keratopathy (11/41, 26.8%). There were 34/59 (57.6%) episodes of culture-positive graft keratitis; Streptococcus pneumoniae and Staphylococcus aureus were each isolated in 5/34 (14.7%) culture-positive episodes. In all, 35/59 (59.3%) episodes of microbial keratitis occurred in 22 previously failed grafts and 3 de novo graft failures. Gram-negative keratitis was more likely to cause reduced BCVA after (chi2-test, P=0.02). Median graft duration was 49.5 months (SD=43.7 months). Failed grafts were significantly older (median 69 vs 27 months, P=0.009).ConclusionThis represents the longest published follow-up data on microbial keratitis and is the only of its kind in the United Kingdom. The incidence of 5.4% is comparable to that within the developed world. Graft age was significantly associated with graft failure in microbial keratitis; the ongoing risk of microbial keratitis warrants providing patients with long-term open access to hospital eye services. PMID- 29386618 TI - Botulinum toxin as an initial therapy for management of sixth nerve palsies caused by nasopharyngeal carcinomas. AB - PurposeThe purpose of this study is to evaluate the efficacy and safety of botulinum toxin injection as a primary treatment for strabismus in a cohort of patients with nasopharyngeal carcinoma (NPC)-related chronic sixth nerve palsy.Patients and methodsWe retrospectively reviewed all cases of NPC-related sixth nerve palsy receiving botulinum toxin injection in the Hong Kong Eye Hospital between January 2009 and January 2016. Only cases with diplopia for at least 6 months; and failed a trial of Fresnel prism therapy were recruited. We excluded cases with prior strabismus surgery and multiple cranial nerve palsies. Patients were offered botulinum toxin injection as primary treatment for their strabismus and were given further injections or offered surgery if diplopia persisted. Success with botulinum toxin was defined as a final distant orthophoria of <15 PD in primary gaze, no diplopia in primary position, and no head turn, as measured 6 months after the last injection, without requiring a second treatment.ResultsA total of 25 patients were included in the study. All patients received concurrent chemo-radiotherapy for NPC. There was a statistically significant reduction in the mean deviation at distant after the last injection compared to that at presentation (P<0.001, Wilcoxin signed rank test). Overall, 7 patients (28%) achieved clinical success and 15 patients (64%) remained diplopia-free by repeated botulinum toxin injections alone. Nine patients went on to receive definitive surgery and all achieved good ocular alignment after surgery. Transient ptosis or vertical deviation was seen in 7 patients, which resolved within 3 months and no serious complications arose from the treatment in our series.ConclusionsBotulinum toxin injection is a relatively less-invasive alternative to surgery that can be done under a topical anesthesia setting, which improves patient's quality of life via reduction in diplopia. It is a recommendable initial option in patients with chronic nerve palsies who may have higher risks associated with strabismus surgery. PMID- 29386619 TI - Cataract surgery patient-reported outcome measures: a head-to-head comparison of the psychometric performance and patient acceptability of the Cat-PROM5 and Catquest-9SF self-report questionnaires. AB - Background Cataract surgery is the most frequently undertaken NHS surgical procedure. Visual acuity (VA) provides a poor indication of visual difficulty in a complex visual world. In the absence of a suitable outcome metric, recent efforts have been directed towards the development of a cataract patient-reported outcome measure (PROM) of sufficient brevity, precision, and responsiveness to be implementable in routine high volume clinical services.Aim To compare and contrast the two most promising candidate PROMs for routine cataract surgery.Method The psychometric performance and patient acceptability of the recently UK developed five-item Cat-PROM5 questionnaire was compared with the English translation of the Swedish nine-item Catquest-9SF using Rasch-based performance metrics and qualitative semistructured interviews.Results Rasch-based performance was assessed in 822 typical NHS cataract surgery patients across four centres in England. Both questionnaires demonstrated good to excellent performance for all metrics assessed, including Person Reliability Indices of 0.90 (Cat-PROM5) and 0.88 (Catquest-9SF), responsiveness to surgery (Cohen's standardized effect size) of 1.45 SD (Cat-PROM5) and 1.47 SD (Catquest-9SF) and they were highly correlated with each other (R=0.85). Qualitative assessments confirmed that both questionnaires were acceptable to patients, including in the presence of ocular comorbidities. Preferences were expressed for the shorter Cat PROM5, which allowed patients to map their own issues to the questions as opposed to the more restrictive specific scenarios of Catquest-9SF.Conclusion The recently UK developed Cat-PROM5 cataract surgery questionnaire is shorter, with performance and patient acceptability at least as good or better than the previous 'best of class' Catquest-9SF instrument. PMID- 29386621 TI - Nucleotide resolution mapping of influenza A virus nucleoprotein-RNA interactions reveals RNA features required for replication. AB - Influenza A virus nucleoprotein (NP) association with viral RNA (vRNA) is essential for packaging, but the pattern of NP binding to vRNA is unclear. Here we applied photoactivatable ribonucleoside enhanced cross-linking and immunoprecipitation (PAR-CLIP) to assess the native-state of NP-vRNA interactions in infected human cells. NP binds short fragments of RNA (~12 nucleotides) non uniformly and without apparent sequence specificity. Moreover, NP binding is reduced at specific locations within the viral genome, including regions previously identified as required for viral genome segment packaging. Synonymous mutations designed to alter the predicted RNA structures in these low-NP-binding regions impact genome packaging and result in virus attenuation, whereas control mutations or mutagenesis of NP-bound regions have no effect. Finally, we demonstrate that the sequence conservation of low-NP-binding regions is required in multiple genome segments for propagation of diverse mammalian and avian IAV in host cells. PMID- 29386620 TI - Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. AB - Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram positive bacteria poses a viable therapeutic alternative for highly drug resistant Gram-negative pathogens expressing mcr-1. PMID- 29386622 TI - Taxonomy of anaerobic digestion microbiome reveals biases associated with the applied high throughput sequencing strategies. AB - In the past few years, many studies investigated the anaerobic digestion microbiome by means of 16S rRNA amplicon sequencing. Results obtained from these studies were compared to each other without taking into consideration the followed procedure for amplicons preparation and data analysis. This negligence was mainly due to the lack of knowledge regarding the biases influencing specific steps of the microbiome investigation process. In the present study, the main technical aspects of the 16S rRNA analysis were checked giving special attention to the approach used for high throughput sequencing. More specifically, the microbial compositions of three laboratory scale biogas reactors were analyzed before and after addition of sodium oleate by sequencing the microbiome with three different approaches: 16S rRNA amplicon sequencing, shotgun DNA and shotgun RNA. This comparative analysis revealed that, in amplicon sequencing, abundance of some taxa (Euryarchaeota and Spirochaetes) was biased by the inefficiency of universal primers to hybridize all the templates. Reliability of the results obtained was also influenced by the number of hypervariable regions under investigation. Finally, amplicon sequencing and shotgun DNA underestimated the Methanoculleus genus, probably due to the low 16S rRNA gene copy number encoded in this taxon. PMID- 29386623 TI - Locating Order-Disorder Phase Transition in a Cardiac System. AB - To prevent sudden cardiac death, predicting where in the cardiac system an order disorder phase transition into ventricular fibrillation begins is as important as when it begins. We present a computationally efficient, information-theoretic approach to predicting the locations of the wavebreaks. Such wavebreaks initiate fibrillation in a cardiac system where the order-disorder behavior is controlled by a single driving component, mimicking electrical misfiring from the pulmonary veins or from the Purkinje fibers. Communication analysis between the driving component and each component of the system reveals that channel capacity, mutual information and transfer entropy can locate the wavebreaks. This approach is applicable to interventional therapies to prevent sudden death, and to a wide range of systems to mitigate or prevent imminent phase transitions. PMID- 29386624 TI - A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. AB - Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression. PMID- 29386625 TI - Crystal structure of a Ca2+-dependent regulator of flagellar motility reveals the open-closed structural transition. AB - Sperm chemotaxis toward a chemoattractant is very important for the success of fertilization. Calaxin, a member of the neuronal calcium sensor protein family, directly acts on outer-arm dynein and regulates specific flagellar movement during sperm chemotaxis of ascidian, Ciona intestinalis. Here, we present the crystal structures of calaxin both in the open and closed states upon Ca2+ and Mg2+ binding. The crystal structures revealed that three of the four EF-hands of a calaxin molecule bound Ca2+ ions and that EF2 and EF3 played a critical role in the conformational transition between the open and closed states. The rotation of alpha7 and alpha8 helices induces a significant conformational change of a part of the alpha10 helix into the loop. The structural differences between the Ca2+- and Mg2+-bound forms indicates that EF3 in the closed state has a lower affinity for Mg2+, suggesting that calaxin tends to adopt the open state in Mg2+-bound form. SAXS data supports that Ca2+-binding causes the structural transition toward the closed state. The changes in the structural transition of the C terminal domain may be required to bind outer-arm dynein. These results provide a novel mechanism for recognizing a target protein using a calcium sensor protein. PMID- 29386626 TI - Strong constraint on modelled global carbon uptake using solar-induced chlorophyll fluorescence data. AB - Accurate terrestrial biosphere model (TBM) simulations of gross carbon uptake (gross primary productivity - GPP) are essential for reliable future terrestrial carbon sink projections. However, uncertainties in TBM GPP estimates remain. Newly-available satellite-derived sun-induced chlorophyll fluorescence (SIF) data offer a promising direction for addressing this issue by constraining regional-to global scale modelled GPP. Here, we use monthly 0.5 degrees GOME-2 SIF data from 2007 to 2011 to optimise GPP parameters of the ORCHIDEE TBM. The optimisation reduces GPP magnitude across all vegetation types except C4 plants. Global mean annual GPP therefore decreases from 194 +/- 57 PgCyr-1 to 166 +/- 10 PgCyr-1, bringing the model more in line with an up-scaled flux tower estimate of 133 PgCyr-1. Strongest reductions in GPP are seen in boreal forests: the result is a shift in global GPP distribution, with a ~50% increase in the tropical to boreal productivity ratio. The optimisation resulted in a greater reduction in GPP than similar ORCHIDEE parameter optimisation studies using satellite-derived NDVI from MODIS and eddy covariance measurements of net CO2 fluxes from the FLUXNET network. Our study shows that SIF data will be instrumental in constraining TBM GPP estimates, with a consequent improvement in global carbon cycle projections. PMID- 29386627 TI - The consequences of niche and physiological differentiation of archaeal and bacterial ammonia oxidisers for nitrous oxide emissions. AB - High and low rates of ammonium supply are believed to favour ammonia-oxidising bacteria (AOB) and archaea (AOA), respectively. Although their contrasting affinities for ammonium are suggested to account for these differences, the influence of ammonia concentration on AOA and AOB has not been tested under environmental conditions. In addition, while both AOB and AOA contribute to nitrous oxide (N2O) emissions from soil, N2O yields (N2O-N produced per NO2--N generated from ammonia oxidation) of AOA are lower, suggesting lower emissions when AOA dominate ammonia oxidation. This study tested the hypothesis that ammonium supplied continuously at low rates is preferentially oxidised by AOA, with lower N2O yield than expected for AOB-dominated processes. Soil microcosms were supplied with water, urea or a slow release, urea-based fertiliser and 1 octyne (inhibiting only AOB) was applied to distinguish AOA and AOB activity and associated N2O production. Low ammonium supply, from mineralisation of organic matter, or of the fertiliser, led to growth, ammonia oxidation and N2O production by AOA only, with low N2O yield. High ammonium supply, from free urea within the fertiliser or after urea addition, led to growth of both groups, but AOB dominated ammonia oxidation was associated with twofold greater N2O yield than that dominated by AOA. This study therefore demonstrates growth of both AOA and AOB at high ammonium concentration, confirms AOA dominance during low ammonium supply and suggests that slow release or organic fertilisers potentially mitigate N2O emissions through differences in niche specialisation and N2O production mechanisms in AOA and AOB. PMID- 29386629 TI - Molecular interaction of 1-aminocyclopropane-1-carboxylate deaminase (ACCD) producing endophytic Streptomyces sp. GMKU 336 towards salt-stress resistance of Oryza sativa L. cv. KDML105. AB - 1-aminocyclopropane-1-carboxylate deaminase (ACCD)-producing endophytic Streptomyces sp. GMKU 336 and its ACCD-deficient mutant were inoculated into Thai jasmine rice Khao Dok Mali 105 cultivar (Oryza sativa L. cv. KDML105) under salt stress (150 mM NaCl) conditions. The results clearly indicated that Streptomyces sp. GMKU 336 significantly increased plant growth, chlorophyll, proline, K+, Ca+, and water contents; but decreased ethylene, reactive oxygen species (ROS), Na+, and Na+/K+ ratio when compared to plants not inoculated and those inoculated with the ACCD-deficient mutant. Expression profiles of stress responsive genes in rice in association with strain GMKU 336 were correlated to plant physiological characteristics. Genes involved in the ethylene pathway, ACO1 and EREBP1, were significantly down-regulated; while acdS encoding ACCD in Streptomyces sp. GMKU 336 was up-regulated in vivo. Furthermore, genes involved in osmotic balance (BADH1), Na+ transporters (NHX1 and SOS1), calmodulin (Cam1-1), and antioxidant enzymes (CuZn-SOD1 and CATb) were up-regulated; whereas, a gene implicated in a signaling cascade, MAPK5, was down-regulated. This work demonstrates the first time that ACCD-producing Streptomyces sp. GMKU 336 enhances growth of rice and increases salt tolerance by reduction of ethylene via the action of ACCD and further assists plants to scavenge ROS, balance ion content and osmotic pressure. PMID- 29386628 TI - Single-cell measurement of ammonium and bicarbonate uptake within a photosymbiotic bioeroding sponge. AB - Some of the most aggressive coral-excavating sponges host intracellular dinoflagellates from the genus Symbiodinium, which are hypothesized to provide the sponges with autotrophic energy that powers bioerosion. Investigations of the contribution of Symbiodinium to host metabolism and particularly inorganic nutrient recycling are complicated, however, by the presence of alternative prokaryotic candidates for this role. Here, novel methods are used to study nutrient assimilation and transfer within and between the outer-layer cells of the Indopacific bioeroding sponge Cliona orientalis. Combining stable isotope labelling, transmission electron microscopy (TEM) and nanoscale secondary ion mass spectrometry (NanoSIMS), we visualize and measure metabolic activity at the individual cell level, tracking the fate of 15N-ammonium and 13C-bicarbonate within the intact holobiont. We found strong uptake of both inorganic sources (especially 13C-bicarbonate) by Symbiodinium cells. Labelled organic nutrients were translocated from Symbiodinium to the Symbiodinium-hosting sponge cells within 6 h, and occasionally to other sponge cells within 3 days. By contrast, prokaryotic symbionts were not observed to participate in inorganic nutrient assimilation in the outer layers of the sponge. Our findings strongly support the metabolic interaction between the sponge and dinoflagellates, shedding light on the ecological advantages and adaptive capacity of photosymbiotic bioeroding sponges in oligotrophic marine habitats. PMID- 29386630 TI - Quantifying the influence of temperature on hand, foot and mouth disease incidence in Wuhan, Central China. AB - Hand, foot and mouth disease (HFMD) is a substantial burden throughout Asia, but the effects of temperature pattern on HFMD risk are inconsistent. To quantify the effect of temperature on HFMD incidence, Wuhan was chosen as the study site because of its high temperature variability and high HFMD incidence. Daily series of HFMD counts and meteorological variables during 2010-2015 were obtained. Distributed lag non-linear models were applied to characterize the temperature HFMD relationship and to assess its variability across different ages, genders, and types of child care. Totally, 80,219 patients of 0-5 years experienced HFMD in 2010-2015 in Wuhan. The cumulative relative risk of HFMD increased linearly with temperature over 7 days (lag0-7), while it presented as an approximately inverted V-shape over 14 days (lag0-14). The cumulative relative risk at lag0-14 peaked at 26.4 degrees C with value of 2.78 (95%CI: 2.08-3.72) compared with the 5th percentile temperature (1.7 degrees C). Subgroup analyses revealed that children attended daycare were more vulnerable to temperature variation than those cared for at home. This study suggests that public health actions should take into consideration local weather conditions and demographic characteristics. PMID- 29386631 TI - The intrinsically disordered Tarp protein from chlamydia binds actin with a partially preformed helix. AB - Tarp (translocated actin recruiting phosphoprotein) is an effector protein common to all chlamydial species that functions to remodel the host-actin cytoskeleton during the initial stage of infection. In C. trachomatis, direct binding to actin monomers has been broadly mapped to a 100-residue region (726-825) which is predicted to be predominantly disordered, with the exception of a ~10-residue alpha-helical patch homologous to other WH2 actin-binding motifs. Biophysical investigations demonstrate that a Tarp726-825 construct behaves as a typical intrinsically disordered protein; within it, NMR relaxation measurements and chemical shift analysis identify the ten residue WH2-homologous region to exhibit partial alpha-helix formation. Isothermal titration calorimetry experiments on the same construct in the presence of monomeric G-actin show a well defined binding event with a 1:1 stoichiometry and Kd of 102 nM, whilst synchrotron radiation circular dichroism spectroscopy suggests the binding is concomitant with an increase in helical secondary structure. Furthermore, NMR experiments in the presence of G-actin indicate this interaction affects the proposed WH2-like alpha-helical region, supporting results from in silico docking calculations which suggest that, when folded, this alpha-helix binds within the actin hydrophobic cleft as seen for other actin-associated proteins. PMID- 29386632 TI - A 5-year field study showed no apparent effect of the Bt transgenic 741 poplar on the arthropod community and soil bacterial diversity. AB - China is currently the only country that has commercialized genetically engineered tree species, and this has attracted worldwide attention. As a perennial tree species, transgenic poplar has a long growth cycle and needs to be tested for long-term ecological risks. The main purpose of this study was to explore the ecological safety of perennial transgenic poplars in arthropod community, physical and chemical properties of soil, gene flow, and soil microbial diversity. The study found transgenic poplars could effectively inhibit the number of pests. Moreover, transgenic poplar 741 did not affect the stability of the arthropod community. Studies on the microbial diversity of poplar showed that transgenic poplars did not affect the physical and chemical properties of the soil and the soil microbial community structure. Furthermore, the microbial community structure was obviously affected by location and season. The results showed that a 5-year-old transgenic 741 poplar did not pose an ecological risk, and did not affect the microbial community structure or functional diversity. This study provides a reference for the ecological security evaluation of transgenic poplars, and provides a theoretical basis for promoting the commercialization of transgenic poplars. PMID- 29386633 TI - A peculiar low-luminosity short gamma-ray burst from a double neutron star merger progenitor. AB - Double neutron star (DNS) merger events are promising candidates of short gamma ray burst (sGRB) progenitors as well as high-frequency gravitational wave (GW) emitters. On August 17, 2017, such a coinciding event was detected by both the LIGO-Virgo gravitational wave detector network as GW170817 and Gamma-Ray Monitor on board NASA's Fermi Space Telescope as GRB 170817A. Here, we show that the fluence and spectral peak energy of this sGRB fall into the lower portion of the distributions of known sGRBs. Its peak isotropic luminosity is abnormally low. The estimated event rate density above this luminosity is at least [Formula: see text] Gpc-3 yr-1, which is close to but still below the DNS merger event rate density. This event likely originates from a structured jet viewed from a large viewing angle. There are similar faint soft GRBs in the Fermi archival data, a small fraction of which might belong to this new population of nearby, low luminosity sGRBs. PMID- 29386634 TI - Engraftment of Human Pluripotent Stem Cell-derived Progenitors in the Inner Ear of Prenatal Mice. AB - There is, at present, no curative treatment for genetic hearing loss. We have previously reported that transuterine gene transfer of wild type CONNEXIN30 (CX30) genes into otocysts in CX30-deleted mice could restore hearing. Cell transplantation therapy might be another therapeutic option, although it is still unknown whether stem cell-derived progenitor cells could migrate into mouse otocysts. Here, we show successful cell transplantation of progenitors of outer sulcus cell-like cells derived from human-derived induced pluripotent stem cells into mouse otocysts on embryonic day 11.5. The delivered cells engrafted more frequently in the non-sensory region in the inner ear of CX30-deleted mice than in wild type mice and survived for up to 1 week after transplantation. Some of the engrafted cells expressed CX30 proteins in the non-sensory region. This is the first report that demonstrates successful engraftment of exogenous cells in prenatal developing otocysts in mice. Future studies using this mouse otocystic injection model in vivo will provide further clues for developing treatment modalities for congenital hearing loss in humans. PMID- 29386635 TI - An optimal strategy to solve the Prisoner's Dilemma. AB - Cooperation is a central mechanism for evolution. It consists of an individual paying a cost in order to benefit another individual. However, natural selection describes individuals as being selfish and in competition among themselves. Therefore explaining the origin of cooperation within the context of natural selection is a problem that has been puzzling researchers for a long time. In the paradigmatic case of the Prisoner's Dilemma (PD), several schemes for the evolution of cooperation have been proposed. Here we introduce an extension of the Replicator Equation (RE), called the Optimal Replicator Equation (ORE), motivated by the fact that evolution acts not only at the level of individuals of a population, but also among competing populations, and we show that this new model for natural selection directly leads to a simple and natural rule for the emergence of cooperation in the most basic version of the PD. Contrary to common belief, our results reveal that cooperation can emerge among selfish individuals because of selfishness itself: if the final reward for being part of a society is sufficiently appealing, players spontaneously decide to cooperate. PMID- 29386636 TI - Adherence to diet recommendations and risk of abdominal aortic aneurysm in the Malmo Diet and Cancer Study. AB - The research examining the association between quality of diet and abdominal aortic aneurysm (AAA) is scarce. The aim of the present study was to explore the association between diet quality and development of AAA for middle-aged individuals in the Malmo Diet and Cancer Study (MDCS), a prospective cohort study with baseline data collection carried out between 1991 and 1996. At baseline, the study participants who were eligible for this study (n = 26133) documented their dietary habits in a food diary and questionnaire. Incident AAA cases during an average of 20.7 years of follow-up were identified by using registers. A diet quality index consisting of six components, saturated fat, polyunsaturated fat, fibre, sucrose, fruits and vegetables and fish and shellfish, was used to assess the diet quality. After adjusting for potential confounders, the diet quality index was not associated with incident AAA. However, a tendency of decreased risk was observed among individuals adhering to recommendations for fruit and vegetables compared with non-adherence. When comparing the risk of more extreme intake groups, high intakes of both fruits and vegetables were associated with decreased risk. PMID- 29386637 TI - Ultrathin graphene oxide membranes on freestanding carbon nanotube supports for enhanced selective permeation in organic solvents. AB - Among the various factors required for membranes in organic solvent separations, the stability of membrane supports is critical in the preparation of membranes with universal chemical stability, mechanical flexibility, and high flux. In this study, nanoporous freestanding carbon nanotube (CNT) films were fabricated and utilized as supports for enhanced permeation in organic solvents. The excellent chemical stability of the CNT support allowed it to withstand various organic solvents such as toluene, acetone, and dimethylformamide. In addition, the structural stability and high pore density of CNT supports allowed the deposition of an ultrathin selective layer for an enhanced-flux membrane. Membrane performance was demonstrated by depositing a thin graphene oxide (GO) layer on the CNT support; GO was selected because of its high chemical stability. CNT supported GO membranes effectively blocked molecules with molecular weight larger than ~800 g mol-1 while allowing the fast permeation of small molecules such as naphthalene (permeation was 50 times faster than that through thick GO membranes) and maintaining selective permeation in harsh solvents even after 72 hours of operation. We believe that the developed CNT support can provide fundamental insights in utilizing selective materials toward organic solvent membranes. PMID- 29386638 TI - Methylation-based enrichment facilitates low-cost, noninvasive genomic scale sequencing of populations from feces. AB - Obtaining high-quality samples from wild animals is a major obstacle for genomic studies of many taxa, particularly at the population level, as collection methods for such samples are typically invasive. DNA from feces is easy to obtain noninvasively, but is dominated by bacterial and other non-host DNA. The high proportion of non-host DNA drastically reduces the efficiency of high-throughput sequencing for host animal genomics. To address this issue, we developed an inexpensive capture method for enriching host DNA from noninvasive fecal samples. Our method exploits natural differences in CpG-methylation density between vertebrate and bacterial genomes to preferentially bind and isolate host DNA from majority-bacterial samples. We demonstrate that the enrichment is robust, efficient, and compatible with downstream library preparation methods useful for population studies (e.g., RADseq). Compared to other enrichment strategies, our method is quick and inexpensive, adding only a negligible cost to sample preparation. In combination with downstream methods such as RADseq, our approach allows for cost-effective and customizable genomic-scale genotyping that was previously feasible in practice only with invasive samples. Because feces are widely available and convenient to collect, our method empowers researchers to explore genomic-scale population-level questions in organisms for which invasive sampling is challenging or undesirable. PMID- 29386639 TI - From genes to networks. PMID- 29386640 TI - Invasions reduce fire-risk. PMID- 29386643 TI - Mitochondrial genetic haplogroups and incident obesity: a longitudinal cohort study. AB - BACKGROUND/OBJECTIVES: A small number of case-control studies have suggested that mitochondrial haplogroups could be associated with obesity. We examined whether obesity risk was influenced by mitochondrial haplogroup in a large North American cohort across an 8-year period. We conducted a longitudinal cohort study including individuals from the Osteoarthritis Initiative. SUBJECTS/METHODS: Mitochondrial haplogroups were determined by sequencing and PCR-RFLP techniques using this nomenclature: HV, JT, KU, IWX, and super HV/others. The strength of the association between mitochondrial haplogroups and incident obesity was quantified with hazard ratios (HRs), adjusted for potential confounders using a Cox's regression analysis. RESULTS: Overall, 2342 non-obese Caucasian participants (56.7% women) with a mean +/- SD age of 62.0 +/- 9.5 years at baseline were included. During a median follow-up of 8 years, 334 individuals ( = 14.3% of baseline population) became obese. After adjusting for nine potential confounders, the haplogroups IWX carried a significant 48% higher risk of obesity (HR = 1.48; 95% CI: 1.02-2.39) compared to the HV haplotype (the most frequent type). CONCLUSION: Only the presence of the IWX haplogroups appears to be linked to increased obesity risk, independent of potential baseline confounders. Future cohort studies are needed to confirm these findings and to determine potential underlying mechanisms. PMID- 29386642 TI - Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. AB - Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor. PMID- 29386641 TI - A naturally occurring epiallele associates with leaf senescence and local climate adaptation in Arabidopsis accessions. AB - Epigenetic variation has been proposed to facilitate adaptation to changing environments, but evidence that natural epialleles contribute to adaptive evolution has been lacking. Here we identify a retrotransposon, named "NMR19" (naturally occurring DNA methylation variation region 19), whose methylation and genomic location vary among Arabidopsis thaliana accessions. We classify NMR19 as NMR19-4 and NMR19-16 based on its location, and uncover NMR19-4 as an epiallele that controls leaf senescence by regulating the expression of PHEOPHYTIN PHEOPHORBIDE HYDROLASE (PPH). We find that the DNA methylation status of NMR19-4 is stably inherited and independent of genetic variation. In addition, further analysis indicates that DNA methylation of NMR19-4 correlates with local climates, implying that NMR19-4 is an environmentally associated epiallele. In summary, we discover a novel epiallele, and provide mechanistic insights into its origin and potential function in local climate adaptation. PMID- 29386644 TI - Femoral ontogeny in humans and great apes and its implications for their last common ancestor. AB - Inferring the morphology of the last common ancestor of humans, chimpanzees and gorillas is a matter of ongoing debate. Recent findings and reassessment of fossil hominins leads to the hypothesis that the last common ancestor was not extant African ape-like. However, an African great-ape-like ancestor with knuckle walking features still remains plausible and the most parsimonious scenario. Here we address this question via an evolutionary developmental approach, comparing taxon-specific patterns of shape change of the femoral diaphysis from birth to adulthood in great apes, humans, and macaques. While chimpanzees and gorillas exhibit similar locomotor behaviors, our data provide evidence for distinct ontogenetic trajectories, indicating independent evolutionary histories of femoral ontogeny. Our data further indicate that anthropoid primates share a basic pattern of femoral diaphyseal ontogeny that reflects shared developmental constraints. Humans escaped from these constraints via differential elongation of femur. PMID- 29386645 TI - Distribution of glycated haemoglobin and its determinants in Korean youth and young adults: a nationwide population-based study. AB - The present study aimed to describe the distribution of and to investigate the factors associated with glycated haemoglobin (HbA1c) values in Korean youth (10 19 years old) and young adults (20-29 years old). Data from the Korea Health and Nutrition Examination Survey (2011-2015) were used. A total of 6,418 participants (male 3,140 [53.2%]) aged 10-29 years were included in the analysis. Percentiles of HbA1c were calculated and HbA1c values were compared according to age, sex, and associated factors. The mean HbA1c values (% [mmol/mol]) were 5.42 +/- 0.01 (35.7 +/- 0.1) for youths and 5.32 +/- 0.01 (34.7 +/- 0.1) for young adults (P < 0.001). Male participants showed significantly higher HbA1c level than females (P < 0.001). When age was grouped into 5-year intervals, HbA1c was the highest in those aged 10-14 years and the lowest in those aged 20-24 years. After controlling for confounding variables, the HbA1c values of youths and male participants were significantly higher than those of young adults and female participants. The present study provides nationally representative data on the distribution of HbA1c values in Korean youth and young adults. There were significant differences in the level of HbA1c according to age and sex. PMID- 29386646 TI - "Gilbert's-like" syndrome as part of a spectrum of persistent unconjugated hyperbilirubinemia in post-chronic hepatitis patients. AB - Gilbert's syndrome (GS) patients present with remittent unconjugated hyperbilirubinemia. In this study, we investigated the correlation between polymorphisms in the gene encoding UDP-glucuronosyltransferase, UGT1A1, and the development of unconjugated hyperbilirubinemia in clinical GS and post-hepatitis hyperbilirubinemia. Blood samples were collected from 285 patients, including 85 patients who were clinically diagnosed with GS, 70 patients who had indirect hyperbilirubinemia during the recovery period of chronic liver diseases, 109 patients with normal hepatic function and 21 chronic active hepatitis patients. All samples were tested for the presence of the *28/*6 UGT1A1 genotype by pyrosequencing. Compared with the GS-control group, a significant difference in variations of the UGT1A1*28/*6 allele gene was found in GS patients. The post hepatitis group showed a significant difference in the UGT1A1*28/*6 allele gene frequency distribution relative to that in the hepatitis control group. There were no significant differences between the GS group and post-hepatitis group in the distribution of the UGT1A1*28/*6 allele gene frequency and UGT1A1 diplotypes. UGT1A1*28/*6 gene polymorphisms in patients who had indirect hyperbilirubinemia while recovering from chronic liver diseases presented similar patterns as those seen for GS patients. These findings suggest that a "Gilbert's-like" syndrome might be part of the spectrum of persistent unconjugated hyperbilirubinemia in post-chronic hepatitis patients. PMID- 29386647 TI - Structural basis of the molecular ruler mechanism of a bacterial glycosyltransferase. AB - The membrane-associated, processive and retaining glycosyltransferase PglH from Campylobacter jejuni is part of the biosynthetic pathway of the lipid-linked oligosaccharide (LLO) that serves as the glycan donor in bacterial protein N glycosylation. Using an unknown counting mechanism, PglH catalyzes the transfer of exactly three alpha1,4 N-acetylgalactosamine (GalNAc) units to the growing LLO precursor, GalNAc-alpha1,4-GalNAc-alpha1,3-Bac-alpha1-PP-undecaprenyl. Here, we present crystal structures of PglH in three distinct states, including a binary complex with UDP-GalNAc and two ternary complexes containing a chemo enzymatically generated LLO analog and either UDP or synthetic, nonhydrolyzable UDP-CH2-GalNAc. PglH contains an amphipathic helix ("ruler helix") that has a dual role of facilitating membrane attachment and glycan counting. The ruler helix contains three positively charged side chains that can bind the pyrophosphate group of the LLO substrate and thus limit the addition of GalNAc units to three. These results, combined with molecular dynamics simulations, provide the mechanism of glycan counting by PglH. PMID- 29386649 TI - Photonic Generation of High Power, Ultrastable Microwave Signals by Vernier Effect in a Femtosecond Laser Frequency Comb. AB - Optical frequency division of an ultrastable laser to the microwave frequency range by an optical frequency comb has allowed the generation of microwave signals with unprecedently high spectral purity and stability. However, the generated microwave signal will suffer from a very low power level if no external optical frequency comb repetition rate multiplication device is used. This paper reports theoretical and experimental studies on the beneficial use of the Vernier effect together with the spectral selective filtering in a double directional coupler add-drop optical fibre ring resonator to increase the comb repetition rate and generate high power microwaves. The studies are focused on two selective filtering aspects: the high rejection of undesirable optical modes of the frequency comb and the transmission of the desirable modes with the lowest possible loss. Moreover, the conservation of the frequency comb stability and linewidth at the resonator output is particularly considered. Accordingly, a fibre ring resonator is designed, fabricated, and characterized, and a technique to stabilize the resonator's resonance comb is proposed. A significant power gain is achieved for the photonically generated beat note at 10 GHz. Routes to highly improve the performances of such proof-of-concept device are also discussed. PMID- 29386648 TI - Engineering yeast for the production of breviscapine by genomic analysis and synthetic biology approaches. AB - The flavonoid extract from Erigeron breviscapus, breviscapine, has increasingly been used to treat cardio- and cerebrovascular diseases in China for more than 30 years, and plant supply of E. breviscapus is becoming insufficient to satisfy the growing market demand. Here we report an alternative strategy for the supply of breviscapine by building a yeast cell factory using synthetic biology. We identify two key enzymes in the biosynthetic pathway (flavonoid-7-O glucuronosyltransferase and flavone-6-hydroxylase) from E. breviscapus genome and engineer yeast to produce breviscapine from glucose. After metabolic engineering and optimization of fed-batch fermentation, scutellarin and apigenin-7-O glucuronide, two major active ingredients of breviscapine, reach to 108 and 185 mg l-1, respectively. Our study not only introduces an alternative source of these valuable compounds, but also provides an example of integrating genomics and synthetic biology knowledge for metabolic engineering of natural compounds. PMID- 29386650 TI - Targeted Knockdown of Overexpressed VEGFA or VEGF164 in Muller cells maintains retinal function by triggering different signaling mechanisms. AB - Oxygen-induced retinopathy (OIR) upregulates Muller cell vascular endothelial growth factor A (VEGFA) that causes intravitreal neovascularization similar to severe retinopathy of prematurity (ROP). Safety concerns exist with anti-VEGF treatment for ROP. We evaluated long-term knockdown of Muller cell-VEGFA with short-hairpin RNAs to VEGFA or VEGF164 via subretinal lentivirus delivery (L VEGFAshRNA, L-VEGF164shRNA) on retinal structure and function in a rat OIR model. Lectin-stained retinal flat mounts analyzed for areas of avascular/total retina (AVA) and intravitreal neovascular/total retina (IVNV) showed initial significantly reduced IVNV by L-VEGFAshRNA and L-VEGF164shRNA compared to control, luciferase-shRNA lentivirus, without late recurrence. Spectral-domain optical coherence tomography (OCT) and immunohistochemical sections (IHC) demonstrated changes in retinal layer thicknesses in L-VEGFAshRNA or L VEGF164shRNA compared to control. Ganzfeld electroretinograms were increased in L-VEGFAshRNA or L-VEGF164shRNA compared to control. Erythropoietin (EPO), brain derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3) mRNAs were increased in L-VEGFAshRNA, but not L VEGF164shRNA retinas. In cultured rat Muller cells, knockdown of VEGF upregulated NT-3 and EPO, whereas treatment with EPO activated neuroprotective signaling. Methods to reduce IVNV by selective knockdown of VEGFA, and particularly VEGF164, in Muller cells may have fewer deleterious effects than nonselective VEGFA inhibition to all cells in the retina. PMID- 29386651 TI - Axial elongation measured by long scan depth optical coherence tomography during pilocarpine-induced accommodation in intraocular lens-implanted eyes. AB - We used an ultra-long scan depth optical coherence tomography (UL-OCT) system to investigate changes in axial biometry of pseudophakic eyes during pilocarpine- induced accommodation. The right eyes from 25 healthy subjects (age range 49 to 84 years) with an intraocular lens (IOL) were imaged twice in the non accommodative and the accommodative states. A custom-built UL-OCT instrument imaged the whole eye. Then accommodation was induced by two drops of 0.5% pilocarpine hydrochloride separated by a 5-minute interval. Following the same protocol, images were acquired again 30 minutes after the first drop. The central corneal thickness (CCT), anterior chamber depth (ACD), IOL thickness (IOLT), and vitreous length (VL) were obtained using custom automated software. The axial length (AL) was calculated by summing the CCT, ACD, IOLT, and VL. With accommodation, ACD increased by +0.08 +/- 0.09 mm, while the VL decreased by 0.04 +/- 0.09 mm (paired t-test each, P<0.05). CCT and IOLT remained constant during accommodation (P > 0.05). The non-accommodative AL was 23.47 +/- 0.93 mm, and it increased by +0.04 +/- 0.04 mm after accommodation (P<0.01). The AL increased and the IOL moved backward during pilocarpine-induced accommodation in pseudophakic eyes. PMID- 29386653 TI - Reflections on the early years of neonatology. Paul R. Swyer: the beginnings of Canadian neonatology at The Hospital for Sick Children in Toronto and insights into his early career. PMID- 29386652 TI - Quasi-reference electrodes in confined electrochemical cells can result in in situ production of metallic nanoparticles. AB - Nanoscale working electrodes and miniaturized electroanalytical devices are valuable platforms to probe molecular phenomena and perform chemical analyses. However, the inherent close distance of metallic electrodes integrated into a small volume of electrolyte can complicate classical electroanalytical techniques. In this study, we use a scanning nanopipette contact probe as a model miniaturized electrochemical cell to demonstrate measurable side effects of the reaction occurring at a quasi-reference electrode. We provide evidence for in situ generation of nanoparticles in the absence of any electroactive species and we critically analyze the origin, nucleation, dissolution and dynamic behavior of these nanoparticles as they appear at the working electrode. It is crucial to recognize the implications of using quasi-reference electrodes in confined electrochemical cells, in order to accurately interpret the results of nanoscale electrochemical experiments. PMID- 29386654 TI - Body size is more important than diet in determining stable-isotope estimates of trophic position in crocodilians. AB - The trophic position of a top predator, synonymous with food-chain length, is one of the most fundamental attributes of ecosystems. Stable isotope ratios of nitrogen (delta15N) have been used to estimate trophic position of organisms due to the predictable enrichment of 15N in consumer tissues relative to their diet. Previous studies in crocodilians have found upward ontogenetic shifts in their 'trophic position'. However, such increases are not expected from what is known about crocodilian diets because ontogenetic shifts in diet relate to taxonomic categories of prey rather than shifts to prey from higher trophic levels. When we analysed dietary information from the literature on the four Amazonian crocodilians, ontogenetic shifts in dietary-based trophic position (TPdiet) were minimal, and differed from those estimated using delta15N data (TPSIA). Thus, ontogenetic shifts in TPSIA may result not only from dietary assimilation but also from trophic discrimination factors (TDF or Delta 15N) associated with body size. Using a unique TDF value to estimate trophic position of crocodilians of all sizes might obscure conclusions about ontogenetic shifts in trophic position. Our findings may change the way that researchers estimate trophic position of organisms that show orders of magnitude differences in size across their life span. PMID- 29386655 TI - Evaluation of Weight Loss Indicators and Laparoscopic One-Anastomosis Gastric Bypass Outcomes. AB - Mini-gastric bypass/One-anastomosis gastric bypass (MGB-OAGB) is an effective bariatric technique for treating overweight and obesity, controlling and improving excess-weight-related comorbidities. Our study evaluated OAGB characteristics and resulting weight evolution, plus surgical success criteria based on various excess weight loss indicators. A prospective observational study of 100 patients undergoing OAGB performed by the same surgical team (two-year follow-up). Surgical characteristics were: surgery duration, associated complications, bowel loop length, hospital stay, and weight loss at 6 postoperative points. 100 patients were treated (71 women, 29 men); mean initial age was 42.61 years and mean BMI, 42.61 +/- 6.66 kg/m2. Mean surgery duration was 97.84 +/- 12.54 minutes; biliopancreatic loop length was 274.95 +/- 23.69 cm. Average hospital stay was 24 hours in 98% of patients; no surgical complications arose. Weight decreased significantly during follow-up (P < 0.001). Greatest weight loss was observed at 12 months postsurgery (68.56 +/- 13.10 kg). Relative weight loss showed significant positive correlation, with greatest weight loss at 12 months and %excess BMI loss > 50% achieved from the 3-month follow-up in 92.46% of patients. OAGB seems to be effective in treating obesity, with short hospital stays. Relative weight loss correlates optimally with absolute outcomes, but both measures should be used to evaluate surgical results. PMID- 29386656 TI - RTF: a rapid and versatile tissue optical clearing method. AB - Tissue optical clearing enables imaging deeper in large volumes with high resolution. Clear T2 is a relatively rapid clearing method with no use of solvents or detergents, hence poses great advantage on preservation of diverse fluorescent labels. However, this method suffers from insufficient tissue transparency, especially for adult mouse brain blocks. In this work, we develop a rapid and versatile clearing method based on Clear T2 , termed RTF (Rapid clearing method based on Triethanolamine and Formamide), aiming for better clearing capability. The results show that RTF can not only efficiently clear embryos, neonatal brains and adult brain blocks, but also preserve fluorescent signal of both endogenous fluorescent proteins and lipophilic dyes, and be compatible with virus labeling and immunostaining. With the good transparency and versatile compatibility, RTF allows visualization and tracing of fluorescent labeling cells and neuronal axons combined with different imaging techniques, showing potentials in facilitating observation of morphological architecture and visualization of neuronal networks. PMID- 29386657 TI - Outcome analyses of a multimodal treatment approach for deep pressure ulcers in spinal cord injuries: a retrospective cohort study. AB - STUDY DESIGN: Retrospective observational cohort study. OBJECTIVES: To describe outcomes, risk factors for complications, and relapse rates associated with the multimodal treatment approach for deep pressure ulcers (PUs) grade IV for the ischium, trochanter major, and sacral regions of patients with traumatic and non traumatic spinal cord injury (SCI). SETTING: The settings comprised two spinal cord units within a maximum care hospital. The treatment of all patients followed the modified interdisciplinary "Basler treatment concept". METHODS: We included all individuals with SCI with a first occurrence of PU grade IV in the buttocks area between August 2008 and December 2012 inclusive, with a maximum follow-up of 3 years. Descriptive, univariate, and bivariate analyses were undertaken, as were group comparisons. RESULTS: In 47 patients aged 18-87 years (mean age: 51 years) a total of 63 fasciocutaneous and myocutaneous flaps were performed. Wound healing was complete after a mean of 34 days (SD = 21). Postoperative mobilisation in a wheelchair was performed after a mean of 46 days (SD = 24). Delayed healing was reported in 18 patients (38%), and revision surgery was necessary in five patients (11%). ASIA impairment scale (AIS) A (p = .001), and male gender (p = .001) were identified as risk factors for delayed wound healing and prolonged inpatient stay. Treatment-associated pneumonia occurred in four cases (11% of all patients, 25% of patients with tetraplegia). Patients were discharged when the time spent sitting in a wheelchair was 2 * 2 h per day; this occurred after a mean of 100 days (SD = 36). PU recurrence was observed in six cases (18%). CONCLUSIONS: Our multimodal treatment concept was found to have complication rates comparable to those in the literature; additionally, this approach might be associated with lower recurrence rates with respect to the literature. To reduce high rates of pneumonia occurrence among patients with tetraplegia, preventive measures need to be established. Further evidence of the efficiency of this complex treatment approach for PU in individuals with SCI is needed. PMID- 29386658 TI - The Spinal Cord Ability Ruler (SCAR) complements the Spinal Cord Independence Measure (SCIM). PMID- 29386659 TI - Comments on the Spinal Cord Ability Ruler. PMID- 29386660 TI - Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation. AB - F-box and WD40 domain protein 7 (FBXW7) is a component of the SKP1-CUL1-F-box protein (SCF) complex that mediates the ubiquitination of diverse oncogenic target proteins. The exploration of FBXW7 mutations in human primary cancer has revealed three mutation hotspots at conserved arginine residues (Arg465, Arg479, and Arg505) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7 R465C , the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7 R468C corresponding to human FBXW7 R465C . Systemic heterozygous knockin of the Fbxw7 R468C mutation resulted in perinatal lethality due to defects in lung development, and occasionally caused an eyes-open at birth phenotype and cleft palate. Furthermore, mice carrying liver-specific heterozygous and homozygous Fbxw7 R468C alleles cooperated with an oncogenic Kras mutation to exhibit bile duct hyperplasia within 8 months of birth and cholangiocarcinoma-like lesions within 8 weeks of birth, respectively. In addition, the substrates affected by the mutant Fbxw7 differed between the embryos, embryonic fibroblasts, and adult liver. This novel conditional knockin Fbxw7 R468C line should be useful to gain a more profound understanding of carcinogenesis associated with mutation of FBXW7. PMID- 29386661 TI - AmrZ is a major determinant of c-di-GMP levels in Pseudomonas fluorescens F113. AB - The transcriptional regulator AmrZ is a global regulatory protein conserved within the pseudomonads. AmrZ can act both as a positive and a negative regulator of gene expression, controlling many genes implicated in environmental adaption. Regulated traits include motility, iron homeostasis, exopolysaccharides production and the ability to form biofilms. In Pseudomonas fluorescens F113, an amrZ mutant presents a pleiotropic phenotype, showing increased swimming motility, decreased biofilm formation and very limited ability for competitive colonization of rhizosphere, its natural habitat. It also shows different colony morphology and binding of the dye Congo Red. The amrZ mutant presents severely reduced levels of the messenger molecule cyclic-di-GMP (c-di-GMP), which is consistent with the motility and biofilm formation phenotypes. Most of the genes encoding proteins with diguanylate cyclase (DGCs) or phosphodiesterase (PDEs) domains, implicated in c-di-GMP turnover in this bacterium, appear to be regulated by AmrZ. Phenotypic analysis of eight mutants in genes shown to be directly regulated by AmrZ and encoding c-di-GMP related enzymes, showed that seven of them were altered in motility and/or biofilm formation. The results presented here show that in P. fluorescens, AmrZ determines c-di-GMP levels through the regulation of a complex network of genes encoding DGCs and PDEs. PMID- 29386662 TI - Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells. AB - The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1beta secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment. PMID- 29386663 TI - Interpretations of autonomous decision-making in antenatal genetic screening among women in China, Hong Kong and Pakistan. AB - The concept of informed choice for antenatal screening consists of Western ideologies, encapsulating individualistic approaches, and may be valued differently by people from countries with more collectivist cultures. This study aimed to explore perceptions of informed choice in antenatal screening in women from China, Hong Kong and Pakistan. A Q-methodology study was conducted during June 2016 to February 2017, in China (Shanghai and Duyun), Hong Kong and Pakistan (Lahore). A total of 299 women rank ordered 41 statements. Following by-person factor analysis, five distinct viewpoints were identified: choice as a maternal responsibility entrusted to doctors; choice as a shared decision led by the mother; choice as a shared decision led by the partner; choice as a responsibility delegated to the partner and doctors; and choice within a religious discourse. The findings highlight ethical dilemmas for healthcare professionals in facilitating informed choice for antenatal screening where policy and practice guidelines adapt predominantly individualistic approaches. Women's preferences for decision-making with health professionals and/or their partner, with minimal emphasis on individual rights, suggest the need for clarification of the role of health professionals in supporting and facilitating decision-making to enhance women's autonomy. Policy and practice guidelines need to be (re)framed to facilitate decision-making processes for antenatal screening using relational approaches to autonomy. PMID- 29386665 TI - Current trends of peri-operative cataract cancellations among consultant ophthalmologists in the United Kingdom. PMID- 29386664 TI - Magneto-optical detection of spin accumulation under the influence of mechanical rotation. AB - The generation of spin-polarised carriers in a non-magnetic material holds the key to realise highly efficient spintronic devices. Recently, it has been shown that the large spin-orbit coupling can generate spin-polarised currents in noble metals such as tungsten and platinum. Especially, if small samples of such metals are rotated on a plane disc in the presence of a perpendicular magnetic field, the orbital angular momentum is altered leading to a segregation of spin up and spin down electrons, i.e., a spin current in the samples. This is manifested via an induced magnetic moment on the metal. In this letter, magneto-optical Kerr effect (MOKE) is used to detect induced magnetic moments which allows remote measurements on metal samples rotating at 100~210 Hz. Our results confirm the mechanical generation of spin-polarised currents via optical detection of spin accumulation. PMID- 29386666 TI - Cataract in patients with diabetes mellitus-incidence rates in the UK and risk factors. AB - AIMS: To analyze the risk of incident cataract (diagnosis or extraction) in patients with or without diabetes focusing on other comorbid conditions, antidiabetic drug use, and diabetes duration. METHODS: The study population comprised newly diagnosed diabetes patients (>=40 years) from the UK-based Clinical Practice Research Datalink (CPRD) between 2000 and 2015, and a random sample of the general population matched for age, sex, general practice, and year of diabetes diagnosis. We assessed cataract incidence rates (IRs) and performed a nested case-control analysis in the diabetic cohort to assess potential risk factors for a cataract. RESULTS: There were 56,510 diabetes patients included in the study. IRs of cataract were 20.4 (95% CI 19.8-20.9) per 1000 person-years (py) in patients with diabetes and 10.8 (95% CI 10.5-11.2) per 1000 py in the general population. IRs increased considerably around the age of 80 years and with a concomitant diagnosis of macular edema. The incidence rate ratio (IRR) was highest in patients of the age group of 45-54 years. In the nested case-control study, we identified 5800 patients with cataract. Risk of cataract increased with increasing diabetes duration (adj. OR 5.14, 95% CI 4.19-6.30 diabetes for >=10 years vs. diabetes <2 years). CONCLUSIONS: According to our study, diabetes is associated with an approximately two-fold increased detection rate of cataract. The risk of cataract associated with diabetes is highest at younger ages. Patients with diabetic macular edema are at an increased risk for cataract as well as patients with long-standing diabetes. PMID- 29386667 TI - Stability Formulation for Integrated Opto-mechanic Phase Shifters. AB - Stability of opto-mechanical phase shifters consisting of waveguides and non signal carrying control beams is investigated thoroughly and a formula determining the physical limitations has been proposed. Suggested formulation is not only beneficial to determine physical strength of the system but also advantageous to guess the response of the output to the fabrication errors. In the iterative analysis of cantilever and double-clamped beam geometrical configurations, the stability condition is revealed under the strong inter dependence of the system parameters such as input power, device length and waveguide separation. Numerical calculations involving effective index modifications and opto-mechanic movements show that well-known cantilever beams are unstable and inadequate to generate phi = 180 degrees phase difference, while double-clamped beam structures can be utilized to build functional devices. Ideal operation conditions are also presented in terms of both the device durability and the controllability of phase evolution. PMID- 29386669 TI - Peer reviewed journal articles. PMID- 29386670 TI - Veterinary Medical Ethics. PMID- 29386668 TI - Expert panel consensus recommendations for home blood pressure monitoring in Asia: the Hope Asia Network. AB - Hypertension is the leading cause of mortality throughout Asia. Home blood pressure monitoring has the potential to improve hypertension control and is a useful adjunct to conventional office blood pressure measurements due to its diagnostic accuracy and prognostic value in predicting cardiovascular outcomes. At present, there are no region-specific guidelines addressing the use of home blood pressure monitoring in Asia. Therefore, an expert panel was convened to address the use of home blood pressure monitoring and develop key recommendations to help guide clinical practice throughout the Asia region. The resulting recommendations support the use of home blood pressure monitoring with a validated device as an accurate adjunct for diagnosing hypertension and predicting cardiovascular outcome. Diagnosis and treatment of hypertension should still be guided by conventional office/clinic blood pressure measurements. The expert panel encourages the incorporation of home blood pressure monitoring into local clinical guidelines and offers practical recommendations to ensure continuity of care where a validated home blood pressure device is not available. PMID- 29386672 TI - The use of ultrasound to evaluate sacrococcygeal epidural injections in cats. AB - Ultrasonography of the lumbosacral and sacrococcygeal spine is described in cats to confirm effective distribution of local anesthetics injected in the sacrococcygeal epidural space. Ultrasound was used to identify the structures of the spinal canal, local anesthetic flow, and to measure the distances between skin and ligamentum flavum. PMID- 29386671 TI - Metronomic administration of lomustine following palliative radiation therapy for appendicular osteosarcoma in dogs. AB - The purpose of this study was to determine if metronomic administration of lomustine following palliative radiation therapy (RT) improved length of palliation and therefore survival in dogs with appendicular osteosarcoma compared to treatment with palliative radiation alone. A search of medical records identified dogs with appendicular osteosarcoma, treated with palliative RT (2 fractions of 8 Gray in a 24 hour time frame, day 0 and day 1; or day 0, 6 hours apart). Data collected included signalment, history, clinical signs, physical examination findings, clinicopathologic abnormalities, extent of disease, response, toxicity, other therapy, survival time, and whether dogs received metronomic lomustine (ML) or not. Of 86 patients, 43 received ML while 43 did not. Median survival time (MST) was not significantly different (P = 0.84), at 184 +/- 17 days for patients which received ML, and 154 +/- 20 days for those which did not. Metronomic lomustine administration was well-tolerated, but it did not improve survival in dogs with palliatively treated osteosarcoma. PMID- 29386674 TI - Malignant rectal melanoma in 2 dogs. AB - Two rare cases of malignant rectal melanoma in dogs are described. Tumors were locally invasive and composed of spindle cells arranged in interweaving bundles, sheets, and nests within preexisting fibrovascular stroma. Mitotic count was high. The diagnosis was achieved based on histopathology and immunohistochemistry for PNL2 and melan-A. PMID- 29386673 TI - Resolution of esophageal dysmotility following treatment of nasal disease in a dog. AB - A 2-year-old Rottweiler dog was evaluated for cough, regurgitation, and nasal discharge, and was subsequently diagnosed with sinonasal aspergillosis and secondary esophageal disease. Following treatment of sinonasal aspergillosis, all clinical signs resolved. To the authors' knowledge, this is the first report of resolution of esophageal dysfunction following treatment of sinonasal aspergillosis. PMID- 29386675 TI - Hypertriglyceridemia and transient corneal lipidosis in a cat following intravenous lipid therapy for permethrin toxicosis. AB - An 8-year-old male neutered domestic shorthair cat developed corneal lipidosis and marked hypertriglyceridemia approximately 36 hours after intravenous lipid therapy (IVLT) for the treatment of permethrin toxicosis. The cat's ocular changes resolved approximately 72 hours after IVLT without treatment. This study reports a rare complication of IVLT. PMID- 29386676 TI - Use of percutaneous cystolithotomy for removal of urethral uroliths in a pot bellied pig. AB - A 6-month-old neutered male pot-bellied pig was presented for an obstructive urethral stone which was successfully removed by percutaneous cystolithotomy (PCCL). The pig recovered well although suspected urethral spasms and pollakiuria persisted for 2 weeks after surgery. The owner reported a good urine stream 2 months after discharge. This novel minimally invasive approach provided excellent visualization and allowed complete evaluation of the lower urinary tract. Percutaneous cystolithotomy holds great promise for the future treatment of various lower urinary tract disorders in this species. PMID- 29386677 TI - Reversible dysphagia secondary to guttural pouch mycosis in a gelding treated medically with voriconazole and surgically with carotid occlusion and esophagostomy. AB - A gelding was diagnosed with dysphagia and left guttural pouch mycosis. Treatments included topical antifungal drugs, systemic voriconazole, and balloon occlusion of the internal carotid artery. Ongoing dysphagia of neurological origin necessitated extra-oral feeding through an esophagostomy tube. Complementary case management included acupuncture. Clinical remission occurred over 10 weeks. PMID- 29386678 TI - Comparison of incisional bursting strength of 2-strand continuous crossing and simple continuous patterns for closure of the equine linea alba. AB - The objective of this study was to assess and compare the bursting pressure and mode of failure of a 2-strand continuous crossing suture pattern and a simple continuous suture pattern for closure of the equine linea alba. No difference in bursting strength or mode of failure was found between the 2 suture patterns. PMID- 29386679 TI - Concentrations of calcium, phosphorus, and vitamin D in human foods are not different among 4 food databases. AB - Concentrations of calcium, phosphorus, and vitamin D in similar foods were compared over 4 international food databases and results demonstrated no differences (P > 0.05) among the values from the databases. Therefore, the use of different food databases for homemade dog and cat diet formulation should not affect the final diet nutrient density prediction for these key nutrients. PMID- 29386680 TI - Correlation between urine color and urine specific gravity in dogs: Can urine color be used to identify concentrated urine? AB - This combined retrospective-prospective study evaluated the correlation between canine urine color (UC) and urine specific gravity (USG). Urine color was positively correlated with USG, but the relationship was not significantly improved by use of a UC chart. Urine color as an indicator of USG is limited as 20% of dark-yellow samples had a USG < 1.030. PMID- 29386682 TI - Veterinary school admission. PMID- 29386681 TI - Struvite urolithiasis with eosinophilic polypoid cystitis in a shih tzu dog. AB - A 7-year-old female spayed shih tzu dog was presented with hematuria of 4 weeks' duration. Radiographs revealed 1 cystic calculus. A polypoid mass was found incidentally during cystotomy and was removed by partial cystectomy. Histopathology revealed eosinophilic polypoid cystitis and urolith analysis reported struvite. A urinary tract infection was treated. PMID- 29386683 TI - Spore concentration and modified host resistance as cause of anthrax outbreaks: A practitioner's perspective. PMID- 29386684 TI - Resistant communication. PMID- 29386685 TI - Intraoral radiographic tips and tricks. PMID- 29386686 TI - General Public Acceptance of Forest Risk Management Strategies in Sweden: Comparing Three Approaches to Acceptability. AB - Global change calls for more active approaches to forest risk management. To avoid unforeseen backlashes, it is necessary to examine the general public's acceptance of the risk management strategies. By drawing on different theoretical approaches (threat and prevention, performance evaluations, and forest cognitions), the present study examines predictors of acceptability in the general public in three counties in Sweden (N = 1,026). As expected, appraisals of threat mediated the effect of threat awareness on belief in risk prevention, and when examining performance evaluations, trust in responsible actors influenced acceptability via procedural satisfaction. However, the threat and prevention approach and the performance evaluation approach only explained low levels of the variance in acceptability of the examined strategies. Nevertheless, stronger ecological forest values, and favoring broadleaved forests, were found to be important to the acceptability of proactively implementing a more diverse forest to meet the expected challenges associated with global climate change. PMID- 29386687 TI - QM/MM through the 1990s: The First Twenty Years of Method Development and Applications. AB - The 2013 Nobel Prize in Chemistry was awarded to the authors of the first two publications utilizing the concept of combined quantum mechanical and molecular mechanical (QM/MM) methods. In celebrating this great event in computational chemistry, we review the early development of combined QM/MM techniques and the associated events that took place through the mid-1990s. We also offer some prospects for the future development of quantum mechanical techniques for macromolecular systems. PMID- 29386688 TI - Religion and National Identification in Europe: Comparing Muslim Youth in Belgium, England, Germany, the Netherlands, and Sweden. AB - How inclusive are European national identities of Muslim minorities and how can we explain cross-cultural variation in inclusiveness? To address these questions, we draw on large-scale school-based surveys of Muslim minority and non-Muslim majority and other minority youth in five European countries (Children of Immigrants Longitudinal Survey [CILS]; Belgium, England, Germany, the Netherlands, and Sweden). Our double comparison of national identification across groups and countries reveals that national identities are less strongly endorsed by all minorities compared with majority youth, but national identification is lowest among Muslims. This descriptive evidence resonates with public concerns about the insufficient inclusion of immigrant minorities in general, and Muslims in particular, in European national identities. In addition, significant country variation in group differences in identification suggest that some national identities are more inclusive of Muslims than others. Taking an intergroup relations approach to the inclusiveness of national identities for Muslims, we establish that beyond religious commitment, positive intergroup contact (majority friendship) plays a major role in explaining differences in national identification in multigroup multilevel mediation models, whereas experiences of discrimination in school do not contribute to this explanation. Our comparative findings thus establish contextual variation in the inclusiveness of intergroup relations and European national identities for Muslim minorities. PMID- 29386689 TI - Seeing Mixed Emotions: The Specificity of Emotion Perception From Static and Dynamic Facial Expressions Across Cultures. AB - Although perceivers often agree about the primary emotion that is conveyed by a particular expression, observers may concurrently perceive several additional emotions from a given facial expression. In the present research, we compared the perception of two types of nonintended emotions in Chinese and Dutch observers viewing facial expressions: emotions which were morphologically similar to the intended emotion and emotions which were morphologically dissimilar to the intended emotion. Findings were consistent across two studies and showed that (a) morphologically similar emotions were endorsed to a greater extent than dissimilar emotions and (b) Chinese observers endorsed nonintended emotions more than did Dutch observers. Furthermore, the difference between Chinese and Dutch observers was more pronounced for the endorsement of morphologically similar emotions than of dissimilar emotions. We also obtained consistent evidence that Dutch observers endorsed nonintended emotions that were congruent with the preceding expressions to a greater degree. These findings suggest that culture and morphological similarity both influence the extent to which perceivers see several emotions in a facial expression. PMID- 29386690 TI - Synthesis and Solution-Phase Characterization of Sulfonated Oligothioetheramides. AB - Nature has long demonstrated the importance of chemical sequence to induce structure and tune physical interactions. Investigating macromolecular structure and dynamics is paramount to understand macromolecular binding and target recognition. To that end, we have synthesized and characterized flexible sulfonated oligothioetheramides (oligo-TEAs) by variable temperature pulse field gradient (PFG) NMR, double electron-electron resonance (DEER), and molecular dynamics (MD) simulations to capture their room temperature structure and dynamics in water. We have examined the contributions of synthetic length (2 12mer), pendant group charge, and backbone hydrophobicity. We observe significant entropic collapse, driven in part by backbone hydrophobicity. Analysis of individual monomer contributions revealed larger changes due to the backbone compared to pendant groups. We also observe screening of intramolecular electrostatic repulsions. Finally, we comment on the combination of DEER and PFG NMR measurements via Stokes-Einstein-Sutherland diffusion theory. Overall, this sensitive characterization holds promise to enable de novo development of macromolecular structure and sequence-structure-function relationships with flexible, but biologically functional macromolecules. PMID- 29386691 TI - Selective adsorption and determination of hexavalent chromium ions using graphene oxide modified with amino silanes. AB - Novel adsorbents are described for the preconcentration of chromium(VI). Graphene oxide (GO) was modified with various amino silanes containing one, two, or three nitrogen atoms in the molecule. These include 3-aminopropyltriethoxysilane (APTES), N-(3-trimethoxysilylpropyl)ethylenediamine (TMSPEDA), and N1-(3 trimethoxysilylpropyl)diethylenetriamine (TMSPDETA). The resulting GO derivatives were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, and energy-dispersive X-ray fluorescence spectrometry (EDXRF). Adsorption studies show that these GO based sorbents are highly selective for Cr(VI) in the presence of Cr(III) at pH 3.5. Although the amino silanes applied in modification of GO contain different numbers of nitrogen atoms, the maximum adsorption capacities of GO derivatives are very similar (13.3-15.1 mg.g-1). Such results are in accordance with spectroscopy studies which show that the amount of amino silanes attached to GO decreases in the order of APTES > TMSPEDA > TMSPDETA. The APTES-modified GO was applied to selective and sensitive extraction of Cr(VI) ions prior to quantitation by low-power EDXRF using the Cr Kalpha line. The Cr(VI) ions need not be eluted from the solid adsorbent. The method has a 0.17 ng.mL-1 detection limit, and the recovery is 99.7 +/- 2.2% at a spiking level of 10 ng.mL-1. The method was successfully applied to the determination of Cr(VI) in water samples. Graphical abstractGraphene oxide adsorbents modified with various amino silanes are described for the preconcentration and speciation of trace and ultratrace levels of chromium ions. PMID- 29386692 TI - Basic self-knowledge and transparency. AB - Cogito-like judgments, a term coined by Burge (1988), comprise thoughts such as, I am now thinking, I [hereby] judge that Los Angeles is at the same latitude as North Africa, or I [hereby] intend to go to the opera tonight. It is widely accepted that we form cogito-like judgments in an authoritative and not merely empirical manner. We have privileged self-knowledge of the mental state that is self-ascribed in a cogito-like judgment. Thus, models of self-knowledge that aim to explain privileged self-knowledge should have the resources to explain the special self-knowledge involved in cogito judgments. My objective in this paper is to examine whether a transparency model of self-knowledge (i.e., models based on Evans ' 1982 remarks) can provide such an explanation: granted that cogito judgments are paradigmatic cases of privileged self-knowledge, does the transparency procedure explain why this is so? The paper advances a negative answer, arguing that the transparency procedure cannot generate the type of thought constitutive of cogito judgments. PMID- 29386693 TI - Toxic influence of key organic soil pollutants on the total flavonoid content in wheat leaves. AB - Textile dyes and antibiotics are two main classes of environmental pollutants which could be found in soil and water. Those persistent pollutants can have a negative influence on plant growth and development and affect the level of secondary metabolites. In the present work we studied the effect of textile dyes and antibiotics on total leaf flavonoid contents in wheat (Triticum aestivum L.). Contaminant solutions were applied daily using concentrations of 0.5 mg L-1 (lower) and 1.5 mg L-1 (higher dose) for either one or two weeks. We observed that exposure to the higher concentration of textile dyes resulted in a reduction in flavonoid content while antibiotics enhanced flavonoid contents at lower doses of exposure, and reduced at higher doses of exposure. These results suggest that diffuse chronic pollution by artificial organic contaminants can importantly alter antioxidative capacity of plants. PMID- 29386694 TI - Stigmatodiscus pruni, a new dothideomycete with hysteriform ascomata. AB - Stigmatodiscus pruni (Stigmatodiscaceae, Stigmatodiscales) is described and illustrated from corticated dead twigs of Prunus spinosa collected in Austria and France. It is characterised by hysteriform ascomata with two lateral black lips, which are erumpent through the periderm of the host, and a black disc in combination with two-celled, asymmetric brown verruculose ascospores with a distinct sheath. Phylogenetic analyses of a multigene matrix containing a representative selection of Dothideomycetes from four genes (nuc 18S rDNA, nuc 28S rDNA, rpb2 and tef1) revealed a highly supported placement within Stigmatodiscales as sister species to Stigmatodiscus enigmaticus. Micromorphology of the sexual and asexual morph matches the genus Stigmatodiscus, except for the hysteriform shape of the ascomata and the two-celled ascospores. PMID- 29386695 TI - Fungal Systematics and Evolution: FUSE 3. AB - The present study introduces seven new species, one new combination, one new variety and several interesting taxonomical notes and/or geographical records. Most of the new taxa are Ascomycetes, but the study also includes a new variety of a Basidiomycete. Novel species include Gyromitra khanspurensis (Discinaceae, Pezizales, Pezizomycetes) from Pakistan growing near Cedrus deoadara and Paramyrothecium guiyangense and Paramyrothecium verruridum (Stachybotriaceae, Hypocreales, Sordariomycetes) both isolated from soil in China. New species from South Africa are Sclerostagonospora elegiae on culm litter of Elegia equisetacea, Sclerostagonospora fusiformis on culm litter of Thamnochortus spicigerus, Sclerostagonospora pinguis on culm litter of Cannomois virgata and Sclerostagonospora sulcata on culm litter of Ischyrolepis subverticellata (Phaeosphaeriaceae, Pleosporales, Dothideomycetes). Hapalocystis berkeleyi var. kickxii with its basionym Hypoxylon kickxii is shown to be a taxon on species level and thus recombined as Hapalocystis kickxii (Sydowiellaceae, Diaporthales, Sordariomycetes), and it is lecto- and epitypified. The new variety Pluteus romellii var. luteoalbus (Pluteaceae, Agaricales, Agaricomycetes) growing on a mossy fallen stem of a deciduous tree is described from Czech Republic. Cortinarius scaurocaninus (Cortinariaceae, Agaricales, Agaricomycetes) is new for Austria, Humicola grisea (Chaetomiaceae, Sordariales, Sordariomycetes) is an interesting new record for Chile. Two taxa are reported as new for Turkey: the lichenicolous fungus Opegrapha parasitica (Opegraphaceae, Arthoniales, Arthoniomycetes) growing partly immersed in the thallus of Aspicilia and the lichen Rinodina zwackhiana (Physciaceae, Teloschistales, Lecanoromycetes) from calcareous rock. Finally, Xerula strigosa (Physalacriaceae, Agaricales, Agaricomycetes), described from China, is confirmed to be present also in Pakistan. PMID- 29386696 TI - The Role of Racial Identity and Implicit Racial Bias in Self-Reported Racial Discrimination: Implications for Depression Among African American Men. AB - Racial discrimination is conceptualized as a psychosocial stressor that has negative implications for mental health. However, factors related to racial identity may influence whether negative experiences are interpreted as instances of racial discrimination and subsequently reported as such in survey instruments, particularly given the ambiguous nature of contemporary racism. Along these lines, dimensions of racial identity may moderate associations between racial discrimination and mental health outcomes. This study examined relationships between racial discrimination, racial identity, implicit racial bias, and depressive symptoms among African American men between 30 and 50 years of age (n = 95). Higher racial centrality was associated with greater reports of racial discrimination, while greater implicit anti-Black bias was associated with lower reports of racial discrimination. In models predicting elevated depressive symptoms, holding greater implicit anti-Black bias in tandem with reporting lower racial discrimination was associated with the highest risk. Results suggest that unconscious as well as conscious processes related to racial identity are important to consider in measuring racial discrimination, and should be integrated in studies of racial discrimination and mental health. PMID- 29386697 TI - Large Field of View Scanning Fluorescence Lifetime Imaging System for Multimode Optical Imaging of Small Animals. AB - We describe a scanning fluorescence lifetime imaging (SFLIM) system that provides a large field of view (LFOV), using a femtosecond (fs) pulsed laser, for multi mode optical imaging of small animals. Fluorescence lifetime imaging (FLIM) can be a useful optical method to distinguish between fluorophores inside small animals. However, difficulty arises when LFOV is required in FLIM using a fs pulsed laser for the excitation of the fluorophores at low wavelengths (<500nm), primarily because the field of view of the pulsed blue excitation light generated from the second harmonic of the fs pulsed light is limited to about a centimeter in diameter due to the severe scattering and absorption of the light inside tissues. Here, we choose a scanning method in order to acquire a FLIM image with LFOV as one alternative. In the SFLIM system, we used a conventional cooled CCD camera coupled to an ultra-fast time-gated intensifier, a tunable femtosecond laser for the excitation of fluorophores, and an x-y moving stage for scanning. Images acquired through scanning were combined into a single image and then this reconstructed image was compared with images obtained by spectral imaging. The resulting SFLIM system is promising as an alternative method for the FLIM imaging of small animals, containing fluorophores exited by blue light, for LFOV applications such as whole animal imaging. PMID- 29386698 TI - Association between Two Resistin Gene Polymorphisms and Metabolic Syndrome in Jilin, Northeast China: A Case-Control Study. AB - Metabolic syndrome (MetS) is a significant health care problem worldwide and is characterized by increased fasting glucose and obesity. Resistin is a protein hormone produced both by adipocytes and immunocompetent cells, including those residing in adipose tissue, and is believed to modulate glucose tolerance and insulin action. This study examined the association of resistin gene polymorphisms, rs1862513 and rs3745368, and related haplotypes with the development of metabolic syndrome in a Han Chinese population. This case-control study was performed on 3792 subjects, including 1771 MetS cases and 2021 healthy controls from the Jilin province of China. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation (IDF). Logistic regression analysis was used to estimate the relationship between gene polymorphism and MetS. Our results showed that there were no significant associations between MetS and the genotype distributions in four kinds of inheritance models, allele frequencies, and related haplotypes of resistin gene polymorphisms rs1862513 and rs3745368 (all p values > 0.05). Based on our study findings, we concluded that mutations in resistin genes are not associated with the presence of MetS in a Han Chinese population from Jilin province in China. PMID- 29386701 TI - The use of evidence-based guidance to enable reliable and accurate measurements of the home environment. AB - Introduction: High quality guidance in home strategies is needed to enable older people to measure their home environment and become involved in the provision of assistive devices and to promote consistency among professionals. This study aims to investigate the reliability of such guidance and its ability to promote accuracy of results when measurements are taken by both older people and professionals. Method: Twenty-five health professionals and 26 older people participated in a within-group design to test the accuracy of measurements taken (that is, person's popliteal height, baths, toilets, beds, stairs and chairs). Data were analysed with descriptive analysis and the Wilcoxon test. The intra rater reliability was assessed by correlating measurements taken at two different times with guidance use. Results: The intra-rater reliability analysis revealed statistical significance (P < 0.05) for all measurements except for the bath internal width. The guidance enabled participants to take 90% of measurements that they were not able to complete otherwise, 80.55% of which lay within the acceptable suggested margin of variation. Accuracy was supported by the significant reduction in the standard deviation of the actual measurements and accuracy scores. Conclusion: This evidence-based guidance can be used in its current format by older people and professionals to facilitate appropriate measurements. Yet, some users might need help from carers or specialists depending on their impairments. PMID- 29386700 TI - Plasmatic Soluble Receptor for Advanced Glycation End Products as a New Oxidative Stress Biomarker in Patients with Prosthetic-Joint-Associated Infections? AB - Prosthetic joint infection (PJI) is the most common cause of failure of total joint arthroplasty, but a gold standard for PJI diagnosis is still lacking. Advanced glycation end products (AGEs) are proinflammatory molecules inducing intracellular oxidative stress (OS) after binding to their cell membrane receptors (RAGE). The aim of this study was to evaluate plasmatic soluble receptor for advanced glycation end products (sRAGE), as a new OS and infection marker correlating sRAGE to the level of OS and antioxidant defenses, in PJI, in order to explore the possible application of this new biomarker in the early diagnosis of PJI. Plasmatic sRAGE levels (by ELISA assay), plasma antioxidant total defenses (by lag time method), plasma reactive oxygen species (ROS), and thiobarbituric acid reactive substance (TBARS) levels (by colorimetric assay) were evaluated in 11 PJI patients and in 30 matched controls. ROS and TBARS were significantly higher (p < 0.001) while plasma total antioxidant capacity and sRAGE were significantly lower (p < 0.01) in patients with PJI compared to controls. Our results confirm the OS in PJI and show a strong negative correlation between the level of sRAGE and oxidative status, suggesting the plasmatic sRAGE as a potential marker for improving PJI early diagnosis. PMID- 29386703 TI - Combat medical support. PMID- 29386702 TI - A review of thanatosis (death feigning) as an anti-predator behaviour. AB - Abstract: Thanatosis-also known as death-feigning and, we argue more appropriately, tonic immobility (TI)-is an under-reported but fascinating anti predator strategy adopted by diverse prey late on in the predation sequence, and frequently following physical contact by the predator. TI is thought to inhibit further attack by predators and reduce the perceived need of the predator to subdue prey further. The behaviour is probably present in more taxa than is currently described, but even within well-studied groups the precise taxonomic distribution is unclear for a number of practical and ethical reasons. Here we synthesise the key studies investigating the form, function, evolutionary and ecological costs and benefits of TI. This review also considers the potential evolutionary influence of certain predator types in the development of the strategy in prey, and the other non-defensive contexts in which TI has been suggested to occur. We believe that there is a need for TI to be better appreciated in the scientific literature and outline potentially profitable avenues for investigation. Future use of technology in the wild should yield useful developments for this field of study. Significance statement: Anti predatory defences are crucial to many aspects of behavioural ecology. Thanatosis (often called death-feigning) has long been an under-appreciated defence, despite being taxonomically and ecologically widespread. We begin by providing much needed clarification on both terminology and definition. We demonstrate how apparently disparate observations in the recent literature can be synthesised through placing the behaviour within a cost-benefit framework in comparison to alternative behavioural choices, and how aspects of the ecology differentially affect costs and benefits. Extending this, we provide novel insights into why the evolution of thanatosis can be understood in terms of coevolution between predators and prey. We offer further novel hypotheses, and discuss how these can be tested, focussing on how emerging technologies can be of great use in developing our understanding of thanatosis in free-living animals. PMID- 29386699 TI - SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56%) and SFRP5 (70%) in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma. PMID- 29386704 TI - Negative pressure wound therapy in the management of mine blast injuries of lower limbs: Lessons learnt at a tertiary care center. AB - Background: Mine blast injuries of foot are devastating injuries that result in composite tissue loss or amputations. Negative pressure wound therapy has helped in the management of such combat-related wounds. The aim of this study was to report experiences gained in managing such injuries at a tertiary care center. Methods: 17 combatants who sustained mine blast injuries were included in this study. Severity of foot injury was assessed as per Foot and Ankle Severity Score. After wound debridement, negative pressure wound therapy was started and foot defect was appropriately reconstructed. Following wound healing, the foot was assessed for Foot and Ankle Severity Score in terms of impairment. The patients were then suitably rehabilitated by shoe modifications, orthosis, or custom-made prosthesis. Results: Mean age of soldiers who sustained mine blast injuries was 30.2 years. The mean Foot and Ankle Severity Score was 3.76. Temporary wound closure was achieved using negative pressure wound therapy and it prevented local and systemic infection. The defect could be reconstructed appropriately using split skin graft, regional fasciocutaneous flap, or microvascular free flap. Mean time to definitive reconstructive procedure was 16.5 days. Mean Foot and Ankle Severity Score in terms of impairment was 4.11. All soldiers could be rehabilitated and were returned to their respective units and were able to perform sedentary duties assigned to them. Conclusion: The negative pressure wound therapy was helpful in preventing proximal amputations due to mine blast injury and was helpful in satisfactory reconstruction of foot defects. PMID- 29386705 TI - Crew awareness as key to optimizing habitability standards onboard naval platforms: A 'back-to-basics' approach. AB - Background: A healthy habitable environment onboard warships is vital to operational fleet efficiency and fit sea-warrier force. Unique man-machine armament interface issues and consequent constraints on habitability necessitate a multi-disciplinary approach toward optimizing habitability standards. Study of the basic 'human factor', including crew awareness on what determines shipboard habitability, and its association with habitation specifications is an essential step in such an approach. The aim of this study was to assess crew awareness on shipboard habitability and the association between awareness and maintenance of optimal habitability as per specifications. Methods: A cross-sectional descriptive study was carried out among 552 naval personnel onboard warships in Mumbai. Data on crew awareness on habitability was collected using a standardized questionnaire, and correlated with basic habitability requirement specifications. Data was analyzed using Microsoft Excel, Epi-info, and SPSS version 17. Results: Awareness level on basic habitability aspects was very good in 65.3% of crew. Area-specific awareness was maximum with respect to living area (95.3%). Knowledge levels on waste management were among the lowest (65.2%) in the category of aspect-wise awareness. Statistically significant association was found between awareness levels and habitability standards (OR = 7.27). Conclusion: The new benchmarks set in the form of high crew awareness levels on basic shipboard habitability specifications and its significant association with standards needs to be sustained. It entails re-iteration of healthy habitation essentials into training; and holds the key to a fit fighting force. PMID- 29386706 TI - Filaria surveys in the Armed Forces: Need for a revisit. AB - Background: Routine annual filarial surveys are conducted amongst various categories of military personnel and their families as per policies in vogue in the Armed Forces. The neglect and inattention faced by this disease needs to be addressed in terms of policy, provisioning and processes while dealing with filariasis in the Armed Forces. Methods: Routine annual filarial survey was conducted in a garrison during the months of Nov and Dec in 2013 and 2014. Blood slides from 6305 and 10,162 persons were collected in 2013 and 2014 respectively. 546 (60.66%) civilian migratory labourers were also subjected to the filarial survey. Results: Of the blood slides collected amongst service personnel, 41 were positive for mf in 2013 and 29 in 2014 (i.e. a slide positivity rate (SPR) of 0.65% and 0.28% respectively). Out of 546 blood slides of the migratory population, 10 were found mf positive (SPR 1.83%) and three males had lymphedema. Conclusion: It is recommended that routine annual filarial survey conducted in military garrisons should include all personnel belonging to known endemic states. Newer modalities of detection of infection may be considered to replace night blood surveys. An organization-specific surveillance programme on prevention and control of Lymphatic filariasis in the Armed Forces thus may need to be launched so that we can achieve elimination. PMID- 29386708 TI - Occupational health concerns: An analysis of physical activity of submariners. AB - Background: Submarine crew have low physical activity by virtue of their professional requirements. Lack of space and inadequacy of regeneration capabilities render physical activity almost impossible during deployments. However, sufficient data for physical activity levels and trends are required to measure the magnitude of inactivity. Methods: Data was collected from 362 personnel belonging to six submarines and one submarine base using Global Physical Activity Questionnaire. Four study groups were defined: Base, Refit, Operational/Harbour and Operational/Sea. Results: Overall, 30.11% of the crew had insufficient physical activity (4.04% in Base, 5.75% in Refit, 15% in Ops/Harbour and 91.67% in Ops/Sea groups). Of the total physical activity, 48.7% was contributed by activity at work, 18.71% by travel related activity and 32.62% by recreational physical activity. Base group recorded the highest recreational activity of 1468.28 Minutes-per-Week. Recreational activity contributed 43.22% to total physical activity for this group. Mean total physical activity was highest for >=45 years and lowest for <=24 years. >=45 years old also recorded the highest recreational activity. Conclusion: The greatest cause for concern comes from the crew in operational submarines and the younger crew. Physical activity profile of the crew when at sea cannot be changed and greater research is required to assess the long-term health effects of physical inactivity in this group. However, what can be modified are the work schedules for refit submarines and operational submarines when in harbour. Targeted interventions and strategies are required to establish sustainable behaviour patterns with regards to physical activity in these groups. PMID- 29386707 TI - Study of acute hypoxia markers in healthy subjects: Utility in post-crash investigation. AB - Background: Lactic acid is being routinely used as a marker of hypoxia in aircrash investigation. Since lactic acid estimation as a marker of hypoxia in postmortem samples for aircrash investigation is prone to many interfering factors, like the postmortem production and hemolysis. A study was carried out to evaluate other hypoxia markers other than lactic acid which could be later added as markers of hypoxia in postmortem investigations of aircraft accidents. Methods: 25 healthy males of age 20-40 yrs volunteered participants were subjected to an simulated altitude of 15,000 ft for 30 min and the mean plasma concentration of Hypoxia Inducing Factor 1alpha (HIF 1alpha), Erythropoietin (EPO), Vascular Endothelial Growth Factor (VEGF) and lactic acid (LA) were analyzed from their venous blood sample collected at 4 intervals viz. Ground level pre exposure, 15,000 ft at 15 min, 15,000 ft at 30 min and Ground level 3 h post exposure. Results: Statistical analysis revealed significant increase in mean plasma concentration of lactic acid, HIF-1alpha and EPO on exposure for duration of 15 min and 30 min at an altitude of 15,000 ft. Conclusion: Our study reveals that HIF-1alpha and EPO are sensitive to hypoxia exposure as compared to lactic acid and can be used in association with LA as hypoxia markers. However stability of these proteins in postmortem conditions needs to be studied and the potential for estimation of mRNA transcripts of HIF-1alpha and EPO, which would be stable in postmortem conditions, can be explored. PMID- 29386709 TI - The psychological morbidity in the long term after war related bilateral lower limb amputation. AB - Background: To determine the psychological morbidity in the long term after war related bilateral lower limb amputation. Methods: Mental health status was determined by the Symptom Checklist-90-R (SCL-90-R) and a structured psychiatrist interview using Structured Clinical Interview for DSM Disorders-IV (SCID-IV) in 327 male amputees. The survey was 22.3 (SD = 3.9) years after amputation. A one sample t-test was conducted to compare our results with a survey carried out in a rural Iranian population. Results: The mean age of the participants was 42 years (SD = 6.3). Only 22 persons had psychiatric diagnosis and were under treatment. The most common problems on SCL-90-R were somatization, obsessive-compulsive, interpersonal sensitivity, anxiety, and depression. Global severity index (GSI) of the bilateral lower limb amputees (BLLA) (0.88 +/- 0.63) was significantly higher than Iranian population (0.35 +/- 0.28) (p < 0.001). BLLA had significantly higher scores in all subscales of Scl-90-R compared with general population (p < 0.001). Of the total amputees about 39.1% (128 out 327) diagnosed with at least one psychiatric disorder in psychiatrist interview. About 83.9% (N = 115) of the psychiatrist diagnosed disorders were new cases. Mood disorders 37.3% (depression 28.7%) and anxiety disorders 12.2% (obsessive compulsive disorder 9.8%) were the most common disorders in the study group. There was not any relationship between demographic variables and mental disorder (p > 0.05). Conclusion: The high prevalence and especially the large proportion of undiagnosed mental disorders high-light the need for targeted and appropriate psychological interventions in this vulnerable population. PMID- 29386710 TI - Gender differential and implications in the epidemiology of stress fractures among cadets of Indian Armed Forces. AB - Background: Most studies on stress fractures in India have been carried out among recruits as against officer trainees and limited to males. With the continuous induction of women in the Armed Forces, it was decided to carry out a study among officer trainees of the three services and compare the epidemiology among genders. Methods: A prospective study was carried out in 2011-2012 at Training Institutes of the three services where male and female cadets train together. Baseline data was collected for all trainees who joined the academy during the study period. All cadets were followed up for development of stress fractures for which details were taken. Additional information was taken from the Training Institute. Results: A total of 3220 cadets (2612 male and 608 female cadets) were included in the study. Overall 276 cadets were observed to have stress fractures during training - making an incidence of 6.9% for male cadets and 15.8% for female cadets. Females were found to have a significantly higher incidence of stress fractures. Further the distribution and onset of stress fractures in females was observed to be distinct from males. Conclusion: The significant gender differential observed in the study indicates differential role of intrinsic and extrinsic risk factors in the causation of stress fractures among male and female. Special consideration needs to be given to these while planning and implementing measures for prevention. Further studies may be carried out on subject and on the effect of interventions in stress fracture prevention. PMID- 29386712 TI - Cognitive deficits due to thermal stress: An exploratory study on soldiers in deserts. AB - Background: It is well known that environmental factors play an important role in human performance. High temperature and humidity particularly impair mental performance by altering brain neurochemistry and electrolyte disturbance which in turn affect one's overall efficiency. While the physiological responses to environmental heat have been well established, it is less clear about its impact on cognition. Study aims to investigate the impact of thermal strain on cognition. Methods: One hundred (100) healthy soldiers aged between 20 and 30 years who had spent minimum of one year in desert conditions prior to their induction in the study formed sample of the study. The subjects were evaluated on memory and on cognitive functions twice i.e. in the month of February and June. The data so generated was analyzed by appropriate statistical methods. Results: The mean age of the subjects were 25.8 yrs. There was a significant decline in cognitive performance in hot climate as compared to normal weather on Post graduate Institute (PGI) memory scale (P < 0.05). The effect was more marked for tests requiring sustained attention, concentration, psychomotor performance, verbal memory and tests of executive function. Conclusion: The present study is the first study to be conducted in actual desert conditions. Findings revealed a detrimental impact of thermal stress on the cognitive performance of soldiers in deserts. PMID- 29386711 TI - Endothelial markers in high altitude induced systemic hypertension (HASH) at moderate high altitude. AB - Background: Chronic intermittent hypoxia is known to induce systemic arterial hypertension whereas chronic hypoxia causes pulmonary arterial hypertension. High altitude (HA) induced systemic hypertension (HASH) in previously normotensive lowlanders following acclimatisation and prolonged stay at moderate HA is a commonly encountered medical problem. HASH has been attributed to increased sympathetic discharge. Endothelial dysfunction (ED) is implicated in hypertension in the plains hence this study was conducted in HA. This is relevant especially because of the established role of ED in the aetiopathogenesis of HA illnesses. Since hypoxia may induce ED, we aimed at studying the association of endothelial dysfunction with HASH in temporary residents at HA. Methods: In this case-control single-centre study, we evaluated ED, by measuring endothelial molecular markers, soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF) and endothelial selectin (E-Selectin) in 24 cases with HASH and 25 age, sex matched normotensive controls at moderate high altitude (11,500 ft). Results: The levels of sICAM-1 (patients: 214.3 +/- 34.2 MUg/L, controls: 196.2 +/- 28.5 MUg/L; p = 0.049) and VCAM-1 (patients 766.1 +/- 123.4 ng/mL, controls: 668.6 + 117.6 ng/mL; p = 0.007) were statistically higher in the patient group. However, VEGF and E-Selectin were not significantly different between the groups. sICAM-1 significantly correlated with levels of systolic and diastolic blood pressure (r = 0.401, p = 0.003 and 0.486, p = 0.000) respectively. Conclusion: HASH is associated with endothelial dysfunction in form of raised levels of sICAM-1 and VCAM-1. PMID- 29386713 TI - Tungiasis: Outbreak investigation of a zoonosis during overseas deployment. AB - Background: Tungiasis is an ectoparasitosis caused by the sand flea Tunga penetrans. It is endemic in the under privileged communities of Latin America, the Caribbean and Sub Saharan Africa with geographic and seasonal variations even within endemic areas. We describe investigation of an outbreak of Tungiasis in troops deployed as part of UN peacekeeping force in Central Africa. Methods: Tungiasis was diagnosed in an unusually large number of cases of severely pruritic boils over feet in soldiers of a UN peacekeeping battalion. An outbreak investigation was carried out and the outbreak was described in time, place and person distribution. A retrospective cohort study was done to ascertain the associated risk factors. Results: A total of 36 cases were identified of which 33 had laboratory confirmation. Of the 36 cases, 10(27.77%) had only Fortaleza Stage II lesions, 22 (61.11%) a combination of Fortaleza Stage II and III lesions and four (11.11%) cases had a combination of Stage, II, III and IV lesions. Secondary bacterial infection was seen in 25 (69.44%) cases. Epidemiological analysis revealed that it was a common source single exposure outbreak traced to a temporary campsite along one of the patrolling routes. Conclusion: In a Military setting an integrated approach combining health education and environmental control is required to prevent such outbreaks. PMID- 29386714 TI - Forward surgical care: Emerging issues and challenges. AB - War strategies have been evolving with time and battlefield casualty care services have been trying to keep pace with the changing demands. Technological advances in the field of trauma care have revolutionised the way in which erstwhile 'non-salvageable' lives and limbs are managed with more favourable outcome. The quality of Pre-Hospital Trauma Care Services will largely determine the survival statistics of battle casualties. The surgeon has to acknowledge the various resource constraints imposed upon him in the course of delivery of expert trauma care in the battlefield. The philosophy of Tactical Field Care and TACEVAC has, to a great extent, standardized point-of-care services and the manner in which combat casualties are managed. This has resulted in increasing favourable clinical outcome in a demanding, resource restricted and challenging environment. Training of Military Surgeons prior to induction into theatres of combat is an operational imperative and has to be based on validated guidelines promulgated by apex institutes specialised in Combat Casualty Care. CASEVAC hurdles, resource paucity, command and tactical decisions, govern casualty care and impose serious constraints that are not present in an urban setting. This article highlights the basic tenets of battlefield care, the challenges associated with it and the way forward. PMID- 29386715 TI - Aeromedical solutions for aerospace safety. AB - All facets of activity in the speciality of Aviation Medicine are essentially aimed at enhancing aerospace safety. This paper highlights some innovative changes brought about by Aerospace Medicine in the three major fields of the speciality namely, medical evaluation, aeromedical training and research. Based on lab and field studies, military aircrew are now permitted flying with Modifinil as 'Go' Pill and Zolpidem as 'No-Go' Pill during sustained operations. Several other drugs for disabilities like Hypertension and CAD are now permitted for aviators. Comprehensive revision of policy permitting early return to flying is an on-going process. OPRAM courses for all three streams of aircrew in IAF have contributed to reduce aircraft accident rates. Human Engineering Consultancy and expert advice is provided by specialists at IAM as well as those in the field. In future, the country needs to provide better post-service opportunities to aerospace medicine specialists. This, in turn, will attract bright young minds to the specialty. The ISRO Humanin-Space programme will be an exciting challenge for all in this unique field. Aerospace Medicine continues to provide aerospace safety solutions to the IAF and the aviation industry. The nation needs to continue to utilize and support this specialty. PMID- 29386716 TI - Guidelines for medical management of nuclear/radiation emergencies. AB - Management of victim of radiation injury poses a wide spectrum of challenges to the health care provider starting with the evaluation of the damage, the kind of hospitalization and treatment and the regular monitoring of the patient. Undesirable clinical outcomes are probable if prodromal stage evolves rapidly and is severe. Critical systems like neurovascular, gastrointestinal, haematopoietic and cutaneous are afflicted in Acute Radiation Syndrome. Three main elements which are essential for assessment of prognosis and selection of treatment are vomiting onset time, kinetics of depletion of lymphocyte, and chromosome abnormalities. Larger incidents warrant, a well-structured national response system. Health care institutions must develop protocols to respond to radiation exposure related emergencies in tandem with the local response teams. Multidisciplinary approach between clinical specialists, nursing staff and psychological experts is of critical significance. External decontamination, estimation of dose and fluid and electrolyte replacements form part of support therapy. Reverse isolation, antacids, H2 blockers, use of reverse barrier nursing and prophylactic antimicrobials are part of the treatment plan. Patients with severe bone marrow damage will require blood products support. Increased recovery of neutrophils in radiationaccident victims is the rationale for the use of Colony Stimulating Factors. New directions are under evaluation which includes novel cytokine therapies like interleukin-7, keratinocyte growth factor, and thrombopoietin or its analogues. The final decision regarding allogenic haematopoietic stem cell transplant should be considered after considering the irradiation source, particularity of the situations or circumstances, associated injuries and disease. PMID- 29386717 TI - Casualty Air Evacuation: Sine quo non of combat casualty. AB - Management of combat casualties has always been a challenging task. Armed Forces world over have developed effective casualty air evacuation mechanisms. The history of casualty evacuation dates back to 1870s. The first evacuation of casualty by air was during the First World War. The paper highlights the background and evolution of air evacuation in the world and discusses the Indian Scenario of casualty air evacuation. The casualty evacuation capabilities of the aircrafts in the Indian Air Force (IAF) are highlighted. To ensure prompt casualty evacuation, the Armed Forces have a chain of casualty air evacuation, thus ensuring that the injured reach the health care center in the least possible time. An indigenously developed patient transfer unit (PTU) comprising of a trauma care recovery trolley with a complement of a portable ventilator, multipara monitor, infusion pumps and oxygen system is also discussed. In addition, the paper discusses the aeromedical considerations while evacuating casualties by air and contraindications for air evacuation. The advancements in the field of medical technology and medical care has ensured safe air evacuation of casualties and has reduced the morbidity and mortality of casualties, thus boosting the morale of the troops. PMID- 29386718 TI - Health care for children in Indian Armed Forces. AB - Children of Armed Forces personnel constitute 33% of the clientele dependant on our healthcare. Various child health indicators and immunization coverage of Indian Armed Forces children is better than the national figures. With improved patient care, it has been observed that the morbidity and mortality pattern of diseases affecting the children of Armed Forces personnel has shown a change from infectious diseases in the past to more of chronic complex disorders at present. Hospital admissions of children in military hospitals due to nutritional and infectious diseases have reduced and constitute only around 21% of all paediatric hospital admissions. Various factors responsible for this shift are preventive health measures (antenatal care, immunization), Active promotion of health (baby friendly hospital concept, Well baby clinic) curative health services (outpatient services, in-patient care, specialty care, supportive Care) and supportive care reaching beyond like ASHA schools. Presently, we need to handle, life style diseases like obesity, mental stress, teach coping mechanisms for common stressors such as parental separation, family reunification, parental loss, behavioral problems, diseases other than infectious diseases requiring super specialty care. The challenge lies in planning the road ahead for these children and adolescents ensuring a life-course approach. PMID- 29386719 TI - Combat psychiatry: Indian perspective. AB - Indian Armed Forces have been engaged in various combat duties for long. The adverse effect of prolonged and repetitive deployment of troops in these highly stressful environment leads to many combat stress behaviors as well as misconduct behaviors. Preventing, identifying and managing these disruptive behaviors are an essential part of combat psychiatry within the larger domain of combat medicine. Indian Armed Forces have a well-oiled mechanism to handle these issues and military psychiatrists are deeply engaged in providing holistic mental health care to the esteemed clientele. Relevant issues on this subject are elaborated in the article. PMID- 29386720 TI - Combat surgery: Status of tactical abbreviated surgical control. AB - Traditionally injury care meant definitive repair following surgical exploration. However the outcome is poor because of deranged physiology in severely injured. Damage control surgery (DCS) is abbreviated initial procedure with subsequent correction of physiological imbalance, followed by definite repair. Tactical abbreviated surgical control (TASC) is application of principles of DCS techniques in the tactical environment. TASC is applied because of patient related factors (classic damage control) and limitations due to tactical reasons. Non-patient related factors only seen in tactical setting are, large numbers of patients arriving in short span, mobility of forward medical units, limitation of resources, and hostile environment. TASC involves only phase one of classical DCS. Complete correction of physiological imbalances and definitive surgery is carried out at a better equipped static hospital. TASC has shown to improve survival, extends benefit to greater number and helps to conserve precious resources. However TASC has its own limitations. PMID- 29386721 TI - Combat radiology: Challenges and opportunities. AB - Radiology services in a combat situation are essentially centred on assisting the battle field physicians/surgeons to save/salvage life and limb. Timely and accurate detection of type and mapping of extent of injury can aid in making imaging based triage which can be of immense help to the treating physicians/trauma surgeons. With the availability of rapid assessment (clinical as well as imaging based) and quick transport facility, the focus has gradually been shifting from merely limb-saving to life-saving strategies. Providing the right imaging modality at the right time for the right patient at the right place is the need of the hour and will dictate the success of combat casualty care. Although there are limitations in terms of terrain and hostility in a combat scenario, newer developments in the field of Radiodiagnosis and imaging can be optimally utilized for better casualty care services. Point of care Digital/Computed Radiography and basic Ultrasonography for trauma complemented by usage of multidetector computed tomography will go a long way in helping timely and accurate management of victims of blast and ballistic injury in a combat scenario. Following a rigid, easy to understand yet comprehensive protocol and radiology reporting system will be invaluable in the combat scenario despite various limitations. PMID- 29386722 TI - Leadership challenges in multinational medical peacekeeping operations: Lessons from UNIFIL Hospital. AB - Commanding a military multinational and multilingual healthcare facility can be a formidable task with very little margin for error. The authors were in leadership positions of UNIFIL Hospital, unique in its diversity of both staff and clientele. Experience about the challenges faced and methods adopted to overcome them will be shared. Troops from diverse backgrounds differ in their competency, and also in their attitudinal approach to situations. It is imperative for the medical commanders to identify these differences, and work towards harnessing individual strengths to form a cohesive unit. Frequent rotation of team members and thereby difficulty in adapting to new environment makes the tasks more challenging. Challenges can be broadly categorized in those dealing with functional roles (providing medical support) and command and control issues. Linguistic challenges especially in situations where professionals have to work as a coordinated unit remains a major challenge. The threat of medical errors arising out of misunderstandings is very real. Gender sensitization is essential to avoid potential unpleasant situations. Interpersonal conflict can easily go out of hand. The leadership has to be more direct and deliberate relying less on hierarchy and more on direct communication. A strict enforcement of UN standards for equipment and competence, frequent joint medical drills help to overcome interoperability issues and develop mutual confidence. Leadership in multinational UN hospitals is a demanding task with its peculiar set of challenges. A systematic and deliberate approach focused on mutual respect, flexibility and direct leadership can help medical commanders in such situations. PMID- 29386723 TI - Geriatric care: Need of the hour. PMID- 29386724 TI - Osteoporosis among household women: A growing but neglected phenomenon. AB - Background: Osteoporosis is associated with variable morbidity and socio-economic burden and referred as a "silent epidemic" with increasing risk among Indian women. The present study was conducted to find prevalence of osteoporosis. Methods: A descriptive cross-sectional study was conducted in Ranchi city with household women as participants. Data was collected by means of pre-tested structured questionnaire in Hindi language and bone status was screened utilizing calcaneal quantitative ultrasound as a diagnostic tool to estimate bone mineral density from 223 participants and statistical analysis was performed with SPSS software. Results: The mean age of the participants was 37.9 (5.63) and majority (52.5%) of them were vegetarian. The prevalence of osteoporosis was 8.5% (5.2 13%) while 45.7% (39-52.5%) had osteopenia. We found no significant association of osteoporosis and osteopenia with income, physical activity, and dietary patterns on univariate analysis. There was no statistical significant difference between mean age and BMI of participant among normal, osteoporosis, and osteopenia participant (p value >0.5). Multivariate logistic regression analysis shows that 20% increase chances of risk with five years increase in age, the protective effect of physical activity (22%) and non-vegetarian diet (18%) though not statistically significant. Conclusion: This study shows that significant number of women had osteopenia/osteoporosis within 35-40 years age group. Intensive information, education, and communication activities with regard to osteoporosis causative factors and preventive measures targeted to household women may play an important role, if started at young age. PMID- 29386725 TI - Tubercular spondylitis: A review of MRI findings in 80 cases. AB - Background: Tuberculosis of spine is known as tubercular spondylitis or Pott's spine. The vertebral involvement leads to various pathological processes such as abscess formation, cord compression, and gibbus deformity. Magnetic Resonance Imaging (MRI) is the imaging modality of choice which not only helps in diagnosing a case of Pott's spine but also gives valuable information about its impending complications, thereby, aiding in management of these cases. Methods: In this study, MRI scans of 80 proven cases of tubercular spondylitis were studied retrospectively for the various pathological processes affecting the spine. Results: Of the 80 cases included in this study, 68.8% of cases were male and 31.2% of cases were females. Majority of cases were seen in 21-40 yrs age group. Lumbar vertebrae were more commonly affected than the dorsal vertebrae. Contiguous two vertebral involvement was the most common pattern, and skip lesions were seen in 5% of cases. Pre-, paravertebral and epidural soft tissue component was seen in 96.25% and 62.5% of cases, respectively. Intervertebral disc Involvement was noted in 95% of cases, and cord edema was seen in 15% of cases. Conclusion: Tubercular spondylitis or Pott's spine is an extrapulmonary form of tuberculosis which affects the spine. MRI is the imaging modality of choice not only in diagnosing the condition but also in guiding the surgical management. The cases of spinal tuberculosis were systematically analyzed for various pathological lesions which are produced in the spine as the disease progresses. PMID- 29386726 TI - Prevalence of corneal astigmatism before cataract surgery in Western Indian Population. AB - Background: The prevalence and nature of corneal astigmatism among cataract surgery candidates has not been well-documented in Indian population. The purpose of the study is to analyse prevalence and presentation patterns of corneal astigmatism (CA) in cataract surgery candidates. Methods: Keratometric values were measured in patients before cataract extraction. Descriptive statistics of CA were analysed including the assessment with age ranges. Results: Mean CA of 223 eyes of 223 patients [mean age 61 +/- 10 years (range, 29-90 years)] was 0.88 +/- 0.61 (95% CI, 0.80-0.96) with 27.8%, 51.1% and 21.1% having with the rule (WTR), against the rule (ATR) and oblique astigmatism (OBL) respectively. Between 40 and 50 years, ATR exceeds WTR and reaches 100% by 80 years. A trend of less negative CA was seen up to 60 years and then increases up to 90 years. CA was below 0.25 dioptre (D) in 17.5% of eyes, between 0.25 and 1.25 D in 63.7% and >=1.50 D in 18.8% of eyes. Conclusions: Considering CA < 1.25 D in majority of cataract surgery candidates, it is preferable to perform inexpensive keratorefractive procedures rather expensive toric IOLs, especially in developing world. PMID- 29386727 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for rapid identification of Mycobacterium abscessus. AB - Background: Nontuberculous mycobacteria are increasingly being implicated in infections and have become an important cause of health care associated infections. Mycobacterium abscessus, a rapidly growing mycobacteria, is of particular concern as it tends to be resistant to commonly used therapeutic options. Conventional phenotypic methods for speciation of mycobacteria are time consuming, labor intensive and not always reliable. Molecular methods require expertise and are expensive. The study was used to evaluate the use of matrix associated laser desorption ionization-time of flight mass spectrometry (MALDI TOF MS) as a means of rapid identification of M. abscessus. Methods: 35 isolates of rapidly growing Mycobacterium from an outbreak of surgical site infections at a tertiary care hospital were identified using phenotypic methods. The mycobacterial isolates were inactivated and an extraction protocol was followed. These isolates were then analyzed by MALDI biotyper (Bruker Daltonics) using biotyper software 4.0 and the mycobacterial reference database v 2.0. Results: All 35 isolates were identified as M. abscessus by MALDI biotyper but the scores obtained according to guidelines of the company were lower than previous studies with only 23 out of the 35 isolates having scores of greater 1.8 which was described as the minimum score to be achieved for reliable identification. Conclusion: MALDI-TOF MS offers a rapid and inexpensive method for identification of Mycobacteria; however, the scores obtained in our study were lower than reported in other studies. PMID- 29386728 TI - Complete coverage and covering completely: Breast feeding and complementary feeding: Knowledge, attitude, and practices of mothers. AB - Background: Knowing current trends for timely comprehensive action for health promotion practices is an important prerequisite for medical practitioners and policy makers. Methods: A survey of mothers at a Tertiary Care Hospital in central India. Results: On the knowledge front >83.75% of the mothers studied showed good knowledge about breastfeeding and complementary feeding. Similar, but not as encouraging, were the results about attitude, with 76.25% of mothers having a positive attitude. The results of the practices part were varied. The WHO indicators assessed were 'early initiation of breastfeeding' (68.75%), 'exclusive breastfeeding under 6 months' (85%) (however exclusive breast feeding for first 6 months was carried out by only 36.25%), 'introduction of solid, semi solid or soft foods' (48.75%), 'continued breastfeeding at 1 year' (63.75%) and 'continued breastfeeding at 2 years' (6.25%). Conclusions: There is a discrepancy between knowledge and practices. The exclusive breast feeding rates are far from the ideal and there is a decline of continued breast feeding beyond 15 months. This calls for sustained efforts with the aim - 'cover all and cover completely'. The ideal WHO indicator for exclusive breast feeding should be 'exclusive breastfeeding for first 6 months' which will provide information about the completeness of this ideal practice. PMID- 29386729 TI - Risk factors for degenerative aortic valve disease in India: A case control study. AB - Background: Degenerative aortic valve disease often co-exists with coronary artery disease (CAD) and studies done in western populations have shown that it shares the same risk factors which cause CAD. However little is known in this context among Asian Indians. The current study looks into the risk factors of degenerative aortic valve disease in Asian Indian population. Methods: Ninety-one consecutive patients with severe aortic stenosis (AS) reporting for left heart catheterization prior to valve replacement surgery at a tertiary care centre were recruited for the study. They were compared with age and sex matched controls selected from a database of 3200 patients referred for elective diagnostic left heart catheterization for suspected CAD. Following traditional cardiovascular risk factors were assessed in all patients: age, gender, family history of CAD, smoking history, presence of diabetes, hypertension and dyslipidemia. Results: The mean age of the study population was 57.8 +/- 8.2 years (range, 40-80 years). Smoking, family history of CAD and hypercholesterolemia were significantly more prevalent in patients with degenerative AS compared to those with normal valves. No significant difference was noted in the presence of diabetes mellitus. On multivariate logistic regression, family history of premature CAD (OR 3.68; CI 1.38-9.78) smoking history (OR, 2.56; CI, 1.21-5.39), and raised LDL levels (OR, 5.55; CI, 2.63-11.69) were independently associated with the aortic stenosis patient cohort. Conclusions: The study showed a significant association of cardiovascular risk factors with aortic stenosis independent of age and gender in Asian Indian patients. PMID- 29386730 TI - Effect of wrist cooling on aerobic and anaerobic performance in elite sportsmen. AB - Background: Body cooling has been used to increase sporting performance and enhance recovery. Several studies have reported improvement in exercise capacities using forearm and hand cooling or only hand cooling. Wrist cooling has emerged as a portable light weight solution for precooling prior to sporting activity. The Astrand test for aerobic performance and the Wingate test for anaerobic performance are reliable and accurate tests for performance assessment. This study conducted on elite Indian athletes analyses the effects of wrist precooling on aerobic and anaerobic performance as tested by the Astrand test and the Wingate test before and after wrist precooling. Methods: 67 elite sportsmen were administered Wingate and Astrand test under standardised conditions with and without wrist precooling using a wrist cooling device (dhamaSPORT). Paired t-test was applied to study effect on aerobic [VO2 (ml/min/kg)] and anaerobic performance [peak power (W/kg) and average power (W/kg)] and Cohen's d was used to calculate effect size of wrist precooling. Results: After wrist precooling, significant increase of 0.22 (p = 0.014, 95% CI: 0.047, 0.398) in peak power (W/kg) and 0.22 (p < 0.0001, 95% CI: 0.142, 0.291) was observed in average power (W/kg). Although, an increase of 1.38 (p = 0.097, 95% CI: -0.225, 3.012) was observed in VO2 (ml/min/kg), wrist precooling was not significantly effective in aerobic performance. Wrist cooling effect size was smaller in VO2 (Cohen's d = 0.21), peak power (Cohen's d = 0.31) and it was larger in average power (Cohen's d = 0.71). Conclusion: Results show wrist precooling significantly improves anaerobic than aerobic performance of elite sportsmen. PMID- 29386731 TI - Severe ovarian hyperstimulation syndrome: Can we eliminate it through a multipronged approach? AB - Background: Prevention of severe Ovarian Hyperstimulation Syndrome (OHSS), a potentially fatal complication of controlled ovarian hyperstimulation has been the aim of all fertility experts. Various pharmacologic and non-pharmacologic interventions have been instituted but the results have been conflicting. These preventive strategies were administered in isolation or as a combination of few aiming to eliminate this iatrogenic sequel. This study aimed to eliminate severe OHSS by multipronged approach incorporating almost all preventive modalities available in patients at high risk for this dreadful complication. Methods: It was a prospective observational study wherein 112 high risk patients planned for IVF were studied. The multipronged approach was in the form administering calcium gluconate infusion, cabergoline, albumin infusion, GnRH antagonist in luteal phase in addition to elective cryopreservation of embryos. The primary outcome measure was incidence of severe OHSS in the study group and the rate of hospitalisation. The secondary outcome measure was the number of days required for complete recovery and resolution of signs and symptoms. Results: Out of the 112 high risk patients only one patient (1/112; 0.9%) developed severe OHSS with an overall incidence of 0.095% of severe OHSS in all the cycles. There was no biochemical or haematological derangement in any of the high risk patients. Conclusion: Although this is the first study evaluating the multipronged approach in preventing the dreaded complication of severe OHSS, it does add to the knowledge that targeting the various pathophysiological pathways at different time frames will bring about prevention of OHSS but further randomised studies may reveal superiority of one intervention over the other. PMID- 29386732 TI - Functional outcome after arthroscopic management of traumatic recurrent dislocation shoulder using Bankart repair and Remplissage techniques. AB - Background: Recurrent dislocation shoulder is one of the common shoulder injuries encountered by the orthopedic surgeon in clinical practice. Bankart repair using the arthroscopic method has become one of the standard techniques in the management of recurrent dislocation shoulder. Remplissage technique can be used as adjunct to Bankart repair in certain conditions. Method: In this case series, we have assessed the functional outcome and return to activity at midterm follow up after arthroscopic management. Results: 51 patients with traumatic shoulder dislocation were operated using the shoulder arthroscopic technique. Rowe score improved significantly at the latest follow-up. No major complication was noticed in our case series. Conclusion: The shoulder arthroscopy procedure requires special instrumentation and expertise. We believe that this is a less invasive and safe procedure and provides an additional tool in the management of instabilities including in cases of complex recurrent dislocation of the shoulder. PMID- 29386733 TI - 'Jago Grahak Jago': A cross-sectional study to assess awareness about food adulteration in an urban slum. AB - Background: Food adulteration includes various forms of practices, including mixing, substituting, concealing the quality of food, etc. One of the main causes for rampant adulteration is ignorance of consumer regarding their right and responsibilities resulting in faulty buying practices. Hence, the present study was done to assess the knowledge about adulteration among consumers in an urban slum. Methods: A community-based cross-sectional study was done among residents of an urban slum over a period of 2 months. Adults responsible for purchasing groceries for the household were included. A sample size of 100 was taken and pilot-tested questionnaire was administered. All of them were made aware about adulteration. Results: The mean age of the study subjects was 40.2 +/- 11.7 years. Only 7% of the study subjects were illiterate. Good practices like checking of Food Safety and Standards Authority of India (FSSAI) logo (90%), Agmark logo (76%) and nutrition label (65%) are lacking among the majority. The most prominent source of knowledge about adulteration is mass media especially television (65%). Almost 40% of the study subjects are unaware about the consumer empowering initiative 'Jago Grahak Jago'. Factors which had a strong positive relationship with good practices like checking of nutrition label, FSSAI logo, Agmark logo, seal and expiry date are age, education status and socio-economic status (p value <= 0.05). Conclusion: Majority of study subjects are unaware about adulteration. 'Jago Grahak Jago' initiative which empowers the consumers has to be instilled in the minds of consumers. Awareness and motivation will lead to empowerment and end the menace of food adulteration. PMID- 29386734 TI - Zika: An enormous public health challenge for a miniscule virus. AB - Zika virus (ZIKV) infection has recently affected 4 million people across the globe. The World Health Organization has declared Zika a "Public Health Emergency of International Concern". The disease is caused by an arbovirus and transmitted by Aedes mosquitoes. Zika has followed a pattern already set in by Dengue and Chikungunya viruses. The virus exists in sylvatic form with spillovers to humans. The present outbreak in Brazil started in May 2015 and spread rapidly to Latin America and the Caribbean. The rapid spread is due to availability of non-immune population. The main concern of Zika is the association with microcephaly in infants and Guillain-Barre (GB) Syndrome. During the current Zika outbreak in Brazil, incidence of microcephaly in infants has shown a 20-fold rise. Increased incidence of GB Syndrome has been noticed during the 2013 outbreak in French Polynesia, and the current outbreak. However, causality has not been proved. It is possible that the ZIKV may enter and get established in India. Surveillance against the disease needs to be scaled up. Research needs to be undertaken regarding the dynamics of Zika spread and the development of vaccines. Inter sectoral coordination and bottom-up approach along with vector control measures under the ambit of National Vector Borne Disease Control Programme may help fight the virus. PMID- 29386735 TI - Translabyrinthine approach to internal auditory meatus: A retrospective study. AB - Background: Ear and the lateral skull base surgery is challenging and yet fascinating for a Neuro-otologist. A thorough knowledge of the complex anatomy is indispensable for the surgeon in order to provide the best possible care. Methods: The aim of the study was to highlight the present day indications for translabyrinthine approach to IAM from a Neuro-otologist perspective. Results: There were a total of 7 patients who underwent Translabyrinthine approach at our centre. In the present study we have reported cases of Vestibular Schwannoma, Facial nerve schwannoma, Cholesteatoma involving the IAM, Meniere's disease with refractory vertigo which were managed via translabyrinthine approach. We also encountered, probably the first reported case, tuberculoma of the IAM which was clinical suspected to be vestibular schwannoma. Conclusion: The article presents different clinical situations where this approach can be suitably utilized and has been dealt with via a retrospective study encountered at our centre. PMID- 29386736 TI - Laparoscopic laser lithotripsy inside the endocatch bag: An alternative technique for removal of large post lap pyelolithotomy calculi. AB - Large staghorn calculi in unascended pelvic kidneys and in normally located kidneys with anatomy unsuitable for percutaneous nephrolithotomy have to be treated via pyelolithotomy. When performed laparoscopically, the extraction of these staghorn calculi, without extending skin incision at the port site is challenging. We describe the successful use of laparoscopic laser lithotripsy, intracorporeally, with the entrapped calculus inside the endocatch bag, for fragmentation and retrieval without extension of skin incision. PMID- 29386737 TI - Parameatal urethral cyst. AB - Parameatal urethral cyst is a rare clinical entity, resulting in asymptomatic cosmetic concerns, distortion of urinary stream or difficulty in urination. Though they cause considerable parental concerns, natural history is to resolve spontaneously or rarely surgical excision is needed. We report a neonate with asymptomatic parameatal urethral cyst. PMID- 29386738 TI - Managing a case of crowding with associated severe periodontitis. PMID- 29386739 TI - Nasal myiasis by Chrysomya bezziana. PMID- 29386740 TI - Epithelial cyst of spleen presenting as hypersplenism. PMID- 29386741 TI - A case of hypophysitis in a young male patient. PMID- 29386742 TI - Indian Diabetes Risk Score: Use beyond population screening for diabetes. PMID- 29386743 TI - Accreditation of service hospitals: Time to move towards state of readiness. PMID- 29386744 TI - One 'poison' leads to the other: Snake bite while under the influence of alcohol! PMID- 29386745 TI - Treatment Recruitment and Retention of Geriatric Participants With Hoarding Disorder. AB - This study describes the initial contact of 255 potential participants, recruitment of 63 participants, and retention of 57 participants from three geriatric Hoarding Disorder (HD) studies. Patients with HD were easily recruited from the community, primarily through the use of clinician referrals and posted flyers, as evidenced by steady patient flow despite lack of compensation for participation. Contrary to treatment outcomes of late life mood and anxiety disorders, geriatric HD patients are largely retained in clinical research treatment studies. Results demonstrate that older adults with HD can be engaged in treatment. Participants often needed the study staff to provide substantial support, including informal motivational interviewing and problem solving, in scheduling and attending the initial visit. PMID- 29386747 TI - Increased Risk Proneness or Social Withdrawal? The Effects of Shortened Life Expectancy on the Expression of Rescue Behavior in Workers of the ant Formica cinerea (Hymenoptera: Formicidae). AB - In social insects behavioral consequences of shortened life expectancy include, among others, increased risk proneness and social withdrawal. We investigated the impact of experimental shortening of life expectancy of foragers of the ant Formica cinerea achieved by their exposure to carbon dioxide on the expression of rescue behavior, risky pro-social behavior, tested by means of two bioassays during which a single worker (rescuer) was confronted with a nestmate (victim) attacked by a predator (antlion larva capture bioassay) or immobilized by an artificial snare (entrapment bioassay). Efficacy of carbon dioxide poisoning in shortening life expectancy was confirmed by the analysis of ant mortality. Rescue behavior observed during behavioral tests involved digging around the victim, transport of the sand covering the victim, pulling the limbs/antennae/mandibles of the victim, direct attack on the antlion (in antlion larva capture tests), and snare biting (in entrapment tests). The rate of occurrence of rescue behavior was lower in ants with shortened life expectancy, but that effect was significant only in the case of the entrapment bioassay. Similarly, only in the case of the entrapment bioassay ants with shortened life expectancy displayed rescue behavior after a longer latency and devoted less time to that behavior than ants from the control groups. Our results demonstrated that in ant workers shortened life expectancy may lead to reduced propensity for rescue behavior, most probably as an element of the social withdrawal syndrome that had already been described in several studies on behavior of moribund ants and honeybees. PMID- 29386748 TI - Lexical quality and executive control predict children's first and second language reading comprehension. AB - This study compared how lexical quality (vocabulary and decoding) and executive control (working memory and inhibition) predict reading comprehension directly as well as indirectly, via syntactic integration, in monolingual and bilingual fourth grade children. The participants were 76 monolingual and 102 bilingual children (mean age 10 years, SD = 5 months) learning to read Dutch in the Netherlands. Bilingual children showed lower Dutch vocabulary, syntactic integration and reading comprehension skills, but better decoding skills than their monolingual peers. There were no differences in working memory or inhibition. Multigroup path analysis showed relatively invariant connections between predictors and reading comprehension for monolingual and bilingual readers. For both groups, there was a direct effect of lexical quality on reading comprehension. In addition, lexical quality and executive control indirectly influenced reading comprehension via syntactic integration. The groups differed in that inhibition more strongly predicted syntactic integration for bilingual than for monolingual children. For a subgroup of bilingual children, for whom home language vocabulary data were available (n = 56), there was an additional positive effect of home language vocabulary on second language reading comprehension. Together, the results suggest that similar processes underlie reading comprehension in first and second language readers, but that syntactic integration requires more executive control in second language reading. Moreover, bilingual readers additionally benefit from first language vocabulary to arrive at second language reading comprehension. PMID- 29386746 TI - Tomographic phase microscopy: principles and applications in bioimaging [Invited]. AB - Tomographic phase microscopy (TPM) is an emerging optical microscopic technique for bioimaging. TPM uses digital holographic measurements of complex scattered fields to reconstruct three-dimensional refractive index (RI) maps of cells with diffraction-limited resolution by solving inverse scattering problems. In this paper, we review the developments of TPM from the fundamental physics to its applications in bioimaging. We first provide a comprehensive description of the tomographic reconstruction physical models used in TPM. The RI map reconstruction algorithms and various regularization methods are discussed. Selected TPM applications for cellular imaging, particularly in hematology, are reviewed. Finally, we examine the limitations of current TPM systems, propose future solutions, and envision promising directions in biomedical research. PMID- 29386749 TI - Face-to-Face or Telematic Cognitive Stimulation in Patients with Multiple Sclerosis and Cognitive Impairment: Why Not Both? AB - Introduction: Cognitive impairment (CI) affects 40-65% of patients with multiple sclerosis (MS). Few studies address telematic cognitive stimulation (TCS) in MS. The objective of this study is to evaluate the efficacy and impact of telestimulation or distance cognitive stimulation (TCS), with and without the support of face-to-face cognitive stimulation (FCS) in cognitive impairment in MS. Methods: Multicentre, prospective, randomised, controlled study. We will include 98 MS patients with EDSS <= 6, symbol digit modality test (SDMT) <= Pc 25, and Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) > 26 points. Patients will be randomised into 3 groups, a TCS group, a mixed TCS/FCS group, and a control group. CS is performed 3 days a week for 3 months. Processing speed, memory, attention, and executive functions will be rehabilitated. FCS will include ecological exercises and strategies. EDSS and a cognitive evaluation (SDMT, CTMT, PASAT, and TAVEC), MSNQ, psychological impact scales (MSIS), and depression (BDI) will be carried out, baseline, postrehabilitation, and also 6 and 12 months later, to evaluate the effect of CS in the longer term. Conclusion: This study could help to establish the usefulness of TCS or, in its absence, TCS with face-to-face help for CI in MS. The interest lies in the clear benefits of remote rehabilitation in the daily life of patients. PMID- 29386751 TI - Tomatidine Attenuates Airway Hyperresponsiveness and Inflammation by Suppressing Th2 Cytokines in a Mouse Model of Asthma. AB - Tomatidine is isolated from the fruits of tomato plants and found to have anti inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR) and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro, tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice. PMID- 29386750 TI - The Role of Lower Airway Dysbiosis in Asthma: Dysbiosis and Asthma. AB - With the development of culture-independent techniques, numerous studies have demonstrated that the lower airway is not sterile in health and harbors diverse microbial communities. Furthermore, new evidence suggests that there is a distinct lower airway microbiome in those with chronic respiratory disease. To understand the role of lower airway dysbiosis in the pathogenesis of asthma, in this article, we review the published reports about the lung microbiome of healthy controls, provide an outlook on the contribution of lower airway dysbiosis to asthma, especially steroid-resistant asthma, and discuss the potential therapies targeted for lower airway dysbiosis. PMID- 29386752 TI - Different Dietary Proportions of Fish Oil Regulate Inflammatory Factors but Do Not Change Intestinal Tight Junction ZO-1 Expression in Ethanol-Fed Rats. AB - Sixty male Wistar rats were fed a control or an ethanol-containing diet in groups C or E. The fat compositions were adjusted with 25% or 57% fish oil substituted for olive oil in groups CF25, CF57, EF25, and EF57. Hepatic thiobarbituric acid reactive substance (TBARS) levels, cytochrome P450 2E1 protein expression, and tumor necrosis factor- (TNF-) alpha, interleukin- (IL-) 1beta, IL-6, and IL-10 levels, as well as intracellular adhesion molecule (ICAM)-1 levels were significantly elevated, whereas plasma adiponectin level was significantly reduced in group E (p < 0.05). Hepatic histopathological scores of fatty change and inflammation, in group E were significantly higher than those of group C (p < 0.05). Hepatic TBARS, plasma ICAM-1, and hepatic TNF-alpha, IL-1beta, and IL-10 levels were significantly lower, and plasma adiponectin levels were significantly higher in groups EF25 and EF57 than those in group E (p < 0.05). The immunoreactive area of the intestinal tight junction protein, ZO-1, showed no change between groups C and E. Only group CF57 displayed a significantly higher ZO-1 immunoreactive area compared to group C (p = 0.0415). 25% or 57% fish oil substituted for dietary olive oil could prevent ethanol-induced liver damage in rats, but the mechanism might not be related to intestinal tight junction ZO-1 expression. PMID- 29386754 TI - The international politics of geoengineering: The feasibility of Plan B for tackling climate change. AB - Geoengineering technologies aim to make large-scale and deliberate interventions in the climate system possible. A typical framing is that researchers are exploring a 'Plan B' in case mitigation fails to avert dangerous climate change. Some options are thought to have the potential to alter the politics of climate change dramatically, yet in evaluating whether they might ultimately reduce climate risks, their political and security implications have so far not been given adequate prominence. This article puts forward what it calls the 'security hazard' and argues that this could be a crucial factor in determining whether a technology is able, ultimately, to reduce climate risks. Ideas about global governance of geoengineering rely on heroic assumptions about state rationality and a generally pacific international system. Moreover, if in a climate engineered world weather events become something certain states can be made directly responsible for, this may also negatively affect prospects for 'Plan A', i.e. an effective global agreement on mitigation. PMID- 29386753 TI - HIF1alpha-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages. AB - Hypoxia-inducible factor (HIF) 1alpha is a metabolic regulator that plays an important role in immunologic responses. Previous studies have demonstrated that HIF1alpha participates in the M1 polarization of macrophages. To clarify the mechanism of HIF1alpha-induced polarization of M1 macrophage, myeloid-specific HIF1alpha overexpression (Lysm HIF1alpha lsl) mice were employed and the bone marrow-derived and peritoneal macrophages were isolated. RT-PCR results revealed that HIF1alpha overexpression macrophage had a hyperinflammatory state characterized by the upregulation of M1 markers. Cellular bioenergetics analysis showed lower cellular oxygen consumption rates in the Lysm HIF1alpha lsl mice. Metabolomics studies showed that HIF1alpha overexpression led to increased glycolysis and pentose phosphate pathway intermediates. Further results revealed that macrophage M1 polarization, induced by HIF1alpha overexpression, was via upregulating the mRNA expression of the genes related to the glycolysis metabolism. Our results indicate that HIF1alpha promoted macrophage glycolysis metabolism, which induced M1 polarization in mice. PMID- 29386755 TI - Vision 2022. PMID- 29386756 TI - Presidential Address at 43rd Annual Conference of the Indian Association of Pediatric Surgeons (IAPSCON 2017), Kolkata, September 21-24, 2017. PMID- 29386757 TI - Anterior Sagittal Anorectoplasty with External Sphincter Preservation for the Treatment of Recto-vestibular Fistula: A New Approach. AB - Context: To our knowledge, there is no description of anterior sagittal anorectoplasty (ASARP) with external anal sphincter preservation and passing neorectum in the middle of muscle complex under direct vision for the treatment of recto-vestibular fistula (VF). Aim: This study evaluates a new modification combining ASARP with under vision sphincter preservation. Subjects and Methods: This prospective study was conducted on thirty female infants with VF. Procedure starts with a vertical midline incision extending from ectopic opening to posterior limit of external sphincter. Sharp dissection of the fistula is carried out. Artery forceps is passed at the center of muscle complex under vision, then neorectum is placed in the middle of the muscle complex. We introduced a new scoring system based on parental interview assessing functional outcome. Each patient was given a score between 0 and 20; good: 14-20, fair: 7-13, and poor: 0 6. Results: ASARP was performed at a mean age of 2.6 months, a mean weight of 5.2 kg, a mean operative time of 102 min, and a mean hospital stay of 3.6 days. Wound infection occurred in four cases, seven cases had perianal excoriations, six cases had anal stenosis, and only one case complained of anal displacement. Patients followed for a mean of 18.8 months. Majority of our patients (50%) had good score (mean = 16.8), normal frequency, no or mild soiling, normal anal position with no or mild stenosis. Fourteen patients had fair score (mean = 10.5). Only one had poor outcome with severe soiling and perineal excoriation. Conclusion: Our modification offers optimal correction, with minimal sphincteric damage, without additional complexity or difficulties. Scoring system is simple, practical, and truly reflects early functional and parent satisfaction after surgery. PMID- 29386758 TI - Challenges in Management of Pediatric Life-threatening Neck and Chest Trauma. AB - Introduction: Neck and thoracic trauma in children pose unforeseen challenges requiring variable management strategies. Here, we describe some unusual cases. Patients and Methods: Pediatric cases of unusual neck and thoracic trauma prospectively managed from April 2012 to March 2014 at a Level 1 trauma center were studied for management strategies, outcome, and follow-up. Results: Six children with a median age of 5.5 (range 2-10) years were managed. Mechanism of injury was road traffic accident, fall from height and other accidental injury in 2, 3 and 1 patient respectively. The presentation was respiratory distress and quadriplegia, exposed heart, penetrating injury in neck, dysphagia and dyspnea, and swelling over the chest wall in 1, 1, 1, 2 and 1 cases respectively. Injuries included lung laceration, open chest wall, vascular injury of the neck, tracheoesophageal fistula (2), and chest wall posttraumatic pyomyositis. One patient had a flare of miliary tuberculosis. Immediate management included chest wall repair; neck exploration and repair, esophagostomy, gastroesophageal stapling, and feeding jejunostomy (followed by gastric pull-up 8 months later). Chest tube insertion and total parenteral nutrition was required in one each. 2 and 4 patients required tracheostomy and mechanical ventilation. The patient with gastric pull-up developed a stricture of the esophagogastric anastomosis that was revised at 26-month follow-up. At follow-up of 40-61 months, five patients are well. One patient with penetrating neck injury suffered from blindness due to massive hemorrhage from the vascular injury in the neck and brain ischemia with only peripheral vision recovery. Conclusion: Successful management of neck and chest wall trauma requires timely appropriate decisions with a team effort. PMID- 29386759 TI - Tubeless Pediatric Percutaneous Nephrolithotomy: Assessment of Feasibility and Safety. AB - Introduction: Tubeless pediatric percutaneous nephrolithotomy (TL-PCNL) is evolving and adult criteria are being safely applied to children. We examine the feasibility, safety, and outcomes of pediatric TL. Materials and Methods: A retrospective review of pediatric (<=18 years) PCNL patients at our institute was done. Patients eligible for TL but underwent tube (T) PCNL due to surgeon choice or protocol were compared with TL. Only children with 100% stone clearance were included, and those receiving nephrostomy for intraoperative complications were excluded from the study. Demographic, baseline, and stone characteristics were matched. Safety, outcome, and complications were assessed. Group T was classified into large bore (22F-LB) and small bore (16F-SB) based on nephrostomy size. Statistical analysis was done. Results: A total of 46 children were eligible - TL in 17 (37%) and T in 29 (63%). Among T, SB was performed in 6/29 (20.7%) and LB in 23/29 (79.3%). TL had fewer complications. Urinary leak developed in 2 (6.9%) patients in T. Eight (27.6%) patients in T and 3 (17.7%) patients in TL had supracostal access with complications similar to infracostal access. SB had significantly lesser and analgesic requirement than LB. SB and TL had similar LOH and analgesic requirement. Adult expanded criteria such as supracostal access, 2 punctures, prior renal surgery, and larger tract size were feasible. Conclusions: TL is safe, feasible, and less morbid alternative to T in uncomplicated pediatric nephrolithiasis. TL is feasible with supracostal access, 2 punctures, adult tract size (24F), and anomalous kidneys. SB nephrostomy is reasonable when tube is indicated. PMID- 29386760 TI - Multiloculated Cystic Renal Tumors of Childhood: Has the Final Word Been Spoken. AB - Background: Multicystic renal tumors which include cystic nephroma, cystic partially differentiated nephroblastoma (CPDN) and cystic Wilms tumor has been a diagnostic and therapeutic challenge. Histopathological examination has been the only reliable differentiating method. Management of these tumors is still riddled with controversy as a definitive preoperative differentiation between the three has not been possible. Methods: A retrospective evaluation was performed of the treatment strategies employed with nine cases of multicystic renal tumors treated from 2005 to 2015. Results: The median age at presentation was 12 months with all except one being boys. All except two children underwent primary surgery. The median follow-up was 50 months with six children having long-term survival. One child succumbed to the disease process, one died due to an unrelated cause and another was lost to follow-up. Although there was no ambiguity with cases of cystic nephroma (CN) and cystic Wilms tumor, three of the four cases of CPDN had problems. Conclusion: Primary surgery for multicystic renal tumors is safe and should be seriously considered as it prevents overtreatment in cases of CN and early stage CPDN. Further studies are needed to fully understand the biological behavior of CPDN. PMID- 29386761 TI - IschioPubic Osteotomy, A Simple and Effective Technique for Pelvic Ring Closure in Repair of Classic Exstrophy Bladder. AB - Aim: The aim of this study is to report the technique and outcome of ischiopubic (IP) osteotomy for pelvic ring closure in classic exstrophy bladder. Methods: A total of 85 male classic exstrophies were selected based on trapezoid-shaped space between IP ramus on three-dimensional computed tomography pelvis. Using midline scroto-perineal approach, after bladder plate mobilization and radical corporal detachment; the pelvic surface of superior pubic ramus (SPR) was exposed. Above the obturator canal, H-shaped incision was made on periosteum of the SPR. The horizontal line of H was placed above the obturator canal. Rectangular periosteal flaps above and below the horizontal line was raised. In the subperiosteal plane, curved hemostats encircled the SPR that were divided using a bone drill. On the medial aspect of ischial tuberosity, a notch was created as hinge using a bone drill. Forks of bone holding forceps hooked the pubic bone and tightened for its midline approximation, lengthening of the SPR and inward rotation of IP ramus. Linea alba and pubic bones were approximated with interrupted Polygalactin sutures. Results: Midline approximation of pubic bone and linea alba was possible in all. There was no injury to obturator nerve, vessels, or other structures . Conclusions: IP osteotomy is the safe and effective technique of pelvic ring closure in patients with specific pelvic configuration. PMID- 29386762 TI - Antireflux Status Post Roux-en-Y anastomosis: An Experimental Study for Optimal Antireflux Technique. AB - Background: Roux-en-Y hepaticojejunostomy has been a gold standard to establish biliary-enteric anastomosis for various surgical indications, but associated with variable incidences of cholangitis. This experimental study was conducted to report a modification in Roux-en-Y anastomosis for possible better alternative to provide antireflux procedure after Roux-en-Y biliary-enteric anastomosis with the aim to minimize the possibility of reflux and its consequences. Materials and Methods: For experimental study, the required fresh segment of Lamb's small intestine was procured. Three sets of Roux-en-Y anastomosis were created for each experiment. In set 1, there was simple Roux-en-Y anastomosis. In set 2, Roux-en-Y anastomosis along with 4-5 cm long spur between the hepatic and duodenal limbs was created. In set 3, in addition to Roux-en-Y with creation of spur, additional antireflux mechanism was created at the junction of upper two-third and lower one third of the hepatic limb. Saline mixed contrast was infused by infusion pump to raise the intraluminal pressure to more than 10 cm of H2O. X-ray was taken at that time. Results: In set 1, all preparations demonstrated reflux of contrast in the hepatic limb. The set 2 also demonstrated the same findings of 100% reflux in the hepatic limb. In set 3, No reflux was observed in 8 (80%) preparations while remaining 2 (20%) preparations reveal partial reflux. Conclusion: This experimental study suggests that the provision of spur and additional valve may be able to decrease the possibility of reflux in Roux-en-Y biliary-enteric anastomosis. PMID- 29386763 TI - Ileal Cystic Lymphangioma presenting with Acute Appendicitis. AB - Mesenteric lymphatic malformations are rare benign tumors that are most commonly found in children. The presentation of these tumors can be variable. It has been suggested that mesenteric lymphatic malformations are congenital; however, there is evidence that their size may be increased by infection. A 3-year 10-month-old boy presented with rhinorrhea and cough followed by acute abdominal pain. Ultrasonography revealed a lobulated mass in the lower abdomen. Computerized tomography scan of the abdomen diagnosed an inflamed appendix with perforation. Laparotomy revealed a multicystic mass within the mesentery closely adherent to the ileum; with omentum wrapped around. The appendix was dilated and firm. An ileal resection and an appendicectomy were performed. Histology confirmed acute transmural appendicitis with concurrent cystic lymphangioma of the ileal mesentery. Although rare, cystic lymphangioma must be considered in the differential of pediatric acute abdomen. Surgeons must be aware of this association and be reminded to inspect the rest of small bowel during appendicectomy especially if the preoperative imaging is suspicious. PMID- 29386764 TI - Nasal Glial Heterotopia with Cleft Palate. AB - Congenital midline nasal masses are rare anomalies of which nasal glial heterotopia represents an even rarer subset. We report a case of a 25-day-old male child with nasal glial heterotopia along with cleft palate suggesting embryonic fusion anomaly which was treated with excision and primary closure for nasal mass followed by palatal repair at later date. PMID- 29386765 TI - A Rare Case Report of Bilateral Complex Macrocystic Adrenal Hemorrhage Mimicking Fetal Neuroblastoma. AB - Fetal and neonatal adrenal glands are large vascular organs, which make them vulnerable to frequent bleeding. Although neonatal adrenal hemorrhage is commonly reported, it is rarely diagnosed on antenatal sonography. We present a rare case of prenatally diagnosed bilateral adrenal hemorrhage, which mimicked antenatal neuroblastoma. PMID- 29386766 TI - Teratoma Arising from Hepato Duodenal Ligament in the Newborn with Transection of Portal Vein, Hepatic Artery and Common Bile Duct: A Surgical Challenge. AB - A 7-day-old neonate presented with a large intra-abdominal mass adherent to the hilum of the liver encasing the portal triad. During excision, the portal vein, hepatic artery, and common bile duct were injured. The repair was done promptly and needed massive blood transfusion. Histopathology revealed immature teratoma Grade III. Survival in neonate following total transection of portal triad is rare and has not been reported. PMID- 29386767 TI - Abdominoperineal Pull-through with Simultaneous Extravesical Detrussoraphy: An Alternative Surgical Technique for Congenital Pouch Colon with High-grade Vesicoureteric Reflux. AB - Congenital pouch colon (CPC) is frequently associated with vesicoureteric reflux (VUR). These patients require long-term antibiotic prophylaxis and/or an additional surgical intervention for the management of the refluxing system. We propose a single-stage alternative approach in these patients. Two patients diagnosed to have CPC underwent pouch excision and an end colostomy at birth. Further evaluation revealed high-grade reflux in both the patients. At 6 months of age, definitive abdominoperineal pull-through (APPT) surgery along with extravesical detrusorrhaphy was performed. In the follow-up at 1 year, they are thriving well with no urinary complaints. Micturating cystourethrogram revealed complete resolution of VUR. This approach takes the advantage of the anesthesia for APPT and offers a relatively simple and quick solution for the refluxing system, thus, enabling the stoppage of antibiotic prophylaxis and obviating the need for a future endoscopy/surgery. PMID- 29386768 TI - Pediatric Chylopericardium: Treatment Conundrum. AB - Primary chylopericardium is a rare entity in the pediatric population, which is characterized by chyle accumulation in the pericardial sac. Treatment of this rare problem is a management dilemma as no definitive treatment has been found to be curative. We share our experience of treating chylopericardium with minimally invasive surgery. PMID- 29386769 TI - Mesenteric Leiomyoma in Infancy. PMID- 29386770 TI - Plagiarism and Pediatric Surgery Publications. PMID- 29386771 TI - Greetings from the editorial committee. PMID- 29386772 TI - Assessment of the number of root canals in the maxillary and mandibular molars: A radiographic study using cone beam computed tomography. AB - Context: The identification of root canals plays an important role in successful endodontic diagnosis and treatment. An inappropriate identification of canal resulting in incomplete removal of pulp tissue from the root canals is the main reason for the failure of endodontic treatment in molars. Radiographic imaging is an essential investigative tool in successful endodontics. Cone beam computed tomography (CBCT) the imaging is relatively a new method to visualize the roots in all the three planes. Aims: This is a study to assess number of root canals in maxillary and mandibular first and second molars on both the right and left sides using CBCT imaging. Settings and Design: A total of 100 CBCT images, which were available as soft copies on the hard drive of the computer in the Department of Oral Medicine and Radiology were considered for the study. Subjects and Methods: The axial view sections of the maxillary and mandibular arch of 1 mm thickness were examined with a magnification of 250%. The Images were scrolled down from the cementoenamel junction till the apical foramen and the maximum number of canals in each root were recorded. Statistical Analysis Used: The collected data were tabulated (Microsoft Excel 2013) and analyzed by independent t-test using statistical analysis software SPSS. Results: Among the maxillary first molars, 72.5% had 4 canals with 76.5% of mesiobuccal root having 2 canals. 49% of maxillary second molar had 3 canals with 53.5% of mesiobuccal root having 1 canal. 67.5% of mandibular first molar had 3 canals with 96.5% of mesial root having 2 canals. Conclusions: According to this study, the variations in the number of canals were more with respect to maxillary first molars when compared to the other molars. CBCT can provide the clinician with supplemental information about the different root canal configurations for successful root canal treatment. PMID- 29386773 TI - Shear bond strength of different restorative materials to mineral trioxide aggregate and Biodentine. AB - Significance of Study: Mineral trioxide aggregate (MTA) and Biodentine (calcium silicate-based materials) have great importance in dentistry. There is no study comparing the bond strength of Biodentine and MTA for composite, compomer, and compomer or resin-modified glass ionomer (RMGIC). Although many advantages of Biodentine over MTA; in this study, MTA has shown better shear bond strength (SBS) to restorative materials. Aim: Recently, a variety of calcium silicate based materials are often used for pulp capping, perforation repair, and endodontic therapies. After those treatment procedures, teeth are commonly restored with composite resin, (RMGIC materials in pediatric dentistry. The aim of this study was to evaluate the SBS of composite resin (FiltekTM Z250; 3M ESPE, USA), compomer (Dyract XP; LD Caulk/Dentsply, USA), and resin-modified glass ionomer (Photac-Fil Quick Aplicap; 3M ESPE, USA) to white MTA and Biodentine. Materials and Methods: Ninety acrylic cylindrical blocks were prepared and divided into two groups (n = 45). The acrylic blocks were randomly allocated into 3 subgroups; Group-1A: MTA + composite (FiltekTM Z250), Group-1B: MTA + compomer (Dyract XP), Group-1C: MTA + RMGIC (Photac-Fil Quick Aplicap), Group-2A: Biodentine + composite, Group-2B: Biodentine + compomer, Group-2C: Biodentine + RMGIC. The specimens were mounted in Universal Testing Machine. A crosshead speed 1 mm/min was applied to each specimen using a knife-edge blade until the bond between the MTA/Biodentine and restorative material failed. Failure modes of each group were evaluated under polarized light microscope at *40 magnification. Results: There was no statistically significant difference between MTA + Composite resin with MTA + Compomer; and MTA + RMGIC with Biodentine + RMGIC (P > 0.05). There were statistically significant differences between other groups (P < 0.05). Conclusions: The results of the present study displayed that although many advantages of Biodentine over MTA; MTA has shown better SBS to compomer and composite resin materials than Biodentine. PMID- 29386774 TI - Evaluation of the chelating effect of chitosan solubilized in different acids. AB - Aim: This study aimed to compare, through dentin microhardness and colorimetric analysis, the chelating effect of 0.2% chitosan solubilized in different acids. Materials and Methods: The second and third cuts of the cervical region of maxillary central incisors were divided into four quadrants, resulting in eight specimens, which were treated with 50 MUL of solution for 5 min according to their group (n = 10): GI - 0.2% chitosan solubilized in 1% acetic acid; GII - 0.2% chitosan solubilized in 3.3% citric acid; GIII - 0.2% chitosan solubilized in 0.00145% hydrochloric acid; and GIV - 0.2% chitosan solubilized in 0.00112% nitric acid. A control was made from the chelating properties of the following acids: GV - 3.3% citric acid, GVI - 0.00145% hydrochloric acid, GVII - 0.00112% nitric acid, and GVIII - control (distilled water). Afterward, they were subjected to the Knoop microhardness tester with a load of 10 g for 15 s, resulting in three indentations of the root canal toward the cement. The measurements obtained were subjected to the one-way ANOVA test followed by Tukey's test (alpha =0.05). Subsequently dispensing the chitosan solutions, the same were subjected to colorimetric analysis. Results: Chitosan solubilized in acetic acid, followed by chitosan in citric acid, provided a greater reducing effect compared to the other groups. Similar results were observed in the colorimetric analysis. Conclusion: It was concluded that the chelating ability of the chitosan solution solubilized in acetic acid is higher than solubilization in citric, hydrochloric, and nitric acids. PMID- 29386775 TI - The effects of endodontic substances and naturally reducing agents on the bond strength of epoxy resin-based sealer to root dentin. AB - Aim: To evaluate the effects of sodium hypochlorite (NaOCl), chlorhexidine (CHX), and two naturally derived reducing agents on the bond strength of epoxy resin based sealer to root dentin. Materials and Methods: A total of 60 single-rooted human teeth were prepared using ProTaper (Dentsply Tulsa Dental Specialties, Johnson City, TN, USA) and an irrigation protocol including 5% NaOCl or 2% CHX gel, and ethylenediaminetetraacetic acid (EDTA), for smear layer removal. The following subgroups (n = 10) were also assessed according to the naturally derived reducing agent used: no agent (control group); grape seed extract (GSE); and green tea. Root canals were filled with gutta-percha and AH Plus (Dentsply DeTrey, Konstanz, Germany). Bond strength was measured using the push-out test, and statistical analyses were performed using ANOVA; failure patterns (modes) were classified as adhesive, cohesive, or mixed. The types of failure modes were evaluated using the Chi-squared test at alpha =0.05. Results: The irrigation protocols demonstrated similar bond strength values (P > 0.05). However, the Chi squared test revealed significant differences in failure mode among the groups (P < 0.05). An increase in the incidence of adhesive failures was observed for the NaOCl and EDTA groups. The other groups demonstrated a prevalence of mixed and cohesive failures. Conclusion: The irrigation protocols and use of naturally derived reducing agents had no effect on the bond strength of the resin-based sealer to dentin; however, improvement was evident in the adhesion quality of AH Plus to NaOCl-treated root dentin, due to the prevalence of cohesive failure. PMID- 29386776 TI - A comparative evaluation of sealing ability of four root end filling materials using fluid filtration method: An in vitro study. AB - Aim of the Study: The aim of this study was to compare and evaluate the sealing ability of four root end filling materials mineral trioxide aggregate (MTA)-Plus, Biodentine, MTA (MTA Angelus) and glass ionomer cement (GIC) using fluid filtration method. Materials and Methods: Forty-four extracted, human single rooted teeth were collected. The crown of each tooth was decoronated 2 mm above the cementoenamel junction. Canals were negotiated, instrumented, obturated using lateral compaction method. The access cavities were sealed with Cavit. Root end resection and apical root end cavity preparations of 4 mm were made in each specimen. The selected roots were then randomly divided into four groups (n = 11) and restored as follows. Group 1 - GIC, Group 2 - MTA (MTA Angelus), Group 3 - Biodentine, and Group 4 - MTA Plus. The apical microleakage of each specimen was assessed using fluid filtration method at 72 h, 1 month and 3 months. Microleakage in each specimen was recorded in mm (millimeter) and converted to MUl/min/cm H2O. Results: MTA Angelus showed least microleakage followed by Biodentine and MTA Plus. Least sealing ability was seen with GIC. There was statistically significant difference between all the materials at various time intervals. Conclusion: MTA Angelus showed superior sealing ability as a retrograde filling material followed by Biodentine and MTA Plus. PMID- 29386777 TI - Comparative evaluation of three different rotary instrumentation systems for removal of gutta-percha from root canal during endodontic retreatment: An in vitro study. AB - Context: Endodontic retreatment is performed in teeth with endodontic failures. The main goal of retreatment is cleaning and shaping of the root canal with removal of old root filling material. Hand instruments and rotary instruments are mainly used for removing this filling material. Aim of Study: To compare the relative efficacy of three rotary instrumentation systems for removal of gutta percha from root canal during endodontic retreatment. Objective of Study: To find out which NiTi system is more efficacious in retreatment and to check out the efficacy of retreatment with and without use of solvent. Materials and Methods: Sixty freshly extracted, single-rooted human mandibular premolars were instrumented with K-files, and each root canal was filled with gutta-percha and AH Plus (Dentsply Detrey, Konstanz, Germany) sealer using lateral compaction. Specimens were then divided into three experimental groups with twenty specimens each. Groups were then subdivided into ten specimens each. Groups were then retreated either with or without solvent. The removal of gutta-percha was performed using ProTaper retreatment files, Mtwo retreatment files, and R-Endo files after 2 weeks. The amount of root canal filling material remnant in the coronal, middle, and apical thirds was measured using stereomicroscope and computer image analysis program. Statistical Analysis Used: Data were evaluated statistically using analysis of variance. Results: ProTaper group was found to have less remnant filling material as compared to the other groups in coronal and middle thirds, but a significant difference was observed between ProTaper and Mtwo and Mtwo and R-Endo in the nonsolvent groups (P < 0.05). Mtwo group demonstrated less amount of remaining filling material in the nonsolvent group. Conclusions: Both nickel-titanium systems and ProTaper and Mtwo retreatment file systems, were found to be effective in the removal of root canal filling material. However, complete removal of gutta-percha from root canals did not occur with any of the experimental groups. PMID- 29386778 TI - To evaluate and compare the effect of different light-curing modes and different liners on cuspal deflection in premolar teeth restored with bulk filled or incrementally filled composite measured at different time intervals. AB - Aim: The aim of this study is to evaluate and to compare the effect of different light-curing modes and different liners on cuspal deflection in premolar teeth restored with bulk filled or incrementally filled composite measured at different time intervals. Materials and Methods: The study was divided into two parts (Part 1-different curing modes, Part 2-different liner) each with sixty extracted human upper premolar teeth with standardized large mesio-occlusal-distal cavities prepared. Each part was divided into two groups according to the composite used (Group A-Filtek Z350 XT, Group B-Sonic fill). Each group was then divided into three subgroups according to the light-curing modes (soft-start, pulse, and continuous curing mode) and liner (Filtek Z350 XT Flowable, Vitremer) used. The cuspal deflection was then measured with a digital micrometer gauge and subjected to statistically analysis using analysis of variance and Tukey's post hoc test. Results: Sonic fill composite, resin-modified glass ionomer cement (RMGIC) liner and curing with soft-start/pulse curing mode had significantly lower cuspal deflection compared to Filtek Z350 XT, flowable liner, and continuous curing mode, respectively. Conclusion: Sonic fill composite, RMGIC liner under the restorations and composites cured with soft start/pulse curing mode resulted in reduced cuspal deflection. PMID- 29386779 TI - Apical extrusion of debris during root canal preparation using a novel nickel titanium file system: WaveOne gold. AB - Aim: This study was intended to evaluate the amount of apically extruded debris following root canal preparation with three different instrumentation systems. Materials and Methods: Sixty mandibular incisor teeth were selected and randomly divided into three groups (n = 20/group) according to the instrumentation system used: the ProTaper Next (PTN; Dentsply Maillefer, Ballaigues, Switzerland), the Twisted File Adaptive (TFA; SybronEndo, Orange, CA, USA), and the WaveOne Gold (WOG; Dentsply Maillefer, Ballaigues, Switzerland). All apically extruded debris was collected and dried in preweighed glass vials. The mean weight of the apically extruded debris was obtained using a microbalance. The time for root canal preparation was also recorded. The data were analyzed using a one-way analysis of variance. Results: The mean weights of apically extruded debris were 0.00035 +/- 0.00014 g (PTN); 0.00023 +/- 0.0001 g (TFA); and 0.00019 +/- 0.0001 g (WOG) (P < 0.01). The mean preparation time value was 301,13 +/- 62.14 s (PTN); 234.27 +/- 34.88 s (TFA); and 239.8 +/- 58.6 s (WOG) (P < 0.05). Conclusions: The PTN system extruded more debris than the TFA and WOG systems. The TFA and WOG systems were faster than the PTN system. PMID- 29386780 TI - Reliability of cone beam computed tomography as a biopsy-independent tool in differential diagnosis of periapical cysts and granulomas: An In vivo Study. AB - Background: Differential diagnosis of periapical cysts and granulomas is required as their treatment modalities are different. Aim: The aim of this study was to evaluate the efficacy of cone beam computed tomography (CBCT) in the differential diagnosis of periapical cysts from granulomas. Settings and Design: A single centered observational study was carried out in the Department of Conservative Dentistry and Endodontics, Dr. R. Ahmed Dental College and Hospital, using CBCT and dental operating microscope. Methods: Forty-five lesions were analyzed using CBCT scans. One evaluator analyzed each CBCT scan for the presence of the following six characteristic radiological features: cyst like-location, shape, periphery, internal structure, effect on the surrounding structures, and cortical plate perforation. Another independent evaluator analyzed the CBCT scans. This process was repeated after 6 months, and inter- and intrarater reliability of CBCT diagnoses was evaluated. Periapical surgeries were performed and tissue samples were obtained for histopathological analysis. To evaluate the efficacy, CBCT diagnoses were compared with histopathological diagnoses, and six receiver operating characteristic (ROC) curve analyses were conducted. Statistical Analysis Used: ROC curve, Cronbach's alpha (alpha) test, and Cohen Kappa (kappa) test were used for statistical analysis. Results: Both inter- and intrarater reliability were excellent (alpha = 0.94, kappa = 0.75 and 0.77, respectively). ROC curve with regard to >=4 positive findings revealed the highest area under curve (0.66). Conclusion: CBCT is moderately accurate in the differential diagnosis of periapical cysts and granulomas. PMID- 29386781 TI - Efficacy of cone beam computed tomography in the detection of MB2 canals in the mesiobuccal roots of maxillary first molars: An in vitro study. AB - Background: Numerous researches have been done on the permanent maxillary first molars for the presence of an extra canal, especially the mesiobuccal roots for the presence of MB2 canals. Cone beam computed tomography (CBCT) has been used recently in the detection of these canals. However, literature discussing the efficacy and reliability of CBCT in the detection of these canals is scanty. Aims: This study aims to evaluate the efficacy of CBCT as a preoperative diagnostic aid in locating the second mesiobuccal canal in maxillary first molars. Methods: Selected sixty extracted maxillary first molars were placed in the skull base, and CBCT scans were done for evaluating the presence of MB2 canals in the mesiobuccal root. Sectioning of the roots at 3, 5, and 7 mm from the tip was performed and further examined under the microscope for the presence of the MB2 canals. Evaluations were done by two evaluators independently. Results of evaluations were statistically analyzed. Statistical analysis used were standard normal deviation (Z value), interrater reliability (Chronbach's alpha-), P value and receiver operating curve(ROC). Results and Conclusions: Detection rates of MB2 using both the methods did not show any significant difference (P > 0.05). CBCT was found to be a reliable tool for the detection of MB2 canal in maxillary first molar teeth when compared to gold standard sectioning technique. PMID- 29386782 TI - Effect of vital bleaching with solutions containing different concentrations of hydrogen peroxide and pineapple extract as an additive on human enamel using reflectance spectrophotometer: An in vitro study. AB - Aim: This study aims to evaluate the color change in human enamel bleached with three different concentrations of hydrogen peroxide, containing pineapple extract as an additive in two different timings, using reflectance spectrophotometer. Background: The study aimed to investigate the bleaching efficacy on natural teeth using natural enzymes. Materials and Methods: Baseline color values of 10 randomly selected artificially stained incisors were obtained. The specimens were divided into three groups of 20 teeth each: Group 1 - 30% hydrogen peroxide, Group II - 20% hydrogen peroxide, and Group III - 10% hydrogen peroxide. One half of the tooth was bleached with hydrogen peroxide, and other was bleached with hydrogen peroxide and pineapple extract for 20 min (Subgroup A) and 10 min (Subgroup B). Statistical Analysis: The results were statistically analyzed using student's t-test. Results: The mean DeltaE values of Group IA (31.62 +/- 0.9), Group IIA (29.85 +/- 1.2), and Group IIIA (28.65 +/- 1.2) showed statistically significant higher values when compared to the mean Delta E values of Group 1A (25.02 +/- 1.2), Group IIA (22.86 +/- 1.1), and Group IIIA (16.56 +/- 1.1). Identical results were obtained in Subgroup B. Conclusion: The addition of pineapple extract to hydrogen peroxide resulted in effective bleaching. PMID- 29386783 TI - Effect of human, dentin, albumin and lipopolysaccharide on the antibacteerial activity of endodontic activity of endodontic irrigants. AB - Context: Human dentin powder (HD), bovine serum albumin (BSA) and endotoxin (LPS) may affect the antimicrobial activity of irrigating solutions. Aim: To evaluate the inhibitory effect of HD powder, BSA, and LPS on the antibacterial activity of 0.5%, 1%, 2.5%, and 5% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX) gel, BioPure mixture of tetracycline, citric acid, and detergent (MTAD), and QMix. Methods: The direct contact test against Enterococcus faecalis (ATCC 29212) for 2 min, 30-min and 6-h was used. Sterile pyrogen-free water was the negative control. After experimental periods, a neutralizing agent was used. Colony forming units were determined by 10-fold serial dilutions and culture on agar plates. Data were analyzed by Kruskal-Wallis and Dunn's test (alpha = 5%). Results: In the absence of inhibitors, all irrigants eliminated E. faecalis. In contact with HD, all solutions eliminated E. faecalis within 2-min, with the exception of MTAD. In the presence of BSA, only 5% NaOCl killed E. faecalis within 2-min. LPS did not affect the antibacterial effect of any irrigant. At 30 min and at 6-h, all substances eliminated E. faecalis. Conclusions: In the presence of albumin, irrigants needed >2-min to eliminate E. faecalis, except for 5% NaOCl. The same was observed in the presence of dentin when E. faecalis was exposed to MTAD. PMID- 29386784 TI - Evaluation of new technique of sterilization using biological indicator. AB - Background: A novel technique of sterilization of endodontic files is introduced in this article. Aims: Newly introduced sterilization unit, named "SteriFast" is compared with autoclave and glass bead sterilizer using biological indicator. Materials and Methods: Spore strips of Bacillus pumilus were cultured in nutrient broth. This cultured media was used to contaminate the experimental samples of endodontic files. These contaminated files were sterilized using three different techniques. The sterilized files were transferred into nutrient medium under aseptic condition. The results were observed after 24 h, 48 h, and 7 days. Results: The results showed that autoclave and new sterilization device (SteriFast) showed complete sterilization. The files sterilized using glass bead sterilizer showed bacterial growth (80%). Conclusions: Thus, it proves that autoclave and SteriFast are ideal techniques of sterilization of endodontic files. Glass bead sterilizer does not completely sterilize the files. The article also compares SteriFast and autoclave in other aspects such as its design, basic principle, advantages, and disadvantages. The article also describes features and design of SteriFast, used for all kind of small dental instruments. PMID- 29386785 TI - Prevalence of C-shaped canals in mandibular second and third molars in a central India population: A cone beam computed tomography analysis. AB - Introduction: To evaluate the prevalence of C-shaped root canals in mandibular molars using cone beam computed tomography (CBCT) in a subpopulation of Central India. Materials and Methods: CBCT scans of patients from diagnostic imaging center were selected in accordance with the criteria given by Fan et al. (2004) for C-shaped canals. A total of 238 CBCT scans fulfilled the inclusion criteria and thereby divided into two groups: Group 1: Images showing C-shaped canal configuration in mandibular second molars. Group 2: Images showing C-shaped canal configuration in mandibular third molars. The frequency and distribution of canals and their configuration along with the position of lingual/buccal grooves in the images were evaluated, and the data was analyzed. Results: CBCT evaluation showed that 9.7% of second molars and 8% of third molars had C-shaped canals. A prominent buccal groove was seen in these teeth. The data showed a significant difference (P = 0.038) for the presence of such anatomy on the right side for mandibular third molars. Conclusion: The study showed a significant prevalence of C-shaped canal configuration in the subpopulation studied. PMID- 29386786 TI - Evaluation of the incidence of microcracks caused by Mtwo and ProTaper Next rotary file systems versus the self-adjusting file: A scanning electron microscopic study. AB - Introduction: To evaluate the incidence of microcrack formation canal preparation with two rotary nickel-titanium systems Mtwo and ProTaper Next along with the self-adjusting file system. Materials and Methods: One hundred and twenty mandibular premolar teeth were selected. Standardized access cavities were prepared and the canals were manually prepared up to size 20 after coronal preflaring. The teeth were divided into three experimental groups and one control group (n = 30). Group 1: The canals were prepared using Mtwo rotary files. Group 2: The canals were prepared with ProTaper Next files. Group 3: The canals were prepared with self-adjusting files. Group 4: The canals were unprepared and used as a control. The roots were sectioned horizontally 3, 6, and 9 mm from the apex and examined under a scanning electron microscope to check for the presence of microcracks. The Pearson's Chi-square test was applied. Results: The highest incidence of microcracks were associated with the ProTaper Next group, 80% (P = 0.00), followed by the Mtwo group, 70% (P = 0.000), and the least number of microcracks was noted in the self-adjusting file group, 10% (P = 0.068). No significant difference was found between the ProTaper Next and Mtwo groups (P = 0.368) while a significant difference was observed between the ProTaper Next and self-adjusting file groups (P = 0.000) as well as the Mtwo and self-adjusting file groups (P = 0.000). Conclusion: All nickel-titanium rotary instrument systems were associated with microcracks. However, the self-adjusting file system had significantly fewer microcracks when compared with the Mtwo and ProTaper Next. PMID- 29386787 TI - Fracture resistance of posterior teeth restored with high-viscosity bulk-fill resin composites in comparison to the incremental placement technique. AB - Aim: Comparative evaluation of the fracture resistance of maxillary premolar teeth restored with two high-viscosity bulk-fill composites and incrementally placed composite. Materials and Methods: Seventy-five freshly extracted maxillary premolar teeth were selected. Fifteen specimens served as positive control (Group 1). Mesio-occluso-distal cavity preparation was prepared on the rest of the specimens. These specimens were further divided into four groups: unrestored teeth (Group 2), teeth restored with incrementally placed nanocomposite (Group 3), teeth restored with high-viscosity bulk-fill giomer (Group 4), and teeth restored with high-viscosity bulk-fill nanocomposite (Group 5). The specimens were then subjected to compressive axial load using Instron universal testing machine. Data were analyzed using data were analyzed using Statistical package for social sciences software (SPSS v 20.0, IBM Corp.). Results: The positive control group exhibited highest fracture resistance (1104.70 +/- 122.2 N). There was no statistically significant difference seen in between the incrementally placed nanocomposite and high-viscosity nanocomposite (P > 0.05). The fracture resistance values displayed by the high-viscosity bulk-fill giomer were found to be statistically lower than the other two groups. Conclusion: High-viscosity bulk fill nanocomposite may substitute incrementally placed nanocomposite with respect to fracture resistance. PMID- 29386788 TI - A novel technique of sculpting Biodentine in the restoration of iatrogenic dentin loss. AB - Excessive tooth structure loss is a common iatrogenic error encountered during endodontic practice. Conservative treatment planning is essential to maintain the structural integrity in such teeth. This case report elucidates a novel approach in sculpting Biodentine as a dentin substitute followed by internal bleaching and restoration with fiber-reinforced composite. PMID- 29386789 TI - Atypical anatomy of maxillary second premolar with three roots and four canals. AB - Knowledge and understanding the anatomical configuration of individual tooth play a significant role in success of endodontic treatment, in addition to through debridement and obturation of the canals. The canal anatomy of maxillary second premolar has been studied extensively, and the presence of a significant variety of multirooted canals is relatively rare in it. A 27-year-old female reported with a chief complaint of pain in her upper right posterior region for 10 days. On intraoral hard tissue examination, ill-defined access preparation was seen in maxillary right second premolar with exposed pulp. An intraoral periapical radiograph reveals radiolucency involving the pulp space and varied morphology in the same tooth. The occurrence of three roots with four canals in the maxillary second premolar is rare and not documented in the literature so far. This case report describes the nonsurgical endodontic management of such varied anatomical configuration using cone beam computed tomography as an evaluating diagnostic tool. PMID- 29386790 TI - Use of bovine colostrum in periapical defects following surgical endodontics: Two case reports. AB - Periapical lesions are the most common pathological conditions involving teeth which often require surgical intervention. To achieve optimal healing both clinically and radiographically, bone grafts and barrier membranes have been used to fill the periapical defect after degranulation of the lesion. Colostrum is one of the new materials, which has osteoinductive or regenerative potential. The present case reports describe the use of bovine colostrum in the treatment of periapical inflammatory lesion with a follow-up period of 12 months. These case reports suggest that colostrum can be used to fill the periapical defect after degranulation, which has a favorable outcome. PMID- 29386791 TI - Need of research. PMID- 29386792 TI - Realising Aspirations in Implantology. PMID- 29386793 TI - Association between pro-inflammatory cytokine interleukin-33 and periodontal disease in the elderly: A retrospective study. AB - Background: Senescence is a multifactorial process that in humans may be accompanied by inflammation and immune dysfunction in the oral cavity. Notably, periodontal disease, considered one of the most common inflammatory disorders in the oral cavity, has also been linked to the onset of other chronic inflammatory diseases common in the elderly. Thus, investigating immunity and inflammation during senescence may not only illuminate the pathophysiology of periodontal disease, but also identify new therapeutic targets. Materials and Methods: To this end, we retrospectively and systematically reviewed studies of immune molecules associated with periodontal disease. These studies were identified in PubMed from three independent searches based on distinct sets of search terms. Results: The data highlight the need to further investigate inflammatory molecules involved in chronic periodontal disease in the elderly, but strongly suggest that interleukin (IL)-33 is involved. Indeed, various genetic and environmental factors appear to contribute to pathogenesis via IL-33. Conclusion: The IL-33 axis may be promising therapeutic target in elderly patients. PMID- 29386794 TI - Comparative evaluation of cemental abrasion caused by soft and medium bristle hardness toothbrushes at three predetermined toothbrushing forces: An in vitro study. AB - Background: Plaque control has been shown to have a pivotal role in maintaining optimal periodontal health. Toothbrushing as a mechanical plaque control tool is the most popular and effective option for self-performed oral health maintenance. However, the detrimental effects of bristle hardness and force exerted by toothbrushes on the tooth surface are the areas of concern. Objective: The aim of this in vitro study was to evaluate the abrasive effect of two different manual toothbrushes exerting predetermined forces on cemental surfaces of the teeth. Materials and Methods: Sixty extracted first molars were selected. Totally six experimental groups were formed based on the three predetermined forces 1.5, 3, and 4.5 Newton (N) and two types of manual toothbrushes, i.e., soft and medium bristle hardness. Buccal and lingual surfaces were independently brushed for 5000 cycles using specially designed toothbrushing machine. Throughout the experiment, type and quantity of toothpaste were kept constant. Post 5000 cycles of toothbrushing, change in surface roughness was measured using profilometer in microns and change in weight indicating loss of substance was measured in milligrams. Results: Abrasion of cementum is force dependent. Data revealed that both soft and medium bristle hardness toothbrushes cause significant cemental abrasion at 3 and 4.5 N forces. Conclusions: Higher is the force, more is the cemental surface abrasion. Soft bristled toothbrush causes more cemental abrasion than medium bristled toothbrush at 3 and 4.5 N forces. PMID- 29386795 TI - Comparative evaluation of the isolation and quantification of stem cells derived from dental pulp and periodontal ligament of a permanent tooth and to assess their viability and proliferation on a platelet-rich fibrin scaffold. AB - Background: The present study aims to comparatively evaluate the isolation and quantification of stem cells derived from dental pulp and periodontal ligament of a permanent tooth and to assess their viability and proliferation on a platelet rich fibrin (PRF) scaffold. Materials and Methods: A total of 15 systemically healthy individuals between the age group of 15-25 years requiring third molar or orthodontic premolar extractions. Teeth were extracted atraumatically and transported to the laboratory. Stem cells were isolated from dental pulp and periodontal ligament. After attaining more than 90% confluency by the 7th day, these cells were tested for their viability and characterization. Stem cells were also incubated with PRF and viability was assessed on the 7th day. Results: The mean number of cell for dental pulp stem cells (DPSCs) and periodontal ligament stem cell (PDLSC) was statistically insignificant (P > 0.05). The mean live cell viability was compared between DPSC (98.07%) and PDLSC (98%). Both DPSC and PDLSC showed a high percentage of expression of CD73 markers, 30.40% and 29.80%, respectively. However, DPSCs and PDLSCs lacked expression of CD34 expressing only 3.47% and 3.53%, respectively. PRF membrane as a scaffold exhibited no cytotoxic effects on DPCS's or PDLSC's. The cell viability of cells cultured with PRF was statistically insignificant (P > 0.05) when compared to the cells cultured with culture media. Conclusion: The study thus indicates that dental pulp and periodontal ligament are both rich sources of mesenchymal stem cells and can be successfully used for obtaining stem cells. PRF exhibits no cytotoxic effects on the cells and can be used in conjunction with dental stem cells. PMID- 29386796 TI - Comparative evaluation of stress levels before, during, and after periodontal surgical procedures with and without nitrous oxide-oxygen inhalation sedation. AB - Context: Periodontal surgical procedures produce varying degree of stress in all patients. Nitrous oxide-oxygen inhalation sedation is very effective for adult patients with mild-to-moderate anxiety due to dental procedures and needle phobia. Aim: The present study was designed to perform periodontal surgical procedures under nitrous oxide-oxygen inhalation sedation and assess whether this technique actually reduces stress physiologically, in comparison to local anesthesia alone (LA) during lengthy periodontal surgical procedures. Settings and Design: This was a randomized, split-mouth, cross-over study. Materials and Methods: A total of 16 patients were selected for this randomized, split-mouth, cross-over study. One surgical session (SS) was performed under local anesthesia aided by nitrous oxide-oxygen inhalation sedation, and the other SS was performed on the contralateral quadrant under LA. For each session, blood samples to measure and evaluate serum cortisol levels were obtained, and vital parameters including blood pressure, heart rate, respiratory rate, and arterial blood oxygen saturation were monitored before, during, and after periodontal surgical procedures. Statistical Analysis Used: Paired t-test and repeated measure ANOVA. Results: The findings of the present study revealed a statistically significant decrease in serum cortisol levels, blood pressure and pulse rate and a statistically significant increase in respiratory rate and arterial blood oxygen saturation during periodontal surgical procedures under nitrous oxide inhalation sedation. Conclusion: Nitrous oxide-oxygen inhalation sedation for periodontal surgical procedures is capable of reducing stress physiologically, in comparison to LA during lengthy periodontal surgical procedures. PMID- 29386797 TI - Effectiveness of braille and audio-tactile performance technique for improving oral hygiene status of visually impaired adolescents. AB - Background: Visually impaired people encounter numerous challenges in their daily life which makes it a cumbersome task to pay special attention to oral health needs. Furthermore, there is little knowledge about oral health practices among caretakers and visually impaired individuals, due to which oral health is often neglected when compared to the general health. Hence, there was a need to educate visually challenged individuals about oral hygiene practices in a customized format so that the comprehension of brushing techniques could be conveyed at its best. Materials and Methods: The present study was a randomized control trial of sixty visually impaired adolescents who were divided into three groups of 20 each. In Group 1, Braille was used, whereas in Group 2, audio-tactile performance (ATP) technique and in Group 3, a combination of both the methods were used to teach tooth brushing as a part of oral health education. Pre- and post-plaque index score using Silness and Loe (1967) after health education were calculated and tabulated for statistical analysis. Results: The postintervention mean plaque index score increased in Group 1 from 29.45 to 42.98, whereas the mean plaque score decreased in Groups 2 and 3 from 30.83-29.9 to 30.23-18.73, respectively. Intergroup comparison of postplaque index score using Kruskal-Wallis and ANOVA analysis showed significant difference among all three study groups. Conclusion: The combination of Braille and ATP technique of health education served as the most effective medium to teach oral hygiene methods to visually impaired adolescents. PMID- 29386798 TI - Bioactive glass versus autologous platelet-rich fibrin for treating periodontal intrabony defects: A comparative clinical study. AB - Background: To compare treatment modalities: Open flap debridement (OFD) alone (Group I), OFD in combination with PerioGlas(r) (Group II), and OFD in combination with autologous platelet-rich fibrin (PRF) (Group III) for periodontal intrabony defects (IBDs). Aim: To evaluate on clinical and radiographic basis, effectiveness of PerioGlas(r), and PRF in treating IBDs. Settings and Design: IBDs selected on the basis of the inclusion criteria were randomly assigned to Groups I, II, and III by coin toss method. Materials and Methods: The study was conducted on patients reporting to the department of periodontology and oral implantology. Thirty-eight patients with ninety periodontal IBDs of moderate to severe periodontitis were selected and assigned to Groups I, II, and III. In each patient, a minimum number of two sextants were present with pocket depths >=5 mm in at least three teeth. Statistical Analysis: Statistical analysis based on mean values, standard deviation, and P values. Results: Compared to baseline, 9 months postoperatively: (1) mean probing pocket depth reduction for Group I was 3.68 mm +/- 0.72, for Group II was 5.57 mm +/- 1.10, and for Group III was 6.11 mm +/- 0.92. (2) The mean relative attachment level gain for Group I was 4.14 mm +/- 0.76, for Group II was 6.57 mm +/- 1.45, and for Group III was 6.74 mm +/- 1.55. (3) Mean radiographic IBD fill for Group I was 69.29% mm +/- 7.73, for Group II was 74.44% mm +/- 8.57, and for Group III was 75.01% mm +/- 7.85. Conclusion: This study shows marked improvements in the clinical parameters and radiographic outcomes with both PerioGlas(r) and autologous PRF to treat periodontal IBDs as compared to OFD alone. PMID- 29386799 TI - Effectiveness of stevia as a mouthrinse among 12-15-year-old schoolchildren in Nellore district, Andhra Pradesh - A randomized controlled trial. AB - Aim: The aim of this study is to determine the effectiveness of stevia as a daily mouthrinse among 12-15 year-old schoolchildren in Nellore District, Andhra Pradesh. Materials and Methods: A randomized, controlled triple blind trial was carried out among 108 children in B. V. S Municipallity Girls High school in Nellore. Children were randomly allocated into four groups comprising 27 in each group. Four mouthrinses composed of 0.2% chlorhexidine gluconate; 0.05% sodium fluoride, 10.6% stevioside and placebo were provided to the study participants. Plaque index, gingival index, and International Caries Detection and Assessment System (ICDAS) II, respectively, were used for assessing oral condition. The mouthrinsing was carried out for 6 months. Results: Group C showed maximum reduction of 8% and 10% on plaque and gingival scores, respectively, followed by Group A and Group B. However, Group D participants showed 1.5% and 1.8% increase in plaque and gingival scores, respectively. Analysis of ICDAS scores at 6 months indicated that values recorded were same as baseline for all the three groups except that for Group D, there was an increase in the prevalence of cavitated lesion D2-6from 5.6% to 5.8%. Conclusion: Stevia demonstrated very potent antiplaque and antigingivitis properties as compared to other mouthrinses at the end of 6 months trial. PMID- 29386800 TI - Efficacy of local drug delivery of Achyranthes aspera gel in the management of chronic periodontitis: A clinical study. AB - Context: Periodontitis is an inflammatory disease of microbial origin. Locally delivered antimicrobials reduce subgingival flora. Achyranthes aspera gel has antimicrobial, antioxidant, anti-inflammatory, and immunostimulant effects. Aims: To evaluate the efficacy of local drug delivery of A. aspera gel in the management of chronic periodontitis. Materials and Methods: Thirty patients with chronic periodontitis were considered in the study and categorized into two equal groups (Group A: scaling and root planing (SRP) with A. aspera gel, Group B: SRP with placebo gel). Patients were enlisted from the Department of Periodontics, Mamata Dental College and Hospital. The clinical parameters (gingival index, bleeding on probing, probing pocket depth, and clinical attachment level) were recorded at baseline and 3 months. Statistical Analysis Used: All the obtained data were sent for statistical analyses using SPSS version 18. Results: The periodontitis and the Achyranthes were statistically analyzed. A comparison of clinical parameters for test group and control group from baseline to 3 months was done using paired t-test. Intergroup comparison for both the groups was done using independent sample t-test. Conclusions: A. aspera gel when delivered locally along with SRP showed a beneficial effect. A. aspera gel as a non surgical local drug delivery system proved to be without any side effects in the management of periodontitis. A. aspera gel has strong anti-inflammatory effects in addition to its antioxidant activity. PMID- 29386801 TI - Influence of various factors on patient compliance after periodontal therapy: A pilot study. AB - Background: Patient compliance is an important predictor of periodontal prognosis, therapy, and maintenance. Limited studies concentrate up on the factors which affect patient compliance. Thus, the aim of the study is to determine the relationship between sociodemographic data, patient's oral health awareness (OHA) and treatment satisfaction (TS) to patient compliance. Materials and Methods: A total of 150 patients were subjected to a prevalidated questionnaire comprising of thirty questions. Questions covered different aspects such as sociodemographic data, OHA, and level of patient TS. Statistical analysis was done using mean, percentages, and Spearman's correlation coefficient. Results: A sample of 150 people was included into the study of which 93 were females and 67 males with a mean age of 38 years. The total OHA scores when divided into three categories such as 5-7, 8-9, and >10 and plotted against number of missed appointments; the difference found was statistically significant (P < 0.001). The mean TS was divided into four subgroups of score >24, 25-27, 28 30, and >31 and then plotted against the average number of missed appointments, and the difference was found to be statistically significant (P < 0.001). The correlation between the OHA score and number of missed appointments was -0.59 (P < 0.001) and TS score and number of missed appointments was -0.40 (P < 0.001). Conclusion: Within the limitations of the study, it can be concluded that patient education, OHA, and TS are the variables that influence the patient compliance. PMID- 29386802 TI - Evaluation of oral hygiene self-efficacy, knowledge, and motivation among young adults of rural-based tamilian population: A prospective cohort study. AB - Background: Oral hygiene is the most essential factor in the prevention and therapy of many diseases, especially the periodontal disease. The aim of this study was to evaluate the oral hygiene-related knowledge, self-efficacy, and motivation of the young adults of rural-based Tamilian population, with their current oral hygiene practices to assess the effect of patient motivation after initial periodontal therapy. Materials and Methods: A hundred patients filled out questionnaires based on their oral hygiene-related knowledge. Plaque index, gingival index, and gingival bleeding index were recorded and correlated with their questionnaire knowledge. Initial periodontal therapy and motivation were done to all patients. After 6 months, oral health status was evaluated again. Results: There was a lower correlation value with insignificant P value between the questionnaire score and plaque and gingival index score, (r = 0.125, 0.166). However, the correlation between questionnaire score and modified papilla bleeding index score was high (r = 0.254) with significant (P = 0.011). After 6 months following the initial periodontal treatment, significant decrease in all the three indices scores was noted with significant (P < 0.001). Conclusion: Oral hygiene-related motivational approaches targeting rural young adult population has the potential to predict oral hygiene behavior and influences the clinical outcomes. PMID- 29386803 TI - Leiomyoma on gingiva with osseous involvement: An unusual presentation. AB - Leiomyoma is a smooth muscle tumor which rarely turns into malignancy. This is an unusual case report which presents leiomyoma on gingiva with osseous involvement. This case highlights the importance of histopathological examination for the proper diagnosis of any gingival growth. A 28-year-old female patient reported with localized gingival enlargement. The surgical excision was conducted and excised tissue was sent for histopathological examination. On the basis of clinical and histopathological examination, the diagnosis of leiomyoma was made. Leiomyoma reported low recurrence rate in previous literature. However, this lesion recurred within 15 days. After recurrence, the patient was referred to the oncology center for further evaluation and treatment. PMID- 29386805 TI - Peri-implant plastic surgery techniques to hard and soft tissue augmentation in implant rehabilitation. AB - This report presents the clinical results of peri-implant plastic surgical approaches for hard and soft tissues before and during the implant placement in a patient with vertical ridge deformation and a shallow vestibule sulcus, and the subsequently performed prosthetic rehabilitation. The surgical approaches used in this case reduced the crown-height space and crown-to-implant ratio and ensured that the implants were placed in their ideal positions, and peri-implant tissue health was maintained. In conclusion, developments in the peri-implant plastic surgery enable the successful augmentation of hard and soft tissue defects and provide the implant-supported fixed prosthetic rehabilitation. PMID- 29386804 TI - A rare case of plasma cell mucositis in a young patient. AB - Plasma cell mucositis (PCM) is a rare benign proliferative disorder affecting various mucosal surfaces usually seen in elderly patients. In the present case, a 13-year-old young boy reported with the complaint of swollen upper lip and enlarged gums in relation to upper front teeth. The diagnosis of plasma cell mucositis is complex and frequently requires histopathological examination and immunohistochemistry. Management included conventional gingivectomy and intralesional steroid. Regular follow-up of PCM is essential based on the possibility of recurrence, the potential involvement of other mucosal surfaces and unknown potential for malignant transformation. PMID- 29386806 TI - Merge to emerge - An interdisciplinary approach for management of periodontally compromised orthodontically treated patient. AB - In the modern day dental practice, synergy is fundamental. This synergistic effect must exist among various disciplines of dentistry for proper diagnosis, treatment planning, sequencing and execution of treatment in complex and challenging dental situations. Such collaborative effect between an orthodontist and a periodontist is essential as both works with same element, the tooth as crown-root unit with its supporting tissues. The orthodontic treatment is carried out through the medium of periodontium, so a healthy tooth supporting system is an essential prerequisite. Every potential candidate for orthodontic treatment should undergo a thorough periodontal examination. Any lousily diagnosed or conducted orthodontic treatment could be a facilitator of periodontal inflammatory or infectious process especially when the patient's oral hygiene is explicitly deficient. This case report demonstrates a challenging situation to a periodontist where patient had completed her orthodontic treatment but ended up with severe periodontal disease. The patient was thoroughly examined and a comprehensive treatment was planned and executed. Regenerative surgical procedures were done using platelet rich fibrin and hydroxyapitatite bone graft. Patient was followed up for 2 years. As sequelae of surgical procedures, patient had developed black triangles in the anterior region. The patient was unwilling for further perioplastic surgical procedures and further orthodontic treatment, so a gingival prosthesis using valplast was fabricated addressing her esthetic concerns. PMID- 29386807 TI - Evaluation of clinico-pathological reports and recurrence of 20 cases of localized gingival overgrowths. AB - The aim of the present study was to assess the clinico-histopathological picture and to examine the recurrence of various localized hyperplastic gingival growths after their surgical treatment. Twenty patients of localized hyperplastic gingival outgrowth were evaluated in the present clinico-histopathological study. The data regarding age, sex, location, size, and duration of lesion were summarized. After 4 weeks of initial therapy, an excision of the growth with conventional flap surgery was performed. The excised tissues were sent for histopathological analysis, and the lesions were reclassified into four groups. All the patients were recalled after 3 and 6 months to study the recurrence of the growth. Twenty lesions were inspected, the pyogenic granuloma was the most common (55%), followed by peripheral fibroma (25%), peripheral giant cell granuloma (15%), and calcifying fibroblastic fibroma (5%). Out of the twenty lesions evaluated, the pyogenic granuloma was the most common with no recurrence in any case. PMID- 29386808 TI - Dental implants. PMID- 29386809 TI - Oral submucous fibrosis: Newer proposed classification with critical updates in pathogenesis and management strategies. AB - Oral submucous fibrosis (OSMF) is an oral precancerous condition characterized by inflammation and progressive fibrosis of the submucosal tissues resulting in marked rigidity and trismus. OSMF still remains a dilemma to the clinicians due to elusive pathogenesis and less well-defined classification systems. Over the years, many classification systems have been documented in medical literature based on clinical, histopathological, or functional aspects. However, none of these classifications have achieved universal acceptance. Each classification has its own merits and demerits. An attempt is made to provide and update the knowledge of classification system of OSMF so that it can assist the clinicians, beneficial in researches and academics in categorizing this potentially malignant disease for early detection, prompt management, and reducing the mortality. Along with this, pathogenesis and management have also been discussed. PMID- 29386810 TI - Bone augmentation as an adjunct to dental implant rehabilitation in patients with diabetes mellitus: A review of literature. AB - The aim of the present article is to review the success of bone augmentation performed as an adjunct to dental implant rehabilitation in patients with diabetes mellitus. A literature review was conducted in PubMed on this topic, which yielded a total of 102 publications. For inclusion, publications had to be human studies, written in English language and should report on the success of bone augmentation as an adjunct to dental implant rehabilitation in diabetic patients. After screening the titles and abstracts, 11 full texts publications were obtained, of which seven were included in the review. These studies provided data on various bone augmentation techniques such as sinus floor elevation (SFE), guided bone regeneration (GBR), and onlay bone grafting. Even though the current review revealed that there are not many studies reporting data relevant to the analyzed topic, the data obtained suggests that; (1) staged GBR technique should be considered more feasible and predictable for bone augmentation, (2) clinicians must take meticulous care when planning and conducting SFE, and (3) block bone augmentation technique should be avoided. PMID- 29386811 TI - Estimation of gender using cheiloscopy and dermatoglyphics. AB - Background and Objective: Forensic dentistry plays a vital role in detection and resolution of crime, civil proceedings and personal identification. With ever increasing demands placed upon law enforcement to provide sufficient physical evidence linking a perpetrator to a crime, it makes sense to utilize any type of physical characteristic to identify a suspect of an offense. The least invasive and cost-effective procedure among all methods of human identification is the study of lip prints and fingerprints. This study is done to determine the predominant pattern of fingerprint and lip print in males and females and to correlate it for gender identification. Materials and Methods: The study sample comprised 100 individuals (50 males and 50 females) aged between 20 and 50 years; dark-colored lipstick was applied uniformly on the lips. The glued portion of cellophane tape was dabbed first in the center and then pressed uniformly over the corner of lips. Cellophane tape was then stuck to a white chart sheet for the purpose of permanent record. Lip print patterns were analyzed following the classification of Suzuki and Tsuchihashi. The imprint of left thumb was taken on a white chart sheet using a blue ink stamp pad and visualized using magnifying lens. Fingerprints were analyzed by following the classification given by Kucken. Correlation of lip print and fingerprint was analyzed using Chi-square test. Results: The overall correlation of lip prints with fingerprints in males revealed branched lip pattern associated with whorl fingerprint and in females as vertical lip print pattern associated with loop fingerprint. Conclusion: We conclude that the study between lip print and fingerprint can aid in gender determination. PMID- 29386812 TI - The effect of sodium bicarbonate oral rinse on salivary pH and oral microflora: A prospective cohort study. AB - Aim: Present study is designed to explore the effect of sodium bicarbonate oral rinse on salivary pH and oral micro flora. Materials and Methods: Twenty five healthy subjects were recruited for the study in department of dentistry in Era Medical College. Subjects were abstained from tooth brushing overnight pre rinse (control) samples were collected after one hour of dinner and were asked to rinse with pre calibrated freshly prepared sodium bicarbonate solution. The salivary samples were then collected the following morning using sterile gauze in marked bottles. Aerobic bacterial culture was done by plating the sample directly from the swab on the surface of Blood agar and Mac Conkeys media respectively. The colony forming units and ph were calculated for the pre rinse and post rinse saliva sample. Result: Results shows that salivary pH increased significantly after sodium Bicarbonate oral rinse. There was a marginal decrease in number of CFU/ml for bacteria especially Viridans Streptococci, Moraxella species. Conclusion: Sodium Bicarbonate oral rinse may be considered as a cheap and effective alternative for chlorhexidine and alcohol based mouth wash, especially where long duration usage is required. PMID- 29386813 TI - A clinical prospective randomized comparative study on ostyeosynthesis of mandibular anterior fractures following open reduction using lag screws and miniplates. AB - Introduction: The aim of the present study was to compare fixation of mandibular anterior fractures following open reduction using lag screws or miniplates. Materials and Methods: This prospective study was conducted on 20 patients diagnosed with cases of displaced mandibular anterior fractures treated with open reduction and internal fixation. The patients were then randomly allocated to either of two groups - Group A: two 2.5 mm stainless steel lag screws were placed in 10 patients. Group B: two 2.5 mm miniplates were placed in 10 patients for the fixation of fractures. Subsequent follow-up was done on the 1st day, 1st, 4th, and 36th week postoperatively. During every follow-up, patient was assessed clinically for infection, malocclusion, loosening of plate/screw, malunion/nonunion, and masticatory efficiency. Radiographs (orthopantogram) were taken preoperative, 1st, 4th, and 36th postoperative week to compare the osteosynthesis between the two groups. Pain was objectively measured using a visual analog scale. The data collected was subjected to unpaired t-test and paired t-test for statistical analysis. Result: It was found that lag screw placement was rapid in comparison of miniplate placement. 3rd month postoperative assessment revealed Lag screw group to have better biting efficiency, and better bone healing which was statistically significant when compared with miniplate group. Conculsion: Our study suggests that lag screw osteosynthesis can be advocated as a valid treatment modality in the management of mandibular symphysis and parasymphysis fractures. PMID- 29386814 TI - Use of 0.5% bupivacaine with buprenorphine in minor oral surgical procedures. AB - Background: Minor oral surgical procedures are the most commonly performed procedures by oral and maxillofacial surgeons. Performance of painless surgical procedure is highly appreciated by the patients and is possible through the use of local anesthesia, conscious sedation or general anesthesia. Postoperative pain can also be controlled by the use of opioids, as opioid receptors exist in the peripheral nervous system and offers the possibility of providing postoperative analgesia in the surgical patient. The present study compares the efficacy of 0.5% bupivacaine versus 0.5% bupivacaine with 0.3 mg buprenorphine in minor oral surgical procedures. Patients and Methods: The present study was conducted in 50 patients who required minor oral surgical procedures under local anesthesia. Two types of local anesthetic solutions were used- 0.5% bupivacaine with 1:200000 epinephrine in group I and a mixture of 39 ml of 0.5% bupivacaine with epinephrine 1:200000 and 1 ml of 300 MUg buprenorphine (3 MUg/kg)in group II. Intraoperative and postoperative evaluation was carried out for both the anesthetic solutions. Results: The mean duration of postoperative analgesia in bupivacaine group (508.92 +/- 63.30 minutes) was quite less than the buprenorphine combination group (1840.84 +/- 819.51 minutes). The mean dose of postoperative analgesic medication in bupivacaine group (1.64 +/- 0.99 tablets) was higher than buprenorphine combination group (0.80 +/- 1.08 tablets). There was no significant difference between the two groups regarding the onset of action of the anesthetic effect and duration of anesthesia. Conclusion: Buprenorphine can be used in combination with bupivacaine for patients undergoing minor oral surgical procedures to provide postoperative analgesia for a longer duration. PMID- 29386815 TI - Comparison of the effectiveness of Tokuyama and GC II metal primer on the bond strength of acrylic resins to Ti-6Al-7Nb. AB - Statement of Problem: Because of the toxicity of vanadium in Ti-6Al-4V alloy, next generation of titanium alloys is proposed to focus on niobium-containing alloy, but for clinical applications, it is crucial for this alloy to bond with acrylic resins with or without the use of primers. However, literature was lacking about the effect of primers on bonding of autopolymerizing resins to Ti 6Al-7Nb. Objectives: To evaluate the effect of different metal primers on the shear bond strength of acrylic resin to Ti-6Al-7Nb. Materials and Methods: A total of 30 dis-shaped wax patterns (10 mm in diameter and 2 mm thickness) were prepared and casted using Ti-6Al-7Nb. After casting, the disk surfaces were finished with abrasive paper under water. Specimens were equally divided into three groups on the basis of the use of primer: metal primer (GC II metal primer) (Group 1), Universal Tokuyama primer (Group 2), no primer (Group 3). Tape of 50 MUm thickness was applied on each of the specimens. Then, self-cure acrylic resin was mixed and applied on the center part of the tape, on which Bernouilles tube was placed. The tensile bond strength was measured with a universal testing machine. The data were obtained for all the specimens and analyzed using Statistical Package for Social Sciences version 17.0 at a statistically significance level of <0.05. Results: Mean tensile force was maximum for Group 2 (28.58 +/- 39.40 N) and minimum for control Group 3 (6.24 +/- 10.97 N), thereby showing a significant inter-group difference (P < 0.001). On applying post hoc test (Tukey HSD), both the Group 1 and Group 2 showed a statistically significant difference as compared to control Group 3; however, the difference between two experimental groups was not statistically significant (P > 0.05). Conclusions: Tokuyama primer and GC II metal primer had a significant effect on improving the bond strength between autopolymerizing denture base resin and Ti-6Al-7Nb. PMID- 29386816 TI - Aqueous intralesional bleomycin sclerotherapy in lymphatic malformation: Our experience with children and adult. AB - Objectives: Lymphatic malformations (LMs) are aberrant proliferation of sequestrated lymphatic vessels during early embryogenesis and do not communicate directly with the general lymphatic system. The absence of vascular flow is the hallmark of LMs and is usually symptomless apart from painless disfiguring mass with concerns regarding cosmesis. Design: Sclerotherapy has gained prominence as a preferred treatment modality for macrocystic lesions. Here, we present our experience with use of aqueous bleomycin as intralesional sclerosing agent, an economical first-line treatment for macrocystic variant of LMs in children and adults. While bleomycin microsphere in oil has been commonly used in many previous studies, we have used aqueous bleomycin solution as the sclerosing modality which is easily available and economical. Materials and Methods: Twenty seven patients of macrocystic LM including adults and children underwent bleomycin sclerotherapy under ultrasonography guidance. Number of sessions, dose administered, and the response to therapy along with all side effects were noted. Results: Sixteen patients received 3 or less sessions while rest needed 4-6 sessions of sclerotherapy for desired response. The response was excellent in 22 patients while 5 patients showed good response. Eleven patients developed minor side effects in form of fever, local infection, intracystic bleed, and local skin discoloration. Postsclerotherapy, surgery was performed in two patients. Conclusion: The better response in the present study can be attributed to targeting of individual cysts in multiloculated lesion, ultrasound-guided aspiration of the cysts content before drug delivery, and postprocedure compression which increases the contact time between cyst wall and bleomycin reducing the chances of postprocedure seroma formation. Since the drug acts on the endothelial lining of the cyst, volume of the cyst is the major determinant in response. Aqueous bleomycin had comparable results with oil-based microsphere establishing it as an economical alternative treatment modality. PMID- 29386817 TI - Dentascan an excellent tool for assessment of variations in the management of periodontal defects. AB - Background: The purpose of the present study was to envisage the effectiveness of demineralized freeze-dried bone allograft (DFDBA) and bovine bone graft (BBG) for promoting defect fill in periodontal intrabony defects using dentascan. Materials and Methods: A total of 13 subjects (15 intrabony defects) aged between 24 and 56 years affected by moderate to severe periodontitis were randomly divided into Control (CG) and Test groups (TG1 and TG2). In CG only debridement, TG1 debridement plus DFDBA, and TG2 debridement plus BBG were performed. The clinical parameters probing pocket depth (PPD), clinical attachment level (CAL) was used. The radiological analysis was done by dentascan, which is a single-slice spiral computed tomographic scanner. Six months after, regenerative treatment clinical measurements were recorded. The bone fill was assessed using Dentascan as previously mentioned. Results: PPD reduction and CAL gain were significant in all the groups after 6 months whereas, on intergroup comparisons, insignificant finding was observed both at baseline and after 6 months. Coronoapical bone status decreased significantly in all groups, buccolingual measurements decreased significantly in TG1 and TG2, but no such trend was seen in CG. Significant reduction in mesiodistal bone status was noticed only in TG1 whereas insignificant on intergroup comparisons. Conclusion: Dentascan-based analysis attested that DFDBA was superior to BBG. PMID- 29386818 TI - Efficacy of decalcified freeze-dried bone allograft in the regeneration of small osseous defect: A comparative study. AB - Aim: To access the efficacy of decalcified freeze-dried bone allograft (DFDBA) in the regeneration of bone following small osseous defect in minor oral surgery. Objectives: To evaluate the ability of DFDBA to enhance the rate of wound healing and assess radiographic bone density, pain, and infection preoperatively and postoperatively. Materials and Methods: Twenty patients with cysts were assessed. Ten patients were filled with DFDBA (Group 1) and ten without bone graft (Group 2), respectively. Radiographic bone density was assessed on preoperative, intraoperative, and postoperative radiographs on 1st day, 3rd month, and at 6th month using Adobe Photoshop CS6 - Grayscale histogram. Results: Bone density in Group 1 was found to be significantly higher than in Group 2 on 3rd and 6th month postoperatively with a P = 0.024 and P = 0.016 which was statistically significant. The percentage increase in bone density between both the group was determined and yielded no difference over a period of time, but the difference in percentage increase was markedly higher in Group 1 compared to Group 2 at all the time intervals. Conclusion: Bone formed as depicted by bone density is significantly higher when DFDBA is used in small bony defects. PMID- 29386819 TI - Trigeminal schwannoma. AB - Schwannoma is a benign tumor of the nerve sheath arising from the perineural schwann cells. The nerves most commonly involved in schwannomas of the head and neck are the vagus and the cervical sympathetic chain. Trigeminal schwannomas are rare tumours. A 17 year old male patient with a chief complaint of swelling on face was diagnosed as suffering from bening tumor extending from cranial base (from foramen ovale) to the parapharengeal space. Mandibular access osteotomy was done to expose the tumor. Surgical excision of the tumor was done along with the preservation of the nerve. Schwannomas can occur along the pathway of any somatic or sympathetic nerve. Superficial schwannomas require simple exposure and excision but the one which are deep and large, may require complex access osteotomies. Careful surgery is required to preserve the nerve function. Once completely excised, the prognosis is excellent. PMID- 29386820 TI - Fronto-orbital reconstruction using polymethyl methacrylate implant. AB - The objective of this article is to show a case of fronto-orbital reconstruction with prefabricated polymethyl methacrylate prosthesis. A 35-year-old male with alleged history of trauma following road traffic accident 3 months back reported with unaesthetic scar and deformity in right supraorbital region to us. As there was no functional deformity, the management was aimed at correcting the contour and esthetic only. The correction was achieved by overlaying the defect with a polymethyl methacrylate implant fabricated over a three-dimensional stereolithographically printed rapidly prototyped model. Postoperative phase was uneventful and esthetic outcome was satisfactory. The patient after 4-year follow up reported with no discomfort and definite improvement in facial contour. PMID- 29386821 TI - Unilateral swelling of cheek. AB - A 55 year old male patient reported in the department of oral and maxillofacial surgery with a chief complaint of swelling on right side of face from last 2 months. He reported a progressive increase in the swelling. Pain and discomfort was present from last 7 days with increased swelling, and reduced mouth opening. On examination, the face appeared asymmetrical with a swelling in the right cheek which was small, smooth, dome shaped, present approximately 1.5 cm anterior to tragus. Overlying skin was of normal colour. The patient was afebrile. Mouth opening was 25 mm. PMID- 29386822 TI - Osteitis fibrosa cystica of mandible in hyperparathyroidism-jaw tumor syndrome: A rare presentation and review of literature. AB - Brown's tumor, also referred as osteitis fibrosa cystica is a rare nonneoplastic diagnostically challenging consequence of hyperparathyroidism (HPT) which occurs due to increased parathormone secretions in blood, causing excessive calcium resorption from kidneys, bone resorption, and phosphaturia. Brown's tumor is a misnomer, presenting as cystic expansile lesions in bone, often misdiagnosed as neoplastic lesion or granuloma or abscess in bones. It can affect long bones, clavicle, ribs, and pelvis. According to literature, skeletal manifestations of Brown tumor is relatively rare and occurs in <2% of the cases of HPT. We present a case of a female 15-year-old patient who presented with bleeding gums and an expansile lesion in mandible whose previous investigations elsewhere suggested a malignant lesion. However, further investigations revealed it to be Brown's tumor with primary HPT which is a rare genetic disorder, known as HPT-Jaw Tumor Syndrome (HPT-JT). PMID- 29386823 TI - Congenital cyst of the orbit: A case report. AB - Dermoid cyst is an example of choristoma (i.e., tumors that originate from aberrant primordial tissue which result in normal appearing tissue in an abnormal location). This particular type of cyst is formed at the site where 2 suture lines of the skull close during embryonic development, and during this time, dermal or epidermal elements are pinched off which later convert to form cysts. Approximately, 50% of these tumors that involve the head are found in or adjacent to the orbit. This article presents a similar case of the orbital dermoid cyst with its management and also a review on other varieties of dermoid cysts of the head and neck region. PMID- 29386824 TI - Modified orthopedic wire twister for fixing and removing screws in craniomaxillofacial osteosynthesis. AB - Internal fixation is the routinely performed surgical procedure in craniomaxillofacial surgery. At present, available kit for internal fixation includes large number of armamentarium. To overcome and reduce this, we have modified orthopedic wire twister for fixing and removing screws. This single device can replace self-holding screwdrivers with different sizes. PMID- 29386825 TI - Treatment of Melasma with Pulsed-Dye Laser and 1,064-nm Q-Switched Nd:YAG Laser: A Split-Face Study. AB - Background: Melasma is an acquired pigmentary disorder that is often therapeutically challenging. Recent evidence suggests that vascular abnormalities are involved in melasma pathogenesis. Pulsed-dye laser (PDL) is considered as standard therapy for vascular lesions. Objective: To assess the efficacy of PDL combined with low-fluence Q-switched Nd:YAG laser (QSNY) in the treatment of melasma. Methods: Seventeen melasma patients were enrolled in this study. All subjects were treated with a total of nine QSNY treatment sessions at one-week intervals. Three sessions of PDL were additionally performed immediately after QSNY treatment on the half of the face at baseline, week 4, and week 8. The melasma area and the severity index (MASI) score was calculated at the baseline, one week after the last treatment (week 9), as well as at the follow-up 8 weeks after the last treatment (week 16). Dermoscopic images at the baseline were classified as to whether the visibly widened capillaries were detected or not. Results: MASI scores on the PDL+QSNY and QSNY side decreased significantly during the study period. There was no significant difference in the MASI score change between both sides in all periods. However, seven patients who had visibly widened capillaries on dermoscopy showed significant difference in both sides in terms of changes in the MASI score during treatment. Conclusion: PDL combined with QSNY may be considered as a safe and effective treatment for melasma patients who show visibly widened capillaries on dermoscopy. PMID- 29386826 TI - HLA-C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 Alleles Associated to Bullous Pemphigoid in Brazilian Population. AB - Background: Bullous pemphigoid (BP) is an autoimmune disease with bullous vesicles and an incidence of 0.2 to 1.4 per 100,000 inhabitants. Many studies have been published demonstrating the association of pemphigoid with HLA class II system alleles in different populations, however there are no data on the BP, one of the most heterogeneous in the world. Objective: To typify HLA alleles in Brazilians with Bullous pemphigoid. Methods: The study group included 17 Brazilian patients with a confirmed diagnosis of BP from a hospital in Sao Paulo city, southeast Brazil. DNA was extracted from peripheral blood using Qiagen kits and HLA A, B, C, DR and DQ typing was performed using polymerase chain reaction. The control group was composed of a database of 297 deceased donors from the city of Sao Paulo. The statistical significance level was adjusted using the Bonferroni correction depending on the phenotypic frequencies evaluated for HLA class I (A, B and C) and class II (DRB1, DQB1 and DQA1). Results: Our findings show that alleles HLA C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 are associated with the onset of the disease in the Brazilian population, with relative risks of 8.31 (2.46 to 28.16), 3.76 (1.81 to 7.79), 3.57 (1.53 to 8.33), and 4.02 (1.87 to 8.64), respectively (p<0.005). Conclusion: Our data indicate that Brazilian patients with BP present the same genetic predisposition linked to HLA-DQB1*03:01 previously reported in Caucasian and Iranian individuals and our study introduces three new alleles (C*17, DQA1*01:03 and DQA1*05:05) involved in the pathophysiology of BP. PMID- 29386827 TI - Mortality and Comorbidity Profiles of Patients with Bullous Pemphigoid in Korea. AB - Background: Bullous pemphigoid (BP) is a common autoimmune-mediated blistering skin disease that is significantly associated with mortality and morbidity. However, few studies regarding the mortality and comorbidity profiles of BP have been reported in Korea. Objective: To evaluate and compare the mortality, comorbidity profiles, and risk factors between patients with BP who visited our clinic and an age-matched general population of Korea. Methods: We retrospectively evaluated 103 patients diagnosed with BP between 2006 and 2013 at Chonnam National University Hospital in Gwangju, Korea. Results: The 1-year, 2 year, and 5-year mortality rates of the patients were 18.44%, 28.16%, and 42.00%, respectively. The median age was 76 years (range, 41~96 years). The standardized mortality ratio of patients with BP was 1.83 times that of the age- and sex matched general population of Korea. Old age at the time of diagnosis, cardiac disease and renal disease were associated with increased 5-year mortality. In addition, the prevalence of diabetes, stroke, dementia, and Parkinson's disease was higher among BP patients than in the general population. Conclusion: The mortality rate of patients with BP is higher than that of the general Korean population. Korean patients with BP are more likely to have dementia, Parkinson's disease, diabetes, and stroke. Risk factors for increased 5-year mortality include old age at the time of diagnosis and medical comorbidities, especially cardiac disease and renal disease. PMID- 29386828 TI - The Prevalence and Risk Factors of Atopic Dermatitis and Clinical Characteristics according to Disease Onset in 19-Year-Old Korean Male Subjects. AB - Background: The natural course of atopic dermatitis (AD) in infancy, childhood, and adolescence is not yet completely known. Objective: To investigate the prevalence and risk factors of atopic dermatits among 19-year-old Korean male subjects. Methods: All 19-year-old Korean males must undergo medical examination for conscription. We precisely evaluated the prevalence of AD in three Korean provinces using the information from this physical checkup. AD was diagnosed by experienced dermatologists according to the Hanifin and Rajka criteria. The disease severity was assessed by the scoring of atopic dermatitis (SCORAD) index. In order to investigate the risk factors for AD, a questionnaire was administered to all subjects regarding parental atopic history, geographical characteristics of past habitation, past economic status, number of siblings, parental occupation, etc. Results: The point prevalence in the Korean provinces ranged from 1.15% to 1.44%. In multivariable analysis, a parental history of AD was a significant risk factor in all 3 disease-onset groups (infancy, childhood, and adolescent onset). In the infancy-onset group, low economic status was also a significant risk factor for AD. The SCORAD index was significantly higher in AD subjects with early onset and those living in small-sized habitations. Moreover, erythema, edema, lichenification, dryness of skin, and sleep loss appeared to be more severe in early-onset cases. Conclusion: The younger the age of disease onset, the more severe the clinical outcomes in 19-year-old male subjects. In addition, active AD treatment at younger ages might affect the prevalence and the severity of AD in adulthood. PMID- 29386830 TI - Early Detection of Subungual Melanoma In Situ: Proposal of ABCD Strategy in Clinical Practice Based on Case Series. AB - Background: Prevalence of subungual melanoma (SUM) in Asian population is relatively high and early clinical detection improves both quality of life and survival. Objective: We sought to establish screening strategy for SUM in situ. Methods: We retrospectively reviewed medical records of 8 patients pathologically diagnosed as SUM in situ between January 2015 and September 2016. Results: All patients in our study were adults and had solitary lesion. In all cases, longitudinal melanonychia as well as background pigmentation in entire nail plate was observed. Seven (87.5%) cases had periungual pigmentation. Clinical features of SUM in situ can be summarized according to new criteria categorized under initial letters of alphabet, namely nail ABCD of SUM in situ; "A" stands for adult age (age >18 years); "B" for brown bands in brown background; "C" for color in periungual skin; "D" for one digit. Our strategy was to suspect SUM in situ if solitary longitudinal melanonychia in adult was satisfying either "B" or "C" in ABCD. All cases were suspected as SUM in situ under nail ABCD rule, and histological examination confirmed diagnosis. Sensitivity and specificity of nail ABCD was 100% and 96.6%, respectively, regarding our previously published 18 SUM in situ and unpublished 28 nail matrix nevi cases as well as 8 SUM in situ presented here. Conclusion: ABCD rule is simple and sensitive clinical strategy for early detection of SUM in situ. PMID- 29386829 TI - Histopathologic Finding of Perieschar Lesions in Tsutsugamushi Disease Shows Lymphocytic Vasculitis Mimicking Angiocentric Lymphoma. AB - Background: Tsutsugamushi disease is an acute, febrile, infectious disease caused by Orientia tsutsugamushi. Several studies investigating the histopathologic findings of eschars in tsutsugamushi disease reported leukocytoclastic vasculitis and neutrophil infiltration as the major findings. However, these findings may result from secondary changes following tissue necrosis. The histopathologic findings of perieschar lesions may be important to understand the primary changes associated with tsutsugamushi disease. Objective: To investigate characteristic histopathologic features of perieschar lesions and suppose the mechanism of vascular pathophysiological changes associated with tsutsugamushi disease. Methods: We analyzed histopathological slides of perieschar lesions in 12 patients diagnosed with tsutsugamushi disease. Results: In the epidermis, exocytosis of mononuclear cells (75.0%) and basal vacuolar changes (66.7%) were frequent. In the dermis, perivascular, interstitial, and perineural mononuclear cell infiltration (100.0%, 83.3%, and 83.3%, respectively), as well as thrombosis (83.3%), atypical lymphocyte infiltration (91.7%), and mitotic figures (83.3%) were commonly seen. Lymphocytic vasculitis and mononuclear cell infiltration around eccrine glands were found in all cases, but eosinophil infiltration was only found in one patient (8.3%). However, the characteristic findings of eschar lesions, such as leukocytoclastic vasculitis and neutrophil infiltration, were not found in perieschar lesions. Conclusion: The major histopathologic findings in the perieschar lesions of tsutsugamushi disease were lymphocytic vasculitis and atypical lymphocytic infiltration, mimicking lymphoma. Therefore, we suggest that this lesion should be added to the list of pseudolymphomas. To observe these characteristic histopathologic features, we also recommend that skin biopsies should be performed on perieschar lesions, not eschar lesions. PMID- 29386831 TI - Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate Nick End Labeling (TUNEL) Assay to Characterize Histopathologic Changes Following Thermal Injury. AB - Background: Despite the wide application of lasers and radiofrequency (RF) surgery in dermatology, it is difficult to find studies showing the extent of damage dependent on cell death. Objective: We evaluated histopathologic changes following in vivo thermal damage generated by CO2 laser, 1,444 nm long-pulsed neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser and RF emitting electrosurgical unit. Methods: Thermal damage was induced by the above instruments on ventral skin of rat. Specimens were stained with hematoxylin and eosin, along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay, to highlight the degree of irreversible cellular injury. Results: The volume of vaporization was largest with the CO2 laser. Area of cell death area identified by TUNEL assay, when arranged from widest to narrowest, was 1,444 nm LP Nd:YAG laser, CO2 laser, and RF emitting electrosurgical unit. Conclusion: This histopathologic evaluation of the acute characterization of injury across devices may be advantageous for attaining better treatment outcomes. PMID- 29386833 TI - Epidermal Growth Factor Attenuated the Expression of Inflammatory Cytokines in Human Epidermal Keratinocyte Exposed to Propionibacterium acnes. AB - Background: While the beneficial effects of topical epidermal growth factor (EGF) on wound healing have been repeatedly reported, there are few reports about the effects of EGF on inflammatory skin diseases including acne. Objective: To clarify the effects of EGF on acne, it was investigated whether recombinant human EGF (rhEGF) signalling can affect Propionibacterium acnes-induced cytokine expression in human epidermal keratinocytes. Methods: The cultured normal human epidermal keratinocytes (NHK) were co-treated with P. acnes and rhEGF, and mRNA levels of interleukin (IL)-1alpha, IL-8 and tumor necrosis factor (TNF)-alpha; toll-like receptor 2 (TLR2); and nuclear factor kappa B (NF-kappaB) were determined. Specific enzyme-linked immunosorbent assay kits were used to measure the IL-1alpha, IL-8 and TLR2 expression as well as the NF-kappaB activation in P. acnes and rhEGF-treated NHK. After infecting the cultured NHK with live P. acnes, an increased expression of IL-1alpha, IL-8 and TNF-alpha was detected, which was prevented by rhEGF co-treatment. Results: TLR2 and NF-kappaB activity increased after P. acnes treatment, and rhEGF treatment decreased TLR2 expression and NF kappaB activity dose-dependently. The inhibition of EGF receptor by gefitinib attenuated the inhibitory effect of rhEGF on these increased expressions of proinflammatory cytokines and TLR2 and activity of NF-kappaB in NHK stimulated by P. acnes. Conclusion: These results suggest that EGF attenuated P. acnes-induced inflammatory responses, at least in part, through the modulation of TLR2 signalling, and the topical application of rhEGF may be beneficial to relieve the inflammatory reactions of acne. PMID- 29386832 TI - Connective Tissue Growth Factor Neutralization Aggravates the Psoriasis Skin Lesion: The Analysis of Psoriasis Model Mice and Patients. AB - Background: Connective tissue growth factor (CTGF) is a multifunctional cellular protein and playing a role as a central mediator in tissue remodeling and fibrosis. The physiological function of CTGF in psoriasis is unknown. Objective: The purpose of this study was to investigate the function of CTGF in psoriasis using the established imiquimod (IMQ)-induced psoriasis murine model and psoriasis patients. Methods: Anti-CTGF monoclonal antibody was applied to IMQ induced psoriasis mice and those skin were clinically, pathologically and immunologically analyzed. Additionally, CTGF expression was analyzes using skin samples and plasma from psoriasis patients. Results: CTGF expression was observed in the dermis from both IMQ-induced psoriatic mice and psoriasis patients. CTGF inhibition using an anti-CTGF antibody slightly worsened IMQ-induced dermatitis. In addition, the increase of CTGF showed tendency to suppress the psoriatic dermatitis through inhibition of suprabasal cells proliferation and macrophage infiltration in the skin. CTGF was also detected significantly higher in plasma from psoriasis patients comparing with healthy control. Conclusion: Our findings suggest that CTGF could contribute to the healing rather than the worsening of psoriasis skin lesions. PMID- 29386834 TI - Features Causing Confusion between Basal Cell Carcinoma and Squamous Cell Carcinoma in Clinical Diagnosis. AB - Background: Although squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) can be easily diagnosed clinically, proper diagnosis is sometimes difficult when based on clinical information alone. Objective: To know what causes clinical misdiagnosis between SCC and BCC, and evaluate whether dermoscopy can improve diagnostic accuracy. Methods: Clinical and dermoscopic photographs of inversely diagnosed cases (histologically confirmed BCC with a clinical impression of SCC or vice versa) were randomly presented to six dermatologists and the reasons for each correct or incorrect diagnosis were analyzed. Results: Among 154 cases (SCCs or BCCs), 13 cases were inversely diagnosed; 9 SCCs were clinically misdiagnosed as BCC and 4 BCCs were clinically misdiagnosed as SCC. Clinically, scales, pigmentation and rolled border were meaningful factors to discern two carcinomas. Scales without both pigmentation and rolled border was favored for SCC, but BCC favored vice versa. Ulceration, telangiectasia and translucency contributed as confusing factors for proper diagnosis. Dermoscopy improved overall diagnostic accuracy to odds ratio 2.86. Conclusion: SCC has a higher tendency to be clinically misdiagnosed as BCC than vice versa. Pigmentation and rolled border are factors causing misdiagnosis of SCC as BCC and BCC may be misdiagnosed as SCC in the presence of scaling. Dermoscopy seems to improve the clinical diagnostic accuracy but has limitations for some ambiguous lesions. PMID- 29386835 TI - Drug Reaction with Eosinophilia and Systemic Symptoms Associated with Reactivation of Epstein-Barr Virus and/or Cytomegalovirus Leading to Hemophagocytic Syndrome in One of Two Patients. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity reaction characterized by maculopapular rash, exfoliative dermatitis, lymphadenopathy, fever, eosinophilia, and involvement of internal organs. Evidence for reactivation of herpes family viruses has been observed in some DRESS patients, and activated CD8+ T lymphocytes are largely directed against Epstein-Barr virus. Here, we report two cases complicated with this infection. Both patients received antibiotics and non-steroidal anti-inflammatory drugs. These patients manifested clinically with high fever, facial edema, diffuse pruritic erythroderma and maculopapules over the entire body, purpuric rashes in both lower limbs and lymphadenopathy of cervical and inguinal nodes. Laboratory tests revealed abnormal liver function, blood eosinophils, and ferritin levels. The patients recovered completely; however, the female patient developed hemophagocytic syndrome on the 15th day of illness. She developed new itchy rash, and laboratory tests rapidly worsened with fibrinogen levels dramatically reduced to 0.61 g/L. Bone marrow aspiration revealed an increased number of macrophages with hemophagocytosis and a reversed CD4/CD8 ratio of 0.45. These cases suggest that human herpes virus and coagulation function evaluations are necessary in DRESS patients. PMID- 29386836 TI - Asymptomatic Hyperpigmentation without Preceding Inflammation as a Clinical Feature of Citrus Fruits-Induced Phytophotodermatitis. AB - Phytophotodermatitis is a condition that occurs by contact with plants containing phototoxic agents such as furocoumarins and psoralens with subsequent ultraviolet exposure. Phytophotodermatitis typically presents as sharply defined erythematous patches with occasional blistering, sometimes accompanied with pain or itching sensation. In some cases, however, sudden appearance of asymptomatic hyperpigmentation can be the only clinical finding of phytophotodermatitis. Here, we present two patients with sudden development of asymptomatic pigmentation on their hand without preceding inflammation by the contact with citrus fruits containing photosensitizers and subsequent exposure to strong sunlight. As like these patients, phytophotodermatitis can present with only pigmentation without noticeable inflammation especially in dark skinned people. In such cases, physician can sometimes have difficulty in diagnosis of phytophotodermatitis. Therefore, it is important to consider the possibility of phytophotodermatitis through careful history taking, especially in patients who have abruptly developed well-defined hyperpigmentation on sun-exposed areas, to avoid unnecessary test and treatment. PMID- 29386838 TI - Becker's Nevus with Recurrent Eczema Limited to the Nevus Lesion. AB - Several dermatoses have been reported in association with Becker's nevus. Eczematous dermatitis associated with Becker's nevus is extremely rare, described in only two previous case reports. We report a case of 21-year-old male with recurrent eczema lesions which were always localized within the underlying Becker's nevus lesion. This case may be explained as a Wolf's isotopic response like phenomenon. PMID- 29386837 TI - Paraneoplastic Pyoderma Gangrenosum Associated with Rectal Adenocarcinoma. AB - Pyoderma gangrenosum (PG) is a rare chronic neutrophilic dermatosis characterized by painful necrotic ulceration. The most common diseases associated with PG are inflammatory bowel disease, certain rheumatologic and hematologic diseases, and malignancy. Here, we describe the case of a 60-year-old man who presented with pruritic and painful erythematous ulcerative macules and patches on both lower extremities, and was diagnosed with PG based on his clinical and histologic features. His PG became exacerbated despite standard therapy with a high-dose systemic steroid in combination with dapsone and cyclosporine. Systemic evaluation of underlying conditions revealed rectal adenocarcinoma at the rectosigmoid junction (T3N0M0), which was completely removed via Hartmann's procedure followed by adjuvant chemotherapy. Two months after anticancer therapy, his PG was completely healed with hypertrophic scarring. Herein, we present the first case of paraneoplastic PG caused by rectal adenocarcinoma in Korea. PMID- 29386839 TI - Intensely Pruritic Papules and Plaques in Waldenstrom's Macroglobulinemia. AB - Waldenstrom's macroglobulinemia (WM) is lymphoplasmacytoid malignancy that affects B lymphocytes. Cutaneous involvement of WM is rare, but various cutaneous manifestations have been reported. These findings are due to various pathological processes including direct invasion of tumor cells into the skin, deposition of paraproteins, hyperviscosity syndrome, and cryoglobulinemia. A 64-year-old man presented with a 10-day history of pruritic erythematous papules and plaques on his trunk and elbows. The clinical features were suspicious for eczematous dermatitis. However, treatments such as oral antihistamines, topical steroids, ultraviolet light therapy and immunomodulators (dapsone and cyclosporine) were minimally effective. The patient's hemoglobin decreased gradually, and he was referred to the department of hematology. Serum electrophoresis exhibited a monoclonal peak in the beta1 region. The diagnosis of WM was established based on a bone marrow biopsy that revealed 80% lymphoplasma cellularity, staining positive for CD20 and CD79a. However, there was no direct infiltration of tumor cells or immunoglobulin deposition on the skin biopsy. After the patient started rituximab, cyclophosphamide and dexamethasone therapy, anemia and neutropenia gradually improved. His pruritus also markedly subsided. Although there was no evidence of infiltration of WM in the skin lesions, they were thought to be strongly associated with monoclonal gammopathy. This dermatologic feature has not been documented as a nonspecific cutaneous manifestation of WM or monoclonal gammopathy. To clarify the association between intensely pruritic papules/plaques and WM, more reports and further studies could be needed. PMID- 29386840 TI - A Case of Multiple Cutaneous Piloleiomyomas on the Neck. PMID- 29386842 TI - Facial Eruptive Vellus Hair Cysts Occurred after 3% Minoxidil Application. PMID- 29386841 TI - Hypopigmented Mycosis Fungoides Treated with 308 nm Excimer Laser. PMID- 29386843 TI - Tinea Incognito with Folliculitis-Like Presentation: A Case Series. PMID- 29386844 TI - A Case of Acute Generalized Exanthematous Pustulosis after Injection of an Erythropoiesis-Stimulating Agent. PMID- 29386845 TI - Investigating Skin Penetration Following Needle-Free Injection Combined with Fractional Laser and Subcision. PMID- 29386846 TI - The Polyonychia and Distal Phalangeal Bone Underdevelopment on Right Second Toe. PMID- 29386847 TI - Local Hyperthermia Affects Murine Contact Hypersensitivity around Elicitation Phase. PMID- 29386848 TI - Re: Histologic Evidence of New Collagen Formulation Using Platelet Rich Plasma in Skin Rejuvenation: A Prospective Controlled Clinical Study. PMID- 29386849 TI - Re: Histologic Evidence of New Collagen Formulation Using Platelet Rich Plasma in Skin Rejuvenation: A Prospective Controlled Clinical Study: Authors' Reply. PMID- 29386850 TI - Accuracy and Reliability of Subjective Answer about Age of Onset in Psoriasis. PMID- 29386851 TI - Congenital Linear Smooth Muscle Hamartoma with Hypertrichosis: Hair Density on Dermoscopy in Parallel with the Number of Smooth Muscle Bundles. PMID- 29386852 TI - A Case of Atrophoderma Vermiculatum Showing a Good Response to Topical Tretinoin. PMID- 29386853 TI - beta-Catenin Regulates the Expression of cAMP Response Element-Binding Protein 1 in Squamous Cell Carcinoma Cells. PMID- 29386854 TI - The Conical-Shaped, Staged Laser Ablation Technique in the Removal of a Medium Sized Intradermal Nevus. PMID- 29386855 TI - Elephantiasic Graves' Dermopathy in a Patient with Negative Thyroid-Receptor Auto Antibodies. PMID- 29386856 TI - Two-Sample Tests for High-Dimensional Linear Regression with an Application to Detecting Interactions. AB - Motivated by applications in genomics, we consider in this paper global and multiple testing for the comparisons of two high-dimensional linear regression models. A procedure for testing the equality of the two regression vectors globally is proposed and shown to be particularly powerful against sparse alternatives. We then introduce a multiple testing procedure for identifying unequal coordinates while controlling the false discovery rate and false discovery proportion. Theoretical justifications are provided to guarantee the validity of the proposed tests and optimality results are established under sparsity assumptions on the regression coefficients. The proposed testing procedures are easy to implement. Numerical properties of the procedures are investigated through simulation and data analysis. The results show that the proposed tests maintain the desired error rates under the null and have good power under the alternative at moderate sample sizes. The procedures are applied to the Framingham Offspring study to investigate the interactions between smoking and cardiovascular related genetic mutations important for an inflammation marker. PMID- 29386857 TI - A new inequality for the Riemann-Stieltjes integrals driven by irregular signals in Banach spaces. AB - We prove an inequality of the Loeve-Young type for the Riemann-Stieltjes integrals driven by irregular signals attaining their values in Banach spaces, and, as a result, we derive a new theorem on the existence of the Riemann Stieltjes integrals driven by such signals. Also, for any [Formula: see text], we introduce the space of regulated signals [Formula: see text] ([Formula: see text] are real numbers, and W is a Banach space) that may be uniformly approximated with accuracy [Formula: see text] by signals whose total variation is of order [Formula: see text] as [Formula: see text] and prove that they satisfy the assumptions of the theorem. Finally, we derive more exact, rate-independent characterisations of the irregularity of the integrals driven by such signals. PMID- 29386858 TI - Precise large deviations for widely orthant dependent random variables with different distributions. AB - Let [Formula: see text] be a sequence of random variables with different distributions [Formula: see text]. The partial sums are denoted by [Formula: see text], [Formula: see text]. This paper mainly investigates the precise large deviations of [Formula: see text], for the widely orthant dependent random variables [Formula: see text]. Under some mild conditions, the lower and upper bounds of the precise large deviations of the partial sums [Formula: see text], [Formula: see text], are presented. PMID- 29386859 TI - Near-Common-Path Self-Reference Quantitative Phase Microscopy. AB - We report a near-common-path self-reference quantitative phase microscope, wherein a quantitative phase image is formed through the off-axis interference of the sample wave with a 180-degree rotated version of itself. A pair of dove prisms, oriented in different directions, is used to effect the relative transformation between the beams. Our technique features a simple optical design that requires no maintenance, rendering it accessible to nonspecialists in the field of optics. Additionally, its variable magnification and low-noise phase measurement capabilities make it suitable for high-accuracy imaging of biological samples of different sizes. PMID- 29386860 TI - The Absence of a Drug-Disease Interaction Alert Leads to a Child's Death. AB - The absence of a drug-disease interaction alert leads to a child's death. PMID- 29386861 TI - CMS Considering Pharmacy Counter Discounts for Part D Drugs in Future Other Pharmacy Changes Are Likely for 2019. AB - CMS considering pharmacy counter discounts for Part D drugs in the future. PMID- 29386862 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 29386863 TI - Pharmaceutical Approval Update. AB - Benznidazole for pediatric patients with Chagas disease; vestronidase alfa-vjbk (Mepsevii) for adults and children with mucopolysaccharidosis type VII; and hepatitis B vaccine (recombinant), adjuvanted (Heplisav-B), for the prevention of infection caused by all known subtypes of hepatitis B virus in adults. PMID- 29386864 TI - Betrixaban (Bevyxxa): A Direct-Acting Oral Anticoagulant Factor Xa Inhibitor. AB - Betrixaban (Bevyxxa): a direct-acting oral anti-coagulant factor Xa inhibitor. PMID- 29386865 TI - Talk of a "Default" Drug Formulary Rattles Industry: CMS Could Move in That Direction for Marketplace Plans After 2019, but the Discussion Has Already Started. AB - A proposed CMS rule promising to consider a federal default prescription drug benefit after 2019 has startled manufacturers, pharmacy benefit managers, P&T committees, and pharmacies alike. We consider the rationale and potential effects of such a rule. PMID- 29386867 TI - Impact of a Pharmacy-Led Medication Reconciliation Program. AB - Objective: To determine the impact of a pharmacy-led medication reconciliation program at a large community hospital. The magnitude of the benefit of pharmacy led medication reconciliation was evaluated based on the number of medication related discrepancies between nursing triage notes and medication histories performed by pharmacy technicians or students. Discrepancies identified by pharmacy personnel medication histories that required pharmacist intervention on physician admission orders were further classified based on expected clinical impact if the error were to be propagated throughout hospitalization. Methods: A retrospective chart review was performed on 200 patients who met the following inclusion criteria: adults admitted from the emergency department from October 1, 2015, to November 17, 2015, with a medication history collected by medication reconciliation personnel (MRP) containing at least three home medications or one high-risk home medication that was reviewed and reconciled by one of the investigators. The primary endpoint was the number of discrepancies between nursing triage notes and pharmacy personnel medication histories. The secondary endpoint was the percentage of pharmacy interventions categorized as "significant," "serious," or "life threatening" on a medication error severity scale. Additional data points included: number and type of clinical interventions; percent of interventions involving high-risk medications; amount of time spent obtaining medication histories and comparing them to admission orders; number and type of sources used; number of home medications; and percent of admitted patients interviewed by the MRP within 24 hours of admission. Results: In a population of 200 patients, 1,762 medication history discrepancies were identified. MRP-collected histories identified issues involving 46 patients that required pharmacist intervention for a total of 235 interventions, of which 68% were related to errors categorized as significant, serious, or life threatening. Conclusion: Utilization of a pharmacy-led medication reconciliation program decreased the number of significant, serious, and life-threatening medication reconciliation errors upon hospital admission. PMID- 29386866 TI - Osteoporosis: A Review of Treatment Options. AB - Approximately 10 million men and women in the U.S. have osteoporosis,1 a metabolic bone disease characterized by low bone density and deterioration of bone architecture that increase the risk of fractures.2 Osteoporosis-related fractures can increase pain, disability, nursing home placement, total health care costs, and mortality.3 The diagnosis of osteoporosis is primarily determined by measuring bone mineral density (BMD) using noninvasive dual-energy x-ray absorptiometry. Osteoporosis medications include bisphosphonates, receptor activator of nuclear factor kappa-B ligand inhibitors, estrogen agonists/antagonists, parathyroid hormone analogues, and calcitonin.3-6 Emerging therapies utilizing novel mechanisms include a cathepsin K inhibitor and a monoclonal antibody against sclerostin.7,8 While professional organizations have compiled recommendations for the management of osteoporosis in various populations, a consensus has yet to develop as to which is the gold standard; therefore, economic evaluations have been increasingly important to help guide decision-makers. A review of cost-effectiveness literature on the efficacy of oral bisphosphonates has shown alendronate and risedronate to be most cost effective in women with low BMD without previous fractures.9 Guidelines are inconsistent as to the place in therapy of denosumab (Prolia, Amgen). In economic analyses evaluating treatment of postmenopausal women, denosumab outperformed risedronate and ibandronate; its efficacy was comparable to generic alendronate, but it cost more.10 With regard to older men with osteoporosis, denosumab was also found to be cost-effective when compared with bisphosphonates and teriparatide (Forteo, Lilly).11. PMID- 29386868 TI - American Society of Hematology. AB - We review key sessions on Hodgkin's lymphoma, diffuse large B-cell lymphoma, thromboembolism, hemophilia, sickle cell disease, and chronic lymphocytic leukemia. PMID- 29386869 TI - New Antibiotics in Development Target Highly Resistant Gram-Negative Organisms. AB - Upcoming antibacterial agents in the pipeline appear promising, but it is difficult to predict their long-term durability. This article focuses on investigational agents that target resistant gram-negative organisms commonly found in the health care setting. PMID- 29386870 TI - Research Briefs. PMID- 29386871 TI - Oligodendrocyte death, neuroinflammation, and the effects of minocycline in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION). AB - Purpose: Optic nerve (ON) damage following nonarteritic anterior ischemic optic neuropathy (NAION) and its models is associated with neurodegenerative inflammation. Minocycline is a tetracycline derivative antibiotic believed to exert a neuroprotective effect by selective alteration and activation of the neuroinflammatory response. We evaluated minocycline's post-induction ability to modify early and late post-ischemic inflammatory responses and its retinal ganglion cell (RGC)-neuroprotective ability. Methods: We used the rodent NAION (rNAION) model in male Sprague-Dawley rats. Animals received either vehicle or minocycline (33 mg/kg) daily intraperitoneally for 28 days. Early (3 days) ON cytokine responses were evaluated, and oligodendrocyte death was temporally evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Cellular inflammation was evaluated with immunohistochemistry, and RGC preservation was compared with stereology of Brn3a-positive cells in flat mounted retinas. Results: Post-rNAION, oligodendrocytes exhibit a delayed pattern of apoptosis extending over a month, with extrinsic monocyte infiltration occurring only in the primary rNAION lesion and progressive distal microglial activation. Post-induction minocycline failed to improve retinal ganglion cell survival compared with the vehicle treated (893.14 vs. 920.72; p>0.9). Cytokine analysis of the rNAION lesion 3 days post-induction revealed that minocycline exert general inflammatory suppression without selective upregulation of cytokines associated with the proposed alternative or neuroprotective M2 inflammatory pathway. Conclusions: The pattern of cytokine release, extended temporal window of oligodendrocyte death, and progressive microglial activation suggests that selective neuroimmunomodulation, rather than general inflammatory suppression, may be required for effective repair strategies in ischemic optic neuropathies. PMID- 29386872 TI - Mutations in crystallin genes result in congenital cataract associated with other ocular abnormalities. AB - Purpose: This study aims to describe the phenotypes and identify pathogenic mutations in Chinese patients who have congenital cataracts associated with other ocular abnormalities. Methods: Eleven patients from four unrelated Chinese families plus two simplex cases were enrolled in this study. Detailed ophthalmic examinations were performed. DNA samples were isolated from peripheral blood collected from the patients. Next-generation sequencing of known ocular genes was applied to the proband of each family and two simplex cases to find pathogenic variances. PCR and Sanger sequencing were conducted for validation and segregation tests. Results: All 13 patients had congenital cataracts, and other ocular abnormalities were found in some cases. Microcornea was found in 12 subjects, and ocular coloboma was observed in five. Various types of coloboma, including iris, choroid, macular, and optic disc, were described. Five mutations in crystallin genes were identified. Four of the mutations are novel: CRYBB1: p.(Arg230Cys), CRYBB2: p.(Gly149Val), CRYGC: p.(Met44CysfsTer59), and CRYGC: p.(Tyr144Ter). One mutation was reported previously: CRYAA: p.(Arg21Trp). Conclusions: We examined a cohort of Chinese patients with congenital cataracts and studied the phenotypes and genotypes. Extralenticular abnormalities, such as microcornea and ocular coloboma, can also be found in patients with congenital cataracts. The phenotype of congenital cataracts associated with macular and optic disc coloboma was reported for the first time in this study. Four novel mutations and one previously reported mutation were identified. These data expand the mutation spectrum in crystallin genes and enhance our understanding of the phenotypes of congenital cataracts. PMID- 29386874 TI - Effect of 7-methylxanthine on human retinal pigment epithelium cells cultured in vitro. AB - Purpose: To evaluate the effects of 7-methylxanthine (7-MX) on the growth of human retinal pigment epithelium (RPE) cells and to observe the changes in the expression of adenosine receptors (ADORs) in RPE cells upon 7-MX treatment. Methods: Human RPE cells (monolayer at about 80% confluence) were cultured in vitro in the presence or absence of 7-MX. Cell proliferation was evaluated with 3 (4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The cell cycle distribution and apoptosis level were analyzed with flow cytometry. Quantitative PCR and immunofluorescence assay were used to examine the mRNA and protein expression of ADORs. Results: 7-MX at low concentrations had no effect on the proliferation of RPE cells, whereas 100 umol/l 7-MX slightly decreased cell proliferation at 48 h but without a statistically significant difference. The 7 MX treatment was performed at the low concentration of 10 MUmol/l in the following experiments. The proportion of RPE cells in the G1 stage was slightly increased at 24 h (p=0.035) but decreased at 48 h (p=0.0045) upon 7-MX treatment; and the proportion was restored to normal at 72 h. No statistically significant change in apoptosis levels was found in RPE cells cultured with 7-MX. The expression of ADORA1, ADORA2A, and ADORA2B in RPE cells was inhibited by 7-MX treatment at 48 h, while the expression levels appeared to rebound at 72 h. Conclusions: 7-MX has little effect on the proliferation or apoptosis level of human RPE cells; however, in short-term treatment, 7-MX disturbs the proportion of cells in the G1 stage and inhibits the expression of ADORA1, ADORA2A, and ADORA2B. PMID- 29386873 TI - Meta-analysis of transcriptomic changes in optic nerve injury and neurodegenerative models reveals a fundamental response to injury throughout the central nervous system. AB - Purpose: Injury to the central nervous system (CNS) leads to transcriptional changes that effect tissue function and govern the process of neurodegeneration. Numerous microarray and RNA-Seq studies have been performed to identify these transcriptional changes in the retina following optic nerve injury and elsewhere in the CNS following a variety of insults. We reasoned that conserved transcriptional changes between injury paradigms would be important contributors to the neurodegenerative process. Therefore, we compared the expression results from heterogeneous studies of optic nerve injury and neurodegenerative models. Methods: Expression data was collected from the Gene Expression Omnibus. A uniform method for normalizing expression data and detecting differentially expressed (DE) genes was used to compare the transcriptomes from models of acute optic nerve injury (AONI), chronic optic nerve injury (CONI) and brain neurodegeneration. DE genes were split into genes that were more or less prevalent in the injured condition than the control condition (enriched and depleted, respectively) and transformed into their human orthologs so that transcriptomes from different species could be compared. Biologic significance of shared genes was assessed by analyzing lists of shared genes for gene ontology (GO) term over-representation and for representation in KEGG pathways. Results: There was significant overlap of enriched DE genes between transcriptomes of AONI, CONI and neurodegeneration studies even though the overall concordance between datasets was low. The depleted DE genes identified between AONI and CONI models were significantly overlapping, but this significance did not extend to comparisons between optic nerve injury models and neurodegeneration studies. The GO terms overrepresented among the enriched genes shared between AONI, CONI and neurodegeneration studies were related to innate immune processes like the complement system and interferon signaling. KEGG pathway analysis revealed that transcriptional alteration between JAK-STAT, PI3K-AKT and TNF signaling, among others, were conserved between all models that were analyzed. Conclusions: There is a conserved transcriptional response to injury in the CNS. This transcriptional response is driven by the activation of the innate immune system and several regulatory pathways. Understanding the cellular origin of these pathways and the pathological consequences of their activation is essential for understanding and treating neurodegenerative disease. PMID- 29386875 TI - beta-amyloid expression in age-related cataract lens epithelia and the effect of beta-amyloid on oxidative damage in human lens epithelial cells. AB - Purpose: To evaluate the changes in beta-amyloid (Abeta) expression in age related cataract (ARC) lens epithelia and the effect of Abeta on oxidative damage in human lens epithelial cells (HLECs). Methods: Specimens of lens epithelia and aqueous humor were obtained from 255 cataract surgery patients and 48 healthy donor eyes. The ARC samples were divided into four groups according to the Lens Opacities Classification System III, with increasing severity from Group I to Group IV. The HLECs were cultured under healthy or oxidative conditions with or without Abeta pretreatment. Western blot, immunofluorescence, real-time PCR, and enzyme-linked immunosorbent assay were performed to detect Abeta and beta-amyloid precursor protein (APP) expression. beta-secretase activity was analyzed in lens epithelia and HLECs. The effect of Abeta on the viability of HLECs under oxidative conditions was investigated using a cell viability assay. Results: Compared with the healthy group, the Abeta 1-42 expression levels in lens epithelia and Abeta 1-40 expression levels in aqueous humor decreased in Groups I, II, and III (p<0.05) but were unchanged in Group IV. In contrast, APP expression levels increased in Groups I, II, and III (p<0.05) compared with those in the healthy group but were unchanged in Group IV. H2O2-treated HLECs exhibited decreased amounts of Abeta 1-42 and increased amounts of APP. beta-secretase activity decreased in the lens epithelia of all four subgroups of ARCs compared with that in the lens epithelia of healthy subjects and decreased in H2O2-treated HLECs. Furthermore, treatment with nanomolar concentrations (0.2 nM to 10 nM) of Abeta could protect cell viability from oxidative damage. Conclusions: Abeta and APP expression levels exhibited differential changes during the development of ARC, indicating active feedback of this protein processing. Decreased expression of physiologically generated Abeta in the early and mid-stages of ARC development might be one of the potential mechanisms accelerating oxidative stress in HLECs during cataractogenesis. PMID- 29386876 TI - Bortezomib inhibits proliferation, migration, and TGF-beta1-induced epithelial mesenchymal transition of RPE cells. AB - Purpose: Nuclear factor kappa B (NF-kappaB) plays an important role in the epithelial-mesenchymal transition (EMT) of RPE cells. We investigated the effects of a proteasome inhibitor, bortezomib, on the EMT in RPE cells. In addition, we assessed the influence of bortezomib on regulation of the NF-kappaB pathway during this process. Methods: After treatment with various concentrations of bortezomib, cell viability was analyzed with the water-soluble tetrazolium salt-8 assay, cell-cycle regulation was evaluated with flow cytometry, and cell migration was monitored with in vitro wound healing and Transwell migration assays. To induce fibroblastoid transformation, the RPE cells were treated with recombinant human transforming growth factor (TGF)-beta1 (10 ng/ml), and western blot and immunocytochemical analyses were performed to evaluate altered expression of EMT markers after treatment with bortezomib. To verify the effect of bortezomib on shrinkage by myofibroblastic transformation, a contraction assay of the RPE-collagen gel lattice was performed. Results: Treatment with bortezomib decreased RPE viability in a dose-dependent manner, and flow cytometry revealed that these effects were due to arrest of the G2/M phase cell-cycle. In the in vitro wound healing and Transwell migration assays, treatment with 20 nM bortezomib significantly impeded RPE migration. Treatment with bortezomib also significantly inhibited TGF-beta1-induced transdifferentiation of the RPE cells. The effects on proliferation, migration, and the EMT were mediated by regulation of the NF-kappaB signaling pathway. In addition, bortezomib inhibited contraction of the RPE-collagen gel lattices. Conclusions: Bortezomib inhibits myofibroblastic transformation of RPE cells by downregulating NF-kappaB expression and prevents contraction of the RPE-collagen gel matrix. Thus, bortezomib represents a candidate putative therapeutic agent for management of retinal fibrotic diseases. PMID- 29386877 TI - Expression patterns of zebrafish nocturnin genes and the transcriptional activity of the frog nocturnin promoter in zebrafish rod photoreceptors. AB - Purpose: Daily modulation of gene expression is critical for the circadian rhythms of many organisms. One of the modulating mechanisms is based on nocturnin, a deadenylase that degrades mRNA in a circadian fashion. The nocturnin genes are expressed broadly, but their tissue expression patterns differ between mice and the frog Xenopus laevis; this difference suggests that the extent of the regulation of nocturin gene expression varies among species. In this study, we set out to characterize the expression patterns of two zebrafish nocturnin genes; in addition, we asked whether a frog nocturnin promoter has transcriptional activity in zebrafish. Methods: We used reverse transcription (RT)-PCR, quantitative real-time PCR (qRT-PCR), and rapid amplification of cDNA ends (RACE) analysis to determine whether the nocturnin-a and nocturnin-b genes are expressed in the eye, in situ hybridization to determine the cellular expression pattern of the nocturnin-b gene in the retina, and confocal microscopy to determine the protein expression pattern of the transgenic reporter green fluorescent protein (GFP) driven by the frog nocturnin promoter. Results: We found that the amino acid sequences of zebrafish nocturnin-a and nocturnin-b are highly similar to those of frog, mouse, and human nocturnin homologs. Only nocturnin-b is expressed in the eye. Within the retina, nocturnin-b mRNA was expressed at higher levels in the retinal photoreceptors layer than in other cellular layers. This expression pattern echoes the restricted photoreceptor expression of nocturnin in the frog. We also found that the frog nocturnin promoter can be specifically activated in zebrafish rod photoreceptors. Conclusions: The high level of similarities in amino acid sequences of human, mouse, frog, and zebrafish nocturnin homologs suggest these proteins maintain a conserved deadenylation function that is important for regulating retinal circadian rhythmicity. The rod-specific transcriptional activity of the frog nocturnin promoter makes it a useful tool to drive moderate and rod-specific transgenic expression in zebrafish. The results of this study lay the groundwork to study nocturnin-based circadian biology of the zebrafish retina. PMID- 29386879 TI - Full-field ERG as a predictor of the natural course of ABCA4-associated retinal degenerations. AB - Purpose: To assess retinal function in combination with the retinal structure in ABCA4-associated retinal degenerations. Moreover, to evaluate the possibility of predicting the natural course of these disorders. Methods: 34 patients with Stargardt disease or cone rod dystrophy carrying confirmed mutations in ABCA4 were selected from our retinitis pigmentosa (RP) register. Sequence analysis of the entire coding region of the ABCA4 gene was performed. The patients were subdivided into three groups based on their most recent visual fields. Group 1 included ten patients with central scotomas within 10 degrees , group 2 included 19 patients with larger central scotomas of 10-35 degrees , and group 3 included five patients with mere temporal residues. The patients underwent slit-lamp and fundus examinations, visual acuity testing, optical coherence tomography (OCT), fundus photography (color, red-free, and autofluorescence (AF) images), full field electroretinography (ffERG), and multifocal electroretinography (mERG). FfERG and mERG results were analyzed statistically. Total rod and cone function, as well as macular function, was compared between the three groups and of each group to a normal material. In 23 patients who had undergone ffERG on a previous occasion, the 30 Hz flicker implicit time (IT) from the first visit was also analyzed. Results: The ffERG statistics revealed significant differences between the groups regarding cone and rod function with group 1 showing the highest amplitudes and the shortest ITs while group 3 demonstrated the lowest amplitudes and the most delayed ITs. When compared to controls, group 1 did not show any significant changes while groups 2 and 3 demonstrated reduced amplitudes and delayed 30 Hz ITs. Regarding estimation of the natural course, identical results of the 30 Hz IT were encountered for the groups also at the first visit early in the course of disease. Comparison of the mERGs showed significant differences with group 1 demonstrating the highest amplitudes and group 3 the lowest for all rings but rings 2 and 3 in the right eye for which the amplitudes were the second highest. The mERGs for each group were also compared to controls showing reduced mERG amplitudes for all rings in all groups, except group 1, left eye. OCT showed macular attenuation in all patients. Evaluation of the inner and outer photoreceptor junction (IS/OS) morphology revealed alterations related to macular function measured with mERG in all eyes. Eight patients in group 1 showed foveal IS/OS junction loss, one had foveal IS/OS junction disorganization, and one had IS/OS loss also beyond the fovea. In group 2, one patient had IS/OS junction loss confined to the fovea, and the rest showed total loss of IS/OS junctions. Group 3 was devoid of IS/OS junctions. Concerning the AF images, group 1 showed small areas of absent AF in the macula, peripapillary sparing, and flecks of increased and reduced AF in the posterior pole. In group 2, the central areas of absent AF were larger. Flecks of reduced AF were the most dominant and reached beyond the posterior pole. Seven of 19 patients had peripapillary sparing. In group 3, large confluent areas of reduced AF were found in the posterior pole and beyond with small areas of increased AF in the far periphery. No peripapillary sparing was seen. Conclusions: The current study demonstrates a significant difference in total retinal function, as well as macular function, between patients with ABCA4 associated retinal degeneration and a different degree of visual field defects with gradual deterioration of function along with increased visual field constriction. Likewise, the morphological changes, including the deviant AF pattern and loss of IS/OS junctions, that were related to macular function measured with mERG worsened with the degree of visual field defects. Moreover, in these groups of patients with ABCA4-associated retinal degenerations, full-field cone 30 Hz flicker IT seems to be a predictor of the natural course of the disease also on long-term follow-up. PMID- 29386881 TI - The Role of Hostile Attributions in the Associations between Child Maltreatment and Reactive and Proactive Aggression. AB - The present study examined the relations between child maltreatment and reactive and proactive functions of aggression, and whether hostile attribution biases partially accounted for these associations in a sample of 339 college students (mean age = 19; 51% male). Child maltreatment was associated with reactive, but not proactive, aggression, and instrumental hostile attribution biases accounted for this association. Relational hostile attributions were correlated with both reactive and proactive aggression, but did not play a role in the link between child maltreatment and reactive aggression. PMID- 29386880 TI - Human L- and M-opsins restore M-cone function in a mouse model for human blue cone monochromacy. AB - Purpose: Blue cone monochromacy (BCM) is an X-linked congenital vision disorder characterized by complete loss or severely reduced L- and M-cone function. Patients with BCM display poor visual acuity, severely impaired color discrimination, myopia, nystagmus, and minimally detectable cone-mediated electroretinogram. Recent studies of patients with BCM with adaptive optics scanning laser ophthalmoscopy (AOSLO) showed that they have a disrupted cone mosaic with reduced numbers of cones in the fovea that is normally dominated by L and M-cones. The remaining cones in the fovea have significantly shortened outer segments but retain sufficient structural integrity to serve as potential gene therapy targets. In this study, we tested whether exogenously expressed human L- and M-opsins can rescue M-cone function in an M-opsin knockout (Opn1mw-/- ) mouse model for BCM. Methods: Adeno-associated virus type 5 (AAV5) vectors expressing OPN1LW, OPN1MW, or C-terminal tagged OPN1LW-Myc, or OPN1MW-HA driven by a cone specific promoter were injected subretinally into one eye of Opn1mw-/- mice, while the contralateral eye served as the uninjected control. Expression of cone pigments was determined with western blotting and their cellular localization identified with immunohistochemistry. M-cone function was analyzed with electroretinogram (ERG). Antibodies against cone phototransduction proteins were used to study cone outer segment (OS) morphology in untreated and treated Opn1mw /- eyes. Results: We showed that cones in the dorsal retina of the Opn1mw-/- mouse do not form outer segments, resembling cones that lack outer segments in the human BCM fovea. We further showed that AAV5-mediated expression of either human M- or L-opsin individually or combined promotes regrowth of cone outer segments and rescues M-cone function in the treated Opn1mw-/- dorsal retina. Conclusions: Exogenously expressed human opsins can regenerate cone outer segments and rescue M-cone function in Opn1mw-/- mice, thus providing a proof-of concept gene therapy in an animal model of BCM. PMID- 29386882 TI - Cell Colonization Ability of a Commercialized Large Porous Alveolar Scaffold. AB - The use of filling biomaterials or tissue-engineered large bone implant-coupling biocompatible materials and human bone marrow mesenchymal stromal cells seems to be a promising approach to treat critical-sized bone defects. However, the cellular seeding onto and into large porous scaffolds still remains challenging since this process highly depends on the porous microstructure. Indeed, the cells may mainly colonize the periphery of the scaffold, leaving its volume almost free of cells. In this study, we carry out an in vitro study to analyze the ability of a commercialized scaffold to be in vivo colonized by cells. We investigate the influence of various physical parameters on the seeding efficiency of a perfusion seeding protocol using large manufactured bone substitutes. The present study shows that the velocity of the perfusion fluid and the initial cell density seem to impact the seeding results and to have a negative effect on the cellular viability, whereas the duration of the fluid perfusion and the nature of the flow (steady versus pulsed) did not show any influence on either the fraction of seeded cells or the cellular viability rate. However, the cellular repartition after seeding remains highly heterogeneous. PMID- 29386883 TI - Aflibercept for clinically significant diabetic macular edema: 12-month results in daily clinical practice. AB - Purpose: To assess the effectiveness and safety of intravitreal aflibercept in clinically significant diabetic macular edema (DME) in daily clinical practice. Methods: Prospective, open-label, single-center study. Anti-vascular endothelial growth factor naive patients with clinically significant DME received intravitreal injections of aflibercept 2 mg, five monthly doses followed by a fixed schedule every 2 months for 12 months. The mean change in best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) was the primary outcome. Results: The mean BCVA improved significantly as compared with baseline at 12 months of treatment (47.3 [14.2] vs 62.2 [13.9] ETDRS letters, P<0.001). Significant improvement in BCVA was already observed at visit 2 after the loading doses of aflibercept. At 12 months, gains in ETDRS letters were documented in all eyes (100%), with gains >=10 letters in 89.6%, >=15 letters in 65.5%, and >=20 letters in 6.9% (n=2). A significant reduction in central macular thickness from a mean of 460.5 (11.8) MUm at baseline to 229.0 (43.8) MUm at 12 months (P<0.001) was observed. Significant reductions of central macular thickness were already observed after the loading doses and continued lowering throughout the study period. No adverse events occurred. Conclusion: Aflibercept as a first-line therapy was effective and well tolerated for treating clinically significant DME in naive patients in daily practice. Successful results in terms of improvement of visual and reduction in central macular thickness contribute to provide evidence for the positioning of aflibercept as a first-line indication of newly diagnosed clinically significant DME. PMID- 29386884 TI - The UK Paediatric Ocular Trauma Study 2 (POTS2): demographics and mechanisms of injuries. AB - Purpose: Pediatric ocular trauma is an important cause of visual morbidity worldwide, accounting for up to one-third of all ocular trauma admissions. It has long-term implications for those affected and significant economic consequences for healthcare providers. It has been estimated that 90% of all ocular trauma is preventable. Targeted strategies are required to reduce the incidence and the severity of pediatric ocular trauma; this requires an understanding of the epidemiology and characteristics of these injuries and the children involved. Methods: Prospective, observational study of pediatric ocular trauma cases presenting to UK-based ophthalmologists over a 1-year period; reporting cards were distributed by the British Ophthalmological Surveillance Unit, and clinicians were asked to report incidents of acute orbital and ocular trauma in children aged <=16 years requiring inpatient or day-case admission. A validated, standardized questionnaire was sent to reporting ophthalmologists to collect data on the demographics and circumstances of injury. Results: Median age at presentation was 7.7 years, with boys more than twice as likely to be affected than girls (M:F =2.1:1.0). Almost 50% of injuries occurred at home, with 25% occurring in school or nursery. A total of 67% of injuries occurred during play, and 31% involved a sharp implement. Conclusion: Pediatric ocular trauma remains an important public health problem. At least three-quarters of all injuries are preventable through measures, including education of children and responsible adults, restricting access to sharp implements, improving adult supervision, and appropriate use of eye protection. PMID- 29386878 TI - Insight into the molecular genetics of myopia. AB - Myopia is the most common cause of visual impairment worldwide. Genetic and environmental factors contribute to the development of myopia. Studies on the molecular genetics of myopia are well established and have implicated the important role of genetic factors. With linkage analysis, association studies, sequencing analysis, and experimental myopia studies, many of the loci and genes associated with myopia have been identified. Thus far, there has been no systemic review of the loci and genes related to non-syndromic and syndromic myopia based on the different approaches. Such a systemic review of the molecular genetics of myopia will provide clues to identify additional plausible genes for myopia and help us to understand the molecular mechanisms underlying myopia. This paper reviews recent genetic studies on myopia, summarizes all possible reported genes and loci related to myopia, and suggests implications for future studies on the molecular genetics of myopia. PMID- 29386885 TI - Peptides derived from Plasmodium falciparum leucine-rich repeat 1 bind to serine/threonine phosphatase type 1 and inhibit parasite growth in vitro. PMID- 29386886 TI - Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway. AB - Background: Diabetic nephropathy (DN) is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats. Methods: Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d) for 8 weeks, and then blood and urine were collected for measurement of renal function related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways. Results: Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-kappaB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-beta1, TbetaRII, TbetaRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKalpha. Conclusion: In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPKalpha, and inhibition of the NF-kappaB/MCP-1 and TGF-beta1/Smad signaling pathways. These results suggest that thalidomide may have therapeutic potential in diabetic renal injury through the anti-inflammatory pathway. PMID- 29386887 TI - Russian guidelines for the management of COPD: algorithm of pharmacologic treatment. AB - The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A-D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation. PMID- 29386888 TI - Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials. AB - Background: Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods: We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate-vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results: Baseline characteristics distinguishing the pneumonia and non pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion: Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD. PMID- 29386889 TI - Relationship between exercise endurance and static hyperinflation in a post hoc analysis of two clinical trials in patients with COPD. AB - Background: Lung hyperinflation and exercise intolerance are hallmarks of chronic obstructive pulmonary disease (COPD). However, their relationship remains uncertain. A combined analysis of two placebo-controlled, randomized studies examined the effects of the long-acting muscarinic antagonist umeclidinium (UMEC) and long-acting beta2-agonist vilanterol (VI) separately and in combination on static hyperinflation, exercise endurance time (EET), and their relationship in patients with COPD. Methods: Patients with moderate-to-severe stable COPD and resting functional residual capacity >120% predicted were randomized to UMEC/VI 62.5/25 MUg, UMEC 62.5 MUg, VI 25 MUg, or placebo for 12 weeks. Inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), and EET in an endurance shuttle-walk test were measured. In this post hoc analysis, IC/TLC, RV/TLC, and IC were used as hyperinflation markers. Results: After 12 weeks, UMEC/VI and UMEC and VI showed significant improvements in hyperinflation versus placebo when measured by absolute change from baseline in IC/TLC (trough and 3 hours postdose [P<=0.011]). UMEC/VI showed significant improvements versus UMEC and VI in absolute changes in IC/TLC (trough and 3 hours postdose [P<=0.001]). Statistical significance for comparisons with placebo and between treatments for absolute changes in IC and percentage changes in RV/TLC followed similar patterns to those for absolute changes in IC/TLC. UMEC/VI showed significant improvements in EET versus placebo at day 2 and week 12, measured as change from baseline in seconds (P<=0.002) and as a percentage from baseline (P<=0.005). There was a lack of evidence to suggest a correlation between improvements in static hyperinflation and EET at any time point. Conclusion: Although the dual bronchodilator UMEC/VI demonstrated greater improvements in static hyperinflation markers than UMEC or VI and significant improvements in exercise endurance, no direct relationship was observed between static hyperinflation and exercise endurance. PMID- 29386891 TI - Which patients with moderate hypoxemia benefit from long-term oxygen therapy? Ways forward. AB - Long-term oxygen therapy (LTOT) improves prognosis in patients with COPD and chronic severe hypoxemia. The efficacy in moderate hypoxemia (tension of arterial oxygen; on air, 7.4-8.0 kPa) was questioned by a recent large trial. We reviewed the evidence to date (five randomized trials; 1,191 participants, all with COPD). Based on the current evidence, the survival time may be improved in patients with moderate hypoxemia with secondary polycythemia or right-sided heart failure, but not in the absence of these signs. Clinically, LTOT is not indicated in moderate hypoxemia except in the few patients with polycythemia or signs of right-sided heart failure, which may reflect more chronic and severe hypoxemia. PMID- 29386890 TI - Phenotyping COPD exacerbations using imaging and blood-based biomarkers. AB - Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are caused by a variety of different etiologic agents. Our aim was to phenotype COPD exacerbations using imaging (chest X-ray [CXR] and computed tomography [CT]) and to determine the possible role of the blood tests (C-reactive protein [CRP], the N-terminal prohormone brain natriuretic peptide [NT-proBNP]) as diagnostic biomarkers. Materials and methods: Subjects who were hospitalized with a primary diagnosis of AECOPD and who had had CXRs, CT scans, and blood collection for CRP and NT-proBNP were assessed in this study. Radiologist blinded to the clinical and laboratory characteristics of the subjects interpreted their CXRs and CT images. ANOVA and Spearman's correlation were performed to test for associations between these imaging parameters and the blood-based biomarkers NT-proBNP and CRP; logistic regression models were used to assess the performance of these biomarkers in predicting the radiological parameters. Results: A total of 309 subjects were examined for this study. Subjects had a mean age of 65.6+/-11.1 years, 66.7% of them were males, and 62.4% were current smokers, with a mean FEV1 54.4%+/-21.5% of predicted. Blood NT-proBNP concentrations were associated with cardiac enlargement (area under the curve [AUC] =0.72, P<0.001), pulmonary edema (AUC =0.63, P=0.009), and pleural effusion on CXR (AUC =0.64, P=0.01); whereas on CT images, NT-proBNP concentrations were associated with pleural effusion (AUC =0.71, P=0.002). Serum CRP concentrations, on the other hand, were associated with consolidation on CT images (AUC =0.75, P<0.001), ground glass opacities (AUC =0.64, P=0.028), and pleural effusion (AUC =0.72, P<0.001) on CT images. A serum CRP sensitivity-oriented cutoff point of 11.5 mg/L was selected for the presence of consolidation on CT images in subjects admitted as cases of AECOPD, which has a sensitivity of 91% and a specificity of 53% (P<0.001). Conclusion: Elevated CRP may indicate the presence of pneumonia, while elevated NT-proBNP may indicate cardiac dysfunction. These readily available blood-based biomarkers may provide more accurate phenotyping of AECOPD and enable the discovery of more precise therapies. PMID- 29386892 TI - Antibiotic-resistant Pseudomonas aeruginosa infection in patients with bronchiectasis: prevalence, risk factors and prognostic implications. AB - Background and aims: Pseudomonas aeruginosa (PA) is the most common pathogen in bronchiectasis and frequently develops resistance to multiple classes of antibiotics, but little is known about the clinical impacts of PA-resistant (PA R) isolates on bronchiectasis. We, therefore, investigated the prevalence, risk factors and prognostic implications of PA-R isolates in hospitalized bronchiectasis patients. Patients and methods: Between June 2011 and July 2016, data from adult bronchiectasis patients isolated with PA at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. PA was classified as PA-R in case antibiogram demonstrated resistance on at least one occasion. Results: Seven hundred forty-seven bronchiectasis patients were assessed. Of these, 147 (19.7%) had PA isolate in the sputum or bronchoscopic culture. PA-R and PA-sensitive accounted for 88 (59.9%) and 59 (31.1%) patients, respectively. In multivariate model, factors associated with PA-R isolate in bronchiectasis included prior exposure to antibiotics (odds ratio [OR] =6.18), three or more exacerbations in the previous year (OR =2.81), higher modified Medical Research Council dyspnea scores (OR =1.93) and greater radiologic severity (OR =1.15). During follow-up (median: 26 months; interquartile range: 6-59 months), 36 patients died, of whom 24 (66.7%) had PA-R isolate at baseline. However, PA-R isolate was not associated with greater all-cause mortality in bronchiectasis. Conclusion: PA-R infection is common among bronchiectasis patients, mainly determined by prior exposure to antibiotics, frequent exacerbations, more pronounced dyspnea and more severe radiologic involvement. However, PA-R isolate is not an independent risk factor for all-cause mortality in bronchiectasis. PMID- 29386893 TI - Independent determinants of disease-related quality of life in COPD - scope for nonpharmacologic interventions? AB - Purpose: Quality-of-life (QoL) scores in chronic obstructive pulmonary disease (COPD) have a weak relationship with physiologic impairment. We investigated factors associated with poor QoL, focusing on psychological measures potentially amenable to intervention. Patients and methods: We utilized a pre-existing Birmingham (UK) COPD cohort to assess factors associated with QoL impairment (COPD Assessment Test [CAT] scores). Univariate and multivariate regression models were constructed from three categories of variables: demographic, lung function/COPD-related symptoms, and psychosocial/behavioral factors. Results: Analyses were based on self-report questionnaire data from 735 participants. The multivariate model of variables independently associated with CAT included depression, dysfunctional breathing symptoms (Nijmegen score), and illness perception, in addition to COPD symptoms (wheeze, cough), exercise capacity, breathlessness, exacerbations, and deprivation; this model explained 72% of CAT score variation. In a dominance analysis assessing the relative contribution of variables, similar contributions were made by breathlessness (20.2%), illness perception (19.8%), dysfunctional breathing symptoms (17.5%), and depression (12.5%) with other variables contributing <5%. Conclusion: Psychological factors significantly contribute to disease-specific QoL impairment in COPD, and potentially explain the mismatch between objective physiologic impairment and patients' experience of their disease. Interventions targeting psychological factors, illness perception, and dysfunctional breathing should be assessed. PMID- 29386895 TI - Estimating cost savings of pharmacogenetic testing for depression in real-world clinical settings. AB - The burden of depression significantly impacts the patient, the health care system, and society, at large. Medication management guided by pharmacogenetics has been shown to increase therapeutic efficacy and improve symptoms in patients diagnosed with depression, but limited data are available on the cost savings of pharmacogenetic-guided interventions outside of psychiatric clinical specialties. Our study utilizes published health care costs and clinical patient outcome data to model the economic impact of pharmacogenetic-guided treatment for depression in a variety of clinical settings. Assuming a test cost of USD$2,000 for pharmacogenetic testing, the model predicts a savings of USD$3,962 annually per patient with pharmacogenetic-guided medication management. PMID- 29386896 TI - Anxiety and depression in paradoxical insomnia: a case-control study. AB - Purpose: To compare anxiety and depression among patients with paradoxical insomnia (Para-I), patients with psychophysiological insomnia (Psy-I), and normal sleepers (NS). Patients and methods: A cross-sectional case-control study was conducted in patients with Para-I (n=63), patients with Psy-I (n=63), and NS (n=63) from southwest China. The three groups were matched for age (mean age: 42.0+/-10.30 years), gender (per group: male =22; female =41), educational level, and nature of occupation. Anxiety and depression were evaluated using the Self Rating Anxiety Scale and Self-Rating Depression Scale and compared among the groups. Results: Concerning anxiety, patients with Para-I had a significantly higher mean Self-Rating Anxiety Scale score (P<0.05) and significantly higher incidence of anxiety compared to NS (P<0.0167). There were no significant differences between the two insomnia groups on anxiety measures. Concerning depression, patients with Para-I had a significantly higher mean Self-Rating Depression Scale score than patients with Psy-I and NS (both, P<0.05), as well as a significantly higher incidence of moderate to severe depression than in the Psy I group and NS (both, P<0.0167). Conclusion: Both Psy-I and Para-I patients had significantly higher anxiety and depression than NS. Compared to Psy-I, Para-I patients had slightly (but not significantly) lower anxiety and significantly higher depression. PMID- 29386894 TI - A novel sol-gel-derived calcium silicate cement with short setting time for application in endodontic repair of perforations. AB - Mineral trioxide aggregate (MTA) is the most frequently used repair material in endodontics, but the long setting time and reduced mechanical strength in acidic environments are major shortcomings. In this study, a novel sol-gel-derived calcium silicate cement (sCSC) was developed using an initial Ca/Si molar ratio of 3, with the most effective mixing orders of reactants and optimal HNO3 catalyst volumes. A Fourier transform infrared spectrometer, scanning electron microscope with energy-dispersive X-ray spectroscopy, and X-ray powder diffractometer were used for material characterization. The setting time, compressive strength, and microhardness of sCSC after hydration in neutral and pH 5 environments were compared with that of MTA. Results showed that sCSC demonstrated porous microstructures with a setting time of ~30 min, and the major components of sCSC were tricalcium silicate, dicalcium silicate, and calcium oxide. The optimal formula of sCSC was sn200, which exhibited significantly higher compressive strength and microhardness than MTA, irrespective of neutral or pH 5 environments. In addition, both sn200 and MTA demonstrated good biocompatibility because cell viability was similar to that of the control. These findings suggest that sn200 merits further clinical study for potential application in endodontic repair of perforations. PMID- 29386898 TI - Altered intrinsic brain activities in patients with acute eye pain using amplitude of low-frequency fluctuation: a resting-state fMRI study. AB - Objective: Many previous studies have reported that pain symptoms can lead to significant brain function and anatomical changes, whereas the intrinsic brain activity changes in acute eye pain (EP) patients remain unknown. Using the amplitude of low-frequency fluctuation (ALFF) method, this study aimed to evaluate the spontaneous brain activity alterations and their relationships with clinical features in acute EP patients. Participants and methods: A total of 20 patients with EP (15 males and 5 females) and 20 healthy controls (HCs; 15 males and 5 females) closely matched in age, sex, and education underwent resting-state functional magnetic resonance imaging scans. The ALFF method was applied to assess spontaneous brain activity changes. The ALFF values of the EP patients were distinguished from those of the HCs using a receiver operating characteristic curve. Pearson's correlation analysis was used to investigate the relationships between the mean ALFF signal values from many brain regions and the clinical features in EP patients. Results: Compared with the HCs, acute EP patients had significantly lower ALFF in the left and right precentral/postcentral gyrus and left precuneus. In contrast, acute EP patients showed higher ALFF values in the right and left parahippocampal gyri and left caudate. However, no relationship was observed between the mean ALFF signal values from the different areas and clinical manifestations in the acute EP patients. Conclusion: We demonstrated that acute EP patients showed abnormal intrinsic brain activities in the precentral/postcentral gyrus and limbic system, which might provide useful information for explaining neural mechanisms in EP patients. PMID- 29386897 TI - Functional impairment in patients with major depressive disorder: the 2-year PERFORM study. AB - Background: The Prospective Epidemiological Research on Functioning Outcomes Related to Major depressive disorder (PERFORM) study describes the course of depressive symptoms, perceived cognitive symptoms, and functional impairment over 2 years in outpatients with major depressive disorder (MDD) and investigates the patient-related factors associated with functional impairment. Methods: This was a 2-year observational study in 1,159 outpatients with MDD aged 18-65 years who were either initiating antidepressant monotherapy or undergoing their first switch of antidepressant. Functional impairment was assessed by the Sheehan Disability Scale and the Work Productivity and Activity Impairment questionnaire. Patients assessed depression severity using the nine-item Patient Health Questionnaire and severity of perceived cognitive symptoms using the five-item Perceived Deficit Questionnaire. To investigate which patient-related factors were associated with functional impairment, univariate analyses of variance were performed to identify relevant factors that were then included in multivariate analyses of covariance at baseline, month 2, months 6 and 12 combined, and months 18 and 24 combined. Results: The greatest improvement in depressive symptoms, perceived cognitive symptoms, and functional impairment was seen immediately (within 2 months) following initiation or switch of antidepressant therapy, followed by more gradual improvement and long-term stabilization. Improvement in perceived cognitive symptoms was less marked than improvement in depressive symptoms during the acute treatment phase. Functional impairment in patients with MDD was not only associated with severity of depressive symptoms but also independently associated with severity of perceived cognitive symptoms when adjusted for depression severity throughout the 2 years of follow-up. Conclusion: These findings highlight the burden of functional impairment in MDD and the importance of recognizing and managing cognitive symptoms in daily practice. PMID- 29386899 TI - Impact of intravenous thrombolysis on length of hospital stay in cases of acute ischemic stroke. AB - Background: There are limited data available on factors associated with length of stay (LOS) in cases of acute ischemic stroke according to Poisson analysis, which is more appropriate than other methods. Materials and methods: We retrospectively reviewed medical summary charts of patients with acute ischemic stroke in 30 hospitals across northeast Thailand, with the main outcome as LOS. Poisson regression was used to examine factors associated with LOS. Results: We included 898 patients in the analysis; 460 (51.2%) were male. The median age (interquartile; IQR) was 58 (67-75) years and the median LOS was 5 (4-7) days. The median National Institute of Health Stroke Scale (NIHSS [IQR]) was 8 (4-13). Results of the analysis showed that, after controlling for age, stroke severity, atrial fibrillation, and thrombolytic use, significant variables associated with LOS were moderate stroke (incidence rate ratio [IRR] 95% confidence interval [CI] =1.15 [range 1.01-1.30], P=0.040), severe stroke (IRR [95% CI] =1.27 [1.09-1.47], P=0.002), thrombolytic use (IRR [95% CI] =0.68 [0.60-0.76], P<0.001), and atrial fibrillation (IRR [95% CI] =1.15 [1.02-1.30], P=0.023). After adjusting for complications, thrombolytic use remained significantly associated with decreased LOS (IRR [95% CI] =0.74 [0.67-0.83], P=0.001). Other significant factors were atrial fibrillation (IRR [95% CI] =1.14 [1.02-1.28], P=0.018), pneumonia (IRR [95% CI] =1.48 [1.30-1.68], P<0.001), and urinary tract infection (IRR [95% CI] =1.41 [1.14-1.74], P=0.001). Conclusion: According to Poisson analysis, intravenous thrombolysis, atrial fibrillation, pneumonia, and urinary tract infection are associated with LOS in cases of acute ischemic stroke, regardless of age, stroke severity, comorbidities, or complications. PMID- 29386900 TI - Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low dose ticagrelor versus standard dose in East Asians: a systematic review. AB - East Asians are prone to higher systemic exposure and increased risk of bleeding compared to other races after administration of antiplatelet agent(s). The aim of this systematic review was to compare and evaluate the appropriateness of a lower dose versus standard dose of ticagrelor in East Asians. A systematic search was conducted in PubMed, EMBASE, and Cochrane databases for studies comparing low versus standard doses of ticagrelor in East Asian populations; a total of seven studies were included in the review. Pharmacokinetic (PK), pharmacodynamic (PD), clinical efficacy, and safety data were collected. PK data demonstrated that the Cmax and area under the curve (AUC) of ticagrelor increased dose-proportionally. PD data indicated that while the low dose of ticagrelor resulted in less antiplatelet activity in three of the five PD studies, in the other studies, there were no differences between low and standard doses. There were two clinical studies included in this review, which showed that the efficacy was similar between the low and standard doses, but both studies were limited by the number of patients included. While there were generally greater incidence of adverse events observed in the standard ticagrelor dose, the magnitude or actual difference between the two doses is difficult to determine due to lack of consistent data. In East Asians, the appropriateness of the low-dose ticagrelor cannot be determined based on the currently available evidence. Additional large scale and longer duration studies are warranted. PMID- 29386901 TI - Circulating vitamin D concentration and risk of prostate cancer: a dose-response meta-analysis of prospective studies. AB - Background: Though many studies have been performed to elucidate the association between circulating vitamin D and prostate cancer, no conclusive result is available. We carried out a dose-response meta-analysis to quantitatively examine the association of circulating 25-hydroxyvitamin D (25[OH]D) concentration with prostate cancer. Methods: Only prospective studies examining the associations of circulating 25[OH]D concentration with prostate cancer were eligible for the meta analysis. A random-effect meta-analysis was done first, to calculate the summary relative risk (RR) and 95% confidence intervals (CIs) comparing the higher concentration with the lower concentration of 25[OH]D. A dose-response meta analysis using random-effects model was then carried out to evaluate the nonlinearity and calculate the summary RR caused per 10 ng/mL increment. Results: Nineteen prospective cohort or nested case-control studies were included. Higher 25[OH]D concentration was significantly correlated with elevated risk of prostate cancer (RR =1.15, 95% CI 1.06-1.24). No nonlinear relationship was found between 25[OH]D concentration and risk of prostate cancer (P=0.654). Dose-response meta analysis showed that the summary RR caused per 10 ng/mL increment in circulating 25[OH]D concentration was 1.04 (95% CI 1.02-1.06). Subgroup analysis also found a modest dose-response relationship. Funnel plot and Egger's test did not detect publication bias. Conclusion: The findings suggest that highest 25[OH]D concentration is correlated with elevated risk of prostate cancer and a modest dose-response effect exists in this association; however, more studies are needed. PMID- 29386902 TI - Update on subcutaneous methotrexate for inflammatory arthritis and psoriasis. AB - Methotrexate (MTX) is one of the mainstays of treatment for several immune mediated inflammatory joint and skin diseases, especially rheumatoid arthritis (RA) and moderate-to-severe psoriasis. Oral MTX has been used for the treatment of such diseases for decades for many reasons. There is, however, a relevant interpatient variability of clinical and safety outcomes that can also be related to differences in patients' individual pharmacogenomic profile. Orally administered MTX has been found to have a saturable intestinal absorption and nonlinear pharmacokinetics, with significant consequences on drug bioavailability and clinical efficacy. The current evidence shows that parenterally administered MTX results in rapid and complete absorption, higher serum levels, and less variable exposure than oral dosing. The use of parenteral MTX, particularly when administered as a subcutaneous (SC) injection, has recently raised great interest in order to overcome the limitations of oral MTX. The effectiveness and safety of SC MTX have mostly been assessed in rheumatological settings, especially in patients with RA. There are only a limited number of data on SC MTX in juvenile idiopathic arthritis and even fewer in psoriatic disease. Various clinical experiences have suggested that SC MTX is more effective than oral MTX and may provide significant benefit even in patients in whom oral MTX proved to be inadequate. The increased efficacy of SC MTX resulting from higher drug exposure compared with oral MTX has been associated with a similar safety profile and in various reports even with a lower frequency of gastrointestinal complaints. The aim of this article was to review the available literature data on SC MTX treatment of inflammatory arthritis, with special emphasis on RA and psoriasis, examining differences with oral MTX treatment. A brief mention of pharmacokinetics, pharmacodynamic features and pharmacoeconomic considerations is also given. PMID- 29386903 TI - Human-centered design of a personal health record system for metabolic syndrome management based on the ISO 9241-210:2010 standard. AB - Background: Previous studies have demonstrated the effectiveness of information and communication technologies to support healthy lifestyle interventions. In particular, personal health record systems (PHR-Ss) empower self-care, essential to support lifestyle changes. Approaches such as the user-centered design (UCD), which is already a standard within the software industry (ISO 9241-210:2010), provide specifications and guidelines to guarantee user acceptance and quality of eHealth systems. However, no single PHR-S for metabolic syndrome (MS) developed following the recommendations of the ISO 9241-210:2010 specification has been found in the literature. Objective: The aim of this study was to describe the development of a PHR-S for the management of MS according to the principles and recommendations of the ISO 9241-210 standard. Methods: The proposed PHR-S was developed using a formal software development process which, in addition to the traditional activities of any software process, included the principles and recommendations of the ISO 9241-210 standard. To gather user information, a survey sample of 1,187 individuals, eight interviews, and a focus group with seven people were performed. Throughout five iterations, three prototypes were built. Potential users of each system evaluated each prototype. The quality attributes of efficiency, effectiveness, and user satisfaction were assessed using metrics defined in the ISO/IEC 25022 standard. Results: The following results were obtained: 1) a technology profile from 1,187 individuals at risk for MS from the city of Popayan, Colombia, identifying that 75.2% of the people use the Internet and 51% had a smartphone; 2) a PHR-S to manage MS developed (the PHR S has the following five main functionalities: record the five MS risk factors, share these measures with health care professionals, and three educational modules on nutrition, stress management, and a physical activity); and 3) usability tests on each prototype obtaining the following results: 100% effectiveness, 100% efficiency, and 84.2 points in the system usability scale. Conclusion: The software development methodology used was based on the ISO 9241 210 standard, which allowed the development team to maintain a focus on user's needs and requirements throughout the project, which resulted in an increased satisfaction and acceptance of the system. Additionally, the establishment of a multidisciplinary team allowed the application of considerations not only from the disciplines of software engineering and health sciences but also from other disciplines such as graphical design and media communication. Finally, usability testing allowed the observation of flaws in the designs, which helped to improve the solution. PMID- 29386904 TI - KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth. AB - Background: Gliomas are one of the most lethal cancers in the human central nervous system. Despite clinical treatment advancements, the prognosis of patients with glioma remains poor. KDM2B is a histone lysine demethylase, which has been observed in multiple tumors. But the concrete role of KDM2B in gliomas remains to be further illustrated. Methods: The KDM2B expression in gliomas was detected with immunohistochemistry and Western blot assay. Furthermore, knockdown of KDM2B in U87 and U251 glioma cell lines, the proliferation capacity was evaluated by cell viability assay, colon formation assay and flow cytometry in vitro. Western blot assay was used to analyze the p21, EZH2 and cyclinD1 changes followed by knockdown of KDM2B. Results: KDM2B was upregulated in tissues of glioma patients, and the expression was correlated to cancer progression. Downregulation of KDM2B in U87 and U251 glioma cell lines inhibited cell proliferation and arrested cell cycle in G0/G1 phase. In addition, silencing KDM2B promoted the upregulation of p21 while reduced the expression of EZH2 and cyclinD1. Conclusion: Taken together, our results revealed that KDM2B might influence gliomas growth and act as a novel therapeutic target for glioma patients. PMID- 29386905 TI - Experimental study of inhibitory effects of diallyl trisulfide on the growth of human osteosarcoma Saos-2 cells by downregulating expression of glucose-regulated protein 78. AB - Background: Diallyl trisulfide (DATS) is a natural organic sulfur compound isolated from garlic that has good anticancer activity according to many previous reports. There are many studies pointing out that DATS can downregulate expression of the glucose-regulated protein 78 (GRP78), which is associated with poor prognosis and drug resistance in various types of human cancers. However, it remains unknown whether DATS has the same effect on human osteosarcoma cells. This study attempted to clarify the potential molecular mechanisms of the action of DATS in human osteosarcoma Saos-2 cells. Methods: We used an inverted phase microscope and immunofluorescent staining to observe the morphological changes of Saos-2 cells after being cultured in different concentrations of DATS (0, 25, 50, and 100 MUM) for 24 h, or for four time periods (24, 48, 72, and 96 h) in the same DATS concentration (50 MUM). Quantitative real-time polymerase chain reaction and Western blot were used to detect the expression level of GRP78 mRNA and proteins in Saos-2 cells. GRP78 expression was suppressed in Saos-2 cells by utilizing small-interfering RNA, and the cells were subsequently used to study the anti-proliferative effects of DATS treatment. Results: The expression level of GRP78 mRNA and proteins was significantly downregulated due to the increased concentration and effective times of DATS (P<0.05). In addition, there were significant associations between GRP78 silencing and cell proliferation (P<0.05) of DATS treatment. Conclusion: These results indicate that DATS inhibits the growth of human osteosarcoma Saos-2 cells by downregulating the expression of GRP78. PMID- 29386906 TI - Over-expression of ARHGAP18 suppressed cell proliferation, migration, invasion, and tumor growth in gastric cancer by restraining over-activation of MAPK signaling pathways. AB - Globally, gastric cancer is the second-greatest cause of cancer death. ARHGAP18 belongs to the Rho family of GTPases which is involved in cellular migration, invasion, and growth phases. The aim of the present study was to investigate whether ARHGAP18 could regulate cell proliferation, migration, invasion, and related molecular mechanisms in gastric cancer. Cell Counting Kit-8 (CCK-8) assay results showed that following transfection of a recombinant plasmid, over expression of ARHGAP18 inhibited cell viability in MGC-803 and BGC823 cells. Using in vitro transwell analysis, migration and invasion abilities were significantly inhibited in cells with high ARHGAP18 expression. Phosphorylation levels of ERK, JNK, and p38 by Western blot analysis significantly declined after transfection of cells with the ARHGAP18 plasmid. Expression levels of ROCK, MTA1, and MMP-2/9 were detected by real-time polymerase chain reaction and Western blotting, and over-expression of ARHGAP18 decreased the expression levels of ROCK, MTA1, and MMP-9. A further in vivo tumor formation study in nude mice indicated that over-expression of ARHGAP18 delayed the progress of tumor formation. These results indicate that ARHGAP18 could act as a tumor suppressor and may serve as a promising therapeutic strategy for gastric cancer. PMID- 29386907 TI - Exosome-mediated delivery of MALAT1 induces cell proliferation in breast cancer. AB - Background: Breast cancer is the most common cancer in women worldwide. Cancer secreted exosomes have recently been recognized as important mediators of intercellular communication. The aim of this study was to determine the role of exosomal long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in breast cancer progression. Materials and methods: Breast cancer specimens were obtained with informed consent from patients. Quantitative real time polymerase chain reaction (qRT-PCR) was used to detect MALAT1 expression, and cellular proliferation was measured using cell counting kit-8 (CCK-8) assay. Results: MALAT1 was highly expressed in breast cancer tissues and associated with disease progression. Breast cancer exosomes promoted cell proliferation and exosome-mediated MALAT1 to induce cell proliferation. Conclusion: These findings indicated that exosomal MALAT1 could regulate cancer progression and represent a novel strategy for overcoming breast cancer. PMID- 29386908 TI - Multilocus sequence typing and variations in the oprD gene of Pseudomonas aeruginosa isolated from a hospital in China. AB - Objectives: To provide information about the genetic relationships and mechanism underlying carbapenem resistance in Pseudomonas aeruginosa clinical isolates of a hospital in China. Materials and methods: One hundred and sixty P. aeruginosa strains were isolated from a hospital in China. Susceptibility to 14 antimicrobial agents was determined by antimicrobial susceptibility testing. Multilocus sequence typing was used to characterize the genetic backgrounds of these clinical isolates. Forty-five strains were randomly selected for further evaluation of their carbapenem resistance mechanism. Their oprD gene was compared with the PAO1 sequence. Results: Multilocus sequence typing analysis demonstrated that these isolates were highly diverse; 68 sequence types were identified, of which 28 were novel sequence types. Polygenic and eBURST analysis demonstrated genetically similar clones with dissimilar resistance profiles. Among the 45 randomly selected strains associated with carbapenem resistance, 2 were metallo beta-lactamase producers; all the 45 strains were not AmpC overproducers. Sequence analysis revealed a high diversity in the oprD sequences among isolates. Strains susceptible to imipenem and meropenem with shortened L7 and L8 loops in oprD were the major strain types observed in this hospital. Conclusion: This study indicated that oprD provided the main mechanism for carbapenem resistance. The shortened L7 and L8 loops are responsible for carbapenem susceptibility. PMID- 29386909 TI - Distribution of sasX, pvl, and qacA/B genes in epidemic methicillin-resistant Staphylococcus aureus strains isolated from East China. AB - Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Various virulence and antiseptic-resistant factors increase the pathogenicity of MRSA strains and allow for increased infection rates. Purpose: The purpose of this study was to investigate the prevalence and distribution of virulence-associated and antiseptic-resistant genes from epidemic MRSA strains isolated from East China. Methods: A newly designed multiplex PCR assay was used to assess whether the virulence-associated genes sasX and pvl and the chlorhexidine tolerance gene qacA/B were present in 189 clinical isolates of MRSA. Multilocus sequence typing (MLST) and Staphylococcal protein A (spa) typing of these isolates were also performed. The frequency of these genes in isolates with epidemic sequence types (STs) was investigated. Results: Twenty STs and 36 spa types with five epidemic clones (ST5-t311, ST59-t437, ST5-t002, ST239-t030, and ST239-t037) were identified. The prevalence of sasX, pvl, and qacA/B in all isolates was 5.8%, 10.1%, and 20.1%, respectively. The prevalences of these genes in isolates with ST5, ST59, ST239, and other ST genetic backgrounds were all significantly different (P<0.001). Isolates that had the highest frequency of sasX, pvl, or qacA/B were ST239 (33.3%), ST59 (28.9%), and ST5 (34.1%), respectively. The gene distribution pattern from all of the isolates showed that sasX-pvl-qacA/B+, sasX-pvl+qacA/B-, and sasX+pvl-qacA/B- were closely associated with epidemic clones ST5-t311, ST59-t437, and ST239-t037, respectively. Conclusion: There are significant differences in the prevalence of virulence associated and antiseptic-resistant genes in epidemic MRSA strains. Using this information, more effective control and prevention strategies for nosocomial MRSA infections can be developed. PMID- 29386910 TI - Activity of siderophores against drug-resistant Gram-positive and Gram-negative bacteria. AB - Infections by drug-resistant bacteria are life-threatening. As iron is a vital element for the growth of bacteria, iron-chelating agents (siderophores) can be used to arrest their multiplication. Exogenous siderophores - exochelin-MS and deferoxamine-B - were evaluated for their inhibitory activity against methicillin resistant Staphylococcus aureus and metallo-beta-lactamase producers - Pseudomonas aeruginosa and Acinetobacter baumannii - by disc diffusion, micro broth dilution, and turbidimetric growth assays. The drug-resistant isolates were inhibited by the synergistic activity of siderophores and antibiotics. Minimum inhibitory concentration of exochelin-MS+ampicillin for different isolates was between 0.05 and 0.5 mg/mL. Minimum inhibitory concentration of deferoxamine B+ampicillin was 1.0 mg/mL and greater. Iron-chelation therapy could provide a complementary approach to overcome drug resistance in pathogenic bacteria. PMID- 29386911 TI - IL-13 regulates human nasal epithelial cell differentiation via H3K4me3 modification. AB - Introduction: Epigenetic regulation has been shown to play an important role in the development of inflammatory diseases, including chronic rhinosinusitis and nasal polyps. The latter are characterized by epithelial mis-differentiation and infiltration of inflammatory cytokines. H3K4me3 has been shown to be involved in regulating lineage commitment. However, the underlying mechanisms, especially in human nasal epithelial cells (HNEpC), remain underexplored. The objective of this study was to investigate the role of H3K4me3 in HNEpC differentiation treated with the Th2 cytokine IL-13. Patients and methods: The expression levels of mRNA and proteins were investigated using reverse transcription-polymerase chain reaction (RT-PCR) assays and Western blot in nasal polyp tissues and human nasal epithelial cells respectively. We measured these levels of H3K4me3, MLL1 and targeted genes compared with control subjects. Results: We demonstrate that expression of H3K4me3 and its methyltransferase MLL1 was significantly upregulated in IL-13-treated HNEpC. This elevation was also observed in nasal polyps. Expression of cilia-related transcription factors FOXJ1 and DNAI2 decreased, while goblet cell-derived genes CLCA1 and MUC5a increased upon IL-13 treatment. Mechanistically, knockdown of MLL1 restored expression of these four genes induced by IL-13. Conclusion: These findings suggest that H3K4me3 is a critical regulator in control of nasal epithelial cell differentiation. MLL1 may be a potential therapeutic target for nasal inflammatory diseases. PMID- 29386912 TI - Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis. AB - Background/objective: The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) tanezumab administration in osteoarthritis (OA) patients. Materials and methods: Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient's Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Results: Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in tanezumab groups ranged from -3.59 (0.26) to 3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (tanezumab 2.5 mg, n=11 [4.8%]; tanezumab 5 mg, n=8 [3.6%]; tanezumab 10 mg, n=15 [6.6%]). Conclusion: Preliminary results show similar efficacy and safety for both SC and IV administration of tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions. PMID- 29386913 TI - Altered low-frequency oscillation amplitude of resting state-fMRI in patients with discogenic low-back and leg pain. AB - Objective: The aim of this study was to explore the amplitude of intrinsic low frequency oscillations (LFOs) in patients with discogenic low-back and leg pain (LBLP). Participants and methods: We obtained and compared the LFO amplitude from 25 right-handed discogenic LBLP patients (13 males; mean age 55.16+/-1.83 years) and 27 well-matched healthy controls (15 males; mean age 52.96+/-1.63 years). The LFO amplitude was examined using the voxel-wise amplitude of low-frequency fluctuations (ALFFs), and partial correlation analysis was performed to determine the relationship between the regions with altered ALFF values and clinical parameters in discogenic LBLP patients. Results: Compared with healthy controls, the patients with discogenic LBLP showed a significant increase in ALFF in the affective system of the pain matrix (left anterior cingulate cortex, right anterior insula/frontal operculum, and bilateral orbitofrontal cortex) and information-processing regions (middle occipital/temporal gyrus). In addition, a significant decrease in ALFF was observed in the default mode network (DMN; inferior parietal lobule (IPL) and medial prefrontal cortex [mPFC]) and the processing system of the pain matrix (basal ganglia/thalamus/midbrain, postcentral gyrus [PoCG], and fusiform gyrus). Several regions with altered ALFF were associated with disease duration, visual analog scale scores, Barthel index, and fine sensory modality measurements (two-point tactile discrimination of the left and/or right leg). Further operating characteristic curves analysis suggested that the mean ALFF values in the right IPL, left IPL/PoCG, left anterior cingulate cortex, and left mPFC could serve as markers to separate individuals with discogenic LBLP from healthy subjects. Conclusion: Our results revealed widespread abnormalities in ALFF in the pain matrix and information processing regions as well as a decrease in ALFF in the DMN. These results open up an important new avenue to better understand the nature of the link between intrinsic activity and peripheral pain and sensory impairment in discogenic LBLP patients. PMID- 29386914 TI - Young age increases risk for lymph node positivity but decreases risk for non small cell lung cancer death. AB - Non-small cell lung cancer (NSCLC) prognosis and risk of lymph node positivity (LN+) are reference points for reasonable treatments. The aim of the current study was to investigate the effect of age on LN+ and NSCLC death. Data from the Surveillance, Epidemiology, and End Results (SEER) registry were used to identify 82,253 patients with NSCLC diagnosed between 1988 and 2008. All the patients underwent standard lung cancer surgery with lymph node examination. Demographic and clinicopathological parameters were extracted and compared among each age group. Impact of age on LN+ and NSCLC death was evaluated by the Cochran-Armitage trend test and logistic univariate and multivariate analyses for all T stages. Overall, 22,711 (27.60%) patients of the entirety had lymph node metastasis and 28,968 (35.22%) patients died of NSCLC within 5 years. With the increase in age, LN+ rates decreased regardless of T stages (P<0.001), whereas NSCLC-specific mortality increased in stages T1-T3 (P<0.001). Controlling other covariates in multivariable logistic regression, age remained an independent risk factor for LN+ in all T stages (P<0.05) and in stages T1-T3 (P<0.05). Our SEER analysis demonstrated a higher rate of LN+ and lower mortality in younger patients with NSCLC, after accounting for other covariates. PMID- 29386915 TI - Detection of circulating tumor cells in liquid biopsy from Ewing sarcoma patients. AB - Background: Circulating tumor cells (CTCs) analysis is a promising new diagnostic field to estimate risk and monitor treatment efficacy, metastatic relapse, and progression in cancer patients. The study aim was to isolate and characterize CTCs in blood samples of Ewing sarcoma (ES) patients exploiting two main characteristics: CD99 expression and presence of chromosomal translocations. Materials and methods: The method isolated CTCs from peripheral blood (PB) of ES patients. Cell-surface CD99 was a useful marker for CTCs determined using immunomagnetic separation with microbeads and CD99 monoclonal antibody. We tested sensitivity and specificity by detecting CTCs in blood collected from healthy donors and randomly during therapy from 18 ES patients. Evidence of CTCs was confirmed by detection of specific molecular markers using quantitative and digital reverse transcription-polymerase chain reaction targeting EWSR1/FLI1 type 1 and type 2 or EWSR1/ETS-related gene transcripts type 1 and type 9e. Results: Feasibility of finding CTCs in PB of ES patients by immunoseparation with CD99 antibody and magnetic microbeads was demonstrated for the first time. At molecular analysis, three PB specimens tested positive for chimeric EWSR1/FLI1 type 2 and one PB for chimeric EWSR1/FLI1 type 2. CTCs detection was found above a limit of detection of 1 cell/mL of PB. Conclusion: CTCs in PB of ES patients can be identified by this method and in ES CTCs analysis can be used as a liquid biopsy approach for prognostic and predictive purposes. The potential clinical implications of CTCs in PB samples detected by the platform for CTC isolation with molecular confirmation during therapy require further evaluation. PMID- 29386916 TI - Vulvar carcinoma: dilemma, debates, and decisions. AB - Vulvar carcinoma is a rare and aggressive gynecological malignancy. It affects elderly females, with the mean age at diagnosis being 55-60 years. Regional metastasis to inguinal lymph nodes is common. There is a high incidence of pelvic node involvement, especially in those with pathologically positive inguinal nodes. Surgery appears to be the only curative treatment option in the early stages of the disease. But in most patients, surgery is associated with considerable morbidities and psychosexual issues. Hence, in the quest for a less morbid form of treatment, multimodality approaches with various combinations of surgery, chemotherapy, and radiation therapy have been suggested for advanced vulvar cancers. Due to the low incidence of the disease, the level of evidence for the success of these treatment modalities is poor. In countries like India, a heterogeneous incidence of vulvar carcinoma exists across the country, with patients presenting at advanced stages when the option of surgery is often supplemented or replaced by chemotherapy and radiotherapy. In this review, we attempt to study the available published literature and trials and discuss the treatment options in various stages of vulvar carcinoma. PMID- 29386917 TI - Women's perspectives on quality of maternal health care services in Malawi. AB - Despite promotion by many stakeholders to improve maternal health outcome in many developing countries including Malawi, many analysts agree that the utmost success in maternal health will arise if maternal health care services are an unparallel led source for women's health care solutions for any problem related to childbirth. Health advocates worldwide claim that even though maternal services are provided, women's utilization of such services has not been ascertained. The objective of this study was to explore women's perspectives on the quality of health care service delivery in Malawi. This article therefore investigates women's perspectives on the quality of maternal health care services in Malawi. We used six focus group discussions in six health facilities that were selected across Malawi. We found that erratic availability of medical resources and unethical practices among health workers adversely affected quality of maternal health care service delivery. We concluded that the expensive routine operational audits of medical resources and service delivery across health facilities are imperative if women's health outcomes are to be enhanced in Malawi. PMID- 29386918 TI - Bilateral total retinal detachment at birth: a case report of Walker-Warburg syndrome. AB - Walker-Warburg syndrome (WWS) is a disorder characterized by ocular and brain malformations, and congenital muscular dystrophy. Retinal malformations are common in WWS; however, bilateral retinal detachment is a rare occurrence. We present a case of a newborn baby delivered at 36+3 weeks, who was the first living child of consanguineous parents of Turkish origin. On antenatal anomaly scans, the fetus had hydrocephalus that had increased throughout pregnancy, and a diagnosis of hydrancephaly was made at 36 weeks of gestation. Hypotonia, cleft lip and palate, poor suck and absent gag reflex were noted at birth. Ophthalmic examination at the age of 2 days revealed bilateral funnel retinal detachment. B scan ultrasonography confirmed these findings, and magnetic resonance imaging (MRI) of the brain was performed at the age of 13 days to establish a diagnosis. The MRI showed lissencephaly, hydrocephalus and thin rim of brain parenchyma, with a cobblestone appearance of the cortex and pontine and cerebellar hypoplasia, consistent with the diagnosis of WWS. The infant deteriorated and died at 39 days of age from complications associated with the brain anomalies. In summary, bilateral retinal detachment is extremely rare and in association with hydrocephalus and posterior fossa anomalies strongly suggests the diagnosis of WWS. PMID- 29386920 TI - Prevalence and associated factors of contraceptive discontinuation and switching among Bangladeshi married women of reproductive age. AB - Introduction: Contraceptive discontinuation is a worldwide incident that may be connected with low incentive to avoid pregnancy. Contraceptive discontinuation highly contributes to unplanned pregnancy and unwanted births. Objectives: The objective of this study was to observe the prevalence of discontinuation and switching of contraceptive methods among Bangladeshi married women. In addition, the sociodemographic factors associated with contraceptive discontinuation and switching were assessed. Methods: Secondary cross-sectional data was used in this study. A total of 16,273 married Bangladeshi women of reproductive age (15-49 years) were considered in the present study, from the Bangladesh Demographic and Health Survey, 2011. Logistic regression models were used to determine the relationships between key sociodemographic factors and user status. Results: The prevalence of discontinuation and switching of contraceptive method among women were 38.4% and 15.4%, respectively. The logistic regression model demonstrated that women in early reproductive years (25-29 years and 30-34 years) significantly more often (odds ratio [OR] =0.84 and 0.71, respectively) discontinued use of contraceptives. Significantly higher rates of discontinuation were pronounced among women who used the pill (OR =0.72) and injectable contraception users (OR =0.60), had small family size (OR =0.49), lived in a rural community (OR =1.65), and who were less educated (OR =1.55). Conclusion: Contraceptive discontinuation may reflect an association among less education, currently married, and smaller family size. Awareness of contraceptive methods can decrease the burden of unplanned pregnancies and thus progresses the family planning program. PMID- 29386919 TI - Intrauterine device quo vadis? Why intrauterine device use should be revisited particularly in nulliparous women? AB - Background: Long-acting reversible contraceptive (LARC) methods, including intrauterine devices (IUDs) and the contraceptive implant, are considered the best methods for preventing unintended pregnancies, rapid repeat pregnancy, and abortion in young women. An opinion paper of 2012 by the American College of Obstetricians and Gynecologists recommends Mirena and Paragard for use in nulliparous and adolescent women. However, these IUDs are not designed for young women and are not optimal as they often lead to early discontinuation. Objective: This article was written with the objective to respond to the urgent need to improve intrauterine contraception as it is likely that the objectives of LARC will not be met without significant improvement of IUD design. Anatomical variations in size and shape of the uterus are not sufficiently considered, producing harm and suffering, which often lead to early removal of the IUD. Proposed problem solving: The article describes why IUDs should be revisited to meet the challenge of LARC and proposes how to solve these problems. The opinion statement presented here may be considered provocative but is based on hundreds of women with IUD problems who consult or are referred to the practices of the authors of this article due to the disproportion between the IUD and their small uterine cavity. The solution is simple but requires a revision of the current design of IUDs. One-dimensional (longitudinal) IUDs are likely to be the first option. Framed devices with shortened transverse arm and IUDs which adapt to the width of the given uterus are viewed as second best. Conclusion: One of the reasons of the high unintended pregnancy rate in the USA may be the paucity of suitable IUDs. Also, the legal climate in the USA seems to be a problem for developers as many lawsuits have recently been reported. Clinical studies conducted in young nulliparous and adolescent women suggest that IUDs that fit well in the uterine cavity, like a shoe, result in better tolerance, less side effects, and last but not least, higher use continuation rates. PMID- 29386921 TI - A comparison of the expected and actual pain experienced by women during insertion of an intrauterine contraceptive device. AB - Objective: To compare the expected and actual pain experienced with the insertion of intrauterine contraception in women, and to determine whether either of these are related to their personal circumstances, or affected their satisfaction with the procedure. Design: A convenience sample of 89 women aged 15-50 years attending a sexual health clinic for same day intrauterine contraception insertion were given a questionnaire that they completed following the procedure. The women were asked to rate their expectation of pain prior to insertion and to rate the actual pain they experienced immediately after insertion, on a scale of 1-10, with 10 being severe pain. Information on the women's circumstances and their level of satisfaction with the procedure was also obtained. Results: Overall, the median actual pain experienced by women during insertion (4) was significantly lower than the expected pain median (6) (P<0.001). For those women who had not had a previous vaginal delivery, actual pain was significantly higher compared with women who had had a previous vaginal delivery (median [interquartile range]: 6 [3.5-7.5] and 3 [1-5], P<0.001, respectively), but there was no significant difference between expected and actual pain experiences. In women who had a previous vaginal delivery, actual pain was much lower than expected (P<0.001). Neither actual nor expected pain experiences were linked to any other sociodemographic reproductive health or service use factors. Conclusion: All women had a high expectation of pain prior to IUD insertion, but for those who had had a previous vaginal delivery, this was significantly greater than that actually experienced. Satisfaction levels overall were high. Counseling of women should take into account their expected pain prior to IUD insertion and consideration should be given to alternative and additional methods of pain relief in women who have not had a previous vaginal delivery. PMID- 29386922 TI - Animal models of contraception: utility and limitations. AB - Appropriate animal modeling is vital for the successful development of novel contraceptive devices. Advances in reproductive biology have identified novel pathways for contraceptive intervention. Here we review species-specific anatomic and physiologic considerations impacting preclinical contraceptive testing, including efficacy testing, mechanistic studies, device design, and modeling off target effects. Emphasis is placed on the use of nonhuman primate models in contraceptive device development. PMID- 29386923 TI - Prenatal contraceptive counseling and method provision after childbirth. AB - Postpartum contraception is undergoing major changes, not only in timing, but also in content. Failure to provide immediate postpartum contraception contributes to the problems of unintended pregnancies and rapid repeat pregnancy because often the highest-risk women do not return for postpartum care. If they do attend that visit, they have often lost the insurance coverage that would enable them to use the most effective forms of birth control. Most of the issues surrounding early initiation of progestin-only methods and breastfeeding have been favorably resolved. In some cases, insurance coverage for delivery has been expanded to cover the costs of providing intrauterine devices and implants before the woman is discharged home. All of these new opportunities shift the burden of counseling about postpartum contraception onto the shoulders of the prenatal care provider. This article provides information about the advantages and disadvantages of providing immediate postpartum contraception with each of the eligible methods so clinicians can provide the needed counseling both during pregnancy and during hospitalization for delivery. It also provides guidance for initiation of bridging contraception, if needed, to initiate a method for a woman later in the postpartum period. PMID- 29386924 TI - Knowledge, non-use, use and source of information on contraceptive methods among women in various stages of reproductive age in rural Lagos, Southwest Nigeria. AB - Background: Contraceptives are advocated to be used against unwanted pregnancy and sexually transmitted diseases as unsafe abortion contributes to high maternal mortality in Nigeria while unwanted pregnancies have terminated the educational development of many females. Objective: This questionnaire-based survey aimed to describe the knowledge, nonuse, and use of various contraceptive methods among women in different child-bearing age groups in rural Lagos, Nigeria. Materials and methods: Between 2012 and 2013, 816 females in rural communities within Lagos State were surveyed for their knowledge, source of information, and use of contraceptives. They were grouped into early, mid, and late reproductive age. Statistical analysis of data harvested from respondents was carried out using STATA 13 software. Results: In all, 816 females in different stages of reproductive age were involved in the study, among whom 19% were single, 78% married, 3% divorced, and 0.5% widowed. About 6% had no formal education, while the majority (81%) were of the Yoruba ethnic group. Married respondents were approximately thrice more likely to know of contraceptives than single respondents (chi2 =29.9, P=0.000, odds ratio =2.9, 95% confidence interval =1.9, 4.2). Condom use was the most widely known and used method of contraceptive regardless of marital status and reproductive age status. Information about contraceptives was mainly from health facilities among married and divorced women and from school or educational institution among singles. Overall prevalence of contraceptive use was 51.9%. Nonuse of contraceptives was 43% among married women and 67% among singles. Knowledge of contraceptive method was negatively associated with marital status (t=-2.24, P=0.025) but positively associated with source of information on contraceptives (t=20.00, P=0.000). Use of contraceptives was positively associated with stage of reproductive age (t=1.94, P=0.05) and source of information on contraceptives (t=11.22, P=0.000), but negatively associated with marital status (t=-2.79, P=0.005) and religious belief (t=-1.89, P=0.05). Conclusion: Knowledge and use or nonuse of contraceptives could be pivotal in designing adequate prenatal care to prevent unwanted pregnancy and consequently illegal abortion or possible adverse pregnancy outcomes such as low birth weight, preterm birth, and conditions such as small for gestational age. Data from this study can also be used to design penetrating health education on making pregnancy safer or living a healthy female reproductive life. PMID- 29386925 TI - Nomegestrol acetate/17-beta estradiol: a review of efficacy, safety, and patient acceptability. AB - Nomegestrol acetate (NOMAC) 2.5 mg with 17-beta estradiol (E2) 1.5 mg is a new combined oral contraceptive (COC) formulation and is the first monophasic E2 pill to be marketed, having been licensed for use in Europe in 2011. It is available to be taken daily in a regimen of 24 active pills followed by four placebo pills. NOMAC is a highly selective 19-nor progestogen derivative with specific binding to progesterone receptors, anti-estrogenic activity and no androgenic, mineralocorticoid nor glucocorticoid effects. E2 is an estrogen that is identical to endogenous estrogen. While it has been in use for only a short period of time, current evidence suggests that NOMAC/E2 is just as effective, safe, and acceptable as existing COC preparations. Two large Phase III trials conducted in the Americas and across Europe, Australia, and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone (DRSP) 3 mg in combination with ethinyl estradiol (EE) 30 ug (DRSP/EE) groups but this difference was not statistically significant. NOMAC/E2 exhibits a good safety profile and has less effects on cardiovascular risk, hemostatic, metabolic, and endocrine factors in comparison to COCs containing EE in combination with levonorgestrel (LNG) or DRSP. NOMAC/E2 has also been found to cause less breast cell proliferation when compared to E2 alone and has some anti-proliferative effect on human breast cancer cells. NOMAC/E2 is considered acceptable as its compliance, continuation rates, and bleeding patterns were similar to COCs containing DRSP/EE and LNG 150 ug combined with EE 30 ug or LNG 100 ug combined with EE 20 ug (LNG/EE). However, discontinuation was found to be slightly higher in the NOMAC/E2 groups in the two large Phase III trials comparing NOMAC/E2 use with DRSP/EE. As the scientific literature has limited information on NOMAC/E2, further experience with NOMAC/E2 is required. PMID- 29386926 TI - Expulsion and continuation rates after postabortion insertion of framed IUDs versus frameless IUDs - review of the literature. AB - Background: Early intrauterine device (IUD) discontinuation after insertion immediately following aspiration abortion or after early medical abortion occurs as a consequence of expulsion of the IUD or removal due to side effects. These are often the consequence of the uterine forces impacting on the IUD due to spatial discrepancy with the uterine cavity causing pain, abnormal bleeding, and eventually, removal of the IUD. These women are candidates for repeat pregnancy as they often select less-effective methods or no contraception at all. Repeat abortion could be reduced by giving attention to these factors. Study design: In order to have an indication on the magnitude of the problem of IUD expulsion or discontinuation, we searched the MEDLINE database for clinical trials, randomized controlled trials, and prospective observational studies related to immediate postaspiration termination of pregnancy (TOP) and early medical abortion IUD insertion studies that reported IUD expulsion and IUD continuation rates. Results: The search identified 17 clinical trials that were suitable based on the data they presented. The majority concerned T-shape IUDs, inserted immediately following surgical (aspiration) pregnancy termination. Two studies were conducted after medical TOP, and four studies were conducted with the frameless IUD inserted after surgical (vacuum aspiration) TOP. The results showed expulsion rates between 0.8% and 17.3% at 8 weeks, up to 5 years after insertion, respectively. In four studies with the frameless IUD, totaling 553 insertions, the expulsion rate was 0.0% in three of them. Follow-up in the latter studies varied between 5 weeks and 54 months. Reported continuation rates with conventional (framed) IUDs were between 33.8% and 80% at 1 year for studies providing 1 year rates and between 68% and 94.1% for studies reporting continuation rates at 6 months. Studies utilizing frameless IUDs reported 1 year continuation rate over 95%. Conclusion: Frameless IUDs, due to their attachment to the uterine fundus, appear to be better retained by the postabortal uterus when compared with conventional framed IUDs. The absence of a frame ensures compatibility with uterine cavity anatomical dimensions, and may therefore result in improved acceptability and continuation rates in comparison with framed IUDs. Both these characteristics of the frameless IUD could help reduce the number of repeat unwanted pregnancies and subsequent abortions in some cases. PMID- 29386927 TI - Efficacy and safety of an oral contraceptive containing ethinylestradiol 20 ug/drospirenone 3 mg (24/4 regimen) in three indications in the People's Republic of China: a comparison with international studies. AB - While combined oral contraceptives are a popular choice in developed Western countries, they are used by only 1% of women who are married or in a relationship in the People's Republic of China. The purpose of this review is to describe the efficacy and safety of the combined oral contraceptive containing ethinylestradiol (EE) 20 ug/drospirenone 3 mg taken in a 24/4 regimen (YAZ(r); Bayer HealthCare Pharmaceuticals, Berlin, Germany) by Chinese women and to compare these results with those in women assessed in the international studies. Studies of EE 20 ug/drospirenone 3 mg in three different indications (contraception, acne, and premenstrual dysphoric disorder [PMDD]) have been conducted in Chinese women. The results of these three studies indicate that the EE 20 ug/drospirenone 3 mg combined oral contraceptive is a good long-term contraceptive option in Chinese women, providing 99% contraceptive protection over the observed 1-year treatment period, and additionally had a favorable effect on moderate acne vulgaris and relieved the symptoms of PMDD. The contraceptive efficacy, improvement in acne, and relief from PMDD symptoms observed in these studies did not differ from the effects observed in other international studies of EE 20 ug/drospirenone 3 mg, indicating that EE 20 ug/drospirenone 3 mg is as effective in Chinese women as in other ethnicities. Further, EE 20 ug/drospirenone 3 mg demonstrated a similar safety and tolerability profile in women enrolled in the Chinese and international trials, with no unexpected adverse events reported in any of the three Chinese trials. Overall, the efficacy, tolerability, and degree of non-contraceptive benefits with EE 20 ug/drospirenone 3 mg appear similar in Chinese women when compared with those reported in larger studies done at other international centers. PMID- 29386929 TI - Enhancing contraceptive choice for postpartum women in sub-Saharan Africa with the progesterone vaginal ring: a review of the evidence. AB - It is increasingly recognized that women who have just given birth have a high unmet need and require contraceptive protection in the first year postpartum. A majority of women in developing countries do breastfeed exclusively but for short durations, hence they may be sometimes unknowingly exposed to the risk of pregnancy if they are relying on nursing for contraceptive protection. The WHO's Medical Eligibility Criteria for Contraceptive Use recommends the use of different contraceptives in the first year postpartum depending on whether the woman is nursing or not and the time since delivery. Some of the options available for breastfeeding women include implants, IUDs and injectables, which can be obtained only from a trained family planning provider. Since 2013, Population Council has been carrying out a study in Senegal, Nigeria, and Kenya to assess the acceptability of progesterone vaginal ring (PVR) as a new contraceptive option designed specifically for use by breastfeeding women to extend the period of lactational amenorrhea and promote birth spacing. Breastfeeding in sub-Saharan Africa is near universal with fairly long durations, a situation that increases the effectiveness of PVR. Each ring delivers a daily dose of 10 mg of progesterone and can be used continuously up to 3 months with a woman being able to continue with its use up to 1 year (four rings used consecutively). Preliminary results indicate that many women who had used the method found it acceptable and their partners supported its use. Activities aimed at having PVR registered and made available in focal countries are ongoing. Integration of family planning and immunization services for mothers and their newborns will be a key strategy in introducing PVR into targeted health care markets. Given that the use of PVR does not require extensive clinical training, it will be easier to integrate it at all levels of the health system from tertiary health facilities to community-based services. The PVR has been recently included in the WHO Model List of Essential Medicines and the WHO's fifth edition of the Medical Eligibility Criteria for Contraceptive Use which should facilitate its introduction into the public and private sectors. PMID- 29386928 TI - Contraception and endometriosis: challenges, efficacy, and therapeutic importance. AB - Endometriosis is a benign gynecological condition that is estimated to affect 10% of women in the general population and appears to be increasing in incidence. It is an estrogen-dependent inflammatory disease, and is primarily characterized by dysmenorrhea, deep dyspareunia, chronic pelvic pain, and variable effects on fertility. The symptoms may greatly affect quality of life, and symptom control may be the primary aim of initial management, while contraceptive effect is often secondary. It is estimated that 30%-50% of women with endometriosis have an infertility problem, so a considerable number of endometriosis sufferers will require effective, planned contraception to maximize "protection of fertility" and prevent progression of the endometriotic condition. Ideally, this contraception should also provide symptom relief and improvement of physical, mental, and social well-being. At the present time, long-term progestogens appear to be the most effective choice for meeting all of these requirements, but other options need to be considered. It is becoming increasingly recognized that hormonal contraceptive systems are necessary for prevention of disease recurrence following surgical treatment of endometriosis. The personal preferences of the woman are an integral part of the final contraceptive choice. This article discusses the advantages and disadvantages of the contraceptive options available to women with endometriosis. PMID- 29386931 TI - Five-year review of copper T intrauterine device use at the University of Calabar Teaching Hospital, Calabar. AB - Background: The intrauterine devices (IUDs) are widely used contraceptive methods all over the world today. They are effective and recommended for use up to 10 years. They are not without side effects, which often prompt the users to request for removal. Objective: To determine the utilization rate of copper T intrauterine contraceptive device (IUCD), side effects, and request for removal at the University of Calabar Teaching Hospital, Calabar. Methods: The data on usage of the various forms of temporary contraception provided by the Family Planning Clinic of this center from January 1, 2006 to December 31, 2010 were collated. The records of usage of IUCD during same period were carefully studied. Results: During this period, a total of 10,880 users were provided with various forms of contraceptives. Copper T IUD was the commonest form of contraception used at the University of Calabar Teaching Hospital Family Planning Unit over the period under review (2006-2010) with a rate of 4,069 (37.40%). There was a yearly higher request for IUCD over other forms of contraceptives over the period. Of a total of 4,069 users of the copper T IUD method over the period, 1,410 (34.65%) belonged to the age group of 25-29 years. Eleven (4.61%) of the users requested for its removal due to abnormal vaginal bleeding, while five (2.08%) removed theirs due to abnormal vaginal discharge. The major reason for removal was the desire for pregnancy that accounted for 165 (70.26%), while one (0.51%) was removed due to dysmenorrhea. Conclusion: The copper T380A was very effective, safe with fewer side effects, and easily available in this study. The request for removal is also low in our environment. PMID- 29386932 TI - Varying family planning strategies across age categories: differences in factors associated with current modern contraceptive use among youth and adult women in Luanda, Angola. AB - Background: The objective of this study is to identify factors associated with current modern contraceptive use among Angolan women. By differentiating according to age groups (15-24 and 25-49 years), this study aimed to help family planning program planners better tailor interventions to improve utilization of modern contraception. Methods: A household survey was used to collect data from 1,545 women of reproductive age living in Luanda Province, Angola. Data on sociodemographic characteristics, reproductive behavior and intentions, contraceptive knowledge and use, and attitudes and beliefs regarding contraception and abortion were collected. The analyses were stratified based on age: 15-24 years (youth) and 25-49 years (adult). Multivariate logistic regression models were built for each age group, adding different subsets of variables in groups to see how relationships changed across the models. Results: Common factors associated with modern contraceptive use among all ages include education level, perceived contraceptive accessibility, contraceptive knowledge, communication with partner about family planning in last year, and self-efficacy. Exposure to family planning information in the media in the last few months, perceived partner approval of family planning, and marital status were all positively associated with current modern contraceptive use among women aged 15 24 years. Meanwhile, receiving information about family planning from a pharmacy in the last year was uniquely associated with current modern contraceptive use among women aged 25-49 years. Conclusion: Young women in Luanda, Angola seem to have a unique set of factors affecting their contraceptive use. These findings highlight the need for family planning programs to cater services and messages toward specific age groups. PMID- 29386930 TI - Knowledge, attitudes, practices and behaviors associated with female condoms in developing countries: a scoping review. AB - Women in developing countries are at high risk of HIV, sexually transmitted infections, and unplanned pregnancy. The female condom (FC) is an effective dual protective method regarded as a tool for woman's empowerment, yet supply and uptake are limited. Numerous individual, socioeconomic, and cultural factors influence uptake of new contraceptive methods. We reviewed studies of FC knowledge, attitudes, practices, and behaviors across developing countries, as well as available country-level survey data, in order to identify overarching trends and themes. High acceptability was documented in studies conducted in diverse settings among male and female FC users, with FCs frequently compared favorably to male condoms. Furthermore, FC introduction has been shown to increase the proportion of "protected" sex acts in study populations, by offering couples additional choice. However, available national survey data showed low uptake with no strong association with method awareness, as well as inconsistent patterns of use between countries. We identified a large number of method attributes and contextual factors influencing FC use/nonuse, most of which were perceived both positively and negatively by different groups and between settings. Male partner objection was the most pervasive factor preventing initial and continued use. Importantly, most problems could be overcome with practice and adequate support. These findings demonstrate the importance of accounting for contextual factors impacting demand in FC programming at a local level. Ongoing access to counseling for initial FC users and adopters is likely to play a critical role in successful introduction. PMID- 29386933 TI - Contraception for women with diabetes: challenges and solutions. AB - Diabetes mellitus (DM), the most common of metabolic disorders, is a global public health concern. Numbers are rising with 383 million adults currently diagnosed with DM and another 175 million as yet undiagnosed. The rise in cases includes increasing numbers of women of a reproductive age whose reproductive health and contraception need careful consideration. Unintended pregnancy with poor glycemic control at the time of conception increases the chance of adverse pregnancy outcomes including stillbirth, congenital abnormalities, and perinatal mortality. In order to minimize complications, safe and effective contraception is paramount for all women with DM. This is a challenge as women have been found to be reticent to ask for advice, appear to lack understanding of risks, and are less likely to be using contraception than women without DM. The World Health Organization has developed Medical Eligibility Criteria to guide contraceptive choice. Women with DM without complications can choose from the full range of contraceptive methods including hormonal contraception as the advantages of use outweigh any risk. Women with diabetic complications may need specialist advice to assess the risk-benefit equation, particularly in respect of hormonal contraception. Women should be aware that there is no restriction to the use of oral and copper intrauterine emergency contraception methods. There is a need for an integrated approach to diabetes and reproductive health with improved communication between women with DM and their health care providers. Women need to be aware of advice and services and should make their own choice of contraception based on their needs and associated risk factors. Practitioners can offer nonjudgmental guidance working in partnership with women. This will enable discussion of risks and benefits of contraceptive methods and provision of advice dedicated to improving overall health and well-being. PMID- 29386935 TI - Contraceptive prevalence and determinants among women of reproductive age group in Ogbomoso, Oyo State, Nigeria. AB - Background: The fertility rate in Nigeria is 5.7 children per woman. The contraceptive prevalence rate has been found to be low at 15% in 2013, compared to other countries such as the US and Pakistan. Objective: The study aimed to assess the contraceptive prevalence among women of reproductive age in Ogbomoso town, and determinants of use, with a view to make appropriate recommendations that will enhance the uptake of family planning services. Materials and methods: This is a descriptive cross-sectional study conducted with 560 respondents, using a multistage sampling technique. Data were retrieved using a semi-structured, pretested questionnaire. Results: All the respondents were aware of contraception; however, only 49.7% (271) had ever used any method, while 25.4% (69) of the number who had ever used contraception were currently using a method. The methods being used were the traditional type (four [5.9%]), natural type (two [3.0%]), and modern type (63 [91.1%]). The predictors of contraception use included the age group of 40-49 years (odds ratio [OR] 14.1; confidence interval [CI] 3.06-73.24; P=0.0001); the married women were approximately four times more likely to use contraception than the single women (OR 4.5; CI 3.03-6.72; P<0.0001). The women with tertiary level of education were three times more likely to use contraception than those without formal education (OR 3.1; CI 1.13 9.95; P=0.0268), and the odds ratio of respondents with a positive attitude to using contraception more than those with negative attitude was 2 (OR 2; CI 1.41 2.91; P<0.0001). Conclusion: In light of the advantages associated with contraception use, there needs to be a conscious effort, especially among health care workers, to educate women about contraception and encourage its use. PMID- 29386934 TI - Intrauterine devices and risk of uterine perforation: current perspectives. AB - Uterine perforation is an uncommon complication of intrauterine device insertion, with an incidence of one in 1,000 insertions. Perforation may be complete, with the device totally in the abdominal cavity, or partial, with the device to varying degrees within the uterine wall. Some studies show a positive association between lactation and perforation, but a causal relationship has not been established. Very rarely, a device may perforate into bowel or the urinary tract. Perforated intrauterine devices can generally be removed successfully at laparoscopy. PMID- 29386937 TI - Postpartum family planning: current evidence on successful interventions. AB - We reviewed existing evidence of the efficacy of postpartum family planning interventions targeting women in the 12 months postpartum period in low- and middle-income countries. We searched for studies from January 1, 2004 to September 19, 2015, using the US Preventive Services Task Force recommendations to assess evidence quality. Our search resulted in 26 studies: 11 based in sub Saharan Africa, six in the Middle East and North Africa, and nine in Asia. Twenty of the included studies assessed health facility-based interventions. Three were focused on community interventions, two had community and facility components, and one was a workplace program. Overall quality of the evidence was moderate, including evidence for counseling interventions. Male partner involvement, integration with other service delivery platforms, such as prevention of mother to-child transmission of HIV and immunization, and innovative product delivery programs may increase knowledge and use during the postpartum period. Community based and workplace strategies need a much stronger base of evidence to prompt recommendations. PMID- 29386936 TI - Unscheduled bleeding and contraceptive choice: increasing satisfaction and continuation rates. AB - Approximately half (51%) of the 6.6 million pregnancies in the US each year are unintended and half of those pregnancies (54%) occur among women not using contraception. Many women discontinue their contraceptives due to method dissatisfaction. Bothersome unscheduled bleeding is one of the main reasons cited by women for stopping a birth control method. Improving counseling and management of these side effects will aide in increasing satisfaction with contraceptive methods. The following review will discuss the bleeding profiles associated with the contraceptive options available in the US. A valuable resource from the Centers for Disease Control and Prevention, the US Selected Practice Recommendations for Contraceptive Use, will be introduced. Definitions of the types of unscheduled bleeding are included, as well as strategies for treatment for each contraceptive method. The evidence whether or not anticipatory counseling increases continuation rates will also be reviewed. PMID- 29386939 TI - Barriers to accessing and using contraception in highland Guatemala: the development of a family planning self-efficacy scale. AB - Understanding the persistent inequalities in the prevalence rates of family planning and unmet need for family planning between indigenous and nonindigenous women in Guatemala requires localized explorations of the specific barriers faced by indigenous women. Based on social cognitive theory, elicitation interviews were carried out with a purposive sample of 16 young women, aged 20-24 years, married or in union, from the rural districts of Patzun, Chimaltenango, Guatemala. Content analysis was carried out using the constant-comparison method to identify the major themes. Based on this qualitative study, the following barriers are incorporated into the development of a self-efficacy scale: lack of knowledge about and availability of methods, fear of side effects and infertility, husbands being against family planning (and related fears of marital problems and abandonment), pressure from in-laws and the community, and the belief that using contraception is a sin. This is the first evidence-informed self-efficacy scale developed with young adult, indigenous women that addresses the issue of family planning in Latin America. PMID- 29386938 TI - Contraception for women with epilepsy: counseling, choices, and concerns. AB - Approximately 50% of all pregnancies in women with epilepsy (WWE) occur unplanned. This is worrying, given the increased occurrence of obstetrical complications in WWE, including the risk of seizures and their possible consequences for both the mother and the unborn child. Hormonal contraception is usually regarded as highly effective, but it is subject to numerous bidirectional drug interactions with several antiepileptic drugs. These interactions may lead to loss of seizure control or contraceptive failure. Further concerns are loss of bone mineral density and increased seizure activity due to hormonal effects. Many physicians lack sufficient knowledge regarding these issues, and most WWE have never received adequate counseling. Moreover, several studies show that a large proportion of WWE do not take their medicines regularly. This article reviews all of these issues and offers practical recommendations for the management of contraception in WWE. PMID- 29386940 TI - Personalized contraceptive counseling: helping women make the right choice. AB - Unintended pregnancy is a significant problem with medical, social, and economic consequences. Half of unintended pregnancies are a result of no contraceptive use; while the other half results from contraceptive inconsistencies, or method failure. Women have an array of contraceptive options to choose from, each of which differs significantly in terms of usage, efficacy, side effects, risks, and noncontraceptive benefits. Determining the best tool for communication is a challenge. In addition, the choice of contraceptive method differs among women with medical problems. Not all contraceptive methods are suitable for women with certain medical problems. In this review, we discuss different methods of counseling and the tools available for sharing contraception information. PMID- 29386941 TI - Measuring and monitoring quality of care in family planning: are we ignoring negative experiences? AB - Despite decades of emphasis on quality of care, qualitative research continues to describe incidents of poor quality client-provider interactions in family planning provision. Using an emerging framework on disrespect and abuse (D and A) in maternal health services, we reviewed the global published literature for quantitative tools that could be used to measure the prevalence of negative client experiences in family planning programs. The search returned over 7,000 articles, but only 12 quantitative tools included measures related to four types of D and A (non-confidential care, non-dignified care, non-consented care, or discrimination). We mapped individual measurement items to D and A constructs from the maternal health field to identify measurement gaps for family planning. We found significant gaps; current tools are not adequate for determining the prevalence or impact of negative client experiences in family planning programs. Programs need to invest in tools that describe all aspects of client experiences, including negative experiences, to increase accountability and maximize the impact of current investments in family planning programs. PMID- 29386942 TI - Awareness and practice of dual contraception among female tertiary institution students in Ibadan, Nigeria. AB - Purpose: To determine the knowledge, awareness, and factors associated with the practice of dual contraception among female undergraduates in Ibadan, Nigeria. Materials and methods: This is a cross-sectional study using a semi-structured self-administered questionnaire to assess the knowledge and practice of dual contraception among female undergraduates in the University of Ibadan and The Polytechnic, Ibadan. A total of 1,200 undergraduate students were interviewed, and data obtained were analyzed with SPSS Version 18.0. Results: The mean age of the respondents was 22.57+/-3.43 years. Among the respondents, 900 (84.6%) were unmarried, 871 (77.9%) have been sexually exposed, 793 (70.9%) had heard of dual contraception, and 659 (58.9%) had knowledge of dual contraception. Majority (66.8%) of the participants used effective contraception, of whom 423 (56.3%) used condom, while others used other short- or long-term reversible contraception. More than two-thirds (79.2%) of the sexually exposed respondents were aware of dual contraception, but only 465 (41.6%) had practiced it. The main sources of information about dual contraception were from friends and radio (45.3% and 36.1%, respectively). Those who had multiple sexual partners and early coitarche were more likely to use dual contraception (P<0.05). History of previous sexually transmitted infection (odds ratio =3.06, 95% confidence interval [CI] =2.03-4.62) and unwanted pregnancy (odds ratio =3.53, 95% CI =2.62 4.74) were strongly associated with the use of dual contraception. Conclusion: Uptake of dual contraception among the students was low. Efforts need to be concentrated on determining and addressing the challenges that are responsible for the lower uptake of dual contraception among female undergraduates who are at higher risk of unwanted pregnancy and sexually transmitted infections. Promotion of consistent use of dual contraception is pertinent in maximizing the benefits of dual contraception in our environment. PMID- 29386943 TI - Contraceptive options for women with premenstrual dysphoric disorder: current insights and a narrative review. AB - Premenstrual syndrome and its most severe form, premenstrual dysphoric disorder (PMDD), are two well-defined clinical entities that affect a considerable number of women. Progesterone metabolites and certain neurotransmitters, such as gamma aminobutyric acid and serotonin, are involved in the etiology of this condition. Until recently, the only treatment for women with PMDD was psychoactive drugs, such as selective serotonin reuptake inhibitors. Several years ago, there has been evidence of the beneficial role of combined hormonal contraceptives in controlling PMDD symptoms. Oral combined hormonal contraceptives that contain drospirenone in a 24+4-day regimen are the only drugs that have been approved by US Food and Drug Administration for the treatment of PMDD, but there is scientific evidence that other agents, with other formulations and regimens, could also be effective for the treatment of this condition. However, it remains unclear whether the beneficial effect of combined hormonal contraceptives is associated with the type of estrogen or progestogen used or the treatment regimen. PMID- 29386946 TI - Using contraception counseling to further improve adherence. PMID- 29386945 TI - Depo-Provera (depot medroxyprogesterone acetate) use after bariatric surgery. AB - In the US, obesity rates are increasing greatly. The Centers for Disease Control and Prevention estimates that 68.5% of Americans, including 63.9% of adult women older than 20 years, are overweight (body mass index between 25 kg/m2 and 29.9 kg/m2) or obese (body mass index >30 kg/m2). In light of this, it is not surprising that the rates of bariatric surgery have also been increasing. When considering the metabolic changes associated with both bariatric surgery and contraceptive use, in combination with the unique medical considerations of obese women, it is indisputable that clear guidelines are needed when counseling obese patients of reproductive age after bariatric surgery. In this literature review, we focus on depot medroxyprogesterone acetate (DMPA) and the implications of its use in obese women, preweight and postweight loss following bariatric surgery. Both DMPA use and bariatric surgery are known to cause bone loss, but it is still unclear whether there is an additive effect of the two factors on bone loss and whether either of these factors directly leads to an increased risk of bone fracture. The current consensus guidelines do not impose a restriction on the use of DMPA after bariatric surgery. DMPA use is associated with weight gain, and it is unclear whether weight loss blunting occurs with the use of DMPA after bariatric surgery. Prior studies had demonstrated an association with weight gain in adolescents, and therefore, those prescribing DMPA use after bariatric surgery in adolescents should proceed with caution. Adult women do not have a similar response to the use of DMPA. DMPA use has rarely been associated with increased risk of venous thromboembolism (VTE). The obesity-associated increase in VTE should be mitigated by surgically induced weight loss. The concurrent use of DMPA in the post bariatric surgical period should not further increase the risk of VTE. PMID- 29386944 TI - New developments in intrauterine device use: focus on the US. AB - Many more women in the US today rely upon intrauterine devices (IUDs) than in the past. This increased utilization may have substantially contributed to the decline in the percentage of unintended pregnancies in the US. Evidence-based practices have increased the number of women who are medically eligible for IUDs and have enabled more rapid access to the methods. Many women enjoy freedom to use IUDs without cost, but for many the impact of the Affordable Care Act has yet to be realized. Currently, there are three hormonal IUDs and one copper IUD available in the US. Each IUD is extremely effective, convenient, and safe. The newer IUDs have been tested in populations not usually included in clinical trials and provide reassuring answers to older concerns about IUD use in these women, including information about expulsion, infection, and discontinuation. On the other hand, larger surveillance studies have provided new estimates about the risks of complications such as perforation, especially in postpartum and breastfeeding women. This article summarizes significant features of each IUD and provides a summary of the differences to aid clinicians in the US and other countries in advising women about IUD choices. PMID- 29386947 TI - Predictors of non-use of intrauterine contraception among women aged 18-49 years in a general practice setting in the UK. AB - Objectives: Our research examined the barriers to the uptake of intrauterine contraception (IUC) by women in a general practice (GP) setting in the UK. This study reports predictors of non-use of IUC in this context. Design: We used a mixed method Qual/Quant approach in which the initial qualitative research provides a framework for subsequent larger quantitative surveys. Utilizing findings derived from 30 qualitative interviews, a quantitative survey was developed and distributed to a pragmatic sample of 1,195 women, aged 18-49 years, who were recruited through 32 participating GP practices in an area of England, UK. Outcome measures were percentage of attributes or responses in the sample and use or non-use of IUC. Results were analyzed using descriptive statistical analysis and binary logistic regression, using use/non-use as a binary response variable. Results: Attitudinal variables, which were the strongest predictors of non-use of IUC, were an adverse opinion on long-acting aspect of IUC (odds ratio [OR]=8.34), disliking the thought of IUC inside the body (OR=3.138), concerns about IUC causing difficulties becoming pregnant in the future (OR=2.587), concerns about womb damage (OR=2.224), having heard adverse opinions about levonorgestrel-releasing intrauterine system (Mirena(r)) (OR=2.551), having an adverse opinion of having light, irregular periods (OR=2.382) and, having an adverse opinion of having no periods (OR=2.018). Conclusion: Concerns about the long-acting nature of IUC and persisting concerns about the safety of IUC may act as barriers to its use. Information for women, tailored to specifically address these concerns, is needed. Implications: Clinicians should provide more reassurance and information to potential users of IUC to increase their confidence about the possibility of removing IUC early or on request. They should also specifically seek to alleviate concerns about internal damage, damage to the womb, or damage to future fertility from using the methods. PMID- 29386948 TI - Improving adolescent knowledge of emergency contraception: challenges and solutions. AB - Globally, unintended adolescent pregnancies pose a significant burden. One of the most important tools that can help prevent unintended pregnancy is the timely use of emergency contraception (EC), which in turn will decrease the need for abortions and complications related to adolescent pregnancies. Indications for the use of EC include unprotected sexual intercourse, contraceptive failure, or sexual assault. Use of EC is recommended within 120 hours, though is most effective if used as soon as possible after unprotected sex. To use EC, adolescents need to be equipped with knowledge about the various EC methods, and how and where EC can be accessed. Great variability in the knowledge and use of EC around the world exists, which is a major barrier to its use. The aims of this paper were to 1) provide a brief overview of EC, 2) discuss key social determinants affecting knowledge and use of EC, and 3) explore best practices for overcoming the barriers of lack of knowledge, use, and access of EC. PMID- 29386949 TI - Long-acting reversible contraception use among residents in obstetrics/gynecology training programs. AB - Background: The objective of the study was to estimate the personal usage of long acting reversible contraception (LARC) among obstetrics and gynecology (Ob/Gyn) residents in the United States and compare usage between programs with and without a Ryan Residency Training Program (Ryan Program), an educational program implemented to enhance resident training in family planning. Materials and methods: We performed a web-based, cross-sectional survey to explore contraceptive use among Ob/Gyn residents between November and December 2014. Thirty-two Ob/Gyn programs were invited to participate, and 24 programs (75%) agreed to participate. We divided respondents into two groups based on whether or not their program had a Ryan Program. We excluded male residents without a current female partner as well as residents who were currently pregnant or trying to conceive. We evaluated predictors of LARC use using bivariate analysis and multivariable Poisson regression. Results: Of the 638 residents surveyed, 384 (60.2%) responded to our survey and 351 were eligible for analysis. Of those analyzed, 49.3% (95% confidence interval [CI]: 44.1%, 54.5%) reported current LARC use: 70.0% of residents in Ryan Programs compared to 26.8% in non-Ryan Programs (RRadj 2.14, 95% CI 1.63-2.80). Residents reporting a religious affiliation were less likely to use LARC than those who described themselves as non-religious (RRadj 0.76, 95% CI 0.64-0.92). Of residents reporting LARC use, 91% were using the levonorgestrel intrauterine device. Conclusion: LARC use in this population of women's health specialists is substantially higher than in the general population (49% vs. 12%). Ob/Gyn residents in programs affiliated with the Ryan Program were more likely to use LARC. PMID- 29386950 TI - Oral contraceptive and acute intestinal ischemia with mesenteric venous thrombosis: a case report. AB - Background: Venous thrombosis is a serious complication of combined contraceptive usage. However, mesenteric venous thrombosis and intestinal necrosis are infrequently seen in women using oral contraceptives, and in such cases diagnosis is often delayed. Case presentation: We report the case of a 38-year-old obese female patient who presented with acute abdominal pain. A bowel infection was first diagnosed and treated with antibiotics. Contrast-enhanced tomography of the abdomen revealed diffuse ischemia of the small intestine with superior mesenteric thrombosis. Laparotomy with segmental resection of both small and large bowel was performed. No predisposing factor of mesenteric venous thrombosis was demonstrated except association of the combined contraceptive with obesity. Conclusion: This report highlights the need for clinicians to suspect venous mesenteric thrombosis in women of reproductive age with acute abdominal pain and poor physical findings. Detailed personal history including prescriptions should help to quickly and accurately determine the problem. PMID- 29386952 TI - "Side effects affected my daily activities a lot": a qualitative exploration of the impact of contraceptive side effects in Bangladesh. AB - Purpose: In a country like Bangladesh that has made great progress in contraceptive use with one of the lowest levels of fertility and highest levels of contraceptive use, understanding what factors influence women's decisions to discontinue a contraceptive method and not switch to a new method is critical in designing interventions and programs that will help enable Bangladesh to reach its FP2020 goals. Research on side effects has focused on physical manifestations like headaches, moodiness, abdominal pain, and menstrual irregularities. While physical effects alone may stop women from continuing a contraceptive method, less is known about how side effects influence women's daily activities and lives. The purpose of this study is to understand the ways that side effects affect Bangladeshi women's participation in different social settings. Methods: Thirty-five in-depth interviews with married women who recently discontinued or switched to a different contraceptive method were conducted in Sylhet and Khulna Divisions. Interviews explored reasons for discontinuation including experience of side effects and impact of side effects on women's lives. Results: Key themes emerged including that side effects are not only experienced physically but are barriers to women's participation in many aspects of their lives. The spheres of life that most commonly appeared to be influenced by side effects include religion, household, and sexual intimacy irrespective of method used or residence. Conclusion: Family planning providers need to be aware of these additional consequences associated with contraceptive side effects to provide tailored counseling that recognizes these issues and helps women to mitigate them. For Bangladesh to achieve its FP2020 goals, understanding the broader context in which family planning decisions are made vis-a-vis side effects is critical to design programs and interventions that meet all the needs of women beyond just their fertility intentions. PMID- 29386951 TI - Hormonal contraception in women with polycystic ovary syndrome: choices, challenges, and noncontraceptive benefits. AB - Polycystic ovary syndrome (PCOS) is an endocrine disorder among women of reproductive age characterized by chronic anovulation and polycystic ovary morphology and/or hyperandrogenism. Management of clinical manifestations of PCOS, such as menstrual irregularities and hyperandrogenism symptoms, includes lifestyle changes and combined hormonal contraceptives (CHCs). CHCs contain estrogen that exerts antiandrogenic properties by triggering the hepatic synthesis of sex hormone-binding globulin that reduces the free testosterone levels. Moreover, the progestogen present in CHCs and in progestogen-only contraceptives suppresses luteinizing hormone secretion. In addition, some types of progestogens directly antagonize the effects of androgens on their receptor and also reduce the activity of the 5alpha reductase enzyme. However, PCOS is related to clinical and metabolic comorbidities that may limit the prescription of CHCs. Clinicians should be aware of risk factors, such as age, smoking, obesity, diabetes, systemic arterial hypertension, dyslipidemia, and a personal or family history, of a venous thromboembolic event or thrombophilia. This article reports a narrative review of the available evidence of the safety of hormonal contraceptives in women with PCOS. Considerations are made for the possible impact of hormonal contraceptives on endocrine, metabolic, and cardiovascular health. PMID- 29386953 TI - A practical alternative to calculating unmet need for family planning. AB - The standard approach for measuring unmet need for family planning calculates actual, physiological unmet need and is useful for tracking changes at the population level. We propose to supplement it with an alternate approach that relies on individual perceptions and can improve program design and implementation. The proposed approach categorizes individuals by their perceived need for family planning: real met need (current users of a modern method), perceived met need (current users of a traditional method), real no need, perceived no need (those with a physiological need for family planning who perceive no need), and perceived unmet need (those who realize they have a need but do not use a method). We tested this approach using data from Mali (n=425) and Benin (n=1080). We found that traditional method use was significantly higher in Benin than in Mali, resulting in different perceptions of unmet need in the two countries. In Mali, perceived unmet need was much higher. In Benin, perceived unmet need was low because women believed (incorrectly) that they were protected from pregnancy. Perceived no need - women who believed that they could not become pregnant despite the fact that they were fecund and sexually active - was quite high in both countries. We posit that interventions that address perceptions of unmet need, in addition to physiological risk of pregnancy, will more likely be effective in changing behavior. The suggested approach for calculating unmet need supplements the standard calculations and is helpful for designing programs to better address women's and men's individual needs in diverse contexts. PMID- 29386954 TI - Protection for Children Born Through Assisted Reproductive Technologies Act, B.E. 2558: The Changing Profile of Surrogacy in Thailand. AB - The National Legislative Assembly of Thailand has enacted on February 19, 2015 the Protection for Children Born through Assisted Reproductive Technologies Act (ART Act). Its primary objective aims at protecting children born through assisted reproductive technologies and providing the legal procedures that the intended parents must follow. The focus of this article is to discuss the ongoing issues involving assisted reproduction in Thailand. After reviewing the past legal framework surrounding surrogate motherhood and the downsides of the assisted reproductive technology market in Thailand, the article will discuss the new ART Act and its regulatory framework. It will conclude that although the new law contains some flaws and limitations, it has so far been successful in tackling surrogacy trafficking and preventing reproductive scandals from occurring again. PMID- 29386955 TI - Vitamin D deficiency in Saudi Arabians: A reality or simply hype: A meta-analysis (2008-2015). AB - BACKGROUND AND OBJECTIVE: The objective of this systematic review was to determine from published data the prevalence of Vitamin D deficiency in the Saudi population. METHODS: An extensive and meticulous search was conducted for studies published in MEDLINE, EMBASE the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (2008-2015), and the Science Citation Index published data from the Annals of Saudi Medicine and Saudi Medical Journal with the key words: Vitamin D deficiency, insufficiency, and Saudi Arabians. The inclusion criterion was studies published during 2008 to 2015, and studies involving healthy individuals between the age of 18 and 80 years. Binary random- effect model was used to estimate pooled Vitamin D deficiency. Prevalence rates along with overall estimate were presented by forest plot. Heterogeneity test was used to assess the significance of heterogeneity among studies. RESULTS: The authors identified 26 potentially relevant articles, 16 of which met the inclusion criteria. A total of 20,787 patients were analyzed. Sixty-two percent (12,959) were females, and the rest were males. The overall Vitamin D deficiency was 63.5% (95% CI: 53.3, 73.7). CONCLUSIONS: The currently available literature on the Saudi Arabian population suggests that the Vitamin D deficiency is around 60% and not 100% as indicated in some studies. The relatively small number of studies on the population and the different modes of diagnostic methodology used make the issue of correct figures of Vitamin D deficiency contentious. PMID- 29386956 TI - Misconceptions of Parents about Antibiotic use in Upper Respiratory Tract Infections: A survey in Primary Schools of the Eastern Province, KSA. AB - BACKGROUND: Misuse of antibiotics has become a global public health issue for several reasons, one of which is the rapid development of antibiotic resistance that leads to high morbidity and mortality. OBJECTIVES: The objective of this study was to study the misconceptions of parents of primary school children in Dammam, Khobar, and Dhahran about the use of antibiotics for upper respiratory tract (URT) symptoms; and also study perceptions, attitudes, and behavior toward antibiotic use and identify the factors affecting this. MATERIALS AND METHODS: Analytic cross-sectional study of parents in three large cities: Dammam, Khobar, and Dhahran in Saudi Arabia. Study population was parents of children studying in these schools, and were selected multistgae sampling and proportional to population size (PPS). RESULTS: The questionnaire was distributed to 1306 parents. The response rate was 78.9%, 56.6% respondents were mothers with a mean age of 40 +/- 7. Sixty-seven percent of the parents admitted to self-prescription once or more, and the most common reason for self-prescribing, was because they thought the child was not ill enough to be taken to hospital (41.8%). This was followed by 37.7% who used "leftovers". Regarding the attitude toward antibiotic prescription, 62.5% agreed that children should not be given an antibiotic when they have a fever and nasal congestion. In addition, 63.5% agreed that they should give their child antibiotic for ear or throat pain. Around two-thirds agreed that upper respiratory tract infection (URTI) was caused by a virus. Those who obtained their information from primary health-care centers and general practitioners had the lowest median of total knowledge score, and the highest knowledge was for those who obtained information from websites and the social media. Multiple linear regressions revealed that parents whose incomes were high, had high education, had children in private schools were more likely to have good knowledge and highly favorable attitudes and practices toward antibiotic use. CONCLUSION: Thirteen percent had an excellent knowledge, and 52.7% had an intermediate level of knowledge. Of those with excellent knowledge, 58.6% still expected to get antibiotic prescription from a physician for URTI. PMID- 29386957 TI - Factors contributing to the upsurge of water-pipe tobacco smoking among Saudi females in selected Jeddah cafes and restaurants: A mixed method study. AB - BACKGROUND: Despite clear evidence indicating the health hazards of water tobacco smoking (WTS), there is a remarkable increase in the frequency of WTS in the Middle East and the Gulf region, particularly among young girls and women. The objective of this survey was to examine the prevalence of and the reasons for addiction to WTS and study in depth the factors contributing to the increased frequency of WTS among Saudi females. MATERIALS AND METHODS: This study was conducted in different cafes and restaurants in Jeddah using a mixed method approach. A quantitative approach was carried out by a cross-sectional design, in which adult WTS Saudi females (n = 332) were selected from ten cafes. In addition, a qualitative approach was pursued involving five focus group discussions and three in-depth interviews of heavy smokers. Frequencies and percentages were calculated for the categorical variables, and Chi-square test and regression analysis were performed to establish association. Key themes were identified and built upon for the qualitative part. RESULTS: The mean age of female water-pipe (WP) smokers was 32.5 +/- 11.9 years. Addicted to WTS were 39.6% of the women. Significant predictors of smokers' addiction to WTS according to regression analysis (p < 0.05) were increased frequency of WTS, perception that it improved mood, and insistence on carrying one's own WP to restaurants and cafes. Smoking frequency increased in pleasant weather (p = 0.025) and better mood (p = 0.033). This study showed that students and working women were more addicted to WTS (p < 0.001). Those who smoked daily preferred to smoke at home especially when alone (p < 0.001), while the preferred place for those who smoked weekly was restaurants in the company of their friends (p < 0.001). Most of the participants in this study believed that WTS was less harmful and less addictive than cigarette smoking. The only driving force to quit WTS was the effects on their beauty/skin. CONCLUSION: WTS is a public health problem, especially among young girls. Peer pressure, view that it is a fashion symbol, carrying one's own WP and wrong belief that WP was less harmful, improved mood, and effect of the weather are main factors leading to unintentional dependency on WTS. The only driving force to stop WTS is the effect it has on beauty/skin. It is important to understand the reasons behind the upsurge of WTS in this group for appropriate policy for intervention for its prevention and cessation. PMID- 29386958 TI - Health-related quality of life among female university students in Dammam district: Is Internet use related? AB - BACKGROUND: Quality of life (QOL) is defined by the World Health Organization as the individual's perception of his/her position in life, within the context of culture and system of values in which the individual lives, and as relates to his/her objectives, expectations, standards, and concerns. Life in university is so stressful; it can affect health-related QOL (HRQOL). There are many factors that affect HRQOL of university students. The aim of this study was to assess the QOL of female university students in Dammam, Saudi Arabia, and identify factors related to it, with special emphasis on Internet use. MATERIALS AND METHODS: This cross-sectional study surveyed 2516 female students at Imam Abdulrahman Bin Faisal University in Dammam, using a self-administered questionnaire with sections on sociodemographics, score for Internet use/addiction (IA), and an assessment of HRQOL. Two latent factors were extracted: physical component summaries (PCSs) and mental component summaries (MCSs). Bivariate analyses and MANOVA were then performed. RESULTS: The overall PCS and MCS were 69% +/- 19.6 and 62% +/- 19.9, respectively. Almost two-thirds of the students were found to have IA or possible IA. Students whose parents had lower education reported less PCS. Students with high family income reported higher PCS and MCS than those with a lower income. MANOVA model has shown that the higher the IA score, the lower the score of both the PCS and MCS. CONCLUSION: HRQOL in female students was found to be affected by parental educational level, family income, and problematic Internet use. PMID- 29386959 TI - Falls among elderly and its relation with their health problems and surrounding environmental factors in Riyadh. AB - BACKGROUND: Falls among the elderly are one of the major causes of morbidity and mortality worldwide. They constitute the second leading cause of unintentional deaths after road-traffic accidents. The aim of the study was to estimate the prevalence of falls among the elderly and to investigate the factors that contribute to this phenomenon. MATERIALS AND METHODS: A cross-sectional analytical study was conducted in the elderly, over the age of 60, in Riyadh. The sample under scrutiny was estimated to be 357 in total. A pilot study was conducted among 15 subjects. Two questionnaires were used for the interviews which were translated into Arabic using the "Morse Fall Scale." The questionnaires assessed: the participants' previous history of falls, whether a secondary diagnosis had been obtained, whether any ambulatory aids had been used or whether an IV connection had been fitted during convalescence. They also inquired if any gait/transferring device had been used to assist the patient at any time. RESULTS: Out of 357 participants, 206 (57.7%) had a history of falls. Study found an association between the number of falls recorded, the age of the participants, and whether the participant was female. Furthermore, there were statistically significant associations between the history of falls and a condition of impaired health. The results also showed that environmental hazards play a significant role in the occurrence of falls with P <= 0.001, in which 103 (81.7%) of the individuals who were exposed to environmental hazards revealed a history of falls. CONCLUSION: Falls among the elderly are common. Significantly, if the health of the individuals is impaired, and there are contiguous environmental risk factors, these elements combine to play a part in the occurrence of such falls. There is, therefore, a need to design and develop a health awareness program to prevent such problems in the elderly. PMID- 29386960 TI - Predictors and consequences of "Phubbing" among adolescents and youth in India: An impact evaluation study. AB - BACKGROUND: "Phubbing" phenomenon, in the frequent use of a smartphone, describes the habit of snubbing someone in favor of a mobile phone. Its predictors and consequences are few in developed countries, but the literature lacks information on its actual occurrence and impact on adolescents and youth in a developing country such as India. MATERIALS AND METHODS: This impact evaluation study was carried out as part of the Phubbing Project of the University of Poland for 6 months (November 15, 2016-May 15, 2017) on a sample of 400 adolescents and youth selected randomly from the five colleges in the district of Muzaffarnagar of Uttar Pradesh state in India. Data were collected through the Internet using e questionnaires sent to all students. The phubbing predictors' and consequences' scales available in literature were used and data were analyzed by a mixed method to get the study findings. RESULTS: The prevalence of phubbing was 49.3%. The most important predictors associated with phubbers were Internet addiction (p < 0.0001, Odds Ratio 2.26), smartphone addiction (OR 25.9), fear of missing out (OR 18.8), and the lack of self-control (p < 0.0001, OR = 0.73-1.72). Phubbing also had significant consequences on their social health, relationship health, and self-flourishing, and was significantly related to depression and distress. Logistic regression analysis showed significant impact of phubbing predictors on phubbing consequences in phubbers, especially in depressed and distress status. CONCLUSION: Adolescents and youth of India need special guidance from government adolescent clinics or colleges or even families to control this habit in order to promote better physical, mental, and social health. PMID- 29386962 TI - Home-related falls: An underestimated mechanism of injury. AB - BACKGROUND: The home is a leading location for falls, but the epidemiology and outcome of falls at home (FH) have not been adequately described. Our aim was to evaluate FH, particularly in the bathroom. MATERIALS AND METHODS: We conducted a retrospective analysis of patients with a history of FH admitted to the Level I trauma center in Qatar. Patients were divided into Group 1: <60 years and Group 2: 60 year or older, and their data were analyzed and compared. RESULTS: A total of 98 patients with FH in the bathroom with a mean age of 51 +/- 18 years, mostly males (73.5%) were identified over 3 years. One out of every 50 trauma patients admitted was a victim of a fall in the bathroom. Group 2 had significantly more females and sustained a single-site injury. Group 1 had more involvement of alcohol (P = 0.02) and sustained more multiple injuries (44% vs. 23%; P = 0.02). The mean Injury Severity Score and length of hospital stay was comparable among the two groups. Head, abdomen, and facial injuries were significantly higher in Group 1 whereas lower extremity injuries and mortality were significantly higher in Group 2. CONCLUSION: FH, particularly in the bathroom, is an underrecognized mechanism of injury with a unique dichotomous epidemiology based on age. This needs increased public awareness and primary prevention programs for high-risk populations. PMID- 29386961 TI - Painful Diabetic Peripheral Neuropathy among Saudi Diabetic Patients is Common but Under-recognized: Multicenter Cross-sectional study at primary health care setting. AB - OBJECTIVE: The aim of this study was to assess the prevalence of painful diabetic peripheral neuropathy (PDPN) and its associated risk factors in patients with type 2 diabetes mellitus attending primary health care (PHC) in Saudi Arabia. MATERIALS AND METHODS: A multicenter, cross-sectional study evaluated 242 type 2 diabetics who attended the National Guard PHC clinics in Riyadh. Trained physicians obtained the relevant data and medical history and assessed PDPN using the Michigan Neuropathy Screening Instrument. RESULTS: About 35% of patients with type-2 diabetes in this study had painful diabetic peripheral neuropathy. High risk hemoglobin level and poor compliance with treatment were associated with increased odds of PDPN (Odds ratio [OR] =3.121, 95% confidence interval [CI] 1.154-8.444, OR = 3.546, 95% CI 1.531-8.214, respectively). It is noted that only in one patient with PDPN, was their PDPN recognized by physicians. Furthermore, none of our study participants was taking medication to control the pain. CONCLUSIONS: One-third of Saudi Arabia's Type 2 diabetes patients have PDPN. PHC physicians treating diabetes should be more aware of the importance of screening for PDPN and the treatment plan. PMID- 29386963 TI - Diabetes and health awareness in India. PMID- 29386964 TI - Prevalence and spectrum of functional disability of the urban elderly. PMID- 29386965 TI - Author's reply. PMID- 29386966 TI - The psychology of 'regrettable substitutions': Examining consumer judgements of Bisphenol A and its alternatives. AB - Bisphenol A is a chemical used to make certain types of plastics and is found in numerous consumer products. Because scientific studies have raised concerns about Bisphenol A's potential impact on human health, it has been removed from some (but not all) products. What many consumers do not know, however, is that Bisphenol A is often replaced with other, less-studied chemicals whose health implications are virtually unknown. This type of situation is known as a potential 'regrettable substitution', because the substitute material might actually be worse than the material that it replaces. Regrettable substitutions are a common concern among policymakers, and they are a real-world manifestation of the tension that can exist between the desire to avoid risk (known possible consequences that might or might not occur) and ambiguity (second-order uncertainty), which is itself aversive. In this article we examine how people make such trade-offs using the example of Bisphenol A. Using data from Study 1, we show that people have inconsistent preferences toward these alternatives and that choice is largely determined by irrelevant contextual factors such as the order in which the alternatives are evaluated. Using data from Study 2 we further demonstrate that when people are informed of the presence of substitute chemicals, labeling the alternative product as 'free' of Bisphenol A causes them to be significantly more likely to choose the alternative despite its ambiguity. We discuss the relevance of these findings for extant psychological theories as well as their implications for risk, policy and health communication. PMID- 29386967 TI - The Future Hospital: A Business Architecture View. AB - The future hospital is a resilient, physical learning facility featuring digital enhancement and leveraging an ecosystem of platforms for the Internet of Things (IoT) and analytics, achieving patient-centric care delivery via multidisciplinary healthcare provider teams coordinated to meet patients' medical, psychological, social and economic needs. It exists in a just ecosystem that assimilates the care spectrum from healthy living, the prevention of disease to acute care and the rehabilitation of patients recuperating from illnesses. It will take some time for these future hospitals to be built or for current hospitals to evolve and/or transform, but efforts to spread wisdom among the stakeholders, healthcare providers and patients must start now. The development of the digital components can also begin today, as can competency building for the healthcare providers who will be staffing these future hospitals, ensuring that they are equipped with competent staff employing patient-centric care processes that cater to patients' current and future needs. PMID- 29386968 TI - A Review of Staphylococcal Cassette Chromosome mec (SCCmec) Types in Coagulase Negative Staphylococci (CoNS) Species. AB - Coagulase-negative staphylococci (CoNS) are considered low pathogenic organisms. However, they are progressively causing more serious infections with time because they have adapted well to various antibiotics owing to their ability to form biofilms. Few studies have been conducted on CoNS in both, hospital and community acquired settings, especially in Malaysia. Thus, it is important to study their species and gene distributions. A mobile genetic element, staphylococcal cassette chromosome mec (SCCmec), plays an important role in staphylococci pathogenesis. Among CoNS, SCCmec has been studied less frequently than Staphylococcus aureus (coagulase-positive staphylococci). A recent study (8) conducted in Malaysia successfully detected SCCmec type I to VIII as well as several new combination patterns in CoNS species, particularly Staphylococcus epidermidis. However, data are still limited, and further research is warranted. This paper provides a review on SCCmec types among CoNS species. PMID- 29386969 TI - Nutritional Compositions and Antiproliferative Activities of Different Solvent Fractions from Ethanol Extract of Cyphomandra betacea (Tamarillo) Fruit. AB - Background: This study aims to examine various solvent extracts of Cyphomandra betacea (tamarillo) also known as the tree tomato, for their bioactive constituents and antioxidant activity. The study also aims to examine its effect on cancer cell death using two types of cancer cell lines (liver and breast cancer cell). Methods: The first part of the study evaluates the nutritional composition of tamarillo. Then, phytochemical profiling using GC-MS analysis in ethanolic tamarillo extract was conducted. Different fractions of n-butanol, ethyl acetate and aqueous fractions were obtained from the ethanolic extract of tamarillo. Then, the fractions were subjected to the quantification of total phenol (TPC) and flavonoid contents (TFC), free radical scavenging activity (SA) and also antioxidant activity (AOX) assayed by beta-carotene bleaching (BCB) assay. Finally, the capability of the ethanolic extract of tamarillo and different fractions were evaluated for their anticancer properties. Results: Findings from this study revealed that the nutritional composition (ash, protein, carbohydrate and total dietary fiber), and mineral levels (calcium, magnesium, potassium and iron) of tamarillo were moderate. The crude ethanol extract of tamarillo contained the highest phenolic and total flavonoid content. FT-IR analysis revealed the presence of alkanes, carboxylic acid, phenol, alkanes, carboxylic acids, aromatics and nitro compounds. Twelve bioactive constituents in tamarillo have been identified through GC-MS analysis. Cytotoxic activity suggests the potential of ethanolic extracts of tamarillo having a chemopreventive effect on breast and liver cancer cells. Conclusion: This study reveals that tamarillo has substantial antioxidant activity as well as anticancer properties. PMID- 29386970 TI - Detection of Respiratory Viruses from ARTI Patients by xTAG RVP Fast v2 Assay and Conventional Methods. AB - Introduction: Acute respiratory tract infections (ARTIs) are a major cause of morbidity and mortality in paediatric patients. Therefore, early detection of the viral aetiologies of ARTIs is essential for patient management and infection control. In this study, we evaluated the performance of a new multiplex polymerase chain reaction (PCR) assay (xTAG Respiratory Viral Panel [RVP] Fast v2) in the detection of respiratory viruses by comparing it with that of viral culture and direct immunofluorescence (IF) staining. Methods: Nasopharyngeal swab and aspirate samples were collected prospectively from 199 patients who presented with ARTIs at the University Malaya Medical Centre (UMMC) in Kuala Lumpur, Malaysia during a 10-month period. The PCR assay was conducted in parallel with conventional culture and direct IF staining methods. Results: The positive rate of the xTAG RVP Fast v2 assay (78.4%) in detecting respiratory viruses was higher than that of the viral isolation (7.5%) and direct IF (23.1%) methods. Using the xTAG RVP Fast v2 assay, human enterovirus/human rhinovirus (HEV/HRV) was the most frequently detected (46.2%). The xTAG RVP Fast v2 assay revealed mixed infection caused by two or three respiratory viruses in 40 specimens, and these were undetected by the viral isolation and direct IF methods. Conclusion: The xTAG RVP Fast v2 assay was superior to conventional methods in the identification of common respiratory viruses, with higher sensitivity and shorter turnaround times for laboratory results. PMID- 29386971 TI - Recombinant LipL32 Protein Developed Using a Synthetic Gene Detects Leptospira specific Antibodies in Human Serum Samples. AB - Background: Synthetic biology is emerging as a viable alternative for the production of recombinant antigens for diagnostic applications. It offers a safe alternative for the synthesis of antigenic principles derived from organisms that pose a high biological risk. Methods: Here, we describe an enzyme-linked immunosorbent assay (ELISA) using the synthetic recombinant LipL32 (rLipL32) protein expressed in Escherichia coli for the detection of Leptospira-specific antibodies in human serum samples. The rLipL32-based ELISA was compared with a microscopic agglutination test (MAT), which is currently used as the gold standard for the diagnosis of leptospirosis. Results: Our results showed that all the MAT-positive serum samples were positive for Leptospira-specific IgG in an ELISA, while 65% (n = 13) of these samples were also positive for Leptospira specific IgM. In the MAT-negative serum samples, 80% and 55% of the samples were detected as negative by an ELISA for Leptospira-specific IgM and IgG, respectively. Conclusion: An ELISA using the synthetic rLipL32 antigen was able to distinguish Leptospira-specific IgM (sensitivity 65% and specificity 80%) and IgG (sensitivity 100% and specificity 55%) in human serum samples and has the potential to serve as a rapid diagnostic test for leptospirosis. PMID- 29386972 TI - Planimetric and Biomechanical Study of Local Effect of Pulegone on Full Thickness Wound Healing in Rat. AB - Background: Pulegone as principal component of essential oil, reported to have anti-bacterial, antioxidant and anti-inflammatory properties. The present study was aimed to evaluate wound healing activity of pulegone in a rat model. Method: Forty rats were used for excisional and incisional wound healing models. For each model twenty male white Wistar rats were randomly divided into five groups (n = 4) of control (CG), Sham surgery, E1, E2 and E3. Wound size, hydroxyproline content of wound and biomechanical testing were assessed. Result: In E2 animals, the wound size was reduced earlier than in E1 and E2 groups (P = 0.035). However, time had significant effect on wound contraction of all wounds. Hydroxyproline contents in the groups CG, sham surgery, E1, E2 and E3 were found to be 51.25 +/- 3.40, 58.41 +/- 4.62, 68.59 +/- 3.53, 86.32 +/- 3.18, and 74.26 +/- 4.73 mg g-1, respectively. Hydroxyproline contents were increased significantly in E2 compared to E1 and E3 which implied more collagen deposition compared to other experimental groups (P = 0.001). The biomechanical indices, maximum stored energy, stiffness, ultimate strength and yield strength obtained for E2 group were significantly higher than those obtained for E1 and E2 groups (P = 0.002). Conclusion: The pulegone showed a reproducible wound healing potential in rats. PMID- 29386973 TI - Serum Vascular Endothelial Growth Factor (VEGF) as a Biomarker for Disease Activity in Lupus Nephritis. AB - Background: Previous studies have shown that serum VEGF levels were elevated in patients with active systemic lupus erythematosus (SLE), especially in those with lupus nephritis (LN). In this case control study, we aimed to compare serum levels of VEGF in SLE patients between LN, non-LN and healthy participants to determine the association between serum VEGF levels and the activity and histological classes of lupus nephritis. Methods: Blood samples were obtained from 92 SLE patients (46 LN and 46 non-LN) and 26 controls. Data were collected from medical records. Serum VEGF assays were performed by specific, enzyme-linked immunosorbent assay kits (ELISA). Laboratory investigations included urinalysis, urine protein-creatinine ratio, serum creatinine, albumin and VEGF levels. Blood pressure, renal biopsy result and treatment were recorded. LN activity was evaluated using the renal subscale of the British Isles Lupus Assessment Group (rBILAG, 2004). The rBILAG measures blood pressure (diastolic and systolic), urine protein, serum creatinine, calculated glomerular filtration rate (GFR), presence of active urinary sediments and histological evidence of active nephritis. Results: Serum VEGF was elevated in SLE patients with LN compared with the non-LN group and healthy controls. The levels found were significantly higher in the sera of patients with active nephritis compared to those with quiescent nephritis (P = 0.024). The study did not find a statistically significant relationship between serum VEGF levels and histological classes of LN. Conclusion: There was no significant difference of serum VEGF level between LN and non-LN SLE groups and between the non-LN group and healthy controls. However, there were increased levels of serum VEGF in the LN group, especially in patients with active nephritis as compared to quiescent nephritis group. This reflects the role of VEGF in the pathogenesis of lupus nephritis, however the clinical potential of this biomarker needs further study. PMID- 29386974 TI - Target-controlled Infusion Propofol Versus Sevoflurane Anaesthesia for Emergency Traumatic Brain Surgery: Comparison of the Outcomes. AB - Background: The choice of anaesthetic techniques is important for the outcome of traumatic brain injury (TBI) emergency surgery. The objective of this study was to compare patient outcomes for target-controlled infusion (TCI) of propofol and sevoflurane anaesthesia. Methods: A total of 110 severe TBI patients, aged 18-60, who underwent emergency brain surgery were randomised into Group T (TCI) (n = 55) and Group S (sevoflurane) (n = 55). Anaesthesia was maintained in Group T with propofol target plasma concentration of 3-6 MUg/mL and in Group S with minimum alveolar concentration (MAC) of sevoflurane 1.0-1.5. Both groups received TCI remifentanil 2-8 ng/mL for analgesia. After the surgery, patients were managed in the intensive care unit and were followed up until discharge for the outcome parameters. Results: Demographic characteristics were comparable in both groups. Differences in Glasgow Outcome Scale (GOS) score at discharge were not significant between Group T and Group S (P = 0.25): the percentages of mortality (GOS 1) [27.3% versus 16.4%], vegetative and severe disability (GOS 2-3) [29.1% versus 41.8%] and good outcome (GOS 4-5) [43.6% versus 41.8%] were comparable in both groups. There were no significant differences in other outcome parameters. Conclusion: TCI propofol and sevoflurane anaesthesia were comparable in the outcomes of TBI patients after emergency surgery. PMID- 29386975 TI - Balanced Fluid Versus Saline-Based Fluid in Post-operative Severe Traumatic Brain Injury Patients: Acid-Base and Electrolytes Assessment. AB - Background: Normal saline (NS) is a common fluid of choice in neurosurgery and neuro-intensive care unit (ICU), but it does not contain other electrolytes and has the potential to cause hyperchloremic metabolic acidosis with prolonged infusion. These problems may be reduced with the availability of balanced fluid (BF), which becomes a more physiological isotonic solution with the presence of complete electrolyte content. This study aimed to compare the changes in electrolytes and acid-base between NS and BF (Sterofundin(r) ISO) therapy for post-operative severe traumatic brain injury (TBI) patients in neuro-ICU. Methods: Sixty-six severe TBI patients who required emergency craniotomy or craniectomy and were planned for post-operative ventilation were randomised into NS (n = 33) and BF therapy groups (n = 33). The calculation of maintenance fluid given was based on the Holliday-Segar method. The electrolytes and acid-base parameters were assessed at an 8 h interval for 24 h. The data were analysed using repeated measures ANOVA. Results: The NS group showed a significant lower base excess (-3.20 versus -1.35, P = 0.049), lower bicarbonate level (22.03 versus 23.48 mmol/L, P = 0.031), and more hyperchloremia (115.12 versus 111.74 mmol/L, P < 0.001) and hypokalemia (3.36 versus 3.70 mmol/L, P < 0.001) than the BF group at 24 h of therapy. The BF group showed a significantly higher level of calcium (1.97 versus 1.79 mmol/L, P = 0.003) and magnesium (0.94 versus 0.80 mmol/L, P < 0.001) than the NS group at 24 h of fluid therapy. No significant differences were found in pH, pCO2, lactate, and sodium level. Conclusion: BF therapy showed better effects in maintaining higher electrolyte parameters and reducing the trend toward hyperchloremic metabolic acidosis than the NS therapy during prolonged fluid therapy for postoperative TBI patients. PMID- 29386976 TI - Comparison between Sialendoscopy and Conventional Methods in the Treatment of Sialolithiasis. AB - Background: Sialendoscopy is gaining in popularity in treating calculus disease. The delicacy of the instrument and the diameter of the salivary ducts are factors that limit the ability to achieve complete success. There is also continued speculation regarding the utility of the procedure, especially among clinicians who are masters of conventional methods like sialadenectomy and sialodochotomy. Objective: To assess the efficacy of sialendoscopy over conventional methods in treating sialolithiasis. Methods: A prospective case control study was conducted in a tertiary care centre; this study involved 50 patients of sialolithiasis, and it extended over a 36-month period. All had undergone treatment, either by conventional methods or interventional sialendoscopy. All patients with nonpalpable calculi smaller than 6 mm underwent interventional sialendoscopy. Failed sialendoscopies and larger nonpalpable calculi were removed through sialadenectomy. The outcome variables studied included calculus removal, postoperative symptoms, and gland preservation. Results: The success rate in terms of calculus removal by sialendoscopy was 88%, versus 100% by sialadenectomy. The salivary gland was preserved in 88% of the cases in the sialendoscopy group. Only 12% of patients were symptomatic. Conclusion: Sialendoscopy was effective in removing calculi of various sizes; it was definitely superior to conventional methods. Sialadenectomy should be reserved for cases either not suitable for sialendoscopy or in which there was an intervention failure. PMID- 29386977 TI - Sample Size Calculation in Animal Studies Using Resource Equation Approach. AB - Animal research plays an important role in the pre-clinical phase of clinical trials. In animal studies, the power analysis approach to sample size calculation is recommended. Whenever it is not possible to assume the standard deviation and the effect size, an alternative to the power analysis approach is the 'resource equation' approach, which sets the acceptable range of the error degrees of freedom (DF) in an analysis of variance (ANOVA). The aim of this article is to guide researchers in calculating the minimum and maximum numbers of animals required in animal research by reformulating the error DF formulas. PMID- 29386978 TI - Provision of Prosthetic Services Following Lower Limb Amputation in Malaysia. AB - The incidence of lower limb amputation is high across the globe and continues to be a major threat to morbidity and mortality. Consequently, the provision of high quality and effective prosthetics services have been known as an essential component for a successful rehabilitation outcome. In Malaysia, amputation prevalence has been increasing in which several main components of service delivering aspects (such as service intervention, prosthetic personnel) should be anticipated to accommodate for the increasing demand. This article highlights the hurdles experienced in providing prosthetic services in Malaysia from multiple aspects such as financial burden to acquire the prosthesis and lack of expertise to produce quality prosthesis. This paramount issues consequently justify for the urgency to carry out national level survey on the current statistics of lower limb amputation and to ascertain the available workforce to provide a quality prosthetics services. Only with accurate and current information from the national survey, strategies and policies aimed at enhancing the outcome from prosthetics services can be achieved. PMID- 29386979 TI - A Comparison of Ultrasonography, Computerised Tomography, and Conventional MRI Findings for Splenic Nodules Associated with Type 1 Gaucher's Disease with Diffusion-Weighted MRI Findings. AB - A 26-year-old female patient with Type 1 Gaucher's disease (GD) was admitted to our clinic with complaints of stomachache and signs of anemia. The patient underwent ultrasonography (US), computerised tomography (CT), and magnetic resonance imaging (MRI) scan. Imaging studies revealed massive hepatosplenomegaly, choledocolithiasis, and six nodules in the spleen with a mean size of 14 mm. The nodules appeared hyperechoic, hypoechoic, and of mixed echogenicity on the US and hypodense on the CT. While the nodules were observed to be iso-hypointense in T1-weighted (T1WI) images, they appeared to be hyperintense in the T2-weighted (T2WI) images. There were no diffusion restrictions in these nodules that appeared on the diffusion-weighted magnetic resonance imaging (DWI). A nodule located at the lower pole was observed to be hypointense in the T2WI images. The nodule located at the lower pole, which appeared hypointense in T2WI series, had restricted diffusion upon DWI. In this study, we aimed to present the properties of splenic GD nodules using US, CT, and conventional MRI, together with DWI. This case report is the first to apply US, CT, and conventional MRI, together with DWI, to the splenic nodules associated with Gaucher's disease. PMID- 29386980 TI - Rare Clinical Presentation of Tuberculous Meningitis: A Case Report. AB - Introduction: Tuberculosis is the second leading cause of death under the category of infectious diseases, after the human immunodeficiency virus (HIV). Tuberculous meningitis (TBM) constitutes about 5% of all extrapulmonary disease worldwide. This report describes a case of Tuberculous meningitis with rare presentation in a 28-year-old woman, who was treated based on a collection of her social background, clinical findings and Multiplex PCR of tuberculosis. Case presentation: A 28-year-old Malay woman with no significant medical history presented to HUSM with one month history of on and off fever, two weeks history of generalised limbs weakness and one week history of dysphagia. She was reported to have experienced visual hallucination and significant weight loss. Her laboratory result is significant for leukocytosis, elevated ESR and hypernatremia. Non-enhanced and contrast CT scan of the brain showed severe bilateral frontal cerebral atrophy. Cerebral spinal fluid (CSF) for multiplex PCR for Mycobacterium tuberculosis complex was positive. She was promptly started on anti-TB regime combined with dexamethasone. Subsequent follow-up showed significant improvement. Conclusion: This is a rare clinical manifestation of Tuberculous meningitis that demonstrates the importance of recognising and initiating the treatment early to reduce disabilities and improve clinical outcome. PMID- 29386981 TI - [Income and assets of the middle and old age Mexican population]. AB - The purpose of this article is to describe the amount and types of income and assets that the middle and old age population receive and own in Mexico. We use data from the Mexican Health and Aging Study (MHAS) 2001; a prospective panel study with national representation of individuals aged 50 and older. The results confirm the hypotheses of the paper: that the distributions of income and wealth are biased in favor of certain groups, in particular those highly educated; that the majority of the wealth of individuals is in non-financial form; that family help is an important source of income; and that the association between wealth and health is positive in general, which is consistent with the international literature for other countries. In addition, we find that wealth is more equitably distributed than income. We conclude that the wealth indicator offers an additional dimension of analysis than income, with potential to contribute to studies of well-being of the population of middle and old age in Mexico. PMID- 29386983 TI - Is healthcare providers' value-neutrality depending on how controversial a medical intervention is? Analysis of 10 more or less controversial interventions. AB - Background: Swedish healthcare providers are supposed to be value-neutral when making clinical decisions. Recent conducted studies among Swedish physicians have indicated that the proportion of those whose personal values influence decision making (the value-influenced) vary depending on the framing and the nature of the issue. Objective: To examine whether the proportions of value-influenced and value-neutral participants vary depending on the extent to which the intervention is considered controversial. Methods: To discriminate between value-neutral and value-influenced healthcare providers, we have used the same methods in six vignette based studies including 10 more or less controversial interventions. To be controversial was understood as being an intervention where conscientious objections in healthcare have been proposed or an intervention that is against law and regulations. Results: End of life decisions and female reproduction issues are associated with conscientious objection and more or less against regulations, and also resulted in the highest proportions of value-influenced participants. Following routines, which is not in conflict with official values, were associated with one of the lowest proportion of value-influenced participants. The difference between the highest and lowest proportions of value influenced participants among the 10 examined interventions was significant (81.8% (95% confidence interval: 78.1-85.5) versus 34.7% (95% confidence interval: 29.2-40.2)). Conclusion: The study indicates that the proportions of value-neutral participants decrease the more controversial an issue is, and vice versa. In some cases, however, framing effects may potentiate or obscure this association. As a bold hypothesis, we suggest the proportion of value-neutral or value-influenced might indicate how controversial an issue is. PMID- 29386982 TI - Generic quality of life in persons with hearing loss: a systematic literature review. AB - Background: To the best of our knowledge, no empirically based consensus has been reached as to if, and to what extent, persons with hearing loss (HL) have reduced generic Quality of life (QoL). There seems to be limited knowledge regarding to what extent a hearing aid (HA) would improve QoL. The main aim of the present study was to review studies about the relationship between HL and QoL. A supporting aim was to study the association between distress and HL. Methods: Literature databases (Cinahl, Pub Med and Web of Science) were searched to identify relevant journal articles published in the period from January 2000 to March 17, 2016. We performed a primary search pertaining to the relationship between HL, HA and QoL (search number one) followed by a supporting search pertaining to the relationship between distress/mood/anxiety and HL (search number two). After checking for duplications and screening the titles of the papers, we read the abstracts of the remaining papers. The most relevant papers were read thoroughly, leaving us with the journal articles that met the inclusion criteria. Results: Twenty journal articles were included in the present review: 13 were found in the primary search (HL and QoL), and seven in the supporting search (HL and distress). The literature yields equivocal findings regarding the association between generic QoL and HL. A strong association between distress and HL was shown, where distressed persons tend to have a lowered generic QoL. It is suggested that QoL is lowered among HL patients. Some studies suggest an increased generic QoL following the use of HA, especially during the first few months after initiation of treatment. Other studies suggest that HA use is one of several possible factors that contribute to improve generic QoL. Conclusions: The majority of the studies suggest that HL is associated with reduced generic QoL. Using hearing aids seem to improve general QoL at follow-up within the first year. HL is a risk factor for distress. Further research is needed to explore the relationship between HL and generic QoL, in addition to the importance of influencing variables on this relationship. PMID- 29386984 TI - Personalized medicine in colorectal cancer diagnosis and treatment: a systematic review of health economic evaluations. AB - Background: Due to its epidemiological relevance, several studies have been performed to assess the cost-effectiveness of diagnostic tests and treatments in colorectal cancer (CRC) patients. Objective: We reviewed economic evaluations on diagnosis of inherited CRC-syndromes and genetic tests for the detection of mutations associated with response to therapeutics. Methods: A systematic literature review was performed by searching the main literature databases for relevant papers on the field, published in the last 5 years. Results: 20 studies were included in the final analysis: 14 investigating the cost-effectiveness of hereditary-CRC screening; 5 evaluating the cost-effectiveness of KRAS mutation assessment before treatment; and 1 study analysing the cost-effectiveness of genetic tests for early-stage CRC patients prognosis. Overall, we found that: (a) screening strategies among CRC patients were more effective than no screening; (b) all the evaluated interventions were cost-saving for certain willingness-to pay (WTP) threshold; and (c) all new CRC patients diagnosed at age 70 or below should be screened. Regarding patients treatment, we found that KRAS testing is economically sustainable only if anticipated in patients with non-metastatic CRC (mCRC), while becoming unsustainable, due to an incremental cost-effectiveness ratio (ICER) beyond the levels of WTP-threshold, in all others evaluated scenarios. Conclusions: The poor evidence in the field, combined to the number of assumptions done to perform the models, lead us to a high level of uncertainty on the cost-effectiveness of genetic evaluations in CRC, suggesting that major research is required in order to assess the best combination among detection tests, type of genetic test screening and targeted-therapy. PMID- 29386985 TI - Co(II) Coordination in Prokaryotic Zinc Finger Domains as Revealed by UV-Vis Spectroscopy. AB - Co(II) electronic configuration allows its use as a spectroscopic probe in UV-Vis experiments to characterize the metal coordination sphere that is an essential component of the functional structure of zinc-binding proteins and to evaluate the metal ion affinities of these proteins. Here, exploiting the capability of the prokaryotic zinc finger to use different combinations of residues to properly coordinate the structural metal ion, we provide the UV-Vis characterization of Co(II) addition to Ros87 and its mutant Ros87_C27D which bears an unusual CysAspHis2 coordination sphere. Zinc finger sites containing only one cysteine have been infrequently characterized. We show for the CysAspHis2 coordination an intense d-d transition band, blue-shifted with respect to the Cys2His2 sphere. These data complemented by NMR and CD data demonstrate that the tetrahedral geometry of the metal site is retained also in the case of a single-cysteine coordination sphere. PMID- 29386986 TI - Choline Triggers Exacerbations of Chronic Obstructive Pulmonary Disease in Patients Infected with Pseudomonas aeruginosa. AB - Background: Although exacerbations of chronic obstructive pulmonary disease produced by Pseudomonas aeruginosa infections are a major cause of death, the molecular mechanism that produces them is not well known. Here we focused on the energetic basis of dyspnoea, hypercapnia and acidosis symptoms. Methods and Findings: We used an in vivo exacerbation model exposing mice to cigarette smoke and LPS, to mimic emphysema and infections, and choline challenges to trigger exacerbations, that showed 31% increased in the airway resistance for naive mice and 250% for smoke/LPS treatment. Tissue resistance was increased 32%, in naive mice, and 169% for smoke/LPS treatment. A decreased tissue elastance, was confirmed by decreased collagen content and increased alveoli chord length. Consequently, the O2 demanded was 260% greater for smoke/LPS treated mice, to provide the energy required to pump the same volume of air then for naive mice. The extra CO2 produced per ml of air pumped caused hypercapnia and acidosis by 4% decrease in pH.In addition, the bacteria grown with choline had a decrease of 67% in phosphate, 23% ATP and 85% phospholipids with an increase of 57% in polyphosphates, 50% carbohydrates, 100% LPS, consuming 45% less energy relative to the bacteria grown with succinate. Conclusion: choline, released by P. aeruginosa, triggers exacerbation symptoms by increasing lung resistance, O2 consumption and producing more pCO2 in blood with dyspnea, hypercapnia and acidosis. The energetic shift of decreased O2 bacterial demand and increased lung demand benefits the infection, thus restoring the energetic balance on the host will favor P. aeruginosa eradication. PMID- 29386987 TI - Safety aspects of hysteroscopy, specifically in relation to entry and specimen retrieval: a UK survey of practice. AB - Background: The purpose of this study is to evaluate current practice amongst gynaecologists across the UK, regarding safety aspects of inpatient hysteroscopy under anaesthesia, specifically in relation to entry and specimen retrieval.A survey was created using survey monkey. The first round was circulated to all registrar trainees and consultant gynaecologists across Wales. Following a good response, the survey was then circulated to all members of the British Society of Gynaecological Endoscopy (BSGE). Results: There were 212 responses including, 140 consultants, 36 senior registrars, 17 junior registrars and 18 clinical nurse specialists. In total, 136 out of 212 (64.7%) always perform a vaginal examination prior to hysteroscopy. 10.4% always sound the uterus, and 5.2% always dilate the uterus prior to insertion of the hysteroscope. Twenty-three consultants, six senior registrars, three junior registrars and one clinical nurse specialist knew how to position the internal cervical os as visualised through the scope when using a 30 degrees hysteroscope. 35.8% of candidates always perform a post-procedure cavity check, and 9% use suction to flush the cavity to aid vision during the post-procedure cavity check. The majority (76%) predicted dilatation as the stage most likely to cause uterine perforation and predicted the most likely site for perforation as the posterior uterine wall in the anteverted uterus and the anterior uterine wall in the retroverted uterus. Conclusion: This study highlights varied practice across the UK regarding safety aspects of hysteroscopy, in relation to entry and specimen retrieval. There is a need for increased awareness of the risks of hysteroscopy and paramount precautions that should be performed routinely as part of their practice. Standardised guidelines may be a beneficial tool to help bring about this change in practice, leading to a reduction in uterine perforation rates. PMID- 29386988 TI - Clinical characteristic and intraoperative findings of uterine perforation patients in using of intrauterine devices (IUDs). AB - Background: Intrauterine devices (IUDs) are the most popular form of contraception used worldwide; however, IUD is not risk-free. IUD migrations, especially uterine perforations, were frequently occurred in patients. The aim of this study was to investigate the clinical characteristics and intraoperative findings in patients with migrated IUDs. Results: 29 cases of uterine perforation associated with migrated IUDs and 69 control patients were followed between January 2008 to March 2015. Patients who used IUDs within first 6 months from the last delivery experienced a characteristically high rate of the perforation of the uterine wall. A significantly larger number of IUD insertion associated with uterine perforation were performed in rural hospitals or operated at a lower level health care system. There was no clear difference in the age and presented symptoms in patients between two groups. Majority of contraceptive intrauterine devices was the copper-releasing IUDs. Furthermore, patients who used V-shaped IUD showed significantly higher incidence of pelvic adhesions when compared with the users of O-shaped IUDs. Conclusions: Unique clinical characteristics of IUD migration were identified in patients with uterine perforation. Hysteroscopy and/or laparoscopy were the effective approaches to remove the migrated IUDs. Improving operating skills is required at the lower level of health care system. PMID- 29386989 TI - Cadaveric surgery in core gynaecology training: a feasibility study. AB - Background: Fresh frozen cadaver training has been proposed as a better model than virtual reality simulators in laparoscopy training. We aimed to explore the relationship between cadaveric surgical training and increased surgical confidence.To determine feasibility, we devised two 1-day cadaveric surgical training days targeted at trainees in obstetrics and gynaecology. Seven defined surgical skills were covered during the course of the day. The relationship between surgical training and surgical confidence was explored using both quantitative (confidence scores) and qualitative tools (questionnaires). Results: Participants rated a consistent improvement in their level of confidence after the training. They universally found the experience positive and three overarching themes emerged from the qualitative analysis including self-concept, social persuasion and stability of task. Conclusions: It is pragmatically feasible to provide procedure-specific cadaveric surgical training alongside supervised clinical training. This small, non-generalisable study suggests that cadaveric training may contribute to an increase in surgical self-confidence and efficacy. This will form the basis of a larger study and needs to be explored in more depth with a larger population. PMID- 29386990 TI - Evolution of pollen morphology in Loranthaceae. AB - Earlier studies indicate a strong correlation of pollen morphology and ultrastructure with taxonomy in Loranthaceae. Using high-resolution light microscopy and scanning electron microscopy imaging of the same pollen grains, we document pollen types of 35 genera including 15 studied for the first time. Using a molecular phylogenetic framework based on currently available sequence data with good genus-coverage, we reconstruct trends in the evolution of Loranthaceae pollen and pinpoint traits of high diagnostic value, partly confirming earlier intuitive hypotheses based on morphological observations. We find that pollen morphology in Loranthaceae is strongly linked to phylogenetic relationships. Some pollen types are diagnostic for discrete genera or evolutionary lineages, opening the avenue to recruit dispersed fossil pollen as age constraints for dated phylogenies and as independent data for testing biogeographic scenarios; so far based exclusively on modern-day data. Correspondences and discrepancies between palynological and molecular data and current taxonomic/systematic concepts are identified and suggestions made for future palynological and molecular investigations of Loranthaceae. PMID- 29386991 TI - A Whole Brain Staining, Embedding, and Clearing Pipeline for Adult Zebrafish to Visualize Cell Proliferation and Morphology in 3-Dimensions. AB - The field of macro-imaging has grown considerably with the appearance of innovative clearing methods and confocal microscopes with lasers capable of penetrating increasing tissue depths. The ability to visualize and model the growth of whole organs as they develop from birth, or with manipulation, disease or injury, provides new ways of thinking about development, tissue-wide signaling, and cell-to-cell interactions. The zebrafish (Danio rerio) has ascended from a predominantly developmental model to a leading adult model of tissue regeneration. The unmatched neurogenic and regenerative capacity of the mature central nervous system, in particular, has received much attention, however tools to interrogate the adult brain are sparse. At present there exists no straightforward methods of visualizing changes in the whole adult brain in 3 dimensions (3-D) to examine systemic patterns of cell proliferation or cell populations of interest under physiological, injury, or diseased conditions. The method presented here is the first of its kind to offer an efficient step-by-step pipeline from intraperitoneal injections of the proliferative marker, 5-ethynyl 2'-deoxyuridine (EdU), to whole brain labeling, to a final embedded and cleared brain sample suitable for 3-D imaging using optical projection tomography (OPT). Moreover, this method allows potential for imaging GFP-reporter lines and cell specific antibodies in the presence or absence of EdU. The small size of the adult zebrafish brain, the highly consistent degree of EdU labeling, and the use of basic clearing agents, benzyl benzoate, and benzyl alcohol, makes this method highly tractable for most laboratories interested in understanding the vertebrate central nervous system in health and disease. Post-processing of OPT-imaged adult zebrafish brains injected with EdU illustrate that proliferative patterns in EdU can readily be observed and analyzed using IMARIS and/or FIJI/IMAGEJ software. This protocol will be a valuable tool to unlock new ways of understanding systemic patterns in cell proliferation in the healthy and injured brain, brain wide cellular interactions, stem cell niche development, and changes in brain morphology. PMID- 29386992 TI - Intracerebroventricular Administration of 192IgG-Saporin Alters Expression of Microglia-Associated Genes in the Dorsal But Not Ventral Hippocampus. AB - One of important aspects of development of Alzheimer's disease is degeneration of septal cholinergic neurons that innervate the hippocampus. We took advantage of widely used model of cholinergic deficit in the hippocampus, intracerebroventricular administration of 192IgG-saporin (Ig-saporin), to analyze the postponed consequences of cholinergic deficit in different parts of the hippocampus. We studied effects of the immunotoxin on the behavior of rats and gene expression in the dorsal and ventral hippocampus using RNA-seq approach. We found that under normal conditions dorsal and ventral parts of the hippocampus differ in the expression of 1129 protein-coding genes and 49 non-coding RNAs (ncRNAs) and do not differ in the expression of 10 microRNAs, which were detected in both parts of the hippocampus. Ig-saporin-induced degeneration of cholinergic septal neurons did not affect rat behavior in open field, T-maze, and passive avoidance task but impaired memory retention in Morris water maze. To analyze 192Ig-saporin-induced changes in the gene expression, we formed the following groups of genes: genes expressed exclusively in certain cell types (neurons, astrocytes, microglia, oligodendrocytes, and vascular cells) and, among universally expressed genes, a group of genes that encode ribosome-forming proteins. For all groups of genes, the alterations in the gene expression produced by the immunotoxin were stronger in the dorsal as compared to the ventral hippocampus. We found that, among groups of universally expressed genes, Ig-saporin increased the expression of ribosome-forming proteins in both dorsal and ventral hippocampus. Ig-saporin also strongly upregulated expression of microglia-specific genes only in the dorsal hippocampus. A subset of affected microglial genes comprised genes associated with inflammation, however, did not include genes related to acute inflammation such as interleukins-1b, -6, -15, and -18 as well as TNF. The expression of other cell-specific genes (genes specific for neurons, astrocytes, oligodendrocytes, and vascular cells) was unaffected. The data obtained suggest that disturbance of memory-associated behavior after administration of Ig-saporin is associated with upregulation of microglia associated genes in the dorsal but not ventral hippocampus. PMID- 29386993 TI - Glycine Receptor Activation Impairs ATP-Induced Calcium Transients in Cultured Cortical Astrocytes. AB - In central nervous system, glycine receptor (GlyR) is mostly expressed in the spinal cord and brainstem, but glycinergic transmission related elements have also been identified in the brain. Astrocytes are active elements at the tripartite synapse, being responsible for the maintenance of brain homeostasis and for the fine-tuning of synaptic activity. These cells communicate, spontaneously or in response to a stimulus, by elevations in their cytosolic calcium (calcium transients, Ca2+T) that can be propagated to other cells. How these Ca2+T are negatively modulated is yet poorly understood. In this work, we evaluated GlyR expression and its role on calcium signaling modulation in rat brain astrocytes. We first proved that GlyR, predominantly subunits alpha2 and beta, was expressed in brain astrocytes and its localization was confirmed in the cytoplasm and astrocytic processes by immunohistochemistry assays. Calcium imaging experiments in cultured astrocytes showed that glycine (500 MUM), a GlyR agonist, caused a concentration-dependent reduction in ATP-induced Ca2+T, an effect abolished by the GlyR antagonist, strychnine (0.8 MUM), as well as by nocodazole (1 MUM), known to impair GlyR anchorage to the plasma membrane. This effect was mimicked by activation of GABAAR, another Cl--permeable channel. In summary, we demonstrated that GlyR activation in astrocytes mediates an inhibitory effect upon ATP induced Ca2+T, which most probably involves changes in membrane permeability to Cl- and requires GlyR anchorage at the plasma membrane. GlyR in astrocytes may thus be part of a mechanism to modulate astrocyte-to neuron communication. PMID- 29386995 TI - Zinc Binding to S100B Affords Regulation of Trace Metal Homeostasis and Excitotoxicity in the Brain. AB - Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is associated with aging, Alzheimer's disease (AD), motor neuron disease and traumatic brain injury (TBI). Despite gained insights on the structure of S100B, it remains unclear how its calcium and zinc binding properties regulate its function on cellular level. Here we report a novel role of S100B in trace metal homeostasis, in particular the regulation of zinc levels in the brain. Our results show that S100B at increased extracellular levels is not toxic, persists at high levels, and is taken up into neurons, as shown by cell culture and biochemical analysis. Combining protein bioimaging and zinc quantitation, along with a zinc-binding impaired S100B variant, we conclude that S100B effectively scavenges zinc ions through specific binding, resulting in a redistribution of the intracellular zinc pool. Our results indicate that scavenging of zinc by increased levels of S100B affects calcium levels in vitro. Thereby S100B is able to mediate the cross talk between calcium and zinc homeostasis. Further, we investigated a possible new neuro-protective role of S100B in excitotoxicity via its effects on calcium and zinc homeostasis. Exposure of cells to zinc-S100B but not the zinc-binding impaired S100B results in an inhibition of excitotoxicity. We conclude that in addition to its known functions, S100B acts as sensor and regulator of elevated zinc levels in the brain and this metal-buffering activity is tied to a neuroprotective role. PMID- 29386997 TI - Functional Roles of Astrocyte Calcium Elevations: From Synapses to Behavior. AB - Astrocytes are fundamental players in the regulation of synaptic transmission and plasticity. They display unique morphological and phenotypical features that allow to monitor and to dynamically respond to changes. One of the hallmarks of the astrocytic response is the generation of calcium elevations, which further affect downstream cellular processes. Technical advances in the field have allowed to spatially and to temporally quantify and qualify these elevations. However, the impact on brain function remains poorly understood. In this review, we discuss evidences of the functional impact of heterogeneous astrocytic calcium events in several brain regions, and their consequences in synapses, circuits, and behavior. PMID- 29386996 TI - Mitochondrial Division Inhibitor 1 (mdivi-1) Protects Neurons against Excitotoxicity through the Modulation of Mitochondrial Function and Intracellular Ca2+ Signaling. AB - Excessive dynamin related protein 1 (Drp1)-triggered mitochondrial fission contributes to apoptosis under pathological conditions and therefore it has emerged as a promising therapeutic target. Mitochondrial division inhibitor 1 (mdivi-1) inhibits Drp1-dependent mitochondrial fission and is neuroprotective in several models of brain ischemia and neurodegeneration. However, mdivi-1 also modulates mitochondrial function and oxidative stress independently of Drp1, and consequently the mechanisms through which it protects against neuronal injury are more complex than previously foreseen. In this study, we have analyzed the effects of mdivi-1 on mitochondrial dynamics, Ca2+ signaling, mitochondrial bioenergetics and cell viability during neuronal excitotoxicity in vitro. Time lapse fluorescence microscopy revealed that mdivi-1 blocked NMDA-induced mitochondrial fission but not that triggered by sustained AMPA receptor activation, showing that mdivi-1 inhibits excitotoxic mitochondrial fragmentation in a source specific manner. Similarly, mdivi-1 strongly reduced NMDA-triggered necrotic-like neuronal death and, to a lesser extent, AMPA-induced toxicity. Interestingly, neuroprotection provided by mdivi-1 against NMDA, but not AMPA, correlated with a reduction in cytosolic Ca2+ ([Ca2+]cyt) overload and calpain activation indicating additional cytoprotective mechanisms. Indeed, mdivi-1 depolarized mitochondrial membrane and depleted ER Ca2+ content, leading to attenuation of mitochondrial [Ca2+] increase and enhancement of the integrated stress response (ISR) during NMDA receptor activation. Finally, lentiviral knockdown of Drp1 did not rescue NMDA-induced mitochondrial fission and toxicity, indicating that neuroprotective activity of mdivi-1 is Drp1-independent. Together, these results suggest that mdivi-1 induces a Drp1-independent protective phenotype that prevents predominantly NMDA receptor-mediated excitotoxicity through the modulation of mitochondrial function and intracellular Ca2+ signaling. PMID- 29386998 TI - Activation of Group II Metabotropic Glutamate Receptors Suppresses Excitability of Mouse Main Olfactory Bulb External Tufted and Mitral Cells. AB - Metabotropic glutamate receptors (mGluRs) are abundantly expressed in the rodent main olfactory bulb. The function of Group I mGluRs has been investigated in a number of studies, while the actions of Group II mGluRs, which include the mGluR2 and mGluR3 subtypes, have been less well explored. Here, we used electrophysiological approaches in mouse olfactory bulb slices to investigate how Group II mGluR activation and inactivation modifies the activity of external tufted (ET) and mitral cells. The Group II mGluR agonist DCG-IV was found to directly and uniformly reduce the spontaneous discharge of ET and mitral cells. The inhibitory effect of DCG-IV was absent in mitral cells with truncated apical dendrites, indicating a glomerular site of action. DCG-IV did not influence olfactory nerve-evoked monosynaptic responses in ET or mitral cells, indicating that Group II mGluRs do not presynaptically modulate glutamate release from olfactory nerve terminals. In contrast, DCG-IV suppressed polysynaptic responses in periglomerular cells evoked by olfactory nerve stimulation. DCG-IV also inhibited glutamate release from ET cells, and suppressed the spontaneous and olfactory nerve-evoked long-lasting depolarization in mitral cells. Applied alone, Group II receptor antagonists were without effect, suggesting that basal activation of these receptors is nil. These findings suggest that Group II mGluRs inhibit ET and mitral cell activity and further dampen intraglomerular excitatory circuits by suppressing glutamate release. PMID- 29386999 TI - Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by beta hydroxybutyrate. AB - Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing beta hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA 29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 MUM Abeta25-35-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 MUM Abeta25-35-exposed cells, which were all reversed by beta-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 MUM Abeta25-35-exposed cells by beta-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 MUM Abeta25-35. Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3 silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through beta-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of beta hydroxybutyrate on microRNA-29a expression. PMID- 29387000 TI - Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice. AB - Intermittent fasting (IF) was suggested to be a powerful nutritional strategy to prevent the onset of age-related neurodegenerative diseases associated with compromised brain bioenergetics. Whether the application of IF in combination with a mitochondrial insult could buffer the neurodegenerative process has never been explored yet. Herein, we defined the effects of IF in C57BL/6J mice treated once per 24 h with rotenone (Rot) for 28 days. Rot is a neurotoxin that inhibits the mitochondrial complex I and causes dopamine neurons degeneration, thus reproducing the neurodegenerative process observed in Parkinson's disease (PD). IF (24 h alternate-day fasting) was applied alone or in concomitance with Rot treatment (Rot/IF). IF and Rot/IF groups showed the same degree of weight loss when compared to control and Rot groups. An accelerating rotarod test revealed that only Rot/IF mice have a decreased ability to sustain the test at the higher speeds. Rot/IF group showed a more marked decrease of dopaminergic neurons and increase in alpha-synuclein (alpha-syn) accumulation with respect to Rot group in the substantia nigra (SN). Through lipidomics and metabolomics analyses, we found that in the SN of Rot/IF mice a significant elevation of excitatory amino acids, inflammatory lysophospholipids and sphingolipids occurred. Collectively, our data suggest that, when applied in combination with neurotoxin exposure, IF does not exert neuroprotective effects but rather exacerbate neuronal death by increasing the levels of excitatory amino acids and inflammatory lipids in association with altered brain membrane composition. PMID- 29386994 TI - Astroglial Glutamate Signaling and Uptake in the Hippocampus. AB - Astrocytes have long been regarded as essentially unexcitable cells that do not contribute to active signaling and information processing in the brain. Contrary to this classical view, it is now firmly established that astrocytes can specifically respond to glutamate released from neurons. Astrocyte glutamate signaling is initiated upon binding of glutamate to ionotropic and/or metabotropic receptors, which can result in calcium signaling, a major form of glial excitability. Release of so-called gliotransmitters like glutamate, ATP and D-serine from astrocytes in response to activation of glutamate receptors has been demonstrated to modulate various aspects of neuronal function in the hippocampus. In addition to receptors, glutamate binds to high-affinity, sodium dependent transporters, which results in rapid buffering of synaptically-released glutamate, followed by its removal from the synaptic cleft through uptake into astrocytes. The degree to which astrocytes modulate and control extracellular glutamate levels through glutamate transporters depends on their expression levels and on the ionic driving forces that decrease with ongoing activity. Another major determinant of astrocytic control of glutamate levels could be the precise morphological arrangement of fine perisynaptic processes close to synapses, defining the diffusional distance for glutamate, and the spatial proximity of transporters in relation to the synaptic cleft. In this review, we will present an overview of the mechanisms and physiological role of glutamate induced ion signaling in astrocytes in the hippocampus as mediated by receptors and transporters. Moreover, we will discuss the relevance of astroglial glutamate uptake for extracellular glutamate homeostasis, focusing on how activity-induced dynamic changes of perisynaptic processes could shape synaptic transmission at glutamatergic synapses. PMID- 29387001 TI - Rosuvastatin Improves Neurite Outgrowth of Cortical Neurons against Oxygen Glucose Deprivation via Notch1-mediated Mitochondrial Biogenesis and Functional Improvement. AB - Neurogenesis, especially neurite outgrowth is an essential element of neuroplasticity after cerebral ischemic injury. Mitochondria may supply ATP to power fundamental developmental processes including neuroplasticity. Although rosuvastatin (RSV) displays a potential protective effect against cerebral ischemia, it remains unknown whether it modulates mitochondrial biogenesis and function during neurite outgrowth. Here, the oxygen-glucose deprivation (OGD) model was used to induce ischemic injury. We demonstrate that RSV treatment significantly increases neurite outgrowth in cortical neurons after OGD-induced damage. Moreover, we show that RSV reduces the generation of reactive oxygen species (ROS), protects mitochondrial function, and elevates the ATP levels in cortical neurons injured by OGD. In addition, we found that, under these conditions, RSV treatment increases the mitochondrial DNA (mtDNA) content and the mRNA levels of mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF-1). Furthermore, blocking Notch1, which is expressed in primary cortical neurons, reverses the RSV-dependent induction of mitochondrial biogenesis and function under OGD conditions. Collectively, these results suggest that RSV could restore neurite outgrowth in cortical neurons damaged by OGD in vitro, by preserving mitochondrial function and improving mitochondrial biogenesis, possibly through the Notch1 pathway. PMID- 29387002 TI - Evidence for Plastic Processes in Migraine with Aura: A Diffusion Weighted MRI Study. AB - Background: Formerly white matter abnormalities in a mixed group of migraine patients with and without aura were shown. Here, we aimed to explore white matter alterations in a homogeneous group of migraineurs with aura and to delineate possible relationships between white matter changes and clinical variables. Methods: Eighteen patients with aura, 25 migraine patients without aura and 28 controls were scanned on a 1.5T MRI scanner. Diffusivity parameters of the white matter were estimated and compared between patients' groups and controls using whole-brain tract-based spatial statistics. Results: Decreased radial diffusivity (p < 0.036) was found bilaterally in the parieto-occipital white matter, the corpus callosum, and the cingular white matter of migraine with aura (MwA) patients compared to controls. Migraine without aura (MwoA) patients showed no alteration compared to controls. MwA compared to MwoA showed increased fractional anisotropy (p < 0.048) in the left parieto-occipital white matter. In MwA a negative correlation was found between axial diffusivity and disease duration in the left superior longitudinal fascicle (left parieto-occipital region) and in the left corticospinal tract (p < 0.036) and with the number of the attacks in the right superior longitudinal fascicle (p < 0.048). Conclusion: We showed for the first time that there are white matter microstructural differences between these two subgroups of migraine and hence it is important to handle the two groups separately in further researches. We propose that degenerative and maladaptive plastic changes coexist in the disease and the diffusion profile is a result of these processes. PMID- 29387003 TI - Weak but Critical Links between Primary Somatosensory Centers and Motor Cortex during Movement. AB - Motor performance is improved by stimulation of the agonist muscle during movement. However, related brain mechanisms remain unknown. In this work, we perform a functional magnetic resonance imaging (fMRI) study in 21 healthy subjects under three different conditions: (1) movement of right ankle alone; (2) movement and simultaneous stimulation of the agonist muscle; or (3) movement and simultaneous stimulation of a control area. We constructed weighted brain networks for each condition by using functional connectivity. Network features were analyzed using graph theoretical approaches. We found that: (1) the second condition evokes the strongest and most widespread brain activations (5147 vs. 4419 and 2320 activated voxels); and (2) this condition also induces a unique network layout and changes hubs and the modular structure of the brain motor network by activating the most "silent" links between primary somatosensory centers and the motor cortex, particularly weak links from the thalamus to the left primary motor cortex (M1). Significant statistical differences were found when the strength values of the right cerebellum (P < 0.001) or the left thalamus (P = 0.006) were compared among the three conditions. Over the years, studies reported a small number of projections from the thalamus to the motor cortex. This is the first work to present functions of these pathways. These findings reveal mechanisms for enhancing motor function with somatosensory stimulation, and suggest that network function cannot be thoroughly understood when weak ties are disregarded. PMID- 29387004 TI - Pazopanib-Induced Cutaneous Leukocytoclastic Vasculitis: An Exclusion Diagnosis of a Multidisciplinary Approach. AB - In phase II/III trials, cutaneous side effects of pazopanib were reported in less than 20% of patients, with only 1-3% being grade 3/4. We present a case of a 66 year-old man with a previous history of left nephrectomy for a stage II clear cell renal carcinoma. Approximately 18 months later, recurrent disease in the lungs, mediastinum, and left psoas and bulky abdominal/pelvic nodal metastasis were documented. He was initially treated with pazopanib 800 mg q.d. and 1 week after starting this therapy, the patient presented with palpable purpura on his ankles. These lesions regressed within 2 weeks off pazopanib, but had recurred 4 weeks after he resumed medication at 400 mg q.d. Biopsy of the lesions revealed leukocytoclastic vasculitis. Despite tumour response to therapy, pazopanib was discontinued with total resolution of this skin toxicity within 2 weeks of his cutaneous toxicity. To the best of our knowledge, we report a rare yet significant cutaneous adverse reaction to pazopanib. PMID- 29387006 TI - EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management. AB - The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/. PMID- 29387005 TI - [18F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy. AB - Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP in vivo do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP. [18F]-THK5351 is a novel PET-ligand that may afford in vivo visualization and quantification of tau-related alterations. We investigated binding characteristics of [18F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 +/- 7.4 year; N = 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 +/- 7.2 year; N = 4 female) underwent [18F]-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of [18F]-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%; p = 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain [18F]-THK5351 uptake correlated well with clinical severity as measured by PSPRS (R = 0.66; p = 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity (R = 0.79; p = 0.024). Regional [18F]-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the [18F]-THK5351 signal needs to be further evaluated, but nevertheless [18F]-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP. PMID- 29387007 TI - PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case Control Clinical Study in Han Chinese. AB - Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune diseases. However, the potential role of aberrant DNA methylation in allopurinol-SCARs is largely unknown. Objective: To address the knowledge gap between allopurinol-SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from allopurinol-SCARs and allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with allopurinol-SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched allopurinol tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (cytosine-guanine dinucleotide) sites in an independent cohort of 40 allopurinol-SCARs and 48 allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between allopurinol-SCARs and allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 * 10-13), and SCARs and controls (P = 5.93 * 10-15). Conclusions: Our data identified differentially methylated genes between allopurinol-SCARs and allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with allopurinol-SCARs (OR = 30.22, 95%CI = 4.73-192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of allopurinol-SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease associated changes of epigenome precede disease onset, or result from the disease progression, needs further investigation. Comparing the methylation status before patients develop allopurinol-SCARs and after may help examine methylation levels from disease onset to disease progression. PMID- 29387008 TI - Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials. AB - The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240. PMID- 29387009 TI - Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. AB - Introduction: It is a basic principle of the "psychedelic" treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value. Materials and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-Time and DED-by-Time interactions were the primary outcomes of interest. Results: For the interaction of OBN and DED with Time (QIDS SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson's correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05). Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety. Trial Registration: ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797. PMID- 29387010 TI - The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment. AB - The vast majority of states have enacted full or partial medical marijuana (MMJ) programs, causing the number of patients seeking certification for MMJ use to increase dramatically in recent years. Despite increased use of MMJ across the nation, no studies thus far have examined the specific impact of MMJ on cognitive function and related brain activation. In the present study, MMJ patients seeking treatment for a variety of documented medical conditions were assessed prior to initiating MMJ treatment and after 3 months of treatment as part of a larger longitudinal study. In order to examine the effect of MMJ treatment on task related brain activation, MMJ patients completed the Multi-Source Interference Test (MSIT) while undergoing functional magnetic resonance imaging (fMRI). We also collected data regarding conventional medication use, clinical state, and health-related measures at each visit. Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use. PMID- 29387011 TI - Computational and Pharmacological Evaluation of Ferrocene-Based Acyl Ureas and Homoleptic Cadmium Carboxylate Derivatives for Anti-diabetic Potential. AB - We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4 ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4 ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE >= -350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor gamma, 11beta hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE >= -250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3beta, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < -250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1-10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30-120 min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential. PMID- 29387012 TI - Exopolysaccharide Produced by Probiotic Strain Lactobacillus paraplantarum BGCG11 Reduces Inflammatory Hyperalgesia in Rats. AB - The aim of this study was to test the potential of high molecular weight exopolysaccharide (EPS) produced by the putative probiotic strain Lactobacillus paraplantarum BGCG11 (EPS CG11) to alleviate inflammatory pain in Wistar rats. The EPS CG11 was isolated from bacterial surface and was subjected to Fourier transform infrared spectroscopy (FTIR) and thermal analysis. FTIR spectra confirmed the polysaccharide structure of isolated sample, while the thermal methods revealed good thermal properties of the polymer. The antihyperalgesic and antiedematous effects of the EPS CG11 were examined in the rat model of inflammation induced by carrageenan injection in hind paw. The results showed that the intraperitoneal administration of EPS CG11 produced a significant decrease in pain sensations (mechanical hyperalgesia) and a paw swelling in a dose-dependent manner as it was measured using Von Frey anesthesiometer and plethysmometer, respectively. These effects were followed by a decreased expression of IL-1beta and iNOS mRNAs in rat's paw tissue suggesting that the antihyperalgesic and antiedematous effects of the EPS CG11 are related to the suppression of inflammatory response. Additionally, we demonstrated that EPS CG11 exhibits immunosuppressive properties in the peritonitis model induced by carrageenan. Expression levels of pro-inflammatory mediators IL-1beta, TNF-alpha and iNOS were decreased, together with the enhanced secretion of anti inflammatory IL-10 and IL-6 cytokines, while neutrophil infiltration was not changed. To the best of our knowledge, this is the first study which reports an antihyperalgesic effect as the novel property of bacterial EPSs. Given the high demands of pharmaceutical industry for the replacement of commonly used analgesics due to numerous side effects, this study describes a promising natural compound for the future pharmacological testing in the area. PMID- 29387013 TI - PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs. AB - The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 MUg/ml, 88.85 MUg?h/ml, 158.56 MUg?h/ml, 0.048 h-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h?kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC) of florfenicol. The MIC50 and MIC90 were calculated as 1 and 2 MUg/ml. A serotype 2 Streptococcus suis (WH-2), with MIC value similar to MIC90, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 MUg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 MUg/ml. According to inhibitory sigmoid Emax model, plasma AUC0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR), and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (COPD) analyzed from MCS for florfenicol against Streptococcus suis was 1 MUg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against Streptococcus suis after I.M administration. However, it should be validated in clinical practice in the future investigations. PMID- 29387014 TI - Inhibiting beta-Catenin by beta-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy. AB - The beta-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/beta-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both beta-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of beta-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141. In the present study, we utilized SP141 as an exemplary beta-carboline compound to characterize beta-catenin as a molecular target of the beta-carboline compounds and to demonstrate an important role of beta-catenin in the anticancer activity of beta-carboline. We found that the silencing of either beta-catenin or MDM2 largely reduced the anticancer activity of SP141 while the double silencing of both genes almost completely blocked SP141's activity. SP141 directly bound to beta-catenin and inhibited its expression and activity in pancreatic cancer cells in vitro and in vivo. The inhibitory effects of SP141 on beta-catenin were mediated by the ubiquitin-proteasome system in an MDM2-independent manner. In conclusion, these results suggest that SP141 exerts its anticancer activity by dually inhibiting beta-catenin and MDM2. We envision that beta-carboline derivatives can be developed as promising dual inhibitors of beta-catenin and MDM2 for the treatment of advanced pancreatic cancer. PMID- 29387015 TI - Electrodermal Activity Is Sensitive to Cognitive Stress under Water. AB - When divers are at depth in water, the high pressure and low temperature alone can cause severe stress, challenging the human physiological control systems. The addition of cognitive stress, for example during a military mission, exacerbates the challenge. In these conditions, humans are more susceptible to autonomic imbalance. Reliable tools for the assessment of the autonomic nervous system (ANS) could be used as indicators of the relative degree of stress a diver is experiencing, which could reveal heightened risk during a mission. Electrodermal activity (EDA), a measure of the changes in conductance at the skin surface due to sweat production, is considered a promising alternative for the non-invasive assessment of sympathetic control of the ANS. EDA is sensitive to stress of many kinds. Therefore, as a first step, we tested the sensitivity of EDA, in the time and frequency domains, specifically to cognitive stress during water immersion of the subject (albeit with their measurement finger dry for safety). The data from 14 volunteer subjects were used from the experiment. After a 4-min adjustment and baseline period after being immersed in water, subjects underwent the Stroop task, which is known to induce cognitive stress. The time-domain indices of EDA, skin conductance level (SCL) and non-specific skin conductance responses (NS.SCRs), did not change during cognitive stress, compared to baseline measurements. Frequency-domain indices of EDA, EDASymp (based on power spectral analysis) and TVSymp (based on time-frequency analysis), did significantly change during cognitive stress. This leads to the conclusion that EDA, assessed by spectral analysis, is sensitive to cognitive stress in water-immersed subjects, and can potentially be used to detect cognitive stress in divers. PMID- 29387016 TI - Trichosanthes pericarpium Aqueous Extract Enhances the Mobilization of Endothelial Progenitor Cells and Up-regulates the Expression of VEGF, eNOS, NO, and MMP-9 in Acute Myocardial Ischemic Rats. AB - Trichosanthes pericarpium (TP) had been widely used to cure patients of cardiovascular disease for 2,000 years in China. This study aims to extend our previous work to explore the mechanism underlying the protective effect of TP on acute myocardial ischemia (AMI). We hypothesized that TP may display its protective effect on AMI by promoting the mobilization of endothelial progenitor cells (EPC) via up-regulating the expression level of vascular endothelial growth factor (VEGF), endothelial nitric oxide syntheses (eNOS), nitric oxide (NO), and matrix metalloproteinase 9 (MMP-9) in AMI rats. To confirm this hypothesis, we treated AMI model rats with intragastrical administration of TP aqueous extract (TPAE), and examined both changes in the number of CEPC, and the expression levels of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content in these rats. Rats in each group were randomly divided into seven subgroups. From day 1 to 7 following AMI modeling, rats in these subgroups was sequentially phlebotomized from their celiac artery after being anesthetized by chloral hydrate. We found that, compared with the AMI model rats, in rats treated by TPAE, the CEPC counts, the expression of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content all increased more rapidly 7 days after AMI and remained at higher level (P < 0.05 or P < 0.01). Our results showed that, in AMI rats, the TPAE could significantly promote the mobilization of EPC and up regulate the expression level of VEGF, eNOS, NO, and MMP-9 in myocardium and their plasma content. Therefore, our results suggest that TAPE may regulate EPC mobilization through up-regulating the expression level of VEGF, eNOS, NO and MMP 9 in the myocardium of AMI rats. PMID- 29387017 TI - Additive Neuroprotective Effect of Borneol with Mesenchymal Stem Cells on Ischemic Stroke in Mice. AB - Intravenous stem cell transplantation initiates neuroprotection related to the secretion of trophic factor. Borneol, a potential herbal neuroprotective agent, is a penetration enhancer. Here, we aimed to investigate whether they have additive neuroprotective effect on cerebral ischemia. Borneol was given to mice by gavage 3 days before middle cerebral artery occlusion (MCAO) induction until the day when the mice were sacrificed. Mesenchymal stem cells (MSCs) were intravenously injected at 24 h after MCAO induction. Neurological deficits, infarct volume, cell death, and neurogenesis were evaluated. Combined use of MSCs and borneol could more effectively reduce infarction volume and cell apoptosis, enhance neurogenesis, and improve the functional recovery than that of MSCs alone. The findings showed that combined use of borneol and stem cells provided additive neuroprotective effect on cerebral ischemia. However, the supposed effect of borneol on the improved MSC penetration still needs further direct evidence. PMID- 29387019 TI - Cognitive Remediation for Schizophrenia with Focus on NEAR. PMID- 29387020 TI - Efficacy of "Attachment-Based Compassion Therapy" in the Treatment of Fibromyalgia: A Randomized Controlled Trial. AB - Objective: There is a growing interest in evaluating the effectiveness of compassion interventions for treating psychological disorders. The present study evaluated the effectiveness of "attachment-based compassion therapy" (ABCT) in the treatment of fibromyalgia (FM), and the role of psychological flexibility as a mediator of improvements. Methods: A total of 42 patients with FM were randomly assigned to ABCT or relaxation (active control group). Both the intervention and control condition were combined with treatment as usual (TAU). The primary outcome was functional status (FIQ), and the secondary outcomes were clinical severity (CGI-S), pain catastrophizing (PCS), anxiety (HADS-A), depression (HADS D), quality of life (EQ-5D), and psychological flexibility (AAQ-II). Differences between the groups were estimated using mixed-effects models, and mediation assessments were conducted using path analyses. Results: The ABCT group demonstrated superior outcomes compared to the relaxation group, including better FIQ values after treatment (B = -3.01; p = 0.003). Differences in FIQ were maintained at 3-month follow-up (B = -3.33; p = 0.001). The absolute risk reduction in ABCT compared to relaxation increased by 40.0%, with an NNT = 3 based on criteria of >=50% FIQ reduction after treatment. Psychological flexibility had a significant mediating effect on improvements. Conclusion: These results suggest that ABCT combined with TAU appears to be effective in the treatment of FM symptoms. Clinical Trial Registration: http://ClinicalTrials.gov, identifier NCT02454244. PMID- 29387021 TI - Brain-Derived Neurotrophic Factor and Major Depressive Disorder: Evidence from Meta-Analyses. AB - Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) is associated with the pathophysiology of major depressive disorder (MDD). In this mini review, we explored the association between BDNF and MDD using meta-analytic evidence. Our findings indicated that the Val66Met polymorphism in the BDNF gene was not associated with MDD or hippocampal volume in patients with MDD. However, plasma/serum levels of BDNF were decreased in patients with acute MDD compared with healthy controls. Both antidepressant treatment and electroconvulsive therapy increased plasma and serum levels of BDNF in patients with MDD. Val66Met polymorphism in the BDNF gene was associated with an antidepressant response in patients with MDD. Taken together, we did not detect any plausible evidence regarding Val66Met polymorphism in the BDNF gene contributing to a risk of MDD. However, peripheral BDNF levels are decreased in patients with MDD, and the polymorphisms are associated with treatment response. In conclusion, BDNF is best understood to be a biomarker for the state of MDD and its treatment response rather than a risk factor for MDD. PMID- 29387018 TI - Ironing out the Details: Exploring the Role of Iron and Heme in Blood-Sucking Arthropods. AB - Heme and iron are essential molecules for many physiological processes and yet have the ability to cause oxidative damage such as lipid peroxidation, protein degradation, and ultimately cell death if not controlled. Blood-sucking arthropods have evolved diverse methods to protect themselves against iron/heme related damage, as the act of bloodfeeding itself is high risk, high reward process. Protective mechanisms in medically important arthropods include the midgut peritrophic matrix in mosquitoes, heme aggregation into the crystalline structure hemozoin in kissing bugs and hemosomes in ticks. Once heme and iron pass these protective mechanisms they are presumed to enter the midgut epithelial cells via membrane-bound transporters, though relatively few iron or heme transporters have been identified in bloodsucking arthropods. Upon iron entry into midgut epithelial cells, ferritin serves as the universal storage protein and transport for dietary iron in many organisms including arthropods. In addition to its role as a nutrient, heme is also an important signaling molecule in the midgut epithelial cells for many physiological processes including vitellogenesis. This review article will summarize recent advancements in heme/iron uptake, detoxification and exportation in bloodfeeding arthropods. While initial strides have been made at ironing out the role of dietary iron and heme in arthropods, much still remains to be discovered as these molecules may serve as novel targets for the control of many arthropod pests. PMID- 29387022 TI - Magnetic Seizure Therapy in Treatment-Resistant Schizophrenia: A Pilot Study. AB - Objective: Electroconvulsive therapy is effective in treatment-resistant schizophrenia (TRS) but use is limited due to stigma and concerns around cognitive adverse effects. Magnetic seizure therapy (MST) is a promising new neuromodulation technique that uses transcranial magnetic stimulation to induce therapeutic seizures. Studies of MST in depression have shown clinical improvement with a favorable adverse effect profile. No studies have examined the clinical utility of MST in schizophrenia. Methods: We conducted an open-label pilot clinical trial of MST in eight TRS patients. Up to 24 MST treatments were delivered depending on treatment response. We assessed clinical outcome through the Brief Psychiatric Rating Scale (BPRS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Cognitive testing included a neuropsychological test battery, the Autobiographical Memory Inventory (AMI), Montreal Cognitive Assessment (MoCA), and reorientation time. Results: Four patients completed the trial as per protocol. For all patients and for trial completers alone, there was a significant clinical and quality of life improvement. Three met pre-determined criteria for remission (total score <=25 on the BPRS) and one met criteria for response (i.e., >=25% BPRS improvement from baseline for two consecutive assessments). Pre and post neurocognitive data showed no significant cognitive adverse effects apart from a decrease in AMI scores. Conclusion: In this pilot study, MST demonstrated evidence for feasibility in patients with TRS, with promise for clinical efficacy and negligible cognitive side effects. Further study in larger clinical populations is needed. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier NCT01596608. PMID- 29387023 TI - Calculating Retinal Contrast from Scene Content: A Program. AB - This paper describes a computer program for calculating the contrast image on the human retina from an array of scene luminances. We used achromatic transparency targets and measured test target's luminances with meters. We used the CIE standard Glare Spread Function (GSF) to calculate the array of retinal contrast. This paper describes the CIE standard, the calculation and the analysis techniques comparing the calculated retinal image with observer data. The paper also describes in detail the techniques of accurate measurements of HDR scenes, conversion of measurements to input data arrays, calculation of the retinal image, including open source MATLAB code, pseudocolor visualization of HDR images that exceed the range of standard displays, and comparison of observed sensations with retinal stimuli. PMID- 29387024 TI - Commentary: Primary Emotional Systems and Personality: An Evolutionary Perspective. PMID- 29387025 TI - Commentary: Primary Emotional Systems and Personality: An Evolutionary Perspective. PMID- 29387026 TI - Feeling Offended: A Blow to Our Image and Our Social Relationships. AB - The paper presents a survey study that investigates the self-conscious emotion of feeling offended and provides an account of it in terms of a socio-cognitive model of emotions. Based on the qualitative and quantitative analysis of the participants' answers, the study provides a definition of offense and of the feeling of offense in terms of its "mental ingredients," the beliefs and goals represented in a person who feels this emotion, and finds out what are its necessary and aggravating conditions, what are the explicit and implicit causes of offense (the other's actions, omissions, inferred mental states), what negative evaluations are offensive and why. It also shows that the feeling of offense is not only triggered about honor or public image, but it is mainly felt in personal affective relationships. The paper finally highlights that high self esteem may protect a person against the feeling of offense and the constellation of negative emotions triggered by it. PMID- 29387027 TI - Action-Effect Associations in Voluntary and Cued Task-Switching. AB - The literature of action control claims that humans control their actions in two ways. In the stimulus-based approach, actions are triggered by external stimuli. In the ideomotor approach, actions are elicited endogenously and controlled by the intended goal. In the current study, our purpose was to investigate whether these two action control modes affect task-switching differently. We combined a classical task-switching paradigm with action-effect learning. Both experiments consisted of two experimental phases: an acquisition phase, in which associations between task, response and subsequent action effects were learned and a test phase, in which the effects of these associations were tested on task performance by presenting the former action effects as preceding effects, prior to the task (called practiced effects). Subjects either chose freely between tasks (ideomotor action control mode) or they were cued as to which task to perform (sensorimotor action control mode). We aimed to replicate the consistency effect (i.e., task is chosen according to the practiced task-effect association) and non-reversal advantage (i.e., better task performance when the practiced effect matches the previously learned task-effect association). Our results suggest that participants acquired stable action-effect associations independently of the learning mode. The consistency effect (Experiment 1) could be shown, independent of the learning mode, but only on the response-level. The non-reversal advantage (Experiment 2) was only evident in the error rates and only for participants who had practiced in the ideomotor action control mode. PMID- 29387029 TI - Self-presentation in Online Professional Networks: Men's Higher and Women's Lower Facial Prominence in Self-created Profile Images. AB - Men are presented with higher facial prominence than women in the media, a phenomenon that is called face-ism. In naturalistic settings, face-ism effects could be driven by gender biases of photographers and/or by gender differences in self-presentation. The present research is the first to investigate whether women and men themselves create this different facial prominence. In a controlled laboratory study, 61 participants prepared a picture of themselves from a half body photograph, allegedly to be uploaded to their profile for an online professional network. As expected, men cropped their photos with higher facial prominence than women did. However, women and men did not differ in the self presentational motivations, goals, strategies, and personality variables under investigation, so that the observed face-ism effect could not be explained with these variables. Generally, the higher participants' physical appearance self esteem, the higher was their self-created facial prominence. PMID- 29387028 TI - Psychopathological Symptoms under Smog: The Role of Emotion Regulation. AB - Over the past decade, major cities in China have suffered from severe air pollution, which is also known as smog. Despite lay considerations that smog might pose risks for psychopathology, it remains unknown whether it is only linked to affective psychopathology or to a broader range of symptomologies. Moreover, whether individual differences in emotion regulation, a transdiagnostic risk factor for psychopathology, would influence the magnitude of pollution induced symptoms is not well understood. Using a longitudinal design, the current study measured trait emotion regulation and psychopathological symptoms in a sample of university students at Time 1 (without smog, N = 120) and then reassessed for psychopathology at Time 2 (after acute exposure to smog for 1 week, N = 102). The results showed that participants had higher levels of positive symptom distress, obsessive-compulsive symptoms, interpersonal sensitivity, depression, and psychoticism at Time 2. Moreover, reappraisal is negatively associated with smog-induced elevations in psychopathological symptoms only when participants rely heavily on suppression. We discuss the implications of this investigation for both intervention efforts and future work on the contextual factors surrounding the deployment of emotion regulation strategies. PMID- 29387030 TI - Musical Agency during Physical Exercise Decreases Pain. AB - Objectives: When physical exercise is systematically coupled to music production, exercisers experience improvements in mood, reductions in perceived effort, and enhanced muscular efficiency. The physiology underlying these positive effects remains unknown. Here we approached the investigation of how such musical agency may stimulate the release of endogenous opioids indirectly with a pain threshold paradigm. Design: In a cross-over design we tested the opioid-hypothesis with an indirect measure, comparing the pain tolerance of 22 participants following exercise with or without musical agency. Method: Physical exercise was coupled to music by integrating weight-training machines with sensors that control music synthesis in real time. Pain tolerance was measured as withdrawal time in a cold pressor test. Results: On average, participants tolerated cold pain for ~5 s longer following exercise sessions with musical agency. Musical agency explained 25% of the variance in cold pressor test withdrawal times after factoring out individual differences in general pain sensitivity. Conclusions: This result demonstrates a substantial pain reducing effect of musical agency in combination with physical exercise, probably due to stimulation of endogenous opioid mechanisms. This has implications for exercise endurance, both in sports and a multitude of rehabilitative therapies in which physical exercise is effective but painful. PMID- 29387031 TI - Using Neural Networks to Generate Inferential Roles for Natural Language. AB - Neural networks have long been used to study linguistic phenomena spanning the domains of phonology, morphology, syntax, and semantics. Of these domains, semantics is somewhat unique in that there is little clarity concerning what a model needs to be able to do in order to provide an account of how the meanings of complex linguistic expressions, such as sentences, are understood. We argue that one thing such models need to be able to do is generate predictions about which further sentences are likely to follow from a given sentence; these define the sentence's "inferential role." We then show that it is possible to train a tree-structured neural network model to generate very simple examples of such inferential roles using the recently released Stanford Natural Language Inference (SNLI) dataset. On an empirical front, we evaluate the performance of this model by reporting entailment prediction accuracies on a set of test sentences not present in the training data. We also report the results of a simple study that compares human plausibility ratings for both human-generated and model-generated entailments for a random selection of sentences in this test set. On a more theoretical front, we argue in favor of a revision to some common assumptions about semantics: understanding a linguistic expression is not only a matter of mapping it onto a representation that somehow constitutes its meaning; rather, understanding a linguistic expression is mainly a matter of being able to draw certain inferences. Inference should accordingly be at the core of any model of semantic cognition. PMID- 29387033 TI - How Team-Level and Individual-Level Conflict Influences Team Commitment: A Multilevel Investigation. AB - We investigate how two different types of conflict (task conflict and relationship conflict) at two different levels (individual-level and team-level) influence individual team commitment. The analysis was conducted using data we collected from 193 employees in 31 branch offices of a Korean commercial bank. The relationships at multiple levels were tested using hierarchical linear modeling (HLM). The results showed that individual-level relationship conflict was negatively related to team commitment while individual-level task conflict was not. In addition, both team-level task and relationship conflict were negatively associated with team commitment. Finally, only team-level relationship conflict significantly moderated the relationship between individual-level relationship conflict and team commitment. We further derive theoretical implications of these findings. PMID- 29387032 TI - Watching More Closely: Shot Scale Affects Film Viewers' Theory of Mind Tendency But Not Ability. AB - Recent research debates the effects of exposure to narrative fiction on recognition of mental states in others and self, referred to as Theory of Mind. The current study explores the mechanisms by which such effects could occur in fictional film. Using manipulated film scenes, we conducted a between subject experiment (N = 136) exploring how film shot-scale affects viewers' Theory of Mind. Specifically, in our methods we distinguish between the trait Theory of Mind abilities (ToM ability), and the state-like tendency to recognize mental states in others and self (ToM tendency). Results showed that close-up shots (compared to long shots) of a character was associated with higher levels of Theory of Mind tendency, when the facial expression was sad but not when it was neutral. And this effect did not transfer to other characters in the film. There was also no observable effect of character depiction on viewers' general Theory of Mind ability. Together the findings suggest that formal and content features of shot scale can elicit Theory of Mind responses by directing attention toward character mental states rather than improving viewers' general Theory of Mind ability. PMID- 29387034 TI - Narratives of Transgender People Detained in Prison: The Role Played by the Utterances "Not" (as a Feeling of Hetero- and Auto-rejection) and "Exist" (as a Feeling of Hetero- and Auto-acceptance) for the Construction of a Discursive Self. A Suggestion of Goals and Strategies for Psychological Counseling. AB - Purpose: Understanding how transgender people, who committed criminal offenses and are detained in prison, produce a narrative representation of self within different prison contexts. More specifically, this study has been based on two sub-aims: On a paradigmatic level, it has been aimed at critically investigating how the discursive positioning among the Self and the Other might promote the internalization of positive and/or negative attitudes toward the self. On a pragmatic level, it intends to offer some suggestions for goals and strategies of psychological counseling with these inmates inside such highly institutionalized contexts. Method and Materials: In total, 23 in-depth interviews were conducted with transgender women detained in either female or male prison contexts in Italy and Brazil. The lexical, semantic, and semiotic structure of the transcribed interviews has been investigated by adopting the quali-quantitative software Iramuteq for performing statistical text-mining analysis. Frequency, correspondences, and distribution of the most representative utterances across the corpus of data have been accessed and critically analyzed. Results: The findings showed that transgender inmates in Brazil made repeated use of the adverb "not," while the verb "exist" became the most representative word for the Italian sample. In Brazil, indeed, transgender women assumed masculine-driven behavior due to a common imprisonment with cis-gender men. On the contrary, transgender women in Italy are detained in protected sections, where they are allowed to wear female clothing and continue hormonal treatments. Surprisingly, transgender inmates in Italy suffered more violence in a female sector when compared to exclusively male jails. Conclusions: Transgender people represent a challenge for prison administration because it is not clear in which penitentiary context they should be detained. They should receive special attentions in order to face their special needs, which are radically different when compared to other typologies of inmates. Within penitentiary contexts, psychological counseling with transgender women should pay a special attention to the several psycho social dimensions of this existential condition. In particular, psychological counselors should consider its inner complex articulation within different social, cultural and normative contexts. PMID- 29387035 TI - Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis-A Longitudinal Observational Study. AB - Background: Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far. Objective: To explore the influence of alemtuzumab on cognitive impairment in active relapsing remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy. Methods: Extensive neuropsychological assessment was administered to 21 patients with active RRMS at baseline and again after the second treatment with alemtuzumab (mean time span: 15.05 months). Clinical and routine structural neuroimaging markers were explored for their capacity to predict individual courses of cognitive change. Results: Overall cognitive functioning remained stable or improved during the observational period of alemtuzumab treatment on average. Scores on two neuropsychological tests of processing speed significantly improved and clinically relevant individual gains of processing speed were seen in the majority of patients. Linear regression models showed that clinical and routine neuroimaging measures of disease activity could not fully account for these cognitive changes. Conclusion: Results suggest that alemtuzumab treatment in active RRMS stabilizes overall cognitive functioning and furthermore positively affects cognitive processing speed. Changes in processing speed were independent from clinical and structural neuroimaging parameters of disease activity and may thus represent an underrated and independent outcome measure to evaluate treatment effects. PMID- 29387036 TI - Pseudotumor Cerebri and Glymphatic Dysfunction. AB - In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of beta-amyloid in Alzheimer's disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses. PMID- 29387037 TI - Spontaneous Recovery from Unresponsive Wakefulness Syndrome to a Minimally Conscious State: Early Structural Changes Revealed by 7-T Magnetic Resonance Imaging. AB - Background: Determining the early changes of brain structure that occur from vegetative state/unresponsive wakefulness syndrome (VS/UWS) to a minimally conscious state (MCS) is important for developing our understanding of the processes underlying disorders of consciousness (DOC), particularly during spontaneous recovery from severe brain damage. Objective: This study used a multi modal neuroimaging approach to investigate early structural changes during spontaneous recovery from VS/UWS to MCS. Methods: The Coma Recovery Scale-Revised (CRS-R) score, 24-h electroencephalography (EEG), and ultra-high field 7-T magnetic resonance imaging were used to investigate a male patient with severe brain injury when he was in VS/UWS compared to MCS. Using white matter connectometry analysis, fibers in MCS were compared with the same fibers in VS/UWS. Whole-brain analysis was used to compare all fibers showing a 10% increase in density with each other as a population. Results: Based on connectometry analysis, the number of fibers with increased density, and the magnitude of increase in MCS compared to VS/UWS, was greatest in the area of the temporoparietal junction (TPJ), and was mostly located in the right hemisphere. These results are in accordance with the active areas observed on 24-h EEG recordings. Moreover, analysis of different fibers across the brain, showing at least a 10% increase in density, revealed that altered white matter connections with higher discriminative weights were located within or across visual-related areas, including the cuneus_R, calcarine_R, occipital_sup_R, and occipital_mid_R. Furthermore, the temporal_mid_R, which is related to the auditory cortex, showed the highest increase in connectivity to other areas. This was consistent with improvements in the visual and auditory components of the CRS-R, which were greater than other improvements. Conclusion: These results provide evidence to support the important roles for the TPJ and the visual and auditory sensory systems in the early recovery of a patient with severe brain injury. Our findings may facilitate a much deeper understanding of the mechanisms underlying conscious related processes and enlighten treatment strategies for patients with DOC. PMID- 29387038 TI - Systematic Review of Human and Animal Studies Examining the Efficacy and Safety of N-Acetylcysteine (NAC) and N-Acetylcysteine Amide (NACA) in Traumatic Brain Injury: Impact on Neurofunctional Outcome and Biomarkers of Oxidative Stress and Inflammation. AB - Background: No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. N-acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and N-acetylcysteine amide (NACA) post-TBI. Methods: Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted. Results: Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis. Conclusion: Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of scientific literature suggests putative beneficial effects of NAC/NACA treatment for TBI, the lack of well-designed and controlled clinical investigations, evaluating therapeutic outcomes, prognostic biomarkers, and safety profiles, limits definitive interpretation and recommendations for its application in humans at this time. PMID- 29387039 TI - Kynurenic Acid Inhibits the Electrical Stimulation Induced Elevated Pituitary Adenylate Cyclase-Activating Polypeptide Expression in the TNC. AB - Background: Migraine is a primary headache of imprecisely known mechanism, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Intensive research has recently focused on pituitary adenylate cyclase-activating polypeptide (PACAP) and the kynurenine systems as potential pathogenic factors. Aim: We investigated the link between these important mediators and the effects of kynurenic acid (KYNA) and its synthetic analog (KYNA a) on PACAP expression in the rat trigeminal nucleus caudalis (TNC) in a TS stimulation model related to migraine mechanisms. Methods: Adult male Sprague Dawley rats were pretreated with KYNA, KYNA-a, the NMDA receptor antagonist MK 801, or saline (vehicle). Next, the trigeminal ganglion (TRG) was electrically stimulated, the animals were transcardially perfused following 180 min, and the TNC was removed. In the TNC samples, 38 amino acid form of PACAP (PACAP1-38)-like radioimmunoactivity was measured by radioimmunoassay, the relative optical density of preproPACAP was assessed by Western blot analysis, and PACAP1-38 mRNA was detected by real-time PCR. Results and conclusion: Electrical TRG stimulation resulted in significant increases of PACAP1-38-LI, preproPACAP, and PACAP1-38 mRNA in the TNC. These increases were prevented by the pretreatments with KYNA, KYNA-a, and MK-801. This is the first study to provide evidence for a direct link between PACAP and the kynurenine system during TS activation. PMID- 29387040 TI - Effect of Intermittent versus Continuous Light Exposure on Pupillary Light Response, As Evaluated by Pupillometry. AB - Objective: Continuous and intermittent stimuli with green light affect the pupillary light response (PLR) differently. Since the majority of pupillometric studies use blue and red lights, we investigated the effect of continuous and intermittent stimulations on the PLR using red and blue lights. Methods: Seventeen healthy subjects underwent continuous- and intermittent light stimuli, using red (643 nm) and blue light (463 nm). To avoid the influence of pupil size on the amount of light entering the eye, the procedures were repeated with the stimulus-eye in dilated condition. The maximal pupillary constriction and the early redilation phase of post-illumination pupillary response (PIPREarly) represented the mixed response of melanopsin and rod-cone photoreceptors. The late redilation phase of PIPR (PIPRLate) was the marker of melanopsin-containing retinal ganglion cells. Results: Intermittent stimuli with blue light elicited significantly larger maximal contraction during dilated condition (P = 0.001), and larger sustained pupillary contraction under dilated as well as undilated condition (P < 0.001) compared to continuous light exposure. Except the PIPREarly during undilated condition, none of the PIPR metrics were significantly different between intermittent and continuous blue light stimuli. Intermittent red light stimuli elicited also a more sustained pupillary contraction regardless of mydriatic instillation (P <= 0.02). In addition, intermittent red light exposure resulted in a slightly larger PIPREarly under undilated condition (P = 0.02) and a slightly larger PIPRLate under dilated condition (P = 0.049). Except the PIPRLate to continuous red light stimulus, all PIPR parameters were larger when the light was presented after induction of unilateral mydriasis. Conclusion: PLR parameters during and after light exposures depend on both the light stimulation mode and the entrance pupillary size. PMID- 29387041 TI - Neuroprosthetics for Auricular Muscles: Neural Networks and Clinical Aspects. AB - The mammalian external ear houses extrinsic and intrinsic auricular muscles. There are three extrinsic auricular muscles-the posterior, superior, and anterior auricular muscles-and six intrinsic muscles-the helicis major and minor, tragicus, anti-tragicus, transverse and oblique muscles. These muscles have been considered vestigial in humans. However, numerous therapeutic and diagnostic wearable devices are designed to monitor and alleviate the symptoms of neurological disorders, brainstem injuries, emotional states, and auditory functions, by making use of the neural networks of the auricular muscles and their locations, which are easily accessible for ergonomic wearable biomedical devices. They can also serve as a bio-controller of human neuroprosthetics. The functionality of these auricular muscles remains elusive and requires further experimentation for a more in-depth understanding of their anatomy. The aims of this review are (1) to provide a detailed account of the neural networks of the extrinsic and intrinsic auricular muscles, (2) to describe diagnostic and therapeutic functions of these muscles as demonstrated in the current literature, and (3) to outline existing and potential neuroprosthetic applications making use of the auricular muscles and their neural networks. PMID- 29387043 TI - Strategies to Combat Antibiotic Resistance in the Wastewater Treatment Plants. AB - The main goal of this manuscript is to review different treatment strategies and mechanisms for combating the antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARGs) in the wastewater environment. The high amount of antibiotics is released into the wastewater that may promote selection of ARB and ARGs which find their way into natural environments. Emerging microbial pathogens and increasing antibiotic resistance among them is a global public health issue. The propagation and spread of ARB and ARGs in the environment may result in an increase of antibiotic resistant microbial pathogens which is a worldwide environmental and public health concern. A proper treatment of wastewater is essential before its discharge into rivers, lake, or sewage system to prevent the spread of ARB and ARGs into the environment. This review discusses various treatment options applied for combating the spread of ARB and ARGs in wastewater treatment plants (WWTPs). It was reported that low-energy anaerobic-aerobic treatment reactors, constructed wetlands, and disinfection processes have shown good removal efficiencies. Nanomaterials and biochar combined with other treatment methods and coagulation process are very recent strategies regarding ARB and ARGs removal and need more investigation and research. Based on current studies a wide-ranging removal efficiency of ARGs can be achieved depending on the type of genes present and treatment processes used, still, there are gaps that need to be further investigated. In order to find solutions to control dissemination of antibiotic resistance in the environment, it is important to (1) study innovative strategies in large scale and over a long time to reach an actual evaluation, (2) develop risk assessment studies to precisely understand occurrence and abundance of ARB/ARGs so that their potential risks to human health can be determined, and (3) consider operating and environmental factors that affect the efficiency of each treatment mechanism. PMID- 29387042 TI - Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links. AB - Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field. PMID- 29387044 TI - Lauric Acid Is an Inhibitor of Clostridium difficile Growth in Vitro and Reduces Inflammation in a Mouse Infection Model. AB - Clostridium difficile is a Gram-positive, spore-forming anaerobic human gastrointestinal pathogen. C. difficile infection (CDI) is a major health concern worldwide, with symptoms ranging from diarrhea to pseudomembranous colitis, toxic megacolon, sepsis, and death. CDI onset and progression are mostly caused by intestinal dysbiosis and exposure to C. difficile spores. Current treatment strategies include antibiotics; however, antibiotic use is often associated with high recurrence rates and an increased risk of antibiotic resistance. Medium chain fatty acids (MCFAs) have been revealed to inhibit the growth of multiple human bacterial pathogens. Components of coconut oil, which include lauric acid, have been revealed to inhibit C. difficile growth in vitro. In this study, we demonstrated that lauric acid exhibits potent antimicrobial activities against multiple toxigenic C. difficile isolates in vitro. The inhibitory effect of lauric acid is partly due to reactive oxygen species (ROS) generation and cell membrane damage. The administration of lauric acid considerably reduced biofilm formation and preformed biofilms in a dose-dependent manner. Importantly, in a mouse infection model, lauric acid pretreatment reduced CDI symptoms and proinflammatory cytokine production. Our combined results suggest that the naturally occurring MCFA lauric acid is a novel C. difficile inhibitor and is useful in the development of an alternative or adjunctive treatment for CDI. PMID- 29387045 TI - Functional Repertoire of Antibiotic Resistance Genes in Antibiotic Manufacturing Effluents and Receiving Freshwater Sediments. AB - Environments polluted by direct discharges of effluents from antibiotic manufacturing are important reservoirs for antibiotic resistance genes (ARGs), which could potentially be transferred to human pathogens. However, our knowledge about the identity and diversity of ARGs in such polluted environments remains limited. We applied functional metagenomics to explore the resistome of two Croatian antibiotic manufacturing effluents and sediments collected upstream of and at the effluent discharge sites. Metagenomic libraries built from an azithromycin-production site were screened for resistance to macrolide antibiotics, whereas the libraries from a site producing veterinary antibiotics were screened for resistance to sulfonamides, tetracyclines, trimethoprim, and beta-lactams. Functional analysis of eight libraries identified a total of 82 unique, often clinically relevant ARGs, which were frequently found in clusters and flanked by mobile genetic elements. The majority of macrolide resistance genes identified from matrices exposed to high levels of macrolides were similar to known genes encoding ribosomal protection proteins, macrolide phosphotransferases, and transporters. Potentially novel macrolide resistance genes included one most similar to a 23S rRNA methyltransferase from Clostridium and another, derived from upstream unpolluted sediment, to a GTPase HflX from Emergencia. In libraries deriving from sediments exposed to lower levels of veterinary antibiotics, we found 8 potentially novel ARGs, including dihydrofolate reductases and beta-lactamases from classes A, B, and D. In addition, we detected 7 potentially novel ARGs in upstream sediment, including thymidylate synthases, dihydrofolate reductases, and class D beta-lactamase. Taken together, in addition to finding known gene types, we report the discovery of novel and diverse ARGs in antibiotic-polluted industrial effluents and sediments, providing a qualitative basis for monitoring the dispersal of ARGs from environmental hotspots such as discharge sites of pharmaceutical effluents. PMID- 29387046 TI - Desert Dust as a Source of Iron to the Globally Important Diazotroph Trichodesmium. AB - The marine cyanobacterium Trichodesmium sp. accounts for approximately half of the annual 'new' nitrogen introduced to the global ocean but its biogeography and activity is often limited by the availability of iron (Fe). A major source of Fe to the open ocean is Aeolian dust deposition in which Fe is largely comprised of particles with reduced bioavailability over soluble forms of Fe. We report that Trichodesmium erythraeum IMS101 has improved growth rate and photosynthetic physiology and down-regulates Fe-stress biomarker genes when cells are grown in the direct vicinity of, rather than physically separated from, Saharan dust particles as the sole source of Fe. These findings suggest that availability of non-soluble forms of dust-associated Fe may depend on cell contact. Transcriptomic analysis further reveals unique profiles of gene expression in all tested conditions, implying that Trichodesmium has distinct molecular signatures related to acquisition of Fe from different sources. Trichodesmium thus appears to be capable of employing specific mechanisms to access Fe from complex sources in oceanic systems, helping to explain its role as a key microbe in global biogeochemical cycles. PMID- 29387047 TI - Phenotypic Heterogeneity in Sugar Utilization by E. coli Is Generated by Stochastic Dispersal of the General PTS Protein EI from Polar Clusters. AB - Although the list of proteins that localize to the bacterial cell poles is constantly growing, little is known about their temporal behavior. EI, a major protein of the phosphotransferase system (PTS) that regulates sugar uptake and metabolism in bacteria, was shown to form clusters at the Escherichia coli cell poles. We monitored the localization of EI clusters, as well as diffuse molecules, in space and time during the lifetime of E. coli cells. We show that EI distribution and cluster dynamics varies among cells in a population, and that the cluster speed inversely correlates with cluster size. In growing cells, EI is not assembled into clusters in almost 40% of the cells, and the clusters in most remaining cells dynamically relocate within the pole region or between the poles. In non-growing cells, the fraction of cells that contain EI clusters is significantly higher, and dispersal of these clusters is often observed shortly after exiting quiescence. Later, during growth, EI clusters stochastically re form by assembly of pre-existing dispersed molecules at random time points. Using a fluorescent glucose analog, we found that EI function inversely correlates with clustering and with cluster size. Thus, activity is exerted by dispersed EI molecules, whereas the polar clusters serve as a reservoir of molecules ready to act when needed. Taken together our findings highlight the spatiotemporal distribution of EI as a novel layer of regulation that contributes to the population phenotypic heterogeneity with regard to sugar metabolism, seemingly conferring a survival benefit. PMID- 29387048 TI - Infectious Agents and Inflammation: The Role of Microbiota in Autoimmune Arthritis. AB - In higher vertebrates, mucosal sites at the border between the internal and external environments, directly interact with bacteria, viruses, and fungi. Through co-evolution, hosts developed mechanisms of tolerance or ignorance toward some infectious agents, because hosts established "gain of function" interactions with symbiotic bacteria. Indeed, some bacteria assist hosts in different functions, among which are digestion of complex carbohydrates, and absorption and supply of vitamins. There is no doubt that microbiota modulate innate and acquired immune responses starting at birth. However, variations in quality and quantity of bacterial species interfere with the equilibrium between inflammation and tolerance. In fact, correlations between gut bacteria composition and the severity of inflammation were first described for inflammatory bowel diseases and later extended to other pathologies. The genetic background, environmental factors (e.g., stress or smoking), and diet can induce strong changes in the resident bacteria which can expose the intestinal epithelium to a variety of different metabolites, many of which have unknown functions and consequences. In addition, alterations in gut permeability may allow pathogens entry, thereby triggering infection and/or chronic inflammation. In this context, a local event occurring at a mucosal site may be the triggering cause of an autoimmune reaction that eventually involves distant sites or organs. Recently, several studies attributed a pathogenic role to altered oral microbiota in rheumatoid arthritis (RA) and to gut dysbiosis in spondyloarthritis (SpA). There is also growing evidence that different drugs, such as antibiotics and immunosuppressants, can influence and be influenced by the diversity and composition of microbiota in RA and SpA patients. Hence, in complex disorders such RA and SpA, not only the genetic background, gender, and immunologic context of the individual are relevant, but also the history of infections and the structure of the microbial community at mucosal sites should be considered. Here the role of the microbiota and infections in the initiation and progression of chronic arthritis is discussed, as well as how these factors can influence a patient's response to synthetic and biologic immunosuppressive therapy. PMID- 29387049 TI - Growth Promotion and Disease Suppression Ability of a Streptomyces sp. CB-75 from Banana Rhizosphere Soil. AB - An actinomycete strain, CB-75, was isolated from the soil of a diseased banana plantation in Hainan, China. Based on phenotypic and molecular characteristics, and 99.93% sequence similarity with Streptomyces spectabilis NBRC 13424 (AB184393), the strain was identified as Streptomyces sp. This strain exhibited broad-spectrum antifungal activity against 11 plant pathogenic fungi. Type I polyketide synthase (PKS-I) and non-ribosomal peptide synthetase (NRPS) were detected, which were indicative of the antifungal compounds that Streptomyces sp. CB-75 could produce. An ethyl acetate extract from the strain exhibited the lowest minimum inhibitory concentration (MIC) against Colletotrichum musae (ATCC 96167) (0.78 MUg/ml) and yielded the highest antifungal activity against Colletotrichum gloeosporioides (ATCC 16330) (50.0 MUg/ml). Also, spore germination was significantly inhibited by the crude extract. After treatment with the crude extract of Streptomyces sp. CB-75 at the concentration 2 * MIC, the pathogenic fungi showed deformation, shrinkage, collapse, and tortuosity when observed by scanning electron microscopy (SEM). By gas chromatography-mass spectrometry (GC-MS) of the crude extract, 18 chemical constituents were identified; (Z)-13-docosenamide was the major constituent. Pot experiments showed that the incidence of banana seedlings was reduced after using Streptomyces sp. CB-75 treatment. The disease index was 10.23, and the prevention and control effect was 83.12%. Furthermore, Streptomyces sp. CB-75 had a growth-promoting effect on banana plants. The chlorophyll content showed 88.24% improvement, the leaf area, root length, root diameter, plant height, and stem showed 88.24, 90.49, 136.17, 61.78, and 50.98% improvement, respectively, and the shoot fresh weight, root fresh weight, shoot dry weight, and root dry weight showed 82.38, 72.01, 195.33, and 113.33% improvement, respectively, compared with treatment of fermentation broth without Streptomyces sp. CB-75. Thus, Streptomyces sp. CB-75 is an important microbial resource as a biological control against plant pathogenic fungi and for promoting banana growth. PMID- 29387050 TI - Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles. AB - Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis. To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol. Using an inducible promoter to regulate Neurospora crassa erg11, which encodes the major azole target, sterol 14alpha-demethylase, we were able to demonstrate that the CDR4 azole efflux pump can be transcriptionally activated by ergosterol biosynthesis inhibition even in the absence of azoles. By analyzing ergosterol deficient mutants, we demonstrate that the transcriptional responses by cdr4 and, unexpectedly, genes encoding ergosterol biosynthesis enzymes (erg genes) that are responsive to azoles, are not dependent on ergosterol depletion. Nonetheless, deletion of erg2, which encodes C-8 sterol isomerase, also induced expression of cdr4. Deletion of erg2 also induced the expression of erg24, the gene encoding C-14 sterol reductase, but not other tested erg genes which were responsive to erg11 inactivation. This indicates that inhibition of specific steps of ergosterol biosynthesis can result in different transcriptional responses, which is further supported by our results obtained using different ergosterol biosynthesis inhibitors. Together with the sterol profiles, these results suggest that the transcriptional responses by cdr4 and erg genes are associated with accumulation of specific sterol intermediate(s). This was further supported by the fact that when the erg2 mutant was treated with ketoconazole, upstream inhibition overrode the effects by downstream inhibition on ergosterol biosynthesis pathway. Even though cdr4 expression is associated with the accumulation of sterol intermediates, intra- and extracellular sterol analysis by HPLC-MS indicated that the transcriptional induction of cdr4 did not result in efflux of the accumulated intermediate(s). This study demonstrates, by detailed genetic and chemical analysis, that transcriptional responses by a major efflux pump and genes of the ergosterol biosynthesis pathway to ergosterol biosynthesis inhibitors can be independent of the presence of the drugs and are linked with the accumulation of ergosterol intermediate(s). PMID- 29387051 TI - Elevated Serum Lysophosphatidylcholine in Patients with Systemic Lupus Erythematosus Impairs Phagocytosis of Necrotic Cells In Vitro. AB - Objectives: Impaired clearance of dying and dead cells by professional and amateur phagocytes plays a crucial role in the etiology of systemic lupus erythematosus (SLE). While dying, cells expose and release a plethora of eat-me and find-me signals to ensure their timely removal before entering the dangerous stage of secondary necrosis. A well-described chemoattractant for macrophages is dying cell-derived lysophosphatidylcholine (LPC). However, its implications for and/or its association with SLE disease, so far, have not been examined. In the present study, we analyzed the LPC serum concentrations of patients with SLE and rheumatoid arthritis (RA). Subsequently, we examined if and to which extent the measured serum concentrations of LPC and an LPC-rich environment can impact the phagocytosis of necrotic cells. Methods: Sera from patients with SLE, RA, and normal healthy donors (NHD) were characterized for several parameters, including LPC concentrations. Phagocytosis of dead cells by human macrophages in the presence of SLE and NHD sera was quantified. Additionally, the impact of exogenously added, purified LPC on phagocytosis was analyzed. Results: Patients with SLE had significantly increased LPC serum levels, and high serum LPC of SLE patients correlated significantly with impaired phagocytosis of dead cells in the presence of heat-inactivated serum. Phagocytosis in the presence of sera from NHD showed no correlation to LPC levels, but exogenous addition of purified LPC in the range as measured in SLE patients' sera led to a concentration-dependent decrease. Conclusion: Our data show that high levels of LPC as observed in the sera of SLE patients have a negative impact on the clearance of dead cells by macrophages. Chemoattraction requires a concentration gradient. The higher the LPC concentration surrounding a dying or dead cell, the smaller the achievable gradient upon LPC release will be. Thus, it is feasible to assume that elevated LPC levels can interfere with the build-up of a local LPC gradient during cell death, and hence might play a role in the establishment and/or perpetuation of SLE disease. PMID- 29387052 TI - Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model. AB - Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid. PMID- 29387054 TI - Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands. AB - The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor able to recognize both damage-associated and pathogen-associated molecular patterns, and in this respect, there has been much interest in determining the scope of ligands that bind Mincle and how structural modifications to these ligands influence ensuing immune responses. In this review, we will present Mincle ligands of known chemical structure, with a focus on ligands that have been synthetically prepared, such as trehalose glycolipids, glycerol-based ligands, and 6-acylated glucose and mannose derivatives. The ability of the different classes of ligands to influence the innate, and consequently, the adaptive, immune response will be described, and where appropriate, structure activity relationships within each class of Mincle ligands will be presented. PMID- 29387055 TI - Orbital Ectopic Lymphoid Follicles with Germinal Centers in Aquaporin-4-IgG Positive Neuromyelitis Optica Spectrum Disorders. AB - Neuromyelitis optica spectrum disorders (NMOSDs) are important autoimmune central nervous system (CNS) astrocytopathy causing acute myelitis, optic neuritis (ON), and encephalitis associated with significant morbidities and mortality. It is important to diagnose NMOSDs early as they are treatable. The majority of NMOSDs patients are seropositive for aquaporin-4 IgG (AQP4-IgG) autoantibodies, which target CNS aquaporin-4 (AQP4) expressed abundantly in astrocytic foot processes. We report the novel observation of orbital masses containing ectopic lymphoid follicles with germinal centres (GC) in two patients with AQP4-IgG-positive NMOSD. Both patients had severe extensive myelitis with symptomatic or asymptomatic ON, with the ectopic lymphoid structures detected on initial presentation. Histolopathological studies confirmed that the orbital masses contained reactive lymphoid follicles with GC containing B cells and plasma cells. Our observations support that AQP4-IgG positive NMOSDs patients have underlying AQP4 autoimmunity and suggest that ON (symptomatic or asymptomatic) may trigger formation of orbital ectopic GC contributing to development of high affinity AQP4-specific memory B cells and plasma cells, which produce highly pathogenic AQP4-IgG. PMID- 29387057 TI - Exploring Host-Commensal Interactions in the Respiratory Tract. AB - Commensal microbes are currently in the limelight in biomedical research because they play an important role in health and disease. Humans harbor an enormous diversity of commensals in various parts of the body, including the gastrointestinal and respiratory tracts. Advancement in metagenomic and other omic approaches, and development of suitable animal models have provided an unprecedented appreciation into the diversity of commensals, and the intricacies of their intimate communication with the host immune system. Most studies have focused on the host-commensal interaction in the gut, while less is known on this relationship in other sites of the body, such as the respiratory tract. In this article, we review emerging data from human and animal studies on the host responses to respiratory commensals, immune cross-reactivity between commensals and pathogens, and use of commensals as a vaccine delivery system. A better understanding of the delicate interplay between commensals and host may aid in efforts to develop effective vaccines and therapeutics. PMID- 29387056 TI - Lactococcus lactis As a Versatile Vehicle for Tolerogenic Immunotherapy. AB - Genetically modified Lactococcus lactis bacteria have been engineered as a tool to deliver bioactive proteins to mucosal tissues as a means to exert both local and systemic effects. They have an excellent safety profile, the result of years of human consumption in the food industry, as well as a lack of toxicity and immunogenicity. Also, containment strategies have been developed to promote further application as clinical protein-based therapeutics. Here, we review technological advancements made to enhanced the potential of L. lactis as live biofactories and discuss some examples of tolerogenic immunotherapies mediated by mucosal drug delivery via L. lactis. Additionally, we highlight their use to induce mucosal tolerance by targeted autoantigen delivery to the intestine as an approach to reverse autoimmune type 1 diabetes. PMID- 29387058 TI - Adaptive Natural Killer Cells Integrate Interleukin-18 during Target-Cell Encounter. AB - Human cytomegalovirus (HCMV) infection induces adaptations in the natural killer (NK)-cell compartment. Expanded subsets of adaptive NK cells display potent effector functions against cellular targets, despite their apparent unresponsiveness to stimulation with classical dendritic cell-derived cytokines interleukin (IL)-12 and IL-18. However, it remains unclear whether adaptive NK cells have completely lost their ability to sense inflammation via IL-12 and IL 18 or whether these pro-inflammatory signals can be functionally integrated into defined contexts. Here, we demonstrate that adaptive NKG2C+ NK cells can be costimulated by the presence of pro-inflammatory cytokines during target cell induced activation. Cytokine costimulation of adaptive NK cells resulted in elevated interferon (IFN)-gamma and tumor necrosis factor (TNF) production, which promoted protein expression of HLA class I and adhesion molecules as well as transcription of genes involved in antigen processing and antiviral states in endothelial bystander cells in vitro. We further show that IL-18 drove costimulation in functional assays and was sufficient for elevated cytokine production in the absence of IL-12. Hence, adaptive NKG2C+ NK cells-although poorly responsive to IL-12 and IL-18 as an isolated stimulus-integrate IL-18 as a costimulatory signal during target-cell encounter. PMID- 29387059 TI - Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes. AB - Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed-Schistosoma infection and Schistosoma-derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma-derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D. PMID- 29387053 TI - Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage Specific Targets. AB - Today, monoclonal antibodies (mAbs) are a widespread and necessary tool for biomedical science. In the hematological cancer field, since rituximab became the first mAb approved by the Food and Drug Administration for the treatment of B cell malignancies, a number of effective mAbs targeting lineage-specific antigens (LSAs) have been successfully developed. Non-LSAs (NLSAs) are molecules that are not restricted to specific leukocyte subsets or tissues but play relevant pathogenic roles in blood cancers including the development, proliferation, survival, and refractoriness to therapy of tumor cells. In consequence, efforts to target NLSAs have resulted in a plethora of mAbs-marketed or in development-to achieve different goals like neutralizing oncogenic pathways, blocking tumor related chemotactic pathways, mobilizing malignant cells from tumor microenvironment to peripheral blood, modulating immune-checkpoints, or delivering cytotoxic drugs into tumor cells. Here, we extensively review several novel mAbs directed against NLSAs undergoing clinical evaluation for treating hematological malignancies. The review focuses on the structure of these antibodies, proposed mechanisms of action, efficacy and safety profile in clinical studies, and their potential applications in the treatment of hematological malignancies. PMID- 29387060 TI - Gene Expression Analysis Reveals Novel Shared Gene Signatures and Candidate Molecular Mechanisms between Pemphigus and Systemic Lupus Erythematosus in CD4+ T Cells. AB - Pemphigus and systemic lupus erythematosus (SLE) are severe potentially life threatening autoimmune diseases. They are classified as B-cell-mediated autoimmune diseases, both depending on autoreactive CD4+ T lymphocytes to modulate the autoimmune B-cell response. Despite the reported association of pemphigus and SLE, the molecular mechanisms underlying their comorbidity remain unknown. Weighted gene co-expression network analysis (WGCNA) of publicly available microarray datasets of CD4+ T cells was performed, to identify shared gene expression signatures and putative overlapping biological molecular mechanisms between pemphigus and SLE. Using WGCNA, we identified 3,280 genes co expressed genes and 14 co-expressed gene clusters, from which one was significantly upregulated for both diseases. The pathways associated with this module include type-1 interferon gamma and defense response to viruses. Network based meta-analysis identified RSAD2 to be the most highly ranked hub gene. By associating the modular genes with genome-wide association studies (GWASs) for pemphigus and SLE, we characterized IRF8 and STAT1 as key regulatory genes. Collectively, in this in silico study, we identify novel candidate genetic markers and pathways in CD4+ T cells that are shared between pemphigus and SLE, which in turn may facilitate the identification of novel therapeutic targets in these diseases. PMID- 29387061 TI - Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors. AB - Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1b, on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection. PMID- 29387062 TI - Equal Pro-inflammatory Profiles of CCLs, CXCLs, and Matrix Metalloproteinases in the Extracellular Microenvironment In Vivo in Human Dense Breast Tissue and Breast Cancer. AB - The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, 7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-alpha, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible. PMID- 29387063 TI - Monocytes Differentiate to Immune Suppressive Precursors of Metastasis-Associated Macrophages in Mouse Models of Metastatic Breast Cancer. AB - Metastasis-associated macrophages (MAMs) play pivotal roles in breast cancer metastasis by promoting extravasation and survival of metastasizing cancer cells. In a metastatic breast cancer mouse model, we previously reported that circulating classical monocytes (C-MOs) preferentially migrated into the tumor challenged lung where they differentiated into MAMs. However, the fate and characteristics of C-MOs in the metastatic site has not been defined. In this study, we identified that adoptively transferred C-MOs (F4/80lowCD11b+Ly6C+) differentiated into a distinct myeloid cell population that is characterized as F4/80highCD11bhighLy6Chigh and gives rise to MAMs (F4/80lowCD11bhighLy6Clow) within 18 h after migration into the metastatic lung. In mouse models of breast cancer, the CD11bhighLy6Chigh MAM precursor cells (MAMPCs) were commonly found in the metastatic lung, and their accumulation was increased during metastatic tumor growth. The morphology and gene expression profile of MAMPCs were distinct from C MOs and had greater similarity to MAMs. For example MAMPCs expressed mature macrophage markers such as CD14, CD36, CD64, and CD206 at comparable levels with MAMs, suggesting that MAMPCs have committed to a macrophage lineage in the tumor microenvironment. MAMPCs also expressed higher levels of Arg1, Hmox1, and Stab1 than C-MOs to a comparable level to MAMs. Expression of these MAM-associated genes in MAMPCs was reduced by genetic deletion of colony-stimulating factor 1 receptor (CSF1R). On the other hand, transient CSF1R blockade did not reduce the number of MAMPCs in the metastatic site, suggesting that CSF1 signaling is active in MAMPCs but is not required for their accumulation. Functionally MAMPCs suppressed the cytotoxicity of activated CD8+ T cells in vitro in part through superoxide production. Overall, our results indicate that immediately following migration into the metastatic tumors C-MOs differentiate into immunosuppressive cells that have characteristics of monocytic myeloid-derived suppressor cell phenotype and might be targeted to enhance efficacy of immunotherapy for metastatic breast cancer. PMID- 29387064 TI - Epstein-Barr Virus Susceptibility in Activated PI3Kdelta Syndrome (APDS) Immunodeficiency. AB - Activated PI3Kdelta Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kdelta) subunits p110delta or p85delta. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein-Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility. PMID- 29387065 TI - Heterogeneity of the Type I Interferon Signature in Rheumatoid Arthritis: A Potential Limitation for Its Use As a Clinical Biomarker. AB - Introduction: An increased expression of interferon (IFN)-responding genes (IRGs), the so-called IFN signature, has been reported in rheumatoid arthritis (RA). However, some controversy exists concerning its clinical relevance. The main aim of this study is to evaluate whether quantitative and qualitative differences in the activation of the IFN pathway may account for these findings. Methods: The expression of IFN-induced protein 44 (IFI44), IFN-induced protein 44 like (IFI44L), IFN alpha inducible protein 6, and MX dynamin-like GTPase 1 (MX1) was determined in peripheral blood in 98 RA patients (IFI6) and 28 controls. RA patients were classified into groups according to their clinical stage and treatments received: very early RA (VERA), biological disease-modifying antirheumatic drug (bDMARD) naive, and bDMARD. An additional group of 13 RA patients candidates for tumor necrosis factor alpha (TNFalpha) blockade was also recruited. The associations among IRGs were evaluated by network and principal component analyses. Results: The expression of all IRGs was increased in RA to different levels. The IFN score was increased in all RA groups (VERA, bDMARD naive, and bDMARD), but important differences in their degree of activation and in the relationships among IRGs were observed. The IFN score correlated with the accumulated disease activity score 28-joints, and it was found to be a predictor of clinical outcome in VERA. No differences in the IFN score were observed between the bDMARD-naive and bDMARD groups, but opposite associations with the clinical parameters were noted. Interestingly, the correlations among IRGs delineate different pictures between these two groups. The IFN score at baseline predicted poor clinical outcome upon TNFalpha blockade. Although no absolute changes in the IFN score were found, TNFalpha-blockade shifted the associations among IRGs. Conclusion: A certain heterogeneity within the IFN signature can be recognized in RA, depending on the clinical stage. The structure of the IFN signature may be a potential explanation for the controversy in this field and must be considered to decipher its clinical relevancein RA. PMID- 29387066 TI - Development of a Preventive HIV Vaccine Requires Solving Inverse Problems Which Is Unattainable by Rational Vaccine Design. AB - Hypotheses and theories are essential constituents of the scientific method. Many vaccinologists are unaware that the problems they try to solve are mostly inverse problems that consist in imagining what could bring about a desired outcome. An inverse problem starts with the result and tries to guess what are the multiple causes that could have produced it. Compared to the usual direct scientific problems that start with the causes and derive or calculate the results using deductive reasoning and known mechanisms, solving an inverse problem uses a less reliable inductive approach and requires the development of a theoretical model that may have different solutions or none at all. Unsuccessful attempts to solve inverse problems in HIV vaccinology by reductionist methods, systems biology and structure-based reverse vaccinology are described. The popular strategy known as rational vaccine design is unable to solve the multiple inverse problems faced by HIV vaccine developers. The term "rational" is derived from "rational drug design" which uses the 3D structure of a biological target for designing molecules that will selectively bind to it and inhibit its biological activity. In vaccine design, however, the word "rational" simply means that the investigator is concentrating on parts of the system for which molecular information is available. The economist and Nobel laureate Herbert Simon introduced the concept of "bounded rationality" to explain why the complexity of the world economic system makes it impossible, for instance, to predict an event like the financial crash of 2007-2008. Humans always operate under unavoidable constraints such as insufficient information, a limited capacity to process huge amounts of data and a limited amount of time available to reach a decision. Such limitations always prevent us from achieving the complete understanding and optimization of a complex system that would be needed to achieve a truly rational design process. This is why the complexity of the human immune system prevents us from rationally designing an HIV vaccine by solving inverse problems. PMID- 29387067 TI - Brucella Downregulates Tumor Necrosis Factor-alpha to Promote Intracellular Survival via Omp25 Regulation of Different MicroRNAs in Porcine and Murine Macrophages. AB - Brucella spp. impedes the production of pro-inflammatory cytokines by its outer membrane protein Omp25 in order to promote survival and immune evasion. However, how Omp25 regulates tumor necrosis factor (TNF-alpha) expression in different mammalian macrophages remains unclear. In this study, we investigated the potential mechanisms by which Omp25 regulates TNF-alpha expression and found that Omp25-deficient mutant of B. suis exhibited an enhanced TNF-alpha expression compared with wild-type (WT) B. suis, whereas ectopic expression of Omp25 suppressed LPS-induced TNF-alpha production at both protein and mRNA levels in porcine alveolar macrophages (PAMs) and murine macrophage RAW264.7 cells. We observed that Omp25 protein as well as WT B. suis upregulated miR-146a, -181a, 181b, and -301a-3p and downregulated TRAF6 and IRAK1 in both PAMs and RAW264.7 cells, but separately upregulates miR-130a-3p in PAMs and miR-351-5p in RAW264.7. The upregulation of miR-146a or miR-351-5p attenuated TNF-alpha transcription by targeting TRAF6 and IRAK1 at the 3' untranslated region (UTR), resulting in inhibition of NF-kB pathway, while upregulation of miR-130a-3p, -181a, or -301a 3p correlated temporally with decreased TNF-alpha by targeting its 3'UTR in PAMs or RAW264.7 cells. In contrast, inhibition of miR-130a-3p, -146a, -181a, and 301a-3p attenuated the inhibitory effects of Omp25 on LPS-induced TNF-alpha in PAMs, while inhibition of miR-146a, -181a, -301a-3p, and -351-5p attenuated the inhibitory effects of Omp25 in RAW264.7, resulting in an increased TNF-alpha production and decreased intracellular bacteria in both cells. Taken together, our results demonstrate that Brucella downregulates TNF-alpha to promote intracellular survival via Omp25 regulation of different microRNAs in porcine and murine macrophages. PMID- 29387068 TI - Enhanced Antibody Responses in a Novel NOG Transgenic Mouse with Restored Lymph Node Organogenesis. AB - Lymph nodes (LNs) are at the center of adaptive immune responses. Various exogenous substances are transported into LNs and a series of immune responses ensue after recognition by antigen-specific lymphocytes. Although humanized mice have been used to reconstitute the human immune system, most lack LNs due to deficiency of the interleukin (IL)-2Rgamma gene (cytokine common gamma chain, gammac). In this study, we established a transgenic strain, NOG-pRORgammat gammac, in the NOD/shi-scid-IL-2Rgammanull (NOG) background, in which the gammac gene was expressed in a lymph-tissue inducer (LTi) lineage by the endogenous promoter of RORgammat. In this strain, LN organogenesis was normalized and the number of human T cells substantially increased in the periphery after reconstitution of the human immune system by human hematopoietic stem cell transplantation. The distribution of human T cells differed between NOG pRORgammat-gammac Tg and NOG-non Tg mice. About 40% of human T cells resided in LNs, primarily the mesenteric LNs. The LN-complemented humanized mice exhibited antigen-specific immunoglobulin G responses together and an increased number of IL-21+-producing CD4+ T cells in LNs. This novel mouse strain will facilitate recapitulation of human immune responses. PMID- 29387069 TI - NDH-1 Is Important for Photosystem I Function of Synechocystis sp. Strain PCC 6803 under Environmental Stress Conditions. AB - Cyanobacterial NDH-1 interacts with photosystem I (PSI) to form an NDH-1-PSI supercomplex. Here, we observed that absence of NDH-1 had little, if any, effect on the functional fractions of PSI under growth conditions, but significantly reduced the functional fractions of PSI when cells of Synechocystis sp. strain PCC 6803 were moved to conditions of multiple stresses. The significant reduction in NDH-1-dependent functional fraction of PSI was initiated after PSII activity was impaired. This finding is consistent with our observation that the functional fraction of PSI under growth conditions was rapidly and significantly decreased with increasing concentrations of DCMU, which rapidly and significantly suppressed PSII activity by blocking the transfer of electrons from QA to QB in the PSII reaction center. Furthermore, absence of NDH-1 resulted in the PSI limitation at the functionality of PSI itself but not its donor-side and acceptor side under conditions of multiple stresses. This was supported by the result of a significant destabilization of the PSI complex in the absence of NDH-1 but the presence of multiple stresses. Based on the above results, we propose that NDH-1 is important for PSI function of Synechocystis sp. strain PCC 6803 mainly via maintaining stabilization of PSI under conditions of environmental stresses. PMID- 29387070 TI - Short-term Responses of Posidonia australis to Changes in Light Quality. AB - Seagrass meadows are highly productive ecosystems that provide ecosystem services to the coastal zone but are declining globally, particularly due to anthropogenic activities that reduce the quantity of light reaching seagrasses, such as dredging, river discharge and eutrophication. Light quality (the spectral composition of the light) is also altered by these anthropogenic stressors as the differential attenuation of wavelengths of light is caused by materials within the water column. This study addressed the effect of altered light quality on different life-history stages of the seagrass Posidonia australis, a persistent, habitat-forming species in Australia. Aquarium-based experiments were conducted to determine how adult shoots and seedlings respond to blue (peak lambda = 451 nm); green (peak lambda = 522 nm); yellow (peak lambda = 596 nm) and red (peak lambda = 673 nm) wavelengths with a control of full-spectrum light (lambda = 400 700 nm, at 200 MUmol photons m-2 s-1). Posidonia australis adults did not respond to changes in light quality relative to full-spectrum light, demonstrating a capacity to obtain enough photons from a range of wavelengths across the visible spectrum to maintain short-term growth at high irradiances. Posidonia australis seedlings (<4 months old) grown in blue light showed a significant increase in xanthophyll concentrations when compared to plants grown in full-spectrum, demonstrating a pigment acclimation response to blue light. These results differed significantly from negative responses to changes in light quality recently described for Halophila ovalis, a colonizing seagrass species. Persistent seagrasses such as P. australis, appear to be better at tolerating short-term changes in light quality compared to colonizing species when sufficient PPFD is present. PMID- 29387071 TI - Sunflower Hybrid Breeding: From Markers to Genomic Selection. AB - In sunflower, molecular markers for simple traits as, e.g., fertility restoration, high oleic acid content, herbicide tolerance or resistances to Plasmopara halstedii, Puccinia helianthi, or Orobanche cumana have been successfully used in marker-assisted breeding programs for years. However, agronomically important complex quantitative traits like yield, heterosis, drought tolerance, oil content or selection for disease resistance, e.g., against Sclerotinia sclerotiorum have been challenging and will require genome-wide approaches. Plant genetic resources for sunflower are being collected and conserved worldwide that represent valuable resources to study complex traits. Sunflower association panels provide the basis for genome-wide association studies, overcoming disadvantages of biparental populations. Advances in technologies and the availability of the sunflower genome sequence made novel approaches on the whole genome level possible. Genotype-by-sequencing, and whole genome sequencing based on next generation sequencing technologies facilitated the production of large amounts of SNP markers for high density maps as well as SNP arrays and allowed genome-wide association studies and genomic selection in sunflower. Genome wide or candidate gene based association studies have been performed for traits like branching, flowering time, resistance to Sclerotinia head and stalk rot. First steps in genomic selection with regard to hybrid performance and hybrid oil content have shown that genomic selection can successfully address complex quantitative traits in sunflower and will help to speed up sunflower breeding programs in the future. To make sunflower more competitive toward other oil crops higher levels of resistance against pathogens and better yield performance are required. In addition, optimizing plant architecture toward a more complex growth type for higher plant densities has the potential to considerably increase yields per hectare. Integrative approaches combining omic technologies (genomics, transcriptomics, proteomics, metabolomics and phenomics) using bioinformatic tools will facilitate the identification of target genes and markers for complex traits and will give a better insight into the mechanisms behind the traits. PMID- 29387073 TI - Seed Heteromorphism and Effects of Light and Abiotic Stress on Germination of a Typical Annual Halophyte Salsola ferganica in Cold Desert. AB - Seed heteromorphism is a common characteristic of halophyte and an adaptation to the spatial and temporal variations of natural habitats. Differences in dormancy and germination requirements have been documented in heteromorphic seeds of many species, but the mechanisms for maintenance between different status in various populations have not been well-understood. Salsola ferganica is a typical annual halophyte in Chenopodiaceae distributed in cold desert, in the present study, we found that it could produce three distinct types of seed according to the shape and size of winged perianth (WP), which differed in dispersal ability, dormancy and germination behaviors. Our further investigation revealed that light could significantly promote germination of heteromorphic seeds of S. ferganica, and WP inhibited while GA3 enhanced germination, which suggests that S. ferganica seeds possessed a photo-sensitive combined with morphological and non-deep physiological dormancy type, in which light was the dominant factor. Not like other desert plant species, the germinability of heteromorphic seeds of S. ferganica could not sustain for long (only 1-2 years), especially the small seeds, and was affected by storage time, temperature, salinity, even the environmental conditions of the maternal plant. Thus, the differences of characteristics existed among heteromorphic seeds and variations of heteromorphic ratio among different calendar years were presumed as diverse adaptation strategies integrated in the individual mother plant, and might apply important ecological significance for successful reproduction of the species in the unpredictable cold desert. PMID- 29387072 TI - Induction of Terpene Biosynthesis in Berries of Microvine Transformed with VvDXS1 Alleles. AB - Terpenoids, especially monoterpenes, are major aroma-impact compounds in grape and wine. Previous studies highlighted a key regulatory role for grapevine 1 deoxy-D-xylulose 5-phosphate synthase 1 (VvDXS1), the first enzyme of the methylerythritol phosphate pathway for isoprenoid precursor biosynthesis. Here, the parallel analysis of VvDXS1 genotype and terpene concentration in a germplasm collection demonstrated that VvDXS1 sequence has a very high predictive value for the accumulation of monoterpenes and also has an influence on sesquiterpene levels. A metabolic engineering approach was applied by expressing distinct VvDXS1 alleles in the grapevine model system "microvine" and assessing the effects on downstream pathways at transcriptional and metabolic level in different organs and fruit developmental stages. The underlying goal was to investigate two potential perturbation mechanisms, the former based on a significant over-expression of the wild-type (neutral) VvDXS1 allele and the latter on the ex-novo expression of an enzyme with increased catalytic efficiency from the mutated (muscat) VvDXS1 allele. The integration of the two VvDXS1 alleles in distinct microvine lines was found to alter the expression of several terpenoid biosynthetic genes, as assayed through an ad hoc developed TaqMan array based on cDNA libraries of four aromatic cultivars. In particular, enhanced transcription of monoterpene, sesquiterpene and carotenoid pathway genes was observed. The accumulation of monoterpenes in ripe berries was higher in the transformed microvines compared to control plants. This effect is predominantly attributed to the improved activity of the VvDXS1 enzyme coded by the muscat allele, whereas the up-regulation of VvDXS1 plays a secondary role in the increase of monoterpenes. PMID- 29387074 TI - A Novel L-ascorbate Peroxidase 6 Gene, ScAPX6, Plays an Important Role in the Regulation of Response to Biotic and Abiotic Stresses in Sugarcane. AB - The L-ascorbate peroxidase 6 gene (APX6) is one of the most important genes for scavenging H2O2 and plays a vital role in plant resistance to environmental stresses. In this study, a novel ScAPX6 gene (GenBank Accession No. KT907352) was obtained from a sugarcane variety (ROC22). Bioinformatics analysis showed that ScAPX6 has a cDNA length of 1,086 bp and encoded 333 amino acid residues. Subcellular localization confirmed that ScAPX6 was located in the chloroplast. Enhanced growth of Escherichia coli BL21 cells that expressed ScAPX6 showed high tolerance under copper (Cu) stress. Real-time quantitative PCR analysis revealed that ScAPX6 was constitutively expressed wherein with the highest expression levels in sugarcane pith and leaf and the lowest in the root. ScAPX6 was down regulated by salicylic acid (SA), hydrogen peroxide (H2O2), polyethylene glycol (PEG) and sodium chloride (NaCl) stimuli. Interestingly, it was significantly up regulated under the stresses of abscisic acid (ABA) and methyl jasmonate (MeJA) wherein with the highest inducible expression levels at 6 h at 6.0- and 70.0 times higher, respectively than that of control. Overexpression of ScAPX6 in Nicotiana benthamiana leaves enhanced the resistance to the infection of tobacco pathogens Pseudomonas solanacearum and Fusarium solani var. coeruleum. These results implied that ScAPX6 might positively respond to ABA, MeJA, and Cu, but might negatively respond to the stresses of SA, H2O2, PEG, and NaCl. Keeping in view the current investigation, ScAPX6 could be associated with the hypersensitive response (HR) or immunity of sugarcane, which will provide a baseline for the function identification of sugarcane ScAPX6. PMID- 29387075 TI - Quantitative Palynology Informing Conservation Ecology in the Bohemian/Bavarian Forests of Central Europe. AB - In 1927, the first pollen diagram was published from the Bohemian/Bavarian Forest region of Central Europe, providing one of the first qualitative views of the long-term vegetation development in the region. Since then significant methodological advances in quantitative approaches such as pollen influx and pollen-based vegetation models (e.g., Landscape Reconstruction Algorithm, LRA) have contributed to enhance our understanding of temporal and spatial ecology. These types of quantitative reconstructions are fundamental for conservation and restoration ecology because they provide long-term perspectives on ecosystem functioning. In the Bohemian/Bavarian Forests, forest managers have a goal to restore the original forest composition at mid-elevation forests, yet they rely on natural potential vegetation maps that do not take into account long-term vegetation dynamics. Here we reconstruct the Holocene history of forest composition and discuss the implications the LRA has for regional forest management and conservation. Two newly analyzed pollen records from Prasilske jezero and Rachelsee were compared to 10 regional peat bogs/mires and two other regional lakes to reconstruct total land-cover abundance at both the regional- and local-scales. The results demonstrate that spruce has been the dominant canopy cover across the region for the past 9,000 years at both high- (>900 m) and mid-elevations (>700-900 m). At the regional-scale inferred from lake records, spruce has comprised an average of ~50% of the total forest canopy; whereas at the more local-scale at mid-elevations, spruce formed ~59%. Beech established ~6,000 cal. years BP while fir established later around 5,500 cal. years BP. Beech and fir growing at mid-elevations reached a maximum land-cover abundance of 24% and 13% roughly 1,000 years ago. Over the past 500 years spruce has comprised ~47% land-cover, while beech and fir comprised ~8% and <5% at mid elevations. This approach argues for the "natural" development of spruce and fir locally in zones where the paleoecology indicates the persistence of these species for millennia. Contrasting local and regional reconstructions of forest canopy cover points to a patchwork mosaic with local variability in the dominant taxa. Incorporation of paleoecological data in dialogues about biodiversity and ecosystem management is an approach that has wider utility. PMID- 29387076 TI - Improvement of Salt Tolerance Using Wild Rice Genes. AB - Salt stress causes significant reductions in rice production worldwide; thus, improving salt tolerance is a promising approach to meet the increasing food demand. Wild rice germplasm is considered a valuable genetic resource for improving rice cultivars. However, information regarding the improvement of salt tolerance in cultivated rice using wild rice genes is limited. In this study, we identified a salt-tolerant line Dongxiang/Ningjing 15 (DJ15) under salt-stress field conditions from the population of a salt tolerant Dongxiang wild rice * a cultivated rice variety Ningjing16 (NJ16). Genomic resequencing analysis of NJ16, DJ15 and Dongxiang wild rice revealed that the introgressed genomic fragments were unevenly distributed over the 12 chromosomes (Chr.) and mainly identified on Chr. 6, 7, 10, and 11. Using quantitative trait locus (QTL) mapping, we found 9 QTL for salt tolerance (qST) at the seedling stage located on Chr. 1, 3, 4, 5, 6, 8, and 10. In addition, sequence variant analysis within the QTL regions demonstrated that SKC1/HKT8/HKT1;5 and HAK6 transporters along with numerous transcriptional factors were the candidate genes for the salt tolerant QTL. The DJ15/Koshihikari recombinant inbred lines that contained both qST1.2 and qST6, two QTL with the highest effect for salt tolerance, were more tolerant than the parental lines under salt-stress field conditions. Furthermore, the qST6 near isogenic lines with IR29 background were more tolerant than IR29, indicating that qST1.2 and qST6 could improve salt tolerance in rice. Overall, our study indicates that wild rice genes could markedly improve the salt tolerance of cultivated rice. PMID- 29387077 TI - Transmission Efficiency, Preference and Behavior of Bemisia tabaci MEAM1 and MED under the Influence of Tomato Chlorosis Virus. AB - Tomato chlorosis virus (ToCV, genus Crinivirus, family Closteroviridae) is an economically important virus in more than 20 countries. In China, ToCV was first detected in 2013 and has already spread throughout the country. ToCV is transmitted in a semi-persistent manner by the whitefly, Bemisia tabaci, but not seed. In the past two decades, the most invasive MEAM1 and MED have replaced the indigenous B. tabaci in China, and currently MED is the most dominant cryptic species. To better understand the prevalence of ToCV with their vectors, we tested the hypothesis that the rapid spread of ToCV in China is closely related to the dominance of MED. ToCV acquisition and accumulation rate following transmission was significantly higher by MED than MEAM1. In addition, ToCV persisted for more than 4 days in MED but only 2 days in MEAM1. Viruliferous MED preferred non-infected over virus-infected plants, although MED performed better on infected than on non-infected plants. Our combined results support the initial hypothesis that the rapid spread of ToCV is associated with the spread of B. tabaci MED in China. PMID- 29387078 TI - Gbvdr6, a Gene Encoding a Receptor-Like Protein of Cotton (Gossypium barbadense), Confers Resistance to Verticillium Wilt in Arabidopsis and Upland Cotton. AB - Verticillium wilt is a soil-borne disease that can cause devastating losses in cotton production. Because there is no effective chemical means to combat the disease, the only effective way to control Verticillium wilt is through genetic improvement. Therefore, the identification of additional disease-resistance genes will benefit efforts toward the genetic improvement of cotton resistance to Verticillium wilt. Based on screening of a BAC library with a partial Ve homologous fragment and expression analysis, a V. dahliae-induced gene, Gbvdr6, was isolated and cloned from the Verticillium wilt-resistant cotton G. barbadense cultivar Hai7124. The gene was located in the gene cluster containing Gbve1 and Gbvdr5 and adjacent to the Verticillium wilt-resistance QTL hotspot. Gbvdr6 was induced by Verticillium dahliae Kleb and by the plant hormones salicylic acid (SA), methyl jasmonate (MeJA) and ethephon (ETH) but not by abscisic acid (ABA). Gbvdr6 was localized to the plasma membrane. Overexpression of Gbvdr6 in Arabidopsis and cotton enhanced resistance to V. dahliae. Moreover, the JA/ET signaling pathway-related genes PR3, PDF 1.2, ERF1 and the SA-related genes PR1 and PR2 were constitutively expressed in transgenic plants. Gbvdr6-overexpressing Arabidopsis was less sensitive than the wild-type plant to MeJA. Furthermore, the accumulation of reactive oxygen species and callose was triggered at early time points after V. dahliae infection. These results suggest that Gbvdr6 confers resistance to V. dahliae through regulation of the JA/ET and SA signaling pathways. PMID- 29387081 TI - Corrigendum: Reference Genes for qPCR Analysis in Resin-Tapped Adult Slash Pine As a Tool to Address the Molecular Basis of Commercial Resinosis. AB - [This corrects the article on p. 849 in vol. 7, PMID: 27379135.]. PMID- 29387080 TI - Method for the Identification of Taxon-Specific k-mers from Chloroplast Genome: A Case Study on Tomato Plant (Solanum lycopersicum). AB - Polymerase chain reaction and different barcoding methods commonly used for plant identification from metagenomics samples are based on the amplification of a limited number of pre-selected barcoding regions. These methods are often inapplicable due to DNA degradation, low amplification success or low species discriminative power of selected genomic regions. Here we introduce a method for the rapid identification of plant taxon-specific k-mers, that is applicable for the fast detection of plant taxa directly from raw sequencing reads without aligning, mapping or assembling the reads. We identified more than 800 Solanum lycopersicum specific k-mers (32 nucleotides in length) from 42 different chloroplast genome regions using the developed method. We demonstrated that identified k-mers are also detectable in whole genome sequencing raw reads from S. lycopersicum. Also, we demonstrated the usability of taxon-specific k-mers in artificial mixtures of sequences from closely related species. Developed method offers a novel strategy for fast identification of taxon-specific genome regions and offers new perspectives for detection of plant taxa directly from sequencing raw reads. PMID- 29387079 TI - Plant Deubiquitinases and Their Role in the Control of Gene Expression Through Modification of Histones. AB - Selective degradation of proteins in the cell occurs through ubiquitination, which consists of post-translational deposition of ubiquitin on proteins to target them for degradation by proteases. However, ubiquitination does not only impact on protein stability, but promotes changes in their functions. Whereas the deposition of ubiquitin has been amply studied and discussed, the antagonistic activity, deubiquitination, is just emerging and the full model and players involved in this mechanism are far from being completely understood. Nevertheless, it is the dynamic balance between ubiquitination and deubiquitination that is essential for the development and homeostasis of organisms. In this review, we present a detailed analysis of the members of the deubiquitinase (DUB) superfamily in plants and its division in different clades. We describe current knowledge in the molecular and functional characterisation of DUB proteins, focusing primarily on Arabidopsis thaliana. In addition, the striking function of the duality between ubiquitination and deubiquitination in the control of gene expression through the modification of chromatin is discussed and, using the available information of the activities of the DUB superfamily in yeast and animals as scaffold, we propose possible scenarios for the role of these proteins in plants. PMID- 29387082 TI - Comprehensive Characterization of the RNA Editomes in Cancer Development and Progression. AB - RNA editing is a post-transcriptional event that leads to transcriptome diversity and has been shown to play important roles in tumorigenesis. However, dynamical changes and the functional significance of editing events during different cancer stages have not yet been characterized systematically. In this paper, we describe a comprehensive study of the RNA editome of four samples from different cancer stages for the same patient based on analysis of both whole-genome and transcriptome sequencing data. We identified 35,225 and 33,784 RNA editing events for poly(A)+ and poly(A)- RNA sequencing data respectively in all four samples and show that 93 and 90% correspond to cancer stage-specific editing events. We also found that half of editing sites in 3' UTR of coding genes were microRNA targets and most of the sites in the coding regions could lead to non-synonymous amino acid changes. Functional analysis of genes which suffered damaging non synonymous editing events in each cancer stage show the gradual expansion of cancer related pathways accompanied by an increasing malignant grade of the samples. Our study, for the first time to our knowledge, comprehensively profiled and compared the editomes across the different cancer stages and revealed the functional impacts of RNA editing events during cancer development and progression. PMID- 29387083 TI - Genetic Pattern and Demographic History of Salminus brasiliensis: Population Expansion in the Pantanal Region during the Pleistocene. AB - Pleistocene climate changes were major historical events that impacted South American biodiversity. Although the effects of such changes are well-documented for several biomes, it is poorly known how these climate shifts affected the biodiversity of the Pantanal floodplain. Fish are one of the most diverse groups in the Pantanal floodplains and can be taken as a suitable biological model for reconstructing paleoenvironmental scenarios. To identify the effects of Pleistocene climate changes on Pantanal's ichthyofauna, we used genetic data from multiple populations of a top-predator long-distance migratory fish, Salminus brasiliensis. We specifically investigated whether Pleistocene climate changes affected the demography of this species. If this was the case, we expected to find changes in population size over time. Thus, we assessed the genetic diversity of S. brasiliensis to trace the demographic history of nine populations from the Upper Paraguay basin, which includes the Pantanal floodplain, that form a single genetic group, employing approximate Bayesian computation (ABC) to test five scenarios: constant population, old expansion, old decline, old bottleneck following by recent expansion, and old expansion following by recent decline. Based on two mitochondrial DNA markers, our inferences from ABC analysis, the results of Bayesian skyline plot, the implications of star-like networks, and the patterns of genetic diversity (high haplotype diversity and low-to-moderate nucleotide diversity) indicated a sudden population expansion. ABC allowed us to make strong quantitative inferences about the demographic history of S. brasiliensis. We estimated a small ancestral population size that underwent a drastic fivefold expansion, probably associated with the colonization of newly formed habitats. The estimated time of this expansion was consistent with a humid and warm phase as inferred by speleothem growth phases and travertine records during Pleistocene interglacial periods. The strong concordance between our genetic inferences and this historical data could represent the first genetic record of a humid and warm phase in the Pantanal in the period since the Last Interglacial to 40 ka. PMID- 29387085 TI - Preparation and Anticorrosion of Octadecyl Trichlorosilane SAMs for Copper Surface. AB - The self-assembled monolayer (SAM) was prepared using octadecyl trichlorosilane (OTS) in distilled solution on the copper surface. The effect of inhibitor concentration on the rate of inhibition efficiency and corrosion rate in corrosion medium on copper by using polarization curves, electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM) was studied. The results showed that OTS SAMs exhibit the better corrosion resistance; the corrosion potential of copper OTS SAMs protection increased by about 1.02 V, while the corrosion current density decreased to 0.59 MUA/cm2. The corrosion rate is minimized and flattened and can reach 9.2% while the inhibition efficiency reached 95.4%, when the corrosion inhibitor has concentration of 40 ppm. PMID- 29387084 TI - A New Murine Model of Chronic Kidney Disease-Mineral and Bone Disorder. AB - Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which is the main cause of the extensively increased cardiovascular mortality in the CKD population. We now aimed to establish a new murine experimental CKD-MBD model. Dilute brown non-Agouti (DBA/2) mice were fed with high-phosphate diet for 4 (HPD4) or 7 (HPD7) days, then with standard chow diet (SCD) and subsequently followed until day 84. They were compared to DBA/2 mice maintained on SCD during the whole study period. Both 4 and 7 days HPD-fed mice developed phosphate nephropathy with tubular atrophy, interstitial fibrosis, decreased glomerular filtration rate, and increased serum urea levels. The abdominal aorta of HPD treated mice showed signs of media calcification. Histomorphometric analysis of HPD-treated mice showed decreased bone volume/tissue volume, low mineral apposition rate, and low bone formation rate as compared to SCD-fed mice, despite increased parathyroid hormone levels. Overall, the observed phenotype was more pronounced in the HPD7 group. In summary, we established a new, noninvasive, and therefore easy to perform reproducible CKD-MBD model, which showed media calcification, secondary hyperparathyroidism, and low-turnover bone disease. PMID- 29387086 TI - Analytical Strategies Involved in the Detailed Componential Characterization of Biooil Produced from Lignocellulosic Biomass. AB - Elucidation of chemical composition of biooil is essentially important to evaluate the process of lignocellulosic biomass (LCBM) conversion and its upgrading and suggest proper value-added utilization like producing fuel and feedstock for fine chemicals. Although the main components of LCBM are cellulose, hemicelluloses, and lignin, the chemicals derived from LCBM differ significantly due to the various feedstock and methods used for the decomposition. Biooil, produced from pyrolysis of LCBM, contains hundreds of organic chemicals with various classes. This review covers the methodologies used for the componential analysis of biooil, including pretreatments and instrumental analysis techniques. The use of chromatographic and spectrometric methods was highlighted, covering the conventional techniques such as gas chromatography, high performance liquid chromatography, Fourier transform infrared spectroscopy, nuclear magnetic resonance, and mass spectrometry. The combination of preseparation methods and instrumental technologies is a robust pathway for the detailed componential characterization of biooil. The organic species in biooils can be classified into alkanes, alkenes, alkynes, benzene-ring containing hydrocarbons, ethers, alcohols, phenols, aldehydes, ketones, esters, carboxylic acids, and other heteroatomic organic compounds. The recent development of high resolution mass spectrometry and multidimensional hyphenated chromatographic and spectrometric techniques has considerably elucidated the composition of biooils. PMID- 29387087 TI - Kikuchi-Fujimoto Disease in an Old Italian Woman: Case Report and Review of the Literature. AB - Kikuchi-Fujimoto disease (KFD) is a rare, benign, generally self-limiting disease that has higher prevalence in Asian people with a few cases reported in European countries. It generally affects young subjects under 40 years of age and is characterized by regional lymphadenopathy. Here, we present a case of a 66-year old Italian woman who was extensively examined for right unilateral laterocervical lymph nodes associated with fever, night sweats, fatigue, and weight loss. She was diagnosed as having the KFD only after an excision biopsy of the largest laterocervical lymph node and was then managed symptomatically with NSAIDs. We also made a review of the literature for better awareness of the disease among physicians especially in those countries, like Italy, where the disease is not prevalent and may be frequently misdiagnosed. In fact, to our best knowledge, only seven Italian cases of KFD have been published in the last 15 years with patients being younger than 40 years. We finally highlight that it is noteworthy to consider KFD as differential diagnosis of lymphadenopathy even in old patients, and, since a misdiagnosis of lymphoma is actually feasible, an early biopsy has to be taken into account for confirming diagnosis and helping in the timely and appropriate management. PMID- 29387088 TI - Stemness Characteristics of Periodontal Ligament Stem Cells from Donors and Multiple Sclerosis Patients: A Comparative Study. AB - Multiple sclerosis (MS) is the most prevalent and progressive autoimmune disease that affects the central nervous system, and currently, no drug is available for the treatment. Stem cell therapy has received substantial attention in MS treatment. Recently, we demonstrated the immunosuppressive effects of mesenchymal stem cells derived from neural crest-originated human periodontal ligament tissue (hPDLSCs) in an in vivo model of MS. In the present study, we comparatively investigated the stemness properties of hPDLSCs derived from healthy donors and relapsing-remitting MS patients. Stem cell marker expression, cell proliferation, and differentiation capacity were studied. We found that both donor- and MS patient-derived hPDLSCs at early passage 2 showed similar expression of surface antigen markers and cell proliferation rate. Significant level of osteogenic, adipogenic, chondrogenic, and neurogenic differentiation capacities was observed in both donor- and MS patient-derived hPDLSCs. Interestingly, these cells maintained the stemness properties even at late passage 15. Senescence markers p16 and p21 expression was considerably enhanced in passage 15. Our results propose that hPDLSCs may serve as simple and potential autologous stem cell niche, which may help in personalized stem cell therapy for MS patients. PMID- 29387089 TI - Impact of Tissue Harvesting Sites on the Cellular Behaviors of Adipose-Derived Stem Cells: Implication for Bone Tissue Engineering. AB - The advantages of adipose-derived stem cells (AdSCs) over bone marrow stem cells (BMSCs), such as being available as a medical waste and less discomfort during harvest, have made them a good alternative instead of BMSCs in tissue engineering. AdSCs from buccal fat pad (BFP), as an easily harvestable and accessible source, have gained interest to be used for bone regeneration in the maxillofacial region. Due to scarcity of data regarding comparative analysis of isolated AdSCs from different parts of the body, we aimed to quantitatively compare the proliferation and osteogenic capabilities of AdSCs from different harvesting sites. In this study, AdSCs were isolated from BFP (BFPdSCs), abdomen (abdomen-derived mesenchymal stem cells (AbdSCs)), and hip (hip-derived mesenchymal stem cells (HdSCs)) from one individual and were compared for surface marker expression, morphology, growth rate, and osteogenic differentiation capability. Among them, BFPdSCs demonstrated the highest proliferation rate with the shortest doubling time and also expressed vascular endothelial markers including CD34 and CD146. Moreover, the expression of osteogenic markers were significantly higher in BFPdSCs. The results of this study suggested that BFPdSCs as an encouraging source of mesenchymal stem cells are to be used for bone tissue engineering. PMID- 29387090 TI - Long Noncoding RNA uc001pwg.1 Is Downregulated in Neointima in Arteriovenous Fistulas and Mediates the Function of Endothelial Cells Derived from Pluripotent Stem Cells. AB - Recent studies indicate important roles for long noncoding RNAs (lncRNAs) as essential regulators of gene expression. However, the specific roles of lncRNAs in stenotic lesions of arteriovenous fistula (AVF) failure are still largely unknown. We first analyzed the expression profiles of lncRNAs in human stenosed and nonstenotic uremic veins using RNA-sequencing methodology. A total of 19 lncRNAs were found to be differentially expressed in stenotic lesions. Among these, uc001pwg.1 was one of the most significantly downregulated lncRNAs and enriched in both control vein segments and human umbilical vein endothelial cells (HUVECs). Further studies revealed that uc001pwg.1 overexpression could increase nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production in endothelial cells (ECs) derived from human-induced pluripotent stem cells (HiPSCs). Mechanistically, uc001pwg.1 improves endothelial function via mediating MCAM expression. This study represents the first effort of identifying a novel candidate lncRNA for modulating the function of iPSC-ECs, which may facilitate the improvement of stem cell-based therapies for AVF failure. PMID- 29387091 TI - Different Effects of Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor 2 on Myogenic Differentiation of Human Mesenchymal Stem Cells. AB - Insulin-like growth factors (IGFs) are critical components of the stem cell niche, as they regulate proliferation and differentiation of stem cells into different lineages, including skeletal muscle. We have previously reported that insulin-like growth factor binding protein-6 (IGFBP-6), which has high affinity for IGF-2, alters the differentiation process of placental mesenchymal stem cells (PMSCs) into skeletal muscle. In this study, we determined the roles of IGF-1 and IGF-2 and their interactions with IGFBP-6. We showed that IGF-1 increased IGFBP-6 levels within 24 hours but decreased after 3 days, while IGF-2 maintained higher levels of IGFBP-6 throughout myogenesis. IGF-1 increased IGFBP-6 in the early phase as a requirement for muscle commitment. In contrast, IGF-2 enhanced muscle differentiation as shown by the expression of muscle differentiation markers MyoD, MyoG, and MHC. IGF-1 and IGF-2 had different effects on muscle differentiation with IGF-1 promoting early commitment to muscle and IGF-2 promoting complete muscle differentiation. We also showed that PMSCs acquired increasing capacity to synthesize IGF-2 during muscle differentiation, and the capacity increased as the differentiation progressed suggesting an autocrine and/or paracrine effect. Additionally, we demonstrated that IGFBP-6 could enhance the muscle differentiation process in the absence of IGF-2. PMID- 29387092 TI - Mesenchymal Stem Cells Protect Nucleus Pulposus Cells from Compression-Induced Apoptosis by Inhibiting the Mitochondrial Pathway. AB - Objective: Excessive apoptosis of nucleus pulposus cells (NPCs) induced by various stresses, including compression, contributes to the development of intervertebral disc degeneration (IVDD). Mesenchymal stem cells (MSCs) can benefit the regeneration of NPCs and delay IVDD, but the underlying molecular mechanism is poorly understood. This study aimed to evaluate the antiapoptosis effects of bone marrow-derived MSC (BMSC) on rat NPCs exposed to compression and investigate whether the mitochondrial pathway was involved. Methods: BMSCs and NPCs were cocultured in the compression apparatus at 1.0 MPa for 36 h. Cell viability, apoptosis, mitochondrial function, and the expression of apoptosis related proteins were evaluated. Results: The results showed that coculturing with BMSCs increased the cell viability and reduced apoptosis of NPCs exposed to compression. Meanwhile, BMSCs could relieve the compression-induced mitochondrial damage of NPCs by decreasing reactive oxygen species level and maintaining mitochondrial membrane potential as well as mitochondrial integrity. Furthermore, coculturing with BMSCs suppressed the activated caspase-3 and activated caspase 9, decreased the expressions of cytosolic cytochrome c and Bax, and increased the expression of Bcl-2. Conclusions: Our results suggest that BMSCs can protect against compression-induced apoptosis of NPCs by inhibiting the mitochondrial pathway and thus enhance our understanding on the MSC-based therapy for IVDD. PMID- 29387093 TI - High Prevalence of Undernutrition among Children in Gondar Town, Northwest Ethiopia: A Community-Based Cross-Sectional Study. AB - Objective: To assess undernutrition and associated factors among children aged 6 59 months in Gondar Town, northwest Ethiopia. Methods: A community-based cross sectional study was conducted in 2014. Multistage sampling method was used to select study participants. Structured interviewer administered questionnaire and anthropometric measurements were used. Binary logistic regression was fitted to identify associated factors. Results: The prevalences of wasting and stunting were 6.8% and 45.7%, respectively. Higher odds of wasting were observed among children whose fathers were daily laborers (AOR = 2.63), children who had eating problem (AOR = 2.96), and those who were not exclusively breast-fed for the first six months (AOR = 5.63). Similarly, higher odds of stunting were found among female children (AOR = 1.65), children who lived in households having four to six families (AOR = 2.14), and children who did not start breast-feeding within one hour of birth (AOR = 0.67). Conclusion: Childhood undernutrition was a significant problem. Child eating problem, paternal occupation, and exclusive breast-feeding were associated with wasting, whereas family size, child sex, and breast-feeding initiation time were associated with stunting. Therefore, strengthening of early initiation and exclusive breast-feeding, promoting healthcare seeking behavior, and designing social support programme for poor family are recommended to reduce undernutrition. PMID- 29387095 TI - Effects of different activation protocols on cleavage rate and blastocyst production of caprine oocytes. AB - The present study was undertaken to assess the effect of different chemical activators along with 6-DMAP on in vitro matured caprine oocytes. From 4332 ovaries, 14235 cumulus oocyte complexes (COCs) were collected which were matured in TCM-199 medium containing follicle stimulating hormone (FSH) (5 ug/ml), Leutinizing hormone (LH) (10 ug/ml), oestradiol-17beta (1 ug/ml) supplemented with 10% fetal bovine serum, 10% follicular fluid and 3 mg/ml bovine serum albumin (BSA) at 38.5 degrees C and 5% CO2 in an incubator under humidified air for 27 h. In group 1 (control), 3117 in vitro matured oocytes were co incubated with sperms for 18 h in ferttalp medium. In group 2, 3563 in vitro matured oocytes were activated with 7% ethanol for 5-7 min followed by treatment with 2.0 mM DMAP for 4 h in mCR2aa medium. In group 3, 3109 in vitro matured oocytes were activated with 5 MUM ionomycin for 5-7 min followed by treatment with 2.0 mM DMAP for 4 h in mCR2aa medium. In group 4, 3455 in vitro matured oocytes were activated with 5 MUM calcium ionophore for 5-7 min followed by treatment with 2.0 mM DMAP for 4 h in mCR2aa medium. Oocytes were cultured in 50 uL drops of research vitro cleave (RVCL) medium for embryo development. The cleavage rate, morula and blastocyst production in group 1, 2, 3 and 4 were 26.07 +/- 2.37%, 14.91 +/- 2.91 & 1.45 +/- 0.71%, 49.57 +/- 3.79%, 20.07 +/- 2.38% & 5.29 +/- 1.42%, 50.18 +/- 3.59%, 15.26 +/- 2.87% & 1.85 +/- 0.72% and 80.26 +/- 2.30%, 35.33 +/- 2.67 & 7.10 +/- 0.89%, respectively. These results indicated that the activation of in vitro matured oocytes by 5 MUM calcium ionophore for 5-7 min followed by treatment with 2.0 mM DMAP for 4 h is most favorable for parthenogenetic caprine embryos production. PMID- 29387094 TI - Trend of toxocariasis in Iran: a review on human and animal dimensions. AB - One of the neglected soil and/or food-borne diseases with international public health importance is toxocariasis. Human cases are being increasingly reported from Asian, African, Oceania, European and the American countries. Hence, human toxocariasis (HT) is now considered as a major zoonosis with global and regional importance. In Iran, human and animal toxocariasis is an endemic disease with clinical and epidemiologic health problem aspects. Doubtless, understanding the epidemiology and the trend of this important parasitic disease and its affecting factors will provide the establishment of effective prevention and control programs. To better understand the trend of toxocariasis researches in Iran, this study was performed to analyze different aspects of this zoonotic disease including history, life cycle, species, human animals and environmental studies, diagnostic aspects and treatments to find out the gaps, including different aspects of clinical sings in human patients, new and specific recombinant antigens based on the native antigens, new diagnostic tools, especially rapid diagnostic tests, paratenic hosts status and new treatment procedures which is necessary to be investigated in the future studies on this important zoonotic disease. PMID- 29387096 TI - Comparing three superovulation protocols in dromedary camels: FSH, eCG-FSH and hMG. AB - The objective of this study was to compare three superovulation protocols in dromedary camels. Follicular waves of dromedary camel donors (n=6) were synchronized using two GnRH injections. Superovulation was initiated 2 days after the second injection (day 0 of experiment). The experiment was conducted using change over design, where all females received three superovulation treatments one after the other with a resting period of one month in between. Superovulation was carried out for all donors using 390 mg FSH, 1000 IU eCG and 330 mg FSH, or 16.5 ampule hMG (75 i.u. FSH and 75 i.u. LH per ampoule). FSH and hMG were injected twice daily, indecreasing doses, over 5.5 days. Thirty-six h after the last FSH or hMG injection, donors were mated once and received an intravenous injection of the GnRH analogue. The diameter and number of ovarian follicles >=4 mm on day 4 after superovulation and the total number of corpora lutea and follicles >=9 mm on day 7.5 after mating were evaluated by ultrasound examinations. No significant differences were found between the total number of corpora lutea among FSH (13.8 +/- 2.65), eCG-FSH (15 +/- 2.60) and hMG (10.8 +/- 2.30) and the number of expanded hatched blastocysts in FSH (5.7 +/- 2.32), eCG FSH (8.8 +/- 2.10) and hMG (5.8 +/- 2.40) treated donors. This study showed that all three superovulatory protocols could be used successfully and interchangeably in dromedary camels. PMID- 29387097 TI - The use of inulin as fat replacer and its effect on texture and sensory properties of emulsion type sausages. AB - The present study aimed to investigate the possibility of reducing energy content in emulsion type sausages by replacing fat with inulin. In the manufactured product, the fat content was reduced to 6%-18% and replaced by inulin and water. The quality of the resulting product was determined by chemical and texture profile analyses (TPA), color measurement and sensory evaluation. The results showed that replacing fat with inulin led to a significant energy content reduction of up to 64% (with 6% inulin and 12% water). In addition, color measurement, sensory evaluation and TPA were comparable to the traditional product in the inulin treated samples. The overall acceptability of all experimental groups was adequate; therefore, inulin is suggested as a good replacement for fat in emulsion type sausages. PMID- 29387098 TI - Does natural honey act as an alternative to antibiotics in the semen extender for cryopreservation of crossbred ram semen? AB - Antibiotics are added to semen extenders to take care of heavy microbial load, however, their continuous use poses a constant threat of developing antibiotic resistance by the common microbes present in the semen. Our hypothesis was that natural honey, having antibacterial activity and rich in fructose could replace the use of antibiotics and fructose in the semen extender. Twenty-four ejaculates from six crossbred rams were obtained and extended with tris-based extender without (control) and with honey at 2.5% (T1), 5% (T2) and 7% (T3). Sperm quality was measured in terms of percentage sperm motility, live sperm count, intact acrosome and hypo-osmotic swelling test (HOST) reacted spermatozoa. The semen samples at post-thaw were also evaluated for total viable count (colony forming units/ml). At post-thaw, control exhibited significantly (P<0.05) higher sperm motility in comparison to T2 and T3. The percent of live sperm count, intact acrosome and HOST reacted spermatozoa were significantly higher (P<0.05) for control than all other treatment groups at post-thaw. Among treatment groups, T1 maintained significantly higher (P<0.05) percentage of live sperm count, intact acrosome and HOST reacted spermatozoa than T2 and T3. The total viable count at post-thaw was significantly lower (P<0.05) for control than all the treatment groups. In conclusion, honey cannot be used as an alternative to antibiotics to take care of heavy microbial load in semen, however, levels up to 2.5% may be supplemented to semen as an energy source. PMID- 29387099 TI - Regional and mucosal distributions of some intestinal immunoreactive endocrine cells in New Zealand white rabbit (Oryctolagus cuniculus L.). AB - The aim of this study was to detect the regional and mucosal distribution of endocrine cells that secrete gulcagon, somatostatin, Chyholecystokinin-8 (CCK-8), serotonin, secretin, substance P (SP) and histamine in the small and large intestine of New Zealand white rabbit (Oryctolagus cuniculus L.) using immunohistochemical peroxidase-antiperoxidase (PAP) method. It was found that most of the immunoreactive (IR) endocrine cells, which are oval- or spindle shaped, are spotted in the basal parts of the relevant glands. It was noticed that cells in the lamina epithelialis of small and large intestine is linked to the lumen and that the cells in their glands cannot reach the lumen. Immunoreactive cells for glucagon, somatostatin, serotonin, secretin and SP were identified in lamina epithelialis of the small and large intestine. It was seen that secretin, SP and histamine-IR cells are rarely deployed throughout the intestinal tract. It was determined that somatostatin-IR cells were identified throughout the intestinal tract. In conclusion, the immunohistochemical study shows that gastrointestinal tract of this species contained different types of endocrine cells similar to those found in other vertebrate species. However, some species-dependent unique distributions and frequencies of endocrine cells were also observed in the present study. PMID- 29387100 TI - Toxigenic Clostridium difficile in retail packed chicken meat and broiler flocks in northeastern Iran. AB - This study was designed to evaluate the occurrence of Clostridium difficile in both broiler chicken farms and packed chicken parts sold at market places in Mashhad, the second most popular Islamic pilgrimage city after Mecca in northeastern Iran. The fresh faecal samples were obtained from broiler farms, while the chicken packs were purchased from retail outlets across the city at market places and samples were obtained from the necks, thighs, and wings. The selective culture was used for isolation of C. difficile. Out of 40 pooled fresh faecal and 65 packed chicken samples, 14 (35%) and 10 (15.3%) samples were positive, respectively. Some of the C. difficile isolates from chickens packs (7 out of 10, 70%) and faecal samples (5 out of 14, 36%) were detected as toxigenic (A, B and binary toxins) using molecular identification. From 14 isolates of the faecal samples, five isolates were tcdA and tcdB positive, and none was binary toxin positive. The results of the present study suggest that broiler chickens are a potential source of C. difficile, which may infect humans through contact or consumption of chicken meat, although the significance of food contamination is entirely unclear, the role of poultry products as a potential source of the infection should be investigated. PMID- 29387101 TI - Study of TALP and TRIS citrate medium on caprine sperm capacitation and subsequent in vitro embryo production. AB - The aim of the present investigation was to compare Tyrode's albumin lactate pyruvate (TALP) medium and TRIS citrate medium for capacitation of caprine sperm. In experiment 1 capacitation was assessed by chlortetracycline assay and in experiment 2 with in vitro fertilization and embryo development. In experiment 2, cumulus oocyte complexes (COCs) recovered by slicing the caprine ovaries were matured in maturation medium for 27 h in humidified atmosphere at 38.5 degrees C with 5% CO2. After 27 h of culture a total of 2480 in vitro matured oocytes were selected and randomly divided into two groups. Group 1 (n=1124) matured oocytes were fertilized by the spermatozoa capacitated in TALP medium and in group 2 (n=1356) matured oocytes were fertilized by the spermatozoa capacitated in TRIS citrate medium. The results of experiment 1 indicated a comparatively more number of sperms with Chlortetracycline (CTC) Pattern B in TRIS citrate than TALP medium (55.32 +/- 0.91% vs 47.96 +/- 0.20%). In experiment 2, the cleavage rate and blastocyst production were higher following capacitation of spermatozoa in TRIS citrate than TALP medium. In conclusion, TRIS citrate can be used as an alternative and effective media for sperm capacitation to get higher cleavage rate and blastocyst production in goat. PMID- 29387102 TI - Comparative efficacy of serological diagnostic methods and evaluation of polymerase chain reaction for diagnosis of bovine brucellosis. AB - The aim of present study was to compare the diagnostic performance of the different Brucella abortus antigen based serological and molecular tests such as Rose Bengal Plate Test (RBPT), indirect enzyme linked immunosorbent assay (I ELISA) and polymerase chain reaction (PCR). Out of 89 samples, 44 were positive by I-ELISA, 18 by RBPT and 21 by PCR. Substantial agreement was observed between PCR and I-ELISA (kappa=0.48). A slight degree of agreement was observed between RBPT and I-ELISA and PCR (kappa=0.18) and RBPT and PCR (kappa=0.11). Indirect enzyme linked immunosorbent assay detected more samples as positive among these tests. In conclusion, I-ELISA can be routinely used for an accurate and efficient diagnosis of Brucella infection, because the chances of non-detection of an infected animal in I-ELISA are minimal. However, PCR could be used as a supplement and complement test along with I-ELISA for identification and differentiation of bovine brucellosis. PMID- 29387103 TI - The study of microanatomy of intestinal epithelium in the Chinese soft-shelled turtle (Pelodiscus sinensis). AB - The microanatomy of the intestinal epithelium in the Chinese soft-shelled turtle (CST) was studied by light and transmission electron microscopy (TEM). The small intestinal epithelium (SIE) was single layered or pseudostratified. The enterocytes contained mitochondria or mitochondria and lipid droplets. The enterocytes were arranged tightly in the apical parts of epithelium and connected by desmosomes and interdigitations. The large intestinal epithelium (LIE) was pseudostratified and the enterocytes did not contain lipid droplets. Enterocytes were arranged compactly in the apical part, forming spaces in the middle and basal parts of epithelium. Numerous mucous cells were scattered in the epithelium and there were intraepithelial lymphocytes (IELs) with their pseudopodia extended into the intestinal lumen. This study provides detailed features of intestinal epithelium in the Pelodiscus sinensis that could be related to function. In addition, these findings are discussed in relation to other vertebrates. PMID- 29387104 TI - Identification of microRNAs in corpus luteum of pregnancy in buffalo (Bubalus bubalis) by deep sequencing. AB - This study was aimed to identify miRNAs of corpus luteum (CL) in buffaloes during pregnancy. For this study, CL (n=2) were collected from gravid uteri of buffalo and RNA was isolated. Following this, the purity and integrity of RNA was checked and used for deep sequencing using Illumina Hiseq 2500 platform. The reads' quality was checked prior to in silico analyses viz. identification of conserved, novel and target of miRNAs. In this study, out of identified miRNAs (3018), 3013 were known and 5 were novel miRNAs on alignment with reference genomes. In addition, prediction of putative target genes for identified abundant miRNAs revealed several genes viz. HOX, KLF4, NCOR2, CDKN2Z, MAPK7, COX2, PPARA, PTEN, ASS3A, ELK1, CASP3, BCL211, MCL1, CCND2, Cyclin A2 and CDC25A during early pregnancy in buffalo. These predicted target genes have been associated with various cellular house-keeping processes including apoptosis. In conclusion, this study reports the identification of conserved and novel microRNAs (miRNAs) in CL during pregnancy in buffalo by deep sequencing. PMID- 29387105 TI - An uncommon clinical form of foot-and-mouth disease in beef cattle presented with cornual skin lesions. AB - Foot-and-mouth disease (FMD) is a major infectious disease in livestock. The common clinical signs in cattle include epidermal vesicles that are majorly distributed around oronasal cavity, feet and teats. The aim of this report is to document an uncommon clinical form of the disease which comprises the occurrence of classic vesicular lesion in a rarely observed location of the horn vegetative tissue. During Iran's outbreak of FMD in 2013, field investigation, clinical examination and sampling from the affected herds in Qom province were performed. Specimens of mouth epithelium and horn vegetative tissue were collected for virology and histopathologic study. All the samples collected from horns were positive for foot-and-mouth disease virus (FMDV) in both enzyme linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) tests, and the strain of the virus was identified as A05. Surprisingly, all the animals with horn lesion came from beef herds, were less than 12 months old and had more severe signs of the systemic disease. Since the same strain of virus did not cause similar lesions in surrounding dairy cows, it was concluded that occurrence of horn lesions may be more associated with host factors rather than virus strain. PMID- 29387106 TI - Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors. AB - Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 MUM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity. PMID- 29387107 TI - Mitochondrial and caspase pathways are involved in the induction of apoptosis by nardosinen in MCF-7 breast cancer cell line. AB - Natural products isolated from plants provide a valuable source for expansion of new anticancer drugs. Nardosinen (4,9-dihydroxy-nardosin-6-en) is a natural sesquiterpene extracted from Juniperus foetidissima. Recently, we have reported the cytotoxic effects of nardosinen in various cancer cells. The aim of the current study was to investigate the anticancer features of nardosinen as well as its possible molecular mechanisms of the nardosinen cytotoxic effect on breast tumor cells. MTT assay showed that nardosinen notably inhibited cell proliferation in a dose-dependent manner in MCF-7 breast cancer cells. The growth inhibitory effect of nardosinen was associated with the induction of cell apoptosis, activation of caspase-6, increase of reactive oxygen species (ROS), and loss of mitochondrial membrane potentials (DeltaPsim). Western blot assay following treatment with nardosinen showed that the expression levels of the Bax were significantly up-regulated and the expression levels of the Bcl-2 were significantly down-regulated. Our results finally exhibited that nardosinen induces apoptosis in breast cancer cells via the mitochondrial and caspase pathways. PMID- 29387108 TI - The effects of hydroalcoholic extract of Allium elburzense Wendelbo bulb on dexamethasone-induced dyslipidemia, hyperglycemia, and oxidative stress in rats. AB - Recent evidences have suggested the beneficial cardiovascular effects of some plants belonging to the genus Allium. The present study is an attempt to investigate the effects of hydroalcoholic extract of Allium elburzense bulb on dexamethasone-induced dyslipidemia in rats. Total phenolic content of A. elburzense bulb hydroalcoholic extract was determined using Folin-Ciocalteu method. Thirty-six male Wistar albino rats in 6 groups were studied. Group 1 (dyslipidemic control) received dexamethasone (10 mg/kg/day, s.c.) for 7 days, groups 2-4 (treated) received dexamethasone and simultaneously treated orally with 100, 200, or 400 mg/kg of A. elburzense extract, group 5 (normal control) received a single daily injection of normal saline (1 mL/kg, s.c.) and the vehicle orally, and group 6 (reference) received dexamethasone and atorvastatin (40 mg/kg) orally. At the end of experiment, blood glucose, lipid profile, and malondialdehyde (MDA) levels were assessed in serum samples. Livers were processed for histopathological examination. Total phenolic content of A. elburzense extract was estimated to be 33.52 +/- 1.3% mg gallic acid equivalent/g of the dried plant extract. The plant extract significantly reduced serum blood glucose, triglyceride, total cholesterol, low-density lipoprotein-cholesterol, and MDA levels and increased the high density lipoprotein-cholesterol level and also improved liver steatosis compared to the dyslipidemic control group. These results suggest the hydroalcoholic extract of A. elburzense bulb has anti dyslipidemic, anti-hyperglycemic, and antioxidant effects on rats receiving high doses of dexamethasone. PMID- 29387109 TI - Anti-tuberculosis and cytotoxic evaluation of the seaweed Sargassum boveanum. AB - Marine seaweeds produce a variety of compounds with different biological activities, including antituberculosis and anticancer effects. The aim of this study was to investigate anti-tuberculosis activity of Sargassum boveanum (S. boveanum) and cytotoxicity of different fractions of this seaweed. S. boveanum was collected from Persian Gulf. The plant was extracted by maceration with methanol-ethyl acetate solvent. The extract was evaporated and partitioned by Kupchan method to yield hexane, tricholoroethane, chloroform, and butanol partitions. The anti-tuberculosis activity of the crude extract and toxicity of the fractions were investigated using green fluorescent protein reporter microplate assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay methods, respectively. The cell survivals of HeLa cell were decreased by increasing the concentration of the extracts. The IC50 values of hexane, tricholoroethane, chloroform, and butanol partitions were 150.3 +/- 23.10, 437.0 +/- 147.3, 110.4 +/- 33.67, and 1025.0 +/- 15.20 MUg/mL, respectively. The crude extract was not active against tuberculosis. This study reveals that different partitions of S. boveanum have cytotoxic activity against the cancer cell lines. PMID- 29387110 TI - The effect of two different crosslinkers on in vitro characteristics of ciprofloxacin-loaded chitosan implants. AB - The objective of this study was to determine and evaluate a controlled release implant of ciprofloxacin using bovine hydroxyapatite (BHA)-chitosan composite and glutaraldehyde or genipin as crosslinking agents. Ciprofloxacin implants were prepared using BHA, chitosan, ciprofloxacin at 30:60:10 and using three different concentrations of glutaraldehyde or genipin (0.3, 0.5, or 0.7%) as crosslinkers. Implants were formed as mini-tablet with 4.0 mm diameter weighing 100 mg using compression method. Further, the prepared ciprofloxacin implants were characterized for porosity, density, water absorption capacity, swelling, degradation, compressive strength, compatibility (Fourier transforms-infrared spectroscopy (FT-IR)), morphology (scanning electron microscope (SEM)), X-ray diffraction (X-RD), and in vitro drug release. The addition of glutaraldehyde or genipin as crosslinkers in ciprofloxacin implant showed controlled release profile of ciprofloxacin over a time period of 30 days. SEM photomicrograph revealed low porosity of the implant after crosslinking with glutaraldehyde or genipin. The FTIR study confirmed the formation of covalent imine bonds between chitosan and glutaraldehyde. Moreover, the addition of glutaraldehyde or genipin as crosslinkers caused a decrease in the mechanical strength of the implant. Increased concentration of glutaraldehyde or genipin reduced the crystallinity of BHA and chitosan, which were confirmed by X-RD studies. The results obtained from this study indicated that glutaraldehyde or genipin had the potential effect to retard ciprofloxacin release from BHA-chitosan-ciprofloxacin implant for 30 days. PMID- 29387111 TI - Chronic exposure to arsenic and high fat diet additively induced cardiotoxicity in male mice. AB - Diet is one of the important risk factors that could potentially affect arsenic induced cardiotoxicity. The present study was undertaken to investigate the effect of high fat diet on arsenic-induced cardiotoxicity in mice. Mice were divided into six different groups (n = 12), two control groups received either low fat diet (LFD) or high fat diet (HFD) along with deionized drinking water and four test groups given LFD + 25 ppm arsenic, LFD + 50 ppm arsenic, HFD + 25 ppm arsenic, and HFD + 50 ppm arsenic in drinking water for 5 months. The body weight, heart weight to body weight ratio, cardiac biochemical markers, lipid profile, and histological examination of heart were evaluated. The results demonstrated that arsenic exposure led to a significant decrease in heart glutathione level, catalase enzyme activity, and a significant increase in reactive oxygen species (ROS), malondialdehyde levels, and biochemical enzymes. The administration of HFD resulted in above-mentioned changes as well as an alteration in lipid profile; however, arsenic exposure alone or along with HFD caused a reduction in lipid profile factors, except HDL level. Our results revealed that HFD increased arsenic-induced heart injury in the mice. This effect may be because of reduction in antioxidant activities and/or increase in oxidative stress and ROS in mice heart tissues. These findings could be important for clinical intervention to protect against or prevent arsenic-induced cardiotoxicity in humans. PMID- 29387112 TI - Estrogen stimulates adenosine receptor expression subtypes in human breast cancer MCF-7 cell line. AB - Estrogen is a steroid hormone that plays a key role in the development and regulation of reproductive system. It has been shown that estrogen is related to breast cancer development through binding to its receptors. In order to uncover the estrogen effects on adenosine receptor expression, estrogen-positive MCF-7 cells were used to treat with agonist and antagonist of estrogen and then the mRNA expression of adenosine receptor subtypes were evaluated. Estrogen-positive MCF-7 cells were treated with various concentrations of 17beta estradiol (E2) as an estrogen agonist, and ICI 182,780 as an estrogen antagonist. The gene expression of adenosine receptor subtypes were detected by real time RT-PCR. The results of MTT assay showed that E2 increased cell viability in a dose dependent manner. The expression pattern of all adenosine receptor subtypes are as follow; A2b > A1 > A2a > A3 in untreated MCF-7 cells. Obtained results showed that E2 incubation at 0.001-0.01 MUM led to up-regulation of A1ARs, A2aARs and A3ARs dose dependently. E2 at 0.001 MUM also had no significant effect on A2bARs expression but, at higher doses induced a considerable decrease in mRNA A2bARs expression. Treatment with antagonist confirmed that up-regulation of these receptors is mediated by estrogen receptor. Taken together, our results indicate that treatment of MCF-7 cells with E2 led to up-regulation of adenosine receptors. However, these effects were partially restored by treatment with antagonist suggesting that such effects are mediated by estrogen receptors. PMID- 29387113 TI - Magnesium sulfate protects the heart against carbon monoxide-induced cardiotoxicity in rats. AB - Carbon monoxide (CO), a toxic gas produced via incomplete fossil fuel combustion, has several poisonous effects in the heart including induction of necrosis, apoptosis, and electrocardiogram (ECG) changes. Magnesium sulfate (MS) is a drug with cardioprotective effects especially when used after ischemia/reperfusion. In the current study, we aimed to evaluate MS cardioprotective effects following CO poisoning. Animals were exposed to CO 3000 ppm for 1 h and immediately after the exposure period and on the next 4 days (a total of 5 consecutive doses given on a daily basis), MS (75, 150 and 300 mg/kg) was injected intraperitoneally (i.p.) and ECG was recorded focusing on ST-segment, T-wave, and Q-pathologic wave changes. On day 5, animals were sacrificed and their heart was excised for determination of BAX, BCL2 and Akt expression level using western blot analysis and necrosis investigations. The results showed that MS significantly decreased necrosis and BAX/BCL2 ratio (P < 0.001) while pro-survival protein Akt was significantly increased (P < 0.001). Moreover, CO-induced ST-segment depression, T-wave inversion, and atrioventricular block (AV-block) were decreased following treatment with MS. In conclusion, our results showed that MS could decrease cardiac deleterious effects of CO poisoning including necrosis and apoptosis while increased the expression of Akt, as a cell survival protein. PMID- 29387114 TI - Anti-inflammatory activity of Echium amoenum extract on macrophages mediated by inhibition of inflammatory mediators and cytokines expression. AB - Echium amoenum (Boraginaceae) is an important remedy used for various illnesses. In this study, we investigated the anti-inflammatory effects of E. amoenum in the J774.1A macrophage cell line. We prepared ethyl acetate, dichloromethane and hexane extracts from E. amoenum flowers and examined their possible cytotoxic effects using MTT assay. Lipopolysaccharide (LPS)-stimulated macrophages were treated with the extracts after which we measured nitric oxide (NO) production by Griess method. Inducible NO synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 gene expressions were examined by real time-PCR. IL-1beta and IL-6 cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). The hexane extract with a half maximal inhibitory concentration (IC50) of 39.8 MUg/mL most effectively reduced NO production. Real time-PCR analysis indicated reduced levels of iNOS ((0.05 +/- 0.006 relative fold change (RFC)) and COX2 (0.06 +/- 0.002 RFC) gene expressions with the 100 MUg/mL hexane extract (P < 0.001). IL1-beta, TNF-alpha, and IL-6 gene expression levels decreased at all concentrations of the extract (less than ~ 0.28 RFC). Treatment of LPS-stimulated cells with 100 MUg/mL of the extract reduced IL-1beta secretion to 27.9 +/- 0.21 pg/mL and IL-6 to 555 +/- 166 pg/mL. In conclusion, E. amoenum hexane extract showed the greatest reduction in macrophage NO secretion compared to other extracts. This extract could modulate the inflammatory mode of the macrophages by causing reductions in iNOS and COX2 enzymes as well as IL-1beta, IL-6, and TNF-alpha cytokine levels. The results of this study have shown the anti-inflammatory effects of this plant. Further studies regarding its therapeutic potential in inflammatory disorders are recommended. PMID- 29387115 TI - Synthesis and characterization of some novel diaryl urea derivatives bearing quinoxalindione moiety. AB - Diaryl urea derivatives have exhibited a broad spectrum of biochemical effects and pharmaceutical applications. Several diaryl urea derivatives such as sorafenib, regorafenib, linifanib, and tivozanib and lenvatinib are in clinical trial or clinical use. Therefore, development of small molecules within the diaryl urea scaffold with the ability of binding to variety of enzymes and receptors in the biological system are an interesting topic for researchers. Sorafenib as a diaryl urea derivative is a well-known anticancer agent. Corresponding to available information about biological activities of quinoxaline moieties, based on sorafenib scaffold, several structures were designed by replacement of pyridyl carboxamide group of sorafenib with quinoxalindione moiety. A total of 14 novel compounds in 7 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected followed by O arylation of 4-acetamidophenol with 5-chloro-2-nitroaniline to provide 5-(4 acetamidophenoxy)-2-nitroaniline. Reduction of the nitro group of 5-(4 acetamidophenoxy)-2-nitroaniline and cyclization of diamine N-(4-(3,4 diaminophenoxy) phenyl) acetamides with oxalic acid afforded compound N-(4-((2,3 dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl) acetamides which on deacetylation gave compounds 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones. Then resultant compounds, 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones were reacted by appropriate isocyanates/ carbamates to give the target compounds 1-(4 ((2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl)-3-phenylureas. The structures of compounds confirmed by proton nuclear magnetic resonance (1H NMR), mass spectrum and Fourier transform infrared (FT-IR). PMID- 29387116 TI - Performance of urinalysis tests in screening for significant bacteriuria. PMID- 29387118 TI - Severe mitral regurgitation, an unusual manifestation of chemotherapy-induced cardiotoxicity. AB - Cardiotoxicity is one of the most feared side effects of chemotherapy with enhanced morbidity and mortality in survivors. Arrhythmia, heart failure, myocardial ischemia, hypertension, and thromboembolism are commonly reported as side effects. Hereby, we are reporting a case of severe mitral regurgitation as a complication of chemotherapy. PMID- 29387119 TI - Molecular identification and antifungal susceptibility profile of Candida species isolated from patients with vulvovaginitis in Tehran, Iran. AB - Background: Rapid and accurate identification and evaluation of antifungal susceptibility pattern of Candida isolates are crucial to determine suitable antifungal drugs for the treatment of patients with vulvovaginitis candidiasis. Materials and Methods: Vaginal samples were collected from 150 women with suspicious vaginal candidiasis, and then cultured on Sabouraoud's Dextrose Agar with chloramphenicol to isolate Candida species. After identification of Candida isolates using polymerase chain reaction-restriction fragment length polymorphism technique, antifungal susceptibility testing of four azolic antifungal drugs was carried out using broth microdilution method according to the CLSI M27-A3. Results: Candida species were isolated from eighty suspected patients (61.79%). The most common pathogen was Candida albicans (63.75%). Resistance to fluconazole and ketoconazole was observed in 27.5% and 23.75% of Candida isolates, respectively, and only 2% of Candida isolates were resistant to miconazole. Interestingly, resistance to fluconazole in C. albicans was more than other Candida species. Conclusion: The results indicated that therapy should be selected according to the antifungal susceptibility tests for the prevention of treatment failure and miconazole therapy can be considered as the best therapeutic choice in the management of vulvovaginitis. PMID- 29387117 TI - Therapeutic impacts of microRNAs in breast cancer by their roles in regulating processes involved in this disease. AB - Breast cancer is the most common cancer in women around the world. So far, many attempts have been made to treat this disease, but few effective treatments have been discovered. In this work, we reviewed the related articles in the limited period of time, 2000-2016, through search in PubMed, Scopus database, Google Scholar, and psychology and psychiatry literature (PsycINFO). We selected the articles about the correlation of microRNAs (miRNAs) and breast cancer in the insight into therapeutic applicability from mentioned genetics research databases. The miRNAs as an effective therapy for breast cancer was at the center of our attention. Hormone therapy and chemotherapy are two major methods that are being used frequently in breast cancer treatment. In the search for an effective therapy for breast cancer, miRNAs suggest a promising method of treatment. miRNAs are small, noncoding RNAs that can turn genes on or off and can have critical roles in cancer treatment; therefore, in the near future, usage of these biological molecules in breast cancer treatment can be considered a weapon against most common cancer-related concerns in women. Here, we discuss miRNAs and their roles in various aspects of breast cancer treatment to help find an alternative and effective way to treat or even cure this preventable disease. PMID- 29387120 TI - Premedication with benzodiazepines for upper gastrointestinal endoscopy: Comparison between oral midazolam and sublingual alprazolam. AB - Background: Premedication with orally administered benzodiazepines is effective in reducing anxiety and discomfort related to endoscopic procedures. We evaluated the efficacy and safety of oral midazolam in comparison to sublingual alprazolam as premedication for esophagogastroduodenoscopy (EGD). Materials and Methods: Adult candidates for diagnostic EGD received either oral midazolam (7.5 mg in 15 cc apple juice) or sublingual alprazolam (0.5 mg) 30 min before EGD. Procedural anxiety and pain/discomfort were assessed using 11-point numerical rating scales. Patients' overall tolerance (using a four-point Likert scale) and willingness to repeat the EGD, if necessary, were also assessed. Blood pressure, heart rate, and arterial oxygen saturation were monitored from medication to 30 min after the procedure. Results: Patients experienced a similar reduction in procedural anxiety after medication with oral midazolam and sublingual alprazolam; mean (standard deviation [SD] of 1.86 [1.63] and 2.02 [1.99] points, respectively, P = 0.91). Compared to oral midazolam, pain/discomfort scores were lower with sublingual alprazolam; mean (SD) of 4.80 (3.01) versus 3.68 (3.28), P = 0.024. There was no significant difference between the two groups in patients' tolerance, willingness to repeat the procedure, or hemodynamic events. Conclusion: Oral midazolam and sublingual alprazolam are equally effective in reducing EGD-related anxiety; however, EGD-related pain/discomfort is lower with alprazolam. Both benzodiazepines are equally safe and can be used as premedication for patients undergoing diagnostic EGD. PMID- 29387121 TI - Comparison consequences of Jackson-Pratt drain versus chest tube after coronary artery bypass grafting: A randomized controlled clinical trial. AB - Background: Chest tubes are used in every case of coronary artery bypass grafting (CABG) to evacuate shed blood from around the heart and lungs. This study was designed to assess the effective of Jackson-Pratt drain in compare with conventional chest drains after CABG. Materials and Methods: This was a randomized controlled trial that conducted on 218 patients in Chamran hospital from February to December 2016. Eligible patients were randomized in a 1:1 ratio. Jackson-Pratt drain group had 109 patients who received a chest tube insertion in the pleural space of the left lung and a Jackson-Pratt drain in mediastinum, and Chest tube drainage group had 109 patients who received double chest tube insertion in the pleural space of the left lung and the mediastinum. Results: The incidence of pleural effusions in Jackson-Pratt drain group and chest tube group were not statistically different. The pain score at 2-h in Drain group was significantly higher than chest tube group (P = 0.001), but the trend of pain score between groups was not significantly different (P = 0.097). The frequency of tamponade and atrial fibrillation (AF) were significantly lower in Jackson Pratt drain group (P < 0.05). Conclusion: The Jackson-Pratt drain is equally effective for preventing cardiac tamponade, pleural effusions, and pain intensity in patients after CABG when compared with conventional chest tubes, but was significantly superior regarding efficacy to hospital and Intensive Care Unit length of stay and the incidence of AF. PMID- 29387122 TI - Determining factors influencing survival of breast cancer by fuzzy logistic regression model. AB - Background: Fuzzy logistic regression model can be used for determining influential factors of disease. This study explores the important factors of actual predictive survival factors of breast cancer's patients. Materials and Methods: We used breast cancer data which collected by cancer registry of Kerman University of Medical Sciences during the period of 2000-2007. The variables such as morphology, grade, age, and treatments (surgery, radiotherapy, and chemotherapy) were applied in the fuzzy logistic regression model. Performance of model was determined in terms of mean degree of membership (MDM). Results: The study results showed that almost 41% of patients were in neoplasm and malignant group and more than two-third of them were still alive after 5-year follow-up. Based on the fuzzy logistic model, the most important factors influencing survival were chemotherapy, morphology, and radiotherapy, respectively. Furthermore, the MDM criteria show that the fuzzy logistic regression have a good fit on the data (MDM = 0.86). Conclusion: Fuzzy logistic regression model showed that chemotherapy is more important than radiotherapy in survival of patients with breast cancer. In addition, another ability of this model is calculating possibilistic odds of survival in cancer patients. The results of this study can be applied in clinical research. Furthermore, there are few studies which applied the fuzzy logistic models. Furthermore, we recommend using this model in various research areas. PMID- 29387123 TI - Sonographic diagnosis of proximal median nerve entrapment due to an arteriovenous graft in a hemodialysis patient. PMID- 29387124 TI - Study of the effect of Memantine therapy on the treatment of dyslexia in children. AB - Background: Reading disorder (RD) is one of the important complaints in children with learning disorders (LD) that is prevalent in 4% of children in the United States. Treating this disorder includes education of reading practices and treating psychological disorders, and there are no exact medications prescribed in these children. Memantine has been effective in treating memory problems in Alzheimer Dementia, obsessive-compulsive disorder, autism disorder, and other psychological diseases. The aim of this study is to evaluate the effect of memantine in improving RD in children. Materials and Methods: In this randomized clinical trial, 62 children, with RD in Pediatric Psychiatry Clinics of Noor and Ali-Asghar Hospital in Isfahan from 2015 to 2016, were participated. They were randomly assigned to two groups of equal number, one receiving education plus memantine and the other education plus placebo. RD was evaluated at the beginning, 1 and 3 months after intervention by Iranian standard reading and dyslexia test (Nama). Results: Mean (standard deviation) age of participants was 7.55 (0.60) years. Most of the participants were boy (55%), most having parents in 36-45-year-old age group (52% and 48% for fathers and mothers, respectively), and also most parents in diploma and bachelor educational group (61% and 60% for fathers and mothers, respectively). There were statistical significant difference in trend of total score (P = 0.034), word chain (P < 0.001), rhyming (P < 0.001), text comprehension (P < 0.001), and letter fluency (P = 0.002), subscale between two groups. However, the difference of time trend between two groups was not significant in word reading (P = 0.14), word comprehension (P = 0.06), phoneme deletion (P = 0.12), reading nonwords (P = 0.32), and category fluency (P = 0.06). Conclusion: Adding memantine to educational practices is effective in improving RD in school-age children with LD. PMID- 29387125 TI - Important ethical issues for nanomedicine. PMID- 29387126 TI - Long-Term Effects of TCM Yangqing Kangxian Formula on Bleomycin-Induced Pulmonary Fibrosis in Rats via Regulating Nuclear Factor-kappaB Signaling. AB - Objective: We aimed to evaluate the therapeutic effects and long-term effects of YKF and dissect the potential mechanisms. Materials and Methods: IPF rats were given YKF, prednisone, or pirfenidone, respectively, from day 1 to day 42, followed by a 28-day nonintervention interval through day 70. Forced vital capacity (FVC), histopathology, hydroxyproline (HYP) contents, lung coefficient, blood inflammatory cell populations, inflammatory cytokine levels of the lung tissues, and the expression of proteins involved in nuclear factor- (NF-) kappaB signaling pathway were evaluated on days 7, 14, 28, 42, and 70. Results: HYP contents, Ashcroft scores, lung coefficient, and pulmonary fibrosis blood cell populations increased significantly in IPF rats, while FVC declined. All the above-mentioned parameters were improved in treatment groups from day 7 up to day 70, especially in YKF group. The mRNA and protein expressions of tumor necrosis factor- (TNF-) alpha significantly decreased, while interferon- (IFN-) gamma significantly increased, and phosphorylations of cytoplasm inhibitor of nuclear factor kappa-B kinase beta (IKKbeta), inhibitor of nuclear factor kappa-B alpha (IkappaBalpha), and NF-kappaB were obviously downregulated in YKF group from day 7 to day 70. Conclusion: YKF has beneficial protective and long-term effects on pulmonary fibrosis by anti-inflammatory response and alleviating fibrosis. PMID- 29387127 TI - The Hypocholesterolemic Effects of Eryngium carlinae F. Delaroche Are Mediated by the Involvement of the Intestinal Transporters ABCG5 and ABCG8. AB - Hypercholesterolemia is a metabolic disorder characterized by a high concentration of cholesterol in the blood. Eryngium carlinae is a medicinal plant used to treat lipid diseases. The goal of this work was to evaluate, in a model of hypercholesterolemia in mice, the hypocholesterolemic effect of a hydroalcoholic extract of E. carlinae and its main metabolite, D-mannitol. Biochemical analyses of serum lipids and hepatic enzymes were performed by photocolorimetry. We performed histopathological studies of the liver and the expression of the intestinal cholesterol transporters Abcg5 and Abcg8 was determined by standard western blot method. Our results showed that hydroalcoholic extract at doses of 100 mg/kg and D-mannitol at doses of 10 mg/kg reduced the concentration of both total cholesterol and non-HDL cholesterol, without altering the concentration of HDL cholesterol and without damage to hepatocytes. Treatment with the extract increased Abcg8 intestinal transporter expression, while D-mannitol decreased the expression of the two Abcg5/Abcg8 transporters, compared with the hypercholesterolemic group. Considering that Abcg5/Abcg8 transporters perform cholesterol efflux, our results demonstrate that the lipid-lowering effect of the hydroalcoholic extract may be associated with the increase of Abcg8 expression, but the hypocholesterolemic effect of D mannitol is independent of overexpression of these intestinal transporters and probably they have another mechanism of action. PMID- 29387128 TI - A Herbal Medicine, Gongjindan, in Subjects with Chronic Dizziness (GOODNESS Study): Study Protocol for a Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Clinical Trial for Effectiveness, Safety, and Cost-Effectiveness. AB - This study protocol aims to explore the effectiveness, safety, and cost effectiveness of a herbal medication, Gongjindan (GJD), in patients with chronic dizziness. This will be a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, clinical trial. Seventy-eight patients diagnosed with Meniere's disease, psychogenic dizziness, or dizziness of unknown cause will be randomized and allocated to either a GJD or a placebo group in a 1 : 1 ratio. Participants will be orally given 3.75 g GJD or placebo in pill form once a day for 56 days. The primary outcome measure will be the Dizziness Handicap Inventory score. Secondary outcome measures will be as follows: severity (mean vertigo scale and visual analogue scale) and frequency of dizziness, balance function (Berg Balance Scale), fatigue (Fatigue Severity Scale) and deficiency pattern/syndrome (qi blood yin yang-deficiency questionnaire) levels, and depression (Korean version of Beck's Depression Inventory) and anxiety (State Trait Anxiety Inventory) levels. To assess safety, adverse events, including laboratory test results, will be monitored. Further, the incremental cost effectiveness ratio will be calculated based on quality-adjusted life years (from the EuroQoL five dimensions' questionnaire) and medical expenses. Data will be statistically analyzed at a significance level of 0.05 (two-sided). This trial is registered with ClinicalTrials.gov NCT03219515, in July 2017. PMID- 29387129 TI - A 4-Week Repeated-Dose Oral Toxicity Study of Bojungikgi-Tang in Crl:CD Sprague Dawley Rats. AB - Traditional herbal medicines have been used for centuries in Asian countries. However, recent studies have led to increasing concerns about the safety and toxicity of herbal prescriptions. Bojungikgi-tang (BJIGT), a herbal decoction, has been used in Korea to improve physical strength. To establish the safety information, BJIGT water extract was evaluated in a 4-week repeated-dose oral toxicity test in Crl:CD Sprague Dawley rats. BJIGT was orally administered in daily doses of 0, 500, 1000, and 2000 mg/kg/day for 4 weeks via oral gavage in male and female rats. We examined the mortality, clinical signs, body weight change, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters. No significant changes were observed in mortality, clinical sings, body weight, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters between the control group and the BJIGT treated groups in the rats of both sexes. The results indicate that BJIGT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. Thus, this concentration is considered the nonobservable effect dose in rats and is appropriate for a 13-week subchronic toxicity study. PMID- 29387130 TI - Antigiardial Effect of Kramecyne in Experimental Giardiasis. AB - A variety of drugs are used in giardiasis treatment with different levels of efficiency, presence of side effects, and even formation of resistant strains, so that it is important to search new only-one-dose treatments with high efficiency and less side effects. Kramecyne, an anti-inflammatory compound isolated from methanolic extract of Krameria cytisoides, does not present toxicity, even at doses of 5,000 mg/kg. The objective was to determine the antigiardial effect of kramecyne over Giardia intestinalis in vitro and in vivo and analyze the expression of genes ERK1, ERK2, and AK on kramecyne treated trophozoites by Real Time Polymerase Chain Reaction (RTPCR). The median lethal dose (LD50) was 40 MUg/mL and no morphological changes were observed by staining with blue trypan and light microscopy; experimental gerbil infection was eliminated with 320 MUg/Kg of weight. After treatment there were no differences between intestines from treated and untreated gerbils. Kramecyne did not have significant effect over ERK1 and AK, but there are differences in ERK2 expression (p = 0.04). Results show antigiardial activity of kramecyne; however the mode of action is still unclear and the evaluation of ultrastructural damage and expressed proteins is an alternative of study to understand the action mechanism. PMID- 29387131 TI - Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial. AB - This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18-25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results. Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL (p = 0.001) compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion. Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported. PMID- 29387132 TI - A Study on the Diagnostic Elements of Cold-Heat Pattern Identification by Korean Medicine Doctors: Association with Objective and Subjective Body Temperature. AB - Although the Cold-Heat Pattern is the most important diagnostic factor in Traditional Korean Medicine (TKM), its relationship to body temperature and subjective temperature has not been clearly revealed. In this study, based on clinical data from 551 patients, we classified patients treated with herbal medicines into a Cold-prescription group (CG) and a Heat-prescription group (HG), and we compared the ordinary symptoms between the two groups. Subjective body temperature was higher in the HG than in the CG (OR = 1.68, p < 0.01) and digestive ability was better in the HG than in the CG (expert's questionnaire, OR = 1.91, p < 0.001). However, objectively measured body temperature did not show any significant difference between the HG and CG in both gender groups (p = 0.383 and 0.181 for males and females, resp.). Our study suggests that the subjective body temperature and digestive ability may be the principal diagnostic elements of Cold-Heat Pattern identification by Korean Medicine Doctors. These findings may contribute to the investigation of an objective method to measure the Cold Heat Pattern. PMID- 29387133 TI - Ageing: from inflammation to cancer. AB - Ageing is the major risk factor for cancer development. Hallmark of the ageing process is represented by inflammaging, which is a chronic and systemic low-grade inflammatory process. Inflammation is also a hallmark of cancer and is widely recognized to influence all cancer stages from cell transformation to metastasis. Therefore, inflammaging may represent the biological phenomena able to couple ageing process with cancer development. Here we review the molecular and cellular pathway involved in age-related chronic inflammation along with its potential triggers and their connection with cancer development. PMID- 29387134 TI - Molecular changes associated with increased TNF-alpha-induced apoptotis in naive (TN) and central memory (TCM) CD8+ T cells in aged humans. AB - Background: Progressive T cell decline in aged humans is associated with a deficiency of naive (TN) and central memory (TCM) T cells. We have previously reported increased Tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in TN and TCM T cells in aged humans; however, the molecular basis of increased apoptosis remains to be defined. Since expression of TNF receptors (TNFRs) was reported to be comparable in young and aged, we investigated signaling events downstream of TNFRs to understand the molecular basis of increased TNF-alpha induced apoptosis in aged TN and TCM CD8+ cells. Results: The expression of TRAF 2 and RIP, phosphorylation of JNK, IKKalpha/beta, and IkappaBalpha, and activation of NF-kappaB activation were significantly decreased in TN and TCM CD8+ cells from aged subjects as compared to young controls. Furthermore, expression of A20, Bcl-xL, cIAP1, and FLIP-L and FLIP-S was significantly decreased in TN and TCM CD8+ cells from aged subjects. Conclusions: These data demonstrate that an impaired expression/function of molecules downstream TNFR signaling pathway that confer survival signals contribute to increased apoptosis of TN and TCM CD8+ cells in aged humans. PMID- 29387135 TI - Vaccines for the elderly: current use and future challenges. AB - Age-related changes of the immune system contribute to increased incidence and severity of infections in the elderly. Vaccination is the most effective measure to prevent infections and vaccination recommendations in most countries include specific guidelines for the elderly. Vaccination against influenza and Streptococcus pneumoniae is usually recommended for persons with underlying diseases and for the elderly with heterogeneous age limits between >= 50 years and >= 65 years. Some countries also recommend vaccination against herpes zoster. Several vaccines are recommended for all adults, such as regular booster shots against tetanus/diphtheria/pertussis/polio, or for specific groups, e.g. vaccination against tick-borne encephalitis in endemic areas or travel vaccines. These are also relevant for the elderly. Most currently used vaccines are less immunogenic and effective in the elderly compared to younger adults. Potential strategies to improve their immunogenicity include higher antigen dose, alternative routes of administration, and the use of adjuvants, which were all implemented for influenza vaccines, and induce moderately higher antibody concentrations. Research on universal vaccines against influenza and S. pneumoniae is ongoing in order to overcome the limitations of the current strain specific vaccines. Respiratory syncytial virus causes significant morbidity in the elderly. Novel vaccines against this and other pathogens, for instance bacterial nosocomial infections, have tremendous potential impact on health in old age and are intensively studied by many academic and commercial organizations. In addition to novel vaccine developments, it is crucial to increase awareness for the importance of vaccination beyond the pediatric setting, as vaccination coverage is still far from optimal for the older population. PMID- 29387136 TI - The association of high sensitivity C-reactive protein and incident Alzheimer disease in patients 60 years and older: The HUNT study, Norway. AB - Background: With ageing, long-standing inflammation can be destructive, contributing to development of several disorders, among these Alzheimer's disease (AD). C-reactive protein (CRP) is a relatively stable peripheral inflammatory marker, but in previous studies the association between highly sensitive CRP (hsCRP) and AD have shown inconsistent results. This study examines the association between AD and hsCRP in blood samples taken up to 15 years prior to the diagnoses of 52 persons with AD amongst a total of 2150 persons >=60 years of age. Results: Data from Norway's Nord-Trondelag Health Study (HUNT 2) and the Health and Memory Study (HMS) were linked. The participants had an average age of 73 years, and diagnosed with AD up to 15 years [mean 8.0 (+/-3.9)] following hsCRP measurement. Logistic regression models showed an adverse association between hsCRP and AD in participants aged 60-70.5 (odds ratio: 2.37, 95% CI: 1.01 5.58). Conversely, in participants aged 70.6-94, there was an inverse association between hsCRP and AD (odds ratio: 0.39, 95% CI: 0.19-0.84). When applying multivariate models the findings were significant in individuals diagnosed 0.4-7 years after the hsCRP was measured; and attenuated when AD was diagnosed more than seven years following hsCRP measurement. Conclusions: Our study is in line with previous studies indicating a shift in the association between hsCRP and AD by age: in adults (60-70.5 years) there is an adverse association, while in seniors (>70.6 years) there is an inverse association. If our findings can be replicated, a focus on why a more active peripheral immune response may have a protective role in individuals >=70 years should be further examined. PMID- 29387137 TI - An introduction to instrumental variable assumptions, validation and estimation. AB - The instrumental variable method has been employed within economics to infer causality in the presence of unmeasured confounding. Emphasising the parallels to randomisation may increase understanding of the underlying assumptions within epidemiology. An instrument is a variable that predicts exposure, but conditional on exposure shows no independent association with the outcome. The random assignment in trials is an example of what would be expected to be an ideal instrument, but instruments can also be found in observational settings with a naturally varying phenomenon e.g. geographical variation, physical distance to facility or physician's preference. The fourth identifying assumption has received less attention, but is essential for the generalisability of estimated effects. The instrument identifies the group of compliers in which exposure is pseudo-randomly assigned leading to exchangeability with regard to unmeasured confounders. Underlying assumptions can only partially be tested empirically and require subject-matter knowledge. Future studies employing instruments should carefully seek to validate all four assumptions, possibly drawing on parallels to randomisation. PMID- 29387139 TI - Oxygen Consumption (V'O2) and physical Strainas measured by the occupational activity of cleaning personnel. AB - Background: The aim of the study was to determine the physical effort and energy expenditure needed over a working period of 45-60 min, specifically for the occupational activity of cleaning. The effort was demonstrated in absolute terms (V'O2), in relation to the involved person's maximum physical capacity (peak V'O2) and in relation to the individual aerobic-anaerobic threshold (V'O2 at VT1, the point when lactate starts to accumulate but can be cleared). In addition to this, the aim was to verify the suitability of portable ergospirometry in determining the occupational workload in a real-life setting. Methods: Thirty five cleaners performed a bicycle ergospirometry to determine their maximum physical capacity (peak V'O2 = L/min) and their aerobic-anaerobic threshold (V'O2 at the Ventilatory Threshold 1 [VT1]). This was followed by portable ergospirometry lasting 45-60 min while pursuing regular cleaning activities. Results: Performance V'O2 (the average oxygen consumption over 45-60 min of work- time) was 1.06 L/min or 4.4 METs. This was scarcely lower than the individual V'O2 at VT1 and approached 45% of the maximum physical capacity (peak V'O2). In addition, there was positive feedback regarding the wearability of the portable device. The dropout rate was low. Conclusion: The occupational activity of cleaning was defined as a "committed activity", performed close to the upper limit of the continuous physical capacity (approaching V'O2 at VT1). The positive feedback and a low dropout rate proved good acceptance of portable ergospirometry in this field of work over a 45-60 min period. PMID- 29387138 TI - Tocotrienol is a cardioprotective agent against ageing-associated cardiovascular disease and its associated morbidities. AB - Ageing is a nonmodifiable risk factor that is linked to increased likelihood of cardiovascular morbidities. Whilst many pharmacological interventions currently exist to treat many of these disorders such as statins for hypercholesterolemia or beta-blockers for hypertension, the elderly appear to present a greater likelihood of suffering non-related side effects such as increased risk of developing new onset type 2 diabetes (NODM). In some cases, lower efficacy in the elderly have also been reported. Alternative forms of treatment have been sought to address these issues, and there has been a growing interest in looking at herbal remedies or plant-based natural compounds. Oxidative stress and inflammation are implicated in the manifestation of ageing-related cardiovascular disease. Thus, it is natural that a compound that possesses both antioxidative and anti-inflammatory bioactivities would be considered. This review article examines the potential of tocotrienols, a class of Vitamin E compounds with proven superior antioxidative and anti-inflammatory activity compared to tocopherols (the other class of Vitamin E compounds), in ameliorating ageing related cardiovascular diseases and its associated morbidities. In particular, the potential of tocotrienols in improving inflammaging, dyslipidemia and mitochondrial dysfunction in ageing-related cardiovascular diseases are discussed. PMID- 29387141 TI - Machine-Learning Classifier for Patients with Major Depressive Disorder: Multifeature Approach Based on a High-Order Minimum Spanning Tree Functional Brain Network. AB - High-order functional connectivity networks are rich in time information that can reflect dynamic changes in functional connectivity between brain regions. Accordingly, such networks are widely used to classify brain diseases. However, traditional methods for processing high-order functional connectivity networks generally include the clustering method, which reduces data dimensionality. As a result, such networks cannot be effectively interpreted in the context of neurology. Additionally, due to the large scale of high-order functional connectivity networks, it can be computationally very expensive to use complex network or graph theory to calculate certain topological properties. Here, we propose a novel method of generating a high-order minimum spanning tree functional connectivity network. This method increases the neurological significance of the high-order functional connectivity network, reduces network computing consumption, and produces a network scale that is conducive to subsequent network analysis. To ensure the quality of the topological information in the network structure, we used frequent subgraph mining technology to capture the discriminative subnetworks as features and combined this with quantifiable local network features. Then we applied a multikernel learning technique to the corresponding selected features to obtain the final classification results. We evaluated our proposed method using a data set containing 38 patients with major depressive disorder and 28 healthy controls. The experimental results showed a classification accuracy of up to 97.54%. PMID- 29387142 TI - Gene tree parsimony for incomplete gene trees: addressing true biological loss. AB - Motivation: Species tree estimation from gene trees can be complicated by gene duplication and loss, and "gene tree parsimony" (GTP) is one approach for estimating species trees from multiple gene trees. In its standard formulation, the objective is to find a species tree that minimizes the total number of gene duplications and losses with respect to the input set of gene trees. Although much is known about GTP, little is known about how to treat inputs containing some incomplete gene trees (i.e., gene trees lacking one or more of the species). Results: We present new theory for GTP considering whether the incompleteness is due to gene birth and death (i.e., true biological loss) or taxon sampling, and present dynamic programming algorithms that can be used for an exact but exponential time solution for small numbers of taxa, or as a heuristic for larger numbers of taxa. We also prove that the "standard" calculations for duplications and losses exactly solve GTP when incompleteness results from taxon sampling, although they can be incorrect when incompleteness results from true biological loss. The software for the DP algorithm is freely available as open source code at https://github.com/smirarab/DynaDup. PMID- 29387143 TI - Pattern and nature of Neyshabur train explosion blast injuries. AB - Background: Explosions are classified as both man-made and complex accidents. Explosive events can cause serious damage to people, property, and the environment. This study aimed to investigate the pattern and nature of damage incurred to the victims of the Neyshabur Train Explosion. Methods: The current study is a descriptive cross-sectional study that was retrospectively performed on 99 individuals using census method and documents victims hospitalized due to the Neyshabur train disaster (February 2004) in 2016. In this study, different variables such as age, sex, type of injury, treatment, etc. were examined using a questionnaire and were analyzed using SPSS16. Results: The results showed that 50.5% of victims were males with mean age of 30.33 +/- 4.27 years and most of them were in 20- to 40-year age group. A total of 98 victims were discharged after treatment, and 1 victim died due to the severity of injuries after 3 days of hospitalization. Second type of injuries caused by the explosion accounted for most of the injuries (55.6%), and most treatments (54.5%) were related to the specific field of orthopedics. Conclusion: Handling and transportation of fuels and chemicals via rail transport system is one of the potential hazards that threatens human life. The results showed that the highest numbers of victims were in 20- to 40-year age group, which is the age of economic efficiency. The prevention and reduction of human and financial losses resulting from accidents require proper national planning. PMID- 29387140 TI - Designing and building oncolytic viruses. AB - Oncolytic viruses (OVs) are engineered and/or evolved to propagate selectively in cancerous tissues. They have a dual mechanism of action; direct killing of infected cancer cells cross-primes anticancer immunity to boost the killing of uninfected cancer cells. The goal of the field is to develop OVs that are easily manufactured, efficiently delivered to disseminated sites of cancer growth, undergo rapid intratumoral spread, selectively kill tumor cells, cause no collateral damage and pose no risk of transmission in the population. Here we discuss the many virus engineering strategies that are being pursued to optimize delivery, intratumoral spread and safety of OVs derived from different virus families. With continued progress, OVs have the potential to transform the paradigm of cancer care. PMID- 29387144 TI - HIV-associated Kaposi's sarcoma in Maputo, Mozambique: outcomes in a specialized treatment center, 2010-2015. AB - Background: Kaposi's sarcoma (KS) is a common HIV-associated malignancy associated with disability, pain and poor outcomes. The cornerstone of its treatment is antiretroviral therapy, but advanced disease necessitates the addition of chemotherapy. In high-income settings, this often consists of liposomal anthracyclines, but in Mozambique, the first line includes conventional doxorubicin, bleomycin and vincristine, which is poorly-tolerated. Medecins Sans Frontieres supports the Ministry of Health (MOH) in a specialized HIV and KS treatment center at the Centro de Referencia de Alto Mae in Maputo. Methods: We performed a retrospective analysis of data collected on patients enrolled at the CRAM between 2010 and 2015, extracting routinely-collected clinical information from patient care databases. KS treatment followed national guidelines, and KS staging followed AIDS Clinical Trials Group and MOH criteria. Baseline description of the cohort and patient outcomes was performed. Risk factors for negative outcomes (death or loss to follow-up) were explored using Cox regression. Results: Between 2010 and 2015, 1573 patients were enrolled, and 1210 began chemotherapy. A majority were young adult males. At enrollment, CD4 was < 200 cells/MUl in 45% of patients. Among patients receiving chemotherapy, 78% received combination doxorubicin-bleomycin-vincristine. Among patients receiving chemotherapy, 43% were lost to follow-up and 8% were known to have died. In multivariate regression, the only risk factors identified with poor outcomes were CD4 < 100 cells/MUl at enrollment (Risk ratio 1.5, 95%CI 1.1-2.1, p = 0.02 and having S1 disease (RR 1.7, 95%CI 1.2-2.3, p = 0.001). Discussion: We describe a large cohort of patients receiving care for HIV-associated KS in a specialized clinic in an urban setting. Outcomes were nonetheless unsatisfactory. Efforts should be made to decrease late referrals and entry into care and to increase access to more effective and better-tolerated treatments like liposomal doxorubicin. PMID- 29387145 TI - Provision of emergency obstetric care at secondary level in a conflict setting in a rural area of Afghanistan - is the hospital fulfilling its role? AB - Background: Provision of Emergency Obstetric and Neonatal Care (EmONC) reduces maternal mortality and should include three components: Basic Emergency Obstetric and Neonatal Care (BEmONC) offered at primary care level, Comprehensive EmONC (CEmONC) at secondary level and a good referral system in-between. In a conflict affected province of Afghanistan (Khost), we assessed the performance of an Medecins Sans Frontieres (MSF) run CEmONC hospital without a primary care and referral system. Performance was assessed in terms of hospital utilisation for obstetric emergencies and quality of obstetric care. Methods: A cross-sectional study using routine programme data (2013-2014). Results: Of 29,876 admissions, 99% were self-referred, 0.4% referred by traditional birth attendants and 0.3% by health facilities. Geographic origins involved clustering around the hospital vicinity and the provincial road axis. While there was a steady increase in hospital caseload, the number and proportion of women with Direct Obstetric Complications (DOC) progressively dropped from 21% to 8% over 2 years. Admissions for normal deliveries continuously increased. In-hospital maternal deaths were 0.03%, neonatal deaths 1% and DOC case-fatality rate 0.2% (all within acceptable limits). Conclusions: Despite a high and ever increasing caseload, good quality Comprehensive EmONC could be offered in a conflict-affected setting in rural Afghanistan. However, the primary emergency role of the hospital is challenged by diversion of resources to normal deliveries that should happen at primary level. Strengthening Basic EmONC facilities and establishing an efficient referral system are essential to improve access for emergency cases and increase the potential impact on maternal mortality. PMID- 29387146 TI - What are "good outcomes" for adolescents in public mental health settings? AB - Background: In line with the evidence-based paradigm, routine outcome monitoring and clinical feedback systems are now being recommended and implemented in youth mental health services. However, what constitutes a good outcome for young service users is not fully understood. In order to successfully monitor outcomes that are clinically and personally relevant for the service user that are to benefit from these systems, we need to gain more knowledge of what young service users value as meaningful outcomes of youth mental health services. Aim: To contribute knowledge into what constitutes "good outcomes" from the experiences of adolescent service users in public mental health systems. Methods: A qualitative in-depth study of the experiences and reflections from 22 adolescents aged 14-19 years, currently or recently being in public mental health services. The data material was analyzed using a systematic step-wise consensual qualitative research framework for team-based analysis. Results: An overarching theme of outcome as having developed a stronger autonomy and safer identity emerged from the analysis, with the subsequent five constituent themes, named from the words of the adolescent clients: (1) I've discovered and given names to my emotions, (2) I've started to become the person that I truly am, (3) I've dared to open up and feel connected to others, (4) I've started saying yes where I used to say no, and, (5) I've learned how to cope with challenges in life. Conclusion: "Good outcomes" in youth mental health services should be understood as recovery oriented, sensitive to developmental phases, and based on the personal goals and values of each adolescent client. PMID- 29387147 TI - Global trends in research related to social media in psychology: mapping and bibliometric analysis. AB - Background: Social media, defined as interactive Web applications, have been on the rise globally, particularly among adults. The objective of this study was to investigate the trend of the literature related to the most used social network worldwide (i.e. Facebook, Twitter, LinkedIn, Snapchat, and Instagram) in the field of psychology. Specifically, this study will assess the growth in publications, citation analysis, international collaboration, author productivity, emerging topics and the mapping of frequent terms in publications pertaining to social media in the field of psychology. Methods: Publications related to social media in the field of psychology published between 2004 and 2014 were obtained from the Web of Science. The records extracted were analysed for bibliometric characteristics such as the growth in publications, citation analysis, international collaboration, emerging topics and the mapping of frequent terms in publications pertaining to social media in the field of psychology. VOSviewer v.1.6.5 was used to construct scientific maps. Results: Overall, 959 publications were retrieved during the period between 2004 and 2015. The number of research publications in social media in the field of psychology showed a steady upward growth. Publications from the USA accounted for 57.14% of the total publications and the highest h-index (48).The most common document type was research articles (873; 91.03%). Over 99.06% of the publications were published in English. Computers in Human Behavior was the most prolific journal. The University of Wisconsin-Madison ranked first in terms of the total publications (n = 39). A visualisation analysis showed that personality psychology, experimental psychology, psychological risk factors, and developmental psychology were continual concerns of the research. Conclusions: This is the first study reporting the global trends in the research related to social media in the psychology field. Based on the raw data from the Web of Science, publication characteristics such as quality and quantity were assessed using bibliometric techniques over 12 years. The USA and its institutions play a dominant role in this topic. The most preferred topics related to social media in psychology are personality psychology, experimental psychology, psychological risk factors, and developmental psychology. PMID- 29387148 TI - Making complex interventions work in low resource settings: developing and applying a design focused implementation approach to deliver mental health through primary care in India. AB - Background: Globally, there is a large treatment gap for people with mental disorders, and this gap is especially extreme in Low and Middle Income Countries. This gap can be potentially bridged by integrating evidenced based mental health interventions into primary care, but there is little knowledge about how to do this well, especially in countries with weak health systems. Research into the best implementation approaches is a priority, but in order to do so, it is first necessary to adapt implementation science principles and tools for mental health services in low resource settings. Results: The frameworks that have been used to implement evidence-based behavioral health and health care interventions in High Income Countries do not directly apply to contexts where resources and processes for service delivery and support do not exist. We propose an implementation approach for low resource settings, called design-focused implementation, emphasizing the design of delivery systems using systematic design methods as precursor to implementation in severely resource constrained environments. This approach draws from existing literature in design thinking, quality implementation, improvement science and evaluation and we describe its use in creating the processes, organizations and the enabling environment for integration of mental health service delivery into primary care in India. Conclusions: Design-focused implementation will be useful for guiding research and practice in closing the implementation gap for a wide variety of complex interventions in low resource settings. PMID- 29387149 TI - Mental health literacy of school nurses in the United Arab Emirates. AB - Background: To support promotion, prevention and early intervention for mental illness school nurses need to be mental health literate. Methods: Three hundred and thirty-nine school nurses employed in government and private schools from three Emirates in the UAE were surveyed. A culturally adapted Mental Health Literacy questionnaire comprising three vignettes of fictional characters meeting diagnostic criteria for the target conditions along with the Kessler Psychological Distress Scale (K10) was administered to ascertain school nurses' ability to correctly identify the conditions and to elicit beliefs about helpfulness of treatment interventions and of health care providers for these conditions. Results: Less than 50% of the respondents correctly identified the disorders presented, while accurate identification of evidence-based interventions was also limited. Correlations between level of psychological distress and level of inaccurate survey responses was also revealed, respondents who correctly identified the correct diagnosis of the vignette and the most appropriate interventions were those who had a significantly lower K10 score. Conclusions: Low levels of mental health literacy amongst respondents in combination with potential religious and cultural factors as reported in the literature, highlight the need for curriculum enhancements for future health professionals and a targeted program of culturally appropriate professional development focused on mental health promotion for those in clinical practice. The level of psychological distress noted in this cohort also signals a need to ensure that appropriate supports are available for clinical staff employed in schools. PMID- 29387150 TI - Population genomics analyses of European ibex species show lower diversity and higher inbreeding in reintroduced populations. AB - Restoration of lost species ranges to their native distribution is key for the survival of endangered species. However, reintroductions often fail and long-term genetic consequences are poorly understood. Alpine ibex (Capra ibex) are wild goats that recovered from <100 individuals to ~50,000 within a century by population reintroductions. We analyzed the population genomic consequences of the Alpine ibex reintroduction strategy. We genotyped 101,822 genomewide single nucleotide polymorphism loci in 173 Alpine ibex, the closely related Iberian ibex (Capra pyrenaica) and domestic goat (Capra hircus). The source population of all Alpine ibex maintained genetic diversity comparable to Iberian ibex, which experienced less severe bottlenecks. All reintroduced Alpine ibex populations had individually and combined lower levels of genetic diversity than the source population. The reintroduction strategy consisted of primary reintroductions from captive breeding and secondary reintroductions from established populations. This stepwise reintroduction strategy left a strong genomic footprint of population differentiation, which increased with subsequent rounds of reintroductions. Furthermore, analyses of genomewide runs of homozygosity showed recent inbreeding primarily in individuals of reintroduced populations. We showed that despite the rapid census recovery, Alpine ibex carry a persistent genomic signature of their reintroduction history. We discuss how genomic monitoring can serve as an early indicator of inbreeding. PMID- 29387151 TI - Cancer incidence increasing globally: The role of relaxed natural selection. AB - Cancer incidence increase has multiple aetiologies. Mutant alleles accumulation in populations may be one of them due to strong heritability of many cancers. The opportunity for the operation of natural selection has decreased in the past ~150 years because of reduction in mortality and fertility. Mutation-selection balance may have been disturbed in this process and genes providing background for some cancers may have been accumulating in human gene pools. Worldwide, based on the WHO statistics for 173 countries the index of the opportunity for selection is strongly inversely correlated with cancer incidence in peoples aged 0-49 years and in people of all ages. This relationship remains significant when gross domestic product per capita (GDP), life expectancy of older people (e50), obesity, physical inactivity, smoking and urbanization are kept statistically constant for fifteen (15) of twenty-seven (27) individual cancers incidence rates. Twelve (12) cancers which are not correlated with relaxed natural selection after considering the six potential confounders are largely attributable to external causes like viruses and toxins. Ratios of the average cancer incidence rates of the 10 countries with lowest opportunities for selection to the average cancer incidence rates of the 10 countries with highest opportunities for selection are 2.3 (all cancers at all ages), 2.4 (all cancers in 0-49 years age group), 5.7 (average ratios of strongly genetically based cancers) and 2.1 (average ratios of cancers with less genetic background). PMID- 29387152 TI - Applications of random forest feature selection for fine-scale genetic population assignment. AB - Genetic population assignment used to inform wildlife management and conservation efforts requires panels of highly informative genetic markers and sensitive assignment tests. We explored the utility of machine-learning algorithms (random forest, regularized random forest and guided regularized random forest) compared with FST ranking for selection of single nucleotide polymorphisms (SNP) for fine scale population assignment. We applied these methods to an unpublished SNP data set for Atlantic salmon (Salmo salar) and a published SNP data set for Alaskan Chinook salmon (Oncorhynchus tshawytscha). In each species, we identified the minimum panel size required to obtain a self-assignment accuracy of at least 90% using each method to create panels of 50-700 markers Panels of SNPs identified using random forest-based methods performed up to 7.8 and 11.2 percentage points better than FST-selected panels of similar size for the Atlantic salmon and Chinook salmon data, respectively. Self-assignment accuracy >=90% was obtained with panels of 670 and 384 SNPs for each data set, respectively, a level of accuracy never reached for these species using FST-selected panels. Our results demonstrate a role for machine-learning approaches in marker selection across large genomic data sets to improve assignment for management and conservation of exploited populations. PMID- 29387153 TI - Growth gains from selective breeding in a spruce hybrid zone do not compromise local adaptation to climate. AB - Hybrid zones contain extensive standing genetic variation that facilitates rapid responses to selection. The Picea glauca * Picea engelmannii hybrid zone in western Canada is the focus of tree breeding programs that annually produce ~90 million reforestation seedlings. Understanding the direct and indirect effects of selective breeding on adaptive variation is necessary to implement assisted gene flow (AGF) polices in Alberta and British Columbia that match these seedlings with future climates. We decomposed relationships among hybrid ancestry, adaptive traits, and climate to understand the implications of selective breeding for climate adaptations and AGF strategies. The effects of selection on associations among hybrid index estimated from ~6,500 SNPs, adaptive traits, and provenance climates were assessed for ~2,400 common garden seedlings. Hybrid index differences between natural and selected seedlings within breeding zones were small in Alberta (average +2%), but larger and more variable in BC (average -7%, range -24% to +1%), slightly favoring P. glauca ancestry. The average height growth gain of selected seedlings over natural seedlings within breeding zones was 36% (range 12%-86%). Clines in growth with temperature-related variables were strong, but differed little between selected and natural populations. Seedling hybrid index and growth trait associations with evapotranspiration-related climate variables were stronger in selected than in natural seedlings, indicating possible preadaptation to drier future climates. Associations among cold hardiness, hybrid ancestry, and cold-related climate variables dominated signals of local adaptation and were preserved in breeding populations. Strong hybrid ancestry-phenotype-climate associations suggest that AGF will be necessary to match interior spruce breeding populations with shifting future climates. The absence of antagonistic selection responses among traits and maintenance of cold adaptation in selected seedlings suggests breeding populations can be safely redeployed using AGF prescriptions similar to those of natural populations. PMID- 29387154 TI - Slow and temperature-mediated pathogen adaptation to a nonspecific fungicide in agricultural ecosystem. AB - The spread of antimicrobial resistance and global change in air temperature represent two major phenomena that are exerting a disastrous impact on natural and social issues but investigation of the interaction between these phenomena in an evolutionary context is limited. In this study, a statistical genetic approach was used to investigate the evolution of antimicrobial resistance in agricultural ecosystem and its association with local air temperature, precipitation, and UV radiation. We found no resistance to mancozeb, a nonspecific fungicide widely used in agriculture for more than half a century, in 215 Alternaria alternata isolates sampled from geographic locations along a climatic gradient and cropping system representing diverse ecotypes in China, consistent with low resistance risk in many nonspecific fungicides. Genetic variance accounts for ~35% of phenotypic variation, while genotype-environment interaction is negligible, suggesting that heritability plays a more important role in the evolution of resistance to mancozeb in plant pathogens than phenotypic plasticity. We also found that tolerance to mancozeb in agricultural ecosystem is under constraining selection and significantly associated with local air temperature, possibly resulting from a pleiotropic effect of resistance with thermal and other ecological adaptations. The implication of these results for fungicide and other antimicrobial management in the context of global warming is discussed. PMID- 29387155 TI - Gene flow in Argentinian sunflowers as revealed by genotyping-by-sequencing data. AB - Gene flow can have several different applied consequences, ranging from extinction to the escape of transgenes to the evolution of weedy or invasive lineages. Here, we describe patterns of hybridization and gene flow involving domesticated and wild sunflowers in Argentina. To address the risks of introgression of variants from the cultivated sunflower into invasive wild Helianthus, we used genotyping-by-sequencing (GBS) to genotype 182 samples from 11 sites in Argentina, along with previously published data from samples from the native range (North America), to determine the native source populations of the Argentinian samples and to detect admixture. We unexpectedly discovered two distinctive forms of H. petiolaris in Argentina, one from H. petiolaris subsp. petiolaris as expected, but the other from an unknown source. Extensive admixture was observed among Argentinian sunflowers, largely confirming phenotypic predictions. While many hybrids are F1s, there were signals consistent with introgression from the domesticated sunflower into H. petiolaris. Whether this introgression is incidental or a causal driver of invasiveness is not yet clear, but it seems likely that genes found in the domesticated sunflower genome (whether engineered or not) will quickly find their way into wild Argentinian sunflower populations. PMID- 29387156 TI - Egg size and the adaptive capacity of early life history traits in Chinook salmon (Oncorhynchus tshawytscha). AB - Offspring traits are greatly influenced by maternal effects, and these maternal effects may provide an important pathway through which populations can adapt to changing thermal environments. We investigated the effect of egg size on the among- and within-population variation in early life history traits among introduced Great Lakes Chinook salmon (Oncorhynchus tshawytscha) populations under varying thermal conditions. We reared Chinook salmon from three populations in a common-garden hatchery study at 6.5, 9.4, and 15.2 degrees C and measured a variety of fitness-related traits during development. We found that most of the among-population variation in early life history traits was explained by egg size. However, the contribution of egg size to the among-population variation decreased with an increase in temperature suggesting that other effects, such as genetic, contribute at high temperature. Within populations, egg size explained much of the dam variance and maternal effect for traits in every temperature, whereas egg size generally had little to no influence on the sire variance and heritability. Overall, our results demonstrate the significant contribution egg size makes to shaping early life history phenotypes among and within populations, and suggest that egg size is an important pathway through which offspring phenotypes can evolve on contemporary timescales. PMID- 29387157 TI - Rapid evolution of symbiont-mediated resistance compromises biological control of aphids by parasitoids. AB - There is growing interest in biological control as a sustainable and environmentally friendly way to control pest insects. Aphids are among the most detrimental agricultural pests worldwide, and parasitoid wasps are frequently employed for their control. The use of asexual parasitoids may improve the effectiveness of biological control because only females kill hosts and because asexual populations have a higher growth rate than sexuals. However, asexuals may have a reduced capacity to track evolutionary change in their host populations. We used a factorial experiment to compare the ability of sexual and asexual populations of the parasitoid Lysiphlebus fabarum to control caged populations of black bean aphids (Aphis fabae) of high and low clonal diversity. The aphids came from a natural population, and one-third of the aphid clones harbored Hamiltonella defensa, a heritable bacterial endosymbiont that increases resistance to parasitoids. We followed aphid and parasitoid population dynamics for 3 months but found no evidence that the reproductive mode of parasitoids affected their effectiveness as biocontrol agents, independent of host clonal diversity. Parasitoids failed to control aphids in most cases, because their introduction resulted in strong selection for clones protected by H. defensa. The increasingly resistant aphid populations escaped control by parasitoids, and we even observed parasitoid extinctions in many cages. The rapid evolution of symbiont-conferred resistance in turn imposed selection on parasitoids. In cages where asexual parasitoids persisted until the end of the experiment, they became dominated by a single genotype able to overcome the protection provided by H. defensa. Thus, there was evidence for parasitoid counteradaptation, but it was generally too slow for parasitoids to regain control over aphid populations. It appears that when pest aphids possess defensive symbionts, the presence of parasitoid genotypes able to overcome symbiont-conferred resistance is more important for biocontrol success than their reproductive mode. PMID- 29387158 TI - Applying landscape genomic tools to forest management and restoration of Hawaiian koa (Acacia koa) in a changing environment. AB - Identifying and quantifying the importance of environmental variables in structuring population genetic variation can help inform management decisions for conservation, restoration, or reforestation purposes, in both current and future environmental conditions. Landscape genomics offers a powerful approach for understanding the environmental factors that currently associate with genetic variation, and given those associations, where populations may be most vulnerable under future environmental change. Here, we applied genotyping by sequencing to generate over 11,000 single nucleotide polymorphisms from 311 trees and then used nonlinear, multivariate environmental association methods to examine spatial genetic structure and its association with environmental variation in an ecologically and economically important tree species endemic to Hawaii, Acacia koa. Admixture and principal components analyses showed that trees from different islands are genetically distinct in general, with the exception of some genotypes that match other islands, likely as the result of recent translocations. Gradient forest and generalized dissimilarity models both revealed a strong association between genetic structure and mean annual rainfall. Utilizing a model for projected future climate on the island of Hawaii, we show that predicted changes in rainfall patterns may result in genetic offset, such that trees no longer may be genetically matched to their environment. These findings indicate that knowledge of current and future rainfall gradients can provide valuable information for the conservation of existing populations and also help refine seed transfer guidelines for reforestation or replanting of koa throughout the state. PMID- 29387160 TI - Long-term on-farm participatory maize breeding by stratified mass selection retains molecular diversity while improving agronomic performance. AB - Modern maize breeding programs gave rise to genetically uniform varieties that can affect maize's capacity to cope with increasing climate unpredictability. Maize populations, genetically more heterogeneous, can evolve and better adapt to a broader range of edaphic-climatic conditions. These populations usually suffer from low yields; it is therefore desirable to improve their agronomic performance while maintaining their valuable diversity levels. With this objective, a long term participatory breeding/on-farm conservation program was established in Portugal. In this program, maize populations were subject to stratified mass selection. This work aimed to estimate the effect of on-farm stratified mass selection on the agronomic performance, quality, and molecular diversity of two historical maize populations. Multilocation field trials, comparing the initial populations with the derived selection cycles, showed that this selection methodology led to agronomic improvement for one of the populations. The molecular diversity analysis, using microsatellites, revealed that overall genetic diversity in both populations was maintained throughout selection. The comparison of quality parameters between the initial populations and the derived selection cycles was made using kernel from a common-garden experiment. This analysis showed that the majority of the quality traits evaluated progressed erratically over time. In conclusion, this breeding approach, through simple and low-cost methodologies, proved to be an alternative strategy for genetic resources' on-farm conservation. PMID- 29387159 TI - Effects of inbreeding on a gregarious parasitoid wasp with complementary sex determination. AB - Inbreeding and inbreeding depression are processes in small populations of particular interest for a range of human activities such as animal breeding, species conservation, or pest management. In particular, biological control programs should benefit from a thorough understanding of the causes and consequences of inbreeding because natural enemies experience repetitive bottlenecks during importation, laboratory rearing, and introduction. Predicting the effect of inbreeding in hymenopteran parasitoid wasps, frequently used in biological control programs, is nonetheless a difficult endeavor. In haplodiploid parasitoids, the purge of deleterious alleles via haploid males should reduce genetic load, but if these species also have complementary sex determination (CSD), abnormal diploid males will be produced, which may jeopardize the success of biological control introductions. Mastrus ridens is such a parasitoid wasp with CSD, introduced to control the codling moth, Cydia pomonella (L.). We studied its life history traits in the laboratory under two conditions: inbred (full-sib) and outbred (nonsib) crosses, across five generations, to examine the consequences of inbreeding in this species. We found that in inbred lines, nonreproducing females live less, the number of daughters produced was lower, and sex ratio (proportion of males) and proportion of diploid males were higher. Diploid males were able to produce fertile daughters, but fewer than haploid males. Lineage survival was similar for inbred and outbred lines across the five generations. The most significant decrease in fitness was thus a consequence of the production of diploid males, but this effect was not as extreme as in most other species with CSD, due to the fertility of diploid males. This study highlights the importance of determining the type of sex determination in parasitoid wasps used for biological control, and the importance of maintaining genetic diversity in species with CSD when importation or augmentation is the goal. PMID- 29387161 TI - Optimal management strategy of insecticide resistance under various insect life histories: Heterogeneous timing of selection and interpatch dispersal. AB - Although theoretical studies have shown that the mixture strategy, which uses multiple toxins simultaneously, can effectively delay the evolution of insecticide resistance, whether it is the optimal management strategy under different insect life histories and insecticide types remains unknown. To test the robustness of this management strategy over different life histories, we developed a series of simulation models that cover almost all the diploid insect types and have the same basic structure describing pest population dynamics and resistance evolution with discrete time steps. For each of two insecticidal toxins, independent one-locus two-allele autosomal inheritance of resistance was assumed. The simulations demonstrated the optimality of the mixture strategy either when insecticide efficacy was incomplete or when some part of the population disperses between patches before mating. The rotation strategy, which uses one insecticide on one pest generation and a different one on the next, did not differ from sequential usage in the time to resistance, except when dominance was low. It was the optimal strategy when insecticide efficacy was high and premating selection and dispersal occur. PMID- 29387162 TI - Crop-to-wild gene flow and spatial genetic structure in the closest wild relatives of the cultivated apple. AB - Crop-to-wild gene flow have important evolutionary and ecological consequences and require careful consideration in conservation programs for wild genetic resources of potential use in breeding programs and in assessments of the risk of transgene escape into natural ecosystems. Using 26 microsatellites and a set of 1181 trees, we investigated the extent of introgression from the cultivated apple, Malus domestica, to its three closest wild relatives, M. sylvestris in Europe, M. orientalis in the Caucasus, and M. sieversii in Central Asia. We found footprints of introgression from M. domestica to M. orientalis (3.2% of hybrids), M. sieversii (14.8%), and M. sylvestris (36.7%). Malus sieversii and M. orientalis presented weak, but significant genetic structures across their geographic range. Malus orientalis displayed genetic differentiation with three differentiated populations in Turkey, Armenia, and Russia. Malus sieversii consisted of a main population spread over Central Asia and a smaller population in the Tian Shan Mountains. The low Sp values suggest high dispersal capacities for the wild apple relatives. High potential for crop-to-wild gene flow in apples needs to be considered in the implementation of in situ and ex situ actions for the conservation of wild apple genetic resources potentially useful to plant breeding. PMID- 29387163 TI - Genetic and life-history changes associated with fisheries-induced population collapse. AB - Over the recent years, growing number of studies suggests that intensive size selective fishing can cause evolutionary changes in life-history traits in the harvested population, which can have drastic negative effects on populations, ecosystems and fisheries. However, most studies to date have overlooked the potential role of immigration of fish with different phenotypes as an alternative plausible mechanism behind observed phenotypic trends. Here, we investigated the evolutionary consequences of intensive fishing simultaneously at phenotypic and molecular level in Eurasian perch (Perca fluviatilis L.) population in the Baltic Sea over a 24-year period. We detected marked changes in size- and age distributions and increase in juvenile growth rate. We also observed reduction of age at sexual maturity in males that has frequently been considered to support the hypothesis of fisheries-induced evolution. However, combined individual-based life-history and genetic analyses indicated increased immigration of foreign individuals with different life-history patterns as an alternative mechanism behind the observed phenotypic change. This study demonstrates the value of combining genetic and phenotypic analyses and suggests that replacement or breakdown of locally adapted gene complexes may play important role in impeding the recovery of fish populations. PMID- 29387164 TI - Evolution and spread of glyphosate resistance in Conyza canadensis in California. AB - Recent increases in glyphosate use in perennial crops of California, USA, are hypothesized to have led to an increase in selection and evolution of resistance to the herbicide in Conyza canadensis populations. To gain insight into the evolutionary origins and spread of resistance and to inform glyphosate resistance management strategies, we investigated the geographical distribution of glyphosate resistance in C. canadensis across and surrounding the Central Valley, its spatial relationship to groundwater protection areas (GWPA), and the genetic diversity and population structure and history using microsatellite markers. Frequencies of resistant individuals in 42 sampled populations were positively correlated with the size of GWPA within counties. Analyses of population genetic structure also supported spread of resistance in these areas. Bayesian clustering and approximate Bayesian computation (ABC) analyses revealed multiple independent origins of resistance within the Central Valley. Based on parameter estimation in the ABC analyses, resistant genotypes underwent expansion after glyphosate use began in agriculture, but many years before it was detected. Thus, diversity in weed control practices prior to herbicide regulation in GWPA probably kept resistance frequencies low. Regionally coordinated efforts to reduce seed dispersal and selection pressure are needed to manage glyphosate resistance in C. canadensis. PMID- 29387165 TI - Effects of harvesting of increasing intensities on genetic diversity and population structure of white spruce. AB - Forest harvesting of increasing intensities is expected to have intensifying impacts on the genetic diversity and population structure of postharvest naturally regenerated stands by affecting the magnitude of evolutionary processes, such as genetic drift, gene flow, mating system, and selection. We have tested this hypothesis for the first time by employing widely distributed boreal white spruce (Picea glauca) as a model and controlled, replicated experimental harvesting and regeneration experiment at the EMEND project site (http://www.emendproject.org). We used two approaches. First, genetic diversity and population structure of postharvest natural regeneration after five harvesting treatments (green tree retention of 75%, 50%, 20%, and 10%, and clearcut) were assessed and compared with those of the unharvested control (pristine preharvest old-growth) in two replicates each of conifer-dominated (CD) and mixed-wood (MW) forest, using 10 (six EST (expressed sequence tag) and four genomic) microsatellite markers. Second, genetic diversity and population structure of preharvest old-growth were compared with those of postharvest natural regeneration after five harvesting treatments in the same treatment blocks in one replicate each of CD and MW forests. Contrary to our expectations, genetic diversity, inbreeding levels, and population genetic structure were similar between unharvested control or preharvest old-growth and postharvest natural regeneration after five harvesting treatments, with clearcut showing no negative genetic impacts. The potential effects of genetic drift and inbreeding resulting from harvesting bottlenecks were counterbalanced by predominantly outcrossing mating system and high gene flow from the residual and/or surrounding white spruce. CD and MW forests responded similarly to harvesting of increasing intensities. Simulated data for 10, 50, and 100 microsatellite markers showed the same results as obtained empirically from 10 microsatellite markers. Similar patterns of genetic diversity and population structure were observed for EST and genomic microsatellites. In conclusion, harvesting of increasing intensities did not show any significant negative impact on genetic diversity, population structure, and evolutionary potential of white spruce in CD and MW forests. Our first of its kind of study addresses the broad central forest management question how forest harvesting and regeneration practices can best maintain genetic biodiversity and ecosystem integrity. PMID- 29387166 TI - Temporal patterns of genetic variation in a salmon population undergoing rapid change in migration timing. AB - Though genetic diversity is necessary for population persistence in rapidly changing environments, little is known about how climate-warming influences patterns of intra-population genetic variation. For a pink salmon population experiencing increasing temperatures, we used temporal genetic data (microsatellite = 1993, 2001, 2009; allozyme = 1979, 1981, 1983) to quantify the genetic effective population size (Ne ) and genetic divergence due to differences in migration timing and to estimate whether these quantities have changed over time. We predicted that temporal trends toward earlier migration timing and a corresponding loss of phenotypic variation would decrease genetic divergence based on migration timing and Ne . We observed significant genetic divergence based on migration timing and genetic heterogeneity between early- and late migrating fish. There was also some evidence for divergent selection between early- and late-migrating fish at circadian rhythm genes, but results varied over time. Estimates of Ne from multiple methods were large (>1200) and Ne /Nc generally exceeded 0.2. Despite shifts in migration timing and loss of phenotypic variation, there was no evidence for changes in within-population genetic divergence or Ne over the course of this study. These results suggest that in instances of population stability, genetic diversity may be resistant to climate induced changes in migration timing. PMID- 29387167 TI - Evolutionary dynamics of a rapidly receding southern range boundary in the threatened California Red-Legged Frog (Rana draytonii). AB - Populations forming the edge of a species range are often imperiled by isolation and low genetic diversity, with proximity to human population centers being a major determinant of edge stability in modern landscapes. Since the 1960s, the California red-legged frog (Rana draytonii) has undergone extensive declines in heavily urbanized southern California, where the range edge has rapidly contracted northward while shifting its cardinal orientation to an east-west trending axis. We studied the genetic structure and diversity of these frontline populations, tested for signatures of contemporary disturbance, specifically fire, and attempted to disentangle these signals from demographic events extending deeper into the past. Consistent with the genetic expectations of the 'abundant-center' model, we found that diversity, admixture, and opportunity for random mating increases in populations sampled successively further away from the range boundary. Demographic simulations indicate that bottlenecks in peripheral isolates are associated with processes extending tens to a few hundred generations in the past, despite the demographic collapse of some due to recent fire-flood events. While the effects of recent disturbance have left little genetic imprint on these populations, they likely contribute to an extinction debt that will lead to continued range contraction unless management intervenes to stall or reverse the process. PMID- 29387168 TI - Small effective size limits performance in a novel environment. AB - Understanding what limits or facilitates species' responses to human-induced habitat change can provide insight for the control of invasive species and the conservation of small populations, as well as an arena for studying adaptation to realistic novel environments. Small effective size of ancestral populations could limit the establishment in, or response to, a novel or altered habitat because of low genetic variation for ecologically important traits, and/or because small populations harbor fixed deleterious mutations. I estimated the fitness of individuals from populations of the endangered plant Hypericum cumulicola, of known census and effective size, transplanted into native scrub habitat and unpaved roadsides, which are a novel habitat for this species. I found a significant positive relationship between estimates of population size and mean fitness, but only in the novel roadside habitat. Fitness was more than 200% greater in the roadside habitat than the scrub, mostly due to increased fecundity. These results combined with previous estimates of heterosis in this species suggest that fixed deleterious mutations could contribute to lower fitness of field transplants from small populations in the novel environment. PMID- 29387169 TI - Proximity to agriculture is correlated with pesticide tolerance: evidence for the evolution of amphibian resistance to modern pesticides. AB - Anthropogenic environmental change is a powerful and ubiquitous evolutionary force, so it is critical that we determine the extent to which organisms can evolve in response to anthropogenic environmental change and whether these evolutionary responses have associated costs. This issue is particularly relevant for species of conservation concern including many amphibians, which are experiencing global declines from many causes including widespread exposure to agrochemicals. We used a laboratory toxicity experiment to assess variation in sensitivity to two pesticides among wood frog (Lithobates sylvaticus) populations and a mesocosm experiment to ascertain whether resistance to pesticides is associated with decreased performance when animals experience competition and fear of predation. We discovered that wood frog populations closer to agriculture were more resistant to a common insecticide (chlorpyrifos), but not to a common herbicide (Roundup). We also found no evidence that this resistance carried a performance cost when facing competition and the fear of predation. To our knowledge, this is the first study demonstrating that organophosphate insecticide (the most commonly applied class of insecticides in the world) resistance increases with agricultural land use in an amphibian, which is consistent with an evolutionary response to agrochemicals. PMID- 29387170 TI - Molecular genetics and genomics generate new insights into invertebrate pest invasions. AB - Invertebrate pest invasions and outbreaks are associated with high social, economic, and ecological costs, and their significance will intensify with an increasing pressure on agricultural productivity as a result of human population growth and climate change. New molecular genetic and genomic techniques are available and accessible, but have been grossly underutilized in studies of invertebrate pest invasions, despite that they are useful tools for applied pest management and for understanding fundamental features of pest invasions including pest population demographics and adaptation of pests to novel and/or changing environments. Here, we review current applications of molecular genetics and genomics in the study of invertebrate pest invasions and outbreaks, and we highlight shortcomings from the current body of research. We then discuss recent conceptual and methodological advances in the areas of molecular genetics/genomics and data analysis, and we highlight how these advances will further our understanding of the demographic, ecological, and evolutionary features of invertebrate pest invasions. We are now well equipped to use molecular data to understand invertebrate dispersal and adaptation, and this knowledge has valuable applications in agriculture at a time when these are critically required. PMID- 29387171 TI - Semantic and syntactic interoperability in online processing of big Earth observation data. AB - The challenge of enabling syntactic and semantic interoperability for comprehensive and reproducible online processing of big Earth observation (EO) data is still unsolved. Supporting both types of interoperability is one of the requirements to efficiently extract valuable information from the large amount of available multi-temporal gridded data sets. The proposed system wraps world models, (semantic interoperability) into OGC Web Processing Services (syntactic interoperability) for semantic online analyses. World models describe spatio temporal entities and their relationships in a formal way. The proposed system serves as enabler for (1) technical interoperability using a standardised interface to be used by all types of clients and (2) allowing experts from different domains to develop complex analyses together as collaborative effort. Users are connecting the world models online to the data, which are maintained in a centralised storage as 3D spatio-temporal data cubes. It allows also non experts to extract valuable information from EO data because data management, low level interactions or specific software issues can be ignored. We discuss the concept of the proposed system, provide a technical implementation example and describe three use cases for extracting changes from EO images and demonstrate the usability also for non-EO, gridded, multi-temporal data sets (CORINE land cover). PMID- 29387172 TI - Engineering Yarrowia lipolytica to enhance lipid production from lignocellulosic materials. AB - Background: Yarrowia lipolytica is a common biotechnological chassis for the production of lipids, which are the preferred feedstock for the production of fuels and chemicals. To reduce the cost of microbial lipid production, inexpensive carbon sources must be used, such as lignocellulosic hydrolysates. Unfortunately, lignocellulosic materials often contain toxic compounds and a large amount of xylose, which cannot be used by Y. lipolytica. Results: In this work, we engineered this yeast to efficiently use xylose as a carbon source for the production of lipids by overexpressing native genes. We further increased the lipid content by overexpressing heterologous genes to facilitate the conversion of xylose-derived metabolites into lipid precursors. Finally, we showed that these engineered strains were able to grow and produce lipids in a very high yield (lipid content = 67%, titer = 16.5 g/L, yield = 3.44 g/g sugars, productivity 1.85 g/L/h) on a xylose-rich agave bagasse hydrolysate in spite of toxic compounds. Conclusions: This work demonstrates the potential of metabolic engineering to reduce the costs of lipid production from inexpensive substrates as source of fuels and chemicals. PMID- 29387173 TI - Genome sequence and comparative genomic analysis of a clinically important strain CD11-4 of Janibacter melonis isolated from celiac disease patient. AB - Background: Janibacter melonis and other member of this genus are known to cause bacteremia and serious clinical comorbidities, but there is no study reporting about pathogenicity attributes of J. melonis. Janibacter terrae is known to cause lethal infection. Reporting the genome of J. melonis CD11-4 and comparative genomics with other members of genus has provided some novel insights that can enable us to understand the mechanisms responsible for its pathogenicity in humans. Results: Comparative genomic analysis by Rapid Annotation Server and Technology revealed the presence of similar virulence determinant genes in both J. terrae NBRC 107853T and J. melonis CD11-4. Like J. terrae NBRC 107853T, J. melonis CD11-4 contained two genes responsible for resistance against beta-lactam class of antibiotics and two genes for resistance against fluoroquinolones. Interestingly, J. melonis CD11-4 contained a unique gene coding for multidrug resistance efflux pumps unlike all other members of this genus. It also contained two genes involved in Toxin-antitoxin Systems that were absent in J. terrae NBRC 107853T but were present in some other members of genus. Conclusions: Genome annotations of J. melonis CD11-4 revealed that it contained similar or more virulence repertoire like J. terrae NBRC 107853T. Like other gut pathogens, J. melonis possesses key virulence determinant genes for antibiotic resistance, invasion, adhesion, biofilm formation, iron acquisition and to cope with stress response, thereby indicating that strain J. melonis CD11-4 could be a gut pathogen. PMID- 29387174 TI - Cancer antigen-125 and risk of atrial fibrillation: a systematic review and meta analysis. AB - Background: Cancer antigen-125 (Ca-125) is traditionally recognised as a tumour marker and its role in cardiovascular diseases has been studied only in recent years. Whether Ca-125 is elevated in patients with atrial fibrillation (AF) and its levels predict the risk of AF remains controversial. Therefore, we conducted a systematic review and meta-analysis of the association between Ca-125 levels and AF. Methods: PubMed and EMBASE databases were searched until 1 June 2017 for studies that evaluated the association between Ca-125 and AF. Inclusion criteria included studies that compare Ca-125 in patients with and without AF, or those reporting HRs/ORs for risk of AF stratified by Ca-125 levels. Results: A total of 39 entries were retrieved from the databases, of which 10 studies were included in the final meta-analysis. Ca-125 was significantly higher in patients with AF compared with those in sinus rhythm (mean difference=16 U/mL, 95% CI 2 to 30 U/mL, P<0.05; I2: 98%). Ca-125 significantly increased the risk of AF (HR: 1.39, 95% CI 1.06 to 1.82, P<0.05; I2: 84%). Conclusion: Ca-125 was significantly higher in patients with AF than in those in sinus rhythm, and high Ca-125 is predictive of AF occurrence. However, the high heterogeneity observed means there is an uncertainty in the relationship between Ca-125 and AF, which needs to be confirmed by larger prospective studies. PMID- 29387175 TI - Patient preferences for types of community-based cardiac rehabilitation programme. AB - Introduction: Cardiac rehabilitation (CR) improves mortality, morbidity and quality of life of cardiovascular patients. However, its uptake is poor especially in the hospitals due to long travel distances and office hours constraints. Community-based CR is a possible solution. Objectives: To understand the type of community-based CR preferred and identify patient characteristics associated with certain programme combinations. Methods: A cross-sectional survey was administered to a randomised list of patients at risk for or with cardiovascular diseases at two community-based CR centres. Participants were presented with nine hypothetical choice sets and asked to choose only one of the two alternative programme combinations in each choice set. Attributes include support group presence, cash incentives, upfront deposit and out-of-pocket cost. The counts for each combination were tallied and corrected for repeats. Chi square test and logistic regression were performed to understand the characteristics associated with the preferred CR combination. Results: After correcting for repeats, patients most (85.2%) prefer CR programmes with new group activities, support group, cash rewards, deposit and out-of-pocket cost, and few exercise equipment with physiotherapist presence without the need for monitoring equipment. Patients with more than three bedrooms in their house are less likely (OR 0.367; CI 0.17 to 0.80; P=0.011) to choose the choice with no physiotherapist and few equipment available. Conclusion: This is the first study to explore patients' preferences for different types of community CR. Higher income patients prefer physiotherapist presence and are willing to settle for less equipment. Our study serves as a guide for designing future community-based CR programmes. PMID- 29387176 TI - Investigational therapies targeting the granulocyte macrophage colony-stimulating factor receptor-alpha in rheumatoid arthritis: focus on mavrilimumab. AB - Mavrilimumab (formerly CAM-3001) is a high-affinity, immunoglobulin G4 monoclonal antibody (mAb) against the granulocyte macrophage colony-stimulating factor (GM CSF) receptor-alpha chain. Phase I and II trials in patients with rheumatoid arthritis (RA) treated with mavrilimumab have shown encouraging results with respect to both safety and efficacy. No significant adverse events have so far been noted. The trials have demonstrated significant clinical benefit, meeting primary endpoints. Furthermore, for RA patients treated with mavrilimumab, who were tumour necrosis factor (TNF) inhibitor-inadequate responders, there are encouraging preliminary data indicating benefit and identifying potential biomarkers predictive of patients likely to find benefit. Here, we review the clinical trial data for mavrilimumab and discuss its potential as a treatment for RA in light of the competitive landscape in which it resides. PMID- 29387178 TI - Intra-articular hyaluronan injections for the treatment of osteoarthritis: perspective for the mechanism of action. PMID- 29387177 TI - Management of primary Sjogren's syndrome: recent developments and new classification criteria. AB - For many years primary Sjogren's syndrome (pSS) has been considered an orphan disease, since no specific therapies were recognized as being capable of contrasting the development and progression of this disorder. The treatment of oral and ocular features, as well as of the systemic organ involvement, has been entrusted to the joint management of different subspecialty physicians, like ophthalmologists, otolaryngologists, dentists and rheumatologists. These latter subspecialty doctors are usually more involved in the treatment of systemic extraglandular involvement and, to do it, they have long been using the conventional therapies borrowed by the treatment schedules adopted in other systemic autoimmune diseases. The increasing knowledge of the biological pathways that are operative in patients with pSS, and the parallel development of molecular biology technology, have allowed the production and availability of a number of biological agents able to positively act on different disease mechanisms, and thus are candidates for testing in therapeutic trials. Meanwhile, the scientific community has made a great effort to develop new accurate and validated classification criteria and outcome measures to be applied in the selection of patients to be included and monitored in therapeutic studies. Some of the new-generation biotechnological agents have been tested in a number of open-label and randomized controlled trials that have produced in many cases inconclusive or contradictory results. Behind the differences in trial protocols, adopted outcome measures and predefined endpoints, reasons for such unsatisfactory results can be found in the large heterogeneity of clinical subtypes in the examined cohorts. The future challenge for a substantial advancement in the therapeutic approach to pSS could be to identify the pathologic mechanisms, outcome tools and biomarkers that characterize the different subsets of the disease in order to test carefully selected target therapies with the highest probability of success in each different clinical phenotype. PMID- 29387179 TI - Effect of intermittent administration of teriparatide on the mechanical and histological changes in bone grafted with beta-tricalcium phosphate using a rabbit bone defect model. AB - Grafting beta-tricalcium phosphate (TCP) is a well-established method for restoring bone defects; however, there is concern that the mechanical stability of the grafted beta-TCP is not maintained during bone translation. Teriparatide has an anabolic effect, stimulating bone formation and increasing bone mineral density for the treatment of osteoporosis. The aim of the present study was to evaluate the effect of intermittent teriparatide treatment on changes in bone grafted with beta-TCP using a rabbit bone defect model. Bone defects (5*15 mm) were created in the distal femoral condyle of Japanese white rabbits, and beta TCP granules of two different total porosities were manually grafted. Teriparatide (40 ug/kg) or 0.2% rabbit serum albumin solution as a vehicle control was subcutaneously injected three times per week following the surgery. At 4 or 8 weeks post-surgery, serum samples were obtained and the levels of gamma carboxylated osteocalcin (Gla-OC) were quantified using ELISA. Histomorphometry was also performed using sections of graft sites following staining for tartrate resistant acid phosphatase. Activity and mechanical strength (maximum shear strength, maximum shear stiffness and total energy absorption) were evaluated using an axial push-out load to failure test. Teriparatide treatment significantly increased (P<0.05) the serum levels of Gla-OC, a specific marker for bone formation, suggesting that teriparatide enhances bone formation in beta TCP-grafted rabbits. Furthermore teriparatide increased the degradation of beta TCP by bone remodeling (P<0.05) and promoted the formation of new bone following application of the graft compared with the control group (P<0.01). Furthermore, teriparatide suppressed the reduction in mechanical strength (P<0.05) during bone translation in bone defects grafted with beta-TCP. The results of the present study demonstrate that teriparatide is effective in maintaining the mechanical stability of grafted beta-TCP, possibly by promoting new bone formation. PMID- 29387180 TI - Ultrasound-targeted microbubble destruction-mediated Foxp3 knockdown may suppress the tumor growth of HCC mice by relieving immunosuppressive Tregs function. AB - The aim of the present study was to investigate the effect of Forkhead family transcription factor P3 (Foxp3) knockdown on the function of cluster of differentiation (CD)4+CD25+ regulatory T cell (Tregs) and the tumor growth of a hepatocellular carcinoma (HCC) mouse model. CD4+CD25+ Tregs and CD4+CD25- T cells were sorted from peripheral blood mononuclear cells (PBMCs) of patients with HCC. Then, ultrasound-targeted microbubble destruction (UTMD)-mediated Foxp3-microRNA (miRNA) was transfected into Tregs. Subsequently, CD4+CD25- T cells were co cultured with PBMC and Tregs without Foxp3-miRNA (Foxp3+Tregs) or Tregs with Foxp3-miRNA (Foxp3-Tregs) and the proliferation-inhibition ratio of CD4+CD25- T cells was detected using a Cell Counting Kit-8. Additionally, HCC mice were treated with UTMD-mediated Foxp3-shRNA, the tumor volume was calculated and the content of CD4+ and CD25+ T cells in the blood were detected using flow cytometry. The content of interferon-gamma (IFN-gamma), interleukin (IL)-2, IL 10, transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) in cultural supernatant and serum were detected by ELISA analysis. Foxp3-Tregs significantly reduced the inhibition effect of Foxp3+Tregs on the proliferation of CD4+CD25- T cells (P<0.01). The content of IFN-gamma and IL-2 significantly increased, while IL-10 and TGF-beta significantly decreased in the co-cultured system of Foxp3-Tregs compared with the co-cultured system of Foxp3+Tregs (P<0.01). Following treatment with Foxp3-shRNA, the average tumor volume, ratio of Tregs/CD4+ T cells and level of IL-10, TGF-beta and VEGF significantly decreased, however, the level of IFN-gamma and IL-2 significantly increased compared with un-treated HCC mice (P<0.05). Foxp3 knockdown may suppress the tumor growth of HCC mice through relieving the immunosuppressive function of Tregs. PMID- 29387182 TI - Protective effect of baicalin on fetal lung development in a rabbit model of congenital diaphragmatic hernia. AB - Bacalin has been reported to improve fetal lung growth by increasing fetal lung surfactant phospholipids. Therefore, the present study evaluated the effect of transplacental treatment of baicalin during lung development in rabbits with congenital diaphragmatic hernia (DH) rabbit. DH was induced in fetal rabbit on gestational day 23 and baicalin injections were administered daily until term period. Fetal survival rate, body weight and lung-to-body weight ratio (LBWR) were subsequently measured, and the expression of surfactant protein B (SPB) and Ki-67, and morphometry analysis was determined in lung tissues. It was observed that in baicalin treated group the fetal survival rate and LBWR were decreased compared with the control without DH group. Lung morphometry results suggested that treatment with baicalin did not significantly ameliorate congenital DH, and adventitial and medial thickness were similar to those in the control groups, and less muscularization of vessels measuring 30-60 um. Furthermore, baicalin treatment did not markedly affect the expressions of Ki-67 and SPB in fetuses with DH. Baicalin was demonstrated to improve the morphology of lung in rabbits; however, as it did not induce marked airway changes this present study suggests that baicalin is not suitable for the management of congenital DH. PMID- 29387181 TI - Application of novel targeting nanoparticles contrast agent combined with contrast-enhanced computed tomography during screening for early-phase gastric carcinoma. AB - Gastric cancer is one of the most common human tumors worldwide. The biggest bottleneck is a lack of advanced and sensitive protocols for the diagnosis of patients with early-stage gastric cancer. Therefore, more sensitive methods of diagnosing gastric cancer are urgently required to improve survival rates. In this clinical study, contrast-enhanced computed tomography (CECT) with targeting nanoparticles contrast agent (CECT-TNCA) was used to diagnose early-stage gastric cancer. The specific-targeted tyrosine kinase inhibitors of gastric cancer, including platelet-derived growth factor receptor-beta, Ret and Kit, were used as TNCAs. A total of 484 patients with suspected gastric cancer were voluntarily recruited to investigate the efficacy of CECT-TNCA in the diagnosis of patients with early-stage gastric cancer. Patients with suspected gastric cancer were subjected CT and CECT-TNCA to detect whether gastric tumors existed. TNCA was orally administered before CT and CECT-TNCA (20 min). Our diagnostic data revealed that CECT-TNCA improved sensitivity and provided a new protocol to diagnose tumors in patients with suspected gastric cancer at the early stage. In addition, imaging using CECT-TNCA enabled the visualization of tiny nodules in the gastric area. CECT-TNCA diagnosed 182 patients with suspected gastric cancer as tumor-free. CECT-TNCA confirmed gastric cancer in 302 patients. Our novel diagnosis indicated significantly (P<0.01) differential signal enhancement in the gastric nodules via CECT-TNCA compared with CT, suggesting higher accuracy and the accumulation of TNCA in tumor nodules in the stomach. Furthermore, survival rates of patients detected by early-diagnosis of CECT-TNCA were significantly higher than the mean five-year survival (P<0.01). In conclusion, our investigations demonstrate that the sensibility and accuracy of CT is improved through combination with liposome-encapsulated nanoparticle contrast agent for the diagnosis of early stage gastric cancer when compared with single CT detection. CECT-TNCA improves the accuracy of CT and diagnostic confidence in assessing mural enhancement in patients with suspected gastric cancer. PMID- 29387183 TI - A novel three-dimensional tumorsphere culture system for the efficient and low cost enrichment of cancer stem cells with natural polymers. AB - Cancer stem cells (CSCs) are considered to serve a key role in tumor progression, recurrence and metastasis. Tumorsphere culture is the most important method for enriching CSCs and is widely used in basic research and drug screening. However, the traditional suspension cell culture system has several disadvantages, including low efficiency, high cost and difficult procedure, making it difficult to produce tumorspheres on a large scale. In the present study, two biomaterials, methylcellulose (MC) and gellan gum (GG), were used to construct a novel culture system based on the traditional system. Subsequently, the characteristics of the novel three-dimensional (3D) culture system were evaluated, the design scheme was optimized, and the morphological and biological features of the tumorspheres cultured in this 3D system were compared with the traditional system. The results revealed that the tumorspheres cultured in the novel 3D system presented a higher seeding density and improved morphology, while maintaining stem-like properties. This evidence suggests that a simple, efficient and low-cost culture system that produces tumorspheres on a large scale was successfully constructed, which can be widely used in various aspects of stem cell research. PMID- 29387184 TI - The effect of CYP1A2 gene polymorphism on the metabolism of theophylline. AB - This aim of the study was to investigate the effect of CYP1A2 gene polymorphism on the metabolism of theophylline in minority and Han nationality. A total of 50 cases of Han (Han group) and 50 minority nationalities (ethnic groups) treated with theophylline were selected for the study. The genotype and allele frequencies of the two groups of CYP1A2 gene, G-3113A and G-3860A, were compared to determine the rate of theophylline clearance. The results showed that there was no significant difference in the concentration of the homeostasis and the rate of the theophylline removal rate (P>0.05). There was no significant difference in the genotype and allele frequencies of the CYP1A2 gene, G-3113A and G-3860A apolymorphic site. This study employed a logarithm to determine theophylline clearance in order to correlate it with the normal distribution. The results showed that the theophylline clearance of the two groups of CYP1A2 G 3113A gene loci A allele carriers (AA+GA genotype) was significantly lower than that of the G allele carriers (GG genotype), and a significant difference between the groups was identified (P<0.05). There was no significant difference in the theophylline clearance rates in the two groups for the CYP1A2 gene, G-3860A apolymorphic site (P>0.05). Compared to the GG genotype of the CYP1A2 gene, the G 3113A site AA and GA genotype patients had a low clearance rate in the theophylline, whereas there was no correlation between teh genotypes of the CYP1A2 gene, G-3860A and the rate of theophylline clearance. PMID- 29387185 TI - Porcine reproductive and respiratory syndrome virus suppresses post transcriptionally the protein expression of IFN-beta by upregulating cellular microRNAs in porcine alveolar macrophages in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized to inhibit the response of type I interferon (IFN) both in vivo and in vitro. However, the post-transcriptional mechanism by which PRRSV suppresses type I IFN induction in virus-infected host cells remains unclear. The present study first demonstrated that PRRSV inhibited post-transcriptionally the protein induction of IFN-beta in primary porcine alveolar macrophages (PAMs) during early infection, and the inhibition effect mediated by the Chinese highly pathogenic (HP)-PRRSV was stronger. Next, we analyzed the cellular microRNA (miRNA)-modulated protein expression of porcine IFN-beta by dual firefly/Renilla luciferase reporter assay, transfection of miRNA mimics and inhibitor assay and polyinosinic-polycytidylic acid (poly I:C) treatment of PAMs, showing that porcine miRNAs including let-7b, miR-26a, miR-34a and miR-145 are able to inhibit IFN-beta protein expression in primary PAMs by directly targeting sequences within the porcine IFN-beta 3'UTR locating at 160-181, 9-31, 27-47 and 12-32 bp, respectively. Finally, we confirmed that let-7b, miR-26a, miR-34a and miR-145, were upregulated in PRRSV infected PAMs early in vitro, and the expression level of these miRNAs in HP PRRSV JXwn06-infected PAMs were higher than those in low pathogenic PRRSV HB 1/3.9-infected PAMs. The endogenous cellular miRNA-mediated inhibition of IFN beta induction in PRRSV-infected PAMs early could be relieved by miRNA antagonists. Taken together, our findings suggest for the first time that PRRSV can suppress post-transcriptionally protein expression of IFN-beta by upregulating cellular miRNAs in PAMs in vitro, providing novel insight into mechanisms in relation to the PRRSV-mediated immunomodulation of porcine innate immunity. PMID- 29387186 TI - Effect of recombinant adeno-associated virus expressing calcitonin gene-related peptide on chick embryo umbilical artery vasospasm model. AB - In the present study, a recombinant adeno-associated virus vector containing the calcitonin gene related peptide gene (rAAV-CGRP) was constructed and the therapeutic effect of rAAV-CGRP on a chick umbilical artery vasospasm model induced by chick embryo allantoic cavity hemorrhage was investigated. Fresh specific pathogen-free fertilized chicken eggs were randomly divided into a rAAV CGRP group, an empty vector virus (AAV) group, and a control group, with 24 eggs in each group. An umbilical arterial vasospasm model was established using a needle puncture method on a vein in the chorioallantoic membrane to induce a hemorrhage in the allantoic cavity of 11-day-old chicken embryonated eggs. A total of 24 h after model establishment, 1 ml of rAAV-CGRP and empty vector virus solution of rAAV-CGRP and empty vector virus solution was, respectively, injected into the allantoic cavity in the rAAV-CGRP and AAV groups. Experimental results showed that after 72 h of model establishment, the mortality rates of the 3-, 5- and 7-day subgroups in the rAAV-CGRP group were lower than in the subgroups of the AAV injection group. After 3, 5 and 7 days of model establishment in the rAAV CGRP group, the cross-sectional area of the inner diameter of the umbilical arteries was larger than that of the AAV group; the vessel wall thicknesses of the rAAV-CGRP group were thinner than in the AAV group. In addition, the concentration of CGRP in chick embryo allantoic fluid significantly increased and was several times higher than in the AAV group (P<0.05). In conclusion, administration of rAAV-CGRP through the allantoic cavity may increase the viability of a vasospasm model induced by chick allantoic cavity hemorrhage, significantly improve umbilical artery vasospasm, and increase CGRP expression in the chick embryo allantoic cavity. This approach also provides a novel experimental model for identifying other target genes for the gene therapy of vasospasm. PMID- 29387187 TI - Effect of butylphthalide intervention on experimental autoimmune myositis in guinea pigs. AB - Idiopathic inflammatory myopathies are a group of rare muscular diseases that are characterized by acute, subacute or chronic proximal and symmetric muscle weakness, muscle fiber necrosis and infiltration of inflammatory cells, particularly activated CD8+ cytotoxic T cells and phagocytes. 3-n-butylphthalide (NBP) protects mitochondria and reduces the inflammatory response in multiple disease models. In myositis, it has remained elusive whether NBP can protect muscle cells from muscle fiber injury. Experimental autoimmune myositis (EAM) was induced in a total of 40 guinea pigs by myosin immunization. After 4 weeks, low- or high-dose NBP solution was intraperitoneally injected. Saline solution was used as a negative control. After 10 days, the clinical manifestations were assessed by determining rodent grasping power, histopathological changes, Ca2+ adenosinetriphosphatase (ATPase) activity by an ATPase kit, and mRNA expression of interferon (IFN)-gamma, retinoic acid receptor-related orphan nuclear receptor (ROR)gammat and forkhead box (Fox) p3 in muscle tissue by reverse-transcription quantitative polymerase chain reaction analysis. It was demonstrated that NBP improved the myodynamia of guinea pigs with EAM and reduced the pathological inflammatory cell infiltration in a dose-dependent manner. NBP improved the Ca2+ ATPase activity of the muscle mitochondrial membrane and muscle plasma membrane in animals with EAM. It also reduced the mRNA expression of IFN-gamma and RORgammat, and significantly increased the mRNA expression of Foxp3 in muscle tissue. These results provided a basis for the consideration of NBP as a novel agent for the treatment of myositis and other muscular diseases associated with autoimmunity and inflammation. PMID- 29387188 TI - Non-local diffusion-weighted image super-resolution using collaborative joint information. AB - Due to the clinical durable scanning time and other physical constraints, the spatial resolution of diffusion-weighted magnetic resonance imaging (DWI) is highly limited. Using a post-processing method to improve the resolution of DWI holds the potential to improve the investigation of smaller white-matter structures and to reduce partial volume effects. In the present study, a novel non-local mean super-resolution method was proposed to increase the spatial resolution of DWI datasets. Based on a non-local strategy, joint information from the adjacent scanning directions was taken advantage of through the implementation of a novel weighting scheme. Besides this, an efficient rotationally invariant similarity measure was introduced for further improvement of high-resolution image reconstruction and computational efficiency. Quantitative and qualitative comparisons in synthetic and real DWI datasets demonstrated that the proposed method significantly enhanced the resolution of DWI, and is thus beneficial in improving the estimation accuracy for diffusion tensor imaging as well as high-angular resolution diffusion imaging. PMID- 29387189 TI - The effects of rhEPO intervention for perinatal intrauterine herpes virus infection on preventing brain injury in preterm infants. AB - The ability of recombinant human erythropoietin (rhEPO) to protect preterm infants against perinatal intrauterine herpes virus infection-induced brain injury was studied. In total, 120 women infected with perinatal intrauterine herpes virus were randomized into four groups: A, B, C and D, and were given 1,500 IU (mother, pre-partum), 3,000 IU (mother, pre-partum), 250 IU/kg (infant, post-natal), and no rhEPO, respectively. Hemoglobin (Hb), reticulocyte (Ret), hematocrit (Hct), neuron specific enolase (NSE), myelin basic protein (MBP), and S100 protein B (S100B) levels were measured immediately (T0) and at 1 week (T1), 2 weeks (T2), and 4 weeks (T3) post-delivery. Linear regression analysis was performed to analyze inter-indicator correlation, and ROC risk models were established to determine the predictive value of Hb, Ret and Hct for brain injury immediately after delivery. The brain injury incidence rate of group A (10%) was significantly lower than group D (33.3%) and group B (6.7%) significantly lower than groups C (26.7%) and D. At T0, Hb, Ret and Hct in groups A and B were significantly higher than in group C and D, while from T1 to T3, groups A, B and C showed significantly higher values than group D. NSE, MBP and S100B showed an inverse trend, with groups A and B lower at T0 and groups A, B and C lower from T1-T3. Hb and NSE, MBP and S100B were negatively correlated, while no correlation was found between Ret and NSE, MBP and S100B. Finally, Hct and NSE, MBP and S100B were negatively correlated. The optimal cut-off values for Hb and Hct for brain injury diagnosis immediately post-partum were 170 g/l (sensitivity 99%, specificity 95.7%) and 28.5% (sensitivity 79.4%, specificity 100%), respectively. Ret did not show predictive value. In conclusion, pre-partum rhEPO treatment showed greater protective effects than post-natal administration, and this may be the regulation of Hb and Hct levels in post-natal preterm infants. In addition, a dose-dependent effect was displayed. PMID- 29387190 TI - Combined treatment of vitamin K and teriparatide on bone metabolism and biomechanics in rats with osteoporosis. AB - Postmenopausal osteoporosis is a degenerative disease caused by lack of estrogen whereby bone degeneration exceeds bone formation, resulting in loss of bone mass. Various drugs have been utilized in an attempt to ameliorate bone strength in such patients. The aim of the present study was to compare the effects of vitamin K or teriparatide alone and combined on bone metabolism and biomechanics in rats with osteoporosis. The ovaries of rats were excised to construct a rat model of osteoporosis. Rats were subjected to oral intake of vitamin K or subcutaneous injection of teriparatide or both for 8 weeks. ELISA was used to detect the content of carboxylated-type of osteocalcin (Gla-OC) and C-telopeptide of type I collagen (CTX-I) in serum. Bone density of shaft of femur and metaphyseal bone was measured. Three-point bending test was performed to analyze the load deformation curve of femur. Undecalcified sections of femur were stained with toluidine blue to measure bone histomorphometric static, dynamic and bone resorption parameters. Compared with monotherapy, vitamin K combined with teriparatide significantly increased serum Gla-OC level and the number of osteoblast, decreased serum CTX-I level, reduced the number of osteoclasts and increased bone density and strength. This study showed that the efficacy of vitamin K combined with teriparatide is better than that of monotherapy. This combined treatment can promote bone formation, inhibit bone degradation, and improve bone density and strength. PMID- 29387191 TI - Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the Han Chinese population. AB - The underlying mechanism of recurrent spontaneous abortion (RSA) has remained elusive for many years. Several previous studies have suggested that the killer cell immunoglobulin receptor (KIR) gene family is associated with RSA, however, it is not clear exactly how. The present study detected KIR and human leukocyte antigen-C (HLA-C) genes in 110 Han Chinese women with unexplained RSA and 105 Han Chinese healthy females. The aim of the present study was to determine if certain genotypes were more susceptible to the occurrence of miscarriage. The frequency of KIR genes and different KIR haplotypes in the 2 groups demonstrated no statistical differences. However, in women who had miscarried >=3 times, the frequency of KIR3DL1 was significantly reduced and the BB haplotype frequency was significantly higher compared with the control group. HLA-C2C2 was significantly increased in the KIR AB and KIR BB groups in the RSA groups compared with the control group. The women in the RSA group who had a homozygous HLA-C2C2 had a significantly higher frequency of the 2DS1 gene compared with the control group. The reduction of inhibitory gene and increased activation combinations may induce the activation of uterine natural killer cells, which may reduce the probability of fetal survival. To the best of our knowledge, the present study is the first report demonstrating the association between maternal KIR and HLA-C genes and RSA in women of a Han Chinese ethnicity. The present study revealed that females who miscarry >=3 times may be used as selection criteria for RSA and so may exhibit higher research value. PMID- 29387192 TI - Association of long non-coding RNA GAS5 and miR-21 levels in CD4+ T cells with clinical features of systemic lupus erythematosus. AB - The present study aimed to assess the expression of growth arrest-specific 5 (GAS5) and microRNA (miR)-21 in systemic lupus erythematosus (SLE), and attempted to explore their association with clinical features. CD4+ T cells were isolated from peripheral blood of healthy donors and SLE patients by magnetic-activated cell sorting. GAS5 and miR-21 expression levels in cluster of differentiation (CD)4+ T cells were measured by reverse-transcription quantitative polymerase chain reaction. The results revealed that GAS5 and miR-21 levels were significantly elevated in CD4+ T cells of patients with SLE compared with those in control subjects (P<0.05). Regarding clinical features, SLE patients with ulceration had higher GAS5 expression levels in CD4+ T cells than those without ulceration (P<0.05), and the expression of miR-21 was significantly higher in CD4+ T cells of SLE patients with low levels of complement component 3 (C3) than in those with normal levels of complement C3 (P<0.05). In conclusion, GAS5 and miR-21 in CD4+ T cells may serve as potential biomarkers for the diagnosis and monitoring of the progression of SLE. PMID- 29387193 TI - TASK-1 induces gefitinib resistance by promoting cancer initiating cell formation and epithelial-mesenchymal transition in lung cancer. AB - Cancer initiating cell (CIC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in lung cancer cell invasion and metastasis. They have been shown to occur in gefitinib resistance. Studying the molecular mechanisms of CICs, EMT and acquired gefitinib resistance will enhance the understanding of the pathogenesis and progression of the disease and offer novel targets for effective therapies. TWIK-related acid-sensitive K(+) (TASK-1) is expressed in a subset of non-small-cell lung cancer (NSCLC) cell lines, where it promotes cell proliferation while inhibiting apoptosis. In the present study, TASK-1 was demonstrated to induce gefitinib resistance in the A549 NSCLC cell line. Overexpression of TASK-1 promoted the acquisition of CIC-like traits by A549 cells. CD133, octamer-binding transcription factor 4 (OCT-4) and Nanog have been suggested to be markers of CICs in lung cancer. It was demonstrated that overexpression of TASK-1 promoted CD133, OCT-4 and Nanog protein expression in A549 cells. Increased formation of stem cell-like populations results in EMT of cancer cells. The present study found that overexpression of TASK-1 promoted EMT of A549 cells. Thus, downregulation of TASK-1 may represent a novel strategy for EMT reversal, decreasing CIC-like traits and increasing gefitinib sensitivity of NSCLCs. PMID- 29387194 TI - Changes and significance of inflammatory cytokines in a rat model of cervical spondylosis. AB - The aim of the present study was to dynamically observe and discuss the significance of inflammatory cytokines in cervical degenerative disease induced by unbalanced dynamic and static forces in rats. A total of 60 Sprague Dawley rats were randomized into test (n=45) and control (n=15) groups, which were randomly subdivided into three groups corresponding to assessment at one, three and six months post-operation. The test group included 10, 15 and 20 rats at the corresponding post-operative stage and the control group had five rats at each time-point. By excising cervicodorsal muscles and ligaments, an unbalanced dynamic and static rat model was established in the test group. At one, three and six-months post-operation, venous serum of test and control group rats was collected and inflammatory cytokines in the serum of all rats were quantitatively determined by ELISA. The results revealed that compared with the control group, the interleukin (IL)-1beta, IL-10 and tumor necrosis factor-alpha levels in the test group were significantly increased at one and three months (P<0.05, <0.01 or <0.001), and that IL-12 was significantly increased at three months (P<0.05). However, transforming growth factor-beta1 increased at one month but was significantly decreased at three months (P<0.01). IL-6 did not change significantly throughout the observation period (P>0.05). In conclusion, cervical vertebral stability may be accompanied with changes of inflammatory cytokines. PMID- 29387195 TI - Goodpasture's syndrome in early pregnancy: A case report. AB - Goodpasture's syndrome (GPS) presenting during pregnancy is extremely rare and patients exhibiting hemoptysis and renal dysfunction in early pregnancy are uncommon. The present study reports the case of a 17-year-old diagnosed with GPS during the thirteenth week of pregnancy. Prompt recognition and immediate treatment (steroids and plasma exchange) was initiated. Renal function normalized following treatment and anti-GBM antibody became negative during hospital stay. However, due to irregular follow-up, the patient eventually succumbed. The case highlights that the current treatment plan for GPS should be revised to improve the outcome of pregnancy. In addition, it determines how important it is for obstetricians to consider whether a pregnancy should be terminated to improve the chances of survival of pregnant patients with GPS. PMID- 29387196 TI - Decreased microRNA-181a and -16 expression levels in the labial salivary glands of Sjogren syndrome patients. AB - Sjogren syndrome (SS) is characterized by dysfunction of the exocrine glands, particularly the salivary and lacrimal glands. Thus, labial salivary gland biopsy is useful method for diagnosing SS. The aim of the present study was to investigate the microRNA (miRNA or miR) profile of labial salivary glands obtained from SS patients and to examine the correlation of miR-181a and -16 levels with the pathological grade in SS. miRNA expression in labial salivary gland tissues was profiled in 3 female patients with primary SS and 3 female patients with non-SS sicca syndrome using microarray analysis. In addition, a literature search and miRNA target gene prediction were performed to collect miRNAs involved in SS pathogenesis. Subsequent to integrating all database results, miR-181a and -16 were identified to be associated with the Ro/SS associated antigen A and La/SS-associated antigen B during SS pathogenesis. Therefore, these miRNAs were selected for further verification in labial salivary gland tissues of 28 patients with SS and 18 non-SS sicca syndrome control individuals by quantitative reverse transcription-quantitative polymerase chain reaction. Compared with the control group, 76 miRNAs were upregulated and 51 were downregulated in the labial salivary gland of SS patients according to microarray results. In particular, miR-181a and -16 expression levels in the labial salivary gland of SS patients were decreased in comparison with those in the controls. Furthermore, the decreased expression levels of these miRNAs were associated with the labial salivary pathological focus scores. In conclusion, the present study examined the miRNA profiles in the labial salivary glands of SS patients and detected decreased miR-181a and -16 expression levels compared with the control individuals. Finally, the decreased levels of miR-181a and -16 were associated with the salivary gland pathological focus scores, suggesting that miR-181a and 16 may serve a role in the pathogenesis of SS. PMID- 29387197 TI - The protective effects of GYY4137 on ipsilateral testicular injury in experimentally varicocele-induced rats. AB - The aim of the present study was to evaluate whether morpholin-4-ium 4 methoxyphenyl (morpholino) phosphonodithioate (GYY4137) exhibits a protective effect on ipsilateral testicular injury in experimentally varicocele (VC)-induced rats. A total of 48 rats were randomly divided into the following 6 groups (n=8 each): Group A (control group); group B (sham group); group C (VC group); group D (VC group administered 5 mg/kg/day GYY4137); group E (VC group administered 10 mg/kg/day GYY4137) and group F (VC group administered 20 mg/kg/day GYY4137). Indicators of oxidative stress, apoptosis and inflammation were measured to evaluate the effect of GYY4137 on ipsilateral testicular injury. Compared with groups A and B, rats in group C exhibited severe histological changes and an increase in oxidative stress, apoptosis and inflammation. By contrast, amelioration of testicular damage was evident in the group D, E and F that were treated with GYY4137. These results demonstrate that GYY4137 may be a promising therapy to treat VC as it alleviates oxidative stress, apoptosis and inflammation in experimentally VC-induced rats. PMID- 29387198 TI - Necrosis of osteosarcoma cells induces the production and release of high mobility group box 1 protein. AB - Osteosarcoma is among the commonly observed malignancies worldwide. High-mobility group box 1 protein (HMGB1) is a highly conserved protein and is involved in the progression of various types of human cancer. The aim of the present study was to explore whether the level of HMGB1 was involved in the necrosis of osteosarcoma cells. Doxorubicin (DXR), as an inducer of necrosis, was administered to human osteosarcoma cell lines (MG63, Saos-2 and U2OS), and the results indicated that 0.5 ug/ml DXR significantly induced the necrosis of MG63 cells (P<0.01), while 0.5 and 1.0 ug/ml DXR suppressed the viability of MG63 and U2OS cells (P<0.05), relative to untreated controls. Additionally, treatment with DXR was observed by western blot analysis to markedly increase the expression levels of HMGB1 in MG63 cells, and to significantly increase the levels of secreted HMGB1 in the supernatants of MG63 and U2OS cells (P<0.01). In conclusion, cell necrosis increased the level of HMGB1 in osteosarcoma cells, as well as the level of secreted HMGB1 in cell supernatants. Therefore, HMGB1 may be a potential target in molecular therapy for patients with osteosarcoma. PMID- 29387199 TI - Berberine inhibits the MexXY-OprM efflux pump to reverse imipenem resistance in a clinical carbapenem-resistant Pseudomonas aeruginosa isolate in a planktonic state. AB - Pseudomonas (P.) aeruginosa is an ubiquitous and metabolically versatile opportunistic pathogen and may cause various life-threatening diseases. Due to increasing emergence of resistance to carbapenems, novel drugs with improved antibacterial activities compared with those of traditional antibiotics are required. In the present study, berberine (BEB), a natural isoquinoline alkaloid, was used in combination with imipenem (IMP), a commonly-used carbapenem, to investigate their antibacterial activities against a clinical P. aeruginosa isolate PA012 and the potential mechanism. Screening revealed that the minimum inhibitory concentrations (MICs) of BEB and IMP were 512 and 256 ug/ml, respectively. The combination of BEB (1/4 MIC) and IMP (1/8 MIC) exhibited a synergistic effect with a fractional inhibitory concentration index of 0.375. The synergism of BEB and IMP was also demonstrated in a time-kill test and by scanning electron microscopic observation. Treatment with BEB at 1/4 MIC in combination with IMP at 1/16, 1/8, 1/4 and 1/2 MIC revealed a concentration dependent promoting effect of IMP on the intracellular accumulation of BEB and inhibition of bacterial adhesion. Further analysis of gene expression revealed that BEB (1/4 MIC) combined with IMP (1/8 MIC) decreased MexZ, MexX, MexY and outer membrane protein (Opr)M by 38, 35, 46 and 49% in PA012. In conclusion, these results suggested that IMP had synergistic effects with BEB against the clinical isolate PA012 via inhibition of the MexXY-OprM efflux pump. PMID- 29387200 TI - Advanced oxidation protein products from the follicular microenvironment and their role in infertile women with endometriosis. AB - Endometriosis (EM) is associated with oxidative stress. Advanced oxidation protein products (AOPPs) are novel markers of oxidative stress, which serve an important role as an inflammatory mediator in various chronic diseases. In order to examine the role of AOPPs in infertile women with EM, the present study analyzed the levels of AOPPs, estradiol (E2) and progesterone (P4) in the follicular fluid (FF) of 89 women with or without EM undergoing in vitro fertilization (IVF). The AOPP concentration in the FF of the EM group was significantly higher when compared with that of the control group (51.5+/-22.4 vs. 41.8+/-18.3 umol/l; P<0.05). However, the FF P4 levels and blastocyst rate were significantly lower in the EM group compared with the control group (P4:1,249.6+/-465.4 vs. 1,752.7+/-565.4 ng/ml, P<0.05; blastocyst rate: 0.511+/ 0.322 vs. 0.662+/-0.278; P<0.05). The AOPP concentration and P4 level in the FF presented a significant negative correlation in the EM and control groups, as well as in the total cohort of patients (EM group: r=-0.406, P=0.006; control group: r=-0.315, P=0.035; total: r=-0.421, P<0.001). In addition, there was a significant negative correlation between the FF AOPP concentrations and blastocyst rate in the EM group and in the total cohort (EM group: r=-0.376, P=0.012; total: r=-0.367, P<0.001). In conclusion, these results suggested that AOPPs may be a potentially effective marker for predicting the oocyte quality and outcomes of IVF in infertile women with EM. PMID- 29387201 TI - IL-1beta increases urinary corin in patients with primary proteinuric kidney diseases and in 293 cells. AB - Corin is a serine protease that is important for the regulation of blood pressure and water balance. Corin was initially discovered in the heart, however, it has also been detected in kidney cells, though its function in the kidneys is unclear. To further investigate the function of corin in the kidney, the present study analyzed the levels of corin in urine and blood samples collected from normal individuals and patients with primary proteinuric diseases. The associations between the levels of corin, and the cytokines interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha) were then assessed. The results demonstrated that corin was detectable in the urine and plasma following an enzyme-linked immunosorbent assay; the level of corin in the urine was associated with the level of urinary beta2-microglobulin (P=0.01), which was indicative of renal tubular injury. When compared with normal individuals, the levels of urinary corin in proteinuric patients were markedly increased (P=0.02), and were also associated with IL-1beta (P=0.03). This correlation between corin and IL-1beta was confirmed in vitro using 293 cells. As the IL-1beta concentrations increased (0, 0.1, 1, 10 ng/ml), an elevation in the level of corin was observed in the culture medium (P<0.01); however, the amount of corin was not markedly altered in the cell lysate (P>0.05). In addition, when TNF-alpha reached 10 ng/ml, the level of corin in the medium increased significantly when compared with the control group (0 ng/ml; P=0.02), however, no significant difference in corin levels was detected in the cell lysate. The results suggest that the cytokines IL-1beta and TNF-alpha may increase urinary corin in patients with primary proteinuric kidney diseases. Cytokines may accelerate corin shedding from the cell membrane of renal tubule epithelial cells. These findings indicate that corin may be associated with kidney inflammation and injury. PMID- 29387202 TI - A micro-computed tomographic evaluation of dentinal microcrack alterations during root canal preparation using single-file Ni-Ti systems. AB - The aim of the present study was to evaluate the length of dentinal microcracks observed prior to and following root canal preparation with different single-file nickel-titanium (Ni-Ti) systems using micro-computed tomography (micro-CT) analysis. A total of 80 mesial roots of mandibular first molars presenting with type II Vertucci canal configurations were scanned at an isotropic resolution of 7.4 um. The samples were randomly assigned into four groups (n=20 per group) according to the system used for root canal preparation, including the WaveOne (WO), OneShape (OS), Reciproc (RE) and control groups. A second micro-CT scan was conducted after the root canals were prepared with size 25 instruments. Pre- and postoperative cross-section images of the roots (n=237,760) were then screened to identify the lengths of the microcracks. The results indicated that the microcrack lengths were notably increased following root canal preparation (P<0.05). The alterations in microcrack length in the OS group were more significant compared with those in the WO, RE and control groups (P<0.05). In conclusion, the formation and development of dentinal microcracks may be associated with the movement caused by preparation rather than the taper of the files. Among the single-file Ni-Ti systems, WO and RE were not observed to cause notable microcracks, while the OS system resulted in evident microcracks. PMID- 29387203 TI - Methylation and expression of mismatch repair gene human mutS homolog 2 in myelodysplastic syndromes. AB - As a highly heterogeneous disease, the pathogenesis of myelodysplastic syndrome (MDS) has not been well defined. In the present study, human mutS homolog 2 (hMSH2) promoter methylation was detected with methylation-specific polymerase chain reaction (PCR). The function of hMSH2 was analyzed by microsatellite instability (MSI) detection of BAT-26, and hMSH2 expression was evaluated using reverse transcription-quantitative PCR in 60 patients with MDS. The results revealed methylation of the hMSH2 promoter in 18 patients with MDS who have an overall prevalence of 30% (95% confidence interval, 18.4-41.6%). Among the patients with hMSH2 methylation, 2 patients exhibited MSI. It was demonstrated that hMSH2 promoter methylation was increased in MDS with an increase in Revised International Prognostic Scoring System (IPSS-R) risk, and patients with higher hMSH2 promoter methylation had shorter overall survival by Kaplan-Meier analysis (P=0.011). In addition, it was also observed that decreased hMSH2 mRNA expression was associated with high IPSS-R risk group (high/very high vs. intermediate, P=0.003), and hMSH2 mRNA expression in CD34 positive bone marrow cells was lower compared with that in CD34 negative cells of patients with MDS (P=0.029). Methylation of hMSH2 may be valuable for prognostic evaluation and progression prediction of MDS. Furthermore, hMSH2 may serve a key function in the pathogenesis and prognosis of MDS. PMID- 29387204 TI - Clinical manifestations and epigenetic mechanisms of gastric mucosa associated lymphoid tissue lymphoma and long-term follow-up following Helicobacter pylori eradication. AB - The current study aimed to summarize the clinical manifestations and identify the epigenetic mechanisms of gastric mucosa associated lymphoid tissue (MALT) lymphoma, as well as evaluate the long-term effects of Helicobacter pylori (H. pylori) eradication. A total of 122 patients with marginal zone B-cell lymphoma of primary gastric MALT lymphoma were enrolled in the present study. The clinical manifestations of gastric MALT lymphoma, including symptoms, H. pylori state and endoscopic type, were summarized. The response to therapy was evaluated in patients that underwent H. pylori eradication. Survival analysis was estimated using the Kaplan-Meier method. The expression of microRNA-383 (miR-383) in tumor tissues and cell lines was determined using reverse transcription quantitative polymerase chain reaction. Furthermore, bioinformatic analyses, luciferase reporter assays. and western blot analysis identified zinc finger E-box binding homeobox 2 (ZEB2) as a direct target gene of miR-383. An MTT assay was used to examine the function of miR-383 and ZEB2 in MALT lymphoma. The clinical symptoms of patients with gastric MALT lymphoma were non-specific and included epigastric pain, abdominal discomfort and bleeding. The majority of endoscopic types were classified as ulcer, erosion and mucosa edema. The H. pylori infection rate was 79.5% (97/122) and a total of 47 patients underwent eradication therapy. Lymphoma remission was achieved in 93.6% (44/47) of patients and complete remission (CR) was achieved in 74.4% (35/47). The median follow-up time was 38 months (range, 10 132 months) and the median time taken to achieve CR was 4 months (range, 3-7 months). The estimated 3-year survival rate was 90.3% and the 5-year survival rate was 76.2%. Therefore, it was determined that patients with stage I or II gastric MALT lymphoma are able to undergo H. pylori eradication as a first-line treatment and that the survival rate of patients undergoing this treatment is high. Furthermore, it was determined that the mechanism by which miR-383 and ZEB2 contribute to MALT lymphoma progression is by the targeting of ZEB2 by miR-383, which inhibits the proliferation of cancer cells. PMID- 29387205 TI - miR-144 inhibits growth and metastasis of cervical cancer cells by targeting VEGFA and VEGFC. AB - MicroRNAs (miRs) are aberrantly expressed in various cancer types and have critical roles in their genesis and progression. miR-144 has been identified to be involved in the development of hepatocellular carcinoma and rectal cancer. However, the roles of miR-144 in cervical cancer and the underlying molecular mechanisms have remained elusive. The present study identified that miR-144 was significantly decreased in cervical cancer tissues compared with that in matched normal cervical tissues as well as in metastatic vs. non-metastatic cervical cancer tissues. miR-144 downregulation was significantly associated with the International Federation of Gynecology and Obstetrics stage and lymph node metastasis. In a gain-of function study, miR-144 mimics were transfected into the Hela and C33A cervical cancer cell lines, which led to suppression of cell growth. In addition, overexpression of miR-144 inhibited the migration and invasion of Hela and C33A cells. Furthermore, a bioinformatics analysis identified vascular endothelial growth factor A (VEGFA) VEGFC as two novel target genes of miR-144. Of note, a dual luciferase reporter assay, reverse transcription quantitative polymerase chain reaction analysis and western blot analysis demonstrated that miR-144 repressed the expression of VEGFA and VEGFC by directly targeting to their 3'-untranslated region. Taken together, the results suggested that miR-144 acts as a tumor suppressor in the proliferation and metastasis of cervical cancer cells by directly targeting VEGFA and VEGFC, suggesting that miR-144 may be a novel promising diagnostic and therapeutic biomarker for cervical cancer. PMID- 29387206 TI - Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1. AB - The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem and novel therapeutic strategies are required to prevent and treat T2DM. It has been demonstrated that resveratrol (RSV) may prevent T2DM by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for T2DM prevention. In the present study, a T2DM rat model was established by administering a high fat diet and streptozotocin (STZ) injections. Measurements of blood glucose and insulin confirmed successful establishment of the T2DM model. RSV was used to treat rats with STZ-induced T2DM and the results indicated that RSV reversed the STZ-induced downregulation of peroxisome proliferator activated receptor-gamma coactivator-1alpha, SIRT1 and forkhead box protein O 3a. Furthermore, RSV modulated the activity of superoxide dismutase and malondialdehyde, which are associated with oxidative stress. In vitro, cells from the insulinoma cell line clone 1E were pretreated with palmitic acid (PA) to simulate a high fat environment. The results of reverse transcription quantitative polymerase chain reaction indicated that PA suppressed the expression of SIRT1 in a dose- and time-dependent manner. Furthermore, PA modulated the expression of mitochondrial biogenesis-associated, lipid metabolism associated and beta-cell-associated genes, whereas RSV treatment ameliorated the PA-induced changes in the expression of these genes via SIRT1. The results of the present study suggest that RSV participates in the prevention of T2DM by regulating the expression of mitochondrial genes associated with biogenesis, lipid metabolism and beta-cells via SIRT1. The results of the current study provide an insight into the mechanisms by which SIRT1 inhibits T2DM and may be used as a basis for future studies. PMID- 29387207 TI - Toll-like receptor-9 is involved in the development of B cell stimulating factor induced systemic lupus erythematosus. AB - The objective of the present study was to investigate the role of Toll-like receptor (TLR)-9 in B lymphocyte stimulating factor (BLyS)-induced systemic lupus erythematosus (SLE) in mice. The anti-double stranded (ds)DNA antibody titer, levels of complement proteins (C3 and C4), interleukin (IL)-10 and the disease activity [assessed by the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level] were measured. A total of 21 transgenic female mice (aged 8 10 weeks and weighing 30-40 g) expressing the Epstein-Barr virus membrane antigen, BLLF1, were studied. Mice were randomly divided into the control, the BLyS inhibition and the TLR-9 inhibition groups, with 7 mice in each group. Mice in the blank control group received intraperitoneal injections of normal saline, mice in the BLyS inhibition group received intraperitoneal injections of anti-BR3 monoclonal antibody (5,000 ng/day) and mice in the TLR-9 inhibition group received intraperitoneal injections of anti-human TLR-9 antibody (250 ng/day). The treatment regimens continued for 10 days, followed by the collection of peripheral venous blood. The relative levels of TLR-9 mRNA were measured by reverse transcription-quantitative polymerase chain reaction. Furthermore, the BLyS protein concentration and IL-10 levels were measured by ELISA. TLR-9 mRNA, BLyS, IL-10, anti-dsDNA antibody titer, C3, C4, ESR and CRP levels of the blank control group were significantly higher than those of the other two groups (P<0.05). The differences in comparison of these indexes between the BLyS inhibition and TLR-9 inhibition groups were not statistically significant (P>0.05), with the exception of TLR-9 mRNA and BLyS. In conclusion, the TLR-9 signaling pathway may be important for BLyS-induced SLE, and regulation of the inflammatory immune level. PMID- 29387209 TI - Chemotherapy of metastatic hepatoid adenocarcinoma: Literature review and two case reports with cisplatin etoposide. AB - Hepatoid adenocarcinoma (HAC) is a rare and aggressive cancer subtype with a poor prognosis under metastatic conditions. Currently, there is no specific chemotherapy treatment protocol for advanced stages of the disease. This review evaluates two cases of HAC of gastric cardia with synchronous liver metastasis, which were successfully treated by chemotherapy with cisplatin (25 mg/m2 each day) (day 1 to day 3) and etoposide (100 mg/m2) (day 1 to day 3), every three weeks. A structured literary evaluation and reviewed pertinent articles are additionally presented to analyse the different approaches for the treatment of metastatic HAC (mHAC). The two described case reports demonstrated good partial responses to treatment and one of the two patients exhibited a good prognosis after a 9-year follow-up. A total of 20 case reports concerning the use of chemotherapy in mHAC were presented in the literature, 11 of which were regarding gastric HACs. The two aforementioned cases result in a total of 22 reports, 11 of which exhibited objective responses to chemotherapy, 8 patients demonstrated a partial response and 3 a complete response. The cisplatin-based regimen concerned 55% (12/22) patients and enabled 9 (75%) to exhibit a partial or complete response. A total of three patients exhibited a good prognosis in the long-term follow-up, all of them treated with a cisplatin-based regimen. It was demonstrated that the usual digestive regimens were not efficient in the treatment of HAC. In the absence of prospective trials, it may be hypothesized that cisplatin-based chemotherapy may be the most efficient first-line treatment in mHAC, with a 75% patient response, in accordance with the literature and follow-up cases. PMID- 29387208 TI - Circular RNAs function as competing endogenous RNAs in multiple types of cancer. AB - Circular (circ)RNAs, naturally formed endogenous non-coding RNAs, have received extensive attention in recent years due to their special loop structures and specific function. circRNAs are formed with covalently closed continuous loops and are mainly generated by back-splicing processes or lariat introns from exons and/or introns. Usually, circRNAs are stable, abundant, and evolutionarily conserved in the cytoplasm. circRNAs often exhibit abnormal expression in different diseases, notably in human cancers, and the presence of abundant circRNAs in serum, saliva and exosomes renders them potential diagnostic or predictive biomarkers for diseases, including multiple types of cancer. Presently, certain circRNAs have been reported to function as microRNA sponges and RNA-binding protein sponges to regulate downstream gene transcription, which suggests a potential for circRNAs in cancer diagnosis, prognosis and clinical therapy. The present study assessed the latest advances in the study of circRNAs in cancer, summarized the functions of circRNAs in different types of cancer, highlighted the competing endogenous RNA function of circRNAs in the occurrence and development of human malignancies, and provided evidence for the future application of circRNAs in the diagnosis, prognosis and treatment of multiple types of cancer. PMID- 29387210 TI - Gene expression profile analysis of the bone microenvironment in patients with spinal metastases. AB - The present study aimed to identify the underlying molecular mechanisms associated with spinal metastases. Gene expression profiles in cancellous bone samples from the spines of five patients with spinal metastases, with different primary cancers, and three normal control patients were measured using microarray analysis and subsequently compared. The differentially expressed genes (DEGs) identified were filtered using bioinformatics analyses followed by cluster analysis, gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Finally, a protein-protein interaction network was constructed and analyzed. A total of 152 upregulated and 388 downregulated DEGs were identified. The cluster analysis demonstrated a marked difference between the gene expression profiles of samples from patients with spinal metastases and those from normal patients. The GO terms enriched in the upregulated DEGs were associated with cell death, and those enriched in the downregulated DEGs were associated with the cell cycle. The upregulated DEGs were enriched in signaling pathways associated with tight junctions, and the downregulated DEGs were enriched in signaling pathways associated with porphyrin metabolism. In the PPI network constructed, transcription factor AP-1 and proliferating cell nuclear antigen had the highest connectivity degrees with the upregulated and downregulated DEGs, respectively. The gene expression profile data from the present study provides new insights into the underlying molecular mechanisms of spinal metastases, and will aid in the development of novel anticancer treatments. PMID- 29387211 TI - A retrospective comparison of Escherichia coli and polyethylene glycol-conjugated asparaginase for the treatment of adolescents and adults with newly diagnosed acute lymphoblastic leukemia. AB - Data from clinical trials suggest that polyethylene glycol-conjugated asparaginase (PEG asparaginase) should be recommended as a replacement for Escherichia coli (E. coli) asparaginase in the treatment of pediatric acute lymphoblastic leukemia (ALL) due to its prolonged effect, similar safety profile and convenience. The present study investigated the efficacy and safety of PEG asparaginase in adolescents and adults with newly diagnosed ALL. The clinical data of 122 patients, >=14 years old with de novo ALL, who received either PEG asparaginase or E. coli asparaginase as part of an induction regimen, were retrospectively analyzed. The results revealed that PEG asparaginase had a comparable complete remission rate (95.65 vs. 90.79%), median overall survival time (14.07 vs. 16.29 months) and median relapse-free survival time (10.00 vs. 8.57 months) with E. coli asparaginase. In addition, patients <35 years old receiving PEG asparaginase obtained a higher median RFS time compared with those receiving E. coli asparaginase (10.93 vs. 8.97 months; P=0.037). Patients treated with E. coli asparaginase exhibited a significantly higher incidence of central nervous system leukemia (CNSL) compared with those treated with PEG asparaginase (27.63 vs. 10.87%; P=0.028) during the consolidation phase. Toxic events, including allergy, grade III-IV liver dysfunction, renal function damage and pancreatic lesions were similar between the two groups. A longer duration of coagulation dysfunction (9.80+/-5.51 vs. 6.80+/-4.21 days; P=0.002) and agranulocytosis (18.89+/-8.79 vs. 12.03+/-8.34 days; P<0.01), and a higher incidence of grade IV-V infections (22.73 vs. 7.25%; P=0.018) were observed in the PEG asparaginase group. However, these did not increase bleeding events or infection-associated mortalities. When taking the convenience and superior efficacy in preventing CNSL into consideration, PEG asparaginase is a candidate for first-line treatment of adolescent and adult ALL. A larger prospective clinical trial is required to further confirm this point of view. PMID- 29387212 TI - Wnt4 overexpression promotes thymoma development through a JNK-mediated planar cell polarity-like pathway. AB - Thymoma is the most common neoplasm of the anterosuperior mediastinum. Activation of the Wnt signaling pathway has a role in a variety of human cancers. The present objective was to examine c-Jun N-terminal kinase (JNK) mRNA and protein expression in thymoma cells undergoing apoptosis subsequent to downregulation of Wnt4. Wnt4 and JNK mRNA and protein expression was analyzed by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in 15 thymoma tissues and 6 thymus cyst tissues. Thymoma cells were cultured and transfected with shRNA plasmids targeting the Wnt4 gene. Wnt4 and JNK protein expression was detected by western blot analysis. Apoptosis was analyzed using Wright-Giemsa staining, Hoechst-33342/propidium iodine double staining and flow cytometry. The results showed that Wnt4 and JNK mRNA and protein expression were significantly increased in thymoma compared with normal thymus tissue. Subsequent to transfection, thymoma Wnt4 and JNK mRNA and protein expression were significantly decreased in shRNA-treated groups, with the strongest inhibition being 52.37%. Characteristic apoptotic morphological changes were observed and apoptosis increased. Overall, the present concluded that Wnt4 has an important role in thymoma development, which appears to be activated through a JNK mediated planar cell polarity-like pathway. PMID- 29387213 TI - Knockdown of TBRG4 affects tumorigenesis in human H1299 lung cancer cells by regulating DDIT3, CAV1 and RRM2. AB - The transforming growth factor beta regulator 4 (TBRG4) gene, located on the 7p14 p13 chromosomal region, is implicated in numerous types of cancer. However, the contribution(s) of TBRG4 in human lung cancer remains unknown. In the present study, the expression of TBRG4 mRNA was investigated in the H1299 lung cancer cell line using the quantitative polymerase chain reaction (qPCR) following the knockdown of TBRG4 by a lentivirus-mediated small interfering RNA (siRNA). Results identified that the expression of TBRG4 within H1299 cells was significantly suppressed (P<0.01) by RNA interference, and 586 genes were differentially expressed following TBRG4 silencing. Ingenuity Pathway Analysis (IPA) revealed that these genes were often associated with infectious diseases, organismal injury, abnormalities and cancer functional networks. Further IPA of these networks revealed that TBRG4 knockdown in H1299 cells deregulated the expression of 21 downstream genes, including the upregulation of DNA damage inducible transcript 3 (DDIT3), also termed CCAAT/enhancer-binding protein homologous protein, and downregulation of caveolin 1 (CAV1) and ribonucleotide reductase regulatory subunit M2 (RRM2). Results were validated using qPCR and western blotting. Furthermore, immunohistochemical staining of TBRG4 protein identified that expression was markedly increased in carcinoma compared with in normal tissue. In conclusion, TBRG4 serves a role in the tumorigenesis of lung cancer via deregulation of DDIT3, CAV1 and RRM2. The results of the present study may be important in contributing to our understanding of TBRG4 as a target for lung cancer treatment. PMID- 29387214 TI - Clinical, histological, immunohistochemical and genetic factors associated with measurable response of high-risk canine mast cell tumours to tyrosine kinase inhibitors. AB - The aim of the present prospective-retrospective study was to evaluate the response of high-risk canine mast cell tumours (MCTs) to tyrosine kinase inhibitors (TKIs) and to correlate this with prognostic factors. A total of 24 dogs presented with macroscopic cutaneous MCTs at disease stage II or III, and therefore, at high-risk of associated mortality, were included in the study and treated with masitinib (n=20) or toceranib (n=4). A total of 12/24 dogs achieved an objective response and the overall survival (OS) for all subjects was 113 days. Dogs responding to treatment had a significant increase in OS compared to non-responders (146.5 days vs. 47 days, P=0.02). Internal tandem duplications in exon 11 of the c-kit gene were identified in 6/24 cases. Ki67, KIT immunolabelling and c-kit mutation did not provide information regarding prognosis or prediction of response to TKIs in this population. Initial response to TKIs appears to be the most reliable prognostic factor for survival duration. PMID- 29387215 TI - MicroRNA-204 inhibits cell migration and invasion in human cervical cancer by regulating transcription factor 12. AB - Deregulated microRNAs (miRs) and their roles in carcinogenesis have attracted great attention in recent years. Although miR-204 was reportedly dysregulated in various types of cancer, its function and mechanism in cervical cancer remain unknown. The present study focused on the expression and mechanisms of miR-204 in cervical cancer development. Expression of miR-204 in cervical cancer tissues and non-tumor tissues was measured using PCR analysis. The effect of ectopic expression of miR-204 on cell motility was evaluated using wound-healing and Transwell invasion assays. Luciferase activity and western blot assays were used to verify the regulatory effect of miR-204 on its target gene. It was demonstrated that miR-204 was significantly decreased in primary cervical cancer tissues, and that downregulated miR-204 was associated with lymph node metastasis and poor survival. In addition, it was revealed that ectopic expression of miR 204 significantly inhibited the migratory and invasive ability of cervical cancer cells in vitro. In addition, bioinformatic prediction and experimental validation demonstrated that transcription factor 12 (TCF12) was a direct target of miR-204. Overexpression of TCF12 attenuated the inhibitory effect of miR-204 on cell motility. Taken together, the present data indicated that miR-204 is a metastasis associated gene and may contribute to the progression of cervical cancer by regulating TCF12, providing novel insights, including that miR-204/TCF12 may be an important mechanism for cervical cancer metastasis. PMID- 29387216 TI - Bioinformatics analysis of RNA sequencing data reveals multiple key genes in uterine corpus endometrial carcinoma. AB - In the present study, the RNA sequencing (RNA-seq) data of uterine corpus endometrial carcinoma (UCEC) samples were collected and analyzed using bioinformatics tools to identify potential genes associated with the development of UCEC. UCEC RNA-seq data were downloaded from The Cancer Genome Atlas database. Differential analysis was performed using edgeR software. A false discovery rate <0.01 and |log2(fold change)|>1 were set as the cut-off criteria to screen for differentially expressed genes (DEGs). Differential gene co-expression analysis was performed using R/EBcoexpress package in R. DEGs in the gene co-expression network were subjected to Gene Ontology analysis using the Database for Annotation, Visualization and Integration Discovery. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was also performed on the DEGs using KOBAS 2.0 software. The ConnectivityMap database was used to identify novel drug candidates. A total of 3,742 DEGs were identified among the 552 UCEC samples and 35 normal controls, and comprised 2,580 upregulated and 1,162 downregulated genes. A gene co-expression network consisting of 129 DEGs and 368 edges was constructed. Genes were associated with the cell cycle and the tumor protein p53 signaling pathway. Three modules were identified, in which genes were associated with the mitotic cell cycle, nuclear division and the M phase of the mitotic cell cycle. Multiple key hub genes were identified, including cell division cycle 20, cyclin B2, non-SMC condensin I complex subunit H, BUB1 mitotic checkpoint serine/threonine kinase, cell division cycle associated 8, maternal embryonic leucine zipper kinase, MYB proto-oncogene like 2, TPX2, microtubule nucleation factor and non-SMC condensin I complex subunit G. In addition, the small molecule drug esculetin was implicated in the suppression of UCEC progression. Overall, the present study identified multiple key genes in UCEC and clinically relevant small molecule agents, thereby improving our understanding of UCEC and expanding perspectives on targeted therapy for this type of cancer. PMID- 29387217 TI - Effects of lapatinib on cell proliferation and apoptosis in NB4 cells. AB - Acute promyelocytic leukemia (APL), characterized by the presence of the promyelocytic leukemia (PML)-retinoic acid alpha receptor (RARalpha) fusion protein, responds to treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, drug resistance and side effects restrict the application of these reagents. Hence, the development of novel therapeutic drugs for APL treatment is critical. Lapatinib, a small-molecule tyrosine kinase inhibitor, has been used in the treatment of different tumors. However, it is unclear whether lapatinib exerts antitumor effects on APL. The present study investigated the antitumor effects and potential mechanisms of lapatinib on NB4 cells derived from APL. Cell Counting Kit-8 assay and colony forming analysis indicated that lapatinib inhibited NB4 cell proliferation in a dose-dependent manner. Flow cytometry analysis revealed that lapatinib induced cell cycle arrest at the S phase and promoted cell apoptosis. Furthermore, Liu's staining and Hoechst 33258 staining revelaed that lapatinib treatment induced an apoptotic nuclear phenomenon. Furthermore, lapatinib induced apoptosis by decreasing Bcl-2 and PML-RARalpha levels, and by increasing the levels of Bax, cleaved PARP, cleaved caspase-3 and cleaved caspase-9. In addition, lapatinib increased the levels of phospho-p38 MAPK and phospho-JNK, and decreased the levels of phospho Akt. The p38 inhibitor PD169316 partially blocked lapatinib-induced proliferation inhibition and apoptosis, whereas the JNK inhibitor SP600125 had no such effects. Therefore, treatment with lapatinib may be a promising strategy for APL therapy. PMID- 29387218 TI - Celastrus orbiculatus extracts induce apoptosis and inhibit invasion by targeting the maspin gene in human gastric adenocarcinoma cells. AB - Celastrus orbiculatus Thunb. has been used as a remedy against cancer and inflammatory diseases for thousands of years in China. Maspin is expressed in normal cells and downregulated in prostate tumor cells. The underlying mechanisms between C. orbiculatus extract (COE) and maspin remain unclear. In the present study, 3 target-specific 19-25 nucleotide maspin small interfering RNAs were designed and synthesized to knockdown maspin expression. The effects of COE on MGC-803/maspin- cell proliferation were evaluated by the MTT assay. Apoptosis was measured by flow cytometry. Invasive activity was measured with the Transwell assay and the associated molecular mechanisms were assessed by western blot analysis. The results demonstrated that COE significantly promoted the expression of maspin (P<0.01) to induce apoptosis and inhibit invasion and migration in MGC803 cells. The expression levels of phosphorylated (p)-p38 mitogen-activated protein kinase (MAPK), phospho-extracellular regulated protein kinase (Erk), B cell lymphoma-2-associated X protein and caspase-3 were increased in the MGC 803/maspin- cells in a dose-dependent manner. The Erk, B-cell lymphoma 2, p-Akt, Akt and p-mechanistic target of rapamycin (mTOR) protein in MGC-803/maspin- cells were reduced in a dose-dependent manner. This indicated that COE may inhibit invasion and migration through phosphoinositide 3-kinase/Akt/mTOR and MAPK signaling pathways in MGC-803/maspin- cells. In conclusion, COE has the ability to improve the expression of maspin to induce apoptosis and inhibit invasion and migration in human gastric adenocarcinoma cells. PMID- 29387219 TI - LIM kinase 1 serves an important role in the multidrug resistance of osteosarcoma cells. AB - Multidrug resistance (MDR) is a major challenge for the management of the majority of cancers. The precise molecular mechanisms of MDR remain elusive. In a previous study, a multidrug resistant osteosarcoma model [MG63/vincristine (VCR)] was established by intermittent exposure of MG63 cells to gradually increasing concentrations of VCR. These cells exhibited cross-resistance to multiple structurally and mechanistically unrelated chemotherapeutic agents. The development of MDR was associated with increased expression of LIM kinase 1 (LIMK1). Compared with that in normal human fetal osteoblasts (hFOB) 1.19, the messenger RNA and protein expression of LIMK1 was significantly elevated both in MG63 and U2OS osteosarcoma cells. To observe the expression pattern of LIMK1 in osteosarcoma, immunohistochemical analyses were performed on specimens derived from 6 patients. The results indicated that LIMK1 was expressed to a greater extent in the tumor parenchyma than in the mesenchyme. The role of LIMK1 in MDR was confirmed by transfecting plasmids coding LIMK1-small interfering RNA (siRNA), wild-type-LIMK1 or empty vector into MG63/VCR cells, and measuring the expression of LIMK1 and multidrug resistance protein 1 (MDR1), also known as P gycoprotein (P-gp). The results demonstrated that the level of MDR1/P-gp was positively correlated with the level of LIMK1. This correlation was also shown with the doxorubicin efflux assay and by measuring apoptosis. Specifically, after 6 h of incubation with VCR, 25.6% of the cells transfected with the LIMK1-siRNA plasmid were apoptotic compared with 6.2% in the empty vector group and 1.3% in the group of cells transfected with the wild-type-LIMK1 plasmid. Thus, it was concluded that LIMK1 serves a key role in the MDR of osteosarcoma and functions through MDR1. PMID- 29387220 TI - Network analysis of DEGs and verification experiments reveal the notable roles of PTTG1 and MMP9 in lung cancer. AB - Lung cancer, a malignant tumor, is the most frequently fatal cancer, with poor survival rates in the advanced stages. In order to improve the understanding of this disease, and to improve the outcomes of patients, additional studies are required. In the present study, differentially expressed genes (DEGs) in patients with lung cancer compared with controls were identified. To understand how these DEGs act together to account for the initiation of lung cancer, a protein interaction network and a transcriptional regulatory network were constructed to explore the clusters and pathways in lung cancer, and the results indicated that PTTG1 and MMP9 served major roles in the development of lung cancer in the regulatory system. Consistent with this, mRNA and protein expression levels of PTTG1 and MMP9 were significantly upregulated in lung cancer tissues compared with normal lung tissues. The overexpression of PTTG1 or MMP9 was induced in the human bronchial epithelial BEAS-2B cell line, indicating that increased PTTG1 or MMP9 alone may not only facilitate cell migration, proliferation and induce colony formation, but also suppress cell apoptosis. In summary, PTTG1 and MMP9 were identified as potential targets for therapeutic intervention through gene therapy in lung cancer. PMID- 29387221 TI - Association between LAPTM4B gene polymorphism and susceptibility to and prognosis of diffuse large B-cell lymphoma. AB - Lysosomal protein transmembrane 4beta (LAPTM4B) is an oncogene that is overexpressed in a number of various types of human cancer. There are two known alleles of LAPTM4B: LAPTM4B*1 and LAPTM4B*2. The present study assessed the association between LAPTM4B polymorphisms and the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its prognosis. LAPTM4B genotypes were determined using polymerase chain reaction analysis in 164 DLBCL and 350 healthy control cases. The association between LAPTM4B polymorphisms and the risk of DLBCL was analyzed using unconditional logistic regression. Differences in patient survival were calculated using Kaplan-Meier analysis. The present study indicated no significant differences (P>0.05) in the frequency of LAPTM4B*2 alleles between DLBCL cases (26.5%) and controls (24.1%). The risk of DLBCL was slightly increased in cases with the LAPTM4B*1/2 genotype [odds ratio (OR)=1.160; 95% confidence interval (CI)=0.781-1.724] or the LAPTM4B*2/2 genotype (OR=1.446; 95% CI=0.648-3.227) compared with those with the LAPTM4B*1/1 genotype. There was no significant association between the presence of the LAPTM4B*2 allele and overall survival (OS) and disease-free survival (DFS) in patients with DLBCL (P=0.399 and 0.520, respectively). However, there was a tendency for patients with LAPTM4B*2 and International Prognostic Index (IPI) score 3-5 to have longer OS and DFS (P=0.126 and 0.109, respectively). These findings suggest that genetic polymorphisms of LAPTM4B is not a risk factor for the development of DLBCL, but the LAPTM4B*2 allele may a better prognostic indicator in patients with IPI score 3-5 in DLBCL. PMID- 29387222 TI - Suppression of 14-3-3zeta in cholangiocarcinoma cells inhibits proliferation through attenuated Akt activity, enhancing chemosensitivity to gemcitabine. AB - The protein 14-3-3zeta contributes important regulatory functions in several cellular processes via binding to phosphorylated serine/threonine residues, which promotes cell cycle progression, cell proliferation and anti-apoptosis in multiple types of cancer. The aim of the present study was to investigate the functions of 14-3-3zeta in cholangiocarcinoma (CCA) progression and elucidate the molecular mechanism of 14-3-3zeta expression-mediated protein kinase B (Akt) phosphorylation and chemosensitivity in CCA cells. In the present study, 14-3 3zeta expression was investigated in clinical specimens using immunohistochemistry and compared with the clinicopathological features of patients with CCA. The association between 14-3-3zeta and phosphorylated Akt (pAkt) was determined among the tissues of the same patients using bivariate correlation analysis. The effects of 14-3-3zeta suppression on CCA cell function and gemcitabine sensitivity were investigated using small interfering RNA (siRNA). It was identified that 14-3-3zeta expression was positively correlated with pAkt (P=0.013) and that increased expression of 14-3-3zeta and pAkt were significantly associated with poor overall survival rate and metastasis (P=0.025 and 0.006, respectively). Downregulation of 14-3-3zeta using siRNA in CCA cell lines decreased cell proliferation, resulting in the inhibition of pAkt activity and increasing the protein level of the cell cycle inhibitor p27. The suppression of 14-3-3zeta enhanced the inhibitory effect of gemcitabine on CCA cell proliferation by inducing apoptotic cell death. Taken together, the results of the present study indicated that 14-3-3zeta is a potential target for CCA and may serve as a novel therapeutic approach to enhance chemosensitivity in the treatment of CCA. PMID- 29387223 TI - Telomerase activity in cervical scrapes of women with high-grade cervical disease: A nested case-control study. AB - Epidemiological information on telomerase activity (TA) and development of cervical lesions is scarce. A nested case-control study was carried out within a cohort of Colombian women tested for Human Papillomavirus (HPV). Measurement of TA was done in cervical scrapes of 25 women who developed High Grade Squamous Intraepithelial Lesion (HGSIL) during the first 6 years of follow-up and was compared with that of 104 control women who maintained normal cytology during the entire follow-up. TA was measured by a telomerase repeat amplification protocol ELISA. TA and HPV infections were significantly more frequent in cases than in controls. Likewise, 68% of the cases were positive for both TA and HPV compared with only 7.7% of the controls (P<0.0001). Factors independently associated with increased odds of HGSIL included TA, high risk HPV (hrHPV) infections and multiple parities. When restricted to hrHPV positive women, TA was strongly associated with increased odds of HGSIL (adjusted odds ratio=37.94, 95% confidence interval, 1.64-678.1). In addition to an infection with hrHPV, TA appears to be a significant cofactor for HGSIL. PMID- 29387224 TI - Preliminary screening and identification of differentially expressed metastasis related ncRNAs in ovarian cancer. AB - Ovarian cancer (OC) is an aggressive disease with few valuable biomarkers and effective therapies. In this study, we aimed to elucidate biomarkers associated with OC metastasis into the omentum. We performed comprehensive screening of non coding RNAs (ncRNAs) between matched primary OC and omental metastasis using the Agilent human lncRNA Array V3.0 microarray. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to validate the microarray results at the mRNA level. Microarray revealed 235 ncRNAs changes, and we validated the top four differential changed genes in an additional 27 paired samples with RT qPCR. We found that myocardial infarction associated transcript (MIAT) expression increased in the omentum tissue, while small nucleolar RNA, C/D Box 114 cluster (SNORD114) family members SNORD114-10, SNORD114-2 and SNORD114-11 were downregulated when compared with OC tissue. However, there is no significant difference in SNORD114-2 and SNORD114-11 levels. We thus infer that differential expression of MIAT and SNORD114-10 could play an important role during OC metastasis. These ncRNAs might be useful as pre-diagnostic biomarkers at the early stage of cancer metastasis. PMID- 29387225 TI - MicroRNA-26b-5p regulates cell proliferation, invasion and metastasis in human intrahepatic cholangiocarcinoma by targeting S100A7. AB - The present study aimed to investigate the effects of microRNA expression in intrahepatic cholangiocarcinoma (ICC). It was identified that the expression of microRNA-26b-5p (miR-26b-5p) was downregulated in ICC tissues compared with matched adjacent non-tumor tissues. Furthermore, miR-26b-5p expression was downregulated in metastatic ICC tumor tissues and invasive ICC cell line subpopulations compared with non-metastatic tumor tissue and the parental ICC cells. In vitro studies demonstrated that transfection with an miR-26b-5p mimic inhibited the proliferation, migration and invasion of RBE and HCCC-9810 cells, whereas an miR-26b-5p inhibitor promoted these abilities. S100 calcium-binding protein A7 (S100A7) was predicted as a direct target of miR-26b-5p. Transfection with an miR-26b-5p mimic decreased S100A7 expression, whereas an miR-26b-5p inhibitor increased S100A7 expression. The result of a dual luciferase reporter assay also indicated this interaction. S100A7 was therefore confirmed as a direct target of miR-26b-5p in ICC. The knockdown of S100A7 abrogated the effect of miR 26b-5p on cell migration in RBE and HCCC-9810 cells. In conclusion, the present study demonstrated that miR-26b-5p suppresses the proliferation, migration and invasion of ICC cells by suppressing S100A7. PMID- 29387226 TI - MicroRNA profiles during galectin-9-induced apoptosis of pancreatic cancer cells. AB - Pancreatic cancer is the eighth-leading cause of cancer-associated mortality in males and the ninth-leading cause in females worldwide. Even when diagnosed early enough to be potentially resectable, the prognosis of invasive pancreatic cancer is poor. Galectin-9 (Gal-9) is a tandem-repeat type galectin that has recently been demonstrated to possess an anti-proliferative effect on cancer cells. Therefore, the present study evaluated the effects of Gal-9 on the proliferation of human pancreatic cancer cells and examined the microRNAs that are associated with the antitumor effects of Gal-9. Gal-9 suppressed the proliferation of multiple pancreatic cancer cell lines. In addition, Gal-9 treatment increased the levels of caspase-cleaved keratin 18 and the expression of cytochrome c in pancreatic cancer cell lines. This data suggests that Gal-9 induces intrinsic apoptosis in pancreatic cancer cell lines through the caspase-dependent and caspase-independent pathways. In addition, Gal-9 reduced the expression levels of phosphorylated epidermal growth factor receptor and numerous receptor tyrosine kinases (RTKs). In conclusion, Gal-9 may suppress the growth of human pancreatic cancer cells in vitro. These findings suggest that Gal-9 may be a new therapeutic agent for the treatment of pancreatic cancer. PMID- 29387227 TI - Screening of up- and downregulation of circRNAs in HBV-related hepatocellular carcinoma by microarray. AB - The present study describes circular RNA (circRNA) profiles in three pairs of hepatocellular carcinoma (HCC) tissues and the corresponding adjacent non tumorous tissues (NTs) by microarray. circRNA is a type of endogenous RNA that serve a crucial role in disease development and aberrantly express in a number of types of cancer. In the present study, 3 paired HCC tissues and paired adjacent NTs were collected from HCC surgical specimens from 3 hepatitis B virus-infected patients with HCC. With abundant and varied probes accounting for 5,396 circRNAs, a large number of circRNAs are able to be quantitatively determined. Based on the microarray data, 222,567,556 upregulated circRNAs and 125,439,219 downregulated circRNAs were identified respectively. Further analysis revealed 24 upregulated and 23 downregulated significantly circRNAs (fold-change >=2; P<=0.05) in HCC tissues compared with NTs. By means of computer analysis and database inquiring, the microRNA (miRNA) response elements associated with the abnormally expressed circRNAs were annotated. The present study showed novel evidence determining genome-wide circRNA expression patterns in HCC using microarray analysis. The results demonstrated that clusters of circRNAs were aberrantly expressed in HCC compared with NTs. These circRNAs may be involved in the occurrence and development of HCC. Therefore, the results of the present study may provide a novel approach for improving the understanding of the molecular basis of HCC. Furthermore, the identified circRNAs may be potential biomarkers for the diagnosis of HCC. PMID- 29387228 TI - Oncogenic activity of insulin in the development of non-small cell lung carcinoma. AB - Insulin is associated with the progression of numerous different types of cancer. However, the association between insulin and non-small cell lung carcinoma (NSCLC) remains unknown. The aim of the present study was to evaluate the role of insulin in the proliferation, migration and drug resistance of NSCLC cells, and to determine whether the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway was involved. NSCLC cells were treated with insulin in the absence or presence of LY294002, an inhibitor of the PI3K/Akt pathway. Following co incubation with insulin, cell proliferation and drug resistance were measured by MTT; cell migration was examined by wound healing and Transwell assays; and the expression of cyclin A, proliferating cell nuclear antigen (PCNA), p27, matrix metalloproteinase 3 (MMP3), P-gp and proteins involved in the PI3K/Akt pathway were assessed via western blotting. The results of the current study demonstrated that insulin enhanced the proliferation, migration and drug resistance of NSCLC cells. Correspondingly, insulin upregulated the expression of cyclin A, PCNA, MMP3, P-gp and downregulated p27 expression in NSCLC cells. Following treatment with insulin, it was demonstrated that phospho-Akt expression increased in a dose dependent manner. However, the effects of insulin on NSCLC cells was inhibited by the PI3K/Akt pathway inhibitor LY294002. Therefore, the results of the current study indicate that insulin is associated with the development of NSCLC by activating the PI3K/Akt pathway. This may improve understanding of the mechanism of action of insulin in NSCLC in the future. PMID- 29387230 TI - Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation. AB - Hypoxia is a critical aspect of tumor biology and has been associated with poor prognosis and resistance to traditional therapy. In the present study, differentially expressed genes and microRNAs (miRNAs/miRs) were screened for in the hepatocellular carcinoma (HCC) cell line Huh7 under hypoxic conditions. On the basis of microarray data, 11,508 mRNAs and 58 miRNAs exhibiting >=1.5-fold change in expression under hypoxic conditions were identified. Gene Ontology (GO) and Kyoto Encyclopedia or Genes and Genomes pathway analysis revealed that the differentially expressed genes were primarily involved in cell cycle regulation, cell division, transcription and G-protein-coupled receptor signaling pathways. Using the TargetScan and miRanda software packages with the miRNA-mRNA negative expression network, differentially expressed miRNA targets were predicted. GO analysis revealed that the primary function of these miRNAs was to regulate transcription and phosphorylation. The miRNA-mRNA networks for transcription and phosphorylation were analyzed. Network analysis revealed that the key miRNAs in these networks were miR-19a, miR-34a, miR-29a, mir-196a, miR-25 and miR-1207, whose potential gene targets include DNA-binding proteins, zinc-finger proteins and transcription factors. Certain protein kinases, includingmitogen-activated protein kinase (MAPK) 1, MAPK kinase kinase4 and cyclin-dependent kinase 18, were also revealed to be present in the network. In hypoxic HCC tissue, levels of several key miRNAs implicated in the network analyses (miR-19a, miR-34a, miR-25 and miR-1207) were revealed to exhibit increased expression levels compared with the surrounding tissue. The results of the present study provide evidence that miRNAs serve an important function in transcription and phosphorylation in the hypoxic response of HCC cells. PMID- 29387229 TI - Human papillomavirus genotype affects metastatic rate following radiotherapy in patients with uterine cervical cancer. AB - Human papillomavirus (HPV) infection is well known as a major etiological risk factor associated with carcinogenesis in uterine cervical cancer. However, few reports have investigated the association between HPV genotype and outcome in patients with uterine cervical cancer following radiotherapy (RT). The aim of the present study was to investigate the association between the HPV genotype and clinical outcome following RT in Japanese patients with uterine cervical cancer. Between November 2001 and August 2006, 157 Japanese women with uterine cervical cancer were treated with RT or concurrent chemoradiotherapy with curative intent. Pretreatment, formalin-fixed, paraffin-embedded biopsies were obtained from 83 patients. HPV genotypes were determined using the polymerase chain reaction method. Patients were categorized, according to HPV L1 protein sequence homology, into the HPV alpha-9 (HPV 16, 31, 33, 52, and 58), HPV alpha-7 (HPV 18, 39, 45, 59, and 68) or 'other' (HPV 51 and 56) groups. Associations between HPV genotype and clinical outcome following RT were evaluated. A total of 54 (65.1%) tumors were HPV alpha-9-positive, 13 (15.7%) were HPV alpha-7-positive, 2 (2.4%) were categorized under 'other' and 14 (16.9%) were HPV-negative. There were no significant differences in age, FIGO stage, regional lymph node metastases rate at diagnosis, or concurrent chemotherapy administration between the HPV alpha-9 and alpha-7 groups. The median follow-up period was 52 months (range, 2-156 months). The 5-year disease-free survival rates were 54.5 and 30.8% in the HPV alpha-9 and alpha-7 groups, respectively (P=0.034), and the 5-year distant metastasis rates were 38.0 and 69.2%, respectively (P=0.015). There were no significant differences in the 5-year local control or overall survival (OS) rates between the two groups. HPV genotype affected the 5-year distant metastatic rate, however not the 5-year local control or OS rate in patients with uterine cervical cancer following RT. PMID- 29387231 TI - Long non-coding RNA HOTAIR up-regulates chemokine (C-C motif) ligand 2 and promotes proliferation of macrophages and myeloid-derived suppressor cells in hepatocellular carcinoma cell lines. AB - Accumulating evidence demonstrated that Hox antisense intergenic RNA (HOTAIR) serves essential roles in the development and metastasis of several types of cancer. In hepatocellular carcinoma (HCC), high expression of HOTAIR is associated with poor prognosis, and HOTAIR regulates cell migration and proliferation. However, the downstream molecular targets of HOTAIR depend on the cancer cell types, and little is known about the precise molecular mechanisms of HOTAIR involved in cancer development. The present study investigated the role of HOTAIR in HCC cell lines. Notably, the overexpression of HOTAIR in HCC cell lines did not affect cell migration and proliferation capability. In the microarray analysis, C-C motif chemokine ligand (CCL)2 was identified to be differentially expressed in HOTAIR-overexpressing cells, and it was confirmed that HOTAIR promotes the secretion of CCL2. Furthermore, it was revealed that the proportion of macrophages and myeloid-derived suppressor cells (MDSCs) were increased when peripheral blood mononuclear cells were co-cultured with HOTAIR-overexpressing cells. Collectively, these data suggest that HOTAIR regulates CCL2 expression, which may be involved in the recruitment of macrophages and MDSCs to the tumor microenvironment. PMID- 29387232 TI - MLN4924 neddylation inhibitor promotes cell death in paclitaxel-resistant human lung adenocarcinoma cells. AB - Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8 activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX). The application of MLN4924 promotes apoptosis and DNA damage in A549/PTX and H460/PTX cells. Additionally, MLN4924 abrogated the 3-dimensional growth potential of these cells and inhibited the formation of the A549/PTX and H460/PTX spheroids. Notably, combining MLN4924 with PTX did not exhibit synergy in PTX-resistant NSCLC cells. Taken together, the results of the current study suggest that MLN4924 may be utilized as an effective strategy for the treatment of PTX-resistant NSCLC. PMID- 29387233 TI - Inhibition of prostate cancer growth by immunization with a GM-CSF-modified mouse prostate cancer RM-1 cell vaccine in a novel murine model. AB - Advanced prostate cancer is difficult to treat owing to a lack of effective approaches for disrupting immune tolerance. C57BL/6 male and female mice implanted with viable RM-1 cells represent a novel murine model of advanced prostate cancer for studying antitumor effects following immunization with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-modified RM-1 cell vaccine, which has been described previously. In vitro cytotoxic activity and cytokine secretion experiments were conducted to investigate the antitumor response. The cytotoxicity profile of splenocytes from female mice immunized against RM-1 cells primarily involved cytotoxic T lymphocyte (CTL) lysis and, to a lesser extent, natural killer (NK) cell lysis. NK cell lysis was also observed in males, which exhibited no evidence of CTL lysis. The secretion of interferon gamma in the GM-CSF-modified cell vaccine group was significantly increased compared with the other groups. The level of interleukin-4 was low. To investigate the antitumor immune response further, cluster of differentiation 4 (CD4) T cells and CD8 T cells were analyzed in the spleens and tumors of female mice receiving the GM-CSF-modified RM-1 cell vaccine. Unlike female mice, males exhibited the highest proportion of NK cells in the spleen. NK cells were not detected in the tumor tissue in any of the groups. The difference between the sexes may explain the specificity of the immune response, as females are intolerant to prostate antigens whereas males are. This model is clinically relevant as it translates to human immunology and offers an effective and convenient method for studying immunotherapy for prostate cancer. PMID- 29387234 TI - Cadherin 17 is related to recurrence and poor prognosis of cytokeratin 19 positive hepatocellular carcinoma. AB - A previous study demonstrated that cytokeratin 19 (CK19) expression in hepatocellular carcinoma (HCC) is an indicator of HCC invasiveness, including lymph node metastasis (LNM), tumor infiltration/non-encapsulation and poor prognosis. The exact mechanism by which CK19 expression results in poor prognosis remains unclear. Through the use of an Affymetrix U133A oligonucleotide microarray [20 patients with hepatitis B virus (HBV)-HCC], it was demonstrated that cadherin 17 (CDH17) significantly correlated with CK19 expression (R2, 0.867; P<0.001) in HBV-HCC. Immunohistochemical analysis (114 patients with HBV HCC) also demonstrated a significant correlation between CK19 and CDH17 expressions in primary tumor tissue (R2, 0.414; P<0.001). In addition, CK19 and CDH17 expressions levels revealed a significant association with LNM (P<0.001). Cox regression multivariate analysis demonstrated that indocyanine green retention at 15 min >10% and CDH17 expression were independent prognostic factors for disease free survival (P=0.010 and 0.002, respectively). In vitro studies showed that epidermal growth factor can induce the expression of both CK19 and CDH17, and CDH17 in turn can enhance the expression of CK19 in HCC. In summary, this study demonstrated that the early recurrence and poor prognosis of CK19(+) HCC may be due to the expression of CDH17, a gene known to be associated with vascular invasion, tumor metastasis, and advanced tumor stage of HCC. Thus, novel therapeutics by targeting CDH17 may be beneficial for CK19(+) HCC. PMID- 29387235 TI - Predictive relevance of miR-34a, miR-224 and miR-342 in patients with advanced squamous cell carcinoma of the lung undergoing palliative chemotherapy. AB - Attributing to their pathophysiological role and stability in biological samples, microRNAs (miRNAs) have the potential to become valuable predictive markers for non-small cell lung cancer (NSCLC). Samples of biopsy tissue constitute suitable material for miRNA profiling with the aim of predicting the effect of palliative chemotherapy. The present study group included 81 patients (74 males, 7 females, all smokers or former smokers) with the squamous cell carcinoma (SCC) histological subtype of NSCLC at a late stage (3B or 4). All patients received palliative chemotherapy based on platinum derivatives in combination with paclitaxel or gemcitabine. The expression of 17 selected miRNAs was measured by reverse transcription-quantitative polymerase chain reaction in tumor tissue macrodissected from formalin-fixed paraffin-embedded (FFPE) tissue samples. To predict the effect of palliative chemotherapy, the association between gene expression levels and overall survival (OS) time was analyzed. From the 17 miRNAs of interest, low expression levels of miR-342 and high expression levels of miR 34a and miR-224 were associated with a reduced OS time in subgroups of patients based on smoking status and treatment modality. Using cluster analysis, associations between combinations of miR-34a, -224 and -342 expression levels with patient survival were identified. The present study revealed that patients with the simultaneous high expression of miR-224 and -342 had a similar prognostic outcome to those with the low expression of miR-224 and -342, which was significantly reduced, compared with patients exhibiting high expression of either miR-224 or miR-342 with low expression of the other. We hypothesize that the effect of a particular miRNA is dependent on the expression level of other members of the miRNA network. This finding appears to complicate survival analyses based on individual miRNAs as markers. In conclusion, the present study provides evidence that specific miRNAs were associated with OS time, which may be candidate predictors for the effectiveness of palliative treatment in SCC lung cancer patients. This objective can be better achieved by combining more markers together than by using individual miRNAs. PMID- 29387236 TI - Expression profile and clinical significance of Wnt signaling in human gliomas. AB - Wnt signaling has been identified as a critical regulator of human tumor development in vitro. However, there remains a lack of studies systematically examining the expression pattern and clinical relevance of the core molecules of Wnt signaling in glioma tissues. In the present study, it was identified that the mRNA expression levels of Wnt3a and 5a, and their receptors frizzled 2, 6 and 7 increased, whereas Wnt7b was markedly decreased in glioma relative to non-tumor tissue. The mRNA levels of beta-catenin, adenomatous polyposis coli gene product, glycogen synthase kinase 3beta (GSK3beta) and AXIN1 and its target genes cyclin D1 and AXIN2 did not differ. Similarly, the protein levels of Wnt2b, 3a and 5a were increased in gliomas, while beta-catenin, GSK3beta and cyclin D1 were not. Furthermore, based on data from the R2: Genomics Analysis and Visualization Platform, the expression of Wnt2b and 5a, and frizzled 2, 6 and 7 were highly associated with the prognosis of patients with glioma. Taken together, the results of the present study demonstrate that beta-catenin is not upregulated in gliomas and that the Wnt signaling pathway may promote glioma development via noncanonical or alternative pathways. PMID- 29387237 TI - Bioinformatics analysis of gene expression alterations conferring drug resistance in tumor samples from melanoma patients with EGFR-activating BRAF mutations. AB - Melanoma is a highly malignant tumor of the skin melanocytes. Patients with this cancer have a high frequency (~50%) of oncogenic BRAF mutations, particularly BRAF V600E. Treatments for melanoma often target BRAF mutations or involve mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitors. A major challenge in melanoma treatment is resistance to BRAF inhibitor treatment, which may be enhanced by the BRAF mutation itself and/or epidermal growth factor receptor (EGFR) activation, leading to poor prognosis. However, no effective clinical treatment exists for patients with EGFR-activating feedback. The aim of the present study was to analyze gene expression changes in tumors from patients with EGFR-activating BRAF mutations during development of drug resistance. RNA-seq data was downloaded from the Gene Expression Omnibus (GEO) database for pre- and post-treatment tumor samples from three melanoma patients with EGFR-activating BRAF V600E mutations, and from The Cancer Genome Atlas (TCGA) melanoma database for tumor and non-tumor samples from patients with the BRAF V600E mutation and unknown EGFR activation status. Using functional enrichment and KEGG pathway analyses, the present study analyzed differentially expressed genes (DEGs) between pre- vs. post-treatment data from the GEO database and tumor or non-tumor sample data from the TCGA database. The results of the present study indicated that functional and structural changes to the plasma membrane may be associated with drug resistance. The present study identified 9 DEGs that were significantly different between tumor and non-tumor samples and also between prior to and following treatment. Thus, it was confirmed that patients with EGFR-activating BRAF V600E mutations undergo gene expression changes during disease development, and during therapy. These findings may provide potential directions for melanoma-specific therapy. PMID- 29387238 TI - Identification of expression quantitative trait loci of MTOR associated with the progression of glioma. AB - Mechanistic target of rapamycin (MTOR) encodes a key modulator of cell growth, proliferation, and apoptosis. Previous studies have demonstrated that the dysregulation of MTOR is involved in the development and progression of several types of cancer, including glioma. In the present study, a comprehensive analysis was conducted to examine whether the expression quantitative trait loci (eQTLs) of MTOR are associated with the progression of glioma. Candidate eQTLs of MTOR were obtained from the Genotype-Tissue Expression eQTL Browser. The Kaplan-Meier method and multivariate Cox model were used to analyze the progression-free survival time of glioma patients. Based on the analysis of 138 glioma patients, one eQTL of MTOR, rs4845964, was demonstrated to be significantly associated with the progression of glioma in a dominant manner. The adjusted hazard ratios (HRs) for patients with the AG or AA genotype at rs4845964 were 2.82 [95% confidence interval (CI), 1.27-6.27; P=0.0111] and 2.79 (95% CI, 1.10-7.07; P=0.0312), respectively, compared with those with the GG genotype. When the rs4845964 AG and AA genotypes were combined for analysis, the HR was 2.70 (95% CI, 1.25-5.82; P=0.0114) vs. the GG genotype. Stratified analyses revealed similar associations between the rs4845964 genotypes and the progression of glioma in all subgroups (following stratification by age, sex and tumor grade). These results demonstrate for the first time that the MTOR eQTL rs4845964 is associated with the progression of glioma. PMID- 29387239 TI - Clinical characteristics and disease outcome of patients with non-medullary thyroid cancer and brain metastases. AB - Brain metastases from non-medullary thyroid carcinoma (NMTC) are rare, with a reported frequency of ~1%, and patient survival time is <1 year after diagnosis. The optimal management of brain metastases in this setting continues to be debated. The aim of the present study was to evaluate a series of patients with brain metastases from NMTC attending a single tertiary medical center. The electronic database of Rabin Medical Center was reviewed for all patients with NMTC and distant metastases who were diagnosed and treated between 1970 and 2014. Those with brain metastases were identified and formed the study group. Data were collected from medical records comprising clinicopathological characteristics, time intervals for diagnosis and treatment, treatment modalities and outcome. Of the 172 patients with NMTC and distant metastases, 10 possessed brain metastases. These included 6 females and 4 males of median age 53.5 years (range, 18-81 years). All patients had lung metastases and 7 demonstrated bone metastases. The median interval between the diagnoses of NMTC and brain metastases was 40 months (range, 9-207 months). Of the 10 patients, 1 presented with brain metastases at primary diagnosis. Treatment of the brain metastases consisted of surgery, radiotherapy (external beam, stereotactic), and radioiodine, alone or in combination. A total of 2 patients received tyrosine kinase inhibitors. The median overall survival time from diagnosis of brain metastasis was 15 months. A total of 2 patients remained alive at the last follow-up (32 and 300 months, respectively). The present study demonstrated that brain metastases may occur in <=6% of patients with NMTC and distant metastases. Brain metastases rarely present at diagnosis of NMTC and are associated with metastases in other distant sites. Systematic screening for brain metastases requires consideration in all patients with NMTC and distant metastases. Some patients show an indolent evolution with overall survival of >2 years, supporting an aggressive treatment approach. PMID- 29387240 TI - p38 MAPK-MK2 pathway regulates the heat-stress-induced accumulation of reactive oxygen species that mediates apoptotic cell death in glial cells. AB - Previous studies have demonstratedf that heat stress can induce injury of the central nervous system and lead to neuronal cell apoptosis. However, the molecular mechanisms underlying these cellular changes remain unclear. In the present study, flow cytometry was used to investigate heat-stress-induced apoptosis, and caspase-3 activation was also assessed in neurons. The role of reactive oxygen species (ROS) accumulation in the heat-stress-induced apoptosis of neurons was demonstrated using the antioxidant drug manganese (III) tetrakis (4-benzoic acid)porphyrin. The present study presents evidence that heat stress induces mitogen-activated protein kinase (MAPK) activation in rat malignant glioma F98 cells. Following the inhibition of different MAPKs with a range of specific inhibitors, SB203580 (an inhibitor of p38 MAPK), but not PD98059 (an inhibitor of extracellular signal-regulated kinases) or SP600125 (an inhibitor of c-Jun N-terminal kinases), diminished the production of ROS and apoptosis, and prevented activation of the p38-downstream kinase MAPK-activated protein kinase 2 (MK2) in neurons. Inhibiting MK2 with dominant negative adenoviral constructs or a specific inhibitor significantly decreased normal and heat-stress-induced ROS accumulation and cell apoptosis, whereas inhibition of another kinase downstream of p38 MAPK, MAPK-activated protein kinase 5, by transfection with another adenoviral construct did not exert the same effects. Taken together, these findings indicate that heat stress stimulation induces p38-MK2 pathway activation, which exerts a pro-apoptotic effect by regulating ROS accumulation in neurons. PMID- 29387241 TI - Mitochondrial pathway-mediated apoptosis is associated with erlotinib-induced cytotoxicity in hepatic cells. AB - For advanced non-small-cell lung cancer (NSCLC) with mutations to the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors, including erlotinib are indicated for the first-line treatment. Liver injury is one of the multiple adverse effects of erlotinib and may affect its safety. The present study investigated the mechanism of erlotinib-induced hepatotoxicity in vitro and provided experimental evidence for the screening of potential hepatoprotectors. Erlotinib induced dose-dependent cytotoxicity in human L-02 hepatic cells 72 h after treatment. In other experiments, L-02 cells were treated with erlotinib for 48 h and thereafter exhibited typical features of apoptosis. Erlotinib caused alterations to nuclear morphology, including chromatin condensation and karyopyknosis; it also increased the fraction of late apoptotic cells and regulated apoptotic protein levels, activating caspase-3 and cleaving of poly-ADP ribose polymerase. Furthermore, 48 h exposure to erlotinib disturbed mitochondrial function by decreasing the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-associated X proteins and reducing mitochondrial membrane potential. The results of this in vitro study indicate that erlotinib-induced hepatotoxicity may occur through mitochondrial-pathway-mediated apoptosis. PMID- 29387242 TI - MicroRNA-124-3p directly targets PDCD6 to inhibit metastasis in breast cancer. AB - Breast cancer (BC) is the leading cause of cancer-associated mortality among women worldwide, with a poor 5-year survival rate, particularly among patients with metastatic BC. Previous studies have indicated that the dysregulation of microRNAs (miRNAs/miRs) is associated with carcinogenesis and metastasis. Thus, investigating the underlying molecular mechanisms by which miRNAs mediate their effects may aid in the improvement of BC treatment. In the present study, reverse transcription-quantitative polymerase chain reaction analyses were performed to investigate miR-124-3p expression in BC tissues. The expression of miR-124-3p was significantly decreased in primary BC tissues compared with that in adjacent non tumor tissues. Downregulated miR-124-3p was correlated with lymph node metastasis and a low overall survival time. Wound-healing and Transwell assays revealed that MDA-MB-231 and MCF-7 cell motility was inhibited by miR-124-3p, but was promoted by a miR-124-3p inhibitor. Overexpression of miR-124-3p increased levels of E cadherin, and decreased levels of N-cadherin and Vimentin, indicating that miR 124-3p inhibits the epithelial-mesenchymal transition. In addition, a bioinformatics analysis and subsequent in vitro experiments identified programmed cell death protein 6 (PDCD6) as a direct target of miR-124-3p. Restoration of PDCD6 expression impaired the metastasis inhibitor role of miR-124-3p by promoting cell invasion. Furthermore, the expression of miR-124-3p was inversely associated with PDCD6 mRNA levels in clinical breast tumors. Taken together, these data suggest that miR-124-3p inhibits tumor metastasis by inhibiting PDCD6 expression, and that the miR-124-3p/PDCD6 signaling axis may be a potential target for novel treatments in patients with advanced BC. PMID- 29387243 TI - miR-373-3p promotes lung adenocarcinoma cell proliferation via APP. AB - Previous studies have indicated that lung adenocarcinoma (LUAD) is one of the common human malignancies, and its incidence keeps rising. With the help of microarray technology, downregulation of miR-373-3p was observed in LUAD tissues compared with normal lung tissues. Notably, the present study demonstrated that the expression of amyloid precursor protein (APP) mRNA in LUAD tissues was overexpressed compared with adjacent tissues. Bioinformatic analysis demonstrated that miR-373-3p may interact with the 3' untranslated region of APP mRNA, and then western blot and dual-luciferase reporter gene assays were employed to verify the interaction. Finally, CCK-8 assays were used to measure the tumor suppressing effect of miR-373-3p on A549 and it was demonstrated that overexpression of miR-373-3p may more effectively inhibit the proliferation of A549 compared with APP si-RNA. Overall, the findings suggest that miR-373-3p downregulation partly accounts for APP overexpression and leads to a promotion of cell growth in LUAD. miR-373-3p may therefore act as a valuable target in potential anticancer strategies to treat LUAD. PMID- 29387244 TI - miR-144 suppresses proliferation and induces apoptosis of osteosarcoma cells via direct regulation of mTOR expression. AB - Studied as a type of tumor suppressor, microRNA (miR) performs an important role in growth and apoptosis of various human carcinomas. However, the effects of miR l44 on osteosarcoma growth and apoptosis, as well as possible underlying mechanisms, remain unclear. The present study investigated the expression of miR 144 in osteosarcoma MG-63 and U-2 OS cell lines compared with osteoblast cells. In order to elucidate the effects of miR-144 on osteosarcoma, miR-144 was upregulated in MG-63 and U-2 OS cells by transfecting chemically synthesized miR 144 mimics. Bioinformatics analysis of potential miR-144 target genes was performed using TargetScanHuman 7.0 and confirmed by luciferase assay. This analysis identified mammalian target of rapamycin (mTOR) as a target of miR-144. The present results indicated that the overexpression of miR-144 may significantly inhibit proliferation and promote apoptosis of MG-63 and U-2 cells compared with scramble control. Furthermore, the effects of miR-144 on osteosarcoma were associated with the mTOR signaling pathway via directly targeting the 3' untranslated region of mTOR mRNA, resulting in a decrease in the level of mTOR protein. In summary, miR-144 was demonstrated to act as a tumor suppressor, which inhibits proliferation and promotes apoptosis of osteosarcoma cell lines. In addition, this effect was mediated by direct targeting on mTOR following inhibition of the mTOR signaling pathway. The present study suggested that miR-144 may be a candidate for the gene therapy of osteosarcoma. PMID- 29387245 TI - TT-1, an analog of melittin, triggers apoptosis in human thyroid cancer TT cells via regulating caspase, Bcl-2 and Bax. AB - Melittin is a 26 amino acid residue antimicrobial peptide with known antitumor activity. In the present study, a novel peptide TT-1, derived from melittin and contained only 11 amino acids, was designed, and its antitumor effect was investigated. The present study is aimed to elucidate the effects and relative mechanisms of TT-1 on a human thyroid cancer cell line (TT) in vitro and in vivo. Cell viability assays, Annexin V/propidium iodide assays, western blotting and quantitative reverse transcription polymerase chain reaction were performed. Furthermore, a tumor-xenograft model was established to investigate the apoptotic mechanisms of TT-1 on TT cells. The results obtained indicated that TT-1 was able to suppress the proliferation of TT cells and exhibited low cytotoxicity to normal thyroid cells in vitro. The apoptotic rates of TT cells were also increased following TT-1 treatment. Additionally, TT-1 stimulated caspase-3, caspase-9 and Bax, and inhibited B-cell lymphoma 2 mRNA and protein expression. Finally, it was also demonstrated that TT-1 is able to markedly suppress tumor growth in a TT-bearing nude mouse model. In summary, TT-1 may inhibit the proliferation of TT cells by inducing apoptosis in vitro and in vivo, indicating that TT-1 may be a potential candidate for the treatment of thyroid cancer. PMID- 29387246 TI - MicroRNA-138 targets SP1 to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells. AB - The identification of microRNAs (miRNAs/miRs) has enabled the improved understanding of the carcinogenesis and progression of hepatocellular carcinoma (HCC). miRNAs are small non-coding RNAs comprised of 19-24 nucleotides that regulate the expression of target genes. In the present study, miR-138 was demonstrated to be downregulated in human HCC tissues and cell lines. Restoration of miR-138 expression repressed the proliferation, migration and invasion of HCC cells. Furthermore, specificity protein 1 (SP1) was identified as a target gene of miR-138 in HCC using bioinformatics analysis, luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis. Knockdown of SP1 produced similar suppressive effects to those induced by miR-138 overexpression in HCC cells. These results indicate that miR-138 targeted SP1 to repress the growth, migration and invasion of HCC cells, and may therefore represent a therapeutic target in human HCC. PMID- 29387247 TI - Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway. AB - The angiopoietin 1 (Ang1)/angiopoietin receptor (Tie2) signaling pathway may have a notable role in the pathogenesis of inflammatory diseases. The abnormal expression of angiopoietin 1 and Tie2 has also been reported in various malignant tumors, including papillary thyroid carcinoma (PTC). However, the role and mechanism of the Ang1/Tie2 pathway in the progression of PTC remains unclear. Therefore, the aims of the present study were to clarify this. Significantly high expression levels of Ang1 and Tie2 were observed in PTC tissues and cell lines. Furthermore, MTT and wound-healing assays revealed that the Ang1-mediated stimulation of human PTC cells resulted in increased proliferation and migration. Conversely, the downregulation of Tie2 levels using short hairpin RNA targeted at Tie2 abrogated the Ang1-mediated effect on cell proliferation and migration. In studying the expression of phosphoinositide-3 kinase (PI3K)/RAC serine/threonine protein kinase (Akt) pathway, the upregulation of Ang1/Tie2 was found to be associated with the activation of the PI3K/Akt pathway in PTC. In conclusion, the data from the present study indicated that the Ang1/Tie2 induces PTC oncogenesis via the PI3K/Akt pathway, providing novel insights into human PTC therapy. PMID- 29387248 TI - Downregulated SOX9 mediated by miR-206 promoted cell apoptosis in Legg-Calve Perthes disease. AB - Legg-Calve-Perthes disease (LCPD) commonly onsets in adolescents, and threatens their health. However, the potential mechanism underlying LCPD remains unclear. MicroRNA (miR)-206 and SRY-box 9 (SOX9) serve an important role in chondrocytes; however, their role in LCPD remains ambiguous. In the present study, whether miR 206 and SOX9 mediated cell apoptosis in dexamethasone (DEX)-induced LCPD was investigated. The chondrocytes of the LCPD and normal control group were isolated from clinical tissues. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-206 and SOX9 mRNA. Western blotting was used to measure the protein level of SOX9. A combination of Annexin V-fluorescein isothiocyanate flow cytometry was used to assess cell apoptosis. The association between miR-206 and SOX9 was detected using a luciferase reporter assay. miR-206 was overexpressed while SOX9 was downregulated in chondrocytes treated with DEX obtained from patients with LCPD. miR-206 targeted SOX9 to regulate its expression. Overexpression of miR-206 promoted cell apoptosis in TC28, while it was reversed by SOX9 overexpression. TC28 cells pretreated with DEX significantly promoted cell apoptosis, while cells transfected with miR-206 inhibitor significantly reversed the effect; however, downregulated SOX9 abolished the effects of miR-206 inhibitor. SOX9 mediated by miR-206 possibly contributed to the pathogenesis of LCPD. The results of the present study suggest that miR-206 and SOX9 function as important therapeutic targets for the future of clinical therapy. PMID- 29387249 TI - Chronic obstructive pulmonary disease: More than meets the eye. AB - Chronic obstructive pulmonary disease (COPD) is a major health problem which had not received the attention commensurate with the magnitude of its global burden. This is finally changing with the help of a vibrant community of health-care professionals, public officials, and academic researchers. Advances in characterization of the disease, treatment options, imaging modalities, and better understanding of the comorbidities promise to revolutionize how the disease is managed. COPD should no longer augur despair among physicians and patients. PMID- 29387250 TI - An underestimated cause of chronic cough: The Protracted Bacterial Bronchitis. AB - Chronic cough in childhood is associated with a high morbidity and decreased quality of life. Protracted bacterial bronchitis (PBB) seems to be the second most common cause of chronic cough in children under 6 years of age. Its main clinical feature is represented by wet cough that worsens when changing posture and improves after the introduction of antibiotics. Currently, the mainstay of PBB treatment is a 2-week therapy with a high dose of antibiotics, such as co amoxiclav, to eradicate the infection and restore epithelial integrity. It is very important to contemplate this disease in a child with chronic cough since the misdiagnosis of PBB could lead to complications such as bronchiectasis. Clinicians, however, often do not consider this disease in the differential diagnosis and, consequently, they are inclined to change the antibiotic therapy rather than to extend it or to add steroids. Data sources of this review include PubMed up to December 2016, using the search terms "child," "chronic cough," and "protracted bacterial bronchitis." PMID- 29387251 TI - Cardio-autonomic functions and sleep indices before and after coronary artery bypass surgery. AB - BACKGROUND: Earlier studies showed a short-term impairment of cardio-autonomic functions following coronary artery bypass grafting (CABG). There is a lack of consistency in the time of recovery from this impairment. Studies have attributed the post-CABG atrial fibrillation to preexisting obstructive sleep apnea (OSA) without an objective sleep assessment. The aim of this study was to evaluate the effect of CABG on cardio-autonomic and hemodynamic functions and on OSA indices in patients with ischemic heart disease (IHD). METHODS: Cardio-autonomic function using heart rate variability indices, hemodynamic parameters, and sleep studies were performed in 26 patients with stable IHD before, on day-6, and day-30 post CABG surgery. RESULTS: The high-frequency powers of normalized R-R intervals significantly (P = 0.002) increased from the preoperative value of 46.09 to 66.52 on day-6 and remained unchanged on day-30 postsurgery. In contrary, the low frequency powers of normalized R-R interval decreased from 53.91 to 33.48 during the same period (P = 0.002) and remained unchanged on day 30 postsurgery. Baroreceptor sensitivity, obstructive and central apnea indices, desaturation index, and lowest O2 saturation were not significantly different between preoperative, day-6, and day-30 postsurgery. CONCLUSION: Our study revealed that recovery of autonomic functions following CABG occurs as early as 30 days of postsurgery. CABG does not seem to have short-term effects on sleep study indices. However, long-term effects need further evaluation. PMID- 29387252 TI - Graphic warnings and text warning labels on cigarette packages in Riyadh Kingdom of Saudi Arabia: Awareness and perceptions. AB - BACKGROUND: Graphic warning labels have been shown to be effective in smoking initiation and cessation and were implemented in Saudi Arabia in 2012. To date, no study has assessed the effectiveness of these labels and the Saudi population's perceptions on the effectiveness of cigarette health warning labels. METHODS: We used a cross-sectional qualitative study comprising of nine focus groups among 3 different community group members including health-care workers, adult women and adult men. We conducted in-depth interviews among community leaders. Both focus groups and interviews assessed awareness levels and elicited perceptions about health warning labels on cigarette boxes currently used in the Kingdom of Saudi Arabia. RESULTS: While most participants in the study were aware and supported the use of graphic warning labels on cigarette packages, the awareness of the specific details on the labels was low. Participants perceived the effectiveness of current labels somewhat vague in smoking cessation and advocated for stronger and more aggressive graphics. Community leaders, however, preferred text-only labels and did not support aggressive labels which were deemed culturally and religiously inappropriate. CONCLUSIONS: The study suggests that while graphic warning labels are perceived as necessary on cigarette packages the currently used messages are not clear and therefore do not serve their intended purposes. Measures should be undertaken to ensure that pictorial cigarette labels used in Saudi Arabia are culturally and ethnically appropriate and are rotated on a regular basis to ensure salience among smokers and nonsmokers alike. PMID- 29387253 TI - Primary pulmonary lymphoepithelioma-like carcinoma in Singapore. AB - BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of nonsmall cell lung cancer (NSCLC) predominantly reported in East Asia. We aimed to evaluate clinical characteristics, diagnosis, treatment, and prognosis of PPLELC in Singapore. METHODS: Retrospective review of all patients diagnosed with PPLELC at our center between 2000 and 2014. RESULTS: All 28 patients were Chinese, 67.9% were female, and the median age was 58 years (range37-76 years). Majority (89.3%) were never smokers and 53.6% asymptomatic at diagnosis. About 28.6% presented with Stage I/II disease, 25% had Stage III disease, and 46.4% had Stage IV disease. All patients with Stage I/II disease underwent lobectomy without adjuvant treatment. Four out of 7 patients with Stage III disease underwent surgery with or without adjuvant therapy while the rest received chemoradiation. Twelve out of 13 patients with Stage IV disease received chemotherapy with or without radiotherapy. At the end of 2016, survival data were available for all 28 patients. Two-year survival rates for Stage I/II, Stage III, and Stage IV disease were 100%, 85.7%, and 61.5%, respectively, while survival was 100%, 85.7%, and 9.6%, respectively, at five years. CONCLUSION: The majority (46.4%) of patients presented with metastatic disease. For those with Stage I-III disease, 5-year survival for PPLELC was better than other NSCLC subtypes. Multimodality treatment including surgery could be considered in locally advanced disease. In Stage IV disease, it tended to approximate that of NSCLC. PMID- 29387254 TI - Admission predictability of children with acute asthma. AB - OBJECTIVES: We aimed to evaluate the seasonal variations of acute asthma presentation in children and the utility of the pediatric asthma score (PAS) and its components in early admission prediction. METHODS: As part of a randomized controlled trial addressing the clinical efficacy of budesonide nebulization in the treatment of acute asthma in children, the PAS was measured at baseline, 1st, 2nd, 3rd, and 4th h from the start of medications. Decision of admission was taken at or beyond the 2nd h. RESULTS: Out of a total 906 emergency department (ED) visits with moderate-to-severe acute asthma, 157 children were admitted. June to September had the lowest number of visits. The admission-to-discharge ratio varied throughout the year. During the ED stay, between baseline and 3rd h, admission predictability of the total score improved progressively with a small difference between the 2nd and 3rd h. The total score remained the strongest predictor of admission at every time point compared to its individual components. The drop of PAS from baseline to the 2nd h was not a good predictor of admission. Oxygen saturation (OS) and respiratory rate (RR) had relatively higher predictability than other components. CONCLUSIONS: Decision of admission could be made to many children with moderate-to-severe acute asthma at the 2nd h of ED stay based on their total PAS. OS and RR should be part of any scoring system to evaluate acute asthma in children. PMID- 29387255 TI - Comparison of positional and rapid eye movement-dependent sleep apnea syndromes. AB - AIM: We aimed to compare the clinical, epidemiological, and polysomnographic features of rapid eye movement (REM)-dependent obstructive sleep apnea syndrome (OSAS) and positional OSAS which are two separate clinical entities. METHODS: Between January 2014 and December 2015, at the Akdeniz University Medical Faculty Hospital, patients who were diagnosed REM-dependent and positional OSAS with polysomnography were retrospectively studied. RESULTS: In this study, 1727 patients were screened consecutively. Five hundred and eighty-four patients were included in the study. Of the patients, 24.6% (140) were diagnosed with REM dependent OSAS and 75.4% (444) were diagnosed as positional OSAS. Female predominance was found in REM-dependent OSAS (P < 0.001). The mean total apnea hypopnea index (AHI), non-REM AHI, and supine AHI in REM-dependent OSAS were 14.73, 9.24, and 17.73, respectively, and these values were significantly lower when compared with positional OSAS (P < 0.001). Patients diagnosed with REM dependent OSAS had a statistically significant tendency to be overweight (P < 0.001). For REM-dependent OSAS, total pulse rate, supine pulse rate, and REM pulse rate were statistically higher than positional OSAS (P < 0.001). CONCLUSION: Positional OSAS is a clinical entity that is more common than REM dependent OSAS. OSAS severity is higher in positional OSAS than REM-dependent OSAS. REM-dependent OSAS is observed more commonly in women. PMID- 29387257 TI - Deciphering a case of pulmonary hypertension in a young female: Partial anomalous pulmonary venous drainage the culprit. AB - Partial anomalous pulmonary venous drainage (PAPVD) is a rare congenital cardiac defect and is associated with sinus venosus atrial septal defect. While most cases are asymptomatic, a patient can present with pulmonary hypertension (PHTN) and it can be difficult to diagnose. Here, we discuss the case of a young female with PHTN who was found to have two right-sided PAPVD. Through this case, authors try to emphasize the importance of meticulous and thorough investigation when evaluating PHTN, which allows for correct diagnosis and a timely intervention before PHTN becomes irreversible. PMID- 29387258 TI - Description of a new rare alpha-1 antitrypsin mutation in Naples (Italy): PI*M S Napoli. AB - Alpha-1 antitrypsin deficiency is a rare and often underdiagnosed hereditary disorder, which mainly affects the Caucasian population. We report a case of a noncystic fibrosis bronchiectasis patient in the absence of emphysema associated with low serum alpha-1-antitrypsin (AAT) level, in the absence of the most common defective alleles associated with AAT deficiency (PI*S and PI*Z) but with a new mutation in heterozygosis. This mutation is characterized by the substitution in the coding region of exon 3, of a guanine (G) for a thymine (T), generating the replacement of a glutamine (Gln) by a histidine (His) in codon 212 (cod 212 GlnCAG > HisCAT), corresponds to a new S allelic variant. This mutation, never identified before, is called S-Napoli. PMID- 29387259 TI - Consultation time for the pulmonary patient. PMID- 29387256 TI - The effects of diurnal intermittent fasting on the wake-promoting neurotransmitter orexin-A. AB - BACKGROUND: Food restriction has been demonstrated to increase the alertness in different species and to increase the levels of the wake-promoting neurotransmitter orexin. We hypothesized that diurnal intermittent fasting (DIF) increases orexin-A levels during fasting. Therefore, we conducted this study to assess the effects of DIF, during the month of Ramadan, on orexin, while controlling for lifestyle changes that may accompany Ramadan such as sleep duration, bedtime and wake time, energy expenditure, light exposure, and food. METHODS: Eight young healthy volunteers (mean age, 25.4 +/- 3.5 years) reported to the laboratory on three occasions: (1) 4 weeks before Ramadan while performing DIF for 1 week outside the month of Ramadan (fasting outside Ramadan); (2) 1 week before Ramadan (nonfasting baseline) (BL); and (3) during the 2nd week of Ramadan while performing DIF (Ramadan). Plasma levels of orexin-A were measured using an enzyme immunoassay five times at 22:00, 02:00, 04:00, 06:00, and 11:00. Caloric intake, light exposure, and sleep schedule were maintained during the participants' stays in the laboratory in the three study periods. RESULTS: Orexin A levels increased in the daytime during fasting and decreased at night compared to BL. The differences in orexin-A levels between DIF and BL were significant at 06:00, 11:00, 22:00, and 02:00. CONCLUSIONS: DIF increases orexin-A levels in the plasma during fasting hours. This finding supports findings from animal studies showing that fasting increases alertness. PMID- 29387260 TI - Pulmonary consequences of hypothyroidism. PMID- 29387261 TI - Duration of antibiotic therapy for critically ill patients with bloodstream infections: A retrospective observational in Saudi Arabia. PMID- 29387262 TI - Exercise or physical activity and cognitive function in adults with type 2 diabetes, insulin resistance or impaired glucose tolerance: a systematic review. AB - Background: Diabetes is an important risk factor for cognitive impairment. Although some studies suggest that physical exercise can minimize age-related cognitive declines or improve brain morphology or function, benefits in diabetes or impaired glucose tolerance are unclear. Therefore, our aim was to evaluate the efficacy of exercise or physical activity on cognition in adults with type 2 diabetes, insulin resistance or impaired glucose tolerance. Methods: An electronic search for studies published from the earliest record until February 2017 was conducted using Medline, EMBASE, SPORTDiscus, CINAHL, and PsycINFO. Any experimental or observational study designs were included, as long as they were conducted in individuals of any age with type 2 diabetes, insulin resistance or impaired glucose tolerance, and they directly examined exercise/physical activity effects on cognitive outcomes or the relationship between changes in cognition and changes in either insulin resistance and glucose homeostasis. Study quality was assessed using the PEDro scale; data on participant and intervention characteristics and outcomes were extracted. Results: Six studies enrolling 2289 participants met the eligibility criteria. Quality was modest and effect sizes variable and mostly small or negligible. Overall, four of the six studies (67%) reported significant benefits of greater exercise/physical activity participation for some aspects of cognition, but only 26% of cognitive outcomes were significant across all trials. Clinical improvements in insulin resistance/glucose homeostasis were related to improvements in cognitive function in three studies. Overall results were inconsistent, with benefits varying across exercise types and cognitive domains. Conclusions: Literature does not provide evidence that physical activity or exercise interventions contribute to a better cognitive function in patients with type 2 diabetes or impaired glucose tolerance. Large-scale, long-term, robust randomized controlled trials are required to determine if exercise improves cognition in this high-risk cohort, and to investigate putative mechanistic links between cognition, body composition, metabolism, and inflammation in diabetes and related metabolic syndromes. PMID- 29387263 TI - Dispositional Mindfulness and Psychological Health: a Systematic Review. AB - Interest in the influence of dispositional mindfulness (DM) on psychological health has been gathering pace over recent years. Despite this, a systematic review of this topic has not been conducted. A systematic review can benefit the field by identifying the terminology and measures used by researchers and by highlighting methodological weaknesses and empirical gaps. We systematically reviewed non-interventional, quantitative papers on DM and psychological health in non-clinical samples published in English up to June 2016, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A literature search was conducted using PsycINFO, PubMED, Medline and Embase, and 93 papers met the inclusion criteria. Within these, three main themes emerged, depicting the relationship between DM and psychological health: (1) DM appears to be inversely related to psychopathological symptoms such as depressive symptoms, (2) DM is positively linked to adaptive cognitive processes such as less rumination and pain catastrophizing and (3) DM appears to be associated with better emotional processing and regulation. These themes informed the creation of a taxonomy. We conclude that research has consistently shown a positive relationship between DM and psychological health. Suggestions for future research and conceptual and methodological limitations within the field are discussed. PMID- 29387264 TI - Mindfulness, Acceptance and Defusion Strategies in Smokers: a Systematic Review of Laboratory Studies. AB - The psychological flexibility model (PFM) provides a framework for understanding and treating behavioural dysregulation in addictions. Rather than modulating the intensity of subjective experience, interventions based on, or consistent with, the PFM (PFM interventions) seek to alter the individual's relationship to internal states, such as craving, negative affect and drug-related thoughts, using mindfulness, acceptance and related strategies. Experimental (non-clinical) studies in smokers have examined the effects of specific isolated strategies informed by or consistent with the PFM (PFM strategies). Here, we systematically review these studies and determine the extent to which they conform to methodological standards indicative of high levels of internal validity. Eligible studies were identified through electronic database searches and assessed for the presence of specific methodological features. Provisional aggregate effect sizes were determined depending on availability of data. Of 1499 screened publications, 12 met the criteria. All examined aspects of private subjective experience relevant to abstinence (craving n = 12; negative affect n = 10), demonstrating effects favouring PFM strategies relative to inactive control conditions. However, only six assessed outcome domains consistent with the PFM and provided no consistent evidence favouring PFM strategies. Overall, most studies had methodological limitations. As such, high-quality experimental studies continue to be needed to improve our understanding of necessary and/or sufficient constituents of PFM-guided smoking cessation interventions. Recommendations for future research are discussed. PMID- 29387265 TI - Impact of Mindfulness-Based Teacher Training on MBSR Participant Well-Being Outcomes and Course Satisfaction. AB - Growing interest in mindfulness-based programs (MBPs) has resulted in increased demand for MBP teachers, raising questions around safeguarding teaching standards. Training literature emphasises the need for appropriate training and meditation experience, yet studies into impact of such variables on participant outcomes are scarce, requiring further investigation. This feasibility pilot study hypothesised that participant outcomes would relate to teachers' mindfulness-based teacher training levels and mindfulness-based teaching and meditation experience. Teachers (n = 9) with different MBP training levels delivering mindfulness-based stress reduction (MBSR) courses to the general public were recruited together with their course participants (n = 31). A teacher survey collected data on their mindfulness-based teacher training, other professional training and relevant experience. Longitudinal evaluations using online questionnaires measured participant mindfulness and well-being before and after MBSR and participant course satisfaction. Course attendees' gains after the MBSR courses were correlated with teacher training and experience. Gains in well being and reductions in perceived stress were significantly larger for the participant cohort taught by teachers who had completed an additional year of mindfulness-based teacher training and assessment. No correlation was found between course participants' outcomes and their teacher's mindfulness-based teaching and meditation experience. Our results support the hypothesis that higher mindfulness-based teacher training levels are possibly linked to more positive participant outcomes, with implications for training in MBPs. These initial findings highlight the need for further research on mindfulness-based teacher training and course participant outcomes with larger participant samples. PMID- 29387266 TI - Efficacy of a Mindfulness-Based Mobile Application: a Randomized Waiting-List Controlled Trial. AB - Although several hundreds of apps are available that (cl)aim to promote mindfulness, only a few methodologically sound studies have evaluated the efficacy of these apps. This randomized waiting-list controlled trial therefore tested the hypothesis that one such app (the VGZ Mindfulness Coach) can achieve immediate and long-term improvements of mindfulness, quality of life, general psychiatric symptoms, and self-actualization. One hundred ninety-one experimental participants received the VGZ Mindfulness Coach, which offers 40 mindfulness exercises and background information about mindfulness without any form of therapeutic guidance. Compared to 186 control participants, they reported large (Cohen's d = 0.77) and statistically significant increases of mindfulness after 8 weeks and small-to-medium increases of the Observing, Describing, Acting with awareness, Nonjudging, and Nonreactivity mindfulness facets as measured with the Five Facet Mindfulness Questionnaire (Cohen's d = 0.66, 0.26, 0.49, 0.34, and 0.43, respectively). Also, there were large decreases of general psychiatric symptoms (GHQ-12; Cohen's d = -0.68) and moderate increases of psychological, social, and environmental quality of life (WHOQOL-BREF; Cohen's d = 0.38, 0.38, and 0.36, respectively). Except for social quality of life, these gains were maintained for at least 3 months. We conclude that it is possible to achieve durable positive effects on mindfulness, general psychiatric symptoms, and several aspects of quality of life at low costs with smartphone apps for mindfulness such as the VGZ Mindfulness Coach. PMID- 29387267 TI - A Randomised Controlled Trial of a Brief Online Mindfulness-Based Intervention on Paranoia in a Non-Clinical Sample. AB - Paranoia is common and distressing in the general population and can impact on health, emotional well-being and social functioning, such that effective interventions are needed. Brief online mindfulness-based interventions (MBIs) have been shown to reduce symptoms of anxiety and depression in non-clinical samples; however, at present, there is no research investigating whether they can reduce paranoia. The current study explored whether a brief online MBI increased levels of mindfulness and reduced levels of paranoia in a non-clinical population. The mediating effect of mindfulness on any changes in paranoia was also investigated. One hundred and ten participants were randomly allocated to either a 2-week online MBI including 10 min of daily guided mindfulness practice or to a waitlist control condition. Measures of mindfulness and paranoia were administered at baseline, post-intervention and 1-week follow-up. Participants in the MBI group displayed significantly greater reductions in paranoia compared to the waitlist control group. Mediation analysis demonstrated that change in mindfulness skills (specifically the observe, describe and non-react facets of the FFMQ) mediated the relationship between intervention type and change in levels of paranoia. This study provides evidence that a brief online MBI can significantly reduce levels of paranoia in a non-clinical population. Furthermore, increases in mindfulness skills from this brief online MBI can mediate reductions in non-clinical paranoia. The limitations of the study are discussed. PMID- 29387268 TI - Compassion for Others and Self-Compassion: Levels, Correlates, and Relationship with Psychological Well-being. AB - Compassion for others and self-compassion are assumed to be closely related concepts. Yet, as they have been mostly studied separately, little is known about their relationship and to what extent they differ or resemble each other with respect to their correlates. This cross-sectional study aimed to gain knowledge on their mean levels, interrelationship, and relationships to psychological well being and demographic factors. A community sample of 328 adults completed a series of standardized self-report questionnaires to assess compassion for others, self-compassion, depressive symptoms, negative affect, and positive affect. Results showed that compassion for others and self-compassion were not significantly related. Self-compassion was more strongly related to negative and positive indicators of affect than compassion for others. Compassion for others was higher in women than in men, and in low educated individuals compared to higher educated individuals. In contrast, self-compassion was lower in low educated individuals. Future research can build up on these findings to enlarge the understanding of how compassion for others and self-compassion relate and differ from each other. PMID- 29387269 TI - Inflammatory Markers and Plasma Lipids in HIV Patients: A Correlation Analysis Study. AB - Background: Recent evidence suggests that HIV infection, even with treatment, increases the risk of coronary heart disease (CHD) and that both chronic inflammation and traditional risk factors play key roles in HIV-associated CHD. Subjects and Methods: Patients (N=152), attending Harare HIV clinic, 26% of them male and 82% of them on antiretroviral therapy (ART), were studied. Inflammatory markers comprising of cytokines such as pro-inflammatory tumor necrosis factor alpha, (TNF-alpha), anti-inflammatory interleukin 10, (IL-10) and highly sensitive C reactive protein (hsCRP) together with lipids were assayed using enzyme linked immunosorbent assay (ELISA), immuno-turbidimetric and enzymatic assays, respectively. Correlation analysis of inflammatory markers versus lipid profiles was carried out using bivariate regression analysis. Results: Anti inflammatory cytokine IL-10 and inflammatory hsCRP levels were elevated when measured in all the HIV positive patients, while TNF-alpha and lipid levels were within normal ranges. Pro-inflammatory TNF-alpha was significantly higher in ART naive patients than ART-experienced patients, whereas the reverse was observed for anti-inflammatory IL-10 and anti-atherogenic HDL-C. Correlation analysis indicated a significant positive linear association between IL-10 and total cholesterol (TC) levels but no other correlations were found. Conclusion: High cytokine ratio (TNF-alpha/IL-10) indicates higher CHD risk in ART-naive patients compared to the ART-exposed. The CHD risk could be further strengthened by interplay between inflammatory markers and high prevalence of low HDL-C. Lack of correlation between pro-inflammatory markers (hsCRP and TNF-alpha) with lipid fractions and correlation between anti-inflammatory IL-10 with artherogenic TC were unexpected findings, necessitating further studies in future. PMID- 29387271 TI - Molecular Docking, Pharmacophore, and 3D-QSAR Approach: Can Adenine Derivatives Exhibit Significant Inhibitor Towards Ebola Virus? AB - Introduction: Ebola Virus Disease (EVD) is caused by Ebola virus, which is often accompanied by fatal hemorrhagic fever upon infection in humans. This virus has caused the majority of deaths in human. There are no proper vaccinations and medications available for EVD. It is pivoting the attraction of scientist to develop the potent vaccination or novel lead to inhibit Ebola virus. Methods & Materials: In the present study, we developed 3D-QSAR and the pharmacophoric model from the previous reported potent compounds for the Ebola virus. Results & Discussion: Results & Discussion: The pharmacophoric model AAAP.116 was generated with better survival value and selectivity. Moreover, the 3D-QSAR model also showed the best r2 value 0.99 using PLS factor. Thereby, we found the higher F value, which demonstrated the statistical significance of both the models. Furthermore, homological modeling and molecular docking study were performed to analyze the affinity of the potent lead. This showed the best binding energy and bond formation with targeted protein. Conclusion: Finally, all the results of this study concluded that 3D-QSAR and Pharmacophore models may be helpful to search potent lead for EVD treatment in future. PMID- 29387270 TI - Plasma L-Carnitine and L-Lysine Concentrations in HIV-Infected Patients. AB - Background: Virus infections are associated with significant alterations in host cells amino acids profiles that support biosynthetic demands necessary for production of viral progeny. Amino acids play an important role in the pathogenesis of all virus-related infections both as basic substrates for protein synthesis and as regulators in many metabolic pathways. Objective: Our aim was to determine the changes in plasma L-carnitine levels and its amino acid precursor (L-lysine) in HIV-infected patients. Methods: We performed a case-control study of 430 HIV-1 infected males (non-vegetarians) without any restriction in the nourishment, before highly active antiretroviral therapy (HAART) and 125 HIV-1 subjects after the introduction of HAART who were periodically monitored in the Municipal Center of HIV/AIDS prophylaxis, Surgut, Russian Federation. Results: The plasma total (TC) and free (FC) L-carnitine concentrations markedly decreased with the clinical stages of HIV infection. The mean plasma TC, FC and L-lysine levels were significantly lower in asymptomatic stage (A) and advanced CDC stages (B, C) HIV-infected patients compared with our reference values. The total and free L-carnitine and its amino acid precursor concentrations mild increased in HIV-infected subjects after the introduction of HAART.Our data revealed that L lysine amino acid and its derivative (TC) levels were negatively correlated with viral load and inversely with CD4 count lymphocytes in the total cohort. Conclusion: The study results show that there was evidence for an association between plasma L-carnitine, L-lysine and HIV-1 RNA levels, immunological markers and clinical stages of HIV infection. The obtained data indicate that level changes of these host essential nutritional elements can play an important role in the HIV life cycle. These findings are important for understanding the pathophysiology of HIV infection and must be considered in further research for the development of new approaches in the treatment of the disease. PMID- 29387272 TI - Effects on Sperms' Quality of Selegiline in Aged Rats. AB - Background: Selegiline is used to treat Parkinsonian patients. Other indications of its use have recently been discovered. Objective: Scouting special and beneficial side effects of selegiline treatment. Method: Two-year old male Wistar rats were daily treated with 0.25 mg/kg of selegiline s.c. (subcutaneous injection). The rats were sacrificed following a four-weeks' treatment. Results: Mass of testes, number of sperms, progressive motility of sperms, and their viability definitely increased. Conclusion: Selegiline can successfully be used to stop/counterbalance certain symptoms of aging. PMID- 29387273 TI - Prodrugs of NSAIDs: A Review. AB - Intoroduction: Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action. Methods & Materials: The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects. Results: As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs. Conclusion: This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding). PMID- 29387274 TI - Synthesis and Biological Evaluation of Novel Hybrid Molecules Containing Purine, Coumarin and Isoxazoline or Isoxazole Moieties. AB - Introduction: The 1,3-dipolar cycloaddition reactions of nitrile oxides formed in situ (in the presence of NCS and Et3N) from the oximes of (purin-9 yl)acetaldehyde or (coumarinyloxy)acetaldehyde with allyloxycoumarins or 9 allylpurines, respectively resulted in 3,5-disubstituted isoxazolines. The similar reactions of propargyloxycoumarins or 9-propargylpurines led to 3,5 disubstituted isoxazoles by treatment with PIDA and catalytic amount of TFA. Methods: The new compounds were tested in vitro as antioxidant agents and inhibitors of soybean lipoxygenase LO, AChE and MAO-B. Results: The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 4k and 4n presented LO inhibitory activity. Conclusion: Compound 13e presents an antioxidant significant profile combining anti-LO, anti-AChE and anti-MAO-B activities. PMID- 29387275 TI - Ezqsar: An R Package for Developing QSAR Models Directly From Structures. AB - Background: Quantitative Structure Activity Relationship (QSAR) is a difficult computational chemistry approach for beginner scientists and a time consuming one for even more experienced researchers. Method and Materials: Ezqsar which is introduced here addresses both the issues. It considers important steps to have a reliable QSAR model. Besides calculation of descriptors using CDK library, highly correlated descriptors are removed, a provided data set is divided to train and test sets, descriptors are selected by a statistical method, statistical parameter for the model are presented and applicability domain is investigated. Results: Finally, the model can be applied to predict the activities for an extra set of molecules for a purpose of either lead optimization or virtual screening. The performance is demonstrated by an example. Conclusion: The R package, ezqsar, is freely available via https://github.com/shamsaraj/ezqsar, and it runs on Linux and MS-Windows. PMID- 29387276 TI - The Effect of Strain Hardening on the Dynamic Response of Human Artery Segments. AB - Background: When subjected to time-dependent blood pressure, human arteries undergo large deformations, exhibiting mainly nonlinear hyperelastic type of response. The mechanical response of arteries depends on the health of tissues that comprise the artery walls. Typically, healthy arteries exhibit convex strain hardening under tensile loads, atherosclerotic parts exhibit stiffer response, and aneurysmatic parts exhibit softening response. In reality, arterial dynamics is the dynamics of a propagating pulse, originating in heart ventricle, propagating along aorta, bifurcating, etc. Artery as a whole cannot be simulated as a lump ring, however its cross section can be simulated as a vibrating ring having a phase lag with respect to the other sections, creating a running pressure wave. A full mathematical model would require fluid-solid interaction modeling continuity of blood flow in a compliant vessel and a momentum equation. On the other hand, laboratory testing often uses small-length arteries, the response of which is covered by the present work. In this way, material properties that change along the artery length can be investigated. Objective: The effect of strain hardening on the local dynamic response of human arteries (excluding the full fluid-structure interaction) is examined through appropriate hyperelastic models related to the health condition of the blood vessel. Furthermore, this work aims at constituting a basis for further investigation of the dynamic response of arteries accounting for viscosity. Method: The governing equation of motion is formulated for three different hyperelastic material behaviors, based on the constitutive law proposed by Skalak et al., Hariton, and Mooney-Rivlin, associated with the hardening behavior of healthy, atherosclerotic, and aneurysmatic arteries, respectively. The differences between these modelling implementations are caused by physiology, since aneurysmatic arteries are softer and often sclerotic arteries are stiffer than healthy arteries. The response is investigated by proper normalization of the involved material parameters of the arterial walls, geometry of the arteries, load histories, time effects, and pre-stressing. The effect of each problem parameter on the arterial response has been studied. The peak response of the artery segment is calculated in terms of radial displacements, principal elongations, principal stresses, and strain-energy density. The validity of the proposed analytical models is demonstrated through comparison with previous studies that investigate the dynamic response of arterial models. Results: Important metrics that can be useful to vascular surgery are the radial deformation and the maximum strain-energy density along with the radial resonance frequencies. These metrics are found to be influenced heavily by the nonlinear strain-hardening characteristics of the model and the longitudinal pre-stressing. Conclusion: The proposed formulation permits a systematic and generalizable investigation, which, together with the low computational cost of analysis, makes it a valuable tool for calculating the response of healthy, atherosclerotic, and aneurysmatic arteries. The radial resonance frequencies can explain certain murmures developed in stenotic arteries. PMID- 29387278 TI - Khat (Catha Edulis) as a Risk Factor for Cardiovascular Disorders: Systematic Review and Meta-Analysis. AB - Background: About 20 million people worldwide are believed to be using khat. Although some studies reported that khat chewing might result in cardiovascular disorders, conclusive evidence is limited. Method: The objective of this review was to synthesize the best available evidence for the effect of khat on the cardiovascular system. Databases searched were PubMed, Cochrane database of systematic reviews, CINAHL, poplin, LILACS, MedNar and Scopus. All papers included in the review were subjected to rigorous appraisal using the Joanna Briggs Institute (JBI) standardized critical appraisal tool. Review Manager Software (Revman 5.3) was used for meta-analysis and effect size and the 95% confidence interval (CI) was calculated. Result: Data was extracted from 10 articles. Our meta-analysis included 9,207 subjects, (2123 chewers and 7084 non chewers, respectively) to elucidate the effect of khat on heart rate, diastolic and systolic blood pressure. The mean diastolic and systolic blood pressure of khat chewers was higher than the non-chewers with a mean difference of 5.1 mmHg, 95%CI [2.7,7.5] and 7.9 mmHg, 95%CI [2.65, 13.18], respectively. Similarly, the heart rate of the chewers remained consistently higher, making the mean difference of 6.9 beats/min, 95%CI [0.5, 13.3]. In addition, khat was found to have either a causative or worsening effect on stroke, myocardial infarction and heart failure. Conclusion: We showed that khat chewing could significantly affect the cardiovascular system through its effect on heart rate and blood pressure. Therefore, health promotion should be aimed to encourage quitting khat chewing. PMID- 29387277 TI - The Role of Echocardiography in the Optimization of Cardiac Resynchronization Therapy: Current Evidence and Future Perspectives. AB - Background: Cardiac resynchronization therapy (CRT) has become a mainstay in the management of heart failure. Up to one-third of patients who received resynchronization devices do not experience the full benefits of CRT. The clinical factors influencing the likelihood to respond to the therapy are wide QRS complex, left bundle branch block, female gender, non-ischaemic cardiomyopathy (highest responders), male gender, ischaemic cardiomyopathy (moderate responders) and narrow QRS complex, non-left bundle branch block (lowest, non-responders). Objective: This review provides a conceptual description of the role of echocardiography in the optimization of CRT. Method: A literature survey was performed using PubMed database search to gather information regarding CRT and echocardiography. Results: A total of 70 studies met selection criteria for inclusion in the review. Echocardiography helps in the initial selection of the patients with dyssynchrony, which will benefit the most from optimal biventricular pacing and provides a guide to left ventricular (LV) lead placement during implantation. Different echocardiographic parameters have shown promise and can offer the possibility of patient selection, response prediction, lead placement optimization strategies and optimization of device configurations. Conclusion: LV ejection fraction along with specific electrocardiographic criteria remains the cornerstone of CRT patient selection. Echocardiography is a non-invasive, cost-effective, highly reproducible method with certain limitations and accuracy that is affected by measurement errors. Echocardiography can assist with the identification of the appropriate electromechanical substrate of CRT response and LV lead placement. The targeted approach can improve the haemodynamic response, as also the patient-specific parameters estimation. PMID- 29387279 TI - Pulmonary Artery Hypertension and Related Complications Associated to Left Atrial Myxoma. PMID- 29387280 TI - Omega-3 Hastens and Omega-6 Delays the Progression of Neuropathology in a Murine Model of Familial ALS. AB - Background: Amyotrophic lateral sclerosis (ALS) is a progressive disease of motor neurons that has no cure or effective treatment. Any approach that could sustain minor motor function during terminal stages would improve quality of life. Objective: We examined the impact of omega-3 (Omega-3) and Omega-6, on motor neuron function in mice expressing mutant human superoxide dismutase-1 (SOD-1), which dominantly confers familial ALS and induces a similar sequence of motor neuron decline and eventual death when expressed in mice. Method: Mice received standard diets supplemented with equivalent amounts of Omega-3 and Omega-6 or a 10x increase in Omega-6 with no change in Omega-3 commencing at 4 weeks of age. Motor function and biochemical/histological parameters were assayed by standard methodologies. Results: Supplementation with equivalent Omega-3 and Omega-6 hastened motor neuron pathology and death, while 10x Omega-6 with no change in Omega-3 significantly delayed motor neuron pathology, including preservation of minor motor neuron function during the terminal stage. Conclusion: In the absence of a cure or treatment, affected individuals may resort to popular nutritional supplements such as Omega-3 as a form of "self-medication". However, our findings and those of other laboratories indicate that such an approach could be harmful. Our findings suggest that a critical balance of Omega-6 and Omega-3 may temporarily preserve motor neuron function during the terminal stages of ALS, which could provide a substantial improvement in quality of life for affected individuals and their caregivers. PMID- 29387281 TI - A Cohort Study of the Patterns of Third Molar Impaction in Panoramic Radiographs in Saudi Population. AB - Objectives: To evaluate the epidemiological patterns of third molar impaction in a cohort of patients living in the north of Saudi Arabia. Materials and Methods: A retrospective cohort study comprised of analysing 2550 Orthopantomograms (OPGs) belonging to patients who attended Aljouf University College of Dentistry between September 2013 and December 2015. OPGs were examined to determine the frequency of third molar impaction, their levels of eruption and angulations. Mixed effects logistic regression analysis was performed to calculate adjusted odds ratios. Data were weighted by age and sex based on population regional estimates. Results: 1551 patients (60.8%) with a mean age of 33.5 years-old (95%CI: 32.9 to 34) demonstrated 2650 impacted third molars. Third molars were more likely present in patients aged from 20 to 39 years-old (p<0.001); and in mandible more than maxilla (p<0.001). It showed highest vertical impaction and higher impaction rate in mandible than maxilla. Level A impaction was the most common among other levels by 1365 (53.5%). Vertical impaction was the most common pattern (1354 patients; 53.1%). Mesioangular impaction ranked second in mandible, while distoangular impaction ranked second in maxilla. There was no statistically significant difference between males and females concerning impaction frequency, depth levels and angulations. Conclusion: Impacted third molars is still a public health concern among youth and young adults. Vertically impacted mandibular third molars with their occlusal plane at the same level as the occlusal plane of adjacent tooth is the most prevalent pattern of third molar impaction in the northern region of Saudi Arabia. PMID- 29387283 TI - Bilateral Elongated Mandibular Coronoid Process and Restricted Mouth Opening: A Case Report. AB - Introduction: Mandibular coronoid process hyperplasia is an uncommon congenital or developmental temporomandibular joint disorder, characterized by elongation of the coronoid process, which may cause limited mandibular movement as a consequence of interference between the hyperplastic coronoid process and the medial surface of the zygomatic arch. Methods: Mandibular coronoid process hyperplasia commonly affects males in the second decade of life and the exact aetiology and pathogenesis is unknown. The condition can be uni- or bilateral. Progressive painless reduction in mouth opening is the main clinical finding and computed tomography is the most reliable imaging modality for confirming the diagnosis. Results: Surgical intervention involving coronoidectomy and long-term intensive postoperative physiotherapy is the treatment of choice for mandibular coronoid process hyperplasia with impingement on the zygomatic bone and limited mouth opening. However, surgically induced fibrosis and the tendency for mandibular coronoid process regrowth may cause relapse and renewed limited mouth opening. Vigorous physical therapy should therefore be initiated shortly after surgery. Conclusion: The purpose of this case report is to present the clinical and radiographic features of elongated mandibular coronoid process in an 18-year old male with limited mouth opening, and to discuss the various surgical treatment modalities. PMID- 29387282 TI - A Review Over Benefits and Drawbacks of Combining Sodium Hypochlorite with Other Endodontic Materials. AB - Introduction: As the root canal system considered to be complex and unpredictable, using root canal irrigants and medicaments are essential in order to enhance the disinfection of the canal. Sodium hypochlorite is the most common irrigant in endodontics. Despite its excellent antimicrobial activity and tissue solubility, sodium hypochlorite lacks some important properties such as substantivity and smear layer removing ability. Objective: The aim of this review was to address benefits and drawbacks of combining sodium hypochlorite with other root canal irrigants and medicaments. Discussion: According to the reviewed articles, NaOCl is the most common irrigation solution in endodontics. However, it has some drawbacks such as inability to remove smear layer. One of the drawbacks of NaOCl is its inability to remove the smear layer and lack of substantivity. Conclusion: The adjunctive use of other materials has been suggested to improve NaOCl efficacy. Nevertheless, further studies are required in this field. PMID- 29387284 TI - Correlation with Caries Lesion Depth of The Canary System, DIAGNOdent and ICDAS II. AB - Introduction: The aim of this study was to correlate lesion depth of natural caries, measured with Polarized Light Microscopy (PLM), to Canary Numbers (CN) derived from The Canary SystemTM (CS), numerical readings from DIAGNOdent (DD), and lesion scores from ICDAS II. Methods: A total of 20 examination sites on extracted human molars and premolars were selected. The selected examination sites consisted of healthy and enamel caries on smooth and occlusal surfaces of each tooth. Two blinded dentists ranked each examination site using ICDAS II and the consensus score for each examined site was recorded. The same examination sites were scanned with CS and DD, and the CN and DD readings were recorded. After all the measurements were completed, the readings of the three caries detection methods were validated with a histological method, Polarized Light Microscopy (PLM). PLM performed by blinded examiners was used as the 'gold standard' to confirm the presence or absence of a caries lesion within each examined site and to determine caries lesion depth. Results: Pearson's coefficients of correlation with caries lesion depth of CNs, DD readings and ICDAS scores were 0.84, 0.21 and 0.77, respectively. Mean +/- SD CN for sound sites (n=3), caries lesion depths <800 um (n=11), and caries lesion depths >800 um (n=6) were 11+/-1, 55+/-15, and 75+/-22, respectively. Mean +/- SD DD readings for sound sites, caries lesion depths <800 um, and caries lesion depths >800 um were 1+/-1, 7+/-11, and 8+/-9, respectively. Mean +/- SD ICDAS II scores for sound sites, caries lesion depths <800 um, and caries lesion depths >800 um were 0+/-0, 2+/-1, and 2+/-1, respectively. The intra-operator repeatability for the Canary System was .953 (0.913, 0.978). Conclusion: This study demonstrated that the CS exhibits much higher correlation with caries lesion depth compared to ICDAS II and DD. CS may provide the clinician with more information about the size and position of the lesion which might help in monitoring or treating the lesion.The present extracted tooth study found that The Canary System correlates with caries lesion depth more accurately that ICDAS II and DIAGNOdent. PMID- 29387285 TI - Evaluation of Breath-Holding Test in Assessment of Peripheral Chemoreflex Sensitivity in Patients with Chronic Heart Failure. AB - Background: The sensitivity of peripheral chemoreflex is a marker of the severity of heart failure and the prognosis of the outcome in these patients. The assessment of chemosensitivity in these patients remains an actual problem. Objective: The aim of the study was to explore the relationship between a Breath Holding Test (BHT) and single-breath carbon dioxide test and to evaluate the reliability of both tests in patients with Heart Failure (HF). Method: The study was performed in 43 patients with chronic heart failure. All subjects underwent BHT and single-breath carbon dioxide (CB-CO2), the evaluation of both tests was repeated a month later. Relationship of two test was evaluated by correlation analysis. Reliability was assessed with calculation of Standard Error of Measurement (SEM), Coefficient of Variation (CV) and Intraclass Correlation Coefficient (ICC). Results: The duration of the breath-holding was inversely correlated to the result of CB-CO2 test (r = -0.86 at first measurement and r = 0.79 after a month) The ICC was 0.87 (95%CI: 0.78-0.93) for SB-CO2 test and 0,93 (95%CI: 0.88-0.96) for BHT, the CV was 24% for SB-CO2 and 13% for BHT. SEM for SB CO2 test was 0.04 L / min / mmHg and limits of variation was 0.11 L / min / mmHg; SEM for BHT was 3.6 sec and limits of variation was10 sec. Conclusion: Breath holding test is a reliable and safe method for assessing the sensitivity of peripheral chemoreflex to carbon dioxide in patients with heart failure. PMID- 29387286 TI - Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA. AB - Background: Early treatment of rheumatoid arthritis (RA) results in better long term outcomes. However, the optimal therapeutic window has not been clearly established. Objective: To determine the clinical outcome of Puerto Ricans with RA receiving early treatment with conventional and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) based on the American College of Rheumatology (ACR) definition of early RA. Methods: A cross-sectional study was performed in a cohort of Puerto Ricans with RA. Demographic features, clinical manifestations, disease activity, functional status, and pharmacotherapy were determined. Early treatment was defined as the initiation of DMARDs (conventional and/or biologic) in less than 6 months from the onset of symptoms attributable to RA. Patients who received early (< 6months) and late (>=6 months) treatments were compared using bivariate and multivariate analyses. Results: The cohort comprised 387 RA patients. The mean age at study visit was 56.0 years. The mean disease duration was 14.9 years and 337 (87.0%) patients were women. One hundred and twenty one (31.3%) patients received early treatment. In the multivariate analysis adjusted for age and sex, early treatment was associated with better functional status, lower probability of joint deformities, intra-articular injections and joint replacement surgeries, and lower scores in the physician's assessments of global health, functional impairment and physical damage of patients. Conclusion: Using the ACR definition of early RA, this group of patients treated with DMARDs within 6 months of disease had better long-term outcomes with less physical damage and functional impairment. PMID- 29387287 TI - Postoperative Evaluation of Health-Related Quality-of-Life (HRQoL) of Patients With Lumbar Degenerative Spondylolisthesis After Instrumented Posterolateral Fusion (PLF): A prospective Study With a 2-Year Follow-Up. AB - Background: Several studies have compared instrumented PLF with other surgical approaches in terms of clinical outcomes, however little is known about the postoperative HRQoL of patients, especially as regards to degenerative spondylolisthesis. Methods: A group of 62 patients, 30 women (48,4%) and 32 men (51,6%) with mean age 56,73 (SD +/- 9,58) years old, were selected to participate in a 2-year follow-up. Their pain was assessed via the visual analogue scale (VAS) for low back pain (VASBP) and leg pain (VASLP) separately. Their HRQoL was evaluated by the Short Form (36) Health Survey (SF-36). Both scales, VAS and SF36, were measured and re-assessed at 10 days, 1 month, 3 months, 6 months, 12 months and 2 years. Results: VASBP, VASLP and each parameter of SF36 presented statistically significant improvement (p<0.01). VASBP, VASLP and SF36 scores did not differ significantly between men and women (p>=0.05). The most notable amelioration of VASBP, VASLP was observed within the first 10 days and the maximum improvement within the first 3 months. From that point, a stabilization of the parameters was observed. The majority of SF36 parameters, and especially PF (physical functioning) and BP (bodily pain), presented statistically significant improvement within the follow up depicting a very similar improvement pattern to that of VAS. Conclusion: We conclude that instrumented PLF ameliorates impressively the HRQoL of patients with degenerative spondylolisthesis after 2 years of follow-up, with pain recession being the most crucial factor responsible for this improvement. PMID- 29387288 TI - Accuracy of Component Orientation and Leg Length Adjustment in Total Hip Arthroplasty Using Image-free Navigation. AB - Purpose: The purpose of this study was to examine the accuracy of implant orientation and leg length in total hip arthroplasty (THA) with an image-free navigation system based on a comparison of the intraoperative navigation and postoperative CT evaluations. Material and Methods: A consecutive series of 111 patients (118 hips) who underwent THA using the current version of the image-free navigation system constituted the basic study population. Subsequently, a total of 101 patients (108 hips) meeting the inclusion and exclusion criteria were selected as study subjects for the analysis. THA was performed using an image free navigation system that was capable of adjusting both the prosthetic position and leg length. Postoperative CT examination was performed for all study subjects, and the prosthetic position and leg length were measured on CT images using the image analysis software. Subsequently, the intraoperative navigation results and the corresponding values obtained from the postoperative CT measurements were compared to test the accuracy of the navigation system. Results: The average discrepancies between the intra- and postoperative assessments were 6.8 degrees , 3.7 degrees , and 5.7 degrees for cup anteversion, cup inclination, and stem anteversion, respectively. The corresponding value in leg length averaged 4.1 mm. Conclusion: Average discrepancies between the intra- and postoperative measurements were less than 10 degrees in all prosthetic alignment parameters and less than 5 mm in leg length. Intraoperative assessments with the use of the image-free navigation in THA could afford satisfactory result. PMID- 29387289 TI - Pain and Opioid use Outcomes Following Minimally Invasive Sacroiliac Joint Fusion with Decortication and Bone Grafting: The Evolusion Clinical Trial. AB - Purpose: This report documents six-month results of the first 50 patients treated in a prospective, multi-center study of a minimally invasive (MI) sacroiliac (SI) joint fusion system. Patients and Methods: This cohort includes 50 patients who had MI SI joint fusion surgery and completed 6 month follow-up. Average age at baseline was 61.5, 58% were female, and SI joint-related pain duration was >=2yrs in 54.0% of patients. Visual Analog Scale (VAS) SI joint pain, Oswestry Disability Index (ODI), quality of life and opioid use were assessed preoperatively and at 6 months. Results: At 6 months, mean VAS pain demonstrated a significant reduction from 76.2 at baseline to 35.1 (54% reduction, p<0.0001), with 72% of patients attaining the minimal clinically important difference (MCID, >=20 point improvement). Mean ODI improved from 55.5 to 35.3 at 6 months (p < 0.001), with 56% of patients achieving the MCID (>=15 point improvement). Prior to surgery 33/50 (66%) of patients were taking opioids, but by 6 months the number of patients taking opioids had decreased by 55% to 15/50 (30%). Few procedural complications were reported. Two procedure-related events required hospitalization: a revision procedure (2%) for nerve impingement and one case of ongoing low back pain. Conclusion: Analysis of patients treated with MI SI joint fusion using the SImmetry System demonstrated that the procedure can be performed safely and results in significant improvements in pain, disability, and opioid use at 6 months. Longer term follow-up in this study will determine whether these improvements are durable, as well as the associated radiographic fusion rates. PMID- 29387290 TI - The MAX Statistic is Less Powerful for Genome Wide Association Studies Under Most Alternative Hypotheses. AB - Genotypic association studies are prone to inflated type I error rates if multiple hypothesis testing is performed, e.g., sequentially testing for recessive, multiplicative, and dominant risk. Alternatives to multiple hypothesis testing include the model independent genotypic chi2 test, the efficiency robust MAX statistic, which corrects for multiple comparisons but with some loss of power, or a single Armitage test for multiplicative trend, which has optimal power when the multiplicative model holds but with some loss of power when dominant or recessive models underlie the genetic association. We used Monte Carlo simulations to describe the relative performance of these three approaches under a range of scenarios. All three approaches maintained their nominal type I error rates. The genotypic chi2 and MAX statistics were more powerful when testing a strictly recessive genetic effect or when testing a dominant effect when the allele frequency was high. The Armitage test for multiplicative trend was most powerful for the broad range of scenarios where heterozygote risk is intermediate between recessive and dominant risk. Moreover, all tests had limited power to detect recessive genetic risk unless the sample size was large, and conversely all tests were relatively well powered to detect dominant risk. Taken together, these results suggest the general utility of the multiplicative trend test when the underlying genetic model is unknown. PMID- 29387291 TI - A forward-adjoint operator pair based on the elastic wave equation for use in transcranial photoacoustic computed tomography. AB - Photoacoustic computed tomography (PACT) is an emerging imaging modality that exploits optical contrast and ultrasonic detection principles to form images of the photoacoustically induced initial pressure distribution within tissue. The PACT reconstruction problem corresponds to an inverse source problem in which the initial pressure distribution is recovered from measurements of the radiated wavefield. A major challenge in transcranial PACT brain imaging is compensation for aberrations in the measured data due to the presence of the skull. Ultrasonic waves undergo absorption, scattering and longitudinal-to-shear wave mode conversion as they propagate through the skull. To properly account for these effects, a wave-equation-based inversion method should be employed that can model the heterogeneous elastic properties of the skull. In this work, a forward model based on a finite-difference time-domain discretization of the three-dimensional elastic wave equation is established and a procedure for computing the corresponding adjoint of the forward operator is presented. Massively parallel implementations of these operators employing multiple graphics processing units (GPUs) are also developed. The developed numerical framework is validated and investigated in computer19 simulation and experimental phantom studies whose designs are motivated by transcranial PACT applications. PMID- 29387293 TI - Modulation of Multidrug Resistance Gene Expression by Coumarin Derivatives in Human Leukemic Cells. AB - The presence of multidrug resistance (MDR) in tumor cells is considered as the major cause of failure of cancer chemotherapy. The mechanism responsible for the phenomenon of multidrug resistance is explained, among others, as overexpression of membrane transporters primarily from the ABC family which actively remove cytostatics from the tumor cell. The effect of 20 coumarin derivatives on the cytotoxicity and expression of MDR1, MRP1, BCRP, and LRP genes (encoding proteins responsible for multidrug resistance) in cancer cells was analyzed in the study. The aim of this research included determination of IC10 and IC50 values of selected coumarin derivatives in the presence and absence of mitoxantrone in leukemia cells and analysis of changes in the expression of genes involved in multidrug resistance: MDR1, MRP, LRP, and BCRP after 24-hour exposure of the investigated cell lines to selected coumarins in the presence and absence of mitoxantrone in IC10 and IC50 concentrations. The designed research was conducted on 5 cell lines derived from the human hematopoietic system: CCRF/CEM, CEM/C1, HL 60, HL-60/MX1, and HL-60/MX2. Cell lines CEM/C1, HL-60/MX1, and HL-60/MX2 exhibit a multidrug resistance phenotype. PMID- 29387292 TI - Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen-Induced HIF-1-eNOS-NO Pathway. AB - Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid-reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK-FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia-inducible factor 1 (HIF-1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF-1, and kallistatin antisense RNA abolishes oxygen-induced eNOS and HIF-1 expression, indicating a role of kallistatin in mediating mild oxygen's stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF-1-induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin-mediated HIF-1 and eNOS synthesis. In summary, oxidative stress induces down- or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise induced HIF-1-eNOS-NO pathway. PMID- 29387294 TI - Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke. AB - Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke. PMID- 29387295 TI - The Effect of a Short-Term Exposure to Lead on the Levels of Essential Metal Ions, Selected Proteins Related to Them, and Oxidative Stress Parameters in Humans. AB - The present study was designed to explore the possible influence of subacute exposure to lead on the levels of selected essential metals, selected proteins related to them, and oxidative stress parameters in occupationally exposed workers. The study population included 36 males occupationally exposed to lead for 36 to 44 days. Their blood lead level at the beginning of the study was 10.7 +/- 7.67 MUg/dl and increased to the level of 49.1 +/- 14.1 MUg/dl at the end of the study. The levels of calcium, magnesium, and zinc increased significantly after lead exposure compared to baseline by 3%, 3%, and 8%, respectively, while the level of copper decreased significantly by 7%. The malondialdehyde (MDA) level and the activities of catalase (CAT) and superoxide dismutase (SOD) did not change due to lead exposure. However, the level of lipid hydroperoxides (LPH) in serum increased significantly by 46%, while the level of erythrocyte lipofuscin (LPS) decreased by 13%. The serum levels of essential metals are modified by a short-term exposure to lead in occupationally exposed workers. A short-term exposure to lead induces oxidative stress associated with elevated levels of LPH but not MDA. PMID- 29387296 TI - Exercise Training under Exposure to Low Levels of Fine Particulate Matter: Effects on Heart Oxidative Stress and Extra-to-Intracellular HSP70 Ratio. AB - Fine particulate matter (PM2.5) promotes heart oxidative stress (OS) and evokes anti-inflammatory responses observed by increased intracellular 70 kDa heat shock proteins (iHSP70). Furthermore, PM2.5 increases the levels of these proteins in extracellular fluids (eHSP70), which have proinflammatory roles. We investigated whether moderate and high intensity training under exposure to low levels of PM2.5 modifies heart OS and the eHSP70 to iHSP70 ratio (H-index), a biomarker of inflammatory status. Male mice (n = 32), 30 days old, were divided into six groups for 12 weeks: control (CON), moderate (MIT) and high intensity training (HIT), exposure to 5 MUg of PM2.5 daily (PM2.5), and moderate and high intensity training exposed to PM2.5 (MIT + PM2.5 and HIT + PM2.5 groups). The CON and PM2.5 groups remained sedentary. The MIT + PM2.5 group showed higher heart lipid peroxidation levels than the MIT and PM2.5 groups. HIT and HIT + PM2.5 showed higher heart lipid peroxidation levels and lower eHSP70 and H-index levels compared to sedentary animals. No alterations were found in heart antioxidant enzyme activity or iHSP70 levels. Moderate exercise training under exposure to low levels of PM2.5 induces heart OS but does not modify eHSP70 to iHSP70 ratio (H-index). High intensity exercise training promotes anti-inflammatory profile despite exposure to low levels of PM2.5. PMID- 29387297 TI - Smile Train: Making the Grade in Global Cleft Care. AB - The global medical and psychological burden of cleft lip and palate is large, especially in low- and middle-income countries. For decades, medical missions have sought to alleviate this burden; however, there are significant barriers to providing sustainable, high-quality cleft care using the mission model. Smile Train, an international children's charity founded in 1999, has developed a scalable model which provides support to local partner hospitals and surgeons around the world. Smile Train partners with hospitals to support cleft care treatment across the developing world. Partner hospitals are held to strict safety and quality standards. Local or regional providers are primarily used to train medical personnel. A quality assurance process developed by the Smile Train's Medical Advisory Board is used to assess cleft surgery cases and suggest additional review and training as needed. Surgical candidates are systematically evaluated and must meet specific medical criteria to ensure safety. Experienced anesthetists adhere to Smile Train's safety and quality protocols including anesthesia guidelines. Smile Train and its partners have provided more than 1.2 million safe, high-quality cleft surgical treatments since 1999. Smile Train has sponsored more than 3,000 hands-on training opportunities, 30,000 opportunities to participate in cleft conferences, and 40,000 virtual cleft training opportunities. Through rigorous self-governance and its sustainable, scalable model, this organization has elevated the standard of cleft care in the developing world. PMID- 29387299 TI - Psychological Impact of Facial Trauma. AB - Examination of the mental state of patients suffering from facial trauma is rarely ever recorded, let alone screening them for posttraumatic stress disorders (PTSDs) or generalized anxiety disorder. Providing early support to the patient in light of such psychological conditions can improve the overall quality of life. The aim of this study was to perform a literature review to assess the relation of mental state disorders to facial trauma in terms of their prevalence, assess screening methodology, and also to evaluate the prognosis of individuals subjected to psychological intervention/screening at an early stage of clinical examination. Research databases such as ScienceDirect, Google Scholar, PubMed, and Medline were searched using the keywords "psychological trauma," "facial trauma," and "PTSD." Only meta-analyses, systematic reviews, and original research articles in the English language were included in the study. Correspondence to journal editors and clinician opinions were excluded from the study. Out of a total of 459 results, only 8 articles satisfied the inclusion criteria of the study. The literature review showed that patients suffering from orofacial trauma had significantly increased levels of mental state disorders such as PTSD and generalized anxiety disorder, more so in victims of assault. The results of this literature review clearly point toward an increased prevalence of mental state disorders in patients suffering from facial trauma, which warrants for early intervention in this regard to improve the quality of life of these patients. PMID- 29387298 TI - Prosthetics in Facial Reconstruction. AB - Reconstruction of the head and neck can be a challenging undertaking owing to numerous considerations for successful rehabilitation. Although head and neck defects were once considered irretrievably morbid and associated with a poor quality of life, advances in surgical technique has immensely contributed to the well-being of these patients. However, all patients are not suitable surgical candidates and many have sought nonsurgical options for functional and cosmetic restoration. As such, the advent of prostheses has ameliorated those concerns and provided a viable alternative for select patient populations. Prosthetic reconstruction has evolved significantly over the past decade. Advances in biocompatible materials and imaging adjuncts have spurred further discovery and forward progress. A multidisciplinary approach to head and neck reconstruction focused on appropriate expectations and patient-centered goals is most successfully coordinated by a team of head and neck surgeons, maxillofacial surgeons, and prosthetic specialists. The aim of this article is to provide a comprehensive review of the current trends for prosthetic rehabilitation of head and neck defects, and further elaborate on the limitations and advancements in the field. PMID- 29387300 TI - Surgical Anatomy of the Cervical Part of the Hypoglossal Nerve. AB - Iatrogenic injuries to cranial nerves, half of which affect the hypoglossal nerve, occur in up to 20% of surgical procedures involving the neck. The risk of injury could be minimized by in-depth knowledge of its positional and relational anatomy. Forty-one hypoglossal nerves were dissected from cadaveric specimens and positions described in relation to the internal carotid artery (ICA), external carotid artery (ECA), carotid bifurcation, mandible, hyoid bone, mastoid process, and the digastric tendon. The distance of the nerve from where it crossed the ICA and ECA to the carotid bifurcation was 29.93 (+/-5.99) mm and 15.19 (+/-6.68) mm, respectively. The point where it crossed the ICA was 12.24 (+/-3.71) mm superior to the greater horn of hyoid, 17.16 (+/-4.40) mm inferior to the angle of the mandible, and 39.08 (+/-5.69) mm from tip of the mastoid. The hypoglossal nerve loop was inferior to the digastric tendon in 73% of the cases. The hypoglossal nerves formed high loops in this study population. Caution should be exercised during surgical procedures in the neck. The study also revealed that the mastoid process is a reliable fixed landmark to locate the hypoglossal nerve. PMID- 29387301 TI - Incidence and Risk Factors of Inferior Rectus Muscle Palsy in Pediatric Orbital Blowout Fractures. AB - The aim of this study was to evaluate the incidence, clinical features, and risk factors of sustaining inferior rectus (IR) palsy in a group of pediatric patients with orbital floor blowout fractures. We performed a retrospective case review of sequential cases of pediatric orbital floor blowout fractures (<18 years old) from 2000 to 2013 in a tertiary ophthalmic center in Singapore. A total of 48 patients were included in our study, of whom 5 had IR palsy (10.4%). Patients with IR palsy had a higher mean age (16.4 +/- 1.5 years) compared with patients without IR palsy (12.4 +/-3.3 years), had significantly ( p < 0.05) worse preoperative motility, and had significantly greater proportion developing postoperative hypertropia (100%) compared with patients without IR palsy (4.7%). Our series of pediatric blowout fractures demonstrated IR palsy prevalence and clinical features for IR palsy which may be distinct to the pediatric group. PMID- 29387302 TI - Systemic Preoperative Antibiotics with Mandible Fractures: Are They Indicated at the Time of Injury? AB - Mandible fractures are the most common result of facial trauma. The proximity of oral flora to the site of both the injury and resulting surgical instrumentation makes managing infection a unique challenge. The benefit of antibiotic prophylaxis at the time of surgical treatment of mandible fractures is well established. However, the routine use of antibiotics between the time of injury and surgery is of unclear benefit. We aim to define the role of antibiotics in the preoperative period: from the time of injury to surgical intervention. Demographic and clinical data were collected retrospectively on all patients who were treated for mandible fracture by the Division of Plastic and Reconstructive Surgery at our institution between 2003 and 2013. The use of both preoperative (between injury and surgery) and perioperative (at the time of surgery) systemic antibiotics was recorded along with the incidence of postoperative infections and other complications. Complete data were available for 269 patients. Of the 216 patients who received preoperative antibiotics, 22 (10%) developed an infection postoperatively. Of the 53 patients who did not receive preoperative antibiotics, 2 (4%) developed infection ( p = 0.184). Likewise, preoperative antibiotics were not significantly associated with hardware complication rates. In our retrospective review, the use of antibiotics between injury and surgical repair had no impact on postoperative infection rates. These data suggest that preoperative antibiotic use may actually be associated with an increased incidence of postoperative infection. Our results do not support the routine use of antibiotics between injury and surgical repair in patients with mandible fractures. PMID- 29387303 TI - Multi-institutional Analysis of Surgical Management and Outcomes of Mandibular Fracture Repair in Adults. AB - Mandibular fractures are rare, most commonly occurring in young male patients who present with facial trauma. The etiology, incidence, and presentation vary among previous publications depending on cultural and socioeconomic factors of the region of origin. This multi-institutional study aims to present demographic characteristics, surgical treatment, and clinical outcomes of surgical repair of mandible fractures in the United States. An analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) adult databases of the years 2006 through 2014 was performed identifying 940 patients with an International Classification of Diseases, version 9 (ICD-9) diagnosis of either closed or open fracture of the mandible. Preoperative, perioperative, and postoperative details were categorized and evaluated for these two cohorts. Multivariate analysis was performed to detect risk factors related to any complications. Patients were predominantly male (85.7%), young with a mean age of 34.0 +/- 14.8 years, and relatively healthy with body mass index of 23.6 +/- 8.2 and an American Society of Anesthesiologists (ASA) class of 1 or 2 (84.4%). However, more than half were regular smokers (51.1%). The top five most frequent procedures performed for mandibular repair were exclusively open surgical approaches with internal, external, or interdental fixation in both cohorts. Patients with open fractures were more often admitted as emergencies, treated inpatient, required longer operative times, and presented with more contaminated wounds ( p < 0.05). Overall, medical (1.7%) and surgical complications (3.7%) were low. A high ASA class 3 or above and emergency operations were identified as risk factors for medical adverse events. Despite frequent concomitant injuries after trauma and a diverse array of mandibular injury types, our patient sample demonstrated favorable outcomes and low complication rates. Open surgical techniques were the most common procedures in this study representing the American population. PMID- 29387304 TI - Soft-Tissue Chondroma in the Preauricular Region: An Unusual Presentation. AB - Chondroma is a benign cartilaginous tumor composed of mature hyaline cartilage and represents only 2.38% of all osteocartilaginous tumors; cases that arise in the preauricular region are rarely found in the literature. This article presents an 80-year-old man with preauricular swelling on the right side and pain with no limitation of joint motion. This patient was evaluated by preoperative clinical manifestation, fine needle aspiration, ultrasound, and magnetic resonance imaging (MRI) scans. The MRI shows a solid lobulated lesion between the masseter muscle and the parotid gland whereas fine-needle aspiration did not provide a diagnosis. Based on these images and the patient's indications and symptoms, a surgical intervention was performed. It is possible to identify three different types of chondromas in the parotid region based on their location. Among the cases of chondroma in the literature, only six originating in the soft tissue of the parotid region have been reported, including this one. PMID- 29387305 TI - Craniomaxillofacial Fibrous Dysplasia: Conservative Treatment and Maxillary Osteotomy Using the Schuchardt-Kufner Technique. AB - Fibrous dysplasia (FD) is a disturbance of the mesenchymal tissue that accounts for 2.5% of all bone tumors and more than 7% of nonmalignant bone tumors. In the craniomaxillofacial region, FD affects the calvaria, skull base, zygoma, and jaws, the prevalent site being the maxilla (50% of cases). Therapy for craniomaxillofacial FD is surgical. The goals of surgery are to prevent functional disorders and restore facial symmetry, volume, and contour. In this article, we present a case of a young female patient affected by right orbital zygomatic-maxillary FD. She had developed facial asymmetry and malocclusion that were corrected using the Schuchardt-Kufner osteotomy technique. PMID- 29387306 TI - Ectopic Molar Removal from the Ramus/Condyle Unit: A Minimally Invasive Approach. AB - Ectopic molars within the mandibular ramus/condyle unit, although rare, present a unique challenge to the surgeon. Multiple approaches have been described in the literature for their removal. A review of the English literature on the subject of mandibular ectopic molars and their epidemiology, etiology, indications for removal, and surgical techniques was completed. In addition, a case report is presented of an ectopic mandibular molar in the mid-ramus region which was removed via a minimally invasive, intraoral, technique combining the use of endoscopy and piezoelectric surgery. The authors advocate this technique as it offers the following advantages: avoidance of injury to branches of the facial nerve, unaesthetic scars, and sialocele formation; maximization of surgical field visualization with limited dissection; ability for safe sectioning of the tooth with minimal risks to adjacent structures; and precise bone removal, reducing the risk of iatrogenic or postoperative mandible fracture. PMID- 29387307 TI - Bone Allograft Segment Covered with a Vascularized Fibular Periosteal Flap: A New Technique for Pediatric Mandibular Reconstruction. AB - The free vascularized fibular graft is nowadays the preferred technique for pediatric mandibular reconstruction. Despite the versatility and proven efficacy for restoring the facial appearance and maxillomandibular function, those mandibular reconstructions with free vascularized fibula associate difficulties for a simultaneous restoration of the alveolar height and facial contour, which are derived from the height discrepancy between the fibula and the native mandible. In addition, the donor-site growth and morbidity are of special concern in the pediatric patient. We report a novel technique for pediatric mandibular reconstruction, in an 11-year-old girl, using a combination of a bone allograft segment with a vascularized fibular periosteal flap (VFPF), after resection of an Ewing sarcoma located at the right body of the mandible. The patient has showed optimal cosmetic, functional, and radiological outcomes, which have been maintained for 2.5 years, without detecting donor-site complications. Through this original technique, and based on the powerful osteogenic and vasculogenic properties of the pediatric VFPFs, we could effectively reconstruct a large mandibular defect providing a functional and aesthetic reconstruction, while avoiding the potential morbidity associated with the fibula resection. PMID- 29387309 TI - Correction of a Posttraumatic Orbital Deformity Using Three-Dimensional Modeling, Virtual Surgical Planning with Computer-Assisted Design, and Three-Dimensional Printing of Custom Implants. AB - We describe a case of complex, posttraumatic skull and orbital deformities that were evaluated and treated with advanced computer technology, including virtual surgical planning, three-dimensional (3D) modeling, and printed patient custom implants (PCI) fabricated by 3D printing. A 50-year-old man presented to our craniofacial referral center 1 year after failed reduction of complex left orbital, zygomatic, and frontal bone fractures due to a motorcycle collision. The patient's chief complaint was debilitating diplopia in all fields of gaze. On examination, he had left enophthalmos, left canthal displacement, lower eyelid ectropion, vertical orbital dystopia, and a laterally and inferiorly displaced, comminuted zygoma with orbital rim and frontal bone defects. The normal orbit was mirrored to precisely guide repositioning of the globe, orbital reconstruction, and cranioplasty. Preinjury appearance with normal globe position was restored with complete resolution of diplopia. Modern 3D technology allows the surgeon to better analyze complex orbital deformities and precisely plan surgical correction with the option of printing a PCI. These techniques were successfully applied to resolve a case of debilitating diplopia and aesthetic deficits after facial trauma. Further application of advanced 3D computer technology can potentially improve the results of severe orbital and craniofacial trauma reconstruction. PMID- 29387308 TI - Contemporary Trends in the Management of Posttraumatic Cerebrospinal Fluid Leaks. AB - The objective of this review is to provide an overview on the diagnosis and management of traumatic cerebrospinal fluid (CSF) leaks. This comprehensive review explores controversies associated with the management of CSF leaks as well as a review of the most contemporary literature. The scope of this article covers both traumatic CSF leaks of the middle and anterior cranial fossae. PMID- 29387310 TI - Can People Judge the Veracity of Their Intuitions? AB - People differ in the belief that their intuitions produce good decision outcomes. In the present research, we sought to test the validity of these beliefs by comparing individuals' self-reports with measures of actual intuition performance in a standard implicit learning task, exposing participants to seemingly random letter strings (Studies 1a-b) and social media profile pictures (Study 2) that conformed to an underlying rule or grammar. A meta-analysis synthesizing the present data (N = 400) and secondary data by Pretz, Totz, and Kaufman found that people's enduring beliefs in their intuitions were not reflective of actual performance in the implicit learning task. Meanwhile, task-specific confidence in intuition bore no sizable relation with implicit learning performance, but the observed data favoured neither the null hypothesis nor the alternative hypothesis. Together, the present findings suggest that people's ability to judge the veracity of their intuitions may be limited. PMID- 29387311 TI - Education as an Antidote to Cynicism: A Longitudinal Investigation. AB - Although cynical beliefs about human nature yield numerous adverse consequences for individuals' life outcomes and well-being, very little is known about factors that counteract the development of cynical beliefs. Drawing from the literature on the "education effect" describing the importance of education in overcoming close-mindedness and negative views of others, we propose that education can represent an antidote to cynicism. The results of two large-scale longitudinal studies showed that education was associated with lower levels of cynicism over time spans of 4 and 9 years. Longitudinal mediation analyses underscored the role of individual differences in perceived constraints, a facet of personal control, as the psychological mechanism underlying the education effect: Higher education is associated with a reduced perception of constraints, which is in turn related to less endorsement of cynical beliefs. PMID- 29387312 TI - Digesters in traditional Persian medicine. AB - Background: Functional gastrointestinal diseases are common in general populations and comprise more than 40% visits to gastroenterologists. Treatment options of gastrointestinal diseases have been limited. There are a few medications for functional gastrointestinal diseases and some of medications are not available in the market or in the place where the patient lives. Traditional Persian medicine (TPM) is a branch of alternative and traditional medicine based on individual viewpoint and humoral theory, focuses on lifestyle modification and uses natural products to manage the patients. Methods: In this study, a set of compound drugs known as digesters (jawarishes) and other applications are described based on main TPM text books. Results: Jawarishes have different formulations containing various medicinal herbs used for better food digestion and improved gastric functions and also used for other disorders including reinforcing the brain, heart, liver and some therapeutic approaches. Conclusions: By reviewing medieval Persian pharmaceutical manuscripts, we can conclude that many herbs are effective in different systems of the body and improve gastric functions. Zingiber officinalis and Piper nigrum are mixed together to get various formulations. The variety of jawarishes formulations and their different clinical applications can indicate continuity of their use. PMID- 29387313 TI - A systematic review on reminder systems in physical therapy. AB - Background: The main goal of physical therapy is to help the patient gain a better health status. Several studies have investigated the use of reminders to prevent such failures on the patients' side. This article presents a systematic review of the literature concerning reminders in physical therapy. Methods: Databases were searched until May 2017 and literatures were found from April 1992 until 2017. The literature recruitment strategy was based on applying several keywords and Medical Subject Heading (MeSH) combination running against title and abstract, including concepts such as reminder, physical therapy. The finally selected articles were categorized through reminder aspects such as how, who feedback. Data were extracted according to PRISMA guidelines. Results: In 47% of studies, the reminder was sent to the patients, 29% to the physical therapists and 12% to the caretaker team. In 24% of the studies, paper-based letters were main medium for reminders while the rest were various types of media like emails and SMS mobile text messages. 35% of the articles showed positive effects of the reminders. Conclusions: Many reminder methods consisted of SMS, phone calls, letters, emails and notices on the wall were used in physical therapy. Reminders may be used to improve patients' adherence to exercise programs. PMID- 29387314 TI - Trends in epidemiology of Hepatitis B and C Infections in Ilam Province: National Notifiable Diseases Surveillance System data. AB - Background: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the main causes of severe liver failure worldwide. This study was conducted to evaluate the incidence rate and trend of these infections over six successive years from 2008 to 2013 in Ilam Province, western Iran. Methods: We studied the registered data of HBV and HCV based on the National Notifiable Diseases Surveillance System in Ilam Province from 2008 to 2013. Incidence rate per 100,000 populations was estimated for HBV and HCV infections through location, years and age groups of patients. Results: The overall incidence rate per 100,000 populations from 2008 to 2013 for HBV infection was 9.57, 5.83, 16.26, 12.44, 21.89 and 13.93, respectively. The corresponding values for HCV infection were 0.55, 0.72, 1.44, 2.69, 1.24 and 1.93, respectively and these trends for both the HBV and HCV infections were increasing. The major distribution of HBV and HCV infections was 25-44 years of age. Both HBV and HCV infections were more common in males, urban areas and married patients. Forty-one percent of cases were carriers and history of surgery was the common risk factor. Conclusions: Our results showed that HBV and HCV are prevalent in the middle-age group. Despite effective vaccination against hepatitis B, optimized blood donor screening and better sterilization procedures for blood products, trend of HBV and HCV in Ilam are increasing. Further studies should address the role other risk factors in the trend of HBV and HCV. PMID- 29387315 TI - Risk factors of hepatitis B virus infection among blood donors in Duhok city, Kurdistan Region, Iraq. AB - Background: Hepatitis B virus (HBV) infection is a public health problem. The lack of information about the seroprevalence and risk factors is an obstacle for preventive public health plans to reduce the burden of viral hepatitis. Therefore, this study was conducted in Iraq, where no studies had been performed to determine the prevalence and risk factors of HBV infection. Methods: Blood samples were collected form 438 blood donors attending blood bank in Duhok city. Serum samples were tested for HBV core-antibodies (HBcAb) and HBV surface-antigen (HBsAg) by ELISA. Various risk factors were recorded and multivariate analysis was performed. Results: 5/438 (1.14%) of the subjects were HBsAg positive (HBsAg and HBcAb positive) and 36/438 (8.2%) were HBcAb positive. Hence, 41 cases were exposed to HBV and data analysis was based on that. Univariate analysis showed that there were significant associations between history of illegitimate sexual contact, history of alcohol or history of dental surgeries and HBV exposure (p<0.05 for all). Then, multivariate analysis was conducted to find HBV exposure predictive factors. It was found that history of dental surgery was a predictive factor for exposure to the virus (P=0.03, OR: 2.397). Conclusions: This study suggested that the history of dental surgery was predictive for HBV transmission in Duhok city. Further population-based study is needed to determine HBV risk factors in the society and public health plan based on that should be considered. PMID- 29387316 TI - Anti-coagulation therapy following coronary endarterectomy in patient with coronary artery bypass graft. AB - Background: Since there is a lack of research on postoperative anticoagulation protocol in patients undergoing coronary artery bypass graft (CABG) / coronary endarterectomy (CE), we recommend a new protocol for anticoagulation in these patients. Methods: In this double-blind randomized clinical trial study, 52 patients undergoing CABG / CE entered the study and were divided into two groups. In group 1, the patients were given warfarin(international normalized ratio (INR) between 2-3) together with 80 mg aspirin daily for 3 months. In group 2, the patients were given 75 mg plavix daily together with 80 mg aspirin daily for 3 months. We evaluated patients with electrocardiography, echocardiography and checking ceratin phosphokinase MB and troponin I in the several stages. The data were analysed SPSS Version18 software. Results: There was no significant difference between pre and post-operative Ejection fraction in patients with plavix (P=0.21) and warfarin (P=0.316) regimen. However, wall mrotion score was significantly better in clopidogrel - aspirin patients in late (3 months) post operation (p<0.001). Conclusions: Since warfarin has serious hemorrhagic complications and requires closed monitoring of serum drug activity by serial INR checking, it is recommended that clopidogrel - aspirin can be the preferred alternative anticoagulation therapy in CABG / CE patients. PMID- 29387317 TI - Analgesic effects of lidocaine-ketorolac compared to lidocaine alone for intravenous regional anesthesia. AB - Background: Intravenous regional anesthesia is a simple and reliable method for upper extremity surgery. In order to increase the quality of blocks and reduce the amount of pain, many drugs are used with lidocaine. In this study, the effect of ketorolac-lidocaine in intravenous regional anesthesia was investigated. Methods: 40 patients undergoing elective upper limb with America Society of Anesthesiologists class I and II were selected and randomly divided into two groups. The first group of 20 patients received 200 mg of lidocaine, and the second group, 200 mg of lidocaine with 20 mg of ketorolac. In both groups, the drug was diluted to 40 ml. In both groups, the onset of sensory block, onset of tourniquet pain, the onset of pain after opening the tourniquet, score of postoperative pain and analgesic prescription in the first 24 hours, during 1, 6, 12 and 24 hours were studied. A measure of the quality of analgesia was evaluated by VAS. Results: The mean onset of tourniquet pain in the two groups was not significantly different (P=0.443). In the ketorolac group, the onset of pain after opening the tourniquet was significantly longer than lidocaine group (p<0.001). The mean postoperative pain score during the first 24 hours after surgery in the ketorolac group was significantly lower than lidocaine group (p<0.001). The average number of analgesia prescription during the 24 hours after operation was significantly lower in ketorolac group than lidocaine group (p<0.001). Conclusions: Adding ketorolac to lidocaine for regional anesthesia can reduce the postoperative pain for up to 24 hours after opening the tourniquet. PMID- 29387318 TI - Acupuncture for chronic nonpulsatile tinnitus: A randomized clinical trial. AB - Background: There is challenge to find an effective treatment for tinnitus. Few studies were done on the effects of acupuncture on tinnitus. This study evaluated the effect of acupuncture on chronic non-pulsatile tinnitus. Methods: This randomized double-blind clinical trial was conducted from December 2014 to September 2015. Patients suffering from chronic non-pulsatile tinnitus were randomly allocated into two groups: acupuncture vs. placebo. They were treated in 15 sessions and at the end of the fifteenth sessions and 3 weeks after completion of the treatment, visual analog scale (VAS) for tinnitus loudness and tinnitus severity index (TSI) questionnaires were completed. Results: The case group included 26 males and 18 females, and in the control group there were 27 males and 17 females: with mean age of 49.11+/-1.07 and 55.20+/-8.33 years, respectively (p=0.005). TSI and VAS before treatment were 43.84+/-2.81 and 9.56+/ 0.43 in cases and 43.52+/-2.94 and 9.54+/-0.45 in controls, respectively. Both measures improved after 15 sessions in cases to 24.82+/-1.04 and 2.88+/-0.33, and to 33.16+/-1.24 and 7.86+/-0.23 in controls. The changes of TSI and VAS were significant in all groups (p<0.001). TSI and VAS in acupuncture group were lower than placebo group in each session (p<0.001), except TSI in the tenth session (p=0.392). Conclusions: Acupuncture is effective in reducing the loudness and severity of tinnitus and can be a useful treatment for nonpulsatile chronic tinnitus. PMID- 29387319 TI - The efficacy and safety of two different doses of caffeine in respiratory function of preterm infants. AB - Background: Caffeine is widely used for prevention of apnea and helps successful extubation from mechanical ventilation. It facilitates the transition from invasive to noninvasive support and reduces duration of continuous positive airway pressure (CPAP) in preterm infants. The optimum caffeine dose in preterm infants has not been well-studied in terms of benefits and risks. We compared efficacy and safety of once versus twice-daily caffeine dose in premature infants. Methods: This study was a randomized clinical trial conducted in Bu-Ali Sina Teaching Hospital, Sari. Patients with gestational age of <37 weeks were included. Both groups received 20 mg/kg loading dose of caffeine intravenously followed by maintenance dose of 5 mg/kg/day in group 1 or 2.5 mg/kg every 12 hours in group 2. Extubation failure, CPAP failure and possibly adverse reactions were evaluated. Results: The mean of gestational age and birth weight were 32.27+/-3.23 (weeks) and 1824.5+/-702.54 (gr), respectively. The rate of extubation and CPAP failure and length of NICU stay were lower in twice-daily group with no statistically significant difference. The means of O2 saturations on the first three days of caffeine therapy were higher in twice-daily-group. Caffeine was generally safe and well tolerated. Conclusions: This study, which assayed short-term effects of caffeine, showed that twice daily caffeine maintenance dose was related to more benefits in facilitating extubation or prevention of CPAP failure in preterm infants. However, there was not statistically significant difference between two groups. PMID- 29387320 TI - Relationship between beta-Thalassemia minor and Helicobacter pylori infection. AB - Background: Until now, no study has been reported investigating the association between beta-thalassemia minor and Helicobacter pylori (H. pylori) infection. This study was designed to compare H. pylori infection rate between beta thalassemia minor patients and healthy controls. Methods: A number of 100 beta thalassemia minor patients (50 males, 50 females) and 100 gender-matched healthy controls were prospectively recruited in this study in a period of 3 months. The study population consisted of the people who referred to a health center in Babol, North of Iran, for premarital counseling. H. pylori status was assessed by measuring the anti-H. pylori IgG antibodies using enzyme-linked immunosorbent assay. Demographic information and informed consent were collected from all participants. Results: The overall H. pylori infection rate was 43%. The infection was significantly more prevalent in thalassemia patients (53%) than in the controls (33%) in both univariate (OR=2.29, 95% CI: 1.3-4.06) and multivariable analyses (OR=2.05, 95% CI: 1.12-3.76). Age was the only significant factor which was positively correlated with the infection in beta-thalassemia minor cases (OR=1.11, 95% CI: 1.02-1.2). Gender, blood groups, residency, and education level were not related to the infection. Conclusions: According to the results, it can be concluded that beta-thalassemia minor patients are possibly more susceptible to H. pylori infection than healthy people. Further studies are needed to discover more about the exact mechanisms of increased susceptibility to H. pylori infection in beta-thalassemia minor patients. PMID- 29387321 TI - Fecal calprotectin Level in patients with IBD and noninflammatory disease of colon: a study in Babol, Northern, Iran. AB - Background: Inflammatory bowel disease (IBD) is a chronic disease with a relapsing course of inflammation in the digestive system. Endoscopy and histopathology are the golden standard methods for detection and assessment of IBD. A distinct increase of fecal calprotectin level can be a useful marker for the diagnosis of IBD. The aim of this study was to evaluate the fecal calprotectin level in patients with IBD and without inflammatory diseases of the colon. Methods: Calprotectin levels of patients referred to the Ayatollah Rouhani Hospital of Babol, northern Iran with clinical symptoms of colon disease were evaluated. After a week, colonoscopy and biopsy were performed on all patients and they were divided into two groups. The first group included patients with confirmed IBD and the second group included patients with diseases other than IBD, patients with IBS and healthy persons. Then the measured fecal calprotectin level was compared between the two groups before colonoscopy. Results: We observed correlation between calprotection in these two groups (p<0.0001). 38 (86.8%) patients in the case group and 5 (13.2%) patients in the control group had positive fecal calprotectin test and 12 (23.1%) patients in the case group and 40 (76.9%) patients in the control group had negative results. Basad on ROC curve, the cutoff point of calprotectin was 127.65 with 73% sensitivity and 89% specificity. The area under the curve was 0.83 with 95% confidence interval, 0.74 0.91 (p<0.0001). Conclusions: The results pointed to this fact that fecal calprotectin can be a noninvasive marker in differentiating IBD from IBS. PMID- 29387322 TI - BCR-ABL fusion genes and laboratory findings in patients with chronic myeloid leukemia in northeast Iran. AB - Background: A specific chromosomal abnormality, the Philadelphia chromosome (BCR ABL fusion), is present in all patients with chronic myeloid leukemia (CML). The b2a2 and b3a2 fusion mRNAs encode p210 fusion protein p210 and e1a2 encode p190. The aim of this study was to evaluate the frequency of BCR-ABL fusion transcript variants in Northeast of Iranian CML patients and to compare the laboratory results of our patients. Methods: This study was conducted in 85 peripheral blood and bone marrow samples of CML patients. Ribonucleic acid (RNA) was extracted by a commercial kit, RT- PCR for identifying BCR-ABL fusions was carried out by using designed primers and the PCR products were electrophoresed in agarose gels. Finally, statistical analysis was performed for variant frequency identification and their comparison was performed. Results: All patients examined were positive for BCR/ABL rearrangement. Fusion of b3a2 was detected in 53 (62.35%) patients, b2a2 in 25 (29.41), e1a2 in 1 (1.17%) and coexpression of b3a2 and e1a2 in 6 (7.05%) patients. There were significant differences between the mean age in patients with b3a2 positive ( 44.07 years) and in b3a2 negative group (50.35 years) however, no significant differences were seen between sex and b2a2 (P=0.61), b3a2 (P=0.79) and e1a2 (P=0.20). Conclusions: This study showed higher frequency b3a2 than b2a2 and e1a2 transcripts in CML patients in Northeast Iran and there was no association between e1a2 transcripts frequencies and monocytosis in peripheral blood. PMID- 29387323 TI - Tumor necrosis factor- alpha, adiponectin and their ratio in gestational diabetes mellitus. AB - Background: It has been suggested that inflammation might be implicated in the gestational diabetes mellitus (GDM) complications, including insulin resistance. The aims of the current study were to explore maternal circulating values of TNF alpha, adiponectin and the adiponectin/TNF-alpha ratio in women with GDM compared with normal pregnancy and their relationships with metabolic syndrome biomarkers. Methods: Forty women with GDM and 40 normal pregnant women were included in the study. Commercially available enzyme-linked immunosorbent assay methods were used to measure serum levels of TNF-alpha and total adiponectin. Results: Women with GDM had higher values of TNF-alpha (225.08+/-27.35 vs 115.68+/-12.64 pg/ml, p<0.001) and lower values of adiponectin (4.50+/-0.38 vs 6.37+/-0.59 ug/ml, p=0.003) and the adiponectin/TNF-alpha ratio (4.31+/-0.05 vs 4.80+/-0.07, P<0.001) than normal pregnant women. The adiponectin/TNF-alpha ratio showed negative correlations with insulin resistance (r=-0.68, p<0.001) and triglyceride (r=-0.39, p=0.014) and a positive correlation with insulin sensitivity (r=0.69, p<0.001). Multiple linear regression analysis showed that values of the adiponectin /TNF-alpha ratio were independently associated with insulin resistance. Binary logistic regression analysis showed that GDM was negatively associated with adiponectin /TNF-alpha ratio. Conclusions: In summary, the adiponectin/TNF-alpha ratio decreased significantly in GDM compared with normal pregnancy. The ratio might be an informative biomarker for assessment of pregnant women at high risk of insulin resistance and dyslipidemia and for diagnosis and therapeutic monitoring aims in GDM. PMID- 29387324 TI - Development and validation of a Semi-quantitative food frequency questionnaire among older people in north of Iran. AB - Background: The study was conducted to assess reliability of modified semi quantitative food frequency questionnaire (SQFFQ) as a part of the Amirkola Health and Aging Project (AHAP). Methods: The study was carried out in a sample of 200 men and women aged 60 years and older. A 138-item SQFFQ and two 24-hour dietary recalls were completed. The reliability of SQFFQ was evaluated by comparing eighteen food groups, energy and nutrient intakes derived from both methods using Spearman and Pearson's correlation coefficients for food groups and nutrients, respectively. Bland-Altman plots and Pitman's tests were applied to compare the two dietary assessment methods. Results: The mean (SD) age of subjects was 68.16 (6.56) years. The average energy intake from 24-hour dietary recalls and the SQFFQ were 1470.2 and 1535.4 kcal/day, respectively. Spearman correlation coefficients, comparing food groups intake based on two dietary assessment methods ranged from 0.25 (meat) to 0.62 (tea and coffee) in men and from 0.39 (whole grains) to 0.60 (sugars) in women. Pearson correlation coefficients for energy and macronutrients were 0.53 for energy to 0.21 for zinc in male and 0.71 for energy to 0.26 for vitamin C in females. The Pitman's test reflected the reasonable agreement between the mean energy and macronutrients of the SQFFQ and 24-hour recalls. Conclusions: The modified SQFFQ that was designed for the AHAP was found to be reliable for assessing the intake of several food groups, energy, micro-and macronutrients. PMID- 29387325 TI - Stimulant use in medical students and residents requires more careful attention. AB - Background: Stimulant pharmaceuticals are abused among academic students to elevate mood, improve studying, intellectual capacity, memory and concentration, and increase wakefulness. This study was designed to evaluate the current situation of stimulant use among medical students and residents of Babol University of Medical Sciences. Methods: This cross-sectional study was conducted among 560 medical students and clinical residents of Babol University of Medical Sciences during the academic year 2014-2015. A self-administered questionnaire was used for data collection. Results: Four hundred and forty-four (79.3%) students filled out the questionnaires. 49 (11%) individuals reported amphetamine and methylphenidate (ritalin) use. The mean age of the stimulant drug users was 24.6+/-4.8 years. The main initiator factor was to improve concentration (29 persons; 59.2%). There were significant statistical correlations between stimulant drugs abuse and male gender, living in dormitor in residence and internship and past medical history of psychiatric disorders (depression, attention deficit hyperactivity disorder and substance abuse) (p<0.05).16 (32%) students started the drug use on their friends' advice; 15 (30%) due to self medication and 12 (24%) persons with physician's prescription. Conclusions: Because of significant prevalence of stimulant use, regulatory governmental policies and also planning to improve essential life skills, awareness about the side effects and complications of these drugs, screening of at-risk college students and early identification of the abusers are suggested. PMID- 29387326 TI - Performance of electrophysiologic study in an asymptomatic patient with type 2 intermittent Brugada syndrome: To do or not to do. AB - Background: Brugada syndrome (BrS) is an inherited channelopathy, which is associated with sudden cardiac death due to rapid polymorphic VT or VF. There is no definite consensus regarding the management of asymptomatic patients. Some experts advocate close follow-up; others propose the programmed stimulation for risk stratification. We aimed to evaluate the benefit of complete atrial and ventricular stimulation in patients with BrS and palpitation. Case Presentation: A 30-year-old man was admitted to our hospital because of a family history of sudden cardiac death (SCD) at age less than 45 years. He complained of self terminated episodes of palpitation with no history of syncope. Baseline ECG showed incomplete right bundle branch block (RBBB) and saddle-back-like ST deviation in V1. Flecainide challenge test (FCT) revealed Brugada pattern. Complete EPS was done for evaluation of VT/VF inducibility and probable concomitant supraventricular arrhythmias.Programmed atrial stimulation showed inducible typical slow-fast AVNRT with AH jump 75 msec. Successful slow pathway ablation was done. There was no inducible ventricular arrhythmia. Conclusions: Patients with drug-induced BrS, positive family history of SCD and also episodes of palpitation, benefit from complete EPS. However, ICD implementation is not recommended in asymptomatic patients with drug-induced BrS and negative EPS for ventricular stimulation. PMID- 29387327 TI - Association of Limb-Girdle muscular dystrophy with multiple sclerosis: A case report. AB - Background: The association of limb-girdle muscular dystrophy (LGMD) with other neurological disorders is uncommon. Case presentation: We report a 25-year-old female with LGMD who suffered from slowly progressive proximal muscular weakness and atrophy since she was 12 years of age. The patient recently presented with acute loss of left side visual acuity. After evaluation, findings were suggestive of multiple sclerosis. Conclusions: This is the first report of LGMD in association with MS. The simultaneous occurrence of MS with myopathies may be incidental but there may be a genetic susceptibility for both diseases. This comorbidity may influence the treatment of MS. PMID- 29387328 TI - Sarcoidosis and spondyloarthritis: A coincidence or common etiopathogenesis? AB - Background: Sarcoidosis is a multisystem granulomatous disease. Co-existence with spondyloarthritis (SA) has been more described as an adverse effect of anti-TNF alpha therapy than an association. We report herein a case of a typical sarcoidosis confirmed by histological proofs and an advanced SA with a bamboo column. Case Presentation: A 48-years-old woman presented with inflammatory back pain for 5 years and ankle swelling for 1 year. On physical examination, she had an exaggerated dorsal kyphosis and disappearance of lumbar lordosis with limitation in motion of the cervical and lumbar spine. Laboratory tests did not show an inflammatory syndrome or hypercalcemia. Plain radiographies of the spine and pelvic revealed a triple ray appearance with sacroiliitis grade 4. Chest radiography and CT confirmed the presence of bilateral hilar lymph nodes and parenchymal nodes. Bronchoscopy and biopsies were performed showing non-calcified granulomatous reaction without cell necrosis. The diagnosis of SA was performed based on 9 points of Amor criteria associated with pulmonary sarcoidosis. She was treated with 15 mg per week of methotrexate and 1mg/kg/day of prednisone for pulmonary disease with good outcomes. Conclusions: Sarcoidosis may be associated to SA besides paradoxical drug effect. The same physio pathological pathways mediate by TNF alpha are arguments for association than hazardous coincidence. PMID- 29387329 TI - A new delivery model to increase adherence to methadone maintenance treatment. PMID- 29387331 TI - Acute severe ulcerative colitis: latest evidence and therapeutic implications. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease of the colorectum which results from a complex interplay between environmental, genetic and microbial factors. One-fifth of patients with UC will experience an acute flare requiring hospitalization. This is a medical emergency and requires prompt recognition and multidisciplinary management. In patients who fail first-line therapy after approximately 3-5 days of intravenous steroids, medical rescue therapy is indicated with either infliximab (IFX) or cyclosporine (CsA). Optimal dosing strategies for IFX are uncertain, with several retrospective studies suggesting an association between an intensified or accelerated IFX induction regimen and lower colectomy rates, although prospective studies are warranted. In patients not responding to medical rescue therapy, or in those with fulminant colitis, urgent colectomy is indicated. Longer prognosis is suboptimal, with half of patients requiring colectomy within 5 years of presentation with acute severe UC (ASUC). PMID- 29387330 TI - Novel therapies and current clinical progress in hemophilia A. AB - The evolution of hemophilia treatment and care is a fascinating one but has been fraught with many challenges at every turn. Over the last 50 years or so patients with hemophilia and providers have witnessed great advances in the treatment of this disease. With these advances, there has been a dramatic decrease in the mortality and morbidity associated with hemophilia. Even with the remarkable advancements in treatment, however, new and old challenges continue to plague the hemophilia community. The cost of factor replacement and the frequency of infusions, especially in patients with severe hemophilia on prophylaxis, remains a significant challenge for this population. Other challenges include obtaining reliable venous access, especially in younger patients, and the development of neutralizing alloantibodies (inhibitors). The development of extended half-life products, a bispecific antibody which mimics the coagulation function of factor VIII (FVIII) and inhibition of anticoagulation proteins such as antithrombin with antibodies, aptamers or RNA interference technology have offered novel therapeutic approaches to overcome some of these existing challenges. Additionally, ongoing gene therapy research offers a way to possibly cure hemophilia. These novel treatment tools in conjunction with the establishment of an increasing number of comprehensive hemophilia centers and worldwide advocacy efforts have continued to push the progress of hemophilia care to new frontiers. This review highlights and summarizes these novel therapeutic approaches and the current clinical progress of hemophilia A. PMID- 29387332 TI - A novel gene's role in an ancient mechanism: secreted Frizzled-related protein 1 is a critical component in the anterior-posterior Wnt signaling network that governs the establishment of the anterior neuroectoderm in sea urchin embryos. AB - The anterior neuroectoderm (ANE) in many deuterostome embryos (echinoderms, hemichordates, urochordates, cephalochordates, and vertebrates) is progressively restricted along the anterior-posterior axis to a domain around the anterior pole. In the sea urchin embryo, three integrated Wnt signaling branches (Wnt/beta catenin, Wnt/JNK, and Wnt/PKC) govern this progressive restriction process, which begins around the 32- to 60-cell stage and terminates by the early gastrula stage. We previously have established that several secreted Wnt modulators of the Dickkopf and secreted Frizzled-related protein families (Dkk1, Dkk3, and sFRP 1/5) are expressed within the ANE and play important roles in modulating the Wnt signaling network during this process. In this study, we use morpholino and dominant-negative interference approaches to characterize the function of a novel Frizzled-related protein, secreted Frizzled-related protein 1 (sFRP-1), during ANE restriction. sFRP-1 appears to be related to a secreted Wnt modulator, sFRP3/4, that is essential to block Wnt signaling and establish the ANE in vertebrates. Here, we show that the sea urchin sFRP3/4 orthologue is not expressed during ANE restriction in the sea urchin embryo. Instead, our results indicate that ubiquitously expressed maternal sFRP-1 and Fzl1/2/7 signaling act together as early as the 32- to 60-cell stage to antagonize the ANE restriction mechanism mediated by Wnt/beta-catenin and Wnt/JNK signaling. Then, starting from the blastula stage, Fzl5/8 signaling activates zygotic sFRP-1 within the ANE territory, where it works with the secreted Wnt antagonist Dkk1 (also activated by Fzl5/8 signaling) to antagonize Wnt1/Wnt8-Fzl5/8-JNK signaling in a negative feedback mechanism that defines the outer ANE territory boundary. Together, these data indicate that maternal and zygotic sFRP-1 protects the ANE territory by antagonizing the Wnt1/Wnt8-Fzl5/8-JNK signaling pathway throughout ANE restriction, providing precise spatiotemporal control of the mechanism responsible for the establishment of the ANE territory around the anterior pole of the sea urchin embryo. PMID- 29387333 TI - Vascular affection in relation to oxidative DNA damage in metabolic syndrome. AB - Introduction: Obesity has become an important issue affecting both males and females. Obesity is now regarded as an independent risk factor for atherosclerosis-related diseases. Metabolic syndrome is associated with increased risk for development of cardiovascular disease. Urinary 8-oxo-7,8-dihydro-2' deoxyguanosine concentration has been used to express oxidation status. Methods: Twenty-seven obese patients with metabolic syndrome, 25 obese patients without metabolic syndrome and 31 healthy subjects were included in our study. They were subjected to full history and clinical examination; fasting blood sugar (FBS), 2 hour post prandial blood sugar (2HPP), lipid profile, urinary 8-oxo-7,8-dihydro 2'-deoxyguanosine and carotid duplex, A/B index and tibial diameters were all assessed. Results: There was a statistically significant difference (p = 0.027) in diameter of the right anterior tibial artery among the studied groups, with decreased diameter of the right anterior tibial artery in obese patients with metabolic syndrome compared to those without metabolic syndrome; the ankle brachial index revealed a lower index in obese patients with metabolic syndrome compared to those without metabolic syndrome. There was a statistically insignificant difference (p = 0.668) in the 8-oxodG in the studied groups. In obese patients with metabolic syndrome there was a positive correlation between 8 oxodG and total cholesterol and LDL. Conclusion: Urinary 8-oxodG is correlated to total cholesterol and LDL in obese patients with metabolic syndrome; signifying its role in the mechanism of dyslipidemia in those patients. Our study highlights the importance of anterior tibial artery diameter measurement and ankle brachial index as an early marker of atherosclerosis, and how it may be an earlier marker than carotid intima-media thickness. PMID- 29387334 TI - Hypersensitivity reactions to human insulin analogs in insulin-naive patients: a systematic review. AB - Objective: The objective of this study was to raise awareness of hypersensitivity reactions to human insulin analogs (HIAs) in insulin-naive patients and encourage consistent and detailed reporting of HIA reactions. Data sources: A search of PubMed, MEDLINE and International Pharmaceutical Abstracts using the terms 'insulin' and 'hypersensitivity' was completed with English language, humans, and publication date after 1 January 1990 as limits. Study selection and data extraction: The initial search identified 598 articles. These titles and abstracts were reviewed for relevance (e.g. mention of HIA) resulting in the exclusion of 477 articles. The full texts of the remaining titles were evaluated in addition to each article's references to identify additional reports meeting criteria (n = 14). Upon extensive review, 118 articles were excluded for not meeting prespecified inclusion criteria, resulting in 17 articles. Data synthesis: Evidence supporting hypersensitivity reactions to HIAs was variable, potentially due to a variety of causes (e.g. difficulty identifying a true case of hypersensitivity reaction to HIAs). Inconsistencies were noted for the identification, confirmatory testing, management, and reporting of these reactions. Management strategies included use of insulin desensitization protocols, antihistamines, steroids, immunosuppressant/immunomodulator therapies, conversion to noninsulin therapies, and pancreas transplantation. Conclusions: Complete and consistent identification, evaluation, management, and reporting of these reactions is essential. Specific aspects of the patient's history should be reported, including previous insulin exposure, the specific HIAs used, duration of use prior to the reaction, a clear timeline of the reaction, and discussion of precipitating events or confounding factors. PMID- 29387335 TI - Contemporary utilization of antithrombotic therapy for stroke prevention in patients with atrial fibrillation: an audit in an Australian hospital setting. AB - Background: To document antithrombotic utilization in patients with nonvalvular atrial fibrillation (NVAF), particularly, recently approved NOACs (nonvitamin K antagonist oral anticoagulants) and warfarin; and identify factors predicting the use of NOACs versus warfarin. Methods: A retrospective audit was conducted in an Australian hospital. Data pertaining to inpatients diagnosed with atrial fibrillation (AF) admitted between January and December 2014 were extracted. This included patient demographics, risk factors (stroke, bleeding), social history, medical conditions, medication history, medication safety issues, medication adherence, and antithrombotic prescribed at admission and discharge. Results: Among 199 patients reviewed, 84.0% were discharged on antithrombotics. Anticoagulants (+/- antiplatelets) were most frequently (52.0%) prescribed (two thirds were prescribed warfarin, the remainder NOACs), followed by antiplatelets (33.0%). Among 41 patients receiving NOACs, 59.0% were prescribed rivaroxaban, 24.0% dabigatran, and 17.0% apixaban. Among patients aged 75 years and over, antiplatelets were most frequently used (37.0%), followed by warfarin (33.0%), then NOACs (14.0%). Compared with their younger counterparts, patients aged 75 years and over were significantly less likely to receive NOACs (14.0% versus 28.0%, p = 0.01). Among the 'most eligible' patients (Congestive Cardiac Failure, Hypertension (, Age ? 75 years, Age= 65-74 years, Diabetes Mellitus, Stroke/ Transient Ischaemic Attack/ Thromboembolism, Vascular disease, Sex female[CHA2DS2 VASc] score ?2 and no bleeding risk factors), 46.0% were not anticoagulated on discharge. Patients with anaemia (68.0% versus 86.0%, p = 0.04) or a history of bleeding (65.0% versus 87.0%, p = 0.01) were less likely to receive antithrombotics compared with those without these risk factors. Warfarin therapy was less frequently prescribed among patients with cognitive impairment compared with patients with no cognitive issues (12.0% versus 23.0%, p = 0.01). Multivariate logistic regression modelling identified that patients with renal impairment were 3.6 times more likely to receive warfarin compared with NOACs (odds ratio = 3.6, 95% confidence interval = 0.08-0.90, p = 0.03, 60.0% correctly predicted; Cox and Snell R2 = 0.51, Nagelkerke R2 = 0.69). Conclusion: Despite the availability of NOACs, warfarin remains a preferred treatment option, particularly among patients with renal impairment. The high proportion of eligible patients still being prescribed antiplatelet therapy or 'no therapy' needs to be addressed. PMID- 29387336 TI - Influence of stroke and bleeding risk on prescribing of oral anticoagulants in older inpatients; has the availability of direct oral anticoagulants changed prescribing? AB - Background: Little is known about changes in prescribing practices in Australia since the introduction of the direct oral anticoagulants (DOACs). Our objective was to examine if the availability of DOACs has coincided with a change in prescribing of oral anticoagulants in older hospital inpatients with regard to risk factors for stroke and bleeding. Methods: A prospective observational study was conducted between October 2012 and August 2015 of inpatients aged over 60 years initiated on an oral anticoagulant in a large metropolitan, tertiary referral, public teaching hospital in Australia. Treatment groups were patients who commenced an oral anticoagulant prior to inclusion of DOACs on the formulary and those who commenced after the introduction of DOACs. Subgroup analyses were conducted in patients with atrial fibrillation (AF). Differences in clinical characteristics and risk for stroke and bleeding were calculated using the CHADS2 and HAS-BLED scores, respectively, were examined. Results: A total of 289 patients were included. Inpatients prescribed an oral anticoagulant after the introduction of DOACs were significantly older, a greater proportion were female and more likely to have had a prior stroke. This was associated with a statistically higher CHADS2 score in the post-DOAC group. Similar findings were observed when limiting the sample to patients with AF. Patients with AF who were at greatest likelihood of having a bleeding event were less likely to be treated with a DOAC. Conclusion: Since the introduction of the DOACs, patients who may have previously received no therapy or suboptimal treatment were now more likely to be receiving anticoagulation, suggesting an appropriate change in prescribing practice. PMID- 29387338 TI - Polypills for the secondary prevention of cardiovascular disease: effective in improving adherence but are they safe? AB - International guidelines recommend blood pressure-lowering therapy, statins and aspirin for people who have had a cardiovascular event but use of these medications is low, particularly for lower income countries. Clinical trials have demonstrated that combining these medications into a single pill or capsule (a 'polypill') improves adherence, systolic blood pressure and low density lipoprotein cholesterol compared with usual care in secondary prevention. Uptake of polypill-based care has been underwhelming, possibly due to safety concerns. Overall, results from the clinical trials of polypill use among people who have had a cardiovascular event show no immediate safety concerns. Increased use and adherence to medications will always be associated with side effects however use within a combination medication has not been shown to be any less safe than individual component medications. Research investigating the relative consequences of nonadherence to a polypill compared with individual components would be useful. PMID- 29387337 TI - Interventions to reduce medication errors in neonatal care: a systematic review. AB - Background: Medication errors represent a significant but often preventable cause of morbidity and mortality in neonates. The objective of this systematic review was to determine the effectiveness of interventions to reduce neonatal medication errors. Methods: A systematic review was undertaken of all comparative and noncomparative studies published in any language, identified from searches of PubMed and EMBASE and reference-list checking. Eligible studies were those investigating the impact of any medication safety interventions aimed at reducing medication errors in neonates in the hospital setting. Results: A total of 102 studies were identified that met the inclusion criteria, including 86 comparative and 16 noncomparative studies. Medication safety interventions were classified into six themes: technology (n = 38; e.g. electronic prescribing), organizational (n = 16; e.g. guidelines, policies, and procedures), personnel (n = 13; e.g. staff education), pharmacy (n = 9; e.g. clinical pharmacy service), hazard and risk analysis (n = 8; e.g. error detection tools), and multifactorial (n = 18; e.g. any combination of previous interventions). Significant variability was evident across all included studies, with differences in intervention strategies, trial methods, types of medication errors evaluated, and how medication errors were identified and evaluated. Most studies demonstrated an appreciable risk of bias. The vast majority of studies (>90%) demonstrated a reduction in medication errors. A similar median reduction of 50-70% in medication errors was evident across studies included within each of the identified themes, but findings varied considerably from a 16% increase in medication errors to a 100% reduction in medication errors. Conclusion: While neonatal medication errors can be reduced through multiple interventions aimed at improving the medication use process, no single intervention appeared clearly superior. Further research is required to evaluate the relative cost-effectiveness of the various medication safety interventions to facilitate decisions regarding uptake and implementation into clinical practice. PMID- 29387339 TI - miR-26a inhibits atherosclerosis progression by targeting TRPC3. AB - Background: Atherosclerosis, a chronic multi-factorial vascular disease, has become a predominant cause of a variety of cardiovascular disorders. miR-26a was previously reported to be involved in atherosclerosis progression. However, the underlying mechanism of miR-26a in atherosclerosis remains to be further explained. Methods: High-fat diet (HFD)-fed apolipoprotein E (apoE)-/- mice and oxidized low-density lipoprotein (ox-LDL)-stimulated human aortic endothelial cells (HAECs) were established as in vivo and in vitro models of atherosclerosis. RT-qPCR and western blot analysis were performed to measure the expression of miR 26a and transient receptor potential canonical 3 (TRPC3), respectively. Binding between miR-26a and TRPC3 was predicted with bioinformatics software and verified using a dual luciferase reporter assay. The effects of miR-26a on the lipid accumulation, atherosclerotic lesion, and inflammatory response in HFD-fed apoE-/ mice were investigated by a colorimetric enzymatic assay system, hematoxylin eosin and oil-Red-O staining, and ELISA, respectively. Additionally, the effects of miR-26a or combined with TRPC3 on cell viability, apoptosis and the nuclear factor-kappa B (NF-kappaB) pathway in ox-LDL-stimulated HAECs were evaluated by MTT assay, TUNEL assay, and western blot, respectively. Results: miR-26a was downregulated in HFD-fed apoE-/- mice and ox-LDL-stimulated HAECs. miR-26a overexpression inhibited the pathogenesis of atherosclerosis by attenuating hyperlipidemia, atherosclerotic lesion and suppressing inflammatory response in HFD-fed apoE-/- mice. Moreover, miR-26a overexpression suppressed inflammatory response and the NF-kappaB pathway, promoted cell viability and inhibited apoptosis in ox-LDL-stimulated HAECs. Additionally, TRPC3 was demonstrated to be a direct target of miR-26a. Enforced expression of TRPC3 reversed the effects of miR-26a on cell viability, apoptosis, and the NF-kappaB pathway in ox-LDL-treated HAECs. Conclusions: miR-26a alleviated the development of atherosclerosis by regulating TRPC3, providing a potential target for atherosclerosis treatment. PMID- 29387340 TI - Stevens-Johnson syndrome/toxic epidermal necrolysis and erythema multiforme drug related hospitalisations in a national administrative database. AB - Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme (EM) are immunologically-mediated dermatological disorders commonly triggered by drug exposure and/or other external agents. We aimed to characterise SJS/TEN- and EM-drug-related hospitalisations in a nationwide administrative database, focusing on demographic and clinical characteristics, and in the most frequently implicated drug classes. Methods: We analysed all drug related hospitalisations with associated diagnosis of SJS/TEN or EM in Portuguese hospitals between 2009 and 2014. We compared gender, age, comorbidities, length of stay, and in-hospital mortality and estimated the number of episodes per million packages sold of drug classes. Predictors of in-hospital mortality were investigated in both conditions by logistic regression. Results: There were 132 SJS/TEN-related and 122 EM-related hospitalisations. Incidence and in-hospital mortality of SJS/TEN episodes (24.2%) were consistent with previous studies. HIV co-infection was more common among SJS/TEN hospitalisations (9 vs. 2% with EM; P = 0.009). Liver disease, advanced age, and a TEN diagnosis, were significantly associated with higher risk of mortality in patients with SJS/TEN. The highest numbers of SJS/TEN and EM episodes per million drug packages sold were observed for antivirals (8.7 and 1.5, respectively), antineoplastic/immunosuppressive drugs (5.6 and 3.9, respectively) and hypouricaemic drugs (5.0 and 2.4, respectively). Conclusions: SJS/TEN in-hospital mortality is high, and its risk factors include advanced age, liver disease, and TEN diagnosis. The drug classes most frequently associated with these conditions include antivirals, hypouricaemic drugs and antineoplastic/immunosuppressive drugs. Administrative databases seem useful in the study of SJS/TEN drug-related hospitalisations, yielding results consistent with previous studies and on a nationwide basis. PMID- 29387341 TI - Chiropractic student choices in relation to indications, non-indications and contra-indications of continued care. AB - Background: The quality of health care provider clinical decisions has long been recognized as variable. Research has focused on clinical decision making with the aim of improving patient outcomes. No studies have looked at chiropractic students' abilities in this regard. Method: In 2016, advanced students from two Australian chiropractic programs (N = 444) answered a questionnaire on patient case scenarios for neck and low back pain (LBP). We selected 7 scenarios representing the three categories; continuing care, non-indicated care, and contraindicated care. This represented a total of 21 tested scores. Comparisons of correct answers were made a) for program years 3, 4 and 5, and b) between the three categories of care. Results: In almost 1/3 of scenarios, correct scores were 70% or greater. Best results were for two neck pain cases (simple and with spinal cord involvement). Continued care showed most improvements with study year. However, the scenarios that reflected non-indication for continued care had much worse results and did not improve in higher years. For the obvious contraindicated neck scenario, the results were good from the beginning and progressively improved and for a contraindicated LBP scenario the results started poorly in year 3 but improved over the program years. Conclusions: Although student responses were generally good, there is still room for improvement, especially for non-indicated care. The quality of students' clinical decisions can be measured and thus has the potential to be used by chiropractic educators and regulatory bodies to identify student's in need of assistance as well as to monitor chiropractic programs in relation to student competence. Trial registration: Not applicable. PMID- 29387342 TI - Efficacy of intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B for post-neurosurgical intracranial infections due to MDR/XDR Acinectobacter baumannii: a retrospective cohort study. AB - Background: Post-neurosurgical intracranial infections caused by multidrug resistant or extensively drug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality. In this study, we analyzed the therapeutic efficacy of intravenous combined with intrathecal/intracerebral ventricle injection of polymyxin B for this type of intracranial infection. Methods: This retrospective study was conducted from January 2013 to September 2017 at the Second Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou,China) and included 61 cases for which cerebrospinal fluid (CSF) cultures were positive for multidrug-resistant or extensively drug-resistant A. baumannii after a neurosurgical operation. Patients treated with intravenous and intrathecal/intracerebral ventricle injection of polymyxin B were assigned to the intrathecal/intracerebral group, and patients treated with other antibiotics without intrathecal/intracerebral injection were assigned to the intravenous group. Data for general information, treatment history, and the results of routine tests and biochemistry indicators in CSF, clinical efficiency, microbiological clearance rate, and the 28-day mortality were collected and analyzed. Results: The rate of multidrug-resistant or extensively drug-resistant A. baumannii infection among patients who experienced an intracranial infection after a neurosurgical operation was 33.64% in our hospital. The isolated A. baumannii were resistant to various antibiotics, and most seriously to carbapenems (100.00% resistance rate to imipenem and meropenem), cephalosporins (resistance rates of 98.38% to cefazolin, 100.00% to ceftazidime, 100.00% to cefatriaxone, and 98.39% to cefepime). However, the isolated A. baumannii were completely sensitive to polymyxin B (sensitivity rate of 100.00%), followed by tigecycline (60.66%) and amikacin (49.18%). No significant differences in basic clinical data were observed between the two groups. Compared with the intravenous group, the intrathecal/intracerebral group had a significantly lower 28-day mortality (55.26% vs. 8.70%, P = 0.01) and higher rates of clinical efficacy and microbiological clearance (95.65% vs. 23.68%, P < 0.001; 91.30% vs. 18.42%, P < 0.001, respectively). Conclusions: Intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B is an effective regimen for treating intracranial infections caused by multidrug-resistant or extensively drug resistant A. baumannii. PMID- 29387343 TI - Multi-drug resistant Acinetobacter species: a seven-year experience from a tertiary care center in Lebanon. AB - Background: Acinetobacter species have become increasingly common in the intensive care units (ICU) over the past two decades, causing serious infections. At the American University of Beirut Medical Center, the incidence of multi-drug resistant Acinetobacter baumannii (MDR-Ab) infections in the ICU increased sharply in 2007 by around 120%, and these infections have continued to cause a serious problem to this day. Methods: We conducted a seven-year prospective cohort study between 2007 and 2014 in the ICU. Early in the epidemic, a case control study was performed that included MDR-Ab cases diagnosed between 2007 and 2008 and uninfected controls admitted to the ICU during the same time. Results: The total number of patients with MDR-Ab infections diagnosed between 2007 and 2014 was 128. There were also 99 patients with MDR-Ab colonization without evidence of active infection between 2011 and 2014. The incidence of MDR-Ab transmission was 315.4 cases/1000 ICU patient-days. The majority of infections were considered hospital-acquired (84%) and most consisted of respiratory infections (53.1%). The mortality rate of patients with MDR-Ab ranged from 52% to 66%. Conclusion: MDR-Ab infections mostly consisted of ventilator-associated pneumonia and were associated with a very high mortality rate. Infection control measures should be reinforced to control the transmission of these organisms in the ICU. PMID- 29387344 TI - Antimicrobial effect of copper alloys on Acinetobacter species isolated from infections and hospital environment. AB - Background: An increased proportion of Gram-negative bacteria have recently been reported among etiologic agents of infection. In Poland, Acinetobacter baumannii is a big problem for hospitals, especially intensive care units. Touch surfaces made from materials with antimicrobial properties, especially copper alloys, are recommended as a supplementary method of increasing biological safety in the hospital environment. Aim of the study: The objective of this study is to determine the susceptibility to selected copper alloys of three clinical Acinetobacter baumannii strains, one Acinetobacter lwoffi and an A. pittii strain isolated from the hospital environment. Material and method: The modification of the Japanese Standard, which the ISO 22196:2011 norm was used for testing antimicrobial properties of CuZn37, CuSn6 and CuNi18Zn20 and Cu-ETP and stainless steel as positive and negative control, respectively. Results: The highest cidal efficiency, expressed as both time and the degree of reduction of the initial suspension density, against all of the tested Acinetobacter strains was found for ETP copper. But, the results of our study also confirmed effective activity (bacteriocidal or bacteriostatic) of copper alloys selected for the study, contrary to the stainless steel. The reduction in bacterial suspension density is significantly different depending on the strain and copper alloy composition. Conslusions: The results of our study confirmed the effective antibacterial activity of copper and its selected alloys against clinical Acinetobacter baumannii and Acinetobacter lwoffii strains, and Acinetobacter pittii strain isolated from the hospital environment. PMID- 29387346 TI - Drug resistant tuberculosis in Saudi Arabia: an analysis of surveillance data 2014-2015. AB - Background: There is limited data that investigates the national rates of drug resistant tuberculosis (TB) in Saudi Arabia.This study aimed to estimate the rates of multi-drug-resistant tuberculosis (MDR-TB), rifampicin-resistant tuberculosis (RR-TB), and monoresistance (MR) in Saudi Arabia. Methods: A retrospective cohort study was conducted on all TB cases reported to the National TB Control and Prevention Program (NTCPP) registry at the Saudi Ministry of Health between January 1, 2014 and December 31, 2015. A total of 2098 TB patients with positive TB cultures were included in the study. Subgroup analyses and multivariate binary logistic regression models were performed with IBM SPSS 23.0. Results: Of the total TB cases, 4.4% (95% CI: 3.59%-5.40%) were found to have MDR TB. The rates of MR were 3.8% (95% CI: 2.99%-4.67%) for ethambutol, 5.4% (95% CI: 4.50%-6.49%) for pyrazinamide, 10.2% (95% CI: 5.89%-11.52%) for isoniazid, 11% (95% CI: 9.70%-12.43%) for streptomycin, and 5.9% (95% CI: 4.90%-6.96%) for rifampicin. The high rates of MDR and RR-TB were found among the younger age group, female gender, and those who had a previous history of TB. We also discovered that renal failure tends to increase the risk of rifampicin resistance. Conclusions: National TB data in Saudi Arabia shows that the rate of MDR-TB was similar to the global rate reported by the World Health Organization (WHO). It is a relatively high rate as compared to Western countries. The proportion of MDR/RR-TB patients tends to be higher in the younger age group, female gender, and in patients with a previous history of TB treatment. Effective strategies for prevention of all multi-drug-resistant TB cases are warranted. PMID- 29387345 TI - Higher third-generation cephalosporin prescription proportion is associated with lower probability of reducing carbapenem use: a nationwide retrospective study. AB - Background: The ongoing extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) pandemic has led to an increasing carbapenem use, requiring release of guidelines for carbapenem usage in France in late 2010. We sought to determine factors associated with changes in carbapenem use in intensive care units (ICUs), medical and surgical wards between 2009 and 2013. Methods: This ward-level multicentre retrospective study was based on data from French antibiotic and multidrug-resistant bacteria surveillance networks in healthcare facilities. Antibiotic use was expressed in defined daily doses per 1000 patient-days. Factors associated with the reduction in carbapenem use (yes/no) over the study period were determined from random-effects logistic regression model (493 wards nested within 259 healthcare facilities): ward characteristics (type, size...), ward antibiotic use (initial antibiotic use [i.e., consumption of a given antibiotic in 2009], initial antibiotic prescribing profile [i.e., proportion of a given antibiotic in the overall antibiotic consumption in 2009] and reduction in the use of a given antibiotic between 2009 and 2013) and regional ESBL-PE incidence rate in acute care settings in 2011. Results: Over the study period, carbapenem consumption in ICUs (n = 85), medical (n = 227) and surgical wards (n = 181) was equal to 73.4, 6.2 and 5.4 defined daily doses per 1000 patient-days, respectively. Release of guidelines was followed by a significant decrease in carbapenem use within ICUs and medical wards, and a slowdown in use within surgical wards. The following factors were independently associated with a higher probability of reducing carbapenem use: location in Eastern France, higher initial carbapenem prescribing profile and reductions in consumption of fluoroquinolones, glycopeptides and piperacillin/tazobactam. In parallel, factors independently associated with a lower probability of reducing carbapenem use were ICUs, ward size increase, wards of cancer centres, higher initial third-generation cephalosporin (3GC) prescribing profile and location in high-risk regions for ESBL-PE. Conclusions: Our study suggests that a decrease in 3GCs in the overall antibiotic use and the continuation of reduction in fluoroquinolone use, could allow reducing carbapenem use, given the well-demonstrated role of 3GCs and fluoroquinolones in the occurrence of ESBL-PE. Thus, antibiotic stewardship programs should target wards with higher 3GC prescription proportions to reduce them. PMID- 29387347 TI - The efficacy of ampicillin compared with ceftriaxone on preventing cesarean surgical site infections: an observational prospective cohort study. AB - Background: Cesarean surgical site infections (SSIs) can be prevented by proper preoperative antibiotic prophylaxis. Differences in antibiotic selection in clinical practice exist according to obstetricians' preferences despite clear guidelines on preoperative antibiotic prophylaxis. This study aimed to compare the efficacy of ampicillin and ceftriaxone in preventing cesarean SSIs. Methods: The observational prospective cohort study was conducted at a tertiary hospital in Thailand from 1 January 2007 to 31 December 2012. Propensity scores for ceftriaxone prophylaxis were calculated from potential influencing confounders. The cesarean SSI rates of the ceftriaxone group vs. those of the ampicillin prophylactic group were estimated by multilevel mixed-effects Poisson regression nested by propensity score. Results: Data of 4149 cesarean patients were collected. Among these, 911 patients received ceftriaxone whereas 3238 patients received ampicillin as preoperative antibiotic prophylaxis. The incidence of incisional SSIs was (0.1% vs. 1.2%; p = 0.001) and organ space SSIs was (1.2% vs. 2.9%; p = 0.003) in the ceftriaxone group compared with the ampicillin group. After adjusting for confounders, the rate ratios of incisional and organ/space SSIs in the ceftriaxone compared with the ampicillin group did not differ (RR, 0.23; 95% CI 0.03-1.78), and (RR, 1.62; 95% CI 0.83-3.18), respectively. Conclusion: These data indicate no difference exists between ampicillin and ceftriaxone to prevent SSIs after cesarean section. Ampicillin may be used as antibiotic prophylaxis in cesarean section. PMID- 29387348 TI - AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression. AB - Background: Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson's disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death. RAGE, receptor of AGEs, is activated by interaction with AGEs and mediates AGE-induced cytotoxicity. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown. Methods: Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type (WT) and G2019S transgenic mice, we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining. We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots. Results: We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls. Furthermore, we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells. Conclusions: These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation mediated progressive neuronal loss in PD. PMID- 29387349 TI - Response surface optimization of ultrasonic-assisted extraction of carotenoids from oil palm (Elaeis guineensis Jacq.) fronds. AB - Oil palm (Elaeis guineensis Jacq.) fronds (OPF) are the most abundant oil palm solid wastes that are generated during oil palm agriculture and harvest. Palm oil and some other palm wastes have been reported to contain high concentrations of carotenoids with vital bioactive properties. However, the extraction and quantification of carotenoids from OPF have not been reported. In this study, ultrasonic-assisted extraction, HPLC-FLD for quantification, and response surface methodology (RSM) for optimization of beta-carotene, lutein, and zeaxanthin from OPF extracts were investigated. The effects of extraction temperature (X1: 30-70 degrees C), extraction time (X2: 10-50 min), and solvent-sample ratio (X3: 10-50 mL/g) on the recovery of beta-carotene (Y1), lutein (Y2), and zeaxanthin (Y3) were investigated using three-level Box-Behnken design (BBD) experiment. At a desirability of 1, the optimum extraction conditions for beta-carotene (30.14 degrees C, 37.11 min, and 23.18 mL/g), lutein (30.00 degrees C, 39.09 min, and 19.24 mL/g), and zeaxanthin (30.09 degrees C, 36.76 min, and 22.38 mL/g) yielded carotenoid concentrations of 17.95 MUg/g dry weight (DW), 261.99 MUg/g DW, and 29.99 MUg/g DW, respectively. PMID- 29387350 TI - Royal jelly enhances antigen-specific mucosal IgA response. AB - The effective uptake of antigens (Ags) by specialized M cells of gut-associated lymphoid tissues is an important step in inducing an efficient intestinal mucosal immune response. In this study, royal jelly (RJ) was found to stimulate the differentiation of M-like cells from human Caco-2 cells in an in vitro M cell model. Furthermore, RJ and protease-treated royal jelly (pRJ) efficiently enhanced transcytosis of FluoSpheres(r) carboxylate-modified microspheres from the apical side to the basolateral side in the model. Therefore, we evaluated the ability of pRJ to induce efficient mucosal immune responses in an in vivo nonhuman primate. Continuous oral administration of commercially available pRJ resulted in a significant enhacement of the antigen-specific IgA response in stool sample. Interestingly, Caco-2 monolayer assay demonstrated that ether extracts from pRJ efficiently increased the expression level of a universal M cell marker, glycoprotein 2 (gp2). These findings suggest that pRJ exhibits mucosal immunomodulatory properties via stimulation of effective uptake of Ags through M cells. PMID- 29387351 TI - Chemical, mineral composition, and sensory acceptability of cocoyam-based recipes enriched with cowpea flour. AB - The study was conducted to improve cocoyam-based recipes (steamed cocoyam paste [ebiripo], ikokore, and fried cocoyam balls [ojojo]) using different blends of cocoyam and cowpea flours (100:0, 80:20, 70:30, 60:40, and 50:50). The proximate composition, mineral composition, and sensory qualities of the recipes were determined using standard analytical procedures. The recipes had significantly (P < 0.05) higher contents of protein, fat, crude fiber, iron, zinc, sodium, and phosphorus compared with the control recipe (100% cocoyam flour). The protein content was highest in all recipes containing 50:50 cocoyam: cowpea flour (10.79%, 10.56%, 10.36% for ojojo, ikokore, and ebiripo, respectively). However, ikokore had higher iron (2.5 mg), phosphorus (92.5 mg), and zinc (1.92 mg) contents than ebiripo and ojojo. While the 80:20 recipe for ebiripo had significantly (P < 0.05) higher flavor and overall acceptability scores compared with other recipes. In conclusion, enrichment of cocoyam-based recipes with cowpea flour improved the proximate composition, mineral composition, and sensory acceptability of the foods. PMID- 29387352 TI - Microbial contribution to spoilage of African breadfruit (Artocarpus communis, Forst) during storage. AB - The contributions of microorganisms in the deterioration of African breadfruit during storage were investigated in this study. Matured fruits of the seedless variety of the African breadfruit (Artocarpus communis, Forst) were stored under different temperature conditions and morphological changes observed at 24-h intervals for 120 h. Spoilage of breadfruit was observed after 72 h with microbial growth. Although all the fruits in the different media deteriorated by the 72nd hour (this was revealed in morphology and confirmed by the proximate analysis which showed an increase in %crude protein in all the stored fruits), microbial growth was observed only in those fruits stored at room temperature and in water, and there was no significant microbial growth in fruits stored in refrigerator, freezer, and vinegar. A higher rate of deterioration (i.e., higher %crude protein) was observed in morphology of fruits which had microbial growth during storage (i.e., those stored in the room, under water, and refrigerator) than in those stored fruits with no significant microbial growth. The difference between the %crude protein in fruits where there is microbial growth and that of the fruits where there is no microbial growth (i.e., freezer and vinegar) proved to be significant (P <= 0.05). The study thus reveals that microorganisms play a substantial role in the spoilage of African breadfruit. A strain of the Aspergillus sp., two strains of the Penicillium sp., and a strain of the Molinia sp. were isolated as fungal spoilage organisms. Bacillus sp. and Pseudomonas sp. strains were isolated as bacteria spoilage organisms. PMID- 29387353 TI - Effect of processing methods on the chemical composition of Vitex doniana leaf and leaf products. AB - Fresh leaves of Vitex doniana were subjected to different food processing methods such as drying, blanching and drying, fermentation of the leaf extract as well as blanching and fermentation of the leaf extract. The proximate composition, mineral and vitamin contents of the fresh and processed leaves were subsequently determined, using standard methods. The results shows that V. doniana leaf and products had the following ranges of proximate parameters: 0.07-17.29% protein, 1.85-6.33% fiber, 0.47-6.55% ash, 10.86-95.67% moisture, 0.05-1.29% fat, and 3.61 58.08% carbohydrate. The level of micronutrients detected were generally high and ranged as follows: minerals - Ca (13.38-59.50 mg/100 g), Fe (3.0-18.00 mg/100 g), Na (0.37-1.29 mg/100 g), and vitamins C (1.5-32.98 mg/100 g), A (54.6-3583.26 IU), E (3.11-53.36 mg/100 g), and B2 (0.01-9.63 mg/100 g). However, the various processing methods used led to significant (P < 0.05) decrease of micronutrients in the extracts, while it caused significant (P < 0.05) increase in the protein, fat, and ash content of the oven-dried sample. PMID- 29387354 TI - Influence of treatments in the quality of Nile tilapia (Oreochromis niloticus) fillets. AB - In this study, the influence of different treatments was evaluated: nonwashing, washing in chlorinated water and washing/soaking in chlorinated water and sodium chloride on the quality of Nile tilapia (Oreochromis niloticus) fillets during storage at 1.0 +/- 0.5 degrees C through daily analysis of pH, moisture, and lipids content. Microbiological analysis and growth modeling for mesophilic and psychrotrophic bacteria and Staphylococcus sp. were also carried out. Finally, we confirmed the microbiological safety through sensory analyses. The main results suggest that fillets washed or soaked in chlorinated water and sodium chloride present clear and narrower blood line coloration; that is, they are less oxidized than those that received other treatments and are microbiologically safe for use within 12 days of storage. It was concluded that the treatments in chlorinated and salinized water favored the quality maintenance of fillets. PMID- 29387355 TI - Functional properties of Ditaxis heterantha proteins. AB - Ditaxis heterantha is a plant of the Euphorbiaceae family that grows in semiarid regions of Mexico. It produces yellow pigmented seeds that are used for coloring of foods. The seeds contain about 20% of proteins. Proteins of D. heterantha were extracted and fractionated on the basis of solubility. Three main protein fractions were obtained: glutelins, 488 +/- 0.5; albumins, 229 +/- 2; and total globulins, 160 +/- 1 g/kg. The amino acid profile was evaluated for each fraction and protein isolated, where the protein isolate contains essential amino acids such as Val, Phe, Tyr, and Leu. A calorimetric study showed that globulins and glutelins have a high denaturing temperature between 100 and 106 degrees C, while albumins showed a denaturing temperature at 76 degrees C. The protein isolate and its fractions exhibited functional properties: the isolated protein demonstrated good oil-holding capacity of 40.7 g/kg. Foam capacity (FC) and foam stability (FS) were observed principally in glutelins and globulins where FC maximum was 330% and the FS was 28 min. The emulsifying capacity was observed in the same fractions of glutelins and globulins, followed by albumins. However, the glutelin fraction in particular was the only fraction that exhibited emulsifying stability at pH 5, 6, and 7. Gelling capacity was observed in albumins and globulins. This study indicated that protein isolated from D. heterantha could be used in food formulations due to its essential amino acid profile. Glutelin could be used as an emulsifying additive. Additionally, glutelin and globulin were stable at temperatures above 100 degrees C; this is an important factor in food industry, principally in heat processes. PMID- 29387357 TI - Pomegranate seed clustering by machine vision. AB - Application of new procedures for reliable and fast recognition and classification of seeds in the agricultural industry is very important. Recent advances in computer image analysis made applicable the approach of automated quantitative analysis in order to group cultivars according to minor differences in seed traits that would be indiscernible in ocular inspection. In this work, in order to cluster 20 cultivars of pomegranate seed, nine image features and 21 physicochemical properties of them were extracted. The aim of this study was to evaluate if the information extracted from image of pomegranate seeds could be used instead of time-consuming and partly expensive experiments of measuring their physicochemical properties. After data reduction with principal component analysis (PCA), different kinds of overlapping between these two types of data were controlled. The results showed that clustering base on all variables of image features contain more similar cultivars with clustering base on physicochemical properties (66.67% for cluster 1, 75% for cluster 2, and 50% for cluster 3). Therefore, by applying image analysis technique, the seeds almost were placed in different pomegranate clusters without spending time and additional costs. PMID- 29387358 TI - Internal preference mapping of milk-fruit beverages: Influence of color and appearance on its acceptability. AB - The individual preferences of 100 consumers between 20 and 30 years old for the color of 16 milk-fruit juice beverages (MFJB) were investigated by preference mapping technique. Consumers were asked to evaluate, just by looking at the samples, how much they liked them (from "Extremely dislike" to "Extremely like"). The color of the samples was analyzed by two different instrumental techniques. Results obtained from the instrumental color measurement showed the wide diversity in hues of the beverages available in the market, and correlations between techniques proved that both of them were appropriate to analyze color. Results showed that participants preferred samples with orangish appearance instead of those with a whiter look. Anyway, punctuations given by the consumers suggest that generally, color of these products is not highly evaluated by consumers, as the best mean punctuation was 6.6. PMID- 29387356 TI - Surveillance and diagnosis of zoonotic foodborne parasites. AB - Foodborne parasites are a source of human parasitic infection. Zoonotic infections of humans arise from a variety of domestic and wild animals, including sheep, goats, cattle, camels, horses, pigs, boars, bears, felines, canids, amphibians, reptiles, poultry, and aquatic animals such as fishes and shrimp. Therefore, the implementation of efficient, accessible, and controllable inspection policies for livestock, fisheries, slaughterhouses, and meat processing and packaging companies is highly recommended. In addition, more attention should be paid to the education of auditors from the quality control (QC) and assurance sectors, livestock breeders, the fishery sector, and meat inspection veterinarians in developing countries with high incidence of zoonotic parasitic infections. Furthermore, both the diagnosis of zoonotic parasitic infections by inexpensive, accessible, and reliable identification methods and the organization of effective control systems with sufficient supervision of product quality are other areas to which more attention should be paid. In this review, we present some examples of successful inspection policies and recent updates on present conventional, serologic, and molecular diagnostic methods for zoonotic foodborne parasites from both human infection and animal-derived foods. PMID- 29387359 TI - In vitro digestibility of hydrothermally modified Bambara groundnut (Vigna subterranean L.) starch and flour. AB - In-vitro digestibility and functional properties of Bambara groundnut (Vigna subterranean) (BG) flour, and its native and hydrothermally modified starches were investigated. The isolated native starch (BNS) was modified by annealing at 50 degrees C for 48 hr (BAS), and heat-moisture treated at 100 degrees C for 16 hr at 25% moisture level (BHS). The crude protein of BG flour was 16.88%. The amylose content of the flour and native starch was 6.10% and 27.70%, respectively. Hydrothermal modification increased the gelatinization profile of the starch but reduces its pasting properties. Swelling and solubility of the flour and starches increased with increase in temperature. X-ray diffraction revealed BNS and BAS exhibited "Type C" crystallinity pattern while BHS was "Type A." The BNS granule was oval, its diameter between 22 and 30 MUm, with no significant change in the morphology of BAS and BHS. The BG flour had 33% resistant starch and 11.63% digestible starch. Heat-moisture treatment enhanced the resistant starch content of the native starch significantly. PMID- 29387360 TI - Malting and fermentation effects on antinutritional components and functional characteristics of sorghum flour. AB - The research was aimed to observe the effect of malting and fermentation on antinutritional component and functional characteristics of sorghum flour. For whole sorghum flour, cleaned sorghum grain was milled to pass through 40 mesh sieve. For malting, cleaned sorghum grain was steeped in 0.2% calcium hydroxide solution for 24 hr and then germinated for 48 hr at 90% RH and 27 +/- 2 degrees C. Sprout was removed, dried in hot air oven at 50 +/- 2 degrees C for 24 hr and milled to pass through 40 mesh sieve. For fermented sorghum flour, 13.3 mg% diastase and 2 mg % pepsin (on the basis of whole sorghum flour weight) was added to cooked (88 +/- 2 degrees C) sorghum flour and left for 1 hr. Lactobacillus plantarum (107 cfu/g) was inoculated and incubated at temperature 30 +/- 2 degrees C for 48 hr. The fermented slurry was dried at 50 +/- 2 degrees C in hot air oven for 24 hr and milled to pass through 40 mesh sieve. The lower yield of sorghum flour was obtained compared to whole and malted sorghum flour. Germination of sorghum reduced phytate, tannin, and oxalate by 40%, 16.12% and 49.1%, respectively, whereas fermentation of sorghum flour reduced above by 77%, 96.7% and 67.85%, respectively. There was no significant change in hydrogen cyanide in malted sorghum flour compared to whole sorghum flour, but fermentation of sorghum flour reduced hydrogen cyanide by 52.3%. Bulk density and viscosity was significantly reduced by the malting and fermentation, whereas water absorption capacity and oil absorption capacity was markedly increased by the malting and fermentation. Fermented flour was good due to reduced ANF and improved functional property despite of lower yield. PMID- 29387361 TI - Binding of volatile aroma compounds to can linings with different polymeric characteristics. AB - Flavor compounds have been shown to interact with packaging materials either by scalping, the movement of flavorings from the food product to the package, or by flavor release, movement of flavorings from the package to the food. Work has elucidated the parameters important for the scalping of flavor compounds to polyolefin packaging materials, but very little work has been conducted examining the scalping of flavor compounds by can lining materials. Can linings composed of three different polymers, polyolefin, acrylic, epoxy, were studied for binding of volatile flavor compounds (octanal, nonanal, decanal, eugenol, d-limonene) at room temperature over a 2-week period. Solid phase microextraction (SPME) was used with gas chromatography mass spectrometry to identify and quantify volatile compounds. Flavor compounds were studied at concentrations around 4-1,000 ppb. Fourier transform infrared spectroscopy was used to verify can lining polymer chemistry. Almost complete binding of all five of the volatile compounds studied was observed over 9-14 days at room temperature for each of the can lining chemistries. The number of time data points limited our ability to determine the order and rate constants of binding. This model system appears to be a valuable for investigating flavor binding of polymeric can lining materials. PMID- 29387362 TI - Assessment of heavy metals and microbial contamination of gari from Liberia. AB - Cassava is a staple mostly eaten in the form of gari, after rice in Liberia. The local method of gari processing often leads to product contamination, thus, a study was done to assess the heavy metals and microbial contamination of gari in eight counties of the country. A total of sixty-one gari samples were collected and packaged in an airtight polyethylene bag for analyses, using standard methods. Results depict that the mean of the heavy metals in the gari samples is iron (Fe) 43.87 ppm, copper (Cu) 0.94 ppm, zinc (Zn) 5.49 ppm and aluminum (Al) 257.45 ppm. Yellow gari had the highest Fe (64.90 ppm), Cu (1.25 ppm) and Zn (7.85 ppm) content, but with the least Al content (87.15 ppm). The Fe content was lower in groundnut-fortified gari (42.93 ppm), and the Cu (0.70 ppm) and Zn (3.50 ppm) content were lower in groundnut-moringa-fortified gari. The samples and counties have no significant statistical effect (p > .05) on the heavy metals composition of the products. No microbial growth was observed in groundnut fortified and groundnut-moringa-fortified gari but with coconut-fortified gari having the highest total fungi count of 800 CFU/g. The major fungi identified in the gari samples are Penicillium and Aspergillus spps., but with their counts within the regulated level. Therefore, the gari consumed in Liberia are safe except for the high Fe and Al content, which needs to be addressed with the use of unpainted stainless steel materials as food contact surfaces. PMID- 29387363 TI - In situ production of active vitamin B12 in cereal matrices using Propionibacterium freudenreichii. AB - The in situ production of active vitamin B12 was investigated in aqueous cereal based matrices with three strains of food-grade Propionibacterium freudenreichii. Matrices prepared from malted barley flour (33% w/v; BM), barley flour (6%; BF), and wheat aleurone (15%; AM) were fermented. The effect of cobalt and the lower ligand 5,6-dimethylbenzimidazole (DMBI) or its natural precursors (riboflavin and nicotinamide) on active B12 production was evaluated. Active B12 production was confirmed by UHPLC-UV-MS analysis. A B12 content of 12-37 MUg.kg-1 was produced in BM; this content increased 10-fold with cobalt and reached 940-1,480 MUg.kg-1 with both cobalt and DMBI. With riboflavin and nicotinamide, B12 production in cobalt-supplemented BM increased to 712 MUg.kg-1. Approximately, 10 MUg.kg-1 was achieved in BF and AM and was increased to 80 MUg.kg-1 in BF and 260 MUg.kg-1 in AM with cobalt and DMBI. The UHPLC and microbiological assay (MBA) results agreed when both cobalt and DMBI or riboflavin and nicotinamide were supplemented. However, MBA gave ca. 20%-40% higher results in BM and AM supplemented with cobalt, indicating the presence of human inactive analogues, such as pseudovitamin B12. This study demonstrates that cereal products can be naturally fortified with active B12 to a nutritionally relevant level by fermenting with P. freudenreichii. PMID- 29387364 TI - Consumer acceptability of gluten-free cookies containing raw cooked and germinated pinto bean flours. AB - Beany and grassy flavors in raw edible bean flours reduce consumer acceptability of bean-based baked products. In order to improve consumer acceptability, beans may be further processed by cooking and germination. However, these operations drive up the cost of end-products. Therefore, it is necessary to develop formulations, using raw edible bean flours that have acceptable sensory attributes. In this study, cooked, germinated, and germinated/steam-blanched (GSB) pinto bean flours were used to make gluten-free cookies, and their sensory characteristics evaluated to determine how their consumer acceptability scores compared. Taste panelists (31) graded cookies made from raw pinto beans with an overall value of 6 on a 9-point hedonic scale (p < .05). This rating was not significantly different from cookies formulated with germinated and GSB flours. Therefore, gluten-free cookies can be made using raw pinto bean flours at a 40% inclusion level, with similar sensory characteristics as those prepared with flours treated by cooking and germination. Instrumental measurement of cookie hardness and color showed no significant difference in hardness, but significant differences in color. The germinated bean flour produced cookies with a significantly lower L* value and significantly higher a*, b*, Chroma and hue values compared to the other treatments. There was no significant difference in the cookie spread ratio. Proximate composition, water absorption index (WAI), water solubility index (WSI) and gelatinization properties of the flour treatments were characterized. PMID- 29387365 TI - Quality properties of puffed corn snacks incorporated with sesame seed powder. AB - Puffed corn snacks are tasty and affordable cereal-based food products which have a relatively poor nutritional quality. Sesame seed is a rich source of essential amino and fatty acids, phenolic compounds, tocopherols, and antioxidants. In this study, puffed corn snacks were produced by incorporating sesame powder at 0% (control sample), 5%, 10%, and 15% levels in its formulation and stored at room temperature (24 degrees C) for 60 days. Fatty acid composition, tocopherol, sesamin and sesamolin, phenolic compounds, peroxide value (PV), acidity (AV), and sensory evaluation of the samples were determined. The results indicate that oleic acid content increased and palmitic acid decreased significantly (p < .05) in all the samples at 10% and 15% inclusion levels. The content of phenolic compounds, gamma-tocopherols, sesamin, and sesamolin had significant increases in all the formulated samples. PV results indicated that the formulated samples had a higher stability when the ratio of sesame powder was increased, while the AV values showed a significant increase during storage. Incorporation of 10% sesame powder in the snack formulation had a positive effect on the stability, sensory, and nutritional quality of the product. This approach can be used to modify nutritional quality of this food product and introduce to food market as a relatively healthy snack. PMID- 29387366 TI - Toxicological parameters of albino rats fed with extruded snacks from Aerial yam (Dioscoria bulbifera) and African breadfruit seed (Treculia africana). AB - In this study, safety of novel food from aerial yam and Treculia africana, underutilized food materials with high-nutritive value and health benefits were investigated. Animal experiment involving the use of thirty (30) male albino rats was conducted for 28 days.Thereafter, rats in all groups were sacrificed and blood samples collected for biochemical analysis and hematological assay. Some vital organs were harvested and used for histological analysis. Biochemical and hematological parameters were not significantly p <= .05 different among the treatment and controls. However there was an increase in monocytes, which is a reflection of immune boosting potential of the novel snack. No significant pathological changes were observed in liver and kidney of rats fed with this snack. Rats showed no signs of toxicity within the study period. These findings suggest that product may be safe and useful as an Immune adjuvant. PMID- 29387367 TI - Influence of processing conditions on apparent viscosity and system parameters during extrusion of distiller's dried grains-based snacks. AB - A combination of different levels of distillers dried grains processed for food application (FDDG), garbanzo flour and corn grits were chosen as a source of high protein and high-fiber extruded snacks. A four-factor central composite rotatable design was adopted to study the effect of FDDG level, moisture content of blends, extrusion temperature, and screw speed on the apparent viscosity, mass flow rate or MFR, torque, and specific mechanical energy or SME during the extrusion process. With increase in the extrusion temperature from 100 to 140 degrees C, apparent viscosity, specific mechanical energy, and torque value decreased. Increase in FDDG level resulted in increase in apparent viscosity, SME and torque. FDDG had no significant effect (p > .5) on mass flow rate. SME also increased with increase in the screw speed which could be due to the higher shear rates at higher screw speeds. Screw speed and moisture content had significant negative effect (p < .05) on the torque. The apparent viscosity of dough inside the extruder and the system parameters were affected by the processing conditions. This study will be useful for control of extrusion process of blends containing these ingredients for the development of high-protein high-fiber extruded snacks. PMID- 29387368 TI - The influence of pulsed electric fields and microwave pretreatments on some selected physicochemical properties of oil extracted from black cumin seed. AB - Application of novel technologies such as microwave and pulsed electric fields (PEF) might increase the speed and efficiency of oil extraction. In the present research, PEF (3.25 kV/cm electric field intensity and 30 pulse number) and microwave (540 W for 180 s) pretreatments were used to study the process of oil extraction from black cumin (Nigella sativa) seeds. After applying the selected pretreatments, the oil of seeds was extracted with the use of a screw press and the extraction efficiency, refractive index, oil density, color index, oxidative stability, and chemical components of oil and protein of meal were evaluated. The achieved results expressed that PEF and microwave pretreatments increased the oil extraction efficiency and its oxidative stability. Different pretreatments didn't have any significant influence on the refractive index of black cumin seed oil (p>.05). When microwave and PEF were used, the oil density showed an enhancement as the following: 1.51% and 0.96%, respectively in comparison with the samples with no pretreatments. Evaluation of the extracted oils, using GC/MS analysis indicated that thymoquinone was the dominant phenolic component in the black cumin oil. Finally, the SEM analysis revealed that microwave and PEF can be useful in the extraction of oil from black cumin seeds since these treatments damaged cell walls and facilitated the oil extraction process. PMID- 29387369 TI - Free amino nitrogen concentration correlates to total yeast assimilable nitrogen concentration in apple juice. AB - Yeast assimilable nitrogen (YAN) is essential for yeast growth and metabolism during apple (Malus x domestica Borkh.) cider fermentation. YAN concentration and composition can impact cider fermentation kinetics and the formation of volatile aroma compounds by yeast. The YAN concentration and composition of apples grown in Virginia, USA over the course of two seasons was determined through analysis of both free amino nitrogen (FAN) and ammonium ion concentration. FAN was the largest fraction of YAN, with a mean value of 51 mg N L-1 FAN compared to 9 mg N L-1 ammonium. Observed YAN values ranged from nine to 249 mg N L-1, with a mean value of 59 mg N L-1. Ninety-four percent of all samples analyzed in this study contained <140 mg N L-1 YAN, a concentration generally considered the minimum level needed in grape-based wines for yeast to fully utilize all of the fermentable sugars. FAN concentration was correlated with total YAN concentration, but ammonium concentration was not. Likewise, there was no correlation between FAN and ammonium concentration. PMID- 29387370 TI - Synthesis of descriptive sensory attributes and hedonic rankings of dried persimmon (Diospyros kaki sp.). AB - This work aimed to characterize the sensory attributes of hot air-dried persimmon (Diospyros kaki) chips, correlate these attributes with consumer hedonic information, and, by doing so, present recommendations for cultivars that are most suitable for hot-air drying. A trained sensory panel evaluated dried persimmon samples (representing 40 cultivars) for flavor, taste/aftertaste, and texture. In addition, in each of two tests conducted in different years, more than 100 consumers provided hedonic evaluations of 21 unique samples in a ranking task with a balanced incomplete block design. A partial least squares regression model correlating the mean hedonic ranking to the trained panel data was developed using the data from the first consumer panel. The predictions from the model were correlated with the second panel to verify the model. It was found that including taste, aftertaste, and texture data (but not specific flavor attribute data) produced a predictive model (Spearman's rho=0.83). This indicates that flavor is likely secondary to taste and texture in dried persimmon chips. Using the validated predictive model, 6 of the 40 persimmon cultivars tested are recommended for a dried chip product; these cultivars are 'Fuyu', 'Lycopersicon', 'Maekawa Jiro', 'Nishimura Wase', 'Tishihtzu', and 'Yotsumizo'. PMID- 29387371 TI - Antihyperglycemic and antidyslipidemic activity of Musa paradisiaca-based diet in alloxan-induced diabetic rats. AB - This study was aimed at investigating the antihyperglycemic and antidyslipidemic activity of Musa paradisiaca-based diets in alloxan-induced diabetic mellitus rats. Diabetes was induced by a single intraperitoneal injection of alloxan (150 mg/kg b.w) in 48 randomly selected rats. The rats were randomly grouped into four as follows: normal rats fed Dioscorea rotundata-based diet, diabetic control rats fed D. rotundata-based diet, diabetic rats fed D. rotundata-based diet and administered metformin (14.2 mg/kg body weight) orally per day, and diabetic rats fed M. paradisiaca-based diet. Body weight and fasting blood glucose level were monitored, on 28th days the rats were sacrificed, liver was excised. Thereafter, the hyperglycemic and dyslipidemic statii of the induced diabetic animals were determined. The M. paradisiaca-based diet significantly (p < .05) reversed the levels of fasting blood glucose, with significant (p < .05) increase in insulin and glycogen concentrations. The diet also increased the activity of hexokinase with significant reduction (p < .05) in glucose-6-phosphatase and fructose-1-6 diphosphatase activities. M. paradisiaca-based diet demonstrated significant reduction (p < .05) in cholesterol, triacylglycerol (TG), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and significant increase (p < .05) in high-density lipoprotein (HDL) compared with those of diabetic control group. Also, M. paradisiaca-based diet significantly (p < .05) reversed the activities of aspartate aminotransferase and alanine aminotransferase when compared with diabetic control animals. The consumption of this diet may be useful in ameliorating hyperglycemia and dyslipidemia in diabetes mellitus patients. PMID- 29387372 TI - Effect of isolation techniques on the characteristics of pigeon pea (Cajanus cajan) protein isolates. AB - In this study, the effect of different isolation techniques on the isolated proteins from pigeon pea was investigated. Water, methanol, ammonium sulfate, and acetone were used for the precipitation of proteins from pigeon pea. Proximate composition, and antinutritional and functional properties of the pigeon pea flour and the isolated proteins were measured. Data generated were statistically analyzed. The proximate composition of the water-extracted protein isolate was moisture 8.30%, protein 91.83%, fat 0.25%, ash 0.05%, and crude fiber 0.05%. The methanol-extracted protein isolate composition was moisture 7.87%, protein 91.83%, fat 0.17%, and ash 0.13%, while crude fiber and carbohydrates were not detected. The composition of the ammonium sulfate-extracted protein isolate was moisture 7.73%, protein 91.73%, fat 0.36, ash 0.13%, and crude fiber 0.67%. The acetone-extracted protein isolate composition was moisture 8.03%, protein 91.50%, ash 0.67%, and fat 0.30%, but crude fiber and carbohydrates were not detected. The isolate precipitated with ammonium sulfate displayed the highest foaming capacity (37.63%) and foaming stability (55.75%). Isolates precipitated with methanol and acetone had the highest water absorption capacity (160%). Pigeon pea protein isolates extracted with methanol and ammonium sulfate had the highest oil absorption capacity of 145%. Protein isolates recovered through acetone and methanol had the highest emulsifying capacity of 2.23% and emulsifying stability of 91.47%, respectively. The proximate composition of the recovered protein isolates were of high purity. This shows the efficiency of the extraction techniques. The isolates had desirable solubility index. All the isolation techniques brought significant impact on the characteristics of the isolated pigeon pea protein. PMID- 29387373 TI - Visual evaluation of sliced Italian salami by image analysis. AB - Visual inspection is an important part of quality control not only for manufacturers but also for retailers and consumers. The object of this investigation was to determine fat content in sliced salami by means of image analysis. The image analysis procedure is applied to digital images of sliced Italian salami produced in 16 different salami factories (A-P). The image analysis method described in this work is nondestructive and the necessary equipment is cheap. It extracts directly interpretable parameters of fat particle morphology (e.g., area, roundness) and number of fat particles from 15 digital images for each sample (A-P). The correlations between the fat features extracted from the images with the chemical fat content measured on the samples were also studied. Good relationships were found between the fat particle characteristics measured by image analysis procedure and the percentage of chemically extractable fat by correlation (R2=0.75) and principal component analysis. PMID- 29387374 TI - Sensory evaluation of biscuits enriched with artichoke fiber-rich powders (Cynara scolymus L.). AB - The artichoke by-products from the canning industry are mainly used for silage, being minimally revaluated. The ways of extraction of by-products of artichoke into fiber-rich powders modify their industrial applications in biscuits, as the sensory evaluation may change compared with the reference fiber (Pea fiber, P) used with commercial biscuit. In this sensory study biscuits enriched with fiber rich powders of artichoke (W, Ca) are compared with biscuits with the same percentage of the reference fiber (P) and control biscuits without fiber (B). For most of the sensory attributes of the biscuits enriched with artichoke fiber-rich powders were perceived similar to the biscuits with the commercial reference fiber (P). The good sensory behavior of the biscuits with artichoke fiber-rich powders during two storage conditions applied may confirm that the artichoke by products would be a suitable substitute for pea fiber in oven-baked products, like wholemeal biscuits with high-fiber content. PMID- 29387375 TI - Anthocyanin pigment stability of Cornus mas-Macrocarpa under treatment with pH and some organic acids. AB - The use of colors in food industry is essential for the creation of new products or their improvement. As an important pigment group, anthocyanin could be used as a natural coloring pigment in foods. This study aims at exploring strategies that result in color stability of anthocyanin in pear-shaped variety of blueberry (Cornus mas-Macrocarpa). In this study, the effects of different pH values (1, 2, 3, 4) as well as various concentrations (0, 120, 240, 480, 960 mg/L) of five copigments, including tannic, caffeic, benzoic, and coumaric acids, on anthocyanin copigment complexes (ratio 1:1) were investigated. The studied copigments were tannic, caffeic, benzoic, and coumaric acids. Anthocyanin was influenced by the highest concentration of 960 mg/L copigment in the presence of different pHs. Five groups were considered, one of which contained anthocyanin without copigment and the rest consisted of copigments. To evaluate the response of copigmentation through spectrophotometer, absorbance from samples was measured after 30 min of adding copigment to anthocyanin in the range of 450-600 nm wavelengths. The results showed that caffeic acid possessed the greatest anthocyanin stability compared to other copigments and it was the best copigment. An increase in the concentrations of copigments led to a higher level of anthocyanin stability and changes in hyperchromic and bathochromic. Moreover, the results revealed that the strongest hyperchromic effect for all organic acids was observed in pH 2, and the strongest bathochromic changes were observed in pH 4. PMID- 29387376 TI - Orange-fleshed sweet potato (Ipomoea batatas) composite bread as a significant source of dietary vitamin A. AB - Refining food recipes with orange-fleshed sweet potato (OFSP) has the potential to improve dietary intake of vitamin A. The objectives of this study were to utilize OFSP in the development of two composite bread types and to assess their contribution to dietary intake of vitamin A using the dietary reference intake of lactating mothers. Two composite OFSP-wheat flour bread recipes-vita butter bread and vita tea bread-were developed by incorporating 46% OFSP puree in existing 100% wheat flour bread recipes consumed by Ghanaians. A paired-preference test was used to profile the appearance, aroma, sweetness, and overall degree of liking of the vita butter bread and vita tea bread and their respective 100% wheat flour bread types. Weighed bread intake by lactating mothers (n = 50) was used to estimate the contribution to dietary vitamin A based on the trans beta carotene content. The developed vita butter bread and vita tea bread were most preferred by at least 77% (p < .05) of consumers (n = 310) for all the attributes considered. The average daily intake by the lactating mothers for vita butter bread was 247 g, and for vita tea bread was 196 g. The trans beta-carotene content of vita butter bread and vita tea bread were found to be 1.333 mg/100 g and 0.985 mg/100 g, respectively. The estimated trans-beta-carotene intake was 3,293 MUg/day (vita butter) and 1,931 MUg/day (vita tea) based on the weighed bread intake, respectively, meeting 21% and 12% of the daily requirement (1,300 MUg RAE/day) for lactating mothers, the life stage group with the highest vitamin A requirement. OFSP therefore could composite wheat flour to bake butter and tea bread, and will contribute to significant amount of dietary intake of vitamin A. PMID- 29387377 TI - Mycofloral profile and the radiation sensitivity (D10 values) of solar dried and gamma irradiated Pleurotus ostreatus (Jacq.Ex. Fr.) Kummer fruitbodies stored in two different packaging materials. AB - The presence of fungi in our foods poses serious health risks as some genera of fungi may produce certain mycotoxins which have carcinogenic, mutagenic, teratogenic, and immunosuppressive effect on humans and animals alike. Fruitbodies of Pleurotus ostreatus were solar dried at a moisture content of 12.5 +/- 0.2% and stored in polythene and polypropylene packs, gamma irradiated at doses of 0 (control), 1, 2, 3, 4, and 5 kGy at a dose rate of 1.7 kGy/hr from a Cobalt 60 source (SLL, 515, Hungary) and stored at room temperature 28-30 degrees C for a period of 12 months. Mycological analyses were done at intervals of 0, 3, 6, and 12 months. A total of eleven (11) fungi belonging to eight fungal genera were isolated on both Cooke's and DRBC media; Aspergillus (A. niger, A. flavus, A. fumigatus, A. tamarii), Rhizopus (R. oligosporus), Mucor (M. racemosus), Fusarium (F. oxysporum), Penicillium (Penicillium sp.), Trichoderma (T. viride), and Rhodotorula sp. were recorded. There was a significant (p < .05) reduction in initial mycofloral population by an average of 2.2 log cycles as well as in species numbers with increasing doses of radiation. Radiation sensitivity (D10 values) also ranged between 1.68-2.78 kGy. Gamma irradiation treatment is one way which can enhance food safety through the reduction in potential pathogens and has been recommended as part of a comprehensive program to enhance food safety. PMID- 29387378 TI - Microwave-assisted extraction and ultrasound-assisted extraction for recovering carotenoids from Gac peel and their effects on antioxidant capacity of the extracts. AB - The peel of Gac fruit (Momordica cochinchinensis Spreng.) contains high levels of bioactive compounds, especially carotenoids which possess significant antioxidant capacities. However, the peel of Gac is regarded as a waste from the production of carotenoid-rich oil from Gac fruit. In this study, carotenoids of Gac peel were extracted by microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE) using ethyl acetate as extraction solvent. The effect of extraction time and different levels of microwave and ultrasonic powers on the yield of total carotenoid and antioxidant capacity of the extracts were investigated. The results showed that an extraction at 120 W for 25 min and an extraction at 200 W for 80 min were the most effective for MAE and UAE of the Gac peel samples, respectively. The maximum carotenoid and antioxidant capacity yields of UAE were significantly higher than those of the MAE. The antioxidant capacity of extract obtained by the UAE was also significantly higher that of the conventional extraction using the same ratio of solvent to material. The results showed that both MAE and UAE could be used to reduce the extraction time significantly in comparison with conventional extraction of Gac peel while still obtained good extraction efficiencies. Thus, MAE and UAE are recommended for the improvement of carotenoid and antioxidant capacity extraction from Gac peel. PMID- 29387379 TI - Effects of 3 months continuous intake of supplement containing Pantoea agglomerans LPS to maintain normal bloodstream in adults: Parallel double-blind randomized controlled study. AB - In this study, the effects on the maintenance of normal bloodstream by lipopolysaccharide (LPS) were investigated in the parallel-group randomized double-blind study using supplement containing Pantoea agglomerans LPS (201.5 MUg/tablet as LPS). Screening was previously performed in the implementation of the study. Adult males and females with normal value to borderline (healthy subjects) in the hematologic parameters, for which reference values were given, were chosen in this study. The period of ingestion of the supplement was 3 months. As the result, a significant decrease in the rate of change (the ratio when the baseline was 1) of HbA1c, which is a glycative stress marker, was found in the group which ingested LPS supplement after 3 months. Also, a significant increase in the number of fingertip capillary vessels was found compared with the control group. From these results, the effects of the maintenance of bloodstream by ingestion of LPS were shown. PMID- 29387380 TI - Nutritional value of raw Canavalia ensiformis and its utilization as partial replacement for soybean meal in the diet of Clarias gariepinus (Burchell, 1822) fingerlings. AB - The nutritional value of raw Jack bean meal (Canavalia ensiformis) as a partial substitute for soybeans meal was investigated in this study. Preliminary investigation on nutrient composition revealed that lysine, histidine, and phenylalanine were significantly higher in C. ensiformis seed meal compared to soybean meal. However, crude protein and other essential amino acids were significantly lower. Feeding trial was then conducted to investigate the effect of replacing about 40% soybeans meal (at 58.8% inclusion) with C. ensiformis in the diet of Clarias gariepinus. The result obtained after 56 days revealed that fingerlings could tolerate up to 20% replacement without significant effect on growth and nutrient utilization. Beyond this, growth was significantly reduced. Survivals of the fish also follow a similar trend as stated above. It was concluded that dietary inclusion of raw C. ensiform meal should not be beyond 11% (or 20% replacement for soybeans meal included at 58.8%) in the diet of C. gariepinus. PMID- 29387381 TI - Small amounts of ethanol attenuate folic acid stability in acidic beverages during storage. AB - Folic acid (FA) is an essential compound involved in important biochemical processes and is used to fortify various food products. FA in fortified acidic beverages decomposes during storage due to H+ attack. FA stability in acidic beverages is a serious problem as food fortification should guarantee labeled FA concentrations until the expiry date. In this study, we investigated the influence of ethanol (EtOH) on FA depletion using a model acidic beverage and observed that small amounts of EtOH, derived from added flavor, promoted FA depletion. FA depletion was promoted by only small amounts of EtOH, but not by acetonitrile. This suggested that FA decomposition might be accelerated by EtOH, which surrounds FA molecules in solution due to selective solvation. In the development of FA-fortified beverages, EtOH content should be decreased or removed altogether, to prevent accelerating FA decomposition. PMID- 29387382 TI - Evaluation of the glycemic indices of three commonly eaten mixed meals in Okada, Edo State. AB - People do not generally eat single or individual meals; rather they eat mixed meals, consisting of two or more individual meals. These mixed meals usually have glycemic indices which differ from that of the individual food type. This study was aimed at evaluating the glycemic indices of three commonly consumed mixed meals eaten in Okada; rice and beans (test food 1), rice and plantain (test food 2), beans and plantain (test food 3). Two hundred and forty healthy subjects aged between 18 and 30 participated in this study. They were randomized into three groups of eighty persons each, and fed with the standard food (50 g glucose) on day one and one of the test foods on day two, after an overnight fast. Blood samples were taken at 0, 30, 60, 90, and 120 min after the food had been eaten. The results showed that the Glycemic Index (GI) values for the test foods were high: 86.60 (test food 1), 89.74 (test food 2), 86.93(test food 3). The incremental increase in blood glucose was monitored and calculated for each food and when compared with that of the standard food (glucose), there was significant differences (p < .036) for test food 1 and (p < .068) for test food 3; both at 30 min. At 120 min, no significant differences in blood glucose levels were observed (p > .05). The results from this study indicated that the GI of the mixed meals was affected by the constituent nutrient and the response is also affected by the proportion of each nutrient. Our findings show that the selected test foods (mixed meals) consumed in Okada have high GI values. PMID- 29387383 TI - Nutritional, physicochemical, and functional properties of protein concentrate and isolate of newly-developed Bambara groundnut (Vigna subterrenea L.) cultivars. AB - Bambara groundnut is an indigenous African vegetable grown mainly for human food and animal feed due to its high protein content. Different factors like varieties and origin can influence the chemical composition of Bambara groundnut cultivars. Therefore, the aims of this study are to produce defatted flour and protein concentrate from newly developed Bambara groundnut cultivars [Accessions No: TVSU 5 - Bambara Groundnut White (BGW) and TVSU 146 - Bambara Groundnut Brown (BGB)] and compare their nutritional, physicochemical, and functional properties with market sample [Bambara groundnut commercial (BGC)]. Higher protein content was observed in BGW (20.73%) and BGB (20.14%) as compared to BGC (18.50%). Also, the fat and ash contents of BGB and BGW were higher than that of BGC. Also, the new varieties were found to contain higher levels of some essential fatty acids such as linoleic and linolenic acids. The concentration of thiamine, riboflavin, niacin, pantothenic, ascorbic acids, pyrodoxine, alpha tocopherol, and vitamin K were also significantly higher in the two new varieties. The new varieties were good sources of magnesium, calcium, iron, manganese, sodium, and potassium. The oil and water absorption and swelling capacities of whole, defatted, and protein concentrate flour of the new varieties increase with increase in temperature. The defatted flour and protein concentrate of brown Bambara groundnut was found to exhibit high emulsifying activity and stability at different pH's and salt concentrations. The new varieties possess significantly higher foaming capacity and stability than the commercial variety. The results obtained from this study have shown the potential for the industrial and household use of the new Bambara groundnut cultivars into shelf stable protein products and could be a useful ingredient in food formulations. PMID- 29387384 TI - A decade bibliometric analysis of global research on leishmaniasis in Web of Science database. AB - Background: Leishmaniasis is an extremely relevant tropical disease, with global distribution. It still remains a main public health concern in low-income countries, and it is necessary to support more research on this common disease. Thus, a bibliometric analysis of the global scientific production on leishmaniasis was carried out. Methods: All the articles registered in Web of Science with the subject of leishmaniasis between 2006 and 2015 were analysed, using Pajek and VOS viewer as tools. Results: 13,658 records in the field of leishmaniasis were indexed in the Web of Science database for this ten-year study period (2006-2015). This shows that studies on leishmaniasis have been growing, from 1071 in 2006 to 1537 in 2015. "Sundar S" is the most active researcher in the field of leishmaniasis, compiling and participating in 232 Articles. Brazil ranks first in scientific production, by performing 3315 studies on leishmaniasis. The United States, United Kingdom and Australia had the most collaboration in performing the studies of leishmaniasis with each other. In addition, PLOS NEGLECTED TROPICAL DISEASES published the most articles, with 483. Conclusion: Our data shows an increase in the number of publications in the field of leishmaniasis. In addition, Brazil, USA, and India lead scientific production on leishmaniasis research. PMID- 29387385 TI - Functional characterization of oligopeptide transporter 1 of dairy cows. AB - Background: It is well known that peptides play a vital role in the nutrition and health of dairy cows. Bovine oligopeptide transporter 1 (bPepT1) is involved in the peptide transport process in the gastrointestinal tracts of dairy cows. However, little information is known in the characteristics of bPepT1. Therefore, the purpose of this study was to characterize bPepT1 functionally using a mammalian cell expression system. The uptake of radiolabeled dipeptide glycyl sarcosine ([3H]-Gly-Sar) into the bPepT1-transfected Chinese hamster ovary cells was measured at various pH and substrate concentrations and with or without 15 other small peptides that contained Met or Lys. Results: Western blot results showed that the abundance of bPepT1 protein in the jejunum and ileum are the highest in the gastrointestinal tract of dairy cows. The uptake of [3H]-Gly-Sar by bPepT1-Chinese hamster ovary cells was dependent on time, pH, and substrate concentration, with a low Km value of 0.94 +/- 0.06 mmol/L and a maximum velocity of 20.80 +/- 1.74 nmol/(mg protein * 5 min). Most of the di- and tripeptides were the substrates of bPepT1, based on substrate-competitive studies. However, bPepT1 has a higher affinity to the peptides with shorter chains, greater hydrophobicity, and negative or neutral charges. Conclusions: These results demonstrated for the first time the functional characteristics of bPepT1, and they provide a new insight and better understanding into its vital role in absorbing a wide range of peptides from the digestive tract of dairy cows. PMID- 29387386 TI - Body condition score prior to parturition is associated with plasma and adipose tissue biomarkers of lipid metabolism and inflammation in Holstein cows. AB - Background: Previous research has revealed a strong inflammatory response within adipose (AT) tissue during the transition into lactation. Whether this effect is a result of oxidative stress induced by lipolysis and fatty acid oxidation associated with differences in prepartum body condition score remains to be determined. The objectives of this study were to investigate systemic biomarkers of energy balance and inflammation and the expression of lipid metabolism- and inflammation-related genes in AT during the transition period in dairy cows. Results: Twenty multiparous Holstein cows were retrospectively divided by body condition score (BCS) prior to parturition into two groups (10 cows/group): BCS <= 3.25 (LoBCS) and BCS >= 3.75 (HiBCS). Subcutaneous adipose tissue was biopsied from the tail-head region at d - 10, 7 and 20 relative to parturition. Plasma was used to evaluate biomarkers of energy balance (EBAL) [free fatty acids (NEFA), glycerol, insulin] and inflammation [IL-1beta, haptoglobin, myeloperoxidase, and reactive oxygen metabolites (ROM)]. Although insulin concentration was not affected by BCS, NEFA was overall greater and glycerol lower in HiBCS cows. Greater activity of myeloperoxidase in plasma coincided with increased haptoglobin and IL-1beta postpartum in LoBCS cows. Among genes related with oxidative stress, the expression of the cytosolic antioxidant enzyme SOD1 was greater in LoBCS compared to HiBCS. Cows in LoBCS compared with HiBCS had greater overall expression of ABDH5 and ATGL along with ADIPOQ, indicating enhanced basal lipolysis and secretion of adiponectin. Expression of CPT1A, ACADVL, and ACOX1 was greater overall in HiBCS than LoBCS indicating enhanced NEFA oxidation. Although the temporal increase in plasma NEFA regardless of BCS coincided with the profile of CPT1A, the gradual decrease in genes related with re esterification of NEFA (PCK1) and glycerol efflux (AQP7) coupled with an increase in glycerol kinase (GK) suggested some stimulation of NEFA utilization within adipose tissue. This idea is supported in part by the gradual decrease in insulin regardless of BCS. Although expression of the inflammation-related gene toll-like receptor 4 (TLR4) was greater in HiBCS versus LoBCS cows at -10 d, expression of TLR9 was greater in HiBCS versus LoBCS at 20 d. These profiles did not seem to be associated with concentrations of pro-inflammatory biomarkers or ROM. Conclusions: Overall, data indicated that cows with BCS 3.25 or lower before calving experienced greater alterations in systemic inflammation and basal lipolysis without excessive increases in NEFA plasma concentrations. Despite the greater plasma NEFA around parturition, cows with BCS 3.75 or higher seemed to have a more active system for catabolism of NEFA and utilization of glycerol within adipose tissue. A linkage between those pathways and risk of disorders postpartum remains to be determined. PMID- 29387387 TI - Case finding of Alpha-1 antitrypsin deficiency: never wasted time! PMID- 29387389 TI - Oral administration of salmon cartilage proteoglycan extends the survival of allografts in mice. AB - Proteoglycan (PG) is a complex glycohydrate that is widely distributed in the extracellular matrix. Oral administration of PG extracted from salmon nasal cartilage has been reported to attenuate the severity and proinflammatory cytokine responses in mouse experimental colitis, autoimmune encephalomyelitis, collagen-induced arthritis and obesity-induced inflammation. In the present study, the effects of salmon nasal cartilage PG on skin allografts were investigated in a mouse model. Oral administration of PG prolonged the survival of skin grafts within 10 days of transplantation. Although PG failed to inhibit allograft rejection at the final stage of transplantation, PG attenuated the cell infiltration in the skin under the transplanted site. PMID- 29387388 TI - Increased serum chemerin level to predict early onset of aortic valve stenosis. AB - Inflammation appears to be the cause of aortic valve (AoV) stenosis and identification of predictive biomarkers is therefore imperative. The aim of the current study was to evaluate the potential role of serum chemerin and fibroblast growth factor-21 (FGF-21) in the pathogenesis of the disease. A total of 102 patients were selected based on certain criteria and divided into an aortic stenosis group and a control group. Patients with AoV stenosis were subdivided into three groups depending on the severity according to the echocardiography criteria: Aortic jet velocity, Vmax (m/sec); mean pressure gradient, PG (mmHg); aortic valve area (AVA), cm2; and indexed AVA, cm2/m2. Patients were graded as: Severe: Vmax >4 m/sec, PG >40 mmHg, AVA <1.0 cm2, indexed AVA <0.6; moderate: Vmax 3.0-4.0 m/sec, PG 20-40 mmHg, AVA 1.0-1.5 cm2, indexed AVA 0.60-0.85; mild: Vmax 2.5-2.9 m/sec, PG <20 mmHg, AVA >1.5 cm2, indexed AVA >0.85. ELISA was used for the detection of chemerin and FGF-21. Post-hoc analysis with Tukey's correction was performed. The highest chemerin levels were found in mild and moderate AoV stenosis and decreased along with the grade of severity, compared with the control group. The FGF-21 level was increased in all the stenosis groups, reaching the highest level at severe stenosis. Receiver-operating characteristic analysis of chemerin in all the AoV stenosis groups without grading the severity included, area under the curve (AUC)=0.76; 0.70-0.80= fair; P<0.001 and for mild AoV stenosis was AUC=0.82; 0.80-0.90= good; P<0.001. In conclusion, chemerin is a good diagnostic biomarker for mild AoV stenosis, while FGF-21 is a moderate diagnostic marker. PMID- 29387390 TI - Mutation analysis of Leber's hereditary optic neuropathy using a multi-gene panel. AB - The present study investigates the spectrum and incidence of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in a Han population using a multi-gene panel with 46 LHON-associated mutations among 13 mitochondrial genes. A total of 23 mutations were observed in a cohort of 275 patients and 281 control subjects using multi-gene panel analysis. The causative mutations associated with LHON were identified to be m.11778G>A, m.14484T>C, m.3460 G>A, m.3635G>A, m.3866T>C and m.3733G>A, responsible for 70.55% cases in the patient cohort. The secondary mutations in the Chinese LHON population were m.12811T>C, m.11696 G>A, m.3316G>A, m.3394T>C, m.14502T>C, m.3497C>T, m.3571C>T, m.12338T>C, m.14693A>G, m.4216T>C and m.15951A>G, with incidences of 5.09, 4.36, 4.00, 4.00, 4.00, 2.55, 1.82, 1.82, 1.45, 1.09 and 1.09%, respectively. Besides three hotspot genes, MT-ND1, MT-ND4 and MT-ND6, MT-ND5 also had a high incidence of secondary mutations. Those mutations reported as rare causative mutations in a European LHON population, m.3376G>A, m.3700G>A and m.4171C>A, m.10663T>C, m.13051G>A, m.14482C>G/A, m.14495A>G and m.14568C>T were undetected in the present study. The primary and secondary mutations associated with LHON in the present multi-gene panel will advance the current understanding of the clinical phenotype of LHON, and provide useful information for early diagnosis. PMID- 29387391 TI - Low levels of linoleic acid and alpha-linolenic acid and high levels of arachidonic acid in plasma phospholipids are associated with hypertension. AB - Dietary fat is an important determinant in the development and progression of high blood pressure (BP), a major risk factor for cardiovascular diseases and mortality. The aim of the present study was to determine the association between plasma phospholipid fatty acids and hypertension in Japanese men. The plasma level of linoleic acid (LA) in the subjects with hypertension (systolic BP >=140 mmHg and/or diastolic BP >=90 mmHg) was identified to be significantly higher than that in the healthy controls. Following adjustment for age, body mass index, physical activity, smoking status, alcohol consumption, salt intake, and serum levels of glucose and hemoglobin A1c, higher plasma levels of LA and alpha linolenic acid (ALA), and lower levels of arachidonic acid (AA) were significantly associated with a lower prevalence of hypertension. The odds ratio (OR) for the highest quartile (Q4) versus the lowest quartile (Q1) of LA was 0.17 (P=0.003), the OR for Q4 versus Q1 of ALA was 0.26 (P=0.042) and the OR for Q4 versus Q1 of AA was 2.04 (P=0.047). These results indicate that elevated levels of LA and ALA, and reduced levels of AA in the plasma prevent hypertension. PMID- 29387392 TI - Effect of recombinant human prourokinase on thrombolysis in a rabbit model of thromboembolic stroke. AB - The aim of the present study was to investigate the efficacy of recombinant human prourokinase (rhPro-UK) on thromboembolic stroke in rabbits. A total of 210 rabbits were used in experiments. The 180 thromboembolic stroke rabbits were divided into three therapeutic time windows with six groups in each time window (n=10). The model group was administered saline, the reagent groups were administered rhPro-UK (2.5*, 5* and 10*104 U/kg), and the positive control groups were administered 5*104 urokinase (UK) U/kg and 4.5 mg/kg recombinant human tissue plasminogen activator via intravenous infusion at 3, 4.5 and 6 h after embolism. The remaining 30 rats (that had not undergone occlusion by autologous blood clots) served as a sham group and were administered saline. The radioactive intensity was detected using a medical gamma counter before and after the administration of the drug for 15, 30, 45, 60, 75, 90, 105 and 120 min. At 24 h after treatment, the brain samples were coronally sliced into 5 mm sections and hemorrhage was estimated used a semiquantitative method by counting the number of section faces with hemorrhaging. The plasma was collected for prothrombin time, activated partial thromboplastin time, fibrinogen and thrombin time tests using a solidification method with a blood coagulation factor analyzer. In addition, alpha2-antiplasmin (alpha2-AP) was evaluated using ELISA methods using a RT-6100 microplate reader. At the 3 h time point, the thrombolysis rate of rhPro-UK(2.5*, 5* and 10*104 U/kg) was 21.5% (P<0.05), 36.8% (P<0.001) and 55.0% (P<0.001), respectively together with patency rates of 10% (P>0.05), 40% (P<0.05) and 70% (P<0.001). Furthermore, alpha2-AP levels were reduced by 5.3% (P>0.05), 5.3% (P>0.05) and 18.1% (P<0.05). At the 4.5 h time point, the thrombolysis rate was 18.8% (P<0.05), 29.9% (P<0.01) and 49.0% (P<0.001) together with patency rates of 10% (P>0.05), 30% (P<0.05) and 50% (P<0.01), and alpha2-AP levels were reduced by 2.4% (P>0.05), 6.5% (P>0.05) and 17.8% (P<0.05). At the 6 h time point, the thrombolysis rate was 14.7% (P<0.05), 24.1%(P<0.01) and 35.7% (P<0.001) together with patency rates of 20% (P>0.05), 30% (P<0.05) and 40% (P<0.01), and alpha2-AP levels were reduced by 5.7% (P>0.05), 12.7% (P>0.05) and 22.2% (P<0.01). No significant differences (P>0.05) were identified between rhPro-UK (2.5*, 5* and 10*104 U/kg) and the model group regarding hemorrhage type, size and blood coagulation factors at the different time points. Thus, rhPro-UK promoted thrombolysis and recanalization (patency rate), with reduced risk of cerebral hemorrhage, and thus exerted protective effects on cerebral ischemia rabbits. PMID- 29387393 TI - Denosumab as a potential therapeutic option for leiomyosarcoma with osteoclast like giant cells: A case report. AB - Bone leiomyosarcoma is a rare primary osseous malignant tumor with a high metastatic potential. Similar to other bone sarcomas, high histological grade and tumor stage are predictive of a poor outcome. We herein present our experience with treating a 64-year-old woman with bone leiomyosarcoma accompanied by multiple bone metastases. A biopsy revealed occasional osteoclast-like giant cells. In addition to radiation therapy, the osteoclastogenesis inhibitor denosumab was administered but the patient did not undergo adjuvant chemotherapy or surgery. Good clinical and short-term radiological responses to denosumab have been observed for 2 years. Therefore, denosumab may represent a viable treatment option without the need for adjuvant chemotherapy. PMID- 29387394 TI - Multiple intracranial metastases from postoperative giant sarcomatoid malignant pleural mesothelioma: A case report and literature review. AB - Sarcomatoid malignant pleural mesothelioma (SMPM) is a rare tumor with poor response to treatment and a dismal prognosis. Distant metastases are not uncommon and usually appear at the late stages of the disease. However, cerebral metastases have rarely been documented. We herein report a case of a giant sarcomatoid carcinoma of the pleura in a 41-year-old male patient with no history of exposure to asbestos, who presented with a chief complaint of left-sided chest pain for 1 month. Extrapleural pneumonectomy and rib excision were performed. At 5 months after the surgery, the patient was diagnosed with multiple intracranial metastatic neoplasms and succumbed to the disease soon thereafter. The aim of the present case report was to emphasize this rare metastatic pattern and aggressive clinical course of SMPM, with a supplementary review of the previously published literature. PMID- 29387395 TI - Two-stage study of lung cancer risk modification by a functional variant in the 3'-untranslated region of SMAD5 based on the bone morphogenetic protein pathway. AB - Increasing evidence supports a key role for the bone morphogenetic protein (BMP) signaling pathway in lung vasculogenesis and angiogenesis. Genetic variations in BMP genes have been found to be correlated with cancer risk. In particular, the mutation in the 3'-untranslated region of BMPs may significantly affect gene function, leading to cancer susceptibility. The aim of the present study was to determine whether genetic variations in the components of the BMP family are associated with lung cancer risk. A total of 314 tag single-nucleotide polymorphisms were identified in 18 genes, which are considered to either compose or regulate BMPs, and their association with lung cancer risk was evaluated in a two-stage case-control study with 4,680 cases and controls. A consistently significant association of SMAD5 rs12719482 with elevated lung cancer risk was observed in the three types of sources of populations (adjusted additive model in the combined population: Odds ratio=1.32, 95% confidence interval: 1.16-1.51). The lung cancer risk statistically significantly increased with the increasing number of variant alleles of SMAD5 rs12719482 in a dose-dependent pattern (P for trend=4.9*10-5). Consistent evidence was identified for a significant interaction between the rs12719482 and cigarette smoking, performed as either a continuous or discrete variable. These findings indicated that SMAD5 rs12719482 may be a possible candidate marker for susceptibility to lung cancer in the Chinese population. PMID- 29387396 TI - Impact of body mass index on clinicopathological outcomes in patients with renal cell carcinoma without anorexia-cachexia syndrome. AB - Although obesity defined by a high body mass index (BMI) is generally associated with increased risk of renal cell carcinoma (RCC), low BMI has paradoxically been associated with increased tumor aggressiveness and poor prognosis. As anorexia cachexia syndrome (ACS) is associated with decreased BMI and is frequently observed in patients with advanced RCC, the present study investigated the association of BMI with tumor aggressiveness and prognosis in RCC in relation to ACS. The association of BMI with clinicopathological parameters was analyzed in 503 consecutive patients who underwent surgery for RCC. Kaplan-Meier curves and rates of overall survival (OS) stratified by BMI were also compared in relation to the presence or absence of ACS, defined as the presence of anorexia or malaise, and/or weight loss and/or hypoalbuminemia. Low BMI was significantly associated with high-grade tumors (P=0.0027) and the presence of distant metastasis (P=0.0025), and patients with a lower BMI had significantly shorter OS than those with a higher BMI (P=0.0441). Patients with ACS had a significantly lower BMI (mean, 21.5 kg/m2) than those without ACS (mean, 23.5 kg/m2; P<0.0001) and had significantly shorter OS than those without ACS (P<0.0001). On multivariate analysis, ACS was an independent predictor of short OS [P=0.0089; hazard ratio (HR), 2.21; 95% confidence interval (CI), 1.22-3.92] and short cancer-specific survival (P=0.0308; HR, 2.03; 95% CI, 1.07-3.78); however, BMI was not (P=0.5440 and P=0.6804, respectively). In the 413 patients without ACS at initial presentation, BMI was not associated with any clinicopathological parameters or OS (log-rank, P=0.4591). BMI itself was not a predictor of survival in patients without ACS, and the association between low BMI and increased tumor aggressiveness and poor prognosis could be due to ACS. PMID- 29387397 TI - Impact of the histological phenotype of extrahepatic bile duct carcinoma. AB - The classification of histological phenotypes was originally conceived for pancreatic intraductal papillary mucinous neoplasms. Recently, it has been introduced for extrahepatic cholangiocarcinoma. The aim of the present study was to clarify the associations between histological phenotype and clinicopathological features of extrahepatic cholangiocarcinoma, using 99 cases of surgically-resected extrahepatic cholangiocarcinoma. All cases were divided into one of two histological phenotypes: Biliary-type (BT; 56 cases, 56.6%) or metaplastic-type (MT; 43 cases, 43.4%). The clinicopathological features were compared between these two phenotypes. BT tumors exhibited significantly poorer differentiation, more frequent lymph node metastasis (BT vs. MT, 42.9 vs. 30.2%; P=0.042), more severe venous invasion (v2-3: BT vs. MT, 64.3 vs. 23.3%; P<0.001), and more severe perineural invasion (ne2-3: BT vs. MT, 78.6 vs. 48.8%, P=0.002). Furthermore, the overall (P=0.015) and disease-free (P=0.003) survival times were significantly decreased in patients with BT vs. MT tumors. In conclusion, extrahepatic cholangiocarcinoma with a BT phenotype has greater malignant potential, and may be an important predictive factor for poor prognosis. PMID- 29387398 TI - Potential role of post-treatment follow-up FDG-PET CT to detect mandibular osteoradionecrosis: A case report. AB - It was hypothesized that fluorodeoxyglucose (FDG) uptake on post-treatment follow up positron emission tomography with computed tomography (PET CT; using PET CT to monitor and rule out recurrence and metastasis of head and neck carcinoma) would be useful for detecting and understanding the disease state of osteoradionecrosis (ORN) of the jaw. The present study included 14 patients who developed mandibular ORN following radiation therapy (RT) for head and neck cancer and underwent follow-up PET CT several times following RT. Areas exhibiting FDG uptake were retrospectively assessed on post-treatment follow-up PET CT images and were classified into three types: Spot type: Only spot accumulation of FDG; localized type: Accumulation of FDG restricted to within the bone resorption area; extensive type: Accumulation of FDG extending into surrounding soft tissue. PET classification at the time of clinical diagnosis of mandibular ORN in the 14 patients demonstrated the extensive type in 43%, localized type in 36% and spot type in 21%. An increased area of FDG uptake around the ORN was revealed retrospectively on post-treatment follow-up FDG PET-CT images in 50% of patients. Alterations in PET classification included spot type to localized type in 36% and localized type to extensive type in 14%. A significantly increased number of patients with extensive-type ORN (P=0.026) required surgery. Post-treatment follow-up FDG-PET CT may be useful for early detection and better understanding of ORN. PMID- 29387399 TI - S-1 vs. paclitaxel plus carboplatin as adjuvant chemotherapy for completely resected stage II/IIIA non-small-cell lung cancer. AB - The majority of patients with completely resected stage II or IIIA non-small-cell lung cancer (NSCLC) require adjuvant chemotherapy to improve survival following surgery. In the present trial, the 2-year disease-free survival (DFS), and the feasibility and safety of S-1 as an adjuvant chemotherapy for advanced lung cancer were evaluated. A total of 40 patients with completely resected stage II or IIIA NSCLC were enrolled and randomized to receive postoperative chemotherapy with either up to 4 cycles of paclitaxel plus carboplatin (arm A) or with up to 1 year of S-1 (arm B). The primary endpoint was 2-year DFS. The secondary endpoints were feasibility and toxicity. A total of 40 patients were enrolled, but 3 were excluded in accordance with the exclusion criteria. The remaining 37 patients were analyzed. The 2-year DFS rate was 54.2% in arm A and 84.2% in arm B. Overall, 15/18 (83.3%) patients completed 4 cycles of paclitaxel plus carboplatin and 13/19 (68.4%) completed 1-year of S-1adjuvant chemotherapy. Of the 18 (16.7%) patients in arm A, 3 experienced grade 3 or 4 adverse events, while none in arm B experienced such events. Therefore, S-1 chemotherapy for patients with completely resected stage II or IIIA NSCLC was a feasible and safe regimen, and it may therefore be considered as a potential adjuvant chemotherapy option for advanced NSCLC. PMID- 29387400 TI - Primary skeletal muscle lymphoma: A case report. AB - Primary lymphomas of the bone or skeletal muscle are rare. Three mechanisms of lymphomatous involvement of the muscle have been described, namely direct invasion from adjacent involved lymph nodes or bone, metastatic spread and, least commonly, primary muscle lymphoma. We herein present a rare case of primary mucle non-Hodgkin lymphoma with a description if the associated clinicopathological findings and a review of the relevant literature. A 41-year-old female patient was referred to our hospital with a painful mass in the right lower extremity. Following resection and histopathological examination, a diffuse large B-cell lymphoma originating from the muscle with cutaneous and subcutanenous infiltration was diagnosed. The patient received chemotherapy with six cycles of cyclophosphamide, hydroxydaunomycin, oncovin and prednisone (CHOP regimen) and a complete radiological response was achieved after six cycles of treatment. PMID- 29387401 TI - Near-infrared intraoperative imaging during resection of an anterior mediastinal soft tissue sarcoma. AB - Sarcomas are rare malignancies that are generally treated with multimodal therapy protocols incorporating complete local resection, chemotherapy and radiation. Unfortunately, even with this aggressive approach, local recurrences are common. Near-infrared intraoperative imaging is a novel technology that provides real time visual feedback that can improve identification of disease during resection. The presented study describes utilization of a near-infrared agent (indocyanine green) during resection of an anterior mediastinal sarcoma. Real-time fluorescent feedback provided visual information that helped the surgeon during tumor localization, margin assessment and dissection from mediastinal structures. This rapidly evolving technology may prove useful in patients with primary sarcomas arising from other locations or with other mediastinal neoplasms. PMID- 29387402 TI - A retrospective survey of the last 3 months of life in patients carrying glioblastoma: Clinical treatments and profiles. AB - Glioblastoma is one of the most common types of primary brain tumor. In situations of local recurrence, physicians can suggest either specific palliative anticancer treatments (SPAT; surgery, chemotherapy, radiotherapy) or best supportive care (BSC). The objective of the present study was to identify clinical factors that may have influenced the continuation or cessation of SPAT during the final 3 months of life in patients with glioblastoma. In the present retrospective single-center study, all records of patients treated for glioblastoma, who succumbed to the disease between June 2006 and February 2014, were assessed. All selected patients were divided into two groups, according to treatments received during the last 3 months of life: The SPAT and BSC groups. A total of 148 patients were included: 81 patients in the SPAT group (group A) and 67 patients in the BSC group (group B). A performance status equal to 0 was observed for 17.3% of patients in group A vs. 6% in group B. Following progression, chemotherapy was administered in 39.5% of cases in group A vs. 20.9% of cases in group B (P=0.0149). The mean number of lines of chemotherapy administered in group A was equal to 1.44+/-0.77 as compared with 1.06+/-0.67 in group B (P=0.0017). SPAT are utilized frequently among patients approaching mortality due to a glioblastoma. Certain factors, including the utilization of novel chemotherapy after the first progression or number of lines of chemotherapy previously administered, may have influenced physicians' decisions whether to continue with the SPAT or not. PMID- 29387403 TI - Prospective validation of patient fatigue questionnaire (FACIT-F) for fatigue assessment in nab-paclitaxel plus gemcitabine therapy. AB - Following the recent introduction of a stronger regimen for pancreatic carcinoma, patients undergoing chemotherapy present high incidences of fatigue. The feasibility and validity of evaluating fatigue by questionnaire for patients with unresectable pancreatic cancer (URPC) receiving this recent regimen of chemotherapy remains unclear. Enrolled patients completed the Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACIT-F, version 4), a questionnaire regarding additional concerns, a numerical rating scale test concerning loss of appetite, an evaluation of degree of pain and sensory disorder, and the Patient Neurotoxicity Questionnaire (PNQ) before undergoing nab paclitaxel plus gemcitabine therapy. Questionnaires and tests were completed on registration day, and then weekly during therapy over an 8-week period as the initial two cycles of continuous regimen. This trial is registered on the UMIN Clinical Trials Registry (UMIN000021758). Between April 2016 and September 2016, 10 consecutive patients with URPC, including metastatic (n=4) and locally advanced pancreatic (n=6) cancer, were registered, and scheduled for nab paclitaxel plus gemcitabine therapy. The mean maximum values of fatigue degree increased from mean baseline values in all categories of the questionnaire (6 500%). The degree of fatigue presented a spike pattern over a 4-week scheduled period as one cycle of regimen in time-sequence diagram regarding 10/13 (77%) questionnaires. The PNQ concerning sensory/motor disorder also demonstrated a spike pattern and an increase from the baseline as the number of administrations. It is valid and feasible to assess fatigue by FACIT-F questionnaire for patients with URPC undergoing nab-paclitaxel plus gemcitabine therapy, and to detect detailed changes in accordance with scheduled cycles of chemotherapy regimen. PMID- 29387404 TI - Prognostic value of urokinase plasminogen activator system in non-small cell lung cancer: A systematic review and meta-analysis. AB - Current relevant research suggests there are significant differences between the expression of the urokinase plasminogen activator (uPA) system in cancer tissues and in normal tissues. However, the potential effectiveness of the uPA system as a prognostic biomarker of non-small cell lung cancer (NSCLC) remains unclear. In the present study, a systematic review and meta-analysis were performed to evaluate the relevance of the uPA system in the prognosis of patients with NSCLC. Using the PubMed, EMBASE, Web of Science and Cochrane Library databases, data from relevant academic journal articles were extracted and subjected to analysis. Associations between expression profiles pertaining to the uPA system and the overall survival (OS) of patients with NSCLC were analyzed. The study incorporated data from 11 independent journal articles and these reports included a total of 937 patients with NSCLC. The meta-analysis results revealed that increased expression of urokinase plasminogen activator (uPA) and PA inhibitor type 1 (PAI-1) exhibited no significant association with poor OS [hazard ratio (HR)-uPA=1.07 (0.87-1.31), P=0.53; HR-PAI-1=1.02 (0.63-1.65), P=0.94]. Similarly, reduced expression of PAI type 2 (PAI-2) did not significantly correlate with poor OS [HR-PAI-2=1.58 (0.64-3.90); P=0.32]. Notably, however, a significant association was observed between increased expression levels of uPA receptor (uPAR) and poor OS for NSCLC [HR-uPAR=1.50 (1.04-2.15); P=0.03]. Therefore, the expression of uPAR in the uPA system of patients with NSCLC could be used as a novel clinical biomarker to evaluate the prognosis of NSCLC. The utilization of this biomarker may provide a platform for the further development of targeted drugs for the treatment of NSCLC. PMID- 29387405 TI - Effect of dutasteride on castration-resistant prostate cancer. AB - It has previously been demonstrated that the intratumoral generation of the potent androgen dihydrotestosterone (DHT), contributes critically to the progression of prostate cancer and its castration-resistant form, castration resistant prostate cancer (CRPC). Circulating testosterone is converted into DHT by 5alpha-reductase (SRD5A). Dutasteride is a dual inhibitor of type I and II SRD5A. The present study assessed the effectiveness of dutasteride in the treatment of CRPC. Between 2010 and 2013, CRPC was diagnosed in 41 patients at the Tokyo Metropolitan Tama Medical Center. Following diagnosis, the patients received 0.5 mg dutasteride daily. The patients' median age was 77.3 years (range, 63-90). Bone metastases were recognized in 12 patients. All the patients received dexamethasone. Twenty-four (59%) patients had previously undergone chemotherapy, while 11 (27%) received docetaxel, and 24 (59%) estramustine. The prostatic-specific antigen (PSA) level declined in 17 (41%) patients from the baseline value, following dutasteride treatment. The median value for the PSA decrease was 23% (range, 4.3-89.8%), and the median duration of the response was 4 months (range, 1-10). The PSA response rate (defined as >50% decline in PSA from the baseline value) was recognized in 7 (17%) patients. The median duration of the response was 3 months (range, 2-10). Dutasteride was efficacious against CRPC in certain patients and may be a promising option in CRPC treatment. A prospective randomized trial is necessary to verify the efficacy of dutasteride. PMID- 29387406 TI - Lung cancer patients with synchronous colon cancer. AB - Lung and colon cancers are two of the most common malignancies, which, in some cases, may develop synchronously. In the present study, the treatment and outcome of patients with synchronous lung and colon cancers were reviewed. During a 76 month study period, from April 2009 up to July 2016, 17 (0.54%) of 3,102 patients with lung cancer were diagnosed with colon cancer within 1 month. Heavy smoking and obesity were not specific factors in these patients. A total of 9 patients succumbed to lung cancer during the study period. Survival in asymptomatic patients was longer compared with that in symptomatic patients (median survival, 80 vs. 23.2 months, respectively; P=0.007). Although the incidence of synchronous occurrence of these two cancers may be low, particularly in patients diagnosed incidentally, such patients should be treated accordingly. Future genetic and epidemiological studies are required to elucidate the potential connection between lung and colon cancer. PMID- 29387407 TI - Effect on prostate volume following neoadjuvant treatment with an androgen receptor inhibitor monotherapy versus castration plus an androgen receptor inhibitor in prostate cancer patients intended for curative radiation therapy: A randomised study. AB - To avoid pubic arch interference, prostate cancer patients are treated with neoadjuvant androgen deprivation therapy (ADT) to achieve prostate volume (PV) reduction prior to radiation treatment. The aim of the present randomised study was to compare the effects on PV of two regimens of ADT, an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. Consecutive patients with non-metastatic prostate cancer were included in a randomised neoadjuvant study, comparing an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. PV was assessed prior to the start of endocrine neoadjuvant treatment and prior to the start of radiation therapy (RT). PV assessment was performed by transrectal ultrasound. A total of 110 patients were included. Final sample constituted 88 (80%) patients due to lack of PV information. Castration plus an androgen receptor inhibitor was more effective in PV reduction compared with an androgen receptor inhibitor alone (P<0.001). Planning target volume decreased in the combination arm. There was no significant difference in clinical or demographic or length of neoadjuvant hormonal treatment between the groups. Overall, a significantly larger PV reduction was achieved by castration plus androgen receptor inhibitor, as compared with androgen receptor inhibitor monotherapy. The PV reduction, however, appeared not to translate into better health associated quality of life during the subsequently given curative intended combined EBRT and HDR-brachytherapy. Potential differences between these two treatments regarding anti-tumor effects on micro metastatic disease and radiation potentiating effect remains to be addressed in future prospective trials. PMID- 29387408 TI - Long-responders to anti-HER2 therapies: A case report and review of the literature. AB - Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects. PMID- 29387409 TI - Fertility preservation in post-pubescent female cancer patients: A practical guideline for clinicians. AB - Increasing accessibility of fertility preservation (FP) options has permitted women to retain fertility following anticancer therapies. Several published guidelines have made recommendations for FP however their implementation into practice is currently unknown. In this review, we aim to provide oncology clinicians practical information about FP options for post-pubescent female cancer patients and recommendations for care delivery in order to answer preliminary questions and help triage whether FP referral is appropriate. Herein, we present a resource for oncology providers to guide them with FP discussions. Key points that are discussed in this critical review include: i) All cancer patients beginning a new plan of care should be informed of potential fertility risk. ii) If a woman requests further information on FP interventions, referral to a FP clinic should be made. iii) Given the evolving technologies in this area, patients should be informed of those which are proven and unproven, with oocyte and embryo preservation recognized as standard practice. iv) Random start (independent of menstrual cycle day) techniques are available to minimize oncologic treatment delays. v) Specific protocols for ovarian stimulation may be center-specific. vi) There is unlikely an increased cancer recurrence risk as a result of stimulation protocols in women with hormone-sensitive cancers. vii) Lastly, given the absence of consensus in the literature, routine use of GnRH analogs is not recommended for all cancer patients, however may be considered in select cases, such as high-risk women in whom definitive FP is not possible or feasible. PMID- 29387410 TI - MicroRNA-23a/24-2/27a as a potential diagnostic biomarker for cancer: A systematic review and meta-analysis. AB - An increasing number of studies have proven that microRNAs play an important role in the occurrence, development and prognosis of various types of cancer. As a vital gene cluster, the microRNA (miR)-23a/24-2/27a cluster may be an important marker for predicting cancer prognosis and tumor progression. A search was conducted through PubMed, Medline and the Cochrane Library to identify studies investigating the association between the miR-23a/24-2/27a cluster and cancer, and the identified related studies were included in the present meta-analysis. The strength of the association was assessed by hazard ratio (HR) and its 95% confidence interval (95% CI). A total of 21 studies were included in this meta analysis. The results indicated that a high level of miR-23a exerted a significant effect on overall survival (OS) (HR=2.33, 95% CI: 1.18-4.58; P=0.014), but not on disease-free survival (DFS)/recurrence-free survival (RFS) (HR=1.13, 95% CI: 0.37-3.44; P=0.836). There was an obvious statistically significant association between OS and the expression of miR-24 (HR=2.49, 95% CI: 1.84-3.37; P=0.000), particularly in the digestive system (pooled HR=2.99, 95% CI: 2.17-4.13, P=0.000). In addition, the result suggested a statistically significant association between the expression of miR-27a and OS (pooled HR=1.89, 95% CI: 1.32-2.69; P=0.001), as well as DFS/RFS/progression-free survival (HR=2.19, 95% CI: 1.29-3.70; P=0.003), particularly in renal cell carcinoma (HR=2.30, 95% CI: 1.16-4.67; P=0.017). A subgroup analysis by ethnicity, cancer type and statistical methodology was performed. There was no obvious publication bias. In conclusion, the present study demonstrated that the miR-23a/24-2/27a cluster may be a useful marker for predicting cancer prognosis and tumor progression. PMID- 29387411 TI - Phospholipase C epsilon-1 gene polymorphisms and prognosis of esophageal cancer patients from a high-incidence region in northern China. AB - Recent genome-wide association studies identified susceptibility loci for esophageal squamous cell carcinoma (ESCC), the most common histological type of esophageal cancer, in the phospholipase C epsilon-1 gene (PLCE1). The aim of the present study was to investigate whether polymorphisms of PLCE1 were associated with the prognosis of ESCC patients in a high-incidence region of northern China. The PLCE1 rs2274223 A/G and rs11599672T/G single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-ligase detection reaction method in 207 ESCC patients with survival information. The mean age +/- standard deviation of the 207 ESCC patients was 60.3+/-7.9 years. Sex, age, smoking status and family history of upper gastrointestinal cancer were not found to be associated with the survival time of ESCC patients. The mean survival time of rs2274223 SNP A/A, A/G and G/G genotype carriers were 42.9, 43.4 and 46.3 months, respectively; for rs11599672 SNP T/T, T/G and G/G genotype carriers the survival time were 42.8, 43.8 and 42.7 months, respectively. There was no significant difference in survival time among the ESCC patients with different genotypes of rs2274223 and rs11599672 SNPs. In conclusion, PLCE1 rs227423 and rs11599672 SNPs cannot be used as predictive markers for the survival of ESCC patients from a high-incidence region of northern China. PMID- 29387412 TI - Neurological variability in chemotherapy-induced posterior reversible encephalopathy syndrome associated with thrombotic microangiopathy: Case reports and literature review. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headaches, seizures, a confusional state and visual disturbances associated with transient predominantly bilateral posterior white mater magnetic resonance imaging lesions. It is primarily reported in the setting of hypertension, acute renal failure, peripartum eclampsia, autoimmune disease, immunosuppression and chemotherapy. Thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) has also been reported as potential PRES inducer. The present study reviews two cases of patients with PRES, associated with TMA caused by chemotherapy. Their clinical and imaging data, and the relevant literature were reviewed. Patient 1 presented with TMA-induced PRES following mitomycin-C for metastatic colon adenocarcinoma. Treatment with steroids, plasma exchange, intravenous immunoglobulins, aspirin, antihypertensive drugs, and diuretics resulted in resolution of the neurological and imaging deficits. Patient 2 presented with TMA-induced PRES following gemcitabine for metastatic breast carcinoma. Treatment was ineffective and the patient deteriorated despite verapamil, dexamethasone, and plasma exchange. In this report, the relevant literature regarding pathogenesis, treatment and prognosis of chemotherapy-induced PRES associated with TMA was reviewed. We conclude that several chemotherapy agents may cause PRES through various pathogenic mechanisms, leading to clinical variability and divergent response to therapy. PMID- 29387413 TI - Incidental finding of papillary thyroid carcinoma on CT examination of mandibular lesion: Case report. AB - The number of significant incidental findings identified on radiographic examinations has increased. In total, 169 patients, 87 males and 82 females, with a mean age of 67.3 years (range, 17-92 years), as well as 65 patients (38.5%), 43 (66.2%) female and 22 (33.8%) male had abnormal findings in the thyroid for one year in our institution. Thyroid nodules are the most common incidental findings on oral and maxillofacial evaluations. Computed tomography (CT) and magnetic resonance imaging (MRI) examination are frequently used to detect thyroid abnormality. The present study reported a case of papillary thyroid carcinoma (PTC) detected following CT and MRI examination of a mandibular lesion. The CT examination of the oral and maxillofacial region included the thyroid, which must be examined carefully to detect various diseases, including PTC. Collaboration between radiologists and clinicians is important to manage these incidental findings. PMID- 29387414 TI - Role of P-selectin in thromboembolic events in patients with cancer. AB - The objective of the present study was to evaluate the role of P-selectin in patients with cancer with suspected thromboembolic events (TEEs). Patients with cancer have a four times greater risk of developing TEEs. P-selectin is a glycoprotein that has the function of facilitating the interaction (adhesion) of leukocytes with the endothelium, or with platelets. There is a well-defined relationship between P-selectin and thrombosis; however, it is likely that the cut-off value of P-selectin for patients with cancer should be considered differently from that of the general population. In the present report, a prospective cross-sectional study was performed with patients of the Cancer Hospital of Barretos who were suspected of having TEEs. Among the 178 study participants, 167 (93.82%) were suspected of having deep vein thrombosis, while 59 of them (35.33%) were confirmed as such; and 11 (6.18%) were suspected of having pulmonary thromboembolism, while 3 of them were confirmed as such (27.69%). The mean results obtained were: P-selectin, 25.37 ng/ml; and D-dimer, 2,181.22 ng/ml. The P-selectin levels averaged 33.60 ng/ml with the confirmed TEE group compared with 20.40 ng/ml with the unconfirmed TEE group, with a standard deviation of 23.35 compared with 6.92 (P<0.001); and the level of D-dimer was 4,615.38 ng/ml compared with 977.52 ng/ml, with a standard deviation of 6,460.54 compared with 2,145.50 (P<0.001). Multiple logistic regression adjusted for distant metastases and the Eastern Cooperative Oncology Group (ECOG) score (2,3 and 4) were constructed. The cut-off value of P-selectin for patients with cancer was identified to be different from that reported in the literature for the general population, and the models using D-dimer and P-selectin therefore have been demonstrated to be a potentially useful tool to be used in a panel of tests to predict TEEs, either independently or in a prediction score. PMID- 29387415 TI - Significance of serum neural precursor cell-expressed developmentally downregulated protein 9 in melanoma. AB - Neural precursor cell-expressed developmentally downregulated protein 9 (NEDD9) is a promoter for various cellular functions that result in tumorigenesis. The aim of the present study was to analyse the serum levels of NEDD9 in melanoma patients in order to evaluate its prognostic, predictive and diagnostic value. Data from 112 melanoma patients were retrospectively analyzed and ELISA assays were used to measure serum NEDD9 concentration. The median serum NEDD9 levels of the patients were significantly higher compared with those of the controls. Serum NEDD9 was not found to be associated with any of the clinicopathological parameters, and was also not found to be prognostic for survival in melanoma. Therefore, serum NEDD9 may be of diagnostic value in melanoma, but its usefulness in prognosis remains controversial. The important role of NEDD9 in tumor angiogenesis necessitates efforts to elucidate its interactions with the tumor microenvironment and its potential as a therapeutic target for malignancies. PMID- 29387416 TI - Lacrimal myoepithelial carcinoma ex recurrent pleomorphic adenoma: A clinicopathological report and review of the literature. AB - Myoepithelial carcinoma is an uncommon malignant tumor of the lacrimal gland, composed of neoplastic myoepithelial cells with an infiltrative growth. The present study describes a unique case of progressive proptosis and blindness of the right eye in a 68-year-old woman following total tumor removal for lacrimal pleomorphic adenoma. Clinical study, surgical exploration, and pathology revealed lacrimal myoepithelial carcinoma ex recurrent pleomorphic adenoma, T2N0M0. In addition, 18 cases of lacrimal myoepithelial tumor that have been previously described in the literature are reviewed. The application of clinical, radiological, histopathologic, and immunohistochemical investigations may help to reach the definite diagnosis. Criteria for malignancy of lacrimal myoepithelial tumor should be the same as salivary myoepithelial tumor diagnosis, until long term outcome data for a larger number of patients with lacrimal myoepithelial carcinoma become available. PMID- 29387417 TI - Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. AB - Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer. PMID- 29387418 TI - Comparative analysis of cerebrospinal fluid metabolites in Alzheimer's disease and idiopathic normal pressure hydrocephalus in a Japanese cohort. AB - Background: Alzheimer's disease (AD) is a most common dementia in elderly people. Since AD symptoms resemble those of other neurodegenerative diseases, including idiopathic normal pressure hydrocephalus (iNPH), it is difficult to distinguish AD from iNPH for a precise and early diagnosis. iNPH is caused by the accumulation of cerebrospinal fluid (CSF) and involves gait disturbance, urinary incontinence, and dementia. iNPH is treatable with shunt operation which removes accumulated CSF from the brain ventricles. Methods: We performed metabolomic analysis in the CSF of patients with AD and iNPH with capillary electrophoresis mass spectrometry. We assessed metabolites to discriminate between AD and iNPH with Welch's t-test, receiver operating characteristic (ROC) curve analysis, and multiple logistic regression analysis. Results: We found significant increased levels of glycerate and N-acetylneuraminate and significant decreased levels of serine and 2-hydroxybutyrate in the CSF of patients with AD compared to the CSF of patients with iNPH. The ROC curve analysis with these four metabolites showed that the area under the ROC curve was 0.90, indicating good discrimination between AD and iNPH. Conclusions: This study identified four metabolites that could possibly discriminate between AD and iNPH, which previous research has shown are closely related to the risk factors, pathogenesis, and symptoms of AD. Analyzing pathway-specific metabolites in the CSF of patients with AD may further elucidate the mechanism and pathogenesis of AD. PMID- 29387419 TI - Predicting contrast-induced nephropathy after CT pulmonary angiography in the critically ill: a retrospective cohort study. AB - Background: It is uncertain whether we can predict contrast-induced nephropathy (CIN) after CT pulmonary angiography (CTPA). This study compared the ability of a validated CIN prediction score with the Pulmonary Embolism Severity Index (PESI) in predicting CIN after CTPA. Methods: This cohort study involved critically ill adult patients who required a CTPA to exclude acute pulmonary embolism (PE). Patients with end-stage renal failure requiring dialysis were excluded. CIN was defined as an elevation in plasma creatinine concentrations > 44.2MUmol/l (or 0.5 mg/dl) within 48 h after CTPA. Results: Of the 137 patients included, 77 (51%) were hypotensive, 54 (39%) required inotropic support, and 68 (50%) were mechanically ventilated prior to the CTPA. Acute PE was confirmed in 21 patients (15%) with 14 (10%) being bilateral. CIN occurred in 56 patients (41%) with 35 (26%) required dialysis subsequent to CTPA. The CIN prediction score had a good ability to discriminate between patients with and without developing CIN (Area under the receiver-operating-characteristic (AUROC) curve 0.864, 95% confidence interval [CI] 0.795-0.916) and requiring subsequent dialysis (AUROC 0.897, 95% CI 0.833-0.942) and was better than the PESI in predicting both outcomes (AUROC 0.731, 95% CI 0.649-0.804 and 0.775, 95% CI 0.696-0.842, respectively). A CIN risk score > 10 and 12 had an 82.1 and 85.7% sensitivity and 81.5 and 78.4% specificity to predict subsequent CIN and dialysis, respectively. The CIN prediction model tended to underestimate the observed risks of dialysis, but this was improved after recalibrating the slope and intercept of the original prediction equation. Conclusions: The CIN prediction score had a good ability to discriminate between critically ill patients with and without developing CIN after CTPA. Used together for critically ill patients with suspected acute PE, the CIN prediction score and PESI may be useful to inform clinicians when the benefits of a CTPA scan will outweigh its potential harms. PMID- 29387420 TI - Barriers and facilitators to hospital pharmacists' engagement in medication safety activities: a qualitative study using the theoretical domains framework. AB - Background: Hospital pharmacists play a central role in medication safety activities. However, in Ethiopia, this role has been launched recently and little is known regarding the current status of this extended service. Using the Theoretical Domains Framework (TDF), we aimed to identify the barriers and facilitators to hospital pharmacists' engagement in medication safety activities across various public hospitals in the Amhara region of Ethiopia. Methods: Eight focus group discussions, using an interview guide that was drawn upon the TDF, were conducted with 44 hospital pharmacists to explore their beliefs regarding their involvement in clinical services. Group discussions were audio-recorded, transcribed verbatim, and analysed using directed content analysis based on the TDF. Relevant domains were identified by applying relevance criteria to each of the domains in the TDF. Results: Content analysis revealed six domains that influence hospital pharmacists' engagement in medication safety activities. These domains included 'Knowledge', 'Skills', 'Environmental context and resources', 'Motivations and goals', 'Social influences' and 'Social/professional role'. Most hospital pharmacists believed knowledge gap was an issue, as was the lack of training and supportive skills although some expressed as they were competent enough for their skills in identifying medication related problems. Most participants were very much enthusiastic for their extended roles and were positive towards the future of the profession; however, competing priorities along with the lack of remuneration and awareness (of other health care professionals) regarding the profession's role were barriers to service delivery. There were also a number of resource constraints, such as staffing, infrastructure and government funding, and acceptance rate of pharmacist's recommendation that were likely to influence the clinical practice of pharmacists. Conclusion: Using the TDF, this study identified a wide range of barriers and facilitators to hospital pharmacists' engagement in medication safety activities in resource-limited settings. There existed considerable interrelationships between domains that were perceived to influence hospital pharmacists' behaviours, and this may assist in designing behaviour change interventions that target common behavioural domains. PMID- 29387421 TI - Reasons for Accident and Emergency department attendance by people with chronic obstructive pulmonary disease or heart failure: recipients and providers' perspectives. An exploratory study. AB - Introduction: Fifteen million people are affected by one or more long-term conditions in England. The cost of caring for this patient group increases every year. Several studies have been conducted to find out why people with those conditions choose to access Accident and Emergency (A&E) frequently. To our knowledge, there is no study that compares the three groups (patients, family members and hospital clinicians), and this approach may enhance understanding of A&E admissions in England. Therefore, an exploratory study was undertaken to identify key factors that contribute to A&E admissions as perceived by patients with chronic obstructive pulmonary disease (COPD) and heart failure (HF), their family members (or carers) and hospital clinicians. Methods: A mixed methods approach was undertaken: (1) semistructured interviews with patients and their family members (or carers) and (2) a self-developed survey with hospital clinicians. A purposive sample of 15 patients (9 COPD, 6 HF), 6 family members and carers (2 COPD, 4 HF) and 13 hospital clinicians (5 doctors, 8 nurses) participated in the study. Results: The patients' main reason for A&E admission was severe exacerbation of their symptoms and all three parties (patients, family members or carers, hospital clinicians) agreed with this decision. Three key factors were highlighted in relation to A&E attendance: (1) patients' health seeking behaviour, (2) perceptions about general practitioner (GP) and A&E services by patients and (3) patients' attitudes towards managing their own conditions. Conclusions: Improving patients' perceptions of GP services in the management of exacerbations of HF and COPD will be important to increase patients' trust in GP services so that patients will access primary care in a timely manner to prevent exacerbations of symptoms that require A&E admission. This may be achieved by developing a close collaboration between the patients, family members (carers) and hospital clinicians over time. PMID- 29387422 TI - Chronic obstructive pulmonary disease associated with biomass fuel use in women: a systematic review and meta-analysis. AB - Introduction: Chronic obstructive pulmonary disease (COPD) is a major and growing cause of morbidity and mortality worldwide. The global prevalence of COPD is growing faster in women than in men. Women are often exposed to indoor pollutants produced by biomass fuels burning during household activities. Methods: We conducted a meta-analysis to establish the association between COPD and exposure to biomass smoke in women.Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched MEDLINE and Scopus databases in 31December 2016, with the terms: "wood", "charcoal", "biomass", "solid fuels", "organic fuel", "biofuel", "female", "women", "COPD", "chronic bronchitis", "emphysema", "chronic obstructive pulmonary disease". Studies were eligible if they were case-control or cross-sectional studies involving exposure to indoor biomass smoke, conducted at any time and in any geographic location. Fixed effects or random-effects meta-analysis was used to generate pooled OR. Results: 24 studies were included: 5 case-control studies and 19 cross-sectional studies. Biomass-exposed individuals were 1.38 times more likely to be diagnosed with COPD than non-exposed (OR 1.38, 95% CI 1.28 to 1.57).Spirometry-diagnosed COPD studies failed to show a significant association (OR 1.20, 95% CI 0.99 to 1.40). Nevertheless, the summary estimate of OR for chronic bronchitis (CB) was significant (OR 2.11, 95% CI 1.70 to 2.52). The pooled OR for cross-sectional studies and case-control studies were respectively 1.82 (95% CI 1.54 to 2.10) and 1.05 (95% CI 0.81 to 1.30). Significant association was found between COPD and biomass smoke exposure for women living as well in rural as in urban areas. Conclusions: This study showed that biomass smoke exposure is associated with COPD in rural and urban women.In many developing countries, modern fuels are more and more used alongside traditional ones, mainly in urban area. Data are needed to further explore the benefit of the use of mixed fuels for cooking on respiratory health, particularly on COPD reduction. PMID- 29387423 TI - Occurrence of preterm calving in Great Britain and associations with milk production and reproductive performance in dairy cattle. AB - This study describes the occurrence of preterm calving in Great Britain and evaluates its associations with subsequent milk production and reproductive performances and survival on farm of dairy cows. A total of 53 British dairy farms and 5759 animals with detailed breeding and milk recording data available were used to form two study groups: preterm calving (calving occurring between days 266 and 277 of gestation) and full-term calving (calving occurring at 278 days of gestation and over). Mixed effects models were implemented to compare milk production, clinical cases of mastitis and number of services per conception between groups. Kaplan-Meier curves and Cox regression analyses compared time from calving to conception, calving interval and survival on farm between groups. Preterm calving cows showed significantly lower milk yield (P<0.01) and butter fat per cent (P=0.02), increased milk protein per cent (P=0.01), longer survival on farm (P<0.01), and a tendency for shorter calving to conception intervals and fewer services per conception, although other factors were involved in the reproduction outcomes. Experiencing a preterm calving is associated with lower milk production and longer survival times on farm. Potential risk factors for preterm calving, such as infectious diseases, diet and husbandry practices, should be further investigated. PMID- 29387424 TI - Effects of disease severity distribution on the performance of quantitative diagnostic methods and proposal of a novel 'V-plot' methodology to display accuracy values. AB - Background: Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test's performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests. Methods and findings: We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Cholrapid and Cholgold) by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V plot of accuracies). Conclusion: No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard. PMID- 29387425 TI - Comparison of tricuspid annular plane systolic excursion with fractional area change for the evaluation of right ventricular systolic function: a meta analysis. AB - Background: Accurate determination of right ventricular ejection fraction (RVEF) is challenging because of the unique geometry of the right ventricle. Tricuspidannular plane systolic excursion (TAPSE) and fractional area change (FAC) are commonly used echocardiographic quantitative estimates of RV function. Cardiac MRI (CMRI) has emerged as the gold standard for assessment of RVEF. We sought to summarise the available data on correlation of TAPSE and FAC with CMRI derived RVEF and to compare their accuracy. Methods: We searched PubMed, EMBASE, Web of Science, CINAHL, ClinicalTrials.gov and the Cochrane Library databases for studies that assessed the correlation of TAPSE or FAC with CMRI-derived RVEF. Data from each study selected were pooled and analysed to compare the correlation coefficient of TAPSE and FAC with CMRI-derived RVEF. Subgroup analysis was performed on patients with pulmonary hypertension. Results: Analysis of data from 17 studies with a total of 1280 patients revealed that FAC had a higher correlation with CMRI-derived RVEF compared with TAPSE (0.56vs0.40, P=0.018). In patients with pulmonary hypertension, there was no statistical difference in the mean correlation coefficient of FAC and TAPSE to CMR (0.57vs0.46, P=0.16). Conclusions: FAC provides a more accurate estimate of RV systolic function (RVSF) compared with TAPSE. Adoption of FAC as a routine tool for the assessment of RVSF should be considered, especially since it is also an independent predictor of morbidity and mortality. Further studies will be needed to compare other methods of echocardiographic measurement of RV function. PMID- 29387427 TI - Early versus newer generation devices for transcatheter aortic valve implantation in routine clinical practice: a propensity score matched analysis. AB - Aim: Contemporary data comparing early versus newer generation transcatheter heart valve (THV) devices in routine clinical practice are lacking. We sought to compare the safety and efficacy of early versus newer generation THVs in unselected patients undergoing transcatheter aortic valve implantation (TAVI). Methods and results: We performed a propensity score matched analysis of patients undergoing transfemoral TAVI at a single centre with early versus newer generation devices between 2007 and 2016. Patients were matched for balloon expandable versus self-expandable valves and Society of Thoracic Surgeons score. The primary end point was the Valve Academic Research Consortium (VARC)-2 early safety composite end point at 30 days. Among the 391 matched pairs, no differences between early (21.2%) and newer generation (20.8%) THVs regarding the early safety composite end point (HR 0.98, 95% CI 0.72 to 1.33, P=0.88) were observed. The rates of valve embolisation (0.8% vs 4.2%, P=0.005), bleeding events (24.8% vs 32.0%, P=0.028) and moderate-to-severe paravalvular regurgitation (PVR) (3.1% vs 12.1%, P<0.001) were lower among patients receiving newer generation devices. Conversely, patients treated with early generation THVs less frequently experienced annulus rupture (0% vs 2.0%, P=0.008). Conclusion: Newer compared with early generation THV devices were associated with a lower rate of valve embolisation, PVR and bleeding events. PMID- 29387428 TI - 'Porcelain aorta': a proposed definition and classification of ascending aortic calcification. AB - Introduction: 'Porcelain aorta' is listed in the second consensus document of the Valve Academic Research Consortium as a risk factor in aortic valve replacement. However, the extent of circumferential involvement is poorly defined with great variability in reported incidence. We present a simple, reproducible classification to describe the extent of aortic calcification and thus appropriately define 'porcelain aorta', aiding clinical decision-making and registry data collection. Methods: 175 consecutive CT aortograms were reviewed. The aorta was divided into three sections, and each section divided into quadrants. These were individually scored using a 5-point scale (0-no calcification, 5-complete contiguous calcification).Results for each quadrant were summated for each segment to provide an indication of the distribution of calcification. Results: Only one patient (0.6%) had a 'true' porcelain aorta, defined as contiguous calcification across all quadrants at any aortic level. Intraobserver and interobserver variation was excellent for the ascending aorta (K=0.85-0.88 and 0.81-0.96, respectively) while the interobserver variation in the transverse arch was good at 0.75. Conclusions: Our data suggest the incidence of 'true' porcelain aorta may be significantly lower than reported in the literature. The predominance of calcification within the anterior wall of the proximal ascending aorta and the superior wall of the transverse arch may be clinically important. Application of this quick, simple and reproducible grading system, with no requirement for advanced software, may provide a tool to support accurate assessment of focal aortic calcification and its relationship to subsequent procedural risk. PMID- 29387429 TI - Residual cardiovascular risk in individuals on lipid-lowering treatment: quantifying absolute and relative risk in the community. AB - Objective: The residual cardiovascular disease (CVD) risk in individuals on long term lipid-lowering treatment (LLT) in the general population is not well described. Methods: We estimated absolute CVD risks by age and sex for different categories of low-density lipoprotein cholesterol (LDL-C) levels, stratified by LLT status, and assessed subclinical carotid atherosclerosis in 3012 Framingham Study participants (mean age, 58.4 years; 55% women) free of CVD. Individuals were categorised into five groups: (1) LDL-C <100 mg/dL without LLT; (2) LDL-C >=100 mg/dL to <130 mg/dL without LLT; (3) LDL-C <130 mg/dL on LLT; (4) LDL-C >=130 mg/dL without LLT; and (5) LDL-C >=130 mg/dL on LLT. Results: Individuals in groups 3-5 had significantly more carotid atherosclerosis compared with group 1. During follow-up (median, 13.7 years), 548 CVD events occurred. Individuals on LLT (groups 3 and 5) had substantial residual CVD risk (26.7 (95% CI 19.5 to 34.0) and 24.1 (95% CI 16.2 to 31.9) per 1000 person-years, respectively), representing approximately three times the risk for untreated individuals with LDL <100 mg/dL (group 1: 9.0 (95% CI 6.8 to 11.3) per 1000 person-years). Absolute CVD risks rose with age and were slightly greater in men than in women. After adjustment for traditional risk factors, groups 3-5 displayed increased hazards for CVD (HR=1.47, 1.42 and 1.54, respectively) compared with group 1. Further adjustment for carotid atherosclerosis modestly attenuated these results. Conclusions: There is substantial residual CVD risk in individuals on LLT, compared with participants with optimal LDL-C (<100 mg/dL), even when LDL-C levels <130 mg/dL are reached. PMID- 29387430 TI - Body mass index as a risk factor for coronary events and mortality in patients with type 1 diabetes. AB - Objective: To investigate the potential relationship between body mass index (BMI) and the risk for myocardial infarction and coronary death in patients with type 1 diabetes. Methods: We studied patients with type 1 diabetes included in the Swedish National Diabetes Registry during 2002-2004 and followed them until a discharge diagnosis for myocardial infarction, acute coronary event, death or until 31 December 2011. Cox regression was used to estimate relative risks. Results: In 17 499 patients with type 1 diabetes (mean age 39.4 years; mean BMI 25.2 kg/m2), 819 were diagnosed with myocardial infarction as a primary or secondary diagnosis during a mean follow-up of 8.5 years (maximum 9.9 years). Estimated with Cox regression, there was no significant effect of increased BMI on the risk of myocardial infarction (HR 1.4 (95% CI 0.7 to 2.5) in the group with BMI >35 kg/m2 compared with BMI 18.5-25 kg/m2. There was no association between BMI and coronary mortality, acute coronary events or all-cause mortality after adjusting for other known risk factors. Underweight patients (BMI <18.5 kg/m2) had increased hazard for coronary (HR 5.0 (95% CI 1.5 to 16.9)) and all cause mortality (HR 5.4 (95% CI 3.1 to 9.6)) compared with BMI 18.5-25 kg/m2. Conclusions: Among patients with type 1 diabetes, increased BMI is not a significant independent risk factor for myocardial infarction or coronary death after adjustment for other risk factors. Low BMI (less than 18.5 kg/m2) is associated with mortality from coronary or any cause. PMID- 29387426 TI - Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis. AB - Because serum magnesium does not reflect intracellular magnesium, the latter making up more than 99% of total body magnesium, most cases of magnesium deficiency are undiagnosed. Furthermore, because of chronic diseases, medications, decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency. Certain individuals will need to supplement with magnesium in order to prevent suboptimal magnesium deficiency, especially if trying to obtain an optimal magnesium status to prevent chronic disease. Subclinical magnesium deficiency increases the risk of numerous types of cardiovascular disease, costs nations around the world an incalculable amount of healthcare costs and suffering, and should be considered a public health crisis. That an easy, cost-effective strategy exists to prevent and treat subclinical magnesium deficiency should provide an urgent call to action. PMID- 29387431 TI - Transcatheter and Doppler waveform correlation in transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has become the preferred therapy for treatment of severe aortic stenosis in patients at intermediate to high risk of perioperative mortality following surgical aortic valve replacement. Haemodynamic assessment is an integral part of the procedure, and it is crucial for the operator to have an in-depth understanding of the haemodynamic alterations that occur during balloon aortic valvuloplasty and transcatheter valve deployment. Comprehension of the haemodynamic tracings is also pivotal for early recognition of periprocedural complications. With expanding indications for TAVR, it is imperative for members of the structural heart team to have an in depth, nuanced understanding of transcatheter haemodynamic waveforms and their correlation with echocardiographic Doppler waveforms that are obtained periprocedurally during TAVR. This review provides a collection of transcatheter haemodynamic tracings and their corresponding Doppler echocardiography correlates that are demonstrative of physiological alterations and pathological lesions (complications) that occur during TAVR. PMID- 29387432 TI - SuPAR predicts postoperative complications and mortality in patients with asymptomatic aortic stenosis. AB - Background: We evaluated whether early measurement of soluble urokinase plasminogen activator receptor (suPAR) could predict future risk of postoperative complications in initially asymptomatic patients with mild-moderate aortic stenosis (AS) undergoing aortic valve replacement (AVR) surgery. Methods: Baseline plasma suPAR levels were available in 411 patients who underwent AVR surgery during follow-up in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox analyses were used to evaluate suPAR in relation to all-cause mortality and the composite endpoint of postoperative complications (all-cause mortality, congestive heart failure, stroke and renal impairment) occurring in the 30-day postoperative period. Results: Patients with initially higher levels of suPAR were at increased risk of postoperative mortality with a HR of 3.5 (95% CI 1.4 to 9.0, P=0.008) and postoperative complications with a HR of 2.7 (95% CI 1.5 to 5.1, P=0.002), per doubling in suPAR. After adjusting for the European System for Cardiac Operative Risk Evaluation or Society of Thoracic Surgeons risk score, suPAR remained associated with postoperative mortality with a HR 3.2 (95% CI 1.2 to 8.6, P=0.025) and 2.7 (95% CI 1.0 to 7.8, P=0.061); and postoperative complications with a HR of 2.5 (95% CI 1.3 to 5.0, P=0.007) and 2.4 (95% CI 1.2 to 4.8, P=0.011), respectively. Conclusion: Higher baseline suPAR levels are associated with an increased risk for postoperative complications and mortality in patients with mild-moderate, asymptomatic AS undergoing later AVR surgery. Further validation in other subsets of AS individuals are warranted. Trial registration number: NCT00092677; Post-results. PMID- 29387434 TI - Beating heart minimally invasive mitral valve surgery in patients with previous sternotomy: the operative technique and early outcomes. AB - Objective: Reoperative mitral valve surgery is increasingly required and can be associated with significant morbidity and mortality. The beating heart minimally invasive mitral valve surgery has a proposed benefit in avoiding the risks of repeat sternotomy, with reducing the need for adhesiolysis and cardioplegia reperfusion injury. We describe our experience with such a technique in patients with previous sternotomy. Methods: A retrospective study was performed and all patients undergoing surgery of mitral valve through a right limited thoracotomy without application of an aortic cross-clamp (beating heart) as a redo cardiac surgery between January 2006 and January 2015 were included (n=25). Perioperative data as well as the operative technique are presented. Results: Six patients (24%) had two previous sternotomies and one (4%) had three previous sternotomies. Mitral valve repair was performed in 11 patients (44%). No patient required conversion to median sternotomy. Inotropic support beyond 4 hours after operation was required in seven patients (28%). Ventilation time was less than 12 hours in 14 patients (56%) with another six patients (24%) extubated within 24 hours after surgery. Postoperative course was complicated with cerebrovascular accident in two patients (8%). In-hospital mortality was 4% (n=1). There was no 30-day mortality after discharge. Conclusions: Reoperative mitral valve surgery can be safely performed through a limited right thoracotomy approach on a beating heart while on full cardiopulmonary bypass. The technique can be associated with potentially shorter operation, shorter cardiopulmonary bypass and a less complicated recovery. PMID- 29387433 TI - Optimal antiplatelet strategy after transcatheter aortic valve implantation: a meta-analysis. AB - Objective: International guidelines recommend the use of dual antiplatelet therapy (DAPT) after transcatheter aortic valve implantation (TAVI). The recommended duration of DAPT varies between guidelines. In this two-part study, we (1) performed a structured survey of 45 TAVI centres from around the world to determine if there is consensus among clinicians regarding antiplatelet therapy after TAVI; and then (2) performed a systematic review of all suitable studies (randomised controlled trials (RCTs) and registries) to determine if aspirin monotherapy can be used instead of DAPT. Methods: A structured electronic survey regarding antiplatelet use after TAVI was completed by 45 TAVI centres across Europe, Australasia and the USA. A systematic review of TAVI RCTs and registries was then performed comparing DAPT duration and incidence of stroke, bleeding and death. A variance weighted least squared metaregression was then performed to determine the relationship of antiplatelet therapy and adverse events. Results: 82.2% of centres routinely used DAPT after TAVI. Median duration was 3 months. 13.3% based their practice on guidelines. 11 781 patients (26 studies) were eligible for the metaregression. There was no benefit of DAPT over aspirin monotherapy for stroke (P=0.49), death (P=0.72) or bleeding (P=0.91). Discussion: Aspirin monotherapy appears to be as safe and effective as DAPT after TAVI. PMID- 29387436 TI - Very delayed lupus nephritis: a report of three cases and literature review. AB - Lupus nephritis (LN) affects up to 50% of patients with Systemic Lupus Erythematosus (SLE) and is associated with a worse prognosis. LN usually develops within the first 5 years of the onset of the disease. We report three patients with very delayed LN (DLN) diagnosed after 15 or more years after SLE diagnosis. The three patients were non-Caucasian women with adolescent or adult-onset SLE. Each had antinuclear, anti-dsDNA and anti-Ro antibodies. Hydroxychloroquine was prescribed for each. Their disease courses were characterised by sporadic non renal flares controlled by steroids and, in two cases, by one cycle of rituximab. Unexpectedly, they developed proteinuria, haematuria and lowering of estimated glomerular filtration rate with clinical signs of renal disease. LN was confirmed by renal biopsy. Reviewing them, each showed serological signs of increasing disease activity (rising levels of anti-dsDNA antibodies and fall in C3) that predated clinical or laboratory signs of LN by 1-3 years. Reviewing the literature, we found a lack of knowledge about DLN starting more than 15 years after SLE diagnosis. With the increasing life expectancy of patients with SLE it is likely that more cases of very DLN will emerge. PMID- 29387435 TI - Mouse models of lupus: what they tell us and what they don't. AB - Lupus is a complex heterogeneous disease characterised by autoantibody production and immune complex deposition followed by damage to target tissues. Animal models of human diseases are an invaluable tool for defining pathogenic mechanisms and testing of novel therapeutic agents. There are perhaps more applicable murine models of lupus than any other human disease. There are spontaneous models of lupus, inducible models of lupus, transgenic-induced lupus, gene knockout induced lupus and humanised mouse models of lupus. These mouse models of lupus have contributed significantly to our knowledge of the pathogenesis of lupus and served as valuable preclinical models for proof of concept for new therapies. Despite their utility, mouse models of lupus have their distinct limitations. Although similar, mouse and human immune systems are different and thus one cannot assume a mechanism for disease in one is translatable to the other. Efficacy and toxicity of compounds can vary significantly between humans and mice, also limiting direct translation. Finally, the heterogeneous aspects of human lupus, both in clinical presentation, underlying pathogenesis and genetics, are not completely represented in current mouse models. Thus, proving a therapy or mechanism of disease in one mouse model is similar to proving a mechanism/therapy in a limited subset of human lupus. These limitations, however, do not marginalise the importance of animal models nor the significant contributions they have made to our understanding of lupus. PMID- 29387437 TI - Associations between type I interferon and antiphospholipid antibody status differ between ancestral backgrounds. AB - Objective: The type I interferon pathway is activated in many patients with systemic lupus erythematosus (SLE), and anti-double-stranded DNA (dsDNA) and anti RNA binding protein autoantibodies are correlated with high interferon-alpha (IFNalpha) activity. We studied whether antiphospholipid (APL) antibodies, which should not stimulate Toll-like receptors, are also associated with high levels of IFNalpha activity. Methods: Serum IFNalpha activity was measured in patients with SLE using the WISH cell bioassay. IgG APL, anti-RBP and anti-dsDNA antibodies were measured in the clinical laboratory, and standard clinical cut-offs were used to define the positive results. Results: High IFNalpha activity was associated with anti-RBP and anti-dsDNA antibodies in all three ancestral backgrounds. Strikingly, African-American subjects with a positive APL antibody test had higher IFNalpha activity than those without IgG APL antibodies. This was not shared with other ancestral backgrounds. This finding was independent of other autoantibody profiles, and clinical features did not differ between IgG APL antibody positive versus negative African-American patients. Conclusion: The difference in association between IFNalpha activity and IgG APL status between ancestral backgrounds supports differences in molecular pathogenesis. This may suggest B cell hyperactivity in the setting of type I IFN in African-Americans and could suggest ways to individualise therapy. PMID- 29387438 TI - Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease. AB - Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. RNF213 is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously reported in other pediatric patients. PMID- 29387439 TI - Assessment of knowledge and education relating to asthma during pregnancy among women of childbearing age. AB - Background: Misconceptions about medications' safety can lead pregnant women with asthma to stop their medications, resulting in asthma-related neonatal morbidity and mortality. Our aim was to assess the level of pregnancy-related asthma knowledge and education about asthma medications' safety, among women of childbearing age with a history of bronchial asthma. Methods: A cross-sectional survey of convenience sample of outpatient clinic attendees of Pulmonary, Family Medicine and Obstetrics & Gynecology among women of childbearing age with history of asthma at King Abdulaziz Medical City, Riyadh, Saudi Arabia. Participants (n = 171) completed a questionnaire to determine levels of education and knowledge, as well as attitudes and practice relating to asthma treatment. Results: Among participants, 77.1% were pregnant at the time of the survey, 77.8% had used asthma medications during current or previous pregnancy, 70.8% of all respondents who ever been pregnant believed in the safety of asthma medications during pregnancy, 49.1% had received education about asthma, and 46.8% had been educated about the safety of asthma medications during pregnancy. Responses indicated that 46.8% had stopped (or expressed the desire to stop) asthma medications during pregnancy, and 48% believed asthma medications would harm them and their babies more than asthma itself, but 92.4% expressed that they would be willing to use asthma medications during pregnancy if their safety was confirmed by a physician. Education level and employment status were both associated with an increased likelihood of having received asthma education (p values <0.001 and <0.001 respectively), and with awareness of the safety of the medications during pregnancy (p values <0.001 and <0.003 respectively). Conclusion: Further efforts is to be taken to develop a program where female asthmatic patients are taught about asthma and its medications' safety during pregnancy. PMID- 29387440 TI - Patient pain drawing is a valuable instrument in assessing the causes of exercise induced leg pain. AB - Aim: We validated patientpain drawing (PPD) in establishing the diagnosis of chronic anterior compartment syndrome (CACS) in patients with exercise-induced leg pain. Methods: The study comprised 477 consecutive patients, all suspected of having CACS. The diagnosis was based on the patient's history, a thorough clinical examination and measurements of intramuscular pressure (IMP) following an exercise test. Patients completed a PPD before their hospital visit. Two independent orthopaedic surgeons diagnosed the causes of leg pain based only on the PPD at least 1 year after admission. Based on the results of diagnostic tests, the patients were divided into three groups: CACS (n=79), CACS with comorbidity (n=89) and non-CACS (n=306). Results: The sensitivity of the PPD to identify CACS correctly was 67% (observer 1) and 75% (observer 2). The specificity was 65% and 54%, respectively. The interobserver agreement (n=477) was 80%, and the kappa value was 0.55. The interobserver agreement was 77%, and the kappa value was 0.48 among 168 CACS patients with or without comorbidity. The interobserver agreement was 85%, and the kappa value was 0.56 in 79 CACS, and CACS was correctly diagnosed in 79% (observer 1) and 82% (observer 2). The test retest showed the same results for the two observers, with an intraobserver agreement of 84%, while the test-retest reliability coefficient was 0.7. Comorbidity was found in 53% of CACS patients. Conclusion: PPD might be a valuable instrument in diagnosing the causes of exercise-induced leg pain. It is useful in identifying CACS with and without comorbidity. PMID- 29387441 TI - Severity and pattern of injuries caused by Swiss wrestling (Schwingen): first retrospective study at a level I University Emergency Department in Switzerland. AB - Background: This article addresses typical injury patterns related to the traditional Swiss folk wrestling, 'Schwingen'. This is a fight between two competitors with its own rules, grips and throws. A variety of injuries have been occasionally reported. The aim of this study was to characterise all cases of Schwingen injuries treated in the University Hospital of Bern from January 2006 to July 2016. Methods: To assess the frequency, type and outcome of Schwingen injuries, database search was performed of all inpatient and outpatient cases related to Schwingen that were admitted to Bern University Hospital from January 2006 to December 2016. Results: A total of 32 such patients could be identified. Apart from a single woman, all patients were male. 31 of the 32 players were Swiss. One patient was admitted to the intermediate care unit, eight patients underwent surgery, two were hospitalised for further treatment and two were given a plaster. 17 other patients were given medications such as painkillers. One was dismissed without further treatment and another one left the hospital on his own. Typical injury patterns varied from simple lesions to distortions and fractures as well as head injuries and other neurological complications. Conclusion: The majority of injuries caused by Schwingen are not life threatening. Nevertheless, there is always the potential of head injuries and neurological deficits. Apart from the economic loss due to treatment costs and sick leave, these injuries can be disabling for life. It should therefore be obligatory for all players to evaluate preventive measures. PMID- 29387442 TI - Effects of an 8-week strength training intervention on tibiofemoral joint loading during landing: a cohort study. AB - Objectives: To use a musculoskeletal model of the lower limb to evaluate the effect of a strength training intervention on the muscle and joint contact forces experienced by untrained women during landing. Methods: Sixteen untrained women between 18 and 28 years participated in this cohort study, split equally between intervention and control groups. The intervention group trained for 8 weeks targeting improvements in posterior leg strength. The mechanics of bilateral and unilateral drop landings from a 30 cm platform were recorded preintervention and postintervention, as was the isometric strength of the lower limb during a hip extension test. The internal muscle and joint contact forces were calculated using FreeBody, a musculoskeletal model. Results: The strength of the intervention group increased by an average of 35% (P<0.05; pre: 133+/-36 n, post: 180+/-39 n), whereas the control group showed no change (pre: 152+/-36 n, post: 157+/-46 n). There were only small changes from pre-test to post-test in the kinematics and ground reaction forces during landing that were not statistically significant. Both groups exhibited a post-test increase in gluteal muscle force during landing and a lateral to medial shift in tibiofemoral joint loading in both landings. However, the magnitude of the increase in gluteal force and lateral to medial shift was significantly greater in the intervention group. Conclusion: Strength training can promote a lateral to medial shift in tibiofemoral force (mediated by an increase in gluteal force) that is consistent with a reduction in valgus loading. This in turn could help prevent injuries that are due to abnormal knee loading such as anterior cruciate ligament ruptures, patellar dislocation and patellofemoral pain. PMID- 29387443 TI - Is it necessary to adjust current creatine kinase reference ranges to reflect levels found in professional footballers? AB - Objective: We aimed to explore the validity of applying current reference ranges of the enzyme creatine kinase (CK) when analysing the medical status of professional footballers and to offer a more functional CK reference range for professional footballers. Methods: A sample of 27 professional male footballers competing in The Football League Championship was analysed. The single sample Wilcoxon signed-rank test was used to compare the CK distribution of the study group with that of a control group of military personnel reported in the literature. Results: The median values for study group and the published control group were 284 U/L and 124 U/L, respectively (P<0.001) suggesting that the average CK activity of professional footballers is higher than that of the normal healthy military population. Conclusion: Ethnicity, sex, age and physical exercise are factors that likely influence CK levels among various populations. From our analysis, we recommend a new 95% reference interval of 64.9 U/L to 1971.7 U/L for professional footballers. PMID- 29387444 TI - Comparison of standing postural control and gait parameters in people with and without chronic low back pain: a cross-sectional case-control study. AB - Objective: Differences in postural control and gait have been identified between people with and without chronic low back pain (CLBP); however, many previous studies present data from small samples, or have used methodologies with questionable reliability. This study, employing robust methodology, hypothesised that there would be a difference in postural control, and spatiotemporal parameters of gait in people with CLBP compared with asymptomatic individuals. Methods: This cross-sectional case-control study age-matched and gender-matched 16 CLBP and 16 asymptomatic participants. Participants were assessed barefoot (1) standing, over three 40 s trials, under four posture challenging conditions (2) during gait. Primary outcome was postural stability (assessed by root mean squared error of centre of pressure (CoP) displacement (CoPRMSEAP) and mean CoP velocity (CoPVELAP), both in the anteroposterior direction); gait outcomes were hip range of movement and peak moments, walking speed, cadence and stride length, assessed using force plates and a motion analysis system. Results: There were no differences between groups in CoPRMSEAP (P=0.26), or CoPVELAP (P=0.60) for any standing condition. During gait, no differences were observed between groups for spatiotemporal parameters, maximum, minimum and total ranges of hip movement, or peak hip flexor or extensor moments in the sagittal plane. Conclusions: In contrast to previous research, this study suggests that people with mild to moderate CLBP present with similar standing postural control, and parameters of gait to asymptomatic individuals. Treatments directed at influencing postural stability (eg, standing on a wobble board) or specific parameters of gait may be an unnecessary addition to a treatment programme. PMID- 29387445 TI - Predictive ability of a comprehensive incremental test in mountain bike marathon. AB - Objectives: Traditional performance tests in mountain bike marathon (XCM) primarily quantify aerobic metabolism and may not describe the relevant capacities in XCM. We aimed to validate a comprehensive test protocol quantifying its intermittent demands. Methods: Forty-nine athletes (38.8+/-9.1 years; 38 male; 11 female) performed a laboratory performance test, including an incremental test, to determine individual anaerobic threshold (IAT), peak power output (PPO) and three maximal efforts (10 s all-out sprint, 1 min maximal effort and 5 min maximal effort). Within 2 weeks, the athletes participated in one of three XCM races (n=15, n=9 and n=25). Correlations between test variables and race times were calculated separately. In addition, multiple regression models of the predictive value of laboratory outcomes were calculated for race 3 and across all races (z-transformed data). Results: All variables were correlated with race times 1, 2 and 3: 10 s all-out sprint (r=-0.72; r=-0.59; r=-0.61), 1 min maximal effort (r=-0.85; r=-0.84; r=-0.82), 5 min maximal effort (r=-0.57; r=-0.85; r= 0.76), PPO (r=-0.77; r=-0.73; r=-0.76) and IAT (r=-0.71; r=-0.67; r=-0.68). The best-fitting multiple regression models for race 3 (r2=0.868) and across all races (r2=0.757) comprised 1 min maximal effort, IAT and body weight. Conclusion: Aerobic and intermittent variables correlated least strongly with race times. Their use in a multiple regression model confirmed additional explanatory power to predict XCM performance. These findings underline the usefulness of the comprehensive incremental test to predict performance in that sport more precisely. PMID- 29387446 TI - Acetazolamide reduces exercise capacity following a 5-day ascent to 4559 m in a randomised study. AB - Objective: To assess whether acetazolamide (Az), used prophylactically for acute mountain sickness (AMS), alters exercise capacity at high altitude. Methods: Az (500 mg daily) or placebo was administered to 20 healthy adults (aged 36+/-20 years, range 21-77), who were paired for age, sex, AMS susceptibility and weight, in a double-blind, randomised manner. Participants ascended over 5 days to 4559 m, then exercised to exhaustion on a bicycle ergometer, while recording breath-by breath gas measurements. Comparisons between groups and matched pairs were done via Mann-Whitney U and Pearson's chi2 tests, respectively. Results: Comparing paired individuals at altitude, those on Az had greater reductions in maximum power output (Pmax) as a percentage of sea-level values (65+/-14.1 vs 76.6+/-7.4 (placebo); P=0.007), lower VO2max (20.7+/-5.2 vs 24.6+/-5.1 mL/kg/min; P<0.01), smaller changes from rest to Pmax for VO2 (9.8+/-6.2 vs 13.8+/-4.9 mL/kg/min; P=0.04) and lower heart rate at Pmax (154+/-25 vs 167+/-16, P<0.01) compared with their placebo-treated partners. Correlational analysis (Pearson's) indicated that with increasing age Pmax (r=-0.83: P<0.005) and heart rate at Pmax (r=-0.71, P=0.01) reduced more in those taking Az. Conclusion: Maximum exercise performance at altitude was reduced more in subjects taking Az compared with placebo, particularly in older individuals. The age-related effect may reflect higher tissue concentrations of Az due to reduced renal excretion. Future studies should explore the effectiveness of smaller Az doses (eg, 250 mg daily or less) in older individuals to optimise the altitude-Az-exercise relationships. PMID- 29387447 TI - Prospective monitoring of health problems among recreational runners preparing for a half marathon. AB - Objectives: While the health benefits of running are legitimately advocated, participation in running can also lead to health problems. There is a high range of reported prevalence rates especially of running-related overuse injuries in high-level athletes and during competition. Little consensus exists for acute injuries and illnesses especially in recreational runners. Therefore, the aim of this study was to record the prevalence of health problems in recreational long distance runners preparing for an event. Methods: Recreational runners aged 18-65 years who were registered 13 weeks prior to a half-marathon running event were invited to take part in this study. Participants were prospectively monitored weekly over 13 weeks by applying a standardised surveillance system for injuries and illnesses (Oslo Sports Trauma Research Center questionnaire). From this, prevalence and severity of acute and overuse injuries, as well as illnesses, were calculated. Results: We received 3213 fully answered questionnaires from 327 participants (40.7% female, 40.9+/-11.7 years of age, 31.5+/-21.1 km weekly mileage, 8.3+/-7.8 years of running experience). At any point in time over the preparation phase, 37.3% of the participants had health problems. Overuse injuries were the major burden (18%). They were followed by illnesses (14.1%) and acute injuries (7.9%). The median weekly severity score was 56.5 (IQR 37.0-58.0). Conclusion: The high prevalence of health problems in our cohort suggests that future efforts are needed to further specify the underlying mechanism and develop adequate prevention strategies for recreational runners. PMID- 29387448 TI - Association between frontal plane knee control and lower extremity injuries: a prospective study on young team sport athletes. AB - Background/aim: Poor frontal plane knee control can manifest as increased dynamic knee valgus during athletic tasks. The purpose of this study was to investigate the association between frontal plane knee control and the risk of acute lower extremity injuries. In addition, we wanted to study if the single-leg squat (SLS) test can be used as a screening tool to identify athletes with an increased injury risk. Methods: A total of 306 basketball and floorball players participated in the baseline SLS test and a 12-month injury registration follow up. Acute lower extremity time-loss injuries were registered. Frontal plane knee projection angles (FPKPA) during the SLS were calculated using a two-dimensional video analysis. Results: Athletes displaying a high FPKPA were 2.7 times more likely to sustain a lower extremity injury (adjusted OR 2.67, 95% CI 1.23 to 5.83) and 2.4 times more likely to sustain an ankle injury (OR 2.37, 95% CI 1.13 to 4.98). There was no statistically significant association between FPKPA and knee injury (OR 1.49, 95% CI 0.56 to 3.98). The receiver operating characteristic curve analyses indicated poor combined sensitivity and specificity when FPKPA was used as a screening test for lower extremity injuries (area under the curve of 0.59) and ankle injuries (area under the curve of 0.58). Conclusions: Athletes displaying a large FPKPA in the SLS test had an elevated risk of acute lower extremity and ankle injuries. However, the SLS test is not sensitive and specific enough to be used as a screening tool for future injury risk. PMID- 29387449 TI - 'Recover quicker, train harder, and increase flexibility': massage therapy for elite paracyclists, a mixed-methods study. AB - Objectives: Massage therapy (MT) enhances recovery by reducing pain and fatigue in able-bodied endurance athletes. In athletes with disabilities, no studies have examined similar MT outcomes, yet participation in sport has increased by >1000 athletes from 1996 to 2016 Olympic games. We examined the effect of MT on pain, sleep, stress, function and performance goals on the bike, as well as quality of life off the bike, in elite paracycling athletes. Methods: This is a quasi experimental, convergent, parallel, mixed-methods design study of one team, with nine paracycling participants, in years 2015 and 2016. One-hour MT sessions were scheduled one time per week for 4 weeks, and then every other week for the duration of the time the athlete was on the team and/or in the study. Closed and open-ended survey questions investigating athlete goals, stress, sleep, pain and muscle tightness were gathered pre and post each MT session, and every 6 months for health-related quality of life. Quantitative analysis timepoints include baseline, 4-6 months of intervention and final visit. Additional qualitative data were derived from therapists' treatment notes, exit surveys, and follow-up emails from the athletes and therapists. Results: Significant improvement was found for sleep and muscle tightness; quantitative results were reinforced by athlete comments indicating MT assisted in their recovery while in training. There were no improvements in dimensions measuring quality of life; qualitative comments from athletes suggest reasons for lack of improvement. Conclusion: This real world study provides new information to support MT for recovery in elite paracyclists. PMID- 29387450 TI - Two approaches reveal a new paradigm of 'switchable or genetics-influenced allele specific DNA methylation' with potential in human disease. AB - Imprinted genes are vulnerable to environmental influences during early embryonic development, thereby contributing to the onset of disease in adulthood. Monoallelic methylation at several germline imprints has been reported as DNMT1 dependent. However, which of these two epigenetic attributes, DNMT1-dependence or allelic methylation, renders imprinted genes susceptible to environmental stressors has not been determined. Herein, we developed a new approach, referred to as NORED, to identify 2468 DNMT1-dependent DNA methylation patterns in the mouse genome. We further developed an algorithm based on a genetic variation independent approach (referred to as MethylMosaic) to detect 2487 regions with bimodal methylation patterns. Two approaches identified 207 regions, including known imprinted germline allele-specific methylation patterns (ASMs), that were both NORED and MethylMosaic regions. Examination of methylation in four independent mouse embryonic stem cell lines shows that two regions identified by both NORED and MethylMosaic (Hcn2 and Park7) did not display parent-of-origin dependent allelic methylation. In these four F1 hybrid cell lines, genetic variation in Cast allele at Hcn2 locus introduces a transcription factor binding site for MTF-1 that may predispose Cast allelic hypomethylation in a reciprocal cross with either C57 or 129 strains. In contrast, each allele of Hcn2 ASM in J1 inbred cell line and Park7 ASM in four F1 hybrid cell lines seems to exhibit similar propensity to be either hypo- or hypermethylated, suggesting a 'random, switchable' ASM. Together with published results, our data on ASMs prompted us to propose a hypothesis of regional 'autosomal chromosome inactivation (ACI)' that may control a subset of autosomal genes. Therefore, our results open a new avenue to understand monoallelic methylation and provide a rich resource of candidate genes to examine in environmental and nutritional exposure models. PMID- 29387452 TI - Transcriptome-wide identification of the RNA-binding landscape of the chromatin associated protein PARP1 reveals functions in RNA biogenesis. AB - Recent studies implicate Poly (ADP-ribose) polymerase 1 (PARP1) in alternative splicing regulation, and PARP1 may be an RNA-binding protein. However, detailed knowledge of RNA targets and the RNA-binding region for PARP1 are unknown. Here we report the first global study of PARP1-RNA interactions using PAR-CLIP in HeLa cells. We identified a largely overlapping set of 22 142 PARP1-RNA-binding peaks mapping to mRNAs, with 20 484 sites located in intronic regions. PARP1 preferentially bound RNA containing GC-rich sequences. Using a Bayesian model, we determined positional effects of PARP1 on regulated exon-skipping events: PARP1 binding upstream and downstream of the skipped exons generally promotes exon inclusion, whereas binding within the exon of interest and intronic regions closer to the skipped exon promotes exon skipping. Using truncation mutants, we show that removal of the Zn1Zn2 domain switches PARP1 from a DNA binder to an RNA binder. This study represents a first step into understanding the role of PARP1 RNA interaction. Continued identification and characterization of the functional interplay between PARPs and RNA may provide important insights into the role of PARPs in RNA regulation. PMID- 29387451 TI - Dihydroartemisinin selectively inhibits PDGFRalpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRalpha protein. AB - To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRalpha) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRalpha, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and metastasis of PDGFRalpha-positive ovarian cancer in vitro and in vivo. A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRalpha is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRalpha inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRalpha-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy. PMID- 29387453 TI - Advancing Care for Family Caregivers of persons with dementia through caregiver and community partnerships. AB - Background: There are currently 15 million Americans who provide over 80% of the care required by their family members with Alzheimer's disease and other dementias. Yet care for caregivers continues to be fragmented and few evidence based interventions have been translated into routine clinical care and therefore remain inaccessible to most family caregivers. To address this gap, the Caring for the Caregiver program is being developed at UT Health San Antonio, School of Nursing to improve support services and health outcomes for family caregivers. Our purpose is to describe the engagement process undertaken to assess caregiver and community needs and how findings are informing program development. Methods: We are using a model of public engagement that consists of communication of information, collection of information from stakeholders, and collaboration where stakeholders are partners in an exchange of information to guide program activities. An assessment of the community was undertaken to identify resources/services for family caregivers. Subsequently, stakeholders were invited to a community-academic forum to discuss strategies to build on existing strengths for family caregiving and to identify gaps in care. Detailed notes were taken and all discussions were recorded and transcribed for analysis. Data were analyzed using thematic content analysis. Results: We conducted site visits with 15 community agencies, interviewed 13 family caregivers, and attended community events including support groups and health and senior fairs. Fifty-three diverse stakeholders attended the community-academic forum. Participants identified existing assets within our community to support family caregivers. Consistent among groups was the need to increase awareness in our community about family caregivers. Themes identified from the discussion were: making the invisible visible, you don't know what you don't know, learning too late, and anticipating and preparing for the future. Conclusions: Incorporating caregiver and community stakeholders was critical to ensure that the priorities of our community are addressed in a culturally responsive accessible program for family caregivers. The forum served as important mechanism to partner with the community and will be an annual event where we can continue to work with our stakeholders around needs for practice, education, and research. PMID- 29387454 TI - Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans. AB - Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbidities in MHO. The study included 29 African-American obese individuals, 8 MHO and 21 metabolically abnormal obese (MAO). Unbiased transcriptome-wide network analysis was carried out to identify molecular modules of co-expressed genes that are collectively associated with MHO. Network analysis identified a group of 23 co-expressed genes, including ribosomal protein genes (RPs), which were significantly downregulated in MHO subjects. The three pathways enriched in the group of co-expressed genes are EIF2 signaling, regulation of eIF4 and p70S6K signaling, and mTOR signaling. The expression of ten of the RPs collectively predicted MHO status with an area under the curve of 0.81. Triglycerides/HDL (TG/HDL) ratio, an index of insulin resistance, was the best predictor of the expression of genes in the MHO group. The higher TG/HDL values observed in the MAO subjects may underlie the activation of endoplasmic reticulum (ER) and related-stress pathways that lead to a chronic inflammatory state. In summary, these findings suggest that controlling ER stress and/or ribosomal stress by downregulating RPs or controlling TG/HDL ratio may represent effective strategies to prevent or delay the occurrence of metabolic disorders in obese individuals. PMID- 29387455 TI - Macular pigment optical density in a Brazilian sample. AB - Background: To evaluate macular pigment optical density (MPOD) and to identify its determinants in a sample of Brazilian individuals. Methods: This was a cross sectional study. One hundred three healthy individuals had both eyes photographed using a Visucam 500 digital fundus camera (Carl Zeiss Meditec, Jena, Germany) in combination with the MPOD module. Four variables were obtained: maximum MPOD, mean MPOD, MPOD volume, and MPOD area. Demographic data and information on lifestyle habits were also collected. Results: Mean MPOD was 0.14 density unit +/ 0.05. MPOD was not influenced by gender, smoking history, or refractive error. MPOD was significantly higher among black individuals than among white and biracial individuals. There was a positive but low correlation between MPOD and age. Conclusion: This study found MPOD values to be similar to those found in European samples but lower than other studies performed on Asian and Australian samples. This is the first data regarding MPOD in a South American Population. PMID- 29387456 TI - Foreword. PMID- 29387457 TI - Whatever Happened to Measuring Ventricular Contractility in Heart Failure? AB - Attempts have been made to assess and measure ventricular contractility in patients and whether it can be used to identify heart failure. Due to the assumption that if the contractility of all the muscle fibres in a heart were lower, could it be called heart failure? Early attempts involved the assumption of a model of muscle that had a contractile unit in series with an elastic element, but this was found to be incorrect. Further attempts applied the series elastic model but this model also proved challenging. However, one method has assessed changes in contractility in a given patient, in response to an intervention, but could not compare contractility in a patient with heart failure with a normal person. End-systolic pressure-volume (ESPV) is regarded as a more correct index of contractility and this method was used to confirm changes in contractility from beat to beat during AF, showing results that end-systolic volume varied and indicating a shift of ESPV from beat to beat. This review will discuss the difficulty in measurement, the complicated nature of myocardial fibre orientation and hypertrophy, and whether myocardial contractility failure precipitates increased global heart failure. PMID- 29387458 TI - Natriuretic Peptide-based Screening and Prevention of Heart Failure. AB - There is increasing interest in the concept of personalised medicine, whereby conditions with common pathophysiologies are targeted together, and also using biomarkers to identify patients who will most benefit from certain interventions. Several data sets indicate that natriuretic peptides are effective in refining risk prediction for heart failure and cardiovascular disease and add predictive power to conventional risk factors. To date two trials have tested the approach of using natriuretic peptides as part of a strategy to identify those at highest risk of cardiovascular events: St. Vincent's Screening to Prevent Heart Failure (STOP-HF) and N-terminal Pro-brain Natriuretic Peptide Guided Primary Prevention of Cardiovascular Events in Diabetic Patients (PONTIAC). These have shown natriuretic peptide-based screening and targeted prevention can reduce heart failure and left ventricular dysfunction and other major cardiovascular events. This approach is now part of North American guidelines. PMID- 29387460 TI - The Role of Automated 3D Echocardiography for Left Ventricular Ejection Fraction Assessment. AB - Ejection fraction is one of the most powerful determinants of prognosis and is a crucial parameter for the determination of cardiovascular therapies in conditions such as heart failure, valvular conditions and ischaemic heart disease. Among echocardiographic methods, 3D echocardiography has been attributed as the preferred one for its assessment, given an increased accuracy and reproducibility. Full-volume multi-beat acquisitions are prone to stitching artefacts due to arrhythmias and require prolonged breath holds. Single-beat acquisitions exhibit a lower temporal resolution, but address the limitations of multi-beat acquisitions. If not fully automated, 3D echocardiography remains time consuming and resource-intensive, with suboptimal observer variability, preventing its implementation in routine practice. Further developments in hardware and software, including fully automated knowledge-based algorithms for left ventricular quantification, may bring 3D echocardiography to a definite turning point. PMID- 29387459 TI - The Prognostic Role of Tissue Characterisation using Cardiovascular Magnetic Resonance in Heart Failure. AB - Despite significant advances in heart failure diagnostics and therapy, the prognosis remains poor, with one in three dying within a year of hospital admission. This is at least in part due to the difficulties in risk stratification and personalisation of therapy. The use of left ventricular systolic function as the main arbiter for entrance into clinical trials for drugs and advanced therapy, such as implantable defibrillators, grossly simplifies the complex heterogeneous nature of the syndrome. Cardiovascular magnetic resonance offers a wealth of data to aid in diagnosis and prognostication. The advent of novel cardiovascular magnetic resonance mapping techniques allows us to glimpse some of the pathophysiological mechanisms underpinning heart failure. We review the growing prognostic evidence base using these techniques. PMID- 29387461 TI - Hypertension and Frailty Syndrome in Old Age: Current Perspectives. AB - Hypertension is both a health problem and a financial one globally. It affects nearly 30 % of the general population. Elderly people, aged >=65 years, are a special group of hypertensive patients. In this group, the overall prevalence of the disease reaches 60 %, rising to 70 % in those aged >=80 years. In the elderly population, isolated systolic hypertension is quite common. High systolic blood pressure is associated with an increased risk of cardiovascular disease, cerebrovascular disease, peripheral artery disease, cognitive impairment and kidney disease. Considering the physiological changes resulting from ageing alongside multiple comorbidities, treatment of hypertension in elderly patients poses a significant challenge to treatment teams. Progressive disability with regard to the activities of daily life, more frequent hospitalisations and low quality of life are often seen in elderly patients. There is discussion in the literature regarding frailty syndrome associated with old age. Frailty is understood to involve decreased resistance to stressors, depleted adaptive and physiological reserves of a number of organs, endocrine dysregulation and immune dysfunction. The primary dilemma concerning frailty is whether it should only be defined on the basis of physical factors, or whether psychological and social factors should also be included. Proper nutrition and motor rehabilitation should be prioritised in care for frail patients. The risk of orthostatic hypotension is a significant issue in elderly patients. It results from an autonomic nervous system dysfunction and involves maladjustment of the cardiovascular system to sudden changes in the position of the body. Other significant issues in elderly patients include polypharmacy, increased risk of falls and cognitive impairment. Chronic diseases, including hypertension, deteriorate baroreceptor function and result in irreversible changes in cerebral and coronary circulation. Concurrent frailty or other components of geriatric syndrome in elderly patients are associated with a worse perception of health, an increased number of comorbidities and social isolation of the patient. It may also interfere with treatment adherence. Identifying causes of non-adherence to pharmaceutical treatment is a key factor in planning therapeutic interventions aimed at increasing control, preventing complications, and improving long-term outcomes and any adverse effects of treatment. Diagnosis of frailty and awareness of the associated difficulties in adhering to treatment may allow targeting of those elderly patients who have a poorer prognosis or may be at risk of complications from untreated or undertreated hypertension, and for the planning of interventions to improve hypertension control. PMID- 29387462 TI - Dilemmas in the Dosing of Heart Failure Drugs: Titrating Diuretics in Chronic Heart Failure. AB - Despite advances in medical therapy over the past few decades, the incidence of heart failure hospitalisation continues to rise. Diuretics are the most common therapy used to treat heart failure as they relieve congestion. However, there is a lack of guidance on how to best use these medications. Guidelines support the use of diuretics at the lowest clinically effective dose but do not specify a diuretic strategy beyond that. Here we review the diuretics available for treatment, potential mechanisms of diuretic resistance and ways to address this in the ambulatory setting, and review tools that have been developed to help guide diuretic use in the treatment of chronic heart failure. PMID- 29387463 TI - Applying Heart Failure Management to Improve Health Outcomes: But WHICH One? AB - We report on our learning from many years of research testing the value of nurse led, multidisciplinary, home-based management of heart failure. We discuss and highlight the key challenges we have experienced in testing this model of care relative to alternatives and evolving patient population. Accordingly, we propose a pragmatic approach to adapt current models of care to meet the needs of increasingly complex (and costly) patients with multimorbidity. PMID- 29387464 TI - Value of Telemonitoring and Telemedicine in Heart Failure Management. AB - The use of telemonitoring and telemedicine is a relatively new but quickly developing area in medicine. As new digital tools and applications are being created and used to manage medical conditions such as heart failure, many implications require close consideration and further study, including the effectiveness and safety of these telemonitoring tools in diagnosing, treating and managing heart failure compared to traditional face-to-face doctor-patient interaction. When compared to multidisciplinary intervention programs which are frequently hindered by economic, geographic and bureaucratic barriers, non invasive remote monitoring could be a solution to support and promote the care of patients over time. Therefore it is crucial to identify the most relevant biological parameters to monitor, which heart failure sub-populations may gain real benefits from telehealth interventions and in which specific healthcare subsets these interventions should be implemented in order to maximise value. PMID- 29387466 TI - Quality of Physician Adherence to Guideline Recommendations for Life-saving Treatment in Heart Failure: an International Survey. AB - QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) showed that good physician adherence to guideline recommendations for angiotensin converting enzyme inhibitors/angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists and ivabradine, with prescription of at least 50 % of recommended dosages, was associated with better 6-month outcomes than moderate or poor adherence. Poor adherence was associated with higher all-cause mortality (hazard ratio 2.21; 95 % CI [1.42-3.44]; p=0.001) and combined heart failure hospitalisation or death (hazard ratio 1.26; 95 % CI [1.08-1.71]; p=0.024) compared with good adherence. Heart failure hospitalisation is a good opportunity to review a patient's medication and to optimise guideline adherence. PMID- 29387465 TI - Predictors of Post-discharge Mortality Among Patients Hospitalized for Acute Heart Failure. AB - Acute Heart Failure (AHF) is a " multi-event disease" and hospitalisation is a critical event in the clinical course of HF. Despite relatively rapid relief of symptoms, hospitalisation for AHF is followed by an increased risk of death and re-hospitalisation. In AHF, risk stratification from clinically available data is increasingly important in evaluating long-term prognosis. From the perspective of patients, information on the risk of mortality and re-hospitalisation would be helpful in providing patients with insight into their disease. From the perspective of care providers, it may facilitate management decisions, such as who needs to be admitted and to what level of care (i.e. floor, step-down, ICU). Furthermore, risk-stratification may help identify patients who need to be evaluated for advanced HF therapies (i.e. left-ventricle assistance device or transplant or palliative care), and patients who need early a post-discharge follow-up plan. Finally, risk stratification will allow for more robust efforts to identify among risk markers the true targets for therapies that may direct treatment strategies to selected high-risk patients. Further clinical research will be needed to evaluate if appropriate risk stratification of patients could improve clinical outcome and resources allocation. PMID- 29387467 TI - Sleep-Disordered Breathing During Congestive Heart Failure: To Intervene or Not to Intervene? AB - Sleep-disordered breathing is common in heart failure patients and is associated with increased morbidity and mortality. Central sleep apnea occurs more commonly in heart failure-reduced ejection fraction, and obstructive sleep apnea occurs more frequently in heart failure with preserved ejection fraction. Although the two types of sleep-disordered breathing have distinct pathophysiologic mechanisms, both contribute to abnormal cardiovascular consequences. Treatment with continuous positive airway pressure for obstructive sleep apnea in heart failure has been well defined, whereas treatment strategies for central sleep apnea in heart failure continue to evolve. Unilateral transvenous neurostimulation has shown promise for the treatment of central sleep apnea. In this paper, we examine the current state of knowledge of treatment options for sleep-disordered breathing in heart failure. PMID- 29387468 TI - The Future Role of Cardio-oncologists. AB - Cardiovascular (CV) disease and cancer remain the two most common causes of mortality in developed countries; however, progress in the treatment of malignant diseases significantly improved survival of oncological patients. Similarly, there is an increased number of the patients with malignancy who have a history of CV disease or an increased CV risk. Rates of CV problems from cancer-related therapeutics are high, and cardiotoxicity is the second most common cause of morbidity and mortality in cancer survivors. Therefore, there is a need for the development of an efficient programme to manage the problem of cardiotoxicity with the aim to decrease morbidity and mortality in patients and to improve their quality of life. For this purpose, cardio-oncological clinics should be an essential part of the strategy. PMID- 29387469 TI - Development of a German fracture register to assess current fracture care and improve treatment quality: A feasibility study. AB - Continuous evaluation of current treatment methods is crucial in orthopaedic trauma surgery.Existing fracture registries substantially contribute to improving fracture care and quality of life in trauma patients.Currently there is no universal German fracture register recording the patient-centred outcome of non surgical as well as surgical fracture treatment in all anatomical regions.Conclusions regarding nationwide fracture treatment and quality of care are only significant to a limited extent. Cite this article: EFORT Open Rev 2017;2:474-477. DOI: 10.1302/2058-5241.2.160086. PMID- 29387470 TI - Arthroscopic remplissage: Is it still an option? AB - Posterolateral humeral head defects can be large and engage on the anterior glenoid, and they usually contribute to anterior shoulder instability in 40% to 90% of cases.The purpose of this study is to evaluate the results of the largest series of patients who underwent arthroscopic remplissage with Bankart repair for recurrent anterior shoulder instability due to associated Bankart lesions, with large and engaging (> 25% involvement) humeral Hill-Sachs defects (HSDs).A total of 51 patients underwent arthroscopic Bankart repair with remplissage technique for the treatment of recurrent anterior glenohumeral instability with large and medial HSDs. Pre-operative imaging in all patients identified a Bankart lesion with an associated HSD that involved > 25% of the humeral head. The Rowe score was used to assess the patients clinically.A total of 46 patients were male. The mean age of the patients was 28.7 years (18 to 43). The mean follow-up period was 31 months (20 to 39). At the final follow-up, three patients reported recurrence of instability (two dislocations and one subluxation). The mean Rowe score improved to 95.4 points (function, 45.5 of 50; stability, 26.4 of 30; motion, 8 of 10; pain, 8 of 10).The arthroscopic remplissage technique with Bankart repair gave satisfactory results and is still considered to be an effective, safe and reliable procedure for treatment of glenohumeral instability in cases with large and medial HSDs. Cite this article: EFORT Open Rev 2017;2:478-483. DOI: 10.1302/2058-5241.2.160070. PMID- 29387471 TI - Subscapularis tendon tears: Management and arthroscopic repair. AB - Tears of the subscapularis tendon have been under-recognised until recently. Therefore, a high index of suspicion is essential for diagnosis.A directed physical examination, including the lift-off, belly-press and increased passive external rotation can help identify tears of the subscapularis.All planes on MR imaging should be carefully evaluated to identify tears of the subscapularis, retraction, atrophy and biceps pathology.Due to the tendency of the tendon to retract medially, acute and traumatic full-thickness tears should be repaired. Chronic tears without significant degeneration should be considered for repair if no contraindication exists.Arthroscopic repair can be performed using a 30-degree arthroscope and a laterally-based single row repair; one anchor for full thickness tears ? 50% of tendon length and two anchors for those ? 50% of tendon length.Biceps pathology, which is invariably present, should be addressed by tenotomy or tenodesis.Timing of post-operative rehabilitation is dictated by the size of the repair and the security of the repair construct. The stages of rehabilitation typically involve a period of immobilisation followed by range of movement exercises, with a delay in active internal rotation (IR) and strengthening in IR. Cite this article: EFORT Open Rev 2017;2:484-495. DOI: 10.1302/2058-5241.2.170015. PMID- 29387472 TI - Return to sport after total or unicompartmental knee arthroplasty: An informative guide for residents to patients. AB - Knee arthroplasty survival rate - either UKA or TKA - is currently 95%, greater than it was ten years ago, but has not been specifically evaluated in very active patients practicing sport at a high intensity.The terms and conditions of return to physical activities are decided by the surgeon, the rehabilitation or Sports Medicine doctor, who needs to make sure that postoperative rehabilitation has been conducted optimally. Specifically, range of movement must be complete, muscular strengthening has to be sufficient and balance must be recovered by proprioception. Only after this stage (i.e. three to six months after surgery) can physical activities be resumed.Return to sport must be gentle and progressive, with moderate activities limited to short sessions. Progressively the patient will be able to return to intermediate activities, provided that he/she possesses the adequate level of technique for the sport.This up-to-date review for young surgeons and residents aims to provide an informative guide for patients regarding sport following knee arthroplasty. Cite this article: EFORT Open Rev 2017;2:496-501. DOI: 10.1302/2058-5241.2.170037. PMID- 29387473 TI - Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a Phase 2 clinical trial. AB - The hemagglutinination inhibition (HI) response remains the gold standard used for the licensure of influenza vaccines. However, cell-mediated immunity (CMI) deserves more attention, especially when evaluating H5N1 influenza vaccines that tend to induce poor HI response. In this study, we measured the humoral response (HI) and CMI (flow cytometry) during a Phase II dose-ranging clinical trial (NCT01991561). Subjects received two intramuscular doses, 21 days apart, of plant derived virus-like particles (VLP) presenting the A/Indonesia/05/2005 H5N1 influenza hemagglutinin protein (H5) at the surface of the VLP (H5VLP). The vaccine was co-administrated with Alhydrogel(r) or with a glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). We demonstrated that low doses (3.75 or 7.5 MUg H5VLP) of GLA-SE-adjuvanted vaccines induced HI responses that met criteria for licensure at both antigen doses tested. Alhydrogel adjuvanted vaccines induced readily detectable HI response that however failed to meet licensure criteria at any of three doses (10, 15 and 20 MUg) tested. The H5VLP also induced a sustained (up to 6 months) polyfunctional and cross-reactive HA-specific CD4+ T cell response in all vaccinated groups. Interestingly, the frequency of central memory Th1-primed precursor cells before the boost significantly correlated with HI titers 21 days after the boost. The ability of the low dose GLA-SE-adjuvanted H5VLP to elicit both humoral response and a sustained cross-reactive CMI in healthy adults is very attractive and could result in significant dose-sparing in a pandemic situation. PMID- 29387474 TI - Gamma-interferon exerts a critical early restriction on replication and dissemination of yellow fever virus vaccine strain 17D-204. AB - Live attenuated viruses are historically among the most effective viral vaccines. Development of a safe vaccine requires the virus to be less virulent, a phenotype that is historically arrived by empirical evaluation often leaving the mechanisms of attenuation unknown. The yellow fever virus 17D live attenuated vaccine strain has been developed as a delivery vector for heterologous antigens; however, the mechanisms of attenuation remain elusive. The successful and safe progress of 17D as a vaccine vector and the development of live attenuated vaccines (LAVs) to related flaviviruses requires an understanding of the molecular mechanisms leading to attenuation. Using subcutaneous infection of interferon-deficient mouse models of wild type yellow fever virus (WT YFV) pathogenesis and 17D mediated immunity, we found that, in the absence of type I IFN (IFN-alpha/beta), type II interferon (IFN-gamma) restricted 17D replication, but not that of WT YFV, by 1-2 days post-infection. In this context, IFN-gamma responses protected 17D-infected animals from mortality, largely restricted the virus to lymphoid organs, and eliminated viscerotropic disease signs such as steatosis in the liver and inflammatory cell infiltration into the spleen. However, WT YFV caused a disseminated infection, gross liver pathology, and rapid death of the animals. In vitro, IFN-gamma treatment of myeloid cells suppressed the replication of 17D significantly more than that of WT YFV, suggesting a direct differential effect on 17D virus replication. Together these data indicate that an important mechanism of 17D attenuation in vivo is increased sensitivity to IFN-gamma stimulated responses elicited early after infection. PMID- 29387476 TI - Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. AB - Background: Immune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea. The main objective of this study was to analyse symptoms (ie, grade of diarrhoea), endoscopic and histological features and response to management in immune checkpoint inhibition related colitis (IRC). Patients and methods: We retrospectively analysed patients who developed diarrhoea on checkpoint inhibition and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated between August 2010 and March 2016 for metastatic melanoma or non-small cell lung cancer. Severity of IRC was scored using the endoscopic Mayo score and the van der Heide score. Results: Out of a cohort of 781 patients, 92 patients were identified who developed diarrhoea and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated with monotherapy anticytotoxic T lymphocyte antigen-4, antiprogrammed death receptor-1 or a combination of both. All patients had symptoms of diarrhoea (grade 1: 16%; grade 2: 39% and grade 3: 44%). A complete colonoscopy was performed in 62 (67%) patients, of whom 42 (68%) had a pancolitis (>=3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores, the presence of ulcers or histological features. In 54 episodes of diarrhoea (56%), patients received one or more cycles infliximab for steroid-refractory colitis. Patients with higher endoscopic severity scores, ulcers and/or a pancolitis needed infliximab more often. Conclusions: The correlation between grade of diarrhoea and endoscopic or histological features for severity of colitis is poor. Patients with higher endoscopic severity scores, ulcers or a pancolitis needed the addition of infliximab more often. Therefore, endoscopy may have value in the evaluation of the severity of IRC and may help in decision making for optimal management. PMID- 29387475 TI - Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. AB - This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context. PMID- 29387477 TI - Value of surgical resection and timing of therapy in patients with pancreatic cancer at high risk for positive margins. AB - Background: Surgical resection remains the best chance at long-term survival in pancreatic cancer, though margin-positive resections are associated with diminished survival. We examined the effect of margin-positive resection on survival, as well as the role and timing of additional therapies through the National Cancer Database (NCDB). Patients and methods: Patients with stage IIA III pancreatic adenocarcinoma diagnosed from 2004 to 2013 were identified in NCDB. Survival was compared using univariate and multivariate Cox proportional hazards modelling for patients who underwent surgery with negative (R0), microscopically positive (R1) and macroscopically positive (R2) margins or non surgical treatment. We further analysed patients by margin status, timing of additional therapy (neoadjuvant therapy (NAT) vs adjuvant therapy (AT) vs none) and clinical stage. Results: We analysed 44 852 patients. Median survival (MS) for patients who did not undergo surgery was 10.3 months, compared with 19.7 months for R0 (P<0.001), 14.3 months for R1 (P<0.001) and 9.8 months (P=0.07) for R2 resections. NAT (MS 23.2 months) was associated with improved survival compared with AT (MS 21.5 months) in negative-margin patients and equivalent (MS 17.6 months) to AT (MS 16.8 months) in positive-margin patients. Survival for stage III NAT positive-margin patients (MS 19.8 months) was equivalent to AT after negative margins (MS 18.4 months, P=1.00). Improved R0 rates were seen with NAT (88% vs 81%, P<0.001), especially in stage III patients (85% vs 59%, P<0.001). Conclusion: R1 resections portend poorer survival than R0 but do not negate the benefit of surgery when additional therapy is given. NAT was associated with improved R0 rates and improved survival for stage III positive margin patients. PMID- 29387479 TI - Widespread rash in lung adenocarcinoma. PMID- 29387478 TI - Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. AB - Objectives: Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis, with a median survival measured in weeks, and few treatment options. Outcomes of a retrospective cohort of patients with LMD that were treated with intrathecal interleukin-2 (IT IL-2) were reviewed to assess the long-term efficacy of this therapy. Methods: The records of metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug study were reviewed. IL-2 (1.2 mIU) was administered intrathecally via Ommaya reservoir up to five times per week in the inpatient setting for 4 weeks; patients with good tolerance and clinical benefit received maintenance IT IL-2 every 1-3 months thereafter. Results: The cohort included 43 patients. The median age of the patients was 47 years (range 18-71), and 32 (74%) were male. 23 patients (53%) had positive cerebrospinal fluid (CSF) cytology and radiographic evidence of LMD, 8 (19%) had positive CSF cytology only, 9 (21%) had radiographic evidence only and 3 (7%) were diagnosed based on pathology review after craniotomy. The median overall survival (OS) from initiation of IT IL-2 was 7.8 months (range, 0.4-90.8 months), with 1-year, 2 year and 5-year OS rates of 36%, 26% and 13%. The presence of neurological symptoms (HR 2.1, P=0.03), positive baseline CSF cytology (HR 4.1, P=0.001) and concomitant use of targeted therapy (HR 3.0, P=0.02) was associated with shorter OS on univariate analysis. All patients developed symptoms due to increased intracranial pressure which was managed with supportive medications and/or CSF removal, and there were no treatment-related deaths. Conclusion: These results demonstrate that despite their historically dismal prognosis a subset of metastatic melanoma patients with LMD treated with IT IL-2 can achieve long-term survival, but these data need to be verified in a prospective trial setting. PMID- 29387481 TI - New therapeutic targets in the inflammatory microenvironment. PMID- 29387480 TI - Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case. AB - Background: Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients. Patient and methods: HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay). Results: We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease. Conclusion: The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy. PMID- 29387482 TI - Biosimilars. PMID- 29387483 TI - Surgery of the primary tumour in patients presenting with de novo metastatic breast cancer: to do or not to do? PMID- 29387484 TI - Enhanced Axial Resolution of Wide-Field Two-Photon Excitation Microscopy by Line Scanning Using a Digital Micromirror Device. AB - Temporal focusing multiphoton microscopy is a technique for performing highly parallelized multiphoton microscopy while still maintaining depth discrimination. While the conventional wide-field configuration for temporal focusing suffers from sub-optimal axial resolution, line scanning temporal focusing, implemented here using a digital micromirror device (DMD), can provide substantial improvement. The DMD-based line scanning temporal focusing technique dynamically trades off the degree of parallelization, and hence imaging speed, for axial resolution, allowing performance parameters to be adapted to the experimental requirements. We demonstrate this new instrument in calibration specimens and in biological specimens, including a mouse kidney slice. PMID- 29387485 TI - The Comparison of the Surgical Outcome for the Full-Thickness Macular Hole with/without Lamellar Hole-Associated Epiretinal Proliferation. AB - Aims: To compare the surgical outcome of pars plana vitrectomy (PPV) for full thickness macular hole (FTMH) with and without lamellar hole-associated epiretinal proliferation (LHEP). Methods: This retrospective study included 158 eyes of 158 patients with FTMH treated with PPV. The following variables were analyzed: sex, age, preoperative best corrected visual acuity (pre-BCVA), BCVA 6 months after the surgery (6M-BCVA), the axial length of eye, the minimum diameter of FTMH, the diameter of basal side of FTMH, postoperative continuity of subfoveal ellipsoid zone (EZ) and external limiting membrane (ELM), and the preoperative presence of LHEP. Results: Twenty-eight eyes had FTMH with LHEP and 130 without LHEP. The mean +/- SD age (years) was 72.6 +/- 7.9 and 68.6 +/- 8.7, respectively (p = 0.02). 6M-BCVA was 0.38 +/- 0.30 and 0.26 +/- 0.25, respectively (p = 0.03). The diameter of basal side of FTMH (MUm) was 901.5 +/- 404.9 and 658.9 +/- 288.1, respectively (p = 0.00027). EZ was disrupted in 24 eyes and 63 eyes, respectively (p = 0.00071). ELM was disrupted in 15 eyes and 23 eyes, respectively (p = 0.00015). The FTMH diameters and the presence of LHEP were inversely correlated with the continuity of EZ and ELM. Conclusion: The preoperative appearance of LHEP could be one of the prognostic factor for the treatment of FTMH. PMID- 29387486 TI - Treatment Outcome of Carcinoma Vulva Ten-Year Experience from a Tertiary Cancer Centre in South India. AB - Background: Carcinoma vulva is a rare disease accounting for 1.3% of all gynaecological malignancies. The present study is a 10-year retrospective review of our experience of the surgical options, morbidity, failure pattern, and survival for invasive carcinoma vulva. Materials and Methods: Retrospective analysis of case records of 39 patients who underwent surgery for invasive vulval cancer between 2004 and 2013 in the Department of Surgical Oncology at the Government Royapettah Hospital, Chennai. Results: The median age was 55 years. Radical vulvectomy was the preferred surgery. 31 patients underwent lymphadenectomy. Seroma formation and groin skin necrosis were the most common postoperative complications. With a median follow-up of 32 months, 8 patients (20.5%) developed recurrence (systemic = 1, regional = 4, and local = 3). The estimated 5-year disease-free survival (DFS) was 65.4% and the overall survival (OS) was 85.1%. On univariate analysis, stage and lymph node involvement significantly affected OS. Nodal involvement with extracapsular spread (ECS) significantly affected both DFS and OS. Conclusion: The treatment of carcinoma vulva should be individualized with multidisciplinary cooperation. The paucity of data, especially from India, necessitates the need for more studies, preferably multicentric, keeping in mind the low prevalence. PMID- 29387487 TI - Antecedents and Consequences of Therapeutic Communication in Iranian Nursing Students: A Qualitative Research. AB - In recent years, particular attention has been paid to nursing students' therapeutic communication (TC) with patients, due to a strong emphasis on patient centered education in the Iranian healthcare reform. However, various studies have highlighted the poor communication of future nurses. Therefore, researchers have used qualitative methodology to shed light on the antecedents and consequences of nursing students' TC and promote it. We carried out a conventional content analysis using semistructured interviews with a purposefully selected sample of 18 participants, including nursing instructors, students, and patients in hospitals affiliated to Tehran University of Medical Sciences. "Communication readiness," "predisposing factors," and "continuity of care" were identified as the three major themes. "Communication readiness" consisted of "physical readiness," "academic readiness," and "developmental readiness." "Predisposing factors" included "contextual factors" and "educational condition." "Continuity of care" included "patient satisfaction" and "improving nursing student's motivation to communicate with patients." "Communication readiness" and "predisposing factors" constitute the antecedents of nursing student's TC with patients, and "continuity of care" is considered as its consequence. More attention needs to be paid by the regulators to TC instruction in both theoretical and clinical educational curriculum. Furthermore, all nurses must be informed about the importance of TC in promoting patient outcomes and quality of care. PMID- 29387488 TI - Genistein Exposure Interferes with Pharmacokinetics of Celecoxib in SD Male Rats by UPLC-MS/MS. AB - Objective: To discuss the effects of genistein on the metabolism of celecoxib in vitro and in vivo. Method: In vitro, the effects of genistein on the metabolism of celecoxib were studied using rat and human liver microsomes. In vivo, pharmacokinetics of celecoxib was evaluated in rats with or without genistein. Fifteen Sprague-Dawley (SD) rats were randomized into three groups: celecoxib (A group), celecoxib and 50 mg/kg genistein (B group), and celecoxib and 100 mg/kg genistein (C group). Single dose of 33.3 mg/kg celecoxib was orally administered 30 min after genistein ig. At 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after celecoxib administration, 300-400 ul blood samples were collected and the concentration of celecoxib was analyzed by ultrahigh-performance liquid chromatography-tandem mass spectrometry system. Result: Genistein showed notable inhibitory effects on three microsomes. It affected pharmacokinetics of celecoxib in vivo experiments. Genistein had dramatically ability to suppress CYP2C9*1 and *3. After pretreatment with genistein, AUC and Cmax of the C group were higher than B group. CLz/F of C group was lower than the B group. Conclusion: Genistein inhibits the conversion of celecoxib in vitro and in vivo. So, the dosage of celecoxib should be adjusted if it was used associated with genistein. PMID- 29387489 TI - Acute Hepatitis E Virus Infection in Two Geographical Regions of Nigeria. AB - Hepatitis E virus (HEV) remains a major public health concern in resource limited regions of the world. Yet data reporting is suboptimal and surveillance system is inadequate. In Nigeria, there is dearth of information on prevalence of acute HEV infection. This study was therefore designed to describe acute HEV infection among antenatal clinic attendees and community dwellers from two geographical regions in Nigeria. Seven hundred and fifty plasma samples were tested for HEV IgM by Enzyme Linked Immunosorbent Assay (ELISA) technique. The tested samples were randomly selected from a pool of 1,115 blood specimens previously collected for viral hepatitis studies among selected populations (pregnant women, 272; Oyo community dwellers, 438; Anambra community dwellers, 405) between September 2012 and August 2013. One (0.4%) pregnant woman in her 3rd trimester had detectable HEV IgM, while community dwellers from the two study locations had zero prevalence rates of HEV IgM. Detection of HEV IgM in a pregnant woman, especially in her 3rd trimester, is of clinical and epidemiological significance. The need therefore exists for establishment of a robust HEV surveillance system in Nigeria and especially amidst the pregnant population in a bid to improve maternal and child health. PMID- 29387490 TI - Selection and Characterization of Potential Baker's Yeast from Indigenous Resources of Nepal. AB - The study aims to isolate the yeast strains that could be used effectively as baker's yeast and compare them with the commercial baker's yeast available in the market of Nepal. A total of 10 samples including locally available sources like fruits, Murcha, and a local tree "Dar" were collected from different localities of Bhaktapur, Kavre, and Syangja districts of Nepal, respectively. Following enrichment and fermentation of the samples, 26 yeast strains were isolated using selective medium Wallerstein Laboratory Nutrient Agar. From the differential tests which included morphological and microscopic observation and physiological and biochemical characterization such as nitrate reduction and lactose utilization tests, 8 strains were selected as possible Saccharomyces strain. The selected strains were further assessed for their efficient leavening ability by tests such as ethanol tolerance, osmotolerance, invertase test, and stress exclusion test. The three most potent strains ENG, MUR3B, and SUG1 isolated from grape, Murcha, and sugarcane, respectively, were used in the fermentation and baking of dough. These strains also carried a possibility of being used as industrial baker's yeast. PMID- 29387491 TI - Rare Case of Cocaine-Induced Aortic Aneurysm: A Near Dissection Event. AB - Cocaine use has been associated with cardiovascular complications such as coronary atherosclerosis, coronary artery spasm, cardiac arrhythmias, acute myocardial infarction, myocarditis, and dilated cardiomyopathies. Aortic dissection is a rare but life-threatening complication of cocaine use. Cocaine and stimulant use can cause aortic aneurysm by increasing the aortic wall stress, and the most feared complications are dissection, rupture, and death. There are no clear guidelines about screening cocaine abusers with CT scan of the chest. We do not know if the number of years of cocaine use or the amount of cocaine use can be associated with higher incidence of aortic aneurysm or dissection. Cocaine induced aortic aneurysm does not have any specific clinical feature. Common presentation is chest discomfort or chest pain. This common presentation is bewildering enough for clinicians to think of more common causes of chest pain like myocardial infarction and myocarditis. The sudden onset of severe, sharp, stabbing chest or back pain is suggestive of aortic dissection. Here, we present a young otherwise healthy patient with chronic cocaine use presenting with chest pain and found to have significant size aortic aneurysm. PMID- 29387492 TI - A Case of Cardiac Calcified Amorphous Tumor Presenting with Concomitant ST Elevation Myocardial Infarction and Occipital Stroke and a Brief Review of the Literature. AB - Cardiac calcified amorphous tumor (CAT) is an extremely rare benign intracavitary tumor of the heart. It may mimic other cardiac tumors and can present with signs or symptoms of systemic embolization. There are limited data regarding CAT in the literature. We report a case of a 68-year-old woman with a cardiac CAT and mitral annular calcification (MAC), who presented with acute ST-elevation myocardial infarction (STEMI) and occipital stroke. After extensive review of the literature, we believe that this case is possibly the first description of a cardiac CAT presenting with STEMI. The CAT was surgically removed, and the diagnosis was confirmed by histology. The patient tolerated the surgery and reported no events at 6-month follow-up. PMID- 29387493 TI - Accelerated Tooth Movement with Orthodontic Mini-Screws. AB - This case report outlines the possibility of accelerated tooth movement with the combination of microosteoperforation and mini-screws. A 14-year-old male patient presented Class II malocclusion with maxillary incisor protrusion. Upper first premolars were extracted, and after leveling, accelerated canine distalization started. For pre- and postdistalization times, amount of distalization, periodontal health, and root resorption were assessed. Within the limitations of this case report, micro-osteoperforations with mini-screw have a potential for shortening the treatment time. PMID- 29387494 TI - Early Orthopaedic Treatment of Hemifacial Microsomia. AB - The aim of this paper is to report treatment effects of functional therapy in a growing patient affected by hemifacial microsomia (HM). According to Kaban's classification, the patient was classified as grade IIa as she presented all mandibular and temporomandibular joint components and a normal shaped, hypoplastic mandible. The therapeutic approach included the use of an asymmetrical functional activator (AFA) to stimulate the growth of the affected side and consequently to improve symmetry of the mandible and maxillary deficiency. Further effects were the lengthening of the mandibular ramus, restoration of occlusion, and expansion of soft tissues. PMID- 29387495 TI - Endobronchial Foreign Body Presenting as Exacerbation of Asthma. AB - Airway foreign bodies are a leading cause of death among children and require urgent recognition by medical personnel. While most cases are diagnosed readily from a clinical history of acute respiratory distress, some cases remain more indolent and present later. We report the case of a 7-year-old boy who aspirated a "LEGO" toy and presented with a week history of increasing respiratory distress compatible with known asthma. Despite a normal chest X-ray, a low-dose computed tomography showed the presence of a foreign body in the left main bronchus, which was subsequently removed by fiberoptic bronchoscopy. Our case serves to reemphasize the importance of considering airway foreign bodies as a cause of respiratory distress, especially in young children. PMID- 29387496 TI - A Rare Clinical Presentation of Cholangiocarcinoma. AB - Cholangiocarcinoma is an uncommon tumor, often diagnosed in the context of obstructive jaundice. Brain metastasis rarely occurs with the cerebellum being a rare site of spread of this type of tumor. Few cases of cholangiocarcinoma have been reported in the literature and this type of tumor is associated with a very poor outcome. We present a very rare form of clinical presentation of cholangiocarcinoma with neurologic symptoms due to cerebellar metastases. PMID- 29387497 TI - A Novel Mutation in ACTG2 Gene in Mother with Chronic Intestinal Pseudoobstruction and Fetus with Megacystis Microcolon Intestinal Hypoperistalsis Syndrome. AB - Background. A novel mutation in the ACTG2 gene is described in a pregnant patient followed up for chronic intestinal pseudoobstruction (CIPO) during pregnancy and her fetus with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS). Case. 24-year-old gravida 1 para 1 with CIPO and persistent nausea and vomiting in pregnancy, admitted at 28 weeks of gestation. Ultrasound revealed a fetus measuring greater than the 95th percentile, polyhydramnios, and megacystis. At delivery, the newborn was noted to have an enlarged bladder, microcolon, and intolerance of oral intake. Genetic testing of mother and child revealed a novel mutation in the ACTG2 gene (C632F>A, p.R211Q). Conclusion. This is the first case in the literature describing a novel mutation in ACTG2 associated with visceral myopathy affecting both mother and fetus/neonate. Visceral myopathy should be included in the differential diagnosis of megacystis diagnosed by ultrasound, and suspicion should increase with family history of CIPO or MMIHS. PMID- 29387498 TI - Plasmablastic Lymphoma with Coexistence of Chronic Lymphocytic Leukemia in an Immunocompetent Patient: A Case Report and Mini-Review. AB - Background: Plasmablastic lymphoma (PBL) is a rare, aggressive B-cell lymphoma with poor prognosis usually found in the oral cavity of HIV-positive patients. Chronic lymphocytic leukemia (CLL) is an indolent B-cell lymphoma with a variable clinical course. Transformation of CLL to PBL as Richter's syndrome is rare while coexistence of CLL and PBL at diagnosis is even rarer. Case Report: We describe a case of a male immunocompetent patient with an ileum-cecum valve mass and a soft tissue mass at the left humerus with histologic evidence of PBL with coexistence of CLL in the bone marrow and peripheral blood. Amputation of the patient's left arm was inevitable, and the patient was started on bortezomib and dexamethasone. However, prolonged hospitalization was complicated by aspiration pneumonia, and the patient passed away. Conclusions: No standard of care exists for patients with PBL, and prognosis remains dismal. Concomitant presentation of hematological malignancies becomes increasingly recognized, and further insight is needed in order to delineate whether they originate from the same clone or from different ones. PMID- 29387499 TI - Sickle Cell Beta-Plus Thalassemia with Subcapsular Hematoma of the Spleen. AB - While splenic complications like hypersplenism, sequestration crisis, and infarction are commonly reported in sickle cell variants like sickle cell beta plus thalassemia, splenic rupture with hematoma is rare. We present a case of a 32-year-old young male who presented with dull left upper quadrant pain who was found to have multiple subcapsular splenic lacerations and hematoma on abdominal imaging. Hemoglobin electrophoresis confirmed sickle cell beta-plus thalassemia in the patient. There was no history of trauma, and rest of the workup for possible cause of spontaneous rupture of spleen was negative. With the patient refusing splenectomy, he was managed conservatively. Clinicians need to be aware of this rare complication of sickle cell variants. PMID- 29387500 TI - Treatment of Pelvic Organ Prolapse in a Patient with a Thermal Burn Wound Caused by Hot Stone Therapy, a Traditional Thai Treatment. AB - A 72-year-old woman presented with a 1-month history of an incarcerated uterine prolapse along with an infected wound at the anterior uterine wall. She had previously undergone the traditional Thai practice Yue Fai, or "lying by the fire," as performed by postpartum women. However, her uterus was burned by the extremely high temperature involved in the practice; it subsequently became infected and incarcerated. Pelvic examination revealed stage IV genitourinary prolapse according to the POP-Q classification. An ill-defined ulcer measuring 6.5 * 4.5 cm was present in the anterior wall of the uterus, and a 2.0 cm diameter ulcer was present in the right posterior wall of the uterus. The patient was treated symptomatically with broad-spectrum antibiotics, local estrogen therapy, analgesic and anti-inflammatory agents, and antiseptic dressing of the ulcerated area. After alleviation of all symptoms, the ulcer almost completely healed. She was advised to undergo definitive surgical treatment for the prolapsed uterus. PMID- 29387501 TI - Simultaneous Noncentered Photoactivated Chromophore for Keratitis-Corneal Collagen Cross-Linking and Penetrating Keratoplasty for Treatment of Severe Marginal Fusarium spp. Keratitis: A Description of a New Surgical Technique. AB - The purpose of this article is to describe the use of simultaneous noncentered photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK CXL) combined with penetrating keratoplasty in the treatment of a severe marginal Fusarium spp. keratitis case with imminent corneal perforation. It is a retrospective case report study; it was performed by collecting clinical data, images, video, and postoperative evaluations. The clinical control of the infection was accomplished, despite difficulties in obtaining antifungal medications due to the patient's extremely poor socioeconomic status and essentially nonexistent health insurance. We can conclude that combining simultaneous decentered PACK-CXL with centered penetrating keratoplasty appears to be a safe and effective way of treating patients with fungal marginal keratitis with corneal perforation, in which regular penetrating keratoplasty alone would leave fungal elements in the receptor corneal tissue, which would predispose to infection of the graft. PMID- 29387502 TI - Treatment of Generalized Anxiety Disorder with Gabapentin. AB - Gabapentin is frequently used in the treatment of anxiety disorders. However, there are no randomized controlled trials on the effectiveness of this medication in generalized anxiety disorder (GAD), and there are only a few case reports. We present a case of a 59-year-old female with a psychiatric history of GAD. The patient discontinued benzodiazepines after more than 7 years of daily treatment which led to rebound anxiety, benzodiazepine withdrawal symptoms, and suicidal ideation. She was psychiatrically hospitalized and started on gabapentin. Over the next 10 months of outpatient follow-up, she attempted to taper off gabapentin due to personal preference to limit medications. During this time, we observed a clear dose-response pattern of gabapentin on GAD symptoms. In the absence of controlled studies, these findings may offer important information about the effectiveness of gabapentin in GAD. PMID- 29387503 TI - Serological Investigation of Peste Des Petits Ruminants in East Shewa and Arsi Zones, Oromia Region, Ethiopia. AB - Peste des petits ruminant (PPR) is an economically important disease of small ruminants with a rapidly expanding geographical distribution. There are fragmented reports to the occurrence and distribution of the disease in Ethiopia. A total of 700 serum samples were collected from goats and sheep to detect the presence of antibody against PPR virus using Competitive Enzyme-Linked Immunosorbent Assay (C-ELISA). An overall PPR seropositivity was reported to be 48.43% in the area. There is no statistically significant difference in the seroprevalence of the disease between sheep and goats (50.85% and 46.68%), respectively. However, there was statistically significant variation (P < 0.05) in the seroprevalence of the disease in young (33.9%) and adult (55.8%) age categories. The seroprevalence in male and female was 42.07% and 50.09%, respectively, where the variation was statistically not significant (P > 0.05). High seroprevalence of Peste des petites ruminants in the study area indicated the virus circulation and endemicity of the disease. The disease causes substantial economic losses by affecting the livelihood of the farmers. Therefore, control measures should be put in place to minimize the loss associated with the disease. PMID- 29387504 TI - HPLC-CUPRAC post-column derivatization method for the determination of antioxidants: a performance comparison between porous silica and core-shell column packing. AB - Background: An HPLC method employing a post-column derivatization strategy using the cupric reducing antioxidant capacity reagent (CUPRAC reagent) for the determining antioxidants in plant-based materials leverages the separation capability of regular HPLC approaches while allowing for detection specificity for antioxidants. Methods: Three different column types, namely core-shell and porous silica including two chemically different core-shell materials (namely phenyl-hexyl and C18), were evaluated to assess potential improvements that could be attained by changing from a porous silica matrix to a core-shell matrix. Tea extracts were used as sample matrices for the evaluation specifically looking at catechin and epigallocatechin gallate (EGCG). Results: Both the C18 and phenyl hexyl core-shell columns showed better performance compared to the C18 porous silica one in terms of separation, peak shape, and retention time. Among the two core-shell materials, the phenyl-hexyl column showed better resolving power compared to the C18 column. Conclusions: The CUPRAC post-column derivatization method can be improved using core-shell columns and suitable for quantifying antioxidants, exemplified by catechin and EGCG, in tea samples. PMID- 29387505 TI - Implementation of Epic Beaker Anatomic Pathology at an Academic Medical Center. AB - Background: Beaker is a relatively new laboratory information system (LIS) offered by Epic Systems Corporation as part of its suite of health-care software and bundled with its electronic medical record, EpicCare. It is divided into two modules, Beaker anatomic pathology (Beaker AP) and Beaker Clinical Pathology. In this report, we describe our experience implementing Beaker AP version 2014 at an academic medical center with a go-live date of October 2015. Methods: This report covers preimplementation preparations and challenges beginning in September 2014, issues discovered soon after go-live in October 2015, and some post go-live optimizations using data from meetings, debriefings, and the project closure document. Results: We share specific issues that we encountered during implementation, including difficulties with the proposed frozen section workflow, developing a shared specimen source dictionary, and implementation of the standard Beaker workflow in large institution with trainees. We share specific strategies that we used to overcome these issues for a successful Beaker AP implementation. Several areas of the laboratory-required adaptation of the default Beaker build parameters to meet the needs of the workflow in a busy academic medical center. In a few areas, our laboratory was unable to use the Beaker functionality to support our workflow, and we have continued to use paper or have altered our workflow. In spite of several difficulties that required creative solutions before go-live, the implementation has been successful based on satisfaction surveys completed by pathologists and others who use the software. However, optimization of Beaker workflows has continued to be an ongoing process after go-live to the present time. Conclusions: The Beaker AP LIS can be successfully implemented at an academic medical center but requires significant forethought, creative adaptation, and continued shared management of the ongoing product by institutional and departmental information technology staff as well as laboratory managers to meet the needs of the laboratory. PMID- 29387506 TI - Electrospun aniline-tetramer-co-polycaprolactone fibres for conductive, biodegradable scaffolds. AB - Conjugated polymers have been proposed as promising materials for scaffolds in tissue engineering applications. The restricted processability and biodegradability of conjugated polymers limit their use for biomedical applications however. Here we synthesised a block-co-polymer of aniline tetramer and PCL (AT-PCL), and processed it into fibrous non-woven scaffolds by electrospinning. We showed that fibronectin (Fn) adhesion was dependant on the AT PCL oxidative state, with a reduced Fn unfolding length on doped membranes. Furthermore, we demonstrated the cytocompatibility and potential of these membranes to support the growth and osteogenic differentiation of MC3T3-E1 over 21 days. PMID- 29387507 TI - Classic and Non-Classic Features in Pseudohypoparathyroidism: Case Study and Brief Literature Review. AB - Pseudohypoparathyroidism is a rare condition that is due to a defect in the stimulatory G-protein coupled receptor, resulting in end-organ resistance to parathyroid hormone. Hereditary forms of pseudohypoparathyroidism present with certain classic features such as obesity, short stature, brachydactyly, and intellectual disability. Constellation of these physical features is known as Albright's hereditary osteodystrophy. In this case, 41-year-old male presented with the classic features of pseudohypoparathyroidism and with 59 lbs weight gain over six months. It was determined that the cause of the patient's weight gain was due to concomitant hypothyroidism, which is a common association. There are several non-classic features and associated pathologies associated with pseudohypoparathyroidism. These conditions should be regularly screened for and assessed when a patient presents with pseudohypoparathyroidism. PMID- 29387508 TI - Does Frequency of ST-Segment Elevation Myocardial Infarction Presentation Impact Quality of Care? AB - Objectives The volume of ST-Segment Elevation Myocardial Infarctions (STEMIs) presenting to an emergency department (ED) has been shown to affect treatment quality measures and patient outcomes. Almost half of ST-elevation-myocardial infarction (STEMI) patients in New Brunswick (NB) present directly to community hospitals. This study seeks to determine if the quality of care received by STEMI patients presenting to EDs in NB is related to the volume of STEMI presentations at that center. Methods This retrospective registry-based study used data from the STEMI database at the New Brunswick Heart Centre (NBHC), identifying 1196 cases of STEMI in NB, Canada, between December 2010 and April 2013. Patients were stratified into three groups based on the annual volume of STEMIs seen at the presenting center. Quality of care determinants, consisting of the percent of cases adhering to door-to-ECG (D2E), ECG-to-needle (E2N), and door-to-needle (D2N) time guidelines were then compared between groups. Results The mean age of the 1188 cases identified was 61.3 years, 73.8% were male, and 69.0% received thrombolysis. There was no difference in the rate of guideline adherence between the high, medium, and low-volume centers. The total rates of guideline adherence were 43.7%, 44.9%, and 47.5% for the D2E, E2N, and D2N times, respectively. Conclusion We did not identify any relationship between the rates of adherence with STEMI care guidelines and the volume of STEMI patients presenting to a center. Adherence rates were lower than in previously reported series from other regions. Further efforts should be undertaken to identify the causes of delayed STEMI diagnosis and treatment in our population and to implement system changes to improve standards of care. PMID- 29387509 TI - Anal Melanoma in an Elderly Woman Masquerading as Hemorrhoid. AB - Anal melanoma is a rare and aggressive neoplasm of the anal canal seen in the elderly population in the six or seventh decade of their lives. Presentation is usually nonspecific and diagnosis is often delayed or missed initially. The management is surgical and prognosis is poor. Here we present a case of anal melanoma in an elderly patient masquerading as hemorrhoid. PMID- 29387511 TI - Extraosseous Ewing's Sarcoma of the Pancreas: An Uncommon but Treatable Disease. AB - Extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is a rare but aggressive and malignant tumor, and has been reported in various sites such as the lungs, biliary tract, kidney, prostate, stomach, esophagus, oral cavity, salivary glands, urinary bladder, uterus, cervix, gonads, and vagina. However, the pancreas is considered to be an extremely uncommon site and only a handful of cases have been published to date. We present here another case of a pancreatic ES/PNET. Our case intensifies the importance to recognize this rare type of tumor in the pancreas as there is a broad spectrum of tumors with a similar morphology that includes sheets of small, round blue cells. As observed in our present case, this problem is markedly challenged when the tumor site of origin is uncertain. PMID- 29387510 TI - Accessory Ossicles of the Foot and Ankle: Disorders and a Review of the Literature. AB - Accessory ossicles of the foot and ankle are normal variants of bone development that usually remain asymptomatic. However, they may be involved in various disorders and become a source of pain such as in fractures, dislocations, degenerative changes, osteonecrosis, osteoarthritis, osteochondral lesions, avascular necrosis, and irritation or impingement of adjacent soft tissues. Hence, during the assessment of the situations above, knowledge about these little-known ossicles could be very important to reach the correct diagnosis. Recent studies in the literature have mostly focused on the most frequent 9-12 accessory bones. In this review, 24 types of accessory ossicle are described. These ossicles are accessory navicular bone, os peroneum, os trigonum, os intermetatarseum, os vesalianum. os subfibulare, os subtibiale, os calcaneus secundarius, os calcanei accessorium, os supratalare, os sustentaculi, os talotibiale, os tali accessorium, talus secundarius, os subcalcis, os cuboideum secundarium, os supranaviculare, os infranaviculare, os paracuneiforme, os intercuneiforme, os cuneometatarsale I tibiale, os cuneometatarsale plantare, os cuneo-I metatarsale-II dorsale, and os aponeurosis plantaris. The clinical importance of these bones should be known thoroughly to reduce unnecessary orthopedic consultations and misdiagnosis. This article describes the clinical importance of the accessory ossicles and their possible pathological conditions. Understanding the possible disorders of the accessory ossicles of the foot and ankle can provide a more accurate diagnostic process. PMID- 29387512 TI - Mycobacteremia from Crushed Hydromorphone Tablet Injection. AB - Mycobacterium abscessus is a fast growing, non-tubercular mycobacterium (NTM) found in water. NTM bacteremia is usually seen in immunocompromised patients who have intravascular catheters. Mycobacterium abscessus bacteremia is often caused by exposure to contaminated water supply in hemodialysis units. A 28-year-old female with poorly controlled diabetes mellitus, end stage renal disease (on hemodialysis via Ash catheter), and recurrent deep vein thrombosis presented to the hospital with proximal right leg deep vein thrombosis. On day nine of admission, the patient spiked a fever. Blood cultures revealed Mycobacterium abscessus bacteremia. The patient was observed to be crushing oral hydromorphone and injecting it into her ash catheter using needles retrieved from the sharps disposal container in her room. Although the Michigan Automated Prescription System (MAPS) report for narcotic abuse was unremarkable, a thorough review of her electronic medical chart revealed multiple hospitalizations with drug seeking behavior. This is the first reported case of crushed oral opioid injection resulting in mycobacteremia. Injecting crushed opioids has become more prevalent. Many opioid abusers resort to injecting them in order to achieve the psychotropic effects quicker. A heightened awareness about nontraditional modes of prescription drug abuse and surveillance by prescribers is necessary. This case raises an ethical question: should such patients be prescribed narcotics in the future, as the outcome of injecting oral medications can be fatal. PMID- 29387513 TI - Paired Ear Creases of the Helix (PECH): A Possible Physical Sign. AB - Diagonal ear lobe creases, often known as Frank's sign, are a folding in the skin of the ear lobe. Many studies have found an association between diagonal ear lobe creases and coronary artery disease. To our knowledge, this is the first report of paired ear creases of the helix. They may have similar relevance to cardiovascular disease as the diagonal ear lobe creases. We report the case of a 68-year-old South Asian man with coronary artery disease and a diagonal ear lobe crease. On closer inspection of the auricle, he also had ear creases on the helix on the same side. We postulate that diagonal ear lobe creases and paired ear creases of the helix are formed due to pressure during sleep on a hard surface. The pathophysiological association of these creases to coronary artery disease and metabolic syndrome are not well understood. We report a new possible sign: paired ear creases of the helix which may have similar clinical significance as the diagonal ear lobe crease with respect to cardiovascular disease. PMID- 29387514 TI - Case Report of Bone Marrow-Sparing Proton Therapy Craniospinal Irradiation for Central Nervous System Myelomatosis. AB - Central nervous system (CNS) involvement is rare but it is an increasingly recognized complication of the multiple myeloma. The craniospinal radiotherapy is a standard treatment option, however, it may be challenging to deliver due to hematologic toxicity in the patients with multiple prior systemic therapies. We report a case of CNS myelomatosis in a patient with prior stem cell transplant multiple systemic therapies treated with bone marrow-sparing proton therapy craniospinal irradiation, with the dramatic clinical response and minimal hematologic toxicity. PMID- 29387515 TI - Salvage Hypofractionated Radiotherapy in a Progressive Radiation-Induced Angiosarcoma: A Case Report. AB - We report a case of a long-term local control and survival achieved in a patient affected by radiation-induced angiosarcoma (RIA). A 57-year-old woman had a history of breast-conserving surgery and radiation therapy for primary breast cancer. Eight years after the mastectomy, multiple nodal progression was diagnosed as RIA and subsequentially treated by salvage lymph node dissection followed by adjuvant intensified radiotherapy to control the residual disease. Two and a half years later, the patient is alive and cancer-free. This experience shows that radiotherapy may have the potential to be a feasible and effective treatment to control RIA progression, and it may also play a role in the management of RIA as adjuvant. PMID- 29387516 TI - An immune-modulating formula comprising whey peptides and fermented milk improves inflammation-related remote organ injuries in diet-induced acute pancreatitis in mice. AB - It has been demonstrated that an immune-modulating enteral formula enriched with whey peptides and fermented milk (IMF) had anti-inflammatory effects in some experimental models when it was administered before the induction of inflammation. Here, we investigated the anti-inflammatory effects of the IMF administration after the onset of systemic inflammation and investigated whether the IMF could improve the remote organ injuries in an acute pancreatitis (AP) model. Mice were fasted for 12 hours and then fed a choline-deficient and ethionine-supplemented diet (CDE diet) for 24 hours to induce pancreatitis. In experiment 1, the diet was replaced with a control enteral formula, and mice were sacrificed at 24-hour intervals for 96 hours. In experiment 2, mice were randomized into control and IMF groups and received the control formula or the IMF respectively for 72 hr or 96 hr. In experiment 1, pancreatitis was induced by the CDE diet, and inflammatory mediators were elevated for several days. Remote organ injuries such as splenomegaly, hepatomegaly, and elevation of the hepatic enzymes developed. A significant strong positive correlation was observed between plasma MCP-1 and hepatic enzymes. In experiment 2, the IMF significantly improved splenomegaly, hepatomegaly, and the elevation of hepatic enzymes. Plasma MCP-1 levels were significantly lower in the IMF group than in the control group. Nutrition management with the IMF may be useful for alleviating remote organ injuries after AP. PMID- 29387518 TI - Effect of administrating polysaccharide from black currant (Ribes nigrum L.) on atopic dermatitis in NC/Nga mice. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease that causes dry skin and functional disruption of the skin barrier. AD is often accompanied by allergic inflammation. AD patient suffer from heavy itching, and their quality of life is severely affected. Some pharmaceuticals for AD have some side effects such as skin atrophy. So it is necessary to develop mild solutions such as food ingredients without side effects. There are various causes of AD. It is especially induced by immunological imbalances such as IFN-gamma reduction. IFN gamma has an important role in regulating IgE, which can cause an allergy reaction. NC/Nga mice develop AD and IgE hyperproduction. In a previous study, we revealed that administration of polysaccharide from black currant (R. nigrum) has an effect on immunomodulation. It induces IFN-gamma production from myeloid dendritic cells. We named this polysaccharide cassis polysaccharide (CAPS). In this report, we studied the effect of administering CAPS on atopic dermatitis in NC/Nga mice. Thirty NC/Nga mice that developed symptoms of atopic dermatitis were used. We divided them into three groups (control, CAPS administration 12 mg/kg/day, CAPS administration 60 mg/kg/day). For 4 weeks, we evaluated clinical score, serum IgE levels, gene expression of spleen, and skin pathology. We revealed that CAPS administration improves atopic dermatitis symptoms. We also found that CAPS administration suppresses IgE hyperproduction and induces IFN gamma gene transcription in the spleen. Finally, we confirmed that CAPS administration suppresses mast cell migration to epidermal skin. These results indicated that CAPS has an effect on AD. PMID- 29387517 TI - Effect of Lactobacillus casei strain Shirota-fermented milk on metabolic abnormalities in obese prediabetic Japanese men: a randomised, double-blind, placebo-controlled trial. AB - An obesity-related prediabetic state is characterised by metabolic abnormalities such as post-glucose load hyperglycaemia and dyslipidaemia and consequently increases the risk for type 2 diabetes and cardiovascular disease. This study aimed to investigate the effects of Lactobacillus casei strain Shirota (LcS) on metabolic abnormalities in obese prediabetic subjects in a randomised, double blind, placebo-controlled trial. Herein, 100 obese subjects (body mass index >=25), who had moderate post-load hyperglycaemia (1-hr post-load plasma glucose (PG) levels >=180 mg/dl during the oral glucose tolerance test), consumed LcS fermented milk or placebo milk daily for 8 weeks. The post-load PG and fasting blood markers were evaluated. Although post-load PG levels were not significantly different between the groups, 1-hr post-load PG, glycoalbumin, and HbA1c levels decreased at 8 weeks compared with the baseline levels only in the LcS group (p=0.036, p=0.002, and p=0.006, respectively). The reduction in glycoalbumin levels was statistically significantly greater in the LcS group than in the placebo group (p=0.030). Stratified analyses revealed significantly improved 1-hr post-load PG and glycoalbumin levels in the LcS group compared with the placebo group among subjects with severe glucose intolerance (2-hr post-load PG levels higher than the median at baseline; p=0.036 and p=0.034, respectively). In terms of lipidic outcomes, total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels were significantly lower in the LcS group than in the placebo group (p=0.023, p=0.022, and p=0.008, respectively). These findings suggest that LcS may favourably affect metabolic abnormalities in obese prediabetic subjects, though the effects on glycaemic control may be limited. PMID- 29387519 TI - Impacts of glyphosate-based herbicides on disease resistance and health of crops: a review. AB - Based on experimental data from laboratory and field, numerous authors have raised concern that exposure to glyphosate-based herbicides (GBHs) may pre dispose crops to damage by microbial pathogens. In this review, we distinguish and evaluate two principal pathways by which GBHs may affect the susceptibility of crops to disease: pathway 1-via disruptions to rhizosphere microbial ecology, and pathway 2-via restriction of nutrients to crops. We conclude that GBHs have the potential to undermine crop health in a number of ways, including: (i) impairment of the innate physiological defences of glyphosate-sensitive (GS) cultivars by interruption of the shikimic acid pathway; (ii) impairment of physiological disease defences has also been shown to occur in some glyphosate resistant (GR) cultivars, despite their engineered resistance to glyphosate's primary mode of action; (iii) interference with rhizosphere microbial ecology (in particular, GBHs have the potential to enhance the population and/or virulence of some phytopathogenic microbial species in the crop rhizosphere); and finally, (iv) the as yet incompletely elucidated reduction in the uptake and utilisation of nutrient metals by crops. Future progress will best be achieved when growers, regulators and industry collaborate to develop products, practices and policies that minimise the use of herbicides as far as possible and maximise their effectiveness when used, while facilitating optimised food production and security. PMID- 29387520 TI - Longitudinal Mediation Analysis with Time-varying Mediators and Exposures, with Application to Survival Outcomes. AB - In this paper, we study the effect of a time-varying exposure mediated by a time varying intermediate variable. We consider general longitudinal settings, including survival outcomes. At a given time point, the exposure and mediator of interest are influenced by past covariates, mediators and exposures, and affect future covariates, mediators and exposures. Right censoring, if present, occurs in response to past history. To address the challenges in mediation analysis that are unique to these settings, we propose a formulation in terms of random interventions based on conditional distributions for the mediator. This formulation, in particular, allows for well-defined natural direct and indirect effects in the survival setting, and natural decomposition of the standard total effect. Upon establishing identifiability and the corresponding statistical estimands, we derive the efficient influence curves and establish their robustness properties. Applying Targeted Maximum Likelihood Estimation, we use these efficient influence curves to construct multiply robust and efficient estimators. We also present an inverse probability weighted estimator and a nested non-targeted substitution estimator for these parameters. PMID- 29387522 TI - Polymorphism in the 1:1 Charge-Transfer Complex DBTTF-TCNQ and Its Effects on Optical and Electronic Properties. AB - The organic charge-transfer (CT) complex dibenzotetrathiafulvalene - 7,7,8,8 tetracyanoquinodimethane (DBTTF-TCNQ) is found to crystallize in two polymorphs when grown by physical vapor transport: the known alpha-polymorph and a new structure, the beta-polymorph. Structural and elemental analysis via selected area electron diffraction (SAED), X-ray photoelectron spectroscopy (XPS), and polarized IR spectroscopy reveal that the complexes have the same stoichiometry with a 1:1 donor:acceptor ratio, but exhibit unique unit cells. The structural variations result in significant differences in the optoelectronic properties of the crystals, as observed in our experiments and electronic-structure calculations. Raman spectroscopy shows that the alpha-polymorph has a degree of charge transfer of about 0.5e, while the beta-polymorph is nearly neutral. Organic field-effect transistors fabricated on these crystals reveal that in the same device structure both polymorphs show ambipolar charge transport, but the alpha-polymorph exhibits electron-dominant transport while the beta-polymorph is hole-dominant. Together, these measurements imply that the transport features result from differing donor-acceptor overlap and consequential varying in frontier molecular orbital mixing, as suggested theoretically for charge-transfer complexes. PMID- 29387521 TI - Male Obesity: Epigenetic Origin and Effects in Sperm and Offspring. AB - Purpose of Review: The prevalence of obesity has increased substantially in the current generations of Western countries, and the burden of obesity-related complications has been growing steadily. In men, obesity is not only a major risk factor for serious chronic diseases, concern is growing that the reproductive capacity, and more particularly, their offspring's health may be affected. Obesity-related impaired spermatogenesis is associated with a decrease in microscopic and molecular sperm characteristics and pregnancy success. We hypothesize that epigenetics is an important mediator explaining interactions between an obesogenic environment and sperm/offspring outcomes. Recent Findings: Recent studies have explored inter- and transgenerational epigenetic effects in sperm cells and in offspring. Father-to-child effects have been reported in relation to preconceptional nutritional and life-style related factors. Summary: Here, we summarize the current understanding about obesity and molecular or epigenetic underlying mechanisms in sperm. We identify the obesogenic environment of the father before conception as a potential origin of health or disease in the offspring and include it as part of a new concept, the Paternal Origins of Health and Disease (POHaD). PMID- 29387523 TI - Undiagnosed chicken meat aspiration as a cause of difficult-to-ventilate in a boy with traumatic brain injury. AB - Introduction: Bronchoscopy is a commonly used procedure in the context of aspiration in the Intensive Care Unit setting. Despite its ability to remove mucus plug and undigested gastric contents, aspiration of gastric content into the trachea is one of the most feared complications among anesthesiologist. Discussion: The scenario is made worst if the aspiration causes acute hypoxemic respiratory failure immediately post intubation. However, in the event of desaturation, the quick decision to proceed with bronchoscopy is a challenging task to the anesthesiologist without knowing the causes. Case presentation: We present a case of a 12-year-old boy who had a difficult-to-ventilate scenario post transferring and immediately connected to ventilator in operation theatre (OT) from portable ventilator from the emergency department. She was successfully managed by bronchoscopy. Conclusion: Special attention should be given to the difficult-to-ventilate scenario post intubation of traumatic brain injury patient prior to operation. Prompt diagnosis and bronchoscope-assisted removal of foreign body was found to be a successful to reduce morbidity and mortality. PMID- 29387524 TI - Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study. AB - Objective: Using diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings. Method: Pre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 +/- 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender. Results: Within the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 +/- 0.19 MUm2/ms and 1.34 +/- 0.20 MUm2/ms at baseline and follow-up respectively, P < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy (r = 0.47, P = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 +/- 0.04 MUm2/ms and 0.058 +/- 0.03 MUm2/ms in female and male respectively, P = 0.01). Sub analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period. Conclusion: The significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males. PMID- 29387525 TI - Priming production: Neural evidence for enhanced automatic semantic activity preceding language production in schizophrenia. AB - Introduction: Lexico-semantic disturbances are considered central to schizophrenia. Clinically, their clearest manifestation is in language production. However, most studies probing their underlying mechanisms have used comprehension or categorization tasks. Here, we probed automatic semantic activity prior to language production in schizophrenia using event-related potentials (ERPs). Methods: 19 people with schizophrenia and 16 demographically matched healthy controls named target pictures that were very quickly preceded by masked prime words. To probe automatic semantic activity prior to production, we measured the N400 ERP component evoked by these targets. To determine the origin of any automatic semantic abnormalities, we manipulated the type of relationship between prime and target such that they overlapped in (a) their semantic features (semantically related, e.g. "cake" preceding a < picture of a pie >, (b) their initial phonemes (phonemically related, e.g. "stomach" preceding a < picture of a starfish >), or (c) both their semantic features and their orthographic/phonological word form (identity related, e.g. "socks" preceding a < picture of socks >). For each of these three types of relationship, the same targets were paired with unrelated prime words (counterbalanced across lists). We contrasted ERPs and naming times to each type of related target with its corresponding unrelated target. Results: People with schizophrenia showed abnormal N400 modulation prior to naming identity related (versus unrelated) targets: whereas healthy control participants produced a smaller amplitude N400 to identity related than unrelated targets, patients showed the opposite pattern, producing a larger N400 to identity related than unrelated targets. This abnormality was specific to the identity related targets. Just like healthy control participants, people with schizophrenia produced a smaller N400 to semantically related than to unrelated targets, and showed no difference in the N400 evoked by phonemically related and unrelated targets. There were no differences between the two groups in the pattern of naming times across conditions. Conclusion: People with schizophrenia can show abnormal neural activity associated with automatic semantic processing prior to language production. The specificity of this abnormality to the identity related targets suggests that that, rather than arising from abnormalities of either semantic features or lexical form alone, it may stem from disruptions of mappings (connections) between the meaning of words and their form. PMID- 29387526 TI - Performance monitoring in lung cancer patients pre- and post-chemotherapy using fine-grained electrophysiological measures. AB - No previous event-related potentials (ERPs) study has explored the error-related negativity (ERN) - an ERP component indexing performance monitoring - associated to cancer and chemotherapy-induced cognitive impairment in a lung cancer population. The aim of this study was to examine differences in performance monitoring in a small-cell lung cancer group (SCLC, C +) 1-month following chemotherapy and two control groups: a non-small cell lung cancer patient group (NSCLC, C -) prior to chemotherapy and a healthy control group (HC). Seventeen SCLC (C +) underwent a neuropsychological assessment and an ERP study using a flanker and a stop-signal paradigm. This group was compared to fifteen age-, gender- and education-matched NSCLC (C -) and eighteen HC. Between 20 and 30% of patients in both lung cancer groups (C + and C -) met criteria for cognitive impairment. Concerning ERPs, lung cancer patients showed lower overall hit rate and a severe ERN amplitude reduction compared to HC. Lung cancer patients exhibited an abnormal pattern of performance monitoring thus suggesting that chemotherapy and especially cancer itself, may contribute to cognitive deterioration. ERN appeared as an objective laboratory tool sensitive to cognitive dysfunction in cancer population. PMID- 29387527 TI - High brain serotonin levels in migraine between attacks: A 5-HT4 receptor binding PET study. AB - Migraine has been hypothesized to be a syndrome of chronic low serotonin (5-HT) levels, but investigations of brain 5-HT levels have given equivocal results. Here, we used positron emission tomography (PET) imaging of the 5-HT4 receptor as a proxy for brain 5-HT levels. Given that the 5-HT4 receptor is inversely related to brain 5-HT levels, we hypothesized that between attacks migraine patients would have higher 5-HT4 receptor binding compared to controls. Eighteen migraine patients without aura (migraine free >48 h), and 16 age- and sex-matched controls underwent PET scans after injection of [11C]SB207145, a specific 5-HT4 receptor radioligand. An investigator blinded to group calculated a neocortical mean [11C]SB207145 binding potential (BPND). Three migraine patients reported a migraine attack within 48 h after the scan and were excluded from the primary analysis. Comparing 15 migraine patients and 16 controls, we found that migraine patients have significantly lower neocortical 5-HT4 receptor binding than controls (0.60 +/- 0.09 vs. 0.67 +/- 0.05, p = .024), corrected for 5-HTTLPR genotype, sex and age. We found no association between 5-HT4 receptor binding and attack frequency, years with migraine or time since last migraine attack. Our finding of lower 5-HT4 receptor binding in migraine patients is suggestive of higher brain 5-HT levels. This is in contrast with the current belief that migraine is associated with low brain 5-HT levels. High brain 5-HT levels may represent a trait of the migraine brain or it could be a consequence of migraine attacks. PMID- 29387528 TI - Cortical folding alterations in fetuses with isolated non-severe ventriculomegaly. AB - Neuroimaging of brain diseases plays a crucial role in understanding brain abnormalities and early diagnosis. Of great importance is the study of brain abnormalities in utero and the assessment of deviations in case of maldevelopment. In this work, brain magnetic resonance images from 23 isolated non-severe ventriculomegaly (INSVM) fetuses and 25 healthy controls between 26 and 29 gestational weeks were used to identify INSVM-related cortical folding deviations from normative development. Since these alterations may reflect abnormal neurodevelopment, our working hypothesis is that markers of cortical folding can provide cues to improve the prediction of later neurodevelopmental problems in INSVM subjects. We analyzed the relationship of ventricular enlargement with cortical folding alterations in a regional basis using several curvature-based measures describing the folding of each cortical region. Statistical analysis (global and hemispheric) and sparse linear regression approaches were then used to find the cortical regions whose folding is associated with ventricular dilation. Results from both approaches were in great accordance, showing a significant cortical folding decrease in the insula, posterior part of the temporal lobe and occipital lobe. Moreover, compared to the global analysis, stronger ipsilateral associations of ventricular enlargement with reduced cortical folding were encountered by the hemispheric analysis. Our findings confirm and extend previous studies by identifying various cortical regions and emphasizing ipsilateral effects of ventricular enlargement in altered folding. This suggests that INSVM is an indicator of altered cortical development, and moreover, cortical regions with reduced folding constitute potential prognostic biomarkers to be used in follow-up studies to decipher the outcome of INSVM fetuses. PMID- 29387529 TI - The hippocampal network model: A transdiagnostic metaconnectomic approach. AB - Purpose: The hippocampus plays a central role in cognitive and affective processes and is commonly implicated in neurodegenerative diseases. Our study aimed to identify and describe a hippocampal network model (HNM) using trans diagnostic MRI data from the BrainMap(r) database. We used meta-analysis to test the network degeneration hypothesis (NDH) (Seeley et al., 2009) by identifying structural and functional covariance in this hippocampal network. Methods: To generate our network model, we used BrainMap's VBM database to perform a region to-whole-brain (RtWB) meta-analysis of 269 VBM experiments from 165 published studies across a range of 38 psychiatric and neurological diseases reporting hippocampal gray matter density alterations. This step identified 11 significant gray matter foci, or nodes. We subsequently used meta-analytic connectivity modeling (MACM) to define edges of structural covariance between nodes from VBM data as well as functional covariance using the functional task-activation database, also from BrainMap. Finally, we applied a correlation analysis using Pearson's r to assess the similarities and differences between the structural and functional covariance models. Key findings: Our hippocampal RtWB meta-analysis reported consistent and significant structural covariance in 11 key regions. The subsequent structural and functional MACMs showed a strong correlation between HNM nodes with a significant structural-functional covariance correlation of r = .377 (p = .000049). Significance: This novel method of studying network covariance using VBM and functional meta-analytic techniques allows for the identification of generalizable patterns of functional and structural abnormalities pertaining to the hippocampus. In accordance with the NDH, this framework could have major implications in studying and predicting spatial disease patterns using network-based assays. PMID- 29387531 TI - Diagnostic accuracy of semiautomatic lesion detection plus quantitative susceptibility mapping in the identification of new and enhancing multiple sclerosis lesions. AB - Purpose: To evaluate the diagnostic accuracy of a novel non-contrast brain MRI method based on semiautomatic lesion detection using T2w FLAIR subtraction image, the statistical detection of change (SDC) algorithm (T2w + SDC), and quantitative susceptibility mapping (QSM). This method identifies new lesions and discriminates between enhancing and nonenhancing lesions in multiple sclerosis (MS). Methods: Thirty three MS patients who had MRIs at two different time points with at least one new Gd-enhancing lesion on the 2nd MRI were included in the study. For a reference standard, new lesions were identified by two neuroradiologists on T2w and post-Gd T1w images with the help of T2w + SDC. The diagnostic accuracy of the proposed method based on QSM and T2w + SDC lesion detection (T2w + SDC + QSM) for assessing lesion enhancement status was determined. Receiver operating characteristic (ROC) analysis was performed to compute the optimal lesion susceptibility cutoff value. Results: A total of 165 new lesions (54 enhancing, 111 nonenhancing) were identified. The sensitivity and specificity of T2w + SDC + QSM in predicting lesion enhancement status were 90.7% and 85.6%, respectively. For lesions >=50 mm3, ROC analysis showed an optimal QSM cutoff value of 13.5 ppb with a sensitivity of 88.4% and specificity of 88.6% (0.93, 95% CI, 0.87-0.99). For lesions >=15 mm3, the optimal QSM cutoff was 15.4 ppb with a sensitivity of 77.9% and specificity of 94.0% (0.93, 95% CI, 0.89 0.97). Conclusion: The proposed T2w + SDC + QSM method is highly accurate for identifying and predicting the enhancement status of new MS lesions without the use of Gd injection. PMID- 29387530 TI - Connectivity derived thalamic segmentation in deep brain stimulation for tremor. AB - The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing. PMID- 29387532 TI - FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort. AB - Background/aims: In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias. Methods: We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as "typical-AD", "atypical-AD" (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), "non-AD" (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or "negative" patterns. To perform the statistical analyses, the individual patterns were grouped either as "AD dementia vs. non-AD dementia (all diseases)" or as "FTD vs. non-FTD (all diseases)". Abeta42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated. Results: The multivariate logistic model identified FDG-PET "AD" SPM classification (Expbeta = 19.35, 95% C.I. 4.8-77.8, p < 0.001) and CSF Abeta42 (Expbeta = 6.5, 95% C.I. 1.64-25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The "FTD" SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expbeta = 14, 95% C.I. 3.1-63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expbeta = 17.9, 95% C.I. 4.55-70.46, p < 0.001). Conclusions: Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers. PMID- 29387534 TI - White matter changes in treatment refractory schizophrenia: Does cognitive control and myelination matter? AB - Widespread white matter abnormalities have been reported in schizophrenia, a disorder frequently characterised as a dysconnection syndrome. White matter connectivity in schizophrenia has been predominantly investigated using diffusion weighted imaging, with reductions in fractional anisotropy throughout the brain often interpreted as an indicator of abnormal myelination. However, diffusion weighted imaging lacks specificity and as such a number of microstructural factors besides myelin may be contributing to these results. We utilised multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in medicated patients with chronic schizophrenia, stratified by treatment response status, and healthy controls, in order to assess myelin water fraction (MWF) in these groups. In addition, we assessed cognitive control using the Stroop task to investigate how response inhibition relates to myelination in patients and controls. Both treatment resistant (n = 22) and treatment responsive (n = 21) patients showed reduced MWF compared to healthy controls (n = 24) in bilateral fronto-occipital fasciculi, particularly evident in the vicinity of the striatum und extending to the cerebellum, with no difference between patient groups. Patients showed greater reaction time interference on the Stroop task compared to healthy controls, with no difference between patient groups. Stroop interference was significantly negatively correlated with MWF in the corpus callosum across groups, and MWF differences in this region mediated the behavioural group effects on the Stroop task. These findings support the suitability of mcDESPOT as a myelin-specific measure of abnormal connectivity in schizophrenia, and suggest that treatment resistant schizophrenia is not characterised by more severe abnormalities in myelination or cognitive control compared to treatment responsive schizophrenia. PMID- 29387533 TI - Disrupted brain network topology in chronic insomnia disorder: A resting-state fMRI study. AB - This study investigated the topological characteristics of brain functional networks in chronic insomnia disorder (CID) patients. The resting-state functional magnetic resonance imaging and graph theory analysis method were applied to investigate the brain functional connectome patterns among 45 CID patients and 32 healthy controls. The brain functional connectome was constructed by thresholding partial correlation matrices of 90 brain regions from an automated anatomical labeling atlas. The topologic properties of brain functional connectomes at both global and nodal levels were tested. The CID patients had decreased number of module (p = .014) and hierarchy (p = .038), and increased assortativity (p = .035). Furthermore, some brain regions located in the default mode network, dorsal attention network, and sensory-motor network in these patients showed altered nodal centralities. Within these areas, the node betweenness of right central paracentral lobule had positive correlation with the Pittsburgh Sleep Quality Index score (R = 0.319, p = .039). The results imply that functional disruptions of CID patients may be related to disruptions in global and regional topological organization of the brain functional connectome, and provide new and important insights to understand the pathophysiological mechanisms of CID. PMID- 29387536 TI - An interaction between warfarin and cannabidiol, a case report. AB - *An interaction between warfarin and cannabidiol is described*The mechanisms of cannabidiol and warfarin metabolism are reviewed*Mechanism of the interaction is proposed*INR should be monitored in patients when cannabinoids are introduced. PMID- 29387535 TI - Prevalence and molecular characterisation of Acanthocephala in pinnipedia of the North and Baltic Seas. AB - Harbour seals (Phoca vitulina) and grey seals (Halichoerus grypus) are final hosts of acanthocephalans in the German North and Baltic Seas. Parasitic infections in seals can cause pathological changes, which may result in deteriorated health of the host. Common gastrointestinal parasites of harbour and grey seals are acanthocephalans and a number of 275 of 2460 (11.2%) investigated seals from 1996 to 2013 were infected with Corynosoma spp. (Acanthocephala, Polymorphidae). The prevalence showed a wave-like pattern: it increased from 1.2% and 0.4% in 1996 and 1997, respectively, to 23.9% during the second phocine distemper epizootic in 2002 and decreased to 6.2% in 2004. In 2005, prevalence peaked again with 25.0% followed by a decrease to 9.3% in 2009 and an increase to 38.5% in 2012. Statistical analysis revealed that harbour seals originating from the North Sea showed a higher prevalence than grey seals, whereas no significant difference between grey and harbour seals from the Baltic Sea was observed. Furthermore, juvenile pinnipedia from the North Sea were significantly less infected with Corynosoma spp. than seals older than seven month. Molecular species identification as well as phylogenetic relationship analysis among the detected Corynosoma species were achieved by sequencing and comparisons of the ribosomal ITS1-5.8S-ITS2-complex and cytochrome-c-oxidase I gene. Molecular analysis resulted in a newly arranged distribution of Acanthocephala in the North Sea as in contrast to previous studies, C. strumosum could not be confirmed as predominant species. Instead, C. magdaleni and a C. magdaleni isolate (isolate Pv1NS) with an atypical number of longitudinal rows of hooks at the proboscis were detected. Furthermore, morphological and molecular analyses indicate the possible finding of a cryptic species (Candidatus Corynosoma nortmeri sp. nov.). PMID- 29387538 TI - Overcoming left bundle branch block by permanent His bundle pacing: Evidence of longitudinal dissociation in the His via recordings from a permanent pacing lead. PMID- 29387537 TI - Continuous wave laser diodes enable fast optoacoustic imaging. AB - Pulsed laser diodes may offer a smaller, less expensive alternative to conventional optoacoustic laser sources; however they do not provide pulse rates faster than a few tens of kHz and emit at wavelengths only within the near infrared region. We investigated whether continuous wave (CW) laser diodes, which are available in visible and near-infrared regions, can be good optoacoustic light sources when overdriven with a peak current >40-fold higher than the CW absolute maximum. We found that overdriven CW diodes provided ~10 ns pulses of ~200 nJ/pulse and repetition rates higher than 600 kHz without being damaged, outperforming many pulsed laser diodes. Using this system, we obtained images of phantoms and mouse ear and human arm in vivo, confirming their use in optoacoustic imaging and sensing. PMID- 29387539 TI - Prenatal diagnosis and management of junctional ectopic tachycardia. PMID- 29387540 TI - Spastic occlusion of coronary artery during cryoballoon pulmonary vein isolation. PMID- 29387541 TI - Atrial standstill in a pediatric patient with associated caveolin-3 mutation. PMID- 29387542 TI - Dislodgement of circular mapping catheter electrode in the left atrium: A near miss. PMID- 29387543 TI - Resolution of the functional retrograde right bundle branch block during antidromic atrioventricular reciprocating tachycardia. PMID- 29387544 TI - Bidirectional ventricular tachycardia in ischemic cardiomyopathy during ablation. PMID- 29387545 TI - Obstacles preventing biventricular pacing mitigated with lead extraction and His bundle pacing to achieve effective cardiac resynchronization. PMID- 29387546 TI - Novel technique to avoid diaphragmatic paralysis during focal ablation of a non pulmonary vein trigger mapped to the crista terminalis. PMID- 29387547 TI - Migration of an implantable loop recorder into the pleural space. PMID- 29387548 TI - Percutaneous electrosurgical technique for treatment of subclavian vein occlusion: Application of transcaval techniques. PMID- 29387549 TI - Intermittent loss of capture in a His bundle pacemaker: What is the cause? PMID- 29387550 TI - Case report: Guillain-Barre syndrome with pneumococcus - A new association in pediatrics. AB - Guillain-Barre Syndrome, an acute flaccid paralysis known to be caused by recent Gastro-intestinal infections mainly campylobacter, and Respiratory infections mainly mycoplasma pneumoniae and influenza. One reported case of severe invasive pneumococcal disease in a 68 year old female, that presented with Austrian's triad of meningitis, pneumonia and endocarditis, and progressed to develop Guillain Barre syndrome, an association never been documented before. We present a case of 13 year old male, presented with hypoactivity and inability to bare his own weight, developed septic shock due to pneumococcus with Acute Respiratory Distress Syndrome, and was found to have neurological findings of Guillain-Barre Syndrome. A new association in pediatric age group, never been reported before. PMID- 29387551 TI - Combined immunotherapy for advanced prostate cancer: Empowering the T cell army. PMID- 29387552 TI - Effect of Blumea balsamifera extract on the phase and morphology of calcium oxalate crystals. AB - Objective: Calcium oxalate crystals are found in majority of kidney stones with calcium oxalate monohydrate (COM) as one of the primary types of kidney stones. Various methods of treatment exist, including herbal treatment in the Philippines that uses the medicinal herb Blumea balsamifera (B. balsamifera). Methods: The effect of B. balsamifera extract on the morphology of calcium oxalate crystals was studied by light microscopy, image analysis, powder X-ray diffraction and scanning electron microscopy. Results: The extract decreased the crystal size by 5.22%-82.62% depending on the degree of supersaturation. Through analysis of the projected area of the crystals, the extract was found to shift the phase of the crystals from COM to calcium oxalate dihydrate (COD). This shift in phase is significant with a COM to COD shift of 88.26% at 0.5 mg/mL of extract and 91.53% at 1.0 mg/mL of extract. Scanning election microscopic (SEM) images revealed aggregation of crystals at 0 mg/mL of extract. At 1.0 mg/mL of extract, the scanning electron micrographs showed discernible crystal unit boundaries. Conclusion: B. balsamifera extract was observed to have decreased crystal size, shifted crystal phase from COM to COD and prevented the aggregation of calcium oxalate crystals. PMID- 29387553 TI - Intermittent androgen deprivation therapy in patients with prostate cancer: Connecting the dots. AB - Intermittent androgen deprivation therapy (IADT) is now being increasingly opted by the treating physicians and patients with prostate cancer. The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects, and reduced treatment costs. IADT may also delay the progression to castration resistant prostate cancer. However, the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials. Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer, e.g., population characteristics (both demographic and clinical), study design, treatment regimen, on- and off-treatment criteria, duration of active treatment, endpoints, and analysis. The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs. continuous androgen deprivation therapy for the treatment of prostate cancer. The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes, especially the disease (tumor) burden. Based on evidence, potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer. PMID- 29387554 TI - Testosterone replacement maintains smooth muscle content in the corpus cavernosum of orchiectomized rats. AB - Objective: To evaluate the effects of testosterone (T) on the maintenance of corpus cavernosum (CC) structure and apoptosis. Methods: Animals were divided into three groups: sham operation group (n = 8) underwent sham operation; Orchiectomized (Orchiec)+ oily vehicle group (n = 8) underwent bilateral orchiectomy and received a single dose of oily vehicle by intramuscular injection (i.m.) 30 days after orchiectomy; and Orchiec + T group (n = 8) underwent bilateral orchiectomy and received a single dose of T undecanoate 100 mg/kg i.m. 30 days after the surgery. Animals were euthanized 60 days after the beginning of the experiment with an anesthetic overdose of ketamine and xylazine. Blood samples and penile tissue were collected on euthanasia. Azan's trichrome staining was used to evaluate smooth muscle, Weigert's Fucsin-Resorcin staining was used to evaluate elastic fibers and Picrosirius red staining was used to evaluate collagen. Apoptosis was evaluated using TUNEL technique. Results: T levels decreased in Orchiec + oily vehicle when compared to sham operation and Orchiec + T groups (p < 0.001). T deprivation reduced trabecular smooth muscle content and penile diameter and T replacement maintained both parameters (p = 0.005 and p = 0.001, respectively). No difference was observed in the content of sinusoidal space (p = 0.207), elastic fibers (p = 0.849), collagen (p = 0.216) and in apoptosis (p = 0.095). Conclusion: Normal testosterone levels maintain CC smooth muscle content and do not influence elastic fibers, collagen content and apoptotic index. Further studies should be performed in order to investigate the mechanisms by which androgen mediates its effects on CC structure. PMID- 29387555 TI - A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma. AB - Objective: Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. Methods: Combination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan-Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). Results: Among 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001). Conclusion: RISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools. PMID- 29387556 TI - Pretreatment neutrophil-to-lymphocyte ratio predicts worse survival outcomes and advanced tumor staging in patients undergoing radical cystectomy for bladder cancer. AB - Objective: To determine the role of neutrophil-to-lymphocyte ratio (NLR) in prognosticating survival outcomes in patients with advanced/metastatic urothelial bladder cancer. Methods: We retrospectively reviewed 84 patients undergoing radical cystectomy (RC) for UCB from January 2002 to June 2012. NLR was computed (median: 5 days) prior to surgery. No patients received neoadjuvant chemotherapy. NLR was analyzed as a continuous variable and a cut-off point of 2.7 was obtained, with a statistical receiver operating characteristics of 0.74. Kaplan Meier curves, multivariate Cox proportional hazard and logistics regression models were used to predict NLR association with survival outcomes. Results: The median follow-up period was 30.1 months (range: 3.2-161.7) owing to high recurrence rate and subsequent mortalities, compared to the median 64.7 months in patients alive at the end of study period. NLR >=2.7 was associated with worse survival outcomes (5-year disease-specific survival: 22% vs 58%, p = 0.017, 95%CI: 1.193-6.009; 5-year overall survival: 23% vs 60%, p = 0.008, 95%CI: 1.322 6.147). Furthermore, on multivariate analyses, higher NLR was independently associated with higher recurrence rate (p = 0.007, HR =6.999, 95%CI: 1.712 28.606), higher T staging (p = 0.021, HR = 3.479, 95%CI: 1.212-9.990) and lymph node involvement (p = 0.009, HR = 4.534, 95%CI: 1.465-14.034). Conclusion: This study suggests that NLR can be an inexpensive novel factor for patients risk stratification pre-operatively. This improves patient counseling and identifies patients who may benefit from multimodal treatment. PMID- 29387557 TI - Patients with small prostates and low-grade intravesical prostatic protrusion - A urodynamic evaluation. AB - Objective: Despite high-grade intravesical prostatic protrusion (IPP) being closely related to bladder outlet obstruction (BOO), up to 21% of patients with low IPP remain obstructed. This study evaluates the characteristics and urodynamic findings of men with small prostates and low IPP. Methods: One hundred and fourteen men aged >50 years old with lower urinary tract symptoms (LUTS) were assessed with symptoms, uroflowmetry, serum prostate-specific antigen (PSA), transabdominal ultrasound measurement of prostate volume (PV), IPP and post-void residual urine (PVRU). All patients underwent pressure flow studies. Patients with PV < 30 mL and IPP <= 10 mm were examined for parameters correlating with BOO or impaired detrusor contractility. Results: Thirty-six patients had PV < 30 mL and IPP <10 mm. Nine patients (25.0%) had urodynamic BOO, all with normal bladder contractility. Fourteen patients (38.9%) had poor detrusor contractility and all had no BOO. PV, PVRU and IPP were significantly associated with BOO, with IPP showing greatest positive correlation. Both Qmax and IPP were significantly associated with detrusor contractility. At 5-year follow-up, most patients responded to medical therapy. Only three out of nine patients (33.3%) with BOO eventually underwent surgery, and all had a high bladder neck seen on the resectoscope. Only one patient (7.1%) with poor detrusor contractility eventually required surgery after repeat pressure flow study revealed BOO. Conclusion: In men with small prostates and low IPP, the presence of BOO is associated with higher PV, PVRU and IPP, and most respond well to medical management. BOO can possibly be explained by elevation of the bladder neck by a small subcervical adenoma. PMID- 29387558 TI - Anterior perineal hernia after anterior exenteration. AB - Perineal hernia is a rare complication of anterior exenteration. We reported this complication after an anterior exenteration for bladder cancer with bleeding complication requiring packing and second-look laparotomy. Perineal approach is a simple and effective method for repair of perineal hernia. PMID- 29387559 TI - Inadvertent placement of a urinary catheter into the ureter: A report of 3 cases and review of the literature. AB - We describe three cases of inadvertent placement of the urinary catheter into the ureter. An 85-year-old gentleman on long-term indwelling catheter (IDC) for neurogenic bladder presented with fever and right flank pain. CT of abdomen and pelvis demonstrated the tip of the IDC to be located within the right vesicoureteric junction with acute right hydronephrosis and acute pyelonephritis. A 74-year-old woman, on long-term IDC for neurogenic bladder was found to have hydronephrosis on ultrasound imaging. Contrast-enhanced CT intravenous pyelography done subsequently showed the IDC was in the right distal ureter. A 47 year-old lady, on IDC for urinary retention and voiding dysfunction likely secondary to schizophrenia and anti-psychotic medications, presented with raised creatinine. A non-enhanced CT of her abdomen and pelvis was done and showed that the tip of the urethral IDC was located up to the left vesicoureteric junction. In all patients, the hydronephrosis resolved after changing the catheter and they were well on discharge. We also review the literature to identify the incidence, outcomes and possible risk factors. To our knowledge, only 20 cases have been reported thus far in the English literature. Although serious complications can occur, the incidence is very low. One risk factor that has been identified is long-term catheterization in patients with neurogenic bladder. We do not recommend routine imaging after catheterization in this group of patients. However, we should still be mindful of the possibility of this occurrence and evaluate and treat as necessary when clinical suspicion arises. PMID- 29387560 TI - Successful removal of a penoscrotal constricting ring in a 49-year-old male. AB - Placement of constricting devices around the penis and scrotum for autoerotic purposes or increasing sexual performance represents a well-known challenge for urologists and can result in serious complications. The removal of the constricting devices can be challenging and often requires resourcefulness and multidisciplinary approach. We report one case of successful removal of a penoscrotal constricting metal ring in a 49-year-old male using a hand-held orthopaedic saw under ketamine and midazolam sedation in the emergency department. PMID- 29387561 TI - High incidence of low vitamin B12 levels in Estonian newborns. AB - Vitamin B12 deficiency seems to be more common worldwide than previously thought. However, only a few reports based on data from newborn screening (NBS) programs have drawn attention to that subject. In Estonia, over the past three years, we have diagnosed 14 newborns with congenital acquired vitamin B12 deficiency. Therefore, the incidence of that condition is 33.8/100,000 live births, which is considerably more than previously believed. None of the newborns had any clinical symptoms associated with vitamin B12 deficiency before the treatment, and all biochemical markers normalized after treatment, which strongly supports the presence of treatable congenital deficiency of vitamin B12. During the screening period, we began using actively ratios of some metabolites like propionylcarnitine (C3) to acetylcarnitine (C2) and C3 to palmitoylcarnitine (C16) to improve the identification of newborns with acquired vitamin B12 deficiency. In the light of the results obtained, we will continue to screen the congenital acquired vitamin B12 deficiency among our NBS program. Every child with aberrant C3, C3/C2 and C3/C16 will be thoroughly examined to exclude acquired vitamin B12 deficiency, which can easily be corrected in most cases. PMID- 29387562 TI - The impact of consanguinity on the frequency of inborn errors of metabolism. AB - Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders present in all ethnic groups. We investigated the frequency of consanguinity among parents of newborns with IEM diagnosed by neonatal screening. Data were obtained from 15 years of expanded newborn screening for selected IEM with autosomal recessive mode of inheritance, a national screening program of newborns covering the period from 2002 until April 2017. Among the 838,675 newborns from Denmark, the Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included in this study. These results were crosschecked against medical records. Information on consanguinity was extracted from medical records and telephone contact with the families. Among ethnic Danes, two cases of consanguinity were identified in 93 families (2.15%). Among ethnic minorities there were 20 cases of consanguinity among 33 families (60.6%). Consequently, consanguinity was 28.2 times more frequent among descendants of other geographic place of origin than Denmark. The frequency of consanguinity was conspicuously high among children of Pakistani, Afghan, Turkish and Arab origin (71.4%). The overall frequency of IEM was 25.5 times higher among children of Pakistani, Turkish, Afghan and Arab origin compared to ethnic Danish children (5.35:10,000 v 0.21:10,000). The frequency of IEM was 30-fold and 50-fold higher among Pakistanis (6.5:10,000) and Afghans (10.6:10,000), respectively, compared to ethnic Danish children. The data indicate a strong association between consanguinity and IEM. These figures could be useful to health professionals providing antenatal, pediatric, and clinical genetic services. PMID- 29387563 TI - Ascaris in the urinary tract: A case report and review of the literature. PMID- 29387564 TI - International remittances, cash transfer assistance and voter turnout in Mexico. AB - Most research on the political consequences of international migration conceptualizes financial remittances as being a substitute for state-provided assistance. This paper tests the actual validity of this assumption. Using data from the 2012-2016 Americas Barometer, the analysis confirms previous findings on the negative impact of financial remittances on electoral turnout intentions. However it reveals that this effect does not vary according to an individual's beneficiary status of Conditional Cash Transfer (CCT) assistance. This finding is corroborated using data aggregated at the municipal level within Mexico. Accordingly, voter turnout rates in a given municipality for the 2012 presidential election are negatively associated with the percentage of households receiving remittances in that municipality. However, this association does not vary with the spending on CCT assistance within a given municipality. The evidence thus suggests that financial remittances undermine electoral participation through mechanisms other than the substitution of state-sponsored assistance, and as such further research is needed for us to discover what is really going on here. PMID- 29387565 TI - Assessing heavy metal toxicity in sediments of Chennai Coast of Tamil Nadu using Energy Dispersive X-Ray Fluorescence Spectroscopy (EDXRF) with statistical approach. AB - The concentration of some heavy metals: Al, Ca, K, Fe, Ti, Mg, Mn, V, Cr, Zn, Ni and Co in sediments from Pulicat Lake to Vadanemmeli along Chennai Coast, Tamil Nadu has been determined using EDXRF technique. The mean concentrations of Mg, Al, K, Ca, Ti, Fe, V, Cr, Mn, Co, Ni, and Zn were found to be 1918, 25436, 9832, 9859, 2109, 8209, 41.58, 34.14, 160.80, 2.85. 18.79 and 29.12 mg kg-1 respectively. These mean concentrations do not exceed the world crustal average. The level of pollution attributed to heavy metals was evaluated using several pollution indicators in order to determine anthropogenically derived contaminations. Enrichment Factor (EF), Geoaccumulation Index (Igeo), Contamination Factor (CF) and Pollution Load Index (PLI) were used in evaluating the contamination status of sediments. Enrichment Factors (EF) reveal the anthropogenic sources of V, Cr, Ni and Zn Geoaccumulation Index (Igeo) results reveal that the study area is not contaminated by the heavy metals. Similar results were also obtained by using pollution load index (PLI). The results of pollution indices indicates that most of the locations were not polluted by heavy metals. Multivariate statistical analysis performed using principal components and clustering techniques were used to identify the source of the heavy metals. The result of statistical procedures indicate that heavy metals in sediments are mainly of natural origin. This study provides a relatively novel technique for identifying and mapping the distribution of metal pollutants and their sources in sediment. PMID- 29387566 TI - Moringa oleifera extract (Lam) attenuates Aluminium phosphide-induced acute cardiac toxicity in rats. AB - Background: Moringa oleifera extract (Lam) has many antioxidant and protective properties. Objective: to investigate the antioxidant activities of Lam in counteracting the high oxidative stress caused by acute sub-lethal aluminium phosphide (AlP) intoxication in rat heart. These activities will be detected by histopathological examination and some oxidative stress biomarkers. Methods: a single sub-lethal dose of Alp (2 mg/kg body weight) was administered orally, and Lam was given orally at a dose (100 mg/kg body weight) one hour after receiving AlP to rats. Results: aluminium phosphide caused significant cardiac histopathological changes with a significant increase in malondialdehyde (MDA); lipid peroxidation marker; and a significant depletion of antioxidant enzymes (catalase and glutathione reductase). However, treatment with Lam protected efficiently the cardiac tissue of intoxicated rats by increasing antioxidants levels with slight decreasing in MDA production compared to untreated group. Conclusions: This study suggested that Moringa oleifera extract could possibly restore the altered cardiac histopathology and some antioxidant power in AlP intoxicated rats, and it could even be used as adjuvant therapy against AlP induced cardiotoxicity. PMID- 29387567 TI - Conditioning on What? Heterogeneous Contributions and Conditional Cooperation. AB - We experimentally investigate how different information about others' individual contributions affects people's willingness to cooperate in a one-shot linear public goods game. We find that when information about individual contributions is provided, contributions are generally higher than when only average information is available. This effect is particularly strong when others' individual contributions are relatively homogeneous. When both types of information are provided, this effect is moderated. In the case of individual feedback we find the willingness to contribute to be higher the lower the variation in others' contributions, but with pronounced heterogeneity in individuals' reactions. While the majority of people are mainly guided by others' average contributions, more people follow the bad example of a low contributor than the good example of a high contributor. Overall, we provide evidence that information (and lack thereof) about others' individual contributions affects people's willingness to cooperate in systematic ways. PMID- 29387568 TI - Assessment of natural radioactivity in various commercial tiles used for building purposes in Nigeria. AB - In this study, we evaluated the activity concentration of natural radionuclides (226Ra, 232Th and 40K) for fifteen (15) different brands of tile samples used for building purposes in Nigeria. The tile samples were analyzed using High purity Germanium gamma detector. The mean activity concentrations of 226Ra, 232Th, and 40K were observed to be 61.1 +/- 5.5 Bq/kg, 70.2 +/- 6.08 Bq/kg and 514.7 +/- 59.8 Bq/kg respectively. Various hazard indices such as absorbed dose rate, external and internal hazard index, annual effective dose rate, Gamma activity Index (Igamma) and Alpha Index (Ialpha) were calculated. The obtained results showed that the mean radium equivalent activity (Raeq), the absorbed dose rate (D), external and internal hazard index, the annual effective dose (AEDR) equivalent, Gamma activity Index (Igamma) and Alpha Index (Ialpha) were: 204.42 Bq/kg, 177.61 nGyh-1, 0.55, 0.77, 0.96 mSvyr-1, 0.74 and 0.32 respectively. The average value of radium equivalent obtained in this study is less than that of the recommended value of 370 Bq/kg but the average values of the other radiological hazards for some samples are found to be slightly above international recommended values except Hex, Hin and AEDE which are within the international reference value of unity. The measured concentrations of these radioactive materials were correlated with other previous result obtained from similar tile materials used in other countries and found to be in good agreement with the international standard, however, the tiles are recommended for decoration purposes in Nigeria. PMID- 29387569 TI - Anorexia: Highlights in Traditional Persian medicine and conventional medicine. AB - Objective: Anorexia and impaired appetite (Dysorexia) are common symptoms with varying causes, and often need no serious medical intervention. Anorexia nervosa (AN) is a chronic psychiatric disease with a high mortality rate. In Traditional Persian Medicine (TPM), anorexia is a condition in which anorexic patients lose appetite due to dystemperament. This review aims to discuss the common points of traditional and conventional approaches rather than introducing Persian medical recommendations suitable for nowadays use. Materials and Methods: For this purpose, Avicenna's Canon of Medicine, main TPM resources and important databases were reviewed using the related keywords. Results: Despite complex hormonal explanation, etiology of AN in conventional approach is not completely understood. In TPM approach, the etiology and recommended interventions are thoroughly defined based on humoral pathophysiology. In TPM approach, disease states are regarded as the result of imbalances in organs' temperament and humors. In anorexia with simple dystemperament, the physician should attempt to balance the temperament using foods and medicaments which have opposite quality of temperament. Lifestyle, spiritual diseases (neuro - psychological) and gastrointestinal worms are the other causes for reducing appetite. Also, medicines and foods with warm temperaments (such as Pea soup and Mustard) are useful for these patients (cold temperament). Conclusion: Although the pathophysiology of AN in TPM is different in comparison with conventional views, TPM criteria for treatment this disorder is similar to those of current medicine. Recommending to have spiritual support and a healthy lifestyle are common in both views. Simple safe interventions recommended by TPM may be considered as alternative medical modalities after being confirmed by well-designed clinical trials. PMID- 29387570 TI - Protective effect of crocin against d-galactose-induced aging in mice. AB - Objective: Aging is a multifactorial phenomenon, which attribute to different diseases and abnormalities in living systems. Oxidative stress, which is an important factor in aging, exacerbates this process via different mechanisms. Crocin (CR), one of the active components of saffron showed strong antioxidant effects. In the present study, anti-aging property of crocin was investigated in mice. Materials and Methods: The model of aging was induced using administration of d-galactose (500 mg/kg, s. c.) for 42 days. Animals were treated with crocin (10, 20, 40 mg/kg, i.p.) during treatment with d-galactose. At the end of treatment, levels of malondialdehyde (MDA) as a lipid peroxidation marker and glutathione content (GSH) in the liver and brain were measured. Also, biochemical factors including liver enzymes (ALT and AST), male sex hormones including testosterone and dehydroepiandrosterone-sulfate (DHEA-SO4) and pro-inflammatory markers such as tumor necrosis factor -alpha (TNF-alpha) and interlukine-6 (IL-6) in serum, were evaluated. Results: Administration of d-galactose led to induction of lipid peroxidation in liver and brain tissues, as well as elevation of AST, ALT, and pro-inflammatory cytokines and reduction of male sex hormones levels in serum. Interestingly, treatment of animals with crocin (10, 20 and 40 mg/kg) diminished lipid peroxidation in the liver and brain tissues while elevated GSH content. Also, a decline in serum levels of TNF-alpha and IL-6 and an elevation of male sex hormones were observed following treatment with crocin. Conclusion: Administration of crocin reduced d-galactose-induced aging in mice through inhibition of oxidative stress, reduction of inflammation and elevation of sex hormones. PMID- 29387571 TI - Effects of aqueous extracts of dried calyx of sour tea (Hibiscus sabdariffa L.) on polygenic dyslipidemia: A randomized clinical trial. AB - Objective: Dyslipidemia has been considered as a major risk factor for coronary heart disease. Alternative medicine has a significant role in treatment of dyslipidemia. There are controversial findings regarding the effects of sour tea on dyslipidemia. The aim of this study was to evaluate the impact of aqueous extract of dried calyx of sour tea on polygenic dyslipidemia. Materials and Methods: This clinical trial was done on 43 adults (30-60 years old) with polygenic dyslipidemia that were randomly assigned to the intervention and control groups. The control group was trained in lifestyle modifications at baseline. The intervention group was trained for lifestyle modifications at baseline and received two cups of sour tea daily, and both groups were followed up for 12 weeks. Lipid profile was evaluated at baseline, and six and 12 weeks following the intervention. In addition, dietary and physical activity assessed at baseline for twelve weeks. Results: Mean concentration of total cholesterol, HDL-C and LDL-C significantly decreased by up to 9.46%, 8.33%, and 9.80%, respectively, after 12 weeks in the intervention group in comparison to their baseline values. However, LDL-C/HDL-C ratio significantly increased by up to 3.15%, following 12 weeks in the control group in comparison to their baseline values. This study showed no difference in lipid profiles between the two groups, except for HDL-C concentrations. Conclusion: sour tea may have significant positive effects on lipid profile of polygenic dyslipidemia subjects and these effect might be attributed to its anthocyanins and inflation factor content. Therefore, sour tea intake with recommended dietary patterns and physical activity can be useful in regulation of lipid profile in patients with polygenic dyslipidemia. PMID- 29387572 TI - Assessment of phenolic profile and antioxidant power of five pistachio (Pistacia vera) cultivars collected from four geographical regions of Iran. AB - Objective: In this study, the levels and antioxidant activities of some secondary metabolites isolated from five pistachio (Pistacia vera) cultivars collected from four different geographical regions of Iran, were studied. Materials and Methods: Total phenolic compounds levels were determined by Folin-Ciocalteu method. Total flavonoid content was determined as AlCl3 complex and expressed as mg of quercetin equivalents (QE)/g dry extract and total proantocyanidins content was expressed as mg of catechin equivalents (CA)/g dry extract. In order to evaluated the antioxidant activity of the compounds, DPPH and FRAP assays were used. Results: The highest level of total phenols (156.42 mg GA/g DE), total flavonoids (130.94 mg QE/g DE) and total proantocyanidins (152.816 mg CA/g DE) were obtained in Akbari cultivar from Rafsanjan, followed by Badami-e-sefid and Ahmad aghaei. The lowest amount of total phenolic content (TPC), total flavonoid content (TFC) and total proanthocyanidin content (TPrAC) were found in Badami-e-sefid from Feizabad (128.140 mg GA/g DE, 93.176 mg QE/g DE and 118.870 mg CA/g DE, respectively). Also, a positive correlation (r2=0.9834) was found between antioxidant activity and total phenolic compounds. Conclusion: Pistachio increased their phytochemical compounds to contrast with abiotic stress. Our data could be useful for introducing special characteristics to the plants, and can be considered when planning a new breeding program or choosing a specific cultivar for a particular use. PMID- 29387573 TI - Saffron improved depression and reduced homocysteine level in patients with major depression: A Randomized, double-blind study. AB - Objectives: A correlation between hyperhomocysteinemia, and depression has been reported. Saffron (Crocus sativus) is recommended for treatment of depression; hence, in this study the effect of co-administration of saffron and fluoxetine on plasma homocysteine and depression was evaluated. Material and methods: This was a 4-week randomized and double-blind clinical trial which was conducted from March 2013 to February 2014. In this trial, 40 male and females (20-55 years old) diagnosed with severe depression were selected and following filing the Beck form, were randomly divided into two groups. Experimental group was treated with fluoxetine 20 mg/day and saffron 30 mg /day and the control group received placebo and fluoxetine 20 mg/day for four weeks. Before treatment and at the end of the study, fasting blood samples were collected. For females, blood samples were collected on the third day of their menstrual cycle. Results: A significant reduction of homocysteine levels was observed in both sex in the experimental group compared to before treatment (p<0.04), while no such significant change was observed in the control group. A Beck questionnaire value showed lower level in both groups on the last day of treatment as compared to before treatment. There was no significant difference between the two groups in Beck value neither before nor after treatment. Conclusion: Saffron has beneficial effects on depression and homocysteine level in patients with major depression. PMID- 29387574 TI - Antioxidant and hepatoprotective effects of Artemisia dracunculus against CCl4 induced hepatotoxicity in rats. AB - Objective: The present study was conducted to investigate the antioxidant and hepatoprotective activity of the hydro-alcoholic extract of aerial parts of Artemisiadracunculus (HAAD) against CCl4-induced hepatotoxicity in rats. Materials and Methods: The antioxidant activity was evaluated by reducing power, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 20-azino-bis (3-ethylbenzothiazoline 6-sulfonic acid) (ABTS) assays. Rats were pre-treated with either 50, 100, and 200 mg/kg of HAAD or silymarin (100 mg/kg; served as the positive control group) for 15 days and they received a single dose of CCl4 on the last day. Hepatoprotective effects were investigated by assessment of serum biochemical enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total protein (TP), total bilirubin (TB), malondialdehyde (MDA), and antioxidant enzymes (SOD, CAT, GST and GSH), along with histopathological studies. Results: Total phenolic content was 197.22+/-3.73 mg gallic acid equivalent/g HAAD dry weight. HAAD indicated powerful activity in FRAP, DPPH and ABTS tests. Acute toxicity study showed that the extract had an LD50 of >5000 mg/kg. Oral treatment with HAAD exhibited a significant decrease in the levels of AST, ALT, ALP and TB and an increase in the level of TP. The extract significantly diminished MDA levels. The activities of the antioxidant enzymes were significantly augmented in rats pretreated with HAAD 200 mg/kg. Histopathological examination demonstrated lower liver damage in HAAD-treated groups as compared to CCl4 groups. Conclusion: Our findings indicated hepatoprotective effects of the hydro-alcoholic extract of A. dracunculus on CCl4 induced hepatic damage in rats and suggested that these effects may be produced by reducing oxidative stress. PMID- 29387575 TI - Polyphenols isolated from virgin coconut oil attenuate cadmium-induced dyslipidemia and oxidative stress due to their antioxidant properties and potential benefits on cardiovascular risk ratios in rats. AB - Objective: Literature has confirmed the pathogenic role of cadmium (Cd) and its exposure in the induction of dyslipidemia implicated in the development and increasing incidence of cardiovascular diseases. The current study explored whether polyphenolics isolated from virgin coconut oil (VCO) prevent Cd-induced dyslipidemia and investigate the underlying mechanism of action, in rats. Materials and Methods: Rats were pretreated with VCO polyphenols (10, 20 and 50 mg/kg body weight; orally) 2 weeks prior to concurrent Cd administration (5 mg/kg) for 5 weeks. Subsequently, serum concentrations of lipid and lipoprotein cholesterol and cardiovascular risk ratios were determined. Hepatic activities of superoxide dismutase (SOD) and catalase (CAT) as well as reduced glutathione (GSH) and malondialdehyde (MDA) contents were analyzed. Results: Sub-chronic Cd administration significantly increased the serum levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol while markedly reduced high density lipoprotein cholesterol. Hepatic activities of SOD and CAT as well as GSH content were suppressed by Cd, whereas MDA level was obviously increased. The co administration of VCO polyphenol with Cd remarkably restored lipid profile and cardiovascular risk ratios and stabilized antioxidant defense systems comparable to control group. Conclusion: This is the first study presenting that polyphenols isolated from VCO prevent Cd-induced lipid abnormalities and cardiovascular risk ratios by improving antioxidant defense systems. PMID- 29387576 TI - Evaluation of psychopharmacological and neurosafety profile of Swas Kas Chintamani Ras (SKC) in Swiss-Webster mice. AB - Objectives: Swas Kas Chintamani Ras (SKC) is an ayurvedic preparation indicated for respiratory diseases. Our study was aimed to determine the psychopharmacological and neurosafety profile of SKC. Materials and Methods: Psychopharmacological effects and neurosafety profile of this drug were determined by nine complementary test methods namely, open field, locomotor activity, hole cross, hole board test, elevated plus maze, staircase, forced swimming test, and rotarod test. Male mice (Swiss-Webster strain, 20-40 g body weight) bred in the Animal House of the Department of Pharmacy, Jahangirnagar University, were used for the pharmacological experiments. Results: The drug decreased total ambulation and movement in the central region and standing up behavior and lowered emotional defecation. The drug also made the mice to take a shorter time to come out of the cage. Also, animals spent less time in open arm and the movement in the closed arm and locomotors reduced (p=0.003), where a number of rearing (p=0.04) behaviour indicating possible anxiolytic activity. Also, no signs of anti-depressant activity were observed among SKC-treated group. Conclusion: We concluded that our drug showed no neurotoxic effect and it also showed some beneficial neuropharmacological properties. PMID- 29387577 TI - Disease burden and patient reported outcomes among patients with moderate to severe psoriasis: an ethnography study. AB - Objectives: To assess the impact of psoriasis on health-related quality of life (HRQoL). Methods: An ethnographic study of patients with moderate to severe psoriasis was conducted in the US, France, Germany, Italy, Spain, UK, Brazil, and Canada to explore patients' views on treatment and the impact of psoriasis on HRQoL. Anthropologists and ethnographers spent a minimum of 5.5 hours with each consented patient and filmed their behaviors in everyday situations. Visual data and notes were analyzed to identify HRQoL-related themes. Results: The study included 50 adult patients. Patients described their appearance with disgust and self-loathing. Frustration was expressed due to a perceived lack of control of their lives. Prior to initiation of biologic treatment, daily rituals absorbed a good part of their day, including applying creams, checking one's appearance, and covering the body. Due to a lack of cultural discourse and patient's difficulty in articulating the impact of psoriasis, partners and family did not know how to react nor did they realize the full extent of the problem, and many patients experienced perceived social discrimination due to psoriasis, leaving them with feelings of isolation. Patients established on biologic treatment noticed a significant physical improvement and regained confidence, but psychosocial impacts, including social isolation, remained. Conclusion: This ethnographic study vividly depicted the unarticulated and emotional impact of psoriasis on the everyday lives of patients and presents an effective method of assessing HRQoL in chronic diseases. PMID- 29387579 TI - Optimal management of nail disease in patients with psoriasis. AB - Psoriasis is a common skin disease, with nail involvement in approximately 80% of patients. Nail psoriasis is often associated with psoriatic arthropathy. Involvement of the nails does not always have relationship with the type, gravity, extension, or duration of skin psoriasis. Nail psoriasis can occur at any age and all parts of the nails and the surrounding structures can be affected. Two clinical patterns of nail manifestations have been seen due to psoriasis: nail matrix involvement or nail bed involvement. In the first case, irregular and deep pitting, red spots of the lunula, crumbling, and leukonychia are seen; in the second case, salmon patches, onycholysis with erythematous border, subungual hyperkeratosis, and splinter hemorrhages are observed. These clinical features are more visible in fingernails than in toenails, where nail abnormalities are not diagnostic and are usually clinically indistinguishable from other conditions, especially onychomycosis. Nail psoriasis causes, above all, psychosocial and aesthetic problems, but many patients often complain about functional damage. Diagnosis of nail psoriasis is clinical and histopathology is necessary only in selected cases. Nail psoriasis has an unpredictable course but, in most cases, the disease is chronic and complete remissions are uncommon. Sun exposure does not usually improve and may even worsen nail psoriasis. There are no curative treatments. Treatment of nail psoriasis includes different types of medications, from topical therapy to systemic therapy, according to the severity and extension of the disease. Moreover, we should not underestimate the use of biological agents and new therapy with lasers or iontophoresis. This review offers an investigation of the different treatment options for nail psoriasis and the optimal management of nail disease in patients with psoriasis. PMID- 29387578 TI - Fumaric acid esters in the management of psoriasis. AB - Fumaric acid esters (FAE) are small molecules with immunomodulating, anti inflammatory, and anti-oxidative effects. FAE were introduced as a systemic psoriasis treatment in 1959 and empirically developed further between 1970 and 1990 in Germany, Switzerland, and the Netherlands. The development of FAE as psoriasis treatment did not follow the traditional drug development phases. Nonetheless, in 1994 FAE were approved in Germany for the treatment of severe plaque psoriasis. FAE are currently one of the most commonly used treatments in Germany, and FAE are increasingly being used as an unlicensed treatment in several other European countries. To date, six randomized controlled trials and 29 observational studies have evaluated FAE in a combined total of 3,439 patients. The efficacy and safety profile of FAE is favorable. About 50%-70% of patients achieve at least 75% improvement in psoriasis severity after 16 weeks of treatment. Common adverse events of FAE include gastrointestinal complaints and flushing symptoms, which lead to treatment discontinuation in up to 40% of patients. Lymphocytopenia, eosinophilia, and proteinuria are commonly observed during FAE treatment, but rarely require treatment discontinuation. The long-term safety profile of continuous FAE treatment is favorable without an increased risk for infections, malignancies, or other serious adverse events. There are no known drug-interactions for FAE. The 2009 European evidence-based S3-guidelines on psoriasis treatment recommend FAE and suggest it as a first-line systemic treatment for moderate-to-severe plaque psoriasis. This review is aimed to give an overview of FAE treatment in the management of psoriasis. PMID- 29387580 TI - Clinical potential of brodalumab in the management of psoriasis: the evidence to date. AB - Brodalumab is an anti-IL-17 receptor monoclonal antibody currently in development for the treatment of moderate-to-severe plaque psoriasis. With many systemic psoriasis therapies to choose from, and several newer agents in development, physicians need up to date evidence for the use of these drugs. A PubMed search was conducted through August 1, 2014 to identify randomized controlled trials and systematic reviews of brodalumab for the treatment of psoriasis. Results of Phase I and II trials, as well as a few smaller studies, have provided promising data on efficacy, safety, health-related quality of life, pharmacokinetics, and changes in lesional skin. Early Phase III data continue to support the use of brodalumab as a potentially valuable option for the treatment of psoriasis. PMID- 29387581 TI - Psoriasis in childhood: effective strategies to improve treatment adherence. AB - Psoriasis is a relatively common chronic inflammatory skin disease in children for which there is no cure. Most children have mild disease that can be managed with topical therapy as opposed to phototherapy or systemic therapy. Despite the mild presentation of psoriasis in most children, the disease can have a significant impact on quality of life due to the need for ongoing treatment, the frequently visible nature of the cutaneous manifestations, and the social stigma that is associated with psoriasis. Adherence to treatment, in particular topical therapy, is often poor in adults and compromises response to therapy and medical provider management strategies. Multiple factors that may contribute to nonadherence in adults with psoriasis have been identified, including lack of education on the disease and expectations for management, issues related to ease of use and acceptability of topical medications, and anxiety regarding possible medication side effects. There is currently no published data on adherence in the pediatric psoriasis population; however, poor adherence is often suspected when patients fail to respond to appropriate therapy. General strategies used to assess adherence in other pediatric disease populations can be applied to children with psoriasis, and interventions that reflect experience in other chronic dermatologic disorders such as atopic dermatitis may also be helpful for medical providers caring for children with psoriasis. PMID- 29387582 TI - Epidemiology and treatment of psoriasis: a Brazilian perspective. AB - Psoriasis is a chronic immune-mediated systemic disease that is influenced by genetic and environmental factors, is associated with comorbidities, and has a negative impact on the quality of life of affected individuals. The prevalence of psoriasis varies among different ethnic groups, but this topic has not been studied in Brazil to date. In this review, we evaluate the epidemiology and treatment of psoriasis from a Brazilian perspective. We focused on studies that involved Brazilian subjects. The prevalence of psoriasis in Brazil is estimated to be 2.5%, but no population study has been performed previously. Environmental factors, such as tropical climate, in association with genetic factors, such as miscegenation, may exert a beneficial impact on the course and frequency of psoriasis in Brazil. A number of studies have advanced our understanding of the cardiovascular, ophthalmic, and oral comorbidities that are associated with psoriasis. Concerns about biological therapy, such as endemic leprosy, human T cell lymphotropic virus (HTLV), and tuberculosis infections, are discussed. The nonavailability of treatment options for psoriasis in the public health system contradicts the Brazilian Society of Dermatology guidelines, stimulating the judicialization of access to medicines in psoriasis care. PMID- 29387583 TI - Subcutaneous methotrexate for symptomatic control of severe recalcitrant psoriasis: safety, efficacy, and patient acceptability. AB - Background: Although oral methotrexate is an effective first-line traditional systemic therapy for psoriasis, the use of the subcutaneous form of methotrexate for the treatment of psoriasis has not been fully established. Objective: This study is a literature review of the research related to the safety, efficacy, and patient acceptability of subcutaneous methotrexate for its application in the treatment of severe recalcitrant psoriasis. Methods: Systematic literature searches were conducted of the PubMed, Ovid, and ClinicalTrials.gov databases. Results: Only three relevant sources of literature were found studying subcutaneous methotrexate specifically in the context of psoriasis. Of these, only one clinical trial was found to directly study the use of subcutaneous methotrexate in psoriasis patients; however, results of this study have not been published. The other two literature sources involved a cost-effectiveness analysis and a literature review for subcutaneous methotrexate. OtrexupTM and RasuvoTM are two particular single-use auto-injector modalities of subcutaneous methotrexate that are approved by the US Food and Drug Administration. The equivalents of Rasuvo available in countries outside of the USA are advertised as Metoject(r) or Metex(r). Much more research has been conducted on the use of subcutaneous methotrexate in rheumatoid arthritis patients. Conclusion: There is a lack of original evidence-based studies evaluating the use of subcutaneous methotrexate specifically for the treatment of psoriasis. Based on the more extensively researched data on the safety, efficacy, and patient acceptability of subcutaneous methotrexate in rheumatoid arthritis patients, its application for the treatment of moderate-to-severe psoriasis is promising. More evidence-based studies on psoriasis subjects are needed to explore the practical application of subcutaneous methotrexate as a treatment option for severe recalcitrant psoriasis. PMID- 29387584 TI - Assessing the effectiveness of synthetic and biologic disease-modifying antirheumatic drugs in psoriatic arthritis - a systematic review. AB - Background: Psoriatic arthritis is an inflammatory arthritis the primary manifestations of which are locomotor and skin disease. Although a number of guidelines have been published citing strategies for reducing disease progression, the evidence base for disease-modifying agents is unclear. This forms the focus of this systematic review. Methods: The systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist. We selected randomized controlled trials (RCTs) that looked at the impact of interventions with disease-modifying agents, either synthetic drugs or biologics on musculoskeletal outcomes, notably American College of Rheumatology 20 percent responders. Results were analyzed using Review Manager 5.1.6 (Cochrane Collaboration, Oxford, UK). Whilst our primary focus was on published trials, we also looked at new trials presented in abstract form in 2013-2014 that were not yet published to avoid omitting important and up-to-date information on developing treatments. Results: Our in-depth analysis included 28 trials overall enrolling 5,177 patients published between the 1980s and now as well as limited analysis of some studies in abstract form as described earlier. The most frequently available locomotor outcome measure was the American College of Rheumatology 20 percent responders. The risk ratio for achieving an American College of Rheumatology 20 percent responders response was positive in favor of treatment (risk ratio 2.30; 95% confidence interval 1.78-2.96); however, there was evidence of considerable heterogeneity between trials. Overall randomized controlled trials of established synthetic disease-modifying agents were largely negative (methotrexate, ciclosporin and sulfasalazine) though leflunomide showed a small positive effect. A new synthetic agent, apremilast, did show a positive benefit. For biologics, TNF inhibitors already licensed for use were effective and similar benefits were seen with newer agents including ustekinumab, secukinumab, brodalumab, and abatacept, although the latter did not impact on skin problems. Important limitations of the systematic review included, first, the fact that for many agents there were little data and, second, much of the recent data for newer biologics were only available in abstract form. Conclusion: Conventional disease-modifying agents, with the possible exception of leflunomide, do not show clear evidence of disease-modifying effects in psoriatic arthritis, though a newer synthetic disease-modifying agents, apremilast, appears more effective. Biologic agents appear more beneficial, although more evidence is required for newer agents. This review suggests that it may be necessary to review existing national and international management guidelines for psoriatic arthritis. PMID- 29387585 TI - Psoriasis in pregnancy: challenges and solutions. AB - The available information about the effects of pregnancy on psoriasis and those of psoriasis on pregnancy is almost limited, despite the high frequency of the disease in the general population, as well as in women in reproductive years. Considering the existing evidence, pregnancy does not tend to have a negative influence on psoriasis, as in most women who experience a change in the severity and course of their psoriasis during pregnancy, the change is more likely to be reported as an improvement. This assumption can be applied more convincingly to plaque-type psoriasis, while an exception may be represented by generalized pustular psoriasis, which has been somehow linked to impetigo herpetiformis. Conflicting findings emerged from the few available studies that explored the effect of psoriasis on pregnancy outcomes. Recent studies found an association between moderate-to-severe psoriasis and some pregnancy complications, including pregnancy-induced hypertensive diseases, and have emphasized a trend toward a newborn with low birth weight in patients with psoriasis, especially in those suffering from severe forms. The safety profile during pregnancy is not completely known for many drugs used to treat psoriasis. Moisturizers and low- to moderate-potency topical steroids or ultraviolet B phototherapy represent the first-line therapy for pregnant patients. Many dermatologists may, however, recommend discontinuing all drugs during pregnancy, in consideration of medico legal issues, and also taking into account that common forms of psoriasis do not compromise the maternal and fetal health. Anyway, for those women whose psoriasis improves during pregnancy, the interruption of any therapy for psoriasis can be a reasonable strategy. The objective of this paper was to review the most relevant literature data on psoriasis in pregnancy, trying to give concurrently practical information about clinical and prognostic aspects, as well as counseling and management. PMID- 29387586 TI - Calcipotriol/betamethasone for the treatment of psoriasis: efficacy, safety, and patient acceptability. AB - Background: One of the advances in the treatment of plaque-type psoriasis is combined local therapy with calcipotriol and betamethasone. To provide both ingredients in a two-compound product, efforts have been made to unite calcipotriol and betamethasone because they are usually inactivated when present in the same formulation. This aspect was resolved when carefully designed vehicle components were invented (gel and ointment). This article reviews the efficacy, safety, and patient acceptability of calcipotriol/betamethasone dipropionate. Methods: A literature search of all articles published until February 2015 was performed, including the largest medical databases. The search strategy for evaluating the main topics of this review - efficacy, safety, and patient acceptability - was defined before checking the publications. Results: Seventy references were found and checked for relevance. For efficacy, the proportion of patients whose psoriasis improved was always significantly higher in the two compound group compared to the group treated with the individual substances. In the context of safety, the fixed combination was generally associated with a lower risk of adverse events. In terms of patient acceptability, the fixed combination led to a significant improvement in quality of life. The two-compound product was more convenient to handle and time saving compared to former treatments. Conclusion: Calcipotriol/betamethasone dipropionate in a fixed combination is an effective and well-tolerated medication in mild-to-moderate psoriasis of body and scalp and, in addition, is an evidence-based treatment modality. PMID- 29387587 TI - Improving patient outcomes in psoriasis: strategies to ensure treatment adherence. AB - Psoriasis is a frequent inflammatory disease with a chronic and relapsing course. Therefore, patients with psoriasis are likely to undergo different treatments for long periods of time. Traditionally, therapies used in psoriasis have been associated with poor levels of adherence due to the complexity of the regimens and the poor results obtained with the topical therapies. These poor outcomes are associated with high levels of frustration and anxiety, which decrease adherence and worsen the disease. With the recent introduction of highly efficacious biologic therapies, patients can achieve very good and prolonged responses. However, most patients with psoriasis have mild disease and may be treated with skin-directed therapies. Therefore, it is important to develop strategies to improve adherence in order to achieve better outcomes, and to improve the overall quality of life. Hence, acknowledging the causes of nonadherence is crucial for implementing these strategies. In this summary, we review the causes of nonadherence, and we provide behavioral strategies in order to improve adherence and, ultimately, the outcome of patients with psoriasis. PMID- 29387588 TI - Update on the treatment of psoriasis and psoriatic arthritis - role of apremilast. AB - Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis (PsO). The treatment of PsA can be challenging and includes non-steroidal anti inflammatory drugs, synthetic disease modifying antirheumatic drugs, and biologicals. One novel oral compound that has been recently established for the treatment of PsO and PsA is apremilast, a small molecule PDE4 inhibitor. The inhibition of PDE4 results in increased intracellular cAMP levels and modulates the expression of inflammatory mediators critically involved in PsO and PsA pathogenesis like TNF, IL-12, IL-17, and IL-23. Apremilast received US Food and Drug Administration approval for the treatment of PsO and PsA in 2014 and received approval from the European Medicines Agency in early 2015. This article summarizes the pharmacology of apremilast, its efficacy and safety in clinical studies, and its potential position in modern PsO/PsA management. PMID- 29387589 TI - Links and risks associated with psoriasis and metabolic syndrome. AB - Introduction: Psoriasis has long been considered a systemic inflammatory disease. Lately, it has been strongly associated with obesity, as well as other components of metabolic syndrome, such as dyslipidemia, insulin resistance, and arterial hypertension. Methods: We reviewed the literature of the last decade by using the keywords: psoriasis, metabolic syndrome, and/or obesity in PubMed and Medline. Results: Obesity and psoriasis seem to share similar profiles of systemic inflammation. Serum cytokines such as TNF-alpha, CRP, IL-6, and IL-12 are elevated in both disorders. The more severely an individual is affected with psoriasis, the more likely it is to be obese. This makes the disease an important health care issue, which requires the cooperation of dermatologists with other medical specialists. Discussion: This review attempts to summarize the links and risks that associate psoriasis with obesity, and highlight the concerns and queries for both disorders in the future. PMID- 29387590 TI - Integrating lifestyle-focused approaches into psoriasis care: improving patient outcomes? AB - Psoriasis is one of the most well described cutaneous disorders, with a large body of literature devoted to describing its pathogenesis and treatment. In recent years, attention has turned toward the mechanisms by which lifestyle can impact psoriatic disease, and how lifestyle interventions may help to alleviate cutaneous, rheumatological, and comorbid disease in the setting of psoriasis. The following review explores our current understanding of the interaction between lifestyle factors and psoriasis and describes outcomes of interventions meant to target these factors. PMID- 29387592 TI - Management of scalp psoriasis: current perspectives. AB - Psoriasis is a chronic inflammatory condition. The age of onset, chronicity, physical, and psychosocial consequences of the disease cause psoriasis to have a significant impact on patient quality of life. Scalp psoriasis is no different, and effective treatment results in an improvement in quality of life. Successful management of scalp psoriasis includes topical therapies that are acceptable to the patient for mild-to-moderate disease, and systemic therapies for recalcitrant or moderate-to-severe disease. The most effective topical therapies are corticosteroid products, or combination products with calcipotriol and corticosteroid. Newer vehicle options provide more attractive and pleasing products for patients and may improve adherence. The current perspectives for management of scalp psoriasis are discussed including available data for systemic therapy of severe disease. PMID- 29387593 TI - Assessment and monitoring of biologic drug adverse events in patients with psoriasis. AB - Background: Current treatment guidelines for biologic therapies in psoriasis differ in their recommendation for the monitoring of adverse events. Objective: The aim of this paper was to draw together evidence from the currently available guidelines as a summary of how biologics licensed for the treatment of psoriasis should be monitored for adverse events. Methods: The MEDLINE database was searched to identity the current literature on the safety and screening guidance associated with infliximab, etanercept, adalimumab, ustekinumab, and secukinumab. Limitations: This study was limited by the lack of data evaluating monitoring in patients with psoriasis undergoing treatment with a biologic therapy. Results: This review of the current literature highlights that there are areas of routine screening, which are recommended in current practice, which require further evidence to investigate its true utility. Conclusion: Most screening and monitoring tests performed routinely in clinical practice are supported by minimal clinical evidence, highlighting the need for more studies to evaluate the role and value of the different modalities of screening and monitoring for adverse events in those with psoriasis receiving treatment with biologic therapies. PMID- 29387594 TI - Improving access to home phototherapy for patients with psoriasis: current challenges and future prospects. AB - Introduction: Although the treatment burden for phototherapy in the outpatient setting is considerable, prescription of home-based phototherapy has not been instigated. Home-based phototherapy seems more patient friendly in terms of avoiding the thrice-weekly hospital visits. So why are most treatments still given in a hospital setting? Is home-based treatment less effective? Are there financial barriers? Is the treatment not available? To answer these questions, a literature search was done. Methods: A literature search of PubMed, Embase, and Cochrane Library databases was performed, using the search terms "psoriasis" and "phototherapy". Selection was based on two rounds; the first round involved screening the title and abstract of all records and second involved evaluating the full text of the remaining articles for eligibility according to inclusion and exclusion criteria. Results: In total, 23 publications were included with consensus of both researchers. Overall, the patients reported being very satisfied with home-based phototherapy. Results regarding effectivity in terms of improvement from disease severity and in quality of life were variable but generally positive. Reasons for reluctance varied from medicolegal and social aspects to lack of reimbursement and unfamiliarity on the side of the prescriber. Conclusion: In the treatment for psoriasis, home-based phototherapy is as effective and safe as phototherapy in an outpatient setting. Patients were more satisfied with home-based phototherapy. Factors that negatively influence the prescription of or choice for home-based phototherapy can be summarized in terms of lack of control, lack of knowledge, and lack of a good reimbursement system. PMID- 29387595 TI - Psoriasis and smoking: links and risks. AB - Smoking is a complex environmental exposure influenced by genetic, environmental, and social factors. Nicotine is the principal alkaloid in tobacco that mediates the addicting effects of tobacco products. Tobacco is a mixture of more than 7,000 chemicals, and smoking is recognized as a risk factor for many diseases in humans, including cardiovascular and pulmonary disease and several cancers, and is the single most preventable cause of mortality worldwide. A number of inflammatory immune-related conditions have been associated with smoking, including psoriasis. Smoking affects the onset of psoriasis. In a pooled analysis of 25 case-control studies, the odds ratio of psoriasis among smokers was 1.78 (95% confidence interval [CI]: 1.53-2.06). A dose-effect relationship is also documented. In a pooled analysis of three cohort studies, the risk of incident psoriasis was 1.81 (95% CI: 1.38-2.36) in those who smoked 1-14 cigarettes per day, and 2.29 (95% CI: 1.74-3.01) in those who smoked >=25 cigarettes per day. Smoking also impacts on the clinical severity of psoriasis, its response to treatment, and explains some of the associated comorbidities, eg, cardiovascular disease, inflammatory bowel disease, and several cancers (especially those of the respiratory tract). Data on the role of smoking in psoriatic arthritis are less consistent compared with those concerning psoriasis. Several pathophysiological mechanisms may explain the association of psoriasis with smoking, including oxidative stress, interaction with signaling pathways active in psoriasis, and vascular influences. In conclusion, psoriasis is just one of the many diseases associated with smoking, but it is visible and disabling. Dermatologists could play a major role in reducing the health burden of smoking by influencing the patients to change their behavior. PMID- 29387597 TI - Combining biologic and phototherapy treatments for psoriasis: safety, efficacy, and patient acceptability. AB - Background: The efficacy and safety of biologic and phototherapy in treating moderate-to-severe psoriasis is well known. However, some patients may not respond well to biologic agents or phototherapy on their own and may require combination therapy. Skillfully combining a biologic agent and phototherapy may provide an additive improvement without much increase in risks. Objective: To summarize the current state of evidence for the efficacy and safety of combining biologics with phototherapy in the treatment of moderate-to-severe plaque psoriasis. Methods: We conducted an extensive search on Pubmed database for English language literature that evaluated the use of a combination of biologic and phototherapy for the treatment of moderate-to-severe psoriasis through January 2016. The search included the following key-words: psoriasis, etanercept, adalimumab, infliximab, ustekinumab, biologics, phototherapy, and combination therapy. Results: The primary literature included randomized controlled trials, a head-to-head study, open-label controlled and uncontrolled trials, case series, and case reports. Etanercept was used in over half of the reported cases, but other biologic agents used included ustekinumab, adalimumab, and infliximab. The vast majority of phototherapy was narrowband ultraviolet B (NBUVB) radiation. Most cases reported enhanced improvement with combination therapy. Serious adverse events throughout the study duration were reported in <3% of the patients. Long-term adverse events cannot be excluded. Conclusion: Combination of biologic and phototherapy appears to be a viable clinical strategy in the treatment of moderate-to-severe psoriasis not responsive to monotherapy, despite limitations in the data available. NBUVB in combination with biologics appears to be especially effective. However, the long-term impact of these combinations is yet to be determined. PMID- 29387591 TI - Current knowledge on psoriasis and autoimmune diseases. AB - Psoriasis is a prevalent, chronic inflammatory disease of the skin, mediated by crosstalk between epidermal keratinocytes, dermal vascular cells, and immunocytes such as antigen presenting cells (APCs) and T cells. Exclusive cellular "responsibility" for the induction and maintenance of psoriatic plaques has not been clearly defined. Increased proliferation of keratinocytes and endothelial cells in conjunction with APC/T cell/monocyte/macrophage inflammation leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Despite the identification of numerous susceptibility loci, no single genetic determinant has been identified as responsible for the induction of psoriasis. Thus, numerous other triggers of disease, such as environmental, microbial and complex cellular interactions must also be considered as participants in the development of this multifactorial disease. Recent advances in therapeutics, especially systemic so-called "biologics" have provided new hope for identifying the critical cellular targets that drive psoriasis pathogenesis. Recent recognition of the numerous co-morbidities and other autoimmune disorders associated with psoriasis, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus suggest common signaling elements and cellular mediators may direct disease pathogenesis. In this review, we discuss common cellular pathways and participants that mediate psoriasis and other autoimmune disorders that share these cellular signaling pathways. PMID- 29387598 TI - Psoriasis patients' experiences concerning medical adherence to treatment with topical corticosteroids. AB - Nonadherence to topical treatment of psoriasis is a common cause of treatment failure. This focus group study was conducted to obtain the patients' own experiences and explanations regarding medical adherence. The participants consisted of eight primary adherent patients with moderate psoriasis treated with corticosteroid or corticosteroid-calcipotriol combinations, purposefully sampled by age and sex at a dermatology outpatient clinic. Secondary medical adherence was supported by accessibility of the prescribing physician, the prescriber taking time to listen, having a more manageable disease, using a nonstaining product, and establishing routines around treatment at home. Secondary medical adherence was affected negatively by changes in daily routines, if the treatment influenced the patient's sexual life, having too little time in the consultation room, lack of confidence in the prescriber, diverging information from health care personnel, experiencing side effects, having fear of side effects, impractical formulations of topical products, and impatience regarding time before an effect of the treatment was observed. From this study, the recommendations for the prescribing doctor to improve medical adherence are, the doctor needs to take time to listen to the patient, prescribe a topical product that is easy to apply and less greasy, inform the patients about benefits from treatments, and explain the rationale behind the treatment plan. PMID- 29387599 TI - Psoriasis in children. AB - The clinical presentation, disease associations, and diverse treatment modalities in overcoming the challenges of managing pediatric psoriasis have been extensively summarized in this article. An extensive literature review revealed the differences in presentation of psoriasis during infancy, childhood, and adolescence. We also summarized the latest topical, systemic, and biological modalities in treating recalcitrant psoriasis. The association of psoriasis with juvenile arthritis and obesity and the significant influence of the disease on the children's quality of life were explored. The clinical presentation of psoriasis can evolve during the child's lifespan. While many treatment modalities already exist for treating pediatric psoriasis, some of the new biologics that are approved for adult patients have not been investigated in the pediatric population and no algorithm exists for their use in this population. Large clinical studies in the future will enhance our understanding with regards to their safety and potential implications in pediatric populations. PMID- 29387596 TI - Psoriasis and inflammatory bowel disease: links and risks. AB - Psoriasis and the spectrum of inflammatory bowel diseases (IBD) are chronic, inflammatory, organotropic conditions. The epidemiologic coexistence of these diseases is corroborated by findings at the level of disease, biogeography, and intrafamilial and intrapatient coincidence. The identification of shared susceptibility loci and DNA polymorphisms has confirmed this correlation at a genetic level. The pathogenesis of both diseases implicates the innate and adaptive segments of the immune system. Increased permeability of the epidermal barrier in skin and intestine underlies the augmented interaction of allergens and pathogens with inflammatory receptors of immune cells. The immune response between psoriasis and IBD is similar and comprises phagocytic, dendritic, and natural killer cell, along with a milieu of cytokines and antimicrobial peptides that stimulate T-cells. The interplay between dendritic cells and Th17 cells appears to be the core dysregulated immune pathway in all these conditions. The distinct similarities in the pathogenesis are also reflected in the wide overlapping of their therapeutic approaches. Small-molecule pharmacologic immunomodulators have been applied, and more recently, biologic treatments that target proinflammatory interleukins have been introduced or are currently being evaluated. However, the fact that some treatments are quite selective for either skin or gut conditions also highlights their crucial pathophysiologic differences. In the present review, a comprehensive comparison of risk factors, pathogenesis links, and therapeutic strategies for psoriasis and IBD is presented. Specific emphasis is placed on the role of the immune cell species and inflammatory mediators participating in the pathogenesis of these diseases. PMID- 29387601 TI - Herpes zoster in psoriasis patients undergoing treatment with biological agents: prevalence, impact, and management challenges. AB - As TNF-alpha is a major factor in the immune defense against herpes zoster (HZ); an increased incidence and severity of HZ cases were suspected in patients undergoing treatment with TNF antagonists. Several studies and clinical experience provided evidence that the incidence of HZ increases by twofold to threefold in this patient category. The number of severe cases of HZ, with multisegmental, disseminated cutaneous, and/or systemic involvement, is also increased. Concerning psoriasis patients under biologicals, the clinician should be more alert for an eventual HZ event, in particular during the first year of biological treatment, and be aware of the possibility of more severe HZ cases. HZ may also undergo an age-shift toward younger patients. Rapid identification of risk factors for severe HZ, such as severe prodromal pains and/or the presence of satellite lesions, is recommended. The treatment recommendations of HZ in this patient group are identical to the recently published guidelines for the management of HZ. The live attenuated viral vaccine OKA/Merck strain anti-HZ vaccination is recommended before initiating biological treatment in psoriasis patients. The new adjuvanted anti-HZ vaccine will probably also benefit patients while on biological treatment. PMID- 29387600 TI - Pustular psoriasis: pathophysiology and current treatment perspectives. AB - Psoriasis vulgaris is a chronic inflammatory disease that classically affects skin and joints and is associated with numerous comorbidities. There are several clinical subtypes of psoriasis including the uncommon pustular variants, which are subdivided into generalized and localized forms. Generalized forms of pustular psoriasis include acute generalized pustular psoriasis, pustular psoriasis of pregnancy, and infantile and juvenile pustular psoriasis. Localized forms include acrodermatitis continua of Hallopeau and palmoplantar pustular psoriasis. These subtypes vary in their presentations, but all have similar histopathologic characteristics. The immunopathogenesis of each entity remains to be fully elucidated and some debate exists as to whether these inflammatory pustular dermatoses should be classified as entities distinct from psoriasis vulgaris. Due to the rarity of these conditions and the questionable link to the common, plaque-type psoriasis, numerous therapies have shown variable results and most entities remain difficult to treat. With increasing knowledge of the pathogenesis of these variants of pustular psoriasis, the development and use of biologic and other immunomodulatory therapies holds promise for the future of successfully treating pustular variants of psoriasis. PMID- 29387602 TI - Tacrolimus for the management of psoriasis: clinical utility and place in therapy. AB - Psoriasis affects 1%-3% of the population in the United Kingdom and can convey significant detriment to the physical and mental health of sufferers. Plaques of psoriasis typically affect the extensor skin surfaces and scalp. Less frequently inverse psoriasis can affect more sensitive skin such as the face, genitals, and intertriginous areas. Psoriasis is incurable, but there are a range of treatment modalities that can be used to manage the condition. Treatment options include topical preparations, phototherapy, systemic therapy, and biological agents. Tacrolimus is a macrolide calcineurin inhibitor licensed for immunosuppression in transplant patients and topical administration in atopic dermatitis. Tacrolimus administered orally and in topical form has been shown to produce successful outcomes in patients with psoriasis. Topical tacrolimus is particularly effective for inverse psoriasis, which is likely to be due to the reduced level of induration seen in these psoriatic lesions, which allows greater skin penetrance, compared with hyperkeratotic plaques of psoriasis on the body. It is also notable that the areas affected by inverse psoriasis are more susceptible to adverse effects of topical corticosteroid therapy, and thus a topical preparation without the risk of skin atrophy, telangiectasia, and striae could be a valuable addition to current topical treatment options. Oral tacrolimus has shown efficacy in the treatment of severe, refractory psoriasis. Compared to ciclosporin, systemic tacrolimus may be more suited to a patient population with increased cardiovascular risk. This review will draw together the current literature on topical and oral tacrolimus for the treatment of psoriasis. Efficacy and safety have been evaluated by case reports and randomized controlled trials and comparisons have been made between tacrolimus therapy and standard treatment. PMID- 29387603 TI - Excimer laser for the treatment of psoriasis: safety, efficacy, and patient acceptability. AB - Introduction: The 308 nm excimer laser is a widely used device throughout the field of dermatology for many diseases including psoriasis. Although the laser has demonstrated clinical efficacy, there is a lack of literature outlining the safety, efficacy, and patient acceptability of the excimer laser. Methods: A literature search on PubMed was used with combinations of the terms "excimer", "excimer laser", "308 nm", "psoriasis", "protocol", "safety", "efficacy", acceptability", "side effects", and "dose". The search results were included if they contained information pertaining to excimer laser and psoriasis treatment and description of the safety, efficacy, and patient acceptability of the treatment. Results: The 308 nm excimer laser is generally safe and well tolerated with minimal side effects including erythema, blistering, and pigmentary changes. It has a range of efficacies depending on the protocol used with several different treatment protocols, including the induration protocol, the minimal erythema dose protocol, and the newer minimal blistering dose protocol. Conclusion: Although the excimer laser is not a first-line treatment, it remains an excellent treatment option for psoriasis patients and has been demonstrated to be an effective treatment with little to no side effects. PMID- 29387605 TI - Monitoring treatment response in psoriasis: current perspectives on the clinical utility of reflectance confocal microscopy. AB - Reflectance confocal microscopy (RCM) evaluation of inflammatory skin diseases represents a relatively new technique that, during the past 5 years, has attracted increasing interest, with consequent progressive increment of publications in literature. The success of RCM is directly related to the high need for noninvasive techniques able to both reduce the number of skin biopsies and support clinical diagnosis and patient management. RCM helps to visualize microscopic descriptors of plaque psoriasis (PP) with good reproducibility between observers and a high grade of correspondence with histopathology. Several clinical tests are used for the therapeutic management of PP, but they are limited by subjective interpretation. Skin biopsy presents objective interpretation, but the procedure is invasive and not repeatable. RCM has been used not only for the evaluation of skin cancer or inflammatory skin diseases, but also for monitoring the efficacy of different treatments in PP. In this review, we present some examples of RCM applications in therapeutic psoriasis follow-up. PMID- 29387604 TI - Local effects of adipose tissue in psoriasis and psoriatic arthritis. AB - The structure and physiological state of the local white adipose tissue (WAT) located underneath the lesional psoriatic skin and inside of the joints affected by psoriatic arthritis play an important role in the pathophysiology of these diseases. WAT pads associated with inflammatory sites in psoriasis and psoriatic arthritis are, correspondingly, dermal WAT and articular adipose tissue; these pads demonstrate inflammatory phenotypes in both diseases. Such local WAT inflammation could be the primary effect in the pathophysiology of psoriasis leading to the modification of the local expression of adipokines, a change in the structure of the basement membrane and the release of keratinocytes with consequent epidermal hyperproliferation during psoriasis. Similar articular adipose tissue inflammation can lead to the induction of structural modifications and synovial inflammation in the joints of patients with psoriatic arthritis. PMID- 29387606 TI - Hepatitis B reactivation in psoriasis patients treated with anti-TNF agents: prevention and management. AB - The risk of hepatitis B virus (HBV) reactivation (HBVr) in chronic HBV carriers, in occult HBV patients or in acute HBV patients affected by psoriasis and treated with anti-tumor necrosis factor (TNF)-alpha agents is a clinical practice issue to face with, particularly if the treatment has a long-term maintenance finality. The aims of this review are to examine the current knowledge on HBVr incidence in chronic HBV carriers and potential occult carriers undergoing therapy with biologics for the treatment of psoriasis and psoriatic arthritis; analyze the prophylactic measure to prevent HBV reactivation and define how to manage HBVr in patients treated with biologics. We searched through PubMed, Google Scholar and Scopus databases and evaluated all published manuscripts concerning HBVr in psoriatic patients, both plaque-type and psoriatic arthritis, in treatment with any indicated anti-TNF-alpha. Although anti-TNFs are considered moderate immunosuppressive drugs, the incidence of HBVr in psoriatic patients is lower compared to patients affected by other immune-mediated diseases treated with TNF inhibitors. HBV prophylaxis should be probably reserved to anti-HBs+/anti-HBc+ patients with a viral load <2000 IU/mL and alterations in serum liver enzymes, in order to prevent HBVr. PMID- 29387607 TI - Single-center, noninterventional clinical trial to assess the safety, efficacy, and tolerability of a dimeticone-based medical device in facilitating the removal of scales after topical application in patients with psoriasis corporis or psoriasis capitis. AB - Introduction: Psoriasis is a frequent inflammatory skin disease affecting ~2%-3% of the population in western countries. Scaling of the psoriatic lesions is the most impairing symptom in patients with psoriasis. In contrast to conventional keratolytic treatment concepts containing salicylic acid or urea, a dimeticone based medical device (Loyon(r)) removes scales in a physical way without any pharmacological effect. Objective: To assess the efficacy and tolerability of a dimeticone-based medical device in removal of scales in patients with psoriasis corporis/capitis under real-life conditions. Methods: Forty patients with psoriasis capitis or corporis were included and received once-daily treatments for 7 days. Clinical assessment of the psoriasis area severity index score (psoriasis corporis) and the psoriasis scalp severity index score (psoriasis capitis) was performed and evaluated at baseline, after 3 and 7 days of treatment. Baseline scaling scores and redness scores were calculated for two target lesions of the scalp or the body on a 5-point scale each. Results: For the primary efficacy variable scaling score, a statistically significant decrease was observed after treatment, with a relative reduction in scaling of 36.8% after 7 days of treatment within patients affected by psoriasis capitis. Treatment success was achieved in 76.8% of patients with psoriasis capitis, and time to treatment success was evaluated to be 4.14 days for these patients and 4.33 days for patients suffering from psoriasis corporis. Conclusion: In conclusion, this trial demonstrated that the dimeticone-based medical device is a safe, well tolerated, practicable, and efficient keratolytic compound, which can be well implemented in and recommended for standard therapy of psoriasis. PMID- 29387609 TI - Clinical utility of ixekizumab in the treatment of moderate-to-severe plaque psoriasis. AB - Psoriasis vulgaris is a chronic, immune-mediated systemic disease that affects7.5 million people in the US. It can be treated with many therapies, often in combination, which include topicals, phototherapy, oral systemics, and biologics. Biologic agents target specific components of the immune system involved in the pathogenesis of psoriasis including TNF-alpha, IL-12, IL-17, and IL-23. The biologic ixekizumab, approved for the treatment of moderate-severe plaque psoriasis in the US, targets IL-17. This review describes the role of IL-17 in psoriasis, the mechanism by which ixekizumab targets this cytokine, and the clinical utility of ixekizumab. PMID- 29387608 TI - Nail psoriasis: clinical features, pathogenesis, differential diagnoses, and management. AB - Psoriasis is the skin disease that most frequently affects the nails. Depending on the very nail structure involved, different clinical nail alterations can be observed. Irritation of the apical matrix results in psoriatic pits, mid-matrix involvement may cause leukonychia, whole matrix affection may lead to red lunulae or severe nail dystrophy, nail bed involvement may cause salmon spots, subungual hyperkeratosis, and splinter hemorrhages, and psoriasis of the distal nail bed and hyponychium causes onycholysis whereas that of the proximal nail fold causes psoriatic paronychia. The more extensive the involvement, the more severe is the nail destruction. Pustular psoriasis may be seen as yellow spots under the nail or, in case of acrodermatitis continua suppurativa, as an insidious progressive loss of the nail organ. Nail psoriasis has a severe impact on quality of life and may interfere with professional and other activities. Management includes patient counseling, avoidance of stress and strain to the nail apparatus, and different types of treatment. Topical therapy may be tried but is rarely sufficiently efficient. Perilesional injections with corticosteroids and methotrexate are often beneficial but may be painful and cannot be applied to many nails. All systemic treatments clearing widespread skin lesions usually also clear the nail lesions. Recently, biologicals were introduced into nail psoriasis treatment and found to be very effective. However, their use is restricted to severe cases due to high cost and potential systemic adverse effects. PMID- 29387610 TI - Role of mesenchymal stem cells in the pathogenesis of psoriasis: current perspectives. AB - Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic stromal cells studied for their properties and importance in management of several skin diseases. This review collects and analyzes the emerging published data, which describe the function of MSCs in the pathogenesis of psoriasis. PMID- 29387611 TI - Drug-induced psoriasis: clinical perspectives. AB - Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta blockers, lithium, antimalarial drugs such as (hydroxy)chloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of "classical" nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments. PMID- 29387613 TI - Oral Health Knowledge, Attitude, and Practices of Sharjah Mothers of Preschool Children, United Arab Emirates. AB - Objective: The improvement of children's oral health, a world global health target, is essential to general health and quality of life. Hence, the aim of this study was to assess the knowledge, attitude, and practices of mothers toward their children's oral health in Sharjah, United Arab Emirates (UAE). Materials and Methods: A cross-sectional interview-based study was conducted among 383 mothers of preschool children (average age 3.49 [+1.63 years]) attending Sharjah Dental Center, UAE. Statistical analysis was performed using SPSS software for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Results: Adequate knowledge was found among 58.2% of mothers, 99% exhibited excellent attitude, and only 20% followed good practices toward their children's oral health. Poor knowledge and practice of mothers were significantly associated with mothers' occupation and education. Employed mothers had a significantly higher score of knowledge. Mothers with secondary education and university qualifications had significantly higher scores of practice compared with mothers with primary education. Conclusions: Although mothers had better than average knowledge and excellent attitude toward their children's oral health issues; most of them carried out improper practices. Mothers' educational and employment backgrounds were significant influencing factors. PMID- 29387612 TI - Expression of Vascular Endothelial-Cadherin in Mucoepidermoid Carcinoma: Role in Cancer Development. AB - Objectives: Mucoepidermoid carcinoma (MEC) accounts for 35% of all malignant salivary gland tumors. Previous investigations have shown that vasculogenic mimicry (VM) exists in many cancers which can be used as a prognostic factor of poor prognosis. Elevated expression level of vascular endothelial (VE)-cadherin has been implicated in cancer neovascularization, growth, and progression. The current study aimed to study the presence of VE-cadherin in VM channels and tumor cells in different grades of MEC. Materials and Methods: A total of 63 MEC samples (21 samples in each grade) were collected from the archive of pathology department of Besat Educational Hospital, Hamadan, Iran, from 2002 to 2016. Hematoxylin and eosin staining was performed to confirm the previous diagnosis. The specimens were then processed for immunohistochemistry analysis. Then, periodic acid-Schiff staining was performed. Analyses were conducted through SPSS software version 22.0 (SPSS, Inc., Chicago, IL, USA). Chi-square test was used to examine the differences between categorical variables. Significance level was set at 0.05. Pearson's correlation was used to assess the co-localization of the marker. Results: A total of 63 samples (35 men; 55.6%, and 28 women; 44.4%) were used for immunohistochemical study. There were statistically significant differences between tumor grade and the expression levels of VE-cadherin (P = 0.000), between tumor grade and VM formation (P = 0.000), and also between tumor grade and microvessel density (MVD) (P = 0.000). Additionally, there was a strong positive correlation between tumor grade and VE-cadherin expression level (Pearson's r = 0.875, P < 0.000). Conclusions: Our results may disclose a definite relationship between VE-cadherin expression level, VM, epithelial mesenchymal transition, cancer stem cells, and MVD in MEC samples. Thus, it is reasonable to suggest that VE-cadherin is related to angiogenesis and VM formation in MECs. PMID- 29387614 TI - Effectiveness of Intellectual Distraction on Gagging and Anxiety Management in Children: A Prospective Clinical Study. AB - Objectives: The aim of the present prospective study is to determine the effect of an intellectual colored game (ICG) on the severity of gag reflex (GR) and anxiety in children during dental alginate impression. Materials and Methods: Forty-one children, aging between 5 and 11 years, having a GR varying from normal to moderate had upper alginate impressions. The children's anxiety was evaluated with a facial image scale (FIS) before (T0) and after first failed impression (T1), then, after playing an intellectual colored game (ICG) at T2, while taking an upper alginate impression. Results: 42.9 % of the children had a gag reflex of stage 2 and 31.0 % a facial scale of 3. Initial GR was not significantly associated with the final success of the impression (P =0.260) whereas final impression success was strongly associated with FIS (P <0.001). There was a statistically significant reduction in median GR score from T0 to T2 (P < 0.001) and FIS dropped significantly at T2 with ICG (P < 0.001). Conclusion: This study highlights the clinical performance of the intellectual distraction approach in GR management. PMID- 29387615 TI - Orthodontics and Dental Anatomy: Three-dimensional Scanner Contribution. AB - Aims and Objectives: The objective of this article is to focus on the dental anatomy, its influence on therapeutic choices, and decision in orthodontics. Materials and Methods: A sample of 80 subjects was selected and analyzed. Through the usage of the three-dimensional scanner with the C2000-Cepha and Cepha3DT software, it is now possible to calculate the volume and the dimensions of both crown and root of each tooth and compare them to the literature. Data were collected and statistically evaluated with the StatView software (version 5.0). Results: These references values were compared with those known in the literature redefining our approaches to treatment in orthodontics. Conclusion: The individual anatomical data either unique or in a group of teeth give new insights on the orthodontic therapeutic options. PMID- 29387616 TI - Perception of Professional Female College Students Towards Smile arc Types and Outlook about their Appearance. AB - Aims and Objectives: The aim of this study is to assess the perception of female students about the type of smile arc as well as their outlook about different parameters of esthetics. Materials and Methods: A study was conducted among female students of King Khalid University, Abha, Saudi Arabia. One section of the questionnaire contained pictures having three types of smile arc wherein the respondents had to select any response ranging from 1 to 4 (1 for beautiful, 2 for good, 3 for average, and 4 for poor); besides it included 12 questions regarding the viewpoints of respondents about their smile and dental esthetics. The collected data were analyzed using the statistical package for social services version 16.0 (SPSS Inc., Chicago, IL, USA, 2001). Results: The dental students accounted for least mean score of 1.807 +/- 0.8174 for consonant smile arc while it was 2.692 +/- 0.8053 and 2.235 +/- 0.9074 for information technology (IT) and medical students, respectively. When the individuals were asked whether they had a pleasant smile or not; only 53.8% of the dental students, 76.9% of the IT students, and 66.7% of the medical students responded positively. Conclusion: It was concluded that most of the female dental students were able to identify the consonant smile arc as being more beautiful than the flat and reverse smile arcs whereas lesser medical and IT students could perceive the smile arcs in the same manner. It was also observed that almost all the study participants were quite conscious about their smile attractiveness and dental esthetics. PMID- 29387617 TI - The Effect of Health Education Program Based on Health Belief Model on Oral Health Behaviors in Pregnant Women of Fasa City, Fars Province, South of Iran. AB - Aims and Objectives: Pregnant women are at risk of dental caries and periodontal disease. The purpose of this study was to assess the effectiveness of health education program based on health belief model (HBM) on oral and dental hygiene behaviors in pregnant women in Fasa city. Materials and Methods: This is a clinical trial study carried out on 110 pregnant women selected using random sampling method from health centers in Fasa city in 2016 (55 patients in the experimental group and 55 individuals in control group). Data collection with questionnaire was based on construct HBM, as well as their performance about oral health. At first, two groups completed the questionnaires. And then, the intervention was conducted for the experimental group based on HBM. Four months after intervention, two groups completed the questionnaires twice. To analyze the collected data, the researchers used SPSS version 22 and descriptive and analytical statistics tests such as independent t-test and Chi-square and Mann Whitney test. Results: The age of the pregnant mothers was 28.25 +/- 3.02 years in the experimental group and 27.8 +/- 4.20 years in the control group. Compared to the control group, the experimental group showed a significant increase in their knowledge, perceived susceptibility, perceived severity, perceived benefits, self-efficacy, cues to action, and performance and decrease in perceived barriers 4 months after the intervention. Conclusion: Applying the HBM is very effective for developing an educational program for oral health in pregnant women. Moreover, in the implementation of these programs, control, monitoring, and follow-up educational are recommended. PMID- 29387618 TI - Fracture Resistance of Tilted Premolars Restored with Different Post-Core Systems. AB - Aims and Objective: To assess the effect of root tilt on the fracture resistance and failure pattern of endodontically-treated premolars restored with different post-core systems. Materials and Methods: Ninety endodontically-treated premolars were mounted in acrylic blocks with 0 degrees , 12 degrees , and 24 degrees axial root tilt. Teeth in each group were restored in three subgroups with cast post-core, readymade metal posts and composite cores, and fiber post and composite cores. Crowns of all teeth were prepared coinciding with the long axis of the acrylic blocks to receive all-ceramic crowns. All restored teeth were stressed to record the maximum load at failure and the associated failure pattern. The collected data were statistically analyzed using two-way ANOVA, Tukey's, and Kruskal-Wallis tests at alpha = 0.05 on past software to detect any differences between subgroups. Results: Analysis of the collected data indicated significant differences between the tested subgroups (ANOVA, P = 3.86). Further analysis showed significant difference between all test subgroups and the control (Tukey's, P < 0.05). In general, teeth with 0 degrees tilt seemed more resistant to fracture than the tilted ones. For all groups, teeth restored with fiber post and composite cores (SG3) were more resistant to fracture compared to other post core systems (SG1 and SG2) (Tukey's, P < 0.05). The root fracture was the most commonly seen mode of failure. Conclusions: Root tilting usually affects the fracture resistance of teeth restored with post-core systems. The fiber post and composite cores seemed to be the best choice to restore teeth with different root tilting possibilities. PMID- 29387619 TI - Factors Affecting the Survival Rate of Dental Implants: A Retrospective Study. AB - Aims and Objectives: Dental implants have emerged as new treatment modality for the majority of patients and are expected to play a significant role in oral rehabilitation in the future. The present study was conducted to assess various factors affecting the survival rate of dental implants. Materials and Methods: The present retrospective study was conducted in the Department of Prosthodontics. In this study, 5200 patients with dental implants which were placed during June 2008-April 2015 were included. Exclusion criteria were patients with hormonal imbalance, patients with chronic infectious disease, patients receiving immunosuppressive therapy, pregnant women, drug and alcohol addicts, and patients with severe periodontal diseases. Parameters such as name, age, gender, length of implant, diameter of implant, location of implant, and bone quality were recorded. Data were tabulated and statistically evaluated with IBM SPSS Statistics for Windows, Version 20.0., IBM Corp., Armonk, NY, USA. Results: Out of 5200 patients, 2800 were males and 2400 females. Maximum implants failures (55) were seen in age group above 60 years of age (males - 550, females 700). Age group <40 years (males - 750, females - 550) showed 20 failed implants. Age group 41-60 years (males - 1500, females - 1150) showed 45 failed implants. The difference was nonsignificant (P = 0.21). Maximum implant failure was seen in implants with length >11.5 mm (40/700) followed by implants with <10 mm (20/1650) and 10-11.5 mm (60/2850). The difference was significant (P < 0.05). Maximum implants failure (30/1000) was seen in implants with diameter <3.75 mm followed by implants with diameter >4.5 mm (16/1600) and implants with diameter 3.75-4.5 mm (50/2600). The Chi-square test showed significant results (P < 0.05). Mandibular posterior showed 3.3% implants failure, maxillary posterior revealed 2.2%, maxillary anterior showed 2.1%, and mandibular anterior showed 1% failure rate; this difference was significant (P < 0.05). Type I bone showed 0.3% implant failure, Type II showed 1.95%, Type III showed 3%, and Type IV revealed 0.8% failure rate; this difference was significant (P < 0.05). Conclusion: Age, length of implant, diameter of implant, bone quality, and region of implant are factors determining the survival rate of implants. We found that implant above 11.5 mm length, and with diameter <3.75 mm, placed in the mandibular posterior region, in Type III bone showed maximum failures. PMID- 29387620 TI - Comparative Evaluation of Fracture Resistance of Different Post Systems. AB - Aim: The study was done to evaluate the fracture resistance of carbon, glass fiber, and zirconia posts. Materials and Methods: Forty-five human premolars indicated for orthodontic extraction were subjected to root canal treatment and obturated with gutta-percha. All the teeth were decoronated and mounted in acrylic block. Then, teeth were equally divided into three groups: (a) carbon, (b) glass fiber, and (c) zirconia post group. Post space was prepared and particular post was cemented in post space. Core buildup was made with composite. A compressive load was applied using universal testing machine and fracture force was measured in MPa. The data were tabulated, and statistical evaluation was done using statistical software IBM SPSS Statistics for Windows, version 21.0., IBM Corp., Armonk, NY, USA, using one-way analysis of variance for analysis of difference and Bonferroni post hoc test. Results: Zirconia endodontic post had good fracture resistance (489.2 MPa) when compared with carbon (258.4 MPa) and glass fiber-reinforced post (348.7 MPa). Fracture resistance was statistically significant between test groups P>0.001. Conclusion: The present study concluded that zirconia had good fracture resistance compared to glass fiber and carbon posts. PMID- 29387621 TI - The Relationship between Number of Natural Teeth and Chewing Qat Habit among Adult Yemeni People in Sana'a: A Pilot Study. AB - Aims and Objectives: Several studies have reported associations between the habit of chewing qat and the deterioration of periodontal health among adults in Yemen; however, qat's effect on the number of teeth has not yet been evaluated. The purpose of this observational study was to examine the relationship between the number of natural teeth and qat-chewing status among Yemeni participants. Materials and Methods: The participants were interviewed with a structured questionnaire by a researcher on the day of the dental check-up. The surveyed items were age, sex, chewing-qat status (nonchewer; current chewer, nonsmoker; current chewer and smoker; current chewer, ex-smoker; ex-chewer, never smoked; ex chewer and smoker). The dental examination was conducted with dental mirrors by a single examiner under sufficient artificial light. A linear regression was performed, stratified by sex, with the number of natural teeth as the dependent variable and with age and qat status as independent variables using SAS/STAT software. Results: Results show that age was a significant factor for both males and females having few natural teeth. Females had a higher tooth loss than males. The habit of chewing qat did not affect the number of natural teeth for both males and females. In males, a small, but not significant, relationship between chewing-qat status and the number of natural teeth was found. All smokers were qat chewers. Conclusions: This study highlights for the first time the relationship between having fewer teeth and the habit of chewing qat and provides useful findings for dental health workers to advise people about the benefits of cessation of both qat chewing and smoking. PMID- 29387622 TI - Knowledge, Attitude, and Perceived Confidence in the Management of Medical Emergencies in the Dental Office: A Survey among the Dental Students and Interns. AB - Aims and Objectives: Many situations in the dental office can provoke medical emergencies. Lack of training and inability to overcome the medical emergencies can lead to serious consequences and legal actions. The aim of the study is to investigate and assess the knowledge, attitude, and perceived confidence of dental students and interns in the management of medical emergency. Materials and Methods: A self-administered structured questionnaire was distributed to 153 of the undergraduate dental students and interns in Qassim province. Questionnaire consisted of nineteen questions pertaining to knowledge and awareness regarding syncope, cardiopulmonary resuscitation (CPR), intravenous drugs, measuring vital signs, and handling situation of aspiration of a foreign body, bleeding, and choking. Data were analyzed by Statistical Package for Social Sciences (SPSS) version 21.0. Results: Fifty-seven percent was the response rate received from the questionnaire. Eighty-nine percent and 30% of the participants inquired about the medical history and vital signs before dental treatment, respectively. Only 37% of participants were confident to handle any medical emergency in the dental office. Seventy percent knew the correct location of chest compression and 67% were familiar about the right compression ventilation ratio showing significant difference between academic years and interns (P = 0.003). Females were significantly more aware about the management of bleeding after extraction than the males (65%, and 47%, respectively; P = 0.035). Thirty-five percent and 53% chose the correct management to relieve choking in responsive and unresponsive adult or child, respectively. A total of 28% of the participants reported syncope as the most common emergency situation. Conclusion: Participants were lacking confidence in handling medical emergencies even though the majority of them inquired the medical history. Most of them have a good knowledge regarding CPR, but regarding airway obstruction, the knowledge was not at an acceptable level. Annual basic life support and emergency courses should be mandatory in dental teaching curriculum. PMID- 29387623 TI - Effect of Popping Chocolate and Candy on Enamel Microhardness of Primary and Permanent Teeth. AB - Aims and Objectives: Dental erosion is a common disease in children. Food diets, due to high amounts of juice, soft drinks, chewing gum, and acidic chocolate, are one of the most important risk factors in erosive processes among children. The aim of this study was to evaluate the effect of candy and chocolate on the microhardness of tooth enamel. Materials and Methods: Two types of popping candy and one type of popping chocolate were used in this study. Thirty-three healthy permanent premolar teeth and 33 primary incisor teeth (A or B) were selected. Five grams of each popping chocolate or candy was dissolved with 2 ml of artificial saliva. Subsequently, their pH and titrable acidity (TA) as well as microhardness and surface roughness of enamel were examined in the laboratory. Data were analyzed and evaluated Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY through independent t-test, paired t-test, Tukey test, and ANOVA. Results: The results of this study showed that only the pH of the candies was below the critical pH of the enamel (5.5) and their TA was B = 0.20 and C = 0.21. The most significant effect on the enamel microhardness of the permanent and primary teeth was by the following types of candy: orange flavor (C), strawberry flavor (B), and chocolate (A), respectively. This difference was significant (P < 0.001) and the surface roughness increased after exposure. Conclusions: This study showed that popping chocolate and candy reduces microhardness of enamel. PMID- 29387624 TI - Pain Perception and Personality Trait toward Orthodontic Treatment. AB - Aim: The study was done to evaluate the pain perception, attitude, and personality trait of the patient toward orthodontic treatment. Materials and Methods: In this cross-sectional questionnaire survey, 100 patients were divided into Group 1, 150 (75 males and 75 females) as untreated group and Group 2, 150 as treated group (75 males and 75 females). Evaluation of the patients was done based on pain perception, attitude, and personality trait. Set of questionnaire was used to assess attitude and pain perception on visual analog scale. The data were tabulated, and statistical evaluation was done using statistical software IBM SPSS Statistics for Windows, (Version 21.0. Armonk, NY: IBM Corp.) using t test and Tukey's test. Results: The mean pain perception for Group 1 was 4.8 +/- 1.30 and 4.17 +/- 1.58 in Group 2; the difference was not statistically significant (P = 0.26). The mean value for attitude in Group 1 was 3.57 +/- 1.21, and in Group 2, it was 3.39 +/- 1.60 (P = 0.09). There was statistically significant difference in pain perception between low (L) level to high level (H) neuroticism (P = 0.009). There was significant difference (P = 0.021) in pain for conscientiousness from very low to very high levels which is directly proportional. Conclusion: The present study indicated that attitude, personality traits, and pain perception have a definite role in patient cooperation and success of orthodontic treatment. PMID- 29387625 TI - Knowledge, Attitude, and Awareness among Diabetic Patients in Davangere about the Association between Diabetes and Periodontal Disease. AB - Objective: Diabetes mellitus (DM) is one of the major public health problems. Association of diabetes and periodontitis is widely proven and can influence each other in the development and progression of the disease and its complications, which are largely preventable. Hence, if data could be collected on the knowledge and awareness about the association between DM and periodontal disease, the results could be applied in creating public health campaigns and can bring about lifestyle modification among people. The aim of the present study is to assess the awareness, attitude, and practices of diabetic patients regarding their periodontal health in Davangere city with the objective of enhancing dental health education for this population, which would upgrade their knowledge and awareness. Materials and Methods: The present cross-sectional survey was carried out on 600 diabetic patients from various clinics. A time limit of 3 months was set for the data collection which was then subjected to statistical software SAS 9.2, SPSS 15.0, Stata 10.1, MedCalc 9.0.1, Systat 12.0, and R environment version 2.11.1 for statistical analysis. Results: On correlation of gender and education with overall knowledge of association between periodontal disease and DM, females and participants below secondary school education and lower duration of DM were significantly associated with lack of knowledge. Other questions revealed limited awareness, sources, and need for more information about this association and depicted poor knowledge and attitude toward the oral health. Conclusion: Dental professionals need to create awareness about the importance of maintaining good oral health influencing overall general health in diabetic patients. Oral screening and referral by health professionals to dentists may benefit diabetic patients by improving access to dental care. PMID- 29387626 TI - Clinical Results of the Intra-Arterial Thrombolysis with Stent Retriever Device Weather Perfusion Diffusion Mismatching and Intravenous Tissue Plasminogen Activator Administration. AB - Objective: Intraarterial thrombolysis (IA-Tx) with stent retriever is accepted as an additional treatment for selected patients and the clinical benefit is well reported. Each intravenous tissue plasminogen activator administration (IV-tPA) and perfusion diffusion mismatching (P/D-mismatching) is well known the beneficial effects for recanalization and clinical outcomes. In this report, authors analyzed the clinical outcomes of additional IA-Tx with retrieval stent device, according to the combined IV-tPA and P/D-mismatching or not. Methods: Eighty-one treated IA-Tx with the Solitaire stent retriever device, diagnosed as anterior circulation larger vessel occlusion were included in this study. Computed tomography-angiography (CTA) was done as an initial diagnostic image and acute stroke magnetic resonance image (MRI) followed after the IV-tPA. Forty-two patients were in the tPA group and 39 patients were in the non-tPA group. Recanalization rate, clinically significant hemorrhagic (sICH) and clinical outcomes were recorded according to the IV-tPA and P/D-mismatching. Results: Recanalization rate was 81.0% in IV-tPA group, and it was 69.2% in non-tPA group (p = 0.017). While sICH were 19.9% and 25.6%, respectively (p = 0.328). Neurologic outcomes did not influence by IV-tPA administration or not. But according to the P/D-mismatching, the recanalization rate and sICH were 91.9% and 16.7% in the mismatched group and 46.7% and 46.7% in the matched group (p = 0.008 and p = 0.019, respectively). Conclusion: For patients treated with IA-Tx with retrieval stent, IV-tPA infusion does not influence on the sICH, recanalization rate and neurologic outcomes. But P/D-mismatching was correlated well with sICH, recanalization rate and clinical outcomes. PMID- 29387627 TI - Endovascular Treatments for Ruptured Intracranial Vertebral Artery Dissecting Aneurysms: Experience in 16 Patients. AB - Objective: Intracranial vertebral artery dissecting aneurysms are rare lesions that are considered an important cause of spontaneous subarachnoid hemorrhage. We report our decade-long experience in treating ruptured intracranial vertebral artery dissecting aneurysms. Materials and Methods: This retrospective single center study included 21 consecutive patients between February 2005 and March 2015. Their clinical features included radiologic finding at the initial examination, treatment modality, functional outcome at the last follow-up, mortality, and radiologic outcome at more than 6 months after the initial treatment. Results: All 16 aneurysms were treated endovascularly; aneurysm trapping was performed in 9 patients and vascular reconstruction was performed in 7 patients. For 6 aneurysms involving the posterior inferior cerebellar artery (PICA), the modalities of treatment were aneurysm trapping in 3 patients and vascular reconstruction in 3 patients. The mean duration of follow-up was 29 months (range, 6-70 months). Five patients expired, indicating a mortality rate of 31%. In surviving patients, the unfavorable outcome rate (modified Rankin Scale [mRS] > 2) was 36%. The overall mean mRS for survivors was 1.8. Angiographic follow-up in 11 survivors at 13 months, (range, 6-46 months) revealed recanalization of the aneurysm in one patient. Conclusions: Ruptured intracranial vertebral artery dissecting aneurysm is associated with poor functional outcome and high mortality. More immediate treatments are needed due to the high rebleeding rate in this disease condition. Endovascular treatment may be a useful option for ruptured intracranial vertebral artery dissecting aneurysms. PMID- 29387628 TI - Prepuncture Ultrasound Examination Facilitates Safe and Accurate Common Femoral Artery Access for Transfemoral Cerebral Angiography. AB - Objective: We aimed to introduce our method involving prepuncture ultrasound scan for cannulation of the common femoral artery (CFA) during transfemoral cerebral angiography (TFCA), and to assess the clinical and radiological outcomes. Material and Methods: Our study included 90 patients who underwent prepuncture ultrasound examination of the inguinal area for TFCA between April 2015 and June 2015. Prior to skin preparation and draping of the inguinal area, we identified the CFA and its bifurcation using ultrasound. Based on the ultrasound findings, we marked cruciate lines in the inguinal area. Thereafter, we inserted a puncture needle at the interface between the horizontal and vertical lines at a 30-45 degrees angle, simultaneously palpating the pulsation of the femoral artery. After TFCA was completed, femoral artery angiography was performed in the anteroposterior and oblique directions. Clinical and radiological parameters, including CFA cannulation, the ultrasound scan time, the first pass success rate, the time required for the passage of the wire, and complications, were evaluated. Results: The mean ultrasound scan time of the CFA and its bifurcation was 72.6 seconds, and the mean time between administration of local anesthesia and wire passage was 67.44 seconds. The first pass success rate was 77.8% (70/90 patients), and the CFA puncture rate was 98.8% (89/90 patients). Although minor complications were noted in 7 patients, no patient reported serious complications (a large hematoma [>= 5 cm], pseudoaneurysms, dissection, and/or a retroperitoneal hematoma.). Conclusion: Prepuncture ultrasound examination might be a simple, safe, and accurate technique for cannulation of the CFA during TFCA. PMID- 29387629 TI - Tentorial Dural Arteriovenous Fistulas: A Single-Center Cohort of 12 Patients. AB - Objective: Tentorial dural arteriovenous fistulas usually drain into cortical veins and often present with hemorrhage. Treatment goal is occlusion of the draining vein, either by surgery or endovascular techniques. We present the multimodality treatment results of 12 patients with tentorial dural arteriovenous fistulas. Materials and Methods: Between January 2007 and January 2017, 12 consecutive patients with tentorial dural arteriovenous fistulas were treated. There were 11 men and 1 woman with a mean age of 62 years (range 44-85). Clinical presentation was hemorrhage in 8 (67%), pulsatile tinnitus in 2 (17%) and an incidental finding in 2 (17%). The fistula location was at the tentorium cerebelli in 5 (42%), the torcula Herophilii in 4 (33%) and petroclival in 3 (25%). Results: In 11 patients, arterial embolization with Onyx or PHIL was the primary treatment. Complete obliteration was achieved in one session in 5 (45%) and in 2 sessions in 4 (36%). In 2 patients additional surgery was needed. Primary surgery was performed in 1 patient followed by endovascular coil occlusion via the venous route. One patient with exclusive pial feeders from the posterior inferior cerebellar artery had a clinically silent P3 occlusion during trans arterial embolization. Finally, all 12 fistula were completely occluded, confirmed with angiography after 8-12 weeks. There were no permanent procedural complications. Conclusion: Patients with tentorial dural arteriovenous fistulas were effectively and safely cured with a strategy of endovascular treatment with various techniques and surgery. Surgical and endovascular techniques are complementary in the treatment of these challenging vascular disorders. PMID- 29387630 TI - Usefulness of Plaque Magnetic Resonance Imaging in Identifying High-Risk Carotid Plaques Irrespective of the Degree of Stenosis. AB - Objective: Measurement of the degree of stenosis is not enough to decide on the treatment strategy for patients with carotid stenosis. Plaque morphology examination is needed for such a decision-making. Thus, we evaluated the usefulness of plaque magnetic resonance imaging (MRI) to decide on the modality of treatment for patients with carotid atherosclerotic plaques. Materials and Methods: Fifteen patients presenting with carotid stenosis between 2014 and 2016 were included. They underwent angiography for measurement of the degree of stenosis. Carotid plaques were visualized using MRI. Results: There were six (40%) stable and nine (60%) unstable plaques. Seven symptomatic patients (77.7%) had unstable lesions and two symptomatic patients (33.3%) had stable lesions (p = 0.096). There were six (40%) intraplaque hemorrhage (IPH) cases. There were six symptomatic patients (100%) in the IPH group and three symptomatic patients (33.3%) in the non-IPH group (p = 0.013). The mean stenosis degree was 58.9% in the IPH group and 70.4% in the non-IPH group (p = 0.094). Symptoms occurred irrespective of the degree of the stenosis in the IPH groups. In the IPH group, the recurrent ischemic cerebrovascular event rate was 33.3%. Particularly, the recurrent ischemic cerebrovascular event rate was 66.7% in the IPH group with mild stenosis treated with medications. Conclusion: IPH in plaque MRI is significantly associated with ischemic symptoms and has a high risk for subsequent ischemic cerebrovascular events irrespective of the degree of stenosis. Plaque MRI is a useful tool in predicting symptomatic risks for carotid stenosis irrespective of the degree of such stenosis. PMID- 29387631 TI - Dengue Virus Capsid Interacts with DDX3X-A Potential Mechanism for Suppression of Antiviral Functions in Dengue Infection. AB - Dengue virus is a pathogen of global concern and has a huge impact on public health system in low- and middle-income countries. The capsid protein of dengue virus is least conserved among related flavivirus and there is very limited information on the role of cytosolic proteins that interact with dengue virus capsid. We identified DEAD (Asp-Glu-Ala-Asp) Box Helicase 3, an X-Linked (DDX3X), cytosolic ATP-dependent RNA helicase as a dengue virus capsid-interacting protein. We show that the N-terminal region of capsid is important for interaction with DDX3X, while the N-terminal domain of DDX3X seems to be involved in interaction with dengue capsid. DDX3X was down-regulated in dengue virus infected cells at later stages of infection. Our results show that DDX3X is an antiviral protein as suppression of DDX3X expression by siRNA led to an increase in viral titers and overexpression of DDX3X led to inhibition of viral replication. Knock-down of DDX3X did not affect induction of type I interferon response upon infection suggesting that the effect of DDX3X knock-down is independent of the interferon-dependent pathways that DDX3X modulates under normal conditions. Thus, our study identifies DDX3X as a dengue virus capsid interacting protein and indicates a potential link between the antiviral functions of DDX3X and dengue capsid at later stages of dengue infection. PMID- 29387632 TI - I performed experiments and I have results. Wow, and now? AB - : Writing a scientific article is not an easy task, but it is definitely a great satisfaction to be able to conclude and publish it. Indeed, each publication is a service we make to the entire scientific community and to the advancement of science even before our personal career. There is and there will not be a final book/article for writing a scientific paper. Therefore, some knowledge is a decisive factor to increase the chances of our work being accepted by a specialized scientific journal. The purpose of this editorial is to trace an ideal path, based on our personal experience, useful to properly structure a scientific article, from bibliographic research to cover letter. Articles should not be written in a polished way to gratify one's own ego, but they must be written for anyone who can read and understand them. Level of evidence: V. PMID- 29387633 TI - Spheroid formation and modulation of tenocyte-specific gene expression under simulated microgravity. AB - Background: For tendon tissue engineering, tenocyte-seeded scaffolds are a promising approach. Under conventional 2D culture however, tenocytes show rapid senescene and phenotype loss. We hypothesized that phenotype loss could be counteracted by simulated microgravity conditions. Methods: Human tenocytes were exposed to microgravity for 9 days on a Random Positioning Machine (RPM). Formation of 3D-structures (spheroids) was observed under light microscopy, gene expression was measured by real-time PCR. Cells under conventional 2D-culture served as control group. Results: Simulated microgravity reached a value of as low as 0.003g. Spheroid formation was observed after 4 days, and spheroids showed stable existance to the end of the observation period. After 9 days, spheroids showed a significantly higher gene expression of collagen 1 (Col1A1) compared to adherent cells under microgravity (4.4x, p=0.04) and compared to the control group (5.6x, p=0.02). Gene expression of collagen 3 (COL3A1) was significantly increased in spheroids compared to the control group (2.3x, p=0.03). Gene expressions of the extracellular matrix genes Tenascin C und Fibronectin (TNC and FN) were increased in adherent cells under microgravity compared to the 1g control group, not reaching statistical significance (p=0.1 and p=0.3). For the gene expression of vimentin, no significant alteration was observed both in the adherent cells and in the spheroids compared to the 1g control group. Gene expression of the tenocyte-specific transcription factor scleraxis (SCX) was significantly increased in spheroids compared to the control group (3.7x, p=0.03). Conclusion: Simulated microgravity could counteract tenocyte senescence in vitro and serve as a promising model for scaffold-free 3D cell culturing and tissue engineering. Level of evidence: V (laboratory study). PMID- 29387634 TI - Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression. AB - Background: The skeletal muscle toxicity that accompanies the chemotherapy drug doxorubicin (DOX) may lead to cancer patient weakness and fatigue. This myotoxicity involves myogenic regulatory factor (MRF) disruption which alters muscle integrity and regeneration. Endurance exercise enhances MRF expression and thereby may mitigate DOX-induced MRF disruptions. This study examined the effects of endurance training and DOX treatment on myogenic regulatory factor (MRF) expression. Methods: Male rats were exercise trained (EXER) or remained sedentary (SED) for two weeks. EXER and SED then received either DOX (15 mg/kg) or saline (SAL). Soleus, extensor digitorum longus (EDL), and diaphragm were excised 24 hours post injection, and MRF expression was analyzed. Results: Significant Myf5 drug and activity effects were observed in the soleus with EXER+DOX expressing higher Myf5 than SED+DOX. A significant drug effect was detected in soleus MyoD, and a significant activity effect was detected in soleus Mrf4. No main effects or interactions were observed in the EDL, but in the diaphragm, a significant activity effect was observed for Myf5 with EXER+DOX expressing higher levels than SED+DOX. Conclusion: Doxorubicin treatment increased soleus MRFs and exercise boosted MRF response in soleus and diaphragm suggesting that exercise may enhance regenerative signaling with DOX treatment. Level of evidence: I b, individual randomized controlled trial. PMID- 29387635 TI - The effect of intra-articular allogenic platelet rich plasma in Dunkin-Hartley guinea pig model of knee osteoarthritis. AB - Objectives: To investigate the pathway for disease modifying effect of the PRP in osteoarthritis of knee. Design: Two experimental models (group I and II) of Twelve Dunkin-Hartley guinea pigs each were enrolled as a part of a prospective controlled experimental study. One knee was enrolled for intervention and the other knee of the same animal used as control, the intervention being three intra articular allogenic PRP injections given at a weekly interval. Equal volume of isotonic saline injection were given simultaneously in the control knees. Six animals from each model (subgroup IA, IIA) were euthanized at three months and the remaining six (subgroup IB, IIB) at six months post intervention. Samples of synovial fluid were collected from each knee joint for COMP level analysis by ELISA and bilateral knee joints were harvested for histopathological assessment of articular cartilage and synovium at the time of euthanasia. Results: Mean synovial fluid COMP concentration was significantly lower in PRP treated knees (p<0.05) at three months. On histological examination mean synovitis scores and synovial vascularity were significantly lower in PRP treated knees as compared to controls at both three and six months (p < 0.05). Additionally mean articular cartilage degeneration was significantly lower in PRP treated knees in group 1 only (p<0.05). Conclusion: Our preliminary data from the study has shown some evidence of positive influence of PRP in knee OA, possibly due to its anti inflammatory effect and disease modifying effect, shown by short-term chondro protective effect in PRP injected knees. Level of evidence: V. PMID- 29387636 TI - The time has come to incorporate a greater focus on rate of force development training in the sports injury rehabilitation process. AB - : This narrative and literature review discusses the relevance of Rate of Force Development (RFD) (the slope of the force time curve) for Return To Sport (RTS), its determinants and the influence of training practices on it expression, with the purpose to enhance clinicians' awareness of how RFD training may enhance RTS success. RFD is considered functionally more relevant than maximal muscle strength during certain very fast actions including rapid joint stabilisation following mechanical perturbation. Deficits in RFD are reported following conventional rehabilitation programmes despite full restoration of maximal strength, which may contribute to the less than satisfactory RTS outcomes reported in the literature. RFD determinants vary as a function of time from force onset with a diminishing role of maximal strength as the time available for force development decreases. Factors such as neural activation, fibre type composition and muscle contractile properties influence RFD also and to a much greater extent during the early periods of rapid force development. Conventional resistance training using moderate loads typical of most rehabilitation programmes is insufficient at restoring or enhancing RFD, thus incorporating periodised resistance training programmes and explosive training techniques in the final stages of rehabilitation prior to RTS is recommended. Level of evidence: V. PMID- 29387637 TI - Three-dimensional architecture of the ligamentum teres in the human hip joint. AB - Background: We aimed to investigate the three-dimensional structure of the collagenous fibers of the ligamentum teres (LT) of the human hip and clarify the LT micro-anatomy at the attachment of the femoral head. Methods: Femoral heads and LT were collected during hip arthroplasty. Specimens were cut into 5-10-mm squares, prepared, developed, and observed under a light microscope. Next, specimens were prepared and examined under a scanning electron microscope (SEM). Results: Under optical microscope, LT adhered to the artificial cartilage at the attachment of the femoral head. Under SEM, LT comprised parallelly arranged collagenous fibers and the fine collagenous fibrils were twisted. While the central collagenous fibers of the LT at the attachment of the femoral head penetrated the articular cartilage tissue and reached the ring-shaped bone, fibers at the margin traversed and adhered to the cartilage surface. Conclusion: Articular cartilage and subchondral bone are present at the LT attachment to the femoral head. Although collagenous fibers of the LT show parallel arrangement at the main trunk, they are dispersed at the cartilage surface and not all reach the thin subchondral bone of the femoral head. This could possibly weaken ligament strength at the attachment of the femoral head. Level of evidence: IV. PMID- 29387638 TI - Quantitative analysis of patellar tendon size and structure in asymptomatic professional players: sonographic study. AB - Background: Ultrasonographic abnormalities of the patellar tendon frequently occur in asymptomatic athletes and it is not always clear whether they precede (and may predict) the development of tendinopathy. Objective: This study aimed to investigate by ultrasonography the prevalence of patellar tendon abnormalities in players of "pallapugno" and to establish whether structural tendon abnormalities predict tendinopathy development. Methods: Ultrasound B-mode images of the patellar tendon of both sides were acquired in fourteen throwers. Qualitative assessments of tendon structure and neovascularization and quantitative assessments of tendon thickness, cross sectional area (CSA), and echo-intensity were performed. Results: Qualitative assessments showed a subclinical tendinopathy of the non-dominant tendon in 5 out of 14 throwers (35% of cases), while quantitative assessments showed abnormalities of the non-dominant tendon in 8 out of 14 players (57% of cases). Echo-intensity and CSA were the quantitative variables most discriminant between asymptomatic players without structural tendon abnormalities and those with tendon abnormalities. Two players (2 out of 8 cases: 25%) developed a clinical tendinopathy after a follow-up of six months. Conclusion: The prevalence of subclinical tendinopathy in the non-dominant patellar tendon of throwers was high. Patellar tendon abnormalities at baseline seem to increase the risk of development of subsequent patellar tendinopathy. Level of evidence: II b (individual cohort study). PMID- 29387639 TI - Prevalence, techniques and knowledge of rapid weight loss amongst adult british judo athletes: a questionnaire based study. AB - Background: No investigation has analysed the RWL approaches since new rules by the International Judo Federation (IJF) regarding weigh-ins have been implemented in international competitions in 2014. The current study analyses the prevalence, most common methods and knowledge surrounding the effects of rapid weight loss (RWL) amongst adult UK judo athletes. Additionally, it examines differences in rapid weight loss behaviour (RWLB) between gender, weight-class, competitive level, age RWL began and "high"/"low" knowledge athletes. Methods: A previously validated questionnaire developed to assess RWL in judo athletes was modified by adding a knowledge section and revalidated for content. The questionnaire provided a RWLB score (higher score equated to more aggressive RWL) and a knowledge score (out of 10). 256 athletes (189 males and 66 females, aged 18-67 years) completed the questionnaire between February and April 2015. Unpaired t test, one-way ANOVA-tests and Chi-squared tests were used to test differences of mean RWLB scores and prevalence between groups. Results: The prevalence of RWL was 84%. The most common methods of RWL were increased exercise and decreased food/fluid intake. The mean knowledge score was 6.2+/-2.8, with most incorrect answers regarding physiological effects of RWL. No significant differences in RWLB scores were found between gender, "high"/"low" knowledge athletes or weight classes. Statistically significant differences in RWLB scores were found between different competitive levels (p=0.014) and age RWL began (p<0.01) in males but not in females. Conclusion: RWL is highly prevalent in the UK adult judo population and athletes have moderate knowledge surrounding its effects. In males, RWLB is most aggressive in elite level athletes and those that began RWL at a younger age. Therefore, updated rulings to target elite and youth level athletes should be implemented to reduce dangerous RWL. Level of evidence: IV. PMID- 29387641 TI - MRI evaluation to predict tendon size for knee ligament reconstruction. AB - Background: The aim of this study is to evaluate a possible correlation between specific anthropometric parameters and sizes of knee tendons commonly used for ACL reconstruction. We hypothesized that specific clinical and radiological knee measurements could be better tendon sizes predictors than age, gender, height and weight. Materials and methods: 100 consecutive patients were enrolled and 77 patients met the inclusion criteria of the study. All patients underwent a MRI of the knee with a 1.5 T super conducting MR System. For each patient, anthropometric data such as gender, height, weight, body mass index (BMI) and knee circumference were recorded. Specific MRI knee measurements were performed on each study: patellar tendon (PT) thickness and length, quadriceps tendon (QT) thickness, semitendinosus tendon (ST) diameter, gracilis tendon (GR) diameter, the largest patella and intercondylar width. Results: The mean ST diameter, QT thickness and PT thickness were higher in males than in females. No significant differences were noted between males and females concerning GT diameter and the knee circumference. In addition, male knees had greater patellar and intercondylar width than female knees. Significant, but only weak correlations were found between patient anthropometric data and hamstrings diameter, PT length, and QT and PT thickness. Intercondylar and patellar width present a moderate correlation between PT thickness, PT length and ST diameter. Conclusion: The intercondylar and patellar width presented a moderate correlation with PT thickness, PT length and ST diameter. Further, weak correlations were found between patient anthropometric data (gender, weight, height, BMI) and GR and ST diameter, PT length, and QT and PT thickness. This results may help surgeons during preoperative planning, specifically regarding graft choice and size. Level of evidence: III. PMID- 29387640 TI - Real-time sonoelastography: principles and clinical applications in tendon disorders. A systematic review. AB - Background: Sonoelastography (SE) is a new ultrasound-based method adopted in an increased number of scientific reports to analyse normal and pathological tendons. The aim of this study is to provide a systematic overview of clinical applications of SE in normal and pathological tendons. Methods: A systematic research of PubMed, Ovid, and Cochrane Library electronic databases was performed according to PRISMA guideline. Two Authors searched and evaluated the articles independently; a third Author was involved to solve any disagreement. The Oxford Level of Evidence (LoE) was used to assess each article. Results: There is an increasing interest in the application of SE in the evaluation of healthy and diseased tendons. Many different tendons are amenable for SE evaluation, such as the Achilles and patellar tendons, rotator cuff, common extensor tendons, quadriceps tendon, and the plantar fascia. Conclusion: SE appears to be a very useful diagnostic tool, in particular in tendon pathology. This is a dynamic examination, provides an immediate evaluation of the tissue elasticity, and may be useful in recognizing tendon abnormalities and in implementing the information available with conventional US. Level of evidence: IV. PMID- 29387642 TI - Ultrasonographic assessment of the anterolateral ligament of the knee in healthy subjects. AB - Objective: The aim of our study was to determine inter-observer agreement in the ultrasonographic identification of the anterolateral ligament (ALL) and in the evaluation of its length and thickness in healthy subjects. Methods: 80 healthy volunteers (160 knees) (42 males and 38 females) were enrolled in the study. All subjects underwent ultrasound (US) examination of both knees, performed by two physicians with over ten years of musculoskeletal US experience. In order to keep the ALL under optimal tension, the knee was flexed at approximately 30-35 degrees , slightly internally rotated and length and thickness of the ligament were measured. Results: ALL was identified in 93.8% (150 out of 160) and in 92.5% (148 out of 160) of the knees by Evaluator 1 and Evaluator 2, respectively. Interobserver agreement was substantial to almost perfect for the visualization of the ALL ( =0.90) and for measurements of its length (ICC = 0.83), and strong for measurements of its thickness (ICC = 0.75). Conclusion: In our study on healthy subjects, ALL has been visualized with a high rate of reproducibility. Further studies are needed to see if US may be a reliable and reproducible diagnostic tool in patients with traumatic or degenerative knee disorders. Level of evidence: II, evidence obtained from cohort study. PMID- 29387643 TI - Correlation between time from injury to surgery and the prevalence of ramp and hidden lesions during anterior cruciate ligament reconstruction. A new diagnostic algorithm. AB - Background: Anterior cruciate ligament tears (ACL) are associated with meniscal lesions, that could involve the posterior horn of the medial meniscus (PHMM). A variety of techniques has been proposed to better visualise the postero-medial (PM) compartment. The aim of the study is to evaluate the prevalence of longitudinal tears of peripheral attachment of the PHMM during arthroscopic ACL reconstruction, and to describe a diagnostic algorithm. Methods: 115 patients who underwent arthroscopic ACL reconstruction were enrolled for the study. An anterior and an intercondylar notch visualisation were ordinarily performed. A postero-medial (PM) portal was performed when the instability of the posterior horn was detected. Statistical significance was assessed by a Chi-squared or Fisher's Exact Test for categorical variables, and by a Mann-Whitney U test for continuous variables. Results: We recorded a 9.6% prevalence of lesions of the peripheral attachment of PHMM. Nine ramp lesions and two hidden lesions were diagnosed. Patients treated within 6 months from injury, revealed a statistically significant correlation with a higher prevalence of these lesions. Conclusion: Ramp and hidden lesions are very common ACL rupture associated injuries. Our diagnostic algorithm is a valid and safe option to diagnose these kinds of lesions. A correlation between a longer time from injury than 6 months and a reduced prevalence of these lesions was recorded in our population. Level of evidence: IV. PMID- 29387644 TI - Evaluation of the isokinetic muscle function, postural control and plantar pressure distribution in capoeira players: a cross-sectional study. AB - Background: Capoeira is a cultural practice with Brazilian roots that combines several elements including dance, fighting and body rhythm. Because of the diverse elements involved in its practice, capoeira is excellent at developing the physical and social abilities of its players. The aim of this study was to compare the biomechanical profile of muscle strength, plantar pressure distribution, and postural balance between players and non-players of capoeira. Methods: We evaluated 51 subjects who were allocated into two groups: capoeira group and control group. Subjects were evaluated using a baropodometer (Diasu(r)) and an isokinetic dynamometer (Biodex(r)). Results: When comparing plantar pressure distribution between groups and limbs, there were significant differences in mean load of forefoot (p=0.008) and total load (p=0.001). There were no significant differences between groups and limbs in balance and muscle strength; however, a significant difference was found in quadriceps torque peak (p=0.001) and agonist/antagonist ratio (p=0.001) when comparing these variables between the groups. Conclusion: Capoeira players displayed a tendency to have an asymmetric profile in plantar pressure distribution. No difference was found in balance between groups. Despite the fact that capoeira players showed increased strength of the quadriceps muscle, their agonist/antagonist ratio was more asymmetrical than the control group. Level of evidence: IV. PMID- 29387646 TI - Assessment of patient functional performance in different knee arthroplasty designs during unconstrained squat. AB - Background: In this paper, squat named by Authors unconstrained because performed without constrains related to feet position, speed, knee maximum angle to be reached, was tested as motor task revealing differences in functional performance after knee arthroplasty. It involves large joints ranges of motion, does not compromise joint safety and requires accurate control strategies to maintain balance. Methods: Motion capture techniques were used to study squat on a healthy control group (CTR) and on three groups, each characterised by a specific knee arthroplasty design: a Total Knee Arthroplasty (TKA), a Mobile Bearing and a Fixed Bearing Unicompartmental Knee Arthroplasty (respectively MBUA and FBUA). Squat was analysed during descent, maintenance and ascent phase and described by speed, angular kinematics of lower and upper body, the Center of Pressure (CoP) trajectory and muscle activation timing of quadriceps and biceps femoris. Results: Compared to CTR, for TKA and MBUA knee maximum flexion was lower, vertical speed during descent and ascent reduced and the duration of whole movement was longer. CoP mean distance was higher for all arthroplasty groups during descent as higher was, CoP mean velocity for MBUA and TKA during ascent and descent. Conclusions: Unconstrained squat is able to reveal differences in the functional performance among control and arthroplasty groups and between different arthroplasty designs. Considering the similarity index calculated for the variables showing statistically significance, FBUA performance appears to be closest to that of the CTR group. Level of evidence: III a. PMID- 29387645 TI - Clinical evidence of traditional vs fast track recovery methodologies after total arthroplasty for osteoarthritic knee treatment. A retrospective observational study. AB - Background: During the last years, programs to enhance postoperative recovery and decrease morbidity after total knee arthroplasty, have been developed across a variety of surgical procedures and referred to as "Fast-Track Surgery". In this study we aimed to find some answers in the management of osteoarthritic patients subjected to total knee arthroplasty, by using the Fast-Track methodology. To this purpose we evaluated parameters such as early mobilization of patients, better pain management, bleeding, possible complications, reduced hospitalization time, an overall improved recovery and patient satisfaction. Methods: 132 patients were selected, of which, 95 treated with "Fast Track" method and 37 treated with traditional method (control group). All the patients were hospitalized and underwent the same rehabilitation program for the first three days after surgery. Results: In both groups, the parameters of pain and deformity demonstrated the most rapid improvement, while those of function and movement were normalized as gradual and progressive improvement over the next 2 months. The different functional test used (Barthel, MRC, VAS) showed that the mean values were significantly greater in Fast Track group when compared to the control. Conclusion: The results of the study confirm that the application of the Fast Track protocol in orthopaedics after total knee replacement results in rapid post-surgery recovery. Level of evidence: IV. Case series, low-quality cohort or case-control studies. PMID- 29387647 TI - Orthopaedics injuries in male professional football players in Brazil: a prospective comparison between two divisions. AB - Background: Football is a high-speed contact sport and the risk of injury is high. The objective of this study was to compare the two main divisions (A1 and A2) of the Sao Paulo Football Championship and to perform a correlation analysis of the variables studied. Methods: A prospective study was conducted using an electronic questionnaire previously developed by the Medical Committee of the Sao Paulo Football Federation. The questionnaire was sent to the doctors of the teams playing in the A1 and A2 divisions of the Sao Paulo Football Championship after each round. Setting: 2016 Sao Paulo Football Championship. Results: The comparison of divisions A1 and A2 showed few significant differences among the various variables analysed in this study. The only significant differences were for right-side involvement in division A1 (p=0.044) and morning matches in division A2 (p<0.001). The correlation analysis of the variables studied showed expected associations, including sprains with a higher rate of need for surgery, ultrasound with muscle strains and moderate severity (8-28 days lost) with muscle strains. Conclusion: Despite the differences between the two divisions regarding budgets and team characteristics, there was a little difference in the variables analysed and there were associations such as sprains with a higher rate of need for surgery, ultrasound with muscle strains and moderate severity (8-28 days lost) with muscle strains. Level of evidence: II b, individual cohort study. PMID- 29387648 TI - Early radiographic and clinical outcomes of minimally displaced proximal fifth metatarsal fractures: cast vs functional bandage. AB - Background: The purpose of this non-randomized retrospective study was to investigate outcomes of minimally displaced, proximal 5MTB fractures, treated by a below-knee walking cast or a functional elasticated bandage with a support of a flat hard-soled shoe. Methods: A consecutive patient series was divided into two groups: the cast group (CG) and the functional group (FG). The subjects were radiologically and clinically evaluated according to Mehlhorn and Lawrence-Botte classification, and AOFAS Midfoot score, respectively. Results: 154 patients were followed up for a median of 15 months (range 12-24). There was no significant difference (p > 0.05) among the outcomes of each fracture pattern regarding the treatment choice. However, an earlier return to sports was noted in the FG, while Type-3 fractures achieved the worst results. Conclusion: Type-1 and 2 minimally displaced 5MTB proximal fractures can be successfully treated conservatively without weight-bearing restriction and without benefit of a cast with respect to a functional elasticated bandage. Level of clinical evidence: level III retrospective comparative study. PMID- 29387649 TI - Side-to-side differences in Achilles tendon geometry and mechanical properties following achilles tendon rupture. AB - Background: Recovery of tendon structure has been suggested to play a role in clinical success following Achilles tendon rupture. The purpose of this study was to identify side-to-side differences in tendon geometry and mechanical properties following Achilles tendon rupture and investigate the relationship of tendon structure with clinical outcomes. Methods: Participants within 1 year post complete rupture were included. Tendon geometry and mechanical properties were quantified using B-mode ultrasound imaging and continuous shear wave elastography (cSWE). Clinical outcomes included the heel-rise test. Participant self-reported function was measured using the Achilles tendon Total Rupture Score, Foot and Ankle Outcome Score - quality of life subscale, and the Physical Activity Scale. Results: Twenty participants [mean (SD) age: 42.7(13.6) years, 13 managed surgically] were included. Tendon thickness was greater on the ruptured side (p <0.001) [median (IQR) rupture: 1.38(1.21-1.56) cm, non-rupture: 0.49(0.40-0.52)]. Tendon length to the gastrocnemius was longer (p <0.001) on ruptured [22.8 (21.71 24.31) cm] than non-ruptured [21.66(20.74-23.62) cm] sides. Viscosity was lower on the ruptured side (p <0.001) [median (IQR) rupture: 37.7(30.6-43.3) Pa*s, non rupture: 53.5(48.4-59.6) Pa*s]. Shear modulus was not different between sides. Tendon thickness (rho = 0.675, p = 0.002) and shear modulus (rho = -0.791, p = 0.001) related to total work on the heel-rise test. Conclusion: Ultrasound imaging, including cSWE, can be used to detect side-to-side differences in tendon structure in individuals with Achilles tendon rupture and tendon structure relates to clinical performance. Level of evidence: III b. PMID- 29387650 TI - The effect of strain and age on the mechanical properties of rat Achilles tendons. AB - Background: Achilles tendon (AT) ruptures are common in the middle age population; however, the pathophysiology and influence of age on AT ruptures is not fully understood. This study evaluates the effect and interactions between, strain and age on the in vitro biomechanical properties of ATs. Methods: Bilateral ATs were harvested from 17 young (8 months) and 14 middle-aged (24 months) rats and underwent stress-relaxation using Fung's quasilinear viscoelastic (QLV) modeling and load-to-failure testing. Results: The initial viscoelastic response (parameter B) in middle-age animals was dependent on the amount of strain applied to the tendon and was significantly increased in middle aged animals at higher strain. Higher strain in older animals led to a prolonged relaxation time (parameter tau 2). There was a trend toward an increased magnitude of the relaxation response (parameter C) at higher strain in the middle aged animals. Middle-aged animals had a significantly lower mean stress at ultimate failure (p=0.01), while Young's modulus was similar in both groups (p=0.46). Conclusions: The passive biomechanical properties of the rat AT change with age and the influence stress-relaxation response of the AT, thereby possibly predisposing the AT of older animals to fail at lower loads compared to younger animals. Level of evidence: Not applicable, this is a basic science study. PMID- 29387651 TI - Mini open versus open repair techniques in Achilles tendon rupture: clinical and isokinetic evaluation. AB - Background: The aim of the study was to compare the mini-open to the classic open repair techniques for Achilles tendon ruptures. Methods: We retrospectively evaluated at a minimum of 2 years follow-up 32 subcutaneous Achilles tendon ruptures; 17 underwent mini-open surgery (Group A) and 15 the open technique (Group B). Results: No difference in Achilles Tendon Total Rupture Score and in modified Leppillahti score was observed. With respect to the contralateral side the width of the operated Achilles tendon was 4.07 mm thicker in Group A and 7.67 mm in Group B (p<.05); the calf circumference reduction was respectively 10 mm and 23.75 mm (p<.05). Iso-kinetic peak force measurement of the calf muscle strength showed a loss of 8.21% in Group A versus 17.25% in Group B (p <.05). The mean Patient Satisfaction Score was 96.76 in Group A and 88.67 in Group B (p<.01); respectively 82.3% vs 66.7% of patients were able to return to previous levels of sporting activity. There were two post-operative complications in Group B and one in Group A. Conclusion: Mini-open technique minimizes the risk of complications, leads to an improved tendon healing process and functional recovery with higher patient satisfaction. Level of evidence: IV. PMID- 29387652 TI - Congenital absence of the long head of biceps tendon & its clinical implications: a systematic review of the literature. AB - Background: Multiple reports of congenitally absent long head of biceps tendon (LHBT) have been reported in the literature. However, there is no consensus on the clinical implications of this relatively rare entity. Study Purpose: To systematically review and analyze all studies which have reported absence of LHBT. Methods: PubMed and EMBASE databases were searched. Also, a secondary search was performed by pearling the bibliography of all the full-text articles obtained. Pre defined inclusion criteria was used for abstract screening by two independent observers. Twenty three studies met our inclusion criteria, were included for the final analysis and the data was pooled. The cases were further sub-grouped according to the classification of Dierickx et al. Results: Till date, 35 cases of absent LHBT have been reported. Males and females were equally affected. Eight of these were bilateral and only four cases had other associated congenital anomalies. Majority of the patients presented with shoulder pain (85.7%) while 37.1% had shoulder instability (mainly anterior instability). The ABS type was the most common variant reported. The finding was missed in 60% of the cases on the initial MRI only to be detected later on shoulder arthroscopy. Conclusions: Congenitally absent LHBT may not be as rare as was previously thought to be. Due to the heterogeneity and the low level of evidence of the data available, it is hard to conclude if a congenitally absent LHBT is a cause of shoulder pain/impingement or instability on its own. Level of evidence: IV. PMID- 29387653 TI - Operative treatment for the painful posterior thigh after hamstring autograft harvesting. AB - Background: Semitendinosus (ST) is widely used autograft in anterior cruciate ligament reconstructions (ACLR). Although tendon harvesting is a common procedure, some patients exhibit pain, cramping and dysfunctional at posterior thigh after the ACLR. The formation of the newly regenerated neotendon could be compromised by a new injury or too rapid rehabilitation. We present this clinical entity and the developed surgical technique and share our experience in treatment of these patients. Methods: Ten patients underwent operation where the harvested, retracted and loose muscle (9 ST, 1 gracilis) was reattached again. The delay to the diagnosis and the outcome of the procedure were recorded. Cases were followed and magnetic resonance images (MRI) were included from 2 cases for the demonstration of postoperative healing. Results: Six ST and the gracilis patients with prolonged symptoms had good results and returned to their normal activity level. Preoperative MRI showed increased signal intensity and edema of the harvested and retracted muscles as the sign of compromised healing of the neotendon. Postoperatively, these MRI findings were resolved. Conclusions: In high activity level patients with chronic posterior thigh pain and cramping of the harvested muscle, the stabilization procedure of the poorly healed muscle belly could lead to beneficial outcome. Level of evidence: IV. Case series. PMID- 29387654 TI - Time to recovery of sciatic function index after induced tibialis anterior strain in rats. AB - Background: Muscle strain is a common injury with a high recurrence rate. Due to the heterogeneity of strain injuries, experimental animals provide controlled and reproducible models to investigate such injuries. Sciatic Function Index (SFI) is a clinically feasible method to assess hind limb recovery in rodents after induced injuries. Objectives: To investigate time to recovery of SFI after induced-strain in tibialis anterior (TA) muscle in rats. Methods: Sixteen adult male Wister rats were randomly and equally divided to a normal control group that received no intervention, and TA induced muscle strain group. Muscle strain was induced using an external weight that corresponded to 150% of the animal body weight. SFI was tested only once in the control group. For the muscle strain group, SFI was tested on the 1st, 2nd, 3rd, 4th, 7th, 11th, 20th and 24th days after strain induction. Results: Comparisons between group showed significant difference in SFI on the 1st, 2nd, 3rd and 4th days (p= 0.012, 0.012, 0.012 and 0.028, respectively). Conclusions: In a rat animal model of TA induced muscle strain, functional recovery measured by SFI is evident on the 7th day post injury, which corresponds to the sub-acute phase of injury. Level of evidence: V. PMID- 29387655 TI - Sciatic nerve stiffness is not changed immediately after a slump neurodynamics technique. AB - Background: Neurodynamics techniques aim to assess and improve neural mechanosensitivity. However, there is no in vivo evidence regarding the mechanical effects of these techniques in the nerve stiffness. This study examined the immediate effects of a slump neurodynamics technique in the sciatic nerve shear wave velocity (SWV. i.e. an index of stiffness) using ultrasound based elastography. Methods: Fourteen healthy participants were included in this experiment. Sciatic SWV and ankle passive torque were measured during a passive ankle dorsiflexion motion (2 degrees /s), before and immediately after 3 minutes of slump neurodynamics technique, randomly applied to one lower limb. The contralateral limb served as control. Results: The slump intervention did not change the sciatic SWV (P=0.78), nor the dorsiflexion passive torque (P=0.14), throughout the ankle dorsiflexion motion. Excellent values of intra-rater repeatability (ICC=0.88, 0.68-0.96), and low values of standard error of measurement (0.59 m/s, 0.35-1.15m/s), were observed for the SWV measurements. Conclusions: The sciatic nerve stiffness of healthy participants did not change immediately after a slump neurodynamics technique, suggesting a compliance of the neural tissue to tensile loads. However, these results ought to be confirmed using other neurodynamics techniques and in other populations (e.g. peripheral neuropathies). Level of evidence: III. PMID- 29387656 TI - HCV genetics and genotypes dictate future antiviral strategies. AB - At the end of the 1980s, the hepatitis C virus (HCV) was cloned and formally identified as the cause of the majority of non-A and non-B hepatitis cases. Today, around 170 million people worldwide are infected with HCV, making it five times more common than infection with the human immunodeficiency virus (HIV). Several methods exist which mediate the spread of infection. One of the most common and efficient is sharing or re-using injecting equipment; studies have indicated that 80-90% of individuals in some populations of intravenous drug users test positive in serum HCV assays. Contracting HCV from infected blood transfusions was also a major cause of infection before screening tests were introduced in the early 1990s. Other possible, but less common, methods of infection transmission include mother-to-child during pregnancy, sexual contact and nosocomial acquisition (for example between surgical or dialysis patients). It appears that concurrent HIV-1 infection increases the risk of HCV transmission via the mother-to-child or sexual routes. PMID- 29387657 TI - Insights into the molecular mechanisms of stress and inflammation in ageing and frailty of the elderly. AB - Frailty is a natural state of physical, cognitive and mental decline that is expected in the elderly. The role of inflammation in the pathogenesis of frailty has been hypothesized, and so far many studies have been performed in order to understand the mechanism of action underlying this association. Recent studies support this hypothesis and show a clear association between inflammation, frailty, and age-related disease. Chronic inflammation is key pathophysiologic process that contributes to the frailty directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and other age-related specific diseases. Herein, we investigate the link between chronic inflammation and frailty of the older people. In particular, we present an up-to-date review of the role of cytokines, interleukins, cardiovascular abnormalities, chronic high blood pressure, hyperlipidemia and diabetes in relation to the severity of frailty in the elderly. PMID- 29387658 TI - Subcutaneous Emphysema as a Complication of Tonsillectomy: A Systematic Literature Review and Case Report. AB - Introduction: Subcutaneous and mediastinal emphysema is a rare complication after tonsillectomy. This case presentation and literature review summarizes the existing literature on this unusual complication. Materials and Methods: This study presents a case of a 21-year-old man who developed a cervical subcutaneous emphysema 6 days after tonsillectomy, whereby conservative treatment produced spontaneous resolution. A proper analysis of this case also required undertaking a systematic search in MEDLINE/PubMed and SCOPUS electronic databases concerning this rare complication, without language restrictions. Results: Based on our criteria, we identified 41 reports including 43 individual cases, in which patients were mostly young and equally distributed between the genders (18 males and 23 females, two unknown). The treatment was mainly conservative and consisted of observation and/or antibiotic therapy. Conclusion: Subcutaneous or mediastinal emphysema is an uncommon complication after tonsillectomy. It is important that clinicians become aware of this rare complication, which requires a close monitoring of the patient. PMID- 29387659 TI - Comparison of Application of Mitomycin C Vs Silicon Stenting Vs Conventional Method in Endonasal Dacrocystorhinostomy: A Randomized Controlled Trial of 150 Patients. AB - Introduction: Since the days of Hippocrates, many modifications have been proposed in endonasal dacrocystorhinostomy (DCR), with the use of new drugs and implants showing variable results. The objective of this study was to analyze whether the use of silicon tubing or mitomycin C administration has an added advantage over conventional endonasal DCR. Materials and Methods: A randomized controlled trial of 150 patients between the ages of 6 and 70 years presenting with epiphora was performed. Patients were randomly divided into three groups: endonasal DCR with mitomycin C administration, endonasal DCR with silicon stenting, or conventional endonasal DCR. Patients were followed up on Days 15, 30, 60 and 90 postoperatively for sac syringing to confirm patency. Results: The majority of patients (28.7%) were in the fourth decade of life, with a female predominance (65.3%). Dacrocystitis was most commonly seen in the left eye (58.7%). An intergroup comparison was performed using the Kruskal-Wallis test at the end of 3 and 5 months. The results suggest that the success rate was significantly higher in patients with a silicone stent (P=0.04) as compared with the other two groups, although no significant difference in failure rate was seen between patients on mitomycin C and conventional therapy (P=0.132 at Month 3 and P=0.481 at Month 5, Mann-Whitney U-test). Conclusion: Our study shows that silicone tube stenting had a better success rate compared with the other two groups, with no significant statistical difference between the use of mitomycin C and the conventional technique. PMID- 29387660 TI - Evaluation of Culturally-Familiar Odorants for a Persian Smell Identification Test. AB - Introduction: Processing odor information by the olfactory system depends greatly on the odor concentration. In order to use an odorant in a smell identification test (SIT), the minimum identification concentration (MIC) needs to be determined. Materials and Methods: This study was conducted in 60 healthy native individuals aged 20 to 60 years, selected from patients' companions in a tertiary hospital. In the first step, 25 odorants were presented to evaluate familiarity among the subjects. Then, the MICs for the eligible odorants were measured using the ascending method of limits. Results: Out of 25 odorants, only one (cacao) was distinguished by less than 70% of the subjects, and was therefore removed from the list. The MICs of the remaining 24 odorants ranged from 6.87+/-2.74% for menthol to 27.62+/-18.98% for cantaloupe. There was significant correlation between age and the MIC only for coffee (P=0.02, r=-0.300). There was a significant difference in MIC between men and women only for hazelnut (P=0.03). Conclusion: We present the MICs of 24 culturally-familiar odorants in a sample of the Persian population in a SIT. PMID- 29387661 TI - Patterns and Grade of Velopharyngeal Closure in Candidates for Adenotonsillectomy. AB - Introduction: The most common type of velopharyngeal valve (VPV) closure is a matter of controversy. The aim of this study was to estimate the most common type of VPV closure, including identification of the type and grade of VPV closure among Egyptian children. Materials and Methods: This study included patients who were candidates for adenotonsillectomy. In these cases, video-nasoendoscopy and speech assessment were performed prior to surgery in addition to otorhinolaryngology examination and preoperative laboratory tests. Results: By examination of 97 patients, video-nasoendoscopy of the VPV revealed that 49 patients had coronal VPV closure (50.5%), 48 patients had circular VPV closure (49.5%) and no patients had sagittal VPV closure. Conclusion: Coronal and circular closure are the main types of VPV closure in Arabic-speaking children, as neither sagittal closure nor circular closure with Passavant's ridge were detected in this study. Therefore, revision of the methods of repair for persistent velopharyngeal insufficiency (VPI) is required. PMID- 29387662 TI - Comparison of Olfactory Function before and After Endoscopic Sinus Surgery. AB - Introduction: Olfactory loss in patients with chronic rhinosinusitis has been measured by different methods. However, the results have been variable, and it is not clear whether endoscopic sinus surgery significantly improves olfactory function. This study was performed to evaluate the influence of endoscopic sinus surgery on olfactory function in patients with chronic rhinosinusitis. Materials and Methods: In this prospective analytic study, 73 patients (mean age, 39.63+/ 12.94 years) with a diagnosis of polyps and sinusitis during 2011 were studied. The olfaction test was performed with three solutions; one with no odor (water) and two with phenylethyl alcohol (50% and 90% dilution, respectively). The patients' olfaction state were graded as no olfaction, or low, moderate or good olfaction before and 1 and 3 months after surgery, and was given scores between 0 and 3 and evaluated quantitatively. Results: Right-side olfaction was improved in 68.5% and left side in 67.1% of patients. Mean olfaction score on the right and left side was significantly improved after surgery in comparison with basic scores (before and after on the right side: 0.95+/-0.88 and 2.02+/-1.04; before and after on the left side: 1.02+/-0.84 and 2.00+/-1.21; both P<0.001). Improvement after surgery in cases with left- and right-side anosmia was 66.7% and 61.9%, in low olfaction was 82.3% and 72.7% and in moderate olfaction was 66.7% and 80%. Conclusion: In patients with rhinosinusitis, endoscopic sinus surgery has considerable effect in improving olfactory function. PMID- 29387663 TI - Assessment of Response to Treatment in Patients with Otomycosis. AB - Introduction: Due to the prevalence of otomycosis in the north of Iran, which has a humid climate, this study aimed to examine the recurrence rate of otomycosis in Iranian patients. Materials and Methods: This cross-sectional study was performed in all patients suspected of otomycosis referred to the Otorhinolaryngology Clinic of Ayatollah Rouhani Hospital of Babol. Demographic and clinical data of patients as well as their symptoms were collected in a checklist at referral time and also 14 days after referral. Results: The results showed that 11 (7.3%) cases had a recurrence of otomycosis. There was no significant relationship between the incidence of otomycosis and age or sex (P=0.86 and 0.88, respectively). Septate mycelium was the most observed element on direct examination. Aspergillus flavus was the most common pathogenic agent in culture media, followed by Aspergillus niger and Candida albicans. Conclusion: Based on the results of this research in Babol, the recurrence of otomycosis was 7.3% and was related to swelling and erythema in ear canal. PMID- 29387664 TI - Papillary Thyroid Carcinoma Presenting As a Cystic Neck Lesion: Case Series. AB - Introduction: Papillary thyroid carcinoma (PTC) constitutes 75-85% of all thyroid cancers. PTC usually presents as a subtle, commonly slow-growing, painless thyroid mass or a solitary nodule in the neck. This presentation of a cystic neck lump, without the presence of a thyroid nodule, may imitate the course of a benign disease, thus delaying diagnosis and proper treatment. Case Report: Three cases that had been initially presented as a cystic neck lesion in which a benign etiology was considered primarily were compiled in this study. PTC was only diagnosed after surgical excision of these cystic neck lesions in the first two cases, and after performing fine needle aspiration cytology (FNAC) and an 18fluorine-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG-PET CT) scan in the latter case. Conclusion: PTC can sometimes present as a cystic neck mass; a presentation which is usually related to a benign lesion. This case series emphasizes that patients who appear to have a solitary cystic neck mass must be treated with a high index of clinical suspicion. Although not a first-line imaging modality, 18F-FDG-PET can be extremely useful in assessing patients with a cystic neck lesion, where diagnosis is still uncertain after standard investigations such as ultrasonography and FNAC have been performed. PMID- 29387665 TI - Mandibular Involvement in Recurrent Multifocal Osteomyelitis Associated with SAPHO Syndrome. AB - Introduction: SAPHO syndrome is defined as the association of a group of rare sterile osteoarticular disorders and inflammatory skin diseases whose etiology, although not yet determined, probably involves genetic, immunological and infectious mechanisms. The recurrent multifocal osteomyelitis, an inflammatory disease, can be associated with this syndrome even as a single event. Case Report: A case of a young female patient, with a definite diagnosis of SAPHO and an inflammatory mandibular atypical disease for which therapeutic options with immunosuppressants were being used, is reported. The adverse evolution of the clinical conditions led to the hypothesis that the patient suffered from associated mandibular odontogenic bacterial osteomyelitis. The extraction of all teeth was recommended. After our evaluation, we recommended a conservative treatment, and after 2 months of treatment with an endovenous antibiotic, the patient showed improvement of clinical and laboratory results. Conclusion: Early diagnosis is necessary to avoid successive and unnecessary tooth loss in the treatment of chronic osteomyelitis mandibular. PMID- 29387666 TI - The Role of Lingual Bone Grafting in the Treatment of Displaced Edentulous Mandibular Fracture with Severe Atrophy. AB - Introduction: Treatment of edentulous atrophic mandible with severe atrophy is a challenge based on local conditions and systemic diseases confronted by the age group affected. If bone grafting is indicated, it is often used in lateral or inferior aspects of the mandible. Case Report: A 70-year-old male with a unilateral fracture of the atrophied left mandibular body was managed by lingual bone grafting and inferior border miniplate fixation to prevent two common problems after fracture healing; the need for plate removal before denture fabrication and facial asymmetry in the unilateral body fracture. Conclusion: If bone grafting is indicated in the management of displaced edentulous mandibular fracture with severe atrophy, a combination of plating at the inferior border of the mandible and lingual corticocancellous bone grafting should be considered in treatment planning. PMID- 29387667 TI - Primary Squamous Cell Carcinoma of the Thyroid Gland. AB - Introduction: Primary squamous cell carcinoma (SCC) of the thyroid gland is one of the rarest types of all reported thyroid malignancies worldwide. It is very aggressive in nature and carries a poor prognosis. The surgical resection with adjuvant radiotherapy and chemotherapy is the most recommended treatment despite its poor reported outcome. Case Report: A 74-year-old woman presented with a rapidly progressive neck swelling, with hoarseness and compressive symptoms. Physical examination revealed a multilobulated firm thyroid mass with unilateral vocal cord palsy. Histopathological findings confirmed the diagnosis of SCC while radiological investigations and panendoscopy findings ruled out the possibility of other primary tumors. A surgical intervention was performed; however, the patient eventually succumbed to death prior to undergoing an oncological treatment. Conclusion: With no standard consensus to guide the management plan, SCC of the thyroid gland presents a great challenge for the managing team to come up with the best treatment option, due to its unfavorable rate of survival. PMID- 29387668 TI - Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels. AB - Background: Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Materials and Methods: Forty male rats were randomly allocated to five different groups (n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results: Results revealed that chronic stress had a significantly (P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly (P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly (P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly (P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. Conclusions: It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain. PMID- 29387669 TI - Effect of Religious Cognitive Behavioral Therapy on Religious Obsessive compulsive Disorder (3 and 6 months Follow-up). AB - Background: Obsessive-compulsive disorder (OCD) is a chronic disorder that strongly affects one's life and social, emotional, and occupational functioning. Due to the effect of religious beliefs on phenomenology of OCD, in this paper, we assess the effectiveness of religious cognitive behavioral therapy (CBT) within 3 and 6 months follow-up. Materials and Methods: This study is a clinical trial with follow-ups which last 2 months consisting eight sessions of 1.5 h of religious CBT. The research is conducted in a group of 40, with pre- and post test after 3 and 6 months. Used Yale-Brown OCD symptom scale, before, the end, after 3 months and after 6 months of intervention. Treatment is carried out by a psychiatrist and a clergyman through religious CBT. The trial is held in OCD clinic affiliated with Noor Hospital. Results are analyzed by ANOVA repeated measure with SPSS18. Results: The results showed a considerable decrease in OCD symptoms which remained almost persistent after 3 and 6 months (F = 3/54. P = 0/024). It also shows that religious CBT can leave substantial effect on OCD symptoms; permanency of this intervention after 3 and 6 months is noticeable (P < 0/001). In Conclusion this therapy could be helpful for OCD patients with religious content. Conclusion: RCBT have a positive effect on people with religious obsessive -compulsive. PMID- 29387670 TI - Compare Complication of Classic versus Patent Hemostasis in Transradial Coronary Angiography. AB - Background: Coronary artery disease (CAD) is multifactorial disease, in which thrombotic occlusion and calcification occur usually. New strategies have been made for diagnosis and treatment of CAD, such as transradial catheterization. Hemostasis could be done in two approaches: traditional and patent. Our aim is to find the best approach with lowest complication. Materials and Methods: In a comparative study, 120 patients were recruited and divided randomly into two subgroups, including traditional group (60 patients; 24 females, 36 males; mean age: 64.35 +/- 10.56 years) and patent group (60 patients; 28 females, 32 males; mean age: 60.15 +/- 8.92 years). All demographic data including age, gender, body mass index, and CAD-related risk factors (smoking, diabetes, hypertension) and technical data including the number of catheters, procedure duration, and hemostatic compression time and clinical outcomes (radial artery occlusion [RAO], hematoma, bleeding) were collected. Data were analyzed by SPSS version 16. Results: Our findings revealed that the incidence of RAO was significantly lower in patent groups compared with traditional group (P = 0.041). Furthermore, the difference incidence of RAO was higher in early occlusion compare with late one (P = 0.041). Moreover, there were significant relationship between some factors in patients of traditional group with occlusion (gender [P = 0.038], age [P = 0.031], diabetes mellitus [P = 0.043], hemostatic compression time [P = 0.036]) as well as in patent group (age [P = 0.009], hypertension [P = 0.035]). Conclusion: Our findings showed that RAO, especially type early is significantly lower in patent method compared classic method; and patent hemostasis is the safest method and good alternative for classical method. PMID- 29387671 TI - Comparison of Nasal Mucociliary Function before and after Septorhinoplasty Surgery Using Saccharin Test. AB - Background: This study was carried out to compare mucociliary function (MCF) of nasal cavity before and after septorhinoplasty surgery by saccharin test. Materials and Methods: This study was carried out on 70 patients who needed septorhinoplasty surgery in Kashani and Alzahra Hospital during 2013-2014 to measure MCF. Saccharin test was performed on the patients before surgery and on three more intervals 1 day, 1 week, and on month after ward and the readings were recorded. Saccharin test is performed by placing saccharin granules on the anterior part of inferior turbinate and the time the patient feels the sweet taste is recorded the normal range is below 30 min. Results: Mean of test for each time interval was obtained and comparison of measurements was made reading were mean of saccharin test before surgery (7.74 +/- 1.65 min) the day after surgery (7.75 +/- 1.7 min), on week after surgery (15.04 +/- 3.4), and 1 month after surgery (8.49 +/- 2.08 min). The readings before surgery did not have statistically significant difference with the readings 1 day after surgery P = 0.99, but comparison of test results at other time intervals were significant (P < 0.001). A relative increase in saccharin test time was seen in a period of 1 month after surgery the rise was more noticeable in the 1st week compared to 1 month after surgery. Conclusion: This study in the period after septorhinoplasty surgery MCF undergoes slight impairment that gradually progresses to normal values during 1 month after surgery. PMID- 29387672 TI - Evaluation of Effective Parameters on Quality of Magnetic Resonance Imaging computed Tomography Image Fusion in Head and Neck Tumors for Application in Treatment Planning. AB - Background: In radiation therapy, computed tomography (CT) simulation is used for treatment planning to define the location of tumor. Magnetic resonance imaging (MRI)-CT image fusion leads to more efficient tumor contouring. This work tried to identify the practical issues for the combination of CT and MRI images in real clinical cases. The effect of various factors is evaluated on image fusion quality. Materials and Methods: In this study, the data of thirty patients with brain tumors were used for image fusion. The effect of several parameters on possibility and quality of image fusion was evaluated. These parameters include angles of the patient's head on the bed, slices thickness, slice gap, and height of the patient's head. Results: According to the results, the first dominating factor on quality of image fusion was the difference slice gap between CT and MRI images (cor = 0.86, P < 0.005) and second factor was the angle between CT and MRI slice in the sagittal plane (cor = 0.75, P < 0.005). In 20% of patients, this angle was more than 28 degrees and image fusion was not efficient. In 17% of patients, difference slice gap in CT and MRI was >4 cm and image fusion quality was <25%. Conclusion: The most important problem in image fusion is that MRI images are taken without regard to their use in treatment planning. In general, parameters related to the patient position during MRI imaging should be chosen to be consistent with CT images of the patient in terms of location and angle. PMID- 29387673 TI - Beneficial Effects of Selective Orexin-A Receptor Antagonist in 4-aminopyridine induced Seizures in Male Rats. AB - Background: Orexins are excitatory neuropeptides which stimulate the central regulatory pathways. Orexins increase the penicillin-induced epileptic activity in rats. Orexin-A increases in different types of seizures and its elevated level is the characteristic feature in the epileptic children during polysomnography. Recently, the orexin receptor blockage has been reported to increase seizure threshold in mice; however, effect of the selective orexin-A receptor antagonist (SB-334867) on 4-aminopyridine (4-AP)-induced seizures has not been investigated. Materials and Methods: We used the intraperitoneal injection of 4-AP to induce seizure in male rats. Under urethane anesthesia, SB-334867 (50 and 100 nmol) was injected stereotaxically into the ventral hippocampal commissure. Using video recording, the effects of SB-334867 on electroencephalogram and tonic-clonic convulsions were compared to those that received diazepam or dimethyl sulfoxide (DMSO). Results: SB-334867 significantly decreased the duration of spike trains compared to DMSO-treated rats (P < 0.001) and reduced the duration of convulsive seizures (P < 0.05). Seizure onset was increased significantly by SB-334867, 50 nmol, compared to DMSO (P < 0.05) and diazepam (P < 0.01) treated rats. Conclusion: Antagonism of orexin-A receptor by a low-dose SB-334867 showed protective effects in 4-AP-induced seizure-like activities in anesthetized rats. PMID- 29387674 TI - Effect of Genistein and 17-beta Estradiol on the Viability and Apoptosis of Human Hepatocellular Carcinoma HepG2 cell line. AB - Background: One of the most lethal cancers is hepatocellular carcinoma (HCC). Genistein (GE) is a choice compound for treatment of certain types of cancer. Phytoestrogens are plant derivatives that bear a structural similarity to 17-beta estradiol (E2) and act in a similar manner. They are a group of lipophillic plant compounds with tumorigenic and antitumorigenic effects. E2 has stimulatory and inhibitory effects on cancer cell lines. This study was designed to investigate the antiproliferative and apoptotic effects of GE and E2 on the HCC HepG2 cell line. Materials and Methods: HepG2 cells were cultured and treated with various concentrations of GE and E2 and then 3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl 2H-tetrazolium bromideand flow cytometry assay were performed to determine cell viability and apoptosis. Results: GE and E2 induced apoptosis and inhibited cell growth significantly. Reduction of cell viability by 50% required 20 MUM E2 for E2-treatment groups and 20 MUMGE for GE-treatment groups. The percentage of the GE-treated apoptotic cells was reduced by about 35%, 42%, and 47% (P < 0.001) and that of E2-treated groups 34%, 39%, and 42% (P < 0.001) after 24, 48, and 72 h, respectively. Conclusions: Our experimental work clearly demonstrated that GE and E2 exhibited significant antiproliferative and apoptotic effects on human HCC HepG2 cells. PMID- 29387675 TI - The Effects of Administrated Sildenafil Citrate on Uterine Luminal Epithelium Height Associated with Ovarian Angiogenesis: An Experimental Animal Study. AB - Background: Ovarian angiogenesis (OA) remains in lifetime and normal ovarian function depends to this continual remodeling of a complex vascular system. Endometrial thickness (ET) is one of the strongest predictors of successful implantation and pregnancy. Appropriate OA effects on ET by facilitating of ovarian hormone delivery. Materials and Methods: Thirty adult female mice and twenty adult male mice were purchased. The female mice were divided into three groups: (1) control group without any intervention (n = 10), (2) gonadotropin group: receiving human menopausal gonadotropin (HMG) and human chorionic gonadotropin (n = 10), and (3) gonadotropin and sildenafil citrate (SC) group: receiving HMG and SC administration (n = 10). After mating, animals were deeply anesthetized, and the ovary and uterus was rapidly removed for histology and immunohistochemistry process. Results: Four days after ovarian induction, all three layers of the uterus with specified thickness can be clearly seen. The heights of endometrial epithelial cells in gonadotropin group were not significantly different than those in control group. In gonadotropin and SC group, heights of the cells were significantly (P < 0.05) shorter than control and gonadotropin groups. ETs in all groups were not significantly deferent from each other (P > 0.05 each). Our results of immunohistochemistry survey for ovarian CD31 demonstrated that administrated SC increased OA but not significantly (P > 0.05 each). Conclusion: It may finally conclude that administration of SC does not cause notable alterations in OA and ET; although for realistic decision about the SC effects on aforementioned parameters, more molecular investigations and longer drug consumption period are necessary. PMID- 29387676 TI - Factors Influencing the Incidence of Papilledema in Patients with Cerebral Venous Thrombosis. AB - Background: Cerebral venous thrombosis (CVT) is an uncommon cerebrovascular disease with a wide spectrum of symptoms and severity. This study analyzes the factors influencing the incidence of papilledema in patients with cerebral venous thrombosis. Materials and Methods: In this research 65 patients with CVT were examined between 2011 and 2013, and the patients were followed up one, three, six, and twelve months after the initial diagnosis. They were separated into two groups according to presence or absence of papilledema. We analyzed the frequency of symptoms and risk factors of cerebral venous thrombosis and the intensity of papilledema as time passed, as also the frequency of the involved sinus, in two groups of patients with and without papilledema. Results: This study showed that the most common symptom was headache, with a frequency of 92.3% and the least common symptoms were ataxia and quadriparesis, with a frequency of 1.5%. The most common risk factors were high waist circumference (WC) and oral contraceptive pil (OCP) use, and also in patients with papilledema the intensity is reduced as time passes. Conclusion: This investigation showed that there was no significant relation between the frequency of risk factors and symptoms and intensity of papilledema as time passed in the two groups. The results showed that the most common sinuses involved in patients with papilledema were sagittal and lateral sinuses, which included 66.7%, and the most common sinus involved in patients without papilledema, which was the lateral sinus that included 40%. PMID- 29387677 TI - The Effects of Hydroalcoholic Extract of Nigella sativa Seeds on Serum Estradiol and Prolactin Levels and obstetric Criteria due to Hypothyroidism in Rat. AB - Background: The aim of this study was investigation of the effects of Nigella sativa (NS) seeds on hypothyroid pregnant rats and their progenies. Materials and Methods: Hypothyroidism was induced by propylthiouracil (PTU) 0.03% in drinking water. Female rats were divided into seven groups: control, PTU, PTU-NS (100, 200, and 400 mg/kg), and NS (100 and 400 mg/kg). All treatments were done 20 days before mating and during pregnancy. The weight of rat dams and progenies, number of progenies and serum T4, estradiol and prolactin (PRL) levels in rat dams were measured for all groups. Results: Serum T4 in all PTU-NS groups before mating was significantly increased versus PTU group. Body weight of rat dams before mating in all groups of PTU-NS was increased versus PTU group by P < 0.001, P < 0.05, and P < 0.001, respectively and in NS 100 and NS 400 was increased versus control group (P < 0.001). The number of offspring was significantly decreased in PTU and PTU-NS versus control group. The weight of progenies in NS 400 was higher than control group (P < 0.001) and was increased in PTU-NS 200 and PTU-NS 400 versus PTU group by P < 0.001 and P < 0.05, respectively. Serum PRL level in rat dams in control, PTU, and PTU-NS groups were not statistically different between groups but significantly increased in NS 400 group when compared to control group. Estradiol levels were not significantly different in rat dams at 5 days after delivery. Conclusion: These results demonstrated that feeding of rat dams with NS extract before mating has positive protective effects on progenies. These effects may be due to antioxidant properties of NS in reducing oxidative stress and thyroid damages induced by PTU. PMID- 29387678 TI - A Case of Adams-Oliver Syndrome. AB - Adams-Oliver syndrome (AOS) is a rare congenital disorder with unknown etiology commonly presented with aplasia cutis and terminal limb defects. Central nervous and cardiopulmonary systems may also be affected. It is commonly inherited as an autosomal dominant disorder but autosomal recessive and sporadic cases have also been reported. Here, we present a 10-year-old boy with extensive aplasia cutis congenita and limb anomalies as well as mild pachygyria and focal acrania in neuroimaging. No other internal organ involvement was obvious in this patient. Family history was negative for this syndrome. AOS is a multisystem disorder, and so it is crucial to investigate for internal organ involvements. PMID- 29387679 TI - Niemann-Pick Disease Type C Associated with Fuchs Heterochromic Iridocyclitis. AB - In this study, we report a 26-year-old female case of Niemann-Pick disease type C in association with Fuchs heterochromic iridocyclitis who was admitted with the complaint of ocular pain and redness following trauma. She had mild inflammatory signs and also vertical ocular motility limitations. PMID- 29387680 TI - Effects of Nasal Continuous Positive Airway Pressure and High-Flow Nasal Cannula on Sucking, Swallowing, and Breathing during Bottle-Feeding in Lambs. AB - The use of prolonged respiratory support under the form of high-flow nasal cannula (HFNC) or nasal continuous positive airway pressure (nCPAP) is frequent in newborn infants. Introduction of oral feeding under such nasal respiratory support is, however, highly controversial among neonatologists, due to the fear that it could disrupt sucking, swallowing, and breathing coordination and in turn induce cardiorespiratory events. The recent observation of tracheal aspirations during bottle-feeding in preterm infants under nCPAP justifies the use of animal models to perform more comprehensive physiological studies on the subject, in order to gain further insights for clinical studies. The objective of this study was to assess and compare the impact of HFNC and nCPAP on bottle-feeding in newborn lambs, in terms of bottle-feeding efficiency and safety as well as sucking-swallowing-breathing coordination. Eight full-term lambs were instrumented to record sucking, swallowing, and respiration as well as electrocardiogram and oxygenation. Lambs were bottle-fed in a standardized manner during three randomly ordered conditions, namely nCPAP 6 cmH2O, HFNC 7 L/min, and no respiratory support. Results revealed that nCPAP decreased feeding duration [25 vs. 31 s (control) vs. 57 s (HFNC), p = 0.03] and increased the rate of milk transfer [2.4 vs. 1.9 mL/s (control) vs.1.1 mL/s (HFNC), p = 0.03]. No other indices of bottle-feeding safety or sucking-swallowing-breathing coordination were significantly altered by HFNC or nCPAP. In conclusion, our results obtained in full-term newborn lambs suggest that: (i) nCPAP 6 cmH2O, but not HFNC 7 L/min, increases bottle-feeding efficiency; (ii) bottle-feeding is safe under nCPAP 6 cmH2O and HFNC 7 L/min, with no significant alteration in sucking-swallowing breathing coordination. The present informative and reassuring data in full-term healthy lambs must be complemented by similar studies in preterm lambs, including mild-to-moderate respiratory distress alleviated by respiratory support in order to mimic preterm infants with bronchopulmonary dysplasia and pave the way for clinical studies. PMID- 29387681 TI - Evaluation of a Direct-Instruction Intervention to Improve Movement and Preliteracy Skills among Young Children: A Within-Subject Repeated-Measures Design. AB - Objective: School readiness involves the development of foundational skills such as emergent literacy and fundamental movement skills as well as the capacity to attentively engage in instructional situations. Children do not develop these skills naturally; therefore, they need the opportunity to develop these skills in their early years prior to entering school. The objective of the current study was to evaluate the effectiveness and feasibility of a direct-instruction movement and preliteracy intervention in children aged 3-4 years. Methods: A within-subject repeated-measures design, embedded within a wait-list control study, was used to evaluate the intervention. The intervention was run across 10 weeks with 1 h weekly sessions. Each weekly session consisted of 30-min of movement skill instruction (e.g., through single-step acquisition strategies), 15 min of free play during which time children had access to a variety of equipment (e.g., balls, hula hoops, etc.) or toys (e.g., puzzles, building blocks), and a 15-min interactive reading circle during which children read a storybook and were taught 1-2 preliteracy skills (e.g., alphabet knowledge, narrative knowledge, etc.). A convenience sample of 11 children (mean age = 45.6 months, SD = 7.3) was recruited. All children were assessed four times: baseline (Time 1), pre intervention (Time 2), post-intervention (Time 3), and 5-week follow-up (Time 4). Gross motor skills and preliteracy skills were assessed at each time point. Results: There was a statistically significant effect of time on the change in gross motor skills (Wilks' lambda = 0.09, p = .002), print-concept skills (Wilks' lambda = 0.09, p = .001), and alphabet knowledge (Wilks' lambda = 0.29, p = .046). Post hoc analyses reveal non-significant changes between time 1 and 2 for motor and print-concept skills and significant changes in all three outcomes between time 2 and time 3. Conclusion: Participation in a direct-instruction movement and preliteracy program led to positive improvements in gross motor skills, print-concept knowledge, and alphabet knowledge in 3- to 4-year-old children over time. Future research needs to evaluate the effectiveness of this movement and preliteracy skill intervention on various other indicators of child development and health. Clinical Trial Registration: Play and Pre-Literacy among Young Children (PLAY) NCT02432443. PMID- 29387682 TI - Modified Ride-On Cars and Young Children with Disabilities: Effects of Combining Mobility and Social Training. AB - Background: Research has shown that the use of power mobility devices is safe and beneficial for motor and cognitive development in children with motor disabilities; nevertheless, strong evidence of the benefits for social skill development is limited. This study aimed to examine the effects of combining ride on car training with an adult-directed, social interaction program in a hospital based environment on mobility and social functions in young children with motor disabilities. Methods: This study used a prospective, nonequivalent pretest posttest control group design. Twenty-nine young children with motor disabilities, aged between 1 and 3 years, were recruited from local hospitals in Taiwan. The treatment group (n = 15) underwent 2-h ride-on car training sessions twice per week for a total of 9 weeks in the hospital environment. The control group (n = 14) underwent a 9-week home education program (mean: 200 min/week) focusing on mobility and social skills training. The Chinese version of the Pediatric Evaluation of Disability Inventory, Parenting Stress Index, and Goal Attainment Scaling were administered to all participants before and after the intervention, and at the end of the 9-week follow-up phase. Results: Mobility and social functions significantly improved in both groups after the 9-week intervention, but this improvement was not maintained at the follow-up phase. The treatment group showed significantly better improvement in social function, parenting stress levels, and goal achievement than the control group at posttest. Conclusion: This two-group design study showed the benefits of combining a ride on car use with a family-centered, structured, social interaction program for positive impacts on mobility, social function, and parenting stress levels. The combination of a modified ride-on car and a social training program has the potential to enhance socialization in young children with motor disabilities. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02527499. PMID- 29387683 TI - Monitoring of Tissue Oxygenation: an Everyday Clinical Challenge. AB - Purpose of review: The aim of this article is to study the overview of pathophysiology and clinical application of central venous oxygen saturation monitoring in critically ill patients and during the perioperative period. Recent findings: There are several clinical studies and animal experiments evaluating the effects of goal-directed hemodynamic stabilization on critically ill patients. Recent systematic reviews and meta-analyses found that advanced hemodynamic endpoints-targeted management has a positive effect on outcome in high-risk surgical patients. As all interventions aim to improve tissue oxygenation, it is of utmost importance to monitor the balance between oxygen delivery and consumption. For this purpose, central venous blood gas analysis provides an easily available tool in the everyday clinical practice. The adequate interpretation of central venous oxygen saturation renders the need of careful evaluation of several physiological and pathophysiological circumstances. When appropriately evaluated, central venous oxygen saturation can be a valuable component of a multimodal individualized approach, in which components of oxygen delivery are put in the context of the patients' individual oxygen consumption. In addition to guide therapy, central venous oxygen saturation may also serve as an early warning sign of inadequate oxygen delivery, which would otherwise remain hidden from the attending physician. Summary: With the incorporation of central venous oxygen saturation in the everyday clinical routine, treatment could be better tailored for the patients' actual needs; hence, it may also improve outcome. PMID- 29387684 TI - Aging, Disability, and Informal Caregivers: A Cross-sectional Study in Portugal. AB - Objectives: Aging is pushing states to rethink long-term care policies in several dimensions. This study aims to characterize the reality of dependent older people regarding their demographic and health characteristics, to describe their informal carers and understand the availability of informal care. Methods: A cross-sectional study was developed in Portugal in 2013. Descriptive statistical analyses and binary logistic analysis were conducted. Results: Results show that the informal long-term care sector is primarily aimed at older people with severe limitations in their activities of daily living and at the chronically ill, particularly older women. Additionally, 39.5% of dependent older persons do not have informal care and only receive informal aid in cases of extreme need. Discussion: Results show a critical situation for both social groups (older persons and caregivers) and the prospect of an alarming situation in the near future (aging and reduced availability of informal caregivers) unless a new approach for long-term care is developed. PMID- 29387685 TI - The Stoichiometric Interaction of the Hsp90-Sgt1-Rar1 Complex by CD and SRCD Spectroscopy. AB - While the molecular details by which Hsp90 interacts with Sgt1 and Rar1 were previously described the exact stoichiometric complex that is formed remains elusive. Several possibilities remain that include two asymmetric complexes, Sgt12-Hsp902-Rar12 (two molecules of Sgt1 and Rar1 and one Hsp90 dimer) or Sgt12 Hsp902-Rar11 (with a single Rar1 molecule) and an asymmetric complex (Sgt11 Hsp902-Rar11). The Hsp90-mediated activation of NLR receptors (Nucleotide-binding domain and Leucine-rich Repeat) in the innate immunity of both plants and animals is dependent on the co-chaperone Sgt1 and in plants on Rar1, a cysteine- and histidine-rich domain (CHORD)-containing protein. The exact stoichiometry of such a complex may have a direct impact on NLR protein oligomerization and thus ultimately on the mechanism by which NLRs are activated. CD spectroscopy was successfully used to determine the stoichiometry of a ternary protein complex among Hsp90, Sgt1, and Rar1 in the presence of excess ADP. The results indicated that a symmetric Sgt12-Hsp902-Rar11 complex was formed that could allow two NLR molecules to simultaneously bind. The stoichiometry of this complex has implications on, and might promote, the dimerization of NLR proteins following their activation. PMID- 29387686 TI - Improved in Vitro Folding of the Y2 G Protein-Coupled Receptor into Bicelles. AB - Prerequisite for structural studies on G protein-coupled receptors is the preparation of highly concentrated, stable, and biologically active receptor samples in milligram amounts of protein. Here, we present an improved protocol for Escherichia coli expression, functional refolding, and reconstitution into bicelles of the human neuropeptide Y receptor type 2 (Y2R) for solution and solid state NMR experiments. The isotopically labeled receptor is expressed in inclusion bodies and purified using SDS. We studied the details of an improved preparation protocol including the in vitro folding of the receptor, e.g., the native disulfide bridge formation, the exchange of the denaturating detergent SDS, and the functional reconstitution into bicelle environments of varying size. Full pharmacological functionality of the Y2R preparation was shown by a ligand affinity of 4 nM and G-protein activation. Further, simple NMR experiments are used to test sample quality in high micromolar concentration. PMID- 29387687 TI - Drivers of Live Cattle Price in the Livestock Trading System of Central Cameroon. AB - Livestock production and trade are critical for the food security and welfare of rural households in sub-Saharan Africa. In Cameroon, animal trade consists mainly of live cattle commercialized through livestock markets. Identifying the factors contributing to cattle price formation is critical for designing effective policies for sustainable production and for increasing food availability. In this study, we evaluated the influence of a range of individual- and market-level factors on the price of cattle that were sold in all transactions (n = 118,017) recorded over a 12-month period from 31 livestock markets in the main cattle production area of the country. An information-theoretic approach using a generalized additive mixed-effect model was implemented to select the best explanatory model as well as evaluate the robustness of the identified drivers and the predictive ability of the model. The age and gender of the cattle traded were consistently found to be important drivers of the price (p < 0.01). Also, strong, but complex, relationships were found between cattle prices and both local human and bovine population densities. Finally, the model highlighted a positive association between the number of incoming trading connections of a livestock market and the price of the traded live cattle (p < 0.01). Although our analysis did not account for factors informing on specific phenotypic traits nor breed characteristics of cattle traded, nearly 50% of the observed variation in live cattle prices was explained by the final model. Ultimately, our model gives a large scale overview of drivers of cattle price formation in Cameroon and to our knowledge is the first study of this scale in Central Africa. Our findings represent an important milestone in designing efficient and sustainable animal health management programme in Cameroon and ensure livelihood sustainability for rural households. PMID- 29387689 TI - Re-defining the role of EUS in pancreatic adenocarcinoma in 2017. PMID- 29387688 TI - A Smartphone-Based Application Improves the Accuracy, Completeness, and Timeliness of Cattle Disease Reporting and Surveillance in Ethiopia. AB - Accurate disease reporting, ideally in near real time, is a prerequisite to detecting disease outbreaks and implementing appropriate measures for their control. This study compared the performance of the traditional paper-based approach to animal disease reporting in Ethiopia to one using an application running on smartphones. In the traditional approach, the total number of cases for each disease or syndrome was aggregated by animal species and reported to each administrative level at monthly intervals; while in the case of the smartphone application demographic information, a detailed list of presenting signs, in addition to the putative disease diagnosis were immediately available to all administrative levels via a Cloud-based server. While the smartphone-based approach resulted in much more timely reporting, there were delays due to limited connectivity; these ranged on average from 2 days (in well-connected areas) up to 13 days (in more rural locations). We outline the challenges that would likely be associated with any widespread rollout of a smartphone-based approach such as the one described in this study but demonstrate that in the long run the approach offers significant benefits in terms of timeliness of disease reporting, improved data integrity and greatly improved animal disease surveillance. PMID- 29387690 TI - Pancreatic ductal adenocarcinoma epidemiology and risk assessment: Could we prevent? Possibility for an early diagnosis. PMID- 29387691 TI - Pancreatic ductal adenocarcinoma in 2017: Time to change the therapeutic algorithm? PMID- 29387692 TI - The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective. PMID- 29387693 TI - The resectable pancreatic ductal adenocarcinoma: To FNA or not to FNA? A diagnostic dilemma, introduction. PMID- 29387694 TI - The resectable pancreatic ductal adenocarcinoma: To FNA or not to FNA? A diagnostic dilemma, FNA pros. PMID- 29387695 TI - The resectable pancreatic lesion: To FNA or not to FNA? A diagnostic dilemma, FNA cons. PMID- 29387696 TI - The borderline resectable and locally advanced pancreatic ductal adenocarcinoma: Definition. PMID- 29387698 TI - The borderline resectable/locally advanced pancreatic ductal adenocarcinoma: EUS oriented. PMID- 29387697 TI - The borderline resectable/locally advanced pancreatic ductal adenocarcinoma staging with computed tomography/magnetic resonance imaging. PMID- 29387699 TI - The borderline resectable/locally advanced pancreatic ductal adenocarcinoma: What should be the surgeon's choice? PMID- 29387700 TI - EUS-guided solid pancreatic tumor ablation. PMID- 29387701 TI - How to prepare, handle, read, and improve EUS-FNA and fine-needle biopsy for solid pancreatic lesions: The pathologist's role. PMID- 29387702 TI - Pancreatic solid incidentalomas. PMID- 29387703 TI - New diagnostic techniques for the differential diagnosis of a pancreatic mass: Contrast-enhanced EUS... It doesn't help me.... PMID- 29387704 TI - Contrast-enhanced ultrasound of small focal solid pancreatic lesions: A must! PMID- 29387705 TI - Technique of qualitative and semiquantitative EUS elastography in pancreatic examination. PMID- 29387706 TI - New diagnostic techniques for the differential diagnosis of pancreatic mass: Elastography helps me 100. PMID- 29387707 TI - Biliary drainage in pancreatic cancer: The endoscopic retrograde cholangiopancreatography perspective. PMID- 29387708 TI - EUS-guided biliary drainage: Is it ready for prime time? PMID- 29387709 TI - Therapeutic EUS: Biliary drainage - The interventional radiologist's perspective. PMID- 29387710 TI - Pancreatic fluid collections and necrosectomy with plastic stents versus lumen apposing stents. PMID- 29387711 TI - Post-injury and resolution response to repetitive inhalation exposure to agricultural organic dust in mice. AB - Inhalation of organic dusts in agricultural environments causes airway inflammatory diseases. Despite advances in understanding the airway response to dust-induced inflammation, less is known about the transition from lung injury to repair and recovery. The objective of this study was to define the post inflammation homeostasis events following organic dust-induced lung injury. Using an established protocol, mice were intranasally treated with swine confinement facility organic dust extract (ODE) daily for 3 weeks (repetitive exposure) or treated daily with ODE for 3 weeks followed by no treatment for 1-4 weeks (recovery period) whereupon lavage fluid, lung tissue, and sera were processed. During recovery period, a significant decrease was observed in ODE-induced neutrophil levels after 1 week, lymphocytes at 2 weeks, and macrophages at 4 weeks in the lavage fluid. ODE-induced lung cellular aggregates and bronchiolar compartment inflammation were diminished, but persisted for 4 weeks post-injury. Alveolar inflammation resolved at 3 weeks. ODE-induced lung neutrophils were cleared by 3 weeks, B-cells by 2 weeks, and CD3+CD4+ and CD3+CD8+ T cells by 4 week recovery period. Collectively, these results identify important processes during recovery period following agricultural dust-induced inflammation, and present possible strategies for improving lung repair and resolution. PMID- 29387712 TI - Seizure Detection and Network Dynamics of Generalized Convulsive Seizures: Towards Rational Designing of Closed-Loop Neuromodulation. AB - Objective: Studies have demonstrated the utility of closed-loop neuromodulation in treating focal onset seizures. There is an utmost need of neurostimulation therapy for generalized tonic-clonic seizures. The study goals are to map the thalamocortical network dynamics during the generalized convulsive seizures and identify targets for reliable seizure detection. Methods: Local field potentials were recorded from bilateral cortex, hippocampi, and centromedian thalami in Sprague-Dawley rats. Pentylenetetrazol was used to induce multiple convulsive seizures. The performances of two automated seizure detection methods (line length and P-operators) as a function of different cortical and subcortical structures were estimated. Multiple linear correlations-Granger's Causality was used to determine the effective connectivity. Results: Of the 29 generalized tonic-clonic seizures analyzed, line length detected 100% of seizures in all the channels while the P-operator detected only 35% of seizures. The detection latencies were shortest in the thalamus in comparison to the cortex. There was a decrease in amplitude correlation within the thalamocortical network during the seizure, and flow of information was decreased from thalamus to hippocampal parietal nodes. Significance: The preclinical study confirms thalamus as a superior target for automated detection of generalized seizures and modulation of synchrony to increase coupling may be a strategy to abate seizures. PMID- 29387713 TI - MicroRNA and Putative Target Discoveries in Chrysanthemum Polyploidy Breeding. AB - MicroRNAs (miRNAs), around 22 nucleotides (nt) in length, are a class of endogenous and noncoding RNA molecule that play an essential role in plant development, either by suppressing the transcription of target genes at a transcriptional level or inhibiting translation at a posttranscriptional level. To understand the roles of miRNAs and their target genes in chrysanthemum polyploidy breeding, three sRNA libraries of normal and abnormal embryos after hybridization were performed by RNA-Seq. As a result, a total of 170 miRNAs were identified and there are 41 special miRNAs in cross of paternal chromosome doubling, such as miR169b, miR440, and miR528-5p. miR164c and miR159a were highly expressed in a normal embryo at 18 days after pollination, suggesting the regulatory role at the late stage of embryonic development. miR172c was only detected in the normal embryo at 18 days after pollination, which means that miR172c mainly mediates gene expression in postembryonic development and these genes may promote embryo maturation. Other miRNAs, including miR414, miR2661, and miR5021, may regulate the genes participated in pathways of auxin response and energy metabolism; then they regulate the complex embryonic development together. PMID- 29387714 TI - Start-Up and Aeration Strategies for a Completely Autotrophic Nitrogen Removal Process in an SBR. AB - The start-up and performance of the completely autotrophic nitrogen removal via nitrite (CANON) process were examined in a sequencing batch reactor (SBR) with intermittent aeration. Initially, partial nitrification was established, and then the DO concentration was lowered further, surplus water in the SBR with high nitrite was replaced with tap water, and continuous aeration mode was turned into intermittent aeration mode, while the removal of total nitrogen was still weak. However, the total nitrogen (TN) removal efficiency and nitrogen removal loading reached 83.07% and 0.422 kgN/(m3.d), respectively, 14 days after inoculating 0.15 g of CANON biofilm biomass into the SBR. The aggregates formed in SBR were the mixture of activated sludge and granular sludge; the volume ratio of floc and granular sludge was 7 : 3. DNA analysis showed that Planctomycetes-like anammox bacteria and Nitrosomonas-like aerobic ammonium oxidization bacteria were dominant bacteria in the reactor. The influence of aeration strategies on CANON process was investigated using batch tests. The result showed that the strategy of alternating aeration (1 h) and nonaeration (1 h) was optimum, which can obtain almost the same TN removal efficiency as continuous aeration while reducing the energy consumption, inhibiting the activity of NOB, and enhancing the activity of AAOB. PMID- 29387715 TI - Managing an Older Adult with Cancer: Considerations for Radiation Oncologists. AB - Older adults with cancer present a unique set of management complexities for oncologists and radiation oncologists. Prognosis and resilience to cancer treatments are notably dependent on the presence or risk of "geriatric syndromes," in addition to cancer stage and histology. Recognition, proper evaluation, and management of these conditions in conjunction with management of the cancer itself are critical and can be accomplished by utilization of various geriatric assessment tools. Here we review principles of the geriatric assessment, common geriatric syndromes, and application of these concepts to multidisciplinary oncologic treatment. Older patients may experience toxicities related to treatments that impact treatment effectiveness, quality of life, treatment-related mortality, and treatment compliance. Treatment-related burdens from radiotherapy are increasingly important considerations and include procedural demands, travel, costs, and temporary or permanent loss of functional independence. An overall approach to delivering radiotherapy to an older cancer patient requires a comprehensive assessment of both physical and nonphysical factors that may impact treatment outcome. Patient and family-centered communication is also an important part of developing a shared understanding of illness and reasonable expectations of treatment. PMID- 29387716 TI - PD-L1 Expression in TNBC: A Predictive Biomarker of Response to Neoadjuvant Chemotherapy? AB - Triple negative breast cancer (TNBC) has an aggressive clinical behaviour, with a poorer prognosis compared to other subtypes. Recently, tumor-infiltrating lymphocytes (TILs) have been proposed as a predictive biomarker for a better clinical outcome and pathological response (pR) after neoadjuvant chemotherapy (NACT) in TNBC. These data confirm the role of the immune system in the neoplastic progression and in the response to therapy. We performed a retrospective analysis of 54 pre-NACT biopsies of TNBC and compared both the percentage of stromal TILs and the degree of PD-L1 expression with the extent of pR to standard NACT. A pathological complete response (pCR) was achieved in 35% of cases. Univariate analysis showed (i) a significant association between PD-L1 expression in >=25% of neoplastic cells and the achievement of a pCR (p = 0.024); (ii) a significantly higher frequency of pCR in cases showing >=50% stromal TILs (p < 0.001). However in the multivariate analysis only PD-L1 expression on tumor cells remained significantly associated with pCR (OR = 1,13; 95% CI 1,01-1,27), suggesting that the expression of this biomarker could be associated with a subpopulation of TNBC more likely to respond to chemotherapy. These data need to be confirmed by larger studies. PMID- 29387717 TI - Socioeconomic Status, Frailty, and All-Cause Mortality in Korean Older Adults: A 3-Year Population-Based Prospective Study. AB - Background: Little is known regarding the effects of socioeconomic status (SES) and frailty on mortality in Korea. Objective: This study investigated the combined impact of low SES and frailty on all-cause mortality in Korean older adults. Methods: Study sample at baseline comprised 7,960 community-dwelling adults (56.8% women) aged 65 years and older. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of low SES and frailty for all-cause mortality. Results: Overall, low SES plus frailty resulted in an increased risk of all-cause mortality (HR = 1.56, 95% CI = 1.09-2.23, P = 0.015) even after adjustments for all the measured covariates, as compared with high SES plus nonfrailty (HR = 1). Among older adults aged 65-75 years, the increased mortality risk of either low SES plus nonfrailty (HR = 1.37, 95% CI = 1.02-1.84, P = 0.038) or high SES plus frailty (HR = 2.09, 95% CI = 1.12 3.91, P = 0.021) remained significant even after adjustments for all the covariates, as compared with high SES plus nonfrailty (HR = 1). Conclusion: The current findings suggest that either low SES or frailty is significantly associated with increased all-cause mortality in Korean older adults. PMID- 29387718 TI - Effects of Physical Activity on Motor Skills and Cognitive Development in Early Childhood: A Systematic Review. AB - Objective: This study synthesized literature concerning casual evidence of effects of various physical activity programs on motor skills and cognitive development in typically developed preschool children. Methods: Electronic databases were searched through July 2017. Peer-reviewed randomized controlled trials (RCTs) examining the effectiveness of physical activity on motor skills and cognitive development in healthy young children (4-6 years) were screened. Results: A total of 15 RCTs were included. Of the 10 studies assessing the effects of physical activity on motor skills, eight (80%) reported significant improvements in motor performance and one observed mixed findings, but one failed to promote any beneficial outcomes. Of the five studies investigating the influence of physical activity on cognitive development, four (80%) showed significant and positive changes in language learning, academic achievement, attention, and working memory. Notably, one indicated no significant improvements were observed after the intervention. Conclusions: Findings support causal evidence of effects of physical activity on both motor skills and cognitive development in preschool children. Given the shortage of available studies, future research with large representative samples is warranted to explore the relationships between physical activity and cognitive domains as well as strengthen and confirm the dose-response evidence in early childhood. PMID- 29387720 TI - Study of Nitrogen Removal Performance When Treating Low Carbon Sewage Using External Solid Carbon Sources in SBBR Systems. AB - Based on low carbon wastewater as the research object and using corncob as an external solid carbon source, the performance of corncob organic matter was assessed for its release potential, quantity of release, and safety of use. The effects of varying quantities of the solid carbon source on simultaneous nitrification and denitrification were investigated in a sequencing biofilm batch reactor (SBBR). Results show that the regularity of corncob as solid carbon source material was linear, with released concentrations of heavy metals being below the Chinese national standard limit values for heavy metals according to the surface water environment quality standards (I and II) (GB3838-2002). When temperatures were within 28~31 degrees C, the dissolved oxygen level was 4.0 +/- 0.2 mg/L and the pH conditions were within 7.5~8.0. The optimal quantity for corncob dosing was 5 g per 1.5 L of low carbon wastewater. Following treatment, the average effluent concentrations of NH4+-N and TN were 2.85 mg/L and 4.51 mg/L, respectively. The effluent concentration of NH4+-N, TN had reached the A level national standard of sewage treatment plant pollutant discharge standard (GB18918-2002). PMID- 29387721 TI - 3-Amino-1,2,4-triazole Limits the Oxidative Damage in UVA-Irradiated Dysplastic Keratinocytes. AB - Reactive oxygen species (ROS) generated by UVA irradiation affect the keratinocyte cell membrane, DNA, and proteins and may cause serious injury to the skin. Treating human dysplastic keratinocytes (DOK) with 3-amino-1,2,4-triazole (AMT), a common catalase inhibitor, induced a compensatory mechanism for the hydrogen peroxide detoxification, which included a rise in glutathione peroxidase and glutathione reductase activities. Here, we examined a possible role of AMT in protecting a human DOK cell line against UVA-induced damage. In DOK cells exposed to UVA irradiation, we observed a substantial decrease in antioxidant enzymatic activities, such as catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and an increase in lipid peroxidation and protein oxidation levels. Treating DOK cells with AMT prior to UVA exposure enhanced the activities of glutathione peroxidase, glutathione reductase, and glutathione-S transferase, relative to nontreated cells. The enhanced antioxidant activities were correlated with decreased protein oxidation levels. Based on these results, we suggest that AMT may protect dysplastic keratinocytes against the harmful effects of UVA radiation. PMID- 29387719 TI - Effect of Gonadotropin Types and Indications on Homologous Intrauterine Insemination Success: A Study from 1251 Cycles and a Review of the Literature. AB - Objective: To evaluate the IUI success factors relative to controlled ovarian stimulation (COS) and infertility type, this retrospective cohort study included 1251 couples undergoing homologous IUI. Results: We achieved 13% clinical pregnancies and 11% live births. COS and infertility type do not have significant effect on IUI clinical outcomes with unstable intervention of various couples' parameters, including the female age, the IUI attempt rank, and the sperm quality. Conclusion: Further, the COS used seemed a weak predictor for IUI success; therefore, the indications need more discussion, especially in unexplained infertility cases involving various factors. Indeed, the fourth IUI attempt, the female age over 40 years, and the total motile sperm count <5 * 106 were critical in decreasing the positive clinical outcomes of IUI. Those parameter cut-offs necessitate a larger analysis to give infertile couples more chances through IUI before carrying out other ART techniques. PMID- 29387722 TI - A Comparative Study of Actinidia deliciosa and Garcinia mangostana in Ovariectomy Induced Osteoporosis in Female Wistar Rats. AB - The present study was designed to evaluate antiosteoporotic activity of the fresh juice mixtures obtained from Actinidia deliciosa and Garcinia mangostana as well as the pericarp extract of Garcinia mangostana on postmenopausal osteoporosis. 3 month-old female Wistar rats were ovariectiomized and the treatment began 14 days after ovariectomy and continued for 40 days. Statistically significant changes were noticed in body weight, ash weight, bone mineral content, and femur length and weight followed by serum evaluation and histopathology of femur bone. Administration of the fresh juice mixtures of the fruits of Actinidia deliciosa and Garcinia mangostana prevented ovariectomy-induced bone loss. The administration of the fresh juice mixtures resulted in an increase in the femur length and weight, followed by an increase in the body weight as well as the calcium content obtained from the ash of the femur bone. It is evident that the fresh juice mixtures can be used as a remedy as well as a prophylactic for the prevention of postmenopausal osteoporosis. The present study showed that the combined effect of the fruit juice mixtures of Actinidia deliciosa and Garcinia mangostana was found to be a better treatment for postmenopausal osteoporosis when compared to the pericarp extract of Garcinia mangostana. PMID- 29387723 TI - The Common Mechanisms of Sarcopenia and NAFLD. AB - Current studies have shown that sarcopenia and nonalcoholic fatty liver disease (NAFLD) have similar pathophysiological profiles. The cooccurrence of sarcopenia and NAFLD has been observed in elderly patients. The actions of these conditions are linked, and their treatments are similar. Therefore, studies should be conducted on NAFLD-sarcopenia rather than on NAFLD or sarcopenia. PMID- 29387724 TI - Comparison of the Bone Harvesting Capacity of an Intraoral Bone Harvesting Device and Three Different Implant Drills. AB - The aim of the present study was to compare bone-collecting capacity of bone harvesting device and minimally irrigated low-speed drilling using three implant systems. One bone harvesting device and three commercially available drill systems were compared using the osteotomies on bovine rib bones. The amount of the collected bone particle and particle size (<500 MUm: small, 500-1000 MUm: medium, and >1000 MUm: large) were measured. Total wet (1.535 +/- 0.232 mL) and dry volume (1.147 +/- 0.425 mL) of the bone particles from bone harvesting device were significantly greater than three drill systems (wet volume: 1.225 +/- 0.187 1.27 +/- 0.29 mL and dry volume: 0.688 +/- 0.163-0.74 +/- 0.311 mL) (P < 0.05). In all groups, the amount of large sized particles in wet and dry state was the greatest compared to that of medium and small particles. The dry weight of the bone particles showed the same tendency to volumetric measurement. In conclusion, total bone particles and large sized particles (>1000 MUm) were harvested significantly greater by bone harvesting device than minimally irrigated low speed drilling. The composition of particle size in all harvesting methods was similar to each other. PMID- 29387725 TI - Neutrophil Extracellular Traps Are Pathogenic in Ventilator-Induced Lung Injury and Partially Dependent on TLR4. AB - The pathogenesis of ventilator-induced lung injury (VILI) is associated with neutrophils. Neutrophils release neutrophil extracellular traps (NETs), which are composed of DNA and granular proteins. However, the role of NETs in VILI remains incompletely understood. Normal saline and deoxyribonuclease (DNase) were used to study the role of NETs in VILI. To further determine the role of Toll-like receptor 4 (TLR4) in NETosis, we evaluated the lung injury and NET formation in TLR4 knockout mice and wild-type mice that were mechanically ventilated. Some measures of lung injury and the NETs markers were significantly increased in the VILI group. DNase treatment markedly reduced NETs markers and lung injury. After high-tidal mechanical ventilation, the NETs markers in the TLR4 KO mice were significantly lower than in the WT mice. These data suggest that NETs are generated in VILI and pathogenic in a mouse model of VILI, and their formation is partially dependent on TLR4. PMID- 29387726 TI - Study on Transformation of Ginsenosides in Different Methods. AB - Ginseng is a traditional Chinese medicine and has the extensive pharmacological activity. Ginsenosides are the major constituent in ginseng and have the unique biological activity and medicinal value. Ginsenosides have the good effects on antitumor, anti-inflammatory, antioxidative and inhibition of the cell apoptosis. Studies have showed that the major ginsenosides could be converted into rare ginsenosides, which played a significant role in exerting pharmacological activity. However, the contents of some rare ginsenosides are very little. So it is very important to find the effective way to translate the main ginsenosides to rare ginsenosides. In order to provide the theoretical foundation for the transformation of ginsenoside in vitro, in this paper, many methods of the transformation of ginsenoside were summarized, mainly including physical methods, chemical methods, and biotransformation methods. PMID- 29387727 TI - Decellularized Swine Dental Pulp as a Bioscaffold for Pulp Regeneration. AB - Endodontic regeneration shows promise in treating dental pulp diseases; however, no suitable scaffolds exist for pulp regeneration. Acellular natural extracellular matrix (ECM) is a favorable scaffold for tissue regeneration since the anatomical structure and ECM of the natural tissues or organs are well preserved. Xenogeneic ECM is superior to autologous or allogeneic ECM in tissue engineering for its unlimited resources. This study investigated the characteristics of decellularized dental pulp ECM from swine and evaluated whether it could mediate pulp regeneration. Dental pulps were acquired from the mandible anterior teeth of swine 12 months of age and decellularized with 10% sodium dodecyl sulfate (SDS) combined with Triton X-100. Pulp regeneration was conducted by seeding human dental pulp stem cells into decellularized pulp and transplanted subcutaneously into nude mice for 8 weeks. The decellularized pulp demonstrated preserved natural shape and structure without any cellular components. Histological analysis showed excellent ECM preservation and pulp-like tissue, and newly formed mineralized tissues were regenerated after being transplanted in vivo. In conclusion, decellularized swine dental pulp maintains ECM components favoring stem cell proliferation and differentiation, thus representing a suitable scaffold for improving clinical outcomes and functions of teeth with dental pulp diseases. PMID- 29387728 TI - The Effects of Ex Vivo Administration of Granulocyte-Macrophage Colony Stimulating Factor and Endotoxin on Cytokine Release of Whole Blood Are Determined by Priming Conditions. AB - Background: Lipopolysaccharide- (LPS-) induced tumour necrosis factor alpha (TNFalpha) secretion in critically ill patients can be considered as a measure of immune responsiveness. It can be enhanced by granulocyte-macrophage colony stimulating factor (GM-CSF). We investigated the effect of GM-CSF on ex vivo stimulated cytokine production using various preincubation regimens in healthy donors and patients with sepsis. Results: The maxima for the stimuli occurred 3 hours after stimulation. In donors, there was an increase (p < 0.001) of LPS induced TNFalpha levels following incubation with GM-CSF. The simultaneous incubation with GM-CSF and LPS caused an inhibition of TNFalpha production (p < 0.001). Postincubation with GM-CSF did not yield any difference. In patients, preincubation with GM-CSF yielded an enhanced ex vivo TNFalpha-response when TNFalpha levels were low. Patients with increased TNFalpha concentrations did not show a GM-CSF stimulation effect. The GM-CSF preincubation yielded an increase of IL-8 production in patients and donors. Conclusions: This study demonstrates the immune-modulating properties of GM-CSF depending on the absence or presence of LPS or systemic TNFalpha. The timing of GM-CSF administration may be relevant for the modulation of the immune system in sepsis. The lack of stimulation in patients with high TNFalpha may represent endotoxin tolerance. PMID- 29387729 TI - Clinical Phenotype of Diabetic Peripheral Neuropathy and Relation to Symptom Patterns: Cluster and Factor Analysis in Patients with Type 2 Diabetes in Korea. AB - Objectives: Patients with diabetic peripheral neuropathy (DPN) is the most common complication. However, patients are usually suffering from not only diverse sensory deficit but also neuropathy-related discomforts. The aim of this study is to identify distinct groups of patients with DPN with respect to its clinical impacts on symptom patterns and comorbidities. Methods: A hierarchical cluster analysis and factor analysis were performed to identify relevant subgroups of patients with DPN (n = 1338) and symptom patterns. Results: Patients with DPN were divided into three clusters: asymptomatic (cluster 1, n = 448, 33.5%), moderate symptoms with disturbed sleep (cluster 2, n = 562, 42.0%), and severe symptoms with decreased quality of life (cluster 3, n = 328, 24.5%). Patients in cluster 3, compared with clusters 1 and 2, were characterized by higher levels of HbA1c and more severe pain and physical impairments. Patients in cluster 2 had moderate pain levels but disturbed sleep patterns comparable to those in cluster 3. The frequency of symptoms on each item of MNSI by "painful" symptom pattern showed a similar distribution pattern with increasing intensities along the three clusters. Conclusions: Cluster and factor analysis endorsed the use of comprehensive and symptomatic subgrouping to individualize the evaluation of patients with DPN. PMID- 29387730 TI - Enhancing Exercise Responsiveness across Prediabetes Phenotypes by Targeting Insulin Sensitivity with Nutrition. AB - Exercise is a cornerstone therapy for chronic diseases related to multiorgan insulin resistance. However, not all individuals show the anticipated improvement in insulin sensitivity following exercise and these individuals are considered exercise resistant. Caloric restriction is an approach to enhance the effect of exercise on increasing peripheral and hepatic insulin sensitivity, as replenishing expended calories blunts these benefits. Alternatively, restricting carbohydrate intake, independent of energy balance, following exercise provides an additive effect on peripheral insulin sensitivity when compared to refeeding carbohydrate. Although carbohydrate composition modulates insulin sensitivity, few have studied effects of low glycemic index or whole-grain diets following exercise across prediabetes phenotypes on insulin sensitivity. Herein, we propose the novel hypothesis that the combination of individualized nutrition therapy and exercise should be based on the clinical pathology of prediabetes to overcome exercise resistance and improve responsiveness in people at risk for type 2 diabetes and cardiovascular disease. PMID- 29387733 TI - Natural Immunomodulators. PMID- 29387732 TI - Metabolic Plasticity in Dendritic Cell Responses: Implications in Allergic Asthma. AB - Dendritic cells (DCs) are highly specialized in antigen presentation and play a pivotal role in the initiation, progression, and perpetuation of adaptive immune responses. Emerging immune pathways are being recognized increasingly for DCs and their subsets that differentially regulate T lymphocyte function based on the type and interactions with the antigen. However, these interactions not only alter the signaling process and DC function but also render metabolic plasticity. The current review focuses on the metabolic cues of DCs that coordinate DC activation and differentiation and discuss whether targeting these fundamental cellular processes have implications to control airway inflammation and adaptive immunity. Therefore, strategies using metabolism-based therapeutic manipulation of DC functions could be developed into novel treatments for airway inflammation and asthma. PMID- 29387734 TI - Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. AB - RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy. PMID- 29387731 TI - Cardiovascular Screening for the Asymptomatic Patient with Diabetes: More Cons Than Pros. AB - Diabetes mellitus is associated with an increased risk of coronary heart disease (CHD) morbidity and mortality. Although it frequently coexists with other cardiovascular disease (CVD) risk factors, it confers an increased risk for CVD events on its own. Coronary atherosclerosis is generally more aggressive and widespread in people with diabetes (PWD) and is frequently asymptomatic. Screening for silent myocardial ischaemia can be applied in a wide variety of ways. In nearly all asymptomatic PWD, however, the results of screening will generally not change medical therapy, since aggressive preventive measures, such as control of blood pressure and lipids, would have been already indicated, and above all, invasive revascularization procedures (either with percutaneous coronary intervention or coronary artery bypass grafting) have not been shown in randomized clinical trials to confer any benefit on morbidity and mortality. Still, unresolved issues remain regarding the extent of the underlying ischaemia that might affect the risk and the benefit of revascularization (on top of optimal medical therapy) in ameliorating this risk in patients with moderate to severe ischaemia. The issues related to the detection of coronary atherosclerosis and ischaemia, as well as the studies related to management of CHD in asymptomatic PWD, will be reviewed here. PMID- 29387736 TI - Phosphoglyceride crystal deposition disease mimicking a malignant tumor. AB - A 45-year-old woman who had undergone surgical repair for an atrial septal defect at the age of 7 years presented with multiple anterior mediastinal masses. Positron-emission tomography (PET) with 2-[18F]fluoro-2-deoxy-d-glucose (FDG) revealed high uptake in the masses. The findings were interpreted as mediastinal malignant tumors with dissemination. Biopsy was performed, and the histological diagnosis was phosphoglyceride crystal deposition disease without neoplastic changes. Although phosphoglyceride crystal deposition disease is rare, it should be recognized as a potential interpretive pitfall that mimics a malignant tumor in FDG-PET findings in a patient after cardiac surgery. PMID- 29387737 TI - Data on the effect of Pseudomonas stutzeri E25 and Stenotrophomonas maltophilia CR71 culture supernatants on the mycelial growth of Botrytis cinerea. AB - Plant growth-promoting bacterial endophytes (PGPBEs) produce volatile and diffusible compounds that inhibit phytopathogens (Santoyo et al., 2016) [1]. A recent work by Rojas-Solis and colleagues [2] demonstrated the antifungal effect of volatile organic compounds exerted by the Pseudomonas stutzeri E25 and Stenotrophomonas maltophilia CR71 endophytes, highlighting the production of sulfur-containing compounds such as the antimicrobial volatile dimethyl disulfide (DMDS). The data presented in this article include the effect of two culture supernatants from the same strains, E25 and CR71, on the mycelial growth of the gray mold phytopathogen Botrytis cinerea. These data may help to further evaluate the specific compounds produced by endophyte isolates E25 and CR71 with antifungal activity. This article is submitted as a companion paper to Rojas Solis et al. (2018) [2]. PMID- 29387735 TI - MRI findings of complications related to previous uterine scars. AB - Although the World Health Organization suggests 10-15% as the adequate cesarean delivery rate to assure optimal prognosis for mother and children, cesarean rates have continuously increased worldwide over the last three decades, even in primiparous women. Moreover, uterine scars after myomectomies, complications of obstetrical interventions and more recently, after fetal surgery, are often observed. This review article describes the most commonly seen complications related to prior uterine scars and discusses their imaging findings, with emphasis on the increasing role of Magnetic Resonance Imaging for diagnosis. PMID- 29387738 TI - Ocean currents and acoustic backscatter data from shipboard ADCP measurements at three North Atlantic seamounts between 2004 and 2015. AB - Seamounts are amongst the most common physiographic structures of the deep-ocean landscape, but remoteness and geographic complexity have limited the systematic collection of integrated and multidisciplinary data in the past. Consequently, important aspects of seamount ecology and dynamics remain poorly studied. We present a data collection of ocean currents and raw acoustic backscatter from shipboard Acoustic Doppler Current Profiler (ADCP) measurements during six cruises between 2004 and 2015 in the tropical and subtropical Northeast Atlantic to narrow this gap. Measurements were conducted at seamount locations between the island of Madeira and the Portuguese mainland (Ampere, Seine Seamount), as well as east of the Cape Verde archipelago (Senghor Seamount). The dataset includes two-minute ensemble averaged continuous velocity and backscatter profiles, supplemented by spatially gridded maps for each velocity component, error velocity and local bathymetry. The dataset is freely available from the digital data library PANGAEA at https://doi.pangaea.de/10.1594/PANGAEA.883193. PMID- 29387739 TI - Data and performance profiles applying an adaptive truncation criterion, within linesearch-based truncated Newton methods, in large scale nonconvex optimization. AB - In this paper, we report data and experiments related to the research article entitled "An adaptive truncation criterion, for linesearch-based truncated Newton methods in large scale nonconvex optimization" by Caliciotti et al. [1]. In particular, in Caliciotti et al. [1], large scale unconstrained optimization problems are considered by applying linesearch-based truncated Newton methods. In this framework, a key point is the reduction of the number of inner iterations needed, at each outer iteration, to approximately solving the Newton equation. A novel adaptive truncation criterion is introduced in Caliciotti et al. [1] to this aim. Here, we report the details concerning numerical experiences over a commonly used test set, namely CUTEst (Gould et al., 2015) [2]. Moreover, comparisons are reported in terms of performance profiles (Dolan and More, 2002) [3], adopting different parameters settings. Finally, our linesearch-based scheme is compared with a renowned trust region method, namely TRON (Lin and More, 1999) [4]. PMID- 29387741 TI - Data of piezoelectric vibration energy harvesting of a bridge undergoing vibration testing and train passage. AB - The data presented in this article is in relation to the research article "Vibration energy harvesting based monitoring of an operational bridge undergoing forced vibration and train passage" Cahill et al. (2018) [1]. The article provides data on the full-scale bridge testing using piezoelectric vibration energy harvesters on Pershagen Bridge, Sweden. The bridge is actively excited via a swept sinusoidal input. During the testing, the bridge remains operational and train passages continue. The test recordings include the voltage responses obtained from the vibration energy harvesters during these tests and train passages. The original dataset is made available to encourage the use of energy harvesting for Structural Health Monitoring. PMID- 29387740 TI - Draft genome assembly of Colletotrichum musae, the pathogen of banana fruit. AB - Colletotrichum musae is an important cosmopolitan pathogenic fungus that causes anthracnose in banana fruit. The entire genome of C. musae isolate GM20 (CMM 4420), originally isolated from infected banana fruit from Alagoas State, Brazil, was sequenced and annotated. The pathogen genomic DNA was sequenced on HiSeq Illumina platform. The C. musae GM20 genome has 50,635,197 bp with G + C content of 53.74% and in its present assembly has 2763 scaffolds, harboring 13,451 putative genes with an average length of 1626 bp. Gene prediction and annotation was performed by Funannotate pipeline, using a pattern for gene identification based on BUSCO. PMID- 29387742 TI - Is the hip prosthesis responsible for this rash? PMID- 29387743 TI - Hemorrhagic lesion on the chest wall after trauma. PMID- 29387744 TI - Three-dimensional eyebrows. PMID- 29387745 TI - Intracranial regression of an advanced basal cell carcinoma using sonidegib and itraconazole after failure with vismodegib. PMID- 29387746 TI - Sporotrichosis in the nail-An unusual location and presentation. PMID- 29387747 TI - Cutaneous polyarteritis nodosa resulting from a paclitaxel-eluting balloon angioplasty. PMID- 29387748 TI - Topical ingenol mebutate is effective against plantar warts in immunocompromised patients. PMID- 29387749 TI - Ibrutinib-associated pityriasis rosea-like rash. PMID- 29387750 TI - Balanitis associated with FOLFIRI chemotherapy. PMID- 29387751 TI - Hemorrhagic vesiculobullous eruption on the palms and the soles as presentation of dyshidrosiform bullous pemphigoid. PMID- 29387752 TI - Acquired lymphangioma circumscriptum of the genitals in an individual with chronic hidradenitis suppurativa. PMID- 29387754 TI - Arsenical keratosis secondary to Fowler solution. PMID- 29387753 TI - Paraneoplastic pemphigus mimicking toxic epidermal necrolysis: An underdiagnosed entity? PMID- 29387755 TI - New-onset acrokeratoelastoidosis in an immunosuppressed patient. PMID- 29387756 TI - Prurigo pigmentosa: Case series and differentiation from confluent and reticulated papillomatosis. PMID- 29387757 TI - Successful treatment of mucous membrane pemphigoid with bortezomib. PMID- 29387758 TI - A case of eosinophilic annular erythema as a presenting sign for autoimmune hepatitis. PMID- 29387759 TI - LPIN2 gene mutation in a patient with overlapping neutrophilic disease (pyoderma gangrenosum and aseptic abscess syndrome). PMID- 29387760 TI - Acute generalized exanthematous pustulosis simulating Stevens-Johnson syndrome/toxic epidermal necrolysis associated with the use of vismodegib. PMID- 29387761 TI - Primary cutaneous carcinosarcoma developing after chronic C-arm radiation exposure. PMID- 29387762 TI - Multiple epidermotropic melanoma metastases developing during BRAF and MEK inhibitor therapy. PMID- 29387763 TI - Lichen planopilaris associated with pembrolizumab in a patient with metastatic melanoma. PMID- 29387764 TI - Synchronous presentation of systemic lupus erythematosus and oral reticular lichen planus. PMID- 29387765 TI - Oral melanoacanthoma of the palate: An unusual presentation of an uncommon entity. PMID- 29387766 TI - Black-spot poison ivy, a report of 3 cases with clinicopathologic correlation. PMID- 29387767 TI - Alopecia areata after dupilumab for atopic dermatitis. PMID- 29387768 TI - Vitiligo immune reconstitution inflammatory syndrome (IRIS)-An incidental finding in a tertiary teaching hospital in southeast Nigeria. PMID- 29387769 TI - Random skin biopsy for diagnosis of intravascular large B-cell lymphoma in a patient with hypoxemia and normal lung imaging. PMID- 29387770 TI - Granulomatous drug eruption associated with imipramine. PMID- 29387771 TI - Dermatofibrosarcoma protuberans in pediatric patients: A diagnostic and management challenge. PMID- 29387772 TI - Pancreatitis associated with calciphylaxis successfully treated with sodium thiosulfate. PMID- 29387773 TI - Unilateral, localized bullous pemphigoid in a patient with chronic venous stasis. PMID- 29387774 TI - Dermoscopy of eccrine angiomatous hamartoma: The popcorn pattern. PMID- 29387775 TI - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: Case report of severe multiorgan involvement to perindopril/amlodipine combination antihypertensive. PMID- 29387776 TI - Associated characteristics and impact on recurrence and survival of free-floating tumor fragments in the lumen of fallopian tubes in Type I and Type II endometrial cancer. AB - Objective: This study sought to evaluate characteristics of cases of free floating tumor fragments within the lumen of fallopian tubes ('floaters') on final pathology for Type I and Type II endometrial adenocarcinoma, including relationships with disease recurrence and mortality. Methods: A single institution experience of 1022 consecutive cases of uterine cancer presenting between 2005 and 2010 was retrospectively reviewed, with data extraction from electronic medical records. Associations of floaters with baseline characteristics were studied with logistic regression, and relationships with disease recurrence and survival were assessed with Cox proportional hazards models. Results: Among 816 included cases of Type I or Type II endometrial adenocarcinoma, floaters were identified on final pathology for 20 patients (2.5%). Patient characteristics of cases with floaters mirrored the overall sample. With adjustment, presence of floaters trended towards association with laparoscopic/robotic approach (OR = 3.84; 95%CI 0.98-15.1), and was significantly associated with lymphovascular invasion (OR = 9.65; 95%CI 2.35-39.6) and higher stage disease. Although floaters were associated with increased risk of recurrence in unadjusted analysis (HR = 3.22; 95%CI 1.41-7.37), after adjustment for disease type, stage, and patient comorbidities, no evidence for impact on disease recurrence or overall survival was found. Conclusions: The presence of floaters is rare. Floaters were generally associated with more extensive disease, but no evidence was found to show any independent prognostic impact on risk of recurrence or death. In agreement with prior research, this study found a trend towards association of floaters with laparoscopic/robotic approach, indicating the possibility of floaters sometimes being the result of trauma from uterine manipulator insertion. PMID- 29387777 TI - The Diagnostic Utility and Clinical Impact of After-Hours CT Scans of the Abdomen and Pelvis Investigating Abdominal Pain. AB - Introduction: The aim of this study was to evaluate the diagnostic utility and impact on clinical management of after-hours CT scans investigating abdominal pain in surgical patients. Methods: After-hours CT A/P reports investigating the acute surgical abdomen were compared with clinical outcomes and histopathological findings to assess sensitivity and specificity of CT reporting. Comparisons between CT reports and clinical notes were made. CT scans were categorised as having direct effects on clinical management, ruling out a serious pathology, ruling out a nonserious pathology, or having no effect. Discrepancies between information in case-notes and information provided to radiologists were also analysed. Results: 79 clinical notes were located. After-hours CT demonstrated 91% sensitivity and 82% reporting specificity using clinical outcomes as the standard. In the 26 patients with histopathological findings, CT reports demonstrated 91% sensitivity. In 79.7% of cases, CT scanning had an impact on management. In 35.4% of cases, an indication for scanning was not documented with variation in clinical information in 8.9% of cases. Discussion: This study demonstrates after-hours CT A/P reports result in significant impacts on clinical management of surgical patients with acute abdominal pain. Improvements in providing information when requesting scans are however needed to facilitate accurate reporting. PMID- 29387778 TI - Chemical Composition and Nutritive Benefits of Chicory (Cichorium intybus) as an Ideal Complementary and/or Alternative Livestock Feed Supplement. AB - Chicory is a perennial plant grown in different parts of the world, used as forage for livestock, as folklore remedies, or as a vegetable addition in human diets. There are several varieties of the chicory plant, known differently globally due to its numerous medicinal, culinary, and nutritional qualities. Most parts of the plant contain a potpourri of nutrients ranging within carbohydrates, proteins, vitamins, minerals, soluble fiber, trace elements, and bioactive phenolic compounds, which are responsible for the various nutritive, prophylactic, and therapeutic qualities of chicory. Inulin, coumarins, tannins, monomeric flavonoids, and sesquiterpene lactones are some of the major phytocompounds mostly found in chicory plants. The health-promoting activities attributed to chicory comprise, among others, anti-inflammatory, anticarcinogenic, antiviral, antibacterial, antimutagenic, antifungal, anthelmintic, immune-stimulating, and antihepatotoxic and its antioxidative qualities. As a versatile plant, chicory's chemical composition and use as a suitable livestock feed supplement or as an alternative feed ingredient (AFI) are thus reviewed. PMID- 29387779 TI - Mind Your Step: the Effects of Mobile Phone Use on Gaze Behavior in Stair Climbing. AB - Stair walking is a hazardous activity and a common cause of fatal and non-fatal falls. Previous studies have assessed the role of eye movements in stair walking by asking people to repeatedly go up and down stairs in quiet and controlled conditions, while the role of peripheral vision was examined by giving participants specific fixation instructions or working memory tasks. We here extend this research to stair walking in a natural environment with other people present on the stairs and a now common secondary task: using one's mobile phone. Results show that using the mobile phone strongly draws one's attention away from the stairs, but that the distribution of gaze locations away from the phone is little influenced by using one's phone. Phone use also increased the time needed to walk the stairs, but handrail use remained low. These results indicate that limited foveal vision suffices for adequate stair walking in normal environments, but that mobile phone use has a strong influence on attention, which may pose problems when unexpected obstacles are encountered. PMID- 29387780 TI - Opposing and Complementary Topographic Connectivity Gradients Revealed by Quantitative Analysis of Canonical and Noncanonical Hippocampal CA1 Inputs. AB - Physiological studies suggest spatial representation gradients along the CA1 proximodistal axis. To determine the underlying anatomical basis, we quantitatively mapped canonical and noncanonical inputs to excitatory neurons in dorsal hippocampal CA1 along the proximal-distal axis in mice of both sexes using monosynaptic rabies tracing. Our quantitative analyses show comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Noncanonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum-CA1 input strength systematically increases but the presubiculum-CA1 input strength decreases along the proximal-distal axis. The subiculum input strength cotracks that of the lateral EC, known to be less spatially selective than the medial EC. The functional significance of this organization is verified physiologically for subiculum-to-CA1 inputs. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 representations. PMID- 29387781 TI - PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838. AB - Battlefield blast exposure related to improvised explosive devices (IEDs) has become the most common cause of traumatic brain injury (TBI) in the recent conflicts in Iraq and Afghanistan. Mental health problems are common after TBI. A striking feature in the most recent veterans has been the frequency with which mild TBI (mTBI) and posttraumatic stress disorder (PTSD) have appeared together, in contrast to the classical situations in which the presence of mTBI has excluded the diagnosis of PTSD. However, treatment of PTSD-related symptoms that follow blast injury has become a significant problem. BCI-838 (MGS0210) is a Group II metabotropic glutamate receptor (mGluR2/3) antagonist prodrug, and its active metabolite BCI-632 (MGS0039) has proneurogenic, procognitive, and antidepressant activities in animal models. In humans, BCI-838 is currently in clinical trials for refractory depression and suicidality. The aim of the current study was to determine whether BCI-838 could modify the anxiety response and reverse PTSD-related behaviors in rats exposed to a series of low-level blast exposures designed to mimic a human mTBI or subclinical blast exposure. BCI-838 treatment reversed PTSD-related behavioral traits improving anxiety and fear related behaviors as well as long-term recognition memory. Treatment with BCI-838 also increased neurogenesis in the dentate gyrus (DG) of blast-exposed rats. The safety profile of BCI-838 together with the therapeutic activities reported here, make BCI-838 a promising drug for the treatment of former battlefield Warfighters suffering from PTSD-related symptoms following blast-induced mTBI. PMID- 29387783 TI - Systematic evaluation of levodopa-carbidopa intestinal gel patient-responder characteristics. AB - Levodopa-carbidopa intestinal gel (LCIG, carbidopa-levodopa enteral suspension in the United States) is a treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. The objective of this investigation was to identify the baseline characteristics predictive of treatment response, measured by improvement in motor symptom severity, in advanced PD patients treated with LCIG during a 54-week, open-label phase 3 study. Patients with >=1 h improvement from baseline in "Off" time were categorized as "Responders"; whereas those with <1 h improvement, any worsening, or no post-baseline assessment were "Non Responders". A subgroup of Responders with >=3 h improvement in "Off" time was also examined; this subgroup was identified as "Robust Responders". Baseline demographics and disease characteristics were analyzed and their predictive relationship to change from baseline in normalized "Off" time was assessed. Out of the 324 patients included in the analysis, 272 (84.0%) were categorized as Responders and 52 (16.0%) were Non-Responders. A majority of patients (65.7%) had >=3 h improvement in "Off" time. In general, baseline characteristics were similar between Non-responders, Responders, and the subgroup of Robust Responders. A conditional tree-structured regression analysis identified baseline "Off" time as the only factor that had significant effect on Responder and Robust Responder status. The safety profile of LCIG was similar between patient groups. Overall, this analysis showed that 84% of LCIG-treated advanced PD patients had >=1 h improvement in "Off" time and the number-needed-to-treat to observe one patient responder was 1.19 patients. Notably, Responders and Robust Responders to LCIG were observed across the range of baseline demographics and clinical characteristics examined. PMID- 29387782 TI - Study of the Size and Shape of Synapses in the Juvenile Rat Somatosensory Cortex with 3D Electron Microscopy. AB - Changes in the size of the synaptic junction are thought to have significant functional consequences. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to obtain stacks of serial sections from the six layers of the rat somatosensory cortex. We have segmented in 3D a large number of synapses (n = 6891) to analyze the size and shape of excitatory (asymmetric) and inhibitory (symmetric) synapses, using dedicated software. This study provided three main findings. Firstly, the mean synaptic sizes were smaller for asymmetric than for symmetric synapses in all cortical layers. In all cases, synaptic junction sizes followed a log-normal distribution. Secondly, most cortical synapses had disc-shaped postsynaptic densities (PSDs; 93%). A few were perforated (4.5%), while a smaller proportion (2.5%) showed a tortuous horseshoe shaped perimeter. Thirdly, the curvature was larger for symmetric than for asymmetric synapses in all layers. However, there was no correlation between synaptic area and curvature. PMID- 29387785 TI - Characterization of bone only metastasis patients with respect to tumor subtypes. AB - Metastatic breast cancer (MBC) patients with bone only metastasis (BOM) are a unique population with limited characterization. We identified patients followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis. Tumor subtype (TS) was assessed by initial breast biopsy immunohistochemistry using hormonal receptor (HR) and HER2 status, with four subtypes identified: HR+/HER2-, HR+/HER2+, HR-/HER2-, HR /HER2+. HR+ was defined as estrogen receptor or progesterone receptor >=1%. We identified 1445 patients with BOM, 1048 with TS data available. Among these patients, the majority were HR+/HER2- (78%). Median time from breast cancer diagnosis to first bone metastasis was 2.3 years (95% CI 2.1, 2.5) and varied significantly by TS, with longer time to distant disease in HR+/HER2- patients relative to all other TS (p < .0001). Median overall survival (OS) from breast cancer diagnosis was 8.7 years (95% CI 8.0, 9.7) and varied significantly by TS with poorer OS for HR-/HER2- and HR-/HER2+ patients relative to HR+/HER2- TS (p < .0001). The 442 patients with de novo BOM disease, defined as bone metastasis diagnosis within 4 months of breast cancer diagnosis, had significantly shorter OS (p < .0001). Overall, several higher risk BOM subsets were identified in this analysis, most notably HR-/HER2+ and HR-/HER2- TS and de novo BOM patients. PMID- 29387784 TI - Gene-metabolite profile integration to understand the cause of spaceflight induced immunodeficiency. AB - Spaceflight presents a spectrum of stresses very different from those associated with terrestrial conditions. Our previous study (BMC Genom. 15: 659, 2014) integrated the expressions of mRNAs, microRNAs, and proteins and results indicated that microgravity induces an immunosuppressive state that can facilitate opportunistic pathogenic attack. However, the existing data are not sufficient for elucidating the molecular drivers of the given immunosuppressed state. To meet this knowledge gap, we focused on the metabolite profile of spaceflown human cells. Independent studies have attributed cellular energy deficiency as a major cause of compromised immunity of the host, and metabolites that are closely associated with energy production could be a robust signature of atypical energy fluctuation. Our protocol involved inoculation of human endothelial cells in cell culture modules in spaceflight and on the ground concurrently. Ten days later, the cells in space and on the ground were exposed to lipopolysaccharide (LPS), a ubiquitous membrane endotoxin of Gram-negative bacteria. Nucleic acids, proteins, and metabolites were collected 4 and 8 h post LPS exposure. Untargeted profiling of metabolites was followed by targeted identification of amino acids and knowledge integration with gene expression profiles. Consistent with the past reports associating microgravity with increased energy expenditure, we identified several markers linked to energy deficiency, including various amino acids such as tryptophan, creatinine, dopamine, and glycine, and cofactors such as lactate and pyruvate. The present study revealed a molecular architecture linking energy metabolism and immunodeficiency in microgravity. The energy-deficient condition potentially cascaded into dysregulation of protein metabolism and impairment of host immunity. This project is limited by a small sample size. Although a strict statistical screening was carefully implemented, the present results further emphasize the need for additional studies with larger sample sizes. Validating this hypothesis using an in vivo model is essential to extend the knowledge towards identifying markers of diagnostic and therapeutic value. PMID- 29387787 TI - Ultralow power artificial synapses using nanotextured magnetic Josephson junctions. AB - Neuromorphic computing promises to markedly improve the efficiency of certain computational tasks, such as perception and decision-making. Although software and specialized hardware implementations of neural networks have made tremendous accomplishments, both implementations are still many orders of magnitude less energy efficient than the human brain. We demonstrate a new form of artificial synapse based on dynamically reconfigurable superconducting Josephson junctions with magnetic nanoclusters in the barrier. The spiking energy per pulse varies with the magnetic configuration, but in our demonstration devices, the spiking energy is always less than 1 aJ. This compares very favorably with the roughly 10 fJ per synaptic event in the human brain. Each artificial synapse is composed of a Si barrier containing Mn nanoclusters with superconducting Nb electrodes. The critical current of each synapse junction, which is analogous to the synaptic weight, can be tuned using input voltage spikes that change the spin alignment of Mn nanoclusters. We demonstrate synaptic weight training with electrical pulses as small as 3 aJ. Further, the Josephson plasma frequencies of the devices, which determine the dynamical time scales, all exceed 100 GHz. These new artificial synapses provide a significant step toward a neuromorphic platform that is faster, more energy-efficient, and thus can attain far greater complexity than has been demonstrated with other technologies. PMID- 29387786 TI - Racism as a Unique Social Determinant of Mental Health: Development of a Didactic Curriculum for Psychiatry Residents. AB - Introduction: Mental health disparities based on minority racial status are well characterized, including inequities in access, symptom severity, diagnosis, and treatment. For African Americans, racism may affect mental health through factors such as poverty and segregation, which have operated since slavery. While the need to address racism in medical training has been recognized, there are few examples of formal didactic curricula in the psychiatric literature. Antiracism didactics during psychiatry residency provide a unique opportunity to equip physicians to address bias and racism in mental health care. Methods: With advocacy by residents in the Massachusetts General Hospital/McLean Psychiatry residency program, the Division of Public and Community Psychiatry developed a curriculum addressing racial inequities in mental health, particularly those experienced by African Americans. Four 50-minute interactive didactic lectures were integrated into the required didactic curriculum (one lecture per postgraduate training class) during the 2015-2016 academic year. Results: Of residents who attended lectures and provided anonymous feedback, 97% agreed that discussing racism in formal didactics was at least "somewhat" positive, and 92% agreed that it should "probably" or "definitely" remain in the curriculum. Qualitative feedback centered on a need for more time to discuss racism as well as a desire to learn more about minority mental health advocacy in general. Discussion: Teaching about racism as part of required training conveys the explicit message that this is core curricular material and critical knowledge for all physicians. These lectures can serve as a springboard for dissemination and provide scaffolding for similar curriculum development in medical residency programs. PMID- 29387788 TI - An optical authentication system based on imaging of excitation-selected lanthanide luminescence. AB - Secure data encryption relies heavily on one-way functions, and copy protection relies on features that are difficult to reproduce. We present an optical authentication system based on lanthanide luminescence from physical one-way functions or physical unclonable functions (PUFs). They cannot be reproduced and thus enable unbreakable encryption. Further, PUFs will prevent counterfeiting if tags with unique PUFs are grafted onto products. We have developed an authentication system that comprises a hardware reader, image analysis, and authentication software and physical keys that we demonstrate as an anticounterfeiting system. The physical keys are PUFs made from random patterns of taggants in polymer films on glass that can be imaged following selected excitation of particular lanthanide(III) ions doped into the individual taggants. This form of excitation-selected imaging ensures that by using at least two lanthanide(III) ion dopants, the random patterns cannot be copied, because the excitation selection will fail when using any other emitter. With the developed reader and software, the random patterns are read and digitized, which allows a digital pattern to be stored. This digital pattern or digital key can be used to authenticate the physical key in anticounterfeiting or to encrypt any message. The PUF key was produced with a staggering nominal encoding capacity of 73600. Although the encoding capacity of the realized authentication system reduces to 6 * 10104, it is more than sufficient to completely preclude counterfeiting of products. PMID- 29387789 TI - Superresolution and pulse-chase imaging reveal the role of vesicle transport in polar growth of fungal cells. AB - Polarized growth of filamentous fungi requires continuous transport of biomolecules to the hyphal tip. To this end, construction materials are packaged in vesicles and transported by motor proteins along microtubules and actin filaments. We have studied these processes with quantitative superresolution localization microscopy of live Aspergillus nidulans cells expressing the photoconvertible protein mEosFPthermo fused to the chitin synthase ChsB. ChsB is mainly located at the Spitzenkorper near the hyphal tip and produces chitin, a key component of the cell wall. We have visualized the pulsatory dynamics of the Spitzenkorper, reflecting vesicle accumulation before exocytosis and their subsequent fusion with the apical plasma membrane. Furthermore, high-speed pulse chase imaging after photoconversion of mEosFPthermo in a tightly focused spot revealed that ChsB is transported with two different speeds from the cell body to the hyphal tip and vice versa. Comparative analysis using motor protein deletion mutants allowed us to assign the fast movements (7 to 10 MUm s-1) to transport of secretory vesicles by kinesin-1, and the slower ones (2 to 7 MUm s-1) to transport by kinesin-3 on early endosomes. Our results show how motor proteins ensure the supply of vesicles to the hyphal tip, where temporally regulated exocytosis results in stepwise tip extension. PMID- 29387790 TI - Cross-stream migration of active particles. AB - For natural microswimmers, the interplay of swimming activity and external flow can promote robust directed motion, for example, propulsion against (upstream rheotaxis) or perpendicular to the direction of flow. These effects are generally attributed to their complex body shapes and flagellar beat patterns. Using catalytic Janus particles as a model experimental system, we report on a strong directional response that occurs for spherical active particles in a channel flow. The particles align their propulsion axes to be nearly perpendicular to both the direction of flow and the normal vector of a nearby bounding surface. We develop a deterministic theoretical model of spherical microswimmers near a planar wall that captures the experimental observations. We show how the directional response emerges from the interplay of shear flow and near-surface swimming activity. Finally, adding the effect of thermal noise, we obtain probability distributions for the swimmer orientation that semiquantitatively agree with the experimental distributions. PMID- 29387791 TI - Programming a crystalline shape memory polymer network with thermo- and photo reversible bonds toward a single-component soft robot. AB - The need to support the two most basic functions [three-dimensional (3D)-shaped support and actuation] independently for a typical robot demands that at least two components should be used in its construction. Therefore, component assembly is unavoidable despite the ultimate dream of creating assembly-free robots. We devise a strategy that uses a programmable crystalline shape memory polymer with thermo- and photo-reversible bonds to create a single-component robot. The global 3D-shaped structural support is fabricated via a plasticity-based origami technique enabled by the thermo-reversible bonds. More critically, precisely controlled localized actuation can be programmed into the 3D origami via spatially defined reversible shape memory using the photo-reversible bonds. The overall result is that a polymer thin film can be programmed into various soft robots including a 3D crane and an elephant. Besides reversible shape memory, other types of actuation mechanisms can be potentially introduced via a similar principle. Thus, our strategy represents a general method to create single component soft robots. PMID- 29387792 TI - Disequilibrium biosignatures over Earth history and implications for detecting exoplanet life. AB - Chemical disequilibrium in planetary atmospheres has been proposed as a generalized method for detecting life on exoplanets through remote spectroscopy. Among solar system planets with substantial atmospheres, the modern Earth has the largest thermodynamic chemical disequilibrium due to the presence of life. However, how this disequilibrium changed over time and, in particular, the biogenic disequilibria maintained in the anoxic Archean or less oxic Proterozoic eons are unknown. We calculate the atmosphere-ocean disequilibrium in the Precambrian using conservative proxy- and model-based estimates of early atmospheric and oceanic compositions. We omit crustal solids because subsurface composition is not detectable on exoplanets, unlike above-surface volatiles. We find that (i) disequilibrium increased through time in step with the rise of oxygen; (ii) both the Proterozoic and Phanerozoic may have had remotely detectable biogenic disequilibria due to the coexistence of O2, N2, and liquid water; and (iii) the Archean had a biogenic disequilibrium caused by the coexistence of N2, CH4, CO2, and liquid water, which, for an exoplanet twin, may be remotely detectable. On the basis of this disequilibrium, we argue that the simultaneous detection of abundant CH4 and CO2 in a habitable exoplanet's atmosphere is a potential biosignature. Specifically, we show that methane mixing ratios greater than 10-3 are potentially biogenic, whereas those exceeding 10-2 are likely biogenic due to the difficulty in maintaining large abiotic methane fluxes to support high methane levels in anoxic atmospheres. Biogenicity would be strengthened by the absence of abundant CO, which should not coexist in a biological scenario. PMID- 29387793 TI - Supersaturated calcium carbonate solutions are classical. AB - Mechanisms of CaCO3 nucleation from solutions that depend on multistage pathways and the existence of species far more complex than simple ions or ion pairs have recently been proposed. Herein, we provide a tightly coupled theoretical and experimental study on the pathways that precede the initial stages of CaCO3 nucleation. Starting from molecular simulations, we succeed in correctly predicting bulk thermodynamic quantities and experimental data, including equilibrium constants, titration curves, and detailed x-ray absorption spectra taken from the supersaturated CaCO3 solutions. The picture that emerges is in complete agreement with classical views of cluster populations in which ions and ion pairs dominate, with the concomitant free energy landscapes following classical nucleation theory. PMID- 29387794 TI - Organelle luminal dependence of (+)strand RNA virus replication reveals a hidden druggable target. AB - Positive-strand RNA viruses replicate their genomes in membrane-bounded cytoplasmic complexes. We show that endoplasmic reticulum (ER)-linked genomic RNA replication by brome mosaic virus (BMV), a well-studied member of the alphavirus superfamily, depends on the ER luminal thiol oxidase ERO1. We further show that BMV RNA replication protein 1a, a key protein for the formation and function of vesicular BMV RNA replication compartments on ER membranes, permeabilizes these membranes to release oxidizing potential from the ER lumen. Conserved amphipathic sequences in 1a are sufficient to permeabilize liposomes, and mutations in these sequences simultaneously block membrane permeabilization, formation of a disulfide-linked, oxidized 1a multimer, 1a's RNA capping function, and productive genome replication. These results reveal new transmembrane complexities in positive-strand RNA virus replication, show that-as previously reported for certain picornaviruses and flaviviruses-some alphavirus superfamily members encode viroporins, identify roles for such viroporins in genome replication, and provide a potential new foundation for broad-spectrum antivirals. PMID- 29387795 TI - Emergent hydrodynamic bound states between magnetically powered micropropellers. AB - Hydrodynamic interactions (HIs), namely, solvent-mediated long-range interactions between dispersed particles, play a crucial role in the assembly and dynamics of many active systems, from swimming bacteria to swarms of propelling microrobots. We experimentally demonstrate the emergence of long-living hydrodynamic bound states between model microswimmers at low Reynolds numbers. A rotating magnetic field forces colloidal hematite microparticles to translate at a constant and frequency-tunable speed close to a bounding plane in a viscous fluid. At high driving frequency, HIs dominate over magnetic dipolar ones, and close propelling particles couple into bound states by adjusting their translational speed to optimize the transport of the pair. The physical system is described by considering the HIs with the boundary surface and the effect of gravity, providing an excellent agreement with the experimental data for all the range of parameters explored. Moreover, we show that in dense suspensions, these bound states can be extended to one-dimensional arrays of particles assembled by the sole HIs. Our results manifest the importance of the boundary surface in the interaction and dynamics of confined propelling microswimmers. PMID- 29387796 TI - Witnessing eigenstates for quantum simulation of Hamiltonian spectra. AB - The efficient calculation of Hamiltonian spectra, a problem often intractable on classical machines, can find application in many fields, from physics to chemistry. We introduce the concept of an "eigenstate witness" and, through it, provide a new quantum approach that combines variational methods and phase estimation to approximate eigenvalues for both ground and excited states. This protocol is experimentally verified on a programmable silicon quantum photonic chip, a mass-manufacturable platform, which embeds entangled state generation, arbitrary controlled unitary operations, and projective measurements. Both ground and excited states are experimentally found with fidelities >99%, and their eigenvalues are estimated with 32 bits of precision. We also investigate and discuss the scalability of the approach and study its performance through numerical simulations of more complex Hamiltonians. This result shows promising progress toward quantum chemistry on quantum computers. PMID- 29387797 TI - Soft, smart contact lenses with integrations of wireless circuits, glucose sensors, and displays. AB - Recent advances in wearable electronics combined with wireless communications are essential to the realization of medical applications through health monitoring technologies. For example, a smart contact lens, which is capable of monitoring the physiological information of the eye and tear fluid, could provide real-time, noninvasive medical diagnostics. However, previous reports concerning the smart contact lens have indicated that opaque and brittle components have been used to enable the operation of the electronic device, and this could block the user's vision and potentially damage the eye. In addition, the use of expensive and bulky equipment to measure signals from the contact lens sensors could interfere with the user's external activities. Thus, we report an unconventional approach for the fabrication of a soft, smart contact lens in which glucose sensors, wireless power transfer circuits, and display pixels to visualize sensing signals in real time are fully integrated using transparent and stretchable nanostructures. The integration of this display into the smart lens eliminates the need for additional, bulky measurement equipment. This soft, smart contact lens can be transparent, providing a clear view by matching the refractive indices of its locally patterned areas. The resulting soft, smart contact lens provides real-time, wireless operation, and there are in vivo tests to monitor the glucose concentration in tears (suitable for determining the fasting glucose level in the tears of diabetic patients) and, simultaneously, to provide sensing results through the contact lens display. PMID- 29387798 TI - Collisions of ultracold 23Na87Rb molecules with controlled chemical reactivities. AB - The collision of molecules at ultracold temperatures is of great importance to understand the chemical interactions at the quantum regime. Although much theoretical work has been devoted to this, experimental data are only sparsely available, mainly because of the difficulty in producing ground-state molecules at ultracold temperatures. We report here the creation of optically trapped samples of ground-state bosonic sodium-rubidium molecules with precisely controlled internal states and, enabled by this, a detailed study on the inelastic loss with and without the NaRb + NaRb -> Na2 + Rb2 chemical reaction. Contrary to intuitive expectations, we observed very similar loss and heating, regardless of the chemical reactivities. In addition, as evidenced by the reducing loss rate constants with increasing temperatures, we found that these collisions are already outside the Wigner region although the sample temperatures are sub-microkelvin. Our measurement agrees semiquantitatively with models based on long-range interactions but calls for a deeper understanding on the short range physics for a more complete interpretation. PMID- 29387799 TI - Complete enzyme set for chlorophyll biosynthesis in Escherichia coli. AB - Chlorophylls are essential cofactors for photosynthesis, which sustains global food chains and oxygen production. Billions of tons of chlorophylls are synthesized annually, yet full understanding of chlorophyll biosynthesis has been hindered by the lack of characterization of the Mg-protoporphyrin IX monomethyl ester oxidative cyclase step, which confers the distinctive green color of these pigments. We demonstrate cyclase activity using heterologously expressed enzyme. Next, we assemble a genetic module that encodes the complete chlorophyll biosynthetic pathway and show that it functions in Escherichia coli. Expression of 12 genes converts endogenous protoporphyrin IX into chlorophyll a, turning E. coli cells green. Our results delineate a minimum set of enzymes required to make chlorophyll and establish a platform for engineering photosynthesis in a heterotrophic model organism. PMID- 29387800 TI - Extending voluntary health insurance to the informal sector: experiences and expectations of the informal sector in Kenya. AB - Background: Kenya has made a policy decision to use contributory health insurance as one of its key pre-payment health financing mechanisms. The National Hospital Insurance Fund (NHIF) is the main health insurer in Kenya. While the NHIF has hitherto focused its efforts on providing health insurance coverage to individuals in the formal sector, it has recently broadened its focus to include individuals in the informal sector. This paper provides an analysis of the perceptions, and experiences of informal sector individuals in Kenya with regard to enrolment with the NHIF. Methods: We collected data through key informant interviews (39) in two purposefully selected counties. Study participants were drawn from healthcare facilities contracted by the NHIF, and current, former, and prospective informal sector members. We analyzed data using a grounded approach. Results: Participants felt that the NHIF provided inadequate information about the registration and membership processes as well as benefit entitlements. There was variable and inconsistent communication by the NHIF. There was also variance between the official benefit package and the actual benefits received by members. The NHIF registration requirements and processes presented an administrative barrier to obtaining membership. The NHIF premium level and contribution mechanism presents a financial barrier to current and prospective members. Healthcare providers discriminated against NHIF members compared to cash-payers or private insurance holders. Conclusions: The NHIF could improve enrolment and retention of informal sector individuals by; 1) using communication strategies that are effective at reaching the informal sector, 2) improving the affordability of the premium rates, 3) simplifying the enrolment requirements and process, and 4) strengthening accountability mechanisms between itself and healthcare facilities to ensure that enrolled members receive the benefits that they are entitled to, and that client experience at healthcare facilities are satisfactory. PMID- 29387801 TI - Long term cognitive outcomes of early term (37-38 weeks) and late preterm (34-36 weeks) births: A systematic review. AB - Background: There is a paucity of evidence regarding long-term outcomes of late preterm (34-36 weeks) and early term (37-38 weeks) delivery. The objective of this systematic review was to assess long-term cognitive outcomes of children born at these gestations. Methods: Four electronic databases (Medline, Embase, clinicaltrials.gov and PsycINFO) were searched. Last search was 5 th August 2016. Studies were included if they reported gestational age, IQ measure and the ages assessed. The protocol was registered with the International prospective register of systematic reviews (PROSPERO Record CRD42015015472). Two independent reviewers assessed the studies. Data were abstracted and critical appraisal performed of eligible papers. Results: Of 11,905 potential articles, seven studies reporting on 41,344 children were included. For early term births, four studies (n = 35,711) consistently showed an increase in cognitive scores for infants born at full term (39-41 weeks) compared to those born at early term (37 38 weeks) with increases for each week of term (difference between 37 and 40 weeks of around 3 IQ points), despite differences in age of testing and method of IQ/cognitive testing. Four studies (n = 5644) reporting childhood cognitive outcomes of late preterm births (34 - 36 weeks) also differed in study design (cohort and case control); age of testing; and method of IQ testing, and found no differences in outcomes between late preterm and term births, although risk of bias was high in included studies. Conclusion: Children born at 39-41 weeks have higher cognitive outcome scores compared to those born at early term (37-38 weeks). This should be considered when discussing timing of delivery. For children born late preterm, the data is scarce and when compared to full term (37 42 weeks) did not show any difference in IQ scores. PMID- 29387802 TI - Household air pollution, chronic respiratory disease and pneumonia in Malawian adults: A case-control study. AB - Background: Four million people die each year from diseases caused by exposure to household air pollution. There is an association between exposure to household air pollution and pneumonia in children (half a million attributable deaths a year); however, whether this is true in adults is unknown. We conducted a case control study in urban Malawi to examine the association between exposure to household air pollution and pneumonia in adults. Methods: Hospitalized patients with radiologically confirmed pneumonia (cases) and healthy community controls underwent 48 hours of ambulatory and household particulate matter (ug/m 3) and carbon monoxide (ppm) exposure monitoring. Multivariate logistic regression, stratified by HIV status, explored associations between these and other potential risk factors with pneumonia. Results: 145 (117 HIV-positive; 28 HIV-negative) cases and 253 (169 HIV-positive; 84 HIV-negative) controls completed follow up. We found no evidence of association between household air pollution exposure and pneumonia in HIV-positive (e.g. ambulatory particulate matter adjusted odds ratio [aOR] 1.00 [95% CI 1.00-1.01, p=0.141]) or HIV-negative (e.g. ambulatory particulate matter aOR 1.00 [95% CI 0.99-1.01, p=0.872]) participants. Chronic respiratory disease was associated with pneumonia in both HIV-positive (aOR 28.07 [95% CI 9.29-84.83, p<0.001]) and HIV-negative (aOR 104.27 [95% CI 12.86-852.35, p<0.001]) participants. Conclusions: We found no evidence that exposure to household air pollution is associated with pneumonia in Malawian adults. In contrast, chronic respiratory disease was strongly associated with pneumonia. PMID- 29387803 TI - Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo. AB - Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis. The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods:In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro. In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain. This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest. PMID- 29387804 TI - Rare variants of the 3'-5' DNA exonuclease TREX1 in early onset small vessel stroke. AB - Background: Monoallelic and biallelic mutations in the exonuclease TREX1 cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted. Methods: We sequenced the TREX1 gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). Results: No patients with canonical disease-causing mutations of TREX1 were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of TREX1 and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of TREX1 in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49 1.65 p=0.74). Similarly no association was seen with rare TREX1 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). Conclusions: No patients with early-onset lacunar stroke had genetic evidence of a TREX1-associated monogenic microangiopathy. These results show no evidence of association between rare variants of TREX1 and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history. PMID- 29387806 TI - Water source most suitable for rearing a sensitive malaria vector, Anopheles funestus in the laboratory. AB - Background: The insecticide susceptibility status of Anopheles funestus, one of the main malaria vectors in the Afrotropical regions, remains under-studied due to the difficulty of working with this mosquito species. Collecting their larvae in natural breeding sites, rearing and maintaining them in normal laboratory conditions have been a difficult task. Forced-egg laying technique has been a very good tool to generate eggs from adult mosquitoes collected from the wild but rearing these eggs to obtain satisfying portion as adults has always been the problem. In this study, we optimized the development of mosquito species larvae under standard laboratory conditions for desired production of adult mosquitoes that can be useful for insecticide susceptibility tests. Methods: A forced-egg laying technique was used to obtain eggs from gravid female Anopheles funestus collected from Kpome locality in Benin. Eggs were reared in three different water samples (water from the borehole,and two mineral water namely FIFA and Possotome) and larvae were fed with TetraMin baby fish food. The physico-chemical parameters of the waters were investigated prior to use for egg incubation. Results:In contrast to mineral water that had no contamination, the borehole water source was contaminated with lead (2.5mg/L) and nitrate (118.8mg/L). Egg hatching rates ranged as 91.9 +/- 4.4%, 89.1 +/- 2.5% and 87.9 +/- 2.6% in FIFA, Possotome and borehole water respectively. High emergence of larvae to adult mosquitoes was recorded as in FIFA (74.3%) and Possotome(79.5%) water. No adult mosquito was obtained from larvae reared in borehole water. Conclusions: This study gave insight on the water sources that could be good for rearing to mass produce An. funestus in the laboratory. More analysis with other local mineral water sources in our environments could be considered in the future, hopefully giving better outputs. PMID- 29387807 TI - Perturbation of PALB2 function by the T413S mutation found in small cell lung cancer. AB - Background: Germline mutations in the PALB2 gene are associated with the genetic disorder Fanconi anaemia and increased predisposition to cancer. Disease associated variants are mainly protein-truncating mutations, whereas a few missense substitutions are reported to perturb its interaction with breast cancer susceptibility proteins BRCA1 and BRCA2, which play essential roles in homology directed repair (HDR). More recently, PALB2 was shown to associate with active genes independently of BRCA1, and through this mechanism, safeguards these regions from DNA replicative stresses. However, it is unknown whether PALB2 tumour suppressor function requires its chromatin association. Methods: Mining the public database of cancer mutations, we identified four potentially deleterious cancer-associated missense mutations within the PALB2 chromatin association motif (ChAM). To assess the impact of these mutations on PALB2 function, we generated cell lines expressing PALB2 variants harbouring corresponding ChAM mutations, and evaluated PALB2 chromatin association properties and the cellular resistance to camptothecin (CPT). Additionally, we examined the accumulation of gammaH2A.X and the RAD51 recombinase as readouts of DNA damage signalling and HDR, respectively. Results: We demonstrate that a small cell lung cancer (SCLC)-associated T413S mutation in PALB2 impairs its chromatin association and confers reduced resistance to CPT, the only FDA-approved drug for relapsed SCLC. Unexpectedly, we found a less efficient gammaH2A.X nuclear foci formation in PALB2 T413S expressing cells, whereas a near-normal level of RAD51 nuclear foci was visible. Conclusions: These findings support the importance of PALB2 chromatin association in the suppression of tumours, including SCLC, an unusually aggressive type of cancer with poor prognosis. PALB2 T413S has little impact on RAD51 recruitment, likely due to its intact interaction with BRCA1 and BRCA2. However, this mutant shows inefficient DNA stress signalling. This finding sheds new light on the function of PALB2, playing a role in efficient DNA stress signalling through constitutive chromatin association. PMID- 29387805 TI - Preparatory planning framework for Created Out of Mind: Shaping perceptions of dementia through art and science. AB - Created Out of Mind is an interdisciplinary project, comprised of individuals from arts, social sciences, music, biomedical sciences, humanities and operational disciplines. Collaboratively we are working to shape perceptions of dementias through the arts and sciences, from a position within the Wellcome Collection. The Collection is a public building, above objects and archives, with a porous relationship between research, museum artefacts, and the public. This pre-planning framework will act as an introduction to Created Out of Mind. The framework explains the rationale and aims of the project, outlines our focus for the project, and explores a number of challenges we have encountered by virtue of working in this way. PMID- 29387808 TI - Using mitoribosomal profiling to investigate human mitochondrial translation. AB - Background: Gene expression in human mitochondria has various idiosyncratic features. One of these was recently revealed as the unprecedented recruitment of a mitochondrially-encoded tRNA as a structural component of the large mitoribosomal subunit. In porcine particles this is mt-tRNA Phe whilst in humans it is mt-tRNA Val. We have previously shown that when a mutation in mt-tRNA Val causes very low steady state levels, there is preferential recruitment of mt-tRNA Phe. We have investigated whether this altered mitoribosome affects intra organellar protein synthesis. Methods: By using mitoribosomal profiling we have revealed aspects of mitoribosome behaviour with its template mt-mRNA under both normal conditions as well as those where the mitoribosome has incorporated mt tRNA Phe. Results: Analysis of the mitoribosome residency on transcripts under control conditions reveals that although mitochondria employ only 22 mt-tRNAs for protein synthesis, the use of non-canonical wobble base pairs at codon position 3 does not cause any measurable difference in mitoribosome occupancy irrespective of the codon. Comparison of the profile of aberrant mt-tRNA Phe containing mitoribosomes with those of controls that integrate mt-tRNA Val revealed that the impaired translation seen in the latter was not due to stalling on triplets encoding either of these amino acids. The alterations in mitoribosome interactions with start codons was not directly attributable to the either the use of non-cognate initiation codons or the presence or absence of 5' leader sequences, except in the two bicistronic RNA units, RNA7 and RNA14 where the initiation sites are internal. Conclusions: These data report the power of mitoribosomal profiling in helping to understand the subtleties of mammalian mitochondrial protein synthesis. Analysis of profiles from the mutant mt-tRNA Val cell line suggest that despite mt-tRNA Phe being preferred in the porcine mitoribosome, its integration into the human counterpart results in a suboptimal structure that modifies its interaction with mt-mRNAs. PMID- 29387809 TI - A hidden burden of neonatal illness? A cross-sectional study of all admissions aged less than one month across twelve Kenyan County hospitals. AB - Background: Small and sick newborns need high quality specialised care within health facilities to address persistently high neonatal mortality in low-income settings, including Kenya. Methods: We examined neonatal admissions in 12 public sector County (formerly District) hospitals in Kenya between November 2014 and November 2016. Using data abstracted from newborn unit (NBU) admission registers and paediatric ward (PW) medical records, we explore the magnitude and distribution of admissions. In addition, interviews with senior staff were conducted to understand admission policies for newborns in these facilities. Results: Of the total 80,666 paediatric admissions, 28,884 (35.8%) were aged <=28 days old. 24,212 (83.8%) of newborns were admitted to organisationally distinct NBU and 4,672 (16.2%) to general PW, though the proportion admitted to NBUs varied substantially (range 59.9-99.0%) across hospitals, reflecting widely varying infrastructure and policies. Neonatal mortality was high in NBU (12%) and PW (11%), though varied widely across facilities, with documentation of outcomes poor for the NBU. Conclusion: Improving quality of care on NBUs would affect almost a third of paediatric admissions in Kenya. However, comprehensive policies and strategies are needed to ensure sick newborns on general PWs also receive appropriate care. PMID- 29387810 TI - A Novel Mapping System for Panoramic Mapping of the Left Atrium: Application to Detect and Characterize Localized Sources Maintaining Atrial Fibrillation. AB - Objectives: This study sought to use a novel panoramic mapping system (CARTOFINDER) to detect and characterize drivers in persistent atrial fibrillation (AF). Background: Mechanisms sustaining persistent AF remain uncertain. Methods: Patients undergoing catheter ablation for persistent AF were included. A 64-pole basket catheter was used to acquire unipolar signals, which were processed by the mapping system to generate wavefront propagation maps. The system was used to identify and characterize potential drivers in AF pre- and post-pulmonary vein (PV) isolation. The effect of ablation on drivers identified post-PV isolation was assessed. Results: Twenty patients were included in the study with 112 CARTOFINDER maps created. Potential drivers were mapped in 19 of 20 patients with AF (damage to the basket and noise on electrograms was present in 1 patient). Thirty potential drivers were identified all of which were transient but repetitive; 19 were rotational and 11 focal. Twenty-six drivers were ablated with a predefined response in 22 of 26 drivers: AF terminated with 12 and cycle length slowed (>=30 ms) with 10. Drivers with rotational activation were predominantly mapped to sites of low-voltage zones (81.8%). PV isolation had no remarkable impact on the cycle length at the driver sites (138.4 +/- 14.3 ms pre-PV isolation vs. 137.2 +/- 15.2 ms post-PV isolation) and drivers that had also been identified on pre-PV isolation maps were more commonly associated with AF termination. Conclusions: Drivers were identified in almost all patients in the form of intermittent but repetitive focal or rotational activation patterns. The mechanistic importance of these phenomena was confirmed by the response to ablation. PMID- 29387811 TI - The fabrication of magnetic particle-based chemiluminescence immunoassay for human epididymis protein-4 detection in ovarian cancer. AB - The magnetic particles have a significant influence on the immunoassay detection and cancer therapy. Herein, the chemiluminescence immunoassay combined with the magnetic particles (MPCLIA) was presented for the clinical determination and analysis of human epididymis protein 4 (HE4) in the human serum. Under the optimized experiment conditions, the secure MPCLIA method can detect HE4 in the broader range of 0-1000 pmol/L, with a lower detection limit of 1.35 pmol/L. The satisfactory recovery rate of the method in the serum ranged from 83.62% to 105.10%, which was well within the requirement of clinical analysis. Moreover, the results showed the good correlation with enzyme-linked immunosorbent assay (ELISA), with the correlation coefficient of 0.9589. This proposed method has been successfully applied to the clinical determination of HE4 in the human serum. PMID- 29387812 TI - Crystal structure analysis of human serum albumin complexed with sodium 4 phenylbutyrate. AB - Sodium 4-phenylbutyrate (PB) is an orphan drug for the treatment of urea cycle disorders. It also inhibits the development of endoplasmic reticulum stress, the action of histone deacetylases and as a regulator of the hepatocanalicular transporter. PB is generally considered to have the potential for use in the treatment of the diseases such as cancer, neurodegenerative diseases and metabolic diseases. In a previous study, we reported that PB is primarily bound to human serum albumin (HSA) in plasma and its binding site is drug site 2. However, details of the binding mode of PB to HSA remain unknown. To address this issue, we examined the crystal structure of HSA with PB bound to it. The structure of the HSA-PB complex indicates that the binding mode of PB to HSA is quite similar to that for octanoate or drugs that bind to drug site 2, as opposed to that for other medium-chain length of fatty acids. These findings provide useful basic information related to drug-HSA interactions. Moreover, the information presented herein is valuable in terms of providing safe and efficient treatment and diagnosis in clinical settings. PMID- 29387814 TI - The role of Galphaq/Galpha11 signaling in intestinal epithelial cells. AB - Intestinal homeostasis and the coordinated actions of digestion, absorption and excretion are tightly regulated by a number of gastrointestinal hormones. Most of them exert their actions through G-protein-coupled receptors. Recently, we showed that the absence of Galphaq/Galpha11 signaling impaired the maturation of Paneth cells, induced their differentiation toward goblet cells, and affected the regeneration of the colonic mucosa in an experimental model of colitis. Although an immunohistochemical study showed that Galphaq/Galpha11 were highly expressed in enterocytes, it seemed that enterocytes were not affected in Int-Gq/G11 double knock-out intestine. Thus, we used an intestinal epithelial cell line to examine the role of signaling through Galphaq/Galpha11 in enterocytes and manipulated the expression level of Galphaq and/or Galpha11. The proliferation was inhibited in IEC-6 cells that overexpressed Galphaq/Galpha11 and enhanced in IEC-6 cells in which Galphaq/Galpha11 was downregulated. The expression of T-cell factor 1 was increased according to the overexpression of Galphaq/Galpha11. The expression of Notch1 intracellular cytoplasmic domain was decreased by the overexpression of Galphaq/Galpha11 and increased by the downregulation of Galphaq/Galpha11. The relative mRNA expression of Muc2, a goblet cell marker, was elevated in a Galphaq/Galpha11 knock-down experiment. Our findings suggest that Galphaq/Galpha11-mediated signaling inhibits proliferation and may support a physiological function, such as absorption or secretion, in terminally differentiated enterocytes. PMID- 29387813 TI - Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells. AB - Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of transforming growth factor-beta (TGFbeta), connective tissue growth factor (CTGF), interferon-gamma (IFNgamma) and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN), fibronectin EDA domain (FN EDA), metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-1 (TIMP-1) and peroxisome proliferator associated receptor-gamma (PPARgamma) was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFbeta gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARgamma. In addition, both CTGF and TGFbeta were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses. PMID- 29387816 TI - Rods and cones in an enantiornithine bird eye from the Early Cretaceous Jehol Biota. AB - Extant birds have an extensive spectral range of colour vision among vertebrates, but evidence of colour vision among extinct birds has hitherto been lacking. An exceptionally well-preserved extinct enantiornithine fossil bird from the Early Cretaceous Jiufotang Formation (120 Ma) of Liaoning, China, provides the first report of mineralised soft tissue of a bird eye. Cone cells are identified, which have preserved oil droplets falling between wide ranges of size that can be compared with an extant house sparrow. The size distribution of oil droplets of extant birds demonstrates good correlation between size and the detectable wavelength range of the cone cells: UV-sensitive cones contain the smallest oil droplets, while red-sensitive cones possess the largest. The data suggests that this Early Cretaceous bird could have possessed colour vision. PMID- 29387815 TI - A randomized controlled trial to evaluate the effects of high Protein Complete (lActo) VEgetaRian (PACER) diet in non-diabetic obese Asian Indians in North India. AB - In view of the increasing prevalence of obesity in largely vegetarian Asian Indians, it is important to research a high protein, low carbohydrate vegetarian diet. The present study was designed to evaluate the effects of a "High Protein Complete (lacto) VEgetaRian Diet (Acronym; 'PACER diet'), on weight, body composition and metabolic profiles in non-diabetic obese Asian Indians living in north India. In this 8-week randomized control trial, 102 vegetarian subjects with body mass index (BMI) >25 kg/m2 were randomized to either a test diet (PACER diet; high protein, high fat and moderately low carbohydrate, lacto-vegetarian diet) or control diet (standard vegetarian diet formulated as the dietary guidelines for Asian Indians) after 4 weeks of diet and exercise run-in period. A standard exercise protocol was followed for both groups. Body weight, BMI, waist circumference (WC), blood pressure, fasting plasma glucose (FPG), fasting serum insulin and lipid profile were assessed before and after the intervention. There was significant weight loss along with improvements in cardio-metabolic risk factors among both the groups post intervention. Percent reductions in the intervention group for weight (6.1+/- 2.9; p < 0.001), WC (3.9 +/- 1.7; p < 0.001), FPG (5.9 +/- 3.2; p < 0.001), total cholesterol (10.2 +/- 6.3: p < 0.001), serum triacylglycerol (13.6 +/- 10.6; p < 0.001) and low-density lipoprotein cholesterol (11.9 +/- 7.1; p < 0.001]) were significantly greater than the control diet group. In summary, intervention with a PACER diet (high protein, high fat and moderately low carbohydrate, lacto-vegetarian diet) showed significant improvement in weight loss, body composition and cardio-metabolic profile as compared to a standard vegetarian diet among obese Asian Indians in north India. PMID- 29387817 TI - Fast Image Edge Detection based on Faber Schauder Wavelet and Otsu Threshold. AB - Edge detection is a critical stage in many computer vision systems, such as image segmentation and object detection. As it is difficult to detect image edges with precision and with low complexity, it is appropriate to find new methods for edge detection. In this paper, we take advantage of Faber Schauder Wavelet (FSW) and Otsu threshold to detect edges in a multi-scale way with low complexity, since the extrema coefficients of this wavelet are located on edge points and contain only arithmetic operations. First, the image is smoothed using bilateral filter depending on noise estimation. Second, the FSW extrema coefficients are selected based on Otsu threshold. Finally, the edge points are linked using a predictive edge linking algorithm to get the image edges. The effectiveness of the proposed method is supported by the experimental results which prove that our method is faster than many competing state-of-the-art approaches and can be used in real time applications. PMID- 29387818 TI - An optimized approach for simultaneous horizontal data fragmentation and allocation in Distributed Database Systems (DDBSs). AB - With the substantial ever-upgrading advancement in data and information management field, Distributed Database System (DDBS) is still proven to be the most growingly-demanded tool to handle the accompanied constantly-piled volumes of data. However, the efficiency and adequacy of DDBS is profoundly correlated with the reliability and precision of the process in which DDBS is set to be designed. As for DDBS design, thus, several strategies have been developed, in literature, to be used in purpose of promoting DDBS performance. Off these strategies, data fragmentation, data allocation and replication, and sites clustering are the most immensely-used efficacious techniques that otherwise DDBS design and rendering would be prohibitively expensive. On one hand, an accurate well-architected data fragmentation and allocation is bound to incredibly increase data locality and promote the overall DDBS throughputs. On the other hand, finding a practical sites clustering process is set to contribute remarkably in reducing the overall Transmission Costs (TC). Consequently, consolidating all these strategies into one single work is going to undoubtedly satisfy a massive growth in DDBS influence. In this paper, therefore, an optimized heuristic horizontal fragmentation and allocation approach is meticulously developed. All the drawn-above strategies are elegantly combined into a single effective approach so as to an influential solution for DDBS productivity promotion is set to be markedly fulfilled. Most importantly, an internal and external evaluations are extensively illustrated. Obviously, findings of conducted experiments have maximally been recorded to be in favor of DDBS performance betterment. PMID- 29387820 TI - High-resolution atmospheric emission inventory of the argentine energy sector. Comparison with edgar global emission database. AB - This study presents a 2014 high-resolution spatially disaggregated emission inventory (0.025 degrees * 0.025 degrees horizontal resolution), of the main activities in the energy sector in Argentina. The sub-sectors considered are public generation of electricity, oil refineries, cement production, transport (maritime, air, rail and road), residential and commercial. The following pollutants were included: greenhouse gases (CO2, CH4, N2O), ozone precursors (CO, NOx, VOC) and other specific air quality indicators such as SO2, PM10, and PM2.5. This work could contribute to a better geographical allocation of the pollutant sources through census based population maps. Considering the sources of greenhouse gas emissions, the total amount is 144 Tg CO2eq, from which the transportation sector emits 57.8 Tg (40%); followed by electricity generation, with 40.9 Tg (28%); residential + commercial, with 31.24 Tg (22%); and cement and refinery production, with 14.3 Tg (10%). This inventory shows that 49% of the total emissions occur in rural areas: 31% in rural areas of medium population density, 13% in intermediate urban areas and 7% in densely populated urban areas. However, if emissions are analyzed by extension (per square km), the largest impact is observed in medium and densely populated urban areas, reaching more than 20.3 Gg per square km of greenhouse gases, 297 Mg/km2 of ozone precursors gases and 11.5 Mg/km2 of other air quality emissions. A comparison with the EDGAR global emission database shows that, although the total country emissions are similar for several sub sectors and pollutants, its spatial distribution is not applicable to Argentina. The road and residential transport emissions represented by EDGAR result in an overestimation of emissions in rural areas and an underestimation in urban areas, especially in more densely populated areas. EDGAR underestimates 60 Gg of methane emissions from road transport sector and fugitive emissions from refining activities. PMID- 29387819 TI - Adsorption and photocatalytic performance of bentonite-titanium dioxide composites for methylene blue and rhodamine B decoloration. AB - Bentonite - TiO2 composites were prepared by impregnation of TiO2 and bentonite, followed by microwave irradiation processes. The composites were characterized using FTIR, SEM, XRD, and nitrogen sorption methods. Anatase phase of TiO2 in all composites are observed through XRD diffraction peaks and surface morphology of the composites. The adsorption and photocatalytic capabilities of the composites were tested in liquid phase adsorption of methylene blue and Rhodamine B. The adsorption and photocatalytic degradation experiments were conducted in the presence or absence of UV light irradiation. Langmuir and Freundlich models were employed to correlate the experimental adsorption data, and it was found that Langmuir gave better performance in correlating the experimental data. Modification of Langmuir equation to accommodate photocatalytic degradation process was conducted, and the model could represent the experimental results very well. PMID- 29387821 TI - Evaluation of three cultivars of sweet sorghum as feedstocks for ethanol production in the Southeast United States. AB - Sweet sorghum has become a promising alternative feedstock for biofuel production because it can be grown under reduced inputs, responds to stress more efficiently than traditional crops, and has large biomass production potential. A three-year field study was conducted to evaluate three cultivars of sweet sorghum as bioenergy crops in the Southeast United States (Fort Valley, Georgia): Dale, M81 E and Theis. Parameters evaluated were: plant density, stalk height, and diameter, number of nodes, biomass yield, juice yield, degrees Bx, sugar production, and theoretical ethanol yields. Yields were measured at 85, 99, and 113 days after planting. Plant fresh weight was the highest for Theis (1096 g) and the lowest for Dale (896 g). M81 E reported the highest stalk dry weight (27 Mg ha-1) and Theis reported the lowest (21 Mg ha-1). Theis ranked the highest degrees Bx (14.9), whereas M81 E was the lowest (13.2). Juice yield was the greatest for M81 E (10915 L ha-1) and the lowest for Dale (6724 L ha-1). Theoretical conservative sugar yield was the greatest for Theis (13 Mg ha-1) and the lowest for Dale (9 Mg ha-1). Theoretical ethanol yield was the greatest for Theis (7619 L ha-1) and the lowest for Dale (5077 L ha-1). PMID- 29387822 TI - Circulation of canine parvovirus among dogs living in human-wildlife interface in the Atlantic forest biome, Brazil. AB - Despite of the role of domestic dogs as reservoirs for threatening viral diseases for wild carnivores, few studies have focused to identify circulation of viruses among dogs living in human/wildlife interfaces. To identify canine parvovirus (CPV) types circulating in dogs living in an Atlantic forest biome, faecal samples (n = 100) were collected at the same period (one week) corresponding to each of four areas, during 2014 to 2016 and corresponded to 100 different individuals. CPV was isolated in cell culture from 67 out 100 (67%) samples from healthy dogs. Cytopathic effects were characterized by total or partial cell culture lysis. Genome sequences of CPV-2a (10%), CPV-2b (7%) and CPV-2c (50%) were concomitantly detected by PCR and nucleotide sequencing. The current study addresses the importance of monitoring CPV circulation among dogs presenting potential contact with wildlife species. PMID- 29387823 TI - Amino acid repeats avert mRNA folding through conservative substitutions and synonymous codons, regardless of codon bias. AB - A significant number of proteins in all living species contains amino acid repeats (AARs) of various lengths and compositions, many of which play important roles in protein structure and function. Here, I have surveyed select homopolymeric single [(A)n] and double [(AB)n] AARs in the human proteome. A close examination of their codon pattern and analysis of RNA structure propensity led to the following set of empirical rules: (1) One class of amino acid repeats (Class I) uses a mixture of synonymous codons, some of which approximate the codon bias ratio in the overall human proteome; (2) The second class (Class II) disregards the codon bias ratio, and appears to have originated by simple repetition of the same codon (or just a few codons); and finally, (3) In all AARs (including Class I, Class II, and the in-betweens), the codons are chosen in a manner that precludes the formation of RNA secondary structure. It appears that the AAR genes have evolved by orchestrating a balance between codon usage and mRNA secondary structure. The insights gained here should provide a better understanding of AAR evolution and may assist in designing synthetic genes. PMID- 29387824 TI - Health professionals' perceptions about physical activity promotion in diabetes care within primary health care settings in Oman. AB - Background: As part of formative work to inform an interventional design to increase physical activity (PA) in patients with type 2 diabetes in Oman, this qualitative study aimed to determine health professionals' perception of barriers and opportunities, personnel responsibilities and plausible PA promotional approaches. Methods: Four focus group discussions were carried out with groups of health care professionals (family physicians, dieticians and health educators, managers and general practitioners). All discussions were audio recorded and transcribed. Responses were analysed using a thematic analysis. Results: Barriers to PA reported by participants (n = 29) were identified at three levels: health care system (e.g. deficient PA guidelines); individual (e.g. obstructive social norms) and community (e.g. lack of facilities). Participants felt that a multilevel approach is needed to address perceived barriers and to widen current opportunities. In the presence of various diabetes primary care providers, the potential for dieticians to include individualised PA consultations as part of their role was highlighted. Participants felt that consultations should be augmented by approaches within the community (volunteer support and/or appropriate facilities). However, despite lack of experience with technology supported approaches and motivational tools, the telephone application "WhatsApp" and use of pedometers were considered potentially suitable. The need for training in behaviour change techniques and clearly communicated intervention guidelines was emphasised. Conclusions: A multi-component approach including PA consultations, possibly led by trained dieticians, technological routes for providing support along with community mapping for resources appear to offer promising approaches for further PA intervention studies within diabetes primary health care. PMID- 29387825 TI - Reconstruction of mammalian oocytes by germinal vesicle transfer: A systematic review. AB - Nuclear transfer procedures have been recently applied for clinical and research targets as a novel assisted reproductive technique and were used for increasing the oocyte activity during its growth and maturation. In this review, we summarized the nuclear transfer technique for germinal vesicle stage oocytes to reconstruct the maturation of them. Our study covered publications between 1966 and August 2017. In result utilized germinal vesicle transfer techniques, fusion, and fertilization survival rate on five different mammalian species are discussed, regarding their potential clinical application. It seems that with a study on this method, there is real hope for effective treatments of old oocytes or oocytes containing mitochondrial problems in the near future. PMID- 29387826 TI - The prevalence of, and risk factors for, mycoplasma genitalium infection among infertile women in Ibadan: A cross-sectional study. AB - Background: The association of mycoplasma genitalium (M. genitalium) with infertility has been documented. The infections are asymptomatic and difficult to diagnose. Understanding the associated risk factors will help in facilitating better screening measures for at-risk groups. Objective: The aim was to determine the prevalence of, and risk factors for, M. genitalium infection among infertile women in Ibadan. Materials and Methods: In this cross-sectional study, 402 women (267 infertile and 135 fertile) referred to 2 hospitals in Ibadan between March and November 2015 were enrolled. Information was obtained, using structured questionnaire, on sociodemographic and behavioral characteristics of the respondents while endocervical swabs were obtained for detection of M. genitalium. MgPa gene was diagnosed using the conventional Polymerase chain reaction. Bands corresponding to 495kb were documented as positive for M. genitalium. Results: Among the infertile women, 43 (16.1%) had evidence of M. genitalium infection as against 3 (2.2%) of women without infertility (p<0.001). Associated risk factors included having more than one lifetime sexual partner (OR=10.13, 95% CI: 3.76-33.97); husbands having other sexual partners (OR=12.88, 95% CI: 2.08-90.63); being a serial monogamist (OR=6, 95% CI: 4.35-8.27) and low socio-economic status (OR=2.80, 95% CI: 1.28-6.10). No relationship exists between the previous history of sexually transmitted infections and M. genitalium. Conclusion: The risk factors for M. genitalium infection are similar to those peculiar to other sexually transmitted infections. Its routine screening should be incorporated into the current protocol for microbiological evaluation of infertile women. PMID- 29387827 TI - CXC Ligand 5 cytokine serum level in women with polycystic ovary syndrome and normal body mass index: A case-control study. AB - Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disease and associated with insulin resistance. CXC Ligand 5 (CXCL5) is a new cytokine which is secreted from white adipose tissue during obesity and by blocking insulin signaling pathway inhibits the activity of insulin and promotes insulin resistance. Objective: The aim of this study was to assess serum level of CXCL5 in PCOS women with normal body mass index. Materials and Methods: In this case control study, 30 PCOS women with normal body mass index as the case group and 30 non-PCOS women as the controls were enrolled. Serum levels of CXCL5, insulin and other hormones factors related with PCOS were measured by ELISA method, also the biochemical parameters were measured by autoanalyzer. Results: Significant increases in serum insulin concentration, homeostasis model assessments of insulin resistance, luteinizing hormone, luteinizing hormone/follicle-stimulating hormone, fasting blood sugar, testosterone, and prolactin were observed in the case group compared to the controls. were in the serum level of CXCL5, cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein cholesterol,dehydroepiandrosterone-sulfate, creatinine, and homeostasis model assessment of beta cell function between these two groups. Conclusion: In this study, no significant change was observed in serum concentrations of CXCL5 in PCOS women with normal BMI. PMID- 29387828 TI - Effects of administration of co-trimoxazole and folic acid on sperm quality and histological changes of testes in male rats. AB - Background: Male infertility has been reported following long-term sulfasalazine, however, the precise effects of co-trimoxazole on sperm quality is controversial. Objective: In this study, we evaluated the effects of co-trimoxazole and its co administration with folic acid on sperm quality and histological changes of testes in male rats. Materials and Methods: In this experimental study, 136 male Wistar rats were divided into 9 groups: I (control), II (vehicle) received saline, III: received folic acid (1 mg/kg /daily i.p., and IV- IX received co trimoxazole (30, 60, and 120 mg/kg/daily; i.p.)+folic acid (1 mg/kg/daily; i.p.) for 14 or 28 days. Sperm samples were obtained from each group at the end of 14th and 28th days. Sperm numbers, motility, and viability were evaluated on a hemocytometer. Hematoxylin and Eosin stained testes were done for evaluation ofthe number of Leydig cells, vascularity, spermatids, spermatocytes, and means of seminiferous tubules diameter under light microscopy. Results: Co-trimoxazole treatment for either 14 or 28 days caused a significant decrease in the percentage of sperm number, motility, and viability (p<0.001) compared to the control group. Also, high doses of co-trimoxazole caused a significant decrease in testes structural abnormalities means of seminiferous tubules diameter, spermatids, and spermatogonia) compared to the vehicle group (p<0.001). Folic acid co-administration with co-trimoxazole partially reversed the decrease in sperm quality and structural abnormalities of high doses of co-trimoxazole (60 and 120 mg/kg/daily) (p<0.001). Conclusion: The data showed the adverse effects of co-trimoxazole on sperm quality and testes morphology which was protected partially by folic acid co-administration in rats. The underlying mechanism (s) needs further investigations. PMID- 29387829 TI - The effect of vitamin E and aspirin on the uterine artery blood flow in women with recurrent abortion: A single-blind randomized controlled trial. AB - Background: Recurrent spontaneous abortion has high incidence rate. The etiology is unknown in 30-40%. However high uterine artery resistance is accounted as one of the recurrent abortion reasons. Objective: The objective of the current study was to determine the impacts of vitamin E and aspirin on the uterine artery blood flow in women having recurrent abortions due to impaired uterine blood flow. Materials and Methods: This randomized clinical trial was conducted on 99 women having uterine pulsatility index (PI) more than 2.5 and the history of more than two times abortions. The candidates were categorized into three groups; receiving aspirin, only vitamin E, and aspirin+vitamin E. After 2 months, uterine PIs were compared with each other. Results: All drug regimens caused an enhancement in uterine perfusion with a significant decline in uterine artery PI value. The women receiving vitamin E in accompanied with aspirin had the least mean PI of the uterine artery (p<0.001). The total average PI score of the right and left uterine arteries in groups receiving vitamin E in accompanied with aspirin was lower than the two counterparts significantly (p<0.001). Conclusion: Vitamin E, aspirin and especially their combination are effective in improving uterine artery blood flow in women with recurrent abortion due to impaired uterine blood flow. More well-designed studies are needed to find out whether the enhancement of uterine perfusion may lead to a better pregnancy outcome. PMID- 29387830 TI - Thymoquinone as a natural spermostatic substance in reproductive medicine: An experimental study. AB - Background: Nonoxynol-9 a nonionic surfactant is widely used for its spermicidal effects. Finding new sperm immobilizing agents is necessary because Nonoxynol-9 damages the tissues of female reproductive system. Objective: The aim of this study was to evaluate the effects of Thymoquinone (TQ) as a potential spermostatic compound on the motility and viability of human spermatozoa. Materials and Methods: In this experimental study, the effects of 5, 10, 20, 50, 100 ug/ml, 1 and 10 mg/ml of TQ on normozoospermic semen samples were investigated. Sperm motility and viability were compared between untreated and TQ treated aliquots of each semen sample. To evaluate the effects of TQ on the alteration of mitochondrial membrane potential (MMP), 32 semen samples were examined using 50 ug/ml of TQ. Flow cytometric analysis was performed after staining of spermatozoa with JC-1. Results: Doses above 20 ug/ml of TQ could eventually immobilize all spermatozoa in culture medium. Adding 50 ug/ml of TQ did not significantly diminish the percentage of viable spermatozoa and flow cytometry results revealed that this amount of TQ could decrease sperm MMP. Conclusion: TQ could discontinue the movement of sperm cells in medium without reducing the population of live spermatozoa. It is more likely that TQ exerts its spermostatic action by mitigating the MMP of spermatozoa. Therefore, TQ could be considered as a potential new natural spermostatic chemical. PMID- 29387831 TI - The effects of Salvia officinalis L. on granulosa cells and in vitro maturation of oocytes in mice. AB - Background: Salvia officinalisL. has been used since ancient times but there are little data about effects of this herb on normal reproductive cells. Objective: To investigate the toxicity effects of Salvia officinalis L. on granulosa cells (GCs) and maturation of oocytes. Materials and Methods: GCs and oocytes were extracted from superovulated ovaries of immature mice. The cells were treated with concentrations of 10, 50, 100, 500, and 1000 MUg/ml of Salvia officinalis hydroalcoholic extracts and compared with the control culture. Bioviability, chromatin condensation, estradiol and progesterone concentrations, lipid synthesis, apoptosis, and alkaline phosphatase activity of GCs were measured. In vitro maturation of oocytes by determination of different maturation stages of oocytes including germinal vesicle, germinal vesicle breaks down, and metaphase II were examined. Results: The results revealed that 500 and 1000 MUg/ml concentrations of Salvia officinalisL. were toxic. The most of the GCs were in the early stages of apoptosis in 100 MUg/ml treated culture and cell death happened with 500 MUg/ml treatment. Progesterone concentration was reduced in 100 MUg/ml and higher doses but estradiol concentration and alkaline phosphatase showed opposite effects. The lipid droplets content of GCs reduced significantly in all groups especially in 500 and 1000 MUg/ml. Finally, oocyte's nucleus and cytoplasm showed a high level of condensation, and meiosis rate reduced in all treated cultures. Conclusion: Our findings suggested that higher dose of Salvia officinalis hydroalcoholic extracts inhibits, oocyte maturation, GCs bioviability, proliferation, and secretion. PMID- 29387832 TI - Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats model: An experimental study. AB - Background: Citrullus colocynthis (CCT) is used as the anti-diabetic and antioxidant agent. Polycystic ovarian syndrome (PCOS) is a reproductive disorder which level of gonadotropins and sexual hormones are imbalanced. Objective: We evaluated the effect of CCT hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats' model. Materials and Methods: 40 female adult Wistar rats divided into five groups (n=8each: Group I (control) only injected by sesame oil as estradiol valerate solvent, group II (Sham) was orally received normal saline after estradiol valerate- induced polycystic ovarian syndrome (4 mg/rat estradiol valerate, intramuscularly), and three experimental groups, that after induction of PCOS within 60 days, received orally 50 mg/kg CCT extract (group III), 50mg/kg metformin (group IV), and CCT extract+ metformin (group V) for 20 days. The serum concentration level of luteinizing, testosterone and follicle stimulating hormones were measured using ELISA method and the serum concentration level of glucose were measured using the oxidative method (glucose meter). Histological study of ovary tissue carried out by hematoxylin-eosin staining. Results: There was a significant reduction in luteinizing hormone and testosterone in III-V groups compared to Sham group, whereas follicle stimulating hormone in III-V groups was not significantly changed in comparison with Sham group. Histological investigations showed a significant increase in number of preantral and antral follicles and corpus luteum in the experimental groups compared to group II. Conclusion: Marked improvement in hormonal and histological symptoms of PCOS may be due to CCT effects hence, CCT can potentially be considered as an effective drug for treatment of PCOS. PMID- 29387834 TI - X-ray absorption near edge structure and first-principles spectral investigations of cationic disorder in MgAl2O4 induced by swift heavy ions. AB - Cationic disorder in the MgAl2O4 spinel induced by swift heavy ions was investigated using the X-ray absorption near edge structure. With changes in the irradiation fluences of 200 MeV Xe ions, the Mg K-edge and Al K-edge spectra were synchronously changed. The calculated spectra based on density function theory indicate that the change in the experimental spectra was due to cationic disorder between Mg in tetrahedral sites and Al in octahedral sites. These results suggest a high inversion degree to an extent that the completely random configuration is achieved in MgAl2O4 induced by the high density electronic excitation under swift heavy ion irradiation. PMID- 29387833 TI - Restricting the use of antibiotics in food-producing animals and its associations with antibiotic resistance in food-producing animals and human beings: a systematic review and meta-analysis. AB - Background: Antibiotic use in human medicine, veterinary medicine, and agriculture has been linked to the rise of antibiotic resistance globally. We did a systematic review and meta-analysis to summarise the effect that interventions to reduce antibiotic use in food-producing animals have on the presence of antibiotic-resistant bacteria in animals and in humans. Methods: On July 14, 2016, we searched electronic databases (Agricola, AGRIS, BIOSIS Previews, CAB Abstracts, MEDLINE, Embase, Global Index Medicus, ProQuest Dissertations, Science Citation Index) and the grey literature. The search was updated on Jan 27, 2017. Inclusion criteria were original studies that reported on interventions to reduce antibiotic use in food-producing animals and compared presence of antibiotic resistant bacteria between intervention and comparator groups in animals or in human beings. We extracted data from included studies and did meta-analyses using random effects models. The main outcome assessed was the risk difference in the proportion of antibiotic-resistant bacteria. Findings: A total of 181 studies met inclusion criteria. Of these, 179 (99%) described antibiotic resistance outcomes in animals, and 81 (45%) of these studies were included in the meta-analysis. 21 studies described antibiotic resistance outcomes in humans, and 13 (62%) of these studies were included in the meta-analysis. The pooled absolute risk reduction of the prevalence of antibiotic resistance in animals with interventions that restricted antibiotic use commonly ranged between 10 and 15% (total range 0-39), depending on the antibiotic class, sample type, and bacteria under assessment. Similarly, in the human studies, the pooled prevalence of antibiotic resistance reported was 24% lower in the intervention groups compared with control groups, with a stronger association seen for humans with direct contact with food producing animals. Interpretation: Interventions that restrict antibiotic use in food-producing animals are associated with a reduction in the presence of antibiotic-resistant bacteria in these animals. A smaller body of evidence suggests a similar association in the studied human populations, particularly those with direct exposure to food-producing animals. The implications for the general human population are less clear, given the low number of studies. The overall findings have directly informed the development of WHO guidelines on the use of antibiotics in food-producing animals. Funding: World Health Organization. PMID- 29387835 TI - A fluorescent peptidyl substrate for visualizing peptidyl-prolyl cis/trans isomerase activity in live cells. AB - This communication reports on a fluorescent probe (PPI-P) for imaging active peptidyl-prolyl cis/trans isomerases in live cells. PPI-P is capable of responding to both recombinant and cellular PPIases fluorogenically, and has been shown to specifically image active PPIases in live cells. PMID- 29387836 TI - Alkaline phosphatase-triggered assembly of etoposide enhances its anticancer effect. AB - Etoposide is a cancer-targeting drug but an overdose of etoposide leads to immunosuppression in patients. Therefore, the development of a new strategy to enhance its anticancer effect, while in the meantime alleviating its adverse effects, is important but challenging. In this work, with the assistance of a hydrogelator precursor Nap-Phe-Phe-Tyr(H2PO3)-OH (1P), etoposide phosphate (EP) was subjected to alkaline phosphatase (ALP)-triggered assembly, which obviously enhanced its anticancer efficacy in vitro and in vivo. In vitro tests indicated that the assembly of EP with 1P resulted in a slow release of etoposide and long term inhibitory effects on HeLa cells. In vivo experiments indicated that, compared with those of EP-treated mice, the tumor growth of EP + 1P-treated mice was further inhibited while their body weight loss was alleviated. We envision that our hydrogelator-assisted assembly strategy could be applied to enhance the therapeutic effects of more drugs, while in the meantime alleviating their adverse effects in the future. PMID- 29387837 TI - H-Abstraction reactions by OH, HO2, O, O2 and benzyl radical addition to O2 and their implications for kinetic modelling of toluene oxidation. AB - Alkylated aromatics constitute a significant fraction of the components commonly found in commercial fuels. Toluene is typically considered as a reference fuel. Together with n-heptane and iso-octane, it allows for realistic emulations of the behavior of real fuels by the means of surrogate mixture formulations. Moreover, it is a key precursor for the formation of poly-aromatic hydrocarbons, which are of relevance to understanding soot growth and oxidation mechanisms. In this study the POLIMI kinetic model is first updated based on the literature and on recent kinetic modelling studies of toluene pyrolysis and oxidation. Then, important reaction pathways are investigated by means of high-level theoretical methods, thereby advancing the present knowledge on toluene oxidation. H-Abstraction reactions by OH, HO2, O and O2, and the reactivity on the multi well benzyl oxygen (C6H5CH2 + O2) potential energy surface (PES) were investigated using electronic structure calculations, transition state theory in its conventional, variational, and variable reaction coordinate forms (VRC-TST), and master equation calculations. Exploration of the effect on POLIMI model performance of literature rate constants and of the present calculations provides valuable guidelines for implementation of the new rate parameters in existing toluene kinetic models. PMID- 29387838 TI - Intrinsic optical sectioning with upconverting nanoparticles. AB - Multiphoton microscopy is a powerful technique for imaging due to its deep penetration, low scattering and sectioning power, allowing control on all three axes for both imaging and molecular actuation, but involves expensive femtosecond lasers. We show that lanthanide-based Upconverting Nanoparticles offer an under $1000 solution with the main advantages of multiphoton imaging, including direct optical sectioning in complex 3D samples. PMID- 29387840 TI - Reactivity of amino acid anions with nitrogen and oxygen atoms. AB - For many decades, astronomers have searched for biological molecules, including amino acids, in the interstellar medium; this endeavor is important for investigating the hypothesis of the origin of life from space. The space environment is complex and atomic species, such as nitrogen and oxygen atoms, are widely distributed. In this work, the reactions of eight typical deprotonated amino acids (glycine, alanine, cysteine, proline, aspartic acid, histidine, tyrosine, and tryptophan) with ground state nitrogen and oxygen atoms are studied by experiment and theory. These amino acid anions do not react with nitrogen atoms. However, the reactions of these ions with oxygen atoms show an intriguing variety of ionic products and the reaction rate constants are of the order of 10 10 cm3 s-1. Density functional calculations provide detailed mechanisms of the reactions, and demonstrate that spin conversion is essential for some processes. Our study provides important data and insights for understanding the kinetic and dynamic behavior of amino acids in space environments. PMID- 29387839 TI - PBP bridged [3]ferrocenophane: a bisphosphanylborane with a redox trigger. AB - Stereospecific access to the unprecedented P-B-P bridged [3]ferrocenophane Fe(C5H4PtBu)2BMes is presented. In contrast to acyclic ferrocenylphosphanes, we find evidence for a shift of spin-density from Fe to P upon pyramidal inversion of the P centers in the mono-cation; the latter has a lifetime of tau = 0.31(4) s. PMID- 29387841 TI - Detection of prostate specific antigen (PSA) in human saliva using an ultra sensitive nanocomposite of graphene nanoplatelets with diblock-co-polymers and Au electrodes. AB - Prostate-specific antigen (PSA) is a commonly used biomarker for the detection of prostate cancer (PCa) and there are numerous data available for its invasive detection in the serum and whole blood. In this work, an electrochemical sensing method was devised to detect traces of PSA in human saliva using a hybrid nanocomposite of graphene nanoplatelets with diblock co-polymers and Au electrodes (GRP-PS67-b-PAA27-Au). The pure graphitic composition on filter paper provides significantly high electrical and thermal conductivity while PS67-b PAA27 makes an amphiphilic bridge between GRP units. The sensor utilizes the binding of an anti-PSA antibody with an antigen-PSA to act as a resistor in a circuit providing an impedance change that in turn allows for the detection and quantification of PSA in saliva samples. A miniaturized electrical impedance analyzer was interfaced with a sensor chip and the data were recorded in real time using a Bluetooth-enabled module. This fully integrated and optimized sensing device exhibited a wide PSA range of detection from 0.1 pg mL-1 to 100 ng mL-1 (R2 = 0.963) with a lower limit of detection of 40 fg mL-1. The performance of the biosensor chip was validated with an enzyme-linked immunosorbent assay technique with a regression coefficient as high as 0.940. The advantages of the newly developed saliva-PSA electrical biosensor over previously reported serum PSA electrochemical biosensors include a faster response time (3-5 min) to achieve a stable electrical signal for PSA detection, high selectivity, improved sensitivity, no additional requirement of a redox electrolyte for electron exchange and excellent shelf life. The presented sensor is aimed for clinical commercialization to detect PSA in human saliva. PMID- 29387842 TI - Detecting reactive islands using Lagrangian descriptors and the relevance to transition path sampling. AB - It has been known for sometime now that isomerization reactions, classically, are mediated by phase space structures called reactive islands (RI). RIs provide one possible route to correct for the nonstatistical effects in the reaction dynamics. In this work, we map out the reactive islands for the two dimensional Muller-Brown model potential and show that the reactive islands are intimately linked to the issue of rare event sampling. In particular, we establish the sensitivity of the so called committor probabilities, useful quantities in the transition path sampling technique, to the hierarchical RI structures. Mapping out the RI structure for high dimensional systems, however, is a challenging task. Here, we show that the technique of Lagrangian descriptors is able to effectively identify the RI hierarchy in the model system. Based on our results, we suggest that the Lagrangian descriptors can be useful for detecting RIs in high dimensional systems. PMID- 29387843 TI - A theoretical study of the effect of a non-aqueous proton donor on electrochemical ammonia synthesis. AB - Ammonia synthesis is one of the most studied reactions in heterogeneous catalysis. To date, however, electrochemical N2 reduction in aqueous systems has proven to be extremely difficult, mainly due to the competing hydrogen evolution reaction (HER). Recently, it has been shown that transition metal complexes based on molybdenum can reduce N2 to ammonia at room temperature and ambient pressure in a non-aqueous system, with a relatively small amount of hydrogen output. We demonstrate that the non-aqueous proton donor they have chosen, 2,6-lutidinium (LutH+), is a viable substitute for hydronium in the electrochemical process at a solid surface, since this donor can suppress the HER rate. We also show that the presence of LutH+ can selectively stabilize the *NNH intermediate relative to *NH or *NH2via the formation of hydrogen bonds, indicating that the use of non aqueous solvents can break the scaling relationship between limiting potential and binding energies. PMID- 29387844 TI - Thermally induced hopping model for long-range triplet excitation energy transfer in DNA. AB - We present a theoretical model for long-range triplet excitation energy transfer in DNA sequences of alternating adenine-thymine steps. It consists of thermally induced hops through thymine bases. Intrastrand hops between thymines separated by an AT step are preferred to interstrand hops between thymines in consecutive steps. Our multi-step mechanism is consistent with recent results (L. Antusch, N. Gass and H.-A. Wagenknecht, Angew. Chem., Int. Ed., 2017, 56, 1385-1389) describing a shallow dependence of triplet sensitized DNA damage relative to the distance between the sensitizer and the reacting thymine-thymine pair. PMID- 29387845 TI - Antimicrobial graphene materials: the interplay of complex materials characteristics and competing mechanisms. AB - Graphene materials (GMs) exhibit attractive antimicrobial activities promising for biomedical and environmental applications. However, we still lack full control over their behaviour and performance mainly due to the complications arising from the coexistence and interplay of multiple factors. Therefore, in this minireview, we attempt to illustrate the structure-property-activity relationships of GMs' antimicrobial activity. We first examine the chemical/physical complexity of GMs focusing on five aspects of their materials characteristics: (i) chemical composition, (ii) impurities and imperfections, (iii) lateral dimension, (iv) self-association (e.g., restacking), and (v) composite/hybrid formation. Next, we briefly summarise the current understanding of their antimicrobial mechanisms. Then, we assign the outlined materials characteristics of GMs to the proposed antimicrobial mechanisms. Lastly, we share our vision regarding the future of research and development in this fast-emerging field. PMID- 29387846 TI - Unconventional gas-based bottom-up, meter-area-scale fabrication of hydrogen-bond free g-CN nanorod arrays and coupling layers with TiO2 toward high-efficiency photoelectrochemical performance. AB - Meter-scale uniform g-CN nanorod (NR) arrays were directly grown on an FTO glass using an unprecedented vacuum magnetic filtered arc ion plating system for enhanced photoelectrochemical (PEC) performance. The construction of the g-CN film is based on the substrate deposition of the direct reaction of ionized carbon and nitrogen species, a gas-based bottom-up approach, distinctly different from the traditional powder deposition and thermal vapor pathways. The g-CN film exhibits obvious advantages over conventional ones in the application of PEC: (1) direct reaction of C and N species allows the formation of the g-CN without intralayer hydrogen bonds, which significantly reduces intralayer photogenerated charge carriers transfer resistance; (2) the g-CN exhibits the NR array structure and comprises considerably numerous layers stacking by stacking and vertically standing on the FTO substrate, which facilitates the photogenerated charges transfer and increases the contact area with electrolyte; (3) the robust mechanical strength of the g-CN NR film with the FTO substrate not only favors the effective charge transport but also allows long-term practical application against abrasion; (4) the gas-based bottom-up approach enables the g-CN to easily couple with, including but not limited to, TiO2 NR array to form heterostructures to further improve charge separation. PMID- 29387847 TI - Kinetic Monte Carlo simulations of water ice porosity: extrapolations of deposition parameters from the laboratory to interstellar space. AB - Dust grains in cold, dense interstellar clouds build up appreciable ice mantles through the accretion and subsequent surface chemistry of atoms and molecules from the gas. These mantles, of thicknesses on the order of 100 monolayers, are primarily composed of H2O, CO, and CO2. Laboratory experiments using interstellar ice analogues have shown that porosity could be present and can facilitate diffusion of molecules along the inner pore surfaces. However, the movement of molecules within and upon the ice is poorly described by current chemical kinetics models, making it difficult either to reproduce the formation of experimental porous ice structures or to extrapolate generalized laboratory results to interstellar conditions. Here we use the off-lattice Monte Carlo kinetics model MIMICK to investigate the effects that various deposition parameters have on laboratory ice structures. The model treats molecules as isotropic spheres of a uniform size, using a Lennard-Jones potential. We reproduce experimental trends in the density of amorphous solid water (ASW) for varied deposition angle, rate and surface temperature; ice density decreases when the incident angle or deposition rate is increased, while increasing temperature results in a more-compact water ice. The models indicate that the density behaviour at higher temperatures (>=80 K) is dependent on molecular rearrangement resulting from thermal diffusion. To reproduce trends at lower temperatures, it is necessary to take account of non-thermal diffusion by newly-adsorbed molecules, which bring kinetic energy both from the gas phase and from their acceleration into a surface binding site. Extrapolation of the model to conditions appropriate to protoplanetary disks, in which direct accretion of water from the gas-phase may be the dominant ice formation mechanism, indicate that these ices may be less porous than laboratory ices. PMID- 29387848 TI - Polyacrylamide gel electrophoresis of semiconductor quantum dots and their bioconjugates: materials characterization and physical insights from spectrofluorimetric detection. AB - Colloidal semiconductor quantum dot (QD) nanocrystals have ideal fluorescence properties for bioanalysis and bioimaging, but these materials must be functionalized with an inorganic shell, organic ligand or polymer coating, and conjugated with biomolecules to be useful in such applications. Several different analytical techniques are used to characterize QDs and their multiple layers of functionalization. Here, we revisit poly(acrylamide) gel electrophoresis (PAGE), which has been scarcely used for the characterization of QDs and their bioconjugates in deference to the routine use of agarose gel electrophoresis. We implemented PAGE in a novel "stubby" capillary format with spectrofluorimetric detection, the combination of which enabled more rapid and more detailed characterization of QDs than was possible with both poly(acrylamide) and agarose slab gels. Correlations between the peak photoluminescence (PL) emission wavelength and electropherogram peaks, especially when combined with Ferguson analysis, provided new and significant insight into the key factors that determine the electrophoretic mobility of QDs, and helped to resolve heterogeneity and sub-populations in ensembles of QDs. The method was useful for characterization of the inorganic core/shell nanocrystals, their organic ligand and polymer coatings, and their final bioconjugates, the latter of which were in the form of peptide and protein conjugates. With further development and optimization, we anticipate that capillary PAGE with spectrofluorimetric detection will become a valuable addition to the toolbox of characterization techniques suitable for QDs, their bioconjugates, and other nanoparticle materials as well. PMID- 29387849 TI - Surface-enhanced Raman spectroscopic detection of molecular chemo- and plasmo catalysis on noble metal nanoparticles. AB - The in situ detection of reactions catalyzed by metal NPs is challenging because the underlying chemical transformations occur at interfaces. Surface-enhanced Raman scattering (SERS), a surface-selective, sensitive and label-free vibrational spectroscopic technique, is ideally suited for monitoring of heterogeneous catalysis with high chemical specificity. A major limitation in the past, however, was that small, catalytically active metal NPs do not exhibit the high plasmonic activity required for SERS. This feature article focuses on the design, synthesis and use of bifunctional NPs with both catalytic and plasmonic activity for in situ SERS detection of reactions catalyzed by metal NPs. We focus on model reactions induced by chemical reducing agents such as hydride or molecular hydrogen as well as on plasmon-induced photo-catalysis including both photo-oxidation and photo-reduction. Finally, we highlight the concept of photo recycling on halide-containing silver surfaces for unprecedented multi-electron reduction chemistry. PMID- 29387850 TI - Methods for the synthesis of annulated pyrroles via cyclisation strategies. AB - Pyrrole, pyrrolidine, and indolizidine alkaloids represent important classes of natural products. Historically, these heterocycles and their derivatives have been the focus of significant interest in organic synthesis. In this report, we review the methods that have been employed to synthesise annulated pyrroles via transformations that include: Friedel-Crafts acylations and alkylations, Michael additions, Heck couplings, hydroarylations, carbenoid insertions, and radical cyclisations. PMID- 29387851 TI - Sample preparation affects the nematic-isotropic transition in liquid crystal elastomers: insights from molecular simulation. AB - The features of nematic-isotropic transition in liquid crystal elastomers are important for the potential applications of these materials as sensors and actuators. In this paper, we use molecular simulations to obtain insights into the nature of this transition, focusing on the role of sample preparation leading to different polymer network architectures, as well as on the role of swelling. We perform a series of isostress Monte Carlo simulations in a swollen crosslinked system consisting of soft-core Gay-Berne ellipsoids, finding that the smoothness of the nematic-isotropic transition in irregular samples can be attributed to quenched disorder resulting in a distribution of local transition temperatures, and in the strongly swollen samples to a polymer network-swelling monomers phase separation. PMID- 29387852 TI - An approach towards the synthesis of novel fused nitrogen tricyclic heterocyclic scaffolds via GBB reaction. AB - A concise and efficient one-pot synthesis of novel N-fused tricyclic derivatives has been developed by using the Groebke-Blackburn-Bienayme (GBB) reaction, which involved the reaction of 3-amino-1H-indazoles, aldehydes and isonitriles to afford 2-aryl-5H-imidazo[1,2-b]indazol-3-amine derivatives via a formal [4 + 1] cycloaddition reaction. Furthermore, we describe an unprecedented reaction of chromone-3-carboxaldehydes with 3-amino-1H-indazoles to afford (2 hydroxyphenyl)(pyrimido[1,2-b]indazol-3-yl)methanones in one-pot at ambient temperature. This protocol features a robust method for the one-step construction of new tricyclic rings, column chromatography free methods with a clean reaction profile, high yields, operational simplicity and it tolerates a diverse collection of reactants. PMID- 29387853 TI - An amorphous Si material with a sponge-like structure as an anode for Li-ion and Na-ion batteries. AB - Sponge-like amorphous silicon was prepared by reacting silicon tetrachloride with magnesium powder. When the as-prepared sample was applied as an anode in rechargeable batteries, it exhibited a reversible capacity of 1125 mA h g-1 after 100 cycles at 1 A g-1 for Li-ion batteries (LIBs) and a reversible capacity of 176 mA h g-1 at 100 mA g-1 over 100 cycles for Na-ion batteries (NIBs). PMID- 29387854 TI - Surface wipe and bulk sampling of household dust: arsenic exposure in Cornwall, UK. AB - Dust elemental levels can be expressed as concentrations (bulk samples) or surface loadings (wipe samples). Wipe sampling has not been widely adopted for elements other than lead (Pb). In this study, 433 wipe samples from 130 households in south west England - a region of widespread, natural and anthropogenic arsenic contamination linked with previous mining activities-were analysed to (i) quantify loadings of arsenic (As); (ii) assess the quality of wipe data using QA/QC criteria; (iii) estimate, using published ingestion rates, human exposure to As in dust using loadings and concentrations from 97 bulk samples and (iv) comparatively assess the performance of wipe and bulk sampling using associations with As biomonitoring data (urine, toenails and hair). Good QC performance was observed for wipes: strong agreement between field duplicates, non-detectable contamination of field blank wipes and good reference material recoveries. Arsenic loadings exceeded an existing urban background benchmark in 67 (52%) households. No exceedances of tolerable daily As intake were observed for adult exposure estimates but infant estimates exceeded for 1 household. Infant estimates calculated using bulk concentrations resulted in 4 (3%) exceedances. Neither wipe nor bulk As metrics were sufficiently better predictors of As in biospecimens. Sampling strategies, analytical protocols, exposure metrics and assessment criteria require refinement to validate dust sampling methodologies. PMID- 29387855 TI - DFT coupled with NEGF study of a promising two-dimensional channel material: black phosphorene-type GaTeCl. AB - A stable three-dimensional layered GaTeCl bulk counterpart is first known from experiment since 1980s. In this study, we propose a two-dimensional GaTeCl, the band structure of which has a tendency of intrinsic direct-to-indirect band gap transitions as a result of a decrease in the layer number, while the changes in the band gap value are minor. The GaTeCl monolayer possesses a wide indirect band gap of 3.06 eV and high hole mobility of up to 4710 cm2 V-1 s-1, which, intriguingly, can be converted into direct band-gap semiconductors under a slight tensile strain. The GaTeCl monolayer is calculated to have an ideal cleavage energy of about 32 meV per atom; therefore, the synthesis of GaTeCl monolayer through exfoliation of bulk GaTeCl is available. In this regard, we simulate a monolayer GaTeCl MOSFETs device based on first-principles method quantum transport approach. The underlying device performance could pave the way for it to be a promising candidate as a suitable FET channel material. PMID- 29387856 TI - Milk-derived bioactive peptides protect against oxidative stress in a Caco-2 cell model. AB - Milk and milk-derived products are a relevant source of bioactive peptides, which are also potential components of functional foods. Bioactive peptides exert multiple actions including an antioxidant role. In the present paper, four synthetic peptides (NPYVPR, AVPYPQR, KVLPVPEK, and ARHPHPHLSFM), corresponding to milk-derived peptides were studied. Although with different features, as revealed by RP-HPLC chromatography and MS analysis, the obtained peptides were shown to be taken up by Caco-2 cells arranged in an epithelial monolayer formation. The four peptides were all able to preserve cell viability against induced oxidative stress indicating that they might have a role in the control of oxidative stress. Therefore, an estimation of total thiols and glutathione content was performed after cell treatment with oxidants like hydrogen peroxide (H2O2) or tert-butyl hydroperoxide (TbOOH). The peptides were able to prevent the decrease of both total thiols and glutathione induced by H2O2 or TbOOH, and, in addition, they showed a protective effect on the thiol-related antioxidant enzymes thioredoxin reductase and glutathione reductase. Finally, they caused a decrease of ROS production induced by TbOOH in Caco-2 cells. The reported results highlight the relevant antioxidant role played by bioactive peptides in cells, which adds to other previously known properties. PMID- 29387857 TI - Self-assembling nanostructured intercalates via ion-dipole bonding. AB - A new system of highly ordered self-assembly intercalated polymer/clay nanocomposite is reported. These systems appear to be driven by entropic forces and are nanostructured but self-assemble across the micron scale. The systems exhibit extremely good gas barrier properties which do not fit the traditional tortuous path model of diffusion. In these complexes the intercalated system behaves differently than the bulk polymer. This behaviour can be explained by constrained polymer theory. The paper presents structural characteristics of the intercalates as well as gas barrier properties of films produced with the intercalated systems. A new radical approach to food packaging is proposed and demonstrated. PMID- 29387858 TI - Band alignment and charge transfer predictions of ZnO/ZnX (X = S, Se or Te) interfaces applied to solar cells: a PBE+U theoretical study. AB - The engineering of semiconductor materials for the development of solar cells is of great importance today. Two topics are considered to be of critical importance for the efficiency of Gratzel-type solar cells, the efficiency of charge separation and the efficiency of charge carrier transfer. Thus, one research focus is the combination of semiconductor materials with the aim of reducing charge recombination, which occurs by spatial charge separation. From an experimental point of view, the combining of materials can be achieved by decorating a core with a shell of another material resulting in a core-shell system, which allows control of the desired photoelectronic properties. In this context, a computational simulation is mandatory for the atomistic understanding of possible semiconductor combinations and for the prediction of their properties. Considering the construction of ZnO/ZnX (X = S, Se or Te) interfaces, we seek to investigate the electronic influence of the shell (ZnX) on the core (ZnO) and, consequently, find out which of the interfaces would present the appropriate properties for (Gratzel-type) solar cell applications. To perform this study, we have employed density functional theory (DFT) calculations, considering the Perdew-Burke-Ernzerhof (PBE) functional. However, it is well known that plain DFT fails to describe strong electronic correlated materials where, in general, an underestimation of the band gap is obtained. Thus, to obtain the correct description of the electronic properties, a Hubbard correction was employed, i.e. PBE+U calculations. The PBE+U methodology provided the correct electronic structure properties for bulk ZnO in good agreement with experimental values (99.4%). The ZnO/ZnX interfaces were built and were composed of six ZnO layers and two ZnX layers, which represents the decoration process. The core shell band gap was 2.2 eV for ZnO/ZnS, ~1.71 eV for ZnO/ZnSe and ~0.95 eV for ZnO/ZnTe, which also exhibited a type-II band alignment. Bader charge analysis showed an accumulation of charges in the 6th layer of ZnO for the three ZnO/ZnX interfaces. On the basis of these results, we have proposed that ZnO/ZnS and ZnO/ZnSe core-shell structures can be applied as good candidates (with better efficiency) for photovoltaic devices. PMID- 29387859 TI - Distribution of mercury species and mercury isotope ratios in soils and river suspended matter of a mercury mining area. AB - Mercury (Hg) released by mining activities can be dispersed in the environment, where it is subject to species transformations. Hg isotope ratios have been used to track sources in Hg contaminated areas, although it is unclear to what extent variations in delta-values are attributed to distinct Hg species. Hg was mined as Hg sulphide (cinnabar) in Idrija, Slovenia for centuries. Sediments are loaded with mining-residues (cinnabar and calcine), whereas contaminated soils mainly contain Hg bound to natural organic matter (NOM-Hg) related to atmospheric Hg deposition. Hg released from soils and sediments is transported as suspended matter (SM) in the Idrijca river to the Gulf of Trieste (GT), Italy. We determine Hg isotope ratios in river SM, sediments and soils from the Idrijca-catchment to decipher the Hg isotope ratio variability related to Hg species distribution in different grain-size fractions. delta202Hg values of SM collected from tributaries corresponded to those found in soils ranging from -2.58 to 0.190/00 and from -2.27 to -0.880/00, respectively. Speciation measurements reveal that fine fractions (0.45-20 MUm) are dominated by NOM-Hg, while larger fractions contain more cinnabar. More negative delta202Hg values were related to higher proportions of NOM-Hg, which are predominant in soils and SM. Rain events increase SM-loads in the river, mainly due to resuspension of coarse grain-size fractions of bottom sediments bearing larger proportions of cinnabar, which leads to more positive delta202Hg values. The large magnitude of variation in delta202Hg and the smaller magnitude of variation in Delta199Hg (-0.37 to 0.090/00) are likely related to fractionation during ore roasting. Soil samples with high NOM-Hg content show more negative delta202Hg values and larger variation of Delta199Hg. More negative delta202Hg values in GT sediments were rather linked to distant sedimentation of soil derived NOM-Hg than to sedimentation of autochthonous marine material. Heterogeneity in the Idrija ore and ore processing likely produce large variations in the Hg isotopic composition of cinnabar and released metallic Hg, which complicate the differentiation of Hg sources. Combining Hg isotope measurements with solid phase Hg speciation reveals that Hg isotope ratios rather indicate different Hg species and are not necessarily symptomatic for Hg pollution sources. PMID- 29387861 TI - Fabrication of dual stimuli-responsive multicompartmental drug carriers for tumor selective drug release. AB - There has been increasing attention to the development of multi-stimuli responsive drug carriers for precisely controlled drug release at target disease areas. In this study, pH- and redox-responsive hybrid drug carriers were fabricated by using both ketal-based acid-cleavable precursors and disulfide based reducible precursors via stop-flow lithography. pH- and redox-sensitive drug release of the dual stimuli-responsive hybrid particles was confirmed, demonstrating their feasibility for selective and efficient drug release into tumor tissues in acidic and highly reductive environments. It was also found that the drug release rate of the particles was fine-tuned by modulating monomer compositions in the precursor. Importantly, the dual stimuli-responsive hybrid particles exhibited synergistic, controlled drug release in complex stimuli (both pH and redox stimuli) environments. To achieve tumor-selective combination chemotherapy, multicompartmental drug carriers consist of an acid-degradable compartment and a reducible compartment, which can separately encapsulate individual model drugs in each of the compartments. The multicompartmental particles exhibited independent drug release upon exposure to the corresponding stimulus. The dual stimuli-responsive, multicompartmental particles are effective drug carriers for tumor-selective release of a drug cocktail, leading to synergistic combination chemotherapy. PMID- 29387860 TI - Microfluidic detection of movements of Escherichia coli for rapid antibiotic susceptibility testing. AB - Various nanomechanical movements of bacteria provide a signature of bacterial viability. Most notably, bacterial movements have been observed to subside rapidly and dramatically when the bacteria are exposed to effective antibiotics. Thus, monitoring bacterial movements, if performed with high fidelity, could offer a path to various clinical microbiological applications, including antibiotic susceptibility tests. Here, we introduce a robust and ultrasensitive electrical transduction technique for detecting the nanomechanical movements of bacteria. The technique is based on measuring the electrical fluctuations in a microfluidic channel, which the bacteria populate. The swimming of planktonic bacteria and the random oscillations of surface-immobilized bacteria both cause small but detectable electrical fluctuations. We show that this technique provides enough sensitivity to detect even the slightest movements of a single cell; we also demonstrate an antibiotic susceptibility test in a biological matrix. Given that it lends itself to smooth integration with other microfluidic methods and devices, the technique can be developed into a functional antibiotic susceptibility test, in particular, for urinary tract infections. PMID- 29387862 TI - Molecular investigation of evaporation of biodroplets containing single-strand DNA on graphene surface. AB - In this study, the water droplet behaviour of four different types of single strand DNA with homogeneous base sequence on a graphene substrate during evaporation of the droplet was investigated using molecular dynamics (MD) simulation. The simulation results indicated that the evaporation depended on the DNA sequence. The observed changes can be divided into four parts: (i) vaporization mode, (ii) evaporation flux, (iii) mechanism of single-strand placement on the surface, and (iv) consideration of remaining single strands after evaporation. Our simulation observations indicated different evaporation modes for thymine biodroplets as compared to those for other biodroplets. The evaporation of the thymine biodroplets occurred with an increase in the contact angle, while that of the other biodroplets occur in a constant contact angle mode. Moreover, thymine biodroplets generate the lowest contact line compared to other single strands, and it is always placed far away from the centre of the droplets during evaporation. Investigating variations in the evaporation flux shows that thymine has the highest evaporation flux and guanine has the lowest. Moreover, during initial evaporation, the flux of evaporation increases at the triple point of the biodroplets containing thymine single strands, while it decreases in the other biodroplets. The following observation was obtained from the study of the placement of single strands on the substrate: guanine and thymine interacted slower than other single strands during evaporation with graphene, adenine single strand had a higher folding during evaporation, and guanine single strand showed the lowest end-to-end distance. The investigation of single-strand DNA after evaporation shows that adenine produces the most stable structure at the end of evaporation. In addition, cytosine is the most stretched single-strand DNA due to its lack of internal pi-pi stacking and hydrogen bonding. Therefore, cytosine single strand is more accessible for use in microarrays to detect target single strands. PMID- 29387863 TI - miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha. AB - The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-alpha (HIF-1alpha) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1alpha and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both kinds of rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1alpha expression by targeting the 3' untranslated region (UTR) of HIF-1alpha mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1alpha pathway and attenuated apoptosis caused by hypoxia, while miR 210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF 1alpha directly and suppressing HIF-1alpha pathway activation in vitro. PMID- 29387864 TI - Sirtuin-6 preserves R-spondin-1 expression and increases resistance of intestinal epithelium to injury in mice. AB - Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans. Colitis-derived inflammatory mediators including interferon-gamma and reactive oxygen species strongly inhibited Sirt6 protein expression in young adult mouse colonocyte (YAMC) cells. The susceptibility of the cells to injurious insults was increased after knockdown of Sirt6 expression. In contrast, YAMC cells with Sirt6 overexpression exhibited more resistance to injurious insult. Furthermore, intestinal epithelial-specific Sirt6 (Sirt6IEC-KO) knockout mice exhibited greater susceptibility to dextran sulfate sodium (DSS) induced colitis. RNA sequencing transcriptome analysis revealed that inflammatory mediators such as tumor necrosis factor (TNF)-alpha suppressed expression of R spondin-1 (Rspo1, a critical growth factor for intestinal epithelial cells) in Sirt6-silenced YAMC cells in vitro. In addition, lipopolysaccharide was found to inhibit colonic Rspo1 expression in Sirt6IEC-KO mice but not their control littermates. Furthermore, Sirt6IEC-KO mice with DSS-induced colitis also exhibited in a significant decrease in Rspo1 expression in colons. In vitro, knockdown of Rspo1 attenuated the effect of ectopic expression of Sirt6 on protection of YAMC cells against cell death challenges. In conclusion, Sirt6 plays an important role in protecting intestinal epithelial cells against inflammatory injury in a mechanism associated with preserving Rspo1 levels in the cells. PMID- 29387865 TI - RAGE-aptamer Attenuates the Growth and Liver Metastasis of Malignant Melanoma in Nude Mice. AB - Epidemiological studies have suggested the link between cumulative diabetic exposure and cancer. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) may contribute to the phenomenon. We examined here the effects of DNA aptamer raised against RAGE (RAGE-aptamer) on growth and liver metastasis of G361 melanoma in nude mice. Malignant melanoma cells were intradermally injected into the upper flank region of nude mice, which received continuous administration of RAGE-aptamer (38.4 pmol/day/g body weight) or vehicle intraperitoneally by an osmotic pump up to 42 days. RAGE-aptamer significantly reduced levels of 8-hydroxy-2'-deoxy-guanosine, AGEs, RAGE, proliferating nuclear antigen, cyclin D1, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CD31 and Mac-3, respective markers of endothelial cells and macrophages in tumors of nude mice and suppressed the proliferation and liver metastasis of malignant melanoma. Furthermore, RAGE-aptamer attenuated the AGE-induced oxidative stress generation, proliferation, and VEGF and MCP-1 gene expression in both G361 melanoma cells and endothelial cells. The present findings suggest that RAGE-aptamer could attenuate melanoma growth and liver metastasis in nude mice by suppressing the tumor angiogenesis and macrophage infiltration via inhibition of the AGE-RAGE system. RAGE-aptamer may be a novel therapeutic tool for the treatment of malignant melanoma. PMID- 29387866 TI - Complex pattern of variation in neurocranial ontogeny revealed by CT-scanning. AB - ABSTRACT: The neurocranium of hominid species has been largely studied with reference to the midsagittal plane, with variations being attributed to brain evolution. By contrast, there is limited information on variation in non midsagittal regions, which are the points of insertion of muscles and bony structures related to mastication. This work aims to analyze ontogenetic changes and sexual dimorphism (SD) in midsagittal and non-midsagittal neurocranial structures from a contemporary human sample comprising 138 computed tomography (CT) cranial images of individuals ranging from infants to adults. Morphology of the vault and the base was assessed by registering landmarks and semilandmarks, which were analyzed by geometric morphometrics, and the endocranial volume (EV). The results of regressions and Kruskal-Wallis test indicate that the major size and shape changes in both midsagittal and non-midsagittal regions occur during infancy and juvenility; shape changes are also associated with an increase in EV. The size of the midsagittal vault, the shape of the non-midsagittal vault and the size of the base show an extension of ontogenetic trajectories. Sexes show similar changes in shape but different changes in size. We conclude that brain growth appears to be an important factor influencing the morphology of the neurocranium, at least during infancy and childhood. Subsequent changes may be attributed to osteogenic activity and the differential growth of the brain lobes. Masticatory-related bony structures and muscles may not be strong enough factors to induce independent modifications in non-midsagittal structures. The small influence of the cranial muscles would explain why the human neurocranium is a quite integrated structure. PMID- 29387868 TI - Eastern Baltic region vs. Western Europe: modelling age related changes in the pubic symphysis and the auricular surface. AB - ABSTRACT: Objectives. The present study addresses the following two main questions: a) Is the pattern of skeletal ageing observed in well-known western European reference collections applicable to modern eastern Baltic populations, or are population-specific standards needed? b) What are the consequences for estimating the age-at-death distribution in the target population when differences in the estimates from reference data are not taken into account? Materials and methods. The dataset consists of a modern Lithuanian osteological reference collection, which is the only collection of this type in the eastern Baltic countries (n = 381); and two major western European reference collections, Coimbra (n = 264) and Spitalfields (n = 239). The age-related changes were evaluated using the scoring systems of Suchey-Brooks (Brooks & Suchey 1990) and Lovejoy et al. (1985), and were modelled via regression models for multinomial responses. A controlled experiment based on simulations and the Rostock Manifesto estimation protocol (Wood et al. 2002) was then carried out to assess the effect of using estimates from different reference samples and different regression models on estimates of the age-at-death distribution in the hypothetical target population. Results. The following key results were obtained in this study. a) The morphological alterations in the pubic symphysis were much faster among women than among men at comparable ages in all three reference samples. In contrast, we found no strong evidence in any of the reference samples that sex is an important factor to explain rate of changes in the auricular surface. b) The rate of ageing in the pubic symphysis seems to be similar across the three reference samples, but there is little evidence of a similar pattern in the auricular surface. That is, the estimated rate of age-related changes in the auricular surface was much faster in the LORC and the Coimbra samples than in the Spitalfields sample. c) The results of simulations showed that the differences in the estimates from the reference data result in noticeably different age-at-death distributions in the target population. Thus, a degree bias may be expected if estimates from the western European reference data are used to collect information on ages at death in the eastern Baltic region based on the changes in the auricular surface. d) Moreover, the bias is expected to be more pronounced if the fitted regression model improperly describes the reference data. Conclusions. Differences in the timing of age-related changes in skeletal traits are to be expected among European reference samples, and cannot be ignored when seeking to reliably estimate an age-at-death distribution in the target population. This form of bias should be taken into consideration in further studies of skeletal samples from the eastern Baltic region. PMID- 29387867 TI - Investigations of the relation between birth trauma and pelvic size in females from a medieval gravesite from Lubeck. AB - ABSTRACT: This study proposes that female pelvises showing no birth traumata may have had ideal child-bearing bone constitutions, differing significantly in size and shape from those with severe traumata, resulting in advantages during parturition. Based on this assumption, the female pelvises of a late medieval mass grave from Lubeck have been examined in terms of pelvic osteometric standards in obstetrics, morphological aspects, the degree of birth trauma lesions, and the possible effect of age at death on trauma mark severity. The results imply much wider pelvises (up to 1 cm) in the historical population and a shift in pelvic shape appearances from gynaecoid and platypelloid forms toward android and anthropoid shapes, compared with modern European populations. Furthermore, a significant relation between the appearances of lesions and the age at death was found, while the relations between pelvic size and shape and birth trauma appearances is not significant in this historical skeletal series. PMID- 29387869 TI - Rapid Change in Fentanyl Prevalence in a Community-Based, High-Risk Sample. PMID- 29387870 TI - Rapid Repigmentation of Vitiligo Using Tofacitinib Plus Low-Dose, Narrowband UV-B Phototherapy. PMID- 29387871 TI - Postpartum Depression and Its Long-term Impact on Children: Many New Questions. PMID- 29387872 TI - Blaschkoid Acute Graft-vs-Host Disease. PMID- 29387873 TI - Prevalence and Types of Genital Lesions in Organ Transplant Recipients. AB - Importance: Squamous cell carcinoma (SCC) is the most common skin cancer diagnosed in solid organ transplant recipients (OTRs) and confers significant mortality. The development of SCC in the genital region is elevated in nonwhite OTRs. Viral induction, specifically human papillomavirus (HPV), is hypothesized to play a role in the pathophysiology of these lesions. Objective: To assess the prevalence and types of genital lesions observed in OTRs. Design, Setting, and Participants: This retrospective review included 496 OTRs who underwent full skin examination from November 1, 2011, to April 28, 2017, at an academic referral center. The review was divided into 2 distinct periods before a change in clinical management that took effect on February 1, 2016 (era 1) and after that change (era 2). Patient awareness of genital lesions was assessed. All lesions clinically suggestive of malignant tumors were biopsied and underwent HPV polymerase chain reaction typing. Main Outcomes and Measures: Number and types of genital lesions, proportion of malignant tumors positive for HPV, and patients cognizant of genital lesions. Results: Of the total 496 OTRs, 376 OTRs were evaluated during era 1 (mean [SD] age, 60 years; age range, 32-94 years; 45 [65.2%] male; 164 [43.6%] white) and 120 OTRs were evaluated during era 2 of the study (mean age, 56 years; age range, 22-79 years; 76 [63.3%] male; 30 [25.0%] white). Overall, 111 of the 120 OTRs (92.5%) denied the presence of genital lesions during the history-taking portion of the medical examination. Genital lesions were found in 53 OTRs (44.2%), cutaneous malignant tumors (basal cell carcinoma and SCC in situ) in 6 (5.0%), genital SCC in situ in 3 (4.2%), and condyloma in 29 (24.2%). Eight of the 12 SCC in situ lesions (66.7%) were positive for high-risk HPV. Seven tested positive for HPV-16 and HPV-18, and 1 tested positive for high-risk HPV DNA but could not be further specified. Conclusions and Relevance: Genital lesions in OTRs are common, but awareness is low. All OTRs should undergo thorough inspection of genital skin as a part of routine posttransplant skin examinations. Patients with darker skin types are disproportionately affected by cutaneous genital malignant tumors and should undergo a targeted program of early detection, prevention, and awareness focused on the risk of genital skin cancer after transplant. High-risk HPV subtypes are associated with genital SCC in OTRs. Additional studies are warranted to identify significant risk factors for HPV infection and to assess the utility of pretransplant HPV vaccination in the prevention of cutaneous genital malignant tumors. PMID- 29387875 TI - Trends in Melanoma Incidence Among Non-Hispanic Whites in the United States, 2005 to 2014. PMID- 29387874 TI - Combination of Follicular and Epidermal Cell Suspension as a Novel Surgical Approach in Difficult-to-Treat Vitiligo: A Randomized Clinical Trial. AB - Importance: Epidermal cell suspension (ECS) and follicular cell suspension (FCS) are successful surgical modalities for the treatment of stable vitiligo. However, repigmentation in generalized and acrofacial vitiligo and over acral or bony sites (eg, elbows, knees, iliac crests, and malleoli), which are difficult to treat, is challenging. Objective: To study the efficacy of transplanting a combination of autologous, noncultured ECS and FCS (ECS + FCS) compared with ECS alone in stable vitiligo. Design, Setting, and Participants: A prospective, observer-blinded, active-controlled, randomized clinical trial was conducted at a tertiary care hospital, with treatment administered as an outpatient procedure. Thirty participants who had stable vitiligo with symmetrical lesions were recruited between October 18, 2013, and October 28, 2016. All of the lesions were resistant to medical modalities with minimum lesional stability of 1 year. Intent to-treat analysis was used. Interventions: ECS + FCS was prepared by mixing equal amounts (in cell number) of FCS with ECS. After manual dermabrasion, ECS was applied to 1 lesion and ECS + FCS was applied to the anatomically based paired lesion of the same patient. No adjuvant treatment was given. Main Outcomes and Measures: Patients were followed up at 4, 8, and 16 weeks by a blinded observer and extent of repigmentation, color match, pattern of repigmentation, patient satisfaction and complications were noted. Both the visual and the computerized image analysis methods were used for outcome assessment. Cell suspensions were assessed post hoc for OCT4+ stem cell counts using flow cytometry; expression of stem cell factor and basic fibroblast growth factor was evaluated using quantitative relative messenger RNA expression. Results: Of the 30 patients included in the study, 18 (60%) were women; mean (SD) age was 23.4 (6.4) years. Seventy-four percent of the lesions (62 of 84) were difficult-to-treat vitiligo. ECS + FCS showed superior repigmentation outcomes compared with ECS: extent (76% vs 57%, P < .001), rapidity (48% vs 31%, P = .001), color match (73% vs 61%, P < .001), and patient satisfaction (mean [SD] patient global assessment score, 23.30 [6.89] vs 20.81 [6.61], P = .047). Melanocyte stem cell counts (2% in ECS + FCS vs 0.5% in ECS) as well as expression of basic fibroblast growth factor (11.8 fold) and stem cell factor (6.0-fold) were higher in ECS + FCS suspension (P<.05 for both). Conclusions and Relevance: The findings from this study establish ECS + FCS as a novel approach in vitiligo surgery for attaining good to excellent repigmentation in a short period with good color match, even in difficult-to treat vitiligo. Trial Registration: ctri.nic.in Identifier: CTRI/2017/05/008692. PMID- 29387876 TI - Mortality Rates After the First Diagnosis of Psychotic Disorder in Adolescents and Young Adults. AB - Importance: Individuals with psychotic disorders have increased mortality, and recent research suggests a marked increase shortly after diagnosis. Objective: To use population-based data to examine overall and cause-specific mortality after first diagnosis of a psychotic disorder. Design, Setting, and Participants: This cohort study used records from 5 integrated health systems that serve more than 8 million members in 5 states. Members aged 16 through 30 years who received a first lifetime diagnosis of a psychotic disorder from September 30, 2009, through September 30, 2015, and 2 comparison groups matched for age, sex, health system, and year of diagnosis were selected from all members making an outpatient visit (general outpatient group) and from all receiving a first diagnosis of unipolar depression (unipolar depression group). Exposures: First recorded diagnosis of schizophrenia, schizoaffective disorder, mood disorder with psychotic symptoms, or other psychotic disorder in any outpatient, emergency department, or inpatient setting. Main Outcomes and Measures: Death within 3 years after the index diagnosis or visit date, ascertained from health system electronic health records, insurance claims, and state mortality records. Results: A total of 11 713 members with first diagnosis of a psychotic disorder (6976 [59.6%] men and 4737 [40.4%] women; 2368 [20.2%] aged 16-17 and 9345 [79.8%] aged 18-30 years) were matched to 35 576 outpatient service users and 23 415 members with a first diagnosis of unipolar depression. During the year after the first diagnosis, all cause mortality was 54.6 (95% CI, 41.3-68.0) per 10 000 in the psychotic disorder group compared with 20.5 (95% CI, 14.7-26.3) per 10 000 in the unipolar depression group and 6.7 (95% CI, 4.0-9.4) per 10 000 in the general outpatient group. After adjustment for race, ethnicity, and preexisting chronic medical conditions, the relative hazard of death in the psychotic disorder group compared with the general outpatient group was 34.93 (95% CI, 8.19-149.10) for self inflicted injury or poisoning and 4.67 (95% CI, 2.01-10.86) for other type of injury or poisoning. Risk of death due to heart disease or diabetes did not differ significantly between the psychotic disorder and the general outpatient groups (hazard ratio, 0.78; 95% CI, 0.15-3.96). Between the first and third years after diagnosis, all-cause mortality in the psychotic disorder group decreased from 54.6 to 27.1 per 10 000 persons and injury and poisoning mortality decreased from 30.6 to 15.1 per 10 000 persons. Both rates, however, remained 3 times as high as in the general outpatient group (9.0 per 10 000 for all causes; 4.8 per 10 000 for injury or poisoning). Conclusions and Relevance: Increases in early mortality underscore the importance of systematic intervention for young persons experiencing the first onset of psychosis. Clinicians should attend to the elevated suicide risk after the first diagnosis a psychotic disorder. PMID- 29387877 TI - Course of Cognitive Development From Infancy to Early Adulthood in the Psychosis Spectrum. AB - Importance: Most patients with psychotic disorders experience severe cognitive impairment, but the onset and course of this impairment remain unclear. Moreover, the course of cognitive functions in other psychiatric conditions remains largely unexamined. Objective: To chart the course of general and specific cognitive functions in individuals with psychotic disorders, psychotic experiences, and depression. Design, Setting, and Participants: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective cohort study comprising all live births between April 1, 1991, and December 31, 1992, in Avon, England. The dates of analysis were September 2015 to July 2016. Participants who underwent cognitive testing at ages 18 months and 4, 8, 15, and 20 years and psychiatric assessment at age 18 years were included. Main Outcomes and Measures: Individuals with psychotic disorder, psychosis with depression, psychotic experiences, and depression were compared with controls. Outcomes were full-scale, verbal, and nonverbal IQ at ages 18 months and 4, 8, 15, and 20 years, as well as measures of processing speed, working memory, language, visuospatial ability, and attention at ages 8 and 20 years. Results: The following numbers of individuals were available for analyses in this longitudinal birth cohort study: 511 (238 male [46.6%]) at age 18 months (mean [SD] age, 1.53 [0.03] years), 483 (229 male [47.4%]) at age 4 years (mean [SD] age, 4.07 [0.03] years), 3930 (1679 male [42.7%]) at age 8 years (mean [SD] age, 8.65 [0.29] years), 3783 (1686 male [44.6%]) at age 15 years (mean [SD] age, 15.45 [0.27] years), and 257 (90 male [35.0%]) at age 20 years (mean [SD] age, 20.06 [0.55] years). Individuals with psychotic disorder showed continually increasing deficits between infancy (18 months) and adulthood (20 years) in full-scale IQ (effect size of change [ESDelta] = -1.09, P = .02) and nonverbal IQ (ESDelta = -0.94, P = .008). The depression group showed a small, increasing deficit in nonverbal IQ (ESDelta = 0.29, P = .04) between infancy and adulthood. Between ages 8 and 20 years, the psychotic disorder group exhibited developmental lags (ie, slower growth) in measures of processing speed (ESDelta = -0.68, P = .001), working memory (ESDelta = -0.59, P = .004), and attention (ESDelta = -0.44, P = .001) and large, static deficits in measures of language (ES = -0.87, P = .005) and visuospatial ability (ES = -0.90, P = .001). There was only weak evidence for cognitive deficits in the psychosis with depression group and the psychotic experiences group. Conclusions and Relevance: The findings herein suggest that the origins of psychotic disorder involve dynamic developmental processes, affecting both verbal and nonverbal abilities throughout the first 2 decades of life and leading to increasing dysfunction. These developmental processes do not manifest in other psychiatric disorders, such as psychosis with depression and depression. PMID- 29387879 TI - Investments in Community-Based Longitudinal Studies Continue to Bear Fruit. PMID- 29387880 TI - Outpatient Worsening Heart Failure as a Target for Therapy: A Review. AB - Importance: Hospitalizations for worsening heart failure (WHF) represent an enormous public health and financial burden, with physicians, health systems, and payers placing increasing emphasis on hospitalization prevention. In addition, maximizing time out of the hospital is an important patient-centered outcome. In this review, we discuss the concept of outpatient WHF, highlight the rationale and data for the outpatient treatment of WHF as an alternative to hospitalization, and examine opportunities and strategies for developing outpatient "interceptive" therapies for treatment of worsening symptoms and prevention of hospitalization. Observations: Worsening heart failure has traditionally been synonymous with an episode of in-hospital care for worsening symptoms. While WHF often leads to hospitalization, many patients experience WHF in the outpatient setting and carry a similarly poor prognosis. These findings support WHF as a distinct condition, independent of location of care. For those that are hospitalized, most patients have an uncomplicated clinical course, with diuretics as the only intravenous therapy. Although complicated scenarios exist, it is conceivable that improved tools for outpatient management of clinical congestion would allow a greater proportion of hospitalized patients to receive comparable care outside the hospital. Most patients with WHF have a gradual onset of congestive signs and symptoms, offering a potential window in which effective therapy may abort continued worsening and obviate the need for hospitalization. To date, outpatient WHF has received minimal attention in randomized clinical trials, but this high-risk group possesses key features that favor effective clinical trial investigation. Conclusions and Relevance: As the public health and economic burdens of heart failure continue to grow, recognizing the entity of outpatient WHF is critical. Efforts to reduce heart failure hospitalization should include developing effective therapies and care strategies for outpatient WHF. The outpatient WHF population represents a major opportunity for therapeutic advancements that could fundamentally change heart failure care delivery. PMID- 29387878 TI - Association of Persistent and Severe Postnatal Depression With Child Outcomes. AB - Importance: Maternal postnatal depression (PND) is common and associated with adverse child outcomes. These effects are not inevitable, and it is critical to identify those most at risk. Previous work suggests that the risks of adverse outcomes are increased when PND is severe and persistent, but this has not been systematically studied. Objective: To examine the association between differing levels of persistence and severity of PND and long-term child outcomes. Design, Setting, and Participants: The sample for this observational study comprised participants in the Avon Longitudinal Study of Parents and Children in the United Kingdom. Three thresholds of PND severity-moderate, marked, and severe-were defined using the self-rated Edinburgh Postnatal Depression Scale (EPDS). Depression was defined as persistent when the EPDS score was above the threshold level at both 2 and 8 months after childbirth. For each of these severity and persistence categories, the following were examined: (1) the trajectories of later EPDS scores (6 time points between 21 months and 11 years after childbirth) and (2) child outcomes-behavioral problems at 3.5 years of age, school-leaving mathematics grades at 16 years of age, and depression at 18 years of age. Data analysis was conducted from July 12, 2016, to February 8, 2017. Main Outcomes and Measures: Child behavioral problems at 3.5 years of age using the Rutter total problems scale, school-leaving mathematics grades at 16 years of age extracted from records of external national public examinations, and offspring depression at 18 years of age using the Clinical Interview Schedule-Revised. Results: For the 9848 mothers in the sample, the mean (SD) age at delivery was 28.5 (4.7) years. Of the 8287 children, 4227 (51%) were boys and 4060 (49%) were girls. Compared with women with PND that was not persistent and women who did not score above the EPDS threshold, for all 3 severity levels, women with persistent PND showed elevated depressive symptoms up to 11 years after childbirth. Whether persistent or not, PND doubled the risk of child behavior disturbance. The odds ratio (OR) for child behavioral disturbance for mothers with moderate PND was 2.22 (95% CI, 1.74-2.83), for mothers with marked PND was 1.91 (95% CI, 1.36 2.68), and for mothers with severe PND was 2.39 (95% CI, 1.78-3.22). Persistence of severe PND was particularly important to child development, substantially increasing the risk for behavioral problems at 3.5 years of age (OR, 4.84; 95% CI, 2.94-7.98), lower mathematics grades at 16 years of age (OR, 2.65; 95% CI, 1.26-5.57), and higher prevalence of depression at 18 years of age (OR, 7.44; 95% CI, 2.89-19.11). Conclusions and Relevance: Persistent and severe PND substantially raises the risk for adverse outcome on all child measures. Meeting criteria for depression both early and late in the postnatal year, especially when the mood disturbance is severe, should alert health care professionals to a depression that is likely to be persistent and to be associated with an especially elevated risk of multiple adverse child outcomes. Treatment for this group should be prioritized. PMID- 29387881 TI - Knowledge, Confidence, and Practice Patterns of Speech-Language Pathologists Working With Adults With Traumatic Brain Injury. AB - Purpose: Although speech-language pathologists (SLPs) are important members of the health care team serving adults with traumatic brain injury (TBI) with cognitive-communication disorders, little is known about services SLPs deliver and how they rate their own knowledge and skills. The aims of this study were to identify practice patterns, knowledge, and confidence levels of SLPs working with adults with TBI with cognitive-communication disorders. Method: We surveyed 100 SLPs from rural and urban hospitals, skilled nursing facilities, and outpatient clinics in Wisconsin and analyzed data descriptively. Results: SLPs in this sample had a combination of accurate and inaccurate knowledge related to TBI. Although all participants reported working with individuals with TBI, many participants rated themselves as lacking confidence or knowledge in this practice area. SLPs reported variable use of evidence-based procedures and training related to TBI. Conclusion: Results confirmed the high prevalence of TBI-related practice among SLPs in medical settings, but there was variable knowledge, confidence, and use of current evidence in practice. SLP graduate training programs, individual providers, health care administrators, and the American Speech-Language-Hearing Association can use results from this study to advance and improve SLP clinical services for adults with TBI. PMID- 29387882 TI - Association of Health Care Utilization With Rates of Perforated Appendicitis in Children 18 Years or Younger. AB - Importance: The pediatric perforated appendix rate is a quality metric measured by the Agency for Healthcare Research and Quality (AHRQ) that reflects access to care. The association of health care utilization prior to presentation with appendicitis is unknown. Objective: To determine whether increased health care utilization prior to presentation with appendicitis is associated with lower perforated appendicitis rates in children. Design, Setting, and Participants: Retrospective cohort study of privately insured children drawn from large employer and insurance company administrative data found in the Truven MarketScan national insurance claims database. Cases of appendicitis were identified among 38 348 children 18 years or younger from January 1, 2010, through December 31, 2013, with corresponding primary health care encounters from January 1, 2009, through December 31, 2012. In all, 19 109 eligible children were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for appendicitis after excluding those patients who did not have continuous insurance coverage during the study period. Statistical analysis was performed from September 1, 2016, to October 15, 2017. Exposures: Health care utilization was determined by the number of outpatient clinic encounters for each patient in the 1 to 12 months before presentation with appendicitis. Main Outcomes and Measures: Perforated appendicitis was defined according to the AHRQ by using ICD 9 codes for perforation and hospital length of stay of 3 or more days. Logistic regression models were used for perforated appendicitis after adjustment for age, sex, income, gastrointestinal comorbidities, geographic region, and insurance type. Results: We identified 38 348 children 18 years or younger with ICD-9 diagnosis codes for appendicitis, and 19 109 children remained for analysis after applying exclusion criteria. Of these, 11 422 were boys (59.8%); the mean (SD) age was 12.4 (3.9) years. Of the 19 109 children identified who underwent appendectomy, 5509 (28.8%) presented with perforated appendicitis. Children with perforation had lower outpatient health care utilization in the year before presentation compared with those diagnosed with acute appendicitis (4554 of 5509 children [82.7%] vs 11 937 of 13 600 [87.8%]; P < .001). In the adjusted model, outpatient health care utilization before presentation was associated with lower odds of perforated appendicitis (odds ratio [OR], 0.63; 95% CI, 0.58-0.69; P < .001). This association increased with visit frequency in the year before presentation (OR, 0.86; 95% CI, 0.77-0.95 for 1-2 visits, P = .003; OR, 0.61; 95% CI, 0.55-0.67 for 3-6 visits, P < .001; and OR, 0.43; 95% CI, 0.38-0.48 for >=7 visits [5-18 years], P < .001). Covariates associated with perforation included younger age, geographic region, family income, and higher out-of-pocket insurance plans. Conclusions and Relevance: Among insured children 18 years or younger, increased health care utilization was associated with lower rates of perforated appendicitis. Primary health care relationships may facilitate timely presentation or serve as a marker for health-related self-efficacy, thereby contributing to outcomes for acute surgical conditions. PMID- 29387883 TI - NICE, the NHS, and Cancer Drugs. PMID- 29387885 TI - Evidence of Drug-Free Interventions for Postoperative Pain Management After Total Knee Arthroplasty. PMID- 29387886 TI - Association of Biopsy Procedures During Follow-up for Breast Cancer With Surgical Decision Making in Patients. PMID- 29387884 TI - Incidence and Outcome of Breast Biopsy Procedures During Follow-up After Treatment for Breast Cancer. AB - Importance: No comprehensive data are available regarding the frequency of breast biopsies performed during follow-up of treatment for invasive breast cancer. Objective: To determine how often patients treated for breast cancer require breast biopsies during follow-up. Design, Setting, and Participants: This nationwide population-based cohort study included 41 510 patients 64 years or younger in a commercial insurance database and 80 369 patients 66 years or older in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed with incident invasive breast cancer (stages I-III) from January 1, 2000, through December 31, 2011. Diagnosis and procedural codes were used to identify biopsy rates during follow-up. Data were analyzed from March 3 through October 3, 2017. Main Outcomes and Measures: Cumulative incidence and adjusted risk of breast biopsy and subsequent breast cancer treatment were calculated using the Kaplan-Meier method and Cox proportional hazards regression. All statistical tests were 2 sided. Results: Among the 121 879 patients in the study population, 5- and 10-year overall incidences of breast biopsy were 14.7% and 23.4%, respectively, in the commercial insurance cohort and 11.8% and 14.9%, respectively, in the SEER-Medicare cohort. The 5-year estimated incidence of breast biopsy was higher among women treated with brachytherapy (24.0% in the commercial insurance and 25.0% in the SEER-Medicare cohorts) than among those treated with whole-breast irradiation (16.7% in the commercial insurance and 15.1% in the SEER-Medicare cohorts) and persisted after multivariate adjustment in the commercial insurance (hazard ratio [HR], 1.53; 95% CI, 1.38-1.70; P < .001) and SEER-Medicare (HR, 1.76; 95% CI, 1.63-1.91; P < .001) cohorts. Adjuvant chemotherapy use (HR, 1.31; 95% CI, 1.25-1.37; P < .001) and patient age (>85 vs 66-69 years; HR, 0.40; 95% CI, 0.36-0.44; P < .001) in the SEER-Medicare cohort and endocrine therapy in the commercial insurance (HR, 0.88; 95% CI, 0.82-0.93; P < .001) and SEER-Medicare (HR, 0.91; 95% CI, 0.85-0.97; P = .002) cohorts were independently associated with biopsy. After unilateral mastectomy, the estimated 5-year contralateral breast biopsy rates were 10.4% and 7.7% in the commercial insurance and SEER-Medicare cohorts, respectively. Of the patients with breast biopsy, 1239 of 4158 patients (29.8%) in the commercial insurance cohort and 2258 of 9747 patients (23.2%) in the SEER-Medicare cohort underwent subsequent cancer treatment. Conclusions and Relevance: These data on the need for breast biopsies during follow-up and subsequent treatments from a large cohort of women with commercial insurance and Medicare can be used in the context of therapy-planning discussions and survivorship expectations for patients with breast cancer. PMID- 29387887 TI - Evidence of Drug-Free Interventions for Postoperative Pain Management After Total Knee Arthroplasty-Reply. PMID- 29387888 TI - Premature Cardiac Disease and Death in Women Whose Infant Was Preterm and Small for Gestational Age: A Retrospective Cohort Study. AB - Importance: Women with an infant with preterm birth (PTB) or who was severely small for gestational age (SGA) are at higher future risk of premature cardiovascular disease and related death. Objective: To determine the risk of cardiac disease or death among women with an infant with both PTB and SGA. Design, Setting, and Participants: This population-based cohort study used electronic health records from the province of Ontario, Canada, where health care is universally available, between April 1, 2002, and March 31, 2016. All singleton live births between 23 to 42 weeks' gestation among 710 501 nulliparous women aged 16 to 50 years without prepregnancy cardiac disease were analyzed. Main Outcomes and Measures: Risk of a composite outcome of heart failure, atrial or ventricular dysrhythmia, or all-cause mortality, starting 30 days after the index birth. Hazard ratios were adjusted for maternal age, income quintile, and preeclampsia/eclampsia (each at the index birth), as well as diabetes, chronic hypertension, obesity, dyslipidemia, drug dependence or smoking, and kidney disease (each within 24 months before the index birth date and time-varying from the birth date onward). Results: Of 710 501 singleton live births, 15 082 mothers (2.1%) were older than age 40 years. Relative to having an infant without PTB or severe SGA (4.1 per 10 000 person-years), the incidence rate of the composite outcome of heart failure, dysrhythmia, or death was 11.3 per 10 000 person-years among mothers with an infant with PTB-SGA (crude hazard ratio, 2.79; 95% CI, 1.85 4.21) (adjusted hazard ratio, 1.66; 95% CI, 1.09-2.52). Conclusions and Relevance: Women who had an infant with PTB-SGA may be at higher future risk of premature cardiac disease or death. PMID- 29387890 TI - Error in Abstract. PMID- 29387889 TI - Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. AB - Importance: Current guidelines advocate the use of marine-derived omega-3 fatty acids supplements for the prevention of coronary heart disease and major vascular events in people with prior coronary heart disease, but large trials of omega-3 fatty acids have produced conflicting results. Objective: To conduct a meta analysis of all large trials assessing the associations of omega-3 fatty acid supplements with the risk of fatal and nonfatal coronary heart disease and major vascular events in the full study population and prespecified subgroups. Data Sources and Study Selection: This meta-analysis included randomized trials that involved at least 500 participants and a treatment duration of at least 1 year and that assessed associations of omega-3 fatty acids with the risk of vascular events. Data Extraction and Synthesis: Aggregated study-level data were obtained from 10 large randomized clinical trials. Rate ratios for each trial were synthesized using observed minus expected statistics and variances. Summary rate ratios were estimated by a fixed-effects meta-analysis using 95% confidence intervals for major diseases and 99% confidence intervals for all subgroups. Main Outcomes and Measures: The main outcomes included fatal coronary heart disease, nonfatal myocardial infarction, stroke, major vascular events, and all-cause mortality, as well as major vascular events in study population subgroups. Results: Of the 77 917 high-risk individuals participating in the 10 trials, 47 803 (61.4%) were men, and the mean age at entry was 64.0 years; the trials lasted a mean of 4.4 years. The associations of treatment with outcomes were assessed on 6273 coronary heart disease events (2695 coronary heart disease deaths and 2276 nonfatal myocardial infarctions) and 12 001 major vascular events. Randomization to omega-3 fatty acid supplementation (eicosapentaenoic acid dose range, 226-1800 mg/d) had no significant associations with coronary heart disease death (rate ratio [RR], 0.93; 99% CI, 0.83-1.03; P = .05), nonfatal myocardial infarction (RR, 0.97; 99% CI, 0.87-1.08; P = .43) or any coronary heart disease events (RR, 0.96; 95% CI, 0.90-1.01; P = .12). Neither did randomization to omega-3 fatty acid supplementation have any significant associations with major vascular events (RR, 0.97; 95% CI, 0.93-1.01; P = .10), overall or in any subgroups, including subgroups composed of persons with prior coronary heart disease, diabetes, lipid levels greater than a given cutoff level, or statin use. Conclusions and Relevance: This meta-analysis demonstrated that omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary heart disease. PMID- 29387891 TI - [Comment to "T1-2 glottic cancer treated with radiotherapy and/or surgery"]. PMID- 29387892 TI - Focus on imaging in trauma. PMID- 29387893 TI - CNR 1/18, Societies' Communications. PMID- 29387894 TI - [Oncology in anesthesia and operative intensive care medicine]. PMID- 29387895 TI - [The conspicuous leg]. AB - Symptoms of the leg or of both legs, may indicate a need for evaluation and/or treatment, which must be clarified urgently or even as an emergency situation. Among the diseases which must be considered from a vascular viewpoint are critical limb ischemia, suspicion of deep leg vein thrombosis and special forms of venous insufficiency. With respect to infections erysipelas and the syndrome of infected diabetic foot must be considered as well as peripheral and central leg paresis as orthopedic and neurological disorders, respectively. The current review summarizes the main clinical features of these diseases. Criteria are discussed as to which require the particular capabilities of a hospital and which patients can be managed in an outpatient setting. PMID- 29387896 TI - [Abnormal laboratory results : Plausibility, reliability, and implications]. AB - In outpatient care or the emergency room laboratory tests oftentimes provide the first clues to the medical condition that made the patient seek medical help. Quite commonly, rapid medical decisions are required in these situations. Therefore, laboratory results must be evaluated immediately and interpreted within the broader context of the patient's presentation. During this process test results must be checked for plausibility, their positive and/or negative predictive values for the individual patient must be considered, and finally, the potential clinical implications need to be assessed. The latter in particular is of the utmost importance. This article discusses several laboratory tests commonly ordered for emergency patients and provides some guidance on their relevance in the decision to refer an outpatient to an emergency room or for inpatient care, or whether a patient can be safely diagnosed in the outpatient setting. PMID- 29387897 TI - [Endocrine paraneoplastic syndromes]. AB - Endocrine paraneoplastic syndromes result from the production of bioactive substances from neoplastic cells, of endocrine or neuroendocrine origin. Typically these are located in the lungs, the gastrointestinal tract, pancreas, thyroid gland, adrenal medulla, skin, prostate or breast. In endocrine paraneoplastic syndromes the secretion of peptides, amines or other bioactive substances is always ectopic and not related to the anatomical source. The clinical presentation, however, is indistinguishable from a suspected eutopic endocrine tumor posing a diagnostic challenge. The most common endocrine paraneoplastic syndromes are based on the secretion of antidiuretic hormone (ADH) resulting in hyponatremia, secretion of adrenocorticotropic hormone (ACTH) or rarely corticotropin-releasing hormone (CRH) resulting in Cushing syndrome as well as secretion of growth hormone-releasing hormone resulting in acromegaly. Paraneoplastic endocrine syndromes mainly occur in highly malignant tumors; however, the development of these tumors does not necessarily correlate with tumor stage, malignant potential or prognosis. As endocrine paraneoplastic syndromes are a rare complication, there are hardly any evidence-based therapeutic recommendations. Treatment of the underlying tumor is the first choice and in a palliative setting symptomatic therapy is possible. PMID- 29387898 TI - The superoxide dismutase genes might be required for appropriate development of the ovule after fertilization in Xanthoceras sorbifolium. AB - KEY MESSAGE: Superoxide dismutase genes were expressed differentially along with developmental stages of fertilized ovules in Xanthoceras sorbifolium, and the XsMSD gene silencing resulted in the arrest of fertilized ovule development. A very small percentage of mature fruits (ca. 5%) are produced relative to the number of bisexual flowers in Xanthoceras sorbifolium because seeds and fruits are aborted at early stages of development after pollination. Reactive oxygen species (ROS) in plants are implicated in an extensive range of biological processes, such as programmed cell death and senescence. Superoxide dismutase (SOD) activity might be required to regulate ROS homeostasis in the fertilized ovules of X. sorbifolium. The present study identified five SOD genes and one SOD copper chaperone gene in the tree. Their transcripts were differentially expressed along different stages of fertilized ovule development. These genes showed maximum expression in the ovules at 3 days after pollination (DAP), a time point in which free nuclear endosperm and nucleus tissues rapidly develop. The XsCSD1, XsFSD1 and XsMSD contained seven, eight, and five introns, respectively. Analysis of the 5'-flanking region of XsFSD1 and XsMSD revealed many cis-acting regulatory elements. Evaluation of XsMSD gene function based on virus-induced gene silencing (VIGS) indicated that the gene was closely related to early development of the fertilized ovules and fruits. This study suggested that SOD genes might be closely associated with the fate of ovule development (aborted or viable) after fertilization in X. sorbifolium. PMID- 29387900 TI - [Unresectable intrahepatic cholangiocarcinoma: 50 % resectability after neoadjuvant therapy]. PMID- 29387899 TI - QTL-Seq-based genetic analysis identifies a major genomic region governing dwarfness in rice (Oryza sativa L.). AB - KEY MESSAGE: A major dwarfing region for plant height, asd1, was identified employing the next-generation sequencing-based QTL-Seq approach from a dwarf mutant and is demonstrated to be responsible for the dwarf nature with least penalty on yield in rice. The yield plateauing of modern rice is witnessed since many decades due to the narrow genetic base owing to the usage of a single recessive gene, i.e., semi-dwarf-1 (sd-1) for development of short-statured varieties throughout the world. This calls for the searching of alternate sources for short stature in rice. To this end, we made an attempt to uncover yet another, but valuable dwarfing gene employing next-generation sequencing (NGS) based QTL-Seq approach. Here, we have identified a major QTL governing plant height on chromosome 1, i.e., alternate semi-dwarf 1 (asd1) from an F2 mapping population derived from a cross between a dwarf mutant, LND384, and a tall landrace, INRC10192. Fine mapping of asd1 region employing sequence-based indel markers delimited the QTL region to 67.51 Kb. The sequencing of the QTL region and gene expression analysis predicted a gene that codes for IWS1 (C-terminus family protein). Furthermore, marker-assisted introgression of the asd1 into tall landrace, INRC10192, reduced its plant height substantially while least affecting the yield and its component traits. Hence, this novel dwarfing gene, asd1, has profound implications in rice breeding. PMID- 29387901 TI - [Hemoptysis with a rare cause]. PMID- 29387902 TI - Lnc-ing non-coding RNAs with metabolism and diabetes: roles of lncRNAs. AB - Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and pancreatic beta-cell dysfunction. Deregulated glucose and lipid metabolism are the primary underlying manifestations associated with this disease and its complications. Long non-coding RNAs (lncRNAs) are a novel class of functional RNAs that regulate a variety of biological processes by a diverse interplay of mechanisms including recruitment of epigenetic modifiers, transcriptional and post-transcriptional regulation, control of mRNA decay, and sequestration of transcription factors. Although the underlying causes that define the diabetic phenotype are extremely intricate, most of the studies in the last decades were mostly centered on protein-coding genes. However, current opinion in the recent past has authenticated the contributions of diverse lncRNAs as critical regulatory players during the manifestation of diabetes. The current review will highlight the importance of lncRNAs in regulating cellular processes that govern metabolic homeostasis in key metabolic tissues. A more in-depth understanding of lncRNAs may enable their exploitation as biomarkers or for therapeutic applications during diabetes and its associated complications. PMID- 29387905 TI - [Venereal diseases in a "general practice" in the 17th and early 18th centuries]. AB - The diary of the town physician Johannes Franc (1649-1725), handwritten in Latin, gives-among other diseases-an overview of sexually transmitted infections affecting citizens in Ulm such as syphilis and gonorrhea. Franc reported on his own experiences in the diary and also included many theoretical details on the causes of the diseases and the corresponding therapies, including ethical considerations. Even in ancient times, there are indications of venereal diseases. However, at the latest with the outbreak of syphilis around the year 1495, the treatment and control of the spread of venereal diseases became an important task of medicine. Before gonococci were detected by Neisser in 1879, sexually transmitted diseases were generally seen as a single disease. However, at the beginning of the 18th century, there were several doctors who treated syphilis and gonorrhea as separate entities. Franc was one of them. Examining the milestones in the history of syphilis and gonorrhea, the present article reviews the existing theories that tried to explain the origins of these diseases. Franc's treatment patterns are illustrated. Franc's case reports indicate a fundamental change in the perception of STIs at the end of the 17th/beginning of the 18th century. PMID- 29387903 TI - Structure and dynamics of rotary V1 motor. AB - Rotary ATPases are unique rotary molecular motors that function as energy conversion machines. Among all known rotary ATPases, F1-ATPase is the best characterized rotary molecular motor. There are many high-resolution crystal structures and the rotation dynamics have been investigated in detail by extensive single-molecule studies. In contrast, knowledge on the structure and rotation dynamics of V1-ATPase, another rotary ATPase, has been limited. However, recent high-resolution structural studies and single-molecule studies on V1 ATPase have provided new insights on how the catalytic sites in this molecular motor change its conformation during rotation driven by ATP hydrolysis. In this review, we summarize recent information on the structural features and rotary dynamics of V1-ATPase revealed from structural and single-molecule approaches and discuss the possible chemomechanical coupling scheme of V1-ATPase with a focus on differences between rotary molecular motors. PMID- 29387906 TI - [The role of contrast-enhanced pulse inversion harmonic imaging (CEUS) and contrast-enhanced computed tomography (CECT) in the preoperative diagnosis of renal lesions]. AB - OBJECTIVE: The preoperative assessment of structural and functional changes in renal tumors using contrast-enhanced pulse inversion harmonic imaging (CEUS) and contrast-enhanced computed tomography (CECT). MATERIALS AND METHODS: All consecutive patients referred to two tertiary hospitals for surgery on suspicion of a malignant renal lesion, who had been examined under the predefined study protocol using CEUS and CECT, were prospectively included in the study. All renal lesions suspected of being malignant were subjected to histopathological examination. Lesions expected to be benign were followed up according to the study protocol. The accuracy of CEUS and CECT with the final histology or follow up results and the statistically significant difference between the two imaging techniques was calculated. RESULTS: Over a period of 3 years (2008-2011), 68 of 93 patients examined met the study criteria. The prevalence of malignant tumors in the study was 72%. Fifty four (79%) patients underwent surgery and had a histologically confirmed renal tumor (clear cell carcinoma 45, urothelial papillocarcinoma 4, angiomyolipoma 1, oncytoma 3, xanthogranulomatous pyelonephritis 1) and 14 (21%) patients underwent regular follow-up. Specificity, sensitivity and area under the curve (AUC) reached 57.9%, 98% and 0.779 for CEUS and 52.6%, 98% and 0.753 for CECT. CONCLUSION: The results show that both imaging methods can reliably rule out malignant disease due to absence of enhancement. Taking into consideration that CEUS can be carried out without severe risk or discomfort, it is time to reconsider CEUS as the method of choice for diagnosis, while CECT should be reserved for staging. PMID- 29387907 TI - ["Why visit a medical congress?" : Knowledge transfer between Germany and Sweden using the example of the 1929 DGU meeting in Munich]. AB - Drawing on contemporary publications in German and Swedish/Scandinavian journals and biographies as well as conference proceedings of the German Society of Urology (DGU), this paper examines the Swedish impressions of the 1929 DGU meeting in Munich. It focusses on why the Swedish delegates visited the congress and how they evaluated their congress experiences for their Scandinavian peers. Finally, the article shows to what extent a knowledge transfer from the DGU Congress to Sweden took place. PMID- 29387908 TI - Genotoxicity Biomonitoring Along a Coastal Zone Under Influence of Offshore Petroleum Exploration (Southeastern Brazil). AB - Offshore oil exploration creates threats to coastal ecosystems, including increasing urbanization and associated effluent releases. Genotoxicity biomarkers in mussels were determined across a gradient of coastal zone influences of offshore petroleum exploration in southeastern Brazil. Coastal ecosystems such as estuaries, beaches and islands were seasonally monitored for genotoxicity evaluation using the brown mussel Perna perna. The greatest DNA damage (5.2% +/- 1.9% tail DNA and 1.50/00 +/- 0.80/00 MN) were observed in urban estuaries, while Santana Archipelago showed levels of genotoxicity near zero and is considered a reference site. Mussels from urban and pristine beaches showed intermediate damage levels, but were also influenced by urbanization. Thus, mussel genotoxicity biomarkers greatly indicated the proposed oil exploration and urbanization scenarios that consequently are genetically affecting coastal organisms. PMID- 29387904 TI - Retinoic acid signaling and neurogenic niche regulation in the developing peripheral nervous system of the cephalochordate amphioxus. AB - The retinoic acid (RA) signaling pathway regulates axial patterning and neurogenesis in the developing central nervous system (CNS) of chordates, but little is known about its roles during peripheral nervous system (PNS) formation and about how these roles might have evolved. This study assesses the requirement of RA signaling for establishing a functional PNS in the cephalochordate amphioxus, the best available stand-in for the ancestral chordate condition. Pharmacological manipulation of RA signaling levels during embryogenesis reduces the ability of amphioxus larvae to respond to sensory stimulation and alters the number and distribution of ectodermal sensory neurons (ESNs) in a stage- and context-dependent manner. Using gene expression assays combined with immunohistochemistry, we show that this is because RA signaling specifically acts on a small population of soxb1c-expressing ESN progenitors, which form a neurogenic niche in the trunk ectoderm, to modulate ESN production during elongation of the larval body. Our findings reveal an important role for RA signaling in regulating neurogenic niche activity in the larval amphioxus PNS. Although only few studies have addressed this issue so far, comparable RA signaling functions have been reported for neurogenic niches in the CNS and in certain neurogenic placode derivatives of vertebrates. Accordingly, the here described mechanism is likely a conserved feature of chordate embryonic and adult neural development. PMID- 29387911 TI - Necrotizing soft tissue infection following femoral venous catheter infection. PMID- 29387910 TI - Bone density and microarchitecture in hepatitis C and HIV-coinfected postmenopausal minority women. AB - : We found that HIV+/HCV+ women had 7-8% lower areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) at the spine, hip, and radius (p < 0.01) and 5-7% lower volumetric BMD (vBMD) by central quantitative computed tomography (cQCT) at the spine and hip (p < 0.05). These data suggest that true deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women. INTRODUCTION: aBMD by DXA is lower in persons coinfected with HIV and HCV (HIV+/HCV+) than with HIV monoinfection (HIV+). However, weight is often also lower with HCV infection, and measurement of aBMD by DXA can be confounded by adiposity; we aimed to determine whether true vBMD is also lower in HIV+/HCV+ coinfection. METHODS: We measured aBMD of the lumbar spine (LS), total hip (TH), femoral neck (FN), and ultradistal radius (UDR) by DXA and vBMD of the spine and hip by cQCT and of the distal radius and tibia by high-resolution peripheral QCT (HRpQCT) in 37 HIV+/HCV+ and 119 HIV+ postmenopausal women. Groups were compared using Student's t tests with covariate adjustment by multiple regression analysis. RESULTS: HIV+/HCV+ and HIV+ women were of similar age and race/ethnicity. HIV+/HCV+ women had lower body mass index (BMI) and trunk fat and were more likely to smoke and less likely to have a history of AIDS. In HIV+/HCV+ women, aBMD by DXA was 7-8% lower at the LS, TH, and UDR (p < 0.01). Similarly, vBMD by cQCT was 5-7% lower at the LS and TH (p < 0.05). Between-group differences in LS aBMD and vBMD remained significant after adjustment for BMI, smoking, and AIDS history. Tibial total vBMD by HRpQCT was 10% lower in HIV+/HCV+ women. CONCLUSION: HIV+/HCV+ postmenopausal women had significantly lower spine aBMD and vBMD. These deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women. PMID- 29387909 TI - Hippocampal area CA2: an emerging modulatory gateway in the hippocampal circuit. AB - The hippocampus is a critical brain region for the formation of declarative memories. While social memory had long been attributed to be a function of the hippocampus, it is only of late that the area CA2 of the hippocampus was demarcated as essential for social memory formation. In addition to this distinct role, CA2 possesses unique molecular, structural and physiological characteristics compared to the other CA regions-CA1 and CA3, and the dentate gyrus (DG). CA2 pyramidal neurons are positioned at a location between CA1 and CA3, receiving inputs from CA3 and DG, in addition to forming a powerful disynaptic circuit with direct input from the entorhinal cortical layer II neurons. CA2 also receives direct inputs from the hypothalamic regions and displays a unique expression pattern for receptors for neuromodulators. The location, inputs, and molecular signatures of the area CA2 point to the possibility that CA2 serves as a modulatory gateway that processes information from the entorhinal cortex and CA3, before relaying them onto CA1, the major output of the hippocampus. This review discusses recent findings regarding plasticity and neuromodulation in the CA2 region of the hippocampus, and how this may have the potential to influence plasticity in connecting circuits, and thereby memory and behaviour. PMID- 29387912 TI - Dynamic airway obstruction from a circumferential mass with a free-floating projection: a subacute complication of percutaneous tracheostomy. PMID- 29387913 TI - The ten tips to manage critically ill patients with acute-on-chronic liver failure. PMID- 29387914 TI - Accurate placement of cervical pedicle screws using 3D-printed navigational templates : An improved technique with continuous image registration. AB - OBJECTIVE: Accurate placement of cervical pedicle screws remains a surgical challenge. This study aimed to test the feasibility of using a novel three dimensional (3D-)printed navigational template to overcome this challenge. METHODS: Cervical spines were scanned using computed tomography (CT). A 3D model of the cervical spines was created. The screw trajectory was designed to pass through the central axis of the pedicle. Thereafter, a navigational template was designed by removing the soft tissue from the bony surface in the 3D model. A 3D printer was used to print the navigational template. The screws were then placed in the cadavers following CT scanning. The 3D model of the designed trajectory and the placed screws were registered. The coordinates of the entry and exit points of the designed trajectory and the actual trajectory were recorded. The numbers of qualified points that met the different degrees of accuracy were compared using a chi2 test. RESULTS: A total of 158 screws were placed. Five screws breached the pedicle cortex with a distance <2 mm. There was no significant difference between the pre- and postoperative entry points with a degree of accuracy >=1.7 mm (P = 0.131). Meanwhile, there was no significant difference between the pre- and postoperative exit points with degrees of accuracy >=6.4 mm (P = 0.071). CONCLUSION: A navigational template can be designed by removing the soft tissue from the bony surface in a CT-generated 3D model. This guiding tool may effectively prevent intraoperative drifting and accurately places cervical pedicle screws. PMID- 29387915 TI - Abnormalities associated with congenital scoliosis in high-altitude geographic regions. AB - PURPOSE: To assess the different characteristics of congenital scoliosis between low-altitude geographic regions and high-altitude geographic regions in Chinese population and discuss the role of hypoxia on those differences. METHODS: A total of 120 patients with congenital scoliosis who underwent surgical treatment in our Hospital between January 2009 and October 2017 were identified. Complete data were reviewed, including medical records, X-ray, CT, and MRI pre-operatively. According to the patient's birthplace, they were divided into low-altitude geographic regions (low group) and high-altitude geographic regions (high group). Characteristics of vertebral deformities, rib deformities, and intra-spinal malformations in two groups were analyzed. RESULTS: A total of 397 segments of vertebral deformities were involved in the two groups, of which 136 were involved in high group and 261 in low group. The average segments involved were 4.5 and 2.9, respectively, in two groups. 63.3% patients in high group have rib deformities, which is significantly higher than that of low group (41.1%); and the proportion of patients with complex rib deformities in high group was also higher than that in low group (57.9% VS 24.3%). The incidence of CS associated with intra-spinal malformations in low group was 38.9%, which was similar to those reported previously; however, the incidence of that in high group was 63%, significantly higher than previous reports. CONCLUSION: Our results suggested that CS patients in high-altitude geographic regions might tend to have higher proportion and more severe of rib deformities, and also be more likely to accompany with intra-spinal malformations. So we supposed that hypoxia not only aggravated the proportion and severity of rib deformities, but also affected the development of spinal cord in humans. PMID- 29387916 TI - Incidence of knee height asymmetry in a paediatric population of corrected leg length discrepancy: a retrospective chart review study. AB - PURPOSE: The purpose of the study is to provide a methodology to quantify knee height asymmetry (KHA) and to establish the incidence of knee height asymmetry in a patient population visiting the limb length discrepancy clinic in a paediatric orthopaedic hospital centre. METHOD: A retrospective chart review was performed on all patients who attended the limb length discrepancy clinic and underwent corrective surgery at the Shriners Hospital for Children-Canada from December 2009 to December 2015. Full-standing anteroposterior radiographs were used to measure pre- and post-surgery limb length discrepancy and knee height asymmetry for 52 individuals included in the study. RESULTS: Sixty-seven percent of the studied population had a KHA of 20 mm or less, 25% had a KHA between 20 and 40 mm, and 8% had a KHA of over 40 mm. The average KHA preoperatively for all 52 individuals was 17 +/- 14 mm (range 0-59 mm), which represents roughly 2.5% of total limb length. There was a 3-mm non-significant reduction in KHA size between pre-and post-operative states (p = 0.22). CONCLUSION: The current study provides a method to quantify knee height asymmetry. Using this method, it was shown that knee height asymmetry is frequent in youth with limb length discrepancy in both pre- and post-corrective surgery states. The relatively high incidence of knee height asymmetry highlights the importance to investigate the impact of knee height asymmetry in youth living with a limb length discrepancy. PMID- 29387917 TI - [Head and neck neoplasms : News from the WHO classification of 2017]. PMID- 29387919 TI - Extinction times in the subcritical stochastic SIS logistic epidemic. AB - Many real epidemics of an infectious disease are not straightforwardly super- or sub-critical, and the understanding of epidemic models that exhibit such complexity has been identified as a priority for theoretical work. We provide insights into the near-critical regime by considering the stochastic SIS logistic epidemic, a well-known birth-and-death chain used to model the spread of an epidemic within a population of a given size N. We study the behaviour of the process as the population size N tends to infinity. Our results cover the entire subcritical regime, including the "barely subcritical" regime, where the recovery rate exceeds the infection rate by an amount that tends to 0 as [Formula: see text] but more slowly than [Formula: see text]. We derive precise asymptotics for the distribution of the extinction time and the total number of cases throughout the subcritical regime, give a detailed description of the course of the epidemic, and compare to numerical results for a range of parameter values. We hypothesise that features of the course of the epidemic will be seen in a wide class of other epidemic models, and we use real data to provide some tentative and preliminary support for this theory. PMID- 29387918 TI - The Ratio Fallacy, with Special Reference to the Cardiac Index. AB - When comparing cardiac outputs in children of different sizes, or deciding on the normality of these outputs, we often convert the absolute output to the output per m2 body surface area-the cardiac index. For small infants, this leads to potentially large errors. The best way to evaluate these outputs is to determine their z values. PMID- 29387920 TI - Signatures of historical selection on MHC reveal different selection patterns in the moor frog (Rana arvalis). AB - MHC genes are key components in disease resistance and an excellent system for studying selection acting on genetic variation in natural populations. Current patterns of variation in MHC genes are likely to be influenced by past and ongoing selection as well as demographic fluctuations in population size such as those imposed by post-glacial recolonization processes. Here, we investigated signatures of historical selection and demography on an MHC class II gene in 12 moor frog populations along a 1700-km latitudinal gradient. Sequences were obtained from 207 individuals and consecutively assigned into two different clusters (northern and southern clusters, respectively) in concordance with a previously described dual post-glacial colonization route. Selection analyses comparing the relative rates of non-synonymous to synonymous substitutions (dN/dS) suggested evidence of different selection patterns in the northern and the southern clusters, with divergent selection prevailing in the south but uniform positive selection predominating in the north. Also, models of codon evolution revealed considerable differences in the strength of selection: The southern cluster appeared to be under strong selection while the northern cluster showed moderate signs of selection. Our results indicate that the MHC alleles in the north diverged from southern MHC alleles as a result of differential selection patterns. PMID- 29387921 TI - Long-stay in forensic-psychiatric care in the UK. AB - PURPOSE: Forensic services provide care for mentally disordered offenders. In England this is provided at three levels of security-low, medium and high. Significant number of patients within these settings remain detained for protracted periods of time. This is both very costly and restrictive for individuals. No national studies have been conducted on this subject in England. METHODS: We employed a cross-sectional design using anonymised data from medical records departments in English secure forensic units. Data were collected from a large sample of medium secure patients (n = 1572) as well as the total high secure patient population (n = 715) resident on the census date (01-04-2013). We defined long-stay as a stay of more than 10 years in high, 5 years in medium or 15 years in a mix of high and medium secure settings. Long-stay status was assessed against patient demographic and admission information. RESULTS: We identified a significant proportion of long-stayers: 23.5% in high secure and 18.1% in medium secure care. Amongst medium secure units a large variation in long-stay prevalence was observed from 0 to 50%. Results indicated that MHA section, admission source and current ward type were independent factors associated with long-stay status. CONCLUSION: This study identified a significant proportion of long-stayers in forensic settings in England. Sociodemographic factors identified in studies in individual settings may be less important than previously thought. The large variation in prevalence of long-stayers observed in the medium secure sample warrants further investigation. PMID- 29387922 TI - Accuracy and effectiveness of ultrasound-guided core-needle biopsy in the diagnosis of focal lesions in the salivary glands. AB - OBJECTIVES: To review the diagnostic accuracy of ultrasound-guided core-needle biopsy (CNB) in the diagnosis of salivary gland tumours (SGT). METHODS: Retrospective, institutional review board approved, analysis of the CNB of SGT performed at our centre in 8 years. We used an automatic 18-G spring-loaded device. The final diagnosis was based on surgery in the cases that were operated on, and on clinical evolution and biopsy findings in the rest. RESULTS: Four hundred and nine biopsies were performed in 381 patients (ages, 2-97 years; mean, 55.9). There were two minor complications. Biopsy was diagnostic in 98.3%. There were eight false negatives. The diagnostic values for malignancy were: sensitivity 89.6%, specificity 100%, positive predictive value (PPV) 100% and negative predictive value (NPV) 98%. For the detection of neoplasms were: sensitivity 98.7%, specificity 99%, PPV 99.7% and VPN 96.1%. CONCLUSIONS: Accuracy of CNB in SGT is very high, with a very high sensitivity and an absolutely reliable diagnosis of malignancy. Complication rate is very low. It should be considered the technique of choice when a STG is detected. Normal tissue results warrant repeating biopsy. KEY POINTS: * Ultrasound-guided core biopsy is the technique of choice in salivary glands nodules * Sensitivity, specificity for detecting neoplasms (which should be resected) are around 99% * Diagnosis of malignancy in core-biopsy is absolutely reliable * A CNB result of "normal tissue", however, warrants repeating the biopsy * Complication rate is very low. PMID- 29387923 TI - Association between histological features of epicardial adipose tissue and coronary plaque characteristics on computed tomography angiography. AB - The means by which epicardial adipose tissue (EAT) could influence coronary plaque progression biologically remain unclear. We investigated the association between the histological findings of EAT and coronary plaque characteristics assessed by coronary computed tomography angiography (CCTA). We enrolled 34 patients in whom one or more coronary plaques containing non-calcified components were detected on CCTA before cardiac surgery [coronary artery bypass graft (CABG) or non-CABG]. We evaluated visceral adipose tissue (VAT) area, EAT volume, and coronary plaque characteristics including minimum computed tomography density (CTD) and vascular Remodeling Index (RI). Lower CTD and higher RI were considered as high-risk characteristics, and coronary plaque with both CTD < 39 Hounsfield units and RI > 1.05 was defined as two-characteristic plaque (2-CP). The numbers of CD68+ macrophages and CD31+ microvessels were assessed in six random high power fields (400*) of EAT samples obtained during cardiac surgery. The entire cohort showed a wide range of EAT volume, which were similar between patients with 2-CP and those without. Patients with 2-CP had more amounts of EAT macrophages (85 +/- 38 versus 45 +/- 22, p = 0.0005) and vascularity (62 +/- 33 versus 37 +/- 19, p = 0.013) than those without. On multivariate analyses adjusted for age, sex, coronary risk factors, statin use, type of surgery, VAT area, EAT volume, and coronary calcium score, the presence of 2-CP showed significant correlation with increased EAT macrophages (beta = 0.65, p = 0.014) and vascularity (beta = 0.74, p = 0.0053). Our findings support the hypothesis that EAT biologic activities are associated with coronary plaque vulnerability. PMID- 29387925 TI - Correction to: Post-operative cognitive decline (POCD) after gynaecologic surgery: current opinions and future applications. AB - The original version of this article unfortunately contained a mistake. The given names and family names of all authors were interchanged. PMID- 29387924 TI - Anatomical features of the aortic root in aortic stenosis and a novel approach for transcatheter aortic valve implantation. AB - A narrow and calcified sinotubular junction (STJ) represents a risk for ascending aortic dissection after balloon-expandable transcatheter aortic valve implantation (TAVI). The aim of this study was to assess computed tomography (CT) based aortic root morphology in patients with aortic stenosis (AS), and to evaluate the feasibility of a two-step inflation technique that we devised for TAVI using the SAPIEN 3 in patients with a narrow and calcified STJ. We retrospectively analyzed the STJ diameter (STJD) as well the as aortic annulus diameter (AAD) and STJ calcification using CT imaging in 412 patients undergoing TAVI. We defined a "narrow STJ" as a minimum STJD that was smaller than the diameter corresponding to a 10% oversized annulus area, and a "calcified STJ" as an STJ calcification angle > 90 degrees . A "narrow and calcified STJ" was identified in 54 patients (13.1%) of patients. Among them, we performed TAVI using the two-step inflation technique with SAPIEN 3 in 20 patients and compared with 11 patients that underwent the conventional inflation procedure. Two-step inflation was successfully performed without ascending aortic dissection in all 20 patients. The effective orifice area index at discharge in these 20 patients was similar to that in 11 patients who underwent the conventional inflation procedure for a "narrow and calcified STJ" [1.40 (1.20-1.51) vs. 1.33 (1.18-1.41) cm2/m2, p = 0.23]. Although further assessment is required, the two-step inflation technique with the SAPIEN 3 is feasible for a narrow and calcified STJ. PMID- 29387926 TI - Glioblastoma multiforme: another potential application for 68Ga-PSMA PET/CT as a guide for targeted therapy. PMID- 29387927 TI - Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. AB - PURPOSE: In the 2010 WHO classification, a Ki-67 proliferation index of 20% is the cut-off between intermediate-grade and high-grade gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN). However, in clinical practice, tumours with a Ki-67 index of >15% are often considered high grade and treated with chemotherapy. In 40-70% of high-grade NENs, somatostatin receptors are overexpressed, enabling peptide receptor radionuclide therapy (PRRT) to be performed. We investigated the role of PRRT with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. METHODS: A total of 33 patients with advanced GEP-NENs, positive somatostatin receptor imaging (SRI+) and a Ki-67 proliferation index ranging from 15% to 70% were treated with Lu-PRRT. A cumulative activity of 18.5 GBq or 27.8 GBq of 177Lu-DOTATATE was administered in four or five cycles. Receiver operating characteristic (ROC) curve analysis was used to determine the best threshold of Ki-67 expression to predict disease progression. RESULTS: All patients completed the intended treatment. The median follow-up was 43 months (range 3-69 months). Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%. The median progression-free survival (PFS) was 23 months (95% CI 14.9 31.0 months) and the median overall survival was 52.9 months (95% CI 17.1-68.9 months). ROC curve analysis at 23 months revealed that the best Ki-67 index cut off was 35%. In 23 patients (70%) the Ki-67 index was <=35% and in 10 patients (30%) the Ki-67 index was in the range 36-70%. The DCR in the former group was 87% and 30% in the latter. The median PFS was 26.3 months (95% CI 18.4-37.7 months) and 6.8 months (95% CI 2.1-27 months), respectively (p = 0.005). CONCLUSIONS: Lu-PRRT showed antitumour activity in SRI+ GEP-NENs of intermediate and high-grade. DCR and PFS were significantly better in patients with a Ki-67 index of <=35% than in those with a Ki-67 index of >35%. On the basis of these results, PRRT should be considered as a therapeutic option in patients with high grade SRI+ GEP-NENs, in particular those with a Ki-67 proliferation index of <=35%. PMID- 29387928 TI - Mutation rates at 42 Y chromosomal short tandem repeats in Chinese Han population in Eastern China. AB - Mutation analysis of 42 Y chromosomal short tandem repeats (Y-STRs) loci was performed using a sample of 1160 father-son pairs from the Chinese Han population in Eastern China. The results showed that the average mutation rate across the 42 Y-STR loci was 0.0041 (95% CI 0.0036-0.0047) per locus per generation. The locus specific mutation rates varied from 0.000 to 0.0190. No mutation was found at DYS388, DYS437, DYS448, DYS531, and GATA_H4. DYS627, DYS570, DYS576, and DYS449 could be classified as rapidly mutating Y-STRs, with mutation rates higher than 1.0 * 10-2. DYS458, DYS630, and DYS518 were moderately mutating Y-STRs, with mutation rates ranging from 8 * 10-3 to 1 * 10-2. Although the characteristics of the Y-STR mutations were consistent with those in previous studies, mutation rate differences between our data and previous published data were found at some rapidly mutating Y-STRs. The single-copy loci located on the short arm of the Y chromosome (Yp) showed relatively higher mutation rates more frequently than the multi-copy loci. These results will not only extend the data for Y-STR mutations but also be important for kinship analysis, paternal lineage identification, and family relationship reconstruction in forensic Y-STR analysis. PMID- 29387929 TI - The STARflo glaucoma implant: preliminary 12 months results. AB - PURPOSE: The STARflo glaucoma implant is a drainage-free system designed for the operative treatment of refractory open-angle glaucoma. The purpose of this study is to investigate the safety and efficacy of the STARflo implant. The results of 12 months follow-up are presented in patients with open-angle glaucoma, PEX glaucoma, and congenital glaucoma. METHODS: A prospective study with a total of over 29 patients (36 eyes), in which the suprachoroidal implantation of the STARflo was indicated for long-term intraocular pressure reduction, is still in process and evaluation. RESULTS: The reduction of intraocular pressure was satisfying after 12 months with an average intraocular pressure of 15.0 (+/- 2.5) mmHg in comparison to 21.08 (+/- 7.29) mmHg preoperatively. There was a significant 66.7% reduction in local glaucoma drops 12 months postoperatively (p < 0.001). Twenty-five percent of the eyes needed further surgery to regulate the intraocular pressure. No intraoperative complications have been reported after the implantation of STARflo. Postoperative complications include hyphema and fibrin formation in the anterior chamber, which were completely resorbed after the first postoperative month. A postoperative intraocular pressure (IOP) elevation was the most common complication after the first 3 months. CONCLUSIONS: The STARflo implant appears to be a safe and effective alternative treatment method for patients with refractory open-angle glaucoma compared to conventional glaucoma surgery. PMID- 29387930 TI - An auxin-induced beta-type endo-1,4-beta-glucanase in poplar is involved in cell expansion and lateral root formation. AB - MAIN CONCLUSION: PtrGH9A7, a poplar beta-type endo-1,4-beta-glucanase gene induced by auxin, promotes both plant growth and lateral root development by enhancing cell expansion. Endo-1,4-beta-glucanase (EGase) family genes function in multiple aspects of plant growth and development. Our previous study found that PtrCel9A6, a poplar EGase gene of the beta subfamily, is specifically expressed in xylem tissue and is involved in the cellulose biosynthesis required for secondary cell wall formation (Yu et al. in Mol Plant 6:1904-1917, 2013). To further explore the functions and regulatory mechanism of beta-subfamily EGases, we cloned and characterized another poplar beta-type EGase gene PtrGH9A7, a close homolog of PtrCel9A6. In contrast to PtrCel9A6, PtrGH9A7 is predominantly expressed in parenchyma tissues of the above-ground part; in roots, PtrGH9A7 expression is specifically restricted to lateral root primordia at all stages from initiation to emergence and is strongly induced by auxin application. Heterologous overexpression of PtrGH9A7 promotes plant growth by enhancing cell expansion, suggesting a conserved role for beta-type EGases in 1,4-beta-glucan chains remodeling, which is required for cell wall loosening. Moreover, the overexpression of PtrGH9A7 significantly increases lateral root number, which might result from improved lateral root primordium development due to enhanced cell expansion. Taken together, these results demonstrate that this beta-type EGase induced by auxin signaling has a novel role in promoting lateral root formation as well as in enhancing plant growth. PMID- 29387931 TI - Prospective randomized controlled trial of postoperative early intravesical chemotherapy with pirarubicin (THP) for solitary non-muscle invasive bladder cancer comparing single and two-time instillation. AB - PURPOSE: Single immediate intravesical instillation of chemotherapy after transurethral resection of bladder tumor (TURBT) has been the gold standard treatment for patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Herein, we conducted a multicenter prospective randomized controlled trial in Japan, comparing recurrence-free survival between single and two-time instillation of pirarubicin (THP) for solitary NMIBC. METHODS: Between 2005 and 2009, 257 patients with solitary NMIBC were enrolled and randomized to single instillation of THP (30 mg/50 mL) immediately after TURBT (Group A) or two time instillation of THP immediately after and 1 day after TURBT (Group B). The primary endpoint was recurrence-free survival. Secondary endpoints included rates of recurrence and adverse effects, including hematuria, micturition pain, difficult urination, pollakiuria, systemic symptoms, and other complications. This study was registered as UMIN C000000266. RESULTS: Of 257 patients, 99 in Group A and 102 in Group B could be evaluated for recurrence. Median follow-up was 71 months. The overall recurrence rate was 39 and 31%, respectively (p = 0.2704). Although the 5-year recurrence-free survival rates were 55.9% and 67.7% in groups A and B, respectively, the difference between groups was not significant (p = 0.2031). No significant differences in adverse effects were observed between groups, except for pollakiuria (7 vs 22%, p = 0.0031). Multivariate analyses did not show that the treatment group was a significant risk factor for bladder cancer recurrence. CONCLUSIONS: Postoperative two-time intravesical instillation of THP was not superior to single immediate instillation for preventing recurrence after complete resection of a solitary NMIBC. PMID- 29387932 TI - Comparison of super-mini PCNL (SMP) versus Miniperc for stones larger than 2 cm: a propensity score-matching study. AB - PURPOSE: To compare the efficacy and safety of Super-mini percutaneous nephrolithotomy (SMP, F12-F14) and Miniperc (F18) in the treatment of renal stones of 2-4 cm in size. METHODS: A prospective comparative analysis of outcomes of patients who underwent SMP and Miniperc for treatment of 2-4 cm renal stones was conducted between July 2014 and January 2017. Demographic data, stone criteria, operative technique, complications, blood transfusion, hemoglobin decrease, stone-free rate (SFR) and length of hospital stay were compared between the two groups. Propensity score-matching (PSM) analysis was performed to further compare the outcomes between the two groups. RESULTS: 79 and 257 patients underwent SMP and Miniperc, respectively. After matching, 73 patients in each group were included. The stone burden was comparable for both groups (3.0 +/- 1.1 vs 3.2 +/- 0.7 cm, p = 0.577). Mean operation time was not significant different between two groups (p = 0.115), while the hospital stay of SMP was much shorter than Miniperc (2.6 +/- 1.4 vs 5.2 +/- 1.8, p < 0.0001). Both groups had similar SFRs in postoperative 1 day and at 1 month follow-up (p = 0.326, p = 0.153), while SMP achieved a markedly higher tubeless rate than Miniperc (84.9 vs 47.9%, p < 0.0001). The total complication rate was significantly lower in SMP (16.4 vs 41.1%, p = 0.0001), and the SIRS rate was markedly lower in SMP group (1.4 vs 12.3%, p = 0.009). CONCLUSIONS: SMP is equally effective as Miniperc in the treatment of moderate renal calculi, and has the significant advantage in hospital duration and tubeless rate. PMID- 29387933 TI - Macroinvertebrate and fish communities in the watershed of a re-constructed Mediterranean water body: link to the ecological potential. AB - The role of benthic macroinvertebrate and fish communities for assessing the ecological quality of an artificial re-constructed, after 50 years of dryness, Mediterranean water body (Karla Reservoir, Greece) is presented. Moreover, we provide knowledge on the structure of the biological communities and their functioning role, for inspiring feature actions that will contribute to biodiversity protection and ecosystem services. Water (physicochemical parameters), benthic macroinvertebrates, and fish were monitored during a 2-year survey (2013-2015) in Karla and Kalamaki reservoirs and the inflowing ditches. A clear temporal pattern was evident for all sampling stations studied, differentiating the low- and high-flow period samples as to their physicochemical parameters. Redundancy analysis (RDA) revealed NO3-N, total nitrogen and total dissolved phosphorous as the most significant environmental parameters in explaining benthic invertebrate variance in ditches. Generally, tolerant to organic pollution macroinvertebrate taxa were abundant in ditches and reservoirs, while the fish fauna in Karla was composed almost exclusively of planktivorous and invertivorous species. Macroinvertebrate (GLBiI) and fish (GLFI) indices classified the ecological quality of Karla Reservoir as "poor" while ditches were classified as "bad" according to HESY-2. The anthropogenic pressures applied in the catchment and the benefits of improving water quality are discussed in the context of the implementation of Water Framework Directive 2000/60/EC for introducing sustainable management plans, taking into account some ecological restoration principles. PMID- 29387934 TI - [Rust-colored conjunctival and sub-conjunctival discolorations : Differential diagnosis of conjunctival melanosis]. PMID- 29387935 TI - [Picosecond infrared laser fiber-assisted sclerostomy (PIRL-FAST) : A first proof of principle analysis]. AB - INTRODUCTION: The aim of this study was an analysis of the feasibility of a picosecond infrared laser fiber-assisted sclerostomy (PIRL-FAST) using a novel sapphire fiber and different energy levels of the picosecond laser. METHOD: The laser-assisted sclerostomy was carried out with a newly generated sapphire fiber of the PIRL-HP2-1064 OPA-3000 (Attodyne, Canada). Immediately after the intervention, the eyes were fixed in phosphate-buffered 3.5% formaldehyde. For subsequent histological analysis the eyes were cut into 4 MUm thick sections and stained with hematoxylin and eosin (H&E, Merck, Darmstadt, Germany). All preparations were then scanned and digitalized using the MIRAX SCAN (Carl Zeiss Microimaging GmbH, Jena, Germany). RESULTS: The pulse energies 150 MUJ (N = 4), 175 MUJ (N = 6), 200 MUJ (N = 7) and 250 MUJ (N = 6) were selected. Within the framework of this first feasibility analysis 400 MUm (10 sequential sections) of the sclerotomies were evaluated. The mean area of PIRL-FAST showed a dependency on the pulse energy applied. The diameter of the collateral damage zone (CDZ) depended on the pulse energy used. The largest CDZ could be measured using the highest pulse energy in this experiment (250 MUJ). The environmental scanning electron microscope (ESEM) results revealed circular smooth sclerostomy wall with only minimal change of tissue ultrastructure. CONCLUSION: The PIRL-FAST using sapphire fibers is a new minimally invasive instrument to provide robust stenting from the anterior chamber to the subconjunctival space. Since the PIRL has proven to work efficiently in sectioning several tissues with minimal collateral damage these first proof of principle experiments might pave the way for a new minimally invasive glaucoma surgery strategy. We have already initiated experiments to analyze the wound healing and scar formation in vivo. PMID- 29387937 TI - A systematic approach for finding the objective function and active constraints for dynamic flux balance analysis. AB - Dynamic flux balance analysis (DFBA) has become an instrumental modeling tool for describing the dynamic behavior of bioprocesses. DFBA involves the maximization of a biologically meaningful objective subject to kinetic constraints on the rate of consumption/production of metabolites. In this paper, we propose a systematic data-based approach for finding both the biological objective function and a minimum set of active constraints necessary for matching the model predictions to the experimental data. The proposed algorithm accounts for the errors in the experiments and eliminates the need for ad hoc choices of objective function and constraints as done in previous studies. The method is illustrated for two cases: (1) for in silico (simulated) data generated by a mathematical model for Escherichia coli and (2) for actual experimental data collected from the batch fermentation of Bordetella Pertussis (whooping cough). PMID- 29387936 TI - A randomized controlled intervention of workplace-based group cognitive behavioral therapy for insomnia. AB - PURPOSE: Sleep disturbance is common in the working population, often associated with work stress, health complaints and impaired work performance. This study evaluated a group intervention at work, based on cognitive behavioral therapy (CBT) for insomnia, and the moderating effects of burnout scores at baseline. METHODS: This is a randomized controlled intervention with a waiting list control group. Participants were employees working at least 75% of full time, reporting self-perceived regular sleep problems. Data were collected at baseline, post intervention and at a 3-month follow-up through diaries, wrist-actigraphy and questionnaires including the Insomnia Severity Index (ISI) and the Shirom-Melamed Burnout Questionnaire (SMBQ). Fifty-one participants (63% women) completed data collections. RESULTS: A multilevel mixed model showed no significant differences between groups for sleep over time, while there was a significant effect on insomnia symptoms when excluding participants working shifts (N = 11) from the analysis (p = 0.044). Moreover, a moderating effect of baseline-levels of burnout scores was observed on insomnia symptoms (p = 0.009). A post-hoc analysis showed that individuals in the intervention group with low burnout scores at baseline (SMBQ < 3.75) displayed significantly reduced ISI scores at follow-up, compared to individuals with high burnout scores at baseline (p = 0.005). CONCLUSIONS: Group CBT for insomnia given at the workplace did not reduce sleep problems looking at the group as a whole, while it was indicated that the intervention reduced insomnia in employees with regular daytime work. The results also suggest that workplace-based group CBT may improve sleep in employees with primary insomnia if not concomitant with high burnout scores. PMID- 29387939 TI - Object discrepancy modulates feature prediction across eye movements. AB - Object perception across saccadic eye movements is assumed to result from integrating two information sources: incoming peripheral object information and information from a foveal prediction (Herwig and Schneider, J Exp Psychol Gen 143(5):1903-1922, 2014, Herwig, J Vis 15(16), 7, 2015). Predictions are supposed to be based on transsaccadic associations of peripheral and foveal object information. The main function of these predictions may be to conceal discrepancies in resolution and locations across saccades. Here we ask how predictions are affected by discrepancies between peripheral and foveal objects. Participants learned unfamiliar transsaccadic associations by making saccades to objects whose shape systematically changed during the saccade. Importantly, we manipulated the size of this change between participants to induce different magnitudes of object discrepancy. In a subsequent test, we found that judgment shifts of peripheral shape perception toward the predicted foveal input depended on change size during acquisition. Specifically, the contribution of prediction decreased for large changes but did not reach zero, showing that even for large changes (i.e., square to circle or vice versa) the prediction was not ignored completely. These findings indicate that object discrepancy during learning determines how much the resulting foveal prediction contributes to perception in the periphery. PMID- 29387938 TI - Post-mortem inference of the human hippocampal connectivity and microstructure using ultra-high field diffusion MRI at 11.7 T. AB - The human hippocampus plays a key role in memory management and is one of the first structures affected by Alzheimer's disease. Ultra-high magnetic resonance imaging provides access to its inner structure in vivo. However, gradient limitations on clinical systems hinder access to its inner connectivity and microstructure. A major target of this paper is the demonstration of diffusion MRI potential, using ultra-high field (11.7 T) and strong gradients (750 mT/m), to reveal the extra- and intra-hippocampal connectivity in addition to its microstructure. To this purpose, a multiple-shell diffusion-weighted acquisition protocol was developed to reach an ultra-high spatio-angular resolution with a good signal-to-noise ratio. The MRI data set was analyzed using analytical Q-Ball Imaging, Diffusion Tensor Imaging (DTI), and Neurite Orientation Dispersion and Density Imaging models. High Angular Resolution Diffusion Imaging estimates allowed us to obtain an accurate tractography resolving more complex fiber architecture than DTI models, and subsequently provided a map of the cross regional connectivity. The neurite density was akin to that found in the histological literature, revealing the three hippocampal layers. Moreover, a gradient of connectivity and neurite density was observed between the anterior and the posterior part of the hippocampus. These results demonstrate that ex vivo ultra-high field/ultra-high gradients diffusion-weighted MRI allows the mapping of the inner connectivity of the human hippocampus, its microstructure, and to accurately reconstruct elements of the polysynaptic intra-hippocampal pathway using fiber tractography techniques at very high spatial/angular resolutions. PMID- 29387941 TI - Species distribution of kobs (Kobus kob) in the Shai Hills Resource Reserve: an exploratory analysis. AB - The well-being of a species fundamentally rests on understanding its biology, home range, and distribution. The highly seasonal distribution of kobs poses conservation and management difficulties, particularly because of the capricious nature of the ever-changing ecological and vegetation dynamics of the ecosystem. Assessing the distribution of kobs and their associated vegetation provides insight into the vulnerability and conservation status of the species. Species distribution and habitat suitability maps were developed and created respectively for the management of kobs in the Shai Hills Resource Reserve. Kob presence data collected was analyzed using the spatial analyst and Hawth's tool in the ArcGIS software where the gradients of kob distribution within the protected area landscape were plotted and mapped. Seven environmental variables including location, land cover/use, slope/elevation, nearness to dams and rivers, temperature, and rainfall were considered to have effect on kob distribution pattern and as such used in the development of species distribution and habitat suitability maps. The results indicated that kobs in the Shai Hills Resource Reserve (SHRR) assume a clumped or contagious distribution pattern where individual kobs are aggregated in patches. Rainfall, temperature, nearness to dams and rivers, slope/elevation, and land cover/use had influence in kob distribution. Of all the cataloged habitats, 86, 13, and 1% were moderately suitable, suitable, and unsuitable, respectively. Long-term survival of species depends on adequately large areas of suitable habitats and opportunities for home range activities between such areas. As such, it is recommended that suitable habitats for kobs be dedicated and designated as conservation areas, especially areas along the western boundary. PMID- 29387940 TI - Bisphenol A is not associated with a 5-year incidence of type 2 diabetes: a prospective nested case-control study. AB - AIMS: The relationship between bisphenol A (BPA) and diabetes remains controversial. This study aims to investigate whether serum BPA level could predict the 5-year incidence of type 2 diabetes (T2D). METHODS: A nested case control study was performed among Chinese who participated in the environment, inflammation and metabolic diseases study (2008-2013). Of the 3510 subjects who were free of diabetes, 232 subjects developed diabetes during the 5-year follow up. Cases and controls were matched for age and gender by a ratio of 1:1. Homoeostasis model assessment was used to estimate basal beta-cell function (HOMA beta) and insulin resistance (HOMA-IR). Participants were stratified into tertiles based on low, median and high baseline serum BPA levels. Regression models were used to analyze the relationship between serum BPA concentration and the incidence of T2D. RESULTS: At baseline, no significant difference in serum BPA concentration was observed between patients with T2D and controls [1.3 (0.3, 3.7) vs. 1.6 (0.4, 3.9) MUmol/L, P = 0.199]; serum BPA concentration was positively associated with fasting plasma glucose (r = 0.27, P < 0.001); however, neither HOMA-beta nor HOMA-IR correlated with serum BPA concentration. During the follow-up, baseline BPA levels could not predict the 5-year T2D incidence, whether or not adjusted for the potential confounders such as body mass index and blood pressure. [Low BPA tertile was the reference, OR 0.66 (95% CI 0.30, 1.44) for median, OR 0.93 (95% CI 0.41, 2.13) for high.] CONCLUSION: BPA is not associated with a 5-year T2D incidence. These data do not support previous cross sectional study that BPA exerted a detrimental effect on glucose metabolism. PMID- 29387943 TI - Life Threatening Complications Post-Liposuction. AB - BACKGROUND: Liposuction is one of the most commonly performed aesthetic procedures. It is performed worldwide as an outpatient procedure. However, the complications are underestimated and underreported by caregivers. We present a case of delayed diagnosis of bilothorax secondary to liver and gallbladder injury after tumescent liposuction. METHODS: A 26-year-old female patient was transferred to our emergency department from an aesthetic clinic with worsening dyspnea, tachypnea and fatigue. She had undergone extensive liposuction of the thighs, buttocks, back and abdomen 5 days prior to presentation. RESULTS: A chest X-ray showed significant right-sided pleural effusion. Thoracentesis was performed and drained bilious fluid. CT scan of the abdomen revealed pleural, liver and gall bladder injury. An exploratory laparoscopy confirmed the findings, the collections were drained; cholecystectomy and intraoperative cholangiogram were performed. The patient did very well postoperatively and was discharged home in 2 days. CONCLUSION: Even though liposuction is considered a simple office based procedure, its complications can be fatal. The lack of strict laws that exclusively place this procedure in the hands of medical professionals allow these procedures to still be done by less experienced hands and in outpatient based settings. Our case serves to highlight yet another unique but potentially fatal complication of liposuction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29387944 TI - What is minimally invasive surgery? PMID- 29387942 TI - Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. AB - Neutrophils are becoming recognized as highly versatile and sophisticated cells that display de novo synthetic capacity and potentially prolonged lifespan. Emerging concepts such as neutrophil heterogeneity and plasticity have revealed that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional characteristics. Indeed, these newly described neutrophil subsets will undoubtedly add to the already complex interactions between neutrophils and other immune cell types for an effective immune response. The interactions between neutrophils and monocytes/macrophages enable the host to efficiently defend against and eliminate foreign pathogens. However, it is also becoming increasingly clear that these interactions can be detrimental to the host if not tightly regulated. In this review, we will explore the functional cooperation of neutrophil and monocytes/macrophages in homeostasis, during acute inflammation and in various disease settings. We will discuss this in the context of cardiovascular disease in the form of atherosclerosis, an autoimmune disease mainly occurring in the kidneys, as well as the unique intestinal immune response of the gut that does not conform to the norms of the typical immune system. PMID- 29387945 TI - Comment on "Efficacy of a single intra-articular injection of ultra-high molecular weight hyaluronic acid for hip osteoarthritis: a randomized controlled study". PMID- 29387946 TI - The concentration of fear: mice's behavioural and physiological stress responses to different degrees of predation risk. AB - Predation is an unavoidable and dangerous fact in the lifetime of prey animals and some sign of the proximity of a predator may be enough to trigger a response in the prey. We investigated whether different degrees of predation risk by red foxes (Vulpes vulpes) evoke behavioural and physiological stress responses in wood mice (Apodemus sylvaticus). We examined the variation in mice responses due to individual factors (sex and reproductive status) and related them to the concentration of the volatile compounds from fox faeces over time. In our experiment, we introduced predation cues into four plots, each subjected to a different concentration treatment (0, 10, 50 and 100% concentration of fresh faeces of red fox), based on the following outline: initial odourless phase 0, phase1 in which predation treatment was renewed daily, and phase 2 in which we renewed the treatment only on the first day. Wood mice were live trapped during all three phases and the physiological response was measured non-invasively by analysing faecal corticosterone metabolites (FCM) in freshly collected faeces. Data were analysed by Generalized Linear Mixed Models. Overall, males were trapped less often than females, and reproductively active individuals from both sexes avoided traps more than non-reproductively active individuals, especially in medium- and high- concentration plots. Variations in FCM concentrations were explained by plot, the interaction between plot and treatment phase, and the interaction between the treatment phase and the reproductive status. During phase 1, we detected a significant rise in FCM levels that increased with predator faecal odour concentration. Additionally, reproductively active individuals showed a strong physiological response during both phases 1 and 2 in all plots, except the control plot. Our results indicated that wood mice are able to discriminate different degrees of predation risk, which allows them to trigger gradual changes in their behavioural and physiological stress responses. PMID- 29387947 TI - Environmental Stewardship: A Conceptual Review and Analytical Framework. AB - There has been increasing attention to and investment in local environmental stewardship in conservation and environmental management policies and programs globally. Yet environmental stewardship has not received adequate conceptual attention. Establishing a clear definition and comprehensive analytical framework could strengthen our ability to understand the factors that lead to the success or failure of environmental stewardship in different contexts and how to most effectively support and enable local efforts. Here we propose such a definition and framework. First, we define local environmental stewardship as the actions taken by individuals, groups or networks of actors, with various motivations and levels of capacity, to protect, care for or responsibly use the environment in pursuit of environmental and/or social outcomes in diverse social-ecological contexts. Next, drawing from a review of the environmental stewardship, management and governance literatures, we unpack the elements of this definition to develop an analytical framework that can facilitate research on local environmental stewardship. Finally, we discuss potential interventions and leverage points for promoting or supporting local stewardship and future applications of the framework to guide descriptive, evaluative, prescriptive or systematic analysis of environmental stewardship. Further application of this framework in diverse environmental and social contexts is recommended to refine the elements and develop insights that will guide and improve the outcomes of environmental stewardship initiatives and investments. Ultimately, our aim is to raise the profile of environmental stewardship as a valuable and holistic concept for guiding productive and sustained relationships with the environment. PMID- 29387948 TI - Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek new therapeutic targets, such as the Hippo signaling pathway and cell cycle regulatory genes from the Aurora kinase family. The present study quantified the expression level of genes encoding components of the Hippo signaling pathway (LATS1, LATS2, YAP, and TAZ), AURKA and AURKB in CML patients at different stages of the disease, who were resistant or sensitive to imatinib mesylate therapy, and in healthy individuals. The expression levels of the target genes were correlated with the CML Sokal's prognostic score. The most striking results were the LATS2 and AURKA overexpression in CML patients, the overexpression of TAZ and AURKB in CML patients at advanced phases and TAZ in CML IM-resistant. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family, either alone or in combination, can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis. PMID- 29387949 TI - Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma. AB - Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy. PMID- 29387950 TI - Polyaniline/MWCNTs/starch modified carbon paste electrode for non-enzymatic detection of cholesterol: application to real sample (cow milk). AB - Nanocomposite materials are potentially revolutionizing many technologies, including sensors. In this paper, we described the application of "PANI/MWCNTs/Starch" modified carbon paste electrode (PCS-CPE) as a simple and highly sensitive cholesterol sensor. This novel nano-composite material has integrated nano-morphology, where polyaniline could interact effectively with the additives; pi-pi stacking "MWCNTs," and covalently bonded with starch. Specific binding sites (sugar chains), better electro-catalytic properties and fast electron transfer facilitated the oxidation of cholesterol. Fourier transform infrared spectra confirmed the interaction of cholesterol with the composite material. The sensing response of PCS was measured by cyclic voltammetry and chronoamperometry (0.1 M PBS-5 used as supporting electrolyte). As the amount of cholesterol increased in the test solution, cyclic voltammograms showed a rise of peak current (cathodic and anodic). Under the normal experimental conditions, the developed sensor exhibited wide linear dynamic range (0.032 to 5 mM) (upper limit is due to lack of solubility of cholesterol), high sensitivity (800 MUAmM-1 cm 2), low detection limit (0.01 mM) and shorter response time (within 4-6 s). Analytical specificity, selectivity, and sensitivity during cholesterol estimation were compared with the response of some other analytes (ascorbic acid, glucose, l-dopa, urea and lactic acid). This novel sensor was successfully applied to estimate cholesterol in cow milk (used as a model real sample). The sensing platform is highly sensitive and shows a linear response towards cholesterol without using any additional redox mediator or enzyme, thus this material is extremely promising for the realization of a low-cost integrated cholesterol sensor device. Graphical abstract Cyclic voltammetric response of cholesterol of composite modified carbon paste capillary electrode. PMID- 29387951 TI - Simultaneous dispersive liquid-liquid microextraction derivatisation and gas chromatography mass spectrometry analysis of subcritical water extracts of sweet and sour cherry stems. AB - Cherry stems have been used in traditional medicine mostly for the treatment of urinary tract infections. Extraction with subcritical water, according to its selectivity, efficiency and other aspects, differs substantially from conventional extraction techniques. The complexity of plant subcritical water extracts is due to the ability of subcritical water to extract different chemical classes of different physico-chemical properties and polarities in a single run. In this paper, dispersive liquid-liquid microextraction (DLLME) with simultaneous derivatisation was optimised for the analysis of complex subcritical water extracts of cherry stems to allow simple and rapid preparation prior to gas chromatography-mass spectrometry (GC-MS). After defining optimal extracting and dispersive solvents, the optimised method was used for the identification of compounds belonging to different chemical classes in a single analytical run. The developed sample preparation protocol enabled simultaneous extraction and derivatisation, as well as convenient coupling with GC-MS analysis, reducing the analysis time and number of steps. The applied analytical protocol allowed simple and rapid chemical screening of subcritical water extracts and was used for the comparison of subcritical water extracts of sweet and sour cherry stems. Graphical abstract DLLME GC MS analysis of cherry stem extracts obtained by subcritical water. PMID- 29387952 TI - Photoinduced electron transfer from polymer-templated Ag nanoclusters to G quadruplex-hemin complexes for the construction of versatile biosensors and logic gate applications. AB - In this paper, fluorescent Ag nanoclusters (Ag NCs) templated by hyperbranched polyethyleneimine (PEI) are utilized as a versatile probe through the photoinduced electron transfer (PET) between PEI-Ag NCs and G-quadruplex-hemin complexes. In the presence of hemin and target molecule, the specific conjugation with its aptamer induces the conformational change of the DNA sequence, releasing the G-quadruplex sequence part. Once the G-quadruplex-hemin complexes are introduced, electron transfer from the PEI-Ag NCs to G-quadruplex-hemin complexes occurs, resulting in fluorescence quenching. Through changing the sensing DNA sequence, this novel PET system enables the specific detection of target DNA and adenosine triphosphate (ATP) with the wide linear range of 1-200 nM and 5-500 nM, respectively, and the corresponding limit of detection as low as 0.3 nM for target DNA and 1.5 nM for ATP. In addition, the proposed method is successfully applied to the determination of ATP in human serum samples with satisfactory recoveries, and a logic gate is fabricated using target molecules and hemin as inputs and the fluorescence signal of PEI-Ag NCs as an output. PMID- 29387953 TI - Molecular and stable isotopic evidence for the occurrence of nitrite-dependent anaerobic methane-oxidizing bacteria in the mangrove sediment of Zhangjiang Estuary, China. AB - Nitrite-dependent anaerobic methane oxidation (n-damo), which is mediated by "Candidatus Methylomirabilis oxyfera-like" bacteria, is unique in linking the carbon and nitrogen cycles. However, the niche and activity of n-damo bacteria in the mangrove ecosystem have not been confirmed. Here, we report the occurrence of the n-damo process in the mangrove wetland of the Zhangjiang Estuary, China. The widespread occurrence of n-damo bacteria in mangrove wetland was confirmed using real-time quantitative polymerase chain reaction (qPCR) assay, which showed that the abundance of Methylomirabilis oxyfera-like bacterial 16S rRNA and pmoA genes ranged from 2.43 * 106 to 2.09 * 107 and 2.07 * 106 to 3.38 * 107copies per gram of dry soil in the examined sediment cores. The highest amount of targeting genes was all detected in the upper layer (0-20 cm). Phylogenetic analyses of n-damo bacterial 16S rRNA and pmoA genes illustrated the depth-specific distribution and high diversity of n-damo bacteria in the mangrove wetland. Stable isotope experiments further confirmed the occurrence of n-damo in the examined mangrove sediments, and the potential n-damo rates ranged from 25.93 to 704.08 nmol CO2 per gram of dry soil per day at different depths of the sediment cores, with the n-damo being more active in the upper layer of the mangrove sediments. These results illustrate the existence of active M. oxyfera-like bacteria and indicate that the n-damo process is a previously overlooked microbial methane sink in the mangrove wetlands. PMID- 29387954 TI - Comparative study to develop a single method for retrieving wide class of recombinant proteins from classical inclusion bodies. AB - The formation of inclusion bodies (IBs) is considered as an Achilles heel of heterologous protein expression in bacterial hosts. Wide array of techniques has been developed to recover biochemically challenging proteins from IBs. However, acquiring the active state even from the same protein family was found to be an independent of single established method. Here, we present a new strategy for the recovery of wide sub-classes of recombinant protein from harsh IBs. We found that numerous methods and their combinations for reducing IB formation and producing soluble proteins were not effective, if the inclusion bodies were harsh in nature. On the other hand, different practices with mild solubilization buffers were able to solubilize IBs completely, yet the recovery of active protein requires large screening of refolding buffers. With the integration of previously reported mild solubilization techniques, we proposed an improved method, which comprised low sarkosyl concentration, ranging from 0.05 to 0.1% coupled with slow freezing (- 1 degrees C/min) and fast thaw (room temperature), resulting in greater solubility and the integrity of solubilized protein. Dilution method was employed with single buffer to restore activity for every sub-class of recombinant protein. Results showed that the recovered protein's activity was significantly higher compared with traditional solubilization/refolding approach. Solubilization of IBs by the described method was proved milder in nature, which restored native-like conformation of proteins within IBs. PMID- 29387955 TI - 4-Hydroxybenzaldehyde sensitizes Acinetobacter baumannii to amphenicols. AB - Bacterial metabolism modulated by environmental chemicals could alter antibiotic susceptibility. 4-Hydroxybenzaldehyde (4-HBA), which cannot support the growth of Acinetobacter baumannii, exhibited synergism only with amphenicol antibiotics including chloramphenicol (CAM) and thiamphenicol. Interestingly, this synergistic effect was not observed with other growth-supporting, structurally similar compounds such as 4-hydroxybenzoate. Transcriptomic analysis demonstrated that genes involved in protocatechuate metabolism (pca genes) and osmotic stress (bet genes) were significantly upregulated by 4-HBA and CAM treatment. The 14C labeled CAM influx was lower in a pcaK1 (encoding a transporter of protocatechuate) deletion mutant and was higher in the pcaK1 overexpressing cells relative to that in the wild type upon 4-HBA treatment. Our kinetic data using 14C-labeled CAM clearly showed that CAM uptake is possibly through facilitated diffusion. Deletion of pcaK1 did not result in the elimination of CAM influx, indicating that CAM does not enter only through PcaK1. The amount of 4-HBA in the culture supernatant was, however, unaffected during the test conditions, validating that it was not metabolized by the bacteria. CAM resistant A. baumannii cells derived by serial passages through CAM-amended media exhibited lower level of pcaK1 gene expression. These results led us to conclude that the activation of PcaK1 transporter is probably linked to cellular CAM susceptibility. This is the first report showing a relationship between CAM influx and aromatic compound metabolism in A. baumannii. PMID- 29387956 TI - Predictive Factors for Intestinal Transmural Necrosis in Patients with Acute Mesenteric Ischemia. AB - BACKGROUND: Acute mesenteric ischemia (AMI) is a serious and potentially fatal condition. No definite parameter can predict transmural bowel necrosis in patients with AMI to justify early surgical intervention. The current study aimed to identify the clinical, laboratory, and radiologic parameters that can successfully predict the onset of intestinal transmural necrosis in patients with AMI. PATIENTS AND METHODS: Records of patients with AMI in the period of January 2013 to October 2017 were reviewed. Clinical parameters as patients' symptoms, vital signs, and signs of peritonitis along with the results of laboratory and radiologic investigations were analyzed to identify predictive factors for intestinal transmural necrosis using binary logistic regression analysis. RESULTS: One hundred and one patients (70 males) with mean age of 55 years were included. Venous occlusion was the cause of AMI in 78 (77.3%) patients and arterial occlusion in 23 (22.7%) patients. Twenty-two patients completed conservative treatment successfully, whereas 79 patients required exploratory laparotomy. On laparotomy, six patients were found to have viable bowel. Overall, 28 patients had viable bowel and 73 had bowel necrosis. The significant independent predictors for transmural bowel necrosis were mesenteric arterial occlusion (OR: 26.5, p = 0.02), leukocytosis (OR: 1.3, p < 0.0001), acidosis (OR: 3.8, p = 0.04), free intraperitoneal fluid (OR: 4.21, p = 0.005), and combined portal vein and SMV thrombosis in CT scan (OR: 3.4, p = 0.026). CONCLUSION: The independent predictors for transmural bowel necrosis were mesenteric arterial occlusion, leukocytosis, acidosis, free intraperitoneal fluid, and combined portal vein and SMV thrombosis in CT scan. PMID- 29387957 TI - Interdepartmental Spread of Innovations: A Multicentre Study of the Enhanced Recovery After Surgery Programme. AB - BACKGROUND: Spread of evidence-based innovations beyond pioneering settings is essential to improve quality of care. This study aimed to evaluate the influence of a national project to implement 'Enhanced Recovery After Surgery' (ERAS) among colorectal teams on the spread of this innovation to gynaecological procedures. METHODS: A retrospective observational multicentre study was performed of a consecutive sample of patients who underwent major elective gynaecological surgery in 2012-2013. Ten Dutch hospitals (294 patients) had participated in a colorectal breakthrough project implementing ERAS on a nationwide basis and were assigned to the intervention group. Thirteen hospitals (390 patients) that had not participated in this project acted as controls. Outcome measures were time to functional recovery and total length of postoperative hospital stay. Multilevel models adjusted for clustering and baseline demographics were used for analysis. The uptake of ten selected perioperative care elements was evaluated for each hospital. RESULTS: The estimated mean difference (95% confidence interval) between the intervention and control hospitals was -0.3 (-0.9 to 0.3) days in the time to recovery and 0.2 (-0.8 to 1.3) days in the total length of hospital stay. The mean (+/- standard deviation) absolute rate of implemented perioperative care elements per hospital was 28.9 +/- 14.9% in the control, versus 29.3 +/- 11.1% in the intervention group (p = 0.934). CONCLUSION: Initial implementation effects seem to be restricted to the participating teams and do not automatically spread to other surgical teams in the same hospital. PMID- 29387958 TI - The Effect of Human-Immunodeficiency Virus Status on Outcomes in Penetrating Abdominal Trauma: An Interim Analysis. AB - BACKGROUND: The purpose of this study was to determine whether the outcomes of hemodynamically stable patients undergoing exploratory laparotomy for penetrating abdominal trauma differed as a result of their HIV status. METHODS: This was an observational, prospective study from February 2016 to May 2017. All hemodynamically stable patients with penetrating abdominal trauma requiring a laparotomy were included. The mechanism of injury, the HIV status, age, the penetrating abdominal trauma index (PATI), and the revised trauma score (RTS) were entered into a binary logistic regression model. Outcome parameters were in hospital death, morbidity, admission to intensive care unit (ICU), relaparotomy within 30 days, and length of stay longer than 30 days. RESULTS: A total of 209 patients, 94% male, with a mean age of 29 +/- 10 years were analysed. Twenty eight patients (13%) were HIV positive. The two groups were comparable. Ten (4.8%) laparotomies were negative. There were two (0.96%) deaths, both in the HIV negative group. The complication rate was 34% (n = 72). Twenty-nine patients (14%) were admitted to the ICU. A higher PATI, older age, and a lower RTS were significant risk factors for ICU admission. After 30 days, 12 patients (5.7%) were still in hospital. Twenty-four patients (11%) underwent a second laparotomy. The PATI score was the single independent predictor for complications, relaparotomy, and hospital stay longer than 30 days. CONCLUSIONS: Preliminary results reveal that HIV status does not influence outcomes in patients with penetrating abdominal trauma. PMID- 29387959 TI - Trauma Care in Mongolia: INTACT Evaluation and Recommendations for Improvement. AB - INTRODUCTION: Injury is the third leading cause of death in Mongolia, with a 29% increase in motor vehicle fatalities over the past decade. Half of the population lives outside the urbanized capital of Ulaanbaatar, where access to care is limited. This study evaluates and describes the Mongolian trauma system and makes recommendations for improvements. METHODS: Hospital-level data were collected, and an International Assessment of Capacity for Trauma (INTACT) score (0-10) was calculated. INTACT is a validated measure for evaluating trauma capacity in developing countries based on resource availability; a score of 10 reflects ideal staffing and equipment. The survey was administered to key staff members at 10 rural and urban hospitals in spring 2016. INTACT scores were calculated for each hospital and compared to expected INTACT scores based on the World Health Organization Guidelines for Essential Trauma Care (GETC). RESULTS: Ulaanbaatar enjoys a centralized prehospital transportation service and two appropriately resourced tertiary hospitals. Rural Mongolians rely upon regionally located tertiary facilities with similar capabilities. INTACT scores for secondary-level hospitals (n = 2) failed to meet expected GETC minimums, as did 2 of 4 primary facilities. There are no national standards guiding prehospital care, triage, or transfer. No outpatient rehabilitation facilities exist within Mongolia. CONCLUSION: The Mongolian trauma system utilizes regionalized care to provide emergency services. Among surveyed hospitals, 60% met GETC standards. Areas for improvement include increased resourcing of primary and secondary facilities, development of rural prehospital systems, adoption of universal standards for patient care, and creation of post-acute rehabilitation facilities. PMID- 29387960 TI - Nonoperative Management of Blunt Splenic Trauma in Patients with Traumatic Brain Injury: Feasibility and Outcomes. AB - INTRODUCTION: Preventing secondary insult to the brain is imperative following traumatic brain injury (TBI). Although TBI does not preclude nonoperative management (NOM) of splenic injuries, development of hypotension in this setting may be detrimental and could therefore lead trauma surgeons to a lower threshold for operative intervention and a potentially higher risk of failure of NOM (FNOM). We hypothesized that the presence of a TBI in patients with blunt splenic injury would lead to a higher risk of FNOM. METHODS: Patients with blunt splenic injury were selected from the National Trauma Data Bank research datasets from 2007 to 2011. TBI was defined as AIS head >= 3 and FNOM as patients who underwent a spleen-related operation after 2 h from admission. TBI patients were compared to those without head injury. The primary outcome was FNOM. RESULTS: Of 47,713 patients identified, 41,436 (86.8%) underwent a trial of NOM. FNOM was identical (10.6 vs. 10.8%, p = 0.601) among patients with and without TBI. TBI patients had lower adjusted odds for FNOM (AOR 0.66, p < 0.001), even among those with a high grade splenic injury (AOR 0.68, p < 0.001). No difference in adjusted mortality was noted when comparing TBI patients with and without FNOM (AOR 1.01, p = 0.95). CONCLUSIONS: NOM of blunt splenic trauma in TBI patients has higher adjusted odds for success. This could be related to interventions targeting prevention of secondary brain injury. Further studies are required to identify those specific practices that lead to a higher success rate of NOM of splenic trauma in TBI patients. PMID- 29387961 TI - Which Patients Require Extended Thromboprophylaxis After Colectomy? Modeling Risk and Assessing Indications for Post-discharge Pharmacoprophylaxis. PMID- 29387962 TI - Long-term results of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer. AB - PURPOSE: The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m2 on day 8 plus oral S-1 at a dosage of 40 mg/m2 twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years. RESULTS: Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4-74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5-27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively. CONCLUSION: Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC. PMID- 29387963 TI - S-1 (Teysuno) and gemcitabine in Caucasian patients with unresectable pancreatic adenocarcinoma. AB - PURPOSE: Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients. METHODS: In this observational cohort study, we analyzed efficacy and toxicity prospectively. RESULTS: From July 2012 to July 2014, 64 patients received at least one cycle of GemS-1. 16 patients started therapy with gemcitabine and capecitabine (GemCap) but switched to GemS-1 after median 3 cycles of GemCap due to toxicity (hand-foot syndrome). 48 patients received GemS-1 as initial therapy. For the complete cohort, median age was 68 years (range 44-80); 22 patients (34%) had locally advanced PC; 42 patients (66%) had metastatic disease. Five patients had received prior adjuvant therapy with gemcitabine and 9 pts had received prior first-line therapy. The most common adverse event was fatigue (86%), however, only grade 3 in 3%. Five patients (8%) developed febrile neutropenia. Median PFS was 8.1 (95% CI 6.9-9.0) months and median OS was 11.7 (95% CI 10.7-13.1) months in the whole GemS-1 population. In the 48 patients starting with GemS-1, median PFS was 7.7 (95% CI 6.7-8.9) months and median OS was 11.5 (95% CI 9.7-12.3) months. CONCLUSIONS: The combination of gemcitabine and S-1 is safe and associated with promising efficacy in a Caucasian population; however, this needs to be confirmed in prospective clinical trials. PMID- 29387964 TI - Role of TPMT and ITPA variants in mercaptopurine disposition. AB - PURPOSE: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. METHODS: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. RESULTS: Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/ug DNA, p = 0.007, ITPALA 465 vs. 387 fmol/ug DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/ug DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001). CONCLUSIONS: TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy. PMID- 29387965 TI - Cell biology of glioblastoma multiforme: from basic science to diagnosis and treatment. AB - First described in the 1800s, glioblastoma multiforme (GBM), a class IV neoplasm with astrocytic differentiation, as per the revised 2016 World Health Organization classification of tumors of the central nervous system (CNS) is the most common malignant tumor of the CNS. GBM has an extremely wide set of alterations, both genetic and epigenetic, which yield a great number of mutation subgroups, some of which have an established role in independent patient survival and treatment response. All of those components not only represent a closed cycle but are also relevant to the tumor biological behavior and resistance to treatment as they form the pathobiological behavior and clinical course. The presence of different triggering mutations on the background of the presence of key mutations in the GBM stem cells (GBMsc) further separates GBM as primary arising de novo from neural stem cell precursors developing into GBMsc and secondary, by means of aggregated mutations. Some of the change in cellular biology in GBM can be observed via light microscope as they form the cellular and tissue hallmarks of the condition. Changes in genetic information, resulting in alteration, suppression and expression of genes compared to their physiological levels in healthy astrocytes lead to not only cellular, but also extracellular matrix reorganization. These changes result in a multiform number of micromorphological and purely immunological/biochemical forms. Therefore, in the twenty-first century the term multiforme, previously outcast from nomenclatures, has gained new popularity on the background of genotypic diversity in this neoplastic entry. PMID- 29387967 TI - Health Policy and Dementia. AB - PURPOSE OF REVIEW: The anticipated number of persons with dementia continues to grow, and the US has insufficiently planned to provide and pay for care for this large population. RECENT FINDINGS: A number of significant clinical trials aiming to prevent or cure dementia, including Alzheimer's disease, have not demonstrated success. Because of the lack of efficacious treatments, and the fact that brain changes associated with dementia may begin decades before symptoms, we can predict that efforts to cure or prevent dementia will not succeed in time for millions of people in the baby boomer generation. Because of the anticipated increase in people suffering with dementia in the coming years, US health policy must address major gaps in how to provide and pay for dementia care. Reliance on Medicaid and Medicare as currently structured will not sustain the necessary care, nor can families alone provide all necessary dementia care. Innovative forms of providing long-term care and paying for it are crucially needed. PMID- 29387966 TI - Glutamatergic mechanisms in L-DOPA-induced dyskinesia and therapeutic implications. AB - Overactivation of the glutamatergic synapse leading to maladaptive synaptic plasticity in the basal ganglia is a well-demonstrated process involved in the onset of L-DOPA-induced dyskinesia (LID). Changes in glutamate release are paralleled by compensatory modifications of the expression and/or synaptic localization of both ionotropic and metabotropic glutamate receptors (mGluRs). Accordingly, compounds targeting N-methyl-D-aspartate glutamate receptors (NMDARs) and specific subtypes of metabotropic glutamate receptors (mGluR4 and mGluR5) have been tested both in preclinical and clinical studies. At present, amantadine, a low-affinity non-competitive NMDAR antagonist, represents the only recommended add-on agent with a moderate anti-dyskinetic activity. The present review describes recent advances in basic research, preclinical and early clinical studies in the attempt of identifying innovative strategies for an accurate modulation of both pre- and postsynaptic glutamate receptors to reduce the severity of LID. Even if a complete understanding of LID molecular bases is still lacking, several compounds demonstrated an anti-dyskinetic activity in preclinical and early clinical studies. These results indicate that modulation of the glutamatergic system remains one of the most promising pharmacological strategies in the field. PMID- 29387969 TI - Thermal and shape topological robustness of heat switchers using nematic liquid crystals. AB - One interesting way to control heat is to use devices designed by transformation thermics, where artificial media are used. However, once manufactured (either repelling or concentrating heat, for example), besides being mono-purpose, such devices are designed according to a specific geometric boundary conditions. Another problem is the temperature dependence of the materials employed, since their properties are sometimes considered temperature-invariant. In this paper, we show that a previously proposed bi-objective heat switcher (Phys. Rev. E 89, 020501(R) (2014)) is in fact robust against temperature and geometric deformations, due to the topological properties of the molecular nematic orientation. Using a geometrical approach for heat propagation, by performing finite element simulations, we show that a device made by concentric cylinders with thermotropic nematic liquid crystal between them, sustains its functionality even with their molecular thermal conductivities depending on the temperature, achieving a 60% increase and a 44% decrease in the heat flux for each mode. Utilizing topological arguments we show that deformations on the surface of the outer cylinder do not break the operating mode (repeller or concentrator). We present a comparison between our geometrical approach and the transformation thermodynamics to give an additional explanation for the obtained results. We hope the presented device is useful for heat control under mechanical and thermal influence of the external environment. PMID- 29387968 TI - Long-term survival with modern therapeutic agents against metastatic melanoma vemurafenib and ipilimumab in a daily life setting. AB - Despite new therapeutic options, metastatic melanoma remains to be one of the most fatal tumors. With the development of BRAF inhibitors and immune checkpoint inhibitors, overall survival could be prolonged significantly for the first time. Clinical studies implied that even long-term survival is possible with both types of drugs, but predictive markers are so far missing. In this study, we analyzed survival data from patients that received the first-in-class substances vemurafenib and ipilimumab, respectively, during the time period from registration of the drugs until availability of combination treatments. We aimed to evaluate the possibility of long-term survival in a daily life setting and to characterize patients that benefit from these drugs in order to gain insight into predictive attributes. Eighty patients were evaluated who were treated with either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was analyzed. Subgroup analysis was performed for patients who were still alive 24 months after induction of therapy (long-term survival). Median overall survival (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative predictors of long-term survival in the vemurafenib group were brain and liver metastases, as well as elevated LDH, S100beta and liver enzymes. For ipilimumab, an increase in lymphocytes and eosinophils during course of treatment correlated with long-term survival. Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach. Combination of drugs and observational studies in larger patient cohorts are necessary to further validate our findings. PMID- 29387970 TI - Experimental infection of Marmota monax with a novel hepatitis A virus. AB - To establish an animal model for the newly identified Marmota Himalayana hepatovirus, MHHAV, so as to develop a better understanding of the infection of hepatitis A viruses. Five experimental woodchucks (Marmota monax) were inoculated intravenously with the purified MHHAV from wild woodchuck feces. One animal injected with PBS was defined as a control. Feces and blood were routinely collected. After the animals were subjected to necropsy, different tissues were collected. The presence of viral RNA and negative sense viral RNA was analyzed in all the samples and histopathological and in situ hybridization analysis was performed for the tissues. MHHAV infection caused fever but no severe symptoms or death. Virus was shed in feces beginning at 2 dpi, and MHHAV RNA persisted in feces for ~2 months, with a biphasic increase, and in blood for ~30 days. Viral RNA was detected in all the tissues, with high levels in the liver and spleen. Negative-strand viral RNA was detected only in the liver. Furthermore, the animals showed histological signs of hepatitis at 45 dpi. MHHAV can infect M. monax and is associated with hepatic disease. Therefore, this animal can be used as a model of HAV pathogenesis and to evaluate antiviral and anticancer therapeutics. PMID- 29387971 TI - Efficacy of doxorubicin after progression on carboplatin and paclitaxel in advanced or recurrent endometrial cancer: a retrospective analysis of patients treated at the Brazilian National Cancer Institute (INCA). AB - The treatment of endometrial cancer (EC) is challenging. There is no standard of care for patients who progressed after carboplatin and paclitaxel (CT) and all available drugs show a small response and poor long-term survival in this scenario. The objective of this study was to evaluate the efficacy and toxicity profile of palliative doxorubicin after progression to CT therapy in advanced or recurrent EC. A retrospective review of the Brazilian National Cancer Institute database between 2009 and 2013 was performed, and all patients with recurrent and advanced EC treated with palliative doxorubicin after progression on CT were included. Progression-free survival (PFS), overall survival (OS), objective response rates as well as toxicity were evaluated. A total of 33 patients were enrolled, with a median age of 65.7 years. Objective responses were documented in 12.1% (3.0% of complete responses and 9.1% of partial responses). The median PFS was 4.4 months, and the median OS was 8.1 months for patients exposed to doxorubicin. The most common adverse event was anemia observed in 60.6% of patients. This retrospective study suggests that doxorubicin has a modest activity in patients with advanced or recurrent EC after treatment with CT. PMID- 29387972 TI - Effect of cardiac resynchronization therapy on mitral valve geometry: a novel aspect as "reversed mitral remodeling". AB - Amelioration of the valvular geometry is a possible mechanism for mitral regurgitation (MR) improvement in patients receiving cardiac resynchronization therapy (CRT). We aimed to establish the precise definition, incidence, and predictors of reversed mitral remodeling (RMR), as well as the association with MR improvement and short-term CRT outcome. Ninety-five CRT recipients were retrospectively evaluated for the end-point of "MR response" defined as the absolute reduction in regurgitant volume (RegV) at 6 months. To identify RMR, changes in mitral deformation indices were tested for correlation with MR response and further analyzed for functional and echocardiographic CRT outcomes. Overall, MR response was observed in 50 patients (53%). Among the echocardiographic indices, the change in tenting area (TA) had the highest correlation with the change in RegV (r = 0.653, p < 0.001). The mean TA significantly decreased in MR responders (4.15 +/- 1.05 to 3.67 +/- 1.01 cm2 at 6 months, p < 0.001) and increased in non-responders (3.68 +/- 1.04 to 3.98 +/- 0.97 cm2, p = 0.014). The absolute TA reduction was used to identify patients with RMR (47%) which was found to be associated with higher rates of functional improvement (p = 0.03) and volumetric CRT response (p = 0.036) compared to those without RMR. Non-ischemic etiology and the presence of LBBB independently predicted RMR at multivariate analysis. In conclusion, reduction in TA is a reliable index of RMR, which relates to MR response, and functional and echocardiographic improvement with CRT. LBBB and non-ischemic etiology are independent predictors of RMR. PMID- 29387973 TI - Reproductive success of two male morphs in a free-ranging population of Bornean orangutans. AB - The reproductive success of male primates is not always associated with dominance status. For example, even though male orangutans exhibit intra-sexual dimorphism and clear dominance relationships exist among males, previous studies have reported that both morphs are able to sire offspring. The present study aimed to compare the reproductive success of two male morphs, and to determine whether unflanged males sired offspring in a free-ranging population of Bornean orangutans, using 12 microsatellite loci to determine the paternity of eight infants. A single flanged male sired most of the offspring from parous females, and an unflanged male sired a firstborn. This is consistent with our observation that the dominant flanged male showed little interest in nulliparous females, whereas the unflanged males frequently mated with them. This suggests that the dominant flanged male monopolizes the fertilization of parous females and that unflanged males take advantage of any mating opportunities that arise in the absence of the flanged male, even though the conception probability of nulliparous females is relatively low. PMID- 29387974 TI - Is the fatigue an adverse event of the second generation of hormonal therapy? Data from a literature-based meta-analysis. AB - New hormonal therapies have enriched the therapeutic armamentarium for patients with castration-resistant prostate cancer (CRPC). Fatigue is one of the most common adverse events registered in phase III trials of these new drugs. The aim of this article is to perform a meta-analysis based on all available literature data focused on the risk rate (RR) of fatigue from new hormonal agent-based therapy in patients with CRPC. A total of 11,751 cases were included from 11 randomized trials. The analysis revealed that the second generation of hormonal therapies increased the RR of any-grade fatigue (RR = 1.27) and grade 3-4 fatigue (RR = 1.25). This last adverse event was always higher in a pre-chemotherapy setting. In conclusion, given the limitations of a literature-based study, rather than a meta-analysis based on individual patients' data, our study confirmed the increase in the RR for any-grade and grade 3-4 fatigue during the second generation of hormonal therapies, with particular attention being paid to grade 3 4 in the pre-chemotherapy setting of the disease. PMID- 29387976 TI - ABO blood group and the risk of post-thrombotic syndrome. AB - Post-thrombotic syndrome (PTS) has been associated to DVT recurrence, increased FVIII, inflammatory biomarker plasma levels, and persistence of vein obstruction. These same features have also been widely reported in non-O blood type subjects. Our aim was to investigate the correlation between the incidence of PTS and ABO blood types. Consecutive patients referred to the Department of Medicine of University of Padua between January 2004 and January 2012 following the diagnosis of a first episode of proximal DVT were enrolled. The presence of PTS was assessed via the Villalta scale at predefined time points (3, 6, 12, 18, 24, 36 months). Hazard ratio (HR) for PTS development was calculated in non-O (exposed) vs O blood (unexposed) type patients. Out of 671 eligible patients, 606 were enrolled. Overall, 192 (31.7%) patients developed PTS: 142 (34.5%) non-O and 50 (25.6%) O blood type patients. Individuals with non-O blood group were associated with a significantly higher risk to develop PTS (HR 1.53, 95% CI, 1.05-2.24; p = 0.028) than O group. Non-O blood type might be a risk factor for the development of PTS. PMID- 29387975 TI - A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors. AB - BRCA2is the main susceptibility gene known to be involved in the pathogenesis of breast cancer. It plays an important role in maintaining the genome stability by homologous recombination through DNA double-strand breaks repairing, by interacting with various other proteins including RAD51, DSS1, RPA, MRE11, PALB2, and p53. BRCA2-deficient cells show the abnormalities of chromosome number. BRCA2 is also found to be involved in centrosome duplication specifically in the metaphase to anaphase transition. Inactivation or depletion of BRCA2 leads to centrosome amplification that results in unequal separation of chromosomes. BRCA2 localizes with central spindle and midbody during telophase and cytokinesis. Inactivation or depletion of BRCA2 leads to multinucleation of cell. Around 2000 mutations have been reported in BRCA2 gene. BRCA2-deficient tumors are being taking into consideration for targeted cancer therapy by using different inhibitors like poly ADP-ribose polymerase and thymidylate synthase. The present review focusses on the role of BRCA2 in various critical cellular processes based on the mechanistic approaches. Mutations reported in the BRCA2 gene in various ethnic groups till date have also been compiled with an insight into the functional aspects of these alterations. The therapeutic strategies for targeting BRCA2-deficient tumors have also been targeted. PMID- 29387977 TI - Relapse of acute promyelocytic leukemia in the external auditory canal confirmed by PML/RARA dual-fusion and RARA break-apart fluorescence in situ hybridization. PMID- 29387978 TI - Prognostic value of epidermal growth factor receptor mutations and histologic subtypes with lung adenocarcinoma. AB - The epidermal growth factor receptor (EGFR) mutation status has become one of the most important factors in the treatment of non-small cell lung cancer. However, the relationship between EGFR mutation and the histologic subtype of lung adenocarcinoma remains to be fully elucidated. We examined the relationship between the predominant subtype of adenocarcinoma and the prognosis and investigated the correlation between a new subtype of adenocarcinoma and EGFR mutations. This study included 182 patients with adenocarcinoma who underwent complete resection. The rate of EGFR mutation-positive patients was significantly higher among female patients, never smokers, patients with small tumors (< 3 cm in size), patients with well-differentiated tumors, and patients with a pStage I classification. The rates of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant subtype were high in male EGFR mutation-positive patients. The prevalence of the acinar and papillary predominant subtypes was high among EGFR mutation-positive female patients, as was AIS, MIA, and the lepidic-predominant subtype. The progression-free survival (PFS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (75.8 vs 67.1%, p = 0.03). However, the multivariate analysis of clinicopathologic and histologic factors did not reveal the prognostic impact of the EGFR mutation status on PFS. The overall survival (OS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (93.7 vs 63.4%, p < 0.01). However, in the multivariate analysis the EGFR mutation status was not significantly associated with OS. PMID- 29387979 TI - Effects of land use on arbuscular mycorrhizal fungal communities in Estonia. AB - Arbuscular mycorrhizal (AM) fungal communities vary across habitat types, as well as across different land use types. Most relevant research, however, has focused on agricultural or other severely human-impacted ecosystems. Here, we compared AM fungal communities across six habitat types: calcareous grassland, overgrown ungrazed calcareous grassland, wooded meadow, farmyard lawn, boreonemoral forest, and boreonemoral forest clear-cut, exhibiting contrasting modes of land use. AM fungi in the roots of a single host plant species, Prunella vulgaris, and in its rhizosphere soil were identified using 454-sequencing from a total of 103 samples from 12 sites in Estonia. Mean AM fungal taxon richness per sample did not differ among habitats. AM fungal community composition, however, was significantly different among habitat types. Both abandonment and land use intensification (clearcutting; trampling combined with frequent mowing) changed AM fungal community composition. The AM fungal communities in different habitat types were most similar in the roots of the single host plant species and most distinct in soil samples, suggesting a non-random pattern in host-fungal taxon interactions. The results show that AM fungal taxon composition is driven by habitat type and land use intensity, while the plant host may act as an additional filter between the available and realized AM fungal species pool. PMID- 29387980 TI - Hyperpyrexia and high fever as a predictor for serious bacterial infection (SBI) in children-a systematic review. AB - : It is not clear if children with high fever are at increased risk for serious bacterial infection (SBI). Our aim was to systematically review if children suffering from high fever are at high risk for SBI. Our data sources were Embase, Medline, and Pubmed; from their inception until the last week of March 2017. The study selection were of cohort and case control studies comparing the incidence of SBI in children with hyperpyrexia with children with fever of 41 degrees C or less, and children with a temperature higher than 40 degrees C, with children with fever of 40 degrees C or less. Two reviewers independently pooled studies for detailed review using a structured data-collection form. We calculated the odds ratio and 95% confidence intervals (CI) for SBI, assuming a random-effects model. A sub-group analysis was conducted. In our results, 11 studies met the inclusion criteria. Two studies showed that children with hyperpyrexia are at higher risk for SBI (OR 1.96 95% CI 1.3-1.97). An increased risk for SBI in children with high fever (OR 3.21 95% CI 1.67; 6.22). SBI in infants with temperature over 40 degrees C was higher compared to infants with lower degree of fever (OR 6.3 95% CI 4.44; 8.95). On older children, the risk for SBI was only slightly higher in children with fever above 40 degrees C. The limitation of the study is the small amount of studies and that the heterogeneity of the studies was very high. CONCLUSION: Young infants with temperature higher than 400 degrees C are at increased risk for SBI. Risk of SBI in older children with temperature > 400C is minimal. What is known: * An association between high fever and increased risk for SBI was reported in young infants. * Based on only two studies from the 1970s and 1980s, hyperpyrexia is associated with increased risk for SBI. What is new: * Infants under the age of 3 months with fever > 40 degrees C were found to have increased risk for SBI. * Risk of SBI in older children with temperature > 40 degrees C is minimal. PMID- 29387981 TI - Relationship between serum 25-hydroxyvitamin D and red blood cell indices in German adolescents. AB - : Since the impact of vitamin D on red blood cell formation has not been well studied, we aimed at assessing the putative link between serum 25-hydroxyvitamin D (25[OH]D) concentrations and hematological markers of erythropoiesis in a large cohort of German adolescents aged 11 to 17 years. In total, 5066 participants from the population-based, nationally representative KiGGS study (Kinder- und Jugendgesundheitssurvey, German Health Interview and Examination Survey for Children and Adolescents) were grouped into either tertiles or clinically accepted cutoff levels for serum 25(OH)D. Results demonstrated significant and inverse correlations between 25(OH)D levels and several hematological parameters including hemoglobin concentration (r = - 0.04, p = 0.003), mean corpuscular hemoglobin (r = - 0.11, p < 0.001), red blood cell count (r = - 0.04, p = 0.002), and soluble transferrin receptor (r = - 0.1, p < 0.001), whereas, in contrast, serum 25(OH)D was positively correlated to the mean corpuscular volume of erythrocytes (r = 0.08, p < 0.001). Multinomial regression models adjusted for clinically relevant confounders confirmed statistically significant differences between the two strata of 25(OH)D groups with respect to red blood cell markers (hemoglobin concentration, red blood cell count, mean corpuscular volume, and corpuscular hemoglobin, as well as iron and soluble transferrin receptor). CONCLUSIONS: The link between serum 25(OH)D and several important hematological parameters may point to an inhibitory role of vitamin D in the regulation of erythropoiesis in adolescents. What is Known: * The physiological effects of vitamin D on calcium homeostasis and bone metabolism have been established. * However, much less is known about the impact of circulating vitamin D on erythropoiesis. What is New: * Data from the KiGGS study in German adolescents demonstrated significant associations between serum vitamin D concentrations and red blood cell indices. * Further studies should be conducted to decipher the underlying mechanisms of vitamin D on erythropoiesis. PMID- 29387982 TI - Serum creatinine during physiological perinatal dehydration may estimate individual nephron endowment. AB - : It is well known that the nephron endowment of healthy subjects is highly variable and that individual nephron mass has potentially important implications both in health and disease. However, nephron count is technically impossible in living subjects. Based on the observation of an increase in serum creatinine (sCr) in otherwise healthy newborns with solitary kidney during the physiological perinatal dehydration, we hypothesized that perinatal sCr might be helpful in identifying healthy subjects with a reduced nephron mass. In the framework of a study on blood pressure in babies (NeoNeph), sCr of normal Caucasian neonates was determined 48-96 h after birth and their association with a family history of arterial hypertension (AH) was analyzed. SCr was determined in 182 normal newborns (90 males) at a mean of 61 +/- 8 h after birth (range 46-82). Newborns with paternal AH had a higher mean sCr (0.97 + 0.28 mg/dL) then newborns without paternal AH (0.73 + 0.28 mg/dL; p = 0.006). No differences in mean sCr were found in relation with mother or grandparent's history of AH. CONCLUSION: The association between parental AH and high sCr during perinatal dehydration supports the hypothesis that the latter is a promising tool for identifying normal subjects with a reduced nephron mass with potential important implications in prevention and in understanding the individual outcome of renal and extrarenal diseases (including AH). What is Known: * Nephron endowment of healthy subjects is highly variable and individual nephron mass has potentially important implications both in health and disease however nephron count is not feasible in living subjects. What is New: * Serum creatinine during perinatal dehydration is a possible biomarker for identifying normal subjects with a reduced nephron mass. PMID- 29387984 TI - Generation of PTEN knockout bone marrow mesenchymal stem cell lines by CRISPR/Cas9-mediated genome editing. AB - The tumor suppressor PTEN is involved in the regulation of cell proliferation, lineage determination, motility, adhesion and apoptosis. Loss of PTEN in the bone mesenchymal stem cells (BMSCs) was shown to change their function in the repair tissue. So far, the CRISPR/Cas9 system has been proven extremely simple and flexible. Using this system to manipulate PTEN gene editing could produce the PTEN-Knocking-out (PTEN-KO) strain. We knocked out PTEN in MSCs and validated the expression by PCR and Western blot. To clarify the changes in proliferation, CCK 8 assay was applied. In support, living cell proportion was assessed by Trypan blue staining. For osteogenic and adipogenic induction, cells were cultured in different media for 2 weeks. Oil red staining and alizarin red staining were performed for assessment of osteogenic or adipogenic differentiation. The expression of Id4, Runx2, ALP and PPARgamma was examined by qPCR and immunocytochemistry staining. The PTEN-KO strain was identified by sequencing. The PTEN-KO cells had an increased cell viability and higher survival compared with the wild type. However, decreased expression of Runx2 and PPARgamma was found in the PTEN loss strain after induction, and consistently decreased osteogenic or adipogenic differentiation was observed by alizarin and oil red staining. Together, PTEN-KO strain showed an increased proliferation capability but decreased multi-directional differentiation potential. When BMSCs serve as seed cells for tissue engineering, the PTEN gene may be used as an indicator. PMID- 29387983 TI - Factors involved in early lenvatinib dose reduction: a retrospective analysis. AB - Lenvatinib, a multi-tyrosine kinase inhibitor, has been proven to be an effective treatment option for patients with iodine-131-refractory thyroid cancer. Many adverse effects of lenvatinib have been reported; thus, dose reduction is common. However, a few studies have analyzed the causes of lenvatinib dose reduction in daily clinical practice. Here, we investigate the factors involved in early lenvatinib dose reduction to analyze lenvatinib dose modification. We analyzed 20 thyroid cancer patients who began receiving lenvatinib at the Kumamoto University Hospital Cancer Center from July 2015 to November 2016. Patients were classified into the following groups based on the time until first withdrawal or dose reduction in lenvatinib: group A (early, <= 10 days) and group B (other, > 10 days). Patients' clinical features and reasons for withdrawal or dose reduction were analyzed. The age range of patients was 54-91 years, and the median observation period was 293 days. There were no significant differences in the administered line of lenvatinib; the presence/absence of primary residual tumors; or the history of hypertension, proteinuria, and diarrhea between the two groups (A, n = 7; B, n = 13). The cause for initial withdrawal or dose reduction was grade 3 hypertension in all group A patients, which was significantly higher than that in group B (p = 0.0001). Our results suggest that early blood pressure control may be effective as a method to maintain the lenvatinib dose intensity. PMID- 29387985 TI - Genetic polymorphism of calcium-sensing receptor in women with breast cancer. AB - Breast cancer is a disease of unknown etiology, whose major risk factors are genetic alterations. Polymorphism of the calcium-sensing receptor (CaSR) has been a focus of some recent studies, due to a probable association with breast cancer risk and tumor aggressiveness. A relationship between polymorphic rs17251221 variant of the CaSR gene, and allele G (considered a gain-of-function mutation) and breast cancer risk has been stressed, despite the paucity of studies found in the literature. The present study involved 137 women (69 women with breast cancer case; and 68 controls without breast cancer) who had 3 ml of peripheral blood drawn for DNA study. Genomic DNA was extracted from leukocytes by genotyping technique with real-time polymerase chain reaction. The AG genotype (rs17251221) was present in 13 women (18.84%) from the case group and in 8 (11.76%) women from the control group (p = 0.3434), while the GG genotype (rs17251221) did not occur in any group. In contrast, no statistically significant difference was observed between the AG genotype of variant rs17251221 in premenopausal case and control women (p = 0.71). There was also no statistically significant difference between postmenopausal case and control patients (p = 0.6851). In the current study, CaSR gene polymorphism of SNP variant rs17251221 did not show any statistically significant association with breast cancer, in both premenopausal and postmenopausal women. PMID- 29387986 TI - Initial symptom presentation after high school football-related concussion varies by time point in a season: an initial investigation. AB - BACKGROUND: Schedule-based and in-season factors (e.g., competition type) have been shown to be associated with symptom reporting patterns and injury severity in sport-related concussion (SRC). To determine if acute neurocognitive and symptom presentation following SRC differ by time point within a high school football season. METHODS: Multicenter ambispective cohort of high school football players who sustained a SRC (N = 2594). Timing (early, mid, and late season) of SRC was based on median dates for the start of the pre-season, regular season, and playoffs of each states' football schedules. Analysis of covariance (ANCOVA) investigated differences across season period groups for: (1) neurocognitive test scores, (2) total symptom scores (TSS), and (3) individual symptom increases from baseline within 1-week post-injury. RESULTS: Significant group differences were observed in TSS, F(2, 2589) = 15.40, p < 0.001, etap2 = 0.01, and individual symptom increases from baseline, F(2, 2591) = 16.40, p < 0.001, etap2 = 0.01. Significant increases were seen from baseline to both midseason and late season in both TSS, chi2 = 24.40, p < 0.001, Phi = 0.10 and individual symptoms, chi2 = 10.32, p = 0.006, Phi = 0.10. Post hoc tests indicated a linear trend, with late season injured athletes reporting approximately twice the TSS (13.10 vs. 6.77) and new symptoms (5.70 vs. 2.68) as those with early-season injuries. CONCLUSION: In a cohort of American high school football student-athletes, those suffering SRC in the late-season time period had increased acute symptom burden. SRC sustained later in-season may require more conservative management. PMID- 29387987 TI - Detailed pathologic analysis on the co-occurrence of non-seminomatous germ cell tumor subtypes in matched orchiectomy and retroperitoneal lymph node dissections. AB - The frequency of co-occurrence between germ cell tumor (GCT) components in non seminomatous germ cell tumor (NSGCT) orchiectomy specimens and their correlation with histologic findings in subsequent retroperitoneal lymph node dissection (RPLND) specimens have not been well characterized. The objective of the study was to report the first detailed clinicopathologic analysis of NSGCT orchiectomy and RPLND samples to determine the likelihood and agreement of the co-occurrence of GCT components. A total of 118 consecutive patients with NSGCT treated between 1988 and 2012 who underwent both orchiectomy and RPLND at a single academic tertiary care center were analyzed. Statistical analysis of co-occurrence likelihood and agreement of GCT components was performed, both within and between orchiectomy and RPLND specimens. Embryonal carcinoma was the most frequent component present in orchiectomy specimens, and there were multiple significant associations between orchiectomy GCT components; seminoma occurred less frequently with embryonal carcinoma (OR 0.29 [95% confidence interval (CI) 0.11 0.75]; p < 0.01), and teratoma more frequently occurred with choriocarcinoma (OR 9.64 [95% CI 1.22-76.12]; p = 0.01). Presence of teratoma in the orchiectomy specimen predicted for a fourfold increase in distant metastasis on multivariate analysis (HR 4.92 [1.14-18.9]; p = 0.02). The only significant association of co occurrence in the RPLND specimen was between embryonal carcinoma and teratoma (OR 0.01 [95% CI 0-0.07]; p < 0.001), where it was significantly less likely for them to occur together. Our findings are limited by their retrospective nature. The co occurrence of GCT components within orchiectomy specimens does not appear to be a completely random process. However, there is less agreement and more randomness between the occurrence of the GCT components in matched orchiectomy and RPLND samples. In this report, we look at the co-occurrence of different GCT components within matched orchiectomy and RPLND pathology specimens and show that co occurrence is not a completely random process. PMID- 29387988 TI - Using marker gene analysis instead of mixed lymphocyte reaction assay for identification of functional CD4+FOXP3+ regulatory T cells. AB - OBJECTIVE: To establish a quick analytical method using quantitative PCR for marker gene analysis to identify the functions of iTreg cells and subsequently curtail the harvest time for iTreg cells. RESULTS: The data from the marker gene analysis indicated that varying proportions of iTreg cells could reveal the various expression levels of these genes. FoxP3 expression increased to a considerable degree. By using the same iTreg population, the mixed lymphocyte reaction assay was conducted for 5 days. The suppression percentage of T-cells was dependent on the proportion of iTreg cells, indicating that gene expression levels can represent the biological functions of iTreg cells. By using human peripheral blood mononuclear cells for Treg cell induction, the marker gene expression analysis showed a difference between iTreg cells and uninduced T cells. CONCLUSION: Marker gene analysis requires only 1 day to identify the functions of human iTreg cells can save time in clinical application and might prevent graft-versus-host disease occurrence effectively. PMID- 29387989 TI - Effects of Estrogen on the Gastrointestinal Tract. AB - Estrogen is a kind of steroid compound that has extensive biologic activities. The effect of estrogen is pleiotropic, affecting multiple systems in the body. There is accumulating evidence that estrogen has important effects on the gastrointestinal tract. Longer exposure to estrogen may decrease the risk of gastric cancer. Use of the anti-estrogen drug tamoxifen might increase the risk of gastric adenocarcinoma. Estrogen receptor beta may serve as a target for colorectal cancer prevention. In addition, estrogen has been reported to be closely related to the mucosal barrier, gastrointestinal function and intestinal inflammation. However, the role of estrogen in the gastrointestinal tract has not been systematically summarized. In this review, we aim to provide an overview of the role of estrogen in the gastrointestinal tract and evaluate it from various aspects, including estrogen receptors, the mucosal barrier, intestinal inflammation and gastrointestinal tract tumors, which may provide the basis for the development of therapeutic strategies to manage gastrointestinal diseases. PMID- 29387991 TI - Smoking and susceptibility to rheumatoid arthritis in a Swedish population-based case-control study. AB - Smoking is one of the most established risk factors for rheumatoid arthritis (RA). The aim of this study was to estimate how age at smoking debut, smoking cessation, duration, intensity, and cumulative dose of smoking influence the risk of developing anti-citrullinated peptide antibodies (ACPA) positive and ACPA negative RA. The present report is based on a Swedish population-based, case control study with incident cases of RA (3655 cases, 5883 matched controls). Using logistic regression models, subjects with different smoking habits were compared regarding risk of developing the two variants of RA, by calculating odds ratios (OR) with 95% confidence intervals (CI). Smoking increased the risk of developing both ACPA positive (OR 1.9, 95% CI 1.7-2.1) and ACPA negative RA (OR 1.3, 95% CI 1.2-1.5). For both subsets of RA, there seemed to be a threshold (~ 2.5 pack years for ACPA positive RA and ~ 5 pack years for ACPA negative RA) below which no association between smoking and RA occurred. A dose-response association was observed between cumulative dose of smoking and risk of developing ACPA positive RA (p value for trend < 0.0001). Duration of smoking had a higher influence on the association between smoking and RA than did intensity of smoking. For both subsets of RA, the detrimental effect of smoking decreased after smoking cessation. Twenty years after smoking cessation, there was no longer an association between smoking and risk of ACPA negative RA, whereas the association between smoking and ACPA positive RA risk persisted and was dependent on the cumulative dose of smoking. Smoking increases the risk of both subsets of RA with a more pronounced influence on the risk of ACPA positive RA. Preventive measures in order to reduce smoking are essential and may result in a decline in RA incidence. PMID- 29387990 TI - Hypervigilance to a Gluten-Free Diet and Decreased Quality of Life in Teenagers and Adults with Celiac Disease. AB - BACKGROUND AND AIMS: Avoidance of gluten is critical for individuals with celiac disease (CD), but there is also concern that "extreme vigilance" to a strict gluten-free diet may increase symptoms such as anxiety and fatigue, and therefore, lower quality of life (QOL). We examined the associations of QOL with energy levels and adherence to, and knowledge about, a gluten-free diet. METHODS: This is a cross-sectional prospective study of 80 teenagers and adults, all with biopsy-confirmed CD, living in a major metropolitan area. QOL was assessed with CD-specific measures. Dietary vigilance was based on 24-h recalls and an interview. Knowledge was based on a food label quiz. Open-ended questions described facilitators and barriers to maintaining a gluten-free diet. RESULTS: The extremely vigilant adults in our sample had significantly lower QOL scores than their less vigilant counterparts [(mean (SD): 64.2 (16.0) vs 77.2 (12.2), p = 0.004]. Extreme vigilance was also associated with greater knowledge [5.7 (0.7) vs 5.1 (0.8), p = 0.035]. Adults with lower energy levels had significantly lower overall QOL scores than adults with higher energy levels [68.0 (13.6) vs 78.9 (13.0), p = 0.006]. Patterns were similar for teenagers. Cooking at home and using internet sites and apps were prevalent strategies used by the hypervigilant to maintain a strict gluten-free diet. Eating out was particularly problematic. CONCLUSION: There are potential negative consequences of hypervigilance to a strict gluten-free diet. Clinicians must consider the importance of concurrently promoting both dietary adherence and social and emotional well-being for individuals with CD. PMID- 29387992 TI - SMER28 is a mTOR-independent small molecule enhancer of autophagy that protects mouse bone marrow and liver against radiotherapy. AB - Effective cytoprotectors that are selective for normal tissues could decrease radiotherapy and chemotherapy sequelae and facilitate the safe administration of higher radiation doses. This could improve the cure rates of radiotherapy for cancer patients. Autophagy is a cytoplasmic cellular process that is necessary for the clearance of damaged or aged proteins and organelles. It is a strong determinant of post-irradiation cell fate. In this study, we investigated the effect of the mTOR-independent small molecule enhancer of autophagy (SMER28) on mouse liver autophagy and post-irradiation recovery of mouse bone marrow and liver. SMER28 enhanced the autophagy flux and improved the survival of normal hepatocytes. This effect was specific for normal cells because SMER28 had no protective effect on hepatoma or other cancer cell line survival in vitro. In vivo subcutaneous administration of SMER28 protected mouse liver and bone marrow against radiation damage and facilitated survival of mice after lethal whole body or abdominal irradiation. These findings open a new field of research on autophagy-targeting radioprotectors with clinical applications in oncology, occupational, and space medicine. PMID- 29387993 TI - Perceptual judgments via sensory-motor interaction assisted by cortical GABA. AB - Recurrent input to sensory cortex, via long-range reciprocal projections between motor and sensory cortices, is essential for accurate perceptual judgments. GABA levels in sensory cortices correlate with perceptual performance. We simulated a neuron-astrocyte network model to investigate how top-down, feedback signaling from a motor network (Nmot) to a sensory network (Nsen) affects perceptual judgments in association with ambient (extracellular) GABA levels. In the Nsen, astrocytic transporters modulated ambient GABA levels around pyramidal cells. A simple perceptual task was implemented: detection of a feature stimulus presented to the Nsen. The Nmot showed distinct perceptual behaviors: hit, fault, and miss. A hit is a correct response to the stimulus, a fault is a wrong response to the stimulus, and a miss is no response to the stimulus. In hits, the feedback signaling increased the gain of Nsen pyramidal cells and accelerated the reaction speed of Nmot pyramidal cells to the stimulus. Without feedback signaling, the Nsen but not Nmot responded to the stimulus, resulting in a miss. With too strong feedback signaling, the Nmot resulted in a fault, namely, stimulus-insensitive but not stimulus-sensitive pyramidal cells wrongly responded. Balancing the feedforward and feedback signaling formed a coherent, ongoing-spontaneous neuronal state, by which the highest hit rate was achieved. A transient reduction in local ambient GABA levels, triggered by the stimulus, contributed to accelerating the reaction speed under noisy environmental conditions. Adjusting the basal ambient GABA level ensured high hit rates. We suggest that motor cortex feedback may accelerate reaction speed to sensory stimulation by promoting coherency in ongoing-spontaneous neuronal activity between sensory and motor cortices, thereby achieving prompt perceptual judgments. Spatiotemporal modulation of ambient GABA levels, possibly by astrocytic transporters, assists in making reliable perceptual judgments. PMID- 29387995 TI - The challenge of sustainability in healthcare systems: frequency and cost of diagnostic procedures in end-of-life cancer patients. AB - BACKGROUND: Literature data on the overuse and misuse of diagnostic procedures leading to end-of-life aggressiveness are scarce due to the limited amount of estimated economic waste. This study investigated the potential overuse of diagnostic procedures in a population of end-of-life patients. METHODS: This is a retrospective study on consecutive advanced patients admitted into two Italian hospices. Frequency and relative costs of X-ray imaging, CT scans, MRI, and interventional procedures prescribed in the 3 months before admission were collected in patient electronic charts and/or in administrative databases. We conducted a deeper analysis of 83 cancer patients with a diagnosis of at least 1 year before admission to compare the number of examinations performed at two distant time periods. RESULTS: Out of 541 patients, 463 (85.6%) had at least one radiological exam in the 3 months before last admission. The mean radiological exam number was 3.9 +/- 3.2 with a relative mean cost of 278.60 +/- 270.20 ? per patient with a statistically significant (p < 0.001) rise near death. In the 86 patient group, a higher number of procedures was performed in the last 3 months of life than in the first quarter of the year preceding last admission (38.43 +/- 28.62 vs. 27.95 +/- 23.21, p < 0.001) with a consequent increase in cost. CONCLUSIONS: Patients nearing death are subjected to a high level of "diagnostic aggressiveness." Further studies on the integration of palliative care into the healthcare pathway could impact the appropriateness of interventions, quality of care, and, ultimately, estimated costs. PMID- 29387994 TI - Patient and oncologist perceptions regarding symptoms and impact on quality-of life of oral mucositis in cancer treatment: results from the Awareness Drives Oral Mucositis PercepTion (ADOPT) study. AB - PURPOSE: This descriptive cross-sectional survey aims to assess the level of concordance between the perspectives of oncologists and those of patients regarding oral mucositis (OM) symptoms, and the impact of OM on various aspects of daily living and concurrent cancer management. METHODS: Oncologists involved in OM management (n = 105), and patients who developed OM during cancer treatment (n = 175), were recruited from seven Asian countries. Oncologists completed a face-to-face, quantitative interview; patients completed a face-to-face interview, and a self-reported questionnaire. RESULTS: Oncologists and patients ranked treatment-induced OM among the three most important toxicities of cancer therapy requiring intervention. The most frequent OM symptoms reported by patients were oral ulcers (74%), dry mouth (73%), and difficulty swallowing (62%). Oncologists expected mild OM symptoms to last slightly longer than 1 week, whereas patients reported mild symptoms for more than 2 weeks. In mild-to moderate OM, oncologists underestimated patients' pain experience. Overall, only 45% of oncologists said they would initiate OM prophylaxis when cancer therapy started. Of the 87% of patients who said they used their prescribed medications, only 16% reported using prophylactically prescribed medication. While oncologists' concerns related to the delays and interruptions of cancer treatment, patients tended to focus on the effects of OM on eating, drinking, and talking. CONCLUSIONS: Oncologists' and patients' perceptions about treatment induced OM differ. To overcome discordant perspectives, there is a need to raise general awareness and improve proactive management of OM. As noted in recent guidelines, supportive cancer care is critical for ensuring optimal therapy and for improving the patient's experience. PMID- 29387996 TI - Fertility information needs and concerns post-treatment contribute to lowered quality of life among young adult female cancer survivors. AB - BACKGROUND: Cancer treatment may lead to premature menopause and infertility. Young adult female cancer survivors (YAFCS) are often concerned about their fertility and future family-building options, but research is limited on how concerns may affect more general quality of life (QOL) domains. This study examined how fertility factors relate to QOL among YAFCS who received gonadotoxic therapy. METHOD: A national sample of YAFCS completed an online, anonymous survey. The survey included investigator-designed questions about perceived fertility information needs (five items; Cronbach's alpha = .83) and general QOL (four items; alpha = .89), the Reproductive Concerns after Cancer Scale (RCACS) and Decisional Conflict Scale (DCS). Analyses included Pearson's correlation, t tests, and stepwise regression. RESULTS: Participants (N = 314) were an average of 30 years old (SD = 4.1) and 5 years (SD = 5.4) post-treatment; 31% reported being infertile and 19% had undergone fertility preservation (FP). Overall, QOL was relatively high (M = 7.3, SD = 1.9, range 0-10) and did not vary by fertility status (t[272] = .743, p = .46), prior FP (t[273] = .53, p = .55) or sociodemographic/clinical factors (p's > .05) except socioeconomic indicators (p's < .05).In separate models, greater unmet fertility information needs (beta = - .19, p = .004) and, among fertile women, greater reproductive concerns (beta = .26, p = .001) related to lower QOL. Among fertile women without prior FP, greater decisional distress about future FP related to lower QOL (beta = - .19, p = .03). CONCLUSIONS: These preliminary findings suggest that unaddressed fertility information needs, concerns, and decision distress may affect general QOL among post-treatment YAFCS who hope to have children in the future. Future work should identify ways to optimally incorporate fertility counseling and support resources into survivorship care programs, including referrals to reproductive specialists as appropriate. PMID- 29387997 TI - Denosumab versus bisphosphonates in patients with advanced cancers-related bone metastasis: systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Bone metastasis is reported to be associated with poor quality of life, and increased risk of hospitalization. We aim to synthesize evidence from published randomized controlled trials (RCTs) which compared the efficacy of denosumab versus bisphosphonates in patients with advanced cancers. METHODS: We searched for all published RCTs in the following electronic databases: PubMed, Scopus, Web of Science, and Cochrane Central. Retrieved records were screened for eligibility. Time-to-event data were pooled as hazard ratio (HR) using the generic inverse-variance method and dichotomous data were pooled as relative risk (RR) in a random-effect model. We used Review Manager 5.3 for windows. RESULTS: Six unique RCTs with a total of 7722 patients were included. Overall effect estimates favored denosumab group in comparison to intravenous (IV) bisphosphonates in the following terms: time to first skeletal-related events (HR 0.92, 95% CI [0.86, 0.98], p = 0.01), time to subsequent skeletal-related event (RR 0.92, 95% CI [0.86, 0.99], p = 0.03), and radiation to bone (RR 0.81, 95% CI [0.71, 0.92], p = 0.02). Denosumab group was associated with increased risk of grade 3 or 4 hypocalcaemia (RR 1.99, 95% CI [1.11, 3.54], p = 0.02) and reduced risk of renal impairment or toxicity (RR 0.75, 95% CI [0.61, 0.91], p = 0.003) in comparison to IV bisphosphonates group. Pooled studies were homogenous. CONCLUSION: Denosumab showed a favorable significant impact on delaying the time to first skeletal-related event and reducing the incidence of radiation to the bone event in comparison to bisphosphonates, with similar efficacy regarding overall survival and time to disease progression. Further large-scale and long term studies are needed to clarify the long-term efficacy and safety of both regimens. PMID- 29387998 TI - Emotional and Behavioral Problems in Children and Adolescents in Central Kenya. AB - Emotional and behavioral problems (EBP) during childhood and adolescence are a common concern for parents and mental health stakeholders. However, little has been documented about their prevalence in Kenyan children and adolescents. This study aimed to close this gap. The study included Child Behavior Checklist reports from 1022 Kenyan parents on their children (ages 6-18 years) and Youth Self-Reports from 533 adolescents (ages 12-18) living in Kenya's Central Province. EBP in Kenya are highly prevalent compared to multi-cultural standards for parent reports, with 27 and 17% scoring in the borderline and clinical range, respectively. Based on parent reports, younger children scored higher on EBP than older children, and higher on internalizing problems. Based on self-reports girls scored higher than boys, particularly on internalizing problems. The study provides evidence on elevated parent-reported EBP in Kenyan youths. Mental health providers should focus on interventions that reduce EBP in Kenyan youths. PMID- 29387999 TI - Root caries prevention via sodium fluoride, chlorhexidine and silver diamine fluoride in vitro. AB - Uncertainty exists as to how to best prevent root caries development. The aim of the present study was to compare sodium fluoride (NaF), chlorhexidine (CHX) and silver diamine fluoride (SDF) varnishes (V) and rinses (R) regarding their caries preventive effect in an artificial caries biofilm model. 140 bovine root dentin samples were cut, polished and embedded. Samples were allocated to seven treatment groups (n = 20/group): Four varnishes (applied once prior biofilm challenge): 38% SDF (SDFV), 35% CHX-varnish (CHXV), 22,600 ppm NaF-varnish (NaFV), placebo-varnish (PV); two rinses (applied once daily during biofilm challenge): 500 ppm NaF solution (NaFR), 0.1% CHX solution (CHXR); one untreated group. Caries was induced in a multi-station, continuous-culture Lactobacillus rhamnosus GG (LGG) biofilm model. Bacteria were inoculated 1 * daily, while 2% sucrose was supplied 8 */day followed by artificial saliva for 10 min. After 12 days, mineral loss (DeltaZ) was measured in the effect area and adjacent to the varnished areas. Bacterial counts were assessed on de-Man-Rogosa-Sharpe agar. DeltaZ was significantly lower in the NaFR group compared with all other groups. Varnishes did not significantly prevent mineral loss in adjacent areas. None of the agents had a significant antimicrobial effect on LGG. Regular fluoride rinses showed highest root caries-preventive effect. PMID- 29388000 TI - [Defi catches on : Implementation of a curriculum for resuscitation in secondary schools]. AB - BACKGROUND: Sudden cardiac arrest is still one of the most frequent causes of death. Teaching resuscitation in schools was already successfully implemented in Scandinavian countries. Following a recommendation of the conference of german stateministers of education in June 2014, additional tuition for resuscitation is to be implemented in german schools starting in seventh grade. METHODS: The present study aimed to assess the level of knowledge of seventh grade students in the field of life support and to implement curricular standards for resuscitation courses in secondary schools. Using a standardized questionnaire, students in seventh grade of five schools in Cologne were interrogated about their knowledge on resuscitation and defibrillation. This assessment was taken as basis for developing a curricular teaching concept by the Cologne heart centre in cooperation with the department of biology and technical didactics at the University of Cologne. This tutorial concept was integrated in scholar plans for the first time in the school year 2014/2015. At the end of the school year the students' knowledge got reevaluated. RESULTS: As expected, the technical knowledge of the interviewed students is low, however confidence in their own abilities is high. Most of the interviewed persons would be willing to perform chest compressions (72,26%) and dare using an automated external defibrillator (AED, 64,38%). The exact position of defibrillator pads cannot be precisely indicated by most students (8,40%), compression point, -depth and -frequency are known by just one third of students. Already one-time performance of the live saving lesson resulted in a clear increase of knowledge about resuscitation. CONCLUSIONS: The willingness to perform resuscitation measures and confidence in their own abilities are high in seventh grade students. Therefore, the recommendation of the conference of german stateministers of education in June 2014 addresses the right target group. Long-term success of the presented educational concept will be analysed and reported in a longitudinal study. PMID- 29388001 TI - PPARbeta in yellow catfish Pelteobagrus fulvidraco: molecular characterization, tissue expression and transcriptional regulation by dietary Cu and Zn. AB - Peroxisome proliferator-activated receptor beta (PPARbeta) is a ligand-activated transcription factor that plays critical roles in the regulation of many important physiological processes. In this study, PPARbeta was cloned and characterized in yellow catfish Pelteobagrus fulvidraco. PPARbeta cDNA was 2350 bp in length with an open reading frame (ORF) of 1530 bp, encoding 509 amino acids, a 5'-untranslated region (UTR) of 474 bp, and a 3'-UTR of 346 bp. Similar to mammals, PPARbeta protein was predicted to consist of four domains, the A/B domain, DNA-binding domain (DBD), D domain, and ligand-binding domain (LBD). The DBD contained two zinc fingers with eight conserved cysteine residues. The predicted secondary structure of LBD consisted of 12 highly conserved alpha helices and a small beta-sheet of 4 strands. In addition, PPARbeta was widely expressed across the tested tissues (liver, heart, muscle, intestine, brain, spleen, kidney, fat, ovary, and gill), but at the variable levels. Furthermore, the transcriptional responses of PPARbeta by dietary Cu and Zn levels were also investigated. Dietary Cu levels showed no significant effects on PPARbeta mRNA levels in the liver and intestine; in contrast, dietary Zn levels upregulated the hepatic PPARbeta mRNA levels, but not in the intestine. The present study serves to increase our understanding into the function of the PPARbeta gene in fish. PMID- 29388002 TI - Leading God's People: Perceptions of Influence Among African-American Pastors. AB - Religious leaders, particularly African-American pastors, are believed to play a key role in addressing health disparities. Despite the role African-American pastors may play in improving health, there is limited research on pastoral influence. The purpose of this study was to examine African-American pastors' perceptions of their influence in their churches and communities. In-depth interviews were conducted with 30 African-American pastors and analyzed using a grounded theory approach. Three themes emerged: the historical role of the church; influence as contextual, with pastors using comparisons with other pastors to describe their ability to be influential; and a reciprocal relationship existing such that pastors are influenced by factors such as God and their community while these factors also aid them in influencing others. A conceptual model of pastoral influence was created using data from this study and others to highlight factors that influence pastors, potential outcomes and moderators as well as the reciprocal nature of pastoral influence. PMID- 29388003 TI - Autism Prevalence and Severity in Bedouin-Arab and Jewish Communities in Southern Israel. AB - The vast majority of autism spectrum disorder (ASD) research focuses on Caucasian populations in western world countries. While it is assumed that autism rates are similar across ethnic groups regardless of genetic background and environmental exposures, few studies have specifically examined how autism prevalence and severity may differ between majority and minority populations with distinct characteristics. Therefore, we evaluated ethnic differences in ASD prevalence and severity of Bedouin-Arab and Jewish children in the south of Israel. We compared demographic and clinical characteristics of 104 children from a Bedouin-Arab minority with 214 Jewish children who were referred to the main ASD clinic in Southern Israel with suspected communication disorders. Data were obtained from medical records. Jewish children's referral rates were almost 6 times more than that of Bedouin-Arab referral rates (21:1000 and 3.6:1000, respectively). The percentage of high functioning children with ASD was much higher in Jewish than in Bedouin-Arab children (29.6 and 2.6%, respectively). Bedouin-Arab children showed more severe autistic manifestations. Moreover, Bedouin-Arab children were more likely than Jewish children to have additional diagnosis of intellectual disability (14.5 and 6.9%, respectively). Autism prevalence and severity differs markedly between the Bedouin-Arab and Jewish populations in the south of Israel. Most striking is the almost complete absence of children with high-functioning autism in the Bedouin community. A better understanding of the causes for autism prevalence and severity differences across ethnic groups is crucial for revealing the impact of multiple genetic and environmental factors that may affect autism development in each group. PMID- 29388004 TI - A cost-conscious approach to robotic adrenalectomy. AB - In recent years, the use of robotic-assisted adrenalectomy (RA) has increased; however, many surgeons question its reported higher cost. In this study, we review our experience and strategies to reduce the cost of RA comparing it to Laparoscopic adrenalectomy (LA). Since May of 2010, 122 consecutive patients underwent minimally invasive adrenalectomy (58 RAs and 64 LA) by a high-volume adrenal surgeon at our institution. A cost analysis was performed for RA versus LA. Cost calculations included anesthesia professional fee, procedure time and consumables fees. The calculated relative costs were $3527 for RA and $3430 for LA (p = 0.59). The average anesthesia time was 172.4 and 178.3 min for RA and LA, respectively (p = 0.40). The mean procedure times (skin-skin) were 124.4 min for RA and 129.1 min for LA (p = 0.50). Procedure time for the retroperitoneal approach was significantly shorter than the transabdominal approach for both the RA (101.2 vs. 126.6 min, p = 0.001) and LA group (104.4 vs. 135.4 min, p = 0.001). The average consumables fees were $1106 for RA versus $1009 for LA (p = 0.62). The average post-operative hospital stay was 1.7 days for RA and 1.9 days for LA (p = 0.18). This study shows that anesthesia and procedure times for RA were similar to those of LA. It also demonstrates that limiting the number of robotic instruments and energy devices while utilizing an experienced surgical team can keep the costs of RA comparable to those of LA. PMID- 29388005 TI - Integration of a formal robotic-assisted surgical training program into obstetrics/gynecology residency curricula. PMID- 29388006 TI - Glycan recognition by human blood mononuclear cells with an emphasis on dendritic cells. AB - Dendritic cells (DCs) play crucial roles in innate and adaptive immune response, for which reason targeting antigen to these cells is an important strategy for improvement of vaccine development. To this end, we explored recognition of DCs lectins by glycans. For selection of the glycan "vector", a library of 229 fluorescent glycoprobes was employed to assess interaction with the CD14low/ CD16+CD83+ blood mononuclear cell population containing the DCs known for their importance in antigen presentation to T-lymphocytes. It was found that: 1) the glycan-binding profiles of this CD14low/-CD16+CD83+ subpopulation were similar but not identical to DCs of monocyte origin (moDCs); 2) the highest percentage of probe-positive cells in this CD14 low/-CD16+CD83+ subpopulation was observed for GalNAcalpha1-2Galbeta (Adi), (Neu5Acalpha)3 and three mannose-reach glycans; 3) subpopulation of CD14low/-CD16+ cells preferentially bound 4'-O-Su-LacdiNAc. Considering the published data on specificity of DCs binding, the glycans showing particular selectivity for the CD14 low/-CD16+CD83+ cells are likely interacting with macrophage galactose binding lectin (MGL), siglec-7 and dectin-2. In contrast, DC-SIGN is not apparently involved, even in case of mannose-rich glycans. Taking into consideration potential in vivo competition between glycan "vectors" and glycans within glycocalyx, attempting to target vaccine to DCs glycan-binding receptors should focus on Adi and (Neu5Acalpha)3 as the most promising vectors. PMID- 29388007 TI - The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma. AB - Immunotherapy plays an important role in cancer treatment. Biomarkers that can predict response, including tumor-infiltrating lymphocytes (TILs), are in the spotlight of many studies. This cohort study was designed to evaluate the role of CD4+ and CD8+ TILs as predictive factors for response to anti PD-1 treatment in patients with metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma. We evaluated the expression of CD4+ and CD8+ TILs in tissue samples of 56 patients with metastatic NSCLC or melanoma treated with anti-PD1 immunotherapy. The study included 30 patients with melanoma and 26 with NSCLC. An association was found between CD8+/CD4+ TILs ratio and response to anti-PD1 treatment in both cancers. Regarding melanoma patients, ratios of CD8+/CD4+ lower than 2 predicted lack of response to treatment (0%) (p = 0.006), while CD8+/CD4+ ratios higher than 2.7 had an 81.3% response rate (p = 0.0001). In addition, we found that the presence of more than 1900/mm2 of CD8+ lymphocytes in the melanoma tumor predicted a 90% response to therapy. In the metastatic NSCLC group, tumors with CD8+ lymphocyte count under 886/mm2 showed low response rates (16.7%, p = 0.046). When the CD8+ lymphocyte count was in the range of 886-1899/mm2, the response rate was high (60%, p = 0.017). In CD8+/CD4+ ratios lower than 2, the response rate was low (13.3%), and in ratios higher than 2, response rates ranged between 43 and 50% (p = 0.035). The use of CD8+/CD4+ TILs ratios in tumor biopsies may predict response to anti-PD1 treatment in metastatic melanoma and NSCLC. PMID- 29388008 TI - Biomarkers in Graft-Versus-Host Disease: from Prediction and Diagnosis to Insights into Complex Graft/Host Interactions. AB - PURPOSE OF REVIEW: Acute graft versus host disease (aGVHD) is a frequent cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation (alloHCT), with few effective treatment options beyond systemic steroids. Discovery of biomarkers for aGVHD may provide insight into the pathophysiology of aGVHD and suggest novel mechanisms for treatment. RECENT FINDINGS: We highlight biomarkers within innate immune activation, T-cell mediated tissue damage, endothelial damage, dysbiosis, and poor wound healing that can be obtained prior to transplant, in the early transplant period, or at the onset of aGVHD. aGVHD biomarkers have predictive and prognostic utility but also suggest novel mechanisms of recipient tissue damage and impaired regenerative capacity. These mechanisms should be further studied and tested in therapeutic clinical trials to improve outcomes post-alloHCT. PMID- 29388009 TI - Enhanced Production of Poly-gamma-glutamic acid by Overexpression of the Global Anaerobic Regulator Fnr in Bacillus licheniformis WX-02. AB - Poly-gamma-glutamic acid is a multi-functional biopolymer with various applications. ATP supply plays an important role in poly-gamma-glutamic acid (gamma-PGA) synthesis. Global anaerobic regulator Fnr plays a key role in anaerobic adaptation and nitrate respiration, which might affect ATP generation during gamma-PGA synthesis. In this study, we have improved gamma-PGA production by overexpression of Fnr in Bacillus licheniformis WX-02. First, the gene fnr was knocked out in WX-02, and the gamma-PGA yields have no significant differences between WX-02 and the fnr-deficient strain WXDeltafnr in the medium without nitrate (BFC medium). However, the gamma-PGA yield of 8.95 g/L, which was produced by WXDeltafnr in the medium with nitrate addition (BFCN medium), decreased by 74% compared to WX-02 (34.53 g/L). Then, the fnr complementation strain WXDeltafnr/pHY-fnr restored the gamma-PGA synthesis capability, and gamma PGA yield was increased by 13% in the Fnr overexpression strain WX/pHY-fnr (39.96 g/L) in BFCN medium, compared to WX/pHY300 (35.41 g/L). Furthermore, the transcriptional levels of narK, narG, and hmp were increased by 5.41-, 4.93-, and 3.93-fold in WX/pHY-fnr, respectively, which led to the increases of nitrate consumption rate and ATP supply for gamma-PGA synthesis. Collectively, Fnr affects gamma-PGA synthesis mainly through manipulating the expression level of nitrate metabolism, and this study provides a novel strategy to improve gamma-PGA production by overexpression of Fnr. PMID- 29388010 TI - Usefulness of acceleration time ratio in diagnosis of internal carotid artery origin stenosis. AB - PURPOSE: The acceleration time (AcT) ratio of the internal carotid artery (ICA) is increased in ICA stenosis. However, there are few reports that have directly compared the AcT ratio to digital subtraction angiography (DSA) findings. METHODS: We evaluated 177 vessels with DSA and carotid artery ultrasonography. The AcT ratio was calculated as AcT of the ICA (ICA-AcT)/AcT of the ipsilateral common carotid artery (CCA). We evaluated the correlation of DSA-NASCET stenosis with the origin of the ICA or the peak systolic velocity (ICApsv) in the stenotic region, ICApsv/peak systolic velocity of the CCA (CCApsv), ICA-AcT, and AcT ratio. Sensitivity and specificity for stenosis >= 70% were calculated based on the ICApsv, ICApsv/CCApsv, ICA-AcT, and AcT ratio. RESULTS: Using NASCET criteria, 34 vessels had 70% or greater stenosis. DSA-NASCET showed a significant positive correlation with ICApsv, ICApsv/CCApsv, ICA-AcT, and AcT ratio (p < 0.0001). When the cut-off value for ICApsv was set at 176 cm/s, ICApsv/CCApsv at 2.42, ICA-AcT at 0.095 s, and the AcT ratio at 1.35, the sensitivity was 97.1, 97.1, 82.4, and 97.1%, and the specificity was 94.4, 91.0, 83.2, and 83.2%, for DSA-NASCET >= 70%, respectively. CONCLUSION: The AcT ratio is a beneficial parameter for evaluating ICA stenosis as well as ICApsv and ICApsv/CCApsv. PMID- 29388011 TI - Pulmonary neuroendocrine carcinomas-evidence for a spectrum of differentiation. PMID- 29388012 TI - Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement. AB - Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI. PMID- 29388014 TI - The landscape of genetic alterations in ameloblastomas relates to clinical features. AB - Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey. In good agreement with previously published data, we observed BRAF mutations almost exclusively in mandibular tumors, SMO mutations predominantly in maxillary tumors, and single mutations in EGFR, KRAS, and NRAS. KRAS, NRAS, PIK3CA, PTEN, CDKN2A, FGFR, and CTNNB1 mutations co-occurred in the background of either BRAF or SMO mutations. Strikingly, multiple mutations were exclusively observed in European patients, in solid ameloblastomas and were associated with a very high risk for recurrence. In contrast, tumors with a single BRAF mutation revealed a lower risk for relapse. We here establish a comprehensive landscape of mutations in the MAPK and hedgehog signaling pathways relating to clinical features of ameloblastoma. Our data suggest that ameloblastomas harboring single BRAF mutations are excellent candidates for neo adjuvant therapies with combined BRAF/MEK inhibitors and that the risk of recurrence maybe stratified based on the mutational spectrum. PMID- 29388013 TI - Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. AB - Among lung neuroendocrine tumours (Lung-NETs), typical carcinoid (TC) and atypical carcinoid (AC) are considered separate entities as opposed to large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). By means of two-way clustering analysis of previously reported next-generation sequencing data on 148 surgically resected Lung-NETs, six histology-independent clusters (C1 -> C6) accounting for 68% of tumours were identified. Low-grade Lung-NETs were likely to evolve into high-grade tumours following two smoke-related paths. Tumour composition of the first path (C5 -> C1 -> C6) was coherent with the hypothesis of an evolution of TC to LCNEC, even with a conversion of SCLC featuring tumours to LCNEC. The second path (C4 -> C2-C3) had a tumour composition supporting the evolution of AC to SCLC-featuring tumours. The relevant Ki-67 labelling index varied accordingly, with median values being 5%, 9% and 50% in the cluster sequence C5 -> C1 -> C6, 12% in cluster C4 and 50-60% in cluster C2-C3. This proof-of-concept study suggests an innovative view on the progression of pre-existing TC or AC to high-grade NE carcinomas in most Lung-NET instances. PMID- 29388015 TI - Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies. AB - PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p <= 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size <= 1 versus > 1-2.5 cm (1.45, 1.47), age >= 50 versus < 50 year (0.61, 0.84) and year >= 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (<= 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making. PMID- 29388016 TI - A retrospective prognostic evaluation analysis using the 8th edition of the American Joint Committee on Cancer staging system for breast cancer. AB - PURPOSE: Breast cancer is a group of diseases with different intrinsic molecular subtypes. However, anatomic staging alone is insufficient to determine prognosis. The present study analyzed the prognostic value of the American Joint Committee for Cancer (AJCC) 8th edition cancer staging system. METHODS: This retrospective, single-center study included breast cancer cases diagnosed from January 1999 to December 2008. We restaged patients based on the 8th edition AJCC cancer staging system and analyzed the prognostic value of the anatomic and prognostic staged groups. Follow-up data including disease-free survival (DFS), overall survival (OS), and clinic-pathological data were collected to analyze the differences between the two staging subgroups. RESULTS: The study enrolled 7458 breast cancer patients with a 98.7-month median follow-up. Both the 5-year DFS and OS were significantly different between the anatomic and prognostic staged groups. The 5 year OS according to disease subtype was as follows: hormone receptor positive/human epidermal growth factor receptor 2-negative [HR(+)/HER2(-)], 90.9%; HR(+)/HER2(+), 84.7%; HR(-)/HER2(+), 81.1%; and HR(-)/HER2(-), 80.9%. According to the anatomic stage, the 5-year OS of patients with stage III HR(+)/HER2(-) disease was superior to that of patients with stage II HR(-)/HER2( ) disease (88.3 vs. 86.5%). Per the prognostic stage, both the 5-year DFS and OS rates of patients with stage II HR(-)/HER2(-) disease were higher than those of patients with stage III HR(+)/HER2(-) disease (90.1 and 94.3% vs. 79.1 and 88.9%). CONCLUSIONS: The prognostic staging system is a refined version of the anatomic staging system and encourages a more personalized approach to breast cancer treatment. PMID- 29388017 TI - Systematical analysis of lncRNA-mRNA competing endogenous RNA network in breast cancer subtypes. AB - BACKGROUND: Breast cancer is one of the most common solid tumors in women involving multiple subtypes. However, the mechanism for subtypes of breast cancer is still complicated and unclear. Recently, several studies indicated that long non-coding RNAs (lncRNAs) could act as sponges to compete miRNAs with mRNAs, participating in various biological processes. METHODS: We concentrated on the competing interactions between lncRNAs and mRNAs in four subtypes of breast cancer (basal-like, HER2+, luminal A and luminal B), and analyzed the impacts of competing endogenous RNAs (ceRNAs) on each subtype systematically. We constructed four breast cancer subtype-related lncRNA-mRNA ceRNA networks by integrating the miRNA target information and the expression data of lncRNAs, miRNAs and mRNAs. RESULTS: We constructed the ceRNA network for each breast cancer subtype. Functional analysis revealed that the subtype-related ceRNA networks were enriched in cancer-related pathways in KEGG, such as pathways in cancer, miRNAs in cancer, and PI3k-Akt signaling pathway. In addition, we found three common lncRNAs across the four subtype-related ceRNA networks, NEAT1, OPI5-AS1 and AC008124.1, which played specific roles in each subtype through competing with diverse mRNAs. Finally, the potential drugs for treatment of basal-like subtype could be predicted through reversing the differentially expressed lncRNA in the ceRNA network. CONCLUSION: This study provided a novel perspective of lncRNA involved ceRNA network to dissect the molecular mechanism for breast cancer. PMID- 29388018 TI - Endovascular Stent-Graft Repair of Spontaneous Isolated Dissection of the Superior Mesenteric Artery. AB - PURPOSE: The aim of this study was to determine the short-term clinical outcomes, safety, and efficacy of covered stents implantation for patients with spontaneous isolated dissection of the superior mesenteric artery (SMA). MATERIALS AND METHODS: Between October 2013 and December 2016, 12 patients (mean age, 50.0 +/- 6.2 years; range 38-62 years) with spontaneous isolated dissection of SMA received endovascular treatment with the placement of covered stents at our institution. Patients' clinical characteristics were analyzed including sex, age, medical history, risk factors, symptoms, and diagnostic imaging modality. The technical and clinical successes of covered stents placement were retrospectively analyzed. Standard follow-up protocol included abdominal computed tomography angiography and clinical examinations at 1, 3, 6, and 12 months and annually thereafter to confirm patients' general condition. RESULTS: All dissections were located at the anterior wall and around the convex curvature of SMA. The mean length of the SMA dissection was 37.8 +/- 31.5 mm (range 6.9-105.0 cm). Immediate technical success was defined as normal blood flow in the SMA and no contrast medium in the false lumen achieved in all patients. The mean duration of follow up was 26.9 +/- 7.2 months (range 16-36 months). Abdominal CT angiography demonstrated that no patients experienced endoleak or stent stenosis during follow-up. CONCLUSIONS: For symptomatic spontaneous isolated dissection of SMA in patients without aneurysms rupture and bowel necrosis, endovascular treatment with covered stents may be a safe and effective treatment option with a good short-term outcome. PMID- 29388019 TI - Volume Reduction in Enlarged Kidneys in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Prior to Renal Transplant with Transcatheter Arterial Embolization (TAE): A Systematic Review and Meta-Analysis. AB - PURPOSE: Symptomatically enlarged kidneys observed in autosomal dominant polycystic kidney disease (ADPKD) patients can lead to compression symptoms and contraindications to renal transplantation. Surgical nephrectomy can be utilized to increase space in the abdomen prior to renal transplantation; however, not all individuals are appropriate candidates for this procedure. Transcatheter arterial embolization (TAE) of the renal arteries can provide a noninvasive way to reduce renal volume in ADPKD. MATERIALS AND METHODS: We performed a systematic literature review on the usage of TAE to reduce renal volume prior to kidney transplantation and to relief compression symptoms in ADPKD. PubMed, Web of Science, and Cochrane Library were searched for articles focused on the usage of TAE to reduce renal volume in symptomatic enlarged kidneys. Renal volume data were compiled, and meta-analysis was performed with three or more studies. RESULTS: Six papers satisfied the inclusion and exclusion criteria. Significant renal volume reduction was observed by 12 months in all studies. Success of TAE was measured with three clinical outcomes: removal of contraindication for renal transplant, relief of compression symptoms, and pulmonary function test. Proportionality meta-analysis of three studies measuring relief of compression symptoms showed no significant differences in heterogeneity (p = 0.4543). CONCLUSION: Current studies conclude that TAE is an effective and minimally invasive option for reduction in renal volume in order to optimize patient outcome for renal transplantation and for relief of compression symptoms. Further prospective studies involving increased sample size and multiple centers should be pursued to establish evidence-based guidelines. PMID- 29388020 TI - Challenging TIPS in Liver Transplant Recipients: The Pull-Through Technique to Address Piggyback Anastomosis. AB - PURPOSE: The hepatic vein access during transjugular intrahepatic portosystemic shunt (TIPS) can be challenging in liver transplant recipient patients, especially when piggyback anastomosis was performed. We described a modified technique and reviewed the clinical outcomes of TIPS in transplanted patients. MATERIALS AND METHODS: From 2015 to 2016, 8 patients with history of liver transplantation using a three-hepatic vein piggyback technique for venous anastomosis underwent a TIPS in our institution. Indications were refractory ascites (n = 7) or variceal bleeding (n = 1). When the hepatic vein access failed via the standard jugular route, a pull-through technique was used: After puncturing the right hepatic vein under ultrasound guidance, a guidewire and a vascular sheath were advanced, then the guidewire was snared in the inferior vena cava and retrieved though the jugular access, and the hepatic vein was catheterized along the guidewire. The safety and technical success rates of this technique and the clinical outcomes of the study population were retrospectively assessed. RESULTS: Seven of 8 patients (87.5%) required the pull-through technique to access a hepatic vein. No complications of the percutaneous access of the hepatic vein were found at the one-day and one-month ultrasound Doppler examinations. Among 7 patients who had refractory ascites, 3 had complete resolution of ascites (43%), and one had moderate improvement. One patient with refractory infected ascites on severe graft failure and one with massive bleeding died soon after the procedure. CONCLUSION: A pull-through technique following percutaneous puncture of a hepatic vein is a safe technique for performing a TIPS in liver transplant recipients with piggyback anastomosis complicated by acute hepatic vein angulation. PMID- 29388021 TI - Relationship of aspiration pneumonia to cognitive impairment and oral condition: a cross-sectional study. AB - OBJECTIVES: The objective of this study was to investigate the relationship of the incidence of aspiration pneumonia to cognitive impairment and the oral condition. MATERIALS AND METHODS: A total of 1174 elderly patients were analyzed in a cross-sectional study. Cognitive function was evaluated by the Clinical Dementia Rating scale and the oral condition was evaluated by inspection and palpation. Swallowing was examined in 196 patients by video-endoscopic evaluation. The Mann-Whitney U test or chi-square test was used for statistical analysis. Conditional logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Loss of posterior occlusion, impaired tongue movements, and impaired cognition were factors significantly related to aspiration pneumonia. The incidence of aspiration pneumonia was higher in patients with both cognitive impairment and loss of posterior occlusion compared with those having either factor alone (OR: 5.16). There was no statistical association between impaired swallowing and the incidence of aspiration pneumonia in elderly patients with normal cognitive function (cognitive impairment, OR: 3.45; normal function, OR: 0.94). CONCLUSION: Co-existence of cognitive impairment and oral frailty significantly enhances the risk of aspiration pneumonia. CLINICAL RELEVANCE: Early and simple evaluation of the oral condition and cognitive function can predict the risk of aspiration pneumonia. PMID- 29388022 TI - Assessment of condylar morphology and position using MSCT in an Asian population. AB - OBJECTIVES: The purpose of the present study was to investigate the volume, surface, morphometric index (MI), and position of the condyle in a normal population by applying Mimics 17.0 software. Then, the difference between left and right sides, sex, and age can be explored, which will contribute to establish the reference value of condylar morphology and position in normal individuals, and help us to study characteristics of condylar morphology and position in abnormal individuals. MATERIALS AND METHODS: Three-hundred subjects were enrolled in our study from the radiology department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. They were divided into three groups according to the age: group 1 (18-24 years old), group 2 (25-34 years old), and group 3 (35 44 years old). Each group included 100 subjects (with 50 males and 50 females). They were examined using multislice computed tomography (MSCT) after that. All images of condyle were reconstructed by Mimics 17.0 software, so as to measure the volume, surface, and MI of condyle, and to analyze the position of condyle in the articular fossa by means of joint spaces. RESULTS: The differences of condylar volume, surface, and MI between left and right sides were not obvious (P > 0.05). The condylar volume and surface were greater in males than females (P < 0.05), while their condylar MI existed no difference (P > 0.05). No statistical differences were found in volume and surface among three age groups. However, the MI of group 1 was statistically lower than that of group 3 (P < 0.05). On the other hand, no significant differences were found between left and right condylar position (P > 0.05). Nevertheless, there were significant differences of condylar position regarding the gender and age (P < 0.05). CONCLUSIONS: This study showed no significant differences in condylar morphology and position between left and right sides, but factors of gender and age were proven to have a certain influence on the morphology and position of the condyle. This information can be clinically useful in establishing the diagnostic criteria for condylar morphology and position in the normal Asian population. CLINICAL RELEVANCE: Examination of condylar morphology and position is important for evaluating the abnormalities and bony changes that affect the temporomandibular joint (TMJ). So, this will be conducive to the diagnosis and the evaluation of therapeutic effect of temporomandibular joint diseases. Also, it is important to evaluate these indexes prior to commencing orthodontic treatment, because TMJ abnormalities play a critical role in orthodontic treatment planning. PMID- 29388023 TI - Effects of an oral bisphosphonate and three intravenous bisphosphonates on several cell types in vitro. AB - OBJECTIVE: To analyze the influence of an oral bisphosphonate and compare the potency to intravenous bisphosphonates on various cell types as regards the rarity of bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) caused by oral bisphosphonate. MATERIALS AND METHODS: A viability assay (MTT), a migration assay (Boyden chamber), and an apoptosis assay (Caspase-Glo(r) 3/7) were performed to analyze the effect of bisphosphonates on human fibroblasts, umbilical vein endothelial cells (HUVEC), and osteoblasts. RESULTS: Alendronate and intravenous bisphosphonates suppressed cell viability and migration, and induced apoptosis in all tested cell types. Alendronate had a greater impact than ibandronate on the characteristics in fibroblasts and osteoblasts but not as strong as zoledronate. CONCLUSIONS: The incidence of BP-ONJ in oral bisphosphonate treatment is reported to be much lower than that in intravenous bisphosphonates. However, the influences of alendronate on human cells were at least as strong as ibandronate, although it was lower than zoledronate. CLINICAL RELEVANCE: Alendronate showed strong enough effects to suppress human somatic cells and was comparable to certain intravenous bisphosphonates in potency. This study suggests that the lower incidence of BP-ONJ in alendronate treatment is not originated by its potency, but might be due to the low bioavailability of alendronate, lower dosing on a daily basis, and having no additional therapies. PMID- 29388024 TI - Intraspecific variation in exploratory behavior and elevational affinity in a widely distributed songbird. AB - Populations of the same species can vary substantially in their behavioral and morphometric traits when they are subject to different environmental pressures, which may lead to the development of different adaptive strategies. We quantified variation in exploratory behavior and morphometric traits among two rufous collared sparrow populations that occur at low and high elevations in central Chile. Moreover, we used census and delta2H values of feather and blood to evaluate migration. We found that individual sparrows inhabiting high elevations were larger and showed more intense exploratory behavior in comparison with those that were captured at lower elevation. Moreover, we observed a steady decline in sparrow abundance during the winter and similar delta2H values for blood collected in the winter and summer at this site, which were significantly lower than blood delta2H values observed at low elevation. This pattern suggests that individuals do not move long distances during winter, and likely they remain at similar elevations in refuge habitats. As predicted, our results support the existent of different adaptive strategies among populations of the same species, and suggest that the combination of behavioral, morphometric, and stable isotope data is a novel and robust integrative approach to assess differences in adaptation across environmental gradients. PMID- 29388025 TI - Spatial variation in anthropogenic mortality induces a source-sink system in a hunted mesopredator. AB - Lethal carnivore management is a prevailing strategy to reduce livestock predation. Intensity of lethal management varies according to land-use, where carnivores are more intensively hunted on farms relative to reserves. Variations in hunting intensity may result in the formation of a source-sink system where carnivores disperse from high-density to low-density areas. Few studies quantify dispersal between supposed sources and sinks-a fundamental requirement for source sink systems. We used the black-backed jackal (Canis mesomelas) as a model to determine if heterogeneous anthropogenic mortality induces a source-sink system. We analysed 12 microsatellite loci from 554 individuals from lightly hunted and previously unhunted reserves, as well as heavily hunted livestock- and game farms. Bayesian genotype assignment showed that jackal populations displayed a hierarchical population structure. We identified two genetically distinct populations at the regional level and nine distinct subpopulations at the local level, with each cluster corresponding to distinct land-use types separated by various dispersal barriers. Migration, estimated using Bayesian multilocus genotyping, between reserves and farms was asymmetric and heterogeneous anthropogenic mortality induced source-sink dynamics via compensatory immigration. Additionally some heavily hunted populations also acted as source populations, exporting individuals to other heavily hunted populations. This indicates that heterogeneous anthropogenic mortality results in the formation of a complex series of interconnected sources and sinks. Thus, lethal management of mesopredators may not be an effective long-term strategy in reducing livestock predation, as dispersal and, more importantly, compensatory immigration may continue to affect population reduction efforts as long as dispersal from other areas persists. PMID- 29388026 TI - Blinded by the light? Nearshore energy pathway coupling and relative predator biomass increase with reduced water transparency across lakes. AB - Habitat coupling is a concept that refers to consumer integration of resources derived from different habitats. This coupling unites fundamental food web pathways (e.g., cross-habitat trophic linkages) that mediate key ecological processes such as biomass flows, nutrient cycling, and stability. We consider the influence of water transparency, an important environmental driver in aquatic ecosystems, on habitat coupling by a light-sensitive predator, walleye (Sander vitreus), and its prey in 33 Canadian lakes. Our large-scale, across-lake study shows that the contribution of nearshore carbon (delta13C) relative to offshore carbon (delta13C) to walleye is higher in less transparent lakes. To a lesser degree, the contribution of nearshore carbon increased with a greater proportion of prey in nearshore compared to offshore habitats. Interestingly, water transparency and habitat coupling predict among-lake variation in walleye relative biomass. These findings support the idea that predator responses to changing conditions (e.g., water transparency) can fundamentally alter carbon pathways, and predator biomass, in aquatic ecosystems. Identifying environmental factors that influence habitat coupling is an important step toward understanding spatial food web structure in a changing world. PMID- 29388027 TI - Risk Assessment Integrated QbD Approach for Development of Optimized Bicontinuous Mucoadhesive Limicubes for Oral Delivery of Rosuvastatin. AB - Statins are widely prescribed for hyperlipidemia, cancer, and Alzheimer's disease but are facing some inherent challenges such as low solubility and drug loading, higher hepatic metabolism, as well as instability at gastric pH. So, relatively higher circulating dose, required for exerting the therapeutic benefits, leads to dose-mediated severe toxicity. Furthermore, due to low biocompatibility, high toxicity, and other regulatory caveats such as product conformity, reproducibility, and stability of conventional formulations as well as preferentially higher bioabsorption of lipids in their favorable cuboidal geometry, enhancement in in vivo biopharmaceutical performance of Rosuvastatin could be well manifested in Quality by Design (QbD) integrated cuboidal-shaped mucoadhesive microcrystalline delivery systems (Limicubes). Here, quality-target product-profile (QTPPs), critical quality attributes (CQAs), Ishikawa fishbone diagram, and integration of risk management through risk assessment matrix for failure mode and effects analysis (FMEA) followed by processing of Plackett Burman design matrix using different statistical test for the first time established an approach to substantiate the claims that controlling levels of only these three screened out independent process variables, i.e., Monoolein (B = 800-1100 MUL), Poloxamer (C = 150-200 mg), and stirring speed (F = 700-1000 rpm) were statistically significant to modulate and improve the biopharmaceutical performance affecting key attributes, viz., average particle size (Y1 = 1.40-2.70 MU), entrapment efficiency (Y2 = 62.60-88.80%), and drug loading (Y3 = 0.817 1.15%), in QbD-enabled process. The optimal performance of developed Limicubes exhibited an average particle size of 1.8 +/- 0.2 MU, entrapment efficiency 80.32 +/- 2.88%, and drug loading 0.93 +/- 0.08% at the level of 1100 MUL (+ 1), 200 mg (+ 1), and 700 rpm (- 1) for Monoolein, Poloxamer, and stirring speed, respectively. PMID- 29388028 TI - Total arch replacement versus debranching thoracic endovascular aortic repair for aortic arch aneurysm: what indicates a high-risk patient for arch repair in octogenarians? AB - OBJECTIVES: This study aimed to reveal the differences in intermediate outcomes between TAR and d-TEVAR in octogenarians and to identify risk factors for adverse events after aortic arch repair in octogenarians. METHODS: We reviewed medical records of 125 patients aged > 80 years who underwent surgical intervention for aortic aneurysm between 2008 and 2016. Of these, 60 underwent conventional TAR (43 men; age, 82 +/- 2.2 years) and 65 underwent d-TEVAR (49 men; age, 84 +/- 3.4 years). RESULTS: Freedom from all causes of mortality at 2 and 4 years was similar (80 and 66% in TAR, 80 and 51% in d-TEVAR, p = 0.17). Freedom from aortic death at 2 and 4 years was similar (88 and 88% in TAR, 87 and 76% in d-TEVAR, p = 0.86). Using Cox regression analysis, chronic obstructive pulmonary disease (COPD) [hazard ratio (HR), 6.0; p = 0.008], malignancy (HR, 8.8; p = 0.004), previous cardiac and thoracic aortic surgery (required median sternotomy) (HR, 65.9; p = 0.012), perioperative stroke (HR, 12.6; p = 0.012), and postoperative pneumonia (HR, 5.8; p = 0.026) were identified as independent positive predictors of overall postoperative mortality for TAR, whereas neurological dysfunction (HR, 3.0; p = 0.016) and perioperative stroke (HR, 12.1; p = 0.023) were identified for d-TEVAR. CONCLUSIONS: TAR in octogenarians with COPD and/or malignancy showed higher mortality rates; d-TEVAR is more appropriate in these situations. The prevention of perioperative stroke, which is related with poor prognosis in both the groups, is critical. PMID- 29388030 TI - The effect of subscapularis tenotomy in athletes operated on for recurrent anterior shoulder dislocation. AB - PURPOSE: Some authors consider preservation of the subscapularis tendon as one of the most important elements for a successful long-term outcome in patients operated on with open capsulorrhaphy for recurrent anterior shoulder dislocation. The purpose of this study was to evaluate whether vertical tenotomy of the subscapularis tendon might affect internal rotation strength recovery in patients operated on with open capsulorrhaphy for recurrent anterior shoulder dislocation. METHODS: Ninety-six patients were retrospectively followed up at a mean of 72.5 months. They underwent clinical evaluation, Rowe and Walch-Duplay scoring scales, the Visual Analog Scale (VAS), and dynamometric measurements (side-to-side) of internal and external rotation, forward elevation, and abduction. All patients were athletes: 25% were practising risk-free sports, 44% contact sports, 14.5% sports with cocking of the arm, and 14.5% high-risk sports activities. RESULTS: Five (5.2%) recurrences were registered, and all patients returned to pre operative sports activity. The Rowe score was 98.12, the Walch-Duplay score 92.25, and the VAS score 0.1. Dynamometric assessment showed no significant differences (side-to-side) in internal rotation (p = 0.34), external rotation (p = 0.9), flexion (p = 0.7), and abduction (p = 0.7). Dominant arms showed better results than non-dominant arms (p < 0.01). CONCLUSION: Complete tenotomy of the subscapularis tendon does not seem to negatively affect internal rotation strength recovery or external rotation movement in athletes. PMID- 29388029 TI - Longevity in vivo of primary cell wall cellulose synthases. AB - KEY MESSAGE: Our work focuses on understanding the lifetime and thus stability of the three main cellulose synthase (CESA) proteins involved in primary cell wall synthesis of Arabidopsis. It had long been thought that a major means of CESA regulation was via their rapid degradation. However, our studies here have uncovered that AtCESA proteins are not rapidly degraded. Rather, they persist for an extended time in the plant cell. Plant cellulose is synthesized by membrane embedded cellulose synthase complexes (CSCs). The CSC is composed of cellulose synthases (CESAs), of which three distinct isozymes form the primary cell wall CSC and another set of three isozymes form the secondary cell wall CSC. We determined the stability over time of primary cell wall (PCW) CESAs in Arabidopsis thaliana seedlings, using immunoblotting after inhibiting protein synthesis with cycloheximide treatment. Our work reveals very slow turnover for the Arabidopsis PCW CESAs in vivo. Additionally, we show that the stability of all three CESAs within the PCW CSC is altered by mutations in individual CESAs, elevated temperature, and light conditions. Together, these results suggest that CESA proteins are very stable in vivo, but that their lifetimes can be modulated by intrinsic and environmental cues. PMID- 29388031 TI - Synthesis of sulfur-containing heterocycles via ring enlargement. AB - The current review deals with the use of ring expansion reactions for the synthesis of sulfur-containing heterocycles. Ring enlargement offers by far a convenient method for the synthesis of 'medium-sized ring systems', which are usually difficult to obtain or even produced in low yields. These reactions are often catalytically processed starting from a single cyclic precursor and, therefore, are superior to alternative classical iterative synthetic approaches in terms of atomic and conversion efficiency. The current review aims to shed light on the synthetic approaches that exist to afford medium-sized sulfur heterocycles from preexisting smaller rings (e.g., three-, four-, five-, six- and seven-membered rings). PMID- 29388032 TI - The diagnostic value of preoperative inflammatory markers in craniopharyngioma: a multicenter cohort study. AB - To compare the different levels of preoperative inflammatory markers in peripheral blood samples between craniopharyngioma (CP) and other sellar region tumors so as to explore their differential diagnostic value. The level of white blood cell (WBC), neutrophil, lymphocyte, monocyte, platelet, albumin, neutrophil lymphocyte ratio (NLR), derived NLR (dNLR), platelet lymphocyte ratio (PLR), monocyte lymphocyte ratio (MLR) and prognostic nutritional index (PNI) were compared between the CP and other sellar region tumors. A receiver operating characteristics (ROC) curve analysis was performed to evaluate the diagnostic significance of the peripheral blood inflammatory markers and their paired combinations for CP including its pathological types. Patients with CP had higher levels of pre-operative WBC, lymphocyte and PNI. The papillary craniopharyngioma (PCP) group had higher neutrophil count and NLR than the adamantinomatous craniopharyngioma (ACP) and healthy control groups whereas the ACP group had higher platelet count and PNI than the PCP and healthy control groups. There were not any significant differences in preoperative inflammatory markers between the primary and recurrent CP groups. The AUC values of WBC, neutrophil, NLR + PLR and dNLR + PLR in PCP were all higher than 0.7. Inflammation seems to be closely correlated with CP's development. The preoperative inflammatory markers including WBC, neutrophil, NLR + PLR and dNLR + PLR may differentially diagnose PCP, pituitary tumor (PT) and Rathke cleft cyst (RCC). In addition, some statistical results in this study indirectly proved previous experimental conclusions and strictly matched CP's biological features. PMID- 29388033 TI - Rechallenge with bevacizumab in patients with glioblastoma progressing off therapy. AB - Rechallenge with temozolomide has been shown to be a valid option in selected patients with progressive glioblastoma. Herein, we assessed the efficacy of rechallenge with bevacizumab in glioblastoma patients progressing off therapy. We retrospectively identified and analyzed the characteristics of patients with glioblastoma rechallenged with a bevacizumab-based chemotherapy regimen after having received bevacizumab as first-line treatment in association with temozolomide radiochemotherapy or at recurrence in association with temozolomide, CCNU or irinotecan. Twenty-five patients were identified. In all included patients, the first bevacizumab treatment resulted in an objective response and was discontinued for reasons other than disease progression (adverse event n = 9, physician or patient decision n = 16). Median duration of first bevacizumab treatment was 6 months (range: 2-58 months). None of the patients presented a rebound effect after bevacizumab discontinuation. The median interval between discontinuation of first bevacizumab treatment and bevacizumab rechallenge was 8.9 months (range: 2-58 months). At this time, bevacizumab was given in association with lomustine (n = 17), temozolomide (n = 6), irinotecan (n = 1), or alone (n = 1). Bevacizumab rechallenge resulted in an objective response in 15 patients (60%). Median progression-free survival was 6.7 months and overall survival was 9.6 months after bevacizumab rechallenge. Timing of first bevacizumab treatment (as first-line treatment or at recurrence) was not associated with the duration of response after treatment rechallenge. In the present series, patients who responded to bevacizumab and in whom this treatment was discontinued in the absence of tumor progression seemed to benefit from rechallenge with a bevacizumab-based chemotherapy regimen. PMID- 29388034 TI - Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma. AB - We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age >= 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients >= 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age >= 70 with KPS >= 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment. PMID- 29388035 TI - Prior Authorization as a Potential Support of Patient-Centered Care. AB - We discuss the role of prior authorization (PA) in supporting patient-centered care (PCC) by directing health system resources and thus the ability to better meet the needs of individual patients. We begin with an account of PCC as a standard that should be aimed for in patient care. In order to achieve widespread PCC, appropriate resource management is essential in a healthcare system. This brings us to PA, and we present an idealized view of PA in order to argue how at its best, it can contribute to the provision of PCC. PA is a means of cost saving and as such it has mixed success. The example of the US demonstrates how implementation of PA has increased health inequalities whereas best practice has the potential to reduce them. In contrast, systems of universal coverage, like those in Europe, may use the cost savings of PA to better address individuals' care and PCC. The conclusion we offer therefore is an optimistic one, pointing towards areas of supportive overlap between PCC and PA where usually the incongruities are most evident. PMID- 29388036 TI - Anaplastic plasmacytoma: a rare tumor presenting as a pathological fracture in a younger adult. AB - Solitary plasmacytoma is the rarest type of plasma cell neoplasm, and the anaplastic form is even more uncommon. Plasmacytoma most commonly originates in bone and predominantly affects older patients. We describe the case of a 35-year old woman with solitary osseous anaplastic plasmacytoma that presented initially with a pathological fracture following minor trauma. The patient was immunocompetent and had no predisposing conditions for a plasma cell tumor. Left lower extremity radiographs revealed an oblique fracture of the distal femur, and CT imaging indicated a primary osseous lesion at the fracture site. MRI confirmed the diagnosis of pathological fracture. Initial surgical pathology of the lesion was concerning because it could have been an osteosarcoma. Further immunostaining demonstrated CD138 positivity and kappa light chain restriction, confirming the diagnosis of plasmacytoma. In addition, the presence of marked anaplastic cellular changes confirmed the anaplastic variant. Further workup showed no evidence of multiple myeloma. This case is unusual given the age and gender of the patient. Awareness of the anaplastic variant of plasmacytoma is important to avoid erroneous diagnoses. PMID- 29388038 TI - Bladder cancer presenting with acrometastases: a different cause of foot pain. AB - Acrometastasis means tumor seeding distally to the elbow or the knee and is an uncommon event. Foot acrometastases occur in 0.58% of patients with skeletal metastases overall, and only about 10% of these are caused by bladder cancer. We present a case of bladder cancer manifesting with insidious foot pain, caused by multiple lytic lesions located solely at the left foot. It was suspected after whole-body CT and later confirmed by biopsy result. We enumerate the differential diagnosis of distal extremity lytic lesions for educational purposes and review the literature listing similar published cases. PMID- 29388039 TI - Molecular assembly of recombinant chicken type II collagen in the yeast Pichia pastoris. AB - Effective treatment of rheumatoid arthritis can be mediated by native chicken type II collagen (nCCII), recombinant peptide containing nCCII tolerogenic epitopes (CTEs), or a therapeutic DNA vaccine encoding the full-length CCOL2A1 cDNA. As recombinant CCII (rCCII) might avoid potential pathogenic virus contamination during nCCII preparation or chromosomal integration and oncogene activation associated with DNA vaccines, here we evaluated the importance of propeptide and telopeptide domains on rCCII triple helix molecular assembly. We constructed pC- and pN-procollagen (without N- or C-propeptides, respectively) as well as CTEs located in the triple helical domain lacking both propeptides and telopeptides, and expressed these in yeast Pichia pastoris host strain GS115 (his4, Mut+) simultaneously with recombinant chicken prolyl-4-hydroxylase alpha and beta subunits. Both pC- and pN-procollagen monomers accumulated inside P. pastoris cells, whereas CTE was assembled into homotrimers with stable conformation and secreted into the supernatants, suggesting that the large molecular weight pC-or pN-procollagens were retained within the endoplasmic reticulum whereas the smaller CTEs proceeded through the secretory pathway. Furthermore, resulting recombinant chicken type II collagen pCalpha1(II) can induced collagen-induced arthritis (CIA) rat model, which seems to be as effective as the current standard nCCII. Notably, protease digestion assays showed that rCCII could assemble in the absence of C- and N-propeptides or telopeptides. These findings provide new insights into the minimal structural requirements for rCCII expression and folding. PMID- 29388037 TI - Pseudotumor in metal-on-metal hip arthroplasty: a comparison study of three grading systems with MRI. AB - OBJECTIVE: Pseudotumors, a well-known complication of metal-on-metal total hip arthroplasty (MoM THA), are well identified on metal artifact-reducing sequences magnetic resonance imaging (MARS-MRI). Several MRI grading systems are described in the orthopedic literature, but their validity is unknown in large clinical studies. Our study was undertaken to describe the classification of pseudotumors in a preselected cohort divided into high- and low-risk patients, using three pseudotumor grading systems applied on MARS-MRI, and to determine the interobserver reliability of the grading systems. PATIENTS AND METHODS: A retrospective study was performed on 377 consecutive patients (240 MRI scans) treated with an M2a-38 and Taperloc stem combination (Biomet, Warsaw, IN, USA). Patients were divided into a high-risk and a low-risk group based on previous published risk factors. Two observers determined the presence of pseudotumors using three different pseudotumor grading systems for classifying MARS-MRI results. RESULTS: The prevalence of pseudotumors as determined with MARS-MRI was 59% in our high-risk group, 0% in the low-risk group and 43% in the control group. Serum cobalt values were increased in the high-risk group. The kappa values of the Anderson, Hauptfleisch and Matthies grading system scores were 0.43, 0.44, and 0.49 respectively. CONCLUSIONS: High-risk patients are at a high risk for pseudotumor development. No pseudotumor development was found in low risk patients. Interobserver reliability scored best with the Matthies system, but all three grading systems showed only a moderate agreement. PMID- 29388040 TI - Microbial treatment in chronic constipation. AB - Chronic functional constipation is a kind of common intestinal disease that occurs in children, adults and elderly people. This disease not only causes great influence to physiological function, but also results in varying degrees of psychological barriers. At present, constipation treatments continue to rely on traditional methods such as purgative therapy and surgery. However, these approaches can disrupt intestinal function. Recent research between intestinal diseases and gut microbiota has gradually revealed a connection between constipation and intestinal flora disturbance, providing a theoretical basis for microbial treatment in chronic constipation. Microbial treatment mainly includes probiotic preparations such as probiotics, prebiotics, synbiotics and fecal microbiota transplantation (FMT). Due to its safety, convenience and curative effect, probiotic preparations have been widely accepted, especially gradually developed FMT with higher curative effects. Microbial treatment improves clinical symptoms, promotes the recovery of intestinal flora, and has no complications during the treatment process. Compared with traditional treatments, microbial treatment in chronic constipation has advantages, and is worthy of further promotion from clinical research to clinical application. PMID- 29388041 TI - Post-infarct cardiac injury, protection and repair: roles of non-cardiomyocyte multicellular and acellular components. AB - Following myocardial infarction (MI), cardiomyocytes and infarct size are the focus of our attention when evaluating the extent of cardiac injury, efficacy of therapies or success in repairing the damaged heart by stem cell therapy. Numerous interventions have been shown by pre-clinical studies to be effective in limiting infarct size, and yet clinical trials designed accordingly have yielded disappointing outcomes. The ultimate goal of cardiac protection is to limit the adverse cardiac remodeling. Accumulating studies have revealed that post-infarct remodeling can be attenuated without infarct size limitation. To reconcile this, one needs to appreciate the significance of various cellular and acellular myocardial components that, like cardiomyocytes, undergo significant damage and dysfunction, which impact the ultimate cardiac injury and remodelling. Microvascular injury following ischemia-reperfusion may influence infarct size and promote inflammation. Myocardial injury evokes innate immunity with massive inflammatory infiltration that, although essential for the healing process, exacerbates myocardial injury and damage to extracellular matrix leading to dilative remodeling. It is also important to consider the multiple non cardiomyocyte components in evaluating therapeutic efficacy. Current research indicates the pivotal role of these components in achieving cardiac regeneration by cell therapy. This review summarizes findings in this field, highlights a broad consideration of therapeutic targets, and recommends cardiac remodeling as the ultimate target. PMID- 29388043 TI - Longitudinal AddiQoL scores may identify higher risk for adrenal crises in Addison's disease. AB - PURPOSE: Several studies have shown a reduced quality of life (QoL) in patients with Addison's disease (AD), but investigations of QoL over a long-term course are lacking. Adrenal crises (AC) are life-threatening complications in AD. The purpose of this prospective study was to test whether the repeated use of QoL questionnaires can detect prodromal periods of an AC. METHODS: 110 patients with AD were asked to complete the disease specific-QoL questionnaire AddiQoL and a short questionnaire about adverse events once monthly over a period of ten months. AC was defined if at least two of the following symptoms were reported: (a) hypotension, (b) nausea or vomiting, (c) severe fatigue, (d) documented hyponatremia, hyperkalemia, or hypoglycemia, and subsequent parenteral glucocorticoid administration was carried out. RESULTS: Prevalence of AC was 10.9/100 patient years. AddiQoL scores in patients with AC showed a trend (p = 0,08) to a wider fluctuation over time. Subjective precrises not meeting the criteria for AC were reported by 31 patients who had significantly lower AddiQoL scores (p = 0,018). CONCLUSIONS: These are the first data showing the course of QoL during a period of ten months in patients with AD. Incidence of AC exceeds previous data. Our data show, that subjective precrises in AD associate with lower QoL. AC, as well as precrises affect intraindividual AddiQol-scores over time with a trend to a stronger fluctuation. Longitudinal AddiQol scores and self reporting of precrises via patient diaries are additional clinical tools to identify higher risk for critical events. PMID- 29388042 TI - Prenatal Maternal Distress: A Risk Factor for Child Anxiety? AB - The deleterious association between various types of prenatal maternal psychological distress (PNMS, anxiety, depression, psychological distress, stress) and childhood anxiety symptomatology (internalizing behaviors, anxiety symptoms) has been established using both retrospective and prospective longitudinal studies across varied demographic cohorts and throughout development. Yet, the existing literature cannot claim maternal distress during pregnancy to be a specific risk factor for anxiety symptomatology, as studies utilizing such observational designs are unable to adequately account for confounding of potential genetic factors and the postnatal environment. In this review, we examine studies that attempt to minimize such confounding and thus disentangle the unique intrauterine exposure effect of varying types of PNMS on childhood anxiety symptomatology. Such methodologies include paternal versus maternal comparison studies, sibling comparisons, prenatal cross-fostering designs and timing of exposure studies (including disaster studies). Of the identified studies, findings indicate that prenatal maternal distress is likely to constitute a risk factor for anxiety symptomatology, although more studies are needed to replicate current findings in order to determine whether there are clear differences in effects across specific types of PNMS and for specific subpopulations. We review the methodological limitations and strengths of the literature prior to exploring avenues of future research and implications for theory and clinical practice. PMID- 29388044 TI - MiR-145 improves macrophage-mediated inflammation through targeting Arf6. AB - PURPOSE: To explore the relationship between miR-145 and ADP ribosylation factor 6 (Arf6) in regulating macrophage-mediated inflammation. METHODS: THP-1 cells were induced by 160 nM of phorbol 12-myristate 13-acetate (PMA) for 48 h to differentiate to macrophages and then were treated with LPS (100 ng/ml) for 8 h to simulate chronic metabolic inflammation in vitro. Dual-luciferase reporter assay was performed. MiR-145 siRNA and LV-ARF6-RNAi were used to up or down regulate miR-145 and Arf6 expression in THP-1 cells, respectively. Omental adipose tissue from patients in surgical ward were collected to detect the expression of miR-145, Arf6 and production of proinflammatory cytokines. Patients were divided into three groups according to their body mass index and history of diabetes. RESULTS: Dual-luciferase reporter assays showed the direct down regulation of Arf6 by miR-145. Forty-eight-hour-transfection of miR-145 inhibitor resulted in significant increase of Arf6, IL-1beta, TNF-alpha and IL-6 as well as phosphorylation of p65 in NF-kappaB pathway in THP-1 cells, which, inversely, were reversed by overexpressing miR-145. In addition, down-regulation of Arf6 in macrophages reduced expression and secretion of cytokines. Expression of miR-145 was found to be attenuated in the omental adipose tissue of obese patients and diabetics with greater Arf6 expression, confirming the role of miR-145 in regulating macrophage-mediated inflammation targeting Arf6. CONCLUSIONS: By means of reducing the expression of Arf6 and subsequent signal transduction via NF kappaB, miR-145 plays a role in inhibiting the secretion of inflammatory factors and then improving the inflammatory status. MiR-145 might be one of the candidates for anti-inflammatory treatment for metabolic diseases. PMID- 29388045 TI - IGF-1-based screening reveals a low prevalence of acromegaly in patients with obstructive sleep apnea. AB - PURPOSE: Recent epidemiologic studies suggest a high prevalence of acromegaly. The prevalence of obstructive sleep apnea syndrome (OSAS) in acromegaly patients ranges from 47 to 70%. A recent study identified 2 patients with acromegaly among 567 OSAS patients. However, it remains unclear whether screening for acromegaly among OSAS patients is necessary. The aim was to screen for acromegaly among OSAS patients by measuring IGF-1 levels and performing confirmatory tests if necessary. METHODS: We performed a prospective cross-sectional diagnostic study on the prevalence of acromegaly in patients with OSAS. A total of 507 patients with a confirmed diagnosis of OSAS (357 male, 150 female) were screened. RESULTS: Seven male and three female patients (1.97% of total) were positively screened for elevated IGF-1 levels. Nine out of ten patients suppressed growth hormone levels during OGTT excluding acromegaly, whereas one individual was identified to have acromegaly according to established criteria (1/507, prevalence 0.2%). Analysis of the data showed no correlation between elevated IGF-1 values and the severity of OSAS or BMI. CONCLUSIONS: Our data demonstrate a low prevalence of acromegaly in patients with OSAS. Until data from population-based studies is available we suggest restricting screening for acromegaly in OSAS to those patients who have additional clinical features of acromegaly. PMID- 29388046 TI - The effect of vitamin D supplementation on thyroid autoantibody levels in the treatment of autoimmune thyroiditis: a systematic review and a meta-analysis. AB - PURPOSE: Although observational studies suggested that vitamin D plays a role in autoimmune thyroiditis (AIT), intervention trials yielded inconsistent findings. We therefore conducted a systematic review and a meta-analysis to evaluate the effects of Vitamin D on decreasing autoantibodies in patients with AIT. METHOD: We identified all studies that assessed the changes of TPO-Ab and Tg-Ab in patients with AIT under the treatment of vitamin D from PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and VIP Database. RESULTS: Six randomized controlled trials (RCTs) were included in this systematic review representing a total of 344 patients with AIT. The results showed that Vitamin D supplementation significantly dropped TPO-Ab titers [three studies, random effects standardized mean difference (SMD): -1.11, 95% CI -1.52 to -0.70, P < 0.01] at six months, but not at no more than 3 months [random effects SMD: -0.12, 95% CI: -0.69 to 0.44, P = 0.67]. As compared with control group, participants who received vitamin D supplementation demonstrated significantly lower Tg-Ab [random effects SMD: -0.55, 95% CI: -1.05 to -0.04, P = 0.033]. In addition, no serious adverse effect was reported. CONCLUSIONS: The current evidence suggests that vitamin D supplementation could decrease serum TPO Ab and Tg-Ab titers of patients with AIT in the short-term (about six months). More high quality studies are needed to further confirm the effects, especially the long-term effects of Vitamin D supplementation on thyroid autoantibodies levels in the treatment of AIT. PMID- 29388047 TI - Self-reported protein intake and properties of bone in community-dwelling older individuals. AB - : This study revealed that a quick and simple estimation of protein intake was related to measures of bone density and area in 70-year-old individuals. Furthermore, these associations were mediated by muscle mass when investigating peripheral measurement sites such as arms and legs. PURPOSE: Recent evidence suggests that dietary protein is beneficial for bone health in older individuals, but less is known about the influence of muscle mass on this relationship. This cross-sectional study aimed to investigate associations among protein intake, bone health, and muscle mass in 2332 men and women aged 70 years. METHODS: Volumetric bone mineral density of the radius and tibia was measured using peripheral quantitative computed tomography. Using dual-energy X-ray absorptiometry, we measured areal bone mineral density (aBMD) at the L1-L4 vertebrae, radius, and femoral neck, together with appendicular lean mass. Participants reported their average meal size and proportion of meat/fish intake. Associations were investigated using multiple linear regression models, adjusted for multiple covariates. RESULTS: Self-reported protein intake was associated with aBMD of the femoral neck (beta = 0.082) and L1-L4 vertebrae (beta = 0.063) in men (both p < 0.05) after adjusting for multiple covariates, including appendicular muscle mass. No significant association was detected among women. In addition, protein intake was associated with tibial cortical area (beta = 0.08), periosteal circumference (beta = 0.072), radial aBMD (beta = 0.064), and trabecular area (beta = 0.078) in men (all p < 0.05), although these associations were attenuated after adjustment for appendicular muscle mass (all p > 0.05). CONCLUSION: Self-reported protein intake was associated with bone properties in 70-year-old men. The strength of these associations in peripheral bone sites may be partially mediated by muscle mass from protein intake. PMID- 29388049 TI - Does Marijuana Use at Ages 16-18 Predict Initiation of Daily Cigarette Smoking in Late Adolescence and Early Adulthood? A Propensity Score Analysis of Add Health Data. AB - Given the declining trend in adolescent cigarette smoking and increase in general access to marijuana, it is important to examine whether marijuana use in adolescence is a risk factor for subsequent cigarette smoking in late adolescence and early adulthood. Preliminary evidence from a very small number of studies suggests that marijuana use during adolescence is associated with later smoking; however, to control confounding, previously published studies used regression adjustment, which is susceptible to extrapolation when the confounder distributions differ between adolescent marijuana users and non-users. The current study uses propensity score weighting, a causal inference method not previously used in this area of research, to weight participants based on their estimated probability of exposure given confounders (the propensity score) to balance observed confounders between marijuana users and non-users. The sample consists of participants of Add Health (a nationally representative dataset of youth followed into adulthood) who were 16-18, with no history of daily cigarette smoking at baseline (n = 2928 for female and 2731 for male sub-samples). We assessed the effect of adolescent marijuana use (exposure, ascertained at wave 1) on any daily cigarette smoking during the subsequent 13 years (outcome, ascertained at wave 4). Analyses suggest that for females (but not males) who used marijuana in adolescence, marijuana use increased the risk for subsequent daily smoking: OR = 1.71, 95% CI = (1.13, 2.59). We recommend that adolescent marijuana use be viewed as a possible risk factor for subsequent initiation of daily cigarette smoking in women. PMID- 29388048 TI - Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis. AB - PURPOSE: To explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis. METHODS: Patients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics). Independent genotyping and two-phase data transfer mitigated bias. The primary analysis compared the effect of DrotAA in IRP+ and IRP- groups on in-hospital 28-day mortality. Secondary endpoints included time to death in hospital; intensive care unit (ICU)-, hospital-, and ventilator-free days; and overall DrotAA treatment effect on mortality. RESULTS: Six hundred and ninety-two patients treated with DrotAA were successfully matched to 1935 patients not treated with DrotAA. Genotyping was successful for 639 (DrotAA) and 1684 (nonDrotAA) matched patients. The primary hypothesis of a genotype-by-treatment interaction (assessed by conditional logistic regression analysis) was not significant (P = 0.30 IRP A; P = 0.78 IRP B), and there was no significant genotype by treatment interaction for any secondary endpoint. CONCLUSIONS: Neither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality. ClinicalTrials.gov registration NCT01486524. PMID- 29388050 TI - Aspiration Therapy As a Tool to Treat Obesity: 1- to 4-Year Results in a 201 Patient Multi-Center Post-Market European Registry Study. AB - PURPOSE: The objective of this post-market study was to evaluate long-term safety and efficacy of aspiration therapy (AT) in a clinical setting in five European clinics. MATERIALS AND METHODS: The AspireAssist(r) System (Aspire Bariatrics, Inc. King of Prussia, PA) is an endoscopic weight loss therapy utilizing a customized percutaneous endoscopic gastrostomy tube and an external device to aspirate approximately 30% of ingested calories after a meal, in conjunction with lifestyle counseling. A total of 201 participants, with body mass index (BMI) of 35.0-70.0 kg/m2, were enrolled in this study from June 2012 to December 2016. Mean baseline BMI was 43.6 +/- 7.2 kg/m2. RESULTS: Mean percent total weight loss at 1, 2, 3, and 4 years, respectively, was 18.2% +/- 9.4% (n/N = 155/173), 19.8% +/- 11.3% (n/N = 82/114), 21.3% +/- 9.6% (n/N = 24/43), and 19.2% +/- 13.1% (n/N = 12/30), where n is the number of measured participants and N is the number of participants in the absence of withdrawals or lost to follow-up. Clinically significant reductions in glycated hemoglobin (HbA1C), triglycerides, and blood pressure were observed. For participants with diabetes, HbA1C decreased by 1% (P < 0.0001) from 7.8% at baseline to 6.8% at 1 year. The only serious complications were buried bumpers, experienced by seven participants and resolved by removal/replacement of the A-Tube, and a single case of peritonitis, resolved with a 2-day course of intravenous antibiotics. CONCLUSION: This study establishes that aspiration therapy is a safe, effective, and durable weight loss therapy in people with classes II and III obesity in a clinical setting. TRIAL REGISTRATION: ISRCTN 49958132. PMID- 29388051 TI - Cognitive Development of Toddlers: Does Parental Stimulation Matter? AB - OBJECTIVE: To examine the impact of quality of early stimulation on cognitive functioning of toddlers living in a developing country. METHODS: The developmental functioning of 150 toddlers in the age range of 12-30 mo (53% boys; Mean = 1.76 y, SD = 0.48) was assessed by the mental developmental index of the Developmental Assessment Scale for Indian Infants (DASII). The StimQ questionnaire- toddler version was used to measure cognitive stimulation at home. The questionnaire consists of four subscales including availability of learning materials (ALM), reading activities (READ), parent involvement in developmental activities (PIDA), and parent verbal responsivity (PVR). Multivariate regression analysis was used to predict cognitive scores using demographic (age of child), socio-economic status (SES) (income, parental education), and home environment (subscale scores of StimQ) as independent variables. RESULTS: Mean Mental Development Index (MDI) score was 91.5 (SD = 13.41), nearly one-fifth (17.3%) of the toddlers had MDI scores less than 80 (cognitive delay). Children with cognitive delay, relative to typically developing (TD, MDI score >= 80) cohort of toddlers, had significantly lower scores on all the subscales of StimQ and the total StimQ score. Despite the overall paucity of learning materials available to toddlers, typical developing toddlers were significantly more likely to have access to symbolic toys (P = 0.004), art materials (P = 0.032), adaptive/fine motor toys (P = 0.018), and life size toys (P = 0.036). Multivariate regression analysis results indicated that controlling for confounding socio-economic status variables, higher parental involvement in developmental activities (PIDA score) and higher parental verbal responsivity (PVR score) emerged as significant predictors of higher MDI scores and explained 34% of variance in MDI scores (F = 23.66, P = 0.001). CONCLUSIONS: Disparities in child development emerge fairly early and these differences are not all linked to economic disparities. There is a need to develop evidence-based parenting interventions for primary prevention of developmental problems, especially in resource poor countries. PMID- 29388052 TI - Imaging of non-neoplastic duodenal diseases. A pictorial review with emphasis on MDCT. AB - : A wide spectrum of abnormalities can affect the duodenum, ranging from congenital anomalies to traumatic and inflammatory entities. The location of the duodenum and its close relationship with other organs make it easy to miss or misinterpret duodenal abnormalities on cross-sectional imaging. Endoscopy has largely supplanted fluoroscopy for the assessment of the duodenal lumen. Cross sectional imaging modalities, especially multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI), enable comprehensive assessment of the duodenum and surrounding viscera. Although overlapping imaging findings can make it difficult to differentiate between some lesions, characteristic features may suggest a specific diagnosis in some cases. Familiarity with pathologic conditions that can affect the duodenum and with the optimal MDCT and MRI techniques for studying them can help ensure diagnostic accuracy in duodenal diseases. The goal of this pictorial review is to illustrate the most common non malignant duodenal processes. Special emphasis is placed on MDCT features and their endoscopic correlation as well as on avoiding the most common pitfalls in the evaluation of the duodenum. TEACHING POINTS: * Cross-sectional imaging modalities enable comprehensive assessment of duodenum diseases. * Causes of duodenal obstruction include intraluminal masses, inflammation and hematomas. * Distinguishing between tumour and groove pancreatitis can be challenging by cross sectional imaging. * Infectious diseases of the duodenum are difficult to diagnose, as the findings are not specific. * The most common cause of nonvariceal upper gastrointestinal bleeding is peptic ulcer disease. PMID- 29388053 TI - miR15a and miR16 in Chilean type 1 diabetes patients: possible association with apoptosis, inflammatory, or autoimmunity markers. AB - AIM: Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by the progressive destruction of beta cells, mediated by the interaction between T cells and several cytokines. The pathogenesis of T1D has established its possible relationship with miRNAs. In this study, we analyze the expression profile of miR 15a and miR-16 in peripheral blood mononuclear cells (PBMCs) and their possible association with apoptosis, inflammation, or autoimmunity markers. PATIENTS AND METHODOLOGY: 38 T1D patients and 41 control subjects were recruited. mRNAs were analyzed by means of qPCR and TaqMan probes. PBMCs were treated with different concentrations of glucose (baseline, 11 and 25 mM) with or without an inflammatory stimulus as TNF-alpha (10 ng/ml). RESULTS: A decrease in the levels of the miR-15a expression in basal conditions is observed in T1D patients compared to healthy control subjects (relative units 0.5 vs. 1.8, p < 0.05). This change in miR-15a and miR-16 is not affected by the addition of TNF-alpha. No association is observed with inflammatory markers (IL-6, TNF-alpha, vCAM) or apoptosis (bcl2 expression). The relationship with immunological markers shows an interaction effect between miR16 and IA-2 (p < 0.03). CONCLUSION: TNF-alpha does not affect the expression profile of miR-15a and miR16 in PBMCs. A weak correlation is observed between miR-16 and with the autoimmunity profile (IA-2 autoantibody). PMID- 29388054 TI - p16, p21, and p53 proteins play an important role in development of pancreatic intraepithelial neoplastic. AB - BACKGROUND: Deregulation of cell cycle takes place during the development of many cancers as well as pancreatic ductal adenocarcinoma (PDA), which develops from precursor lesions, most frequently including pancreatic intraepithelial neoplasia (PanIN). AIMS: The aim of this study was to evaluate and compare the expression of p16, p21, and p53 proteins taking part in the regulation of the cell cycle in normal pancreatic ducts and pancreatic intraepithelial neoplasia at its various advancing stages. METHODS: The expressions of p16, p21, and p53 were assessed immunohistochemically in 70 patients with different pancreatic diseases (pancreatic ductal adenocarcinoma, pancreatitis, and pancreatic cysts), showing also pancreatic intraepithelial neoplasia. The results correlated with chosen clinicopathological parameters. RESULTS: Our study revealed a difference in p16, p21, and p53 expressions between normal pancreatic ducts and various stages of PanIN. p16 expression progressively decreased, whereas p21 and p53 increased from normal pancreas to PanIN 1, 2, and 3. The expression of p21 was associated with age, p53 with PanIN location in the pancreas and p16 with the type of primary diseases. Simultaneously, we observed a directly proportional relationship between the expression of p21 and p53 proteins and inversely proportional between the p16 and the p21 and p53 proteins. CONCLUSIONS: p16, p21, and p53 proteins play an important role in the deregulation of the cell cycle and participate in the development of pancreatic intraepithelial neoplasia. Immunohistochemical evaluation of their expressions may be helpful in the diagnosis of PanIN. PMID- 29388056 TI - Treatment Preferences in Germany Differ Among Apheresis Patients with Severe Hypercholesterolemia. AB - BACKGROUND: Severe hypercholesterolemia is a major risk factor of death in patients with coronary heart disease. New adjunctive drug therapies (proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) have gained approval in Europe and the USA. OBJECTIVE: In this empirical study, we documented preferences regarding adjuvant drug therapy in apheresis-treated patients with severe familial hypercholesterolemia. METHODS: We conducted a systematic literature search to identify patient-relevant outcomes in patients with severe hypercholesterolemia currently undergoing apheresis. Data were used to generate a semi-structured qualitative interview that enabled seven patient-relevant characteristics with three levels each to be identified. For the discrete choice experiment, an experimental design (7 * 3) was generated using NGene Software that consisted of 96 choices divided into eight blocks. The survey was conducted between November 2015 and April 2016 using computer-assisted personal interviews. RESULTS: The survey was completed by 348 patients (64.9% male). The random parameter logit estimation showed predominance for the attribute 'reduction of LDL-C (low-density lipoprotein cholesterol) level'. 'Risk of myopathy' and 'frequency of apheresis' dominated next. Within the random parameter logit estimation, all coefficients were significant (P <= 0.01). The latent class analysis identified three patient groups. The first group (126 patients) found 'reduction of LDL-C level in blood' to be most important. This group focused solely on this treatment outcome independently of apheresis frequency or additional injections. The second group (106 patients) focused on three attributes: 'frequency of apheresis', 'risk of myopathy', and 'reduction of LDL-C level in blood'. Respondents clearly considered a high frequency of apheresis to have a negative impact. The third group (116 patients) demonstrated the highest preference for apheresis. These patients have adjusted to apheresis for > 10 years. CONCLUSION: Regarding patient preference, clinical efficacy seems to dominate. Hence, 'reduction of LDC-C in blood' was ranked highest above patient relevant modes of administration and adverse effects. In the patient groups identified, reduction of apheresis was important for only a subsegment (30%) of patients. Another 30% wanted effective LDL-C reduction by whatever means necessary. Most strikingly, another 30% preferred higher frequencies of apheresis. PMID- 29388055 TI - Prosthetic versus surgical rehabilitation in patients with maxillary defect regarding the quality of life: systematic review. AB - PURPOSE: To assess the ability of prosthetic rehabilitation versus surgical rehabilitation in improving the QOL for patients with maxillary defects. MATERIAL AND METHODS: A systematic search of PubMed, Scopus data base, Cochrane database, Ovid database, and Latin America & Caribbean database for articles published before September 2017 was performed by two independent reviewers. A manual search of articles published from January 2000 to September 2017 was also conducted. Only English studies were included which evaluate the QoL in patients with head and neck cancers. Any confusion between the two independent reviewers was resolved by means of a moderated discussion between the reviewers. RESULTS: Five studies fulfilled the inclusion criteria for this study. Many parameters were used regarding evaluation of QOL as the EORTC Head and Neck 35 assessment, UW QOL, OHIP-14, VAS, OFS, MHI, HAD, Body Satisfaction Scale, Oral symptom check list, Swallowing, Diet consist, Pain control, Postoperative complication, and Speech. Two studies supported the surgical line of treatment for improving the QOL as compared to the prosthetic one; another two studies showed a statistically insignificant improvement in the patients' QOL with the surgical line, while only one revealed insignificant difference in QoL with both lines of treatment. CONCLUSIONS: Surgical rehabilitation provides a better line of treatment in improving the QOL for patients with maxillary defects. On the other hand, prosthetic has proved effectiveness in the immediate post-surgical times as temporary strategy, and it has represented a good alternative when the surgical obturation is compromised. PMID- 29388057 TI - Utility of Radionuclide Bone Scintigraphy in Complex Regional Pain Syndrome. AB - PURPOSE OF REVIEW: To describe the current understanding of the role of three phase bone scintigraphy (TPBS) in the diagnosis and management of complex regional pain syndrome (CRPS), discuss its advantages and limitations, and present three examples of TPBS patterns typically seen in CRPS patients. RECENT FINDINGS: CRPS is a debilitating disorder frequently presenting with pain to ordinarily non-painful stimuli, redness, swelling, following fractures, stroke, myocardial infarction, surgery, or even minor trauma, and its diagnosis, based on clinical criteria and supportive imaging findings, is difficult. Of the available adjunctive diagnostic imaging modalities, radionuclide bone scintigraphy using a TPBS protocol is the most sensitive and specific for detecting abnormalities commonly seen with this condition-classically, increased periarticular uptake on delayed phase of TPBS, with variable increased uptake on perfusion phases, depending on chronicity. Recent studies have (1) demonstrated a more heterogeneous correlation of TPBS findings with CRPS diagnosis using the current Budapest criteria than in studies using older criteria, (2) pointed to the utility of novel quantitative scintigraphic techniques, and (3) highlighted the value of the early perfusion phases of TPBS in predicting treatment response. TPBS remains a valuable imaging adjunct to clinical diagnosis of CRPS. In combination with a multi-modal analgesic approach, TPBS can be used to follow disease course and potentially treatment response, although prospective trials are needed to further delineate its role. PMID- 29388059 TI - Retroperitoneal Mucinous Neoplasm Arising from Colonic Duplication Cyst. PMID- 29388060 TI - How Is Rectal Cancer Managed: a Survey Exploring Current Practice Patterns in Canada. AB - INTRODUCTION: Locally advanced rectal cancers are most often treated with neoadjuvant chemoradiation followed by surgical resection. However, there are differing opinions surrounding management of rectal cancer, including a lack of consensus on the optimal time interval between chemoradiation and surgery, and the management of patients with complete clinical response following neoadjuvant therapy. This study seeks to summarize management trends for rectal cancer among a sample of Canadian surgeons. METHODS: A 14-question survey was distributed to surgeons across Canada managing rectal cancer. Surgeons were identified from the membership lists of the Canadian Association of General Surgeons and the Canadian Society of Colon and Rectal Surgeons. Web-based questionnaires were distributed by email. RESULTS: A total of 115 surgeons were emailed the survey with a response rate of 38.4%. Approximately 50% of surgeon responders had been in practice for more than 10 years, with the majority practicing in academic centers. Half were considered high-volume rectal cancer surgeons with more than 20 cases per year. All surgeons used magnetic resonance imaging for staging of rectal cancer, but only 50% presented all rectal cancer cases at multidisciplinary cancer conferences. The majority of surgeons applied minimally invasive techniques for surgical resection, including the utilization of transanal endoscopic microsurgery (TEMs) and transanal minimally invasive surgery (TAMIS); however, only a small fraction performed high-volume transanal total mesorectal excision (taTME). Regarding the management of complete clinical response (cCR) following neoadjuvant chemoradiation, less than 5% chose the watch and wait management strategy for all patients and 40% did not use it at all. The majority of surgeons reported waiting between eight and 10 weeks between chemoradiation and surgery, and 40% made that decision regardless of patient or tumor factors. CONCLUSION: The majority of surveyed surgeons use MRI for pelvic staging and discuss rectal cancer cases at multidisciplinary cancer conference. Many are using minimally invasive techniques; however, the use of taTME is not yet widespread. Surgeons currently favor longer intervals from neoadjuvant chemoradiation to surgery, and the management strategy for patients with complete clinical response remains controversial. Great variability exists in rectal cancer management, thus presenting an opportunity for improvements by adopting standardization and centralization of rectal cancer management. PMID- 29388058 TI - Effect of systemic administration of lipopolysaccharides derived from Porphyromonas gingivalis on gene expression in mice kidney. AB - Although an association between periodontitis and chronic kidney disease (CKD) has been suggested, the mechanism involved remains unclear. Herein, we examined the global gene expression profile in a mouse model that showed no acute inflammation in the kidney following stimulation with lipopolysaccharides (LPS) derived from Porphyromonas gingivalis (PG-LPS). The mice were injected with PG LPS at a concentration of 5 mg/kg intraperitoneally, every 3 days, for 1 month. Microarray analysis was used to identify 10 genes with the highest expression levels in the kidney stimulated with PG-LPS. Among them, the functions of five genes (Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1) were known. The upregulation of these genes was confirmed by quantitative polymerase chain reaction assay. Furthermore, we examined whether the expression of these upregulated genes were altered in endothelial cells derived from the kidney, in vitro. The mRNA expression levels of all five genes were significantly higher in the experimental group than in the controls (no LPS stimulation; *p < 0.05). In conclusion, the responses noted in the kidney may have arisen mainly from the endothelial cells. Moreover, upregulation of the expression levels of Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1 may be associated with the pathogenesis of CKD. PMID- 29388061 TI - Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results. AB - BACKGROUND: Understanding the molecular mechanisms of colorectal cancer has evolved during the last decade ushering the era of personalized medicine. Alteration of BRAF and PI3K is common in colorectal cancer, and can affect several signaling pathways including EGFR (epidermal growth factor receptor). The aim of this meta-analysis is to evaluate the clinical role of PI3K and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer (MCRC) receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor as first-line therapy. METHODS: A literature search was performed to identify studies exploring the association between PI3K/BRAF mutations and clinical outcomes of KRAS wild type mCRC patients treated with anti-EGFR as a first-line therapy. The primary clinical outcome was overall response rate (ORR). The secondary outcomes included progression-free survival (PFS) and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effect model or random effect model according to heterogeneity between studies. RESULTS: Ten studies with 1470 mCRC patients (357 for PI3K studies and 1113 from BRAF studies) met selection criteria. We observed a trend towards lower ORR in patients with PI3K mutations (3 studies, 357 patients; ORR = 14.3% in mutant-type PI3K vs. 52.4% in wild-type PIK3CA [95% CI - 0.12-0.02]; P = 0.13). Patients with mutant type PI3K have significant shorter PFS (3 studies, 357 patients, 3.8 vs. 4.15 months, HR = 1.36; [95% CI 1.04-1.77]; P = 0.02]), and OS (3 studies, 357 patients, 14.17 vs. 16.3 months, HR = 1.50; [95% CI 1.14-1.97]; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significantly lower ORR (7 studies, 1113 patients; ORR = 33% vs. 39%; [95% CI - 0.16-0.01]; P = 0.03), shorter PFS (5 studies, 814 patients, 3.9 vs. 5.7 months, HR = 1.72; [95% CI 1.47-2.01]; P = 0.00001), and shorter OS (4 studies, 766 pts., 9.1 vs. 18.9 months, HR = 1.22; [95% CI 1.04-1.44]; P = 0.01) compared to those with wild-type. CONCLUSION: This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K. PMID- 29388062 TI - Are Oximes Still Indicated for Acute Organophosphorus Insecticide Self-Poisoning? PMID- 29388063 TI - Medical Cannabis for Neuropathic Pain. AB - PURPOSE OF REVIEW: Many cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications. Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain. RECENT FINDINGS: We examined current basic scientific research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain. These studies involved patients with diverse etiologies of neuropathic pain and included medical cannabis with different THC concentrations and routes of administration. Multiple RCTs demonstrated efficacy of medical cannabis for treating neuropathic pain, with number needed to treat (NNT) values similar to current pharmacotherapies. Although limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain. The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoid ratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain. PMID- 29388064 TI - Hiding behind the veil: an ominous chest X-ray. PMID- 29388065 TI - Radial artery spasm treatment by radial, median, or musculocutaneous nerve block? A potential therapeutic dilemma. PMID- 29388066 TI - Infections in patients on BCR-ABL tyrosine kinase inhibitor therapy: cases and review of the literature. AB - The introduction of BCR-ABL-tyrosine kinase inhibitors (TKI) for treatment of hematologic malignancies has made a significant impact on patient outcome. Contingent upon their targeted and off-target activity, therapy-associated infectious complications may occur. We present a case of cytomegalovirus pneumonitis and a case of adenovirus hemorrhagic cystitis in two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia on BCR-ABL TKI treatment and review the literature to summarize the infectious complications based on clinical data. As life-threatening infections may occur, treating physicians should maintain a heightened awareness in patients treated with BCR ABL TKIs. Based on the frequent reports of hepatitis B virus (HBV) reactivation under the treatment BCR-ABL TKIs, screening for and prophylactic therapy of chronic HBV infection should be considered. Similarly, patients would benefit from screening for and treatment of latent tuberculosis. PMID- 29388069 TI - Development of SCoT-Based SCAR Marker for Rapid Authentication of Taxus Media. AB - Taxus media is an important species in the family Taxaceae with high medicinal and commercial value. Overexploitation and illegal trade have led T. media to a severe threat of extinction. In addition, T. media and other Taxus species have similar morphological traits and are easily misidentified, particularly during the seedling stage. The purpose of this study is to develop a species-specific marker for T. media. Through a screening of 36 start codon targeted (SCoT) polymorphism primers, among 15 individuals of 4 Taxus species (T. media, T. chinensis, T. cuspidate and T. fuana), a clear species-specific DNA fragment (amplified by primer SCoT3) for T. media was identified. After isolation and sequencing, a DNA sequence with 530 bp was obtained. Based on this DNA fragment, a primer pair for the sequence-characterized amplified region marker was designed and named MHSF/MHSR. PCR analysis with primer pair MHSF/MHSR revealed a clear amplified band for all individuals of T. media but not for T. chinensis, T. cuspidate and T. fuana. Therefore, this marker can be used as a quick, efficient and reliable tool to identify T. media among other related Taxus species. The results of this study will lay an important foundation for the protection and management of T. media as a natural resource. PMID- 29388068 TI - Characterizing left ventricular mechanical and electrical activation in patients with normal and impaired systolic function using a non-fluoroscopic cardiovascular navigation system. AB - PURPOSE: Cardiac disease frequently has a degenerative effect on cardiac pump function and regional myocardial contraction. Therefore, an accurate assessment of regional wall motion is a measure of the extent and severity of the disease. We sought to further validate an intra-operative, sensor-based technology for measuring wall motion and strain by characterizing left ventricular (LV) mechanical and electrical activation patterns in patients with normal (NSF) and impaired systolic function (ISF). METHODS: NSF (n = 10; ejection fraction = 62.9 +/- 6.1%) and ISF (n = 18; ejection fraction = 35.1 +/- 13.6%) patients underwent simultaneous electrical and motion mapping of the LV endocardium using electroanatomical mapping and navigational systems (EnSiteTM NavXTM and MediGuideTM, Abbott). Motion trajectories, strain profiles, and activation times were calculated over the six standard LV walls. RESULTS: NSF patients had significantly greater motion and systolic strains across all LV walls than ISF patients. LV walls with low-voltage areas showed less motion and systolic strain than walls with normal voltage. LV electrical dyssynchrony was significantly smaller in NSF and ISF patients with narrow-QRS complexes than ISF patients with wide-QRS complexes, but mechanical dyssynchrony was larger in all ISF patients than NSF patients. The latest mechanical activation was most often the lateral/posterior walls in NSF and wide-QRS ISF patients but varied in narrow-QRS ISF patients. CONCLUSIONS: This intra-operative technique can be used to characterize LV wall motion and strain in patients with impaired systolic function. This technique may be utilized clinically to provide individually tailored LV lead positioning at the region of latest mechanical activation for patients undergoing cardiac resynchronization therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01629160. PMID- 29388070 TI - Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response. AB - Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients. PMID- 29388073 TI - Vertical modeling: analysis of competing risks data with a cure fraction. AB - In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set. PMID- 29388067 TI - Oncogenic and Tumor-Suppressive Roles of MicroRNAs with Special Reference to Apoptosis: Molecular Mechanisms and Therapeutic Potential. AB - MicroRNAs (miRNAs) are the non-coding class of minute RNA molecules that negatively control post-transcriptional regulation of various functional genes. These miRNAs are transcribed from the loci present in the introns of functional or protein-coding genes, exons of non-coding genes, or even in the 3' untranslated region (3'-UTR). They have potential to modulate the stability or translational efficiency of a variety of target RNA [messenger RNA (mRNA)]. The regulatory function of miRNAs has been elucidated in several pathological conditions, including neurological (Alzheimer's disease and Parkinson's disease) and cardiovascular conditions, along with cancer. Importantly, miRNA identification in cancer progression and invasion has evolved as an incipient era in cancer treatment. Several studies have shown the influence of miRNAs on various cancer processes, including apoptosis, invasion, metastasis and angiogenesis. In particular, apoptosis induction in tumor cells through miRNA has been extensively studied. The biphasic mode (up- and down-regulation) of miRNA expression in apoptosis and other cancer processes has already been determined. The findings of these studies could be utilized to develop potential therapeutic strategies for the management of various cancers. The present review critically describes the oncogenic and tumor suppressor role of miRNAs in apoptosis and other cancer processes, therapy resistance, and use of their presence in the body fluids as biomarkers. PMID- 29388072 TI - Pharmacotherapeutic Management of Breast Cancer in Elderly Patients: The Promise of Novel Agents. AB - As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level. Breast cancer biology has been incompletely deciphered in this age group. New therapeutic agents continue to expand the available treatment options at every stage, and for each subtype of breast cancer. In the estrogen receptor-positive subtype, agents to overcome endocrine resistance have been introduced; CDK 4/6 and mTOR inhibitors have already been approved in this setting. In addition, more potent agents targeting the HER2 pathway are actively being trialed. Besides trastuzumab, pertuzumab, or lapatinib, new agents like neratinib or PI3K inhibitors are currently being tested in clinical trials. Finally, even though chemotherapy remains the cornerstone of the treatment of triple negative tumors, alternative promising approaches such as immunotherapy, notably antibodies against PD-1/PD-L1 or targeted therapies (PARP or androgen inhibitors), are currently being investigated in this specific subtype. PMID- 29388074 TI - Correction to: Aerobic but not Resistance Exercise Can Induce Inflammatory Pathways via Toll-Like 2 and 4: a Systematic Review. AB - ERRATUM: The original article [1] mistakenly omits a grant acknowledgement; thus, the authors would like to acknowledge that the original article was supported by FAPESP 2015/20082-7. PMID- 29388071 TI - Yoga for the Management of Cancer Treatment-Related Toxicities. AB - PURPOSE OF REVIEW: To (1) explain what yoga is, (2) summarize published literature on the efficacy of yoga for managing cancer treatment-related toxicities, (3) provide clinical recommendations on the use of yoga for oncology professionals, and (4) suggest promising areas for future research. RECENT FINDINGS: Based on a total of 24 phase II and one phase III clinical trials, low intensity forms of yoga, specifically gentle hatha and restorative, are feasible, safe, and effective for treating sleep disruption, cancer-related fatigue, cognitive impairment, psychosocial distress, and musculoskeletal symptoms in cancer patients receiving chemotherapy and radiation and cancer survivors. Clinicians should consider prescribing yoga for their patients suffering with these toxicities by referring them to qualified yoga professionals. More definitive phase III clinical trials are needed to confirm these findings and to investigate other types, doses, and delivery modes of yoga for treating cancer related toxicities in patients and survivors. PMID- 29388075 TI - MR-based motion correction for cardiac PET parametric imaging: a simulation study. AB - BACKGROUND: Both cardiac and respiratory motions bias the kinetic parameters measured by dynamic PET. The aim of this study was to perform a realistic positron emission tomography-magnetic resonance (PET-MR) simulation study using 4D XCAT to evaluate the impact of MR-based motion correction on the estimation of PET myocardial kinetic parameters using PET-MR. Dynamic activity distributions were obtained based on a one-tissue compartment model with realistic kinetic parameters and an arterial input function. Realistic proton density/T1/T2 values were also defined for the MRI simulation. Two types of motion patterns, cardiac motion only (CM) and both cardiac and respiratory motions (CRM), were generated. PET sinograms were obtained by the projection of the activity distributions. PET image for each time frame was obtained using static (ST), gated (GA), non-motion corrected (NMC), and motion-corrected (MC) methods. Voxel-wise unweighted least squares fitting of the dynamic PET data was then performed to obtain K1 values for each study. For each study, the mean and standard deviation of K1 values were computed for four regions of interest in the myocardium across 25 noise realizations. RESULTS: Both cardiac and respiratory motions introduce blurring in the PET parametric images if the motion is not corrected. Conventional cardiac gating is limited by high noise level on parametric images. Dual cardiac and respiratory gating further increases the noise level. In contrast to GA, the MR based MC method reduces motion blurring in parametric images without increasing noise level. It also improves the myocardial defect delineation as compared to NMC method. Finally, the MR-based MC method yields lower bias and variance in K1 values than NMC and GA, respectively. The reductions of K1 bias by MR-based MC are 7.7, 5.1, 15.7, and 29.9% in four selected 0.18-mL myocardial regions of interest, respectively, as compared to NMC for CRM. MR-based MC yields 85.9, 75.3, 71.8, and 95.2% less K1 standard deviation in the four regions, respectively, as compared to GA for CRM. CONCLUSIONS: This simulation study suggests that the MR-based motion-correction method using PET-MR greatly reduces motion blurring on parametric images and yields less K1 bias without increasing noise level. PMID- 29388077 TI - Description of Komagataella mondaviorum sp. nov., a new sibling species of Komagataella (Pichia) pastoris. AB - Five methylotrophic strains (UCDFST 71-1024T, UCDFST 54-11.16, UCDFST 54-11.141, UCDFST 68-967.1 and UCDFST 74-1030) from the Phaff Yeast Culture Collection (University of California Davis, USA) that were originally designated as Pichia pastoris were found to represent a novel Komagataella species. Strains of Komagataella mondaviorum sp. nov. UCDFST 71-1024T(type strain) = CBS 15017, UCDFST 54-11.16, UCDFST 54-11.141, UCDFST 68-967.1, and UCDFST 74-1030 were isolated in USA, respectively, from cottonwood tree Populus deltoides in 1971 (Davis, CA), slime flux of Quercus sp. in 1954 (CA), exudate of black oak Q. kelloggii in 1954 (Central Sierra Nevada. CA), dry frass from Salix sp. in 1968 (Soleduck Road, Olympic National Park, WA) and from flux of hackberry tree Celtis sp. in 1974 (CA). The new species was differentiated from Komagataella kurtzmanii, Komagataella pastoris, Komagataella phaffii, Komagataella populi, Komagataella pseudopastoris and Komagataella ulmi by divergence in gene sequences for D1/D2 LSU rRNA, ITS1-5.8S-ITS2, RNA polymerase subunit I and translation elongation factor-1alpha. Komagataella mondaviorum sp. nov. is registered in MycoBank under MB 821789. PMID- 29388078 TI - Complications and recurrence rates of patients with Ehlers-Danlos syndrome undergoing ventral hernioplasty: a case series. AB - PURPOSE: Ventral hernia repair is one of the most frequently performed surgical procedures, though recurrences are common. Recurrence can be caused by impaired collagen formation or maturation; hence, patients with Ehlers-Danlos syndrome (EDS) are potentially at increased risk for hernia recurrence. EDS causes altered collagen metabolism, though little is known about the influence of EDS on ventral hernioplasty outcomes. This study aims to analyze these patients to report complication rates, recurrence rates, and, if possible, to give recommendations for surgical intervention. METHODS: A retrospective analysis between January 2000 and January 2017 was performed in a university hospital Belgium (UZ Ghent). Data on baseline characteristics, primary surgery, and hernias were extracted from patients' medical charts. Noted endpoints were postoperative complications and recurrences. RESULTS: Fourteen patients (50% males) were included. Ten (71%) had an incisional hernia and four (29%) had a primary ventral hernia. Median age was 45 years (IQR 37.75-52.75), median BMI was 24.82 (IQR 22.43-26.87). Four patients (29%) smoked, one patient (7.1%) had diabetes mellitus, and five patients (36%) had an aneurysm of the abdominal aorta. All patients underwent elective open hernioplasty with mesh reinforcement. Three patients (21%) had a postoperative complication (two infections, one seroma). Recurrence rate was 7.1% (one patient). CONCLUSIONS: This series describes 14 patients with a median follow-up of 50 months and a recurrence rate of 7.1%. The low recurrence rate could be explained by the use of large meshes that reinforce the entire midline to compensate for the reduced collagen strength in EDS patients. PMID- 29388076 TI - Rotavirus Vaccines: Effectiveness, Safety, and Future Directions. AB - Rotavirus is the leading cause of diarrheal death among children < 5 years old worldwide, estimated to have caused ~ 215,000 deaths in 2013. Prior to rotavirus vaccine implementation, > 65% of children had at least one rotavirus diarrhea illness by 5 years of age and rotavirus accounted for > 40% of all-cause diarrhea hospitalizations globally. Two live, oral rotavirus vaccines have been implemented nationally in > 100 countries since 2006 and their use has substantially reduced the burden of severe diarrheal illness in all settings. Vaccine efficacy and effectiveness estimates suggest there is a gradient in vaccine performance between low child-mortality countries (> 90%) and medium and high child-mortality countries (57-75%). Additionally, an increased risk of intussusception (~ 1-6 per 100,000 vaccinated infants) following vaccination has been documented in some countries, but this is outweighed by the large benefits of vaccination. Two additional live, oral rotavirus vaccines were recently licensed and these have improved on some programmatic limitations of earlier vaccines, such as heat stability, cost, and cold-chain footprint. Non-replicating rotavirus vaccines that are parenterally administered are in clinical testing, and these have the potential to reduce the performance differential and safety concerns associated with live oral rotavirus vaccines. PMID- 29388079 TI - Comment to: What is the evidence for the use of biologic or biosynthetic meshes in abdominal wall reconstruction. F. Kockerling, N. N. Alam, S. A. Antoniou, I. R. Daniels, F. Famiglietti, R. H. Fortelny, M. M. Heiss, F. Kallinowski, I. Kyle Leinhase, F. Mayer, M. Miserez, A. Montgomery, S. Morales-Conde, F. Muysoms, S. K. Narang, A. Petter-Puchner, W. Reinpold, H. Scheuerlein, M. Smietanski, B. Stechemesser, C. Strey, G. Woeste, N. J. Smart. PMID- 29388080 TI - What is the evidence for the use of biologic or biosynthetic meshes in abdominal wall reconstruction? AB - INTRODUCTION: Although many surgeons have adopted the use of biologic and biosynthetic meshes in complex abdominal wall hernia repair, others have questioned the use of these products. Criticism is addressed in several review articles on the poor standard of studies reporting on the use of biologic meshes for different abdominal wall repairs. The aim of this consensus review is to conduct an evidence-based analysis of the efficacy of biologic and biosynthetic meshes in predefined clinical situations. METHODS: A European working group, "BioMesh Study Group", composed of invited surgeons with a special interest in surgical meshes, formulated key questions, and forwarded them for processing in subgroups. In January 2016, a workshop was held in Berlin where the findings were presented, discussed, and voted on for consensus. Findings were set out in writing by the subgroups followed by consensus being reached. For the review, 114 studies and background analyses were used. RESULTS: The cumulative data regarding biologic mesh under contaminated conditions do not support the claim that it is better than synthetic mesh. Biologic mesh use should be avoided when bridging is needed. In inguinal hernia repair biologic and biosynthetic meshes do not have a clear advantage over the synthetic meshes. For prevention of incisional or parastomal hernias, there is no evidence to support the use of biologic/biosynthetic meshes. In complex abdominal wall hernia repairs (incarcerated hernia, parastomal hernia, infected mesh, open abdomen, enterocutaneous fistula, and component separation technique), biologic and biosynthetic meshes do not provide a superior alternative to synthetic meshes. CONCLUSION: The routine use of biologic and biosynthetic meshes cannot be recommended. PMID- 29388081 TI - Loss of Angelman Syndrome Protein E6AP Disrupts a Novel Antagonistic Estrogen Retinoic Acid Transcriptional Crosstalk in Neurons. AB - Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2-15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A, which is located in this region, and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e.g., autism and Rett syndromes). We have shown that E6AP also acts as a coactivator of the estrogen receptor (ER). ER is a ligand-induced transcription factor that exerts potent and wide-ranging effects on the developing brain. Furthermore, the expression pattern of ER in the brain overlaps with that of E6AP. Up till now, all the published studies have examined the role of the ubiquitin-protein ligase activity of E6AP in the development of AS, and it is not known what role the newly discovered coactivation functions of E6AP and ER plays in the pathology of AS. Here, we demonstrate that E6AP and ER co-immunoprecipitate and are in the same protein complex in neuronal cells (Neuro2a). In addition, both colocalize in nuclear and cytoplasmic compartments of the mouse hippocampal neurons and Neuro2a cells. Moreover, we identified a novel E6AP and ER direct transcriptional regulation of a gene Cyp26b1 known to be involved in learning and memory processes. This transcriptional regulation involves recruitment of E6AP and ER to a newly discovered functional estrogen response element (ERE) located at the Cyp26b1 gene promoter and is associated with transcription permissive epigenetic events leading to increase of active transcription of the gene in neurons upon estrogen treatment. This novel transcriptional regulation was also validated in the AS mouse model where E6AP expression is abrogated in the mouse brain. In fact, Cyp26b1 expression is decreased by 31% in AS mice versus age-matched control (Ctrl) mice hippocampi. Also, retinoic acid transcriptional signaling was shown to be amplified as evidenced by specific increased Rarbeta and decreased Erbb4 mRNA expression in AS mice versus Ctrl mice hippocampi. These transcript level changes were also supported by the same trend of changes at the protein level. Collectively, our data present a proof of principle that the transcriptional coactivation function of E6AP may have a crucial role in the pathobiology of AS. This function, yet to be thoroughly investigated, reveals the possibility of harnessing the antagonistic estrogen-retinoic acid transcriptional signaling crosstalk and potentially other unknown effectors for the investigation of important possible targets as putative novel treatment modalities and venues for reversing neurological manifestations in AS and related syndromes like ASDs. PMID- 29388082 TI - Brain-Derived Neurotrophic Factor Prevents Depressive-Like Behaviors in Early Symptomatic YAC128 Huntington's Disease Mice. AB - Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic stage of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of HD and can occur a decade before the manifestation of motor symptoms. We used the YAC128 transgenic mice (which develop motor deficits at a later stage, allowing more time to study depressive behaviors without the confounding effects of motor impairment) to test the effects of intranasal brain-derived neurotrophic factor (BDNF) treatment for 15 days in the occurrence of depressive-like behaviors. Using multiple well validated behavioral tests, we found that BDNF treatment alleviated anhedonic and depressive-like behaviors in the YAC128 HD mice. Furthermore, we also investigated whether the antidepressant-like effects of BDNF were associated with an increase in adult hippocampal neurogenesis. However, BDNF treatment only increased cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of wild-type (WT) mice, without altering these parameters in their YAC128 counterparts. Moreover, BDNF treatment did not cause an increase in the number of dendritic branches in the hippocampal DG when compared with animals treated with vehicle. In conclusion, our results suggest that non-invasive administration of BDNF via the intranasal route may have important therapeutic potential for treating mood disturbances in early-symptomatic HD patients. PMID- 29388083 TI - 18F-FPYBF-2, a new F-18-labelled amyloid imaging PET tracer: first experience in 61 volunteers and 55 patients with dementia. AB - OBJECTIVE: Recently, we developed a benzofuran derivative for the imaging of beta amyloid plaques, 5-(5-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N methylpyridin-2-amine (18F-FPYBF-2) (Ono et al., J Med Chem 54:2971-9, 2011). The aim of this study was to assess the feasibility of 18F-FPYBF-2 as an amyloid imaging PET tracer in a first clinical study with healthy volunteers and patients with various dementia and in comparative dual tracer study using 11C-Pittsburgh Compound B (11C-PiB). METHODS: 61 healthy volunteers (age: 53.7 +/- 13.1 years old; 19 male and 42 female; age range 24-79) and 55 patients with suspected dementia [Alzheimer's Disease (AD); early AD: n = 19 and moderate stage AD: n = 8, other dementia: n = 9, mild cognitive impairment (MCI): n = 16, cognitively normal: n = 3] for first clinical study underwent static head PET/CT scan using 18 F - FPYBF-2 at 50-70 min after injection. 13 volunteers and 14 patients also underwent dynamic PET scan at 0-50 min at the same instant. 16 subjects (volunteers: n = 5, patients with dementia: n = 11) (age: 66.3 +/- 14.2 years old; 10 males and 6 females) were evaluated for comparative study (50-70 min after injection) using 18F-FPYBF-2 and 11C-PiB on separate days, respectively. Quantitative analysis of mean cortical uptake was calculated using Mean Cortical Index of SUVR (standardized uptake value ratio) based on the established method for 11C-PiB analysis using cerebellar cortex as control. RESULTS: Studies with healthy volunteers showed that 18F-FPYBF-2 uptake was mainly observed in cerebral white matter and that average Mean Cortical Index at 50-70 min was low and stable (1.066 +/- 0.069) basically independent from age or gender. In patients with AD, 18F-FPYBF-2 uptake was observed both in cerebral white and gray matter, and Mean Cortical Index was significantly higher (early AD: 1.288 +/- 0.134, moderate AD: 1.342 +/- 0.191) than those of volunteers and other dementia (1.018 +/- 0.057). In comparative study, the results of 18F-FPYBF-2 PET/CT were comparable with those of 11C-PiB, and the Mean Cortical Index (18F-FPYBF-2: 1.173 +/- 0.215; 11C PiB: 1.435 +/- 0.474) showed direct proportional relationship with each other (p < 0.0001). CONCLUSIONS: Our first clinical study suggest that 18F-FPYBF-2 is a useful PET tracer for the evaluation of beta-amyloid deposition and that quantitative analysis of Mean Cortical Index of SUVR is a reliable diagnostic tool for the diagnosis of AD. PMID- 29388084 TI - Unexplained cough: it is time to rule out Sjogren's syndrome. AB - Sjogren's syndrome is associated with chronic cough, but sicca symptoms are missing from cough evaluation guidelines. We evaluated patients with unexplained cough for undiagnosed Sjogren's syndrome. Patients referred to our pulmonary clinic (Sheba Medical Center, 2009 to 2012) with unexplained cough and concomitant dry eyes were selected for evaluation. Unexplained cough was defined as chronic cough of unknown etiology despite algorithm-based evaluation and treatment. Patients were evaluated in a dedicated clinic by a pulmonologist, rheumatologist, and ophthalmologist specializing in autoimmune disease. Patients completed the Leicester Cough Questionnaire, spirometry, antibody testing for anti Ro/La, ophthalmologic examination with visual acuity, eyelid, ocular surface fluorescein staining, tear break-up time and Schirmer's test, full slit lamp, and fundus examinations. Four-year follow-up was conducted by telephone questionnaire. We identified 24 patients among which 22 (21 females) agreed for evaluation. Eight patients (36%), seven initially, and one during follow-up were diagnosed with Sjogren's syndrome (SS) (six secondary and two primary SS). At 4 year follow-up, cough tended to persist and improve in only 37% with SS. These include 2 (Scl and RA) who received rituximab and 1 (stage 1 sarcoidosis) with spontaneous improvement. In contrast, cough improved in most (64%) patients without SS; the majority (eight/nine) report intensified disease-specific treatment (five allergic and three GERD). We describe patients in whom unexplained chronic cough was associated with dry eyes. Focused workup revealed undiagnosed Sjogren's syndrome in 36%. Dry eyes, with or without SS, is under recognized and should be added to diagnostic algorithms for unexplained cough. PMID- 29388085 TI - Comparison of hyaluronic acid and PRP intra-articular injection with combined intra-articular and intraosseous PRP injections to treat patients with knee osteoarthritis. AB - The aim of this study was to evaluate the benefit provided by intraosseous infiltration combined with intra-articular injection of platelet-rich plasma to treat mild and moderate stages of knee joint degeneration (Kellgren-Lawrence score II-III) compared with other treatments, specifically intra-articular injection of PRP and of HA. Eighty-six patients with grade II to grade III knee OA according to the Kellgren-Lawrence classification were randomly assigned to intra-articular combined with intraosseous injection of PRP (group A), intra articular PRP (group B), or intra-articular HA (group C). Patients in group A received intra-articular combined with intraosseous injection of PRP (administered twice, 2 weeks apart). Patients in group B received intra-articular injection of PRP every 14 days. Patients in group C received a series of five intra-articular injections of HA every 7 days. All patients were evaluated using the Visual Analogue Scale (VAS) and Western Ontario and McMaster Universities (WOMAC) score before the treatment and at 1, 3, 6, 12, and 18 months after treatment. There were significant improvements at the end of the 1st month. Notably, group A patients had significantly superior VAS and WOMAC scores than were observed in groups B and C. The VAS scores were similar in groups B and group C after the 6th month. Regarding the WOMAC scores, groups B and C differed at the 1st, 3rd, 6th, and 12th months; however, no significant difference was observed at the 18th month. The combination of intraosseous with intra-articular injections of PRP resulted in a significantly superior clinical outcome, with sustained lower VAS and WOMAC scores and improvement in quality of life within 18 months. PMID- 29388087 TI - Testing for medical school selection: What are prospective doctors' experiences and perceptions of the GAMSAT and what are the consequences of testing? AB - Written tests for selection into medicine have demonstrated reliability and there is accumulating evidence regarding their validity, but we know little about the broader impacts or consequences of medical school selection tests from the perspectives of key stakeholders. In this first Australian study of its kind, we use consequential validity as a theoretical lens to examine how medical school students and applicants view and experience the Graduate Medical Schools Admission Test (GAMSAT), and the consequences of testing. Participants (n = 447) were recruited from five graduate-entry medical schools across Australia and a publicly available online test preparation forum. An online survey was used to gather demographic information, and quantitative and qualitative data. Quantitative data were analysed via descriptive statistics and qualitative data were thematically analysed. The findings showed there was a considerable financial burden associated with preparing for and sitting the GAMSAT and moderate agreement regarding the GAMSAT as a fair selection method. The main unintended consequences of using the GAMSAT as a selection tool included barriers related to test affordability and language, and socialisation into the hidden curriculum of medicine. Selection tools such as the GAMSAT have some limitations when the goals are to support equitable participation in medicine and professional identity development. Our study highlights the value interpretive and theoretically-informed research in contributing to the evidence base on medical school selection. PMID- 29388086 TI - Long-term disease and patient-reported outcomes of a continuous treat-to-target approach in patients with early rheumatoid arthritis in daily clinical practice. AB - Patients in real life may differ from those in clinical trials. The aim of this study is to report 5-year outcomes of a continuous treat-to-target (T2T) approach in patients with rheumatoid arthritis (RA) in daily clinical practice. In the Dutch RhEumatoid Arthritis Monitoring cohort, all patients with a clinical diagnosis of RA were treated according to a protocolled T2T strategy, aimed at 28 joint Disease Activity Score (DAS28) < 2.6. Outcomes were percentages of patients in distinct levels of disease activity, mean course of DAS28 and prevalence of sustained (drug-free) remission. Also, data on functional disability (Health Assessment Questionnaire) and health-related quality of life (Short-Form 36) were examined. Mean DAS28 improved from 4.93 (95% CI 4.81-5.05) at baseline to 2.49 (95% CI 2.35-2.63) after 12 months and remained stable thereafter. Percentages of patients at 12 months with DAS28 < 2.6 (remission), DAS28 >= 2.6 and <= 3.2 (low disease activity), DAS28 > 3.2 and <= 5.1 (moderate disease activity) and DAS28 > 5.1 (high disease activity) were 63, 16, 18 and 3%, respectively. Sustained remission (DAS28 < 2.6 during >= 6 months) was observed at least once in 84% of the patients and drug-free remission (DAS28 < 2.6 during >= 6 months after withdrawal of all disease-modifying anti-rheumatic drugs) in 36% of the patients. Functional disability and health-related quality of life significantly improved during the first 24 weeks. Continuous application of T2T in real-life RA patients leads to favourable disease- and patient-related outcomes. PMID- 29388088 TI - How basic psychological needs and motivation affect vitality and lifelong learning adaptability of pharmacists: a structural equation model. AB - Insufficient professional development may lead to poor performance of healthcare professionals. Therefore, continuing education (CE) and continuing professional development (CPD) are needed to secure safe and good quality healthcare. The aim of the study was to investigate the hypothesized associations and their directions between pharmacists' basic psychological needs in CE, their academic motivation, well-being, learning outcomes. Self-determination theory was used as a theoretical framework for this study. Data were collected through four questionnaires measuring: academic motivation, basic psychological needs (BPN), vitality and lifelong learning adaptability of pharmacists in the CE/CPD learning context. Structural equation modelling was used to analyze the data. Demographic factors like gender and working environment influenced the observed scores for frustration of BPN and factors like training status and working experience influenced the observed scores for academic motivation. A good model fit could be found only for a part of the hypothesized pathway. Frustration of BPN is positively directly related to the less desirable type of academic motivation, controlled motivation (0.88) and negatively directly related to vitality (- 1.61) and negatively indirectly related to learning outcomes in CE. Fulfillment or frustration of BPN are important predictors for well-being and learning outcomes. Further research should be conducted to discover how we can prevent these needs from being frustrated in order to design a motivating, vitalizing and sustainable CE/CPD system for pharmacists and other healthcare professionals. Basic psychological needs are very important predictors for well-being and learning outcomes. Further research should be conducted to discover how we can prevent these needs from being frustrated in order to design a motivating, vitalizing and sustainable CE/CPD system for pharmacists and other healthcare professionals. PMID- 29388089 TI - Intraosseous pseudomeningocele of the mobile spine: a case report and review of the literature. AB - BACKGROUND: Pseudomeningoceles most commonly occur due to prior trauma or surgery and are often located in the posterior paraspinous tissues. Here, we report a case of an intraosseous pseudomeningocele that mimicked an intra-osseous T2 hyperintense lesion in the L1 vertebral body. CASE DESCRIPTION: A 64-year-old male presented with back, left lateral thigh and left knee pain lasting several months. He had no prior history of trauma or surgery. Radiographs of the lumbar spine showed mild levoscoliotic curvature of the lumbar spine, Baastrup's changes between the spinous processes, multilevel degenerative disc disease and facet arthropathy. Magnetic resonance imaging (MRI) of the lumbar spine performed without intravenous contrast showed severe spinal canal stenosis from L1-L2 to L3 L4 and moderate spinal canal stenosis at L4-L5. MRI also showed a 2.5-cm T2 hyperintense lesion involving the posterior aspect of the L1 vertebral body, with questionable contiguity with cerebrospinal fluid. Computed tomography (CT) myelogram was performed instead of biopsy. CT myelogram showed contiguity of the lesion with the intrathecal contrast and a rent in the posterior longitudinal ligament and anterior dura consistent with an intraosseous pseudomeningocele. The patient opted for non-operative management of the pseudomeningocele and his lumbar stenosis due to medical comorbidities. CONCLUSIONS: This case illustrates a rare case of an intra-osseous pseudomeningocele and highlights the importance of CT myelogram for diagnosis. PMID- 29388090 TI - Shaping conservative spinal services with the Spine Tango Registry. AB - PURPOSE: This study reports the results of a registry data collection project within a secondary care spinal osteopathy service. METHODS: Clinical and demographic data were collected using the Spine Tango Conservative registry data collection tool. Outcomes were assessed using the Numerical Pain Rating Scale (NPRS), Oswestry Disability Index (ODI), Neck Disability Index (NDI), COMI Low Back Conservative (COMI-LBC), COMI Neck Conservative (COMI-NC) and EQ5D. Global treatment outcome (GTO), satisfaction with care and therapeutic complications were reported using the Spine Tango Patient Self Assessment form (STPSA). The correlation of GTO and PROM change scores was analysed using Spearman's rank correlation coefficient. RESULTS: 262 patients presented during the study period. 100% of patients had chronic spinal pain and 98.8% had previously received other interventions for the same episode. Mean (standard deviation) improvements by PROM: NPRS low back 2.1 (2.5); NPRS neck 2.3 (2.3); COMI-LBC 2.1 (2.2); COMI-NC 2.0 (1.7); ODI 10.5 (12.1); NDI 14.5 (12.2); EQ5D 0.2 (0.3). 83.2% of patients reported that osteopathy had 'helped a lot' or 'helped'. 96.2% of patients were 'very satisfied' or 'satisfied' with care. There were no serious therapeutic complications. CONCLUSIONS: The secondary care spinal osteopathy service demonstrated high satisfaction, few therapeutic complications and positive outcomes on all PROMs. Registry participation has facilitated robust clinical governance and the data support the use of osteopaths to deliver a conservative spinal service in this setting. Registry data collection is a significant administrative and clinical task which should be structured to minimise burden on patients and resources. These slides can be retrieved under Electronic Supplementary Material. PMID- 29388091 TI - Expert's comment concerning Grand Rounds case entitled "Type V osteogenesis imperfecta undergoing surgical correction for scoliosis" by M. Jones et al. (Eur Spine J; 2018: doi 10.1007/s00586-018-5465-8). PMID- 29388092 TI - Expert's comment concerning Grand Rounds case entitled "Posterolateral cervical transpedicular corpectomy for the surgical management of metastatic tumor" by M.H. Pham et al. (Eur Spine J; 2018: DOI 10.1007/s00586-018-5466-7). PMID- 29388093 TI - In response to: phenylephrine and paradoxically increased muscle tissue oxygenation: is the mechanism related to local venoconstriction or augmented venous return? PMID- 29388094 TI - A technical review of the history, development and performance of the anaesthetic conserving device "AnaConDa" for delivering volatile anaesthetic in intensive and post-operative critical care. AB - There is a shift in critical care to adopt volatile anaesthetics as sedatives for certain patients using mechanical ventilation. Accompanying this shift is a growing body of literature describing the advantages or disadvantages of using isoflurane or sevoflurane for long term sedation. This practise requires a cost effective, efficient and safe means to deliver these drugs that can simultaneously operate with modern critical care ventilators and ventilation protocols while protecting the care environment and care workers from excessive exposure to the drugs. The anaesthetic conserving device ("AnaConDa", Sedana Medical) is one device that delivers a safe sedative dose of either isoflurane or sevoflurane to a patient using existing critical care ventilators, common syringe pumps and gas monitors. The device is essentially a small disposable anaesthetic vaporizer and HME filter combined into one airway component. Similar to an HME filter, the device reflects moisture back to the patient, but also reflects 90% of the anaesthetic by adsorbing and releasing the drug using a proprietary carbon filament reflecting medium. This reflection reduces the total amount of anaesthetic needed, reducing that which is exhausted or scavenged upon exhalation. It can be used for 24 h of sedation, and fits into current critical care ventilator circuits almost without modifications. This article will describe the physical characteristics of the device, how it works, its development history and the performance parameters under which it can be used. PMID- 29388095 TI - Disparities in Health Care Coverage Among U.S. Born and Mexican/Central American Born Labor Workers in the U.S. AB - We examined health insurance coverage among U.S. and Mexican/Central American (M/CA) born labor workers living in the U.S. Using data from the 2010-2015 National Health Interview Survey, we employed logistic regression models to examine health insurance coverage and covariates among U.S. and M/CA born labor workers. Prevalence ratios between U.S. and M/CA born workers were also obtained. U.S. born workers had double the prevalence of insurance coverage. Regarding private insurance coverage, U.S. born workers had a higher prevalence of coverage compared to their M/CA born counterparts. Among foreign born workers with U.S. citizenship, the odds of having insurance coverage was greater than that of noncitizens. Additionally, those who had lived in the U.S. for 10 or more years had higher odds of having health insurance coverage. Disparities in health care coverage exist between U.S. born and foreign born labor workers. PMID- 29388096 TI - Activation-Induced Cytidine Deaminase Aided In Vitro Antibody Evolution. AB - Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by converting deoxycytidines (dC) to deoxyuracils (dU) which then can induce other mutations, and plays a central role in introducing diversification of the antibody repertoire in B cells. Ectopic expression of AID in bacteria and non-B cells can also lead to frequent mutations in highly expressed genes. Taking advantage of this feature of AID, in recent years, systems coupling in vitro somatic hypermutation and mammalian cell surface display have been developed, with unique benefits in antibody discovery and optimization in vitro. Here, we provide a protocol for AID mediated in vitro protein evolution. A CHO cell clone bearing a single gene expression cassette has been constructed. The gene of an interested protein for in vitro evolution can be easily inserted into the cassette by dual recombinase-mediated cassette exchange (RMCE) and constantly expressed at high levels. Here, we matured an anti-TNFalpha antibody as an example. Firstly, we obtained a CHO cell clone highly displaying the antibody by dual RMCE. Then, the plasmid expressing AID is transfected into the CHO cells. After a few rounds of cell sorting-cell proliferation, mutant antibodies with improved features can be generated. This protocol can be applied for improving protein features based on displaying levels on cell surface and protein-protein interaction, and thus is able to enhance affinity, specificity, and stability besides others. PMID- 29388097 TI - Analyzing Mouse B Cell Responses Specific to LCMV Infection. AB - B cell responses play a central role in humoral immunity, which protects an individual from invading pathogens by antigen-specific antibodies. Understanding the basic principles of the B cell responses during viral infection is of substantial importance for anti-viral vaccine development. In inbred mice, lymphocytic choriomeningitis virus (LCMV) infection elicits robust and typical T cell-dependent B cell responses, including germinal center reaction, memory B cell formation, and a long-lived plasma cell pool in bone marrow. Therefore, this system represents an ideal model to investigate anti-viral B cell responses. In this protocol, we describe how to propagate and quantify LCMV and successfully establish an acute LCMV infection in mice. This protocol also provides three different techniques to analyze B cell responses specific to an acute LCMV infection: the identification of germinal center (GC) B cells and follicular helper CD4 T (TFH) cells from the spleens and lymph nodes via flow cytometry, titration of LCMV-specific IgG in the serum after LCMV infection using an enzyme linked immunosorbent assay (ELISA) analysis, and detection of LCMV-IgG secreted plasma cells from bone marrow with an enzyme-linked immunospot (ELISPOT) assay. PMID- 29388098 TI - Expression of Exogenous Genes in Murine Primary B Cells and B Cell Lines Using Retroviral Vectors. AB - B cells, after activation, can undergo class-switch recombination and somatic hypermutation of their immunoglobulin genes, and can differentiate into memory cells and plasma cells. Expressing genes in altered versions in primary B cells and B cell lines is an important approach to understanding how B cell receptor signaling leads to B cell activation and differentiation. Recombinant retrovirus based transduction is the most efficient method to deliver exogenous genes for expression in B cells. In this chapter, we describe streamlined protocols for using recombinant retroviral vectors to transduce both murine primary B cells and B cell lines. PMID- 29388099 TI - Biophysical Techniques to Study B Cell Activation: Single-Molecule Imaging and Force Measurements. AB - Cells of the adaptive immune system recognize pathogenic peptides through specialized receptors on their membranes. The engagement of these receptors with antigen leads to cell activation, which induces profound changes in the cell including cytoskeleton remodeling and membrane deformation. During this process, receptors and signaling molecules undergo spatiotemporal reorganization to form signaling microclusters and the immunological synapse. The cytoskeletal and membrane dynamics also leads to exertion of forces on the cell-substrate interface. In this chapter we describe two techniques-one for single-molecule imaging of B cell receptors to measure their diffusive properties as cells get activated on supported lipid bilayers; and the second for visualizing and quantifying cellular forces using elastic surfaces to stimulate T and B cells. PMID- 29388100 TI - DNA-Based Probes for Measuring Mechanical Forces in Cell-Cell Contacts: Application to B Cell Antigen Extraction from Immune Synapses. AB - The production of antibodies requires the expansion and selection of high affinity B cell clones. This process is initiated by antigen uptake through the B cell receptor (BCR), which recognizes and binds antigen displayed on the surface of an antigen-presenting cell (APC). To acquire the antigen, B cells use myosin contractility to physically pull BCR-antigen clusters from the APC membrane. These mechanical forces influence association and dissociation rates of BCR antigen bonds, resulting in affinity-dependent acquisition of antigen by B cells. Mechanical regulation of B cell antigen acquisition from APCs remains poorly understood, although the recent development of DNA-based force sensors has enabled the measurement of mechanical forces generated in B cell-APC contacts. In this chapter, we describe a protocol to design, synthesize, and purify DNA-based force sensors to measure B cell antigen extraction forces using fluorescence microscopy. PMID- 29388101 TI - Deriving Quantitative Cell Biological Information from Dye-Dilution Lymphocyte Proliferation Experiments. AB - The dye-dilution assay is a powerful tool to study lymphocyte expansion dynamics. By combining time course dye-dilution experiments with computational analysis, quantitative information about cell biological parameters, such as percentage of cells dividing, time of division, and time of death, can be produced. Here, we describe the method to generate quantitative cell biological insights from dye dilution experiments. We describe experimental methods for generating dye dilution data with murine lymphocytes and then describe the computational data analysis workflow using a recently developed software package called FlowMax. The aim is to interpret the dye-dilution data quantitatively and objectively, such that cell biological parameters can be reported with an appropriate measure of confidence, which in turn depends on the quality and quantity of available data. PMID- 29388102 TI - Flow Cytometry Analysis of mTOR Signaling in Antigen-Specific B Cells. AB - B lymphocytes and their differentiated daughter cells are charged with responding to invading pathogens and producing protective antibodies against these pathogens. The physiology of B cells is intimately connected with the function of the B cell antigen receptor (BCR). Upon activation of BCR, transmembrane signals are generated, and several downstream pathways are activated, which provide a primary directive for the cell's subsequent response. mTOR is a serine/threonine kinase that controls cell proliferation and metabolism in response to a diverse range of extracellular stimuli. The activation of mTOR signaling downstream of PI3K/Akt activity by B cell receptor (BCR) engagement has been generally assumed to be essential for B cell responses. This chapter seeks to present two protocols to evaluate mTOR activity in B cells bearing BCR specific to 4-hydroxy-3 nitrophenylacetyl (NP)-hapten. PMID- 29388103 TI - Ex Vivo Culture Assay to Measure Human Follicular Helper T (Tfh) Cell-Mediated Human B Cell Proliferation and Differentiation. AB - Upon priming by antigens, B cells undergo activation, proliferation, and differentiation into antibody-secreting cells. During thymus-dependent (TD) antibody responses, the proliferation and differentiation of antigen-primed B cells essentially rely on the helper function from CD4+ T cells. Follicular helper T (Tfh) cells constitute a specialized Th subset that localizes in close proximity to B cells and supports B cell proliferation and differentiation through co-stimulatory receptors and cytokines. Impaired Tfh-mediated B cell proliferation and differentiation were observed in patients with immunodeficiency, while overactivation of this process may lead to dysregulated immune responses seen in autoimmune disorders. Here, we describe an ex vivo coculture assay using circulating Tfh cells and B cells isolated from human blood. This method can be used to examine the function of patients' B cells for proliferation, differentiation, and antibody secretion, mediated by the physiological help from Tfh cells. PMID- 29388104 TI - B Cell Receptor Signaling and Compartmentalization by Confocal Microscopy. AB - Binding of antigen to the B cell receptor (BCR) triggers both BCR signaling and endocytosis simultaneously. BCR signaling pathways and their regulation have been studied extensively by both biochemical methods and flow cytometry, resulting in a comprehensive understanding of the temporal dynamics of the signaling enzymes and effector proteins. However, spatial regulation of these signaling pathways in subcellular pathways is relatively poorly understood. Here, we describe a method to study the spatio-temporal distribution of phosphorylated-kinases in antigen activated B cells by confocal microscopy. This method can also be applied to other cell types where it is of interest to understand the spatial distribution of signaling enzymes and their effector proteins. PMID- 29388105 TI - Imaging the Interactions Between B Cells and Antigen-Presenting Cells. AB - In vivo, B cells are often activated by antigens that are displayed on the surface of antigen-presenting cells (APCs). Binding of membrane-associated antigens to the B cell receptor (BCR) causes rapid cytoskeleton-dependent changes in the spatial organization of the BCR and other B cell membrane proteins, leading to the formation of an immune synapse. This process has been modeled using antigens attached to artificial planar lipid bilayers or to plasma membrane sheets. As a more physiological system for studying B cell-APC interactions, we have expressed model antigens in easily transfected adherent cell lines such as Cos-7 cells. The model antigens that we have used are a transmembrane form of a single-chain anti-Igkappa antibody and a transmembrane form of hen egg lysozyme that is fused to a fluorescent protein. This has allowed us to study multiple aspects of B cell immune synapse formation including cytoskeletal reorganization, BCR microcluster coalescence, BCR-mediated antigen gathering, and BCR signaling. Here, we provide protocols for expressing these model antigens on the surface of Cos-7 cells, transfecting B cells with siRNAs or with plasmids encoding fluorescent proteins, using fixed cell and live cell fluorescence microscopy to image B cell-APC interactions, and quantifying APC-induced changes in BCR spatial organization and signaling. PMID- 29388106 TI - In Vivo Tracking of Particulate Antigen Localization and Recognition by B Lymphocytes at Lymph Nodes. AB - The development of experimental systems that allow in vivo antigen tracking as well as the study of B cell dynamics in real time and in situ, have transformed our understanding of the "how, when and where" B lymphocytes find antigen at secondary lymphoid organs in the last 10 years. Here, I described one of these experimental models, which uses highly fluorescent particulate antigen and B cell receptor (BCR)-transgenic B cells labeled with long-term fluorescent probes, combined with confocal and multiphoton microscopy. PMID- 29388107 TI - Study B Cell Antigen Receptor Nano-Scale Organization by In Situ Fab Proximity Ligation Assay. AB - The B cell antigen receptor (BCR) is found to be non-randomly organized at nano scale distances on the B cell surface. Studying the organization and relocalization of the BCR is thus likely to provide new clues to understand the activation of the BCR. Indeed, with the in situ Fab proximity ligation assay (Fab PLA), we now obtain proofs for the dissociation activation of BCRs and start to gain insight into how the relocalization of B cell surface signaling molecules could activate the cells. This chapter describes our methods to study the nano scale organization of B cell surface receptors and co-receptors with Fab-PLA. PMID- 29388108 TI - Single-Particle Tracking of Cell Surface Proteins. AB - Single-particle tracking has been used extensively to advance our understanding of the plasma membrane and the mechanisms controlling the movement of cell surface proteins. These studies provide fundamental insights into the regulation of membrane receptor activation and the assembly of signaling clusters. Here, we describe a method to label and track B cell receptor (BCR) and other cell surface proteins and how this method can be adapted to simultaneously track two molecular species or examine the movement of membrane proteins in relation to membrane microdomains. We recently used this method to study the role of the actin cytoskeleton in the regulation of B cell receptor dynamics at the cell surface. PMID- 29388109 TI - The Use of Intravital Two-Photon and Thick Section Confocal Imaging to Analyze B Lymphocyte Trafficking in Lymph Nodes and Spleen. AB - Intravital two-photon laser scanning microscopy (TP-LSM) has allowed the direct observation of immune cells in intact organs of living animals. In the B cell biology field TP-LSM has detailed the movement of B cells in high endothelial venules and during their transmigration into lymph organs; described the movement and positioning of B cells within lymphoid organs; outlined the mechanisms by which antigen is delivered to B cells; observed B cell interacting with T cells, other cell types, and even with pathogens; and delineated the egress of B cells from the lymph node (LN) parenchyma into the efferent lymphatics. As the quality of TP-LSM improves and as new fluorescent probes become available additional insights into B cell behavior and function await new investigations. Yet intravital TP-LSM has some disadvantages including a lower resolution than standard confocal microscopy, a narrow imaging window, and a shallow depth of imaging. We have found that supplementing intravital TP-LSM with conventional confocal microscopy using thick LN sections helps to overcome some of these shortcomings. Here, we describe procedures for visualizing the behavior and trafficking of fluorescently labeled, adoptively transferred antigen-activated B cells within the inguinal LN of live mice using two-photon microscopy. Also, we introduce procedures for fixed thick section imaging using standard confocal microscopy, which allows imaging of fluorescently labeled cells deep in the LN cortex and in the spleen with high resolution. PMID- 29388110 TI - Time-Lapse Forster Resonance Energy Transfer Imaging by Confocal Laser Scanning Microscopy for Analyzing Dynamic Molecular Interactions in the Plasma Membrane of B Cells. AB - For decades, various Forster resonance energy transfer (FRET) techniques have been developed to measure the distance between interacting molecules. FRET imaging by the sensitized acceptor emission method has been widely applied to study the dynamical association between two molecules at a nanometer scale in live cells. Here, we provide a detailed protocol for FRET imaging by sensitized emission using a confocal laser scanning microscope to analyze the interaction of the B cell receptor (BCR) with the Lyn-enriched lipid microdomain on the plasma membrane of live cells upon antigen binding, one of the earliest signaling events in BCR-mediated B cell activation. PMID- 29388111 TI - Understanding of B Cell Receptor Signaling Through a Photo-Activatable Antigen Presentation System. AB - Antibody responses are initiated by the binding of antigens to cell surface expressed B cell receptors (BCRs) that trigger signaling cascades resulting in the activation of B cells. However, it has been difficult to study these cascades due to their fast, dynamic, and transient nature. Using a conventional antigen presenting system, such as planar lipid bilayers (PLBs), the initial events during B cell activation have been difficult to be captured. Here, we describe the general procedures for the utilization of a photoactivatable antigen presenting system in the combination with a high speed live cell imaging method to investigate the early activation events in the same B cells in response to antigen stimulation. PMID- 29388112 TI - Use of Streptolysin O-Induced Membrane Damage as a Method of Studying the Function of Lipid Rafts During B Cell Activation. AB - B-lymphocytes have the ability to repair their plasma membranes following injury, such as by bacterial cholesterol-dependent cytolysins. The repair process includes the removal of the pore from the inflicted region of the plasma membrane via lipid raft-mediated internalization. Lipid rafts are critical for B cell receptor (BCR) activation. Cholesterol-dependent pore forming bacterial toxins provide a useful tool for examining the role of lipid rafts in B cell activation and the underlying cellular mechanisms. This method serves as a great alternative of known cholesterol disruption reagents such as filipin, nystatin, and methyl beta-cyclodextrin. Here, we describe a method of damaging primary murine B cell plasma membranes with the Streptococcus pyogenes cytolysin, Streptolysin O (SLO), and monitoring levels of damage, repair and BCR activation. PMID- 29388113 TI - Visualization and Quantitative Analysis of the Actin Cytoskeleton Upon B Cell Activation. AB - The formation of the immunological synapse upon B cell activation critically depends on the rearrangement of the submembranous actin cytoskeleton. Polymerization of actin monomers into filaments provides the force required for B cell spreading on the antigen-presenting cell (APC). Interestingly, the actin network also participates in cellular signaling at multiple levels. Fluorescence microscopy plays a critical role in furthering our understanding of the various functions of the cytoskeleton, and has become an important tool in the studies on B cell activation. The actin cytoskeleton can be tracked in live cells with various fluorescent probes binding to actin, or in fixed cells typically with phalloidin staining. Here, we present the usage of TIRF microscopy and an image analysis workflow for studying the overall density and organization of the actin network upon B cell spreading on antigen-coated glass, a widely used model system for the formation of the immunological synapse. PMID- 29388114 TI - Participation in Home Visitation is Associated with Higher Utilization of Early Intervention. AB - Objectives To determine whether participation in a home visiting program increases and expedites utilization of early intervention services for suspected developmental delays. Methods Children participating in Every Child Succeeds (ECS), a large home visiting (HV) program serving greater Cincinnati, between 2006 and 2012, were propensity score matched to a sample of children identified from birth records who did not receive services from ECS. Data were linked to early intervention (EI) data acquired from the Ohio Department of Health. Descriptive statistics were employed to evaluate success of the matching. Chi square and log-rank tests evaluated whether the proportion of children accessing EI and the time to EI services differed for families participating in HV compared to eligible children not participating. Logistic regression and Cox proportional hazards regression modeled the associations. Results Among 3574 HV and 3574 comparison participants, there was no difference in the time to EI service utilization; however a higher percentage of HV participants accessed services. Overall, 6% of the HV group and 4.3% of the comparison group accessed services (p = 0.001). Modeling revealed an odd ratio = 1.43 [95% confidence interval (CI) 1.16-1.78, p value = 0.001] and hazard ratio = 1.42 [95% CI 1.15-1.75, p value = 0.001]. Differences in utilization were greatest directly after birth and between approximately 2 and 3 years. Conclusions for Practise Participation in home visiting was associated with greater utilization of EI services during two important developmental time points, demonstrating that home visiting may serve as an important resource for facilitating access to early intervention services. PMID- 29388115 TI - Breastfeeding, Parenting, and Infant Attachment Behaviors. AB - Objectives Infants and toddlers need secure attachments in order to develop the social competence required to successfully navigate later peer and adult relationships. Breastfeeding is a parenting factor that has been associated with child emotional development-specifically the attachment between children and their mothers. Yet, this link may simply be the result of other parenting behaviors that are associated with breastfeeding. Thus, our objective is to examine whether the link between infant attachment behaviors and breastfeeding endures when accounting for a broad array of in-depth measures of parenting. Methods We use the Early Childhood Longitudinal Study of children from 9 months to 2 years of age collected by the National Center for Education Statistics. Using Ordinary Least Squares regression, data analyses examine the association between the Toddler Attachment Sort-45 (TAS-45) measures of toddler-parent attachment (infant attachment security and temperamental dependency) and breastfeeding practices. We also examine individual items of the TAS-45 to isolate specific attachment behaviors that have the strongest associations with breastfeeding. Results We find an enduring link between children who are predominantly breastfed for six or more months and infant attachment security. However, we find no evidence that breastfeeding is linked to a child's temperamental dependency. Of the nine items used to examine infant attachment behaviors, we find that breastfed children are rated as having slightly higher scores on two measures ("warm and cuddly," "cooperative") and lower scores on one measure ("demanding/angry"). Conclusions for Practice Breastfeeding has an important link to the child's use of their caregiver as a secure base for exploration and a place of comfort when distressed (infant attachment security). Yet, breastfeeding does not appear to reduce a child's temperamental dependency or level of clinginess as measured by how demanding, fussy or distressed the child becomes when separated. PMID- 29388116 TI - On using multiple imputation for exploratory factor analysis of incomplete data. AB - A simple multiple imputation-based method is proposed to deal with missing data in exploratory factor analysis. Confidence intervals are obtained for the proportion of explained variance. Simulations and real data analysis are used to investigate and illustrate the use and performance of our proposal. PMID- 29388117 TI - Correlation of FANCM expression with clinical factors in luminal B breast cancer. AB - BACKGROUND: The genotype of Fanconi Anemia complementation group M (FANCM) was previously found to be associated with breast cancer risk in several populations. Here, we studied the expression of FANCM and its correlation with clinical characteristics in Chinese patients with breast cancer. METHODS: We performed an immunohistochemical study of FANCM protein in clinical breast cancer tissues from 310 patients along with 44 adjacent tissues. RESULTS: FANCM protein level is lower in triple-negative breast cancer tissues than in other subtypes (P = 0.008). In addition, high FANCM expression correlated with pathology type IDC (P = 0.040), estrogen receptor positive (P < 0.001), progesterone receptor positive (P = 0.001), and low Ki-67 status (P = 0.003). Multivariate analysis revealed that FANCM status was an independent prognostic factor for overall survival (P = 0.017) in luminal B breast cancer. CONCLUSIONS: FANCM levels are significantly associated with different subtypes of human breast cancer. Specifically, FANCM could play a role in the progression of luminal B breast cancer. PMID- 29388118 TI - Dynamic cardiac PET imaging: Technological improvements advancing future cardiac health. PMID- 29388119 TI - Transsphenoidal pituitary surgery: comparison of two sellar reconstruction techniques and their effect on postoperative cerebrospinal fluid leakage. AB - Transsphenoidal surgery is a common procedure in patients with pituitary adenomas. Several techniques have been previously postulated to achieve sufficient sellar reconstruction to avoid cerebrospinal fluid (CSF) leakage. We analyzed our institutional database concerning two sellar reconstruction techniques and development of postoperative CSF leakage. From 2009 to 2015, 255 patients underwent transsphenoidal pituitary surgery at our institution. According to the technique used for sellar reconstruction, patients were divided into two groups: (1) with muscle patch and fibrin glue and (2) with fibrin glue alone. Postoperative CSF leakage occurred in 7% of the patients. Occurrence of postoperative CSF leakage did not differ significantly between both sellar reconstruction techniques (p = 0.2). Patients who underwent sellar reconstruction with fibrin glue alone had significantly shorter operating time (p < 0.0001), as well as shorter length of hospital stay (p = 0.01). On multivariate analysis, occurrence of intraoperative CSF leakage was the only predictor for postoperative CSF leakage (p < 0.0001). The present data suggests that sellar reconstruction after transsphenoidal pituitary surgery seems to be equally effective in preventing postoperative CSF leakage. However, the use of fibrin glue alone results in shorter hospital stay and operating time without exposing patients to more frequent CSF leakage. PMID- 29388121 TI - Techniques for Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy. PMID- 29388120 TI - The application of the unruptured intracranial aneurysm treatment score: a retrospective, single-center study. AB - The unruptured intracranial aneurysm treatment score (UIATS) was published in April 2015 as a multidisciplinary consensus regarding treatment of unruptured intracranial aneurysms (UIA). As a tertiary center with focus on vascular neurosurgery, we aimed to investigate whether our treatment decision-making in patients with UIA has been in accordance with the recently published UIATS. A retrospective analysis of patients admitted to our center with UIA was performed. UIATS was applied to all identified UIA. Three decision groups were defined: (a) UIATS favoring treatment, (b) UIATS favoring observation, and (c) UIATS inconclusive. These results were then compared to our clinical decisions. Spearman's rank-order correlation (rho) was run to determine the relationship between the UIATS and our clinical decisions. Cases of discrepancies between UIATS and our clinical decisions were then examined for complications, defined as periprocedural adverse events in treated aneurysms, or aneurysm rupture in untreated aneurysms. Ninety-three patients with 147 UIA were included. A total of 118/147 (80.3%) UIA were treated. In 70/118 (59.3%), UIATS favored treatment, in 18/118 (15.3%), it was inconclusive, and in 30/118 (25.4%), it favored observation. A total of 29/147 (19.7%) UIA were not treated. In 15/29 (51.7%), UIATS favored observation, in 9/29 (31%), it favored treatment, and in 5/29 (17.2%), it was inconclusive (rho = 0.366, p < 0.01). Discrepancies between UIATS and our clinical decisions did not correlate with complications (rho = 0.034, p = 0.714). Our analysis shows that our more intuitive clinical decision-making has been in line with UIATS. Our treatment decisions did not correlate with an increased rate of complications. PMID- 29388122 TI - Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas. AB - BACKGROUND: The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen. METHODS: Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m2/day and ifosfamide 2.5 g/m2/day on days 1-4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002 2005). Fifty-one additional patients were identified from a retrospective chart review (2005-2014). RESULTS: The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2-83.7%), 55.9% (95% CI 44.5-70.2%), and 87.2% (95% CI 77.9-96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated >= 90% pathologic response. Wound complications occurred in 32% (24/76) of patients. DISCUSSION: Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients. PMID- 29388123 TI - Staging Laparoscopy Not Only Saves Patients an Incision, But May Also Help Them Live Longer. AB - BACKGROUND: Approximately 20-40% of patients with "resectable" pancreatic adenocarcinoma (PDAC) by imaging criteria have metastatic disease on exploration. Our aim was to assess the potential impact of staging laparoscopy versus upfront laparotomy in "resectable" patients found to have metastatic PDAC. METHODS: Clinicopathologic data was retrospectively collected for all patients with PDAC undergoing an operation with curative intent between 2001-2015 at a single institution. RESULTS: Of the 1001 patients undergoing surgical evaluation, 151 had unsuspected metastatic PDAC. Staging laparoscopy was performed in 59% (89/151) of patients, while 41% (62/151) underwent an exploratory laparotomy with or without prophylactic bypass. There were no differences in patient demographics and preoperative CA 19-9 levels between the staging laparoscopy and exploratory laparotomy groups. However, staging laparoscopy was more often performed for pancreatic body/tail lesions (85% vs 60% for pancreatic head lesions, p < 0.001). Patients who only underwent laparoscopy started palliative chemotherapy more quickly (17.9 days vs 39.9 days in the laparotomy group, p < 0.001). There was no difference in the 30 day or lifetime incidence of postoperative cholangitis, gastric outlet obstruction, or biliary stent placement between groups. The median overall survival for the staging laparoscopy group (11.4 months) was significantly longer than the laparotomy group (8.3 months, p < 0.001). In a cox regression analysis adjusting for clinicopathologic variables, staging laparoscopy was associated with significantly improved overall survival when compared to the laparotomy group (HR 0.53, 95% C.I. 0.34-0.82, p = 0.005). CONCLUSION: For patients diagnosed with metastatic PDAC at the time of surgical exploration, staging laparoscopy was associated with a shorter time to chemotherapy and improved overall survival when compared to those explored without laparoscopy. PMID- 29388124 TI - Impact of Malnutrition After Gastrectomy for Gastric Cancer on Long-Term Survival. AB - BACKGROUND: Preoperative malnutrition can worsen morbidity and mortality; however, the role of postgastrectomy nutritional status remains unclear. Our purpose was to clarify whether malnutrition after gastrectomy could predict long term survival. METHODS: Patients with pathological stage I, II, and III gastric cancer who underwent gastrectomy between 2002 and 2013 were included. The nutrition risk index (NRI) was evaluated before and at 1, 3, 6 and 12 months after gastrectomy. The patients were divided into normal (NRI > 97.5) or malnutrition (NRI <= 97.5) groups, and we compared the correlations of clinicopathological characteristics, surgical treatment, and overall survival between the two groups. RESULTS: Among the 760 participants, patients in the malnutrition group were significantly older and had higher incidences of comorbidity and advanced cancer than the patients in the normal group. Multivariate analysis showed that overall survival was poorer in the malnutrition group before gastrectomy [hazard ratio (HR) 1.68] and at 1 month (HR 1.77), 3 months (HR 2.18), 6 months (HR 1.81) and 12 months (HR 2.17) after gastrectomy (all p < 0.01). Malnutrition at 1 and 3 months after gastrectomy was significantly associated with poor cause-specific survival. Total gastrectomy, preoperative malnutrition, older age, and adjuvant chemotherapy were independent risk factors of postoperative malnutrition at 12 months postgastrectomy. CONCLUSIONS: Malnutrition before gastrectomy and at 1, 3, 6 and 12 months after gastrectomy significantly and adversely affects overall survival. Nutritional interventions to lessen the impact of postoperative malnutrition offer hope for prolonged survival. PMID- 29388125 TI - Integrating mercury research and policy in a changing world. PMID- 29388126 TI - A review of global environmental mercury processes in response to human and natural perturbations: Changes of emissions, climate, and land use. AB - We review recent progress in our understanding of the global cycling of mercury (Hg), including best estimates of Hg concentrations and pool sizes in major environmental compartments and exchange processes within and between these reservoirs. Recent advances include the availability of new global datasets covering areas of the world where environmental Hg data were previously lacking; integration of these data into global and regional models is continually improving estimates of global Hg cycling. New analytical techniques, such as Hg stable isotope characterization, provide novel constraints of sources and transformation processes. The major global Hg reservoirs that are, and continue to be, affected by anthropogenic activities include the atmosphere (4.4-5.3 Gt), terrestrial environments (particularly soils: 250-1000 Gg), and aquatic ecosystems (e.g., oceans: 270-450 Gg). Declines in anthropogenic Hg emissions between 1990 and 2010 have led to declines in atmospheric Hg0 concentrations and HgII wet deposition in Europe and the US (- 1.5 to - 2.2% per year). Smaller atmospheric Hg0 declines (- 0.2% per year) have been reported in high northern latitudes, but not in the southern hemisphere, while increasing atmospheric Hg loads are still reported in East Asia. New observations and updated models now suggest high concentrations of oxidized HgII in the tropical and subtropical free troposphere where deep convection can scavenge these HgII reservoirs. As a result, up to 50% of total global wet HgII deposition has been predicted to occur to tropical oceans. Ocean Hg0 evasion is a large source of present-day atmospheric Hg (approximately 2900 Mg/year; range 1900-4200 Mg/year). Enhanced seawater Hg0 levels suggest enhanced Hg0 ocean evasion in the intertropical convergence zone, which may be linked to high HgII deposition. Estimates of gaseous Hg0 emissions to the atmosphere over land, long considered a critical Hg source, have been revised downward, and most terrestrial environments now are considered net sinks of atmospheric Hg due to substantial Hg uptake by plants. Litterfall deposition by plants is now estimated at 1020-1230 Mg/year globally. Stable isotope analysis and direct flux measurements provide evidence that in many ecosystems Hg0 deposition via plant inputs dominates, accounting for 57-94% of Hg in soils. Of global aquatic Hg releases, around 50% are estimated to occur in China and India, where Hg drains into the West Pacific and North Indian Oceans. A first inventory of global freshwater Hg suggests that inland freshwater Hg releases may be dominated by artisanal and small-scale gold mining (ASGM; approximately 880 Mg/year), industrial and wastewater releases (220 Mg/year), and terrestrial mobilization (170-300 Mg/year). For pelagic ocean regions, the dominant source of Hg is atmospheric deposition; an exception is the Arctic Ocean, where riverine and coastal erosion is likely the dominant source. Ocean water Hg concentrations in the North Atlantic appear to have declined during the last several decades but have increased since the mid-1980s in the Pacific due to enhanced atmospheric deposition from the Asian continent. Finally, we provide examples of ongoing and anticipated changes in Hg cycling due to emission, climate, and land use changes. It is anticipated that future emissions changes will be strongly dependent on ASGM, as well as energy use scenarios and technology requirements implemented under the Minamata Convention. We predict that land use and climate change impacts on Hg cycling will be large and inherently linked to changes in ecosystem function and global atmospheric and ocean circulations. Our ability to predict multiple and simultaneous changes in future Hg global cycling and human exposure is rapidly developing but requires further enhancement. PMID- 29388131 TI - Extracellular RNAs: A New Awareness of Old Perspectives. AB - Extracellular RNA (exRNA) has recently expanded as a highly important area of study in biomarker discovery and cancer therapeutics. exRNA consists of diverse RNA subpopulations that are normally protected from degradation by incorporation into membranous vesicles or by lipid/protein association. They are found circulating in biofluids, and have proven highly promising for minimally invasive diagnostic and prognostic purposes, particularly in oncology. Recent work has made progress in our understanding of exRNAs-from their biogenesis, compartmentalization, and vesicle packaging to their various applications as biomarkers and therapeutics, as well as the new challenges that arise in isolation and purification for accurate and reproducible analysis. Here we review the most recent advancements in exRNA research. PMID- 29388132 TI - Overview of Protocols for Studying Extracellular RNA and Extracellular Vesicles. AB - Understanding the role of extracellular RNA (exRNA) has emerged as an exciting avenue for biomarker, therapeutic, as well as basic cell-cell communication applications and discoveries. Multiple protocols, kits, and procedures have been developed in the last decade to allow fractionation as well as isolation of subpopulations of macromolecules of interest found in biofluids. Here, we introduce the protocols decision tree developed by the Extracellular RNA Communication Consortium and available on their website (exRNA portal), and compare all methods currently available to the exRNA field and report pros and cons for each platform. PMID- 29388129 TI - Linking science and policy to support the implementation of the Minamata Convention on Mercury. AB - The Minamata Convention on Mercury, with its objective to protect human health and the environment from the dangers of mercury (Hg), entered into force in 2017. The Convention outlines a life-cycle approach to the production, use, emissions, releases, handling, and disposal of Hg. As it moves into the implementation phase, scientific work and information are critically needed to support decision making and management. This paper synthesizes existing knowledge and examines three areas in which researchers across the natural sciences, engineering, and social sciences can mobilize and disseminate knowledge in support of Hg abatement and the realization of the Convention's objective: (1) uses, emissions, and releases; (2) support, awareness raising, and education; and (3) impacts and effectiveness. The paper ends with a discussion of the future of Hg science and policy. PMID- 29388133 TI - Extracellular RNA Isolation from Cell Culture Supernatant. AB - Extracellular RNAs are emerging as novel biomarkers and mediators of intercellular communication. Various methods to isolate RNA from biofluids and cell culture supernatants have been previously used by investigators. Here, we describe several standardized protocols for the isolation of RNAs from cell culture supernatants that utilize commercially available kits and reagents. PMID- 29388127 TI - Challenges and opportunities for managing aquatic mercury pollution in altered landscapes. AB - The environmental cycling of mercury (Hg) can be affected by natural and anthropogenic perturbations. Of particular concern is how these disruptions increase mobilization of Hg from sites and alter the formation of monomethylmercury (MeHg), a bioaccumulative form of Hg for humans and wildlife. The scientific community has made significant advances in recent years in understanding the processes contributing to the risk of MeHg in the environment. The objective of this paper is to synthesize the scientific understanding of how Hg cycling in the aquatic environment is influenced by landscape perturbations at the local scale, perturbations that include watershed loadings, deforestation, reservoir and wetland creation, rice production, urbanization, mining and industrial point source pollution, and remediation. We focus on the major challenges associated with each type of alteration, as well as management opportunities that could lessen both MeHg levels in biota and exposure to humans. For example, our understanding of approximate response times to changes in Hg inputs from various sources or landscape alterations could lead to policies that prioritize the avoidance of certain activities in the most vulnerable systems and sequestration of Hg in deep soil and sediment pools. The remediation of Hg pollution from historical mining and other industries is shifting towards in situ technologies that could be less disruptive and less costly than conventional approaches. Contemporary artisanal gold mining has well-documented impacts with respect to Hg; however, significant social and political challenges remain in implementing effective policies to minimize Hg use. Much remains to be learned as we strive towards the meaningful application of our understanding for stakeholders, including communities living near Hg-polluted sites, environmental policy makers, and scientists and engineers tasked with developing watershed management solutions. Site-specific assessments of MeHg exposure risk will require new methods to predict the impacts of anthropogenic perturbations and an understanding of the complexity of Hg cycling at the local scale. PMID- 29388134 TI - Use of a Hollow Fiber Bioreactor to Collect Extracellular Vesicles from Cells in Culture. AB - Current approaches for collection of extracellular vesicles (EV) are based on classical cell culture media production. This involves collection from cells grown in flasks, and can require multiple rounds of centrifugation or filtration, followed by ultracentrifugation or density gradient centrifugation. There are several limitations of these approaches, for example, they require a large input volume, the yield and concentration is low, and the process is time consuming. Most cell cultures require the use of fetal bovine serum which contains a large amount of endogenous EV that can contaminate isolations of cell-derived EVs. The use of cell cultures within a hollow fiber bioreactor could address many of these limitations and produce a continuous source of highly concentrated EVs without contamination from serum EVs, and that are suitable for downstream applications. PMID- 29388135 TI - Isolation of Extracellular RNA from Serum/Plasma. AB - Extracellular RNAs are initiating increased interest due to their potentials in serving as novel biomarkers, mediators of intercellular communication, and therapeutic applications. As a newly emerging field, one of the main obstacles is the lack of standardized protocols for RNA isolations. Here we describe protocols for commercially available kits that have been modified to yield consistent results for isolation of extracellular RNA from both whole serum/plasma and extracellular vesicle-enriched serum/plasma samples. PMID- 29388136 TI - Isolation of Extracellular RNA from Bile. AB - The study of extracellular RNA has been recently reported as a tool for biomarker discovery. Extracellular vesicles can be isolated from different types of body fluids which contain protein, mRNA, and noncoding RNA. Extracellular RNA isolated from bile could be a useful tool for analyzing biliary tract diseases or cancer. Herein, we describe protocols based on modifications of commercially available kits for the collection, processing, and isolation of extracellular RNA from bile. PMID- 29388128 TI - Modulators of mercury risk to wildlife and humans in the context of rapid global change. AB - Environmental mercury (Hg) contamination is an urgent global health threat. The complexity of Hg in the environment can hinder accurate determination of ecological and human health risks, particularly within the context of the rapid global changes that are altering many ecological processes, socioeconomic patterns, and other factors like infectious disease incidence, which can affect Hg exposures and health outcomes. However, the success of global Hg-reduction efforts depends on accurate assessments of their effectiveness in reducing health risks. In this paper, we examine the role that key extrinsic and intrinsic drivers play on several aspects of Hg risk to humans and organisms in the environment. We do so within three key domains of ecological and human health risk. First, we examine how extrinsic global change drivers influence pathways of Hg bioaccumulation and biomagnification through food webs. Next, we describe how extrinsic socioeconomic drivers at a global scale, and intrinsic individual-level drivers, influence human Hg exposure. Finally, we address how the adverse health effects of Hg in humans and wildlife are modulated by a range of extrinsic and intrinsic drivers within the context of rapid global change. Incorporating components of these three domains into research and monitoring will facilitate a more holistic understanding of how ecological and societal drivers interact to influence Hg health risks. PMID- 29388137 TI - Cushioned-Density Gradient Ultracentrifugation (C-DGUC): A Refined and High Performance Method for the Isolation, Characterization, and Use of Exosomes. AB - Exosomes represent one class of extracellular vesicles that are thought to be shed by all cell types. Although the exact nature of exosome biogenesis and function remains incompletely understood, they are increasingly recognized as a source of intercellular communication in health and disease. Recent observations of RNA exchange via donor cell-derived exosomes that exert genetic regulation in recipient cells have led to a boon into exosome research. The excitement and promise of exosomes as a new therapeutic avenue for human pathologies remain limited by challenges associated with their isolation from culture media and biofluids. The introduction of new methodologies to facilitate the isolation of exosomes has simultaneously raised concerns related to the reproducibility of studies describing exosome effector functions. Even high-speed ultracentrifugation, the first and long considered gold standard approach for exosome isolation has recently been noted to be subject to uncontrolled variables that could impact functional readouts of exosome preparations. This chapter describes principles and methods that attempt to overcome such limitations by first concentrating exosomes in a liquid cushion and subsequently resolving them using density gradient ultracentrifugation. Our approach avoids possible complications associated with direct pelleting onto plastic tubes and allows for further purification of exosomes from dense protein aggregates. PMID- 29388138 TI - Magnetic Particle-Based Immunoprecipitation of Nanoscale Extracellular Vesicles from Biofluids. AB - Analysis of nanoscale extracellular vesicles (nsEVs) present in blood, cell culture media, and other biofluids has shown tremendous promise in enabling the development of noninvasive blood-based clinical diagnostic tests, predicting and monitoring the efficacy of treatment programs, and providing molecular level insights into pathology that can enlighten new drug targets in the contexts of health conditions such as cancer and Alzheimer's Disease (AD). In this chapter, we present methods for using magnetic particle-based immunoprecipitation to enrich highly purified populations of nsEVs directly from plasma, serum, and other biofluids. These methods enable downstream analysis of nsEV protein and nucleic acid constituents in the contexts of both global omics profiling and quantification of individual protein or nucleic acid species of interest. Additionally, these methods allow the researcher to either enrich total nsEV populations or enrich nsEVs derived from a particular tissue type from the overall nsEV population. The methods described here are compatible with parallel processing of dozens of biofluid samples and can be valuable tools for enabling nsEV analyses that have high translational relevance in the development of both novel therapeutics and noninvasive diagnostic assays. PMID- 29388139 TI - Enrichment of Extracellular Vesicle Subpopulations Via Affinity Chromatography. AB - Extracellular vesicles (EVs) are secreted nanoscale particles that transfer biomolecular cargo between cells in multicellular organisms. EVs play a variety of roles in intercellular communication and are being explored as potential vehicles for delivery of therapeutic biomolecules. However, EVs are highly heterogeneous in composition and biogenesis route, and this poses substantial challenges for understanding the role of EVs in biology and for harnessing these mechanisms for therapeutic applications, for which purifying therapeutic EVs from mixed EV populations may be necessary. Currently, technologies for isolating EV subsets are limited by overlapping physical properties among EV subsets. To meet this need, here we report an affinity chromatography-based method for enriching a specific EV subset from a heterogeneous EV starting population. By displaying an affinity tagged protein (tag-protein) on the EV surface, tagged EVs may be specifically isolated using simple affinity chromatography. Moreover, recovered EVs are enriched in the tag-protein relative to the starting population of EVs and relative to EVs purified from cell culture supernatant by standard differential centrifugation. Furthermore, chromatographically enriched EVs confer enhanced delivery of a cargo protein to recipient cells (via enhancing the amount of cargo protein per EV) relative to EVs isolated by centrifugation. Altogether, affinity chromatographic enrichment of EV subsets is a viable and facile strategy for investigating EV biology and for harnessing EVs for therapeutic applications. PMID- 29388140 TI - Detection and Analysis of Non-vesicular Extracellular RNA. AB - Although extracellular vesicles (EVs) are by far the most studied carriers of extracellular small RNAs involved in cell-to-cell communication, most extracellular small RNAs are actually present as soluble vesicle-free supramolecular complexes. Several proteins have been described as the counterparts of these RNase-protected complexes. Here we describe a method for the purification and analysis of non-vesicular extracellular RNA derived from the conditioned media of mammalian cell culture. Focus on this fraction will increase our understanding on extracellular RNA biology, while serving as a source for biomarker discovery complementary to EVs. PMID- 29388141 TI - Isolation of Plasma Lipoproteins as a Source of Extracellular RNA. AB - Plasma lipoproteins are essential vehicles of lipid distribution for cellular energy and structural requirements as well as for excretion of lipid excess. Imbalances in lipoprotein metabolism are known to contribute to metabolic diseases ranging from vascular inflammation and atherosclerosis to obesity and diabetes. The lipid and protein cargo carried by lipoprotein subclasses have long been the focus of studies exploring the contribution of plasma lipoproteins in health and in metabolic disorders. More recent studies have revealed the presence of noncoding RNA as a new form of cargo carried by plasma lipoproteins. Lipoprotein-associated microRNAs have been identified to distribute differentially among plasma lipoprotein subclasses and contribute to cellular signaling. These findings highlight plasma lipoprotein-associated RNA as a potential source of biological signaling and warrant a renewed interest in the study of plasma lipoprotein biology. This chapter describes principles and methods based on density ultracentrifugation and size exclusion chromatography for the isolation of plasma lipoproteins as a source of extracellular RNA. PMID- 29388142 TI - Droplet Digital PCR for Quantitation of Extracellular RNA. AB - Cell-to-cell communication involves the release of biological molecules into the extracellular space and their uptake by recipient cells. These molecules include RNA that can modulate cellular signaling and biological processes. To study extracellular RNA, highly sensitive and precise methods for their detection are needed. Digital polymerase chain reaction (dPCR) can be a useful method for detecting and analyzing extracellular RNA. The sensitivity of digital PCR can exceed that of quantitative PCR for low abundance targets such as extracellular RNA. PMID- 29388143 TI - Preparation of Small RNA NGS Libraries from Biofluids. AB - Next generation sequencing (NGS) is a powerful method for transcriptome analysis. Unlike other gene expression profiling methods, such as microarrays, NGS provides additional information such as splicing variants, sequence polymorphisms, and novel transcripts. For this reason, NGS is well suited for comprehensive profiling of the wide range of extracellular RNAs (exRNAs) in biofluids. ExRNAs are of great interest because of their possible biological role in cell-to-cell communication and for their potential use as biomarkers or for therapeutic purposes. Here, we describe a modified protocol for preparation of small RNA libraries for NGS analysis. This protocol has been optimized for use with low input exRNA-containing samples, such as plasma or serum, and has modifications designed to reduce the sequence-specific bias typically encountered with commercial small RNA library construction kits. PMID- 29388144 TI - Multiplexed Detection and Quantitation of Extracellular Vesicle RNA Expression Using NanoString. AB - Several different types of RNA molecules such as microRNAs (miRNAs) have been detected within extracellular vesicles in the circulation. The detection and potential utility of these as disease biomarkers requires the ability to detect their presence with adequate sensitivity and to quantitate their expression. The potential for circulating miRNA to serve as biomarkers can be evaluated through their detection in association with specific disease states. Multiplexed detection of several miRNA simultaneously can be useful for discovery studies. We describe the analysis of miRNA from biological fluids like plasma and serum using the Nanostring nCounter platform. Assays can be used to quantitate the expression of miRNA using direct detection based on hybridization to target specific color coded probes followed by counting each color-coded barcode digitally. PMID- 29388145 TI - Milk-derived Extracellular Vesicles for Therapeutic Delivery of Small Interfering RNAs. AB - As endogenous biological nanoparticles capable of uptake by cells, extracellular vesicles (EVs) have the capacity to deliver their RNA cargo to recipient cells. The use of EVs as a drug delivery system remains in its infancy, and there are several barriers to the use of EV for this purpose. Amongst these is the need to ensure that adequate amounts of EV are available. The use of milk-derived EV provides a scalable approach and loading of these EVs with RNA is possible with the use of chemical transfection reagents. This method describes the use of milk derived EV for delivery of small interfering RNA. These EVs were shown to be taken up by hepatocellular carcinoma cells in vitro, with a reduction in the expression of target gene. PMID- 29388146 TI - Loading of Extracellular Vesicles with Hydrophobically Modified siRNAs. AB - Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics. Small, endogenous extracellular vesicles (EVs) have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into vesicles are lacking. Here we describe the efficient loading of hydrophobically modified siRNAs (hsiRNAs) into EVs upon co-incubation, without altering vesicle size distribution or integrity. This method is expected to advance the development of EV-based therapies for the treatment of a broad range of disorders. PMID- 29388147 TI - Prevalence and trend of isolated and complicated congenital hydrocephalus and preventive effect of folic acid in northern China, 2005-2015. AB - Congenital hydrocephalus (CH) was a major birth defect of the central nervous system besides neural tube defects (NTDs). Few studies have focused on both the prevalence and trend of isolated and complicated CH in China. Data were drawn from a population-based birth defects surveillance program in five rural counties in northern China from 2005 to 2015. All livebirths and pregnancy terminations at any gestational age affected with CH were recorded. The prevalence and trend of isolated and complicated CH were examined. During the 11-year period, a total of 176,223 births and 357 CH cases were recorded, resulting in a prevalence rate of 20.3 CH cases per 10,000 births. Of the CH cases, 146 were isolated CH, resulting in a prevalence rate of 8.3 per 10,000 births. The pre-perinatal prevalence (<28 gestational weeks) was higher than the perinatal prevalence for both isolated and total CH. The prevalence rates of total and isolated CH showed a similar downward trend during the 11-year period. This downward trend was statistically significant after 2009 (p < 0.05), when a massive folic acid supplementation program was introduced. Although it decreased over time, the prevalence of CH remains high in this population which has a high prevalence of neural tube defects. PMID- 29388149 TI - Preface: Special Issue-College Experiences for Students with Autism Spectrum Disorder. PMID- 29388148 TI - Child, Maternal and Demographic Factors Influencing Caregiver-Reported Autistic Trait Symptomatology in Toddlers. AB - Current research on children's autistic traits in the general population relies predominantly on caregiver-report, yet the extent to which individual, caregiver or demographic characteristics are associated with informants' ratings has not been sufficiently explored. In this study, caregivers of 396 Singaporean two-year olds from a birth cohort study completed the Quantitative Checklist for Autism in Toddlers. Children's gender, cognitive functioning and birth order, maternal age, and ethnic group membership were not significant predictors of caregiver-reported autistic traits. Poorer child language development and higher maternal depressive symptoms significantly predicted more social-communicative autistic traits, while lower maternal education predicted more behavioural autistic traits. Children's language and informants' educational level and depressive symptomatology may need to be considered in caregiver-reports of autistic traits. PMID- 29388150 TI - Rv0646c, an esterase from M. tuberculosis, up-regulates the host immune response in THP-1 macrophages cells. AB - The genome sequence of Mycobacterium tuberculosis revealed the presence of several hydrolases involved in lipid metabolism including the members of Lip gene family. Rv0646c (LipG) is one of them. It is annotated as putative esterase/lipase because of the presence of consensus sequence 'GXSXG.' The gene was cloned, expressed, and purified in E. coli. It showed 22 U/mg specific activity with pNP-butyrate as a preferred substrate. However, it actively worked on substrates with short chain. The enzyme was optimally active at 50 degrees C/pH 8.0 and also stable up to 50 degrees C and in a lower pH range (pH 6-8). The Km, Vmax, and catalytic efficiency of the enzyme were calculated to be 500 uM, 58.82 umoles/min/ml, and 3.92 uM/min, respectively. Homology modeling of Rv0646c revealed the presence of a canonical putative catalytic triad (Ser123, His279, and Asp251). The esterase activity was abolished in the presence of serine hydrolase inhibitors, THL and PMSF. Various antigenic epitopes were predicted in Rv0646c. The protein mounted significantly high antibody response against the sera of extrapulmonary and MDR-TB patients. Rv0646c up-regulated the production of various pro-inflammatory cytokines (TNF-alpha and IFN-gamma), chemokine (IL-8), and nitric oxide in THP-1-derived macrophages. The secretion of IL-6 from macrophages was also found to be elevated in response to Rv0646c. The treatment resulted in the increased level of reactive oxygen species. Conclusively, Rv0646c could be classified as esterase having vast immunogenic property by eliciting strong humoral response as well as cell-mediated immunity. PMID- 29388151 TI - P16 promotes the growth and mobility potential of breast cancer both in vitro and in vivo: the key role of the activation of IL-6/JAK2/STAT3 signaling. AB - P16 is the product of cyclin-dependent kinase 2 (CDKN2A) gene and plays multi pronged roles in the cancer progression. Breast cancer (BC) is the most commonly diagnosed cancer type among females. In the current study, the potential function of P16 in the growth and metastasis of BC was investigated. Firstly, the expression statuses of P16 in different cancer types were investigated using Oncomine database and validated with corresponding cancer cell lines. Afterwards, the expression of P16 was knocked down in BC cell line BT-549 and the effect on the cell proliferation, sensitivity to paclitaxel (TAX), apoptosis, migration, and invasion abilities was assessed using CCK-8, Edu, flow cytometry, scratch, and transwell assays, respectively. The influence of P16 inhibition and P16 overexpression on the activity of IL-6/JAK/STAT3 signaling was explored. Additionally, the effect of P16 inhibition on the tumor growth was verified with a BC xenograft mice model. The abnormal expression of P16 was detected in BC cell line BT-549 as well as colorectal cancer and osteosarcoma cell lines. The inhibition of P16 suppressed the cell proliferation, invasion, and migration abilities while induced the apoptosis and sensitivity to TAX in BT-549 cells. At molecular level, P16 knockdown inhibited the expression of IL6ST and Survivin, and the phosphorylation of JAK2 and STAT3. However, the induced expression of P16 in P16-knockdown BT-549 cells restored the activity of IL-6/JAK2/STAT3 pathway. The results of in vitro assays were confirmed with BC xenograft models: the inhibition of P16 decreased the tumor growth rate. Findings outlined in the current study demonstrated that the inhibition of P16 decreased the growth and metastasis potential of BC cells by inhibiting IL-6/JAK2/STAT3 signaling. PMID- 29388152 TI - Novel miR-sc4 regulates the proliferation and migration of Schwann cells by targeting Cdk5r1. AB - The proliferation and migration of Schwann cells are critical for the repair and regeneration of injured peripheral nerves. Noncoding RNAs, especially microRNAs (miRNAs), have been demonstrated to participate in regulating the biological behaviors of Schwann cells. Numerous differentially expressed novel miRNAs have been identified in the injured sciatic nerve stumps previously by Solexa sequencing. In the current research, we studied the biological function of a novel miRNA, miR-sc4, in detail. Outcomes from proliferation and migration assays suggested that miR-sc4 played an inhibitory role on the proliferation and migration of Schwann cells. Results from bioinformatic analysis, luciferase reporter assay, and rescue experiments suggested that miR-sc4 executed its effect through directly targeting cyclin-dependent kinase 5 activator 1 (Cdk5r1). Collectively, our current study revealed the biological functions of a novel miRNA, showed the effect of miR-sc4 in Schwann cell phenotypic changes, and thus indicated the involvement of miRNAs in peripheral nerve repair and regeneration. PMID- 29388154 TI - Exposure to the antifouling chemical medetomidine slows development, reduces body mass, and delays metamorphosis in wood frog (Lithobates sylvaticus) tadpoles. AB - Antifouling chemicals have a long history of causing toxicity to aquatic organisms. We measured growth and developmental timing in wood frog tadpoles exposed to the antifouling chemical medetomidine (10 nM-10 MUM) starting at two different developmental stages in static renewal experiments. For tadpoles hatched from egg masses and exposed for 3 weeks to 100 nM and 1 MUM, head width/total body length ratio was significantly shorter compared to control. For field-collected tadpoles at Gosner stage 24-25 and exposed for 2 weeks, 1 and 10 MUM medetomidine significantly slowed development as measured by Gosner stage. Medetomidine (1 and 10 MUM) significantly increased the time to metamorphosis by over 16 days on average, and at 100 nM and 1 MUM, it significantly decreased mass at metamorphosis. We discuss the possible effects of antifouling chemicals containing medetomidine on globally threatened groups such as amphibians. PMID- 29388155 TI - Fate of Lu(III) sorbed on 2-line ferrihydrite at pH 5.7 and aged for 12 years at room temperature. I: insights from ICP-OES, XRD, ESEM, AsFlFFF/ICP-MS, and EXAFS spectroscopy. AB - Two-line ferrihydrite (2LFh) was aged for 12 years under ambient conditions and sheltered from light in the presence of Lu(III) used as surrogate for trivalent actinides. 2LFh aging produced hematite rhombohedra with overgrown acicular goethite particles. Analysis of the homogeneous suspension by asymmetrical flow field-flow fractionation (AsFlFFF) coupled to ICP-MS indicated that particles have a mean hydrodynamic diameter of about 140 nm and the strong correlation of the Fe and Lu fractograms hinted at a structural association of the lanthanide with the solid phase(s). Unfortunately, recoveries were low and thus results cannot be considered representative of the whole sample. The suspension was centrifuged and X-ray absorption spectroscopy (XAS) at the Lu L 3 -edge on the settled particles indicated that Lu(III) is sixfold coordinated by oxygen atoms, pointing to a retention by structural incorporation within particles. This result is consistent with AsFlFFF results on the same suspension without centrifugation. The detection of next nearest Fe and O atoms were consistent with the structure of goethite, ruling out incorporation within hematite. After centrifugation of the suspension, only nanoparticulate needle-like particles, very likely goethite, could be detected in the supernatant by ESEM. AsFlFFF data of the supernatant were comparable to that obtained for the homogeneous suspension, whereas XAS indicated that Lu(III) is predominantly present as dissolved species in the supernatant. Results from both techniques can be interpreted as a major fraction of Lu present as aqueous ions and a minor fraction as structurally incorporated. Findings from this study are corroborated by STEM-HAADF data and results from DFT calculations in a companion paper. PMID- 29388156 TI - Unexpected potential protective associations between outdoor air pollution and cataracts. AB - Air pollution is one of the biggest public health issues, and the eye is continuously exposed to multiple outdoor air pollution. However, to date, no large-scale study has assessed the relationship between air pollutants and cataracts. We investigated associations between outdoor air pollution and cataracts in the Korean population. A population-based cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, including 18,622 adults more than 40 years of age. The presence of cataracts and their subtypes were evaluated by ophthalmologists. Air pollution data (levels of particulate matter, ozone, nitrogen dioxide, and sulfur dioxide) for the 2 years prior to the ocular examinations were collected from national monitoring stations. The associations of multiple air pollutants with cataracts were assessed by multivariate logistic regression analyses. Sociodemographic factors and previously known risk factors for cataracts were controlled as covariates (model 1 included sociodemographic factors, sun exposure, and behavioral factors, while model 2 further included clinical factors). Higher ozone concentrations were protectively associated with overall cataract which included all subtypes [single pollutant model: 0.003 ppm increase-model 1 (OR 0.89, p = 0.014), model 2 (OR 0.87, p = 0.011); multi-pollutant model: 0.003 ppm increase-model 1 (OR 0.80, p = 0.002), model 2 (OR 0.87, p = 0.002)]. Especially, higher ozone concentrations showed deeply protective association with nuclear cataract subtype [0.003 ppm increase-single pollutant model: model 2 (OR 0.84, p = 0.006), multi-pollutant model: model 2 (OR 0.73, p < 0.001)]. Higher tropospheric ozone concentrations showed protective associations with overall cataract and nuclear cataract subtype in the Korean population. PMID- 29388153 TI - Ellagic acid in suppressing in vivo and in vitro oxidative stresses. AB - Oxidative stress is a biological condition produced by a variety of factors, causing several chronic diseases. Oxidative stress was, therefore, treated with natural antioxidants, such as ellagic acid (EA). EA has a major role in protecting against different diseases associated with oxidative stress. This review critically discussed the antioxidant role of EA in biological systems. The in vitro and in vivo studies have confirmed the protective role of EA in suppressing oxidative stress. The review also discussed the mechanism of EA in suppressing of oxidative stress, which showed that EA activates specific endogenous antioxidant enzymes and suppresses specific genes responsible for inflammation, diseases, or disturbance of biochemical systems. The amount of EA used and duration, which plays a significant role in the treatment of oxidative stress has been discussed. In conclusion, EA is a strong natural antioxidant, which possesses the suppressing power of oxidative stress in biological systems. PMID- 29388157 TI - Evaluating the effect of rain on the fate of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) accumulated in polluted trees in Amman, Jordan. AB - Open combustion of solid waste is one of the main sources of the emission of dioxin and dioxin-like compounds (DLCs). Ambient dioxin will eventually undergo depositions on soils and tree leaves. Pine trees have shown an ability to store dioxin in their needles allowing biomonitoring of dioxin atmospheric concentrations. Infiltration can transport dioxin to greater depths into the ground, on one hand, while vaporization can allow dioxin to return back to the atmosphere on the other. Several studies evaluated the migration of dioxin between two compartments; however, few studies have attempted to understand the fate of non-conservative PCDDs and PCDFs in an unsteady state system of more than two mediums. This study focused on the transportation of dioxin between polluted trees and the underlying soil through the effect of rain water. For approximately 10 years, pine trees in this study have been exposed to emissions generated by the open combustion of municipal solid waste (MSW) from a fixed location. Soil samples located further from the point source had generally lower dioxin concentrations. Dioxin concentrations were correlated to distance from the source using least square regression. Soil samples below contaminated trees had dioxin concentrations 10-35% greater than the calculated measurements for the same spots using the regression model. By detecting these spikes in concentrations, it was possible to identify pools of dioxin found directly under the contaminated trees indicating a rinsing effect of rain water on the stored dioxin on the trees' needles. PMID- 29388158 TI - Effects of Blackcurrant and Dietary Fibers on Large Intestinal Health Biomarkers in Rats. AB - This study examined the effects of anthocyanin-rich blackcurrant extract and dietary fibers individually and their combinations on biomarkers of large intestinal health in rats. After six weeks of feeding, rats fed diets with blackcurrant gained significantly less body weight and reduced their food intake resulting in a lower food efficiency compared with those rats fed control diets. Combining dietary fiber (apple or broccoli) with blackcurrant in the diet was more effective in reducing the body weight gain and food intake. Cecal bacterial populations and short-chain fatty acids differed between the experimental diets. Blackcurrants significantly altered the bacterial populations by increasing the abundance of Bacteroides-Prevotella-Porphyromonas group and Lactobacillus spp., while decreasing the abundance of Bifidobacterium spp. and Clostridium perfringens. Propionic acid concentrations were increased by the diets with blackcurrant. Butyric acid concentrations were increased by dietary fiber supplementation. Dietary fiber increased the number of goblet cells in the colon. Diets with blackcurrant were more effective in altering the biomarkers of large intestinal health than those without blackcurrant. PMID- 29388159 TI - Provocation of clinically significant left ventricular outflow tract obstruction by postural change in patients with sigmoid septum. PMID- 29388160 TI - Correction to: The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease. AB - In the original version of this article, the name of one of the authors is not correct. The correct name should be W. A. Linke, which is shown correctly in the authorgroup section above. PMID- 29388161 TI - Modified end-to-side double-layer open pancreaticogastrostomy after Whipple procedure: surgical tips for a safe anastomosis. AB - Pancreatic fistula (PF) remains the Achilles' heel of pancreaticoduodenectomy (PD). Pancreaticogastrostomy (PG) appears to be associated with a lower risk of postoperative leak according to recent evidence. We started to fashion PG, especially in soft pancreas, modifying the original technique described by Bassi. At our institution, 105 PD procedures were carried out from January 2011 to December 2016; pancreatic-enteric continuity was restored by PG in 35 cases. Superior mesenteric/portal vein resection/reconstruction was necessary in three patients. A total of 34/35 patients underwent PG with an open anterior gastrostomy approach. Briefly, our double-layer PG anastomosis (illustrated by a video) starts with a posterior row of interrupted absorbable 4/0 monofilament sutures including the gastric serosa and the pancreatic capsule. It is essential to mobilize the left pancreas for 4-5 cm and to shape the posterior gastrostomy shorter than the pancreatic stump. After a wide anterior auxiliary gastrostomy the pancreas is invaginated into the stomach and an interrupted row of sutures between the posterior gastric wall (full-thickness) and the body of the pancreatic stump is fashioned. The anterior gastrostomy is closed with an absorbable running suture. Finally, a further layer of sutures is applied over the posterior suture line between the gastric serosa and the pancreatic capsule. The 90-day postoperative mortality was nihil. No biliary leakage was detected and the overall PF rate was 11.4% (4/35) according to the ISGPF study group. Only one patient suffered a grade B PF (in this case, PG was carried out only through a posterior gastrostomy), whereas three patients had a minor (grade A) PF. Our modified PG proved to be safe and easy to perform, while it carried excellent outcomes even in the setting of soft pancreas. Despite the limited number of cases, such modified PG appears promising, particularly for pancreatic remnants at higher risk of PF. PMID- 29388162 TI - Epidemiological investigation of Borrelia burgdorferi in horses in the municipality of Sinop-MT, Brazil. AB - Borrelia burgdorferi sensu stricto is the main etiological agent of Lyme disease (LD) in the USA. In Brazil, it is believed that a similar spirochete is the causal agent of the Baggio-Yoshinari syndrome (BYS), a zoonosis also transmitted by ticks, whose clinical manifestations are similar to those of LD. Despite the epidemiological importance, there are no studies reporting the presence and the prevalence of B. burgdorferi among horses in Mato Grosso State. The aim of this study was to detect and measure the frequency of IgG antibodies anti-B. burgdorferi American strain G39/40 in horses in the municipality of Sinop, MT Brazil, using the indirect enzyme-linked immunosorbent assay (ELISA) for serological diagnosis. Blood samples from 367 horses were collected in 81 farms. An epidemiological questionnaire was applied during the visits to obtain information related to the animals and the farms. From the 367 horses, 214 were positive for B. burgdorferi sensu stricto according to the results of the ELISA test, representing an apparent prevalence of 54.04% [CI = 0.4548051-0.6237234]. Concomitantly, 89 blood samples were taken for molecular analysis by nested polymerase chain reaction (PCR). According to the PCR test results, none of the samples were reactive, although 53 of these samples were reactive according to ELISA. Seventy five farms (92.59%) had at least one reactive horse for B. burgdorferi. Our results support the hypothesis of the presence of anti-Borrelia spp. antibodies in horses in Mato Grosso, reaching a high animal prevalence. Besides that, leisure/sport purposes proved to be a risk factor, with an odds ratio of 3.16. These findings clearly indicate the need of borreliosis control in Sinop and make a significant contribution to the knowledge of the disease in Mato Grosso. PMID- 29388163 TI - Evidence of subclinical foot-and-mouth disease virus infection in young calves born from clinically recovered cow under natural condition. AB - Foot-and-mouth disease (FMD) is a highly contagious and economically important, transboundary viral disease of cloven-hoofed animals. It is known that an asymptomatic, persistent FMD virus (FMDV) infection may occur subsequent to acute or subclinical FMDV infection in adult ruminants. However, virus persistence in young calves has not been studied. In the current investigation, FMDV infection parameters were examined for calves born to FMD-clinically recovered cows (CRC), asymptomatic cows from infected herds (ASC) and cows from with no history of FMD (NHF). The study was conducted in natural condition after FMD outbreaks in two dairy herds in India. No calves described herein had any clinical signs of FMD. Six out of 12 calves born to CRC had detectable FMDV RNA in oesophageal pharyngeal fluid consistent with asymptomatic FMDV infection. Three of the 12 calves of CRC group had seroreactivity against FMDV non-structural proteins. One calf had detectable FMDV RNA at two consecutive samplings at 2 months apart. However, infectious FMDV was not isolated from any calf in the study. None of the calves in the ASC or NHF groups had any evidence of FMDV infection. Overall, these data are consistent with earlier report on calves having been infected in utero. Further investigation of FMDV persistence in calves under controlled conditions may lead to greater understanding of the viral pathogenesis. PMID- 29388164 TI - Improved progression-free and event-free survival in myeloma patients undergoing PBSCH receiving a cyclophosphamide + G-CSF regimen than G-CSF alone. AB - Two regimens are commonly used for peripheral blood hematopoietic stem cell harvesting (PBSCH) in multiple myeloma: high-dose cyclophosphamide (HD-CY) + granulocyte-colony stimulating factor (G-CSF), and G-CSF alone. The objective of the present study was to evaluate the anti-myeloma effect of the PBSCH regimen including HD-CY. We retrospectively assessed harvesting efficiency, complications, and anti-myeloma effects in 115 patients receiving HD-CY + G-CSF (HD-CY group) and 32 patients receiving G-CSF alone (G-alone group). We collected > 2 * 106 CD34-positive cells/kg from 93 and 75% of patients in the HD-CY and G alone groups, respectively (P = 0.0079). The mean HSC count was also higher in the HD-CY group. No severe complications were observed in the G-alone group, whereas 66% of patients in the HD-CY group were treated with intravenous antibiotics. The median progression-free and event-free survival (PFS and EFS) were longer in the HD-CY group than in the G-alone group (28 vs. 18 months and 25 vs. 13 months, respectively; P = 0.0127 and 0.0139), with no difference in median overall survival. HD-CY showed anti-myeloma effect, as verified by prolonged EFS and PFS, when a vincristine, doxorubicin, and dexamethasone regimen was administered as induction before PBSCH. PMID- 29388165 TI - Cloning and expansion of antigen-specific T cells using iPS cell technology: development of "off-the-shelf" T cells for the use in allogeneic transfusion settings. AB - Recent advances in adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) have led to moderate therapeutic anti-cancer effects in clinical trials. However, a critical issue, namely that CTLs collected from patients are easily exhausted during expansion culture, has yet to be solved. To address this issue, we have been developing a strategy which utilizes induced pluripotent stem cell (iPSC) technology. This strategy is based on the idea that when iPSCs are produced from antigen-specific CTLs, CTLs regenerated from such iPSCs should show the same antigen specificity as the original CTLs. Pursuing this idea, we previously succeeded in regenerating melanoma antigen MART1-specific CTLs, and more recently in producing potent CTLs expressing CD8alphabeta heterodimer. We are now developing a novel method by which non-T derived iPSCs are transduced with exogenous T cell receptor genes. If this method is applied to Human Leukocyte Antigen (HLA) haplotype-homozygous iPSC stock, it will be possible to prepare "off-the-shelf" T cells. As a first-in-human trial, we are planning to apply our strategy to relapsed acute myeloid leukemia patients by targeting the WT1 antigen. PMID- 29388166 TI - Current status and progress of lymphoma management in China. AB - Lymphoma is a large group of lymphoid hematopoietic malignancies including Hodgkin lymphoma and non-Hodgkin's lymphoma. The various subtypes of lymphoma are different in clinical features, response to treatment and prognoses. The relative frequency of specific subtypes of lymphoma varies geographically. The mature T cell lymphoma is much more common in East Asia compared with Western countries. Chemotherapy plays an important role in the treatment of lymphoma. With advances in understanding the biology and genetics of lymphoma, many new agents are used in the treatment of lymphoma. In mainland China, some new agents and new combination chemotherapy regimens showed high efficacy and good tolerability. Chidamide, a histone deacetylase inhibitor, has been approved for the treatment of relapsed or refractory peripheral T cell lymphoma by the China Food and Drug Administration. Anti-programmed death 1 antibodies and chimeric antigen receptor engineered T cells have been explored for lymphoma immunotherapy in Chinese patients. Advances in the treatment have substantially increased the likelihood of cure for patients with lymphoma. PMID- 29388168 TI - Advanced native-kidney carcinoma in a heart- and kidney-transplanted patient: a case report. AB - Malignancies are one of the leading causes of death in long-term surviving transplant recipients. Dose and prolonged durations of immunosuppressive regimens are considered the main cause, through a direct oncogenic effect and a renowned interaction on physiological anti-viral and anti-oncogenic immune response. Specific neoplasms are known to occur with different frequencies according to the transplanted organ. As a consequence, imaging screenings have been implemented in many graft surveillance programs, although a wide consensus on the timing and modality has not been concurred. There are little data available in the literature regarding incidence of de-novo malignancies in multi-organ recipients. We report the case of a 66-year-old man who developed a renal mass 10 years after a combined heart-kidney transplant. PMID- 29388167 TI - Surface Induced Dissociation Coupled with High Resolution Mass Spectrometry Unveils Heterogeneity of a 211 kDa Multicopper Oxidase Protein Complex. AB - Manganese oxidation is an important biogeochemical process that is largely regulated by bacteria through enzymatic reactions. However, the detailed mechanism is poorly understood due to challenges in isolating and characterizing these unknown enzymes. A manganese oxidase, Mnx, from Bacillus sp. PL-12 has been successfully overexpressed in active form as a protein complex with a molecular mass of 211 kDa. We have recently used surface induced dissociation (SID) and ion mobility-mass spectrometry (IM-MS) to release and detect folded subcomplexes for determining subunit connectivity and quaternary structure. The data from the native mass spectrometry experiments led to a plausible structural model of this multicopper oxidase, which has been difficult to study by conventional structural biology methods. It was also revealed that each Mnx subunit binds a variable number of copper ions. Becasue of the heterogeneity of the protein and limited mass resolution, ambiguities in assigning some of the observed peaks remained as a barrier to fully understanding the role of metals and potential unknown ligands in Mnx. In this study, we performed SID in a modified Fourier transform-ion cyclotron resonance (FTICR) mass spectrometer. The high mass accuracy and resolution offered by FTICR unveiled unexpected artificial modifications on the protein that had been previously thought to be iron bound species based on lower resolution spectra. Additionally, isotopically resolved spectra of the released subcomplexes revealed the metal binding stoichiometry at different structural levels. This method holds great potential for in-depth characterization of metalloproteins and protein-ligand complexes. Graphical Abstract ?. PMID- 29388169 TI - A case of unilateral nephrectomy performed for autosomal dominant polycystic kidney disease with marked unilateral enlargement. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the occurrence of multiple cysts that increase the size of both kidneys, progressively reducing kidney function. Usually the cysts occur bilaterally, and there is no difference in the degree of cyst enlargement between the left and right. Here, we report a case of ADPKD in which kidney size increased markedly on the left side and was accompanied by severe abdominal distension and discomfort. Renal dynamic scintigraphy revealed a severe reduction in function of the left kidney compared with the right. Open left nephrectomy was performed. No change in renal function was observed postoperatively [preoperative estimated glomerular filtration rate (eGFR): 57.6 mL/min/1.73 m2, 3-month postoperative eGFR: 56.4 mL/min/1.73 m2], and the abdominal symptoms subsided. When one kidney is markedly larger than the other, the cause and status of the laterality should be evaluated by using renal dynamic scintigraphy in addition to other examinations such as computed tomography or magnetic resonance imaging. Unilateral nephrectomy should be considered as a potential treatment. PMID- 29388170 TI - Never say never in medicine: successful pregnancy in a hemodialysis patient despite tubal ligation. PMID- 29388171 TI - Combined membranous nephropathy and tubulointerstitial nephritis as a rare renal manifestation of IgG4-related disease: a case-based literature review. AB - IgG4-related disease (IgG4-RD) is a newly recognized immune-mediated multisystemic disease characterized by a fibro-inflammatory condition with tissue infiltration of IgG4-positive plasma cells and often associated with elevated serum IgG4 levels. Typical renal involvement of IgG4-RD presents as tubulointerstitial nephritis (TIN), membranous or membranoproliferative nephropathy. We are presenting a case with combined IgG4 membranous nephropathy and TIN, as well as a literature review on pathophysiology, diagnosis and treatment of IgG4-RD. A 62-year-old man presented with weight loss and fatigue. Labs showed significant proteinuria and hematuria with elevated serum creatinine (2.5 mg/dL). CT/PET scan found scattered lymphadenopathy without increased FDG uptake. Kidney biopsy showed glomerular lesions as well as severe interstitial fibrosis and tubular atrophy. Immunohistochemistry study was negative for anti phospholipase A2 receptor antibodies and showed interstitial lymphocytic infiltration with IgG4 positive plasma cells. Patient also had elevated serum IgG4 level and IgG4 to total IgG ratio. Prednisone treatment was initiated soon after the diagnosis was made, patient responded well with proteinuria and hematuria both resolved. IgG4-related disease (IgG4-RD) is a newly increasingly recognized immune-mediated multisystemic disease; IgG4-related membranous nephropathy should be included in the differential diagnosis for patients with proteinuria. PMID- 29388172 TI - [A Rare Cause of Perinatal Postrenal Failure with Megalourethra]. AB - We present a case of a premature infant with a presumed obstructive uropathy found to be a megalourethra leading to a perinatal postrenal failure. A megalourethra - an uncommon cause of urethral dilatation - is a congenital, non obstructive anomaly of the penile erectile tissue. We think that a distal stenosis resulted in dysplasia of the penile tissue and an aspect of a megalourethra. Further diagnostic workup included urinary tract sonograms, a voiding cystourethrogram and MAG3 scintigrafy. Initially the patient was managed with supportive care such as a suprapubic urinary catheter, followed by surgical intervention (Bengt Johanson). PMID- 29388173 TI - Prescription of Benzodiazepines and Related Drugs in Patients with Mild Cognitive Deficits and Alzheimer's Disease. AB - INTRODUCTION: Benzodiazepines and related drugs (BZDR) should be avoided in patients with cognitive impairment. We evaluated the relationship between a BZDR treatment and the health status of patients with Alzheimer's disease (AD). METHODS: Cross-sectional study in 395 AD patients using bivariate and multiple logistic analyses to assess correlations between the prescription of BZDR and patients' characteristics (cognitive and functional capacity, health-related quality of life (HrQoL), neuropsychiatric symptoms). RESULTS: BZDR were used in 12.4% (n=49) of all participants. In bivariate analyses, the prescription was associated with a lower HrQoL, a higher need of care, and the presence of anxiety. Multivariate models revealed a higher risk of BZDR treatment in patients with depression (OR 3.85, 95% CI: 1.45 - 10.27). Community-dwelling participants and those treated by neurologists/psychiatrists had a lower risk of receiving BZDR (OR 0.33, 95% CI: 0.12 - 0.89 and OR 0.16, 95% CI: 0.07 - 0.36). DISCUSSION: The inappropriate use of BZDR conflicts with national and international guidelines. We suggest evaluating indications and treatment duration and improving the knowledge of alternative therapies in healthcare institutions. PMID- 29388174 TI - GSK-3 Inhibitors: A Double-Edged Sword? - An Update on Tideglusib. AB - GSK-3 inhibitors are an emerging tool for clinical interventions in human diseases and represent a niche area in combinational therapy. They possess diverse facets in applications of nervous system disorders, Type 2 diabetes, regenerative medicine and cancer. However, conflicting reports suggest the controversial role of GSK-3 inhibitors in cancers. This review aims to highlight the rise of GSK-3 inhibitors as tools for molecular-targeted research and its shift to a promising drug candidate. The review also focuses on key GSK-3 inhibitors and their roles in cancer and regenerative medicine with special emphasis to tideglusib. In addition, the decisive roles of GSK-3 in various molecular pathways will be concisely reviewed. Finally, this review concludes the emergence of GSK-3 inhibitors as a 'double-edged sword' in the treatment against human diseases cautioning researchers about the potential ramifications of off target pharmacological effects. PMID- 29388175 TI - Early Stage Graves' Disease is Uniformly Accompanied by Orbital Immune Activity even in Patients who Fail to Develop Orbithopathy during Follow-up. AB - PURPOSE: Graves' orbitopathy (GO) is a complication of Graves' disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. METHODS: Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. RESULTS: During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45+/ 1.72 MBq/cm3 vs. 9.18+/-1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45+/-1.36 MBq/cm3, p<0.05). CONCLUSIONS: We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear. PMID- 29388176 TI - High Dose of A Conjugated Linoleic Acid Mixture Increases Insulin Resistance in Rats Fed Either A Low Fat or A High Fat Diet. AB - Obesity and related diseases are becoming more prevalent. Conjugated linoleic acid (CLA) might be a useful coadjutant treatment helping to decrease fat mass. However, the precise impact of CLA is unclear because the decreased body fat mass is followed by an increase in insulin resistance. This study aimed to evaluate some of the consequences of a high dose of CLA in rats fed a normal low fat or a high fat diet for 30 days. Male Wistar rats were separated into 4 groups (each n = 10): Control group receiving 7% fat (soybean oil); CLA group receiving 4% soybean oil and 3% CLA mixture; animal fat (AF) group, receiving 45% fat (lard); and animal fat plus CLA (AF+CLA) group, receiving 42% lard and 3% CLA mixture. The CLA mixture contained 39.32 mole% c9,t11-CLA and 40.50 mole% t10,c12-CLA. After 30 days, both CLA groups (CLA and AF+CLA groups) developed insulin resistance, with an increase in glucose in the fasting state and in an insulin tolerance test. The CLA group had increased liver weight and percentage of saturated fatty acids in liver and adipose tissue. Feeding the high fat diet resulted in increased hepatic triacylglycerol accumulation and this was exacerbated by dietary CLA. It is concluded that a high dose of CLA mixture increases insulin resistance and exacerbates hepatic steatosis when combined with a high fat diet. PMID- 29388177 TI - Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia. AB - Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ) induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) alpha-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment. PMID- 29388178 TI - Antral Follicle Diameter Variance Within Each Ovary May Be A Predictor For Poor Response In Cases With Normal Ovarian Reserve. AB - OBJECTIVES: To determine the predictive value of antral follicle diameter variance within each ovary for ovarian response in cases with normal ovarian reserve tests. METHODS: This is a prospective observational study. One hundred and thirty nine infertile women who underwent ART in IVF-ICSI unit of Zeynep Kamil women and children's Health Training and research hospital between January 2017 to June 2017 were recruited. Blood samples were collected on day 2/day 3 for assessment of serum FSH and estradiol. Trans-vaginal sonography was done for antral follicle count. During antral follicle count, in order to determine antral follicle diameter variance, diameters of the largest and smallest follicles were recorded. Variance was calculated by subtracting the smallest diameter from the largest one. Following ovarian stimulation with antagonist protocol, poor response was determined in cases with total oocyte number<=3. Ovarian reserve tests and antral follicle diameter variance were utilized to predict cases with poor response in women with normal ovarian reserve. RESULTS: Antral follicle diameter variance both in right (AUC=0.737, P<0.001) and left (AUC=0.651, P<0.05) ovaries significantly predicted poor ovarian response. Variance>3.5 mm was found to have 75% sensitivity to predict poor response. Basal serum FSH with estradiol levels and AFC failed to predict poor response (P>0.05). Other significant predictors for poor response were day 5 estradiol level and estradiol level at trigger day (P<0.05). In multivariate regression analysis, both AFC and antral follicle diameter variance in the right ovary were found to be significantly associated with clinical pregnancy, on the other hand peak estradiol concentration and antral follicle diameter variance in the right ovary were significantly associated with poor response. CONCLUSION: Antral follicle diameter variance may be utilized to predict poor ovarian response in cases with normal ovarian reserve. PMID- 29388179 TI - The PCOS Patients differ in Lipid Profile According to their Phenotypes. AB - : Polycystic ovary syndrome (PCOS) affects 4-18% of women of reproductive age. The number of reports exploring the lipid profiles among PCOS patients and number of studied patients are limited. The aim of our study was to assess the lipid profile separately in lean and non-lean women with polycystic ovary syndrome divided according to hyperandrogenemia, defined as free androgen index (FAI)>=5. The second aim was to compare the lipid profiles among lean and non-lean PCOS patients with respect to hyperandrogenemia and regularity of menstruation cycles. We evaluated 232 patients from Department of Endocrinological Gynecology, Jagiellonian University Medical College in Krakow diagnosed with PCOS. The population consisted of 166 lean and 66 non-lean women. We observed higher levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) in lean patients with FAI<5 than in lean patients with FAI>=5. There were no differences in lipid profile between non-lean patients with FAI>=5 and non-lean patients with FAI<5. Among lean patients higher total cholesterol levels were observed in those with irregular menstruation cycles and FAI<5 than in patients with FAI>=5 and regular cycles. There were no differences in lipid profiles between four phenotypes among non-lean PCOS patients. CONCLUSIONS: The results of our study showed differences in lipid profile between lean PCOS patients according to their phenotype based on androgens' level. This effect was abandoned by fat tissue mass in non-lean ones. Further studies should be conducted to explore these associations. PMID- 29388180 TI - Exploring Data Quality Management within Clinical Trials. AB - BACKGROUND: Clinical trials are an important research method for improving medical knowledge and patient care. Multiple international and national guidelines stipulate the need for data quality and assurance. Many strategies and interventions are developed to reduce error in trials, including standard operating procedures, personnel training, data monitoring, and design of case report forms. However, guidelines are nonspecific in the nature and extent of necessary methods. OBJECTIVE: This article gathers information about current data quality tools and procedures used within Australian clinical trial sites, with the aim to develop standard data quality monitoring procedures to ensure data integrity. METHODS: Relevant information about data quality management methods and procedures, error levels, data monitoring, staff training, and development were collected. Staff members from 142 clinical trials listed on the National Health and Medical Research Council (NHMRC) clinical trials Web site were invited to complete a short self-reported semiquantitative anonymous online survey. RESULTS: Twenty (14%) clinical trials completed the survey. Results from the survey indicate that procedures to ensure data quality varies among clinical trial sites. Centralized monitoring (65%) was the most common procedure to ensure high-quality data. Ten (50%) trials reported having a data management plan in place and two sites utilized an error acceptance level to minimize discrepancy, set at <5% and 5 to 10%, respectively. The quantity of data variables checked (10 100%), the frequency of visits (once-a-month to annually), and types of variables (100%, critical data or critical and noncritical data audits) for data monitoring varied among respondents. The average time spent on staff training per person was 11.58 hours over a 12-month period and the type of training was diverse. CONCLUSION: Clinical trial sites are implementing ad hoc methods pragmatically to ensure data quality. Findings highlight the necessity for further research into "standard practice" focusing on developing and implementing publically available data quality monitoring procedures. PMID- 29388181 TI - Using EHR Data to Detect Prescribing Errors in Rapidly Discontinued Medication Orders. AB - BACKGROUND: Previous research developed a new method for locating prescribing errors in rapidly discontinued electronic medication orders. Although effective, the prospective design of that research hinders its feasibility for regular use. OBJECTIVES: Our objectives were to assess a method to retrospectively detect prescribing errors, to characterize the identified errors, and to identify potential improvement opportunities. METHODS: Electronically submitted medication orders from 28 randomly selected days that were discontinued within 120 minutes of submission were reviewed and categorized as most likely errors, nonerrors, or not enough information to determine status. Identified errors were evaluated by amount of time elapsed from original submission to discontinuation, error type, staff position, and potential clinical significance. Pearson's chi-square test was used to compare rates of errors across prescriber types. RESULTS: In all, 147 errors were identified in 305 medication orders. The method was most effective for orders that were discontinued within 90 minutes. Duplicate orders were most common; physicians in training had the highest error rate (p < 0.001), and 24 errors were potentially clinically significant. None of the errors were voluntarily reported. CONCLUSION: It is possible to identify prescribing errors in rapidly discontinued medication orders by using retrospective methods that do not require interrupting prescribers to discuss order details. Future research could validate our methods in different clinical settings. Regular use of this measure could help determine the causes of prescribing errors, track performance, and identify and evaluate interventions to improve prescribing systems and processes. PMID- 29388182 TI - Green Quantification Strategy Combined with Chemometric Analysis for Triglycerides in Seeds Used in Traditional Chinese Medicine. AB - Triglycerides are the primary constituents of some seed kernels used in traditional Chinese medicine. Quality control of seed kernels containing multiple components with an environmentally friendly method is indispensable for establishing their quality standards (called monographs) in pharmacopeia. Using coix seeds (Semen Coicis) as an example, a green quantification strategy was proposed by combining C8 core-shell particles with single standard to determine multicomponent technologies to quantify seven triglycerides simultaneously. A core-shell column, namely, Halo C8 (3.0 * 100 mm, 2.7 um), was used. Methanol was used as the mobile phase at a flow rate of 0.3 mL/min, enabling UV detection of the elutes. Seven triglycerides were well separated in 20 min, and simultaneously quantified using triolein as a single standard. The conversion factor for each standard was set as 1.0 on ELSD, while for the conversion factors at 203 nm, the values increased with the reduction of linoleate. The recovery values were all in the range of 97 - 107% (RSD < 3.0%). The RSD values of precision, including intraday and intermediate precision, were < 3.0% when the total content of triglycerides was calculated. The linearity reached r >= 0.9990, and the limit of quantitation reached 40 - 70 ng. Forty-nine batches of coix seeds from four different places of origins and eight batches of adulterants were evaluated and differentiated using principal component analysis. In addition, the validated method was used successfully to quantity seven triglycerides in Semen Persicae, Semen Armeniacae Amarum, and Semen Pruni. PMID- 29388183 TI - Aspalathin from Rooibos (Aspalathus linearis): A Bioactive C-glucosyl Dihydrochalcone with Potential to Target the Metabolic Syndrome. AB - Aspalathin is a C-glucosyl dihydrochalcone that is abundantly present in Aspalathus linearis. This endemic South African plant, belonging to the Cape Floristic region, is normally used for production of rooibos, a herbal tea. Aspalathin was valued initially only as precursor in the formation of the characteristic red-brown colour of "fermented" rooibos, but the hype about the potential role of natural antioxidants to alleviate oxidative stress, shifted interest in aspalathin to its antioxidant properties and subsequently, its potential role to improve metabolic syndrome, a disease condition interrelated with oxidative stress. The potential use of aspalathin or aspalathin-rich rooibos extracts as a condition-specific nutraceutical is hampered by the limited supply of green rooibos (i.e., "unfermented" plant material) and low levels in "fermented" rooibos, providing incentive for its synthesis. In vitro and in vivo studies relating to the metabolic activity of aspalathin are discussed and cellular mechanisms by which aspalathin improves glucose and lipid metabolism are proposed. Other aspects covered in this review, which are relevant in view of the potential use of aspalathin as an adjunctive therapy, include its poor stability and bioavailability, as well as potential adverse herb-drug interactions, in particular interference with the metabolism of certain commonly prescribed chronic medications for hyperglycaemia and dyslipidaemia. PMID- 29388185 TI - The Association of A Number of Risk Factors With Depression in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy. AB - PURPOSE: To identify factors affecting depressive symptoms in patients undergoing androgen-deprivation therapy (ADT) to treat prostate cancer. MATERIALS AND METHODS: The patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing ADT participated. To assess depressive symptoms, the Beck Depression Inventory (BDI) was used. To identify the risk factors affecting depressive symptoms, univariate regression and multiple linear regression analyses were implemented. RESULTS: The mean (+/- SD) age, age when initiating ADT, duration of ADT, serum testosterone level and BDI scores of participants (n = 45) were 73.9 +/- 7.9 years, 72 +/- 8.5 years, 33 +/- 31.6 months, 214.9 +/- 219.5 ng/dL and 18 +/- 13.5 points. The androgen dependent and independent were 26 and 9 patients. Eight of these androgen-independent patients underwent concurrent chemotherapy. Twenty-one patients were treated with bicalutamide and 24 with leuprolide. Of the clinical variables affecting BDI scores, the type of ADT drug (P < 0.001), serum testosterone level (P = 0.003), and age at diagnosis (P < 0.001) were significant. CONCLUSION: Efforts to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing ADT to treat prostate cancer who are using an LHRH agonist (leuprolide), have low testosteronelevel, or are older at the age when initiating ADT. PMID- 29388186 TI - Laser-puncture Versus Electrosurgery-incision of the Ureterocele in Neonatal Patients. AB - PURPOSE: To compare the holmium-laser puncture and electrosurgery-incision in neonates with intravesical ureterocele. MATERIALS AND METHODS: We retrospectively analyzed the results of laser-puncture of ureterocele (LP group) in 12 patients (mean age 9.8 days, range 4-28) and electrosurgery-incision in 20 patients (ES group) (mean age 10.2 days, range 6-28), treated at our institution. Patients had their records reviewed for preoperative findings, endoscopic procedure description, and postoperative outcomes. RESULTS: There was the need for retreatment in one (8.3%) patient in LP group and in four (20%) patients in ES group (P = .626). Duration of general anesthesia in LP and ES groups was 16 (range, 10-24) minutes and 15 (range, 10-20) minutes, respectively (P = .355). There was no statistically significant difference in terms of hospitalization (LF group one day, ES group 1.35 days) (P = .286). Complications were not found in LP group. There were two (10%) patients with pyelonephritis after the treatment in ES group (P = .516). After one month, obstruction was observed on ultarsound examination in one (8.3%) and two (10%) patients, respectively. After three months, obstructionwas not found in any patient in both groups. After six months, vesicoureteral reflux was found in one (8.3%) patient after laser-puncture of the ureterocele and in 13 (65%) patients after electrosurgery-incision (P = .003). CONCLUSION: Both laser-puncture and electrosurgery-incision endoscopic techniques are highly effective in relieving the obstruction. There is no significant difference regarding hospitalization, need for retreatment and the occurrence of complications. The incidence of de novo vesicoureteral reflux is significantly lower in patients treated with holmium-laser, as well as the need for upper pole partial nephrectomy. PMID- 29388184 TI - Imaging the Unimaginable: Desorption Electrospray Ionization - Imaging Mass Spectrometry (DESI-IMS) in Natural Product Research. AB - Imaging mass spectrometry (IMS) has recently established itself in the field of "spatial metabolomics." Merging the sensitivity and fast screening of high throughput mass spectrometry with spatial and temporal chemical information, IMS visualizes the production, location, and distribution of metabolites in intact biological models. Since metabolite profiling and morphological features are combined in single images, IMS offers an unmatched chemical detail on complex biological and microbiological systems. Thus, IMS-type "spatial metabolomics" emerges as a powerful and complementary approach to genomics, transcriptomics, and classical metabolomics studies. In this review, we summarize the current state-of-the-art IMS methods with a strong focus on desorption electrospray ionization (DESI)-IMS. DESI-IMS utilizes the original principle of electrospray ionization, but in this case solvent droplets are rastered and desorbed directly on the sample surface. The rapid and minimally destructive DESI-IMS chemical screening is achieved at ambient conditions and enables the accurate view of molecules in tissues at the um-scale resolution. DESI-IMS analysis does not require complex sample preparation and allows repeated measurements on samples from different biological sources, including microorganisms, plants, and animals. Thanks to its easy workflow and versatility, DESI-IMS has successfully been applied to many different research fields, such as clinical analysis, cancer research, environmental sciences, microbiology, chemical ecology, and drug discovery. Herein we discuss the present applications of DESI-IMS in natural product research. PMID- 29388187 TI - Combined effects of peer presence, social cues, and rewards on cognitive control in adolescents. AB - Developmental scientists have examined the independent effects of peer presence, social cues, and rewards on adolescent decision-making and cognitive control. Yet, these contextual factors often co-occur in real world social situations. The current study examined the combined effects of all three factors on cognitive control, and its underlying neural circuitry, using a task to better capture adolescents' real world social interactions. A sample of 176 participants ages 13 25, was scanned while performing an adapted go/no-go task alone or in the presence of a virtual peer. The task included brief positive social cues and sustained periods of positive arousal. Adolescents showed diminished cognitive control to positive social cues when anticipating a reward in the presence of peers relative to when alone, a pattern not observed in older participants. This behavioral pattern was paralleled by enhanced orbitofrontal activation. The results demonstrate the synergistic impact of social and reward influences on cognitive control in adolescents. PMID- 29388188 TI - The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. AB - BACKGROUND: The lack of objective diagnostic criteria renders pyoderma gangrenosum (PG) a diagnosis of exclusion. The diagnostic approaches proposed to date have not been systematically evaluated. Thus, PG remains a challenging and frequently misdiagnosed disorder. OBJECTIVES: To develop and assess a comprehensive, yet clinically practicable, sensitive diagnostic scoring system for PG. METHODS: Clinical history and images of a total of 60 participants with previously confirmed PG located on the lower extremity and a control cohort of 50 patients with venous leg ulcers were retrospectively evaluated by expert teams at two tertiary dermatological centres specializing in wound care using a newly developed diagnostic scoring system composed of 10 criteria. RESULTS: The three major diagnostic criteria are rapidly progressing disease, assessment of relevant differential diagnoses and a reddish-violaceous wound border (prevalent in 98% of patients with PG). Minor criteria (evident in 61-95% of patients with PG) include amelioration by immunosuppressant drugs, characteristically irregular shape of ulceration, extreme pain > 4/10 on a visual analogue scale and localization of lesion at the site of the trauma. Three additional criteria (observed in up to 60% of patients with PG) encompass suppurative inflammation in histopathology, undermined wound borders and systemic disease associated. A total score value of 10 points or higher indicates a high likelihood of PG and differentiates PG from venous leg ulcers. The initial letters of the above-listed criteria form the acronym PARACELSUS. CONCLUSIONS: The PARACELSUS score represents a novel, easily implementable, effective and sensitive diagnostic tool for PG. PMID- 29388189 TI - Inequalities in zoster disease burden: a population-based cohort study to identify social determinants using linked data from the U.K. Clinical Practice Research Datalink. AB - BACKGROUND: Zoster vaccination was introduced in England in 2013, where tackling health inequalities is a statutory requirement. However, specific population groups with higher zoster burden remain largely unidentified. OBJECTIVES: To evaluate health inequalities in zoster disease burden prior to zoster vaccine introduction in England. METHODS: This population-based cohort study used anonymized U.K. primary care data linked to hospitalization and deprivation data. Individuals aged >= 65 years without prior zoster history (N = 862 470) were followed from 1 September 2003 to 31 August 2013. Poisson regression was used to obtain adjusted rate ratios (ARRs) for the association of sociodemographic factors (ethnicity, immigration status, individuals' area-level deprivation, care home residence, living arrangements) with first zoster episode. Possible mediation by comorbidities and immunosuppressive medications was also assessed. RESULTS: There were 37 014 first zoster episodes, with an incidence of 8.79 [95% confidence interval (CI) 8.70-8.88] per 1000 person-years at risk. In multivariable analyses, factors associated with higher zoster rates included care home residence (10% higher vs. those not in care homes), being a woman (16% higher vs. men), nonimmigrants (~30% higher than immigrants) and white ethnicity (for example, twice the rate compared with those of black ethnicity). Zoster incidence decreased slightly with increasing deprivation (ARR most vs. least deprived 0.96 (95% CI 0.92-0.99) and among those living alone (ARR 0.96, 95% CI 0.94-0.98). Mediating variables made little difference to the ARR of social factors but were themselves associated with increased zoster burden (ARR varied from 1.11 to 3.84). CONCLUSIONS: The burden of zoster was higher in specific sociodemographic groups. Further study is needed to ascertain whether these individuals are attending for zoster vaccination. PMID- 29388190 TI - Association study of genetic variation in the autophagy lysosome pathway genes and risk of eight kinds of cancers. AB - The autophagy lysosome pathway is essential to maintain cell viability and homeostasis in response to many stressful environments, which is reported to play a vital role in cancer development and therapy. However, the association of genetic alterations of this pathway with risk of cancer remains unclear. Based on genome-wide association study data of eight kinds of cancers, we used an adaptive rank truncated product approach to perform a pathway-level and gene-level analysis, and used a logistic model to calculate SNP-level associations to examine whether an altered autophagy lysosome pathway contributes to cancer susceptibility. Among eight kinds of cancers, four of them showed significant statistics in the pathway-level analysis, including breast cancer (p = 0.00705), gastric cancer (p = 0.00880), lung cancer (p = 0.000100) and renal cell carcinoma (p = 0.00190). We also found that some autophagy lysosome genes had signals of association with cancer risk. Our results demonstrated that inherited genetic variants in the overall autophagy lysosome pathway and certain associated genes might contribute to cancer susceptibility, which warrant further evaluation in other independent datasets. PMID- 29388191 TI - Sirolimus for treatment of Kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon: a retrospective cohort study. PMID- 29388192 TI - Frontal lobe epileptic seizures are accompanied by elevated pitch during verbal communication. AB - The objective of our study was to assess alterations in speech as a possible localizing sign in frontal lobe epilepsy. Ictal speech was analyzed in 18 patients with frontal lobe epilepsy (FLE) during seizures and in the interictal period. Matched identical words were analyzed regarding alterations in fundamental frequency (fo) as an approximation of pitch. In patients with FLE, fo of ictal utterances was significantly higher than fo in interictal recordings (p = 0.016). Ictal fo increases occurred in both FLE of right and left seizure origin. In contrast, a matched temporal lobe epilepsy (TLE) group showed less pronounced increases in fo, and only in patients with right-sided seizure foci. This study for the first time shows significant voice alterations in ictal speech in a cohort of patients with FLE. This may contribute to the localization of the epileptic focus. Increases in fo were interestingly found in frontal lobe seizures with origin in either hemisphere, suggesting a bilateral involvement to the planning of speech production, in contrast to a more right-sided lateralization of pitch perception in prosodic processing. PMID- 29388193 TI - EOMES-positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers. AB - The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naive human CD4+ T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation. Moreover, the protein expression of the T-box transcription factor Eomesodermin (EOMES) was increased in T cells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naive CD4+ T cells. There was no difference in the frequency of other CD4+ T-cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES+ CD4+ T cells was observed in synovial fluid of RA patients with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, we propose a novel mechanism of action of PTPN22 risk allele through the generation of cytotoxic CD4+ T cells and identify EOMES+ CD4+ T cells as a relevant T-cell subset in RA pathogenesis. PMID- 29388195 TI - Vaccines for preventing influenza in healthy children. AB - BACKGROUND: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. This is an update of a review published in 2011. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions. OBJECTIVES: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 12), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1966 to 31 December 2016), Embase (1974 to 31 December 2016), WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017). SELECTION CRITERIA: Randomised controlled trials comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy children under 16 years. Previous versions of this review included 19 cohort and 11 case-control studies. We are no longer updating the searches for these study designs but have retained the observational studies for historical purposes. DATA COLLECTION AND ANALYSIS: Review authors independently assessed risk of bias and extracted data. We used GRADE to rate the certainty of evidence for the key outcomes of influenza, influenza-like illness (ILI), complications (hospitalisation, ear infection), and adverse events. Due to variation in control group risks for influenza and ILI, absolute effects are reported as the median control group risk, and numbers needed to vaccinate (NNVs) are reported accordingly. For other outcomes aggregate control group risks are used. MAIN RESULTS: We included 41 clinical trials (> 200,000 children). Most of the studies were conducted in children over the age of two and compared live attenuated or inactivated vaccines with placebo or no vaccine. Studies were conducted over single influenza seasons in the USA, Western Europe, Russia, and Bangladesh between 1984 and 2013. Restricting analyses to studies at low risk of bias showed that influenza and otitis media were the only outcomes where the impact of bias was negligible. Variability in study design and reporting impeded meta-analysis of harms outcomes.Live attenuated vaccinesCompared with placebo or do nothing, live attenuated influenza vaccines probably reduce the risk of influenza infection in children aged 3 to 16 years from 18% to 4% (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.41; 7718 children; moderate certainty evidence), and they may reduce ILI by a smaller degree, from 17% to 12% (RR 0.69, 95% CI 0.60 to 0.80; 124,606 children; low-certainty evidence). Seven children would need to be vaccinated to prevent one case of influenza, and 20 children would need to be vaccinated to prevent one child experiencing an ILI. Acute otitis media is probably similar following vaccine or placebo during seasonal influenza, but this result comes from a single study with particularly high rates of acute otitis media (RR 0.98, 95% CI 0.95 to 1.01; moderate certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. Vaccinating children may lead to fewer parents taking time off work, although the CI includes no effect (RR 0.69, 95% CI 0.46 to 1.03; low certainty evidence). Data on the most serious consequences of influenza complications leading to hospitalisation were not available. Data from four studies measuring fever following vaccination varied considerably, from 0.16% to 15% in children who had live vaccines, while in the placebo groups the proportions ranged from 0.71% to 22% (very low-certainty evidence). Data on nausea were not reported.Inactivated vaccinesCompared with placebo or no vaccination, inactivated vaccines reduce the risk of influenza in children aged 2 to 16 years from 30% to 11% (RR 0.36, 95% CI 0.28 to 0.48; 1628 children; high certainty evidence), and they probably reduce ILI from 28% to 20% (RR 0.72, 95% CI 0.65 to 0.79; 19,044 children; moderate-certainty evidence). Five children would need to be vaccinated to prevent one case of influenza, and 12 children would need to be vaccinated to avoid one case of ILI. The risk of otitis media is probably similar between vaccinated children and unvaccinated children (31% versus 27%), although the CI does not exclude a meaningful increase in otitis media following vaccination (RR 1.15, 95% CI 0.95 to 1.40; 884 participants; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. We identified no data on parental working time lost, hospitalisation, fever, or nausea.We found limited evidence on secondary cases, requirement for treatment of lower respiratory tract disease, and drug prescriptions. One brand of monovalent pandemic vaccine was associated with a sudden loss of muscle tone triggered by the experience of an intense emotion (cataplexy) and a sleep disorder (narcolepsy) in children. Evidence of serious harms (such as febrile fits) was sparse. AUTHORS' CONCLUSIONS: In children aged between 3 and 16 years, live influenza vaccines probably reduce influenza (moderate-certainty evidence) and may reduce ILI (low-certainty evidence) over a single influenza season. In this population inactivated vaccines also reduce influenza (high-certainty evidence) and may reduce ILI (low-certainty evidence). For both vaccine types, the absolute reduction in influenza and ILI varied considerably across the study populations, making it difficult to predict how these findings translate to different settings. We found very few randomised controlled trials in children under two years of age. Adverse event data were not well described in the available studies. Standardised approaches to the definition, ascertainment, and reporting of adverse events are needed. Identification of all global cases of potential harms is beyond the scope of this review. PMID- 29388194 TI - Family conflict, chaos, and negative life events predict cortisol activity in low income children. AB - Childhood poverty is hypothesized to increase risk for mental and physical health problems at least in part through dysregulation of the hypothalamic-pituitary adrenal axis. However, less is known about the specific psychosocial stressors associated with cortisol reactivity and regulation for children living in poverty. The current study investigates negative life events, household chaos, and family conflict in preschool and middle childhood as potential predictors of cortisol regulation in low-income 7-10 year olds (N = 242; M age = 7.9 years). Participants were assessed in preschool and participated in a follow-up assessment in middle childhood, during which diurnal free cortisol and free cortisol reactivity to the Trier Social Stress Test for Children (TSST-C) were assessed. Household chaos during preschool predicted a more blunted diurnal cortisol slope in middle childhood. Greater negative life events during preschool and greater concurrent family conflict were associated with increased free cortisol reactivity in middle childhood. PMID- 29388196 TI - Vaccines for preventing influenza in healthy adults. AB - BACKGROUND: The consequences of influenza in adults are mainly time off work. Vaccination of pregnant women is recommended internationally. This is an update of a review published in 2014. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated due to their lack of influence on the review conclusions. OBJECTIVES: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy adults, including pregnant women. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE (January 1966 to 31 December 2016), Embase (1990 to 31 December 2016), the WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017), as well as checking the bibliographies of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy individuals aged 16 to 65 years. Previous versions of this review included observational comparative studies assessing serious and rare harms cohort and case-control studies. Due to the uncertain quality of observational (i.e. non-randomised) studies and their lack of influence on the review conclusions, we decided to update only randomised evidence. The searches for observational comparative studies are no longer updated. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We rated certainty of evidence for key outcomes (influenza, influenza-like illness (ILI), hospitalisation, and adverse effects) using GRADE. MAIN RESULTS: We included 52 clinical trials of over 80,000 people assessing the safety and effectiveness of influenza vaccines. We have presented findings from 25 studies comparing inactivated parenteral influenza vaccine against placebo or do-nothing control groups as the most relevant to decision making. The studies were conducted over single influenza seasons in North America, South America, and Europe between 1969 and 2009. We did not consider studies at high risk of bias to influence the results of our outcomes except for hospitalisation.Inactivated influenza vaccines probably reduce influenza in healthy adults from 2.3% without vaccination to 0.9% (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.36 to 0.47; 71,221 participants; moderate-certainty evidence), and they probably reduce ILI from 21.5% to 18.1% (RR 0.84, 95% CI 0.75 to 0.95; 25,795 participants; moderate-certainty evidence; 71 healthy adults need to be vaccinated to prevent one of them experiencing influenza, and 29 healthy adults need to be vaccinated to prevent one of them experiencing an ILI). The difference between the two number needed to vaccinate (NNV) values depends on the different incidence of ILI and confirmed influenza among the study populations. Vaccination may lead to a small reduction in the risk of hospitalisation in healthy adults, from 14.7% to 14.1%, but the CI is wide and does not rule out a large benefit (RR 0.96, 95% CI 0.85 to 1.08; 11,924 participants; low-certainty evidence). Vaccines may lead to little or no small reduction in days off work ( 0.04 days, 95% CI -0.14 days to 0.06; low-certainty evidence). Inactivated vaccines cause an increase in fever from 1.5% to 2.3%.We identified one RCT and one controlled clinical trial assessing the effects of vaccination in pregnant women. The efficacy of inactivated vaccine containing pH1N1 against influenza was 50% (95% CI 14% to 71%) in mothers (NNV 55), and 49% (95% CI 12% to 70%) in infants up to 24 weeks (NNV 56). No data were available on efficacy against seasonal influenza during pregnancy. Evidence from observational studies showed effectiveness of influenza vaccines against ILI in pregnant women to be 24% (95% CI 11% to 36%, NNV 94), and against influenza in newborns from vaccinated women to be 41% (95% CI 6% to 63%, NNV 27).Live aerosol vaccines have an overall effectiveness corresponding to an NNV of 46. The performance of one- or two-dose whole-virion 1968 to 1969 pandemic vaccines was higher (NNV 16) against ILI and (NNV 35) against influenza. There was limited impact on hospitalisations in the 1968 to 1969 pandemic (NNV 94). The administration of both seasonal and 2009 pandemic vaccines during pregnancy had no significant effect on abortion or neonatal death, but this was based on observational data sets. AUTHORS' CONCLUSIONS: Healthy adults who receive inactivated parenteral influenza vaccine rather than no vaccine probably experience less influenza, from just over 2% to just under 1% (moderate-certainty evidence). They also probably experience less ILI following vaccination, but the degree of benefit when expressed in absolute terms varied across different settings. Variation in protection against ILI may be due in part to inconsistent symptom classification. Certainty of evidence for the small reductions in hospitalisations and time off work is low. Protection against influenza and ILI in mothers and newborns was smaller than the effects seen in other populations considered in this review.Vaccines increase the risk of a number of adverse events, including a small increase in fever, but rates of nausea and vomiting are uncertain. The protective effect of vaccination in pregnant women and newborns is also very modest. We did not find any evidence of an association between influenza vaccination and serious adverse events in the comparative studies considered in this review. Fifteen included RCTs were industry funded (29%). PMID- 29388197 TI - Vaccines for preventing influenza in the elderly. AB - BACKGROUND: The consequences of influenza in the elderly (those age 65 years or older) are complications, hospitalisations, and death. The primary goal of influenza vaccination in the elderly is to reduce the risk of death among people who are most vulnerable. This is an update of a review published in 2010. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions. OBJECTIVES: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in the elderly. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (1966 to 31 December 2016); Embase (1974 to 31 December 2016); Web of Science (1974 to 31 December 2016); CINAHL (1981 to 31 December 2016); LILACS (1982 to 31 December 2016); WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017); and ClinicalTrials.gov (1 July 2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs assessing efficacy against influenza (laboratory confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. We considered any influenza vaccine given independently, in any dose, preparation, or time schedule, compared with placebo or with no intervention. Previous versions of this review included 67 cohort and case-control studies. The searches for these trial designs are no longer updated. DATA COLLECTION AND ANALYSIS: Review authors independently assessed risk of bias and extracted data. We rated the certainty of evidence with GRADE for the key outcomes of influenza, ILI, complications (hospitalisation, pneumonia), and adverse events. We have presented aggregate control group risks to illustrate the effect in absolute terms. We used them as the basis for calculating the number needed to vaccinate to prevent one case of each event for influenza and ILI outcomes. MAIN RESULTS: We identified eight RCTs (over 5000 participants), of which four assessed harms. The studies were conducted in community and residential care settings in Europe and the USA between 1965 and 2000. Risk of bias reduced our certainty in the findings for influenza and ILI, but not for other outcomes.Older adults receiving the influenza vaccine may experience less influenza over a single season compared with placebo, from 6% to 2.4% (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.27 to 0.66; low-certainty evidence). We rated the evidence as low certainty due to uncertainty over how influenza was diagnosed. Older adults probably experience less ILI compared with those who do not receive a vaccination over the course of a single influenza season (3.5% versus 6%; RR 0.59, 95% CI 0.47 to 0.73; moderate certainty evidence). These results indicate that 30 people would need to be vaccinated to prevent one person experiencing influenza, and 42 would need to be vaccinated to prevent one person having an ILI.The study providing data for mortality and pneumonia was underpowered to detect differences in these outcomes. There were 3 deaths from 522 participants in the vaccination arm and 1 death from 177 participants in the placebo arm, providing very low-certainty evidence for the effect on mortality (RR 1.02, 95% CI 0.11 to 9.72). No cases of pneumonia occurred in one study that reported this outcome (very low-certainty evidence). No data on hospitalisations were reported. Confidence intervaIs around the effect of vaccines on fever and nausea were wide, and we do not have enough information about these harms in older people (fever: 1.6% with placebo compared with 2.5% after vaccination (RR 1.57, 0.92 to 2.71; moderate-certainty evidence)); nausea (2.4% with placebo compared with 4.2% after vaccination (RR 1.75, 95% CI 0.74 to 4.12; low-certainty evidence)). AUTHORS' CONCLUSIONS: Older adults receiving the influenza vaccine may have a lower risk of influenza (from 6% to 2.4%), and probably have a lower risk of ILI compared with those who do not receive a vaccination over the course of a single influenza season (from 6% to 3.5%). We are uncertain how big a difference these vaccines will make across different seasons. Very few deaths occurred, and no data on hospitalisation were reported. No cases of pneumonia occurred in one study that reported this outcome. We do not have enough information to assess harms relating to fever and nausea in this population.The evidence for a lower risk of influenza and ILI with vaccination is limited by biases in the design or conduct of the studies. Lack of detail regarding the methods used to confirm the diagnosis of influenza limits the applicability of this result. The available evidence relating to complications is of poor quality, insufficient, or old and provides no clear guidance for public health regarding the safety, efficacy, or effectiveness of influenza vaccines for people aged 65 years or older. Society should invest in research on a new generation of influenza vaccines for the elderly. PMID- 29388198 TI - Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). AB - BACKGROUND: During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper-response are associated with increased chance of cycle cancellation. Hyper-response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti Mullerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies. SELECTION CRITERIA: We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration. MAIN RESULTS: We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT-algorithm studiesFour trials compared an ORT-based algorithm to a non ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I2=0%, moderate-quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT-based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT-based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs. AUTHORS' CONCLUSIONS: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate-quality evidence suggests that ORT-based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT-based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS. PMID- 29388199 TI - Medicare Accountable Care Organizations of Diverse Structures Achieve Comparable Quality and Cost Performance. AB - OBJECTIVE: To examine whether an empirically derived taxonomy of Accountable Care Organizations (ACOs) is associated with quality and spending performance among patients of ACOs in the Medicare Shared Savings Program (MSSP). DATA SOURCES: Three waves of the National Survey of ACOs and corresponding publicly available Centers for Medicare & Medicaid Services performance data for NSACO respondents participating in the MSSP (N = 204); SK&A Office Based Physicians Database from QuintilesIMS. STUDY DESIGN: We compare the performance of three ACO types (physician-led, integrated, and hybrid) for three domains: quality, spending, and likelihood of achieving savings. Sources of performance variation within and between ACO types are compared for each performance measure. PRINCIPAL FINDINGS: There is greater heterogeneity within ACO types than between ACO types. There were no consistent differences in quality by ACO type, nor were there differences in likelihood of achieving savings or overall spending per-person-year. There was evidence for higher spending on physician services for physician-led ACOs. CONCLUSIONS: ACOs of diverse structures perform comparably on core MSSP quality and spending measures. CMS should maintain its flexibility and continue to support participation of diverse ACOs. Future research to identify modifiable organizational factors that account for performance variation within ACO types may provide insight as to how best to improve ACO performance based on organizational structure and ownership. PMID- 29388201 TI - Benefits of and Barriers to Pharmacogenomics-Guided Treatment for Major Depressive Disorder. AB - Antidepressants have reduced the symptom burden for many Major Depressive Disorder (MDD) patients, but drug-related side effects and treatment resistance continue to present major challenges. Pharmacogenomics represents one approach to enhance antidepressant efficacy and avoid adverse reactions, but concerns remain with regard to the overall "value equation," and several barriers must be overcome to achieve the full potential of MDD pharmacogenomics. PMID- 29388200 TI - Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. AB - Natural killer (NK) cells exhibit strong cytotoxic activity against tumor cells without prior sensitization, and have the potential to exert antibody-dependent cellular cytotoxicity (ADCC). In this clinical trial, we examined the safety and efficacy of the use of NK cells, generated using a novel expansion system, in combination with IgG1 antibodies for the treatment of advanced gastric or colorectal cancers. Treatment consisted of trastuzumab- or cetuximab-based chemotherapy, plus adoptive NK cell therapy. For administration of expanded NK cells, dose escalation with a sequential 3 + 3 design was performed in three steps, at doses of 0.5 * 109 , 1.0 * 109 , and 2.0 * 109 cells/injection (N = 9). After 3 days of IgG1 antibody administration, patients were infused with expanded NK cells three times at triweekly intervals. NK cell populations expanded with our system were confirmed as being enriched in NK cells (median 92.9%) with high expression of NKG2D (97.6%) and CD16 (69.6%). The combination therapy was very well tolerated with no severe adverse events. Among six evaluable patients, four presented stable disease (SD) and two presented progressive disease. Of the four SD patients, three showed an overall decrease in tumor size after combination therapy. Immune monitoring suggested that combination therapy enhanced whole blood IFN-gamma production and reduced peripheral regulatory T cells (Tregs). In conclusion, this phase I trial provides evidence of good tolerability, induction of Th1 immune responses, and preliminary anti-tumor activity for this combination therapy, in patients with advanced gastric and colorectal cancer that have received previous therapy. PMID- 29388202 TI - An overview of cervical cancer epidemiology and prevention in Scandinavia. AB - New technologies such as human papillomavirus (HPV) testing and vaccination necessitate comprehensive policy analyses to optimize cervical cancer prevention. To inform future Scandinavian-specific policy analyses, we aimed to provide an overview of cervical cancer epidemiology and existing prevention efforts in Denmark, Norway and Sweden. We compiled and summarized data on current prevention strategies, population demography and epidemiology (for example, age-specific HPV prevalence and cervical cancer incidence over time) for each Scandinavian country by reviewing published literature and official guidelines, performing registry based analyses using primary data and having discussions with experts in each country. In Scandinavia, opportunistic screening occurred as early as the 1950s and by 1996, all countries had implemented nationwide organized cytology-based screening. Prior to implementation of widespread screening and during 1960-66, cervical cancer incidence was considerably higher in Denmark than in Norway and Sweden. Decades of cytology-based screening later (i.e. 2010-2014), cervical cancer incidence has been considerably reduced and has converged across the countries since the 1960s, although it still remains lowest in Sweden. Generally, Scandinavian countries face similar cervical cancer burdens and utilize similar prevention approaches; however, important differences remain. Future policy analyses will need to evaluate whether these differences warrant differential prevention policies or whether efforts can be streamlined across Scandinavia. PMID- 29388203 TI - Diagnosis of a lymphoma associated with human herpes virus 8 aided by flow cytometric immunophenotyping. PMID- 29388204 TI - Interaction of replication protein A with two acidic peptides from human Bloom syndrome protein. AB - Bloom syndrome protein (BLM) is one of five human RecQ helicases which maintain genomic stability. Interaction of BLM with replication protein A (RPA) stimulates the DNA unwinding ability of BLM. The interaction is expected to be crucial in the DNA damage response. Although this stimulation of BLM by RPA is of particular importance in cancer cells, the precise binding surfaces of both proteins are not well understood. In this study, we show by fluorescence polarisation anisotropy that both acidic surface peptides of BLM specifically bind to the RPA70N domain of RPA. Our NMR analysis and docking models show that the basic cleft region of RPA70N is the binding site for both peptides and that the acidic peptide/basic cleft interaction governs RPA-BLM binding. PMID- 29388205 TI - Isolated Daily Headache Associated With Falcine Xanthoma. PMID- 29388206 TI - Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide. AB - High-quality data on liver cancers by probable cause are scarce in many regions of the world. The United Nations recently set a goal of eliminating viral hepatitis as a major public health threat by 2030. We aimed to estimate the number of new cases of cancers attributable to hepatitis B virus (HBV) and hepatitis C virus (HCV) at a global, regional and country level, and by development status. We used data on the prevalence of HBV and HCV in hepatocellular carcinoma from a systematic review including 119,000 cases in 260 studies covering 50 countries. A statistical model was constructed to extrapolate empirical data to countries without prevalence data. Country-specific numbers of liver cancer cases attributable to HBV and HCV were calculated using data from GLOBOCAN 2012. Globally, 770,000 cases of liver cancer occurred worldwide in 2012, of which 56% (95% CI: 52-60) were attributable to HBV and 20% (95% CI: 18 22) to HCV. Currently, HBV causes approximately two out of three cases of liver cancer in less developed countries but one in four cases in more developed countries and shows a much higher degree of geographical aggregation in Eastern Asia and sub-Saharan Africa than HCV. These estimates help set priorities for liver cancer prevention. High-coverage HBV vaccination will be transformational in HBV-endemic countries but the prevention of HCV transmission and the treatment of chronic carriers of both viruses requires new scalable solutions. PMID- 29388207 TI - Radiologic indicators for prediction of difficult laryngoscopy in patients with cervical spondylosis. AB - BACKGROUND: We identified the most useful variables for prediction of difficult laryngoscopy in patients with cervical spondylosis according to physical indicators and preoperative skeletal X-ray and soft tissue MRI measurements. We hypothesized that there was a closer association between difficult laryngoscopy and radiologic indicators. METHODS: We randomly enroled 315 patients undergoing elective cervical spine surgery and analysed the radiological and physical data in predicting difficult laryngoscopy. RESULTS: We identified five variables that were most useful in predicting difficult laryngoscopy: the inter-incisor gap (P = 0.006), modified Mallampati test score (P = 0.004), distance from the highest point of the hyoid bone to the mandibular body (P < 0.001), most antero-inferior point of the upper central incisor tooth (P < 0.001), and length of the epiglottis (P = 0.002). Binary multivariate logistic regression analyses identified three factors that were independently associated with difficult laryngoscopy: the Mallampati score, distance from the hyoid bone to the mandibular body, and the anterior-inferior point of the upper central incisor tooth. The odds ratios and 95% confidence intervals were 1.547 (1.029-2.327), 1.222 (1.139-1.310), and 1.224 (1.133-1.322), respectively. The AUC for hyoid bone distance to mandibular body (0.832) was larger than that of anterior inferior point of the upper central incisor tooth (0.802, P > 0.05) and that of modified Mallampati test (0.602, P < 0.05). CONCLUSION: Distance from the highest point of the hyoid bone to the mandibular body appears to be the most accurate indicator for difficult laryngoscopy in patients with cervical spondylosis. PMID- 29388208 TI - Association between tubal ligation and endometrial cancer risk: A Swedish population-based cohort study. AB - Tubal ligation results in less advanced stages and lower risk of metastatic spread at diagnosis of endometrial cancer (EC) but the primary preventive effect of the procedure is unclear. In a Swedish nationwide population-based cohort study, we crosslinked registry data for tubal ligation, EC, and death for Swedish women between 1973 and 2010. All women were followed until EC, emigration, hysterectomy for non-cancerous reasons, death, or end of follow-up. Primary outcome was incidence of EC and secondary outcome overall survival. We calculated adjusted incidence rates (IR) per 100,000 person-years and hazard ratios (HR) using Cox regression models. A total of 35,711 cases of EC were identified among 5,385,186 women. The IR of EC among exposed was 17.7 (95% CI 15.7-19.9) versus 29.0 (95% CI 28.7-29.3) among unexposed (per 100,000 women years). Exposed individuals had significantly reduced risk of EC (HR 0.73, 95% CI 0.65-0.83). The mortality rate among women with EC was 72% lower in exposed compared to unexposed (IR 1,441; 95% CI 1,089-1,907 and IR 5,136; 95% CI 5,065-5,209, respectively) which following adjustment corresponded to a HR of 0.71 (95% CI 0.49-1.03). Tubal ligation was associated with lower risk of EC as well as mortality rates in women with EC. Elective tubal ligation may be adopted in future cancer preventive strategies but must be balanced against the irreversibility of the procedure, which preclude further unassisted reproduction. PMID- 29388209 TI - The role of the miR-200 family in epithelial-mesenchymal transition in colorectal cancer: a systematic review. AB - Colorectal cancer (CRC) is associated with significant morbidity and mortality as many patients are diagnosed with advanced stage disease. MicroRNAs are small, noncoding RNA molecules that have a major role in gene expression regulation and are dysregulated in CRC. The miR-200 family is involved in epithelial-mesenchymal transition (EMT). This systematic review describes the roles of the miR-200 family in EMT in CRC. A search of electronic databases (PubMed and Embase) was conducted between January 2000 and July 2017. Both in vitro and human studies reporting on the miR-200 family and CRC were included. Studies describing molecular pathways and the role of the miR-200 family in the diagnostic and therapeutic management of CRC were analyzed. Thirty-four studies (22 in vitro and 18 human studies) were included. miR-200 family expression is regulated epigenetically and via transcriptional factor regulation. In vitro studies show that transfection of miR-200 family members into chemo-resistant colon cancer cell lines results in improved chemo-sensitivity and epithelial phenotype restoration. There is intra-tumoral variability in the tissue expression of miR 200 family members with decreased expression at the invasive front. Clinical studies in CRC patients have shown decreased primary tumor tissue expression of miR-429, miR-200a and miR-200c may be associated with worse survival. Conversely, increased blood levels of miR-141, miR-200a and miR-200c may be associated with worse outcomes. The miR-200 family has a central role in EMT. The miR200 family has potential for both prognostic and therapeutic management of CRC. PMID- 29388210 TI - Sub-dimensions of trait emotional intelligence and health: A critical and systematic review of the literature. AB - Despite a growing number of studies on the role of the multidimensional construct of trait emotional intelligence (EI) in health, most have focused on global EI, without examining the role of the sub-dimensions. The present systematic review aimed to highlight the current knowledge about self-reported health associated with trait-EI sub-dimensions in general and clinical populations. We searched for the articles including valid self-report scales of trait-EI and health (mental or physical or general) in general and clinical samples. Based on 42 studies, the majority of studies was based on mental health with cross-sectional designs and the TMMS scale, in the general population. Few studies have been focused on physical health and clinical population. The description of studies results revealed that trait-EI sub-dimensions are associated to a greater extent with better mental health, rather than with physical and general health. Furthermore, intrapersonal dimensions, and especially emotion regulation, have stronger effects on health than interpersonal dimensions. Finally, patients with a clinical disorder present lower trait-EI sub-dimensions than the general population. This review supports the importance of focusing on the sub-dimensions of trait-EI to understand better the role of EI in health. The use of scales exclusively based on emotional competences in health contexts is recommended. Developing interventions targeting emotional competences according to the emotional profiles and contexts of individuals could be beneficial to improve health and disease adjustment. PMID- 29388211 TI - Influence of the FSBI Small Research Grants scheme: an analysis and appraisal. AB - The FSBI Small Research Grants scheme has been running for 25 years, after its initiation during the Society's 25th Anniversary in 1992, while the Wyn Wheeler Grant for retired researchers was started during the 40th Anniversary year. Over this time some L560 000 has been awarded to researchers and it is argued that this has made a disproportionately positive contribution on fish research and researchers as evidenced by journal articles produced as a result of initial FSBI funding and the career trajectories of some recipients. These grants also reflect the international reach of the Society, and the increasing involvement of female researchers in fish research. PMID- 29388212 TI - Preparation of fish waste silage and its effect on the growth performance and meat quality of broiler chickens. AB - BACKGROUND: This experiment was conducted to evaluate the effects of replacing soybean meal with fish-waste silage (FWS) in diets on growth performance and meat quality in broiler chickens. Fish waste (FW) was fermented with molasses and Lactobacillus plantarum and Aspergillus oryzae for 15 days. A total of 240 day old male Cobb 500 broiler chickens were used in a 42-day experiment in which the birds were randomly allotted to one of five dietary treatments (containing 0, 30, 60, 90, and 120 g kg-1 FWS) in a completely randomized design. RESULTS: Results indicated that the fermentation process significantly reduced pH and ether extract, but it increased crude protein content and lactic acid bacteria count in FW. The use of FWS significantly improved daily weight gain and feed conversion ratio of broilers. The amount of thiobarbiturate-reducing substances and lipid content in chicken's meat fed diet containing FWS was significantly lower than in the group fed a control diet. CONCLUSION: In conclusion, the microbial fermentation process is effective in improving nutritive values of FW. Feeding up to 120 g kg-1 FWS also improves the performance and meat quality of birds and can be used as a suitable protein source in broiler chickens' diet. (c) 2018 Society of Chemical Industry. PMID- 29388213 TI - Elemental fingerprint as a cerebrospinal fluid biomarker for the diagnosis of Parkinson's disease. AB - The diagnosis of Parkinson's disease (PD) still lacks objective diagnostic markers independent of clinical criteria. Cerebrospinal fluid (CSF) samples from 36 PD and 42 age-matched control patients were subjected to inductively coupled plasma-sector field mass spectrometry and a total of 28 different elements were quantified. Different machine learning algorithms were applied to the dataset to identify a discriminating set of elements yielding a novel biomarker signature. Using 19 stably detected elements, the extreme gradient tree boosting model showed the best performance in the discrimination of PD and control patients with high specificity and sensitivity (78.6% and 83.3%, respectively), re-classifying the training data to 100%. The 10 times 10-fold cross-validation yielded a good area under the receiver operating characteristic curve of 0.83. Arsenic, magnesium, and selenium all showed significantly higher mean CSF levels in the PD group compared to the control group (p = 0.01, p = 0.04, and p = 0.03). Reducing the number of elements to a discriminating minimum, we identified an elemental cluster (Se, Fe, As, Ni, Mg, Sr), which most importantly contributed to the sample discrimination. Selenium was identified as the element with the highest impact within this cluster directly followed by iron. After prospective validation, this elemental fingerprint in the CSF could have the potential to be used as independent biomarker for the diagnosis of PD. Next to their value as a biomarker, these data also argue for a prominent role of these highly discriminating six elements in the pathogenesis of PD. PMID- 29388214 TI - Evaluating the genetic status of a closed colony of titi monkeys (Callicebus cupreus) using multigenerational pedigrees. AB - Pedigree metrics are essential for investigating colony genetic structure. The genetic structure of a closed Callicebus cupreus colony was examined using multigenerational pedigrees. Inbreeding was low, but genetic drift caused the loss of founder genome representation. Pedigrees can be used to detect founder representation and prevent bottlenecks and allele loss. PMID- 29388215 TI - GC-MS olfactometric and LC-DAD-ESI-MS/MS characterization of key odorants and phenolic compounds in black dry-salted olives. AB - BACKGROUND: Olives are processed in different ways depending on consumption habits, which vary between countries. Different de-bittering methods affect the aroma and aroma-active compounds of table olives. This study focused on analyzing the aroma and aroma-active compounds of black dry-salted olives using gas chromatography-mass spectrometry-olfactometry (GC-MS-O) techniques. RESULTS: Thirty-nine volatile compounds which they have a total concentration of 29 459 ug kg-1 , were determined. Aroma extract dilution analysis (AEDA) was used to determine key aroma compounds of table olives. Based on the flavor dilution (FD) factor, the most powerful aroma-active compounds in the sample were methyl-2 methyl butyrate (tropical, sweet; FD: 512) and (Z)-3-hexenol (green, flowery; FD: 256). Phenolic compounds in table olives were also analyzed by LC-DAD-ESI-MS/MS. A total of 20 main phenolic compounds were identified and the highest content of phenolic compound was luteolin-7-glucoside (306 mg kg-1 ), followed by verbascoside (271 mg kg-1 ), oleuropein (231 mg kg-1 ), and hydroxytyrosol (3,4 DHPEA) (221 mg kg-1 ). CONCLUSION: Alcohols, carboxylic acids, and lactones were qualitatively and quantitatively the dominant volatiles in black dry-salted olives. Results indicated that esters and alcohols were the major aroma-active compounds. (c) 2018 Society of Chemical Industry. PMID- 29388216 TI - Transfusion-associated circulatory overload in a pediatric intensive care unit: different incidences with different diagnostic criteria. AB - BACKGROUND: The incidence of transfusion-associated circulatory overload (TACO) is not well known in children, especially in pediatric intensive care unit (PICU) patients. STUDY DESIGN AND METHODS: All consecutive patients admitted over 1 year to the PICU of CHU Sainte-Justine were included after they received their first red blood cell transfusion. TACO was diagnosed using the criteria of the International Society of Blood Transfusion, with two different ways of defining abnormal values: 1) using normal pediatric values published in the Nelson Textbook of Pediatrics and 2) by using the patient as its own control and comparing pre- and posttransfusion values with either 10 or 20% difference threshold. We monitored for TACO up to 24 hours posttransfusion. RESULTS: A total of 136 patients were included. Using the "normal pediatric values" definition, we diagnosed 63, 88, and 104 patients with TACO at 6, 12, and 24 hours posttransfusion, respectively. Using the "10% threshold" definition we detected 4, 15, and 27 TACO cases in the same periods, respectively; using the "20% threshold" definition, the number of TACO cases was 2, 6, and 17, respectively. Chest radiograph was the most frequent missing item, especially at 6 and 12 hours posttransfusion. Overall, the incidence of TACO varied from 1.5% to 76% depending on the definition. CONCLUSION: A more operational definition of TACO is needed in PICU patients. Using a threshold could be more optimal but more studies are needed to confirm the best threshold. PMID- 29388217 TI - Prevalence of piscine orthoreovirus and salmonid alphavirus in sea-caught returning adult Atlantic salmon (Salmo salar L.) in northern Norway. AB - Heart and skeletal muscle inflammation (HSMI) caused by piscine orthoreovirus (PRV) and pancreas disease (PD) caused by salmonid alphavirus (SAV) are among the most prevalent viral diseases of Atlantic salmon farmed in Norway. There are limited data about the impact of disease in farmed salmon on wild salmon populations. Therefore, the prevalence of PRV and SAV in returning salmon caught in six sea sites was determined using real-time RT-PCR analyses. Of 419 salmon tested, 15.8% tested positive for PRV, while none were positive for SAV. However, scale reading revealed that 10% of the salmon had escaped from farms. The prevalence of PRV in wild salmon (8%) was significantly lower than in farm escapees (86%), and increased with fish length (proxy for age). Sequencing of the S1 gene of PRV from 39 infected fish revealed a mix of genotypes. The observed increase in PRV prevalence with fish age and the lack of phylogeographic structure of the virus could be explained by virus transmission in the feeding areas. Our results highlight the need for studies about the prevalence of PRV and other pathogens in Atlantic salmon in its oceanic phase. PMID- 29388219 TI - Contemporary Issues in Women's Health. PMID- 29388218 TI - Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise. AB - KEY POINTS: We investigated the contribution of group III/IV muscle afferents to carotid baroreflex resetting during electrically evoked (no central command) and voluntary (requiring central command) isometric knee extension exercise. Lumbar intrathecal fentanyl was used to attenuate the central projection of MU-opioid receptor-sensitive group III/IV leg muscle afferent feedback. Spontaneous carotid baroreflex control was assessed by loading and unloading the carotid baroreceptors with a variable pressure neck chamber. Group III/IV muscle afferents did not influence spontaneous carotid baroreflex responsiveness at rest or during exercise. Afferent feedback accounted for at least 50% of the exercise induced increase in the carotid baroreflex blood pressure and heart rate operating points, adjustments that are critical for an appropriate cardiovascular response to exercise. These findings suggest that group III/IV muscle afferent feedback is, independent of central command, critical for the resetting of the carotid baroreflex blood pressure and heart rate operating points, but not for spontaneous baroreflex responsiveness. ABSTRACT: This study sought to comprehensively investigate the role of metabolically and mechanically sensitive group III/IV muscle afferents in carotid baroreflex responsiveness and resetting during both electrically evoked (EVO, no central command) and voluntary (VOL, requiring central command) isometric single-leg knee-extension (15% of maximal voluntary contraction; MVC) exercise. Participants (n = 8) were studied under control conditions (CTRL) and following lumbar intrathecal fentanyl injection (FENT) to inhibit MU-opioid receptor-sensitive lower limb muscle afferents. Spontaneous carotid baroreflex control of mean arterial pressure (MAP) and heart rate (HR) were assessed following rapid 5 s pulses of neck pressure (NP, +40 mmHg) or suction (NS, -60 mmHg). Resting MAP (87 +/- 10 mmHg) and HR (70 +/- 8 bpm) were similar between CTRL and FENT conditions (P > 0.4). In terms of spontaneous carotid baroreflex responsiveness, FENT did not alter the change in MAP or HR responses to NP (+13 +/- 5 mmHg, P = 0.85; +9 +/- 3 bpm; P = 0.99) or NS (-13 +/- 5 mmHg, P = 0.99; -24 +/- 11 bpm; P = 0.49) at rest or during either exercise protocol, which were of a remarkably similar magnitude to rest. In contrast, FENT administration reduced the exercise-induced resetting of the operating point for MAP and HR during both EVO (116 +/- 10 mmHg to 100 +/- 15 mmHg and 93 +/- 14 bpm to 82 +/- 10 bpm) and VOL (107 +/- 13 mmHg to 100 +/- 17 mmHg and 89 +/- 10 bpm to 72 +/- 10 bpm) exercise bouts. Together, these findings document that group III/IV muscle afferent feedback is critical for the resetting of the carotid baroreflex MAP and HR operating points, independent of exercise induced changes in central command, but not for spontaneous carotid baroreflex responsiveness. PMID- 29388220 TI - Integrin diversity brings specificity in mechanotransduction. AB - Cells sense and respond to the biochemical and physical properties of the extracellular matrix (ECM) through adhesive structures that bridge the cell cytoskeleton and the surrounding environment. Integrin-mediated adhesions interact with specific ECM proteins and sense the rigidity of the substrate to trigger signalling pathways that, in turn, regulate cellular processes such as adhesion, motility, proliferation and differentiation. This process, called mechanotransduction, influenced by the involvement of different integrin subtypes and their high ECM-ligand binding specificity, contributes to the cell-type specific mechanical responses. In this review, we describe how the expression of particular integrin subtypes affects cellular adaptation to substrate rigidity. We then explain the role of integrins and associated proteins in mechanotransduction, focusing on their specificity in mechanosensing and force transmission. PMID- 29388221 TI - Simultaneous determination of gelsemine and koumine in rat plasma by UPLC-MS/MS and application to pharmacokinetic study after oral administration of Gelsemium elegans Benth extract. AB - A simple, rapid and sensitive method using UPLC-MS/MS was established and validated for simultaneous determination of gelsemine and koumine in rat plasma after oral administration of Gelsemium elegans Benth extract. Plasma was performed with methanol precipitation and berberine was chosen as the internal standard. Plasma samples were separated on an Acquity UPLC(r) BEH C18 column (3.0 * 50 mm, 1.7 MUm) with gradient elution using acetonitrile and 0.1% formic acid aqueous solution as the mobile phase at a flow rate of 0.4 mL/min. Multiple reaction monitoring mode in positive ion mode was utilized for detection. The calibration curves were linear over the range of 0.2-100 ng/mL for gelsemine and 0.1-50 ng/mL for koumine, with the lower limits of quantification 0.2 and 0.1 ng/mL, respectively. The intra- and inter-precision and accuracy were well within the acceptable ranges. The developed method was successfully applied to an in vivo pharmacokinetic study in rat after oral administration of 10 mg/kg Gelsemium elegans Benth extract. PMID- 29388222 TI - Workers' compensation and the working poor: Occupational health experience among low wage workers in federally qualified health centers. AB - BACKGROUND: The working poor are at highest risk of work-related injuries and have limited access to occupational health care. OBJECTIVES: To explore community health centers (CHCs) as a venue for accessing at risk workers; and to examine the experience, knowledge, and perceptions of workers' compensation (WC) among the working poor. METHODS: Key informant interviews were conducted among patients in waiting rooms of rural and urban CHCs. RESULT: Fifty-one interviews of minority workers across sectors identified 23 prior work-related injuries and mixed experiences with the WC system. Barriers to reporting and ways to overcome these barriers were elucidated. CONCLUSIONS: Patients in CHCs work in jobs that put them at risk for work-related injuries. CHCs are a good site for accessing at risk workers. Improving occupational healthcare and appropriate billing of WC insurance should be explored, as should best practices for employers to communicate WC laws to low wage workers. PMID- 29388223 TI - Aberrant breast tissue in complete androgen insensitivity syndrome. PMID- 29388224 TI - Ablation of the carotid bodies in disease: meeting its adverse effects. PMID- 29388225 TI - Effect of nanoparticles of silver on redox status and the accumulation of Ag in chicken tissues. AB - BACKGROUND: The aim of the study was to verify the hypothesis that there are doses of silver nanoparticles (Ag-NPs) that improve antioxidant defence in chickens without compromising their growth performance and health. RESULTS: The results of our study suggest that, irrespective of the concentration, the administration of Ag-NPs (5 nm) at a dose not exceeding 54 mg/bird has no negative effect on the growth performance of chickens. The administration of Ag NPs (5 nm) in the amount of 2.87 to 63.74 mg/bird does not cause silver to accumulate in the breast muscle. The ingestion of 2.87 mg/bird was found to result in the accumulation of this element in the wall of the small intestine and in the liver, and a further increase in the dose increases the accumulation of Ag in these tissues. Accumulation of Ag in the heart of the chickens was not observed until the dose reached 22.5 mg/bird. CONCLUSION: Our research has shown that the application of Ag-NPs (5 nm), especially at doses greater than the 'no observable adverse effect level' (NOAEL) of 9.47 mg/bird, can induce oxidative reactions in the blood, small intestinal wall, liver and breast muscle of chickens. (c) 2018 Society of Chemical Industry. PMID- 29388226 TI - Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing. AB - OBJECTIVE: Non-invasive prenatal detection of aneuploidies can be achieved with high accuracy through sequencing of cell-free maternal plasma DNA in the maternal blood plasma. However, false positive and negative non-invasive prenatal testing (NIPT) results remain. Fetoplacental mosaicism is the main cause for false positive and false negative NIPT. We set out to develop a method to detect placental chromosomal mosaicism via genome-wide circulating cell-free maternal plasma DNA screening. METHOD: Aneuploidy detection was combined with fetal fraction determination to enable the detection of placental mosaicism. This pipeline was applied to whole genome sequencing data derived from 19 735 plasma samples. Following an abnormal NIPT, test results were validated by conventional invasive prenatal or postnatal genetic testing. RESULTS: Respectively 3.2% (5/154), 12.8% (5/39), and 13.3% (2/15) of trisomies 21, 18, and 13 were predicted and confirmed to be mosaic. The incidence of other, rare autosomal trisomies was ~0.3% (58/19,735), 45 of which were predicted to be mosaic. Twin pregnancies with discordant fetal genotypes were predicted and confirmed. CONCLUSION: This approach permits the non-invasive detection of fetal autosomal aneuploidies and identifies pregnancies with a high risk of fetoplacental mosaicism. Knowledge about the presence of chromosomal mosaicism in the placenta influences risk estimation, genetic counseling, and improves prenatal management. PMID- 29388227 TI - Letter by Palacios-Rubio et al. regarding article "Oversensing of transthoracic excitation stimuli in contemporary pacemakers". PMID- 29388228 TI - Subgroup identification in dose-finding trials via model-based recursive partitioning. AB - An important task in early-phase drug development is to identify patients, which respond better or worse to an experimental treatment. While a variety of different subgroup identification methods have been developed for the situation of randomized clinical trials that study an experimental treatment and control, much less work has been done in the situation when patients are randomized to different dose groups. In this article, we propose new strategies to perform subgroup analyses in dose-finding trials and discuss the challenges, which arise in this new setting. We consider model-based recursive partitioning, which has recently been applied to subgroup identification in 2-arm trials, as a promising method to tackle these challenges and assess its viability using a real trial example and simulations. Our results show that model-based recursive partitioning can be used to identify subgroups of patients with different dose-response curves and improves estimation of treatment effects and minimum effective doses compared to models ignoring possible subgroups, when heterogeneity among patients is present. PMID- 29388229 TI - Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding. AB - BACKGROUND: Endoscopic band ligation (EBL) is used for primary (PP) and secondary prophylaxis (SP) of variceal bleeding. Current guidelines recommend combined use of non-selective beta-blockers (NSBBs) and EBL for SP, while in PP either NSBB or EBL should be used. AIM: To assess (re-)bleeding rates and mortality in cirrhotic patients receiving EBL for PP or SP for variceal bleeding. METHODS: (Re-)bleeding rates and mortality were retrospectively assessed with and without concomitant NSBB therapy after first EBL in PP and SP. RESULTS: Seven hundred and sixty-six patients with oesophageal varices underwent EBL from 01/2005 to 06/2015. Among the 284 patients undergoing EBL for PP, n = 101 (35.6%) received EBL only, while n = 180 (63.4%) received EBL + NSBBs. In 482 patients on SP, n = 163 (33.8%) received EBL only, while n = 299 (62%) received EBL + NSBBs. In PP, concomitant NSBB therapy neither decreased bleeding rates (log-rank: P = 0.353) nor mortality (log-rank: P = 0.497) as compared to EBL alone. In SP, similar re-bleeding rates were documented in EBL + NSBB vs EBL alone (log-rank: P = 0.247). However, EBL + NSBB resulted in a significantly lower mortality rate (log-rank: P<0.001). A decreased risk of death with EBL + NSBB in SP (hazard ratio, HR: 0.50; P<0.001) but not of rebleeding, transplantation or further decompensation was confirmed by competing risk analysis. Overall NSBB intake reduced 6-months mortality (HR: 0.53, P = 0.008) in SP, which was most pronounced in patients without severe/refractory ascites (HR: 0.37; P = 0.001) but not observed in patients with severe/refractory ascites (HR: 0.80; P = 0.567). CONCLUSIONS: EBL alone seems sufficient for PP of variceal bleeding. In SP, the addition of NSBB to EBL was associated with an improved survival within the first 6 months after EBL. PMID- 29388231 TI - Ultrasound Imaging for Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is challenging to assess even with recent advancements in computed tomography and magnetic resonance imaging. Ultrasound (US) imaging has previously been less utilized in TBI compared to conventional imaging because of limited resolution in the intracranial space. However, there have been substantial improvements in contrast-enhanced US and development of novel techniques such as intravascular US. Also, continued research provides further insight into cerebrovascular parameters from transcranial Doppler imaging. These advancements in US imaging provides the community of TBI imaging researchers and clinicians new opportunities in clinically monitoring and understanding the pathologic mechanisms of TBI. PMID- 29388230 TI - Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation. AB - KEY POINTS: Although adenosine 2A (A2A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A2A ) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A2A receptor siRNA injections. A2A receptor siRNA injections selectively knocked down A2A receptors in cholera toxin B-subunit-identified phrenic motor neurons, sparing cervical non-phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A2A receptors relevant to A2A receptor-induced phrenic motor facilitation. Upregulation of A2A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury. ABSTRACT: Cervical spinal adenosine 2A (A2A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A2A receptors for pMF are unknown. This is an important question since the physiological outcome of A2A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A2A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A2A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 +/- 2%). Intrapleural siRNA injections were used to selectively knock down A2A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A2A receptor knock down was verified by a ~45% decrease in A2A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P < 0.05). There was no evidence for knock-down in cervical non-phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, pMF induced by cervical (C3-4) intrathecal injections of the A2A receptor agonist CGS21680 was greatly attenuated in siA2A (21%) versus siNT treated rats (147%; P < 0.01). There were no significant effects of siA2A on phrenic burst frequency. Collectively, our results support the hypothesis that phrenic motor neurons express the A2A receptors relevant to A2A receptor-induced pMF. PMID- 29388232 TI - Effects of season on boar semen parameters and antioxidant enzymes in the south subtropical region in Brazil. AB - Although boar semen productivity is affected by seasonality, its effects are not equal among different regions which raise concerns regarding the profitability of boar stud farms. Therefore, the goals of this study were (i) to evaluate the seasonal effect on semen production in a commercial boar stud farm located in a subtropical climate region and (ii) to verify whether the activities of superoxide dismutase and glutathione peroxidase in spermatozoa and seminal plasma were associated with seminal traits of fresh and cooled semen. Nine boars were collected twice per season, and routine seminal parameter analyses were performed together with superoxide dismutase and glutathione peroxidase activities in seminal plasma and spermatozoa. Despite a reduction in sperm concentration in spring and summer, most seminal parameters were constant year-round. Temperature humidity index was higher in the summer compared to spring, autumn and winter (p < .05). Superoxide dismutase activity in spermatozoa was increased in summer compared to autumn and winter (p < .05). The activities of both enzymes in seminal plasma and spermatozoa glutathione peroxidase remained unaltered throughout the seasons. In conclusion, seasonality showed little influence in overall boar seminal parameters despite microclimatic differences among seasons, and spermatozoa collected during summer increased superoxide dismutase activity. PMID- 29388233 TI - Impact of weight loss on sperm DNA integrity in obese men. AB - The objective of the study was to determine whether weight loss in obese men improves their fertility with respect to DNA fragmentation index and morphology. Collected fertility parameters included DFI and morphology. Body mass index (BMI) was calculated for all patients with comparisons to their fertility parameters before and after weight loss using paired t test and chi-square tests. The mean BMI was significantly higher in group 1, before weight loss (33.18 kg/m2 ), than in group 2, after weight loss (30.43 kg/m2 ). Overall, 53.3% of men had DFI <20% while 43.8% had a DFI between 20% and 40%, and 2.9% of men had DFI >40%. The mean DFI of participants was higher before weight loss (20.2%) and had improved significantly after weight loss (17.5%) (p = <.001). The weight loss had significant positive correlation with percentage of DFI. There was a significant improvement in morphology after weight loss (p = <.05). In one of the largest cohorts of male fertility and obesity, DFI and morphology demonstrated significant relationship with adiposity, possibly contributing to subfertility in this population. PMID- 29388234 TI - Telepresent Focused Assessment With Sonography for Trauma Examination Training Versus Traditional Training for Medical Students: A Simulation-Based Pilot Study. AB - OBJECTIVES: Telepresent education is becoming an important modality in medical education, as it provides a means for instructors to lead education sessions via videoconferencing technologies. This study aimed to compare the effectiveness of telepresent ultrasound training versus traditional in-person ultrasound training. METHODS: Medical student cohorts were educated by either traditional in-person instruction or telementoring on how to perform a focused assessment with sonography for trauma (FAST) examination. Effectiveness was evaluated by pre- and post-multiple-choice tests (knowledge), confidence surveys, and summative simulation scenarios (hands-on FAST simulation). Formative simulation scenario debriefings were evaluated by each student using the Debriefing Assessment for Simulation in Healthcare student version (DASH-SV). RESULTS: Each method of instruction had significant increases in knowledge, confidence, and hands-on FAST simulation performance (P < .05). The collective increase in knowledge was greater for the in-person group, whereas the improvement in FAST examination performance during simulations was greater for the telementored group. Confidence gains were comparable between the groups. The DASH-SV scores were significantly higher for the in-person group for each criterion; however, both methods were deemed effective via median scoring. CONCLUSIONS: Telepresent education is a viable option for teaching the FAST examination to medical students. PMID- 29388235 TI - Optimizing performance of BreastScreen Norway using value of information in graphical models. AB - This study proposes a method to optimize the performance of BreastScreen Norway through a stratified recommendation of tests including independent double or single reading of the screening mammograms and additional imaging with or without core needle biopsy. This is carefully evaluated by a value of information analysis. An estimated graphical probabilistic model describing the relationship between a set of risk factors and the corresponding risk of breast cancer is used for this analysis, together with a Bayesian network modeling screening test results conditional on the true (but unknown) breast cancer status of a woman. This study contributes towards evaluating a possibility of improving the efficiency of the screening program, where all women aged 50 to 69 are invited every second year, regardless of individual risk factors. Our stratified recommendation of tests is dependent on the probability that an asymptomatic woman has developed breast cancer at the time she is invited to a screening. PMID- 29388236 TI - Clear Cell Hidradenoma: Characteristic Imaging Features on Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging. AB - OBJECTIVES: The purpose of this study was to evaluate the imaging features of clear cell hidradenoma on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). METHODS: The radiologic and pathologic databases at 2 medical institutions were searched retrospectively from 2004 to 2016 to identify patients with a diagnosis of clear cell hidradenoma. Ultrasonographic, CT, and MRI features were described, and pathologic specimens were reviewed. RESULTS: There were 5 female and 4 male patients. The mean patient age was 48.9 years (range, 28-70 years). Five patients underwent only US; 2 patients underwent only CT; 1 patient underwent both US and CT; and 1 patient underwent US and MRI. Most of the tumors were located primarily in the subcutaneous fat layer. The mean tumor size was 18.4 mm. On US, 6 masses had a heterogeneous echo texture, including an anechoic portion with protruding echogenic portions. Two masses had multiple septa in the anechoic portion. On color Doppler US, blood flow was both central and peripheral in 5 patients. All 3 cases seen on CT presented as a low-attenuation mass with an enhanced solid internal nodule. On MRI, the mass showed heterogeneous signal intensity on T2 weighted images and enhancement of the peripheral wall and internal solid component on contrast-enhanced T1-weighted images. CONCLUSIONS: Clear cell hidradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, appears as a cystic mass with an internal solid nodule, and occasionally has multiple septa on US, CT, and MRI. PMID- 29388237 TI - Safety and efficacy of fetal surgery techniques to close a spina bifida defect in the fetal lamb model: A systematic review. AB - OBJECTIVE: To determine the safety and efficacy of different neurosurgical techniques for closure of spina bifida (SB) in the fetal lamb model. METHOD: Systematic review of studies reporting on fetal lambs undergoing induction and closure of SB compared with non-operated normal lambs (negative controls) and/or lambs not undergoing closure of the defect (positive controls). Primary outcomes were (1) survival at birth (safety) and/or (2) presence of Somatosensory Evoked Potentials on hind limbs and/or improvement in quantitative histological spinal cord findings and/or reversal of hindbrain herniation (efficacy). RESULTS: Out of 1311, 36 full-text articles were eligible. Nineteen were included for quality assessment. Due to high bias, only 2 adequately powered studies were included in the final analysis. An open approach using a 2-layer closure (muscle flap or acellular-dermal-matrix patch plus skin) was the only safe (patch + skin) and effective (both techniques) technique for prenatal closure in this animal model. No comparable level of evidence was identified for other techniques. CONCLUSION: The experimental literature on prenatal SB closure underscores the lack of standardization. At present, there is animal experimental evidence that a 2-layer closure by hysterotomy is safe and effective. This technique is currently clinically used in a subset of patients. As new clinical techniques are introduced, it would seem logic to preclinically validate them against this experimental standard. PMID- 29388238 TI - Argon attenuates multiorgan failure following experimental aortic cross-clamping. AB - AIMS: Argon has been shown to prevent ischaemic injuries in several scenarios of regional ischaemia. We determined whether it could provide a systemic effect in a model of multiorgan failure (MOF) induced by aortic cross-clamping. METHODS: Anaesthetized rabbits were submitted to aortic cross-clamping (30 min) and subsequent reperfusion (300 min). They were either ventilated with oxygen enriched air throughout the protocol [fraction of inspired oxygen (FiO2 ) = 30%; control group) or with a mixture of 30% oxygen and 70% argon (argon groups). In a first group treated with argon ('Argon-Total'), its administration was started 30 min before ischaemia and maintained throughout the protocol. In the two other groups, the administration was started either 30 min before ischaemia ('Argon Pre') or at the onset of reperfusion ('Argon-Post'), for a total duration of 2 h. Cardiovascular, renal and inflammatory endpoints were assessed throughout protocol. RESULTS: Compared with control, shock was significantly attenuated in Argon-Total and Argon-Pre but not Argon-Post groups (e.g. cardiac output = 62+/-5 vs. 29 +/- 5 ml min-1 kg-1 in Argon-Total and control groups at the end of the follow-up). Shock and renal failure were reduced in all argon vs. control groups. Histopathological examination of the gut showed attenuation of ischaemic lesions in all argon vs. control groups. Blood transcription levels of interleukin (IL) 1beta, IL-8, IL-10 and hypoxia-inducible factor 1alpha were not significantly different between groups. CONCLUSION: Argon attenuated clinical and biological modifications of cardiovascular, renal and intestinal systems, but not the inflammatory response, after aortic cross-clamping. The window of administration was crucial to optimize organ protection. PMID- 29388239 TI - Non-Scientific Criteria for Belief Sustain Counter-Scientific Beliefs. AB - Why is evolutionary theory controversial among members of the American public? We propose a novel explanation: allegiance to different criteria for belief. In one interview study, two online surveys, and one nationally representative phone poll, we found that evolutionists and creationists take different justifications for belief as legitimate. Those who accept evolution emphasize empirical evidence and scientific consensus. Creationists emphasize not only the Bible and religious authority, but also knowledge of the heart. These criteria for belief remain predictive of views about evolution even when taking into account other related factors like religion, political affiliation, and education. Each view is supported by its own internally specified criteria for what constitutes a justified belief. Changing minds may thus require changing epistemic norms. PMID- 29388241 TI - Oral health of the Latin American elders: What we know and what we should do Position paper of the Latin American Oral Geriatric Group of the International Association for Dental Research. AB - OBJECTIVE: The purpose of this review was to gather information and discuss oral health status of older people in the Latin American and Caribbean region (LAC). BACKGROUND: Scarce data are available to portrait the oral situation of older people in the region. MATERIAL AND METHODS: This review paper is the result of a meeting of the IADR's Latin American Geriatric Oral Research Group held in Porto Alegre, Brazil, in November of 2016, part of the activities of an IADR Regional Development Programme (RDP). A group of researchers from 8 countries of LAC held a discussion using 5 questions related to the oral health situation of older Latin Americans, the most appropriate strategies to face the problem and the challenges for the future, with an open discussion format. In a second step, a group of 6 experts refined the answers and reviewed the existent literature. RESULTS: The review of the evidence revealed that only a few LAC countries have information, which suggests the need for multinational efforts to understand the oral health status and programmes in place. Of the few studies available, it is possible to observe poor oral health as a common feature of older adults in the region. CONCLUSION: There is a need for the development of national surveys and standardised tools for the assessment of oral health in older adults. Also, intense advocacy to modify and influence public health policies in the different countries of the LAC is strongly recommended. PMID- 29388240 TI - Oversensing of transthoracic excitation stimuli in contemporary pacemakers. PMID- 29388242 TI - Large scale ab initio modeling of structurally uncharacterized antimicrobial peptides reveals known and novel folds. AB - Antimicrobial resistance within a wide range of infectious agents is a severe and growing public health threat. Antimicrobial peptides (AMPs) are among the leading alternatives to current antibiotics, exhibiting broad spectrum activity. Their activity is determined by numerous properties such as cationic charge, amphipathicity, size, and amino acid composition. Currently, only around 10% of known AMP sequences have experimentally solved structures. To improve our understanding of the AMP structural universe we have carried out large scale ab initio 3D modeling of structurally uncharacterized AMPs that revealed similarities between predicted folds of the modeled sequences and structures of characterized AMPs. Two of the peptides whose models matched known folds are Lebocin Peptide 1A (LP1A) and Odorranain M, predicted to form beta-hairpins but, interestingly, to lack the intramolecular disulfide bonds, cation-pi or aromatic interactions that generally stabilize such AMP structures. Other examples include Ponericin Q42, Latarcin 4a, Kassinatuerin 1, Ceratotoxin D, and CPF-B1 peptide, which have alpha-helical folds, as well as mixed alphabeta folds of human Histatin 2 peptide and Garvicin A which are, to the best of our knowledge, the first linear alphabetabeta fold AMPs lacking intramolecular disulfide bonds. In addition to fold matches to experimentally derived structures, unique folds were also obtained, namely for Microcin M and Ipomicin. These results help in understanding the range of protein scaffolds that naturally bear antimicrobial activity and may facilitate protein design efforts towards better AMPs. PMID- 29388243 TI - Prenatal acupuncture: Women's expectations and satisfaction and influence on labor. AB - BACKGROUND: Use of prenatal acupuncture for labor preparation is common, but there is still conflicting evidence with respect to its objective obstetric benefits. There is little information on women's expectations and subjective experiences with acupuncture treatments. METHODS: In this retrospective cohort study, a validated questionnaire on women's treatment satisfaction was sent to women who had received prenatal acupuncture at the obstetric clinic of the Medical University of Graz, Austria within the last 3 years. The electronic obstetric database was used to extract detailed clinical and obstetric data of women who received acupuncture and delivered at the hospital. For comparison, obstetric data were matched with a control group of women without prenatal acupuncture, who had given birth at the hospital during the study period. RESULTS: The questionnaire was sent to 150 women, out of which 70 (46.7%) completed and returned the questionnaire. Analysis of the questionnaire indicated good overall satisfaction (mean sum score 26.22 +/- 4.72) with acupuncture treatment-97.1% indicated that they were very or quite satisfied. Responders did not differ from nonresponders, except for the time between delivery and questionnaire (P = .015). Comparisons between the deliveries after prenatal acupuncture (n = 144) and the matched control deliveries (n = 576) showed no statistical significant differences in the length of labor and use of analgesics. CONCLUSION: Prenatal acupuncture is likely to have positive effects on pregnant women, aside from an objective influence on labor duration and pain. PMID- 29388245 TI - Case of psoriatic patient who maintains long-term remission after anti-hepatitis C virus agents and ustekinumab treatment. PMID- 29388244 TI - Quantitative assessment of metal dysregulation in beta-thalassemia patients in comparison with healthy controls by ICP-MS and chemometric analyses. AB - beta-Thalassemia is one of the most common inherited disorders and is widely distributed throughout the world. Owing to severe deficiencies in red blood cell production, blood transfusion is required to correct anemia for normal growth and development but causes additional complications owing to iron overload. The aim of this study is to quantify the biometal dysregulations in beta-thalassemia patients as compared with healthy controls. A total of 17 elements were analyzed in serum samples of beta-thalassemia patients and healthy controls using ICP-MS followed by chemometric analyses. Out of these analyzed elements, 14 showed a significant difference between healthy and disease groups at p < 0.05 and fold change >3. A PLS-DA model revealed an excellent separation with 89.8% sensitivity and 97.2% specificity and the overall accuracy of the model was 92.2%. This metallomic study revealed that there is major difference in metallomic profiling of beta-thalassemia patients specifically in Co, Mn, Ni, V and Ba, whereas the fold changes in Co, Mn, V and Ba were found to be greater than that in Fe, providing evidence that, in addition to Fe, other metals are also altered significantly and therefore chelation therapy for other metals may also needed in beta-thalassemia patients. PMID- 29388246 TI - Modeling Reference Production as the Probabilistic Combination of Multiple Perspectives. AB - While speakers have been shown to adapt to the knowledge state of their addressee in choosing referring expressions, they often also show some egocentric tendencies. The current paper aims to provide an explanation for this "mixed" behavior by presenting a model that derives such patterns from the probabilistic combination of both the speaker's and the addressee's perspectives. To test our model, we conducted a language production experiment, in which participants had to refer to objects in a context that also included a visually misleading object (e.g., a crayon shaped like a Lego brick) whose function was either known to both partners, or known just to the speaker but not the addressee. Modeling results indicate that the experimental findings cannot be explained by assuming that speakers tailor a referring expression solely to their own perspective or to the perspective of their addressee. Instead, accounting for the behavioral pattern requires an approach where both perspectives influence the choice of referring expressions. Nevertheless, in our situation, speakers consider their partner's perspective more than their own. PMID- 29388247 TI - Association between provider type and cesarean birth in healthy nulliparous laboring women: A retrospective cohort study. AB - BACKGROUND: Term nulliparous women have the greatest variation across hospitals and providers in cesarean rates and therefore present an opportunity to improve quality through optimal care. We evaluated associations between provider type and mode of birth, including examination of intrapartum management in healthy, laboring nulliparous women. METHODS: Retrospective cohort study using prospectively collected perinatal data from a United States academic medical center (2005-2012). The sample included healthy nulliparous women with spontaneous labor onset and term, singleton, vertex fetus managed by either obstetricians or certified nurse-midwives. Univariate and multivariate logistic regression was used to compare labor interventions and mode of birth by provider type. RESULTS: A total of 1339 women received care by an obstetrician (n = 749) or nurse-midwife (n = 590). The cesarean rate was 13.4% (179/1339). Adjusting for maternal and pregnancy characteristics, care by obstetricians was associated with an increased risk of unplanned cesarean birth (adjusted odds ratio [aOR] 1.48 [95% confidence interval {CI} 1.04-2.12]) compared with care by midwives. Obstetricians more frequently used oxytocin augmentation (aOR 1.41 [95% CI 1.10 1.80]), neuraxial anesthesia (aOR 1.69 [95% CI 1.29-2.23]), and operative vaginal delivery with forceps or vacuum (aOR 2.79 [95% CI 1.75-4.44]). Adverse maternal or neonatal outcomes were not different by provider type across all modes of birth, but were more frequent in women with cesarean than vaginal births. DISCUSSION: In low-risk nulliparous laboring women, care by obstetricians compared with nurse-midwives was associated with increased risk of labor interventions and operative birth. Changes in labor management or increased use of nurse-midwives could decrease the rate of a first cesarean in low-risk laboring women. PMID- 29388248 TI - Genomic variation in Pekin duck populations developed in three different countries as revealed by whole-genome data. AB - It is well known that both British and American Pekin ducks originated from China. However, the populations differ substantially in production performance, but the genetic changes involved are still poorly understood. Herein, we sequenced 24 individual Pekin ducks (eight from each population) with an average sequencing depth of more than 45* for each population (mean coverage of 6.29 per individual). Among these populations from three different countries, we identified a large number of SNPs and indels as well as many unique population variants, which can be used as population-specific molecular markers. Genomic comparisons among the three duck populations revealed many candidate genes as well as pathways and Gene Ontology categories that are putatively associated with meat yield in the British population, growth in the American population and brain development in all three populations. These findings will enable a better understanding of the artificial selection history of Pekin ducks and provide a valuable resource for future research on the breeding of this species. PMID- 29388249 TI - Dispersal ecology of deadwood organisms and connectivity conservation. AB - Limited knowledge of dispersal for most organisms hampers effective connectivity conservation in fragmented landscapes. In forest ecosystems, deadwood-dependent organisms (i.e., saproxylics) are negatively affected by forest management and degradation globally. We reviewed empirically established dispersal ecology of saproxylic insects and fungi. We focused on direct studies (e.g., mark-recapture, radiotelemetry), field experiments, and population genetic analyses. We found 2 somewhat opposite results. Based on direct methods and experiments, dispersal is limited to within a few kilometers, whereas genetic studies showed little genetic structure over tens of kilometers, which indicates long-distance dispersal. The extent of direct dispersal studies and field experiments was small and thus these studies could not have detected long-distance dispersal. Particularly for fungi, more studies at management-relevant scales (1-10 km) are needed. Genetic researchers used outdated markers, investigated few loci, and faced the inherent difficulties of inferring dispersal from genetic population structure. Although there were systematic and species-specific differences in dispersal ability (fungi are better dispersers than insects), it seems that for both groups colonization and establishment, not dispersal per se, are limiting their occurrence at management-relevant scales. Because most studies were on forest landscapes in Europe, particularly the boreal region, more data are needed from nonforested landscapes in which fragmentation effects are likely to be more pronounced. Given the potential for long-distance dispersal and the logical necessity of habitat area being a more fundamental landscape attribute than the spatial arrangement of habitat patches (i.e., connectivity sensu strict), retaining high-quality deadwood habitat is more important for saproxylic insects and fungi than explicit connectivity conservation in many cases. PMID- 29388250 TI - Transverse slot antennas for high field MRI. AB - PURPOSE: Introduce a novel coil design using an electrically long transversely oriented slot in a conductive sheet. THEORY AND METHODS: Theoretical considerations, numerical simulations, and experimental measurements are presented for transverse slot antennas as compared with electric dipole antennas. RESULTS: Simulations show improved central and average transmit and receive efficiency, as well as larger coverage in the transverse plane, for a single slot as compared to a single dipole element. Experiments on a body phantom confirm the simulation results for a slot antenna relative to a dipole, demonstrating a large region of relatively high sensitivity and homogeneity. Images in a human subject also show a large imaging volume for a single slot and six slot antenna array. High central transmit efficiency was observed for slot arrays relative to dipole arrays. CONCLUSION: Transverse slots can exhibit improved sensitivity and larger field of view compared with traditional conductive dipoles. Simulations and experiments indicate high potential for slot antennas in high field MRI. Magn Reson Med 80:1233-1242, 2018. (c) 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29388251 TI - When I say ... stress. PMID- 29388252 TI - The Power of a "Maverick" in Collaborative Problem Solving: An Experimental Investigation of Individual Perspective-Taking Within a Group. AB - Integrating different perspectives is a sophisticated strategy for developing constructive interactions in collaborative problem solving. However, cognitive aspects such as individuals' knowledge and bias often obscure group consensus and produce conflict. This study investigated collaborative problem solving, focusing on a group member interacting with another member having a different perspective (a "maverick"). It was predicted that mavericks might mitigate disadvantages and facilitate perspective taking during problem solving. Thus, 344 university students participated in two laboratory-based experiments by engaging in a simple rule-discovery task that raised conflicts among perspectives. They interacted with virtual partners whose conversations were controlled by multiple conversational agents. Results show that when participants interacted with a maverick during the task, they were able to take others' perspectives and integrate different perspectives to solve the problem. Moreover, when participants interacted in groups with a positive mood, groups with a maverick outperformed groups having several perspectives. PMID- 29388253 TI - 99m Tc-labeled DTPA-colchicine dimer with improved tumor uptake. AB - This work reports the synthesis, radiolabeling, and biological studies of 99m Tc diethylene triamine pentaacetic acid (DTPA)-colchicine dimer in tumor-bearing mice. The novel colchicine dimer was successfully synthesized by conjugation of DTPA to 2 colchicine biomolecules. The ligand could be labeled by 99m Tc in high yield to get 99m Tc-DTPA-colchicine dimer, which was hydrophilic and stable at room temperature. Biodistribution and imaging studies in tumor-bearing mice showed that 99m Tc-DTPA-colchicine dimer accumulated in the tumor with improved uptake and retention. The results indicate the need for synthetic modification of the parent colchicine derivative and the 99m Tc-chelate with a view to improve the tumor-targeting efficacy and in vivo kinetic profiles. PMID- 29388254 TI - Wave-CAIPI ViSTa: highly accelerated whole-brain direct myelin water imaging with zero-padding reconstruction. AB - PURPOSE: This study introduces a highly accelerated whole-brain direct visualization of short transverse relaxation time component (ViSTa) imaging using a wave controlled aliasing in parallel imaging (CAIPI) technique, for acquisition within a clinically acceptable scan time, with the preservation of high image quality and sufficient spatial resolution, and reduced residual point spread function artifacts. METHODS: Double inversion RF pulses were applied to preserve the signal from short T1 components for directly extracting myelin water signal in ViSTa imaging. A 2D simultaneous multislice and a 3D acquisition of ViSTa images incorporating wave-encoding were used for data acquisition. Improvements brought by a zero-padding method in wave-CAIPI reconstruction were also investigated. RESULTS: The zero-padding method in wave-CAIPI reconstruction reduced the root-mean-square errors between the wave-encoded and Cartesian gradient echoes for all wave gradient configurations in simulation, and reduced the side-main lobe intensity ratio from 34.5 to 16% in the thin-slab in vivo ViSTa images. In a 4 * acceleration simultaneous-multislice scenario, wave-CAIPI ViSTa achieved negligible g-factors (gmean /gmax = 1.03/1.10), while retaining minimal interslice artifacts. An 8 * accelerated acquisition of 3D wave-CAIPI ViSTa imaging covering the whole brain with 1.1 * 1.1 * 3 mm3 voxel size was achieved within 15 minutes, and only incurred a small g-factor penalty (gmean /gmax = 1.05/1.16). CONCLUSION: Whole-brain ViSTa images were obtained within 15 minutes with negligible g-factor penalty by using wave-CAIPI acquisition and zero padding reconstruction. The proposed zero-padding method was shown to be effective in reducing residual point spread function for wave-encoded images, particularly for ViSTa. PMID- 29388255 TI - Glaucomatous progression in the retinal nerve fibre and retinal ganglion cell inner plexiform layers determined using optical coherence tomography-guided progression analysis. AB - BACKGROUND: To investigate the characteristics of glaucomatous progression in circumpapillary retinal nerve fibre layer (RNFL) and macular retinal ganglion cell-inner plexiform layer (GCIPL) determined using optical coherence tomography guided progression analysis (OCT-GPA). METHODS: Serial OCT images of 527 glaucomatous eyes with greater than four OCT tests were screened. Among them, 106 (20.1 per cent) eyes with progression in either RNFL or GCIPL determined using OCT-GPA were included. Based on the agreement of progression detection between RNFL and GCIPL, the eyes were classified into the 'RNFL progression earlier group', 'GCIPL progression earlier group', or 'simultaneous progression group'. The type of progression was classified as diffuse, localised or mixed. RESULTS: Among the 106 eyes with progression, 100 (94.3 per cent) showed RNFL progression and 83 (78.3 per cent) showed GCIPL progression. Fifty-four (50.9 per cent), 13 (12.3 per cent), and 39 (36.8 per cent) eyes were classified into the RNFL progression earlier group, GCIPL progression earlier group, and simultaneous progression group, respectively. Diffuse-type progression was found in three (three per cent) eyes with RNFL progression and 32 (38.6 per cent) eyes with GCIPL progression. The most common location of progression was the 7 o'clock sector (42.0 per cent) in the RNFL and the inferotemporal sector (39.8 per cent) in the GCIPL. CONCLUSIONS: The most common characteristic of RNFL and GCIPL progression determined using OCT-GPA was localised thinning in the inferotemporal area. Progression was more frequently found in the RNFL than in the GCIPL, and diffuse-type progression was more frequent in the GCIPL than in the RNFL. PMID- 29388256 TI - A Self-Organizing Approach to Subject-Verb Number Agreement. AB - We present a self-organizing approach to sentence processing that sheds new light on notional plurality effects in agreement attraction, using pseudopartitive subject noun phrases (e.g., a bottle of pills). We first show that notional plurality ratings (numerosity judgments for subject noun phrases) predict verb agreement choices in pseudopartitives, in line with the "Marking" component of the Marking and Morphing theory of agreement processing. However, no account to date has derived notional plurality values from independently needed principles of language processing. We argue on the basis of new experimental evidence and a dynamical systems model that the theoretical black box of notional plurality can be unpacked into objectively measurable semantic features. With these semantic features driving structure formation (and hence agreement choice), our model reproduces the human verb production patterns as a byproduct of normal processing. Finally, we discuss how the self-organizing approach might be extended to other agreement attraction phenomena. PMID- 29388257 TI - Triterpenes from leaves of Cheiloclinium cognatum and their in vivo antiangiogenic activity. PMID- 29388258 TI - Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis. AB - The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate 1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4 2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF. PMID- 29388259 TI - Retrieval practice enhances the ability to evaluate complex physiology information. AB - OBJECTIVE: Many investigations have shown that retrieval practice enhances the recall of different types of information, including both medical and physiological, but the effects of the strategy on higher-order thinking, such as evaluation, are less clear. The primary aim of this study was to compare how effectively retrieval practice and repeated studying (i.e. reading) strategies facilitated the evaluation of two research articles that advocated dissimilar conclusions. A secondary aim was to determine if that comparison was affected by using those same strategies to first learn important contextual information about the articles. METHODS: Participants were randomly assigned to learn three texts that provided background information about the research articles either by studying them four consecutive times (Text-S) or by studying and then retrieving them two consecutive times (Text-R). Half of both the Text-S and Text-R groups were then randomly assigned to learn two physiology research articles by studying them four consecutive times (Article-S) and the other half learned them by studying and then retrieving them two consecutive times (Article-R). Participants then completed two assessments: the first tested their ability to critique the research articles and the second tested their recall of the background texts. RESULTS: On the article critique assessment, the Article-R groups' mean scores of 33.7 +/- 4.7% and 35.4 +/- 4.5% (Text-R then Article-R group and Text-S then Article-R group, respectively) were both significantly (p < 0.05) higher than the two Article-S mean scores of 19.5 +/- 4.4% and 21.7 +/- 2.9% (Text-S then Article S group and Text-R then Article-S group, respectively). There was no difference between the two Article-R groups on the article critique assessment, indicating those scores weren't affected by the different contextual learning strategies. CONCLUSION: Retrieval practice promoted superior critical evaluation of the research articles, and the results also indicated the strategy enhanced the recall of background information. PMID- 29388260 TI - Liponeurofibroma: Clinicopathological features and histogenesis. AB - A neurofibroma is a common cutaneous benign tumor of neural origin. Various histological variants have been reported. Recently, sporadic reports of fatty variants have been reported but their clinicopathological features have not been well studied. The purpose of this study was to examine liponeurofibroma, and to report the distinctive clinicopathological features and histogenesis in comparison with the classic form. A retrospective study was performed on 130 cases. Immunohistochemical staining was performed for S100, factor VIIIa, perilipin and vascular endothelial growth factor. Masson's trichrome stain was also used. Intratumoral adipocytes were examined with transmission electron microscopy. Thirty-two (24.6%) cases were classified as liponeurofibroma on microscopic examination. This variant was more common in patients with neurofibromatosis type 1, older age and female sex. The most prevalent location was the head and neck. Intratumoral fat deposits showed differences in morphology and size compared with subcutaneous fat on light microscopy. Neurofibromatosis type 1 had the highest odds of fatty change in liponeurofibroma. In sporadic cases, fatty change can be caused by senescence, chronic injury, or tissue hypoxia secondary to internal or external stimuli. Further investigation is needed to identify the pathomechanism of fatty change in various cutaneous neoplasms, including neurofibroma. PMID- 29388261 TI - SALMFamide2 and serotonin immunoreactivity in the nervous system of some acoels (Xenacoelomorpha). AB - Acoel worms are simple, often microscopic animals with direct development, a multiciliated epidermis, a statocyst, and a digestive parenchyma instead of a gut epithelium. Morphological characters of acoels have been notoriously difficult to interpret due to their relative scarcity. The nervous system is one of the most accessible and widely used comparative features in acoels, which have a so-called commissural brain without capsule and several major longitudinal neurite bundles. Here, we use the selective binding properties of a neuropeptide antibody raised in echinoderms (SALMFamide2, or S2), and a commercial antibody against serotonin (5-HT) to provide additional characters of the acoel nervous system. We have prepared whole-mount immunofluorescent stainings of three acoel species: Symsagittifera psammophila (Convolutidae), Aphanostoma pisae, and the model acoel Isodiametra pulchra (both Isodiametridae). The commissural brain of all three acoels is delimited anteriorly by the ventral anterior commissure, and posteriorly by the dorsal posterior commissure. The dorsal anterior commissure is situated between the ventral anterior commissure and the dorsal posterior commissure, while the statocyst lies between dorsal anterior and dorsal posterior commissure. S2 and serotonin do not co-localise, and they follow similar patterns to each other within an animal. In particular, S2, but not 5-HT, stains a prominent commissure posterior to the main (dorsal) posterior commissure. We have for the first time observed a closed posterior loop of the main neurite bundles in S. psammophila for both the amidergic and the serotonergic nervous system. In I. pulchra, the lateral neurite bundles also form a posterior loop in our serotonergic nervous system stainings. PMID- 29388263 TI - Feasibility of utilizing near-infrared fluorescence imaging with indocyanine green for super-selective arterial clamping in pure laparoscopic partial nephrectomy. PMID- 29388262 TI - Retreat from Stress: Rattling in a Planar Coordination. AB - Thermoelectric devices convert heat flow to charge flow, providing electricity. Materials for highly efficient devices must satisfy conflicting requirements of high electrical conductivity and low thermal conductivity. Thermal conductivity in caged compounds is known to be suppressed by a large vibration of guest atoms, so-called rattling, which effectively scatters phonons. Here, the crystal structure and phonon dynamics of tetrahedrites (Cu,Zn)12 (Sb,As)4 S13 are studied. The results reveal that the Cu atoms in a planar coordination are rattling. In contrast to caged compounds, chemical pressure enlarges the amplitude of the rattling vibration in the tetrahedrites so that the rattling atom is squeezed out of the planar coordination. Furthermore, the rattling vibration shakes neighbors through lone pairs of the metalloids, Sb and As, which is responsible for the low thermal conductivity of tetrahedrites. These findings provide a new strategy for the development of highly efficient thermoelectric materials with planar coordination. PMID- 29388264 TI - Multimodality Imaging of Silica and Silicon Materials In Vivo. AB - Recent progress in the development of silica- and silicon-based multimodality imaging nanoprobes has advanced their use in image-guided drug delivery, and the development of novel systems for nanotheranostic and diagnostic applications. As biocompatible and flexibly tunable materials, silica and silicon provide excellent platforms with high clinical potential in nanotheranostic and diagnostic probes with well-defined morphology and surface chemistry, yielding multifunctional properties. In vivo imaging is of great value in the exploration of methods for improving site-specific nanotherapeutic delivery by silica- and silicon-based drug-delivery systems. Multimodality approaches are essential for understanding the biological interactions of nanotherapeutics in the physiological environment in vivo. The aim here is to describe recent advances in the development of in vivo imaging tools based on nanostructured silica and silicon, and their applications in single and multimodality imaging. PMID- 29388266 TI - Adenocarcinoma predominant pattern subtyping and nuclear grading in cytology: Is there a role in prognostication of advanced pulmonary adenocarcinomas? AB - INTRODUCTION: Primary lung adenocarcinomas (ADs) show varied architectural patterns, and pattern-based subtyping of ADs is currently recommended due to prognostic implications. Predicting AD patterns on cytology is challenging; however, cytological nuclear features appear to correlate with histological grade and survival in early stage lung ADs. The feasibility and value of AD pattern prediction and nuclear grading on cytology in advanced lung ADs is not known. We aimed to predict patterns and analyse nuclear features on cytology and evaluate their role in prognostication. METHODS: One-hundred patients of Stage III/IV lung AD with available matched cytology and histology samples were included. Cyto patterns based on cell arrangement patterns (flat sheets vs three-dimensional clusters vs papillae) and cyto-nuclear score based on nuclear features (size, shape, contour), nucleoli (macronucleoli vs prominent vs inconspicuous), and nuclear chromatin were determined, and correlated with predominant histological pattern observed on the matched small biopsy and outcome. RESULTS: Higher cyto nuclear scores were observed with high-grade histo-patterns (solid, micropapillary and cribriform), while the predicted cyto-patterns did not correspond to the predominant pattern on histology in 77% cases. Highest cyto histo agreement was observed for solid pattern (72%). High grade histo-patterns and cyto-nuclear scores > 3 showed a trend towards inferior survival (not significant). CONCLUSIONS: Nuclear grade scoring on cytology is simple to perform, and is predictive of high grade patterns. Its inclusion in routine reporting of cytology samples of lung ADs may be valuable. PMID- 29388267 TI - Corrigendum. PMID- 29388265 TI - The curli regulator CsgD mediates stationary phase counter-silencing of csgBA in Salmonella Typhimurium. AB - Integration of horizontally acquired genes into transcriptional networks is essential for the regulated expression of virulence in bacterial pathogens. In Salmonella enterica, expression of such genes is repressed by the nucleoid associated protein H-NS, which recognizes and binds to AT-rich DNA. H-NS-mediated silencing must be countered by other DNA-binding proteins to allow expression under appropriate conditions. Some genes that can be transcribed by RNA polymerase (RNAP) associated with the alternative sigma factor sigmaS or the housekeeping sigma factor sigma70 in vitro appear to be preferentially transcribed by sigmaS in the presence of H-NS, suggesting that sigmaS may act as a counter-silencer. To determine whether sigmaS directly counters H-NS-mediated silencing and whether co-regulation by H-NS accounts for the sigmaS selectivity of certain promoters, we examined the csgBA operon, which is required for curli fimbriae expression and is known to be regulated by both H-NS and sigmaS . Using genetics and in vitro biochemical analyses, we found that sigmaS is not directly required for csgBA transcription, but rather up-regulates csgBA via an indirect upstream mechanism. Instead, the biofilm master regulator CsgD directly counter silences the csgBA promoter by altering the DNA-protein complex structure to disrupt H-NS-mediated silencing in addition to directing the binding of RNAP. PMID- 29388268 TI - AgI -Induced Switching of DNA Binding Modes via Formation of a Supramolecular Metallacycle. AB - The histidine derivative L1 of the DNA intercalator naphthalenediimide (NDI) forms a triangular AgI complex (C2). The interactions of L1 and of C2 with DNA were studied by circular dichroism (CD) and UV/Vis spectroscopy and by viscosity studies. Different binding modes were observed for L1 and for C2, as the AgI complex C2 is too large in size to act as an intercalator. If AgI is added to the NDI molecule that is already intercalated into a duplex, higher order complexes are formed within the DNA duplex and cause disruptions in the helical duplex structure, which leads to a significant decrease in the characteristic CD features of B-DNA. Thus, via addition of a metal we show how a classic and well known organic intercalator unit can be turned into a partial metallo insertor. We also show how electrochemical impedance spectroscopy (EIS) can be used to probe DNA binding modes on DNA films that are immobilized on gold surfaces. PMID- 29388269 TI - Self-Assembly of Enzyme-Like Nanofibrous G-Molecular Hydrogel for Printed Flexible Electrochemical Sensors. AB - Conducting hydrogels provide great potential for creating designer shape-morphing architectures for biomedical applications owing to their unique solid-liquid interface and ease of processability. Here, a novel nanofibrous hydrogel with significant enzyme-like activity that can be used as "ink" to print flexible electrochemical devices is developed. The nanofibrous hydrogel is self-assembled from guanosine (G) and KB(OH)4 with simultaneous incorporation of hemin into the G-quartet scaffold, giving rise to significant enzyme-like activity. The rapid switching between the sol and gel states responsive to shear stress enables free form fabrication of different patterns. Furthermore, the replication of the G quartet wires into a conductive matrix by in situ catalytic deposition of polyaniline on nanofibers is demonstrated, which can be directly printed into a flexible electrochemical electrode. By loading glucose oxidase into this novel hydrogel, a flexible glucose biosensor is developed. This study sheds new light on developing artificial enzymes with new functionalities and on fabrication of flexible bioelectronics. PMID- 29388270 TI - Equilibration of Imine-Linked Polymers to Hexagonal Macrocycles Driven by Self Assembly. AB - Macrocycles based on directional bonding and dynamic covalent bond exchange can be designed with specific pore shapes, sizes, and functionality. These systems retain many of the design criteria and desirable aspects of two-dimensional (2D) covalent organic frameworks (COFs) but are more easily processed. Here we access discrete hexagonal imine-linked macrocycles by condensing a truncated analogue of 1,3,5-tris(4-aminophenyl)benzene (TAPB) with terephthaldehyde (PDA). The monomers first condense into polymers but eventually convert into hexagonal macrocycles in high yield. The high selectivity for hexagonal macrocycles is enforced by their aggregation and crystallization into layered structures with more sluggish imine exchange. Their formation and exchange processes provide new insight into how imine-linked 2D COF simultaneously polymerize and crystallize. Solutions of these assembled macrocycles were cast into oriented, crystalline films, expanding the potential routes to 2D materials. PMID- 29388271 TI - New findings in non-invasive imaging of cutaneous endometriosis: Dermoscopy, high frequency ultrasound and reflectance confocal microscopy. AB - BACKGROUND: Cutaneous endometriosis (CE) is rare and its dermoscopic features were reported only in 3 patients. The aim of this study was to examine a case of pigmented CE with multiple non-invasive imaging techniques, to compare the obtained images with histopathology and to define their utility in an early diagnosis of the disease. CASE REPORT: We performed dermoscopy, high-frequency ultrasound (HFUS), in vivo and ex vivo reflectance confocal microscopy (RCM) of a pigmented CE arising on the caesarean scar of a phototype IV patient, along with histologic studies. Dermoscopy showed a greyish background and a brownish pigmentation. HFUS shows well-demarcated anechoic areas corresponding to ectopic endometrial tissue at histopathologic examination. RCM and OCT only showed the alterations of the epidermis. CONCLUSION: High-frequency ultrasound could represent a very useful tool for an early diagnosis of CE and its usefulness could be tested in patients with unusual cyclical pain, even before skin lesion appearance. RCM allowed the visualization of skin surface modification due to underlying endometriosic tissue. Dermoscopy showed a new aspect that was probably related to the mix of blood extravasation (ie, greyish background) and epidermal pigmentation (ie, brown pigmentation). PMID- 29388272 TI - Isosamidin, an extract of Peucedanum japonicum, inhibits phenylephrine-mediated contractions of the human prostate in vitro. AB - Isosamidin is a pharmacologically active compound extracted from Peucedanum japonicum which is used as a health food in East Asia. Our preliminary animal data suggested that isosamidin may have sufficient potency to treat patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia or overactive bladder. However, the efficacy of isosamidin in humans is unknown. Here, we examined whether isosamidin inhibits agonist-stimulated contractions in isolated human bladder and prostate tissue strips in vitro. Human bladder and prostate strips obtained from 9 to 10 male patients, respectively, were suspended in organ baths. After administration of isosamidin (10, 30, and 100 MUM), concentration-response curves to agonists (acetylcholine or phenylephrine) were constructed by cumulatively increasing agonist concentration. Isosamidin inhibited phenylephrine-stimulated contractions of isolated human prostate tissue strips in a concentration-dependent manner, with significant differences observed between control and 100 MUM isosamidin. In contrast, isosamidin had no effect on acetylcholine-stimulated contractions of isolated human bladder tissue strips. Isosamidin may have pharmacological potency in the treatment of male patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Clinical studies are needed to confirm the efficacy and safety of isosamidin in humans. PMID- 29388273 TI - Secretion of wild-type factor IX upon readthrough over F9 pre-peptide nonsense mutations causing hemophilia B. AB - Pre-peptide regions of secreted proteins display wide sequence variability, even among highly homologous proteins such as coagulation factors, and are intracellularly removed, thus potentially favoring secretion of wild-type proteins upon suppression of nonsense mutations (translational readthrough). As models we selected F9 nonsense mutations with readthrough-favorable features affecting the pre-peptide and pro-peptide regions of coagulation factor IX (FIX), which cause hemophilia B (HB). Only the p.Gly21Ter (c.61G > T) in the variable pre-peptide hydrophobic core significantly responded (secretion, 4.1 +/- 0.5% of wild-type; coagulant activity, 4.0 +/- 0.3%) to the readthrough-inducer geneticin. Strikingly, for the p.Gly21Ter mutation, the resulting specific coagulant activity (0.96 +/- 0.11) was compatible with normal function, thus suggesting secretion of FIX with wild-type features upon readthrough and removal of pre-peptide. Expression of the predicted readthrough-deriving missense variants (Gly21Trp/Cys/Arg) revealed a preserved specific activity (ranging from 0.84 to 0.98), thus supporting our observation. Conversely, rescue of the p.Cys28Ter (c.84T > A) and p.Lys45Ter (c.133A > T) was prevented by constraints of adjacent cleavage sites, a finding consistent with the association of most missense mutations affecting these regions with severe or moderate HB. Overall, our data indicate that suppression of nonsense mutations in the pre-peptide core preserves mature protein features, thus making this class of mutations preferred candidates for therapeutic readthrough. PMID- 29388274 TI - Community-Level Exposure to the Rural Mining Industry: The Potential Influence on Early Adolescent Alcohol and Tobacco Use. AB - PURPOSE: Rural youth have higher rates of alcohol and tobacco use compared to their urban counterparts. However, the economic dependence of rural communities may differentially influence risk behaviors. While research has shown that adults working in mining have elevated rates of alcohol and tobacco use, the influence of living in a mining community on early adolescent substance use is unknown. METHODS: Using data from a representative sample of 4,535 middle school students in a state with heavy reliance on mining, we conducted weighted logistic regression to investigate whether community-level mining economic dependence influences rural-urban differences in adolescent alcohol and tobacco use. All models adjusted for sociodemographics, military family involvement, parental monitoring, and length of residence. FINDINGS: Over one quarter of the sampled students lived in rural counties and approximately half of these counties met the USDA mining economic typology. After stratifying rural counties by mining and nonmining economic dependence, students in rural mining counties had significantly higher odds of all measures of alcohol use (AORs ranged from 1.83 to 3.99) and tobacco use (AORs ranged from 1.61 to 5.05) compared to students in urban counties. Only use of smokeless tobacco was higher among students in rural nonmining counties. CONCLUSIONS: Our findings demonstrate rural-urban disparities in adolescent substance use that are particularly pronounced among youth living in counties with economic dependence on mining. Future research on this subject should include a wider range of community-level factors that may have specific relevance in rural settings to inform the development of population-level interventions. PMID- 29388276 TI - Involvement of nurses in end-of-life discussions for severely disabled children. AB - BACKGROUND: In children with profound intellectual and multiple disabilities (PIMD), discussions about end-of-life decisions (EoLDs) are comparatively common. Nurses play a crucial role in the care for these children, yet their involvement in EoLD discussions is largely unknown. The objective of this research was to investigate the involvement in the hospital of nurses in discussions with parents and physicians about EoLDs for children with PIMD. METHOD: In a retrospective, qualitative study, we conducted semi-structured interviews with the nurses of 12 children with PIMD for whom an EoLD was made within the past 2 years. RESULTS: Parents primarily discuss EoLDs with nurses before and after the meeting with the physician. Nurses who were involved in EoL discussions with parents and physicians assisted them by giving factual information about the child and by providing emotional support. Some nurses, especially nurses from ID-care services, were not involved in EoL discussions, even if they had cared for the child for a long period of time. Some of the nurses had moral or religious objections to carrying out the decisions. CONCLUSION: Most nurses were not involved in EoL discussions with parents and physicians in the hospital. Excluding nurses from EoL discussions can cause them moral distress. The involvement of nurses in EoL discussions for children with PIMD should be improved, especially by involving nurses from ID-care services. Because these nurses are usually familiar with the child, they can be valuable sources of information about the child's quality of life. PMID- 29388277 TI - Promoter polymorphisms in TGFB1 and IL10 genes influence tumor dendritic cells infiltration, development and prognosis of colorectal cancer. AB - BACKGROUND: Anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-beta1 have a complex role in the development of colorectal cancer (CRC). Dendritic cells (DCs) are the cellular component of the inflammatory microenvironment in the tumor and infiltration of tumors by DCs is associated with better prognosis and fewer metastases. METHODS: In the present study, we explored the role of two single nucleotide polymorphisms (SNPs) in the promoter regions of TGFB1 and IL10 genes and their associations with infiltrating DCs in CRC.A case-control study was designed. Genotyping was performed via the polymerase chain reaction-restriction fragment length polymorphism method and DC infiltration was determined immunohistochemically. RESULTS: For the TGFBeta1 509C/T SNP, we found that the T allele was less frequent in patients than in controls (p = 0.031) and the TT-genotype had a 2.74-fold lower risk for CRC than the CC-genotype (odds ratio = 0.365, 95% confidence interval = 0.15-0.88, p = 0.015). Additionally, the TT carriers had the shortest median survival (14.4 months) (p = 0.045). The C-allele genotypes had a significantly longer survival compared to TT carriers (p = 0.018). The CC genotype was associated with a lower cellular density of CD11c in the invasive margin of the tumor (p = 0.033), whereas there was an opposite finding for CD83+ DCs (p = 0.037). Carriers of A allele genotypes of the IL10 -1080A/G SNP had significantly lower CD83+ cells (p = 0.046) in the tumor invasive margin. CONCLUSIONS: The T-allele of the TGFB1 509C/T SNP might be a protective factor for development of CRC, although, in the course of the disease, this variant allele might be associated with more unfavorable prognosis of the patients. PMID- 29388278 TI - Walls or Bridges: "No Gobbledygook": The International Psycho-Oncology Society 2017 Sutherland Award Lecture. AB - Illness, health, and wellness happen in social contexts. The present political environment is highly divisive and plays to the most primitive fears of people. Never have the stakes been so high. History is replete with putative leaders who create walls that separate people in ways that inevitably leads to dehumanization, suffering, and eventually violence. Timely and openly shared psychosocial insights by experts in mental health into the evil consequences of "wall builders" are essential to the physical, mental, and spiritual health of individuals and nations. For health care professionals (in particular) to ignore the dangers posed by the ill equipped self-serving leaders who now dominate the news and exploit the dark psyche of the world stage would be at the very least unethical and at worst collusion in repeating the sins of the past. This article first recognizes the impact of leaders who, at great personal costs, have built bridges (with relentless compassion and courage) where only chasms existed before. Although international politics may seem like a universe away, in which people may (erroneously) feel powerless to influence change, our home health care settings can be dramatically improved and humanized by the application of universally accepted humanistic values. Health care, as it is practiced today, is an anachronism at multiple levels. Supportive care in general and psychosocial values specifically offer a more inclusive and realistic alternative. Based on an inclusive staff leadership model, a strategic, hands-on, practical, and compassionate approach to creating and implementing supportive care programs of excellence is described. Finally, potentially fruitful areas in which supportive care and psychosocial values can provide leadership as bridges to more accessible, affordable, and humanistic care are provided for contemplation. PMID- 29388275 TI - A randomized dose-response trial of aerobic exercise and health-related quality of life in colon cancer survivors. AB - OBJECTIVE: To examine the dose-response effects of aerobic exercise on health related quality of life (HRQoL) among colon cancer survivors. METHODS: Thirty nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min.wk-1 of aerobic exercise (low-dose) and 300 min.wk-1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. RESULTS: Over 6 months, the low dose group completed 141 +/- 10 min.wk-1 of aerobic exercise, and the high-dose group completed 247 +/- 11 min.wk-1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (Ptrend = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (Ptrend = 0.025), the Pittsburgh Sleep Quality Index (Ptrend = 0.049), and the Fatigue Symptom Inventory (Ptrend = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. CONCLUSION: Higher doses of aerobic exercise, up to 300 min.wk-1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors. PMID- 29388280 TI - Area of residual tumor is a robust prognostic marker for patients with rectal cancer undergoing preoperative therapy. AB - The aim of this study was to elucidate differences in the histological features of rectal cancer between patients treated with preoperative chemoradiotherapy and those treated with preoperative chemotherapy. Area of residual tumor (ART) was also evaluated for its utility as a potential prognostic marker between them. Sixty-eight patients with rectal cancer who underwent sphincter-saving surgery were enrolled in this study. Of these, 39 patients received preoperative chemoradiotherapy (CRT group) and 29 patients received preoperative (neoadjuvant) chemotherapy (NAC group). Area of residual tumor was determined by using morphometric software. Tumors in the two groups were compared for differences in their histological features and clinical outcomes. Tumors in the CRT and NAC groups varied greatly with regard to their histological features after preoperative therapy. Tumors in the CRT group showed more marked fibrosis than those in the NAC group. The total ART were significantly smaller in tumors in the CRT group than those in the NAC group. However, in circumferential resection margin-negative pathologic stage 0-III cases, clinical outcomes were not statistically different between the CRT and NAC groups. Both ART and pathologic TNM classification were associated with clinical outcome in preoperative CRT and NAC groups, but Dworak regression grade and fibrotic change were not. Tumors in those undergoing preoperative CRT and NAC were shown to differ significantly in their histological features. Area of residual tumor-based assessment may provide useful prognostic information, regardless of preoperative therapy. PMID- 29388281 TI - Validation of the Pain Coping Questionnaire in Finnish. AB - OBJECTIVE: The Pain Coping Questionnaire (PCQ), the first validated pain coping measurement developed specifically for children, has lacked proper validation in Finnish. The original PCQ by Reid et al. (Pain 1998; 76; 83-96) comprises eight first-order and three higher-order scales. The aim herein was to determine the factor structure and validity of the Finnish PCQ translation in Finnish children. METHODS: Exploratory factor analysis was used for the first-order and higher order classification of 91 recruited patients aged 8-15. Cronbach's alpha was used for reliability. Relationships between the Children's Depression Inventory, patient-reported pain frequency and pain coping strategies were examined. RESULTS: Analyses were executed with 38 items; one was excluded. A structure of eight-first-order (Internalizing/Catastrophizing [IC], Positive Self-Statements [PSS], Information Seeking [IS], Seeking Social Support [SSS], Cognitive Distraction [CD], Externalizing [EXT], Behavioural Distraction [BD], Problem Solving [PS]) and three higher-order scales (Approach [APP], Emotion-Focused Avoidance [EFA], Distraction [DIS]) proved the most consistent. Four first-order scales (PSS, CD, EXT, BD) emerged as identical to the original solution. Internal consistency reliability coefficients for all individual first- and second-order scales were satisfactory. A higher CDI score was positively related to EFA and negatively to DIS, and pain frequency positively related to APP and EFA. CONCLUSION: The exploratory factor analysis of the PCQ provided a both culturally and statistically satisfactory structure in the Finnish translation. This supports the reliability and validity of the PCQ in future national use and the value of the questionnaire also outside English-speaking countries. SIGNIFICANCE: This study showed both culturally and statistically satisfactory factor structure of PCQ in the Finnish translation. This result supports reliability and validity of the PCQ in the national use in the future. The result shows that the PCQ is a reliable method to be used in different linguistic and cultural surroundings and, thus, encourages using it in various countries. The data consist of two patient groups, adolescents with JIA and musculoskeletal pain. Pain and specifically coping with pain are important aspects of clinical work. A valid pain coping scale may enhance distinguishing vulnerable pain coping style in children and adolescent before pain becomes chronic. PMID- 29388282 TI - Protein-protein interactions controlling interfacial aggregation of rhIL-1ra are not described by simple colloid models. AB - We investigated the effects of protein-protein interaction strength on interfacial viscoelastic properties and aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) at silicone oil-water interfaces. Osmotic second virial coefficients determined by static light scattering were used to quantify protein-protein interactions in bulk solution. Attractive protein-protein interactions dominated at low ionic strengths and their magnitude decreased with increasing ionic strength, in contrast to repulsive interactions that would be expected based on uniformly charged sphere models. Interfacial shear rheometry was used to characterize rhIL-1ra interfacial layers. More attractive protein-protein interactions in bulk solution correlated with stronger interfacial gels. Thioflavin-T fluorescence measurements indicated that the intermolecular beta-sheet content of rhIL-1ra incubated in the presence of silicone oil-water interfaces correlated with gel strength. Siliconized syringes were used to probe the effects of mechanical perturbation of the interfacial gel layers. When rhIL-1ra solutions in siliconized glass syringes were subjected to end-over-end rotation, monomeric rhIL-1ra was lost from solution, and particles containing aggregated protein were released into the bulk aqueous phase. The loss of monomeric rhIL-1ra in response to mechanical perturbation was highest under the conditions where the strongest gels were observed. Aggregation of rhIL-1ra was strictly interface-induced and growth of aggregates in the bulk solution was not observed, even in the presence of particles released from silicone oil-water interfaces. PMID- 29388283 TI - Supramolecular Stimuli-Responsive Microgels Crosslinked by Tannic Acid. AB - The application of biomolecules as building blocks is substantial for the design of bioinspired dynamic nanomaterials with tailored properties. In this communication, the facile synthesis of aqueous supramolecular temperature responsive microgels is reported using the natural polyphenol tannic acid (TA) as physical crosslinker. The precipitation polymerization of N-vinylcaprolactam in the presence of this polyphenol leads to the formation of well-defined microgels crosslinked by hydrogen bonds. A systematic variation of the tannic acid content leads to tailored microgel properties. The obtained microgels exhibit reversible temperature-dependent swelling/deswelling and undergo pH-triggered degradation in aqueous solutions. PMID- 29388285 TI - Incarcerated urachal remnant. PMID- 29388284 TI - Pain-relieving effectiveness, quality of life and tolerability of repeated capsaicin 8% patch treatment of peripheral neuropathic pain in Scandinavian clinical practice. AB - CONTEXT: Clinical trials have demonstrated the efficacy and safety of the capsaicin 8% patch in patients with peripheral neuropathic pain (PNP); however, few studies have assessed this treatment in a clinical practice. OBJECTIVE: To determine whether treatment and re-treatment with the capsaicin 8% patch reduce PNP intensity in clinical practice. METHODS: Three non-interventional, observational studies were concurrently conducted in Denmark, Norway and Sweden. Patients with probable or definite PNP received one or two treatments with the capsaicin 8% patch according to usual clinical practice. All analyses were performed on combined data. RESULTS: Overall, 382 and 181 patients received treatment and re-treatment, respectively, with the capsaicin 8% patch. At the group level, a significant reduction in mean level of 'usual pain' intensity (Numerical Pain Rating Scale) over the last 24 h' score was observed from baseline to Weeks 2 through 8 [-1.05 (95% confidence interval: -1.27, 0.82); p < 0.001] with 28% and 31% of patients reporting a >=30% reduction in pain after first treatment and re-treatment, respectively. Improvements in health-related quality of life (EQ-5D-3L index) and overall health status (Patient Global Impression of Change) were observed early (Week 1) and throughout the treatment periods. Most application site reactions subsided within a week after treatment. Following treatment and re-treatment, 57% and 71% of patients, respectively, were willing to undergo further treatment with the capsaicin 8% patch. CONCLUSION: In Scandinavian clinical practice, capsaicin 8% patch treatment was associated with significant reductions in pain intensity and was well tolerated with over half of patients willing to undergo re-treatment. PMID- 29388286 TI - Evaluation of childhood nutrition by dietary survey and stable isotope analyses of hair and breath. AB - OBJECTIVES: The natural abundances of carbon, nitrogen, and sulfur stable isotopes in hair, and of carbon isotopes in breath serve as quantitative biomarkers of protein and carbohydrate sources, but applicability of isotopes for evaluating children's diet has not been demonstrated. In this study, we sought to describe the stable isotope patterns observed in the hair and breath of children and to assess dietary variations in relation to age and ethnicity, hypothesizing that these would reflect dietary differences across age and ethnic groups and would correlate with intake variables derived from a Food Frequency Questionnaire. METHODS: Data were obtained from a cross-sectional study of non Hispanic white (N = 115) and Hispanic (N = 97) children, aged 9-16 years, in Salt Lake City, Utah. Sampling included a hair sample, breath samples (AM and PM), and a youth/adolescent food questionnaire (YAQ). Hair was analyzed for carbon (delta13 C), nitrogen (delta15 N), and sulfur (delta34 S) isotopes, and breath samples for delta13 CAM/PM of respired CO2 . RESULTS: Non-Hispanic whites had lower delta13 C, delta15 N, delta13 CAM , and delta13 CPM values than Hispanics. Hair delta13 C and delta15 N values were correlated with protein sources, particularly for non-Hispanics. Breath delta13 C values were correlated with carbohydrate sources, particularly for Hispanic students. Non-Hispanic white students reported greater intake of total protein, animal protein, dairy, and grain than Hispanic students. Hispanic students reported higher intake of carbohydrates, particularly sweetened beverages. CONCLUSION: While YAQ and stable isotope data reflected strong cultural influences in diet, no significant gender based nor age-based differences were detected. Significant covariation between YAQ and isotopes existed and demonstrate the potential of stable isotopes for characterizing children's diet. PMID- 29388287 TI - Impact of uneven sample morphology on mass resolving power in linear MALDI-TOF mass spectrometry: A comprehensive theoretical investigation. AB - This work discusses the correlation between the mass resolving power of matrix assisted laser desorption/ionization time-of-flight mass analyzers and extraction condition with an uneven sample morphology. Previous theoretical calculations show that the optimum extraction condition for flat samples involves an ideal ion source design and extraction delay. A general expression of spectral feature takes into account ion initial velocity, and extraction delay is derived in the current study. The new expression extends the comprehensive calculation to uneven sample surfaces and above 90% Maxell-Boltzmann initial velocity distribution of ions to account for imperfect ionization condition. Calculation shows that the impact of uneven sample surface or initial spatial spread of ions is negligible when the extraction delay is away from the ideal value. When the extraction delay approaches the optimum value, the flight-time topology shows a characteristic curve shape, and the time-domain mass spectral feature broadens with an increase in initial spatial spread of ions. For protonated 2,5-dihydroxybenzoic acid, the mass resolving power obtained from a sample of 3-MUm surface roughness is approximately 3.3 times lower than that of flat samples. For ions of m/z 3000 coexpanded with 2,5-dihydroxybenzoic acid, the mass resolving power in the 3-MUm surface roughness case only reduces roughly 7%. Comprehensive calculations also show that the mass resolving power of lighter ions is more sensitive to the accuracy of the extraction delay than heavier ions. PMID- 29388289 TI - Corrigendum. PMID- 29388288 TI - Effect of local wound infiltration with ketamine versus dexmedetomidine on postoperative pain and stress after abdominal hysterectomy, a randomized trial. AB - BACKGROUND AND OBJECTIVES: Postoperative pain and stress elicit hormonal changes. We aimed at comparing the effects of wound infiltration with ketamine versus dexmedetomidine on postoperative pain and stress response. METHODS: This double blinded study included ninety patients scheduled for total abdominal hysterectomy and were randomly assigned into three groups to receive local wound infiltration with 40 mL of 0.25% bupivacaine (group C), plus 2 mg/kg ketamine (group K) or 2 MUg/kg dexmedetomidine (group D). Primary outcome was postoperative morphine consumption; secondary outcomes included first request of analgesia, VAS scores at rest and movement (VAS-R/M) and side effects. Serum cortisol, prolactin and glucose levels at baseline, pre-infiltration, 6 and 24 h postoperatively were measured. RESULTS: Rescue analgesia was less in K (6.80 +/- 3.19 mg) and D (8.39 +/- 3.86 mg) compared to C (13.33 +/- 4.01 mg) (p < 0.05). First request of analgesia was delayed in K (7.60 +/- 4.16 h) and D (6.00 +/- 3.73 h) compared to C (4.20 +/- 1.13 h) (p < 0.05). Both VAS and R/M were significantly lower in K (all over 24 h) and D (for 8 and 4 h, respectively) compared to C. Stress markers were significantly lower in K and D compared to C at 6 and 24 h, and in K compared to D at 24 h (p < 0.05). CONCLUSIONS: Local wound infiltration with ketamine or dexmedetomidine added to bupivacaine had an opioid-sparing effect, delayed first request of rescue analgesia, and attenuated postoperative stress response, especially with ketamine in patients underwent total abdominal hysterectomy. PMID- 29388290 TI - The effect of peri-transplant plasmapheresis in the prevention of recurrent FSGS. AB - Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post-transplant. But the effectiveness of this expensive, time-consuming process of plasmapheresis in the prevention of FSGS recurrence is still unclear. We retrospectively reviewed all pediatric cases of FSGS in our center that received a kidney transplant and compared the transplant and patient outcomes of those transplanted after 2006 who received pretransplant plasmapheresis to those prior to 2006 who did not. Of the 57 children with FSGS, 31 and 26 were transplanted before and after 2006, respectively. The cohorts differed significantly in keeping with the center immunosuppression protocol changes, and prior to 2006, the recipients were significantly younger. All children with FSGS transplanted after 2006 underwent three and one sessions of 1.0 plasma volume/exchange plasmapheresis with fresh frozen plasma replacement prior to the transplant in living and deceased donors, respectively, in addition to five sessions of every other day post-transplant pheresis. The incidence (27% vs 26%, P = 1.0) and time to recurrence of FSGS in the kidney allograft (P = .22) were not significantly different in patients that did and did not undergo prophylactic plasmapheresis. We need to re-evaluate the role of preemptive plasmapheresis in the prevention of FSGS recurrence in a prospective multicenter study. PMID- 29388291 TI - Comparison of tuberculin skin test and interferon gamma release assay for diagnosis of latent tuberculosis infection in pediatric candidates of renal transplantation. AB - IGRA has been approved as an alternative in vitro test to diagnose Mycobacterium TB infection. This study aimed to assess the diagnostic value of TST in comparison with QFT assay to detect LTBI among Iranian children candidate for renal transplantation. This cross-sectional study was performed on 31 children who were candidate for renal transplantation admitted to Ali Asghar Children's Hospital and Rasoul Akram Hospital, Tehran, Iran, from 2013 to 2014. TST and QFT were performed for all patients. QFT was negative in all patients, while TST was positive only in one case. Both tests results were negative in 30 patients, yielding an accuracy rate of 96.7% for TST to diagnose LTBI when compared to QFT. In conclusion, compared to QFT, TST is still a valuable diagnostic tool with high accuracy rate for diagnosis of LTBI in children candidates for renal transplantation and can still be used as an accurate test for screening Mycobacterium TB infection. PMID- 29388292 TI - Efficacy of oral fluralaner for the treatment of Demodex gatoi in two shelter cats. PMID- 29388293 TI - Crystal structures of the extracellular domains of the CrRLK1L receptor-like kinases ANXUR1 and ANXUR2. AB - Catharanthus roseus Receptor-Like Kinase 1-like (CrRLK1L) proteins contain two tandem malectin-like modules in their extracellular domains (ECDs) and function in diverse signaling pathways in plants. Malectin is a carbohydrate-binding protein in animals and recognizes a number of diglucosides; however, it remains unclear how the two malectin-like domains in the CrRLK1L proteins sense the ligand molecule. In this study, we reveal the crystal structures of the ECDs of ANXUR1 and ANXUR2, two CrRLK1L members in Arabidopsis thaliana that have critical functions in controlling pollen tube rupture during the fertilization process. We show that the two malectin-like domains in these proteins pack together to form a rigid architecture. Unlike animal malectin, these malectin-like domains lack residues involved in binding to the diglucosides, suggesting that they have a distinct ligand-binding mechanism. A cleft is observed between the two malectin like domains, which might function as a potential ligand-binding pocket. PMID- 29388294 TI - You do something to me, something deep inside. PMID- 29388295 TI - Thermal pain tolerance and pain rating in normal subjects: Gender and age effects. AB - BACKGROUND: Thermal detection thresholds and thermal pain thresholds are important in quantitative sensory testing. Although they have been well studied for assessing somatosensory function, the investigation of thermal pain tolerance has been insufficient. The aim of this study was to explore the characteristics of thermal pain tolerance and pain ratings in healthy subjects. METHODS: Cold pain tolerance (CPTol) and heat pain tolerance (HPTol) were tested in 213 healthy adults aged 18-81 years recruited from the local community. The thermal detection and thermal pain thresholds were also tested to investigate the association with pain tolerance. The visual analogue scale (VAS) was used for assessing pain severity immediately after the thermal pain and tolerance tests. RESULTS: The normality of the CPTol and HPTol was acceptable. Most participants rated the pain induced by the CPTol and HPTol testing as moderate. HPTol was lower in women than in men (p = 0.001), but CPTol did not differ between sexes. The pain ratings of CPTol and HPTol did not differ between sexes, but significant age effects were observed. The association of the tolerance temperature with pain ratings was weak, while those of pain ratings for CPTol and HPTol were strong (r = 0.87). CONCLUSIONS: Women were more sensitive to tolerance heat pain stimuli. Younger participants reported more pain for thermal pain and tolerance tests. SIGNIFICANCE: Thermal pain tolerance and pain rating for the thermal pain tolerance temperature depend on gender and age. Women are more sensitive to heat temperatures, young people rate more pain, and the pain ratings of heat and cold are strongly correlated. PMID- 29388296 TI - Scalable, Stereocontrolled Formal Syntheses of (+)-Isoschizandrin and (+) Steganone: Development and Applications of Palladium(II)-Catalyzed Atroposelective C-H Alkynylation. AB - Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium-catalyzed atroposelective C-H alkynylation and its application in gram scale, stereocontrolled formal syntheses of (+)-isoschizandrin and (+)-steganone. tert-Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee). PMID- 29388297 TI - Improving older people's life satisfaction via social networking site use: Evidence from China. AB - OBJECTIVE: This study aimed to examine the pathways by which social networking sites (SNSs) can improve older people's life satisfaction. METHODS: We conducted an online survey in China that lasted eight weeks. Respondents were required to report their demographic characteristics and feelings regarding SNS use. Data were analysed using SPSS 20 and Amos 21. RESULTS: We collected 596 valid samples. The empirical results show that SNS use improves older people's life satisfaction by reducing their loneliness and improving their self-efficacy. Social support alleviates the negative effect of loneliness and enhances the positive effect of self-efficacy on life satisfaction. Sex differences and education differences were significant. Men and less educated people had higher levels of life satisfaction. CONCLUSION: Policymakers should offer support to SNSs targeting older people and encourage them to provide more useful services. SNS operators should encourage social support among older users and pay attention to sex differences and education differences. PMID- 29388298 TI - Alkynes From Furans: A General Fragmentation Method Applied to the Synthesis of the Proposed Structure of Aglatomin B. AB - Furans are versatile synthons in organic chemistry. Described is a general method for transforming furans into alkynes by dual C-C double-bond cleavage. The reaction is proposed to proceed by sequential [4+2] cycloaddition between furan and singlet oxygen and a formal retro-(3+2) fragmentation of the endoperoxide intermediate. A wide array of furans, including those derived from sapogenins, are amenable to this reaction, thus providing the corresponding alkynoic acids in up to 88 % yields. The synthetic utility was demonstrated by a seven-step synthesis of the proposed structure of a pregnane natural product, aglatomin B, from a known intermediate. PMID- 29388299 TI - Titanium Phosphonate Based Metal-Organic Frameworks with Hierarchical Porosity for Enhanced Photocatalytic Hydrogen Evolution. AB - Photocatalytic hydrogen production is crucial for solar-to-chemical conversion process, wherein high-efficiency photocatalysts lie in the heart of this area. A photocatalyst of hierarchically mesoporous titanium phosphonate based metal organic frameworks, featuring well-structured spheres, a periodic mesostructure, and large secondary mesoporosity, are rationally designed with the complex of polyelectrolyte and cathodic surfactant serving as the template. The well structured hierarchical porosity and homogeneously incorporated phosphonate groups can favor the mass transfer and strong optical absorption during the photocatalytic reactions. Correspondingly, the titanium phosphonates exhibit significantly improved photocatalytic hydrogen evolution rate along with impressive stability. This work can provide more insights into designing advanced photocatalysts for energy conversion and render a tunable platform in photoelectrochemistry. PMID- 29388300 TI - Korean translation and validation of the Community Commitment Scale for preventing social isolation in older adults. AB - AIM: The Community Commitment Scale was developed in Japan to measure communities' ability to prevent older adults' social isolation, including socializing and belonging in the community. We translated the scale into Korean (the Community Commitment Scale-Korean version [CCS-K]), and determined its internal consistency, concurrent validity and construct validity. METHODS: Self report questionnaires were administered to 326 local volunteers (82.8% women, 65.3% aged >=60 years) in Korea. Internal consistency was analyzed with Cronbach's alpha. To evaluate the concurrent validity of the CCS-K, we used the Brief Sense of Community Index, the revised Generative Concern Scale and ratings of two questions that addressed helping elderly neighbors. RESULTS: The Cronbach's alpha coefficient for the CCS-K was 0.68. The correlation coefficients between the CCS-K and Brief Sense of Community Index or Generative Concern Scale, were 0.40 and 0.33 (P < 0.001), respectively. ANOVAs comparing the CCS-K between confidence levels for the two questions that addressed helping elderly neighbors showed large or medium-sized relationships (eta2 = 0.14 and eta2 = 0.08). A confirmatory factor analysis showed the CCS-K had adequate fit to the data (goodness of fit index = 0.965, adjusted goodness of fit index = 0.934, comparative fit index = 0.956 and root mean square error of approximation = 0.067). CONCLUSIONS: The CCS-K has acceptable internal consistency, concurrent validity and construct validity among Korean local volunteers. Thus, we can conclude that the CCS-K can be effectively applied. Geriatr Gerontol Int 2018; 18: 806-812. PMID- 29388301 TI - Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity. AB - The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nm against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target. PMID- 29388302 TI - Cytotoxic T-lymphocyte therapy for post-transplant lymphoproliferative disorder after solid organ transplantation in children. AB - EBV-CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV-CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third-party EBV-CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV-CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV-CTLs were derived from human leukocyte antigen-typed, EBV-seropositive third-party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV-CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12-144) and median post-transplant interval of 8 months (range: 2-107). Seven had monomorphic, two had polymorphic, and one had Hodgkin-type PTLD. All were of B cell origin and EBV-positive on histology. EBV-CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft-versus-host disease or opportunistic infections. EBV-CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity. PMID- 29388303 TI - Large Charge-Transfer Energy in LiFePO4 Revealed by Full-Multiplet Calculation for the Fe L3 -edge Soft X-ray Emission Spectra. AB - We analyzed the Fe 3d electronic structure in LiFePO4 /FePO4 (LFP/FP) nanowire with a high cyclability by using soft X-ray emission spectroscopy (XES) combined with configuration-interaction full-multiplet (CIFM) calculation. The ex situ Fe L2,3 -edge resonant XES (RXES) spectra for LFP and FP are ascribed to oxidation states of Fe2+ and Fe3+ , respectively. CIFM calculations for Fe2+ and Fe3+ states reproduced the Fe L3 RXES spectra for LFP and FP, respectively. In the calculations for both states, the charge-transfer energy was considerably larger than those for typical iron oxides, indicating very little electron transfer from the O 2p to Fe 3d orbitals and a weak hybridization on the Fe-O bond during the charge-discharge reactions. PMID- 29388304 TI - Disseminated fungal infection by Aureobasidium pullulans in a renal transplant recipient. AB - Renal transplant recipients are on long-term potent immunosuppressive therapy, which makes them highly vulnerable to opportunistic fungal infections. Dematiaceous, or dark-pigmented saprophytic fungi, are being increasingly seen as opportunistic pathogens of mycoses in immunosuppressed patients. One of these is Aureobasidium pullulans, which is a black yeast-like dematiaceous fungus found ubiquitously in the environment that can cause various opportunistic human infections. Most infections occur by traumatic inoculation, such as keratitis and cutaneous lesions; disseminated mycoses are very rare and occur only in severely immunocompromised patients. We report a case of disseminated fungal infection due to A. pullulans in a pediatric patient who underwent renal transplant. The use of voriconazole and vacuum-assisted closure along with surgical drainage most likely contributed to the patient's positive outcome. PMID- 29388305 TI - A High-Performance Application Specific Integrated Circuit for Electrical and Neurochemical Traumatic Brain Injury Monitoring. AB - This paper presents the first application specific integrated chip (ASIC) for the monitoring of patients who have suffered a Traumatic Brain Injury (TBI). By monitoring the neurophysiological (ECoG) and neurochemical (glucose, lactate and potassium) signals of the injured human brain tissue, it is possible to detect spreading depolarisations, which have been shown to be associated with poor TBI patient outcome. This paper describes the testing of a new 7.5 mm2 ASIC fabricated in the commercially available AMS 0.35 MUm CMOS technology. The ASIC has been designed to meet the demands of processing the injured brain tissue's ECoG signals, recorded by means of depth or brain surface electrodes, and neurochemical signals, recorded using microdialysis coupled to microfluidics based electrochemical biosensors. The potentiostats use switchedcapacitor charge integration to record currents with 100 fA resolution, and allow automatic gain changing to track the falling sensitivity of a biosensor. This work supports the idea of a "behind the ear" wireless microplatform modality, which could enable the monitoring of currently non-monitored mobile TBI patients for the onset of secondary brain injury. PMID- 29388306 TI - Prospective, randomized comparison of 3-dimensional computed tomography guidance versus TEE data for left atrial appendage occlusion (PRO3DLAAO). AB - BACKGROUND: Preliminary data comparing 3-dimensional computed tomography (3D-CT) to transesophageal echocardiography (TEE) for left atrial appendage occlusion (LAAO) indicates that 3D-CT provides more accurate measurements and improves case planning. Therefore, we conducted a pilot study comparing 3D-CT to TEE in occluder selection accuracy and procedural efficiency. METHODS: From May 2016 to February 2017, 24 patients were prospectively randomized to undergo LAAO using either TEE or 3D-CT. The primary endpoint was device accuracy while the secondary endpoints included # devices per case, # guide catheters used per case, # fluoroscopy angles used, procedure time, fluoroscopy time, radiation dose, and major adverse events (stroke, MI, device embolization, perforation, death). RESULTS: Procedure success was 100% and 92% for the 3D-CT and 2D-TEE cohorts respectively. Accuracy for 1st device selection 92% and 27% (P = .01) for 3D-CT and 2D-TEE respectively but with intra-procedural upsizing in the 2D-TEE cohort, the 2D-TEE cohort accuracy increased to 64% while the 3D-CT groups 92% was accurate (P = .33). Case planning using 3D-CT was significantly more efficient with respect to device utilization (CT 1.33 +/- 0.7 vs. 2D-TEE 2.5 +/- 1.2 P = .01), guide catheters (CT 1 vs. 2D-TEE 1.7 +/- 0.8 P = .01) and procedure time (3D-CT 55 +/- 17 min vs. 2D-TEE 73 +/- 24 min P < .05). One major adverse event, a stroke occurred in the 2D-TEE group. CONCLUSION: In this single-center pilot study, CT guided LAAO case planning was associated with improved device selection accuracy and procedural efficiency. This study data supports the notion that comprehensive 3D assessment significantly simplifies LAAO, minimizing the time and number of steps needed. PMID- 29388307 TI - Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors. AB - Several BCR-ABL1 tyrosine kinase inhibitors (TKIs) are approved for the first line treatment of chronic phase chronic myeloid leukaemia (CML). Disease control is achieved in the vast majority of patients and disease-specific survival is excellent. Consequently, there is now emphasis on managing comorbidities and minimising treatment-related toxicity. Second-generation TKIs have cardiovascular risks that are greater than with imatinib treatment, but these risks must be balanced against the superior CML responses encountered with more potent TKIs. Cardiovascular risk should be assessed at baseline using a locally validated model based on the Framingham risk equation. Clinicians involved in the care of CML patients should be aware of the vascular complications of TKIs and manage cardiovascular risk factors early to mitigate treatment-related risks. Reversible risk factors, such as dyslipidaemia, smoking, diabetes and hypertension, should be addressed. We summarise the available data on cardiovascular complications in CML patients treated with TKIs. Using the latest evidence and collective expert opinion, we provide practical advice for clinicians to assess, stratify and manage cardiovascular risk in people with CML receiving TKI therapy. PMID- 29388308 TI - Transcatheter versus surgical aortic valve replacement in patients at low surgical risk: A meta-analysis of randomized trials and propensity score matched observational studies. AB - BACKGROUND: Although transcatheter aortic valve replacement (TAVR) is officially indicated for high risk aortic stenosis (AS) patients, the procedure is increasingly being performed in patients who are not at high surgical risk, including a substantial number of low risk patients. However, data on the benefit of TAVR in this patient population is limited. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies with propensity score matching (PSM) of TAVR versus surgical aortic valve replacement (SAVR) in patients who are at low surgical risk. The primary outcome was all-cause mortality. The secondary outcomes included stroke, myocardial infarction, bleeding, and various procedural complications. RESULTS: Six studies (2 RCTs and 4 PSM studies) totaling 3,484 patients were included. Follow-up ranged from 3 months to 3 years (median 2 years). The short-term mortality was similar with either TAVR or SAVR (2.2% for TAVR and 2.6% for SAVR, RR 0.89, 95% CI 0.56-1.41, P = 0.62), however, TAVR was associated with increased risk for intermediate-term mortality (17.2% for TAVR and 12.7% for SAVR, RR 1.45, 95% CI 1.11-1.89, P = 0.006). In terms of periprocedural complications, TAVR was associated with reduced risk for bleeding and renal failure and an increase in vascular complications and Pacemaker implantation. CONCLUSIONS: In patients who are at low surgical risk, TAVR seems to be associated with increased mortality risk. Until more data in this population is available, SAVR should remain the treatment of choice for these patients. PMID- 29388309 TI - The influence of genetics, defensive chemistry and the fungal microbiome on disease outcome in whitebark pine trees. AB - The invasive fungal pathogen Cronartium ribicola infects and kills whitebark pine (Pinus albicaulis) throughout western North America. Whitebark pine has been proposed for listing under the Endangered Species Act in the USA, and the loss of this species is predicted to have severe impacts on ecosystem composition and function in high-elevation forests. Numerous fungal endophytes live inside whitebark pine tissues and may influence the severity of C. ribicola infection, either directly by inhibition of pathogen growth or indirectly by the induction of chemical defensive pathways in the tree. Terpenes, a form of chemical defence in pine trees, can also influence disease. In this study, we characterized fungal endophyte communities in whitebark pine seedlings before and after experimental inoculation with C. ribicola, monitored disease progression and compared fungal community composition in susceptible vs. resistant seedlings in a common garden. We analysed the terpene composition of these same seedlings. Seed family identity or maternal genetics influenced both terpenes and endophyte communities. Terpene and endophyte composition correlated with disease severity, and terpene concentrations differed in resistant vs. susceptible seedlings. These results suggest that the resistance to C. ribicola observed in natural whitebark pine populations is caused by the combined effects of genetics, endophytes and terpenes within needle tissue, in which initial interactions between microbes and hosts take place. Tree genotype, terpene and microbiome combinations associated with healthy trees could help to predict or reduce disease severity and improve outcomes of future tree breeding programmes. PMID- 29388310 TI - Acute scrotum in the setting of acute necrotizing pancreatitis: a surprise. PMID- 29388312 TI - Effect of sarcopenia on the outcomes after pancreaticoduodenectomy for distal cholangiocarcinoma. AB - BACKGROUND: The relationship between sarcopenia and patient outcomes after pancreaticoduodenectomy (PD) for distal cholangiocarcinoma (DCC) remains unclear. We assessed the impact of sarcopenia on the outcomes after PD for DCC. METHODS: We retrospectively analysed 65 patients who underwent PD for DCC. The quality of skeletal muscle indicated by the psoas muscle mass index (PMI) were measured on pre-operative computed tomography images. The impact of pre-operative sarcopenia on short- and long-term outcomes was evaluated. RESULTS: Regarding short-term surgical outcomes, there were no marked differences between the high and low PMI groups. Regarding long-term oncological outcomes, the rates of recurrence (23.5% versus 58.3%, P = 0.011) was significantly lower in the high PMI group than in the low PMI group. Furthermore, the recurrence-free survival and disease-specific survival were longer in the high PMI group (P = 0.023 and P = 0.043, respectively). On multivariate analyses, low PMI was an independent predictor of recurrence (hazard ratio (HR) 11.06; P = 0.022) and disease-specific death (HR 11.88; P = 0.043). CONCLUSIONS: Our findings suggested an association between pre operative sarcopenia and poor long-term oncological outcomes after PD for DCC. PMID- 29388311 TI - The British Association of Urological Surgeons (BAUS) radical prostatectomy audit 2014/2015 - an update on current practice and outcomes by centre and surgeon case volume. AB - OBJECTIVES: To describe contemporary radical prostatectomy (RP) practice using the British Association of Urological Surgeons (BAUS) data and audit project and to observe differences in practice in relation to surgeon or centre case-volume. PATIENTS AND METHODS: Data on 13 920 RP procedures performed by 179 surgeons across 86 centres were recorded on the BAUS data and audit platform between 1 January 2014 and 31 December 2015. This equates to ~95% of total RPs performed over this period when compared to Hospital Episode Statistics (HES) data. Centre case-volumes were categorised as 'high' (>200), 'medium' (100-200) and 'low' (<100); surgeon case-volumes were categorised as 'high' (>100) and 'low' (<100). Differences in surgical practice and selected outcome measures were observed between groups. All data and volume categories were for the combined 2-year period. RESULTS: The median number of RPs performed over the 2-year period was 63.5 per surgeon and 164 per centre. Overall, surgical approach was robot assisted laparoscopic RP (RALP) in 65%, laparoscopic RP (LRP) in 23%, and open RP (ORP) in 12%. The dominant approach in high-case-volume centres and by high-case volume surgeons was RALP (74.3% and 69.2%, respectively). There was a greater percentage of ORPs reported by low-volume surgeons and centres when compared to higher volume equivalents. In all, 51.6% of all patients in this series underwent RP in high-case-volume centres using robot-assisted surgery (RAS). High-case volume surgeons performed nerve-sparing (NS) procedures on 57.3% of their cases; low-volume surgeons performing NS on 48.2%. Overall, lymph node dissection (LND) rates were very similar across the groups. An 'extended' LND was more commonly performed in high-volume centres (22.1%). The median length of stay (LOS) was lowest in patients undergoing RALP at high-volume centres (1 day) and highest in ORP across all volume categories (3-4 days). Reported pT2 positive surgical margin (PSM) rate varied by technique, centre volume, and surgeon volume. In general, observed PSM rates were lower when RALP was the surgical approach (14.4%) and when high-volume surgeons were compared to low-volume surgeons (13.6% vs 17.7%). Transfusion rates were highest in ORP across all centres and surgeons (2.96-4.49%) compared to techniques using a minimally-invasive approach (0.25 2.41%). Training cases ranged from 0.5% in low-volume centres to 6.0% in high volume centres. CONCLUSIONS: Compliance with data registration for centres and surgeons performing RP is high in the present series. Most RPs were performed in high-case-volume centres and by high-case-volume surgeons, with the most common approaches being minimally invasive and specifically RAS. High-case-volume centres and surgeons reported higher rates of extended LND and training cases. Higher-case-volume surgeons reported lower pT2 PSM rates, whilst the most marked differences in transfusion rates and LOS were seen when ORP was compared to minimally invasive approaches. Caution must be applied when interpreting these differences on the basis of this being registry data - causality cannot be assumed. PMID- 29388313 TI - Deep learning approaches for detection and removal of ghosting artifacts in MR spectroscopy. AB - PURPOSE: To make use of deep learning (DL) methods to detect and remove ghosting artifacts in clinical magnetic resonance spectra of human brain. METHODS: Deep learning algorithms, including fully connected neural networks, deep convolutional neural networks, and stacked what-where auto encoders, were implemented to detect and correct MR spectra containing spurious echo ghost signals. The DL methods were trained on a huge database of simulated spectra with and without ghosting artifacts that represent complex variations of ghost-ridden spectra, transformed to time-frequency spectrograms. The trained model was tested on simulated and in vivo spectra. RESULTS: The preliminary results for ghost detection are very promising, reaching almost 100% accuracy, and the DL ghost removal methods show potential in simulated and in vivo spectra, but need further refinement and quantitative testing. CONCLUSIONS: Ghosting artifacts in spectroscopy are problematic, as they superimpose with metabolites and lead to inaccurate quantification. Detection and removal of ghosting artifacts using traditional machine learning approaches with feature extraction/selection is difficult, as ghosts appear at different frequencies. Here, we show that DL methods perform extremely well for ghost detection if the spectra are treated as images in the form of time-frequency representations. Further optimization for in vivo spectra will hopefully confirm their "ghostbusting" capacity. Magn Reson Med 80:851-863, 2018. (c) 2018 International Society for Magnetic Resonance in Medicine. PMID- 29388314 TI - Silent aspiration predicts mortality in older adults with aspiration pneumonia admitted to acute hospitals. AB - AIM: Aspiration pneumonia is a common disease resulting in poor outcomes for older adults. It is known that silent aspiration might lead to aspiration pneumonia, but its role in this is unclear. The aim of the present study was to investigate whether silent aspiration is associated with mortality in aspiration pneumonia patients. METHODS: A multicenter (acute hospital) study including 170 aspiration pneumonia patients was carried out. Cough latency time after inhalation of 1% citric acid mist was used to assess silent aspiration. Patients were divided into two groups: silent aspirator (SA) and no-SA groups based on the latency time of >=29/<29 s. RESULTS: The mean age of the participants was 84.0 +/ 8.8 years. A total of 82% of them had moderate aspiration pneumonia. A total of 99 (58.2%) patients were in the SA group. Silent aspiration patients were more likely to be inactive compared with those in the no-SA group (Barthel Index score 5 [IQR 0-45] vs 30 [IQR 5-65], P = 0.023) and had worse oral conditions (Oral Health Assessment Tool score 5.3 +/- 3.2 vs 3.8 +/- 3.1, P = 0.003). Nine of the SA patients and one of the no-SA patients (P = 0.047) died within a month. Multivariate regression analysis showed that silent aspiration was associated with mortality after adjusting for confounders (odds ratio 2.65, 95% CI 1.01 6.98, P = 0.049). CONCLUSIONS: Silent aspiration detected by a cough latency test can predict 1-month mortality in older patients with aspiration pneumonia. More studies are required to investigate whether enhancing cough reflex treatments would help patients recover from aspiration pneumonia. Geriatr Gerontol Int 2018; 18: 828-832. PMID- 29388315 TI - Microbiological survey of commercial tattoo and permanent makeup inks available in the United States. AB - AIMS: Tattooing and use of permanent makeup (PMU) has dramatically increased over the last decade, with a concomitant increase in ink-related infections. The aim of this study was to determine whether micro-organisms are present, and if so, the number and their identification in the commercial tattoo and PMU inks available in the United States. METHODS AND RESULTS: We surveyed 85 unopened tattoo and PMU inks, purchased from 13 companies. We incubated 100 MUl of ink samples on trypticase soy agar plates for bacterial growth, 7H10 Middlebrook medium for mycobacterial growth, and Sabouraud dextrose medium for fungal growth. In total, 42 inks were contaminated with micro-organisms (49%). Thirty-three inks were contaminated with bacteria, 2 inks with fungi, and 7 inks had both bacterial and fungal growth. Mycobacteria were not detected in any of the examined tattoo and PMU inks. In 26 inks, microbial concentrations ranged between 101 and 103 CFU per ml, but higher counts (>103 CFU per ml) were recorded in 16 inks. We identified 83 bacteria by their 16S rDNA sequences, including 20 genera and 49 species. Strains of Bacillus spp. (53%) were dominant, followed by Lysinibacillus fusiformis (7%) and Pseudomonas aeruginosa (5%). Thirty-four (41%) possibly clinically relevant strains were identified, including P. aeruginosa, Dermacoccus barathri and Roseomonas mucosa, some of which have been previously reported to be associated with human skin infections. CONCLUSIONS: The results indicate that commercial tattoo and PMU inks on the US market surveyed in this study contain a wide range of micro-organisms, including pathogenic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbial contaminants in tattoo and PMU inks are an emerging safety concern for public health. This study provides evidence that microbial contamination of tattoo and PMU inks available in the United States is more common than previously thought and highlights the importance of monitoring these products for potentially pathogenic micro-organisms. PMID- 29388316 TI - Long-term survival after transcatheter versus surgical aortic valve replacement for aortic stenosis: A meta-analysis of observational comparative studies with a propensity-score analysis. AB - OBJECTIVES: To synthesize evidence regarding long-term survival after transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) for severe aortic stenosis (AS) from real-world clinical practice, we performed a meta-analysis of observational studies with a propensity score analysis and >=3-year follow-up. METHODS: Databases including MEDLINE and EMBASE were searched through April 2017 using PubMed and OVID. Eligible studies were observational comparative studies with a propensity-score analysis of TAVI versus SAVR enrolling patients with severe AS and reporting >=3-year all-cause mortality as an outcome. A hazard ratio (HR) with its 95% confidence interval (CI) of follow-up (including early) mortality for TAVI versus SAVR was extracted from each individual study. RESULTS: Our search identified 14 eligible studies enrolling a total of 4,197 patients. A pooled analysis of all the 14 studies demonstrated a statistically significant 54% increase in mortality with TAVI relative to SAVR (HR, 1.54; 95% CI, 1.31-1.81; P for effect < 0.00001; P for heterogeneity = 0.14; I2 = 30%). Several sensitivity analyses did not substantially change the statistically significant benefit for SAVR. There was no evidence of significant publication bias. CONCLUSIONS: On the basis of a meta analysis of 14 observational comparative studies with a propensity-score analysis including a total of >=4,000 patients, TAVI is associated with worse >=3-year overall survival than SAVR. PMID- 29388317 TI - Very-short-answer questions: reliability, discrimination and acceptability. AB - CONTEXT: Single-best-answer questions (SBAQs) have been widely used to test knowledge because they are easy to mark and demonstrate high reliability. However, SBAQs have been criticised for being subject to cueing. OBJECTIVES: We used a novel assessment tool that facilitates efficient marking of open-ended very-short-answer questions (VSAQs). We compared VSAQs with SBAQs with regard to reliability, discrimination and student performance, and evaluated the acceptability of VSAQs. METHODS: Medical students were randomised to sit a 60 question assessment administered in either VSAQ and then SBAQ format (Group 1, n = 155) or the reverse (Group 2, n = 144). The VSAQs were delivered on a tablet; responses were computer-marked and subsequently reviewed by two examiners. The standard error of measurement (SEM) across the ability spectrum was estimated using item response theory. RESULTS: The review of machine-marked questions took an average of 1 minute, 36 seconds per question for all students. The VSAQs had high reliability (alpha: 0.91), a significantly lower SEM than the SBAQs (p < 0.001) and higher mean item-total point biserial correlations (p < 0.001). The VSAQ scores were significantly lower than the SBAQ scores (p < 0.001). The difference in scores between VSAQs and SBAQs was attenuated in Group 2. Although 80.4% of students found the VSAQs more difficult, 69.2% found them more authentic. CONCLUSIONS: The VSAQ format demonstrated high reliability and discrimination and items were perceived as more authentic. The SBAQ format was associated with significant cueing. The present results suggest the VSAQ format has a higher degree of validity. PMID- 29388318 TI - Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant. AB - BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT. PMID- 29388319 TI - Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant. AB - Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes. PMID- 29388320 TI - Geometric accuracy of the MR imaging techniques in the presence of motion. AB - Magnetic Resonance Imaging (MRI) is increasingly being used for improving tumor delineation and tumor tracking in the presence of respiratory motion. The purpose of this work is to design and build an MR compatible motion platform and to use it for evaluating the geometric accuracy of MR imaging techniques during respiratory motion. The motion platform presented in this work is composed of a mobile base made up of a flat plate and four wheels. The mobile base is attached from one end and through a rigid rod to a synchrony motion table by Accuray(r) placed at the end of the MRI table and from the other end to an elastic rod. The geometric accuracy was measured by placing a control point-based phantom on top of the mobile base. In-house software module was used to automatically assess the geometric distortion. The blurring artifact was also assessed by measuring the Full Width Half Maximum (FWHM) of each control point. Our results were assessed for 50, 100, and 150 mm radial distances, with a mean geometric distortion during the superior-inferior motion of 0.27, 0.41, and 0.55 mm, respectively. Adding the anterior-posterior motion, the mean geometric distortions increased to 0.4, 0.6, and 0.8 mm. Blurring was observed during motion causing an increase in the FWHM of ~30%. The platform presented in this work provides a valuable tool for the assessment of the geometric accuracy and blurring artifact for MR during motion. Although the main objective was to test the spatial accuracy of an MR system during motion, the modular aspect of the presented platform enables the use of any commercially available phantom for a full quality control of the MR system during motion. PMID- 29388321 TI - Design and optimization of biocompatible polycaprolactone/poly (l-lactic-co glycolic acid) scaffolds with and without microgrooves for tissue engineering applications. AB - This study investigated the effects of smooth and microgrooved membrane blends, with different polycaprolactone (PCL)/ poly(lactic-co-glycolic acid) (PLGA) ratios on the viability, proliferation, and adhesion of different mammalian cell types. The polymer matrices with and without microgrooves, obtained by solvent casting, were characterized by field-emission scanning electron microscopy, atomic force microscopy, contact angle and Young's modulus. Blend characterization showed an increase in roughness and stiffness of membranes with 30% PLGA, without any effect on the contact angle value. Pure PCL significantly decreased the viability of Vero, HaCaT, RAW 264.7, and human fetal lung and gingival fibroblast cells, whereas addition of increasing concentrations of PLGA led to a reduced cytotoxicity. Increased proliferation rates were observed for all cell lines. Fibroblasts adhered efficiently to smooth membranes of the PCL70/PLGA30 blend and pure PLGA, compared to pure PCL and silicone. Microgrooved membranes promoted similar cell adhesion for all groups. Microstructured membranes (15 and 20-MUm wide grooves) promoted suitable orientation of fibroblasts in both PCL70/PLGA30 and pure PLGA, as compared to pure PCL. Neuronal cells of the dorsal root ganglion exhibited an oriented adhesion to all the tested microgrooved membranes. Data suggest a satisfactory safety profile for the microgrooved PCL70/PLGA30 blend, pointing out this polymer combination as a promising biomaterial for peripheral nerve regeneration when cell orientation is required. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1522 1534, 2018. PMID- 29388322 TI - Responsive eLearning exercises to enhance student interaction with metabolic pathways. AB - Successful learning of biochemistry requires students to engage with the material. In the past this often involved students writing out pathways by hand, and more recently directing students to online resources such as videos, songs, and animated slide presentations. However, even these latter resources do not really provide students an opportunity to engage with the material in an active fashion. As part of an online introductory metabolism course that was developed at our university, we created a series of twelve online interactive activities using Adobe Captivate 9. These activities targeted glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, the citric acid cycle, and fatty acid oxidation. The interactive exercises consisted of two types. One involved dragging objects such as names of enzymes or allosteric modifiers to their correct drop locations such as a particular point in a metabolic pathway, a specific enzyme, and so forth. A second type involved clicking on objects, locations within a pathway, and so forth, in response to a particular question. In both types of exercises, students received feedback on their decisions in order to enhance learning. The student feedback received on these activities was very positive, and indicated that they found them to increase their confidence in the material and that they had learned the key principles of each pathway. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):223 229, 2018. PMID- 29388324 TI - Taxane chemotherapy vs antiandrogen agents as first-line therapy for metastatic castration-resistant prostate cancer. AB - OBJECTIVES: To assess treatment patterns and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy or antiandrogen therapy. PATIENTS AND METHODS: Patients initiating first-line antiandrogen therapy (abiraterone, enzalutamide) or chemotherapy (taxane) between October 2012 and September 2014 were retrospectively identified in the US Veterans Health Administration database. The impact of antiandrogen therapy vs chemotherapy on overall survival (OS) and time to discontinuation was assessed using Cox proportional hazard models, adjusting for prior androgen deprivation therapy (ADT) duration and available prognostic factors. RESULTS: Overall, 1445 patients were evaluable, of whom 1108 received antiandrogen therapy and 337 received chemotherapy (docetaxel). On multivariable analysis and propensity score analysis, the OS times for antiandrogen therapy vs chemotherapy were not significantly different (hazard ratio [HR] 1.041, 95% confidence interval (CI) 0.853-1.270, P = 0.694, and HR 1.047, 95% CI 0.861-1.273, P = 0.644, respectively). Time to discontinuation was shorter for chemotherapy vs antiandrogen therapy (HR 2.339, 95% CI 1.969-2.779; P < 0.001). Prior ADT duration above the median was associated with longer OS (HR 0.566, 95% CI 0.464 0.690; P < 0.001) and time to discontinuation (HR 0.831, 95% CI 0.699-0.988; P = 0.036) in the antiandrogen therapy cohort and not the chemotherapy cohort, while prior ADT duration below the median was associated with higher prostate specific antigen (PSA) response rate in the chemotherapy vs antiandrogen therapy cohort (61.5% vs 51.1%; P = 0.024). The treatment-free interval after discontinuation was longer after first-line chemotherapy vs antiandrogen therapy (mean 53 vs 39 days; P = 0.030). CONCLUSION: After adjusting for key prognostic factors in this large mCRPC dataset, the OS was similar for first-line chemotherapy vs antiandrogen therapy despite shorter time to discontinuation with chemotherapy and longer treatment-free interval after first-line chemotherapy. These hypothesis-generating data also suggest that duration of prior ADT may assist in the selection of patients for chemotherapy vs antiandrogen therapy. PMID- 29388323 TI - Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders. AB - INTRODUCTION: Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident-intruder confrontations to study the brain corticostriatal-function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB1 receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures. AIMS AND METHODS: The investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid like molecules and changes in the transcriptome. RESULTS: Stressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicotinic alpha 6. The cannabinoid agonist WIN55212.2 diminished locomotor activity while the inverse agonist increased the distance travelled in the center of the open field. Upon CB1 activation, N oleoylethanolamide and N-palmitoylethanolamide, two AEA congeners that do not interact directly with cannabinoid receptors, were enhanced in the striatum. The co-administration with both cannabinoids induced an up-regulation of striatal FK506 binding protein 5. The inverse agonist in controls reversed the effects of WIN55212.2 on motor activity. When Rimonabant was injected under stress, the cortical levels of 2-arachidonoylglycerol were maximum. The agonist and the antagonist influenced the cortical expression of cholinergic receptor nicotinic alpha 6 and serotonin transporter neurotransmitter type 4 in opposite directions, while their co-administration tended to produce a null effect under stress. CONCLUSIONS: The endocannabinoid system had a direct effect on serotoninergic neurotransmission and glucocorticoid signaling. Cholinergic receptor nicotinic alpha-6 was shown to be deregulated in response to stress and following synthetic cannabinoid drugs thus could confer vulnerability to cannabis addiction and psychosis. Targeting the receptors of endocannabinoids and endocannabinoid-like mediators might be a valuable option for treating stress-related neuropsychiatric symptoms. PMID- 29388325 TI - Does intensity modulation increase target dose calculation errors of conventional algorithms for lung SBRT? AB - PURPOSE: Conventional dose algorithms (Type A and Type B) for lung SBRT can display considerable target dose errors compared to Type-C algorithms. Intensity modulated techniques (IMRT/VMAT) are increasingly being utilized for lung SBRT. Therefore, our study aimed to assess whether intensity modulation increased target dose calculation errors by conventional algorithms over conformal techniques. METHODS: Twenty lung SBRT patients were parallely planned with both IMRT and dynamic conformal arc (DCA) techniques using a Type-A algorithm, and another 20 patients were parallely planned with IMRT, VMAT, and DCA using a Type B algorithm. All 100 plans were recalculated with Type-C algorithms using identical beam and monitor unit settings, with the Type-A/Type-B algorithm dose errors defined using Type-C recalculation as the ground truth. Target dose errors for PTV and GTV were calculated for a variety of dosimetric end points. Using Wilcoxon signed-rank tests (p < 0.05 for statistical significance), target dose errors were compared between corresponding IMRT/VMAT and DCA plans for the two conventional algorithms. The levels of intensity modulation were also evaluated using the ratios of MUs in the IMRT/VMAT plans to those in the corresponding DCA plans. Linear regression was used to study the correlation between intensity modulation and relative dose error magnitudes. RESULTS: Overall, larger errors were found for the Type-A algorithm than for the Type-B algorithm. However, the IMRT/VMAT plans were not found to have statistically larger dose errors from their corresponding DCA plans. Linear regression did not identify a significant correlation between the intensity modulation level and the relative dose error. CONCLUSION: Intensity modulation did not appear to increase target dose calculation errors for lung SBRT plans calculated with conventional algorithms. PMID- 29388326 TI - Discovery of novel 5-methyl-1H-pyrazole derivatives as potential antiprostate cancer agents: Design, synthesis, molecular modeling, and biological evaluation. AB - Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration-resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl 1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability compared with 10e in human liver microsomes. PMID- 29388327 TI - Primary small intestinal volvulus after laparoscopic rectopexy for rectal prolapse. AB - Primary small intestinal volvulus is defined as torsion in the absence of congenital malrotation, band, or postoperative adhesions. Its occurrence as an early postoperative complication is rare. A 40-year-old woman presented with rectal prolapse, and laparoscopic rectopexy was uneventfully performed. She could not have food on the day after surgery. She started oral intake on postoperative day 3 but developed abdominal pain after the meal. Contrast-enhanced CT revealed torsion of the small intestinal mesentery. An emergent laparotomy showed small intestinal volvulus, without congenital malformation or intestinal adhesions. We diagnosed it as primary small intestinal volvulus. The strangulated intestine was resected, and reconstruction was performed. The patient recovered uneventfully after the second surgery. To the best of our knowledge, this is the first report of primary small intestinal volvulus occurring after rectopexy for rectal prolapse. Primary small intestinal volvulus could be a postoperative complication after laparoscopy. PMID- 29388328 TI - Genotype and malocclusion in patients with osteogenesis imperfecta. AB - OBJECTS: To investigate the relationship between genotype and severity of malocclusion in osteogenesis imperfecta (OI). SETTING AND SAMPLE POPULATION: A total of 49 patients participated in this cross-sectional study (age range: 5-19 years; 28 females; diagnoses: OI type I, N = 7; OI type III, N = 11; OI type IV, N = 27; OI type V, N = 2; OI type VI, N = 2). MATERIALS AND METHODS: Sequence analysis of COL1A1/COL1A2 and other OI-related genes was compared to the Peer Assessment Rating (PAR), an index reflecting the severity of malocclusion. RESULTS: The mutation spectrum was as follows: COL1A1, N = 22; COL1A2, N = 22, IFITM5, N = 2; SERPINF1, N = 2; no mutation detected, N = 1). Compared to patients with COL1A1 mutations, patients with COL1A2 mutations had significantly higher scores for total PAR, anterior cross-bite, anterior open bite and anteroposterior buccal occlusion. Males with COL1A2 mutations had significantly higher total PAR scores than females (median 36 vs 30, P = .047, Mann-Whitney test). Exploratory correlation between age and buccal vertical occlusion was noted in patients with COL1A2 mutations (Spearman correlation: r = .46, P = .03, power = .50). Two patients with OI type V (caused by IFITM5 mutations) had total PAR scores of 44 and 21. Both patients scored high for "segment." Patients with OI type VI (due to SERPINF1 mutations) scored similar to OI type V for "centreline." Considerable difference was observed in the total PAR score between the 2 patients with OI type VI. They had total PAR of 43 and 2. CONCLUSION: Type of disease-causing mutation affects the severity of malocclusion in individuals with OI. PMID- 29388329 TI - Incidence, puberty, and fertility in 45,X/47,XXX mosaicism: Report of a patient and a literature review. PMID- 29388330 TI - Facing addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, OFFICE OF THE SURGEON GENERAL Washington, DC, USA: U.S. Department of Health and Human Services, 2016 382 pp. online (grey literature): https://addiction.surgeongeneral.gov/. PMID- 29388331 TI - Facing addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, OFFICE OF THE SURGEON GENERAL Washington, DC, USA: U.S. Department of Health and Human Services, 2016 382 pp. Online (grey literature): https://addiction.Surgeongeneral.Gov/. PMID- 29388332 TI - A tentative win for the people of Auckland in New Zealand's liquor licensing court. PMID- 29388335 TI - Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease, which requires long term, safe and effective treatment. Apremilast, a small-molecule PDE4 inhibitor, has been introduced as psoriasis (and psoriatic arthritis) treatment in Europe in 2015. OBJECTIVE: We analysed and report the efficacy and safety of apremilast in the first 51 patients with psoriasis that have undergone treatment with this novel small molecule in our outpatient clinic. METHOD: Our primary endpoint was the evaluation of clinical response to apremilast according to the percentage of Psoriasis Area Severity Index (PASI) reduction (DeltaPASI) at 16 weeks after treatment initiation. Secondary endpoints were the evaluation at week 16 of (i) PASI; (ii) Dermatology Life Quality Index (DLQI); (iii) Physician Global Assessment (PGA); (iv) Psoriasis Scalp Severity Index (PSSI); and (v) the percentage of patients who achieved DeltaPASI50, DeltaPASI75, DeltaPASI90 and DeltaPASI100; (vi) adverse events (AE); (vii) reasons for drug discontinuation; and (viii) drug survival. RESULTS: About 59.3% of the patients who remained on apremilast achieved at least DeltaPASI75 at week 16, while 11.1% achieved combined 50% <= PASI < 75% and DLQI <= 5 (satisfactory response) adequate enough to maintain treatment. Five patients (18.5%) also achieved DeltaPASI100. Patients discontinued apremilast (28%), mostly during the first 4 weeks due to adverse events (12%) with gastrointestinal symptoms being the most common, and later due to lack of efficacy (16%). A statistically significant improvement of PASI, DLQI, PGA and PSSI scores was observed after 4 and 16 weeks of treatment relative to pretreatment measurements. CONCLUSION: Apremilast is a safe and efficacious treatment for psoriasis patients as it produces DeltaPASI75 and DeltaPASI50 responses combined with DLQI <= 5 in 16 weeks in 70.4% of the patients. These results, from a real-world setting, confirm the efficacy and safety of apremilast which has been demonstrated in large phase III clinical trials. PMID- 29388334 TI - Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey. AB - Atopic dermatitis is a chronic inflammatory skin disease. The objective of this study was to characterize the burden of atopic dermatitis in Japanese adult patients relative to the general population. Japanese adults (>=18 years) with a self-reported diagnosis of atopic dermatitis and adult controls without atopic dermatitis/eczema/dermatitis were identified from the 2013 Japan National Health and Wellness Survey. Atopic dermatitis patients were propensity-score matched with non-atopic dermatitis controls (1:2 ratio) on demographic variables. Patient reported outcome data on comorbidities, mood and sleep disorders, health-related quality of life, work productivity and activity impairment, and health-care resource utilization were analyzed in atopic dermatitis patients and matched controls. A total of 638 Japanese adult patients with atopic dermatitis were identified, of whom 290 (45.5%) rated their disease as "moderate/severe" and 348 (54.5%) as "mild". The analysis cohort comprised 634 atopic dermatitis patients and 1268 matched controls. Atopic dermatitis patients reported a significantly higher prevalence of arthritis, asthma, nasal allergies/hay fever, anxiety, depression and sleep disorders compared with controls (all P < 0.001). Atopic dermatitis patients also reported a significantly poorer health-related quality of life, higher overall work and activity impairment, and higher health-care resource utilization (all P < 0.001). Self-rated disease severity was not associated with disease burden, except for a significantly higher overall work and activity impairment. In conclusion, Japanese adult patients with atopic dermatitis reported a substantial disease burden relative to adults without atopic dermatitis, suggesting an unmet need for effective strategies targeting disease management. PMID- 29388336 TI - Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform. PMID- 29388337 TI - 1,3,5-Triazino Peptide Derivatives: Synthesis, Characterization, and Preliminary Antileishmanial Activity. AB - A library of short di-, tri-, and tetra-peptides with an s-triazine moiety at the N terminus and either an amide or ethyl ester C terminus was prepared in solution and on the solid phase. The two remaining positions of the s-triazine moiety were substituted with methoxy, morpholino, or piperidino groups. All the synthesized peptide derivatives were analyzed by HPLC and fully characterized by IR spectroscopy, 1 H and 13 C NMR spectroscopy, elemental analysis, and mass spectrometry (MALDI TOF/TOF). A preliminary study of the antileishmanial activity of the 1,3,5-triazinyl peptide derivatives revealed that four dipeptide amide derivatives showed higher antipromastigote or antiamastigote activity than the reference standard drug miltefosine with no significance acute toxicity. PMID- 29388338 TI - Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA.IT trial. PMID- 29388339 TI - January 2018 at a glance: biomarkers, co-morbidities and mechanical circulatory support. PMID- 29388340 TI - Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: First descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. AB - The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi's homuncio ("Monstrorum Historia", 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century "Buffon's Histoire Naturelle" and "Cruveilhier's Anatomie Pathologique du Corps Human". The first English language report on NF1 was made by Akenside in 1768 and the first systematic review by Robert William Smith in 1849, while Virchow's pupil, Friedrich Daniel von Recklinghausen, in 1882, was the first to understand the origin of skin tumors and to name them neurofibromas. The touching story of Joseph C. Merrick (the "Elephant man," (who had Proteus syndrome and not NF1), in 1884, played an important role in the later misconception of NF1, as did the novel by Vicotr Hugo on the hunchback Quasimodo. The studies by van der Hoeve (1921), Yakovlev and Guthrie (1931), and Van Bogaert (1935), categorized "von Recklinghausen's" neurofibromatosis among the phakomatoses and the neurocutaneous syndromes. The first known mention of an acoustic neuroma (at autopsy) is attributed to Eduard Sandifort (1777 AD) while John H. Wishart made the earliest autoptic description of neurofibromatosis type 2 (NF2), in 1822, in a 21-year-old man with bilateral acoustic neuromas, who manifested signs since his infancy (Wishart subtype NF2). Smith likely described the first case of schwannomatosis in 1849. Older, Virchow, von Recklinghausen, and Verocay first classified "neuromas" and Masson and Penfield first used the word "schwannoma" taking it from Theodore Schwann's works. In 1903 Henneberg and Koch described NF2 in detail. Young, Eldridge, and Gardner, in the late '70, established NF2 as a distinct familial entity (Gardner subtype NF2). Schwannomatosis, the late entry of the different forms of neurofibromatosis, was credited in the middle '90. PMID- 29388341 TI - Antitumor activity of antibody against cytotoxic T lymphocyte epitope peptide of lymphocyte-specific protein tyrosine kinase. AB - Although humoral responses against CTL epitope peptides from lymphocyte-specific protein tyrosine kinase (Lck) antigen have been observed in the majority of healthy donors and cancer patients, the biological activity of the antibody has not been determined. We investigated the biological activity of mAb against CTL epitope peptide of Lck antigen at positions 486-494 (anti-Lck-486 mAb). This mAb induced dendritic cell maturation from murine bone marrow cells by the immune complex form in vitro, and inhibited tumor growth in association with a suppression of tumor-infiltrating T cells, including T regulatory cells in a murine model using female BALB/cCrlCrlj mice (H-2Kd ). More potent tumor inhibition was observed when this mAb was given prior to peptide vaccination. These results may help to unveil the biological activity of anti-Lck peptide antibodies against CTL epitope peptides. PMID- 29388342 TI - Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment. AB - The endogenous peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonist Oleoylethanolamide (OEA) inhibits eating in rodents, mainly by delaying the onset of meals. The underlying mechanisms of OEA-induced anorexia, however, remain unclear. Animals treated with high OEA doses were shown to display signs of discomfort and impaired locomotion. Therefore, we first examined whether the impaired locomotion may contribute to OEA's anorectic effect. Second, it is controversial whether abdominal vagal afferents are necessary for OEA's anorectic effect. Thus, we explored alternative peripheral neural pathways mediating IP OEA's anorectic effect by performing a celiac-superior mesenteric ganglionectomy (CGX) or a subdiaphragmatic vagal deafferentation (SDA) alone or in combination. Exogenously administered OEA at a commonly used dose (10 mg/kg BW, IP) concurrently reduced food intake and compromised locomotor activity. Attempts to dissociate both phenomena using the dopamine D2/D3 receptor agonist Quinpirole (1 mg/kg BW, SC) failed because Quinpirole antagonized both, OEA-induced locomotor impairment and delay in eating onset. CGX attenuated the prolongation of the latency to eat by IP OEA, but neither SDA nor CGX prevented IP OEA-induced locomotor impairment. Our results indicate that IP OEA's anorectic effect may be secondary to impaired locomotion rather than due to physiological satiety. They further confirm that vagal afferents do not mediate exogenous OEA's anorectic effects, but suggest a role for spinal afferents in addition to an alternative, nonneuronal signaling route. PMID- 29388343 TI - Genetic epidemiology of porcine epidemic diarrhoea virus circulating in China in 2012-2017 based on spike gene. AB - A porcine epidemic diarrhoea outbreak first occurred in southern China at the end of 2010 and afterwards the disease spread throughout the country. Spike gene is divergent and important for understanding the genetic relations of porcine epidemic diarrhoea virus field strains, the epidemiological status of the virus and vaccine development. In this study, S1 regions of spike gene of 1,235 selected strains collected from 2012 to 2017 in China were clustered along with 25 references of spike sequences mainly from China. The phylogenetic analysis demonstrates that these sequences of S1 regions were genetically more diverse with time. In all strains, G1a, G1b, G2a and G2b clusters accounted for 1.9%, 9.6%, 32.2% and 56.3%, respectively, namely G2a and G2b were the two most prevalent clusters in China. Furthermore, we made a more detailed classification for G2 group based on phylogenetic tree, in which G2a was divided into two subgroups, and G2b was separated into four subgroups. PMID- 29388344 TI - Evaluating the effectiveness of intensive versus non-intensive image interpretation education for radiographers: a randomised control trial study protocol. AB - Radiographer commenting systems have not been successfully implemented in many Australian hospitals, despite evidence of their benefit and adoption elsewhere, such as the United Kingdom. An important contributor to the lack of widespread adoption of radiographer commenting in Australia (and likely elsewhere) is the limited availability of accessible education options for radiographers. The purpose of this randomised controlled trial is to compare the effectiveness of the same image interpretation education program delivered over an intensive 2-day period (intensive format) versus a series of shorter regular workshops (non intensive format). The study design is a multicentre, stratified (by years of experience) two group parallel-arm single-blind (assessor blinded) randomised controlled trial. Participants will be allocated to one of the two groups: (1) intensive format of education or (2) non-intensive format of education in a 1:1 ratio. Participants will undergo assessments before education, at 1 week post intervention completion and at 12 weeks post-intervention completion. Findings from this trial will be of relevance to radiographers seeking image interpretation training as well as organisations providing image interpretation education to prepare clinical staff for participation in a radiographer commenting system. A limitation of the trial is that the sample will be inclusive of radiographers, and findings may not be able to be directly extrapolated to other clinical disciplines (e.g. junior doctors, physiotherapists or nurse practitioners). PMID- 29388345 TI - A novel class of human 15-LOX-1 inhibitors based on 3-hydroxycoumarin. AB - Inflammations, sensitivities, and some cancers in mammals are intimately linked to the activity of lipo-oxygenase enzymes. Owing to the importance of these enzymes, mechanistic studies, product analysis, and synthesis of inhibitors have expanded. In this study, a series of hydroxycoumarins, methoxy-3-hydroxy coumarins, and 7-alkoxy-3-hydroxy coumarins were synthesized and evaluated as potential inhibitors of human 15-LOX-1. Among the synthetic coumarins, 7-methoxy 3-hydroxycoumarin derivative demonstrated potent inhibitory activity and the compound, 5f, showed the best result. Radical scavenging assessment, IC50 , HNMR, and DPPH bleaching results indicate that the electronic properties are the major factors for the lipo-oxygenase inhibition potency of the synthetic coumarins. Based on the theoretical studies, it was suggested that the mesomeric effect of the substituent at the seventh position of the benzene ring is one of the major factors in the stability of the oxy-radical intermediate. PMID- 29388346 TI - Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling. AB - Plateable human hepatocytes with human plasma were utilized to generate the uptake transporter kinetic data for pravastatin, an organic anion-transporting polypeptide (OATP) transporter substrate. The active hepatic uptake of pravastatin was determined with a Jmax value of 134.4 pmol/min/million cells and Km of 76.77 uM in plateable human hepatocytes with human plasma. The physiologically-based pharmacokinetic (PBPK) model with incorporation of these in vitro kinetic data successfully simulated the i.v. pharmacokinetic profile of pravastatin without applying scaling factor (the mean predicted area under the curve (AUC) is within 1.5-fold of the observed). Furthermore, the PBPK model also adequately described the oral plasma concentration-time profiles of pravastatin at different dose levels. The current investigation demonstrates an approach allowing us to build upon the translation of in vitro OATP uptake transporter data to in vivo, with a hope of utilizing the in vitro data for the prospective human pharmacokinetic (PK) prediction. PMID- 29388347 TI - Confidence and Prediction Intervals for Pharmacometric Models. AB - Supporting decision making in drug development is a key purpose of pharmacometric models. Pharmacokinetic models predict exposures under alternative posologies or in different populations. Pharmacodynamic models predict drug effects based on exposure to drug, disease, or other patient characteristics. Estimation uncertainty is commonly reported for model parameters; however, prediction uncertainty is the key quantity for clinical decision making. This tutorial reviews confidence and prediction intervals with associated calculation methods, encouraging pharmacometricians to report these routinely. PMID- 29388348 TI - Benign and malignant collision tumors of melanocytic skin lesions with hemangioma: Dermoscopic and reflectance confocal microscopy features. AB - BACKGROUND: Though the combination/collision of nevi or lentigo simplex and hemangiomas is frequent, the malignant collision tumor melanoma-hemangioma is exceptional and can sometime clinically simulate a benign collision. To date, a series of collision tumors of hemangiomas associated with either benign or malignant melanocytic skin lesions (MSL) has yet to be studied by non-invasive imaging and clinico-pathologic correlates. METHODS: We present 10 cases of patients with collision tumors of hemangioma with different MSL including: 2 in situ lentigo-maligna melanoma, 1 invasive melanoma, 5 melanocytic nevi, and 2 lentigo simplex. The clinical aspect along with the dermoscopic and reflectance confocal microscopy (RCM) features is described and compared with histopathologic findings. RESULTS: Dermoscopic examination allows to recognize a dark ring in malignant collision melanoma-hemangioma and a jelly ring sign in benign collision of nevi/lentigo simplex-hemangioma. These peculiar features were confirmed by RCM and histopathologic findings. CONCLUSION: Two simple dermoscopic clues confirmed by RCM features can be proposed to help distinguish between benign and malignant collisions tumors. PMID- 29388349 TI - Differential relations of executive functioning to borderline personality disorder presentations in adolescents. AB - Borderline personality disorder (BPD) in adolescents is highly complex and heterogeneous. Within the disorder, research has suggested the existence of at least two subgroups: one with predominantly internalizing psychopathology features and one with predominantly externalizing psychopathology features. One process that may differentiate these groups is executive functioning (EF), given that poor EF is linked to externalizing psychopathology. Against this background, the current study used a multi-informant approach to examine whether adolescent patients with predominantly externalizing BPD presentations experience greater deficits in EF than adolescent patients with predominantly internalizing presentations. The sample included inpatient adolescents ages 12-17 (M = 15.26; SD = 1.51). Analyses revealed that multiple EF domains distinguished the BPD subgroups. More specifically, adolescents with externalizing presentations exhibited greater difficulties in broad domains related to global executive functioning, metacognition and behavioural regulation and specific domains related to inhibitory control, working memory, planning/organizing, monitoring and organization of materials. While this study is the first to examine EF and adolescent BPD in the context of internalizing and externalizing psychopathology, alternative approaches to examining this question are discussed. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29388350 TI - Nanogenerator for Biomedical Applications. AB - In the past 10 years, the development of nanogenerators (NG) has enabled different systems to operate without external power supply. NG have the ability to harvest the mechanical energies in different forms. Human body motions and activities can also serve as the energy source to drive NG and enable self powered healthcare system. In this review, a summary of several major actual applications of NG in the biomedical fields is made including the circulatory system, the neural system, cell modulation, microbe disinfection, and biodegradable electronics. Nevertheless, there are still many challenges for NG to be actually adopted in clinical applications, including the miniaturization, duration, encapsulation, and output performance. It is also very important to further combine the NG development more precisely with the medical principles. In future, NG can serve as highly promising complementary or even alternative power suppliers to traditional batteries for the healthcare electronics. PMID- 29388351 TI - Ileal vaginoplasty as vaginal reconstruction in transgender women and patients with disorders of sex development: an international, multicentre, retrospective study on surgical characteristics and outcomes. AB - OBJECTIVE: To describe the surgical outcomes of ileal vaginoplasty in transgender women and patients with disorders of sex development (DSD). PATIENTS AND METHODS: Transgender women and patients with DSD, who underwent ileal vaginoplasty at the VU University Medical Center Amsterdam, University Hospital Trieste, University Hospital Essen, and Belgrade University Hospital, were retrospectively identified. A chart review was performed, recording surgical technique, intraoperative characteristics, complications, and re-operations. RESULTS: We identified a total of 32 patients (27 transgender and five non-transgender), with a median (range) age of 35 (6-63) years. Ileal vaginoplasty was performed as the primary procedure in three and as a revision procedure in the remaining 29. The mean (sd) operative time was 288 (103) min. The procedure was performed laparoscopically (seven patients) or open (25). An ileal 'U-pouch' was created in five patients and a single lumen in 27. Intraoperative complications occurred in two patients (one iatrogenic bladder damage and one intraoperative blood loss necessitating transfusion). The median (range) hospitalisation was 12 (6-30) days. Successful neovaginal reconstruction was achieved in all. The mean (sd) achieved neovaginal depth was 13.2 (3.1) cm. The median (range) clinical follow up was 35 (3-159) months. In one patient a recto-neovaginal fistula occurred, which lead to temporary ileostomy. Introital stenosis occurred in four patients (12.5%). CONCLUSION: Ileal vaginoplasty can be performed with few intra- and postoperative complications. It appears to have similar complication rates when compared to sigmoid vaginoplasty. It now seems to be used predominantly for revision procedures. PMID- 29388352 TI - Surfactant selection for a liquid foam-bed photobioreactor. AB - A novel liquid foam-bed photobioreactor has been shown to hold potential as an innovative technology for microalgae production. In this study, a foam stabilizing agent has been selected which fits the requirements of use in a liquid foam-bed photobioreactor. Four criteria were used for an optimal surfactant: the surfactant should have good foaming properties, should not be rapidly biodegradable, should drag up microalgae in the foam formed, and it should not be toxic for microalgae. Ten different surfactants (nonionic, cationic, and anionic) and two microalgae genera (Chlorella and Scenedesmus) were compared on the above-mentioned criteria. The comparison showed the following facts. Firstly, poloxameric surfactants (Pluronic F68 and Pluronic P84) have acceptable foaming properties described by intermediate foam stability and liquid holdup and small bubble size. Secondly, the natural surfactants (BSA and Saponin) and Tween 20 were easily biodegraded by bacteria within 3 days. Thirdly, for all surfactants tested the microalgae concentration is reduced in the foam phase compared to the liquid phase with exception of the cationic surfactant CTAB. Lastly, only BSA, Saponin, Tween 20, and the two Pluronics were not toxic at concentrations of 10 CMC or higher. The findings of this study indicate that the Pluronics (F68 and P84) are the best surfactants regarding the above-mentioned criteria. Since Pluronic F68 performed slightly better, this surfactant is recommended for application in a liquid foam-bed photobioreactor. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:711-720, 2018. PMID- 29388353 TI - Clinical patterns and management of primary mucosal melanoma: a single centre experience. AB - BACKGROUND: Primary mucosal melanomas (MM) are rare neoplasms arising from melanocytes in mucosal membranes. Delayed diagnosis and aggressive disease biology contribute to a poorer prognosis. The clinical patterns of MMs treated in a large tertiary centre, and the differences between MMs in the head and neck versus other anatomical sites are described. METHODS: A retrospective review of 43 patients diagnosed with MM in the head and neck, urogenital, esophageal and anorectal sites from 1993 to 2015 was conducted. RESULTS: Distribution of head and neck, urogenital and gastrointestinal MM were 42, 30 and 28% respectively. Disease extent was local in 44%, regional in 40% and distal in 12% at diagnosis. Head and neck MMs were more likely to be diagnosed at an earlier stage as compared to other sites (P = 0.04). Surgery was performed with curative intent in 72%, while 2% had palliative surgery for symptom control. Of the remaining patients who did not undergo surgery, four had palliative chemotherapy and/or radiotherapy. Median disease-free survival was 13 months (1-179 months). There was a significantly longer time to locoregional recurrence in head and neck MM (16 months) compared to other sites (11 months) (P = 0.03). The 2-year overall survival was also significantly higher in head and neck MM (P = 0.003). CONCLUSION: MM of the head and neck is diagnosed at an earlier stage and associated with a longer time to locoregional recurrence. Surgical resection is the mainstay of treatment and may offer long-term survival benefit in selected patients. PMID- 29388354 TI - Clinical and histopathological aspects of an alopecia syndrome in captive Andean bears (Tremarctos ornatus). AB - BACKGROUND: Captive Andean bears (Tremarctos ornatus) develop a distinct alopecic syndrome of unknown aetiology. HYPOTHESIS/OBJECTIVES: To describe the histological features of healthy Andean bear skin, to define the clinical and histopathological features of Andean bears with signs of alopecia, and to propose an aetiopathogenesis. ANIMALS: Eighteen healthy Andean bears housed in 12 European zoos and 13 Andean bears with mild to severe alopecia housed in nine European zoos. METHODS: Two surveys describing signalment and clinical features of affected bears; follicular density was measured in a single healthy bear using a dermatoscope; cytological samples were collected by tape stripping from two healthy and three alopecic bears; skin biopsies were collected for histological evaluation from healthy and alopecic bears; immunohistochemistry (CD3, AE1/AE3 cytokeratins) was performed when lymphocytic inflammation was observed. RESULTS: The syndrome is an acquired, slowly progressive alopecia. Bears are otherwise healthy. Histological features include a dermal inflammatory infiltrate composed of T lymphocytes and eosinophils; atrophy of hair follicles at the level of or below the isthmus, and lymphocytic infiltration of hair follicles and the epidermis. Multinucleated giant cells were present in the outer root sheaths of hair follicles in five bears. CONCLUSION AND CLINICAL IMPORTANCE: Andean bear alopecia syndrome is an acquired, progressive alopecia with histological features consistent with a lymphocytic immune-mediated reaction directed against follicular sheaths and the epidermis. Trigger factors have not been identified. Further studies are indicated to define the features of this multifactorial syndrome. PMID- 29388355 TI - Extraction of bioactive compounds against cardiovascular diseases from Lentinula edodes using a sequential extraction method. AB - Three extraction methods were sequentially combined to obtain fractions from Lentinula edodes (shiitake mushrooms) containing bioactive compounds against cardiovascular diseases (CVDs). Fruiting bodies were first extracted with plain water, obtained residue was then submitted to supercritical fluid extraction (SFE) and remaining residue submitted to hot water extraction. Sequential design allowed reutilization of the nonextracted material as raw material for the successive extractions increasing extraction yields and separating interesting compounds. Obtained fractions contained different amounts of beta-glucans, chitins, eritadenine, lenthionine, ergosterol, proteins/peptides and phenolic compounds conferring them different bioactivities. Water soluble fractions showed high antioxidant activities (ABTS+* and DPPH* scavenging capacity and reducing power), they were also able to inhibit one of the main enzymes involved in hypertension (angiotensin-I converting enzyme) and the key enzyme of cholesterol metabolism (3-hydroxy-3-methylglutaryl coenzyme A reductase). The latter inhibitory activity was also noticed in SFE extracts although ergosterol and other lipid-like molecules were isolated. Dietary fibers were separated in the third extraction. Therefore, with this sequential extraction procedure bioactive compounds against CVDs can be selectively separated from a single batch of shiitake powder. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:746-755, 2018. PMID- 29388357 TI - Airway obstruction produces widespread sympathoexcitation: role of hypoxia, carotid chemoreceptors, and NTS neurotransmission. AB - Obstructive sleep apnea (OSA) is the most common respiratory disturbance of sleep and is closely associated to cardiovascular diseases. In humans, apnea increases respiratory effort and elevates muscle sympathetic nerve activity (SNA), but the primary stimulus for the SNA activation has not been identified. We recently developed a model of apnea in rodents using acute airway obstruction. In this study, we employed this model to test whether the elevation in SNA was mediated by hypoxia, carotid chemoreceptors, or neurotransmission in the nucleus tractus solitarius (NTS). In anesthetized, male Sprague-Dawley rats, airway obstruction (20s) increased phrenic nerve activity (PNA), arterial blood pressure (ABP), and lumbar, renal, and splanchnic SNA. The changes in SNA were similar across all three sympathetic nerves. Inactivation of chemoreceptors by hyperoxia (100% O2 ) or surgical denervation of carotid chemoreceptors attenuated, but did not eliminate, the changes in SNA and ABP produced by airway obstruction. To interrupt afferent information from carotid chemoreceptor and extracarotid afferents to the hindbrain, airway obstruction was performed before and after NTS microinjection of the GABAA agonist muscimol or a cocktail of NMDA and non-NMDA antagonists. Inhibition of NTS neurons or blockade of glutamatergic receptors attenuated the increase in lumbar SNA, splanchnic SNA, renal SNA, and PNA. Collectively, these findings suggest that PNA and SNA responses induced by airway obstruction depend, in part, on chemoreceptors afferents and glutamatergic neurotransmission in the NTS. PMID- 29388358 TI - Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study. AB - BACKGROUND: We assessed associations between first-trimester metformin use for pregestational diabetes and specific major birth defects. METHODS: We compared risks associated with first-trimester metformin use by diabetic women to nondiabetic women on no diabetes medication; we calculated crude odds ratios by exact logistic regression and adjusted by inverse probability weighting. Confounding by diabetes was assessed by comparing risks for metformin-exposed diabetic women to those for insulin-exposed diabetics and nondiabetics treated with metformin for subfertililty. RESULTS: Among 9,279 nonmalformed controls and 24,375 malformed cases, diabetics who used metformin (with or without insulin) had increased adjusted odds ratios (aORs) for several birth defects associated with diabetes. However, women treated with metformin for subfertility had aORs similar to or lower than those for diabetic metformin users, and many approximated the null. For atrial septal defect secundum, anorectal defects, and limb reduction defects, the estimates for metformin when used for subfertility were 2-3-fold. CONCLUSION: While metformin use for diabetes was associated with an increased risk of many birth defects, when metformin was used for subfertility most defects had aORs that approximated the null, while only three defects had modestly increased aORs, two of which had lower confidence bounds that included the null. Our study does not suggest that metformin poses an appreciable risk for major birth defects, but further studies are necessary. PMID- 29388356 TI - Advances in Carbon Nanotubes-Hydrogel Hybrids in Nanomedicine for Therapeutics. AB - In spite of significant advancement in hydrogel technology, low mechanical strength and lack of electrical conductivity have limited their next-level biomedical applications for skeletal muscles, cardiac and neural cells. Host guest chemistry based hybrid nanocomposites systems have gained attention as they completely overcome these pitfalls and generate bioscaffolds with tunable electrical and mechanical characteristics. In recent years, carbon nanotube (CNT) based hybrid hydrogels have emerged as innovative candidates with diverse applications in regenerative medicines, tissue engineering, drug delivery devices, implantable devices, biosensing, and biorobotics. This article is an attempt to recapitulate the advancement in synthesis and characterization of hybrid hydrogels and provide deep insights toward their functioning and success as biomedical devices. The improved comparative performance and biocompatibility of CNT-hydrogels hybrids systems developed for targeted biomedical applications are addressed here. Recent updates toward diverse applications and limitations of CNT hybrid hydrogels is the strength of the review. This will provide a holistic approach toward understanding of CNT-based hydrogels and their applications in nanotheranostics. PMID- 29388359 TI - Comments on "Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents". PMID- 29388361 TI - Self-Continuity Moderates the Association Between Peer Victimization and Depressed Affect. AB - Two longitudinal studies conducted with early adolescents (ages 10-13) examined the hypothesis that self-continuity, or the degree to which individuals feel that they remain the same person over time regardless of how their specific characteristics may change, would moderate the association between victimization and depressed affect. Both Study 1 (N = 141) and Study 2 (N = 100) provided evidence of the moderating role of self-continuity as a buffer on the effect of peer victimization. Study 2 confirmed that self-continuity had a moderating effect after controlling for academic performance, number of friends, self esteem, self-concept clarity, hopelessness, and self-blame. Findings support self continuity as being protective with regard to negative peer environments. PMID- 29388360 TI - Beneficial effects of thyroid hormone on adipose inflammation and insulin sensitivity of obese Wistar rats. AB - Thyroid hormones play an important role in glucose metabolism and there is evidence of increased prevalence of thyroid dysfunction in obese and diabetic patients. This study aimed at evaluating the thyroid function and the effects of the triiodothyronine (T3) treatment on glycemia control, insulin sensitivity and subclinical inflammation in cafeteria-diet-induced obesity in rats. Obesity was induced in male Wistar rats by offering a cafeteria diet and a subset of the obese rats was treated with T3 (1.5 MUg per 100 g of body weight) for a 28-day period. The pituitary-thyroid axis was evaluated by molecular and biochemical parameters. Cytokine content was measured in the serum as well as in the mesenteric and epididymal white adipose tissue. Obese rats exhibited impairment of glycemia control, increased content of inflammatory cytokines in mesenteric white adipose tissue, decreased serum thyrotropin (TSH) concentration and increased sodium/iodide symporter (NIS) and TSH receptor (TSHR) protein content in thyroid gland. T3 treatment improved insulin sensitivity, glucose tolerance, and reduced inflammatory cytokine content in mesenteric white adipose tissue. In the thyroid gland NIS, TSHR, and thyroperoxidase (TPO) content were reduced while thyroglobulin (TG) content was increased by T3. The thyrotrophic response to negative feedback exerted by T3 was preserved in obese rats. The present data reinforce the beneficial effects of T3 treatment of obese rats on the improvement of insulin sensitivity and on the negative modulation of inflammatory cytokine expression in adipose tissue. Moreover, we have evidenced that the pituitary thyroid axis is affected in obese rats, as illustrated by the impaired TSH secretion. PMID- 29388362 TI - Directed evolution of an endoinulinase from Talaromyces purpureogenus toward efficient production of inulooligosaccharides. AB - Inulinases are fructofuranosyl hydrolases that target the beta-2,1 linkage of inulin and hydrolyze it into fructose, glucose and inulooligosaccharides (IOS), the latter are of growing interest as dietary fibers. Inulinases from various microorganisms have been purified, characterized and produced for industrial applications. However, there remains a need for inulinases with increased catalytic activity and better production yields to improve the hydrolysis process and fulfill the growing industrial demands for specific fibers. In this study, we used directed enzyme evolution to increase the yield and activity of an endoinulinase enzyme originated from the filamentous fungus Talaromyces purpureogenus (Penicillium purpureogenum ATCC4713). Our directed evolution approach yielded variants showing up to fivefold improvements in soluble enzyme production compared to the starting point which enabled high-yield production of highly purified recombinant enzyme. The distribution of the enzymatic reaction products demonstrated that after 24 h of incubation, the main product (57%) had a degree of polymerization of 3 (DP3). To the best of our knowledge, this is the first application of directed enzyme evolution to improve inulooligosaccharide production. The approach enabled the screening of large genetic libraries within short time frames and facilitated screening for improved enzymatic activities and properties, such as substrate specificity, product range, thermostability and pH optimum. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:868-877, 2018. PMID- 29388363 TI - Zoonotic pathogens from feral swine that pose a significant threat to public health. AB - The natural fecundity of suids, great ability to adapt to new habitats and desire for local hunting opportunities leading to translocation of feral pigs to regions where they are not yet established have all been instrumental in the home range expansion of feral swine. Feral swine populations in the United States continue to expand, wreaking havoc on agricultural lands, further compromising threatened and endangered species, and posing a microbiological threat to humans, domestic livestock and companion animals. This manuscript thoroughly reviews zoonotic diseases of concern including brucellosis, bovine tuberculosis, leptospirosis, enteric pathogens, both Salmonella spp. and shiga toxin-producing Escherichia coli, and hepatitis E. These pathogens are not a comprehensive list of microbes that are capable of infecting both humans and feral swine, but rather have been selected as they are known to infect US feral swine, direct transmission between wild suids and humans has previously been documented, or they have been shown to be readily transmitted during processing or consumption of feral swine pork. Humans that interact directly or indirectly with feral swine are at much higher risk for the development of a number of zoonotic pathogens. Numerous case reports document transmission events from feral swine and wild boar to humans, and the resulting diseases may be mild and self-limiting, chronic or fatal. Individuals that interact with feral swine should take preventative measures to minimize the risk of disease transmission and all meat should be thoroughly cooked. Additionally, public health campaigns to increase knowledge of the risks associated with feral swine are imperative. PMID- 29388364 TI - Education-based disparities in knowledge of novel health risks: The case of knowledge gaps in HIV risk perceptions. AB - OBJECTIVE: Risk perception is a key determinant of preventive health behaviour, but when asked, some individuals indicate they do not know their health risk. Low education is associated with both lack of knowledge about health risk and with the persistence and exacerbation of gaps in knowledge about health issues. This study uses the context of an emerging infectious disease threat to explore the hypothesis that the education-don't know risk relation results from differences in knowledge about the health issue of interest. Specifically, we examine whether patterns of change over time follow theoretical predictions that disparities in risk knowledge would increase over time in less educated sectors of the population (knowledge gap hypothesis). DESIGN: Secondary analysis of population representative behavioural surveillance survey. METHOD: We analysed data from the 1993 to 2000 Behavior Risk Factor Surveillance System surveys, which measured education and perceived HIV/AIDS risk in a population sample collected separately in each survey year; don't know responses were coded. RESULTS: In each year, individuals with higher education were less likely to respond don't know. The absolute prevalence of don't know responding dropped over time; nonetheless, there was an increase over time in the magnitude of the pattern of lower education being associated with greater don't know responding. CONCLUSIONS: We found support for the knowledge gap hypothesis. Over time, populations with greater education gained more knowledge about their HIV risk than populations with lower education. Results highlight the need to carefully consider health communication strategies to reach and address those individuals with low education and health knowledge. Statement of contribution What is already known on this subject? A meaningful potion of the population answers 'don't know' when asked to report their risk for health problems, indicating a lack of risk perception in the domain. Previous studies have shown that level of education is associated with don't know responding - those with lower educational attainment are more likely to respond don't know. The education-don't know responding relation suggests that lack of health information and health domain knowledge might be a factor in lacking risk perception, but this mechanism has not been previously tested. What does this study add? Patterns of changes in don't know responding over time as population-level knowledge of a health risk increase are consistent with the health information/health knowledge hypothesis outlined above. As population knowledge of HIV/AIDS risk in the United States increased over time (indicated by declining overall rates of don't know responses), the relation of education level to don't know responding actually became stronger. The pattern of change over time is the classic 'knowledge gap hypothesis' pattern, which has not been previously demonstrated for knowledge of personal health risk. The knowledge gap response pattern supports the health information/health knowledge hypothesis. PMID- 29388366 TI - Atomic Layer Co3 O4 Nanosheets: The Key to Knittable Zn-Air Batteries. AB - Flexible, wearable, and portable energy storage devices with high-energy density are crucial for next-generation electronics. However, the current battery technologies such as lithium ion batteries have limited theoretical energy density. Additionally, battery materials with small scale and high flexibility which could endure the large surface stress are highly required. In this study, a yarn-based 1D Zn-air battery is designed, which employs atomic layer thin Co3 O4 nanosheets as the oxygen reduction reaction/oxygen evolution reaction catalyst. The ultrathin nanosheets are synthesized by a high-yield and facile chemical method and show a thickness of only 1.6 nm, corresponding to few atomic layers. The 1D Zn-air battery shows high cycling stability and high rate capability. The battery is successfully knitted into clothes and it shows high stability during the large deformation and knotting conditions. PMID- 29388365 TI - Collagen-derived peptides modulate CD4+ T-cell differentiation and suppress allergic responses in mice. AB - INTRODUCTION: Collagen peptides have been widely used as a food supplement. After ingestion of collagen peptides, oligopeptides containing hydroxyproline (Hyp), which are known to have some physiological activities, are detected in peripheral blood. However, the effects of collagen-peptide administration on immune response are unclear. In the present study, we tested the effects of collagen-peptide ingestion on allergic response and the effects of collagen-derived oligopeptides on CD4+ T-cell differentiation. METHODS: BALB/c mice fed a collagen-peptide diet were immunized with ovalbumin (OVA), and their serum IgE and IgG levels, active cutaneous anaphylaxis, and cytokine secretion by splenocytes were examined. Naive CD4+ T cells were stimulated with anti-CD3 and anti-CD28 in the presence of collagen-derived oligopeptides, and the expression of IFN-gamma, IL-4, and Foxp3 was analyzed. RESULTS: In an active anaphylaxis model, oral administration of collagen peptides suppressed serum OVA-specific immunoglobulin E (IgE) production and diminished anaphylaxis responses. In this model, the ingestion of collagen peptides skewed the pattern of cytokine production by splenocytes toward T-helper (Th) type 1 and regulatory T (Treg) cells. In vitro T-helper cell differentiation assays showed that Hyp-containing oligopeptides promoted Th1 differentiation by upregulating IFN-gamma-induced signal transducer and activator of transcription 1 (STAT1) signaling. These oligopeptides also promoted the development of Foxp3+ Treg cells in response to antigen stimulation in the presence of TGF-beta. CONCLUSIONS: Collagen-peptide ingestion suppresses allergic responses by skewing the balance of CD4+ T cells toward Th1 and Treg cells and seems to be a promising agent for preventing allergies and inflammatory diseases. PMID- 29388367 TI - Tuning a Protein-Labeling Reaction to Achieve Highly Site Selective Lysine Conjugation. AB - Activated esters are widely used to label proteins at lysine side chains and N termini. These reagents are useful for labeling virtually any protein, but robust reactivity toward primary amines generally precludes site-selective modification. In a unique case, fluorophenyl esters are shown to preferentially label human kappa antibodies at a single lysine (Lys188) within the light-chain constant domain. Neighboring residues His189 and Asp151 contribute to the accelerated rate of labeling at Lys188 relative to the ~40 other lysine sites. Enriched Lys188 labeling can be enhanced from 50-70 % to >95 % by any of these approaches: lowering reaction temperature, applying flow chemistry, or mutagenesis of specific residues in the surrounding protein environment. Our results demonstrated that activated esters with fluoro-substituted aromatic leaving groups, including a fluoronaphthyl ester, can be generally useful reagents for site-selective lysine labeling of antibodies and other immunoglobulin-type proteins. PMID- 29388368 TI - Covalent immobilization of halohydrin dehalogenase for efficient synthesis of epichlorohydrin in an integrated bioreactor. AB - Halohydrin dehalogenase (HHDH)-mediated dehalogenation of 1,3-dichloro-2-propanol (1,3-DCP) is a key step in the chemoenzymatic synthesis of epichlorohydrin (ECH) from glycerol. In this study, a covalent immobilization strategy was employed to enhance the stability of Agrobacterium tumefaciens HHDH using epoxy resin ES-103B as a carrier. Under optimal conditions, the activity recovery of ES-103B immobilized HHDH (HHDH@ES-103B) was 62.4% and the specific activity was 1604 U/g. The HHDH@ES-103B exhibited excellent thermostability, with a half-life of 68.6 days at 40 degrees C, which is 8.0-times higher than that of the free HHDH. A semicontinuous biotransformation of 1,3-DCP to ECH was performed using HHDH@ES 103B as biocatalyst in a recirculating packed bed reactor (RPBR), resulting in an ECH yield of 94.2%, with an average productivity of 5.2 g/L/h. The RPBR system exhibited a high operational stability and even after 50 cycles of reaction, it retained > 90% of the initial conversion. Furthermore, an integrated bioprocess based on in situ product recovery (ISPR) was developed in RPBR to overcome product inhibition. The integrated bioreactor equipped with an external macroporous adsorption resin HZD-9 column led to another 1.6-fold increase in ECH productivity to 8.46 g/L/h. This improved stability and reusability of HHDH@ES 103B demonstrated its potential for the biotransformation of 1,3-DCP to ECH. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:784-792, 2018. PMID- 29388369 TI - Large bowel obstruction due to adhesion bands following right nephrectomy and transplanted pelvic kidney. PMID- 29388370 TI - The role of continuous renal replacement therapy in the management of acute kidney injury associated with sinusoidal obstruction syndrome following hematopoietic cell transplantation. AB - Maintaining fluid balance, pre- and post-MA-HCT is essential and usually requires frequent administration of diuretics. Hepatic sinusoidal obstructive syndrome is potentially life-threatening, especially when associated with AKI and MOF. This study describes six patients who developed AKI-associated SOS and diuretic resistant FO who subsequently underwent CRRT using standardized management guidelines for fluid balance post-HCT. Retrospective chart review was done for HCT patients between September 2011 and October 2013 at a tertiary care children's hospital. Thirty-four patients underwent MA-HCT in the study period. Six patients had SOS complicated by diuretic-resistant FO and underwent CRRT. Defibrotide was used in three patients. Median time on CRRT was 10.5 days. Sixty six percent (N = 4 of 6) of patients had full resolution of SOS symptoms with a mortality rate of 34% (N = 2 of 6). Among patients who had full recovery of SOS symptoms, one patient developed AKI, end-stage renal diseases and underwent kidney transplantation 34-months post-HCT. Thus, of six included patients, two died and one developed ESRD with only 50% (N = 3 of 6) good outcome. Use of a standardized, evidence-based fluid balance protocol and early initiation of CRRT for HCT-related AKI/SOS was associated with good outcomes. PMID- 29388371 TI - Are you interested in joining the BACCN national board? PMID- 29388372 TI - Midlands Region Study Day Update - Reinvigorating the Region. PMID- 29388373 TI - BACCN Twitter chats. PMID- 29388374 TI - DID YOU KNOW? Critical Care Unit Membership is now available. PMID- 29388375 TI - Regional news and events. PMID- 29388376 TI - What's in this Issue. PMID- 29388378 TI - 33rd Annual BACCN Conference 2018: Sustainability in Excellence - The Future of Critical Care. PMID- 29388377 TI - Recognition and response to the deteriorating patient. PMID- 29388379 TI - Free-Standing Hybrid Graphene Paper Encapsulating Nanostructures for High Cycle Life Supercapacitors. AB - The incorporation of spacers between graphene sheets has been investigated as an effective method to improve the electrochemical performance of graphene papers (GPs) for supercapacitors. Here, we report the design of free-standing GP@NiO and GP@Ni hybrid GPs in which NiO nanoclusters and Ni nanoparticles are encapsulated into graphene sheets through electrostatic assembly and subsequent vacuum filtration. The encapsulated NiO nanoclusters and Ni nanoparticles can mitigate the restacking of graphene sheets, providing sufficient spaces for high-speed ion diffusion and electron transport. In addition, the spacers strongly bind to graphene sheets, which can efficiently improve the electrochemical stability. Therefore, at a current density of 0.5 A g-1 , the GP@NiO and GP@Ni electrodes exhibit higher specific capacitances of 306.9 and 246.1 F g-1 than the GP electrode (185.7 F g-1 ). The GP@NiO and GP@Ni electrodes exhibit capacitance retention of 98.7 % and 95.6 % after 10000 cycles, demonstrating an outstanding cycling stability. Additionally, the GP@NiO?GP@Ni delivers excellent cycling stability (93.7 % after 10 000 cycles) and high energy density. These free standing encapsulated hybrid GPs have great potential as electrode for high performance supercapacitors. PMID- 29388380 TI - Values exchange: using online technology to raise awareness of values and ethics in radiography education. AB - INTRODUCTION: Ethics and values are increasingly significant aspects of patient centred healthcare. While it is widely agreed that ethics and values are essential for healthcare delivery, there is also an acknowledgement that these are areas that are challenging to teach. The purpose of this study is to report a small-scale evaluative research project of a web-based technology with the educational potential to facilitate learning in relation to ethics, values, self reflection and peer-based learning. METHODS: Five diagnostic radiography students took part in a semi-structured focus group with the aim of exploring their experiences of using Values Exchange, an online ethical decision-making framework, to examine practice-based ethical issues. Transcripts were interrogated for key themes. RESULTS: From the thematic analysis three major themes emerged, understanding and appreciating others, addressing the theory practice gap and delivering a safe and effective learning environment. Perceived limitations of the platform included students' fear of misinterpreted responses and possibility of poor group dynamics. CONCLUSIONS: There are varied approaches to how ethics and values are taught and assessed within health-related environments. Values Exchange is one such teaching tool and has been investigated and described positively by radiography students in this study. Online teaching tools can have a positive effect in helping students identify their own values but require skilled implementation to reap positive rewards. PMID- 29388381 TI - Another chemically masked drug: p-tosyl methylamphetamine. PMID- 29388382 TI - Variability and interpretation of communication taxonomy during robot-assisted surgery: do we all speak the same language? AB - OBJECTIVE: To investigate and analyse the different ways surgeons communicate with bedside assistants during robot-assisted surgery (RAS). METHODS: We retrospectively reviewed video and audio recordings of 26 RAS procedures (23 prostatectomies and three cystectomies). Three cameras and eight lapel microphones were used to record the operating theatre environment. We identified five common tasks and categorized them into 'specific', 'non-specific' and 'unclear' categories. We also determined the frequency, time to execute the task, inconveniences and acknowledgements associated with each category. The most efficient category was the one that took the shortest duration to accomplish and was associated with the fewest inconveniences. RESULTS: A total of 1 000 requests were made by three surgeons for six bedside assistants by three surgeons. The five identified tasks were: instrument change; clipping; suction; irrigation; and retraction. For instrument change, non-specific requests were the most frequent compared with the other categories (77% vs 18% vs 5%; P < 0.001). For suction, specific requests were the most frequently used of the three categories (73% vs 27% vs 0%; P < 0.001) and this task was associated with the fewest inconveniences (38% vs 62%; P = 0.01). For clipping, irrigation and retraction, both specific and non-specific requests were similar in terms of their frequency, action time and inconveniences. Comparing complete vs incomplete requests, incomplete requests had significantly shorter median action time (5 vs 8 s; P < 0.001) but did not significantly differ in terms of inconveniences and acknowledgement. CONCLUSION: To our knowledge, this is the first study to provide a detailed analysis of communication during RAS. It lays a foundation for standardized taxonomy to improve communication, surgical efficiency and patient safety. PMID- 29388383 TI - Multicentric retrospective analysis of platinum-pemetrexed regimens as first-line therapy in non-squamous non-small cell lung cancer patients: A "snapshot" from clinical practice. AB - BACKGROUND: The major challenge for treating non-squamous (non-Sq) non-small cell lung cancer (NSCLC) patients without actionable biomarkers is the actual selection of proper treatment, weighing expected clinical outcomes and safety profile. METHODS: Consecutive non-Sq NSCLC patients were treated with platinum pemetrexed (PP) doublets in clinical practice. Subgroup analyses were conducted in patients treated with standard (s)PP and modified (m)PP doublets (because of age, performance status, and/or comorbidities) and in patients treated with cisplatin-based and carboplatin-based PP doublets. Activity, efficacy, safety, and toxicities were evaluated. RESULTS: From November 2009 to April 2017, 111 patients were treated: 87 (78.4%) with sPP and 24 (21.6%) with mPP; 76 (68.5%) with cisplatin-based and 35 (31.5%) with carboplatin-based regimens. The objective response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were 49.0%, 7, and 13 months in the entire patient population, respectively. We found no significant differences in ORR, median PFS, and median OS between sPP and mPP. Cisplatin-based PP showed higher ORR (53.7%) versus carboplatin-based PP (38.7%) and longer PFS (7 vs. 6 months; P = 0.028) and OS (18 vs. 11 months; P = 0.006). We confirm that carboplatin has a better toxicity profile than cisplatin. The received dose-intensities were ~80% of standard full doses. CONCLUSIONS: Accurate management allowed us to treat the majority of advanced non-Sq NSCLC patients with PP combination therapy without significant differences in ORR, median PFS, and median OS. Even considering the selection bias, our data seems to confirm the greater effectiveness of cisplatin based over carboplatin-based regimens. PMID- 29388384 TI - Clinicopathological characteristics and molecular analysis of primary pulmonary mucoepidermoid carcinoma: Case report and literature review. AB - Primary pulmonary mucoepidermoid carcinoma (PMEC) is extremely rare. Herein, we report a case of a 71-year-old male patient with high-grade PMEC involving the right upper lobe that was successfully resected via lobectomy. As a result of invasion into the pleural and paratracheal lymph nodes, four cycles of adjuvant chemotherapy with paclitaxel and carboplatin were administered. There were no signs of relapse during 10 months of follow-up. Furthermore, we reviewed the literature and summarized the surgical approaches, prognostic factors, and underlying genetic mechanisms of PMEC, which will benefit clinical treatment. PMID- 29388386 TI - Tunable Microscale Porous Systems with Dynamic Liquid Interfaces. AB - Solid microscale porous material systems have attracted more attention in recent years due to their various potential applications, such as energy source transportations, biomedical devices, wastewater treatments, phase separations, etc. However, such systems are still plagued with many issues including fouling, mechanical fragility, inability to self-heal, and low recyclability that restrict them for further industrial applications. Dynamic liquid-based microscale porous material systems, especially porous surfaces and membranes, provide a new opportunity for resolving these issues and possess many benefits, such as antifouling, slippery, transparent, recovery, self-healing, and recycling properties. This Concept is mainly concerned with how to obtain tunable microscale porous systems with dynamic liquid interfaces, and their applications from the surfaces to membranes. The authors hope this concept will attract interest of scientists in areas related to the rapid development and application of various liquid-based porous systems. PMID- 29388385 TI - Randomized Controlled Trial Examining the Ripple Effect of a Nationally Available Weight Management Program on Untreated Spouses. AB - OBJECTIVE: For married couples, when one spouse participates in weight loss treatment, the untreated spouse can also experience weight loss. This study examined this ripple effect in a nationally available weight management program. METHODS: One hundred thirty dyads were randomized to Weight Watchers (WW; n = 65) or to a self-guided control group (SG; n = 65) and assessed at 0, 3, and 6 months. Inclusion criteria were age >= 25 years, BMI 27 to 40 kg/m2 (>= 25 kg/m2 for untreated spouses), and no weight loss contraindications. WW participants received 6 months of free access to in-person meetings and online tools. SG participants received a weight loss handout. Spouses did not receive treatment. RESULTS: Untreated spouses lost weight at 3 months (WW = -1.5 +/- 2.9 kg; SG = 1.1 +/- 3.3 kg) and 6 months (WW = -2.2 +/- 4.2 kg; SG = -1.9 +/- 3.6 kg), but weight losses did not differ by condition. Overall, 32.0% of untreated spouses lost >= 3% of initial body weight by 6 months. Baseline weight was significantly correlated within couples (r = 0.26; P < 0.01) as were weight loss trajectories (r = 0.52; P < 0.001). CONCLUSIONS: Evidence of a ripple effect was found in untreated spouses in both formal and self-guided weight management approaches. These data suggest that weight loss can spread within couples, and that widely available lifestyle programs have weight loss effects beyond the treated individual. PMID- 29388387 TI - Safety and efficacy of ulnar artery approach for percutaneous cardiac catheterization: Systematic review and meta-analysis. AB - BACKGROUND: Trans-radial access has rapidly become the standard for percutaneous coronary procedures in the last decade. As proceduralists overcome the learning curve and become more competent in trans-radial access, alternative safe access sites such as the ulnar artery have been increasingly used for emergent and elective procedures. The aim of this study was to synthesize the best available evidence of the impact on major adverse cardiac events (MACE) of ulnar artery compared to radial artery cardiac catheterization. METHODS: This review considered randomized controlled trials that included adult patients who had a percutaneous coronary procedure via the radial or ulnar artery. The intervention of interest was the use of ulnar compared to radial artery for cardiac catheterization. An extensive search was undertaken for published and unpublished trials up to May 2017. Methodological quality was assessed independently by two reviewers using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) checklist. Data were analyzed using Review Manager. RESULTS: A total of six trials were included in the review. There was no statistically significant difference in the incidence of MACE between patients who underwent trans-ulnar or trans-radial artery catheterization (OR 0.90; 95% CI 0.65-1.25). Complications associated with access including hematoma formation, (n = 6 trials) pseudo-aneurysm, and arterio-venous fistulae formation (n = 5 trials), were investigated in a total of 5,276 patients, with no difference in these complications noted between the two groups. There were no differences in arterial access time, fluoroscopy time, and contrast load between the two groups. CONCLUSIONS: There is evidence to support safe use of the ulnar artery as an alternative to the radial artery for access for cardiac catheterization. PMID- 29388388 TI - Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. AB - OBJECTIVE: To determine how best to use magnetic resonance imaging (MRI) and targeted MRI/ultrasonography fusion biopsy for early detection of prostate cancer (PCa) in men with elevated prostate-specific antigen (PSA) concentrations and whether it can be cost-effective. METHODS: A Markov model of PCa onset and progression was developed to estimate the health and economic consequences of PCa screening with MRI. Patients underwent PSA screening from ages 55 to 69 years. Patients with elevated PSA concentrations (>4 ng/mL) underwent MRI, followed by targeted fusion or combined (standard + targeted fusion) biopsy on positive MRI, and standard or no biopsy on negative MRI. Prostate Imaging Reporting and Data System (PI-RADS) score on MRI was used to determine biopsy decisions. Deaths averted, quality-adjusted life-years (QALYs), cost and incremental cost effectiveness ratio (ICER) were estimated for each strategy. RESULTS: With a negative MRI, standard biopsy was more expensive and had lower QALYs than performing no biopsy. The optimum screening strategy (ICER $23 483/QALY) recommended combined biopsy for patients with PI-RADS score >=3 and no biopsy for patients with PI-RADS score <3, and reduced the number of screening biopsies by 15%. Threshold analysis suggests MRI continues to be cost-effective when the sensitivity and specificity of MRI and combined biopsy are simultaneously reduced by 19 percentage points. CONCLUSIONS: Our analysis suggests MRI followed by targeted MRI/ultrasonography fusion biopsy can be a cost-effective approach to the early detection of PCa. PMID- 29388389 TI - One-pot strategy for on-site enzyme production, biomass hydrolysis, and ethanol production using the whole solid-state fermentation medium of mixed filamentous fungi. AB - The efficient use of renewable lignocellulosic feedstocks to obtain biofuels and other bioproducts is a key requirement for a sustainable biobased economy. This requires novel and effective strategies to reduce the cost contribution of the cellulolytic enzymatic cocktails needed to convert the carbohydrates into simple sugars, in order to make large-scale commercial processes economically competitive. Here, we propose the use of the whole solid-state fermentation (SSF) medium of mixed filamentous fungi as an integrated one-pot strategy for on-site enzyme production, biomass hydrolysis, and ethanol production. Ten different individual and mixed cultivations of commonly used industrial filamentous fungi (Aspergillus niger, Aspergillus oryzae, Trichoderma harzianum, and Trichoderma reesei) were performed under SSF and the whole media (without the extraction step) were used in the hydrolysis of pretreated sugarcane bagasse. The cocultivation of T. reesei with A. oryzae increased the amount of glucose released by around 50%, compared with individual cultivations. The release of glucose and reducing sugars achieved using the whole SSF medium was around 3-fold higher than obtained with the enzyme extract. The addition of soybean protein (0.5% w/w) during the hydrolysis reaction further significantly improved the saccharification performance by blocking the lignin and avoiding unproductive adsorption of enzymes. The results of the alcoholic fermentation validated the overall integrated process, with a volumetric ethanol productivity of 4.77 g/L.h, representing 83.5% of the theoretical yield. These findings demonstrate the feasibility of the proposed one-pot integrated strategy using the whole SSF medium of mixed filamentous fungi for on-site enzymes production, biomass hydrolysis, and ethanol production. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:671-680, 2018. PMID- 29388390 TI - Acute Oral Administration of Single-Walled Carbon Nanotubes Increases Intestinal Permeability and Inflammatory Responses: Association with the Changes in Gut Microbiota in Mice. AB - With the increasing production and widespread potential applications of single walled carbon nanotubes (SWCNTs), the possible impacts of oral administration of SWCNTs on gastrointestinal tract at currently occupational exposure limits and potential biomedical applications should be concerned. To address the concerns, mice are orally administrated of SWCNTs at doses of 0.05, 0.5, and 2.5 mg kg-1 body weight per day for 7 d. The investigation shows that SWCNT treatment had promoted intestinal injuries at the acute dose of 2.5 mg kg-1 per day, including increase of histological lesion scores, intestinal permeability, and proinflammatory cytokine (IL-1beta, IL-6, and TNF-alpha) secretion. Analysis of gut microbiota composition using 16S rRNA gene sequencing approach reveals that acute oral administration of SWCNTs induces significant shifts of the predominant microbe phyla from Firmicutes to Bacteroidetes and increases abundance of proinflammatory bacteria Alitipes_uncultured_bacterium and Lachnospiraceae bacterium A4. These notable findings suggest that SWCNT-induced intestinal injury is linked to SWCNT interaction with intestinal tract and gut bacteria and the consequent triggering of "metabolic inflammation" responses. Furthermore, the study has shown that oral administration of carbon nanomaterials, including SWCNTs, multiwalled CNTs, and graphene oxide, can lead to different inflammatory responses and specific alteration in gut microbiota in mice. PMID- 29388391 TI - Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene. AB - BACKGROUND: Syndromic brain malformations comprise a large group of anomalies with a birth prevalence of about 1 in 1,000 live births. Their etiological factors remain largely unknown. To identify causative mutations, we used whole exome sequencing (WES) in aborted fetuses and children with syndromic brain malformations in which chromosomal microarray analysis was previously unremarkable. METHODS: WES analysis was applied in eight case-parent trios, six aborted fetuses, and two children. RESULTS: WES identified a novel de novo mutation (p.Gly268Arg) in ACTB (Baraitser-Winter syndrome-1), a homozygous stop mutation (p.R2442*) in ASPM (primary microcephaly type 5), and a novel hemizygous X-chromosomal mutation (p.I250V) in SLC9A6 (X-linked syndromic mentaly retardation, Christianson type). Furthermore, WES identified a de novo mutation (p.Arg1093Gln) in BAZ1A. This mutation was previously reported in only one allele in 121.362 alleles tested (dbSNP build 147). BAZ1A has been associated with neurodevelopmental impairment and dysregulation of several pathways including vitamin D metabolism. Here, serum vitamin-D (25-(OH)D) levels were insufficient and gene expression comparison between the child and her parents identified 27 differentially expressed genes. Of note, 10 out of these 27 genes are associated to cytoskeleton, integrin and synaptic related pathways, pinpointing to the relevance of BAZ1A in neural development. In situ hybridization in mouse embryos between E10.5 and E13.5 detected Baz1a expression in the central and peripheral nervous system. CONCLUSION: In syndromic brain malformations, WES is likely to identify causative mutations when chromosomal microarray analysis is unremarkable. Our findings suggest BAZ1A as a possible new candidate gene. PMID- 29388392 TI - Gellan Gum Hydrogels with Enzyme-Sensitive Biodegradation and Endothelial Cell Biorecognition Sites. AB - The survival of a biomaterial or tissue engineered construct is mainly hampered by the deficient microcirculation in its core, and limited nutrients and oxygen availability to the implanted or colonizing host cells. Aiming to address these issues, we herein propose bioresponsive gellan gum (GG) hydrogels that are biodegradable by metalloproteinase 1 (MMP-1) and enable endothelial cells adhesion and proliferation. GG is chemically functionalized with divinyl sulfone (DVS) and then biofunctionalized with thiol cell-adhesive peptides (T1 or C16) to confer GG endothelial cell biorecognition cues. Biodegradable hydrogels are then formed by Michael type addition of GGDVS or/and peptide-functionalized GGDVS with a dithiol peptide crosslinker sensitive to MMP-1. The mechanical properties (6 to 5580 Pa), swelling (17 to 11), MMP-1-driven degradation (up to 70%), and molecules diffusion coefficients of hydrogels are tuned by increasing the polymer amount and crosslinking density. Human umbilical cord vein endothelial cells depict a polarized elongated morphology when encapsulated within T1-containing hydrogels, in contrast to the round morphology observed in C16-containing hydrogels. Cell organization is favored as early as 1 d of cell culture within the T1-modified hydrogels with higher concentration of peptide, while cell proliferation is higher in T1-modified hydrogels with higher modulus. In conclusion, biodegradable and bioresponsive GGDVS hydrogels are promising endothelial cell responsive materials that can be used for vascularization strategies. PMID- 29388393 TI - Cryopreservation of chicken blastodermal cells and their quality assessment by flow cytometry and transmission electron microscopy. AB - The goal of this study was to evaluate effect of slow freezing and vitrification methods on the viability of chicken blastodermal cells (BCs). Proper aliquot of isolated BCs were diluted in the freezing medium composed of 10% DMSO and frozen in the freezing vessel BICELL to reach desired temperature up to -80 degrees C. Then samples were immersed in liquid nitrogen. Other cell aliquot was vitrified in solution containing 10% DMSO and samples were immediately immersed in the liquid nitrogen. The viability of fresh and frozen/thawed BCs was evaluated using Trypan blue method and flow cytometry. Flow cytometry analysis was provided by DRAQ5 dye in combination with Live-Dead kit. Overall, this technique provides both quantitative and qualitative information about BCs. Results obtained from Trypan blue method showed significant differences (P < 0.05) between control (8.37 +/- 1.04%) slow freezing (83.73 +/- 2.72%) and vitrification group (84.39 +/- 1.77%) in the percentage of Trypan blue positive (necrotic) BCs. Moreover, differences (P < 0.05) between control and slow freezing (5.08 +/- 1.94%, 73.31 +/- 3.90%) and control and vitrification group (2.97 +/- 0.30%, 79.02 +/- 1.56%) in results on portion of necrotic cells (DRAQ5+ /LD+ ) analyzed by flow cytometry were also observed. The large percentage of necrotic BCs was found in all freezing methods. However, based on ultrastructural analysis, our study showed, that BCs contain lipid granules which prevent successful freezing even though different methods of cryopreservation were used. Thus, freezing of BCs probably required subsequent culture to eliminate lipid droples and yolk granules in the cells, which could possibly improve the success. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:778-783, 2018. PMID- 29388395 TI - Welcome to HLA population reports. PMID- 29388394 TI - Composition of gut microbiota in obese and normal-weight Mexican school-age children and its association with metabolic traits. AB - BACKGROUND: Childhood obesity is a serious public health problem in Mexico. Adult gut microbiota composition has been linked to obesity, but few studies have addressed the role of gut microbiota in childhood obesity. OBJECTIVES: The aim of this study is to compare gut microbiota composition in obese and normal-weight children and to associate gut microbiota profiles with amino acid serum levels and obesity-related metabolic traits. METHODS: Microbial taxa relative abundance was determined by 16S rRNA sequencing in 67 normal-weight and 71 obese children aged 6-12 years. Serum amino acid levels were measured by mass spectrometry. Associations between microbiota composition, metabolic parameters and amino acid serum levels were tested. RESULTS: No significant differences in phyla abundances or Firmicutes/Bacteroidetes ratios were observed between normal-weight and obese children. However, Bacteroides eggerthii abundance was significantly higher in obese children and correlated positively with body fat percentage and negatively with insoluble fibre intake. Additionally, Bacteroides plebeius and unclassified Christensenellaceae abundances were significantly higher in normal-weight children. Abundance of both these species correlated negatively with phenylalanine serum levels, a metabolite also found to be associated with obesity in Mexican children. CONCLUSIONS: The study identified bacterial species associated with obesity, metabolic complications and amino acid serum levels in Mexican children. PMID- 29388396 TI - Assessing Similarity Among Individual Tumor Size Lesion Dynamics: The CICIL Methodology. AB - Mathematical models of tumor dynamics generally omit information on individual target lesions (iTLs), and consider the most important variable to be the sum of tumor sizes (TS). However, differences in lesion dynamics might be predictive of tumor progression. To exploit this information, we have developed a novel and flexible approach for the non-parametric analysis of iTLs, which integrates knowledge from signal processing and machine learning. We called this new methodology ClassIfication Clustering of Individual Lesions (CICIL). We used CICIL to assess similarities among the TS dynamics of 3,223 iTLs measured in 1,056 patients with metastatic colorectal cancer treated with cetuximab combined with irinotecan, in two phase II studies. We mainly observed similar dynamics among lesions within the same tumor site classification. In contrast, lesions in anatomic locations with different features showed different dynamics in about 35% of patients. The CICIL methodology has also been implemented in a user-friendly and efficient Java-based framework. PMID- 29388397 TI - Biomaterials for Regenerative Medicine Approaches for the Anterior Segment of the Eye. AB - The role of biomaterials in tissue engineering and regenerative medicine strategies to treat vision loss associated with damage to tissues in the anterior segment of the eye has been studied for several years. This has mostly involved replacement and support for the cornea and conjunctiva. These are complex tissues with specific functional requirements for different parts of the tissue. Amniotic membrane (AM) is used in clinical practice to transplant autologous or allogenic cells to the corneal surface. Fibrin gels have also progressed to clinical use under specific conditions. Alternatives to AM such as collagen gels, other natural materials, for example keratin and silks, and synthetic polymers have received considerable attention in laboratory and animal studies. This experience is building a body of evidence to demonstrate the potential of tissue engineering and regenerative medicine in corneal and conjunctival reconstruction and can also lead to other applications in the anterior segment of the eye, for example, the trabecular meshwork. There is a real clinical need for new procedures to overcome vision loss but there are also opportunities for developments in ocular applications to lead to biomaterials innovations for use in other clinical areas. PMID- 29388398 TI - Use of the Nursing Outcomes Classification for Falls and Fall Prevention by Nurses in South Korea. AB - PURPOSE: To estimate the use of the Nursing Outcomes Classification (NOC) for falls and fall prevention. METHODS: This cross-sectional, descriptive study enrolled 196 registered nurses in South Korea. FINDINGS: Outcome assessments for falls and fall prevention were performed for 30-50% of hospitalized patients. The NOC outcomes related to falls and fall prevention were used more in surgical units than medical units. CONCLUSIONS: The performance rates of the outcomes related to falls and fall prevention were not high in hospitalized patients. IMPLICATIONS FOR NURSING PRACTICE: Strategies should be developed to increase the use of the NOC by nurses for fall prevention. In this way, nurses' contributions to patient outcomes would be recognized and the safety of patients would be enhanced. PMID- 29388399 TI - An Unusual Case of Meningioma Showing Increased CaSR Expression with Parathyroid Carcinoma. PMID- 29388400 TI - The Association between Persistent Hypertriglyceridemia and the Risk of Diabetes Development: The Kangbuk Samsung Health Study. AB - BACKGROUND: Hypertriglyceridemia is known to have an association with increased risks of insulin resistance and diabetes. The aim of this study was to investigate the risk of diabetes mellitus, according to changes in the concentrations of triglycerides, over time. METHODS: A total of 15,932 non diabetic participants (mean age 43.2 years, 68% men) who attended five consecutive annual health check-ups at Kangbuk Samsung Hospital, between January 2010 and December 2014, were recruited. Participants were classified according to their triglyceride concentrations; normal (<150 mg/dL) and abnormal (>=150 mg/dL). According to the triglyceride levels in 2010 and 2012, subjects were divided into four groups: normal-normal, normal-abnormal, abnormal-normal, and abnormal-abnormal. The risk for incident diabetes was assessed in 2014. RESULTS: Among the total subjects, 67.5% belonged to the normal-normal group, 8.6% to the normal-abnormal group, 9.4% to the abnormal-normal group, and 14.5% to the abnormal-abnormal group. A total of 234 subjects (1.5%) were newly diagnosed with diabetes, between 2010 and 2014. Over 4 years, 1%, 1.5%, 2.1%, and 3.0% of the subjects developed diabetes in the normal-normal, normal-abnormal, abnormal normal, and abnormal-abnormal groups, respectively. When the risk for incident diabetes was analyzed in the groups, after adjusting the confounding variables, a 1.58-fold increase in the risk of diabetes (95% confidence interval [CI], 1.10 to 2.26) was observed in the participants with persistent hypertriglyceridemia (abnormal-abnormal group). This was attenuated by further adjustments for body mass index (BMI) (hazard ratio, 1.25; 95% CI, 0.86 to 1.80). CONCLUSION: In this large study population, persistent hypertriglyceridemia, over a period of 2 years, was significantly associated with the risk of incident diabetes, which was attenuated after adjustment for BMI. PMID- 29388401 TI - Comparison of Immunohistochemistry and Direct Sanger Sequencing for Detection of the BRAF(V600E) Mutation in Thyroid Neoplasm. AB - BACKGROUND: The BRAF(V600E) mutation is the most common genetic alteration identified in papillary thyroid carcinoma (PTC). Because of its costs effectiveness and sensitivity, direct Sanger sequencing has several limitations. The aim of this study was to evaluate the efficiency of immunohistochemistry (IHC) as an alternative method to detect the BRAF(V600E) mutation in preoperative and postoperative tissue samples. METHODS: We evaluated 71 patients who underwent thyroid surgery with the result of direct sequencing of the BRAF(V600E) mutation. IHC staining of the BRAF(V600E) mutation was performed in 49 preoperative and 23 postoperative thyroid specimens. RESULTS: Sixty-two patients (87.3%) had PTC, and of these, BRAF(V600E) was confirmed by direct sequencing in 57 patients (91.9%). In 23 postoperative tissue samples, the BRAF(V600E) mutation was detected in 16 samples (70%) by direct sequencing and 18 samples (78%) by IHC. In 24 fine needle aspiration (FNA) samples, BRAF(V600E) was detected in 18 samples (75%) by direct sequencing and 16 samples (67%) by IHC. In 25 core needle biopsy (CNB) samples, the BRAF(V600E) mutation was detected in 15 samples (60%) by direct sequencing and 16 samples (64%) by IHC. The sensitivity and specificity of IHC for detecting the BRAF(V600E) mutation were 77.8% and 66.7% in FNA samples and 99.3% and 80.0% in CNB samples. CONCLUSION: IHC could be an alternative method to direct Sanger sequencing for BRAF(V600E) mutation detection both in postoperative and preoperative samples. However, application of IHC to detect the BRAF(V600E) mutation in FNA samples is of limited value compared with direct sequencing. PMID- 29388402 TI - Association between White Blood Cell Counts within Normal Range and Hemoglobin A1c in a Korean Population. AB - BACKGROUND: We examined whether white blood cell (WBC) count levels within normal range, could be associated with hemoglobin A1c (HbA1c) levels. METHODS: Among the 11,472 people (>=19 years of age) who participated in the 2011 to 2012 Korea National Health and Nutrition Examination, subjects with chronic disease or illness, including 807 patients with diabetes currently taking anti-diabetic medications and/or 1,149 subjects with WBC levels <4,000 or >10,000/MUL were excluded. RESULTS: Overall, adjusted HbA1c levels increased across the WBC quartiles (5.55%+/-0.01%, 5.58%+/-0.01%, 5.60%+/-0.01%, and 5.65%+/-0.01%, P<0.001) after adjusting for confounding factors, such as age, gender, fasting plasma glucose, college graduation, smoking history, waist circumference, presence of hypertension, serum total cholesterol, serum triglyceride, and presence of anemia. The adjusted proportions (%) of HbA1c levels of >=5.7%, >=6.1%, and >=6.5% showed significant increases across WBC quartiles (P<0.001, P=0.002, and P=0.022, respectively). Logistic regression analyses of WBC quartiles for the risk of HbA1c levels of >=5.7%, >=6.1%, and >=6.5%, using the variables above as covariates, showed that the odds ratios of the fourth quartile of WBCs were 1.59 (95% confidence interval [CI], 1.35 to 1.89; P<0.001), 1.78 (95% CI, 1.31 to 2.42; P<0.001), and 2.03 (95% CI, 1.13 to 3.64; P=0.018), using the first quartile of WBCs as the reference. CONCLUSION: HbA1c levels were positively associated with WBC levels within normal range in a general adult population. PMID- 29388403 TI - [Glenoid bone loss after infected total shoulder prosthesis removal]. PMID- 29388404 TI - [A rare cause of negative explora tory laparotomy in severe blunt trauma]. AB - We report the case of a young man involved in a high velocity road traffic accident. He presented with multiple injuries and a shock. This shock was suspected to be caused by an intra-abdominal bleeding and an exploratory laparotomy was performed. The procedure did not identify any intra-abdominal bleeding and the source of bleeding was found lately: an intramuscular active bleeding in the dorsal and lumbar muscular compartments. This case was discussed in our local mortality and morbidity meeting. PMID- 29388405 TI - [Vitamin D deficiency during pregnancy : what's the local situation ?] AB - Vitamin D deficiency is a worldwide health problem, also during pregnancy. Inadequate maternal vitamin D status in pregnancy is associated with poor fetal growth, impaired bone development and rickets in infants after birth. Furthermore, higher rates of preeclampsia and gestational diabetes are associated with low maternal vitamin D status during pregnancy. Toxicity of vitamin D is rare. Most countries recommend vitamin D supplementation during pregnancy but guidelines are controversial and inadequate compared to real mother's and child's needs. Wath's the best strategy to follow and supplement mother during pregnancy? In a study carried out at the maternity clinic Notre-Dame des Bruyeres (CHU Liege), we studied for a year the vitamin D concentrations of young women at start of pregnancy and of others after delivery to evaluate the local situation and management of vitamin D status during pregnancy. We did not collect the cord blood samples in this study. However, this is a project we would like to achieve soon. This would allow us to compare the vitamin D results of the mother at the time of delivery, to those of the cord blood of their respective child. PMID- 29388406 TI - [Could we consider that radiotherapy is effective outside the irradiation area ? The abscopal effect]. AB - Radiotherapy is known for its action on local tumoral control. However, it is also able to induce immunomodulatory effects at a systemic level. The abscopal effect (from latin ab scopus which means "away from the target") is an illustration of this phenomenon. It is defined as a tumor regression observed outside and at a distance of the irradiation fields. The potential application of this effect of treatment in disseminated cancers is a fast-growing field of research. The optimal therapeutic strategy to achieve this effect remains unknown. PMID- 29388407 TI - [The add-on value of preoperative anesthesic consultation and the role of the general practitioner]. AB - The goal of anesthesia preoperative consultation is to better document comorbid patient's disease, selectively order investigations, optimize pre-existing medical conditions, to prepare the most adequate plan of anesthesia. PMID- 29388408 TI - [Delivery site for foetus with congenital heart disease : CHU of Liege experience and international recommandations]. AB - Optimal choice of delivery site after a diagnosis of congenital heart disease (CHD) improves neonatal mortality and morbidity. We report the CHU of Liege experience and review the international recommendations. Between 2011 and 2016, 54 fetuses were diagnosed with CHD in our service. Retrospectively we estimated the appropriateness of the site of delivery considering the postnatal outcome. We confronted our experience with the recent international recommendations for in utero transfer to a tertiary center. The latter are based on the risk of hemodynamic instability at birth but differ for the ductal-dependent cardiopathy. The postanatal evolution and the low emergency transfer rate (4 %) in our series demonstrate the quality of our policy. We propose to validate the French transfer in utero recommendations for our obstetrical department, especially for ductal dependent cardiopathy. PMID- 29388409 TI - [Should clinicians care about health literacy ? A stimulating framework for reflection on the effectiveness of care]. AB - "Health literacy" refers to the ability to find, understand and use health information. It is a relatively new concept, which is becoming increasingly important but remains little known by clinicians. Still, insufficient levels of health literacy in our patients are common, underestimated and negatively associated with numerous health indicators. A set of practical tools are already available to the clinician. The aim of this article is to present the concept to clinicians and emphasize how it could revitalize reflection on the effectiveness of our interventions in the field. Physicians could take a leadership role in putting the concept of health literacy on the agenda for health care quality improvement. PMID- 29388410 TI - [High anion gap metabolic acidosis (pyroglutamic acidosis) induced by chronic acetaminophen use]. AB - Acetaminophen is the most consumable analgesic in the world in the form of medical prescription or self-medication. It is one of the active ingredients most often involved in voluntary poisoning. Lethal dose of acetaminophen classically induces acute hepatic failure on hepatic necrosis. Chronic intake of sub-lethal doses (i.e. near recommended therapeutic doses) of acetaminophen in the presence of certain risk factors may be responsible for another much less recognized pathological manifestation: severe metabolic acidosis with an increased anion gap due to the accumulation of 5-oxoproline or pyroglutamic acid. PMID- 29388411 TI - [SGLT2 inhibitor or GLP-1 receptor agonist in a patient with type 2 diabetes and cardiovascular disease ?] AB - Two classes of antidiabetic agents have shown a cardiovascular and renal protection in patients with type 2 diabetes and high cardiovascular risk. Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, and liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, were granted a reduction of major cardiovascular events and mortality after the positive results of EMPA-REG OUTCOME and LEADER outcome trials, respectively. Protection mechanisms most probably differ between the two pharmacological classes and are perhaps complementary. The question that may arise in clinical practice is to know which drug should be selected between these two options in a patient with type 2 and established cardiovascular disease, before considering a potential combination. The aim of this article is to discuss about the best therapeutic choice according to the patient individual profile and the specificities of each molecule. PMID- 29388412 TI - Enhancing imaging contrast via weighted feedback for iterative multi-image phase retrieval. AB - Iterative phase retrieval (IPR) has developed into a feasible and simple computational method to retrieve a complex-valued sample. Due to coherent illumination, the reconstructed image quality is degraded by speckle noise arising from a laser. Accordingly, partially coherent illumination has been introduced to alleviate this restriction. We apply weighted feedback modality into multidistance and multiwavelength phase retrieval to realize high-contrast and fast imaging. In simulation, it is proved that IPR based on weighted feedback accelerates the convergence in partially coherent illumination and speckle illumination. In experiment, the resolution chart and biological specimen are reconstructed in lensless and lens-based systems, which also demonstrate the performance of weighted feedback. This work provides a simple and high-contrast imaging modality for IPR. Also, it facilitates compact and flexible experimental implementation for label-free imaging. PMID- 29388413 TI - Hemodynamic signal changes during saliva and water swallowing: a near-infrared spectroscopy study. AB - Here, we compared the hemodynamic response observed during swallowing of water or saliva using near-infrared spectroscopy (NIRS). Sixteen healthy adults swallowed water or saliva in a randomized order. Relative concentration changes in oxygenated and deoxygenated hemoglobin during swallowing were assessed. Both swallowing tasks led to the strongest NIRS signal change over the bilateral inferior frontal gyrus. Water swallowing led to a stronger activation over the right hemisphere while the activation focus for saliva swallowing was stronger left lateralized. The NIRS time course also differed between both swallowing tasks especially at the beginning of the tasks, which might be a sign of differences in task effort. Our results show that NIRS is a sensitive measure to reveal differences in the topographical distribution and time course of the hemodynamic response between distinct swallowing tasks and might be therefore an adequate diagnostic and therapy tool for swallowing difficulties. PMID- 29388414 TI - [Diagnostic accuracy of endocervicoscopy as preoperative tool to improve the excisional treatment of cervical preneoplastic lesions]. AB - BACKGROUND: The aim of this study was to evaluate the diagnostic accuracy of endocervicoscopy as a preoperative examination to improve the outcome of the excisional treatment (LEEP) of high-grade cervical preneoplastic lesions. METHODS: Patients with histologic diagnosis of CIN II-CIN III undergoing LEEP divided in two groups: in group A (85 women) a preoperative endocervicoscopy was performed, in group B (85 women) no additional examination was performed before LEEP. The size of the surgical specimen (H, D, W) and the margins of the lesion were evaluated. RESULTS: Seventy-four women in group A and 80 in group B completed the follow-up. group A showed significant correlation between colposcopic examination and endocervicoscopic examination (P=0.001, k=0.30) and between endocervicoscopic and definitive histological examination (P<0.05, k=0.16). The depth of the operative sample was significantly lower (P<0.0001) in group A (0.91+/-0.4) than in group B (1.58+/-0.2), group A showed fewer patients B with positive endocervical margins than group B (3 vs. 17, P<002). Colposcopic, cytological and virological follow-up did not show significant differences between the two groups. CONCLUSIONS: Endocervicoscopy as preoperative tool for excisional treatment of cervical lesions showed high diagnostic effectiveness and allows to perform a conservative surgery. PMID- 29388415 TI - Innovations in imaging modalities for recurrent and metastatic prostate cancer: a systematic review. AB - INTRODUCTION: The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer. In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic prostate cancer (PCa), exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. EVIDENCE ACQUISITION: The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017. A wide search was performed including the combination of following words: "Prostate" AND "Cancer" AND ("Metastatic" OR "Recurrent") AND "imaging" AND ("MRI" OR "PET"). The selection procedure followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) principles and is presented using a PRISMA flow chart. EVIDENCE SYNTHESIS: Novel imaging techniques, as multiparametric magnetic resonance imaging (MRI), whole-body MRI and Choline and prostate-specific membrane antigen (PSMA) PET imaging techniques are currently revolutioning the treatment planning in patients with advanced and metastatic PCa, allowing a better characterization of the disease. Multiparametric MRI performs well in the detection of local recurrences, with sensitivity rates of 67 98% and overall diagnostic accuracy of 83-93%, depending on the type of magnetic field strength (1.5 vs. 3T). Whole body MRI instead shows a high specificity (>95%) for bone metastases. PET imaging, and in particular PSMA PET/CT, showed promising results in the detection of both local and distant recurrences, even for low PSA values (<0.5 ng/mL). Sensitivity varies from 77-98% depending on PSA value and PSA velocity. CONCLUSIONS: Whole body-MRI, NaF PET, Choline-PET/CT and PSMA PET/CT are flourishing techniques which find great application in the field of recurrent and metastatic PCa, in the effort to reduce treatment of "PSA only" and rather focus our therapies on clinical tumor entities. Standardization is urgently needed to allow adequate comparison of results and diffusion on a large scale. PMID- 29388416 TI - Teeth agenesis evaluation in an Italian sample of complete unilateral and bilateral cleft lip and palate patients. AB - BACKGROUND: The aim of this study was to evaluate the prevalence and the distribution of teeth agenesis inside and outside the cleft area in an Italian population with a non-syndromic unilateral (UCLP) and bilateral (BCLP) cleft lip and palate. METHODS: Two hundred thirty-three digital panoramic radiographs (151 females, 82 males) of patients between seven and fifteen years old were recruited from the maxillo-facial surgery clinic of the San Bortolo Hospital of Vicenza according with the following inclusion criteria: unilateral or bilateral cleft lip and palate, no other syndromes, no previous orthodontic treatment, no previous teeth extractions and good quality of digital panoramic radiographs. Statistical analyses were carried using Chi-squared test (P value <0.05). RESULTS: One hundred sixty subjects out of 233 (68.67%) presented with agenesis of at least 1 missing permanent tooth. The prevalence of hypodontia is significantly more frequent in BCLP patients than UCLP ones with a total of 153 missing teeth (51.34%). The most frequent missing tooth is the lateral incisor in the upper left side (37.6%) followed by the lateral incisor in the upper right side (29.2%), the upper second premolars, the upper central incisors and the upper canine. CONCLUSIONS: This study is the first that evaluates the prevalence and distribution of hypodontia in an Italian population with cleft lip and palate. The higher congenital absence of dental elements in this group than healthy general patients is an important aspect to consider for a functional and aesthetic oral rehabilitation. PMID- 29388417 TI - Tooth-borne distraction osteogenesis versus conventional Le Fort I in maxillary advancement of cleft lip and palate patients. AB - BACKGROUND: Distraction osteogenesis (DO) is rapidly becoming a mainstream surgical technique for correction of maxillary deficiency. The aim of this study was to compare the effectiveness of a newly designed tooth-borne osteogenic distraction device with conventional Le Fort 1 osteotomy in maxillary advancement of cleft lip and palate patients. METHODS: The DO group consisted of 10 subjects (7 males, 3 females) with a mean age of 21.2 (SD 4.2) years. In these patients, the newly designed distraction device which exerted force anteroposteriorly was cemented after mobilization of the maxilla. After a latency period of 7 days, the distractor was activated twice daily by a total amount of 0.5 mm per day. The activation was continued for 3 weeks. After an 8-week consolidation period, the distraction appliance was removed. Cephalograms of DO patients were obtained at the start of distraction and at the end of consolidation. The Le Fort 1 group consisted of 11 subjects (6 males, 5 females) with a mean age of 22.3 (SD 3.7) years. Pre and postsurgery lateral cephalograms were obtained. t-test and paired t-test were used to evaluate the data. RESULTS: At the end of treatment, the SNA angle of Le Fort 1 patients increased by 5.5 degrees (SD 2.3) (P<0.001) and the SNA angle of DO patients increased by 3.4 degrees (SD 2) (P<0.001). CONCLUSIONS: Current evidence suggests that both conventional Le Fort 1 and tooth-borne osteogenic distraction device can effectively advance the maxilla forward in patients with cleft lip. PMID- 29388418 TI - Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms. AB - Hereditary hemochromatosis (HH), a disease marked by chronic iron overload from insufficient expression of the hormone hepcidin, is one of the most common genetic diseases. One form of HH (type III) results from mutations in transferrin receptor-2 (TfR2). TfR2 is postulated to be a part of signaling system that is capable of modulating hepcidin expression. However, the molecular details of TfR2's role in this system remain unclear. TfR2 is predicted to bind the iron carrier transferrin (Tf) when the iron saturation of Tf is high. To better understand the nature of these TfR-Tf interactions, a binding study with the full length receptors was conducted. In agreement with previous studies with truncated forms of these receptors, holo-Tf binds to the TfR1 homologue significantly stronger than to TfR2. However, the binding constant for Tf-TfR2 is still far above that of physiological holo-Tf levels, inconsistent with the hypothetical model, suggesting that other factors mediate the interaction. One possible factor, apo-Tf, only weakly binds TfR2 at serum pH and thus will not be able to effectively compete with holo-Tf. Tf binding to a TfR2 chimera containing the TfR1 helical domain indicates that the differences in the helical domain account for differences in the on rate of Tf, and nonconserved inter-receptor interactions are necessary for the stabilization of the complex. Conserved residues at one possible site of stabilization, the apical arm junction, are not important for TfR1-Tf binding but are critical for the TfR2-Tf interaction. Our results highlight the differences in Tf interactions with the two TfRs. PMID- 29388419 TI - GABA Detection with Nano-ITIES Pipet Electrode: A New Mechanism, Water/DCE Octanoic Acid Interface. AB - Interface between two immiscible electrolyte solutions (ITIES) supported on the orifice of a pipet have become a powerful platform to detect a broad range of analytes. We present here the detection of gamma-aminobutyric acid (GABA) with the nanoITIES pipet electrodes for the first time. GABA has a net charge of zero in an aqueous solution at pH ~ 7, and it has not previously been detected at ITIES. In this work, we demonstrated GABA detection at ITIES in an aqueous solution at pH ~ 7, where we introduced a novel detection strategy based on "pH modulation from the oil phase". To the best of our knowledge, this is the first report of such. Current increases linearly with increasing concentrations of GABA, ranging from 0.25 mM to 1.0 mM. The measured half-wave transfer potential of GABA is -0.401 +/- 0.010 V ( n = 22) vs E1/2,TBA. The measured diffusion coefficient for GABA detection at nanoITIES pipet electrode is 6.09 (+/-0.58) * 10-10 m2/s ( n = 5). Experimental results indicate that protons generated from octanoic acid dissociation in the oil phase do not come out from the oil phase into the aqueous phase; neither were protons produced in the aqueous phase. NanoITIES pipet electrodes with radii of 320-340 nm were used in the current study. This new strategy and knowledge presented here lays the groundwork for the future development of ITIES pipet electrodes, especially for the detection of electrochemically nonredox active analytes. PMID- 29388420 TI - Memristive Synapses with Photoelectric Plasticity Realized in ZnO1-x/AlOy Heterojunction. AB - With the end of Moore's law in sight, new computing architectures are urgently needed to satisfy the increasing demands for big data processing. Neuromorphic architectures with photoelectric learning capability are good candidates for energy-efficient computing for recognition and classification tasks. In this work, artificial synapses based on the ZnO1-x/AlOy heterojunction were fabricated and the photoelectric plasticity was investigated. Versatile synaptic functions such as photoelectric short-term/long-term plasticity, paired-pulse facilitation, neuromorphic facilitation, and depression were emulated based on the inherent persistent photoconductivity and volatile resistive switching characteristics of the device. It is found that the naturally formed AlOy layer provides traps for photogenerated holes, resulting in a significant persistent photoconductivity effect. Moreover, the resistive switching can be attributed to the electron trapping/detrapping at the trapping sites in the AlOy layer. PMID- 29388421 TI - Electrorheological Fluids with High Shear Stress Based on Wrinkly Tin Titanyl Oxalate. AB - Electrorheological (ER) fluids are considered as a type of smart fluids because their rheological characteristics can be altered through an electric field. The discovery of giant ER effect revived the researchers' interest in the ER technological area. However, the poor stability including the insufficient dynamic shear stress, the large leakage current density, and the sedimentation tendency still hinders their practical applications. Herein, we report a facile and scalable coprecipitation method for synthesizing surfactant-free tin titanyl oxalate (TTO) particles with tremella-like wrinkly microstructure (W-TTO). The W TTO-based ER fluids exhibit enhanced ER activity compared to that of the pristine TTO because of the improved wettability between W-TTO and the silicone oil. In addition, the static yield stress and leakage current of W-TTO ER fluids also show a fine time stability during the 30 day tests. More importantly, the dynamic shear stress of W-TTO ER fluids can remain stable throughout the shear rate range, which is valuable for their use in engineering applications. The results in this work provided a promising strategy to solving the long-standing problem of ER fluid stability. Moreover, this convenient route of synthesis may be considered a green approach for the mass production of giant ER materials. PMID- 29388422 TI - Room-Temperature-Synthesized High-Mobility Transparent Amorphous CdO-Ga2O3 Alloys with Widely Tunable Electronic Bands. AB - In this work, we have synthesized Cd1-xGaxO1+delta alloy thin films at room temperature over the entire composition range by radio frequency magnetron sputtering. We found that alloy films with high Ga contents of x > 0.3 are amorphous. Amorphous Cd1-xGaxO1+delta alloys in the composition range of 0.3 < x < 0.5 exhibit a high electron mobility of 10-20 cm2 V-1 s-1 with a resistivity in the range of 10-2 to high 10-4 Omega cm range. The resistivity of the amorphous alloys can also be controlled over 5 orders of magnitude from 7 * 10-4 to 77 Omega cm by controlling the oxygen stoichiometry. Over the entire composition range, these crystalline and amorphous alloys have a large tunable intrinsic band gap range of 2.2-4.8 eV as well as a conduction band minimum range of 5.8-4.5 eV below the vacuum level. Our results suggest that amorphous Cd1-xGaxO1+delta alloy films with 0.3 < x < 0.4 have favorable optoelectronic properties as transparent conductors on flexible and/or organic substrates, whereas the band edges and electrical conductivity of films with 0.3 < x < 0.7 can be manipulated for transparent thin-film transistors as well as electron transport layers. PMID- 29388423 TI - Gas-Phase Oxidation of Allyl Acetate by O3, OH, Cl, and NO3: Reaction Kinetics and Mechanism. AB - Allyl acetate (AA) is widely used as monomer and intermediate in industrial chemicals synthesis. To evaluate the atmospheric outcome of AA, kinetics and mechanism of its gas-phase reaction with main atmospheric oxidants (O3, OH, Cl, and NO3) have been investigated in a Teflon reactor at 298 +/- 3 K. Both absolute and relative rate methods were used to determine the rate constants for AA reactions with the four atmospheric oxidants. The obtained rate constants (in units of cm3 molecule-1 s-1) are (1.8 +/- 0.3) * 10-18, (3.1 +/- 0.7) * 10-11, (2.5 +/- 0.5) * 10-10, and (1.1 +/- 0.4) * 10-14, for reactions with O3, OH, Cl, and NO3, respectively. While results for reactions with O3, OH and Cl are in good agreement with previous studies, the kinetics for the reaction with NO3 is reported for the first time in this study. On the basis of determined rate constants, the tropospheric lifetimes of AA are tauO3 = 9 days, tauOH = 5 h, tauCl = 5 days, tauNO3 = 2 days. On the basis of the products study, reaction mechanisms for these oxidations have been proposed and the reaction products were detected using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) and Fourier transform infrared spectroscopy (FTIR). Results show that the main products formed in these reactions are carbonyl compounds. In particular, 2 oxoethyl acetate was detected in all four AA oxidation reactions. Compared to previous studies, several new products were determined for reactions with OH and Cl. These results form a set of comprehensive kinetic data for AA reactions with main atmospheric oxidants and provide a better understanding of the degradation and atmospheric outcome of unsaturated acetate esters in the troposphere, during both daytime and nighttime. PMID- 29388424 TI - Unveiling the Fundamental Role of Temperature in RRAM Switching Mechanism by Multiscale Simulations. AB - Even though resistance switching memories (RRAMs) can be potentially employed in a broad variety of fields, such as electronics and brain science, they are still affected by issues that prevent their application in circuitry. These problems are a consequence of the lack of detailed knowledge about the physical processes occurring in the device. In this work, we propose multiscale simulations, combining kinetic Monte Carlo and finite difference methods, to shed light on the yet-unclear switching process occurring in the valence change RRAMs, which are believed to work as a consequence of the drift and diffusion of crystalline defects that act as dopants. Results show that the height of the defect diffusion barrier influences the switching process, the retention, and the switching time. In particular, nonvolatile switching can be achieved only by means of the fundamental role of temperature variations induced by Joule heating if the diffusion barriers of the defects are larger than ~1 eV. High barriers prevent defects from hopping when no voltage is applied. During the transition from the high-resistance to the low-resistance state of the device, a heating stage of the material precedes the defect drift because the applied electric field by itself is not enough to lead to a drift velocity such that switching is achieved within microseconds. The temperature increase has, therefore, the double effect of activating the motion of the defects and enhancing their drift velocity. The switching process can occur only if a sufficiently high temperature is reached thanks to the Joule effect. On the basis of these findings, the RRAM design could aim at a better temperature management to achieve at the same time reproducibility and reliability. PMID- 29388425 TI - Rhodium(III)-Catalyzed Synthesis of Spiropiperidine Derivatives via C-H Activation. AB - Spiropiperidine derivatives, an important class of bioactive molecules, were synthesized under mild conditions by rhodium(III)-catalyzed intramolecular ArC-H activation. This reaction provides a novel route to highly substituted tricyclic spiropiperidines in good to excellent yields. Under acidic conditions the resulting enamines reacted with pendant amides to afford spiropiperidines derivatives possessing an original tetracyclic structure. PMID- 29388426 TI - Persimmon Tannin Decreased the Glycemic Response through Decreasing the Digestibility of Starch and Inhibiting alpha-Amylase, alpha-Glucosidase, and Intestinal Glucose Uptake. AB - Regulation of postprandial blood glucose levels is an effective therapeutic proposal for type 2 diabetes treatment. In this study, the effect of persimmon tannin on starch digestion with different amylose levels was investigated both in vitro and in vivo. Oral administration of persimmon tannin-starch complexes significantly suppressed the increase of blood glucose levels and the area under the curve (AUC) in a dose-dependent manner compared with starch treatment alone in an in vivo rat model. Further study proved that persimmon tannin could not only interact with starch directly but also inhibit alpha-amylase and alpha glucosidase strongly, with IC50 values of 0.35 and 0.24 mg/mL, separately. In addition, 20 MUg/mL of persimmon tannin significantly decreased glucose uptake and transport in Caco-2 cells model. Overall, our data suggested that persimmon tannin may alleviate postprandial hyperglycemia through limiting the digestion of starch as well as inhibiting the uptake and transport of glucose. PMID- 29388427 TI - Low-Frequency Noise in Layered ReS2 Field Effect Transistors on HfO2 and Its Application for pH Sensing. AB - Layered rhenium disulfide (ReS2) field effect transistors (FETs), with thickness ranging from few to dozens of layers, are demonstrated on 20 nm thick HfO2/Si substrates. A small threshold voltage of -0.25 V, high on/off current ratio of up to ~107, small subthreshold swing of 116 mV/dec, and electron carrier mobility of 6.02 cm2/V.s are obtained for the two-layer ReS2 FETs. Low-frequency noise characteristics in ReS2 FETs are analyzed for the first time, and it is found that the carrier number fluctuation mechanism well describes the flicker (1/f) noise of ReS2 FETs with different thicknesses. pH sensing using a two-layer ReS2 FET with HfO2 as a sensing oxide is then demonstrated with a voltage sensitivity of 54.8 mV/pH and a current sensitivity of 126. The noise characteristics of the ReS2 FET-based pH sensors are also examined, and a corresponding detection limit of 0.0132 pH is obtained. Our studies suggest the high potential of ReS2 for future low-power nanoelectronics and biosensor applications. PMID- 29388428 TI - Improving Unipolar Resistive Switching Uniformity with Cone-Shaped Conducting Filaments and Its Logic-In-Memory Application. AB - Resistive random access memory (RRAM) with inherent logic-in-memory capability exhibits great potential to construct beyond von-Neumann computers. Particularly, unipolar RRAM is more promising because its single polarity operation enables large-scale crossbar logic-in-memory circuits with the highest integration density and simpler peripheral control circuits. However, unipolar RRAM usually exhibits poor switching uniformity because of random activation of conducting filaments and consequently cannot meet the strict uniformity requirement for logic-in-memory application. In this contribution, a new methodology that constructs cone-shaped conducting filaments by using chemically a active metal cathode is proposed to improve unipolar switching uniformity. Such a peculiar metal cathode will react spontaneously with the oxide switching layer to form an interfacial layer, which together with the metal cathode itself can act as a load resistor to prevent the overgrowth of conducting filaments and thus make them more cone-like. In this way, the rupture of conducting filaments can be strictly limited to the tip region, making their residual parts favorable locations for subsequent filament growth and thus suppressing their random regeneration. As such, a novel "one switch + one unipolar RRAM cell" hybrid structure is capable to realize all 16 Boolean logic functions for large-scale logic-in-memory circuits. PMID- 29388429 TI - All-Ambient Processed Binary CsPbBr3-CsPb2Br5 Perovskites with Synergistic Enhancement for High-Efficiency Cs-Pb-Br-Based Solar Cells. AB - All-inorganic CsPbBr3 perovskite solar cells display outstanding stability toward moisture, light soaking, and thermal stressing, demonstrating great potential in tandem solar cells and toward commercialization. Unfortunately, it is still challenging to prepare high-performance CsPbBr3 films at moderate temperatures. Herein, a uniform, compact CsPbBr3 film was fabricated using its quantum dot (QD) based ink precursor. The film was then treated using thiocyanate ethyl acetate (EA) solution in all-ambient conditions to produce a superior CsPbBr3-CsPb2Br5 composite film with a larger grain size and minimal defects. The achievement was attributed to the surface dissolution and recrystallization of the existing SCN- and EA. More specifically, the SCN- ions were first absorbed on the Pb atoms, leading to the dissolution and stripping of Cs+ and Br- ions from the CsPbBr3 QDs. On the other hand, the EA solution enhances the diffusion dynamics of surface atoms and the surfactant species. It is found that a small amount of CsPb2Br5 in the composite film gives the best surface passivation, while the Br rich surface decreases Br vacancies (VBr) for a prolonged carrier lifetime. As a result, the fabricated device gives a higher solar cell efficiency of 6.81% with an outstanding long-term stability. PMID- 29388430 TI - Interface Anchored Effect on Improving Working Stability of Deep Ultraviolet Light-Emitting Diode Using Graphene Oxide-Based Fluoropolymer Encapsulant. AB - The graphene oxide (GO)-based fluoropolymer is first proposed as an interface encapsulant to improve the light extraction efficiency and achieve the ultralong working stability of deep ultraviolet light-emitting diodes (DUV-LEDs), benefitting from its superior interface performance based on an anchored effect. For the GO-based fluoropolymer composite, the anchored structure is designed to effectively and tightly rivet the quartz lens on the DUV-LED chip by using the interface reaction between GO embedded in fluoropolymer and 3 aminopropyltriethoxy-silane grafted on the surfaces. Experimental results show that on the basis of the interface anchored effect, the air voids in the interface layer of DUV-LED are reduced by 84%, leading to an improvement of the light output power by 15% and a decrease of the junction temperature by 5%, by virtue of the sealing characteristics of the 0.10 wt % GO-based fluoropolymer. In addition, the steady working time is dramatically improved by 660% and it was attributed to the good interface anchored bonding of the 0.10 wt % GO-based fluoropolymer. This novel graphene oxide-based fluoropolymer is believed to provide a feasible and effective interface encapsulant to improve the performance of DUV-LEDs. PMID- 29388431 TI - Diverted Total Synthesis of the Baulamycins and Analogues Reveals an Alternate Mechanism of Action. AB - The baulamycins were identified as in vitro siderophore biosynthesis inhibitors. Diverted total synthesis was used to construct the natural products and eight strategic analogues, three of which had improved inhibitory activity. Biological testing then revealed that membrane damage is the predominant mode of action in Staphylococcus aureus cells. PMID- 29388432 TI - Synthesis of Hierarchical Silica/Titania Hollow Nanoparticles and Their Enhanced Electroresponsive Activity. AB - Wrinkled silica nanoparticle (WSN)-based hollow SiO2/TiO2 nanoparticles (W-HNPs) with hierarchically arrayed internal surfaces were prepared via the combination of sol-gel, TiO2 coating, and etching of core template techniques. The hierarchical internal surface of W-HNPs was attained using WSNs as a core template. Compared with SiO2 sphere-templated hollow SiO2/TiO2 nanoparticles (S HNPs) with flat inner surfaces, W-HNPs displayed distinctive surface areas, TiO2 loading amounts, and dielectric properties arising from the hierarchical internal surface. The unique properties of W-HNPs were further investigated as an electrorheological (ER) material. W-HNP-based ER fluids exhibited ca. 1.9-fold enhancement in the ER efficiency compared to that of S-HNP-based ER fluids. Such enhancement was attributed to the unique inner surface of W-HNPs, which effectively enhanced the polarizability by increasing the number of charge accumulation sites, and to the presence of the high-dielectric TiO2. This study demonstrated the advantages, in terms of practical ER applications, of hollow nanomaterials having uniquely arrayed internal spaces. PMID- 29388433 TI - Post hoc analysis of plasma amino acid profiles: towards a specific pattern in autism spectrum disorder and intellectual disability. AB - Objectives Autism spectrum disorders and intellectual disability present a challenge for therapeutic and dietary management. We performed a re-analysis of plasma amino acid chromatography of children with autism spectrum disorders ( n = 22) or intellectual disability ( n = 29) to search for a metabolic signature that can distinguish individuals with these disorders from controls ( n = 30). Methods We performed univariate and multivariate analyses using different machine learning strategies, from the raw data of the amino acid chromatography. Finally, we analysed the metabolic pathways associated with discriminant biomarkers. Results Multivariate analysis revealed models to discriminate patients with autism spectrum disorders or intellectual disability and controls from plasma amino acid profiles ( P < 0.0003). Univariate analysis showed that autism spectrum disorder and intellectual disability patients shared similar differences relative to controls, including lower glutamate ( P < 0.0001 and P = 0.0002, respectively) and serine ( P = 0.002 for both) concentrations. The multivariate model ( P < 6.12.10-7) to discriminate between autism spectrum disorders and intellectual disability revealed the involvement of urea, 3-methyl-histidine and histidine metabolism. Biosigner analysis and univariate analysis confirmed the role of 3-methylhistidine ( P = 0.004), histidine ( P = 0.003), urea ( P = 0.0006) and lysine ( P = 0.002). Conclusions We revealed discriminant metabolic patterns between autism spectrum disorders, intellectual disability and controls. Amino acids known to play a role in neurotransmission were discriminant in the models comparing autism spectrum disorders or intellectual disability to controls, and histidine and b-alanine metabolism was specifically highlighted in the model. PMID- 29388434 TI - Improved technical success and radiation safety of adrenal vein sampling using rapid, semi-quantitative point-of-care cortisol measurement. AB - : Objective Primary aldosteronism is a curable cause of hypertension which can be treated surgically or medically depending on the findings of adrenal vein sampling studies. Adrenal vein sampling studies are technically demanding with a high failure rate in many centres. The use of intraprocedural cortisol measurement could improve the success rates of adrenal vein sampling but may be impracticable due to cost and effects on procedural duration. Design Retrospective review of the results of adrenal vein sampling procedures since commencement of point-of-care cortisol measurement using a novel single-use semi quantitative measuring device for cortisol, the adrenal vein sampling Accuracy Kit. MEASUREMENTS: Success rate and complications of adrenal vein sampling procedures before and after use of the adrenal vein sampling Accuracy Kit. Routine use of the adrenal vein sampling Accuracy Kit device for intraprocedural measurement of cortisol commenced in 2016. Results Technical success rate of adrenal vein sampling increased from 63% of 99 procedures to 90% of 48 procedures ( P = 0.0007) after implementation of the adrenal vein sampling Accuracy Kit. Failure of right adrenal vein cannulation was the main reason for an unsuccessful study. Radiation dose decreased from 34.2 Gy.cm2 (interquartile range, 15.8-85.9) to 15.7 Gy.cm2 (6.9-47.3) ( P = 0.009). No complications were noted, and implementation costs were minimal. Conclusions Point-of-care cortisol measurement during adrenal vein sampling improved cannulation success rates and reduced radiation exposure. The use of the adrenal vein sampling Accuracy Kit is now standard practice at our centre. PMID- 29388435 TI - Guelph Family Health Study's Home-Based Obesity Prevention Intervention Increases Fibre and Fruit Intake in Preschool-Aged Children. AB - PURPOSE: The Guelph Family Health Study (GFHS) pilot was designed to examine the feasibility and effectiveness of a home-based obesity prevention intervention on health behaviours and obesity risk. The objective of this analysis was to determine the effect of the 6-month intervention on preschool-aged children's dietary intakes. METHODS: Families with children aged 1.5-5 years old were randomized to receive one of the following: 4 home visits with a health educator as well as tailored emails and mailed incentives (4HV; n = 19 children); 2 home visits with a health educator as well as tailored emails and mailed incentives (2HV; n = 14 children); or general health advice through emails (control; n = 12 children). Three-day food records were completed by parents for their children before and after the 6-month intervention and analyzed for 3-day average intakes of energy, nutrients, and MyPlate food groups. RESULTS: After the 6-month intervention, the 4HV group had significantly higher fibre intake and the 4HV and 2HV groups had significantly higher fruit intake, both compared with the control group. CONCLUSIONS: This study provides support for a home-based intervention approach to improve the diet quality of preschool-aged children. PMID- 29388436 TI - X-ray, structural assignment and molecular docking study of dihydrogeodin from Aspergillus Terreus TM8. AB - A re-cultivation of the thermophilic fungus Aspergillus terreus TM8, and working up of its extract afforded the dichloro-benzophenone derivative, dihydrogeodin (1) in addition to the butyrolactones I (2), V (3) and VI (4). A literature surveying revealed one recent structural assignment trial for dihydrogeodin (1), however, with some inaccuracies. We report herein a full assignment of dihydrogeodin (1) using extensive study of 1D, 2D NMR and ESI HR mass data. For the first time as well, we report the planar structure of 1 using X-ray crystallography. Docking and molecular dynamic simulation of dihydrogeodin (1) on the isomerase cyclophilin A has revealed its significant potential activity as an antiviral and immunosuppressive agent. PMID- 29388437 TI - Migraine and the risk of incident hypertension among women. AB - Background Few studies have examined whether migraine is associated with an increased risk of incident hypertension. Methods We performed a prospective cohort study among 29,040 women without hypertension at baseline. Women were classified as having active migraine with aura, active migraine without aura, a past history of migraine, or no history of migraine. Incident hypertension was defined as new physician diagnosis or newly self-reported systolic or diastolic blood pressure >=140 mmHg or >=90 mmHg respectively. Cox proportional hazards models were used to evaluate the association between migraine and incident hypertension. Results During a mean follow-up of 12.2 years, 15,176 incident hypertension cases occurred. Compared to those with no history of migraine, women who experience migraine with aura had a 9% increase in their risk of developing hypertension (95% CI: 1.02, 1.18); women who experience migraine without aura had a 21% increase in their risk of developing hypertension (95% CI: 1.14, 1.28); and women with a past history of migraine had a 15% increase in their risk of developing hypertension (95% CI: 1.07, 1.23). Conclusions Women with migraine have a higher relative risk of developing hypertension compared to women without migraine. PMID- 29388439 TI - Two new secondary metabolites from a mangrove-derived fungus Cladosporium sp. JJM22. AB - Two new compounds (1 and 2), together with six known compounds (3-8), were obtained from the Cladosporium sp. JJM22, an endophytic fungus isolated from the stem bark of the mangrove plant Ceriops tagal collected in South China Sea. Their structures were elucidated on the basis of detailed spectroscopic analysis. The absolute configurations of 1 and 2 were confirmed by the comparison of optical rotation and the CD data with those of known compounds. The inhibitory activities of the isolated compounds against six terrestrial pathogenic bacteria and human cervical carcinoma Hela cell line were evaluated. Compound 3 exhibited a broad spectrum of antibacterial activities. PMID- 29388438 TI - Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities. AB - The distributed network of lymph vessels and nodes in the body, with its complex architecture and physiology, presents a major challenge for whole-body lymphatic targeted drug delivery. To gather physiological and pathological information of the lymphatics, near-infrared (NIR) fluorescence imaging of NIR fluorophores is used in clinical practice due to its tissue-penetrating optical radiation (700 900 nm) that safely provides real-time high-resolution in vivo images. However, indocyanine green (ICG), a common clinical NIR fluorophore, is unstable in aqueous environments and under light exposure, and its poor lymphatic distribution and retention limits its use as a NIR lymphatic tracer. To address this, we investigated in mice the distribution pathways of a novel nanoparticle formulation that stabilises ICG and is optimised for lymphatic drug delivery. From the subcutaneous space, ICG particles provided selective lymphatic uptake, lymph vessel and node retention, and extensive first-pass lymphatic distribution of ICG, enabling 0.2 mm and 5-10 cell resolution of lymph vessels, and high signal-to-background ratios for lymphatic vessel and node networks. Soluble (free) ICG readily dissipated from lymph vessels local to the injection site and absorbed into the blood. These unique characteristics of ICG particles could enable mechanistic studies of the lymphatics and diagnosis of lymphatic abnormalities. PMID- 29388441 TI - Corrigendum. PMID- 29388442 TI - Liver function assessment by indocyanine green plasma disappearance rate in patients with intra-abdominal hypertension after "non-hepatic" abdominal surgery. AB - BACKGROUND AND OBJECTIVE: Liver function assessment in patients with intra abdominal hypertension (IAH) after major abdominal surgery is complex and often confounding. Elevated intra-abdominal pressure (IAP) often occurs after major abdominal surgery, and is associated with decreased abdominal blood flow and organ dysfunction, and it could cause abdominal compartment syndrome (ACS), which is a life-threatening condition. Plasma disappearance rate (PDR) of indocyanine green (ICG) and ICG retention rate after 15 min (R15) were used to evaluate liver function and as a prognostic parameter after major abdominal surgery. METHODS: In this prospective/observational study, 51 patients were followed in the surgical intensive care unit after major abdominal surgery (operation of the small and large intestine, stomach, pancreas, spleen, or resection of the abdominal aorta), 29 had IAH. The PDR-ICG and R15 were analyzed 24 h after surgery concurrently with IAP, APP, bilirubin, AST, ALT, prothrombin time, albumin, cardiac index, arterial lactate, oxygen delivery, MAP (mean arterial pressure), APACHE II (acute physiology and chronic health evaluation), SOFA (sequential organ failure assessment), and SAPS II (simplified acute physiology score). IAH has been defined as a peak intra-abdominal pressure (IAP) value of >=12 mmHg, at a minimum, as two standardized measurements obtained 1-6 h apart. RESULTS: The PDR ICG measured 24 h after surgery was not different among groups (20.95% [SD = 10.34] vs 25.40% [SD = 7.42]), p = .094. ICG R15 was significantly higher in patients with IAH, 11.10% [SD = 13.82] vs 8.30 [SD = 11.46], p < .05, respectively. The PDR/ICG value was significantly lower in non-survivors than survivors (16.82 [SD = 10.87] vs 24.35 [SD = 8.48], p < .05). CONCLUSIONS: The results suggest that PDR/ICG and ICG R15 are useful dynamic tests for evaluation of complex liver function and survival prediction after major abdominal surgery in patients with IAH. PMID- 29388443 TI - Prevalence and correlates of anal sex among secondary school students in Cape Town, South Africa. AB - Research efforts have overlooked anal sex as a risk factor for adolescents' acquisition of HIV despite the high rates of HIV among South African youth. Here, we report findings from a survey conducted in 2012 among secondary school youth, ages 16-24, in Cape Town. 937 adolescents completed a pencil-and-paper survey. Eleven and 31% of female and male youth, respectively, reported ever having anal sex. By comparison, 59% and 78% of female and male youth reported ever having vaginal sex. The percentage of youth reporting lifetime rates of anal sex increased with age: 32% of 20-to-24 year olds had anal sex compared to 16% of 16 to-17-year olds. When the sample was stratified by sex, this difference appeared to be driven by older male, but not female, sexual behavior. Despite noted differences in prevalence rates by sex, both boys and girls who had anal sex were more likely than their same-sex peers who had vaginal sex to report sexual coercion victimization and perpetration experiences and inconsistent condom use. Interestingly, some differences in HIV motivation, information, and behavioral skills were noted for youth who had vaginal sex versus youth who had never had sex; scores were largely similar for youth who had anal sex versus youth who had never had sex however. Together, these findings suggest that anal sex is not uncommon and may be an important marker for other HIV risk behaviors in at least one lower income South African community. Anal sex needs to be explicitly discussed in adolescent HIV prevention and healthy sexuality programing, incorporating age-relevant scenarios about negotiating condoms and other healthy relationship behaviors (e.g., refusing sex when it is not wanted). PMID- 29388444 TI - Hepatotoxic effect of subacute vincristine administration activates necrosis and intrinsic apoptosis in rats: protective roles of broccoli and Indian mustard. AB - This study investigated the hepatotoxic effect of long-term vincristine (VCR) administration in rats and to assess if an individual or combined therapy with Indian mustard and broccoli afforded protection. Signs of hepatotoxicity, including altered liver architecture and higher serum levels of ALT and AST, were seen in VCR-treated rats. Concomitantly, the impaired antioxidant potential and higher mRNA levels of IL-12 and IL-4, which are markers of apoptosis, were seen in rat livers. VCR treatment induced hepatocyte apoptosis, shown by the up regulation of mRNA and protein levels of 53, increased protein levels of cleaved caspase-3 and Bax, and reduced levels of intracellular ATP and BCl-2mRNA and protein. Although individual administration of mustard or broccoli partially ameliorated all these responses, the combined therapy of both extracts resulted in the maximum improvement. Thus, the long-term administration of VCR is hepatotoxic and induces apoptosis; however, the combined therapy of both extracts mitigated these effects. PMID- 29388445 TI - Effects of bisphenol A on antioxidant system and lipid profile in rats. AB - We investigated the effects of bisphenol A (BPA) on antioxidant system enzymes, blood lipid profile and histologic structure of liver and pancreas in rats. We used 40 8-week-old male Wistar albino rats. The animals were divided into five groups of eight: control, vehicle, BPA-5, BPA-50 and BPA-500. BPA was dissolved in ethanol, then mixed with corn oil. The control group was untreated. The vehicle group was given the ethanol-corn oil mixture. The BPA 5, BPA 50 and BPA 500 groups were given 5, 50, and 500 ug/kg body weights/day, respectively. After 8 weeks, blood and tissue samples were obtained from the animals and plasma GSH, TBARS, SOD, GPx, CAT, NO, total cholesterol, triglyceride, HDL, LDL, insulin and glucose were measured. The sections were stained using histochemical and immunohistochemical methods. BPA significantly decreased the levels of GSH, SOD, GPx and CAT, and increased the levels of TBARS and NO in plasma. There was no significant difference among the groups in plasma insulin and glucose levels. The percentage of insulin immunoreactive cells in islets increased significantly in the BPA-500 group. The H-score of the BPA-5 and BPA-50 groups decreased significantly compared to controls. We found that BPA caused oxidative stress and disruption of pancreatic beta-cell function. Therefore, BPA is a risk factor for animal and human health. PMID- 29388446 TI - The Development of a Provincial Food and Nutrition Strategy through Cross-Sector Collaboration. AB - A whole-system perspective is critical in efforts to create a healthy population and a productive, equitable, and sustainable food system. In 2009, the Ontario Collaborative Group on Healthy Eating and Physical Activity undertook a bold initiative to develop a comprehensive provincial strategy encompassing the entire food system. The Ontario Food and Nutrition Strategy was shaped through extensive consultation with diverse stakeholders. This strategy identified strategic directions and priority actions for productive, equitable, and sustainable food systems intended to promote the health and well-being of all Ontarians. Paramount to the strategy is a collaborative governance mechanism allowing for a cross government, multistakeholder coordinated approach to food policy development. Key actors participated in a collective impact process to develop a theory of change and potential governance model. Different models for collaborative work were examined and a governance model for a multistakeholder coordinated provincial mechanism was proposed. Lessons learned from this process will inform others involved in food systems work at the provincial, regional, or local level and may pave the way towards successful inter-sectoral action on priority recommendations geared towards improved nutrition-related and food systems outcomes. PMID- 29388447 TI - Just Sentences: Human rights to enable participation and equity for prisoners and all. AB - Article 19 of the Universal Declaration of Human Rights holds up the right to opinion and expression for all. Just Sentences was a prison-based language literacy pilot project for men, delivered by a speech-language pathologist at Risdon Prison in Tasmania, Australia. The pilot provided input into the various interpretative permutations of "just sentences". It enabled skills of opinion and expression. This commentary takes language and social reciprocity to be privileged drivers of personal agency and pro-social personal freedom. It notes the role of hope as an agent of positive change, including in desistance from crime. It describes the project and shares the reflections of the speech-language pathologist who delivered it. PMID- 29388448 TI - Corrigendum. PMID- 29388449 TI - Lifestyle and self-management determinants of hypertension control in a sample of Australian adults. AB - BACKGROUND: Poor hypertension control can increase the risk of cardiovascular, renal and kidney diseases, and increase the social and economic burden of the disease. METHODS: This study aimed to explore the lifestyle and self-management skills (medication adherence, self-monitoring, self-efficacy) determinants of hypertension control in a sample of hypertensive Australians. In a cross sectional design, a total of 233 hypertensive adults completed a survey. Hypertension control was categorised as good control if hypertensive individuals managed to reduce their blood pressure (BP) < 140/90 mmHg, otherwise it was categorised as poor control. Data were analysed using bivariate analysis and hierarchical logistic regression. RESULTS: 55% of the participants had poor BP control. A significantly higher frequency of poor BP self-monitoring was observed in individuals with poor control compared to their counterparts. Poor self monitoring and a sedentary lifestyle were associated with higher odds of poor control (OR: 5.33, 95% CI: 1.78 - 15.93; p < 0.01, and OR: 4.69, 95% CI: 1.00 - 22.25; p < 0.05, respectively). No significant association was observed between other variables and hypertension control. CONCLUSION: Successful BP control for hypertensive individuals may require interventions and strategies that assist with improving BP self-monitoring skills and increasing physical activity. PMID- 29388450 TI - Effectiveness, immunogenicity and safety of one vs. two-dose varicella vaccination:a meta-analysis. AB - BACKGROUND: Despite high 1-dose vaccination coverage, breakthrough varicella infections still occur. Therefore, 2-dose vaccination is recommended to enhance the immune response to the virus. However, the reported incremental vaccine effectiveness (VE) of 2-dose vaccination varies widely among studies. METHODS: To determine the overall effectiveness, immunogenicity and safety of one vs. two dose varicella vaccination, we searched five databases for articles published during 1995-2017. RESULTS: The incremental VE/efficacy of 2-dose vaccination was 79% (95% confidence interval [CI]: 56%-90%) in randomized controlled trials,63% (95% CI: 36%-79%) in cohort studies and 81% (95% CI: 65%-90%) in case-control studies. Regarding immunogenicity, the pooled standardized mean differences (SMD) of geometric mean titer (GMT) and the pooled relative risk (RR) of seroconversion for 2-dose vs. 1-dose vaccine were 562.44 (95% CI: 471.78-653.10) and 1.03 (95% CI: 1.02-1.04), respectively. Children who received second dose vaccination were at increased risk of grade 3 redness (RR: 4.93, 95% CI: 1.89 - 12.87) and swelling of any intensity (RR: 1.34, 95% CI: 1.08 - 1.66). CONCLUSIONS: Two-dose varicella vaccination resulted in higher levels of immunogenicity and provided superior protection than 1-dose vaccination. Safety profiles showed 2-dose vaccination was well tolerated but the incidence of grade 3 redness and of any intensity was significantly higher. PMID- 29388451 TI - L-carnitine counteracts prepubertal exposure to cisplatin induced impaired sperm in adult rats by preventing germ cell apoptosis. AB - We investigated the possible protective effects of L-carnitine on cisplatin induced prepubertal gonadotoxicity and on adult sperm. Prepubertal 30-day-old male rats were divided randomly into three groups: control (n = 12), cisplatin exposed (n = 16) and carnitine treated after cisplatin exposure (n = 16). Rats in the experimental groups were injected with a single dose of cisplatin. L carnitine was injected 1 h before cisplatin administration and for the following 3 days for the cisplatin + carnitine group. The rats were sacrificed at 31 or 90 days old and their testes were harvested for morphometric and histopathological analysis. Testes of 31-day-old prepubertal rats were examined for germ cell apoptosis using the TUNEL method and for proliferation using PCNA immunostaining. The morphology, motility, quantity and vitality of sperm in epididymal fluid samples of adult 90-day-old rats also were evaluated. L-carnitine treatment reduced testicular damage and the number of TUNEL positive cells significantly, while the number of PCNA positive cells in the cisplatin + carnitine group increased compared to the cisplatin group. During the adult period, epididymal sperm count and viability were improved in rats treated with L-carnitine before prepubertal cisplatin injection. L-carnitine may reduce late testicular and spermatic damage caused by cisplatin administration to prepubertal rats by inducing germ cell proliferation and preventing apoptosis. PMID- 29388452 TI - Different competing risks models for different questions may give similar results in arthroplasty registers in the presence of few events. AB - Background and purpose - In arthroplasty registry studies, the analysis of time to revision is complicated by the competing risk of death. There are no clear guidelines for the choice between the 2 main adjusted analysis methods, cause specific Cox and Fine-Gray regression, for orthopedic data. We investigated whether there are benefits, such as insight into different aspects of progression to revision, to using either 1 or both regression methods in arthroplasty registry studies in general, and specifically when the length of follow-up is short relative to the expected survival of the implants. Patients and methods - Cause-specific Cox regression and Fine-Gray regression were performed on total hip (138,234 hips, 124,560 patients) and knee (139,070 knees, 125,213 patients) replacement data from the Dutch Arthroplasty Register (median follow-up 3.1 years, maximum 8 years), with sex, age, ASA score, diagnosis, and type of fixation as explanatory variables. The similarity of the resulting hazard ratios and confidence intervals was assessed visually and by computing the relative differences of the resulting subdistribution and cause-specific hazard ratios. Results - The outcomes of the cause-specific Cox and Fine-Gray regressions were numerically very close. The largest relative difference between the hazard ratios was 3.5%. Interpretation - The most likely explanation for the similarity is that there are relatively few events (revisions and deaths), due to the short follow up compared with the expected failure-free survival of the hip and knee prostheses. Despite the similarity, we recommend always performing both cause specific Cox and Fine-Gray regression. In this way, both etiology and prediction can be investigated. PMID- 29388453 TI - 53BP1 loss suppresses the radiosensitizing effect of icotinib hydrochloride in colorectal cancer cells. AB - BACKGROUND: This study aimed to investigate the influence of the expression of P53-binding protein 1 (53BP1), a key component in DNA damage repair pathways, on the radiosensitizing effect of icotinib hydrochloride in colorectal cancer and to elucidate the mechanisms underlying this influence. MATERIALS AND METHODS: Real time RT-PCR and Western blotting were performed to verify the gene-knockout effect of 53BP1 small hairpin RNA (ShRNA), and colony formation assay was employed to investigate the influence of 53BP1 downregulation on the radiosensitizing effect of icotinib hydrochloride in HCT116 cells. Cell apoptosis, cell cycle distributions, and histone H2AX (gamma-H2AX) fluorescence foci after 53BP1 knockdown were evaluated. Relative protein expression in the ataxia telangiectasia mutated kinase (ATM)-checkpoint kinase-2 (CHK2)-P53 pathway was measured by Western blot analysis to unravel the molecular mechanisms linking the pathway to the above phenomena. RESULTS: Icotinib hydrochloride increased the radiosensitivity of HCT116 cells; however, this effect was suppressed by the downregulation of 53BP1 expression, a change that inhibited cell apoptosis, increased the percentage of HCT116 cells arrested in S-phase and inhibited the protein expression of key molecules in the ATM-CHK2-P53 apoptotic pathway. CONCLUSION: Our studies confirmed that the loss of 53BP1 serves as a negative regulator of the radiosensitizing effect of icotinib in part by suppressing the ATM-CHK2-P53 apoptotic pathway. PMID- 29388455 TI - Dielectric barrier discharge and jet type plasma surface modifications of hybrid polymeric poly (epsilon-caprolactone)/chitosan scaffolds. AB - In this study, dry air plasma jet and dielectric barrier discharge Ar + O2 or Ar + N2 plasma modifications and their effects on wettability, topography, functionality and biological efficiency of the hybrid polymeric poly (epsilon caprolactone)/chitosan scaffolds were reported. The samples treated with Ar + O2 dielectric barrier discharge plasma (80 sccm O2 flow rate, 3-min treatment) or with dry air plasma jet (15-cm nozzle-sample distance, 13-min treatment) had the closest wettability (49.11 +/- 1.83 and 53.60 +/- 0.95, respectively) to the commercial tissue culture polystyrene used for cell cultivation. Scanning electron microscopy images and X-ray photoelectron spectrometry analysis showed increase in topographical roughness and OH/NH2 functionality, respectively. Increased fluid uptake capacity for the scaffolds treated with Ar + O2 dielectric barrier discharge plasma (73.60% +/- 1.78) and dry air plasma jet (72.48% +/- 0.75) were also noted. Finally, initial cell attachment as well as seven-day cell viability, growth and proliferation performances were found to be significantly better for both plasma treated scaffolds than for untreated scaffolds. PMID- 29388454 TI - Obesity, acute kidney injury and mortality in patients with sepsis: a cohort analysis. AB - Although the prognostic effect of obesity has been studied in critically ill patients its impact on outcomes of septic patients and its role as a risk factor for acute kidney injury (AKI) is not consensual. We aimed to analyze the impact of obesity on the occurrence of AKI and on in-hospital mortality in a cohort of critically ill septic patients. This study is retrospective including 456 adult patients with sepsis admitted to the Division of Intensive Medicine of the Centro Hospitalar Lisboa Norte (Lisbon, Portugal) between January 2008 and December 2014. Obesity was defined as a body mass index of 30 kg/m2 or higher. The Kidney Disease Improving Global Outcomes classification was used to diagnose and classify patients developing AKI. AKI occurred in 87.5% of patients (19.5% with stage 1, 22.6% with stage 2 and 45.4% with stage 3). Obese patients developed AKI more frequently than non-obese patients (92.8% versus 85.5%, p = .035; unadjusted OR 2.2 (95% CI: 1.04-4.6), p = .039; adjusted OR 2.31 (95% CI: 1.07-5.02), p = .034). The percentage of obese patients, however, did not differ between AKI stages (stage 1, 25.1%; stage 2, 28.6%; stage 3, 15.4%; p = .145). There was no association between obesity and mortality (p = .739). Of note, when comparing AKI patients with or without obesity in terms of in-hospital mortality there were also no significant differences between those groups (38.4% versus 38.4%, p = .998). Obesity was associated with the occurrence of AKI in critically ill patients with sepsis; however, it was not associated with in-hospital mortality. PMID- 29388457 TI - Avoidable 30-day mortality analysis and failure to rescue in dysvascular lower extremity amputees. AB - Background and purpose - An enhanced treatment program may decrease 30-day mortality below 20% after lower extremity amputations (LEA). The potential and limitations for further reduction are unknown. We analyzed postoperative causes of 30-day mortality, and assessed failure to rescue (FTR) rate in LEA patients who followed an enhanced treatment program. Patients and methods - Medical charts of 195 primary LEA procedures were reviewed independently by 3 of the authors, and deaths during hospitalization following amputation were classified according to consensus. Results - 31 patients died within 30 days after surgery. 4 deaths were classified as "definitely unavoidable," 4 as "probably unavoidable," and 23 as "FTR." Patients who died had a higher incidence of sepsis, pneumonia, and acute myocardial infarction compared with those alive. A log binominal regression analysis adjusted for age, sex, ASA score, diabetes, nursing home admission, transfemoral amputation (TFA), and BMI showed that the risk of 30-day mortality was increased for TFA (RR =2.3, 95% CI 1.1-4.8) and for patients with diabetes (RR =2.7, 95% CI 1.3-5.6). The FTR rate (patients with 30-day mortality/all patients with a severe postoperative complication) was 30%. Of the FTR deaths, 20 at some point had active lifesaving care curtailed. Interpretation - Future initiatives should be directed at enhanced sepsis and pneumonia prophylactic actions, in addition to close monitoring of hemodynamics in anemic patients, with the potential to further reduce morbidity and mortality rates. PMID- 29388456 TI - Advances in liquid biopsy on-chip for cancer management: Technologies, biomarkers, and clinical analysis. AB - Liquid biopsy, as a minimally invasive method of gleaning insight into the dynamics of diseases through a patient fluid sample, has been growing in popularity for cancer diagnosis, prognosis, and monitoring. While many technologies have been developed and validated in research laboratories, there has also been a push to expand these technologies into other clinical settings and as point of care devices. In this article, we discuss and evaluate microchip based technologies for circulating tumor cell (CTC), exosome, and circulating tumor nucleic acid (ctNA) capture, detection, and analysis. Such integrated systems streamline otherwise multiple-step, manual operations to get a sample-to answer quantitation. In addition, analysis of disease biomarkers is suited to point of care settings because of ease of use, low consumption of sample and reagents, and high throughput. We also cover the basics of biomarkers and their detection in biological fluid samples suitable for liquid biopsy on-chip. We focus on emerging technologies that process a small patient sample with high spatial-temporal resolution and derive clinically meaningful results through on chip biomarker sensing and downstream molecular analysis in a simple workflow. This critical review is meant as a resource for those interested in developing technologies for capture, detection, and analysis platforms for liquid biopsy in a variety of settings. PMID- 29388458 TI - Temporal trends in hip fracture incidence, mortality, and morbidity in Denmark from 1999 to 2012. AB - Background and purpose - While development in hip fracture incidence and mortality is well examined, none has yet looked at the temporal trends regarding prevalence of co-morbidities. Therefore we investigated changes in incidence of first hip fracture, co-morbidity prevalence, 30 day- and 1-year mortality in hip fracture patients in the Danish population during the period 1999 to 2012. Patients and methods - Patients >18 years admitted with a fractured hip in Denmark between 1996 and 2012 were identified with data for the period 1999-2012 being analyzed regarding prevalence of co-morbidities, incidence, and mortality. Results - 122,923 patients were identified. Incidence in the whole population declined but sex-specific analysis showed no changes for men. For the whole study population, 30-day and 1-year mortality remained unchanged. Age at time of first hip fracture also remained unchanged. Of the included co-morbidities a decrease in prevalence of malignancy and dementia in women was found while there was an increase in the prevalence of all remaining co-morbidities, except hemi- or paraplegia for both sexes, rheumatic diseases for women, and for men diabetes with complications, myocardial infarction, AIDS/HIV, and malignancy. Interpretation - While hip fracture incidence declined for women it was unchanged for men; likewise, 30-day and 1-year mortality rates together with age at first fracture remained unchanged. When these results are compared with the relatively large increase in the prevalence of co-morbidities, it does not seem likely that the increased disease burden is affecting either the incidence or the mortality. PMID- 29388459 TI - Letter to the Editor: Combined effects of hypoxia and heat: importance of hypoxic dose. PMID- 29388460 TI - Reply to "Letter to the Editor: Combined effects of hypoxia and heat: importance of hypoxic dose". PMID- 29388461 TI - The infraclavicular approach for Paget-Schroetter syndrome. AB - Introduction Paget-Schroetter syndrome is a rare effort thrombosis of the axillary-subclavian vein, mainly occurring in young male patients. Current management involves immediate catheter directed thrombolysis, followed by surgical decompression of the subclavian vein. This has been invariably performed using a transaxillary or supraclavicular approach. However, the subclavian vein crosses the first rib anteriorly just behind the manubrium and can also be accessed via an infraclavicular incision. Methods MEDLINE(r) and EmbaseTM were searched for all studies on outcomes in patients undergoing infraclavicular first rib resection for treatment of Paget-Schroetter syndrome. Measured outcomes included freedom from reintervention, secondary patency and symptom resolution. Studies on neurogenic, arterial and iatrogenic venous thoracic outlet syndrome were not included. Findings Six studies (involving 268 patients) were eligible. The overall secondary venous patency rate was 98.5%. There was freedom from reintervention in 89.9% of cases and among those patients with reocclusion, 84.0% had chronic thrombosis (symptom duration >14 days), with 76.2% having a venous segment stenosis of >2cm. Only 3 of the 27 patients remained occluded despite reintervention. The infraclavicular approach provides excellent exposure to the subclavian vein and allows reconstruction when required. Moreover, this approach enables complete resection of the extrinsic compression that precipitated the initial thrombotic event, with excellent long-term patency rates. In conclusion, the infraclavicular route may have significant advantages compared with the transaxillary or supraclavicular approaches for successful and durable treatment of Paget-Schroetter syndrome. PMID- 29388463 TI - Endogenous markers for kidney function in children: a review. AB - Although glomerular filtration rate (GFR) in children can be measured using a gold-standard technique following injection of an exogenous marker, this invasive and cumbersome technique is not widely available and GFR is commonly estimated using serum levels of endogenous markers. Creatinine, urea, cystatin C, beta trace protein, and beta-2 microglobulin are well-established endogenous markers of kidney function. These markers differ in site of production and effects of diet and medication, as well as renal-tubular handling and extra-renal elimination. For each marker, different methods are available for measurement. Importantly, the measurements of creatinine and cystatin C have recently been standardized with the introduction of international reference standards. In order to allow estimation of GFR from serum marker concentrations, different equations for estimated GFR (eGFR) have been developed in children, using simple or more complex regression strategies with gold standard GFR measurements as a dependent variable. As a rule, estimation strategies relying on more than one marker - either by calculating the average of single parameter equations or by using more complex equations incorporating several parameters - outperform eGFR estimations using only a single marker. This in-depth review will discuss the physiology, measurement and clinical use of creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin in children. It will also address the generation of eGFR equations in children and provide an overview of currently available eGFR equations for the pediatric age group. PMID- 29388462 TI - Safety and tolerability of new-generation anti-obesity medications: a narrative review. AB - The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit. PMID- 29388464 TI - Unraveling the role of motoneuron autophagy in ALS. AB - In recent years, the role of autophagy in the pathogenesis of most neurodegenerative diseases has transitioned into a limbo of protective or detrimental effects. Genetic evidence indicates that mutations in autophagy regulatory genes can result in the occurrence of amyotrophic lateral sclerosis (ALS), suggesting a physiological role of the pathway to motoneuron function. However, experimental manipulation of autophagy in ALS models led to conflicting results depending on the intervention strategy and the disease model used. A recent work by the Maniatis group systematically explored the role of cell specific autophagy in motoneurons at different disease stages, revealing surprising and unexpected findings. Autophagy activity at early stages may contribute to maintaining the structure and function of neuromuscular junctions, whereas at later steps of the disease it has a pathogenic activity possibly involving cell-nonautonomous mechanisms related to glial activation. This new study adds a new layer of complexity in the field, suggesting an intricate interplay between proteostasis alterations, the time-differential function of autophagy in neurons, and muscle innervation in ALS. PMID- 29388465 TI - Understanding the Impact of Fibromyalgia on Men: Findings From a Nationwide Survey. AB - Fibromyalgia (FM) is a serious condition that affects approximately four million people in the United States, and is underdiagnosed in men. The objective of this study was to understand this phenomenon by examining multiple impacts of fibromyalgia on men in regard to interactions in society and the U.S. health system. A qualitative survey was administered to 1,163 respondents both online and in-person in Tennessee, Virginia, Maryland, and Washington, DC. Thematic analyses of the survey responses suggest that men with FM have negative experiences with (1) physical and mental health, (2) quality of life, (3) relationships, and (4) careers as a result of FM. Interactions with health-care providers were deterred by (1) potential for misdiagnosis or dismissal of symptoms, (2) stigma of having a condition primarily affecting women, (3) differences in treatment of men and women with FM, and (4) need for health education resources. These findings dictate a need to improve communication between health-care providers and male FM patients. PMID- 29388466 TI - Reactive oxygen species induced Ca2+ influx via TRPV4 and microvascular endothelial dysfunction in the SU5416/hypoxia model of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevations in pulmonary arterial pressure, in part due to formation of occlusive lesions in the distal arterioles of the lung. These complex lesions may comprise multiple cell types, including endothelial cells (ECs). To better understand the molecular mechanisms underlying EC dysfunction in PAH, lung microvascular endothelial cells (MVECs) were isolated from normoxic rats (N-MVECs) and rats subjected to SU5416 plus hypoxia (SuHx), an experimental model of PAH. Compared with N-MVECs, MVECs isolated from SuHx rats (SuHx-MVECs) appeared larger and more spindle shaped morphologically and expressed canonical smooth muscle cell markers smooth muscle-specific alpha-actin and myosin heavy chain in addition to endothelial markers such as Griffonia simplicifolia and von Willebrand factor. SuHx-MVEC mitochondria were dysfunctional, as evidenced by increased fragmentation/fission, decreased oxidative phosphorylation, and increased reactive oxygen species (ROS) production. Functionally, SuHx-MVECs exhibited increased basal levels of intracellular calcium concentration ([Ca2+]i) and enhanced migratory and proliferative capacity. Treatment with global (TEMPOL) or mitochondria-specific (MitoQ) antioxidants decreased ROS levels and basal [Ca2]i in SuHx-MVECs. TEMPOL and MitoQ also decreased migration and proliferation in SuHx-MVECs. Additionally, inhibition of ROS-induced Ca2+ entry via pharmacologic blockade of transient receptor potential vanilloid-4 (TRPV4) attenuated [Ca2]i, migration, and proliferation. These findings suggest a role for mitochondrial ROS induced Ca2+ influx via TRPV4 in promoting abnormal migration and proliferation in MVECs in this PAH model. PMID- 29388468 TI - PLCgamma1-PKCepsilon-IP3R1 signaling plays an important role in hypoxia-induced calcium response in pulmonary artery smooth muscle cells. AB - Hypoxia-induced pulmonary vasoconstriction (HPV) is attributed to an increase in intracellular Ca2+ concentration ([Ca2+]i) in pulmonary artery smooth muscle cells (PASMCs). We have reported that phospholipase C-gamma1 (PLCgamma1) plays a significant role in the hypoxia-induced increase in [Ca2+]i in PASMCs and attendant HPV. In this study, we intended to determine molecular mechanisms for hypoxic Ca2+ and contractile responses in PASMCs. Our data reveal that hypoxic vasoconstriction occurs in pulmonary arteries, but not in mesenteric arteries. Hypoxia caused a large increase in [Ca2+]i in PASMCs, which is diminished by the PLC inhibitor U73122 and not by its inactive analog U73433 . Hypoxia augments PLCgamma1-dependent inositol 1,4,5-trisphosphate (IP3) generation. Exogenous ROS, hydrogen peroxide (H2O2), increases PLCgamma1 phosphorylation at tyrosine-783 and IP3 production. IP3 receptor-1 (IP3R1) knock-down remarkably diminishes hypoxia- or H2O2-induced increase in [Ca2+]i. Hypoxia or H2O2 increases the activity of IP3Rs, which is significantly reduced in protein kinase C-epsilon (PKCepsilon) knockout PASMCs. A higher PLCgamma1 expression, activity, and basal [Ca2+]i are found in PASMCs, but not in mesenteric artery smooth muscle cells from mice exposed to chronic hypoxia (CH) for 21 days. CH enhances H2O2- and ATP-induced increase in [Ca2+]i in PASMCs and PLC-dependent, norepinephrine-evoked pulmonary vasoconstriction. In conclusion, acute hypoxia uniquely causes ROS-dependent PLCgamma1 activation, IP3 production, PKCepsilon activation, IP3R1 opening, Ca2+ release, and contraction in mouse PASMCs; CH enhances PASM PLCgamma1 expression, activity, and function, playing an essential role in pulmonary hypertension in mice. PMID- 29388467 TI - Emerging therapeutics in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a progressive and often fatal illness presenting with nonspecific symptoms of dyspnea, lower extremity edema, and exercise intolerance. Pathologically, endothelial dysfunction leads to abnormal intimal and smooth muscle proliferation along with reduced apoptosis, resulting in increased pulmonary vascular resistance and elevated pulmonary pressures. PH is subdivided into five World Health Organization groups based on the disease pathology and specific cause. While there are Food and Drug Administration approved medications for the treatment of pulmonary arterial hypertension (PAH; Group 1 PH), as well as for chronic thromboembolic PH (Group 4 PH), the morbidity and mortality remain high. Moreover, there are no approved therapies for other forms of PH (Groups 2, 3, and 5) at present. New research has identified molecular targets that mediate vasodilation, anti-inflammatory, and antifibrotic changes within the pulmonary vasculature. Given that PAH is the most commonly studied form of PH worldwide and because recent studies have led to better mechanistic understanding of this devastating disease, in this review we attempt to provide an updated overview of new therapeutic approaches under investigation for the treatment of PH, with a particular focus on PAH, as well as to offer guidelines for future investigations. PMID- 29388469 TI - Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice. AB - Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown. To address this gap in our understanding of Akap1, we exposed wild-type ( wt) and Akap1-/- mice to 100% oxygen for 48 h, a time point associated with lung damage in the murine model of ALI. We found that under hyperoxia, Akap1-/- mice display increased levels of proinflammatory cytokines, immune cell infiltration, and protein leakage in lungs, as well as increased alveolar capillary permeability compared with wt controls. Further analysis revealed that Akap1 deletion enhances lung NF-kappaB p65 activity as assessed by immunoblotting and DNA-binding assay and mitochondrial autophagy-related markers, PINK1 and Parkin. Ultrastructural analysis using electron microscopy revealed that Akap1 deletion was associated with remarkably aberrant mitochondria and lamellar bodies in type II alveolar epithelial cells. Taken together, these results demonstrate that Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice. PMID- 29388471 TI - Person perception from changing emotional expressions: primacy, recency, or averaging effect? AB - Dynamic changes in emotional expressions are a valuable source of information in social interactions. As the expressive behaviour of a person changes, the inferences drawn from the behaviour may also change. Here, we test the possibility that dynamic changes in emotional expressions affect person perception in terms of stable trait attributions. Across three experiments, we examined perceivers' inferences about others' personality traits from changing emotional expressions. Expressions changed from one emotion ("start emotion") to another emotion ("end emotion"), allowing us to disentangle potential primacy, recency, and averaging effects. Drawing on three influential models of person perception, we examined perceptions of dominance and affiliation (Experiment 1a), competence and warmth (Experiment 1b), and dominance and trustworthiness (Experiment 2). A strong recency effect was consistently found across all trait judgments, that is, the end emotion of dynamic expressions had a strong impact on trait ratings. Evidence for a primacy effect was also observed (i.e. the information of start emotions was integrated), but less pronounced, and only for trait ratings relating to affiliation, warmth, and trustworthiness. Taken together, these findings suggest that, when making trait judgements about others, observers weigh the most recently displayed emotion in dynamic expressions more heavily than the preceding emotion. PMID- 29388470 TI - Safety and efficacy of ipragliflozin in elderly versus non-elderly Japanese patients with type 2 diabetes mellitus: a subgroup analysis of the STELLA-LONG TERM study. AB - BACKGROUND: This subgroup analysis of STELLA-LONG TERM interim data explored the long-term safety and efficacy of ipragliflozin in non-elderly vs. elderly Japanese type 2 diabetes mellitus (T2DM) patients. RESEARCH DESIGN AND METHODS: STELLA-LONG TERM is an ongoing 3-year prospective surveillance study of Japanese T2DM patients receiving ipragliflozin 50 mg once daily. In this subgroup analysis, patient characteristics, laboratory variables, and adverse drug reactions (ADRs) were compared between non-elderly (<65 years) and elderly (>=65 years) patients. RESULTS: Non-elderly patients had significantly higher body mass index and low-density lipoprotein cholesterol than elderly patients (P < 0.001). The proportion of patients with hemoglobin A1c (HbA1c) <8.0% was significantly higher among elderly patients (P < 0.001). HbA1c, fasting plasma glucose, and body weight significantly decreased from baseline to 3 and 12 months in both groups (all P < 0.05 vs. baseline). The ADR incidence was 10.83% vs. 10.42% in non-elderly and elderly patients. The incidence of skin complications was 0.98% vs. 1.65% and that of renal disorder was 0.47% vs. 0.95% in non-elderly and elderly patients (both P = 0.003). CONCLUSIONS: Ipragliflozin was effective in non-elderly and elderly Japanese T2DM patients in a real-world clinical setting. The incidence of renal disorder and skin complications was significantly higher in elderly vs. non-elderly patients. PMID- 29388472 TI - Empathic accuracy: age differences from adolescence into middle adulthood. AB - This study investigated age differences in empathic accuracy, the ability to correctly perceive others' emotions, in a sample of 151 boys and men from three age groups: adolescents (Mage = 16 years, SD = 1.04), young adults (Mage = 29 years, SD = 2.78), and middle-aged adults (Mage = 50 years, SD = 3.07). All participants viewed nine newly developed film clips, each depicting a boy or a man reliving one of three emotions (anger, sadness, or happiness), while talking about an autobiographical memory. Adolescents and middle-aged men were less accurate than young men, and these age differences were associated with parallel age differences in fluid-mechanical abilities. In addition, age differences in vocabulary, one indicator of crystallized-pragmatic intelligence, were associated with age differences in empathic accuracy in adolescent and young, but not middle aged, men. Within the limitations of cross-sectional data, this study provides evidence for the idea that empathic accuracy is an effortful task that requires cognitive resources and, thus, may show a normative increase until young adulthood followed by periods of stability and decline in subsequent decades. PMID- 29388473 TI - Normative data for the Rey Auditory Verbal Learning Test in the older French Quebec population. AB - OBJECTIVE: The aim of this study was to establish normative data for the Rey Auditory Verbal Learning Test, a test assessing verbal episodic memory, in the older French-Quebec population. METHOD: A total of 432 French-speaking participants aged between 55 and 93 years old, from the Province of Quebec (Canada), were included in the study. Using multiple regression analyses, normative data were developed for five variable of interest, namely scores on trial 1, sum of trials 1 to 5, interference list B, immediate recall of list A, and delayed recall of list A. RESULTS: Results showed that age, education, and sex were associated with performance on all variables. Equations to calculate the expected score for a participant based on sex, age, and education level as well as the Z score were developed. CONCLUSION: This study provides clinicians with normative data that take into account the participants' sociodemographic characteristics, thus giving a more accurate interpretation of the results. PMID- 29388474 TI - Behind the potential evolution towards prion resistant species. AB - Historically, the observation of naturally occurring cases of prion disease led to the classification of different susceptibility grades and to the designation of prion resistant species. However, the development of highly efficient in vitro prion propagation systems and the generation of ad hoc transgenic models allowed determining that leporidae and equidae families have been erroneously considered resistant to prion infection. On the contrary, similar approaches revealed an unexpected high level of resistance of the canidae family. In PLoS Pathogens [ 1 ], we describe experiments directed toward elucidating which are the determinants of the alleged prion resistance of this family. Studies based on the sequence of the canine prion protein coupled with structural in silico analysis identified a key residue probably implicated in this resistance. Cell and brain-based PMCA highlighted that the presence of aspartic or glutamic acid at codon 163 of the canid PrP, strongly inhibits prion replication in vitro. Transgenic animals carrying this substitution in mouse PrP were resistant to prion infection after intracerebral challenge with different mouse prion strains. The confirmation of the importance of this substitution and its exclusivity in this family, suggests it could have been evolutionarily favored, due to their diet based on carrion and small ruminants. PMID- 29388475 TI - Massive weight loss following deep brain stimulation of the nucleus accumbens in a depressed woman. AB - Obese individuals share behavioral characteristics with drug/alcohol addicts as well as obsessive compulsive disease. Deep brain stimulation (DBS) has been used successfully in these disorders, thus warranting an evaluation in obesity. A woman with treatment-resistant depression as well as severe obesity was selected for DBS of the nucleus accumbens (NAcc) bilaterally with depression being the primary and obesity being the secondary target of treatment. Compared to earlier bariatric surgery, the patient showed accelerated weight loss after DBS. Also, depression was significantly reduced. The current case suggests that DBS of the NAcc warrants further evaluation in patients unresponsive to other treatments. PMID- 29388476 TI - Neurotoxic, cytotoxic, apoptotic and antiproliferative effects of some marine algae extracts on the NA2B cell line. AB - Oxidative stress contributes to cancer pathologies and to apoptosis. Marine algae exhibit cytotoxic, antiproliferative and apoptotic effects; their metabolites have been used to treat many types of cancer. We investigated in culture extracts of Petalonia fascia, Jania longifurca and Halimeda tuna to determine their effects on mouse neuroblastoma cell line, NA2B. NA2B cells were treated with algae extracts, and the survival and proliferation of NA2B cells were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of algae extracts on oxidative stress in NA2B cells also were investigated using nitric oxide synthase (NOS) immunocytochemistry and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling. We observed significant neurite inhibition with moderate damage by the neurotoxicity-screening test (NST) at IC50 dilutions of the extracts. MTT demonstrated that J. longifurca extracts were more toxic than P. fascia and H. tuna extracts. We found an increase of endothelial and inducible NOS immunostaining for oxidative stress and TUNEL analysis revealed increased apoptosis after application of extract. Our findings suggest that the algae we tested may have potential use for treatment of cancer. PMID- 29388478 TI - Yoruba culture and the resilience of HIV-positive adolescent girls in Nigeria. AB - Although there is a growing body of research exploring the influence of culture on the resilience of African youth, few studies have examined how culture constrains or enables resilience among HIV-positive adolescent girls from the perspective of the young women themselves. This paper reports on the findings from a qualitative study of five purposively selected girls living with HIV in Ibadan, Nigeria. By analysing data drawn mainly from interviews and observations, we explored how cultural influences promote or limit resilience in participants. Social-ecological resilience theory was used to document and interpret the findings. While some cultural values and perceptions enable resilience, others constrain participants' resilience trajectories. However, the girls were able to navigate through these constraints using their cultural identities and coping strategies, such as future dreams, emotional and physical resources linked to spirituality and networks of friends and families. Findings have implications for policymakers, researchers and programmers in strengthening the health and resilience of young people in the face of HIV. PMID- 29388477 TI - Aflatoxin B1, ochratoxin A and zearalenone in sorghum grains marketed in Tunisia. AB - A total of 64 samples of sorghum (37 Tunisian sorghum samples and 27 Egyptian sorghum samples) were collected during 2011-2012 from markets in Tunisia. Samples were analysed for contamination with aflatoxin B1, ochratoxin A and zearalenone by High-Performance Liquid Chromatography Coupled with Fluorescence Detection (HPLC-FLD). Aflatoxin B1 was found in 38 samples in the range 0.03-31.7 ug kg-1. Ochratoxin A was detected in 24 samples with concentrations ranging from 1.04 to 27.8 ug kg-1. Zearalenone was detected in 21 samples and the concentration varied between 3.7 and 64.5 ug kg-1. ANOVA analysis of the influence of the country of origin on the incidence and concentration of mycotoxins in the samples studied showed no significant difference (P > 0.05) between the two batches of samples for each of the three mycotoxins studied. The studied mycotoxins contaminate sorghum and may also co-exist because of the diversity of the mycobiota in this cereal. PMID- 29388479 TI - Matrix proteins of enveloped viruses: a case study of Influenza A virus M1 protein. AB - Influenza A virus, a member of the Orthomyxoviridae family of enveloped viruses, is one of the human and animal top killers, and its structure and components are therefore extensively studied during the last decades. The most abundant component, M1 matrix protein, forms a matrix layer (scaffold) under the viral lipid envelope, and the functional roles as well as structural peculiarities of the M1 protein are still under heavy debate. Despite multiple attempts of crystallization, no high resolution structure is available for the full length M1 of Influenza A virus. The likely reason for the difficulties lies in the intrinsic disorder of the M1 C-terminal part preventing diffraction quality crystals to be grown. Alternative structural methods including synchrotron small angle X-ray scattering (SAXS), atomic force microscopy, cryo-electron microscopy/tomography are therefore widely applied to understand the structure of M1, its self-association and interactions with the lipid membrane and the viral nucleocapsid. These methods reveal striking similarities in the behavior of M1 and matrix proteins of other enveloped RNA viruses, with the differences accompanied by the specific features of the viral lifecycles, thus suggesting common interaction principles and, possibly, common evolutional ancestors. The structural information on the Influenza A virus M1 protein obtained to the date strongly suggests that the intrinsic disorder in the C-terminal domain has important functional implications. PMID- 29388480 TI - BMI Health Report Cards: Parents' Perceptions and Reactions. AB - In 2003, Arkansas became the first state to require body mass index (BMI) testing in public schools to raise awareness of the growing obesity epidemic among children and adolescents. Limited information exists regarding the effectiveness of school-based BMI screening programs. The purpose of this study was to determine if BMI health report cards affected parents' knowledge or actions regarding their child's health and to determine the accuracy of parents' perceptions of their child as underweight, normal weight, or overweight according to their child's BMI. A questionnaire was developed with the help of physical educators, pediatricians, and exercise scientists to determine parents' perceptions and behaviors regarding BMI report cards. The questionnaire was distributed to parents/guardians of children who sought medical care at two pediatrician's offices in Arkansas. Based on responses to survey questions, parents are not making changes to their child's diet and exercise habits if their child is classified as "at risk" or "overweight." However, parents did report that BMI health report cards are influencing their knowledge about their child's health. The majority of parents in the study (approximately 66%) did not accurately perceive their child's BMI category. PMID- 29388482 TI - A Grounded Theory of the Process of Spiritual Change Among Homicide Survivors. AB - Grounded theory was used to generate a mid-range theory of the process of spiritual change in the lives of survivors of homicide victims. Theoretical sampling guided the selection of 30 participants from a larger study of spiritual change after homicide ( N = 112). Individual interviews were analyzed using a four-step sequence of line-by-line, focused, axial, and selective coding. Analysis generated a closed theory consisting of three fluids, consecutive but nonlinear stages. Each stage consisted of an overarching process and a state of being in the world: (a) Disintegrating: living in a state of shock; (b) Reckoning: living in a state of stagnation; (c) Recreating and reintegrating the self: living in a state of renewal. Movement through the stages was fueled by processes of spiritual connection that yielded changes that permeated the theory. Findings can be used to help practitioners address the processes that drive spiritual change in the lives of homicide survivors. PMID- 29388481 TI - Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) which we and others have reported to mediate suppression of anti-tumor immune responses. AIM: In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients. METHODS: Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as Lin-HLA-DR-CD33+CD11b+; and Treg cells were defined as CD4+CD25+CD127-/low. RESULTS: Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and Tregs as compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers of MDSCs and Treg cells, respectively as compared to early diagnosed patients (i.e., before chemotherapy). After induction of chemotherapy, the numbers of MDSCs and Treg cells showed higher increases and decreases, respectively as compared to the numbers in patients during chemotherapy. CONCLUSION: Our results indicate that B-ALL patients harbor high numbers of both MDSCs and Tregs cells. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger number of B-ALL patients at different treatment stages. PMID- 29388484 TI - Caralluma fimbriata and metformin protection of rat pancreas from high fat diet induced oxidative stress. AB - A high fat diet promotes oxidative stress, which contributes to the development of pancreatic fibrosis. We compared the protective effects of a hydroalcoholic extract of Caralluma fimbriata (CFE) to metformin (Met) in the pancreas of Wistar rats fed a high fat diet. The experimental animals were divided into five groups: control (C), treated with CFE (C + CFE), treated with high fat diet (HFD), high fat diet treated with CFE (HFD + CFE), and high fat diet treated with metformin (Met) (HFD + Met). CFE was administered orally to groups C + CFE and HFD + CFE rats for 90 days. Met was given to the HFD + Met group. After 90 days, oxidative stress markers in the pancreas including reduced glutathione (GSH), lipid oxidation (LO), protein oxidation (PO), and activities of antioxidant and polyol pathway enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH) were assayed and tissue histology was examined. Establishment of oxidative stress in high fat diet fed rats was verified by elevated LO and PO, decreased GSH, decreased activities of antioxidants and increased activities of polyol pathway enzymes. Oxidative stress was prevented in HFD + CFE and HFD + Met groups. Group C + CFE exhibited improved antioxidant status compared to group C. CFE treatment prevented high fat diet induced acinar cell degeneration, necrosis, edema and hemorrhage. CFE could be used as adjuvant therapy for preventing or managing high fat diet induced pancreatic damage. PMID- 29388485 TI - Treatment Trends, Complications, and Effects of Comorbidities on Distal Radius Fractures. AB - BACKGROUND: Distal radius fractures (DRFs) are the most common upper extremity fractures in adults. This study seeks to elucidate the impact age, fracture type, and patient comorbidities have on the current treatment of DRFs and risk of complications. We hypothesized that comorbidities rather than age would relate to the risk of complications in the treatment of DRFs. METHODS: A retrospective review of data was performed for patients treated between 2007 and 2014 using Truven Health MarketScan Research Databases. Patients who sustained a DRF were separated into "closed" versus "open" treatment groups, and the association between patient demographics, treatment type, and comorbidities with complication rates was analyzed, along with the trend of treatment modalities throughout the study time interval. RESULTS: In total, 155 353 DRFs were identified; closed treatment predominated in all age groups with the highest percentage of open treatment occurring in the 50- to 59-year age group. Between 2007 and 2014, there was an increase in the rate of open reduction and internal fixation (ORIF) in all age groups <90 with the largest increase (11%) occurring in the 70- to 79-year age group. Higher complication rates were observed in the open treatment group in all ages <90 years with a trend toward decreasing complication rates as age increased. Comorbidities were more strongly associated with the risk of developing complications than age. CONCLUSIONS: Closed treatment of DRFs remains the predominant treatment method among all age groups, but DRFs are increasingly being treated with ORIF. Emphasis on the patients' comorbidities rather than chronological age should be considered in the treatment decision-making process of elderly patients with DRFs. PMID- 29388486 TI - Distal Radius Allograft Reconstruction Utilizing a Step-Cut Technique After En Bloc Tumor Resection. AB - BACKGROUND: En bloc resection of the distal radius is a common treatment for advanced and recurrent giant cell tumors and less commonly for sarcoma. Various reconstructive options exist, including ulnar transposition, osteoarticular autograft and allograft, and allograft arthrodesis. We present a technique of reconstruction using a distal radius bulk allograft with a step-cut to allow for precise restoration of proper length and to promote bony union. METHODS: Preoperative templating is performed with affected and contralateral radiographs to assess the size of the expected bony defect, location of the step-cut, and the optimal size of the distal radius allograft required. A standard dorsal approach to the distal radius is utilized, and the tumor is resected. A proximal row carpectomy is performed, and the plate/allograft construct is applied to the remaining host bone. Iliac crest bone graft is harvested and introduced at the graft-bone interface and radiocarpal arthrodesis sites. RESULTS: We have previously reported outstanding union rates with the step-cut technique compared with a standard transverse cut. CONCLUSIONS: The technique described provides reproducible union and stabilization of the wrist and forearm with adequate function following en bloc resection of the distal radius for tumor. PMID- 29388487 TI - Direct Cost Comparison of Open Carpal Tunnel Release in Different Venues. AB - BACKGROUND: The increased efficiency and cost savings have led many surgeons to move their practice away from the traditional operating room (OR) or outpatient surgery center (OSC) and into the clinic setting. With the cost of health care continuing to rise, the venue with the lowest cost should be utilized. We performed a direct cost analysis of a single surgeon performing an open carpal tunnel release in the OR, OSC, and clinic. METHODS: Four treatment groups were prospectively studied: the hospital OR with monitored anesthesia care (OR-MAC), OSC with MAC (OSC-MAC), OSC with local anesthesia (OSC-local), and clinic with local anesthesia (clinic). To determine direct costs, a detailed inventory was recorded including the weight and disposal of medical waste. Indirect costs were not included. RESULTS: Five cases in each treatment group were prospectively recorded. Average direct costs were OR ($213.75), OSC-MAC ($102.79), OSC-local ($55.66), and clinic ($31.71). The average weight of surgical waste, in descending order, was the OR (4.78 kg), OSC-MAC (2.78 kg), OSC-local (2.6 kg), and the clinic (0.65 kg). Using analysis of variance, the clinic's direct costs and surgical waste were significantly less than any other setting ( P < .005). CONCLUSIONS: The direct costs of an open carpal tunnel release were nearly 2 times more expensive in the OSC compared with the clinic and almost 7 times more expensive in the OR. Open carpal tunnel release is more cost-effective and generates less medical waste when performed in the clinic versus all other surgical venues. PMID- 29388488 TI - Feasibility of biogas and energy generation from poultry manure in Brazil. AB - The aim of the present study is to experimentally measure the volume and composition of biogas produced from the anaerobic biodigestion of laying-hen manure from poultry farms in Itanhandu-MG, Brazil, so that the biogas can be used to generate energy. Two experiments (E1 and E2) were used to characterise the biogas quantities and compositions at room temperature and at a controlled temperature of 36 degrees C, respectively. The biogas production and calculated net power from the exploitation of biogas energy were compared with the results obtained from methods proposed by the Environmental Company of the State of Sao Paulo (CETESB, an acronym in Portuguese) using the 'Biogas: Generation and energy use - effluent and rural waste' software 1.0, Brasilia-DF, Brazil. In addition, after a time equal to the hydraulic retention time subsequent to biodigester loading, the parameters were analysed and correlated with the organic matter content in the substrates. The effluents were subsequently compared with verify the degree of degradability. The biogas volumes were estimated to be 0.143 m3 kg VTS-1 for E1 and 0.283 m3 kg VTS-1 for E2. If the poultry farm considered in this case study uses manure to generate energy, then the estimated energy generation based on the data from experiments E1 and E2 will result in net energy values of 683 MW h y-1 and 27,160 MW h y-1, given 620 MW h y-1 for sludge heating in E2. The energy production values from the simulations of the E1 and E2 experiments did not demonstrate economic viability under the studied conditions. PMID- 29388489 TI - Neighborhood Contexts and Marijuana Use Among Urban Dwelling Emerging Adult Men. AB - Neighborhoods are key socio-environmental contexts for marijuana use during emerging adulthood. This study examined the relationships between neighborhood context, traditional masculine norms (status, toughness, and anti-femininity), and marijuana use among 119 majority African American emerging adult men in a small urban community. Poisson regression models were used to determine the associations between neighborhood problems, social cohesion, and marijuana use. Moderator effects were examined to determine if masculinities modified these associations. Neighborhood problems and social cohesion were positively associated with marijuana use. Men who had a lower endorsement of some traditional masculine norms had greater marijuana use compared to men with a higher endorsement of these norms. These findings have implications for intervention strategies and policies. PMID- 29388490 TI - The small GTPase RAB37 functions as an organizer for autophagosome biogenesis. AB - Macroautophagy/autophagy is a catabolic process that is essential for cellular homeostasis. How autophagosomal vesicle forms in a spatio-temporally regulated manner remains elusive. Our recent study revealed that small GTPase, RAB37 (RAB37, member RAS oncogene family), functions as a key organizer of autophagosomal membrane biogenesis. RAB37 interacts with ATG5 (autophagy related 5) and promotes autophagosome formation by modulating ATG12-ATG5-ATG16L1 complex assembly. These findings provide new insights into autophagy regulation. PMID- 29388491 TI - Letter to the Editor involving in the article "Gene expression of insulin receptor, insulin-like growth factor increases and insulin-like growth factor binding protein-3 reduces with increase in prostate size in benign prostatic hyperplasia". PMID- 29388492 TI - Leptin and chronic kidney diseases. AB - Chronic kidney diseases (CKD), a common outcome of various kidney diseases, cause a series of refractory complications, which lead to great economic burdens on patients. The clinical outcomes of CKD depend on various factors, including metabolic disorders. Leptin, a peptide hormone, produced in adipose tissues, plays an important role in regulating food consumption and energy expenditure. Leptin also influences the immune system and hematopoiesis. Increased leptin status is observed in CKD, leptin deficiency attenuates the immune response in nephritis. Conversely, leptin inhibits the development of obesity, which is closely associated glomerular disorder. Now, the precise role of leptin in CKD remains elusive. This review will give an integrated understanding of the potential role of leptin and its interactions with other signal molecules in CKD. PMID- 29388495 TI - Veracity in big data: How good is good enough. AB - Veracity, one of the five V's used to describe big data, has received attention when it comes to using electronic medical record data for research purposes. In this perspective article, we discuss the idea of data veracity and associated concepts as it relates to the use of electronic medical record data and administrative data in research. We discuss the idea that electronic medical record data are "good enough" for clinical practice and, as such, are "good enough" for certain applications. We then propose three primary issues to attend to when establishing data veracity: data provenance, cross validation, and context. PMID- 29388496 TI - A computerized algorithm to capture patient's past preeclampsia and eclampsia history from prenatal clinical notes. AB - Prenatal clinical notes in electronic medical records contain a wealth of information on pregnancy complications and outcomes. Extracting this critical information provides a unique opportunity for risk assessment to identify at-risk patients who may benefit from early monitoring and intervention. We developed and validated a rule-based computerized algorithm called PregHisEx to characterize past obstetrical history (preeclampsia/eclampsia) by mining prenatal clinical notes for women delivered in 2012 within a large healthcare maintenance organization. The algorithm successfully identified cases with past history of preeclampsia/eclampsia: 2984 definite and 479 probable cases at sentence level; 2419 definite and 348 probable cases at note level; and 762 definite and 82 probable cases at pregnancy episode level. Validation conducted on a random sample of 200 notes using PregHisEx yielded 88.0 percent sensitivity, 98.9 percent specificity, 91.7 percent positive predictive value, 98.3 percent negative predictive value, and F-score of 0.90. The high-performing PregHisEx can be applied for other prenatal conditions. PMID- 29388497 TI - Risk of cancer after primary total hip replacement: The influence of bearings, cementation and the material of the stem. AB - Background and purpose - Despite the increasing number of total hip replacements (THRs), their systemic influence is still not known. We have studied the influence of specific features of THRs-the bearing surface, the use of bone cement and the material of the stem-on the cancer incidence. Patients and methods - In a retrospective cohort study we identified 8,343 patients with THRs performed at Valdoltra Hospital from September 1, 1997 to December 31, 2009. Patient data were linked to national cancer and population registries. The standardized incidence ratios (SIR) and Poisson regression relative risks (RR) were calculated for all and specific cancers. Results - General cancer risk in our cohort was comparable to the population risk. Comparing with population, the risk of prostate cancer was statistically significantly higher in patients with metal-on-metal bearings (SIR =1.35); with metal-on-polyethylene bearings (SIR =1.30), with non-cemented THRs (SIR =1.40), and with titanium alloy THRs (SIR =1.41). In these last 3 groups there was a lower risk of hematopoietic tumors (SIR =0.69; 0.66 and 0.66 respectively). Risk of kidney cancer was significantly higher in the non-metal-on-metal, non-cemented, and titanium alloy groups (SIR =1.30; 1.46 and 1.41 respectively). Risk of colorectal and lung cancer was significantly lower in the investigated cohort (SIR =0.82 and 0.83, respectively). Risk for all cancers combined as well as for prostate and skin cancer, shown by Poisson analysis, was higher in the metal-on-metal group compared with non-metal-on-metal group (RR =1.56; 2.02 and 1.92, respectively). Interpretation - Some associations were found between the THRs' features, especially a positive association between metal-on-metal bearings, and specific cancers. PMID- 29388498 TI - Can carcinoembryonic antigen replace computed tomography in response evaluation of metastatic colorectal cancer? AB - INTRODUCTION: Response Evaluation Criteria in Solid Tumours (RECISTs 1.1) define computed tomography (CT) as the gold standard in response evaluation of patients with metastatic colorectal cancer (mCRC) who are undergoing chemotherapy. The aim of this study was to evaluate whether carcinoembryonic antigen (CEA), which is cheaper and easier to perform, can replace repeated CT. MATERIAL AND METHODS: The study included 66 patients with non-resectable mCRC participating in a phase I-II study. CEA values were determined, and CT images were taken every 2 months. CT images were externally and retrospectively reviewed according to the RECIST 1.1 criteria. Different cut-off values for CEA change in percent (DeltaCEA%) compared with baseline or nadir value underwent testing to find patients with disease control (that is stable disease, partial or complete response) at 2, 4, 6 and 8 months, in order to identify those who could have continued with chemotherapy based on CEA values alone. CT verification is needed in progressive disease (PD), and therefore identifying PD patients was our secondary endpoint. RESULTS: The results showed that by using a cut-off value of 0 for DeltaCEA%, disease control was seen in all patients at all measuring points (negative predictive value (NPV) = 1.0). Secondarily, increasing CEA was able to identify all PD patients (sensitivity (Se) = 1.0) and in 50-74% of the patients increasing CEA provided a lead time to PD on upcoming CT. It was possible to replace CT with CEA in all patients with decreasing CEA, meaning that 23-47% of CT scans could have been avoided at any given time point. CONCLUSION: When the CEA level at a certain measuring point is the same or lower than CEA at baseline or at nadir (the measuring point with the lowest CEA value) during treatment, CEA can replace CT. PMID- 29388499 TI - Temperature-induced recovery of a bioactive enzyme using polyglycerol dendrimers: correlation between bound water and protein interaction. AB - Enzyme application has gained importance over the past decade in bioprocess, biomedical, and pharmaceutical fields. We found that polyglycerol dendrimers (PGDs), which are biocompatible molecules, can recover alcohol dehydrogenase (ADH) from aqueous solution under elevated temperature. A low concentration of PGD (5 wt.%) is sufficient for the recovery of high enzymatic activity, although a high concentration (25-75 wt.%) of glycerol is generally required to stabilize ADH. The enzymatic activity of ADH in suspension with PGDs is over 60% but it is only 10% in that with glycerol. The results of osmolarity and spin-lattice relaxation time (T1) of water measurements in the presence of PGDs suggest that increased amounts of bound water to PGD molecules trigger aggregation along with the direct interaction with ADH. PGDs therefore represent good potential additives for direct recovery of enzymes from aqueous solutions. PMID- 29388500 TI - A detailed description of the short-term musculoskeletal and cognitive effects of prolonged standing for office computer work. AB - Due to concerns about excessive sedentary exposure for office workers, alternate work positions such as standing are being trialled. However, prolonged standing may have health and productivity impacts, which this study assessed. Twenty adult participants undertook two hours of laboratory-based standing computer work to investigate changes in discomfort and cognitive function, along with muscle fatigue, movement, lower limb swelling and mental state. Over time, discomfort increased in all body areas (total body IRR [95% confidence interval]: 1.47[1.36 1.59]). Sustained attention reaction time (beta = 18.25[8.00-28.51]) deteriorated, while creative problem solving improved (beta = 0.89[0.29-1.49]). There was no change in erector spinae, rectus femoris, biceps femoris or tibialis anterior muscle fatigue; low back angle changed towards less lordosis, pelvis movement increased, lower limb swelling increased and mental state decreased. Body discomfort was positively correlated with mental state. The observed changes suggest replacing office work sitting with standing should be done with caution. Practitioner Summary: Standing is being used to replace sitting by office workers; however, there are health risks associated with prolonged standing. In a laboratory study involving 2 h prolonged standing discomfort increased (all body areas), reaction time and mental state deteriorated while creative problem solving improved. Prolonged standing should be undertaken with caution. PMID- 29388501 TI - Karyoptosis: A novel type of cell death caused by chronic autophagy inhibition. AB - Macroautophagy/autophagy influences onset and progression of several human neurodegenerative diseases, because of its critical role as a regulator of neuronal proteostasis and organelle quality control. In many neurodegenerative diseases, impairment in autophagy is thought to play a fundamental part in the terminal phases of cellular degeneration and death. However, the ultimate mechanism of neuronal cell death remains elusive. In a recent study we have identified a new form of regulated cell death, which arises upon autophagy inhibition. PMID- 29388502 TI - Feeling low, thinking slow? Associations between situational cues, mood and cognitive function. AB - Within-person changes in mood, which are triggered by situational cues, for example someone's location or company, are thought to affect contemporaneous cognitive function. To test this hypothesis, data were collected over 6 months with the smartphone application (app) moo-Q that prompted users at random times to rate their mood and complete 3 short cognitive tests. Out of 24,313 people across 154 countries, who downloaded the app, 770 participants submitted 10 or more valid moo-Q responses (mean = 23; SD = 18; range 10-207). Confirming previous research, consistent patterns of association emerged for 6 different situation cues with mood and cognitive function: For example, being alone rather than with others when completing the app resulted in worse mood but better cognitive task performance. Notwithstanding, changes in mood and cognitive function were not coupled. The advantages and challenges of using smartphone technology for studying mood and cognitive function are discussed. PMID- 29388503 TI - beta-secretase inhibitors for Alzheimer's disease: identification using pharmacoinformatics. AB - In this study we searched for potential beta-site amyloid precursor protein cleaving enzyme1 (BACE1) inhibitors using pharmacoinformatics. A large dataset containing 7155 known BACE1 inhibitors was evaluated for pharmacophore model generation. The final model (R = 0.950, RMSD = 1.094, Q2 = 0.901, se = 0.332, [Formula: see text] = 0.901, [Formula: see text] = 0.756, sp = 0.468, [Formula: see text] = 0.667) was revealed with the importance of spatial arrangement of hydrogen bond acceptor and donor, hydrophobicity and aromatic ring features. The validated model was then used to search NCI and InterBioscreen databases for promising BACE1 inhibitors. The initial hits from both databases were sorted using a number of criteria and finally three molecules from each database were considered for further validation using molecular docking and molecular dynamics studies. Different protonation states of Asp32 and Asp228 dyad were analysed and best protonated form used for molecular docking study. Observation of the number of binding interactions in the molecular docking study supported the potential of these molecules being promising inhibitors. Values of RMSD, RMSF, Rg in molecular dynamics study and binding energies unquestionably explained that final screened molecules formed stable complexes inside the receptor cavity of BACE1. Hence, it can be concluded that the final screened six compounds may be potential therapeutic agents for Alzheimer's disease. PMID- 29388504 TI - From physiology and nutrition to biological sciences, and back again! PMID- 29388505 TI - Gender Differences in Sexual Attraction and Moral Judgment: Research With Artificial Face Models. AB - Sexual attraction in humans is influenced by cultural or moral factors, and some gender differences can emerge in this complex interaction. A previous study found that men dissociate sexual attraction from moral judgment more than women do. Two experiments consisting of giving attractiveness ratings to photos of real opposite-sex individuals showed that men, compared to women, were significantly less influenced by the moral valence of a description about the person shown in each photo. There is evidence of some processing differences between real and artificial computer-generated faces. The present study tests the robustness of Gonzalez-Alvarez's findings and extends the research to an experimental design using artificial face models as stimuli. A sample of 88 young adults (61 females and 27 males, average age 19.32, SD = 2.38) rated the attractiveness of 80 3D artificial face models generated with the FaceGen Modeller 3.5 software. Each face model was paired with a "good" and a "bad" (from a moral point of view) sentence depicting a quality or activity of the person represented in the model (e.g., she/he is an altruistic nurse in Africa vs. she/he is a prominent drug dealer). Results were in line with the previous findings and showed that, with artificial faces as well, sexual attraction is less influenced by morality in men than in women. This gender difference is consistent with an evolutionary perspective on human sexuality. PMID- 29388506 TI - Need for Uniqueness Determines Reactions to Web-Based Personalized Advertising. AB - The presented empirical study among a sample of n = 256 participants addressed the relationship between consumers' need for uniqueness and their reactions to web-based personalized advertising. Drawing on regulatory focus theory, we argue that the consumers' need for uniqueness dimensions creative choice and similarity avoidance may relate to promotion and prevention regulatory orientations, respectively. Accordingly, we hypothesized that creative choice and similarity avoidance would differentially predict self-reported approach and avoidance behavior toward personalized advertising. These direct relationships were further expected to be mediated by subjective evaluations of personalized advertising (i.e., perceived value and irritation). In line with these hypotheses, we found that creative choice predicted approach behavior through increased web-based personalized advertising value, whereas similarity avoidance predicted avoidance behavior through increased irritation. Creative choice also predicted decreased irritation, which in turn was related to decreased approach behavior. In sum, the results suggest that the consumers' need for uniqueness dimensions should not be investigated as a composite, as they seem to reflect different regulatory orientations and are therefore likely to evoke different affective, cognitive, and behavioral responses. PMID- 29388507 TI - Long-range gamma phase synchronization as a compensatory strategy during working memory in high-performing patients with schizophrenia. AB - Working memory deficits in schizophrenia may be associated with impairments in the integration of neural activity across a distributed network of cortical areas. However, evaluation of the contribution of this integration to working memory impairments in patients is severely confounded by behavioral performance. In the present multidimensional-neuroimaging study, measures of neural oscillations at baseline and during a working memory task, baseline gamma aminobutyric acid (GABA) level in the left dorsolateral prefrontal cortex (DLPFC), and behavioral performance were obtained. Controlling behavioral performance by recruiting only "high-performing" patients with schizophrenia, we investigated whether the strength of cross-area communications differs between patients with schizophrenia and healthy participants under accurate and equivalent behavioral performance. Results of phase-locking value indicated that these high-performing patients recruited significantly more between frontal and occipital regions in the left hemisphere, t(13) = -2.16, p = .05, Cohen's d = 1.20, and between frontal and temporal regions in the right hemisphere, t(13) = 2.63, p = .02, Cohen's d = -1.46. These cross-area communication patterns may be associated with visuoverbal and visuospatial working memory networks of the left and right hemispheres, respectively. Moreover, correlations of patient's cross area communication with in vivo GABA levels of the left DLPFC revealed a significant positive relationship (r = .77, p = .04), demonstrating that the critical role of GABA functions in gamma band oscillations may go beyond local neuronal assemblies in the left DLPFC. Altogether, these exploratory findings point to the heterogeneity among schizophrenia patients and highlight the notion that high-performing patients may engage in potential compensatory mechanisms and may represent a subgroup of patients that may be categorically or dimensionally divergent in psychopathology. PMID- 29388508 TI - Retrieving autobiographical experience of painful events in a phantom limb: brain concomitants in a case report. AB - We report the case of a patient who had an important experience with painful events, allowing the investigation of brain concomitants to painful (P) memories in fMRI. The patient had to recall P events that were contrasted with non-painful (NP) memories. Painful memories of the right lower limb activated the left paracentral lobule,fronto-insular operculum and superior parietal cortex. Additionally, whilst the recall of non-painful events activated the hippocampus, the recall of painful events did not enhance the hippocampal signal to significant levels. These suggest that brain activations differ for the autobiographical recall of painful and non-painful memories. PMID- 29388509 TI - In Memoriam Professor Dr. Albert Lacquet (1904-2003). PMID- 29388510 TI - Impact of supersaturation ratio on phosphorus recovery from synthetic anaerobic digester supernatant through a struvite crystallization fluidized bed reactor. AB - Over the past few decades, several technologies have been developed to recover phosphorus (P) as struvite from wastewater. Although these technologies have achieved reasonable P-removal efficiencies, these technologies are associated with several shortcomings such as high capital and operating costs, longer crystallization time and production of low-quality product. This study focussed on the development of an efficient technology by designing a new fluidized bed reactor (FBR) and determining its optimum operating conditions. The supersaturation ratio is the most important process parameter for struvite recovery. This study exerted effort to establish a range of supersaturation ratios in order to achieve optimum P-removal and recovery with a lesser amount of fine crystals produced. Bench-scale FBR used in this study was able to accomplish 90% P-removal with 18% P-recovery. P-removal efficiency was observed to be increasing with an increase in the initial supersaturation ratio up to a value of 6.5. On the other hand, an increase in the supersaturation ratio resulted in a lower P-recovery efficiency with an increase in fines production. The supersaturation ratio from 5.5 to 6.0 was found to be optimum for efficient operation of the reactor. PMID- 29388511 TI - Impaired transport of intrinsically disordered proteins through the Sec61 and SecY translocon; implications for prion diseases. AB - The prion protein (PrP) is composed of two major domains of similar size. The structured C-terminal domain contains three alpha-helical regions and a short two stranded beta-sheet, while the N-terminal domain is intrinsically disordered. The analysis of PrP mutants with deletions in the C-terminal globular domain provided the first hint that intrinsically disordered domains are inefficiently transported into the endoplasmic reticulum through the Sec61 translocon. Interestingly, C-terminally truncated PrP mutants have been linked to inherited prion disease in humans and are characterized by inefficient ER import and the formation of neurotoxic PrP conformers. In a recent study we found that the Sec61 translocon in eukaryotic cells as well as the SecY translocon in bacteria is inherently deficient in translocating intrinsically disordered proteins. Moreover, our results suggest that translocon-associated components in eukaryotic cells enable the Sec61 complex to transport secretory proteins with extended unstructured domains such as PrP and shadoo. PMID- 29388513 TI - Age-Related Changes in Field Dependence-Independence and Implications for Geriatric Rehabilitation: A Review. AB - Human aging is a dynamic life-long process and an inevitable experience. As the average age of the world's population rises, demands for effective geriatric rehabilitation dramatically increase. An important consideration for enhancing geriatric behavioral interventions is to better understand aging characteristics in perceptual, cognitive, and motor performances. A general shift in cognitive style from field independence to field dependence has been consistently observed during human aging, as older adults show a greater tendency to rely on environmental information, presumably reflecting a neuro-compensatory mechanism of reducing top-down control and relying instead on bottom-up processing. These changes in cognitive style can impact motor skill learning and relearning and, consequently, affect geriatric rehabilitation and behavioral treatments. In this article, we review research related to the cognitive style of field dependence and independence, and its dynamic associations with aging. We also identify implications of cognitive style for geriatric rehabilitation and explore future research. PMID- 29388512 TI - Meta-analysis of cognitive performance in fibromyalgia. AB - INTRODUCTION: Fibromyalgia is a condition with symptoms of pain, physical function difficulties, and emotional problems, but is also characterized by complaints of poor cognition (often called "FibroFog"). Over the last two decades, a number of studies have examined cognitive differences between individuals with and without fibromyalgia. The purpose of the current study was to conduct a quantitative synthesis of these differences across multiple cognitive domains. METHOD: Following Cochrane guidelines, we identified 37 eligible studies for analysis where persons with fibromyalgia (total n = 964) were compared to participants from age-matched control groups without fibromyalgia (total n = 1025) on a range of neuropsychological measures. Group differences between persons with fibromyalgia and healthy controls were examined for cognitive domains including processing speed, long- and short-term memory, and executive functions (inhibitory control, set shifting, updating, and accessing). Random-effect meta-analyses were conducted to determine effect sizes for these differences in cognitive performance. RESULTS: Fibromyalgia was significantly and negatively associated with performance on all domains of cognitive function. The largest effect size was found for inhibitory control (g = 0.61), followed by memory (g = 0.51 for short-term, 0.50 for long-term memory). The smallest cognitive difference between those with fibromyalgia and controls was for set shifting (g = 0.30). CONCLUSION: These findings support the hypothesis that the self-reported cognitive impact of fibromyalgia is also found in objective neuropsychological measures. Routine screening for cognitive dysfunction in those with fibromyalgia may be warranted in addition to assessment of the traditional fibromyalgia symptoms. PMID- 29388514 TI - Maternal verbally aggressive behavior in early infancy is associated with blood pressure at age 5-6. AB - Early life stress has been shown to contribute to alterations in biobehavioral regulation. Whereas many different forms of childhood adversities have been studied in relation to cardiovascular outcomes, very little is known about potential associations between caregivers' verbally aggressive behavior and heart rate and blood pressure in the child. This prospective study examined whether maternal verbally aggressive behavior in early infancy is associated with heart rate or blood pressure at age 5-6. In the Amsterdam Born Children and their Development study, a large prospective, population-based birth cohort, maternal verbally aggressive behavior was assessed by questionnaire in the 13th week after birth. The child's blood pressure and heart rate were measured during rest at age 5-6 (n=2553 included). Maternal verbally aggressive behavior in infancy was associated with a higher systolic blood pressure (SBP) both in supine and sitting position after adjustment for sex, height and age (SBP supine B=1.01 mmHg; 95% CI [0.06; 1.95] and SPB sitting B=1.29 mmHg; 95% CI [0.12; 2.46]). Adjustment for potential confounding variables, such as other mother-infant dyad aspects, family hypertension and child's BMI, only slightly attenuated the associations (SBP supine B=0.99 mmHg; 95% CI [0.06; 1.93] and SPB sitting B=1.11 mmHg; 95% CI [ 0.06; 2.27]). Maternal verbally aggressive behavior was not associated with diastolic blood pressure or heart rate at age 5-6. Maternal verbally aggressive behavior might be an important early life stressor with negative impact on blood pressure later in life, which should be further investigated. Possible underlying mechanisms are discussed. PMID- 29388515 TI - Medicare and the care of First Nations, Metis and Inuit. AB - The Canada Health Act 1984 (CHA) is considered foundational to Canada's publicly funded health care system (known as Medicare). The CHA provides for the federal transfer of funding to the provinces/territories, in exchange for provincial/territorial adherence to Medicare's key principles of universality; comprehensiveness; portability; accessibility; and, public administration. Medicare is a decentralized health care system, managed independently by Canada's 10 provincial and three territorial governments, allowing for regional adaptations to fit varying degrees of urbanity, remoteness and needs. The Act is silent on its relationship to the Indigenous health care system - what some have described as Canada's 14th health care system. The CHA has not kept pace with Indigenous self-government activities that have since spread across Canada. It has unfortunately crystallized the federal/provincial/territorial/Indigenous jurisdictional fragmentation that perpetuates health inequities and has failed to clarify these jurisdictions' obligations towards Indigenous peoples. As a result of these omissions, access to health services remains a concern for many Indigenous Canadians, resulting in poorer outcomes and premature mortality. In this paper, I argue that Medicare renewal must: make an explicit commitment to Indigenous health equity; clarify jurisdictional obligations; establish effective mechanisms for addressing areas of jurisdictional dispute and/or confusion; and explicitly recognize First Nations and Inuit health care services as integral yet distinct systems, that nevertheless must be welcomed to seamlessly work with provincial health care systems to ensure continuity of care. PMID- 29388516 TI - Salt intake and dietary sources of salt on weekdays and weekend days in Australian adults. AB - OBJECTIVE: To assess if there is a difference in salt intake (24 h urine collection and dietary recall) and dietary sources of salt (Na) on weekdays and weekend days. DESIGN: A cross-sectional study of adults who provided one 24 h urine collection and one telephone-administered 24 h dietary recall. SETTING: Community-dwelling adults living in the State of Victoria, Australia. SUBJECTS: Adults (n 598) who participated in a health survey (53.5 % women; mean age 57.1 (95 % CI 56.2, 58.1) years). RESULTS: Mean (95 % CI) salt intake (dietary recall) was 6.8 (6.6, 7.1) g/d and 24 h urinary salt excretion was 8.1 (7.8, 8.3) g/d. Mean dietary and 24 h urinary salt (age-adjusted) were 0.9 (0.1, 1.6) g/d (P=0.024) and 0.8 (0.3, 1.6) g/d (P=0.0017), respectively, higher at weekends compared with weekdays. There was an indication of a greater energy intake at weekends (+0.6 (0.02, 1.2) MJ/d, P=0.06), but no difference in Na density (weekday: 291 (279, 304) mg/MJ; weekend: 304 (281, 327) mg/MJ; P=0.360). Cereals/cereal products and dishes, meat, poultry, milk products and gravy/sauces accounted for 71 % of dietary Na. CONCLUSIONS: Mean salt intake (24 h urine collection) was more than 60 % above the recommended level of 5 g salt/d and 8-14 % more salt was consumed at weekends than on weekdays. Substantial reductions in the Na content of staple foods, processed meat, sauces, mixed dishes (e.g. pasta), convenience and takeaway foods are required to achieve a significant consistent reduction in population salt intake throughout the week. PMID- 29388517 TI - A brief history of antidepressant drug development: from tricyclics to beyond ketamine. AB - OBJECTIVE: Although monoaminergic-targeted drugs have prompted great advances in the development of treatments for depression, the need for new options persists, since these drugs still have a delayed clinical effect and most patients do not respond properly to them. Recently, the observation of the antidepressant effects of ketamine brought on a new wave of studies regarding the comprehension of the neurobiology of depression and the development of new and more effective antidepressant drugs. METHODS: Thus, in this paper, we present a historical review of the development of monoaminergic antidepressant drugs and the role of ketamine as the introductory agent of a new era in the research of the neurobiology of depression. RESULTS: Firstly, we review how the pharmacological treatment for major depression started, and we point out the main drugs discovered, the researchers involved, and how the studies developed have contributed to the understanding of the neurobiology of depression. Secondly, the major problems regarding the clinical efficacy and acceptance of these drugs are discussed, and the introduction of the glutamatergic system as a target for antidepressant drugs is presented. Finally, we review how ketamine revealed itself as an exciting option towards obtaining pharmacological agents to treat depression, through the understanding of biological markers. Discussion Ketamine contributed to confirm that different targets of the glutamatergic system and neurotrophic pathways are strictly related to the neurobiology of depression. There are several antidepressant drugs based on ketamine's mechanism of action already in the pipeline, and glutamatergic-targeted antidepressants may be on the market in the near future. PMID- 29388518 TI - How Community and Public Health Partnerships Contribute to Disaster Recovery and Resilience. AB - OBJECTIVE: To summarize ways that networks of community-based organizations (CBO), in partnership with public health departments, contribute to community recovery from disaster. METHODS: The study was conducted using an online survey administered one and 2 years after Hurricane Sandy to the partnership networks of 369 CBO and the New York Department of Health and Mental Hygiene. The survey assessed the structure and durability of networks, how they were influenced by storm damage, and whether more connected networks were associated with better recovery outcomes. RESULTS: During response and recovery, CBOs provide an array of critical public health services often outside their usual scope. New CBO partnerships were formed to support recovery, particularly in severely impacted areas. CBOs that were more connected to other CBOs and were part of a long-term recovery committee reported greater impacts on the community; however, a partnership with the local health department was not associated with recovery impacts. CONCLUSION: CBO partners are flexible in their scope of services, and CBO partnerships often emerge in areas with the greatest storm damage, and subsequently the greatest community needs. National policies will advance if they account for the dynamic and emergent nature of these partnerships and their contributions, and clarify the role of government partners. (Disaster Med Public Health Preparedness. 2018;12:635-643). PMID- 29388519 TI - Pharmaceutical policy reform in Canada: lessons from history. AB - Canada is the only country with a broad public health system that does not include universal, nationwide coverage for pharmaceuticals. This omission causes real hardship to those Canadians who are not well-served by the existing patchwork of limited provincial plans and private insurance. It also represents significant forgone benefits in terms of governments' ability to negotiate drug prices, make expensive new drugs available to patients on an equitable basis, and provide integrated health services regardless of therapy type or location. This paper examines Canada's historical failure to adopt universal pharmaceutical insurance on a national basis, with particular emphasis on the role of public and elite ideas about its supposed lack of affordability. This legacy provides novel lessons about the barriers to reform and potential methods for overcoming them. The paper argues that reform is most likely to be successful if it explicitly addresses entrenched ideas about pharmacare's affordability and its place in the health system. Reform is also more likely to achieve universal coverage if it is radical, addressing various components of an effective pharmaceutical program simultaneously. In this case, an incremental approach is likely to fail because it will not allow governments to contain costs and realize the social benefits that come along with a universal program, and because it means forgoing the current promising conditions for achieving real change. PMID- 29388520 TI - Development of a tool to measure the number of foods and beverages consumed by children using National Health and Nutrition Examination Survey (NHANES) FFQ data. AB - OBJECTIVE: There is currently no standard, objective definition of selective eating. This is partially because normative values for the number of different foods eaten by US children have not been established. The present study objectives were to: (i) perform exploratory analysis on the number of different foods, beverages, and total foods and beverages consumed by US children aged 2-18 years over a year's time, and the types of foods consumed by those in the lowest 2.5th percentile; and (ii) determine whether those values differ according to demographic variables and weight status. DESIGN: Secondary analysis of cross sectional FFQ data. Differences in number of foods, beverages, and total foods and beverages were analysed using one-way ANOVA. SETTING: National Health and Nutrition Examination Survey (NHANES) for the years 2003-2006. SUBJECTS: Non institutionalized US children aged 2-18 years. RESULTS: The mean number of different foods and beverages consumed across the sample was 83.2. There were no significant differences by gender, BMI, race or food security categories. There was a difference in beverage consumption by age category, with children aged 12 18 years consuming a significantly higher number of different beverages compared with each of the other two age categories (i.e. 2-5 years and 6-11 years). CONCLUSIONS: Normative values for the number of foods and drinks reported as consumed by children over the past 12 months may be a useful measure for researchers. Future research validating this measure is needed before cut-off values can be used to develop a definition of selective eating. PMID- 29388521 TI - External validity and anchoring heuristics: application of DUNDRUM-1 to secure service gatekeeping in South Wales. AB - : Aims and method Structured clinical judgement tools provide scope for the standardisation of forensic service gatekeeping and also allow identification of heuristics in this decision process. The DUNDRUM-1 triage tool was completed retrospectively for 121 first-time referrals to forensic services in South Wales. Fifty were admitted to medium security, 49 to low security and 22 remained in open conditions. RESULTS: DUNDRUM-1 total scores differed appropriately between different levels of security. However, regression revealed heuristic anchoring on the 'legal process' and 'immediacy of risk due to mental disorder' items. Clinical implications Patient placement was broadly aligned with DUNDRUM-1 recommendations. However, not all triage items informed gatekeeping decisions. It remains to be seen whether decisions anchored in this way are effective. Declaration of interest Dr Mark Freestone gave permission for AUC values from Freestone et al. (2015) to be presented here for comparison. PMID- 29388522 TI - Vitamin D in patients with intellectual and developmental disability in secure in patient services in the North of England, UK. AB - : Aims and method To assess the benefits of the introduction of routine vitamin D serum sampling for all patients admitted to a secure in-patient hospital in the North of England providing medium security, low security and rehabilitation services for offenders with intellectual and developmental disability. The vitamin D levels of 100 patients were analysed at baseline. Those with insufficient or deficient levels were offered treatment and retested after 1 year. Vitamin D levels were analysed in the context of level of security, seasonality of test and co-prescription of psychotropic medications. RESULTS: Eighty-three per cent of patients had suboptimal vitamin D levels at initial test (41% deficient and 42% insufficient). This was seen among established patients and new admissions. Regression analysis of baseline vitamin D levels revealed no differences for levels of security, seasonality, whether patients were taking antipsychotic or anticonvulsant medication, or length of stay. Patients with deficiency or insufficiency were all offered supplementation. Those who opted in had significantly higher vitamin D levels at follow-up, compared with those who declined treatment. Clinical implications Established and newly admitted patients in our secure mental health services had substantial levels of vitamin D insufficiency. In the light of the morbidities that are associated with deficient vitamin D levels, routine screening and the offer of supplementation is advisable. Declaration of interest None. PMID- 29388523 TI - Antidepressants in paediatric depression: do not look back in anger but around in awareness. AB - In this paper, we summarise and critique a network meta-analysis (NMA) of antidepressant efficacy and tolerability for paediatric depression and an accompanying editorial. Although we agree that many of the extant studies are flawed, this meta-analysis showed clear efficacy of fluoxetine in the NMA, and for sertraline and escitalopram in pairwise analyses. Consequently, these papers underestimate the benefits of antidepressants for paediatric depression, and provide support for current practice guideline, which recommends the use of an antidepressant if the patient does not respond to psychotherapy. In these circumstances, fluoxetine should be the first choice, with escitalopram and sertraline as alternatives. Declaration of interest D.A.B. receives royalties from Guilford Press, has or will receive royalties from the electronic self-rated version of the C-SSRS from eResearch Technology, Inc., is on the editorial board of UpToDate, and is a reviewer for Healthwise. R.D.G. serves as an expert witness for the US Department of Justice, Pfizer, Wyeth and GSK; and is the founder of Adaptive Testing Technologies. P.W. receives personal fees from Lundbeck and Takeda. B.D. reports a licensing agreement with Lundbeck for a psychosocial treatment manual for depression. No other disclosures were reported. PMID- 29388524 TI - Weekday and seasonal patterns in psychiatric referrals in three major London A&E departments, 2012-2014. AB - : Aims and method To identify temporal and demographic trends in referrals made to psychiatric liaison services. Routine clinical data from 16 105 individual referrals from three central London accident and emergency (A&E) departments to psychiatric liaison services from 2012 to 2014 were obtained and analysed using the Clinical Record Interactive Search (CRIS). RESULTS: Referrals from A&E to psychiatric liaison services increased 16% over the 3-year study period. There were fewer referrals to psychiatric liaison services in winter months compared with other seasons. There were fewer referrals to psychiatric liaison services over the weekend compared with weekdays (average 15.4 daily weekday referrals v. 13.2 weekend, z = 5.1, P < 0.001), and weekend referrals were slightly less likely to result in admission to psychiatric hospital (11.3% v. 12.8%, respectively, chi2 = 6.33, P = 0.01). Clinical implications Psychiatric staffing in A&E and inpatient psychiatric wards requires planning to meet temporal and regional variations in the pattern of demand. Declaration of interest None. PMID- 29388525 TI - Neurologists' detection and recognition of mental disorder in a tertiary in patient neurological unit. AB - : Aims and method Psychiatric disorders are common in neurological in-patients, but they are under-recognised and undertreated. We investigated the frequency of detection of mental disorder and referral to psychiatric services in a regional neuroscience centre. The results were compared with the expected prevalence. All in-patient referrals received in 2014 from the in-patient wards of the regional neuroscience centre and acute neurological unit were reviewed. RESULTS: A total of 129 ward referrals were identified; of these, 78 were from the regional in patient neurological unit, which comprised 11.4% of the total of 679 admissions to that unit. Clinical implications A spectrum of neuropsychiatric conditions were recognised by neurologists, but overall rates of recognition were low. To address the problem of under-recognition, routine screening with validated assessment tools can represent a cost-effective and acceptable method to detect psychiatric disorders in an in-patient neurological setting. Declaration of Interest None. PMID- 29388526 TI - Liaison psychiatry for older adults in the general hospital: service activity, development and outcomes. AB - : Aims and method This study used data collected to describe the activity, case load characteristics and outcome measures for all patients seen during a 6-year period. RESULTS: The service reviewed 2153 patients over 6 years with referral rates and case-load characteristics comparable to those described in a previous study period. The team saw 82% of patients on the day they were referred. Data and outcome measures collected showed significant complexity in the cases seen and statistically significant improvement in Health of the Nation Outcome Scales (HoNOS) scores following service input. Clinical implications The outcome measures used were limited, but the study supports the need for specialist liaison psychiatry for older adults (LPOA) services in the general hospital. The Framework of Outcome Measures - Liaison Psychiatry has now been introduced, but it remains unclear how valid this is in LPOA. It is of note that cost effectiveness secondary to service input and training activities are not adequately monitored. Declaration of interest None. PMID- 29388527 TI - Against the stream: Antidepressants are not antidepressants - an alternative approach to drug action and implications for the use of antidepressants. AB - Although antidepressants are regarded as effective and specific treatments, they are barely superior to placebo in randomised trials, and differences are unlikely to be clinically relevant. The conventional disease-centred understanding of drug action regards antidepressants as targeting an underlying brain process, but an alternative 'drug-centred' view suggests they are psychoactive substances that modify normal mental states and behaviour. These alterations, such as numbing of emotions, may reduce feelings of depression, and also create amplified placebo effects in randomised trials. Patients should be informed that there is no evidence that antidepressants work by correcting a chemical imbalance, that antidepressants have mind-altering effects, and that evidence suggests they produce no noticeable benefit compared with placebo. Declaration of interest The author is co-chairperson of the Critical Psychiatry Network. PMID- 29388528 TI - Completed audit cycle to explore the use of the STOPP/START toolkit to optimise medication in psychiatric in-patients with dementia. AB - : Aims and method To explore the use of the STOPP/START toolkit in older psychiatric in-patients with dementia. Clinical records and current drug charts were reviewed against STOPP/START criteria for all in-patients (n = 86) on six specialist dementia wards. RESULTS: Benzodiazepines, antipsychotics and opiates were most commonly prescribed inappropriately. The most common unprescribed medication groups were statins, calcium supplements and vitamin D supplements. There was an overall reduction of 7% in comorbidities and 8% in the number of prescriptions. t-test showed a significant drop in average comorbidities between both audits, t(1) = 23.920, P = 0.027, and in average prescriptions per patient, t(1) = 28.808, P = 0.022. There was no difference in the number of patients receiving polypharmacy, t(1) = 7.500, P = 0.084, or receiving medication with a high risk of adverse drug reactions, t(1) = 6.857, P = 0.092. Clinical implications The STOPP/START toolkit highlighted the importance of collaborative working between doctors, clinical pharmacists and nursing staff, and could provide old age psychiatrists with a structured tool to identify inappropriate prescribing of non-psychiatric medications. Declaration of interests None. PMID- 29388529 TI - Disparities in plain, tap and bottled water consumption among US adults: National Health and Nutrition Examination Survey (NHANES) 2007-2014. AB - OBJECTIVE: Differences in bottled v. tap water intake may provide insights into health disparities, like risk of dental caries and inadequate hydration. We examined differences in plain, tap and bottled water consumption among US adults by sociodemographic characteristics. DESIGN: Cross-sectional analysis. We used 24 h dietary recall data to test differences in percentage consuming the water sources and mean intake between groups using Wald tests and multiple logistic and linear regression models. SETTING: National Health and Nutrition Examination Survey (NHANES), 2007-2014. SUBJECTS: A nationally representative sample of 20 676 adults aged >=20 years. RESULTS: In 2011-2014, 81.4 (se 0.6) % of adults drank plain water (sum of tap and bottled), 55.2 (se 1.4) % drank tap water and 33.4 (se 1.4) % drank bottled water on a given day. Adjusting for covariates, non Hispanic (NH) Black and Hispanic adults had 0.44 (95 % CI 0.37, 0.53) and 0.55 (95 % CI 0.45, 0.66) times the odds of consuming tap water, and consumed B=-330 (se 45) ml and B=-180 (se 45) ml less tap water than NH White adults, respectively. NH Black, Hispanic and adults born outside the fifty US states or Washington, DC had 2.20 (95 % CI 1.79, 2.69), 2.37 (95 % CI 1.91, 2.94) and 1.46 (95 % CI 1.19, 1.79) times the odds of consuming bottled water than their NH White and US-born counterparts. In 2007-2010, water filtration was associated with higher odds of drinking plain and tap water. CONCLUSIONS: While most US adults consumed plain water, the source (i.e. tap or bottled) and amount differed by race/Hispanic origin, nativity status and education. Water filters may increase tap water consumption. PMID- 29388530 TI - GENES AND GINI: WHAT INEQUALITY MEANS FOR HERITABILITY. AB - Research has established that genetic differences among people explain a greater or smaller proportion of the variation in life outcomes in different environmental conditions. This review evaluates the results of recent educationally relevant behavioural genetic studies and meta-analyses in the context of recent trends in income and wealth distribution. The pattern of results suggests that inequality and social policies can have profound effects on the heritability of educational attainment and achievement in a population (Gene Gini interplay). For example, heritability is generally higher at greater equality levels, suggesting that inequality stifles the expression of educationally relevant genetic propensities. The review concludes with a discussion of the mechanisms of Gene-Gini interplay and what the findings mean for efforts to optimize education for all people. PMID- 29388531 TI - Consumption of processed food dietary patterns in four African populations. AB - OBJECTIVE: To identify predominant dietary patterns in four African populations and examine their association with obesity. DESIGN: Cross-sectional study.Setting/SubjectsWe used data from the Africa/Harvard School of Public Health Partnership for Cohort Research and Training (PaCT) pilot study established to investigate the feasibility of a multi-country longitudinal study of non-communicable chronic disease in sub-Saharan Africa. We applied principal component analysis to dietary intake data collected from an FFQ developed for PaCT to ascertain dietary patterns in Tanzania, South Africa, and peri-urban and rural Uganda. The sample consisted of 444 women and 294 men. RESULTS: We identified two dietary patterns: the Mixed Diet pattern characterized by high intakes of unprocessed foods such as vegetables and fresh fish, but also cold cuts and refined grains; and the Processed Diet pattern characterized by high intakes of salad dressing, cold cuts and sweets. Women in the highest tertile of the Processed Diet pattern score were 3.00 times more likely to be overweight (95 % CI 1.66, 5.45; prevalence=74 %) and 4.24 times more likely to be obese (95 % CI 2.23, 8.05; prevalence=44 %) than women in this pattern's lowest tertile (both P<0.0001; prevalence=47 and 14 %, respectively). We found similarly strong associations in men. There was no association between the Mixed Diet pattern and overweight or obesity. CONCLUSIONS: We identified two major dietary patterns in several African populations, a Mixed Diet pattern and a Processed Diet pattern. The Processed Diet pattern was associated with obesity. PMID- 29388532 TI - Validation of a picture book to be used in a pan-European dietary survey. AB - OBJECTIVE: To validate a picture book for estimation of food portion sizes using two approaches: (i) 'perception' of food portions by comparison with a series of food photos; and (ii) 'conceptualization and memory', using the same photos to estimate the amount of served food one hour after self-served food portions. DESIGN: Each partner developed a country-specific picture book based on the so called EPIC-Soft picture book. Representative and common photo series were chosen achieving approximately 25 % of the original picture book (n 23). Three portions from each photo series were randomly selected. SETTING: The study was performed within the Pilot study in the view of a Pan-European dietary survey - Adolescents, adults and elderly (PILOT-PANEU) project. SUBJECTS: A sample of adolescents and adults was recruited in five countries: Bulgaria (n 103), Finland (n 34), Germany (n 69), Hungary (n 62) and Portugal (n 77). RESULTS: Among the portions of the corresponding photo series and depending on the type of food, from 18 % (cheese) to 96 % (ratatouille) of participants chose the correct portions. In the perception study, agreement between the portions shown and reported was substantial (intraclass correlation coefficient (ICC)=0.805) and the mean difference was very low. In the memory study, agreement between the served and reported portions was lower than in the perception study (ICC=0.536). Agreement also seemed to decrease as the appearance of food on the plate differed from food in the picture. CONCLUSIONS: Overall, the picture series selected can be applied in future intake surveys to quantify foods similar to those depicted in the pictures. PMID- 29388534 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 11, of the IJSEM. PMID- 29388533 TI - Chronic disease burden predicts food insecurity among older adults. AB - OBJECTIVE: Increased out-of-pocket health-care expenditures may exert budget pressure on low-income households that leads to food insecurity. The objective of the present study was to examine whether older adults with higher chronic disease burden are at increased risk of food insecurity. DESIGN: Secondary analysis of the 2013 Health and Retirement Study (HRS) Health Care and Nutrition Study (HCNS) linked to the 2012 nationally representative HRS. SETTING: USA. SUBJECTS: Respondents of the 2013 HRS HCNS with household incomes <300 % of the federal poverty line (n 3552). Chronic disease burden was categorized by number of concurrent chronic conditions (0-1, 2-4, >=5 conditions), with multiple chronic conditions (MCC) defined as >=2 conditions. RESULTS: The prevalence of food insecurity was 27.8 %. Compared with those having 0-1 conditions, respondents with MCC were significantly more likely to report food insecurity, with the adjusted odds ratio for those with 2-4 conditions being 2.12 (95 % CI 1.45, 3.09) and for those with >=5 conditions being 3.64 (95 % CI 2.47, 5.37). CONCLUSIONS: A heavy chronic disease burden likely exerts substantial pressure on the household budgets of older adults, creating an increased risk for food insecurity. Given the high prevalence of food insecurity among older adults, screening those with MCC for food insecurity in the clinical setting may be warranted in order to refer to community food resources. PMID- 29388535 TI - Marivivens niveibacter sp. nov., isolated from the seawater of tropical mangrove. AB - A novel bacterial strain, designated HSLHS2T, was isolated from the seawater of a tropical mangrove forest. Cells of strain HSLHS2T were found to be aerobic, Gram stain-negative, non-flagellated, non-motile, short rods. Oxidase- and catalase positive. Growth was observed at 5-40 degrees C (optimum, 35 degrees C), at pH 6.0-10.0 (optimum pH 8.0) and in 0-10 % NaCl (optimum 2 %, w/v). Strain HSLHS2T shared highest 16S rRNA gene sequence similarity with Celeribacter halophilus ZXM137T (95.4 %), but formed a distinct phyletic lineage and coherent phylogenetic cluster associated with Marivivens donghaensis AM-4T (95.1 %). The dominant fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0. The respiratory quinone was determined to be Q-10. The polar lipids comprised phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, three unidentified aminolipids, four unidentified lipids, five unidentified phospholipids. The DNA G+C contents was 54.6 mol%. The combined genotypic and phenotypic data indicated that strain HSLHS2T represents a novel species of the genus Marivivens, for which the name Marivivensniveibacter sp. nov. is proposed. The type strain is HSLHS2T (=KCTC 52588T=MCCC 1A06712T). PMID- 29388536 TI - Natronolimnobius aegyptiacus sp. nov., an extremely halophilic alkalithermophilic archaeon isolated from the athalassohaline Wadi An Natrun, Egypt. AB - An obligately aerobic extremely halophilic alkalithermophilic archaeon, strain JW/NM-HA 15T, was isolated from the sediments of Wadi An Natrun in Egypt. Phylogenetic analysis based on 16S rRNA and rpoB' gene sequences indicated that it belongs to the family Natrialbaceae of the order Natrialbales. The closest relatives were Natronolimnobius baerhuensis IHC-005T and Natronolimnobius innermongolicus N-1311T (95.3 and 94.5 % 16S rRNA gene sequence similarity, respectively). Genome relatedness between strain JW/NM-HA 15T and its neighbours was evaluated using average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity with the values of 75.7-85.0, 18.1-20.0, and 70.2 71.0%, respectively. Cells were obligately aerobic, rod-shaped, non-motile, Gram stain-negative and chemo-organotrophic. The strain grew in the presence of 2.57 M to saturating Na+ (optimum 3.25-4.60 M Na+), at pH55 degrees C 7.5-10.5 (optimum pH55 degrees C 9.0-9.5), and at 30-56 degrees C (optimum 52 degrees C). The major polar lipids consisted of phosphatidylglycerol, methylated phosphatidylglycerolphosphate and two phospholipids. The complete genome size of strain JW/NM-HA 15T is approximately 3.93 Mb, with a DNA G+C content of 64.1 mol%. On the basis of phylogenetic features, genomic relatedness, phenotypic and chemotaxonomic data, strain JW/NM-HA 15T was thus considered to represent a novel species within the genus Natronolimnobius, for which the name Natronolimnobius aegyptiacus sp. nov. is proposed. The type strain is JW/NM-HA 15T (=ATCC BAA 2088T =DSM 23470T). PMID- 29388537 TI - Blad-containing oligomer: a novel fungicide used in crop protection as an alternative treatment for tinea pedis and tinea versicolor. AB - PURPOSE: The lack of novel antifungal drugs and the increasing incidence and severity of fungal infections are major concerns worldwide. Herein, we tested the activity of the Blad-containing oligomer (BCO), a new antifungal molecule already in use for agriculture, on Malassezia spp. and dermatophytes, the causal agents of human tinea versicolor and tinea pedis. Given the lack of a standard method for Malassezia susceptibility testing and the plethora of published methods, we also developed an improved method for this genus. METHODOLOGY: The efficacy of BCO was assessed in vitro and compared to that of the drugs currently utilized in the treatment of tinea versicolor (fluconazole and itraconazole) and tinea pedis (itraconazole and terbinafine). For dermatophytes, the standard microdilution broth-based method was used, with small adjustments, and several broth formulations and inocula sizes were tested to develop an improved susceptibility method for Malassezia spp. RESULTS: We successfully developed a microdilution broth-based method with considerable advantages over other available methods, and used it for all in vitro susceptibility tests of Malassezia spp. isolates. We report that, on a molar basis, BCO was more effective than fluconazole or itraconazole on most strains of Malassezia spp. isolated from clinical samples (n=29). By contrast, BCO was less effective than itraconazole or terbinafine on the common dermatophytes Trichophyton rubrum and Trichophyton interdigitale. CONCLUSION: These data place BCO as a promising drug for the treatment of Malassezia-associated skin diseases. Further in vivo studies are now required to ascertain its applicability in the clinical setting. PMID- 29388538 TI - Improving the detection of carbapenemase-producing organisms (CPO) in a low prevalence setting: evaluation of four commercial methods and implementation of an algorithm of testing. AB - PURPOSE: Carbapenemase-producing organisms (CPOs) can be resistant to almost all beta-lactams and represent an increasing threat in healthcare facilities. Detection of these organisms in routine diagnostic laboratories is difficult; here we evaluate four commercially available CPO detection assays and assess their suitability for the clinical laboratory. METHODOLOGY: A panel of 95 clinical multidrug-resistant organisms (22 NDM, 24 OXA-48, 19 VIM, 4 OXA-23, 3 KPC, 4 NDM+OXA-48, 1 OXA23+NDM, 1 IMI, 1 IMP-1, 9 ESBL, 3 derepressed AmpC and 4 inducible AmpC producers) were tested by the RESIST-3 O.K.N., RapidEC CarbaNP, Acuitas Resistome and Xpert Carba-R assays.Results/Key Findings. The commercial assays performed well, with high sensitivities (96.2-100 %) and specificities (all, 100 %). The RapidEC CarbaNP and Acuitas Resistome were able to detect the broadest range of carbapenemase genotypes. The RESIST-3 O.K.N. and Xpert CarbaR had the shortest turnaround times, whilst the RapidEC CarbaNP was the only assay included in this study that could detect previously undescribed genotypes. CONCLUSION: Using an algorithm of the RapidEC CarbaNP, followed by either the RESIST-3 O.K.N. (Enterobacteriaceae) or the Xpert Carba-R (Pseudomonas aeruginosa and Acinetobacter spp.) on suspect CPOs allowed rapid in-house detection and genotyping of a high proportion of CPOs, reducing turnaround time by up to 7 days. PMID- 29388539 TI - Sphingobacterium bovisgrunnientis sp. nov., isolated from yak milk. AB - A novel Gram-negative, rod shaped, non-motile bacterium, designated strain YK2T, was isolated from yak milk from Leh, India. The strain was positive for oxidase- and catalase-activities and negative for starch hydrolysis, nitrate reduction, citrate utilization, urease, lysine decarboxylase and ornithine decarboxylase activities. The predominant fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH, iso C17 : 1omega9c and C16 : 1omega7c and/or C16 : 1omega6c and/or iso-C15 : 0 2-OH (summed feature 3). The major polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid and six unidentified lipids. The DNA G+C content of the strain was 38.9 mol%. The 16S rRNA gene sequence analysis indicated that strain YK2T was a member of the genus Sphingobacterium and closely related to Sphingobacterium alimentarium and Sphingobacterium composti with pair-wise sequence similarity of 98.3 and 97.9 %, respectively. The sequence similarity to other members of the genus Sphingobacterium was between 92.6 to 96.3 %. Phylogenetic analysis showed that strain YK2T clustered with Sphingobacterium alimentarium and together clustered with Sphingobacterium composti. DNA-DNA hybridization of strain YK2T with Sphingobacterium alimentarium WCC 4521T and Sphingobacterium composti T5-12T showed a relatedness of only 38 and 54 %, respectively. Based on the phenotypic characteristics and on phylogenetic inference, it appears that strain YK2T represents a novel species of the genus Sphingobacterium, for which the name Sphingobacterium bovisgrunnientis sp. nov. is proposed. The type strain of Sphingobacterium bovisgrunnientis sp. nov. is YK2T (=MTCC 12631T=KCTC 52685T=JCM 31951T). PMID- 29388540 TI - Comparative characterisation of the biofilm-production abilities of Staphylococcus epidermidis isolated from human skin and platelet concentrates. AB - PURPOSE: Staphylococcus epidermidis is the predominant contaminant of platelet concentrates (PCs), a blood product used to treat patients with platelet deficiencies. This microorganism is able to form surface-attached aggregates (biofilms) in human skin. Herein, the abundance of S. epidermidis biofilm producers in contaminated PCs compared to skin isolates was explored. Furthermore, the potential positive selection of S. epidermidis biofilm-producers during the blood donation process and PC manufacturing was investigated. METHODOLOGY: Twenty-four S. epidermidis isolates obtained from contaminated PCs and 48 S. epidermidis isolates obtained from the venipuncture area of human volunteers were compared for their ability to form biofilms in laboratory media and in PCs using a semi quantitative crystal violet assay. Also, the presence of the biofilm-associated icaA and icaD genes was assessed by PCR amplification.Results/Key findings.Biofilm production in laboratory media showed a higher number of S. epidermidis biofilm-producers in the skin-derived group (43.7 %) compared to the PC-derived isolates (25 %). However, all skin and PC isolates formed biofilms in PCs. The prevalence of ica-positive biofilm-producer isolates was similar in PC and skin isolates (16.6 and 18.8 %, respectively). In contrast, the abundance of ica-negative biofilm-producers was lower in PC isolates compared to skin isolates (8.3 vs 25 %, respectively). CONCLUSION: Positive selection of S. epidermidis biofilm-producers during blood donation and PC manufacturing was not observed. Interestingly, ica-negative biofilm-producers seem to be negatively affected by skin disinfection, blood processing and PC storage. Furthermore, this study shows that S. epidermidis adopts a biofilm forming phenotype in PCs regardless of its genetic background or origin. PMID- 29388541 TI - Erratum: Aliifodinibius salicampi sp. nov., a moderately halophilic bacterium isolated from a grey saltern. PMID- 29388542 TI - Alteromonas oceani sp. nov., isolated from deep-sea sediment of a hydrothermal field. AB - A novel rod-shaped, Gram-stain-negative, aerobic bacterium, designated S35T, was isolated from deep-sea sediment collected from the Pacmanus hydrothermal field, Manus Basin, Papua New Guinea. Strain S35T grew optimally at 28 degrees C, at pH 7.0-8.0 and in the presence of 2.0 % (w/v) NaCl. 16S rRNA gene sequence analysis indicated that strain S35T shared 97.38-98.55% similarity with the type strains of Alteromonas lipolytica, Alteromonas mediterranea and Aestuariibacterhalophilus. Phylogenetic analysis showed that strain S35T belonged to the genus Alteromonas. The strain contained ubiquinone-8 as the predominant respiratory lipoquinone. Summed feature 3 (C16 : 1omega7c and/or C16 : 1omega7c), summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0 were the major fatty acids. The DNA G+C content of strain S35T was 51.3 mol%. These results indicated that strain S35T represents a novel species of the genus Alteromonas, for which the name Alteromonas oceani sp. nov. (type strain S35T=KCTC 52449T=CGMCC 1.16029T) is proposed. PMID- 29388543 TI - Jannaschia confluentis sp. nov., isolated from the junction between the ocean and a freshwater spring. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated JSSK-16T, was isolated from the place where the ocean and a freshwater spring meet at Jeju Island, South Korea. Strain JSSK-16T grew optimally at 30 degrees C, at pH 6.5-8.0 and in the presence of 2.0-4.0 % (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain JSSK-16T joined the clade comprising the type strains of Jannaschia species. Strain JSSK-16T exhibited 16S rRNA gene sequence similarity values of 97.5 and 97.1 % to the type strains of Jannaschia donghaensis and Jannaschia faecimaris, respectively, and of 94.1-96.6 % to the type strains of the other Jannaschia species. Strain JSSK-16T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c, 11-methyl C18 : 1omega7c and C18 : 0 as the major fatty acids. The major polar lipids detected in strain JSSK-16T were phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. The DNA G+C content of strain JSSK-16T was 68.8 mol% and its DNA-DNA relatedness values with the type strains of J. donghaensis and J. faecimaris were 18 and 12, respectively. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain JSSK-16T is separated from recognized species of the genus Jannaschia. On the basis of the data presented, strain JSSK-16T is considered to represent a novel species of the genus Jannaschia, for which the name Jannaschia confluentis sp. nov. is proposed. The type strain is JSSK-16T (=KACC 19436T=KCTC 62137T=NBRC 113018T). PMID- 29388544 TI - Colwellia echini sp. nov., an agar- and carrageenan-solubilizing bacterium isolated from sea urchin. AB - A novel bacterial strain, A3T, was isolated from the intestines of the sea urchin Strongylocentrotus droebachiensis collected in Oresund, Denmark. The strain was Gram-reaction-negative, rod-shaped and facultatively anaerobic, and displayed growth at 5-25 degrees C (optimum 20 degrees C), pH 7-9 (optimum at pH 7) and 1 6 % (w/v) NaCl (optimum 3 %). Furthermore, strain A3T grew on agar, agarose, kappa-carrageenan, alginate and laminarin as sole carbon source. Complete liquefaction of agar and kappa-carrageenan was observed on solid plate media as a result of enzymatic activities. Major fatty acids were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The respiratory quinones were determined to be ubiquinones Q-8 (92 %) and Q-7 (8 %), and polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The DNA G+C content was 36.9 mol%. Phylogenetical analyses based on the 16S rRNA gene showed that the bacterium was affiliated with the genus Colwellia within the Alteromonadaceae of the Gammaproteobacteria. The level of 16S rRNA gene sequence similarity between strain A3T and its closest relatives in the genus Colwellia (C. psychrerythraea ATCC 27364T and C. asteriadis KMD 002T) was 97.5 %. The average nucleotide identity between strain A3T and other members of Colwellia was 78.6-80.5 %, and DNA-DNA hybridization prediction revealed values of less than 23 % relatedness between strain A3T and other Colwellia species. The phenotypic, phylogenetic and genomic analyses support the hypothesis that strain A3T represents a novel species of the genus Colwellia, for which the name Colwellia echini sp. nov. is proposed. The type strain is A3T (=LMG 30125T=NCIMB 15095T). PMID- 29388545 TI - Thermostaphylospora grisealba gen. nov., sp. nov., isolated from mushroom compost and transfer of Thermomonospora chromogena Zhang et al. 1998 to Thermostaphylospora chromogena comb. nov. AB - A novel thermophilic actinomycete, designated strain 3-12XT, was isolated from mushroom compost in Guangxi University, Nanning, China. The novel isolate contained meso-diaminopimelic acid as the diagnostic diamino acid and the whole cell sugars were glucose and ribose. The predominant menaquinones were MK-9(H4) and MK-9(H6). The polar phospholipids were diphosphatidylglycerol, hydroxy phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside, ninhydrin-positive phosphoglycolipids and glycolipids. Major fatty acids were so C16 : 0 and C17 : 0. The G+C content of the genomic DNA was 74.6 %. The 16S rRNA gene sequence analysis showed that the closest phylogenetic neighbour of strain 3 12XT was Thermomonospora chromogena ATCC 43196T (97.0 %), other closely related strains all belonged to the family Streptosporangiaceae and showed more than 6 % divergence. The chemotaxonomic characteristics of strain 3-12XT were significantly different from Thermomonospora chromogena ATCC 43196T and DNA-DNA hybridization showed low relatedness (48.6-55.6 %) between them, so they should be different species. Thermomonospora chromogena was removed from the genus Thermomonospora by Zhang et al. 1998 on the basis of phylogenetic, chemotaxonomic and phenotypic evidence, but its taxonomic position remains uncertain. Based on the phenotypic and phylogenetic data, strain 3-12XT represents a novel species in a new genus in the family Streptosporangiaceae. The name Thermostaphylospora griseoalba gen. nov., sp. nov. is proposed. The type strain of Thermostaphylospora grisealba is 3-12XT (=DSM 46781T=CGMCC 4.7160T). We also propose transferring Thermomonospora chromogenaZhang et al. 1998 to Thermostaphylospora chromogena comb. nov. (type strain ATCC 43196T=JCM 6244T). PMID- 29388546 TI - Roseomonas deserti sp. nov., isolated from crude oil contaminated desert sand. AB - Two dark pink pigmented bacterial strains (M3T and M11) were isolated from crude oil contaminated desert sand from Kuwait. Both strains were Gram-stain-negative and small-rod to oval-shaped bacteria. Strains M3T and M11 grew at 13-42 degrees C (optimum, 30-35 degrees C) and pH 6.5-9.0 (optimum, 7.0-7.5). No additional NaCl was required for the growth of both strains. The genomic DNA G+C content of strains M3T and M11 were 69.5 and 69.0 mol%, respectively. Both strains were closely related and the mean DNA-DNA hybridization value was 92+/-1 %. 16S rRNA gene sequence comparisons of both strains indicated that they belong to the genus Roseomonas. Strains M3T and M11 had a sequence similarity of 97.3 and 97.4 % with Roseomonas oryzae JC288T, respectively. Both strains had <97 % 16S rRNA gene sequence similarity with other members of the genus Roseomonas. Strain M3T showed 18+/-2 and 13+/-2 % reassociation (based on DNA-DNA hybridization) with R. oryzae KCTC 42542T and Roseomonas cervicalis KACC 11686T, respectively. The major cellular fatty acids (>5 %) were identified as C18 : 1omega6c/C18 : 1omega7c, C16 : 1omega6c/C16 : 1omega7c and C16 : 0 in both strains. Both strains showed diphosphatidylglycerol, phosphatidylglycerol, phosphatidyl-ethanolamine, phosphatidylcholine and unidentified glycolipid as major polar lipids. Based on distinct phenotypic, genotypic and phylogenetic differences from the previously described taxa, we propose the classification of strains M3T and M11 as representative of a novel species in the genus Roseomonas, for which the name Roseomonas deserti sp. nov. is suggested. The type strain is M3T (=KEMB 2255 459T=JCM 31275T). PMID- 29388547 TI - Chlamydia trachomatis inhibits the production of pro-inflammatory cytokines in human PBMCs through induction of IL-10. AB - PURPOSE: Previous research demonstrated that IL-10 was up-regulated in Chlamydia trachomatis-infected cells and that exogenous IL-10 was able to inhibit the secretion of pro-inflammatory cytokines by infected cells. However, the mechanisms are not well understood. The aim of this study was to investigate the mechanisms for up-regulation of IL-10 and inhibition of pro-inflammatory cytokine secretion in C. trachomatis-stimulated peripheral blood mononuclear cells (PBMCs). METHODOLOGY: Human PBMCs were isolated from the blood of healthy human donors by standard Ficoll-Hypaque density gradient centrifugation. Cells were exposed to C. trachomatis in the presence or absence of MEK inhibitor U0126, the p38 inhibitor SB203580, the STAT3 inhibitor Ruxolitinib or anti-human IL-10 antibody. Cytokines were measured from culture supernatants using ELISA kits. Cells were harvested for real-time quantitative PCR to determine IL-10 mRNA levels and for Western blot assay to detect the expression of ERK1/2, p-ERK1/2, p38, p-p38, STAT3 and p-STAT3. RESULTS: Both mRNA and protein levels of IL-10 were up-regulated in stimulated cells, and the production of IL-10 was reduced when cells were treated with U0126 or SB203580. The expression of cytokines IL-6, IL-8 and TNF-alpha was enhanced in stimulated cells treated with anti-human IL-10 antibody. Moreover, neutralization of IL-10 resulted in a significant decrease of phosphorylated STAT3 in stimulated cells. Ruxolitinib caused a significant increase in the production of IL-6, IL-8 and TNF-alpha in stimulated cells. CONCLUSION: IL-10 is up-regulated in an ERK- and p38-dependent fashion in stimulated human PBMCs. IL-10 inhibits the production of pro-inflammatory cytokines by activating the JAK/STAT signalling pathway. PMID- 29388548 TI - Hymenobacter rubripertinctus sp. nov., isolated from Antarctic tundra soil. AB - A red-pigmented, Gram-reaction-negative, aerobic, non-motile and rod-shaped bacterium, designated NY03-3-30T, was isolated from a soil sample collected from Inexpressible Island, Northern Victoria Land of the Antarctic Ross Orogen, and subjected to a polyphasic taxonomic study. Growth occurred at 4-28 degrees C (optimum 20 degrees C) and at pH 6.0-9.0 (optimum pH 7.0). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NY03-3-30T belonged to the genus Hymenobacter in the family Cytophagaceae. 16S rRNA gene sequence similarities between strain NY03-3-30T and the type strains of Hymenobacter species with validly published names ranged from 92.7 to 96.2 %. Strain NY03-3 30T contained summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0, C16 : 0, C16 : 1omega5c, anteiso-C15 : 0 and summed feature 4 (iso-C17 : 1-I and/or anteiso-C17 : 1-B) as major cellular fatty acids, MK-7 as the respiratory quinone and phosphatidylethanolamine as the main polar lipid. The DNA G+C content of strain NY03-3-30T was 59.4 mol%. On the basis of phylogenetic, physiological and chemotaxonomic data, strain NY03-3-30T is considered to represent a novel species of genus Hymenobacter, for which the name Hymenobacter rubripertinctus sp. nov. is proposed. The type strain is NY03-3-30T (=CCTCC AB 2017095T=KCTC 62163T). PMID- 29388549 TI - Sphingomonas rhizophila sp. nov., isolated from rhizosphere of Hibiscus syriacus. AB - A Gram-stain-negative, aerobic, non-motile, rod-shaped, catalase-positive and oxidase-positive bacteria (THG-T61T), was isolated from rhizosphere of Hibiscus syriacus. Growth occurred at 10-37 degrees C (optimum 25-30 degrees C), at pH 5.0-9.0 (optimum 7.0) and in the presence of 0-2.0 % NaCl (optimum without NaCl supplement). Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG-T61T were identified as Sphingomonas ginsengisoli KCTC 12630T (97.9 %), Sphingomonas jaspsi DSM 18422T (97.8 %), Sphingomonas astaxanthinifaciens NBRC 102146T (97.4 %), Sphingomonassediminicola KCTC 12629T (97.2 %), 'Sphingomonas swuensis' KCTC 12336 (97.1 %) and Sphingomonas daechungensis KCTC 23718T (96.9 %). The isoprenoid quinone was ubiquinone-10 (Q 10). The major fatty acids were C16 : 0, C17 : 1omega6c, summed feature 4 (iso C15 : 0 2-OH and/or C16 : 1omega7c) and summed feature 7 (C18 : 1omega7c, C18 : 1omega9t and/or C18 : 1omega12t). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid, one unidentified lipid, one unidentified phospholipid, one unidentified glycolipid and one unidentified phosphoglycolipid. The polyamine was homospermidine. The DNA G+C content of strain THG-T61T was 65.6 mol%. The DNA-DNA relatedness values between strain THG-T61T and its closest reference strains were less than 49.2 %, which is lower than the threshold value of 70 %. Therefore, strain THG-T61T represents a novel species of the genus Sphingomonas, for which the name Sphingomonas rhizophila sp. nov. is proposed. The type strain is THG T61T (=KACC 19189T=CCTCC AB 2016245T). PMID- 29388551 TI - Fundamental differences. AB - The differences between beta- and gamma-actin are deeper than those between the amino acid sequences of these two proteins. PMID- 29388552 TI - PGC-1: The Energetic Regulator in Cardiac Metabolism. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1s (PGC-1s) can induce the expression of several downstream genes that play pivotal roles in the regulation of mitochondrial biogenesis and metabolism in the heart. Moreover, PGC-1 signaling pathways have also been reported to play a critical role in cardioprotection. Given the significance of PGC-1 coactivators, we summarize the current literature on the molecular mechanisms and roles of PGC-1s in cardiac metabolism. Thus, in this review, we first introduce the basic knowledge regarding PGC-1 signaling pathways. We then discuss their roles in heart metabolism. Moreover, we describe several significant treatments that target the PGC-1 signaling pathway. This review presents the significant roles of PGC-1s in cardiac metabolism and may contribute to the promotion of PGC-1 signaling pathway as a novel therapeutic target. PMID- 29388550 TI - Leishmania infantum, Dirofilaria spp. and other endoparasite infections in kennel dogs in central Italy. AB - Prevalence and risk factors of Leishmania infantum, Dirofilaria spp. and other potentially zoonotic or canine-specific endoparasite infections were assessed in 639 kennel dogs from central Italy. To this end, individual blood and fecal samples were examined using parasitological, immunological and molecular techniques. The presence of compatible clinical pictures, as well as age and gender were considered as putative risks factors. To evaluate risk factors, multivariable analysis with logistic regression and univariable analysis with a Chi square test and a Fischer's exact test were performed. Overall, 52.6% of dogs (95% CI 48.6-56.5) were found positive, while 39.6% of dogs (95% CI 35.8-43.5) were infected by potentially zoonotic species. Leishmania infantum and Dirofilaria repens showed prevalences of 2.5% (95% CI 1.5-4.1) and 2.8% (95% CI 1.7-4.5), respectively. The prevalence of cardiorespiratory parasites was 7.8% (95% CI 5.9-10.3) and included the species Angiostrongylus vasorum, Eucoleus aerophilus, Eucoleus boehmi and D. immitis; the latter showed a prevalence of 0.2% (95% CI 0.001-1). Intestinal parasites were significantly prevalent (38.8%, 95% CI 35-42.7) and they consisted mainly of species of major zoonotic concern, including ancylostomatids, Toxocara canis, Giardia duodenalis, Dipylidium caninum, Taeniidae, Strongyloides stercoralis and Cryptosporidium parvum. Endoparasites were significantly prevalent in clinically suspected dogs. Leishmania infantum and cardiorespiratory nematodes were prevalent in older dogs, while intestinal parasites were prevalent in younger dogs. Results show high dog and public health risks in kennels in central Italy, and suggest the need for more effective control measures. PMID- 29388553 TI - Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease. AB - The endoplasmic reticulum (ER) is an organelle present in most eukaryotic cells and plays a pivotal role in lipid metabolism. ER dysfunction, specifically ER stress (ERS), is a pathophysiological response involved in lipid metabolism and cardiovascular lesions. Therefore, suppression of ERS may improve lipid metabolic disorders and reduce cardiovascular risk. Herein, we focus on novel breakthroughs regarding the roles of ERS in lipid metabolism and cardiovascular disease (CVD), as well as the internal mechanisms of ERS and its status as a potential therapeutic target. This review highlights recent advances in ERS, the regulation of which might be helpful for both basic research and clinical drug design for lipid metabolic disorders and CVD. PMID- 29388554 TI - Radiation situation dynamics at the Andreeva Bay site for temporary storage of spent nuclear fuel and radioactive waste over the period 2002-2016. AB - The Coastal Technical Base (CTB) No569 at Andreeva Bay was established in the early 1960s and intended for the refueling of nuclear submarine reactors and temporary storage of spent nuclear fuel (SNF) and radioactive waste (RW). In 2001, the base was transferred to the Russian Ministry for Atomic Energy and the site remediation began. The paper describes in detail the radiation situation change at the technical site in Andreeva Bay from 2002-2016, the period of preparation for the most critical phase of remedial work: removal of spent fuel assemblies. The analysis of aggregated indicators and data mining were used. The article suggests the best number and location of checkpoints needed to ensure sufficient accuracy of the radiation situation description. The fractal properties of the radiation field are studied using the Hurst index. The relationship between checkpoints was assessed using the method of searching for checkpoint communities. The decrease in the integral of the ambient dose equivalent rate (ADER) at the technical site was evaluated by the method of time series decomposition. Three components of time series were identified: trend, seasonal and residual. The trend of the ADER integral over the technical site is a monotonic decreasing function, where the initial and final values differ tenfold. Taking into account that 137Cs dominates the radiation situation on site, it is clear that the ADER due to the radionuclide decay will have decreased by 1.4 times. It is estimated that only a small proportion of 137Cs has migrated off-site. Therefore, approximately a sevenfold decrease in dose rate is mainly due to remediation activities of personnel. During the year, the seasonal component varies the ADER integral by a factor of two, due to snowfall. The residual component reflects the uncertainty of the ADER integral calculation and phases of active SNF and RW management. The methods developed are used to support the optimization of remediation work as well as regulatory supervision of occupational radiation protection. PMID- 29388555 TI - Extreme temperature stability of thermally insulating graphene-mesoporous-silicon nanocomposite. AB - We demonstrate the thermal stability and thermal insulation of graphene mesoporous-silicon nanocomposites (GPSNC). By comparing the morphology of GPSNC carbonized at 650 degrees C as-formed to that after annealing, we show that this nanocomposite remains stable at temperatures as high as 1050 degrees C due to the presence of a few monolayers of graphene coating on the pore walls. This does not only make this material compatible with most thermal processes but also suggests applications in harsh high temperature environments. The thermal conductivity of GPSNCs carbonized at temperatures in the 500 degrees C-800 degrees C range is determined through Raman spectroscopy measurements. They indicate that the thermal conductivity of the composite is lower than that of silicon, with a value of 13 +/- 1 W mK-1 at room temperature, and not affected by the thin graphene layer, suggesting a role of the high concentration of carbon related-defects as indicated by the high intensity of the D-band compared to G band of the Raman spectra. This morphological stability at high temperature combined with a high thermal insulation make GPSNC a promising candidate for a broad range of applications including microelectromechanical systems and thermal effect microsystems such as flow sensors or IR detectors. Finally, at 120 degrees C, the thermal conductivity remains equal to that at room temperature, attesting to the potential of using our nanocomposite in devices that operate at high temperatures such as microreactors for distributed chemical conversion, solid oxide fuel cells, thermoelectric devices or thermal micromotors. PMID- 29388556 TI - Bioinspired wingtip devices: a pathway to improve aerodynamic performance during low Reynolds number flight. AB - Birds are highly capable and maneuverable fliers, traits not currently shared with current small unmanned aerial vehicles. They are able to achieve these flight capabilities by adapting the shape of their wings during flight in a variety of complex manners. One feature of bird wings, the primary feathers, separate to form wingtip gaps at the distal end of the wing. This paper presents bio-inspired wingtip devices with varying wingtip gap sizes, defined as the chordwise distance between wingtip devices, for operation in low Reynolds number conditions of Re = 100 000, where many bird species operate. Lift and drag data was measured for planar and nonplanar wingtip devices with the total wingtip gap size ranging from 0% to 40% of the wing's mean chord. For a planar wing with a gap size of 20%, the mean coefficient of lift in the pre-stall region is increased by 7.25%, and the maximum coefficient of lift is increased by 5.6% compared to a configuration with no gaps. The nonplanar wingtip device was shown to reduce the induced drag. The effect of wingtip gap sizes is shown to be independent of the planarity/nonplanarity of the wingtip device, thereby allowing designers to decouple the wingtip parameters to tune the desired lift and drag produced. PMID- 29388557 TI - Electronic properties of Pu19Os simulating beta-Pu: the strongly correlated Pu phase. AB - We established the basic electronic properties of zeta-Pu19Os, which is a close analogue to beta-Pu, and its low-temperature variety, eta-Pu19Os. Their magnetic susceptibility is 15% higher than for delta-Pu. A specific heat study of zeta Pu19Os shows a soft lattice similar to delta-Pu, leading to a low Debye temperature Theta D = 101 K. The linear electronic coefficient gamma related to the quasiparticle density of states at the Fermi level points to a higher value, 55 +/- 2 mJ (mol Pu K2)-1, compared to 40 mJ (mol K2)-1 for delta-Pu. The results confirm that beta-Pu is probably the most strongly correlated Pu phase, as had been indicated by resistivity measurements. The volume and related Pu-Pu spacing is clearly not the primary tuning parameter for Pu metal, as the beta-Pu density stands close to the ground-state alpha-phase and is much higher than that for delta-Pu. The eta-Pu19Os phase has a record gamma-value of 74 +/- 2 mJ (mol Pu K2)-1. The enhancement is not reproduced by LDA+DMFT calculations in the fcc structure, which suggests that multiple diverse sites can be the key to the understanding of beta-Pu. PMID- 29388558 TI - Enhancement of ZnO-based flexible nano generators via a sol-gel technique for sensing and energy harvesting applications. AB - Zinc oxide (ZnO) is a remarkable inorganic semiconductor with exceptional piezoelectric properties compared to other semiconductors. However, in comparison to lead-based hazardous piezoelectric materials, its properties have undesired limitations. Here we report a 5~6 fold enhancement in piezoelectric features via chemical doping of copper matched to intrinsic ZnO. A flexible piezoelectric nanogenerator (F-PENG) device was fabricated using an unpretentious solution process of spin coating, with other advantages such as robustness, low-weight, improved adhesion, and low cost. The device was used to demonstrate energy harvesting from a standard weight as low as 4 gm and can work as a self-powered mass sensor in a broad range of 4 to 100 gm. The device exhibited a novel energy harvesting technique from a wind source due to its inherent flexibility. At three different velocities (10~30 m s-1) and five different angles of attack (0~180 degrees), the device validated the ability to discern different velocities and directions of flow. The device will be useful for mapping the flow of air apart from harvesting the energy. The simulation was done to verify the underlining mechanism of aerodynamics involved. PMID- 29388559 TI - Fermi-level tuning of the Dirac surface state in (Bi1-x Sb x )2Se3 thin films. AB - We report on the electronic states and the transport properties of three dimensional topological insulator (Bi1-x Sb x )2Se3 ternary alloy thin films grown on an isostructural Bi2Se3 buffer layer on InP substrates. By angle resolved photoemission spectroscopy, we clearly detected Dirac surface states with a large bulk band gap of 0.2-0.3 eV in the (Bi1-x Sb x )2Se3 film with x = 0.70. In addition, we observed by Hall effect measurements that the dominant charge carrier converts from electron (n-type) to hole (p-type) at around x = 0.7, indicating that the Fermi level can be controlled across the Dirac point. Indeed, the carrier transport was shown to be governed by Dirac surface state in 0.63 ? x ? 0.75. These features suggest that Fermi-level tunable (Bi1-x Sb x )2Se3-based heterostructures provide a platform for extracting exotic topological phenomena. PMID- 29388560 TI - Pseudomorphic GeSiSn, SiSn and Ge layers in strained heterostructures. AB - The GeSiSn, SiSn layer growth mechanisms on Si(100) were investigated and the kinetic diagrams of the morphological GeSiSn, SiSn film states in the temperature range of 150 degrees C-450 degrees C at the tin content from 0% to 35% were built. The phase diagram of the superstructural change on the surface of Sn grown on Si(100) in the annealing temperature range of 0 degrees C-850 degrees C was established. The specular beam oscillations were first obtained during the SiSn film growth from 150 degrees C to 300 degrees C at the Sn content up to 35%. The transmission electron microscopy and x-ray diffractometry data confirm the crystal perfection and the pseudomorphic GeSiSn, SiSn film state, and also the presence of smooth heterointerfaces between GeSiSn or SiSn and Si. The photoluminescence for the multilayer periodic GeSiSn/Si structures in the range of 0.6-0.8 eV was detected. The blue shift with the excitation power increase is observed suggesting the presence of a type II heterostructure. The creation of tensile strained Ge films, which are pseudomorphic to the underlying GeSn layer, is confirmed by the results of the formation and analysis of the reciprocal space map in the x-ray diffractometry. The tensile strain in the Ge films reached the value in the range of 0.86%-1.5%. The GeSn buffer layer growth in the Sn content range from 8% to 12% was studied. The band structure of heterosystems based on pseudomorphic GeSiSn, SiSn and Ge layers was calculated and the valence and conduction band subband position dependences on the Sn content were built. Based on the calculation, the Sn content range in the GeSiSn, SiSn, and GeSn layers, which corresponds to the direct bandgap GeSiSn, SiSn, and Ge material, was obtained. PMID- 29388561 TI - Optimization of pillar electrodes in subretinal prosthesis for enhanced proximity to target neurons. AB - OBJECTIVE: High-resolution prosthetic vision requires dense stimulating arrays with small electrodes. However, such miniaturization reduces electrode capacitance and penetration of electric field into tissue. We evaluate potential solutions to these problems with subretinal implants based on utilization of pillar electrodes. APPROACH: To study integration of three-dimensional (3D) implants with retinal tissue, we fabricated arrays with varying pillar diameter, pitch, and height, and implanted beneath the degenerate retina in rats (Royal College of Surgeons, RCS). Tissue integration was evaluated six weeks post-op using histology and whole-mount confocal fluorescence imaging. The electric field generated by various electrode configurations was calculated in COMSOL, and stimulation thresholds assessed using a model of network-mediated retinal response. MAIN RESULTS: Retinal tissue migrated into the space between pillars with no visible gliosis in 90% of implanted arrays. Pillars with 10 MUm height reached the middle of the inner nuclear layer (INL), while 22 MUm pillars reached the upper portion of the INL. Electroplated pillars with dome-shaped caps increase the active electrode surface area. Selective deposition of sputtered iridium oxide onto the cap ensures localization of the current injection to the pillar top, obviating the need to insulate the pillar sidewall. According to computational model, pillars having a cathodic return electrode above the INL and active anodic ring electrode at the surface of the implant would enable six times lower stimulation threshold, compared to planar arrays with circumferential return, but suffer from greater cross-talk between the neighboring pixels. SIGNIFICANCE: 3D electrodes in subretinal prostheses help reduce electrode-tissue separation and decrease stimulation thresholds to enable smaller pixels, and thereby improve visual acuity of prosthetic vision. PMID- 29388562 TI - Stability and carrier transport properties of phosphorene-based polymorphic nanoribbons. AB - Few-layer black phosphorene has recently attracted significant interest in the scientific community. In this paper, we consider several polymorphs of phosphorene nanoribbons (PNRs) and employ deformation potential theory within the effective mass approximation, together with density functional theory, to investigate their structural, mechanical and electronic properties. The results show that the stability of a PNR strongly depends on the direction along which it can be cut from its 2D counterpart. PNRs also exhibit a wide range of line stiffnesses ranging from 6 * 1010 eV m-1 to 18 * 1011 eV m-1, which has little dependence on the edge passivation. Likewise, the calculated electronic properties of PNRs show them to be either a narrow-gap semiconductor (E g < 1 eV) or a wide-gap semiconductor (E g > 1 eV). The carrier mobility of PNRs is found to be comparable to that of black phosphorene. Some of the PNRs show an n-type (p type) semiconducting character owing to their higher electron (hole) mobility. Passivation of the edges leads to n-type <-> p-type transition in many of the PNRs considered. The predicted novel characteristics of PNRs, with a wide range of mechanical and electronic properties, make them potentially suitable for use in nanoscale devices. PMID- 29388564 TI - Melioidosis. PMID- 29388563 TI - Levo-Tetrahydropalmatine Attenuates Progression of Abdominal Aortic Aneurysm in an Elastase Perfusion Rat Model via Suppression of Matrix Metalloproteinase and Monocyte Chemotactic Protein-1. AB - BACKGROUND Levo-tetrahydropalmatine (L-THP) is a tetrahydro protoberberine isoquinoline alkaloid obtained from the genera Stephania and Corydalis. In the present research, we evaluated the effects of L-THP on the progression of aortic aneurysms (AAs) in experimental rats induced with perfusion of elastase. MATERIAL AND METHODS Thirty-six Sprague-Dawley rats were divided into sham-operated, control, and L-THP treated groups (n=12 in each group). The rats in the control group and the L-THP group received intra-aortic perfusion of elastase to induce AAs; the sham-operated group received perfusion of saline. The rats in the L-THP group received a dose of 15 mg/kg/day, the control and the sham group received saline treatment. The animals were evaluated for aortic diameters (ADs) and systolic blood pressure (SBP) just before and after the elastase perfusion, and 24 days after perfusion. The extracts of the aortas were evaluated by western blotting and immunohistochemistry. RESULTS In the control group, a significant increase in aortic size was observed (p<0.05) compared to the sham group after 24 days post-perfusion, whereas the L-THP group showed a decrease in diameter compared to the control group (p<0.05). The SBP increased significantly in the control group compared to the sham group. The L-THP group showed reduction in SBP, exhibited decreased expression of metalloproteinase and monocyte chemotactic protein-1, and the tissue samples also exhibited significant decreased levels of iNOS compared to the control group. L-THP treatment prevented loss of vascular smooth muscle cells (VSMCs) of the aortic walls. CONCLUSIONS L-THP inhibited progression of AAs in rats by curbing inflammation, oxidative stress, and conserving VSMCs, suggesting a new therapeutic approach for managing AAs. PMID- 29388565 TI - Phylogenetic rooting using minimal ancestor deviation. AB - Ancestor-descendent relations play a cardinal role in evolutionary theory. Those relations are determined by rooting phylogenetic trees. Existing rooting methods are hampered by evolutionary rate heterogeneity or the unavailability of auxiliary phylogenetic information. Here we present a rooting approach, the minimal ancestor deviation (MAD) method, which accommodates heterotachy by using all pairwise topological and metric information in unrooted trees. We demonstrate the performance of the method, in comparison to existing rooting methods, by the analysis of phylogenies from eukaryotes and prokaryotes. MAD correctly recovers the known root of eukaryotes and uncovers evidence for the origin of cyanobacteria in the ocean. MAD is more robust and consistent than existing methods, provides measures of the root inference quality and is applicable to any tree with branch lengths. PMID- 29388566 TI - Inflammation: New insights from PET imaging. PMID- 29388568 TI - Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells. AB - Melanoma is the deadliest type of skin cancer. CD20+ melanoma stem cells (CSCs) are pivotal for metastasis and initiation of melanoma. Therefore, selective elimination of CD20+ melanoma CSCs represents an effective treatment to eradicate melanoma. Salinomycin has emerged as an effective drug toward various CSCs. Due to its poor solubility, its therapeutic efficacy against melanoma CSCs has never been evaluated. In order to target CD20+ melanoma CSCs, we designed salinomycin loaded lipid-polymer nanoparticles with anti-CD20 aptamers (CD20-SA-NPs). Using a single-step nanoprecipitation method, salinomycin-loaded lipid-polymer nanoparticles (SA-NPs) were prepared, then CD20-SA-NPs were obtained through conjugation of thiolated anti-CD20 aptamers to SA-NPs via a maleimide-thiol reaction. CD20-SA-NPs displayed a small size of 96.3 nm, encapsulation efficiency higher than 60% and sustained drug release ability. The uptake of CD20-SA-NPs by CD20+ melanoma CSCs was significantly higher than that of SA-NPs and salinomycin, leading to greatly enhanced cytotoxic effects in vitro, thus the IC50 values of CD20-SA-NPs were reduced to 5.7 and 2.6 MUg/mL in A375 CD+20 cells and WM266-4 CD+ cells, respectively. CD20-SA-NPs showed a selective cytotoxicity toward CD20+ melanoma CSCs, as evidenced by the best therapeutic efficacy in suppressing the formation of tumor spheres and the proportion of CD20+ cells in melanoma cell lines. In mice bearing melanoma xenografts, administration of CD20-SA-NPs (salinomycin 5 mg.kg-1.d-1, iv, for 60 d) showed a superior efficacy in inhibition of melanoma growth compared with SA-NPs and salinomycin. In conclusion, CD20 is a superior target for delivering drugs to melanoma CSCs. CD20 SA-NPs display effective delivery of salinomycin to CD20+ melanoma CSCs and represent a promising treatment for melanoma. PMID- 29388569 TI - Retraction: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation. PMID- 29388570 TI - Erratum: Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells. PMID- 29388571 TI - Erratum: Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma. PMID- 29388572 TI - Melioidosis. AB - Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis, a life-threatening infection that is estimated to account for ~89,000 deaths per year worldwide. Diabetes mellitus is a major risk factor for melioidosis, and the global diabetes pandemic could increase the number of fatalities caused by melioidosis. Melioidosis is endemic across tropical areas, especially in southeast Asia and northern Australia. Disease manifestations can range from acute septicaemia to chronic infection, as the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells, and the bacteria can manipulate the host's immune responses and signalling pathways to escape surveillance. The majority of patients present with sepsis, but specific clinical presentations and their severity vary depending on the route of bacterial entry (skin penetration, inhalation or ingestion), host immune function and bacterial strain and load. Diagnosis is based on clinical and epidemiological features as well as bacterial culture. Treatment requires long term intravenous and oral antibiotic courses. Delays in treatment due to difficulties in clinical recognition and laboratory diagnosis often lead to poor outcomes and mortality can exceed 40% in some regions. Research into B. pseudomallei is increasing, owing to the biothreat potential of this pathogen and increasing awareness of the disease and its burden; however, better diagnostic tests are needed to improve early confirmation of diagnosis, which would enable better therapeutic efficacy and survival. PMID- 29388573 TI - Management of gastroesophageal reflux disease in pediatric patients: a literature review. AB - Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, is a physiologic process that occurs throughout the day in healthy infants and children. Gastroesophageal reflux disease (GERD) occurs when gastric contents flow back into the esophagus and produce symptoms. The most common esophageal symptoms are vomiting and regurgitation. Lifestyle changes are the first-line therapy in both GER and GERD; medications are explicitly indicated only for patients with GERD. Surgical therapies are reserved for children with intractable symptoms or who are at risk for life-threatening complications of GERD. The laparoscopic Nissen antireflux procedure is the gold standard for the treatment of this pathology. A literature search on PubMed and Cochrane Database was conducted with regard to the management of GERD in children to provide a view of state-of-the-art treatment of GERD in pediatrics. PMID- 29388575 TI - Parental practice of child car safety in Enugu, Southeast Nigeria. AB - Child safety restraints and seat belts are regarded as the most successful safety and cost-effective protective devices available to vehicle occupants, which have saved millions of lives. This cross-sectional descriptive study evaluated the practice and use of child car restraints (CCRs) among 458 purposively selected respondents resident in two local government areas in Enugu State, Nigeria. Self administered questionnaires were sent to parents of children attending private schools who owned a car. Chi-square and multivariate analyses were used to assess the determinants of the use of car restraints in children among respondents. In all, 56% and 45% of adults and children, respectively, used car restraints regularly. The awareness of child safety laws and actual use of age-appropriate CCRs among respondents was negatively and weakly correlated (r=-0.121, P=0.310). Only respondent's use of seat belt during driving (P=0.001) and having being cautioned for non-use of CCRs (P=0.005) maintained significance as determinants of the use of CCRs in cars on multivariate analysis. The most frequent reasons given for the non-use of CCRs included the child being uncomfortable, 64 (31%); restraints not being important, 53 (26%), and restraints being too expensive, 32 (15%). Similarly, for irregular users, exceptions for non-use included the child being asleep (29%), inadequate number of CCRs (22%), and the child being sick (18%). There is a need for a strategy change to enforce the use of CCRs in Nigeria. PMID- 29388574 TI - Impact of an interprofessional oral health education program on health care professional and practice behaviors: a RE-AIM analysis. AB - Background: Early childhood caries is the most common chronic childhood condition and largely preventable. Access to oral health preventive services (OHPS) for children at risk for caries is suboptimal and could be expanded if they were provided by non-dental professionals. Many state Medicaid programs in the USA now reimburse non-dental professionals for OHPS but require that they receive oral health education (OHE) to be reimbursed. Few OHE programs have been evaluated. Methods: We evaluated the impact of Colorado's OHE program on professional- and practice-level behaviors regarding the provision of OHPS to children by measuring its reach, effectiveness, adoption, implementation, and maintenance (ie, using the Reach Effectiveness Adoption Implementation Maintenance [RE-AIM] framework) with Medicaid claims data, online surveys, and key informant interviews. Results: From 2009 to 2012, the proportion of young, low-income children receiving OHPS from a medical professional increased 16-fold. We surveyed 703 OHE participants; post-OHE response rates were 61% at 12 months, 34% at 24 months (2009 participants), and 39% at 12 months (2011 participants). Respondents reported confidence in providing OHPS; favorable oral health knowledge, attitudes, and beliefs; and were providing OHPS to most eligible children. Approximately half of the practices had initiated practice-level changes to support program implementation and maintenance. Few barriers were reported to care. Eighteen interviewees reported factors facilitating program diffusion, which included quality materials, community need, and reimbursement; barriers included lack of time to provide services, resources to purchase supplies, and referral dentists. Conclusion: This evaluation of a state interprofessional OHE program shows evidence of program diffusion and identifies facilitating factors and barriers to having medical professionals provide OHPS. PMID- 29388576 TI - Tympanostomy tubes: patient selection and special considerations. AB - Indications for tympanostomy tube (TT) placement in children with chronic serous effusions and hearing loss are fairly well established. The use of TTs for children with recurrent acute otitis media (rAOM) has not been studied as extensively as for those with hearing loss from middle-ear effusions. There is a subset of children who fall outside established guidelines for either of the preceding categories who may benefit from TT placement. The indications for TT placement in children with middle-ear disease are discussed. PMID- 29388567 TI - Nitric oxide signalling in cardiovascular health and disease. AB - Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)-NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability. PMID- 29388577 TI - Profile of infliximab in the treatment of pediatric Crohn's disease. AB - In recent years, a novel biologic therapy with monoclonal antibodies against tumor necrosis factor-alpha has revolutionized the treatment of Crohn's disease. Infliximab, the first biologic agent, has been demonstrated to considerably improve both clinical and endoscopic outcomes. In view of the growing popularity of infliximab in the management of Crohn's disease, we review the profile of the agent in the treatment of this disease in a pediatric setting. PMID- 29388578 TI - Treating pediatric atopic dermatitis: current perspectives. AB - Atopic dermatitis (AD) is a chronic, inflammatory skin condition which affects millions of people worldwide. It is most commonly seen in children but may also progress into adulthood. Management of this complex disease requires a multi pronged approach which can address the myriad of issues which underscore its development. Avoidance of triggering factors is imperative in establishing consistent control of skin irritation while daily moisturization can be very effective in skin barrier repair and maintenance. Judicious use of anti inflammatory medications has been shown to make a significant impact on both treatment as well as prevention of disease. Unfortunately, pruritus, a key feature of AD, has proven much harder to control. Finally, awareness of the risks of colonization and infection in patients with AD should be incorporated into their surveillance and management plans. While our understanding has progressed greatly regarding this disease, further research is still needed regarding future directions for both treatment and prevention. PMID- 29388579 TI - Clinical management of tuberous sclerosis complex over the lifetime of a patient. AB - Tuberous sclerosis complex (TSC) is a genetic disorder characterized by nonmalignant tumors (hamartomas) that can occur in various organ systems, including the brain, kidneys, lungs, skin, eyes, and heart. Clinical manifestations of TSC can occur at any age, thereby making the diagnosis difficult. No typical disease presentation is known, and the clinical presentation usually differs between pediatric and adult patients. Furthermore, variable penetrance of the genetic mutation causes a range of disease severity from very mild to severe, and affected individuals can go undetected for years because many of the clinical manifestations of TSC lack specificity. Once a diagnosis is made, TSC management strategies should be tailored to address the symptoms and risks most relevant to the age of the patient. Improved understanding of the genetic basis of TSC and of the central issue of mTOR overactivation has led to use of pharmacotherapies such as the mTOR inhibitors everolimus and sirolimus in the treatment of TSC disease. In Phase II and III studies, everolimus has demonstrated efficacy and safety in the treatment of both brain (subependymal giant cell astrocytoma) and renal (angiomyolipoma) manifestations associated with TSC. It is important to bear in mind that TSC is a lifelong condition, and for those diagnosed as children, a continuum of care will be needed as they transition from pediatric to adult health services. Clearly identifying the likely differences among diagnosis, monitoring, and management of pediatric and adult patients with TSC is an important step in enabling efficiencies to be maximized without compromising the care provided to patients. PMID- 29388580 TI - Martial arts intervention decreases pain scores in children with malignancy. AB - Background: Martial arts intervention in disease has been mostly limited to adult inflammatory, musculoskeletal, or motor diseases, where a mechanical intervention effects positive change. However, the application and benefit to pain management in childhood malignancy are not well described. Here, we assess the effects of defined martial arts intervention in children with cancer with respect to their pain perception and management. Methods: Sixty-four children with childhood malignancies were enrolled in a martial arts program, which encompassed both meditation and movement modalities. Pain scores (0-10) were recorded pre- and post- 1-hour session intervention. Pain scores were crossed by total visits and tabulated by whether participant pain reduced at least 1 unit, stayed the same, or increased in intensity immediately after (post) participation session. Differences in pain scores were further compared by age and sex. Results: Prepain and postpain scale data were measured for 64 participants, 43 males (67.2%) and 21 females (32.8%), ranging from 3 years to 19 years. Preintervention and postintervention data were obtained for 223 individual session visits. Mean number of patient participation visits was 1.8+/-1.6 (range one to nine visits). Of 116 individual measured sessions where the participants began with a pain score of at least 1, pain intensity reduced >=1 unit in 85.3% (99/116) of visits, remained the same in 7.8% (9/116), and increased in 6.9% (8/116). For the majority (96.3%; 77/80) of sessions, participants began with a prepain intensity score of at least 5-10 with reduction in pain intensity following the session. The overall mean pain score presession visit was reduced by40% (pre: 5.95+/-2.64 and post: 3.03+/-2.45 [95% CI: 2.34-3.50]; P<=0.001). Median pain intensity scores had greater reductions with increased age of participants (3-6 years [-1], 7-10 years [-2], 11-14 years [-3], and 15-19 years [-4]). Conclusion: Martial arts intervention can provide a useful modality to decrease pain in childhood cancer, with greater effect achieved with higher baseline pain scores and patient age. Martial arts intervention may improve patient compliance with respect to medical and surgical management, thus reducing disease morbidity and health care costs. PMID- 29388581 TI - Methods to improve joint attention in young children with autism: a review. AB - We provide an overview of studies in the past 10 years (2004-2014) that have aimed to improve joint attention (JA) in young children at risk for, or with, autism spectrum disorder. Thirteen randomized controlled trial (RCT) interventions were found, which received particular focus. Three studies used intervention methods with a developmental orientation and focused on caregiver mediated methods. Others used combined developmental and behavioral approaches and delivered intervention via trained interventionists, caregivers, and teachers. Interventions ranged widely in density, both with respect to the amount of intervention delivered weekly and the total duration of intervention. Fourteen single-subject research design (SSRD) studies and one quasi-experimental pre-post design study were also included. Notably absent in the RCTs were studies using only behavioral methods, while behavioral methods dominated in the SSRDs. The outcomes of the RCTs using combined behavioral and developmental methods generally demonstrate short-term social communication gains. While some studies demonstrated long-term maintenance and positive outcomes in related areas such as language, many did not. The mixed results for language outcomes indicate a need for further investigation. In addition, future studies should further examine participants' developmental readiness and intervention dose in relation to outcome, as well as aim to isolate active ingredients of interventions. PMID- 29388583 TI - Acute respiratory infections in young Ethiopian children. PMID- 29388582 TI - Management options for pediatric patients who stutter: current challenges and future directions. AB - Stuttering is a speech disorder, with onset often occurring in the preschool years. The prevalence of stuttering in young children is much higher than that in the general population, suggesting a high rate of recovery. However, we are unable to predict which children will recover without treatment, and it is widely acknowledged that stuttering therapy during childhood provides the best safeguard against chronic stuttering. This review reports on current evidence-based stuttering treatment options for preschoolers through to adolescents. We discuss the clinical challenges associated with treating pediatric clients who stutter at different stages of development and explore potential areas of treatment research that might serve to advance current clinical practice in the future. PMID- 29388584 TI - Language and emotional abilities in children with Williams syndrome and children with autism spectrum disorder: similarities and differences. AB - Williams syndrome (WS) is a genetic disease with a relatively homogeneous profile: relatively well-preserved language, impaired cognitive activities, and hypersociability. Autism spectrum disorder (ASD) refers to a group of individuals with impairments in aspects of communication and a particular pattern of language acquisition. Although ASD and WS are polar opposites when it comes to communication abilities (language and emotion) and social behavior, comparisons between WS and ASD are still rare in the literature. ASD and WS are both associated with general language and developmental delays. Difficulties in social interaction and general pragmatic difficulties are reported in both ASD and WS, but are more pervasive in ASD. Regarding facial emotion recognition, the two syndromes differ markedly in sensitivity to human faces. Despite the heterogeneity of these two groups, only a few studies with children have paid sufficient attention to participant recruitment and study design. A number of aspects need to be taken into account (eg, small age range, homogeneity of the subgroups, matching with typically developing children) if scientific results are to inform the design of intervention programs for children with neurodevelopmental disorders such as ASD and WS. PMID- 29388586 TI - Sudden infant death syndrome: an unrecognized killer in developing countries. AB - Sudden infant death syndrome (SIDS) is defined as the sudden unexpected death of an infant <1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. SIDS contributes to infant mortality and resulted in ~15,000 deaths globally in 2013. Most of the risk factors of SIDS are common in developing countries; yet, there has been little interest in SIDS by researchers in Africa. This review looks at the extent of the attention given to SIDS in a developing country like Nigeria, and factors responsible for the scarce data concerning this significant cause of mortality. PMID- 29388587 TI - Impact of interprofessional oral health care. PMID- 29388585 TI - Safety and efficacy of aripiprazole for the treatment of pediatric Tourette syndrome and other chronic tic disorders. AB - Tourette syndrome is a childhood-onset chronic tic disorder characterized by multiple motor and vocal tics and often accompanied by specific behavioral symptoms ranging from obsessionality to impulsivity. A considerable proportion of patients report significant impairment in health-related quality of life caused by the severity of their tics and behavioral symptoms and require medical intervention. The most commonly used medications are antidopaminergic agents, which have been consistently shown to be effective for tic control, but are also associated with poor tolerability because of their adverse effects. The newer antipsychotic medication aripiprazole is characterized by a unique mechanism of action (D2 partial agonism), and over the last decade has increasingly been used for the treatment of tics. We conducted a systematic literature review to assess the available evidence on the efficacy and safety of aripiprazole in pediatric patients with Tourette syndrome and other chronic tic disorders (age range: 4-18 years). Our search identified two randomized controlled trials (involving 60 and 61 participants) and ten open-label studies (involving between six and 81 participants). The majority of these studies used two validated clinician-rated instruments (Yale Global Tic Severity Scale and Clinical Global Impression scale) as primary outcome measures. The combined results from randomized controlled trials and open-label studies showed that aripiprazole is an effective, safe, and well-tolerated medication for the treatment of tics. Aripiprazole-related adverse effects (nausea, sedation, and weight gain) were less frequent compared to other antidopaminergic medications used for tic management and, when present, were mostly transient and mild. The reviewed studies were conducted on small samples and had relatively short follow-up periods, thus highlighting a need for further trials to assess the long-term use of aripiprazole in pediatric patients with Tourette syndrome and other chronic tic disorders with measurement of its efficacy using both clinician-rated and self-report scales. PMID- 29388590 TI - Erratum: Factors associated with acute respiratory infection in children under the age of 5 years: evidence from the 2011 Ethiopia Demographic and Health Survey [Corrigendum]. AB - [This corrects the article on p. 9 in vol. 6.]. PMID- 29388589 TI - Adherence to WHO breastfeeding guidelines among HIV positive mothers in Southern Ethiopia: implication for intervention. AB - Background: Breastfeeding reduces major causes of infant mortality and morbidity. On the other hand, it is a major mode of vertical HIV transmission. In developing countries like Ethiopia, HIV positive mothers are advised to continue breastfeeding up to 12 months. But there is scarce literature regarding the mothers' adherence to continued breastfeeding recommendations. Therefore, the objective of this study is to assess HIV positive mothers' adherence to the infant feeding recommendations of the new World Health Organization (WHO) guidelines for HIV-exposed infants aged >=6 months. Methods: A cross-sectional study was conducted in health institutions with antiretroviral therapy and prevention of mother to child transmission facilities in Sidama Zone, Southern Ethiopia. Health institutions were considered as clusters and cluster sampling technique was employed. A total of 184 HIV positive mothers with their infants registered at respective health institutions were recruited and assessed for their infant breastfeeding practices. Descriptive statistics (frequency, mean, median, and standard deviation) were computed to describe the breastfeeding practices of HIV positive mothers. Result: Almost all (181 [98.4%]) of the HIV exposed infants were "ever breastfed". Among those mothers who had ever breastfed, 158 (87.3%) initiated breastfeeding within an hour of delivery and 157 (85.8%) had fed their babies colostrum while 31 (16.8%) gave prelacteal food to their infants. The prevalence of continued breastfeeding at 1 year was (54.5%) (46.9% for urban mothers and 75% for rural mothers). Seventy-one percent (70.9%) of HIV positive mothers practiced "on demand" breastfeeding. Twenty nine percent of infants aged 6-11 months and 47.8% of infants aged >=12 months were no longer breastfed. The mean (+/- standard deviation) duration of breastfeeding was 7.8 (+/-3.1) months (95% confidence interval: 6.9-8.7). Conclusion: The 2010 WHO guidelines and recommendations on breastfeeding duration for HIV positive mothers was not adhered to after 6 months of age. Promotion and counseling of optimal breastfeeding practice for HIV positive mothers based on the updated WHO guideline is an appropriate intervention. However, further research is recommended to evaluate the acceptance of the new 2010 WHO guideline by the health professionals and HIV positive mothers. PMID- 29388591 TI - Erratum: Adverse birth outcome: a comparative analysis between cesarean section and vaginal delivery at Felegehiwot Referral Hospital, Northwest Ethiopia: a retrospective record review [Corrigendum]. AB - [This corrects the article on p. 65 in vol. 7.]. PMID- 29388588 TI - Pediatric neurocysticercosis: current challenges and future prospects. AB - Neurocysticercosis (NCC) is an acquired infection of the nervous system caused by encysted larvae of Taenia solium. It is a major cause of epilepsy in the tropics and the commonest cause of focal seizures in North Indian children. T. solium teniasis-cysticercosis is considered a parasitic "Neglected Tropical Diseases" endemic throughout Southeast Asia. NCC in children has pleomorphic manifestations depending on the location, number and viability of the cysts, and host response. Even with advancing knowledge of the disease manifestations, many aspects related to diagnosis and treatment, particularly in children, still remain controversial and pose challenges to clinical practice. There is no gold standard test to diagnose NCC and the management recommendations are still emerging. This review provides an overview of diagnosis of NCC in children and its management with special focus on current challenges and future prospects. PMID- 29388592 TI - Adverse birth outcome: a comparative analysis between cesarean section and vaginal delivery at Felegehiwot Referral Hospital, Northwest Ethiopia: a retrospective record review. AB - Introduction: Some studies favor elective cesarean delivery, and other surveys benefit vaginal delivery, while others emphasize that the quality of care during labor, birth, and immediate postpartum period plays a great role than the route of delivery. However, little information is locally available regarding the incidences of adverse birth outcome with respect to the route of delivery. Methods: This study was a retrospective analysis of eligible patient records that included 3,003 pregnant women who had undergone either cesarean or vaginal delivery from July 1, 2012, to June 31, 2013. Pretested questionnaire was used to collect the data. The completeness and consistency of the data were checked, cleaned, and double entered to EPI-INFO 3.5.2 and analyzed with SPSS V20. Independent sample t-test and chi-square test were conducted to compare the outcome of vaginal delivery and cesarean section (CS) using index variables. Significance was taken at P<0.05. Results: Among the enrolled women, 760 mothers had CS delivery and the remaining 2,243 mothers delivered vaginally. Children born through CS (mean =6.83, standard deviation =1.31) had a significantly lower first-minute Apgar score than those in the vaginal delivery group (mean =7.19, standard deviation =1.18, P=0.001). Similarly, the observed respiratory distress syndrome (c2=0.09, P=0.793) and neonatal transfer rate to neonatal intensive care unit (c2=0.086, P=0.766) were more in neonates delivered by CS than those in the vaginally delivered group. Besides, the observed neonatal death (c2=0.675, P=0.411) and maternal death (c2= 8.878, P=0.003) were higher among CS deliveries compared with vaginal deliveries. Conclusion: Neonatal and maternal morbidity and mortality appear to be more in CS than in vaginal delivery. Therefore, decision to perform CS should be based on clear, compelling, and well-supported justifications. PMID- 29388593 TI - Management of venous thrombosis in the pediatric patient. AB - The incidence of venous thromboembolism in children has increased significantly over the past decade. The evaluation and management of the child with venous thromboembolism, while based on the adult experience, has its own particularities dictated by the differences in the hemostatic system of the newborn and child. The current review addresses the evaluation of pediatric patient with thrombosis as well as the established and emerging treatment interventions. PMID- 29388594 TI - The prevalence of urinary tract infection in children with severe acute malnutrition: a narrative review. AB - This article aims to review the current evidence which shows that the prevalence of urinary tract infection (UTI) has been increasing in children with severe acute malnutrition (SAM). UTI remains one of the most common causes of febrile illness in pediatric practice. Most studies conducted among hospitalized children with complicated SAM have reported high prevalence rates of UTI. Clearly, the knowledge of baseline risk of UTI can help clinicians to make informed diagnostic and therapeutic decisions in these children. From the global reports reviewed in this article, UTI prevalence rates range from as low as 6% to as high as 37% in developing countries, while the most common bacterial isolates from urine cultures are Gram-negative coliform organisms such as Escherichia coli and Klebsiella species. These findings form the basis for the current diagnostic and therapeutic guidelines for clinicians managing children with complicated SAM. With the reported high prevalence of UTI among these children and concerns over antibiotic resistance, more extensive data are required using standardized microbiological methods. Thus, the assessment of the performance of urine dipsticks and microscopy against the gold standard urine culture is an important step toward strengthening the evidence for the therapeutic guidelines for UTI in children with SAM. PMID- 29388595 TI - Outcomes and benefits of pediatric cochlear implantation in children with additional disabilities: a review and report of family influences on outcomes. AB - The number of children with hearing loss with additional disabilities receiving cochlear implantation has increased dramatically over the past decade. However, little is known about their auditory and speech and language development following implantation. The purpose of this review is to evaluate the effects of cochlear implantation on the most common genetic and developmental disorders in children with hearing loss. Benefits of cochlear implantation for children with autism spectrum disorder, developmental delay, CHARGE syndrome, cerebral palsy, learning disorders, Usher syndrome, Waardenburg syndrome, and attention deficit/hyperactivity disorder are reviewed. Our review indicates that children with hearing loss and additional disabilities benefit from cochlear implantation, especially when implanted early. Thus, early interventions seem as important for these children as for deaf children without additional disabilities. Comparisons of outcomes across these disabilities indicate that children with little to no cognitive impairment (eg, Waardenburg sydrome, attention deficit hyperactivity disorder) have better outcomes than those with greater deficits in intellectual functioning (eg, autism, CHARGE syndrome). In addition, parents of children with hearing loss and additional disabilities report higher levels of parenting stress and greater child behavior problems than those without comorbid diagnoses. However, these parents are as sensitive when interacting with their children as parents with typically developing children using cochlear implantation. Given these results, it is critical to evaluate these children's developmental milestones to provide early implantation and intervention, appropriately counsel families regarding realistic expectations for the implant, and facilitate family adaptation. PMID- 29388596 TI - Anemia and undernutrition among children aged 6-23 months in two agroecological zones of rural Ethiopia. AB - Background: Child malnutrition during the first 1,000 days, commencing at conception, can have lifetime consequences. This study assesses the prevalence of anemia and undernutrition among children aged 6-23 months in midland and lowland agroecological zones of rural Ethiopia. Methods: Cross-sectional data examining sociodemographic, anthropometry, hemoglobin levels, and meal frequency indicators were collected from 216 children aged 6-23 months and their mothers randomly selected from eight rural kebele (villages). Results: Of 216 children, 53.7% were anemic, and 39.8%, 26.9%, and 11.6% were stunted, underweight, and wasted, respectively. The prevalence of anemia was higher in the lowland agroecological zone (59.5%) than the midland (47.6%). Among those children who were stunted, underweight, and wasted, 63.5%, 66.7%, and 68.0% were anemic, respectively. Child anemia was significantly associated with the child not achieving minimum meal frequency, sickness during the last 2 weeks before the survey, stunting and low body mass index, and with maternal hemoglobin and handwashing behavior. The prevalence of stunting was higher in the lowland agroecological zone (42.3%) than the midland (36.2%). The predictors of stunting were age and sex of the child, not achieving MMF, maternal body mass index, and age. As maternal height increases, the length for age of the children increases (P=0.003). Conclusion: The overall prevalence of anemia and undernutrition among children aged 6-23 months in these study areas is very high. The prevalence was higher in the lowland agro-ecological zone. Health information strategies focusing on both maternal and children nutrition could be sensible approaches to minimize stunting and anemia. PMID- 29388598 TI - Factors associated with acute respiratory infection in children under the age of 5 years: evidence from the 2011 Ethiopia Demographic and Health Survey. AB - Background: Acute respiratory tract infection (ARI) remains the major cause of child mortality in Sub-Saharan Africa. Various factors are associated with its occurrence and vary by context. However, available large-scale, population-based data are not fully exploited to identify locally relevant risk factors. The objective of this study was to identify factors associated with ARI in children under the age of 5 years in Ethiopia. Methods: Further analysis of the 2011 Ethiopia Demographic and Health Survey was carried out involving 11,645 children under the age of 5 years and their mothers. Information relevant to the current study was extracted from the main data set and a working data set was prepared. A complex survey logistic regression analysis was applied. Results: Acute ARI in this study was associated with severe malnutrition. Children who were severely wasted were highly likely to develop ARI (adjusted odds ratio [AOR] 1.7; 95% confidence interval [CI] 1.1-2.5). ARI was less likely to occur in children from families with an educated father and professional mother (AOR 0.4; 95% CI 0.2-0.6 and AOR 0.1; 95% CI 0.01-0.6, respectively). Conclusion: Malnourished children from a lower socioeconomic category are more likely to suffer from ARI. Targeting disadvantaged children for effective interventions can help reduce the burden of morbidity and death due to ARI. PMID- 29388597 TI - Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome. AB - Autism spectrum disorder (ASD) is a genetically determined neurodevelopmental brain disorder presenting with restricted, repetitive patterns of behaviors, interests, and activities, or persistent deficits in social communication and social interaction. ASD is characterized by many different clinical endophenotypes and is potentially linked with certain comorbidities. According to current recommendations, children with ASD are at risk of having alimentary tract disorders - mainly, they are at a greater risk of general gastrointestinal (GI) concerns, constipation, diarrhea, and abdominal pain. GI symptoms may overlap with ASD core symptoms through different mechanisms. These mechanisms include multilevel pathways in the gut-brain axis contributing to alterations in behavior and cognition. Shared pathogenetic factors and pathophysiological mechanisms possibly linking ASD and GI disturbances, as shown by most recent studies, include intestinal inflammation with or without autoimmunity, immunoglobulin E mediated and/or cell-mediated GI food allergies as well as gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity linked with functional abdominal pain, and dysautonomia linked with GI dysmotility and gastroesophageal reflux. Dysregulation of the gut microbiome has also been shown to be involved in modulating GI functions with the ability to affect intestinal permeability, mucosal immune function, and intestinal motility and sensitivity. Metabolic activity of the microbiome and dietary components are currently suspected to be associated with alterations in behavior and cognition also in patients with other neurodegenerative diseases. All the above-listed GI factors may contribute to brain dysfunction and neuroinflammation depending upon an individual patient's genetic vulnerability. Due to a possible clinical endophenotype presenting as comorbidity of ASD and GI disorders, we propose treating this situation as an "overlap syndrome". Practical use of the concept of an overlap syndrome of ASD and GI disorders may help in identifying those children with ASD who suffer from an alimentary tract disease. Unexplained worsening of nonverbal behaviors (agitation, anxiety, aggression, self-injury, sleep deprivation) should alert professionals about this possibility. This may shorten the time to diagnosis and treatment commencement, and thereby alleviate both GI and ASD symptoms through reducing pain, stress, or discomfort. Furthermore, this may also protect children against unnecessary dietary experiments and restrictions that have no medical indications. A personalized approach to each patient is necessary. Our understanding of ASDs has come a long way, but further studies and more systematic research are warranted. PMID- 29388599 TI - Resource and cost considerations in treating hypoplastic left heart syndrome. AB - Hypoplastic left heart syndrome (HLHS) was a uniformly fatal diagnosis before 1983, when surgical treatment was first undertaken with the Norwood I operation as the first of 3-staged operations. Since then, operative survival rate of stage I has risen from 53% to over 90% in the current era, not only thanks to technical advances in surgery but also through prenatal diagnosis and imaging, enhanced cardiopulmonary bypass technology, better perioperative intensive care, and closer interstage monitoring. The improvements in patient outcomes achieved through rigorous multidisciplinary teamwork have come at a tremendous cost in manpower and resources, making HLHS still a challenge to all congenital heart programs, established or emerging. We review the various surgical steps to treat HLHS and their current expected outcomes, and put into perspective cost considerations compared to other more "simple" congenital heart defects. PMID- 29388600 TI - Efficacy and safety of ustekinumab in adolescents. AB - The biologic agent ustekinumab is a human monoclonal antibody that binds to the p40 subunit shared by interleukins (ILs) 12 and 23. The antibody is able to prevent binding of cytokines to the IL-12Rbeta1 cell surface receptor and therefore may prevent IL-23 driven activation of the IL-23/Th 17 axis of inflammation. The anti-inflammatory activity has been beneficial in adult psoriasis. Ustekinumab has been approved in the United States for the treatment of adults with psoriasis and psoriatic arthritis. Approval in children and adolescents has not been granted by the US Food and Drug Administration. Subcutaneous injections of ustekinumab are administered at baseline, week 4 and every 12 weeks thereafter, a regimen that is particularly appealing to young patients who do not like more frequent injections at home. The product is attractive because, although it works through an immune system mechanism, the selective activity is such that the drug has not been associated with many of the side effects attributed to other immunosuppressive medications. Case reports of ustekinumab for pediatric psoriasis have shown promising results, and the recent Phase III CADMUS trial tested the agent in adolescents aged 12-17 years with psoriasis, using standard dose 0.75 mg/kg (<=60 kg), 45 mg (>60-<=100 kg), and 90 mg (>100 kg) or half-standard dosing 0.375 mg/kg (<=60 kg), 22.5 mg (>60-<=100 kg), and 45 mg (>100 kg) with a loading dosage at week 0 and week 4. Psoriasis area and severity index-75 was achieved in more than three-quarters of patients in full and half dosing by 12 weeks, and psoriasis area and severity index-90 in 54.1% and 61.1% of half and full dosage by 12 weeks, respectively. Ustekinumab was generally well tolerated in adolescents, with some patients developing antibodies, and nasopharyngitis being the major adverse event. Ustekinumab is a promising agent in adolescent psoriasis that appears to be well tolerated. The best monitoring plan and usage in younger patients still remain to be defined. PMID- 29388601 TI - Probiotics and infantile atopic eczema. AB - Pediatric eczema is a common disease which causes economic and social burden. Its incidence differs among the societies, with an incidence reported to reach up to 20% in developed countries. Eczema is the first allergic disease seen in the childhood, and it is recognized as a precursor for the development of atopic diseases such as asthma, allergic rhinitis, and food allergy in the forthcoming years of children. Increased incidence of eczema in recent years has led to new research in epidemiology, prevention, and intervention of this disease. It is no doubt important to treat itching, rash, and excoriation of the skin; however, treatment of pediatric eczema should not be considered only as a treatment of skin lesions. Considering skin treatment as the tip of the iceberg, proper management of the allergic processes can be accepted as the rest of the iceberg. The role of probiotics in the prevention of atopic eczema is yet to be clarified. Evidence presented by existing studies suggesting that probiotics may prevent pediatric eczema is not strong enough. A positive effect, if any, may be related with onset time, dose, duration, and use of specific probiotics. To date, there is no strong evidence for use of probiotics in the treatment of eczema; however, administration of probiotics in breast-feeding mothers in the prenatal period and in infants in the postnatal period can be accepted as a safe and helpful option in the prevention of eczema. Nevertheless, there are still questions to be answered in the future about probiotic administration for eczema. Clinical use of probiotics will gradually become more widespread when these questions are answered. Based on current information, the administration of probiotics for pediatric eczema topic is addressed in this review. PMID- 29388602 TI - Clinical and epidemiological characteristics of severe community-acquired pneumonia in children after introduction of the 10-valent pneumococcal vaccine. AB - Background: Pneumonia is an important cause of morbimortality in Brazil, despite the extensive vaccination coverage and the socioeconomic improvement in the past years. Objective: To describe the epidemiological and clinical characteristics of severe community-acquired pneumonia in children after the introduction of the 10 valent pneumococcal conjugate vaccine (PCV10). Methods: A prospective study included children <5 years old hospitalized for pneumonia between October 2010 and September 2013 in a tertiary hospital. Newborns and children with comorbidities were excluded. Pneumonia classification followed the clinical and radiological criteria established by World Health Organization (WHO). Clinical history, nutritional status, immunizations, diagnosis, disease course, and prognosis were analyzed. Results: Among 452 children, almost 70% were <2 years, with no sex differences, and 10% had weight-for-age z score below than -2.0. Family income was up to one minimum wage in half the households, and 40% of mothers had completed high school. The suitability of both influenza and PCV10 vaccine schedules was ~50%. The first medical care happened later than 72 hours after the onset of symptoms in 42% of cases. Pneumonia was classified as severe or very severe in 83.9% of patients and for 23% as complicated. Global mortality was 1.5%. Hypoxia, diagnosed in 51.5% of children, looked like a better prognosis predictor than the WHO classification. Conclusion: New strategies for health care are necessary, such as the incorporation of peripheral saturometry as the "fifth signal", investment in vaccine coverage, and the adequacy of hospital infrastructure for assistance of severely affected patients. PMID- 29388604 TI - Weighted Vest Use during Dietary Weight Loss on Bone Health in Older Adults with Obesity. AB - Background: To examine the effects of daily weighted vest use during a dietary weight loss intervention, on (a) hip and spine bone mineral density (aBMD), and (b) biomarkers of bone turnover, in older adults with obesity. Methods: 37 older (70.1 +/- 3.0 years) adults with obesity (BMI=35.3 +/- 2.9) underwent a 22 week dietary weight loss intervention (1100-1300 kcal/day) with (Diet+Vest; n=20) or without (Diet; n=17) weighted vest use (goal: 10+ h/day; weight added incrementally based on amount of weight lost). Total body weight; DXA-acquired aBMD of the total hip, femoral neck and lumbar spine; and biomarkers of bone turnover (OC, BALP, P1NP, CTX) were measured at baseline and follow up. General linear models, adjusted for baseline values of the outcome and gender, were used to examine intervention effects. Results: Average weight loss was significant in both groups (-11.2 +/- 4.4 kg and -11.0 +/- 6.3 kg, Diet+Vest and Diet groups, respectively), with no difference between groups (p=0.91). Average weighted vest use was 6.7 +/- 2.2 h/day. No significant changes in aBMD or biomarkers were observed, although trends were noted for total hip aBMD and BALP. Loss in total hip aBMD was greater in the Diet group compared with Diet+Vest (Delta: -18.7 [29.3, -8.1] mg/cm2 versus -6.1 [-15.7, 3.5] mg/cm2; p=0.08). BALP increased in the Diet+Vest group by 3.8% (Delta: 0.59 [-0.33, 1.50] MUg/L) and decreased by 4.6% in the Diet group (Delta: -0.70 [-1.70, 0.31] MUg/L, p=0.07). Conclusion: Weighted vest use during weight loss may attenuate loss of hip aBMD and increase bone formation in older adults with obesity. Further study is warranted. PMID- 29388603 TI - Posttraumatic stress in school-age children and adolescents: medical providers' role from diagnosis to optimal management. AB - Millions of children and adolescents each year are exposed to potentially traumatic events (PTEs), placing them at risk for posttraumatic stress (PTS) disorder symptoms. Medical providers play an important role in the identification and treatment of PTS, as they are typically the initial point of contact for families in the wake of a PTE or during a PTE if it is medically related (eg, injury/illness). This paper offers a review of the literature focused on clinical characteristics of PTS, the assessment and diagnosis of PTS, and current effective treatments for PTS in school-age children and adolescents. The clinical presentation of PTS is often complex as symptoms may closely resemble other internalizing and externalizing disorders. A number of screening and evaluation tools are available for medical providers to assist them in the accurate diagnosis of PTS. Treatment options are available for youth at minimal risk of PTS as well as for those with more intensive needs. Additional training regarding trauma-informed medical care may benefit medical providers. By taking a trauma informed approach, rooted in a solid understanding of the clinical presentation of PTS in children and adolescents, medical providers can ensure PTS does not go undetected, minimize the traumatic aspects of medical care, and better promote health and well-being. PMID- 29388605 TI - Prognostic scores and biomarkers for pediatric community-acquired pneumonia: how far have we come? AB - This article aimed to review the current prognostic and diagnostic tools used for community-acquired pneumonia (CAP) and highlight those potentially applicable in children with CAP. Several scoring systems have been developed to predict CAP mortality risk and serve as guides for admission into the intensive care unit. Over the years, clinicians have adopted these tools for improving site-of-care decisions because of high mortality rates in the extremes of age. The major scoring systems designed for geriatric patients include the Pneumonia Severity Index and the confusion, uremia, respiratory rate, blood pressure, age >65 years (CURB-65) rule, as well as better predictors of intensive care unit admission, such as the systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH (SMART-COP) score, the Infectious Diseases Society of America/American Thoracic Society guidelines, the criteria developed by Espana et al as well as the systolic blood pressure, oxygenation, age and respiratory rate (SOAR) criteria. Only the modified predisposition, insult, response and organ dysfunction (PIRO) score has so far been applied to children with CAP. Because none of the tools is without its limitations, there has been a paradigm shift to incorporate biomarkers because they are reliable diagnostic tools and good predictors of disease severity and outcome, irrespective of age group. Despite the initial preponderance of reports on their utility in geriatric CAP, much progress has now been made in demonstrating their usefulness in pediatric CAP. PMID- 29388606 TI - Links and risks associated with adenotonsillectomy and obesity. AB - Adenotonsillectomy (A&T) is a very common surgical procedure in children. Over the past 20 years the principal indication for A&T in children has changed from recurrent adenotonsillitis to obstructive sleep apnea. The physiopathology of obstructive sleep apnea syndrome (OSAS) is multifactorial and obesity has been shown to be one of the main factors correlated with its occurrence. On the other hand, the prevalence and severity of childhood obesity have become a veritable epidemic problem in the past 30 years. So the increasing prevalence of obesity in children and high prevalence of obstructive sleep apnea in obese children implies that an increasing number of these children will present for A&T. Due to more prevalent anatomical alterations of the oronasopharyngeal airways, it is often difficult to predict operation success in obese children. However, previous studies supports that although the risk of presence of residual symptoms of OSAS and airway-related perioperative complication in obese may be more than nonobese group, A&T is effective to reduce obstructive symptoms and improve quality of life in obese children with OSAS. PMID- 29388607 TI - Difficult-to-treat-pediatric Crohn's disease: focus on adalimumab. AB - Adalimumab is a fully humanized anti-tumor necrosis factor alpha monoclonal antibody that was recently granted regulatory approval in the USA for the treatment of moderate to severe Crohn's disease (CD) in children. Like infliximab, the first biologic agent used to treat pediatric CD, regulatory approval was secured many years following approval for adults. The long delay between adult and pediatric approval has led to many years of off-label use of adalimumab, although it is anticipated that the use of adalimumab may further increase with official regulatory approval. To date, pediatric literature on the use of adalimumab for treatment of CD is limited, and pediatric practitioners have mostly extrapolated from research and experience provided by the adult literature. The aim of this paper is to review the literature regarding adalimumab for the treatment of pediatric CD, and includes a review of landmark adult studies as well as the pivotal pediatric study that facilitated regulatory approval. We also discuss the role of anti-tumor necrosis factor alpha agents including adalimumab in the current treatment paradigm for pediatric CD. PMID- 29388608 TI - Treating pediatric plaque psoriasis: challenges and solutions. AB - Psoriasis is a T-lymphocyte-mediated chronic inflammatory disorder involving the skin and joints. Nearly 3.5% of the population has been diagnosed to have psoriasis. In a dermatology department, almost one-third of psoriasis patients are in the pediatric age group. With an annual prevalence of up to 0.71%, childhood psoriasis can now be regarded as a frequently seen chronic inflammatory skin disorder having a significant impact on the quality of life. Based on the age of onset, psoriasis in children can be broadly classified as infantile psoriasis that can be mostly self-limited, psoriasis having an early onset, which needs specific treatment, and psoriasis that is associated with arthritis. Treating a child with psoriasis is a challenge, considering the physical development, body metabolism, rate of cutaneous absorption, and metabolism of drugs, which are quite different from those of the adults. The long duration of sun exposure for the rest of their life makes it more demanding while considering phototherapy in children. Long-term treatment of psoriasis, with phototherapy or drugs, needs critical evaluation in children. Hence, a thorough understanding of the disease in all its aspects will certainly help manage childhood psoriasis better. Timely diagnosis and adequate management not only arrest progression but also minimize the psychological burden caused by the disease, averting disfiguring states and evolution into a metabolic syndrome. PMID- 29388609 TI - DiaFit: The Development of a Smart App for Patients with Type 2 Diabetes and Obesity. AB - Background: Optimal management of chronic diseases, such as type 2 diabetes (T2D) and obesity, requires patient-provider communication and proactive self management from the patient. Mobile apps could be an effective strategy for improving patient-provider communication and provide resources for self management to patients themselves. Objective: The objective of this paper is to describe the development of a mobile tool for patients with T2D and obesity that utilizes an integrative approach to facilitate patient-centered app development, with patient and physician interfaces. Our implementation strategy focused on the building of a multidisciplinary team to create a user-friendly and evidence-based app, to be used by patients in a home setting or at the point-of-care. Methods: We present the iterative design, development, and testing of DiaFit, an app designed to improve the self-management of T2D and obesity, using an adapted Agile approach to software implementation. The production team consisted of experts in mobile health, nutrition sciences, and obesity; software engineers; and clinicians. Additionally, the team included citizen scientists and clinicians who acted as the de facto software clients for DiaFit and therefore interacted with the production team throughout the entire app creation, from design to testing. Results: DiaFit (version 1.0) is an open-source, inclusive iOS app that incorporates nutrition data, physical activity data, and medication and glucose values, as well as patient-reported outcomes. DiaFit supports the uploading of data from sensory devices via Bluetooth for physical activity (iOS step counts, FitBit, Apple watch) and glucose monitoring (iHealth glucose meter). The app provides summary statistics and graphics for step counts, dietary information, and glucose values that can be used by patients and their providers to make informed health decisions. The DiaFit iOS app was developed in Swift (version 2.2) with a Web back-end deployed on the Health Insurance Portability and Accountability Act compliant-ready Amazon Web Services cloud computing platform. DiaFit is publicly available on GitHub to the diabetes community at large, under the GNU General Public License agreement. Conclusions: Given the proliferation of health-related apps available to health consumers, it is essential to ensure that apps are evidence-based and user-oriented, with specific health conditions in mind. To this end, we have used a software development approach focusing on community and clinical engagement to create DiaFit, an app that assists patients with T2D and obesity to better manage their health through active communication with their providers and proactive self-management of their diseases. PMID- 29388610 TI - Antibiotic prescribing practice in the management of cough or diarrhea among children attending hospitals in Addis Ababa: a cross-sectional study. AB - Background: Irrational use of antibiotics is a global problem. Failure to follow clinical guidelines is one of the main reasons for irrational use of antibiotics. Cough and/or diarrhea are the main childhood illnesses in Ethiopia, and health care providers are expected to follow the national guideline while managing these illnesses. This study tried to assess the extent of adherence to the guideline while managing cases of childhood diarrhea and/or cough. Methods: The study was conducted in 23 hospitals in Addis Ababa. Data were collected prospectively from April to June 2016 using a structured questionnaire. A total of 1,073 children aged 2-59 months who visited the hospitals for cough or diarrhea during the study period were included in the study. Equal number of cases were allocated to each hospital and consecutive cases were included in the study until the calculated sample size was attained for each hospital. Data collectors approached cases after they were seen by the health care provider. SPSS version 20 was used to analyze the data. Result: Of the total number of cases, an antibiotic was prescribed for 794 (74.0%) of the children. Cotrimoxazol 209 (26.3%), amoxicillin 185 (23.3%), and cephalosporines 174 (21.9%) were the three most commonly prescribed antibiotics. Six hundred eighty-eight (86.6%) of the prescriptions were determined to be inappropriate. Of the inappropriate prescriptions, 631 (91.7%) were for prescribing antibiotics when not necessary and 57 (8.3%) were for prescribing the wrong spectrum of antibiotics. Using multivariate analysis, a child not having diarrhea was independently associated with appropriate antibiotic prescription (adjusted odds ratio =0.261, 95% confidence interval: 0.095-0.714). The prescriber being qualified as a pediatrician was an independent predictor of inappropriate antibiotic prescription (adjusted odds ratio =9.967, 95% confidence interval: 4.221-23.532). Conclusion: The magnitude of inappropriate antibiotic prescription while managing cough and/or diarrhea in our setting was high. It needs urgent action to prevent emergence of antibiotic resistant microorganisms. PMID- 29388611 TI - Spotlight on taliglucerase alfa in the treatment of pediatric patients with type 1 Gaucher disease. AB - Gaucher disease (GD) is a heritable storage disorder caused by functional defects of the lysosomal acid beta-glucosidase and the accumulation of glucosylceramide within macrophages, resulting in multiple organ dysfunction. There are three commercially available enzyme replacement therapy (ERT) products for the treatment of GD type 1 (GD1): imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems; imiglucerase requires postproduction deglycosylation to expose terminal alpha-mannose residues, which are required for mannose receptor-mediated uptake by target macrophages. These steps are critical to the success of ERT for the treatment of visceral and hematologic manifestations of GD. Taliglucerase alfa is the first US Food and Drug Administration-approved plant-cell-expressed recombinant human protein, using carrot root cell cultures. Furthermore, it does not require postproduction glycosidic modifications. It is indicated for treatment of adults with GD1 in the US, Israel, Australia, Canada, Chile, Brazil, and other countries, and it is additionally approved for the treatment of pediatric patients in the US, Australia, and Canada and for the treatment of hematologic manifestations in pediatric patients with Type 3 GD in Canada and other countries. Our review focuses on the role of taliglucerase alfa in the pediatric population. A literature search through PubMed (from 1995 up till November 2016) of English language articles was performed with the following terms: Gaucher disease, lysosomal storage disease, taliglucerase. Secondary and tertiary references were obtained by reviewing related articles as well as the website www.Clinicaltrials.gov. It has been demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in pediatric, ERT-naive patients with symptomatic GD1, as well as for those patients previously treated with imiglucerase. PMID- 29388612 TI - Managing acute abdominal pain in pediatric patients: current perspectives. AB - Acute abdominal pain in pediatric patients has been a challenge for providers because of the nonspecific nature of symptoms and difficulty in the assessment and physical examination in children. Although most children with acute abdominal pain have self-limited benign conditions, pain may be a manifestation of an urgent surgical or medical condition where the biggest challenge is making a timely diagnosis so that appropriate treatment can be initiated without any diagnostic delays that increase morbidity. This is weighed against the need to decrease radiation exposure and avoid unnecessary operations. Across all age groups, there are numerous conditions that present with abdominal pain ranging from a very simple viral illness to a life-threatening surgical condition. It is proposed that the history, physical examination, laboratory tests, and imaging studies should initially be directed at differentiating surgical versus nonsurgical conditions both categorized as urgent versus nonurgent. The features of the history including patient's age, physical examination focused toward serious conditions, and appropriate tests are highlighted in the context of making these differentiations. Initial testing and management is also discussed with an emphasis on making use of surgeon and radiologist consultation and the need for adequate follow-up and reevaluation of the patient. PMID- 29388613 TI - Understanding kangaroo care and its benefits to preterm infants. AB - The holding of an infant with ventral skin-to-skin contact typically in an upright position with the swaddled infant on the chest of the parent, is commonly referred to as kangaroo care (KC), due to its simulation of marsupial care. It is recommended that KC, as a feasible, natural, and cost-effective intervention, should be standard of care in the delivery of quality health care for all infants, regardless of geographic location or economic status. Numerous benefits of its use have been reported related to mortality, physiological (thermoregulation, cardiorespiratory stability), behavioral (sleep, breastfeeding duration, and degree of exclusivity) domains, as an effective therapy to relieve procedural pain, and improved neurodevelopment. Yet despite these recommendations and a lack of negative research findings, adoption of KC as a routine clinical practice remains variable and underutilized. Furthermore, uncertainty remains as to whether continuous KC should be recommended in all settings or if there is a critical period of initiation, dose, or duration that is optimal. This review synthesizes current knowledge about the benefits of KC for infants born preterm, highlighting differences and similarities across low and higher resource countries and in a non-pain and pain context. Additionally, implementation considerations and unanswered questions for future research are addressed. PMID- 29388614 TI - Indications and contraindications to transoral thyroidectomy. AB - Patient motivation to avoid neck scarring has been a strong impetus in the development of remote access approaches to the thyroid, including transoral robotic or endoscopic thyroidectomy vestibular approach (TOR/ETVA). TOR/ETVA continues to become more prevalent given its early success in North America and the demonstration of its safety and efficacy in Asia. As more surgeons perform this procedure, it is important that specific and uniform indications and contraindications exist to prevent surgical complications due to poor patient selection. In this article, we review the existing English literature regarding TOR/ETVA and compile the inclusion and exclusion criteria of individual authors for both robotic and endoscopic techniques to date. We then resolve differences in the existing literature to provide recommended indications and contraindications to TOR/ETVA based on both our review and our own experience with TOR/ETVA to date. The following are our resultant recommended indications for TOR/ETVA: patient history of hypertrophic scarring or motivation to avoid a cervical neck incision with a maximal thyroid diameter <= 10 cm and dominant nodule <=6 cm, with one of the following pathologic criteria; benign lesion, multinodular goiter, indeterminate nodule, or suspicious lesions/well differentiated thyroid carcinomas <= 2 cm. Recommended contraindications to TOR/ETVA are as follows: history of head & neck surgery, history of head, neck, or upper mediastinal irradiation, inability to tolerate general anesthesia, evidence of clinical hyperthyroidism, preoperative recurrent laryngeal nerve palsy, lymph node metastasis, extrathyroidal extension including tracheal or esophageal invasion, oral abscesses, substernal thyroidal extension, or failure to meet inclusion criteria as above. Relative contraindications include smoking and other oral pathology, and surgeons should be aware that morbid obesity may make it difficult to raise skin flaps. PMID- 29388615 TI - Congenital central hypoventilation syndrome: diagnostic and management challenges. AB - Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with failure of central control of breathing and of the autonomic nervous system function due to a mutation in the paired-like homeobox 2B (PHOX2B) gene. Affected patients have absent or negligible ventilatory sensitivity to hypercapnia and hypoxemia, and they do not exhibit signs of respiratory distress when challenged with hypercarbia or hypoxia. The diagnosis of CCHS must be confirmed with PHOX2B gene mutation. Generally, the PHOX2B mutation genotype can aid in anticipating the severity of the phenotype. They require ventilatory support for life. Home assisted ventilation options include positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and diaphragm pacing via phrenic nerve stimulation, but each strategy has its associated limitations and challenges. Since all the clinical manifestations of CCHS may not manifest at birth, periodic monitoring and early intervention are necessary to prevent complications and improve outcome. Life-threatening arrhythmias can manifest at different ages and a normal cardiac monitoring study does not exclude future occurrences leading to the dilemma of timing and frequency of cardiac rhythm monitoring and treatment. Given the rare incidence of CCHS, most health care professionals are not experienced with managing CCHS patients, particularly those with diaphragm pacers. With early diagnosis and advances in home mechanical ventilation and monitoring strategies, many CCHS children are surviving into adulthood presenting new challenges in their care. PMID- 29388616 TI - Pediatric case of acute right-sided abdominal pain: diagnosis is not always appendicitis. AB - Omental infarction (OI) is a rare cause of acute abdominal pain occurring in 0.1% of children, which is typically diagnosed during surgery for suspected appendicitis. We present the case of a 7-year-old Pakistani girl. She presented with acute, severe, progressive, right-sided abdominal pain, which was present for 12 hours before presentation. No constitutional symptoms such as fever, anorexia, nausea or vomiting were present. Clinical examination revealed an adequately growing child following the 50th centile. She had severe generalized abdominal tenderness with rebound tenderness and guarding, mainly on the right lower abdominal quadrant, with all other system examinations normal. She had mildly increased inflammatory markers, and her initial abdominal ultrasound scan result was within normal limits. She had laparoscopic surgery following a diagnosis of suspected acute appendicitis; however, an intraoperative diagnosis of OI was made. This was later confirmed by histopathology. This case report highlights the importance of including OI in the differential diagnosis list of acute abdominal pain in children, in addition to the importance of computed tomography (CT) as the gold standard tool to aid diagnosis. In the presence of typical symptoms and signs of OI, a CT scan can assist and guide the management of similar cases. This course of action is suggested for the reason that OI typically runs a self-limited course and conservative care may be the most appropriate recommended course of action. Consequently, unnecessary operations could be avoided due to the diagnosis confirmation of studying images. PMID- 29388617 TI - Childhood body mass index and risk of adult pancreatic cancer. AB - Background: Excess weight in adulthood is one of the few modifiable risk factors for pancreatic cancer, and height has associations as well. This leads to question whether body weight and height in childhood are associated with adult pancreatic cancer. Objective: To examine if childhood body mass index (BMI; kg/m2) and height are associated with pancreatic cancer in adult life. Methods: We linked 293,208 children born from 1930-1982 in the Copenhagen School Health Records Register who had measured values of weights and heights at ages 7-13 years with the Danish Cancer Registry to identify incident pancreatic cancer cases from 1968-2012. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regressions. Results: During 8,207,015 person-years of follow-up, 1,268 pancreatic cancer cases were diagnosed. Childhood BMI z-scores at ages 7-13 years were positively and significantly associated with pancreatic cancer in men and women up to age 70 years; beyond age 70 the associations diminished. The HRs of pancreatic cancer were 1.13 (95% CI: 1.05-1.21) and 1.18 (95% CI: 1.09-1.27) per BMI z-score at ages 7 and 13 years, respectively. A BMI >=1.5 z-score at ages 7, 10 and 13 years was positively and significantly associated with pancreatic cancer; however, the effect did not differ from having a BMI z-score >=1.5 at only one of these ages. Positive, albeit non-statistically significant, associations were identified with height. Conclusions: BMI at all ages from 7-13 years is positively and linearly associated with adult pancreatic cancer; the higher the BMI, the higher the risk. Excess childhood BMI may be indicative of processes initiated early in life that lead to this cancer. Prevention of childhood adiposity may decrease the burden of pancreatic cancer in adults. PMID- 29388618 TI - Preoperative management of children with esophageal atresia: current perspectives. AB - Esophageal atresia remains one of the most challenging congenital anomalies of the newborn. In recent years, because of the advances in prenatal diagnosis, neonatal critical care, and surgical procedures, overall outcomes have improved substantially, including for premature children. Nowadays, most of the research is focused on medium- and long-term morbidity, with particular reference to respiratory and gastroesophageal problems; the high frequency of late sequelae in esophageal atresia warrants regular and multidisciplinary checkups throughout adulthood. Surprisingly, there are few studies on the impact of prenatal diagnosis and there is continuing debate over the prenatal and preoperative management of these complex patients. In this review, we analyze the literature surrounding current knowledge on the management of newborns affected by esophageal atresia, focusing on prenatal management and preoperative assessment. PMID- 29388619 TI - Central neck dissection via the transoral approach. AB - There has been a strong impetus for the development of remote access approaches to the central neck. The primary motivation for this has been to alleviate the negative impact that some patients may perceive from a central neck scar. Numerous approaches have been described; however the only approach that provides midline access and equivalent visualization of the bilateral thyroid lobes and paratracheal basins is transoral neck surgery (TONS). TONS has been shown to be safe and effective in performing thyroidectomy, parathyroidectomy, and central neck dissection (CND) via both the endoscopic and robotic techniques. In contrast with other remote access techniques, it provides the surgeon with familiar views of the bilateral recurrent laryngeal nerves (RLN) at their insertion site in concert with equivalent access to both paratracheal basins, thus uniquely facilitating safe and comprehensive CND. Though feasible and safe, CND via TONS is not appropriate in all cases. CND via TONS should only be performed with concomitant transoral total thyroidectomy, either prophylactically if the surgeon routinely performs prophylactic CND, or therapeutically if there is newly found evidence of nodal metastasis in the central compartment at the time of surgery. We base these recommendations on both the recent American Head and Neck Society (AHNS) consensus statement for indications for transcervical CND and the baseline indications for TONS. PMID- 29388620 TI - Steroid-resistant nephrotic syndrome: past and current perspectives. AB - Patients with steroid-resistant nephrotic syndrome (SRNS) represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of progressing to end-stage renal disease. Appropriate treatment of SRNS requires an adequate understanding of the historical treatment, renal histopathology, and genetics associated with the disease. The aim of this review is to present a comprehensive appraisal of the history, role of renal biopsy, genetics, and treatment of SRNS. PMID- 29388622 TI - Erratum: Nuclear factor-kappaB signaling negatively regulates high glucose induced vascular endothelial cell damage downstream of the extracellular signal regulated kinase/c-Jun N-terminal kinase pathway. AB - [This corrects the article DOI: 10.3892/etm.2017.4999.]. PMID- 29388621 TI - Functional constipation in children: challenges and solutions. AB - This review intends to update what is known about and what is still a challenge in functional constipation (FC) in children regarding epidemiology, pathophysiology, diagnosis, and management. Although FC is a common childhood problem, its global burden remains unknown as data from parts of the world are missing. Another problem is that there is a large variation in prevalence due to differences in study methods and defining age groups. The pathophysiology of FC remains unclear to date but is probably multifactorial. Withholding behavior is likely to be the most important factor in toddlers and young children. Genetics may also play a role since many patients have positive family history, but mutations in genes associated with FC have not been found. Over the past years, different diagnostic criteria for FC in infants and children have been proposed. This year, Rome IV criteria have been released. Compared to Rome III, it eliminates two diagnostic criteria in children under the age of 4 who still wear diapers. Physical examination and taking a thorough medical history are recommended, but other investigations such as abdominal radiography, transabdominal recto-ultrasonography, colonic transit time, rectal biopsies, and colon manometry are not routinely recommended. Regarding treatment, guidelines recommend disimpaction and maintenance therapy with polyethylene glycol (PEG) with or without electrolytes. But experience shows that acceptability, adherence, and tolerance to PEG are still a challenge. Counseling of parents and children about causes of FC is often neglected. Recent studies suggest that behavior therapy added to laxative therapy improves the relief of symptoms. Further homogeneous studies, better-defined outcomes, and studies conducted in primary care are needed. PMID- 29388623 TI - Response to: Lessons from Popper for science, paradigm shifts, scientific revolutions and exercise physiology. PMID- 29388624 TI - Assessment of serum zinc, selenium, and prolactin concentrations in critically ill children. AB - Background: In critically ill patients, there are reduced stores of antioxidants, which are associated with increased organ failure and even higher mortality. Trace elements, especially zinc and selenium, are the cornerstone of the antioxidant defense in acute systemic inflammatory response syndrome. Prolactin (PRL) is the counterregulatory stress hormone that prevents cortisol/stress induced lymphocyte apoptosis. The aim of our study is to detect the serum levels of zinc, selenium, and PRL hormone as important immunomodulators in critically ill children and to investigate the relationship between these immunomodulators and the severity of illness. Subjects and methods: This was a prospective study that included two groups; group 1: 50 critically ill children within 72 hours of intensive care unit admission, and group 2: 30 healthy children as controls. Blood samples were collected from the two groups for zinc, selenium, and PRL level measurement. Results: Zinc and PRL levels were found to be decreased in critically ill children compared to control group, and these levels were inversely correlated with organ failure index and pediatric logistic organ dysfunction scores. Selenium levels were decreased in patients with sepsis and in patients with multiple organ failure. Conclusion: Serum concentrations of zinc and PRL are generally low in critically ill children, with a greater decrease in patients with sepsis and in the presence of multiple organ failure. The levels of zinc and PRL are inversely correlated with severity of illness. Selenium levels were decreased in patients with sepsis and in patients with multiple organ failure. PMID- 29388625 TI - Erratum: Relations between Automatically Extracted Motion Features and the Quality of Mother-Infant Interactions at 4 and 13 Months. AB - [This corrects the article on p. 2178 in vol. 8, PMID: 29326626.]. PMID- 29388627 TI - Septic arthritis in children: diagnosis and treatment. AB - Acute septic arthritis in children is usually hematogenous. It is more common in boys, and it most often affects the large joints of the lower limb. Diagnosis is based on cultures obtained from the infected joint and is supported by C-reactive protein blood test or ultrasound imaging. Staphylococcus aureus is the most common causative agent and is the primary target for empiric treatment. First generation cephalosporins and clindamycin are suitable antibiotics. Vancomycin is utilized in areas with high rates of clindamycin- and methicillin-resistant S. aureus. After a short intravenous administration of 2-4 days, a total course of 2 weeks is sufficient in uncomplicated cases. Early antibiotic treatment has significantly improved the prognosis in high-income settings, but uncomplicated recovery is compromised if the treatment is delayed. Complications such as symptomatic osteoarthritis or avascular necrosis of the femoral head develop slowly. A long follow-up of 1-2 years is required to detect all possible sequelae. PMID- 29388626 TI - Dietary intervention in the management of phenylketonuria: current perspectives. AB - Phenylketonuria (PKU) is a well-described inborn error of amino acid metabolism that has been treated for >60 years. Enzyme deficiency causes accumulation of phenylalanine (Phe) and if left untreated will lead to profound and irreversible intellectual disability in most children. Traditionally, it has been managed with a low-Phe diet supplemented with a Phe-free protein substitute although newer treatment options mainly in combination with diet are available for some subgroups of patients with PKU, for example, sapropterin, large neutral amino acids, and glycomacropeptide. The diet consists of three parts: 1) severe restriction of dietary Phe; 2) replacement of non-Phe l-amino acids with a protein substitute commonly supplemented with essential fatty acids and other micronutrients; and 3) low-protein foods from fruits, some vegetables, sugars, fats and oil, and special low-protein foods (SLPF). The prescription of diet is challenging for health professionals. The high-carbohydrate diet supplied by a limited range of foods may program food preferences and contribute to obesity in later life. Abnormal tasting and satiety-promoting protein substitutes are administered to coincide with peak appetite times to ensure their consumption, but this practice may impede appetite for other important foods. Intermittent dosing of micronutrients when combined with l-amino acid supplements may lead to their poor bioavailability. Much work is required on the ideal nutritional profiling for special SLPF and Phe-free l-amino acid supplements. Although non diet treatments are being studied, it is important to continue to fully understand all the consequences of diet therapy as it is likely to remain the foundation of therapy for many years. PMID- 29388628 TI - Patterns of admission and factors associated with neonatal mortality among neonates admitted to the neonatal intensive care unit of University of Gondar Hospital, Northwest Ethiopia. AB - Introduction: The neonatal period is a highly vulnerable time for an infant completing many of the physiologic adjustments required for life outside the uterus. As a result, there are high rates of morbidity and mortality. The three major causes of mortality in developing countries include prematurity, infection, and perinatal asphyxia. The aim of this study was to identify the patterns of neonatal admission and factors associated with mortality among neonates admitted at the Neonatal Intensive Care Unit (NICU) of University of Gondar Hospital. Materials and methods: A retrospective cross-sectional study was conducted among all admitted neonates in the NICU of University of Gondar referral hospital from December 1, 2015 to August 31, 2016. Information was extracted retrospectively during admission from patient records and death certificates, using a pretested questionnaire. The data were entered and analyzed using SPSS version 20, and p values <0.05 were considered statistically significant. Results: A total of 769 neonates was included in the study. There were 448 (58.3%) male neonates, and 398 (51.8%) neonates were rural residents. More than two-thirds of the 587 deliveries (76.3%) were performed in tertiary hospitals. Neonatal morbidity included hypothermia 546 (71%), sepsis 522 (67.9%), prematurity 250 (34.9%), polycythemia 242 (31.5%), hypoglycemia 142 (18.5), meconium aspiration syndrome 113 (14.7%), and perinatal asphyxia 96 (12.5%). The overall mortality was 110 (14.3%; 95% confidence interval [CI]: 11.9-16.9) of which 69 (62.7%) deaths occurred in the first 24 hours of age. In the multivariate analysis, mortality was associated with perinatal asphyxia (adjusted odds ratio [AOR]: 5.97; 95% CI: 3.06-11.64), instrumental delivery (AOR: 2.99; 95% CI: 1.08-8.31), and early onset neonatal sepsis (AOR: 2.66; 95% CI: 1.62-6.11). Conclusion: Hypothermia, sepsis, and prematurity were the main reasons for NICU admission. Neonates often died within the first 24 hours of age. Implementing a better referral link and timely intervention could decrease neonatal mortality and morbidities in Gondar, Ethiopia. PMID- 29388629 TI - Development and preliminary validation of a new screening questionnaire for identifying atopic children. AB - Background: Allergic diseases represent a frequent and increasing condition affecting children. A screening questionnaire allowing an easy identification of children with symptoms of allergic diseases may improve management and clinical outcome. The aim of this study was to develop and validate an easy-to-use screening questionnaire to detect children requiring further allergological evaluations. Methods: A 10-item questionnaire, evaluating the presence and the history of the most frequent allergic conditions affecting children, including allergic asthma, allergic rhinitis and conjunctivitis, food allergy, and atopic dermatitis, was developed and administered to 214 parents of children from 5 to 10 years of age (163 with allergic disease and 51 healthy, nonallergic children). Validation was performed by Pearson's correlation between the clinical diagnosis and the responses to the questionnaire. Internal consistency was computed by Cronbach's alpha correlation coefficient. Sensitivity and specificity of the novel questionnaire were assessed by the receiver operating characteristic (ROC) curve. Results: Validation analysis of the new children atopy (ChAt) questionnaire showed good internal consistency with a Cronbach's alpha of 0.757. Responses to the items evaluating the presence of individual allergic conditions significantly correlated with the clinical diagnosis (p<0.001). The ROC curve showed an area of 0.956 and identified a cutoff value >2 of the ChAt questionnaire total score for detection of allergy (sensitivity =0.92 and specificity =0.902). Conclusion: The novel ChAt questionnaire represents a simple tool able to detect the presence of all major allergic diseases in a pediatric population allowing an early identification of allergic multimorbidity and potentially facilitating clinical management. PMID- 29388630 TI - Corrigendum: Teaching Undergraduate Students to Visualize and Communicate Public Health Data with Infographics. AB - [This corrects the article on p. 315 in vol. 5, PMID: 29226120.]. PMID- 29388631 TI - The individual time trial as an optimal control problem. AB - In a cycling time trial, the rider needs to distribute his power output optimally to minimize the time between start and finish. Mathematically, this is an optimal control problem. Even for a straight and flat course, its solution is non-trivial and involves a singular control, which corresponds to a power that is slightly above the aerobic level. The rider must start at full anaerobic power to reach an optimal speed and maintain that speed for the rest of the course. If the course is flat but not straight, then the speed at which the rider can round the bends becomes crucial. PMID- 29388632 TI - Pediatric melanoma: incidence, treatment, and prognosis. AB - The purpose of this review is to outline recent advancements in diagnosis, treatment, and prevention of pediatric melanoma. Despite the recent decline in incidence, it continues to be the deadliest form of skin cancer in children and adolescents. Pediatric melanoma presents differently from adult melanoma; thus, the traditional asymmetry, border irregularity, color variegation, diameter >6 mm, and evolution (ABCDE) criteria have been modified to include features unique to pediatric melanoma (amelanotic, bleeding/bump, color uniformity, de novo/any diameter, evolution of mole). Surgical and medical management of pediatric melanoma continues to derive guidelines from adult melanoma treatment. However, more drug trials are being conducted to determine the specific impact of drug combinations on pediatric patients. Alongside medical and surgical treatment, prevention is a central component of battling the incidence, as ultraviolet (UV) related mutations play a central role in the vast majority of pediatric melanoma cases. Aggressive prevention measures targeting sun safety and tanning bed usage have shown positive sun-safety behavior trends, as well as the potential to decrease melanomas that manifest later in life. As research into the field of pediatric melanoma continues to expand, a prevention paradigm needs to continue on a community-wide level. PMID- 29388634 TI - Spotlight on eltrombopag in the treatment of children with chronic immune thrombocytopenia. AB - Pediatric data on the use of thrombopoietin receptor agonists are fairly limited. The recent approval of eltrombopag by the US Food and Drug Administration for children aged >=1 year, based on data from two randomized, placebo-controlled clinical trials, may lead to the increased use of this drug in clinical practice, and therefore, it is important to have a basic understanding of the biology, pharmacokinetics, safety, and efficacy of the medication. PMID- 29388633 TI - Vitamin D deficiency and anemia risk in children: a review of emerging evidence. AB - There has been renewed scientific interest in the sequelae of vitamin D deficiency, given the emerging evidence on the diverse biologic functions of vitamin D, besides its fundamental role in bone and mineral metabolism. For the past decade, the evidence in the medical literature pointing to a relationship between anemia risk and vitamin D deficiency has been accumulating. This paper critically reviews the current evidence linking vitamin D deficiency to anemia risk in children. The synthesized evidence indicates that the studies, which were preponderantly conducted among the adult population, not only reported a bidirectional relationship between vitamin D deficiency and anemia but also showed a racial effect. In studies conducted among children, similar results were reported. Although the causal association of vitamin D deficiency with anemia risk (especially iron-deficiency anemia) remains debatable, the noncalcemic actions of the vitamin and its analogs hold prospects for several novel clinical applications. There is, however, unanimity in many reports suggesting that vitamin D deficiency is directly associated with anemia of chronic disease or inflammation. Despite the advances in unraveling the role of vitamin D in iron homeostasis, further research is still required to validate causality in the relationship between vitamin D deficiency and anemia, as well as to determine its optimal dosing, the ideal recipients for therapeutic intervention, and the preferred analogs to administer. PMID- 29388635 TI - Adopted youth and sleep difficulties. AB - Sleep is a critical component of healthy development for youth, with cascading effects on youth's biological growth, psychological well-being, and overall functioning. Increased sleep difficulties are one of many disruptions that adopted youth may face throughout the adoption process. Sleep difficulties have been frequently cited as a major concern by adoptive parents and hypothesized in the literature as a problem that may affect multiple areas of development and functioning in adopted youth. However, there is limited research exploring this relationship. Using a biopsychosocial framework, this paper reviews the extant literature to explore the development, maintenance, and impact of sleep difficulties in adopted youth. Finally, implications for future research and clinical interventions are outlined. PMID- 29388636 TI - Current perspectives on the optimal management of infantile hemangioma. AB - Infantile hemangiomas (IHs) are the most common benign tumor of infancy. As our understanding of their pathobiology has evolved, treatment has become more focused and tailored to specifically treat IH while minimizing adverse effects. Propranolol has gained FDA approval as the first medical therapy for a traditionally surgical disease. This review provides readers with an overview of IH, treatment modalities, and addresses specific considerations in IH disease management. PMID- 29388637 TI - Evolution of membrane oxygenator technology for utilization during pediatric cardiopulmonary bypass. AB - The development of the membrane oxygenator for pediatric cardiopulmonary bypass has been an incorporation of ideology and technological advancements with contributions by many investigators throughout the past two centuries. With the pursuit of this technological achievement, the ability to care for mankind in the areas of cardiac surgery has been made possible. Heart disease can affect anyone within the general population, but one such segment that it can affect from inception includes children. Currently, congenital heart defects are the most common birth defects nationally and worldwide. A large meta-analysis study from 1930 to 2010 was conducted in review of published medical literature totaling 114 papers with a study population of 24,091,867 live births, and divulged a staggering incidence of congenital heart disease involving 164,396 subjects with diverse cardiac illnesses. The prevalence of these diseases increased from 0.6 per 1,000 live births from 1930-1934 to 9.1 per 1,000 live births after 1995. These data reveal an emphasis on a growing public health issue regarding congenital heart disease. This discovery displays a need for heightened awareness in the scientific and medical industrial community to accelerate investigative research on emerging cardiovascular devices in an effort to confront congenital anomalies. One such device that has evolved over the past several decades is the pediatric membrane oxygenator. The pediatric membrane oxygenator, in conjunction with the heart lung machine, assists in the repair of most congenital cardiac defects. Numerous children born with congenital heart disease with or without congestive heart failure have experienced improved clinical outcomes in quality of life, survival, and mortality as a result of the inclusion of this technology during their cardiac surgical procedure. The purpose of this review is to report a summary of the published medical and scientific literature related to development of the pediatric membrane oxygenator from its conceptual evolutionary stages to artificially supporting whole body perfusion in the modern pediatric cardiac surgical setting. PMID- 29388640 TI - Multiionic effects on the capacitance of porous electrodes. AB - The rapid and reversible ionic electrosorption in the electrical double layers (EDLs) of moderately charged micropores in contact with a solution is the main concept underlying capacitive energy and desalination devices. For the usual operating conditions, the ion concentration is large enough for the confinement of ions to play an important role in their distribution in the EDL. On the other hand, although most laboratory experiments have been carried out with simple salt solutions, realistic applications require a proper analysis of the effect of the different ionic species existing in natural waters. Here we focus on the role of multiionic solutions on the double layer structure. For this purpose, a model is presented in which the EDL overlap and the existence of a Stern layer are considered. It is also taken into account that the ions can be tightly packed by using the Carnahan-Starling model. This model is applied to analyze the structure of the EDL with multiionic solutions containing divalent ions. The predictions of this model are found to largely differ from those of the better known Bikerman equation, and are more realistic. It is demonstrated that the presence of tiny amounts of divalent ions in the bulk is enough to dominate the EDL behavior, and hence, its capacitance, energy storage, and desalination properties. PMID- 29388639 TI - Selective determination of semi-volatile thiophene compounds in water by molecularly imprinted polymer thin films with direct headspace gas chromatography sulfur chemiluminescence detection. AB - Water-compatible molecularly imprinted polymer (MIP) thin films are coupled with headspace gas chromatography sulfur chemiluminescence detection (HS-GC-SCD) to create a new approach for the determination of trace concentrations of thiophene compounds in water samples. Thiophene compounds are persistent, typically petrogenic, organic pollutants of concern due to their potential for biomagnification and bioaccumulation, mutagenicity, and carcinogenicity in terrestrial and aquatic fauna. Identification and quantitation in water, particularly following oil spills, is a priority. Following adsorption of the thiophenes to the MIPs, the MIP-bound analytes are analyzed directly by HS-GC SCD, with minimal sample manipulation and virtually no organic solvent. Calibration curves of spiked seawater were linear from 5 MUg L-1 to 100 MUg L-1 and limits of detection (LOD) were in the range of 0.24-0.82 MUg L-1. Low matrix effects were observed in the analysis of thiophene compounds in seawater making the method suitable for use in fresh and saline waters without modification. Acceptable reproducibility was obtained for analysis of thiophene compounds from spiked seawater samples at RSDs <=7.0% (n = 3). PMID- 29388638 TI - Developing ciprofloxacin analogues against plant DNA gyrase: a novel herbicide mode of action. AB - Ciprofloxacin has been shown to exhibit potent herbicidal activity through action against plant DNA gyrase, presenting a novel mode of action. Analogues of ciprofloxacin have been prepared with increased herbicidal activity and diminished antibacterial activity, compared to ciprofloxacin, as demonstrated using model systems. PMID- 29388641 TI - Conflicting effect of chemical doping on the thermoelectric response of ordered PEDOT aggregates. AB - Poly(3,4-ethylenedioxythiophene) (PEDOT) semiconductor plays a relevant role in the development of organic thermoelectric (TE) devices for low-power generation. While dopant counterions are usually needed to provide electrical conductivity, their overall effects on the thermoelectric response of the systems are unknown and uncontrolled. Here, we present a first principles study of the electronic and thermal transport of PEDOT crystalline assemblies, specifically analysing the role played by tosylate dopants on the thermoelectric figure of merit of the doped system. Our results demonstrate that, beside the desired charging effect, the presence of dopants impacts the bulk configuration by inflating the packing structure and worsening the intrinsic transport properties of the PEDOT host. This provides a rationale for the necessity of controlling the optimal amount and the structural incorporation of dopant in order to maximize the thermoelectric response of organic materials. PMID- 29388642 TI - Modeling the adsorption equilibrium of small-molecule gases on graphene: effect of the volume to surface ratio. AB - In most technological applications involving liquids or gases interacting with solids, the first event is the adsorption of molecules onto a solid surface. Here, we focus on the theoretical understanding of adsorption equilibrium at the solid-gas interface. In the limit of physisorption, we find that adsorption probability is independent of the initial concentration of monomers, whereas it varies with the available volume to surface ratio, which depends on the experimental setup. This theoretical finding is verified numerically by molecular dynamics simulations of five small-molecule gases physisorbing on graphene. The simulations provide quantitative estimates of the adsorption free energy, which are used to benchmark analytical and numerical integrations of the corresponding partition functions. The significance of the above theoretical result is analyzed in the context of molecular self-assembly at surfaces and interfaces. Our interpretation indicates that there exist (at least) two distinct pathways for 2D self-assembly, which may or may not involve the formation of a 2D disordered intermediate. Also, it predicts that the critical concentration for self-assembly may be shifted by varying the aspect ratio of the experimental setup. PMID- 29388643 TI - Triarylmethyl-based 2D covalent networks: virtual screening of chemical functionalisation for optimising strain-induced property control. AB - Two-dimensional covalent networks based on triarylmethyl (TAM) radical monomers have been proposed as versatile materials whose unpaired electrons may be externally localised/delocalised through the application of external uniaxial strain. This phenomenon arises through the strain-induced variance of the dihedral twist angles of the aryl rings within the network, and allows the control of important physico-chemical properties (e.g. magnetic interactions, electronic band gap). In order to experimentally realise such materials, one must find a compromise between the kinetic stability of the TAM monomers (through sterically protecting the radical centre with the appropriate aryl ring functionalisation) and the structural flexibility of the resulting material (provided by low intra-ring steric hindrance). In this work, through an efficient search procedure based on force field-based screening, employing ~1750 calculations, followed by selected accurate electronic structure calculations, we provide support for the experimental viability of TAM-based 2D networks with highly controllable properties. PMID- 29388644 TI - Exotic species with explicit noble metal-noble gas-noble metal linkages. AB - We present a study of the isoelectronic Pt2Ng2F4 and [Au2Ng2F4]2+ species with noble gas atoms (Ng = Kr, Xe, Rn) acting as links bridging the two noble metal atoms. The stability of the species is investigated using several thermodynamic, kinetic and reactivity indicators. The results are compared against [AuXe4]2+, which is thermodynamically unstable in the gas phase but is stabilized in the solid state to the point that it has been experimentally detected as [AuXe4](Sb2F11)2 (S. Seidel and K. Seppelt, Science, 2000, 290, 117-118). Our results indicate that improving upon [AuXe4]2+, these exotic combinations between the a priori non-reactive noble metals and noble gases lead to metastable species, and, therefore, they have the possibility of existing in the solid state under adequate conditions. Our calculations include accurate energies and geometries at both the CCSD/SDDALL and MP2/SDDALL levels. We offer a detailed description of the nature of the bonding interactions using orbital and density based analyses. The computational evidence suggests partially covalent and ionic interactions as the stabilization factors. PMID- 29388645 TI - Enhancing electrical energy storage capability of dielectric polymer nanocomposites via the room temperature Coulomb blockade effect of ultra-small platinum nanoparticles. AB - Introducing a high dielectric constant (high-k) nanofiller into a dielectric polymer is the most common way to achieve flexible nanocomposites for electrostatic energy storage devices. However, the significant decrease of breakdown strength and large increase of dielectric loss has long been known as the bottleneck restricting the enhancement of practical energy storage capability of the nanocomposites. In this study, by introducing ultra-small platinum (<2 nm) nanoparticles, high-k polymer nanocomposites with high breakdown strength and low dielectric loss were prepared successfully. Core-shell structured polydopamine@BaTiO3 (PDA@BT) and core-satellite ultra-small platinum decorated PDA@BT (Pt@PDA@BT) were used as nanofillers. Compared with PDA@BT nanocomposites, the maximum discharged energy density of the Pt@PDA@BT nanocomposites is increased by nearly 70% because of the improved energy storage efficiency. This research provides a simple, promising and unique way to enhance energy storage capability of high-k polymer nanocomposites. PMID- 29388646 TI - The S-functionalized Ti3C2 Mxene as a high capacity electrode material for Na-ion batteries: a DFT study. AB - MXenes are attracting much attention as electrode materials due to their excellent energy storage properties and electrical conductivity, and the energy storage capacities were found to strongly depend on the surface terminal groups. Here S-functionalized Ti3C2 as a representative MXene material is designed. Our density functional theory (DFT) calculations are performed to investigate the geometric and electronic properties, dynamic stability, and Na storage capability of Ti3C2, Ti3C2O2 and Ti3C2S2 systems. The Ti3C2S2 monolayer is proved to show metallic behavior and has a stable structure, and meanwhile it also exhibits a low diffusion barrier and high storage capacity (up to Ti3C2S2Na4 stoichiometry) for Na ion batteries (NIBs). The superior properties such as good electrical conductivity, fast charge-discharge rates, low open circuit voltage (OCV), and high theoretical Na storage capacity, make the Ti3C2S2 monolayer a promising anode material for NIBs compared to the Ti3C2O2 monolayer. More importantly, similar to the Ti3C2S2 monolayer, other MXenes with a high charge density difference and suitable lattice constant can be formed, and thus the energy storage properties are worth further study. This finding will be useful to the design of anode materials for NIBs. PMID- 29388647 TI - N terminal N-methylation modulates chiral centre induced helical (CIH) peptides' biophysical properties. AB - The effects of N-methylation on CIH peptides' biophysical properties were systematically studied. N-Methylation at the N terminal NH could help improve the peptides' cellular uptake with a retained helical conformation. This N methylation strategy could also be applied to longer peptides to improve their stability and cellular uptake. PMID- 29388648 TI - Facile synthesis of Bi/BiVO4 composite ellipsoids with high photocatalytic activity. AB - BiVO4-based composites have been extensively investigated as promising photocatalysts due to their strong visible-light absorption. In this work, novel Bi/BiVO4 composites with excellent photocatalytic performance were firstly fabricated via a simple hydrothermal method, using BiVO4 as a self-sacrificing template and N2H4.H2O as a reductant. In the hydrothermal process, partial BiVO4 was reduced to form metallic Bi nanoparticles, which were deposited on the surface of BiVO4. The Bi content in the Bi/BiVO4 composites could be easily tuned by controlling the concentration of the N2H4.H2O solution. The photocatalytic performance of the Bi/BiVO4 composites was examined by studying the photodecomposition of RhB under visible-light illumination. The experimental results revealed that the Bi/BiVO4 composites exhibit high visible-light photocatalytic activity for the photodegradation of RhB compared with that of pure BiVO4. This enhanced photocatalytic activity likely originates from the strong visible-light absorption and high separation efficiency of photogenerated electron-hole pairs by Bi nanoparticles. This work presents a new approach for the development of Bi/BiVO4 composite photocatalysts with high activity and stability. PMID- 29388649 TI - Intrinsic hydrophilic nature of epitaxial thin-film of rare-earth oxide grown by pulsed laser deposition. AB - Herein, we report a systematic study of water contact angle (WCA) of rare-earth oxide thin-films. These ultra-smooth and epitaxial thin-films were grown using pulsed laser deposition and then characterized using X-Ray diffraction (XRD), Rutherford backscattering spectroscopy (RBS), and atomic force microscopy (AFM). Through both the traditional sessile drop and the novel f-d method, we found that the films were intrinsically hydrophilic (WCA < 10 degrees ) just after being removed from the growth chamber, but their WCAs evolved with an exposure to the atmosphere with time to reach their eventual saturation values near 90 degrees (but always stay 'technically' hydrophilic). X-Ray photoelectron spectroscopy analysis was used to further investigate qualitatively the nature of hydrocarbon contamination on the freshly prepared as well as the environmentally exposed REO thin-film samples as a function of the exposure time after they were removed from the deposition chamber. A clear correlation between the carbon coverage of the surface and the increase in WCA was observed for all of the rare-earth films, indicating the extrinsic nature of the surface wetting properties of these films and having no relation to the electronic configuration of the rare-earth atoms as proposed by Azimi et al. PMID- 29388650 TI - Towards substrate engineering of graphene-silicon Schottky diode photodetectors. AB - Graphene-silicon Schottky diode photodetectors possess beneficial properties such as high responsivities and detectivities, broad spectral wavelength operation and high operating speeds. Various routes and architectures have been employed in the past to fabricate devices. Devices are commonly based on the removal of the silicon-oxide layer on the surface of silicon by wet-etching before deposition of graphene on top of silicon to form the graphene-silicon Schottky junction. In this work, we systematically investigate the influence of the interfacial oxide layer, the fabrication technique employed and the silicon substrate on the light detection capabilities of graphene-silicon Schottky diode photodetectors. The properties of devices are investigated over a broad wavelength range from near-UV to short-/mid-infrared radiation, radiation intensities covering over five orders of magnitude as well as the suitability of devices for high speed operation. Results show that the interfacial layer, depending on the required application, is in fact beneficial to enhance the photodetection properties of such devices. Further, we demonstrate the influence of the silicon substrate on the spectral response and operating speed. Fabricated devices operate over a broad spectral wavelength range from the near-UV to the short-/mid-infrared (thermal) wavelength regime, exhibit high photovoltage responses approaching 106 V W-1 and short rise- and fall-times of tens of nanoseconds. PMID- 29388651 TI - NANoPoLC algorithm for correcting nanoparticle concentration by sample polydispersity. AB - Variability in the polydispersity of colloidal nanoparticles results in significant differences in the total number of nanoparticles available for the determination of their concentration, which ultimately affects their bioavailability and biodistribution. In the current work, we developed a novel algorithm, named Nanoparticle Polydispersity Corrector (NANoPoLC), which was shown to render a more realistic calculation of the actual nanoparticle concentration in solution. PMID- 29388652 TI - Near infrared harvesting dye-sensitized solar cells enabled by rare-earth upconversion materials. AB - Dye-sensitized solar cells (DSSCs) have been deemed as promising alternatives to silicon solar cells for the conversion of clean sunlight energy into electricity. A major limitation to their conversion efficiency is their inability to utilize light in the infrared (IR) spectral range, which constitutes almost half the energy of the sun's radiation. This fact has elicited motivations and endeavors to extend the response wavelength of DSSCs to the IR range. Photon upconversion through rare-earth ions constitutes one of the most promising approaches toward the goal of converting near-IR (NIR) or IR light into visible or ultraviolet light, where DSSCs typically have high sensitivity. In the present review, we summarize recent progress based on the utilization of various upconversion materials and device structures to improve the performance of dye-sensitized solar cells. PMID- 29388653 TI - Photomechanical motion of diarylethene molecular crystal nanowires. AB - Crystalline nanowires composed of the photochromic diarylethene derivative 1,2 bis(2,4-dimethyl-5-phenyl-3-thienyl)perfluorocyclopentene (1a) are prepared and characterized. 200 nanometer diameter wires with a length of 60 microns are grown by slow solvent annealing in a porous anodic aluminum oxide template. The nanowires are oriented crystals, as determined by X-ray diffraction measurements, and can be liberated by dissolving the template in acid. They exhibit pronounced bending when exposed to ultraviolet light that can be reversed by visible light irradiation. The bending-unbending sequence can be repeated for more than 10 cycles without fatigue. This robustness results from the ability of the nanowires to maintain their crystallinity during the forward and reverse reactions. The small diameter of these nanowires allows them to achieve curvatures that are at least 40 times greater (200 mm-1versus 5 mm-1) than those observed for micron thick diarylethene needles. This first demonstration of photomechanical nanostructures based on diarylethene photochromism opens up the possibility of making more complicated structures composed of this high-performance photochrome. PMID- 29388654 TI - Passive membrane penetration by ZnO nanoparticles is driven by the interplay of electrostatic and phase boundary conditions. AB - The internalization of nanoparticles through the biological membrane is of immense importance for biomedical applications. A fundamental understanding of the lipid specificity and the role of the membrane biochemical and physical forces at play in modulating penetration are lacking. The current understanding of nanoparticle-membrane interaction is drawn mostly from computational studies and lacks sufficient experimental evidence. Herein, using confocal fluorescence imaging and potentiometric dye-based fluorimetry, we first investigated the interaction of ZnONP in both multi-component and individual lipid membranes using cell-like giant unilamellar vesicles to dissect the lipid specificity; also, we investigated the changes in membrane order, anisotropy and hydrophobicity. ZnONP was found to interact with phosphatidylinositol and phosphatidylcholine head group-containing lipids specifically. We further investigated the interaction of ZnONP with three physiologically relevant membrane conditions varying in composition and dipole potential. We found that ZnONP interaction leads to a photoinduced enhancement of the partial-to-complete phase separation depending upon the membrane composition and cholesterol content. Interestingly, while the lipid order of a partially-phase-separated membrane remained unchanged upon ZnONP crowding, a fully-phase-separated membrane showed an increase in the lipid order. Strikingly, ZnONP crowding induced a contrasting effect on the fluorescence anisotropy of the membrane upon binding to the two membrane conditions, in line with the measured diffusion coefficient. ZnONP seems to preferentially penetrate through the liquid disordered areas of the membrane and the boundaries of the phase-separated regions driven by the interplay between the electrostatics and phase boundary conditions, which are collectively dictated by the composition and ZnONP-induced lipid reorganization. The results may lead to a greater understanding of the interplay of membrane parameters and ZnONP interaction in driving passive penetration. PMID- 29388656 TI - Fluctuating potentials in GaAs:Si nanowires: critical reduction of the influence of polytypism on the electronic structure. AB - In this work, the effects of Si doping in GaAs nanowires (NWs) grown on GaAs (111)B by molecular beam epitaxy with different Si doping levels (nominal free carrier concentrations of 1 * 1016, 8 * 1016, 1 * 1018 and 5 * 1018 cm-3) are deeply investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), grazing incidence X-ray diffraction (GID), photoluminescence (PL) and cathadoluminescence (CL). TEM results reveal a mixture of wurtzite (WZ) and zinc-blende (ZB) segments along the NW axis independently of the Si doping levels. GID measurements suggest a slight increase of the ZB fraction with the Si doping. Low temperature PL and CL spectra exhibit sharp lines in the energy range 1.41-1.48 eV, for the samples with lower Si doping levels. However, the emission intensity increases and is accompanied by a clear broadening of the observed lines for the samples with higher Si doping levels. The staggered type-II band alignment only determines the optical properties of the lower doping levels in GaAs:Si NWs. For the higher Si doping levels, the electronic energy level structure of the NWs is determined by electrostatic fluctuating potentials intimately related to the amphoteric behavior of the Si dopant in GaAs. For the heavily doped NWs, the estimated depth of the potential wells is ~96-117 meV. Our results reveal that the occurrence of the fluctuating potentials is not dependent on the crystalline phase and shows that the limitation imposed by the polytypism can be overcome. PMID- 29388658 TI - Electronic and mechanical characteristics of stacked dimer molecular junctions. AB - Break-junction measurements are typically aimed at characterizing electronic properties of single molecules bound between two metal electrodes. Although these measurements have provided structure-function relationships for such devices, there is little work that studies the impact of molecule-molecule interactions on junction characteristics. Here, we use a scanning tunneling microscope based break-junction technique to study pi-stacked dimer junctions formed with two amine-terminated conjugated molecules. We show that the conductance, force and flicker noise of such dimers differ dramatically when compared with the corresponding monomer junctions and discuss the implications of these results on intra- and inter-molecular charge transport. PMID- 29388660 TI - Effective and diastereoselective preparation of dispiro[cyclopent-3' ene]bisoxindoles via novel [3 + 2] annulation of isoindigos and MBH carbonates. AB - A novel and diastereoselective [3 + 2] annulation of isoindigos and Morita-Baylis Hillman carbonates has been developed for the highly efficient and one-step preparation of highly steric dispiro[cyclopent-3'-ene]bisoxindoles with two all carbon quaternary spirocenters and three adjacent cycles in excellent yields (up to >99%) and diastereoselectivities (up to >20 : 1) under mild conditions within a few minutes. A series of dispiro[cyclopent-3'-ene]bisoxindoles were obtained and scale-up experiment was conducted with excellent results demonstrating the potential applications of this protocol. PMID- 29388667 TI - Arginine-selective bioconjugation with 4-azidophenyl glyoxal: application to the single and dual functionalisation of native antibodies. AB - Here, we introduce 4-azidophenyl glyoxal (APG) as an efficient plug-and-play reagent for the selective functionalisation of arginine residues in native antibodies. The selective reaction between APG and arginines' guanidine groups allowed a facile introduction of azide groups on the monoclonal antibody trastuzumab (plug stage). These pre-functionalised antibody-azide conjugates were then derivatised during the "play stage" via a biorthogonal cycloaddition reaction with different strained alkynes. This afforded antibody-fluorophore and antibody-oligonucleotide conjugates, all showing preserved antigen selectivity and high stability in human plasma. Due to a lower content of arginines compared to lysines in native antibodies, this approach is thus attractive for the preparation of more homogeneous conjugates. This method proved to be orthogonal to classical lysine-based conjugation and allowed straightforward generation of dual-payload antibody. PMID- 29388669 TI - Information, support, and follow-up offered to women who experienced severe maternal morbidity. AB - OBJECTIVE: To determine what information, support, and follow-up were offered to women who had experienced severe maternal morbidity (SMM). METHODS: The present retrospective case review included patients who experienced SMM (admission to intensive care during pregnancy or up to 42 days postpartum) who had previously been reviewed for potential preventability as part of a nationwide New Zealand study performed between January 1 and December 31, 2014. Data were audited to ascertain documented evidence of an event debrief or explanation; referral to social support and/or mental health services; a detailed discharge letter; and a follow-up appointment with a specialist. RESULTS: Of 257 patients who experienced SMM, 23 (8.9%) were offered all four components of care, 99 (38.5%) an event debrief, 102 (39.7%) a referral to social support and/or mental health services, 148 (57.6%) a detailed discharge letter, and 131 (51.0%) a follow-up appointment. CONCLUSIONS: Many women who had experienced SMM did not receive explanatory information about their illness, an offer of psychosocial support, or a follow-up appointment prior to discharge from hospital. It is incumbent on clinicians and the maternity care system to improve these aspects of care for all women experiencing a potentially life-changing SMM event to minimize the risk and burden of long-term mental illness. PMID- 29388670 TI - Zika virus outbreaks and treatment in pregnant women in Ho Chi Minh City, Vietnam. PMID- 29388671 TI - Bulleyaconitine A prevents Ti particle-induced osteolysis via suppressing NF kappaB signal pathway during osteoclastogenesis and osteoblastogenesis. AB - Balanced bone resorption and bone formation are vital for bone homeostasis. Excessive osteoclastic bone resorption in this process can cause a variety of bone disorders including osteoporosis, aseptic prosthetic loosening and tumor associated bone destruction. Bulleyaconitine A (BLA) is a natural compound that has been widely used for pain treatment but its role in osteolysis has not yet been investigated. In this study, we verified for the first time that BLA inhibited osteoclast formation, the mRNA expression of osteoclast-related genes and osteoclastic bone resorption by inhibiting NF-kappaB signal pathway and downstream NFATc1 expression. Meanwhile, BLA had a stimulatory effect in osteoblast differentiation and mineralization. Furthermore, BLA showed preventive effect in Ti particle-induced osteolysis model in vivo. Together, all our data demonstrated that BLA suppressed osteoclastogenesis and promoted osteoblastogenesis via suppressing NF-kappaB signal pathway and could be an alternative therapeutic choice against bone loss. PMID- 29388672 TI - Use of the purple line to diagnose cervical dilatation and fetal head station during labor. PMID- 29388673 TI - Expanding the clinical and genetic spectra of NKX6-2-related disorder. AB - Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole-exome or whole-genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype-phenotype correlation. PMID- 29388674 TI - Pain self-management plus nurse-led support in young adults with irritable bowel syndrome: Study protocol for a pilot randomized control trial. AB - Irritable bowel syndrome (IBS) is a functional gut disorder that typically manifests in early adult years. IBS patients report that pain is the most distressing symptom with the greatest impact on quality of life. Pain-sensitivity genes and the gut microbiome may influence severity of symptoms as well as response to self-management (SM) interventions. Based on current understanding of the science of SM, pain neurophysiology, and the gut-brain axis, our team developed a pain SM intervention to be added to evidence-based self-management instruction to increase the individual's SM knowledge and skills (self-efficacy, self-regulation, and goal-setting). The purpose of this randomized controlled longitudinal pilot study is to examine the feasibility, acceptability, and preliminary effectiveness of the IBS-pain SM intervention on IBS-pain SM behaviors and related health outcomes. A sample of 80 young adults (age 18-29 years old) will be recruited and randomly assigned to the experimental or control group. Both groups will receive 10 electronic video modules focused on IBS-pain SM knowledge and skills. The experimental group also will receive nurse-led one on-one phone consultations to facilitate monitoring and problem-solving. All participants will be followed over 12 weeks. Primary outcomes will be measured at baseline, 6 weeks, and 12 weeks, including IBS-pain SM behaviors, quality of life, and well-being. The influence of pain-sensitivity genes and the gut microbiome on IBS-pain SM behaviors and health outcomes also will be assessed. PMID- 29388675 TI - Influenza vaccines in immunosuppressed adults with cancer. AB - BACKGROUND: This is an update of the Cochrane review published in 2013, Issue 10.Immunosuppressed cancer patients are at increased risk of serious influenza related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear. OBJECTIVES: To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all-cause mortality, preferably at the end of the influenza season. Influenza-like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza-related mortality and immunogenicity were defined as secondary outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases. SELECTION CRITERIA: Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case-control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post-autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta-analysis could not be performed because of different outcome and denominator definitions in the included studies. MAIN RESULTS: We identified six studies with a total of 2275 participants: five studies comparing vaccination with no vaccination, and one comparing adjuvanted vaccine with non-adjuvanted vaccine. Three studies were RCTs, one was a prospective observational cohort study and two were retrospective cohort studies.For the comparison of vaccination with no vaccination we included two RCTs and three observational studies, including 2202 participants. One study reported results in person-years while the others reported results per person. The five studies were performed between 1993 and 2015 and included adults with haematological diseases (three studies), patients following bone marrow transplantation (BMT) (two studies) and solid malignancies (three studies).One RCT and two observational studies reported all-cause mortality; the RCT showed similar mortality rates in both arms (odds ratio (OR) 1.25 (95% CI 0.43 to 3.62; 1 study, 78 participants, low-certainty evidence)); and the observational studies demonstrated a significant association between vaccine receipt and lower risk of death, adjusted hazard ratio 0.88 (95% CI 0.78 to 1; 1 study, 1577 participants, very low-certainty evidence) in one study and OR 0.42 (95% CI 0.24 to 0.75; 1 study, 806 participants, very low-certainty evidence) in the other. One RCT reported a reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in one RCT and the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. One RCT showed a reduction in hospitalisations following vaccination, while an observational study found no difference. No life threatening or persistent adverse effects from vaccination were reported. The strength of evidence was limited by the low number of included studies and by their low methodological quality and the certainty of the evidence for the mortality outcome according to GRADE was low to very low.For the comparison of adjuvanted vaccine with non-adjuvanted vaccine, we identified one RCT, including 73 patients. No differences were found for the primary and all secondary outcomes assessed. Mortality risk ratio was 0.54 (95% CI 0.05 to 5.73; low-certainty evidence) in the adjuvanted vaccine group. The quality of evidence was low due to the small sample size and the large confidence intervals for all outcomes. AUTHORS' CONCLUSIONS: Observational data suggest lower mortality and infection related outcomes with influenza vaccination. The strength of evidence is limited by the small number of studies and low grade of evidence. It seems that the evidence, although weak, shows that the benefits overweigh the potential risks when vaccinating adults with cancer against influenza. However, additional placebo or no-treatment controlled RCTs of influenza vaccination among adults with cancer is ethically questionable.There is no conclusive evidence regarding the use of adjuvanted versus non-adjuvanted influenza vaccine in this population. PMID- 29388676 TI - Network Meta-Analysis Comparing the Efficacy of Therapeutic Treatments for Bronchiolitis in Children. AB - BACKGROUND: This study aims to compare placebo (PBO) and 7 therapeutic regimens namely, bronchodilator agents (BAs), hypertonic saline (HS), BA +/- HS, corticosteroids (CS), epinephrine (EP), EP +/- CS, and EP +/- HS-to determine the optimal bronchiolitis treatment. METHODS: We plotted networks using the curative outcome of several studies and specified the relations among the experiments by using mean difference, standardized mean difference, and corresponding 95% credible interval. The surface under the cumulative ranking curve (SUCRA) was used to separately rank each therapy on clinical severity score (CSS) and length of hospital stay (LHS). RESULTS: This network meta-analysis included 40 articles from 1995 to 2016 concerning the treatment of bronchiolitis in children. All 7 therapeutic regimens displayed no significant difference to PBO with regard to CSS in our study. Among the 7 therapies, BA performed better than CS. As for LHS, EP and EP +/- HS had an advantage over PBO. Moreover, EP and EP +/- HS were also more efficient than BA. The SUCRA results showed that EP +/- CS is most effective, and EP +/- HS is second most effective with regard to CSS. With regard to LHS, EP +/- HS ranked first, EP +/- CS ranked second, and EP ranked third. CONCLUSIONS: We recommend EP +/- CS and EP +/- HS as the first choice for bronchiolitis treatment in children because of their outstanding performance with regard to CSS and LHS. PMID- 29388677 TI - Effects of Emulsifier, Overrun and Dasher Speed on Ice Cream Microstructure and Melting Properties. AB - : Ice cream is a multiphase frozen food containing ice crystals, air cells, fat globules, and partially coalesced fat globule clusters dispersed in an unfrozen serum phase (sugars, proteins, and stabilizers). This microstructure is responsible for ice cream's melting characteristics. By varying both formulation (emulsifier content and overrun) and processing conditions (dasher speed), the effects of different microstructural elements, particularly air cells and fat globule clusters, on ice cream melt-down properties were studied. Factors that caused an increase in shear stress within the freezer, namely increasing dasher speed and overrun, caused a decrease in air cell size and an increase in extent of fat destabilization. Increasing emulsifier content, especially of polysorbate 80, caused an increase in extent of fat destabilization. Both overrun and fat destabilization influenced drip-through rates. Ice creams with a combination of low overrun and low fat destabilization had the highest drip-through rates. Further, the amount of remnant foam left on the screen increased with reduced drip-through rates. These results provide a better understanding of the effects of microstructure components and their interactions on drip-through rate. PRACTICAL APPLICATIONS: Manipulating operating and formulation parameters in ice cream manufacture influences the microstructure (air cells, ice crystals, and fat globule clusters). This work provides guidance on which parameters have most effect on air cell size and fat globule cluster formation. Further, the structural characteristics that reduce melt-down rate were determined. Ice cream manufacturers will use these results to tailor their products for the desired quality attributes. PMID- 29388679 TI - Viral etiologies and epidemiology of patients with acute respiratory infections based on sentinel hospitals in Gansu Province, Northwest China, 2011-2015. AB - Understanding etiological role and epidemiological profile is needed to improve clinical management and prevention of acute respiratory infections (ARIs). A 5 year prospective study about active surveillance for outpatients and inpatients with ARIs was conducted in Gansu province, China, from January 2011 to November 2015. Respiratory specimens were collected from patients and tested for eight respiratory viruses using polymerase chain reaction (PCR) or reverse transcription polymerase chain reaction (RT-PCR). In this study, 2768 eligible patients with median age of 43 years were enrolled including pneumonia (1368, 49.2%), bronchitis (435, 15.7%), upper respiratory tract infection or URTI (250, 9.0%), and unclassified ARI (715, 25.8%). Overall, 29.2% (808/2768) were positive for any one of eight viruses, of whom 130 cases were identified with two or more viruses. Human rhinovirus (HRV) showed the highest detection rate (8.6%), followed by influenza virus (Flu, 7.3%), respiratory syncytial virus (RSV, 6.1%), human coronavirus (hCoV, 4.3%), human parainfluenza (PIV, 4.0%), adenovirus (ADV, 2.1%), human metapneumovirus (hMPV, 1.6%), and human bocavirus (hBoV, 0.7%). Compared with URTI, RSV was more likely identified in pneumonia (chi2 = 12.720, P < 0.001) and hCoV was more commonly associated with bronchitis than pneumonia (chi2 = 15.019, P < 0.001). In patients aged less than 5 years, RSV showed the highest detection rate and hCoV was the most frequent virus detected in adults and elderly. The clear epidemical seasons were observed in HRV, Flu, and hCoV infections. These findings could serve as a reference for local health authorities in drawing up further plans to prevent and control ARIs associated with viral etiologies. PMID- 29388678 TI - A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. AB - BACKGROUND: Combined oral contraceptives (COCs) containing various progestogens could be associated with differential risks for venous thromboembolism (VTE). OBJECTIVE: To evaluate the comparative risks of VTE associated with the use of low-dose (less than 50 MUg ethinyl estradiol) COCs containing different progestogens. SEARCH STRATEGY: PubMed and the Cochrane Library were searched from database inception through September 15, 2016, by combining search terms for oral contraception and venous thrombosis. SELECTION CRITERIA: Studies reporting VTE risk estimates among healthy users of progestogen-containing low-dose COCs were included. DATA COLLECTION AND ANALYSIS: A random-effects model was used to generate pooled adjusted risk ratios and 95% confidence intervals; subgroup and sensitivity analyses assessed the impact of monophasic-COC use and study-level characteristics. MAIN RESULTS: There were 22 articles included in the analysis. The use of COCs containing cyproterone acetate, desogestrel, drospirenone, or gestodene was associated with a significantly increased risk of VTE compared with the use of levonorgestrel-containing COCs (pooled risk ratios 1.5-2.0). The analysis restricted to monophasic COC formulations with 30 MUg of ethinyl estradiol yielded similar findings. After adjustment for study characteristics, the risk estimates were slightly attenuated. CONCLUSIONS: Compared with the use of levonorgestrel-containing COCs, the use of COCs containing other progestogens could be associated with a small increase in risk for VTE. PMID- 29388680 TI - Development of an efficient host-vector system of Ruminiclostridium josui. AB - Although Ruminiclostridium josui (formerly Clostridium josui), a strictly anaerobic mesophilic cellulolytic bacterium, is a promising candidate for biomass utilization via consolidated bioprocessing, its host-vector system has not yet been established. The existence of a restriction and modification system is a significant barrier to the transformation of R. josui. Here, we partially purified restriction endonuclease RjoI from R. josui cell extract using column chromatography. Further characterization showed that RjoI is an isoschizomer of DpnI, recognizing the sequence 5'-Gmet ATC-3', where the A nucleotide is Dam methylated. RjoI cleaved the recognition sequence between the A and T nucleotides, producing blunt ends. We then successfully introduced plasmids prepared from Escherichia coli C2925 (dam- /dcm- ) into R. josui by electroporation. The highest transformation efficiency of 6.6 * 103 transformants/MUg of DNA was obtained using a square-wave pulse (750 V, 1 ms). When the R. josui cel48A gene, devoid of the dockerin-encoding region, cloned into newly developed plasmid pKKM801 was introduced into R. josui, a truncated form of RjCel48A, RjCel48ADeltadoc, was detected in the culture supernatant but not in the intracellular fraction. This is the first report on the establishment of fundamental technology for molecular breeding of R. josui. PMID- 29388681 TI - Temporal dominance of sensations and preferences of Brazilians and Slovakians: A cross-cultural study of cachacas stored with woods from the Amazon rainforest. AB - BACKGROUND: Brazilians and Slovakians evaluated the temporal profile and the acceptability of cachaca stored with different woods (Cumarurana (CM), Jatoba (JT) and, Louro-vermelho (LV), which are found in the Amazon rainforest, and also oak), with the aim of performing a cross-cultural comparison of the dynamic profile of the attributes perceived in the cachacas and the sensorial acceptance of the samples. RESULTS: Important differences were observed between the temporal sensorial profiles generated by the two groups and their preferences. Brazilians preferred cachacas stored with the traditional wood, oak, followed by those stored with JT and CM. In contrast, Slovakians preferred cachacas stored with JT, followed by those stored with LV and oak. For both countries, the dominance of wood flavor and vanilla attributes at the end of the analysis time was positively associated with acceptance, while the dominance of off-flavors and the wood flavor attribute at the beginning of the analysis time was negatively associated with acceptance for Brazilians and Slovakians, respectively. CONCLUSION: Brazilians preferred cachaca stored with oak wood, and Slovakians preferred cachaca stored with JT wood, with acceptability being strongly associated with the dominance of wood flavor and vanilla attributes at the end of the evaluation time. (c) 2018 Society of Chemical Industry. PMID- 29388682 TI - A comprehensive look at the effect of processing on peanut (Arachis spp.) texture. AB - BACKGROUND: Relationships between process and peanut texture have only been studied in Hypogaea species, and focused on very limited processing conditions. In this study, 94 samples were prepared from a combination of 12 raw materials (Arachis hypogaea and fastigiata cultivars) and 11 roasting conditions (maceration in water, aqueous glucose and at different pH values followed by frying or baking). Texture was analyzed by a trained sensory panel (spectrum method) and large deformation compression tests (TA/XT2), and the microstructure probed with confocal microscopy and X-ray tomography. RESULTS: The impact of maceration on 'crispy', 'crunchy' and 'hardness' sensory attributes was significantly larger when adding glucose in this step, whereas the effect of pH was minor. The relationship held for both fried and baked peanuts as well as for both A. hypogaea and fastigiata subspecies. The degree of alveolation was similar in differently processed peanuts, even though sensory attributes were significantly different. CONCLUSIONS: Maceration in different media can yield large textural changes in both peanut species, for both baking and frying. Maceration in glucose solutions can induce much larger textural changes than maceration in water. Quantitative data on alveolation show that microstructure disruption through steam generation cannot explain all the texture differences among processed peanuts. (c) 2018 Society of Chemical Industry. PMID- 29388683 TI - The feasibility and safety of transvaginal bilateral salpingo-oophorectomy. AB - OBJECTIVE: To investigate the feasibility and safety of transvaginal bilateral salpingo-oophorectomy (BSO). METHODS: The present retrospective case series included consecutive women who underwent transvaginal BSO at a single general gynecology unit at Weston General Hospital, Weston-super-Mare, UK, between February 1, 2011, and July 31, 2014. Transvaginal BSO procedures were performed by an experienced surgeon. Feasibility and safety outcomes were reviewed from patient case notes. RESULTS: There were 127 patients included in the analysis. In all, 109 patients underwent transvaginal BSO at the time of vaginal hysterectomy, whereas 18 women underwent this procedure following a previous vaginal hysterectomy. Transvaginal BSO was successful in 126 (99.2%) patients; adverse events occurred among nine (7.1%) patients, including a single occurrence of ureteric injury that was detected and repaired intraoperatively. CONCLUSION: The present study demonstrated that transvaginal BSO was a feasible and safe procedure when conducted by an experienced surgeon. PMID- 29388684 TI - Effect of genetic background on the stability of sunflower fatty acid composition in different high oleic mutations. AB - BACKGROUND: The effect of genetic background on the stability of fatty acid composition in sunflower near isogenic lines (NILs) carrying high-oleic Pervenets (P) or high-oleic NM1 mutations was studied. The materials were field-tested in different locations and at different sowing dates to evaluate a wide range of environmental conditions. Relationships were established between the fatty acids and the minimum night temperature (MNT) and the response was characterized. RESULTS: A genetic background effect for the fatty acid composition was found in both groups of NILs. The NM1-NILs showed an oleic level higher than 910 g kg-1 and they were more stable across environments with a zero or low dependence on the genetic background; on the other hand, high oleic materials bearing the P mutation showed lower levels of oleic acid, with a higher variation in fatty acid composition and a highly significant dependence on the genetic background. CONCLUSION: The NM1 mutation is the best option to develop ultra-high oleic sunflower oil that is stable across environments and genetic backgrounds, making its agronomical production more efficient and predictable. (c) 2018 Society of Chemical Industry. PMID- 29388685 TI - More bang for the buck? Can arbuscular mycorrhizal fungal communities be characterized adequately alongside other fungi using general fungal primers? PMID- 29388686 TI - HEV seroprevalence can significantly change after re-assessment. PMID- 29388687 TI - Interventions for weight reduction in obesity to improve survival in women with endometrial cancer. AB - BACKGROUND: Diagnoses of endometrial cancer are increasing secondary to the rising prevalence of obesity. Obesity plays an important role in promoting the development of endometrial cancer, by inducing a state of unopposed oestrogen excess, insulin resistance and inflammation. It also affects treatment, increasing the risk of surgical complications and the complexity of radiotherapy planning, and may additionally impact on subsequent survival. Weight-loss interventions have been associated with improvements in breast and colorectal cancer-specific survival as well as a reduction in the risk of cardiovascular disease, a frequent cause of death in endometrial cancer survivors. OBJECTIVES: To determine the impact of weight-loss interventions, in addition to standard management of endometrial cancer, on overall survival and the frequency of adverse events.Secondary objectives include an assessment of weight-loss interventions on endometrial cancer-specific survival, weight loss achieved, cardiovascular event frequency and quality of life both overall and stratified according to patient body mass index (BMI), where possible. SEARCH METHODS: This review searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase and reference lists of articles, trial registries, and international gynaecological oncology conference abstracts from inception to January 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions to facilitate weight loss in overweight or obese women undergoing treatment for, or previously treated for, endometrial cancer were selected. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed trial quality, and extracted data with disagreements resolved by a third review author. Study authors were contacted to obtain missing data, including details of any adverse events. MAIN RESULTS: We included three RCTs in the review, randomising a total of 161 overweight and obese women with endometrial cancer. All studies compared combined behavioural and lifestyle interventions to facilitate weight loss through dietary modification and increased physical activity. The included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow-up (attrition rate up to 29%).Combined behaviour and lifestyle interventions were not associated with improved overall survival (risk ratio (RR mortality), 0.23 95% confidence interval (CI) 0.01 to 4.55, P = 0.34, one RCT, 37 participants; very low-certainty evidence) compared with usual care at 24 months. There was no evidence that such interventions were associated with improvements in cancer-specific survival or cardiovascular event frequency as no cancer related deaths, myocardial infarctions or strokes were reported in the included studies. None of the included RCTs reported data for the outcome of recurrence free survival. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six months (mean difference (MD) -1.88 kg, 95% CI -5.98 to 2.21 kg, P = 0.37, three RCTs, 131 participants, I2= 0%; low certainty evidenc e)or 12 months (MD -8.98 kg, 95% CI -19.88 to 1.92 kg, P = 0.11, two RCTs, 91 participants, I2= 0%; very low-certainty evidence) when compared with usual care. Combined behaviour and lifestyle interventions were not associated with increased quality of life, when measured using either the SF-12 Physical Health questionnaire or FACT-G at six months (FACT-G MD 2.51, 95% CI 5.61 to 10.64, P = 0.54, two RCTs, 95 participants, I2= 83%; very low-certainty evidence), or by FACT-G alone at 12 months (MD 2.77, 95% CI -0.65 to 6.20, P = 0.11, two RCTs, 89 participants, I2= 0%; very low-certainty evidence) when compared with usual care. No serious adverse events, for example hospitalisation or deaths, were reported in included trials. Lifestyle and behavioural interventions were associated with a higher risk of musculoskeletal symptoms (RR 19.03, 95% CI 1.17, 310.52, P = 0.04, two RCTs, 91 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is currently insufficient high-quality evidence to determine the effect of combined lifestyle and behavioural interventions on survival, quality of life, or significant weight loss in women with a history of endometrial cancer compared to those receiving usual care. The limited evidence suggests that there is little or no serious or life-threatening adverse effects due to these interventions, although musculoskeletal problems were increased, presumably due to increased activity levels. Our conclusion is based on low- and very low-quality evidence from a small number of trials and very few patients. We therefore have very little confidence in the evidence: the true effect of weight-loss interventions in obese women with endometrial cancer is currently not known.Further methodologically-rigorous, adequately-powered RCTs are required with follow-up of 5 to 10 years duration. These should focus on the effects of varying dietary modification regimens, pharmacological treatments associated with weight loss and bariatric surgery on survival, quality of life, weight loss and adverse events. PMID- 29388688 TI - Empirical Equations to Predict the Characteristics of Hyporheic Exchange in a Pool-Riffle Sequence. AB - The hyporheic zone is the saturated interstitial space surrounding a stream. Water actively moves into, through, and out of the hyporheic zone, resulting in hyporheic exchange (HE), which is crucial to the physicochemical and biological processes in these systems. The HE in pool-riffle sequences is one of the most common forms of HE and has received a vast amount of attention. This study aimed to derive empirical equations to predict the scale, median residence time (RT), and flux of HE in a single pool-riffle sequence by considering stream discharge, bedform geometry, streambed hydraulic conductivity, and groundwater flow. The resulting equations, which were derived using previously published data, allow quick approximations of the mean depth, median RT, and flux of HE in a single pool-riffle sequence. Therefore, these equations can be used to conveniently and efficiently generate insights into the physicochemical and biological processes, facilitating the prediction of water quality and the restoration of HE in stream rehabilitation. The overall framework of the derived equations is also generally applicable to considering HE with additional influential factors (e.g., stream width, sinuosity, bed slope, alluvial depth) and cases with more available data. PMID- 29388689 TI - Physical and chemical quality characteristics and antioxidant properties of strawberry cultivars (Fragaria * ananassa Duch.) in Greece: assessment of their sensory impact. AB - BACKGROUND: There are many factors determining the strawberry organoleptic profile and they are difficult to define. In this study, the sensory, physical, and chemical quality characteristics, the antioxidant properties as examined using ferric reducing antioxidant power (FRAP) and 1-diphenyl-2-picrylhydrazyl (DPPH) assays, the lactone concentration, and the FaFAD1 expression of ripe strawberries (cv. Camarosa, Florida Fortuna, and Sabrina) from Greece were evaluated and their interrelationships were investigated. RESULTS: 'Camarosa' had the highest antioxidant capacity and polyphenol content, although significant intra-cultivar variations of sugars, solid soluble content/titratable acidity (SSC/TA), red color intensity, sweetness, and hardness were recorded. In 'Sabrina' there was a constant lactone presence and FaFAD1 expression; it also had the lowest ascorbic acid content, the highest pH, SSC/TA index, firmness, and sweetness. 'Fortuna' showed the lowest sweetness and aroma indices, whereas 'Camarosa' had intermediate ones. Overall, firmness was correlated with hardness, while pH and SSC/TA index correlated with juiciness and sweetness. Both gamma decalactone and gamma-dodecalactone concentrations were correlated with FaFAD1 expression and pH, but they did not solely determine the aroma sensory perception. In total, FRAP values were positively correlated with ascorbic acid and polyphenol content, and negatively with pH. CONCLUSIONS: Significant inter- and intra-cultivar variation was recorded, revealing the impact of the genotype and underlining the effect of microenvironmental and cultivation conditions on quality and sensory perception. (c) 2018 Society of Chemical Industry. PMID- 29388690 TI - Effect of liver pate enrichment with flaxseed oil and flaxseed extract on lipid composition and stability. AB - BACKGROUND: There is an increase interest from food technologists in the improvement of the nutritional value of meat products, especially their lipid profile and shelf life. The aim of this study was to determine the effect of animal fat replacement with flaxseed oil (20%) and flaxseed extract addition (0.05%-0.25%) on changes in composition and stability of liver pate lipid fractions. RESULTS: Replacement of animal fat with flaxseed oil was observed to lower the saturated and monoenoic fatty acid in the product's fatty acid profile by around 12% and to raise the polyene fatty acid contribution by more than 70% when compared to the control. The replacement also resulted in enriching the pate with phytosterols (beta-sitosterol, campesterol, and cycloartenol). The addition of 0.05% and 0.10% ethanol flaxseed extract significantly slowed down lipid oxidation changes during storage of the pate. CONCLUSIONS: The study showed that a storage-stable meat product - liver pate - characterized by a high nutritional value can be designed through the addition of flax oil rich in unsaturated fatty acids and flaxseed extract. The addition of 0.05% of the extract was found to be sufficient to improve the liver pate's oxidative stability; it can thus be recommended for this type of product. (c) 2018 Society of Chemical Industry. PMID- 29388691 TI - Comparison of dual trigger with combination GnRH agonist and hCG versus hCG alone trigger of oocyte maturation for normal ovarian responders. AB - OBJECTIVE: To investigate whether dual triggering of oocyte maturation with a gonadotropin-releasing hormone (GnRH) agonist and standard dose of human chorionic gonadotropin (hCG) can improve clinical outcomes for normal ovarian responders in GnRH antagonist cycles. METHODS: The present retrospective cohort study included women aged up to 40 years with normal ovarian response who underwent in vitro fertilization and/or intracytoplasmic sperm injection under the GnRH antagonist protocol at Nanfang Hospital, China, between January 1 and December 31, 2015. Patients were grouped by whether oocyte maturation was triggered with GnRH agonist plus 5000-10 000 IU of hCG (dual trigger) or hCG alone. The primary outcome was live delivery rate. RESULTS: There were 325 women included; 224 in the dual trigger group and 101 in the hCG alone group. The live delivery rate did not differ significantly between the groups (P=0.083). The mean number of retrieved oocytes was similar in the two groups (P=0.719), but the mean number of two-pronuclear embryos (P=0.004), the mean number of embryos available (P=0.001), and the mean number of high-quality embryos (P=0.011) was higher in the dual trigger group. CONCLUSIONS: Dual trigger of oocyte maturation was not associated with any change in the live delivery rate but was associated with improvements in the quantity and quality of embryos; it could optimize pregnancy outcomes for normal ovarian responders. PMID- 29388692 TI - Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings. AB - Maytansinoids, the potent cytotoxic derivatives of the alkaloid maytansine are used as payloads in antibody maytansinoid conjugates. This article reviews clinical and preclinical hepatotoxicity observed with antibody maytansinoid conjugates used to treat cancer. Specific aspects of drug distribution, metabolism and excretion that may impact hepatotoxicity are reviewed vis-a-vis the kind of maytansinoid in the conjugate, cleavable or non-cleavable linkers, linker-payload combinations, drug to antibody ratio, metabolite formation, hepatic enzyme induction in relation to drug-drug interactions and species, age and gender differences. The article also sheds light on factors that may protect the liver from toxic insults. PMID- 29388693 TI - Activation of PPARdelta attenuates neurotoxicity by inhibiting lipopolysaccharide triggered glutamate release in BV-2 microglial cells. AB - Neuroinflammation-associated release of glutamate from activated microglia has been implicated in the progression of neurodegenerative diseases. However, the regulatory mechanisms underlying this glutamate release are poorly understood. Here, we show that peroxisome proliferator-activated receptor delta (PPARdelta) modulates neurotoxicity by inhibiting glutamate release in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Activation of PPARdelta by GW501516, a specific PPARdelta agonist, inhibited glutamate release in BV-2 cells. This effect of GW501516 was significantly blocked by shRNA-mediated knockdown of PPARdelta and by treatment with GSK0660, a specific PPARdelta antagonist, indicating that PPARdelta is associated with blockade of glutamate release. Additionally, GW501516-activated PPARdelta suppressed generation of reactive oxygen species and expression of gp91phox, a functional subunit of NADPH oxidase 2, in BV-2 cells stimulated with LPS. The inhibitory effect of GW501516 on gp91phox expression and glutamate release was further potentiated in the presence of AG490, a specific inhibitor of janus kinase 2 (JAK2), leading to the inhibition of signal transducer and activator of transcription 1 (STAT1). By contrast, GW501516 upregulated the expression of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK2. Furthermore, neurotoxicity induced by conditioned media from LPS-stimulated BV-2 cells was significantly reduced when conditioned media from BV-2 cells treated with both LPS and GW501516 were used. These results indicate that PPARdelta attenuates LPS-triggered neuroinflammation by enhancing SOCS1-mediated inhibition of JAK2/STAT1 signaling, thereby inhibiting neurotoxicity associated with glutamate release. PMID- 29388695 TI - Microgravity modulation of syncytin-A expression enhance osteoclast formation. AB - Microgravity (MUXg) experienced by astronauts during space flights causes accelerated bone loss. However, the molecular basis of MUXg induced bone loss in space is unclear. Osteoclast (OCL) is the primary bone-resorbing cell. We previously demonstrated that simulated MUXg promotes OCL formation. In this study, we identified that MUXg induces syncytin-A expression in RAW264.7 preosteoclast cells without RANKL stimulation. We further tested the effect of osteotropic factors such as CXCL5 and 1,25(OH)2 D3 to regulate the syncytin-A expression in preosteoclast cells subjected to MUXg compared to ground based (Xg) cultures. CXCL5 (25 ng/mL) and 1,25(OH)2 D3 (10 ng/mL) increased syncytin-A expression under Xg conditions. However, MUXg alone upregulates syncytin-A expression compared to Xg control preosteoclast cells. Confocal microscopy using Lyso-Tracker identified syncytin-A expression co-localized with lysosomes in preosteoclast cells. Acridine orange staining showed RANKL elevated autophagy activity in these cells. Further, siRNA suppression of syncytin-A significantly inhibits autophagy activity in RAW264.7 cells. In addition, knockdown of syncytin A expression inhibits MUXg increased OCL formation in mouse bone marrow cultures. Thus, our findings suggest that targeting syncytin-A expression may be an effective countermeasure to control bone loss under microgravity conditions. PMID- 29388694 TI - An Extension of the Perseverative Cognition Hypothesis to Posttraumatic Stress Disorder Symptomatology: Cardiovascular Recovery in Relation to Posttraumatic Stress Disorder Severity and Cognitive Appraisals of Stress. AB - Beyond the construct of cardiovascular reactivity, the measurement of cardiovascular recovery from stress represents an important index of exaggerated physiological arousal and disease risk. Cardiovascular recovery in posttraumatic stress disorder (PTSD) has not received adequate attention. The present study examined whether cardiovascular recovery following an oral speaking stressor was associated with the severity of PTSD symptoms, and whether cognitive stress appraisals of threat and challenge were significantly associated with PTSD severity and recovery. The sample consisted of 50 trauma-exposed civilian women ranging from 19 to 49 years of age (M = 30.9, SD = 7.8). The PTSD severity indices were quantified based on structured interview. Cardiovascular recovery was assessed at two posttask time points as percentage return to baseline; the recovery measures consisted of impedance cardiography-derived cardiac output (CO) and total peripheral resistance (TPR), heart rate and blood pressure. Total PTSD severity was associated with less CO recovery, r = -.39, p = .006; this effect was similar across PTSD symptom categories, with significant correlations ranging from r = -.30 to r = -.44. However, only PTSD severity in the avoidance cluster was associated with less TPR recovery, r = -.29, p = .047. Total PTSD severity was associated with greater threat appraisal, r = .30, p = .035, and greater threat appraisal was associated with less CO recovery, r = -.33, p = .019. Results partially support the theory that greater PTSD severity and cognitive appraisals of threat contribute to less cardiovascular recovery when confronted with a stress-inducing situation. PMID- 29388696 TI - RBM3 expression is upregulated by NF-kappaB p65 activity, protecting cells from apoptosis, during mild hypothermia. AB - The RNA-binding protein RBM3, a cold shock protein whose expression is elevated under hypothermic conditions, plays an important role in cell survival; however, little is known about the mechanism underlying the mild hypothermia-mediated regulation of RBM3 expression and apoptosis. Here we show that the transcription factor NF-kappaB p65 is phosphorylated at Ser276 and activates RBM3 gene transcription via binding to a particular element within the promoter region in response to induced hypothermia, elevating the protein expression, and suppressing apoptosis. Treatment with caffeic acid phenethyl ester (CAPE), a potent and specific inhibitor that suppresses the translocation of NF-kappaB p65 from the cytoplasm to the nucleus, resulted in decreased levels of RBM3 mRNA and protein and increased incidence of apoptosis despite cells were cultured under hypothermic conditions. Overexpression of RBM3 abolished the induction of apoptosis in cells treated with CAPE, indicating that NF-kappaB p65-upregulated RBM3 expression is necessary for the suppression of apoptosis. In addition, experiments with cells overexpressing RBM3 supported the finding demonstrating that the mild hypothermia-mediated higher expression of RBM3 suppressed the induction of apoptosis. Conversely, experiments with cells deficient in RBM3 supported the finding demonstrating that the CAPE-mediated loss of RBM3 induced apoptosis. These results suggest that NF-kappaB p65 is a critical mediator of mild hypothermia, to which cells are exposed as an extracellular environment, and a central inducer of RBM3 expression, which is responsible for preventing cells from apoptosis. Moreover, CAPE may have a potential for the application to a therapeutic agent for the treatment of cancers. PMID- 29388697 TI - Emerging roles of long non-coding RNAs in the toxicology of environmental chemicals. AB - Environmental chemicals (ECs) are drawing great attention to their effects on health and their toxicological mechanisms are being investigated. Long non-coding RNA (lncRNA) is a class of RNA with more than 200 nucleotides and does not have protein coding potential. Recently, it is emerging as a star molecule that participates in a wide range of physiological and pathological processes. It has been reported to be abnormally expressed in diseases. As an epigenetic factor, lncRNAs play an important role in the response of organisms to environmental stress. Their roles in the toxicity of ECs are being identified. Altered expression profiles of lncRNAs have been explored after exposure to ECs. Various kinds of ECs are reported to disturb the expression of lncRNAs in vitro and in vivo. Then, dysregulated lncRNAs can affect the expression of target genes directly or indirectly via regulating the level of microRNAs. The network among lncRNAs, microRNAs and mRNAs can initiate or impede specific signaling pathway and lead to adverse outcome upon exposure to ECs. Recovery of the lncRNAs level by overexpression or knockdown technology diminished the effect induced by ECs. In the review, biological roles of lncRNAs are depicted. The lncRNAs involved in the toxicology are summarized. Types of ECs that have been reported to affect the expression of lncRNAs are categorized. The interaction between various types of ECs and lncRNAs is discussed. PMID- 29388698 TI - Silibinin protects human endothelial cells from high glucose-induced injury by enhancing autophagic response. AB - Silibin, a flavonoid from the seeds of Silybum marianum (L.) Gaertn. (Asteraceae) has been reported to produce curative properties in diabetes. Autophagy is generated by a vast array of insults for removal of damaged proteins and organelles from the cell. Inadequate autophagy promotes endothelial cells dysfunction and delays in diabetic ulcers recovery. We hypothesized that silibinin could protect endothelial cells against high glucose-induced damage by engaging autophagic responses. HUVECs viability was evaluated by MTT assay. The Griess method and TBARS assay were used to monitor changes in the levels of nitric oxide and malondialdehyde, respectively. ROS generation was recorded in DCFDA-stained cells analyzed by flow cytometry. To investigate the role of silibinin on migration, we used scratch test. The level of autophagy proteins LC3, Becline-1, and P62 were measured by Western blotting. Our data showed that silibinin had potential to increase cell survival after exposure to high glucose condition. Total levels of oxidative stress markers were profoundly reduced and the activity of GSH was increased by silibinin. High glucose suppressed HUVECs migration to the scratched area. However, a significant increase in cell migration was observed after exposure to silibinin. Autophagy was blocked at the late stage by high glucose concentration and silibinin initiated an autophagic response by reducing P62 and enhancing Beclin-1 and LC3-II-LC3-I ratio. These effects were blocked by autophagy inhibitor of 3-Methyladenine. These observations suggest that silibinin could protect HUVECs from high glucose induced-damage possibly by activation of autophagy pathway. PMID- 29388699 TI - Lessons from Bialowieza Forest on the history of protection and the world's first reintroduction of a large carnivore. AB - Understanding how the relationships between large carnivores and humans have evolved and have been managed through centuries can provide relevant insights for wildlife conservation. The management history of many large carnivores has followed a similar pattern, from game reserved for nobility, to persecuted pests, to conservation targets. We reconstructed the history of brown bear (Ursus arctos) management in Bialowieza Forest (Poland and Belarus) based on a detailed survey of historical literature and Russian archives. From the end of the Middle Ages to the end of 18th century, the brown bear was considered "animalia superiora" (i.e., game exclusively reserved for nobility and protected by law). Bears, also a source of public entertainment, were not regarded as a threat. Effective measures to prevent damages to traditional forest beekeeping were already in practice. In the beginning of 19th century, new game-management approaches allowed most forest officials to hunt bears, which became the primary target of hunters due to their valuable pelt. This, together with an effective anticarnivore policy enhanced by bounties, led to bear extirpation in 1879. Different approaches to scientific game management appeared (planned extermination of predators and hunting levels that would maintain stable populations), as did the first initiatives to protect bears from cruel treatment in captivity. Bear reintroduction in Bialowieza Forest began in 1937 and represented the world's first reintroduction of a large carnivore motivated by conservation goals. The outbreak of World War II spoiled what might have been a successful project; reproduction in the wild was documented for 8 years and bear presence for 13. Soft release of cubs born in captivity inside the forest but freely roaming with minimal human contact proved successful. Release of captive human-habituated bears, feeding of these bears, and a lack of involvement of local communities were weaknesses of the project. Large carnivores are key components of ecosystem-function restoration, and site-specific histories provide important lessons in how to preserve them for the future. PMID- 29388700 TI - Neonatal treatment with fluoxetine improves mitochondrial respiration and reduces oxidative stress in liver of adult rats. AB - Recent studies have shown that exposure to fluoxetine treatment induces excessive production of ROS, and alters the antioxidant defense system in various tissues and cell types, mainly the liver. When fluoxetine is administered intraperitoneally, the drug rapidly reaches high concentrations in the liver, has potentially multiple toxic effects on energy metabolism in rat liver mitochondria. The aim of this study was to evaluate the effect of pharmacological treatment with fluoxetine during critical period for development on the mitochondrial bioenergetics and oxidative stress in liver of rat adult. To perform this study, the rat pups received Fx, or vehicle (Ct) from postnatal day 1 to postnatal day 21 (ie, during lactation period). We evaluated mitochondrial oxygen consumption, respiratory control ratio, ROS production, mitochondrial swelling by pore opening, oxidative stress biomarkers, and antioxidant defense in liver of rats at 60 days of age. Our studies have shown, that treatment with Fx during the lactation period resulted in reduced body mass gain, improvement of the mitochondrial respiratory capacity, induced higher mitochondrial resistance to calcium ion preventing the mitochondrial permeability transition pore opening, as well as decreased oxidative stress biomarkers, and increased the SH levels and enzymes antioxidant activities (SOD, CAT, GST) in liver of treated rats at 60 days of age. These findings suggest that pharmacological treatment with fluoxetine during critical period of development result in positive changes in liver of rats, as improvement of the mitochondrial bioenergetics and hepatic oxidative metabolism that persist in adulthood. PMID- 29388701 TI - The desmin network is a determinant of the cytoplasmic stiffness of myoblasts. AB - BACKGROUND INFORMATION: The mechanical properties of cells are essential to maintain their proper functions, and mainly rely on their cytoskeleton. A lot of attention has been paid to actin filaments, demonstrating their central role in the cells mechanical properties, but much less is known about the participation of intermediate filament (IF) networks. Indeed the contribution of IFs, such as vimentin, keratins and lamins, to cell mechanics has only been assessed recently. We study here the involvement of desmin, an IF specifically expressed in muscle cells, in the rheology of immature muscle cells. Desmin can carry mutations responsible for a class of muscle pathologies named desminopathies. RESULTS: In this study, using three types of cell rheometers, we assess the consequences of expressing wild-type (WT) or mutated desmin on the rheological properties of single myoblasts. We find that the mechanical properties of the cell cortex are not correlated to the quantity, nor the quality of desmin expressed. On the contrary, the overall cell stiffness increases when the amount of WT or mutated desmin polymerised in cytoplasmic networks increases. However, myoblasts become softer when the desmin network is partially depleted by the formation of aggregates induced by the expression of a desmin mutant. CONCLUSIONS: We demonstrate that desmin plays a negligible role in the mechanical properties of the cell cortex but is a determinant of the overall cell stiffness. More particularly, desmin participates to the cytoplasm viscoelasticity. SIGNIFICANCE: Desminopathies are associated with muscular weaknesses attributed to a disorganisation of the structure of striated muscle that impairs the active force generation. The present study evidences for the first time the key role of desmin in the rheological properties of myoblasts, raising the hypothesis that desmin mutations could also alter the passive mechanical properties of muscles, thus participating to the lack of force build up in muscle tissue. PMID- 29388703 TI - Gender Differences in Neurocognitive Performance Among Children With Posttraumatic Stress Disorder and Mild Traumatic Brain Injury. AB - Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are frequent sequelae after motor vehicle accidents (MVAs). These two pathologies often have overlapping neurocognitive deficits across several domains, such as attention, memory, and executive functions. The present study was an effort to examine the contribution of gender to these overlapping symptoms. To this end, psychodiagnostic and neuropsychological data were collected on 61 children and adolescents 3 months following MVA. All participants were diagnosed with PTSD, and about half (n = 33) also received a diagnosis of mTBI. Analyses of variance revealed significant interactions between gender and mTBI (etap2=.15), such that girls with mTBIs preformed significantly worse than noninjured girls on measures of executive functions (Cohen's d = 3.88) and sustained attention (Cohen's d = 3.24). Boys, on the other hand, did not differ significantly on any of those measures, irrespective of TBI injury status. Similarly, comparisons to the normative population revealed that, whereas boys showed impaired neurocognitive performances regardless of TBI status, impaired performances in girls were limited to those cases in which the girls were comorbid for PTSD and mTBI. It appears then that whereas PTSD alone might explain boys' reduced neurocognitive performance, among girls the comorbidity of PTSD and mTBI is required to account for performance deficits. PMID- 29388702 TI - Fibrin glue mediated delivery of bone anabolic reagents to enhance healing of tendon to bone. AB - Tendon graft healing in bone tunnels for the fixation of intra-articular ligament reconstructions may limit clinical outcome by delaying healing. This study assesses the effects of hydrogel-mediated delivery of bone anabolic growth factors in a validated model of tendon-to-bone tunnel healing. Forty-five Wistar rats were randomly allocated into three groups (BMP2-treated, GSK126-treated, and placebo). All animals underwent a tendon-to-bone tunnel reconstruction. Healing was evaluated at 4 weeks by biomechanical assessment, micro-computed tomography (bone mineral density, bone volume, cross sectional area of bone tunnels), and traditional histology. Adverse events associated with the hydrogel-mediated delivery of drugs were not observed. Results of our biomechanical assessment demonstrated favorable trends in animals treated with bone anabolic factors for energy absorption (P = 0.116) and elongation (P = 0.054), while results for force to failure (P = 0.691) and stiffness (P = 0.404) did not show discernible differences. Cross sectional areas for BMP2-treated animals were reduced, but neither BMP2 nor GSK126 administration altered bone mineral density (P = 0.492) or bone volume in the bone tunnel. These results suggest a novel and positive effect of bone anabolic factors on tendon-to-bone tunnel healing. Histological evaluation confirmed absence of collagen fibers crossing the soft tissue-bone interface indicating immature graft integration as expected at this time point. Our study indicates that hydrogel-mediated delivery of BMP2 and GSK126 appears to be safe and has the potential to enhance tendon-to-bone tunnel healing in ligament reconstructions. PMID- 29388704 TI - A novel anti-cancer agent, FPDHP, induces anoikis in various human cancer cells through activation of calpain, and downregulation of anoikis-related molecules. AB - Resistance to anoikis and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. Anoikis is a type of apoptosis induced by inadequate cell/extracellular matrix (ECM) attachment and an attractive anti-cancer therapeutic strategy in cancer chemotherapeutic field. Therefore, the development of anoikis-inducing agents is useful and promising to overcome cancer. When FPDHP, a novel anoikis-inducing agent, was treated within 3 h, FPDHP induced massive cell detachment in various human cancer cells, irrespective of apoptosis. Moreover, FPDHP decreased the expression of integrins, FAK, focal adhesion signaling effectors (talin1 and talin2), tight junction proteins (ZO-1, ZO-2, and ZO-3), transcriptional mediators of epithelial mesenchymal transition (EMT) (Snail1 and Snail2), and anoikis-related protein, such as Mcl-1 (L). Interestingly, Caki/ZO-2 and Caki/alpha6 are significantly suppressed the FPDHP-mediated cell detachment, and the constitutive active form of Akt and overexpression of Mcl-1 (L) partially inhibited the cellular detachment induced by FPDHP. On the other hand, when FPDHP was treated for more than 12 h, FPDHP induced caspase-dependent apoptosis and release of AIF and cytochrome c from mitochondria. Furthermore, FPDHP down regulated Mcl-1 (L) at post-transcriptional level, and overexpression of Mcl-1 (L) partially attenuated the apoptosis induced by FPDHP. Additionally, PD150606, a calpain inhibitor, attenuated FPDHP-mediated cell detachment and apoptosis. Taken together, these results suggest that FPDHP possesses anoikis-inducing activity or potential making cancer cells susceptible to anoikis, and may be developed as a novel active compound for cancer treatment. PMID- 29388705 TI - Echocardiography in transcatheter aortic valve implantation-Part 1-Transthoracic echocardiography. AB - Transcatheter aortic valve replacement (TAVR) has been a revolutionary technique in the treatment of degenerative aortic valve stenosis. Selection of appropriate patients and appropriate valve size is crucial for improved patient outcome. Echocardiographic imaging is a critical component for patient selection and plays an important role in the selection of valve size, procedural guidance, and patient follow-up. This review discusses role of echocardiography in patient selection, device implantation, and postimplant follow-up for the first generation CoreValve as used in pivotal trial. Same TTE imaging principles apply to the second- and third-generation self-expandable valves as well as the balloon expandable valves. Multiple case examples are used to illustrate imaging principles pre- and post-TAVR. In addition, case examples to demonstrate complications post-TAVR are shown. PMID- 29388706 TI - Nell-1-DeltaE, a novel transcript of Nell-1, inhibits cell migration by interacting with enolase-1. AB - NELL-1 is a secreted protein that was originally found to be upregulated in pathologically fusing and fused sutures in non-syndromic unilateral coronal synostosis patients. Apart from the ability of NELL-1 to promote osteogenesis in long and craniofacial bones, NELL-1 reportedly inhibits the formation of several benign and malignant tumors. We previously identified a novel transcript of Nell 1 that lacked a calcium-binding epidermal growth factor (EGF)-like domain compared with full-length Nell-1; this new transcript was named Nell-1-DeltaE. Three obvious structural differences between these two isoforms were revealed by homology modeling. Furthermore, the recombinant Nell-1-DeltaE protein, but not the full-length Nell-1 protein, inhibited cell migration in vitro. However, full length Nell-1 and Nell-1-DeltaE proteins were present in similar subcellular locations and displayed similar expression patterns in both the intracellular and extracellular spaces. The results from the co-immunoprecipitation and liquid chromatography/tandem mass spectrometry analyses using two cell lines demonstrated that Nell-1-DeltaE but not full-length Nell-1 interacted with enolase-1 in the extracellular spaces of both cell lines. The results of wound healing assays using ENO-1-overexpressing cells treated with full-length Nell 1/Nell-1-DeltaE suggested that Nell-1-DeltaE inhibited cell migration by interacting with ENO-1. Our study indicated that the novel transcript Nell-1 DeltaE, but not full-length Nell-1, might be a candidate tumor suppressor factor for basic research and clinical practice. PMID- 29388707 TI - Is there "brain OAB" and how can we recognize it? International Consultation on Incontinence-Research Society (ICI-RS) 2017. AB - AIMS: In light of mounting evidence supporting the association of brain regions with the control of urine storage and voiding, the high placebo effect in OAB studies as well as certain anecdotal observations from clinical practice with OAB patients, the role of the brain in OAB was explored. METHODS: At the ICI-RS 2017 meeting, a panel of Functional Urologists and Basic Scientists presented literature data generating a proposal to discuss whether there is "brain OAB" and how we could recognize it. RESULTS: Existing data point toward organic brain causes of OAB, in particular concerning white matter disease (WMD) and aging, but with currently speculative mechanisms. Imaging techniques have revealed connectivity changes between brain regions which may explain brain-peripheral interactions in OAB patients, further to acknowledged structural and functional changes in the central nervous system (CNS). Furthermore, psychological disorders like stress and depression have been identified as causes of OAB, with animal and human studies proposing a neurochemical and neuroendocrine pathophysiological basis, involving either the serotoninergic system or the hypothalamic-pituitary adrenal axis. Finally, childhood data suggest that OAB could be a developmental disorder involving the CNS, although childhood OAB could be a different condition than that of adults in many children. CONCLUSIONS: Future research should aim to identify the pathogenesis of WMD and the aging processes affecting the brain and the bladder, with possible benefits in prevention strategies, as well as connectivity disorders within the CNS, the pathophysiology of OAB in childhood and the neurochemical pathways connecting affective disorders with OAB. PMID- 29388708 TI - Variation in traction forces during cell cycle progression. AB - BACKGROUND INFORMATION: Tissue morphogenesis results from the interplay between cell growth and mechanical forces. While the impact of geometrical confinement and mechanical forces on cell proliferation has been fairly well characterised, the inverse relationship is much less understood. Here, we investigated how traction forces vary during cell cycle progression. RESULTS: Cell shape was constrained on micropatterned substrates in order to distinguish variations in cell contractility from cell size increase. We performed traction force measurements of asynchronously dividing cells expressing a cell-cycle reporter, to obtain measurements of contractile forces generated during cell division. We found that forces tend to increase as cells progress through G1, before reaching a plateau in S phase, and then decline during G2. CONCLUSIONS: While cell size increases regularly during cell cycle progression, traction forces follow a biphasic behaviour based on specific and opposite regulation of cell contractility during early and late growth phases. SIGNIFICANCE: These results highlight the key role of cellular signalling in the regulation of cell contractility, independently of cell size and shape. Non-monotonous variations of cell contractility during cell cycle progression are likely to impact the mechanical regulation of tissue homoeostasis in a complex and non-linear manner. PMID- 29388709 TI - Topiramate as Monotherapy or Adjunctive Treatment for Posttraumatic Stress Disorder: A Meta-Analysis. AB - Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition for which clinicians sometimes turn to anticonvulsants as a treatment for symptoms. This study was a systematic review and meta-analysis of randomized controlled trials (RCT) that have assessed the efficacy of topiramate as monotherapy or adjunctive therapy, compared to placebo, for the treatment of PTSD in adults. Prescribers may be reluctant to turn to topiramate, given the commonly reported side effects of impaired cognition, sedation, fatigue, and headache. We searched PubMed, PsycInfo, and Cochrane Central databases for relevant trials. Five studies were identified as RCTs and thus met inclusion criteria; one additional nonpublished study was identified via phone contact with its authors. Of these six studies, one was excluded from the statistical meta-analysis due to its high dropout rate (16 of 40 participants). One of these studies was excluded from a stratified analysis of symptom types because this subscale data were unavailable. For overall symptomatology, topiramate showed a medium, but not significant effect, standardized mean difference (SMD) = 0.55, p = .082. Topiramate showed a small and significant reduction of hyperarousal symptoms, SMD = 0.35, 95% CI [0.029, 0.689], p = .033. Topiramate did not significantly reduce reexperiencing symptoms, SMD = 0.29, 95% CI [-0.019, 0.597], p = .067, or avoidance symptoms, SMD = 0.20, 95% CI [-0.105, 0.509], p = .198. Results did not differ significantly between veteran and nonveteran subjects, or between topiramate as monotherapy and adjunctive therapy. Further studies on topiramate will clarify its role in PTSD treatment. PMID- 29388710 TI - Psychobiological Responses to Aerobic Exercise in Individuals With Posttraumatic Stress Disorder. AB - Previous reports have shown improvements in mood and increases in endocannabinoids in healthy adults following a session of aerobic exercise, but it is unclear whether adults with posttraumatic stress disorder (PTSD) experience similar responses. The purpose of this study was to examine psychobiological responses (plasma endocannabinoids [eCBs], mood, and pain) to aerobic exercise in a sample of adults with a diagnosis of PTSD (n = 12) and healthy controls (n = 12). Participants engaged in an aerobic exercise session in which they ran on a treadmill for 30 min at a moderate intensity (70 to 75% maximum heart rate [MHR]). Results indicated improvements in mood states and reductions in pain for both groups following exercise, ds = 0.19 to 1.53. Circulating concentrations of N-arachidonylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), and oleoylethanolamide (OEA) significantly increased (ps = .000 to .050) following the aerobic exercise session for both groups. There were no significant time, group, or interaction effects (ps = .062 to .846) for palmitoylethanolamide (PEA) and 2-oleoylglycerol (2-OG). Although eCBs increased significantly for both groups, within-group effect size calculations indicated the healthy controls experienced a greater magnitude of change for AEA when compared with adults with PTSD, d = 1.21 and d = 0.45, respectively; as well as for 2-AG, d = 0.43 and d = 0.21, respectively. The findings from this study indicated that adults with and without PTSD reported significant mood improvements following 30 min of moderate intensity aerobic exercise. In addition, the endocannabinoid system was activated in adults with and without PTSD, although effect sizes suggest that adults with PTSD may have a blunted endocannabinoid response to exercise. PMID- 29388711 TI - The prolactin-release inhibitor paeoniflorin suppresses proliferation and induces apoptosis in prolactinoma cells via the mitochondria-dependent pathway. AB - Prolactinomas are the most prevalent functional pituitary adenomas that cause chronic pathological hyperprolactinemia. Prolactin is known to promote cell growth and inhibit apoptosis in cells. Paeoniflorin is the principal component of radix Paeoniae alba (the main ingredient in some traditional herbal formulas clinically used for hyperprolactinemia-associated disorders). Recent findings from intensive studies have suggested that paeoniflorin regulates cell proliferation and apoptosis in many cell lines. However, the effects of paeoniflorin in pituitary tumor cells remain unknown. Here the results by the Cell Counting Kit-8 and colony formation assays showed that paeoniflorin concentration-dependently decreased cell viability in both MMQ and GH3 cells and colony formation in GH3 cells, suggesting inhibition of cell proliferation by paeoniflorin. By flow cytometry, paeoniflorin was found to increase apoptotic rate in MMQ cells. Mechanistically, Western blot results revealed that paeoniflorin enhanced protein expression of cleave caspase-9 and -3, and Bax, whereas it suppressed Bcl-2 protein expression in MMQ cells. Furthermore, paeoniflorin upregulated phosphorylated p53 protein expression, but it decreased prolactin concentration and prolactin protein expression in both MMQ and GH3 cells. Thus, the present results demonstrate that paeoniflorin inhibits cell proliferation and induces the mitochondrial pathway-mediated apoptosis in prolactinoma cells. These antitumor property is associated with inhibition of prolactin secretion. Our findings may provide new insight into the mechanisms underlying improving prolactinoma-associated disorders of paeoniflorin-enriched herbs and formulas. PMID- 29388712 TI - Toxicokinetics of cadmium in Palaemon varians postlarvae under waterborne and/or dietary exposure. AB - The present study assessed cadmium uptake and depuration rates in the euryhaline estuarine shrimp Palaemon varians under different exposure routes. Postlarval shrimp were exposed for 4 d under different exposure routes: contaminated water, contaminated diet, and a 2-way exposure scenario where both contaminated water and diet were used. After exposure, postlarval shrimp were transferred to a clean medium and fed a noncontaminated diet for 96 h. Bioaccumulation via the different exposure routes was modeled with a standard first-order, one-compartment toxicokinetics model and one with an additional parameter reflecting an inert fraction or storage compartment. The simultaneous 2-way exposure (through water and diet) resulted in accumulation being almost twice as high as the sum of the individual exposure routes, thus indicating that accumulation from multiple routes may be more than additive. Cadmium uptake from water was faster than uptake from food maintained for 48 h at that same cadmium concentration. Shrimp were unable to eliminate cadmium from their body, showing no depuration during 96 h after exposure via different routes, thus suggesting that a longer depuration period is needed. Model comparisons did not provide a significantly better fit when the model included the presence of an inert fraction. The present study highlights the importance of assessing accumulation using multiple exposure routes compared with individual routes because the latter may underestimate bioaccumulation. Environ Toxicol Chem 2018;37:1614-1622. (c) 2018 SETAC. PMID- 29388713 TI - Rs13293512 polymorphism located in the promoter region of let-7 is associated with increased risk of radiation enteritis in colorectal cancer. AB - RE (Radiation enteritis) has been characterized by the inflammation reaction, and in this study, we aim to explore inflammatory cytokines and underlying mechanism involved in the pathogenesis of RE. Luciferase assay was performed to explore whether polymorphism affected the expression of let-7, and also validated let-7 directly regulated f IL-6 expression. Then Elisa was performed to study the mechanism of rs13293512 polymorphism associated with enteritis occurrence. And Western-blot and real-time PCR were performed to verify the relationship between let-7 and IL-6. 380 colorectal cancer patients were recruited, and all participants were genotyped. We found that occurrence probability of enteritis patients carried CC genotype (32%) was much higher than that in TT and TC groups (15%). In addition, we showed that the presence of the minor (C) allele of the polymorphism in the promoter region of let-7 substantially reduced the transcription activity of let-7, furthermore, we validated that let-7 directly regulated IL-6 expression by using luciferase reporter system. Moreover, IL-6 was highly expressed in peripheral blood and colonic mucosa samples genotyped as CC compared to those in TT and TC groups, furthermore, IL-6 was highly expressed in peripheral blood and colonic mucosa samples from participants with enteritis than without enteritis, whereas let-7 was highly expressed in peripheral blood and colonic mucosa samples genotyped as TT and TC compared to those in CC groups. Let 7 polymorphism (rs13293512) was associated with risk of RE in the colorectal cancer patients who received radiotherapy. PMID- 29388715 TI - Ultra-high-density mapping of left atrial and pulmonary vein macroreentry using double conduction gaps. PMID- 29388714 TI - "I didn't want to be in charge and yet I was": Bereaved caregivers' accounts of providing home care for family members with advanced cancer. AB - OBJECTIVE: To describe bereaved caregivers' experiences of providing care at home for patients with advanced cancer, while interacting with home care services. METHODS: Caregivers of patients who had completed a 4-month randomized controlled trial of early palliative care versus standard oncology care were recruited 6 months to 5 years after the patient's death. All patients except one (control) had eventually received palliative care. In semi-structured interviews, participants were asked about their experiences of caregiving. Grounded theory guided all aspects of the study. RESULTS: Sixty-one bereaved caregivers (30 intervention, 31 control) were interviewed, including spouses (33), adult children (19), and other family (9). There were no differences in themes between control and intervention groups. The core category of Taking charge encompassed caregivers' assumption of active roles in care, often in the face of inadequate formal support. There were 4 interrelated subcategories: (1) Navigating the system-navigating the complexities of the home care system to access resources and supports; (2) Engaging with professional caregivers-interacting with visiting personnel to advocate for consistency and quality of care; (3) Preparing for death-seeking out information about what to expect at the end of life; and (4) Managing after death-managing multiple administrative responsibilities in the emotionally charged period following death. CONCLUSIONS: Caregivers were often thrust into assuming control in order to compensate for deficiencies in formal palliative home care services. Policies, quality indicators, and guidelines are needed to ensure the provision of comprehensive, interdisciplinary home palliative care. PMID- 29388716 TI - Functionalization of Metal-Organic Frameworks for Photoactive Materials. AB - Metal-organic frameworks (MOFs) are intriguing platforms with multiple functionalities. Additional functionalization of MOFs generates novel materials for various applications. Here, three main topics are examined regarding the functionalization of MOFs for use as photoactive materials. The first is chemical approaches for postsynthetic modification of the metal clusters and organic linkers in MOFs; that is, sites on pore surfaces and chemical trapping of photoactive moieties within the pores, which create materials with chemical functionalities for water splitting and CO2 reduction by light. The second topic focuses on the functionalization of MOFs for photochemical response and the versatile applications of such materials. State-of-the-art research on functionalizing MOFs through photochemical reactions on the pore surface and within the pores as guests is also summarized. The third topic introduces the functionalization of MOFs for photofunctional materials, including photoluminescent tuning and integration, photoluminescent LED devices and barcodes, and photophysical applications for chemical sensing. Finally, conclusions and perspectives on the fields are given. PMID- 29388717 TI - Coupling Influences SMM Properties for Pure 4 f Systems. AB - Increasing both the energy barrier for magnetization reversal and the coercive field of the hysteresis loop are significant challenges in the field of single molecule magnets (SMMs). Coordination geometries of lanthanide ions and magnetic interactions between lanthanide ions are both important for guiding the magnetic behavior of SMMs. We report a high energy barrier of 657 K (457 cm-1 ) in a diamagnetic-ion-diluted lanthanide chain compound with a constrained bisphenoid symmetry (D2d ); this energy barrier is substantially higher than the barrier of 567 K (394 cm-1 ) of the non-diluted chain compound with intrachain ferromagnetic interactions. Although intrachain magnetic interaction lowers the energy barrier for magnetization reversal, it can greatly enhance the coercive fields and zero field remanence of the hysteresis loops, which is crucial for the rational design of high-performance SMMs. Factors related to the coordination sphere of the lanthanide center, which govern the high magnetic relaxation barriers through the second excited Kramer's doublets and the magnetic interactions that affect the hysteresis loops, were revealed through ab initio calculations. PMID- 29388718 TI - Neonatal respiratory distress syndrome and underlying mechanisms in cloned cattle. AB - Neonatal respiratory distress is a major mortality factor in cloned animals, but the pathogenesis of this disease is rarely investigated. In this study, four neonatal cloned cattle, born after full-term gestation, exhibited symptoms of neonatal respiratory distress syndrome (NRDS), which included symptoms of hyaline membrane disease as well as disordered surfactant homeostasis in their collapsed lungs. No differences in DNA methylation or histone modifications correlated with the suppressed SPB and SPC transcription observed in the cloned cattle group (p > 0.05), whereas TTF-1 occupancy at SPB and SPC promoter regions in cloned cattle was significantly reduced to 24% and 20% that of normal lungs, respectively (SPB, p < 0.05; SPC, p < 0.01). Decreased TTF1 expression, dysregulation of SPB and SPC transcription by TTF-1, and disordered proteolytic processing of Surfactant protein B precursor together potentially contribute to the disruption of surfactant homeostasis and NRDS in bovine clones. Elucidation of the associated mechanisms should facilitate the development of novel preventive or therapeutic strategies to reduce the mortality rate of cloned animals and to improve the efficiency of SCNT technology. PMID- 29388720 TI - Which Factors Control the Nucleophilic Reactivities of Enamines? AB - Changes in rate constants, equivalent to changes in Gibbs energies of activation DeltaG? , are commonly referred to as kinetic effects and differentiated from thermodynamic effects (Deltar G degrees ). Often, little attention is paid to the fact that structural effects on DeltaG? are composed of a thermodynamic (Deltar G degrees ) and a truly kinetic (intrinsic) component (DeltaG0? ), as expressed by the Marcus equation. Rate and equilibrium constants have been determined for a number of reactions of enamines with benzhydrylium ions (Aryl2 CH+ ), which has allowed the determination of Marcus intrinsic barriers and a differentiated analysis of structure-reactivity relationships. To our knowledge, this is the first report in which the Lewis basicity of a piCC bond towards carbon-centered Lewis acids (for example, carbenium ions) has quantitatively been determined. The synthesis, structures, and properties of deoxybenzoin-derived enamines ArCH=C(Ph)NR2 , which have been designed as reference nucleophiles for the future quantification of electrophilic reactivities, are explicitly described. PMID- 29388719 TI - Multi-compartmental diffusion characterization of the human cervical spinal cord in vivo using the spherical mean technique. AB - The purpose of this work was to evaluate the feasibility and reproducibility of the spherical mean technique (SMT), a multi-compartmental diffusion model, in the spinal cord of healthy controls, and to assess its ability to improve spinal cord characterization in multiple sclerosis (MS) patients at 3 T. SMT was applied in the cervical spinal cord of eight controls and six relapsing-remitting MS patients. SMT provides an elegant framework to model the apparent axonal volume fraction vax , intrinsic diffusivity Dax , and extra-axonal transverse diffusivity Dex_perp (which is estimated as a function of vax and Dax ) without confounds related to complex fiber orientation distribution that reside in diffusion MRI modeling. SMT's reproducibility was assessed with two different scans within a month, and SMT-derived indices in healthy and MS cohorts were compared. The influence of acquisition scheme on SMT was also evaluated. SMT's vax , Dax , and Dex_perp measurements all showed high reproducibility. A decrease in vax was observed at the site of lesions and normal appearing white matter (p < 0.05), and trends towards a decreased Dax and increased Dex_perp were seen. Importantly, a twofold reduction in acquisition yielded similarly high accuracy with SMT. SMT provides a fast, reproducible, and accurate method to improve characterization of the cervical spinal cord, and may have clinical potential for MS patients. PMID- 29388721 TI - World bleeding disorders registry: The pilot study. PMID- 29388722 TI - Driving the Crystallization of Zeolites. AB - The synthesis of zeolites with new structures and/or improved properties heavily relies on trial and error efforts that are not entirely blind, as the large empirical background accumulated for the last 7 decades can be, to some extent, rationalized and purposefully used to make new materials. The so-called structure directing factors may be combined to promote (or frustrate) the crystallization of a particular structure. This personal account opens with the concept of geoinspiration, as suggested by Prof. Ruiz-Hitzky, and its application to zeolite synthesis. We then provide a concise overview of structure-direction in the synthesis of zeolites and detail examples, both new and from the literature, on how they can be combined to drive the crystallization towards (or away from) structures displaying particular features. PMID- 29388723 TI - Helicobacter pylori infection increases the risk of developing preeclampsia: A meta-analysis of observational studies. AB - BACKGROUND: Helicobacter pylori has been previously linked with preeclampsia on the basis of altered angiogenesis and activation of inflammatory cytokines. PURPOSE: The purpose of the present systematic review is to summarise current evidence concerning the correlation of the two diseases. MATERIALS AND METHODS: We searched the Medline (1966-2017), Scopus (2004-2017), Clinicaltrials.gov (2008 2017) EMBASE (1980-2017), and Cochrane Central Register of Controlled Trials CENTRAL (1999-2017) databases. We selected all observational studies (both prospective and retrospective) that reported the incidence of preeclampsia among women with H. Pylori infection. Statistical meta-analysis was performed with the RevMan 5.3 software. RESULTS: Fourteen studies were finally included in this review, which included a total number of 9787 women. Nine percentage of these had preeclampsia (879 women). The evaluation of studies with the ROBINS-I tool revealed low to moderate risk of bias. H. pylori IgG seropositivity was significantly more prevalent in preeclamptic than in healthy pregnant women (9391 women, OR: 2.32, 95% CI [1.55, 3.46]). The frequency of anti-CagA antibodies was also higher in pregnancies complicated with preeclampsia (3275 women, OR: 3.97, 95% CI [1.55, 10.19]). CONCLUSION: The findings of our study support that H. pylori infection doubles the risk of developing preeclampsia. The exact pathophysiological processes, however, remain poorly investigated and future experimental studies are needed to shed light on the underlying mechanisms. PMID- 29388724 TI - Adiposity Associated Plasma Linoleic Acid is Related to Demographic, Metabolic Health and Haplotypes of FADS1/2 Genes in Irish Adults. AB - SCOPE: This study examines to what extent plasma linoleic acid (LA) is modified by adiposity, and explores any association between plasma LA, demographics, dietary intakes, markers of metabolic health, and haplotypes of the fatty acid desaturase (FADS) 1/2 genes. METHODS AND RESULTS: A total of 820 participants with fasting blood samples from the Irish National Adult Nutrition Survey are studied. Plasma fatty acids are determined using GC-MS. Fifteen SNPs of FADS 1/2 genes are genotyped. Plasma LA decreases, while gamma-linoleic acid and dihomo gamma-linoleic acid increases in overweight/obese participants (p <= 0.002). Participants in the highest quartile of plasma LA show decreased plasma markers of de novo lipogenesis, insulin resistance, and of inflammation (TNF-alpha, PAI 1) (p <= 0.005). Adiposity (waist circumference and body fat) is strongly inversely associated with plasma LA accounting for 11.8% of variance observed, which is followed by FADS1/2 haplotypes (3.9%), quantity and quality of carbohydrate intakes (3.8%), dietary PUFA intakes (3.7%), systolic blood pressure (3.6%), and age (3.2%). CONCLUSION: Plasma LA is inversely associated with adiposity, followed by haplotypes of FADS1/2 genes, carbohydrate intakes, and dietary PUFA intakes. The association observed between plasma LA and adiposity may be linked to decreased de novo lipogenesis, insulin resistance, and inflammation. PMID- 29388725 TI - Recent Advances in Ring-Opening Functionalization of Cycloalkanols by C-C sigma Bond Cleavage. AB - Cycloalkanols prove to be privileged precursors for the synthesis of distally substituted alkyl ketones and polycyclic aromatic hydrocarbons (PAHs) by virtue of cleavage of their cyclic C-C bonds. Direct functionalization of cyclobutanols to build up other chemical bonds (e. g., C-F, C-Cl, C-Br, C-N, C-S, C-Se, C-C, etc.) has been achieved by using the ring-opening strategy. Mechanistically, the C-C cleavage of cyclobutanols can be involved in two pathways: (a) transition metal catalyzed beta-carbon elimination; (b) radical-mediated 'radical clock' type ring opening. The recent advances of our group for the ring-opening functionalization of tertiary cycloalkanols are described in this account. PMID- 29388726 TI - Isolation of an Eleven-Atom Polydentate Carbon-Chain Chelate Obtained by Cycloaddition of a Cyclic Osmium Carbyne with an Alkyne. AB - Carbon ligands have long played an important role in organometallic chemistry. However, previous examples of all-carbon chelating ligands are limited. Herein, we present a novel complex with an eleven-atom carbon chain as a polydentate chelating ligand. This species was formed by the [2+2+2] cycloaddition reaction of two equivalents of an alkyne with an osmapentalyne that contains the smallest carbyne bond angle (127.9 degrees ) ever observed. Density functional calculations revealed that electron-donating groups play a key role in the stabilization of this polydentate carbon-chain chelate. This process is also the first [2+2+2] cycloaddition reaction of an alkyne with a late-transition-metal carbyne complex. This study not only enriches the chemistry of polydentate carbon chain chelates, but also deepens our understanding of the chelating ability of carbon ligands. PMID- 29388727 TI - Special AT-rich sequence binding protein 1 is required for maintenance of T cell receptor responsiveness and development of experimental autoimmune encephalomyelitis. AB - The genome organizer special AT-rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL-17- and IFN-gamma-producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen-inducible SATB1 deletion system, SATB1cKO-ER-Cre mice, was used. Encephalitogenic T cells from MOG35-55-immunized SATB1cKO-ER-Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell-mediated autoimmune diseases. PMID- 29388728 TI - Promoting rural academic and community partnerships in the independent state of rural Australia. PMID- 29388730 TI - Visiting the Limits between a Highly Strained 1-Zirconacyclobuta-2,3-diene and Chemically Robust Dizirconacyclooctatetraene. AB - The reaction of the allene precursor Li2 (Me3 SiC3 SiMe3 ) with [Cp2 ZrCl2 ] (Cp=cyclopentadienyl) was examined. The selective formation of hitherto unknown linear, allene-bridged dizirconocene complexes [(Cp2 ZrCl)2 {-MU-(Me3 Si)C3 (SiMe3 )-}] and [(Cp2 Zr)2 {-MU-(Me3 Si)C3 (SiMe3 )-}2 ] was observed. Upon sigma coordination of the allenediyl unit to {Cp2 Zr}, pyrophoric Li2 (Me3 SiC3 SiMe3 ) is tamed stepwise to yield a surprisingly robust 1,5-dizirconacyclooctatetra 2,3,6,7-ene with cumulated double bonds. This complex is unexpectedly inert against moisture, air, water and acetone. Surprisingly, it degrades under MS conditions to give the highly strained 1-zirconacyclobuta-2,3-diene. All compounds isolated have been fully characterised and the molecular structures are discussed. The stability and reactivity of these complexes are rationalised by DFT computations. PMID- 29388731 TI - Characterization of a novel HLA-DRB1*07 allele, DRB1*07:83. AB - A new DRB1*07 allele, DRB1*07:83, was described in a Caucasian Spanish donor. PMID- 29388733 TI - Attempts to Lose Weight Among US Children: Importance of Weight Perceptions from Self, Parents, and Health Professionals. AB - OBJECTIVE: The objective of this study was to investigate how perceptions of weight by children themselves, parents, and health professionals influence children's persistent attempts to lose weight. METHODS: The sample included 4,914 children aged 8 to 15 years from the 2005 to 2014 National Health and Nutrition Examination Survey (representing 20.7 million children). Data were analyzed using logistic regression models. RESULTS: About 34.2% never made an effort to lose weight, whereas 28.2% made persistent attempts to lose weight. Children's persistent attempts to lose weight were highly related to their own BMI percentile. Children's self-perceptions of overweight increased the odds of persistent attempts to lose weight more than sevenfold. Health professionals' perceptions that children were overweight increased the odds of persistent attempts to lose weight almost threefold. However, parents' perceptions of children as overweight had a relatively small though significant influence on children's attempts to lose weight. CONCLUSIONS: As perceptions of children's weight status play big roles in children's attempts to lose weight, interventions focusing on increasing accuracy of perceptions may help promote healthy weight loss efforts. Although parents are key agents in controlling their children's weight gain, especially among minority school-aged children, the study findings also emphasize the greater importance of health professionals on children's attempts to lose weight across different racial/ethnic groups. PMID- 29388734 TI - A new HLA-DQB1*04 allele, HLA-DQB1*04:01:05, identified in a Korean individual. AB - HLA-DQB1*04:01:05 differs from DQB1*04:01:01 by a single nucleotide substitution at codon 30 (TAC>TAT). PMID- 29388735 TI - Worsening renal function definition is insufficient for evaluating acute renal failure in acute heart failure. AB - AIMS: Whether or not the definition of a worsening renal function (WRF) is adequate for the evaluation of acute renal failure in patients with acute heart failure is unclear. METHODS AND RESULTS: One thousand and eighty-three patients with acute heart failure were analysed. A WRF, indicated by a change in serum creatinine >=0.3 mg/mL during the first 5 days, occurred in 360 patients while no WRF, indicated by a change <0.3 mg/dL, in 723 patients. Acute kidney injury (AKI) upon admission was defined based on the ratio of the serum creatinine value recorded on admission to the baseline creatinine value and placed into groups based on the degree of AKI: no-AKI (n = 751), Class R (risk; n = 193), Class I (injury; n = 41), or Class F (failure; n = 98). The patients were assigned to another set of four groups: no-WRF/no-AKI (n = 512), no-WRF/AKI (n = 211), WRF/no AKI (n = 239), and WRF/AKI (n = 121). A multivariate logistic regression model found that no-WRF/AKI and WRF/AKI were independently associated with 365 day mortality (hazard ratio: 1.916; 95% confidence interval: 1.234-2.974 and hazard ratio: 3.622; 95% confidence interval: 2.332-5.624). Kaplan-Meier survival curves showed that the rate of any-cause death during 1 year was significantly poorer in the no-WRF/AKI and WRF/AKI groups than in the WRF/no-AKI and no-WRF/no-AKI groups and in Class I and Class F than in Class R and the no-AKI group. CONCLUSIONS: The presence of AKI on admission, especially Class I and Class F status, is associated with a poor prognosis despite the lack of a WRF within the first 5 days. The prognostic ability of AKI on admission may be superior to WRF within the first 5 days. PMID- 29388736 TI - Active Search for Computer-aided Drug Design. AB - We consider lead discovery as active search in a space of labelled graphs. In particular, we extend our recent data-driven adaptive Markov chain approach, and evaluate it on a focused drug design problem, where we search for an antagonist of an alphav integrin, the target protein that belongs to a group of Arg-Gly-Asp integrin receptors. This group of integrin receptors is thought to play a key role in idiopathic pulmonary fibrosis, a chronic lung disease of significant pharmaceutical interest. As an in silico proxy of the binding affinity, we use a molecular docking score to an experimentally determined alphavbeta6 protein structure. The search is driven by a probabilistic surrogate of the activity of all molecules from that space. As the process evolves and the algorithm observes the activity scores of the previously designed molecules, the hypothesis of the activity is refined. The algorithm is guaranteed to converge in probability to the best hypothesis from an a priori specified hypothesis space. In our empirical evaluations, the approach achieves a large structural variety of designed molecular structures for which the docking score is better than the desired threshold. Some novel molecules, suggested to be active by the surrogate model, provoke a significant interest from the perspective of medicinal chemistry and warrant prioritization for synthesis. Moreover, the approach discovered 19 out of the 24 active compounds which are known to be active from previous biological assays. PMID- 29388732 TI - Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe. AB - OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naive subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) <=500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL >=24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naive patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r. PMID- 29388737 TI - Thermally Stable TiO2 - and SiO2 -Shell-Isolated Au Nanoparticles for In Situ Plasmon-Enhanced Raman Spectroscopy of Hydrogenation Catalysts. AB - Raman spectroscopy is known as a powerful technique for solid catalyst characterization as it provides vibrational fingerprints of (metal) oxides, reactants, and products. It can even become a strong surface-sensitive technique by implementing shell-isolated surface-enhanced Raman spectroscopy (SHINERS). Au@TiO2 and Au@SiO2 shell-isolated nanoparticles (SHINs) of various sizes were therefore prepared for the purpose of studying heterogeneous catalysis and the effect of metal oxide coating. Both SiO2 - and TiO2 -SHINs are effective SHINERS substrates and thermally stable up to 400 degrees C. Nano-sized Ru and Rh hydrogenation catalysts were assembled over the SHINs by wet impregnation of aqueous RuCl3 and RhCl3 . The substrates were implemented to study CO adsorption and hydrogenation under in situ conditions at various temperatures to illustrate the differences between catalysts and shell materials with SHINERS. This work demonstrates the potential of SHINS for in situ characterization studies in a wide range of catalytic reactions. PMID- 29388738 TI - Imaging molecular signatures for clinical detection of scleroderma in the hand by multispectral photoacoustic elastic tomography. AB - Scleroderma (SD) is a rare autoimmune disease, which is divided into 2 categories: the localized SD and systemic SD. The localized SD mainly causes skin thickening of the fingers, whereas the systemic SD can further affect the blood vessels and internal organs. In this pilot study, the multispectral photoacoustic elastic tomography (PAET) imaging technique was used to recover the quantitative physiological and elastic properties of biological tissues for the diagnosis of SD. Three healthy subjects and 3 SD patients were recruited and clinically examined by a rheumatologist, and then their hand/fingers were scanned by both magnetic resonance imaging and our home-made photoacoustic imaging system. Physiological parameters including oxygen saturation (ST O2 ), deoxy-hemoglobin (Hb) and oxy-hemoglobin (HbO2 ) concentrations and mechanical properties such as bulk elastic modulus images were reconstructed using the developed PAET reconstruction method. Our imaging results demonstrated that the physiological and elastic parameters exhibit striking differences between the SD and normal fingers, indicating that these biomarkers can serve as molecular signatures for early detection of SD. These quantitative physiological properties and bulk modulus may also pave a new path for improved understanding the pathological mechanism of SD. PMID- 29388740 TI - Formation of NiCo2 V2 O8 Yolk-Double Shell Spheres with Enhanced Lithium Storage Properties. AB - Complex nanostructures with multi-components and intricate architectures hold great potential in developing high-performance electrode materials for lithium ion batteries (LIBs). Herein, we demonstrate a facile self-templating strategy for the synthesis of metal vanadate nanomaterials with complex chemical composition of NiCo2 V2 O8 and a unique yolk-double shell structure. Starting with the Ni-Co glycerate spheres, NiCo2 V2 O8 yolk-double shell spheres are synthesized through an anion-exchange reaction of Ni-Co glycerate templates with VO3- ions, followed by an annealing treatment. By virtue of compositional and structural advantages, these NiCo2 V2 O8 yolk-double shell spheres manifest outstanding lithium storage properties when evaluated as anodes for LIBs. Impressively, an extra-high reversible capacity of 1228 mAh g-1 can be retained after 500 cycles at a high current density of 1.0 Ag-1 . PMID- 29388739 TI - Transparent Wood Smart Windows: Polymer Electrochromic Devices Based on Poly(3,4 Ethylenedioxythiophene):Poly(Styrene Sulfonate) Electrodes. AB - Transparent wood composites, with their high strength and toughness, thermal insulation, and excellent transmissivity, offer a route to replace glass for diffusely transmitting windows. Here, conjugated-polymer-based electrochromic devices (ECDs) that switch on-demand are demonstrated using transparent wood coated with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) as a transparent conducting electrode. These ECDs exhibit a vibrant magenta-to clear color change that results from a remarkably colorless bleached state. Furthermore, they require low energy and power inputs of 3 mWh m-2 at 2 W m-2 to switch due to a high coloration efficiency (590 cm2 C-1 ) and low driving voltage (0.8 V). Each device component is processed with high-throughput methods, which highlights the opportunity to apply this approach to fabricate mechanically robust, energy-efficient smart windows on a large scale. PMID- 29388741 TI - Successful delivery in an patient with afibrinogenemia after three abortions: A case report and review of the literature. PMID- 29388743 TI - Tropical Medicine & International Health. PMID- 29388742 TI - A prospective surveillance study of inhibitor development in haemophilia A patients following a population switch to a third-generation B-domain-deleted recombinant factor VIII. AB - INTRODUCTION: Following a provincial tender, most subjects with haemophilia A in Quebec switched their treatment to a third-generation recombinant B-domain deleted factor VIII (FVIII). AIM: Our objective was to evaluate the incidence of inhibitor development and FVIII recovery in patients following the switch of factor replacement therapy. METHODS: One hundred and thirty-five subjects were enrolled and tested for FVIII activity and inhibitors every 6 months during 1 year. Subjects with mild haemophilia A or current inhibitors were excluded. Data on demographics, bleeds and FVIII usage were collected. RESULTS: A total of 125 switchers and 10 non-switchers were enrolled. Most subjects had severe haemophilia A (95.6%) and were on prophylaxis (89.6%). Mean FVIII recovery was similar at 0, 6 and 12 months postswitch. Two switchers developed de novo inhibitors in the 6 months postswitch, one of which was transient. No recurrent inhibitor was observed. A small but significant increase in FVIII usage was observed for adult switchers and the whole cohort of switchers and non-switchers. There was an increase in the annualized bleeding rate (ABR) for non-joint bleeds for the whole cohort of switchers. However, no significant differences were observed in ABR for joint bleeds. CONCLUSION: Our surveillance study shows comparable inhibitor development to similar published studies. A significant increase in FVIII utilization was noted for the whole cohort, switchers and non switchers. Lastly, no clinically significant changes were observed in ABR for joint bleeds, but a difference for non-joint bleed ABRs was observed in switchers. PMID- 29388744 TI - Bare laser-synthesized Au-based nanoparticles as nondisturbing surface-enhanced Raman scattering probes for bacteria identification. AB - The ability of noble metal-based nanoparticles (NPs) (Au, Ag) to drastically enhance Raman scattering from molecules placed near metal surface, termed as surface-enhanced Raman scattering (SERS), is widely used for identification of trace amounts of biological materials in biomedical, food safety and security applications. However, conventional NPs synthesized by colloidal chemistry are typically contaminated by nonbiocompatible by-products (surfactants, anions), which can have negative impacts on many live objects under examination (cells, bacteria) and thus decrease the precision of bioidentification. In this article, we explore novel ultrapure laser-synthesized Au-based nanomaterials, including Au NPs and AuSi hybrid nanostructures, as mobile SERS probes in tasks of bacteria detection. We show that these Au-based nanomaterials can efficiently enhance Raman signals from model R6G molecules, while the enhancement factor depends on the content of Au in NP composition. Profiting from the observed enhancement and purity of laser-synthesized nanomaterials, we demonstrate successful identification of 2 types of bacteria (Listeria innocua and Escherichia coli). The obtained results promise less disturbing studies of biological systems based on good biocompatibility of contamination-free laser-synthesized nanomaterials. PMID- 29388745 TI - Multiphoton dynamic imaging of the effect of chronic hepatic diseases on hepatobiliary metabolism in vivo. AB - In this study, intravital multiphoton microscopy was used to quantitatively investigate hepatobiliary metabolism in chronic pathologies of the liver. Specifically, through the use of the probe molecule 6-carboxyfluorescein diacetate, the effects of liver fibrosis, fatty liver, and hepatocellular carcinoma on the metabolic capabilities of mouse liver were investigated. After the acquisition of time-lapse images, a first order kinetic model was used to calculate rate constant resolved images of various pathologies. It was found that the ability of the liver to metabolically process the probe molecules varies among different pathologies, with liver fibrosis and fatty liver disease negatively impacted the uptake, processing, and excretion of molecules. The approach demonstrated in this work allows the study of the response of hepatic functions to different pathologies in real time and is useful for studying processes such as pharmacokinetics through direct optical imaging. PMID- 29388746 TI - Thrombopoietin levels in Quebec platelet disorder-Implications for the mechanism of thrombocytopenia. PMID- 29388748 TI - Another Year, Another Reflection. PMID- 29388751 TI - Rational Design of an Efficient Halotolerant Enzymatic System for In Vitro One Pot Synthesis of Cytidine Diphosphate Choline. AB - Salt accumulation often impedes cytidine diphosphate choline (CDP-choline) in vitro biosynthetic process. In this work a halotolerant in vitro enzymatic system is developed to solve this problem. It applies a halotolerant choline-phosphate cytidylyltransferase (CCT) obtained from rational design instructed by a unique strategy, which refers to one of the features of naturally occurring halophilic enzymes. By increasing acidic residues on protein surface where is most variable with respect to amino acid in the sequence alignment with other CCT, the mutants are obtained. The mutants represent higher catalytic activities and IC50 values (inhibit activity by 50%) at high-salt concentrations. Furthermore, when the halotolerant CCT is applied to in vitro one-pot biosynthesis of CDP-choline, the maximum titer and productivity are 161 +/- 3.5 mM and 6.2 +/- 0.1 mM L-1 h-1 , respectively. When acetate concentration increases, it still keeps relatively high reaction rate and is 2.2-fold higher than process using wild-type CCT (3.87 mM L-1 h-1 comparing with 1.74 mM L-1 h-1 ). This halotolerant system has great potential for industrial use, and the rational design concept can be applied to modify other enzymes, addressing the salt accumulation problem in in vitro systems, and gives insight into resolving by-product inhibition during reaction. PMID- 29388750 TI - High proportion of patients with bleeding of unknown cause in persons with a mild to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). AB - INTRODUCTION: Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce. AIM: We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs. RESULTS: Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder. CONCLUSION: The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females. PMID- 29388753 TI - Acute gastroenteritis: evidence-based management of pediatric patients [digest]. AB - Although most cases of acute gastroenteritis require minimal medical intervention, severe dehydration and hypoglycemia may develop in cases of prolonged vomiting and diarrhea. The mainstay of treatment for mild-to-moderately dehydrated patients with acute gastroenteritis should be oral rehydration solution. Antiemetics allow for improved tolerance of oral rehydration solution, and, when used appropriately, can decrease the need for intravenous fluids and hospitalization. This issue reviews the common etiologies of acute gastroenteritis, discusses more-severe conditions that should be considered in the differential diagnosis, and provides evidence-based recommendations for management of acute gastroenteritis in patients with mild-to-moderate dehydration, severe dehydration, and hypoglycemia. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice]. PMID- 29388752 TI - Iron Oxide Nanoparticles Synergize with Erlotinib to Suppress Refractory Non Small Cell Lung Cancer Cell Proliferation Through the Inhibition of ErbB/PI3K/AKT and PTEN Activation. AB - Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib and gefitinib, are currently approved for the management of NSCLC. However, primary and acquired resistances to EGFR-TKIs are the major obstacles in the treatment of NSCLC. These resistances have been associated with the development of secondary mutations in EGFR or continued oncogenic signaling despite TKI treatment. In this study, NSCLC cells with wild-type EGFR, A549, H460, H358, H157 which do not respond to EGFR TKIs, were used. We investigated whether a combination therapy of erlotinib plus iron oxide nanoparticles (IONPs) could sensitize NSCLC cells to erlotinib-induced cancer inhibition. In the 4 NSCLC cells investigated, erlotinib and IONPs combination therapy obviously inhibited NSCLC proliferation in vitro and in vivo, compared with erlotinib treatment alone. This effect was not dependent on erlotinib dose. Activation of ErbB3 was observed in these refractory NSCLC cells. Combined with IONPs, erlotinib could block ErbB3 activity and induce the expression of PTEN, which in turn inhibited the downstream PI3KAKT signaling pathway. These data demonstrate the therapeutic potential of biocompatible IONPs in combination with EGFR-TKIs in NSCLC, thus expanding and repurposing the current therapy for NSCLC. PMID- 29388754 TI - Emergency department management of patients with thermal burns [digest]. AB - Thermal burn injuries are a significant cause of morbidity and mortality worldwide. In addition to treatment of the burns, emergency clinicians must assess for inhalation injury, exposure to toxic gases, and related traumatic injuries. Priorities for emergency resuscitation include stabilization of airway and breathing, intravenous fluid administration, pain control, and local wound care. Special populations, including children and pregnant women, require additional treatment considerations. Referral to specialized burn care for select patients is necessary to improve long-term outcomes. This article reviews thermal burn classification and evidence-based treatment strategies. [Points & Pearls is a digest of Emergency Medicine Practice.]. PMID- 29388755 TI - The Obesity Epidemic and the Potential of Augmented Reality PMID- 29388756 TI - An Analysis of Patient Safety Incident Reports Associated with Electronic Health Record Interoperability AB - Background: With the widespread use of electronic health records (EHRs) for many clinical tasks, interoperability with other health information technology (health IT) is critical for the effective delivery of care. While it is generally recognized that poor interoperability negatively impacts patient care, little is known about the specific patient safety implications. Understanding the patient safety implications will help prioritize interoperability efforts around architectures and standards.Objectives: Our objectives were to (1) identify patient safety incident reports that reflect EHR interoperability challenges with other health IT, and (2) perform a detailed analysis of these reports to understand the health IT systems involved, the clinical care processes impacted, whether the incident occurred within or between provider organizations, and the reported severity of the patient safety events.Methods: From a database of 1.735 million patient safety event (PSE) reports spanning multiple provider organizations, 2625 reports that were indicated as being health IT related by the event reporter were reviewed to identify EHR interoperability related reports. Through a rigorous coding process 209 EHR interoperability related events were identified and coded.Results: The majority of EHR interoperability PSE reports involved interfacing with pharmacy systems (i.e. medication related), followed by laboratory, and radiology. Most of the interoperability challenges in these clinical areas were associated with the EHR receiving information from other health IT systems as opposed to the EHR sending information to other systems. The majority of EHR interoperability challenges were within a provider organization and while many of the safety events reached the patient, only a few resulted in patient harm.Conclusions: Interoperability efforts should prioritize systems in pharmacy, laboratory, and radiology. Providers should recognize the need to improve EHRs interfacing with other health IT systems within their own organization. PMID- 29388757 TI - Effect of GNI on Infant Mortality Rate in Low Income, Lower Middle Income, Upper Middle Income and High Income Countries. AB - Global disparities in health form a complex issue adversely affecting much of the world's population. What has been found is that national income and other general socio-economic factors are strong determinants of population health (Houweling, 2005 & Schell, 2007). In countries where resources are less, people are much less healthy than people living in rich countries. In wealthier countries that have made immense progress in health indicators, the resulting change in age structure and morbidity and mortality patterns portends even greater financial demands on the health sector.This study noted the trends in several health indicators versus economic indicators and related it to low income, lower middle income, upper middle income and high income countries. We noted that there is improvement in all health indicators along with an increasing GNI per Capita and GDP. In low income regions though, the rate of improvement is slower as opposed to high income countries. However, there is progress, which is leading to an increase in aging population. PMID- 29388758 TI - Evaluation of the Family Medicine Practice in Ankara Province by Family Physicians. AB - Turkey's family physician or practice system was established in the beginning of the 2010 across Turkey's 81 provinces and provides low- cost health care, preventive and curative basic medical services to the population. Public health centers across Turkey have now become Family Health Centers (ASMs) as part of Turkey's efforts to harmonize its health care system with that of the European Union. The aim of This study is to analyze and evaluate the implementation and performance of Family Practice in Ankara province by family physicians. A questionnaire form of 42 question was designed and used to determine opinions of the physicians about effective service & quality improvement, patient-physician relationship, efficiency in the area of responsibility, productivity, job satisfaction and equity. The result of the study shows that family physicians were defined to be generally satisfied with the system and performance implementation and significant differences were found according to work seniority, gender and productivity of the participants. Finally this study should be taken within it's limitation. The work seniority and gender was one of the most important factor to improve satisfactions and productivity for family physicians in Turkey. The sample size was representative for the country, however, one limitation might be considered the increase of sample size in future research if appropriate funding became available in the future. This study did not have any source of funding. PMID- 29388759 TI - Graphene Size-Dependent Multifunctional Properties of Unidirectional Graphene Aerogel/Epoxy Nanocomposites. AB - Unidirectional graphene aerogels (UGAs) with tunable densities, degrees of alignment, and electrical conductivities are prepared by varying the average size of precursor graphene oxide (GO) sheets between 1.1 and 1596 MUm2. UGAs prepared using ultralarge GO (UL-UGA) outperform those made from small GO in these properties. The UL-UGA/epoxy composites prepared by infiltrating liquid epoxy resin into the porous UGA structure exhibit an excellent electrical conductivity of 0.135 S/cm, along with an ultralow percolation threshold of 0.0066 vol %, which is one of the lowest values ever reported for all graphene-based composites. Owing to their three-dimensional interconnected network, a high degree of alignment, and effective reduction, UL-UGAs effectively enhance the fracture toughness of epoxy by 69% at 0.11 vol % graphene content through unique toughening mechanisms, such as crack pinning, crack deflection, interfacial debonding, and graphene rupture. These aerogels and composites can be mass produced thanks to the facile, scalable, and cost-efficient fabrication process, which will find various multifunctional applications. PMID- 29388760 TI - MOF-Templated Fabrication of Hollow Co4N@N-Doped Carbon Porous Nanocages with Superior Catalytic Activity. AB - Metallic Co4N catalysts have been considered as one of the most promising non noble materials for heterogeneous catalysis because of their high electrical conductivity, great magnetic property, and high intrinsic activity. However, the metastable properties seriously limit their applications for heterogeneous water phase catalysis. In this work, a novel Co-metal-organic framework (MOF)-derived hollow porous nanocages (PNCs) composed of metallic Co4N and N-doped carbon (NC) were synthesized for the first time. This hollow three-dimensional (3D) PNC catalyst was synthesized by taking advantage of Co-MOF as a precursor for fabricating 3D hollow Co3O4@C PNCs, along with the NH3 treatment of Co-oxide frames to promote the in situ conversion of Co-MOF to Co4N@NC PNCs, benefiting from the high intrinsic activity and electron conductivity of the metallic Co4N phase and the good permeability of the hollow porous nanostructure as well as the efficient doping of N into the carbon layer. Besides, the covalent bridge between the active Co4N surface and PNC shells also provides facile pathways for electron and mass transport. The obtained Co4N@NC PNCs exhibit excellent catalytic activity and stability for 4-nitrophenol reduction in terms of low activation energy (Ea = 23.53 kJ mol-1), high turnover frequency (52.01 * 1020 molecule g-1 min-1), and high apparent rate constant (kapp = 2.106 min-1). Furthermore, its magnetic property and stable configuration account for the excellent recyclability of the catalyst. It is hoped that our finding could pave the way for the construction of other hollow transition metal-based nitride@NC PNC catalysts for wide applications. PMID- 29388761 TI - Development of a Microfluidic Open Interface with Flow Isolated Desorption Volume for the Direct Coupling of SPME Devices to Mass Spectrometry. AB - Technologies that efficiently integrate the sampling and sample preparation steps with direct introduction to mass spectrometry (MS), providing simple and sensitive analytical workflows as well as capabilities for automation, can generate a great impact in a vast variety of fields, such as in clinical, environmental, and food-science applications. In this study, a novel approach that facilitates direct coupling of Bio-SPME devices to MS using a microfluidic design is presented. This technology, named microfluidic open interface (MOI), which operates under the concept of flow-isolated desorption volume, consists of an open-to-ambient desorption chamber (V <= 7 MUL) connected to an ionization source. Subsequently, compounds of interest are transported to the ionization source by means of the self-aspiration process intrinsic of these interfaces. Thus, any ionization technology that provides a reliable and constant suction, such as electrospray ionization (ESI), atmospheric-pressure chemical ionization (APCI), or inductively coupled plasma ionization (ICP), can be hyphenated to MOI. Using this setup, the desorption chamber is used to release target compounds from the coating, while the isolation of the flow enables the ionization source to be continuously fed with solvent, all without the necessity of employment of additional valves. As a proof of concept, the design was applied to an ESI-MS/MS system for experimental validation. Furthermore, numerical simulations were undertaken to provide a detailed understanding of the fluid flow pattern inside the interface, then used to optimize the system for better efficiency. The analytical workflow of the developed Bio-SPME-MOI-MS setup consists of the direct immersion of SPME fibers into the matrix to extract/enrich analytes of interest within a short period of time, followed by a rinsing step with water to remove potentially adhering proteins, salts, and/or other interfering compounds. Next, the fiber is inserted into the MOI for desorption of compounds of interest. Finally, the volume contained in the chamber is drained and moved toward the electrospray needle for ionization and direct introduction to MS. Aiming to validate the technology, the fast determination of selected immunosuppressive drugs (e.g., tacrolimus, cyclosporine, sirolimus, and everolimus) from 100 MUL of whole blood was assessed. Limits of quantitation in the subppb range were obtained for all studied compounds. Good linearity (r2 >= 0.99) and excellent precision, with (8%) and without (14%) internal standard correction, were attained. PMID- 29388762 TI - Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk. AB - The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands. These two domains are joined together by a stretch of amino acids that is referred to as the "stalk". Studies of other class B GPCRs suggest that the stalk may act as hinge, allowing the ECD to adopt multiple conformations. It is unclear what the role of the stalk is within CLR and whether RAMPs can influence its function. Therefore, this study investigated the role of this region using an alanine scan. Effects of mutations were measured with all three RAMPs through cell surface expression, cAMP production and, in select cases, radioligand binding and total cell expression assays. Most mutants did not affect expression or cAMP signaling. CLR C127A, N140A, F142A, and L144A impaired cell surface expression with all three RAMPs. T125A decreased the potency of all peptides at all receptors. N128A, V135A, and L139A showed ligand-dependent effects. While the stalk appears to play a role in CLR function, the effect of RAMPs on this region seems limited, in contrast to their effects on the structure of CLR in other receptor regions. PMID- 29388763 TI - Rethinking Intensification of Constructed Wetlands as a Green Eco-Technology for Wastewater Treatment. PMID- 29388765 TI - Systematic Dissection of Sequence Elements Controlling sigma70 Promoters Using a Genomically-Encoded Multiplexed Reporter Assay in E. coli. AB - Promoters are the key drivers of gene expression and are largely responsible for the regulation of cellular responses to time and environment. In E. coli , decades of studies have revealed most, if not all, of the sequence elements necessary to encode promoter function. Despite our knowledge of these motifs, it is still not possible to predict the strength and regulation of a promoter from primary sequence alone. Here we develop a novel multiplexed assay to study promoter function in E. coli by building a site-specific genomic recombination mediated cassette exchange (RMCE) system that allows for the facile construction and testing of large libraries of genetic designs integrated into precise genomic locations. We build and test a library of 10,898 sigma70 promoter variants consisting of all combinations of a set of eight -35 elements, eight -10 elements, three UP elements, eight spacers, and eight backgrounds. We find that the -35 and -10 sequence elements can explain approximately 74% of the variance in promoter strength within our dataset using a simple log-linear statistical model. Neural network models can explain greater than 95% of the variance in our dataset, and show the increased power is due to nonlinear interactions of other elements such as the spacer, background, and UP elements. PMID- 29388764 TI - Comparative Cardiopulmonary Effects of Particulate Matter- And Ozone-Enhanced Smog Atmospheres in Mice. AB - This study was conducted to compare the cardiac effects of particulate matter (PM)- (SA-PM) and ozone(O3)-enhanced (SA-O3) smog atmospheres in mice. Based on our previous findings of filtered diesel exhaust we hypothesized that SA-O3 would cause greater cardiac dysfunction than SA-PM. Radiotelemetered mice were exposed to either SA-PM, SA-O3, or filtered air (FA) for 4 h. Heart rate (HR) and electrocardiogram were recorded continuously before, during and after exposure. Both SA-PM and SA-O3 increased heart rate variability (HRV) but only SA-PM increased HR. Normalization of responses to total hydrocarbons, gas-only hydrocarbons and PM concentration were performed to assess the relative contribution of each phase given the compositional variability. Normalization to PM concentration revealed that SA-O3 was more potent in increasing HRV, arrhythmogenesis, and causing ventilatory changes. However, there were no differences when the responses were normalized to total or gas-phase only hydrocarbons. Thus, this study demonstrates that a single exposure to smog causes cardiac effects in mice. Although the responses of SA-PM and SA-O3 are similar, the latter is more potent in causing electrical disturbances and breathing changes potentially due to the effects of irritant gases, which should therefore be accounted for more rigorously in health assessments. PMID- 29388766 TI - Role of (1,3) {Cu-Cu} Interaction on the Magneto-Caloric Effect of Trinuclear {CuII-GdIII-CuII} Complexes: Combined DFT and Experimental Studies. AB - Molecular refrigeration is found to be of great interest in the field of coordination chemistry, and GdIII ion based complexes are particularly attractive, as they exhibit a large magneto-caloric effect (MCE). As the magnetic coupling in GdIII clusters is difficult to control, other avenues to enhance the MCE values have been explored and incorporation of 3d metal ions in the cluster aggregation with GdIII yielding {3d-Gd} clusters are targeted. Among the transition-metal ions, the CuII ion is particularly attractive, as it does not possess any anisotropy, and in this regard, several di- and polynuclear {Cu-Gd} clusters are reported to yield attractive MCE values. While the role of near neighbor {Cu-Gd} interactions in the MCE has been explored in detail, how the next-nearest-neighbor interaction influences the MCE has not been explored. To explore the importance of next-nearest-neighbor (1,3) {Cu-Cu} interaction, we have undertaken detailed density functional studies on five trinuclear {CuII GdIII-CuII} complexes that are reported in the literature. In addition, we also report the synthesis and magnetic and EPR studies of a novel complex [(CuSALen)2Gd(NO3)3] (6; where SALen is N,N'-ethylenebis(salicylaldiminato)). Both magnetic and EPR studies reveal an S = 9/2 ground state for 6 with a very small zero-field splitting parameter (+0.01 cm-1), which aid in the achievement of a large MCE value for this molecule. Magnetization data collected for 6 yield a magnetic entropy change (-DeltaSm) of 17 J kg-1 K-1 at 3.5 K by employing a 7 T magnetic field. Our calculations on all six complexes reveal that {Cu-Gd} exchange is ferromagnetic in nature, while the next-nearest-neighbor {Cu-Cu} exchange is found to vary from a weak ferromagnetic to a moderate antiferromagnetic interaction. In all of the cases studied, simulated susceptibility data are in excellent agreement with the experimental data, offering confidence in the computed J values. In addition, we have developed a mechanism of magnetic coupling for {CuII-GdIII-CuII} trinuclear complexes, where the role of formally empty 5d, 6s, and 6p orbitals of GdIII ion is established. In particular, our studies reveal that the next-nearest-neighbor {Cu-Cu} interaction is strongly correlated to Cu-Gd-Cu angle, with both smaller and larger angles yielding stronger antiferromagnetic exchange. The antiferromagnetic {Cu-Cu} interaction diminishes the gap between the ground S = 9/2 state and first excited S = 7/2 state, leading to enhancement of MCE values. In contrast to the general belief that weak interactions are desired for large MCE, our study advocates targeting a stronger antiferromagnetic {Cu-Cu} interaction to obtain larger MCE values in this class of clusters. PMID- 29388767 TI - Kinetic Parameters of trans Scission by Extended HDV-like Ribozymes and the Prospect for the Discovery of Genomic trans-Cleaving RNAs. AB - Hepatitis delta virus (HDV)-like ribozymes are self-cleaving catalytic RNAs with a widespread distribution in nature and biological roles ranging from self scission during rolling-circle replication in viroids to co-transcriptional processing of eukaryotic retrotransposons, among others. The ribozymes fold into a double pseudoknot with a common catalytic core motif and highly variable peripheral domains. Like other self-cleaving ribozymes, HDV-like ribozymes can be converted into trans-acting catalytic RNAs by bisecting the self-cleaving variants at non-essential loops. Here we explore the trans-cleaving activity of ribozymes derived from the largest examples of the ribozymes (drz-Agam-2 family), which contain an extended domain between the substrate strand and the rest of the RNA. When this peripheral domain is bisected at its distal end, the substrate strand is recognized through two helices, rather than just one 7 bp helix common among the HDV ribozymes, resulting in stronger binding and increased sequence specificity. Kinetic characterization of the extended trans-cleaving ribozyme revealed an efficient trans-cleaving system with a surprisingly high KM', supporting a model that includes a recently proposed activation barrier related to the assembly of the catalytically competent ribozyme. The ribozymes also exhibit a very long koff for the products (~2 weeks), resulting in a trade-off between sequence specificity and turnover. Finally, structure-based searches for the catalytic cores of these ribozymes in the genome of the mosquito Anopheles gambiae, combined with sequence searches for their putative substrates, revealed two potential ribozyme-substrate pairs that may represent examples of natural trans-cleaving ribozymes. PMID- 29388768 TI - Stepwise Mechanism of Temperature-Dependent Coacervation of the Elastin-like Peptide Analogue Dimer, (C(WPGVG)3)2. AB - Elastin-like peptides (ELPs) are distinct, repetitive, hydrophobic sequences, such as (VPGVG) n, that exhibit coacervation, the property of reversible, temperature-dependent self-association and dissociation. ELPs can be found in elastin and have been developed as new scaffold biomaterials. However, the detailed relationship between their amino acid sequences and coacervation properties remains obscure because of the structural flexibility of ELPs. In this study, we synthesized a novel, dimeric ELP analogue (H-C(WPGVG)3-NH2)2, henceforth abbreviated (CW3)2, and analyzed its self-assembly properties and structural factors as indicators of coacervation. Turbidity measurements showed that (CW3)2 demonstrated coacervation at a concentration much lower than that of its monomeric form and another ELP. In addition, the coacervate held water soluble dye molecules. Thus, potent and distinct coacervation was obtained with a remarkably short sequence of (CW3)2. Furthermore, fluorescence microscopy, dynamic light scattering, and optical microscopy revealed that the coacervation of (CW3)2 was a stepwise process. The structural factors of (CW3)2 were analyzed by molecular dynamics simulations and circular dichroism spectroscopy. These measurements indicated that helical structures primarily consisting of proline and glycine became more disordered at high temperatures with concurrent, significant exposure of their hydrophobic surfaces. This extreme change in the hydrophobic surface contributes to the potent coacervation observed for (CW3)2. These results provide important insights into more efficient applications of ELPs and their analogues, as well as the coacervation mechanisms of ELP and elastin. PMID- 29388769 TI - Oxonitridosilicate Oxides RE26Ba6[Si22O19N36]O16:Eu2+ (RE = Y, Tb) with a Unique Layered Structure and Orange-Red Luminescence for RE = Y. AB - The oxonitridosilicate oxides RE26Ba6[Si22O19N36]O16:Eu2+ (RE = Y, Tb) were synthesized by high-temperature reaction in a radiofrequency furnace starting from REF3, RE2O3 (RE = Y, Tb), BaH2, Si(NH)2, and EuF3. The structure elucidation is based on single-crystal X-ray data. The isotypic materials crystallize in the monoclinic space group Pm (no. 6) [Z = 3, a = 16.4285(8), b = 20.8423(9), c = 16.9257(8) A, beta = 119.006(3) degrees for RE = Y and a = 16.5465(7), b = 20.9328(9), c = 17.0038(7) A, beta = 119.103(2) degrees for RE = Tb]. The unique silicate layers are made up from Q1-, Q2-, and Q3-type Si(O/N)4- as well as Q4 type SiN4-tetrahedra, forming three slightly differing types of cages. The corresponding 3-fold superstructure as well as pronounced hexagonal pseudosymmetry complicated the structure elucidation. Rietveld refinement on powder X-ray diffraction data, energy-dispersive X-ray spectroscopy and infrared spectroscopy support the findings from single-crystal X-ray data. When excited with UV to blue light, Y26Ba6[Si22O19N36]O16:Eu2+ shows broad orange-red luminescence (lambdaem = 628 nm, fwhm ~ 125 nm/3130 cm-1). An optical band gap of 4.2 eV was determined for the doped compound by means of UV/vis spectroscopy. PMID- 29388771 TI - Accurate Thermochemistry for Organic Cations via Error Cancellation using Connectivity-Based Hierarchy. AB - Connectivity-Based Hierarchy (CBH) is an effective error-cancellation scheme for the determination of chemically accurate thermochemical properties of a variety of organic and biomolecules. Neutral molecules and open-shell radicals have already been treated successfully by this approach utilizing inexpensive computational methods such as density functional theory. Herein, we present an extension of the method to a new class of molecules, specifically, organic cations. Because of the presence of structural rearrangements involving hydrogen migrations as well as unusual structures such as bridged cations, the application of the standard CBH protocol to a test set of 25 cations leads to significant errors due to ineffective bond-type matching. We propose an adjusted protocol to overcome such limitations to achieve highly effective error cancellation. The modified CBH methods, in conjunction with a wide range of density functionals, reproduce G4 energies for the test set of organic cations accurately within 1-2 kcal/mol at a reduced computational cost. PMID- 29388770 TI - A Dual Reporter Iodinated Labeling Reagent for Cancer Positron Emission Tomography Imaging and Fluorescence-Guided Surgery. AB - The combination of early diagnosis and complete surgical resection offers the greatest prospect of curative cancer treatment. An iodine-124/fluorescein-based dual-modality labeling reagent, 124I-Green, constitutes a generic tool for one step installation of a positron emission tomography (PET) and a fluorescent reporter to any cancer-specific antibody. The resulting antibody conjugate would allow both cancer PET imaging and intraoperative fluorescence-guided surgery. 124I-Green was synthesized in excellent radiochemical yields of 92 +/- 5% (n = 4) determined by HPLC with an improved one-pot three-component radioiodination reaction. The A5B7 carcinoembryonic antigen (CEA)-specific antibody was conjugated to 124I-Green. High tumor uptake of the dual-labeled A5B7 of 20.21 +/- 2.70, 13.31 +/- 0.73, and 10.64 +/- 1.86%ID/g was observed in CEA-expressing SW1222 xenograft mouse model (n = 3) at 24, 48, and 72 h post intravenous injection, respectively. The xenografts were clearly visualized by both PET/CT and ex vivo fluorescence imaging. These encouraging results warrant the further translational development of 124I-Green for cancer PET imaging and fluorescence guided surgery. PMID- 29388772 TI - Effects of Plume Hydrodynamics and Oxidation on the Composition of a Condensing Laser-Induced Plasma. AB - High-temperature chemistry in laser ablation plumes leads to vapor-phase speciation, which can induce chemical fractionation during condensation. Using emission spectroscopy acquired after ablation of a SrZrO3 target, we have experimentally observed the formation of multiple molecular species (ZrO and SrO) as a function of time as the laser ablation plume evolves. Although the stable oxides SrO and ZrO2 are both refractory, we observed emission from the ZrO intermediate at earlier times than SrO. We deduced the time-scale of oxygen entrainment into the laser ablation plume using an 18O2 environment by observing the in-growth of Zr18O in the emission spectra relative to Zr16O, which was formed by reaction of Zr with 16O from the target itself. Using temporally resolved plume-imaging, we determined that ZrO formed more readily at early times, volumetrically in the plume, while SrO formed later in time, around the periphery. Using a simple temperature-dependent reaction model, we have illustrated that the formation sequence of these oxides subsequent to ablation is predictable to first order. PMID- 29388773 TI - Sydnone Reporters for Highly Fluorogenic Copper-Free Click Ligations. AB - Bioorthogonal fluorescent turn-on reactions are attractive for the sensitive real time detection of a variety of phenomena including bioconjugation, chemical reactivity, and material assembly. Herein we describe the use of 3,4 disubstituted sydnones, a singular class of mesoionic dipoles, for highly fluorescent turn-on copper-free click cycloadditions with the fluorogenic dibenzocyclooctyne Fl-DIBO. Coherent with time-dependent density functional theory calculations, the pyrazole cycloadducts were found to be highly fluorescent with compelling photophysical properties including excellent fluorescence enhancement (up to 240-fold), high quantum yields (over 45%), and large Stokes shift (over 100 nm). Furthermore, the good stability and reactivity of 4-chlorosydnones with Fl-DIBO allowed us to employ them as chemical reporters for the challenging detection of modified-proteins in complex cellular extracts, with exquisite specificity in no-wash conditions. This novel fluorogenic system significantly expands our chemical biology toolbox and should be beneficial in countless applications. PMID- 29388774 TI - Highly Stable, Ultrasmall Polymer-Grafted Nanobins (usPGNs) with Stimuli Responsive Capability. AB - Highly stable and stimuli/pH-responsive ultrasmall polymer-grafted nanobins (usPGNs) have been developed by grafting a small amount (10 mol %) of short (4.3 kDa) cholesterol-terminated poly(acrylic acid) (Chol-PAA) into an ultrasmall unilamellar vesicle (uSUV). The usPGNs are stable against fusion and aggregation over several weeks, exhibiting over 10-fold enhanced cargo retention in biologically relevant media at pH 7.4 in comparison with the parent uSUV template. Coarse-grained molecular dynamics (CGMD) simulations confirm that the presence of the cholesterol moiety can greatly stabilize the lipid bilayer. They also show extended PAA chain conformations that can be interpreted as causing repulsion between colloidal particles, thus stabilizing them against fusion. Notably, CGMD predicted a clustering of the Chol-PAA chains on the lipid bilayer under acidic conditions due to intra- and interchain hydrogen bonding, leading to the destabilization of local membrane areas. This explains the experimental observation that usPGNs can be triggered to release a significant amount of cargo upon acidification to pH 5. These developments put the lipid-bilayer-embedded Chol-PAA in stark contrast with traditional poly(acrylic acid) systems where the molar mass (Mn) of the polymer chains must exceed 16.5 kDa to achieve stimuli responsive changes in conformation. They also distinguish the small usPGNs from the much-larger polymer-caged nanobin platform where the Chol-PAA chains must be covalently cross-linked to engender stimuli-responsive behaviors. PMID- 29388776 TI - Synthesis of a C-Nucleoside Phosphonate by Base-Promoted Epimerization. AB - The efficient synthesis of a [2'S] C-nucleoside phosphonate and its corresponding prodrug has been realized. A phosphonomethoxy group was stereoselectively introduced at the anomeric 5'-carbon atom through glycosylation of a benzoyl protected [5'R]-acetoxy-[2'R]-9-deazaadenine. An unexpected epimerization at the 2'-position of the sugar moiety occurred upon removal of the protecting groups, but this was further exploited as a key reaction for improved synthesis of the target compound. PMID- 29388775 TI - Premutilin Synthase: Ring Rearrangement by a Class II Diterpene Cyclase. AB - Biosynthesis of the complex diterpenoid antibiotic pleuromutilin relies on a bifunctional (di)terpene synthase, and here site-directed mutagenesis was used to knockout either of the two active sites. This enabled characterization of the novel ring contracted intermediate produced by the initiating class II diterpene cyclase active site. Quantum chemical calculations further indicate the importance of reactant configuration for this intriguing ring rearrangement. PMID- 29388777 TI - Copper-Mediated Trifluoromethylation-Allylation of Arynes. AB - An unprecedented three-component copper-mediated vicinal trifluoromethylation allylation of arynes is described. A wide range of structurally diverse trifluoromethylated allylarenes can be quickly assembled in one step. The application of the method has been demonstrated in the expedient synthesis of the CF3-containing analogue of the antispasmodic drug papaverine. The new reactivity of the [CuCF3] reagent, which is generated from the inexpensive industrial byproduct fluoroform, is revealed with unique advantages. PMID- 29388778 TI - Electron-Beam-Induced Synthesis of Hexagonal 1 H-MoSe2 from Square beta-FeSe Decorated with Mo Adatoms. AB - Two-dimensional (2D) materials have generated interest in the scientific community because of the advanced electronic applications they might offer. Powerful electron beam microscopes have been used not only to evaluate the structures of these materials but also to manipulate them by forming vacancies, nanofragments, and nanowires or joining nanoislands together. In this work, we show that the electron beam in a scanning transmission electron microscope (STEM) can be used in yet another way: to mediate the synthesis of 2D 1 H-MoSe2 from Mo decorated 2D beta-FeSe and simultaneously image the process on the atomic scale. This is quite remarkable given the different crystal structures of the reactant (square lattice beta-FeSe) and the product (hexagonal lattice 1 H-MoSe2). The feasibility of the transformation was first explored by theoretical calculations that predicted that the reaction is exothermic. Furthermore, a theoretical reaction path to forming a stable 1 H-MoSe2 nucleation kernel within pure beta FeSe was found, demonstrating that the pertinent energy barriers are smaller than the energy supplied by the STEM electron beam. PMID- 29388779 TI - Bronsted Acids Enable Three Molecular Rearrangements of One 3-Alkylidene-2H-1,2 oxazine Molecule into Distinct Heterocyles. AB - This work describes three different strategies to structurally rearrange one 3 alkylidene-2H-1,2-oxazine molecule into three distinct heterocycles using HOTf, propiolic acid, and silica gel, respectively. The mechanisms of these rearrangement reactions involve three independent routes, including (i) Bronsted acid catalysis, (ii) a synergetic action of Bronsted acids and anions, (iii) a surface-directed chemoselectivity. PMID- 29388780 TI - Copper-Catalyzed Decarboxylative/Click Cascade Reaction: Regioselective Assembly of 5-Selenotriazole Anticancer Agents. AB - A simple and efficient Cu-catalyzed decarboxylative/click reaction for the preparation of 1,4-disubstituted 5-arylselanyl-1,2,3-triazoles from propiolic acids, diselenides, and azides has been developed. The mechanistic study revealed that the intermolecular AAC reaction of an alkynyl selenium intermediate occurred. The resulting multisubstituted 5-seleno-1,2,3-triazoles were tested for in vitro anticancer activity by MTT assay, and compounds 4f, 4h, and 4p showed potent cancer cell-growth inhibition activities. PMID- 29388781 TI - Strategies to Avoid Underdiagnosing Pit-and-Fissure Caries. AB - Traditionally, testing for whether pit-and-fissure caries should be restored involved probing with a sharp explorer and evaluating resistance to withdrawal (ie, "stick"). Alternative visual methods of evaluation and classification have been proposed, validated, and accepted formally in the core curriculum on caries management in both Europe and North America. This article examines the resistance to occlusal breakdown of fluoridehardened enamel despite progression of underlying dentin caries with accompanying difficulty in diagnosis. Traditional methods of pit-and-fissure caries diagnosis, including radiographs or fissure probing with an explorer, have been shown to be inaccurate and potentially destructive. The clinical process of using the visual/tactile International Caries Detection and Assessment System (ICDAS) and/or the Caries Classification System (CCS) is described and illustrated through case examples. PMID- 29388782 TI - Dental Care as a Safe and Essential Part of a Healthy Pregnancy. AB - Oral health is essential for general health and well-being, and this is especially so during pregnancy. Pregnancy may present challenges to the oral health of the mother, mainly because of adaptations in basic physiology. However, many mothers-to-be and their health professionals, both prenatal and dental, are unsure as to the safety of providing dental care during pregnancy. National guidelines, together with recommendations from numerous state-level and professional organizations, consistently indicate that provision of dental care is both safe and essential during pregnancy. Pregnancy also provides opportunities for the oral health of both infant and new mother after delivery that can set the infant on a lifetime pathway that minimizes preventable oral disease. This review summarizes guidelines for dental care during pregnancy, provides an overview of physiologic changes that occur and their relevance to oral health and dental care delivery, outlines risk factors for oral conditions, and considers timely preventive strategies. It also underscores the need for interprofessional collaboration with the perinatal team to optimize the quality of healthcare and ensure positive outcomes. PMID- 29388783 TI - Treatment of Peri-implantitis Using a Combined Decontaminative and Regenerative Protocol: Case Report. AB - Peri-implantitis is a long-term complication that frequently occurs after implant surgery. Several treatment methods have been proposed that are aimed at arresting the disease and potentially regenerating bone defects related to it. The use of a combination of proposed decontaminative treatments could possibly improve outcomes. In this case report the authors describe a combined mixed protocol, in which chemical decontamination and a laser-assisted decontamination technique are used in a surgical regenerative approach to successfully manage and treat a case of peri-implantitis. The combined surgical and antimicrobial protocol described can be a suitable treatment option in cases in which implants show severe bone resorption as a result of peri-implant disease. PMID- 29388784 TI - Managing Ridge Resorption After Tooth Extraction Using Partial Extraction Therapy. AB - Achieving successful long-term esthetic outcomes in implant dentistry requires that the height and width of the facial or buccal alveolar bone wall and, subsequently, the peri-implant tissues be maintained. Partial extraction therapy (PET) can be used to reduce the risk of facio-lingual collapse after tooth loss and improve the preservation of alveolar bone height and blood supply. This article demonstrates the use of PET for treatment of a hopeless tooth in the esthetic zone. After removal of the fractured maxillary central incisor, an implant was placed and restored with excellent esthetic, functional, and periodontal results. PMID- 29388785 TI - Techniques to Optimize Color Esthetics, Bonding, and Peri-implant Tissue Health With Titanium Implant Abutments. AB - Due to their exceptional biological and mechanical properties, titanium and its alloys are commonly used in both dental implants and implant abutments, upon which prostheses can be attached. The gray color of titanium metal, however, can elicit esthetic problems, as it has the potential to show through a translucent ceramic restorative material. Various solutions have been proposed and used to attempt to overcome esthetic issues associated with titanium. This article describes a simple, economical technique to color titanium abutments and components utilizing anodization, resulting in light reflection and color enhancement through a natural physics phenomenon known as light interference patterns. A technique for improving the bonding capabilities of cement to the abutment is also discussed. PMID- 29388786 TI - Critical Factors for Successful Restorations: Light-Curing, Light-Energy Monitoring, and Matrices. PMID- 29388787 TI - Soft-Tissue Grafting Techniques Associated With Immediate Implant Placement. AB - Immediate implant placement often presents challenges in terms of predictably obtaining soft-tissue coverage over the implant site. While delayed implant placement offers the ability for soft tissues to grow and invade the extraction socket making their attachment around implants more predictable, immediate implant placement poses a significant risk of bacterial invasion towards the implant surface as a result of insignificant soft-tissue volume. Soft-tissue grafting techniques have often been proposed for use during immediate implant placement to augment soft-tissue deficiencies, including the use of either palatal connective tissue grafts (CTGs) or collagen-derived scaffolds. However, both of these approaches have significant drawbacks in that CTGs are harvested with high patient morbidity and collagen scaffolds remain avascular and acelluar posing a risk of infection/implant contamination. More recently, platelet-rich fibrin (PRF) has been proposed as an economical and biological means to speed soft-tissue wound healing. In combination with immediate implant placement, PRF offers an easily procurable low-cost regenerative modality that offers an efficient way to improve soft-tissue attachment around implants. Furthermore, the supra-physiological concentration of defense-fighting leukocytes in PRF, combined with a dense fibrin meshwork, is known to prevent early bacterial contamination of implant surfaces, and the biological concentrations of autologous growth factors in PRF is known to increase tissue regeneration. This article discusses soft-tissue grafting techniques associated with immediate implant placement, presents several cases demonstrating the use of PRF in routine immediate implant placement, and further discusses the biological and economic advantages of PRF for the management of soft-tissue grafting during immediate implant placement. PMID- 29388788 TI - Correction of Large Oro-antral Communications From Previously Failed Implant Treatment: Reconstruction of Hard and Soft Tissues. AB - As dental implants become more popular for the treatment of partial and total edentulism and treatment of "terminal dentitions," techniques for the management of the atrophic posterior maxillae continue to evolve. Although dental implants carry a high success rate long term, attention must be given to the growing numbers of revisions or retreatment of cases that have had previous dental implant treatment and/or advanced bone replacement procedures that, due to either poor patient compliance, iatrogenic error, or poor quality of the pre-existing alveolar and/or soft tissues, have led to large osseous defects, possibly with deficient soft-tissue volume. In the posterior maxillae, where the poorest quality of bone in the oral cavity exists, achieving regeneration of the alveolar bone and adequate volume of soft tissue remains a complex procedure. This is made even more difficult when dealing with loss of dental implants previously placed, aggressive bone reduction required in various implant procedures, and/or residual sinus infections precluding proper closure of the oral wound margins. The purpose of this article is to outline a technique for the total closure of large oro antral communications, with underlying osseous defects greater than 15 mm in width and 30 mm in length, for which multiple previous attempts at closure had failed, to achieve not only the reconstruction of adequate volume and quality of soft tissues in the area of the previous fistula, but also total regeneration of the osseous structures in the area of the large void. PMID- 29388789 TI - Controlled Palatal Harvest Technique for Harvesting a Palatal Subepithelial Connective Tissue Graft. AB - Subepithelial connective tissue grafts (SCTGs) have been extensively used to augment soft-tissue volume on dental implants and natural teeth. The authors present a technique called the controlled palatal harvest (CPH) to obtain SCTGs. CPH provides an alternative to the trap-door and single-incision techniques currently utilized. The objective of this article is to describe this harvesting technique for SCTGs. A case report is presented in which the CPH technique was successfully used to obtain a SCTG. Contrary to current techniques where the SCTG is usually taken from the palatal (bone) side, this technique involves the dissection of a thick split-thickness flap in which the graft is harvested from the raised flap. Further, an L-shaped incision (with an anterior release) improves visibility and dexterity during dissection of the connective tissue graft. This technique enables the operator to maintain a certain minimum overlying flap thickness, and excellent control is ensured over the thickness of the harvested SCTG. The thickness of theremaining connective tissue overlying the palatal can also be controlled by the operator. Thus, the chances of leaving behind a thin tissue covering the palatal bone are reduced, minimizing necrosis and flap sloughing, which further improves grafting success. While the CPH can be used as an alternative to currently employed conventional harvest techniques, it may require greater operator skill. To the best of the authors' knowledge, this is the first report that documents such a technique. PMID- 29388790 TI - Use of CAD/CAM in Second-Stage Implant Surgery to Achieve Improved Final Restoration Esthetics, Natural Gingival Appearance. AB - To achieve a predictable esthetic outcome when using an implant-supported crown for rehabilitation of an edentulous space, computer-aided design/computer-aided manufacturing (CAD/CAM) technology can be utilized in the second stage of implant surgery to scan, mill, and restore the implant site all in one office visit. In this case report, an implant for a first molar was restored with a CAM-fabricated hybrid ceramic crown, designed using CEREC(r) 4.4 software. A 3-dimensional scan was taken chairside at the time of uncovering the implant using powder-free intraoral scanning. Specific design features were implemented to control peri implant soft-tissue growth to meet the patient's esthetic expectations and achieve an outstanding clinical outcome. This report emphasizes the value of using a CAD/CAM-milled crown in achieving an emergence profile in second-stage surgery, describes a polymer-infiltrated-ceramic-network material as a potential biomaterial for implant restoration, and discusses the importance of taking a digital impression to capture details for improved restoration esthetics and longevity. PMID- 29388791 TI - The Controlled Palatal Harvest (CPH) Technique for Harvesting a Palatal Subepithelial Connective Tissue Graft. AB - The use of methamphetamines is a significant public health concern not only in America but worldwide. The consequences of this drug's use are widespread, having major physiologic and psychological effects that are damaging to users' bodies and well-being. Meth use wreaks havoc on one's oral health, with the effects including demineralization of tooth surfaces, carious lesions, inflammation of the periodontium, and more. In addition to examining the neurotoxic effects that methamphetamines have on the brain, this article will discuss how dental professionals can approach treatment of individuals who are affected by this debilitating drug, utilizing a strategy that combines caries arrest with oral hygiene improvement and disease prevention. It will also review the use of various products to help establish a neutral oral pH and enhance enamel remineralization. PMID- 29388792 TI - Transcription factor GATA6: a novel marker and putative inducer of ductal metaplasia in biliary atresia. AB - Biliary atresia (BA), a neonatal liver disease, is characterized by obstruction of extrahepatic bile ducts with subsequent cholestasis, inflammation, and progressive liver fibrosis. To gain insights into the pathophysiology of BA, we focused attention on GATA6, a transcription factor implicated in biliary development. Early in fetal development GATA6 expression is evident in cholangiocytes and hepatocytes, but by late gestation it is extinguished in hepatocytes. Utilizing a unique set of BA liver samples collected before and after successful portoenterostomy (PE), we found that GATA6 expression is markedly upregulated in hepatocytes of patients with BA compared with healthy and cholestatic disease controls. This upregulation is recapitulated in two murine models simulating bile duct obstruction and intrahepatic bile ductule expansion. GATA6 expression in BA livers correlates with two established negative prognostic indicators (age at PE, degree of intrahepatic bile ductule expansion) and decreases after normalization of serum bilirubin by PE. GATA6 expression in BA livers correlates with expression of known regulators of cholangiocyte differentiation ( JAGGED1, HNF1beta, and HNF6). These same genes are upregulated after enforced expression of GATA6 in human hepatocyte cell models. In conclusion, GATA6 is a novel marker and a putative driver of hepatocyte cholangiocyte metaplasia in BA, and its expression in hepatocytes is downregulated after successful PE. NEW & NOTEWORTHY A pathological hallmark in the liver of patients with biliary atresia is ductular reaction, an expansion of new bile ductules that are thought to arise from conversion of mature hepatocytes. Here, we show that transcription factor GATA6 is a marker and potential driver of hepatocyte ductal metaplasia in biliary atresia. Hepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy. PMID- 29388793 TI - Radiographic patterns of recurrence and pathologic correlation in malignant gliomas treated with bevacizumab. AB - : Interpretation of MRI abnormalities in patients with malignant gliomas (MG) treated with bevacizumab is challenging. Recent reports describe quantitative analyses of diffusion-weighted imaging abnormalities not available in standard clinical settings, to differentiate tumor recurrence from treatment necrosis. We retrospectively reviewed bevacizumab treated MG patients who underwent surgery or autopsy to correlate radiographic recurrence patterns with pathologic findings. 32 patients with MG (26 glioblastoma, three anaplastic astrocytoma and three anaplastic oligodendroglioma) were identified. Recurrence patterns: local enhancing (n = 23), distant enhancing (n = 1), nonenhancing (n = 7) and leptomeningeal (n = 1). HISTOLOGY: tumor (n = 25), mixed tumor/necrosis (n = 5) and all necrosis (n = 2). On diffusion-weighted imaging, 5/32 had restricted diffusion (three mixed and two necrosis). Irrespective of radiographic recurrence pattern, tumor was found in 94% of cases. Restricted diffusion correlated with necrosis. PMID- 29388795 TI - The Longitudinal Effects of Expressive Writing on Victims of Relational Transgressions. AB - This study investigated the longitudinal effects of written disclosure on physiological and communicative health outcomes for victims of severe relational transgressions in dating relationships. Participants were assigned to a two-step writing condition, a benefit-finding condition, or a control condition to write once a day for three consecutive days on the same topic. Testosterone and forgiveness communication were assessed twice over the course of one-month. The results demonstrate that conditional forgiveness levels were higher for participants in both experimental conditions than in the control condition, whereas neither of the experimental conditions reduced testosterone levels. Across the writing conditions, testosterone levels were negatively associated with conditional forgiveness and positively associated with direct forgiveness. Finally, the results revealed that linguistic features in the writing predicted levels of testosterone and conditional forgiveness. PMID- 29388794 TI - The role of visceral and subcutaneous adipose tissue measurements and their ratio by magnetic resonance imaging in subjects with prediabetes, diabetes and healthy controls from a general population without cardiovascular disease. AB - OBJECTIVE: To study the relationship of area- and volumetric-based visceral and subcutaneous adipose tissue (VAT and SAT) by MRI and their ratio in subjects with impaired glucose metabolism from the general population. METHODS: Subjects from a population-based cohort with established prediabetes, diabetes and healthy controls without prior cardiovascular diseases underwent 3 T MRI. VAT and SAT were assessed as total volume and area on a single slice, and their ratio (VAT/SAT) was calculated. Clinical covariates and cardiovascular risk factors, such as hypertension and glycemic state were assessed in standardized fashion. Univariate and adjusted analyses were conducted. RESULTS: Among 384 subjects (age: 56.2 +/- 9.2 years, 58.1% male) with complete MRI data available, volumetric and single-slice VAT, SAT and VAT/SAT ratio were strongly correlated (all >r = 0.89). Similarly, VAT/SATvolume ratio was strongly correlated with VATvolume but not with SAT (r = 0.72 and r = -0.21, respectively). Significant higher levels of VAT, SAT and VAT/SAT ratio were found in subjects with impaired glucose metabolism (all p <= 0.01). After adjustment for potential cardiovascular confounders, VATvolume and VAT/SATvolume ratio remained significantly higher in subjects with impaired glucose metabolism (VATvolume = 6.9 +/- 2.5 l and 3.4 +/- 2.3 l; VAT/SATvolume ratio = 0.82 +/- 0.34 l and 0.49 +/- 0.29 l in patients with diabetes and controls, respectively, all p < 0.02), whereas the association for SATvolume attenuated. Additionally, there was a decreasing effect of glycemic status on VAT/SATvolume ratio with increasing body mass index and waist circumference (p < 0.05). CONCLUSIONS: VATvolume and VAT/SATvolume ratio are associated with impaired glucose metabolism, independent of cardiovascular risk factors or MRI-based quantification technique, with a decreasing effect of VAT/SATvolume ratio in obese subjects. Advances in knowledge: Quantification of VATvolume and VAT/SATvolume ratio by MRI represents a reproducable biomarker associated with cardiometabolic risk factors in subjects with impaired glucose metabolism, while the association of VAT/SATvolume ratio with glycemic state is attenuated in obese subjects. PMID- 29388796 TI - A Content Analysis of How Sexual Behavior and Reproductive Health are Being Portrayed on Primetime Television Shows Being Watched by Teens and Young Adults. AB - Television is a leading source of sexual education for teens and young adults, thus it is important to understand how sexual behavior and reproductive health are portrayed in popular primetime programming. This study is a media content analysis of the 19 top-rated scripted English-language primetime television shows aired between January 1, 2015 and May 31, 2015, and viewed by American youth audiences 12-24 years of age. The purpose of this study is to assess how sex/sexuality and reproductive health are being portrayed in a popular medium that reaches many adolescent and young adult audiences. Themes used for this analysis include youth pregnancy/parenting, mentoring/guidance of youth regarding sexual behavior, sex/sexuality, body image/identity, sexual violence/abuse/harassment, gender identity/sexual orientation, and reproductive health. Themes have been classified in one of the following six categories: visual cues, brief mentions, dialogue, minor storylines, major storylines, and multi-episode storylines. Our findings indicate that narratives providing educational information regarding the risks and consequences of sexual behavior were missing from the television shows we analyzed and that storylines promoting low risk sexual behavior were rare. Sexual violence and abuse, casual sex among adults, lack of contraception use, or no portrayal of consequences of risky behaviors were common. Compared to prior research, we found an emergent theme normalizing non-heterosexual gender identity and sexual orientation. Our findings have important implications as exposure to popular media shapes the perceptions and behaviors of teens and young adults. This study has the potential to shed light on the need to create stories and narratives in television shows watched by American teens and young adults with educational messages regarding the risks and consequences of sexual behavior. PMID- 29388797 TI - Development and Formative Evaluation of a Communication Skills Training Program for Persons with Rheumatic and Musculoskeletal Diseases. AB - OBJECTIVE: Our aim was to develop and evaluate a two-module training program (KOKOS-Rheuma) specifically designed to enhance the ability of persons with rheumatic and musculoskeletal diseases to communicate in various everyday situations. DESIGN: KOKOS-Rheuma deals with communication at work (particularly superiors), with physicians, acquaintances, strangers and staff members of authorities and institutions and focuses on communication skills such as "saying no" and "giving and receiving feedback." Members of the German League against Rheumatism (GLR) were trained to deliver the program to self-help groups over two sessions or in a full-day session. The participants, trainers and observers completed a short evaluation form after each module or at the end of the full-day session. MAIN OUTCOME MEASURES: The evaluation was based on 232 participant, 51 trainer, and 8 observer evaluation forms. RESULTS: The participants rated all aspects of the training as good. The training was rated higher in the single session format. The great majority would recommend the course to other people. CONCLUSION: After the revision of the training manual, KOKOS-Rheuma can be recommended for inclusion in the training schedule of the GLR. We recommend that future trainers receive more extensive preparation for delivering the course that highlights the preparation time required. PMID- 29388799 TI - The Needle and the Damage Done: Framing the Heroin Epidemic in the Cincinnati Enquirer. AB - This case study focuses on the Cincinnati Enquirer's coverage of the heroin epidemic. The Enquirer started the first heroin beat in January 2016, and it could serve as a model for other news organizations. Reporters used combinations of episodic, thematic, public health, and crime and law enforcement frames in their coverage. These news frames are discussed in terms of how individualism collectivism, geographic location, available resources, and social determinants inform journalistic and societal discussions of the heroin epidemic in terms of solutions instead of responsibility or blame. PMID- 29388798 TI - Preoperative evaluation of neurovascular relationship in trigeminal neuralgia by three-dimensional fast low angle shot (3D-FLASH) and three-dimensional constructive interference in steady-state (3D-CISS) MRI sequence. AB - OBJECTIVE: The purpose of the study was to evaluate the value of high-resolution three-dimensional fast low angle shot (3D-FLASH) and three-dimensional constructive interference in steady-state (3D-CISS) MRI sequence solely or the combination of both in the visualization of neurovascular relationship in patients with trigeminal neuralgia (TN). METHODS: 65 patients with unilateral TN underwent 3D-FLASH and 3D-CISS imaging were retrospectively studied. Neurovascular relationship at the intracisternal segment of trigeminal nerve was reviewed by two experienced neuroradiologist, who was blinded to the clinical details. The imaging results were compared with the operative findings in all patients. RESULTS: The accuracy and positive rates of the 3D-FLASH + CISS imaging (98.46, 92.31%) in judging the symptomatic side according to the presence of vascular contacts were higher than those of 3D-CISS (90.77%, 84.62) or 3D-FLASH (89.23, 83.08%) sequence. In addition, the statistical analysis showed the sensitivity and accuracy of 3D-FLASH + CISS imaging was higher than that of 3D FLASH (p < 0.05). The 3D-FLASH + CISS imaging was more accurate in determining the type of offending vessel than 3D-CISS or 3D-FLASH imaging. CONCLUSION: The retrospective study demonstrates that the combination of 3D-FLASH with 3D-CISS sequence well delineates the relationship between intracisternal segment of trigeminal nerve and adjacent vessels in terms of increased positive rates and accuracy. Advances in knowledge: The study firstly dealt with the combination of 3D-CISS and 3D-FLASH imaging in TN. PMID- 29388801 TI - Desire or Disease? Framing Obesity to Influence Attributions of Responsibility and Policy Support. AB - The way we describe health threats affects perceptions of severity and preferred solutions to reduce risk. Most people agree obesity is a problem, but differ in how they attribute responsibility for development and decline of the disease. We explored effects of message framing on attributions of responsibility and support for public obesity policies using a 3 * 2 factorial design. Participants read one of six versions of a health message describing the negative effects of obesity. Message frames influenced respondent attributions and their support for policies to reduce obesity. Those who read a message that assigned agency to the disease (e.g., Obesity causes health problems) endorsed genetics as the cause to a greater degree than those who read a semantically equivalent message that instead assigned agency to people (e.g., Obese people develop health problems). In contrast, assigning agency to people rather than to the disease prompted higher attributions of individual responsibility and support for public policies. Explicit message frames that directly connected responsibility for obesity to either individual or societal factors had no effect on respondent perceptions. Findings suggest explicit arguments may be less effective in shifting perceptions of health threats than arguments embedded in agentic message frames. The results demonstrate specific message features that influence how people attribute responsibility for the onset and solution of obesity. PMID- 29388800 TI - Stromal fibrosis: imaging features with diagnostic contribution of diffusion weighted MRI. AB - OBJECTIVE: To describe magnetic resonance imaging (MRI) and ultrasonography findings of breast stromal fibrosis (SF) and compare apparent diffusion coefficient (ADC) stromal fibrosis values with breast cancer and normal parenchyma. METHODS: 45 patients (ages 22-74) with histopathologically proven SF who underwent MRI were included in this study. Their MRI and ultrasonography features were examined and categorized. The mean ADC values for SF, contralateral normal parenchyma, and breast malignancy of the control group values were calculated and compared among each other. RESULTS: The vast majority of SF on sonography showed features suggestive of malignancy: (1) irregular in shape 25/45 (55%); (2) indistinct in margin 27/45 (60%); and (3) hypoechoic 39/45 (87%) with posterior acoustic shadowing 11/45 (24%). An SF MRI showed a mass in 12/45 (26%) and non-mass enhancement in 33/45 (74%), mostly with irregular (8/12; 67%) shape. Non-mass lesions showed heterogeneous (12/33), clumped (9/33), and homogenous (9/33) enhancement. The initial SF contrast uptake rate varied between slow (57%), rapid (22%), and medium (21%). Delayed SF enhancement may be persistent (66%) or plateau (34%). Small cysts were located around/near 21 (47%) of lesions. Ductal ectasia was found in 14 (31%) of all patients. Mean ADCs of parenchyma, SF, and malignancy were 1.32 +/- 0.32, 1.23 +/- 0.25, and 0.99 +/- 0.24 * 10-3 mm2 sec-1, respectively. CONCLUSION: SF often mimics breast carcinoma on imaging and leads the radiology-pathology disagreement. In terms of distinguishing SF from malignancy, ADC could be a significant and promising value in diffusion weighted MRI along with conventional sequences. Slow initial uptake with delayed persistent contrast enhancement in a non-mass lesion with relatively higher ADC values are very helpful for differentiating SF from malignancy. The presence of small cysts and ductal ectasia were common findings around/near the SF. Advances in knowledge: A quantitative analysis for measuring ADC values along with additional MRI features can be very helpful in distinguishing SF from malignant lesions. PMID- 29388802 TI - Graphic and Arousing? Emotional and Cognitive Reactions to Tobacco Graphic Health Warnings and Associated Quit-Related Outcomes Among Low SEP Population Groups. AB - Research on graphic health warnings (GHWs) indicates that beyond changing cognitions about the health effects of smoking, GHWs evoke emotional reactions that can influence quit-related outcomes. Emotions can be classified based on valence (positive or negative) and arousal (calm or excited). However, although considerable research has examined the differential effectiveness of positive versus negative GHW-evoked emotions, research investigating the role of arousal activation in quit-related behaviors is scarce. This study examined associations between quit-related outcomes (intention and attempt to quit) and GHWs-evoked negative emotions classified as high and low in arousal activation as well as cognitive reactions among smokers of low socioeconomic position (SEP). It also examined whether perceived health risks of smoking moderate the relationship between emotional and cognitive reactions to GHWs and quit-related outcomes. Data were collected from low SEP smokers in three Massachusetts communities. Participants were screened and randomized to view one of the nine GHWs initially proposed for use by the U.S. Food and Drug Administration (FDA) and answered pre- and post-exposure questions. Results showed that GHW-evoked negative emotions high in arousal activation and cognitive reactions were both significantly associated with intention to quit during immediate post-test, controlling for age, warning label difference, and prior quit intention. However, these associations did not hold for quit attempts at follow-up. Perceived health risks of smoking moderated the association between cognitive reactions to GHWs and quit attempts at follow-up. The findings suggest that not all negative emotions evoked by GHWs are effective. Negative emotions high in arousal activation may be more effective in influencing quit-related behavioral intentions in low SEP groups. Additionally, unlike emotional reactions, cognitive reactions to GHWs may have effects that last relatively longer, but only among smokers who had low levels of perceived health risks of smoking at baseline. PMID- 29388803 TI - Multiplexed electrochemical detection of three cardiac biomarkers cTnI, cTnT and BNP using nanostructured ZnO-sensing platform. AB - AIM: Development of a label-free multiplexed point-of-care diagnostic device for a panel of cardiac biomarkers - cardiac troponin-T (cTnT), troponin-I (cTnI) and B-type natriuretic peptide (BNP). METHODS: A nonfaradaic electrochemical immunoassay designed with anisotropic high surface area ZnO nanostructures grown using low-temperature hydrothermal methods was selectively immobilized with capture antibodies. Multiplexed detection in human serum using ZnO nanostructures based on complementary electrochemical measurement techniques - electrochemical impedance spectroscopy and Mott-Schottky. RESULTS: Linear signal response for detection of three biomarkers in human serum with dynamic range of 1 pg/ml-100 ng/ml and limit of detection at 1 pg/ml and low signal response to background interferences was achieved. CONCLUSION: First demonstration of simultaneous detection of three cardiac biomarkers in clinically relevant range with sensor's analytical performance and linear response of detection showed potential utility in screening clinical samples for early diagnosis of acute myocardial infarction and chronic heart failure. PMID- 29388804 TI - The Relationship Between Midday Napping And Neurocognitive Function in Early Adolescents. AB - OBJECTIVE/BACKGROUND: The impact of midday napping on neurocognitive function in adolescents has not been well established. This study aimed to investigate the relationship between self-reported midday-napping behaviors and neurocognitive function in early adolescents. PARTICIPANTS: The sample was comprised of 363 early adolescents (12.00 +/- 0.38 years old) from Jintan, China. METHODS: Midday napping, nighttime sleep duration, and sleep quality were measured by self reported questionnaires. Neurocognitive function was measured by the Penn Computerized Neurocognitive Battery (accuracy and reaction times). Generalized linear regression was used to analyze the relationships. RESULTS: Sixty-four percent of our sample took more than 3 naps per week, and 70.11% reported nap durations of over 30 min. Participants with higher frequencies or longer durations of midday napping reported significantly better nighttime sleep quality (p < 0.05). Adjusted models showed that frequent nappers (5-7d/week) were significantly associated with heightened accuracy on tasks that measured sustained attention and nonverbal reasoning and faster reaction times on spatial memory compared with other frequency groups (ps < 0.05). For napping duration subgroups, early adolescents who took naps of any length were estimated to have faster reaction speeds on the sustained attention task compared with participants who never napped (ps < 0.05). However, only nappers with a moderate duration (31 60 min) tended to achieve both faster speeds (beta = -38.28, p = 0.02) and better accuracy (beta = 3.90, p = 0.04) on the sustained attention task. CONCLUSIONS: Our findings suggest that there is an association between habitual midday napping and neurocognitive function in early adolescents, especially in China, where midday napping is a cultural practice. PMID- 29388805 TI - Bioactive peptides from selected latin american food crops - A nutraceutical and molecular approach. AB - This review reported an updated survey on the molecular functional properties of bioactive peptides derived from different Latin American ancient grains such as Maize, common Bean, Amaranth, Quinoa and Chia seeds. Seed storage proteins ecrypt in their sequences diverse peptides associated with a wide range of beneficial effects on the human health and the most studied are antihypertensive, anti cholesterolemic, antioxidant, anti-inflammatory, anticancer, antimicrobial and immunomodulatory properties. Additionally, in the last decades molecular properties have been also used for their characterization to understand their activities and it makes them highly attractive to be incorporated into food formulations and to complement or replace some conventional cereal grains. Due to the nutraceutical effects, today, these seeds are one of the main gastronomic trends of consumption worldwide due to their nutritional benefits and are part of the shopping lists of many people, among them vegetarians, vegans, celiacs or lovers of raw food. These seeds are a legacy of pre-Columbian civilizations reason why in our time they are considered as "Superfoods of the Gods", "The pre hispanic superfoods of the future" and "The new golden seeds of the XXI century". PMID- 29388806 TI - The use of functionally graded dental crowns to improve biocompatibility: a finite element analysis. AB - In post-core crown restorations, the significant mismatch between stiffness of artificial crowns and dental tissues leads to stress concentration at the interfaces. The aim of the present study was to reduce the destructive stresses by using a class of inhomogeneous materials called functionally graded materials (FGMs). For the purpose of the study, a 3-dimentional computer model of a premolar tooth and its surrounding tissues were generated. A post-core crown restoration with various crown materials, homogenous and FGM materials, were simulated and analyzed by finite element method. Finite element and statistical analysis showed that, in case of oblique loading, a significant difference (p < 0.05) was found at the maximum von Mises stresses of the crown margin between FGM and homogeneous crowns. The maximum von Mises stresses of the crown margin generated by FGM crowns were lower than those generated by homogenous crowns (70.8 vs. 46.3 MPa) and alumina crown resulted in the highest von Mises stress at the crown margin (77.7 MPa). Crown materials of high modulus of elasticity produced high stresses at the cervical region. FGM crowns may reduce the stress concentration at the cervical margins and consequently reduce the possibility of fracture. PMID- 29388807 TI - Spectrum of MRI brain lesion patterns in neuromyelitis optica spectrum disorder: a pictorial review. AB - Neuromyelitis optica is a neurotropic autoimmune inflammatory disease of the central nervous system traditionally thought to exclusively involve the optic nerves and spinal cord. With the discovery of the disease-specific aquaporin-4 antibody and the increasing recognition of clinical and characteristic imaging patterns of brain involvement in what is now termed neuromyelitis optica spectrum disorder (NMOSD), MRI now plays a greater role in diagnosis of NMOSD based on the 2015 consensus criteria and in distinguishing it from other inflammatory disorders, particularly multiple sclerosis (MS). Several brain lesion patterns are highly suggestive of NMOSD, whereas others may serve as red flags. Specifically, long corticospinal lesions, hemispheric cerebral white matter lesions and periependymal lesions in the diencephalon, dorsal brainstem and white matter adjacent to lateral ventricles are typical of NMOSD. In contrast, juxtacortical, cortical, or lesions perpendicularly oriented to the surface of the lateral ventricle suggests MS as the diagnosis. Ultimately, a strong recognition of the spectrum of MRI brain findings in NMOSD is essential for accurate diagnosis, and particularly in differentiating from MS. This pictorial review highlights the spectrum of characteristic brain lesion patterns that may be seen in NMOSD and further delineates findings that may help distinguish it from MS. PMID- 29388809 TI - Developmental Contributions to Emotional Awareness. AB - The Levels of Emotional Awareness Scale (LEAS) has received considerable support as a reliable and valid measure of individual differences in emotional awareness (EA) since the original report involving 40 participants (Lane, Quinlan, Schwartz, Walker, & Zeitlin, 1990 ). However, the hypothesized developmental nature of EA (conceptualized as a cognitive skill) has thus far only been examined in that 1 early study. Here we report multiple regression analyses on the entire sample of 94 participants who completed the LEAS as part of that original study, as well as the same developmental and affective measures used in the original report. We first observed that different developmental measures, including the Object Relations Inventory and the Sentence Completion Test of Ego Development, accounted for unique portions of the variance in LEAS scores. We also observed that higher LEAS scores were associated with greater within category variance in the self-reported positive and guilt- and shame-related emotions people reported experiencing on a typical day. Based on these findings, we introduce a 3-dimensional cognitive-developmental framework that LEAS scores plausibly track, including (a) the transition from focusing on external/physical to internal/psychological characteristics, (b) greater conceptual complexity, and (c) self-other differentiation. We then discuss the implications of this framework for understanding the nature of EA and for future research. PMID- 29388808 TI - Evaluation of periprostatic neurovascular fibers before and after radical prostatectomy by means of 1.5 T MRI diffusion tensor imaging. AB - OBJECTIVE: To evaluate if diffusion tensor imaging (DTI) is able to detect changes of periprostatic neurovascular fibers (PNFs) before and after radical prostatectomy (RP), and if these changes are related to post-surgical urinary incontinence and erectile dysfunction. METHODS: 22 patients (mean age 62.6 years) with biopsy-proven prostate cancer underwent 1.5 T DTI before and after RP. The number, fractional anisotropy (FA) values and length of PNFs before and after RP were compared using Student's t-test. Each patient filled out two questionnaires before and after RP, one for the evaluation of urinary continence (ICIQ-SF) and one for the evaluation of erectile function (IIEF-5). The ratios of the number, FA values and length of PNFs before and after RP (DTI B-A RATIOs) and the ratios between the scores obtained before and after RP for both ICIQ-SF and IIEF-2 (ICIQ SF B-A RATIOs and IIEF-2 B-A RATIOs) were calculated to perform the Kendall's tau test between them. RESULTS: There was a statistically significant decrease of the number of PNFs after RP at base, midgland, and apex (p < 0.01) and of FA values at midgland (p < 0.05), with positive statistically significant correlation between the DTI B-A RATIOs of the number of PNFs and IIEF-2 B-A RATIOs (p < 0.05, rho = 0.47). CONCLUSION: DTI was able to detect that the decrease of the number of the PNFs after RP was statistically related to the post-surgical erectile dysfunction (p < 0.05). Advances in knowledge: This work demonstrates that: (1) 1.5 T MRI DTI is able to detect the decrease of the number and of the FA of PNFs after prostatectomy; (2) the decrease of the number of PNFs after prostatectomy is related with the post-surgical erectile dysfunction; (3) 1.5 T MRI DTI has demonstrated to be a reproducible technique in detecting the changes of the PNFs induced by RP, with high interobserver agreement. PMID- 29388811 TI - Conflict Management by Physicians: A Heavy Hand in Preference-Sensitive Decisions. PMID- 29388810 TI - Knowledge Gaps in the Perioperative Management of Adults with Obstructive Sleep Apnea and Obesity Hypoventilation Syndrome. An Official American Thoracic Society Workshop Report. AB - The purpose of this workshop was to identify knowledge gaps in the perioperative management of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS). A single-day meeting was held at the American Thoracic Society Conference in May, 2016, with representation from many specialties, including anesthesiology, perioperative medicine, sleep, and respiratory medicine. Further research is urgently needed as we look to improve health outcomes for these patients and reduce health care costs. There is currently insufficient evidence to guide screening and optimization of OSA and OHS in the perioperative setting to achieve these objectives. Patients who are at greatest risk of respiratory or cardiac complications related to OSA and OHS are not well defined, and the effectiveness of monitoring and other interventions remains to be determined. Centers involved in sleep research need to develop collaborative networks to allow multicenter studies to address the knowledge gaps identified below. PMID- 29388812 TI - Abnormal Lung Function in HIV-infected Adults: An Under-recognized Risk Factor for Early Mortality. PMID- 29388813 TI - The Relationship between CFTR Genotype and Exercise Tolerance in Cystic Fibrosis. PMID- 29388814 TI - Cystic Lesions on Lung Cancer Screening Chest Computed Tomography: When Should We Be Concerned? PMID- 29388815 TI - Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock Adaptive Clinical Trial. AB - Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size. Clinical Trial registered with www.clinicaltrials.gov (NCT02508649). PMID- 29388816 TI - Bilateral Indwelling Pleural Catheters for Pleural Effusions Secondary to Nonmalignant Superior Vena Cava Obstruction. PMID- 29388817 TI - Dietary Influences on Asthma: The Generational Impact of a Sweet Tooth? PMID- 29388818 TI - Treating Cystic Fibrosis Pulmonary Exacerbations: In the Hospital with a Physician or at Home under Your Own Supervision? PMID- 29388819 TI - Susceptibility to Inhalational Lung Injury: We Need More Than the FEV1. PMID- 29388820 TI - The "Obesity Paradox" in Chronic Obstructive Pulmonary Disease: Can It Be Resolved? PMID- 29388821 TI - Diagnosis of Chronic Obstructive Pulmonary Disease: Breathing New Life into an Old Debate. PMID- 29388823 TI - What Is Sarcoidosis? PMID- 29388822 TI - Improving the Assessment of Implicit Motives Using IRT: Cultural Differences and Differential Item Functioning. AB - Researchers have long been interested in studying differences in implicit motive between different groups. Implicit motives are typically measured by scoring text that respondents have written in response to picture cues. Recently, research on the measurement of implicit motives has made progress through the application of a dynamic Thurstonian item-response theory model (DTM; Lang, 2014 ) that captures 2 basic motivational processes in motivational research: motive competition and dynamic reduction of motive strength after a motive has been acted out. In this article, the authors use the DTM to investigate differential item functioning (DIF) in implicit motive measures. The article first discusses DIF in the context of the DTM. The authors then conduct a DIF analysis of data from a study that used a picture set of the Operant Motive Test (OMT; Kuhl & Scheffer, 2002) with participants from Cameroon, Germany, and Costa Rica. Results showed no evidence of DIF in 9 pictures and some evidence for DIF in 3 pictures. The authors show a partial invariance model can be specified and use this partial invariance model to study latent mean differences between Cameroon, Germany, and Costa Rica. The discussion focuses on the use of IRT DIF methods in future research on implicit motives. PMID- 29388824 TI - Research Priorities in Pathophysiology for Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Research Statement. AB - BACKGROUND: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are common conditions; the co-occurrence of these diseases, called the overlap syndrome (OVS), has been associated with poor health outcomes. PURPOSE: The purpose of this Official American Thoracic Society Research Statement is to describe pathophysiology, epidemiology, outcomes, diagnostic metrics, and treatment of OVS, as well as to identify important gaps in knowledge and make recommendations for future research. METHODS: Clinicians and researchers with expertise in sleep medicine, pulmonary medicine, or both were invited to participate. Topics were divided among the participants according to their interest and expertise. A literature search was conducted; the search was not a formal systematic review. Evidence was considered and supplemented with the panelists' nonsystematic clinical observations. Important knowledge gaps were identified. RESULTS: Recommendations for research to fill existing knowledge gaps were made. The recommendations were formulated by discussion and consensus. CONCLUSIONS: Many important questions about OVS exist. This American Thoracic Society Research Statement highlights the types of research that leading clinicians and researchers believe will have the greatest impact on better understanding the spectrum of disease, improving diagnosis, and optimizing therapy. PMID- 29388825 TI - Perfectionistic Cognitions: Stability, Variability, and Changes Over Time. AB - The construct of perfectionistic cognitions is defined as a state-like construct resulting from a perfectionistic self-schema and activated by specific situational demands. Only a few studies have investigated whether and how perfectionistic cognitions change across different situations and whether they reflect stable between-person differences or also within-person variations over time. We conducted 2 studies to investigate the variability and stability of 3 dimensions of perfectionistic cognitions while situational demands changed (Study 1) and on a daily level during a highly demanding period of time (Study 2). The results of both studies revealed that stable between-person differences accounted for the largest proportion of variance in the dimensions of perfectionistic cognitions and that these differences were validly associated with between-person differences in affect. The frequency of perfectionistic cognitions increased during students' first semester at university, and these average within-person changes were different for the 3 dimensions of perfectionistic cognitions (Study 1). In addition, there were between-person differences in the within-person changes that were validly associated with concurrent changes in closely related constructs (unpleasant mood and tense arousal). Within-person variations in perfectionistic cognitions were also validly associated with variations in unpleasant mood and tense arousal from day to day (Study 2). PMID- 29388826 TI - Assessment of impacted and partially impacted lower third molars with panoramic radiography compared to MRI-a proof of principle study. AB - OBJECTIVES: Third molars often require surgical removal. Since three-dimensional radiological assessment is often indicated in difficult cases to avoid surgical complications, the radiation burden has to be considered. Here, MRI may offer a dose-free alternative to conventional X-ray techniques. The aim of this retrospective analysis was to evaluate the assessment quality of MRI compared to panoramic radiography in impacted and partially impacted lower third molars. METHODS: Panoramic radiographs and MRI scans of 28 Caucasian patients were assessed twice by four investigators. Wisdom teeth were classified according to Juodzbalys and Daugela 2013. RESULTS: When radiological lower third molar assessments with panoramic radiography and MRI were compared, staging concurred in 73% in the first round of assessments and 77% in the second. CONCLUSIONS: The presented study demonstrates that MRI not only provides much the same information that panoramic radiography usually does, but also has the advantages of a dose free three-dimensional view. This may facilitate and shorten third molar surgery. Image interpretation, however, can differ depending on training and experience. PMID- 29388827 TI - A Couples-Oriented Intervention for Positive Airway Pressure Therapy Adherence: A Pilot Study of Obstructive Sleep Apnea Patients and Their Partners. AB - BACKGROUND: Partner involvement can influence positive airway pressure (PAP) therapy use among patients with obstructive sleep apnea (OSA). This study assessed the feasibility, acceptability, and preliminary efficacy of a couples oriented education and support (CES) intervention for PAP adherence. PARTICIPANTS: Thirty newly diagnosed OSA patients and their partners were randomly assigned to one of three groups: an education and support intervention directed at both patient and partner (CES), an education and support intervention directed only at the patient (PES), or usual care (UC). METHODS: Feasibility and acceptability were assessed through enrollment and posttreatment program evaluations, respectively. Assessments of sleep quality, daytime sleepiness, and daytime function were obtained from both patients and partners at baseline and 3 months after PAP initiation. Objective PAP adherence was assessed at 1 week, 1 month, and 3 months. RESULTS: Recruitment and attrition data suggest adequate feasibility. All patients and partners in the CES group reported that the intervention was helpful. Patients in the CES and PES groups increased their PAP adherence over the first month of treatment, whereas PAP adherence decreased over this period in the UC group. For patients, large to medium effects for sleep quality (d = -1.01), daytime sleepiness (d = -0.51), and daytime function (d = 0.51) were found for the CES group. The PES and UC groups effect sizes were large to small for sleep quality (d = -0.94; d = -0.40), daytime sleepiness (d = -0.42; d = -0.82), and daytime function (d = 0.41; d = 0.57), respectively. For partners, large effects for daytime sleepiness (d = -1.31) and daytime function (d = 1.54) and small to medium effect for sleep quality (d = -0.31) were found for the CES group. Worsening of sleep quality (d = 0.65) and no change in daytime sleepiness or daytime function were found for the PES group. For the UC group, medium to large effects were found for sleep quality (d = -0.77), daytime sleepiness (d = -0.77), and daytime function (d = 0.65). CONCLUSIONS: The findings of this pilot study provide support for taking a couples intervention approach to improve PAP adherence. PMID- 29388829 TI - Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM CSF- and M-CSF-derived Macrophages. PMID- 29388830 TI - Dissecting Asthma Transcriptomics: Does Site Matter? PMID- 29388831 TI - Reply to: Quantitative Histology Seriously Flawed by Lack of Lung Volume Measurement. PMID- 29388832 TI - Quantitative Histology Seriously Flawed by Lack of Lung Volume Measurement. PMID- 29388833 TI - Elucidating the Pathogenesis of Nontuberculous Mycobacterial Lung Disease: Lesson from the Six Blind Men and the Elephant. PMID- 29388834 TI - The Long Noncoding RNA LnRPT Puts the Brakes on Pulmonary Artery Smooth Muscle Cell Proliferation. PMID- 29388835 TI - Polymorphonuclear Leukocytes in Pulmonary Hypertension and Fibrosis: Not Always What They Appear to Be. PMID- 29388836 TI - A Twist on Pulmonary Vascular Remodeling: Endothelial to Mesenchymal Transition? PMID- 29388838 TI - Untangling chronic pain and post-concussion symptoms: the significance of depression. AB - OBJECTIVES: Post-concussion-like symptoms (PCS) are common in patients without a history of brain injury, such as those with chronic pain (CP). This exploratory study examined neuro-cognitive and psychological functioning in patients with PCS following mild traumatic brain injury (mTBI) or CP, to assess unique and overlapping phenomenology. METHODS: In this case-control study, participants (n = 102) with chronic symptoms after mTBI (n = 45) were matched with mTBI recovered (n = 31) and CP groups (n = 26), on age, gender, ethnicity and education. Psychological status, cognitive functioning, health symptoms, beliefs and behaviours were examined. RESULTS: Participants who had not recovered from an mTBI and participants with CP did not differ in terms of PCS symptoms, quality of life, distress or illness behaviours, however, the CP group endorsed fewer subjective cognitive problems, more negative expectations about recovery and more distress (p < 0.05). On cognitive testing participants who had not recovered from an mTBI demonstrated greater difficulties with attention (p < 0.01) although differences disappeared when depression was controlled in the analyses. CONCLUSIONS: Unique patterns associated with each condition were evident though caution is required in attributing PCS and cognitive symptoms to a brain injury in people with mTBI presenting with chronic pain and/or depression. Psychological constructs such as illness and recovery beliefs appear to be important to consider in the development of treatment interventions. PMID- 29388839 TI - Development of a Short Form of the Abridged Big Five-Dimensional Circumplex Model to Aid with the Organization of Personality Traits. AB - Although there has been widespread consensus on the use of the Five-Factor Model (FFM) of general personality functioning in personality research, there are various, diverse models of the lower order traits of the FFM domains. Given the usefulness of these finer grained traits, it is imperative to integrate facets proposed across a variety of models and eventually reach consensus on the lower level traits of the FFM. Due to its depth and coverage, the Abridged Big Five Dimensional Circumplex (AB5C) model potentially provides a useful framework for organizing various faceted models due to its conceptual organization and inclusiveness. The only measure of this model-the IPIP-AB5C-has shown promise, but is limited by its length (i.e., 485 items). This study developed an abbreviated version of the IPIP-AB5C using an iterative process including item response theory methods. The shorter version maintained key features of the long form including a factor structure that matched the full form as well as facets that correlated in expected ways with other FFM measures. Building on this support, the short form was used to contextualize and organize the facets from 2 commonly used measures. PMID- 29388837 TI - Adenovirus Lacking E1b Efficiently Induces Cytopathic Effect in HPV-16-Positive Murine Cancer Cells via Virus Replication and Apoptosis. AB - Conditionally replicative adenoviruses (CRAds) replicate poorly in murine cancer cells; however, E1b-deleted CRAds may replicate effectively in HPV16-E6/E7 positive murine cancer cells (TC-1). The HPV16 E7 open reading frame encodes functions analogous to these deleted adenovirus E1 proteins. In this study, an E1b-deleted CRAd (Adhz60) was evaluated for its ability to replicate and induce oncolysis in TC-1 cells. Adhz60-mediated oncolysis was similar in TC-1 and HeLa cells. Productive viral replication was evident based on expression of E1A and hexon, production of infectious virus progeny, and Adhz60-induced apoptosis. The results suggest that TC-1 murine cancer cells allow Adhz60 replication and oncolysis. PMID- 29388840 TI - Patient perspectives on quality and access to healthcare after brain injury. AB - PRIMARY OBJECTIVE: To gather information about brain injury (BI) survivors' long term healthcare needs, quality, barriers and facilitators. RESEARCH DESIGN: Qualitative content analysis of data gathered in focus groups using semi structured interviews. METHODS: Forty-four community-dwelling adults participated at two clinical research centres in Seattle, Washington and New York, New York. Participants were asked open-ended questions about their experiences with healthcare in the community with regard to care needs, utilization, access, barriers and facilitators to health management. RESULTS: Central themes emerged across three categories: 1) barriers to healthcare access/utilization, 2) facilitators to healthcare access/utilization, and 3) suggestions for improving healthcare after BI. The importance of communication as both a facilitator and barrier to care was mentioned by most participants. Compensatory strategies and external tools were identified as key facilitators of medical self-management. Finally, improving clinicians' knowledge about BI emerged as a potential solution to address health needs of individuals with chronic BI. CONCLUSIONS: Additional efforts need to be made to improve access to appropriate healthcare and increase the ability for individuals to successfully navigate the healthcare system. Findings suggest several specific, low-cost modifications to healthcare delivery and strategies for improving medical self-management that can maximize long-term health maintenance for BI survivors. PMID- 29388841 TI - The distinct optic disk and peripapillary appearance in Donnai-Barrow syndrome. AB - INTRODUCTION: Biallelic mutations in low-density lipoprotein-related protein 2 (LRP2) cause the multi-system Donnai-Barrow syndrome (facio-oculo-acoustico-renal syndrome). Although Donnai-Barrow syndrome is recognized as a form of vitreo retinopathy, the ocular phenotype has not been well defined. The purpose of this study is to document the disk and peripapillary appearance in Donnai-Barrow syndrome. METHODS: Retrospective cases series (five children with low vision from a consanguineous Emirati family known to harbor LRP2 mutation (NM_004525.2: c.7564T>C; p.Y42522H)). RESULTS: All five children had high myopia (spherical equivalent from -15 to -22). One had an ophthalmic phenotypic pathognomonic for Knobloch syndrome, and genetic testing confirmed a homozygous novel COL18A1 mutation (NM_130455.3: c.2978_2987del; p.Pro993Leufs*35) with heterozygosity for the LRP2 mutation. The other four children, confirmed to be homozygous for the LRP2 mutation, had hypertelorism and down-slanting palpebral fissures. Three had spontaneous retinal detachment (two bilateral and one unilateral) with complicated post-surgical courses following retinal detachment repair. The three eyes (two children) without retinal detachment had a consistent unique optic nerve head appearance, with thin emanating vessels and multiple rings of depigmentation that made it difficult to discern the edge of the apparently small and recessed neuroretinal rim. This distinct appearance was also present in the post-surgical eyes which were not phthisical and seemed present in the single published posterior pole image found during literature review. CONCLUSIONS: A distinctive optic nerve head dysgenesis is part of Donnai-Barrow syndrome and can help distinguish its ocular phenotype from other vitreo-retinopathies associated with high myopia. PMID- 29388842 TI - Prediction of lower extremity motor recovery in persons with severe lower extremity paresis after stroke. AB - OBJECTIVE: To investigate the extent of motor recovery and predict the prognosis of lower extremity (LE) recovery in patients with severe LE paresis after stroke Methods: 137 patients with severe LE paresis after stroke were recruited from a local medical centre. Voluntary LE movement was assessed with the LE subscale of the Stroke Rehabilitation Assessment of Movement (STREAM-LE). Univariate and stepwise regression analyses were used to investigate 25 clinical variables (including demographic, neuroimaging, and behavioural variables) for finding the predictors of LE recovery. RESULTS: The STREAM-LE at discharge (DCSTREAM-LE) of the participants covered a very wide range (0-19). Specifically, 5.1% of the participants were nearly completely recovered, 11.7% were moderately recovered, 36.5% were slightly recovered, and 46.7% remained severely paralysed. 'Score of STREAM-LE at admission (ADSTREAM-LE)' and 'volume of lesion and oedema') were significant predictors of LE movement at discharge, explaining 25.1% of the variance of the DCSTREAM-LE (p < 0.001). CONCLUSIONS: LE motor recovery varied widely in our participants, indicating that patients' recovery might not follow simple rules. The low predictive power (about a quarter) indicates that LE motor recovery in patients with severe LE paresis after stroke was hardly predictive. PMID- 29388843 TI - Comparison of efficacy between long-pulsed Nd:YAG laser and pulsed dye laser to treat rosacea-associated nasal telangiectasia. AB - BACKGROUND: Rosacea is characterized by erythema on face, especially erythema and linear telangiectasia on the nose. Currently, various vascular lasers are used for treatment, and among them, are long-pulsed Nd:YAG(LPNY) and pulsed dye laser (PDL). OBJECTIVES: This study compared the efficacy of LPNY and PDL in treating rosacea-associated nasal telangiectasia. METHODS: Patients with rosacea who showed erythema and telangiectasia on the nose were included. Each patient was treated with PDL on the left side of the nasal bridge, and LPNY on the right side, three times with 4-week intervals. At the end of the treatment, two independent dermatologists evaluated overall treatment response compared with baseline. RESULTS: The physician's assessment of treatment concluded that good improvement was seen in six PDL and seven LPNY patients, and excellent improvement five PDL and four LPNY patients. There was no significant difference (p = 0.62, 95%CI) between the groups. Overall improvement was similar; however, LPNY induced a greater response in thick, dilated vessels, while erythema with mild telangiectasia was more responsive to PDL. CONCLUSION: Both LPNY and PDL are effective in treating rosacea-associated nasal telangiectasia. If LPNY is used properly to avoid side effects with careful consideration, it can also be used as a good modality. PMID- 29388844 TI - The effects of concussion on rapid picture naming in children. AB - PRIMARY OBJECTIVE: The purpose of this investigation was to examine children's accuracy and speed when asked to name rapidly images following a concussion. The authors predicted that children with a recent concussion would not differ in accuracy from peers, but would be slower. RESEARCH DESIGN: Children with and without a recent concussion were compared on their accuracy and speed of naming objects, and speed was correlated with time since injury. METHODS AND PROCEDURES: Fifty-eight participants, aged 10-22 years, 32 within one month of concussion and 26 age-matched participants with no history of concussion, rapidly viewed and verbally named 107 illustrations of common objects, and sensitive measures of response time were recorded. MAIN OUTCOMES AND RESULTS: Groups did not differ in rate of accuracy, but children with recent injury responded significantly more slowly. A trajectory of recovery was calculated, providing qualified evidence for a longer timeline of recovery than the typical two-week period. CONCLUSIONS: These findings affirm the presence of this naming latency effect in children, explore the duration of this effect over the course of recovery, and add nuance to inconsistently reported chronic naming deficits following concussion, informing recommendations for return to full academic and recreational participation. PMID- 29388845 TI - The Effect of Optive and Optive Advanced Artificial Tears on the Healthy Tear Film. AB - PURPOSE: To evaluate the impact of Optive (Allergan, Irvine, CA) and Optive Advanced (Allergan, Irvine, CA) on tear film stability and quality during a one hour observation period when compared to saline (Pfizer, Perth, WA). METHODS: This was a double-masked, cross-over study. Twenty participants attended three visits, randomly receiving either Optive, Optive Advanced or saline. Oculus Keratograph 5M (Oculus, Arlington, WA, USA), non-invasive keratograph break-up time (NIKBUT), Lipiview (TearScience Inc, Morrisville, NC, USA), lipid layer thickness (LLT) and comfort were measured prior to and 5, 15 and 60 min after drop instillation. RESULTS: Optive Advanced demonstrated a significant increase in LLT between baseline (57.5 +/- 12.3 nm) and both 5 min (67.5 +/- 18.8 nm, p = 0.04) and 15 min (68.9 +/- 17.3 nm, p = 0.04) but not 60 min (61.6 +/- 14.3 nm, p = 0.47). Optive and saline were not different between timepoints for LLT (p > 0.05). There was no difference between timepoints for any of the drops for NIKBUT (p = 0.75). Comfort was significantly better at 5 min compared to baseline for Optive (8.3 +/- 1.2 and 7.3 +/- 1.4, respectively, p = 0.03) but not different for Optive Advance or saline (p > 0.05). CONCLUSIONS: Optive Advanced increased LLT for 15 min following instillation, returning to baseline within one hour. This did not however, translate into an improvement in tear film stability over this time period. Only Optive demonstrated an improvement in comfort. PMID- 29388846 TI - Protective effects of fermented honeybush (Cyclopia intermedia) extract (HU-018) against skin aging: a randomized, double-blinded, placebo-controlled study. AB - BACKGROUND: Oxidative stress and photodamage resulting from ultraviolet radiation exposure play key roles in skin aging. Fermented Cyclopia intermedia, which is used to brew honeybush tea, exerts antioxidant and anti-wrinkle effects by inhibiting reactive oxygen species production and downregulating matrix metalloproteinase activity. OBJECTIVES: This randomized, double-blinded, placebo controlled study aimed to evaluate the efficacy and safety of fermented honeybush (Cyclopia intermedia) extract (HU-018) for skin rejuvenation. METHODS: 120 Korean subjects with crow's feet wrinkles were randomized to receive either low-dose extract (400 mg/day), high-dose extract (800 mg/day), or placebo (negative control, only dextran) for 12 weeks. Wrinkles were evaluated using JANUS(r) and PRIMO pico(r). Skin elasticity, hydration and transepidermal water loss were measured. RESULTS: Global skin wrinkle grade was significantly improved in both low-dose and high-dose groups compared to placebo group, as well as for skin hydration and elasticity. Both the low- and high-dose groups showed significantly decreased TEWL compared to the placebo group. There were no adverse effects during the entire study period. CONCLUSION: Our data indicate that HU-018 is effective for improving skin wrinkles, elasticity, and hydration. Therefore, daily supplementation with fermented honeybush could be helpful for protecting against skin aging. PMID- 29388847 TI - The role of TNF alpha polymorphism and expression in susceptibility to nasal polyposis. AB - OBJECTIVE: In this study, we first performed a meta-analysis to assess the role of single-nucleotide polymorphism (SNP) within tumor necrosis factor alpha (TNF alpha) gene and TNF alpha expression in the risk of nasal polyposis. METHODS: STATA 12.0 software was utilized to conduct the Mantel-Haenszel statistics, Cohen statistics, Begg's test, Egger's tests and sensitivity analysis. RESULTS: We systemically carried out the database retrieval and initially identified 486 articles. After screening, 15 articles were included in our meta-analysis. For TNF alpha rs1800629 G/A SNP, compared with control group, an increased risk of nasal polyposis of case group was observed in the models of A vs. G [p (P value of association) = 0.009, OR (odds ratio) = 1.35], GA vs. GG (p = 0.001, OR = 1.69), GA+AA vs. GG (p = 0.010, OR = 1.47). The similar results were observed in Caucasian subgroup (p < 0.05, OR > 1). For TNF alpha rs361525 G/A SNP, no significant difference between control and case group was detected (all p > 0.05). In addition, a significant difference exists between case and control groups in the meta-analyses of TNF alpha expression in nasal mucosal cells, secreted TNF alpha (p < 0.05, OR > 1), but not serum TNF alpha (p = 0.090). CONCLUSION: The present meta-analysis revealed that TNF alpha rs1800629, increased TNF alpha expression and secretion of nasal mucosal cells were associated with an increased risk of nasal polyposis. PMID- 29388848 TI - Primary orbital melanoma: a case series and literature review. AB - Primary orbital melanoma (POM) is a very rare condition. We report further four cases and review all previously reported cases. We present a multicentre retrospective review of patients with POM. Clinical, radiological, surgical, histological, and follow-up data is presented. Four patients with POM were identified between 2000 and 2013. All presented with proptosis and diplopia without reduced vision. Two had known pre-existing blue cell naevi. All were stage T1N0M0. All underwent exenteration with adjuvant radiotherapy. All are disease free at follow-up durations of 24-151 months. The present three cases and review of all cases in the literature suggest a higher likelihood of disease-free survival from primary exenteration (7/8 disease-free survival, 1/8 death from metastatic disease) than wide local excision (7/16 disease-free survival, 9 recurrence or metastasis of whom 4 died). Adjuvant radiotherapy may additionally improve outcomes. PMID- 29388849 TI - The influence of post-acute rehabilitation length of stay on traumatic brain injury outcome: a retrospective exploratory study. AB - OBJECTIVE: Data regarding length of stay (LOS) in a rehabilitation programme after traumatic brain injury (TBI) are limited. The goal of this study was to examine the effect of LOS and disability on outcome following TBI. METHODS: Records from patients in a multidisciplinary rehabilitation programme at least 3 months after TBI were analysed retrospectively to study the influence of LOS on functional outcome at different levels of disability. Functional status was determined by the Mayo-Portland Adaptability Inventory (MPAI) and the Community Integration Questionnaire (CIQ). Patients were further grouped by time since injury of 3-12 months or over 1 year. RESULTS: Those with a mild and moderate disabilities and over 1 year chronicity showed improvements after 90 days of rehabilitation. Patients with a severe disability and over 1 year chronicity required at least 180 days to show improvements. Moderately and severely disabled patients with an injury chronicity of 3-12 months showed improvements in the MPAI after 90 days. However, further improvement was observed after 180 days in the severely disabled group. CONCLUSIONS: Results suggest that both, level of disability and injury chronicity, should be considered when determining LOS. Data also show an association between LOS and changes in the MPAI and CIQ. PMID- 29388850 TI - Neurophysiological and cognitive impairment following repeated sports concussion injuries in retired professional rugby league players. AB - BACKGROUND: Concussion is regarded as a common injury in rugby league, however no studies have explored the long-term neurophysiological and cognitive effects of repeated concussion injuries in this sport. METHODS: Former professional rugby athletes (n = 25) were compared to 25 age-matched participants with no history of a concussion. All participants completed standardised motor dexterity, reaction time, and cognitive tasks for working memory, associative learning and rule acquisition and reversal. Single-pulse transcranial magnetic stimulation (TMS) acquired motor evoked potentials and cortical silent period (cSP), as well as paired-pulse TMS for short latency intracortical inhibition and long intracortical inhibition (LICI). RESULTS: Compared to controls, dexterity and visuomotor reaction time was slower in the rugby group compared to controls (p = 0.02, p < 0.01, respectively). The rugby group also demonstrated poorer cognitive performance than controls (p range 0.02 to < 0.01). TMS revealed significantly reduced cSP at suprathreshold stimulation intensities (p range 0.02 to <0.01), and increased LICI (p = 0.03) in the rugby group. DISCUSSION: These findings of motor and cognitive changes, along with neurophysiological alterations, particularly with intracortical inhibition, nearly two decades post-concussion provides evidence for long-term sequelae for athletes with a history of repeated head trauma in contact sports. PMID- 29388851 TI - From 'miserable minority' to the 'fortunate few': the other end of the mild traumatic brain injury spectrum. AB - OBJECTIVES: This study, as part of the UPFRONT-study, aimed to study the patients that report zero complaints early after injury, a group that we named the 'fortunate few'. We focused on their demographic, clinical and premorbid characteristics, and examined whether they would remain asymptomatic. Moreover, we investigated the influence of anxiety and depression (HADS), and determined outcome (GOS-E) and quality of life (WHOQOL-BREF) 1 year after injury. METHODS: Patients with MTBI (Glasgow Coma Scale score 13-15), without complaints 2 weeks after injury were included. Follow-up took place at 3, 6 and 12 months after injury. RESULTS: Of the entire UPFRONT-cohort (n = 1151), 10% (n = 119) reported zero complaints 2 weeks after injury. More than half of these patients (57%) developed complaints at a later stage (M = 2, p < .001). Patients with secondary complaints had higher anxiety (p = .004) and depression (p = .002) scores, leading to less favourable outcome (p = .014) and a lower quality of life (p = .006) 1 year after injury compared to patients that remained asymptomatic. CONCLUSION: One in 10 patients with mTBI report zero complaints early after injury. Although they seem fully recovered early after injury, a substantial part may develop secondary complaints leading to less favourable outcome and lower quality of life, warranting further research of this interesting group. PMID- 29388852 TI - Associations between vitamin D receptor polymorphisms and susceptibility to Behcet's disease: A meta-analysis. AB - BACKGROUND: The vitamin D receptor (VDR) gene polymorphisms have been reported to be related to the development of Behcet's disease (BD). However, the results have been inconsistent among diverse populations. Therefore, this comprehensive meta analysis has been designed to assess a more accurate association between VDR polymorphisms and BD susceptibility. METHODS: An electronic literature search was conducted to identify eligible studies. Pooled odds ratios (OR) with corresponding 95% confidence interval (CI) were calculated in different genetic models to assess this association. RESULTS: A total of six separate comparisons comprised of 468 cases and 516 controls were included in the meta-analysis model. The meta-result demonstrated that A allele of ApaI (A vs. a: 1.54 95% CI = 1.04 2.26, P = 0.029), and F allele of FokI (F vs. f: OR = 0.58, 95% CI = 0.45-0.76, P = 0.007) polymorphisms were associated with the risk of BD in total and African populations, respectively. This significant association was also found in recessive and homozygotes models. Subgroup analysis indicated that FokI variant among Africans and ApaI variant among Caucasian were significantly associated with the risk of BD. No relationship was found between Bsmi and TaqI polymorphisms and BD risk. CONCLUSION: This meta-analysis demonstrated the association between FokI and ApaI polymorphisms in VDR gene with the risk of BD, providing insights into the potential role of vitamin D receptor in the pathogenesis of BD. PMID- 29388853 TI - Identification of IL2RG and CYBB mutations in two Chinese primary immunodeficiency patients by whole-exome sequencing. AB - BACKGROUND: Primary immunodeficiency diseases are a group of genetic disorders that lead to increased propensity to a variety of infections, sometimes with fatal outcomes. METHOD: In this study, whole-exome sequencing (WES) was used to identify mutations in two patients suspected of having primary immunodeficiency. Sanger sequencing was used to confirm the results in the patients and their family. RESULT: One patient was diagnosed as X-linked severe combined immunodeficiency (X-SCID) and another patient as X-linked chronic granulomatous disease (X-CGD) by WES. Sequencing analysis of IL2RG gene revealed a novel mutation (c.794T>A, p.I265N) and CYBB gene revealed a missense mutation (c.935T>A, p.M312K). DISCUSSION AND CONCLUSION: This study identifies one novel mutation in the IL2RG gene and another, previously described mutation in the CYBB genes. It is the first report establishing a diagnosis of X-SCID and X-CGD using WES in Chinese patients. PMID- 29388854 TI - Effects of music production on cortical plasticity within cognitive rehabilitation of patients with mild traumatic brain injury. AB - OBJECTIVE: We explored the effects of playing the piano on patients with cognitive impairment after mild traumatic brain injury (mTBI) and, addressed the question if this approach would stimulate neural networks in re-routing neural connections and link up cortical circuits that had been functional inhibited due to disruption of brain tissue. Functional neuroimaging scans (fMRI) and neuropsychological tests were performed pre-post intervention. METHOD: Three groups participated, one mTBI group (n = 7), two groups of healthy participants, one with music training (n = 11), one baseline group without music (n = 12). The music groups participated in 8 weeks music-supported intervention. RESULTS: The patient group revealed training-related neuroplasticity in the orbitofrontal cortex. fMRI results fit well with outcome from neuropsychological tests with significant enhancement of cognitive performance in the music groups. Ninety per cent of mTBI group returned to work post intervention. CONCLUSION: Here, for the first time, we demonstrated behavioural improvements and functional brain changes after 8 weeks of playing piano on patients with mTBI having attention, memory and social interaction problems. We present evidence for a causal relationship between musical training and reorganisation of neural networks promoting enhanced cognitive performance. These results add a novel music-supported intervention within rehabilitation of patients with cognitive deficits following mTBI. PMID- 29388855 TI - Comparative Analysis of State Trauma Triage Criteria vs. Paramedic Discretion. AB - OBJECTIVE: The Florida Adult Trauma Triage Criteria (FATTC) define specific parameters concerning injury mechanism and physiologic data that prompt paramedics to initiate a trauma alert and necessitate transport to a trauma center. In the state of Florida, paramedics are also given discretion to bring patients to the trauma center who do not meet those criteria. Our aim was to compare the injury characteristics and outcomes of adult patients who were evaluated in our trauma center after activation due to FATTC criteria vs. paramedic discretion (PD) and to identify predictors of PD. METHODS: This retrospective study included all patients 18 years and older evaluated in our trauma center from January 1, 2007, to December 31, 2014. Descriptive statistics were computed for all variables. Bivariate and multivariate analyses were performed to compare demographic, injury severity, and outcome differences between groups. RESULTS: A total of 13,963 patients met FATTC during the study period, and 1,811 were brought in by PD. PD patients had lower injury severity and crude mortality. Regression modeling of demographic and injury variables found that only the combination of older age and higher heart rate predicted PD when both were lower than FATTC alone. CONCLUSIONS: While PD patients were less seriously injured and had lower mortality, they experienced similar lengths of stay and resource utilization after presentation. Paramedics may be able to identify patients at risk for poor outcomes who would otherwise not be captured by FATTC. PMID- 29388856 TI - Comparison of Lidocaine and Atropine on Fentanyl-Induced Cough: A Randomized Controlled Study. AB - OBJECTIVE OF THE STUDY: Fentanyl and atropine are drugs used for analgesia during induction and for premedication, respectively. The aim of this study was to observe the effect of atropine used for premedication on cough developing in association with fentanyl use during anesthesia induction. METHODS: This was a single-blind, prospective, multi-arm, parallel, randomized clinical trial involving 120 patients between ages 3 and 15 years undergoing general anesthesia. Patients were randomized into three groups: a control group (Group C), an atropine group (Group A), and a lidocaine group (Group L). RESULTS: Incidence of cough was 45% (n = 16) in Group C, 16% (n = 6) in Group A, and 16% in Group L (n = 6) (p = 0.009). Cough was moderate in two cases in Group A and in two in Group L, and mild in all others in these groups. In Group C, cough was mild in seven cases, moderate in six, and severe in two. CONCLUSION: We determined that premedication with atropine suppressed the incidence and severity of fentanyl induced cough during induction of general anesthesia. We think that, due to its antimuscarinic effect, atropine is as effective as lidocaine as a premedication. PMID- 29388857 TI - Development of a simple driving simulator and determination of the reference range of normative performance. AB - OBJECTIVE: To establish the reference range for assessment items of the 'Simple Driving Simulator' (SiDS) in a normative population and to compare performance of age-matched young adults with a traumatic brain injury (TBI) to this reference data. METHODS AND PROCEDURES: Normative ranges were calculated from the data of 445 participants in the control group. Three performance ranges were established: 'normal', 'borderline' and 'impaired' defined using standard deviation cutoff values in the control group. The performance of 28 patients with a TBI, aged 18 35 years, was evaluated. The performance score for the TBI group in the 'impaired range' was calculated for each test item and used to make a synthetic judgment regarding the clinical value of the SiDS. MAIN OUTCOMES AND RESULTS: In the control group, only 0.6% of the participants exhibited a performance in the impaired range on >2 items, compared to 33.2% for the TBI group. CONCLUSIONS: We provide evidence that impaired performance on <=2 items of the SiDS provides a sensitive criterion of 'driving fitness' in young adults after a TBI. PMID- 29388858 TI - A Purification Technique for Adipose-Derived Stromal Cell Cultures Leads to a More Regenerative Cell Population. AB - It has been demonstrated that adipose-derived stromal cells (ASCs) are a regenerative cell population with potential uses for bone and cartilage regeneration. However, the biomarker expression and heterogeneity of the population has not been thoroughly characterized. By analyzing biomarker expression, we aimed to understand the composition of ASC populations extracted using a common extraction technique in comparison to ASC populations given an additional purification step. Human adipose tissue samples were collected, and ASCs were extracted from these samples using a common, published extraction technique (primary extraction). These cells were cultured and half were given an additional purification. The primarily-extracted and purified cell populations were analyzed for biomarkers that correspond to specific cell types. The addition of the purification technique reduced the number of cells expressing hematopoietic and endothelial biomarkers and did not cause the yield of mesenchymal stem cell biomarker-expressing cells to decrease. Biomarkers corresponding to erythrocytes and lymphocytes were lost during the primary extraction, and biomarkers corresponding to most granulocytes and progenitor cells were lost during the additional purification. Biomarkers identifying dendritic cells, monocytes/macrophages, neutrophils, vascular endothelial cells, smooth muscle cells, and pericytes were upregulated in purified cell populations while those identifying fibroblasts and adipocytes were downregulated. Pluripotency biomarkers were more highly expressed in purified cell populations. These results demonstrate that the most commonly utilized adipose tissue recovery and ASC extraction technique leads to a heterogeneous cell population in which further purification of this population, as described in this manuscript, isolates a cell subset that has more regenerative potential. PMID- 29388860 TI - To test or not to test: A study examining the return rates of rosacea patients treated with a pulsed dye laser. AB - : Pulsed dye laser (PDL) is an effective treatment option for erythematotelangiectatic rosacea. The use of a test spot allows patients to experience the procedure on a small area prior to further treatment. The purpose of this study was to elucidate whether the use of a no charge test spot influenced return rates for further PDL treatment. Data were obtained retrospectively using International Classification of Diseases (ICD)-10 codes for rosacea. Sixty charts were identified: 26 patients initially received a PDL test area free of charge, whereas 34 patients initially underwent full PDL treatment. Patients who experienced the test spot laser treatment had a lower return rate compared to those that directly underwent full PDL treatment. However, this difference was not statistically significant (Fisher's exact test p = 0.2883). Future studies evaluating and identifying factors that influence PDL return rates are needed. ABBREVIATIONS: ETR: Erythematotelangiectatic rosacea; PDL: pulsed dye laser; ICD: International classification of diseases. PMID- 29388859 TI - Inhibitory effects of candesartan on KCa3.1 potassium channel expression and cell culture and proliferation in peripheral blood CD4+T lymphocytes in Kazakh patients with hypertension from the Xinjiang region. AB - BACKGROUND AND AIM: Increasing evidence confirms that potassium channels are essential for lymphocyte activation, suggesting an involvement in the development of hypertension. Moreover, chronic inflammation is regarded as a direct or indirect manifestation of hypertension, highlighting the theoretical mechanisms. In this study, we investigated changes in KCa3.1 potassium channel expression in the blood of hypertensive and healthy Kazakh people in north-west China. METHODS: Flow cytometry technology was used for T-lymphocyte subtype analysis. Changes in the messenger RNA and protein expression of the KCa3.1 potassium channel in CD4+ T lymphocytes were detected using real-time quantitative polymerase chain reaction and western blots, using CD4+ T-cell samples from hypertensive Kazakh patients divided into candesartan and TRAM-34 treatment groups, and healthy case controls. Peripheral blood CD4+ T lymphocytes were activated and proliferated in vitro and then incubated for 0, 24, and 48 h under various treatment conditions. Changes in CD4+ T-lymphocytic proliferation were determined using Cell Counting Kit-8 and electron microscope photography. RESULTS: Expression of KCa3.1 was significantly higher in the hypertensive patients than in the controls (p < 0.05). Compared with the healthy group, Kazakh hypertensive patients had a reduced proportion of CD4+ T lymphocytes (p < 0.05).Candesartan and TRAM-34 intervention for 24 h and 48 h inhibited the expression of Kv1.3 and KCa3.1 at mRNA and protein level (p < 0.05). CONCLUSIONS: Increase in functional KCa3.1 channels expressed in CD4+ T lymphocytes of Kazakh patients with hypertension was blocked by candesartan, providing theoretical support for hypertension treatment at the cellular ion channel level. Candesartan may potentially regulate hypertensive inflammatory responses by inhibiting T-lymphocytic proliferation and KCa3.1 potassium channel expression in CD4 + T lymphocytes. PMID- 29388861 TI - Poor performance status, urban residence and female sex predict inferior survival in pediatric advanced stage mature B-NHL in an Indian tertiary care center. AB - BACKGROUND: Advanced stage is a known prognostic factor in B-Non-Hodgkin Lymphoma (NHL); however, factors within advanced stage and overall data on pediatric B-NHL from India are lacking. METHODS: This is a retrospective study wherein all consecutive pediatric (<=18 years) patients of advanced stage B-NHL (St. Jude stage 3 and 4) treated at our center from Jan 2003 to June 2016 with BFM-90 protocol were evaluated for outcome and pathology review. RESULTS: Total 140 patients were analyzed with median age 8 years; M:F ratio was 5.2:1; 36% patients presented within 30 days of symptom onset and 58% had rural residence. Burkitt lymphoma (66%) was commonest histopathological subtype; bone marrow was involved in 15% and CSF in 8% cases. Undernourishment was observed in 30% patients and 51% had ECOG performance status of 3&4. At 5 years, EFS was 52 +/- 4% (CI 0.43-0.60) and OS was 61 +/- 4% (CI 0.52-0.68). On multivariate analysis, poor performance status (p < 0.001) and urban residence (p = 0.016) emerged as significant negative prognostic factors for EFS; while for OS, female sex (p = 0.006), poor performance status (p < 0.001) and urban residence (p = 0.023) predicted inferior outcome. CONCLUSION: This is the largest study from south Asia on advanced stage pediatric B-NHL and it suggests undernourishment, poor performance status and gender bias to be unique features at presentation. Although, outcomes are comparable with other data from resource-challenged nations, yet they are 15-20% inferior than trial data from other developed countries. Further, poor performance status, female sex and urban residence for poor outcome were identified as unique prognostic factors. PMID- 29388862 TI - HLA-G Gene Polymorphism in Egyptian Patients with Non-Hodgkin Lymphoma and its Clinical Outcome. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) is a major cancer in Egypt and worldwide and has many risk factors including genes involved in the immune response. AIM: we investigated the HLA-G 14bp gene polymorphism as a risk factor for NHL and its clinic pathologic features. The study involved 150 patients with NHL and 100 healthy control. Full histories, clinical examination, C.T scan and laboratory investigations such as CBC, LDH, ?2microglobulin and HCV RNA by qualitative real time PCR were performed for all subjects. HLA-G 14bp ins/del gene polymorphism was determined by PCR. RESULTS: in our study, del/del, ins/del and dominant genotypes increased the risk of NHL by 11.01, 10.55 and 10.88 fold respectively (p<0.001) but the recessive genotype did not increase the risk of NHL (p=0.112). Cases with the del allele had a greater risk of NHL than those with the ins allele (p<0.001). del/del and ins/del genotypes were significantly associated with higher LDH and ?2microglobulin levels (p<0.001), lower Hb and platelet values (p<0.001), extra nodal sites (p=0.001), poor performance status (p=0.04) and relapse (p=0.001). Conclusions: the results suggest that HLA-G 14bp ins/del gene polymorphism is a risk factor for NHL in our Egyptian population and is associated with poor clinical pathological features. ABBREVIATIONS: Non-Hodgkin lymphoma (NHL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Epstein-Barr virus (EBV), human T-cell lymphotropic/leukemia virus-1 (HTLV-1). PMID- 29388863 TI - Saved by the Pupillometer! - A role for pupillometry in the acute assessment of patients with traumatic brain injuries? AB - There is good evidence that pupil reactivity is useful for prognostication in acute head injuries. Despite this, most pupil assessments are subjective and are performed by physicians who may not be experts. They can therefore be unreliable. We present a case of a patient with seemingly irreversible demise from an acute traumatic subdural haematoma. This was determined by assessment of his pupils, which were non-reactive to light at the time of arrival to the neurosurgical theatre. He was transferred to the neurointensive care for brainstem death testing, where assessment by objective pupillometry determined that his pupils were in fact reactive. He made a good recovery following subsequent surgery to evacuate his subdural haematoma. We propose the widespread adoption of objective pupillometers in the assessment of acute head-injured patients and offer our case as an example of how an objective and accurate assessment can make a difference to patients' outcome. PMID- 29388864 TI - The Effect of Low-Dose Aspirin on Dry Eye Parameters and Ocular Surface Disease Index Questionnaire. AB - PURPOSE: To evaluate the effects of acetylsalicylic acid (aspirin) on tear film parameters and dry eye disease. METHODS: Fifty-seven patients using low-dose aspirin regularly for antiaggregant purposes as well as 49 controls, who required antiaggregant treatment but who had not yet started, were included in the study. Tear osmolarity, tear break-up time (TBUT), Schirmer and Oxford grading of ocular surface staining were performed on all patients and dry eye symptomatology was assessed using the ocular surface disease index questionnaire (OSDI). RESULTS: The mean osmolarity was 302.11 +/- 16.22 mOsm/L in the aspirin group and 313.88 +/- 19.57 mOsm/L in the control group (P < 0.01). The mean Schirmer's score was 24.16 +/- 10.52 mm and 21.94 +/- 10.11 mm (P = 0.232), TBUT was 13.61 +/- 3.31 s and 10.39 +/- 4.46 s (P < 0.01), OSDI score was 5.15 +/- 5.98 and 16.94 +/- 14.17 (P < 0.01), and Oxford score was 0.12 +/- 0.33 and 0.12 +/- 0.44 in aspirin and control groups, respectively (P = 0.99). Dry eye diagnosis was lower in the aspirin group, but statistical significance was present only in TBUT and osmolarity-based dry eye diagnosis (P <= 0.01). In terms of symptom-based dry eye diagnosis with the threshold of OSDI >=23, none of the aspirin group had dry eye diagnosis, whereas 32.6% of the control group had the diagnosis (P < 0.01). CONCLUSIONS: The use of low-dose aspirin might be great option for treatment of ocular surface inflammatory disease through increasing TBUT and decreasing tear osmolarity with a resultant symptomatic satisfaction. PMID- 29388865 TI - Multiple Rap1 effectors control Epac1-mediated tightening of endothelial junctions. AB - Epac1 and Rap1 mediate cAMP-induced tightening of endothelial junctions. We have previously found that one of the mechanisms is the inhibition of Rho-mediated tension in radial stress fibers by recruiting the RhoGAP ArhGAP29 in a complex containing the Rap1 effectors Rasip1 and Radil. However, other mechanisms have been proposed as well, most notably the induction of tension in circumferential actin cables by Cdc42 and its GEF FGD5. Here, we have investigated how Rap1 controls FGD5/Cdc42 and how this interconnects with Radil/Rasip1/ArhGAP29. Using endothelial barrier measurements, we show that Rho inhibition is not sufficient to explain the barrier stimulating effect of Rap1. Indeed, Cdc42-mediated tension is induced at cell-cell contacts upon Rap1 activation and this is required for endothelial barrier function. Depletion of potential Rap1 effectors identifies AF6 to mediate Rap1 enhanced tension and concomitant Rho-independent barrier function. When overexpressed in HEK293T cells, AF6 is found in a complex with FGD5 and Radil. From these results we conclude that Rap1 utilizes multiple pathways to control tightening of endothelial junctions, possibly through a multiprotein effector complex, in which AF6 functions to induce tension in circumferential actin cables. PMID- 29388866 TI - Diagnostic Electron Microscopy of Retina. AB - The electron microscopy techniques were used in various fields as an analytical technique under in vitro conditions, which provides the sufficient resolution for better visualization and interpretation. This review gives a brief overview of the analytical application of transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques and critical findings in different retinal pathologies. This review article aims to improvise understanding of retinal microstructures for clinicians which will help to improve the interpretation of the current advanced imaging techniques. PMID- 29388867 TI - Is catheter-directed foam sclerotherapy more effective than the usual foam sclerotherapy for treatment of the great saphenous vein? AB - Objective This retrospective study presents the long-term results of catheter directed foam sclerotherapy of the great saphenous vein. Method From January 2003 to June 2017, 277 patients with varices and great saphenous vein incompetence were treated with echo-guided foam sclerotherapy. Forty-six patients were treated with long-catheters guided by foam sclerotherapy. Foaming was carried out with sodium-tetra-decyl-sulphate. Results Results were examined in the two groups: A (long-catheters) and B (other procedures). The median overall follow-up was 52.1 months. In the A-group, the complete occlusion rate was 34/46 pts (73.9%) and partial occlusion was 10/46 (21.7%). In the B-group, respectively, 130/231 (56.2%) and 90/231 (38.9%). Comparisons between groups were statistically significant (p = 0.023; p = 0.021). Failures involved, respectively, 2/46 (4.3%) and 11/231 (4.7%) with no statistical significance. The complication rates were similar in the two groups. Conclusions In this long-term experience (median follow-up exceeding four years), foam-guided sclerotherapy of the great saphenous vein with a long-catheter turned out to be more effective than the usual foam guided sclerotherapy. PMID- 29388868 TI - Pathophysiology of telangiectasias of the lower legs and its therapeutic implication: A systematic review. AB - Objective Telangiectasias of the lower legs are intradermal dilatations of the subpapillary venous plexus, but their pathophysiology and risk factors are still largely unknown. The purpose of this review is to summarize the current knowledge on the pathophysiology and risk factors for telangiectasias. Methods A systematic review of the literature indexed in Medline completed with textbooks and European phlebology journals from the French, Swiss, and German phlebology societies was performed. Results A multitude of risk factors and several pathophysiological hypotheses, such as reflux, arterio-venous micro-shunts, parietal, and connective tissue abnormalities, are described in the literature. The different hypotheses are discussed and put in a clinical perspective, in particular their therapeutic implications for phlebologists. Conclusion In conclusion, pathophysiology and risk factors of telangiectasias are still largely unknown, and a better understanding could improve treatment results and reduce recurrence. PMID- 29388869 TI - First novel synthesis of triazole thioglycosides as ribavirin analogues. AB - This study reports a novel and efficient method for the synthesis of the first reported novel class of triazole thioglycosides. These series of compounds were designed through the reaction of potassium cyanocarbonimidodithioate 2 with hydrazine derivatives 3a-d in EtOH at room temperature to give the corresponding potassium 5-amino-1H-1,2,4-triazole-3-thiolates 4a-d. The latter compounds were treated with tetra-O-acetyl-alpha-D-glucopyranosyl bromide 6a and tetra-O-acetyl alpha-D-galactopyranosyl bromide 6b in DMF at room temperature to give in high yields the corresponding triazole thioglycosides 7a-h. Treatment of triazole salts 4a-d with hydrochloric acid afforded the corresponding 3-mercaptotriazoles 5a-d. Compounds 5a-d were then reacted with bromoperacetylated sugars 6a,b in sodium hydride-DMF at ambient temperature to afford the thioglycosyl compounds 7a h. Ammonolysis of the triazole thioglycosides 7a-h afforded the corresponding free thioglycosides 8a-h. The scope and limitation of the method is demonstrated. The structure of the reaction products was confirmed on the basis of their elemental analysis and spectral data (IR, 1H NMR, MS and 13C NMR). PMID- 29388871 TI - Vacuolin-1 potently and reversibly inhibits autophagy by activating Rab5. PMID- 29388870 TI - Characterization of cell-cell junction changes associated with the formation of a strong endothelial barrier. AB - A principal function of endothelial cells is the formation of a barrier between the blood and tissues. This barrier arises from the physical connections at cell cell junctions, which includes cytoskeletal tight junction and adherens junction proteins. Methods that alter barrier function must therefore affect these cell cell connections. The blood brain barrier (BBB) represents perhaps the most selective endothelial barrier, which arises from endothelial cell interactions with astrocytes and pericytes. Even in non-central nervous system (CNS) endothelial cells, barrier properties can be enhanced, mimicking the BBB, through induction of intercellular junctions, by either direct co-culture with astrocytes, supplementation with astrocyte conditioned medium (ACM) and/or pharmacologic enhancement of cAMP. To understand how cell-cell junctions change during endothelial barrier enhancement, we examined the effects of ACM and/or cAMP donors added to standard media on human umbilical vein endothelial cells (HUVEC). HUVEC cultured with cAMP-elevating agents had the most enhanced barrier function as measured by Electric Cell-substrate Impedance Sensing (ECIS(r)), a real-time, label-free, impedance based method of studying cell barrier properties. However, subtle differences in actin and cell-cell junction proteins were seen across all four culture conditions. cAMP-elevating agents also triggered the redistribution of ZO-1 and VE-cadherin to cell-cell junctions, and intensified the actin microfilament network at the cell cortex. Using a VE cadherin FRET-force sensor, we observed a decrease in VE-cadherin force in HUVEC cultured with ACM with cAMP donors. Our data indicate cAMP elevation induces both junctional strengthening and reduced VE-cadherin forces. Additionally, treatment with an inhibitor of formin, which reduced actin stress fibers, enhanced barrier function. These data suggest that barrier function is modulated both through the trafficking of proteins to cell-cell junctions, and through the modulation and a relaxation of mechanical force through adherens junctions as intercellular junctional complexes become established. PMID- 29388873 TI - Collaboration and prospective memory: comparing nominal and collaborative group performance in strangers and couples. AB - To perform prospective memory (PM) tasks in day-to-day life, we often enlist the help of others. Yet the effects of collaboration on PM are largely unknown. Adopting the methodology of the "collaborative recall paradigm", we tested whether stranger dyads (Experiment 1) and intimate couples (Experiment 2) would perform better on a "Virtual Week" task when working together or each working separately. In Experiment 1, we found evidence of collaborative inhibition: collaborating strangers did not perform to their pooled individual potential, although the effect was modulated by PM task difficulty. We also found that the overall collaborative inhibition effect was attributable to both the retrospective and prospective components of PM. In Experiment 2 however, there was no collaborative inhibition: there was no significant difference in performance between couples working together or separately. Our findings suggest potential costs of collaboration to PM. Intimate relationships may reduce the usual costs of collaboration, with implications for intervention training programmes and for populations who most need PM support. PMID- 29388872 TI - Improving titer while maintaining quality of final formulated drug substance via optimization of CHO cell culture conditions in low-iron chemically defined media. AB - During biopharmaceutical process development, it is important to improve titer to reduce drug manufacturing costs and to deliver comparable quality attributes of therapeutic proteins, which helps to ensure patient safety and efficacy. We previously reported that relative high-iron concentrations in media increased titer, but caused unacceptable coloration of a fusion protein during early-phase process development. Ultimately, the fusion protein with acceptable color was manufactured using low-iron media, but the titer decreased significantly in the low-iron process. Here, long-term passaging in low-iron media is shown to significantly improve titer while maintaining acceptable coloration during late phase process development. However, the long-term passaging also caused a change in the protein charge variant profile by significantly increasing basic variants. Thus, we systematically studied the effect of media components, seed culture conditions, and downstream processing on productivity and quality attributes. We found that removing beta-glycerol phosphate (BGP) from basal media reduced basic variants without affecting titer. Our goals for late-phase process development, improving titer and matching quality attributes to the early-phase process, were thus achieved by prolonging seed culture age and removing BGP. This process was also successfully scaled up in 500-L bioreactors. In addition, we demonstrated that higher concentrations of reactive oxygen species were present in the high iron Chinese hamster ovary cell cultures compared to that in the low-iron cultures, suggesting a possible mechanism for the drug substance coloration caused by high-iron media. Finally, hypotheses for the mechanisms of titer improvement by both high-iron and long-term culture are discussed. PMID- 29388874 TI - A meta-analysis of the antiviral activity of the HBV-specific immunotherapeutic TG1050 confirms its value over a wide range of HBsAg levels in a persistent HBV pre-clinical model. AB - Pre-clinical models mimicking persistent hepatitis B virus (HBV) expression are seldom, do not capture all features of a human chronic infection and due to their complexity, are subject to variability. We report a meta-analysis of seven experiments performed with TG1050, an HBV-targeted immunotherapeutic, 1 in an HBV persistent mouse model based on the transduction of mice by an adeno-associated virus coding for an infectious HBV genome (AAV-HBV). To mimic the clinical diversity seen in HBV chronically infected patients, AAV-HBV transduced mice displaying variable HBsAg levels were treated with TG1050. Overall mean percentages of responder mice, displaying decrease in important clinical parameters i.e. HBV-DNA (viremia) and HBsAg levels, were 52% and 51% in TG1050 treated mice, compared with 8% and 22%, respectively, in untreated mice. No significant impact of HBsAg level at baseline on response to TG1050 treatment was found. TG1050-treated mice displayed a significant shorter Time to Response (decline in viral parameters) with an Hazard Ratio (HR) of 8.3 for viremia and 2.6 for serum HBsAg. The mean predicted decrease for TG1050-treated mice was 0.5 log for viremia and 0.8 log for HBsAg, at the end of mice follow-up, compared to no decrease for viremia and 0.3 log HBsAg decrease for untreated mice. For mice receiving TG1050, a higher decline of circulating viremia and serum HBsAg level over time was detected by interaction term meta-analysis with a significant treatment effect (p = 0.002 and p<0.001 respectively). This meta-analysis confirms the therapeutic value of TG1050, capable of exerting potent antiviral effects in an HBV-persistent model mimicking clinical situations. PMID- 29388875 TI - Secretory autophagy of lysozyme in Paneth cells. AB - Secretion of antimicrobial proteins is an important host defense mechanism against bacteria, yet how secretory cells maintain function during bacterial invasion has been unclear. We discovered that Paneth cells, specialized secretory cells in the small intestine, react to bacterial invasion by rerouting a critical secreted antibacterial protein through a macroautophagy/autophagy-based secretion system termed secretory autophagy. Mice harboring a mutation in an essential autophagy gene, a mutation which is common in Crohn disease patients, cannot reroute their antimicrobial cargo during bacterial invasion and thus have compromised innate immunity. We showed that this alternative secretion system is triggered by both a cell-intrinsic mechanism, involving the ER stress response, and a cell-extrinsic mechanism, involving subepithelial innate immune cells. Our findings uncover a new role for secretory autophagy in host defense and suggest how a mutation in an autophagy gene can predispose individuals to Crohn disease. PMID- 29388877 TI - Response to this letter to the editor. PMID- 29388876 TI - Relapse and Craving in Alcohol-Dependent Individuals: A Comparison of Self Reported Determinants. AB - BACKGROUND: Negative affective states and alcohol-related stimuli increase risk of relapse in alcohol dependence. In research and in clinical practice, craving is often used as another important indicator of relapse, but this lacks a firm empirical foundation. OBJECTIVES: The goal of the present study is to explore and compare determinants for relapse and craving, using Marlatt's (1996) taxonomy of high risk situations as a template. METHODS: We conducted semi-structured interviews with 20 alcohol-dependent patients about their most recent relapse and craving episodes. Interview transcripts were carefully reviewed for their thematic content, and codes capturing the thematic content were formulated. RESULTS: In total, we formulated 42 relapse-related codes and 33 craving-related codes. Descriptions of craving episodes revealed that these episodes vary in frequency and intensity. The presence of alcohol-related stimuli (n = 11) and experiencing a negative emotional state (n = 11) were often occurring determinants of craving episodes. Both negative emotional states (n = 17) and testing personal control (n = 11) were viewed as important determinants of relapses. Craving was seldom mentioned as a determinant for relapse. Additionally, participants reported multiple determinants preceding a relapse, whereas craving episodes were preceded by only one determinant. CONCLUSIONS: Patient reports do not support the claim that craving by itself is an important proximal determinant for relapse. In addition, multiple determinants were present before a relapse. Therefore, future research should focus on a complexity of different determinants. PMID- 29388878 TI - Autophosphorylation site Y428 is essential for the in vivo activation of CERK1. AB - Autophosphorylation of PRR is a critical event for the activation of immune signaling in plant. However, the detailed function of these phosphorylation sites is still not well understood. We analyzed the function of an autophosphorylation site of Arabidopsis CERK1, Y428, in immune signaling. Biochemical characterization of CERK1 mutants transiently expressed in N. benthamiana indicated that Y428 plays a crucial role for the in vivo activation of CERK1, differently from the previous observation by the in vitro kinase assay with its cytoplasmic domain. Similar discrepancy between in vitro and in vivo kinase assay was also reported for the corresponding phosphorylation site of EFR, suggesting that these conserved tyrosine residues play important roles for the activation of both RD and non-RD RLKs. PMID- 29388879 TI - An interpretative phenomenological analysis of the experiences of older people self-managing cancer pain at home. AB - Cancer is predominantly an illness affecting older people, yet there is a higher risk of under-treated pain in this age group. Many older people are required to self-manage their cancer pain at home but this is currently an under-researched and poorly understood area. We explored the experiences of older adults who self manage cancer pain at home using an Interpretative Phenomenological Analytic approach. Eight older adults (aged 72-85 years) were recruited from a hospital in the United Kingdom and interviewed using a semi-structured questionnaire. Themes which emerged from the analysis suggest the self-management of cancer pain involves a perceived loss of control followed by a temporal process of gaining control over pain. Subordinate themes reflected the physical and social restrictions caused by pain; leading to fears regarding familial burden. Participants utilized inner strengths, past experiences, and social support to cope. Successful self-management of cancer pain in late life is conceptualized utilizing a positive psychology framework. PMID- 29388880 TI - Assessment of the efficacy of group counselling using cognitive approach on knowledge, attitude, and decision making of pregnant women about modes of delivery. AB - The choice of casarean deliveries by mothers is highly influenced by inadequate knowldge and negative attitudes towards vaginal birth. In this semi-experimental study, we compared knowledge, attitude, and decision making about modes of delivery between nulliparous pregnant women who received eight sessions of group consultation and those who took routine prenatal education. Contrary to the control group, the improvement of knowledge and attitudes were significant in the consultation group (p < 0.001), as well as mothers' decisions for vaginal birth (p = 0.03). Group consultation is an appropriate approach to improving knowledge, attitudes, and tendencies of mothers toward natural birth. PMID- 29388881 TI - The case for considering rather than ignoring race/ethnicity in substance abuse research. PMID- 29388882 TI - Attitudes and behaviors of family physicians regarding occupational diseases. AB - OBJECTIVES: The incidence of occupational diseases (ODs) is below expectations. The approaches of family physicians are very important. In this study, we aimed to evaluate attitudes and behaviors of family physicians about ODs. METHODS: The questionnaire was first sent to family physicians via e-mail. Of 3663 responders, 3090 replies were included to study. RESULTS: 44.1% of them stated they obtained detailed occupational history. In logistic regression analysis, physicians who obtained detailed occupational history, discussed their patient's health with an occupational physician, had education about ODs and those who stated that they wanted to receive training in ODs were more likely to refer their patient. CONCLUSION: In this study, it was determined that those who received education on ODs and those who have worked as workplace physician obtained occupational history, knew occupational diseases hospitals and wanted to receive further education. PMID- 29388884 TI - The Effects of Twitter Users' Gender and Weight on Viral Behavioral Intentions Toward Obesity-Related News. AB - In this study, male and female participants were exposed to identical news stories covering obesity topics paired with tweets from Twitter users. Our study aimed at understanding how obesity-related news combined with user-generated social media posts (i.e., tweets) affect consumers' evaluations of online content and viral behavioral intentions (the intentions to like, share, and comment). An experiment (N = 316) explored how gender and weight of a Twitter user (tweeter) affect participants' evaluations and viral behavioral intentions toward news stories. Participants differed in their evaluations of and viral behavioral intentions for news stories as a function of Twitter users' gender and weight, as well as participants' gender. While participants expressed more favorable attitudes toward news stories paired with tweets by overweight than healthy females (with the opposite true for tweets by male users), participants expressed greater viral behavioral intentions for news stories paired with tweets by healthy weight than overweight user. These effects were more pronounced among male than female participants. Findings are discussed within the context of social media posts and their persuasive effects in relation to attitude and behavior changes. PMID- 29388885 TI - Results from a randomized trial evaluating a hospital-school transition support model for students hospitalized with traumatic brain injury. AB - OBJECTIVE: To evaluate the utility of the STEP model, a systematic hospital school transition protocol for children hospitalized for TBI. SETTING: Five children's hospitals in Colorado, Ohio, and Oregon. PARTICIPANTS: Hundred families of children with mild, complicated mild, moderate, or severe TBI. DESIGN: Randomized controlled trial (RCT); participants were randomized while hospitalized to the STEP (a standardized hospital-school transition protocol for children treated for TBI) or usual care condition. MAIN MEASURES: Questionnaire about child's special education eligibility status, support services, and academic accommodations; Achenbach Child Behaviour Checklist (CBCL); Behaviour Rating Inventory of Executive Function (BRIEF); Child and Adolescent Scale of Participation (CASP); Child and Adolescent Scales of Environment (CASE) Results: There were no significant effects, indicating that STEP participants did not differ from usual care participants on any study outcome at one month post discharge or at one-year follow-up. CONCLUSION: The lack of significant findings in this study does not imply that effective hospital-to-school transition programming is unnecessary. Rather, the findings raise important questions regarding timing and dosage/intensity of intervention, appropriate measurement of outcomes, and fidelity of programme delivery. The study highlights difficulties involved in the conduct of community-based RCTs in the paediatric TBI population. PMID- 29388883 TI - Two new Geosmithia species in G. pallida species complex from bark beetles in eastern USA. AB - Species of Geosmithia are cosmopolitan but understudied fungi, and most are associated with phloem-feeding bark beetles on various woody hosts. We surveyed 207 bark and ambrosia beetles from 37 species in the eastern USA for associated fungi. The community is dominated by species in the G. pallida species complex (GPSC) and included several Geosmithia isolates that appear to be new to science. The new Geosmithia isolates exhibited the characteristic brownish-colored colonies typical for the G. pallida species complex and were phylogenetically resolved as two genealogically exclusive lineages based on a concatenated multilocus data set based on the internal transcribed spacers (ITS) of the nuc rDNA (ITS1-5.8S-ITS2 = ITS), and the translation elongation factor 1-alpha (TEF1 alpha), beta-tubulin (TUB2), and RNA polymerase II second largest subunit (RPB2) genes. Two new Geosmithia species, G. brunnea and G. proliferans, are proposed, and their morphological traits and phylogenetic placements are presented. PMID- 29388886 TI - Measuring intention to refer: Older adults and social service agencies. AB - The public is encouraged to engage in socially responsible behaviors such as helping people get needed services, possibly by referring them. However, referral behavior is little researched. Informed by the theory of planned behavior, intent to refer older adults in need to the Connecticut's Gatekeeper Program (GP) which identifies elders at risk and connects them with community resources was studied and the Social Service Agency Referral Scale (SSARS) was developed. Senior center attendees, seniors who received GP training, and referrers to the state's GP were involved. SSARS and its subscales were internally consistent (Cronbach's alpha = .90, with alpha >= .733 for each subscale). SSARS was strongly correlated with a validated social responsibility scale (r = .48). Knowledge gained from the training enhanced the associated intention subscale. With little modification, SSARS could be used to elucidate similar efforts. Additionally, the process used to create SSARS could be replicated to develop related instruments. PMID- 29388887 TI - Mutations in ATP6AP2 cause autophagic liver disease in humans. AB - The biogenesis of the proton pump V-ATPase commences with the assembly of the proton pore sector V0 in the endoplasmic reticulum (ER). This process occurs under the control of a group of assembly factors whose mutations have recently been shown to cause glycosylation disorders with overlapping phenotypes in humans. Using whole exome sequencing, we demonstrate that mutations of the accessory V-ATPase subunit ATP6AP2 cause a similar disease characterized by hepatosteatosis, lipid abnormalities, immunodeficiency and cognitive impairment. ATP6AP2 interacts with members of the V0 assembly complex, and its ER localization is crucial for V-ATPase activity. Moreover, ATP6AP2 mutations can cause developmental defects and steatotic phenotypes when introduced into Drosophila. Altogether, our data suggest that these phenotypes are the result of a pathogenetic cascade that includes impaired V-ATPase assembly, defective lysosomal acidification, reduced MTOR signaling and autophagic misregulation. PMID- 29388889 TI - Editorial. PMID- 29388890 TI - Biosurfactant-assisted phytoremediation of multi-contaminated industrial soil using sunflower (Helianthus annuus L.). AB - This study evaluated the use of commercial rhamnolipid biosurfactant supplementation in the phytoremediation of a soil via sunflower (Helianthus annuus L.) cultivation. The soil, obtained from an industrial area, was co contaminated with heavy metals and petroleum hydrocarbons. The remediation tests were monitored for 90 days. The best results for removal of contaminants were obtained from the tests in which the sunflower plants were cultivated in soil with 4 mg kg-1 of the rhamnolipid. Under these conditions, reductions of 58% and 48% were obtained in the total petroleum hydrocarbon (TPH) and polycyclic aromatic hydrocarbon (PAH) concentrations, respectively; reductions in the concentrations of the following metals were also achieved: Ni (41%), Cr (30%), Pb (29%), and Zn (20%). The PCR-DGGE analysis of soil samples collected before and after the treatments verified that the plant cultivation and biosurfactants supplementation had little effect on the structure of the dominant bacterial community in the soil. The results indicated that sunflower cultivation with the addition of a biosurfactant is a viable and efficient technology to treat soils co-contaminated with heavy metals and petroleum hydrocarbons. PMID- 29388891 TI - Reorganization of the Journal's Editorial Board to Improve the Journal's Productivity and Efficiency. PMID- 29388893 TI - Mechanisms of Change in Treatments of Personality Disorders: Commentary on the Special Section. AB - Ueli Kramer has assembled an eclectic and original set of articles on mechanisms of change in the treatment of borderline personality disorder. They largely focus on patient variables. Several authors make the point that developmentally based variables may have more predictive power than symptom-based variables. Several other articles illustrate that changes occur early in treatments and studying their mechanisms is a promising approach that could have longer term significance. These articles document the variety of research methodologies that can be used to study mechanisms of change and the potential clinical significance of doing this. For showing the field the potential of such research, we owe Dr. Kramer our gratitude. PMID- 29388892 TI - Food safety traits of mussels and clams: distribution of PCBs, PBDEs, OCPs, PAHs and PFASs in sample from different areas using HRMS-Orbitrap(r) and modified QuEChERS extraction followed by GC-MS/MS. AB - Reviewing the presence of contaminant residues is important both for food safety and for monitoring of environmental pollution. Here, the occurrence of 6 polychlorinated biphenyls (PCBs), 15 organochlorine pesticides (OCPs), 7 polybrominated diphenyl ethers (PBDEs), 4 polycyclic aromatic hydrocarbons (PAHs) and 17 perfluoroalkyl substances (PFASs) was evaluated in mussels and clams. A liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) and an innovative QuEChERS extraction followed by gas chromatography-tandem mass spectrometry (GC-MS/MS) methods were developed, validated and applied. We demonstrate good linearity, repeatability and accuracy of these methods, confirming that they are suitable for the analyses of mollusc samples. The prevalence of PCBs, OCPs and PAHs was higher in mussels than in clams. For PFASs, contamination was higher in clams than in mussels. The samples were all compliant with the regulations, and, for the compounds without legislative limits, a risk assessment confirmed that the values were lower than the tolerable intakes. PMID- 29388894 TI - Coping Action Patterns as Mechanisms of Change Across Psychotherapies: Three Case Examples of Personality Disorders With Recurrent Major Depression. AB - Maladaptive coping has been shown to be related to increased symptoms of distress and lower levels of well-being, whereas the use of adaptive coping has been shown to diminish distress and improve functioning. This suggests that change in coping may constitute a significant mechanism of change in psychotherapy. Utilizing a novel observer-rating method for assessing coping, the current report examined changes in overall coping functioning (OCF) in three participants with diverse personality disorders who were undergoing two different types of psychotherapy (cognitive-behavioral therapy and dynamic therapy) for recurrent major depression. Results showed that overall coping functioning improved in two cases and remained stable in a third. Preliminary findings, based on a detailed examination of changes in specific coping patterns, suggest that improvement may differ according to severity of personality pathology. As hypothesized, coping improved in both types of psychotherapy. Thus, overall results suggest that coping may constitute an important general mechanism of change. PMID- 29388895 TI - The Role of Negative Affect and Self-Concept Clarity in Predicting Self-Injurious Urges in Borderline Personality Disorder Using Ecological Momentary Assessment. AB - Deficits in identity as well as negative affect have been shown to predict self injurious and suicidal behaviors in individuals with borderline personality disorder (BPD). However, less is known about the interactive effects of these two predictors. We examined the moderating effect of a particular component of identity, self-concept, on the relationship between negative affect and self injurious urges utilizing ecological momentary assessments. Outpatients diagnosed with either BPD (n = 36) or any anxiety disorder but no BPD (n = 18) completed surveys throughout the day over a 21-day period. Higher levels of momentary negative affect predicted greater subsequent urges to self-injure, but only when self-concept clarity was low (z = -3.60, p < .01). This effect did not differ between diagnostic groups. The results suggest that self-concept clarity has a protective effect against self-injurious urges in light of high negative affect, and that this effect may be transdiagnostic. PMID- 29388896 TI - Emotion Regulation and Social Cognition as Functional Targets of Mechanism-Based Psychotherapy in Major Depression With Comorbid Personality Pathology. AB - This article characterizes functional systems as targets of integrated modular psychotherapy for episodes of major depression (MD) with a comorbid condition of borderline personality disorder (BPD) or chronic depression (CD). Both types of comorbidities to MD are conceptualized as a trait-like concept dominated by impairments in interpersonal functioning. Despite differences in psychopathology, existing data show significant similarities in impairments of emotion regulation and social cognition in BPD and CD, thought to reflect common disease mechanisms linked to early-life adversity. The preexistence of BPD and CD and related functional impairments inhibits the remission of episodic MD and calls for mechanism-based interventions that complement existing treatments of MD by targeting these dysfunctions. Contemporary methods of psychotherapy already provide interventions to address such complicated states of comorbidity by specifically improving dysfunctions of emotion regulation and social cognition. We suggest a layout of modular interventions that can address identified dysfunctions in comorbid MD. PMID- 29388897 TI - Mechanisms of Change in Treatments of Personality Disorders: Commentary on the Special Section. AB - Considerable progress has been made in the psychotherapeutic treatment of patients with personality disorders (PDs). Once engendering a pervasive therapeutic nihilism, PDs are starting to be viewed as treatable with a much better prognosis than previously thought. Evidence from several randomized controlled trials demonstrating the effectiveness of various forms of psychotherapy, coupled with findings from several longitudinal studies, suggests that such increased clinical optimism is warranted. However, the persistent focus on treatment brands obscures our understanding of the mechanisms through which benefits are actually realized. This article considers emerging trends in PD treatment research, exemplified by the series of articles contained within this special section, that attempt to identify more precisely the mechanisms of therapeutic change. It is only through such work that we will be able to accomplish further refinement of effective strategies, create possibilities for true integration of therapies, and achieve real progress in the field for the betterment of our patients. PMID- 29388898 TI - Mechanisms of Change in Treatments of Personality Disorders: Commentary on the Special Section. AB - Personality disorders (PDs) come in a large variety of presentations, severely affect the individual's social and emotional functioning, and are notoriously complex to treat. To make treatments for individuals with PDs more potent, there is a need to better understand how and why these treatments work. The articles assembled for this special section propose potential mechanisms of change within PD patients that may be addressed in future process-outcome research. Although the studies are exploratory and were limited by their scope and heterogeneity of their samples, they illustrate the importance of process research as nomothetic and idiographic building blocks toward a multifaceted understanding of change processes in PDs and their treatment. In this discussion, the authors aim to foster interest in the potential mechanisms of change in PD treatments and inspire further research by providing several methodological considerations for future process-outcome research and its potential clinical implications. PMID- 29388899 TI - Change in Biased Thinking in a Treatment Based on the Motive-Oriented Therapeutic Relationship for Borderline Personality Disorder. AB - Biased thinking is a common feature of patients presenting with borderline personality disorder (BPD). For the treatment of BPD, it was shown that the individualizing of the treatment, by using the motive-oriented therapeutic relationship (MOTR), had a beneficial short-term effect on process and outcome. So far, it remains unclear what the role of early change in biased thinking is in these treatments. The present study aims to assess whether there is a link between the MOTR, change in biased thinking, and outcome. The sample (N = 60) is based on a randomized controlled trial with two conditions: (a) 30 patients in a 10-session version of psychiatric management, and (b) 30 patients in a 10-session version of psychiatric management augmented with the MOTR. For each patient, three sessions (intake, middle, late) were selected, transcribed, and rated using the Cognitive Errors Rating Scale (CERS). An overall decrease of negative cognitive errors during 10 sessions of treatment was observed, independently of the treatment condition. No specific effect related to change in biased thinking may be attributed to the individualizing of the treatment. These results are discussed with regard to mechanisms of change in treatments for BPD, in particular with regard to the central role that biased thinking, as well as the MOTR, might play early in treatment. PMID- 29388900 TI - Mechanisms of Change in Treatments of Personality Disorders: Introduction to the Special Section. AB - The present introduction to the Special Section on Mechanisms of Change in Treatments of Personality Disorders explains the value of research focusing on processes of change in psychotherapy by referring to a variety of methodologies. Whereas outcome for these treatments has been repeatedly demonstrated, it remains an open question what the core psychobiological features of change are. Taking a radically empirical perspective, this introduction focuses on patient and therapeutic relationship variables, such as emotional and socio-cognitive processing. The six empirical articles of the Special Section are introduced, as are the three discussions of the Special Section. PMID- 29388901 TI - Alliance Rupture and Resolution in Dialectical Behavior Therapy for Borderline Personality Disorder. AB - The aim of this exploratory study was to investigate alliance rupture and resolution processes in the early sessions of a sample of clients who underwent 1 year of standard dialectical behavior therapy (DBT) for borderline personality disorder (BPD). Participants were three recovered and three unrecovered clients drawn from the DBT arm of a randomized controlled trial that compared the clinical and cost-effectiveness of DBT and general psychiatric management. Alliance rupture and resolution processes were coded using the observer-based Rupture Resolution Rating Scale. Unrecovered clients evidenced a higher frequency of withdrawal ruptures than recovered clients. Withdrawal ruptures tended to persist for unrecovered clients despite the degree of resolution in the prior session, unlike for recovered clients, for whom the probability of withdrawal ruptures decreased as the degree of resolution increased. This study suggests that alliance rupture and resolution processes in early treatment differ between recovered and unrecovered clients in DBT for BPD. PMID- 29388902 TI - Attachment-Related Regulatory Processes Moderate the Impact of Adverse Childhood Experiences on Stress Reaction in Borderline Personality Disorder. AB - In this study, the authors explored whether attachment insecurity moderates the effects of adverse childhood experiences on stress reactivity in the context of borderline personality disorder (BPD). Participants were 113 women (39 with BPD, 15 with some BPD criteria present, 59 without any BPD symptoms) who participated in the Trier Social Stress Test. Saliva samples were collected before and after the stressor and assayed for salivary alpha-amylase (sAA) and cortisol. Adverse childhood experiences were measured using the Childhood Trauma Questionnaire, and attachment by the Experiences in Close Relationships-Revised questionnaire. Results revealed that attachment avoidance and a combination of more adverse childhood experiences and attachment insecurity resulted in higher sAA levels and differences in reactivity to the stressor. Interactions between attachment anxiety and adverse childhood experiences were related to blunted cortisol reactivity. The results suggest that the influence of adverse childhood experiences on stress regulation in BPD may be moderated by attachment-related regulatory processes. PMID- 29388904 TI - Breast MR Imaging before Surgery: Outcomes in Patients with Invasive Lobular Carcinoma by Using Propensity Score Matching. AB - Purpose To investigate the association between preoperative breast magnetic resonance (MR) imaging and surgical outcomes in patients with invasive lobular carcinoma (ILC) by using propensity score matching to decide whether MR examination is beneficial in the ILC subtype of breast cancer. Materials and Methods The authors identified 603 patients with ILC who underwent surgery between January 2005 and December 2016. Of the 603 patients, 369 (61.2%) underwent MR imaging. The authors calculated the MR detection rate of additional lesions that were occult at mammography and ultrasonography and analyzed any alterations in surgical management. After propensity score matching, 196 pairs of patients were allocated to the groups, and the 17 possible confounding variables regarding patient and tumor characteristics and various clinical features were well balanced between the patients who underwent MR imaging and those who did not. Surgical outcomes were compared. Results Of the 369 patients who underwent MR imaging, additional lesions were detected in 145 (39.3%); 95 of the 145 patients (65.5%) had malignant lesions. A change in surgical management occurred because of MR findings in 94 of the 369 patients (25.5%). According to pathologic findings, this change was appropriate for 84 of the 94 patients (89.4%). In the propensity score-matched analysis, breast MR imaging was associated with lower odds of repeat surgery (odds ratio, 0.140; P < .001) and similar likelihood of initial mastectomy (odds ratio, 0.876; P = .528) and final mastectomy (odds ratio, 0.744; P = .151) compared with patients without breast MR imaging. Conclusion Preoperative MR imaging is useful for detecting additional synchronous malignancy and significantly reducing the likelihood of repeat surgery without increasing the rate of mastectomy in patients with ILC. (c) RSNA, 2018. PMID- 29388905 TI - Profile of patients with spinal cord injuries in Kwazulu-Natal, South Africa: Implicactions for vocational rehabilitation. AB - OBJECTIVES: To describe the demographic and socio-economic profiles, and injury related characteristics of people who sustain SCIs in KZN in order to provide baseline information to instigate a model that guides employment outcomes amongst PLWSCI. DESIGN: Retrospective analysis of medical files was done. SETTING: King Dinizulu Hospital Spinal Unit (KDHSU), this being the biggest provider of acute care for people who sustain SCI in KwaZulu-Natal and the Eastern Cape Provinces, South Africa was the setting for our study. PARTICIPANTS: Medical files of individuals who sustained SCI between 2009 and 2012 were perused (n = 1049) were perused and 188 met the inclusion criteria. OUTCOME MEASURES: Key information from the KDHSU patient's files were extracted using a tool developed using literature and the international spinal cord injury core data set. RESULTS: The average annual incidence rate was 12.3 per 100 000 population. The male to female ratio was 6:4 with the mean age of 36.69 years, ranging from 16-64. Out of those employed (34%), 72% were working fulltime, mostly in the service industry (31%) and 59% were classified as laborers. The majority (61%) of the participants completed high school. The major cause of SCI was non-traumatic (54%) and 66% were classified as incomplete (ASIA). Furthermore, 80% were classified as paraplegia and 19% tetraplegia. The mean LOS was 42.9 days, ranging from 1-764 days, influenced by level of injury, completeness and classification of injury and surgical intervention. CONCLUSION: The profile of SCI in KwaZulu-Natal is slightly different when compared to other provinces in South Africa and the rest of Africa. There is a need to use epidemiological information (including factors that influence employment) to develop rehabilitation models to guide employment outcomes amongst people living with spinal cord injuries in KZN. PMID- 29388903 TI - In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F (2S,4R)-4-Fluoroglutamine. AB - Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq +/- 118, <100 MUg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. (c) RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930. PMID- 29388906 TI - Identification of antibiotic mycelia residue in protein rich feed using on near infrared microscopy imaging. AB - Antibiotic mycelial residues (AMRs) added to animal feeds easily lead to drug resistance that affects human health and environment. However, there is a lack of effective detection methods, especially a fast and convenient detection technology, to distinguish AMRs from other components in animal feeds. To develop effective detection methods, two types of global Mahalanobis distance (GH) algorithms based on near-infrared microscopy (NIRM) imaging are proposed. The aim of this study is to investigate the feasibility of using NIRM imaging to identify AMRs in soybean meals. We prepared 15 mixed samples containing 5% AMRs using three types of soybean meals and four types of AMRs. The GH algorithm was used to identify non-soybean meals among the mixed samples. The hierarchical cluster analysis was employed to verify the recognition accuracy. The results indicate that use of the GH algorithm could identify soybean meals with AMR at a level as low as 5%. PMID- 29388907 TI - Ethnic variations regarding clinical profiles and symptom representation in prisoners with psychotic disorders. AB - BACKGROUND: Black and minority ethnic (BME) groups are known to have higher prevalences of psychotic disorders and are over-represented in western penitentiaries and forensic psychiatric institutions. Research from regular mental healthcare settings suggests that they could show different and more severe psychotic symptoms. Aims To explore ethnic variations in severity of symptomatology of BME and non-BME detainees with psychotic disorders. METHOD: In this study, 824 patients with psychotic disorders from seven different ethnic groups, imprisoned in a penitentiary psychiatric centre in the Netherlands, were compared on symptom severity and symptom representation using the BPRS-E clinical interview. Data were analysed by means of a multilevel analysis. RESULTS: BME patients with psychotic disorders are over-represented in forensic psychiatry, and symptom profiles of prisoners with psychotic disorders vary by ethnicity. Additionally, severity levels of overall psychopathology differ between ethnic groups: patients with an ethnic majority status show more severe levels of psychopathology compared with BME patients. CONCLUSIONS: There are differences in symptom severity and symptom profiles between BME patients and non-BME patients. Disregarding these differences could have an adverse effect on the outcome of the treatment. Possible explanations and clinical impact are discussed. Declaration of interest None. PMID- 29388908 TI - Qualitative systematic review of barriers and facilitators to patient-involved antipsychotic prescribing. AB - BACKGROUND: Despite policy and practice mandates for patient involvement, people with serious mental illness often feel marginalised in decisions about antipsychotic medication. Aims To examine stakeholder perspectives of barriers and facilitators to involving people with serious mental illness in antipsychotic prescribing decisions. METHOD: Systematic thematic synthesis. RESULTS: Synthesis of 29 studies identified the following key influences on involvement: patient's capability, desire and expectation for involvement, organisational context, and the consultation setting and processes. CONCLUSIONS: Optimal patient involvement in antipsychotic decisions demands that individual and contextual barriers are addressed. There was divergence in perceived barriers to involvement identified by patients and prescribers. For example, patients felt that lack of time in consultations was a barrier to involvement, something seldom raised by prescribers, who identified organisational barriers. Patients must understand their rights to involvement and the value of their expertise. Organisational initiatives should mandate prescriber responsibility to overcome barriers to involvement. Declaration of interest None. PMID- 29388909 TI - Effectiveness of automated appointment reminders in psychosis community services: a randomised controlled trial. AB - We report on the first open-label, parallel group randomised controlled trial of automated appointment reminders in a psychosis community service in the UK. Ninety-five patients were randomly allocated to receiving/not receiving automated messaging reminders 7 days and 1 day before appointments. All 'Attended' and 'Missed' appointment outcomes over 6 months were analysed using cluster regression analysis. Reminded appointments were significantly more frequently attended than non-reminded appointments (unadjusted odds ratio (OR) = 3.54, 95% CI 1.36-9.22, P = 0.01; adjusted OR = 2.95, 95% CI 1.05-8.85, P < 0.05). Automated messaging reminders can provide a robust strategy for promoting engagement with psychosis services. Declaration of interest The authors have no competing financial interests to declare in relation to the current work. Sarah McAllister was supported by a King's Undergraduate Research Fellowship. PMID- 29388910 TI - A symptom-based approach to treatment of psychosis in autism spectrum disorder in October 2017. AB - The optimal management of autism with psychosis remains unclear. This report describes a 22-year-old man with autism and psychosis who was referred to a tertiary-level specialist psychosis service, following a 6-year history of deterioration in mental health starting around the time of sitting GCSE examinations and an episode of bullying at school. We describe the individualised symptom-based approach that was effective in his treatment. Declaration of interest The authors declare no conflict of interest. PMID- 29388911 TI - Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit. AB - Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP induces non-productive tetramers, resulting in different holoenzymes. The tetramer forms by interactions between ATP-cones, shown by a 2.45 A crystal structure. We also present evidence for an MnIIIMnIV metal center. In summary, lack of an ATP-cone domain in the catalytic subunit was compensated by transfer of the domain to the radical-generating subunit. To our knowledge, this represents the first observation of transfer of an allosteric domain between components of the same enzyme complex. PMID- 29388912 TI - Multiple kinases inhibit origin licensing and helicase activation to ensure reductive cell division during meiosis. AB - Meiotic cells undergo a single round of DNA replication followed by two rounds of chromosome segregation (the meiotic divisions) to produce haploid gametes. Both DNA replication and chromosome segregation are similarly regulated by CDK oscillations in mitotic cells. Yet how these two events are uncoupled between the meiotic divisions is unclear. Using Saccharomyces cerevisiae, we show that meiotic cells inhibit both helicase loading and helicase activation to prevent DNA replication between the meiotic divisions. CDK and the meiosis-specific kinase Ime2 cooperatively inhibit helicase loading, and their simultaneous inhibition allows inappropriate helicase reloading. Further analysis uncovered two previously unknown mechanisms by which Ime2 inhibits helicase loading. Finally, we show that CDK and the polo-like kinase Cdc5 trigger degradation of Sld2, an essential helicase-activation protein. Together, our data demonstrate that multiple kinases inhibit both helicase loading and activation between the meiotic divisions, thereby ensuring reductive cell division. PMID- 29388915 TI - [#MeToo in medicine]. PMID- 29388913 TI - Dopamine-dependent scaling of subthalamic gamma bursts with movement velocity in patients with Parkinson's disease. AB - Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson's disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson's disease. PMID- 29388914 TI - Piecewise-Stationary Motion Modeling and Iterative Smoothing to Track Heterogeneous Particle Motions in Dense Environments. AB - One of the major challenges in multiple particle tracking is the capture of extremely heterogeneous movements of objects in crowded scenes. The presence of numerous assignment candidates in the expected range of particle motion makes the tracking ambiguous and induces false positives. Lowering the ambiguity by reducing the search range, on the other hand, is not an option, as this would increase the rate of false negatives. We propose here a piecewise-stationary motion model (PMM) for the particle transport along an iterative smoother that exploits recursive tracking in multiple rounds in forward and backward temporal directions. By fusing past and future information, our method, termed PMMS, can recover fast transitions from freely or confined diffusive to directed motions with linear time complexity. To avoid false positives, we complemented recursive tracking with a robust inline estimator of the search radius for assignment (a.k.a. gating), where past and future information are exploited using only two frames at each optimization step. We demonstrate the improvement of our technique on simulated data especially the impact of density, variation in frame to frame displacements, and motion switching probability. We evaluated our technique on the 2D particle tracking challenge dataset published by Chenouard et al. in 2014. Using high SNR to focus on motion modeling challenges, we show superior performance at high particle density. On biological applications, our algorithm allows us to quantify the extremely small percentage of motor-driven movements of fluorescent particles along microtubules in a dense field of unbound, diffusing particles. We also show with virus imaging that our algorithm can cope with a strong reduction in recording frame rate while keeping the same performance relative to methods relying on fast sampling. PMID- 29388916 TI - [Nudgeing a sleep deprived nation]. PMID- 29388917 TI - [Non-cardiac chest pain and its association with persistent chest pain and poor mental well-being]. AB - INTRODUCTION: An estimated 50-75% of visits to cardiac emergency departments are due to chest pain which is non-cardiac in nature (non-cardiac chest pain (NCCP). This study evaluates the prevalence of NCCP in the emergency departments at Landspitali, and assesses its association with continued chest-pain post discharge, mental well--being and the information-provision provided to NCCP patients during hospitalization. MATERIAL AND METHODS: Participants were 390 patients (18-65 years) presenting with chest pain to the cardiac emergency or the general emergency department at Landspitali from October 2015-May 2016. Measurements included questionnaires assessing somatic symptoms, mental well being and quality of life, and questions regarding continued chest-pain and information-provision during hospitalization. RESULTS: In total 72% of participants (282) were considered having NCCP while 24% (92) had cardiac disease. NCCP patients experienced a similar burden of somatic and depressive symptoms, but slightly more anxiety and mental distress than cardiac patients. Equal proportions (60%) of NCCP and cardiac patients reported having experienced chestpain post discharge. Continued chest-pain was, however, associated with greater anxiety (beta=0.18, p<0.001) and depression (beta=0.18, p<0.003) among NCCP patients. Thirty percent of NCCP patients lacked instructions of how to respond to continued chest-pain and only 40% received information regarding other possible causes of chest pain. CONCLUSION: NCCP was prevalent among patients presenting to emergency departments at Landspitali. The majority of NCCP patients experienced continued chest-pain after discharge, and such pain experience was associated with mental distress. A third of NCCP patients lacked information about possible causes for the pain and advice about coping with symptoms. PMID- 29388919 TI - Ultra-thin alumina and silicon nitride MEMS fabricated membranes for the electron multiplication. AB - In this paper we demonstrate the fabrication of large arrays of ultrathin freestanding membranes (tynodes) for application in a timed photon counter (TiPC), a novel photomultiplier for single electron detection. Low pressure chemical vapour deposited silicon nitride (Si x N y ) and atomic layer deposited alumina (Al2O3) with thicknesses down to only 5 nm are employed for the membrane fabrication. Detailed characterization of structural, mechanical and chemical properties of the utilized films is carried out for different process conditions and thicknesses. Furthermore, the performance of the tynodes is investigated in terms of secondary electron emission, a fundamental attribute that determines their applicability in TiPC. Studied features and presented fabrication methods may be of interest for other MEMS application of alumina and silicon nitride as well, in particular where strong ultra-thin membranes are required. PMID- 29388918 TI - [Physical activity and sleep in Icelandic adolescents]. AB - INTRODUCTION: Physical activity and sleep are major determinants of overall health. According to international recommendations, adolescents should engage in moderate to vigorous physical activity for at least 60 min each day and sleep eight to ten hours each night. The association between physical activity and sleep in adolescents is not well known. The aim of the study was to estimate a) the proportion of Icelandic adolescents that achieves recommended physical activity and sleep, b) if there is an association between physical activity and sleep patterns, and c) sex differences in physical activity and sleep. MATERIAL AND METHODS: A total of 411 adolescents from the 10th grade in six schools in Reykjavik were invited to participate in a cross-sectional study in the spring of 2015. Valid data was obtained from 106 boys and 160 girls. Objective and subjective measures of physical activity and sleep were made by wrist-worn accelerometers and a questionnaire. RESULTS: Almost half of the participants fulfilled the physical activity recommendations according to the questionnaire. Although 51.1% reported usually getting enough sleep, only 22.9% achieved the recommended sleep length according to objective assessment. No associations were observed between sleep and subjective physical activity. Girls had higher accelerometer-measured physical activity than boys on non-school days (p<0.01), but weekly averages were not different between sexes. Girls and boys did not differ in subjective or objective measures of sleep. CONCLUSION: The behavior of Icelandic adolescents does not reflect recommended amount of sleep and physical activity. Only 22.9% obtained the recommended sleep length and just 11.3% fulfilled recommendations of both sleep and physical activity. PMID- 29388920 TI - Arrays of suspended silicon nanowires defined by ion beam implantation: mechanical coupling and combination with CMOS technology. AB - We present the fabrication, operation, and CMOS integration of arrays of suspended silicon nanowires (SiNWs). The functional structures are obtained by a top-down fabrication approach consisting in a resistless process based on focused ion beam irradiation, causing local gallium implantation and silicon amorphization, plus selective silicon etching by tetramethylammonium hydroxide, and a thermal annealing process in a boron rich atmosphere. The last step enables the electrical functionality of the irradiated material. Doubly clamped silicon beams are fabricated by this method. The electrical readout of their mechanical response can be addressed by a frequency down-mixing detection technique thanks to an enhanced piezoresistive transduction mechanism. Three specific aspects are discussed: (i) the engineering of mechanically coupled SiNWs, by making use of the nanometer scale overhang that it is inherently-generated with this fabrication process, (ii) the statistical distribution of patterned lateral dimensions when fabricating large arrays of identical devices, and (iii) the compatibility of the patterning methodology with CMOS circuits. Our results suggest that the application of this method to the integration of large arrays of suspended SiNWs with CMOS circuitry is interesting in view of applications such as advanced radio frequency band pass filters and ultra-high-sensitivity mass sensors. PMID- 29388921 TI - Charge-transfer channel in quantum dot-graphene hybrid materials. AB - The energy band theory of a classical semiconductor can qualitatively explain the charge-transfer process in low-dimensional hybrid colloidal quantum dot (QD) graphene (GR) materials; however, the definite charge-transfer channels are not clear. Using density functional theory (DFT) and time-dependent DFT, we simulate the hybrid QD-GR nanostructure, and by constructing its orbital interaction diagram, we show the quantitative coupling characteristics of the molecular orbitals (MOs) of the hybrid structure. The main MOs are derived from the fragment MOs (FOs) of GR, and the Cd13Se13 QD FOs merge with the GR FOs in a certain proportion to afford the hybrid system. Upon photoexcitation, electrons in the GR FOs jump to the QD FOs, leaving holes in the GR FOs, and the definite charge-transfer channels can be found by analyzing the complex MOs coupling. The excited electrons and remaining holes can also be localized in the GR or the QD or transfer between the QD and GR with different absorption energies. The charge transfer process for the selected excited states of the hybrid QD-GR structure are testified by the charge difference density isosurface. The natural transition orbitals, charge-transfer length analysis and 2D site representation of the transition density matrix also verify the electron-hole delocalization, localization, or coherence chacracteristics of the selected excited states. Therefore, our research enhances understanding of the coupling mechanism of low dimensional hybrid materials and will aid in the design and manipulation of hybrid photoelectric devices for practical application in many fields. PMID- 29388922 TI - Integrated parabolic nanolenses on MicroLED color pixels. AB - A parabolic nanolens array coupled to the emission of a nanopillar micro-light emitting diode (LED) color pixel is shown to reduce the far field divergence. For a blue wavelength LED, the total emission is 95% collimated within a 0.5 numerical aperture zone, a 3.5x improvement over the same LED without a lens structure. This corresponds to a half-width at half-maximum (HWHM) line width reduction of 2.85 times. Using a resist reflow and etchback procedure, the nanolens array dimensions and parabolic shape are formed. Experimental measurement of the far field emission shows a HWHM linewidth reduction by a factor of 2x, reducing the divergence over the original LED. PMID- 29388923 TI - Fabrication of Ag-decorated BiOBr-mBiVO4 dual heterojunction composite with enhanced visible light photocatalytic performance for degradation of malachite green. AB - A visible light active Ag-decorated BiVO4-BiOBr dual heterojunction photocatalyst was prepared using a facile hydrothermal method, followed by the photodeposition of Ag. The photocatalytic activity of the synthesized samples was investigated by monitoring the change in malachite green (MG) concentration upon visible light irradiation. The synthesized sample was highly effective for the degradation of non-biodegradable MG. The enhanced activity observed was ascribed to the efficient separation and transfer of charge carriers across the dual heterojunction structure as verified by photoluminescence measurements. The removal of MG was primarily initiated by hydroxyl radicals and holes based on scavenger's effect. To gain insight into the degradation mechanism, both high performance liquid chromatography and high resolution-quantitative time of flight, electrospray ionization mass spectrometry measurements during the degradation process were carried out. The degradation primarily followed the hydroxylation and N-demethylation process. A possible reaction pathway is proposed on the basis of all the information obtained under various experimental conditions. PMID- 29388926 TI - [The role of the neurophysiological methods in the assessment of the effectiveness of the rehabilitation of sensorimotor disturbances associated with the lesions of the central nervous system at the spinal cord level]. AB - AIM: The objective of the present study was the evaluation and comparison of the effectiveness of the differential approaches to the neurorehabilitation of the somatosensory disturbances in the patients presenting with the spinal cord lesions. MATERIALS AND METHODS: A total of 68 patients with spinal cord lesions were enrolled in the study, including 38 suffering from vascular myelopathy, 18 with the consequences of extramedullar meningioma surgery, 12 with the sequelae of acute transverse myelitis. The control groups was comprised of were 55 subjects. All the participants of the study underwent rehabilitation which included robotized mechanotherapy, stabilography, neuro-muscular stimulation, kinesiotherapy, physical therapy, ergotherapy, massage, etc. Transcranial magnetic stimulation (TMS) and evaluation of somatosensory evoked potentials (SSEP) were carried out before and after the therapy. RESULTS: In those patients who received personalized therapy, significant changes of TMS parameters (central motor conduction time at rest and in facilitation probe), but not SSEP ones were registered. Moreover, the patients who had undergone personalized therapy exhibited better clinical results than in the absence of such treatment. CONCLUSION: The results of the study gave evidence that neurorehabilitation had produced the more pronounced beneficial influence as regards the correction of motor disturbances even though the disturbances of the somatosensory functions proved to be more resistant to therapy. The data obtained suggest that taking into consideration the afferent deficit has to be mandatory for the purpose of planning the neurorehabilitative treatment of the patients suffering from sensorimotor disturbances associated with the lesions of the central nervous system at the spinal cord level. TMS and SSEP have to be utilized as the tools for the objective evaluation of the effectiveness of the neurorehabilitation process in such patients. PMID- 29388925 TI - Blood will out: vascular contributions to Alzheimer's disease. AB - The fundamental pathology in Alzheimer's disease (AD) is neuronal dysfunction leading to cognitive impairment. The amyloid-beta peptide (Abeta), derived from amyloid precursor protein, is one driver of AD, but how it leads to neuronal dysfunction is not established. In this Review, I discuss the complexity of AD and possible cause-and-effect relationships between Abeta and the vascular and hemostatic systems. AD can be considered a multifactorial syndrome with various contributing pathological mechanisms. Therefore, as is routinely done with cancer, it will be important to classify patients with respect to their disease signature so that specific pathologies, including vascular pathways, can be therapeutically targeted. PMID- 29388924 TI - Fructose metabolism and metabolic disease. AB - Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease. PMID- 29388927 TI - [The comparative analysis of the influence of the supervised exercise training and home-based exercise training on the psychological status of the following coronary artery bypass grafting]. AB - : This article was designed to report the results of the comparative analysis of the influence of the home-based exercise training (HBT) and the supervised exercise training in the form of the controlled training (CVT) under conditions of outpatient rehabilitative treatment on the patients' quality of life (QoL) and psychological status (including manifestations of anxiety and depression) following coronary artery bypass grafting (CABG). AIM: The objective of the present study was to evaluate the consequences of the application of different programs of physical rehabilitation under the outpatient conditions on the psychoemotional status and quality of life of the patients who had undergone coronary artery bypass grafting. MATERIALS AND METHODS: A total of 114 male patients suffering from coronary artery disease (CAD) who had undergone CABG were available for the examination. All the patients were allocated to three groups. Group 1 was comprised of the patients (n=36) treated with the use of the supervised cycling training (SCT) while group 2 consisted of the patients who had to perform home-based walking training (HBWT) (n=36). The group of comparison included 42 patients. The psychophysiological assessment was carried out based on the Beck Depression Inventory (BDI) and the Spielberger-Hanin Personal and Reactive Anxiety Scale. The quality of life (QoL) was assessed with the use of the SF-36 questionnaire. All the patients were examined prior to surgery, 1.4 months and 1 year after CABG. RESULTS: The study has demonstrated the most pronounced improvement in the quality of life of the patients following the 3 month supervised cycling training after CABG that was manifested as the decrease of anxiety and depression. The minimal changes in the psychological and emotional status were documented in the absence of any exercise training integrated into the postoperative rehabilitation program. Only the moderate improvement of QoL was observed in the patients treated with the application of the 3-month home based walking training program after CABG. The positive effects of the three month exercise training were evened out within 1 year after its initiation. DISCUSSION: It has been shown that the effectiveness of HBT is somewhat lower than that of CVT in terms of the influence on the psychoemotional status of the patients following CABG. This finding is at variance with the results reported by the foreign authors and should provide a basis for the enhancement of the effectiveness of the post-CABG rehabilitation programs to be implemented under conditions of the medical facilities, their principal objective being the education of the patients in safe and efficient methods for the pots-surgical self-rehabilitation with the emphasis placed on the measures intended for the improvement of the approaches to monitoring the compliance of the patients with the prescribed recommendations and for increasing their motivation to observe as long as possible the advices given by the health care professionals. CONCLUSION: The home-based walking training of moderate intensity provides a safe, easy to perform, and readily available tool for a large number of patients who underwent coronary artery bypass grafting even though it is somewhat less effective than the supervised cycling training. The effects of both rehabilitation modalities are rather short-term. PMID- 29388928 TI - [The influence of the technique for the post-isometric relaxation of the muscles of the lumbosacral region of the spine on the manifestations of the flexion contracture in the hip joint in the men at the age of 50-60 years following amputation of the lower limb at the hip level in the course of the rehabilitation process]. AB - AIM: The objective of the present study was to evaluate the outcome the application of the technique for the post-isometric relaxation of the muscles of the lumbosacral region of the spine and of the lumbosacral junction as a component of the combined rehabilitation on the manifestations of the flexion contracture in the hip joint in the men at the age of 50-60 years following amputation of the lower limb at the hip level throughout the course of the rehabilitative process. MATERIALS AND METHODS: A total of 243 patients who had undergone ablation of a femur available for the examination. 153 of them were treatment with the use of the technique for the post-isometric relaxation of the muscles of the lumbosacral region of the spine and of the lumbosacral junction. The control group was comprised of the remaining 90 patients treated without the application of the technique for post-isometric relaxation. The analysis of the degree of flexion contracture of the hip joint on the side of ablation was carried out by means of the Thomas test. RESULTS: The results of the study give evidence that that use of the technique for the post-isometric relaxation of muscles of the lumbar spine and sacroiliac joint makes it possible to reduce the time needed to decrease the severity of contracture of the hip joint during the rehabilitation process. CONCLUSION: The data obtained provide a basis for recommending the inclusion of the technique for the post-isometric relaxation of muscles of the lumbar spine and the lumbosacral junction into the program of the combined rehabilitation of the patients who had undergone ablation of a femur. PMID- 29388929 TI - [The experience with the application of the selective electro-stimulation impacts in the children presenting with the disturbances of the locomotor function]. AB - AIM: The objective of the present study was the improvement of the effectiveness of medical rehabilitation of the children presenting with the disturbances of the locomotor function using a "LymphaVision" apparatus for the selective electrical stimulation. MATERIALS AND METHODS: The study included 42 patients with movement disorders divided into two groups depending on the method of non-drug therapy. The main group was comprised of the patients receiving the treatment by electrical stimulation with the use of the "LymphaVision" apparatus while the remaining patients made up the group of comparison (they were treated with by means of Vermel electrophoresis with the use of a 1% sodium bromide solution). The increase of the muscular strength evaluated based on the scoring system and the number of motor skills were used as the criteria of the effectiveness of the treatment. The applied Statistica for Windows package, version 6.0 ("StatSoft", USA). Was employed for the statistical analysis of the data obtained. The significance and number of differences between two independent samples of the quantitative features were assessed using the Mann-Whitney U test. The Wilcoxon matched pairs test was used to compare the two matched groups. RESULTS: The children comprising the group treated by means of selective exposure to electrical stimulation with the use of the "LymphaVision" apparatus in the course of the rehabilitation process exhibited a significant increase in the strength of the muscles of the lower extremities and the trunk over the baseline values (p=0.003 and p=0.04 respectively) and acquired a significantly greater number of the new motor skills (p=0.02). CONCLUSION: The application of the proposed method is characterized by the highly pronounced clinical efficiency. This approach is pathogenetically well-substantiated for the treatment of the children presenting with the locomotor disorders developing as the consequences of perinatal lesions in the central nervous system and promotes the restoration of the capabilities of the child's body, such as normalization of the muscle tone, increase of the motor activity and muscle strength. PMID- 29388930 TI - [The marketing evaluation of the consumers' preference as regards the use of medicinal and medicinal table mineral waters]. AB - : The development of modern technologies in physiotherapy with the use of mineral waters, the expansion of the assortment of the medicinal and medicinal table waters as well as increasing the competitive advantages of domestic products require the more extensive marketing survey of the consumers' preferences in the market of mineral waters. AIM: The objective of the present study was the marketing evaluation of the consumers' preference in the segment of medicinal and medicinal table mineral waters in the city of Moscow. MATERIALS AND METHODS: The survey involved 697 consumers of medicinal and medicinal table mineral waters. The sampling was carried out by the deterministic quota method. The field research was conducted by means of personal verbal interviews (32%) and the CATI to Web method (phone recruiting and on-line questioning) (68%) with the use of the structured questionnaire. Positioning was carried out making use of the two dimensional schematic map and scoring assessment on an individual basis with calculation of integrated indicators. RESULTS: The marketing evaluation has demonstrated that the principal motive for purchasing mineral waters in more than 40% of respondents was the treatment and prevention of various diseases including disturbances in the urogenital system as well as digestive and respiratory disorders that appear to be the most frequent reasons for the consumption of mineral waters. The main factors that form the preferences of the consumers as regards the use of a concrete variety of mineral waters were elucidated. Of crucial importance for approximately 40% of the consumers (p<0.01) proved to be their health condition, the medical indications, and the available information about the therapeutic effectiveness of one or another type of mineral waters. Other factors were the quality of mineral water, its cost, the manufacturer and/or place of production, the attractiveness of the packaging, etc. CONCLUSION: The evaluation of the positioning of the mineral water consumers' preferences made it possible to identify the most preferable products in the group of medicinal mineral waters and in the group of medicinal table mineral waters. The mechanisms governing the formation of the consumers' preferences as regards the use of various mineral waters have been clarified in the course of the present study. PMID- 29388931 TI - [The therapeutic and recreational potential of the "Goryachy Plyazh" physiotherapeutic facility on the Kunashir island]. AB - : The ever increasing attention to the further development of the health resort business and touristic activities in this country implies the necessity of the proper scientifically sound substantiation for the more efficient exploitation of the available spa and health resort resources of the Russian Far East as well as the ample recreational potential of this region taking into consideration that they have not been completely utilized during the preceding period. AIM: The objective of the present study was to evaluate the of the "Goryachy Plyazh (Hot Beach)" physiotherapeutic facility on the Kunashir island. MATERIALS AND METHODS: We have studies the chemical, bacteriological, and radiological properties of thermal waters from the natural sources located in the vicinity of the "Goryachy Plyazh" physiotherapeutic facility. The medical potential of the area was assessed in accordance with the methodological guidelines No96/226 on drawing up the bioclimatic passport approved by the Ministry of Public Health of the Russian Federation on the 7thFebruary of 1997. RESULTS: We have proposed the aggregate indicator of the therapeutic and recreational potential making it possible to evaluate the totality of health-improving properties in the combination with the landscape and climatic characteristics of the locality of interest. The neighbourhood of the "Goryachy Plyazh" physiotherapeutic facility on the Kunashir island was found to harbour the sources of mineral waters of various types. Specifically, siliceous thermal waters of varying ionic composition (e.g. containing chlorides, sodium, silicium, and boron) of the Omsk and Ursdon types are suitable for multipurpose therapeutic utilization including the protracted internal application for the treatment of chronic gastritis and other intestinal problems, diseases of liver and endocrine system, as well as metabolic disorders. Mineral water of the Kul'dursky type can be used for the external use in the form of bathing and other hydrotherapeutic procedures for the management and prevention of the diseases of various dermatoses, the diseases of the nervous, musculoskeletal, and genitourinary systems. CONCLUSION: The results of the study give evidence of the ample aggregate therapeutic and recreational potential of the localities in the neighbourhood of the "Goryachy Plyazh" physiotherapeutic facility located on the Kunashir island amounting to 76.5% which suggests the very promising prospects for the further development and utilization of this territory for the health resort business and touristic activities. PMID- 29388932 TI - [Rehabilitation of the patients following the endoprosthetic replacement of the joints of the lower extremities]. AB - The present article is the analytical review of the literature pertaining to the problem of rehabilitation of the patients following the endoprosthetic replacement of joints of the lower extremities. The relevance of the problem of interest for medical rehabilitation is beyond any doubt. The traditional methods for the rehabilitation of the patients do not always lead to the desired results. The authors discuss in detail the need for and the contemporary approaches to the rehabilitation of the patients who had undergone reconstructive surgery and arthroplasty of the joints of the lower extremities. The pathogenetically-based three-stage algorithm for medical rehabilitation is proposed. PMID- 29388933 TI - [The application of the modern phototherapeutic technologies for the medical rehabilitation of the children]. AB - This literature review is focused on the application of polychromatic and monochromatic polarized light for the treatment of various diseases of the childhood including those in the newborns and the premature babies. The analysis of the data of scientific research gives evidence of the beneficial effect of polychromatic polarized light on the clinical course of various skin diseases in the newborn children. Moreover, the improved immunological and reparative processes were revealed after the surgical interventions for congenital heart defects in the newborns. The light-induced changes in the skin contribute to the realization of therapeutic effects of polarized polychromatic light in such children's diseases as atopic dermatitis, bronchitis, bronchial asthma, neurogenic urinary bladder dysfunction, and the traumatic injuries of the limbs. The biologically positive physiological effects of monochromatic polarized light are known to contribute to the improvement of the clinical and functional status in the children presenting with bronchial asthma and in the patients frequently suffering from acute respiratory diseases. The versatility of the biological effects of polarized light taken together with the possibility of its application from the first days of the child's life, the short duration of the procedure, the absence of unpleasant sensations and contact between the damaged surface and the device as well as the simplicity of using the equipment determine the promising prospects for the use of the proposed method in the clinical pediatric practice. PMID- 29388934 TI - [The application of the physical factors for the medical rehabilitation of the children presenting with neurogenic dysfunction of the bladder]. AB - This article describes the modern technologies for the medical rehabilitation of the children presenting with neurogenic dysfunction of the bladder aimed at improving the act of urination at all levels of innervation. The most frequent variant of neurogenic dysfunction of the bladder in the children is the hyper reflexive one; it is this variant in which the most pronounced disorders of urodynamics due to intravesical hypertension and detrusor hypoxia are observed. The urodynamic disorders are known to contribute to the formation of the characteristic clinical picture associated with the hyper-reflexive urinary bladder dysfunction in the children characterized by the mandatory urination syndrome, pollakiuria, imperative urges, and mandatory urinary incontinence in the combination with enuresis. The treatment of urinary bladder dysfunction includes both behavioural and medication therapeutic modalities. The "golden standard" for the pharmacotherapy of neurogenic bladder dysfunction of the hyper reflexive type in the childhood is the use of M-cholinoblockers, such as oxybutynin. The popularity of the physiotherapeutic methods is attributable to their influence on the main links of pathogenesis, the absence of side effects, and the possibility of application in the children of the early age. The combined treatment of neurogenic bladder dysfunction includes the use of a wide range of physiotherapeutic methods the action of which is aimed at regulating the act of urination at all levels of innervation of the bladder, normalizing the tone of the muscles of the bladder, eliminating sphincter insufficiency, improving circulation and accelerating the maturation of the neuromuscular apparatus of the pelvic organs. At present, the natural and preformed methods of physiotherapy are finding the wide application for the management of neurogenic dysfunction of the bladder in the children in the conjunction with therapeutic physical exercises, massage, and the biological feedback (BFB) technique. PMID- 29388935 TI - [Physical therapy: prospects for the systematic development]. AB - The author presents a review of the experimental and clinical studies that have formed the basis of modern physiotherapy as a science, academic discipline, and clinical specialty. The analysis of the attributes of modern physical therapy has been undertaken with special reference to the definitions of the concepts, categories, classifications, therapeutic physical factors, and physical treatment methods that provide the basis of modern physical therapy. The directions of scientific and practical development of physiotherapy in the currently adopted system of organization of the medical care services in Russia are determined. The discussion presents arguments for the introduction of new concepts, terms, classifications, and treatment methods. The prerequisites for the formation of such notions and ideas, their composition and structure as well as the role of the therapeutic physical factors in the system of treatment and preventive measures are considered. The basic methodological approaches (both evidence-based and systematic) which are in line with modern physiotherapeutic research programs are substantiated. Special attention is given in the article to the currently adopted system of the training of physiotherapists accepting present-day ideas and practicing modern approaches in their practical work. The principal way to carry out this task under the present-day conditions is through education in a three-stage manner in accordance with the main categories of physical therapy. The current status and assessment of the use of the concepts of evidence-based and translational medicine in physiotherapy are discussed together with the prospects for its further systematic development and practical application. PMID- 29388936 TI - [The department of balneology and physical medicine of the S.M. Kirov's Military medical academy 75 years anniversary]. AB - The article highlights the history of the creation of the Department of balneology and physiotherapy at the S.M. Kirov Military-medical academy and the stages of its development. Employees of the Academy have a priority in the scientific substantiation of main principles of physical medicine and rehabilitation. They stood at the forefront of development of scientific schools and research institutions. The article presents the main achievements of the Department in academic, research and clinical work. PMID- 29388937 TI - Characterization of homodimer interfaces with cross-linking mass spectrometry and isotopically labeled proteins. AB - Cross-linking coupled with mass spectrometry (XL-MS) has emerged as a powerful strategy for the identification of protein-protein interactions, characterization of interaction regions, and obtainment of structural information on proteins and protein complexes. In XL-MS, proteins or complexes are covalently stabilized with cross-linkers and digested, followed by identification of the cross-linked peptides by tandem mass spectrometry (MS/MS). This provides spatial constraints that enable modeling of protein (complex) structures and regions of interaction. However, most XL-MS approaches are not capable of differentiating intramolecular from intermolecular links in multimeric complexes, and therefore they cannot be used to study homodimer interfaces. We have recently developed an approach that overcomes this limitation by stable isotope-labeling of one of the two monomers, thereby creating a homodimer with one 'light' and one 'heavy' monomer. Here, we describe a step-by-step protocol for stable isotope-labeling, followed by controlled denaturation and refolding in the presence of the wild-type protein. The resulting light-heavy dimers are cross-linked, digested, and analyzed by mass spectrometry. We show how to quantitatively analyze the corresponding data with SIM-XL, an XL-MS software with a module tailored toward the MS/MS data from homodimers. In addition, we provide a video tutorial of the data analysis with this protocol. This protocol can be performed in ~14 d, and requires basic biochemical and mass spectrometry skills. PMID- 29388938 TI - Genome editing of bread wheat using biolistic delivery of CRISPR/Cas9 in vitro transcripts or ribonucleoproteins. AB - This protocol is an extension to: Nat. Protoc. 9, 2395-2410 (2014); doi:10.1038/nprot.2014.157; published online 18 September 2014In recent years, CRISPR/Cas9 has emerged as a powerful tool for improving crop traits. Conventional plant genome editing mainly relies on plasmid-carrying cassettes delivered by Agrobacterium or particle bombardment. Here, we describe DNA-free editing of bread wheat by delivering in vitro transcripts (IVTs) or ribonucleoprotein complexes (RNPs) of CRISPR/Cas9 by particle bombardment. This protocol serves as an extension of our previously published protocol on genome editing in bread wheat using CRISPR/Cas9 plasmids delivered by particle bombardment. The methods we describe not only eliminate random integration of CRISPR/Cas9 into genomic DNA, but also reduce off-target effects. In this protocol extension article, we present detailed protocols for preparation of IVTs and RNPs; validation by PCR/restriction enzyme (RE) and next-generation sequencing; delivery by biolistics; and recovery of mutants and identification of mutants by pooling methods and Sanger sequencing. To use these protocols, researchers should have basic skills and experience in molecular biology and biolistic transformation. By using these protocols, plants edited without the use of any foreign DNA can be generated and identified within 9-11 weeks. PMID- 29388939 TI - Correction: Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. AB - In the published version of this paper, some of the columns in the last three rows of Table 3 were mistakenly transposed. The corrected table appears below. In col. 6 of the row for DNMT3A, "S3" was published in the original article. However, in the revised table for the corrigendum, it has been corrected to "S1". In col. 6 of the row for SON, "S3" was published in the original article. However, in the revised table for the corrigendum, it has been corrected to "S2". PMID- 29388940 TI - Anticipated responses of early adopter genetic specialists and nongenetic specialists to unsolicited genomic secondary findings. AB - PURPOSE: Secondary findings from genomic sequencing are becoming more common. We compared how health-care providers with and without specialized genetics training anticipated responding to different types of secondary findings. METHODS: Providers with genomic sequencing experience reviewed five secondary-findings reports and reported attitudes and potential clinical follow-up. Analyses compared genetic specialists and physicians without specialized genetics training, and examined how responses varied by secondary finding. RESULTS: Genetic specialists scored higher than other providers on four-point scales assessing understandings of reports (3.89 vs. 3.42, p = 0.0002), and lower on scales assessing reporting obligations (2.60 vs. 3.51, p < 0.0001) and burdens of responding (1.73 vs. 2.70, p < 0.0001). Nearly all attitudes differed between findings, although genetic specialists were more likely to assert that laboratories had no obligations when findings had less-established actionability (p < 0.0001 in interaction tests). The importance of reviewing personal and family histories, documenting findings, learning more about the variant, and recommending familial discussions also varied according to finding (all p < 0.0001). CONCLUSION: Genetic specialists felt better prepared to respond to secondary findings than providers without specialized genetics training, but perceived fewer obligations for laboratories to report them, and the two groups anticipated similar clinical responses. Findings may inform development of targeted education and support. PMID- 29388941 TI - Making pretest genomic counseling optional: lessons from the RAVE study. PMID- 29388942 TI - Correction: Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. AB - The abstract to this article contained errors in the Results and Conclusions section. The corrected sections are shown below. PMID- 29388944 TI - Considerations in healthcare reform for patients and families with genetic diseases: a statement of the American College of Medical Genetics and Genomics. AB - Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers, to help them provide quality medical genetic services. Adherence to these recommendations does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these recommendations. PMID- 29388943 TI - Correction: Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. AB - Zoe McDonald, BSc, was omitted from the list of article coauthors. Her name should have been included as the seventh author, following Clare Elizabeth Hunt. Her affiliation is Victorian Clinical Genetics Services, Parkville, Victoria, Australia. The authors regret the error. PMID- 29388945 TI - Reconsidering the duty to warn genetically at-risk relatives. AB - The duty to warn genetically at-risk relatives of patients is one of the most misunderstood legal and ethical issues affecting clinical genetics. The legal doctrines are often associated with three state appellate court cases beginning in the mid-1990s. Since the HIPAA Privacy Rule went into effect in 2003, the duty to warn must be accomplished by warning the patient of the genetic nature of a diagnosed disorder or genetic risk and the necessity of warning at-risk relatives. Health-care providers are neither required nor permitted to warn at risk relatives without the consent of their patients. Having warnings issued by the patient most closely aligns with traditional ethical principles and the interests of the parties. Physicians and other health-care providers can assist their patients by preparing jargon-free explanations of the genetic risk and offering consultation or referral services. In the future, the need for warnings is less likely to be triggered by diagnoses and more likely to be based on predictive information derived from genome sequencing and other technologies and data sources. PMID- 29388946 TI - Interpretation of genomic sequencing: variants should be considered uncertain until proven guilty. PMID- 29388948 TI - Clinical validity of phenotype-driven analysis software PhenoVar as a diagnostic aid for clinical geneticists in the interpretation of whole-exome sequencing data. AB - PURPOSE: We sought to determine the diagnostic yield of whole-exome sequencing (WES) combined with phenotype-driven analysis of variants in patients with suspected genetic disorders. METHODS: WES was performed on a cohort of 51 patients presenting dysmorphisms with or without neurodevelopmental disorders of undetermined etiology. For each patient, a clinical geneticist reviewed the phenotypes and used the phenotype-driven analysis software PhenoVar (http://phenovar.med.usherbrooke.ca/) to analyze WES variants. The prioritized list of potential diagnoses returned was reviewed by the clinical geneticist, who selected candidate variants to be confirmed by segregation analysis. Conventional analysis of the individual variants was performed in parallel. The resulting candidate variants were subsequently reviewed by the same geneticist, to identify any additional potential diagnoses. RESULTS: A molecular diagnosis was identified in 35% of the patients using the conventional analysis, and 17 of these 18 diagnoses were independently identified using PhenoVar. The only diagnosis initially missed by PhenoVar was rescued when the optional "minimal phenotypic cutoff" filter was omitted. PhenoVar reduced by half the number of potential diagnoses per patient compared with the conventional analysis. CONCLUSION: Phenotype-driven software prioritizes WES variants, provides an efficient diagnostic aid to clinical geneticists and laboratories, and should be incorporated in clinical practice. PMID- 29388947 TI - Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project. AB - PURPOSE: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. METHODS: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. RESULTS: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 degrees C or 65 degrees C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). CONCLUSION: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic. PMID- 29388949 TI - A literature review at genome scale: improving clinical variant assessment. AB - PURPOSE: Over 150,000 variants have been reported to cause Mendelian disease in the medical literature. It is still difficult to leverage this knowledge base in clinical practice, as many reports lack strong statistical evidence or may include false associations. Clinical laboratories assess whether these variants (along with newly observed variants that are adjacent to these published ones) underlie clinical disorders. METHODS: We investigated whether citation data including journal impact factor and the number of cited variants (NCV) in each gene with published disease associations-can be used to improve variant assessment. RESULTS: Surprisingly, we found that impact factor is not predictive of pathogenicity, but the NCV score for each gene can provide statistical support for prediction of pathogenicity. When this gene-level citation metric is combined with variant-level evolutionary conservation and structural features, classification accuracy reaches 89.5%. Further, variants identified in clinical exome sequencing cases have higher NCVs than do simulated rare variants from the Exome Aggregation Consortium database within the same set of genes and functional consequences (P < 2.22 * 10-16). CONCLUSION: Aggregate citation data can complement existing variant-based predictive algorithms, and can boost their performance without the need to access and review large numbers of papers. The NCV is a slow-growing metric of scientific knowledge about each gene's association with disease. PMID- 29388950 TI - Enhancing the potential of enantioselective organocatalysis with light. AB - Organocatalysis-catalysis mediated by small chiral organic molecules-is a powerful technology for enantioselective synthesis, and has extensive applications in traditional ionic, two-electron-pair reactivity domains. Recently, organocatalysis has been successfully combined with photochemical reactivity to unlock previously inaccessible reaction pathways, thereby creating new synthetic opportunities. Here we describe the historical context, scientific reasoning and landmark discoveries that were essential in expanding the functions of organocatalysis to include one-electron-mediated chemistry and excited-state reactivity. PMID- 29388951 TI - Early Middle Palaeolithic culture in India around 385-172 ka reframes Out of Africa models. AB - Luminescence dating at the stratified prehistoric site of Attirampakkam, India, has shown that processes signifying the end of the Acheulian culture and the emergence of a Middle Palaeolithic culture occurred at 385 +/- 64 thousand years ago (ka), much earlier than conventionally presumed for South Asia. The Middle Palaeolithic continued at Attirampakkam until 172 +/- 41 ka. Chronologies of Middle Palaeolithic technologies in regions distant from Africa and Europe are crucial for testing theories about the origins and early evolution of these cultures, and for understanding their association with modern humans or archaic hominins, their links with preceding Acheulian cultures and the spread of Levallois lithic technologies. The geographic location of India and its rich Middle Palaeolithic record are ideally suited to addressing these issues, but progress has been limited by the paucity of excavated sites and hominin fossils as well as by geochronological constraints. At Attirampakkam, the gradual disuse of bifaces, the predominance of small tools, the appearance of distinctive and diverse Levallois flake and point strategies, and the blade component all highlight a notable shift away from the preceding Acheulian large-flake technologies. These findings document a process of substantial behavioural change that occurred in India at 385 +/- 64 ka and establish its contemporaneity with similar processes recorded in Africa and Europe. This suggests complex interactions between local developments and ongoing global transformations. Together, these observations call for a re-evaluation of models that restrict the origins of Indian Middle Palaeolithic culture to the incidence of modern human dispersals after approximately 125 ka. PMID- 29388952 TI - Reconciling divergent trends and millennial variations in Holocene temperatures. AB - Cooling during most of the past two millennia has been widely recognized and has been inferred to be the dominant global temperature trend of the past 11,700 years (the Holocene epoch). However, long-term cooling has been difficult to reconcile with global forcing, and climate models consistently simulate long-term warming. The divergence between simulations and reconstructions emerges primarily for northern mid-latitudes, for which pronounced cooling has been inferred from marine and coastal records using multiple approaches. Here we show that temperatures reconstructed from sub-fossil pollen from 642 sites across North America and Europe closely match simulations, and that long-term warming, not cooling, defined the Holocene until around 2,000 years ago. The reconstructions indicate that evidence of long-term cooling was limited to North Atlantic records. Early Holocene temperatures on the continents were more than two degrees Celsius below those of the past two millennia, consistent with the simulated effects of remnant ice sheets in the climate model Community Climate System Model 3 (CCSM3). CCSM3 simulates increases in 'growing degree days'-a measure of the accumulated warmth above five degrees Celsius per year-of more than 300 kelvin days over the Holocene, consistent with inferences from the pollen data. It also simulates a decrease in mean summer temperatures of more than two degrees Celsius, which correlates with reconstructed marine trends and highlights the potential importance of the different subseasonal sensitivities of the records. Despite the differing trends, pollen- and marine-based reconstructions are correlated at millennial-to-centennial scales, probably in response to ice-sheet and meltwater dynamics, and to stochastic dynamics similar to the temperature variations produced by CCSM3. Although our results depend on a single source of palaeoclimatic data (pollen) and a single climate-model simulation, they reinforce the notion that climate models can adequately simulate climates for periods other than the present-day. They also demonstrate that amplified warming in recent decades increased temperatures above the mean of any century during the past 11,000 years. PMID- 29388953 TI - Generating carbyne equivalents with photoredox catalysis. AB - Carbon has the unique ability to bind four atoms and form stable tetravalent structures that are prevalent in nature. The lack of one or two valences leads to a set of species-carbocations, carbanions, radicals and carbenes-that is fundamental to our understanding of chemical reactivity. In contrast, the carbyne a monovalent carbon with three non-bonded electrons-is a relatively unexplored reactive intermediate; the design of reactions involving a carbyne is limited by challenges associated with controlling its extreme reactivity and the lack of efficient sources. Given the innate ability of carbynes to form three new covalent bonds sequentially, we anticipated that a catalytic method of generating carbynes or related stabilized species would allow what we term an 'assembly point' disconnection approach for the construction of chiral centres. Here we describe a catalytic strategy that generates diazomethyl radicals as direct equivalents of carbyne species using visible-light photoredox catalysis. The ability of these carbyne equivalents to induce site-selective carbon-hydrogen bond cleavage in aromatic rings enables a useful diazomethylation reaction, which underpins sequencing control for the late-stage assembly-point functionalization of medically relevant agents. Our strategy provides an efficient route to libraries of potentially bioactive molecules through the installation of tailored chiral centres at carbon-hydrogen bonds, while complementing current translational late-stage functionalization processes. Furthermore, we exploit the dual radical and carbene character of the generated carbyne equivalent in the direct transformation of abundant chemical feedstocks into valuable chiral molecules. PMID- 29388954 TI - Pollen weighs in on a climate conundrum. PMID- 29388955 TI - How warp-speed evolution is transforming ecology. PMID- 29388956 TI - Steps to the digital Silk Road. PMID- 29388957 TI - Israeli fossils are the oldest modern humans ever found outside of Africa. PMID- 29388958 TI - A bioinformatics workshop in a box. PMID- 29388959 TI - A non-tailed twist in the viral tale. PMID- 29388960 TI - The scientist who predicted ice-sheet collapse - 50 years ago. PMID- 29388961 TI - Why science blogging still matters. PMID- 29388962 TI - The serendipity test. PMID- 29388963 TI - Don't reject evidence from CFS therapies. PMID- 29388964 TI - Nature journals tighten rules on non-financial conflicts. PMID- 29388965 TI - Include mentoring skills in hiring and promotion criteria. PMID- 29388966 TI - As Cape Town water crisis deepens, scientists prepare for 'Day Zero'. PMID- 29388967 TI - Reactive carbon species tamed for synthesis. PMID- 29388968 TI - Data visualization tools drive interactivity and reproducibility in online publishing. PMID- 29388969 TI - A rude awakening from tumour cells. PMID- 29388970 TI - Take peer pressure out of peer review. PMID- 29388971 TI - Gender bias goes away when grant reviewers focus on the science. PMID- 29388974 TI - Owls for peace: how conservation science is reaching across borders in the Middle East. PMID- 29388975 TI - Re-evaluate yellow fever risk in Asia-Pacific region. PMID- 29388977 TI - The struggle to do no harm. PMID- 29388976 TI - Unique oil spill in East China Sea frustrates scientists. PMID- 29388978 TI - Make your science count. PMID- 29388979 TI - Anti-Darwin comments in India outrage scientists. PMID- 29388980 TI - Regeneration writ large. PMID- 29388983 TI - Doomsday approaches, Moon prize cancelled and sci-fi icon dies. PMID- 29388982 TI - Dispense with redundant P values. PMID- 29388984 TI - Better mentoring stands to boost junior researchers' mental health. PMID- 29388985 TI - The dark side of light. PMID- 29388987 TI - Pamela Sklar (1959-2017). PMID- 29388988 TI - Effect of GCAA stabilizing loops on three- and four-way intramolecular junctions. AB - Tetraloops are a common way of changing the melting behavior of a DNA or RNA structure without changing the sequence of the stem. Because of the ubiquitous nature of tetraloops, our goal is to understand the effect a GCAA tetraloop, which belongs to the GNRA family of tetraloops, has on the unfolding thermodynamics of intramolecular junctions. Specifically, we have described the melting behavior of intramolecular three-way and four-way junctions where a T5 loop has been replaced with a GCAA tetraloops in different positions. Their thermodynamic profiles, including DeltanNa+ and DeltanW, were analyzed based on the position of the tetraloop. We obtained between -16.7 and -27.5 kcal mol-1 for all junctions studied. The experimental data indicates the influence of the GCAA tetraloop is primarily dictated by the native unfolding of the junction; if the tetraloop is placed on a stem that unfolds as a single domain when the tetraloop is not present, it will unfold as a single domain when the tetraloop is present but with a higher thermal stability. Conversely, if the tetraloop is placed on a stem which unfolds cooperatively with other stems when the tetraloop is not present, the tetraloop will increase the thermal stability of all the stems in the melting domain. The oligonucleotide structure and not the tetraloop itself affects ion uptake; three-way junctions do not gain an increase in ion uptake, but four-way junctions do. This is not the case for water immobilization, where the position of the tetraloop dictates the amount of water immobilized. PMID- 29388989 TI - Direct oxidative isoperfluoropropylation of terminal alkenes via hexafluoropropylene (HFP) and silver fluoride. AB - A copper-mediated oxidative isoperfluoropropylation of unactivated terminal alkenes with commercially available hexafluoropropylene (HFP) has been developed. With operational simplicity of the procedure and broad substrate applicability, this strategy provides a general and straightforward way for the construction of C(sp3)-C3F7-i bonds. A variety of allylic isoperfluoropropylated compounds have been efficiently synthesized using this strategy. PMID- 29388991 TI - In situ formation of large pore silica-MnO2 nanocomposites with H+/H2O2 sensitivity for O2-elevated photodynamic therapy and potential MR imaging. AB - A cancer cell-specific, endogenous H+/H2O2-activated, and O2 self-sufficient nanocomposite is engineered and characterized. Such NPs, with good biocompatibility and rapid response to intracellular H+/H2O2, have demonstrated improved therapeutic effects in targeted cancer cells and activated MR signals in vitro, providing a promising strategy for effective PDT against tumor hypoxia. PMID- 29388992 TI - Modifying bis(triflimide) ionic liquids by dissolving early transition metal carbamates. AB - The authors report the first modification of ionic liquids with metal carbamates. A selection of homoleptic N,N-dialkylcarbamates of group 4 and 5 metals, M(O2CNR2)n, were dissolved in bis(trifluoromethylsulfonyl)imide-based ionic liquids, i.e. [bmim][Tf2N] and [P(oct)4][Tf2N], at 293 K. The resulting solutions were characterized by means of IR, UV and NMR spectroscopy, and the data were compared to those of the respective metal compounds. Notably, the dissolution process did not proceed with the release of any of the original carbamato ligands, thus preserving the intact coordination frame around the metal centre. The solvation process of Ti(O2CNiPr2)4, as a model species, in [bmim][Tf2N] was rationalized by DFT calculations. As a comparative study, solutions of NbF5 and MCl5 (M = Nb, Ta) in [bmim][Tf2N] were also investigated, revealing the possible occurrence of solvent anion coordination to the metal centres. PMID- 29388990 TI - The inverse electron-demand Diels-Alder reaction as a new methodology for the synthesis of 225Ac-labelled radioimmunoconjugates. AB - The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans cyclooctene (TCO) facilitates the efficient radiosynthesis of 225Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings. PMID- 29388993 TI - Emerging investigator series: methylmercury speciation and dimethylmercury production in sulfidic solutions. AB - Alkylated mercury species (monomethylmercury, MeHg, and dimethylmercury, DMeHg) exhibit significant bioaccumulation, and pose significant risks to ecosystems and human health. Although decades of research have been devoted to understanding MeHg formation and degradation, little is known about the DMeHg formation in aquatic systems. Here, we combine complementary experimental and computational approaches to examine MeHg speciation and DMeHg formation in sulfidic aqueous solutions, with an emphasis on the formation and decomposition of the binuclear bis(methylmercuric(ii)) sulfide complex (CH3Hg)2S. Experimental data indicate that the reaction 2CH3Hg+ + HS- ? (CH3Hg)2S + H+ has a log K = 26.0 +/- 0.2. Thus, the binuclear (CH3Hg)2S complex is likely to be the dominant MeHg species under high MeHg concentrations typically used in experimental investigations of MeHg degradation by sulfate-reducing bacteria (SRB). Our finding of a significant abiotic removal mechanism for MeHg in sulfidic solutions through the formation of relatively insoluble (CH3Hg)2S suggests careful reexamination of reported "oxidative demethylation" of MeHg by SRB and perhaps other obligate anaerobes. We provide evidence for slow decomposition of (CH3Hg)2S to DMeHg and HgS, with a first-order rate constant k = 1.5 +/- 0.4 * 10-6 h-1. Quantum chemical calculations suggest that the reaction proceeds by a novel mechanism involving rearrangement of the (CH3Hg)2S complex facilitated by strong Hg-Hg interactions that activate a methyl group for intramolecular transfer. Predictions of DMeHg formation rates under a variety of field and laboratory conditions indicate that this pathway for DMeHg formation will be significant in laboratory experiments utilizing high MeHg concentrations, favoring (CH3Hg)2S formation. In natural systems with relatively high MeHg/[H2S]T ratios (the oxic/anoxic interface, for example), DMeHg production may be observed, and warrants further investigation. PMID- 29388995 TI - Enantioselectivity in CPA-catalyzed Friedel-Crafts reaction of indole and N tosylimines: a challenge for guiding models. AB - Qualitative reaction models or predicting guides are a very useful outcome of theoretical investigations of organocatalytic reaction mechanism that allow forecasting of the degree and sense of the enantioselectivity of reactions involving novel substrates. However, application of these models can be unexpectedly challenging in reactions affected by a large number of conformations and potential control of the enantioselectivity by different reaction steps. The QM/MM study of the Friedel-Crafts reaction between indole and the N-tosylimide of benzaldehyde catalysed by different CPA reveals that the reaction consists of two CPA-assisted steps: the addition of the two reagents to yield a Wheland intermediate, and its re-aromatization. The relevance of the second step depends on the catalyst: it changes the sense of the expected stereoselectivity for a BINOP-derived CPA but is irrelevant in the reaction catalysed by a VAPOL-derived imidodiphosphoric acid catalyst. Although the relative energies of the TSs can be rationalized considering the steric interactions with the catalyst, the possibility of additional H-bonds, or the relative stability of the conformation of the reagents, predicting the enantioselectivity is not possible using qualitative guides. PMID- 29388994 TI - QM/MM studies on the excited-state relaxation mechanism of a semisynthetic dTPT3 base. AB - Semisynthetic alphabets can potentially increase the genetic information stored in DNA through the formation of unusual base pairs. Recent experiments have shown that near-visible-light irradiation of the dTPT3 chromophore could lead to the formation of a reactive triplet state and of singlet oxygen in high quantum yields. However, the detailed excited-state relaxation paths that populate the lowest triplet state are unclear. Herein, we have for the first time employed the QM(MS-CASPT2//CASSCF)/MM method to explore the spectroscopic properties and excited-state relaxation mechanism of the aqueous dTPT3 chromophore. On the basis of the results, we have found that (1) the S2(1pipi*) state of dTPT3 is the initially populated excited singlet state upon near-visible light irradiation; and (2) there are two efficient relaxation pathways to populate the lowest triplet state, i.e. T1(3pipi*). In the first one, the S2(1pipi*) system first decays to the S1(1npi*) state near the S2/S1 conical intersection, which is followed by an efficient S1 -> T1 intersystem crossing process at the S1/T1 crossing point; in the second one, an efficient S2 -> T2 intersystem crossing takes place first, and then, the T2(3npi*) system hops to the T1(3pipi*) state through an internal conversion process at the T2/T1 conical intersection. Moreover, an S2/S1/T2 intersection region is found to play a vital role in the excited-state relaxation. These new mechanistic insights help in understanding the photophysics and photochemistry of unusual base pairs. PMID- 29388996 TI - Effect of point mutations on the ultrafast photo-isomerization of Anabaena sensory rhodopsin. AB - Anabaena sensory rhodopsin (ASR) is a particular microbial retinal protein for which light-adaptation leads to the ability to bind both the all-trans, 15-anti (AT) and the 13-cis, 15-syn (13C) isomers of the protonated Schiff base of retinal (PSBR). In the context of obtaining insight into the mechanisms by which retinal proteins catalyse the PSBR photo-isomerization reaction, ASR is a model system allowing to study, within the same protein, the protein-PSBR interactions for two different PSBR conformers at the same time. A detailed analysis of the vibrational spectra of AT and 13C, and their photo-products in wild-type ASR obtained through femtosecond (pump-) four-wave-mixing is reported for the first time, and compared to bacterio- and channelrhodopsin. As part of an extensive study of ASR mutants with blue-shifted absorption spectra, we present here a detailed computational analysis of the origin of the mutation-induced blue-shift of the absorption spectra, and identify electrostatic interactions as dominating steric effects that would entail a red-shift. The excited state lifetimes and isomerization reaction times (IRT) for the three mutants V112N, W76F, and L83Q are studied experimentally by femtosecond broadband transient absorption spectroscopy. Interestingly, in all three mutants, isomerization is accelerated for AT with respect to wild-type ASR, and this the more, the shorter the wavelength of maximum absorption. On the contrary, the 13C photo-reaction is slightly slowed down, leading to an inversion of the ESLs of AT and 13C, with respect to wt-ASR, in the blue-most absorbing mutant L83Q. Possible mechanisms for these mutation effects, and their steric and electrostatic origins are discussed. PMID- 29388997 TI - Enhanced adhesion of ZnO nanowires during in situ scanning electron microscope peeling. AB - The interfacial adhesion behaviour of a ZnO nanowire-Si substrate system is investigated using an in situ scanning electron microscope (SEM) mechanical peeling technique. The peel front of a nanowire advances via stick-slip events, and an equilibrium between the driving and resistant force to separation occurs immediately prior to a slip event. The interfacial adhesion energy is one order higher than that predicted theoretically by van der Waals interactions. The enhanced adhesion is primarily attributed to chemical and electrostatic interfacial interactions induced by electron irradiation. This work demonstrates that the operating environment of a nanoscale system could dramatically influence its adhesion behaviour. These findings are expected to have significant implications for interpreting the adhesion behaviour exhibited by a 1D nanostructure-substrate system when applying different testing methodologies, and for the fabrication of future NEMS devices. PMID- 29388998 TI - Solid-phase nucleation free-energy barriers in truncated cubes: interplay of localized orientational order and facet alignment. AB - The nucleation of ordered phases from the bulk isotropic phase of octahedron-like particles has been studied via Monte Carlo simulations and umbrella sampling. In particular, selected shapes that form ordered (plastic) phases with various symmetries (cubic and tetragonal) are chosen to unveil trends in the free-energy barrier heights (DeltaG*'s) associated with disorder to order transitions. The shapes studied in this work have truncation parameter (s) values of 0.58, 0.75, 0.8 and 1. The case of octahedra (s = 1.0) is studied to provide a counter example where the isotropic phase nucleates directly into a (Minkowski) crystal phase rather than a rotator phase. The simulated DeltaG*'s for these systems are compared with those previously reported for hard spheres and truncated cubes with s = 0.5 (cuboctahedra, CO) and s = 2/3 (truncated octahedra, TO). The comparison shows that, for comparable degrees of supersaturation, all rotator phases nucleate with smaller DeltaG*'s than that of the hard sphere crystal, whereas the octahedral crystal nucleates with a larger DeltaG*. Our analysis of near-critical translationally ordered nuclei of octahedra shows a strong bias towards an orientational alignment which is incompatible with the tendency to form facet-to facet contacts in the disordered phase, thus creating an additional entropic penalty for crystallization. For rotator phases of octahedra-like particles, we observe that the strength of the localized orientational order correlates inversely with DeltaG*. We also observe that for s > 0.66 shapes and similar to octahedra, configurations with high facet alignment do not favor high orientational order, and thus DeltaG*'s increase with truncation. PMID- 29388999 TI - Wettability control of droplet durotaxis. AB - Durotaxis refers to cell motion directed by stiffness gradients of an underlying substrate. Recent work has shown that droplets also move spontaneously along stiffness gradients through a process reminiscent of durotaxis. Wetting droplets, however, move toward softer substrates, an observation seemingly at odds with cell motion. Here, we extend our understanding of this phenomenon, and show that wettability of the substrate plays a critical role: while wetting droplets move in the direction of lower stiffness, nonwetting liquids reverse droplet durotaxis. Our numerical experiments also reveal that Laplace pressure can be used to determine the direction of motion of liquid slugs in confined environments. Our results suggest new ways of controlling droplet dynamics at small scales, which can open the door to enhanced bubble and droplet logic in microfluidic platforms. PMID- 29389000 TI - Imido-P(v) trianion supported enantiopure neutral tetrahedral Pd(ii) cages. AB - Charge-neutral chiral hosts are attractive due to their ability to recognize a wide range of guest functionalities and support enantioselective processes. However, reports on such charge-neutral cages are very scarce in the literature. Here, we report an enantiomeric pair of tetrahedral Pd(ii) cages built from chiral tris(imido)phosphate trianions and oxalate linkers, which exhibit enantioselective separation capabilities for epichlorohydrin, beta-butyrolactone, and 3-methyl- and 3-ethyl cyclopentanone. PMID- 29389003 TI - Performance tuning of giant electrorheological fluids by interfacial tailoring. AB - Giant electrorheological (GER) fluids exhibit a high yield stress due to saturation surface polarization from contact between neighboring particles. To fine-tune the competitive performance of GER fluids, we modified the surface of the GER particles by adding silicone polyether, which strongly adsorbed at the solid-liquid interface and significantly influenced the dispersion, GER effect and electrical current density of the GER fluid. We discovered that a small amount of silicone polyether could improve the dispersion and reduce the electrical current density of the fluid. However, the steric hindrance effect suppressed the GER performance. Ultimately, an optimal solution was obtained by making tradeoffs among the dispersion, current density, viscosity, anti sedimentation and ER effect. These tradeoffs were effective because they provided repetitive stability and wide opportunities for industrial usage. PMID- 29389007 TI - Eumelanin-Fe3O4 hybrid nanoparticles for enhanced MR/PA imaging-assisted local photothermolysis. AB - In this work, we report on biodegradable eumelanin-Fe3O4 hybrid nanoparticles (euMel-Fe3O4 NPs) for multiple imaging-assisted local photothermolysis. The euMel Fe3O4 NPs are rationally prepared via a facile one-step co-precipitation method in the aqueous phase in the presence of eumelanin. The obtained NPs exhibited high stability and aqueous dispersity. euMel-Fe3O4 NPs could provide T2-weighted magnetic resonance (MR) and photoacoustic (PA) imaging contrast enhancement prior to the treatment, due to their high r2 relaxivity that was determined to be 245.88 mM-1 s-1 (a value higher than those for other commercially available iron oxide NPs) and good PA signal intensity. Besides, with effective NIR absorbance, the euMel-Fe3O4 NPs promoted an effective photothermolysis treatment in an experimental mouse model of cancer. Cytotoxicity and in vivo histological examination demonstrated no appreciable toxicity. Our work suggests that euMel Fe3O4 NPs could be proposed as a potential class of theranostic nanoplatform with multiple imaging modalities for cancer therapy. PMID- 29389009 TI - Reply. PMID- 29389008 TI - The unique evolution of the carbohydrate-binding module CBM20 in laforin. AB - Laforin catalyses glycogen dephosphorylation. Mutations in its gene result in Lafora disease, a fatal progressive myoclonus epilepsy, the hallmark being water insoluble, hyperphosphorylated carbohydrate inclusions called Lafora bodies. Human laforin consists of an N-terminal carbohydrate-binding module (CBM) from family CBM20 and a C-terminal dual-specificity phosphatase domain. Laforin is conserved in all vertebrates, some basal metazoans and a small group of protozoans. The present in silico study defines the evolutionary relationships among the CBM20s of laforin with an emphasis on newly identified laforin orthologues. The study reveals putative laforin orthologues in Trichinella, a parasitic nematode, and identifies two sequence inserts in the CBM20 of laforin from parasitic coccidia. Finally, we identify that the putative laforin orthologues from some protozoa and algae possess more than one CBM20. PMID- 29389010 TI - Changes in bone mineral density and bone turnover markers during treatment with teriparatide in pregnancy- and lactation-associated osteoporosis. AB - CONTEXT: Teriparatide (TPTD) therapy has been proposed as a potential treatment strategy in severe cases of pregnancy- and lactation-associated osteoporosis (PLO) characterized by the occurrence of fragility fractures in the third trimester or early postpartum. OBJECTIVE: To investigate the changes in bone mineral density (BMD) and bone turnover markers in patients with PLO with and without TPTD treatment. DESIGN: Retrospective cohort study. PATIENTS: Thirty-two patients with PLO who presented with multiple vertebral fractures to a tertiary institution between 2007 and 2015 were included. MEASUREMENTS: Changes in BMD at the lumbar spine (LSBMD) and proximal femur after 12 months of daily subcutaneous injections of 20 MUg TPTD (n = 27) were assessed. Subjects who rejected the TPTD treatment were used as controls (n = 5). RESULTS: LSBMD increased in both subjects treated with TPTD and controls, with greater increases in the TPTD group (15.5 +/- 6.6% vs 7.5 +/- 7.1%, P = .020) after adjustment for age and baseline LSBMD. During follow-up, serum levels of osteocalcin (OCN) and C-telopeptide of type I collagen (CTX) increased significantly in the TPTD group. In multivariate linear regression models, TPTD treatment (adjusted beta = 7.92, P = .032) and younger age (adjusted beta = 1.06, P = .046), but not baseline LSBMD, body mass index, serum OCN level and CTX level, were independently associated with greater increases in LSBMD. CONCLUSIONS: In patients with PLO, LSBMD at 12 months increased in both the TPTD-treated and control groups. TPTD treatment and younger age were associated with greater increases in LSMBD irrespective of baseline LSBMD. PMID- 29389012 TI - Consequences of Long-Term Oral Bisphosphonate Treatment. PMID- 29389013 TI - Texture analysis of cardiac cine magnetic resonance imaging to detect nonviable segments in patients with chronic myocardial infarction. AB - PURPOSE: To investigate the ability of texture analysis to differentiate between infarcted nonviable, viable, and remote segments on cardiac cine magnetic resonance imaging (MRI). METHODS: This retrospective study included 50 patients suffering chronic myocardial infarction. The data were randomly split into training (30 patients) and testing (20 patients) sets. The left ventricular myocardium was segmented according to the 17-segment model in both cine and late gadolinium enhancement (LGE) MRI. Infarcted myocardium regions were identified on LGE in short-axis views. Nonviable segments were identified as those showing LGE >= 50%, and viable segments those showing 0 < LGE < 50% transmural extension. Features derived from five texture analysis methods were extracted from the segments on cine images. A support vector machine (SVM) classifier was trained with different combination of texture features to obtain a model that provided optimal classification performance. RESULTS: The best classification on testing set was achieved with local binary patterns features using a 2D + t approach, in which the features are computed by including information of the time dimension available in cine sequences. The best overall area under the receiver operating characteristic curve (AUC) were: 0.849, sensitivity of 92% to detect nonviable segments, 72% to detect viable segments, and 85% to detect remote segments. CONCLUSION: Nonviable segments can be detected on cine MRI using texture analysis and this may be used as hypothesis for future research aiming to detect the infarcted myocardium by means of a gadolinium-free approach. PMID- 29389011 TI - Reprogramming cell fate with artificial transcription factors. AB - Transcription factors (TFs) reprogram cell states by exerting control over gene regulatory networks and the epigenetic landscape of a cell. Artificial transcription factors (ATFs) are designer regulatory proteins comprised of modular units that can be customized to overcome challenges faced by natural TFs in establishing and maintaining desired cell states. Decades of research on DNA binding proteins and synthetic molecules has provided a molecular toolkit for ATF design and the construction of genome-scale libraries of ATFs capable of phenotypic manipulation and reprogramming of cell states. Here, we compare the unique strengths and limitations of different ATF platforms, highlight the advantages of cooperative assembly, and present the potential of ATF libraries in revealing gene regulatory networks that govern cell fate choices. PMID- 29389014 TI - Occupational asthma risk from exposures to toluene diisocyanate: A review and risk assessment. AB - BACKGROUND: Toluene Diisocyanate (TDI) is a known respiratory sensitizer linked to occupational asthma (OA). To better manage worker risks, an appropriate characterization of the TDI-OA dose-risk relationship is needed. METHODS: The literature was reviewed for data suitable for dose-response modeling. Previous study data were fit to models to derive prospective occupational exposure limits (OELs), using benchmark dose (BMD) and low-dose extrapolation approaches. RESULTS: Data on eight TDI-exposed populations were suitable for analysis. There were 118 OA cases in a population contributing 13 590 person-years. The BMD-based OEL was 0.4 ppb. The OEL based on low-dose extrapolation to working lifetime extra risk of 1/1000 was 0.3 ppb. CONCLUSIONS: This study synthesized epidemiologic data to characterize the TDI-OA dose-risk relationship. This approach yielded prospective OEL estimates below recent recommendations by the American Conference of Governmental Industrial Hygienists, but given significant study limitations, this should be interpreted with caution. Confirmatory research is needed. PMID- 29389015 TI - Foster care promotes adaptive functioning in early adolescence among children who experienced severe, early deprivation. AB - BACKGROUND: Experiences in early life lay the foundation for later development and functioning. Severe psychosocial deprivation, as experienced by children in early institutional care, constitutes an adverse experience with long-term negative consequences. The Bucharest Early Intervention Project sought to examine the effects of foster care as an alternative to institutional care for abandoned infants in Romanian institutions. METHODS: At a mean age of 22 months, institutionalized children were randomized to foster care or care as usual. At age 12 years, we followed-up with 98 of these children (50 randomized to foster care), as well as assessed 49 never institutionalized comparison children. Adaptive functioning was assessed across seven domains-mental health, physical health, substance use, risk-taking behavior, family relations, peer relations, and academic performance. Children at or above the threshold for adaptive functioning in at least six of seven domains were classified as having overall adaptive functioning in early adolescence. RESULTS: Among all children who had experienced severe early deprivation, 40% exhibited adaptive functioning. Children randomized to foster care were significantly more likely to exhibit adaptive functioning at age 12 years than children in the care as usual condition (56% vs. 23%). In support of external validity, children who met the threshold for adaptive functioning at age 12 years had higher IQs and were more physiologically responsive to stress. Among children randomized to foster care, children placed prior to age 20 months were more likely to meet the threshold for adaptive functioning than those placed after this age (79% vs. 46%). CONCLUSIONS: This study provides causal evidence that placing children into families following severe deprivation increases the likelihood of adaptive functioning in early adolescence. PMID- 29389016 TI - Complement factor H protects mice from ischemic acute kidney injury but is not critical for controlling complement activation by glomerular IgM. AB - Natural IgM binds to glomerular epitopes in several progressive kidney diseases. Previous work has shown that IgM also binds within the glomerulus after ischemia/reperfusion (I/R) but does not fully activate the complement system. Factor H is a circulating complement regulatory protein, and congenital or acquired deficiency of factor H is a strong risk factor for several types of kidney disease. We hypothesized that factor H controls complement activation by IgM in the kidney after I/R, and that heterozygous factor H deficiency would permit IgM-mediated complement activation and injury at this location. We found that mice with targeted heterozygous deletion of the gene for factor H developed more severe kidney injury after I/R than wild-type controls, as expected, but that complement activation within the glomeruli remained well controlled. Furthermore, mice that are unable to generate soluble IgM were not protected from renal I/R, even in the setting of heterozygous factor H deficiency. These results demonstrate that factor H is important for limiting injury in the kidney after I/R, but it is not critical for controlling complement activation by immunoglobulin within the glomerulus in this setting. IgM binds to glomerular epitopes after I/R, but it is not a significant source of injury. PMID- 29389017 TI - A dedicated breast-PET/CT scanner: Evaluation of basic performance characteristics. AB - PURPOSE: Application of advanced imaging techniques, such as PET and x ray CT, can potentially improve detection of breast cancer. Unfortunately, both modalities have challenges in the detection of some lesions. The combination of the two techniques, however, could potentially lead to an overall improvement in diagnostic breast imaging. The purpose of this investigation is to test the basic performance of a new dedicated breast-PET/CT. METHODS: The PET component consists of a rotating pair of detectors. Its performance was evaluated using the NEMA NU4 2008 protocols. The CT component utilizes a pulsed x ray source and flat panel detector mounted on the same gantry as the PET scanner. Its performance was assessed using specialized phantoms. The radiation dose to a breast during CT imaging was explored by the measurement of free-in-air kerma and air kerma measured at the center of a 16 cm-diameter PMMA cylinder. Finally, the combined capabilities of the system were demonstrated by imaging of a micro-hot-rod phantom. RESULTS: Overall, performance of the PET component is comparable to many pre-clinical and other dedicated breast-PET scanners. Its spatial resolution is 2.2 mm, 5 mm from the center of the scanner using images created with the single sliced-filtered-backprojection algorithm. Peak NECR is 24.6 kcps; peak sensitivity is 1.36%; the scatter fraction is 27%. Spatial resolution of the CT scanner is 1.1 lp/mm at 10% MTF. The free-in-air kerma is 2.33 mGy, while the PMMA-air kerma is 1.24 mGy. Finally, combined imaging of a micro-hot-rod phantom illustrated the potential utility of the dual-modality images produced by the system. CONCLUSION: The basic performance characteristics of a new dedicated breast-PET/CT scanner are good, demonstrating that its performance is similar to current dedicated PET and CT scanners. The potential value of this system is the capability to produce combined duality-modality images that could improve detection of breast disease. The next stage in development of this system is testing with more advanced phantoms and human subjects. PMID- 29389018 TI - Top-down and bottom-up characterization of nitrated birch pollen allergen Bet v 1a with CZE hyphenated to an Orbitrap mass spectrometer. AB - Tyrosine (Tyr) residues of the major pollen allergen of birch Betula verrucosa, Bet v 1a, were nitrated by peroxynitrite. This modification enhances the allergenicity. Modified tyrosines were identified by analyzing intact allergen variants in combination with top-down and bottom-up approaches. Therefore, a laboratory-built sheath-liquid assisted ESI interface was applied for hyphenation of CE to an Orbitrap mass spectrometer to localize individual nitration sites. The major focus was on identification of primary nitration sites. The top-down approach unambiguously identified Tyr 5 as the most prominent modification site. Fragments from the allergen core and the C-terminal part carried up to three potential nitration sites, respectively. Thus, a bottom-up approach with tryptic digest was used as a complementary strategy which allowed for the unambiguous localization of nitration sites within the respective peptides. Nitration propensity for individual Tyr residues was addressed by comparison of MS signals of nitrated peptides relative to all cognates of homolog primary sequence. Combined data identified surface exposed Tyr 5 and Tyr 66 as major nitration sites followed by less accessible Tyr 158 whereas Tyr 81, 83 and 150 possess a lower nitration tendency and are apparently modified in variants with higher nitration levels. PMID- 29389021 TI - The evolution of HIV-1 entry phenotypes as a guide to changing target cells. AB - Through a twist of fate the most common form of HIV-1, as defined by entry phenotype, was not appreciated until recently. The entry phenotype is closely linked to the target cell and thus to virus-host interactions and pathogenesis. The most abundant form of HIV-1 uses CCR5 as the coreceptor and requires a high density of CD4 for efficient entry, defining its target cell as the CD4+ memory T cell. This is the transmitted form of the virus, the form that is found in the blood, and the form that rebounds from the latent reservoir. When CD4+/CCR5+ T cells become limiting the virus evolves to use alternative target cells to support viral replication. In the CNS, the virus can evolve to use a cell that displays only a low density of CD4, while maintaining the use of CCR5 as the coreceptor. When this evolutionary variant evolves, it must be sustaining its replication in either macrophages or microglial cells, which display only a low density of CD4 relative to that on T cells. In the blood and lymphoid system, the major switch late in disease is from T cells expressing CD4 and CCR5 to T cells expressing CD4 and CXCR4, with a change in coreceptor specificity. Thus the virus responds in two different ways to different environments when its preferred target cell becomes limiting. PMID- 29389020 TI - CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses. AB - Neonatal CD71+ erythroid cells are thought to have immunosuppressive functions. Recently, we demonstrated that CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm labor (PTL) are reduced to levels similar to those of term neonates; yet, their functional properties are unknown. Herein, we investigated the functionality of CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm or term labor. CD71+ erythroid cells from neonates born to women who underwent PTL displayed a similar mRNA profile to that of those from term neonates. The direct contact between preterm or term neonatal CD71+ erythroid cells and maternal mononuclear immune cells, but not soluble products from these cells, induced the release of proinflammatory cytokines and a reduction in the release of TGF-beta. Moreover, PTL-derived neonatal CD71+ erythroid cells (1) modestly altered CD8+ T cell activation; (2) inhibited conventional CD4+ and CD8+ T-cell expansion; (3) suppressed the expansion of CD8+ regulatory T cells; (4) regulated cytokine responses mounted by myeloid cells in the presence of a microbial product; and (5) indirectly modulated T-cell cytokine responses. In conclusion, neonatal CD71+ erythroid cells regulate neonatal T-cell and myeloid responses and their direct contact with maternal mononuclear cells induces a proinflammatory response. These findings provide insight into the biology of neonatal CD71+ erythroid cells during the physiologic and pathologic processes of labor. PMID- 29389019 TI - Modulating inflammation through the negative regulation of NF-kappaB signaling. AB - Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-kappaB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-kappaB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-kappaB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies. PMID- 29389023 TI - Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain. AB - Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes throughout life is coming to light. The "senescence machinery" has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the beneficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases. PMID- 29389022 TI - Age- and CGG repeat-related slowing of manual movement in fragile X carriers: A prodrome of fragile X-associated tremor ataxia syndrome? AB - BACKGROUND: Fragile X premutation carriers are at increased risk for fragile X associated tremor ataxia syndrome (FXTAS), but to date we know little about prediction of onset and rate of progression and even less about treatment of this neurodegenerative disease. Thus, the longitudinal study of carriers, and the identification of potential biomarkers and prodromal states, is essential. Here we present results of baseline assessments from an ongoing longitudinal project. METHODS: The cohort consisted of 73 men, 48 with the fragile X mental retardation 1 (FMR1) premutation (55-200 cytosine-cytosine-guanine or CGG repeats) and 25 well-matched controls (< 40 repeats) aged between 40 and 75 years. At enrollment, none met criteria for FXTAS or had any clinically significant tremor or ataxia by blinded neurological examination. The battery consisted of measures of visual memory, spatial working memory, response inhibition, motor speed and control, planning and problem solving, sustained attention, and a standardized movement disorder evaluation. RESULTS: Contrary to expectations, there were no significant differences between premutation carriers and controls on any measure of executive function. However, the premutation carriers had significantly longer manual movement and reaction times than controls, and the significant interaction between CGG repeat and age revealed the slowest movement times among older carriers with higher CGG repeat alleles. A subset of premutation carriers had marginally lower scores on the ataxia evaluation, and they performed no differently from controls on the parkinsonism assessment. CONCLUSION: Early developing cerebellar or fronto-motor tract white matter changes, previously documented in MRI studies, may underlie motor slowing that occurs before clinically observable neurological symptoms associated with FXTAS. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29389024 TI - Factors affecting growth from heat-treated spores of non-proteolytic Clostridium botulinum. AB - Heat treatment of spores of non-proteolytic Clostridium botulinum at 85 degrees C for 120 min followed by enumeration of survivors on a medium containing lysozyme resulted in a 4.1 and 4.8 decimal reduction in numbers of spores of strains 17B (type B) and Beluga (type E), respectively. Only a small proportion of heated spores formed colonies on medium containing lysozyme; this proportion could be increased by treatments designed to increase the permeability of heated spores. The results indicate that the germination system in spores of non-proteolytic Cl. botulinum was destroyed by heating, that lysozyme could replace this germination system, and that treatments that increased the permeability of the spore coat could increase the proportion of heated spores that germinated on medium containing lysozyme. These results are important in relation to the assessment of heat-treatments required to reduce the risk of survival and growth of non proteolytic Clostridium botulinum in processed (pasteurized) refrigerated foods for extended storage. PMID- 29389025 TI - Potential of solid state fermentation for production of ergot alkaloids. AB - Production of total ergot alkaloids by Claviceps fusiformis in solid state fermentation was 3.9 times higher compared to that in submerged fermentation. Production was equal in the case of Claviceps purpurea but the spectra of alkaloids were advantageous with the use of solid state fermentation. The data establish potential of solid state fermentation which was not explored earlier for production of ergot alkaloids. PMID- 29389026 TI - The use of the bacteriocin, nisin, as a preservative in pasteurized liquid whole egg. AB - Nisin used at a level of 5 mg/1 resulted in a significant increase in refrigerated shelf life of pasteurized liquid whole egg from between 6-11 d to 17 20 d. In the first of two trials, nisin also protected the liquid egg from growth of Bacillus cereus. Bacillus cereus was not presented in the egg in the second trial. Effective residual levels of nisin were detected in the liquid egg post pasteurization. PMID- 29389027 TI - Luminescence-based detection of Erwinia carotovora associated with rotting potato tubers. AB - A luminescence-based marker system has been used to follow rotting of potato tubers by Erwinia carotovora. The early stages of infection could be detected by visual observation of areas of luminescence developing from the point of inoculation. During later stages luminescence was limited to peripheral regions and to central regions where the structure of the potato was destroyed. Luminometry demonstrated reduction in aerobic activity of infecting cells due to oxygen limitation. The system enables rapid and sensitive detection of active marked populations and distinction between aerobic and fermentative activity. PMID- 29389028 TI - Effect of triazole fungicides on lipid metabolism of Saccharomyces cerevisiae. AB - The triazole fungicide (Flusilazole) modified the sterol content of Saccharomyces cerevisiae. The plasma membrane fluidity was altered by the presence of methyl sterol which increased with the flusilazole concentration. On the other hand, the short free fatty acids (C6 to C14) and the unsaturated free fatty acids increased in the cells, while the short free fatty acids decreased in the medium. PMID- 29389029 TI - A novel method for the transport and long-term storage of cultures and samples in an anaerobic atmosphere. AB - Nylon-aluminium-polyethylene laminated, sealable bags provided a more economical and flexible method of transportation, incubation and storage than anaerobic jars. The bags were used with a special heat sealer and 'Anaerocult-A' sachets to remove oxygen. The environment inside the bags remained oxygen-free for at least 3 years. PMID- 29389030 TI - Pseudomonas syringae pv. japonica (Mukoo 1955) Dye et al. 1980 is a junior synonym of Ps. syringae pv. syringae van Hall 1902. AB - An investigation of the biochemical, nutritional and pathogenic reactions of strains of Pseudomonas syringae pv. japonica and Ps. syringae pv. syringae showed them to be indistinguishable. Pseudomonas syringae pv. japonica is a junior synonym of Ps. syringae pv. syringae. PMID- 29389031 TI - Chromosomally-determined induced tolerance to copper in Escherichia coli. AB - Pre-exposure of Echerichia coli to sub-lethal concentrations of cupric sulphate induced copper tolerance: pre-exposed (habituated) organisms were essentially unaffected by concentrations of Cu2+ which completely prevented colony formation by non-habituated ones. The observed copper tolerance was not dependent on the selection of copper-resistant mutants but resulted from a phenotypic change in the organisms during the pre-exposure period. PMID- 29389032 TI - Efficacy of medicinal plant (Andrographis peniculata) extract on aflatoxin production and growth of Aspergillus flavus. AB - The efficacies of four different concentrations (3, 5, 8 and 10 mg/ml) of an aqueous extract of the Andrographis peniculata were tested on growth and aflatoxin production by Aspergillus flavus in liquid SMKY medium. The maximum inhibition of aflatoxin production and growth of A. flavus were marked at 10 mg/ml (i.e. 78.6% aft. B1 and 75.1% growth). Growth and aflatoxin production were co-related processes. PMID- 29389033 TI - Importance of medium pH in solid state fermentation for growth of Schwanniomyces castellii. AB - Utilization of soluble starch by Schwanniomyces castellii in a solid state fermentation system was highest in unbuffered medium when initial and final pH of the medium were 6.5-7.0 and 4.0-4.6, respectively. An economic strategy involving the use of urea as a sole nitrogen source in medium with initial pH of 6.5 allowed maximum substrate utilization in the absence of buffer and without any contamination in column fermenter. PMID- 29389034 TI - The detection of Salmonella enteritidis and S. typhimurium using immunomagnetic separation and conductance microbiology. AB - A rapid method for detection of Salmonella in milk powder is described. The technique involves immunomagnetic separation of Salmonella from pre-enrichment broths using new commercially-available materials, and detection using conductance measurements. Salmonella detection was enhanced by reducing the number and types of competing bacteria present and concentrating the number of Salmonella in the final assay. After a 6 h pre-incubation period Salmonella enteritidis, from an initial inoculum size of 20 cells/ml, were detected in 7.5 h by conductance. PMID- 29389035 TI - The effect of recovery medium on the estimated heat-inactivation of spores of non proteolytic Clostridium botulinum. AB - Heating spores of non-proteolytic strains of Clostridium botulinum at 85 degrees C, followed by enumeration of survivors on a highly nutrient medium indicated a 5 decimal kill in less than 2 min. The inclusion of lysozyme or egg yolk emulsion in the recovery medium substantially increased apparent spore heat-resistance, with as little as 0.1 MUg lysozyme/ml sufficient to give an increase in the number of survivors. After heating at 85 degrees C for 2 min between 0.1% and 1% of the spores of 11 strains (5 type B, 4 type E, 2 type F) formed colonies on medium containing 10 MUg lysozyme/ml. Enumeration of survivors on a medium containing lysozyme showed that heating at 85 degrees C for 5 min resulted in an estimated 2.6 decimal kill of spores of strain 17B (type B). These findings are important in the assessment of heat-treatments required to ensure the safety with respect to non-proteolytic Clostridium botulinum of processed (pasteurized) refrigerated foods for extended storage such as sous-vide foods. PMID- 29389036 TI - Listeria monocytogenes serotypes in Italian meat products. AB - Listeria monocytogenes was isolated and enumerated in Italian fresh ground beef, fresh pork meat and industrial sausages. All the samples contained less than 2000 L. monocytogenes/g of meat. The main serotype isolated was 1/2c (56.9%). Other serotypes isolated included 1/2a, 1/2b, 3c, 4b and 4c. A prevalence of less virulent serotypes over more virulent was thus noted. It seems that the low incidence of listeriosis from these products is related to the low concentration and virulence of L. monocytogenes present. PMID- 29389037 TI - Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial. AB - BACKGROUND: Atrial fibrillation (AF) increases risk of stroke 5-fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD. HYPOTHESIS: Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke. METHODS: This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]). RESULTS: A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66-1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88-1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64). CONCLUSIONS: Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints. PMID- 29389038 TI - Investigating capillary electrophoresis-mass spectrometry for the analysis of common post-translational modifications. AB - Capillary electrophoresis coupled to mass spectrometry is a very efficient analytical method for the analysis of post-translational modifications because of its high separation efficiency and high detection sensitivity. Here we applied CE MS using three differently coated separation capillaries for in-depth analysis of a set of 70 synthetic post-translationally modified peptides (including phosphorylation, acetylation, methylation, and nitration). We evaluated the results in terms of peptide detection and separation characteristics and found that the use of a neutrally coated capillary resulted in highest overall signal intensity of singly modified peptides. In contrast, the use of a bare-fused silica capillary was superior in the identification of multi-phosphorylated peptides (12 out of 15 were identified). Fast separations of approximately 12 min could be achieved using a positively coated capillary, however, at the cost of separation efficiency. A comparison to nanoLC-MS revealed that multi phosphorylated peptides interact with the RP material very poorly so that these peptides were either washed out or elute as very broad peaks from the nano column which results in a reduced peptide identification rate (7 out of 15). Moreover, the methods applied were found to be very well suited for the analysis of the acetylated, nitrated and methylated peptides. All 36 synthetic peptides, which exhibit one of those modifications, could be identified regardless of the method applied. As a final step in this study and as a proof of principle, the phosphoproteome enriched from PC-12 pheochromocytoma cells was analyzed by CE-MS resulting in 5686 identified and 4088 quantified phosphopeptides. We compared the characterized analytes to those identified by a nanoLC-MS proteomics study and found that less than one third of the phosphopeptides were identical, which demonstrates the benefit by combining different approaches quite impressively. PMID- 29389039 TI - Single-trial log transformation is optimal in frequency analysis of resting EEG alpha. AB - The appropriate definition and scaling of the magnitude of electroencephalogram (EEG) oscillations is an underdeveloped area. The aim of this study was to optimize the analysis of resting EEG alpha magnitude, focusing on alpha peak frequency and nonlinear transformation of alpha power. A family of nonlinear transforms, Box-Cox transforms, were applied to find the transform that (a) maximized a non-disputed effect: the increase in alpha magnitude when the eyes are closed (Berger effect), and (b) made the distribution of alpha magnitude closest to normal across epochs within each participant, or across participants. The transformations were performed either at the single epoch level or at the epoch-average level. Alpha peak frequency showed large individual differences, yet good correspondence between various ways to estimate it in 2 min of eyes closed and 2 min of eyes-open resting EEG data. Both alpha magnitude and the Berger effect were larger for individual alpha than for a generic (8-12 Hz) alpha band. The log-transform on single epochs (a) maximized the t-value of the contrast between the eyes-open and eyes-closed conditions when tested within each participant, and (b) rendered near-normally distributed alpha power across epochs and participants, thereby making further transformation of epoch averages superfluous. The results suggest that the log-normal distribution is a fundamental property of variations in alpha power across time in the order of seconds. Moreover, effects on alpha power appear to be multiplicative rather than additive. These findings support the use of the log-transform on single epochs to achieve appropriate scaling of alpha magnitude. PMID- 29389040 TI - Validation of nomograms for overall survival, cancer-specific survival, and recurrence in carcinoma of the major salivary glands. AB - BACKGROUND: The purpose of this study was to investigate the performance of the Memorial Sloan Kettering Cancer Center salivary carcinoma nomograms predicting overall survival, cancer-specific survival, and recurrence with an external validation dataset. METHODS: The validation dataset comprised 123 patients treated between 2010 and 2015 at our institution. They were evaluated by assessing discrimination (concordance index [C-index]) and calibration (plotting predicted vs actual probabilities for quintiles). RESULTS: The validation cohort (n = 123) showed some differences to the original cohort (n = 301). The validation cohort had less high-grade cancers (P = .006), less lymphovascular invasion (LVI; P < .001) and shorter follow-up of 19 months versus 45.6 months. Validation showed a C-index of 0.833 (95% confidence interval [CI] 0.758-0.908), 0.807 (95% CI 0.717-0.898), and 0.844 (95% CI 0.768-0.920) for overall survival, cancer-specific survival, and recurrence, respectively. CONCLUSION: The 3 salivary gland nomograms performed well using a contemporary validation dataset, despite limitations related to sample size, follow-up, and differences in clinical and pathology characteristics between the original and validation cohorts. PMID- 29389041 TI - Programmable and Multifunctional DNA-Based Materials for Biomedical Applications. AB - DNA encodes the genetic information; recently, it has also become a key player in material science. Given the specific Watson-Crick base-pairing interactions between only four types of nucleotides, well-designed DNA self-assembly can be programmable and predictable. Stem-loops, sticky ends, Holliday junctions, DNA tiles, and lattices are typical motifs for forming DNA-based structures. The oligonucleotides experience thermal annealing in a near-neutral buffer containing a divalent cation (usually Mg2+ ) to produce a variety of DNA nanostructures. These structures not only show beautiful landscape, but can also be endowed with multifaceted functionalities. This Review begins with the fundamental characterization and evolutionary trajectory of DNA-based artificial structures, but concentrates on their biomedical applications. The coverage spans from controlled drug delivery to high therapeutic profile and accurate diagnosis. A variety of DNA-based materials, including aptamers, hydrogels, origamis, and tetrahedrons, are widely utilized in different biomedical fields. In addition, to achieve better performance and functionality, material hybridization is widely witnessed, and DNA nanostructure modification is also discussed. Although there are impressive advances and high expectations, the development of DNA-based structures/technologies is still hindered by several commonly recognized challenges, such as nuclease instability, lack of pharmacokinetics data, and relatively high synthesis cost. PMID- 29389042 TI - Intraoperative monitoring of marginal mandibular nerve during neck dissection. AB - BACKGROUND: The purpose of this study was to assess the efficacy of intraoperative nerve integrity monitoring (NIM) to prevent marginal mandibular nerve injuries during neck dissection. METHODS: This prospective study compared 36 patients undergoing NIM-assisted neck dissection from July 2014 to March 2015 to a cohort of 35 patients subjected to neck dissection over an identical period of time before the technique was introduced. We also assessed possible correlations between marginal mandibular nerve injuries and other factors, such as anthropometric measurements, presence of clinical neck metastases, type of neck dissection, and site of primary tumor. RESULTS: The incidence of marginal mandibular nerve paralyses was significantly lower among the group of patients undergoing NIM-assisted neck dissection (P = .021). There was no significant difference in the duration of the procedure, and the technique resulted in a limited increase of cost. No other factor seemed to influence the onset of marginal mandibular nerve palsy. CONCLUSION: In our opinion, NIM is a valuable aid for preventing marginal mandibular nerve injuries during neck dissection. PMID- 29389043 TI - Postoperative day 1 levels of parathyroid as predictor of occurrence and severity of hypocalcaemia after total thyroidectomy. AB - BACKGROUND: Hypocalcaemia is a common and serious complication after thyroidectomy. The purpose of this study is to assess the effectiveness of first postoperative day parathyroid hormone (PTH) measurement in order to predict the presence and severity of postthyroidectomy hypocalcaemia. METHODS: One hundred consecutive cases undergoing total thyroidectomy in a tertiary referral center were prospectively assessed. Preoperative measurements of PTH were compared with postoperative levels in the first morning after surgery. All cases of hypocalcaemia were recorded and evaluated with regard to preoperative and postoperative levels of PTH. RESULTS: A decrease of 56% of PTH levels on the first postoperative day could accurately predict postoperative hypocalcaemia with a sensitivity and specificity of 80%. CONCLUSION: Serum PTH levels on the first postoperative day may be used as a reliable predictive marker for calcium supplementation need and even prolonged hospitalization in cases undergoing total thyroidectomy. PMID- 29389044 TI - Synergistically Active NiCo2 S4 Nanoparticles Coupled with Holey Defect Graphene Hydrogel for High-Performance Solid-State Supercapacitors. AB - Nickel cobalt sulfide nanoparticles embedded in holey defect graphene hydrogel (HGH) that exhibit highly porous structures and uniform nickel cobalt sulfide nanoparticle sizes are successfully prepared by a facile solvothermal hydrothermal method. As an electrode material for supercapacitors, the as prepared NiCo2 S4 @HGH shows ultra-high specific capacitances of 1000 F g-1 and 800 F g-1 at 0.5 and 6 A g-1 , respectively, owing to the outstanding electrical conductivity of HGH and high specific capacitance of NiCo2 S4 . After 2100 charge/discharge cycles at a current density of 6 A g-1 , 96.6 % of the specific capacitance was retained, signifying the superb durability of NiCo2 S4 @HGH. Moreover, remarkable specific capacitance (312.6 F g-1 ) and capacity retention (87 % after 5000 cycles) at 6 A g-1 were displayed by the symmetric solid-state supercapacitor fabricated by using NiCo2 S4 @HGH electrodes. These auspicious supercapacitor performances demonstrate that the as-developed solvothermal hydrothermal approach can be widely used to prepare graphene-coupled binary metal sulfides for high-performance supercapacitor applications. PMID- 29389045 TI - Critical Impact of Peptidoglycan Precursor Amidation on the Activity of l,d Transpeptidases from Enterococcus faecium and Mycobacterium tuberculosis. AB - The bacterial cell wall peptidoglycan contains unusual l- and d-amino acids assembled as branched peptides. Insight into the biosynthesis of the polymer has been hampered by limited access to substrates and to suitable polymerization assays. Here we report the full synthesis of the peptide stem of peptidoglycan precursors from two pathogenic bacteria, Enterococcus faecium and Mycobacterium tuberculosis, and the development of a sensitive post-derivatization assay for their cross-linking by l,d-transpeptidases. Access to series of stem peptides showed that amidation of free carboxyl groups is essential for optimal enzyme activity, in particular the amidation of diaminopimelate (DAP) residues for the cross-linking activity of the l,d-transpeptidase LdtMt2 from M. tuberculosis. Accordingly, construction of a conditional mutant established the essential role of AsnB indicating that this DAP amidotransferase is an attractive target for the development of anti-mycobacterial drugs. PMID- 29389046 TI - The molecular basis of essential fatty acid limitation in Daphnia magna: A transcriptomic approach. AB - It is widely accepted that in many food webs, the trophic transfer efficiency among primary producers and herbivores is determined by the nutritional value of primary producers. In pelagic freshwater and marine ecosystems, secondary production by herbivorous crustacean zooplankton is often limited by the seston's content of essential omega3 polyunsaturated fatty acids (omega3 PUFAs). However, little is known about the genetic network behind the positive relationship between phytoplankton omega3 PUFA content and zooplankton growth and reproduction. In our experimental study, we analysed gene expression changes of the freshwater cladoceran Daphnia magna under different food regimes differing in their omega3 PUFA composition. To disentangle omega3 PUFA effects from other factors, we fed D. magna with different pure phytoplankton cultures (i.e., algal and cyanobacterial diets) with or without supplementing the essential omega3 PUFA eicosapentaenoic acid (EPA). As hypothesized, we observed enhanced growth on diets supplemented with EPA. We applied an Illumina RNA-seq approach to D. magna from different diet treatments to find and monitor genes that are regulated dependent on EPA availability. Of 26,646 potential protein products (mapped to the D. magna genome), we identified transcriptomic signatures driven by the different food sources. Further analyses revealed specific candidate genes involved in EPA metabolism, irrespective of the basal food source. This allows a first functional annotation of previously uncharacterized genes involved in the EPA-specific response of D. magna and may finally provide a link to molecular processes connected to omega3 PUFA metabolism and conversion and thus trophic transfer efficiency in pelagic food webs. PMID- 29389047 TI - Multiscale energy reallocation during low-frequency steady-state brain response. AB - Traditional task-evoked brain activations are based on detection and estimation of signal change from the mean signal. By contrast, the low-frequency steady state brain response (lfSSBR) reflects frequency-tagging activity at the fundamental frequency of the task presentation and its harmonics. Compared to the activity at these resonant frequencies, brain responses at nonresonant frequencies are largely unknown. Additionally, because the lfSSBR is defined by power change, we hypothesize using Parseval's theorem that the power change reflects brain signal variability rather than the change of mean signal. Using a face recognition task, we observed power increase at the fundamental frequency (0.05 Hz) and two harmonics (0.1 and 0.15 Hz) and power decrease within the infra slow frequency band (<0.1 Hz), suggesting a multifrequency energy reallocation. The consistency of power and variability was demonstrated by the high correlation (r > .955) of their spatial distribution and brain-behavior relationship at all frequency bands. Additionally, the reallocation of finite energy was observed across various brain regions and frequency bands, forming a particular spatiotemporal pattern. Overall, results from this study strongly suggest that frequency-specific power and variability may measure the same underlying brain activity and that these results may shed light on different mechanisms between lfSSBR and brain activation, and spatiotemporal characteristics of energy reallocation induced by cognitive tasks. PMID- 29389048 TI - Comparison the clinical outcomes with altered versus conventional fractionated radiotherapy plus concurrent chemotherapy for advanced nasopharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to compare the long-term survivals between altered fractionated and conventional fractionated radiotherapy with the same concurrent chemoradiotherapy (concurrent CRT) for patients with advanced nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed 203 patients with NPC who received radiotherapy (RT) by either a conventional fractionated (70 74 Gy/35-37 fractions/7-8 weeks) or altered fractionated (72-75 Gy/45 fractions/6 weeks) schedule plus the same concurrent CRT. RESULTS: The patient characteristics between conventional fractionated and altered fractionated groups showed similar distribution. The 5-year rates of nasopharyngeal failure-free, neck failure-free, and distant metastasis failure-free survival between conventional fractionated and altered fractionated groups were 88% versus 86% (P = .7781), 95% versus 93% (P = .4176), and 76% versus 73% (P = .4029), respectively. The overall survival (OS; 5-year rates were 64% versus 62%; P = .4812) and progression-free survival (PFS; 5-year rates were 67% versus 63%; P = .3829) rates also showed no significant differences. The acute and late toxicities were similar between both groups. CONCLUSION: Altered fractionated and conventional fractionated RT achieved similar survival outcome when concurrent CRT strategy was used for advanced NPC. PMID- 29389049 TI - Biodistribution, Clearance, and Long-Term Fate of Clinically Relevant Nanomaterials. AB - Realization of the immense potential of nanomaterials for biomedical applications will require a thorough understanding of how they interact with cells, tissues, and organs. There is evidence that, depending on their physicochemical properties and subsequent interactions, nanomaterials are indeed taken up by cells. However, the subsequent release and/or intracellular degradation of the materials, transfer to other cells, and/or translocation across tissue barriers are still poorly understood. The involvement of these cellular clearance mechanisms strongly influences the long-term fate of used nanomaterials, especially if one also considers repeated exposure. Several nanomaterials, such as liposomes and iron oxide, gold, or silica nanoparticles, are already approved by the American Food and Drug Administration for clinical trials; however, there is still a huge gap of knowledge concerning their fate in the body. Herein, clinically relevant nanomaterials, their possible modes of exposure, as well as the biological barriers they must overcome to be effective are reviewed. Furthermore, the biodistribution and kinetics of nanomaterials and their modes of clearance are discussed, knowledge of the long-term fates of a selection of nanomaterials is summarized, and the critical points that must be considered for future research are addressed. PMID- 29389050 TI - Highly Functionalized beta-Cyclodextrins by Solid-Supported Synthesis. AB - Using covalent capture, a high yielding selective mono-functionalization of heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-beta-CD with a 5-mercaptopentyl functional group has been achieved. Here, we demonstrate the immobilization of the mono-thiol functionalized beta-CD on PEGA resin via a disulfide bond, enabling solid-phase elaboration of the remaining six primary amines. To showcase the potential of this method, the amines were elaborated to tripeptides through standard Fmoc-peptide chemistry. A small library of CD-tripeptide conjugates was generated which, when reduced from the solid support, could be tagged at the released thiol with an environmentally sensitive fluorophore. The resulting library of sensors showed potential for the differential sensing of various bile salts. The described methodology provides a rapid and versatile route to synthesize highly functionalized libraries of CD derivatives that may be tailored towards applications in sensing, catalysis, and multivalent displays. PMID- 29389052 TI - Umpolung at Boron: Ancillary-Ligand-Induced Formation of Boron-Based Donor Ligands from Phosphine-Boranes. AB - Easy-to-prepare eta2 -coordinated phosphine-borane ligands are demonstrated to liberate hydrogen upon treatment with different sigma-donor/pi-acceptor ligands (CO, tBuNC, CN- ). Depending on the utilized ancillary ligand, different reaction pathways are observed, ranging from simple hydride protonation to iron-boron bond formation and subsequent rearrangement to pincer-type ligands based on a tricoordinate boron centre. The last-named reactivity is in line with a formal umpolung at the boron centre from a Lewis acidic borane to a Lewis basic boron based donor ligand. PMID- 29389051 TI - Frequency-dependent tACS modulation of BOLD signal during rhythmic visual stimulation. AB - Transcranial alternating current stimulation (tACS) has emerged as a promising tool for modulating cortical oscillations. In previous electroencephalogram (EEG) studies, tACS has been found to modulate brain oscillatory activity in a frequency-specific manner. However, the spatial distribution and hemodynamic response for this modulation remains poorly understood. Functional magnetic resonance imaging (fMRI) has the advantage of measuring neuronal activity in regions not only below the tACS electrodes but also across the whole brain with high spatial resolution. Here, we measured fMRI signal while applying tACS to modulate rhythmic visual activity. During fMRI acquisition, tACS at different frequencies (4, 8, 16, and 32 Hz) was applied along with visual flicker stimulation at 8 and 16 Hz. We analyzed the blood-oxygen-level-dependent (BOLD) signal difference between tACS-ON vs tACS-OFF, and different frequency combinations (e.g., 4 Hz tACS, 8 Hz flicker vs 8 Hz tACS, 8 Hz flicker). We observed significant tACS modulation effects on BOLD responses when the tACS frequency matched the visual flicker frequency or the second harmonic frequency. The main effects were predominantly seen in regions that were activated by the visual task and targeted by the tACS current distribution. These findings bridge different scientific domains of tACS research and demonstrate that fMRI could localize the tACS effect on stimulus-induced brain rhythms, which could lead to a new approach for understanding the high-level cognitive process shaped by the ongoing oscillatory signal. PMID- 29389053 TI - A case-control study of end-of-life treatment preferences and costs following advance care planning for adults with end stage kidney disease. AB - AIM: To examine the efficacy of advance care planning (ACP) to improve the likelihood that end-stage kidney disease (ESKD) patient's preferences will be known and adhered to at end-of-life. METHODS: A case-control study of a nurse-led ACP program in adults with ESKD from a major tertiary hospital. The primary outcome was the proportion of patients whose preferences were known (by substitute decision maker and/or clinicians) and adhered to by their treating doctors. Secondary measures were health system resource use and costs ($AUD) for a nurse-led ACP intervention in the last 12-months of life. RESULTS: In total, 57 cases (38 men, mean age 73.8 years) and 57 historical controls (38 men, mean age 74.0 years) were included. Cases (38/57, 67%) were significantly more likely than controls (15/57, 26%) to have their preferences known and adhered to by their treating doctor at end-of-life (p<0.001). Cases (33/40, 83%) were also significantly more likely to withdraw from dialysis in accordance with their preferences than controls (11/33, 33%) (p<0.001). For cases, the average hospital costs in the last 12 months of life was AUD $99,077 (SD = $71,002) per patient. The total cost of the ACP program in 2010/11 was AUD $26,821. CONCLUSION: ACP was associated with improvements in end-of-life care preferences known and adhered to for people with ESKD. PMID- 29389055 TI - Cutaneous granulomas in a patient with common variable immunodeficiency disease. PMID- 29389054 TI - Streamlined Synthesis and Evaluation of Teichoic Acid Fragments. AB - Teichoic acids (TAs) are key components of the Gram-positive bacterial cell wall that are composed of alditol phosphate repeating units, decorated with alanine or carbohydrate appendages. Because of their microhetereogeneity, pure well-defined TAs for biological or immunological evaluation cannot be obtained from natural sources. We present here a streamlined automated solid-phase synthesis approach for the rapid generation of well-defined glycosylated, glycerol-based TA oligomers. Building on the use of a "universal" linker system and fluorous tag purification strategy, a library of glycerolphosphate pentadecamers, decorated with various carbohydrate appendages, is generated. These are used to create a structurally diverse TA-microarray, which is used to reveal, for the first time, the binding preferences of anti-LTA (lipoteichoic acids) antibodies at the molecular level. PMID- 29389056 TI - Winners and losers of national and global efforts to reconcile agricultural intensification and biodiversity conservation. AB - Closing yield gaps within existing croplands, and thereby avoiding further habitat conversions, is a prominently and controversially discussed strategy to meet the rising demand for agricultural products, while minimizing biodiversity impacts. The agricultural intensification associated with such a strategy poses additional threats to biodiversity within agricultural landscapes. The uneven spatial distribution of both yield gaps and biodiversity provides opportunities for reconciling agricultural intensification and biodiversity conservation through spatially optimized intensification. Here, we integrate distribution and habitat information for almost 20,000 vertebrate species with land-cover and land use datasets. We estimate that projected agricultural intensification between 2000 and 2040 would reduce the global biodiversity value of agricultural lands by 11%, relative to 2000. Contrasting these projections with spatial land-use optimization scenarios reveals that 88% of projected biodiversity loss could be avoided through globally coordinated land-use planning, implying huge efficiency gains through international cooperation. However, global-scale optimization also implies a highly uneven distribution of costs and benefits, resulting in distinct "winners and losers" in terms of national economic development, food security, food sovereignty or conservation. Given conflicting national interests and lacking effective governance mechanisms to guarantee equitable compensation of losers, multinational land-use optimization seems politically unlikely. In turn, 61% of projected biodiversity loss could be avoided through nationally focused optimization, and 33% through optimization within just 10 countries. Targeted efforts to improve the capacity for integrated land-use planning for sustainable intensification especially in these countries, including the strengthening of institutions that can arbitrate subnational land-use conflicts, may offer an effective, yet politically feasible, avenue to better reconcile future trade-offs between agriculture and conservation. The efficiency gains of optimization remained robust when assuming that yields could only be increased to 80% of their potential. Our results highlight the need to better integrate real-world governance, political and economic challenges into sustainable development and global change mitigation research. PMID- 29389057 TI - Specific Isolation of Glycoproteins with Mesoporous Zirconia-Polyoxometalate Hybrid. AB - A novel mesoporous zirconia-polyoxometalate ZrO2 -P8 W48 hybrid was prepared using a surfactant-assisted solvent evaporation technique. The acid-base reaction between the Zr-OH groups of zirconium oxides and P8 W48 was followed by self assembly with an amphiphilic triblock copolymer as template to obtain a polyoxometalate-based hybrid. The ZrO2 -P8 W48 hybrid was characterized by Fourier-transform infrared spectroscopy (FT-IR), thermal gravimetric assay (TGA), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDXS), X-ray diffraction (XRD), and nitrogen sorption/desorption. Owing to the multiple hydrogen-bonding interactions between the P8 W48 moiety and the hydroxyl groups of glycoproteins, the ZrO2 -P8 W48 hybrid exhibited highly selective isolation of glycoproteins from complex matrices that included various non-glycoproteins. The retained glycoproteins could be readily recovered using a 0.01 mol L-1 cetane trimethyl ammonium bromide (CTAB) solution as stripping reagent, with recovery rates of 92, 100, 100, 100, and 74% for the five target glycoproteins, Ovalbumin (Ova), conalbumin (ConA), immunoglobulin G from human serum (IgG), gamma-globulin from bovine milk (gamma-Glo), and horseradish peroxidase (HRP), respectively. The ZrO2 -P8 W48 hybrid was successfully applied to the isolation of glycoproteins from egg white and human serum samples, as confirmed by SDS-PAGE and LC-MS/MS assays. PMID- 29389058 TI - Endoscopic suturing for the management of recurrent dislodgment of percutaneous endoscopic gastrostomy-jejunostomy tube. AB - OBJECTIVE: To describe a novel technique for the prevention of recurrent percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube dislodgements and assess its feasibility and efficacy. This technique utilizes endoscopic suturing to secure the PEG-J tube to the gastric wall. METHODS: This was a retrospective analysis of consecutive cases of recurrent PEG-J tube dislodgements referred to a single endoscopist between June 2016 and June 2017, using an endoscopic suturing system to secure the PEG-J tube directly to the gastric wall. Technical success rates, the procedure time and related adverse events were analyzed. RESULTS: There were five patients in total (three females). The procedure was technically successful in all patients. There were no procedure-related adverse events. The mean duration of follow-up was 7.8 +/- 5.1 months. Two patients had accidental dislodgement at 8.5 and 12 months, respectively. There were no other unintended dislodgements. CONCLUSION: Endoscopic suturing with internal fixation of PEG-J tube is a safe and feasible approach to manage recurrent unintended dislodgements. PMID- 29389059 TI - Wettability of pear leaves from three regions characterized at different stages after flowering using the OWRK method. AB - BACKGROUND: A better understanding of leaf surface wettability is critical to improve the adhesion of liquid pesticides. Leaf surface wettability is dependent on the property of the liquid as well as the physical and chemical properties of the leaf, which vary with climate and growth stage. The aim of this study was to characterize the wettability of pear leaves from three different climatic regions at different stages after flowering. RESULTS: The contact angles of different test liquids were measured on both adaxial and abaxial pear leaf surfaces and the Owens-Wendt-Rabel-Kaelble (OWRK) method was used to calculate surface free energy (SFE) and its polar and non-polar components. The results demonstrated that the SFE of both the adaxial and abaxial surface of the pear leaf, and the proportion of polar component, increased with increasing time after flowering. At early growth stages, pear leaves were highly hydrophobic, similar to a polytetrafluoroethylene surface, whereas at later growth stages, pear leaves were hydrophobic, more similar to a polymethylmethacrylate surface. Also, the SFE differed with climatic region. Factors influencing these changes are discussed. CONCLUSION: Changes in contact angles and SFE correlated with the change of the leaf surface wettability. Leaves became easier to wet (higher SFE), with an overall increasing polar component to the surface, with increasing age after flowering. As expected, changes in wettability were found in pear leaves at different stages after flowering and in different regions (P < 0.05). Pear leaves from Yuanping were easier to wet than leaves from Yuci and Linyi, and adaxial surfaces were easier to wet than abaxial surfaces. These results provide beneficial information for the application of agrochemicals for improved wetting and spreading behavior. (c) 2018 Society of Chemical Industry. PMID- 29389060 TI - Synthesis of molecularly imprinted dye-silica nanocomposites with high selectivity and sensitivity: Fluorescent imprinted sensor for rapid and efficient detection of tau-fluvalinate in vodka. AB - An imprinted fluorescent sensor was fabricated based on SiO2 nanoparticles encapsulated with a molecularly imprinted polymer containing allyl fluorescein. High fluorine cypermethirin as template molecules, methyl methacrylate as functional monomer, and allyl fluorescein as optical materials synthesized a core shell fluorescent molecular imprinted sensor, which showed a high and rapid sensitivity and selectivity for the detection of tau-fluvalinate. The sensor presented appreciable sensitivity with a limit of 13.251 nM, rapid detection that reached to equilibrium within 3 min, great linear relationship in the relevant concentration range from 0 to 150 nM, and excellent selectivity over structural analogues. In addition, the fluorescent sensor demonstrated desirable regeneration ability (eight cycling operations). The molecularly imprinted polymers ensured specificity, while the fluorescent dyes provided the stabile sensitivity. Finally, an effective application of the sensor was implemented by the detection of tau-fluvalinate in real samples from vodka. The molecularly imprinted fluorescent sensor showed a promising potential in environmental monitoring and food safety. PMID- 29389062 TI - Double CH Activation of a Masked Cationic Bismuth Amide. AB - The transformation of C-H bonds into more reactive C-M bonds amenable to further functionalization is of fundamental importance in synthetic chemistry. We demonstrate here that the transformation of neutral bismuth compounds into their cationic analogues can be used as a strategy to facilitate CH activation reactions. In particular, the double CH activation of bismuth-bound diphenyl amide, (NPh2 )- , is reported along with simple one-pot procedures for the functionalization of the activated positions. The organometallic products of the first and second CH activation steps were isolated in high yields. Analysis by NMR spectroscopy, single-crystal X-ray diffraction, and DFT calculations revealed unusual ground-state properties (e.g., ring strain, moderate heteroaromaticity), and provided mechanistic insight into the formation of these compounds. PMID- 29389061 TI - The miR-203/SNAI2 axis regulates prostate tumor growth, migration, angiogenesis and stemness potentially by modulating GSK-3beta/beta-CATENIN signal pathway. AB - Dysregulation of microRNA expression plays a pivotal role in the initiation and progression of a variety of human carcinomas including prostate cancer. Our previous studies have demonstrated that the silence of miR-203 contributes to the invasiveness of malignant breast cancer cells by targeting SNAI2. However, the effects and underlying mechanisms of miR-203/SNAI2 axis in prostate cancer have not been elucidated. The aim of this study is to explore the effects of miR 203/SNAI2 axis on the biological characteristics of prostate carcinomas both in vitro and in vivo. We found that miR-203 was significantly downregulated in prostate cancer cell lines compared with immortalized prostate epithelial cells using semi-quantitative PCR and real-time PCR, as well as in clinical prostate cancer tissues compared to normal tissues using TCGA analysis. Functionally, miR 203 inhibited prostate cancer cell proliferation, migration, endothelial cell tube formation and cancer stemness in vitro. Meanwhile, overexpression of miR-203 suppressed SNAI2 expression both in DU145 and PC3 cells. In addition, the in vivo study showed that miR-203 suppressed tumorigenicity, metastasis and angiogenesis of DU145 cells. Ectopic expression of SNAI2 rescued the inhibitory effects of miR 203 both in vitro and in vivo. Importantly, the EMT markers CDH1 and VIMENTIN were modulated by the miR-203/SNAI2 axis. Furthermore, the GSK-3beta/beta-CATENIN signal pathway was suppressed by miR-203 and could be reactivated by SNAI2. Taken together, this research unveiled the function of miR-203/SNAI2 axis in tumorigenesis, angiogenesis, stemness, metastasis and GSK-3beta/beta-CATENIN signal pathway in prostate cancer and gave insights into miR-203/SNAI2-targeting therapy for prostate cancer patients. (c) 2018 IUBMB Life, 70(3):224-236, 2018. PMID- 29389063 TI - Primary cutaneous angiomatoid melanoma. PMID- 29389064 TI - Tracheal advancement with myomucosal island flap for partial laryngopharyngectomy defect reconstruction. AB - BACKGROUND: Restoring the anatomy and function of a partial laryngopharyngectomy with hemicricoid defect is an extremely challenging area in head and neck cancer surgery. Procedures such as tracheal autotransplantation described for these defects are complex and attempted in very few centers. Therefore, the purpose of this article was to share our technique of reconstructing such defects with tracheal advancement with myomucosal island flap for laryngopharyngeal defect (TAMMIL), which allows functional reconstruction of the larynx. METHOD: A 49-year old man with carcinoma of the right pyriform sinus, postneoadjuvant chemotherapy with progressive disease underwent vertical partial laryngopharyngectomy. The resultant defect was reconstructed with tracheal advancement and islanded facial artery myomucosal (FAMM) flap. RESULT: The patient is 1-year postsurgery, free of disease, decannulated, and taking oral feeds. Video fluoroscopy showed no evidence of aspiration. CONCLUSION: This technique is single-staged, easier compared to existing techniques, aids "like-for-like" reconstruction, and allows surgical organ preservation in selected laryngeal and hypopharyngeal cancers. PMID- 29389065 TI - First molecular genetic evidence for automictic parthenogenesis in cockroaches. AB - Parthenogenesis is an asexual mode of reproduction that plays an important role in the evolution of sex, sociality, and reproduction strategies in insects. Some species of cockroach exhibit thelytoky, a type of parthenogenesis in which female offspring are produced without fertilization. However, the cytological and genetic mechanisms of parthenogenesis in cockroaches are not well understood. Here we provide the first molecular genetic evidence that cockroaches can reproduce through automixis. Using the American cockroach Periplaneta americana, we performed microsatellite analysis to investigate the genetic relationship between parthenogenetically produced nymphs and the parent virgin females, and found that all parthenogenetic offspring were homozygous for autosomal microsatellite markers, whereas the female parents were heterozygous. In addition, flow cytometry analysis revealed that the parthenogenetic offspring were diploid. Taken together, our results demonstrate that P. americana exhibits automixis-type thelytoky, in which diploidy is restored by gamete duplication or terminal fusion. These findings highlight the unique reproduction strategies of cockroaches, which are more varied than was previously recognized. PMID- 29389066 TI - Gastric carbonic anhydrase IX deficiency: At base, it is all about acid. PMID- 29389067 TI - Localized pretibial bullous pemphigoid arising in a patient on pembrolizumab for metastatic melanoma. PMID- 29389069 TI - Proteomics with Mass Spectrometry Imaging: Beyond Amyloid Typing. AB - Detection and typing of amyloid deposits in tissues are two crucial steps in the management of systemic amyloidoses. The presence of amyloid deposits is routinely evaluated through Congo red staining, whereas proteomics is now a mainstay in the identification of the deposited proteins. In article number 1700236, Winter et al. [Proteomics 2017, 17, Issue 22] describe a novel method based on MALDI-MS imaging coupled to ion mobility separation and peptide filtering, to detect the presence of amyloid in histology samples and to identify its composition, while preserving the spatial distribution of proteins in tissues. PMID- 29389068 TI - Tolvaptan in Chinese cirrhotic patients with ascites: A randomized, placebo controlled phase 2 trial. AB - OBJECTIVE: To evaluate tolvaptan as a novel therapeutic option for Chinese patients with liver cirrhosis-associated ascites in a phase 2 clinical trial. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial was conducted in patients with insufficient responses to combination therapies of an oral loop diuretic and an aldosterone antagonist. Reduction in body weight and abdominal circumference, increase in 24-h cumulative urine volume and improvement in serum sodium level from baseline to the end of treatment in the tolvaptan groups (15 mg/day or 30 mg/day orally) were compared with those in the placebo group. Drug safety was also assessed. RESULTS: Sixty-two patients were allocated to the placebo group, 56 to the tolvaptan 15-mg group and 63 to the tolvaptan 30 mg group. Their mean changes in body weight were -0.5 +/- 1.6 kg, -2.1 +/- 2.0 kg and -1.9 +/- 2.0 kg, respectively. Body weight reductions in both tolvaptan groups were significantly greater than that in the placebo group (difference 1.6, 95% confidence interval [CI] -2.5 to -0.8, and difference -1.4, 95% CI, -2.2 to -0.7, both P < 0.0001). The administration of tolvaptan also significantly reduced the abdominal circumference, increased 24-h cumulative urine volume and serum sodium level compared with placebo. The most common adverse events in the tolvaptan groups were constipation, diarrhea, dry mouth and thirst, with no severe adverse events observed. CONCLUSION: Tolvaptan at 15 mg/day significantly reduced the body weight and abdominal circumference in patients with liver cirrhosis-associated ascites, which needs to be confirmed in a phase 3 trial. PMID- 29389070 TI - Reply. PMID- 29389071 TI - Combinatorial Probes for High-Throughput Electrochemical Analysis of Circulating Nucleic Acids in Clinical Samples. AB - The analysis of circulating tumour nucleic acids (ctNAs) provides a minimally invasive way to assess the mutational spectrum of a tumour. However, effective and practical methods for analyzing this emerging class of markers are lacking. Analysis of ctNAs using a sensor-based approach has notable challenges, as it is vital to differentiate nucleic acids from normal cells from mutation-bearing sequences emerging from tumours. Moreover, many genes related to cancer have dozens of different mutations. Herein, we report an electrochemical approach that directly detects genes with mutations in patient serum by using combinatorial probes (CPs). The CPs enable detection of all of the mutant alleles derived from the same part of the gene. As a proof of concept, we analyze mutations of the EGFR gene, which has more than 40 clinically relevant alterations that include deletions, insertions, and point mutations. Our CP-based approach accurately detects mutant sequences directly in patient serum. PMID- 29389072 TI - Structures and disulfide cross-linking of de novo designed therapeutic mini proteins. AB - Recent advances in computational protein design now enable the massively parallel de novo design and experimental characterization of small hyperstable binding proteins with potential therapeutic activity. By providing experimental feedback on tens of thousands of designed proteins, the design-build-test-learn pipeline provides a unique opportunity to systematically improve our understanding of protein folding and binding. Here, we review the structures of mini-protein binders in complex with Influenza hemagglutinin and Bot toxin, and illustrate in the case of disulfide bond placement how analysis of the large datasets of computational models and experimental data can be used to identify determinants of folding and binding. PMID- 29389073 TI - A fungal mock community control for amplicon sequencing experiments. AB - Microbial ecology has been profoundly advanced by the ability to profile complex microbial communities by sequencing of marker genes amplified from environmental samples. However, inclusion of appropriate controls is vital to revealing the limitations and biases of this technique. "Mock community" samples, in which the composition and relative abundances of community members are known, are particularly valuable for guiding library preparation and data processing decisions. I generated a set of three mock communities using 19 different fungal taxa and demonstrate their utility by contrasting amplicon sequencing data obtained for the same communities under modifications to PCR conditions during library preparation. Increasing the number of PCR cycles elevated rates of chimera formation, and of errors in the final data set. Extension time during PCR had little impact on chimera formation, error rate or observed community structure. Polymerase fidelity impacted error rates significantly. Despite a high error rate, a master mix optimized to minimize amplification bias yielded profiles that were most similar to the true community structure. Bias against particular taxa differed among ITS1 vs. ITS2 loci. Preclustering nearly identical reads substantially reduced error rates, but did not improve similarity to the expected community structure. Inaccuracies in amplicon sequence-based estimates of fungal community structure were associated with amplification bias and size selection processes, as well as variable culling rates among reads from different taxa. In some cases, the numerically dominant taxon was completely absent from final data sets, highlighting the need for further methodological improvements to avoid biased observations of community profiles. PMID- 29389074 TI - Turning noise into order on the cell surface: Resonant activation of molecular highlighters. PMID- 29389075 TI - Characterization of the novel HLA-C*16:116 allele by sequencing-based typing. AB - HLA-C*16:116 differs from HLA-C*16:01:01:01 by single-nucleotide substitution at position 30. PMID- 29389076 TI - Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen. AB - The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance. The 90% log-transformed confidence intervals (CIs) for bazedoxifene Cmax , 96% to 144%, and AUC, 85% to 134%, were slightly above the bioequivalence limits of 80% to 125%. The 90% log transformed CIs for ibuprofen pharmacokinetic parameters were within these limits (Cmax , 92%-122%; AUC, 94%-106%). The increase in bazedoxifene plasma concentrations when combined with ibuprofen versus bazedoxifene alone is unlikely to be clinically significant. The lack of interaction between bazedoxifene and ibuprofen suggests that they may be coadministered without dose adjustment. PMID- 29389077 TI - Nitinol basket-assisted pars plana vitrectomy for retained lens material removal. AB - PURPOSE: To evaluate the usefulness of different types of nitinol baskets to capture, lift and hold the lens material, dropped during a complicated phacoemulsification, as an adjunctive surgical tool in vitreoretinal surgery and to evaluate the outcomes and complication of this new surgical technique in a small series of patients. METHODS: Patients who underwent pars plana vitrectomy (PPV) for retained lens fragments operated during December 2014 and March 2015 at the Academic Medical Center (AMC), Amsterdam, were included in this study. The PPV was performed using different settings and types of nitinol stone extractors (NSE). Three different stone extractors were used for the above-mentioned purpose. Preoperative (pre-op) and postoperative (post-op) data including best corrected visual acuity at 6 months follow-up visit, intra- and postoperative complications were recorded. RESULTS: Seven eyes of seven patients with a follow up of 6 months were included in this study. All the vitrectomies were performed the same day of the complicated cataract extraction. Mean pre-op Snellen visual acuity was 20/160; mean post-op visual acuity was 20/32. No complications were encountered due to the use of the NSE intraocularly. No retinal breaks were observed due to traction of the catheter at the site of insertion or due to his movement in and out the vitreous cavity. CONCLUSION: The use of the nitinol lens cage seemed feasible and showed no complications in our small group of patients. It made easier the management of dropped nucleus without the need for a larger scleral opening also in case of very hard lens. PMID- 29389078 TI - Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. AB - Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts. Generally, plasma exposure was greater with the 2% cream and decreased from day 1 to day 21. Median Tmax ranged from 1 to 4 hours. Preliminary efficacy results were similar between the 1% and 2% concentrations, with the 1% cream showing better tolerability based on 3 subjects in the 2% cohort who discontinued treatment because of systemic AEs. The efficacy and safety of 1% tapinarof support results of previous positive studies that used a different formulation. However, conclusions in the present study are limited because of the open-label design and small number of participants. The 1% cream was selected as the concentration for use in future studies because of its lower AE incidence and efficacy comparable to the 2% cream. PMID- 29389079 TI - Immune response-related genes associated to blocking midgut dengue virus infection in Aedes aegypti strains that differ in susceptibility. AB - Aedes (Stegomyia) aegypti, the principal global vector of dengue viruses, has differences in its susceptibility to dengue virus infection. We compared the global expression of genes in the midguts of Colombian Ae. aegypti dengue susceptible (Cali-S) and dengue-refractory (Cali-MIB) field derived strains after ingesting either a sugarmeal, a bloodmeal, or a bloodmeal containing dengue virus serotype 2 (DENV-2). Microarray-based transcriptome analysis among treatments indicated a total of 4725 transcripts with differential expression between the two strains. Eleven genes were selected from different functional groups based on their significant up or down expression levels as well as reports in the literature suggesting they are associated with dengue virus elimination. We measured mRNA abundance of these 11 genes at 0, 8, 24, and 36 h postinfection using quantitative real time PCR (qPCR) to confirm the microarray results and assess any temporal patterns. Four genes were selected (Gram-negative binding protein-GNBP [AAEL009176], Niemann Pick Type-C2-NPC2 [AAEL015136], Keratinocyte lectin [AAEL009842], and Cathepsin-b [AAEL007585]) for knockdown experiments using RNA interference (RNAi) methodology to determine the phenotype (DENV-2 susceptible or refractory). Silencing GNBP, Cathepsin-b and Keratinocyte lectin reduced the percentage of mosquitoes with disseminated virus in the Cali-S strain to 8%, 20%, and 12% respectively compared with 96% in the controls. Silencing of NPC2 increased the percentage of mosquitos with disseminated virus infections in Cali-MIB to 66% compared with 35% in the controls. This study provides insight into genes that may contribute to the Cali-S susceptible and Cali-MIB refractory phenotypes in Ae. aegypti. PMID- 29389080 TI - Identification of Host-Response in Cerebral Malaria Patients Using Quantitative Proteomic Analysis. AB - PURPOSE: The objective of this study was to study the altered proteome in the frontal lobe of patients with CM. Unbiased analysis of differentially abundant proteins could lead to identification of host responses against Plasmodium falciparum infection, which will aid in better understanding of the molecular mechanism of pathophysiology in CM. EXPERIMENTAL DESIGN: TMT-based quantitative proteomic analysis using high-resolution mass spectrometry is employed. In brief, proteins are isolated from frontal lobe samples, which are collected at autopsy from three cases of CM and three control subjects. Equal amounts of protein from each case are digested using trypsin and labeled with different TMT reagents. The pooled sample is fractionated using strong cation exchange chromatography and analyzed on Orbitrap Fusion in triplicates. For accurate quantitation of peptides, the samples are analyzed in MS3 mode. The data is searched against a combined database of human and P. falciparum proteins using Sequest and Mascot search engines. RESULTS: A total of 4174 proteins are identified, of which, 107 are found to be differentially abundant in the test samples with significant p value (<0.05). Proteins associated with biological processes such as innate immune response, complement system, coagulation, and platelet activation are found to be elevated in CM cases. In contrast, proteins associated with myelination, oxidative phosphorylation, regulation of reactive oxygen species, and sodium and calcium ions transport are found to be depleted in response to CM. In addition, three P. falciparum proteins exclusively in CM brain samples are also identified. CONCLUSIONS AND CLINICAL RELEVANCE: The study signifies neuronal assault due to axonal injury, altered sodium and calcium ion channels, deregulated inflammation and demyelination as a part of host response to CM. Enhanced oxidative stress, repressed oxidative phosphorylation, and demyelination of axons may contribute to the severity of the disease. Further validation of these results on a large cohort can provide leads in the development of neuroprotective therapies for CM. PMID- 29389082 TI - February 2018. PMID- 29389081 TI - Zwitterionic Hydrobromic Acid Carriers for the Synthesis of 2-Bromopropionic Acid from Lactide. AB - A convenient and highly efficient way of synthesizing 2-bromopropionic acid (2 BrPA) from lactide is presented. The procedure uses ionic liquids obtained from the addition of HBr to ammonium-based zwitterions as the solvent and bromination agent. The buffered HBr acidity, high polarity, and charge stabilizing character of the ionic liquid (IL) enable the synthesis of 2-BrPA with excellent selectivity. The best results are obtained with an imidazolium-based IL, that is, 1-(4-butanesulfonic acid)-3-methylimidazolium bromide ([MIMBS]Br). The HBr loading and water content of the IL are crucial parameters for the bromination reaction. The formed 2-BrPA product can be selectively isolated by extraction from the IL, and the unconverted substrate remains in the [MIMBS]Br IL for the next run. Successful recycling of the IL over four cycles is demonstrated. PMID- 29389084 TI - Special Issue: Updated ICCS/ESCCA PNH guidelines. PMID- 29389083 TI - Are we any closer to treating liver fibrosis (and if no, why not)? AB - This review provides a personal view on anti-fibrosis therapy in the liver. The worst clinical consequence of liver fibrosis is the development of liver cirrhosis and portal hypertension. Etiology is a decisive factor which determines patterns of fibrous septa and subsequent vascular remodeling, which is essential for the development of portal hypertension. Removing or controlling the disease causing agent, i.e. anti-viral treatment for hepatitis, is the essential first step for treating chronic liver diseases and can reverse fibrosis in some settings. However, removing etiology is not always sufficient to prevent fibrosis from progressing towards cirrhosis and portal hypertension. In liver diseases such as severe alcoholic hepatitis and massive parenchymal loss, the formation of vascular anastomoses between portal to central veins based on bridging fibrosis results in cirrhosis and portal hypertension. For these patients, anti-fibrotic treatment is crucial and urgent. Unfortunately, a lack of understanding how fibrosis contributes to vascular remodeling caused by and combined with a lack of suitable experimental models that recapitulate human liver diseases, has hampered the development of successful anti-fibrotic drugs for clinical use to date. PMID- 29389085 TI - Too much of a good thing! additional studies in this issue. PMID- 29389086 TI - Introduction to ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria and related disorders. PMID- 29389087 TI - Disassembly of Multicompartment Polymer Micelles in Spatial Sequence Using an Electrostatic Field and Its Application for Release in Chronological Order. AB - Multicompartment micelles (MCPs), comprising sequences of repeated elemental discoid parts connected by fasciculus, were formed by self-assembly of polystyrene-block-poly(2-vinyl pyridine)-block-poly(ethylene oxide). Using an electrostatic field, the MCPs can be disassembled through consequent release of small spherical micelles. During this disassembly process, release of loaded species can be achieved from the micelles in chronological order. Two location selected cargos (mitoxantrone (MTNT) and fluorescein isothiocyanate (FITC)) in the outer and inner compartments of the micelles can be released in chronological order. Under the applied electrostatic field (intensity: 16 kV cm-1 ), the loaded MTNT was rapidly released with more than 80 % release, whereas the loaded FITC was slowly released with less than 20 % release in 12 h. At a later stage (after more than 12 h), the loaded MTNT was slowly released with less than 20 % release, while the loaded FITC was rapidly released with more than 80 % release. PMID- 29389088 TI - FACT-Hep increases the accuracy of survival prediction in HCC patients when added to ECOG Performance Status. AB - BACKGROUND AND AIM: The Eastern Cooperative Oncology Group Performance Status (ECOG PS) is a strong predictor of survival for patients with hepatocellular carcinoma (HCC), and is used with liver function and tumour burden in the Barcelona Clinic Liver Cancer (BCLC) staging system. This work assesses whether the health-related quality of life (HRQL), measured by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire, discriminates HCC patients in terms of survival and adds prognostic information to ECOG PS. METHODS: A total of 242 patients participating in the prospective Bern HCC Cohort at the University Hospital Bern were analysed. The relationship between FACT-Hep and sociodemographic and clinical factors, including survival, were assessed. An analysis on treatment subgroups was performed using Kaplan-Meier curves and Long Rank test. Additionally, the ability to predict overall survival was compared between the ECOG PS and FACT-Hep total and subscales using Nagelkerke pseudo-R2 . RESULTS: FACT-Hep subscales were significantly worse in females and in patients with limited liver function. FACT-Hep total and all subscales, except the social/family well-being subscale showed significant differences between ECOG PS groups and were significant predictors of survival. ECOG PS groups, followed by the functional well-being subscale, were the best at predicting survival. In the resection subgroup, significant differences in OS regarding to HRQL were found. When adding the functional well-being subscale to ECOG PS, the accuracy of the survival prediction was significantly increased. CONCLUSION: HRQL assessed by the FACT-Hep questionnaire is a reliable prognostic predictor of survival for patients with HCC and it adds prognostic information to the ECOG PS. PMID- 29389089 TI - Pulmonary safety of ophthalmic beta-blockers: a nationwide registry-based cohort study. AB - PURPOSE: Ophthalmic beta-blockers, used in the treatment of increased intraocular pressure, are known to cause pulmonary adverse effects. Few, if any, studies have quantified the extent of the problem in a real-life population. In this nationwide study, we assess the pulmonary safety of patients initiating treatment with ophthalmic beta-blockers. METHODS: Using the Danish Nationwide Registries from 1995 to 2012, we identified all individuals aged 20-90 years who initiated monotherapy with an intraocular pressure-lowering drug, with or without concomitant obstructive pulmonary disease. Risks of (i) switching to another drug and (ii) new onset of obstructive pulmonary disease during a 90-day follow-up were examined by cumulative risk and logistic regression models adjusted for available covariates. RESULTS: The cohort consisted of 97 463 individuals. Odds ratios for drug switch in individuals without concomitant obstructive pulmonary disease (n = 86 568) were as follows: 1.47 for beta-blockers (95% confidence interval (CI): 1.35-1.61; p < 0.001), 2.68 for parasympathomimetics (95% CI: 2.32 3.10; p < 0.001) and 4.80 for alfa-2-agonists (95% CI: 4.17-5.53; p < 0.001). Odds ratios in individuals with concomitant obstructive pulmonary disease (n = 10 895) were as follows: 2.61 for parasympathomimetics (95% CI: 1.83-3.72; p < 0.001), 2.96 for beta-blockers (95% CI: 2.31-3.78; p < 0.001) and 3.54 for alfa-2 agonists (95% CI: 2.56-4.88; p < 0.001). There was no significant association between treatment class and new onset of obstructive pulmonary disease (p = 0.30). CONCLUSION: Ophthalmic beta-blockers were associated with an increased risk of drug switch. However, the absolute risk was very small. No increased risk of new onset of obstructive pulmonary disease was found. Our data suggest that more patients might be eligible for ophthalmic beta-blockers. PMID- 29389090 TI - Implications of DSM-5 for Health Care Organizations and Mental Health Policy. AB - The American Psychiatric Association (APA) has made major changes in the way mental illness is conceptualized, assessed, and diagnosed in its new diagnostic manual, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, and has far reaching implications for health care organizations and mental health policy. This paper reviews the four new principles in DSM-5: 1) A spectrum (also called "dimensional") approach to the definition of mental illness; 2) recognition of the role played by environmental risk factors related to stress and trauma in predisposing, precipitating, and perpetuating mental illness; 3) cultural relativism in diagnosis and treatment of mental illness; and 4) recognizing the adverse effects of psychiatric medications on patients. Each of these four principles will be addressed in detail. In addition, four major implications for health care organizations and mental health policy are identified as: 1) prevention; 2) client-centered psychiatry; 3) mental health workers retraining; and 4) medical insurance reform. We conclude that DSM- 5's new approach to diagnosis and treatment of mental illness will have profound implications for health care organizations and mental health policy, indicating a greater emphasis on prevention and cure rather than long-term management of symptoms. PMID- 29389091 TI - Is Accreditation Sufficient? A Case Study and Argument for Transparency when Government Regulatory Authority is Delegated. PMID- 29389092 TI - Common Risk Factors Associated with Adolescent and Young Adult Depression. AB - Depression is one of the leading causes of disability for all ages and genders in the United States. Historically, depression had been viewed as a condition that only affected older adults; however, in recent years health professionals have recognized depression as a serious condition also affecting adolescence and young adults. The purpose of this study was to identify whether gender was a risk factor of depression within the adolescent and young adult population as literature shows that depression can impact growth and development, school performance, peer or family relationship and at times can be fatal. Data from the 2005-2006 National Health and Nutrition Examination Survey was studied to gain understanding into the predictive relationship between adolescent depression and gender. The hypothesis that gender is a predictive factor for depression in this population was supported. PMID- 29389093 TI - Nicotine alters progesterone and estradiol levels during the first trimester of pregnancy in Wistar rats. AB - OBJECTIVE: This study was designed to investigate the effect of nicotine on serum progesterone and estradiol levels as possible cause of abortion during first trimester of gestation in female Wistar rats. METHODS: Fourteen female rats with regular estrous cycles in the same phase of cycle were divided into two groups (Control and Nicotine-treated) with each group receiving 1ml of distilled water and 1mg/kg of nicotine respectively for the first seven days of pregnancy (GD1 7). The animals were sacrificed on the 8th day and blood samples were collected for hormonal analyses. Ovaries and uteruses were excised, weighed, and prepared for histological study. RESULTS: This study revealed a significant decrease in serum progesterone and estradiol levels in the nicotine-treated group when compared to controls. The histological findings equally showed degeneration in the cytoarchitecture of the ovary of the nicotine-treated group. CONCLUSION: The observed hormonal imbalances and alteration in the cytoarchitecture of the ovary caused by nicotine in the first trimester of pregnancy may result in abortion during this period. PMID- 29389094 TI - Policy Making to Build Relationships: A Grounded Theory Analysis of Interviews and Documents Relating to H1N1, Ebola, and the U.S. Public Health Preparedness Network. AB - In the last five years, the American public health emergency preparedness and response system has been tested by two significant threats, H1N1 and Ebola. While neither proved as dangerous as initially feared, these viruses highlighted on going issues with collaborations in the field of public health and health care. Strengths were identified within the network, but also challenges that must be resolved before the U.S. faces a major pandemic. Employing interview data from public health emergency response practitioners and documentary evidence from the H1N1 and Ebola responses, this qualitative analysis uses the grounded theory approach to identify key areas for collaborative improvement. The grounded theory developed calls for a stronger policy framework at the federal level to facilitate more collaboration between U.S. agencies and facilitate more collaboration at the state and local level. PMID- 29389095 TI - Effect of Physician IT Use on Practice Performance. AB - The role of information technology (IT) remains important within the medical community. However, little is known about the extent to which practicing physicians improve practice performance by having and utilizing IT at the national level. The present study, analyzing a national physician survey (n = 4,720), seeks to explore associations of IT availability and utilization with practice performance at the national level. The multivariate regression analysis results suggest that patient information IT functionality upholds physician advantages in annual income but prescription drug IT functionality was reversely linked to annual income. We also found a negative association of patient information IT functionality with patient visit volume. Our study results revealed mixed findings. Not all IT functionalities would offer benefits to practicing physicians. Our data suggest that patient information IT functionality can moderate cost concerns related to IT investment among providers. PMID- 29389099 TI - Correlates and Consequences of Nursing Staff Job Insecurity. AB - The health care system, and hospitals, underwent considerable restructuring and downsizing in the early to mid-1900s in several countries as governments cut costs to reduce their budget deficits. Studies of the effects of these efforts on nursing staff and hospital functioning in various countries generally reported negative impacts with threats to job security emerging as an important outcome of these changes. Health care restructuring and hospital downsizing is again being implemented as governments struggle to reduce deficits at a time of worldwide economic recession in 2008/2010. This study examines correlates and consequences of job insecurity among Canadian nursing staff, with a focus on nurses' well being. Data were collected from 290 nursing staff working in hospitals in Ontario, Canada. Feelings of job insecurity in the sample as a whole were relatively low. Personal demographics and work situation characteristics were generally uncorrelated with feelings of job insecurity. Consistent with previous findings, perceived job insecurity was once again associated with less favorable work and well-being outcomes. Some suggestions for more successful approaches to addressing levels of subjective job insecurity are offered. PMID- 29389100 TI - Using Focus Groups to Modify the Workplace Affective Commitment Multidimensional Questionnaire (WACMQ) for use in Health Care. AB - BACKGROUND: The Workplace Affective Commitment Multidimensional Questionnaire (W ACMQ) measures affective commitment towards eight work-related targets. While this questionnaire was developed in the business sector, we believe that the multi-target conceptualization of affective commitment has applicability to complex health care contexts where providers of care, in the production and delivery of care, likely develop commitment toward a multiplicity of targets. Affective commitment is a strong predictor of extra-role workplace behavior; indispensable behaviors which enable health systems to function. OBJECTIVE: The aim of this psychometric exercise is to content validate the WACMQ questions for use in health care. METHODS: Two focus groups were conducted, consisting of nurses working in acute care and emergency hospitals in Ontario. Linguistic validation and cognitive debriefing were used. RESULTS: A total of 14 modifications to the wording of items on the original WACMQ questionnaire were made. CONCLUSIONS: This modified version of the WACMQ reflects the need for researchers in health care settings to acknowledge the complex context of health care and the attendant complexities of worker attitudes. Health care workers can experience affective commitment toward leadership (clinical or administrative), co-workers (nurses or interprofessional), patients, their profession, organization, work or tasks. Further, in some health care settings, features like union membership may have important implications when examining affective commitment or behaviors. Psychometric properties of the modified WACMQ will be established in an upcoming study that will examine the relationships between extra-role behaviors, commitment, perceived organizational support and justice within acute care and emergency departments of hospitals operating in Ontario. PMID- 29389105 TI - Chlorinated Polyfluorinated Ether Sulfonates Exhibit Higher Activity toward Peroxisome Proliferator-Activated Receptors Signaling Pathways than Perfluorooctanesulfonate. AB - Chlorinated polyfluorinated ether sulfonates (Cl-PFAESs) are the alternative products of perfluorooctanesulfonate (PFOS) in the metal plating industry in China. The similarity in chemical structures between Cl-PFAESs and PFOS makes it reasonable to assume they possess similar biological activities. In the present study, we investigated whether Cl-PFAESs could induce cellular effects through peroxisome proliferator-activated receptors (PPARs) signaling pathways like PFOS. By using fluorescence competitive binding assay, we found two dominant Cl-PFAESs (6:2 Cl-PFAES and 8:2 Cl-PFAES) bound to PPARs with affinity higher than PFOS. Based on the luciferase reporter gene transcription assay, the two Cl-PFAESs also showed agonistic activity toward PPARs signaling pathways with potency similar to (6:2 Cl-PFAES) or higher than (8:2 Cl-PFAES) PFOS. Molecular docking simulation showed the two Cl-PFAESs fitted into the ligand binding pockets of PPARs with very similar binding mode as PFOS. The cell function results showed Cl-PFAESs promoted the process of adipogenesis in 3T3-L1 cells with potency higher than PFOS. Taken together, we found for the first time that Cl-PFAESs have the ability to interfere with PPARs signaling pathways, and current exposure level of 6:2 Cl PFAES in occupational workers has exceeded the margin of safety. Our study highlights the potential health risks of Cl-PFAESs as PFOS alternatives. PMID- 29389104 TI - Performance assessment of diffuse optical spectroscopic imaging instruments in a 2-year multicenter breast cancer trial AB - We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received multiple DOSI scans prior to and during 3- to 6-month NAC. The impact of three sources of error on accuracy and precision, including different operators, instruments, and calibration standards, was evaluated using a broadband reflectance standard and two different solid tissue-simulating optical phantoms. Instruments showed <0.0010 mm-1 (10.3%) and 0.06 mm-1 (4.7%) deviation in broadband absorption andreduced scattering, respectively, over the 2-year duration of ACRIN-6691. These variations establish a useful performance criterion for assessing instrument stability. The proposed procedures and tests are not limited to DOSI; rather, they are intended to provide methods to characterize performance of any instrument used in translational optical imaging. PMID- 29389106 TI - 3D Nitrogen, Sulfur-Codoped Carbon Nanomaterial-Supported Cobalt Oxides with Polyhedron-Like Particles Grafted onto Graphene Layers as Highly Active Bicatalysts for Oxygen-Evolving Reactions. AB - The extensive research and developments of highly efficient oxygen electrode electrocatalysts to get rid of the kinetic barriers for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are very important in energy conversion and storage devices. Especially, exploring nonprecious metal alternatives to replace traditional noble metal catalysts with high cost and poor durability is the paramount mission. In this paper, we utilize property-flexible ZIF-67 and sulfur-functionalized graphene oxide to obtain a cobalt, nitrogen, and sulfur codoped nanomaterial with 3D hierarchical porous structures, owing to their rich dopant species and good conductivity. The crosslinked structures of polyhedron particles throughout the whole carbon framework speeds up the mass transportation and charge-delivery processes during oxygen-evolving reactions. Also, by exploring the location and coordination type of sulfur dopants, we emphasize the effects of sulfone and sulfide functional groups anchored into the graphitic structure on enhancing the catalytic abilities for ORR and OER. To note, compared to the noble metal electrocatalysts, the best-performing CoO@Co3O4/NSG-650 (0.79 V) is 40 mV less active than the commercial Pt/C catalyst (0.83 V) for ORR and merely 10 mV behind IrO2 (1.68 V) for OER. Besides, the metric between ORR and OER difference for CoO@Co3O4/NSG-650 to evaluate its overall electrocatalytic activity is 0.90 V, surpassing 290 and 430 mV over Pt/C (1.19 V) and IrO2 (1.33 V). Comprehensively, the as-prepared CoO@Co3O4/NSG-650 indicates excellent bifunctional catalytic activities for ORR and OER, which shows great potential for replacing noble metal catalysts in the application of fuel cells and metal air batteries. PMID- 29389107 TI - Glycine Perturbs Local and Global Conformational Flexibility of a Transmembrane Helix. AB - Flexible transmembrane helices frequently support the conformational transitions between different functional states of membrane proteins. While proline is well known to distort and destabilize transmembrane helices, the role of glycine is still debated. Here, we systematically investigated the effect of glycine on transmembrane helix flexibility by placing it at different sites within the otherwise uniform leucine/valine repeat sequence of the LV16 model helix. We show that amide deuterium/hydrogen exchange kinetics are increased near glycine. Molecular dynamics simulations reproduce the measured exchange kinetics and reveal, at atomic resolution, a severe packing defect at glycine that enhances local hydration. Furthermore, glycine alters H-bond occupancies and triggers a redistribution of alpha-helical and 310-helical H-bonds. These effects facilitate local helix bending at the glycine site and change the collective dynamics of the helix. PMID- 29389108 TI - Strongly Coupled Metal Oxide/Reassembled Carbon Nitride/Co-Pi Heterostructures for Efficient Photoelectrochemical Water Splitting. AB - The photoelectrochemical application of carbon nitride is extremely exciting because of the meta-free components, low cost, nontoxicity, and appropriate band positions. To construct carbon nitride-based heterostructures, a conventional ultrasonic exfoliation method is usually used to fabricate dispersion of ultrathin nanosheets. However, the outstretched structure and the poor dispersity inevitably result in the poor interfacial contact between different materials. To solve this problem, hydrolyzed carbon nitride suspension was used as a homogeneous precursor for the fabrication of composite photoanodes. The in situ reassembly of one-dimensional nanofibers resulted in the formation of uniform and ultrathin carbon nitride nanoarchitectures on the surface of Fe2O3 nanorod arrays. Because of the strongly coupled interfaces and the deposition of Co-Pi water oxidation cocatalysts, the as-synthesized heterostructured photoanodes exhibited three-fold increased photocurrent density and good stability, compared to pristine Fe2O3. The significantly improved photoactivity of the Fe2O3/reassembled carbon nitride/Co-Pi heterostructures was ascribed to the decreased interfacial conductivity and facilitated charge separation. This material designing strategy was further used to construct TiO2/carbon nitride, ZnO/carbon nitride, and WO3/carbon nitride heterostructures. The incorporation of hydrolyzed carbon nitride could remarkably enhance the photoelectrochemical performance of these metal oxide photoanodes. Thus, this work provides a new paradigm for designing carbon nitride-based composite nanostructures for efficient and stable solar fuel production. PMID- 29389109 TI - Tuning Wet Adhesion of Weak Polyelectrolyte Multilayers. AB - Weak polyelectrolyte multilayers (PEMs) assembled by the layer-by-layer method are known to become tacky upon contact with water and behave as a viscoelastic fluid, but this wet adhesive property and how it can be modified by external stimuli has not yet been fully explored. We present here a study on the wet adhesive performance of PEMs consisting of branched poly(ethylene imine) and poly(acrylic acid) under controlled conditions (e.g., pH, type of salt, and ionic strength) using a 90 degrees peel test. The multilayers demonstrate stick-slip behavior and fail cohesively in nearly all cases. The peel force is the highest at neutral pH, and it decreases in both acidic/basic environments because of inhibited polyelectrolyte mobility. The addition of salts with various metal ions generally reduces the peel force, and this effect tracks with the ionic strength. When transition metal ions are used, their ability to form coordination bonds increases the peel force, with two exceptions (Cu2+ and Zn2+). With a transition metal ion such as Fe3+, the peel force first increases as a function of the concentration and then eventually decreases. The peel force increases proportionally to the peel rate. The films are also characterized via zeta potential (when assembled onto colloidal particles) and shear rheometry. This work provides insight into both the wet adhesive properties of PEMs and the interactions between PEMs and metal ions. PMID- 29389110 TI - In Situ Observation of Light Illumination-Induced Degradation in Organometal Mixed-Halide Perovskite Films. AB - Organometal mixed-halide perovskite materials hold great promise for next generation solar cells, light-emitting diodes, lasers, and photodetectors. Except for the rapid progress in the efficiency of perovskite-based devices, the stability issue over prolonged light illumination has severely hindered their practical application. The deterioration mechanism of organometal halide perovskite materials under light illumination has seldom been conducted to date, which is indispensable to the understanding and optimization of photon-harvesting process inside perovskite-based optoelectronic devices. Here, explicit degradation pathways and comprehensive microscopic understandings of white-light induced degradation have been put forward for two organometal mixed-halide perovskite materials (e.g., MAPbI3-xClx and MAPbBr3-xClx) under high vacuum conditions. In situ compositional analysis and real-time film characterizations reveal that the decomposition of both mixed-halide perovskites starts at the grain boundaries, leading to the formation of hydrocarbons and ammonia gas with the residuals of PbI2(Cl), Pb, or PbClxBr2-x in the films. The degradation has been correlated to the localized trap states that induce strong coupling between photoexcited carriers and the crystal lattice. PMID- 29389112 TI - Biosynthesis of the Klebsiella oxytoca Pathogenicity Factor Tilivalline: Heterologous Expression, in Vitro Biosynthesis, and Inhibitor Development. AB - Tilvalline is a pyrrolo[4,2]benzodiazepine derivative produced by the pathobiont Klebsiella oxytoca and is the causative toxin in antibiotic associated hemorrhagic colitis (AAHC). Heterologous expression of the tilivalline biosynthetic gene cluster along with in vitro reconstitution of the respective NRPS (NpsA, ThdA, NpsB) was employed to reveal a nonenzymatic indole incorporation via a spontaneous Friedel-Crafts-like alkylation reaction. Furthermore, the heterologous system was used to generate novel tilivalline derivatives by supplementation of respective anthranilate and indole precursors. Finally, it could be shown that salicylic and acetylsalicylic acid inhibit the biosynthesis of tilivalline in K. oxytoca liquid culture, presumably by blocking the peptidyl carrier protein ThdA, pointing toward a potential application in combination therapy to prevent or alleviate the symptoms of AAHC. PMID- 29389113 TI - Theoretical Investigation of the Electronic Properties of Three Vanadium Phthalocyaninato (Pc) Based Complexes: PcV, PcVO, and PcVI. AB - The electronic properties of three vanadium phthalocyaninato (Pc) based complexes (PcV, PcVO, and PcVI; I-III, respectively) were theoretically investigated and corresponding VL2,3-edge XAS spectra modeled. Ground state (GS) DFT outcomes indicated that II is more stable than III by 141 kcal/mol; moreover, the Ziegler transition state method allowed us to estimate the PcV-X bond dissociation energy and to quantify sigma/pi contributions to the V-X interaction. As such, the Nalewajski-Mrozek V-X and V-N bond multiplicity indexes (V-O/V-I = 2.48/1.22; V-N = 0.64, 0.51, and 0.58 in I-III, respectively) state that the V-X bond strength and nature affect the V-N interaction. The coordination of X to V in the I -> II/I -> III reactions implies the transfer of two/one electrons from I to X. In both cases, the oxidation involves only the V ion; moreover, V 3d based orbitals from which electrons are transferred were identified. Literature I/IIL2,3-edge XAS data were modeled by exploiting the DFT/ROCIS method. The same protocol was adopted to predict IIIL2,3-edge XAS spectra. Theoretical results indicated that, along the whole series, spectral features lying at the lowest excitation energies (EEs) are mostly generated by states having the same GS spin multiplicity and involve 2pV -> SOMO (single occupied molecular orbital) single electronic excitations. XAS features at higher EEs include only states with the same GS spin multiplicity in I, while states with both DeltaS = 0 and DeltaS = +1 (S = total spin quantum number) are present in II and III with significant, in some cases prevailing, contributions from metal to ligand charge transfer (MLCT) excitations. Beyond the role played by MLCT transitions in determining XAS patterns, it is noteworthy that they involve only Pc-based empty orbitals with no participation of the X-based virtual levels. PMID- 29389111 TI - Evidence of a General Acid-Base Catalysis Mechanism in the 8-17 DNAzyme. AB - DNAzymes are catalytic DNA molecules that can perform a variety of reactions. Although advances have been made in obtaining DNAzymes via in vitro selection and many of them have been developed into sensors and imaging agents for metal ions, bacteria, and other molecules, the structural features responsible for these enzymatic reactions are still not well understood. Previous studies of the 8-17 DNAzyme have suggested conserved guanines close to the phosphodiester transfer site may play a role in the catalytic reaction. To identify the specific guanine and functional group of the guanine responsible for the reaction, we herein report the effects of replacing G1.1 and G14 (G; p Ka,N1 = 9.4) with analogues with a different p Ka at the N1 position, such as inosine (G14I; p Ka,N1 = 8.7), 2,6-diaminopurine (G14diAP; p Ka,N1 = 5.6), and 2-aminopurine (G14AP; p Ka,N1 = 3.8) on pH-dependent reaction rates. A comparison of the pH dependence of the reaction rates of these DNAzymes demonstrated that G14 in the bulge loop next to the cleavage site, is involved in proton transfer at the catalytic site. In contrast, we did not find any evidence of G1.1 being involved in acid-base catalysis. These results support general acid-base catalysis as a feasible strategy used in DNA catalysis, as in RNA and protein enzymes. PMID- 29389115 TI - Identification of a Unique Inhibitor-Binding Site on Choline Kinase alpha. AB - Choline kinase alpha (ChoKalpha) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKalpha, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear. One particular inhibitor, designated TCD-717, has recently completed phase I clinical trials. Cell culture and in vitro studies support the powerful inhibitory effect TCD-717 has on ChoKalpha, but an examination of the inhibitor's interaction with the ChoKalpha enzyme has been missing prior to this work. Here we detail the 2.35 A structure of ChoKalpha in complex with TCD-717. Examination of this structure in conjunction with kinetic assays reveals that TCD-717 does not bind directly in the choline pocket as do previously characterized ChoKalpha inhibitors, but rather in a proximal but novel location near the surface of the enzyme. The unique binding site identified for TCD-717 lends insight for the future design of more potent in vivo inhibitors for ChoKalpha. PMID- 29389114 TI - Biphilic Organophosphorus-Catalyzed Intramolecular Csp2-H Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations. AB - A small-ring phosphacycloalkane (1,2,2,3,4,4-hexamethylphosphetane, 3) catalyzes intramolecular C-N bond forming heterocyclization of o-nitrobiaryl and -styrenyl derivatives in the presence of a hydrosilane terminal reductant. The method provides scalable access to diverse carbazole and indole compounds under operationally trivial homogeneous organocatalytic conditions, as demonstrated by 17 examples conducted on 1 g scale. In situ NMR reaction monitoring studies support a mechanism involving catalytic PIII/PV?O cycling, where tricoordinate phosphorus compound 3 represents the catalytic resting state. For the catalytic conversion of o-nitrobiphenyl to carbazole, the kinetic reaction order was determined for phosphetane catalyst 3 (first order), substrate (first order), and phenylsilane (zeroth order). For differentially 5-substituted 2-nitrobiphenyls, the transformation is accelerated by electron-withdrawing substituents (Hammett factor rho = +1.5), consistent with the accrual of negative charge on the nitro substrate in the rate-determining step. DFT modeling of the turnover-limiting deoxygenation event implicates a rate-determining (3 + 1) cheletropic addition between the phosphetane catalyst 3 and 2-nitrobiphenyl substrate to form an unobserved pentacoordinate spiro-bicyclic dioxazaphosphetane, which decomposes via (2 + 2) cycloreversion giving 1 equiv of phosphetane P-oxide 3.[O] and 2 nitrosobiphenyl. Experimental and computational investigations into the C-N bond forming event suggest the involvement of an oxazaphosphirane (2 + 1) adduct between 3 and 2-nitrosobiphenyl, which evolves through loss of phosphetane P oxide 3.[O] to give the observed carbazole product via C-H insertion in a nitrene like fashion. PMID- 29389116 TI - Dual-Bioinspired Design for Constructing Membranes with Superhydrophobicity for Direct Contact Membrane Distillation. AB - Water flux and durability are the two critical parameters that are closely associated with the practical application of membrane distillation (MD). Herein, we report a facile approach to fabricate superhydrophobic polyimide nanofibrous membranes (PI NFMs) with hierarchical structures, interconnected pores, and high porosity, which was derived from the electrospinning, dual-bioinspired design, and fluorination processes. Bioinspired adhesive based on polydopamine /polyethylenimine (PDA/PEI) composite was first linked onto membrane substrates and then assembled lotus leaf hierarchical structure by binding the negatively charged silica nanoparticles (SiO2 NPs) via electrostatic attraction. The resultant superhydrophobic PI NFMs exhibit a water contact angle of 152 degrees , robust hot water resistance of 85 degrees C, and high water entry pressure of 42 kPa. Moreover, the membrane with omniphobicity presents high water flux over 31 L m-2 h-1 and high salts rejection of ~100% as well as robust durability for treating high salinity wastewater containing typical low surface tension and dissolved contaminants (Delta T = 40 degrees C). Significantly, the novel dual bioinspired method can be used as a universal tool to modify various materials with hierarchical structures, which is expected to provide more effective alternative membranes for MD and even for other selective wetting separation fields. PMID- 29389117 TI - Revised Theoretical Model on Enantiocontrol in Phosphoric Acid Catalyzed H Transfer Hydrogenation of Quinoline. AB - The enantioselective H-transfer hydrogenation of quinoline by Hantzsch ester is a relevant example of Bronsted acid catalyzed cascade reactions, with phosphoric acid being a privileged catalyst. The generally accepted mechanism points out the hydride transfer step as the rate- and stereodetermining step, however computations based on these models do not totally fit with experimental observations. We hereby present a computational study that enlightens the stereochemical outcome and quantitatively reproduces the experimental enantiomeric excesses in a series of H-transfer hydrogenations. Our calculations suggest that the high stereocontrol usually attained with BINOL-derived phosphoric acids results mostly from the steric constraints generated by an aryl substituent of the catalyst, which hinders the access of the Hantzsch ester to the catalytic site and enforces approach through a specific way. It relies on a new model involving the preferential assembly of one of the stereomeric complexes formed by the chiral phosphoric acid and the two reaction partners. The stereodetermining step thus occurs prior to the H-transfer step. PMID- 29389118 TI - Total Synthesis of ent-Ascospiroketal B. AB - Ascospiroketal B was isolated from a marine-derived fungus as a structurally unique polyketide possessing a rare tricyclic core including 5,5-spiroketal-gamma lactone. An asymmetric total synthesis of ent-ascospiroketal B was achieved using an original synthetic route. The synthesis included the stereoselective construction of 5,5-spiroketal for ascospiroketal B and stereocontrolled construction of a quaternary asymmetric carbon by rearrangement of a trisubstituted epoxide. PMID- 29389119 TI - Large and Small Assembly: Combining Functional Macromolecules with Small Peptides to Control the Morphology of Skeletal Muscle Progenitor Cells. AB - The material properties of natural tissues, such as skeletal muscle, are highly sophisticated and are synthetically challenging to mimic. Using natural biomacromolecules to functionalize self-assembled peptide (SAP) hydrogels has the potential to increase the utility of these materials by more closely reproducing the natural cellular environment. Here, to demonstrate that a conserved co assembly pathway can retain distinct function, the biocompatible peptide derivative Fmoc-FRGDF was co-assembled with either a sulfated polysaccharide, fucoidan, or the provisional matrix proteoglycan, versican. Our results demonstrate that thermodynamically driven co-assembly with biologically active macromolecules is facile, stable, and does not affect the final assembled nanostructure. Biologically, the incorporation of these functionally distinct molecules had no effect on C2C12 myoblast proliferation and viability but strongly altered their morphology. The surface area of myoblasts cultured on the fucoidan scaffold was reduced at 24 and 72 h post seeding, with a reduction in the formation of multinucleated syncytia. Myoblasts cultured on versican scaffolds were smaller compared to cells grown on the empty vector scaffolds at 24 h but not 72 h post seeding, with multinucleated syncytia formation being unaffected. This work allows programmed and distinct morphological effects of cell behavior, paving the way for further mechanistic studies. PMID- 29389120 TI - Structure and Hydrogenation Properties of a HfNbTiVZr High-Entropy Alloy. AB - A high-entropy alloy (HEA) of HfNbTiVZr was synthesized using an arc furnace followed by ball milling. The hydrogen absorption mechanism was studied by in situ X-ray diffraction at different temperatures and by in situ and ex situ neutron diffraction experiments. The body centered cubic (BCC) metal phase undergoes a phase transformation to a body centered tetragonal (BCT) hydride phase with hydrogen occupying both tetrahedral and octahedral interstitial sites in the structure. Hydrogen cycling of the alloy at 500 degrees C is stable. The large lattice strain in the HEA seems favorable for absorption in both octahedral and tetrahedral sites. HEAs therefore have potential as hydrogen storage materials because of favorable absorption in all interstitial sites within the structure. PMID- 29389121 TI - An Anti-Inflammatory PPAR-gamma Agonist from the Jellyfish-Derived Fungus Penicillium chrysogenum J08NF-4. AB - An investigation of the jellyfish-derived fungus Penicillium chrysogenum J08NF-4 led to the isolation of two new meroterpene derivatives, chrysogenester (1) and 5 farnesyl-2-methyl-1-O-methylhydroquinone (2), and four known farnesyl meroterpenes. Docking analysis of 1 showed that it binds to PPAR-gamma in the same manner as the natural PPAR-gamma agonist amorfrutin B (7). Compound 1 activated PPAR-gamma in murine Ac2F liver cells and increased nuclear PPAR-gamma protein levels in murine RAW 264.7 macrophages. Because one of the main biological functions of PPAR-gamma agonists is to suppress inflammatory response, an in vitro study was performed to explore the anti-inflammatory potency of 1 and the mechanism involved. In RAW 264.7 macrophages, 1 inhibited phosphorylation of the NF-kappaB p65 subunit and suppressed the expression of the pro-inflammatory mediators iNOS, NO, COX-2, TNF-alpha, IL-1beta, and IL-6. We propose 1 suppresses inflammatory responses by activating PPAR-gamma and subsequently downregulating the NF-kappaB signaling pathway, thus reducing the expressions of pro inflammatory mediators. PMID- 29389122 TI - Cyclizidine-Type Alkaloids from Streptomyces sp. HNA39. AB - Eight new cyclizidine-type alkaloids (1-8) and one known alkaloid (9) were identified from the chemical investigations of a marine-derived actinomycete, Streptomyces sp. HNA39. Among these alkaloids, compounds 3, 7, and 8 contain a chlorine atom, and the known alkaloid, (+)-ent-cyclizidine (9), is now first reported as a natural product. Their structures were elucidated by extensive NMR spectroscopic analysis and HRESIMS data. The absolute configurations of all of the compounds were established by ECD calculations. Cytotoxicity evaluations of all of the compounds showed that compound 2 exhibited significant activity against the PC3 and HCT116 human-cancer-cell lines with IC50 values of 0.52 +/- 0.03 and 8.3 +/- 0.1 MUM, respectively. Interestingly, compounds 2, 5, 7, and 8 exhibited moderate inhibition against the ROCK2 protein kinase with IC50 values from 7.0 +/- 0.8 to 42 +/- 3 MUM. PMID- 29389123 TI - Molecular Design, Synthesis, and Asymmetric Catalysis of a Hexacoordinated Chiral Phosphate Ion. AB - We describe the design, synthesis, and characterization of a chiral hexacoordinated phosphate ion that features an octahedral P(V) core consisting of two N,N,O-tridentate backbones. We further demonstrate that the corresponding hydrogen phosphate acts as an effective catalyst for a highly enantioselective Pictet-Spengler-type reaction, wherein the relationship between the structure of the chiral phosphate ion and its ability to dictate the absolute stereochemistry is revealed in conjunction with precise structural elucidation of the phosphate ion. PMID- 29389124 TI - Shedding Light on the Protonation States and Location of Protonated N Atoms of Adenine in Metal-Organic Frameworks. AB - We report the syntheses and structures of five metal-organic frameworks (MOFs) based on transition metals (NiII, CuII, and ZnII), adenine, and di-, tri-, and tetra-carboxylate ligands. Adenine, with multiple N donor sites, was found to coordinate to the metal centers in different binding modes including bidentate (through N7 and N9, or N3 and N9) and tridentate (through N3, N7, and N9). Systematic investigations of the protonation states of adenine in each MOF structure via X-ray photoelectron spectroscopy revealed that adenine can be selectively protonated through N1, N3, or N7. The positions of H atoms connected to the N atoms were found from the electron density maps, and further supported by the study of C-N-C bond angles compared to the literature reports. DFT calculations were performed to geometrically optimize and energetically assess the structures simulated with different protonation modes. The present study highlights the rich coordination chemistry of adenine and provides a method for the determination of its protonation states and the location of protonated N atoms of adenine within MOFs, a task that would be challenging in complicated adenine-based MOF structures. PMID- 29389126 TI - Quasi-2D Heisenberg Antiferromagnets [CuX(pyz)2](BF4) with X = Cl and Br. AB - Two Cu2+ coordination polymers [CuCl(pyz)2](BF4) 1 and [CuBr(pyz)2](BF4) 2 (pyz = pyrazine) were synthesized in the family of quasi two-dimensional (2D) [Cu(pyz)2]2+ magnetic networks. The layer connectivity by monatomic halide ligands results in significantly shorter interlayer distances. Structures were determined by single-crystal X-ray diffraction. Temperature-dependent X-ray diffraction of 1 revealed rigid [Cu(pyz)2]2+ layers that do not expand between 5 K and room temperature, whereas the expansion along the c-axis amounts to 2%. The magnetic susceptibility of 1 and 2 shows a broad maximum at ~8 K, indicating antiferromagnetic interactions within the [Cu(pyz)2]2+ layers. 2D Heisenberg model fits result in J? = 9.4(1) K for 1 and 8.9(1) K for 2. The interlayer coupling is much weaker with | J?| = 0.31(6) K for 1 and 0.52(9) K for 2. The electron density, experimentally determined and calculated by density functional theory, confirms the location of the singly occupied orbital (the magnetic orbital) in the tetragonal plane. The analysis of the spin density reveals a mainly sigma-type exchange through pyrazine. Kinks in the magnetic susceptibility indicate the onset of long-range three-dimensional magnetic order below 4 K. The magnetic structures were determined by neutron diffraction. Magnetic Bragg peaks occur below TN = 3.9(1) K for 1 and 3.8(1) K for 2. The magnetic unit cell is doubled along the c-axis ( k = 0, 0, 0.5). The ordered magnetic moments are located in the tetragonal plane and amount to 0.76(8) MUB/Cu2+ for 1 and 0.6(1) MUB/Cu2+ for 2 at 1.5 K. The moments are coupled antiferromagnetically both in the ab plane and along the c-axis. The Cu2+ g-tensor was determined from electron spin resonance spectra as g x = 2.060(1), g z = 2.275(1) for 1 and g x = 2.057(1), g z = 2.272(1) for 2 at room temperature. PMID- 29389127 TI - Modeling the Reactions Catalyzed by Coenzyme B12 Dependent Enzymes: Accuracy and Cost-Quality Balance. AB - The reactions catalyzed by coenzyme B12 dependent enzymes are formally initiated by the homolytic cleavage of a carbon-cobalt bond and a subsequent or concerted H atom-transfer reaction. A reasonable model chemistry for describing those reactions should, therefore, account for an accurate description of both reactions. The inherent limitation due to the necessary system size renders the coenzyme B12 system a suitable candidate for DFT or hybrid QM/MM methods; however, the accurate description of both homolytic Co-C cleavage and H-atom transfer reactions within this framework is challenging and can lead to controversial results with varying accuracy. We present an assessment study of 16 common density functionals applied to prototypical model systems for both reactions. H-abstraction reactions were modeled on the basis of four reference reactions designed to resemble a broad range of coenzyme B12 reactions. The Co-C cleavage reaction is treated by an ONIOM(QM/MM) setup that is in excellent agreement with solution-phase experimental data and is as accurate as full DFT calculations on the complete model system. We find that the meta-GGAs TPSS-D3 and M06L-D3 and the meta-hybrid M06-D3 give the best overall performance with MUEs for both types of reactions below 10 kJ mol-1. Our recommended model chemistry allows for a fast and accurate description of coenzyme B12 chemistry that is readily applicable to study the reactions in an enzymatic framework. PMID- 29389125 TI - Biomimetic Stereoselective Sulfa-Michael Addition Leads to Platensimycin and Platencin Sulfur Analogues against Methicillin-Resistant Staphylococcus aureus. AB - Several sulfur-containing platensimycin (PTM) and platencin (PTN) analogues, with activities comparable to the parent natural products, have recently been discovered from microorganisms, implying a biomimetic route to diversify the PTM and PTN scaffolds for structure-activity relationship study. We present here a substrate-directed and scaleable semisynthetic strategy to make PTM and PTN sulfur analogues with excellent diasteroselectivity, without using any chiral catalysts. Most of the sulfur analogues showed strong activities against clinical Staphylococcus aureus isolates, with minimum inhibitory concentrations of 0.5-2 MUg mL-1. Density functional theory calculations were in agreement with the observed selectivity for these analogues and suggest that the conformation restraints of the terpene cages of PTM and PTN on the transition states determine the si-face attack selectivity. PMID- 29389128 TI - Molecular and Kinetic Models for High-Rate Thermal Degradation of Polyethylene. AB - Thermal degradation of polyethylene is studied under the extremely high rate temperature ramps expected in laser-driven and X-ray ablation experiments-from 1010 to 1014 K/s in isochoric, condensed phases. The molecular evolution and macroscopic state variables are extracted as a function of density from reactive molecular dynamics simulations using the ReaxFF potential. The enthalpy, dissociation onset temperature, bond evolution, and observed cross-linking are shown to be rate dependent. These results are used to parametrize a kinetic rate model for the decomposition and coalescence of hydrocarbons as a function of temperature, temperature ramp rate, and density. The results are contrasted to first-order random-scission macrokinetic models often assumed for pyrolysis of linear polyethylene under ambient conditions. PMID- 29389129 TI - First-Principle Investigations of the Interaction between CO and O2 with Group 11 Atoms on a Defect-Free MgO(001) Surface. AB - In this contribution, we investigate the interaction between CO and O2 with metal atoms of group 11 deposited on a defect-free magnesium oxide surface using density functional theory with periodic point charge embedding. We present the first transversal study of the adsorption and coadsorption of CO and O2 on coinage metal adatoms deposited on metal oxide surfaces from the perspective of single-atom catalysis. Various analysis tools shed light on the binding situation of the metal atoms to the substrate as well as on the situation of the two molecules on the different metal centers. Our analysis demonstrates that cooperative electronic effects enhance the stability of CO upon coadsorption with O2 for all three metal centers. Our results also explain the lack of catalytic activity of group 11 metal atoms with respect to CO oxidation under thermal conditions as a competition between OC-O2 bond activation and surface diffusion, leading to metal atom agglomeration. Additionally, it is shown how coadsorption of CO and O2 on Au/Mg(001) could pave the way to single-atom photocatalysis. PMID- 29389130 TI - The X40*10 Halogen Bonding Benchmark Revisited: Surprising Importance of (n-1)d Subvalence Correlation. AB - We have re-evaluated the X40*10 benchmark for halogen bonding using conventional and explicitly correlated coupled cluster methods. For the aromatic dimers at small separation, improved CCSD(T)-MP2 "high-level corrections" (HLCs) cause substantial reductions in the dissociation energy. For the bromine and iodine species, (n-1)d subvalence correlation increases dissociation energies and turns out to be more important for noncovalent interactions than is generally realized; (n-1)sp subvalence correlation is much less important. The (n-1)d subvalence term is dominated by core-valence correlation; with the smaller cc-pVDZ-F12-PP and cc pVTZ-F12-PP basis sets, basis set convergence for the core-core contribution becomes sufficiently erratic that it may compromise results overall. The two factors conspire to generate discrepancies of up to 0.9 kcal/mol (0.16 kcal/mol RMS) between the original X40*10 data and the present revision. PMID- 29389131 TI - Regioselective Sulfenylation of alpha'-CH3 or alpha'-CH2 Groups of alpha,beta Unsaturated Ketones with Heterocyclic Thiols. AB - A rare regioselective sulfenylation of alpha'-CH3 or alpha'-CH2 bonds adjacent to alpha,beta-unsaturated ketones using dimethyl sulfoxide as an oxidant and a substoichiometric amount of aq HI as an additive is described. This methodology employs a strong acid such as aq HI or iodine and exhibits a high regioselectivity without undergoing conjugate addition, which is difficult to achieve under the cross dehydrogenative coupling method. PMID- 29389132 TI - Anomalous Li Storage Capability in Atomically Thin Two-Dimensional Sheets of Nonlayered MoO2. AB - Since the first exfoliation and identification of graphene in 2004, research on layered ultrathin two-dimensional (2D) nanomaterials has achieved remarkable progress. Realizing the special importance of 2D geometry, we demonstrate that the controlled synthesis of nonlayered nanomaterials in 2D geometry can yield some unique properties that otherwise cannot be achieved in these nonlayered systems. Herein, we report a systematic study involving theoretical and experimental approaches to evaluate the Li-ion storage capability in 2D atomic sheets of nonlayered molybdenum dioxide (MoO2). We develop a novel monomer assisted reduction process to produce high quality 2D sheets of nonlayered MoO2. When used as lithium-ion battery (LIB) anodes, these ultrathin 2D-MoO2 electrodes demonstrate extraordinary reversible capacity, as high as 1516 mAh g-1 after 100 cycles at the current rate of 100 mA g-1 and 489 mAh g-1 after 1050 cycles at 1000 mA g-1. It is evident that these ultrathin 2D sheets did not follow the normal intercalation-cum-conversion mechanism when used as LIB anodes, which was observed for their bulk analogue. Our ex situ XPS and XRD studies reveal a Li storage mechanism in these 2D-MoO2 sheets consisting of an intercalation reaction and the formation of metallic Li phase. In addition, the 2D-MoO2 based microsupercapacitors exhibit high areal capacitance (63.1 mF cm-2 at 0.1 mA cm 2), good rate performance (81% retention from 0.1 to 2 mA cm-2), and superior cycle stability (86% retention after 10,000 cycles). We believe that our work identifies a new pathway to make 2D nanostructures from nonlayered compounds, which results in an extremely enhanced energy storage capability. PMID- 29389133 TI - Strain Control of Exciton-Phonon Coupling in Atomically Thin Semiconductors. AB - Semiconducting transition metal dichalcogenide (TMDC) monolayers have exceptional physical properties. They show bright photoluminescence due to their unique band structure and absorb more than 10% of the light at their excitonic resonances despite their atomic thickness. At room temperature, the width of the exciton transitions is governed by the exciton-phonon interaction leading to strongly asymmetric line shapes. TMDC monolayers are also extremely flexible, sustaining mechanical strain of about 10% without breaking. The excitonic properties strongly depend on strain. For example, exciton energies of TMDC monolayers significantly redshift under uniaxial tensile strain. Here, we demonstrate that the width and the asymmetric line shape of excitonic resonances in TMDC monolayers can be controlled with applied strain. We measure photoluminescence and absorption spectra of the A exciton in monolayer MoSe2, WSe2, WS2, and MoS2 under uniaxial tensile strain. We find that the A exciton substantially narrows and becomes more symmetric for the selenium-based monolayer materials, while no change is observed for atomically thin WS2. For MoS2 monolayers, the line width increases. These effects are due to a modified exciton-phonon coupling at increasing strain levels because of changes in the electronic band structure of the respective monolayer materials. This interpretation based on steady-state experiments is corroborated by time-resolved photoluminescence measurements. Our results demonstrate that moderate strain values on the order of only 1% are already sufficient to globally tune the exciton-phonon interaction in TMDC monolayers and hold the promise for controlling the coupling on the nanoscale. PMID- 29389134 TI - Atomically Intercalating Tin Ions into the Interlayer of Molybdenum Oxide Nanobelt toward Long-Cycling Lithium Battery. AB - Atomic intercalation of different agents into 2D layered materials can engineer the intrinsic structure on the atomic scale and thus tune the physical and chemical properties for specific applications. Here we successfully introduce tin (Sn) atoms into the interlayer of alpha-MoO3 nanobelts forming a new MoO3-Sn intercalation with ultrastable structure. Combining with theoretical calculations, our synchrotron radiation-based characterizations and electron microscope observations clearly reveal that the intercalated Sn atoms could bond with five O atoms, forming a pentahedral structure. Subsequently, the Sn-O bonds induce a less distorted [MoO6] octahedral structure, resulting in a unique structure that is distinct with pristine alpha-MoO3 or any other molybdenum oxides. Employed as anode for lithium-ion battery, the as-prepared MoO3-Sn nanobelts display a much higher capacity of 520 mAhg-1 at 500 mAg-1 than alpha MoO3 nanobelts (291 mAhg-1), with a Coulombic efficiency of 99.5%. Moreover, owing to the strong intercalation from Sn ions, the MoO3-Sn nanobelts pose superior cyclability, durability, and reliability. PMID- 29389135 TI - Tuning Drop Motion by Chemical Chessboard-Patterned Surfaces: A Many-Body Dissipative Particle Dynamics Study. AB - Controlling the motion of liquid drops on the solid surface has broad technological implications. In this study, the many-body dissipative particle dynamics (MDPD) was employed to study the drop behaviors on chemical chessboard patterned surfaces formed by square or triangular tiles. The scaling relationship of the model was established based on the surface tension, viscosity, and density of a real fluid, and an improved contact angle measurement technique was introduced to the MDPD system. For drops on a horizontal plane with different tile sizes, the equilibrium morphology was examined. The critical Bond number, that is, the critical dimensionless force which is required to unpin the drop, was found strongly affected by the size and the shape of the tiles. Once the droplet begins to move, the tile pattern and the size strongly affect the velocity fluctuation while weakly affect the average velocity. Interestingly, besides the common straight forward path, two more route patterns (zigzag and oblique) were observed by only tuning the tile angle, indicating that the advancing routes of the drop may vary according to the tile angle. To the author's knowledge, this phenomenon has not been reported in the literature. This study provides a valuable tool to explore the possibility of passive control of the drop's motion by energy-free chemical heterogeneous surfaces and thus is helpful for engineers to design a surface that could manipulate the drop motion without external energy. PMID- 29389136 TI - High-Quality CH3NH3PbI3 Films Obtained via a Pressure-Assisted Space-Confined Solvent-Engineering Strategy for Ultrasensitive Photodetectors. AB - High-quality organic-inorganic hybrid perovskite films are crucial for excellent performance of photoelectric devices. Herein, we demonstrate a pressure-assisted space-confined solvent-engineering strategy to grow highly oriented, pinhole-free thin films of CH3NH3PbI3 with large-scale crystalline grains, high smoothness, and crystalline fusion on grain boundaries. These single-crystalline grains vertically span the entire film thickness. Such a film feature dramatically reduces recombination loss and then improves the transport property of charge carriers in the films. Consequently, the photodetector devices, based on the high quality CH3NH3PbI3 films, exhibit high photocurrent (105 MUA under 671 nm laser with a power density of 20.6 mW/cm2 at 10 V), good stability, and, especially, an ultrahigh on/off ratio (Ilight/Idark > 2.2 * 104 under an incident light of 20.6 mW/cm2). These excellent performances indicate that the high-quality films will be potential candidates in other CH3NH3PbI3-based photoelectric devices. PMID- 29389137 TI - Investigating the Role of the Organic Cation in Formamidinium Lead Iodide Perovskite Using Ultrafast Spectroscopy. AB - Organic cation rotation in hybrid organic-inorganic lead halide perovskites has previously been associated with low charge recombination rates and (anti)ferroelectric domain formation. Two-dimensional infrared spectroscopy (2DIR) was used to directly measure 470 +/- 50 fs and 2.8 +/- 0.5 ps time constants associated with the reorientation of formamidinium cations (FA+, NH2CHNH2+) in formamidinium lead iodide perovskite thin films. Molecular dynamics simulations reveal the FA+ agitates about an equilibrium position, with NH2 groups pointing at opposite faces of the inorganic lattice cube, and undergoes 90 degrees flips on picosecond time scales. Time-resolved infrared measurements revealed a prominent vibrational transient feature arising from a vibrational Stark shift: photogenerated charge carriers increase the internal electric field of perovskite thin films, perturbing the FA+ antisymmetric stretching vibrational potential, resulting in an observed 5 cm-1 shift. Our 2DIR results provide the first direct measurement of FA+ rotation inside thin perovskite films, and cast significant doubt on the presence of long-lived (anti)ferroelectric domains, which the observed low charge recombination rates have been attributed to. PMID- 29389138 TI - Synthesis of Chiral 1,2-Oxazinanes and Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes. AB - The first catalytic enantioselective nitroso aldol reaction of distal dialdehydes is reported. The reaction is catalyzed by simple l-proline at room temperature and subsequent reduction delivered biologically potent and synthetically versatile N-O bond containing five- and six-membered heterocycles, 1,2 oxazinanes, and isoxazolidines in high yields and excellent enantioselectivities (up to >99% ee). The method was further exploited to prepare chiral 3 hydroxypiperidines and -pyrrolidines that are otherwise difficult to access. PMID- 29389139 TI - Inhibitor-GCPII Interaction: Selective and Robust System for Targeting Cancer Cells with Structurally Diverse Nanoparticles. AB - Glutamate carboxypeptidase II (GCPII) is a membrane protease overexpressed by prostate cancer cells and detected in the neovasculature of most solid tumors. Targeting GCPII with inhibitor-bearing nanoparticles can enable recognition, imaging, and delivery of treatments to cancer cells. Compared to methods based on antibodies and other large biomolecules, inhibitor-mediated targeting benefits from the low molecular weight of the inhibitor molecules, which are typically stable, easy-to-handle, and able to bind the enzyme with very high affinity. Although GCPII is established as a molecular target, comparing previously reported results is difficult due to the different methodological approaches used. In this work, we investigate the robustness and limitations of GCPII targeting with a diverse range of inhibitor-bearing nanoparticles (various structures, sizes, bionanointerfaces, conjugation chemistry, and surface densities of attached inhibitors). Polymer-coated nanodiamonds, virus-like particles based on bacteriophage Qbeta and mouse polyomavirus, and polymeric poly(HPMA) nanoparticles with inhibitors attached by different means were synthesized and characterized. We evaluated their ability to bind GCPII and interact with cancer cells using surface plasmon resonance, inhibition assay, flow cytometry, and confocal microscopy. Regardless of the diversity of the investigated nanosystems, they all strongly interact with GCPII (most with low picomolar Ki values) and effectively target GCPII-expressing cells. The robustness of this approach was limited only by the quality of the nanoparticle bionanointerface, which must be properly designed by adding a sufficient density of hydrophilic protective polymers. We conclude that the targeting of cancer cells overexpressing GCPII is a viable approach transferable to a broad diversity of nanosystems. PMID- 29389140 TI - Live Cell Microscopy: A Physical Chemistry Approach. AB - Probing dynamics of intracellular components using physical chemistry techniques is a remarkable bottom-up approach for understanding the structures and functions of a biological cell. In this "Feature Article", we give an overview on local polarity, solvation, viscosity, acid-base property, red-ox processes (thiol disulfide exchange), and gene silencing at selected intracellular components inside a live cell. Significant differences have been observed between cancer cells and their noncancer counterparts. We demonstrate that thiol-disulfide exchange, calcium oscillation, and gene silencing are manifested in time dependence of fluorescence intensity. We show that fluorescent gold nanoclusters may be used in drug delivery (e.g., doxorubicin) and selective killing of cancer cells. Further, we discuss dynamics and structural changes of DNA quadruplexes and i-motifs, induced by different external conditions (e.g., pH) and additives (e.g., K+ and other target specific small molecules). We demonstrate that peptidomimetic analogues have high specificity over double-stranded DNA for binding with i-motifs and G-quadruplexes. These results may have significant biological implications. PMID- 29389141 TI - Romantic involvement: A protective factor for psychological health in racially diverse young sexual minorities. AB - Sexual minority youth experience elevated rates of internalizing disorders; it is, therefore, important to identify protective factors that decrease risk for psychological distress in this population. In this study, we examined whether involvement in a romantic relationship, a well-established protective factor for mental health among heterosexual adults, is also protective for young sexual minorities. Using eight waves of data provided by a community sample of 248 racially diverse sexual minority youth (ages 16-20 years at baseline), we assessed within-person associations between relationship involvement and psychological distress. Results from multilevel structural equation models indicated that, overall, participants reported less psychological distress at waves when they were in a relationship than when they were not. However, findings differed as a function of race/ethnicity and sexual orientation. Specifically, although relationship involvement predicted lower psychological distress for Black and gay/lesbian participants, the association was not present for White participants and, for bisexuals, relationship involvement predicted higher distress. In addition, relationship involvement reduced the negative association between victimization based on sexual minority status and psychological distress, suggesting a stress-buffering effect that did not differ based on demographic factors. Together, these findings suggest that being in a romantic relationship may promote mental health for many, but not all, young sexual minorities, highlighting the importance of attending to differences among subgroups of sexual minorities in research, theory, and efforts to reduce mental health disparities. (PsycINFO Database Record PMID- 29389142 TI - A randomized controlled trial of financial incentives to low income pregnant women to engage in smoking cessation treatment: Effects on post-birth abstinence. AB - OBJECTIVE: Evaluate the effectiveness of monetary incentives for increasing engagement in smoking cessation treatment and improving 6-month abstinence in low income pregnant smokers. METHOD: Two-group randomized clinical trial recruiting low-income (Medicaid-registered) pregnant smokers receiving assistance through a perinatal support program. Participants were randomized to either an incentive (n = 505) or control condition (n = 509). All participants were offered identical smoking cessation counseling at contacts. Incentive condition participants received incentives for attending pre- and postbirth treatment contacts: $25 for each of 6 prebirth provider visits, $25-40 for each of 4 postbirth home visits at Weeks 1, 2, 4, and 6 (total = $130), $20 for each of 5 postbirth counseling calls and $40 for biochemically verified abstinence at the Week 1 and 6-month visits. Control condition participants received only $40 for attendance at the Week 1 and 6-month postbirth visits ($40 each). MAIN OUTCOMES: Primary outcome was biochemically confirmed 7-day point-prevalence abstinence at 6-month postbirth follow-up. Secondary outcomes included number of home visits and phone calls taken over the first 6 months postbirth; biochemically confirmed abstinence at postbirth Week 1 visit; and self-reported smoking status at 2- and 4-month visits. RESULTS: Incentive condition participants had a higher biochemically confirmed abstinence rate at 6-month postbirth than controls (14.7% vs. 9.2%, respectively: p < .01). This effect was mediated by incentive condition participants' greater acceptance of postbirth home visits and counseling calls. CONCLUSIONS: Moderate incentive payments for smoking treatment engagement (a mean of ~$214 paid) increased low-income pregnant smokers' engagement and success in smoking cessation treatment. (PsycINFO Database Record PMID- 29389143 TI - Congruence of therapeutic bond perceptions and its relation to treatment outcome: Within- and between-dyad effects. AB - OBJECTIVE: The present study investigates the association between congruence of patients' and therapists' perceptions of the therapeutic bond and symptom improvement. METHOD: Bond congruence-outcome associations were examined on the within- and between-dyad level for 580 patients (mainly depression and anxiety) receiving cognitive-behavioral therapy. Symptom change was assessed on a session to-session level as well as from pre- to posttreatment. For the between-dyad analyses, the truth and bias model was applied. For the within-dyad analyses, polynomial regression and response surface analysis were conducted. RESULTS: On the between-dyad level, higher temporal congruence between patients' and therapists' bond ratings (i.e., their correlation) was associated with better treatment outcomes. Additionally, the average discrepancy between therapists' and patients' bond ratings showed a significant quadratic association with treatment outcome. A tendency for therapists to moderately rate the bond lower than their patients' showed lowest posttreatment symptom scores. On the within-dyad level, we found that when patients' and therapists' ratings were in "agreement," higher bond scores were associated with fewer next-session symptoms. For "disagreement," the results showed that if therapists rated the bond as weak, whereas their patients rated it as strong, higher subsequent symptom distress was observed than if patients rated the bond as weak and their therapists rated it as strong. CONCLUSIONS: The present study highlights the importance of therapists being vigilant to session-to-session changes in the therapeutic bond to adjust their interventions accordingly. (PsycINFO Database Record PMID- 29389144 TI - Context-dependent control of attention capture: Evidence from proportion congruent effects. AB - There are several independent demonstrations that attentional phenomena can be controlled in a context-dependent manner by cues associated with differing attentional control demands. The present set of experiments provide converging evidence that attention-capture phenomena can be modulated in a context-dependent fashion. We determined whether methods from the proportion congruent literature (listwide and item- and context-specific proportion congruent designs) that are known to modulate distractor interference effects in Stroop and flanker tasks are capable of modulating attention capture by salient feature singletons. Across experiments we found evidence that attention capture can be modulated by listwide, item-specific, and context-specific manipulations of proportion congruent. We discuss challenges associated with interpreting results from proportion congruent studies but propose that our findings converge with existing work that has demonstrated context-dependent control of attention capture. (PsycINFO Database Record PMID- 29389145 TI - Overlapping brain network and alpha power changes suggest visuospatial attention effects on driving performance. AB - When humans perform prolonged, continuous tasks, their performance fluctuates. The etiology of these fluctuations is multifactorial, but they are influenced by changes in attention reflected in underlying neural dynamics. Previous work with electroencephalography has suggested that prestimulus alpha power is a neural signature of attention allocation with higher power portending relatively poorer performance. The functional mechanisms subserving these changes in alpha power and behavior are postulated to be the result of networked neural activity that permits flexibility in the allocation of attention. Here, we directly examine the similarity between prestimulus alpha connectivity and power in relation to performance fluctuations in a continuous driving task. Participants were asked to maintain their vehicle in the center of a simulated highway, and we evaluated their performance by randomly perturbing the vehicle and assessing their steering correction. We then used the 3 seconds of neural activity before the unexpected event to derive alpha functional connectivity in the first analysis and alpha power in the second analysis, and we employed linear regression to separately investigate their relationship to 3 metrics of driving performance (lane deviation, reaction time (RT), and heading error). We find that the locations involved in our network analysis also show the strongest modulation of alpha activity. Interestingly, the network pattern suggests a posterior to anterior directionality, consistent with bottom-up theories of attention, and these results may reflect a gain control model of attention in which ongoing attention is modulated through coordinated, network activity. (PsycINFO Database Record PMID- 29389146 TI - Mother-father-adolescent triadic concordance and discordance on home environment factors and adolescent disordered eating behaviors. AB - INTRODUCTION: This study utilizes triadic data to examine the association between mother-father-adolescent concordance (agreement) and discordance (disagreement) on home environment factors (i.e., parental encouragement of dieting, family functioning) and adolescent unhealthy weight control behaviors and binge eating. METHOD: A subsample of adolescent-mother-father triads (n = 833; adolescents ages 10-22) from two coordinated population-based studies (EAT 2010 and F-EAT) were used. Poisson regression analysis was used to estimate the relative risks of each eating disordered behavior. RESULTS: Triads were more concordant (range 9-42%) than discordant (range 4-24%). Triadic agreement that parents did not encourage dieting was associated with a lower risk of adolescent eating disordered behaviors in some triadic combinations. Additionally, triadic concordance on high family functioning was also associated with a lower risk of adolescent eating disordered behaviors among some triadic combinations. DISCUSSION: Results suggest that triadic concordance on healthy home environment factors is associated with fewer adolescent disordered eating behaviors in some triads. Family based interventions may want to consider focusing on strategies to help move mother father-adolescent triads closer on seeing the home environment more similarly. Future research is needed on triadic concordance/discordance and disordered eating behaviors to confirm study results and to inform the development of family based interventions. (PsycINFO Database Record PMID- 29389147 TI - Global proofing a collaborative care telemental health intervention in Brazil. AB - Rural proofing ensures that policies, practice guidelines, strategies, and techniques can be applied to rural populations with approximately equal benefit as what would be obtained in urban areas. Extending this concept internationally, the authors argue the importance of global proofing mental health strategies developed in well-resourced, high-income areas in order to determine their appropriateness in areas that have resource poverty such as middle- and low income countries. An example is used to illustrate both rural and global proofing. Through this example, the authors demonstrate how they proofed urban inspired models of mental health care in rural areas of the United States. The result is a model of rural mental health care that emphasizes collaborative care and telemental health. This model is now being global proofed in Brazil. The authors describe the application of this model in a remote rural town in Brazil. Consistent with World Health Organization recommendations, the integration of mental health care into primary care medical settings is being discovered as essential to addressing mental health disparities worldwide. (PsycINFO Database Record PMID- 29389148 TI - Acculturation, family cohesion, and mental health among Latinos living with HIV on the U.S.-Mexico border. AB - OBJECTIVE: The objective of the study was to investigate whether acculturation to U.S. culture is associated with greater posttraumatic stress disorder (PTSD) symptomatology through diminished family cohesion among Latinos living with HIV on the U.S.-Mexico border. METHOD: Baseline survey data were analyzed from a sample of Latinos seeking HIV care from a publicly funded HIV clinic in El Paso, Texas. We used a regression-based bootstrapping approach to test our mediation hypothesis. RESULTS: A total of 248 Latinos living with HIV completed the survey, with 96.4% being of Mexican descent, 19.4% female (gender self-identification), and 63.7% nonheterosexual (sexual orientation self-identification). Family cohesion mediated the relationship between U.S. acculturation and PTSD symptom scores (a1 * b1 = .03, 95% confidence interval [.01-.06]), an effect independent of acculturation to Latino culture. CONCLUSIONS: Acculturation to U.S. culture may negatively impact mental health through weakening family bonds in this vulnerable population. (PsycINFO Database Record PMID- 29389149 TI - The association of perceived discrimination and depressive symptoms among Chinese, Korean, and Vietnamese Americans. AB - OBJECTIVES: Few studies have investigated ethnic differences in discrimination and depressive symptoms, and the link between them among foreign-born Asian Americans. This study identifies if depressive symptoms and perceived discrimination differ by Asian ethnicity, and if perceived discrimination is associated with depressive symptoms among foreign-born Chinese, Korean, and Vietnamese Americans. METHODS: This study uses data from the Asian American Liver Cancer Prevention Program (N = 600). Using nonprobability sampling, foreign-born Asian American adults (58% female, Mage = 47.3 years, SD = 11.82) were recruited from the community in the Baltimore-Washington Metropolitan Area. Perceived discrimination was defined using everyday and major discrimination scales; the Centers for Epidemiological Studies-Depression Scale defined the outcome of depressive symptoms. Multiple logistic regressions were conducted to determine if this association exists. RESULTS: A high prevalence of depressive symptoms (one third to one fifth per ethnicity) and ethnic differences between foreign-born Chinese, Korean, and Vietnamese Americans were found; increased perceived discrimination was associated with worse depressive symptomology. Those with "high" and "mild discrimination" had greater odds of being depressed than those who had never experienced discrimination; those with "unfair treatment" had greater odds of being depressed than those who had none. Major experiences of discrimination were less common and less likely associated with depressive symptoms than everyday experiences. CONCLUSIONS: Foreign-born Asian Americans experience substantial discrimination and depressive symptoms. Future studies should stratify by Asian ethnicity and examine the differences between minor and major experiences of discrimination to provide appropriate mental health prevention and treatment for this population. (PsycINFO Database Record PMID- 29389150 TI - Family communication with teens at clinical high-risk for psychosis or bipolar disorder. AB - Previous research has found that family problem-solving interactions are more constructive and less contentious when there is a family member with bipolar disorder compared with schizophrenia. The present study extended this research by examining whether family problem-solving interactions differ between clinical high-risk (CHR) stages of each illness. Trained coders applied a behavioral coding system (O'Brien et al., 2014) to problem-solving interactions of parents and their adolescent child, conducted just prior to beginning a randomized trial of family-focused therapy. The CHR for psychosis sample included 58 families with an adolescent with attenuated positive symptoms, brief intermittent psychosis, or genetic risk and functional deterioration; the CHR for bipolar disorder sample included 44 families with an adolescent with "unspecified" bipolar disorder or major depressive disorder and at least one first or second degree relative with bipolar I or II disorder. When controlling for adolescent gender, age, functioning, and parent education, mothers of youth at CHR for psychosis displayed significantly more conflictual and less constructive communication than did mothers of youth at CHR for bipolar disorder. Youth risk classification did not have a significant relationship with youths' or fathers' communication behavior. The family environment among help-seeking adolescents may be more challenging for families with an adolescent at CHR for psychosis compared with bipolar illness. Accordingly, families of adolescents at clinical high-risk for psychosis may benefit from more intensive or focused communication training than is required by families of adolescents at clinical high-risk for bipolar disorder or other mood disorders. (PsycINFO Database Record PMID- 29389152 TI - Developmental and contextual correlates of mental health and help-seeking among Asian American college students. AB - Guided by an integrative contextual framework of immigrant youth development (Garcia Coll & Marks, 2012), this study investigated the potential role of developmental (e.g., ethnic identity) and contextual factors (e.g., perceived discrimination, stereotyping) in mental health outcomes and help-seeking attitudes, and variations across gender and nativity among Asian American college students. Online surveys assessing perceived subtle and blatant racism, ethnic identity, the internalization of the model minority stereotype, depressive symptoms, anxiety symptoms, and attitudes toward seeking help from mental health professionals were administered to Asian American college student participants (n = 465) from diverse ethnic backgrounds and geographic regions in the United States. The findings support prior research indicating that perceived subtle racism and blatant racism are positively associated with depressive and anxiety symptoms. Further, only certain dimensions of ethnic identity and internalization of the model minority stereotype were found to be associated with mental health outcomes and help-seeking attitudes. The findings did not indicate a significant association between perceived racism and help-seeking attitudes. There were also no significant differences in the relationships among variables across gender and nativity, with the exception of the association between ethnic identity and help seeking attitudes across gender. The study identified potential risk and protective factors in mental health, while underscoring the multidimensional aspects of social and contextual factors that contribute to mental health and help seeking among Asian American college students. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389153 TI - Can an unpredictable childhood environment enhance working memory? Testing the sensitized-specialization hypothesis. AB - Although growing up in an adverse childhood environment tends to impair cognitive functions, evolutionary-developmental theory suggests that this might be only one part of the story. A person's mind may instead become developmentally specialized and potentially enhanced for solving problems in the types of environments in which the person grew up. In the current research, we tested whether these specialized advantages in cognitive function might be sensitized to emerge in currently uncertain contexts. We refer to this as the sensitized-specialization hypothesis. We conducted experimental tests of this hypothesis in the domain of working memory, examining how growing up in unpredictable versus predictable environments affects different facets of working memory. Although growing up in an unpredictable environment is typically associated with impairments in working memory, we show that this type of environment is positively associated with those aspects of working memory that are useful in rapidly changing environments. Importantly, these effects emerged only when the current context was uncertain. These theoretically derived findings suggest that childhood environments shape, rather than uniformly impair, cognitive functions. (PsycINFO Database Record PMID- 29389151 TI - Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. AB - OBJECTIVE: To evaluate whether a history of traumatic brain injury (TBI) with reported loss of consciousness (LOC) is a risk factor for earlier onset of Alzheimer's disease (AD) in an autopsy-confirmed sample. METHOD: Data from 2,133 participants with autopsy-confirmed AD (i.e., at least Braak neurofibrillary tangle stages III to VI and CERAD neuritic plaque score moderate to frequent) were obtained from the National Alzheimer's Coordinating Center (NACC). Participants were categorized by presence/absence of self-reported remote (i.e., >1 year prior to their first Alzheimer's Disease Center visit) history of TBI with LOC (TBI+ vs. TBI-). Analyses of Covariance (ANCOVA) controlling for sex, education, and race compared groups on clinician-estimated age of symptom onset and age of diagnosis. RESULTS: Average age of onset was 2.34 years earlier (p = .01) for the TBI+ group (n = 194) versus the TBI- group (n = 1900). Dementia was diagnosed on average 2.83 years earlier (p = .002) in the TBI+ group (n = 197) versus the TBI- group (n = 1936). Using more stringent neuropathological criteria (i.e., Braak stages V-VI and CERAD frequent), both age of AD onset and diagnosis were 3.6 years earlier in the TBI+ group (both p's < .001). CONCLUSIONS: History of TBI with reported LOC appears to be a risk factor for earlier AD onset. This is the first study to use autopsy-confirmed cases, supporting previous investigations that used clinical criteria for the diagnosis of AD. Further investigation as to possible underlying mechanisms of association is needed. (PsycINFO Database Record PMID- 29389154 TI - Parochial cooperation in nested intergroup dilemmas is reduced when it harms out groups. AB - In intergroup settings, humans often contribute to their in-group at a personal cost. Such parochial cooperation benefits the in-group and creates and fuels intergroup conflict when it simultaneously hurts out-groups. Here, we introduce a new game paradigm in which individuals can display universal cooperation (which benefits both in- and out-group) as well as parochial cooperation that does, versus does not hurt the out-group. Using this set-up, we test hypotheses derived from group selection theory, social identity, and bounded generalized reciprocity theory. Across three experiments we find, first, that individuals choose parochial over universal cooperation. Second, there was no evidence for a motive to maximize differences between in- and out-group, which is central to both group selection and social identity theory. However, fitting bounded generalized reciprocity theory, we find that individuals with a prosocial value orientation display parochial cooperation, provided that this does not harm the out-group; individualists, in contrast, display parochialism whether or not nut it hurts the out-group. Our findings were insensitive to cognitive taxation (Experiments 2-3), and emerged even when universal cooperation served social welfare more than parochialism (Experiment 3). (PsycINFO Database Record PMID- 29389155 TI - HIV-risk reduction intervention for juvenile offenders on probation: The PHAT Life group randomized controlled trial. AB - OBJECTIVE: Juvenile offenders report high rates of sexual risk taking, increasing the possibility of HIV. This 2-arm group randomized controlled trial tested the efficacy of PHAT Life, a sexual risk reduction program, compared with a time matched health promotion program for youth on probation. METHOD: Male and female 13- to 17-year-olds (M = 16.08; SD = 1.09) recently arrested and placed on probation at an Evening Reporting Center were eligible for the study. Youth were 66% male, and 90% African American. Teens self-reported their sexual behavior (condom use, number of sexual partners) at baseline and 6 months. Retention was 85%. RESULTS: Youth were randomized to PHAT Life (n = 163) or a health promotion program (n = 147). Among youth reporting the highest risk at baseline (a composite measure of multiple partners and inconsistent condom use), those who received PHAT Life were over 4 times more likely than the control group to report a lower level of risk (i.e., no sex or one partner plus consistent condom use) by 6 months, OR = 4.28 with 95% CI [1.37, 13.38], SE = 0.58, p = .01. Among sexually active teens who reported sexual debut before 12-years-old, those who received PHAT Life reported significantly fewer sexual partners at 6-months than controls, partial eta squared = .32, p = .002. CONCLUSIONS: Findings support PHAT Life's efficacy to reduce sexual risk for juvenile offenders on probation. Future research should examine how best to disseminate PHAT Life to ensure that it is self-sustaining within the juvenile justice system. (PsycINFO Database Record PMID- 29389156 TI - Relationship of "don't know" responses to cancer knowledge and belief questions with colorectal cancer screening behavior. AB - OBJECTIVE: Answering "I don't know" (DK) to survey questions that assess risk perceptions is common and occurs more often among disenfranchised groups. Because these groups also are at greater disease risk, statistically omitting or recoding DK responses may disproportionately exclude or misrepresent responses from marginalized groups and misinform intervention efforts. Because little is known about how the DK response is related to health behaviors, we examined whether the relation between DK response and colorectal cancer (CRC) screening behavior differed, depending on the construct queried (knowledge vs. beliefs). METHOD: Data from the Awareness and Beliefs about Cancer survey of U.S. adults aged 50 years or older (N = 1406) were used. Cancer symptom knowledge, cancer beliefs, and CRC screening history were assessed. DK response options were not offered but were recorded if spontaneously provided. Logistic regression tested whether DK response on knowledge and belief scales were associated with CRC screening. RESULTS: Adjusting for demographic factors, responding DK on >=1 belief item was associated with lower odds of having been screened for CRC in the last 5 years, p < .001, whereas DK response on >=1 knowledge item was unassociated with screening, p = .48. DK responders to belief items were even less likely to have been screened than participants with negative beliefs about cancer, p = .011. CONCLUSION: DK responses are differentially associated with CRC screening, depending on the construct queried, suggesting different mechanisms may underlie DK responding or its relationship with screening. Addressing construct-specific causes of DK response may improve survey research and the interventions based on them. (PsycINFO Database Record PMID- 29389158 TI - The psychological roots of anti-vaccination attitudes: A 24-nation investigation. AB - OBJECTIVE: Strengthening of antivaccination movements in recent decades has coincided with unprecedented increases in the incidence of some communicable diseases. Many intervention programs work from a deficit model of science communication, presuming that vaccination skeptics lack the ability to access or understand evidence. However, interventions focusing on evidence and the debunking of vaccine-related myths have proven to be either nonproductive or counterproductive. Working from a motivated reasoning perspective, we examine the psychological factors that might motivate people to reject scientific consensus around vaccination. To assist with international generalizability, we examine this question in 24 countries. METHODS: We sampled 5,323 participants in 24 countries, and measured their antivaccination attitudes. We also measured their belief in conspiracy theories, reactance (the tendency for people to have a low tolerance for impingements on their freedoms), disgust sensitivity toward blood and needles, and individualistic/hierarchical worldviews (i.e., people's beliefs about how much control society should have over individuals, and whether hierarchies are desirable). RESULTS: In order of magnitude, antivaccination attitudes were highest among those who (a) were high in conspiratorial thinking, (b) were high in reactance, (c) reported high levels of disgust toward blood and needles, and (d) had strong individualistic/hierarchical worldviews. In contrast, demographic variables (including education) accounted for nonsignificant or trivial levels of variance. CONCLUSIONS: These data help identify the "attitude roots" that may motivate and sustain vaccine skepticism. In so doing, they help shed light on why repetition of evidence can be nonproductive, and suggest communication solutions to that problem. (PsycINFO Database Record PMID- 29389157 TI - Weight and weight control behaviors of Latinas and their social ties. AB - OBJECTIVE: Shared behaviors have been implicated in the clustering of obesity among socially connected people. This study determined how weight and weight control behaviors of participants and their social ties are related and how these factors are associated with weight change in participants. METHOD: Adult Latinas participating in a lifestyle intervention completed an egocentric network measure of weight and weight control behaviors. Participant weight was objectively measured at baseline and 12 months. Multivariable regression models determined the relationship between weight and weight control behaviors of participants and their social ties. RESULTS: Participants and their social ties shared similarities in weight control behaviors and weight change. Participants who reported social ties that had lost weight were more likely to eat small portions and low-fat foods, but those with social ties that had gained weight were more likely to use herbal supplements. Participants who reported more social ties who exercised, drank liquid meal replacements, took herbal supplements, and self weighed were more likely to lose weight whereas those with fewer social ties that exercised were more likely to gain weight. Weight loss and weight gain by social ties predicted participant weight loss and weight gain, respectively. CONCLUSIONS: Given that weight and weight control behaviors of Latinas reflect that of their social ties, targeting existing social networks for lifestyle interventions may more effectively improve and sustain health-promoting behaviors and outcomes. (PsycINFO Database Record PMID- 29389159 TI - The role of parent and child self-regulation in children's glycemic control. AB - OBJECTIVE: Type 1 diabetes mellitus (T1DM) is a lifelong, metabolic disorder, typically arising in childhood and adolescence. Despite recent advances in diabetes management techniques, glycemic control remains substandard for many individuals This study examined the role of parental and child self-regulation in predicting effective glycemic control in children and adolescents with Type 1 diabetes mellitus (T1DM). METHOD: Sixty-three families (with children aged 3-18 years) with T1DM participated. Child, maternal, and paternal measures of temperament, including surgency (behavioral self-regulation), negative affect (emotional selfregulation), and effortful control (cognitive self-regulation) were collected, along with demographic information and haemoglobin A1c (glycemic control). RESULTS: Higher parental and child effortful control was associated with better glycemic control. Higher child negative emotionality was associated with poorer glycemic control. No significant interactions between child and parent measures were identified. CONCLUSIONS: Both parental and child self regulation play an independent role in glycemic control, and serve as targets for intervention in improving diabetes management in children and adolescents. (PsycINFO Database Record PMID- 29389160 TI - Does a "stoplight!" improve processing a stoplight? Cross-modal influences of time-compressed spoken denotations on automotive icon classification. AB - Findings from three experiments support the conclusion that semantic auditory primes facilitate processing of complex warning icons in the automotive context. In Experiment 1, we used a cross-modal icon identification task with auditory primes and visual icons as targets, presented in a high perceptual load context. Responses were faster for congruent priming in comparison to neutral or incongruent priming. This effect also emerged for different levels of time compression of auditory primes. In Experiment 2, participants took part in a driving simulation with target icons on a gantry road sign. Participants had to categorize the color of the icons. Again, compressed auditory primes facilitated responses in cases of congruency (compared with incongruent and neutral primes). This result was replicated in Experiment 3 with more complex responses (i.e., braking, switching lanes). Our results suggest semantic object-based auditory visual interactions, which rapidly increase the denoted target object's salience. (PsycINFO Database Record PMID- 29389161 TI - The role of estimator variables in eyewitness identification. AB - Estimator variables are factors that can affect the accuracy of eyewitness identifications but that are outside of the control of the criminal justice system. Examples include (1) the duration of exposure to the perpetrator, (2) the passage of time between the crime and the identification (retention interval), (3) the distance between the witness and the perpetrator at the time of the crime. Suboptimal estimator variables (e.g., long distance) have long been thought to reduce the reliability of eyewitness identifications (IDs), but recent evidence suggests that this is not true of IDs made with high confidence and may or may not be true of IDs made with lower confidence. The evidence suggests that though suboptimal estimator variables decrease discriminability (i.e., the ability to distinguish innocent from guilty suspects), they do not decrease the reliability of IDs made with high confidence. Such findings are inconsistent with the longstanding "optimality hypothesis" and therefore require a new theoretical framework. Here, we propose that a signal-detection-based likelihood ratio account-which has long been a mainstay of basic theories of recognition memory naturally accounts for these findings. (PsycINFO Database Record PMID- 29389162 TI - Individual differences in search and monitoring for color targets in dynamic visual displays. AB - Many real-world tasks now involve monitoring visual representations of data that change dynamically over time. Monitoring dynamically changing displays for the onset of targets can be done in two ways: detecting targets directly, post-onset, or predicting their onset from the prior state of distractors. In the present study, participants' eye movements were measured as they monitored arrays of 108 colored squares whose colors changed systematically over time. Across three experiments, the data show that participants detected the onset of targets both directly and predictively. Experiments 1 and 2 showed that predictive detection was only possible when supported by sequential color changes that followed a scale ordered in color space. Experiment 3 included measures of individual differences in working memory capacity (WMC) and anxious affect and a manipulation of target prevalence in the search task. It found that predictive monitoring for targets, and decisions about target onsets, were influenced by interactions between individual differences in verbal and spatial WMC and intolerance of uncertainty, a characteristic that reflects worry about uncertain future events. The results have implications for the selection of individuals tasked with monitoring dynamic visual displays for target onsets. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389163 TI - Why consumers misattribute sponsorships to non-sponsor brands: Differential roles of item and relational communications. AB - Brands engaged in sponsorship of events commonly have objectives that depend on consumer memory for the sponsor-event relationship (e.g., sponsorship awareness). Consumers however, often misattribute sponsorships to nonsponsor competitor brands, indicating erroneous memory for these relationships. The current research uses an item and relational memory framework to reveal sponsor brands may inadvertently foster this misattribution when they communicate relational linkages to events. Effects can be explained via differential roles of communicating item information (information that supports processing item distinctiveness) versus relational information (information that supports processing relationships among items) in contributing to memory outcomes. Experiment 1 uses event-cued brand recall to show that correct memory retrieval is best supported by communicating relational information when sponsorship relationships are not obvious (low congruence). In contrast, correct retrieval is best supported by communicating item information when relationships are obvious (high congruence). Experiment 2 uses brand-cued event recall to show that, against conventional marketing recommendations, relational information increases misattribution, whereas item information guards against misattribution. Results suggest sponsor brands must distinguish between item and relational communications to enhance correct retrieval and limit misattribution. Methodologically, the work shows that choice of cueing direction is critical in differentially revealing patterns of correct and incorrect retrieval with pair relationships. (PsycINFO Database Record PMID- 29389164 TI - Motivated reconstruction: The effect of brand commitment on false memories. AB - Across 5 studies, we examine the effect of prior brand commitment on the creation of false memories about product experience after reading online product reviews. We find that brand commitment and the valence of reviews to which consumers are exposed, interact to affect the incidence of false memories. Thus, highly committed consumers are more susceptible to the creation of false experience memories on exposure to positive versus negative reviews, whereas low commitment consumers exhibit similar levels of false memories in response to both positive and negative reviews. Further, these differences across brand commitment are attenuated when respondents are primed with an accuracy motivation, suggesting that the biasing effects of commitment are likely because of the motivation to defend the committed brand. Finally, we find that differences in false memories subsequently lead to differences in intentions to spread word-of-mouth (e.g., recommend the product to friends), suggesting that the consequences of false product experience memories can be significant for marketers and consumers. Our findings contribute to the literatures in false memory and marketing by documenting a motivated bias in false memories because of brand commitment. (PsycINFO Database Record PMID- 29389165 TI - An update on Experimental and Clinical Psychopharmacology: Something old, something new, something borrowed, something green? AB - In this editorial, the author provides an update on Experimental and Clinical Psychopharmacology in several areas. First, the journal will continue to accept original research reports and full reviews as it has in past years. The author hopes to still receive outstanding manuscripts in the journal's primary areas of strength, such as clinical research on alcohol use and cigarette smoking. The journal will also continue to publish an annual special issue on a current topic in the field. Second, the journal now accepts brief communications, brief reviews, and case reports. The authors sees these new formats as opportunities to publish cutting edge, novel findings that may not be suitable as original research reports or full reviews-such work would previously not have fit with the journal. Third, the author has borrowed an idea from colleagues who serve as editors for other journals in the field: the addition of an editorial fellowship at Experimental and Clinical Psychopharmacology. Finally, the "something green" part of the title refers to the new, bright green cover color of the print version of the journal. (PsycINFO Database Record PMID- 29389166 TI - Effects of N-Methyl-D-aspartate (NMDA) antagonists ketamine, methoxetamine, and phencyclidine on the odor span test of working memory in rats. AB - The glutamate hypothesis proposes that N-Methyl-D-aspartate (NMDA) receptor hypofunction underlies cognitive and perhaps other schizophrenic symptoms. The present study used the odor span task to assess the effects of NMDA antagonists on remembering multiple stimuli in rodents. This task uses an incrementing nonmatching-to-sample procedure in which responses to a new olfactory stimulus are reinforced on each trial, whereas responses to previously presented stimuli are not. NMDA antagonists have been associated with memory impairments in a variety of animal models; however, there are inconsistencies across different NMDA antagonists and tasks used. The current study compared the acute effects of phencyclidine (PCP), ketamine (KET), and the novel NMDA antagonist methoxetamine (MXE) on responding in the odor span task and a simple discrimination control task. PCP and MXE impaired odor span accuracy at doses that did not impair simple discrimination in most rats; however, the effects of KET were less selective. Within-session analyses indicated that the effects of PCP and MXE depended on the number of stimuli to remember, that is, impairment only occurred when the memory load was relatively high. These effects of PCP and MXE were consistent with the hypothesis that NMDA antagonists may interfere with working memory, but the basis for less selective results with KET are unclear. (PsycINFO Database Record PMID- 29389167 TI - Adolescent d-amphetamine exposure enhances the acquisition of cocaine self administration in male and female rats. AB - Diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) has risen drastically over the past 20 years in the United States and abroad. Amphetamine-based prescription stimulants are the most prescribed treatment for ADHD and the diversion of these drugs has also increased. Reports indicate 61% of individuals with an ADHD medication prescription have sold or shared their medication. Exposure to prescription stimulants, especially for those without an ADHD diagnosis, may increase susceptibility to drugs of abuse. The present study aimed to model ADHD medication misuse during adolescence in male and female rats. The primary dependent measure was the acquisition of intravenous cocaine self administration. Male and female, Long-Evans rats were exposed to d-amphetamine (0.7 mg/kg, i.p.) or saline in adolescence (35-41 days old), during which locomotor activity was measured. At approximately 75 days old, animals were implanted with jugular catheters. All animals then entered a 15-day acquisition procedure with no prior operant training. Finally, following acquisition all animals responded on a progressive-ratio (PR) schedule to obtain 0, 0.1, 0.3, and 1.0 mg/kg/infusion cocaine. Animals exposed to amphetamine acquired cocaine self administration faster than saline-exposed controls when the acquisition criterion was operationally defined as two consecutive days with 12 infusions or greater. Discrete-time hazard modeling also found amphetamine exposure to increase the likelihood of acquiring cocaine self-administration. There were no differences detected during PR testing. These data suggest that individuals with histories of prescription stimulant misuse may be at increased risk to use other drugs of abuse. (PsycINFO Database Record PMID- 29389168 TI - Using deviance regulation theory to target marijuana use intentions among college students. AB - Several large epidemiological studies have shown increasing trends on a number of indices of marijuana use among college age samples. This may be due to changing attitudes about marijuana use linked to legalization efforts. Interventions that can target problematic use on a broad scale are lacking. Recent research has shown that deviance regulation theory (DRT) can be used to design effective web based substance use interventions. DRT relies on the interplay between perceived norms and an appropriately framed message about the given behavior. The current study examines the use of DRT to change marijuana use intentions. Participants (n = 694 college students) completed measures of marijuana use and marijuana use norms. They were then assigned to receive a positively framed message about marijuana abstainers or a negatively framed message about marijuana users. Following the manipulation, participants rated intentions to use marijuana over the next three months. Consistent with DRT, there was an interaction between message frame and marijuana use norms. The positive frame attenuated the association between marijuana use norms and use intentions. A negative frame resulted in the lowest levels of use intentions among those with low use norms. Results suggest that DRT may be used to modify use intentions in college students, a population that has shown increasing rates of use. (PsycINFO Database Record PMID- 29389169 TI - Daily associations between alcohol and sexual behavior in young adults. AB - We tested within-person effects of alcohol on sexual behavior among young adults in a longitudinal burst design (N = 213, 6,487 days) using data collected from a previously published parent study. We differentiated effects of alcohol on likelihood of sexual activity versus use of protection against sexually transmitted diseases (STDs) or pregnancy on intercourse occasions by testing a multilevel multinomial model with 4 outcomes (no sex, oral sex without intercourse, protected intercourse, and unprotected intercourse). At the within person level, effects of alcohol were hypothesized to be conditional upon level of intoxication (i.e., curvilinear effect). We also tested effects of four between-person moderators: gender, typical length of relationship with sexual partners, and two facets of self-control (effortful control and reactivity). Consistent with our hypothesis, low-level intoxication was associated with increased likelihood of engaging in oral sex or protected intercourse (relative to no sex) but was not related to likelihood of unprotected intercourse. The effect of intoxication on unprotected versus protected intercourse was an accelerating curve, significantly increasing likelihood of unprotected intercourse at high levels of intoxication. Between-person factors moderated associations between intoxication and sexual behavior. Effects of intoxication on both protected and unprotected intercourse were diminished for individuals with more familiar sexual partners. Effortful control exhibited a protective effect, reducing the effects of intoxication on likelihood of unprotected intercourse. Hypothesized effects of reactivity were not supported. Intoxication was a stronger predictor of oral sex and protected intercourse (but not unprotected intercourse) for women relative to men. Results highlight the inherent complexities of the alcohol-sexual behavior nexus. (PsycINFO Database Record PMID- 29389171 TI - Examining the use of visual performance feedback in drug treatment court. AB - A key component of drug courts is regular status hearings in which the judge reviews client progress and imposes sanctions or rewards for infractions or achievements; however, little is known about whether drug court clients fully understand the reasons for judicial responses and make clear connections between their behavior and judicially imposed consequences. Thus, we hypothesized that providing graphic performance feedback would improve clients' perceptions of procedural justice and increase the likelihood of success. This study examines the feasibility, acceptability, and preliminary efficacy of a visual performance feedback (VPF) procedure designed to improve judge-client communication during status hearings. Seventy-five adult misdemeanor drug court participants were randomized to a VPF (n = 37) or status hearings as usual (n = 38) condition. In the VPF condition, the judge projected and described two graphs for each client (i.e., abstinence rates, treatment attendance for the past two months). Outcomes included feasibility, client and stakeholder acceptability, urinalysis-confirmed abstinence, treatment attendance, perceptions of procedural justice, and duration of client-judge interactions. Findings revealed a high level of judge adherence to the VPF (feasibility), client and stakeholder acceptability of the VPF procedure, and significantly longer client-judge interactions in the VPF condition. No significant differences were observed for client-level efficacy outcomes. Overall, this study demonstrated that providing VPF to drug court clients during judicial status hearings is feasible and acceptable. Future fully powered trials of the VPF procedure are needed to further examine its efficacy in improving outcomes for drug court clients. (PsycINFO Database Record PMID- 29389170 TI - Effects of varenicline on cognitive performance in heavy drinkers: Dose-response effects and associations with drinking outcomes. AB - Varenicline reduces drinking in people with alcohol use disorder, but little is known about the mechanisms underlying this effect. Varenicline targets alpha4beta2 and alpha7 nicotinic acetylcholine receptors, which are associated with several cognitive functions such as working memory. Varenicline may improve drinking outcomes by enhancing cognitive functioning. The current manuscript reports on cognitive outcomes from a placebo-controlled, double-blind human laboratory experiment examining the effects of varenicline on drinking behavior (Verplaetse et al., 2016a). Participants were 55 adult heavy drinkers who met criteria for an alcohol use disorder. They were randomized to receive varenicline (1 mg/day, 2 mg/day) or placebo. They completed a baseline assessment of cognitive functioning (i.e., digits backward task, continuous performance task) before starting medication. After a medication titration period, they attended a laboratory session (post medication Day 8) where they completed the cognitive assessment battery and an alcohol-primed ad libitum drinking task. Blood was collected to measure plasma varenicline levels. Varenicline produced dose dependent improvements in working memory. Although there was no significant effect of oral varenicline dose on response time on the continuous performance task, participants with higher levels of plasma varenicline showed greater improvement of reaction time (RT). Among participants receiving 2 mg/day varenicline, larger improvements in working memory were associated less drinking, although mediation analyses did not find a significant indirect effect. These findings suggest that varenicline can improve working memory above baseline levels in heavy drinkers. Varenicline may reduce rates of alcohol use by improving working memory. (PsycINFO Database Record PMID- 29389172 TI - A meta-analysis of nonsystematic responding in delay and probability reward discounting. AB - Delay discounting (DD) and probability discounting (PD) are behavioral measures of choice that index sensitivity to delayed and probabilistic outcomes, which are associated with a range of negative health-related outcomes. Patterns of discounting tend to be predictable, where preferences for immediate (vs. delayed) and certain (vs. probabilistic) rewards change as a function of delay and probability. However, some participants yield nonsystematic response patterns (NSR) that cannot be accounted for by theories of choice and could have implications for the validity of discounting-related experiments. Johnson and Bickel (2008) outline an algorithm for identifying NSR patterns in discounting, but the typical frequency of and methodological predictors of NSR patterns are not yet established in the extant literature. In this meta-analytic review, we identified papers for analysis by searching Web of Science, PubMed, and PsycInfo databases until November 8, 2015 for experiments identifying nonsystematic responders using Johnson and Bickel's algorithm. This yielded 114 experiments with nonsystematic data reported. The overall frequency of NSR across DD and PD studies was 18% and 19%, respectively. Nonmonetary outcomes (e.g., drugs, food, sex) yielded significantly more NSR patterns than did discounting for monetary outcomes. Participants recruited from a university setting had significantly more NSR patterns than did participants recruited from nonuniversity settings. Our review also indicates that researchers are inconsistent in whether or how they report NSR in discounting studies, which is relevant for a clearer understanding of the behavioral mechanisms that underlie impulsive choice. We make several recommendations regarding the assessment of NSR in discounting research. (PsycINFO Database Record PMID- 29389173 TI - Evaluation of the Problem Behavior Frequency Scale-Teacher Report Form for assessing behavior in a sample of urban adolescents. AB - This study evaluated the structure and validity of the Problem Behavior Frequency Scale-Teacher Report Form (PBFS-TR) for assessing students' frequency of specific forms of aggression and victimization, and positive behavior. Analyses were conducted on two waves of data from 727 students from two urban middle schools (Sample 1) who were rated by their teachers on the PBFS-TR and the Social Skills Improvement System (SSIS), and on data collected from 1,740 students from three urban middle schools (Sample 2) for whom data on both the teacher and student report version of the PBFS were obtained. Confirmatory factor analyses supported first-order factors representing 3 forms of aggression (physical, verbal, and relational), 3 forms of victimization (physical, verbal and relational), and 2 forms of positive behavior (prosocial behavior and effective nonviolent behavior), and higher-order factors representing aggression, victimization, and positive behavior. Strong measurement invariance was established over gender, grade, intervention condition, and time. Support for convergent validity was found based on correlations between corresponding scales on the PBFS-TR and teacher ratings on the SSIS in Sample 1. Significant correlations were also found between teacher ratings on the PBFS-TR and student ratings of their behavior on the Problem Behavior Frequency Scale-Adolescent Report (PBFS-AR) and a measure of nonviolent behavioral intentions in Sample 2. Overall the findings provided support for the PBFS-TR and suggested that teachers can provide useful data on students' aggressive and prosocial behavior and victimization experiences within the school setting. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389174 TI - Examining the measurement invariance of a modified CES-D for American Indian and non-Hispanic White adolescents and young adults. AB - Existing measures of depression may not perform adequately for American Indian (AI) people, including adolescents and young adults. The National Longitudinal Study of Adolescent to Adult Health (Add Health) is utilizing modified long- and short-form versions of the Center for Epidemiologic Studies Depression (CES-D) scale in study waves, scales that had not been examined for measurement invariance (MI) with AI adolescents or young adults. To help fill this knowledge gap, in this study we analyzed secondary restricted data from Add Health in assessing the cross-cultural MI of the 19-item CES-D-based scale employed in Add Health Wave 1 and the 10-item, short-form version administered in Wave 4 between AI and non-Hispanic White adolescents and young adults. We also tested the longitudinal MI of the 10-item CES-D-based scale between adolescence (Wave 1) and young adulthood (Wave 4) within each racial group. Results illustrated that the 19-item scale exhibited cross-cultural MI in Wave 1 for 1-, 2-, and 3-factor solutions. A 4-factor solution, which had the best overall fit for both groups, was partially cross-culturally invariant. The 10-item scale showed cross-cultural MI for a 2-factor solution at both waves, with 1-factor solutions exhibiting partial MI. However, within-group longitudinal MI with the 10-item scale was not supported for any tested solution for either AI or non-Hispanic White respondents. These findings support the cross-cultural MI of Add Health CES-D based items for AI and non-Hispanic White adolescents and young adults, while highlighting the importance of examining latent construct MI over time between adolescence and young adulthood. (PsycINFO Database Record PMID- 29389175 TI - Comparability of Structured Interview of Reported Symptoms (SIRS) and Structured Interview of Reported Symptoms-Second Edition (SIRS-2) classifications with external response bias criteria. AB - Rogers, Sewell, and Gillard (2010) released a revised version of the Structured Interview of Reported Symptoms (SIRS; Rogers, Bagby, & Dickens, 1992), the SIRS 2, which introduced several new scales, indices, and a new classification model with the overall goal of improving its classification of genuine versus feigned presentations. Since the release of the SIRS-2, several concerns have been raised regarding the quality of the SIRS-2 development and validation samples and the method used to calculate classification accuracy estimates. To further explore issues related to the clinical utility of the SIRS-2, the current study examined associations of the SIRS and SIRS-2 with the Minnesota Multiphasic Personality Inventory-2-Restructured Form (Ben-Porath & Tellegen, 2008/2011) validity scales in separate samples of disability claimants and criminal defendants. Results indicate that the SIRS-2 reduced the number of feigning classifications. Additional analyses suggest that the Modified Total Index and Supplementary Scale Index do not assess the test-taking strategy that Rogers and colleagues (2010) intended the indices to capture. External data indicates that evaluees reclassified on the SIRS-2 in nonfeigning categories exhibited feigned symptoms of psychopathology. Indeed, we found that SIRS-identified feigners showed significant evidence of overreporting on the Minnesota Multiphasic Personality Inventory-2-Restructured Form validity scales, regardless of their SIRS-2 classification. The current study highlights the overall weakness in clinical utility of the SIRS-2. Implications of these results for both clinical and forensic settings are discussed. (PsycINFO Database Record PMID- 29389176 TI - Psychometric properties of the Italian version of the Personality Assessment Inventory (PAI). AB - The Personality Assessment Inventory (PAI) has been translated into different languages (e.g., Spanish, German, and Greek) and several authors investigated psychometric properties, internal structure, and the convergent validity of translated versions of the PAI. Recently, an Italian version of the test has been published, but its psychometric properties has never been explored. The aims of the present study were: (a) to examine the hypothesized subscale structure of scales that have subscales, (b) to evaluate the internal structure of the 22 PAI full scales, and (c) to report on the convergent validity of the PAI scales with the Millon Clinical Multiaxial Inventory-III (MCMI-III) scales. The sample consisted of 1,538 participants recruited from all over Italy. Our findings provided support to the cross-cultural applicability of the PAI and contributed to enhance confidence in the validity and utility of the PAI. (PsycINFO Database Record PMID- 29389178 TI - Does ease mediate the ease-of-retrieval effect? A meta-analysis. AB - A wealth of literature suggests individuals use feelings in addition to facts as sources of information for judgment. This paper focuses on a manipulation in which participants list either a few or many examples of a given type, and then make a judgment. Instead of using the number of arguments or evidence strength, participants are hypothesized to use the subjective ease of generating examples as the primary input to judgment. This result is commonly called the ease-of retrieval effect, and the feeling of ease is typically assumed to mediate the effect. We use meta-analytic methods across 142 papers, 263 studies, and 582 effect sizes to assess the robustness of the ease-of-retrieval effect, and whether or not the effect is mediated by subjective ease. On average, the standard few-versus-many manipulation exhibits a medium-sized effect. In experimental conditions designed to replicate the standard effect, about a third to half of the total effect is mediated by subjective ease. This supports the standard explanation, but suggests that other mediators are present. Further, we find evidence of publication bias that reduces the standard effect by up to 1 third. We also find that (a) moderator manipulations that differ from the standard manipulation lead to smaller, often reversed effects that are not as strongly mediated by ease, (b) several manipulations of theory-based moderators (e.g., polarized attitudes, misattribution) yield strong theory-consistent effects, (c) method-based moderators have little or no effects on the results, and (d) the mediation results are robust with respect to assumptions about error structure. (PsycINFO Database Record PMID- 29389179 TI - Improving the global identification of bipolar spectrum disorders: Meta-analysis of the diagnostic accuracy of checklists. AB - Shifting definitions and differences in the conceptualization of bipolar disorders have contributed to long diagnostic delays, poor reliability, and inconsistent findings. Rating scales are independent of clinical judgment and offer a reliable way to assess manic symptoms, making them good tools to improve both clinical and research diagnoses of bipolar disorder. However, there are dozens of candidates, with few obvious distinguishing characteristics, making it difficult to select one. Our goal was to metaanalyze the diagnostic accuracy of rating scales designed to identify [hypo]manic symptoms. Additionally, we explored potential moderator variables including global region, translation into a different language, and sample composition. Nearly 4000 articles were identified with searches in PubMed and PsycINFO, yielding 127 effect sizes from 103 studies that met the following inclusion criteria: (a) statistics reported by which a standardized effect size could be calculated, (b) participants age 18 + years, (c) reference diagnoses made by semistructured/structured diagnostic interview, (d) results published in English. Multivariate mixed regression models accounted for multiple effect sizes nested within sample. One hundred twenty seven effect sizes across 14 rating scales were evaluated. There was significant heterogeneity across effect sizes; Cochran's Q(126 df) = 1622.08, p < .00005, and substantial variance components both within (sigma2 = .057) and between samples (sigma2 = .253). Four measures performed similarly well and significantly better than some competitors after controlling for design and reporting features. The best rating scales offer an inexpensive, efficient way to improve research and clinical diagnostic processes across diverse populations, and could also complement formal diagnoses for examining secular and cultural trends. (PsycINFO Database Record PMID- 29389177 TI - Emotion fingerprints or emotion populations? A meta-analytic investigation of autonomic features of emotion categories. AB - The classical view of emotion hypothesizes that certain emotion categories have a specific autonomic nervous system (ANS) "fingerprint" that is distinct from other categories. Substantial ANS variation within a category is presumed to be epiphenomenal. The theory of constructed emotion hypothesizes that an emotion category is a population of context-specific, highly variable instances that need not share an ANS fingerprint. Instead, ANS variation within a category is a meaningful part of the nature of emotion. We present a meta-analysis of 202 studies measuring ANS reactivity during lab-based inductions of emotion in nonclinical samples of adults, using a random effects, multilevel meta-analysis and multivariate pattern classification analysis to test our hypotheses. We found increases in mean effect size for 59.4% of ANS variables across emotion categories, but the pattern of effect sizes did not clearly distinguish 1 emotion category from another. We also observed significant variation within emotion categories; heterogeneity accounted for a moderate to substantial percentage (i.e., I2 >= 30%) of variability in 54% of these effect sizes. Experimental moderators epiphenomenal to emotion, such as induction type (e.g., films vs. imagery), did not explain a large portion of the variability. Correction for publication bias reduced estimated effect sizes even further, increasing heterogeneity of effect sizes for certain emotion categories. These findings, when considered in the broader empirical literature, are more consistent with population thinking and other principles from evolutionary biology found within the theory of constructed emotion, and offer insights for developing new hypotheses to understand the nature of emotion. (PsycINFO Database Record PMID- 29389180 TI - If John is taller than Jake, where is John? Spatial inference from magnitude comparison. AB - We regularly compare magnitudes and describe these comparisons to other people. This article reports 9 experiments that examine how messages about the relative magnitude of two items affect inferences about the items' spatial arrangement. Native English speakers were given sentences such as "One tree is taller than the other," and their beliefs about the left-right arrangement of the objects were probed. Across a wide range of dimensions and tasks, the choice of comparative shaped spatial inference: "Smaller" comparatives (e.g., shorter, lighter, less) led to the belief that the small item was on the left, whereas "larger" comparatives (e.g., longer, heavier, more) led to the belief that the small item was on the right. These inferences match the tendency of message senders to choose comparatives based on spatial layout, such that purely ordinal magnitude comparisons communicate information about the spatial arrangement of the compared objects. There was also evidence for a canonical "small-large" inference, consistent with the tendency of English speakers to associate "small" with "left" and "large" with "right"; however, this effect was task-dependent, indicating a flexible, language-based mapping rather than an immutable bias. Finally, there was evidence that the choice of comparative influenced the salience of particular response options. These results help to elucidate the deep interconnections between language, space, and magnitude: Linguistic tokens and structures reflect physical reality and, in turn, shape mental representations of the physical world. (PsycINFO Database Record PMID- 29389181 TI - Listeners and readers generalize their experience with word meanings across modalities. AB - Research has shown that adults' lexical-semantic representations are surprisingly malleable. For instance, the interpretation of ambiguous words (e.g., bark) is influenced by experience such that recently encountered meanings become more readily available (Rodd et al., 2016, 2013). However, the mechanism underlying this word-meaning priming effect remains unclear, and competing accounts make different predictions about the extent to which information about word meanings that is gained within one modality (e.g., speech) is transferred to the other modality (e.g., reading) to aid comprehension. In two Web-based experiments, ambiguous target words were primed with either written or spoken sentences that biased their interpretation toward a subordinate meaning, or were unprimed. About 20 min after the prime exposure, interpretation of these target words was tested by presenting them in either written or spoken form, using word association (Experiment 1, N = 78) and speeded semantic relatedness decisions (Experiment 2, N = 181). Both experiments replicated the auditory unimodal priming effect shown previously (Rodd et al., 2016, 2013) and revealed significant cross-modal priming: primed meanings were retrieved more frequently and swiftly across all primed conditions compared with the unprimed baseline. Furthermore, there were no reliable differences in priming levels between unimodal and cross-modal prime test conditions. These results indicate that recent experience with ambiguous word meanings can bias the reader's or listener's later interpretation of these words in a modality-general way. We identify possible loci of this effect within the context of models of long-term priming and ambiguity resolution. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389182 TI - The effect of feedback delay on perceptual category learning and item memory: Further limits of multiple systems. AB - Delayed feedback during categorization training has been hypothesized to differentially affect 2 systems that underlie learning for rule-based (RB) or information-integration (II) structures. We tested an alternative possibility: that II learning requires more precise item representations than RB learning, and so is harmed more by a delay interval filled with a confusable mask. Experiments 1 and 2 examined the effect of feedback delay on memory for RB and II exemplars, both without and with concurrent categorization training. Without the training, II items were indeed more difficult to recognize than RB items, but there was no detectable effect of delay on item memory. In contrast, with concurrent categorization training, there were effects of both category structure and delayed feedback on item memory, which were related to corresponding changes in category learning. However, we did not observe the critical selective impact of delay on II classification performance that has been shown previously. Our own results were also confirmed in a follow-up study (Experiment 3) involving only categorization training. The selective influence of feedback delay on II learning appears to be contingent on the relative size of subgroups of high-performing participants, and in fact does not support that RB and II category learning are qualitatively different. We conclude that a key part of successfully solving perceptual categorization problems is developing more precise item representations, which can be impaired by delayed feedback during training. More important, the evidence for multiple systems of category learning is even weaker than previously proposed. (PsycINFO Database Record PMID- 29389183 TI - Mood state dissociates conflict adaptation within tasks and across tasks. AB - The present study investigated the influence of mood state (positive vs. negative) on the cognitive control process of conflict adaptation. A task switching paradigm was applied, allowing to assess conflict adaptation both within tasks and across tasks. A success-failure manipulation was applied for mood induction. Within-task conflict adaptation tended to be larger in negative mood than in positive mood, in line with previous findings in the literature. Across-task conflict adaptation was also observed, but only in the positive mood group: Participants in positive mood showed larger conflict adaptation than participants in negative mood. We suggest that different cognitive mechanisms underlie this double dissociation: Within-task conflict adaptation is enhanced in negative mood because response conflict is aversive in nature, and is therefore congruent to negative mood states. Between-task conflict adaptation is only present in positive mood because of less distinct task representations under positive mood, leading conflict adaptation to transfer to the other task. The data show that influences of mood state on cognitive control are multifaceted, with some control processes being enhanced and others attenuated in negative relative to positive mood. (PsycINFO Database Record PMID- 29389184 TI - How listening to music affects reading: Evidence from eye tracking. AB - The current research looked at how listening to music affects eye movements when college students read natural passages for comprehension. Two studies found that effects of music depend on both frequency of the word and dynamics of the music. Study 1 showed that lexical and linguistic features of the text remained highly robust predictors of looking times, even in the music condition. However, under music exposure, (a) readers produced more rereading, and (b) gaze duration on words with very low frequency were less predicted by word length, suggesting disrupted sublexical processing. Study 2 showed that these effects were exacerbated for a short period as soon as a new song came into play. Our results suggested that word recognition generally stayed on track despite music exposure and that extensive rereading can, to some extent, compensate for disruption. However, an irrelevant auditory signal may impair sublexical processing of low frequency words during first-pass reading, especially when the auditory signal changes dramatically. These eye movement patterns are different from those observed in some other scenarios in which reading comprehension is impaired, including mindless reading. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389185 TI - Distinctiveness and the attentional boost effect. AB - The typical pattern of results in divided attention experiments is that subjects in a full attention (FA) condition perform markedly better on tests of memory than subjects in a divided attention (DA) condition which forces subjects to split their attention between studying to-be-remembered stimuli and completing some peripheral task. Nevertheless, recent research has revealed an exception wherein stimuli presented concurrently with targets in a detection task are better remembered than stimuli which co-occur with distractors. Research on this phenomenon-the Attentional Boost Effect (ABE)-has demonstrated that the ABE is reduced or eliminated for words made distinct by their word frequency or orthographic properties-forms of secondary distinctiveness. However, it is unclear how primary distinctiveness effects may interact with the ABE. The current study observed how perceptual and semantic manipulations of primary distinctiveness via the isolation paradigm interact with the ABE, and revealed these interactions to be fundamentally different than those of secondary distinctiveness. Specifically, whereas the effects of secondary distinctiveness in earlier studies were found to be redundant with the ABE, the current study demonstrated that items characterized by primary distinctiveness enhanced memory performance independently of the ABE. (PsycINFO Database Record PMID- 29389186 TI - The sandwich priming paradigm does not reduce lexical competitor effects. AB - We investigated the mechanisms underlying sandwich priming, a procedure in which a brief preprime target presentation precedes the conventional mask-prime-target sequence, used to study orthographic similarity. Lupker and Davis (2009) showed the sandwich paradigm enhances orthographic priming effects: With primes moderately related to targets, sandwich priming produced significant facilitation, but conventional priming did not. They argued that unlike conventional priming, sandwich priming is not susceptible to an uncontrolled counteractive inhibitory process, lexical competition, that cancels out moderate facilitation effects. They suggest lexical competition is eliminated by preactivating the target's representation, privileging the target over similar lexical units (competitors). As such, it better measures orthographic relatedness between primes and targets, a key purpose of many priming studies. We tested whether elimination of lexical competition could indeed account for the observed orthographic priming boost with sandwich priming. In three lexical decision experiments and accompanying simulations with a competitive network model, we compared priming effects in three preprime procedures: no preprime (conventional), identity (target) preprime (sandwich), and competitor preprime (included to exacerbate lexical competition). The related prime conditions consisted of replaced-letters, shared neighbor (one-letter-different from both competitor preprime and target), and transposed-all-letter nonword primes. Contrary to the model's predictions, the competitor preprime did not attenuate (Experiment 1) or even reverse the priming effect (Experiment 2). Moreover, the competitor enabled facilitatory priming that was absent with no preprime (Experiment 3). These data suggested that the sandwich orthographic boost could not be attributed to reduced lexical competition but rather to prelexical processes in word recognition. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389187 TI - Fluctuation in cognitive engagement during reading: Evidence from concurrent recordings of postural and eye movements. AB - The present study utilized a novel methodological combination of eye tracking and postural movement recordings to study task-induced changes in cognitive engagement during expository text reading. Thirty-three participants read an expository text with a specific task in mind while their eye and postural movements were concurrently recorded, and after reading recalled the text from memory. The results showed that readers spent longer total fixation time and had better memory for task-relevant than irrelevant text information. During the course of reading, head-to-screen distance and the speed of head motion decreased more for relevant than irrelevant text segments. The results support the dynamic engagement hypothesis: there is task-induced fluctuation in cognitive engagement during reading. Moreover, the results suggest two types of engagement processes: transient and sustained engagement. The former refers to fast, momentary changes, whereas the latter refers to slower changes in the level of engagement observed across the reading task. The novel combination of eye and postural movement recordings proved to be useful in studying how readers embody the cognitive task demands during reading. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389188 TI - Context specificity of automatic influences of memory. AB - It has often been shown that intentional recollection is influenced by context manipulations, such as context reinstatement (e.g., Smith, 2013; Smith & Vela, 2001), but whether or not automatic retrieval (e.g., Jacoby, 1991) is likewise context dependent remains an open question. Here, we present two experiments that examined effects of context manipulations on indirect measures of memory. The first experiment tested anagram completion, and the second experiment used word fragment completion to test effects of context reinstatement; both experiments found reinstatement effects. To address potential problems of explicit contamination, we also asked participants if they were aware of the priming manipulations. Separating participants according to their test awareness showed effects of context manipulations for both aware and unaware participants. A greater effect size was found for aware participants only in Experiment 1, in which participants had enough time on each test trial for recollection to be used. We conclude that context reinstatement does affect automatic retrieval. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389189 TI - Explaining recollection without remembering. AB - Recollection without remembering is a counterintuitive phenomenon that violates a traditional assumption of source memory models-namely, that accurate item memory is a necessary precondition for remembering source details that accompanied an item's presentation. The dual-recollection model explains recollection without remembering as a by-product of the contrasting effects of target and context recollection on item tests versus source tests. We pitted that explanation against 2 others that preserve the traditional assumption, one based on hypothesized testing artifacts and the other derived from multivariate signal detection theory. Our experiments focused on a manipulation that, according to dual-recollection theory, should drive source memory and item memory in opposite directions. In 2 experiments, studied items were tagged with 3 source details (voice gender, taxonomic category, and list), such that either (a) the 3 details were consistent with each other or (b) 1 detail was inconsistent with the other 2. As predicted, source memory was better but item memory was worse when source details were consistent with each other. The recollection without remembering effect was observed in both experiments, and as predicted by dual-recollection theory, it was more robust when item memory was worse than when it was better. A further instance of recollection without remembering was detected that involved distractors rather than presented items. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389190 TI - Explaining the association between music training and reading in adults. AB - We sought to clarify whether the positive association between music lessons and reading ability is explained better by shared resources for processing pitch and temporal information, or by general cognitive abilities. Participants were native and nonnative speakers of English with varying levels of music training. We measured reading ability (comprehension and speed), music-perception skills (melody and rhythm), general cognitive ability (nonverbal intelligence, short term memory, and working memory), and socioeconomic status (SES; family income, parents' education). Reading ability was associated positively with music training, English as a native language, and general cognitive ability. The association between reading and music training was significant after SES, native language, and music-perception skills were controlled. After general cognitive abilities were held constant, however, there was no longer an association between reading and music training. These findings suggest that the association between reading ability and music training is a consequence of general cognitive abilities. (PsycINFO Database Record PMID- 29389191 TI - Phonologically-based priming in the same-different task with L1 readers. AB - The present experiment provides an investigation of a promising new tool, the masked priming same-different task, for investigating the orthographic coding process. Orthographic coding is the process of establishing a mental representation of the letters and letter order in the word being read which is then used by readers to access higher-level (e.g., semantic) information about that word. Prior research (e.g., Norris & Kinoshita, 2008) had suggested that performance in this task may be based entirely on orthographic codes. As reported by Lupker, Nakayama, and Perea (2015a), however, in at least some circumstances, phonological codes also play a role. Specifically, even though their 2 languages are completely different orthographically, Lupker et al.'s Japanese-English bilinguals showed priming in this task when masked L1 primes were phonologically similar to L2 targets. An obvious follow-up question is whether Lupker et al.'s effect might have resulted from a strategy that was adopted by their bilinguals to aid in processing of, and memory for, the somewhat unfamiliar L2 targets. In the present experiment, Japanese readers responded to (Japanese) Kanji targets with phonologically identical primes (on "related" trials) being presented in a completely different but highly familiar Japanese script, Hiragana. Once again, significant priming effects were observed, indicating that, although performance in the masked priming same-different task may be mainly based on orthographic codes, phonological codes can play a role even when the stimuli being matched are familiar words from a reader's L1. (PsycINFO Database Record PMID- 29389192 TI - Postcategorical auditory distraction in short-term memory: Insights from increased task load and task type. AB - Task-irrelevant speech impairs short-term serial recall appreciably. On the interference-by-process account, the processing of physical (i.e., precategorical) changes in speech yields order cues that conflict with the serial ordering process deployed to perform the serial recall task. In this view, the postcategorical properties (e.g., phonology, meaning) of speech play no role. The present study reassessed the implications of recent demonstrations of auditory postcategorical distraction in serial recall that have been taken as support for an alternative, attentional-diversion, account of the irrelevant speech effect. Focusing on the disruptive effect of emotionally valent compared with neutral words on serial recall, we show that the distracter-valence effect is eliminated under conditions-high task-encoding load-thought to shield against attentional diversion whereas the general effect of speech (neutral words compared with quiet) remains unaffected (Experiment 1). Furthermore, the distracter-valence effect generalizes to a task that does not require the processing of serial order the missing-item task-whereas the effect of speech per se is attenuated in this task (Experiment 2). We conclude that postcategorical auditory distraction phenomena in serial short-term memory (STM) are incidental: they are observable in such a setting but, unlike the acoustically driven irrelevant speech effect, are not integral to it. As such, the findings support a duplex-mechanism account over a unitary view of auditory distraction. (PsycINFO Database Record PMID- 29389193 TI - Outcome predictability biases cued search. AB - Within the domain of associative learning, there is substantial evidence that people (and other animals) select among environmental cues on the basis of their reinforcement history. Specifically, people preferentially attend to, and learn about, cueing stimuli that have previously predicted events of consequence (a predictiveness bias). By contrast, relatively little is known about whether people prioritize some (to-be-predicted) outcome events over others on the basis of their past experience with those outcomes (a predictability bias). The present experiments assessed whether the prior predictability of a stimulus results in a learning bias in a contingency learning task, as such effects are not anticipated by formal models of associative learning. Previously unpredictable stimuli were less readily learned about than previously predictable stimuli. This pattern is unlikely to reflect the use of strategic search processes or blocking of learning by the context. Instead we argue that our findings are most consistent with the operation of a biased learning mechanism. (PsycINFO Database Record PMID- 29389194 TI - Gender congruency from a neutral point of view: The roles of gender classes and conceptual connotations. AB - The question of whether language affects thought is long-standing, with grammatical gender being one of the most contended instances. Empirical evidence focuses on the gender congruency effect, according to which referents of masculine nouns are conceptualized more strongly as male and those of feminine nouns more strongly as female. While some recent studies suggest that this effect is driven by conceptual connotations rather than grammatical properties, research remains theoretically inconclusive because of the confounding of grammatical gender and conceptual connotations in gendered (masculine or feminine) nouns. Taking advantage of the fact that German also includes a neuter gender, the current study attempted to disentangle the relative contributions of grammatical properties and connotations to the emergence of the gender congruency effect. In three pairs of experiments, neuter and gendered nouns were compared in an Extrinsic Affective Simon Task based on gender associations, controlled for a possible role of gender-indicating articles. A congruency effect emerged equally strongly for neuter and gendered nouns, but disappeared when including connotations as covariate, thereby effectively excluding grammatical gender as the (only) driving force for this effect. Based on a critical discussion of these findings, we propose a possible mechanism for the emergence of the effect that also has the potential to accommodate conflicting patterns of findings from previous research. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389195 TI - The dimensionality of reasoning: Inductive and deductive inference can be explained by a single process. AB - Three-experiments examined the number of qualitatively different processing dimensions needed to account for inductive and deductive reasoning. In each study, participants were presented with arguments that varied in logical validity and consistency with background knowledge (believability), and evaluated them according to deductive criteria (whether the conclusion was necessarily true given the premises) or inductive criteria (whether the conclusion was plausible given the premises). We examined factors including working memory load (Experiments 1 and 2), individual working memory capacity (Experiments 1 and 2), and decision time (Experiment 3), which according to dual-processing theories, modulate the contribution of heuristic and analytic processes to reasoning. A number of empirical dissociations were found. Argument validity affected deduction more than induction. Argument believability affected induction more than deduction. Lower working memory capacity reduced sensitivity to argument validity and increased sensitivity to argument believability, especially under induction instructions. Reduced decision time led to decreased sensitivity to argument validity. State-trace analyses of each experiment, however, found that only a single underlying dimension was required to explain patterns of inductive and deductive judgments. These results show that the dissociations, which have traditionally been seen as supporting dual-processing models of reasoning, are consistent with a single-process model that assumes a common evidentiary scale for induction and deduction. (PsycINFO Database Record PMID- 29389197 TI - Best, second-best, and good-enough explanations: How they matter to reasoning. AB - There is a wealth of evidence that people's reasoning is influenced by explanatory considerations. Little is known, however, about the exact form this influence takes, for instance about whether the influence is unsystematic or because of people's following some rule. Three experiments investigate the descriptive adequacy of a precise proposal to be found in the philosophical literature, to wit, that we should infer to the best explanation, provided certain additional conditions are met. The first experiment studies the relation between the quality of an explanation and people's willingness to infer that explanation when only one candidate explanation is given. The second experiment presents participants always with two explanations and investigates the effect of the presence of an alternative on the participants' willingness to infer the target explanation. Although Experiments 1 and 2 manipulate explanation quality and willingness to infer to the best explanation between participants, Experiment 3 manipulates those measures within participants, thereby allowing to study the influence of explanatory considerations on inference at the individual level. The third experiment also studies the connection between explanation quality, willingness to infer, and metacognitive confidence in the decision to infer. The main conclusions that can be drawn from these experiments are that (a) the quality of an explanation is a good predictor of people's willingness to accept that explanation, and a better predictor than the prior probability of the explanation, and (b) if more than one possible explanation is given, people are the less willing to infer the best explanation the better they deem the second best explanation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389196 TI - Imagining counterfactual worlds in autism spectrum disorder. AB - Two experiments are presented that explore online counterfactual processing in autism spectrum disorder (ASD) using eye-tracking. Participants' eye movements were tracked while they read factual and counterfactual sentences in an anomaly detection task. In Experiment 1, the sentences depicted everyday counterfactual situations (e.g., If Joanne had remembered her umbrella, her hair would have been dry/wet when she arrived home). Sentences in Experiment 2 depicted counterfactual versions of real world events (e.g., If the Titanic had not hit an iceberg, it would have survived/sunk along with all the passengers). Results from both experiments suggest that counterfactual understanding is undiminished in adults with ASD. In fact, participants with ASD were faster than Typically Developing (TD) participants to detect anomalies within realistic, discourse-based counterfactuals (Experiment 1). Detection was comparable for TD and ASD groups when understanding could be grounded in knowledge about reality (Experiment 2), though the 2 groups used subtly different strategies for responding to and recovering from counterfactual inconsistent words. These data argue against general difficulties in global coherence and complex integration in ASD. (PsycINFO Database Record PMID- 29389198 TI - The use of phonological representations in guiding eye movements in the visual world paradigm. AB - Across two visual world paradigm (VWP) experiments, Salverda and Tanenhaus (2010) observed an effect of orthographic overlap between targets and competitors in the absence of an effect of phonological overlap when mapping spoken targets onto briefly previewed printed arrays. They concluded that the use of orthographic knowledge can precede use of phonological knowledge during language-mediated mapping in the printed word variant of the VWP. The present experiments aimed to follow up on these studies to examine whether and when phonological and orthographic representations are used during language-mediated mapping. In Experiments 1 and 3, competitors shared high or low phonological overlap with the target but the same degree of orthographic overlap, and in Experiments 2 and 4, orthographic overlap differed between the competitors whereas phonological overlap was held constant. Overlap was manipulated between displays in Experiments 1 and 2 and within display in Experiments 3 and 4. In contrast with Salverda and Tanenhaus' (2010) findings, preferential viewing of the high over the low phonological overlap competitor was observed in Experiment 3, whereas effects of orthographic overlap were unreliable and temporally nondistinct in Experiments 2 and 4. These findings suggest that the use of phonological representations precedes the use of orthographic representations during mapping of spoken targets onto printed arrays in the VWP. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389199 TI - Age differences in selective memory of goal-relevant stimuli under threat. AB - When faced with threat, people often selectively focus on and remember the most pertinent information while simultaneously ignoring any irrelevant information. Filtering distractors under arousal requires inhibitory mechanisms, which take time to recruit and often decline in older age. Despite the adaptive nature of this ability, relatively little research has examined how both threat and time spent preparing these inhibitory mechanisms affect selective memory for goal relevant information across the life span. In this study, 32 younger and 31 older adults were asked to encode task-relevant scenes, while ignoring transparent task irrelevant objects superimposed onto them. Threat levels were increased on some trials by threatening participants with monetary deductions if they later forgot scenes that followed threat cues. We also varied the time between threat induction and a to-be-encoded scene (i.e., 2 s, 4 s, 6 s) to determine whether both threat and timing effects on memory selectivity differ by age. We found that age differences in memory selectivity only emerged after participants spent a long time (i.e., 6 s) preparing for selective encoding. Critically, this time dependent age difference occurred under threatening, but not neutral, conditions. Under threat, longer preparation time led to enhanced memory for task-relevant scenes and greater memory suppression of task-irrelevant objects in younger adults. In contrast, increased preparation time after threat induction had no effect on older adults' scene memory and actually worsened memory suppression of task-irrelevant objects. These findings suggest that increased time to prepare top-down encoding processes benefits younger, but not older, adults' selective memory for goal-relevant information under threat. (PsycINFO Database Record PMID- 29389200 TI - Estimating the reliability of emotion measures over very short intervals: The utility of within-session retest correlations. AB - Short measures are commonly used when conducting research involving emotions. However, obtaining appropriate estimates of reliability for short measures is traditionally problematic and is a reoccurring concern in emotion research. To address this issue, we compare the within-session test-retest and factor analysis methods for estimating the reliability of items in the Positive and Negative Affect Schedule-Expanded Form. Results indicate that within-session test-retest (rXX(d)) estimates outperform the factor analysis method by demonstrating stronger relationships with item properties relevant to reliability and validity related criteria. In addition, rXX(d) estimates appropriately generalize across samples with various instruction stems and prevent corrections for attenuation greater than 1.00. Therefore, we encourage researchers to use the corresponding average item-level rXX(d) estimates reported here to correct for attenuation when examining single items from the Positive and Negative Affect Schedule-Expanded Form if a test-retest design is not feasible. (PsycINFO Database Record PMID- 29389201 TI - Expressive suppression tendencies, projection bias in memory of negative emotions, and well-being. AB - The current research extends prior research linking negative emotions and emotion regulation tendencies to memory by investigating whether (a) naturally occurring negative emotions during routine weekly life are associated with more negatively biased memories of prior emotional experiences-a bias called projection; (b) tendencies to regulate emotions via expressive suppression are associated with greater projection bias in memory of negative emotions; and (c) greater projection bias in memory is associated with poorer future well-being. Participants (N = 308) completed a questionnaire assessing their general tendencies to engage in expressive suppression. Then, every week for 7 weeks, participants reported on (a) the negative emotions they experienced across the current week (e.g., "This week, I felt 'sad'"), (b) their memories of the negative emotions they experienced the prior week (e.g., "Last week, I felt 'sad'"), and (c) their well-being. First, participants demonstrated significant projection bias in memory: Greater negative emotions in a given week were associated with remembering emotions in the prior week more negatively than those prior emotions were originally reported. Second, projection bias in memory of negative emotions was greater for individuals who reported greater tendencies to regulate emotions via expressive suppression. Third, greater projection bias in memory of negative emotions was associated with reductions in well-being across weeks. These 3 novel findings indicate that (a) current negative emotions bias memory of past emotions, (b) this memory bias is magnified for people who habitually use expressive suppression to regulate emotions, and (c) this memory bias may undermine well-being over time. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389202 TI - Not just bad actions: Affective concern for bad outcomes contributes to moral condemnation of harm in moral dilemmas. AB - Moral dilemmas typically entail directly causing harm (said to violate deontological ethics) to maximize overall outcomes (said to uphold utilitarian ethics). The dual process model suggests harm-rejection judgments derive from affective reactions to harm, whereas harm-acceptance judgments derive from cognitive evaluations of outcomes. Recently, Miller, Hannikainen, and Cushman (2014) argued that harm-rejection judgments primarily reflect self-focused-rather than other-focused-emotional responses, because only action aversion (self focused reactions to the thought of causing harm), not outcome aversion (other focused reactions to witnessing suffering), consistently predicted dilemma responses. However, they assessed only conventional relative dilemma judgments that treat harm-rejection and outcome-maximization responses as diametric opposites. Instead, we employed process dissociation to assess these response inclinations independently. In two studies (N = 558), we replicated Miller and colleagues' findings for conventional relative judgments, but process dissociation revealed that outcome aversion positively predicted both deontological and utilitarian inclinations-which canceled out for relative judgments. Additionally, individual differences associated with affective processing-psychopathy and empathic concern-correlated with the deontology but not utilitarian parameter. Together, these findings suggest that genuine other oriented moralized concern for others' well-being contribute to both utilitarian and deontological response tendencies, but these tendencies nonetheless draw upon different psychological processes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389203 TI - Mixed emotions: Network analyses of intra-individual co-occurrences within and across situations. AB - This study revisits the structure of emotions by using a co-occurrence network analysis. While previous studies have examined the structure of emotions primarily through interindividual correlations, we investigated how often and which specific positive and negative emotions occur together within individuals. Two studies were conducted with high school students, one (N = 21,678) using retrospective emotion measures (open-ended questions and 28 rated items) and the other (N = 472) using in-the-moment emotion measures (experience sampling). As in previous studies, positive and negative emotion ratings were negatively correlated across individuals, and this negative correlation became stronger when measurement error was controlled. Nevertheless, network analyses of both the open ended responses and of emotion rating scales found frequent co-occurrences between both positive and negative emotions within individuals and within situations. Across all networks, happy, tired, and stressed were among the most frequent emotions that occurred together with emotions of opposite valence. The network analyses presented in this article open new directions to the long lasting debate about the structure of emotions by revealing co-occurrences that interindividual correlations would not show. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389204 TI - Why are injuries disgusting? Comparing pathogen avoidance and empathy accounts. AB - According to pathogen-avoidance perspectives on disgust, injuries, gore, mutilation, or body-envelope violations elicit disgust because they have infectious potential. Here, an alternative explanation is proposed: People empathically simulate an observed injury, leading to unpleasant vicarious feelings, and for lack of a more accurate word, they describe the feelings as disgust. In Study 1, factor analysis of participants' disgust ratings showed that injury items emerged as a separate factor from pathogen items. A behavioral experiment in Study 2 demonstrated that subjects were less willing to touch dressings that had ostensibly been in contact with infections compared with dressings that had contacted equally disgusting injuries, suggesting that the disgust reported toward injuries is not based on an appraisal of contamination threat. Analysis of participants' subjective feeling descriptions in Study 3 revealed that injury stimuli were predominantly associated with feelings of empathy and vicarious pain, rather than the prototypical disgust feelings associated with infection stimuli. Study 4 showed that the level of disgust reported toward injuries was more strongly predicted by perceived pain and horror than by perceived infectiousness, whereas disgust toward infections was equally well predicted by perceived infectiousness and perceived pain and horror. Together, these findings support the hypothesis that disgust reported toward injuries describes an unpleasant vicarious experience based on empathy, which is not the same emotion as the prototypical disgust elicited by pathogen cues. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389205 TI - Disgust as a mechanism for decision making under risk: Illuminating sex differences and individual risk-taking correlates of disgust propensity. AB - The emotion disgust motivates costly behavioral strategies that mitigate against potentially larger costs associated with pathogens, sexual behavior, and moral transgressions. Because disgust thereby regulates exposure to harm, it is by definition a mechanism for calibrating decision making under risk. Understanding this illuminates two features of the demographic distribution of this emotion. First, this approach predicts and explains sex differences in disgust. Greater female disgust propensity is often reported and discussed in the literature, but, to date, conclusions have been based on informal comparisons across a small number of studies, while existing functionalist explanations are at best incomplete. We report the results of an extensive meta-analysis documenting this sex difference, arguing that key features of this pattern are best explained as one manifestation of a broad principle of the evolutionary biology of risk taking: for a given potential benefit, males in an effectively polygynous mating system accept the risk of harm more willingly than do females. Second, viewing disgust as a mechanism for decision making under risk likewise predicts that individual differences in disgust propensity should correlate with individual differences in various forms of risky behavior, because situational and dispositional factors that influence valuation of opportunity and hazard are often correlated across multiple decision contexts. In two large-sample online studies, we find consistent associations between disgust and risk avoidance. We conclude that disgust and related emotions can be usefully examined through the theoretical lens of decision making under risk in light of human evolution. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389206 TI - Vicarious social touch biases gazing at faces and facial emotions. AB - Research has suggested that interpersonal touch promotes social processing and other-concern, and that women may respond to it more sensitively than men. In this study, we asked whether this phenomenon would extend to third-party observers who experience touch vicariously. In an eye-tracking experiment, participants (N = 64, 32 men and 32 women) viewed prime and target images with the intention of remembering them. Primes comprised line drawings of dyadic interactions with and without touch. Targets comprised two faces shown side-by side, with one being neutral and the other being happy or sad. Analysis of prime fixations revealed that faces in touch interactions attracted longer gazing than faces in no-touch interactions. In addition, touch enhanced gazing at the area of touch in women but not men. Analysis of target fixations revealed that touch priming increased looking at both faces immediately after target onset, and subsequently, at the emotional face in the pair. Sex differences in target processing were nonsignificant. Together, the present results imply that vicarious touch biases visual attention to faces and promotes emotion sensitivity. In addition, they suggest that, compared with men, women are more aware of tactile exchanges in their environment. As such, vicarious touch appears to share important qualities with actual physical touch. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389207 TI - Beyond essentialism: Cultural differences in emotions revisited. AB - The current research offers an alternative to essentialism for studying cultural variation in emotional experience. Rather than assuming that individuals always experience an emotion in the same way, our starting point was that the experience of an emotion like anger or shame may vary from one instance to another. We expected to find different anger and shame experience types, that is, groups of people who differ in the instances of anger and shame that they experience. We proposed that studying cultural differences in emotional experience means studying differences in the distribution of these types across cultural contexts: There should be systematic differences in the types that are most common in each culture. Students from the United States, Japan, and Belgium (N = 928) indicated their emotional experiences in terms of appraisals and action tendencies in response to 15 hypothetical anger or shame situations. Using an inductive clustering approach, we identified anger and shame types who were characterized by different patterns of anger and shame experience. As expected, we found that the distribution of these types differed across the three cultural contexts: Of the two anger types, one was common in Japan and one in the United States and Belgium; the three shame types were each most prevalent in a different cultural context. Participants' anger and shame types were primarily predicted by their culture of origin (with an accuracy of 72.3% for anger and 74.0% for shame) and not, or much less, by their ethnic origin, socioeconomic status, gender, self construal, or personality. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389208 TI - Effects of incidental emotions on moral dilemma judgments: An analysis using the CNI model. AB - Effects of incidental emotions on moral dilemma judgments have garnered interest because they demonstrate the context-dependent nature of moral decision-making. Six experiments (N = 727) investigated the effects of incidental happiness, sadness, and anger on responses in moral dilemmas that pit the consequences of a given action for the greater good (i.e., utilitarianism) against the consistency of that action with moral norms (i.e., deontology). Using the CNI model of moral decision-making, we further tested whether the three kinds of emotions shape moral dilemma judgments by influencing (a) sensitivity to consequences, (b) sensitivity to moral norms, or (c) general preference for inaction versus action regardless of consequences and moral norms (or some combination of the three). Incidental happiness reduced sensitivity to moral norms without affecting sensitivity to consequences or general preference for inaction versus action. Incidental sadness and incidental anger did not show any significant effects on moral dilemma judgments. The findings suggest a central role of moral norms in the contribution of emotional responses to moral dilemma judgments, requiring refinements of dominant theoretical accounts and supporting the value of formal modeling approaches in providing more nuanced insights into the determinants of moral dilemma judgments. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389209 TI - Through the eyes of the beholder: Simulated eye-movement experience ("SEE") modulates valence bias in response to emotional ambiguity. AB - Although some facial expressions provide clear information about people's emotions and intentions (happy, angry), others (surprise) are ambiguous because they can signal both positive (e.g., surprise party) and negative outcomes (e.g., witnessing an accident). Without a clarifying context, surprise is interpreted as positive by some and negative by others, and this valence bias is stable across time. When compared to fearful expressions, which are consistently rated as negative, surprise and fear share similar morphological features (e.g., widened eyes) primarily in the upper part of the face. Recently, we demonstrated that the valence bias was associated with a specific pattern of eye movements (positive bias associated with faster fixation to the lower part of the face). In this follow-up, we identified two participants from our previous study who had the most positive and most negative valence bias. We used their eye movements to create a moving window such that new participants viewed faces through the eyes of one our previous participants (subjects saw only the areas of the face that were directly fixated by the original participants in the exact order they were fixated; i.e., Simulated Eye-movement Experience). The input provided by these windows modulated the valence ratings of surprise, but not fear faces. These findings suggest there are meaningful individual differences in how people process faces, and that these differences impact our emotional perceptions. Furthermore, this study is unique in its approach to examining individual differences in emotion by creating a new methodology adapted from those used primarily in the vision/attention domain. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29389210 TI - Adolescents who experienced negative alcohol-related consequences are willing to experience these consequences again in the future. AB - Alcohol use and risky single occasion drinking are common among adolescents and are associated with a higher risk of various negative social, physical, academic, or sexual consequences. Studies have shown that among college students, willingness to experience negative consequences is associated with a higher likelihood of experiencing these consequences in the future. However, it remains unclear how experiencing negative consequences influences adolescents' willingness to experience them again. Based on a representative sample of 1,333 alcohol-using 14- to 15-year-olds (47.9% female), a path model was used to examine the associations between risky drinking, negative social and physical consequences, and willingness to experience the specific consequence in the future. As hypothesized, more frequent risky drinking was positively associated with experiencing negative consequences (i.e., saying or doing embarrassing things, regretted sexual experiences, impairment of schoolwork, problems with parents/friends, accident or injury, hangover, vomiting, memory lapses). Contrary to our second hypothesis, adolescents who experienced a negative consequence were also consistently willing to experience it in the future. Findings suggest that adolescents may see the experience of negative consequences as a necessary evil to attain the positive consequences. Prevention efforts may benefit from focusing on ways of attaining positive consequences by promoting alternatives to engaging in risky drinking practices, as well as reducing negative consequences (e.g., by promoting protective behavioral strategies). (PsycINFO Database Record PMID- 29389211 TI - Hypersexuality associated with paliperidone. AB - We report a case of unusual sexual symptoms in a 43-year-old female patient with schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition), who was being treated with a depot formulation of paliperidone palmitate, an atypical antipsychotic medication. The symptoms included increased sexual desire, sexual preoccupation, constant drive for intercourse, and sexual arousal with unrelated stimuli such as urination. Potential neurochemical mechanisms have been elucidated for this symptomatology. Paliperidone palmitate has broad neuropharmacological effects, which might have contributed to the development of this rare clinical condition. (PsycINFO Database Record PMID- 29389212 TI - Negative mood-induced alcohol-seeking is greater in young adults who report depression symptoms, drinking to cope, and subjective reactivity. AB - Acute negative mood powerfully motivates alcohol-seeking behavior, but it remains unclear whether sensitivity to this effect is greater in drinkers who report depression symptoms, drinking to cope, and subjective reactivity. To examine these questions, 128 young adult alcohol drinkers (ages 18-25) completed questionnaires of alcohol use disorder symptoms, depression symptoms, and drinking to cope with negative affect. Baseline alcohol choice was measured by preference to enlarge alcohol versus food thumbnail images in two-alternative forced-choice trials. Negative mood was then induced by depressive statements and music, before alcohol choice was tested. Subjective reactivity was indexed by increased sadness pre- to post-mood induction. Baseline alcohol choice correlated with alcohol dependence symptoms (p = .001), and drinking coping motives (ps <= .01). Mood induction increased alcohol choice and subjective sadness overall (ps < .001). The mood-induced increase in alcohol choice was associated with depression symptoms (p = .007), drinking to cope (ps <= .03), and subjective reactivity (p = .007). The relationship between mood-induced alcohol choice and drinking to cope remained significant after covarying for other drinking motives. Furthermore, the three predictors (depression, drinking to cope, and subjective reactivity) accounted for unique variance in mood-induced alcohol choice (ps >= .03), and collectively accounted for 18% of the variance (p < .001). These findings validate the pictorial alcohol choice task as sensitive to the relative value of alcohol and acute negative mood. The findings also accord with the core prediction of negative reinforcement theory that sensitivity to the motivational impact of negative mood on alcohol-seeking behavior may be an important mechanism that links depression and alcohol dependence. (PsycINFO Database Record PMID- 29389213 TI - Tobacco withdrawal among opioid-dependent smokers. AB - Prevalence of cigarette smoking among opioid-dependent individuals is 6-fold that of the general U.S. adult population and their quit rates are notoriously poor. One possible reason for the modest cessation outcomes in opioid-dependent smokers may be that they experience more severe tobacco withdrawal upon quitting. In this secondary analysis, we evaluated tobacco withdrawal in opioid-dependent (OD) smokers versus smokers without co-occurring substance use disorders (SUDs). Participants were 47 methadone- or buprenorphine-maintained smokers and 25 non SUD smokers who completed 1 of several 2-week studies involving daily visits for biochemical monitoring, delivery of financial incentives contingent on smoking abstinence, and assessment of withdrawal via the Minnesota Nicotine Withdrawal Scale (MNWS). Prior to quitting smoking, OD smokers presented with higher baseline withdrawal scores than non-SUD smokers (1.7 +/- 0.2 vs. 0.7 +/- 0.2, respectively; F[1, 63] = 7.31, p < .001). Withdrawal scores in both groups decreased over the subsequent 2-week period with no group differences, F(1, 910) = 0.50, p = .48. A similar pattern was observed on craving (i.e., Desire to Smoke item of MNWS), although the trajectory of decrease over time on this item was also moderated by gender. Overall, there was no difference in withdrawal during biochemically verified smoking abstinence between OD and non-SUD smokers, suggesting that elevated withdrawal severity following quitting may not be a major factor contributing to the poor cessation outcomes consistently observed among OD smokers. Further scientific efforts are needed to improve our understanding of the high smoking rates and modest cessation outcomes in this challenging population. (PsycINFO Database Record PMID- 29389214 TI - Unethical and inept? The influence of moral information on perceptions of competence. AB - While moral character heavily influences global evaluations of others (Goodwin, Piazza, & Rozin, 2014), its causal effect on perceptions of others' competence (i.e., one's knowledge, skills, and abilities) is less clear. We found that people readily use information about another's morality when judging their competence, despite holding folk intuitions that these domains are independent. Across 6 studies (n = 1,567), including 2 preregistered experiments, participants judged targets who committed hypothetical transgressions (Studies 1 and 3), cheated on lab tasks (Study 2), acted selfishly in economic games (Study 4), and received low morality ratings from coworkers (Study 5 and 6) as less competent than control or moral targets. These findings were specific to morality and were not the result of incidentally manipulating impressions of warmth (Study 4), nor were they fully explained by a general halo effect (Studies 2 and 3). We hypothesized that immoral targets are seen as less competent because their immoral actions led them to be viewed as low in social intelligence. Studies 4 and 5 supported this prediction, demonstrating that social intelligence was a more reliable mediator than perceptions of self-control or general intelligence. An experimental test of this mediation argument found that presenting targets as highly socially intelligent eliminated the negative effect of immoral information on judgments of competence (Study 6). These results suggest that information about a person's moral character readily influences perceptions of their competence. (PsycINFO Database Record PMID- 29389215 TI - Deep neural networks are more accurate than humans at detecting sexual orientation from facial images. AB - We show that faces contain much more information about sexual orientation than can be perceived or interpreted by the human brain. We used deep neural networks to extract features from 35,326 facial images. These features were entered into a logistic regression aimed at classifying sexual orientation. Given a single facial image, a classifier could correctly distinguish between gay and heterosexual men in 81% of cases, and in 71% of cases for women. Human judges achieved much lower accuracy: 61% for men and 54% for women. The accuracy of the algorithm increased to 91% and 83%, respectively, given five facial images per person. Facial features employed by the classifier included both fixed (e.g., nose shape) and transient facial features (e.g., grooming style). Consistent with the prenatal hormone theory of sexual orientation, gay men and women tended to have gender-atypical facial morphology, expression, and grooming styles. Prediction models aimed at gender alone allowed for detecting gay males with 57% accuracy and gay females with 58% accuracy. Those findings advance our understanding of the origins of sexual orientation and the limits of human perception. Additionally, given that companies and governments are increasingly using computer vision algorithms to detect people's intimate traits, our findings expose a threat to the privacy and safety of gay men and women. (PsycINFO Database Record PMID- 29389216 TI - The bipolarity of affect and depressive symptoms. AB - People differ in the extent to which they experience positive (PA) and negative affect (NA) rather independently or as bipolar opposites. Here, we examine the proposition that the nature of the relation between positive and negative affect in a person's emotional experience is indicative of psychological well-being, in particular the experience of depressive symptoms, typically characterized by diminished positive affect (anhedonia) and increased negative affect (depressed mood). In three experience sampling studies, we examine how positive and negative affective states are related within people's emotional experience in daily life and how the degree of bipolarity of this relation is associated with depressive symptom severity. In Study 1 and 2, we show both concurrently and longitudinally that a stronger bipolar PA-NA relationship is associated with, and in fact is predicted by, higher depressive symptom severity, even after controlling for mean levels of positive and negative affect. In Study 3, we replicate these findings in a daily diary design, with the two conceptually related main symptoms of depression, sadness, and anhedonia, as specific manifestations of high NA and low PA, respectively. Across studies, additional analyses indicate these results are robust across different time scales and various PA and NA operationalizations and that affective bipolarity shows particular specificity toward depressive symptomatology, in comparison with anxiety symptoms. Together, these findings demonstrate that depressive symptoms involve stronger bipolarity between positive and negative affect, reflecting reduced emotional complexity and flexibility. (PsycINFO Database Record PMID- 29389217 TI - Foot Kinetics and Kinematics Profile in Type 2 Diabetes Mellitus with Peripheral Neuropathy: A Hospital Based Study from South India. AB - BACKGROUND: A kinetic change in thefoot like altered plantar pressure is the most common etiological risk factor for causing foot ulcers among people with diabetes mellitus. Kinematic alterations in joint angle and spatiotemporal parameters of the gait have also been frequently observed in participants with diabetes peripheral neuropathy. Diabetes peripheral neuropathy is the most common long term standing complication of type 2 diabetes mellitus. It leads to various micro and macrovascular related complication of the foot. There is a gap in theliteraturefor biomechanical evaluation and assessment in type 2 diabetes mellitus with peripheral neuropathy in Indian population. The aim of the study was to assess and determine the biomechanical changes including kinetics and kinematics of foot among diabetic peripheral neuropathy. METHODS: The cross sectional study was conducted at Diabetic Foot Clinic, Kasturba Hospital, Manipal University, Manipal, Karnataka, India. A total of 120 participants with type 2 diabetes mellitus and peripheral neuropathywere recruited under the purposive sampling method. Participants with any active ulceration or amputation were excluded from the study. RESULTS: The mean age, height, weight, body mass index, duration of diabetes was 57+/-14 year, 164+/-11cm, 61+/-18kg, 24+/- 3, 12+/-7 year respectively. There were significant changes in overall biomechanical profile along with clinical manifestations of diabetes peripheral neuropathy.The regression analysis showed statistical significance for dynamic maximum plantar pressure at forefoot with age, weight, height, duration of diabetes, body mass index, knee & ankle joint angle at toe-off phase of gait cycle,pinprick sensation and ankle reflex (R=.71,R =.55, F (12, 108)=521.9 kPa, p=.002) Conclusions: From the present study, we conclude that people with type 2 diabetes mellitus and peripheral neuropathy have significant changes in their foot kinetics and kinematicsparameters. Therefore, they could be at higher risk of foot ulceration with underlying neuropathy and biomechanically associated problems. PMID- 29389220 TI - Uncovering the Mechanisms Underlying Congenital Lung Malformations. Can We Improve Treatments? PMID- 29389219 TI - Outcomes of Latarjet Versus Distal Tibia Allograft for Anterior Shoulder Instability Repair: A Matched Cohort Analysis. AB - BACKGROUND: Anterior glenoid reconstruction with fresh distal tibia allograft (DTA) has been described for management of recurrent shoulder instability, with encouraging early outcomes; however, no comparative data with the Latarjet procedure are available. PURPOSE: The purpose of this study was to compare the clinical outcomes between patients undergoing DTA and a matched cohort of patients undergoing Latarjet. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A review was conducted of prospectively collected data for patients with a minimum 15% anterior glenoid bone loss who underwent shoulder stabilization via either the DTA or Latarjet procedure and had a minimum follow-up of 2 years. Consecutive patients undergoing DTA were matched in a 1-to-1 format to patients undergoing Latarjet by age, body mass index, history of contact sports, and number of previous shoulder operations. Patients were evaluated pre- and postoperatively with a physical examination and the following outcome assessments: Simple Shoulder Test, visual analog scale, American Shoulder and Elbow Surgeons, Western Ontario Shoulder Instability Index, and Single Assessment Numeric Evaluation. Complications, reoperations, and episodes of recurrent instability were analyzed. Statistical analysis was performed with Student t tests, with P < .05 considered significant. RESULTS: A total of 100 patients (50 Latarjet, 50 DTA) with a mean +/- SD age of 25.6 +/- 6.1 years were analyzed at 45 +/- 20 months (range, 24-111) after surgery. Thirty-two patients (64%) in each group underwent prior ipsilateral shoulder surgery (range, 1-3). Patients undergoing DTA had significantly greater glenoid bone loss defects when compared with patients undergoing Latarjet (28.6% +/- 7.4% vs 22.4% +/- 10.3%, P = .001). Patients in both groups experienced significant improvements in all outcome scores after surgery ( P < .05 for all). No significant differences were found in postoperative scores between the Latarjet and DTA groups: visual analog scale (0.67 +/- 0.97 vs 1.83 +/- 2.31), American Shoulder and Elbow Surgeons (91.06 +/- 8.78 vs 89.74 +/- 12.66), Western Ontario Shoulder Instability Index (74.30 +/- 21.84 vs 89.69 +/- 5.50), or Single Assessment Numeric Evaluation (80.68 +/- 7.21 vs 90.08 +/- 13.39) ( P > .05 for all). However, patients in the Latarjet group had superior Simple Shoulder Test outcomes ( P = .011). There were 10 complications (10%) for the entire cohort, including 5 in the Latarjet group (3 of which required reoperation) and 5 in the DTA group (3 of which required reoperation). The overall recurrent instability rate was 1% (1 patient). CONCLUSION: Fresh DTA reconstruction for recurrent anterior shoulder instability results in a clinically stable joint with similar clinical outcomes as the Latarjet procedure. Longer-term studies are needed to determine if these results are maintained over time. PMID- 29389222 TI - 2017 Acknowledgment of Reviewers. PMID- 29389221 TI - The Augmentation of Revision Anterior Cruciate Ligament Reconstruction With Modified Iliotibial Band Tenodesis to Correct the Pivot Shift: A Computer Navigation Study. AB - BACKGROUND: Iliotibial band (ITB) tenodesis improves stability and functional outcomes when added to anterior cruciate ligament (ACL) reconstruction. Its precise indications are unknown. Persistence of the pivot shift after revision ACL reconstruction may be one indication. HYPOTHESIS: The addition of ITB tenodesis for a persistent pivot shift after revision ACL reconstruction will improve stability and activity levels. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Adults with recurrent ACL ruptures underwent revision ACL reconstruction, followed by a pivot-shift test before the surgery ended. If the pivot shift was grade 0 or 1, no further surgery was performed (group 1). If it was grade 2 or 3, ITB tenodesis was performed (group 2). The pivot-shift test was performed, graded, and measured using computer navigation before revision ACL reconstruction and after revision ACL reconstruction with and without ITB tenodesis. Tegner activity scores were obtained 2 years after surgery. Groups were compared with regard to anterior translation and internal rotation during the pivot shift as well as Tegner activity scores ( P < .05). RESULTS: There were 20 patients in group 1 and 18 in group 2. The mean anterior translation improved in group 1, from 17.7 +/- 3.5 mm to 6.6 +/- 1.9 mm, and group 2, from 18.5 +/- 3.3 mm to 6.1 +/- 1.2 mm, after revision ACL reconstruction ( P < .001), with no difference between the groups ( P = .15). After ITB tenodesis, the reduction in anterior translation in group 2 (5.3 +/- 1.5 mm) became greater than that in group 1 (6.6 +/- 1.9 mm) ( P = .03). In both groups after revision ACL reconstruction, there was a reduction in internal rotation (group 1: 24.2 degrees +/- 4.0 degrees to 10.3 degrees +/- 1.1 degrees ; group 2: 25.4 degrees +/- 3.7 degrees to 14.6 degrees +/- 2.8 degrees ; P < .001), but this change was less in group 2 ( P = .02). After ITB tenodesis, internal rotation in group 2 (8.3 degrees +/- 2.6 degrees ) became less than that in group 1 (10.3 degrees +/- 1.1 degrees ) ( P = .02). The mean Tegner activity scores in group 1 were 8.1 +/- 1.1 before surgery and 7.4 +/- 0.9 after surgery, while in group 2 they were 7.0 +/- 1.3 and 7.2 +/- 0.4, respectively, and not significantly different ( P = .29). CONCLUSION: ITB tenodesis improved laxity, although it did not affect activity levels, when there was a persistent pivot shift after revision ACL reconstruction. CLINICAL RELEVANCE: An indication to perform ITB tenodesis is the persistence of a grade >=2 pivot shift after revision ACL reconstruction. PMID- 29389223 TI - Relationship Between Kinematic and Physiological Indices During Braking Events of Different Intensities. AB - Objective To study the relationship between physiological indices and kinematic indices during braking events of different intensities. Background Based on mental workload theory, driving and other task demands may generate changes in physiological indices, such as the driver's heart rate and skin conductance. However, no attempts were made to associate changes in physiological indices with changes in vehicle kinematics that result from the driver attempts to meet task demands. Method Twenty-five drivers participated in a field experiment. We manipulated braking demands using roadside signs to communicate the speed (km/h) before braking (50 or 60) and the target speed for braking (30 or to a complete stop). In an additional session, we asked drivers to brake as if they were responding to an impending collision. We analyzed the relationship between the intensities of braking events as measured by deceleration values (g) and changes in heart rate, heart rate variability, and skin conductance. Results All physiological indices were associated with deceleration intensity. Especially salient were the differences in physiological indices between the intensive (|g| > 0.5) and nonintensive braking events. The strongest relationship was between braking intensity and skin conductance. Conclusions Skin conductance, heart rate, and heart rate variability can mirror the mental workload elicited by varying braking intensities. Application Associating vehicle kinematics with physiological indices related to short-term driving events may help improve the performance of driver assistance systems. PMID- 29389225 TI - Erratum. PMID- 29389226 TI - Erratum. PMID- 29389224 TI - Perspectives on Palliative Care in Cancer Clinical Trials: Diverse Meanings from Multidisciplinary Cancer Care Providers. AB - BACKGROUND: Palliative care (PC) is often misunderstood as exclusively pertaining to end-of-life care, which may be consequential for its delivery. There is little research on how PC is operationalized and delivered to cancer patients enrolled in clinical trials. OBJECTIVE: We sought to understand the diverse perspectives of multidisciplinary oncology care providers caring for such patients in a teaching hospital. METHODS: We conducted qualitative semistructured interviews with 19 key informants, including clinical trial principal investigators, oncology fellows, research nurses, inpatient and outpatient nurses, spiritual care providers, and PC fellows. Questions elicited information about the meaning providers assigned to the term "palliative care," as well as their experiences with the delivery of PC in the clinical trial context. Using grounded theory, a team-based coding method was employed to identify major themes. RESULTS: Four main themes emerged regarding the meaning of PC: (1) the holistic nature of PC, (2) the importance of symptom care, (3) conflict between PC and curative care, and (4) conflation between PC and end-of-life care. Three key themes emerged with regard to the delivery of PC: (1) dynamics among providers, (2) discussing PC with patients and family, and (3) the timing of PC delivery. CONCLUSION: There was great variability in personal meanings of PC, conflation with hospice/end-of life care, and appropriateness of PC delivery and timing, particularly within cancer clinical trials. A standard and acceptable model for integrating PC concurrently with treatment in clinical trials is needed. PMID- 29389227 TI - Single Incision Versus Conventional Laparoscopic Sleeve Gastrectomy for Morbid Obesity: A Meta-Analysis. AB - INTRODUCTION: The purpose of this study was to review the existing evidence on obese patients treated with single-incision laparoscopic sleeve gastrectomy (SILSG) or conventional laparoscopic sleeve gastrectomy (LSG), to compare the perioperative parameters and outcomes of the two bariatric procedures. MATERIALS AND METHODS: A systematic literature search was performed in PubMed, Scopus, and Cochrane library, in accordance with the PRISMA guidelines. Seventeen articles met the inclusion criteria and incorporated 3843 patients. RESULTS: This study reveals comparable mean operative time, length of hospital stay, and complications between the two approaches. The SILSG approach was associated with enhanced cosmetic results, but increased incisional hernia rate. CONCLUSIONS: These outcomes should be treated with caution given the small number of included comparative studies. Well-designed, randomized controlled studies, comparing LSG to SILSG, are necessary to assess further their clinical outcomes. PMID- 29389228 TI - Searching for Evidence-Based Reassurance Where None Could Be Found. PMID- 29389229 TI - Controversies in the Management of Clinical Stage I Seminoma: Carboplatin a Decade in-Time to Start Backing Out. PMID- 29389230 TI - Reply to L. Kennedy et al. PMID- 29389231 TI - Walking the Dividing Line: The Challenges of Being a Doctor-Patient. PMID- 29389232 TI - How Should We Assess Benefit in Patients Receiving Checkpoint Inhibitor Therapy? PMID- 29389233 TI - Grace and Forgiveness. PMID- 29389234 TI - Duration of Anti-Programmed Death-1 Therapy in Advanced Melanoma: How Much of a Good Thing Is Enough? AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 53-year-old healthy man presented with recurrent in-transit melanoma of the right lower extremity. Eight years prior he had undergone wide local excision and sentinel lymph node biopsy for invasive melanoma of the anteromedial aspect of the distal right thigh. Pathology revealed an ulcerated melanoma, Breslow depth 3.5 mm, and with one involved micrometastatic inguinal lymph node. Staging studies did not demonstrate distant metastases. Superficial inguinal node dissection was performed and did not identify any additional metastatic nodes of 14 retrieved for a final pathologic staging of T3bN1aM0 (stage IIIB) cutaneous melanoma. He received 12 months of adjuvant high-dose interferon alfa-2b. Two years later, he developed a 1.2-cm subcutaneous focus of in-transit recurrence approximately 4 cm proximal to the original melanoma site in the right thigh, which was treated with surgical resection followed by adjuvant radiotherapy. Over the next 4 years, he underwent six additional surgeries for isolated in-transit recurrences affecting the same limb. He was referred for therapeutic options at the time of his latest in transit recurrence. Examination revealed three palpable subcutaneous nodules in the right thigh in the setting of lymphedema. A core biopsy confirmed recurrent melanoma (Fig 1). Whole-body fluorodeoxyglucose positron emission tomography imaging revealed at least 17 hypermetabolic cutaneous and subcutaneous nodules in the right thigh, four fluorodeoxyglucose-avid nodules below the right knee, but no distant metastases (Fig 2A). Brain magnetic resonance imaging was normal. His serum chemistry profile, including lactate dehydrogenase, was normal. Molecular analysis demonstrated presence of BRAF V600E mutation in the tumor. After multidisciplinary evaluation, an isolated limb infusion procedure of the right lower extremity was not believed to be feasible, secondary to the proximal extent of the recurrence. Therapy was initiated with pembrolizumab at 2 mg/kg intravenously every 3 weeks. PMID- 29389235 TI - The Right to Live and to Die. PMID- 29389236 TI - Response to Cost-Effectiveness Analysis of Zoledronic Acid Once Per Month, Zoledronic Acid Once Every 3 Months, and Denosumab Once Per Month in Women With Breast Cancer and Skeletal Metastases. PMID- 29389237 TI - Influence of Age on Sleeve Gastrectomy Results. AB - INTRODUCTION: Sleeve gastrectomy (SG) has been a booming technique for 10 years. Bariatric surgery in patients over 50 years can be an effective solution on weight loss and comorbidities. The association with the nutritional and psychological care is essential to allow a true change of life mode. We are studying the mid-term (3-year) outcomes after SG in patients over 50 years of age. METHODS: This retrospective study analyzes patients treated between January 2011 and December 2013. The 129 patients were divided into three groups: under 35 years (n = 52), 35-50 years (n = 49), and over 50 years (n = 28). RESULTS: The excess weight loss at 3 years were 75% for the under 35 years, 82% for the 35-50 years, and 69% for the over 50 years. Follow-up compliance at 3 years was 66%, 68%, 75%, respectively. Comorbidities were improved in all three groups with no significant difference for each comorbidity. CONCLUSION: SG is an effective technique on weight and comorbidities. The results at 3 years are similar in patients over the age of 50 who seem more able to follow up and change lifestyle. PMID- 29389238 TI - Inflammatory Diseases of the Gut. AB - Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract whose prevalence has been dramatically increasing over the past decade. New studies have shown that IBD is the second most common chronic inflammatory disease worldwide after rheumatoid arthritis, affecting millions of people mainly in industrialized countries. Symptoms of IBD include frequent bloody diarrhea, abdominal cramping, anorexia, abdominal distension, and emesis. Although the exact etiology is unknown, it has been postulated that immunological, microbial, environmental, nutritional, and genetic factors contribute to the pathogenesis and severity of IBD. Today, no treatment has consistently been shown to be successful in treating IBD. This review summarizes current research on the epidemiology, etiology, pathophysiology, and existing treatment approaches, including pharmaceutical and nutritional options for IBD. PMID- 29389239 TI - Effects of Bevacizumab, Ranibizumab, and Aflibercept on MicroRNA Expression in a Retinal Pigment Epithelium Cell Culture Model of Oxidative Stress. AB - PURPOSE: This study aimed to evaluate the effects of bevacizumab, ranibizumab, and aflibercept on the microRNA (miRNA) expression in human retinal pigment epithelium cell (ARPE-19) culture model of oxidative stress. METHODS: Control cells were cultured in the hydrogen peroxide (H2O2)-free medium. In H2O2 group ARPE-19 cells were exposed to 600 MUM H2O2 alone for 18 h. In study groups, cells were preincubated with bevacizumab, ranibizumab, and aflibercept (1.25-2.5, 0.5 and 2.0 mg/mL, respectively) for 3 h before H2O2 exposure. Another group of ARPE 19 cells were incubated with drugs for 3 h without H2O2 exposure. Cell viability and vascular endothelial growth factor (VEGF) levels were evaluated by MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and enzyme-linked immunosorbent assay. The expression levels of 1,152 miRNAs were determined by quantitative real-time PCR. RESULTS: Incubation with 600 MUM H2O2 alone for 18 h decreased cell viability by ~50%. Cell viability was greater in the anti-VEGF drug groups compared with the H2O2 group, but the differences were not significant (P > 0.05). VEGF levels were significantly lower in the anti-VEGF drug groups compared with the H2O2 group (P < 0.05 for all study groups), with no significant differences between the study groups (P > 0.05). Incubation with anti VEGF drugs alone had no effect on miRNA expression in ARPE-19 cells. However, preincubation with bevacizumab, ranibizumab, and aflibercept significantly altered the profile of H2O2-modulated miRNA expression. CONCLUSIONS: Preincubation with anti-VEGF drugs can alter the miRNA expression profile in response to H2O2-induced oxidative stress, and these drugs may have epigenetic effects. PMID- 29389240 TI - High Altitude and Cancer Mortality. AB - Thiersch, Markus, and Erik R. Swenson. High altitude and cancer mortality. High Alt Med Biol 19:116-123, 2018.-Humans living at high altitude (HA) are exposed to chronic (hypobaric) hypoxia. Despite the permanent stress of hypoxic exposure, humans populating HA areas have reduced cancer mortality over a broad spectrum of cancer types. In fact, the majority of the physiological adaptive processes at HA occurring in response to hypoxia might be the driving force for reduced cancer mortality at HA. In this review, we summarize epidemiological and animal studies that compare cancer incidence and cancer mortality between HA and low altitude or between hypoxia and normoxia, respectively. We discuss the potential role of oxygen-independent and oxygen-dependent mechanisms that might contribute to reduced cancer mortality at HA. Reactive oxygen species and their detoxification as well as the hypoxia-inducible factors are especially promising targets and may be related to why cancer mortality is reduced at HA. In addition, we briefly discuss two aspects with a proven impact on tumorigenesis, namely the immune system and tumor surveillance as well as HA-induced metabolic changes. Further animal and clinical studies are clearly needed to explain why cancer mortality is reduced at HA and to decide whether HA or hypoxia-based therapeutic approaches could be implemented for cancer treatment. However, exposure to HA activates multiple adaptive mechanisms (oxygen independent and oxygen dependent) sharing common pathways as well as activating counteracting pathways, which complicate the identification of specific HA-induced mechanisms of tumor suppression. PMID- 29389241 TI - Development of a 99mTc-Labeled CXCR4 Antagonist Derivative as a New Tumor Radiotracer. AB - Due to high expression of CXCR4 (CXC chemokine receptor type 4) receptors in many tumors and metastasis, synthesis and labeling of CXCR4 receptor-targeted analogs as tumor imaging agents have been encouraged. Herein, CXCR4 receptor-targeted peptide antagonist was prepared and thereafter its labeling with 99mTc by a bifunctional chelating agent and tricine coligand was developed. Radiotracer purity, stability, and tumor cell binding were assessed. Bioevaluation of radiotracer was performed in mice bearing xenograft tumor. More than 95% labeling yield and stability up to 24 hours were observed. Radiotracer-related tumor accumulation was 3.61 +/- 0.15% ID/g at 1 hour postinjection. High stability and specific tumor uptake are important characteristics of the radiotracer that could nominate this as a targeted imaging agent in the future. PMID- 29389242 TI - The National Network of State Perinatal Quality Collaboratives: A Growing Movement to Improve Maternal and Infant Health. AB - State Perinatal Quality Collaboratives (PQCs) are networks of multidisciplinary teams working to improve maternal and infant health outcomes. To address the shared needs across state PQCs and enable collaboration, Centers for Disease Control and Prevention, in partnership with March of Dimes and perinatal quality improvement experts from across the country, supported the development and launch of the National Network of PQCs National Network of Perinatal Quality Collaboratives (NNPQC). This process included assessing the status of PQCs in this country and identifying the needs and resources that would be most useful to support PQC development. National representatives from 48 states gathered for the first meeting of the NNPQC to share best practices for making measurable improvements in maternal and infant health. The number of state PQCs has grown considerably over the past decade, with an active PQC or a PQC in development in almost every state. However, PQCs have some common challenges that need to be addressed. After its successful launch, the NNPQC is positioned to ensure that every state PQC has access to key tools and resources that build capacity to actively improve maternal and infant health outcomes and healthcare quality. PMID- 29389244 TI - Pyrethroid epidemiology: a quality-based review. AB - Pyrethroids are commonly used around the home and in agricultural production to control insects. Human contact to one or more pyrethroid insecticides is likely. Numerous epidemiology studies have evaluated the association between health outcomes in humans and pyrethroid exposure. The purpose of this review was to identify and evaluate the quality of pyrethroid-related epidemiology studies that addressed chronic health effects, and compare findings with animal toxicology studies. We evaluated the quality of 61 studies published between 2000 and 2016 by using elements of outcome, exposure metric, exposure level, and study design. None of the 61 publications demonstrated strong quality for all elements. A few of the outcome measures were strong, particularly those relying upon medical diagnoses. Most of the pyrethroid epidemiology studies used a poor exposure metric, relying upon a single sample of pyrethroid urinary metabolites, which is subject to misclassification of past exposures. In addition, many studies were a cross-sectional design, preventing an evaluation of the temporality of the exposure-disease association. Furthermore, none of the effects observed in the epidemiological literature was concordant with toxicological effects noted in extensive testing of pyrethroids in animals. In order to provide more robust data on potential health outcomes from low dose exposure to pyrethroid insecticides, future epidemiological studies should fully characterize an adverse outcome, include exposure validation components, and quantify exposure over time. PMID- 29389245 TI - Effect of dietary arachidonic acid supplementation on acute muscle adaptive responses to resistance exercise in trained men: a randomized controlled trial. AB - Arachidonic acid (ARA), a polyunsaturated omega-6 fatty acid, acts as precursor to a number of prostaglandins with potential roles in muscle anabolism. It was hypothesized that ARA supplementation might enhance the early anabolic response to resistance exercise (RE) by increasing muscle protein synthesis (MPS) via mammalian target of rapamycin (mTOR) pathway activation and/or the late anabolic response by modulating ribosome biogenesis and satellite cell expansion. Nineteen men with >=1 yr of resistance-training experience were randomized to consume either 1.5 g daily ARA or a corn-soy-oil placebo in a double-blind manner for 4 wk. Participants then undertook fasted RE (8 sets each of leg press and extension at 80% 1-repetition maximum), with vastus lateralis biopsies obtained before exercise, immediately postexercise, and at 2, 4, and 48 h of recovery. MPS (measured via stable isotope infusion) was not different between groups ( P = 0.212) over the 4-h recovery period. mTOR pathway members p70 S6 kinase and S6 ribosomal protein were phosphorylated postexercise ( P < 0.05), with no difference between groups. 45S preribosomal RNA increased 48 h after exercise only in ARA ( P = 0.012). Neural cell adhesion molecule-positive satellite cells per fiber increased 48 h after exercise ( P = 0.013), with no difference between groups ( P = 0.331). Prior ARA supplementation did not alter the acute anabolic response to RE in previously resistance-trained men; however, at 48 h of recovery, ribosome biogenesis was stimulated only in the ARA group. The findings do not support a mechanistic link between ARA and short-term anabolism, but ARA supplementation in conjunction with resistance training may stimulate increases in translational capacity. NEW & NOTEWORTHY Four weeks of daily arachidonic acid supplementation in trained men did not alter their acute muscle protein synthetic or anabolic signaling response to resistance exercise. However, 48 h after exercise, men supplemented with arachidonic acid showed greater ribosome biogenesis and a trend toward greater change in satellite cell content. Chronic arachidonic acid supplementation does not appear to regulate the acute anabolic response to resistance exercise but may augment muscle adaptation in the following days of recovery. PMID- 29389246 TI - Increasing cerebral blood flow reduces the severity of central sleep apnea at high altitude. AB - Earlier studies have indicated an important role for cerebral blood flow in the pathophysiology of central sleep apnea (CSA) at high altitude, but were not decisive. To test the hypothesis that pharmacologically altering cerebral blood flow (CBF) without altering arterial blood gas (ABGs) values would alter the severity of CSA at high altitude, we studied 11 healthy volunteers (8M, 3F; 31 +/ 7 yr) in a randomized placebo-controlled single-blind study at 5,050 m in Nepal. CBF was increased by intravenous (iv) acetazolamide (Az; 10 mg/kg) plus intravenous dobutamine (Dob) infusion (2-5 MUg.kg-1.min-1) and reduced by oral indomethacin (Indo; 100 mg). ABG samples were collected and ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) were measured by rebreathing and steady state techniques before and after drug/placebo. Duplex ultrasound of blood flow in the internal carotid and vertebral arteries was used to measure global CBF. The initial 3-4 h of sleep were recorded by full polysomnography. Intravenous Az + Dob increased global CBF by 37 +/- 15% compared with placebo ( P < 0.001), whereas it was reduced by 21 +/- 8% by oral Indo ( P < 0.001). ABGs and HVR were unchanged in both interventions. HCVR was reduced by 28% +/- 43% ( P = 0.1) during intravenous Az +/- Dob administration and was elevated by 23% +/- 30% ( P = 0.05) by Indo. During intravenous Az + Dob, the CSA index fell from 140 +/- 45 (control night) to 48 +/- 37 events/h of sleep ( P < 0.001). Oral Indo had no significant effect on CSA. We conclude that increasing cerebral blood flow reduced the severity of CSA at high altitude; the likely mechanism is via a reduction in the background stimulation of central chemoreceptors. NEW & NOTEWORTHY This work is significant because it shows convincingly for the first time in healthy volunteers that increasing cerebral blood flow will reduce the severity of central sleep apnea in a high-altitude model, without the potentially confounding effects of altering partial pressure of arterial carbon dioxide or the ventilatory response to hypoxia. The proposed mechanism of action is that of increasing the removal of locally produced CO2 from the central chemoreceptors, causing the reduction in hypercapnic ventilatory response, hence reducing loop gain. PMID- 29389247 TI - Greater fluid loss does not fully explain the divergent hemodynamic balance mediating postexercise hypotension in endurance-trained men. AB - Following exercise, mean arterial pressure (MAP) is reduced ~5-10 mmHg from preexercise baseline. In nonendurance-trained males, postexercise hypotension results from peripheral vasodilation not offset by increased cardiac output (CO). By contrast, postexercise hypotension occurs through a reduction in CO from preexercise baseline in endurance-trained males. The reason(s) explaining these divergent responses remain unknown. Exercise at fixed percentage of peak oxygen consumption (Vo2peak) is associated with a greater rate of metabolic heat production in trained individuals and therefore elevated sweat rates, both when compared with untrained individuals. We hypothesized that greater fluid loss would explain the postexercise reduction in CO of endurance-trained males. Twelve endurance-trained males (Trained: Vo2peak, 64 +/- 5 ml O2.kg-1.min-1) cycled for 60 min at 60% Vo2peak (Trained60%). On separate days, 12 nonendurance trained males (Untrained: Vo2peak, 49 +/- 3 ml O2.kg-1.min-1) cycled at 1) 60% Vo2peak (Untrained60%), and 2) a rate of heat production equivalent to that achieved by the Trained group (UntrainedMatched). Fluid loss was similar between Trained60% ( 1.32 +/- 0.20 kg) and UntrainedMatched (-1.32 +/- 0.23 kg; P = 0.99) but was greater in these conditions relative to Untrained60% (-0.95 +/- 0.11 kg; both P < 0.01). During the final 30 min of postexercise supine recovery, MAP was similarly reduced by 5 +/- 2 mmHg in all three conditions ( P = 0.91). The reduction in MAP was mediated by a 0.5 +/- 0.3 l/min reduction in CO from baseline in Trained60% ( P = 0.01). In contrast, CO returned to baseline following exercise during UntrainedMatched and Untrained60% (both P >= 0.30). These data demonstrate that greater fluid loss does not fully explain the divergent postexercise hemodynamic responses observed in trained relative to untrained males. NEW & NOTEWORTHY Even when matched for exercise-induced fluid loss, cardiac output was decreased in trained males but returned to baseline following exercise in their untrained counterparts. However, as per our hypothesis, reductions in stroke volume were similar between groups. This suggests that exercise-induced fluid loss is an important determinant of the stroke volume response during recovery but factors affecting heart rate such as exercise intensity and/or heat stress are also important determinants of postexercise hemodynamics. PMID- 29389250 TI - Scandinavian Total Ankle Replacement: 15-Year Follow-up. AB - BACKGROUND: Over the past decade, total ankle arthroplasty (TAA) has become a mainstay in the treatment of end-stage ankle arthritis. Currently in its fourth generation, the Scandanavian Total Ankle Replacement (STAR) is the only 3-piece mobile bearing ankle prosthesis available in the United States. Our current study reports implant survivorship at 15 years and patient outcomes for a subset of these survivors available for study. METHODS: Eighty-four TAAs were performed between 1998 and 2000. Metal component survivorship at 15 years was calculated with a Kaplan-Meier curve. Twenty-four (29%) of 84 patients were available for participation with a minimum 15-year follow-up. Any radiographic changes were documented. All additional procedures and complications were recorded. Clinical findings, self-reported performance and pain evaluations, and AOFAS ankle/hindfoot scores were noted. RESULTS: Metal implant survival was 73% at 15 years. Of the 24 patients available for clinical evaluation, 18 of 24 patients (70.7%) had no change in prosthetic alignment from the immediate postoperative radiograph. Only 1 subtalar fusion was required for symptomatic adjacent joint arthritis. Three patients sustained a broken polyethylene component. AOFAS scores improved from an average of 39.6 points preoperatively, to an average of 71.6. More than half (52.4%) of patients with retained implants required an additional surgical procedure; 3 required 2 additional procedures. The average time to subsequent procedure was 10.2 years. CONCLUSION: Our small cohort demonstrated STAR ankles with retention at 9 years were highly likely to survive to 15 years, and patients continued to have significant improvement in pain relief and minimal decrease in function. At 15 years from TAA, metal survivorship was 73%. As with all ankle replacements, supplementary procedures were common. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29389248 TI - Role of gp130 in basal and exercise-trained skeletal muscle mitochondrial quality control. AB - The IL-6 cytokine family activates intracellular signaling pathways through glycoprotein-130 (gp130), and this signaling has established regulatory roles in muscle glucose metabolism and proteostasis. Although the IL-6 family has been implicated as myokines regulating the muscles' metabolic response to exercise, gp130's role in mitochondrial quality control involving fission, fusion, mitophagy, and biogenesis is not well understood. Therefore, we examined gp130's role in basal and exercise-trained muscle mitochondrial quality control. Muscles from C57BL/6, skeletal muscle-specific gp130 knockout (KO) mice, and C2C12 myotubes, were examined. KO did not alter treadmill run-to-fatigue or indices of mitochondrial content [cytochrome- c oxidase (COX) activity] or biogenesis (AMPK, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, mitochondrial transcription factor A, and COX IV). KO increased mitochondrial fission 1 protein (FIS-1) while suppressing mitofusin-1 (MFN-1), which was recapitulated in myotubes after gp130 knockdown. KO induced ubiquitin-binding protein p62, Parkin, and ubiquitin in isolated mitochondria from gastrocnemius muscles. Knockdown of gp130 in myotubes suppressed STAT3 and induced accumulation of microtubule-associated protein-1 light chain 3B (LC3)-II relative to LC3-I. Suppression of myotube STAT3 did not alter FIS-1 or MFN-1. Exercise training increased muscle gp130 and suppressed STAT3. KO did not alter the exercise training induction of COX activity, biogenesis, FIS-1, or Beclin-1. KO increased MFN-1 and suppressed 4-hydroxynonenal after exercise training. These findings suggest a role for gp130 in the modulation of mitochondrial dynamics and autophagic processes. NEW & NOTEWORTHY Although the IL-6 family of cytokines has been implicated in the regulation of skeletal muscle protein turnover and metabolism, less is understood about its role in mitochondrial quality control. We examined the glycoprotein-130 receptor in the regulation of skeletal muscle mitochondria quality control in the basal and exercise-trained states. We report that the muscle glycoprotein-130 receptor modulates basal mitochondrial dynamics and autophagic processes and is not necessary for exercise-training mitochondrial adaptations to quality control. PMID- 29389251 TI - The Rapid Escalation of Fentanyl in Illicit Drug Evidence in Allegheny County, Pennsylvania, 2010-2016. AB - Opioid overdose deaths in the United States quadrupled from 1999 (n = 8050 deaths) to 2015 (n = 33 091 deaths), and the number of deaths associated with synthetic opioids, such as fentanyl, increased from 3105 deaths in 2013 to nearly 20 000 deaths in 2016. Given this rapid increase, timely surveillance for drugs in circulation is crucial. However, current surveillance systems used to track drug overdoses do not detect new drugs in circulation quickly. We studied the change in the presence of fentanyl in "stamp bag" drug evidence in Allegheny County, Pennsylvania, from 2010 through 2016. Stamp bags are small wax packets with individual stamps that contain mixtures of drugs, most commonly heroin, that law enforcement officers seize and retain as legal evidence. The proportion of stamp bags determined to contain fentanyl or a fentanyl analog was 2.1% in 2014 and rose sharply to 17.1% in 2016. Monitoring the chemical makeup of drug evidence items could help public health authorities identify drug use trends in their jurisdictions. PMID- 29389252 TI - Risk Factors and Predictive Model Development of Thirty-Day Post-Operative Surgical Site Infection in the Veterans Administration Surgical Population. AB - BACKGROUND: Surgical site infection (SSI) complicates approximately 2% of surgeries in the Veterans Affairs (VA) hospitals. Surgical site infections are responsible for increased morbidity, length of hospital stay, cost, and mortality. Surgical site infection can be minimized by modifying risk factors. In this study, we identified risk factors and developed accurate predictive surgical specialty-specific SSI risk prediction models for the Veterans Health Administration (VHA) surgery population. METHODS: In a retrospective observation study, surgical patients who underwent surgery from October 2013 to September 2016 from 136 VA hospitals were included. The Veteran Affairs Surgical Quality Improvement Program (VASQIP) database was used for the pre-operative demographic and clinical characteristics, intra-operative characteristics, and 30-day post operative outcomes. The study population represents 11 surgical specialties: neurosurgery, urology, podiatry, otolaryngology, general, orthopedic, plastic, thoracic, vascular, cardiac coronary artery bypass graft (CABG), and cardiac valve/other surgery. Multivariable logistic regression models were developed for the 30-day post-operative SSIs. RESULTS: Among 354,528 surgical procedures, 6,538 (1.8%) had SSIs within 30 days. Surgical site infection rates varied among surgical specialty (0.7%-3.0%). Surgical site infection rates were higher in emergency procedures, procedures with long operative duration, greater complexity, and higher relative value units. Other factors associated with increased SSI risk were high level of American Society of Anesthesiologists (ASA) classification (level 4 and 5), dyspnea, open wound/infection, wound classification, ascites, bleeding disorder, chemotherapy, smoking, history of severe chronic obstructive pulmonary disease (COPD), radiotherapy, steroid use for chronic conditions, and weight loss. Each surgical specialty had a distinct combination of risk factors. Accurate SSI risk-predictive surgery specialty specific models were developed with number of variables ranging from 9 to 21 and the C-index ranging from 0.63 to 0.81, indicating acceptable discrimination. The decile plot of predicted versus observed SSI rates showed strong calibration. CONCLUSIONS: Surgery specialty-specific risk factors of 30-day post-operative SSI rates have been identified for a variety of surgery specialties. Accurate SSI risk-predictive surgery specialty-specific SSI predictive models have been developed and validated for the VHA surgery population. These models can be used to develop optimal preventive measures for high-risk patients, patient-centered care planning, and surgical quality improvement. PMID- 29389254 TI - Resumenes al Espanol. PMID- 29389253 TI - Bovine Milk Comparative Proteome Analysis from Early, Mid, and Late Lactation in the Cattle Breed, Malnad Gidda (Bos indicus). AB - Bovine milk is important for both veterinary medicine and human nutrition. Understanding the bovine milk proteome at different stages of lactation has therefore broad significance for integrative biology and clinical medicine as well. Indeed, different lactation stages have marked influence on the milk yield, milk constituents, and nourishment of the neonates. We performed a comparative proteome analysis of the bovine milk obtained at different stages of lactation from the Indian indigenous cattle Malnad Gidda (Bos indicus), a widely available breed. The milk differential proteome during the lactation stages in B. indicus has not been investigated to date. Using high-resolution mass spectrometry-based quantitative proteomics of the bovine whey proteins at early, mid, and late lactation stages, we identified a total of 564 proteins, out of which 403 proteins were found to be differentially abundant at different lactation stages. As is expected of any body fluid proteome, 51% of the proteins identified in the milk were found to have signal peptides. Gene ontology analyses were carried out to categorize proteins altered across different lactation stages based on biological process and molecular function, which enabled us to correlate their significance in each lactation stage. We also investigated the potential pathways enriched in different lactation stages using bioinformatics pathway analysis tools. To the best of our knowledge, this study represents the first and largest inventory of milk proteins identified to date for an Indian cattle breed. We believe that the current study broadly informs both veterinary omics research and the emerging field of nutriproteomics during lactation stages. PMID- 29389255 TI - Assessing Character Strengths in Youth With Intellectual Disability: Reliability and Factorial Validity of the VIA-Youth. AB - This article reports the results of an examination of the endorsement, reliability, and factorial validity of the VIA-Youth and assessment of character strengths and virtues developed for the general population in youth with and without intellectual disability. Findings suggest that, generally, youth with intellectual disability endorsed character strengths as being like them at lower levels, although few differences were significant. Issues related to measurement, particularly the establishment of measurement invariance, emerged for some virtues. Reliability of the scale was similar across the two groups. Implications for future research and practice are discussed. PMID- 29389256 TI - Use of Transition Resources by Primary Care Providers for Youth With Intellectual and Developmental Disabilities. AB - Youth with intellectual and developmental disabilities (IDD) often experience difficulties with successful transition from pediatric to adult healthcare. A consultative Transition Clinic for youth with IDD was piloted as a quality improvement project, and assessed the engagement of primary care providers (PCPs) for transition planning after patients were seen in clinic. Although many PCPs found the clinic and resources useful, individual and systemic barriers often prohibited them from participating in transition planning for this patient population. These findings highlight systemic barriers that need to be addressed to ensure successful transition, as well as the need for a specialized Transition Clinic with involvement of specialists with expertise in IDD, such as Developmental-Behavioral Pediatrics, to assist throughout transition process. PMID- 29389258 TI - Resumes en Francais. PMID- 29389257 TI - The Perceived Role of Direct Support Professionals in the Health Promotion Efforts of Adults With Developmental Disabilities Receiving Support Services. AB - Direct support professionals (DSPs) play a large social role in the lives of people with developmental disabilities (DD) and have the potential to influence their health behaviors. Six qualitative focus groups ( n = 48) were conducted with DD community agency administrators, DSPs, family members and adults with DD to better understand the perceived role of DSPs in the health promotion efforts of those with DD. Findings from this study suggest that DSPs experience several barriers when trying to promote the health of those with DD, one of which is fear of violating the rights of people with DD. Future work should identify ways to overcome the barriers experienced by DSPs, so that they can better assist people with DD with health promotion efforts. PMID- 29389259 TI - Participant Direction for People With Intellectual and Developmental Disabilities in Medicaid Home and Community Based Services Waivers. AB - Participant direction allows people with intellectual and developmental disabilities (IDD) and/or their families to direct services; in doing so, participant direction shifts participants from passive recipients to active consumers. Medicaid encourages, but does not require, states to allow participant direction. The aim of this study was to examine if and how states permitted participant direction in Medicaid HCBS 1915(c) waivers for people with IDD. We analyzed HCBS waivers from across the country to determine frequency of participant direction, expenditures directed toward participant direction, and states' goals for utilization of participant direction. Our findings revealed a disconnect between the large number of waivers that allowed participant direction, and states' extremely low goals for actual utilization of participant direction. PMID- 29389260 TI - Reproductive Cancer Treatment Hospitalizations of U.S. Women With Intellectual and Developmental Disabilities. AB - There is a dearth of existing research on the treatment of reproductive cancers among women with intellectual and developmental disabilities (IDD). This study analyzed the 2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample and compared the prevalence of reproductive cancer treatment hospitalization discharges among women with and without IDD. Discharges linked to women with IDD had higher incidences of cancer of the uterus and lower prevalence of cancer of the cervix. Moreover, discharges linked to women with IDD indicated these women were younger, had longer hospital stays, and were more likely to have public insurance coverage. Therefore, further research and targeted interventions to increase cancer prevention and screening are urgently needed. PMID- 29389261 TI - Life Outcomes and Higher Education: The Need for Longitudinal Research Using a Broad Range of Quality of Life Indicators. AB - Higher education is increasingly becoming an option for young adults with intellectual disability (ID). Although initial evaluations of postsecondary education for this population have been promising, a broader "quality of life" framework needs to be adopted in order to truly understand the impact of these programs. Moreover, researchers and program evaluators must collect longitudinal data that follows former students for multiple years and uses multiple measures. We conducted a pilot evaluation of the life outcomes of students who had attended at least two semesters in Kentucky's supported higher education program for students with ID, collecting data on life status and experiences using measures from the National Core Indicators-Adult Consumer Survey. The findings from this pilot study show better outcomes for young adults who participated in a postsecondary education program compared to young adults who did not, but these findings need to be considered in light of several limitations. In many respects, our data provided more new questions than answers. Recommendations for collecting and evaluating broad-based, longitudinal data to gain insight into the potential benefits of postsecondary education for people with intellectual disability are discussed. PMID- 29389262 TI - New Laser Ruler Instrument for Making Measurements Through an Endoscope. PMID- 29389263 TI - Use of the Miniarthroscopic Drill in Choanal Atresia Repair: How we do it. PMID- 29389264 TI - Neonatal Hearing Screening with Otoscopy, Auditory Brain Stem Response, and Otoacoustic Emissions. AB - A study was performed to investigate the relationship between external and middle ear factors and hearing screening results by auditory brain stem response (ABR) and transient evoked otoacoustic emissions (EOAEs). The ears of 200 well newborns aged 5 hours to 48 hours underwent screening by ABR and EOAEs, followed by otoscopic examination. The pass rates for ABR and EOAE screening were 88.5% and 79%, respectively. On otoscopic examination, 13% (53 of 400) ears had occluding vernix obscuring the view of the tympanic membrane. Cleaning of vernix was attempted in ears that failed ABR or EOAE screening. Seventeen ears that failed ABR were cleaned, and 12 (71%) of them passed repeat ABR. Thirty-three ears that failed EOAE screening were cleaned, and 22 (67%) of them passed repeat emissions testing. Cleaning vernix increased the pass rates for ABR and EOAE screening to 91.5% and 84%, respectively. Decreased tympanic membrane mobility was found in 9% of ears that could be evaluated otoscopically. Increased failure rates for both ABR and EOAE screening were found in infant ears with decreased tympanic membrane mobility, but significance testing could not be performed because of inadequate sample size. Prevalence of occluding external canal vernix and middle ear effusion as a function of increasing infant age were studied. Implications for newborn hearing screening are discussed. PMID- 29389265 TI - Superior Thyroid Artery Arising from the Common Carotid Artery. PMID- 29389267 TI - Technique for Promoting Healing of Complex Tracheostomy Wounds. PMID- 29389266 TI - Otolaryngic Manifestations in Children Presenting with Apparent Life-Threatening Events. AB - Apparent life-threatening event (ALTE) is a term used to characterize an event of unknown cause after an infant is found limp, cyanotic, bradycardic, and/or requiring resuscitation. Like sudden infant death syndrome (SIDS), ALTE is a general term used until a precise diagnosis can be established. The relationship between ALTE and SIDS has not been clearly defined, although 7 to 15 percent of children with ALTE die of SIDS. If children with ALTE are at greater risk for SIDS, morbidity and mortality may be prevented if the underlying pathology can be identified and corrected or closely monitored. The otolaryngologist is being consulted more frequently to evaluate children who have been through an ALTE to help elucidate any underlying pathology that may have caused the near-death experience. This retrospective chart review reports the evaluation of 30 infants with ALTE requiring consultation by the Division of Pediatric Otolaryngology at the Children's Memorial Hospital in Chicago during a 3-year period. We reviewed the literature and here compare our findings with current animal models. Of the 30 children evaluated, 53% had gastroesophageal reflux, 40% had laryngeal abnormalities, 13% had tracheal abnormalities, and 10% had pharyngeal abnormalities. Thirteen percent of the children had nonotolaryngic anomalies identified during evaluation. Surgical intervention was required in 10 patients and medical treatment was used in 18. When evaluating a child with ALTE, a complete history and physical examination, evaluation for gastroesophageal reflux, assessment for upper airway obstruction by radiographs and endoscopy, and a multidisciplinary approach are recommended. (Otolaryngol Head Neck Surg 1997;116:575-9.). PMID- 29389268 TI - Cost-Effective Evaluation of Asymmetric Sensorineural Hearing Loss with Focused Magnetic Resonance Imaging. AB - The poor sensitivity of audiometric brain stem response for small vestibular schwannomas (acoustic neuromas) creates a dilemma for the physician evaluating a patient with signs and symptoms of retrocochlear disease. Magnetic resonance imaging is recognized as the gold standard for the evaluation of these problems, but if a complete examination of the internal auditory canals and head is done on every patient, the cost is high. Although less expensive, screening with audiometric brain stem response risks missing up to 33% of small tumors. Therefore we developed a focused magnetic resonance imaging sequence for evaluation of patients with asymmetric sensorineural hearing loss and/or nonpulsatile tinnitus. The protocol includes a T1-weighted sagittal localizer, pregadolinium and post-gadolinium T1-weighted 3-mm contiguous axial slices through the internal auditory canal and the region of the cerebellopontine angle, and T2-weighted axial images through the entire brain. Total scanning time is about 12 minutes, and the estimated cost is $300 to $500. We retrospectively reviewed the imaging records of 485 screening examinations done during an 18 month period. Twenty-four patients had diagnoses definitely or probably producing the hearing loss for an overall positive rate of 5%. By eliminating the need for follow-up audiometric or electrophysiologic studies, we believe a focused magnetic resonance imaging-based diagnostic scheme is actually more cost effective on a cost-per-patient basis. PMID- 29389269 TI - Problems and Pitfalls in Community-Based Outcomes Research. AB - OBJECTIVE: To assess the feasibility of multisite community-based outcomes research. DESIGN: Prospective observational study of variations in treating acute external otitis by otolaryngologists and primary care practitioners. SETTING: Community-based independent otolaryngology practices. PARTICIPANTS: Patients with external otitis treated by otolaryngologists in Project Solo, a nonprofit, grassroots organization of independent physicians united for quality, patient advocacy, and cost containment. METHODS: Confidential (bar-coded), disease specific outcomes questionnaires completed by patients (12 items) and by participating physicians (15 items). Response to treatment was measured with a follow-up patient questionnaire (3 items). RESULTS: Nine patients were recruited from 5 of 29 enrolled otolaryngologists. Primary care practitioners were more likely to prescribe oral antimicrobials than otolaryngologists (100% vs. 44%, p = 0.03), but less likely to insert a wick in the external auditory canal (11 % vs. 78%, p = 0.02). Poor recruitment was caused by an overly long and complex survey, data collection at multiple time points, lack of time during office hours, cumbersome data collection requirements, inadequate ongoing communication, and a lack of enthusiasm for the project. CONCLUSIONS: Future efforts at implementing a multisite outcomes study will require shorter questionnaires, smoother integration of the survey process with regular office flow, simplified procedures for data exchange, frequent communication with data collection sites, and motivational programs for participating physicians and their office staff. PMID- 29389270 TI - Outcome Analysis of the Transglabellar/Subcranial Approach for Lesions of the Anterior Cranial Fossa: A Comparison with the Classic Craniotomy Approach. AB - The classic approach to anterior skull base lesions uses bifrontal craniotomies together with lateral rhinotomies. This approach requires frontal lobe retraction and is associated with postoperative anosmia and the development of frontal lobe encephalomalacia. The transglabellar/subcranial approach permits removal of anterior skull base lesions without frontal lobe retraction and avoids facial scars. No studies to date, however, have directly compared the two approaches in terms of patient morbidity. The present retrospective study compares the two approaches when used for the removal of anterior skull base lesions in terms of estimated blood loss, number of transfusions, number of days in the hospital and intensive care unit, and postoperative complications. Twenty patients with anterior skull base lesions were examined. The classic approach was used on 10, and the transglabellar/subcranial route was used on 10. When compared with the classic approach, the transglabellar/subcranial approach resulted in a lower estimated blood loss and subsequent transfusion rate, fewer days in the hospital and intensive care unit, and lower numbers and less severe types of complications. Furthermore, visualization of the tumors before resection with the transglabellar/subcranial approach allowed preservation of olfaction in virtually all of these patients. Although this study represents a small sample population, the results are sufficiently impressive to favor the transglabellar/subcranial approach for the removal of a variety of anterior skull base lesions. PMID- 29389271 TI - Giant Cholesteatoma Presenting as a Postauricular Mass. PMID- 29389272 TI - Minimizing Upper Lip and Incisor Teeth Paresthesias in Approaches to Transsphenoidal Surgery. AB - Currently popular transsphenoidal approaches to the pituitary include sublabial, external rhinoplasty, alotomy, and transnasal techniques. The conventional sublabial approach remains the workhorse method despite postoperative lip edema, potential difficulty for denture wearers, and troublesome persistent upper lip and incisor teeth numbness. We traced the courses of the nasopalatine, infraorbital, and anterior superior alveolar nerves in 41 cadaveric half-head dissections to determine the exact contribution to upper lip and incisor teeth innervation. We then conducted a retrospective patient survey of 25 sublabial, 28 external rhinoplasty, 23 alotomy, and 12 transnasal approaches to the hypophysis to assess the incidence of upper lip and incisor teeth paresthesias lasting longer than 1 month. We conclude that rhinoplastic techniques are superior to the sublabial approach in limiting upper lip and incisor teeth numbness without compromising neurosurgical exposure for hypophysectomy. PMID- 29389273 TI - Prospective, Longitudinal Quality-of-Life Study of Patients With Head and Neck Cancer: A Feasibility Study Including the EORTC QLQ-C30. AB - Despite modern advances in the treatment of head and neck cancer, the survival rate fails to improve. Considering the different treatment modalities involved, quality of life has been thought of as an additional end point criterion for use in clinical trials. A Nordic protocol to measure the quality of life of head and neck cancer patients before, during, and after treatment was established. Before the study, a pilot study was done with this protocol. The main purpose of this pilot study was to find out whether this cancer population would answer quality pf-life questionnaires repeatedly (six times) over a 1-year period and whether the chosen questionnaires-a core questionnaire (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C30)), a tumor-specific questionnaire, and a psychological distress measure (Hospital Anxiety and Depression scale (HAD))-were sensitive for changes to functions and symptoms during the study year. The results presented in this article all refer to the pilot study. Forty-eight consecutive patients agreed to participate in the study. The most common tumor locations were the oral cavity (17) and the larynx (12). Almost all patients received combined treatment: 45 of 48 radiation therapy, 18 of 48 chemotherapy, and 17 of 48 surgery. After the primary treatment, 40 patients had complete tumor remission. Four of the 48 patients did not answer any questionnaires and were therefore excluded from the study. Of the remaining 44 patients, 3 died during the study year, and another 6 withdrew for various reasons. Thirty-five (85%) of the 41 patients alive at the 1 year follow-up answered all six questionnaires and thus completed the study. Mailed questionnaires were used throughout the study. All questionnaires were well accepted and found to be sensitive to changes during the study year. The greatest variability was found for symptoms and functions related specifically to head and neck cancer. The symptoms were swallowing difficulties, hoarse voice, sore mouth, dry mouth, and problems with taste. They all showed the same pattern, with an increase of symptoms during and just after finishing the treatment. The HAD scale revealed a high level of psychological distress, with 21% probable cases of psychiatric morbidity at diagnosis. In conclusion, it was shown that the study design and questionnaires were feasible for the forthcoming prospective quality-of-life assessment of Swedish and Norwegian head and neck cancer patients. PMID- 29389274 TI - Electrocochleography in Retrosigmoid Vestibular Nerve Section for Intractable Vertigo Caused by Meniere's Disease. AB - Interest in electrocochleography has increased in recent years because of the discovery of an elevated summating potential to action potential amplitude ratio (SP/AP ratio) in patients with endolymphatic hydrops caused by Meniere's disease or perilymph fistula. It was the purpose of this investigation to determine whether the intraoperative SP/AP ratio will decrease after vestibular nerve section in patients with intractable Meniere's disease. Fourteen patients with medically intractable classic Meniere's disease underwent retrosigmoid vestibular nerve section. Intraoperative transtympanic electrocochleography was performed with alternating click stimuli presented at 95 dB HL. In all patients the SP/AP ratio was recorded before the skin incision ("baseline" condition) and after the dura was closed ("closing" condition). Statistical analysis was applied to the recorded data. In 11 (79%) patients, the SP/AP ratio was found to be elevated above 0.30 in the baseline state. In 13 (93%) patients, the SP/AP ratio decreased more than 25% after the nerve was sectioned. These results were highly statistically significant (p < 0.001). We conclude that the SP/AP ratio does decrease in patients with Meniere's disease after undergoing retrosigmoid vestibular nerve section and offer a possible explanation. (Otolaryngol Head Neck Surg 1997;116:593-6.). PMID- 29389275 TI - Phrenic Nerve Paralysis after Doxycycline Sclerotherapy for Chylous Fistula. PMID- 29389276 TI - Predictors of Residency Performance: A Follow-up Study. AB - In a 1990 study we investigated resident applicant characteristics associated with successful matching into otolaryngology. 1 Of the 175 applicants studied, 87 matched, for a 49.7% success rate. Successful matching was much more likely for applicants with a history of excellent academic achievement in medical school. Of the 88 applicants who did not match during the year that was originally studied, 30 matched to otolaryngology in subsequent years. Of the 58 who never matched in otolaryngology, there is no evidence of board certification for 30. Of the other 28, 12 are board certified in anesthesia; 3 in radiology; 2 each in family medicine, internal medicine, general surgery, psychiatry, and physical medicine, and rehabilitation; and 1 each in pathology, emergency medicine, and dermatology. Of the total of 117 who matched in otolaryngology, 109 began residency training, and 107 finished otolaryngology training. Program directors answered questionnaires about 100 of 107 of these residents, detailing aspects of residency performance. The only correlation found between a highly satisfactory residency performance and characteristics that could be evaluated at the time of interviewing for residency positions was with excellent academic performance in medical school. PMID- 29389277 TI - Metastatic Malignant Mesothelioma to the Tonsil. PMID- 29389278 TI - Combined Surgery and Radiation Therapy for Squamous Cell Carcinoma of the Hypopharynx. AB - Squamous cell carcinoma of the hypopharynx remains a highly lethal disease. This article documents our experience with 132 patients undergoing surgical management of squamous cell carcinoma of the hypopharynx, of whom 80% received postoperative radiation therapy. Local-regional control was obtained in 61% of the patients. Five-year overall and disease-free survival rates were 30% and 41%, respectively. Prognosis was better in patients with limited disease: local disease permitting larynx-sparing surgery, N0/N1 clinical neck, and stage I/II/III disease. Cancer of the hypopharynx remains an aggressive entity associated with poor prognosis. Novel strategies stressing improved local-regional control with prevention of distant metastasis are warranted. PMID- 29389279 TI - Endoscopic Approach to Traumatic Visual Loss. AB - OBJECTIVE: To review our experience with the use of endoscopic optic nerve decompression in traumatic blindness. METHOD: We did a retrospective analysis of patients with traumatic blindness that underwent endoscopic decompression of the optic canal to determine postoperative visual acuity and correlate if to preoperative visual loss and intraoperative findings. The setting was a Level I university trauma center. We identified 8 patients treated with both surgery and steroids over a 10-month period beginning in 1993 (Seven males, one female). RESULTS: Four of six patients with total blindness (no light perception) had improvements in visual acuity. In three patients, visual acuity returned to preinjury levels. One patients with total blindness was operated on 6 weeks after injury and had a visual acuity of 20/800 at 1-year follow-up. Two patients with hand motion preoperatively had improvement in visual acuity. In one patient, vision returned to normal (20/20), and in the other it improved to 20/200). Five patients were operated on after megadose steroid treatment for at least 48 hours failed; four of five noted dramatic improvements in visual acuity. CONCLUSION: The endoscopic approach may be used to successfully decompress the optic nerve in traumatic blindness. PMID- 29389280 TI - Trace Elements in Head and Neck Cancer Patients: Zinc Status and Immunologic Functions. AB - In this study we have assessed zinc status and zinc-dependent cell-mediated immune functions (interleukin-2 production by mononuclear cells, natural killer cell lytic activity, and interleukin-1beta production by mononuclear cells) in adult patients with squamous cell carcinoma of the upper aerodigestive tract at diagnosis and before any therapy was instituted. Inasmuch as significant interactions between zinc, copper, and iron exist, we also assayed the plasma copper level, serum iron level, and total iron-binding capacity in our patients. We recruited 30 cancer subjects and 21 control subjects. On the basis of cellular zinc criteria, we diagnosed a mild deficiency of zinc in 53% of cancer subjects. The plasma zinc level was not decreased in our subjects. A univariate analysis was applied by use of one-way analysis of variance comparing study variables among the three study groups (controls and zinc-deficient and zinc-sufficient cancer patients) and Tukey's multiple comparison test, and we showed that interleukin-2 production and natural killer lytic activity were decreased in zinc deficient cancer patients. Interleukin-1beta production (ELISA assay) was increased in both zinc-deficient and zinc-sufficient groups. Plasma copper level was not different, but the iron utilization was decreased in both groups of cancer subjects. We conclude that zinc deficiency and zinc-dependent immunologic dysfunctions are present in more than half of the patients with head and neck cancer in the Detroit area. PMID- 29389281 TI - Author's Reply. PMID- 29389282 TI - Use of Steerable Forceps in Endoscopic Sinus Surgery. PMID- 29389283 TI - Changes in Otoacoustic Emissions and Auditory Brain Stem Response after C/s Platinum Exposure in Gerbils. AB - Ototoxicity associated with cis-platinum administration commonly presents as hearing loss and tinnitus. The hearing loss is usually an irreversible, high frequency sensorineural loss. Histologic studies in humans and animals suggest that the outer hair cells (OHCs) are most susceptible to cis-platinum. Evoked otoacoustic emissions (EOAE), as a measure of outer hair cell function, are potentially useful in following ototoxic insults involving OHCs. Distortion product otoacoustic emissions (DPOAE) test frequency-specific regions of the cochlea and therefore may be particularly well suited for monitoring ototoxic injuries. We measured distortion product otoacoustic emissions, at f2 = 2, 4, 6, 8, 10, and 12 kHz, in gerbils after a single large dose of cis-platinum. Animals treated with saline served as controls. The findings were compared to auditory brain stem evoked response (ABR) thresholds, using tone pips of the same frequencies. The DPOAE and ABR thresholds were measured before treatment and again 2, 5, and 14 days after drug administration. The changes in DPOAE were compared with the changes in ABR. No treatment effect was noted in the 2-day group. Animals treated with c/s-platinum demonstrated significant elevation of DPOAE and ABR thresholds compared with control animals at 5 and 14 days. There was no significant difference between the threshold changes in the 5-and 14-day groups. PMID- 29389284 TI - Risk of Lung Cancer Among Patients with Head and Neck Cancer. AB - A cohort of 5180 patients with head and neck cancer, who were part of the tumor registry of the Surveillance, Epidemiology, and End Results area of western Washington State, was followed up for as many as 15 years to determine the risk of lung cancer. A sample of 522 patients from this cohort was interviewed to determine smoking history. Lung cancer developed in 356 (6.9%) of the 5180 patients. The overall annual incidence of lung cancer remained relatively constant between approximately 1.0% and 2.0% during the 15 years of follow-up. Men had an increased risk of lung cancer compared with women (relative risk (RR) = 1.56; 95% confidence interval (CI) = 1.18 to 2.03). Compared with patients with oral cavity cancer (RR = 1.00), the relative risk of lung cancer developing by the site of the index tumor was 0.63 (95% CI = 0.40 to 0.98) for lip, 1.12 (95% CI = 0.81 to 1.56) for intrinsic larynx, 1.73 (95% CI = 1.21 to 2.47) for oropharynx, 1.84 (95% CI = 1.16 to 2.92) for hypopharynx, and 2.28 (95% CI = 1.60 to 3.24) for extrinsic larynx. Among the 522 patients who were interviewed, men smoked more than women (p < 0.0001), and patients with laryngeal or pharyngeal cancer smoked more than patients with cancer of the lip or the oral cavity (p > 0.05). Among patients with head and neck cancer, the risk of lung cancer is highest for men and for patients with cancer of the pharynx or extrinsic larynx. These findings may be explained by differences in smoking consumption. PMID- 29389285 TI - Management of Congenital Atresia of the External Auditory Canal. AB - The management of a unilateral congenital atresia of the external auditory canal is nonuniform and debated. Various surgical approaches, timing, coordination with microtia repair, and variable hearing improvements all contribute to the debate regarding management of this entity. This paper outlines our craniofacial team approach to the congenital unilateral atresia and microtia in children. Selection criteria, timing of repair, coordination with microtia repair, surgical results, and pitfalls will be discussed. The results of surgery in 16 patients with unilateral congenital atresia of the external auditory canal and 2 children with bilateral atresia will be presented. Repair of the atresia was undertaken in children 5 years or older who had pneumatized mastoids and middle ears. Replacement of the malleus/incus complex with a partial ossicular reconstruction prosthesis improved closure of the air-bone gap. Drawbacks included meatal stenosis and deepithelization of the split thickness skin graft lining the external auditory canal. Repair of the unilateral congenital atresia is a demanding and challenging problem but one in which excellent results are achievable. PMID- 29389286 TI - Stoma Recurrence After Laryngectomy. PMID- 29389287 TI - Nodular Thyroid Disease in Children and Adolescents. AB - Thyroid nodules in children are extremely uncommon. Most thyroid nodules, both benign and malignant, present as asymptomatic neck masses. A thyroid nodule in a child is significant because of the risk of malignancy. A review of medical records at our institution demonstrated 71 patients 20 years of age and younger with surgically managed thyroid nodules, of which 45 were benign and 26 were malignant. Our diagnostic workup, including serum thyroid studies, radiologic evaluation, and fine-needle aspiration, is discussed. Because of the possibility of malignancy, we recommend that all solitary thyroid nodules be excised in children unless fine-needle aspiration definitively determines a benign histology. The extent and type of surgical management is controversial and is still subject to much debate. Partial thyroidectomy appears adequate for benign disease, but even though there is no statistical difference in survival, we recommend total thyroidectomy for the management of malignant disease. PMID- 29389288 TI - Primary Peripheral T-Cell Lymphoma of the Acoustic Nerve. PMID- 29389289 TI - Hyperbaric Oxygen Therapy. PMID- 29389290 TI - Extended Temporal Bone Resection for Squamous Cell Carcinoma. AB - OBJECTIVE: The aim of this study was to assess the surgical results of a series of patients from this unit who underwent extended temporal bone resection for recurrent squamous cell carcinoma as a salvage procedure. DESIGN: The surgical records of 15 patients were analyzed in detail. Each patient had salvage surgery in the form of an extended temporal bone resection with supraomohyoid block dissection, dural grafting, and free microvascular forearm or scalp rotation flap repair for recurrent squamous cell carcinoma in a radical mastoid cavity. RESULTS: Radical surgery yielded a 47% 5-year survival. Twenty-nine percent of the survivors had temporal lobe involvement that necessitated a partial excision of the temporal lobe of the brain. Histologic evidence of local lymph node involvement in the supraomohyoid neck dissection was present in 13% of cases. Those who died did so in the first postoperative year. All those with poorly differentiated tumors died. The survivors had well or moderately differentiated tumors. CONCLUSIONS: Radiotherapy alone or partial temporal bone resection, most commonly a radical mastoidectomy with or without preoperative or postoperative radiotherapy is used by the majority of otolaryngologists in treating squamous cell carcinoma of the temporal bone. The 5-year survival rate after this treatment remains depressingly low and the prognosis gloomy, particularly for advanced tumors. The findings in this series of extended temporal bone resections as salvage surgery in recurrent disease is encouraging, and radical surgery combined with radiotherapy from the outset may give much better 5-year survival figures in the future than the conventional partial temporal bone resection and radiotherapy. (Otolaryngol Head Neck Surg 1997;116:617-23.). PMID- 29389291 TI - Impact of Surgical Treatment on Paranasal Fungal Infections in Bone Marrow Transplant Patients. AB - Invasive fungal sinusitis can develop in immunosuppressed patients. A more complex problem is immunosuppressed patients who have undergone bone marrow transplantation. For a prolonged period, they are both neutropenic and thrombocytopenic. Survival in these patients is poor, and the role for extensive surgical intervention for sinus disease has to be weighed against the risk and the potential that this is a systemic disease. Between January 1983 and June 1993, 29 bone marrow transplant recipients with documented invasive fungal infections of the sinuses and paranasal tissues required surgical intervention. This represents 1.7% of the total 1692 bone marrow transplants performed. There were 22 allogeneic, 6 autologous, and 3 unrelated donor transplants, with two patients receiving two separate grafts. Underlying diseases included 24 hematologic malignancies and 5 other disorders, including 1 aplastic anemia and 1 solid tumor. The mortality rate from the initial fungal infection was 62%. Twenty seven percent resolved the initial infections but subsequently died of other causes. All patients received medical management, such as amphotericin, rifampin, and colony-stimulating factors, in addition to surgical intervention. Surgical management ranged from minimally invasive procedures to extensive resections including medial maxillectomies. Sixty-one percent of the patients who died of the initial infection had undergone extensive surgical procedures versus 55% of those who resolved the infection. Recovery of neutrophil counts was required to clear the infection but did not necessarily predict a good outcome because 50% of those who died of the infection had experienced neutrophil recovery. White blood cell counts at the time of surgery were not significantly different between the two groups. Prognosis was poor when cranial and orbital involvement and/or bony erosion occurred. PMID- 29389292 TI - Amyloidosis. PMID- 29389293 TI - Contextual Treatment of Dissociative Identity Disorder. AB - Evidence for the effectiveness of contextual therapy, a new approach for treating adult survivors of prolonged child abuse (PCA), is provided via case studies of three women with Dissociative Identity Disorder (DID). Contextual therapy is based on the premise that it is not only traumatic experiences that account for PCA survivors' psychological difficulties. Even more fundamentally, many survivors grow up in an interpersonal context in which adequate resources for secure attachment and acquisition of adaptive living skills are not available. As a result, they are left with lasting deficits that undermine not only their current functioning, but also their ability to cope with reliving their traumatic memories in therapy. The primary focus of this treatment approach, therefore, is on developing capacities for feeling and functioning better in the present, rather than on extensive exploration and processing of the client's trauma history or, in the case of DID, of identity fragments. Treatment of the three cases presented ranged from eight months to two and one-half years' duration, and culminated in very positive outcomes. The women's reports of achievements, such as obtaining and maintaining gainful employment, greater self-sufficiency, and the establishment of more intimate and gratifying relationships, indicated marked improvements in daily functioning. Objective test data obtained at admission and discharge, and in one case, at follow-up, documented substantial reductions in dissociative, posttraumatic stress, depressive, and other symptoms. PMID- 29389294 TI - Masochistic and Sadistic Ego States. AB - A theory describing the development of alternating, dissociated, victim/masochistic and perpetrator/sadistic ego states in persons who grew up with abusive primary caretakers will be proposed and a paradigm for treatment will be derived from the theory. Alternating ego states can be observed throughout the spectrum of dissociative disorders, from Borderline Personality to Dissociative Identity Disorder. Dependence on an abusive caretaker creates a series of relational dilemmas for the child. To maintain attachment, abuse must be dissociated, but to protect the self from abuse, need for attachment must be disavowed. Disorganized attachment may result. Incompatible internal working models, using parallel masochistic and sadistic defensive strategies, may be developed and elaborated into ego states. Masochistic and sadistic defenses are ultimately maladaptive, because they require dissociation of need for either self protection or attachment. Each defensive attempt at resolving a relational dilemma leads to another impasse, a change in defensive strategy, and perhaps a shift in ego state. When alternating ego states are understood as evolving from defensive schemas developed to negotiate the dilemmas of attachment to an abuser, the following therapeutic techniques can be derived: (1) identifying adaptive needs and maladaptive defenses, (2) interpreting ego state switches as attempts to resolve relational dilemmas, (3) gradually bridging dissociation between states, (4) using transference and countertransference to understand relational patterns, and (5) cultivating more adaptive interpersonal skills within the therapeutic relationship. PMID- 29389295 TI - The Challenges of Treatment. PMID- 29389296 TI - Obsessive Compulsive Spectrum Disorders in Individuals with Dissociative Disorders. AB - The spectrum of Obsessive Compulsive Disorders is briefly presented. The phenomenological and neurophysiological overlap of these conditions with dissociation is described. Three case reports are used to illustrate these overlaps. All three cases have histories of early childhood trauma, dissociative symptoms and features of Obsessive Compulsive Spectrum Disorders that have proven to be treatment resistant with previous cognitive/behavioural and pharmacological interventions. The three cases illustrate that, in at least some individuals with dissociative disorders, a psychodynamic understanding of their Obsessive Compulsive symptoms is an important part of their successful treatment. PMID- 29389297 TI - Establishing Safety with Patients with Dissociative Identity Disorder. AB - The incidence of self-mutilation and suicidality among patients with dissociative disorders is quite high. It is necessary for clinicians working with this population to be adept at dealing with safety problems. This article presents a sequence of basic steps that can be used when helping dissociative patients establish safety, a discussion of the functions of self-destructiveness, and an overview of specific experiences and thinking patterns that contribute to self destructiveness among dissociative patients. PMID- 29389298 TI - Factitious and Malingered Dissociative Identity Disorder. AB - This paper compares the clinical features of 18 persons given a diagnosis of factitious or malingered Dissociative Identity Disorder with those of 18 matched persons who were given a diagnosis of genuine Dissociative Identity Disorder, taken from a sample of 129 second opinion consultations. Clinical features suggesting a factitious diagnosis or malingering included having a score above 60 on the Dissociative Experiences Scale (DES), reporting dissociative symptoms inconsistent with the reporting on the DES, being able to tell a chronological life story and to sequence temporal events, using the first person over a range of affect, being able to express strong negative affect, bringing "proof of a dissociative diagnosis to the consultation, having told persons other than close confidants about the alleged abuse or alleged dissociative diagnosis, reporting alleged abuse that was inconsistent with the medical or psychiatric history or volunteering allegations of cult or ritualized abuse, telling of alleged abuse without accompanying shame, guilt, or suffering, having been involved in community self-help groups, not having symptoms of co-morbid posttraumatic stress disorder, and having obvious secondary gain in having a dissociative diagnosis. Given the potential legal ramifications of making afalse positive diagnosis of Dissociative Identity Disorder and recognizing that the treatment for persons with valid dissociative psychopathology differs from the treatment of factitious illness, it is prudent to be able to separate the two groups. PMID- 29389299 TI - Dependency in the Treatment of Complex Posttraumatic Stress Disorder and Dissociative Disorders. AB - Dependency is a major and ubiquitous issue in the treatment of chronically traumatized patients, such as those with complex posttraumatic stress disorder (PTSD), trauma-related borderline personality disorder, and dissociative disorders. Within this context, the concept of dependency is often paired with pejorative adjectives, and is dichotomized and negatively compared to a preferred state of independence. This paper explores prevailing sociocultural and theoretical beliefs regarding dependency in the psychotherapy of trauma survivors, provides a working definition of dependency, offers an analysis of its complex nature, and describes the theory of structural dissociation, which helps illuminate the often contradictory manifestations of dependency in chronically traumatized patients. A distinction is made between secure and insecure dependency. Finally, this paper outlines the collaborative therapeutic process required to manage insecure dependency productively within a phase-oriented treatment model. Countertransference responses that interfere with a patient's conflicts regarding dependency are also discussed. PMID- 29389302 TI - Commentary on Bowe et al, "The State of the Otolaryngology Match: A Review of Applicant Trends, 'Impossible' Qualifications, and Implications". AB - An objective evidence-based review of the metrics used to evaluate applicants entering our field ultimately found these figures to have upward trends without any major correlation to performance in residency. The rise of these metrics coincides with a yearly drop in senior applicants, and in 2017, nearly 10% of programs did not match their contingent. The causes of unmatched spots must be examined to ensure that the field of otolaryngology can continue to grow and attract medical students who will excel in our field. Considerations into revising the applicant selection process, early introduction and mentorship within the otolaryngology field, and changes to the current otolaryngology interview process are discussed. PMID- 29389303 TI - Clinical Consensus Statement: Balloon Dilation of the Sinuses. AB - Objective To develop a clinical consensus statement on the use of sinus ostial dilation (SOD) of the paranasal sinuses. Methods An expert panel of otolaryngologists was assembled to represent general otolaryngology and relevant subspecialty societies. The target population is adults 18 years or older with chronic or recurrent rhinosinusitis (with or without nasal polyps, with or without prior sinus surgery) for whom SOD is being recommended, defined as endoscopic use of a balloon device to enlarge or open the outflow tracts of the maxillary, frontal, or sphenoid sinuses, as a standalone procedure or with endoscopic surgery. A modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. Results After 3 iterative Delphi method surveys, 13 statements met the standardized definition of consensus while 45 statements did not. The clinical statements were grouped into 3 categories for presentation and discussion: (1) patient criteria, (2) perioperative considerations, and (3) outcomes. Strong consensus was obtained for not performing SOD in patients without sinonasal symptoms or positive findings on computed tomography (CT) in patients with symptoms only of headache or sleep apnea without criteria for sinusitis. In addition, strong consensus was met that CT scan of the sinuses was necessary before performing SOD and that surgeons need to understand and abide by regulations set forth by the US Food and Drug Administration if they choose to reuse/reprocess devices. Conclusion Expert panel consensus may provide helpful information for the otolaryngologist considering the use of SOD for the management of patients with a diagnosis of rhinosinusitis. This panel reached consensus on a number of statements that defined the use of SOD as inappropriate in the management of a variety of symptoms or diseases in the absence of underlying sinusitis. When patients meet the definition of chronic sinusitis as confirmed by CT scan, SOD of the sinuses can be indicated and/or effective in certain scenarios. Additional consensus statements regarding proper setting and safeguards for performing the procedure are described. PMID- 29389304 TI - Is the Program-Specific Paragraph Responsible for Declining Application Numbers? A Commentary. AB - An alarming trend of declining applications to otolaryngology-head and neck surgery has surfaced over the past 3 years. There are many possible explanations for this decline, and a recent publication has implicated "impossible" qualifications as the reason for this decline. While these qualifications may deter a significant number of potential applicants, they have not changed significantly in the past 5 years and do not seem to explain a sudden decline. This commentary argues that the program-specific paragraph, which was introduced in 2015, may be at least in part responsible. PMID- 29389305 TI - An Analysis of the Open Payment Database in Neurotology. AB - Since the introduction of the Sunshine Act in 2010 and Open Payments Database (OPD) in 2013, a significant amount of data has been collected on physicians and the payments received through ties with pharmaceutical and medical device companies. To date, a study within the field of otology and neurotology using data from the 2015 OPD has not been conducted. As such, we assessed the validity and accuracy of OPD information for otologists and neurotologists (O&Ns). Of the 126 physicians listed as O&Ns in the OPD, 25 were actually general otolaryngologists, and 1 was a cardiologist. In addition, 88 O&Ns were misclassified by the OPD as general otolaryngologists. A total of 1156 payments, summing $1,966,204, were made to O&Ns as a whole, with 646, 507, and 3 payments classified as general, research, and ownership/investment interests, respectively. Analysis of OPD data for O&Ns demonstrates a significant financial relationship between O&N physicians and industry, as well as noteworthy inaccuracies in the OPD that likely affect other subspecialties. PMID- 29389306 TI - Response to "Commentary on: 'Endoscopic Lateral Cartilage Graft Tympanoplasty'". PMID- 29389308 TI - Highlights from the Current Issue: February 2018. PMID- 29389307 TI - Commentary on: "Endoscopic Lateral Cartilage Graft Tympanoplasty". PMID- 29389309 TI - Standardization and optimization of fluorescence in situ hybridization (FISH) for HER-2 assessment in breast cancer: A single center experience. AB - Accurate assessment of human epidermal growth factor receptor 2 (HER-2) is crucial in selecting patients for targeted therapy. Commonly used methods for HER 2 testing are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Here we presented the implementation, optimization and standardization of two FISH protocols using breast cancer samples and assessed the impact of pre analytical and analytical factors on HER-2 testing. Formalin fixed paraffin embedded (FFPE) tissue samples from 70 breast cancer patients were tested for HER 2 using PathVysionTM HER-2 DNA Probe Kit and two different paraffin pretreatment kits, Vysis/Abbott Paraffin Pretreatment Reagent Kit (40 samples) and DAKO Histology FISH Accessory Kit (30 samples). The concordance between FISH and IHC results was determined. Pre-analytical and analytical factors (i.e., fixation, baking, digestion, and post-hybridization washing) affected the efficiency and quality of hybridization. The overall hybridization success in our study was 98.6% (69/70); the failure rate was 1.4%. The DAKO pretreatment kit was more time efficient and resulted in more uniform signals that were easier to interpret, compared to the Vysis/Abbott kit. The overall concordance between IHC and FISH was 84.06%, kappa coefficient 0.5976 (p < 0.0001). The greatest discordance (82%) between IHC and FISH was observed in IHC 2+ group. A standardized FISH protocol for HER-2 assessment, with high hybridization efficiency, is necessary due to variability in tissue processing and individual tissue characteristics. Differences in the pre-analytical and analytical steps can affect the hybridization quality and efficiency. The use of DAKO pretreatment kit is time saving and cost-effective. PMID- 29389310 TI - Tobacco Use Among Middle and High School Students in Pennsylvania. AB - We analyzed data from the 2014-2015 Pennsylvania Youth Tobacco Survey to determine prevalence of tobacco use among middle and high school students. For the first time, questions on current (past 30-day) use of electronic cigarettes (e-cigarettes) were included in the survey. For current use, e-cigarettes were the most commonly used tobacco product among middle school students (2.3%; 95% confidence interval [CI], 1.4%-3.2%), and cigarettes were the most commonly used tobacco product among high school students (11.0%; 95% CI, 8.1%-13.8%). Given the changing landscape of tobacco products, collection of comprehensive data on tobacco use, including frequency, is important for monitoring behaviors among adolescents. PMID- 29389311 TI - E-Cigarette Use Among Adolescents Not Susceptible to Using Cigarettes. AB - INTRODUCTION: Research suggests that adolescents who use electronic cigarettes (e cigarettes), including adolescents not susceptible to smoking cigarettes (ie, those who have never smoked cigarettes and are not attitudinally susceptible to using cigarettes), are more likely to initiate using cigarettes or other combustible tobacco products than adolescents who do not use e-cigarettes. In this study, we examined correlates of e-cigarette use and susceptibility among adolescents not susceptible to future cigarette smoking. METHODS: We used data on high school students from the 2015 North Carolina Youth Tobacco Survey (n = 1,627). SAS logistic regression survey procedures were used to account for the complex survey design and sampling weights. RESULTS: Increasing perceived harm of e-cigarettes was associated with lower odds of susceptibility to using e cigarettes (adjusted odds ratio [AOR] = 0.79; 95% confidence interval [CI], 0.65 0.96) and current use of e-cigarettes (AOR = 0.43; 95% CI, 0.25-0.72). Similar patterns were found for perceived harm of secondhand e-cigarette vapor. Exposure to e-cigarette vapor in indoor or outdoor public places was positively associated with susceptibility to using e-cigarettes (AOR = 1.96; 95% CI, 1.33-2.91) and with current e-cigarette use (AOR = 5.69; 95% CI, 2.57-12.61). CONCLUSION: To prevent initiation of e-cigarette use, particularly among adolescents not susceptible to smoking cigarettes, educational campaigns could target harm perceptions associated with e-cigarettes. In addition, regulations that limit adolescents' exposure to e-cigarettes in public places may decrease e-cigarette use by nonsusceptible adolescents. PMID- 29389312 TI - Neighborhood Environmental Health and Premature Death From Cardiovascular Disease. AB - INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in the United States and disproportionately affects racial/ethnic minority groups. Healthy neighborhood conditions are associated with increased uptake of health behaviors that reduce CVD risk, but minority neighborhoods often have poor food access and poor walkability. This study tested the community-driven hypothesis that poor access to food at the neighborhood level and poor neighborhood walkability are associated with racial disparities in premature deaths from CVD. METHODS: We examined the relationship between neighborhood-level food access and walkability on premature CVD mortality rates at the census tract level for the city of Atlanta using multivariable logistic regression models. We produced maps to illustrate premature CVD mortality, food access, and walkability by census tract for the city. RESULTS: We found significant racial differences in premature CVD mortality rates and geographic disparities in food access and walkability among census tracts in Atlanta. Improved food access and walkability were associated with reduced overall premature CVD mortality in unadjusted models, but this association did not persist in models adjusted for census tract population composition and poverty. Census tracts with high concentrations of minority populations had higher levels of poor food access, poor walkability, and premature CVD mortality. CONCLUSION: This study highlights disparities in premature CVD mortality and neighborhood food access and walkability at the census tract level in the city of Atlanta. Improving food access may have differential effects for subpopulations living in the same area. These results can be used to calibrate neighborhood-level interventions, and they highlight the need to examine race-specific health outcomes. PMID- 29389313 TI - Using Behavior Over Time Graphs to Spur Systems Thinking Among Public Health Practitioners. AB - Public health practitioners can use Behavior Over Time (BOT) graphs to spur discussion and systems thinking around complex challenges. Multiple large systems, such as health care, the economy, and education, affect chronic disease rates in the United States. System thinking tools can build public health practitioners' capacity to understand these systems and collaborate within and across sectors to improve population health. BOT graphs show a variable, or variables (y axis) over time (x axis). Although analyzing trends is not new to public health, drawing BOT graphs, annotating the events and systemic forces that are likely to influence the depicted trends, and then discussing the graphs in a diverse group provides an opportunity for public health practitioners to hear each other's perspectives and creates a more holistic understanding of the key factors that contribute to a trend. We describe how BOT graphs are used in public health, how they can be used to generate group discussion, and how this process can advance systems-level thinking. Then we describe how BOT graphs were used with groups of maternal and child health (MCH) practitioners and partners (N = 101) during a training session to advance their thinking about MCH challenges. Eighty-six percent of the 84 participants who completed an evaluation agreed or strongly agreed that they would use this BOT graph process to engage stakeholders in their home states and jurisdictions. The BOT graph process we describe can be applied to a variety of public health issues and used by practitioners, stakeholders, and researchers. PMID- 29389314 TI - Optical and surface plasmonic approaches to characterize extracellular vesicles. A review. AB - Extracellular vesicles (EVs) have been recognized as messengers delivering various active molecules between cells. This feature of EVs drew the attention of clinicians as well as researchers from different fields. However, exciting ideas to employ EVs as means of drug delivery or to test them as biomarkers of cellular status require very thoughtful and attentive approaches to the selection of analytical techniques for EV characterization. Optical and surface plasmonic analytical methods offer a researcher an invaluable opportunity to use already sized and/or quantified EVs in further functional cell-based assays and in focused biochemical tests (nucleic acid and protein arrays, etc.). Moreover, a high sensitivity and relative flexibility of surface plasmonic sensors open a possibility to develop instruments performing quantitative, metrical and EV surface/content analysis in a single device. This review aims to consider the applicability of established and modern optical techniques as well as novel surface plasmonic approaches for different aspects of EV analysis. PMID- 29389315 TI - Diethyldithiocarbamate enhanced chemical generation of volatile palladium species, their characterization by AAS, ICP-MS, TEM and DART-MS and proposed mechanism of action. AB - Comprehensive investigation of chemical generation of volatile species (VSG) of palladium for detection by analytical atomic and mass spectrometry and, specifically, the mechanistic aspects of their formation and tentative identification are presented. VSG was achieved in a flow injection mode using a generator that permitted rapid mixing of acidified sample with NaBH4 reductant. Atomization in a diffusion flame with detection by atomic absorption spectrometry was exclusively used for optimization of generation conditions while inductively coupled plasma mass spectrometry was utilized to investigate overall system efficiency and analytical metrics of the VSG system for potential ultratrace analysis. Sodium diethyldithiocarbamate (DDTC) served as a crucial reaction modifier, enhancing overall system efficiency 9-fold. Combinations of modifiers, Triton X-100 and Antifoam B surfactants provided a synergistic effect to yield a further 2-fold enhancement of VSG. The overall system efficiency was in the range 16-22%, with higher efficiencies correlating with higher Pd concentrations. The contribution of co-generated aerosol to the overall system efficiency, determined by means of concurrent measurement of added Cs, was negligible - less than 0.1%. The nature of the volatile species was investigated using several approaches, but principally by transmission electron microscopy (TEM) after their collection on a grid, and by direct analysis in real time (DART) using high resolution orbitrap mass spectrometry. These experiments suggest a parallel but dual-route mechanism of VSG of Pd, one attributed to generation of a volatile DDTC chelate of Pd and a second to nanoparticle formation. PMID- 29389316 TI - Regulating immobilization performance of metal-organic coordination polymers through pre-coordination for biosensing. AB - We propose a method for regulating biomolecules immobilization performance of metal-organic coordination polymers (MOCPs) through pre-coordination for highly sensitive biosensing. 2,5-dimercapto-1,3,4-thiadiazole (DMcT) was used as organic monomers. Firstly, using CuCl2 as the source of metal ions to form short oligomers with DMcT (MOCPsCu), which can regulate the length of ligands through pre-coordination. Then exploiting NaAuCl4 as the source of Au ions to coordinate both short oligomers and biomolecules (MOCPsCu+Au), since Au ions can coordinate with both N and S atoms. Through controlling the concentration of CuCl2, oligomers with desired length could be readily obtained to prepare MOCPsCu+Au framework with controllable porosity and enzyme entrapment efficiency. Thus MOCPsCu+Au offers several advantages including improved mass transfer efficiency and biocatalytic sensitivity than conventional MOCPs using single metal ions. Glucose oxidase (GOx) was used as the representative biomolecule, the entrapment ratio of enzyme in MOCPsCu+Au case reached an extreme value of 100%. These MOCPsCu+Au biocomposites modified electrode also showed greatly enhanced biocatalytic sensitivity (127 MUA cm-2 mM-1) and very low detection limit (58 nM), compared with those reported analogues. The new materials/strategy may create new avenue to regulate the performance of ligand-constructed polymers and their composites for entrapment-based applications. PMID- 29389317 TI - Semi-automated set-up for exhaustive micro-electromembrane extractions of basic drugs from biological fluids. AB - Manual handling of microliter volumes of samples and reagents is usually prone to errors and may have direct consequence on the overall performance of microextraction process. Direct connection of a syringe pump and a disposable microextraction unit using flexible polymeric tubing was employed for semi automated liquid handling in micro-electromembrane extraction (MU-EME). A three phase MU-EME system was formed by consecutive withdrawal of microliter volumes of donor solution, free liquid membrane (FLM) and acceptor solution into the unit. Excellent repeatability and accuracy of the withdrawal sequence was achieved for solution volumes typically used in MU-EME (1-5 MUL) as well as excellent correlation between the initially withdrawn and the finally collected solution volumes. MU-EMEs were initiated by application of d.c. electric potential to the terminal aqueous solutions and specific MU-EME parameters were optimized in order to ensure complete transfer of model analytes from donor to acceptor solution. Exhaustive MU-EMEs of three basic drugs, nortriptyline, papaverine and haloperidol, were achieved from 1.3 MUL of acidified donor solution (10 mM HCl) across 2.5 MUL of FLM (1-ethyl-2-nitrobenzene) into 1.3 MUL of acidified acceptor solution (25 mM HCl) in 10 min at 150 V. The three drugs were also exhaustively extracted from salt- and protein-containing standard solutions, human urine and human plasma with extraction recoveries ranging from 79 to 102%. Resulting acceptor solutions were analysed by capillary electrophoresis with ultraviolet detection (CE-UV) and the MU-EME-CE-UV method was characterized by good linearity (coefficients of determination >= 0.992), high repeatability (RSD values <= 6.5%) and limits of detection <= 0.15 mg/L. PMID- 29389318 TI - Ionic liquid based ultrasound assisted dispersive liquid-liquid micro-extraction for simultaneous determination of 15 neurotransmitters in rat brain, plasma and cell samples. AB - Neurotransmitters are signaling molecules which play a key role in the central nervous system allowing signal transmission in the neuronal synapses. The role of these compounds is very crucial in the biological systems. A rapid, sensitive, economical and derivatisation free method has been developed for the analysis of 15 neurotransmitters in a single run on liquid chromatography tandem mass spectrometry. These 15 neurotransmitters are categorized into 5 groups on the basis of their fragmentation pattern. The proposed method "ionic liquid based ultrasound assisted dispersive liquid-liquid microextraction" hyphenated with tandem mass spectrometry is the first report for the analysis of neurotransmitters in cell samples along with other two matrices (rat brain and plasma). All the parameters that influence the extraction efficiency are optimized with aid of response surface methodology and desirability profile. Under these optimized conditions the developed method has been validated. The limit of detection was in the range of (1) 0.021-0.912 MUg L-1 for rat brain samples, (2) 0.028-0.978 MUg L-1 for plasma samples and (3) 0.025-0.945 MUg L-1 for cell samples with good linearity behavior for all analytes in the concentration range of 0.04-200 MUg L-1 in all the three matrices. The coefficient of determination for all the neurotransmitters was found in the range of (1) (R2) >= 0.996 to 0.999 for rat brain samples and (2) (R2) >= 0.991 to 0.999 for plasma and cell samples. The intra-day and inter-day variations were found less than (1) 1.78% and 8.94% for rat brain samples, (2) 1.83% and 8.37% for plasma samples and (3) 1.64% and 8.04% for cell samples respectively. The method has mean recoveries varied between (1) 81-128% for brain samples, (2) 88 107% for plasma samples and (3) 91-104% for cell samples at different spiking levels. The optimized and validated method was found free from matrix interferences and successfully applied for quantitative determination of 15 neurotransmitters in the rat brain, plasma and cell samples. PMID- 29389319 TI - Sodium dodecyl sulfate removal during electrospray ionization using cyclodextrins as simple sample solution additive for improved mass spectrometric detection of peptides. AB - Sodium dodecyl sulfate (SDS) removal is a vital procedure in SDS-assisted bottom up proteomics because SDS affects the quality of the data in electrospray ionization mass spectrometry (ESI-MS). SDS removal methods provide efficient removal of SDS and improved peptide analysis, but would usually require time, specialised devices, and experienced analysts. Here, by simple addition of gamma cyclodextrin (gamma-CD) to the solution at concentrations 1 to 2x the SDS in the sample, the SDS related signals in positive ionization ESI-MS can be significantly removed (70-99% reduction), without an additional sample manipulation step of extraction or purification. The mechanism for removal is based on the formation of tightly bound CD-SDS inclusion complexes, which hampered the generation of positively charged SDS multimers during ESI. For a sample with peptides (glu-val-phe, tyr-tyr-tyr, and bradykinin) and 3 mM SDS where 6 mM gamma-CD was added, the %signal recoveries of peptides calculated by comparison with signals from standard samples without SDS were 49-59%. The space charge effect by SDS on bradykinin was also reduced, increasing the signal for bradykinin 12x in the presence of gamma-CD. For a protein (bovine serum albumin, BSA) digest with 3 mM SDS, which is an expected concentration in trypsin treated samples, a noticeable 7-fold improvement in the peptide to SDS signal ratio and a 91% reduction of SDS signals were observed upon addition of 6 mM gamma-CD. However, there were only small changes in the ESI-MS intensities for the BSA peptides (compared to without addition of gamma-CD). This new approach to SDS signal removal using CDs in ESI-MS may find use in proteomic studies. PMID- 29389320 TI - Integration of paper-based microarray and time-of-flight secondary ion mass spectrometry (ToF-SIMS) for parallel detection and quantification of molecules in multiple samples automatically. AB - With its low-cost fabrication and ease of modification, paper-based analytical devices have developed rapidly in recent years. Microarrays allow automatic analysis of multiple samples or multiple reactions with minimal sample consumption. While cellulose paper is generally used, its high backgrounds in spectrometry outside of the visible range has limited its application to be mostly colorimetric analysis. In this work, glass-microfiber paper is used as the substrate for a microarray. The glass-microfiber is essentially chemically inert SiOx, and the lower background from this inorganic microfiber can avoid interference from organic analytes in various spectrometers. However, generally used wax printing fails to wet glass microfibers to form hydrophobic barriers. Therefore, to prepare the hydrophobic-hydrophilic pattern, the glass-microfiber paper was first modified with an octadecyltrichlorosilane (OTS) self-assembled monolayer (SAM) to make the paper hydrophobic. A hydrophilic microarray was then prepared using a CO2 laser scriber that selectively removed the OTS layer with a designed pattern. One microliter of aqueous drops of peptides at various concentrations were then dispensed inside the round patterns where OTS SAM was removed while the surrounding area with OTS layer served as a barrier to separate each drop. The resulting specimen of multiple spots was automatically analyzed with a time-of-flight secondary ion mass spectrometer (ToF-SIMS), and all of the secondary ions were collected. Among the various cluster ions that have developed over the past decade, pulsed C60+ was selected as the primary ion because of its high secondary ion intensity in the high mass region, its minimal alteration of the surface when operating within the static-limit and spatial resolution at the ~MUm level. In the resulting spectra, parent ions of various peptides (in the forms [M+H]+ and [M+Na]+) were readily identified for parallel detection of molecules in a mixture. By normalizing the ion intensity of peptides with respect to the glass-microfiber matrix ([SiOH]+), a linear calibration curve for each peptide was generated to quantify these components in a mixture. PMID- 29389321 TI - Attenuated Total Reflectance Fourier Transformation Infrared spectroscopy fingerprinted online monitoring of the kinetics of circulating Butyrylcholinesterase enzyme during metabolism of bambuterol. AB - We have described a continuous flow ATR-FTIR method for measuring some of the Butyrylcholinesterase enzyme kinetics (Km and Vmax). This is done by developing a circulating system to be close as much as possible to the human circulation using human serum as a source of the enzyme with adjusted pH, isotonicity and temperature to give the maximum affinity of the enzyme towards its substrate (bambuterol). The experiment was running continuously for 90 min to monitor the production of terbutaline from the zero time of its appearance with a measured spectrum in each minute using ZnSe prism. The method was selective and successful for determination of Vmax to be 8.16 * 10-8 mol/min/ml and Km to be 2.28 * 10-5 mol, showing high affinity of the enzyme towards its prodrug substrate Bambuterol. This study critically probes the quantitative ability of the ATR-FTIR method for terbutaline, which was validated according to ICH guidelines showing high accuracy 100.39% and high selectivity towards the produced terbutaline, as the produced spectrums considered as fingerprint of each compound. PMID- 29389322 TI - A new 3D printed radial flow-cell for chemiluminescence detection: Application in ion chromatographic determination of hydrogen peroxide in urine and coffee extracts. AB - A new polymer flow-cell for chemiluminescence detection (CLD) has been designed and developed by diverging multiple linear channels from a common centre port in a radial arrangement. The fabrication of radial flow-cell by 3D PolyJet printing and fused deposition modeling (FDM) has been evaluated, and compared with a similarly prepared spiral flow-cell design commonly used in chemiluminescence detectors. The radial flow-cell required only 10 h of post-PolyJet print processing time as compared to ca. 360 h long post-PolyJet print processing time required for the spiral flow-cell. Using flow injection analysis, the PolyJet 3D printed radial flow-cell provided an increase in both the signal magnitude and duration, with an average increase in the peak height of 63% and 58%, peak area of 89% and 90%, and peak base width of 41% and 42%, as compared to a coiled tubing spiral flow-cell and the PolyJet 3D printed spiral flow-cell, respectively. Computational fluid dynamic (CFD) simulations were applied to understand the origin of the higher CLD signal obtained with the radial flow-cell design, indicating higher spatial coverage near the inlet and lower linear velocities in the radial flow-cell. The developed PolyJet 3D printed radial flow cell was applied in a new ion chromatography chemiluminescence based assay for the detection of H2O2 in urine and coffee extracts. PMID- 29389324 TI - Increasing the Complement of Therapeutic Options in Bullous Pemphigoid. AB - Bullous pemphigoid is a potentially life-threatening autoantibody-mediated dermatosis characterized by blister formation. Experimental mouse models of bullous pemphigoid feature complement-induced inflammation and tissue damage. Kasprick et al. now provide preclinical data that utilize ex vivo human skin assays and support testing of complement inhibition as a therapeutic strategy in human bullous pemphigoid. PMID- 29389323 TI - SERS of cells: What can we learn from cell lysates? AB - Surface-enhanced Raman spectroscopy (SERS) is a promising and emerging technique to analyze the cellular environment. We developed an alternative, rapid and label free SERS-based method to get information about the cellular environment by analyzing cells lysates, thus avoiding the need to incorporate nanoparticles into cells. Upon sonicating and filtrating cells, we obtained lysates which, mixed with Au or Ag nanoparticles, yield stable and repeatable SERS spectra, whose overall profile depends on the metal used as substrate, but not on the buffer used for the lysis process. Bands appearing in these spectra were shown to arise mostly from the cytosol and were assigned to adenine, guanine, adenosine and reduced glutathione (GSH). Spectral differences among various cell types also demonstrated that this approach is suitable for cell type identification. PMID- 29389325 TI - UV-B-Induced Erythema in Human Skin: The Circadian Clock Is Ticking. AB - Acute exposure of skin to UV-B causes DNA damage and sunburn erythema in both mice and humans. Previous studies documented time-of-day-related differences in sunburn responses after UV-B exposure in mice. Because humans are diurnal and mice are nocturnal, the circadian rhythm in human skin was hypothesized to be in opposite phase to the rhythm in mice. A study by Nikkola et al. demonstrates that humans are more prone to sunburn erythema after evening exposure to solar UV-B radiation as compared with morning exposure. PMID- 29389326 TI - Propionibacterium acnes Strains Differentially Regulate the Fate of Th17 Responses in the Skin. AB - Agak et al. demonstrate that different strains of Propionibacterium acnes, a bacterium colonizing pilosebaceous units in healthy skin and acne, have the ability to induce T helper type 17 cells secreting either IFN-gamma or IL-10 and exhibiting either pathogenic or protective properties, respectively. This work contributes to growing evidence indicating that the phenotype of T helper type 17 cells is largely dependent on their microbiological environment. PMID- 29389327 TI - Clinical, Epidemiological, and Molecular Heterogeneity in Acral Melanoma. AB - Acral melanoma comprises a poorly characterized and distinct type of melanoma, in terms of differing roles of UVR, molecular substrate, distribution among all ethnicities, and poor prognosis. Haugh et al. explore clinical, histological, and molecular aspects of acral melanomas and provide insights into the complexity of these tumors. PMID- 29389328 TI - Erratum. PMID- 29389329 TI - Erratum. PMID- 29389331 TI - SnapshotDx Quiz: February 2018. PMID- 29389330 TI - Research Techniques Made Simple: Pharmacoepidemiology Research Methods in Dermatology. AB - Clinical trials have several important limitations for evaluating the safety of new medications, leading to many adverse events not being identified until the postmarketing period. Descriptive studies, including case reports, case series, cross-sectional, and ecologic studies, help identify potential safety signals and generate hypotheses. Further research using analytic study methods, including case-control studies and cohort studies, are necessary to determine if an association truly exists and to better understand the potential for causation. Pharmacoepidemiology research examines the use and effects of drugs when used in large populations of patients, using a variety of study designs and biostatistical techniques to reduce the confounding and systematic error associated with observational research. Understanding the strengths and limitations of pharmacoepidemiology research techniques is necessary to interpret the validity of drug safety studies, guiding both individual patient decisions and broader public health decisions. PMID- 29389332 TI - Cells to Surgery Quiz: February 2018. PMID- 29389333 TI - Targeted cancer therapies: Oral health care implications. AB - BACKGROUND: Targeted treatments have been incorporated into oncology protocols, often with more traditional therapies, and are not totally free of adverse reactions, some of which affect the orofacial region. METHODS: The authors searched PubMed, the Cochrane Library, and the US Food and Drug Administration Approved Drug Products database to identify reported adverse effects of targeted agents in the orofacial region as well as other implications in oral health care. Their principal focus was the relatively newer category of molecularly targeted drugs which are called small molecules (SMs). RESULTS: The authors identified several categories of SMs and biological agents (for example, monoclonal antibodies) with adverse effects in the orofacial region. The oral and perioral regions are also fields for which there are therapeutic applications for targeted therapies, particularly to treat malignant neoplasms such as head and neck cancers. CONCLUSIONS: SMs are the most rapidly growing group of targeted cancer treatments. Patients receiving SMs and other targeted antineoplastic agents may require oral medicine advice and special-care dentistry. PRACTICAL IMPLICATIONS: In this narrative review, the authors focus mainly on the orofacial adverse effects of targeted cancer therapies and outline many of the agents that are in use so the dentally focused reader can familiarize themselves with these adverse effects and agents. PMID- 29389335 TI - Need for diagnostic-centric care in dentistry: A case study from the Marshfield Clinic Health System. AB - BACKGROUND: The study objective was to evaluate the workflow of dental providers who use the existing electronic dental record (EDR) system at a large regional health care system to establish a diagnostic-centric culture as part of their dental practice. A further goal focused on identifying when improvements to the workflow and design of the EDR may be indicated. METHODS: Dental procedures performed on patients and corresponding International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses were retrospectively mined from Marshfield Clinic's enterprise data warehouse. All dental procedures performed were selected and paired with corresponding diagnostic codes documented by dental providers. Frequency of documented diagnosis was further analyzed by characterizing correspondence with their ranking order in the diagnosis column with and without a scroll bar within the EDR user interface (UI). Accuracy of selecting appropriate ICD-9-CM for the corresponding Code on Dental Procedure and Nomenclature (CDT) was checked for 10% (n = 6,187) of the procedure-diagnosis pairs. RESULTS: Of the 61,511 unique procedures documented using 147 CDTs, 11% (6,914 procedures) had a corresponding "not available" option associated under the diagnoses column, whereas 89% (54,597) of dental procedures were associated with a corresponding ICD-9-CM diagnostic code. Overall tendency of dental providers to select the first or last options from the diagnostic list with a scroll bar was noted. Appropriateness of documenting corresponding ICD-9-CM to CDT procedures indicated 98% accuracy. CONCLUSION: EDR UI design greatly affected documentation process. Redesigning the EDR UI from the results will increase both the quality and utility of clinical documentation. PMID- 29389334 TI - Intimate partner violence screening in the dental setting: Results of a nationally representative survey. AB - BACKGROUND: The dental setting is a potential venue for identifying patients experiencing intimate partner violence (IPV). The study objective was to assess dentists' current practices and attitudes about IPV screening. METHODS: A nationally representative survey of US general dentists assessed dentists' use of health history forms that queried about IPV and their acceptance of IPV screening as part of their professional roles. Parsimonious Poisson regression models were used in multivariable analysis to estimate risk ratios for the 2 dependent variables. RESULTS: Almost all dentists did not include a question to screen for IPV on their patient history forms. More than one-half of dentists also did not know of a referral place for patients experiencing IPV and did not believe that IPV screening should be part of their professional roles. CONCLUSIONS: Uptake of IPV screening and favorable attitudes toward screening were low among dentists studied. However, prior IPV training and clinical knowledge plus awareness of IPV referral mechanisms were positively associated with greater screening uptake and attitudes. PRACTICAL IMPLICATIONS: The inclusion of brief, focused IPV interventions in dental education and the establishment of collaborations between dentists and IPV agencies for referral mechanisms, in conjunction with an overall shift in dentists' attitudes about their professional responsibilities, may facilitate IPV screening uptake in the dental setting. PMID- 29389336 TI - Bleeding frequency of patients taking ticagrelor, aspirin, clopidogrel, and dual antiplatelet therapy after tooth extraction and minor oral surgery. AB - BACKGROUND: Perioperative bleeding complications of ticagrelor, a newer oral antiplatelet, has not been studied in dentistry. Studies about bleeding status after oral surgical procedures in patients receiving continued antiplatelet therapy are also limited. We investigated the effects of continuing aspirin, clopidogrel, ticagrelor, or dual antiplatelet therapy on the frequency of bleeding events in patients undergoing tooth extractions or minor oral surgery. METHODS: In this retrospective study, patient demographic characteristics, medical history, type of antiplatelet therapy, dental procedures, and perioperative bleeding associated with tooth extraction or other minor oral surgical procedures were obtained from the dental records of 222 patients. Bleeding was classified as normal, mild, moderate, or severe. RESULTS: One hundred sixty-eight patients (75.7%) had 1 or more teeth extracted, and 54 patients (24.3%) underwent other minor oral surgical procedures. The most common single antiplatelet regimen was aspirin (n = 123; 55.4%), followed by clopidogrel (n = 22; 9.9%) and ticagrelor (n = 17; 7.7%). Sixty patients (27%) received dual antiplatelet therapy. The overall frequency of postoperative bleeding was 4.9% (11 of 222). The frequencies of postoperative bleeding in the aspirin, clopidogrel, ticagrelor, and dual antiplatelet therapy groups were 3.2%, 4.5%, 5.9%, and 8.3%, respectively (P >= .5). None of the patients experienced prolonged bleeding. CONCLUSIONS: Patients taking aspirin, clopidogrel, ticagrelor, and dual antiplatelet therapy experienced acceptable rates of controllable postoperative bleeding after tooth extraction or minor oral surgical procedures. PRACTICAL IMPLICATIONS: In accordance with recommendations from published studies and guidelines, antiplatelet medications, including dual antiplatelet therapy, should not be interrupted for tooth extractions or minor oral surgery. PMID- 29389337 TI - Digital versus conventional impressions for full-coverage restorations: A systematic review and meta-analysis. AB - BACKGROUND: The primary objective of this systematic review was to investigate the survival of full-coverage restorations fabricated by using digital impressions (DIs) versus that of those fabricated by using conventional impressions. The authors also compared secondary outcomes of marginal and internal fit and occlusal and interproximal contacts. TYPES OF STUDIES REVIEWED: The authors conducted a systematic literature search in multiple databases to identify clinical trials with no restrictions by publication type, date, or language. The authors assessed study-level risk of bias and outcome-level strength of evidence. The authors performed a meta-analysis by using a random effects model. RESULTS: Ten studies met the inclusion criteria. The authors identified no studies in which the investigators compared the impression techniques with respect to survival of full-coverage restorations. Mean differences for marginal gap and internal gap were -9.0 micrometers (95% confidence interval, -18.9 to 0.9) and -15.6 MUm (95% confidence interval, -42.6 to 11.4), respectively. Studies assessing internal gap were substantially heterogeneous (I2 = 72%; P = .003). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Research is lacking to draw robust conclusions about the relative benefits of DIs in terms of restoration survival. Low-quality evidence for marginal fit and internal fit suggested similar performance for both techniques. Evidence quality for interproximal contact and occlusal contact was very low and insufficient to draw any conclusions regarding how the impression techniques compared. Given the uncertainty of the evidence, results should be interpreted with caution. With increasing popularity and adoption of digital scanners by dentists, pragmatic practice-based trials involving standardized, patient-centered outcomes may improve confidence in the comparative effectiveness of DIs. PMID- 29389338 TI - Dietary assessment and counseling for dental erosion. AB - BACKGROUND AND OVERVIEW: Dental erosion occurs after exposure to intrinsic or extrinsic acids. Exposure to intrinsic gastrointestinal acids is associated with anorexia nervosa, bulimia nervosa, rumination syndrome, or gastroesophageal reflux. Extrinsic dietary acids from foods or beverages also can cause erosion, particularly when exposure is prolonged by holding or swishing behaviors. CONCLUSIONS: Clinicians should screen patients exhibiting dental erosion for anorexia nervosa, bulimia nervosa, rumination syndrome, and gastroesophageal reflux disease. Clinicians should screen patients without a medical explanation for their erosion for exposure to acidic foods and beverages, particularly for habits that prolong exposure. PRACTICAL IMPLICATIONS: Identification of intrinsic and extrinsic acid exposures and recommendations to minimize exposures are important to prevent erosion and maintain oral health. PMID- 29389339 TI - Segmental odontomaxillary dysplasia: An underrecognized entity. AB - BACKGROUND AND OVERVIEW: Segmental odontomaxillary dysplasia (SOD) is a characteristic developmental abnormality that demonstrates posterior maxillary enlargement, dental abnormalities, altered bone trabeculation, and possible cutaneous findings. Only 62 cases have been reported in the English-language literature. CASE DESCRIPTION: The authors described 3 newly diagnosed cases of SOD, all found in the left posterior maxilla in adolescent female patients; they reviewed the literature to elucidate this rare entity. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Because of the complexity and variety of associated dental and craniofacial features, patients with SOD may seek diagnosis from various dental and medical providers. The signs of SOD are characteristic, yet the condition is largely underrecognized among health care professionals, which may lead to unnecessary treatment. PMID- 29389340 TI - Ethics of using live patients for licensing board examinations. PMID- 29389341 TI - Your teeth and jaws under pressure. PMID- 29389342 TI - Should Dental Care Make a Transition? PMID- 29389343 TI - Hanging the digital shingle: Dental ethics and search engine optimization. PMID- 29389345 TI - Guest Editor's response. PMID- 29389344 TI - Letters. PMID- 29389346 TI - Correction. PMID- 29389347 TI - Correction. PMID- 29389348 TI - Correction. PMID- 29389349 TI - Correction. PMID- 29389350 TI - Dental considerations and the role of prosthodontics and maxillofacial prosthetics in facial transplantation. AB - BACKGROUND: Facial transplantation (FT) is a challenging reconstructive endeavor that requires the expertise of a multidisciplinary team. The specific role of maxillofacial prosthodontists has not yet been reported in detail. METHODS: This review considers the contributions of prosthodontists throughout the FT process, from patient selection and dental evaluation to long-term dental rehabilitation of the transplant patient postoperatively. Moreover, considerations of dental management are evaluated. RESULTS: In the almost 40 FT reported in the literature, the most consistently documented contribution by prosthodontists is the fabrication of a donor mask to maintain donor integrity. Though infrequently reported, prosthodontists have the potential to plan and perform a variety of dental procedures and follow-up plans. CONCLUSIONS: When applicable, facial transplant teams are tasked with providing optimal stomatognathic function and dental occlusion to recipients with severe facial disfigurement. The maxillofacial prosthodontist's contribution is crucial to the long-term dental restoration of the edentulous facial transplant candidate, in addition to the fabrication of the donor mask which fulfills the team's ethical responsibilities. PRACTICAL IMPLICATIONS: Maxillofacial prosthodontists play a pivotal role in facial transplantation, particularly when jaw segments are intended for transplantation. PMID- 29389351 TI - 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. PMID- 29389353 TI - Clash of Oral P2Y12 Receptor Inhibitors in Acute Coronary Syndromes. PMID- 29389352 TI - Memory as Perception of the Past: Compressed Time inMind and Brain. AB - In the visual system retinal space is compressed such that acuity decreases further from the fovea. Different forms of memory may rely on a compressed representation of time, manifested as decreased accuracy for events that happened further in the past. Neurophysiologically, "time cells" show receptive fields in time. Analogous to the compression of visual space, time cells show less acuity for events further in the past. Behavioral evidence suggests memory can be accessed by scanning a compressed temporal representation, analogous to visual search. This suggests a common computational language for visual attention and memory retrieval. In this view, time functions like a scaffolding that organizes memories in much the same way that retinal space functions like a scaffolding for visual perception. PMID- 29389354 TI - Biomarker-Guided Versus Guideline-Based Treatment of Patients With Heart Failure: Results From BIOSTAT-CHF. AB - BACKGROUND: Heart failure guidelines recommend up-titration of angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), beta blockers, and mineralocorticoid receptor antagonists (MRAs) to doses used in randomized clinical trials, but these recommended doses are often not reached. Up titration may, however, not be necessary in all patients. OBJECTIVES: This study sought to establish the role of blood biomarkers to determine which patients should or should not be up-titrated. METHODS: Clinical outcomes of 2,516 patients with worsening heart failure from the BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure) were compared between 3 theoretical treatment scenarios: scenario A, in which all patients are up-titrated to >50% of recommended doses; scenario B, in which patients are up-titrated according to a biomarker-based treatment selection model; and scenario C, in which no patient is up-titrated to >50% of recommended doses. The study conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths or heart failure hospitalizations at 24 months for all 3 scenarios. RESULTS: Estimated death or hospitalization rates in 1,802 patients with available (bio)markers were 16%, 16%, and 26%, respectively, in the ACE inhibitor/ARB up-titration scenarios A, B, and C. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. If up titration was successful in all patients, an estimated 9.8, 1.3, and 12.3 events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy, respectively. Similar numbers were 9.9, 4.7, and 13.1 if up-titration treatment decision was based on a biomarker-based treatment selection model. CONCLUSIONS: Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-titrated. PMID- 29389355 TI - Can Biomarker Panels Predict Response to Pharmacotherapy in Heart Failure? PMID- 29389357 TI - Is it Like Night and Day, or Weekend? PMID- 29389356 TI - Trends in Survival After In-Hospital Cardiac Arrest During Nights and Weekends. AB - BACKGROUND: Survival after in-hospital cardiac arrest (IHCA) is lower during nights and weekends (off-hours) compared with daytime during weekdays (on-hours). As overall IHCA survival has improved over time, it remains unknown whether survival differences between on-hours and off-hours have changed. OBJECTIVES: This study sought to examine temporal trends in survival differences between on hours and off-hours IHCA. METHODS: We identified 151,071 adults at 470 U.S. hospitals in the Get with the Guidelines-Resuscitation registry during 2000 to 2014. Using multivariable logistic regression with generalized estimating equations, we examined whether survival trends in IHCA differed during on-hours (Monday to Friday 7:00 am to 10:59 pm) versus off-hours (Monday to Friday 11:00 pm to 6:59 am, and Saturday to Sunday, all day). RESULTS: Among 151,071 participants, 79,091 (52.4%) had an IHCA during off-hours. Risk-adjusted survival improved over time in both groups (on-hours: 16.0% in 2000, 25.2% in 2014; off hours: 11.9% in 2000, 21.9% in 2014; p for trend <0.001 for both). However, there was no significant change in the survival difference over time between on-hours and off-hours, either on an absolute (p = 0.75) or a relative scale (p = 0.059). Acute resuscitation survival improved significantly in both groups (on-hours: 56.1% in 2000, 71% in 2014; off-hours: 46.9% in 2000, 68.2% in 2014; p for trend <0.001 for both) and the difference between on-hours and off-hours narrowed over time (p = 0.02 absolute scale, p < 0.001 relative scale). In contrast, although post-resuscitation survival also improved over time in both groups (p for trend < 0.001 for both), the absolute and relative difference persisted. CONCLUSIONS: Despite an overall improvement in survival, lower survival in IHCA during off hours compared with on-hours persists. PMID- 29389358 TI - Coronary Adventitial and Perivascular Adipose Tissue Inflammation in Patients With Vasospastic Angina. AB - BACKGROUND: Recent studies suggested that perivascular components, such as perivascular adipose tissue (PVAT) and adventitial vasa vasorum (VV), play an important role as a source of various inflammatory mediators in cardiovascular disease. OBJECTIVES: The authors tested their hypothesis that coronary artery spasm is associated with perivascular inflammation in patients with vasospastic angina (VSA) using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). METHODS: This study prospectively examined 27 consecutive VSA patients with acetylcholine-induced diffuse spasm in the left anterior descending artery (LAD) and 13 subjects with suspected angina but without organic coronary lesions or coronary spasm. Using CT coronary angiography and electrocardiogram-gated 18F-FDG PET/CT, coronary PVAT volume and coronary perivascular FDG uptake in the LAD were examined. In addition, adventitial VV formation in the LAD was examined with optical coherence tomography, and Rho-kinase activity was measured in circulating leukocytes. RESULTS: Patient characteristics were comparable between the 2 groups. CT coronary angiography and ECG-gated 18F-FDG PET/CT showed that coronary PVAT volume and coronary perivascular FDG uptake significantly increased in the VSA group compared with the non-VSA group. Furthermore, optical coherence tomography showed that adventitial VV formation significantly increased in the VSA group compared with the non-VSA group, as did Rho-kinase activity. Importantly, during the follow-up period with medical treatment, both coronary perivascular FDG uptake and Rho-kinase activity significantly decreased in the VSA group. CONCLUSIONS: These results provide the first evidence that coronary spasm is associated with inflammation of coronary adventitia and PVAT, where 18F-FDG PET/CT could be useful for disease activity assessment. (Morphological and Functional Change of Coronary Perivascular Adipose Tissue in Vasospastic Angina [ADIPO-VSA Trial]; UMIN000016675). PMID- 29389359 TI - The Forgotten Vascular Layer in the Forgotten Coronary Disorder. PMID- 29389361 TI - Trial of Embryonic Stem Cell-Derived Cardiac Progenitor Cells: An Encouraging Start. PMID- 29389360 TI - Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. AB - BACKGROUND: In addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage specific cells. OBJECTIVES: This study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction. METHODS: Six patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months. RESULTS: The protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months. CONCLUSIONS: This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900). PMID- 29389362 TI - Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory. AB - The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory. PMID- 29389364 TI - Prevalence of Cardiac Amyloidosis in Patients Referred for Transcatheter Aortic Valve Replacement. PMID- 29389365 TI - Cardiac Resynchronization Therapy for End-Stage Hypertrophic Cardiomyopathy: The Need for Disease-Specific Criteria. PMID- 29389366 TI - Altered HDL Remodeling and Functionality in Familial Hypercholesterolemia. PMID- 29389367 TI - The Difficulty in Identifying Pregnancy-Associated Coronary Artery Dissection Using Nationwide Inpatient Databases. PMID- 29389363 TI - A New Educational Framework to Improve Lifelong Learning for Cardiologists. AB - Lifelong learning is essential for the practicing cardiologist. Present lifelong learning mechanisms are stagnant and at risk for not meeting the needs of currently practicing cardiologists. With the increasing burden of cardiovascular disease, growing complexity of patient care, and ongoing pressures of nonclinical responsibilities, educational programming must evolve to meet the demands of the contemporary cardiovascular professional. A paradigm shift, replete with modern and practical educational tools, is needed in the lifelong learning armamentarium. Emerging evidence of novel educational strategies in graduate medical education supports the promise of broader application of these tools to different stages of professional life. In this commentary from the Fellows-in Training Section Leadership Council, the authors propose 3 novel educational tools-personalized learning, adaptive learning, and the flipped classroom-to improve lifelong learning to meet the educational needs of fellows-in-training to practicing cardiologists alike. PMID- 29389368 TI - Pregnancy-Associated Spontaneous Coronary Artery Dissection: A Different Presentation Although Perhaps Not Such a Distinct Condition. PMID- 29389369 TI - Pregnancy-Associated Coronary Artery Dissection: A Therapeutic Dilemma. PMID- 29389370 TI - Reply: Pregnancy-Associated Coronary Artery Dissection: A Therapeutic Dilemma. PMID- 29389372 TI - Should We Recommend Cardiac Rehabilitation in Patients With Spontaneous Coronary Artery Dissection? PMID- 29389371 TI - Reply: Sex, Gender, and Reproductive History Are Critical Variables for Spontaneous Coronary Artery Dissection Research. PMID- 29389373 TI - Reply: Should We Recommend Cardiac Rehabilitation in Patients With Spontaneous Coronary Artery Dissection? PMID- 29389374 TI - Correction. PMID- 29389375 TI - Invited Commentary. PMID- 29389376 TI - Subtotal Cholecystectomy as a Last Resort for Complicated Gallstone Disease. PMID- 29389377 TI - Appropriate Use of Stents to Prevent Biliary Complications after Living Donor Liver Transplantation. PMID- 29389378 TI - Possible Optimal Donor Site for Multiple Lymph Node Transfers. PMID- 29389379 TI - Open vs Minimally Invasive Approach in Pancreatic Surgery: Where Are We? PMID- 29389381 TI - February 2018 Featured Articles, Volume 226. PMID- 29389380 TI - Randomized Studies Are Ongoing: In Reply to Ramacciato and colleagues. PMID- 29389382 TI - Challenges in Interpreting Multivariable Mendelian Randomization: Might "Good Cholesterol" Be Good After All? PMID- 29389383 TI - Declining Hip Fracture Rates in Dialysis Patients: Is This Winning the War? PMID- 29389384 TI - The United States Needs a National Policy on Dialysis for Undocumented Immigrants With ESRD. PMID- 29389385 TI - Erratum Regarding "Ultrasound Monitoring to Detect Access Stenosis in Hemodialysis Patients: A Systematic Review" (Am J Kidney Dis. 2008;51(4):630 640). PMID- 29389386 TI - Hypomagnesemia in a Patient With an Eating Disorder. PMID- 29389388 TI - Women and kidney disease: reflections on World Kidney Day 2018. PMID- 29389389 TI - Case definitions and approaches for surveillance of chronic kidney disease in agricultural communities in Central America: policy implications. PMID- 29389390 TI - Hippo pathway deficiency and recovery from heart failure after myocardial infarction: potential implications for kidney disease. PMID- 29389391 TI - REPRISE: tolvaptan in advanced polycystic kidney disease. PMID- 29389392 TI - Lemmings into the sea or back across the bridge? The fate of albumin in nephrotic syndrome. AB - An intact glomerular filtration barrier is essential for maintaining plasma albumin levels. However, the capacity of the proximal tubule to reabsorb filtered albumin and the subsequent fate of this protein are hotly debated. Weyer et al. find that knockout of megalin and cubilin receptors in a nephrotic mouse model causes no further reduction in plasma albumin levels, suggesting that albumin retrieval by the proximal tubule does not contribute significantly to albumin homeostasis. PMID- 29389393 TI - Not all vascular smooth muscle cell exosomes calcify equally in chronic kidney disease. AB - Prevention of medial calcification in patients with chronic kidney disease requires the maintenance of vascular smooth muscle cell fitness. To preserve viability under chronic kidney disease-induced stress, vascular smooth muscle cells increase exosome formation and release, but the result is aggravated pathological calcification. Now Chen et al. report that microvesicles from calcifying vascular smooth muscle cells may propagate procalcifying signals to normal vascular smooth muscle cells. To help design effective strategies to impair procalcifying cell-to-cell communication, this commentary updates the current understanding of the main regulators of microvesicle/exosome biogenesis and secretion. PMID- 29389394 TI - Plasmacytoid dendritic cells: important players in human kidney allograft rejection. AB - Plasmacytoid dendritic cells are a unique dendritic cell subset that bridges innate and adaptive immune responses. They release high amounts of type I interferons in response to viral and bacterial infection. Plasmacytoid dendritic cells are thought to act as key players in renal allograft rejection, but the underlying mechanisms are unclear. Ruben et al. now demonstrate that granulocyte/macrophage colony-stimulating factor produced by renal epithelial cells is important to induce plasmacytoid dendritic cell maturation and indirect antigen presentation triggering allogeneic immune responses. PMID- 29389395 TI - Neutrophil extracellular traps in ischemic AKI: new way to kill. AB - Neutrophil extracellular traps, originally discovered as a mechanism to combat microbial infection, have recently been implicated in tissue damage including acute kidney injury. Raup-Konsavage et al. now present further insights to demonstrate a critical role of neutrophil peptidyl arginine deiminase-4 in the formation of neutrophil extracellular trap, inflammation, and tissue damage in ischemic acute kidney infection. Targeting peptidyl arginine deiminase-4 and/or neutrophil extracellular trap may offer a new therapeutic strategy for acute kidney infection. PMID- 29389396 TI - Does dialysis modality affect the development of cognitive impairment? AB - Neumann and colleagues attempted to investigate whether dialysis modality (peritoneal dialysis compared to hemodialysis) could affect changes in neurocognition. Their study highlights all the challenges of such research. These include using appropriate tests to investigate cognition, challenges of comparing people on different modalities considering that different types of people chose these, and reasons for dropout that affect assessment of neurocognition during follow-up. More studies in this area are needed to inform patient choice. PMID- 29389397 TI - Molecular, histological, and clinical phenotyping of diabetic nephropathy: valuable complementary information? AB - The incidence and prevalence of diabetic kidney disease is increasing. Observational and interventional studies suggest that the pathophysiology varies between individuals and within a patient over time. There is a huge clinical need to describe the molecular processes that modulate diabetic kidney disease. "Omics" experiments combined with bioinformatical analysis tools might allow for profiling of patients on an individual or at least group level to improve prediction of prognosis and guide targeted therapy. PMID- 29389398 TI - Levamisole in relapsing steroid-sensitive nephrotic syndrome: where do we stand? AB - Many patients with steroid-sensitive nephrotic syndrome develop a relapsing course; therefore, alternative treatment may be necessary to avoid steroid toxicity. In this issue, a multicenter controlled study in relapsing steroid sensitive nephrotic syndrome shows the effectiveness of levamisole. Time to first relapse was significantly increased compared with placebo. In addition, possible differential treatment effects were suggested for subgroups: patients with frequent relapses might have a superior response to those with steroid dependency. PMID- 29389399 TI - Lightsheet fluorescence microscopy of branching human fetal kidney. PMID- 29389400 TI - Severe neonatal hypertension revealing arterial tortuosity syndrome. PMID- 29389401 TI - The Case | Acute kidney injury, flank pain, and kidney calcifications in an 80 year-old woman. PMID- 29389402 TI - Pediatric Keratoprosthesis: A Promise Unfulfilled. PMID- 29389403 TI - Open Search or Rotating Leadership: Thoughts Concerning Selecting Chairs for an Academic Ophthalmology Department. PMID- 29389404 TI - Solitary Retinal Capillary Hemangioma with Nonlipid Exudative Retinal Detachment. PMID- 29389405 TI - XEN Implant-Related Endophthalmitis. PMID- 29389406 TI - Imaging of Neovascular Membrane Over a Choroidal Osteoma by OCT Angiography. PMID- 29389407 TI - OCT of Anterior Capsular Opacification in the Visual Axis. PMID- 29389408 TI - Epidermal Growth Factor Receptor Inhibitor Induced Trichomegaly and Poliosis. PMID- 29389409 TI - Re: Keel et al.: The prevalence of diabetic retinopathy in Australian adults with self-reported diabetes: The National Eye Health Survey (Ophthalmology. 2017;124:977-984). PMID- 29389410 TI - Reply. PMID- 29389411 TI - Re: Economides et al.: Capturing the moment of fusion loss in intermittent exotropia (Ophthalmology. 2017;124;496-504). PMID- 29389412 TI - Re: Guy et al.: Gene therapy for Leber hereditary optic neuropathy: low-and medium-dose visual results (Ophthalmology. 2017;124:1621-1634). PMID- 29389413 TI - Reply. PMID- 29389414 TI - Reply. PMID- 29389415 TI - Re: Schlenker et al.: Efficacy, safety, and risk factors for failure of standalone ab interno gelatin microstent implantation versus standalone trabeculectomy (Ophthalmology. 2017;124:1579-1588). PMID- 29389416 TI - Reply. PMID- 29389417 TI - 2017 European Society for Vascular Surgery guidelines for management of carotid and vertebral artery disease. PMID- 29389418 TI - Invited commentary. PMID- 29389419 TI - Late type II endoleaks after endovascular aneurysm repair require intervention more frequently than early type II endoleaks. AB - OBJECTIVE: Type II endoleaks (T2ELs) are commonly observed after endovascular aneurysm repair (EVAR). We sought to determine whether time at onset of T2ELs correlated with the need to intervene based on sac expansion or rupture. METHODS: Between 1998 and 2015, 462 EVARs performed at our institution had duplex ultrasound surveillance in our accredited noninvasive vascular laboratory. Computed tomography and arteriography were reserved for abnormal duplex ultrasound findings. The need for intervention for T2ELs was classified according to time at onset after EVAR. Interventions for T2ELs were performed only for sac expansion >5 mm or rupture. We defined early-onset T2ELs as <1 year after EVAR and delayed or late onset as >1 year of follow-up. RESULTS: Of the 462 EVARs, 96 patients (21%) developed T2ELs after implantation. Of these, 65 (68%) had early and 31 (32%) had late onset (mean, 12 months; range, 1-112 months). Early T2ELs resolved without treatment in 75% (49/65) of cases compared with only 29% (9/31) of late T2ELs (P < .0001). Intervention was required for only 8% (5/65) of patients with early T2ELs (5 sac expansions, 0 ruptures) compared with 55% (17/31) for late T2ELs (16 sac expansions, 1 rupture; P < .0001). The remaining patients were observed for persistent T2ELs with no sac growth (17% [11/65] early vs 16% [5/31] late; P = .922). CONCLUSIONS: Less than one-third (29%) of T2ELs that develop after 1 year will resolve spontaneously and about half (55%) will require intervention for sac growth or rupture. T2ELs that develop >1 year after EVAR should be followed up with a more frequent surveillance protocol and perhaps with a lower threshold to intervene. PMID- 29389420 TI - Invited commentary. PMID- 29389421 TI - Invited commentary. PMID- 29389422 TI - Invited commentary. PMID- 29389423 TI - Invited commentary. PMID- 29389424 TI - Liver perfusion dependent on superior mesenteric artery aneurysm. PMID- 29389425 TI - Systematic review and meta-analysis of high-pressure intermittent limb compression for the treatment of intermittent claudication. AB - BACKGROUND: High-pressure intermittent limb compression (HPILC) has been proposed as an alternative treatment of disabling intermittent claudication. The objective of this study was to conduct a systematic review and meta-analysis of randomized controlled trials evaluating the efficacy of HPILC in improving walking distance in patients with intermittent claudication. METHODS: A search through December 31, 2016, was performed to identify all randomized controlled trials evaluating the efficacy of HPILC for the management of intermittent claudication. Applicable studies were assessed for quality and pooled using Cochrane systematic review guidelines. The primary outcome measured was absolute claudication distance (ACD). A random-effects model was used for meta-analysis. RESULTS: Eight studies eligible for inclusion were identified. These studies had a combined total of 290 subjects, 172 of whom were randomized to HPILC. All studies identified an increase in walking distance for subjects receiving compression therapy. On meta analysis, the mean difference of ACD from baseline to follow-up among subjects receiving compression compared with controls was 125 m (95% confidence interval, 58.38-191.63 m; P < .01). CONCLUSIONS: HPILC is associated with a significant increase in ACD compared with controls. Limb compression appears to be an effective, noninvasive treatment option for patients with intermittent claudication. However, there are few studies comparing limb compression with other commonly used therapies. Further studies are needed to better guide the use of HPILC in the treatment of claudication. PMID- 29389427 TI - Invited commentary. PMID- 29389426 TI - Registry Assessment of Peripheral Interventional Devices (RAPID): Registry assessment of peripheral interventional devices core data elements. AB - OBJECTIVE: The current state of evaluating patients with peripheral artery disease and more specifically of evaluating medical devices used for peripheral vascular intervention (PVI) remains challenging because of the heterogeneity of the disease process, the multiple physician specialties that perform PVI, the multitude of devices available to treat peripheral artery disease, and the lack of consensus about the best treatment approaches. Because PVI core data elements are not standardized across clinical care, clinical trials, and registries, aggregation of data across different data sources and physician specialties is currently not feasible. METHODS: Under the auspices of the U.S. Food and Drug Administration's Medical Device Epidemiology Network initiative-and its PASSION (Predictable and Sustainable Implementation of the National Registries) program, in conjunction with other efforts to align clinical data standards-the Registry Assessment of Peripheral Interventional Devices (RAPID) workgroup was convened. RAPID is a collaborative, multidisciplinary effort to develop a consensus lexicon and to promote interoperability across clinical care, clinical trials, and national and international registries of PVI. RESULTS: The current manuscript presents the initial work from RAPID to standardize clinical data elements and definitions, to establish a framework within electronic health records and health information technology procedural reporting systems, and to implement an informatics-based approach to promote the conduct of pragmatic clinical trials and registry efforts in PVI. CONCLUSIONS: Ultimately, we hope this work will facilitate and improve device evaluation and surveillance for patients, clinicians, health outcomes researchers, industry, policymakers, and regulators. PMID- 29389428 TI - Seeing light and shadows: A commentary on the 2017 European Society for Vascular Surgery carotid guidelines. PMID- 29389429 TI - Conceptualizing treatment of uncomplicated type B dissection using the IDEAL framework. AB - OBJECTIVE: The objective of this study was to introduce a new framework, called IDEAL (idea, development, exploration, assessment, and long-term study), to guide physicians, investigators, and regulatory agencies through the life cycle of device development and procedural refinement. METHODS: This review describes the IDEAL framework and illustrates its application for treatment of uncomplicated type B dissection (uTBD) as an example of this process. RESULTS: Components of IDEAL are summarized and applied to devices used to treat uTBD. Treatment of uTBD is currently in the exploration phase, with concurrent assessment and long-term study being facilitated by detailed registries. CONCLUSIONS: The application of IDEAL to the development and monitoring of technologies standardizes the nomenclature, facilitates evidence-based practice, and enhances the innovation process. PMID- 29389430 TI - New endovascular repair code set for 2018. PMID- 29389431 TI - The MIPS APM scoring standard. PMID- 29389432 TI - Regarding "Cryopreserved venous allograft is an acceptable conduit in patients with current or prior angioaccess graft infection". PMID- 29389433 TI - Regarding "Data, guidelines, and practice of revascularization for claudication". PMID- 29389434 TI - Reply. PMID- 29389436 TI - Correction. PMID- 29389435 TI - Regarding "Exercise training for intermittent claudication". PMID- 29389437 TI - Correction. PMID- 29389438 TI - Correction. PMID- 29389439 TI - Correction. PMID- 29389440 TI - Our Volunteers-Celebrating a Century of the AAOMS. PMID- 29389441 TI - Oral/Head and Neck Oncologic and Reconstructive Surgery: The Creation of a Subspecialty in Oral and Maxillofacial Surgery. PMID- 29389442 TI - Describing how children with life threatening complex chronic conditions die. PMID- 29389443 TI - BabyBIG has BIG advantages for treatment of infant botulism. PMID- 29389445 TI - 50 Years Ago in The Journal of Pediatrics: The Antepartum Diagnosis of Genetic Diseases. PMID- 29389446 TI - Born too early for friends? PMID- 29389447 TI - Tiny babies can be sugary sweet-how hard should we work to control this? PMID- 29389448 TI - 50 Years Ago in The Journal of Pediatrics: Differential Cyanosis in Congenital Heart Disease. PMID- 29389444 TI - Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures. AB - OBJECTIVE: To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. STUDY DESIGN: A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. RESULTS: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children >=12 years of age and markedly reduced in children <12 years of age. CONCLUSIONS: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02186652. PMID- 29389449 TI - Reply. PMID- 29389450 TI - Smart use of vaccines. PMID- 29389451 TI - Neurobehavioral phenotypes in preterm children. PMID- 29389452 TI - 50 Years Ago in The Journal of Pediatrics: The Rationale for Genetic Counseling. PMID- 29389454 TI - 50 Years Ago in The Journal of Pediatrics: Atypical Exanthem after Exposure to Natural Measles: Eleven Cases in Children Previously Inoculated with Killed Vaccine. PMID- 29389453 TI - Hospitalist Medicine-Chairs' Perspective of Specialty Status and Training Requirements. PMID- 29389455 TI - 50 Years Ago in The Journal of Pediatrics: Phenylketonuria: Evaluation of Therapy and Verification of Diagnosis. PMID- 29389456 TI - [After three years in semFYC: Working Group Health Based on Emotions Who are we? What do we do? What is our intention?] PMID- 29389457 TI - ? PMID- 29389458 TI - An Initiative to Change Inpatient Practice: Leveraging the Patient Medical Home for Postdischarge Follow-Up. AB - BACKGROUND: The standard of care for hospital discharge planning includes arranging follow-up appointments, usually with a primary care provider. However, follow-up phone calls instead of face-to-face visits may be an appropriate alternative for some patients. This option was explored within the framework of the US Department of Veterans Affairs (VA) patient-centered medical home model of care, the Patient Aligned Care Team. METHODS: At a VA hospital, a pilot study was conducted on the use of phone calls from members of a patient's medical home as posthospital discharge follow-up rather than the traditional face-to-face provider model. Inpatient providers were educated about the phone follow-up alternative, and this option was standardized as part of discharge planning rounds. RESULTS: During Phase 1 at one clinic over three months, 17 of 118 eligible patients received phone call follow-up (14.4% of discharges) instead of traditional face-to-face follow-up. During Phase 2, data from Phase 1 were analyzed, and staff at the other eight clinic sites were trained. After the expansion of the initiative to all regional clinic sites in Phase 3, 76 of 447 eligible discharges (17.0%) were scheduled for phone follow-up. As a balancing metric, there were no significant differences in rates of 30-day emergency department (ED) utilization (11.9% and 5.9%, (p = 0.47)) or nonelective rehospitalization (16.8% and 17.6%, (p = 0.93)) between these groups during Phase 1. CONCLUSION: This initiative changed provider practices to use phone call follow-up for select patients instead of face-to-face provider visits after hospital discharge, without significantly increasing rates of 30-day ED utilization or rehospitalization. PMID- 29389459 TI - 'Who's Covering This Patient?' Developing a First-Contact Provider (FCP) Designation in an Electronic Health Record. AB - BACKGROUND: Safe and efficient inpatient care depends on accurate identification of the licensed independent practitioner (LIP) primarily responsible for each admitted patient. The inability to do so has far-reaching consequences, including poor communication among care teams, delays in patient care (including critical result reporting), and significant threats to patient safety. METHODS: At the University of Chicago Medical Center, an 800-bed academic hospital, a new Epic feature, called First-Contact Provider (FCP), was developed to identify the responsible LIP for each inpatient. The number of patients with only one designated FCP at a given time was audited daily. To ensure correct technical function, the number of Best Practice Advisories (BPAs) alerting of no documented FCP was measured. The number of inpatient critical lab values reported directly to LIPs was measured as a proxy for the accuracy of FCP in identifying the correct LIP. RESULTS: During the nine-month study period, the average daily inpatient census was 568 and the average monthly critical lab volume was 1,727. By the end of the study, the weekly mean percentage of patients with one FCP documented at noon reached 98.6%. The weekly mean number of BPAs dropped from 5,313/day to less than 50/day. The monthly mean percentage of critical results reported directly to LIPs increased from a pre-FCP baseline of 18.0% to 87.8%. CONCLUSION: FCP largely solved the far-reaching problem of accurate LIP identification for hospitalized patients. This, in turn, significantly improved the ability to report inpatient critical lab values directly to LIPs. PMID- 29389460 TI - Improving Antimicrobial Stewardship Programs: A Call for Papers. PMID- 29389461 TI - Antibiotic Stewardship Grows Up. PMID- 29389462 TI - The Expanding Role of Antimicrobial Stewardship Programs in Hospitals in the United States: Lessons Learned from a Multisite Qualitative Study. AB - BACKGROUND: Misuse of antibiotics can lead to the development of antibiotic resistance, which adversely affects morbidity, mortality, length of stay, and cost. To combat the threat of antimicrobial resistance, The Joint Commission and the Centers for Medicare & Medicaid Services have initiated or proposed requirements for hospitals to have antimicrobial stewardship programs (ASPs), but implementation remains challenging. A key-informant interview study was conducted to describe the characteristics and innovative strategies of leading ASPs. METHODS: Semistructured interviews were conducted with 12 program leaders at four ASPs in the United States, chosen by purposive sampling on the basis of national reputation, scholarship, and geography. Questions focused on ASP implementation, program structure, strengths, weaknesses, lessons learned, and future directions. Content analysis was used to identify dominant themes. RESULTS: Three major themes were identified. The first was evolution of ASPs from a top-down structure to a more diffuse approach involving unit-based pharmacists, multidisciplinary staff, and shared responsibility for antimicrobial prescribing under the ASPs' leadership. The second theme was integration of information technology (IT) systems, which enabled real-time interventions to optimize antimicrobial therapy and patient management. The third was barriers to technology integration, including limited resources for data analysis and poor interoperability between software systems. CONCLUSION: The study provides valuable insights on program implementation at a sample of leading ASPs across the United States. These ASPs used expansion of personnel to amplify the ASP's impact and integrated IT resources into daily work flow to improve efficiency. These findings can be used to guide implementation at other hospitals and aid in future policy development. PMID- 29389463 TI - Temporal Trends in Fall Rates with the Implementation of a Multifaceted Fall Prevention Program: Persistence Pays Off. AB - BACKGROUND: Most fall prevention programs are only modestly effective, and their sustainability is unknown. An academic medical center implemented a series of fall prevention interventions from 2001 to 2014. METHODS: The medical center's series of fall prevention interventions were as follows: reorganized the Falls Committee (2001), started flagging high-risk patients (2001), improved fall reporting (2002), increased scrutiny of falls (2005), instituted hourly nursing rounds (2006), reorganized leadership systems (2007), standardized fall prevention equipment (2008), adapted to a move to a new hospital building (2008), routinely investigated root causes (2009), mitigated fall risk during hourly nursing rounds (2009), educated patients about falls (2011), and taught nurses to think critically about risk (2012). To evaluate temporal trends in falls and injury falls, piecewise negative binomial regression with study unit-level random effects was used to analyze structured validated data sets available since 2003. RESULTS: From July 2003 through December 2014, the crude fall rate declined from 3.07 to 2.22 per 1,000 patient days, and injury falls declined from 0.77 to 0.65 per 1,000 patient days. Nonsignificant increases in falls occurred after nurses started rounding hourly and after the move to the new hospital. On the basis of regression models, significant declines occurred after nurses began to mitigate fall risk during hourly rounds (p = 0.009). CONCLUSION: Instituting incremental changes for more than a decade was associated with a meaningful (about 28%) and sustained decline in falls, although the rate of decline varied over time. Hospitals interested in reducing falls but concerned about competing clinical and financial priorities may find an incremental approach to be effective. PMID- 29389464 TI - Surveying Care Teams after in-Hospital Deaths to Identify Preventable Harm and Opportunities to Improve Advance Care Planning. AB - BACKGROUND: Reviewing in-hospital deaths is one way of learning how to improve the quality and safety of care. Postdeath surveys sent to the care team for patients who died may have a role in identifying opportunities for improvement. As part of a quality improvement initiative, a postdeath care team survey was developed to explore how it might augment the existing process for learning from deaths. METHODS: A survey was sent to the care team for all inpatient deaths on the hospital medicine and medical ICU services at one institution. Survey responses were reviewed to identify cases that required further investigation. An iterative process of inductive coding was used to create a coding taxonomy to classify survey response free-text comments. RESULTS: During the distribution period (September 25, 2015-December 28, 2015), 82 patients died, and 191 care team members were surveyed. Responses (138; 72.3% response rate) were collected through January 28, 2016. Based on the survey responses, 5 patients (6.1%) not identified by other review processes were investigated further, resulting in the identification of several important opportunities for improvement. The free-text comment analysis revealed themes around the importance of advance care planning in seriously ill patients, as well as evidence of the emotional and psychological strain on clinicians who care for patients who die. CONCLUSION: Postdeath care team surveys can augment mortality review processes to improve the way hospitals learn from deaths. Free-text comments on such surveys provide information not otherwise identified during traditional mortality review processes, including the importance of advance care planning and the strain on clinicians whose patients die. PMID- 29389465 TI - A Novel Bedside-Focused Ward Surveillance and Response System. AB - BACKGROUND: Rapid response systems (RRSs) have been universally adopted in much of the developed world; yet, despite broad implementation, their success has often been limited. Even with successful systems, there is a small body of evidence regarding effective organizational elements that are responsible for improved outcomes. New organizational processes were implemented that restructured the existing RRS, and the impact on the number of rapid response team (RRT) alerts, cardiac arrest, and mortality rates was evaluated. METHODS: A prospective five-year before-and-after comparison of adult ward patient outcomes was conducted at a community regional medical center. The key intervention was expanded administrative oversight of the system, which led to (1) restructuring the content and depth of ward nurse education regarding early recognition of at risk patients; (2) system changes empowering prompt mobilization of the RRT; (3) development of RRT treatment protocols; and (4) a more frequent and comprehensive data collection and analysis for system compliance and performance improvement. RESULTS: Some 28,914 patients were observed in the 24-month control period, and 39,802 patients were observed in the 33-month intervention period. RRT activations increased from 10.2 to 48.8/1,000 discharges (p <0.001), ward cardiac arrest decreased from 3.1 to. 2.4/1000 discharges (p = 0.04), hospital mortality decreased from 3.8% to 3.2% (p <0.001), and the observed-to-expected ratio decreased from 1.5 to 1.0 (p <0.001). CONCLUSION: Expanded administrative involvement of an existing RRS that focused on early recognition of patient deterioration by the bedside nurse led to improved performance of the system, with a significant increase in number of RRTs and decreases in cardiac arrests and hospital mortality. PMID- 29389467 TI - The effect of massage on acceleration and sprint performance in track & field athletes. AB - PURPOSE: To examine the acute effects of pre-competition massage on acceleration and sprint performance in collegiate track and field athletes. METHODS: Seventeen collegiate male (n = 9) and female (N = 8) track and field athletes participated in the study. Athletes were assigned to a counterbalanced, repeated measures designed experiment testing four treatment conditions of a pre-competition massage, dynamic warm-up, combination of a massage and warm-up, and a placebo ultrasound. RESULTS: The reliability between treatments was very high (ICC range: 0.94-0.98) and displayed a high internal consistency (Cronbach alpha = 0.96). Inter-item correlations for treatments were strong at all time intervals (20-m r = 0.74-0.90; 30-m r = 0.87-0.95; 60-m r = 0.88-0.95). There were no significant differences between the four treatments and performance (p = 0.70). Massage decreased 60-meter sprint performance in comparison to the traditional warm-up, although the combination of the massage and warm-up appeared to have no greater difference than the warm-up alone. CONCLUSIONS: Massage prior to competition remains questionable due to a lack of effectiveness in improving sprint performance. Further, pre-competition massage may not be more effective as a pre event modality, over a traditional warm-up. PMID- 29389468 TI - Prevalence and pattern of usage of complementary and alternative medicine among south Indian asthma patients in a tertiary care hospital. AB - OBJECTIVES: The study aimed to investigate the prevalence of CAM users among asthmatic patients in a tertiary care South Indian hospital. METHODS: Prospective, cross sectional study was conducted in 394 asthmatic patients. RESULTS: 30.4% of the patients used CAM therapies. The most commonly used CAM treatment was herbal medicine followed by pranayama (controlled breathing exercises). Most of the CAM users were found to be in lower middle class. The baseline characteristics of the CAM users and the non CAM users were found to be similar except for education and socioeconomic status (p < .008). Among the CAM users, none of the patients disclosed about their CAM treatment to their pulmonologists. CONCLUSION: Patients must be educated about CAM therapies and they must be advised to discuss all their treatment related issues with treating clinicians. Healthcare professionals should be familiar with the merits and demerits of using CAM therapy so that they could provide proper guidance to their patients. PMID- 29389469 TI - Women's perspectives towards traditional and complementary medicine used to conceive, during pregnancy and the postpartum period. AB - OBJECTIVES: This study aims to explore pregnant and postpartum women's understanding of the meaning of traditional and complementary medicine (T&CM) and how that may affect their T&CM use. METHODS: A cross-sectional study was conducted using self-administered questionnaires. Data collected from 374 women were analysed and represented via descriptive statistics. RESULTS: Out of the 374 participants, 285 (76.2%) reported using at least one type of T&CM to conceive, during pregnancy or in the postpartum period. The majority of the participants identified that T&CM is all about plants or natural products without chemicals or drugs (n = 267, 71.4%, p < .001). The category of T&CM with the highest usage was biological based therapies (n = 272, 95.4%), while the lowest was energy therapies (n = 8, 2.8%). The most commonly used T&CM was the traditional Malay massage (n = 170, 59.6%). The main sources of information and recommendations for using T&CM came from their family members or friends (n = 199, 69.8%). Almost half of the participants incurred minimum expenditures of MYR100 and below on the T&CM used (n = 137, 48.1%) and there was no significant difference between pregnant and postpartum women (p = .056). CONCLUSION: This study reveals that many women are practising T&CM when trying to conceive and during pregnancy and the postpartum period even though they are aware that there is insufficient evidence on its safety and efficacy. Therefore, further studies are needed in order to gain sufficient clinical evidence that could be used to structure better guidelines for T&CM practices and services in Malaysia. PMID- 29389470 TI - Aromatherapy massage with lavender essential oil and the prevention of disability in ADL in patients with osteoarthritis of the knee: A randomized controlled clinical trial. AB - BACKGROUND: Knee osteoarthritis is considered as one of the most prevalent musculoskeletal disorders which leads to joint degeneration and consequently disability in activities of daily living. This study aimed to evaluate the effects of aromatherapy massage with lavender essence on activities of daily living of patients with knee osteoarthritis. METHODS: This is a single-blinded, randomized clinical trial. A total of 90 patients with osteoarthritis of the knee referring to the outpatient rheumatology clinics affiliated to Birjand University of Medical Sciences were selected via convenience sampling method. The participants were randomly assigned into three groups: intervention group (aromatherapy massage with lavender essential oil), placebo group (massage with almond oil) and control group (without massage). The activities of daily living of patients was evaluated according to the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at baseline, immediately after the intervention, 1 week, and 4 weeks after the intervention. Data were analyzed using SPSS statistical software version 16. RESULTS: The activities of daily living of patients were significantly improved immediately and 1 week after the intervention in the intervention group compared with their initial status (p < .001) and that of the control group (p < .001 and p = .03 respectively). However, 4 weeks after the intervention, there was no significant difference between the groups according to the Western Ontario and McMaster Universities Osteoarthritis index (p = .95). CONCLUSION: Aromatherapy massage with lavender essential oil may reduce the incidence of activities of daily living disability in patients with osteoarthritis of the knee. However, further studies are required to confirm findings of this study. PMID- 29389471 TI - Does abdominal massage improve gastrointestinal functions of intensive care patients with an endotracheal tube?: A randomized clinical trial. AB - INTRODUCTION: Gastrointestinal dysfunction is one of the most common problems among patients hospitalized in intensive care units. Currently, medicinal and non medicinal methods are being used to prevent gastrointestinal problems. Among non medicinal methods, abdominal massage is considered as a relatively acceptable method. The present study aims to examine the effect of abdominal massage on gastrointestinal functions of the intensive care patients with an endotracheal tube. MATERIALS AND METHODS: In this clinical trial, 70 intensive care patients with an endotracheal tube were chosen by convenience sampling and allocated to an intervention or a control group randomly. In the intervention group, a 15-min abdominal massage was conducted twice a day for three days, while the control group received only routine cares. The abdominal circumference, gastric residual volume, times of defecation, and frequency of constipation were measured. RESULTS: Gastric residual volume decreased significantly in the intervention group and increased significantly in the control group; however, there was no significant difference between two groups (P = .15). There was a significant difference between two groups regarding abdominal circumference and it was decreased in the intervention group (P < .001). The defecation times significantly increased in the intervention group (P = .002). After the intervention, the prevalence of constipation was significantly decreased in the intervention group (P = .008). CONCLUSION: The results revealed that abdominal massage could improve gastrointestinal functions in enterally fed patients with an endotracheal tube. It is suggested to use abdominal massage as an adjunct therapy for improving gastrointestinal functions in intensive care patients. PMID- 29389472 TI - Acupuncture therapy improves vascular hemodynamics and stiffness in middle-age hypertensive individuals. AB - Acupuncture (ACU) is becoming a more common practice among hypertensive individuals. However, the reported therapeutic effects of ACU in lowering brachial blood pressure (BP) are ambiguous. Therefore, evaluating more sensitive markers of arterial functioning might unveil the protective effects of ACU on hypertension. We examined the effects of an 8-week ACU therapy intervention on vascular hemodynamics and stiffness in middle-age hypertensive individuals. Participants were randomly assigned to either ACU (n = 23) or a control group (n = 22). Brachial and aortic BP, wave reflection (AIx) and arterial stiffness (SI) were measured before and after 8 weeks. There was a significant group x time interaction (P < 0.05) for brachial and aortic BP, AIx and SI which significantly decreased (P < 0.05) following ACU but not after control. ACU led to reductions in brachial and aortic BP, wave reflection and arterial stiffness in middle-age hypertensive individuals. ACU might be effective in the prevention and treatment of hypertension. PMID- 29389473 TI - Impact of serial gait analyses on long-term outcome of hippotherapy in children and adolescents with cerebral palsy. AB - The aim of this study was to obtain data of gait parameters on predicting long term outcome of hippotherapy. In 20 participants (4-19 years; GMFCS levels I to III) with cerebral palsy (CP), gait and balance abilities were examined after 10 m walking test using a portable motion recorder. Hippotherapy was associated with increased Gross Motor Function Measure (GMFM)-66 at 1 year from the baseline (P < 0.001). Hippotherapy increased stride length, walking speed, and mean acceleration and decreased horizontal/vertical displacement ratio over time (P < 0.05). Stride length and mean acceleration at 6 weeks predicted the elevation of GMFM-66 score. These data suggest that 1-year outcome of hippotherapy on motor and balance functions can be assessed from the early phase by serial monitoring of the gait parameters. PMID- 29389474 TI - Effects of Rosmarinus officinalis L. on memory performance, anxiety, depression, and sleep quality in university students: A randomized clinical trial. AB - OBJECTIVE: To evaluate the effects of oral rosemary on memory performance, anxiety, depression, and sleep quality in university students. METHODS: In this double-blinded randomized controlled trial, the 68 participating students randomly received 500 mg rosemary and placebo twice daily for one month. Prospective and retrospective memory performance, depression, anxiety and sleep quality of the students were measured using Prospective and Retrospective Memory Questionnaire, Hospital Anxiety and Depression Scale, and Pittsburgh Sleep Quality Inventory at baseline and after one month. RESULTS: The scores of all the scales and subscales except the sleep latency and sleep duration components of Pittsburgh Sleep Quality Inventory were significantly decreased in the rosemary group in comparison with the control group after one month. CONCLUSIONS: Rosemary as a traditional herb could be used to boost prospective and retrospective memory, reduce anxiety and depression, and improve sleep quality in university students. PMID- 29389475 TI - Antibacterial action of Tropical honey on various bacteria obtained from diabetic foot ulcer. PMID- 29389476 TI - Efficacy of yoga training in chronic obstructive pulmonary disease patients: A systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the impact of yoga training in patients with chronic obstructive pulmonary disease (COPD). METHOD: A literature search was performed in PubMed, Cochrane Library, Embase, CINAHL, and Web of Science for relevant studies published before June 2017. Quality assessment, sensitivity analysis and heterogeneity were performed. Stata12.0 software was used for statistical analysis. RESULTS: Ten studies were eligible for this analysis. There were significantly greater improvements in 6MWD (p = 0.000), Borg scale scores (p = 0.018), FEV1 Value (p = 0. 013), PaCO2 (p = 0.037), SGRQ scores (p = 0. 000) and CAT scores (p = 0.009) in yoga training patients. No statistically significant difference was observed in the FEV1/FVC (p = 0.75), FEV1 predicted value (p = 0.057) and FVC (p = 0.05). CONCLUSIONS: This meta-analysis indicates that yoga training can be an acceptable and appropriated adjunctive rehabilitation program for COPD patients. PMID- 29389477 TI - Inter-expert agreement and similarity analysis of traditional diagnoses and acupuncture prescriptions in textbook- and pragmatic-based practices. AB - This study examined (1) the agreement of acupuncture experts with textbook prescriptions and among themselves, and (2) the association between similar traditional diagnoses and textbook acupuncture prescriptions, examining whether pragmatic practice (i.e., modifying prescriptions according to personal clinical practice) alters such an association. A computational analysis quantified the diagnosis-prescription association from a textbook. Eight acupuncture experts were independently interviewed. Experts modified the textbook prescriptions according to their pragmatic practice. Experts mostly agreed (19-90%) or strongly agreed (0-29%) with the textbook prescriptions, with no-better-than-chance agreement on their ratings (Light's kappa = 0.036, CI95% = [0.003; 0.081]). The number of manifestations in traditional diagnoses weakly explains the variability (Spearman's rho = 0.260, p = 0.038) of the number of acupoints in prescriptions. The association between similar traditional diagnoses and acupuncture prescriptions is strong in the textbook (gamma = 0.720, CI95% = [0.658, 0.783]), whereas pragmatic practice had little effect on this association (gamma = 0.724 0.769). PMID- 29389478 TI - Reasons for and perceived benefits of utilizing complementary and alternative medicine in U.S. adults with migraines/severe headaches. AB - We estimated prevalence rates of complementary and alternative medicine (CAM) use by reason for use (treatment, wellness, or both), and examined perceived benefits of using CAM among U.S. adults with migraines/severe headaches. The 2012 National Health Interview Survey, which represents non-institutionalized adults with migraines/severe headaches (n = 4447 unweighted), were used. Of the study sample, 41.3% used some form of CAM in the past year. Nearly a third of them (29.6%) used CAM for wellness only and 59% used CAM for both wellness and treatment. In given six self-reported perceived benefits, those who used CAM for wellness only and for a combination of both treatment and wellness had higher likelihoods of reporting benefits for all categories (p < 0.05), except for better sleep, when compared to those who used CAM for treatment only. CAM use was associated with an improvement in several health-related quality of life outcomes in U.S. adults with migraines/severe headaches. PMID- 29389479 TI - Integrative health care - Toward a common understanding: A mixed method study. AB - OBJECTIVE: To generate a multidisciplinary stakeholder-informed definition of integrative health care (IHC). METHODS: A mixed-method study design was used, employing the use of focus groups/semi-structured interviews (phase-1) and document analysis (phases 2 and 3). Phase-1 recruited a purposive sample of Australian health consumers/health providers. Phase-2 interrogated websites of international IHC organisations for definitions of IHC. Phase-3 systematically searched bibliographic databases for articles defining IHC. Data were analysed using thematic analysis. RESULTS: Data were drawn from 54 health consumers/providers (phase-1), 23 IHC organisation webpages (phase-2) and 23 eligible articles (phase-3). Seven themes emerged from the data. Consensus was reached on a single, 65-word definition of IHC. CONCLUSION: An unambiguous definition of IHC is critical to establishing a clearer identity for IHC, as well as providing greater clarity for consumers, health providers and policy makers. In recognising the need for a clearer description, we propose a scientifically grounded, multi-disciplinary stakeholder-informed definition of IHC. PMID- 29389480 TI - Complementary and alternative medicine use among Iranian patients attending urban outpatient general practices. AB - OBJECTIVE: To determine the frequency of use of different types of CAM among patients who attended outpatient general practices (GP). METHODS: CAM use, type, reason, administration, satisfaction, and disclosure to physician were documented by interviewing 360 patients. RESULTS: A total of 192 individuals (53.3%) reported that they were using or had used at least one form of CAM therapy (a total of 343 CAM therapies). The five most commonly used CAM therapies were, respectively, vitamin supplements (105 subjects, 54.7%), traditional herbal products (80 cases, 41.7%), mineral supplements (58 cases, 30.2%), herbal medicines (49 cases, 25.5%) and dietary therapies (18 cases, 9.4%); 240 therapies (70%) were self-prescribed. CONCLUSION: A substantial number of the patients had used CAM on their own; one-third of these patients did not have sufficient knowledge about the therapies used. Health care providers should be aware of this practice by the patients and seek information about CAM usage. PMID- 29389481 TI - A systematic review on Chinese herbal treatment for radiotherapy-induced xerostomia in head and neck cancer patients. AB - BACKGROUND: Over 80% of head and neck cancer patients suffer from radiotherapy induced xerostomia (dry mouth). Xerostomia affects cancer patients' quality of life, and xerostomia sometimes persists throughout the patients' lifetime. This review aimed to evaluate the effectiveness and safety of Chinese herbs in relieving radiotherapy induced xerostomia. METHODS: Systematic searches were conducted on 6 databases (English and Chinese). Studies published up till May 2017 were considered for inclusion. RESULTS: A final 14 RCTs (total 994 head and neck cancer patients undergoing radiotherapy) compared Chinese herbs with no herbs, were included in analysis. Very low to moderate quality of evidence found Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications (such as oral mucositis and loss of appetite) in head and neck cancer patients. CONCLUSION: There is limited evidence that Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications in head and neck cancer patients. PMID- 29389482 TI - The influence of ball-juggling on emotional states, blood pressure and sleep quality among medical students during end-of-year exam preparation. AB - Juggling-exposure therapy has been employed in the management of anxiety and post traumatic stress disorder. However, there is little evidence of the effectiveness of juggling-exposure in improving emotional states in subclinical conditions. This study aimed at evaluating the effect of a course of juggling on emotional states, sleep quality and blood pressure among medical students at a critical stage of their academic training. Blood pressure, psychometric and quality of sleep assessments were performed pre- and post-examination period for two groups of students: juggling-exposed (n = 9) and non-juggling-exposed (n = 11). Juggling exposure consisted of practice-drills for one hour per week during the period spanning the student's scheduled exams. Comparisons were made between quantitative measures that were collected pre- and post-the course of juggling drills. Differences in scores and measures were expressed as percentage-change and compared between non-juggling and juggling groups. Overall, there was a decrease in depression and anxiety scores between the pre-to post-exam periods. This decrease was statistically significant for both non-juggling and juggling groups with respect to anxiety, but only the juggling-exposed group had a significant reduction regarding depression scores. However, when calculated as percentage-change over the pre-to post-exam period, there was no significant difference in any of the parameters for either of the two groups. Practicing juggling drills had an influence on emotional states. PMID- 29389483 TI - The acceptability and potential benefits of mindfulness-based interventions in improving psychological well-being for adults with advanced cancer: A systematic review. AB - OBJECTIVE: In spite of supportive care for people affected by cancer being well recognized as a priority for research, there is little solid evidence of the effectiveness of psychological interventions using mindfulness for those with advanced cancer. This systematic review aims to describe, evaluate and synthesize the acceptability and potential benefits of mindfulness-based interventions (MBIs) for the psychological well-being of people with advanced cancers. METHODS: Eight databases were searched and terms related to advanced stages of cancer and mindfulness were combined systematically to identify relevant published literature. Inclusion criteria were studies with adults only and all types of cancer at stages III and IV. There was considerable variety in the MBI treatment packages including in the extent and centrality of mindfulness in the interventions. RESULTS: Of 312 identified studies, only 8 included MBIs for people with advanced cancer rather than their families or carers. Results from these studies suggests that MBIs are acceptable and beneficial to the advanced cancer population, improving quality of life, use of mindfulness skills, acceptance of their cancer situation and reduction in depression and anxiety. Some adaptations were recommended however regarding delivery, simplified briefer MBIs, abbreviated session time, flexibility concerning locality of treatment and a minimized questionnaire burden for this group. CONCLUSIONS: MBI packages reviewed in this study had evidence of acceptability and of effectiveness, indicating potential benefit for this population. Individualized, including home based interventions may be optimal to allow critically ill patients to participate in treatment. In future, MBIs adapted to the needs of various advanced cancer patients are recommended to address the gap in the field and improve health care. PMID- 29389484 TI - Effect of spiritual counseling on spiritual well-being in Iranian women with cancer: A randomized clinical trial. AB - OBJECTIVES: This study examined the effect of spiritual counseling on the spiritual well-being of Iranian women with cancer. DESIGN AND SETTING: a randomized clinical trial was conducted on 42 female cancer patients who were randomized to either an 8-week spiritual counseling intervention (n = 21) or a control group that received routine education/care (n = 21). Spiritual well-being (SWB) was assessed before and after the 8-week spiritual counseling program using Paloutzian and Ellison's (1983) Spiritual Well-Being Scale (SWBS). RESULTS: There were no significant differences on SWBS and its two subscales scores (RWB and EWB) between intervention and control groups at baseline (p > .05). After intervention, there was a significant mean difference in SWB (p = .001), RWB (p = .013) and EWB (p = .001) in two groups. CONCLUSIONS: Spiritual counseling is associated with significant improvements in SWB in Iranian women with cancer. Interventions that acknowledge the spiritual needs of these patients should be incorporated into conventional treatments. PMID- 29389485 TI - Massage therapy in cortisol circadian rhythm, pain intensity, perceived stress index and quality of life of fibromyalgia syndrome patients. AB - We investigate the effects of a massage therapy program (MTP) in cortisol concentration (CC), intensity of pain, quality of life and perceived stress index of fibromyalgia patients. Volunteers (n = 24, aged 26-55 years) were treated with MT, twice a week for three months. They answered the Fibromyalgia Impact Questionnaire (FIQ), Perceived Stress Questionnaire (PSQ) and McGill Pain Questionnaire (MPQ-Br), and collected saliva to evaluate CC before and after the end of each month. The MT had improvement in quality of life, according to the FIQ results, and promoted reduction in PSQ values after the second (PSQ2-0.62 +/- 0.04vsPSQ0-0.71 +/- 0.04) and third month (PSQ3-0.64 +/- 0.04vsPSQ0-0.71 +/- 0.04). The MTP also promoted reduction in pain after the third month (MQP-Br1 44.50 +/- 2.15vsMQP-Br4-35.38 +/- 3.71). Despite PSQ reduction, the CC were not affected by the program. This pilot suggests that this treatment improved quality of life, reduced perceived stress index and pain in these volunteers. PMID- 29389486 TI - Changes in female veterans' neck pain following chiropractic care at a hospital for veterans. AB - OBJECTIVE: To determine if U.S. female veterans had demonstrable improvements in neck pain after chiropractic management at a Veterans Affairs (VA) hospital. METHODS: This was a retrospective cross-sectional study of medical records from female veterans attending a VA chiropractic clinic for neck pain from 2009 to 2015. Paired t-tests were used to compare baseline and discharge numeric rating scale (NRS) and Neck Bournemouth Questionnaire (NBQ) scores with a minimum clinically important difference (MCID) set at a 30% change from baseline. RESULTS: Thirty-four veterans met the inclusion criteria and received a mean of 8.8 chiropractic treatments. For NRS, the mean score improvement was 2.7 (95%CI, 1.9-3.5, p < .001). For the NBQ, the mean score improvement was 13.7 (95%CI, 9.9 17.5, p < .001). For the MCID, the average percent improvement was 45% for the NRS and 38% for the NBQ. CONCLUSION: Female veterans with neck pain experienced a statistically and clinically significant reduction in NRS and NBQ scores. PMID- 29389489 TI - Current and Future Applications of Telemedicine to Optimize the Delivery of Care in Chronic Liver Disease. PMID- 29389487 TI - The effect of music on pain and anxiety of women during labour on first time pregnancy: A study from Turkey. AB - OBJECTIVE: This study aims at analyzing the effect of music on pain and anxiety felt by women in labor during their first pregnancy. METHOD: When the pregnant women in the experimental group progressed into the active phase of the labor, they were made to listen to music in Acemasiran mode with earplugs for 3 h (20 min of listening with 10-min breaks). FINDINGS: It was observed that after the first-hour women indicated that their pain was statistically less in the experimental group. Trait anxiety scores of the women in labor were similar for experimental and control groups. Following the practice, state anxiety average scores became lower in favor of the experimental group and the correlation was statistically significant. CONCLUSION: In order to facilitate women's coping with labor pain and improve their wellbeing with the activity during the labor, musicotherapy, a non-pharmacological method, is an effective, simple and economical method. PMID- 29389490 TI - Reply. PMID- 29389492 TI - Correction. PMID- 29389491 TI - Reply. PMID- 29389493 TI - Letter to the editor in response to "Minimal clinically important difference for pain on the VAS scale and the relation to quality of life in women with endometriosis" by Wickstrom and Edelstam. PMID- 29389494 TI - Contraindications in planned home birth in Iceland: A retrospective cohort study. AB - OBJECTIVES: Icelandic national guidelines on place of birth list contraindications for home birth. Few studies have examined the effect of contraindication on home birth, and none have done so in Iceland. The aim of this study was to examine whether contraindications affect the outcome of planned home birth or have a different effect at home than in hospital. METHODS: The study is a retrospective cohort study on the effect of contraindications for home birth on the outcome of planned home (n = 307) and hospital (n = 921) birth in 2005-2009. Outcomes were described for four different groups of women, by exposure to contraindications (unexposed vs. exposed) and planned place of birth (hospital vs. home). Linear and logistic regression analysis was used to evaluate the effect of the contraindications under study and to detect interactions between contraindications and planned place of birth. RESULTS: The key findings of the study were that contraindications were related to higher rates of adverse maternal and neonatal outcomes, regardless of place of birth; women exposed to contraindications had higher rates of adverse outcomes in planned home birth; and healthy, unexposed women had higher rates of adverse outcomes in planned hospital birth. Contraindications significantly increased the risk of transfer in labour and postpartum haemorrhage in planned home births. CONCLUSION: The defined contraindications for home birth had a negative effect on maternal and neonatal outcomes in Iceland, regardless of place of birth. The study results do not contradict the current national guidelines on place of birth. PMID- 29389495 TI - Practices used by midwives during the second stage of labor to facilitate birth - Are they related to perineal trauma? PMID- 29389496 TI - Who takes responsibility for contraception, according to young Australian women? AB - OBJECTIVE: Developments in reversible forms of female contraception are more advanced than developments in male contraception - which are still limited to the condom. These technological advancements have arguably shaped views around who should take responsibility for contraception. We investigate the notion that responsibility relates to gender-specific contraceptives. METHODS: We aimed to explore young women's reports of contraceptive responsibility based on the last time they had sex, using demographic and free-text data from 1906 women who completed a longitudinal survey about contraceptive use. We analysed four patterns of responsibility: the woman took responsibility; the sexual partner took responsibility; both took responsibility; neither took responsibility. RESULTS: Our quantitative analyses found significant differences between the four groups on the following variables: contraceptive use at last sex, relationship status, ever been pregnant, parity, and medical consultations for contraception in the past six months. Our qualitative analysis identified distinct variability within and between the four patterns of responsibility in terms of contraceptive use and gender responsible. CONCLUSIONS: These findings challenge the gendered portrayal of contraceptive responsibility, in that women's responsibility is not necessarily tied to women-specific methods and vice versa. We encourage increased dialogue around contraceptive responsibility and decision-making in both clinical and educational settings. PMID- 29389497 TI - Australian women's experiences of a rural medical termination of pregnancy service: A qualitative study. PMID- 29389498 TI - 'Without ultrasound you can't reach the best decision' - Midwives' experiences and views of the role of ultrasound in maternity care in Dar Es Salaam, Tanzania. AB - OBJECTIVE: To explore Tanzanian midwives' experiences and views of the role of obstetric ultrasound in relation to clinical management of pregnancy, and in situations where maternal and fetal health interests conflict. METHOD: In 2015, five focus group discussions were conducted with midwives (N = 31) at three public referral hospitals in the Dar es Salaam region as part of the CROss Country Ultrasound Study (CROCUS). RESULTS: Ultrasound was described as decisive for proper management of pregnancy complications. Midwives noted an increasing interest in ultrasound among pregnant women. However, concerns were expressed about the lack of ultrasound equipment and staff capable of skilful operation. Further, counselling regarding medical management was perceived as difficult due to low levels of education among pregnant women. CONCLUSION: Ultrasound has an important role in management of pregnancy complications. However, lack of equipment and shortage of skilled healthcare professionals seem to hamper use of obstetric ultrasound in this particular low-resource setting. Increased availability of obstetric ultrasound seems warranted, but further investments need to be balanced with advanced clinical skills' training as barriers, including power outages and lack of functioning equipment, are likely to continue to limit the provision of pregnancy ultrasound in this setting. PMID- 29389499 TI - From passive passenger to participating co-pilot - Pregnant women's expectations of being able to access their online journal from antenatal care. AB - OBJECTIVE: The aim of the study was to describe pregnant women's expectations of being able to access their electronic health records from antenatal care. METHODS: Nine pregnant women passing 25 full gestational weeks were interviewed individually. Collected data were analysed with an inductive approach using content analysis. The study was performed in antenatal care units in southern Sweden. RESULTS: The following five categories emerged from the analysis: Being able to achieve increased participation, being able to have more control, being more knowledgeable about the pregnancy, identification of possible risks, and perceptions of one's own well-being can predict usage. The five categories led to one main category: 'Shift in power - from passive passenger to participating co pilot'. CONCLUSION: The pregnant women expected that having access to electronic health records would give them more control, make them more knowledgeable and increase their participation. Access to electronic health records may empower pregnant women and contribute to a more person-centred approach. This could provide greater knowledge for the woman and her partner about her health, thus, allowing them to make evidence-based choices in relation to the newborn baby and the woman's health. PMID- 29389500 TI - Fertility decision-making under certainty and uncertainty in cancer patients. AB - OBJECTIVE: The objective of this study was to understand how reproductive-age women with breast cancer make fertility-related decisions. METHODS: Using grounded theory methodology, we collected data from 11 reproductive-age women with breast cancer between March and August 2016. Verbatim transcriptions were analyzed using constant comparative analysis and open, axial, and selective coding. RESULTS: "Fertility Decision-Making under Certainty and Uncertainty" emerged as a core category. Fertility decision-making started with the participants' "values and preferences" about having a child. In making a decision, there were certainty ("Information" and "Emotional support") and uncertainty ("Time constraints," "Recurrent risk," "Labeling," and "Unmet needs") factors. Participants had more uncertainty factors than certainty factors, and healthcare professionals' services accounted for one of the uncertainty factors. CONCLUSIONS: After fertility preservation counseling, women with cancer made difficult decisions in stressful situations without sufficient healthcare information and support. Tailored information should be provided to individual women in collaboration between oncology and reproductive health professionals. PMID- 29389501 TI - "Longing for individual recognition" - Pregnant women's experiences of midwives' counselling on physical activity during pregnancy. AB - OBJECTIVE: The aims to explore among pregnant women were their experiences of lifestyle counselling provided by a midwife in antenatal care, addressing health promotion with special focus on physical activity during pregnancy, and factors influencing the trustworthiness of counselling conducted by a midwife. METHODS: This qualitative study collected data from 14 pregnant, primiparous or multiparous women in gestational week 35-36 using in-depth interviews. The data were collected in Sweden in 2015. Qualitative content analysis was applied. RESULTS: The theme "Longing for fulfilment of individual needs and expectations" emerged during analysis, including four categories; "Being exposed to unsatisfying counselling"; "Appreciating supportive and trustworthy counselling"; "Wrestling with cultures", and "Dealing with physical activity in daily life". The results indicated that some participants experienced limited counselling that was characterized by lack of knowledge, support, and trustworthiness in the midwife. Other participants reported valuable encouragement and support by the midwife. Participants were longing for individual recognition instead of receiving general advice on physical activity that was designed for all pregnant women. CONCLUSIONS: Individual counselling on physical activity during pregnancy based on the participant's individual needs was desired. On the contrary, the participants could experience the midwife as having her own agenda, insufficient knowledge and primarily focusing on medical surveillance. There is a need of increased level of knowledge among midwives in antenatal care, regarding lifestyle and lifestyle change during pregnancy. This may enhance promotion of a healthy lifestyle for the pregnant woman during counselling. PMID- 29389503 TI - "Dad - a practical guy in the shadow": Fathers' experiences of their paternal role as a father during early discharge after birth and readmission of their newborns. AB - OBJECTIVES: The aim is to explore how new fathers experience early discharge after birth and readmission of their newborn in relation to their role and involvement as a father. Fathers of today are active participants during pregnancy, birth and in the care of the newborn. Still studies demonstrate that health care professionals are unsuccessful at involving fathers in ante- and postnatal care. How fathers experience their paternal role in the early postnatal period may affect the well-being of the new family. STUDY DESIGN: A qualitative study inspired by the hermeneutic approach. Data was collected through telephone interviews. The study was conducted in the Region of Southern Denmark in a University Hospital setting. Convenience sampling was applied. Eight fathers were included from November 2015 till February 2016 and six were interviewed. RESULTS: The data analysis revealed three categories: Early discharge - ups and downs, Readmission -waiting but being in good hands, and Practical guy in the shadow. CONCLUSIONS: Our study points at fathers being comfortable with being discharged early, but experienced insecurity when at home. The fathers experienced to be categorized by health care professionals as the practical guy, who had to assist the mother. Yet fathers saw themselves as equal to the mothers. Fathers also saw themselves in the shadow of the mother and showed greater considerations for the mother's feelings than their own. Fathers can be insecure in their paternal role when being met as just the practical guy. PMID- 29389502 TI - The prevalence of sick leave: Reasons and associated predictors - A survey among employed pregnant women. AB - OBJECTIVE: We aimed to investigate the prevalence of sick leave and self-reported reasons given for sick leave during pregnancy. Furthermore, we aimed to estimate the frequency of long-term sick leave during pregnancy in relation to pre baseline maternal characteristics and to identify predictors of long-term sick leave. METHOD: Data from 508 employed pregnant women seeking antenatal care was collected by questionnaires from August 2015 to March 2016. The questionnaires, which were filled in at 20 and 32 weeks of gestation, provided information on maternal characteristics, the number of days spent on sick leave and the associated reasons. Descriptive statistics and logistic regression analysis were applied. RESULTS: The prevalence of sick leave was 56% of employed pregnant women in the first 32 weeks of gestation and more than one in four reported long-term sick leave (>20 days, continuous or intermittent). Low back pain was the reason most frequently stated. Fewer than one in ten stated that their sick leave was due to work-related conditions. Positive predictors of long-term sick leave were multiparity, pre-pregnancy low back pain and mental disease, while an advanced degree education was a negative predictor. CONCLUSIONS: The prevalence of sick leave was 56% in the first 32 weeks of gestation and more than one in four women reported long-term sick leave. The majority of reasons for sick leave were pregnancy-related and low back pain was the most frequently given reason. PMID- 29389504 TI - Norwegian obstetricians' experiences of the use of ultrasound in pregnancy management. A qualitative study. AB - OBJECTIVE: To explore obstetricians' experiences and views of the use of obstetric ultrasound in clinical management of pregnancy. METHODS: A qualitative interview study was undertaken in 2015 with obstetricians (N = 20) in Norway as part of the CROss Country Ultrasound Study (CROCUS). RESULTS: Three categories developed during analyses. 'Differing opinions about ultrasound and prenatal diagnosis policies' revealed divergent views in relation to Norwegian policies for ultrasound screening and prenatal diagnosis. Down syndrome screening was portrayed as a delicate and frequently debated issue, with increasing ethical challenges due to developments in prenatal diagnosis. 'Ultrasound's influence on the view of the fetus' illuminated how ultrasound influenced obstetricians' views of the fetus as a 'patient' and a 'person'. They also saw ultrasound as strongly influencing expectant parents' views of the fetus, and described how ultrasound was sometimes used as a means of comforting women when complications occurred. 'The complexity of information and counselling' revealed how obstetricians balanced the medical and social aspects of the ultrasound examination, and the difficulties of 'delivering bad news' and counselling in situations of uncertain findings. CONCLUSION: This study highlights obstetricians' experiences and views of ultrasound and prenatal diagnosis in Norwegian maternity care and the challenges associated with the provision of these services, including counselling dilemmas and perceived differences in expectations between caregivers and expectant parents. There was notable diversity among these obstetricians in relation to their support of, and adherence to Norwegian regulations about the use of ultrasound, which indicates that the care pregnant women receive may vary accordingly. PMID- 29389505 TI - Well-being, diabetes management and breastfeeding in mothers with type 1 diabetes - An explorative analysis. AB - OBJECTIVES: The aim was to explore and investigate associations between well being, diabetes management and breastfeeding in mothers with type 1 diabetes mellitus (T1DM) up to six months postpartum. METHODS: An explorative analysis of self-reported questionnaires measuring general well-being, sense of coherence, self-efficacy of diabetes management and experiences of diabetes management during breastfeeding, which were distributed to 155 mothers with T1DM at two months and at six months after childbirth. The questionnaires were answered by 128 (82.5%) at two months and 137 (88.4%) at six months after birth. Statistical analysis included; descriptive statistics, Wilcoxon sign-rank test, sign test and Spearman's correlation coefficient (rs). RESULTS: The majority of the mothers had fairly high levels of general well-being and diabetes management but a quarter had a low sense of coherence at both two and six months after birth. A weak association was found between more unstable blood glucose levels and lower general well-being at two months postpartum, but no other associations with erratic glycaemia was found. Those with lower grades of general well-being and sense of coherence had a higher need of professional support to manage their diabetes than they were offered, at both two and six months. CONCLUSION: To develop more optimal care routines for mothers with T1DM after childbirth, further studies are needed to identify those most in need of additional support. PMID- 29389506 TI - Academy Members and Agriculture: A Winning Combination. PMID- 29389507 TI - Communicating the Dietary Guidelines: Tools for Professionals. PMID- 29389509 TI - Stress, Anxiety, and Weight Gain among University and College Students: A Systematic Review. AB - BACKGROUND: Stress and anxiety levels are elevated among university and college students. Although high stress levels can lead to an increase in adiposity, it is not clear whether stress and anxiety experienced when in university or college have an influence on students' weight. OBJECTIVE: The aim of this systemic review was to investigate whether stress and anxiety levels encountered during university and college enrollment were associated with higher adiposity or weight changes among students. METHOD: A search strategy was used to identify peer reviewed studies published between 1985 and March 2017 using the following databases: Medline using Ovid; PubMed, CINAHL using EBSCO, Embase using Ovid, PSYCHINFO, and Open Access Theses and Dissertation. Two reviewers independently assessed the title, abstract, and then the full article of the studies that met the inclusion criteria. Data were extracted and quality assessment was conducted for the included studies. RESULTS: Twenty-five observational studies were identified in this review (23 cross-sectional and two longitudinal); 11 found that there was no association between stress and body mass index or weight change. In addition, five studies did not find a significant association between anxiety and body mass index. A few studies revealed stress and anxiety might be associated with higher or lower weight status, thus there is a possibility that stress can increase or decrease weight, demonstrating that a bidirectional influence on body mass index may exist. CONCLUSIONS: The current data in this review are inadequate to draw firm conclusions about the role of stress on weight change in university and college students. The inconsistency of results in the literature reviewed for this article suggest that a focus on longitudinal studies with adequate sample size would better evaluate the relationship between stress or anxiety and its influence on weight status or weight change among college and university students. PMID- 29389508 TI - Nutrition Facts Panels: Who Uses Them, What Do They Use, and How Does Use Relate to Dietary Intake? AB - BACKGROUND: Nutrition labels are a low-cost tool with the potential to encourage healthy eating habits. OBJECTIVE: To investigate correlates of frequent Nutrition Facts label use, describe the types of label information most often used, and measure how label use relates to dietary intake in young adults. DESIGN: Cross sectional population-based study of young adults participating in Project Eating and Activity in Teens and Young Adults-IV. PARTICIPANTS/SETTING: Surveys and food frequency questionnaires were completed during 2015-2016 by young adults (N=1,817; weighted sample=49% women) aged 25 to 36 years. MAIN OUTCOME MEASURES: Nutrition Facts label use, frequency of using specific information on labels, and dietary intake. STATISTICAL ANALYSES PERFORMED: Relative risks and adjusted means were used to examine how demographic, behavior, and weight-related factors were associated with Nutrition Facts panel use, and how label use related to dietary outcomes. Associations with P values <0.05 were considered statistically significant. RESULTS: Approximately one-third (31.4%) of participants used Nutrition Facts labels "frequently." Use was significantly higher for women; for participants with high education and income; among those who prepared food regularly; among those who were physically active; among those with a weight status classified as overweight; and among those who were trying to lose, gain, or maintain weight. Label components used most often included sugars (74.1%), total calories (72.9%), serving size (67.9%), and the ingredient list (65.8%). Nutrition Facts label users consumed significantly more fruits, vegetables, and whole grains and fewer sugar-sweetened beverages, compared with nonusers. Nutrition Facts label users ate significantly more frequently at sit-down restaurants but less frequently at fast-food restaurants compared with nonusers. CONCLUSIONS: Although Nutrition Facts label use was associated with markers of better dietary quality in a population-based sample of young adults, only one third of participants used labels frequently. Methods to improve label use should be studied, particularly through leveraging weight- or health-related goals (eg, interest in making healthier food choices), and meeting consumer preferences concerning label content. PMID- 29389510 TI - Picky Eaters Improved Diet Quality in a Randomized Behavioral Intervention Trial in Youth with Type 1 Diabetes. AB - BACKGROUND: Children who are picky eaters typically demonstrate persistent food refusal and poor diet quality and may be resistant to intervention. OBJECTIVE: This study tested whether pickiness moderated the effect of a nutrition intervention on diet quality in youth with type 1 diabetes, hypothesizing that the intervention effect would be smaller among picky relative to nonpicky eaters. DESIGN: The study was an 18-month randomized clinical trial. PARTICIPANTS: Youth age 8.0 to 16.9 years (n=136) with type 1 diabetes duration >=1 year, receiving care at an outpatient diabetes center in Boston, MA, and a parent, participated from 2010 to 2013. INTERVENTION: The intervention integrated motivational interviewing, active learning, and applied problem solving to increase whole plant food intake. MAIN OUTCOME MEASURES: Whole plant food density (WPFD, cup/oz equivalents per 1,000 kcal target food groups), Healthy Eating Index-2005 (HEI2005, measures conformance to US dietary guidelines), and dietary variety were calculated from 3-day food records completed at six different times. Parents completed the pickiness subscale of the Child Feeding Questionnaire. STATISTICAL ANALYSES PERFORMED: Mean WPFD and HEI2005 were estimated using the population ratio method; standard errors were computed using jackknife variance-covariance estimation. Overall P value comparing groups across visits was derived using the chi2 test. RESULTS: Baseline diet quality was lower in picky than in nonpicky eaters. No intervention effect on pickiness or dietary variety was seen. In stratified analyses, the intervention effect on diet quality was significant for picky eaters only (WPFD P=0.0003; HEI2005 P=0.04). Among picky eaters, diet quality in the treatment group improved, whereas diet quality in the control group remained low. Diet quality of nonpicky eaters in the intervention group changed to a lesser degree. CONCLUSIONS: The intervention resulted in increased diet quality in picky eaters, whereas no intervention effect was seen in nonpicky eaters. Findings suggest that diet quality of picky eaters can be improved without changing their underlying pickiness. PMID- 29389512 TI - What Does the Academy of Nutrition and Dietetics Foundation Do for Academy Members? PMID- 29389511 TI - Position of the Academy of Nutrition and Dietetics: The Role of Medical Nutrition Therapy and Registered Dietitian Nutritionists in the Prevention and Treatment of Prediabetes and Type 2 Diabetes. AB - It is the position of the Academy of Nutrition and Dietetics that for adults with prediabetes or type 2 diabetes, medical nutrition therapy (MNT) provided by registered dietitian nutritionists (RDNs) is effective in improving medical outcomes and quality of life, and is cost-effective. MNT provided by RDNs is also successful and essential to preventing progression of prediabetes and obesity to type 2 diabetes. It is essential that MNT provided by RDNs be integrated into health care systems and public health programs and be adequately reimbursed. The Academy's evidence-based nutrition practice guidelines for the prevention of diabetes and the management of diabetes document strong evidence supporting the clinical effectiveness of MNT provided by RDNs. Cost-effectiveness has also been documented. The nutrition practice guidelines recommend that as part of evidence based health care, providers caring for individuals with prediabetes or type 2 diabetes should be referred to an RDN for individualized MNT upon diagnosis and at regular intervals throughout the lifespan as part of their treatment regimen. Standards of care for three levels of diabetes practice have been published by the Diabetes Care and Education Practice Group. RDNs are also qualified to provide additional services beyond MNT in diabetes care and management. Unfortunately, barriers to accessing RDN services exist. Reimbursement for services is essential. Major medical and health organizations have provided support for the essential role of MNT and RDNs for the prevention and treatment of type 2 diabetes. PMID- 29389513 TI - Wnt Ligands as a Part of the Stem Cell Niche in the Intestine and the Liver. AB - The term "Wnt signaling" does not refer to one uniform signal transduction cascade. Instead, it describes the multiple discrete signals elicited by Wnt ligands following their interaction with distinct receptor complexes. The interaction of stem cells with niche cells is coordinated by the involvement of different signaling pathways, including Wnt signaling. The stem cell populations are highly sensitive to modulation of Wnt pathway activity. Wnt signaling is of paramount importance for stem cell self-renewal, survival, proliferation, differentiation, movement, and cell polarity. Aberrant activation of Wnt/beta catenin signaling is associated with the pathology of many types of cancer, such as colorectal cancer and hepatocellular carcinoma. Importantly, although often initiated by mutation(s) downstream of the Wnt-receptor complex, the progression of colorectal cancer still seems to be augmented by Wnt ligand-mediated signaling. This chapter focuses on the role of Wnt ligands in the intestine and the liver during homeostasis and cancer. PMID- 29389514 TI - Of Wnts and Ribosomes. AB - Wnt proteins are secreted glycoproteins that activate different intracellular signal transduction pathways. They regulate cell proliferation and are required for proper embryonic development. Misregulation of Wnt signaling can result in various diseases including cancer. In most circumstances, cell growth is essential for cell division and thus cell proliferation. Therefore, several reports have highlighted the key role of Wnt proteins for cell growth. Ribosomes represent the cellular protein synthesis machinery and cells need to be equipped with an appropriate number of ribosomes to allow cell growth. Recent findings suggest a role for Wnt proteins in regulating ribosome biogenesis and we here summarize these findings representing a previously unknown function of Wnt proteins. Understanding this role of Wnt signaling might open new avenues to slow down proliferation by drugs for instance in cancer therapy. PMID- 29389515 TI - Wnt Signaling in Skeletal Muscle Development and Regeneration. AB - Wnt is a family of signaling molecules involved in embryogenesis, adult tissue repair, and cancer. They activate canonical and noncanonical Wnt signaling cascades in target cells. Several studies, within the last decades, showed that several Wnt ligands are involved in myogenesis and both canonical and noncanonical Wnt pathways regulate muscle formation and the maintenance of adult tissue homeostasis. In this review, we provide a comprehensive overview of the roles of Wnt signaling during muscle development and an updated description of Wnt functions during muscle repair. Lastly, we discuss the crosstalk between Wnt and TGFbeta signaling pathways in skeletal muscle. PMID- 29389517 TI - Wnt Signaling in Stem Cells and Cancer Stem Cells: A Tale of Two Coactivators. AB - Wnt signaling in stem cells plays critical roles in development, normal adult physiology, and disease. In this chapter, we focus on the role of the Wnt signaling pathway in somatic stem cell biology and its critical role in normal tissue homeostasis and cancer. Wnt signaling can both maintain potency and initiate differentiation in somatic stem cells, depending on the cellular and environmental context. Based principally on studies from our lab, we will explain the dichotomous behavior of this signaling pathway in determining stem cell fate decisions, placing special emphasis on the interaction of beta-catenin with either of the two highly homologous Kat3 coactivator proteins, CBP and p300. We will also discuss our results, both preclinical and clinical, demonstrating that small molecule modulators of the beta-catenin/Kat3 coactivator interaction can be safely utilized to shift the balance between maintenance of potency and initiation of differentiation. PMID- 29389518 TI - Wnt Signaling in Adult Epithelial Stem Cells and Cancer. AB - Wnt/beta-catenin signaling is integral to the homeostasis and regeneration of many epithelial tissues due to its critical role in adult stem cell regulation. It is also implicated in many epithelial cancers, with mutations in core pathway components frequently present in patient tumors. In this chapter, we discuss the roles of Wnt/beta-catenin signaling and Wnt-regulated stem cells in homeostatic, regenerative and cancer contexts of the intestines, stomach, skin, and liver. We also examine the sources of Wnt ligands that form part of the stem cell niche. Despite the diversity in characteristics of various tissue stem cells, the role(s) of Wnt/beta-catenin signaling is generally coherent in maintaining stem cell fate and/or promoting proliferation. It is also likely to play similar roles in cancer stem cells, making the pathway a salient therapeutic target for cancer. While promising progress is being made in the field, deeper understanding of the functions and signaling mechanisms of the pathway in individual epithelial tissues will expedite efforts to modulate Wnt/beta-catenin signaling in cancer treatment and tissue regeneration. PMID- 29389519 TI - Chemical Modulation of WNT Signaling in Cancer. AB - Genetically based observations stemming from defects in development and in regeneration form the foundation of our understanding regarding how the secreted WNT proteins control coordinated cell fate decision-making in adult tissues. At the same time, our anticipation of potential benefits and unwanted toxicities associated with candidate anticancer agents targeting WNT signal transduction are also reliant upon this blueprint of WNT-associated physiology. Despite the long established role of WNT signaling in cancer, the emergence of WNT signaling as a suppressor of immunological attack in melanoma reveals an unanticipated anticancer potential in targeting WNT signaling. Here we review the literature associated with WNT signaling in cancer and discuss potential challenges that may be associated with the chemical attack of this important cellular process in achieving therapeutic goals. Although a number of small molecules targeting WNT signaling are introduced here, we center our discussion on antagonists of the WNT acyltransferase porcupine (PORCN) given the recent entry of two candidate molecules in clinical testing. PMID- 29389520 TI - The Wnt Signaling Landscape of Mammary Stem Cells and Breast Tumors. AB - Attention has been focused on Wnt signaling in the mouse mammary gland for several decades, firstly by the discovery of several Wnt loci among the oncogenes revealed by MMTV-based insertional mutagenesis screening of mouse mammary gland, and then by the remarkable visualization of Wnt-dependent specification of mammary placodes in embryonic skin. This review aims to summarize the impact of recent data for our understanding of the roles of Wnt signaling in these roles. The amount and identity of both familiar and novel Wnt signaling components is examined for mouse mammary epithelial cells. The hierarchical arrangement of mammary epithelial cell progenitors and stem cells inferred from the study of isolated cells is reinterpreted in an era that has demonstrated almost limitless cellular plasticity. Functional definitions of stem and progenitor activities are reevaluated with the discovery of novel stem cell activities and regulators, and we draw parallels with the arrangement of replication-competent cells in other tissues. Although Wnt signaling is highly oncogenic for mouse mammary epithelia, the data supporting Wnt signaling as a tumor driver for human breast cancer are still flimsy, and there is little support for the recruitment of normal Wnt dependent breast stem cells as tumor precursor cells for either mouse or human. We discuss possible explanations for this paradox and questions still unanswered, including the potential impact of recent discoveries of Wnt-secreting microenvironments, oncogenic changes in the Rspo/Lgr/Ubiquitin ligase amplifier complex, as they could apply to breast tissues, and the feedback suppression of Wnt signaling that characterizes its developmental activity and may hide Wnt signatures in tumors. PMID- 29389516 TI - Wnt Signaling in Kidney Development and Disease. AB - Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, beta catenin-dependent and noncanonical, beta-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/beta-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients. PMID- 29389521 TI - The Central Role of Wnt Signaling and Organoid Technology in Personalizing Anticancer Therapy. AB - The Wnt pathway is at the heart of organoid technology, which is set to revolutionize the cancer field. We can now predetermine a patient's response to any given anticancer therapy by exposing tumor organoids established from the patient's own tumor. This cutting-edge biomedical platform translates to patients being treated with the correct drug at the correct dose from the outset, a truly personalized and precise medical approach. A high throughput drug screen on organoids also allows drugs to be tested in limitless combinations. More recently, the tumor cells that are resistant to the therapy given to a patient were selected in culture using the patient's organoids. The resistant tumor organoids were then screened empirically to identify drugs that will kill the resistant cells. This information allows diagnosis in real-time to either prevent tumor recurrence or effectively treat the recurring tumor. Furthermore, the ability to culture stem cell-derived epithelium as organoids has enabled us to begin to understand how a stem cell becomes a cancer cell or to pin-point the genetic alteration that underlies a given genetic syndrome. Here we summarize these advances and the central role of Wnt signaling, and identify the next challenges for organoid technology. PMID- 29389523 TI - Wnt Signaling in the Central Nervous System: New Insights in Health and Disease. AB - Since its discovery, Wnt signaling has been shown to be one of the most crucial morphogens in development and during the maturation of central nervous system. Its action is relevant during the establishment and maintenance of synaptic structure and neuronal function. In this chapter, we will discuss the most recent evidence on these aspects, and we will explore the evidence that involves Wnt signaling on other less known functions, such as in adult neurogenesis, in the generation of oscillatory neural rhythms, and in adult behavior. The dysfunction of Wnt signaling at different levels will be also discussed, in particular in those aspects that have been found to be linked with several neurodegenerative diseases and neurological disorders. Finally, we will address the possibility of Wnt signaling manipulation to treat those pathophysiological aspects. PMID- 29389524 TI - Preface. PMID- 29389525 TI - "International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017": Will this pull us up out of the quagmire of confusing definitions and criteria? PMID- 29389522 TI - Wnt Signaling in Hematological Malignancies. AB - Leukemia and lymphoma are a wide encompassing term for a diverse set of blood malignancies that affect people of all ages and result in approximately 23,000 deaths in the United States per year (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Hematopoietic stem cells (HSCs) are tissue-specific stem cells at the apex of the hierarchy that gives rise to all of the terminally differentiated blood cells, through progressively restricted progenitor populations, a process that is known to be Wnt-responsive. In particular, the progenitor populations are subject to uncontrolled expansion during oncogenic processes, namely the common myeloid progenitor and common lymphoid progenitor, as well as the myeloblast and lymphoblast. Unregulated growth of these cell-types leads to mainly three types of blood cancers (i.e., leukemia, lymphoma, and myeloma), which frequently exhibit deregulation of the Wnt signaling pathway. Generally, leukemia is caused by the expansion of myeloid progenitors, leading to an overproduction of white blood cells; as such, patients are unable to make sufficient numbers of red blood cells and platelets. Likewise, an overproduction of lymphocytes leads to clogging of the lymph system and impairment of the immune system in lymphomas. Finally, cancer of the plasma cells in the blood is called myeloma, which also leads to immune system failure. Within each of these three types of blood cancers, there are multiple subtypes, usually characterized by their timeline of onset and their cell type of origin. Of these, 85% of leukemias are encompassed by the four most common diseases, that is, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL); AML accounts for the majority of leukemia-related deaths (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Through understanding how HSCs are normally developed and maintained, we can understand how the normal functions of these pathways are disrupted during blood cancer progression; the Wnt pathway is important in regulation of both normal and malignant hematopoiesis. In this chapter, we will discuss the role of Wnt signaling in normal and aberrant hematopoiesis. Our understanding the relationship between Wnt and HSCs will provide novel insights into therapeutic targets. PMID- 29389526 TI - Are we ready for a quality revolution? PMID- 29389527 TI - Crunching health expenditure numbers: important but treacherous terrain. PMID- 29389528 TI - Quality of care for paediatric admissions: is a score-based approach viable? PMID- 29389529 TI - Tranexamic acid for postpartum haemorrhage: a major advance. PMID- 29389530 TI - Indigenous languages and global health. PMID- 29389531 TI - The complexity of biological events. PMID- 29389532 TI - Malaria innovations: pursuing value in an evolving market. PMID- 29389533 TI - Does immunity after Zika virus infection cross-protect against dengue? PMID- 29389534 TI - Authorship trends in The Lancet Global Health. PMID- 29389536 TI - Pakistan's slow progress towards gender parity. PMID- 29389535 TI - How feasible is pharmaceutical regulation in India? PMID- 29389537 TI - Equitable access to global health internships: a documentary short. PMID- 29389538 TI - Mental health nurses and disaster response in Sierra Leone. PMID- 29389539 TI - Correction to Lancet Glob Health 2018; 6: e84-94. PMID- 29389540 TI - Correction to Lancet Glob Health 2018; 6: e34. PMID- 29389541 TI - Association of the Paediatric Admission Quality of Care score with mortality in Kenyan hospitals: a validation study. AB - BACKGROUND: Measuring the quality of hospital admission care is essential to ensure that standards of practice are met and continuously improved to reduce morbidity and mortality associated with the illnesses most responsible for inpatient deaths. The Paediatric Admission Quality of Care (PAQC) score is a tool for measuring adherence to guidelines for children admitted with acute illnesses in a low-income setting. We aimed to explore the external and criterion-related validity of the PAQC score by investigating its association with mortality using data drawn from a diverse sample of Kenyan hospitals. METHODS: We identified children admitted to Kenyan hospitals for treatment of malaria, pneumonia, diarrhoea, or dehydration from datasets from three sources: an observational study, a clinical trial, and a national cross-sectional survey. We extracted variables describing the process of care provided to patients at admission and their eventual outcomes from these data. We applied the PAQC scoring algorithm to the data to obtain a quality-of-care score for each child. We assessed external validity of the PAQC score by its systematic replication in datasets that had not been previously used to investigate properties of the PAQC score. We assessed criterion-related validity by using hierarchical logistic regression to estimate the association between PAQC score and the outcome of mortality, adjusting for other factors thought to be predictive of the outcome or responsible for heterogeneity in quality of care. FINDINGS: We found 19 065 eligible admissions in the three validation datasets that covered 27 hospitals, of which 12 969 (68%) were complete cases. Greater guideline adherence, corresponding to higher PAQC scores, was associated with a reduction in odds of death across the three datasets, ranging between 9% (odds ratio 0.91, 95% CI 0.84-0.99; p=0.031) and 30% (0.70, 0.63-0.78; p<0.0001) adjusted reduction per unit increase in the PAQC score, with a pooled estimate of 17% (0.83, 0.78-0.89; p<0.0001). These findings were consistent with a multiple imputation analysis that used information from all observations in the combined dataset. INTERPRETATION: The PAQC score, designed as an index of the technical quality of care for the three commonest causes of admission in children, is also associated with mortality. This finding suggests that it could be a meaningful summary measure of the quality of care for common inpatient conditions and supports a link between process quality and outcome. It might have potential for application in low-income countries with similar disease profiles and in which paediatric practice recommendations are based on WHO guidelines. FUNDING: The Wellcome Trust. PMID- 29389543 TI - Studies on prevention of obesity, metabolic syndrome, diabetes, cardiovascular diseases and cancer by tea. AB - Tea, a popular beverage made from leaves of the plant Camellia sinensis, has been studied extensively in recent decades for its beneficial health effects in the prevention of obesity, metabolic syndrome, diabetes, cancer, and other diseases. Whereas these beneficial effects have been convincingly demonstrated in most laboratory studies, results from human studies have not been consistent. Some studies demonstrated that weight reduction, alleviation of metabolic syndrome and risk reduction in diabetes were only observed in individuals who consume 3-4 cups of tea (600-900 mg tea catechins) or more daily. This chapter reviews some of these studies, the possible mechanisms of actions of tea constituents, and the challenges in extrapolating laboratory studies to human situations. PMID- 29389542 TI - Tranexamic acid for treatment of women with post-partum haemorrhage in Nigeria and Pakistan: a cost-effectiveness analysis of data from the WOMAN trial. AB - BACKGROUND: Sub-Saharan Africa and southern Asia account for almost 85% of global maternal deaths from post-partum haemorrhage. Early administration of tranexamic acid, within 3 h of giving birth, was shown to reduce the risk of death due to bleeding in women with post-partum haemorrhage in the World Maternal Antifibrinolytic (WOMAN) trial. We aimed to assess the cost-effectiveness of early administration of tranexamic acid for treatment of post-partum haemorrhage. METHODS: For this economic evaluation we developed a decision model to assess the cost-effectiveness of the addition of tranexamic acid to usual care for treatment of women with post-partum haemorrhage in Nigeria and Pakistan. We used data from the WOMAN trial to inform model parameters, supplemented by estimates from the literature. We estimated costs (calculated in 2016 US$), life-years, and quality adjusted life-years (QALYs) with and without tranexamic acid, calculated incremental cost-effectiveness ratios (ICERs), and compared these to threshold values in each country. Costs were assessed from the health-care provider perspective and discounted at 3% per year in the base case analysis. We did a series of one-way sensitivity analyses and probabilistic sensitivity analysis to assess the robustness of the results to parameter uncertainty. FINDINGS: Early treatment of post-partum haemorrhage with tranexamic acid generated an average gain of 0.18 QALYs at an additional cost of $37.12 per patient in Nigeria and an average gain of 0.08 QALYs at an additional cost of $6.55 per patient in Pakistan. The base case ICER results were $208 per QALY in Nigeria and $83 per QALY in Pakistan. These ICERs were below the lower bound of the cost effectiveness threshold range in both countries. The ICERs were most sensitive to uncertainty in parameter inputs for the relative risk of death due to bleeding with tranexamic acid, the discount rate, the cost of the drug, and the baseline probability of death due to bleeding. INTERPRETATION: Early treatment of post partum haemorrhage with tranexamic acid is highly cost-effective in Nigeria and Pakistan, and is likely to be cost-effective in countries in sub-Saharan Africa and southern Asia with a similar baseline risk of death due to bleeding. FUNDING: London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation. PMID- 29389544 TI - Convenient isolation of strictinin-rich tea polyphenol from Chinese green tea extract by zirconium phosphate. AB - Zirconium phosphate (ZrP) was prepared and employed to separate strictinin-rich tea polyphenol from Chinese green tea extracts. The influences of ZrP calcination temperatures, green tea extraction conditions, and the amounts of ZrP on the isolation of strictinin-rich tea polyphenol were evaluated; the absorption and desorption dynamics of strictinin on ZrP were also determined. Our results revealed that the HPLC content of strictinin increased from 4.96% in 70% ethanol extract of green tea to 58.2% in isolated strictinin-rich tea polyphenol obtained by ZrP-900 (ZrP calcined at 900 degrees C). Furthermore, the suitable time for both strictinin absorption and desorption was 4 hours at 37 degrees C. The method developed here consisted of easy steps such as ZrP absorption, water washing, and 0.4% phosphoric acid solution desorption, which may facilitate the detection and isolation of strictinin from different samples. PMID- 29389545 TI - Fatty acid composition and antibacterial potential of Cassia tora (leaves and stem) collected from different geographic areas of India. AB - The comparative analysis of the fatty acid composition of Cassia tora (leaves and stem) was determined using gas chromatography-mass spectrometry. Twenty-seven fatty acids were identified in C. tora (leaves and stem) which was collected from three different geographical areas of India: Lucknow (Uttar Pradesh), Nainital (Uttarakhand), and Bhavnagar (Gujarat), coded as CT-1, CT-2, and CT-3, respectively. The gas chromatography-mass spectrometry analysis showed the presence of various saturated and unsaturated fatty acids. The major fatty acids found were palmitic acid, linoleic acid, linolenic acid, margaric acid, melissic acid, and behenic acid. The highest amounts of saturated fatty acids were found in leaves of C. tora collected from Bhavnagar (Gujarat) (60.7% +/- 0.5%). Thus, the study reveals that C. tora has a major amount of nutritionally important fatty acids, along with significant antimicrobial potential. Fatty acids play a significant role in the development of fat products with enhanced nutritional value and clinical application. Remarkable differences were found in the present study between fatty acid profiles of C. tora collected from different locations in India. To the best of our knowledge there is no previously reported comparative study of the fatty acids of C. tora. PMID- 29389546 TI - A comparative analysis for the volatile compounds of various Chinese dark teas using combinatory metabolomics and fungal solid-state fermentation. AB - A total of 98 compounds including 20 aldehydes, eight arenes, six acids, 17 alcohols, 13 ketones, nine esters, nine methoxyphenolics, three alkenes, seven alkanes, and six other components were tentatively identified in six Chinese dark teas (CDTs) using gas chromatography-mass spectrometry. Multivariate statistical analysis revealed that dark teas from Yunnan and Guangxi provinces could be classified into one group, and other CDTs belonged to the other cluster. The diagnostic volatile compounds being responsible for CDTs' discrimination were observed as (E,E)-2,4-decadienal, methoxyphenolics, geraniol, alpha-terpineol, 2,4-heptadienal, cis-jasmone, linalool oxides, and 2-nonenal. Furthermore, mature tea leaves were separately fermented using Eurotium cristatum and Aspergillus niger. The results showed that E. cristatum increased the contents of cis jasmone, alpha-terpineol, beta-ionone, nonanal, and 2-pentylfuran, whereas A. niger advanced the levels of geraniol, linalool oxides, 9,12-octadecadienoic acid, and beta-ionone after short-term fermentation. Fungus species may contribute to forming the flavor of Chinese dark teas by affecting the volatile compounds during postfermentation. PMID- 29389547 TI - Nutritional composition in the chia seed and its processing properties on restructured ham-like products. AB - Low-fat meat products always have harder texture, lower juiciness, and worse flavor. Due to their higher water-holding, water absorption, and organic molecule absorption, chia seeds (CHIA) have been applied in powders, nutrition bars, breads, and cookies. Hence, the objectives of this study were to: (1) analyze the nutritional compositions in CHIA; and (2) look for the possible application of CHIA on restructured ham-like products. CHIA has high amounts of alpha-linolenic acid, crude polysaccharides, and also contains essential amino acids, minerals, and polyphenols. Regarding processing properties of CHIA, a combination of CHIA and carrageenan (CA) increased (p<0.05) production yield of restructured ham-like products. A scanning electron microscope observation indicated that CHIA and CA addition can assist an emulsification in this ham-like product. Addition of 0.5% CA and 1.0% CHIA in this ham-like product showed the similar overall acceptance as products with added fat. Following storage at 4 degrees C, higher (p<0.05) purge and centrifugation losses, as well as hardness of this ham-like product can be improved by adding CHIA and CA. CHIA addition also resulted in lower (p<0.05) lipid and protein oxidation, especially a 1.0% addition. In summary, due to both nutritional addition and improvements on physicochemical and sensorial properties of restructured ham-like products, CHIA seeds have great potential on the development of healthy and good-quality meat products. PMID- 29389548 TI - Optimal conditions for cordycepin production in surface liquid-cultured Cordyceps militaris treated with porcine liver extracts for suppression of oral cancer. AB - Cordycepin is one of the most crucial bioactive compounds produced by Cordyceps militaris and has exhibited antitumor activity in various cancers. However, industrial production of large amounts of cordycepin is difficult. The porcine liver is abundant in proteins, vitamins, and adenosine, and these ingredients may increase cordycepin production and bioconversion during C. militaris fermentation. We observed that porcine liver extracts increased cordycepin production. In addition, air supply (2 h/d) significantly increased the cordycepin level in surface liquid-cultured C. militaris after 14 days. Moreover, blue light light-emitting diode irradiation (16 h/d) increased cordycepin production. These findings indicated that these conditions are suitable for increasing cordycepin production. We used these conditions to obtain water extract from the mycelia of surface liquid-cultured C. militaris (WECM) and evaluated the anti-oral cancer activity of this extract in vitro and in vivo. The results revealed that WECM inhibited the cell viability of SCC-4 oral cancer cells and arrested the cell cycle in the G2/M phase. Oxidative stress and mitochondrial dysfunction (mitochondrial fission) were observed in SCC-4 cells treated with WECM for 12 hours. Furthermore, WECM reduced tumor formation in 7,12 dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis through the downregulation of proliferating cell nuclear antigen, vascular endothelial growth factor, and c-fos expression. The results indicated that porcine liver extracts irradiated with blue light light-emitting diode and supplied with air can be used as a suitable medium for the growth of mycelia and production of cordycepin, which can be used in the treatment of oral cancer. PMID- 29389549 TI - Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues. AB - Stem cell products and its clinical applications have been widely discussed in recent years, particularly when the Japanese "induced pluripotent stem cells" founder Dr. Yamanaka was awarded as Nobel Prize laureate in 2013. For decades, major progresses have been achieved in the stem cell biology field, and more and more evidence showed that skin stem cells are involved in the process of skin repair. Stem/progenitor cells of the epidermis are recognized to play the most essential role in the tissue regeneration of skin. In this review, we first illustrated basic stem cell characteristics and various stem cell subtypes resided in the skin. Second, we provided several literatures to elucidate how stem/progenitor cells collaborate in the process of skin repair with the evidence from animal model studies and in vitro experiments. Third, we also introduced several examples of skin cell products on the pharmaceutic market and the ongoing clinical trials aiming for unmet medical difficulties of skin. Last but not least, we summarized general reviewing concerns and some disputatious issues on dermatological cell products. With this concise review, we hope to provide further beneficial suggestions for the development of more effective and safer dermatological stem/progenitor cell products in the future. PMID- 29389550 TI - Vegetable, fruit, and phytonutrient consumption patterns in Taiwan. AB - Phytonutrients may play important roles in human health and yet only recently a few studies have described phytonutrient consumption patterns, using data obtained from daily consumption methods. We aimed to estimate the phytonutrient content in Taiwanese diets and analyzed main food sources of 10 major phytonutrients. In this study, food items and dietary data gathered with the 24 hour dietary recall from 2908 participants in the 2005-2008 Nutrition and Health Survey in Taiwan were used to create a food phytonutrient database with 933 plant based foods through integrating database, literature search, and chemical analysis and to appraise phytonutrient consumption status of participants. SUDAAN (Survey Data Analysis) was used for generating weighted phytonutrient intake estimates and for statistical testing. In Taiwanese adults, ~20% met the recommended number of servings for fruits and 30% met that for vegetables from the Taiwan Food-Guide recommendations. However, only 7.4% consumed the recommended numbers for both fruits and vegetables. Those meeting the recommendations tended to be older and with more females compared with those who did not. Phytonutrient intake levels were higher in meeters than nonmeeters. More than 60% of alpha-carotene, lycopene, hesperetin, epigallocatechin 3-gallate, and isoflavones came from a single phytonutrient-specific food source. In addition, sweet potato leaf, spinach, and water spinach were among the top three sources of multiple phytonutrients. Cross-comparison between this study and two previous studies with similar methodology showed higher mean levels of lycopene and quercetin in the United States, anthocyanidins in Korea, and lutein and zeaxanthin in Taiwan. The Taiwanese phytonutrient pattern is different from that of the Korean and American. It would be interesting to relate phytonutrient patterns to health profiles in the future. PMID- 29389551 TI - Hypocholesterolemic activity of indigenous probiotic isolate Saccharomyces cerevisiae ARDMC1 in a rat model. AB - The aim of this study was to investigate probiotic attributes of Saccharomyces cerevisiae ARDMC1 isolated from traditional rice beer starter cake and its hypocholesterolemic effects on Wistar rats fed a high-cholesterol diet. The indigenous isolate ARDMC1 showed potential probiotic characteristics such as tolerance to simulated gastrointestinal stress conditions, autoaggregation properties, and adhesion to intestinal epithelium Caco-2 cell line. In addition, ARDMC1 isolate exhibited in vitro cholesterol assimilation properties in media supplemented with cholesterol. Furthermore, administration of probiotic isolate to rats fed a hypercholesterolemic diet resulted in significant reduction of serum total cholesterol, low-density lipoprotein cholesterol, and triglyceride at the end of 42 days. The present study envisages ARDMC1 as a promising starter culture for the preparation of functional foods with properties to combat cardiovascular diseases. PMID- 29389552 TI - Characterization of an extracellular beta-glucosidase from Dekkera bruxellensis for resveratrol production. AB - Polygonum cuspidatum is a widely grown crop with a rich source of polydatin (also called piceid) for resveratrol production. Resveratrol is produced from piceid via enzymatic cleavage of the sugar moiety of piceid. In this study, Dekkera bruxellensis mutants were selected based on their high p-nitrophenyl-beta-d glucopyranoside and piceid conversion activities. The enzyme responsible for piceid conversion was a heterodimeric protein complex that was predominantly secreted to the extracellular medium and consisted of two subunits at an equal ratio with molecular masses of 30.5 kDa and 48.3 kDa. The two subunits were identified as SCW4p and glucan-beta-glucosidase precursor in D. bruxellensis. Both proteins were individually expressed in Saccharomyces cerevisiae exg1Delta mutants, which lack extracellular beta-glucosidase activity, to confirm each protein's enzymatic activities. Only the glucan-beta-glucosidase precursor was shown to be a secretory protein with piceid deglycosylation activity. Our pilot experiments of piceid bioconversion demonstrate the possible industrial applications for this glucan-beta-glucosidase precursor in the future. PMID- 29389553 TI - Protective effect of Nelumbo nucifera extracts on beta amyloid protein induced apoptosis in PC12 cells, in vitro model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly. beta-Amyloid (Abeta) has been proposed to play a role in the pathogenesis of AD. Deposits of insoluble Abeta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease, but the underlying signaling pathways are poorly understood. In order to develop antidementia agents with potential therapeutic value, we examined the inhibitory effect of the Nelumbo nucifera seed embryo extracts on to the aggregated amyloid beta peptide (agg Abeta1-40)-induced damage of differentiated PC-12 cells (dPC-12), a well-known cell model for AD. In the present study, seed embryos of N. nucifera were extracted with 70% methanol in water and then separated into hexane, ethyl acetate, n-butanol, and water layers. Among them, only the n-butanol layer showed strong activity and was therefore subjected to separation on Sephadex LH-20 chromatography. Two fractions showing potent activity were found to significantly inhibit Abeta1-40 toxicity on dPC-12 cells in increasing order of concentration (10-50 MUg/mL). Further purification and characterization of these active fractions identified them to be flavonoids such as rutin, orientin, isoorientin, isoquercetrin, and hyperoside. 2,2-Diphenyl-1-picrylhydrazyl hydrate scavenging activity of the extracts was also carried out to ascertain the possible mechanism of the activity. PMID- 29389554 TI - Antioxidant activity and anticancer effect of ethanolic and aqueous extracts of the roots of Ficus beecheyana and their phenolic components. AB - This study aimed to investigate the antioxidant and anticancer effects of ethanolic and aqueous extracts of the roots of Ficus beecheyana (EERFB and AERFB) and their phenolic components. In this study, total phenolic content and antioxidant activity of EERFB were higher than those of AERFB. Major phenolic compounds in the extracts were gallic acid, p-hydroxybenzoic acid, caffeic acid, chlorogenic acid, p-coumaric acid, and rutin; which were identified by high performance liquid chromatography. Flow cytometric analysis of HL-60 cells exposed to EERFB showed that the percentage of apoptotic cells increased in a dose-dependent manner. EERFB treatment resulted in the loss of mitochondrial membrane potential and induced the apoptosis of HL-60 cells through a Fas- and mitochondrial-mediated pathway. Finally, pretreatment with general caspase-9/-3 inhibitors prevented EERFB from inhibiting cell viability in HL-60 cells. Our finding suggests that EERFB is an agent that may have antioxidant activity and inhibit the growth of cancer cells. PMID- 29389555 TI - Composition of phenolic compounds and antioxidant attributes of Cyclea gracillima Diels extracts. AB - Cyclea gracillima Diels is a Taiwanese native medicinal herb. However, there are currently few relevant reports on its biochemical activity. In this study, the antioxidant attributes of the ethanol and hot water extracts of this herb were assayed using in vitro models, including the following: 2,2-diphenyl-1-(2,4,6 trinitrophenyl)-hydrazyl radical scavenging, Trolox equivalent antioxidant capacity, reducing power, and chelating ferrous ions. The following biochemical models were also assayed: inhibition of human low density lipoprotein oxidation, inhibition of human erythrocyte hemolysis, and scavenging oxygen radicals in human blood. The composition and content of flavonoids and phenolic acids in these extracts were also analyzed. The results showed that these extracts with high polyphenol levels presented remarkable antioxidant effects in all assays, especially when extracted with ethanol. Six phenolic acids (mainly ferulic acid, sinapic acid, and syringic acid) and 12 flavonoids (mainly narigenin, myricetin, naringin, and apigenin) were found in these extracts. PMID- 29389556 TI - The effects of Ficus carica on the activity of enzymes related to metabolic syndrome. AB - The present study aimed to investigate the effects of the various parts of Ficus carica L. (figs) on antioxidant, antidiabetic, and antiobesogenic effects in vitro. Fruit, leaves, and stembark of the F. carica plant were sequentially extracted using organic and inorganic solvents and their total polyphenol and flavonoid contents were estimated. The effects of the extracts on antioxidative, antidiabetic (inhibition of alpha-amylase and alpha-glucosidase enzymes), and antiobesogenic (antilipase) activities were measured using several experimental models. The fruit ethanolic extract contained a high quantity of polyphenols and flavonoids (104.67+/-5.51 MUg/mL and 81.67+/-4.00 MUg/mL) compared with all other extracts. The activity of the ethanolic extract of F. carica fruit was significantly (p<0.05) higher than all other extracts and parts of the plant in terms of antioxidative, antidiabetic, and antiobesogenic effects. The IC50 values of the fruit ethanolic extract in terms of antioxidative (134.44+/-18.43 MUg/mL), and inhibition of alpha-glucosidase (255.57+/-36.46 MUg/mL), alpha-amylase (315.89+/-3.83 MUg/mL), and pancreatic lipase (230.475+/-9.65 MUg/mL) activity indicate that the activity of fruit ethanolic extract is better than all other extracts of the plant. The gas chromatography-mass spectroscopy analysis of the fruit ethanolic extract showed the presence of a number of bioactive compounds such as butyl butyrate, 5-hydroxymethyl furfural, 1-butoxy-1-isobutoxy butane, malic acid, tetradecanoic acid, phytol acetate, trans phytol, n-hexadecanoic acid, 9Z,12Z-octadecadienoic acid, stearic acid, sitosterol, 3,5-dihydroxy-6 methyl-2,3-dihydro-4H-pyran-4-one, and 2,4,5-trimethyl-2,4-dihydro-3H-pyrazol-3 one. The results of this study suggest that the ethanolic extract of the fruit of F. carica may have potential antidiabetic and antiobesogenic agents. PMID- 29389557 TI - A novel protein from edible fungi Cordyceps militaris that induces apoptosis. AB - Cordyceps militaris is a dietary therapeutic fungus that is an important model species in Cordyceps research. In this study, we purified a novel protein from the fruit bodies of C. militaris and designated it as Cordyceps militaris protein (CMP). CMP has a molecular mass of 18.0 kDa and is not glycosylated. Interestingly, CMP inhibited cell viability in murine primary cells and other cell lines in a time- and dose-dependent manner. Using trypan blue staining and a lactate dehydrogenase release assay, we showed that CMP caused cell death in the murine hepatoma cell line BNL 1MEA.7R.1. Furthermore, the frequency of BNL 1MEA.7R.1 cells at the sub-G1 stage was increased by CMP. Apoptosis, as determined by Annexin V and propidium iodide analysis, indicated that CMP could mediate BNL 1MEA.7R.1 apoptosis, but not necrosis. After coincubation with CMP, a decrease in mitochondria potential was detected using 3,3'-dihexyloxacarbocyanine iodide. These results suggest that CMP is a harmful protein that induces apoptosis through a mitochondrion-dependent pathway. Stability experiments demonstrated that heat treatment and alkalization degraded CMP and further destroyed its cell-death-inducing ability, implying that cooking is necessary for food containing C. militaris. PMID- 29389558 TI - Anti-inflammatory effect of cinnamaldehyde and linalool from the leaf essential oil of Cinnamomum osmophloeum Kanehira in endotoxin-induced mice. AB - Cinnamomum osmophloeum Kanehira is a Taiwan native plant that belongs to genus Cinnamomum and is also known as pseudocinnamomum or indigenous cinnamon. Its leaf is traditionally used by local people in cooking and as folk therapy. We previously demonstrated the chemical composition and anti-inflammatory effect of leaf essential oil of Cinnamomum osmophloeum Kanehira of linalool chemotype in streptozotocin-induced diabetic rats and on endotoxin-injected mice. The aim of the present study is to evaluate whether cinnamaldehyde and linalool the active anti-inflammatory compounds in leaf essential oil of Cinnamomum osmophloeum Kanehira. Before the injection of endotoxin, C57BL/6 mice of the experimental groups were administered cinnamaldehyde (0.45 or 0.9 mg/kg body weight) or linalool (2.6 or 5.2 mg/kg body weight), mice of the positive control group were administered the leaf essential oil (13 mg/kg body weight), and mice of the negative group were administered vehicle (corn oil, 4 mL/kg body weight) by gavage every other day for two weeks. All mice received endotoxin (i.p. 10 mg/mL/kg body weight) the next day after the final administration and were killed 12 h after the injection. Normal control mice were pretreated with vehicle followed by the injection with saline. None of the treatment found to affect body weight or food or water intake of mice before the injection of endotoxin. Cinnamaldehyde and linalool were found significantly reversed endotoxin-induced body weight loss and lymphoid organ enlargement compared with vehicle (P < 0.05). Both compounds also significantly lowered endotoxin-induced levels of peripheral nitrate/nitrite, interleukin (IL)-1beta, IL-18, tumor necrosis factor (TNF) alpha, interferon (IFN)-gamma, and High-mobility group box 1 protein (HMGB-1), and levels of nitrate/nitrite, IL-1beta, TNF-alpha, and IFN-gamma in spleen and mesenteric lymph nodes (MLNs) (P < 0.05). Endotoxin-induced expression of toll like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), myeloid differentiation protein 2 (MD2), Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and caspase-1 in spleen and mesenteric lymph nodes (MLNs) were inhibited by all tested doses of cinnamaldehyde and linalool (P < 0.05). Subsequently, the activation of nuclear factor (NF)-kappaB and the activity of caspase-1 in spleen and MLNs were also suppressed by these two compounds (P < 0.05). In addition, cinnamaldehyde and linalool at the dose equivalent to their corresponding content in the tested dose of the leaf essential oil, which was 0.9 mg/kg and 5.2 mg/kg, respectively, showed similar or slightly less inhibitory activity for most of these inflammatory parameters compared with that of the leaf essential oil. Our data confirmed the potential use of leaf essential oil of Cinnamomum osmophloeum Kanehira as an anti inflammatory natural product and provide evidence for cinnamaldehyde and linalool as two potent agents for prophylactic use in health problems associated with inflammations that being attributed to over-activated TLR4 and/or NLRP3 signaling pathways. PMID- 29389559 TI - The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter. AB - Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10 150 MUM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB 231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10-150 MUM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (alpha-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis. PMID- 29389560 TI - Selected essential oils inhibit key physiological enzymes and possess intracellular and extracellular antimelanogenic properties in vitro. AB - Essential oils (EOs) extracted from six medicinal herbs and food plants [Cinnamomum zeylanicum (CZ), Psiadia arguta (PA), Psiadia terebinthina (PT), Citrus grandis (CGp), Citrus hystrix (CH), and Citrus reticulata (CR)] were studied for any inhibitory potential against key physiological enzymes involved in diabetes (alpha-glucosidase), skin aging (collagenase and elastase), and neurodegenerative disorders (acetylcholinesterase). Kinetic studies of the active EOs on the aforementioned enzymes were determined using Lineweaver-Burk plots. The intracellular and extracellular antimelanogenic potential of the EOs were evaluated on B16F10 mouse melanocytes. CH and CR were found to significantly inhibit (2.476 +/- 0.13 MUg/mL and 3.636 +/- 0.10 MUg/mL, respectively) acetylcholinesterase, compared with galantamine (3.989 +/- 0.16 MUg/mL). CH inhibited collagenase (50% inhibitory concentration 28.71 +/- 0.16 MUg/mL) compared with the control (24.45 +/- 0.19 MUg/mL). The percentage inhibition in the elastase assay of CH was 63.21% compared to the positive control (75.09%). In addition, CH, CR, CGp, CZ, and PT were found to significantly inhibit alpha glucosidase (276.70 +/- 0.73 MUg/mL, 169.90 +/- 0.58 MUg/mL, 240.60 +/- 6.50 MUg/mL, 64.52 +/- 0.69 MUg/mL, and 313.0 +/- 5.0 MUg/mL, respectively), compared to acarbose (448.80 +/- 0.81 MUg/mL). Active EOs showed both uncompetitive and competitive types of inhibition. The EOs also inhibited intracellular (50% inhibitory concentration 15.92 +/- 1.06 MUg/mL, 23.75 +/- 4.47 MUg/mL, and 28.99 +/- 5.70 MUg/mL for CH, CR, and CGp, respectively) and extracellular (< 15.625 MUg/mL for CH, CR, CGp, and PT) melanin production when tested against B16F10 mouse melanocytes. Results from the present study tend to show that EOs extracted from these medicinal plants can inhibit key enzymes and may be potential candidates for cosmetic and pharmaceutical industries. PMID- 29389561 TI - Application of corona electrical discharge plasma on modifying the physicochemical properties of banana starch indigenous to Taiwan. AB - Corona electrical discharge (CED) belongs to an atmospheric pressure cold plasma. In this study, raw banana starch (indigenous to Taiwan), which contained resistant starch and amylose at a level of 58.4 g/100 g and 14.5 g/100 g, respectively, was treated by CED at 30 kV/cm, 40 kV/cm, and 50 kV/cm for 3 minutes. After the CED treatment, starch analyses showed that there were no apparent changes in the resistant starch and amylose contents. Only surface and nonpenetrative damage caused by plasma etching at different voltage strengths were observed on the starch granules. The CED treatments reduced the total area of diffraction peak, gelatinization enthalpy (by -21% to -38%), and different pasting behaviors including peak viscosity, breakdown, final viscosity, and setback. The CED treatments were capable of increasing relative crystallinity and gelatinization temperature. This study revealed the potential of CED plasma technology as a tool to modify the characteristics of banana starch. PMID- 29389562 TI - The inhibition of advanced glycation end-products by five fractions and three main flavonoids from Camellia nitidissima Chi flowers. AB - Camellia nitidissima Chi (CNC), belonging to Camellia genus (Theaceae family), is a medicinal and edible plant in China. Among the whole plant, the CNC flowers are especially precious, but the biological activities and the compositions of the CNC flowers are unknown. In this study, inhibiting effects on the formation of advanced glycation end-products (AGEs) of five CNC flowers fractions and three isolated compounds were investigated, these three compounds are two flavonoid glycosides and one flavanol, namely kaempferol 3-O-[2,3,4-Tri-O-acetyl-alpha-L rhamnopyranosyl-(1->3)-2,4-di-O-acetyl-alpha-L-rhamnopyranosyl-(1->6)]-beta-D glucopyranoside, kaempferol 3-O-[2,3,4-Tri-O-acetyl-alpha-L-rhamnopyranosyl-(1 >3)-4-O-acetyl-alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside and catechin. Among these five fractions, the ethyl acetate fraction showed the highest total phenolic contents and inhibiting effects on AGE formation. Bovine serum albumin (BSA)-glucose and BSA-methylglyoxal assay showed that the ethyl acetate fraction inhibited AGE formation by 74.49% and 34.3% at 1 mg/mL, respectively. As the main components, these three compounds also showed remarkable inhibiting effects on AGE formation by scavenging methylglyoxal, next two catechin-carbonyl adducts were identified using HPLC-ESI-MS/MS. The results showed that the CNC flowers had remarkable inhibiting effects on the formation of AGEs. The primary structure-activity relationship showed (1) the glycosides could reduce the inhibiting effects compared to kaempferol and (2) the acetyl at position 2''' in compound 1 had no remarkable influence of the inhibiting effects on AGE formation compared to compound 2. PMID- 29389563 TI - Non-destructive profiling of volatile organic compounds using HS-SPME/GC-MS and its application for the geographical discrimination of white rice. AB - The authenticity determination of white rice is crucial to prevent deceptive origin labeling and dishonest trading. However, a non-destructive and comprehensive method for rapidly discriminating the geographical origins of white rice between countries is still lacking. In the current study, we developed a volatile organic compound based geographical discrimination method using headspace solid-phase microextraction coupled to gas chromatography-mass spectrometry (HS-SPME/GC-MS) to discriminate rice samples from Korea and China. A partial least squares discriminant analysis (PLS-DA) model exhibited a good classification of white rice between Korea and China (accuracy = 0.958, goodness of fit = 0.937, goodness of prediction = 0.831, and permutation test p-value = 0.043). Combining the PLS-DA based feature selection with the differentially expressed features from the unpaired t-test and significance analysis of microarrays, 12 discriminatory biomarkers were found. Among them, hexanal and 1 hexanol have been previously known to be associated with the cultivation environment and storage conditions. Other hydrocarbon biomarkers are novel, and their impact on rice production and storage remains to be elucidated. In conclusion, our findings highlight the ability to rapidly discriminate white rice from Korea and China. The developed method maybe useful for the authenticity and quality control of white rice. PMID- 29389564 TI - Extended aroma extract dilution analysis profile of Shiikuwasha (Citrus depressa Hayata) pulp essential oil. AB - Shiikuwasha pulp is an important raw material for producing citrus essential oils. The volatile aroma composition of pulp essential oil was evaluated using gas chromatography (GC) methods, and its aroma profile was assessed using GC olfactometry with an extended aroma extract dilution analysis (AEDA) technique in regard to alterations of odor strength and sensorial perception throughout serial dilution steps. The essential oil comprised a mixture of 55 aroma compounds, including monoterpene hydrocarbon, sesquiterpene hydrocarbon, alcohol, aldehyde, ester, and oxide compounds. The predominant compounds were limonene [57.36% (4462.80 mg/100 g of pulp)] and gamma-terpinene [25.14% (1956.21 mg/100 g of pulp)]. However, linalool was identified as one of the key aroma components providing the highest flavor dilution factor in AEDA, whilst three sesquiterpene hydrocarbons (delta-elemene, germacrene B, and bicyclosesquiphellandrene) and two esters (heptyl acetate and decyl acetate) had superior relative flavor activities. The extended AEDA profile identified variations in assessed odor perceptions, intensity, and duration of aroma components over dilution, whereas the 12 most odor-active compounds showed comparable odor strengths. PMID- 29389565 TI - Rapid characterization of metabolites in soybean using ultra high performance liquid chromatography coupled with electrospray ionization quadrupole time-of flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) and screening for alpha glucosidase inhibitory and antioxidant properties through different solvent systems. AB - This work was the first to investigate on the simultaneous characterization of metabolite profiles in soybean using UPLC-ESI-Q-TOF-MS/MS. Twenty two compositions were observed within 14 min from the methanol extract and confirmed as twelve isoflavones of three types and ten soyasaponins (Ab, Af, I-III, alphag, betag, betaa, gammag, and gammaa). Moreover, the patterns of two chemicals showed considerable differences in seven solvent systems by HPLC analysis and their optimal extraction was achieved by 70% methanol (isoflavone: 4102.69 MUg/g; soyasaponin: ten peaks). The second abundant isoflavones were detected in 50% methanol (4054.39 MUg/g), followed by 30% methanol, 100% methanol, 10% methanol, CH2Cl2, and acetone extracts with 3134.03, 2979.49, 1681.33, 366.19, and 119.00 MUg/g, respectively. Soyasaponins exhibited similar tendencies as those of isoflavones. The highest total phenolic was found as 2.10 +/- 0.05 mg GAE/g in 70% methanol with remarkable differences by comparing other extracts. Specifically, this extract showed potent alpha-glucosidase inhibitory (81%) and antioxidant capacities (DPPH: 93% and ABTS: 95%) at a concentration of 1.0 mg/mL. Our results may be contributed to enhancing the value to functional foods and evaluating the secondary metabolites concern to antioxidant properties using solvent system in soybean. PMID- 29389566 TI - A novel poly (glycine) biosensor towards the detection of indigo carmine: A voltammetric study. AB - The electrochemical behavior of indigo carmine (IC) at poly (glycine) modified carbon paste electrode (PGMCPE) was investigated by cyclic and differential pulse voltammetry. The oxidation peak of IC was observed in phosphate buffer of pH 6.5. The influence of different pH, scan rate, and concentration were analyzed. The probable reaction mechanism involved in the oxidation of IC was also proposed. Results showed that PGMCPE a remarkable electrocatalytic activity for the oxidation of IC under optimal conditions. The electrocatalytic response of the sensor was proportional to the IC concentration in the range of (2 * 10-6-1 * 10 5 M) and (1.5 * 10-5-6 * 10-5 M) with a limit of detection 11 * 10-8 M and limit of quantification 3.6 * 10-7 M. The modified electrode demonstrated many advantages such as simple preparation, high sensitivity, low detection of limit, excellent catalytic activity, short response time, and remarkable antifouling property toward IC and its oxidation product. PMID- 29389567 TI - Determination of carnosic acid in Rosmarinus officinalis L. using square wave voltammetry and electrochemical behavior. AB - A new, fast, sensitive and simple voltammetric method is established for the direct determination of carnosic acid (CA). And the electroreduction of carnosic acid (CA) was studied using electrochemical methods. The number of electrons transferred in electrode mechanisms were calculated for reversible and adsorption controlled electrochemical reduction of CA at 17 mV versus Ag/AgCl at pH 7.0 in Britton-Robinson buffer (BR) on a hanging mercury drop electrode. Square-wave voltammetry was developed and validated for direct determination of CA. Square wave parameters were optimized as accumulation potential = 0.0 mV, accumulation time = 5 s, frequency = 50 Hz, pulse amplitude = 50 mV, and staircase step potential = 5 mV. The developed method displays three linear responses from 2 to 9 MUM, 10 to 30 and 40 to 90 MUM for carnosic acid with a correlation coefficient of 0.996, 0.999 and 0.999. The detection limits were found to be 1.5 MUM, 4.0 MUM and 40.1 MUM, respectively. The interference effect of most common organic and inorganic species was investigated. Proposed method was successfully applied for determination of CA in natural extract of rosemary and the average content was determined as 11.9 +/- 1.0 (MUg CA/1 g rosemary). The results were in agreement with that obtained by HPLC-UV comparison method. The developed method can be widely used in routine quality control of herbal materials as well as other in foods, medicinal, pharmaceutical and environmental analysis. PMID- 29389569 TI - Functional components in Scutellaria barbata D. Don with anti-inflammatory activity on RAW 264.7 cells. AB - The objectives of this study were to determine the variety and amount of various functional components in Scutellaria barbata D. Don as well as study their anti inflammatory activity on RAW 264.7 cells. Both ethanol and ethyl acetate extracts were shown to contain the functional components including phenolics, flavonoids, chlorophylls, and carotenoids, with the former mainly composed of phenolics and flavonoids, and the latter of carotenoids and chlorophylls. Both extracts could significantly inhibit (p < 0.05) the production of lipopolysaccharide-induced nitric oxide, prostaglandin E2, interlukin-6, and interlukin-1beta, as well as the expressions of phosphor extracellular signal-regulated kinase and phosphor-c Jun N-terminal kinase (p-JNK), but failed to retard tumor necrosis factor-alpha expression. Both ethanol and ethyl acetate extracts had a dose-dependent anti inflammatory activity on RAW 264.7 cells. Furthermore, the anti-inflammatory efficiency can be varied for both ethanol and ethyl acetate extracts, which can be attributed to the presence of different varieties and amounts of functional components, as mentioned above. This finding suggested that S. Barbata extract may be used as an anti-inflammatory agent for possible future biomedical application. PMID- 29389568 TI - Efficacy of protein rich pearl powder on antioxidant status in a randomized placebo-controlled trial. AB - Pearl is one of the well-known traditional Chinese medicine (TCM) prescribed for treating various skin and bone related disorders due to its abundant proteins and mineral contents. The present investigation focused on antioxidation and life span prolonging effects from different extracts of pearl powder. During in vitro studies, various oxidative indices were evaluated, along with lifespan-prolonging effect were checked using wild-type Caenorhabditis elegans. For the clinical trial, 20 healthy middle-aged subjects were recruited and separated into 2 groups as experimental and placebo group, who received 3 g of pearl powder/d (n = 10) and 3 g of placebo/d (n = 10) for 8 weeks, respectively. During the initial, 2nd, 4th, 6th, 8th and 10th weeks the blood samples were collected for biochemical analysis. The protein extract of pearl powder recorded maximum (p < 0.05) antioxidant activity (20-68%) as well as efficiently prolonged the life span of C. elegans by 18.87%. Pearl powder supplemented subjects showed a substantial increase (p < 0.05) in total antioxidant capacity from 0.45 to 0.69 mM, total thiols from 0.23 to 0.29 mM, Glutathione content from 5.89 to 9.19 MUM, enzymic antioxidant activity (SOD-1248 to 1308; Gpx-30 to 32; GR-2.4 to 2.9) as well as considerably suppressed the lipid peroxidation products from 4.95 to 3.27 MUM. The outcome of both in-vitro and in-vivo antioxidant activity inferred that protein extract of pearl powder was a potent antioxidant and thereby prolonged the lifespan of C. elegans. Hence, pearl powder could be recommended for treating various age-related degenerative disorders. PMID- 29389570 TI - Methods for efficient analysis of tocopherols, tocotrienols and their metabolites in animal samples with HPLC-EC. AB - Tocopherols and tocotrienols, collectively known as vitamin E, have received a great deal of attention because of their interesting biological activities. In the present study, we reexamined and improved previous methods of sample preparation and the conditions of high-performance liquid chromatography for more accurate quantification of tocopherols, tocotrienols and their major chain degradation metabolites. For the analysis of serum tocopherols/tocotrienols, we reconfirmed our method of mixing serum with ethanol followed by hexane extraction. For the analysis of tissue samples, we improved our methods by extracting tocopherols/tocotrienols directly from tissue homogenate with hexane. For the analysis of total amounts (conjugated and unconjugated forms) of side chain degradation metabolites, the samples need to be deconjugated by incubating with beta-glucuronidase and sulfatase; serum samples can be directly used for the incubation, whereas for tissue homogenates a pre-deproteination step is needed. The present methods are sensitive, convenient and are suitable for the determination of different forms of vitamin E and their metabolites in animal and human studies. Results from the analysis of serum, liver, kidney, lung and urine samples from mice that had been treated with mixtures of tocotrienols and tocopherols are presented as examples. PMID- 29389571 TI - Codissolution of calcium hydrogenphosphate and sodium hydrogencitrate in water. Spontaneous supersaturation of calcium citrate increasing calcium bioavailability. AB - The sparingly soluble calcium hydrogenphosphate dihydrate, co-dissolving in water during dissolution of freely soluble sodium hydrogencitrate sesquihydrate as caused by proton transfer from hydrogencitrate to hydrogenphosphate, was found to form homogenous solutions supersaturated by a factor up to 8 in calcium citrate tetrahydrate. A critical hydrogencitrate concentration for formation of homogeneous solutions was found to depend linearly on dissolved calcium hydrogenphosphate: [HCitr2-] = 14[CaHPO4] - 0.05 at 25 degrees C. The lag phase for precipitation of calcium citrate tetrahydrate, as identified from FT-IR spectra, from these spontaneously formed supersaturated solutions was several hours, and the time to reach solubility equilibrium was several days. Initial calcium ion activity was found to be almost independent of the degree of supersaturation as determined electrochemically. The supersaturated solutions had a pH around 4.7, and calcium binding to hydrogencitrate as the dominant citrate species during precipitation was found to be exothermic with a determined association constant of 357 L mol-1 at 25 degrees C for unit ionic strength, and DeltaH degrees = -22 +/- 2 kJ mol-1, DeltaS degrees = -26 +/- 8 J K-1 mol-1. Calcium binding to hydrogencitrate and, more importantly, to citrate is suggested to decrease the rate of precipitation by lowering the driving force of precipitation, and becoming important for the robust spontaneous supersaturation with perspectives for design of functional foods with increased calcium bioavailability. PMID- 29389572 TI - Metabolic profiling investigation of Fritillaria thunbergii Miq. by gas chromatography-mass spectrometry. AB - Thunberg fritillary bulb (the dry bulbs of Fritillaria thunbergii Miq.), a traditional Chinese Medicine, is widely applied as an expectorant and antitussive. In this investigation, the primary metabolites of bulbs, flowers, leaves, and stems of F. thunbergii were analyzed by gas chromatography-mass spectrometry. Principal component analysis, partial least squares-discriminate analysis, orthogonal projection to latent structures-discriminate analysis, and heat map analysis showed that there were dissimilar metabolites, and a negative correlation between amino acids and saccharides in different analytes. Furthermore, carbodiimide, tryptophan, glucose-6-phosphate, xylose, 2 piperidinecarboxylic acid, monoamidomalonic acid, phenylalanine, and histidine were found to play an important role in the plant metabolism net of F. thunbergii. PMID- 29389573 TI - Investigation of borneols sold in Taiwan by chiral gas chromatography. AB - Borneol is a monoterpene that is widely used in traditional Chinese medicine. There are two different products sold in Taipei's traditional Chinese medicine market, natural and chemically synthesized borneol. Chemically synthesized borneol contains four stereoisomers, (+)-isoborneol, (-)-isoborneol, (-)-borneol, and (+)-borneol. The ratio of these four isomers in chemically synthesized and natural borneol products was determined by gas chromatography mass spectrometry. A huge variation between these products is highlighted in this survey. The results suggest that the Food and Drug Administrations in Asian countries should establish a regulatory standard regarding the ratio of the four different borneol isomers in both natural and chemically synthesized borneol. PMID- 29389574 TI - Detection of lithospermate B in rat plasma at the nanogram level by LC/MS in multi reaction monitoring mode. AB - Low bioavailability and high binding affinity to plasma proteins led to the difficulty for the quantitative detection of lithospermate B (LSB) in plasma. This study aimed to develop a protocol for detecting LSB in plasma. A method was employed to quantitatively detect LSB of 5-500 ng/mL by LC/MS spectrometry in multi reaction monitoring mode via monitoring two major fragments with m/z values of 519 and 321 in the MS2 spectrum. To set up an adequate extraction solution to release LSB captured by plasma proteins, recovery yields of LSB extracted from rat plasma acidified by formic acid or HCl in the presence or absence of EDTA and caffeic acid were detected and compared using the above quantitative method. High recovery yield (~90%) was achieved when LSB (5-500 ng/mL) mixed in rat plasma was acidified by HCl (5 M) in the presence of EDTA (0.5 M) and caffeic acid (400 MUg/mL). The lower limit of detection and the lower limit of quantification for LSB in the spiked plasma were calculated to be 1.8 and 5.4 ng/mL, respectively. Good accuracy (within +/-10%) and precision (less than 10%) of intra- and inter day quality controlled samples were observed. Oral bioavailability of LSB in rat model was detected via this optimized extraction method, and the maximum plasma concentration (Cmax) was found to be 1034.3 +/- 510.5 MUg/L at tmax around 10 min, and the area under the plasma concentration-time curve (AUC) was 1414.1 +/- 851.2 MUg.h/L. PMID- 29389575 TI - Simultaneous determination of four amides in Saururus chinensis by matrix solid phase dispersion and high-performance liquid chromatography method. AB - A rapid and simple analytical method was established for the determination of four amides (N-p-trans-coumaroyltyramine, aristolactam AII, sauristolactam and aristolactam BII) in Saururus chinensis by matrix solid phase dispersion (MSPD) and high-performance liquid chromatography-diode array detector (HPLC-DAD). In the optimized MSPD, 0.2 g S. chinensis powder was blended with 0.4 g silica gel, and 5 mL methanol was selected as elution solvent. The MSPD extraction achieved higher extraction recovery of four amides, and required less sample, solvent and preparation time, comparing with the conventional methods (Soxhlet and ultrasonic extraction). The assay was performed on a TSK gel ODS-100Z column (4.6 mm * 250 mm, 5 MUm) at 30 degrees C. Acetonitrile and 0.4% acetic acid aqueous solution was used as mobile phase by gradient elution at the flow rate of 1.0 mL/min. The detection wavelength was 280 nm. All the analytes showed good linear regression (R2 >= 0.9998) within the concentration ranges. The validated method showed good precision and stability with relative standard deviations (RSDs) <= 3.18%. The recoveries were in the range of 96.57-99.65%, with RSDs less than 2.74%. PMID- 29389576 TI - Hepatoprotective effect of the ethanol extract of Polygonum orientale on carbon tetrachloride-induced acute liver injury in mice. AB - Polygonum orientale L. (Polygonaceae) fruits have various medicinal uses, but their hepatoprotective effects have not yet been studied. This study investigated the hepatoprotective activity of the ethanolic extract of P. orientale (POE) fruits against carbon tetrachloride (CCl4)-induced acute liver injury (ALI). Mice were pretreated with POE (0.1, 0.5, and 1.0 g/kg) or silymarin (0.2 g/kg) for 5 consecutive days and administered a dose of 0.175% CCl4 (ip) on the 5th day to induce ALI. Blood and liver samples were collected to measure antioxidative activity and cytokines. The bioactive components of POE were identified through high-performance liquid chromatography (HPLC). Acute toxicity testing indicated that the LD50 of POE exceeded 10 g/kg in mice. Mice pretreated with POE (0.5, 1.0 g/kg) experienced a significant reduction in their serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels and reduction in the extent of liver lesions. POE reduced the malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) levels, and increased the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in liver. HPLC revealed peaks at 11.28, 19.55, and 39.40 min for protocatechuic acid, taxifolin, and quercetin, respectively. In summary, the hepatoprotective effect of POE against CCl4-induced ALI was seemingly associated with its antioxidant and anti-proinflammatory activities. PMID- 29389577 TI - Urine specimen validity test for drug abuse testing in workplace and court settings. AB - In recent decades, urine drug testing in the workplace has become common in many countries in the world. There have been several studies concerning the use of the urine specimen validity test (SVT) for drug abuse testing administered in the workplace. However, very little data exists concerning the urine SVT on drug abuse tests from court specimens, including dilute, substituted, adulterated, and invalid tests. We investigated 21,696 submitted urine drug test samples for SVT from workplace and court settings in southern Taiwan over 5 years. All immunoassay screen-positive urine specimen drug tests were confirmed by gas chromatography/mass spectrometry. We found that the mean 5-year prevalence of tampering (dilute, substituted, or invalid tests) in urine specimens from the workplace and court settings were 1.09% and 3.81%, respectively. The mean 5-year percentage of dilute, substituted, and invalid urine specimens from the workplace were 89.2%, 6.8%, and 4.1%, respectively. The mean 5-year percentage of dilute, substituted, and invalid urine specimens from the court were 94.8%, 1.4%, and 3.8%, respectively. No adulterated cases were found among the workplace or court samples. The most common drug identified from the workplace specimens was amphetamine, followed by opiates. The most common drug identified from the court specimens was ketamine, followed by amphetamine. We suggest that all urine specimens taken for drug testing from both the workplace and court settings need to be tested for validity. PMID- 29389578 TI - A novel UV-photolysis approach with acetone and isopropyl alcohol for the rapid determination of fluoride in organofluorine-containing drugs by spectrophotometry. AB - A UV photolysis decomposition (UVPD) method for the determination of fluoride in fluorine containing pharmaceuticals by spectrophotometry is reported. It is based on the use of high intensity UV-irradiation in the presence of a digesting solution comprising a mixture of acetone and isopropanol. For the optimization of the UVPD procedure, three bulk drugs (levofloxacin, nebivolol and efavirenz) were chosen as representatives of three diverse compounds containing a single fluorine atom, two fluorine atoms, and trifluoromethyl groups respectively. Operational conditions of the UVPD method, such as concentration and volume of reagents (acetone and isopropyl alcohol), and UV irradiation time (1-6 minutes) were optimized. The efficiency of digestion was evaluated by the determination of fluoride in sample digests. Using the developed method, it was possible for complete conversion of the organofluoride to free fluoride ion for its subsequent determination by spectrophotometry based on bleaching of Zr-xylenol orange-color complex. Quantitative recovery (>98%) of the fluorine in the drug samples could be achieved using a mixture of 2% acetone + 2% isopropyl alcohol + 0.003% Na2CO3 in just 5 minutes of UV irradiation, which can be considered an important aspect considering the difficulties involved in the cleavage of the CF bond. Accuracy was evaluated by comparison of results obtained by the UVPD method with the values estimated using formula weight of the compound and no statistical difference was observed between the results. Therefore, the proposed method is suitable for application in routine analysis of fluoride in organofluorine containing drugs. PMID- 29389579 TI - A randomized, double-blind clinical study of the effects of Ankascin 568 plus on blood lipid regulation. AB - Hyperlipidemia and inflammation play important roles in the development and progression of atherosclerosis. Atherosclerosis is regarded as an inflammatory response of blood vessels to injury at the start of atherosclerotic plaque formation, which then leads to cardiovascular events. Edible fungi of the Monascus species have been used as traditional Chinese medicines in East Asia for several centuries. The fermented products of Monascus purpureus NTU 568 possess a number of functional secondary metabolites including the anti-inflammatory pigments monascin and ankaflavin. Compounds derived from M. purpureus have been shown to have hypolipidemic effects. We aimed to evaluate the effects of M. purpureus NTU 568 fermentation product an extract (Ankascin 568 plus) containing monascin and ankaflavin on blood lipids in volunteers with borderline high levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) by conducting a 12-week randomized, double-blind, placebo-controlled, adaptive design study. This study enrolled 40 subjects aged 18-65 years from a population of patients with TC and LDL-C levels of >=180 mg/dL and 130-190 mg/dL, respectively. Measured endpoints included lipid profile, liver, kidney and thyroid function, electrolyte balance, creatinine phosphokinase, and fasting blood glucose. After 4 weeks of treatment (500 mg Ankascin 568 plus/day), the changes in the lipid levels showed that the active products had a more favorable effect than the placebo. Compared to the baseline, statistically significant decreases of 11.9% and 19.0% were observed in TC and LDL-C levels, respectively (p < 0.05 for all pairs). This study demonstrated that subjects administered one 500 mg capsule of Ankascin 568 plus for more than 4 weeks exhibited a significant reduction in serum TC and LDL-C levels. Therefore, Ankascin 568 plus may be a potentially useful agent for the regulation of blood lipids and the treatment of coronary artery diseases. PMID- 29389580 TI - Development and validation of an LC-MS/MS method for quantification of NC-8 in rat plasma and its application to pharmacokinetic studies. AB - ent-16-Oxobeyeran-19-N-methylureido (NC-8) is a recently synthesized derivative of isosteviol that showed anti-hepatitis B virus (HBV) activity by disturbing replication and gene expression of the HBV and by inhibiting the host toll-like receptor 2/nuclear factor-kappaB signaling pathway. To study its pharmacokinetics as a part of the drug development process, a highly sensitive, rapid, and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for determining NC-8 in rat plasma. After protein precipitation extraction, the chromatographic separation of the analyte and internal standard (IS; diclofenac sodium) was performed on a reverse-phase Luna C18 column coupled with a Quattro Ultima triple quadruple mass spectrometer in the multiple-reaction monitoring mode using the transitions, m/z 347.31 -> 75.09 for NC-8 and m/z 295.89 -> 214.06 for the IS. The lower limit of quantitation was 0.5 ng/mL. The linear scope of the standard curve was between 0.5 and 500 ng/mL. Both the precision (coefficient of variation; %) and accuracy (relative error; %) were within acceptable criteria of <15%. Recoveries ranged from 104% to 113.4%, and the matrix effects (absolute) were non-significant (CV <= 6%). The validated method was successfully applied to investigate the pharmacokinetics of NC-8 in male Sprague-Dawley rats. The present methodology provides an analytical means to better understand the preliminary pharmacokinetics of NC-8 for investigations on further drug development. PMID- 29389581 TI - Study of forced degradation behavior of pramlintide acetate by HPLC and LC-MS. AB - Pramlintide acetate (Symlin(r)), a synthetic analogue of the human hormone amylin. It was approved in March 2005 as a subcutaneous injection for the adjunctive treatment of patients who have type 1 or 2 diabetes mellitus. The objective of current investigation was to study the degradation behavior of pramlintide acetate under different ICH recommended stress conditions by HPLC and LC-MS. Pramlintide acetate was subjected to stress conditions of hydrolysis (acidic or alkaline), oxidation, photolysis and thermal decomposition. Extensive degradation products were observed under the hydrolysis, oxidation or thermal stress conditions, while minimal degradation was found in the photolytic conditions. Successful separation of drug from the degradation products was achieved by the validated chromatography (RP-HPLC and SCX-HPLC) methods. Subsequent to isolation, the molecular weight of each component was determined by LC-MS. The LC-MS m/z values and fragmentation patterns of 4 impurities matched with the predicted degradation products of pramlintide acetate. PMID- 29389582 TI - Tea silkworm droppings as an enriched source of tea flavonoids. AB - Andraca droppings is the waste excreted from the tea biter Andraca theae. Its chemical constituents and potential medical use, unlike those of the traditional Chinese medicine silkworm droppings, have not been reported yet. To explore new nutraceuticals, the chemical constituents of this substance were investigated. Since the bioactive ingredients are generally present in the EtOAc-soluble fraction, this fraction, obtained from the ethanolic extract of the dried Andraca droppings by liquid-liquid partitioning, was separated by chromatographic methods, including Sephadex LH-20, centrifugal partition chromatography, and RP 18 columns, to produce 14 compounds (1-14). They were characterized as 1,7 dimethyl xanthine (1), three benzoic acids (2, 3, and 5), and 10 flavonoids (4, 6 14). The amount of compounds 6, 7, 10, 13, and 14 in the droppings were 1.7-15.5 fold compared to those of tea leaves. In addition, 1,7-dimethyl xanthine (1) was found present only in the Andraca droppings but absent in tea leaves. Therefore, except for compound 1, which might be transformed from caffeine by microflora in the insect, the compounds were believed not to be absorbed by the worm gut and excreted directly. The present study suggests the Andraca droppings are an enriched source of the bioactive flavonoids from tea leaves and are potential as a useful nutraceutical. PMID- 29389583 TI - Use of a Bayesian approach in the design and evaluation of NCE2s. AB - Taiwan's regulatory agency defines New Chemical Entity 2 (NCE2) as a compound drug that has been approved and marketed for ten years in a top-ten pharmaceutically-advanced country but which is new in Taiwan. To apply for registration of NCE2 in Taiwan, a clinical trial may be conducted in Taiwan to evaluate the efficacy and safety. Since the NCE2 has been approved in at least one of the top-ten pharmaceutically-advanced countries, we can borrow the information from all of the observed data from other countries to synthesize the data from both Taiwan and other countries to assess the NCE2 efficacy. In this paper, we propose a Bayesian approach that uses a mixture of prior information to help evaluate an NCE2's efficacy. Numerical examples illustrate applications of the proposed approach in different scenarios. A method for sample-size determination for such trials is also proposed. PMID- 29389584 TI - The time-dependent effects of St John's wort on cytochrome P450, uridine diphosphate-glucuronosyltransferase, glutathione S-transferase, and NAD(P)H quinone oxidoreductase in mice. AB - Hypericum perforatum [St. John's wort (SJW)] is known to cause a drug interaction with the substrates of cytochrome P450 (P450, CYP) isoforms, mainly CYP3A. This study aims to determine the dose response and time course of the effects of SJW extract on P450s, UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), and NAD(P)H-quinone oxidoreductase (NQO) in mice. The oral administration of SJW extract to male mice at 0.6 g/kg/d for 21 days increased hepatic oxidation activity toward a Cyp3a substrate nifedipine. By extending the SJW treatment to 28 days, hepatic nifedipine oxidation (NFO) and warfarin 7-hydroxylation (WOH) (Cyp2c) activities were increased by 95% and 34%, respectively. Immunoblot analysis of liver microsomal proteins revealed that the Cyp2c protein level was elevated by the 28-day treatment. However, the liver microsomal activities of the oxidation of the respective substrates of Cyp1a, Cyp2a, Cyp2b, Cyp2d, and Cyp2e1 remained unchanged. In the kidney, SJW increased the NFO, but not the WOH activity. The extended 28-day treatment did not alter mouse hepatic and renal UGT, GST, and NQO activities. These findings demonstrate that SJW stimulates hepatic and renal Cyp3a activity and hepatic Cyp2c activity and expression. The induction of hepatic Cyp2c requires repeated treatment for a period longer than the initial induction of Cyp3a. PMID- 29389585 TI - Effects of lemongrass oil and citral on hepatic drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in rats. AB - The essential oil from a lemongrass variety of Cymbopogon flexuosus [lemongrass oil (LO)] is used in various food and aroma industry products and exhibits biological activities, such as anticancer and antimicrobial activities. To investigate the effects of 200 LO (200 mg/kg) and 400 LO (400 mg/kg) and its major component, citral (240 mg/kg), on drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in the liver, male Sprague-Dawley rats were fed a pelleted diet and administered LO or citral by gavage for 2 weeks. After 2 weeks of feeding, the effects of LO and citral on the metabolism and toxicity of acetaminophen were determined. The results showed that rats treated with 400 LO or citral had significantly reduced hepatic testosterone 6beta-hydroxylation and ethoxyresorufin O-deethylation activities. In addition, NAD(P)H:quinone oxidoreductase 1 activity was significantly increased by citral, and Uridine 5' diphospho (UDP) glucurosyltransferase activity was significantly increased by 400 LO in the rat liver. Treatment with 400 LO or citral reduced lipid peroxidation and reactive oxygen species levels in the liver. After acetaminophen treatment, however, LO and citral treatment resulted in little or no change in plasma alanine aminotransferase activity and acetaminophen-protein adducts content in the liver. Our results indicate that LO and citral may change the activities of drug-metabolizing enzymes and reduce oxidative stress in the liver. However, LO and citral may not affect the detoxification of acetaminophen. PMID- 29389586 TI - Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans. AB - This study aimed to investigate the synergy between anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans and Candida glabrata, with the help of a quantitative checkerboard microdilution assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as a viability dye. Apoptotic effects of caspofungin and ferulic acid concentrations (alone and combined) were analyzed for C. albicans and C. glabrata based on annexin V propidium iodide binding capacities using flow cytometric analysis. C. albicans showed a synergistic effect, represented by a fractional inhibitory concentration index of < 0.5, but C. glabrata showed no synergistic effect (fractional inhibitory concentration index > 0.5). Early and late apoptotic effects of caspofungin and ferulic acid concentrations (1 MUg/mL and 1000 MUg/mL) were calculated as 55.7% and 18.3%, respectively, while their necrotic effects were determined as 5.8% and 51.6%, respectively, using flow cytometric analyses. The apoptotic effects of the combination of caspofungin and ferulic acid at concentrations of 1 MUg/mL and 1000 MUg/mL on C. albicans and C. glabrata were 73.0% and 48.7%, respectively. Ferulic acid also demonstrated a synergistic effect in combination with caspofungin against C. albicans. Another possibility is to combine the existing anticandidal drug with phytochemicals to enhance the efficacy of anticandidal drug. PMID- 29389587 TI - Corrigendum to "Chemopreventive effect of natural dietary compounds on xenobiotic induced toxicity" [J Food Drug Anal 25 (2017) 176-186]. PMID- 29389588 TI - Metabolite profiling, antioxidant, and alpha-glucosidase inhibitory activities of germinated rice: nuclear-magnetic-resonance-based metabolomics study. AB - In an attempt to profile the metabolites of three different varieties of germinated rice, specifically black (GBR), red, and white rice, a 1H-nuclear magnetic-resonance-based metabolomics approach was conducted. Multivariate data analysis was applied to discriminate between the three different varieties using a partial least squares discriminant analysis (PLS-DA) model. The PLS model was used to evaluate the relationship between chemicals and biological activities of germinated rice. The PLS-DA score plot exhibited a noticeable separation between the three rice varieties into three clusters by PC1 and PC2. The PLS model indicated that alpha-linolenic acid, gamma-oryzanol, alpha-tocopherol, gamma aminobutyric acid, 3-hydroxybutyric acid, fumaric acid, fatty acids, threonine, tryptophan, and vanillic acid were significantly correlated with the higher bioactivities demonstrated by GBR that was extracted in 100% ethanol. Subsequently, the proposed biosynthetic pathway analysis revealed that the increased quantities of secondary metabolites found in GBR may contribute to its nutritional value and health benefits. PMID- 29389589 TI - Designing a biochip following multiplex polymerase chain reaction for the detection of Salmonella serovars Typhimurium, Enteritidis, Infantis, Hadar, and Virchow in poultry products. AB - Salmonella-contaminated foods, especially poultry-derived foods (eggs, chicken meat), are the major source of salmonellosis. Not only in the European Union (EU), but also in the United States, Japan, and other countries, has salmonellosis been an issue of concern for food safety control agencies. In 2005, EU regulation 1003/2005 set a target for the control and reduction of five target Salmonella enterica serovars-S. Typhimurium, S. Enteritidis, S. Infantis, S. Hadar, and S. Virchow-in breeding flocks. Thus, a simple biochip for the rapid detection of any of these five Salmonella serovars in poultry products may be required. The objectives of this study were to design S. Virchow-specific primers and to develop a biochip for the simultaneous identification of all or any of these five Salmonella serovars in poultry and poultry products. Experimentally, we designed novel polymerase chain reaction (PCR) primers for the specific detection of S. Virchow, S. Infantis, and S. Hadar. The specificity of all these primers and two known primer sets for S. Typhimurium and S. Enteritidis was then confirmed under the same PCR conditions using 57 target strains and 112 nontarget Salmonella strains as well as 103 non-Salmonella strains. Following multiplex PCR, strains of any of these five Salmonella serovars could be detected by a chromogenic biochip deployed with DNA probes specific to these five Salmonella serovars. In comparison with the multiplex PCR methods, the biochip assay could improve the detection limit of each of the Salmonella serovars from N*103 cfu/mL to N*102 cfu/mL sample in either the pure culture or the chicken meat samples. With an 8-hour enrichment step, the detection limit could reach up to N*100 cfu/mL. PMID- 29389590 TI - Ceratonia siliqua honeys from Morocco: Physicochemical properties, mineral contents, and antioxidant activities. AB - Physicochemical properties, main mineral content, and antioxidant activity were determined for eight floral carob honeys collected from different geographical regions of Morocco. Moroccan honeys showed good chemical and nutritional qualities, fulfilling the criteria described in the standard codex for honey. The percentages obtained for ashes were (0.13-0.69%), electrical conductivity (0.36 1.35 mS/cm), water content (17.30-22.80%), pH (4.17-5.05), free acidity (11.0 42.50 meq/kg), lactone acidity (4.0-16.50 meq/kg), and for total acidity (16.50 59.50 meq/kg). In addition, minerals such as K, Na, Mg, Cu, Zn, and Ca of honey samples were determined and potassium was the major mineral in all samples. The antioxidant activities based on the free radical scavenging, reducing power, and total antioxidant activity were investigated, and the antioxidant capacity of the honey samples was correlated with their biochemical constituents such as total phenol and flavonoids content, and the best antioxidant capacity was confirmed by the honey from Taounate. PMID- 29389591 TI - Optimization of culture conditions for gamma-aminobutyric acid production in fermented adzuki bean milk. AB - gamma-Aminobutyric acid (GABA), a nonprotein amino acid, is widely distributed in nature and fulfills several physiological functions. In this study, various lactic acid strains commonly used to produce fermented milk products were inoculated into adzuki bean milk for producing GABA. The high GABA producing strain was selected in further experiment to improve the GABA production utilizing culture medium optimization. The results demonstrated that adzuki bean milk inoculated with Lactobacillus rhamnosus GG increased GABA content from 0.05 mg/mL to 0.44 mg/mL after 36 hours of fermentation, which showed the greatest elevation in this study. Furthermore, the optimal cultural condition to adzuki bean milk inoculated with L. rhamnosus GG to improve the GABA content was performed using response surface methodology. The results showed that GABA content was dependent on the addition of galactose, monosodium glutamate, and pyridoxine with which the increasing ratios of GABA were 23-38%, 24-68%, and 8 36%, respectively. The optimal culture condition for GABA production of adzuki bean milk was found at the content of 1.44% galactose, 2.27% monosodium glutamate, and 0.20% pyridoxine. Under the optimal cultural condition, the amount of GABA produced in the fermented adzuki bean milk was 1.12 mg/mL, which was 22.4 fold higher than that of the unfermented adzuki bean milk (0.05 mg/100 mL). The results suggested that the optimized cultural condition of adzuki bean milk inoculated with L. rhamnosus GG can increase GABA content for consumers as a daily supplement as suggested. PMID- 29389592 TI - Preparation, characterization, and antimicrobial activity of nanoemulsions incorporating citral essential oil. AB - Citral is a typical essential oil used in the food, cosmetic, and drug industries and has shown antimicrobial activity against microorganisms. Citral is unstable and hydrophobic under normal storage conditions, so it can easily lose its bactericide activity. Nanoemulsion technology is an excellent way to hydrophilize, microencapsulate, and protect this compound. In our studies, we used a mixed surfactant to form citral-in-water nanoemulsions, and attempted to optimize the formula for preparing nanoemulsions. Citral-in-water nanoemulsions formed at So 0.4 to 0.6 and ultrasonic power of 18 W for 120 seconds resulted in a droplet size of < 100 nm for nanoemulsions. The observed antimicrobial activities were significantly affected by the formulation of the nanoemulsions. The observed relationship between the formulation and activity can lead to the rational design of nanoemulsion-based delivery systems for essential oils, based on the desired function of antimicrobials in the food, cosmetics, and agrochemical industries. PMID- 29389593 TI - Comprehensive analysis of Polygoni Multiflori Radix of different geographical origins using ultra-high-performance liquid chromatography fingerprints and multivariate chemometric methods. AB - Polygoni Multiflori Radix (PMR) is increasingly being used not just as a traditional herbal medicine but also as a popular functional food. In this study, multivariate chemometric methods and mass spectrometry were combined to analyze the ultra-high-performance liquid chromatograph (UPLC) fingerprints of PMR from six different geographical origins. A chemometric strategy based on multivariate curve resolution-alternating least squares (MCR-ALS) and three classification methods is proposed to analyze the UPLC fingerprints obtained. Common chromatographic problems, including the background contribution, baseline contribution, and peak overlap, were handled by the established MCR-ALS model. A total of 22 components were resolved. Moreover, relative species concentrations were obtained from the MCR-ALS model, which was used for multivariate classification analysis. Principal component analysis (PCA) and Ward's method have been applied to classify 72 PMR samples from six different geographical regions. The PCA score plot showed that the PMR samples fell into four clusters, which related to the geographical location and climate of the source areas. The results were then corroborated by Ward's method. In addition, according to the variance-weighted distance between cluster centers obtained from Ward's method, five components were identified as the most significant variables (chemical markers) for cluster discrimination. A counter-propagation artificial neural network has been applied to confirm and predict the effects of chemical markers on different samples. Finally, the five chemical markers were identified by UPLC quadrupole time-of-flight mass spectrometer. Components 3, 12, 16, 18, and 19 were identified as 2,3,5,4'-tetrahydroxy-stilbene-2-O-beta-d-glucoside, emodin-8 O-beta-d-glucopyranoside, emodin-8-O-(6'-O-acetyl)-beta-d-glucopyranoside, emodin, and physcion, respectively. In conclusion, the proposed method can be applied for the comprehensive analysis of natural samples. PMID- 29389594 TI - Study on the textural and volatile characteristics of emulsion filled protein gels as influenced by different fat substitutes. AB - Emulsion filled protein (EFP) gels were prepared through a cold-set gelation process using denatured protein, and the effects of fat substitutes on the texture and volatile release of EFP gels were investigated. Pre-heating determined the denature degree of protein structure, and higher heating intensity resulted in higher viscosity of the emulsions, and larger storage modulus (G') of the corresponding gels. Oil-reduced EFP gels (15% sunflower oil) were prepared with the addition of fat substitutes (medium chain triglyceride-MCT, maltodextrin, or guar gum), and they showed different properties from the full oil counterpart (20% sunflower oil). The three tested fat substitutes were effective in enhancing G' and stiffness of the gels, while the magnitude was dependent on the content and types of fat substitutes. The increase in the content of MCT or maltodextrin (5-15%) could lead to earlier onset of gelation, but the presence of fat substitutes did not affect the water holding capacities of the gels. With strengthened gel structures by the fat substitutes, oil-reduced gels could have decreased air-gel partition coefficients of the volatiles, particularly the more lipophilic compounds. Among the three fat substitutes, MCT and maltodextrin were more capable to retain volatiles in the gels. PMID- 29389595 TI - Modeling of thermal degradation kinetics of the C-glucosyl xanthone mangiferin in an aqueous model solution as a function of pH and temperature and protective effect of honeybush extract matrix. AB - Mangiferin, a C-glucosyl xanthone, abundant in mango and honeybush, is increasingly targeted for its bioactive properties and thus to enhance functional properties of food. The thermal degradation kinetics of mangiferin at pH3, 4, 5, 6 and 7 were each modeled at five temperatures ranging between 60 and 140 degrees C. First-order reaction models were fitted to the data using non-linear regression to determine the reaction rate constant at each pH-temperature combination. The reaction rate constant increased with increasing temperature and pH. Comparison of the reaction rate constants at 100 degrees C revealed an exponential relationship between the reaction rate constant and pH. The data for each pH were also modeled with the Arrhenius equation using non-linear and linear regression to determine the activation energy and pre-exponential factor. Activation energies decreased slightly with increasing pH. Finally, a multi linear model taking into account both temperature and pH was developed for mangiferin degradation. Sterilization (121 degrees C for 4min) of honeybush extracts dissolved at pH4, 5 and 7 did not cause noticeable degradation of mangiferin, although the multi-linear model predicted 34% degradation at pH7. The extract matrix is postulated to exert a protective effect as changes in potential precursor content could not fully explain the stability of mangiferin. PMID- 29389596 TI - Flavonoid compounds as reversing agents of the P-glycoprotein-mediated multidrug resistance: An in vitro evaluation with focus on antiepileptic drugs. AB - The pharmacoresistance to antiepileptic drugs (AEDs) remains a major unsolved therapeutic need. The overexpression of multidrug transporters, as the P glycoprotein (P-gp), at the level of the blood-brain barrier of epileptic patients has been suggested as a key mechanism underlying the refractory epilepsy. Thus, efforts have been made to search for therapeutically useful P-gp inhibitors. Herein, the strategy of flavonoid/AED combined therapy was exploited as a possible approach to overcome the P-gp-mediated pharmacoresistance. For this purpose, several in vitro studies were performed using Madin-Darby canine kidney II (MDCK II) cells and those transfected with the human multidrug resistance-1 (MDR1) gene, overexpressing the P-gp (MDCK-MDR1). Overall, the results showed that baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin, at 200MUM, produced a marked increase on the intracellular accumulation of rhodamine 123 in MDCK-MDR1 cells, potentially through inhibiting the P-gp activity. In addition, with the exception of lamotrigine, all other AEDs tested (phenytoin, carbamazepine and oxcarbazepine) and their active metabolites (carbamazepine-10,11-epoxide and licarbazepine) demonstrated to be P-gp substrates. Furthermore, the most promising flavonoids as P-gp inhibitors promoted a significant increase on the intracellular accumulation of the AEDs (excluding lamotrigine) and their active metabolites in MDCK-MDR1 cells, evidencing to be important drug candidates to reverse the AED-resistance. Thus, the co-administration of AEDs with baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin should continue to be explored as adjuvant therapy for refractory epilepsy. List of chemical compounds studied in this article: Baicalein (PubChem CID: 5,281,605); Carbamazepine (PubChem CID: 2554); Carbamazepine 10,11-epoxide (PubChem CID: 2555); (-)-Epigallocatechin gallate (PubChem CID: 65064); Kaempferol (PubChem CID: 5280863); Lamotrigine (PubChem CID: 3878); Licarbazepine (PubChem CID: 114709); Oxcarbazepine (PubChem CID: 34312); Phenytoin (PubChem CID: 1775); Silymarin (PubChem CID: 7073228); Quercetin (PubChem CID: 5280343); Verapamil (PubChem CID: 2520). PMID- 29389597 TI - Emulsions stabilized by nanofibers from bacterial cellulose: New potential food grade Pickering emulsions. AB - In the present work, we investigated the formation and stability of Pickering emulsions stabilized by nanoparticles generated from bacterial cellulose (BC) by hydrochloric acid hydrolysis. The resulting particles, called nanofibers, presented a ribbonlike shape with diameters of 30-80nm and range in length from 100nm to several micrometers. The obtained nanofibers showed good hydrophilic and lipophilic properties and had significant ability to reduce the surface tension of oil/water droplets from 48.55+/-0.03 to 34.52+/-0.05mN/m. The oil-in-water Pickering emulsions with a peanut oil concentration of 15% (v/v) were stabilized by only 0.05% (w/v) nanofibers and displayed a narrow droplet size distribution and high intensity with an average droplet size of 15.00+/-0.82nm. The morphological studies confirmed the nano-scaled droplets of emulsions. The effects of pH values and temperatures on the creaming ability and physical stability were also evaluated by zeta-potential and droplet sizes. Results showed that emulsions displayed relatively lower creaming ability at pH<7, while displayed optimal physical stability and dispersibility at pH>=7. The temperature (20-100 degrees C) and time-dependent test (0-4weeks) indicated that the Pickering emulsions stabilized by only 0.05% (w/v) nanofibers displayed excellent stability. Due to the sustainability and good bio-compatibility of nanofibers from BC, the developed emulsions stabilized by low concentration of nanofibers can be used as new food-grade Pickering emulsions and have great potential to deliver lipophilic bioactive substances in food industry. PMID- 29389598 TI - Mycotoxins and beer. Impact of beer production process on mycotoxin contamination. A review. AB - Beer is the most consumed alcoholic beverage in the world. Its contamination with mycotoxins is of public health concern, especially for heavy drinkers. Beer production implies a variety of operations which might impact the initial level of mycotoxins in a positive or negative way. The complexity of these operations do not give to the brewer a complete control on chemical and biochemical reactions that take place in the batch, but the knowledge about mycotoxin properties can help in identifying the operations decreasing their level in foodstuffs and in the development of mitigation strategies. This review discusses available data about mycotoxin evolution during malting and brewing process. The operations that may lead to a decrease in mycotoxin load are found to be steeping, kilning, roasting, fermentation and stabilization operations applied over the process (e.g. clarification). Also, other general decontamination strategies usually employed in food industry, such as hot water treatment of barley, ozonation or even the use of lactic acid bacteria starter cultures during malting or fermentation are considered. PMID- 29389599 TI - Recent developments on the extraction and application of ursolic acid. A review. AB - Ursolic acid (UA) is a pentacyclic triterpenoid widely found in herbs, leaves, flowers and fruits; update information on the major natural sources or agro industrial wastes is presented. Traditional (maceration, Soxhlet and heat reflux) and modern (microwave-, ultrasound-, accelerated solvent- and supercritical fluid) extraction and purification technologies of UA, as well as some patented process, are summarized. The great interest in this bioactive compound is related to the beneficial effects in human health due to antioxidant, antimicrobial, anti inflammatory, hepatoprotective, immunomodulatory, anti-tumor, chemopreventive, cardioprotective, antihyperlipidemic and hypoglycemic activities, and others. UA may augment the resistance of the skin barrier to irritants, prevent dry skin and could be suitable to develop antiaging products. The development of nanocrystals and nanoparticle-based drugs could reduce the side effects of high doses of UA in organisms, and increase its limited solubility and poor bioavailability of UA which limit the potential of this bioactive and the further applications. Commercial patented applications in relation to cosmetical and pharmaceutical uses of UA and its derivatives are surveyed. PMID- 29389600 TI - Variation of volatile terpenes in the edible fungi mycelia Flammulina velutipes and communications in fungus-mite interactions. AB - Many mites rely on fungi for nutrients, and fungi benefit from them with regard to spore dispersal, or nutrient resources. The interactions among mites and fungi are still not clear in most cases. This study analyzed volatile natural products from the liquid and solid cultures of the edible fungi, Flammulina velutipes (Fr.) Sing, and the solid mycelia induced by the storage mite, Tyrophagus putrescentiae Schrank, using HS-SPME-GC-MS/MS. Five new monoterpenes and 30 new sesquiterpenes were isolated from the two cultures of F. velutipes and a newly monoterpene and 14 newly sesquiterpenes found in the solid mycelia induced by the storage mite. Sesquiterpenes were abundant in the mycelial stage of F. velutipe. The mite was attracted by some volatiles from host fungi, dihydrocarveol, cedrol, beta-caryophyllene, alpha-terpilene, beta-pinene and benzaldehyde, analyzed by four-arm olfactometer. Some terpenes induced by T. putrescentiae, such as caryophyllene oxide, bicyclogermacrene, and (-)-spathulenol, would have potential biological function. These results suggest that some volatile sesquiterpenes play an important role in enabling the mite to recognize host fungi. PMID- 29389602 TI - A qualitative exploration of the factors underlying seniors' receptiveness to entomophagy. AB - Entomophagy presents a novel approach to securing a nutritive and environmentally sustainable food source to meet the needs of a growing and ageing population. To date, research exploring the receptiveness of Western consumers towards entomophagy has focused on younger age groups and there has been little examination of the views of older adults. The aims of this study were to (i) explore the factors associated with older people's attitudes towards entomophagy and (ii) identify strategies to encourage seniors to adopt the practice. Interviews were conducted with 77 Western Australian seniors aged 60years and over. The average age of the interviewees was 73years and most were female (n=67). Reflecting the lack of promotion of entomophagy as a desirable eating behaviour, there were very low levels of awareness of the environmental and nutritional advantages of this practice. Most of the interviewed seniors saw entomophagy as a disgusting practice that was incompatible with their cultural beliefs and values, however a small group viewed it as a novel and potentially enjoyable experience. The findings suggest that strategies to target the former group could focus on overcoming the disgust reaction, such as by disguising insects in food and providing guarantees of food safety. Consumption in the latter group could be facilitated by improving knowledge and skills relating to the preparation of insect-based foods. Strategies to increase entomophagy in the Western world need to consider the unique views of different consumer groups towards the practice. PMID- 29389601 TI - Effects of starch from five different botanical sources on the rheological and structural properties of starch-gluten model doughs. AB - Wheat, corn, tapioca, sweet potato and potato starches were independently mixed into starch-gluten model doughs containing 15% (w/w) vital gluten. Rheological properties, including linear viscoelasticity region, frequency dependence and recovery capacity, were studied by strain sweep, frequency sweep, and creep and recovery measurements. Structural properties were also investigated by measuring the disulfide bonds (-SS-) content, SDS-PAGE and low-resolution 1H nuclear magnetic resonance. Wheat starch (WS)-gluten dough had the greatest linear viscoelasticity region (0.190%), lowest frequency dependence (0.128) and greatest recovery capacity (67.39%), while potato starch-gluten dough had the smallest linear viscoelasticity region (0.126%), greatest frequency dependence (0.195) and lowest recovery capacity (54.97%). Furthermore, WS-gluten dough showed the highest disulfide bonds (-SS-) content (3.47MUmol/g), lowest intensity of extracted glutenin bands and highest bond water content (23.20%). This suggested that WS-gluten dough formed stronger starch-gluten interactions compared with those of the other four starch-gluten model doughs. PMID- 29389603 TI - Applying high-resolution melting (HRM) technology to olive oil and wine authenticity. AB - Olive oil and wine production have a worldwide economic impact. Their market reliability is under great concern because of the increasing number of fraud and adulteration attempts. The need for a traceability system in all its extension is crucial particularly for the cases of olive oils and wines with certified labels, in which only a limited number of olives and grapevine varieties, respectively, are allowed in a restricted well-defined geographical area. Molecular markers have been vastly applied to the food sector, and in particular High-Resolution DNA Melting technology has been successfully applied for olive oil and wine authentication, as part of the traceability system. In this review, the applications of HRM and their usefulness for this sector considering, Safety, Security and Authenticity will be reviewed. A broad overview of the HRM technique will be presented, focusing on the aspects that are crucial for its success, in particular the new generation of fluorescent dsDNA dyes used for amplicon detection and quantification, and the data analysis. A brief outlook on the olive oil and wine authenticity procedures, based on new DNA technology advances, and in which way this may influence the future establishment of a traceability system will be discussed. PMID- 29389604 TI - Slow digestible colored rice flour as wall material for microencapsulation: Its impacts on gut bacterial population and metabolic activities. AB - Black waxy and red jasmine rice flour (6.5% and 18.7% amylose content, respectively) were modified using pullulanase followed by heat-moisture treatment (Hydrolyzed-HMT) to produce microcapsules that entrapped L. plantarum TISTR 1465. Hydrolyzed-HMT of colored rice flours showed restricted pasting properties, lower breakdown and higher thermal properties than native flour (p<0.05). Hydrolysis treatment was able to promote a low molecular weight starch that easily formed a crystalline structure after HMT. As a consequence, a significant increase in slowly digestible starch was observed (from 23.7% to 37.0% in waxy type and 22.2% to 34.6% non-waxy type). The survival of L. plantarum TISTR 1465 after simulated gastric fluid (90min) and simulated intestinal fluid (120min) of the Hydrolyzed 36h-HMT black waxy rice was higher (8.07+/-0.13logCFU/g and 7.48+/-0.12logCFU/g) than gum arabic (6.12+/-0.11 and 4.72+/-0.28logCFU/g) and no carrier (3.34+/-0.23 and 0.43+/-0.75logCFU/g) respectively. Moreover, these microcapsules also obtained the highest survival (8.67+/-0.20logCFU/g) after storage for 90days at 4 degrees C. Under scanning electron microscopy, starch granules of the hydrolyzed 36h-HMT were seen as polyhedral shapes in the spherical aggregates that carried the microorganisms and reduced their injury and mortality. Short-chain fatty acids of the hydrolyzed 36h-HMT were much higher than positive control at every fermentation time (p<0.01). The fluorescence in situ hybridization result showed that the prebiotic property of hydrolyzed 36h-HMT black waxy rice can better aid the beneficial probiotic Lactobacillus spp. growth after 24h fermentation than the negative control (from 8.40+/-0.48 to 7.03+/-0.21logCFU/g, p<0.05) and commercial prebiotic Orafti(r)Synergy1 (8.40+/-0.48 to 7.47+/-0.08logCFU/g, p<0.01). Microencapsulation of hydrolyzed black waxy rice flour followed by HMT is proposed as a synbiotic ingredient to apply in synbiotic foods. PMID- 29389605 TI - Vicinal diketones and their precursors in wine alcoholic fermentation: Quantification and dynamics of production. AB - Vicinal diketones produced during wine fermentation influence the organoleptic qualities of wine. Diacetyl and 2,3-pentanedione are well known for their contribution to butter or butterscotch-like flavours. We developed an analysis method to quantify vicinal diketones and their precursors, alpha-acetolactate and alpha-acetohydroxybutyrate, under oenological conditions. Five-fold dilution of the sample in a phosphate-citrate buffer (pH7.0) strongly attenuated matrix effects between the beginning and end of alcoholic fermentation and protected the sample from spontaneous precursor decarboxylation. The use of diacetyl-d6 as an internal reference improved precision by eliminating differences in the derivatization and extraction yields between the internal standard and the analytes. We obtained unexpected results for alcoholic fermentation by Saccharomyces cerevisiae using this approach. Indeed, the level of diacetyl and 2,3-pentanedione throughout fermentation were very low. However, we observed a large quantity of both precursors. The production dynamics of alpha-acetolactate were unconventional and there were two distinct phases of accumulation. The first corresponded to the growth phase, and the second to glucose depletion. There was a rapid decrease of precursor levels at the end of fermentation, but there was still a significant amount of alpha-acetolactate. The amount of precursor remaining at the end of fermentation constitutes a potential source of diacetyl during wine maturation. alpha-Acetohydroxybutyrate accumulated during the growth phase followed by a continuous decrease of its concentration during the stationary phase. Residual quantities of alpha-acetohydroxybutyrate found in wine at the end of fermentation does not constitute a sufficient source of 2,3 pentanedione to affect the aromatic profile. PMID- 29389606 TI - Structural difference of palm based Medium- and Long-Chain Triacylglycerol (MLCT) further reduces body fat accumulation in DIO C57BL/6J mice when consumed in low fat diet for a mid-term period. AB - Medium-and-Long Chain Triacylglycerol (MLCT) is a type of structured lipid that is made up of medium chain, MCFA (C8-C12) and long chain, LCFA (C16-C22) fatty acid. Studies claimed that consumption of MLCT has the potential in reducing visceral fat accumulation as compared to long chain triacylglycerol, LCT. This is mainly attributed to the rapid metabolism of MCFA as compared to LCFA. Our study was designed to compare the anti-obesity effects of a enzymatically interesterified MLCT (E-MLCT) with physical blend of palm kernel and palm oil (B PKOPO) having similar fatty acid composition and a commercial MLCT (C-MLCT) made of rapeseed/soybean oil on Diet Induced Obesity (DIO) C57BL/6J mice for a period of four months in low fat, LF (7%) and high fat, HF (30%) diet. The main aim was to determine if the anti-obesity effect of MLCT was contributed solely by its triacylglycerol structure alone or its fatty acid composition or both. Out of the three types of MLCT, mice fed with Low Fat, LF (7%) E-MLCT had significantly (P<0.05) lower body weight gain (by ~30%), body fat accumulation (by ~37%) and hormone leptin level as compared to both the LF B-PKOPO and LF C-MLCT. Histological examination further revealed that dietary intake of E-MLCT inhibited hepatic lipid accumulation. Besides, analysis of serum profile also demonstrated that consumption of E-MLCT was better in regulating blood glucose compared to B PKOPO and C-MLCT. Nevertheless, both B-PKO-PO and E-MLCT which contained higher level of myristic acid was found to be hypercholesterolemic compared to C-MLCT. In summary, our finding showed that triacylglycerol structure, fatty acid composition and fat dosage play a pivotal role in regulating visceral fat accumulation. Consumption of E-MLCT in low fat diet led to a significantly lesser body fat accumulation. It was postulated that the MLM/MLL/LMM/MML/LLM types of triacylglycerol and C8-C12 medium chain fatty acids were the main factors that contributed to the visceral fat suppressing effect of MLCT. Despite being able to reduce body fat, the so called healthful functional oil E-MLCT when taken in high amount do resulted in fat accumulation. In summary, E-MLCT when taken in moderation can be used to manage obesity issue. However, consumption of E-MLCT may lead to higher total cholesterol and LDL level. PMID- 29389607 TI - Freeze-drying affects the starch digestibility of cooked potato tubers. AB - Freeze-drying (FD) has utility for phytonutrient screening but its reliability for starch measurements is unclear. The impact of FD was tested on total (TS), digestible (DS) and resistant starch (RS) for four potato varieties (PC Red, GG Red, GG Yellow, and Dolbec Yellow). The treatments included: (a) tubers boiled and then cooled for 1h at room temperature (RT) (control; Treatment 1) and 24h at 4 degrees C; (b) tubers boiled and then cooled for 1h at RT with subsequent FD (Treatment 2); and (c) raw tubers that underwent FD, then were rehydrated, boiled, and cooled for 1h at RT (Treatment 3). TS and DS content did not differ between the control samples cooled for 1h or 24h with Treatment 1 but RS content at 24h was higher, which indicated starch retrogradation. Cultivar variations were observed in the percent increase in RS between 24h vs. 1h with the greatest increase in Dolbec Yellow (114.5+/-7.6%). Relative to controls, FD treatments modified measured TS content in three of four varieties including overestimation by 94.2+/-6.5% and 156.0+/-5.2% for GG Yellow with Treatments 2 and 3, respectively. FD caused overestimation of DS and underestimation of RS in the same three varieties relative to controls including overestimation of DS in GG Yellow by 122.9+/-4.7% (Treatment 2) and 205.7+/-13.8% (Treatment 3). PC Red showed the greatest underestimation in RS content compared to controls of 42.5+/ 9.6% and 61.7+/-5.4% in Treatment 2 and 3, respectively. Modifications to cooking and rehydration procedures following FD of raw tuber samples did not improve reliability of TS, DS, and RS measurements. Microscopy showed that cells remained intact following cooking whereas cell wall integrity was reduced when FD followed cooking and that cooking followed by FD led to destruction of cellular structure. We conclude that FD leads to unreliable starch measurements, which was supported by morphological microscopic evidence. For accuracy of starch profile measurements, the use of freshly cooked potato samples is essential. PMID- 29389608 TI - Nutrigenomic studies on hilsa to evaluate flesh quality attributes and genes associated with fatty acid metabolism from the rivers Hooghly and Padma. AB - The Indian shad hilsa (Tenualosa ilisha), a commercially important food fish rich in oils, enjoys high consumer preference in the South Asian countries owing to its unique flavour and culinary properties. The present study was undertaken with the primary objective of determining the flesh quality attributes of hilsa in terms of nutritive value (gross chemical composition, amino acid, fatty acid and mineral composition), pH, water holding capacity (WHC) and expression of genes associated with fatty acid metabolism and flesh quality. Additionally, comparative studies on the flesh quality attributes in hilsa from two distributaries of river Ganga i.e. Hooghly and Padma were also carried out. A high WHC (>80%) suggested juicy and tender nature of hilsa meat. The protein content was 18-21% in hilsa from both the rivers and essential amino acid lysine, valine and functional amino acids leucine and arginine were significantly higher in Hooghly hilsa (P<0.05). The predominance of umami taste amino acids, glutamic acid and aspartic acid and sweet taste amino acids, serine, glycine and alanine in hilsa from both the rivers could be the contributing factors to its unique flavour. The fat content in hilsa from river Hooghly and Padma were found to be 9.94 and 7.84%, respectively. The concentration of flavouring fatty acids like saturated fatty acids (SFA) (myristic acid) and omega (omega)-3 polyunsaturated fatty acids (PUFAs) (linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) were significantly higher in Hooghly hilsa (P<0.05). Among the genes associated with fatty acid metabolism studied, expression of cluster of differentiation (CD36), acetyl CoA oxidase (ACO), fatty acid synthase (FAS), peroxisome proliferator activated receptor beta (PPARbeta), peroxisome proliferator activated receptor gamma (PPARgamma) and desaturase were significantly higher in Padma hilsa (P<0.05), and the change was <2 fold. Comparative gene expression profiling of flesh quality genes (actin, GAPDH, LDH, TPI) showed similar levels of expression in hilsa from both the rivers (P<0.05). The nutrigenomic information generated on various flesh quality attributes of hilsa has enriched the knowledgebase. Further, from comparative nutrient analysis on hilsa from river Hooghly and Padma, it was observed that Hooghly hilsa is superior in terms of oil content, omega-3 PUFAs EPA and DHA and essential amino acids; however, the expression profile of genes associated with flesh quality were found to be similar. Thus, within the scope of the present study, Hooghly hilsa (medium size category, 500-700g size) was found to be nutritionally superior. PMID- 29389609 TI - Shrinkage and porosity evolution during air-drying of non-cellular food systems: Experimental data versus mathematical modelling. AB - In the present work, the impact of glass transition on shrinkage of non-cellular food systems (NCFS) during air-drying will be assessed from experimental data and the interpretation of a 'shrinkage' function involved in a mathematical model. Two NCFS made from a mixture of water/maltodextrin/agar (w/w/w: 1/0.15/0.015) were created out of maltodextrins with dextrose equivalent 19 (MD19) or 36 (MD36). The NCFS made with MD19 had 30 degrees C higher Tg than those with MD36. This information indicated that, during drying, the NCFS with MD19 would pass from rubbery to glassy state sooner than NCFS MD36, for which glass transition only happens close to the end of drying. For the two NCFS, porosity and volume reduction as a function of moisture content were captured with high accuracy when represented by the mathematical models previously developed. No significant differences in porosity and in maximum shrinkage between both samples during drying were observed. As well, no change in the slope of the shrinkage curve as a function of moisture content was perceived. These results indicate that glass transition alone is not a determinant factor in changes of porosity or volume during air-drying. PMID- 29389610 TI - Inulin rich carbohydrates extraction from Jerusalem artichoke (Helianthus tuberosus L.) tubers and application of different drying methods. AB - In this study the operational extraction variables to obtain higher yields of inulin from Jerusalem artichoke tubers (JAT), as well as the optimal conditions to obtain a stable and dispersible powdered product by either spray or freeze drying, were studied. With this purpose, the powder yield, moisture content, water activity and flowability or products obtained by different experimental conditions were analyzed. Inulin rich carbohydrates (IRC) extraction was performed from lyophilized and ground tubers employing distilled hot water as solvent. It was proved that the solid:solvent ratio (S:S) was the critical variable in the extraction process, followed by temperature. Thus, the IRC extraction was optimal without ultrasound assistance, at 76 degrees C, employing a S:S of 1:16, during 90min. In addition, the powder obtained by freeze-drying of the IRC extract showed advantages respect to powders obtained by spray-drying regarding the yield and considering that maltodextrin was not necessary as encapsulation agent. In another hand, spray drying process provided IRC powered materials with appropriate flow properties, and taking into account cost and time of production, this method should be considered as an alternative of freeze drying. PMID- 29389611 TI - Preparation of eggshell membrane protein hydrolysates and culled banana resistant starch-based emulsions and evaluation of their stability and behavior in simulated gastrointestinal fluids. AB - This study aims to evaluate the effect of resistant starch (RS) derived from culled banana on the stability and characteristics of emulsions stabilized by eggshell membrane (ESM) protein hydrolysates. It was observed that incorporation of resistant starch improved the properties of the emulsions. Furthermore, the most stable emulsions developed (using a combination of RS and pretreated alcalase hydrolysates) were assessed for their behavior in an in-vitro gastrointestinal model system and changes in their particle size, zeta potential and morphology were evaluated. It was seen that these emulsions underwent flocculation and coalescence in the presence of pepsin and at higher concentrations of mucin enzyme and further coalescence and fatty acid release were observed after their passage through the small intestine. These insightful results about emulsion behavior in the gastrointestinal tract can be useful for designing delivery systems for controlled release of bioactive compounds. PMID- 29389612 TI - Moisture absorption and dynamic flavor changes in hydrolysed and freeze-dried pine nut (Pinus koraiensis) by-products during storage. AB - In the present study, two different fractions of pine nut (Pinus koraiensis) protein hydrolysate powder (PNPHP1-3kDa and PNPHP3-10kDa) were prepared and stored for fifteen days at 25 degrees C and 50% relative humidity. Changes in moisture absorption, secondary structure and flavor compounds were measured at various time intervals over fifteen days. Results showed that the PNPHP3-10kDa had higher moisture absorption capacity from day 6 to day 15 and that the secondary structure of two PNPHP fractions was changed. Major nine and eight flavor compounds were identified from PNPHP1-3kDa and PNPHP3-10kDa, respectively. PNPHP1-3kDa mainly generated aldehydes and PNPHP3-10kDa generated pyrazines. Finally, the formation of pyrazines was conjectured. The data suggests that Maillard reaction, microbial fermentation and lipid oxidation occurred during storage. The reactions appeared to be strongest by the sixth day. PMID- 29389613 TI - Microbial proteases: Production and application in obtaining protein hydrolysates. AB - The catalytic properties of the proteases have already allowed for their introduction into several industrial processes, such as food, chemical, pharmaceutical, etc. Recent advances in the biotechnology, particularly in the production of protein hydrolysates, have provided an important development of this area. The enzymatic hydrolysis allows for the use of different food protein sources that, after hydrolysis, can be used also as sources of bioactive peptides. Microbial proteases have interesting characteristics in the sense of low cost of production, good stability and specificity representing a powerful tool in the development and production of new protein hydrolysates with characteristics that can be explored industrially. This review aims to describe the production of proteases, the use of microbial proteases in enzymatic hydrolysis, in different industries and to explain the characteristics of such enzymes. PMID- 29389614 TI - Identification and characterization of a calcium dependent bacillopeptidase from Bacillus subtilis CFR5 with novel kunitz trypsin inhibitor degradation activity. AB - The cereals and pulses are considered to be an important component in the food chain due to their proteinaceous nature, but the presence of anti-nutritional factors (KTI) decreases their nutrient absorption rate. Kunitz trypsin inhibitors (KTI) reduce the bioavailability of trypsin and are the primary cause for the existence of various metabolic disorders. To overcome the inhibitory effect of KTI, a KTI degrading protein (BPC) was identified and characterized from Bacillus subtilis CFR5. BPC possesses 60% identity with bacillopeptidase of B. subtilis 168. BPC cleaves at DFVLD and DFFNNY sites of KTI which results in the formation of three inactive KTI fragments. Subsequently, BPC was cloned in pHY300PLK and recombinant protein was used for the biochemical characterization, sequence alignment and mutational studies. The optimal temperature and pH of the BPC was 40 degrees C and 8.0, respectively. BPC is a calcium dependent metalloprotease and its activity was significantly increased by 41.2-fold in the presence of 2.5mM Ca2+. BPC also showed moderate thermostability with the half-life of 4h at 55 degrees C. Site directed mutagenesis studies in recombinant BPC revealed that mutation of Tyr49 with Phe, Tyr64 with Phe, and Pro141 to Arg affects the catalytic activity without affecting the conformation of BPC. Hence, Tyr49, Tyr64 and Pro141 were identified as the unique residues responsible for KTI cleavage. Thus, this study leads to the identification of a novel KTI degrading protease from B. subtilis CFR5 which cleaves and deactivates the kunitz trypsin inhibitor. PMID- 29389615 TI - Soybean soluble polysaccharide enhances absorption of soybean genistein in mice. AB - This study was designed to probe the promoting effects of soybean soluble polysaccharide (SSPS) on bioavailability of genistein in mice and the underlying molecular mechanism. Male Kunming mice (n=8) were administered intragastrically with either saline, SSPS (5mg/kgbw), genistein (100mg/kgbw), or SSPS (5 or 50mg/kgbw) together with genistein (100mg/kgbw) for consecutive 28days. UPLC qTOF/MS analysis showed that co-administration of SSPS and genistein in mice caused significant elevation in the urinary levels of genistein and its metabolites (p<0.05). Furthermore, the fecal excretion of genistein was also enhanced by co-administration of SSPS. However, the feces level of dihydrogenistein, a characteristic metabolite of genistein degraded by gut microorganism, was dose-dependently decreased by the combined treatment of SSPS. Additionally, co-treatment of SSPS with genistein also decreased the small intestinal levels of uridinediphosphate-glucuronosyltransferase (UGT), sulfotransferase (SULT), P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP1), and multidrug resistance-associated protein-2 (MRP2) in mice. These findings suggest that the inhibition of SSPS against small intestinal first pass metabolism of genistein is involved in the promoting effect of genistein bioavailability in mice. PMID- 29389616 TI - Effects of simulated gastrointestinal digestion in vitro on the chemical properties, antioxidant activity, alpha-amylase and alpha-glucosidase inhibitory activity of polysaccharides from Inonotus obliquus. AB - This study was aimed to investigate the impacts of gastrointestinal digestion in vitro on the physicochemical properties and the biological activities of polysaccharides from Inonotus obliquus (UIOPS-1). Results showed that the monosaccharides composition, structure and conformation of polysaccharides were remarkably altered, and the molecular weight (Mw) of UIOPS-1 was steadily decreased from 105.02kDa to 88.97kDa and 36.74kDa after simulated digestion. The reducing ends were increased and the free monosaccharides including d-glucose, d galactose and d-xylose were released suggested that the degradation of UIOPS-1 was caused by disrupting the aggregates and glycosidic bonds. The antioxidant activities of UIOPS-1 were significantly increased after gastric digestion (P<0.05), however, they were decreased after intestinal digestion. The alpha amylase and alpha-glucosidase inhibitory activities of UIOPS-1 were significantly increased after digestion indicating a good control of postprandial hyperglycemia (P<0.001). The results indicated that UIOPS-1 still exhibited antioxidant and antihyperglycemic potential after gastrointestinal digestion, which could be considered as a promising candidate for functional foods. PMID- 29389617 TI - Effects and interactions of gallic acid, eugenol and temperature on thermal inactivation of Salmonella spp. in ground chicken. AB - The combined effects of heating temperature (55 to 65 degrees C), gallic acid (0 to 2.0%), and eugenol (0 to 2.0%) on thermal inactivation of Salmonella in ground chicken were assessed. Thermal death times were determined in bags submerged in a heated water bath maintained at various set temperatures, following a central composite design. The recovery medium was tryptic soy agar supplemented with 0.6% yeast extract and 1% sodium pyruvate. D-values were analyzed by second-order response surface regression for temperature, gallic acid, and eugenol. The observed D-values for chicken with no gallic acid or eugenol at 55, 57.5, 60, 62.5, and 65 degrees C were 21.85, 5.43, 2.83, 0.58, and 0.26min, respectively. A second-order polynomial model developed to inactivate Salmonella was found to be significant (p<0.0001) with a R2=0.95 and a no significant lack of fit (p>0.1073). Efficacy of the additives in increasing the sensitivity of the pathogen to heat was concentration dependent. The model developed in this study can be used by processors to design appropriate thermal process to inactivate Salmonella in chicken products used in the study and thereby, ensuring an adequate degree of protection against risks associated with the pathogen. PMID- 29389618 TI - Evaluation of chlorine dioxide, acidified sodium chlorite and peroxyacetic acid for control of Escherichia coli O157:H7 in beef patties from treated beef trim. AB - The effectiveness of 30 to 400ppm chlorine dioxide (CDO), acidified sodium chlorite (ASC) and peroxyacetic acid (PAA) to control Escherichia coli O157:H7 in beef was examined. Ground beef made from treated meat was vacuum packaged and stored at 4 degrees C for 4d. CDO or ASC concentration by storage time interaction for inactivation of E. coli O157:H7 was significant (P<0.05). Exposure of beef to 200 and 400ppm CDO caused 0.73 and 1.25logcfu/g reduction in the numbers of pathogen, respectively, and an additional 2.08 and 2.25logcfu/g reduction, respectively, occurred at day 4. At 400ppm ASC caused a 0.87logcfu/g reduction and an additional 0.86logcfu/g inactivation at day 4. PAA caused <=0.8logcfu/g reduction in pathogen numbers at <=400ppm. Among tested antimicrobials, CDO was most effective and had a positive interaction with cold storage where additional E. coli O157:H7 inactivation occurred. PMID- 29389619 TI - Dynamics of gas cell coalescence during baking expansion of leavened dough. AB - The investigation of the dynamics of gas cell coalescence, i.e. a phenomenon that deteriorates the homogeneity of the cellular structure of bread crumb, was carried out performing simultaneously measurements of the dough volume, pressure, and viscosity. It was demonstrated that, during the baking expansion of chemically leavened wheat flour dough, the maximum growth rate of the gas cell radius determined from the ratio of pressure exerted by the expanded dough to its viscosity was on average four-fold lower than that calculated from volume changes in the gas phase of the dough. Such a high discrepancy was interpreted as a result of the course of coalescence, and a formula for determination of its rate was developed. The coalescence rate in the initial baking expansion phase had negative values, indicating nucleation of newly formed gas cells, which increased the number of gas cells even by 8%. In the next baking expansion phase, the coalescence rate started to exhibit positive values, reflecting dominance of the coalescence phenomenon over nucleation. The maximum coalescence rates indicate that, during the period of the most intensive dough expansion, the number of gas cells decreased by 2-3% within one second. At the end of the formation of bread crumb, the number of the gas cells declined by 55-67% in comparison with the initial value. The correctness of the results was positively verified using X-ray micro-computed tomography. The developed method can be a useful tool for more profound exploration of the coalescence phenomenon at various stages of evolution of the cellular structure and its determinants, which may contribute to future development of more effective methods for improving the texture and sensory quality of bread crumb. PMID- 29389620 TI - Characterization of free and bound volatile compounds in six Ribes nigrum L. blackcurrant cultivars. AB - This study investigated the profiles of free and bound volatile compounds of six currant cultivars grown in China. Results showed that 166 free and 111 bound volatiles were found in these cultivars with esters and terpenoids as the major volatiles. Additionally, 10 hydroxy esters were detected in these cultivars for the first time. Floral, fruity, and sweet flavors appeared to be the feature aroma in these cultivars, which resulted from the contribution of 17 volatiles. Principal component analysis indicated the cultivar "Fertodi", "Risagar" and "Liangye" had the similar profiles of free and bound volatile compounds, whereas the cultivar "Brodtrop" and "Yadrionaya" exhibited the similarity on their free and bound volatiles. The cultivar "Sofya" showed a different volatile composition. Cluster analysis revealed the cultivar "Fertodi", "Risagar", and "Liangye" had the similar profiles of free and bound volatile compounds, whereas the similar free and bound volatile compositions were observed in the cultivar "Sofya" and "Yadrionaya". This study could provide useful information on quality control of commercial currant products. PMID- 29389621 TI - Effect of electro-activated sweet whey on growth of Bifidobacterium, Lactobacillus, and Streptococcus strains under model growth conditions. AB - Recently, we demonstrated the efficacy of electro-activation to improve the functionalities of whey that can be used as a prebiotic and antioxidant agent through lactulose and Maillard reaction products formation. The aim of the present study was to evaluate the effect of electro-activated sweet whey (EA whey) on growth of probiotics of Bifidobacterium, Lactobacillus, and Streptococcus strains in pure cultures and to compare EA-whey with non-electro activated whey, lactulose, lactose, sucrose, glucose and galactose at different concentrations (1.25, 2.5 and 5%). The bacterial growth was monitored through maximum optical density (ODmax) and maximum growth rate (MUmax) measurements. Moreover, the effects of EA-whey on the growth of L. johnsonii La-1 in the presence of oxygen was assessed. FTIR spectroscopy analyses of the bacterial membrane structure were monitored as a function of EA-whey concentration. The results showed that EA-whey enhanced the growth of all the test bacteria. They clearly demonstrated a promoting bifidogenic effect of EA-whey compared to lactulose. The growth of L. johnsonii La-1 was greatly enhanced under aerobic conditions by the supplementation of the growth medium with EA-whey. This growth promoting effect could be related to the ability of EA-whey to prevent the accumulation of hydrogen peroxide, its high antioxidant capacity and lactulose content. Moreover, FTIR spectra showed that EA-whey acts as an antioxidant in regards to cell membrane lipids oxidation by oxygen species and limited their adverse effect on probiotic bacteria during their growth. Thus, EA-whey, a potential prebiotic and antioxidant, could be used as active ingredient in manufacturing functional fermented dairy products. PMID- 29389622 TI - Systematic evaluation of bioactive components and antioxidant capacity of some new and common bayberry cultivars using an in vitro gastrointestinal digestion method. AB - This study was aimed to investigate the impact of in vitro gastrointestinal digestion on some common and new bayberry cultivars. The contents of total phenolics (246-669mg gallic acid equivalents/kg FW (fresh weight)), flavonoids (116-689mg quercetin-3-O-rutinoside equivalents/kg FW), procyanidins (28-133mg catechin equivalents/kg FW) and anthocyanins (1-7mg cyaniding-3-O-glucoside equivalents/kg FW) were detected in digested cultivars. HPLC-TOF-MS analysis identified 17 phenolic compounds in digested sample. Among all digested cultivars, the new cultivars Anhaizaomei (ABTS, IC50=2.95mg/mL; FRAP, 401.32mg vitamin C equivalents (VCE)/kg FW) and Yingsi (ABTS, IC50=3.28mg/mL; FRAP, 400.81mg VCE/kg FW) showed better in vitro antioxidant capacity. Further cellular assay indicated that the common cultivar Dongkui (2mg/mL) possessed the strongest ROS scavenging activity. The comprehensive evaluation of bioactive components and antioxidant properties using principal component analysis suggests that common cultivar Dongkui, new cultivars Yingsi and Anhaizaomei could be considered as dietary supplements. PMID- 29389623 TI - Protective effect of bioaccessible fractions of citrus fruit pulps against H2O2 induced oxidative stress in Caco-2 cells. AB - Fruit pulps from Navel (N) and Cara Cara (CC) oranges, and Clementine mandarin freshly harvested (M) and refrigerated stored (M12) were used to evaluate the cytoprotective effect of their bioaccessible fractions (BF) against H2O2-induced oxidative stress in Caco-2 cells. BF of samples preserved viability vs. H2O2 treated cells, reaching values similar to controls. Lipid peroxidation was reduced to levels of control cells, but M did not reach control values. ROS and mitochondrial membrane potential changes (Deltapsim) values were reduced compared with H2O2 treated cells, but without achieving control levels. A significant reduction in cell proportions in G1 phase and a significant increase in sub-G1 phase (apoptosis) of cell cycle was shown in H2O2 treated cells, and BF allowed a recovery close to control levels. Thus, BF of samples protect the cells from oxidative stress by preserving cell viability, mitochondrial membrane potential and correct cell cycle progression, and diminishing lipid peroxidation and ROS. PMID- 29389624 TI - Small Brazilian wild fruits: Nutrients, bioactive compounds, health-promotion properties and commercial interest. AB - Brazilian berries present great nutritional, functional and economic characteristics comparable to temperate berries. They constitute an important innovation domain for the food, pharmaceutical and cosmetic industries, due to their positive health effects and market potential. The main objective of this review was to describe the physicochemical, nutritional and biological aspects of six Brazilian small native wild fruits from the Arecaceae (acai, buriti and pupunha), Mirtaceae (camu-camu and jaboticaba) and Malpighiaceae (murici) families, highlighting their antioxidant, anti-lipidaemic, anti-inflammatory, antiproliferative, and antigenotoxic potential among others. It also discussed some relevant topics for new studies that could be of benefit to industry and improve the local economy where these fruits are found. Thus, the dissemination of the works already carried out with these fruits strategically relevant can stimulate new lines of research to consolidate this new field for the food industries. PMID- 29389625 TI - Iron and zinc bioaccessibility of fermented maize, sorghum and millets from five locations in Zimbabwe. AB - The present study is an evaluation of iron and zinc bioaccessibility of fermented maize, sorghum, pearl millet and finger millet from five different locations in Zimbabwe. Iron and zinc contents ranged between 3.22 and 49.7 and 1.25 4.39mg/100gdm, respectively. Fermentation caused a reduction of between 20 and 88% of phytic acid (PA) while a general increase in soluble phenolic compounds (PC) and a decrease of the bound (PC) was observed. Bioaccessibility of iron and zinc ranged between 2.77 and 26.1% and 0.45-12.8%, respectively. The contribution of the fermented cereals towards iron and zinc absolute requirements ranged between 25 and 411% and 0.5-23% with higher contribution of iron coming from cereals that were contaminated with extrinsic iron. Populations subsisting on cereals could be more at risk of zinc rather than iron deficiency. PMID- 29389626 TI - Cold gel-like emulsions of lactoferrin subjected to ohmic heating. AB - Ohmic heating is a technique that has gained increasing attention because of its capacity to produce uniform heating, and claimed electrical influence on the functional and technological properties of treated protein dispersions. The aim of this work was to evaluate the influence of ohmic heating on the properties of cold gel-like emulsions, comparing them with those obtained by conventional heating. The effect of ohmic and conventional heating on physical and structural properties of lactoferrin was also addressed. Ohmic heating treatment resulted in less pronounced aggregation of lactoferrin, when compared to conventional heating. An increase of particle size, turbidity, intrinsic and extrinsic fluorescence values and a decrease of dichroic signal after heat treatment indicated an increase of protein interactions. Emulsions produced from heat treated lactoferrin showed gel-like behavior which was related to the emulsifying capacity of lactoferrin, combined with the emulsification method and the heat pre treatment applied to the protein. Rheological and microstructural properties were intrinsically related to the heat treatment of the protein since ohmic heating produced gel-like emulsions with a less rigid structure. These emulsions could be interesting for food applications containing heat-sensitive ingredients. PMID- 29389627 TI - Paste structure and rheological properties of lotus seed starch-glycerin monostearate complexes formed by high-pressure homogenization. AB - Starch-lipid complexes were prepared using lotus seed starch (LS) and glycerin monostearate (GMS) via a high-pressure homogenization (HPH) process, and the effect of HPH on the paste structure and rheological properties of LS-GMS was investigated. Rapid Visco Analyser (RVA) profiles showed that HPH treatment inhibited the formation of the second viscosity peak of the LS-GMS paste, and the extent of this change was dependent on the level of homogenized pressure. Analysis of the size-exclusion chromatography, light microscopy, and low-field 1H nuclear magnetic resonance results revealed that high homogenized pressure (70 100MPa) decreased molecular weight and size by degrading the branch structure of amylopectin; however, intact LS-GMS granules can optimize the network structure by filler-matrix interaction, which causes free water to transition into immobile water in the starch paste. The steady-shear results showed that the LS-GMS pastes presented non-Newtonian shear-thinning behavior, with higher homogenized pressure producing a smaller hysteresis loop area. During the oscillation process, the LS GMS pastes prepared at 100MPa exhibited the lowest loss tangent values in all the complexes, indicating a stronger resistance to vibration. PMID- 29389628 TI - Effect of different cooking conditions on the profiles of Maillard reaction products and nutrient composition of hairtail (Thichiurus lepturus) fillets. AB - Much attention has been given to investigate the formation of Maillard reaction products in thermal processing food due to potential health risks. This study aimed to the profiles of Maillard reaction products (MRPs) and changes of nutrient composition in hairtail (Thichiurus lepturus) fillets prepared by three cooking method: boiling, baking and frying. The Nepsilon-carboxymethyllysine (CML) level ranged from non-detectable to 4.24mg/100g protein and furosine ranged from 4.25 to 20.95mg/100g protein. The levels of CML and furosine in boiled hairtail fillets were much lower than baked and fried ones. The formation of CML was only affected by the cooking method. The changes of the lipid and moisture content, and thiobarbituric acid-reactive substances (TBARS) content in cooked hairtail fillet had different effects on the formation of different stages of Maillard reaction. Furosine level significantly correlated with absorbance in 420nm (r=0.74, p<0.05) and 280nm (r=0.73, p<0.05) and fluorescence Intensity (FI) (r=0.65, p<0.05), but did not correlate with CML. The CML level linearly correlated with the moisture (r=0.79, p<0.01) and lipid content (r=0.73, p<0.05), and the formation of TBARS value (r=0.92, p<0.01), but did not correlate with the FI. Overall, the findings may help to better control the cooking conditions of hairtail meat based on the profiles of MRPs. PMID- 29389629 TI - Detection of Shiga toxin-producing Escherichia coli (STEC) in ground beef and bean sprouts: Evaluation of culture enrichment conditions. AB - The main purpose of this work was to evaluate culture enrichment conditions, with particular regard to those reported in ISO/TS 13136:2012, for STEC detection in food. The culture media evaluated included mTSB with novobiocin 0-16mg/l (mTSB+N0 16) or acriflavin 12mg/l (mTSB+A12); BPW; mBPWp with acriflavin 10mg/l, cefsulodin 10mg/l, vancomycin 8mg/l (mBPWp+ACV); and mBPWp with cefsulodin 10mg/l, vancomycin 8mg/l (mBPWp+CV). They were used for the growth of STEC O157, O26, O103, O111, O145 and O104 in pure cultures or in artificially contaminated food matrices (ground beef, mung bean sprouts). STEC detection was accomplished using commercially available multiplex real-time PCR assays targeting stx1-stx2 and eae, and serogroup-associated genes. More rapid multiplication of STEC in pure cultures occurred in mBPWp+CV, while an inhibitory effect of novobiocin and acriflavin was observed for some STEC serogroups in media with these selective agents. mBPWp+CV allowed the detection of all serogroups in bean sprouts when inoculated at levels as low as 1CFU/25g. A reduced novobiocin concentration of 2mg/l in mTSB was required for STEC detection in ground beef samples. A temperature of 42 degrees C for the entire duration of the enrichment or 44 degrees C after an initial phase of 6h at 37 degrees C was important to limit the multiplication of non-target bacteria. Results of this study suggest that media and protocols should be adapted to the food being analyzed, since protocols provided in official reference methods may produce insufficient sensitivity. PMID- 29389630 TI - Cagaita fruit (Eugenia dysenterica DC.) and obesity: Role of polyphenols on already established obesity. AB - Polyphenol-rich cagaita (Eugenia dysenterica DC.) extracts (PCE) have previously shown to prevent body weight and adiposity induced by high-fat/high-sucrose (HFS) diet. Whether PCE also exerts protective effects in already developed obesity is unknown. In order to test this hypothesis, male C57BL/6J obese mice (previously feed with a HFS diet for six weeks) were treated with PCE at two doses, 7mg gallic acid equivalent (GAE)/kg body weight (PCE I group), and 14mg GAE/kg body weight (PCE II group) or water (HFS and Chow groups) by oral gavage for eight weeks. PCE did not affect body weight and adiposity of obese mice. However, PCE did protect against dyslipidemia, fasting hyperglycemia, and glucose intolerance, and attenuated both hepatic gluconeogenesis and inflammation as observed by the expression of tumor necrosis factor-alpha and transcriptional factor NF-kappaB. These results indicate that PCE improves glucose homeostasis of obese mice by attenuating hepatic gluconeogenesis and inflammation. PMID- 29389631 TI - Evaluating the sensory properties of unpolished Australian wild rice. AB - Australian wild rices are genetically distinct from commercially cultivated rices and present new opportunities for the development of improved rice cultivars. Before use in rice breeding, the eating and cooking properties of Australian wild rice must first be understood as these are key factors in determining rice quality and consumer acceptance. Samples of Australian wild rice (taxa B) were collected and evaluated together with a commercial Canadian wild rice (Zizania aquatic L.), Oryza sativa L.cv. Nipponbare, and selected commercial rices including long grain, medium grain, basmati, red basmati, and red rice. Cooking profiles were established, physical traits were measured and conventional descriptive analysis techniques were used to compare the sensory properties of the unpolished rices. Twenty six descriptors, together with definitions, were developed with a panel of twelve experienced assessors including aroma, flavour, texture and aftertaste attributes. Results reveal that the Australian wild rice had a mild aroma and flavour similar to that of red rice and red basmati but without the lingering aftertaste. In terms of texture, the wild rice was firmer, and somewhat crunchy and chewy rather than soft and fluffy despite requiring a longer cooking time. The sensory, physical and cooking profiles indicate that Australian wild rice has a high potential for commercialization in itself and provides a suitable genetic source for breeding programs, particularly in the coloured rice market. PMID- 29389632 TI - Evaluation of spoilage potential and volatile metabolites production by Shewanella baltica isolated from modified atmosphere packaged live mussels. AB - Under the current commercial practice, live mussels only have 10days' shelf-life. Observed spoilage indices reduce consumers' acceptance, palatability and shelf life of modified atmosphere packaged (MAP) live mussels. The aims of this study are to isolate specific spoilage bacteria from modified atmosphere packaged live mussels, evaluate isolates for microbial spoilage indices using qualitative methods and volatile metabolites production. Forty-six hydrogen sulphide producing bacteria were isolated and evaluated for trimethylamine n-oxide (TMAO) reduction, proteolytic and lipolytic activities and hydrogen sulphide production. Twenty-eight isolates were obtained from pouch water and 18 from mussel meat. All the isolates could produce H2S on Iron agar at 25 degrees C while 30/46 produced H2S at 4 degrees C and tolerate 0-6% NaCl. Four (4/46) isolates could not hydrolyse mussel protein. Over 80% isolates reduced TMAO to TMA in 3days with the production of H2S. Results of this study shows hydrogen sulphide producing bacteria isolated from MAP live mussels produce microbial spoilage indices. Isolate with highest enzymatic activities and hydrogen sulphide production was identified as Shewanella baltica using 16S rRNA gene. Axenic culture of the isolate was inoculated into sterile mussel broth. Inoculated sample was further stored at 4 degrees C for 10days for spoilage study. Volatile metabolites produced during storage were evaluated using headspace solid phase micro extraction gas chromatography mass spectrometry (HS-SPME GC/MS). A total of 44 compounds were identified in the sample after 10days while 27 compounds were identified in inoculated mussel broth. Group of compounds identified are alcohols, aldehydes, phenol, furans, ketone, esters, organic acid, aromatic hydrocarbons, alkanes, nitrogen and sulphur containing compounds. Dimethyl trisulphide, methyl-phenol, 3,5-octadiene and thiohexene were unique to inoculated mussel broth. Understanding spoilage mechanism and attendant spoilage indices will help in designing effective mussel quality protocols and shelf-life extension. PMID- 29389633 TI - Chemometric characterization of virgin olive oils of the two major Cypriot cultivars based on their fatty acid composition. AB - The effects of the geographical region and the botanical origin of olive oils on the profile of fatty acids isolated from monovarietal virgin olive oils from Cyprus were investigated, in order to establish, for the first time, promising models for authentication and classification of monovarietal virgin olive oils produced on the island. The two dominant Cypriot olive cultivars, Cypriot (ladoelia), and Koroneiki (lianolia), were analyzed for fatty acid composition by GC/FID after preparation of Fatty Acid Methyl Esters from olive oil, using a cold esterification method. The data obtained were analyzed statistically using multivariate and univariate ANOVA, principal components analysis (PCA) and hierarchical cluster analysis. Results showed that the olive oils can be separated into two distinct groups using the FAME data bank obtained from 225 samples. Significant differences in the proportion of some variables such as polyunsaturated linoleic acid, and the ratio C18:1/C18:2 from oils of different varieties and geographical regions were detected. The ratios C18:1/C18:2 and MUFA/PUFA, as well SFA, omega-9 and PUFA showed the higher discriminant power based on the cultivar. PMID- 29389634 TI - Biocontrol strategies for Mediterranean-style fermented sausages. AB - Naturally fermented meat sausages have a long tradition in Mediterranean countries and are one of the most important groups of traditional foods consumed throughout Europe. Despite all the advances in food science and technology and increased regulatory requirements and concerns for safety and quality during the last decades, the challenge to control important foodborne pathogens in this type of meat products still persists. Simultaneously, growing consumer interest in safe, high quality and minimal processed products, with less additives/preservatives have driven the food industry and scientists in a crusade for innovative technologies to maintain the safety of these products by natural means. Biological control (biocontrol) fits well within this tendency. This review summarizes the latest achievements on biocontrol strategies applied to Mediterranean-style fermented sausages, namely: (i) bioprotective cultures; (ii) bacteriocins; and, (iii) essential oils (EOs). PMID- 29389635 TI - Effects of antioxidative substances from seaweed on quality of refined liver oil of leafscale gulper shark, Centrophorus squamosus during an accelerated stability study. AB - Crude liver oil of leafscale gulper shark, Centrophorus squamosus was clarified by sequential degumming, decolorization and vacuum deodorization. The refined oil was added with ethyl acetate extract of seaweeds and various physiochemical parameters were evaluated in a time-reliant accelerated storage study. Significantly greater induction time was observed for the oil supplemented with Sargassum wightii and Sargassum ilicifolium (>4.5h) than other seaweed extracts and control oil (~1h). Among different seaweeds, the ethylacetate extracts of S. wightii maintained the oxidation indices of the refined oil below the marginal limits after the study period. No significant reduction in C20-22 long chain fatty acids (1.19%) in the refined oil added with S. wightii was apparent, and was comparable with the synthetic antioxidants (1.07-1.08%). Spectroscopic fingerprint analysis of marker compounds responsible to cause rancidity signified the efficacy of S. wightii to arrest the development of undesirable oxidation products in the refined oil during storage. The antioxidant compounds, 15-(but-19 enyl)-hexahydro-13,16-dimethyl-11-oxo-1H-isochromen-8-yl benzoate (1) and 10-(but 13-en-12-yl)-5-((furan-3-yl)propyl)-dihydrofuran-9(3H)-one (2) isolated from S. wightii appeared to play a major role to deter the oxidative degradation of refined oil thereby enhancing the storage stability. PMID- 29389637 TI - The effect of buttermilk or buttermilk powder addition on functionality, textural, sensory and volatile characteristics of Cheddar-style cheese. AB - The influence of buttermilk or buttermilk powder addition to cheese milk or cheese curds respectively on cheese functional properties, free fatty acid profiles and subsequent volatile and sensory characteristics was investigated. Buttermilk addition to cheese milk resulted in a softer cheese compared to other cheeses, with a significantly reduced flowability, while buttermilk powder addition had no influence on cheese firmness but cheese flowability was also reduced compared to the control cheese. Larger pools of free fat, higher levels of free fatty acids, volatile compounds and significant differences in sensory profiles associated with off-flavour were also observed with the addition of buttermilk to cheese milk. Application of light microscopy, using toluidine blue stain, facilitated the visualisation of fat globule structure and distribution within the protein matrix. Addition of 10% buttermilk powder resulted in significant increases in volatile compounds originating from proteolysis pathways associated with roasted, green aromas. Descriptive sensory evaluation indicated few differences between the 10% buttermilk powder and the control cheese, while buttermilk cheeses scored negatively for sweaty, barnyard aromas, oxidized and off flavors, correlating with associated volatile aromas. Addition of 10% buttermilk powder to cheese curds results in cheese comparable to the control Cheddar with some variations in volatile compounds resulting in a cheese with similar structural and sensory characteristics albeit with subtle differences in overall cheese flavor. This could be manipulated to produce cheeses of desirable quality, with potential health benefits due to increased phospholipid levels in cheese. PMID- 29389636 TI - Simulated gastrointestinal conditions increase adhesion ability of Lactobacillus paracasei strains isolated from kefir to Caco-2 cells and mucin. AB - Gastrointestinal conditions along the digestive tract are the main stress to which probiotics administrated orally are exposed because they must survive these adverse conditions and arrive alive to the intestine. Adhesion to epithelium has been considered one of the key criteria for the characterization of probiotics because it extends their residence time in the intestine and as a consequence, can influence the health of the host by modifying the local microbiota or modulating the immune response. Nevertheless, there are very few reports on the adhesion properties to epithelium and mucus of microorganisms after passing through the gastrointestinal tract. In the present work, we evaluate the adhesion ability in vitro of L. paracasei strains isolated from kefir grains after acid and bile stress and we observed that they survive simulated gastrointestinal passage in different levels depending on the strain. L. paracasei CIDCA 8339, 83120 and 83123 were more resistant than L. paracasei CIDCA 83121 and 83124, with a higher susceptibility to simulated gastric conditions. Proteomic analysis of L. paracasei subjected to acid and bile stress revealed that most of the proteins that were positively regulated correspond to the glycolytic pathway enzymes, with an overall effect of stress on the activation of the energy source. Moreover, it is worth to remark that after gastrointestinal passage, L. paracasei strains have increased their ability to adhere to mucin and epithelial cells in vitro being this factor of relevance for maintenance of the strain in the gut environment to exert its probiotic action. PMID- 29389638 TI - Predominant mycotoxins, mycotoxigenic fungi and climate change related to wine. AB - Wine is a significant contributor to the economies of many countries. However, the commodity can become contaminated with mycotoxins produced by certain fungi. Most information on mycotoxins in wine is from Spain, Italy and France. Grapes can be infected by mycotoxigenic fungi, of which Aspergillus carbonarius producing ochratoxin A (OTA) is of highest concern. Climate is the most important factor in determining contamination once the fungi are established, with high temperatures being a major factor for OTA contamination: OTA in wine is at higher concentrations in warmer southern Europe than northern. Contamination by fumonisins is a particular concern, related to Aspergillus niger producing these compounds and the fungus being isolated frequently from grapes. Aflatoxins can be present in wine, but patulin is seldom detected. Alternaria mycotoxins (e.g. alternariol) have been frequently observed. There are indications that T-2 toxin may be common. Also, the combined effects of mycotoxins in wine require consideration. No other mycotoxins are currently of concern. Accurate fungal identifications and mycotoxin detection from the fungi are important and a consideration of practical methods are required. There is a diversity of wines that can be contaminated (e.g. red, white, sweet, dry and fortified). The occurrence of OTA is higher in red and sweet than white wines. Steps to control mycotoxins in wine involve good agriculture practices. The effect of climate change on vines and mycotoxins in wine needs urgent consideration by well constructed modelling studies and expert interpretation of existing data. Reliable models of the effect of climate change on vines is a priority: the health of vines affects mycotoxin contamination. A modelling study of OTA in grapes at higher temperatures over 100years is required. Progress has been made in reducing OTA in wine. The other mycotoxins require consideration and the effects of climate change will become crucial. PMID- 29389639 TI - Effects of different cooking methods on the lipids and volatile components of farmed and wild European sea bass (Dicentrarchus labrax). AB - European sea bass is very popular in the Mediterranean area, although very little is known about the possible different behaviours of farmed and wild samples during cooking. This study addresses the effect of microwave cooking, salt crusted and conventional oven baking on the lipids and volatile profile of farmed and wild sea bass. Proton Nuclear Magnetic Resonance did not detect that hydrolysis or oxidation of lipidic components had taken place. However, Solid Phase Microextraction-Gas Chromatography/Mass Spectrometry evidenced that polyunsaturated acyl group oxidation and Maillard-type reactions occurred to a very slight extent, yielding a wide variety of volatile odour-active compounds. Conventional baking enriched fish volatile profile to a higher extent than the other two techniques assayed. In fact, 15 Maillard reaction-derived compounds (pyrroles, alkylpyrazines, alkylthiophenes and 2-ethylpyridine) were only detected in oven-baked samples. Regardless of the cooking method applied, farmed sea bass showed a much richer aromatic profile than did wild samples, having 6 fold higher lipid content than the latter. PMID- 29389640 TI - Protected Designation of Origin (PDO), Protected Geographical Indication (PGI) and Traditional Speciality Guaranteed (TSG): A bibiliometric analysis. AB - Despite the importance of the literature on food quality labels in the European Union (PDO, PGI and TSG), our search did not find any review joining the various research topics on this subject. This study aims therefore to consolidate the state of academic research in this field, and so the methodological option was to elaborate a bibliometric analysis resorting to the term co-occurrence technique. Analysis was made of 501 articles on the ISI Web of Science database, covering publications up to 2016. The results of the bibliometric analysis allowed identification of four clusters: "Protected Geographical Indication", "Certification of Olive Oil and Cultivars", "Certification of Cheese and Milk" and "Certification and Chemical Composition". Unlike the other clusters, where the PDO label predominates, the "Protected Geographical Indication" cluster covers the study of PGI products, highlighting analysis of consumer behaviour in relation to this type of product. The focus of studies in the "Certification of Olive Oil and Cultivars" cluster and the "Certification of Cheese and Milk" cluster is the development of authentication methods for certified traditional products. In the "Certification and Chemical Composition" cluster, standing out is analysis of the profiles of fatty acids present in this type of product. PMID- 29389641 TI - Mineral availability is modified by tannin and phytate content in sorghum flaked breakfast cereals. AB - Mineral availability from sorghum grain in some varieties may be low because of the presence of phytates and tannins. However, heat processing of sorghum may lower tannin and phytate levels and thus improve mineral availability. Sorghum has potential in the manufacture of gluten free breakfast cereals, therefore flaked breakfast cereals were manufactured from whole grains of three contrasting sorghum varieties and compared to that manufactured from whole grain wheat. The content of tannin, phytate, minerals (Ca, Fe and Zn), in vitro mineral availability and phytate: mineral molar ratios were determined in the raw whole grain flours and the cooked flaked breakfast cereal. For all grain varieties, the in vitro mineral availability of flaked breakfast cereal was higher than the raw flours, an effect most probably related to the concomitant reduction in tannins and phytate levels after processing. The in vitro mineral availability of the flaked wheat breakfast cereal was significantly higher than that of all sorghum breakfast cereals, with that manufactured from the brown sorghum IS8237C having the lowest value (p<=0.05). Given that the sorghum varieties in this study gave lower mineral availability than wheat, other sorghum varieties now require evaluation to identify those with improved mineral availability. PMID- 29389642 TI - Migration of antioxidants from polylactic acid films: A parameter estimation approach and an overview of the current mass transfer models. AB - Migration studies of chemicals from contact materials have been widely conducted due to their importance in determining the safety and shelf life of a food product in their packages. The US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA) require this safety assessment for food contact materials. So, migration experiments are theoretically designed and experimentally conducted to obtain data that can be used to assess the kinetics of chemical release. In this work, a parameter estimation approach was used to review and to determine the mass transfer partition and diffusion coefficients governing the migration process of eight antioxidants from poly(lactic acid), PLA, based films into water/ethanol solutions at temperatures between 20 and 50 degrees C. Scaled sensitivity coefficients were calculated to assess simultaneously estimation of a number of mass transfer parameters. An optimal experimental design approach was performed to show the importance of properly designing a migration experiment. Additional parameters also provide better insights on migration of the antioxidants. For example, the partition coefficients could be better estimated using data from the early part of the experiment instead at the end. Experiments could be conducted for shorter periods of time saving time and resources. Diffusion coefficients of the eight antioxidants from PLA films were between 0.2 and 19*10-14m2/s at ~40 degrees C. The use of parameter estimation approach provided additional and useful insights about the migration of antioxidants from PLA films. PMID- 29389643 TI - Microbial inactivation and cytotoxicity evaluation of UV irradiated coconut water in a novel continuous flow spiral reactor. AB - : A continuous-flow UV reactor operating at 254nm wave-length was used to investigate inactivation of microorganisms including bacteriophage in coconut water, a highly opaque liquid food. UV-C inactivation kinetics of two surrogate viruses (MS2, T1UV) and three bacteria (E. coli ATCC 25922, Salmonella Typhimurium ATCC 13311, Listeria monocytogenes ATCC 19115) in buffer and coconut water were investigated (D10 values ranging from 2.82 to 4.54mJ.cm-2). A series of known UV-C doses were delivered to the samples. Inactivation levels of all organisms were linearly proportional to UV-C dose (r2>0.97). At the highest dose of 30mJ.cm-2, the three pathogenic organisms were inactivated by >5 log10 (p<0.05). Results clearly demonstrated that UV-C irradiation effectively inactivated bacteriophage and pathogenic microbes in coconut water. The inactivation kinetics of microorganisms were best described by log linear model with a low root mean square error (RMSE) and high coefficient of determination (r2>0.97). Models for predicting log reduction as a function of UV-C irradiation dose were found to be significant (p<0.05) with low RMSE and high r2. The irradiated coconut water showed no cytotoxic effects on normal human intestinal cells and normal mouse liver cells. Overall, these results indicated that UV-C treatment did not generate cytotoxic compounds in the coconut water. This study clearly demonstrated that high levels of inactivation of pathogens can be achieved in coconut water, and suggested potential method for UV-C treatment of other liquid foods. INDUSTRIAL RELEVANCE: This research paper provides scientific evidence of the potential benefits of UV-C irradiation in inactivating bacterial and viral surrogates at commercially relevant doses of 0-120mJ.cm-2. The irradiated coconut water showed no cytotoxic effects on normal intestinal and healthy mice liver cells. UV-C irradiation is an attractive food preservation technology and offers opportunities for horticultural and food processing industries to meet the growing demand from consumers for healthier and safe food products. This study would provide technical support for commercialization of UV C treatment of beverages. PMID- 29389644 TI - Development of a partial least squares-artificial neural network (PLS-ANN) hybrid model for the prediction of consumer liking scores of ready-to-drink green tea beverages. AB - In order to develop products that would be preferred by consumers, the effects of the chemical compositions of ready-to-drink green tea beverages on consumer liking were studied through regression analyses. Green tea model systems were prepared by dosing solutions of 0.1% green tea extract with differing concentrations of eight flavour keys deemed to be important for green tea aroma and taste, based on a D-optimal experimental design, before undergoing commercial sterilisation. Sensory evaluation of the green tea model system was carried out using an untrained consumer panel to obtain hedonic liking scores of the samples. Regression models were subsequently trained to objectively predict the consumer liking scores of the green tea model systems. A linear partial least squares (PLS) regression model was developed to describe the effects of the eight flavour keys on consumer liking, with a coefficient of determination (R2) of 0.733, and a root-mean-square error (RMSE) of 3.53%. The PLS model was further augmented with an artificial neural network (ANN) to establish a PLS-ANN hybrid model. The established hybrid model was found to give a better prediction of consumer liking scores, based on its R2 (0.875) and RMSE (2.41%). PMID- 29389645 TI - Brea gum as wall material in the microencapsulation of corn oil by spray drying: Effect of inulin addition. PMID- 29389646 TI - A fast semi-quantitative screening for cocoa content in chocolates using MALDI MSI. AB - Chocolate is a popular food bearing a number of different classifications that are differentiated by proportions of cocoa solids, milk and cocoa butter. Literature brings evidence that chocolates with a high percentage of cocoa solids contribute to good health maintenance due to the presence of phenolic compounds. On the other hand, it is known that the productive process, including pre processing, may influence the level of these substances in the finished product. Thus, accurate strategies to measure the levels of this class of molecules that can be highly adaptable throughout the manufacturing process are important to ensure high-quality products. Mass spectrometry is an analytical tool of high sensitivity and specificity that is leading the research in food analysis towards new directions. By using mass spectrometry imaging in direct food analysis, this contribution developed an effective methodology for comparatively establishing the levels of catechin/epicatechin as phenolics content markers for cocoa content in a series of commercial chocolates from a single manufacturer, rendering a versatile tool that can be applied in fast screening of cocoa content in finished products and during manufacturing. PMID- 29389647 TI - Whole cereal grains and potential health effects: Involvement of the gut microbiota. AB - The intakes of whole cereal grains (WCGs) have long been linked to decreased risks of metabolic syndromes (MetS) and several chronic diseases. Owing to the complex range of components of cereals, which may show synergistic activities to mediate these protective effects, the mechanisms by which the benefits of whole cereals arise are not fully understood. The gut microbiota has recently become a new focus of research at the intersection of diet and metabolic health. Moreover, cereals contain various ingredients known as microbiota-accessible substrates that resist digestion in the upper gastrointestinal tract, including resistant starch and non-starch polysaccharides such as beta-glucan and arabinoxylans, making them an important fuel for the microbiota. Thus, WCGs may manipulate the ecophysiology of gut microbiota. In this review, the scientific evidence supporting the hypothesis that WCGs prevent MetS by modulating gut microbiota composition and functions are discussed, with focuses on cereal intake-related mechanisms by which gut microbiota contributes to human health and scientific evidences for the effects of WCGs on modulating gut microbiota. Once strong support for the association among WCGs, gut microbiota and host metabolic health can be demonstrated, particular cereals, their processing technologies, or cereal based foods might be better utilized to prevent and possibly even treat metabolic disease. PMID- 29389648 TI - Pressure Pulse Distortion by Needle and Fiber-Optic Hydrophones due to Nonuniform Sensitivity. AB - Needle and fiber-optic hydrophones have frequency-dependent sensitivity, which can result in substantial distortion of nonlinear or broadband pressure pulses. A rigid cylinder model for needle and fiber-optic hydrophones was used to predict this distortion. The model was compared with measurements of complex sensitivity for a fiber-optic hydrophone and three needle hydrophones with sensitive element sizes ( ) of 100, 200, 400, and . Theoretical and experimental sensitivities agreed to within 12 +/- 3% [root-mean-square (RMS) normalized magnitude ratio] and 8 degrees +/- 3 degrees (RMS phase difference) for the four hydrophones over the range from 1 to 10 MHz. The model predicts that distortions in peak positive pressure can exceed 20% when and spectral index (SI) >7% and can exceed 40% when and SI >14%, where is the wavelength of the fundamental component and SI is the fraction of power spectral density contained in harmonics. The model predicts that distortions in peak negative pressure can exceed 15% when . Measurements of pulse distortion using a 2.25 MHz source and needle hydrophones with , 400, and agreed with the model to within a few percent on the average for SI values up to 14%. This paper 1) identifies conditions for which needle and fiber-optic hydrophones produce substantial distortions in acoustic pressure pulse measurements and 2) offers a practical deconvolution method to suppress these distortions. PMID- 29389649 TI - Improved Super-Resolution Ultrasound Microvessel Imaging With Spatiotemporal Nonlocal Means Filtering and Bipartite Graph-Based Microbubble Tracking. AB - Super-resolution ultrasound microvessel imaging with contrast microbubbles has recently been proposed by multiple studies, demonstrating outstanding resolution with high potential for clinical applications. This paper aims at addressing the potential noise issue in in vivo human super-resolution imaging with ultrafast plane-wave imaging. The rich spatiotemporal information provided by ultrafast imaging presents features that allow microbubble signals to be separated from background noise. In addition, the high-frame-rate recording of microbubble data enables the implementation of robust tracking algorithms commonly used in particle tracking velocimetry. In this paper, we applied the nonlocal means (NLM) denoising filter on the spatiotemporal domain of the microbubble data to preserve the microbubble tracks caused by microbubble movement and suppress random background noise. We then implemented a bipartite graph-based pairing method with the use of persistence control to further improve the microbubble signal quality and microbubble tracking fidelity. In an in vivo rabbit kidney perfusion study, the NLM filter showed effective noise rejection and substantially improved microbubble localization. The bipartite graph pairing and persistence control demonstrated further noise reduction, improved microvessel delineation, and a more consistent microvessel blood flow speed measurement. With the proposed methods and freehand scanning on a free-breathing rabbit, a single microvessel cross-sectional profile with full-width at half-maximum of could be imaged at approximately 2-cm depth (ultrasound transmit center frequency = 8 MHz, theoretical spatial resolution ). Cortical microvessels that are apart can also be clearly separated. These results suggest that the proposed methods have good potential in facilitating robust in vivo clinical super-resolution microvessel imaging. PMID- 29389650 TI - Lorentz Force Electrical-Impedance Tomography Using Linearly Frequency-Modulated Ultrasound Pulse. AB - Lorentz force electrical-impedance tomography (LFEIT) combines ultrasound stimulation and electromagnetic field detection with the goal of creating a high contrast and high-resolution hybrid imaging modality. To reduce the peak stimulation power to the ultrasound transducer in LFEIT, linearly frequency modulated (LFM) ultrasound pulse was investigated in this paper. First, the coherency between LFM ultrasound excitation and the resulting local current density was established theoretically. Then, experiments were done using different agar phantoms of conductivity ranging from 0.2 to 0.5 S/m. The results showed: 1) using electrical signal of peak instantaneous power of 39.54 dBm to the ultrasound transducer, which was 25.5 dB lower than the peak instantaneous power of the high-voltage narrow pulse adopted in traditional LFEIT (65.05 dBm), the LFM ultrasound pulse-based LFEIT can detect the electrical conductivity discontinuity positions precisely; 2) the reconstructed B-scan image of the electrical conductivity discontinuity distribution is comparable to that obtained through LFEIT with high-voltage narrow pulse; and 3) axial resolution of 1 mm was achieved with the experimental setup. The method of LFM ultrasound pulse stimulation and coherent detection initiates an alternative scheme toward the clinical application of LFEIT. PMID- 29389652 TI - Real-Time Blood Velocity Vector Measurement Over a 2-D Region. AB - Quantitative blood velocity measurements, as currently implemented in commercial ultrasound scanners, are based on pulsed-wave (PW) spectral Doppler and are limited to detect the axial component of the velocity in a single sample volume. On the other hand, vector Doppler methods produce angle-independent estimates by, e.g., combining the frequency shifts measured from different directions. Moreover, thanks to the transmission of plane waves, the investigation of a 2-D region is possible with high temporal resolution, but, unfortunately, the clinical use of these methods is hampered by the massive calculation power required for their real-time execution. In this paper, we present a novel approach based on the transmission of plane waves and the simultaneous reception of echoes from 16 distinct subapertures of a linear array probe, which produces eight lines distributed over a 2-D region. The method was implemented on the ULAO OP 256 research scanner and tested both in phantom and in vivo. A continuous real time refresh rate of 36 Hz was achieved in duplex combination with a standard B mode at pulse repetition frequency of 8 kHz. Accuracies of -11% on velocity and of 2 degrees on angle measurements have been obtained in phantom experiments. Accompanying movies show how the method improves the quantitative measurements of blood velocities and details the flow configurations in the carotid artery of a volunteer. PMID- 29389651 TI - Application of Acoustoelasticity to Evaluate Nonlinear Modulus in Ex Vivo Kidneys. AB - Currently, dynamic elastography techniques estimate the linear elastic shear modulus of different body tissues. New methods that investigate other properties of soft tissues such as anisotropy, viscosity, and shear nonlinearity would provide more information about the structure and function of the tissue and might provide a better contrast than tissue stiffness and hence provide more effective diagnostic tools for some diseases. It has previously been shown that shear wave velocity in a medium changes due to an applied stress, a phenomenon called acoustoelasticity (AE). Applying a stress to compress a medium while measuring the shear wave velocity versus strain provides data with which the third-order nonlinear shear modulus can be estimated. To evaluate the feasibility of estimating , we evaluated ten ex vivo porcine kidneys embedded in 10% porcine gelatin to mimic the case of a transplanted kidney. Under assumptions of an elastic incompressible medium for AE measurements, the shear modulus was quantified at each compression level and the applied strain was assessed by measuring the change in the thickness of the kidney cortex. Finally, was calculated by applying the AE theory. Our results demonstrated that it is possible to estimate a nonlinear shear modulus by monitoring the changes in strain and due to kidney deformation. The magnitudes of are higher when the compression is performed progressively and when using a plate attached to the transducer. Nevertheless, the values obtained for are similar to those previously reported in the literature for breast tissue. PMID- 29389653 TI - Accumulated Angle Factor-Based Beamforming to Improve the Visualization of Spinal Structures in Ultrasound Images. AB - In recent years, ultrasound has been increasingly used to guide needle insertion procedures for spinal anesthesia. The primary anatomical targets are facet joints and epidural spaces. For these procedures, accurate visualization of the spine anatomy is of critical importance. Challenges arising from the interactions between the ultrasound beam and spinal structures including tilt caused by specular reflections, off-axis interference, and reverberations often result in weakened and blurred vertebra surfaces. Previously, adaptive beamforming methods have been proposed to improve the resolution and contrast. However, most of these methods are not specialized for improving the contrast of specular targets like bones. In this paper, we propose an accumulated angle factor (AAF)-based beamforming method customized for bone surface enhancement. This approach applies a Hilbert transform on delay compensated channel data across the receive aperture. The accumulated phase change across the receive aperture is then calculated and utilized as the weight in the beamforming output. We compared our method with classical delay and sum (DAS) beamforming method and adaptive beamforming methods such as Wiener, phase coherence factor (PCF), CF, and generalized CF (GCF) beamforming. In 12 volunteer data sets, the mean contrast ratio between the vertebrae surface and the surrounding tissue for DAS, Wiener, PCF, CF, GCF, and the proposed AAF methods are 0.49, 0.64, 0.82, 0.77, 0.76, and 0.91, respectively. The contrast is significantly improved in the proposed method. PMID- 29389654 TI - High-Performance Ultrasound Needle Transducer Based on Modified PMN-PT Ceramic With Ultrahigh Clamped Dielectric Permittivity. AB - A modified Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) polycrystalline ceramic with ultrahigh relative clamped dielectric permittivity ( ) and high piezoelectric properties ( pC/N, ) was used to fabricate high-frequency miniature ultrasound transducers. A 39-MHz high-frequency ultrasound needle transducer with a miniature aperture of 0.4 mm mm was designed and successfully characterized. The fabricated needle transducer had an electromechanical coupling factor of 0.55, large bandwidth of 80% at -6 dB, and low insertion loss of -13 dB. A wire phantom and porcine eyeball imaging study showed good imaging capability of this needle transducer. The transducer performance was found to be superior to that of other needle transducers with miniature apertures, making this modified PMN-PT ceramic based needle transducer quite promising for minimally invasive procedures in medical applications. PMID- 29389655 TI - Ultrasonic Analytic-Signal Responses From Polymer-Matrix Composite Laminates. AB - Ultrasound has been used to inspect composite laminates since their invention but only recently has the response from the internal plies themselves been considered of interest. This paper uses modeling techniques to make sense of the fluctuating and interfering reflections from the resin layers between plies, providing clues to the underlying inhomogeneities in the structure. It shows how the analytic signal, analyzed in terms of instantaneous amplitude, phase, and frequency, allows 3-D characterization of the microstructure. It is found that, under certain conditions, the phase becomes locked to the interfaces between plies and that the first and last plies have characteristically different instantaneous frequencies. This allows the thin resin layers between plies to be tracked through various features and anomalies found in real composite components (ply drops, tape gaps, tape overlaps, and out-of-plane wrinkles), giving crucial information about conformance to design of as-manufactured components. Other types of defects such as delaminations are also considered. Supporting evidence is provided from experimental ultrasonic data acquired from real composite specimens and compared with X-ray computed tomography images and microsections. PMID- 29389656 TI - Fourier Collocation Approach With Mesh Refinement Method for Simulating Transit Time Ultrasonic Flowmeters Under Multiphase Flow Conditions. AB - A numerical model for transit-time ultrasonic flowmeters operating under multiphase flow conditions previously presented by us is extended by mesh refinement and grid point redistribution. The method solves modified first-order stress-velocity equations of elastodynamics with additional terms to account for the effect of the background flow. Spatial derivatives are calculated by a Fourier collocation scheme allowing the use of the fast Fourier transform, while the time integration is realized by the explicit third-order Runge-Kutta finite difference scheme. The method is compared against analytical solutions and experimental measurements to verify the benefit of using mapped grids. Additionally, a study of clamp-on and in-line ultrasonic flowmeters operating under multiphase flow conditions is carried out. PMID- 29389657 TI - Diffraction Effects and Compensation in Passive Acoustic Mapping. AB - Over the last decade, a variety of noninvasive techniques have been developed to monitor therapeutic ultrasound procedures in support of safety or efficacy assessments. One class of methods employs diagnostic ultrasound arrays to sense acoustic emissions, thereby providing a means to passively detect, localize, and quantify the strength of nonlinear sources, including cavitation. Real array element diffraction patterns may differ substantially from those presumed in existing beamforming algorithms. However, diffraction compensation has received limited treatment in passive and active imaging, and measured diffraction data have yet to be used for array response correction. The objectives of this paper were to identify differences between ideal and real element diffraction patterns, and to quantify the impact of diffraction correction on cavitation mapping beamformer performance. These objectives were addressed by performing calibration measurements on a diagnostic linear array, using the results to calculate diffraction correction terms, and applying the corrections to cavitation emission data collected from soft tissue phantom experiments. Measured diffraction patterns were found to differ significantly from those of ideal element forms, particularly at higher frequencies and shorter distances from the array. Diffraction compensation of array data resulted in cavitation energy estimates elevated by as much as a factor of 5, accompanied by the elimination of a substantial bias between two established beamforming algorithms. These results illustrate the importance of using measured array responses to validate analytical field models and to minimize observation biases in imaging applications where quantitative analyses are critical for assessment of therapeutic safety and efficacy. PMID- 29389658 TI - Full Wavefield Analysis and Damage Imaging Through Compressive Sensing in Lamb Wave Inspections. AB - One of the main challenges faced by the structural health monitoring community is acquiring and processing huge sets of acoustic wavefield data collected from sensors, such as scanning laser Doppler vibrometers or ultrasonic scanners. In fact, extracting information that allows the estimation of the damage condition of a structure can be a time-consuming process. This paper presents a damage detection and localization technique based on a compressive sensing algorithm, which significantly allows us to reduce the acquisition time without losing in detection accuracy. The proposed technique exploits the sparsity of the wavefield in different representation domains, such as those spanned by wave atoms, curvelets, and Fourier exponentials to recover the full wavefield and, at the same time, to infer the damage location, based on comparison between the wavefield reconstructions produced by the different representation domains. The procedure is applied to three different setups related to an aluminum plate with a notch, a glass fiber reinforced polymer plate with a notch, and a composite plate with a delamination. The results show that the technique can be applied in a variety of structural components to reduce acquisition time and achieve high performance in defect detection and localization by removing up to 80% of the Nyquist sampling grid. PMID- 29389659 TI - High-Q Tuneable 10-GHz Bragg Resonator for Oscillator Applications. AB - This paper describes the design, simulation, and measurement of a tuneable 9.365 GHz aperiodic Bragg resonator. The resonator utilizes an aperiodic arrangement of non ( /4) low-loss alumina plates ( , loss tangent of to ) mounted in a cylindrical metal waveguide. Tuning is achieved by varying the length of the center section of the cavity. A multi-element bellows/probe assembly is presented. A tuning range of 130 MHz (1.39%) is demonstrated. The insertion loss varies from -2.84 to -12.03 dB while the unloaded Q varies from 43 788 to 122 550 over this tuning range. At 10 of the 13 measurement points, the unloaded Q exceeds 1 00 000, and the insertion loss is above -7 dB. Two modeling techniques are discussed; these include a simple ABCD circuit model for rapid simulation and optimization and a 2.5-D field solver, which is used to plot the field distribution inside the cavity. PMID- 29389660 TI - Not All Noise Is the Same: Fluctuations in Transportation Noise Levels and Arterial Stiffness. PMID- 29389662 TI - Pediatric reference intervals for 1,25-dihydroxyvitamin D using the DiaSorin LIAISON XL assay in the healthy CALIPER cohort. AB - BACKGROUND: 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active vitamin D metabolite, plays a critical role in calcium and phosphate homeostasis. 1,25(OH)2D is measured to assess calcium and phosphate metabolism, particularly during periods of profound growth and development. Despite its importance, no reliable pediatric reference interval exists, with those available developed using adult populations or out-dated methodologies. Using the fully automated chemiluminescence immunoassay by DiaSorin, we established 1,25(OH)2D pediatric reference intervals using healthy children and adolescents from the CALIPER cohort. METHODS: Serum samples from healthy subjects (0 to <19 years) were analyzed for 1,25(OH)2D using the DiaSorin LIAISON XL assay and age-specific reference intervals were established. The Mann-Whitney U-test was used to determine seasonal differences. Pooled neonatal and infantile samples were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine if elevated concentrations during the first year of life may be attributed to cross-reacting moieties. RESULTS: Three reference interval age partitions were required with highest levels in subjects 0 to <1 year (77-471 pmol/L), which declined and narrowed after 1 year (113-363 pmol/L) and plateaued at 3 years (108-246 pmol/L). 1,25(OH)2D concentration was not significantly affected by seasonal variation or sex. Elevated 1,25(OH)2D concentrations in neonatal and infantile samples may be the result of an interfering substance. The absence of 3-epi-1,25-dihydroxyvitamin D in the pooled samples makes it unlikely to be the interfering moiety. CONCLUSIONS: Pediatric reference intervals for 1,25(OH)2D were established to improve test result interpretation in children and adolescents. 1,25(OH)2D is elevated in a proportion of neonates and infants, which may be the result of a cross-reacting moiety. PMID- 29389661 TI - Differential in Vitro Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand-ERalpha Complexes. AB - BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. OBJECTIVES: Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERalpha) complex. METHODS: In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERalpha complex. RESULTS: We demonstrated that BPA and BPAF have agonistic activity for both ERalpha and ERbeta, but BPS has ERalpha-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER-ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERalpha was characterized for the BPA, BPAF, and BPS complexes. CONCLUSION: These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER mediated transcriptional activation, biological activity, and their effects on physiological functions in human health. https://doi.org/10.1289/EHP2505. PMID- 29389663 TI - Harmonization of interpretative comments in laboratory hematology reporting: the recommendations of the Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH-SIBioC). AB - The goal of harmonizing laboratory testing is contributing to improving the quality of patient care and ultimately ameliorating patient outcome. The complete blood and leukocyte differential counts are among the most frequently requested clinical laboratory tests. The morphological assessment of peripheral blood cells (PB) through microscopic examination of properly stained blood smears is still considered a hallmark of laboratory hematology. Nevertheless, a variable inter observer experience and the different terminology used for characterizing cellular abnormalities both contribute to the current lack of harmonization in blood smear revision. In 2014, the Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH SIBioC) conducted a national survey, collecting responses from 78 different Italian laboratories. The results of this survey highlighted a lack of harmonization of interpretative comments in hematology, which prompted the WGDH SIBioC to develop a project on "Harmonization of interpretative comments in the laboratory hematology report", aimed at identifying appropriate comments and proposing a standardized reporting system. The comments were then revised and updated according to the 2016 revision of the World Health Organization classification of hematologic malignancies. In 2016, the Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH SIBioC) published its first consensus based recommendation for interpretative comments in laboratory hematology reporting whit the purpose of evaluating comments and the aim to (a) reducing their overall number, (b) standardizing the language, (c) providing information that could be easily comprehended by clinicians and patients, (d) increasing the quality of the clinical information, and (e) suggesting additional diagnostic tests when necessary. This paper represents a review of the recommendations of the former document. PMID- 29389664 TI - Joint Models of Longitudinal and Time-to-Event Data with More Than One Event Time Outcome: A Review. AB - Methodological development and clinical application of joint models of longitudinal and time-to-event outcomes have grown substantially over the past two decades. However, much of this research has concentrated on a single longitudinal outcome and a single event time outcome. In clinical and public health research, patients who are followed up over time may often experience multiple, recurrent, or a succession of clinical events. Models that utilise such multivariate event time outcomes are quite valuable in clinical decision-making. We comprehensively review the literature for implementation of joint models involving more than a single event time per subject. We consider the distributional and modelling assumptions, including the association structure, estimation approaches, software implementations, and clinical applications. Research into this area is proving highly promising, but to-date remains in its infancy. PMID- 29389665 TI - Acorus calamus: a bio-reserve of medicinal values. AB - Many plants are found to possess reliable pharmacological properties and have started to attract the attention of researchers. One such holistic plant is Acorus calamus, commonly known as sweet flag, belonging to the rhizomatous family Acoraceae. The different parts of this plant, such as the leaves and rhizomes, are used traditionally in different medicinal preparations for the treatment of various ailments including arthritis, neuralgia, diarrhoea, dyspepsia, kidney and liver troubles, eczema, sinusitis, asthma, fevers, bronchitis, hair loss, and other disorders. Many reports have also appeared in mainstream scientific journals confirming its nutritional and medicinal properties. Biochemical analysis of the plant has revealed a large number of secondary metabolites that may be responsible for its rich medicinal properties. Basic scientific research has uncovered the mechanisms by which itexerts its therapeutic effects. Medicinal herbs such as A. calamus are quite promising in the recent therapeutic scenario, with a large number of people favouring remedies and health approaches that are free from the side effects often associated with synthetic chemicals. In this review, we try to summarise the ethno-medicinal uses, botanical descriptions, phytochemical constituents, and biological activity of the plant parts, as well as the molecular targets of A. calamus, which we hope will serve as a good base for further work on this plant. PMID- 29389666 TI - Metabolic features and changes in glucose-induced serum glucagon-like peptide-1 levels in children with hypothalamic obesity. AB - BACKGROUND: Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. METHODS: Subjects included eight patients (six females, aged 9-16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. RESULTS: Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). CONCLUSIONS: Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO. PMID- 29389667 TI - Sarcopenia in diabetic nephropathy: a cross-sectional study. AB - OBJECTIVE: To investigate the relationship between sarcopenia and diabetic nephropathy. METHODS: 56 diabetic patients without complications, 50 diabetic patients with nephropathy, 53 healthy controls included in this present study. Demographic characteristics such as sex, age, anthropometric measurements such as weight, body mass index [BMI], hip circumference, waist circumference and upper arm circumference were measured. Sarcopenia diagnosis was based on European Working Group on Sarcopenia in Older People [EWGSOP] criteria which consist of hand grip strength, 6-meter walking test and muscle mass. RESULTS: The frequency of sarcopenia increased gradually from 15.1% in healthy control group to 21.4% in the diabetes group, and 34% in diabetic nephropathy group (X2 for trend, p = 0.029). The frequency of sarcopenia was similar in diabetes and diabetic nephropathy group. However, the frequency of sarcopenia was higher in diabetic nephropathy than healthy controls (OR = 2.89, CI [1.11-7.51] in logistic regression). CONCLUSION: In the present study, the prevalence of sarcopenia was higher in patients with diabetic nephropathy compared to healthy controls. PMID- 29389668 TI - Facile synthesis of dispersed Ag nanoparticles on chitosan-TiO2 composites as recyclable nanocatalysts for 4-nitrophenol reduction. AB - This paper presents a facile, rapid, and controllable procedure for the recovery of trace Ag+ ions and in situ assembly of well dispersed Ag nanoparticles on chitosan-TiO2 composites through bioaffinity adsorption followed by photocatalytic reduction. The prepared Ag nanoparticles are proven to be efficient and recyclable nanocatalysts for the reduction of 4-nitrophenol to 4 aminophenol in the presence of NaBH4. Well dispersed quasi-spherical Ag NPs are synthesized in 20 min in the designed inner-irradiated photocatalytic system under a wide range of Ag+ concentrations (50-200 mg l-1), temperatures (10 degrees C-25 degrees C) conditions, and UV or visible light irradiation. The synthesized Ag NPs can catalyze the reduction of 4-nitrophenol by NaBH4 at 100% conversion in 120 min and preserve the catalytic activity in five successive cycles. This procedure for trace Ag+ ions recovery and Ag NPs assembly has the potential to be scaled up for the mass production of recyclable Ag nanocatalysts. The present work provides a green and efficient procedure for the conversion of hazardous 4-nitrophenol to industrially important 4-aminophenol and also sheds a light on designing scaled-up procedures for treating high volumes of wastewater with dilute heavy metals to produce recyclable metallic nanocatalysts in aqueous systems. PMID- 29389669 TI - Polyaniline-stabilized electromagnetic wave absorption composites of reduced graphene oxide on magnetic carbon nanotube film. AB - A multi-layered composite with exceptionally high electromagnetic wave-absorbing capacity and performance stability was fabricated via the facile electrophoresis of a reduced graphene oxide network on carbon nanotube (CNT)-Fe3O4-polyaniline (PANI) film. Minimum reflection loss (RL) of -53.2 dB and absorbing bandwidth of 5.87 GHz (< -10 dB) are achieved, surpassing most recently reported CNT- and graphene-based absorbers. In particular, comparing to the original composites, the minimum RL and bandwidth (< -10 dB) maintains 82.5% and 99.7%, respectively, after 20 h charge/discharge cycling, demonstrating high environmental suitability. PMID- 29389670 TI - Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt. AB - Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC. PMID- 29389672 TI - Lacosamide in the Management of Behavioral Symptoms in Frontotemporal Dementia: A 2-Case Report. PMID- 29389671 TI - A controlled human malaria infection model enabling evaluation of transmission blocking interventions. AB - BACKGROUND: Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS: Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum-infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. RESULTS: Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe - fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase - and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. CONCLUSION: We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission blocking interventions in this model. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431637 and NCT02431650. FUNDING: Bill & Melinda Gates Foundation. PMID- 29389673 TI - Low molecular weight heparin versus rivaroxaban in the treatment of venous thromboembolism in gastrointestinal malignancies. AB - : Due to their ease of use, the direct oral anticoagulants (DOACs) are an attractive treatment option for cancer-associated venous thromboembolism (VTE) and have been readily adopted by many clinicians. A recent published study comparing a DOAC (edoxaban) to the current standard-of-care low molecular weight heparin dalteparin for the treatment of cancer-associated thrombosis showed that edoxaban was noninferior to dalteparin for recurrent VTE, but the risk of major bleeding was higher. We present three patients with high-risk gastrointestinal malignancies complicated by cancer-associated VTE with progression of thrombosis while treated with the oral direct Xa inhibitor rivaroxaban. Upon switching therapy to low molecular weight heparin, we found that these patients had clinical and radiologic improvement of VTE. More studies are needed to evaluate the efficacy of rivaroxaban in high-risk gastrointestinal-VTE. We suggest that in some patients, DOACs may not be sufficient for the treatment of VTEs related to high-risk gastrointestinal malignancies. PMID- 29389674 TI - Inherited factor II deficiency with paradoxical hypercoagulability: a case report. AB - : Congenital deficiency of factor II is a very rare autosomal recessive disorder that can result in a bleeding diathesis. Genotypically, individuals are either homozygous for a defective prothrombin gene or a compound heterozygote with different mutated prothrombin genes inherited from each parent. Phenotypically, it is characterized by either a low production of normal prothrombin or a near normal production of dysfunctional prothrombin. Treatment is aimed at restoring normally functioning factor II circulating levels to sufficient concentration for hemostasis. Paradoxical thrombosis in patients born from a nonconsanguineous marriage with factor II deficiency has not been reported. A woman with known congenital factor II deficiency confirmed by history and hemostatic laboratory analysis presented with an unprovoked spontaneous thrombosis of the common femoral vein detected on color Doppler. Venous thrombosis can occur in congenital deficiency of factor II and inferior vena cava filter can be life-saving. PMID- 29389675 TI - Recovery of reproductive function following androgen abuse. AB - PURPOSE OF REVIEW: To summarize recent data on the adverse reproductive consequences of androgen abuse, focusing on the recovery of reproductive function following androgen discontinuation. RECENT FINDINGS: Evidence is mostly based on case reports and observational studies. Androgen abuse leads to a state of hypogonadotropic hypogonadism associated with impaired spermatogenesis, testicular atrophy, gynecomastia as well as menstrual irregularities, virilization and subfertility. Recovery of the hypothalamic-pituitary-gonadal axis following androgen withdrawal depends on the type and characteristics of androgen administration (dose, duration of use) as well as those of the user (age, previous reproductive function). Biochemical and clinical features of hypogonadism may be evident months or even years following androgen discontinuation. To prevent androgen-related adverse effects and accelerate recovery of gonadal function, users take androgens in a cyclical fashion and use drugs such as human chorionic gonadotropin, antiestrogens and aromatase inhibitors, even though there is limited evidence to support efficacy of these strategies. As few studies refer to female androgen users, there is a lack of data concerning recovery from androgen-related reproductive side effects in women. SUMMARY: Androgen abuse has profound and commonly under-recognized effects on the reproductive system; recovery following androgen withdrawal may be prolonged and occasionally incomplete. PMID- 29389676 TI - Decreased Cognitive Functioning After Electroconvulsive Therapy Is Related to Increased Hippocampal Volume: Exploring the Role of Brain Plasticity. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is still the most effective treatment of severe and therapy-refractory major depressive disorder. Cognitive side effects are the major disadvantage of ECT. Cognitive deficits are generally temporary in nature and may be mediated by the hippocampus. Recent studies have shown a temporary increase in hippocampal volume and a temporary decrease in cognitive functioning post-ECT compared with pre-ECT. This study investigates whether these volumetric changes are related to changes in cognitive functioning after ECT. METHODS: Nineteen medication-free patients with treatment-resistant major depressive disorder underwent a whole-brain magnetic resonance imaging scan and a neuropsychological examination (including the Rey auditory verbal learning task, Wechsler Memory Scale Visual Reproduction, fluency, Trail Making Task) within 1 week before and within 1 week after the course of ECT. Electroconvulsive therapy was administered twice a week bitemporally with a brief pulse. A matched healthy control group (n = 18) received the same neuropsychological examination and at a similar interval to that of the patients. RESULTS: Hippocampal volumes increased significantly from pretreatment to posttreatment in patients. Mean performance on cognitive tasks declined, or remained stable, whereas performance in controls generally improved because of retesting effects. The increase in hippocampal volume was related to changes in cognitive performance, indicating that this increase co-occurred with a decrease in cognitive functioning. CONCLUSIONS: Our findings tentatively suggest that the temporal increase in hippocampal volume after treatment, which may result from neurotrophic processes and is thought to be crucial for the antidepressive effect, is also related to the temporary cognitive side effects of ECT. PMID- 29389677 TI - "See Many, Do None, Now We Need Your Help": Airway Management by the Psychiatrist During Electroconvulsive Therapy. PMID- 29389678 TI - Orally Administered Combination of Hyaluronic Acid, Chondroitin Sulfate, Curcumin, and Quercetin in the Prevention of Postcoital Recurrent Urinary Tract Infections: Analysis of 98 Women in Reproductive Age After 6 Months of Treatment. AB - OBJECTIVE: The aim of this study is to assess the efficacy of orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin for the prevention of postcoital recurrent urinary tract infection (UTI) in reproductive age women. METHODS: Ninety-eight consecutive patients in reproductive age affected by UTI were considered for the study. All 98 patients received a combination of HA, CS, curcumin, and quercetin two tablets per diem for the first month and one tablet every day for the next 5 months. We investigate recurrence of UTI with the Urinary Tract Infection Symptoms Assessment and the Pelvic Pain and Urinary Urgency Frequency. The quality of life and sexual function were valued using 36-Item Short Form Survey, Female Sexual Function Index, and the Female Sexual Distress Scale questionnaires. The same investigations were performed at the first visit and after 6 months of treatment. RESULTS: The symptoms associated with UTI significantly decreased after 6 months of treatment, in particular dysuria episodes diminished and number of voiding decreased (P < 0.0001). During the treatment period, only seven patients (7.1%) experienced a UTI recurrence, confirmed by positive urine culture with bacteriuria of greater than 10 colony forming units/mL. The Pelvic Pain and Urinary Urgency Frequency, Female Sexual Function Index, Female Sexual Distress Scale, and 36-Item Short Form Survey showed a statistically significant improvement after 6 months. CONCLUSIONS: Oral administration of a combination of HA, CS, curcumin, and quercetin is a valid and well-tolerated nonantibiotic treatment for prevention of postcoital UTI in reproductive age women. PMID- 29389680 TI - Spread of Quadratus Lumborum Block to the Paravertebral Space Via Intramuscular Injection: A Volunteer Study. AB - BACKGROUND AND OBJECTIVES: Several types of quadratus lumborum block (QLB) are used for postoperative analgesia and are believed to be effective against both somatic and visceral pain via a local anesthetic (LA) effect in the paravertebral space (PVS). However, it remains unclear whether all QLB techniques result in LA spread into the PVS. We hypothesized that LA administered via intramuscular QLB would spread into the paravertebral space and investigated the spread and sensory block area of LA in intramuscular QLB. METHODS: This volunteer study included 5 healthy men and 1 woman, with no previous medical history. Intramuscular QLB and lateral transversus abdominis plane block were performed under real-time ultrasound guidance for comparison of sensory deprivation range. Two days later, the same procedure was performed on the contralateral side of the body. The spread of LA via intramuscular QLB spread to the PVS was assessed 1 hour after the first injections using magnetic resonance imaging. Sensory perception was also evaluated by the pinprick test at 90 minutes after injection. RESULTS: In total, we performed 11 intramuscular QLBs and 11 lateral transversus abdominis plane blocks. Magnetic resonance imaging showed that LA did not spread into the PVS after ultrasound-guided intramuscular QLB. The analgesic area corresponded to the side of the body that was ipsilateral to the block. CONCLUSIONS: Ultrasound guided intramuscular QLBs are not clinically useful for procedures requiring LA spread into the PVS but do result in an ipsilateral analgesic effect in healthy volunteers. CLINICAL TRIAL REGISTRATION: This study was registered at University Hospital Medical Information Network Clinical Trials Registry, UMIN 000019149. PMID- 29389679 TI - Artificial Intelligence in Surgery: Promises and Perils. AB - OBJECTIVE: The aim of this review was to summarize major topics in artificial intelligence (AI), including their applications and limitations in surgery. This paper reviews the key capabilities of AI to help surgeons understand and critically evaluate new AI applications and to contribute to new developments. SUMMARY BACKGROUND DATA: AI is composed of various subfields that each provide potential solutions to clinical problems. Each of the core subfields of AI reviewed in this piece has also been used in other industries such as the autonomous car, social networks, and deep learning computers. METHODS: A review of AI papers across computer science, statistics, and medical sources was conducted to identify key concepts and techniques within AI that are driving innovation across industries, including surgery. Limitations and challenges of working with AI were also reviewed. RESULTS: Four main subfields of AI were defined: (1) machine learning, (2) artificial neural networks, (3) natural language processing, and (4) computer vision. Their current and future applications to surgical practice were introduced, including big data analytics and clinical decision support systems. The implications of AI for surgeons and the role of surgeons in advancing the technology to optimize clinical effectiveness were discussed. CONCLUSIONS: Surgeons are well positioned to help integrate AI into modern practice. Surgeons should partner with data scientists to capture data across phases of care and to provide clinical context, for AI has the potential to revolutionize the way surgery is taught and practiced with the promise of a future optimized for the highest quality patient care. PMID- 29389681 TI - Screening for Depression in Pregnancy and the Postpartum Period. AB - Depression in pregnancy and the postpartum period is common, burdensome, and underrecognized. Guidelines from multiple organizations support routine screening once during pregnancy and again in the postpartum period. A variety of validated patient questionnaires are effective screening tools for pregnant and postpartum women. Universal screening programs can successfully overcome patient, clinician, and system barriers and reduce the burden of disease. Novel approaches include postpartum screening in pediatric settings and the use of e-screening to optimize privacy and facilitate scoring and interpretation. Implementation of universal screening should be a priority for all health systems providing obstetrical care. PMID- 29389682 TI - Is acute kidney injury a harbinger for chronic kidney disease? AB - PURPOSE OF REVIEW: Despite abundant evidence in adults, the relationship between acute kidney injury (AKI) and chronic kidney disease (CKD) remains unanswered in pediatrics. Obstacles to overcome include the challenges defining these entities and the lack of long-term follow-up studies. This review focuses on pediatric populations at high-risk for AKI, the evidence of the long-term effect of AKI on renal health, and biomarkers to detect renal disease. RECENT FINDINGS: AKI in critically ill children and neonates is common and independently associated with adverse outcomes. Patients with diabetes and sickle cell disease along with neonates with necrotizing enterocolitis have been identified as high-risk for AKI. Preterm birth and neonates with AKI have signs of renal dysfunction early in childhood. Urinary biomarkers may identify AKI and CKD earlier than traditional biomarkers, but more work is necessary to determine their clinical utility. Promising technological advances including the ability to determine nephron number noninvasively will expand our ability to characterize the AKI to CKD transition. SUMMARY: AKI is common and associated with poor outcomes. It is probable that AKI is a harbinger to CKD in pediatric populations. However, we currently lack the tools to definitely answer this question and more research is needed. PMID- 29389683 TI - Progression of chronic kidney disease in children - role of glomerular hemodynamics and interstitial fibrosis. AB - PURPOSE OF REVIEW: The aim of this review is to provide an overview of the current advances in the understanding of the mechanisms involved in the progression of chronic kidney disease (CKD) with emphasis on the role of glomerular hemodynamics and tubulointerstitial fibrosis. RECENT FINDINGS: Despite the varied causes of CKD, the progressive destruction of renal tissue processes through a complex common pathway. Current studies have highlighted both the role of the abnormal intrarenal hemodynamics and of the activation of fibrogenic biochemical pathway in the replacement of normal renal structure by extracellular matrix and ultimately by fibrosis. Molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney has been identified. SUMMARY: There is a clear need to understand and elucidate the mechanisms of progression of CKD to develop efficient therapeutic strategies to halt decline of renal function in children. PMID- 29389684 TI - The medical home for children with autism spectrum disorder: an essential element whose time has come. AB - PURPOSE OF REVIEW: The purpose of this review is to describe the role of the medical home in children with autism spectrum disorder (ASD). A high-quality medical home is essential, given the increase in prevalence of ASD and the array of services, community partners, specialists, therapists, and healthcare team members needed to care for this population. RECENT FINDINGS: Providing care through the medical home model results in fewer unmet needs. Care coordination and integration are the aspects of the medical home currently most lacking. Navigating the healthcare landscape for children with ASD may be enhanced with patient navigators, integration of physical and behavioral health, and telehealth services. SUMMARY: Children with ASD have an increased number of medical and mental health needs. Obtaining care via a medical home has been shown to decrease unmet healthcare needs. However, they are less likely to receive care through the medical home model compared with other children with special healthcare needs. Barriers identified by families include a lack of early identification, limited knowledge on educational plans, and unknown community resources. Barriers identified by providers include lack of time, training, and resources. Providing care coordination and family-centered care in a medical home model are essential for children with ASD. PMID- 29389685 TI - Cost-effectiveness of Different Intra-articular Drug Injections on Wrist and/or Elbow Compromise in Patients With Established Rheumatoid Arthritis: Short-term Results of an Open Observational Evaluation. AB - BACKGROUND: Intra-articular (IA) injections are an integral part of the management of rheumatoid arthritis (RA). However, there are few reports regarding the association between drug effectiveness and cost. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of various combinations of IA injections of betamethasone, hyaluronic acid (HA) or etanercept for oligoarthritis in RA. METHODS: Seventy RA patients were assigned to 4 groups according to the IA injection drug(s): betamethasone alone, betamethasone + etanercept, betamethasone + HA, or etanercept alone. Data for the following were collected before and after IA injection: erythrocyte sedimentation rate, C reactive protein (CRP), disease activity score in 28 joints calculated with CRP, and patient global visual analog scale. In addition, power Doppler ultrasonography and gray-scale ultrasonography scores were obtained for synovitis, and passive range of motion of joints was measured. RESULTS: Sixty eight RA patients completed the trial. Compared with patients given etanercept alone, the visual analog scale, power Doppler ultrasonography, and gray-scale ultrasonography scores of each of the other groups were significantly better at each time point. At 1 month, the passive range of motion of joints in patients given betamethasone + HA was significantly better than that of each of the other groups. Synovial hyperplasia improved significantly in all groups, but less so in those given etanercept alone. All other clinical parameters of the 4 groups were similar. The costs per joint for the betamethasone-alone, betamethasone + etanercept, betamethasone + HA, and etanercept-alone groups were, respectively, $7.55, $181.77, $42.68, and $174.22. CONCLUSIONS: Intra-articular injection of betamethasone alone was the most cost-effective treatment for oligoarthritis of RA. Betamethasone combined with HA injection resulted in the best improvement in joint function. PMID- 29389686 TI - Immunoglobulin G4-Related Disease Presenting as Bilateral Arthritis of the Hip Joints. PMID- 29389687 TI - Tocilizumab Cannot Prevent the Development of Bronchiolitis Obliterans in Patients With Castleman Disease-Associated Paraneoplastic Pemphigus. PMID- 29389688 TI - Adult-Onset Still Disease Masquerading as Multiple Organ Failure: Neither Benign Nor So Rare. PMID- 29389689 TI - A Development and Feasibility Study of a Peer Support Telephone Program in Rheumatoid Arthritis. PMID- 29389690 TI - Inflammatory Pseudotumor-Induced Proptosis in a Patient With Relapsing Polychondritis. PMID- 29389691 TI - The Effect of Ischemic Preconditioning on Maximal Swimming Performance. AB - The effect of ischemic preconditioning (IPC) on swimming performance was examined. Using a randomized, crossover design, National-and International-level swimmers (n=20; 14 males, 6 females) participated in three trials (Con, IPC-2h, IPC-24h). Lower-body IPC (4 x 5 min bi-lateral blood-flow restriction at 160-228 mmHg, and 5 min reperfusion) was used 2- (IPC-2h) or 24-h (IPC-24h) before a self selected (100 m, n=15; 200 m, n=5) swimming time-trial (TT). The Con trial used a sham intervention (15 mmHg) 2h prior to exercise. All trials required a 40-min standardized pre-competition swimming warm-up (followed by 20-min rest; replicating pre-competition call room procedures) 1h before TT. Capillary blood (pH, blood gases and lactate concentrations) was taken immediately pre-and post IPC, pre-TT and post-TT. No effects on TT for 100 m (P=0.995; IPC-2h: 64.94+/ 8.33 s; IPC-24h: 64.67+/-8.50 s; Con: 64.94+/- 8.24 s), 200 m (P=0.405; IPC-2h: 127.70+/-10.66 s; IPC-24h: 129.26+/-12.99 s; Con: 130.19+/-10.27 s) or combined total time (IPC-2h: 84.27+/-31.52 s; IPC-24h: 79.87+/-29.72 s; Con: 80.55+/-31.35 s) were observed following IPC. Base excess (IPC-2h: -13.37+/-8.90 mmol?L; Con: 13.35+/-7.07 mmol?L; IPC-24h: -16.53+/-4.65 mmol?L), pH (0.22+/-0.08; all conditions), bicarbonate (IPC-2h: -11.66+/-3.52 mmol?L; Con: -11.62+/-5.59 mmol?L; IPC-24h: -8.47+/-9.02 mmol?L), total carbon dioxide (IPC-2h: -12.90+/ 3.92 mmol?L; Con: -11.55+/-7.61 mmol?L; IPC-24h: 9.90+/-8.40 mmol?L), percentage oxygen saturation (IPC-2h: -0.16+/-1.86%; Con: +0.20+/-1.93%; IPC-24h: +0.47+/ 2.10%) and blood lactate (IPC-2h: +12.87+/-3.62 mmol?L; Con: +12.41+/-4.02 mmol?L; IPC-24h: +13.27+/-3.81 mmol?L) were influenced by swimming TT (P<0.001), but not condition (all P>0.05). No effect of IPC was seen when applied 2- or 24-h before swimming TT on any indices of performance or physiological measures recorded. PMID- 29389693 TI - Validity of combination use of activity record and accelerometry to measure free living total energy expenditure in female endurance runners. AB - Herein, we attempted to prove the validity of a new approach to assessing total energy expenditure (TEE) that combines activity recording and accelerometry in athletes. Eight female endurance runners participated in this study. We measured TEE over 8 days in the regular training season by using the doubly labeled water (DLW) method. In the combined method, an activity record of the rating of perceived exertion (RPE) was used to estimate energy expenditure (EE) during the training period, while a tri-axial accelerometer was used to evaluate EE during the non-training time over the TEE measurement period using the DLW method. Training EE was calculated from the subjects' individual RPE-EE correlations provided by the exercise tolerance test. Resting metabolic rate (RMR) was measured using indirect calorimetry. There were no significant differences in TEE, activity-induced EE (AEE), or physical activity level (PAL; TEE/RMR) between the DLW method and the combined method (TEE, 3032 +/- 344 kcal/day vs. 3033 +/- 495 kcal/day; AEE, 1585 +/- 303 kcal/day vs. 1586 +/- 442 kcal/day; and PAL, 2.68 +/- 0.37 vs. 2.68 +/- 0.48, respectively). Significant positive correlations and no systematic errors were observed in AEE and PAL. Intra-class correlation coefficients were high (TEE, 0.785; AEE, 0.841; and PAL, 0.779, respectively). These findings suggest that the combined method has high validity against the DLW method. Thus, the combined method would be able to estimate free-living TEE in the regular training season for female endurance runners. PMID- 29389692 TI - Optimal Reactive Strength Index: Is It an Accurate Variable to Optimize Plyometric Training Effects on Measures of Physical Fitness in Young Soccer Players? AB - Ramirez-Campillo, R, Alvarez, C, Garcia-Pinillos, F, Sanchez-Sanchez, J, Yanci, J, Castillo, D, Loturco, I, Chaabene, H, Moran, J, and Izquierdo, M. Optimal reactive strength index: is it an accurate variable to optimize plyometric training effects on measures of physical fitness in young soccer players? J Strength Cond Res 32(4): 885-893, 2018-This study aimed to compare the effects of drop-jump training using a fixed drop-box height (i.e., 30-cm [FIXED]) vs. an optimal (OPT) drop-box height (i.e., 10-cm to 40-cm: generating an OPT reactive strength index [RSI]) in youth soccer players' physical fitness. Athletes were randomly allocated to a control group (n = 24; age = 13.7 years), a fixed drop box height group (FIXED, n = 25; age = 13.9 years), or an OPT drop-box height group (OPT, n = 24; age = 13.1 years). Before and after 7 weeks of training, tests for the assessment of jumping (countermovement jump [CMJ], 5 multiple bounds), speed (20-m sprint time), change of direction ability (CODA [Illinois test]), strength {RSI and 5 maximal squat repetition test (5 repetition maximum [RM])}, endurance (2.4-km time trial), and kicking ability (maximal kicking distance) were undertaken. Analyses revealed main effects of time for all dependent variables (p < 0.001, d = 0.24-0.72), except for 20-m sprint time. Analyses also revealed group * time interactions for CMJ (p < 0.001, d = 0.51), depth jump (DJ) (p < 0.001, d = 0.30), 20-m sprint time (p < 0.001, d = 0.25), CODA (p < 0.001, d = 0.22), and 5RM (p < 0.01, d = 0.16). Post hoc analyses revealed increases for the FIXED group (CMJ: 7.4%, d = 0.36; DJ: 19.2%, d = 0.49; CODA: -3.1%, d = -0.21; 5RM: 10.5%, d = 0.32) and the OPT group (CMJ: 16.7%, d = 0.76; DJ: 36.1%, d = 0.79; CODA: -4.4%, d = -0.34; 5RM: 18.1%, d = 0.47). Post hoc analyses also revealed increases for the OPT group in 20-m sprint time ( 3.7%, d = 0.27). Therefore, to maximize the effects of plyometric training, an OPT approach is recommended. However, using adequate fixed drop-box heights may provide a rational and practical alternative. PMID- 29389694 TI - Acute Effects of Ballistic vs Passive Static Stretching Involved in A Pre-Match Warm-Up Regarding Vertical Jump and Linear Sprint Performance in Soccer Players. AB - The purpose of this study was to compare the effects of introducing passive static and ballistic stretching in a standard soccer match warm-up. The variables addressed were the Counter Movement Jump (CMJ), Abalakov jump and the 40 m linear sprint. The sample was composed of 33 male subjects, divided in two age groups. U16 and adult players formed the groups, in order to cross check if there were differences between them. Each group was further subdivided into two groups regarding the type of stretching carried out during the stretching phase. Prior to the warm-up, the tests previously described were assessed. In the experimental phase, standard stretching was carried out consisting of: an initial phase in which players had to execute continuous running; a general phase in which players had to make articulate moves; a technical phase, in which players had to execute exercises with the ball; a 5 vs. 5 small sided game was carried out during the tactical phase; and, in the final phase, activation exercises and sprints were carried out by the players. Eventually, the same variables were assessed again once the warm-up was finished. There were no statistically significant differences between the two types of stretching included in the pre-match warm up. It can be concluded that ballistic and passive static stretching (<10s) did not cause, under these circumstances, any effect in the assessed variables related to soccer performance (linear sprint, CMJ and Abalakov). This has to be considered by coaches when devising soccer related warm-ups. PMID- 29389695 TI - Anthropometric and Athletic Performance Combine Test Results Among Positions Within Grade Levels of High School-Aged American Football Players. AB - Leutzinger, TJ, Gillen, ZM, Miramonti, AM, McKay, BD, Mendez, AI, and Cramer, JT. Anthropometric and athletic performance combine test results among positions within grade levels of high school-aged American football players. J Strength Cond Res 32(5): 1288-1296, 2018-The purpose of this study was to investigate differences among player positions at 3 grade levels in elite, collegiate prospective American football players. Participants' data (n = 7,160) were analyzed for this study (mean height [Ht] +/- SD = 178 +/- 7 cm, mass [Bm] = 86 +/- 19 kg). Data were obtained from 12 different high school American football recruiting combines hosted by Zybek Sports (Boulder, Colorado). Eight 2-way (9 * 3) mixed factorial analysis of variances {position (defensive back [DB], defensive end, defensive lineman, linebacker, offensive lineman [OL], quarterback, running back, tight end, and wide receiver [WR]) * grade (freshmen, sophomores, and juniors)} were used to test for differences among the mean test scores for each combine measure (Ht, Bm, 40-yard [40 yd] dash, proagility [PA] drill, L-cone [LC] drill, vertical jump [VJ], and broad jump [BJ]). There were position-related differences (p <= 0.05) for Ht, 40 yd dash, and BJ, within each grade level and for Bm, PA, LC, and VJ independent of grade level. Generally, the results showed that OL were the tallest, weighed the most, and exhibited the lowest performance scores among positions. Running backs were the shortest, whereas DBs and WRs weighed the least and exhibited the highest performance scores among positions. These results demonstrate the value of classifying high school-aged American football players according to their specific position rather than categorical groupings such as "line" vs. "skill" vs. "big skill" when evaluating anthropometric and athletic performance combine test results. PMID- 29389696 TI - Reliability and Validity of a Medicine Ball-Contained Accelerometer for Measuring Upper-Body Neuromuscular Performance. AB - Roe, G, Shaw, W, Darrall-Jones, J, Phibbs, PJ, Read, D, Weakley, JJ, Till, K, and Jones, B. Reliability and validity of a medicine ball-contained accelerometer for measuring upper-body neuromuscular performance. J Strength Cond Res 32(7): 1915 1918, 2018-The aim of the study was to assess the between-day reliability and validity of a medicine ball-contained accelerometer (MBA) for assessing upper body neuromuscular performance during a throwing task. Ten professional rugby union players partook in the study. Between-day reliability was assessed from the best score attained during 2 sets of 3 throws, on 2 testing occasions separated by 7 days. Validity was assessed against a criterion measure (Optioelectronic system) during 75 throws from a subgroup of 3 participants. The MBA exhibited a small between-day error of 2.2% (90% confidence intervals; 2.0-4.6%) and an almost perfect relationship with a criterion measure (r = 0.91 [90% CIs; 0.87 0.94]). However, the mean bias and standard error were moderate (7.9% [90% CIs; 6.6-9.2%] and 4.9% [90% CIs; 4.2-5.7%], respectively). Practitioners using an MBA to assess neuromuscular performance of the upper body must take into account the overestimation and error associated with such assessment with respect to a criterion measure. However, as the error associated with between-day testing was small and testing is easy to implement in applied practice, an MBA may provide a useful tool for monitoring upper-body neuromuscular performance over time. PMID- 29389697 TI - Pharmacotherapy for primary delusional jealousy, a retrospective observational study of 32 cases with Othello syndrome. AB - To determine whether primary delusional jealousy can be treated effectively with antipsychotics or antidepressants, and whether any clinical variables are associated with response to pharmacotherapy, we carried out a retrospective case series observational study by reviewing clinical records of patients with an International Classification of Disease, 9th ed., diagnostic code of 297 (delusional disorders) who were treated at the Department of Psychiatry of a university affiliated hospital from January 2010 to December 2015. Only those records showing obvious delusional jealousy not secondary to other medical conditions, dementia, or schizophrenia were scrutinized thoroughly with respect to types of pharmacotherapy, treatment response, and other demographic and clinical variables likely to be associated with clinical outcomes. All except one of 32 patients, 16 men and 16 women, between 37 and 79 (60.9+/-10.6) years of age, were treated with low-dose antipsychotics. The general response was favorable as 19 (59.4%) were rated as good and 13 as inadequate responders (seven partial and six limited). Compared with antipsychotic monotherapy, concomitant therapy with antidepressants had a higher rate of good response, although statistically insignificant (75 vs. 53%, P=0.21). Younger age (P=0.01) and presentation at the index visit with their suspected unfaithful spouse were associated with a good response (P=0.036); comorbidity with delusions other than the jealous type was associated with a poor response (P=0.006). The overall outcome for delusional jealousy looks promising if the patients can accept pharmacotherapy in an outpatient setting. PMID- 29389698 TI - Goal-Directed Fluid Resuscitation Protocol Based on Arterial Waveform Analysis of Major Burn Patients in a Mass Burn Casualty. AB - BACKGROUND: Adequate fluid titration during the initial resuscitation period of major burn patients is crucial. This study aimed to evaluate the feasibility and efficacy of a goal-directed fluid resuscitation protocol that used hourly urine output plus the arterial waveform analysis FloTrac (Edwards LifeSciences, Irvine, Calif) system for major burns to avoid fluid overload. METHODS: We conducted a retrospective cohort study of 43 major burn patients at the Tri-Service General Hospital after the Formosa Fun Coast Dust Explosion on June 27, 2015. Because of the limited capacity of intensive care units (ICUs), 23 intubated patients were transferred from the burn wards or emergency department to the ICU within 24 hours. Fluid administration was adjusted to achieve a urine output of 30 to 50 mL/h, cardiac index greater than 2.5 L/min/m, and stroke volume variation (SVV) less than 12%. The hourly crystalloid fluid infusion rate was titrated based on SVV and hourly urine output. RESULTS: Of the 23 critically burned patients admitted to the ICU, 13 patients who followed the goal-directed fluid resuscitation protocol within 12 hours postburn were included in the analysis. The mean age (years) was 21.8, and the mean total body surface area (TBSA) burned (%) was 68.0. The mean Revised Baux score was 106.8. All patients sustained inhalation injury. The fluid volumes administered to patients in the first 24 hours and the second 24 hours (mL/kg/% total body surface area) were 3.62 +/- 1.23 and 2.89 +/- 0.79, respectively. The urine outputs in the first 24 hours and the second 24 hours (mL/kg/h) were 1.13 +/- 0.66 and 1.53 +/- 0.87, respectively. All patients achieved the established goals within 32 hours postburn. In-hospital mortality rate was 0%. CONCLUSIONS: The SVV-based goal-directed fluid resuscitation protocol leads to less unnecessary fluid administration during the early resuscitation phase. Clinicians can efficaciously manage the dynamic body fluid changes in major burn patients under the guidance of the protocol. PMID- 29389700 TI - Breast Reconstruction: A Century of Controversies and Progress. AB - Breast cancer treatment has dramatically changed over the past century. Since Halsted's first description of radical mastectomy in 1882, breast reconstruction has evolved slowly from being considered as a useless or even dangerous procedure by surgeons to the possibility nowadays of reconstructing almost any kind of defect. In this review on the development of breast reconstruction, we outline the historical milestone innovations that led to the current management of the mastectomy defect in an attempt to understand the economic, social and psychological factors, which contributed to slow down its acceptance for several decades. PMID- 29389699 TI - Use of Vascularized Sural Nerve Grafts for Sciatic Nerve Reconstruction After Malignant Bone and Soft Tissue Tumor Resection in the Lower Legs. AB - BACKGROUND: Vascularized nerve grafting is normally associated with a good outcome, but can be difficult to use for nerve reconstruction in patients with long defects of the sciatic nerve given the graft thickness. We report 3 cases of large defect sciatic nerve reconstruction using the bilateral sural nerves of the lower legs harvested together with the fascia and lesser saphenous vein to form a vascularized flap. METHODS: The subjects were 3 patients who required the reconstruction of a 10-cm or longer segment of the sciatic nerve. Priority was given to restoring sensation in the plantar region such that reconstruction of the sensory nerves corresponding to the tibial region. RESULTS: Two patients were followed up for long term. There was some persistent perceptual deficit in the foot, minimal protective sensation had been achieved. CONCLUSIONS: We were able to selectively reconstruct the sensory nerves to achieve sensation in the soles of the feet by using sural nerve grafts from both legs. As the prognosis for the underlying condition in cases necessitating this procedure is often poor, the costs and benefits of reconstruction should always be weighed carefully for each individual patient. PMID- 29389701 TI - Evaluation of Modifications to Tissue-Expander Breast Reconstruction, a Quality Improvement Assessment Within a Private Practice. AB - BACKGROUND: As technology advances, surgical practice evolves over time. The author assesses a new approach to implant-based breast reconstruction and the impact of two changes implemented over several years. METHODS: A series of tissue expander reconstructions performed early in the author's experience were retrospectively compared with a similar number of cases prospectively performed. Demographics, perioperative characteristics, and postoperative outcomes were assessed. RESULTS: Fifty-three patients (87 breasts) were analyzed, 29 treated earlier with one of the early acellular dermal matrices (ADMs) available and 24 current cases using a no-touch operative approach and pliable, perforated ADM. Demographics and perioperative characteristics between the cohorts were comparable. Mean age was 47.6 years, body mass index (BMI) of 25.8 and 18.9% had current or former nicotine use. Immediate reconstruction was performed in 75 (86.2%) breasts. Drains remained in situ 16 +/- 8.9 days, with a significantly lower number of days required in latter patients. At a mean follow-up of 9.6 months, complications included early capsular thickening in 7 (13.2%) patients requiring capsulectomy at the second stage exchange surgery, prosthetic (expander) removal in 3 (3.4%) breasts, significant infection requiring intervention in 3 (5.7%) patients, seroma in 3 (5.7%) patients, 2 (3.8%) cases of wound dehiscence, and 1 (1.9%) case of flap necrosis and hematoma. Incomplete ADM incorporation was observed in 9 (10.3%) breasts. Three reconstructive failures occurred in the early cohort. Patients in the later cohort reported significantly improved BREAST-Q scores (P < 0.005) postoperatively with a high level of satisfaction. CONCLUSIONS: Using a no-touch technique and an ADM designed with functional characteristics advantageous to breast reconstructive surgery appears to have improved patient outcomes. PMID- 29389702 TI - Character of Gluteal Region Morphology in Young Chinese Females. AB - BACKGROUND: The female gluteal morphology is an important secondary sexual characteristic and helps accentuate and define the female body shape. Despite the increasing prevalence of gluteal augmentations in our country, little data exist regarding the morphology of the gluteal region in young Chinese females. This study analyzed a convenience sample of Chinese females and their gluteal region. METHODS: Data, measurements, and photos of the following parameters were taken: age, weight, height, and body mass index (BMI). Morphology was classified into four types: A shape, V shape, round shape, and square shape. Aesthetic characteristics of each buttock were recorded. Height, weight, BMI, and gluteal projection ratio differences in different shape groups were analyzed. RESULTS: The study sample consisted of 103 women, with ages from 23 to 27 years. The V shaped buttock was not found in this sample. The A shape, square shape, and round shape occupied 55.3%, 38.8%, and 5.8% accordingly. Short infragluteal fold, supragluteal fossettes, lateral depression, and V-shaped crease appeared in 42.7%, 14.6%, 11.7%, and 2.9% of samples, respectively. Of the 103 samples, 39 (37.9%) fulfilled the aesthetic gluteal projection(ratio >= 2). The average BMI was statistically significant between each gluteal shape (P = 0.009). Height, weight, and gluteal projection ratio showed no significant difference with the buttock shapes. CONCLUSIONS: We are the first to describe gluteal morphology in young Chinese woman using gluteal anthropometrics. The findings of the study may provide a guideline for plastic surgeons who perform gluteal augmentation in Asian patients. PMID- 29389703 TI - Association Between Cleft Lip and/or Cleft Palate and Family History of Cancer: A Case-Control Study. AB - BACKGROUND: Cleft lip and/or cleft palate (CL +/- P) are among the most common congenital anomalies. Nevertheless, their etiologies remain poorly understood. Several studies have demonstrated increased rates of cancer among patients with CL +/- P and their relatives, as well as increased risk of CL +/- P among family members of cancer survivors. In addition, a number of possible genetic associations between cancer and CL +/- P have been identified. However, these studies are limited by confounding factors that may be prevalent in these patients, such as tobacco exposure and perinatal complications.The purpose of this study was to quantitatively evaluate the association between family history of cancer and development of CL +/- P in the child. METHODS: A case-control study was conducted at the Cleft Hospital and the Bashir Hospital in Gujrat, Pakistan from December 2015 to December 2016. All new cases of CL +/- P at the Cleft Hospital were included. Sociodemographically similar patients without congenital malformations at the Bashir Hospital served as controls. Risk factors associated with CL +/- P were identified through bivariate analyses. Multiple logistic regressions were performed to calculate adjusted odds ratios of developing CL +/- P. RESULTS: There were 137 patients with CL +/- P and 147 controls in the study. The following factors were statistically significantly associated with development of cleft: history of cancer in the family (P < 0.001), complications during pregnancy (P = 0.02), maternal hypertension during pregnancy (P = 0.01), mother not on any medications (P < 0.001), consanguineous marriage (parents are first or second cousins) (P = 0.03), lower socioeconomic status (P < 0.001), having a parent who smokes (P = 0.001), and history of miscarriage (P = 0.01). After adjustment for these variables, having a history of cancer in the family was independently associated with a 5.19 times increased odds of the child being born with CL +/- P (95% confidence interval [CI], 1.57-17.03). Middle-class socioeconomic status (compared with lower) (odds ratio [OR], 0.36; 95% CI, 0.16 0.83), having a smoking parent (OR, 2.12; 95% CI, 1.05-4.28), and history of miscarriage (OR, 4.60; 95% CI, 1.21-17.54) were also statistically significantly associated with CL +/- P within this model. CONCLUSIONS: This study provides evidence for a relationship between CL +/- P and cancer that has been adjusted for confounders traditionally associated with patients with CL +/- P, thereby supporting the evidence of shared environmental and/or genetic etiologies. PMID- 29389704 TI - Versatility of the Medial Femoral Condyle Flap for Extremity Reconstruction and Identification of Risk Factors for Nonunion, Delayed Time to Union, and Complications. AB - BACKGROUND: The medial femoral condyle (MFC) flap has become a popular choice for treatment of small bony defects. We aim to describe outcomes after MFC flap treatment of upper and lower extremity osseous defects and test the null hypothesis that no factors influence risks for nonunion, increased time to union, and complications. METHODS: A retrospective chart review was performed on all patients undergoing MFC free vascularized bone flaps by the senior author between May 2010 and March 2016. Preoperative, intraoperative, and postoperative data were collected. RESULTS: We identified 29 patients for inclusion (22 upper and 7 lower extremity reconstructions) treated with the MFC flap for diagnoses including long bone nonunion, avascular necrosis (AVN), or AVN with nonunion. Mean postoperative follow-up was 56 weeks. The average patient was 38 years old (range = 17-61 years) and had undergone 1.5 previous failed surgeries. Union was achieved in 86% of patients at a mean of 15.8 weeks (83% at 17.9 weeks for the scaphoid). No patient with lunate AVN progressed. There were no intraoperative flap complications or bone flap loss, but 28% underwent additional unplanned surgical procedures. We identified previous surgery as a risk factor for delayed union but did not observe significant risk factors predictive of nonunion or complications requiring unplanned reoperation. CONCLUSIONS: Extremity reconstruction using the MFC corticocancellous flap results in a high rate of union yet minimal donor morbidity for a challenging patient cohort. Previous surgery was a risk factor for increased time to union. PMID- 29389705 TI - Preventive Effect of Synthetic Tryptophan Metabolite on Silicone Breast Implant Induced Capsule Formation. AB - BACKGROUND: In the field of plastic surgery, capsular contracture after silicone breast implant surgery is a major clinical problem. This experimental study confirms that the synthetic tryptophan metabolite N-(3',4'-dimethoxycinnamonyl) anthranilic acid (Tranilast) reduces capsule formation and prevents capsular contracture. METHODS: Eighteen New Zealand white rabbits were divided into 2 groups. In the experimental group, implants were inserted into each rabbit, and oral synthetic tryptophan metabolite was administered daily at a dose of 5 mg/kg in 10 mL of saline. In the control group, rabbits received implants and the same amount of saline without the metabolite. After 2 months, peri-implant tissues were harvested and analyzed. RESULTS: The thickness of the capsules and the inflammatory cell counts were decreased in the experimental group (P < 0.001). The collagen fibers in the experimental group were thinner, less dense, and more organized than in control group. The results of reverse transcription quantitative polymerase chain reaction analysis showed that the genes for transforming growth factor beta1 (P = 0.002), alpha smooth muscle actin (P < 0.001), and collagen types I (P = 0.002) and III (P = 0.004) were underexpressed in the experimental groups. Furthermore, the counts of T-cell immunity-related cytokine presenting cells were decreased in the experimental groups (CD3, 4, 25, 45RA, 45RO, 69, interleukin-2, 4 [P < 0.001], and interferon gamma [P = 0.028]). CONCLUSIONS: This study confirms that a synthetic derivative of a tryptophan metabolite decreases capsule formation and prevents capsular contracture by inhibiting the differentiation of fibroblasts to myofibroblasts, selectively inhibiting collagen synthesis, and decreasing specific T-cell immune responses by changing anti-inflammatory cytokine expression. PMID- 29389706 TI - Management of the Cleft Nasal Tip: An Overview of Classic Techniques and Strategies. AB - The challenges of cleft reconstruction have been present for centuries. However, understanding of the cleft nasal tip and the evolution of techniques decidedly began in the 20th century and refinement continues into the present day. Although a multitude of technical descriptions and case series have been published, a compendium of seminal techniques, which have shaped modern thought, has not been compiled in the literature. In this review, we discuss the anatomical disturbances in the cleft nasal tip anomaly, the timing and strategy of tip correction, and the major classic techniques for management of the cleft nasal tip. In addition, we have categorized the classic techniques into concepts that they embody. PMID- 29389707 TI - Characterizing Breast Deformities After Massive Weight Loss: Utilizing the Pittsburgh Rating Scale to Examine Factors Affecting Severity Score and Surgical Decision Making in a Retrospective Series. AB - BACKGROUND AND OBJECTIVES: Massive weight loss (MWL) can result in variable contour deformities of the breasts. The Pittsburgh Rating Scale (PRS) was designed to describe the multitude of deformities after MWL and recommends operations to consider for surgical improvement. We present the first comprehensive description of breast deformities in a large sample of MWL patients, examine factors affecting the severity of deformities, and report the correlation between PRS score and surgical decision making. METHODS: A retrospective review of all MWL patients presenting for breast surgery at our institution's Life After Weight Loss program from 2004 to 2015 was performed. Information including demographics, body mass indices (BMIs), method of weight loss, and type of surgical intervention was collected. Preoperative breast photographs were blinded and scored according to the PRS. RESULTS: A total of 204 MWL patients were identified; 26% (53) scored 1, 34% (69) scored 2, and 40% (82) scored 3 on the PRS. Greater deformities were seen after weight loss from bariatric surgery versus diet and exercise alone (P = 0.031), in mastopexy versus augmentation/mastopexy (P = 0.001), and in breast reduction versus augmentation/mastopexy patients (P > 0.0001). Patients who underwent reduction mammaplasty had the greatest maximum BMI compared with other procedures (P = 0.016). The PRS scores were positively correlated to maximum BMI (P < 0.001), delta BMI (P < 0.001), and current BMI (P < 0.001). CONCLUSIONS: Massive weight loss patients have variable, and often severe, breast deformities, and the PRS remains a valuable classification tool. Severity scores correlate with BMI, procedure, and weight loss mechanism. Similar scores between mastopexy-only and reduction mammaplasty patients may reflect a composite of personal cosmetic expectations and cost. The PRS scale should also be expanded to include breast reduction as a surgical remedy for PRS grade 3 breast deformities. Understanding breast deformities in this unique population has applications in both preoperative planning and surgical expectations for this unique patient population. PMID- 29389708 TI - Insurance Appeals for Pediatric Reconstructive Surgery: A Micro Cost Analysis and How-to Guide. AB - BACKGROUND: When insurance coverage for pediatric reconstructive procedures is denied, a stressful and time-consuming appeals process ensues. This article discusses the results of a micro cost analysis performed to better understand the time and monetary burden that the insurance process places on our clinic and families. We also advise plastic surgeons on how to appeal insurance denials for necessary reconstructive procedures. METHODS: Our micro cost analysis focused on patients with congenital breast anomalies who were denied insurance coverage during the preservice insurance authorization process. We surveyed staff and family members to determine the steps involved in the insurance process and how long each person spent on each step. We combined this with average compensation data to calculate cost. RESULTS: For the 5 patients included in our analysis, the insurance process took an average of 7.4 hours of institutional time and cost $521.43 per patient. All patients were denied coverage during prior authorization and required a peer-to-peer, and all denials occurred because surgery was deemed cosmetic or not medically necessary. CONCLUSIONS: This analysis estimated the time and monetary cost of the insurance process in our department. Access to care was limited by prior authorization and the opinion of medical directors that these procedures are unnecessary or cosmetic. We encourage plastic surgeons to continue to perform patient-centered outcomes research in their practice to build on literature that proves the functional and psychosocial benefits of reconstructive procedures. PMID- 29389709 TI - Intraocular Pressure and Glaucoma. PMID- 29389710 TI - A Few Steps Toward Improving Glaucoma Diagnostic Accuracy and Understanding Intraocular Pressure. PMID- 29389712 TI - How Healthy Are Survey Respondents Compared with the General Population?: Using Survey-linked Death Records to Compare Mortality Outcomes. AB - BACKGROUND: National surveys are used to capture US health trends and set clinical guidelines, yet the sampling frame often includes those in noninstitutional households, potentially missing those most vulnerable for poor health. Declining response rates in national surveys also represent a challenge, and existing inputs to survey weights have limitations. We compared mortality rates between those who respond to surveys and the general population over time. METHODS: Survey respondents from 20 waves of the National Health Interview Survey from 1990 to 2009 who have been linked to death records through 31 December 2011 were included. For each cohort in the survey, we estimated their mortality rates along with that cohort's mortality rate in the census population using vital statistics records, and differences were examined using Poisson models. RESULTS: In all years, survey respondents had lower mortality rates compared with the general population when data were both weighted and unweighted. Among men, survey respondents in the weighted sample had 0.86 (95% confidence interval = 0.853, 0.868) times the mortality rate of the general population (among women, RR = 0.887; 95% confidence interval, 0.879, 0.895). Differences in mortality are evident along all points of the life course. Differences have remained relatively stable over time. CONCLUSION: Survey respondents have lower death rates than the general US population, suggesting that they are a systematically healthier source population. Incorporating nonhousehold samples and revised weighting strategies to account for sample frame exclusion and nonresponse may allow for more rigorous estimation of the US population's health. PMID- 29389714 TI - Familial hypercholesterolemia: experience from France. AB - PURPOSE OF REVIEW: We provide an overview of molecular diagnosis for familial hypercholesterolemia in France including descriptions of the mutational spectrum, polygenic susceptibility and perspectives for improvement in familial hypercholesterolemia diagnosis. RECENT FINDINGS: Molecular testing for familial hypercholesterolemia is recommended for patients with a LDL-cholesterol level above 190 mg/dl (adults) associated with criteria related to personal and family history of hypercholesterolemia and premature cardiovascular disease. Among the 3381 index cases included with these characteristics in the French registry for familial hypercholesterolemia, 2054 underwent molecular diagnosis and 1150 (56%) were found to have mutations (93.5% in LDL Receptor (LDLR), 4.7% in apolipoprotein B and 1.8% in Proprotein convertase subtilisin/kexin type 9). A total of 416 different pathogenic variants were found in the LDLR gene. Based on gene score calculation, a polygenic origin may be suggested in 36% of nonmutated patients. Involvement of genetic counselors and education of healthcare professionals for genetics of familial hypercholesterolemia are underway with the aim of improving the efficiency of the diagnosis. SUMMARY: Genetic cascade screening for familial hypercholesterolemia is currently implemented in France with the complexity to address the diversity of its molecular cause in index cases. Optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of familial hypercholesterolemia patients. PMID- 29389715 TI - Phenotype of two Polish patients with Schaaf-Yang syndrome confirmed by identifying mutation in MAGEL2 gene. PMID- 29389716 TI - Discussion: The Cost of Contralateral Prophylactic Mastectomy in Women with Unilateral Breast Cancer. PMID- 29389717 TI - Radiation Therapy Will Always Alter Skin in Breast Cancer Treatment. PMID- 29389718 TI - Rectus Femoris Transfer Versus Rectus Intramuscular Lengthening for the Treatment of Stiff Knee Gait in Children With Cerebral Palsy. AB - BACKGROUND: Rectus femoris transfer (RFT) is used to treat stiff knee gait in spastic cerebral palsy. Recently, rectus femoris lengthening has been reported as treatment for stiff knee gait. The purpose of this study was to compare short term outcomes of 2 surgical procedures. METHODS: A retrospective chart review of 23 patients (42 limbs) with diplegic spastic cerebral palsy who had undergone rectus femoris intramuscular lengthening for treatment of stiff knee gait with a Gross Motor Function Classification System level I, II, or III was completed. These patients were matched with a cohort of 23 patients (42 limbs) who had undergone RFTs based on age, sex, Gross Motor Function Classification System level, diagnosis, preoperative Gait Deviation Index, and any simultaneous surgeries. Preoperative and 1 year postoperative motion analysis data and physical examination were compared. RESULTS: There were no significant differences in demographics between the groups. On physical examination, a positive postoperative Duncan-Ely test was seen significantly less often in the transfer limbs (20 vs. 37). Average postoperative quad tone score was 1.56 for the transfer group compared with 2.19 for the lengthening group. No significant postoperative difference was seen between groups in stride length, walking speed, cadence, knee flexion at initial contact, peak knee flexion during loading response, mean knee flexion in stance, peak knee flexion in swing, time to peak knee flexion (% swing), time to peak knee flexion (% gait cycle), Gait Deviation Index or total knee range of motion. There was a difference in time to achieve 90 degrees passive knee flexion with the lengthening group reaching this in 8.3 days and transfer group in 15.3 days (P<0.0001). CONCLUSIONS: Motion analysis parameters showed results of RFT and rectus femoris intramuscular lengthening to be equivalent 1 year postoperatively. Since rectus femoris lengthening is technically less difficult and rehabilitation faster, rectus femoris lengthening may be preferred if long-term follow-up supports these findings. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 29389719 TI - Results of Casting in Severe Curves in Infantile Scoliosis. AB - BACKGROUND: Previous work has demonstrated best results for casting in infantile scoliosis when the curves are small and the child begins casting under 2 years of age. This study examines if casting can delay the need for growth friendly instrumentation in severe curves (50 to 106 degrees) and how the comorbidities of syrinx or genetic syndromes affected outcomes. METHODS: All children undergoing casting for scoliosis at a single institution over an 8-year period were examined. Inclusion criteria included initial curve at first casting of >=50 degrees, age <=3 years at the start of casting, and a minimum follow-up of 3 years. Of 148 children undergoing casting during this period, 44 met our inclusion criteria. All children underwent magnetic resonance imaging. Ten children with a syrinx were identified. Ten children had known genetic syndromes (2 who also had a syrinx). The 26 children without these comorbidities were considered idiopathic. Curve magnitude ranged from 50 to 106 degrees. RESULTS: Nine of the 26 (35%) children in the children with idiopathic curves demonstrated resolution of their curves, while only 3 of the remaining 18 (17%) did. Of the children that did not have resolution of their curves, 14 were maintained over the entire follow-up period to within 15 degrees of their initial curve and 13 were improved 15 degrees or more. Only 5 children had an increase of 15 degrees or more over the follow-up period and 4 of these have undergone growth friendly instrumentation after a mean delay from initial cast of 71 months (range, 18 to 100 mo). CONCLUSION: This study demonstrates that even in severe curves, casting was effective in delaying instrumentation in all cases, and led to curve resolution of the curves in 12 of 44 children. LEVEL OF EVIDENCE: Level III-case control study. PMID- 29389720 TI - Complication Severity Score for Growth-friendly Surgery Has Strong Interrater and Intrarater Agreement. AB - BACKGROUND: Growth-friendly surgery has high complication rates. The Complication Severity Score for growth-friendly surgery was developed to maintain consistency while reporting complications as part of research in this rapidly evolving field. This study evaluates the interrater and intrarater reliability of this complication classification system. METHODS: After Institutional Review Board approval, complications during treatment for early onset scoliosis were identified from a prospectively collected database. Previous validation studies and a 10-case pilot survey determined that 60 cases were needed to represent a minimum of substantial agreement. In total, 63 of 496 cases were selected randomly to evenly represent each severity classification. The cases comprised an internet survey for classification sent to faculty and research coordinators involved in early onset scoliosis research, 3 weeks apart, with questions shuffled between iterations. Fleiss Kappa and Cohen Kappa were used to assess interrater and intrarater agreement, respectively. RESULTS: A total of 20 participants, 12 faculty and 8 research assistants, completed the survey twice. The overall Fleiss Kappa coefficient for interrater agreement from the second round of the survey was 0.86 (95% confidence interval, 0.86-87), which represents substantial agreement. Reviewers agreed almost perfectly on categorizing complications as Device I (0.85), Disease I (0.91), Disease II (0.94), Device IIB (0.92), and Disease IV (0.98). There was substantial agreement for categorizing Device IIA (0.73) and Device III (0.76) complications. Disease III and Device IV were not evaluated in this survey since none of these occurred in the database. There was almost perfect intrarater agreement among faculty (0.87), research coordinators (0.85), and overall (0.86). CONCLUSIONS: There is strong interrater and intrarater agreement for the published complications classification scheme for growing spine surgery. The complication classification system is a reliable tool for standardizing reports of complications with growth-friendly surgery. Adoption of this classification when reporting on growth-friendly surgery is recommended to allow for comparison of complications between treatment modalities. LEVEL OF EVIDENCE: Level I-diagnostic study. PMID- 29389721 TI - Quantitative Assessment of Knee Progression Angle During Gait in Children With Cerebral Palsy. AB - BACKGROUND: Abnormal hip rotation is a common deviation in children with cerebral palsy (CP). Clinicians typically assess hip rotation during gait by observing the direction that the patella points relative to the path of walking, which is referred to as the knee progression angle (KPA). Two kinematic methods for calculating the KPA are compared with each other. Video-based qualitative assessment of KPA is compared with the quantitative methods to determine reliability and validity. METHODS: The KPA was calculated by both direct and indirect methods for 32 typically developing (TD) children and a convenience cohort of 43 children with hemiplegic type CP. An additional convenience cohort of 26 children with hemiplegic type CP was selected for qualitative assessment of KPA, performed by 3 experienced clinicians, using 3 categories (internal, >10 degrees; neutral, -10 to 10 degrees; and external, >-10 degrees). RESULTS: Root mean square (RMS) analysis comparing the direct and indirect KPAs was 1.14+0.43 degrees for TD children, and 1.75+1.54 degrees for the affected side of children with CP. The difference in RMS among the 2 groups was statistically, but not clinically, significant (P=0.019). Intraclass correlation coefficient revealed excellent agreement between the direct and indirect methods of KPA for TD and CP children (0.996 and 0.992, respectively; P<0.001).For the qualitative assessment of KPA there was complete agreement among all examiners for 17 of 26 cases (65%). Direct KPA matched for 49 of 78 observations (63%) and indirect KPA matched for 52 of 78 observations (67%). CONCLUSIONS: The RMS analysis of direct and indirect methods for KPA was statistically but not clinically significant, which supports the use of either method based upon availability. Video-based qualitative assessment of KPA showed moderate reliability and validity. The differences between observed and calculated KPA indicate the need for caution when relying on visual assessments for clinical interpretation, and demonstrate the value of adding KPA calculation to standard kinematic analysis. LEVEL OF EVIDENCE: Level II-diagnostic test. PMID- 29389722 TI - Skeletal muscle mass is controlled by the MRF4-MEF2 axis. AB - PURPOSE OF REVIEW: The review is focused on the unexpected role of myogenic regulatory factor 4 (MRF4) in controlling muscle mass by repressing myocyte enhancer binding factor 2 (MEF2) activity in adult skeletal muscle, and on the emerging role of MEF2 in skeletal muscle growth. RECENT FINDINGS: The MRF4s of the MyoD family (MyoD, MYF5, MRF4, myogenin) and the MEF2 factors are known to play a major role in embryonic myogenesis. However, their function in adult muscle tissue is not known. A recent study shows that MRF4 loss in adult skeletal muscle causes muscle hypertrophy and prevents denervation atrophy. This effect is mediated by MEF2 factors that promote muscle growth, with MRF4 acting as a repressor of MEF2 activity. The role of MEF2 in skeletal muscle growth is supported by the finding that muscle regeneration is impaired by muscle-specific triple knockout of Mef2a, c, and d genes. SUMMARY: The finding that the MRF4-MEF2 axis controls muscle growth opens a new perspective for preventing muscle wasting. A unique feature of this pathway is that MRF4 is exclusively expressed in skeletal muscle, thus reducing the risk that interventions aimed at down regulating MRF4 or interfering with the interaction between MRF4 and MEF2 may have off-target effects in other tissues. PMID- 29389723 TI - Breastfeeding and neurodevelopmental outcomes. AB - PURPOSE OF REVIEW: Breastfeeding has clear short-term benefits for child survival. Concerning its long-term consequences, it has been reported that subjects who had been breastfed would have a better performance in intelligence tests. In this review, we perused the recently published studies on the association of breastfeeding with developmental outcomes. RECENT FINDINGS: A meta analysis published in 2015 reported that intelligence quotient (IQ) was 3.44 points (95% confidence interval: 2.30; 4.58) higher among subjects who had been breastfed, and this association was observed even among those studies that controlled for maternal IQ. In the present review, we identified two studies that reported that duration of breastfeeding was positively associated with IQ in childhood, whereas another study reported that cognitive score at 67.9 years of age was higher among those subjects who had been breastfed for at least 6 months. Furthermore, two studies reported that the small gain in IQ was associated with higher school achievement and income in adulthood. Concerning the possible mechanisms for the effect of breastfeeding on development, children who had been breastfed showed greater gray matter volume in the left and right parietal and left temporal lobes and more activation in the right frontal and temporal lobes for perception tasks, whereas for the language task, the activation was higher in the left temporal lobe. Moreover, it has been reported that subcortical gray matter volume mediated the association between breastfeeding and IQ. SUMMARY: The new studies identified in the review reinforce the evidence that breastfeeding has long-term consequences on performance in intelligence tests. In addition, this association between breastfeeding and development has long-term consequences on human capital, increasing earning ability. PMID- 29389724 TI - From the Editor. PMID- 29389726 TI - End-of-Life Communication: Nurses Cocreating the Closing Composition With Patients and Families. PMID- 29389725 TI - End-of-Life Communication: Nurses Cocreating the Closing Composition With Patients and Families. AB - Communication is imperative for end-of-life decision-making; however, descriptions of key strategies used by nurses are missing. A phenomenological approach was used to interpret interviews from 10 hospice/palliative nurses. The overarching pattern is the closing composition. Key communication strategies/patterns include establishing context, acknowledging through attentive listening, making it safe for them to die, planning goals of care, and being honest. Essential is the awareness that nurse, patient, and family all hold expertise in the subject matter. It is imperative that pre-/postnursing licensure curriculum be expanded to include training in mutual influence communication practices and mentoring in the skill of orchestration. PMID- 29389727 TI - Psychological Factors Affecting Outcomes After Elective Shoulder Surgery. AB - To optimize outcomes following elective shoulder surgery, it is important to address not only the injury or pathology itself, but also the cognitive and emotional factors that may influence a patient's recovery. Depression, anxiety, catastrophic thinking, distress, somatization, and decreased self-efficacy are among the most common psychological factors associated with adverse perioperative events and poor postoperative outcomes. Such factors may manifest at any point during recovery. Validated questionnaires can be used to measure psychological factors preoperatively, thereby enabling earlier intervention that may mitigate any potential negative effect of these factors on the patient's overall outcome. Orthopaedic surgeons must be sensitive to the influence of stress, distress, and limited coping strategies on patients and should learn how best to mitigate the detrimental effects of these factors on outcomes after elective shoulder surgery. PMID- 29389728 TI - Interprofessional competence: Teamwork's secret sauce. PMID- 29389729 TI - A Narrative Review of Cardiovascular Abnormalities After Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND: The recommended cardiac workup of patients with spontaneous intracerebral hemorrhage (ICH) includes an electrocardiogram (ECG) and cardiac troponin. However, abnormalities in other cardiovascular domains may occur. We reviewed the literature to examine the spectrum of observed cardiovascular abnormalities in patients with ICH. METHODS: A narrative review of cardiovascular abnormalities in ECG, cardiac biomarkers, echocardiogram, and hemodynamic domains was conducted on patients with ICH. RESULTS: We searched PubMed for articles using MeSH Terms "heart," "cardiac," hypertension," "hypotension," "blood pressure," "electro," "echocardio," "troponin," "beta natriuretic peptide," "adverse events," "arrhythmi," "donor," "ICH," "intracerebral hemorrhage." Using Covidence software, 670 articles were screened for title and abstracts, 482 articles for full-text review, and 310 extracted. A total of 161 articles met inclusion and exclusion criteria, and, included in the manuscript. Cardiovascular abnormalities reported after ICH include electrocardiographic abnormalities (56% to 81%) in form of prolonged QT interval (19% to 67%), and ST-T changes (19% to 41%), elevation in cardiac troponin (>0.04 ng/mL), and beta-natriuretic peptide (BNP) (>156.6 pg/mL, up to 78%), echocardiographic abnormalities in form of regional wall motion abnormalities (14%) and reduced ejection fraction. Location and volume of ICH affect the prevalence of cardiovascular abnormalities. Prolonged QT interval, elevated troponin-I, and BNP associated with increased in hospital mortality after ICH. Blood pressure control after ICH aims to preserve cerebral perfusion pressure and maintain systolic blood pressure between 140 and 179 mm Hg, and avoid intensive blood pressure reduction (110 to 140 mm Hg). The recipients of ICH donor hearts especially those with reduced ejection fraction experience increased early mortality and graft rejection. CONCLUSIONS: Various cardiovascular abnormalities are common after spontaneous ICH. The workup of patients with spontaneous ICH should involve 12-lead ECG, cardiac troponin-I, as well as BNP, and echocardiogram to evaluate for heart failure. Blood pressure control with preservation of cerebral perfusion pressure is a cornerstone of hemodynamic management after ICH. The perioperative implications of hemodynamic perturbations after ICH warrant urgent further examination. PMID- 29389730 TI - Biomarkers and asthma management: analysis and potential applications. AB - PURPOSE OF REVIEW: Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations. RECENT FINDINGS: Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed. SUMMARY: Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma. PMID- 29389731 TI - Role of epigenetics in the development of childhood asthma. AB - PURPOSE OF REVIEW: Epigenetic marks are emerging as mediators of genetics and the environment on complex disease phenotypes, including childhood asthma and allergy. RECENT FINDINGS: Epigenome-wide association studies over the past year have added to the growing body of evidence supporting significant associations of epigenetic regulation of gene expression and asthma and allergy. Studies in children have identified signatures of eosinophils in peripheral blood, Th2 cell transcription factors and cytokines in peripheral blood mononuclear cells, and epithelial dysfunction in the respiratory epithelium. Importantly, studies at birth have begun to decipher the contribution of epigenetic marks to asthma inception. Few studies have also begun to address the contribution of genetics and the environment to these associations. SUMMARY: Next generation of epigenome wide association studies that will deal with confounders, study the influence of the genetics and environment, and incorporate multiple datasets to provide better interpretation of the findings are on the horizon. Identification of key epigenetic marks that are shaped by genetics and the environment, and impact transcription of specific genes will help us have a better understanding of etiology, heterogeneity and severity of asthma, and will also empower us to develop biologically driven therapeutics and biomarkers for secondary prevention of this disease. PMID- 29389732 TI - Development of allergic sensitization and its relevance to paediatric asthma. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the recent evidence on the distinct atopic phenotypes and their relationship with childhood asthma. We start by considering definitions and phenotypic classification of atopy and then review evidence on its association with asthma in children. RECENT FINDINGS: It is now well recognized that both asthma and atopy are complex entities encompassing various different sub-groups that also differ in the way they interconnect. The lack of gold standards for diagnostic markers of atopy and asthma further adds to the existing complexity over diagnostic accuracy and definitions. Although recent statistical phenotyping studies contributed significantly to our understanding of these heterogeneous disorders, translating these findings into meaningful information and effective therapies requires further work on understanding underpinning biological mechanisms. SUMMARY: The disaggregation of allergic sensitization may help predict how the allergic disease is likely to progress. One of the important questions is how best to incorporate tests for the assessment of allergic sensitization into diagnostic algorithms for asthma, both in terms of confirming asthma diagnosis, and the assessment of future risk. PMID- 29389733 TI - Immune Checkpoint Inhibitor Nivolumab and Radiotherapy in Pretreated Lung Cancer Patients: Efficacy and Safety of Combination. AB - BACKGROUND: In the last decade, the discovery of immune checkpoint inhibitors such as the PD-1 inhibitor, nivolumab, has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Concurrent radiotherapy (RT) is of particular interest in showing the potential role of the combination. OBJECTIVE: The purpose of this study was to retrospectively evaluate the addition of RT to an immune checkpoint inhibitor, nivolumab, with regard to activity and feasibility in pretreated, advanced, or metastatic lung cancer patients at our center. PATIENTS AND METHODS: We retrospectively identified 35 consecutive patients (30 men and 5 women), who received nivolumab for pretreated NSCLC, between March 2015 to December 2016. Fifteen received hypofractionated RT as a palliative measure, and, in these patients, nivolumab was administered at an interval of at least 1 week from the end of RT. RESULTS: The median age was 69 years, and 23 patients (65.7%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1. All patients had previously received at least 1 systemic regimen, and, for only 3 (8.6%), nivolumab was a third-line treatment. The 2 treatment arms, RT-nivolumab and only-nivolumab, were well matched for baseline characteristics. At a median follow-up of 7.4 months, the 1-year overall survival rates were 57.8% for patients treated with RT-nivolumab and 27.4% for patients treated with only-nivolumab (P=0.043). The 1-year progression-free survival in the RT-nivolumab group was 57.8% and 20.6% in the only-nivolumab group (P=0.040). No difference in adverse events was detected. CONCLUSIONS: In conclusion, RT and nivolumab can be combined, obtaining a benefit in overall survival and progression-free survival, without an increase in acute toxicities in pretreated advanced NSCLC patients. Prospective studies are needed to confirm these results. PMID- 29389734 TI - Article Summaries for February-March 2018 Psychosomatic Medicine, Volume 80, Issue 2. PMID- 29389737 TI - Intestinal-type adenocarcinoma of the sinonasal tract: an update. AB - PURPOSE OF REVIEW: Intestinal-type adenocarcinoma (ITAC) is one of the most frequent sinonasal tumors, especially in European countries. The purpose of this article is to review the most recent literature, with special emphasis on biological and genetic profile and treatment guidelines. RECENT FINDINGS: Results on large series support transnasal endoscopic surgery as the technique of choice in the large majority of patients with ITAC. Adjuvant radiotherapy is recommended in advanced-stage and high-grade lesions. More robust data are required to confirm that early-stage, low-grade lesions can be treated with exclusive surgery. The efficacy of new chemotherapy and biotherapy regimens and the added value of heavy particle radiotherapy are currently under evaluation. With a 5 year overall survival ranging between 53 and 83%, which is mainly impacted by local recurrences, ITAC requires a more detailed understanding of its biology. Genetic and biological studies have identified alterations in the molecular pathways of EGFR, MET, and H-RAS which might be considered as potential targets for biotherapy. SUMMARY: Surgery still plays a key role in the treatment of ITAC, but multidisciplinary management is mandatory. Although further validation is needed, the role of nonsurgical treatment strategies is rising, in agreement with the progresses made in the biological profiling of the disease. PMID- 29389738 TI - Effects of Angiotensin-Converting Enzyme Inhibition and Alpha 1-Adrenergic Receptor Blockade on Inflammation and Hemostasis in Human Hypertension. AB - Drugs blocking the renin-angiotensin-aldosterone system may offer benefit on endothelial function, inflammation, and hemostasis in addition to the effects of reducing blood pressure. We examined the contribution of the angiotensin converting enzyme inhibitor ramipril and the alpha 1-adrenergic receptor blocker doxazosin on blood pressure and on markers of inflammation and hemostasis in 59 individuals with mild-to-moderate hypertension randomized to receive double-blind ramipril 10 mg od or doxazosin 8 mg od for 12 weeks. Inflammatory markers (interleukin-6, soluble interleukin-6 receptor, interleukin-8, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and C-reactive protein) and hemostasis (plasminogen activator inhibitor-1 activity, tissue plasminogen activator antigen, thrombin-antithrombin complex, and thrombin generation by calibrated automated thrombogram) were assessed. The treatment reduced blood pressure in both groups. Thrombin-antithrombin complex decreased by treatment, and this was dependent on a reduction in thrombin-antithrombin complex in the ramipril group alone. There were no changes in plasminogen activator inhibitor-1 activity, whereas tissue plasminogen activator antigen increased by ramipril and decreased by doxazosin. Only minor changes were observed in systemic inflammation by treatment. Treatment with ramipril seems to reduce thrombin generation beyond effects on reducing blood pressure. Drugs blocking the renin-angiotensin aldosterone system may reduce atherothrombotic complications beyond their effects to reduce blood pressure. PMID- 29389739 TI - Simvastatin Modulates Interaction Between Vascular Smooth Muscle Cell/Macrophage and TNF-alpha-Activated Endothelial Cell. AB - Cellular interactions between endothelial cell (EC) and vascular smooth muscle cell (VSMC)/macrophages seem to be greatly changed under inflammatory conditions. Although simvastatin could regulate inflammatory transcription factors in EC and VSMC and also could inhibit leukocyte-endothelium interaction, whether it could modulate VSMC/macrophage functions that are induced by tumor necrosis factor alpha (TNF-alpha)-activated EC remained unclear. The purpose of this study was to investigate the effects of simvastatin on VSMC/macrophage functions, which are induced by TNF-alpha-activated EC in coculture system in vitro. The results showed that under noncontacting conditions, simvastatin could reduce the proliferation, apoptosis, and TNF-alpha, IL-6, and vascular endothelial growth factor secretion both in VSMC and macrophage, which is induced by TNF-alpha activated EC. And a hypothesis that simvastatin regulates the interactions and the soluble factors between EC and VSMC/macrophages could be drawn. And that might be a potential anti-atherosclerosis mechanism of simvastatin. PMID- 29389736 TI - Psychological Stress and Mitochondria: A Systematic Review. AB - OBJECTIVE: Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function. METHODS: A systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted. The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria. RESULTS: A total of 23 studies met the inclusion criteria. All studies involved male laboratory animals, and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function, particularly within the brain. Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress. In humans, only six observational studies were available, none with experimental designs, and most only measured biological markers that do not directly reflect mitochondrial function, such as mitochondrial DNA copy number. CONCLUSONS: Overall, evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria. Limitations of current animal and human studies are discussed. Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load. Prospective studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors, emotional states, the resulting neuroendocrine and immune processes, and mitochondrial energetics relevant to mind-body research in humans. PMID- 29389740 TI - Transient Receptor Potential Canonical Channel Blockers Improve Ventricular Contractile Functions After Ischemia/Reperfusion in a Langendorff-perfused Mouse Heart Model. AB - Reperfusion of ischemic myocardium is accompanied by intracellular Ca overload, leading to cardiac dysfunction. However, the mechanisms underlying intracellular Ca overload have yet to be fully elucidated. The mechanism may involve the activation of store-operated Ca entry, which is primarily mediated through the transient receptor potential canonical (TRPC) channels. This study was undertaken to examine the possible involvement of TRPC channels in the development of contractile dysfunction associated with reperfusion of ischemic myocardium using a mouse heart model. The functional expression of TRPC channels was confirmed in mouse ventricular myocytes using immunocytochemistry, Western blotting, and patch clamp experiments. The left ventricular functions were assessed by measuring left ventricular end-diastolic pressure, left ventricular developed pressure, and its first derivatives in a Langendorff-perfused mouse heart subjected to 30 minutes of normothermic (37 degrees C) global ischemia followed by 60 minutes of reperfusion. Under control conditions, left ventricular functions were deteriorated during reperfusion, which was significantly ameliorated by administration of the TRPC channel blockers 2-aminoethoxydiphenyl borate and La during initial 5 minutes of reperfusion. Our findings suggest that TRPC channels are involved in mediating contractile dysfunction during reperfusion of ischemic myocardium and detect TRPC channels as a potential therapeutic target for preventing myocardial ischemia/reperfusion injury. PMID- 29389741 TI - Defining anabolic resistance: implications for delivery of clinical care nutrition. AB - PURPOSE OF REVIEW: Skeletal muscle mass with aging, during critical care, and following critical care is a determinant of quality of life and survival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and recommendations to offset skeletal muscle atrophy with aging and during, as well as following, critical care. RECENT FINDINGS: Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and during disease states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a given dose of protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity induces: anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic inflammation, decreased satellite cell content, and decreased capillary density. Critical illness results in rapid skeletal muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle breakdown. SUMMARY: Insofar as atrophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant of age-induced losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy. Older individuals should perform exercise using both heavy and light loads three times per week, ingest at least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume protein within 2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical therapies in combination with early, enteral, hypocaloric energy (~10-15 kcal/kg/day), and high-protein (>1.2 g/kg/day) provision is recommended. PMID- 29389735 TI - Psychological Stress and Mitochondria: A Conceptual Framework. AB - BACKGROUND: The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psychological states. METHODS: A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress response, and its implementation in behavioral and psychosomatic medicine. RESULTS: Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain, the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates the rate of cellular aging. CONCLUSIONS: This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the resulting emotional responses-both adverse and positive-into clinically meaningful biological and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities to investigate how psychosocial factors influence human health and well-being across the life-span. PMID- 29389743 TI - Mice overexpressing chromogranin A display hypergranulogenic adrenal glands with attenuated ATP levels contributing to the hypertensive phenotype. AB - OBJECTIVE: Elevated circulating chromogranin A (CHGA) is observed in human hypertension. CHGA is critical for granulogenesis and exocytosis of catecholamine stores from secretory large dense core vesicles (LDCV). This study aims to understand the morphological, molecular and phenotypic changes because of excess CHGA and the mechanistic link eventuating in hyper-adrenergic hypertension. METHODS: Blood pressure and heart rate was monitored in mouse models expressing normal and elevated level of CHGA by telemetry. Catecholamine and oxidative stress radicals were measured. Adrenal ultrastructure, LDCV content and mitochondrial abundance were compared and respiration analyzed by Seahorse assay. Effect of CHGA dosage on adrenal ATP content, electron transport chain components and uncoupling protein 2 (UCP-2) were compared in vivo and in vitro. RESULTS: Mice with excess-CHGA displayed hypertensive phenotype, higher heart rate and increased sympathetic tone. They had elevated plasma catecholamine and adrenal ROS levels. Excess-CHGA caused an increase in size and abundance of LDCV and adrenal mitochondria. Nonetheless, they had attenuated levels of ATP. Isolated adrenal mitochondria from mice with elevated CHGA showed higher maximal respiration rates in the presence of protonophore, which uncouples oxidative phosphorylation. Elevated CHGA resulted in overexpression of UCP2 and diminished ATP. In vitro in chromaffin cells overexpressing CHGA, concomitant increase in UCP2 protein and decreased ATP was detected. CONCLUSION: Elevated CHGA expression resulted in underlying bioenergetic dysfunction in ATP production despite higher mitochondrial mass. The outcome was unregulated negative feedback of LDCV exocytosis and secretion, resulting in elevated levels of circulating catecholamine and consequently the hypertensive phenotype. PMID- 29389742 TI - Early antihypertensive treatment and clinical outcomes in acute ischemic stroke: subgroup analysis by baseline blood pressure. AB - BACKGROUND: We studied the effect of early antihypertensive treatment on death, major disability, and vascular events among patients with acute ischemic stroke according to their baseline SBP. METHODS: We randomly assigned 4071 acute ischemic stroke patients with SBP between 140 and less than 220 mmHg to receive antihypertensive treatment or to discontinue all antihypertensive medications during hospitalization. A composite primary outcome of death and major disability and secondary outcomes were compared between treatment and control stratified by baseline SBP levels of less than 160, 160-179, and at least 180 mmHg. RESULTS: At 24 h after randomization, differences in SBP reductions were 8.8, 8.6 and 7.8 mmHg between the antihypertensive treatment and control groups among patients with baseline SBP less than 160, 160-179, and at least 180 mmHg, respectively (P < 0.001 among subgroups). At day 14 or hospital discharge, the primary and secondary outcomes were not significantly different between the treatment and control groups among subgroups. However, there was a significant interaction between antihypertensive treatment and baseline SBP subgroups on death (P = 0.02): odds ratio (95% CI) of 2.42 (0.74-7.89) in patients with baseline SBP less than 60 mmHg and 0.34 (0.11-1.09) in those with baseline SBP at least 180 mmHg. At the 3-month follow-up, the primary and secondary clinical outcomes were not significantly different between the treatment and control groups by baseline SBP levels. CONCLUSION: Early antihypertensive treatment had a neutral effect on clinical outcomes among acute ischemic stroke patients with various baseline SBP levels. Future clinical trials are warranted to test BP-lowering effects in acute ischemic stroke patients by baseline SBP levels. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01840072. PMID- 29389744 TI - Vascular aging and preclinical target organ damage in community-dwelling elderly: the Northern Shanghai Study. AB - OBJECTIVES: Vascular aging represents a mediating step between risk factors and cardiovascular events, and preclinical target organ damage (TOD) integrates the cumulative effect of cardiovascular risk factors. This study is aimed at the relationships between vascular aging and TOD. METHODS: Two thousand and ninety eight participants (45.52% men, aged 71.3 +/- 6.1 years) were recruited from June 2014 to June 2017 from the communities in the northern Shanghai area. Preclinical TOD was assessed in all the participants. Other clinical information was obtained by standard questionnaire. Healthy vascular aging (HVA) was defined as absence of hypertension and a relatively normal carotid-femoral PWV based on participants' age and blood pressure. We fitted logistic regression models to assess the probability of non-HVA in association with all the preclinical TOD. RESULTS: Six hundred and forty-two (30.6%) elderly participants had HVA, and the prevalence of HVA decreased from 30.84% (aged 65-66) to 20.72% (aged >=75). Increased age, increased SBP, metabolic syndrome, increased BMI and family history of premature cardiovascular disease (CVD) were significantly associated with accelerated vascular aging (P = 0.031 to P < 0.001). After multivariate adjustments, accelerated vascular aging was associated with left ventricular diastolic dysfunction (LVDD; OR (95% CI) 1.83 (1.23, 2.71), P = 0.003), left ventricular hypertrophy (LVH; OR (95% CI) 1.97 (1.54, 2.51), P < 0.001) and micro-albuminuria (MAU; OR (95% CI) 1.66 (1.35, 2.03), P < 0.001). CONCLUSION: Management of blood pressure and metabolic profile may help to alleviate vascular aging and accelerated vascular aging is associated with LVH, LVDD and MAU, which may serve as a potential target to reverse cardiac and renal TOD. PMID- 29389745 TI - Safety and Efficacy of Rituximab: Experience of a Single Multiple Sclerosis Center. AB - OBJECTIVES: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. B cells play an important pathogenic role in MS. Rituximab (RTX), a B-cell depleting drug, has been used to treat MS and neuromyelitis optica (NMO). Patient characteristics, safety, and efficacy measures are reviewed to ascertain the therapeutic benefit and safety of RTX in a real-world setting with long-term follow-up. METHODS: This is a retrospective chart review of patients who received RTX at The Ohio State University's MS clinic from January 2005 to October 2016. RESULTS: Of the 64 patient charts reviewed, 23 had a relapsing remitting MS, 17 had primary progressive MS (PPMS), and 24 had NMO. In the relapsing remitting MS cohort, there was an annual relapse rate of 0.005 and 87% were reported as clinically stable at the end of the chart review period. In the primary progressive MS cohort, 47% were reported as clinically stable at the end of the chart review period. In the NMO cohort, there was an annual relapse rate of 0.0074 and 79% were reported as clinically stable at the end of the chart review period. A total of 29 infusion reactions were reported in 21 patients. None were serious and only 1 patient elected to stop RTX due to an adverse event. CONCLUSIONS: Rituximab demonstrated good tolerability and efficacy in cases of both relapsing and progressive forms of MS and NMO. PMID- 29389747 TI - MRI in epilepsy: clinical standard and evolution. AB - PURPOSE OF REVIEW: MRI has a crucial position in the diagnostic routine of epilepsy patients. It relevantly contributes to etiological diagnostics and is indispensable in presurgical evaluation. As modern MRI research has been a boon to clinical neuroscience in general, it also holds the promise of enhancing diagnostics of epilepsy patients; i.e. increasing the diagnostic yield while decreasing the number of MRI-negative patients. Its rapid progress, however, has caused uncertainty about which of its latest developments already are of clinical interest and which still are of academic interest. It is the purpose of this review to clarify what, to the authors' mind, good practice of MRI in epilepsy patient care is today and what it might be tomorrow. RECENT FINDINGS: Progress of diagnostic MRI in epilepsy patients is driven by development of scanner hardware, scanner sequence and data postprocessing. Ultra high-field MRI and elaborate sequences provide datasets of novel quality which can be fed into postprocessing programs extracting pathognomonic features of structural or functional anatomy. The integration of these features by means of computerized classifiers yield previously unsurpassed diagnostic validity. Enthusiasm about Diffusion Tensor Imaging and functional MRI in the evaluation before epilepsy surgery is quelled. SUMMARY: The application of an epilepsy tailored MRI protocol at 3 Tesla followed by meticulous expert evaluation early after the onset of epilepsy is most crucial. It is hoped that future research will result in MRI workups more standardized than today and widely used postprocessing routines analyzing co registered three-dimensional volumes from different modalities. PMID- 29389748 TI - Clinical trials in autism spectrum disorder: evidence, challenges and future directions. AB - PURPOSE OF REVIEW: The purpose of this manuscript is to review the evidence generated by clinical trials of pharmaceuticals in autism spectrum disorder (ASD), describe challenges in the conduct of such trials, and discuss future directions RECENT FINDINGS: Clinical trials in ASD have produced several compounds to adequately support the pharmacological treatment of associated symptom domains: attention deficit hyperactivity disorder (methylphenidate, atomoxetine, and alpha agonists), irritability/aggression (risperidone and aripiprazole), sleep (melatonin), and weight gain associated with atypical antipsychotic use (metformin). However, there is no evidence yet to support the routine use of pharmaceuticals for the treatment of core symptom domains. Challenges in the field include biological heterogeneity within ASD, lack of biomarkers that clarify biological heterogeneity or predict response to treatment, lack of data across the lifespan, and suboptimal outcome measures. SUMMARY: Several compounds have evidence for the treatment of co-occurring symptoms in children and youth with ASD, although pharmacological interventions for core symptoms are still lacking. Identifying the various biologies underling ASD and developing biomarkers that stratify biologically homogeneous populations are both necessary to realize the promise of precision medicine in ASD. PMID- 29389746 TI - Itch and neuropathic itch. AB - Neuropathic itch is a pathological condition that is due to damage within the nervous system. This type of itch can be severe and unrelenting, which has a very negative impact on quality of life. Neuropathic itch is more common than generally appreciated because most types of neuropathic pain have a neuropathic itch counterpart. Unfortunately, much like neuropathic pain, there is a lack of effective treatments for neuropathic itch. Here, we consider the neural basis of itch and then describe how injuries within these neural circuits can lead to neuropathic itch in both animal models and human disease states. PMID- 29389749 TI - Trauma and transfusion in the geriatric patient. AB - PURPOSE OF REVIEW: The percentage of people over the age of 65 is growing rapidly and anesthesiologists must develop a medical understanding that is comprehensive to meet the unique medical needs of this population. The changing physiology of an elderly population makes them extremely vulnerable to trauma and the administration of blood products. Although most of these cases involve orthopedic attention, it is not less dangerous as a blunt trauma case. RECENT FINDINGS: This article addresses some of the main concerns for the anesthesiologists of providing a hemostatic resuscitation in the geriatric population. Should blood that is new lead to better outcomes than blood that was collected more than 14 days from the injury? What role does patient frailty have in trauma and transfusion outcomes? Is the massive transfusion protocol safe for the geriatric population? As this subset of the population grows, the number of patients on anticoagulation therapy will grow. Knowledge of the bone marrow plays an important role in geriatric trauma. How does head trauma in the elderly differ from the younger patient? SUMMARY: The information in this article is by no means comprehensive. Nongeriatric trauma protocols are far from being validated. Applying these protocols to the geriatric protocols must be investigated in terms of safety and benefits. PMID- 29389751 TI - Editorial: Hail and Farewell. PMID- 29389752 TI - Editor's Spotlight/Take 5: 2017 Chitranjan S. Ranawat Award: Does Computer Navigation in Knee Arthroplasty Improve Functional Outcomes in Young Patients? A Randomized Study. PMID- 29389753 TI - 2017 Chitranjan S. Ranawat Award: Does Computer Navigation in Knee Arthroplasty Improve Functional Outcomes in Young Patients? A Randomized Study. AB - BACKGROUND: Proponents of computer-assisted TKA suggest that better alignment of the TKAs will lead to improved long-term patient functional outcome and survivorship of the implants. However, there is little evidence about whether the improved position and alignment of the knee components obtained using computer navigation improve patient function and the longevity of the TKA. QUESTIONS/PURPOSES: The purpose of this study was to determine whether (1) clinical results; (2) radiographic and CT scan results; and (3) the survival rate of TKA components would be better in patients having computer-assisted TKA than results of patients having TKA without computer-assisted TKA. In addition, we determined whether (4) complication rates would be less in the patients with computer-assisted TKA than those in patients with conventional TKA. METHODS: We performed a randomized trial between October 2000 and October 2002 in patients undergoing same-day bilateral TKA; in this trial, one knee was operated on using navigation, and the other knee was operated on without navigation. All 296 patients who underwent same-day bilateral TKA during that period were enrolled. Of those, 282 patients (95%) were accounted for at a mean of 15 years (range, 14 16 years). A total of 79% (223 of 282) were women and the mean age of the patients at the time of index arthroplasty was 59 +/- 7 years (range, 48-64 years). Knee Society knee score, WOMAC score, and UCLA activity score were obtained preoperatively and at latest followup. Radiographic measurements were performed including femorotibial angle, position of femoral and tibial components, level of joint line, and posterior condylar offset. Aseptic loosening was defined as a complete radiolucent line > 1 mm in width around any component or migration of any component. Assessors and patients were blind to treatment assignment. RESULTS: The Knee Society knee (92 +/- 8 versus 93 +/- 7 points; 95% confidence interval [CI], 92-98; p = 0.461) and function scores (80 +/- 11 versus 80 +/- 11 points; 95% CI, 73-87; p = 1.000), WOMAC score (14 +/- 7 versus 15 +/- 8 points; 95% CI, 14-18; p = 0.991), range of knee motion (128 degrees +/- 9 degrees versus 127 degrees +/- 10 degrees ; 95% CI, 100-140; p = 0.780), and UCLA patient activity score (6 versus 6 points; 95% CI, 4-8; p = 1.000) were not different between the two groups at 15 years followup. There were no differences in any radiographic parameters of alignment (on radiography or CT scan) between the two groups. The frequency of aseptic loosening was not different between the two groups (p = 0.918). Kaplan-Meier survivorship of the TKA components was 99% in both groups (95% CI, 93-100) at 15 years as the endpoint of revision or aseptic loosening (p = 0.982). Anterior femoral notching was observed in 11 knees (4%) in the computer-assisted TKA group and none in the conventional TKA group (p = 0.046). CONCLUSIONS: In this randomized trial, with data presented at a minimum of 14 years of followup, we found no benefit to computer navigation in TKA in terms of pain, function, or survivorship. Unless another study at long-term followup identifies an advantage to survivorship, pain, and function, we do not recommend the widespread use of computer navigation in TKA because of its risks (in this series, we observed femoral notching; others have observed pin site fractures) and attendant costs. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29389754 TI - Cochrane in CORR(r): Surgical Interventions (Microfracture, Drilling, Mosaicplasty, and Allograft Transplantation) for Treating Isolated Cartilage Defects of the Knee in Adults. PMID- 29389755 TI - From Bench to Bedside: Stiffness Begone! (in a Needle). PMID- 29389756 TI - Clinical Faceoff: How Does Patient Satisfaction Fit Into the Value Equation? PMID- 29389757 TI - Gendered Innovations in Orthopaedic Science: The Google Memo: Context for Women in Orthopaedics? PMID- 29389758 TI - Is Treatment With Dithiothreitol More Effective Than Sonication for the Diagnosis of Prosthetic Joint Infection? AB - BACKGROUND: Prosthetic joint infection (PJI) is among the most-severe complications of a total joint arthroplasty. Identification of the causal organism is of paramount importance for successful treatment, and sonication of implants may aid in this identification. Dithiothreitol (DTT) treatment has been proposed as an alternative to sonication to improve diagnosis, reduce costs, and improve reliability of the procedure, but its efficacy remains poorly characterized. QUESTIONS/PURPOSES: (1) Are DTT and sonication more sensitive and/or more specific than standard cultures of tissue samples for the diagnosis of PJI? (2) Which test (DTT or sonication) is more sensitive when the clinician does not suspect infection before surgery? (3) Which test (DTT or sonication) is more sensitive when the clinician suspects infection before surgery? METHODS: Two hundred thirty-two patients undergoing revision of a knee or hip arthroplasty were prospectively evaluated in this randomized study. Cultures were performed on five tissue samples from each patient and on fluid obtained by prosthesis treatment in patients randomly assigned to sonication (117 patients) or DTT (115 patients). The reference standard against which cultures (on tissue samples and on fluids from sonication or DTT) were compared was the Musculoskeletal Infection Society definition of PJI. RESULTS: Cultures on sonication and DTT fluids provided higher sensitivity (89% and 91%, respectively) than those on standard cultures of tissue samples (79%; p < 0.001). Among patients in whom infection was not suspected before surgery, the sensitivity of DTT was greater than that for sonication and cultures on tissue samples (100% versus 70% and 50%; p < 0.001). Among patients in whom infection was suspected before surgery, the sensitivity of DTT and sonication were not greater than that for standard cultures (89% and 94% versus 86%). CONCLUSIONS: In this randomized study, we found no difference in sensitivity between DTT and sonication for the detection of PJI, and both of those tests were more sensitive than standard tissue cultures. Thus, cultures of sonication or DTT fluid should be considered important additional tools to standard cultures for definition of PJI and should be considered together with other criteria, especially in settings where infection is not suspected before revision surgery.Level of Evidence Level I, diagnostic study. PMID- 29389759 TI - Staged Revision With Antibiotic Spacers for Shoulder Prosthetic Joint Infections Yields High Infection Control. AB - BACKGROUND: The treatment of periprosthetic joint infection (PJI) of the shoulder with two-stage revision arthroplasty using an antibiotic-loaded cement spacer is established strategy, but there is sparse information regarding the likelihood of infection control and restoration of shoulder. QUESTIONS/PURPOSE: (1) What is the likelihood of infection control after two-stage revision using an antibiotic cement spacer for patients with PJI of the shoulder? (2) What are the improvements in Constant and Murley scores at 2 years after these staged revisions? PATIENTS AND METHODS: Between 2000 and 2013, we treated 48 patients with PJI of the shoulder using two-stage revision including an antibiotic containing cement spacer during the first stage. Of those, 38 (79%) were available for review at a minimum of 24 months (mean, 52 +/- 34 months). Ten patients (21%) were excluded because they were deceased (n = 3), moved abroad (n = 4), or refused followup (n = 3), leaving 38 for analysis in this retrospective study. During the first stage, removal of the prosthesis, debridement, and implantation of a gentamicin and vancomycin-filled cement spacer were performed by four different surgeons followed by antibiotic therapy (2 weeks intravenous plus 10 weeks oral). For the second stage, we generally tried a reverse total shoulder arthroplasty (RTSA; n = 26). In case of severe glenoid destruction, hemiarthroplasty (HA; n = 8) was used as a salvage option. In 14 patients the cement spacer was left in place because the patients refused further surgery or were not operable owing to medical reasons. The primary outcome included the proportion of patients achieving infection control 2 years after the second-stage procedure after implantation of the cement spacer. Infection control was determined as the absence of the Musculoskeletal Infection Society PJI criteria. The clinical outcome assessed with the Constant and Murley scores served as the secondary outcome parameter. A subgroup (RTSA; HA, spacer retention) analysis of the Constant and Murley scores was performed. RESULTS: Successful infection control was achieved in 36 of 38 patients (95%). Patients who underwent treatment with a cement spacer had increased Constant and Murley scores at latest followup compared with their pretreatment scores (mean +/- SD, 27 +/- 19 versus 43 +/- 20; mean difference, 17; 95% CI, 10-24; p = 0.001). For patients who underwent staged treatment followed by second-stage RTSA (n = 23), the Constant and Murley scores increased (mean +/- SD, 31 +/- 20 versus 51 +/- 20; mean difference, 20; 95% CI, 11-30; p = 0.001). The Constant and Murley scores did not improve in patients who underwent HA (mean +/- SD, 22 +/-15 versus 24 +/- 90; mean difference, 3; 95% CI, -10 to 16; p = 0.509) or who retained the spacer (mean +/- SD, 18 +/-12 versus 35 +/-10; mean difference, 19; 95% CI, -5 to 44; p = 0.093). CONCLUSION: Revision arthroplasty using an antibiotic-loaded cement spacer provided successful infection control in patients with periprosthetic shoulder infections in this small, retrospective series. Functional improvement was obtained after reimplantation of a reverse total shoulder prosthesis but was not seen after HA and cement spacer; however, baseline differences among patient groups very likely contributed to these differences, and they should not be attributed to implant selection alone. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29389760 TI - Validating an Algorithm to Predict Adjacent Musculoskeletal Infections in Pediatric Patients With Septic Arthritis. AB - BACKGROUND: Septic arthritis is frequently associated with adjacent infections including osteomyelitis and subperiosteal and intramuscular abscesses. While often clinically indiscernible from isolated septic arthritis, the diagnosis of adjacent infections is important in determining the need for additional surgical intervention. MRI has been used as the diagnostic gold standard for assessing adjacent infection. Routine MRI, however, can be resource-intensive and delay surgical treatment. In this context, there is need for additional diagnostic tools to assist clinicians in determining when to obtain preoperative MRI in children with septic arthritis. In a previous investigation by Rosenfeld et al., an algorithm, based on presenting laboratory values and symptoms, was derived to predict adjacent infections in septic arthritis. The clinical applicability of the algorithm was limited, however, in that it was built from and applied on the same population. The current study was done to address this criticism by evaluating the predictive power of the algorithm on a new patient population. QUESTIONS/PURPOSES: (1) Can a previously created algorithm used for predicting adjacent infection in septic arthritis among pediatric patients be validated in a separate population? METHODS: Records for all pediatric patients (1-18 years old) surgically treated for suspected septic arthritis during a 3-year period were retrospectively reviewed (109 patients). Of these patients, only those with a diagnosis of septic arthritis confirmed by synovial fluid analysis were included in the study population. Patients without confirmation of septic arthritis via synovial fluid analysis, Gram stain, or culture were excluded (34 patients). Patients with absence of MRI, younger than 1 year, insufficient laboratory tests, or confounding concurrent illnesses also were excluded (18 patients), resulting in a total of 57 patients in the study population. Five variables which previously were shown to be associated with risk of adjacent infection were collected: patient age (older than 4 years), duration of symptoms (> 3 days), C reactive protein (> 8.9 mg/L), platelet count (< 310 x 10 cells/uL), and absolute neutrophil count (> 7.2 x 10 cells/uL). Adjacent infections were determined exclusively by preoperative MRI, with all patients in this study undergoing preoperative MRI. MR images were read by pediatric musculoskeletal radiologists and reviewed by the senior author. According to the algorithm we considered the presence of three or more threshold-level variables as a "positive" result, meaning the patient was predicted to have an adjacent infection. Comparing against the gold standard of MRI, the algorithm's accuracy was evaluated in terms of sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: In the new population, the sensitivity and specificity of the algorithm were 86% (95% CI, 0.70-0.95) and 85% (95% CI, 0.64-0.97), respectively. The positive predictive value was determined to be 91% (95% CI, 0.78-0.97), with a negative predictive value of 77% (95% CI, 0.61-0.89). All patients meeting four or more algorithm criteria were found to have septic arthritis with adjacent infection on MRI. CONCLUSIONS: Critical to the clinical applicability of the above-mentioned algorithm was its validation on a separate population different from the one from which it was built. In this study, the algorithm showed reproducible predictive power when tested on a new population. This model potentially can serve as a useful tool to guide patient risk stratification when determining the likelihood of adjacent infection and need of MRI. This better informed clinical judgement regarding the need for MRI may yield improvements in patient outcomes, resource allocation, and cost. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29389761 TI - Classifications In Brief: The Thoracolumbar Injury Classification. PMID- 29389762 TI - Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29389763 TI - Reply to the Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29389764 TI - Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29389765 TI - Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29389766 TI - Reply to the Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29389767 TI - Outcomes of Donation After Cardiac Death Liver Grafts from Donors >= 50 years of Age: A Multi-center Analysis. AB - INTRODUCTION: As the population in the United States continues to age, an increase in the number of potential DCD donors with advanced chronological age can be expected. The aim of this study was to analyze a multi-institutional experience in liver transplantation using DCD donor age >=50 years. METHODS: All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Rochester and Mayo Clinic Arizona from 2002-2016 were included. Recipients of DCD LT were divided into 2 groups: those with donor age >=50 years(N=155) and those with donor age <50 years(N=316). RESULTS: Graft survival was similar between the DCD donor age >=50 group and DCD donor age <50 group(p=0.99). Graft survival at 1-, 3- and 5-years was 87.0%, 75.6% and 71.8% in the DCD donor age >= 50 group and 85.8%, 76.0% and 70.4% in the DCD donor age < 50 group.The rate of total biliary complications (32.3%vs.23.7%; p=0.049) and of anastomotic strictures (16.1%vs.8.2%; p=0.01), were higher in the DCD donor age >=50 compared to the DCD donor age <50 group. No statistical significant difference in the rate of IC (11.6%vs.7.6%; p=0.15) was seen between the 2 groups. Due to homogeneous practice patterns at the involved institutions, additional Cox regression analysis using national data obtained from SRTR was used to evaluate predictors of graft failure in DCD donor age >=50 years. Significant predictors of graft failure included: a calculated MELD score >=30 (p<0.001), mechanical ventilation at the time of transplant (p<0.001), medical condition (in ICU) (p=0.002) and CIT (p<0.001). CONCLUSION: The present study demonstrates that acceptable graft and patient survival can be achieved with the usage of DCD LT with donor age >=50 years. Optimizing recipient selection criteria and minimizing CIT may further improve outcomes. PMID- 29389768 TI - Integrative view on how erythropoietin signaling controls transcription patterns in erythroid cells. AB - PURPOSE OF REVIEW: Erythropoietin (EPO) is necessary and sufficient to trigger dynamic transcriptional patterns that drive the differentiation of erythroid precursor cells into mature, enucleated red cells. Because the molecular cloning and Food and Drug Administration approval for the therapeutic use of EPO over 30 years ago, a detailed understanding of how EPO works has advanced substantially. Yet, the precise epigenetic and transcriptional mechanisms by which EPO signaling controls erythroid expression patterns remains poorly understood. This review focuses on the current state of erythroid biology in regards to EPO signaling from human genetics and functional genomics perspectives. RECENT FINDINGS: The goal of this review is to provide an integrative view of the gene regulatory underpinnings for erythroid expression patterns that are dynamically shaped during erythroid differentiation. Here, we highlight vignettes connecting recent insights into a genome-wide association study linking an EPO mutation to anemia, a study linking EPO-signaling to signal transducer and activator of transcription 5 (STAT5) chromatin occupancy and enhancers, and studies that examine the molecular mechanisms driving topological chromatin organization in erythroid cells. SUMMARY: The genetic, epigenetic, and gene regulatory mechanisms underlying how hormone signal transduction influences erythroid gene expression remains only partly understood. A detailed understanding of these molecular pathways and how they intersect with one another will provide the basis for novel strategies to treat anemia and potentially other hematological diseases. As new regulators and signal transducers of EPO-signaling continue to emerge, new clinically relevant targets may be identified that improve the specificity and effectiveness of EPO therapy. PMID- 29389770 TI - One-step Minimally Invasive Pedicle Screw Instrumentation Using O-Arm and Stealth Navigation. AB - STUDY DESIGN: Description of a navigated, single-step, minimally invasive technique for the placement of pedicle screws. OBJECTIVE: To describe a new technique for minimally invasive placement of pedicle screws in the lumbar spine using O-arm and StealthStation navigation in combination. SUMMARY OF BACKGROUND DATA: Minimally invasive surgical techniques are described in the literature as safe and effective methods for pedicle screw instrumentation. These techniques increase radiation exposure and prompt multiple instrument passes through the pedicle. MATERIALS AND METHODS: In total, 35 adult patients (187 screws) underwent lumbar surgery with pedicle screw placement using the 1- (8 patients/48 screws) or 2-step (27 patients/139 screws) technique. Complications associated with instrumentation were noted. Pedicle screw position was evaluated. RESULTS: Of 187 screws placed, 181 (96.8%) were found to be fully contained within the pedicle (grade 1) and 4 (2.1%) had a breach of <2 mm. In the 1-step technique, no screws were malpositioned. One screw at S1 with inadequate fixation was replaced with a screw 1 mm larger in diameter. In the 2-step technique, 2 screws (1.06% overall) were revised due to inferior breach of the pedicle. No neurological sequelae were noted. Also, 1 screw was deemed too long at S1 and was replaced with a shorter screw. None of the revised pedicle screws caused neuromonitoring changes and the breaches were found intraoperatively on 3D imaging. CONCLUSIONS: Using O-arm and StealthStation navigation with minimally invasive surgical technology for placement of posterior spinal instrumentation is safe, effective, and limits radiation exposure. PMID- 29389769 TI - Using Contact Patterns to Inform HIV Interventions in Persons Who Inject Drugs in Northern Vietnam. AB - OBJECTIVES: Population mixing patterns can greatly inform allocation of HIV prevention interventions such as treatment as prevention or preexposure prophylaxis. Characterizing contact patterns among subgroups can help identify the specific combinations of contact expected to result in the greatest number of new infections. SETTING: Baseline data from an intervention to reduce HIV-related risk behaviors in male persons who inject drugs (PWID) in the Northern Vietnamese province of Thai Nguyen were used for the analysis. METHODS: Egocentric network data were provided by PWID who reported any drug-injection equipment sharing in the previous 3 months. Age-dependent mixing was assessed to explore its epidemiological implications on risk of HIV transmission risk (among those HIV infected) and HIV acquisition risk (among those not infected) in PWID. RESULTS: A total of 1139 PWID collectively reported 2070 equipment-sharing partnerships in the previous 3 months. Mixing by age identified the 30-34 and 35-39 years age groups as the groups from whom the largest number of new infections was transmitted, making them primary targets for treatment as prevention. Among the uninfected, 25-29, 30-35, and 35-39 years age groups had the highest HIV acquisition rate, making them the primary targets for preexposure prophylaxis. CONCLUSIONS: Collection and analysis of contact patterns in PWID is feasible and can greatly inform infectious disease dynamics and targeting of appropriate interventions. Results presented also provide much needed empirical data on mixing to improve mathematical models of disease transmission in this population. PMID- 29389771 TI - Early Electroencephalography Findings in Cardiogenic Shock Patients Treated by Venoarterial Extracorporeal Membrane Oxygenation. AB - OBJECTIVES: We aimed to assess early electroencephalography findings in patients treated by venoarterial extracorporeal membrane oxygenation and their association with neurologic outcome. DESIGN: Single-center observational study. SETTING: Medical ICU of a university hospital. PATIENTS: An early standardized electroencephalography assessment, that is, standard electroencephalography followed by continuous electroencephalography, was performed in consecutive cardiogenic shock patients requiring venoarterial extracorporeal membrane oxygenation. Associations between electroencephalography findings and outcome, defined as a composite of acute brain injury or death at 14 days, were investigated. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients with a median Full Outline of Unresponsiveness score of 4 (interquartile range, 3-6) were studied. Pupillary light reflex, corneal reflex, and cough reflex were preserved in 20 (90%), 17 (77%), and 17 (77%) patients, respectively. Overall, standard electroencephalography findings consisted of diffuse slowing in 21 patients (95%) and severe background abnormalities in 13 patients (59%) (i.e., a discontinuous [n = 5; 23%] and/or an unreactive background [n = 9; 41%]). Severe background abnormalities on standard electroencephalography (poor outcome rate: 69% vs 22%; p = 0.03) and absence of sleep transients on continuous electroencephalography (poor outcome rate: 67% vs 14%; p = 0.02) were associated with a poor outcome, whereas neurologic findings and doses of sedation were not. Patients without sleep transients on continuous electroencephalography tended to have lower Full Outline of Unresponsiveness scores than patients with preserved sleep transients appearing patterns. CONCLUSIONS: In patients treated by venoarterial extracorporeal membrane oxygenation, early severe background abnormalities on standard electroencephalography provide important information on neurologic outcome. The lack of sleep transients on continuous electroencephalography reflects the severity of brain dysfunction and might represent an additional prognostic marker. PMID- 29389750 TI - 18F-florbetapir Positron Emission Tomography-determined Cerebral beta-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery. AB - BACKGROUND: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation. PMID- 29389772 TI - Uncomplicated 90Y Selective Internal Radio Therapy in a Patient With Hepatocellular Carcinoma After Arterial and Portal Vein Embolizations. AB - Selective internal radio therapy (SIRT) with Y-glass microspheres was performed in a cirrhotic patient with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage C) after arterial coil embolization for treatment of intratumoral hemorrhage and planned preoperative right portal vein embolization. Three technetium Tc macro-albumin-aggregate injections were needed to optimize intralesional uptake without extrahepatic deposition. The consecutive SIRT treatment was uncomplicated with a remarkable result. PMID- 29389773 TI - Metabolic Changes in Central Poststroke Pain Following Thalamic Intracerebral Hemorrhage: An 18F-FDG PET Study. AB - PURPOSE: Central poststroke pain (CPSP) is one of the most refractory neuropathic pains following stroke. Injury in the spinothalamic pathway appears crucial for the development of CPSP, but changes in activity in multiple brain regions may also be related. We investigated brain metabolic changes in patients with CPSP following thalamic intracerebral hemorrhage (ICH). METHODS: Forty-three patients with thalamic ICH were examined. Overall brain metabolism was measured with F-FDG PET. Images were analyzed with statistical parametric mapping (SPM12). Patients with CPSP (n = 20) were compared with patients without CPSP (n = 23). In addition, the association between regional brain metabolism and the severity of CPSP was investigated. RESULTS: In comparison to patients in the non-CPSP group, the CPSP group exhibited significant hypometabolism in the ipsilesional precentral, postcentral gyri, and the contralesional cuneus (Puncorrected < 0.001), whereas significant hypermetabolism was found in the medial dorsal nucleus of the contralesional thalamus (Puncorrected < 0.001). In addition, brain metabolism in the ipsilesional Crus I and Crus II of the cerebellum was positively correlated to pain intensity ratings (Puncorrected < 0.001). CONCLUSION: Our findings suggested that an altered state of resting brain metabolism in various brain regions related to sensory processing and cognitive functioning may be involved in the underlying mechanism of CPSP following thalamic ICH. PMID- 29389775 TI - Apolipoprotein L1 nephropathies: 2017 in review. AB - PURPOSE OF REVIEW: To review publications relating to apolipoprotein L1 (APOL1) renal risk variants published 2017. RECENT FINDINGS: The study of APOL1 variants continues to be highly active; 24 articles published in 2017 were selected to highlight. These include clinical studies of kidney disease, kidney transplantation, hypertension, cardiovascular disease, and genetic diversity. Laboratory studies included APOL1 association with vesicle-associated membrane soluble N-ethylmaleimide-sensitive factor activating protein receptor protein and with soluble urokinase-type plasminogen activator receptor, mitochondrial dysfunction, endolysosomal dysfunction, and inflammasome activation. SUMMARY: Our understanding of the role of APOL1 genetic variants and the mechanisms for renal toxicity continues to deepen. It is not yet clear which pathways are most relevant to human disease, and so, the most relevant drug targets remain to be defined. PMID- 29389774 TI - The Value of Regional Cerebral Blood Flow SPECT and FDG PET in Operculoinsular Epilepsy. AB - PURPOSE: Operculoinsular epilepsy (OIE) can be challenging to diagnose. While the value of SPECT cerebral blood flow and PET F-FDG studies for presurgical evaluation of patients with medial temporal lobe epilepsy (MTLE) is well established, it remains unclear whether they can help identify an operculoinsular epileptic focus. This study assesses the value of interictal/ictal regional cerebral blood flow (rCBF) SPECT and FDG PET for OIE diagnosis. METHODS: Eighteen patients with proven OIE who underwent interictal/ictal rCBF SPECT and/or FDG-PET prior to epilepsy surgery were identified from our clinical database and were compared with a group of 18 patients who underwent MTLE surgery. Regional cerebral blood flow SPECT and FDG PET images were reevaluated visually by an expert reader blind to clinical data. RESULTS: Interictal/ictal rCBF SPECT correctly identified an operculoinsular focus in 11 (65%) of 17 OIE patients and was misleading in 3 cases (18%). Secondary activation in areas connected to the insula was often observed. In the MTLE group, the area of maximal increased perfusion was congruent in 12 (75%) of 16 patients and extended to the ipsilateral insula in 1 patient. FDG PET findings were concordant with the epileptic focus in 8 (47%) of 17 OIE patients and were misleading in 4 (24%), whereas they were concordant in all MTLE patients. CONCLUSIONS: Interictal/ictal rCBF SPECT can identify a concordant operculoinsular focus in a significant proportion of OIE patients and offers a valuable diagnostic tool in nonlesional cases. By contrast, the value of interictal FDG PET in this population is more equivocal. PMID- 29389776 TI - Uric acid and cognitive decline: a double-edge sword? AB - PURPOSE OF REVIEW: This narrative review aims to highlight recent findings on the relation between uric acid level and cognitive decline or dementia. RECENT FINDINGS: The antioxidant properties of uric acid, which have supported the hypothesis that uric acid may be neuroprotective, have been questioned by preclinical data. Studies investigating the relation between serum uric acid (SUA) level and Alzheimer disease are mostly cross-sectional, and results are often inconclusive. Similarly, data for an association between uric acid level and cognitive performance are inconsistent. There is some evidence that low SUA level might be associated with Parkinson disease, but studies are limited by methodological heterogeneity and risk of bias. Patients with gout may have decreased risk for Alzheimer disease, but the impact of treatment is unclear. Recent data suggest an increased risk of vascular dementia with high SUA level via increased cerebrovascular burden in older patients. The relation between SUA level and neurologic disorders may be U-shaped. SUMMARY: We lack strong evidence for an association between low SUA level and cognitive decline over time. Conversely, high SUA level might increase the cerebrovascular burden and the risk of vascular dementia; physicians should continue to treat hyperuricemia when appropriate. PMID- 29389777 TI - Aripiprazole Treatment of Compulsive Behaviors Associated With Methylphenidate in a Child With Down Syndrome. PMID- 29389778 TI - Statistics Commentary Series: Commentary No. 25: Measuring Change. PMID- 29389779 TI - Trypophobia Associated With Gabapentin: A Case Report. PMID- 29389780 TI - Editorial: Sara's Story. PMID- 29389781 TI - Editor's Spotlight/Take 5: Polyethylene Wear Increases in Liners Articulating With Scratched Oxidized Zirconium Femoral Heads. PMID- 29389782 TI - Polyethylene Wear Increases in Liners Articulating With Scratched Oxidized Zirconium Femoral Heads. AB - BACKGROUND: Oxidized zirconium (OxZr) femoral heads were introduced in hip arthroplasty to reduce wear of the polyethylene compared with metallic heads and to reduce fracture risk compared with ceramic heads. Severe scratches have been reported on OxZr heads in patients undergoing revision for instability, but whether these scratches contribute to increased acetabular polyethylene wear remains unclear. QUESTIONS/PURPOSES: (1) How is the polyethylene of the acetabular liner affected by damage on the opposing OxZr head? (2) How does damage to the head affect the degree of polyethylene wear? METHODS: We assessed damage and deformation on all retrieved highly crosslinked liners that had articulated against OxZr heads collected at one institution between 2006 and 2013. Two observers used a visual subjective scoring system to assess polyethylene damage on the surface of the 42 retrieved liners. Polyethylene components were also laser scanned to measure dimensional changes to the liner. These outcomes were compared with the severity of scratching on the surface of the articulating OxZr head. We also used a 12-station hip simulator to measure wear over five million cycles (MCs) of pristine liners articulating against nine retrieved OxZr heads with varying degrees of scratching representing a spectrum of little to severe damage and three retrieved ceramic heads with severe metal transfer. RESULTS: Seventeen of the OxZr heads showed severe damage, of which 14 heads had been revised for dislocation. The retrieved liners that had articulated with these heads had greater damage scores for abrasion (mean score 0.4 versus 1.6; p = 0.008) and embedded debris (mean score 0.4 versus 1.4; p = 0.006) compared with liners that had articulated with less damaged heads. Four severely damaged OxZr heads wore at a higher rate than the others in the study with weight loss of 37.7 mg, 30.0 mg, 14.4 mg, and 2.6 mg after the first MC and a steady increase through testing to 5 MCs. Conversely, neither OxZr heads with less damage nor ceramic heads with severe metal transfer produced appreciable wear. CONCLUSIONS: Surface scratching of OxZr heads from recurrent dislocation and reduction maneuvers leads to increased wear of the crosslinked polyethylene used as a bearing surface. CLINICAL RELEVANCE: Patients in whom such instability occurs in the presence of an OxZr head should be followed closely for the possibility of more severe wear. PMID- 29389783 TI - CORR Insights(r): Polyethylene Wear Increases in Liners Articulating With Scratched Oxidized Zirconium Femoral Heads. PMID- 29389784 TI - Why Did You Apply in Orthopaedic Surgery? PMID- 29389785 TI - Edvard Munch and The Scream: A Cry for Help. PMID- 29389786 TI - Forgiveness: A Key Resiliency Builder. PMID- 29389787 TI - Hot-button Items That Can Potentially Destroy Orthopaedic Partnerships. PMID- 29389789 TI - How to Remove a Well-Fixed Porous Tantalum Cone. PMID- 29389788 TI - ACGME Self Study: Strategic Program Review. PMID- 29389790 TI - Femoral Component Varus Malposition is Associated with Tibial Aseptic Loosening After TKA. AB - BACKGROUND: The notion that neutral alignment is mandatory to assure long-term durability after TKA has been based mostly on short-film studies. However, this is challenged by recent long-film studies. QUESTIONS/PURPOSES: We conducted this long-film study to know (1) whether the risk of aseptic revision for nontraumatic reasons was greater among knees with greater than 3 degrees varus or valgus (defined as "outliers") than those that were aligned within 3 degrees of neutral on long-standing mechanical axis (hip to knee) radiographs; and (2) what the failure mechanisms were and whether the malalignment was femoral or tibial in origin, or both, among those in the outlier group. METHODS: Between November 1998 and January 2009 we performed 1299 cemented, posterior cruciate ligament substituting TKAs in 867 patients for primary osteoarthritis. We had inadequate long-standing radiographs to analyze postoperative alignment for 124 of those knees, and an additional 24 were excluded for prespecified reasons. Consequently, 1151 knees were enrolled in our study. Of these, 982 (85%) in 661 patients (620 women and 41 men) who had followup greater than 24 months were analyzed. The knees were divided according to whether the postoperative mechanical axis was neutral (0 degrees +/- 3 degrees ), varus (> 3 degrees ), or valgus (< -3 degrees ) alignment on long-standing radiographs. The survivorships free from aseptic revision for nontraumatic reasons were compared among groups. The mechanical femoral and the tibial component alignment (MFCA and MTCA, respectively) were investigated to know the origin of overall mechanical malalignment of the outlier knees. The mean duration of followup was 8 +/- 4 years (range, 2-17 years). Thirty-five knees (4%) showed aseptic loosening at 7 +/- 4 years (range, 0.1-14 years) and five (1%) showed polyethylene wear at 12 +/ 1 years (range, 10-13 years). Tibial loosening (73%) was the most common reason for aseptic revision followed by femoral loosening (30%). Of this cohort, 687 (70%), 250 (25%), and 45 (5%) knees had overall mechanical neutral, varus, and valgus alignment, respectively. Factors associated with the risk of aseptic revision were identified by Cox regression. RESULTS: The varus outliers (but not the valgus outliers) failed more often than the neutral knees (10% [25 of 250] versus 2% [13 of 687]; odds ratio [OR], 5.8, 95% CI, 2.9-11.5; p < 0.001). Ten year survivorship free from aseptic revision was lower among varus outliers than among knees with neutral alignment (87% [95% CI, 80%-93%] versus 98% [95% CI, 97% 99%]; p = 0.001). Femoral component varus malpositioning was the main origin of the varus outliers (MFCA = 4.2 degrees +/- 2.0 degrees ; MTCA = 0.9 degrees +/- 1.7 degrees ) and was a risk factor for aseptic revision compared with neutral femoral positioning (OR, 14.0; 95% CI, 1.9-105.6; p < 0.001). CONCLUSIONS: This long-film study corresponds to previous short-film studies for the notion that varus malalignment is associated with inferior long-term implant survivorship. Although aseptic loosening occurred most commonly on the tibial side, the primary origin of the overall varus malalignment was femoral component varus malpositioning. Aiming for neutral alignment in TKA still seems to be a reasonable strategy in clinical practice. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29389791 TI - CORR Insights(r): Femoral Component Varus Malposition is Associated with Tibial Aseptic Loosening After TKA. PMID- 29389792 TI - CORR Insights(r): Are TKAs Performed in High-volume Hospitals Less Likely to Undergo Revision Than TKAs Performed in Low-volume Hospitals? PMID- 29389794 TI - CORR Insights(r): Complications in Patients Undergoing Spinal Fusion After THA. PMID- 29389793 TI - Complications in Patients Undergoing Spinal Fusion After THA. AB - INTRODUCTION: Patients with lumbar spine and hip disorders may, during the course of their treatment, undergo spinal fusion and THA. There is disagreement among prior studies regarding whether patients who undergo THA and spinal fusion are at increased risk of THA dislocation and other hip-related complications. QUESTIONS / PURPOSES: Is short or long spinal fusion associated with an increased rate of postoperative complications in patients who underwent a prior THA? PATIENTS AND METHODS: A retrospective study of New York State's Department of Health database (SPARCS) was performed. SPARCS has a unique identification code for each patient, allowing investigators to track the patient across multiple admissions. The SPARCS dataset spans visit data of patients of all ages and races across urban and rural locations. The SPARCs dataset encompasses all facilities covered under New York State Article 28 and uses measures to further representative reporting of data concerning all races. Owing to the nature of the SPARCS dataset, we are unable to comment on data leakage, as there is no way to discern between a patient who does not subsequently seek care and a patient who seeks care outside New York State. ICD-9-Clinical Modification codes identified adult patients who underwent elective THA from 2009 to 2011. Patients who had subsequent spinal fusion (short: 2-3 levels, or long: >= 4 levels) with a diagnosis of adult idiopathic scoliosis or degenerative disc disease were identified. Forty-nine thousand nine hundred twenty patients met the inclusion criteria of the study. In our inclusion and exclusion criteria, there was no variation with respect to the distribution of sex and race across the three groups of interest. Patients who underwent a spinal procedure (short versus long fusion) had comparable age. However, patients who did not undergo a spinal procedure were older than patients who had short fusion (65 +/- 12.4 years versus 63 +/- 10.7 years; p < 0.001). Multivariate binary logistic regression models that controlled for age, sex, and Deyo/Charlson scores were used to investigate the association between spinal fusion and THA revisions, postoperative dislocation, contralateral THAs, and total surgical complications to the end of 2013. A total of 49,920 patients who had THAs were included in one of three groups (no subsequent spinal fusion: n = 49,209; short fusion: n = 478; long fusion: n = 233). RESULTS: Regression models revealed that short and long spinal fusions were associated with increased odds for hip dislocation, with associated odds ratios (ORs) of 2.2 (95% CI, 1.4-3.6; p = 0.002), and 4.4 (95% CI, 2.7-7.3; p < 0.001), respectively. Patients who underwent THA and spinal surgery also had an increased odds for THA revision, with ORs of 2.0 (95% CI, 1.4-2.8; p < 0.001) and 3.2 (95% CI, 2.1-4.8; p < 0.001) for short and long fusion, respectively. However, spinal fusions were not associated with contralateral THAs. Further, short and long spinal fusions were associated with increased surgical complication rates (OR = 2.8, 95% CI, 2.1-3.8, p < 0.001; OR = 5.3, 95% CI, 3.8-7.4, p < 0.001, respectively). CONCLUSION: We showed that spinal fusion in adults is associated with an increased frequency of complications and revisions in patients who have had a prior THA. Specifically, patients who had a long spinal fusion after THA had 340% higher odds of experiencing a hip dislocation and 220% higher odds of having to undergo a revision THA. Further research is necessary to determine whether this relationship is associated with the surgical order, or whether more patient specific surgical goals of revision THA should be developed for patients with a spinal deformity. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29389795 TI - Long-term Mortality After Revision THA. AB - BACKGROUND: Long-term mortality after primary THA is lower than in the general population, but it is unknown whether this is also true after revision THA. QUESTIONS/PURPOSES: We examined (1) long-term mortality according to reasons for revision after revision THA, and (2) relative mortality trends by age at surgery, years since surgery, and calendar year of surgery. METHODS: This retrospective study included 5417 revision THAs performed in 4532 patients at a tertiary center between 1969 and 2011. Revision THAs were grouped by surgical indication in three categories: periprosthetic joint infections (938; 17%); fractures (646; 12%); and loosening, bearing wear, or dislocation (3833; 71%). Patients were followed up until death or December 31, 2016. The observed number of deaths in the revision THA cohort was compared with the expected number of deaths using standardized mortality ratios (SMRs) and Poisson regression models. The expected number of deaths was calculated assuming that the study cohort had the same calendar year, age, and sex-specific mortality rates as the United States general population. RESULTS: The overall age- and sex-adjusted mortality was slightly higher than the general population mortality (SMR, 1.09; 95% CI, 1.05-1.13; p < 0.001). There were significant differences across the three surgical indication subgroups. Compared with the general population mortality, patients who underwent revision THA for infection (SMR, 1.35; 95% CI, 1.24-1.48; p < 0.001) and fractures (SMR, 1.23; 95% CI, 1.11-1.37; p < 0.001) had significantly increased risk of death. Patients who underwent revision THA for aseptic loosening, wear, or dislocation had a mortality risk similar to that of the general population (SMR, 1.01; 95% CI, 0.96-1.06; p = 0.647). The relative mortality risk was highest in younger patients and declined with increasing age at surgery. Although the relative mortality risk among patients with aseptic indications was lower than that of the general population during the first year of surgery, the risk increased with time and got worse than that of the general population after approximately 8 to 10 years after surgery. Relative mortality risk improved with time after revision THA for aseptic loosening, wear, or dislocation. CONCLUSIONS: Shifting mortality patterns several years after surgery and the excess mortality after revision THA for periprosthetic joint infections and fractures reinforce the need for long term followup, not only for implant survival but overall health of patients having THA. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29389796 TI - CORR Insights(r): Long-term Mortality After Revision THA. PMID- 29389797 TI - Curve Progression in Adolescent Idiopathic Scoliosis Does Not Match Skeletal Growth. AB - BACKGROUND: Determining the peak growth velocity of a patient with adolescent idiopathic scoliosis (AIS) is important for timely treatment to prevent curve progression. It is important to be able to predict when the curve-progression risk is greatest to maximize the benefits of any intervention for AIS. The distal radius and ulna (DRU) classification has been shown to accurately predict skeletal growth. However, its utility in predicting curve progression and the rate of progression in AIS is unknown. QUESTIONS/PURPOSES: (1) What is the relationship between radius and ulna grades to growth rate (body height and arm span) and curve progression rate? (2) When does peak curve progression occur in relation to peak growth rate as measured by months and by DRU grades? (3) How many months and how many DRU grades elapse between peak curve progression and plateau? METHODS: This was a retrospective analysis of a longitudinally maintained dataset of growth and Cobb angle data of patients with AIS who presented with Risser Stages 0 to 3 and were followed to maturity at Risser Stage 5 at a single institute with territory-wide school screening service. From June 2014 to March 2016, a total of 513 patients with AIS fulfilled study inclusion criteria. Of these, 195 were treated with bracing at the initial presentation and were excluded. A total of 318 patients with AIS (74% girls) with a mean age of 12 +/- 1.5 years were studied. For analysis, only data from initial presentation to commencement of intervention were recorded. Data for patients during the period of bracing or after surgery were not used for analysis to eliminate potential interventional confounders. Of these 318 patients, 192 were observed, 119 were braced, and seven underwent surgery. Therefore 192 patients (60.4%) who were observed were followed up until skeletal maturity at Risser Stage 5; no patients were lost to followup. The mean curve magnitude at baseline was 21.6 +/- 4.8. Mean followup before commencing intervention or skeletal maturity was 4.3 +/- 2.3 years. Standing body height, arm span, curve magnitude, Risser stage, and DRU classification were studied. A subgroup analysis of 83 patients inclusive of acceleration, peak, and deceleration progression phases for growth and curve progression was studied to determine any time lag between growth and curve progression. Results were described in mean +/- SD. RESULTS: There was positive correlation between growth rate and curve progression rate for body height (r = 0.26; p < 0.001) and arm span (r = 0.26; p < 0.001). Peak growth for body height occurred at radius grade (R) 6 (0.56 +/- 0.29 cm/month) and ulna grade (U) 4 (0.65 +/- 0.31 cm/month); peak change in arm span occurred at R5 (0.67 +/- 0.33 cm/month) and U3 (0.67 +/- 0.22 cm/month); and peak curve progression matched with R7 (0.80 +/- 0.89 cm/month) and U5 (0.84 +/- 0.78 cm/month). Subgroup analysis confirmed that peak curve progression lagged behind peak growth rate by approximately 7 months or one DRU grade. The mean time elapsed between the peak curve progression rate and the plateau phase at R9 U7 was approximately 16 months, corresponding to two DRU grades. CONCLUSIONS: By using a standard skeletal maturity parameter in the DRU classification, this study showed that the maximal curve progression occurs after the peak growth spurt, suggesting that the curve should be monitored closely even after peak growth. In addition, the period of potential curve continuing progression extends nearly 1.5 years beyond the peak growth phase until skeletal maturity. Future studies may evaluate whether by observing the trend of growth and curve progression rates, we can improve the outcomes of interventions like bracing for AIS. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29389798 TI - CORR Insights(r): Curve Progression in Adolescent Idiopathic Scoliosis Does Not Match Skeletal Growth. PMID- 29389799 TI - CORR Insights(r): Is Treatment With Dithiothreitol More Effective Than Sonication for the Diagnosis of Prosthetic Joint Infection? PMID- 29389800 TI - Classifications in Brief: Garden Classification of Femoral Neck Fractures. PMID- 29389801 TI - Impact of Relational Coordination on Nurse Job Satisfaction, Work Engagement and Burnout: Achieving the Quadruple Aim. AB - AIM: To explore how relational coordination, known to enhance quality and efficiency outcomes for patients and hospitals, impacts direct care nurse outcomes such as burnout, work engagement, and job satisfaction, addressing the "Quadruple Aim," to improve the experience of providing care. BACKGROUND: Hospitals are complex organizations in which multiple providers work interdependently, under conditions of uncertainty and time constraints, to deliver safe quality care despite differences in specialization, training, and status. Relational coordination-communicating and relating for the purpose of task integration-is known to improve quality, safety, and efficiency under these conditions, but less is known about its impact on the well-being of direct care providers themselves. METHODS: Surveys measuring relational coordination among nurses and other types of providers as well as job-related outcomes in 5 acute care community hospitals were completed by direct care RNs. RESULTS: Relational coordination was significantly related to increased job satisfaction, increased work engagement, and reduced burnout. CONCLUSIONS: Relational coordination contributes to the well-being of direct care nurses, addressing the Quadruple Aim by improving the experience of providing care. PMID- 29389802 TI - Dioscin inhibits colon cancer cells' growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways. AB - Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38 MAPK activation. PMID- 29389803 TI - Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant. AB - Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies. PMID- 29389804 TI - Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine. AB - Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients. PMID- 29389805 TI - Radiotherapy and risk of implantable cardioverter-defibrillator malfunctions: experimental data from direct exposure at increasing doses. AB - AIM: During radiotherapy, in patients with implantable cardioverter defibrillators (ICDs) malfunctions are considered more likely if doses more than 2 Gy reach the ICD site; however, most malfunctions occur with high-energy (>10 MV) radiations, and the risk is less defined using 6-MV linear accelerators. The purpose of the study is to experimentally evaluate the occurrence of malfunctions in ICDs radiated with a 6-MV linear accelerator at increasing photon doses. METHODS: Thirty-two ICDs from all manufacturers (31 explanted and one demo) were evaluated; all devices with a sufficient battery charge underwent multiple radiations with a 6-MV photon beam reaching a cumulative dose at ICD site of 0.5, 1, 2, 3, 5 and 10 Gy and interrogated after every session. All antitachycardia therapies were left enabled; two ICDs were connected to a rhythm simulator (one simulating a complete atrioventricular block without ventricular activity) and visually monitored by external ECG and the ICD programmer during radiation. RESULTS: Thirteen ICDs were excluded before radiation because of battery depletion; after radiation up to the cumulative dose at the cardiac implantable electronic device site of 10 Gy, in the remaining 19 devices, programmation and battery charge remained unchanged and no switch to safety mode was observed; oversensing, pacing inhibition or inappropriate antitachycardia therapy were neither recorded nor visually observed during radiation. CONCLUSION: With a low energy accelerator, neither malfunctions nor electromagnetic interferences were detected radiating the ICDs at doses usually reaching the ICD pocket during radiotherapy sessions. In this context, magnet application to avoid oversensing and inappropriate therapy seems, therefore, useless. PMID- 29389806 TI - The Experiences of Fathers Whose Spouses Are Hospitalized for Pregnancy Termination Due to Fetal Chromosome Abnormality in Taiwan. AB - BACKGROUND: Hospitals, where most births and terminations of pregnancy take place in modern society, tend to focus on addressing the perinatal loss experiences of mothers rather than fathers. Healthcare providers often overlook the loss experiences of fathers when pregnancy has been terminated because of chromosome abnormality. Little literature exists on the perceptions of these losses from the point of view of fathers in Taiwan. PURPOSE: The aims of this study were to explore and reveal the essence and structure of the experiences of Taiwanese fathers whose spouses are hospitalized for pregnancy termination due to fetal chromosome abnormality. METHODS: A descriptive phenomenological approach was applied to collect data. In-depth interviews using individualized, semistructured, open-ended questions were conducted with 20 fathers whose spouses were hospitalized for termination of pregnancy due to fetal chromosomal abnormalities. Data were analyzed according to Giorgi's methods. RESULTS: The participants described their experiences as distressing and involving painful decisions. Four themes emerged: (a) "a dismayed father: the unexpected process of terminating pregnancy," (b) "a hidden source of grief: neglected care," (c) "a stressful decision: difficulty handling the deceased offspring," and (d) "a regretful father: inadequate treatment of the baby's remains." CONCLUSIONS: Health professionals must better understand the experiences of fathers, learn to be sensitive and empathetic, and keep communication lines open to create and maintain a more compassionate and caring environment. Health professionals should provide the opportunity for fathers to discuss the decisions that they face, treat the deceased infant with dignity, and acknowledge the grief of both parents as qualitatively equal. Both mother and father should receive appropriate care while the mother is in the hospital for a pregnancy termination. PMID- 29389807 TI - A Multidisciplinary Program Reduces Over 24 Hours of Physical Restraint in Neurological Intensive Care Unit. AB - BACKGROUND: Physical restraint (PR) has to be performed in a well-organized, structured, and careful manner. The safety and effectiveness of the PR procedure in clinical practice are crucial to patient care. PURPOSES: The aim of this study was to examine the effect in neurological intensive care units of a multidisciplinary PR reduction program on the overall incidence rate of PR, the monthly rate of PR, and the monthly rate of PR of more than and less than 24 hours, respectively, after controlling for associated factors. METHODS: A before and-after study design was conducted in three neurological intensive care units (total of 45 beds) of a medical center in northern Taiwan. A multidisciplinary PR reduction program was implemented, with four phases of data collection. Data on the number and duration of PR were extracted from a database. In the first preintervention phase, data on the rate (number or frequency) and duration of PR were collected for 12 months before program implementation. The next three data collection phases were 1 month (introduction), 3 months (intermediate), and 6 months (maintenance) after program implementation. The chi-square test, one-way analysis of variance with Scheffe's post hoc tests, and logistic regression method were used for data analysis. RESULTS: The results showed that PR was used 72.8 mean times per month before program implementation. After implementation, the mean times per month fell to 40 after the first postimplementation month (introduction), 53.3 after 3 months (intermediate), and 36.2 after 6 months (maintenance). Implementation of the PR reduction program resulted in a decreased incidence rate of PR from 6.1% to 3.2% (event/total patient day) and a decrease in the percentage of patients who were restrained for more than 24 hours from 69.6% to 34.1%. The results of the logistic regression model showed that PR of more than 24 hours was significantly less in the postintervention phases: introduction phase (odds ratio [OR] = 0.31), intermediate phase (OR = 0.16), and maintenance phase (OR = 0.18). Moreover, PR of more than 24 hours was significantly higher in patients with endotracheal intubation (OR = 1.51) and nasogastric intubation (OR = 2.16) and with Glasgow Coma Scale scores of 6-8 (OR = 2.36), 9-12 (OR = 2.40), and 13-15 (OR = 2.15). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results support that a multidisciplinary collaborative program has the potential to decrease the incidence of PR in neurological intensive care units. A standardized protocol and policies are essential for healthcare professionals to effectively use PR as well as to effectively improve the quality of care that is provided to intensive care patients. PMID- 29389808 TI - Cross-modality Accuracy of Dual-step, Prospectively Electrocardiography-triggered Dual-source Computed Tomorgaphy Compared With Same-day Echocardiography and Cardiac Magnetic Resonance Imaging in the Follow-up of Heart-transplant Patients. AB - PURPOSE: An accurate evaluation of left ventricular volumes, mass, and ejection fraction (EF) and an early exclusion or detection of significant coronary artery disease or cardiac allograft vasculopathy are mandatory for clinical management and prognosis assessment of heart-transplanted patients (HTP). The purpose of this article was to evaluate the role of dual-step prospective electrocardiography-triggered Dual-Source CT (pECGdual-step-DSCT) in HTP for the assessment of left-ventricular function, in comparison with echocardiography (echo) and cardiac magnetic resonance (CMR) performed on the same day, and of the coronary arteries as well. MATERIALS AND METHODS: Left-ventricular EF, end diastolic volume, end-systolic volume, stroke volume, cardiac output (CO), and mass were assessed in 11 HTP by pECGdual-step-DSCT in comparison with CMR and echo performed on the same day. During all the examinations, the heart rate was recorded. CT coronary artery assessment was also performed. RESULTS: Heart rate was lower during DSCT (75.6+/-7.8 bpm; P<0.001). EF resulted slightly lower for DSCT (55.7%+/-5.0%; P>=0.05) in comparison with CMR (57.8%+/-5.3%; P>=0.05) and echo (59.2%+/-5.6%; P>=0.05). DSCT showed statistically significant higher end diastolic volume (153.7+/-24.2 mL), end-systolic volume (67.8+/-11.5 mL), and stroke volume (85.9+/-17.6 mL) (P<0.01 up to 0.001) than CMR, but with a high correlation (P<0.001). Cardiac output was almost similar for DSCT versus CMR, with a very high correlation coefficient (r=0.914; P<0.001). DSCT showed higher mass values than CMR (P<0.001), but with a high correlation (r=0.866; P<0.001). DSCT versus echo results were less correlated. No significant coronary artery disease was detected. CONCLUSION: pECGdual-step-DSCT allows reliable assessment of left-ventricular function in HTP, with good agreement and correlation with CMR, within a global diagnostic approach including coronary artery evaluation in one single-volume acquisition. PMID- 29389809 TI - Diagnostic Accuracy of Coronary Computed Tomography Before Aortic Valve Replacement: Systematic Review and Meta-Analysis. AB - PURPOSE: In aortic stenosis patients referred for surgical and transcatheter aortic valve replacement (AVR), the evidence of diagnostic accuracy of coronary computed tomography angiography (CCTA) has been limited. The objective of this study was to investigate the diagnostic accuracy of CCTA for significant coronary artery disease (CAD) in patients referred for AVR using invasive coronary angiography (ICA) as the gold standard. MATERIALS AND METHODS: We searched databases for all diagnostic studies of CCTA in patients referred for AVR, which reported diagnostic testing characteristics on patient-based analysis required to pool summary sensitivity, specificity, positive-likelihood ratio, and negative likelihood ratio. Significant CAD in both CCTA and ICA was defined by >50% stenosis in any coronary artery, coronary stent, or bypass graft. RESULTS: Thirteen studies evaluated 1498 patients (mean age, 74 y; 47% men; 76% transcatheter AVR). The pooled prevalence of significant stenosis determined by ICA was 43%. Hierarchical summary receiver-operating characteristic analysis demonstrated a summary area under curve of 0.96. The pooled sensitivity, specificity, and positive-likelihood and negative-likelihood ratios of CCTA in identifying significant stenosis determined by ICA were 95%, 79%, 4.48, and 0.06, respectively. In subgroup analysis, the diagnostic profiles of CCTA were comparable between surgical and transcatheter AVR. CONCLUSIONS: Despite the higher prevalence of significant CAD in patients with aortic stenosis than with other valvular heart diseases, our meta-analysis has shown that CCTA has a suitable diagnostic accuracy profile as a gatekeeper test for ICA. Our study illustrates a need for further study of the potential role of CCTA in preoperative planning for AVR. PMID- 29389811 TI - Common Mental Disorders and Sickness Absence: A Register-Linkage Follow-Up Study Among Finnish Municipal Employees. AB - OBJECTIVE: This study examined how common mental disorders (CMD) at different severity levels are associated with short (1 to 3-day), intermediate (4 to 14 day), and long (15+ day) sickness absence (SA) among Finnish municipal employees. METHODS: Survey data collected among the 40 to 60-year-old employees of the City of Helsinki in 2000 to 2002 were prospectively linked with employer's SA register data (N = 6554). Associations of CMD (GHQ-12) with SA in a 5-year follow-up were examined with quasi-Poisson regression. RESULTS: Increasing GHQ-12 scores were associated with a higher number of SA spells. The highest GHQ-12 scores were associated with the highest number of short, intermediate, and long SA spells. Adjusting for social and health-related covariates attenuated the associations but they remained. CONCLUSION: Increasing severity of CMD increased the risk of short, intermediate, and long SA among Finnish employees. CMD should be tackled to prevent SA and promote work-ability among aging employees. PMID- 29389810 TI - Exposure to Oil Spill Chemicals and Lung Function in Deepwater Horizon Disaster Response Workers. AB - OBJECTIVE: The aim of this study was to assess the relationship between total hydrocarbon (THC) exposures attributed to oil spill clean-up work and lung function 1 to 3 years after the Deepwater Horizon (DWH) disaster. METHODS: We used data from the GuLF STUDY, a large cohort of adults who worked on response to the DWH disaster and others who were safety trained but did not work. We analyzed data from 6288 workers with two acceptable spirometry tests. We estimated THC exposure levels with a job exposure matrix. We evaluated lung function using the forced expiratory volume in 1 second (FEV1; mL), the forced vital capacity (FVC; mL), and the FEV1/FVC ratio (%). RESULTS: Lung function measures did not differ by THC exposure levels among clean-up workers. CONCLUSION: We did not observe an association between THC exposure and lung function among clean-up workers 1 to 3 years following the DWH disaster. PMID- 29389813 TI - Total Worker Health(r) Intervention for Construction Workers Alters Safety, Health, Well-Being Measures. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of a 14-week Total Worker Health (TWH) intervention designed for construction crews. METHODS: Supervisors (n = 22) completed computer-based training and self-monitoring activities on team building, work-life balance, and reinforcing targeted behaviors. Supervisors and workers (n = 13) also completed scripted safety and health education in small groups with practice activities. RESULTS: The intervention led to significant (P < 0.05) improvements in family-supportive supervisory behaviors (d = 0.72). Additional significant improvements included reported frequency of exercising 30 minutes/day and muscle toning exercise (d = 0.50 and 0.59), family and coworker healthy diet support (d = 0.53 and 0.59), team cohesion (d = 0.38), reduced sugary snacks and drinks (d = 0.46 and d = 0.46), sleep duration (d = 0.38), and objectively-measured systolic blood pressure (d = 0.27). CONCLUSION: A TWH intervention tailored for construction crews can simultaneously improve safety, health, and well-being. PMID- 29389812 TI - Measuring Best Practices for Workplace Safety, Health, and Well-Being: The Workplace Integrated Safety and Health Assessment. AB - OBJECTIVE: To present a measure of effective workplace organizational policies, programs, and practices that focuses on working conditions and organizational facilitators of worker safety, health and well-being: the workplace integrated safety and health (WISH) assessment. METHODS: Development of this assessment used an iterative process involving a modified Delphi method, extensive literature reviews, and systematic cognitive testing. RESULTS: The assessment measures six core constructs identified as central to best practices for protecting and promoting worker safety, health and well-being: leadership commitment; participation; policies, programs, and practices that foster supportive working conditions; comprehensive and collaborative strategies; adherence to federal and state regulations and ethical norms; and data-driven change. CONCLUSIONS: The WISH Assessment holds promise as a tool that may inform organizational priority setting and guide research around causal pathways influencing implementation and outcomes related to these approaches. PMID- 29389814 TI - A Systemic Review of Transoral Thyroidectomy. AB - BACKGROUND: Transoral thyroidectomy is a kind of "natural orifice transluminal endoscopic surgery (NOTES)" which is now being performed in increasing frequency. However, the safety and feasibility have not been concluded yet. MATERIALS AND METHODS: A systemic literature search was performed in Pubmed, Cochrane, and Embase databases to identify all studies written in English and published up to April 2017. The keywords used were "transoral endoscopic," "transoral robotic," "oral vestibular endoscopic," and "oral vestibular robotic" combined with "thyroidectomy" or "thyroid surgery." RESULTS: Ten articles containing 211 cases matched the review criteria. The weighted average operative time was 119.9 minutes with an average intraoperative blood loss of 35.5 mL while the weighted average length of hospital stay was 4.0 days. The overall conversion rate to open surgery was 1.9%. An overall incidence rate of temporary hypoparathyroidism was 7.1%, temporary recurrent laryngeal nerve injury was 4.3%, whereas of mental nerve palsy was 4.3%. CONCLUSIONS: According to those reviewed literatures, we can conclude that transoral thyroidectomy is safe and feasible in well-selected patients and offers good perioperative and postoperative outcomes. PMID- 29389815 TI - Comorbidities of chronic heart failure - a systemic syndrome requiring cross specialty efforts. PMID- 29389816 TI - Lomitapide in homozygous familial hypercholesterolemia: cardiology perspective from a single-center experience. AB - AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic dyslipidemia characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Frequently, traditional lipid-lowering therapy is ineffective in these patients, and lipoprotein apheresis is required. Lomitapide has been recently approved for HoFH. We reported our experience in HoFH patients treated with lomitapide, evaluating its efficacy and safety profile. METHODS: Probands suspected for familial hypercholesterolemia were extrapolated from the registry of patients admitted to our cardiology department. Dutch Lipid Clinic Network (DLCN) criteria were adopted to diagnose familial hypercholesterolemia clinically. Individuals receiving a definite or probable diagnosis of familial hypercholesterolemia underwent family cascade screening and genetic test. Patients with a genetic diagnosis of HoFH were treated with lomitapide and monitored with serial follow-up visits. RESULTS: Within 1 year of screening, from a population of 3250 patients admitted to our cardiology department, seven probands were selected with a DLCN score greater than 5. A total of two patients resulted genetically homozygotes for familial hypercholesterolemia and started lomitapide. A marked reduction in LDL-C occurred in both patients on lomitapide (78% reduction in patient 1 and 86% in patient 2 already on lipoprotein apheresis, compared with baseline LDL-C), allowing the apheresis treatment to be stopped in the second case. Lomitapide was well tolerated, and both patients experienced only mild gastrointestinal events. CONCLUSION: Lomitapide is an effective and well tolerated cholesterol-lowering drug approved for the treatment of HoFH patients. It would be useful to administer it early in these patients to reduce LDL-C and avoid the development of fatal cardiovascular complications. PMID- 29389817 TI - Early myocardial surgical revascularization after ST-segment elevation myocardial infarction in multivessel coronary disease: bridge therapy is the solution? AB - BACKGROUND: Many ST-segment elevation myocardial infarction (STEMI) patients have a multivessel disease that initially require percutaneous coronary intervention (PCI) of the culprit vessel but subsequently may require coronary artery bypass graft (CABG) of nonculprit vessels. Evidence supports staged revascularization, but the identification of optimal strategies (percutaneous or surgical), the timing and the management of antiplatelet therapy after recent PCI with stenting are matters of great controversies. METHODS: In our retrospective registry, we have enrolled 21 patients presenting with STEMI and multivessel disease, who underwent PCI of the culprit vessel only and then CABG of nonculprit vessels. Demographic, clinical, echocardiographic, angiographic findings, preoperative score, surgical data and postoperative complications were collected. At 21.6 +/- 15.6 months follow-up death, reinfarction and/or cardiovascular and noncardiovascular events were recorded. RESULTS: Patients were 62 +/- 9 years old and had in the most cases a good ejection fraction. At angiography, the culprit lesion was right coronary artery in 16 patients (76%). Angiographic characteristics excluded a staged PCI (SYNTAX score = 31.6 +/- 7.4) and European System for Cardiac Operative Risk Evaluation II resulted low (1.46 +/- 1.01). Following the indication to cardiac surgery after Heart Team discussion, the withdrawal of oral P2Y12 inhibitor was planned and tirofiban intravenous was started. Off-pump CABG was performed after 7.2 +/- 3.2 days. No death, reinfarction and/or cardiovascular and noncardiovascular events occurred at follow-up. CONCLUSION: We can conclude that a careful preoperative selection is mandatory for a good postoperative course and long-term survival and that early staged CABG can, however, be performed using bridge therapy, also after STEMI. PMID- 29389818 TI - Vanished myxoma due to systemic embolization. PMID- 29389819 TI - For beginners in anaesthesia, self-training with an audiovisual checklist improves safety during anaesthesia induction: A randomised, controlled two-centre study. AB - BACKGROUND: Beginners in residency programmes in anaesthesia are challenged because working environment is complex, and they cannot rely on experience to meet challenges. During this early stage, residents need rules and structures to guide their actions and ensure patient safety. OBJECTIVE: We investigated whether self-training with an electronic audiovisual checklist app on a mobile phone would produce a long-term improvement in the safety-relevant actions during induction of general anaesthesia. DESIGN, SETTING AND PARTICIPANTS: During the first month of their anaesthesia residency, we randomised 26 residents to the intervention and control groups. The study was performed between August 2013 and December 2014 in two university hospitals in Germany. INTERVENTION: In addition to normal training, the residents of the intervention group trained themselves on well tolerated induction using the electronic checklist for at least 60 consecutive general anaesthesia inductions. MAIN OUTCOME MEASURES: After an initial learning phase, all residents were observed during one induction of general anaesthesia. The primary outcome was the number of safety items completed during this anaesthesia induction. Secondary outcomes were similar observations 4 and 8 weeks later. RESULTS: Immediately, and 4 weeks after the first learning phase, residents in the intervention group completed a significantly greater number of safety checks than residents in the control group 2.8 [95% confidence interval (CI) 0.4 to 5.1, P = 0.021, Cohen's d = 0.47] and 3.7 (95% CI 1.3 to 6.1, P = 0.003, Cohen's d = 0.61), respectively. The difference between the groups had disappeared by 8 weeks: mean difference in the number of safety checks at 8 weeks was 0.4, 95% CI -2.0 to 2.8, P = 0.736, Cohen's d = 0.07). CONCLUSION: The use of an audiovisual self-training checklists improves safety-relevant behaviour in the early stages of a residency training programme in anaesthesia. PMID- 29389820 TI - Conquering combined thoracic organ and liver transplantation: indications and outcomes for heart-liver and lung-liver transplantation. AB - PURPOSE OF REVIEW: Combined thoracic organ and liver transplantation has been shown to be a viable treatment option for patients with end-stage disease lung or heart and disease. There are increasing number of cases reported in the literature, as the number of institutions utilizing this strategy is growing. Herein, we review the current literature of combined thoracic and liver transplantation. RECENT FINDINGS: A larger number of combined heart or lung and liver transplants (CHLT and CLLT) are being performed. A recent literature search showed approximately 231 CHLT and 89 CLLT and being described. One-year patient survival ranged from 71 to 80% for CLLT and 80-93% for CHLT, respectively. Indications for combined transplant and disease-specific outcomes are still being evaluated. Additionally, salvage modalities such as extracorporeal membrane oxygenation and ex-vivo lung perfusion are also being described. SUMMARY: Combined thoracic and liver transplant continues to be a viable treatment option for patients with end-stage disease that would likely not survive single transplant alone. Salvage modalities, such as extracorporeal membrane oxygenation and ex-vivo lung perfusion, may help in extending candidacy for this combined transplant. Outcomes, to date, are similar to results observed for solitary thoracic organ recipients, justifying CHLT and CLLT as a viable option for these patients. Continued identification of outcomes is needed to justify allocation of dual organs to a single recipient. PMID- 29389821 TI - Early liver transplantation for severe alcoholic hepatitis: moving from controversy to consensus. AB - PURPOSE OF REVIEW: Alcohol-related liver disease is now the most common indication for liver transplant in the United States. Acute alcoholic hepatitis represents a subpopulation with short-term mortality approaching 70% in severe cases - these patients are not typically eligible for liver transplant, as most centers require a period of alcohol abstinence (typically 6 months) prior to transplant. Early liver transplant (prior to a requisite period of abstinence) is being increasingly offered in a minority of U.S. centers. The present review examines clinical and ethical considerations surrounding liver transplant for severe alcoholic hepatitis, key published studies and knowledge gaps, and future directions for clinical research to achieve optimal patient outcomes. RECENT FINDINGS: Since a European pilot study published in 2011, published U.S. original studies in early liver transplantation for severe alcoholic hepatitis are limited to 1 UNOS review, and 2 retrospective single-center studies. A preliminary report from the ACCELERATE-AH consortium show short-term outcomes are acceptable and that use of alcohol posttransplant occurs in 25% of patients. These studies confirm the survival benefit of early liver transplant for alcoholic hepatitis and report rates of alcohol use posttransplant similar to historic cohorts in alcohol-related cirrhosis. SUMMARY: Early liver transplantation for severe alcoholic hepatitis is lifesaving, with acceptable short to intermediate-term patient survival and rates of alcohol use posttransplant. Further study is needed to determine long-term outcomes, and how best to select and manage patients for this new indication for liver transplant. PMID- 29389823 TI - Thirty years after the first intestinal transplantation in 1987: which indications are left in 2018? PMID- 29389822 TI - Management of intestinal failure in middle-income countries, for children and adults. AB - PURPOSE OF REVIEW: Intestinal failure is a life-threatening medical condition that remains as a rare or orphan disease in most countries. The prevalence of intestinal failure and the therapeutic options available in middle-income countries (MIC) remain unclear. We aim to provide an overview on the current differences in management of intestinal failure patients in MIC from Latin America and Asia. RECENT FINDINGS: In order to fulfil the challenge, and after facing the difficulties of going over a topic with scarce available data, from countries with an extreme variety of social and economic problems, which are closely related to the treatment of intestinal failure patients, we have used both the existing publications and personal surveys to draft this document. Our results have shown that there is still significant disparity among MIC over the last years, concepts such as the need for establishing multidisciplinary dedicated teams as well as the need to evolve first home parenteral nutrition (HPN), then rehabilitation, and finally transplantation, have become important signals of an adequate understanding of this evolving field. SUMMARY: The manuscript presents, for the first time, an overview of the different developments and needs to manage intestinal failure patients in MIC from Latin America and Asia. Future discussions will emerge from this manuscript, aiming to pursue the development of registries, guidelines and health policies to continue improving the long-term care of intestinal failure patients in all MIC. PMID- 29389824 TI - Necrotizing Enterocolitis Cases Associated with Nosocomial Enterovirus Transmission in a Neonatal Unit. AB - Infectious agents including viruses are thought to play a role in the pathogenesis of necrotizing enterocolitis, a well-known gastrointestinal emergency in newborns. Enteroviruses are common pathogens in neonates and have been associated with outbreaks in neonatal units. Enterovirus-associated necrotizing enterocolitis has been described in 3 preterms. Spatiotemporal and molecular analyses have provided evidence of nosocomial transmission. PMID- 29389825 TI - Symptoms, Signs and Long-term Prognosis of Vertically Transmitted Chlamydia trachomatis Infections. AB - BACKGROUND: Although Chlamydia trachomatis infection is common in pregnant women, such infections are rarely encountered in infants. To clarify the recognition of C. trachomatis infections in infants, we analyzed symptoms and signs of perinatally acquired chlamydial infection, together with its long-term prognosis in a large population-based patient series. METHODS: A search through 2 national health registries covering 1996-2011, a cohort of 933,823 births, yielded 124 children with a microbiologically confirmed C. trachomatis infection. We then reviewed copies of the children's medical records up to 16 years of age. RESULTS: One-third of the infants with chlamydial conjunctivitis (33/110) had spontaneous blood-stained discharge from the infected eye. The infants with C. trachomatis lower respiratory tract infection were mostly afebrile (30/32), and 15/32 of them had wheezing. Staccato cough was not recorded in any of the infants. The median diagnostic delay from the onset of the symptoms was 13 (range 4-374) days for conjunctivitis and 25 (range 10-149) days for lower respiratory tract infection. One neglected child developed bilateral corneal scars because of an untreated C. trachomatis infection. CONCLUSIONS: Blood-stained discharge was a typical finding in C. trachomatis conjunctivitis. The C. trachomatis-infected infants had severe and prolonged symptoms, but long-term consequences were rare. The diagnostic delay was long, especially among the infants with a C. trachomatis lower respiratory tract infection. PMID- 29389826 TI - Complicated Fusobacterium Sinusitis: A Case Report. AB - Fusobacterium infections and Lemierre syndrome are traditionally associated with pharyngitis. We report 3 cases of Fusobacterium sinusitis that resulted in Pott puffy tumor. One of these cases also had Lemierre Syndrome. We encourage expansion of the clinical spectrum of Lemierre syndrome to include complicated Fusobacterium sinusitis. PMID- 29389827 TI - Detection of Cytomegalovirus in Liver Tissue by Polymerase Chain Reaction in Infants With Neonatal Cholestasis. AB - AIM: Cytomegalovirus (CMV) is associated with neonatal cholestasis (NC). Diagnosis of CMV infection is most often based on either positive blood CMV IgM or CMV blood polymerase chain reaction (PCR). Isolation of CMV in liver tissues in patients with NC has rarely been reported. This study was undertaken to see if CMV is present in liver tissues of patients with NC and evaluate the correlation between positive CMV PCR in liver tissue with the serology and blood PCR. METHODS: This study was conducted in 31 infants with NC from June 2015 to December 2016. All patients underwent blood CMV IgM, blood CMV PCR and liver CMV PCR. Prevalence of CMV in NC based on positive liver CMV PCR was calculated. Sensitivity and specificity of the serologic markers and blood CMV PCR to identify CMV infection in the liver was determined. RESULTS: CMV IgM was positive in 13 (42%) patients, CMV IgG was positive in 26 (84%) patients and blood CMV PCR was positive in 23 (74%) patients. Liver CMV PCR was positive in 16 (52%) patients. Fifteen (48%) patients had biliary atresia (BA), 10 (32%) patients had neonatal hepatitis, 5 (16%) had paucity of bile ducts and 1 (3%) had ascending cholangitis. Of the 16 patients with positive liver CMV PCR, 8 (50%) had BA, 4 (25%) had neonatal hepatitis, 3 (19%) had paucity of bile ducts and 1 (6%) had ascending cholangitis. Sensitivity of blood CMV IgM in relation to liver CMV PCR was 69% and specificity was 61%. Sensitivity of blood CMV PCR was 61% and specificity was 71% when compared with liver CMV PCR. CONCLUSION: CMV is present in the liver tissues of more than half the patients with NC. Serology or blood CMV PCR is apparently not an accurate marker of CMV in the liver tissue. Also, CMV infection in children seems to be associated equally with BA or non-BA neonatal hepatitis. PMID- 29389828 TI - Current management of sarcoidosis I: pulmonary, cardiac, and neurologic manifestations. AB - PURPOSE OF REVIEW: Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation of multiple organ systems. Pulmonary, cardiac, and neurologic involvements have the worst prognosis. Current recommendations for the therapeutic management and follow-up of sarcoidosis involving these critical organs will be reviewed. RECENT FINDINGS: In those sarcoidosis patients requiring immunosuppressive therapy, corticosteroids are used first at varying doses depending on the presenting manifestation. Patients with symptomatic pulmonary, cardiac, or neurologic involvement will be maintained on corticosteroids for at least a year. Many require a second immunosuppressive agent with methotrexate used most commonly. Anti-tumor necrosis factor agents, especially infliximab, are effective and recommendations for their use have been proposed. SUMMARY: Evidence-based treatment guidelines do not exist for most sarcoidosis clinical manifestations. Therefore, clinical care of these patients must rely on expert opinion. Patients are best served by a multidisciplinary approach to their care. Future research to identify environmental triggers, genetic associations, biomarkers for treatment response, and where to position new steroid-sparing immunosuppressive agents is warranted. PMID- 29389829 TI - Therapeutic drug monitoring of biologicals in rheumatoid arthritis: a disconnect between beliefs and facts. AB - PURPOSE OF REVIEW: To give an overview of recently published articles covering therapeutic drug monitoring (TDM) of biological DMARDs (bDMARDs) in rheumatoid arthritis. RECENT FINDINGS: In the last 18 months, two clinical studies and nine reviews were found after a systematic literature search. Most (narrative) reviews conclude that TDM should be used to improve biological treatment in rheumatoid arthritis patients, whereas most of the clinical studies (including 13 studies identified earlier) whenever scrutinized do not support this conclusion. This disconnect between sobering data from prediction studies and test-treatment diagnostic studies and optimistic TDM beliefs in reviews is caused by failure to recognize incorrect study designs, false positives because of lack of validation after explorative multiple testing, cherry picking of studies, and incorrect interpretation of test characteristics. SUMMARY: Serum (anti)-drug level monitoring has been extensively studied in rheumatoid arthritis, but correctly designed and executed interventional prediction studies or test-treatment intervention studies are sparse and mostly negative. In contrast, many reviews advocate use of biological TDM in rheumatoid arthritis. On the basis of current evidence, therapeutic drug monitoring of biologicals cannot be recommended in the treatment of rheumatoid arthritis patients, although two clinical scenarios deserve further study. PMID- 29389830 TI - Emergence and treatment of chikungunya arthritis. AB - PURPOSE OF REVIEW: To review the emergence, clinical features, pathogenesis, and treatment of acute chikungunya (CHIK) fever and chronic CHIK arthritis. RECENT FINDINGS: Since 2004, CHIK, an arboviral infection, has spread throughout the world, infecting millions of people. The illness occurs in two phases: an acute viremic infection followed by chronic arthritis. In less developed countries, there are limited resources and effective treatment. For acutely ill CHIK fever patients, management is symptomatic. The treatment of chronic CHIK arthritis should be determined by an understanding of pathogenesis. Is chronic CHIK arthritis a persistent viral infection or a postinfectious inflammatory process? Multiple proinflammatory cytokines, chemokines, and growth factors have been identified in chronic CHIK arthritis. Attempts to isolate CHIK virus from synovial fluid have been unsuccessful. Given pathogenetic similarities (as well as differences) compared with rheumatoid arthritis and the painful, disabling nature of the arthritis, it is not surprising that disease-modifying antirheumatic drugs such as methotrexate have begun to be used. SUMMARY: CHIK infection has emerged with major arthritic epidemics for which evidence-based therapy is limited. But there is an opportunity to improve the treatment of chronic CHIK arthritis and, from this disease, to gain understanding of the pathogenesis and treatment of inflammatory arthritis more generally. PMID- 29389831 TI - Rheumatoid arthritis treatment in patients with a history of cancer. AB - PURPOSE OF REVIEW: What is the best treatment option in patients with active rheumatoid arthritis who have a history of malignant disease? Rheumatologists are increasingly faced with this question in their daily practice. As uncontrolled high disease activity is an important risk factor for further comorbidities and shortened life expectancy, the treatment has to be effective, without bearing a higher risk for cancer recurrence. What data is available today to guide treatment decisions and how robust is its evidence? RECENT FINDINGS: As patients with prior cancer are usually not included in randomized controlled trials, all data we have to elucidate this topic stems from observational cohort studies, mainly biologics registers established in several European countries. The registries investigated the risk of recurrence of cancer mainly by comparing treatments with csDMARDs and TNF inhibitors. Few results are available so far for the treatment with rituximab. However, because of their observational design, the data can only reflect current clinical practice. Because of the lack of evidence, questions such as: are biologics soon after cancer diagnosis safe, remain. SUMMARY: There is still insufficient data for patients with a very recent history of cancer. However, in patients with cancer being in longer remission, observational data suggest no increased risk of overall cancer recurrence when they are treated either with TNF inhibitors or rituximab. PMID- 29389832 TI - Treatment With Azacitidine in the Context of Palliative Care for a Patient With Acute Myeloid Leukemia Complicating Fanconi Anemia With Biallelic FANCD1/BRCA 2 Mutations. PMID- 29389833 TI - Bronchogenic Cyst: Fluid-thrill Sign on Endobronchial Ultrasound. PMID- 29389834 TI - Assessment of Bronchoscopic Dexterity and Procedural Competency in a Low-fidelity Simulation Model. AB - BACKGROUND: Assessment of competency in bronchoscopy has traditionally been undertaken in clinical settings, however, recent recognition of increased procedural complications and learner anxiety have led to interest in simulation based competency assessment. The aim of this study was to determine if low fidelity simulation-based assessment allows discrimination of competency based on prior experience between bronchoscopists. METHODS: Forty-four participants were allocated to 3 groups based on prior bronchoscopic experience [novices (n=31) with no prior experience, intermediates (n=7) with prior experience of 5 to 10 bronchoscopies, and expert bronchoscopists (n=6) with minimum 200 prior bronchoscopies performed]. Participants performed bronchoscopy in a 3D-printed anatomic airway model and were assessed according to time required to navigate to a target bronchus. Bronchoscopic dexterity was measured using a modified version of the validated Bronchoscopy Skills and Tasks Assessment Tool. RESULTS: Competency based on successful navigation to a target bronchus differed significantly between each group [experts, 12/12 (100%); intermediates, 9/14 (64%); novices, 19/62 (31%); P<0.001]. Bronchoscopic dexterity as measured by modified Bronchoscopy Skills and Tasks Assessment Tool also differed significantly between groups with experts achieving consistently higher scores compared with other 2 groups [median (interquartile range) scores: novices, 3.5 (2.5 to 5); intermediate, 5 (4.5 to 7); experts, 8 (7.5 to 8); P<0.0.001). CONCLUSIONS: Multiple measures demonstrate that low-fidelity simulation-based assessment may reliably discriminate between different levels of skill in performing bronchoscopic navigation and airway inspection. Procedural dexterity of trainees may be assessed in a 0-risk simulation environment. PMID- 29389835 TI - Effects of Acute Salbutamol Intake on Peripheral and Central Fatigue in Trained Men. AB - PURPOSE: Ergogenic effect in physically active subjects has been reported after acute salbutamol (SAL) intake. beta2-Agonists have potential stimulant effects within the central nervous system that could be involved in this ergogenic effect. We hypothesized that acute SAL intake would induce changes in cerebral responses during exercise, with significant improvement in cerebral oxygenation and voluntary activation (VA) contributing to an increase in muscle performance. METHODS: Fourteen trained male subjects (25 +/- 5 yr) performed repeated isometric knee extensions until task failure (TF) after 4 mg (oral) SAL, 800 MUg (inhaled) SAL, or placebo intake. VA, corticospinal excitability, and inhibition assessed by transcranial magnetic stimulation and changes in hemoglobin concentrations assessed by near-infrared spectroscopy were measured before and during the fatiguing task. RESULTS: SAL had no significant effect both at rest and during exercise on prefrontal cortex oxygenation (e.g., changes in oxyhemoglobin concentration at TF: 11.4 +/- 11.1 (4 mg SAL) vs 10.4 +/- 10.6 (800 MUg SAL) vs 10.8 +/- 8.1 MUmol (placebo); P = 0.314) and neuromuscular function (e.g., VA measured by TMS at TF: 90.2% +/- 6.6% vs 92.6% +/- 5.0% vs 90.1% +/- 7.0%; P = 0.760). SAL had no effect on the number of contractions until TF (95 +/ 51 vs 100 +/- 52 vs 93 +/- 47; P = 0.629). CONCLUSIONS: These results indicate that acute SAL intake had no effect on central and peripheral mechanisms of neuromuscular fatigue and did not improve quadriceps endurance. PMID- 29389836 TI - Strength Training Effects on Muscular Regeneration after ACL Reconstruction. AB - PURPOSE: Protracted quadriceps muscle atrophy is observed after anterior cruciate ligament reconstruction (ACL-R). The aim of this study was to assess if quadriceps strength training with eccentric overload (CON/ECC) is more efficient to induce muscle regeneration after ACL-R than conventional concentric/eccentric (CON/ECC) strength training. METHODS: Biopsies from the vastus lateralis muscle were obtained from 37 recreational athletes after 12 wk of regular rehabilitation after ACL-R and again after 12 wk with twice a week of either conventional CON/ECC (n = 16) or CON/ECC (n = 21) one-legged supervised leg-press training. Immunohistochemical analyses were used to determine satellite cell (SC) number (Pax7); activated SC number (Pax7/MyoD); fibers expressing myosin heavy-chain (MHC) I and II, MHC neonatal, and fiber cross-sectional area. Magnetic resonance imaging was performed to measure quadriceps cross-sectional area and isokinetic testing for the measurement of quadriceps strength. RESULTS: CON/ECC induced a significantly (P = 0.002) greater increase in quadriceps cross-sectional area than did CON/ECC. There also was a significant increase in the fiber cross sectional areas of all fiber types and in quadriceps strength, but without significant difference between training groups. Only CON/ECC training led to a significant (P < 0.05) increase in percent type I fibers. After training, the number of MHC I/MHCneo fibers was significantly (P < 0.05) greater in the CON/ECC than after in the CON/ECC group. The proportion of hybrid fibers tended to decrease in both groups; percent type II fibers, SC number, and activated SC number remained unchanged. CONCLUSIONS: CON/ECC leads to significantly greater muscle hypertrophy compared with CON/ECC, but without the hypothesized enhancing effect on SC activation. At the same time, CON/ECC+ induces a less favorable slower muscle phenotype for strong and fast movements. PMID- 29389837 TI - Airway and ventilation management strategies for hemorrhagic shock. To tube, or not to tube, that is the question! AB - : Many standard trauma management guidelines advocate the early use of endotracheal intubation (ETI) and positive pressure ventilation as key treatment interventions in hemorrhagic shock. The evidence for using these airway and ventilation strategies to manage a circulation problem is unclear. The potentially harmful effects of drug-assisted intubation and positive pressure ventilation include reduced cardiac output, apnea, hypoxia, hypocapnea (due to inadvertent hyperventilation), and unnecessarily prolonged on-scene times. Conversely, the beneficial effects of spontaneous negative pressure ventilation on cardiac output are well described. Few studies, however, have attempted to explore the potential advantages of a strategy of delayed intubation and ventilation (together with a policy of aggressive volume replacement) in shocked trauma patients. Given the lack of evidence, the decision making around how, when, and where to subject shocked trauma patients to intubation and positive pressure ventilation remains complex. If providers choose to delay intubation, they must have the appropriate skills to safely manage the airway and recognize the need for subsequent intervention. If they decide to perform intubation and positive pressure ventilation, they must understand the potential risks and how best to minimize them. We suggest that for patients with hemorrhagic shock who do not have a compromised airway and who are able to maintain adequate oxygen saturation (or mentation if monitoring is unreliable), a strategy of delayed intubation should be strongly encouraged. LEVEL OF EVIDENCE: Review article, level IV. PMID- 29389838 TI - Too little too late: Hypotension and blood transfusion in the trauma bay are independent predictors of death in injured children. AB - BACKGROUND: Hypotension is a late finding in pediatric shock despite significant blood loss; consequently, recognition of hemodynamic compromise can be delayed. We sought to describe the impact of late stage shock in children, indicated by hypotension or trauma bay blood transfusion, and quantify the association with poor outcome. METHODS: Children age < 18 from the Pennsylvania Trauma Outcome Study registry (2000-2013) were included. Primary outcome was mortality. Demographics, transfusion volume, vitals and injury severity were recorded. Multivariable logistic regression modeling was performed, with multiple imputation sensitivity analysis for missing data (<8% for all variables). RESULTS: Sixty-four thousand three hundred forty-four subjects were included with median (interquartile range) age, 9 years (4-15 years); 51% interfacility transfers; 2.0% mortality; 4.4% admission hypotension; and 1.6% trauma bay transfusion rate. Overall, 46% of hypotensive patients, 42% of transfused patients, and 63% both hypotensive and transfused died. Hypotension (odds ratio, 12.8; 95% confidence interval, 10.7-15.4; p < 0.001) and transfusion (odds ratio, 3.1; 95% confidence interval, 2.8-3.4; p < 0.001) significantly increased odds of death after controlling for injury severity, penetrating and child abuse mechanisms, admission Glasgow Coma Scale score, and age. Survival curves demonstrated worse survival for transfused patients in early (<24 hours), intermediate (1-5 days), and late (>5 days) periods (all p < 0.001). CONCLUSION: Hypotension and trauma bay blood transfusion are poor prognostic indicators. These events should signal high acuity and prompt immediate and aggressive resuscitation. Earlier recognition of shock and appropriate interventions, including increased availability of blood products to prehospital providers, may facilitate timely hemostatic resuscitation, preventing circulatory collapse and secondary brain injury. LEVEL OF EVIDENCE: Epidemiological, level III. PMID- 29389839 TI - Impact of a statewide trauma system on the triage, transfer, and inpatient mortality of injured patients. AB - BACKGROUND: In 2009, Arkansas implemented a statewide trauma system to address the high rates of mortality and morbidity due to trauma. The principal objective of the Arkansas Trauma System is to transport patients to the appropriate facility based on the injuries of the patients. This study evaluated four metrics that were crucial to system health. These measures included: treatment location, scene triage, admission to nondesignated facilities, and inpatient mortality. Furthermore, the authors sought to quantify how the system is selective toward the severely injured regarding triage and treatment location. The authors hypothesized that system implementation should increase the proportion of patients, particularly the severely injured, treated at Level I/II facilities. The system should increase the proportion of patients, especially the severely injured, admitted to Level I/II facilities directly from the scene. The system should result in fewer patients admitted to nondesignated facilities. Lastly, system implementation should result in fewer inpatient deaths. METHODS: A pre post study design was used for this evaluation. Data from the Arkansas Hospital Discharge data set (2007 through 2012) identified patients who were admitted as a result of their injuries. The ICD-MAP software was used to categorize those with and without severe injuries based on an Injury Severity Score of 16 or greater or head Abbreviated Injury Scale score of 3 or greater. RESULTS: The results indicate that while there was an overall increase in odds of patients being admitted to Level I/II facilities, those with severe injuries were associated with an even greater odds of admission to Level I/II facilities (p < 0.0001). System implementation was also associated with more severely injured patients admitted to Level I/II facilities from the scene. There were also fewer patients admitted to nondesignated hospitals after system implementation (p < 0.0001). System implementation was associated with fewer inpatient deaths (p = 0.02). CONCLUSION: Two years after implementation, the trauma system showed significant progress. The measures evaluated in this study are believed to support the effectiveness of the trauma system. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 29389840 TI - Prevention of all-terrain vehicle injuries: A systematic review from The Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Despite increasing usage since their introduction, there exist no evidence-based guidelines on all-terrain vehicles (ATVs) and injury prevention. While the power and speed of these vehicles has increased over time, advancements in ATV safety have been rare. METHODS: A priori questions about ATV injury pattern and the effect of helmet and safety equipment use and legislation mandating use were developed. A query of MEDLINE, PubMed, Cochrane Library, and Embase for all-terrain vehicle injury was performed. Letters to the editor, case reports, book chapters, and review articles were excluded. Grading of Recommendations Assessment, Development, and Evaluation methodology was used to perform a systematic review and create recommendations. RESULTS: Twenty-eight studies were included. Helmet use reduced traumatic brain injury (TBI). However, studies examining whether legislation mandating helmet use reduced TBI had mixed results. When ATV safety legislation was enforced, overall injury rates and mortality decreased. However, enforcement varied widely and lack of enforcement led to decreased compliance with legislation and mixed results. There was not enough evidence to determine the effectiveness of non-helmet-protective equipment. CONCLUSION: Helmet use when riding an ATV reduced the rate of TBI. ATV safety legislation, when enforced, also reduced morbidity and mortality. Compliance with laws is often low, however, possibly due to poor enforcement. We recommend helmet use when riding on an ATV to reduce TBI. We conditionally recommend implementing ATV safety legislation as a means to reduce ATV injuries, noting that enforcement must go hand in hand with enactment to ensure compliance. PMID- 29389841 TI - Emergency general surgery in geriatric patients: A statewide analysis of surgeon and hospital volume with outcomes. AB - BACKGROUND: Geriatric patients undergoing emergency general surgery (EGS) face significant morbidity and mortality. We assessed how surgeon and hospital volumes affected these outcomes. METHODS: We identified patients at least 65 years old in Maryland's Health Services Cost Review Commission database from 2012 to 2014 who underwent one of 12 EGS procedures, as defined by the American Association for the Surgery of Trauma, and then calculated four outcomes: mortality rate, the incidence of at least one of eight common in-hospital EGS complications, failure to-rescue (death after experiencing a postoperative complication), and the 30-day readmission rate. Median annual volumes of geriatric-EGS procedures divided both surgeons and hospitals into two groups (low volume and high volume). Multivariable logistic regressions calculated associations between the volume groups and outcomes after adjusting for patient, surgeon, and hospital factors, and hospital clusters. RESULTS: We identified 3,832 patients who had an EGS procedure by 302 surgeons (median: 8 geriatric-EGS/year, IQR: 3-18) at 44 hospitals (median: 82 geriatric-EGS/year, IQR: 35-132). While operating on 16.5% of all geriatric-EGS patients, low-volume surgeons had higher risk-adjusted adverse outcomes: mortality (7.0% vs. 4.0%, p = 0.005), in-hospital complications (22.1% vs. 19.7%, p = 0.13), failure-to-rescue (17.3% vs. 12.1%, p = 0.021), and 30-day readmissions (11.2% vs. 10.0%, p = 0.55). After adjustment, low-volume surgeons were associated with higher mortality (adjusted odds ratio [aOR] 1.86, 95% CI [1.21-2.86]) and failure-to-rescue rates (aOR 1.74 [1.09-2.80]) but not in hospital complications (aOR 1.20 [0.95-1.51]) or 30-day readmissions (aOR 1.07 [0.85-1.34]). In contrast, low-volume hospitals relative to high-volume hospitals, and hospitals serving lower proportions of geriatric-EGS patients, were not associated with adverse outcomes. CONCLUSION: Relative to their higher volume counterparts, surgeons performing eight or fewer geriatric-EGS procedures annually were associated with an 86% higher odds of death and 74% higher odds of failure-to-rescue in this elderly EGS patient population. These findings underscore the need for focused care of elderly surgical patients. LEVEL OF EVIDENCE: Prognostic and epidemiological, level IV. PMID- 29389842 TI - Dihydrocodeine Overdoses in a Neonate and in a 14-year-old Girl Who Were Both Genotyped as Cytochrome P450 2D6*1/*10-*36: Comparing Developmental Ages and Drug Monitoring Data With the Results of Pharmacokinetic Modeling. AB - A high activity of cytochrome P450 2D6 (CYP2D6) reportedly leads to toxicity of dihydrocodeine/codeine by increasing toxic potential of their metabolite dihydromorphine/morphine, which are further metabolized to highly active dihydromorphine 6-O-glucuronide and the less active morphine 3-O-glucorinide but rapidly excreted into urine as water-soluble forms. A case of acute respiratory depression after administration of prescribed dihydrocodeine phosphate (2.0 mg/d divided twice a day for 2 days) to a 1-month-old baby boy genotyped as CYP2D6*1/*10-*36 is described. The case is compared with that of a 14-year-old girl, also genotyped as CYP2D6*1/*10-*36, presenting in an agitated state after an overdose (37 mg) of dihydrocodeine phosphate taken as simultaneous ingestion of multiple over-the-counter tablets. In contrast to the rapid clearance of dihydrocodeine from blood in the 14-year-old girl (apparent half-life of 3 hours), the 1-month-old baby boy still had high serum concentrations of dihydrocodeine (400 nmol/L) and dihydromorphine (1.9 nmol/L) 21 hours after the last oral administration of dihydrocodeine-containing cough mixture. The rapid clearance in the 14-year-old girl was mainly attributed to dihydrocodeine glucuronidation and partly attributed to dihydromorphine formation, as determined by liquid chromatography-tandem mass spectrometry analyses. However, the conjugation ratios of dihydrocodeine and dihydromorphine in the neonate were low in comparison with those in the 14-year-old girl and with those measured in 3-, 6 , and 13-year-old control subjects, resulting from the poorly developed glucuronidation potential of the neonate. The current observations suggest that the CYP2D6*1/*10-*36 genotype seen in the 2 Japanese patients may not significantly contribute to the likelihood of dihydrocodeine overdose but highlight the importance of considering age when prescribing dihydrocodeine. PMID- 29389843 TI - Adoptable Interventions, Human Health, and Food Safety Considerations for Reducing Sodium Content of Processed Food Products. AB - Although vital for maintaining health when consumed in moderation, various epidemiological studies in recent years have shown a strong association between excess dietary sodium with an array of health complications. These associations are robust and clinically significant for development of hypertension and prehypertension, two of the leading causes of preventable mortality worldwide, in adults with a high-sodium diet. Data from developed nations and transition economies show worldwide sodium intake of higher than recommended amounts in various nations. While natural foods typically contain a moderate amount of sodium, manufactured food products are the main contributor to dietary sodium intake, up to 75% of sodium in diet of American adults, as an example. Lower cost in formulation, positive effects on organoleptic properties of food products, effects on food quality during shelf-life, and microbiological food safety, make sodium chloride a notable candidate and an indispensable part of formulation of various products. Although low-sodium formulation of each product possesses a unique set of challenges, review of literature shows an abundance of successful experiences for products of many categories. The current study discusses adoptable interventions for product development and reformulation of products to achieve a modest amount of final sodium content while maintaining taste, quality, shelf-stability, and microbiological food safety. PMID- 29389844 TI - Enrichment of Biscuits with Matcha Green Tea Powder: Its Impact on Consumer Acceptability and Acute Metabolic Response. AB - Matcha green tea powder (MGTP) is made with finely ground green tea leaves that are rich in phytochemicals, most particularly catechins. Shortbread biscuits were enriched with MGTP and evaluated for consumer acceptability and potential functional health properties. Baking decreased the content of total catechins by 19% compared to dough, although epimerization increased the amount of (+) gallocatechin gallate at the expense of other catechins such as (-) epigallocatechin gallate. Consumer acceptability tests using a 9-point hedonic scale showed that consumers preferred enriched biscuits with low content of MGTP (2 g of MGTP 100 g-1 of flour), and an increase of sugar content did not significantly improve the acceptability of MGTP-enriched biscuits. Overall, enrichment of biscuits with MGTP did not significantly affect the postprandial glucose or triglyceride response (area under curve) compared to non-enriched biscuits consumed with water or MGTP drink. Enriching biscuits with Matcha green tea is acceptable to consumers, but may not bring significant postprandial effects. PMID- 29389845 TI - Facial Emotion Recognition: A Survey and Real-World User Experiences in Mixed Reality. AB - Extensive possibilities of applications have made emotion recognition ineluctable and challenging in the field of computer science. The use of non-verbal cues such as gestures, body movement, and facial expressions convey the feeling and the feedback to the user. This discipline of Human-Computer Interaction places reliance on the algorithmic robustness and the sensitivity of the sensor to ameliorate the recognition. Sensors play a significant role in accurate detection by providing a very high-quality input, hence increasing the efficiency and the reliability of the system. Automatic recognition of human emotions would help in teaching social intelligence in the machines. This paper presents a brief study of the various approaches and the techniques of emotion recognition. The survey covers a succinct review of the databases that are considered as data sets for algorithms detecting the emotions by facial expressions. Later, mixed reality device Microsoft HoloLens (MHL) is introduced for observing emotion recognition in Augmented Reality (AR). A brief introduction of its sensors, their application in emotion recognition and some preliminary results of emotion recognition using MHL are presented. The paper then concludes by comparing results of emotion recognition by the MHL and a regular webcam. PMID- 29389846 TI - Long-Term Electroclinical and Employment Follow up in Temporal Lobe Epilepsy Surgery. A Cuban Comprehensive Epilepsy Surgery Program. AB - The purpose of this paper is to present a long- term electroclinical and employment follow up in temporal lobe epilepsy (TLE) patients in a comprehensive epilepsy surgery program. Forty adult patients with pharmacoresistant TLE underwent detailed presurgical evaluation. Electroencephalogram (EEG) and clinical follow up assessment for each patient were carried out. The occurrence of interictal epileptiform activity (IEA) and absolute spike frequency (ASF) were tabulated before and after 1, 6, 12, 24 and 72 months surgical treatment. Employment status pre- to post-surgery at the last evaluated period was also examined. Engel scores follow-up was described as follows: at 12 months 70% (28) class I, 10% (4) class II and 19% (8) class III-IV; at 24 months after surgery 55.2% (21) of the patients were class I, 28.9% (11) class II and 15.1% (6) class III-IV. After one- year follow up 23 (57.7%) patients were seizure and aura-free (Engel class IA). These figures changed to 47.3%, and 48.6% respectively two and five years following surgery whereas 50% maintained this condition in the last follow up period. A decline in the ASF was observed from the first year until the sixth year after surgery in relation to the preoperative EEG. The ASF one year after surgery allowed to distinguish "satisfactory" from "unsatisfactory" seizure relief outcome at the last follow up. An adequate social functioning in terms of education and employment in more than 50% of the patients was also found. Results revealed the feasibility of conducting a successful epilepsy surgery program with favorable long term electroclinical and psychosocial functioning outcomes in a developing country as well. PMID- 29389848 TI - Feasibility of Using Gluconolactone, Trehalose and Hydroxy-Propyl Gamma Cyclodextrin to Enhance Bendroflumethiazide Dissolution Using Lyophilisation and Physical Mixing Techniques. AB - PURPOSE: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. METHODS: In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl gamma-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl gamma-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. RESULTS: The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min. CONCLUSIONS: the physical mixing and freeze drying processes significantly increased the percentage of drug release with time. PMID- 29389847 TI - A Phenotyping Method of Giant Cells from Root-Knot Nematode Feeding Sites by Confocal Microscopy Highlights a Role for CHITINASE-LIKE 1 in Arabidopsis. AB - Most effective nematicides for the control of root-knot nematodes are banned, which demands a better understanding of the plant-nematode interaction. Understanding how gene expression in the nematode-feeding sites relates to morphological features may assist a better characterization of the interaction. However, nematode-induced galls resulting from cell-proliferation and hypertrophy hinders such observation, which would require tissue sectioning or clearing. We demonstrate that a method based on the green auto-fluorescence produced by glutaraldehyde and the tissue-clearing properties of benzyl-alcohol/benzyl benzoate preserves the structure of the nematode-feeding sites and the plant nematode interface with unprecedented resolution quality. This allowed us to obtain detailed measurements of the giant cells' area in an Arabidopsis line overexpressing CHITINASE-LIKE-1 (CTL1) from optical sections by confocal microscopy, assigning a role for CTL1 and adding essential data to the scarce information of the role of gene repression in giant cells. Furthermore, subcellular structures and features of the nematodes body and tissues from thick organs formed after different biotic interactions, i.e., galls, syncytia, and nodules, were clearly distinguished without embedding or sectioning in different plant species (Arabidopsis, cucumber or Medicago). The combination of this method with molecular studies will be valuable for a better understanding of the plant biotic interactions. PMID- 29389849 TI - A Decentralized Framework for Multi-Agent Robotic Systems. AB - Over the past few years, decentralization of multi-agent robotic systems has become an important research area. These systems do not depend on a central control unit, which enables the control and assignment of distributed, asynchronous and robust tasks. However, in some cases, the network communication process between robotic agents is overlooked, and this creates a dependency for each agent to maintain a permanent link with nearby units to be able to fulfill its goals. This article describes a communication framework, where each agent in the system can leave the network or accept new connections, sending its information based on the transfer history of all nodes in the network. To this end, each agent needs to comply with four processes to participate in the system, plus a fifth process for data transfer to the nearest nodes that is based on Received Signal Strength Indicator (RSSI) and data history. To validate this framework, we use differential robotic agents and a monitoring agent to generate a topological map of an environment with the presence of obstacles. PMID- 29389850 TI - Maintaining Vitality: Pharmacists' Continuing Professional Education Decision Making in the Upper Midwest. AB - Continuing professional education (CPE) plays an important role in continuing professional development of pharmacists for providing quality pharmaceutical care but also to maintain professional and organizational vitality and meet changing community/population needs. The study objective was to describe and understand factors of importance in selection of CPE credit hours among Upper Midwest pharmacists. A cross-sectional study of licensed pharmacists (n = 1239) in Iowa, Minnesota, Nebraska, North Dakota, and South Dakota included completion of a questionnaire on demographics and CPE decision-making. Factor analysis, t-test, and multivariate analyses were performed using Stata 10.1. Pharmacists placed greatest importance on maintaining licensure (mean = 2.72/3.00), personal interest (mean = 2.57), and self-improvement (mean = 2.42). Community/population need (mean = 1.83) was rated as slightly more important (p < 0.01) by retail/community pharmacists, females, and those with a Doctor of Pharmacy degree or pharmacy residency while business growth/development (mean = 1.33) was rated slightly more important (p < 0.01) by retail/community pharmacists. Despite findings that neither community/population need nor business development were among the most important factors in pharmacists' CPE selection, there exists significant potential for pharmacists to utilize CPE to maintain professional and organizational vitality in the labor market, but more importantly to ensure continued provision of quality pharmaceutical care and patient education. PMID- 29389851 TI - Sensitive and Flexible Polymeric Strain Sensor for Accurate Human Motion Monitoring. AB - Flexible electronic devices offer the capability to integrate and adapt with human body. These devices are mountable on surfaces with various shapes, which allow us to attach them to clothes or directly onto the body. This paper suggests a facile fabrication strategy via electrospinning to develop a stretchable, and sensitive poly (vinylidene fluoride) nanofibrous strain sensor for human motion monitoring. A complete characterization on the single PVDF nano fiber has been performed. The charge generated by PVDF electrospun strain sensor changes was employed as a parameter to control the finger motion of the robotic arm. As a proof of concept, we developed a smart glove with five sensors integrated into it to detect the fingers motion and transfer it to a robotic hand. Our results shows that the proposed strain sensors are able to detect tiny motion of fingers and successfully run the robotic hand. PMID- 29389852 TI - Stress Prediction for Distributed Structural Health Monitoring Using Existing Measurements and Pattern Recognition. AB - The stress in structural steel members is the most useful and directly measurable physical quantity to evaluate the structural safety in structural health monitoring, which is also an important index to evaluate the stress distribution and force condition of structures during structural construction and service phases. Thus, it is common to set stress as a measure in steel structural monitoring. Considering the economy and the importance of the structural members, there are only a limited number of sensors that can be placed, which means that it is impossible to obtain the stresses of all members directly using sensors. This study aims to develop a stress response prediction method for locations where there are insufficent sensors, using measurements from a limited number of sensors and pattern recognition. The detailed improved aspects are: (1) a distributed computing process is proposed, where the same pattern is recognized by several subsets of measurements; and (2) the pattern recognition using the subset of measurements is carried out by considering the optimal number of sensors and number of fusion patterns. The validity and feasibility of the proposed method are verified using two examples: the finite-element simulation of a single-layer shell-like steel structure, and the structural health monitoring of the space steel roof of Shenzhen Bay Stadium; for the latter, the anti-noise performance of this method is verified by the stress measurements from a real world project. PMID- 29389853 TI - Prolonged Corrosion Stability of a Microchip Sensor Implant during In Vivo Exposure. AB - A microelectronic biosensor was subjected to in vivo exposure by implanting it in the vicinity of m. trapezii (Trapezius muscle) from cattle. The implant is intended for the continuous monitoring of glucose levels, and the study aimed at evaluating the biostability of exposed semiconductor surfaces. The sensor chip was a microelectromechanical system (MEMS) prepared using 0.25 um complementary metal-oxide-semiconductor CMOS/BiCMOS technology. Sensing is based on the principle of affinity viscometry with a sensoric assay, which is separated by a semipermeable membrane from the tissue. Outer dimensions of the otherwise hermetically sealed biosensor system were 39 * 49 * 16 mm. The test system was implanted into cattle in a subcutaneous position without running it. After 17 months, the device was explanted and analyzed by comparing it with unexposed chips and systems. Investigations focused on the MEMS chip using SEM, TEM, and elemental analysis by EDX mapping. The sensor chip turned out to be uncorroded and no diminishing of the topmost passivation layer could be determined, which contrasts remarkably with previous results on CMOS biosensors. The negligible corrosive attack is understood to be a side effect of the semipermeable membrane separating the assay from the tissue. It is concluded that the separation has enabled a prolonged biostability of the chip, which will be of relevance for biosensor implants in general. PMID- 29389855 TI - Improvement on the Repair Effect of Electrochemical Chloride Extraction Using a Modified Electrode Configuration. AB - To improve the repair effect of electrochemical chloride extraction, a modified electrode configuration is applied in this investigation. In this configuration, two auxiliary electrodes placed in the anodic and cathodic electrolytes were used as the anode and cathode, respectively. Besides this, the steel in the mortar was grounded to protect it from corrosion. By a comparative experiment, the potential evolution, various ions concentrations (Cl-, OH-, Na+, and K+) in different mortar depths, the corrosion potential, and the current density of the steel were measured. The results indicate that compared to electrochemical chloride extraction with the traditional electrode configuration, this electrochemical chloride extraction method with a modified electrode configuration has a similar chloride removal ratio. Besides this, potential of steel is just about 800 mV for a saturated calomel electrode (SCE) during the treatment, which did not reach the hydrogen evolution potential. The phenomenon of the accumulation of OH-, Na+, and K+ did not occur when the modified electrode configuration is applied. Additionally, higher corrosion potentials and lower corrosion current rates were measured after performing electrochemical chloride extraction with the modified electrode configuration. Additionally, it is a short period of time for the steel to go from activation to passivation. On this basis, the modified electrode configuration may overcome the drawbacks of electrochemical chloride extraction. PMID- 29389856 TI - Study of the Integration of the CNU-TS-1 Mobile Tunnel Monitoring System. AB - A rapid, precise and automated means for the regular inspection and maintenance of a large number of tunnels is needed. Based on the depth study of the tunnel monitoring method, the CNU-TS-1 mobile tunnel monitoring system (TS1) is developed and presented. It can efficiently obtain the cross-sections that are orthogonal to the tunnel in a dynamic way, and the control measurements that depend on design data are eliminated. By using odometers to locate the cross sections and correcting the data based on longitudinal joints of tunnel segment lining, the cost of the system has been significantly reduced, and the interval between adjacent cross-sections can reach 1-2 cm when pushed to collect data at a normal walking speed. Meanwhile, the relative deformation of tunnel can be analyzed by selecting cross-sections from original data. Through the measurement of the actual tunnel, the applicability of the system for tunnel deformation detection is verified, and the system is shown to be 15 times more efficient than that of the total station. The simulation experiment of the tunnel deformation indicates that the measurement accuracy of TS1 for cross-sections is 1.1 mm. Compared with the traditional method, TS1 improves the efficiency as well as increases the density of the obtained points. PMID- 29389854 TI - Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets. AB - Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents. PMID- 29389857 TI - Estimation of Foot Plantar Center of Pressure Trajectories with Low-Cost Instrumented Insoles Using an Individual-Specific Nonlinear Model. AB - Postural control is a complex skill based on the interaction of dynamic sensorimotor processes, and can be challenging for people with deficits in sensory functions. The foot plantar center of pressure (COP) has often been used for quantitative assessment of postural control. Previously, the foot plantar COP was mainly measured by force plates or complicated and expensive insole-based measurement systems. Although some low-cost instrumented insoles have been developed, their ability to accurately estimate the foot plantar COP trajectory was not robust. In this study, a novel individual-specific nonlinear model was proposed to estimate the foot plantar COP trajectories with an instrumented insole based on low-cost force sensitive resistors (FSRs). The model coefficients were determined by a least square error approximation algorithm. Model validation was carried out by comparing the estimated COP data with the reference data in a variety of postural control assessment tasks. We also compared our data with the COP trajectories estimated by the previously well accepted weighted mean approach. Comparing with the reference measurements, the average root mean square errors of the COP trajectories of both feet were 2.23 mm (+/-0.64) (left foot) and 2.72 mm (+/-0.83) (right foot) along the medial-lateral direction, and 9.17 mm (+/-1.98) (left foot) and 11.19 mm (+/-2.98) (right foot) along the anterior posterior direction. The results are superior to those reported in previous relevant studies, and demonstrate that our proposed approach can be used for accurate foot plantar COP trajectory estimation. This study could provide an inexpensive solution to fall risk assessment in home settings or community healthcare center for the elderly. It has the potential to help prevent future falls in the elderly. PMID- 29389858 TI - The Role of Motivation to Reduce Obesity among Elderly People: Response to Priming Temptation in Obese Individuals. AB - The risk of obesity-related disorders is increased among the elderly, so changing eating habits can be an important element of prevention. The main aim of this article is to consider whether looking at pictures that present either fattening food or healthy food may motivate elderly people to change their nutrition habits. Might priming different kinds of food influence the attractiveness of the food for people in late adulthood undergoing obesity therapy? Based on priming theories, we analysed the effects of the conscious processing of stimuli associated with dietary habits in individuals aged with BMI >= 30 kg/m2. Our experiments confirmed the influence of a higher-priority goal of "slimming" on the perception and internalization of nutrition-related stimuli. In response to such stimuli, individuals who are actively involved in weight reduction and health-oriented programs use strategies for resisting temptation and to effectively "slim". We present our findings in the context of their theoretical background and practical application. PMID- 29389859 TI - Role of Galectins in Tumors and in Clinical Immunotherapy. AB - Galectins are glycan-binding proteins that contain one or two carbohydrate domains and mediate multiple biological functions. By analyzing clinical tumor samples, the abnormal expression of galectins is known to be linked to the development, progression and metastasis of cancers. Galectins also have diverse functions on different immune cells that either promote inflammation or dampen T cell-mediated immune responses, depending on cognate receptors on target cells. Thus, tumor-derived galectins can have bifunctional effects on tumor and immune cells. This review focuses on the biological effects of galectin-1, galectin-3 and galectin-9 in various cancers and discusses anticancer therapies that target these molecules. PMID- 29389860 TI - The Effects of Graphene Stacking on the Performance of Methane Sensor: A First Principles Study on the Adsorption, Band Gap and Doping of Graphene. AB - The effects of graphene stacking are investigated by comparing the results of methane adsorption energy, electronic performance, and the doping feasibility of five dopants (i.e., B, N, Al, Si, and P) via first-principles theory. Both zigzag and armchair graphenes are considered. It is found that the zigzag graphene with Bernal stacking has the largest adsorption energy on methane, while the armchair graphene with Order stacking is opposite. In addition, both the Order and Bernal stacked graphenes possess a positive linear relationship between adsorption energy and layer number. Furthermore, they always have larger adsorption energy in zigzag graphene. For electronic properties, the results show that the stacking effects on band gap are significant, but it does not cause big changes to band structure and density of states. In the comparison of distance, the average interlamellar spacing of the Order stacked graphene is the largest. Moreover, the adsorption effect is the result of the interactions between graphene and methane combined with the change of graphene's structure. Lastly, the armchair graphene with Order stacking possesses the lowest formation energy in these five dopants. It could be the best choice for doping to improve the methane adsorption. PMID- 29389862 TI - Moving the Plasmon of LaB6 from IR to Near-IR via Eu-Doping. AB - Lanthanum hexaboride (LaB6) has become a material of intense interest in recent years due to its low work function, thermal stability and intriguing optical properties. LaB6 is also a semiconductor plasmonic material with the ability to support strong plasmon modes. Some of these modes uniquely stretch into the infrared, allowing the material to absorb around 1000 nm, which is of great interest to the window industry. It is well known that the plasmon of LaB6 can be tuned by controlling particle size and shape. In this work, we explore the options available to further tune the optical properties by describing how metal vacancies and Eu doping concentrations are additional knobs for tuning the absorbance from the near-IR to far-IR in La1-xEuxB6 (x = 0, 0.2, 0.5, 0.8, and 1.0). We also report that there is a direct correlation between Eu concentration and metal vacancies within the Eu1-xLaxB6. PMID- 29389863 TI - Energy Level-Based Abnormal Crowd Behavior Detection. AB - The change of crowd energy is a fundamental measurement for describing a crowd behavior. In this paper, we present a crowd abnormal detection method based on the change of energy-level distribution. The method can not only reduce the camera perspective effect, but also detect crowd abnormal behavior in time. Pixels in the image are treated as particles, and the optical flow method is adopted to extract the velocities of particles. The qualities of different particles are distributed as different value according to the distance between the particle and the camera to reduce the camera perspective effect. Then a crowd motion segmentation method based on flow field texture representation is utilized to extract the motion foreground, and a linear interpolation calculation is applied to pedestrian's foreground area to determine their distance to the camera. This contributes to the calculation of the particle qualities in different locations. Finally, the crowd behavior is analyzed according to the change of the consistency, entropy and contrast of the three descriptors for co occurrence matrix. By calculating a threshold, the timestamp when the crowd abnormal happens is determined. In this paper, multiple sets of videos from three different scenes in UMN dataset are employed in the experiment. The results show that the proposed method is effective in characterizing anomalies in videos. PMID- 29389864 TI - Empowering Retailers to Refuse to Sell Tobacco Products to Minors. AB - Tobacco smoking and exposure to secondhand smoke are major environmental risk factors that negatively influence health. It is recommended that tobacco product manufacturers and retailers receive empowerment counseling programs to achieve adolescent health targets. The present study conducted an empowerment counseling session to counsel tobacco product retailers in refusing to sell tobacco products to minors. The three stages of this study were conducted from March 2015 to February 2017. The results revealed that 74% of retailers were selling tobacco products to minors at baseline, 40% at stage two and 15% at stage three. These represent significant reductions in selling tobacco products to minors (all stage differences p < 0.001). However, experimental design studies could be used to examine the empowerment counseling program for preventing tobacco sales to minors in the future. Moreover, health care providers should collaborate with tobacco product retailers to design unique empowerment counseling sessions for specific regions to improve retailers' capabilities for self-management in terms of tobacco hazard prevention. PMID- 29389861 TI - Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer. AB - Altered expression of secreted factors by tumor cells or cells of the tumor microenvironment is a key event in cancer development and progression. In the last decade, emerging evidences supported the autocrine and paracrine activity of the members of the Angiopoietin-like (ANGPTL) protein family in angiogenesis, inflammation and in the regulation of different steps of carcinogenesis and metastasis development. Thus, ANGPTL proteins become attractive either as prognostic or predictive biomarkers, or as novel target for cancer treatment. Here, we outline the current knowledge about the functions of the ANGPTL proteins in angiogenesis, cancer progression and metastasis. Moreover, we discuss the most recent evidences sustaining their role as prognostic or predictive biomarkers for cancer therapy. Although the role of ANGPTL proteins in cancer has not been fully elucidated, increasing evidence suggest their key effects in the proliferative and invasive properties of cancer cells. Moreover, given the common overexpression of ANGPTL proteins in several aggressive solid tumors, and their role in tumor cells and cells of the tumor microenvironment, the field of research about ANGPTL proteins network may highlight new potential targets for the development of future therapeutic strategies. PMID- 29389865 TI - The Listeria monocytogenes Key Virulence Determinants hly and prfA are involved in Biofilm Formation and Aggregation but not Colonization of Fresh Produce. AB - Listeria monocytogenes has been extensively studied as a model facultative intracellular pathogen. While the roles of major virulence factors in host pathogen interactions have been extensively characterized, recent work suggests that some of these factors can also contribute to environmental proliferation of this pathogen. In this study, we characterized two non-hemolytic transposon mutants of strain 2011L-2858 (serotype 1/2b), implicated in the 2011 listeriosis outbreak via whole cantaloupe, for their capacity to form biofilms on polystyrene, aggregate, and colonize cantaloupe rind. One mutant harbored a single mariner-based transposon insertion in hly, encoding the hemolysin Listeriolysin O, while the other harbored a single insertion in prfA, encoding PrfA, a master regulator for hly and numerous other virulence genes. Biofilm formation was significantly reduced in the prfA mutant, and to a lesser extent, in the hly mutant. Inactivation of either hly or prfA significantly reduced L. monocytogenes aggregation. However, both mutants adhered similarly to the wildtype parental strain on cantaloupe rind at either 25 or 37 degrees C. Furthermore, growth and competitive fitness of the mutants on cantaloupe rind was not significantly impacted at either temperature. The findings suggest that, in spite of their involvement in biofilm formation and aggregation, these key virulence determinants may not be required for the ability of L. monocytogenes to colonize fresh produce. PMID- 29389866 TI - Survey of Nonprescription Medication and Antibiotic Use in Patients with Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, and Overlap Syndrome. AB - Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and overlap syndrome (SJS-TEN) are rare, serious skin and mucosa break-down conditions frequently associated with antibiotic use. The role of nonprescription medications alone, or in combination with antibiotics in triggering SJS/TEN, is largely unknown. This study summarized data collected from patient surveys about nonprescription and antibiotic use prior to a SJS/TEN diagnosis. The survey was administered online to members of the U.S. SJS Foundation who had been diagnosed with SJS/TEN or were the parent of a child who had been diagnosed with SJS/TEN. Respondents were asked about nonprescription medications taken within the year before diagnosis, and the approximate point in time before diagnosis that they had taken them. They were also asked about specific prescription medications, including antibiotics, that they took before diagnosis. An estimated 4500 patients received an invitation to complete the survey. 251 patients completed it, resulting in a response rate of 5.6%. The mean age of respondents was 43 years (SD (standard deviation) = 17.3) and 70% were female. 32.3% of respondents indicated that a prescription antibiotic triggered their reaction. 14.1% indicated a nonprescription medication had triggered their SJS/TEN, and 18.1% said a nonprescription medication may have triggered their SJS/TEN. 85.5% of respondents said they took a nonprescription medication within three months of their SJS/TEN diagnosis. Of those respondents who reported that an antibiotic triggered their SJS/TEN, 35.2% reported taking a nonprescription medication within the three months prior to their diagnosis. This survey captured valuable information about nonprescription and antibiotic use in SJS/TEN patients. It is important for future studies to estimate the impact of antibiotics on SJS/TEN, and account for nonprescription medication use in that relationship. PMID- 29389867 TI - Analysis of Transcriptional Responses of the Inflorescence Meristems in Jatropha curcas Following Gibberellin Treatment. AB - Jatropha curcas L. seeds an oilseed plant with great potential for biodiesel production. However, low seed yield, which was limited by its lower female flowers, was a major drawback for its utilization. Our previous study found that the flower number and female-to-male ratio were increased by gibberellin treatment. Here, we compared the transcriptomic profiles of inflorescence meristem at different time points after gibberellic acid A3 (GA3) treatment. The present study showed that 951 differentially expressed genes were obtained in response to gibberellin treatment, compared with control samples. The 6-h time point was an important phase in the response to exogenous gibberellin. Furthermore, the plant endogenous gibberellin, auxin, ethylene, abscisic acid, and brassinolide-signaling transduction pathways were repressed, whereas the genes associated with cytokinin and jasmonic acid signaling were upregulated for 24-h time point following GA3 treatment. In addition, the floral meristem determinacy genes (JcLFY, JcSOC1) and floral organ identity genes (JcAP3, JcPI, JcSEP1-3) were significantly upregulated, but their negative regulator (JcSVP) was downregulated after GA3 treatment. Moreover, the effects of phytohormone, which was induced by exogenous plant growth regulator, mainly acted on the female floral differentiation process. To the best of our knowledge, this data is the first comprehensive analysis of the underlying transcriptional response mechanism of floral differentiation following GA3 treatment in J. curcas, which helps in engineering high-yielding varieties of Jatropha. PMID- 29389868 TI - Variation on Molecular Structure, Crystallinity, and Optical Properties of Dentin Due to Nd:YAG Laser and Fluoride Aimed at Tooth Erosion Prevention. AB - This in vitro study evaluated the compositional, crystalline, and morphological effects promoted by Nd:YAG laser on root dentin, and verified the effects of laser and topical acidulated phosphate fluoride application (APF-gel) on dentin erosion. 180 bovine dentin slabs were randomized into 4 groups (n = 45): G1 untreated, G2-APF-gel (1.23% F-, 4 min), G3-Nd:YAG (1064 nm, 84.9 J/cm2, 10 Hz), and G4-APF-gel application followed by Nd:YAG laser irradiation. The compositional, crystalline, and morphological effects promoted by treatments were investigated on five samples of each experimental group. The other samples were submitted to a 5-day, 10-day, or 15-day erosive and abrasive demineralization and remineralization cycling in order to create erosion lesions. The area and depth of lesions, as well as the optical attenuation coefficient, were assessed, and all data were statistically analysed (p < 0.05). Nd:YAG laser promoted the reduction of carbonate, the formation of tetracalcium phosphate, as well as the melting and recrystallization of the dentin surface. Laser significantly decreased the area and depth of erosion lesions and altered the optical attenuation coefficient when compared to untreated and APF-gel groups, but the association of APF-gel and laser did not promote an additional effect. Nd:YAG laser irradiation can be a promissory treatment to prevent dentin erosion and the abrasion process. PMID- 29389869 TI - Patterns of Self-Medication Behavior for Oral Health Problems Among Adults Living in Riyadh, Saudi Arabia. AB - Self-medication is a widespread behavior worldwide. It is defined as the practice of self-diagnosis and drug prescription without proper professional consultation. Aim: To determine the prevalence and predictors of self-medication for oral health problems among adults living in Riyadh city. Methods: A cross-sectional study based on a structured close-ended questionnaire was distributed among adults visiting shopping malls in all different five regions of Riyadh. A two stage sampling technique was used: cluster and simple random sampling. The questionnaire was composed of two main sections: demographic characteristics and questions assessing the behavior of self-medication. Results: The prevalence of self-medication was found to be 63.25%, with a higher prevalence among females than males. Gender and nationality were significantly associated with self medication. Salt in hot water locally (52.57%) and acetaminophen (47.43%), a type of an analgesic, were, systemically, the most frequently used. Pharmacy shops were the main source of these medicaments (66.01%). Similarly, the advice for using them was mainly given by pharmacists (53.36%). Lack of time was claimed to be the main reason for practicing self-medication (54.55%) with abscess, toothache, and gingival bleeding being the main predictors. Conclusions: Self medication was found to be a common practice among the population of Riyadh city. PMID- 29389870 TI - Fermentability of Novel Type-4 Resistant Starches in In Vitro System. AB - Resistant starches are non-digestible starches that are fermented in the colon by microbiota. These carbohydrates are prebiotic and can be beneficial to consumer health. Many types of resistant starch exist with varying physical properties that may result in differences in fermentability. The objective of this research project was to compare potential prebiotic effects and fermentability of four novel resistant starches using an in vitro fermentation system and measuring changes in total gas production, pH, and formation of SCFAs (short chain fatty acids). Fecal donations were collected from seven healthy volunteers. Four novel resistant starches, modified potato starch (MPS), modified tapioca starch (MTS), and modified maize starches (MMS-1 and MMS-2), were analyzed and compared to polydextrose and short chain fructooligosaccharides (FOS) as controls. After twenty-four hours of fermentation, MPS and MTS responded similarly in gas production (74 mL; 70.6 mL respectively), pH (5.93; 5.93 respectively), and SCFA production (Acetate: 115; 124, Propionate: 21; 26, Butyrate: 29; 31 MUmol/mL respectively). While MMS-1 had similar gas production and individual SCFA production, the pH was significantly higher (6.06). The fermentation of MMS-2 produced the least amount of gas (22 mL), with a higher pH (6.34), and lower acetate production (78.4 MUmol/mL). All analyzed compounds were fermentable and promoted the formation of beneficial SCFAs. PMID- 29389871 TI - A Simple Surface-Enhanced Raman Spectroscopic Method for on-Site Screening of Tetracycline Residue in Whole Milk. AB - Therapeutic and subtherapeutic use of veterinary drugs has increased the risk of residue contamination in animal food products. Antibiotics such as tetracycline are used for mastitis treatment of lactating cows. Milk expressed from treated cows before the withdrawal period has elapsed may contain tetracycline residue. This study developed a simple surface-enhanced Raman spectroscopic (SERS) method for on-site screening of tetracycline residue in milk and water. Six batches of silver colloid nanoparticles were prepared for surface enhancement measurement. Milk-tetracycline and water-tetracycline solutions were prepared at seven concentration levels (1000, 500, 100, 10, 1, 0.1, and 0.01 ppm) and spiked with silver colloid nanoparticles. A 785 nm Raman spectroscopic system was used for spectral measurement. Tetracycline vibrational modes were observed at 1285, 1317 and 1632 cm-1 in water-tetracycline solutions and 1322 and 1621 cm-1 (shifted from 1317 and 1632 cm-1, respectively) in milk-tetracycline solutions. Tetracycline residue concentration as low as 0.01 ppm was detected in both the solutions. The peak intensities at 1285 and 1322 cm-1 were used to estimate the tetracycline concentrations in water and milk with correlation coefficients of 0.92 for water and 0.88 for milk. Results indicate that this SERS method is a potential tool that can be used on-site at field production for qualitative and quantitative detection of tetracycline residues. PMID- 29389873 TI - Impact of the Interaction between Aquatic Humic Substances and Algal Organic Matter on the Fouling of a Ceramic Microfiltration Membrane. AB - The influence of the interaction between aquatic humic substances and the algal organic matter (AOM) derived from Microcystis aeruginosa on the fouling of a ceramic microfiltration (MF) membrane was studied. AOM alone resulted in a significantly greater flux decline compared with Suwannee River humic acid (HA), and fulvic acid (FA). The mixture of AOM with HA and FA exhibited a similar flux pattern as the AOM alone in the single-cycle filtration tests, indicating the flux decline may be predominantly controlled by the AOM in the early filtration cycles. The mixtures resulted in a marked increase in irreversible fouling resistance compared with all individual feed solutions. An increase in zeta potential was observed for the mixtures (becoming more negatively charged), which was in accordance with the increased reversible fouling resistance resulting from enhanced electrostatic repulsion between the organic compounds and the negatively charged ceramic membrane. Dynamic light scattering (DLS) and size exclusion chromatography analyses showed an apparent increase in molecular size for the AOM humics mixtures, and some UV-absorbing molecules in the humics appeared to participate in the formation of larger aggregates with the AOM, which led to greater extent of pore plugging and hence resulted in higher irreversible fouling resistance. PMID- 29389872 TI - Dietary Magnesium and Cardiovascular Disease: A Review with Emphasis in Epidemiological Studies. AB - Magnesium (Mg) is an essential dietary element for humans involved in key biological processes. A growing body of evidence from epidemiological studies, randomized controlled trials (RCTs) and meta-analyses have indicated inverse associations between Mg intake and cardiovascular diseases (CVD). The present review aims to summarize recent scientific evidence on the topic, with a focus on data from epidemiological studies assessing the associations between Mg intake and major cardiovascular (CV) risk factors and CVD. We also aimed to review current literature on circulating Mg and CVD, as well as potential biological processes underlying these observations. We concluded that high Mg intake is associated with lower risk of major CV risk factors (mainly metabolic syndrome, diabetes and hypertension), stroke and total CVD. Higher levels of circulating Mg are associated with lower risk of CVD, mainly ischemic heart disease and coronary heart disease. Further, RCTs and prospective studies would help to clarify whether Mg intake and Mg circulating levels may also protect against other CVDs and CVD death. PMID- 29389874 TI - Game Theory-Based Cooperation for Underwater Acoustic Sensor Networks: Taxonomy, Review, Research Challenges and Directions. AB - Exploring and monitoring the underwater world using underwater sensors is drawing a lot of attention these days. In this field cooperation between acoustic sensor nodes has been a critical problem due to the challenging features such as acoustic channel failure (sound signal), long propagation delay of acoustic signal, limited bandwidth and loss of connectivity. There are several proposed methods to improve cooperation between the nodes by incorporating information/game theory in the node's cooperation. However, there is a need to classify the existing works and demonstrate their performance in addressing the cooperation issue. In this paper, we have conducted a review to investigate various factors affecting cooperation in underwater acoustic sensor networks. We study various cooperation techniques used for underwater acoustic sensor networks from different perspectives, with a concentration on communication reliability, energy consumption, and security and present a taxonomy for underwater cooperation. Moreover, we further review how the game theory can be applied to make the nodes cooperate with each other. We further analyze different cooperative game methods, where their performance on different metrics is compared. Finally, open issues and future research direction in underwater acoustic sensor networks are highlighted. PMID- 29389877 TI - Radial Flow Assay Using Gold Nanoparticles and Rolling Circle Amplification to Detect Mercuric Ions. AB - A novel colorimetric assay employing oligonucleotide-conjugated gold nanoparticle (AuNP probes) and rolling circle amplification (RCA) was developed for simple detection of mercuric ions (Hg2+). The thymine-Hg2+-thymine (T-Hg2+-T) coordination chemistry makes our detection system selective for Hg2+. In the presence of Hg2+, the thymine 12-mer oligonucleotide is unable to act as a primer for RCA due to the formation of T-Hg2+-T before the RCA reaction. However, in the absence of Hg2+, DNA coils as RCA products are generated during the RCA reaction, and is further labeled with AuNP probes. Colorimetric signals that depend on the amount of DNA coil-AuNP probe complexes were generated by drop-drying the reaction solution on nitrocellulose-based paper. As the reaction solution spread radially because of capillary action, the complexes formed a concentric red spot on the paper. The colorimetric signals of the red spots were rapidly measured with a portable spectrophotometer and determined as the DeltaE value, which indicates the calculated color intensity. Our assay displays great linearity (detection limit: 22.4 nM), precision, and reproducibility, thus demonstrating its utility for Hg2+ quantification in real samples. We suggest that our simple, portable, and cost-effective method could be used for on-site Hg2+ detections. PMID- 29389875 TI - Physico-Chemical Conversion of Lignocellulose: Inhibitor Effects and Detoxification Strategies: A Mini Review. AB - A pretreatment of lignocellulosic biomass to produce biofuels, polymers, and other chemicals plays a vital role in the biochemical conversion process toward disrupting the closely associated structures of the cellulose-hemicellulose lignin molecules. Various pretreatment steps alter the chemical/physical structure of lignocellulosic materials by solubilizing hemicellulose and/or lignin, decreasing the particle sizes of substrate and the crystalline portions of cellulose, and increasing the surface area of biomass. These modifications enhance the hydrolysis of cellulose by increasing accessibilities of acids or enzymes onto the surface of cellulose. However, lignocellulose-derived byproducts, which can inhibit and/or deactivate enzyme and microbial biocatalysts, are formed, including furan derivatives, lignin-derived phenolics, and carboxylic acids. These generation of compounds during pretreatment with inhibitory effects can lead to negative effects on subsequent steps in sugar flat form processes. A number of physico-chemical pretreatment methods such as steam explosion, ammonia fiber explosion (AFEX), and liquid hot water (LHW) have been suggested and developed for minimizing formation of inhibitory compounds and alleviating their effects on ethanol production processes. This work reviews the physico-chemical pretreatment methods used for various biomass sources, formation of lignocellulose-derived inhibitors, and their contributions to enzymatic hydrolysis and microbial activities. Furthermore, we provide an overview of the current strategies to alleviate inhibitory compounds present in the hydrolysates or slurries. PMID- 29389878 TI - Amyloid Beta Detection by Faradaic Electrochemical Impedance Spectroscopy Using Interdigitated Microelectrodes. AB - Faradaic electrochemical impedance spectroscopy (f-EIS) in the presence of redox reagent, e.g., [Fe(CN)6]3-/4-, is widely used in biosensors owing to its high sensitivity. However, in sensors detecting amyloid beta (Abeta), the redox reagent can cause the aggregation of Abeta, which is a disturbance factor in accurate detection. Here, we propose an interdigitated microelectrode (IME) based f-EIS technique that can alleviate the aggregation of Abeta and achieve high sensitivity by buffer control. The proposed method was verified by analyzing three different EIS-based sensors: non-faradaic EIS (nf-EIS), f-EIS, and the proposed f-EIS with buffer control. We analyzed the equivalent circuits of nf-EIS and f-EIS sensors. The dominant factors of sensitivity were analyzed, and the impedance change rates via Abeta reaction was compared. We measured the sensitivity of the IME sensors based on nf-EIS, f-EIS, and the proposed f-EIS. The results demonstrate that the proposed EIS-based IME sensor can detect Abeta with a sensitivity of 7.40-fold and 10.93-fold higher than the nf-EIS and the f EIS sensors, respectively. PMID- 29389876 TI - Antibiotic Persistence as a Metabolic Adaptation: Stress, Metabolism, the Host, and New Directions. AB - Persistence is a phenomenon during which a small fraction of a total bacterial population survives treatment with high concentrations of antibiotics for an extended period of time. In conjunction with biofilms, antibiotic persisters represent a major cause of recalcitrant and recurring infections, resulting in significant morbidity and mortality. In this review, we discuss the clinical significance of persister cells and the central role of bacterial metabolism in their formation, specifically with respect to carbon catabolite repression, sugar metabolism, and growth regulation. Additionally, we will examine persister formation as an evolutionary strategy used to tolerate extended periods of stress and discuss some of the response mechanisms implicated in their formation. To date, the vast majority of the mechanistic research examining persistence has been conducted in artificial in vitro environments that are unlikely to be representative of host conditions. Throughout this review, we contextualize the existing body of literature by discussing how in vivo conditions may create ecological niches that facilitate the development of persistence. Lastly, we identify how the development of next-generation sequencing and other "big data" tools may enable researchers to examine persistence mechanisms within the host to expand our understanding of their clinical importance. PMID- 29389879 TI - A New Real-Time Cycle Slip Detection and Repair Method under High Ionospheric Activity for a Triple-Frequency GPS/BDS Receiver. AB - Cycle slip detection and repair is a prerequisite for high-precision global navigation satellite system (GNSS)-based positioning. With the modernization and development of GNSS systems, more satellites are available to transmit triple frequency signals, which allows the introduction of additional linear combinations and provides new opportunities for cycle slip detection and repair. In this paper, we present a new real-time cycle slip detection and repair method under high ionospheric activity for undifferenced Global Positioning System (GPS)/BeiDou Navigation Satellite System (BDS) triple-frequency observations collected with a single receiver. First, three optimal linearly independent geometry-free pseudorange minus phase combinations are selected to correctly and uniquely determine the cycle slips on the original triple-frequency carrier phase observations. Then, a second-order time-difference algorithm is employed for the pseudorange minus phase combinations to mitigate the impact of between-epoch ionospheric residuals on cycle slip detection, which is especially beneficial under high ionospheric activity. The performance of the approach is verified with static GPS/BDS triple-frequency observations that are collected with a 30 s sampling interval under active ionospheric conditions, and observations are manually inserted with simulated cycle slips. The results show that the method can correctly detect and repair cycle slips at a resolution as small as 1 cycle. Moreover, kinematic data collected from car-driven and airborne experiments are also processed to verify the performance of the method. The experimental results also demonstrate that the method is effective in processing kinematic data. PMID- 29389880 TI - Experimental Study of Multispectral Characteristics of an Unmanned Aerial Vehicle at Different Observation Angles. AB - This study investigates multispectral characteristics of an unmanned aerial vehicle (UAV) at different observation angles by experiment. The UAV and its engine are tested on the ground in the cruise state. Spectral radiation intensities at different observation angles are obtained in the infrared band of 0.9-15 MUm by a spectral radiometer. Meanwhile, infrared images are captured separately by long-wavelength infrared (LWIR), mid-wavelength infrared (MWIR), and short-wavelength infrared (SWIR) cameras. Additionally, orientation maps of the radiation area and radiance are obtained. The results suggest that the spectral radiation intensity of the UAV is determined by its exhaust plume and that the main infrared emission bands occur at 2.7 MUm and 4.3 MUm. At observation angles in the range of 0 degrees -90 degrees , the radiation area of the UAV in MWIR band is greatest; however, at angles greater than 90 degrees , the radiation area in the SWIR band is greatest. In addition, the radiance of the UAV at an angle of 0 degrees is strongest. These conclusions can guide IR stealth technique development for UAVs. PMID- 29389881 TI - Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion. AB - BACKGROUND: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. METHODS: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA lesioned rats and Sham-operated rats. RESULTS: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. CONCLUSIONS: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells. PMID- 29389882 TI - Validation of a Method for Cylindrospermopsin Determination in Vegetables: Application to Real Samples Such as Lettuce (Lactuca sativa L.). AB - Reports on the occurrence of the cyanobacterial toxin cylindrospermopsin (CYN) have increased worldwide because of CYN toxic effects in humans and animals. If contaminated waters are used for plant irrigation, these could represent a possible CYN exposure route for humans. For the first time, a method employing solid phase extraction and quantification by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) of CYN was optimized in vegetables matrices such as lettuce (Lactuca sativa). The validated method showed a linear range, from 5 to 500 ng CYN g-1 of fresh weight (f.w.), and detection and quantitation limits (LOD and LOQ) of 0.22 and 0.42 ng CYN g-1 f.w., respectively. The mean recoveries ranged between 85 and 104%, and the intermediate precision from 12.7 to 14.7%. The method showed to be robust for the three different variables tested. Moreover, it was successfully applied to quantify CYN in edible lettuce leaves exposed to CYN-contaminated water (10 ug L 1), showing that the tolerable daily intake (TDI) in the case of CYN could be exceeded in elderly high consumers. The validated method showed good results in terms of sensitivity, precision, accuracy, and robustness for CYN determination in leaf vegetables such as lettuce. More studies are needed in order to prevent the risks associated with the consumption of CYN-contaminated vegetables. PMID- 29389883 TI - Photodynamic Inactivation Potentiates the Susceptibility of Antifungal Agents against the Planktonic and Biofilm Cells of Candida albicans. AB - Photodynamic inactivation (PDI) has been shown to be a potential treatment modality against Candida infection. However, limited light penetration might leave some cells alive and undergoing regrowth. In this study, we explored the possibility of combining PDI and antifungal agents to enhance the therapeutic efficacy of Candida albicans and drug-resistant clinical isolates. We found that planktonic cells that had survived toluidine blue O (TBO)-mediated PDI were significantly susceptible to fluconazole within the first 2 h post PDI. Following PDI, the killing efficacy of antifungal agents relates to the PDI dose in wild type and drug-resistant clinical isolates. However, only a 3-log reduction was found in the biofilm cells, suggesting limited therapeutic efficacy under the combined treatment of PDI and azole antifungal drugs. Using confocal microscopic analysis, we showed that TBO-mediated PDI could partially remove the extracellular polymeric substance (EPS) of biofilm. Finally, we showed that a combination of PDI with caspofungin could result in the complete killing of biofilms compared to those treated with caspofungin or PDI alone. These results clearly indicate that the combination of PDI and antifungal agents could be a promising treatment against C. albicans infections. PMID- 29389884 TI - Long Non-Coding RNAs in Multiple Myeloma. AB - Multiple myeloma (MM) is an incurable disease caused by the malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Although a large fraction of the genome is actively transcribed, most of the transcripts do not serve as templates for proteins and are referred to as non coding RNAs (ncRNAs), broadly divided into short and long transcripts on the basis of a 200-nucleotide threshold. Short ncRNAs, especially microRNAs, have crucial roles in virtually all types of cancer, including MM, and have gained importance in cancer diagnosis and prognosis, predicting the response to therapy and, notably, as innovative therapeutic targets. Long ncRNAs (lncRNAs) are a very heterogeneous group, involved in many physiological cellular and genomic processes as well as in carcinogenesis, cancer metastasis, and invasion. LncRNAs are aberrantly expressed in various types of cancers, including hematological malignancies, showing either oncogenic or tumor suppressive functions. However, the mechanisms of the related disease-causing events are not yet revealed in most cases. Besides emerging as key players in cancer initiation and progression, lncRNAs own many interesting features as biomarkers with diagnostic and prognostic importance and, possibly, for their utility in therapeutic terms as druggable molecules. This review focuses on the role of lncRNAs in the pathogenesis of MM and summarizes the recent literature. PMID- 29389885 TI - 2015 Health Survey of Sao Paulo with Focus in Nutrition: Rationale, Design, and Procedures. AB - This paper describes the design, sampling methods, and data collection procedures, with particular focus on dietary data, used for the 2015 Health Survey of Sao Paulo (Inquerito de Saude de Sao Paulo, 2015 ISA-Capital) with Focus in Nutrition Study (2015 ISA-Nutrition). The ISA is a household cross sectional, population-based survey that uses complex, stratified, multistage sampling to create a representative sample of residents from urban Sao Paulo, Brazil. The 2015 ISA-Nutrition comprised a sub-sample of the 2015 ISA-Capital and intended to include 300 adolescents (aged 12 to 19 years), 300 adults (aged 20 to 59 years), and 300 older adults (aged >=60 years). From February 2015 to February 2016, 1737 individuals answered the first 24-h dietary recall (24HR), and 901 individuals consented to have their blood sample collected, to undergo anthropometric and blood pressure assessment, and to answer the second 24HR. The 2015 ISA-Nutrition aims to evaluate lifestyle-related modifiable factors in Sao Paulo's residents, as well as their association with biochemical and genetic markers, and environmental aspects related to cardiometabolic risk factors. This paper concludes that 2015 ISA-Nutrition may provide valuable insights into the cardiometabolic risk factors in a big city in an upper middle-income country and contribute to the formulation of health and nutritional policies. PMID- 29389886 TI - Spatio-Temporal Dynamic Analysis of Sustainable Development in China Based on the Footprint Family. AB - The existing index systems on sustainable evaluation are mostly based on a multi index comprehensive evaluation method. The main disadvantage of this approach is that the selection and assignment of evaluation indexes are greatly influenced by subjective factors, which can result in poor comparability of results. By contrast, the Footprint Family (including ecological footprint, carbon footprint, and water footprint) is not affected by subjective factors. The Footprint Family also covers the basic tenets of sustainable development. This paper proposes use of a sustainable development evaluation index system based on the principle of the Footprint Family, and including the ecological pressure index (EPI), the ecological occupancy index (EOI), the ecological economic coordination index (EECI), the GHG (Greenhouse Gas) emission index (CEI), the water resources stress index (WSI), and the sustainable development index (SDI). Furthermore, a standard for grading the evaluated results based on global benchmarks is formulated. The results of an empirical study in China were the following. The development situation deteriorated from 1990 to 2015. The results showed that the SDI decreased from a medium level (grade 5) to a lower-medium level (grade 4). The results of this empirical study also showed that the method of evaluation can avoid the influence of subjective factors and can be used in the evaluation of sustainable development for various temporal and spatial conditions. PMID- 29389888 TI - Effect of SiC Nanoparticles on Hot Deformation Behavior and Processing Maps of Magnesium Alloy AZ91. AB - The hot deformation behavior and processing characteristics of AZ91 alloy and nano-SiCp/AZ91 composite were compared at temperature ranges of 523 K-673 K and strain rates of 0.001-1 s-1. Positive impact of SiC nanoparticles on pinning grain boundaries and inhibiting grain growth was not obvious when deformation temperature was below 623 K, but was remarkable when the temperature was above 623 K. By comparing compressive stress-strain curves of AZ91 alloy and nano SiCp/AZ91 composites, the addition of nanoparticles could improve the deformation ability of a matrix alloy under high-temperature conditions. There was no essential difference of deformation mechanism between AZ91 alloy and the composite, but hot deformation activation energy of the composite was significantly lower than that of the AZ91 alloy. The AZ91 alloy and the composite had the same workability region of 600 K-673 K and 0.001-1 s-1, while instability region for the composite was reduced compared with that of AZ91 alloy at high temperature. PMID- 29389887 TI - Improvement of the Chondrocyte-Specific Phenotype upon Equine Bone Marrow Mesenchymal Stem Cell Differentiation: Influence of Culture Time, Transforming Growth Factors and Type I Collagen siRNAs on the Differentiation Index. AB - Articular cartilage is a tissue characterized by its poor intrinsic capacity for self-repair. This tissue is frequently altered upon trauma or in osteoarthritis (OA), a degenerative disease that is currently incurable. Similar musculoskeletal disorders also affect horses and OA incurs considerable economic loss for the equine sector. In the view to develop new therapies for humans and horses, significant progress in tissue engineering has led to the emergence of new generations of cartilage therapy. Matrix-associated autologous chondrocyte implantation is an advanced 3D cell-based therapy that holds promise for cartilage repair. This study aims to improve the autologous chondrocyte implantation technique by using equine mesenchymal stem cells (MSCs) from bone marrow differentiated into chondrocytes that can be implanted in the chondral lesion. The optimized protocol relies on culture under hypoxia within type I/III collagen sponges. Here, we explored three parameters that influence MSC differentiation: culture times, growth factors and RNA interference strategies. Our results suggest first that an increase in culture time from 14 to 28 or 42 days lead to a sharp increase in the expression of chondrocyte markers, notably type II collagen (especially the IIB isoform), along with a concomitant decrease in HtrA1 expression. Nevertheless, the expression of type I collagen also increased with longer culture times. Second, regarding the growth factor cocktail, TGF-beta3 alone showed promising result but the previously tested association of BMP-2 and TGF-beta1 better limits the expression of type I collagen. Third, RNA interference targeting Col1a2 as well as Col1a1 mRNA led to a more significant knockdown, compared with a conventional strategy targeting Col1a1 alone. This chondrogenic differentiation strategy showed a strong increase in the Col2a1:Col1a1 mRNA ratio in the chondrocytes derived from equine bone marrow MSCs, this ratio being considered as an index of the functionality of cartilage. These data provide evidence of a more stable chondrocyte phenotype when combining Col1a1 and Col1a2 siRNAs associated to a longer culture time in the presence of BMP-2 and TGF-beta1, opening new opportunities for preclinical trials in the horse. In addition, because the horse is an excellent model for human articular cartilage disorders, the equine therapeutic approach developed here can also serve as a preclinical step for human medicine. PMID- 29389889 TI - Synthesis of Scutellarein Derivatives with a Long Aliphatic Chain and Their Biological Evaluation against Human Cancer Cells. AB - Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal medicine Erigeron breviscapus (Vant.) Hand-Mazz., which is widely used in China. Recently, accumulating evidence has highlighted the potential role of scutellarin and its main metabolite scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them, compound 6a exhibited the strongest antiproliferative effects on Jurkat (IC50 = 1.80 MUM), HCT-116 (IC50 = 11.50 MUM) and MDA-MB-231 (IC50 = 53.91 MUM). In particular, 6a even showed stronger antiproliferative effects than the positive control NaAsO2 on Jurkat and HCT-116 cell lines. The results showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein. PMID- 29389891 TI - Potential of New Isolates of Dunaliella Salina for Natural beta-Carotene Production. AB - The halotolerant microalga Dunaliella salina has been widely studied for natural beta-carotene production. This work shows biochemical characterization of three newly isolated Dunaliellasalina strains, DF15, DF17, and DF40, compared with D. salina CCAP 19/30 and D. salina UTEX 2538 (also known as D. bardawil). Although all three new strains have been genetically characterized as Dunaliella salina strains, their ability to accumulate carotenoids and their capacity for photoprotection against high light stress are different. DF15 and UTEX 2538 reveal great potential for producing a large amount of beta-carotene and maintained a high rate of photosynthesis under light of high intensity; however, DF17, DF40, and CCAP 19/30 showed increasing photoinhibition with increasing light intensity, and reduced contents of carotenoids, in particular beta carotene, suggesting that the capacity of photoprotection is dependent on the cellular content of carotenoids, in particular beta-carotene. Strong positive correlations were found between the cellular content of all-trans beta-carotene, 9-cis beta-carotene, all-trans alpha-carotene and zeaxanthin but not lutein in the D. salina strains. Lutein was strongly correlated with respiration in photosynthetic cells and strongly related to photosynthesis, chlorophyll and respiration, suggesting an important and not hitherto identified role for lutein in coordinated control of the cellular functions of photosynthesis and respiration in response to changes in light conditions, which is broadly conserved in Dunaliella strains. Statistical analysis based on biochemical data revealed a different grouping strategy from the genetic classification of the strains. The significance of these data for strain selection for commercial carotenoid production is discussed. PMID- 29389892 TI - The Impact of Curviness on Four Different Image Sensor Forms and Structures. AB - The arrangement and form of the image sensor have a fundamental effect on any further image processing operation and image visualization. In this paper, we present a software-based method to change the arrangement and form of pixel sensors that generate hexagonal pixel forms on a hexagonal grid. We evaluate four different image sensor forms and structures, including the proposed method. A set of 23 pairs of images; randomly chosen, from a database of 280 pairs of images are used in the evaluation. Each pair of images have the same semantic meaning and general appearance, the major difference between them being the sharp transitions in their contours. The curviness variation is estimated by effect of the first and second order gradient operations, Hessian matrix and critical points detection on the generated images; having different grid structures, different pixel forms and virtual increased of fill factor as three major properties of sensor characteristics. The results show that the grid structure and pixel form are the first and second most important properties. Several dissimilarity parameters are presented for curviness quantification in which using extremum point showed to achieve distinctive results. The results also show that the hexagonal image is the best image type for distinguishing the contours in the images. PMID- 29389890 TI - P450 Pharmacogenetics in Indigenous North American Populations. AB - Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Metis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy. PMID- 29389893 TI - An Intraoperative Visualization System Using Hyperspectral Imaging to Aid in Brain Tumor Delineation. AB - Hyperspectral imaging (HSI) allows for the acquisition of large numbers of spectral bands throughout the electromagnetic spectrum (within and beyond the visual range) with respect to the surface of scenes captured by sensors. Using this information and a set of complex classification algorithms, it is possible to determine which material or substance is located in each pixel. The work presented in this paper aims to exploit the characteristics of HSI to develop a demonstrator capable of delineating tumor tissue from brain tissue during neurosurgical operations. Improved delineation of tumor boundaries is expected to improve the results of surgery. The developed demonstrator is composed of two hyperspectral cameras covering a spectral range of 400-1700 nm. Furthermore, a hardware accelerator connected to a control unit is used to speed up the hyperspectral brain cancer detection algorithm to achieve processing during the time of surgery. A labeled dataset comprised of more than 300,000 spectral signatures is used as the training dataset for the supervised stage of the classification algorithm. In this preliminary study, thematic maps obtained from a validation database of seven hyperspectral images of in vivo brain tissue captured and processed during neurosurgical operations demonstrate that the system is able to discriminate between normal and tumor tissue in the brain. The results can be provided during the surgical procedure (~1 min), making it a practical system for neurosurgeons to use in the near future to improve excision and potentially improve patient outcomes. PMID- 29389894 TI - Effect of Homogenization on Microstructure Characteristics, Corrosion and Biocompatibility of Mg-Zn-Mn-xCa Alloys. AB - The corrosion behaviors of Mg-2Zn-0.2Mn-xCa (denoted as MZM-xCa alloys) in homogenization state have been investigated by immersion test and electrochemical techniques in a simulated physiological condition. The microstructure features were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM) and electron probe microanalysis (EPMA), and the corrosion mechanism was illustrated using atomic force microscope (AFM), X-ray photoelectron spectroscopy (XPS) and confocal laser scanning microscopy (CLSM). The electrochemical and immersion test verify the MZM-0.38% Ca owns the best corrosion performance with the corrosion rate of 6.27 mm/year. Furthermore, the film layer of MZM-0.38% Ca is more compact and denser than that of others. This improvement could be associated with the combined effects of the suitable content of Zn/Ca dissolving into the alpha-Mg matrix and the modification of Ca-containing compounds by heat-treatment. However, the morphologies were transformed from uniform corrosion to localized pitting corrosion with Ca further addition. It could be explained that the excessive Ca addition can strengthen the nucleation driving force for the second phase formation, and the large volumes fraction of micro-galvanic present interface sites accelerate the nucleation driving force for corrosion propagation. In addition, in vitro biocompatibility tests also show the MZM-0.38% Ca was safe to bone mesenchymal stem cells (BMSCs) and was promising to be utilized as implant materials. PMID- 29389896 TI - A Novel Non-Invasive Selection Criterion for the Preservation of Primitive Dutch Konik Horses. AB - The Dutch Konik is valued from a genetic conservation perspective and also for its role in preservation of natural landscapes. The primary management objective for the captive breeding of this primitive horse is to maintain its genetic purity, whilst also maintaining the nature reserves on which they graze. Breeding selection has traditionally been based on phenotypic characteristics consistent with the breed description, and the selection of animals for removal from the breeding program is problematic at times due to high uniformity within the breed, particularly in height at the wither, colour (mouse to grey dun) and presence of primitive markings. With the objective of identifying an additional non-invasive selection criterion with potential uniqueness to the Dutch Konik, this study investigates the anatomic parameters of the distal equine limb, with a specific focus on the relative lengths of the individual splint bones. Post-mortem dissections performed on distal limbs of Dutch Konik (n = 47) and modern domesticated horses (n = 120) revealed significant differences in relation to the length and symmetry of the 2nd and 4th Metacarpals and Metatarsals. Distal limb characteristics with apparent uniqueness to the Dutch Konik are described which could be an important tool in the selection and preservation of the breed. PMID- 29389897 TI - Rings and Bricks: Expression of Cohesin Components is Dynamic during Development and Adult Life. AB - Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies. PMID- 29389899 TI - Adsorption Behavior of Surfactant on Lignite Surface: A Comparative Experimental and Molecular Dynamics Simulation Study. AB - Experimental and computational simulation methods are used to investigate the adsorption behavior of the surfactant nonylphenol ethoxylate (NPEO10), which contains 10 ethylene oxide groups, on the lignite surface. The adsorption of NPEO10 on lignite follow a Langmuir-type isotherm. The thermodynamic parameters of the adsorption process show that the whole process is spontaneous. X-ray photoelectron spectroscopic (XPS) analysis indicates that a significant fraction of the oxygen-containing functional groups on the lignitic surface were covered by NPEO10. Molecular dynamics (MD) simulations show that the NPEO10 molecules were found to adsorb at the water-coal interface. Moreover, polar interactions are the main effect in the adsorption process. The density distributions of coal, NPEO10, and water molecules along the Z axis show that the remaining hydrophobic portions of the surfactant extend into the solution, creating a more hydrophobic coal surface that repels water molecules. The negative interaction energy calculated from the density profiles of the head and tail groups along the three spatial directions between the surfactant and the lignitic surface suggest that the adsorption process is spontaneous. The self-diffusion coefficients show that the presence of NPEO10 causes higher water mobility by improving the hydrophobicity of lignite. PMID- 29389898 TI - When Immune Cells Turn Bad-Tumor-Associated Microglia/Macrophages in Glioma. AB - As a substantial part of the brain tumor microenvironment (TME), glioma associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell population to an immunosuppressive TME, besides their well-known functional role regarding glioma cell invasion and angiogenesis. Finally, we summarize first therapeutic interventions to target GAMs and their effect on the immunobiology of gliomas, focusing on their interaction with T cells. PMID- 29389895 TI - Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells. AB - Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS OvCas; about 50% of these tumors displayed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes; somatic copy number alterations are frequent in these tumors and some of them are associated with prognosis; defective NOTCH, RAS/MEK, PI3K and FOXM1 pathway signaling is frequent. Other histological subtypes were characterized by a different mutational spectrum: LGS-OvCas have increased frequency of BRAF and RAS mutations; mucinous cancers have mutation in ARID1A, PIK3CA, PTEN, CTNNB1 and RAS. Intensive research was focused to characterize ovarian cancer stem cells, based on positivity for some markers, including CD133, CD44, CD117, CD24, EpCAM, LY6A, ALDH1. Ovarian cancer cells have an intrinsic plasticity, thus explaining that in a single tumor more than one cell subpopulation, may exhibit tumor-initiating capacity. The improvements in our understanding of the molecular and cellular basis of ovarian cancers should lead to more efficacious treatments. PMID- 29389902 TI - QTL Mapping of Fiber Quality and Yield-Related Traits in an Intra-Specific Upland Cotton Using Genotype by Sequencing (GBS). AB - Fiber quality and yield improvement are crucial for cotton domestication and breeding. With the transformation in spinning techniques and multiplicity needs, the development of cotton fiber quality and yield is of great importance. A genetic map of 5178 Single Nucleotide Polymorphism (SNP) markers were generated using 277 F2:3 population, from an intra-specific cross between two upland cotton accessions, CCRI35 a high fiber quality as female and Nan Dan Ba Di Da Hua (NH), with good yield properties as male parent. The map spanned 4768.098 cM with an average distance of 0.92 cM. A total of 110 Quantitative Traits Loci (QTLs) were identified for 11 traits, but only 30 QTLs were consistent in at least two environments. The highest percentage of phenotypic variance explained by a single QTL was 15.45%. Two major cluster regions were found, cluster 1 (chromosome17 D03) and cluster 2 (chromosome26-D12). Five candidate genes were identified in the two QTL cluster regions. Based on GO functional annotation, all the genes were highly correlated with fiber development, with functions such as protein kinase and phosphorylation. The five genes were associated with various fiber traits as follows: Gh_D03G0889 linked to qFM-D03_cb, Gh_D12G0093, Gh_D12G0410, Gh_D12G0435 associated with qFS-D12_cb and Gh_D12G0969 linked to qFY-D12_cb. Further structural annotation and fine mapping is needed to determine the specific role played by the five identified genes in fiber quality and yield related pathway. PMID- 29389903 TI - A Review of Depth and Normal Fusion Algorithms. AB - Geometric surface information such as depth maps and surface normals can be acquired by various methods such as stereo light fields, shape from shading and photometric stereo techniques. We compare several algorithms which deal with the combination of depth with surface normal information in order to reconstruct a refined depth map. The reasons for performance differences are examined from the perspective of alternative formulations of surface normals for depth reconstruction. We review and analyze methods in a systematic way. Based on our findings, we introduce a new generalized fusion method, which is formulated as a least squares problem and outperforms previous methods in the depth error domain by introducing a novel normal weighting that performs closer to the geodesic distance measure. Furthermore, a novel method is introduced based on Total Generalized Variation (TGV) which further outperforms previous approaches in terms of the geodesic normal distance error and maintains comparable quality in the depth error domain. PMID- 29389900 TI - The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. AB - A distinct G-protein coupled receptor that senses changes in extracellular Zn2+, ZnR/GPR39, was found in cells from tissues in which Zn2+ plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, where zinc is essential for cell growth, wound closure, and barrier formation. ZnR/GPR39 activity was also described in neurons that are postsynaptic to vesicular Zn2+ release. Activation of ZnR/GPR39 triggers Galphaq-dependent signaling and subsequent cellular pathways associated with cell growth and survival. Furthermore, ZnR/GPR39 was shown to regulate the activity of ion transport mechanisms that are essential for the physiological function of epithelial and neuronal cells. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner. PMID- 29389904 TI - Random Access for Underwater Acoustic Cellular Systems. AB - In this paper, a random access preamble (RAP) design technique for underwater acoustic cellular systems is proposed. After showing that the conventional RAP used in long term evolution (LTE) systems is not appropriate for underwater acoustic cellular systems, two different types of RAPs (RAP 1 and RAP 2) are proposed to detect the identity of underwater equipment/nodes (UEs) and estimate the time delay between a UE and an underwater base station (UBS) at the physical layer. RAP 1 is generated using a Zadoff-Chu (ZC) sequence where the identity of the UE is mapped to its root index, whereas RAP 2 is generated using a linear frequency modulation (LFM) waveform where the identity of the UE is mapped to its frequency sweeping parameter and frequency shifting parameter. Ambiguity functions (AFs) and cross-ambiguity functions (CAFs) of RAP 1 and RAP 2 are derived to investigate their correlation properties under the effect of time delay and Doppler shift. The performance of RAP detection is investigated by analyzing the detection probabilities and false alarm probabilities of RAP 1 and RAP 2 in a Doppler environment. By evaluating the performances of RAP 1 and RAP 2 in various situations, it is concluded that RAP 2 is more suitable for underwater acoustic cellular systems. The AF and CAF analytically obtained in this paper are shown to be similar to those obtained using experimental data. PMID- 29389901 TI - The Janus Face of NKT Cell Function in Autoimmunity and Infectious Diseases. AB - Natural killer T cells (NKT) are a subset of T lymphocytes bridging innate and adaptive immunity. These cells recognize self and microbial glycolipids bound to non-polymorphic and highly conserved CD1d molecules. Three NKT cell subsets, type I, II, and NKT-like expressing different antigen receptors (TCR) were described and TCR activation promotes intracellular events leading to specific functional activities. NKT can exhibit different functions depending on the secretion of soluble molecules and the interaction with other cell types. NKT cells act as regulatory cells in the defense against infections but, on the other hand, their effector functions can be involved in the pathogenesis of several inflammatory disorders due to their exposure to different microbial or self-antigens, respectively. A deep understanding of the biology and functions of type I, II, and NKT-like cells as well as their interplay with cell types acting in innate (neuthrophils, innate lymphoid cells, machrophages, and dendritic cells) and adaptive immunity (CD4+,CD8+, and double negative T cells) should be important to design potential immunotherapies for infectious and autoimmune diseases. PMID- 29389905 TI - Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia. AB - Acetylcholine is the main transmitter of the parasympathetic vagus nerve. According to the cholinergic anti-inflammatory pathway (CAP) concept, acetylcholine has been shown to be important for signal transmission within the immune system and also for a variety of other functions throughout the organism. The spleen is thought to play an important role in regulating the CAP. In contrast, the existence of a "non-neuronal cardiac cholinergic system" that influences cardiac innervation during inflammation has been hypothesized, with recent publications introducing the heart instead of the spleen as a possible interface between the immune and nervous systems. To prove this hypothesis, we investigated whether selectively disrupting vagal stimulation of the right ventricle plays an important role in rat CAP regulation during endotoxemia. We performed a selective resection of the right cardiac branch of the Nervus vagus (VGX) with a corresponding sham resection in vehicle-injected and endotoxemic rats. Rats were injected with lipopolysaccharide (LPS, 1 mg/kg body weight, intravenously) and observed for 4 h. Intraoperative blood gas analysis was performed, and hemodynamic parameters were assessed using a left ventricular pressure-volume catheter. Rat hearts and blood were collected, and the expression and concentration of proinflammatory cytokines using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were measured, respectively. Four hours after injection, LPS induced a marked deterioration in rat blood gas parameters such as pH value, potassium, base excess, glucose, and lactate. The mean arterial blood pressure and the end diastolic volume had decreased significantly. Further, significant increases in blood cholinesterases and in proinflammatory (IL-1beta, IL-6, TNF-alpha) cytokine concentration and gene expression were obtained. Right cardiac vagus nerve resection (VGX) led to a marked decrease in heart acetylcholine concentration and an increase in cardiac acetylcholinesterase activity. Without LPS, VGX changed rat hemodynamic parameters, including heart frequency, cardiac output, and end diastolic volume. In contrast, VGX during endotoxemia did not significantly change the concentration and expression of proinflammatory cytokines in the heart. In conclusion we demonstrate that right cardiac vagal innervation regulates cardiac acetylcholine content but neither improves nor worsens systemic inflammation. PMID- 29389906 TI - Indole-3-Acetic Acid Biosynthesis Pathways in the Plant-Beneficial Bacterium Arthrobacter pascens ZZ21. AB - Arthrobacter pascens ZZ21 is a plant-beneficial, fluoranthene-degrading bacterial strain found in the rhizosphere. The production of the phytohormone indole-3 aectic acid (IAA) by ZZ21 is thought to contribute to its ability to promote plant growth and remediate fluoranthene-contaminated soil. Using genome-wide analysis combined with metabolomic and high-performance liquid chromatography mass spectrometry (HPLC-MS) analyses, we characterized the potential IAA biosynthesis pathways in A. pascens ZZ21. IAA production increased 4.5-fold in the presence of 200 mg.L-1 tryptophan in the culture medium. The transcript levels of prr and aldH, genes which were predicted to encode aldehyde dehydrogenases, were significantly upregulated in response to exogenous tryptophan. Additionally, metabolomic analysis identified the intermediates indole-3-acetamide (IAM), indole-3-pyruvic acid (IPyA), and the enzymatic reduction product of the latter, indole-3-lactic acid (ILA), among the metabolites of ZZ21, and subsequently also IAM, ILA, and indole-3-ethanol (TOL), which is the enzymatic reduction product of indole-3-acetaldehyde, by HPLC-MS. These results suggest that the tryptophan-dependent IAM and IPyA pathways function in ZZ21. PMID- 29389907 TI - A Sleep Questionnaire for Children with Severe Psychomotor Impairment (SNAKE) Concordance with a Global Rating of Sleep Quality. AB - Sleep problems are a common and serious issue in children with life-limiting conditions (LLCs) and severe psychomotor impairment (SPMI). The "Sleep Questionnaire for Children with Severe Psychomotor Impairment" (Schlaffragebogen fur Kinder mit Neurologischen und Anderen Komplexen Erkrankungen, SNAKE) was developed for this unique patient group. In a proxy rating, the SNAKE assesses five different dimensions of sleep(-associated) problems (disturbances going to sleep, disturbances remaining asleep, arousal and breathing disorders, daytime sleepiness, and daytime behavior disorders). It has been tested with respect to construct validity and some aspects of criterion validity. The present study examined whether the five SNAKE scales are consistent with parents' or other caregivers' global ratings of a child's sleep quality. Data from a comprehensive dataset of children and adolescents with LLCs and SPMI were analyzed through correlation coefficients and Mann-Whitney U testing. The results confirmed the consistency of both sources of information. The highest levels of agreements with the global rating were achieved for disturbances in terms of going to sleep and disturbances with respect to remaining asleep. The results demonstrate that the scales and therefore the SNAKE itself is well-suited for gathering information on different sleep(-associated) problems in this vulnerable population. PMID- 29389908 TI - Assessing Heat Stress and Health among Construction Workers in a Changing Climate: A Review. AB - Construction workers are at an elevated risk of heat stress, due to the strenuous nature of the work, high temperature work condition, and a changing climate. An increasing number of workers are at risk, as the industry's growth has been fueled by high demand and vast numbers of immigrant workers entering into the U.S., the Middle East and Asia to meet the demand. The risk of heat-related illnesses is increased by the fact that little to no regulations are present and/or enforced to protect these workers. This review recognizes the issues by summarizing epidemiological studies both in the U.S. and internationally. These studies have assessed the severity with which construction workers are affected by heat stress, risk factors and co-morbidities associated with heat-related illnesses in the construction industry, vulnerable populations, and efforts in implementing preventive measures. PMID- 29389909 TI - Women's Ideas about the Health Effects of Household Air Pollution, Developed through Focus Group Discussions and Artwork in Southern Nepal. AB - Household air pollution is a major cause of ill health, but few solutions have been effective to date. While many quantitative studies have been conducted, few have explored the lived experiences and perceptions of women who do the cooking, and as a result are those most exposed to household air pollution. In this study, we worked with groups of home cooks, and sought to use art as a means of engaging them in discussions of how household air pollution from cooking affects their lives. In the Terai district of southern Nepal, we held four focus groups that included 26 local women from urban and peri-urban areas, as well as six local artists. The women then met approximately weekly over four months, and produced images related to air pollution. Transcripts from the focus groups were reviewed independently by two authors, who initially categorised data deductively to pre defined nodes, and subsequently inductively reviewed emergent themes. Women identified a number of health effects from air pollution. The main physical effects related to the eye and the respiratory system, and women and young children were seen as most vulnerable. The psychosocial effects of air pollution included reduced food intake by women and lethargy. Suggested solutions included modifications to the cooking process, changing the location of stoves, and increasing ventilation. The main barriers were financial. The lived experiences of women in southern Nepal around the problem of air pollution offers a more nuanced and context-specific understanding of the perceptions and challenges of addressing air pollution, which can be used to inform future interventions. PMID- 29389910 TI - Genome-Wide Identification and Expression Analysis of the HD-Zip Gene Family in Wheat (Triticum aestivum L.). AB - The homeodomain-leucine zipper (HD-Zip) gene family, as plant-specific transcription factors, plays an important role in plant development and growth as well as in the response to diverse stresses. Although HD-Zip genes have been extensively studied in many plants, they had not yet been studied in wheat, especially those involved in response to abiotic stresses. In this study, 46 wheat HD-Zip genes were identified using a genome-wide search method. Phylogenetic analysis classified these genes into four groups, numbered 4, 5, 17 and 20 respectively. In total, only three genes with A, B and D homoeologous copies were identified. Furthermore, the gene interaction networks found that the TaHDZ genes played a critical role in the regulatory pathway of organ development and osmotic stress. Finally, the expression profiles of the wheat HD-Zips in different tissues and under various abiotic stresses were investigated using the available RNA sequencing (RNA-Seq) data and then validated by quantitative real time polymerase chain reaction (qRT-PCR) to obtain the tissue-specific and stress responsive candidates. This study systematically identifies the HD-Zip gene family in wheat at the genome-wide level, providing important candidates for further functional analysis and contributing to the better understanding of the molecular basis of development and stress tolerance in wheat. PMID- 29389911 TI - The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs. AB - Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) they act synergically with conventional antibiotics; (4) they neutralize endotoxins and are active in animal models. However, it is considered that many natural peptides are not suitable for drug development due to stability and biodisponibility problems, or high production costs. This review describes the efforts to overcome these problems and develop new antimicrobial drugs from these peptides or inspired by them. The discovery process of natural AMPs is discussed, as well as the development of synthetic analogs with improved pharmacological properties. The production of these compounds at acceptable costs, using different chemical and biotechnological methods, is also commented. Once these challenges are overcome, a new generation of versatile, potent and long-lasting antimicrobial drugs is expected. PMID- 29389913 TI - Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1. AB - BACKGROUND Shikonin is a component of Chinese herbal medicine. The aim of this study was to investigate the effects of shikonin on cell migration of papillary thyroid cancer cells of the TPC-1 cell line in vitro and expression levels of the phosphate and tensin homolog deleted on chromosome 10 (PTEN) and DNA methyltransferase 1 (DNMT1) genes. MATERIAL AND METHODS The Cell Counting Kit-8 (CCK-8) assay was performed to evaluate the proliferation of TPC-1 papillary thyroid cancer cells, and the normal thyroid cells, HTori-3, in vitro. A transwell motility assay was used to analyze the migration of TPC-1 cells. Western blot was performed to determine the expression levels of PTEN and DNMT1 genes. A methylation-specific polymerase chain reaction (PCR) (MSP) assay was used to evaluate the methylation of PTEN. RESULTS Following treatment with shikonin, the cell survival rate of TPC-1 cells decreased in a dose-dependent manner; the inhibitory effects on HTori-3 cells were less marked. Shikonin inhibited TPC-1 cell migration and invasion in a dose-dependent manner. The methylation of PTEN was suppressed by shikonin, which also reduced the expression of DNMT1 in a dose-dependent manner, and increased the expression of PTEN. Overexpression of DNMT1 promoted the migration of TPC-1 cells and the methylation of PTEN. Levels of protein expression of PTEN in TPC-1 cells treated with shikonin decreased, and were increased by DNMT1 knockdown. CONCLUSIONS Shikonin suppressed the expression of DNMT1, reduced PTEN gene methylation, and increased PTEN protein expression, leading to the inhibition of TPC-1 cell migration. PMID- 29389914 TI - Acute Illnesses and Injuries Related to Total Release Foggers - 10 States, 2007 2015. AB - Total release foggers (TRFs) (also known as "bug bombs") are pesticide products often used indoors to kill insects. After an earlier report found that TRFs pose a risk for acute illness (1), the Environmental Protection Agency required improved labels on TRFs manufactured after September 2012 (2). To examine the early impact of relabeling, the magnitude and characteristics of acute TRF related illness were evaluated for the period 2007-2015. A total of 3,222 TRF related illnesses were identified in 10 participating states, based on three data sources: Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) programs, the California Department of Pesticide Regulation (CDPR) program, and poison control centers (PCCs) in Florida, Texas, and Washington. No statistically significant decline in the overall TRF-illness incidence rate was found. Failure to vacate treated premises during application was the most commonly reported cause of exposure. To reduce TRF-related illness, integrated pest management strategies (3) need to be adopted, as well as better communication about the hazards and proper uses of TRFs. Redesigning TRFs to prevent sudden, unexpected activation might also be useful. PMID- 29389915 TI - Notes from the Field: Public Health Response to a Human Immunodeficiency Virus Outbreak Associated with Unsafe Injection Practices - Roka Commune, Cambodia, 2016. PMID- 29389912 TI - High Levels of Dual-Class Drug Resistance in HIV-Infected Children Failing First Line Antiretroviral Therapy in Southern Ethiopia. AB - Clinical monitoring of pediatric HIV treatment remains a major challenge in settings where drug resistance genotyping is not routinely available. As a result, our understanding of drug resistance, and its impact on subsequent therapeutic regimens available in these settings, remains limited. We investigate the prevalence and correlates of HIV-1 drug resistance among 94 participants of the Ethiopia Pediatric HIV Cohort failing first-line combination antiretroviral therapy (cART) using dried blood spot-based genotyping. Overall, 81% (73/90) of successfully genotyped participants harbored resistance mutations, including 69% (62/90) who harbored resistance to both Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Strikingly, 42% of resistant participants harbored resistance to all four NRTIs recommended for second-line use in this setting, meaning that there are effectively no remaining cART options for these children. Longer cART duration and prior regimen changes were significantly associated with detection of drug resistance mutations. Replicate genotyping increased the breadth of drug resistance detected in 34% of cases, and thus is recommended for consideration when typing from blood spots. Implementation of timely drug resistance testing and access to newer antiretrovirals and drug classes are urgently needed to guide clinical decision-making and improve outcomes for HIV-infected children on first line cART in Ethiopia. PMID- 29389916 TI - Cigarette Brand Preference and Pro-Tobacco Advertising Among Middle and High School Students - United States, 2012-2016. AB - Nearly all adult smokers first try cigarettes before age 18 years (1), and adolescents can show symptoms of nicotine dependence within days to weeks of the onset of occasional cigarette smoking (2). Having a usual cigarette brand among adolescent smokers could reflect exposure and receptivity to pro-tobacco advertising and tobacco product appeal (1). To identify usual cigarette brands smoked among U.S. middle and high school students who were current (past 30-day) cigarette smokers, CDC analyzed data from the 2012-2016 National Youth Tobacco Survey (NYTS). Marlboro, Newport, and Camel were the most commonly reported brands smoked during 2012-2016; in 2016, these three were the brands usually smoked for 73.1% and 78.7% of current cigarette smokers in middle and high school, respectively. These three brands also were the three most commonly identified as having a "favorite cigarette ad" in 2012. Efforts to reduce youth exposure to pro-tobacco advertising could help reduce youth smoking (1,3). PMID- 29389917 TI - Surveillance for Violent Deaths -?National Violent Death Reporting System, 18 States, 2014. AB - PROBLEM/CONDITION: In 2014, approximately 59,000 persons died in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 18 U.S. states for 2014. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. REPORTING PERIOD COVERED: 2014. DESCRIPTION OF SYSTEM: NVDRS collects data from participating states regarding violent deaths. Data are obtained from death certificates, coroner/medical examiner reports, law enforcement reports, and secondary sources (e.g., child fatality review team data, supplemental homicide reports, hospital data, and crime laboratory data). This report includes data from 18 states that collected statewide data for 2014 (Alaska, Colorado, Georgia, Kentucky, Maryland, Massachusetts, Michigan, New Jersey, New Mexico, North Carolina, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, and Wisconsin). NVDRS collates documents for each death and links deaths that are related (e.g., multiple homicides, a homicide followed by a suicide, or multiple suicides) into a single incident. RESULTS: For 2014, a total of 22,098 fatal incidents involving 22,618 deaths were captured by NVDRS in the 18 states included in this report. The majority of deaths were suicides (65.6%), followed by homicides (22.5%), deaths of undetermined intent (10.0%), deaths involving legal intervention (1.3%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force, excluding legal executions), and unintentional firearm deaths (<1%). The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision (ICD-10) and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement. Suicides occurred at higher rates among males, non-Hispanic American Indian/Alaska Natives (AI/AN), non-Hispanic whites, persons aged 45-54 years, and males aged >=75 years. Suicides were preceded primarily by a mental health, intimate partner, substance abuse, or physical health problem or a crisis during the previous or upcoming 2 weeks. Homicide rates were higher among males and persons aged <1 year and 15-44 years; rates were highest among non-Hispanic black and AI/AN males. Homicides primarily were precipitated by arguments and interpersonal conflicts, occurrence in conjunction with another crime, or related to intimate partner violence (particularly for females). When the relationship between a homicide victim and a suspected perpetrator was known, it was most often either an acquaintance/friend or an intimate partner. Legal intervention death rates were highest among males and persons aged 20-44 years; rates were highest among non-Hispanic black males and Hispanic males. Precipitating factors for the majority of legal intervention deaths were alleged criminal activity in progress, the victim reportedly using a weapon in the incident, a mental health or substance abuse problem, an argument or conflict, or a recent crisis. Deaths of undetermined intent occurred more frequently among males, particularly non Hispanic black and AI/AN males, and persons aged 30-54 years. Substance abuse, mental health problems, physical health problems, and a recent crisis were the most common circumstances preceding deaths of undetermined intent. Unintentional firearm deaths were more frequent among males, non-Hispanic whites, and persons aged 10-24 years; these deaths most often occurred while the shooter was playing with a firearm and were most often precipitated by a person unintentionally pulling the trigger or mistakenly thinking the firearm was unloaded. INTERPRETATION: This report provides a detailed summary of data from NVDRS for 2014. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence disproportionately affected persons aged <65 years, males, and certain minority populations. The primary precipitating factors for homicides and suicides were intimate partner problems, interpersonal conflicts, mental health and substance abuse problems, and recent crises. PUBLIC HEALTH ACTION: NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths. For example, North Carolina VDRS data were used to improve case ascertainment of pregnancy-associated suicides, Wisconsin VDRS data were used to develop the statewide suicide prevention strategy, and Colorado VDRS data were used to develop programs and prevention strategies for suicide among veterans. The continued development and expansion of NVDRS to include all U.S. states, territories, and the District of Columbia are essential to public health efforts to reduce the impact of violence. PMID- 29389918 TI - Racial and Ethnic Disparities in Sustained Viral Suppression and Transmission Risk Potential Among Persons Receiving HIV Care - United States, 2014. AB - : Non-Hispanic blacks/African Americans (blacks) represent 12% of the U.S. POPULATION: * However, in 2014 an estimated 43% (471,500) of persons living with diagnosed and undiagnosed human immunodeficiency virus (HIV) infection were blacks (1). In 2016, blacks accounted for 44% of all new HIV diagnoses (2). Although antiretroviral therapy (ART) prescriptions among persons in HIV care increased overall from 89% in 2009 to 94% in 2013, fewer blacks than Hispanics or Latinos (Hispanics) and non-Hispanic whites (whites) were on ART and had a suppressed viral load (<200 HIV RNA copies/mL) in their most recent viral load test result (3). Blacks also might be less likely to have sustained viral suppression over time and to experience longer periods with viral loads >1,500 HIV RNA copies/mL, a level that increases the risk for transmitting HIV (4-7). National HIV Surveillance System (NHSS) data are among those used to monitor progress toward reaching the national goal of reducing health disparities. CDC analyzed NHSS data to describe sustained viral suppression and transmission risk potential by race/ethnicity. Among 651,811 persons with HIV infection diagnosed through 2013 and who were alive through 2014 in 38 jurisdictions with complete laboratory reporting, a lower percentage of blacks had sustained viral suppression (40.8%), than had Hispanics (50.1%) and whites (56.3%). Among persons who were in care (i.e., had at least one viral load test in 2014) and had not achieved sustained viral suppression in 2014, blacks experienced longer periods (52.1% of the 12-month period) with viral loads >1,500 copies/mL, than did Hispanics (47.2%) and white (40.8%). Blacks aged 13-24 years had the lowest prevalence of sustained viral suppression, a circumstance that might increase transmission risk potential. Strengthening interventions that improve access to ART, promote adherence, and address barriers to clinical care and supportive services for all persons with diagnosed HIV infection is important for achieving the national goal of reducing health disparities. PMID- 29389920 TI - Notice to Readers: Change in Continuing Education Activities for MMWR Weekly. PMID- 29389919 TI - QuickStats: Percentage* of Residential Care Communities? That Use Electronic Health Records,S by Community Bed Size - United States, 2016. AB - In 2016, one fourth (26%) of residential care communities used electronic health records (EHRs). The percentage of communities that used EHRs increased with community bed size. The percentage was 12% in communities with 4-10 beds, 28% with 11-25 beds, 35% with 26-50 beds, 43% with 51-100 beds, and 50% with >100 beds using EHRs. PMID- 29389921 TI - Patterns of reintubation in extremely preterm infants: a longitudinal cohort study. AB - BackgroundThe optimal approach for reporting reintubation rates in extremely preterm infants is unknown. This study aims to longitudinally describe patterns of reintubation in this population over a broad range of observation windows following extubation.MethodsTiming and reasons for reintubation following a first planned extubation were collected from infants with birth weight <=1,250 g. An algorithm was generated to discriminate between reintubations attributable to respiratory and non-respiratory causes. Frequency and cumulative distribution curves were constructed for each category using 24 h intervals. The ability of observation windows to capture respiratory-related reintubations while limiting non-respiratory reasons was assessed using a receiver operating characteristic curve.ResultsOut of 194 infants, 91 (47%) were reintubated during hospitalization; 68% for respiratory and 32% for non-respiratory reasons. Respiratory-related reintubation rates steadily increased from 0 to 14 days post extubation before reaching a plateau. In contrast, non-respiratory reintubations were negligible in the first post-extubation week, but became predominant after 14 days. An observation window of 7 days captured 77% of respiratory-related reintubations while only including 14% of non-respiratory cases.ConclusionReintubation patterns are highly variable and affected by the reasons for reintubation and observation window used. Ideally, reintubation rates should be reported using a cumulative distribution curve over time. PMID- 29389923 TI - The opioid epidemic-a fast developing public health crisis in the first world. PMID- 29389924 TI - Incidental findings during a surgical procedure-current practice and ethical implications. AB - AIM: Sometimes during an elective surgical procedure, an abnormality is found which is unrelated to the scheduled procedure. In many instances, immediate treatment of this unexpected pathology is in the patient's medical interests, however, specific patient consent has not been obtained. This study investigates current surgical practice when confronted by an incidental finding (IF), as well as surgeons' views on informed consent in this context. METHOD: An online survey was sent to all practicing surgeons and surgical trainees within New Zealand. Respondents were presented with hypothetical scenarios involving IFs and asked to decide whether or not they would proceed with treatment. Opinion was sought on the factors influencing such decisions and the need for a clause within surgical consent documents to prompt discussion about IFs. RESULTS: 151/450 (33.6%) surgeons and trainees responded. Immediate treatment was more likely with IFs of greater clinical significance, lower-risk procedures and where there was prior consent for IF treatment. A proportion of surgeons did not follow these trends. Although a great deal of variation exists in the way that IFs are dealt with in the consent process, the majority of respondents (111/129, 86%) favoured a clause within a consent form that prompts discussion and seeks consent for the treatment of IFs. CONCLUSION: Responses to the IF scenarios were generally consistent with good practice. While variation in decision-making is to be expected, some decisions were concerning. Most surgeons agree that a clause within the consent form should trigger a discussion of IFs during the consent process. PMID- 29389922 TI - Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data. AB - PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with >99% analytical sensitivity and specificity for single-nucleotide variants and indels <10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings. PMID- 29389925 TI - Incidental findings during a surgical procedure-patient and public perspectives. AB - AIM: During a surgical procedure, incidental findings (IF) may be found and often the immediate treatment is in the patient's best interest. Due to the nature of IFs, specific patient consent cannot be obtained under such circumstances. The dilemma is whether the surgeon should proceed or delay until consent is obtained, as there are significant ethical and legal implications. Following an earlier study of surgeons' preferences for IF management, this report investigates patient and public preferences. METHOD: A questionnaire presented hypothetical scenarios involving IFs and samples of patients and public respondents reported their preference to proceed with treatment or have their surgeon wait to obtain consent. Opinion was sought regarding factors influencing their decisions and if general surgical consent procedures should cover IFs. RESULTS: A sample of 331 respondents from the general public and 368 elective surgery patients were surveyed. Results showed an overall preference to proceed with treatment in 75.1% of the hypothetical scenarios, which increased with IF severity and decreased with procedural risk. Thematic analysis of open-ended questions revealed a number of factors influencing preferences with avoidance of further surgery being most common. Results showed most respondents preferred for information provided in general consent forms though not all were comfortable about this. CONCLUSION: Patient and public preferences to proceed with treatment in hypothetical scenarios were generally consistent with surgeons' reported practice when faced with IFs. The data suggest that an IF clause in the consenting process could help surgeons make clinical decisions best aligned with individual patients' preferences. PMID- 29389926 TI - Treaty of Waitangi in New Zealand public health strategies and plans 2006-2016. AB - AIM: This study examines how public health policy in New Zealand has represented the Treaty of Waitangi (the English version) and te Tiriti o Waitangi (the Maori text) between 2006 to 2016. METHOD: A dataset of 49 public health strategies and plans, published between 2006 and 2016, were secured from the New Zealand Ministry of Health database. A thematic analysis using Braun and Clarke's process was undertaken and then the findings were reviewed against the Maori text of te Tiriti. RESULTS: Twelve documents referred to either te Tiriti or the Treaty. Crown discourses were characterised as i) rhetorical, ii aspirational, iii) practical and/or iv) substantive. We present a matrix of Crown health strategy and plan discourses and analyse their relationship to te Tiriti. DISCUSSION: Public health strategies and plans rarely address Treaty of Waitangi or te Tiriti o Waitangi obligations. This silence is inconsistent with legislative requirements to engage with the Treaty and health equity and is likely to inform health-related Waitangi Tribunal claims [WAI 2575]. Further work needs to be done to strengthen alignment of health policy to fulfil Crown obligations under te Tiriti. PMID- 29389927 TI - Prevalence of hepatitis E virus antibodies and infection in New Zealand blood donors. AB - AIM: Blood transfusion is one route of transmission of hepatitis E virus (HEV). The aim of this study was to assess both the prevalence of HEV antibodies and HEV infection in New Zealand blood donors. METHOD: To determine HEV seroprevalence, donor plasma samples (n=1,013) were tested for HEV antibodies using two commercially available ELISA kits, the Wantai HEV IgG ELISA and the MP Diagnostics HEV ELISA 4.0. To assess the prevalence of HEV infection, pooled plasma samples from individual plasma donors (n=5,000) were tested for HEV RNA using RT-qPCR. Samples that tested HEV antibody positive or gave an equivocal result with either ELISA were also tested for HEV RNA. RESULTS: The HEV seroprevalence in New Zealand blood donors was 9.7% using the Wantai HEV IgG ELISA and 8.1% using the MP Diagnostics HEV ELISA 4.0. The presence of HEV antibodies was significantly and positively correlated with increasing donor age. HEV RNA was not detected in any of the samples tested, indicating no evidence of current infection. CONCLUSION: This study, the largest to date to assess HEV seroprevalence in New Zealand, provides valuable baseline information on HEV seroprevalence and infection in New Zealand blood donors. The seroprevalence rate in New Zealand is similar to that reported in other developed countries. PMID- 29389928 TI - Review of acute symptomatic urolithiasis in Auckland. AB - AIM: To evaluate the incidence of acute symptomatic urolithiasis in the Auckland region. Associated epidemiological factors and stone characteristics were also studied and compared to previous research conducted in order to analyse trends. METHOD: All patients that presented acutely with symptomatic urolithiasis to the Auckland District Health Board (AHDB) between July 2014 and June 2015 were studied. Clinical data was obtained from medical records and population data was based on estimates provided by the Ministry of Health. Two-tailed tests and the Pearson Chi-Square tests were used for analysis. RESULTS: Overall, 1,125 patients (1,328 events) presented with an incidence of 85 per 100,000 per year, which was lower than that reported in 2006. The highest incidence was found among the Middle Eastern ethnic subgroup (0.130 %), followed by Maori (0.102%), Asian (0.087%), European (0.084%) and Pacific (0.041%) ethnicity. Males were more likely to be affected than females. Urolithiasis was most common in the fifth decade of life (25%). Forty-seven percent of the study population presented with multiple stones and 64% had recurrent urolithiasis or were 'high risk' stone formers. Distal ureteric stones <5mm were the most common (27%). Urine cultures were positive in 16% of cases. Seven hundred and thirty-nine (57%) were managed with medical management and ureteroscopy was most commonly performed for those who needed surgical intervention. CONCLUSIONS: The overall incidence of urolithiasis has decreased compared to previous research conducted in Auckland. This deviation could be attributed to the large influx of Asian immigrants observed in this period of time. A caucasian male, between 40-49 years, with a calculus <5mm in the distal ureter with a history of a previous urolithiasis has the highest chance to present with renal colic. PMID- 29389929 TI - Disease recurrence following surgery for colorectal cancer: five-year follow-up. AB - AIM: To describe the patterns of recurrence in a contemporaneous cohort of patients undergoing surgery with curative intent for colorectal adenocarcinoma at a New Zealand hospital with five-year follow-up. METHODS: Patients with colorectal cancer undergoing potentially curative surgery between January 2010 and December 2012 were followed up for a median of 61 months with three-monthly CEA (carcinoembryonic antigen), a colonoscopy after one year and yearly computed tomography scans of the chest, abdomen and pelvis for the first three years. RESULTS: Overall, 59/237 (24.9%) of patients experienced disease recurrence, the most common sites being the liver, followed by the lung and local recurrence. Recurrence rates did not differ significantly between colon and rectal cancer and ranged from 5.1% in stage I to 60% in stage IV. Seventy-three percent of all recurrences were observed within the first 24 months post-operatively. CONCLUSION: While New Zealand outcomes in colorectal cancer have historically compared unfavourably against international standards, the outcomes observed in this cohort are encouraging and may reflect advances in care, including multidisciplinary team discussion, increased use of adjuvant therapy, surgical subspecialisation and protocolled surveillance and follow-up. PMID- 29389930 TI - The American opioid death epidemic-lessons for New Zealand? AB - The US is currently in the grips of an epidemic of opioid drug deaths. The pattern has shifted from prescription opioids to illicit fentanyl in most recent years. In New Zealand there has been concern about prescription opioid drugs, although we have not seen the rapid increase in mortality that has been observed in the US. It is not clear whether we will follow the American pattern, but there may be lessons we can learn from the American experience and develop appropriate surveillance for this potentially significant public health problem. PMID- 29389931 TI - A buzz in the ear! PMID- 29389932 TI - Gaming: a 21st century variant of seated immobility thromboembolism. PMID- 29389933 TI - Playground drinking fountains in 17 local government areas: survey methods and results. AB - Appropriate public access to water is an increasing concern, and to further explore field observation methods for assessing such access, we aimed to survey drinking fountains in playgrounds across many local government areas. We systematically collected data (including photographs) of drinking fountains in randomly selected public playgrounds in 17 local government areas (TLAs) in New Zealand. The time for playground surveys was always less than 15 minutes. We found only one of the 17 TLAs had working drinking fountains in all the playgrounds sampled, and 11 working fountains in all 54 playgrounds (20%). Three had metal discolouration within 1cm of the nozzle. The systematic observation method was relatively quick, making it suitable for local officials and health promoters. PMID- 29389934 TI - Reply to Dr Bendavid's letter: mesh hernia repair is not perfect but it is currently the best treatment available. PMID- 29389935 TI - Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. AB - The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk variant discovery more generally in complex traits. PMID- 29389936 TI - A novel optogenetically tunable frequency modulating oscillator. AB - Synthetic biology has enabled the creation of biological reconfigurable circuits, which perform multiple functions monopolizing a single biological machine; Such a system can switch between different behaviours in response to environmental cues. Previous work has demonstrated switchable dynamical behaviour employing reconfigurable logic gate genetic networks. Here we describe a computational framework for reconfigurable circuits in E.coli using combinations of logic gates, and also propose the biological implementation. The proposed system is an oscillator that can exhibit tunability of frequency and amplitude of oscillations. Further, the frequency of operation can be changed optogenetically. Insilico analysis revealed that two-component light systems, in response to light within a frequency range, can be used for modulating the frequency of the oscillator or stopping the oscillations altogether. Computational modelling reveals that mixing two colonies of E.coli oscillating at different frequencies generates spatial beat patterns. Further, we show that these oscillations more robustly respond to input perturbations compared to the base oscillator, to which the proposed oscillator is a modification. Compared to the base oscillator, the proposed system shows faster synchronization in a colony of cells for a larger region of the parameter space. Additionally, the proposed oscillator also exhibits lesser synchronization error in the transient period after input perturbations. This provides a strong basis for the construction of synthetic reconfigurable circuits in bacteria and other organisms, which can be scaled up to perform functions in the field of time dependent drug delivery with tunable dosages, and sets the stage for further development of circuits with synchronized population level behaviour. PMID- 29389938 TI - Skill (or lack thereof) of data-model fusion techniques to provide an early warning signal for an approaching tipping point. AB - Many coupled human-natural systems have the potential to exhibit a highly nonlinear threshold response to external forcings resulting in fast transitions to undesirable states (such as eutrophication in a lake). Often, there are considerable uncertainties that make identifying the threshold challenging. Thus, rapid learning is critical for guiding management actions to avoid abrupt transitions. Here, we adopt the shallow lake problem as a test case to compare the performance of four common data assimilation schemes to predict an approaching transition. In order to demonstrate the complex interactions between management strategies and the ability of the data assimilation schemes to predict eutrophication, we also analyze our results across two different management strategies governing phosphorus emissions into the shallow lake. The compared data assimilation schemes are: ensemble Kalman filtering (EnKF), particle filtering (PF), pre-calibration (PC), and Markov Chain Monte Carlo (MCMC) estimation. While differing in their core assumptions, each data assimilation scheme is based on Bayes' theorem and updates prior beliefs about a system based on new information. For large computational investments, EnKF, PF and MCMC show similar skill in capturing the observed phosphorus in the lake (measured as expected root mean squared prediction error). EnKF, followed by PF, displays the highest learning rates at low computational cost, thus providing a more reliable signal of an impending transition. MCMC approaches the true probability of eutrophication only after a strong signal of an impending transition emerges from the observations. Overall, we find that learning rates are greatest near regions of abrupt transitions, posing a challenge to early learning and preemptive management of systems with such abrupt transitions. PMID- 29389937 TI - Quality in dementia care: A cross sectional study on the Bio-Psycho-Social competencies of health care professionals. AB - OBJECTIVE: Professionals in dementia-care ought to be able to work within a Bio Psycho-Social model. The objectives were to examine whether dementia-care is delivered in a Bio-Psycho-Social way, to explore the influencing factors and to evaluate the factorial validity of the 'Bio-Psycho-Social-Dementia-Care scale'. DESIGN AND SETTING: 413 healthcare-professionals completed the 'Bio-Psycho-Social Dementia-Care scale'. Differences between groups (settings, professions, years of experience) were calculated with a student's t-test and one-way ANOVA. The facture structure of the scale was evaluated using a confirmatory factor analysis. RESULTS: The factor-analysis confirmed the 5 subscale-structure (1) networking, (2) using the client's expertise, (3) assessment and reporting, (4) professional knowledge and skills and (5) using the environment. (No significant differences were found between professionals in residential care and community care for the subscales 'networking' and 'using the client's expertise'. Professionals in residential care score higher than community care for 'assessment and reporting' (p<0,05) and 'professional knowledge and skills' (p<0,01) but lower for 'using the environment' (p<0,001). The juniors score higher for 'professional knowledge' compared to seniors (p<0,01) and the seniors score better for 'professional experience' (p<0,01). The Cure and Care disciplines and the Therapy disciplines had higher values in 'assessment and reporting' compared to the Social Support disciplines (p<0,001 and p<0.001). The Therapy disciplines scored higher in 'using professional knowledge and skills' compared to the Social Support group (p 0.021) and the Cure and Care disciplines (p<0,001). The Social Support disciplines scored higher in 'using the environment' compared to the Therapy disciplines (p<0.001) and the Cure and care disciplines (p<0.001). CONCLUSION: The Bio-Psycho-Social-Dementia-scale is a valid tool and offers opportunities not only to rate, but also to improve Bio Psycho-Social functioning in dementia-care: increase interdisciplinary collaboration, facilitate assessment, combine the strengths of the different professions and install a heterogeneous team with regard to age and experience. PMID- 29389939 TI - The role of human outdoor recreation in shaping patterns of grizzly bear-black bear co-occurrence. AB - Species' distributions are influenced by a combination of landscape variables and biotic interactions with other species, including people. Grizzly bears and black bears are sympatric, competing omnivores that also share habitats with human recreationists. By adapting models for multi-species occupancy analysis, we analyzed trail camera data from 192 trail camera locations in and around Jasper National Park, Canada to estimate grizzly bear and black bear occurrence and intensity of trail use. We documented (a) occurrence of grizzly bears and black bears relative to habitat variables (b) occurrence and intensity of use relative to competing bear species and motorised and non-motorised recreational activity, and (c) temporal overlap in activity patterns among the two bear species and recreationists. Grizzly bears were spatially separated from black bears, selecting higher elevations and locations farther from roads. Both species co occurred with motorised and non-motorised recreation, however, grizzly bears reduced their intensity of use of sites with motorised recreation present. Black bears showed higher temporal activity overlap with recreational activity than grizzly bears, however differences in bear daily activity patterns between sites with and without motorised and non-motorised recreation were not significant. Reduced intensity of use by grizzly bears of sites where motorised recreation was present is a concern given off-road recreation is becoming increasingly popular in North America, and can negatively influence grizzly bear recovery by reducing foraging opportunities near or on trails. Camera traps and multi-species occurrence models offer non-invasive methods for identifying how habitat use by animals changes relative to sympatric species, including humans. These conclusions emphasise the need for integrated land-use planning, access management, and grizzly bear conservation efforts to consider the implications of continued access for motorised recreation in areas occupied by grizzly bears. PMID- 29389940 TI - Spiral tracing on a touchscreen is influenced by age, hand, implement, and friction. AB - Dexterity impairments are well documented in older adults, though it is unclear how these influence touchscreen manipulation. This study examined age-related differences while tracing on high- and low-friction touchscreens using the finger or stylus. 26 young and 24 older adults completed an Archimedes spiral tracing task on a touchscreen mounted on a force sensor. Root mean square error was calculated to quantify performance. Root mean square error increased by 29.9% for older vs. young adults using the fingertip, but was similar to young adults when using the stylus. Although other variables (e.g., touchscreen usage, sensation, and reaction time) differed between age groups, these variables were not related to increased error in older adults while using their fingertip. Root mean square error also increased on the low-friction surface for all subjects. These findings suggest that utilizing a stylus and increasing surface friction may improve touchscreen use in older adults. PMID- 29389941 TI - Comparative genomics reveals differences in mobile virulence genes of Escherichia coli O103 pathotypes of bovine fecal origin. AB - Escherichia coli O103, harbored in the hindgut and shed in the feces of cattle, can be enterohemorrhagic (EHEC), enteropathogenic (EPEC), or putative non pathotype. The genetic diversity particularly that of virulence gene profiles within O103 serogroup is likely to be broad, considering the wide range in severity of illness. However, virulence descriptions of the E. coli O103 strains isolated from cattle feces have been primarily limited to major genes, such as Shiga toxin and intimin genes. Less is known about the frequency at which other virulence genes exist or about genes associated with the mobile genetic elements of E. coli O103 pathotypes. Our objective was to utilize whole genome sequencing (WGS) to identify and compare major and putative virulence genes of EHEC O103 (positive for Shiga toxin gene, stx1, and intimin gene, eae; n = 43), EPEC O103 (negative for stx1 and positive for eae; n = 13) and putative non-pathotype O103 strains (negative for stx and eae; n = 13) isolated from cattle feces. Six strains of EHEC O103 from human clinical cases were also included. All bovine EHEC strains (43/43) and a majority of EPEC (12/13) and putative non-pathotype strains (12/13) were O103:H2 serotype. Both bovine and human EHEC strains had significantly larger average genome sizes (P < 0.0001) and were positive for a higher number of adherence and toxin-based virulence genes and genes on mobile elements (prophages, transposable elements, and plasmids) than EPEC or putative non-pathotype strains. The genome size of the three pathotypes positively correlated (R2 = 0.7) with the number of genes carried on mobile genetic elements. Bovine strains clustered phylogenetically by pathotypes, which differed in several key virulence genes. The diversity of E. coli O103 pathotypes shed in cattle feces is likely reflective of the acquisition or loss of virulence genes carried on mobile genetic elements. PMID- 29389942 TI - Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants. AB - HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant. Lapatinib showed stable but reverse orientation in binding site of K753E and the highest binding energy among studied HER2-lapatinib complexes but slightly lesser than L755S mutant. Results indicate that K753E has similar profile as L755S mutant for lapatinib. The interacting residues were also found different from other three studied forms as revealed by free energy decomposition and ligplot analysis. PMID- 29389944 TI - Genetic variation in the C-type lectin receptor CLEC4M in type 1 von Willebrand Disease patients. AB - von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, e.g. VWF, ABO, STXBP5 and CLEC4M. This study aims to screen comprehensively for CLEC4M variants and investigate their association with type 1 VWD in the Swedish population. In order to screen for CLEC4M variants, the CLEC4M gene region was re-sequenced and the polymorphic neck region was genotyped in 106 type 1 VWD patients from unrelated type 1 VWD families. Single nucleotide variants (SNV) and variable number tandem repeat (VNTR) allele and genotype frequencies were then compared with 294 individuals from the 1000Genomes project and 436 Swedish control individuals. Re-sequencing identified a total of 42 SNVs. Rare variants showed no accumulation in type 1 VWD patients and are not thought to contribute substantially to type 1 VWD. The only missense mutation (rs2277998, NP_001138379.1:p.Asp224Asn) had a higher frequency in type 1 VWD patients than in controls (4.9%). The VNTR genotypes 57 and 67 were observed at higher frequencies than expected in type 1 VWD patients (6.4% and 6.2%) and showed an increase in patients compared with controls (7.4% and 3.1%). Strong linkage disequilibrium in the CLEC4M region makes it difficult to distinguish between the effect of the missense mutation and the VNTR genotypes. In conclusion, heterozygous VNTR genotypes 57 and 67 of CLEC4M were highly enriched and are the most likely mechanism through which CLEC4M contributes to disease in the Swedish type 1 VWD population. PMID- 29389943 TI - Evolutionary analysis of polyproline motifs in Escherichia coli reveals their regulatory role in translation. AB - Translation of consecutive prolines causes ribosome stalling, which is alleviated but cannot be fully compensated by the elongation factor P. However, the presence of polyproline motifs in about one third of the E. coli proteins underlines their potential functional importance, which remains largely unexplored. We conducted an evolutionary analysis of polyproline motifs in the proteomes of 43 E. coli strains and found evidence of evolutionary selection against translational stalling, which is especially pronounced in proteins with high translational efficiency. Against the overall trend of polyproline motif loss in evolution, we observed their enrichment in the vicinity of translational start sites, in the inter-domain regions of multi-domain proteins, and downstream of transmembrane helices. Our analysis demonstrates that the time gain caused by ribosome pausing at polyproline motifs might be advantageous in protein regions bracketing domains and transmembrane helices. Polyproline motifs might therefore be crucial for co translational folding and membrane insertion. PMID- 29389945 TI - Intermittent hypoxia causes histological kidney damage and increases growth factor expression in a mouse model of obstructive sleep apnea. AB - Epidemiological studies demonstrate an association between obstructive sleep apnea (OSA) and accelerated loss of kidney function. It is unclear whether the decline in function is due to OSA per se or to other confounding factors such as obesity. In addition, the structural kidney abnormalities associated with OSA are unclear. The objective of this study was to determine whether intermittent hypoxia (IH), a key pathological feature of OSA, induces renal histopathological damage using a mouse model. Ten 8-week old wild-type male CB57BL/6 mice were randomly assigned to receive either IH or intermittent air (IA) for 60 days. After euthanasia, one kidney per animal was paraformaldehyde-fixed and then sectioned for histopathological and immunohistochemical analysis. Measurements of glomerular hypertrophy and mesangial matrix expansion were made in periodic acid Schiff stained kidney sections, while glomerular transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and vascular endothelial growth factor-A (VEGF-A) proteins were semi-quantified by immunohistochemistry. The antigen-antibody reaction was detected by 3,3'-diaminobenzidine chromogen where the color intensity semi-quantified glomerular protein expression. To enhance the accuracy of protein semi-quantification, the percentage of only highly-positive staining was used for analysis. Levels of TGF-beta, CTGF and VEGF A proteins in the kidney cortex were further quantified by western blotting. Cellular apoptosis was also investigated by measuring cortical antiapoptotic B cell lymphoma 2 (Bcl-2) and apoptotic Bcl-2-associated X (Bax) proteins by western blotting. Further investigation of cellular apoptosis was carried out by fluorometric terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining. Finally, the levels of serum creatinine and 24-hour urinary albumin were measured as a general index of renal function. Our results indicate that mice exposed to IH have an increased glomerular area (by 1.13 fold, p< 0.001) and expansion of mesangial matrix (by 1.8 fold, p< 0.01). Moreover, the glomerular expressions of TGF-beta1, CTGF and VEGF-A proteins were 2.7, 2.2 and 3.8-fold higher in mice exposed to IH (p< 0.05 for all). Furthermore, western blotting protein analysis demonstrates that IH-exposed mice express higher levels of TGF-beta1, CTGF and VEGF-A proteins by 1.9, 4.0 and 1.6-fold (p< 0.05 for all) respectively. Renal cellular apoptosis was greater in the IH group as shown by an increased cortical Bax/Bcl-2 protein ratio (p< 0.01) and higher fluorometric TUNEL staining (p< 0.001). Finally, 24-hr urinary albumin levels were higher in mice exposed to IH (43.4 MUg vs 9.7 MUg, p< 0.01), while there were no differences in serum creatinine levels between the two groups. We conclude that IH causes kidney injury that is accompanied by glomerular hypertrophy, mesangial matrix expansion, increased expression of glomerular growth factors and an increased cellular apoptosis. PMID- 29389946 TI - The effect of histone deacetylase inhibitors on AHSP expression. AB - Alpha-hemoglobin stabilizing protein (AHSP) is a molecular chaperone that can reduce the damage caused by excess free alpha-globin to erythroid cells in patients with impaired beta-globin chain synthesis. We assessed the effect of sodium phenylbutyrate and sodium valproate, two histone deacetylase inhibitors (HDIs) that are being studied for the treatment of hemoglobinopathies, on the expression of AHSP, BCL11A (all isoforms), gamma-globin genes (HBG1/2), and some related transcription factors including GATA1, NFE2, EKLF, KLF4, and STAT3. For this purpose, the K562 cell line was cultured for 2, 4, and 6 days in the presence and absence of sodium phenylbutyrate and sodium valproate. Relative real time qRT-PCR analysis of mRNA levels was performed to determine the effects of the two compounds on gene expression. Expression of all target mRNAs increased significantly (p < 0.05), except for the expression of BCL11A, which was down regulated (p < 0.05) in the cells treated with both compounds relative to the levels measured for untreated cells. The findings indicated that sodium valproate had a more considerable effect than sodium phenylbutyrate (p < 0.0005) on BCL11A repression and the up-regulation of other studied genes. gamma-Globin and AHSP gene expression continuously increased during the culture period in the treated cells, with the highest gene expression observed for 1 mM sodium valproate after 6 days. Both compounds repressed the expression of BCL11A (-XL, -L, -S) and up regulated GATA1, NFE2, EKLF, KLF4, STAT3, AHSP, and gamma-globin genes expression. Moreover, sodium valproate showed a stronger effect on repressing BCL11A and escalating the expression of other target genes. The findings of this in vitro experiment could be considered in selecting drugs for clinical use in patients with beta-hemoglobinopathies. PMID- 29389947 TI - Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time saving diagnostic approach. AB - BACKGROUND: Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so called "diagnostic odysseys". Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country-are rare. OBJECTIVES: To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital. METHODS: This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated. RESULTS: We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3-70). The mean time elapsed from symptom onset to WES was 11 years (range 3-42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center. CONCLUSIONS: WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients. PMID- 29389949 TI - Model selection and averaging in the assessment of the drivers of household food waste to reduce the probability of false positives. AB - Food waste from households contributes the greatest proportion to total food waste in developed countries. Therefore, food waste reduction requires an understanding of the socio-economic (contextual and behavioural) factors that lead to its generation within the household. Addressing such a complex subject calls for sound methodological approaches that until now have been conditioned by the large number of factors involved in waste generation, by the lack of a recognised definition, and by limited available data. This work contributes to food waste generation literature by using one of the largest available datasets that includes data on the objective amount of avoidable household food waste, along with information on a series of socio-economic factors. In order to address one aspect of the complexity of the problem, machine learning algorithms (random forests and boruta) for variable selection integrated with linear modelling, model selection and averaging are implemented. Model selection addresses model structural uncertainty, which is not routinely considered in assessments of food waste in literature. The main drivers of food waste in the home selected in the most parsimonious models include household size, the presence of fussy eaters, employment status, home ownership status, and the local authority. Results, regardless of which variable set the models are run on, point toward large households as being a key target element for food waste reduction interventions. PMID- 29389948 TI - Photocleavage-based affinity purification of biomarkers from serum: Application to multiplex allergy testing. AB - Multiplex serological immunoassays, such as implemented on microarray or microsphere-based platforms, provide greater information content and higher throughput, while lowering the cost and blood volume required. These features are particularly attractive in pediatric food allergy testing to facilitate high throughput multi-allergen analysis from finger- or heel-stick collected blood. However, the miniaturization and microfluidics necessary for creating multiplex assays make them highly susceptible to the "matrix effect" caused by interference from non-target agents in serum and other biofluids. Such interference can result in lower sensitivity, specificity, reproducibility and quantitative accuracy. These problems have in large part prevented wide-spread implementation of multiplex immunoassays in clinical laboratories. We report the development of a novel method to eliminate the matrix effect by utilizing photocleavable capture antibodies to purify and concentrate blood-based biomarkers (a process termed PC PURE) prior to detection in a multiplex immunoassay. To evaluate this approach, it was applied to blood-based allergy testing. Patient total IgE was purified and enriched using PC-PURE followed by multiplex microsphere-based detection of allergen-specific IgEs (termed the AllerBead assay). AllerBead was formatted to detect the eight most common pediatric food allergens: milk, soy, wheat, egg, peanuts, tree nuts, fin fish and shellfish, which account for >90% of all pediatric food allergies. 205 serum samples obtained from Boston Children's Hospital were evaluated. When PC-PURE was employed with AllerBead, excellent agreement was obtained with the standard, non-multiplex, ImmunoCAP(r) assay (average sensitivity above published negative predictive cutoffs = 96% and average Pearson r = 0.90; average specificity = 97%). In contrast, poor ImmunoCAP(r)-correlation was observed when PC-PURE was not utilized (average sensitivity above published negative predictive cutoffs = 59% and average Pearson r = 0.61; average specificity = 97%). This approach should be adaptable to improve a wide range of multiplex immunoassays such as in cancer, infectious disease and autoimmune disease. PMID- 29389950 TI - Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis. AB - BACKGROUND: Psoriasis (PsO) is a chronic inflammatory disease with predominantly cutaneous manifestations. Approximately one third of patients with PsO develop psoriatic arthritis (PsA), whereas the remaining proportion of patients has isolated cutaneous psoriasis (PsC). These two phenotypes share common immunology, but with different heredity that might in part be explained by genetic variables. METHODS: Using a candidate gene approach, we studied 53 single nucleotide polymorphisms (SNPs) in 37 genes that regulate inflammation. In total, we assessed 480 patients with PsO from DERMBIO, of whom 151 had PsC for 10 years or more (PsC10), 459 patients with PsA from DANBIO, and 795 healthy controls. Using logistic regression analysis, crude and adjusted for age and gender, we assessed associations between genetic variants and PsO, PsC10, and PsA, as well as associations between genetic variants and development of PsA in PsO. RESULTS: Eleven polymorphisms in 10 genes were nominally associated with PsO and/or PsC and/or PsA (P < 0.05). After correction for multiple testing with a false discovery rate of 5%, two SNPs remained significant: TNF (rs361525) was associated with PsO, PsC10, and PsA; and IL12B (rs6887695) was associated with PsO. CONCLUSION: Among a cohort of Danish patients with moderate-to-severe psoriasis, two SNPs in the IL12B and TNF genes were associated with susceptibility of psoriasis. None of the SNPs were specifically associated with isolated cutaneous psoriasis or psoriatic arthritis. PMID- 29389951 TI - Molecular epidemiology of HIV-1 subtype A in former Soviet Union countries. AB - While in other parts of the world it is on decline, incidence of HIV infection continues to rise in the former Soviet Union (FSU) countries. The present study was conducted to investigate the patterns and modes of HIV transmission in FSU countries. We performed phylogenetic analysis of publicly available 2705 HIV-1 subtype A pol sequences from thirteen FSU countries: Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Russia, Ukraine and Uzbekistan. Our analysis showed that the clusters from FSU countries were intermixed, indicating a possible role of transmigration in HIV transmission. Injection drug use was found to be the most frequent mode of transmission, while the clusters from PWID and heterosexual transmission were intermixed, indicating bridging of HIV infection across populations. To control the expanding HIV epidemic in this region, harm reduction strategies should be focused on three modes of transmission, namely, cross-border migration, injection drug use and heterosexual. PMID- 29389952 TI - Comparison of retinal vascular geometry in obese and non-obese children. AB - PURPOSE: Childhood obesity is associated with adult cardiometabolic disease. We postulate that the underlying microvascular dysfunction begins in childhood. We thus aimed to compare retinal vascular parameters between obese and non-obese children. METHODS: This was a cross-sectional study involving 166 children aged 6 to 12 years old in Malaysia. Ocular examination, biometry, retinal photography, blood pressure and body mass index measurement were performed. Participants were divided into two groups; obese and non-obese. Retinal vascular parameters were measured using validated software. RESULTS: Mean age was 9.58 years. Approximately 51.2% were obese. Obese children had significantly narrower retinal arteriolar caliber (F(1,159) = 6.862, p = 0.010), lower arteriovenous ratio (F(1,159) = 17.412, p < 0.001), higher venular fractal dimension (F(1,159) = 4.313, p = 0.039) and higher venular curvature tortuosity (F(1,158) = 5.166, p = 0.024) than non-obese children, after adjustment for age, gender, blood pressure and axial length. CONCLUSIONS: Obese children have abnormal retinal vascular geometry. These findings suggest that childhood obesity is characterized by early microvascular abnormalities that precede development of overt disease. Further research is warranted to determine if these parameters represent viable biomarkers for risk stratification in obesity. PMID- 29389953 TI - Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer. AB - Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non coding RNA (lncRNA) that is a negative prognostic factor for patients with pancreatic cancer and several other tumors. In this study, we show that knockdown of MALAT-1 in Panc1 and other pancreatic cancer cell lines decreases cell proliferation, survival and migration. We previously observed similar results for the lncRNAs HOTTIP and HOTAIR in Panc1 cells; however, RNAseq comparison of genes regulated by MALAT-1 shows minimal overlap with HOTTIP/HOTAIR-regulated genes. Analysis of changes in gene expression after MALAT-1 knockdown shows that this lncRNA represses several tumor suppressor-like genes including N-myc downregulated gene-1 (NDRG-1), a tumor suppressor in pancreatic cancer that is also corepressed by EZH2 (a PRC2 complex member). We also observed that Specificity proteins Sp1, Sp3 and Sp4 are overexpressed in Panc1 cells and Sp knockdown or treatment with small molecules that decrease Sp proteins expression also decrease MALAT-1 expression. We also generated Kras-overexpressing p53L/L;LSL-KrasG12DL/+;p48Cre+/- (p53L/L/KrasG12D) and p53L/+;LSLKrasG12DL/+;p48Cre+/- (p53L/+/KrasG12D) mice which are p53 homo- and heterozygous, respectively. These mice rapidly develop pancreatic ductal adenocarcinoma-like tumors and were crossed with MALAT-1-/- mice. We observed that the loss of one or two MALAT-1 alleles in these Ras overexpressing mice does not significantly affect the time to death; however, the loss of MALAT-1 in the p53-/+ (heterozygote) mice slightly increases their lifespan. PMID- 29389954 TI - Intimate partner violence (IPV): The validity of an IPV screening instrument utilized among pregnant women in Tanzania and Vietnam. AB - BACKGROUND: Intimate partner violence (IPV) is a global problem that affects one third of all women. The present study aims to develop and determine the validity of a screening instrument for the detection of IPV in pregnant women in Tanzania and Vietnam and to determine the minimum number of questions needed to identify IPV. METHOD: An IPV screening instrument based on eight questions was tested on 1,116 Tanzanian and 1,309 Vietnamese women who attended antenatal care before 24 gestational weeks. The women were re-interviewed during their 30th-34th gestational week where the World Health Organization (WHO) IPV questionnaire was used as the gold standard. In all, 255 combinations of eight different questions were first tested on the Tanzanian study population where sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. In the evaluation of the performance of the question combinations, different IPV types and the frequency of abusive acts were considered. The question combinations that performed best in Tanzania were subsequently evaluated in the Vietnamese study population. RESULTS: In Tanzania, a combination of three selected questions including one question on emotional IPV, one on physical IPV and one on sexual IPV was found to be most effective in identifying women who are exposed to at least one type of IPV during pregnancy (sensitivity = .80; specificity = .74). The performance of the identified combination was slightly less effective in Vietnam (sensitivity = .74; specificity = .68). Focusing on different IPV types, the best performance was found for exposure to physical IPV in both Tanzania (sensitivity = .93; specificity = .70) and Vietnam (sensitivity = .96; specificity = .55). In both countries, the sensitivity increased with the frequency of abuse whereas the specificity decreased. CONCLUSION: By asking pregnant women three simple questions we were able to identify women who were exposed to IPV during pregnancy in two different countries. The question combination performed best in assessing physical IPV where it identified 93% and 96% of Vietnamese and Tanzanian women, respectively, who were exposed to physical IPV. PMID- 29389955 TI - "Cyst-ained" research into Heterodera parasitism. PMID- 29389956 TI - Euglena gracilis Z and its carbohydrate storage substance relieve arthritis symptoms by modulating Th17 immunity. AB - Euglena gracilis Z is a microorganism classified as a microalga and is used as a food or nutritional supplement. Paramylon, the carbohydrate storage substance of E. gracilis Z, is reported to affect the immunological system. This study evaluated the symptom-relieving effects of E. gracilis Z and paramylon in rheumatoid arthritis in a collagen-induced arthritis mouse model. The efficacy of both substances was assessed based on clinical arthritis signs, as well as cytokine (interleukin [IL]-17, IL-6, and interferon [IFN]-gamma) levels in lymphoid tissues. Additionally, the knee joints were harvested and histopathologically examined. The results showed that both substances reduced the transitional changes in the visual assessment score of arthritis symptoms compared with those in the control group, indicating their symptom-relieving effects on rheumatoid arthritis. Furthermore, E. gracilis Z and paramylon significantly reduced the secretion of the cytokines, IL-17, IL-6, and IFN-gamma. The histopathological examination of the control group revealed edema, inflammation, cell hyperplasia, granulation tissue formation, fibrosis, and exudate in the synovial membrane, as well as pannus formation and articular cartilage destruction in the femoral trochlear groove. These changes were suppressed in both treatment groups. Particularly, the E. gracilis Z group showed no edema, inflammation, and fibrosis of the synovial membrane, or pannus formation and destruction of articular cartilage in the femoral trochlear groove. Furthermore, E. gracilis Z and paramylon exhibited symptom-relieving effects on rheumatoid arthritis and suppressed the secretion of cytokines IL-17, IL-6, and IFN-gamma. These effects were likely mediated by the regulatory activities of E. gracilis Z and paramylon on Th17 immunity. In addition, the symptom-relieving effects of both substances were comparable, which suggests that paramylon is the active component of Euglena gracilis Z. PMID- 29389957 TI - Genotype distribution and treatment response among incarcerated drug-dependent patients with chronic hepatitis C infection. AB - The prevalence of hepatitis C virus (HCV) infection is disproportionately high among prisoners, especially among those who are drug-dependent. However, current screening and treatment recommendations are inconsistent for this population, and appropriate care is not reliably provided. To address these problems, the present study aimed to identify unique characteristics and clinical manifestations of incarcerated patients with HCV infection. We included incarcerated patients who received treatment with pegylated-interferon combined with ribavirin at Mackay Memorial Hospital in Taitung and were serving sentences at either the Taiyuan Skill Training Institute or the Yanwan Training Institute. HCV genotypes 1 (41.4%), 3 (25.9%), and 6 (24.1%) were the most prevalent in the incarcerated patients. During the study period, we analyzed treatment response among 58 incarcerated patients and compared obtained results with treatment response among 52 patients who were living in the community. Higher sustained virological response rate was observed among patients with incarceration and HCV genotype other than 1. The odds ratios (corresponding 95% confidence intervals) for incarceration and genotype 1 were 2.75 (1.06-7.11) and 0.37 (0.14-0.99), respectively. Better treatment compliance among incarcerated patients might partially explain these results. The results of this study suggest that treatment of prisoners with HCV infection is feasible and effective. More appropriate and timely methods are needed to prevent HCV transmission among injection drug users inside prisons. PMID- 29389958 TI - A mobile health technology platform for quality assurance and quality improvement of malaria diagnosis by community health workers. AB - BACKGROUND: Community health workers (CHWs) play an important role in improving access to services in areas with limited health infrastructure or workforce. Supervision of CHWs by qualified health professionals is the main link between this lay workforce and the formal health system. The quality of services provided by lay health workers is dependent on adequate supportive supervision. It is however one of the weakest links in CHW programs due to logistical and resource constraints, especially in large scale programs. Interventions such as point of care testing using malaria rapid diagnostic tests (RDTs) require real time monitoring to ensure diagnostic accuracy. In this study, we evaluated the utility of a mobile health technology platform to remotely monitor malaria RDT (mRDT) testing by CHWs for quality improvement. METHODS: As part of a large implementation trial involving mRDT testing by CHWs, we introduced the Fionet system composed of a mobile device (Deki Reader, DR) to assist in processing and automated interpretation of mRDTs, which connects to a cloud-based database which captures reports from the field in real time, displaying results in a custom dashboard of key performance indicators. A random sample of 100 CHWs were trained and provided with the Deki Readers and instructed to use it on 10 successive patients. The CHWs interpretation was compared with the Deki Reader's automatic interpretation, with the errors in processing and interpreting the RDTs recorded. After the CHW entered their interpretation on the DR, the DR provided immediate, automated feedback and interpretation based on its reading of the same cassette. The study team monitored the CHW performance remotely and provided additional support. RESULTS: A total of 1251 primary and 113 repeat tests were performed by the 97 CHWs who used the DR. 91.6% of the tests had agreement between the DR and the CHWs. There were 61 (4.9%) processing and 52 (4.2%) interpretation errors among the primary tests. There was a tendency towards lower odds of errors with increasing number and frequency of tests, though not statistically significant. Of the 62 tests that were repeated due to errors, 79% achieved concordance between the CHW and the DR. Satisfaction with the use of the DR by the CHWs was high. CONCLUSIONS: Use of innovative mHealth strategies for monitoring and quality control can ensure quality within a large scale implementation of community level testing by lay health workers. PMID- 29389960 TI - Competitive interactions between native Spartina alterniflora and non-native Phragmites australis depend on nutrient loading and temperature. AB - We explored the nature and impact of competitive interactions between the salt marsh foundational plant Spartina alterniflora and invasive Phragmites australis in New England under varying levels of anthropogenic influence from nutrient loading and temperature warming. Plants were grown with and without competition in mesocosms over a four-month growing season. Mesocosms were split evenly among three levels of nutrient additions and two temperatures varying by an average of ~3 degrees C, manipulated using small greenhouses. We measured aboveground productivity as total biomass, numbers of new stems, and mean stem height. Nutrient enrichment increased all growth parameters, while competition generally reduced aboveground biomass and the production of new stems in both species. Most importantly, smooth cordgrass suffered no negative consequences of competition when no nutrients were added and temperature was elevated. The results of this study suggest that minimizing nutrient loading into coastal marshes could be an important factor in slowing the spread of common reed into the low marsh zone of New England salt marshes as global temperatures continue to warm. PMID- 29389959 TI - Improved tools and strategies for the prevention and control of arboviral diseases: A research-to-policy forum. AB - BACKGROUND: Research has been conducted on interventions to control dengue transmission and respond to outbreaks. A summary of the available evidence will help inform disease control policy decisions and research directions, both for dengue and, more broadly, for all Aedes-borne arboviral diseases. METHOD: A research-to-policy forum was convened by TDR, the Special Programme for Research and Training in Tropical Diseases, with researchers and representatives from ministries of health, in order to review research findings and discuss their implications for policy and research. RESULTS: The participants reviewed findings of research supported by TDR and others. Surveillance and early outbreak warning. Systematic reviews and country studies identify the critical characteristics that an alert system should have to document trends reliably and trigger timely responses (i.e., early enough to prevent the epidemic spread of the virus) to dengue outbreaks. A range of variables that, according to the literature, either indicate risk of forthcoming dengue transmission or predict dengue outbreaks were tested and some of them could be successfully applied in an Early Warning and Response System (EWARS). Entomological surveillance and vector management. A summary of the published literature shows that controlling Aedes vectors requires complex interventions and points to the need for more rigorous, standardised study designs, with disease reduction as the primary outcome to be measured. House screening and targeted vector interventions are promising vector management approaches. Sampling vector populations, both for surveillance purposes and evaluation of control activities, is usually conducted in an unsystematic way, limiting the potentials of entomological surveillance for outbreak prediction. Combining outbreak alert and improved approaches of vector management will help to overcome the present uncertainties about major risk groups or areas where outbreak response should be initiated and where resources for vector management should be allocated during the interepidemic period. CONCLUSIONS: The Forum concluded that the evidence collected can inform policy decisions, but also that important research gaps have yet to be filled. PMID- 29389962 TI - Correction: Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses. AB - [This corrects the article DOI: 10.1371/journal.pone.0160172.]. PMID- 29389961 TI - The Candida albicans stress response gene Stomatin-Like Protein 3 is implicated in ROS-induced apoptotic-like death of yeast phase cells. AB - The ubiquitous presence of SPFH (Stomatin, Prohibitin, Flotillin, HflK/HflC) proteins in all domains of life suggests that their function would be conserved. However, SPFH functions are diverse with organism-specific attributes. SPFH proteins play critical roles in physiological processes such as mechanosensation and respiration. Here, we characterize the stomatin ORF19.7296/SLP3 in the opportunistic human pathogen Candida albicans. Consistent with the localization of stomatin proteins, a Slp3p-Yfp fusion protein formed visible puncta along the plasma membrane. We also visualized Slp3p within the vacuolar lumen. Slp3p primary sequence analyses identified four putative S-palmitoylation sites, which may facilitate membrane localization and are conserved features of stomatins. Plasma membrane insertion sequences are present in mammalian and nematode SPFH proteins, but are absent in Slp3p. Strikingly, Slp3p was present in yeast cells, but was absent in hyphal cells, thus categorizing it as a yeast-phase specific protein. Slp3p membrane fluorescence significantly increased in response to cellular stress caused by plasma membrane, cell wall, oxidative, or osmotic perturbants, implicating SLP3 as a general stress-response gene. A slp3Delta/Delta homozygous null mutant had no detected phenotype when slp3Delta/Delta mutants were grown in the presence of a variety of stress agents. Also, we did not observe a defect in ion accumulation, filamentation, endocytosis, vacuolar structure and function, cell wall structure, or cytoskeletal structure. However, SLP3 over-expression triggered apoptotic-like death following prolonged exposure to oxidative stress or when cells were induced to form hyphae. Our findings reveal the cellular localization of Slp3p, and for the first time associate Slp3p function with the oxidative stress response. PMID- 29389963 TI - Correction: An ImmunoSignature test distinguishes Trypanosoma cruzi, hepatitis B, hepatitis C and West Nile virus seropositivity among asymptomatic blood donors. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005882.]. PMID- 29389964 TI - Modeling and mapping the current and future distribution of Pseudomonas syringae pv. actinidiae under climate change in China. AB - OBJECTIVE: Bacterial canker of kiwifruit caused by Pseudomonas syringae pv. actinidiae (Psa) is a major threat to the kiwifruit industry throughout the world and accounts for substantial economic losses in China. The aim of the present study was to test and explore the possibility of using MaxEnt (maximum entropy models) to predict and analyze the future large-scale distribution of Psa in China. METHOD: Based on the current environmental factors, three future climate scenarios, which were suggested by the fifth IPCC report, and the current distribution sites of Psa, MaxEnt combined with ArcGIS was applied to predict the potential suitable areas and the changing trend of Psa in China. The jackknife test and correlation analysis were used to choose dominant climatic factors. The receiver operating characteristic curve (ROC) drawn by MaxEnt was used to evaluate the accuracy of the simulation. RESULT: The results showed that under current climatic conditions, the area from latitude 25 degrees to 36 degrees N and from longitude 101 degrees to 122 degrees E is the primary potential suitable area of Psa in China. The highly suitable area (with suitability between 66 and 100) was mainly concentrated in Northeast Sichuan, South Shaanxi, most of Chongqing, West Hubei and Southwest Gansu and occupied 4.94% of land in China. Under different future emission scenarios, both the areas and the centers of the suitable areas all showed differences compared with the current situation. Four climatic variables, i.e., maximum April temperature (19%), mean temperature of the coldest quarter (14%), precipitation in May (11.5%) and minimum temperature in October (10.8%), had the largest impact on the distribution of Psa. CONCLUSION: The MaxEnt model is potentially useful for forecasting the future adaptive distribution of Psa under climate change, and it provides important guidance for comprehensive management. PMID- 29389965 TI - Mapping regional livelihood benefits from local ecosystem services assessments in rural Sahel. AB - Most current approaches to landscape scale ecosystem service assessments rely on detailed secondary data. This type of data is seldom available in regions with high levels of poverty and strong local dependence on provisioning ecosystem services for livelihoods. We develop a method to extrapolate results from a previously published village scale ecosystem services assessment to a higher administrative level, relevant for land use decision making. The method combines remote sensing (using a hybrid classification method) and interviews with community members. The resulting landscape scale maps show the spatial distribution of five different livelihood benefits (nutritional diversity, income, insurance/saving, material assets and energy, and crops for consumption) that illustrate the strong multifunctionality of the Sahelian landscapes. The maps highlight the importance of a diverse set of sub-units of the landscape in supporting Sahelian livelihoods. We see a large potential in using the resulting type of livelihood benefit maps for guiding future land use decisions in the Sahel. PMID- 29389966 TI - Revisiting the phylogeography, demography and taxonomy of the frog genus Ptychadena in the Ethiopian highlands with the use of genome-wide SNP data. AB - Understanding the diversification of biological lineages is central to evolutionary studies. To properly study the process of speciation, it is necessary to link micro-evolutionary studies with macro-evolutionary mechanisms. Micro-evolutionary studies require proper sampling across a taxon's range to adequately infer genetic diversity. Here we use the grass frogs of the genus Ptychadena from the Ethiopian highlands as a model to study the process of lineage diversification in this unique biodiversity hotspot. We used thousands of genome-wide SNPs obtained from double digest restriction site associated DNA sequencing (ddRAD-seq) in populations of the Ptychadena neumanni species complex from the Ethiopian highlands in order to infer their phylogenetic relationships and genetic structure, as well as to study their demographic history. Our genome wide phylogenetic study supports the existence of approximately 13 lineages clustered into 3 species groups. Our phylogenetic and phylogeographic reconstructions suggest that those endemic lineages diversified in allopatry, and subsequently specialized to different habitats and elevations. Demographic analyses point to a continuous decrease in the population size across the majority of lineages and populations during the Pleistocene, which is consistent with a continuous period of aridification that East Africa experienced since the Pliocene. We discuss the taxonomic implications of our analyses and, in particular, we warn against the recent practice to solely use Bayesian species delimitation methods when proposing taxonomic changes. PMID- 29389967 TI - RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition. AB - The outlook for patients with advanced renal cell cancer (RCC) has been improved by targeted agents including inhibitors of the PI3 kinase (PI3K)-AKT-mTOR axis, although treatment resistance is a major problem. Here, we aimed to understand how RCC cells acquire resistance to PI3K-mTOR inhibition. We used the RCC4 cell line to generate a model of in vitro resistance by continuous culture in PI3K mTOR kinase inhibitor NVP-BEZ235 (BEZ235, Dactolisib). Resistant cells were cross resistant to mTOR inhibitor AZD2014. Sensitivity was regained after 4 months drug withdrawal, and resistance was partially suppressed by HDAC inhibition, supporting an epigenetic mechanism. BEZ235-resistant cells up-regulated and/or activated numerous proteins including MET, ABL, Notch, IGF-1R, INSR and MEK/ERK. However, resistance was not reversed by inhibiting or depleting these pathways, suggesting that many induced changes were passengers not drivers of resistance. BEZ235 blocked phosphorylation of mTOR targets S6 and 4E-BP1 in parental cells, but 4E-BP1 remained phosphorylated in resistant cells, suggesting BEZ235 refractory mTORC1 activity. Consistent with this, resistant cells over-expressed mTORC1 component RAPTOR at the mRNA and protein level. Furthermore, BEZ235 resistance was suppressed by RAPTOR depletion, or allosteric mTORC1 inhibitor rapamycin. These data reveal that RAPTOR up-regulation contributes to PI3K-mTOR inhibitor resistance, and suggest that RAPTOR expression should be included in the pharmacodynamic assessment of mTOR kinase inhibitor trials. PMID- 29389968 TI - Inferring pregnancy episodes and outcomes within a network of observational databases. AB - Administrative claims and electronic health records are valuable resources for evaluating pharmaceutical effects during pregnancy. However, direct measures of gestational age are generally not available. Establishing a reliable approach to infer the duration and outcome of a pregnancy could improve pharmacovigilance activities. We developed and applied an algorithm to define pregnancy episodes in four observational databases: three US-based claims databases: Truven MarketScan(r) Commercial Claims and Encounters (CCAE), Truven MarketScan(r) Multi state Medicaid (MDCD), and the Optum ClinFormatics(r) (Optum) database and one non-US database, the United Kingdom (UK) based Clinical Practice Research Datalink (CPRD). Pregnancy outcomes were classified as live births, stillbirths, abortions and ectopic pregnancies. Start dates were estimated using a derived hierarchy of available pregnancy markers, including records such as last menstrual period and nuchal ultrasound dates. Validation included clinical adjudication of 700 electronic Optum and CPRD pregnancy episode profiles to assess the operating characteristics of the algorithm, and a comparison of the algorithm's Optum pregnancy start estimates to starts based on dates of assisted conception procedures. Distributions of pregnancy outcome types were similar across all four data sources and pregnancy episode lengths found were as expected for all outcomes, excepting term lengths in episodes that used amenorrhea and urine pregnancy tests for start estimation. Validation survey results found highest agreement between reviewer chosen and algorithm operating characteristics for questions assessing pregnancy status and accuracy of outcome category with 99 100% agreement for Optum and CPRD. Outcome date agreement within seven days in either direction ranged from 95-100%, while start date agreement within seven days in either direction ranged from 90-97%. In Optum validation sensitivity analysis, a total of 73% of algorithm estimated starts for live births were in agreement with fertility procedure estimated starts within two weeks in either direction; ectopic pregnancy 77%, stillbirth 47%, and abortion 36%. An algorithm to infer live birth and ectopic pregnancy episodes and outcomes can be applied to multiple observational databases with acceptable accuracy for further epidemiologic research. Less accuracy was found for start date estimations in stillbirth and abortion outcomes in our sensitivity analysis, which may be expected given the nature of the outcomes. PMID- 29389969 TI - Spatial genetic structure within populations and management implications of the South American species Acacia aroma (Fabaceae). AB - The identification of factors that structure intraspecific diversity is of particular interest for biological conservation and restoration ecology. All rangelands in Argentina are currently experiencing some form of deterioration or desertification. Acacia aroma is a multipurpose species widely distributed throughout this country. In this study, we used the AFLP technique to study genetic diversity, population genetic structure, and fine-scale spatial genetic structure in 170 individuals belonging to 6 natural Argentinean populations. With 401 loci, the mean heterozygosity (HE = 0.2) and the mean percentage of polymorphic loci (PPL = 62.1%) coefficients indicated that the genetic variation is relatively high in A. aroma. The analysis with STRUCTURE showed that the number of clusters (K) was 3. With Geneland analysis, the number of clusters was K = 4, sharing the same grouping as STRUCTURE but dividing one population into two groups. When studying SGS, significant structure was detected in 3 of 6 populations. The neighbourhood size in these populations ranged from 15.2 to 64.3 individuals. The estimated gene dispersal distance depended on the effective population density and disturbance level and ranged from 45 to 864 m. The combined results suggest that a sampling strategy, which aims to maintain a considerable part of the variability contained in natural populations sampled here, would include at least 3 units defined by the clusters analyses that exhibit particular genetic properties. Moreover, the current SGS analysis suggests that within the wider management units/provinces, seed collection from A. aroma should target trees separated by a minimum distance of 50 m but preferably 150 m to reduce genetic relatedness among seeds from different trees. PMID- 29389971 TI - Gene/QTL discovery for Anthracnose in common bean (Phaseolus vulgaris L.) from North-western Himalayas. AB - Common bean (Phaseolus vulgaris L.) is one of the most important grain legume crops in the world. The beans grown in north-western Himalayas possess huge diversity for seed color, shape and size but are mostly susceptible to Anthracnose disease caused by seed born fungus Colletotrichum lindemuthianum. Dozens of QTLs/genes have been already identified for this disease in common bean world-wide. However, this is the first report of gene/QTL discovery for Anthracnose using bean germplasm from north-western Himalayas of state Jammu & Kashmir, India. A core set of 96 bean lines comprising 54 indigenous local landraces from 11 hot-spots and 42 exotic lines from 10 different countries were phenotyped at two locations (SKUAST-Jammu and Bhaderwah, Jammu) for Anthracnose resistance. The core set was also genotyped with genome-wide (91) random and trait linked SSR markers. The study of marker-trait associations (MTAs) led to the identification of 10 QTLs/genes for Anthracnose resistance. Among the 10 QTLs/genes identified, two MTAs are stable (BM45 & BM211), two MTAs (PVctt1 & BM211) are major explaining more than 20% phenotypic variation for Anthracnose and one MTA (BM211) is both stable and major. Six (06) genomic regions are reported for the first time, while as four (04) genomic regions validated the already known QTL/gene regions/clusters for Anthracnose. The major, stable and validated markers reported during the present study associated with Anthracnose resistance will prove useful in common bean molecular breeding programs aimed at enhancing Anthracnose resistance of local bean landraces grown in north-western Himalayas of state Jammu and Kashmir. PMID- 29389972 TI - Availability and accessibility of subsidized mammogram screening program in peninsular Malaysia: A preliminary study using travel impedance approach. AB - Access to healthcare is essential in the pursuit of universal health coverage. Components of access are availability, accessibility (spatial and non-spatial), affordability and acceptability. Measuring spatial accessibility is common approach to evaluating access to health care. This study aimed to determine the availability and spatial accessibility of subsidised mammogram screening in Peninsular Malaysia. Availability was determined from the number and distribution of facilities. Spatial accessibility was determined using the travel impedance approach to represent the revealed access as opposed to potential access measured by other spatial measurement methods. The driving distance of return trips from the respondent's residence to the facilities was determined using a mapping application. The travel expenditure was estimated by multiplying the total travel distance by a standardised travel allowance rate, plus parking fees. Respondents in this study were 344 breast cancer patients who received treatment at 4 referral hospitals between 2015 and 2016. In terms of availability, there were at least 6 major entities which provided subsidised mammogram programs. Facilities with mammogram involved with these programs were located more densely in the central and west coast region of the Peninsula. The ratio of mammogram facility to the target population of women aged 40-74 years ranged between 1: 10,000 and 1:80,000. In terms of accessibility, of the 3.6% of the respondents had undergone mammogram screening, their mean travel distance was 53.4 km (SD = 34.5, range 8 112 km) and the mean travel expenditure was RM 38.97 (SD = 24.00, range RM7.60 78.40). Among those who did not go for mammogram screening, the estimated travel distance and expenditure had a skewed distribution with median travel distance of 22.0 km (IQR 12.0, 42.0, range 2.0-340.0) and the median travel cost of RM 17.40 (IQR 10.40, 30.00, range 3.40-240.00). Higher travel impedance was noted among those who lived in sub-urban and rural areas. In summary, availability of mammogram facilities was good in the central and west coast of the peninsula. The overall provider-to-population ratio was lower than recommended. Based on the travel impedance approach used, accessibility to subsidised mammogram screening among the respondents was good in urban areas but deprived in other areas. This study was a preliminary study with limitations. Nonetheless, the evidence suggests that actions have to be taken to improve the accessibility to opportunistic mammogram screening in Malaysia in pursuit of universal health coverage. PMID- 29389970 TI - Decreased production of class-switched antibodies in neonatal B cells is associated with increased expression of miR-181b. AB - The increased susceptibility to infections of neonates is caused by an immaturity of the immune system as a result of both qualitative and quantitative differences between neonatal and adult immune cells. With respect to B cells, neonatal antibody responses are known to be decreased. Accountable for this is an altered composition of the neonatal B cell compartment towards more immature B cells. However, it remains unclear whether the functionality of individual neonatal B cell subsets is altered as well. In the current study we therefore compared phenotypical and functional characteristics of corresponding neonatal and adult B cell subpopulations. No phenotypic differences could be identified with the exception of higher IgM expression in neonatal B cells. Functional analysis revealed differences in proliferation, survival, and B cell receptor signaling. Most importantly, neonatal B cells showed severely impaired class-switch recombination (CSR) to IgG and IgA. This was associated with increased expression of miR-181b in neonatal B cells. Deficiency of miR-181b resulted in increased CSR. With this, our results highlight intrinsic differences that contribute to weaker B cell antibody responses in newborns. PMID- 29389973 TI - Adipocyte/breast cancer cell crosstalk in obesity interferes with the anti proliferative efficacy of tamoxifen. AB - BACKGROUND: Obesity is a well-known risk factor of breast cancer in post menopausal women that also correlates with a diminished therapeutic response. The influence of adipocytes and their secretome, i.e. adipokines, on the efficacy of hormone therapy has yet to be elucidated. METHODS: We investigated, ex vivo, whether mature adipocytes, differentiated from adipose stem cells of normal weight (MA20) or obese (MA30) women, and their secretions, were able to counteract the effects of tamoxifen (Tx) which is known to decrease neoplastic cell proliferation. RESULTS: In a tridimensional model and in a model of co culture, the anti-proliferative effect of Tx on MCF-7 cancer cells was counteracted by MA30. These two models highlighted two different specific gene expression profiles for genes encoding cytokines or involved in angiogenesis based on the adipocyte microenvironment and the treatment. Thus it notably showed altered expression of genes such as TNFalpha that correlated with IL-6. In addition, leptin, IL-6 and TNFalpha, at concentrations reflecting plasma concentrations in obese patients, decreased the anti-proliferative efficacy of 4 hydroxytamoxifen (a major active metabolite of Tx). CONCLUSIONS: These findings bring insights on adipocytes and mammary cancer cell interactions in Tx therapy, particularly in overweight/obese people. Indeed, patient' adipokine status would give valuable information for developing individual strategies and avoid resistance to treatment. PMID- 29389974 TI - Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics. AB - During tissue development, multipotent progenitors differentiate into specific cell types in characteristic spatial and temporal patterns. We addressed the mechanism linking progenitor identity and differentiation rate in the neural tube, where motor neuron (MN) progenitors differentiate more rapidly than other progenitors. Using single cell transcriptomics, we defined the transcriptional changes associated with the transition of neural progenitors into MNs. Reconstruction of gene expression dynamics from these data indicate a pivotal role for the MN determinant Olig2 just prior to MN differentiation. Olig2 represses expression of the Notch signaling pathway effectors Hes1 and Hes5. Olig2 repression of Hes5 appears to be direct, via a conserved regulatory element within the Hes5 locus that restricts expression from MN progenitors. These findings reveal a tight coupling between the regulatory networks that control patterning and neuronal differentiation and demonstrate how Olig2 acts as the developmental pacemaker coordinating the spatial and temporal pattern of MN generation. PMID- 29389975 TI - Does poor oral health status increase the risk of falls?: The JAGES Project Longitudinal Study. AB - We sought to examine if self-reported oral health conditions regarding difficulty eating tough foods, dry mouth, choking, number of teeth and denture use are associated with incident falls. Our study was based on panel data from the Japan Gerontological Evaluation Study conducted in 2010 and 2013 using self administered questionnaires. Data from 19,995 male and 20,858 female community dwelling older people aged >=65 years without a history of falls within the previous year in 2010 were analyzed. Multilevel logistic regression models were used to determine the association between poor oral health in 2010 and multiple incident falls in 2013 after adjusting for possible confounders and considering differences in municipalities. The percentage of males and females who reported falls in 2013 were 2.4% and 2.1%, respectively. After adjusting for age, educational attainment, equivalized income, depression, self-rated health, instrumental activities of daily living, body mass index, present illness related to falls, social participation, walking in min/day, alcohol drinking status, and municipality population density, dry mouth in males (odds ratio [OR] = 1.41; 95% confidence interval [CI]: 1.12-1.77) and choking in females (OR = 1.64; 95% CI: 1.27-2.11) were significantly associated with incident falls. Difficulty eating tough foods in both sexes and choking in males were marginally associated with incident falls (p<0.1). Females having 10-19 teeth without dentures (OR = 1.63; 95% CI: 1.14-2.31), <=9 teeth with dentures (OR = 1.36; 95% CI: 1.03-1.80), and <=9 without dentures (OR = 1.46; 95% CI: 1.02-2.08) were significantly associated with incident falls compared with those having >=20 teeth, respectively. These findings suggest that poor oral function, having fewer teeth, and not using dentures are predictors of incident falls. Further studies are needed to determine whether improving oral health can reduce the risk of falls. PMID- 29389976 TI - Dynamic re-immunization of off-treatment childhood cancer survivors: An implementation feasibility study. AB - There are no universally approved re-vaccination guidelines for non-transplant pediatric cancer survivors. We hypothesized that by utilizing a response-based re vaccination schedule, we could tailor vaccine schedules in off-treatment cancer survivors. Pre-vaccination antibody levels were obtained in 7 patients at an average of 20 days after the end of treatment date. In those without protective antibody levels, we administered vaccines 3 months after completion of treatment. Revaccinating patients 3 months after the end of treatment date resulted in protective antibody levels for most vaccines. We showed, on a preliminary basis, that vaccinating non-transplanted pediatric cancer survivors can be dynamically implemented in children with recovering immune function. PMID- 29389977 TI - An oxidized abasic lesion inhibits base excision repair leading to DNA strand breaks in a trinucleotide repeat tract. AB - Oxidative DNA damage and base excision repair (BER) play important roles in modulating trinucleotide repeat (TNR) instability that is associated with human neurodegenerative diseases and cancer. We have reported that BER of base lesions can lead to TNR instability. However, it is unknown if modifications of the sugar in an abasic lesion modulate TNR instability. In this study, we characterized the effects of the oxidized sugar, 5'-(2-phosphoryl-1,4-dioxobutane)(DOB) in CAG repeat tracts on the activities of key BER enzymes, as well as on repeat instability. We found that DOB crosslinked with DNA polymerase beta and inhibited its synthesis activity in CAG repeat tracts. Surprisingly, we found that DOB also formed crosslinks with DNA ligase I and inhibited its ligation activity, thereby reducing the efficiency of BER. This subsequently resulted in the accumulation of DNA strand breaks in a CAG repeat tract. Our study provides important new insights into the adverse effects of an oxidized abasic lesion on BER and suggests a potential alternate repair pathway through which an oxidized abasic lesion may modulate TNR instability. PMID- 29389979 TI - How do you perceive this author? Understanding and modeling authors' communication quality in social media. AB - In this study, we leverage human evaluations, content analysis, and computational modeling to generate a comprehensive analysis of readers' evaluations of authors' communication quality in social media with respect to four factors: author credibility, interpersonal attraction, communication competence, and intent to interact. We review previous research on the human evaluation process and highlight its limitations in providing sufficient information for readers to assess authors' communication quality. From our analysis of the evaluations of 1,000 Twitter authors' communication quality from 300 human evaluators, we provide empirical evidence of the impact of the characteristics of the reader (demographic, social media experience, and personality), author (profile and social media engagement), and content (linguistic, syntactic, similarity, and sentiment) on the evaluation of an author's communication quality. In addition, based on the author and message characteristics, we demonstrate the potential for building accurate models that can indicate an author's communication quality. PMID- 29389978 TI - Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment. AB - OBJECTIVES: To characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level. DESIGN: An autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls. METHODS: Plasma marker ('analyte') levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression. RESULTS: Plasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands. CONCLUSIONS: Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC vaccination in the setting of HIV-infection. PMID- 29389980 TI - Comparison of clinical manifestations and antibiotic resistances among three genospecies of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex. AB - The Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex has emerged as a high priority among hospital-acquired pathogens in intensive care units (ICUs), posing a challenge to infection management practices. In this study, the clinical characteristics, antimicrobial susceptibility patterns, and patients outcome among genospecies were retrospectively compared. Samples were taken from the tracheal secretions of 143 patients in the ICU. Genospecies of the ACB complex were discriminated by analysis of the 16S-23S rRNA gene intergenic spacer (ITS) sequence. Univariate and multiple variable logistic regression analyses were performed to identify risk factors for infection and mortality. Three genospecies were isolated: A. baumannii (73, 51.0%), A. nosocomialis (29, 20.3%), and A. pittii (41, 28.7%). The results showed that the distribution of infection and colonization among the three genospecies were the same, while A. baumannii was more resistant to common antibiotics than A. nosocomialis and A. pittii. Advanced age, a long stay in the ICU, acute physiology and chronic health evaluation (APACHE) II score, the use of a mechanical ventilator, and previous antibiotic use were risk factors for patient infection. The APACHE II score was a risk factor for mortality in patients with ACB complex isolated from tracheal secretions. Poor outcome of patients with ACB complex isolated from tracheal secretion appears to be related to the APACHE II score rather than genospecies. PMID- 29389982 TI - Vineyard water status assessment using on-the-go thermal imaging and machine learning. AB - The high impact of irrigation in crop quality and yield in grapevine makes the development of plant water status monitoring systems an essential issue in the context of sustainable viticulture. This study presents an on-the-go approach for the estimation of vineyard water status using thermal imaging and machine learning. The experiments were conducted during seven different weeks from July to September in season 2016. A thermal camera was embedded on an all-terrain vehicle moving at 5 km/h to take on-the-go thermal images of the vineyard canopy at 1.2 m of distance and 1.0 m from the ground. The two sides of the canopy were measured for the development of side-specific and global models. Stem water potential was acquired and used as reference method. Additionally, reference temperatures Tdry and Twet were determined for the calculation of two thermal indices: the crop water stress index (CWSI) and the Jones index (Ig). Prediction models were built with and without considering the reference temperatures as input of the training algorithms. When using the reference temperatures, the best models casted determination coefficients R2 of 0.61 and 0.58 for cross validation and prediction (RMSE values of 0.190 MPa and 0.204 MPa), respectively. Nevertheless, when the reference temperatures were not considered in the training of the models, their performance statistics responded in the same way, returning R2 values up to 0.62 and 0.65 for cross validation and prediction (RMSE values of 0.190 MPa and 0.184 MPa), respectively. The outcomes provided by the machine learning algorithms support the use of thermal imaging for fast, reliable estimation of a vineyard water status, even suppressing the necessity of supervised acquisition of reference temperatures. The new developed on-the-go method can be very useful in the grape and wine industry for assessing and mapping vineyard water status. PMID- 29389981 TI - A high HIV-1 strain variability in London, UK, revealed by full-genome analysis: Results from the ICONIC project. AB - BACKGROUND & METHODS: The ICONIC project has developed an automated high throughput pipeline to generate HIV nearly full-length genomes (NFLG, i.e. from gag to nef) from next-generation sequencing (NGS) data. The pipeline was applied to 420 HIV samples collected at University College London Hospitals NHS Trust and Barts Health NHS Trust (London) and sequenced using an Illumina MiSeq at the Wellcome Trust Sanger Institute (Cambridge). Consensus genomes were generated and subtyped using COMET, and unique recombinants were studied with jpHMM and SimPlot. Maximum-likelihood phylogenetic trees were constructed using RAxML to identify transmission networks using the Cluster Picker. RESULTS: The pipeline generated sequences of at least 1Kb of length (median = 7.46Kb, IQR = 4.01Kb) for 375 out of the 420 samples (89%), with 174 (46.4%) being NFLG. A total of 365 sequences (169 of them NFLG) corresponded to unique subjects and were included in the down-stream analyses. The most frequent HIV subtypes were B (n = 149, 40.8%) and C (n = 77, 21.1%) and the circulating recombinant form CRF02_AG (n = 32, 8.8%). We found 14 different CRFs (n = 66, 18.1%) and multiple URFs (n = 32, 8.8%) that involved recombination between 12 different subtypes/CRFs. The most frequent URFs were B/CRF01_AE (4 cases) and A1/D, B/C, and B/CRF02_AG (3 cases each). Most URFs (19/26, 73%) lacked breakpoints in the PR+RT pol region, rendering them undetectable if only that was sequenced. Twelve (37.5%) of the URFs could have emerged within the UK, whereas the rest were probably imported from sub-Saharan Africa, South East Asia and South America. For 2 URFs we found highly similar pol sequences circulating in the UK. We detected 31 phylogenetic clusters using the full dataset: 25 pairs (mostly subtypes B and C), 4 triplets and 2 quadruplets. Some of these were not consistent across different genes due to inter- and intra-subtype recombination. Clusters involved 70 sequences, 19.2% of the dataset. CONCLUSIONS: The initial analysis of genome sequences detected substantial hidden variability in the London HIV epidemic. Analysing full genome sequences, as opposed to only PR+RT, identified previously undetected recombinants. It provided a more reliable description of CRFs (that would be otherwise misclassified) and transmission clusters. PMID- 29389983 TI - Molecular typing of Legionella pneumophila isolates from environmental water samples and clinical samples using a five-gene sequence typing and standard Sequence-Based Typing. AB - Inadequate discriminatory power to distinguish between L. pneumophila isolates, especially those belonging to disease-related prevalent sequence types (STs) such as ST1, ST36 and ST47, is an issue of SBT scheme. In this study, we developed a multilocus sequence typing (MLST) scheme based on two non-virulence loci (trpA, cca) and three virulence loci (icmK, lspE, lssD), to genotype 110 L. pneumophila isolates from various natural and artificial water sources in Guangdong province of China, and compared with the SBT. The isolates were assigned to 33 STs of the SBT and 91 new sequence types (nSTs) of the MLST. The indices of discrimination (IODs) of SBT and MLST were 0.920 and 0.985, respectively. Maximum likelihood trees of the concatenated SBT and MLST sequences both showed distinct phylogenetic relationships between the isolates from the two environments. More intragenic recombinations were detected in nSTs than in STs, and they were both more abundant in natural water isolates. We found out the MLST had a high discriminatory ability for the disease-associated ST1 isolates: 22 ST1 isolates were assigned to 19 nSTs. Furthermore, we assayed the discrimination of the MLST for 29 reference strains (19 clinical and 10 environmental). The clinical strains were assigned to eight STs and ten nSTs. The MLST could also subtype the prevalent clinical ST36 or ST47 strains: eight ST36 strains were subtyped into three nSTs and two ST47 strains were subtyped into two nSTs. We found different distribution patterns of nSTs between the environmental and clinical ST36 isolates, and between the outbreak clinical ST36 isolates and the sporadic clinical ST36 isolates. These results together revealed the MLST scheme could be used as part of a typing scheme that increased discrimination when necessary. PMID- 29389984 TI - Systematic dysphagia screening and dietary modifications to reduce stroke associated pneumonia rates in a stroke-unit. AB - BACKGROUND AND PURPOSE: While formal screening for dysphagia following acute stroke is strongly recommended, there is little evidence on how multi-consistency screening and dietary modifications affect the rate of stroke-associated pneumonia (SAP). This observational study reports which factors affect formal screening on a stroke-unit and how dietary recommendations relate to SAP. METHOD: Analyses from a database including 1394 patients admitted with acute stroke at our stroke-unit in Austria between 2012 and 2014. Dietary modifications were performed following the recommendations from the Gugging Swallowing Screen (GUSS). Patients evaluated with GUSS were compared to the unscreened patients. RESULTS: Overall, 993 (71.2%) patients were screened with GUSS; of these 50 (5.0%) developed SAP. In the 401 unscreened patients, the SAP rate was similar: 22 (5.5%). Multivariable analysis showed that either mild to very mild strokes or very severe strokes were less likely to undergo formal screening. Older age, pre existing disability, history of hypertension, atrial fibrillation, stroke severity, cardiological and neurological complications, nasogastric tubes, and intubation were significant markers for SAP. Out of 216 patients, 30 (13.9%) developed SAP in spite of receiving nil per mouth (NPO). CONCLUSION: The routine use of GUSS is less often applied in either mild strokes or very severe strokes. While most patients with high risk of SAP were identified by GUSS and assigned to NPO, dietary modifications could not prevent SAP in 1 of 7 cases. Other causes of SAP such as silent aspiration, bacteraemia or central breathing disturbances should be considered. PMID- 29389985 TI - Multiband multi-echo simultaneous ASL/BOLD for task-induced functional MRI. AB - Typical simultaneous blood oxygenation-level dependent (BOLD) and arterial spin labeling (ASL) sequences acquire two echoes, one perfusion-sensitive and one BOLD sensitive. However, for ASL, spatial resolution and brain coverage are limited due to the T1 decay of the labeled blood. This study applies a sequence combining a multiband acquisition with four echoes for simultaneous BOLD and pseudo continuous ASL (pCASL) echo planar imaging (MBME ASL/BOLD) for block-design task fMRI. A multiband acceleration of four was employed to increase brain coverage and reduce slice-timing effects on the ASL signal. Multi-echo independent component analysis (MEICA) was implemented to automatically denoise the BOLD signal by regressing non-BOLD components. This technique led to increased temporal signal-to-noise ratio (tSNR) and BOLD sensitivity. The MEICA technique was also modified to denoise the ASL signal by regressing artifact and BOLD signals from the first echo time-series. The MBME ASL/BOLD sequence was applied to a finger-tapping task functional MRI (fMRI) experiment. Signal characteristics and activation were evaluated using single echo BOLD, combined ME BOLD, combined ME BOLD after MEICA denoising, perfusion-weighted (PW), and perfusion-weighted after MEICA denoising time-series. The PW data was extracted using both surround subtraction and high-pass filtering followed by demodulation. In addition, the CBF/BOLD response ratio and CBF/BOLD coupling were analyzed. Results showed that the MEICA denoising procedure significantly improved the BOLD signal, leading to increased BOLD sensitivity, tSNR, and activation statistics compared to conventional single echo BOLD data. At the same time, the denoised PW data showed increased tSNR and activation statistics compared to the non-denoised PW data. CBF/BOLD coupling was also increased using the denoised ASL and BOLD data. Our preliminary data suggest that the MBME ASL/BOLD sequence can be employed to collect whole-brain task-fMRI with improved data quality for both BOLD and PW time series, thus improving the results of block-design task fMRI. PMID- 29389987 TI - Ten simple rules for writing a popular science book. PMID- 29389986 TI - Combining multi-modality data for searching biomarkers in schizophrenia. AB - Identification of imaging biomarkers for schizophrenia is an important but still challenging problem. Even though considerable efforts have been made over the past decades, quantitative alterations between patients and healthy subjects have not yet provided a diagnostic measure with sufficient high sensitivity and specificity. One of the most important reasons is the lack of consistent findings, which is in part due to single-mode study, which only detects single dimensional information by each modality, and thus misses the most crucial differences between groups. Here, we hypothesize that multimodal integration of functional MRI (fMRI), structural MRI (sMRI), and diffusion tensor imaging (DTI) might yield more power for the diagnosis of schizophrenia. A novel multivariate data fusion method for combining these modalities is introduced without reducing the dimension or using the priors from 161 schizophrenia patients and 168 matched healthy controls. The multi-index feature for each ROI is constructed and summarized with Wilk's lambda by performing multivariate analysis of variance to calculate the significant difference between different groups. Our results show that, among these modalities, fMRI has the most significant featureby calculating the Jaccard similarity coefficient (0.7416) and Kappa index (0.4833). Furthermore, fusion of these modalities provides the most plentiful information and the highest predictive accuracy of 86.52%. This work indicates that multimodal integration can improve the ability of distinguishing differences between groups and might be assisting in further diagnosis of schizophrenia. PMID- 29389988 TI - Implication of trans-11,trans-13 conjugated linoleic acid in the development of hepatic steatosis. AB - SCOPE: Conjugated linoleic acids are linoleic acid isomers found in the diet that can also be produced through bacterial metabolism of polyunsaturated fatty acids. Our objective was to evaluate the contribution of fatty acid metabolites produced from polyunsaturated fatty acids by the gut microbiota in vivo to regulation of hepatic lipid metabolism and steatosis. METHODS AND RESULTS: In mice with depleted n-3 polyunsaturated fatty acids, we observed an accumulation of trans 11,trans-13 CLA and cis-9,cis-11 conjugated linoleic acids in the liver tissue that were associated with an increased triglyceride content and expression of lipogenic genes. We used an in vitro model to evaluate the impact of these two conjugated linoleic acids on hepatic lipid metabolism. In HepG2 cells, we observed that only trans-11,trans-13 conjugated linoleic acids recapitulated triglyceride accumulation and increased lipogenic gene expression, which is a phenomenon that may implicate the nuclear factors sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP). CONCLUSION: The trans-11,trans-13 conjugated linoleic acids can stimulate hepatic lipogenesis, which supports the conclusion that gut microbiota and related metabolites should be considered in the treatment of non-alcoholic liver disease. PMID- 29389989 TI - Comparing fixed sampling with minimizer sampling when using k-mer indexes to find maximal exact matches. AB - Bioinformatics applications and pipelines increasingly use k-mer indexes to search for similar sequences. The major problem with k-mer indexes is that they require lots of memory. Sampling is often used to reduce index size and query time. Most applications use one of two major types of sampling: fixed sampling and minimizer sampling. It is well known that fixed sampling will produce a smaller index, typically by roughly a factor of two, whereas it is generally assumed that minimizer sampling will produce faster query times since query k mers can also be sampled. However, no direct comparison of fixed and minimizer sampling has been performed to verify these assumptions. We systematically compare fixed and minimizer sampling using the human genome as our database. We use the resulting k-mer indexes for fixed sampling and minimizer sampling to find all maximal exact matches between our database, the human genome, and three separate query sets, the mouse genome, the chimp genome, and an NGS data set. We reach the following conclusions. First, using larger k-mers reduces query time for both fixed sampling and minimizer sampling at a cost of requiring more space. If we use the same k-mer size for both methods, fixed sampling requires typically half as much space whereas minimizer sampling processes queries only slightly faster. If we are allowed to use any k-mer size for each method, then we can choose a k-mer size such that fixed sampling both uses less space and processes queries faster than minimizer sampling. The reason is that although minimizer sampling is able to sample query k-mers, the number of shared k-mer occurrences that must be processed is much larger for minimizer sampling than fixed sampling. In conclusion, we argue that for any application where each shared k-mer occurrence must be processed, fixed sampling is the right sampling method. PMID- 29389990 TI - Standardization and reference ranges for whole blood platelet function measurements using a flow cytometric platelet activation test. AB - INTRODUCTION: Platelet function testing with flow cytometry has additional value to existing platelet function testing for diagnosing bleeding disorders, monitoring anti-platelet therapy, transfusion medicine and prediction of thrombosis. The major challenge is to use this technique as a diagnostic test. The aim of this study is to standardize preparation, optimization and validation of the test kit and to determine reference values in a population of 129 healthy individuals. METHODS: Platelet function tests with 3 agonists and antibodies against P-selectin, activated alphaIIbbeta3 and glycoprotein Ib (GPIb), were prepared and stored at -20 degrees C until used. Diluted whole blood was added and platelet activation was quantified by the density of activation markers, using flow cytometry. Anti-mouse Ig kappa particles were included to validate stability of the test and to standardize results. Reference intervals were determined. RESULTS: Blood stored at room temperature (RT) for up to 4h after blood donation and preheated/tested at 37 degrees C resulted in stable results (%CV<10%), in contrast to measuring at RT. The intra-assay %CV was <5%. Incubation of anti-mouse Ig kappa particles with antibodies stored for up to 12 months proved to give a stable fluorescence. The inter-individual variation measured in the 129 individuals varied between 23% and 37% for P-selectin expression and alphaIIbbeta3 activation, respectively. CONCLUSIONS: The current study contributes to the translation of flow cytometry based platelet function testing from a scientific tool to a diagnostic test. Platelet function measurements, using prepared and stored platelet activation kits, are reproducible if executed at 37 degrees C. The reference ranges can be validated in clinical laboratories and ongoing studies are investigating if reduced platelet reactivity in patients with bleeding complications can be detected. PMID- 29389991 TI - Strengths use as a secret of happiness: Another dimension of visually impaired individuals' psychological state. AB - It is well recognized that visual impairments (VI) worsen individuals' mental condition. However, little is known about the positive aspects including subjective happiness, positive emotions, and strengths. Therefore, the purpose of this study was to investigate the positive aspects of persons with VI including their subjective happiness, positive emotions, and strengths use. Positive aspects of persons with VI were measured using the Subjective Happiness Scale (SHS), the Scale of Positive and Negative Experience-Balance (SPANE-B), and the Strengths Use Scale (SUS). A cross-sectional analysis was utilized to examine personal information in a Tokyo sample (N = 44). We used a simple regression analysis and found significant relationships between the SHS or SPANE-B and SUS; on the contrary, VI-related variables were not correlated with them. A multiple regression analysis confirmed that SUS was a significant factor associated with both the SHS and SPANE-B. Strengths use might be a possible protective factor from the negative effects of VI. PMID- 29389992 TI - TRIM proteins: New players in virus-induced autophagy. PMID- 29389993 TI - Effects of six common dietary nutrients on murine intestinal organoid growth. AB - The intestinal epithelium of the gastrointestinal (GI) tract constantly renews itself to absorb nutrients and provide protection for the body from the outside world. Since the intestinal epithelium is constantly exposed to various chemicals and dietary components, it is critical to determine which constituents promote or inhibit intestinal epithelium health and growth rate. Intestinal organoids, three dimensional miniature models of the intestines, represent an ex vivo tool to investigate intestinal physiology and growth patterns. In this study, we measured the growth rates of murine intestinal organoids exposed to various concentrations of different dietary constituents. Results indicate that caffeic acid inhibited organoid growth in a concentration-dependent manner, curcumin exhibited variable effectiveness, and vitamin C had no effect on organoid growth. PMID- 29389994 TI - Factors associated with patient recall of key information in ambulatory specialty care visits: Results of an innovative methodology. AB - While some studies have assessed patient recall of important information from ambulatory care visits, none has done so recently. Furthermore, little is known about features of clinical interactions which are associated with patient understanding and recall, without which shared decision making, a widely shared ideal for patient care, cannot occur. Our objective was to evaluate characteristics of patients and outpatient encounters associated with patient recall of information after one week, along with observation of elements of shared decision making. This was an observational study based on coded transcripts of 189 outpatient encounters, and post-visit interviews with patients 1 week later. Coding used three previously validated systems, adopted for this study. Forty-nine percent of decisions and recommendations were recalled accurately without prompting; 36% recalled with a prompt; 15% recalled erroneously or not at all. Provider behaviors hypothesized to be associated with patient recall, such as open-questioning and "teach back," were rare. Patients with less than high school education recalled 38% of items freely and accurately, while patients with a college degree recalled 65% (p < .0001). In a multivariate model, the total number of items to be recalled per visit, and percentage of utterances in decision-making processes by the provider ("verbal dominance"), were significant predictors of poorer recall. The item count was associated with poorer recall for lower, but not higher, educated patients. PMID- 29389995 TI - Has the free maternal health policy eliminated out of pocket payments for maternal health services? Views of women, health providers and insurance managers in Northern Ghana. AB - INTRODUCTION: The free maternal health policy was implemented in Ghana in 2008 under the National Health Insurance Scheme (NHIS). The policy sought to eliminate out of pocket (OOP) payments and enhance the utilisation of maternal health services. It is unclear whether the policy had altered OOP payments for services. The study explored views on costs and actual OOP payments during pregnancy. The source of funding for payments was also explored. METHODS: A convergent parallel mixed methods design, involving quantitative and qualitative data collection approaches. The study was set in the Kassena-Nankana municipality, a rural area in Ghana. Women (n = 406) who utilised services during pregnancy were surveyed. Also, 10 focus groups discussions (FGDs) were held with women who used services during pregnancy as well as 28 in-depth interviews (IDIs) with midwives/nurses (n = 25) and insurance managers/directors (n = 3). The survey was analysed using descriptive statistics, focussing on costs from the women's perspective. Qualitative data were audio recorded, transcribed and translated verbatim into English where necessary. The transcripts were read and coded into themes and sub themes. RESULTS: The NHIS did not cover all expenses in relation to maternal health services. The overall mean for OOP cost during pregnancy was GHc17.50 (US$8.60). Both FGDs and IDIs showed that women especially paid for drugs and ultrasound scan services. Sixty-five percent of the women used savings, whilst twenty-two percent sold assets to meet the OOP cost. Some women were unable to afford payments due to poverty and had to forgo treatment. Participants called for payments to be eliminated and for the NHIS to absorb the cost of emergency referrals. All participants admitted the benefits of the policy. CONCLUSION: Women needed to make payments despite the policy. Measures should be put in place to eliminate payments to enable all women to receive services and promote universal health coverage. PMID- 29389996 TI - A new item response theory model to adjust data allowing examinee choice. AB - In a typical questionnaire testing situation, examinees are not allowed to choose which items they answer because of a technical issue in obtaining satisfactory statistical estimates of examinee ability and item difficulty. This paper introduces a new item response theory (IRT) model that incorporates information from a novel representation of questionnaire data using network analysis. Three scenarios in which examinees select a subset of items were simulated. In the first scenario, the assumptions required to apply the standard Rasch model are met, thus establishing a reference for parameter accuracy. The second and third scenarios include five increasing levels of violating those assumptions. The results show substantial improvements over the standard model in item parameter recovery. Furthermore, the accuracy was closer to the reference in almost every evaluated scenario. To the best of our knowledge, this is the first proposal to obtain satisfactory IRT statistical estimates in the last two scenarios. PMID- 29389997 TI - Rhodopsin optogenetic toolbox v2.0 for light-sensitive excitation and inhibition in Caenorhabditis elegans. AB - In optogenetics, rhodopsins were established as light-driven tools to manipulate neuronal activity. However, during long-term photostimulation using channelrhodopsin (ChR), desensitization can reduce effects. Furthermore, requirement for continuous presence of the chromophore all-trans retinal (ATR) in model systems lacking sufficient endogenous concentrations limits its applicability. We tested known, and engineered and characterized new variants of de- and hyperpolarizing rhodopsins in Caenorhabditis elegans. ChR2 variants combined previously described point mutations that may synergize to enable prolonged stimulation. Following brief light pulses ChR2(C128S;H134R) induced muscle activation for minutes or even for hours ('Quint': ChR2(C128S;L132C;H134R;D156A;T159C)), thus featuring longer open state lifetime than previously described variants. Furthermore, stability after ATR removal was increased compared to the step-function opsin ChR2(C128S). The double mutants C128S;H134R and H134R;D156C enabled increased effects during repetitive stimulation. We also tested new hyperpolarizers (ACR1, ACR2, ACR1(C102A), ZipACR). Particularly ACR1 and ACR2 showed strong effects in behavioral assays and very large currents with fast kinetics. In sum, we introduce highly light sensitive optogenetic tools, bypassing previous shortcomings, and thus constituting new tools that feature high effectiveness and fast kinetics, allowing better repetitive stimulation or investigating prolonged neuronal activity states in C. elegans and, possibly, other systems. PMID- 29389998 TI - Whom to treat? Factors associated with chemotherapy recommendations and outcomes among patients with NHL at the Uganda Cancer Institute. AB - INTRODUCTION: Cancer treatment options in sub-Saharan Africa are scarce despite an increasing burden of disease. Identification of those cancer patients who would benefit most from the limited resources available would allow broader and more effective therapy. METHODS: We conducted a retrospective analysis of patients over the age of 18 at the time of a pathologic diagnosis of NHL between 2003 and 2010 who were residents of Kyandondo County (Uganda) and presented to the Uganda Cancer Institute for care. RESULTS: A total of 128 patients were included in this analysis. Chemotherapy was recommended to 117 (91.4%) of the patients; the odds of recommending chemotherapy decreased for each additional month of reported symptoms prior to diagnosis. Of the 117 patients to whom chemotherapy was recommended, 111 (86.7%) patients received at least 1 cycle of chemotherapy; HIV infected patients, as well as those with a lower hemoglobin and advanced disease at the time of diagnosis were significantly less likely to complete therapy. Among the patients who initiated chemotherapy, twenty patients died prior to treatment completion (including nine who died within 30 days). Hemoglobin level at the time of presentation was the only variable associated with early mortality in the adjusted model. CONCLUSION: In resource-poor areas, it is essential to align health care expenditures with interventions likely to provide benefit to affected populations. Targeting cancer therapy to those with a favorable chance of responding will not only save limited resources, but will also prevent harm in those patients unlikely to realize an effect of cancer directed therapy. PMID- 29390000 TI - Increasing sensitivity of methane emission measurements in rice through deployment of 'closed chambers' at nighttime. AB - This study comprises field experiments on methane emissions from rice fields conducted with an Eddy-Covariance (EC) system as well as test runs for a modified closed chamber approach based on measurements at nighttime. The EC data set covers 4 cropping seasons with highly resolved emission rates (raw data in 10 Hz frequency have been aggregated to 30-min records). The diel patterns were very pronounced in the two dry seasons with peak emissions at early afternoon and low emissions at nighttime. These diel patterns were observed at all growing stages of the dry seasons. In the two wet seasons, the diel patterns were only visible during the vegetative stages while emission rates during reproductive and ripening stages remained within a fairly steady range and did not show any diel patterns. In totality, however, the data set revealed a very strong linear relationship between nocturnal emissions (12-h periods) and the full 24-h periods resulting in an R2-value of 0.8419 for all data points. In the second experiment, we conducted test runs for chamber measurements at nighttime with much longer deployment times (6 h) as compared to measurements at daylight (typically for 30 min). Conducting chamber measurements at nighttime excluded drastic changes of temperatures and CO2 concentrations. The data also shows that increases in CH4 concentrations remained on linear trajectory over a 6h period at night. While end CH4 concentrations were consistently >3.5 ppm, this long-term enclosure represents a very robust approach to quantify emissions as compared to assessing short-term concentration increases over time near the analytical detection limit. Finally, we have discussed the potential applications of this new approach that would allow emission measurements even when conventional (daytime) measurements will not be suitable. Nighttime chamber measurements offer an alternative to conventional (daytime) measurements if either (i) baseline emissions are at a very low level, (ii) differences of tested crop treatments or varieties are very small or (iii) the objective is to screen a large number of rice varieties for taking advantage of progress in genome sequencing. PMID- 29389999 TI - Chinmo prevents transformer alternative splicing to maintain male sex identity. AB - Reproduction in sexually dimorphic animals relies on successful gamete production, executed by the germline and aided by somatic support cells. Somatic sex identity in Drosophila is instructed by sex-specific isoforms of the DMRT1 ortholog Doublesex (Dsx). Female-specific expression of Sex-lethal (Sxl) causes alternative splicing of transformer (tra) to the female isoform traF. In turn, TraF alternatively splices dsx to the female isoform dsxF. Loss of the transcriptional repressor Chinmo in male somatic stem cells (CySCs) of the testis causes them to "feminize", resembling female somatic stem cells in the ovary. This somatic sex transformation causes a collapse of germline differentiation and male infertility. We demonstrate this feminization occurs by transcriptional and post-transcriptional regulation of traF. We find that chinmo-deficient CySCs upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir) and Female lethal (2)d (Fl(2)d). traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation. Surprisingly, CySC feminization upon loss of chinmo does not require Sxl but does require Vir and Fl(2)d. Consistent with this, we show that both Vir and Fl(2)d are required for tra alternative splicing in the female somatic gonad. Our work reveals the need for transcriptional regulation of tra in adult male stem cells and highlights a previously unobserved Sxl-independent mechanism of traF production in vivo. In sum, transcriptional control of the sex determination hierarchy by Chinmo is critical for sex maintenance in sexually dimorphic tissues and is vital in the preservation of fertility. PMID- 29390001 TI - Acute effects of different dynamic exercises on hamstring strain risk factors. AB - The purpose of the study was to examine the acute effects of different dynamic exercise interventions on hamstring muscle performance. Thirty-six young men with poor hamstring flexibility were randomly assigned to three intervention groups: jogging combined with dynamic open kinetic chain stretching (DS), jogging combined with dynamic closed kinetic chain stretching (lunge with eccentric hamstring windmills, LEC), and jogging only (CON) groups. Hamstring flexibility, muscle stiffness (area under the curve, AUC), joint position sense (JPS), maximal eccentric strength (ECC), and angle of peak torque (APT) were recorded before and immediately after the exercise interventions. The results showed that the hamstring flexibility increased in DS (p < 0.001); muscle stiffness decreased in DS and was lower than jogging (p < 0.001). Moreover, ECC increased in LEC and was higher than jogging and DS (p < 0.001). APT was different among 3 groups (p < 0.001). Decreased accuracy of JPS was found in DS and jogging (p < 0.001). In conclusion, the dynamic closed kinetic chain stretching (LEC) as compared to open kinetic chain stretching (DS) or jogging group, may be an effective technique to enhance muscle performance during the pre-competition warm-up routine. PMID- 29390002 TI - Mortality and years of life lost by colorectal cancer attributable to physical inactivity in Brazil (1990-2015): Findings from the Global Burden of Disease Study. AB - INTRODUCTION: The aims of this study were to estimate all-cause and cause specific mortality and years of life lost, investigated by disability-adjusted life-years (DALYs), due to colorectal cancer attributable to physical inactivity in Brazil and in the states; to analyze the temporal trend of these estimates over 25 years (1990-2015) compared with global estimates and according to the socioeconomic status of states of Brazil. METHODS: Databases from the Global Burden of Disease Study (GBD) for Brazil, Brazilian states and global information were used. It was estimated the total number and the age-standardized rates of deaths and DALYs for colorectal cancer attributable to physical inactivity in the years 1990 and 2015. We used the Socioeconomic Development Index (SDI). RESULTS: Physical inactivity was responsible for a substantial number of deaths (1990: 1,302; 2015: 119,351) and DALYs (1990: 31,121; 2015: 87,116) due to colorectal cancer in Brazil. From 1990 to 2015, the mortality and DALYs due to colorectal cancer attributable to physical inactivity increased in Brazil (0.6% and 0.6%, respectively) and decreased around the world (-0.8% and -1.1%, respectively). The Brazilian states with better socioeconomic indicators had higher rates of mortality and morbidity by colorectal cancer due to physical inactivity (p<0.01). Physical inactivity was responsible for deaths and DALYs due to colorectal cancer in Brazil. CONCLUSIONS: Over 25 years, the Brazilian population showed more worrisome results than around the world. Actions to combat physical inactivity and greater cancer screening and treatment are urgent in the Brazilian states. PMID- 29390003 TI - Correction: Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage. AB - [This corrects the article DOI: 10.1371/journal.pone.0179199.]. PMID- 29390004 TI - The development and application of bioinformatics core competencies to improve bioinformatics training and education. AB - Bioinformatics is recognized as part of the essential knowledge base of numerous career paths in biomedical research and healthcare. However, there is little agreement in the field over what that knowledge entails or how best to provide it. These disagreements are compounded by the wide range of populations in need of bioinformatics training, with divergent prior backgrounds and intended application areas. The Curriculum Task Force of the International Society of Computational Biology (ISCB) Education Committee has sought to provide a framework for training needs and curricula in terms of a set of bioinformatics core competencies that cut across many user personas and training programs. The initial competencies developed based on surveys of employers and training programs have since been refined through a multiyear process of community engagement. This report describes the current status of the competencies and presents a series of use cases illustrating how they are being applied in diverse training contexts. These use cases are intended to demonstrate how others can make use of the competencies and engage in the process of their continuing refinement and application. The report concludes with a consideration of remaining challenges and future plans. PMID- 29390005 TI - Design and construction of an optimized transmit/receive hybrid birdcage resonator to improve full body images of medium-sized animals in 7T scanner. AB - The purpose of this work was to develop an optimized transmit/receive birdcage coil to extend the possibilities of a 7T preclinical MRI system to conduct improved full body imaging in medium-sized animals, such as large New Zealand rabbits. The coil was designed by combining calculation and electromagnetic simulation tools. The construction was based on precise mechanical design and careful building practice. A 16-leg, 20 cm long, 16 cm inner diameter, shielded quadrature hybrid structure was selected. Coil parameters were assessed on the bench and images were acquired on phantoms and rabbits. The results were compared to simulations and data obtained with an available commercial coil. An inexpensive assembly with an increase of 2 cm in useful inner diameter and 50 Omega matching with larger animals was achieved. A reduction in radiofrequency (RF) power demand of 31.8%, an improvement in image uniformity of 18.5 percentage points and an increase in signal-to-noise ratio of up to 42.2% were revealed by phantom image acquisitions, which was confirmed by in vivo studies. In conclusion, the proposed coil extended the possibilities of a preclinical 7T system as it improved image studies in relatively large animals by reducing the RF power demand, and increasing image uniformity and signal-to-noise ratio. Shorter scans and time under anesthesia or reduced RF exposure, resulting in better images and lower animal health risk during in vivo experiments, were achieved. PMID- 29390006 TI - Altering lipid droplet homeostasis affects Coxiella burnetii intracellular growth. AB - Coxiella burnetii is an obligate intracellular bacterial pathogen and a causative agent of culture-negative endocarditis. While C. burnetii initially infects alveolar macrophages, it has also been found in lipid droplet (LD)-containing foamy macrophages in the cardiac valves of endocarditis patients. In addition, transcriptional studies of C. burnetii-infected macrophages reported differential regulation of the LD coat protein-encoding gene perilipin 2 (plin-2). To further investigate the relationship between LDs and C. burnetii, we compared LD numbers using fluorescence microscopy in mock-infected and C. burnetii-infected alveolar macrophages. On average, C. burnetii-infected macrophages contained twice as many LDs as mock-infected macrophages. LD numbers increased as early as 24 hours post infection, an effect reversed by blocking C. burnetii protein synthesis. The observed LD accumulation was dependent on the C. burnetii Type 4B Secretion System (T4BSS), a major virulence factor that manipulates host cellular processes by secreting bacterial effector proteins into the host cell cytoplasm. To determine the importance of LDs during C. burnetii infection, we manipulated LD homeostasis and assessed C. burnetii intracellular growth. Surprisingly, blocking LD formation with the pharmacological inhibitors triacsin C or T863, or knocking out acyl-CoA transferase-1 (acat-1) in alveolar macrophages, increased C. burnetii growth at least 2-fold. Conversely, preventing LD lipolysis by inhibiting adipose triglyceride lipase (ATGL) with atglistatin almost completely blocked bacterial growth, suggesting LD breakdown is essential for C. burnetii. Together these data suggest that maintenance of LD homeostasis, possibly via the C. burnetii T4BSS, is critical for bacterial growth. PMID- 29390007 TI - Fagaceae tree species allocate higher fraction of nitrogen to photosynthetic apparatus than Leguminosae in Jianfengling tropical montane rain forest, China. AB - Variation in photosynthetic-nitrogen use efficiency (PNUE) is generally affected by several factors such as leaf nitrogen allocation and leaf diffusional conductances to CO2, although it is still unclear which factors significantly affect PNUE in tropical montane rain forest trees. In this study, comparison of PNUE, photosynthetic capacity, leaf nitrogen allocation, and diffusional conductances to CO2 between five Fagaceae tree species and five Leguminosae tree species were analyzed in Jianfengling tropical montane rain forest, Hainan Island, China. The result showed that PNUE of Fagaceae was significantly higher than that of Leguminosae (+35.5%), attributed to lower leaf nitrogen content per area (Narea, -29.4%). The difference in nitrogen allocation was the main biochemical factor that influenced interspecific variation in PNUE of these tree species. Fagaceae species allocated a higher fraction of leaf nitrogen to the photosynthetic apparatus (PP, +43.8%), especially to Rubisco (PR, +50.0%) and bioenergetics (PB +33.3%) in comparison with Leguminosae species. Leaf mass per area (LMA) of Leguminosae species was lower than that of Fagaceae species ( 15.4%). While there was no significant difference shown for mesophyll conductance (gm), Fagaceae tree species may have greater chloroplast to total leaf surface area ratios and that offset the action of thicker cell walls on gm. Furthermore, weak negative relationship between nitrogen allocation in cell walls and in Rubisco was found for Castanopsis hystrix, Cyclobalanopsis phanera and Cy. patelliformis, which might imply that nitrogen in the leaves was insufficient for both Rubisco and cell walls. In summary, our study concluded that higher PNUE might contribute to the dominance of most Fagaceae tree species in Jianfengling tropical montane rain forest. PMID- 29390008 TI - Age- and gender-specific reference intervals of TSH and free T4 in an iodine replete area: Data from Korean National Health and Nutrition Examination Survey IV (2013-2015). AB - BACKGROUND: Establishment of the reference interval of thyroid-stimulating hormone (TSH) is critical in the diagnosis of thyroid dysfunction and is affected by age, gender, iodine nutrition, and ethnicity. The aim of this study was to determine the reference intervals of TSH and free thyroxin (FT4) from a large, nationwide data of Korea where iodine intake is more than adequate. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey VI that measured serum TSH, FT4, and thyroid peroxidase antibody from 7,061 individuals (urinary iodine measurement in 6,565). Age- and gender-specific reference intervals were established from 95% confidence limits from the 2.5 to 97.5 percentile of TSH (log-transformed) and FT4 in reference populations. RESULTS: The geometric mean of TSH was 2.16 +/- 0.01 mIU/L, with the lowest value found in the middle aged group (2.04 +/- 0.02 mIU/L) and higher values noted in age groups of 10-19 and over 70 years (2.38 +/- 0.02 and 2.32 +/- 0.07 mIU/L, respectively). The association of TSH and age was U-shaped. The overall reference interval of TSH was 0.59-7.03 mIU/L. Mean FT4 was 1.25 +/- 0.003 ng/dL (16.09 +/- 0.039 pmol/L), and it showed a small but continuous decrease after 20 years of age (P < 0.001). There was a significant positive correlation between TSH and urine iodine concentration (r = 0.154, P < 0.001). CONCLUSIONS: The reference interval of TSH in Korea, where iodine intake is above the requirement, was 0.59 7.03 mIU/L and showed U-shaped change with age, which was a similar pattern to iodine intake. The reference interval of FT4 was 0.92-1.60 ng/dL. The geometric mean and upper limit of TSH were higher than those of Western populations, reflecting the paramount importance of iodine intake on thyroid function. PMID- 29390010 TI - The number of repeated observations needed to estimate the habitual physical activity of an individual to a given level of precision. AB - Physical activity behavior varies naturally from day to day, from week to week and even across seasons. In order to assess the habitual level of physical activity of a person, the person must be monitored for long enough so that the level can be identified, taking into account this natural within-person variation. An important question, and one whose answer has implications for study and survey design, epidemiological research and population surveillance, is, for how long does an individual need to be monitored before such a habitual level or pattern can be identified to a desired level of precision? The aim of this study was to estimate the number of repeated observations needed to identify the habitual physical activity behaviour of an individual to a given degree of precision. A convenience sample of 50 Swedish adults wore accelerometers during four consecutive weeks. The number of days needed to come within 5-50% of an individual's usual physical activity 95% of the time was calculated. To get an idea of the uncertainty of the estimates all statistical estimates were bootstrapped 2000 times. The mean number of days of measurement needed for the observation to, with 95% confidence, be within 20% of the habitual physical activity of an individual is highest for vigorous physical activity, for which 182 days are needed. For sedentary behaviour the equivalent number of days is 2.4. To capture 80% of the sample to within +/-20% of their habitual level of physical activity, 3.4 days is needed if sedentary behavior is the outcome of interest, and 34.8 days for MVPA. The present study shows that for analyses requiring accurate data at the individual level a longer measurement collection period than the traditional 7-day protocol should be used. In addition, the amount of MVPA was negatively associated with the number of days required to identify the habitual physical activity level indicating that the least active are also those whose habitual physical activity level is the most difficult to identify. These results could have important implications for researchers whose aim is to analyse data on an individual level. Before recommendations regarding an appropriate monitoring protocol are updated, the present study should be replicated in different populations. PMID- 29390009 TI - Chemical composition, immunostimulatory, cytotoxic and antiparasitic activities of the essential oil from Brazilian red propolis. AB - Most studies of Brazilian red propolis have explored the composition and biological properties of its ethanolic extracts. In this work, we chemically extracted and characterized the essential oil of Brazilian red propolis (EOP) and assessed its adjuvant, antiparasitic and cytotoxic activities. The chemical composition of EOP was analyzed using gas chromatography with mass spectrometry (GC-MS). EOP was tested for in vitro activity against Trichomonas vaginalis (ATCC 30236 isolate); trophozoites were treated with different concentrations of EOP (ranging from 25 to 500 MUg/mL) in order to establish the MIC and IC50 values. A cytotoxicity assay was performed in CHO-K1 cells submitted to different EOP concentrations. BALB/c mice were used to test the adjuvant effect of EOP. The animals were divided in 3 groups and inoculated as follows: 0.4 ng/kg BW EOP (G1); 50 MUg of rCP40 protein (G2); or a combination of 0.4 ng/kg BW EOP and 50 MUg of rCP40 (G3). Total IgG, IgG1 and IgG2a levels were assessed by ELISA. The major constituent compounds of EOP were methyl eugenol (13.1%), (E)-beta farnesene (2.50%), and delta-amorphene (2.3%). Exposure to EOP inhibited the growth of T. vaginalis, with an IC50 value of 100 MUg/mL of EOP. An EOP concentration of 500 MUg/mL was able to kill 100% of the T. vaginalis trophozoites. The EOP kinetic growth curve showed a 36% decrease in trophozoite growth after a 12 h exposure to 500 MUg/mL of EOP, while complete parasite death was induced at 24 h. With regard to CHO-K1 cells, the CC50 was 266 MUg/mL, and 92% cytotoxicity was observed after exposure to 500 MUg/mL of EOP. Otherwise, a concentration of 200 MUg/mL of EOP was able to reduce parasite proliferation by 70% and was not cytotoxic to CHO-K1 cells. As an adjuvant, a synergistic effect was observed when EOP was combined with the rCP40 protein (G3) in comparison to the administration of each component alone (G1 and G2), resulting in higher concentrations of IgG, IgG1 and IgG2a. EOP is constituted by biologically active components with promising antiparasitic and immunostimulatory activities and can be investigated for the formulation of new vaccines or trichomonacidal drugs. PMID- 29390011 TI - Characterization of chlorophyll binding to LIL3. AB - The light harvesting like protein 3 (LIL 3) from higher plants, has been linked to functions in chlorophyll and tocopherol biosynthesis, photo-protection and chlorophyll transfer. However, the binding of chlorophyll to LIL3 is unclear. We present a reconstitution protocol for chlorophyll binding to LIL3 in DDM micelles. It is shown in the absence of lipids and carotenoids that reconstitution of chlorophyll binding to in vitro expressed LIL3 requires pre incubation of reaction partners at room temperature. We show chlorophyll a but not chlorophyll b binding to LIL3 at a molar ratio of 1:1. Neither dynamic light scattering nor native PAGE, enabled a discrimination between binding of chlorophyll a and/or b to LIL3. PMID- 29390012 TI - Precision grip control while walking down a step in children with unilateral cerebral palsy. AB - AIM: To compare grip force (GF) and load force (LF) coordination while walking down a step between children with unilateral cerebral palsy (UCP) and typically developing (TD) children. METHODS: Twenty-five children with UCP (age 9.3+/-1.7 y) and 25 TD controls (age 9.4+/-2.1 y) walked down a step while holding a grip lift manipulandum. Dynamic and temporal variables were analyzed. The maximum voluntary contraction (MVC) was also assessed. RESULTS: The temporal course was perturbed mainly in the more affected hand of children with UCP when compared to TD children because the increases in GF and LF onset occurred in a reversed order. Compared with the TD controls, the children with UCP presented higher LF values on both hands and a higher GF on the less affected hand. In children with UCP, the GF to LF adaptation was adequate on the less affected hand but overestimated on the more affected hand. Furthermore, children with UCP presented a lower MVC in the more affected hand, leading to a higher percentage of MVC used during the task. INTERPRETATION: Our findings highlight an anticipatory control of precision grip during a stepping down task in children with UCP that is adequate for the less affected hand but altered for the more affected hand. PMID- 29390013 TI - Multiscale mechanisms of nutritionally induced property variation in spider silks. AB - Variability in spider major ampullate (MA) silk properties at different scales has proven difficult to determine and remains an obstacle to the development of synthetic fibers mimicking MA silk performance. A multitude of techniques may be used to measure multiscale aspects of silk properties. Here we fed five species of Araneoid spider solutions that either contained protein or were protein deprived and performed silk tensile tests, small and wide-angle X-ray scattering (SAXS/WAXS), amino acid composition analyses, and silk gene expression analyses, to resolve persistent questions about how nutrient deprivation induces variations in MA silk mechanical properties across scales. Our analyses found that the properties of each spider's silk varied differently in response to variations in their protein intake. We found changes in the crystalline and non-crystalline nanostructures to play specific roles in inducing the property variations we found. Across treatment MaSp expression patterns differed in each of the five species. We found that in most species MaSp expression and amino acid composition variations did not conform with our predictions based on a traditional MaSp expression model. In general, changes to the silk's alanine and proline compositions influenced the alignment of the proteins within the silk's amorphous region, which influenced silk extensibility and toughness. Variations in structural alignment in the crystalline and non-crystalline regions influenced ultimate strength independent of genetic expression. Our study provides the deepest insights thus far into the mechanisms of how MA silk properties vary from gene expression to nanostructure formations to fiber mechanics. Such knowledge is imperative for promoting the production of synthetic silk fibers. PMID- 29390014 TI - Impact of treatment and re-treatment with artemether-lumefantrine and artesunate amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda. AB - BACKGROUND: The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re treatment with ACTs select for drug-resistant P. falciparum parasites. Thus, the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) on the selection of P. falciparum multidrug resistance-1 (Pfmdr1) alleles in clinical settings. METHODS: P. falciparum positive samples were collected from children aged 12-59 months in a clinical trial in DR Congo and Uganda. Pfmdr1 single nucleotide polymorphisms (SNPs) analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP) assays. RESULTS: The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05). Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re treatment with either AL or ASAQ. Comparison between pre-treatment and post treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms. Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11-1.05, p = 0.04) while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42-2.47, p = 1.0). Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms. CONCLUSION: We found limited impact of (re-)treatment with AL or ASAQ on selection for Pfmdr1 variants and haplotypes associated with resistance to partner drugs. These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent P.falciparum infections. Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines. PMID- 29390015 TI - Genetic stability of foot-and-mouth disease virus during long-term infections in natural hosts. AB - Foot-and-mouth disease (FMD) is a severe infection caused by a picornavirus that affects livestock and wildlife. Persistence in ruminants is a well-documented feature of Foot-and-mouth disease virus (FMDV) pathogenesis and a major concern for disease control. Persistently infected animals harbor virus for extended periods, providing a unique opportunity to study within-host virus evolution. This study investigated the genetic dynamics of FMDV during persistent infections of naturally infected Asian buffalo. Using next-generation sequencing (NGS) we obtained 21 near complete FMDV genome sequences from 12 sub-clinically infected buffalo over a period of one year. Four animals yielded only one virus isolate and one yielded two isolates of different serotype suggesting a serial infection. Seven persistently infected animals yielded more than one virus of the same serotype showing a long-term intra-host viral genetic divergence at the consensus level of less than 2.5%. Quasi-species analysis showed few nucleotide variants and non-synonymous substitutions of progeny virus despite intra-host persistence of up to 152 days. Phylogenetic analyses of serotype Asia-1 VP1 sequences clustered all viruses from persistent animals with Group VII viruses circulating in Pakistan in 2011, but distinct from those circulating on 2008-2009. Furthermore, signature amino acid (aa) substitutions were found in the antigenically relevant VP1 of persistent viruses compared with viruses from 2008 2009. Intra-host purifying selective pressure was observed, with few codons in structural proteins undergoing positive selection. However, FMD persistent viruses did not show a clear pattern of antigenic selection. Our findings provide insight into the evolutionary dynamics of FMDV populations within naturally occurring subclinical and persistent infections that may have implications to vaccination strategies in the region. PMID- 29390016 TI - Utility and safety of a novel surgical microscope laser light source. AB - OBJECTIVE: Tissue injuries caused by the thermal effects of xenon light microscopes have previously been reported. Due to this, the development of a safe microscope light source became a necessity. A newly developed laser light source is evaluated regarding its effectiveness and safety as an alternative to conventional xenon light source. METHODS: We developed and tested a new laser light source for surgical microscopes. Four experiments were conducted to compare xenon and laser lights: 1) visual luminance comparison, 2) luminous and light chromaticity measurements, 3) examination and analysis of visual fatigue, and 4) comparison of focal temperature elevation due to light source illumination using porcine muscle samples. RESULTS: Results revealed that the laser light could be used at a lower illumination value than the xenon light (p < 0.01). There was no significant difference in visual fatigue status between the laser light and the xenon light. The laser light was superior to the xenon light regarding luminous intensity and color chromaticity. The focal temperature elevation of the muscle samples was significantly higher when irradiated with xenon light in vitro than with laser light (p < 0.01). CONCLUSION: The newly developed laser light source is more efficient and safer than a conventional xenon light source. It lacks harmful ultraviolet waves, has a longer lifespan, a lower focal temperature than that of other light sources, a wide range of brightness and color production, and improved safety for the user's vision. Further clinical trials are necessary to validate the impact of this new light source on the patient's outcome and prognosis. PMID- 29390017 TI - Different transfer pathways of an organochlorine pesticide across marine tropical food webs assessed with stable isotope analysis. AB - Chlordecone is a persistent organochlorine pesticide used in the banana fields of the French West Indies from 1972 to 1993. Three marine habitats (mangroves, seagrass beds and coral reefs) of two study sites located downstream contaminated rivers were chosen to evaluate the level of contamination of marine food webs. On each habitat, the food chain collected included suspended organic matter, primary producers (macroalgae, algal turf, seagrass), zooplankton, symbiotic organisms (corals, sea anemones), primary consumers (herbivores, suspension feeders, biofilm feeders), omnivores and detritivores (lobsters, fish), secondary consumers (carnivores 1: invertebrate feeders, planktivores) and tertiary consumers (carnivores 2: invertebrate and fish feeders, piscivores). Log-linear regressions of the concentrations of chlordecone versus nitrogen isotopic ratios (delta15N) were used to assess the bioaccumulation of chlordecone along trophic food webs. At each site, bioconcentration and bioamplification take part on the transfer of chlordecone in marine organisms. In mangroves (i.e. close to the source of pollution), lower trophic magnification factors (TMF) indicated that bioconcentration prevailed over bioamplification phenomenon. The opposite phenomenon appeared on coral reefs in which bioconcentration processes were less important and bioamplification pathway became dominant. Far from the source of pollution, molecules of chlordecone seemed to be transfered to organisms mostly via trophic interactions rather than water contact. PMID- 29390018 TI - Facial esthetics and the assignment of personality traits before and after orthognathic surgery rated on video clips. AB - Typically, before and after surgical correction faces are assessed on still images by surgeons, orthodontists, the patients, and family members. We hypothesized that judgment of faces in motion and by naive raters may closer reflect the impact on patients' real life, and the treatment impact on e.g. career chances. Therefore we assessed faces from dysgnathic patients (Class II, III and Laterognathia) on video clips. Class I faces served as anchor and controls. Each patient's face was assessed twice before and after treatment in changing sequence, by 155 naive raters with similar age to the patients. The raters provided independent estimates on aesthetic trait pairs like ugly /beautiful, and personality trait pairs like dominant /flexible. Furthermore the perception of attractiveness, intelligence, health, the persons' erotic aura, faithfulness, and five additional items were rated. We estimated the significance of the perceived treatment related differences and the respective effect size by general linear models for repeated measures. The obtained results were comparable to our previous rating on still images. There was an overall trend, that faces in video clips are rated along common stereotypes to a lesser extent than photographs. We observed significant class differences and treatment related changes of most aesthetic traits (e.g. beauty, attractiveness), these were comparable to intelligence, erotic aura and to some extend healthy appearance. While some personality traits (e.g. faithfulness) did not differ between the classes and between baseline and after treatment, we found that the intervention significantly and effectively altered the perception of the personality trait self-confidence. The effect size was highest in Class III patients, smallest in Class II patients, and in between for patients with Laterognathia. All dysgnathic patients benefitted from orthognathic surgery. We conclude that motion can mitigate marked stereotypes but does not entirely offset the mostly negative perception of dysgnathic faces. PMID- 29390019 TI - Impaired bone healing at tooth extraction sites in CD24-deficient mice: A pilot study. AB - AIM: To use a micro-computed tomography (micro-CT) to quantify bone healing at maxillary first molar extraction sites, and test the hypothesis that bone healing is impaired in CD24-knockout mice as compared with wild-type C57BL/6J mice. MATERIALS AND METHODS: Under ketamine-xylazine general anaesthesia, mice had either extraction of the right maxillary first molar tooth or sham operation. Mice were sacrificed 1 (n = 12/group), 2 (n = 6/group) or 4 (n = 6/group) weeks postoperatively. The right maxillae was disected. Micro-CT was used to quantify differences in bone microstructural features at extrction sites, between CD24 knockout mice and wild-type mice. RESULTS: CD24-Knockout mice displayed impaired bone healing at extraction sites that was manifested as decreased trabecular bone density, and decreased number and thickness of trabeculae. CONCLUSIONS: This pilot study suggests that CD24 plays an important role in extraction socket bone healing and may be used as a novel biomarker of bone quality and potential therapeutic target to improve bone healing and density following alveolar bone injury. PMID- 29390020 TI - Genome analysis of a novel Group I alphabaculovirus obtained from Oxyplax ochracea. AB - Oxyplax ochracea (Moore) is a pest that causes severe damage to a wide range of crops, forests and fruit trees. The complete genome sequence of Oxyplax ochracea nucleopolyhedrovirus (OxocNPV) was determined using a Roche 454 pyrosequencing system. OxocNPV has a double-stranded DNA (dsDNA) genome of 113,971 bp with a G+C content of 31.1%. One hundred and twenty-four putative open reading frames (ORFs) encoding proteins of >50 amino acids in length and with minimal overlapping were predicted, which covered 92% of the whole genome. Six baculoviral typical homologous regions (hrs) were identified. Phylogenetic analysis and gene parity plot analysis showed that OxocNPV belongs to clade "a" of Group I alphabaculoviruses, and it seems to be close to the most recent common ancestor of Group I alphabaculoviruses. Three unique ORFs (with no homologs in the National Center for Biotechnology Information database) were identified. Interestingly, OxocNPV lacks three auxiliary genes (lef7, ie-2 and pcna) related to viral DNA replication and RNA transcription. In addition, OxocNPV has significantly different sequences for several genes (including ie1 and odv-e66) in comparison with those of other baculoviruses. However, three dimensional structure prediction showed that OxocNPV ODV-E66 contain the conserved catalytic residues, implying that it might possess polysaccharide lyase activity as AcMNPV ODV-E66. All these unique features suggest that OxocNPV represents a novel species of the Group I alphabaculovirus lineage. PMID- 29390021 TI - Development of a loop-mediated isothermal amplification (LAMP) assay for rapid screening of ticks and fleas for spotted fever group rickettsia. AB - BACKGROUND: The importance of tick and flea-borne rickettsia infections is increasingly recognized worldwide. While increased focus has shifted in recent years to the development of point-of-care diagnostics for various vector-borne diseases in humans and animals, little research effort has been devoted to their integration into vector surveillance and control programs, particularly in resource-challenged countries. One technology which may be helpful for large scale vector surveillance initiatives is loop-mediated isothermal amplification (LAMP). The aim of this study was to develop a LAMP assay to detect spotted fever group (SFG) rickettsia DNA from field-collected ticks and fleas and compare with published end-point PCR results. METHODOLOGY/PRINCIPAL FINDINGS: A Spotted Fever Group rickettsia-specific loop-mediated isothermal amplification (SFGR-LAMP) assay was developed using primers based on a region of the R. rickettsii 17kDa protein gene. The sensitivity, specificity, and reproducibility of the assay were evaluated. The assay was then compared with the results of end-point PCR assays for pooled tick and flea samples obtained from field-based surveillance studies. The sensitivity of the SFGR-LAMP assay was 0.00001 ng/MUl (25MUl volume) which was 10 times more sensitive than the 17kDa protein gene end-point PCR used as the reference method. The assay only recognized gDNA from SFG and transitional group (TRG) rickettsia species tested but did not detect gDNA from typhus group (TG) rickettsia species or closely or distantly related bacterial species. The SFGR LAMP assay detected the same positives from a set of pooled tick and flea samples detected by end-point PCR in addition to two pooled flea samples not detected by end-point PCR. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first study to develop a functional LAMP assay to initially screen for SFG and TRG rickettsia pathogens in field-collected ticks and fleas. With a high sensitivity and specificity, the results indicate the potential use as a field-based surveillance tool for tick and flea-borne rickettsial pathogens in resource challenged countries. PMID- 29390022 TI - A comparison of methods to assess the antimicrobial activity of nanoparticle combinations on bacterial cells. AB - BACKGROUND: Bacterial cell quantification after exposure to antimicrobial compounds varies widely throughout industry and healthcare. Numerous methods are employed to quantify these antimicrobial effects. With increasing demand for new preventative methods for disease control, we aimed to compare and assess common analytical methods used to determine antimicrobial effects of novel nanoparticle combinations on two different pathogens. METHODS: Plate counts of total viable cells, flow cytometry (LIVE/DEAD BacLight viability assay) and qPCR (viability qPCR) were used to assess the antimicrobial activity of engineered nanoparticle combinations (NPCs) on Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria at different concentrations (0.05, 0.10 and 0.25 w/v%). Results were analysed using linear models to assess the effectiveness of different treatments. RESULTS: Strong antimicrobial effects of the three NPCs (AMNP0-2) on both pathogens could be quantified using the plate count method and flow cytometry. The plate count method showed a high log reduction (>8-log) for bacteria exposed to high NPC concentrations. We found similar antimicrobial results using the flow cytometry live/dead assay. Viability qPCR analysis of antimicrobial activity could not be quantified due to interference of NPCs with qPCR amplification. CONCLUSION: Flow cytometry was determined to be the best method to measure antimicrobial activity of the novel NPCs due to high throughput, rapid and quantifiable results. PMID- 29390023 TI - The effects of substitute multisensory feedback on task performance and the sense of presence in a virtual reality environment. AB - Objective and subjective measures of performance in virtual reality environments increase as more sensory cues are delivered and as simulation fidelity increases. Some cues (colour or sound) are easier to present than others (object weight, vestibular cues) so that substitute cues can be used to enhance informational content in a simulation at the expense of simulation fidelity. This study evaluates how substituting cues in one modality by alternative cues in another modality affects subjective and objective performance measures in a highly immersive virtual reality environment. Participants performed a wheel change in a virtual reality (VR) environment. Auditory, haptic and visual cues, signalling critical events in the simulation, were manipulated in a factorial design. Subjective ratings were recorded via questionnaires. The time taken to complete the task was used as an objective performance measure. The results show that participants performed best and felt an increased sense of immersion and involvement, collectively referred to as 'presence', when substitute multimodal sensory feedback was provided. Significant main effects of audio and tactile cues on task performance and on participants' subjective ratings were found. A significant negative relationship was found between the objective (overall completion times) and subjective (ratings of presence) performance measures. We conclude that increasing informational content, even if it disrupts fidelity, enhances performance and user's overall experience. On this basis we advocate the use of substitute cues in VR environments as an efficient method to enhance performance and user experience. PMID- 29390025 TI - Socio-economic status influences access to second-line disease modifying treatment in Relapsing Remitting Multiple Sclerosis patients. AB - OBJECTIVE: In MS, Socio-Economic status (SES) may influence healthcare and access to disease-modifying treatments (DMTs). Optimising delays to switch patients to a second-line DMT may hamper disease progression most effectively and achieve long term disease control. The objective of this study is to identify the influence of SES on the delay between first and second line DMT in RRMS patients, in Western Normandy, France. METHODS: The association between SES and the delay to access a second-line DMT were studied using data from the MS registry of Western-Normandy including 733 patients with a diagnosis of RRMS during the period in question [1982-2011]. We used the European Deprivation Index (EDI), a score with a rank level inversely related to SES. We performed multivariate adjusted Cox models for studying EDI effect on the delay between first and second line DMT. RESULTS: No significant influence of SES was observed on delay to access a second-line DMT if first-line DMT exposure time was less than 5 years. After 5 years from initiation of first-line treatment the risk of accessing a second-line DMT is 3 times higher for patients with lower deprivation indices (1st quintile of EDI) ([HR] 3.14 95%CI [1.72-5.72], p-value<0.001) compared to patients with higher values (EDI quintiles 2 to 5). INTERPRETATION: In RRMS, a high SES may facilitate access to a second-line DMT a few years after first-line DMT exposure. Greater consideration should also be given to the SES of MS patients as a risk factor in therapeutic healthcare issues throughout medical follow-up. PMID- 29390026 TI - Comparison of self-refraction using a simple device, USee, with manifest refraction in adults. AB - BACKGROUND: The USee device is a new self-refraction tool that allows users to determine their own refractive error. We evaluated the ease of use of USee in adults, and compared the refractive error correction achieved with USee to clinical manifest refraction. METHODS: Sixty adults with uncorrected visual acuity <20/30 and spherical equivalent between -6.00 and +6.00 diopters completed manifest refraction and self-refraction. RESULTS: Subjects had a mean (+/-SD) age of 53.1 (+/-18.6) years, and 27 (45.0%) were male. Mean (+/-SD) spherical equivalent measured by manifest refraction and self-refraction were -0.90 D (+/ 2.53) and -1.22 diopters (+/-2.42), respectively (p = 0.001). The proportion of subjects correctable to >=20/30 in the better eye was higher for manifest refraction (96.7%) than self-refraction (83.3%, p = 0.005). Failure to achieve visual acuity >=20/30 with self-refraction in right eyes was associated with increasing age (per year, OR: 1.05; 95% CI: 1.00-1.10) and higher cylindrical power (per diopter, OR: 7.26; 95% CI: 1.88-28.1). Subjectively, 95% of participants thought USee was easy to use, 85% thought self-refraction correction was better than being uncorrected, 57% thought vision with self-refraction correction was similar to their current corrective lenses, and 53% rated their vision as "very good" or "excellent" with self-refraction. CONCLUSION: Self refraction provides acceptable refractive error correction in the majority of adults. Programs targeting resource-poor settings could potentially use USee to provide easy on-site refractive error correction. PMID- 29390024 TI - Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice. AB - Gammaherpesviruses encode proteins with homology to the cellular purine metabolic enzyme formyl-glycinamide-phosphoribosyl-amidotransferase (FGARAT), but the role of these viral FGARATs (vFGARATs) in the pathogenesis of a natural host has not been investigated. We report a novel role for the ORF75A vFGARAT of murine gammaherpesvirus 68 (MHV68) in infectious virion production and colonization of mice. MHV68 mutants with premature stop codons in orf75A exhibited a log reduction in acute replication in the lungs after intranasal infection, which preceded a defect in colonization of multiple host reservoirs including the mediastinal lymph nodes, peripheral blood mononuclear cells, and the spleen. Intraperitoneal infection rescued splenic latency, but not reactivation. The 75A.stop virus also exhibited defective replication in primary fibroblast and macrophage cells. Viruses produced in the absence of ORF75A were characterized by an increase in the ratio of particles to PFU. In the next round of infection this led to the alteration of early events in lytic replication including the deposition of the ORF75C tegument protein, the accelerated kinetics of viral gene expression, and induction of TNFalpha release and cell death. Infecting cells to deliver equivalent genomes revealed that ORF75A was required for initiating early events in infection. In contrast with the numerous phenotypes observed in the absence of ORF75A, ORF75B was dispensable for replication and pathogenesis. These studies reveal that murine rhadinovirus vFGARAT family members ORF75A and ORF75C have evolved to perform divergent functions that promote replication and colonization of the host. PMID- 29390027 TI - The invasive Red-vented bulbul (Pycnonotus cafer) outcompetes native birds in a tropical biodiversity hotspot. AB - Invasive alien species are a major cause of biodiversity loss globally, but especially on islands where high species richness and levels of endemism accentuate their impacts. The Red vented bulbul (Pycnonotus cafer), a tropical passerine bird that has been introduced widely across locations of high conservation value, is considered an extreme pest. It is currently expanding its range in New Caledonia, one of the world's biodiversity hotspots. Decisive recommendations on management strategies are required urgently to inform local managers and policy makers, but they should be based on quantitative local evidence, not just on expert opinion. The Red-vented bulbul is widely blamed for its impacts on biodiversity, especially through competition. We used data from 2,472 point counts to explore the abundance relationships between the Red-vented bulbul and 14 other species of bird. Our results revealed a negative relationship between the occurrence of the bulbul and the mean abundance of nine species, all native (or endemic, n = 3) to the New Caledonia archipelago. In contrast, the abundance of other introduced species such as Acridotheres tristis (Common myna), Passer domesticus (House sparrow) and Spilopelia chinensis (Spotted dove) were not affected by the Red-vented bulbul. Moreover, temporal trends in the abundance of impacted species suggest that the Red-vented bulbul may cause niche contractions rather than mortality for native species in man-modified habitats. Monitoring and control of the Red-vented bulbul is recommended to prevent on going impacts on native bird communities throughout New Caledonia, and its impact on native bird communities elsewhere should be quantified. PMID- 29390028 TI - Hervey virus: Study on co-circulation with Henipaviruses in Pteropid bats within their distribution range from Australia to Africa. AB - In 2011, an unusually large number of independent Hendra virus outbreaks were recorded on horse properties in Queensland and New South Wales, Australia. Urine from bat colonies adjacent to the outbreak sites were sampled and screened for Hendra and other viruses. Several novel paramyxoviruses were also isolated at different locations. Here one of the novel viruses, named Hervey virus (HerPV), is fully characterized by genome sequencing, annotation, phylogeny and in vitro host range, and its serological cross-reactivity and neutralization patterns are examined. HerPV may have ecological and spatial and temporal patterns similar to Hendra virus and could serve as a sentinel virus for the surveillance of this highly pathogenic virus. The suitability of HerPV as potential sentinel virus is further assessed by determining the serological prevalence of HerPV antibodies in fruit-eating bats from Australia, Indonesia, Papua New Guinea, Tanzania and the Gulf of Guinea, indicating the presence of similar viruses in regions beyond the Australian border. PMID- 29390029 TI - The effects of anxiety and external attentional focus on postural control in patients with Parkinson's disease. AB - BACKGROUND: Although anxiety is a common non-motor outcome of Parkinson's disease (PD) affecting 40% of patients, little attention has been paid so far to its effects on balance impairment and postural control. Improvement of postural control through focusing on the environment (i.e. external focus) has been reported, but the role of anxiety, as a confounding variable, remains unclear. OBJECTIVES: This study aimed to investigate the influence of anxiety and attentional focus instruction on the standing postural control of PD patients. METHODS: Thirty-four patients with PD (17 with high anxiety (HA-PD) and 17 with low anxiety (LA-PD)), as well as 17 gender- and age-matched healthy control subjects (HC) participated in the study. Postural control was evaluated using a combination of two levels of postural difficulty (standing on a rigid force plate surface with open eyes (RO) and standing on a foam surface with open eyes (FO)), as well as three attentional focus instructions (internal, external and no focus). RESULTS: Only the HA-PD group demonstrated significant postural control impairment as compared to the control, as indicated by significantly greater postural sway measures. Moreover, external focus significantly reduced postural sway in all participants especially during the FO condition. CONCLUSION: The results of the current study provide evidence that anxiety influences balance control and postural stability in patients with PD, particularly those with high levels of anxiety. The results also confirmed that external focus is a potential strategy that significantly improves the postural control of these patients. Further investigation of clinical applicability is warranted towards developing effective therapeutic and rehabilitative treatment plans. PMID- 29390030 TI - A test for clinal variation in Artemisia californica and associated arthropod responses to nitrogen addition. AB - The response of plant traits to global change is of fundamental importance to understanding anthropogenic impacts on natural systems. Nevertheless, little is known about plant genetic variation in such responses or the indirect effect of environmental change on higher trophic levels. In a three-year common garden experiment, we grew the shrub Artemisia californica from five populations sourced along a 700 km latitudinal gradient under ambient and nitrogen (N) addition (20 kg N ha-1) and measured plant traits and associated arthropods. N addition increased plant biomass to a similar extent among all populations. In contrast, N addition effects on most other plant traits varied among plant populations; N addition reduced specific leaf area and leaf percent N and increased carbon to nitrogen ratios in the two northern populations, but had the opposite or no effect on the three southern populations. N addition increased arthropod abundance to a similar extent among all populations in parallel with an increase in plant biomass, suggesting that N addition did not alter plant resistance to herbivores. N addition had no effect on arthropod diversity, richness, or evenness. In summary, genetic variation among A. californica populations mediated leaf-trait responses to N addition, but positive direct effects of N addition on plant biomass and indirect effects on arthropod abundance were consistent among all populations. PMID- 29390031 TI - Infectious bursal disease virus infection leads to changes in the gut associated lymphoid tissue and the microbiota composition. AB - Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive poultry disease. IBD virus (IBDV) is the causative agent, which may lead to high morbidity and mortality rates in susceptible birds. IBDV pathogenesis studies have focused mainly on primary lymphoid organs. It is not known if IBDV infection may modify the development of the gut associated lymphoid tissues (GALT) as well as the microbiota composition. The aim of the present study was to investigate the effects of IBDV-infection on the bursa of Fabricius (BF), caecal tonsils (CT) and caecum, and to determine the effects on the gut microbiota composition in the caecum. Commercial broiler chickens were inoculated with a very virulent (vv) strain of IBDV at 14 (Experiment 2) or 15 (Experiment 1) days post hatch (dph). Virus replication, lesion development, immune parameters including numbers of T and B lymphocytes, macrophages, as well as the gut microbiota composition were compared between groups. Rapid IBDV-replication was detected in the BF, CT and caecum. It was accompanied by histological lesions including an infiltration of heterophils. In addition a significant reduction in the total mucosal thickness of the caecum was observed in vvIBDV-infected birds compared to virus-free controls (P < 0.05). vvIBDV infection also led to an increase in T lymphocyte numbers and macrophages, as well as a decrease in the number of B lymphocytes in the lamina propria of the caecum, and in the caecal tonsils. Illumina sequencing analysis indicated that vvIBDV infection also induced changes in the abundance of Clostridium XIVa and Faecalibacterium over time. Overall, our results suggested that vvIBDV infection had a significant impact on the GALT and led to a modulation of gut microbiota composition, which may lead to a higher susceptibility of affected birds for pathogens invading through the gut. PMID- 29390032 TI - Depression in Parkinson's disease: A case-control study. AB - BACKGROUND: To evaluate the association between Parkinson's disease (PD) prognosis and the patient's onset of depression. METHODS: A total of 353 patients with newly-diagnosed PD and a history of depression were enrolled. On the basis of the onset of depression before or after PD diagnosis, we divided participants into PD patients with pre- or post-diagnostic depression. Cox's regression analysis was used to detect risks between the onset of depression and outcomes (including death, accidental injury, dementia, and aspiration pneumonia). The association between the onset of depression and levodopa equivalent dosage (LED) and cumulative equivalent dosage of antidepressants were assessed. RESULTS: PD patients with post-diagnostic depression were associated with significantly higher risks of dementia (adjusted HR = 2.01, p = 0.015), and were older (58.5 +/ 17.7 vs. 53.7 +/- 18.6, p = 0.020) at the time of PD diagnosis than PD patients with pre-diagnostic depression. The higher incident rate of accidental injury was also noted in PD patients with post-diagnostic depression (48.1 vs. 31.3/1000 person-years, HR = 1.60, p = 0.041), but no statistical significance was observed in the adjusted hazard ratio (HR) (HR = 1.52, p = 0.069). Otherwise, mortality, motor condition and severity of depression revealed no significant difference between PD patients with pre-diagnostic and post-diagnostic depression. CONCLUSION: PD patients with post-diagnostic depression had higher incidence of dementia, implying different onset time of depression could be associated with different subtypes and spreading routes which should be examined in follow-up studies. PMID- 29390033 TI - Evaluation of changes arising in the pig mesenchymal stromal cells transcriptome following cryopreservation and Trichostatin A treatment. AB - Cryopreservation is an important procedure in maintenance and clinical applications of mesenchymal stem/stromal cells (MSCs). Although the methods of cell freezing using various cryoprotectants are well developed and allow preserving structurally intact living cells, the freezing process can be considered as a severe cellular stress associated with ice formation, osmotic damage, cryoprotectants migration/cytotoxicity or rapid cell shrinkage. The cellular response to freezing stress is aimed at the restoring of homeostasis and repair of cell damage and is crucial for cell viability. In this study we evaluated the changes arising in the pig mesenchymal stromal cell transcriptome following cryopreservation and showed the vast alterations in cell transcriptional activity (5,575 genes with altered expression) suggesting the engagement in post-thawing cell recovery of processes connected with cell membrane tension regulation, membrane damage repair, cell shape maintenance, mitochondria-connected energy homeostasis and apoptosis mediation. We also evaluated the effect of known gene expression stimulator-Trichostain A (TSA) on the frozen/thawed cells transcriptome and showed that TSA is able to counteract to a certain extent transcriptome alterations, however, its specificity and advantages for cell recovery after cryopreservation require further studies. PMID- 29390035 TI - Correction: Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1. AB - [This corrects the article DOI: 10.1371/journal.pone.0175478.]. PMID- 29390034 TI - Optical imaging of ovarian cancer using a matrix metalloproteinase-3-sensitive near-infrared fluorescent probe. AB - Epithelial ovarian cancer (EOC) is the seventh most common cancer among women worldwide. The 5-year survival rate for women with EOC is only 30%-50%, which is largely due to the typically late diagnosis of this condition. EOC is difficult to detect in its early stage because of its asymptomatic nature. Recently, near infrared fluorescent (NIRF) imaging has been developed as a potential tool for detecting EOC at the molecular level. In this study, a NIRF-sensitive probe was designed to detect matrix metalloproteinase (MMP) activity in ovarian cancer cells. A cyanine fluorochrome was conjugated to the amino terminus of a peptide substrate with enzymatic specificity for MMP-3. To analyze the novel MMP-3 probe, an in vivo EOC model was established by subcutaneously implanting SKOV3 cells, a serous-type EOC cell line, in mice. This novel MMP-3-sensitive probe specifically reacted with only the active MMP-3 enzyme, resulting in a significantly enhanced NIRF emission intensity. Histological analysis demonstrated that MMP-3 expression and activity were enhanced in the stromal cells surrounding the ovarian cancer cells. These studies establish a molecular imaging reporter for diagnosing early stage EOC. Additional studies are required to confirm the early-stage activity of MMP-3 in EOC and its diagnostic and prognostic significance. PMID- 29390036 TI - A non-destructive enzymatic method to extract DNA from arthropod specimens: Implications for morphological and molecular studies. AB - There is a growing necessity to integrate morphological and genetic studies. This paper proposes a new technique that allows DNA extraction of arthropods while still keeping intact the entire morphology of the specimens. The technique uses Proteinase K to dissolve protein tissues and preserve the chitinous exoskeleton of specimens. The method is fast, cheap, non-toxic, and allows for good morphological preparations of specimens retaining much of their tridimensional structure. The methodology works fine with specimens preserved in different kinds of media, such as for dry (pinned) specimens, and specimens preserved in Ethanol. In addition, it allows the extraction of DNA from fresh specimens, as well as from specimens preserved for a long time. The technique works well for morphological studies alone, but allows the generation of an associated genomic library at an individual-scale. Among the advantages of the new technique is the possibility of extracting DNA from the entire specimen (necessary for the study of diseases transmitted by arthropod vectors), while still keeping the morphology intact for correct taxonomic identification. In addition, in comparison with methods that extract DNA from small tissue samples (e.g., from legs or wings), the method allows for the extraction of a larger amount of DNA and is better suited for small specimens. PMID- 29390038 TI - Retraction: Naringin Alleviates Diabetic Kidney Disease through Inhibiting Oxidative Stress and Inflammatory Reaction. PMID- 29390037 TI - In vitro study of dentinal tubule penetration and filling quality of bioceramic sealer. AB - This study aimed to evaluate the dentinal tubule penetration and filling quality of a bioceramic sealer (iRoot SP). Forty-two roots of extracted adult lower incisors were selected. After instrumentation with Protaper Universal to F3, 40 roots were chosen and randomly divided into 4 groups, as follows: iRoot SP single cone group, iRoot SP warm vertical group, AH Plus single cone group, and AH Plus warm vertical group. Before root canal filling, sealers were mixed with Rhodamine B dye for visualization under confocal laser scanning microscope. All samples were sectioned at 2, 4, and 6 mm to apex. Then, the percentages of void areas, gap regions, and segments of sealer that penetrated into dentinal tubules in each section were calculated. Non-parametric test was used for statistical analysis (alpha = 0.05). We found that filling techniques and types of sealer had no statistically significant effects on the occurrence of voids and gaps. The segments of iRoot SP penetrated into dentinal tubules were statistically more than that of AH Plus in both single cone and warm vertical techniques at 2 mm to apex (P < 0.05). Regardless of the filling technique used, iRoot SP can achieve comparable filling quality and better dentinal tubules penetration than AH Plus. Considering the good bioactivity of iRoot SP, it may help improve the seal of root canal system. PMID- 29390039 TI - Serum amyloid A3 is required for normal weight and immunometabolic function in mice. AB - Serum amyloid A (SAA) is an apolipoprotein that is robustly upregulated in numerous inflammatory diseases and has been implicated as a candidate pro inflammatory mediator. However, studies comparing endogenous SAAs and recombinant forms of the acute phase protein have generated conflicting data on the function of SAA in immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to immune-mediated disease, and found that mice lacking SAA3 develop adult-onset obesity and metabolic dysfunction along with defects in innate immune development. Mice that lack SAA3 gain more weight, exhibit increased visceral adipose deposition, and develop hepatic steatosis compared to wild-type littermates. Leukocytes from the adipose tissue of SAA3-/- mice express a pro inflammatory phenotype, and bone marrow derived dendritic cells from mice lacking SAA3 secrete increased levels of IL-1beta, IL-6, IL-23, and TNFalpha in response to LPS compared to cells from wild-type mice. Finally, BMDC lacking SAA3 demonstrate an impaired endotoxin tolerance response and inhibited responses to retinoic acid. Our findings indicate that endogenous SAA3 modulates metabolic and immune homeostasis. PMID- 29390042 TI - JABAWS 2.2 distributed web services for Bioinformatics: protein disorder, conservation and RNA secondary structure. AB - Summary: JABAWS 2.2 is a computational framework that simplifies the deployment of web services for Bioinformatics. In addition to the five multiple sequence alignment (MSA) algorithms in JABAWS 1.0, JABAWS 2.2 includes three additional MSA programs (Clustal Omega, MSAprobs, GLprobs), four protein disorder prediction methods (DisEMBL, IUPred, Ronn, GlobPlot), 18 measures of protein conservation as implemented in AACon, and RNA secondary structure prediction by the RNAalifold program. JABAWS 2.2 can be deployed on a variety of in-house or hosted systems. JABAWS 2.2 web services may be accessed from the Jalview multiple sequence analysis workbench (Version 2.8 and later), as well as directly via the JABAWS command line interface (CLI) client. JABAWS 2.2 can be deployed on a local virtual server as a Virtual Appliance (VA) or simply as a Web Application Archive (WAR) for private use. Improvements in JABAWS 2.2 also include simplified installation and a range of utility tools for usage statistics collection, and web services querying and monitoring. The JABAWS CLI client has been updated to support all the new services and allow integration of JABAWS 2.2 services into conventional scripts. A public JABAWS 2 server has been in production since December 2011 and served over 800 000 analyses for users worldwide. Availability and implementation: JABAWS 2.2 is made freely available under the Apache 2 license and can be obtained from: http://www.compbio.dundee.ac.uk/jabaws. Contact: g.j.barton@dundee.ac.uk. PMID- 29390041 TI - Reference gene selection for molecular studies of dormancy in wild oat (Avena fatua L.) caryopses by RT-qPCR method. AB - Molecular studies of primary and secondary dormancy in Avena fatua L., a serious weed of cereal and other crops, are intended to reveal the species-specific details of underlying molecular mechanisms which in turn may be useable in weed management. Among others, quantitative real-time PCR (RT-qPCR) data of comparative gene expression analysis may give some insight into the involvement of particular wild oat genes in dormancy release, maintenance or induction by unfavorable conditions. To assure obtaining biologically significant results using this method, the expression stability of selected candidate reference genes in different data subsets was evaluated using four statistical algorithms i.e. geNorm, NormFinder, Best Keeper and DeltaCt method. Although some discrepancies in their ranking outputs were noticed, evidently two ubiquitin-conjugating enzyme homologs, AfUBC1 and AfUBC2, as well as one homolog of glyceraldehyde 3-phosphate dehydrogenase AfGAPDH1 and TATA-binding protein AfTBP2 appeared as more stably expressed than AfEF1a (translation elongation factor 1alpha), AfGAPDH2 or the least stable alpha-tubulin homolog AfTUA1 in caryopses and seedlings of A. fatua. Gene expression analysis of a dormancy-related wild oat transcription factor VIVIPAROUS1 (AfVP1) allowed for a validation of candidate reference genes performance. Based on the obtained results it can be recommended that the normalization factor calculated as a geometric mean of Cq values of AfUBC1, AfUBC2 and AfGAPDH1 would be optimal for RT-qPCR results normalization in the experiments comprising A. fatua caryopses of different dormancy status. PMID- 29390040 TI - Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency. AB - Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-gamma-mediated responses, comprising non inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style. PMID- 29390043 TI - Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. PMID- 29390045 TI - Upstream analysis of alternative splicing: a review of computational approaches to predict context-dependent splicing factors. AB - Alternative splicing (AS) has shown to play a pivotal role in the development of diseases, including cancer. Specifically, all the hallmarks of cancer (angiogenesis, cell immortality, avoiding immune system response, etc.) are found to have a counterpart in aberrant splicing of key genes. Identifying the context specific regulators of splicing provides valuable information to find new biomarkers, as well as to define alternative therapeutic strategies. The computational models to identify these regulators are not trivial and require three conceptual steps: the detection of AS events, the identification of splicing factors that potentially regulate these events and the contextualization of these pieces of information for a specific experiment. In this work, we review the different algorithmic methodologies developed for each of these tasks. Main weaknesses and strengths of the different steps of the pipeline are discussed. Finally, a case study is detailed to help the reader be aware of the potential and limitations of this computational approach. PMID- 29390044 TI - Serum Metabolomic Profiling of All-Cause Mortality: A Prospective Analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Cohort. AB - Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high performance liquid chromatography/mass spectrometry-gas chromatography/mass spectrometry. Cox regression estimated mortality hazard ratios (HR) for a one standard-deviation difference in metabolite-signals, and we divided the data into training and test-sets, creating a metabolite risk score of the strongest metabolites in the former to test in the latter. The strongest associations with overall mortality were N-acetylvaline (HR=1.28; P<4.1*10-5, below Bonferroni statistical threshold), and dimethylglycine, 7-methylguanine, C glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23<=HR<=1.32; 5*10 5<=P<=1*10-4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten 3beta,17beta-diol disulfate were statistically significantly associated with CVD mortality (1.49<=HR<=1.62, P<4.1*10-5). No metabolite was associated with cancer mortality at false discovery rate<0.1. Individuals with a one standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test-set (HR=1.4, P=0.05; HR=1.8, P=0.003, respectively). The several serum metabolites and their composite risk score independently associated with all cause and CVD mortality may provide potential leads regarding the molecular basis of mortality. PMID- 29390046 TI - Response to "Associations Among Plasma Total Homocysteine Levels, Circadian Blood Pressure Variation, and Endothelial Function in Hypertension". PMID- 29390047 TI - THE ASSOCIATION BETWEEN PREPREGNANCY BODY MASS INDEX AND RISK OF PRETERM DELIVERY IN A CHINESE POPULATION. PMID- 29390049 TI - Intramural clefts and structural discontinuities in Brugada syndrome: the missing gap? PMID- 29390048 TI - Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients. AB - Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3 year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients. PMID- 29390050 TI - A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. AB - Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1-/- neurons expressing Thorase mutantHis357Argfs*15 display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness. PMID- 29390051 TI - Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study. AB - Aims: Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40-49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population. Methods and results: Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46-0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ. Conclusion: These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes. Trial Registration: Australian New Zealand Clinical Trial Registry (ACTRN12610000374066). PMID- 29390053 TI - Thromboembolisms related to post-operative electrical cardioversions for atrial fibrillation in patients with surgical aortic valve replacement. AB - Aims: Post-operative atrial fibrillation (POAF) is a frequent complication after open-heart surgery, and cardioversions (CV) are commonly performed to restore sinus rhythm. However, little data exists on thrombo-embolic risk related to early post-operative CV and on the recurrence of POAF after CV. CAREAVR study sought to assess the rate of strokes, transient ischaemic attacks (TIA), and mortality shortly after POAF-triggered CV in patients who underwent isolated surgical aortic valve replacement (SAVR) with a bioprosthesis. Methods and results: Altogether 721 patients underwent isolated SAVR with a bioprosthesis at four Finnish university hospitals. During post-operative hospitalization, after patients with prior chronic AF were excluded, 309/634 (48.7%) of patients had at least one episode of POAF [median time (interquartile range) 3 (3) days], and an electrical CV was performed in 113/309 (36.6%) of them. The length of hospital stay was not affected by CV. At 30 days follow-up, the rate of stroke, TIA or mortality was higher in those AF patients who underwent CV vs. those who did not (9.7% vs. 3.6%, P = 0.04, respectively; adjusted hazard ratio 2.63, 95% confidence interval 1.00-6.92, P = 0.05). Similar proportion of patients in both groups were in AF rhythm at discharge (32.7% vs. 35.7%, P = 0.18); and at 3 months (25.0% vs. 23.6%, P = 0.40), respectively. Conclusion: In this real-world population of patients undergoing isolated SAVR, the rate of POAF was nearly 50%. One-third of these patients underwent an electrical CV, and they exhibited over two-fold risk for thromboembolisms and mortality. Cardioversion did not affect the short-term prevalence of AF. PMID- 29390052 TI - Three-Dimensional Analysis of the Human Pancreas. AB - Pancreatic islets are endocrine micro-organs scattered throughout the exocrine pancreas. Islets are surrounded by a network of vasculature, ducts, neurons, and extracellular matrix. Three-dimensional imaging is critical for such structural analyses. We have adapted transparent tissue tomography to develop a method to image thick pancreatic tissue slices (1 mm) with multifluorescent channels. This method takes only 2 to 3 days from specimen preparation and immunohistochemical staining to clearing tissues and imaging. Reconstruction of the intact pancreas visualizes islets with beta, alpha, and delta cells together with their surrounding networks. Capturing several hundred islets at once ensures sufficient power for statistical analyses. Further surface rendering provides clear views of the anatomical relationship between islets and their microenvironment as well as the basis for volumetric quantification. As a proof-of-principle demonstration, we show an islet size-dependent increase of intraislet capillary density and an inverse decrease in sphericity. PMID- 29390054 TI - N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial. PMID- 29390055 TI - Survival and incidence of cardiovascular diseases in participants in a long distance ski race (Vasaloppet, Sweden) compared with the background population. AB - Aims: We studied the relationship between taking part in a long-distance ski race and incidence of cardiovascular diseases (CVDs) to address the hypothesis that lifestyle lowers the incidence. Methods and results: A cohort of 399 630 subjects in Sweden, half were skiers in the world's largest ski race, and half were non skiers. Non-skiers were frequency matched for sex, age, and year of race. Individuals with severe diseases were excluded. The endpoints were death, myocardial infarction, or stroke. The subjects were followed up for a maximum of 21.8 years and median of 9.8 years. We identified 9399 death, myocardial infarction, or stroke events among non-skiers and 4784 among the Vasaloppet skiers. The adjusted hazard ratios (HRs) comparing skiers and non-skiers were 0.52 [95% confidence interval (CI) 0.49-0.54] for all-cause mortality, 0.56 (95% CI 0.52-0.60) for myocardial infarction and 0.63 (95% CI 0.58-0.67) for stroke and for all three outcomes 0.56 (95% CI 0.54-0.58). The results were consistent across subgroups: age, sex, family status, education, and race year. For skiers, a doubling of race time was associated with a higher age-adjusted risk of 19%, and male skiers had a doubled risk than female skiers, with a HR 2.06 (95% CI 1.89-2.41). The outcome analyses revealed no differences in risk of atrial fibrillation between skiers and non-skiers. Conclusion: This large cohort study provides additional support for the hypothesis that individuals with high level of physical activity representing a healthy lifestyle, as evident by their participation in a long-distance ski race, have a lower risk of CVD or death. PMID- 29390056 TI - The functional RNA cargo of bacterial membrane vesicles. AB - Bacteria secrete RNAs, some of which have effects on other cells and on other species as signalling RNAs. Prokaryotic membrane vesicles (MVs) contain a range of RNA types. The MV structure offers protection from degradation as well as receptors to facilitate delivery to target cells. Microscopic imaging and molecular biology analyses have provided evidence to demonstrate that bacterial MVs deliver their RNA into eukaryotic cells. Moreover, in some cases the RNA cargo is demonstrably functional and phenotypic changes can be identified in MV RNA treated target cells. The challenge now is to dissect the effect of MV-RNA on target cells away from the effects of non-RNA components of the MV such as lipopolysaccharide that can co-purify with RNA. PMID- 29390057 TI - Enhanced Hypothalamic NMDA Receptor Activity Contributes to Hyperactivity of HPA Axis in Chronic Stress in Male Rats. AB - Chronic stress stimulates corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus and leads to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this action are unknown. Because chronic stress enhances N-methyl-d aspartate receptor (NMDAR) activity in various brain regions, we hypothesized that augmented NMDAR activity contributes to the hyperactivity of PVN-CRH neurons and the HPA axis in chronic stress. We performed whole-cell patch-clamp recordings on PVN-CRH neurons expressing CRH promoter-driven enhanced green fluorescent protein in brain slices from rats exposed to chronic unpredictable mild stress (CUMS) and unstressed rats. CUMS rats had significantly higher expression levels of the NMDAR subunits GluN1 in the PVN than unstressed rats. Furthermore, puff NMDA-elicited currents, evoked NMDAR currents, and the baseline frequency of the miniature excitatory postsynaptic currents (mEPSCs) in PVN-CRH neurons were significantly larger in CUMS rats than in unstressed rats. The NMDAR specific antagonist 2-amino-5-phosphonopentanoic acid (AP5) significantly decreased the frequency of mEPSCs of PVN-CRH neurons in CUMS rats but did not change the frequency or amplitude of mEPSCs in unstressed rats. Bath application of AP5 normalized the elevated firing activity of PVN-CRH neurons in CUMS rats but not in unstressed rats. In addition, microinjection of the NMDAR antagonist memantine into the PVN normalized the elevated corticosterone (CORT) levels in CUMS rats to the levels in unstressed rats, but did not alter CORT levels in unstressed rats. Our findings suggest that synaptic NMDAR activity is enhanced in CUMS rats and contributes to the hyperactivity of PVN-CRN neurons and the HPA axis. PMID- 29390058 TI - Isotopic labeling with cellular O-glycome reporter/amplification (ICORA) for comparative O-glycomics of cultured cells. AB - Mucin-type O-glycans decorate >80% of secretory and cell surface proteins and contribute to health and disease. However, dynamic alterations in the O-glycome are poorly understood because current O-glycomic methodologies are not sufficiently sensitive nor quantitative. Here we describe a novel isotope labeling approach termed Isotope-Cellular O-glycome Reporter Amplification (ICORA) to amplify and analyze the O-glycome from cells. In this approach, cells are incubated with Ac3GalNAc-Bn (Ac3GalNAc-[1H7]Bn) or a heavy labeled Ac3GalNAc BnD7 (Ac3GalNAc-[2D7]Bn) O-glycan precursor (7 Da mass difference), which enters cells and upon de-esterification is modified by Golgi enzymes to generate Bn-O glycans secreted into the culture media. After recovery, heavy and light Bn-O glycans from two separate conditions are mixed, analyzed by MS, and statistically interrogated for changes in O-glycan abundance using a semi-automated approach. ICORA enables ~100-1000-fold enhanced sensitivity and increased throughput compared to traditional O-glycomics. We validated ICORA with model cell lines and used it to define alterations in the O-glycome in colorectal cancer. ICORA is a useful tool to explore the dynamic regulation of the O-glycome in health and disease. PMID- 29390059 TI - Alcohol intake, ADH1B and ADH1C genotypes, and the risk of colorectal cancer by sex and subsite in the Netherlands Cohort Study. AB - The alcohol-colorectal cancer (CRC) association may differ by sex and ADH1B and ADH1C genotypes. ADH enzymes oxidize ethanol to acetaldehyde, both of which are human carcinogens. The Netherlands Cohort Study includes 120 852 participants, aged 55-69 years at baseline (1986), and has 20.3 years follow-up (case-cohort: nsubcohort = 4774; ncases = 4597). The baseline questionnaire included questions on alcohol intake at baseline and 5 years before. Using toenail DNA, available for ~75% of the cohort, we successfully genotyped six ADH1B and six ADH1C SNPs (nsubcohort = 3897; ncases = 3558). Sex- and subsite-specific Cox hazard ratios and 95% confidence intervals for CRC were estimated comparing alcohol categories, genotypes within drinkers and alcohol categories within genotype strata. We used a dominant genetic model and adjusted for multiple testing. Alcohol intake increased CRC risk in both sexes, though in women only in the (proximal) colon when in excess of 30 g/day. In male drinkers, ADH1B rs4147536 increased (distal) colon cancer risk. In female drinkers, ADH1C rs283415 increased proximal colon cancer risk. ADH1B rs3811802 and ADH1C rs4147542 decreased CRC risk in heavy (>30 g/day) and stable drinkers (compared to 5 years before baseline), respectively. Rs3811802 and rs4147542 significantly modified the alcohol-colon cancer association in women (Pfor interaction = 0.004 and 0.02, respectively). A difference in associations between genotype strata was generally clearer in men than women. In conclusion, men showed increased CRC risks across subsites and alcohol intake levels, while only colon cancer risk was increased in women at heavy intake levels. ADH1B rs3811802 and ADH1C rs4147542 significantly modified the alcohol-colon cancer association in women. PMID- 29390060 TI - Transcriptomic profiling of Clostridium difficile grown under microaerophillic conditions. AB - Clostridium difficile (Cd) is an anaerobic, spore-forming bacterium capable of colonizing the gastrointestinal tract of humans. Colonization usually occurs following antibiotic-induced disruption of the host microbiota, which also leads to an increase in oxygen within the gastrointestinal tract. We sought to understand how Cd responds to this microaerophilic condition that is likely experienced within the host. Transcriptome profiling showed differential regulation of genes involved in sugar metabolism, pyruvate metabolism and stress responses. These data provide insight into potential mechanisms of Cd adaptation to the host environment and should lead to the elucidation unknown mechanisms of Cd oxygen resistance and pathogenesis. PMID- 29390061 TI - Mathematical modelling of glob-driven tear film breakup. AB - Evaporation is a recognized contributor to tear film thinning and tear breakup (TBU). Recently, a different type of TBU is observed, where TBU happens under or around a thick area of lipid within a second after a blink. The thick lipid corresponds to a glob. Evaporation alone is too slow to offer a complete explanation of this breakup. It has been argued that the major reason of this rapid tear film thinning is divergent flow driven by a lower surface tension of the glob (via the Marangoni effect). We examine the glob-driven TBU hypothesis in a 1D streak model and axisymmetric spot model. In the model, the streak or spot glob has a localized high surfactant concentration, which is assumed to lower the tear/air surface tension and also to have a fixed size. Both streak and spot models show that the Marangoni effect can lead to strong tangential flow away from the glob and may cause TBU. The models predict that smaller globs or thinner films will decrease TBU time (TBUT). TBU is located underneath small globs, but may occur outside larger globs. In addition to tangential flow, evaporation can also contribute to TBU. This study provides insights about mechanism of rapid thinning and TBU which occurs very rapidly after a blink and how the properties of the globs affect the TBUT. PMID- 29390062 TI - Child maltreatment risk as a function of poverty and race/ethnicity in the USA. AB - Background: Child maltreatment is a pressing social problem in the USA and internationally. There are increasing calls for the use of a public health approach to child maltreatment, but the effective adoption of such an approach requires a sound foundation of epidemiological data. This study estimates for the first time, using national data, total and type-specific official maltreatment risks while simultaneously considering environmental poverty and race/ethnicity. Methods: National official maltreatment data (2009-13) were linked to census data. We used additive mixed models to estimate race/ethnicity-specific rates of official maltreatment (total and subtypes) as a function of county-level child poverty rates. The additive model coupled with the multilevel design provided empirically sound estimates while handling both curvilinearity and the nested data structure. Results: With increasing county child poverty rates, total and type-specific official maltreatment rates increased in all race/ethnicity groups. At similar poverty levels, White maltreatment rates trended higher than Blacks and Hispanics showed lower rates, especially where the data were most sufficient. For example, at the 25% poverty level, total maltreatment report rates were 6.91% [95% confidence interval (CI): 6.43%-7.40%] for Whites, 6.30% (5.50%-7.11%) for Blacks and 3.32% (2.88%-3.76%) for Hispanics. Conclusions: We find strong positive associations between official child maltreatment and environmental poverty in all race/ethnicity groups. Our data suggest that Black/White disproportionality in official maltreatment is largely driven by Black/White differences in poverty. Our findings also support the presence of a 'Hispanic paradox' in official maltreatment, where Hispanics have lower risks compared with similarly economically situated Whites and Blacks. PMID- 29390063 TI - The Dopamine Receptor D3 Regulates Lipopolysaccharide-Induced Depressive-Like Behavior in Mice. AB - Background: The altered expression and function of dopamine receptor D3 (D3R) in patients and animal models have been correlated with depression disease severity. However, the morphological alterations and biological effects of D3R in the brain after inflammation-induced depressive-like behavior remain elusive. Methods: In the present study, we ascertained the changes of D3R expression in the brain regions after depressive-like behavior induced by peripheral administration of lipopolysaccharide (LPS). Protein levels of proinflammatory cytokines, brain derived neurotrophic factor (BDNF), and extracellular signal-regulated kinase (ERK1/2)-cAMP-response element-binding protein (CREB) signaling pathway after activation or inhibition of D3R in the brain of depressive mice were also investigated. Results: LPS caused a significant reduction of D3R in the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), which are areas related to the mesolimbic dopaminergic system. Pretreatment with pramipexole (PPX), a preferential D3R agonist, showed antidepressant effects on LPS-induced depression-like behavior through preventing changes in LPS-induced proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-1beta, and interleukin-6), BDNF, and ERK1/2-CREB signaling pathway in the VTA and NAc. In opposition, treatment with a D3R selective antagonist NGB 2904 alone made mice susceptible to depression-like effects and caused changes in accordance with the LPS-induced alterations in proinflammatory cytokines, BDNF, and the ERK1/2-CREB signaling pathway in the mPFC and NAc. Conclusions: These findings provide a relevant mechanism for D3R in LPS-induced depressive-like behavior via its mediation of proinflammatory cytokines and potential cross effects between BDNF and the ERK1/2-CREB signaling pathway. PMID- 29390065 TI - Do material, psychosocial and behavioural factors mediate the relationship between disability acquisition and mental health? A sequential causal mediation analysis. AB - Background: There is evidence of a causal relationship between disability acquisition and poor mental health; however, the mechanism by which disability affects mental health is poorly understood. This gap in understanding limits the development of effective interventions to improve the mental health of people with disabilities. Methods: We used four waves of data from the Household, Income and Labour Dynamics in Australia Survey (2011-14) to compare self-reported mental health between individuals who acquired any disability (n=387) and those who remained disability-free (n=7936). We tested three possible pathways from disability acquisition to mental health, examining the effect of material, psychosocial and behavioural mediators. The effect was partitioned into natural direct and indirect effects through the mediators using a sequential causal mediation analysis approach. Multiple imputation using chained equations was used to assess the impact of missing data. Results: Disability acquisition was estimated to cause a five-point decline in mental health [estimated mean difference: -5.3, 95% confidence interval (CI) -6.8, -3.7]. The indirect effect through material factors was estimated to be a 1.7-point difference (-1.7, 95% CI -2.8, -0.6), explaining 32% of the total effect, with a negligible proportion of the effect explained by the addition of psychosocial characteristics (material and psychosocial: -1.7, 95% CI -3.0, -0.5) and a further 5% by behavioural factors (material-psychosocial-behavioural: -2.0, 95% CI -3.4, -0.6). Conclusions: The finding that the effect of disability acquisition on mental health operates predominantly through material rather than psychosocial and behavioural factors has important implications. The results highlight the need for better social protection, including income support, employment and education opportunities, and affordable housing for people who acquire a disability. PMID- 29390064 TI - Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy. AB - Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS). Methods and results: Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events. Conclusion: Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS. PMID- 29390066 TI - Cell-Associated Simian Immunodeficiency Virus Accelerates Initial Virus Spread and CD4+ T-Cell Depletion in the Intestinal Mucosa. AB - Cell-free and cell-associated human immunodeficiency virus (HIV) may differently affect the immune system and the efficacy of prevention strategies. Here we examined mucosal events in simian immunodeficiency virus (SIV) infection, using infected cells together with cell-free virus and cell-free virus alone. Intravenously inoculated SIV-infected cells disseminated virus to the intestine within 16 hours. Infection with both virus forms accelerated viral dissemination in the intestinal mucosa and the loss of mucosal CD4+ T cells as compared to infection with cell-free virus only. As all natural sources of HIV infection contain both virus forms, future prevention studies should focus on efficacy against both cell-free and cell-associated virus. PMID- 29390067 TI - Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051). PMID- 29390068 TI - Evolutionary relationship between the cysteine and histidine rich domains (CHORDs) and Btk-type zinc fingers. AB - Summary: Cysteine and histidine rich domains (CHORDs), implicated in immunity and disease resistance signaling in plants, and in development and signal transduction in muscles and tumorigenesis in animals, are seen to have a cylindrical three-dimensional structure stabilized by the tetrahedral chelation of two zinc ions. CHORDs are regarded as novel zinc-binding domains and classified independently in Pfam and ECOD. Our sequence and structure analysis reveals that both the zinc-binding sites in CHORD possess a zinc ribbon fold and are likely related to each other by duplication and circular permutation. Interestingly, we also detect an evolutionary relationship between each of the CHORD zinc fingers (ZFs) and the Bruton's tyrosine kinase (Btk)-type ZF of the zinc ribbon fold group. Btk_ZF is found in eukaryotic Tec kinase family proteins that are also implicated in signaling pathways in several lineages of hematopoietic cells involved in mammalian immunity. Our analysis suggests that the unique zinc-stabilized fold seen only in the CHORD and Btk_ZFs likely emerged specifically in eukaryotes to mediate diverse signaling pathways. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29390070 TI - No Judge Required: M (By her litigation Friend, Mrs B) V A Hospital; M (Withdrawal of Treatment: Need for Proceedings) (2017) EWCOP 19. AB - The two titles of the judgment on which this commentary is based reflect the fact that its scope was wider than resolving the legal matter at issue between two parties. It records the reasons for Jackson J's decision on a set of facts, it clarifies whether legal proceedings were necessary and the form that they should take, and it explains why the Court of Protection appointed a patient's mother as her litigation friend. The case arose from a request for a declaration that it would be lawful to withdraw clinically assisted nutrition and hydration from a woman with Huntingdon's disease who had been in a minimally conscious state for about one year. The application for withdrawal was supported by everyone whose evidence was heard. Jackson J stated that, in such cases, clinicians would be protected by the Mental Capacity Act 2005, and that court proceedings were therefore unnecessary. He explained that, provided that certain criteria are met, and the circumstances are appropriate, a court may appoint a family member or friend-rather than the Official Solicitor-to act as a litigation friend. This commentary explores the implications of this judgment in the context of very recent clinical developments. PMID- 29390069 TI - Long Noncoding RNA-Associated Transcriptomic Changes in Resiliency or Susceptibility to Depression and Response to Antidepressant Treatment. AB - Background: Recent emergence of long noncoding RNAs in regulating gene expression and thereby modulating physiological functions in brain has manifested their possible role in psychiatric disorders. In this study, the roles of long noncoding RNAs in susceptibility and resiliency to develop stress-induced depression and their response to antidepressant treatment were examined. Methods: Microarray-based transcriptome-wide changes in long noncoding RNAs were determined in hippocampus of male Holtzman rats who showed susceptibility (learned helplessness) or resiliency (nonlearned helplessness) to develop depression. Changes in long noncoding RNA expression were also ascertained after subchronic administration of fluoxetine to learned helplessness rats. Bioinformatic and target prediction analyses (cis- and trans-acting) and qPCR based assays were performed to decipher the functional role of altered long noncoding RNAs. Results: Group-wise comparison showed an overrepresented class of long noncoding RNAs that were uniquely associated with nonlearned helplessness or learned helplessness behavior. Chromosomal mapping within the 5-kbp flank region of the top 20 dysregulated long noncoding RNAs in the learned helplessness group showed several target genes that were regulated through cis- or trans-actions, including Zbtb20 and Zfp385b from zinc finger binding protein family. Genomic context of differentially expressed long noncoding RNAs showed an overall blunted response in the learned helplessness group regardless of the long noncoding RNA classes analyzed. Gene ontology exhibited the functional clustering for anatomical structure development, cellular architecture modulation, protein metabolism, and cellular communications. Fluoxetine treatment reversed learned helplessness-induced changes in many long noncoding RNAs and target genes. Conclusions: The involvement of specific classes of long noncoding RNAs with distinctive roles in modulating target gene expression could confer the role of long noncoding RNAs in resiliency or susceptibility to develop depression with a reciprocal response to antidepressant treatment. PMID- 29390071 TI - Corrigendum to: "Racial/Ethnic Differences in Expectations Regarding Aging Among Older Adults". PMID- 29390072 TI - Quantification of non-coding RNA target localization diversity and its application in cancers. AB - Subcellular localization is pivotal for RNAs and proteins to implement biological functions. The localization diversity of protein interactions has been studied as a crucial feature of proteins, considering that the protein-protein interactions take place in various subcellular locations. Nevertheless, the localization diversity of non-coding RNA (ncRNA) target proteins has not been systematically studied, especially its characteristics in cancers. In this study, we provide a new algorithm, non-coding RNA target localization coefficient (ncTALENT), to quantify the target localization diversity of ncRNAs based on the ncRNA-protein interaction and protein subcellular localization data. ncTALENT can be used to calculate the target localization coefficient of ncRNAs and measure how diversely their targets are distributed among the subcellular locations in various scenarios. We focus our study on long non-coding RNAs (lncRNAs), and our observations reveal that the target localization diversity is a primary characteristic of lncRNAs in different biotypes. Moreover, we found that lncRNAs in multiple cancers, differentially expressed cancer lncRNAs, and lncRNAs with multiple cancer target proteins are prone to have high target localization diversity. Furthermore, the analysis of gastric cancer helps us to obtain a better understanding that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Overall, we systematically studied the target localization diversity of the lncRNAs and uncovered its association with cancer. PMID- 29390073 TI - LYG-202 inhibits activation of endothelial cells and angiogenesis through CXCL12/CXCR7 pathway in breast cancer. AB - Angiogenesis is critical for the growth and metastasis of triple-negative breast cancer (TNBC) and its inhibition reduces the risk of progression of metastatic TNBC. In this study, we investigated that LYG-202, a flavonoid with a piperazine substitution, inhibited angiogenesis induced by conditioned media (CM) from MDA MB-231 cells under hypoxia and revealed its underlying mechanism. The results showed that LYG-202 decreased CXCL12 secretion and CXCR7 expression, leading to suppression of its downstream ERK/AKT/nuclear factor kappa B (NF-kappaB) signaling, which eventually decreased the expression of MMP-2, MMP-9, RhoA and increased VE-cadherin expression in EA.hy 926 cells treated with CM from MDA-MB 231 cells under hypoxia. The decreased migration ability, increased cell adhesion and inhibited CXCR7 pathway by LYG-202 could also be reproduced in human umbilical vein endothelial cells. More importantly, LYG-202 also inhibited tumor angiogenesis and tumor growth of human breast cancer MDA-MB-231 cells in nude mice through CXCL12/CXCR7 pathway. In summary, LYG-202 is a potential agent to prohibit tumor angiogenesis through inhibiting the activation of endothelial cells. PMID- 29390074 TI - The Arabidopsis COPII components, AtSEC23A and AtSEC23D, are essential for pollen wall development and exine patterning. AB - The specialized multilayered pollen wall plays multiple roles to ensure normal microspore development. The major components of the pollen wall (e.g. sporopollenin and lipidic precursors) are provided from the tapetum. Material export from the endoplasmic reticulum (ER) is mediated by coat protein complex II (COPII) vesicles. The Arabidopsis thaliana genome encodes seven homologs of SEC23, a COPII component. However, the functional importance of this diversity remains elusive. Here, we analyzed knockout and knockdown lines for AtSEC23A and AtSEC23D, two of the A. thaliana SEC23 homologs, respectively. Single atsec23a and atsec23d mutant plants, despite normal fertility, showed an impaired exine pattern. Double atsec23ad mutant plants were semi-sterile and exhibited developmental defects in pollen and tapetal cells. Pollen grains of atsec23ad had defective exine and intine, and showed signs of cell degeneration. Moreover, the development of tapetal cells was altered, with structural abnormalities in organelles. AtSEC23A and AtSEC23D exhibited the characteristic localization pattern of COPII proteins and were highly expressed in the tapetum. Our work suggests that AtSEC23A and AtSEC23D may organize pollen wall development and exine patterning by regulating ER export of lipids and proteins necessary for pollen wall formation. Also, our results shed light on the functional heterogeneity of SEC23 homologs. PMID- 29390075 TI - IW-Scoring: an Integrative Weighted Scoring framework for annotating and prioritizing genetic variations in the noncoding genome. AB - The vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, identifying and prioritizing driver candidates with putative functional significance is challenging. To address this, we implemented IW-Scoring, a new Integrative Weighted Scoring model to annotate and prioritise functionally relevant noncoding variations. We evaluate 11 scoring methods, and apply an unsupervised spectral approach for subsequent selective integration into two linear weighted functional scoring schemas for known and novel variations. IW Scoring produces stable high-quality performance as the best predictors for three independent data sets. We demonstrate the robustness of IW-Scoring in identifying recurrent functional mutations in the TERT promoter, as well as disease SNPs in proximity to consensus motifs and with gene regulatory effects. Using follicular lymphoma as a paradigmatic cancer model, we apply IW-Scoring to locate 11 recurrently mutated noncoding regions in 14 follicular lymphoma genomes, and validate 9 of these regions in an extension cohort, including the promoter and enhancer regions of PAX5. Overall, IW-Scoring demonstrates greater versatility in identifying trait- and disease-associated noncoding variants. Scores from IW Scoring as well as other methods are freely available from http://www.snp nexus.org/IW-Scoring/. PMID- 29390076 TI - Unique tRNA gene profile suggests paucity of nucleotide modifications in anticodons of a deep-sea symbiotic Spiroplasma. AB - The position 34 of a tRNA is always modified for efficient recognition of codons and accurate integration of amino acids by the translation machinery. Here, we report genomics features of a deep-sea gut symbiotic Spiroplasma, which suggests that the organism does not require tRNA(34) anticodon modifications. In the genome, there is a novel set of tRNA genes composed of 32 species for recognition of the 20 amino acids. Among the anticodons of the tRNAs, we witnessed the presence of both U34- and C34-containing tRNAs required to decode NNR (A/G) 2:2 codons as countermeasure of probable loss of anticodon modification genes. In the tRNA fragments detected in the gut transcriptome, mismatches expected to be caused by some tRNA modifications were not shown in their alignments with the corresponding genes. However, the probable paucity of modified anticodons did not fundamentally change the codon usage pattern of the Spiroplasma. The tRNA gene profile that probably resulted from the paucity of tRNA(34) modifications was not observed in other symbionts and deep-sea bacteria, indicating that this phenomenon was an evolutionary dead-end. This study provides insights on co evolution of translation machine and tRNA genes and steric constraints of codon anticodon interactions in deep-sea extreme environment. PMID- 29390077 TI - Cwc23 is a component of the NTR complex and functions to stabilize Ntr1 and facilitate disassembly of spliceosome intermediates. AB - Cwc23 is a member of the J protein family, and has been shown to interact with Ntr1, a scaffold protein that interacts with Ntr2 and Prp43 to form the NTR complex that mediates spliceosome disassembly. We show that Cwc23 is also an intrinsic component of the NTR complex, and that it interacts with the carboxyl terminus of Ntr1. Metabolic depletion of Cwc23 concurrently depleted Ntr1 and Ntr2, suggesting a role for Cwc23 in stabilizing these two proteins. Ntr1, Ntr2 and Cwc23 are stoichiometrically balanced, and form a stable heterotrimer. Depletion of Cwc23 from splicing extracts using antibodies resulted in depletion of all three proteins and accumulation of intron-lariat in the splicing reaction. Cwc23 is not required for disassembly of intron-lariat spliceosome (ILS), but facilitates disassembly of spliceosome intermediates after the actions of Prp2 and Prp16 by stabilizing the association of Ntr1 with the spliceosome. Cwc23 has a more limited effect on the association of Ntr1 with the ILS. Our data suggest that Cwc23 is important for maintaining the levels of Ntr1 and Ntr2, and that it also plays a regulatory role in targeting spliceosome intermediates for disassembly. PMID- 29390078 TI - Effect of tedizolid on clinical Enterococcus isolates: in vitro activity, distribution of virulence factor, resistance genes and multilocus sequence typing. AB - Enterococcal infections have become one of the most challenging nosocomial problems. Tedizolid, the second oxazolidinone, is 4-fold to 8-fold more potent in vivo and in vitro than linezolid against enterococci. However, the characteristics of tedizolid related to enterococci isolates in China remain elusive. The aim of this study was to evaluate in vitro activity of tedizolid against enterococcal isolates from patients with infections at a teaching hospital in China and to investigate the correlations between in vitro tedizolid activity against enterococci and the distribution of multilocus sequence types (MLST), resistance genes and virulence factors. A total of 289 non-duplicate Enterococcus faecalis strains and 68 E. faecium strains were isolated. Tedizolid inhibited 95.24% of all enterococcal isolates with an MIC <= 0.5MUg/ml. Seventeen E. faecalis strains had an MIC > 0.5 MUg/ml, and all E. faecium were inhibited at MIC <= 0.5 MUg/ml. The proportion of tedizolid non-susceptible E. faecalis strains with optrA genes was higher than that among tedizolid-susceptible strains. Tedizolid exhibited good in vitro activity against all E. faecium strains, including multidrug-resistant E. faecium carrying tet(M), tet(L), tet(U),erm(A), erm(B) and erm(C) genes. In summary, tedizolid has an advantage (higher sensitivity rate) compared to linezolid among enterococci, except for isolates expressing the plasmid-encoded optrA gene. PMID- 29390079 TI - RUMINANT NUTRITION SYMPOSIUM: Improving the efficiency of nutrient utilization to optimize livestock performance. PMID- 29390081 TI - Construct Validity of the Societal Outreach Scale (SOS). AB - Background: The American Physical Therapy Association (APTA) has been working toward a vision of increasing professional focus on societal-level health. However, performance of social responsibility and related behaviors by physical therapists remain relatively poorly integrated into practice. Promoting a focus on societal outreach is necessary for all health care professionals to impact the health of their communities. Objective: The objective was to document the validity of the 14-item Societal Outreach Scale (SOS) for use with practicing physical therapists. Design: This study used a cross-sectional survey. Methods: The SOS was transmitted via email to all therapists who were licensed and practicing in 10 states in the United States that were purposefully selected to assure a broad representation. A sample of 2612 usable responses was received. Factor analysis was applied to assess construct validity of the instrument. Results: Of alternate models, a 3-factor model best demonstrated goodness of fit with the sample data according to conventional indices (standardized root mean squared residual = .03, comparative fit index .96, root mean square error of approximation = .06). The 3 factors measured by the SOS were labeled Societal Level Health Advocacy, Community Engagement/Social Integration, and Political Engagement. Internal consistency reliability was 0.7 for all factors. The 3 factor SOS demonstrated acceptable validity and reliability. Limitations: Though the sample included a broad representation of physical therapists, this was a single cross-sectional study. Additional confirmatory factor analysis, reliability testing, and word refinement of the tool are warranted. Conclusions: Given the construct validity and reliability of the 3-factor SOS, it is recommended for use as a validated instrument to measure physical therapists' performance of social responsibility and related behaviors. PMID- 29390080 TI - Experimental maps of DNA structure at nucleotide resolution distinguish intrinsic from protein-induced DNA deformations. AB - Recognition of DNA by proteins depends on DNA sequence and structure. Often unanswered is whether the structure of naked DNA persists in a protein-DNA complex, or whether protein binding changes DNA shape. While X-ray structures of protein-DNA complexes are numerous, the structure of naked cognate DNA is seldom available experimentally. We present here an experimental and computational analysis pipeline that uses hydroxyl radical cleavage to map, at single nucleotide resolution, DNA minor groove width, a recognition feature widely exploited by proteins. For 11 protein-DNA complexes, we compared experimental maps of naked DNA minor groove width with minor groove width measured from X-ray co-crystal structures. Seven sites had similar minor groove widths as naked DNA and when bound to protein. For four sites, part of the DNA in the complex had the same structure as naked DNA, and part changed structure upon protein binding. We compared the experimental map with minor groove patterns of DNA predicted by two computational approaches, DNAshape and ORChID2, and found good but not perfect concordance with both. This experimental approach will be useful in mapping structures of DNA sequences for which high-resolution structural data are unavailable. This approach allows probing of protein family-dependent readout mechanisms. PMID- 29390082 TI - An integrative overview of genomic, transcriptomic and proteomic analyses in organohalide respiration research. AB - Organohalide respiration (OHR) is a crucial process in the global halogen cycle and of interest for bioremediation. However, investigations on OHR are hampered by the restricted genetic accessibility and the poor growth yields of many organohalide-respiring bacteria (OHRB). Therefore, genomics, transcriptomics and proteomics are often used to investigate OHRB. In general, these gene expression studies are more useful when the data of the different 'omics' approaches are integrated and compared among a wide range of cultivation conditions and ideally involve several closely related OHRB. Despite the availability of a couple of proteomic and transcriptomic datasets dealing with OHRB, such approaches are currently not covered in reviews. Therefore, we here present an integrative and comparative overview of omics studies performed with the OHRB Sulfurospirillum multivorans, Dehalococcoides mccartyi, Desulfitobacterium spp. and Dehalobacter restrictus. Genes, transcripts, proteins and the regulatory and biochemical processes involved in OHR are discussed, and a comprehensive view on the unusual metabolism of D. mccartyi, which is one of the few bacteria possibly using a quinone-independent respiratory chain, is provided. Several 'omics'-derived theories on OHRB, e.g. the organohalide-respiratory chain, hydrogen metabolism, corrinoid biosynthesis or one-carbon metabolism are critically discussed on the basis of this integrative approach. PMID- 29390083 TI - Deletion of PimE mannosyltransferase results in increased copper sensitivity in Mycobacterium smegmatis. AB - The unique cell envelope structure of Mycobacterium tuberculosis is fundamental to its pathogenesis. Phosphatidylinositol (PI)-anchored glycolipids, such as phosphatidylinositol mannosides (PIMs), lipomannan and lipoarabinomannan, are essential components of the cell envelope widely conserved among mycobacteria, but their roles in the cell envelope integrity are not fully understood. We previously identified PimE in Mycobacterium smegmatis, a nonpathogenic model organism, as a mannosyltransferase that catalyzes the fifth mannose transfer for the biosynthesis of hexamannosyl PIMs. Our analyses, reported here, further demonstrate that the growth of the pimE deletion mutant (DeltapimE) is defective in the presence of copper. We first found that the small colony phenotype of DeltapimE on a solid Middlebrook 7H10 agar surface was alleviated when grown on M63 agar. Comparative analysis of the two media led us to identify copper in Middlebrook 7H10 as the cause of growth retardation seen in DeltapimE. We further demonstrated that DeltapimE is sensitized to several antibiotics, but the increased sensitivities were independent of the presence of copper. We conclude that the deletion of the pimE gene does not cause growth defects under optimal growth conditions, but makes the cell envelope vulnerable to toxic compounds such as copper and antibiotics. PMID- 29390084 TI - Co-complex protein membership evaluation using Maximum Entropy on GO ontology and InterPro annotation. AB - Motivation: Protein-protein interactions (PPI) play a crucial role in our understanding of protein function and biological processes. The standardization and recording of experimental findings is increasingly stored in ontologies, with the Gene Ontology (GO) being one of the most successful projects. Several PPI evaluation algorithms have been based on the application of probabilistic frameworks or machine learning algorithms to GO properties. Here, we introduce a new training set design and machine learning based approach that combines dependent heterogeneous protein annotations from the entire ontology to evaluate putative co-complex protein interactions determined by empirical studies. Results: PPI annotations are built combinatorically using corresponding GO terms and InterPro annotation. We use a S.cerevisiae high-confidence complex dataset as a positive training set. A series of classifiers based on Maximum Entropy and support vector machines (SVMs), each with a composite counterpart algorithm, are trained on a series of training sets. These achieve a high performance area under the ROC curve of <=0.97, outperforming go2ppi-a previously established prediction tool for protein-protein interactions (PPI) based on Gene Ontology (GO) annotations. Availability and implementation: https://github.com/ima23/maxent ppi. Contact: sbh11@cl.cam.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29390086 TI - RE: "IMPACT OF BLAST INJURY ON HEARING IN A SCREENED MALE MILITARY POPULATION". PMID- 29390085 TI - RNentropy: an entropy-based tool for the detection of significant variation of gene expression across multiple RNA-Seq experiments. AB - RNA sequencing (RNA-Seq) has become the experimental standard in transcriptome studies. While most of the bioinformatic pipelines for the analysis of RNA-Seq data and the identification of significant changes in transcript abundance are based on the comparison of two conditions, it is common practice to perform several experiments in parallel (e.g. from different individuals, developmental stages, tissues), for the identification of genes showing a significant variation of expression across all the conditions studied. In this work we present RNentropy, a methodology based on information theory devised for this task, which given expression estimates from any number of RNA-Seq samples and conditions identifies genes or transcripts with a significant variation of expression across all the conditions studied, together with the samples in which they are over- or under-expressed. To show the capabilities offered by our methodology, we applied it to different RNA-Seq datasets: 48 biological replicates of two different yeast conditions; samples extracted from six human tissues of three individuals; seven different mouse brain cell types; human liver samples from six individuals. Results, and their comparison to different state of the art bioinformatic methods, show that RNentropy can provide a quick and in depth analysis of significant changes in gene expression profiles over any number of conditions. PMID- 29390088 TI - Insights Into Polysomnography-Confirmed REM Sleep Behavior Disorder From New Prevalence and Gender Data in the General Population. PMID- 29390087 TI - More than the "Killer Trait": Infection with the Bacterial Endosymbiont Caedibacter taeniospiralis Causes Transcriptomic Modulation in Paramecium Host. AB - Endosymbiosis is a widespread phenomenon and hosts of bacterial endosymbionts can be found all-over the eukaryotic tree of life. Likely, this evolutionary success is connected to the altered phenotype arising from a symbiotic association. The potential variety of symbiont's contributions to new characteristics or abilities of host organisms are largely unstudied. Addressing this aspect, we focused on an obligate bacterial endosymbiont that confers an intraspecific killer phenotype to its host. The symbiosis between Paramecium tetraurelia and Caedibacter taeniospiralis, living in the host's cytoplasm, enables the infected paramecia to release Caedibacter symbionts, which can simultaneously produce a peculiar protein structure and a toxin. The ingestion of bacteria that harbor both components leads to the death of symbiont-free congeners. Thus, the symbiosis provides Caedibacter-infected cells a competitive advantage, the "killer trait." We characterized the adaptive gene expression patterns in symbiont-harboring Paramecium as a second symbiosis-derived aspect next to the killer phenotype. Comparative transcriptomics of infected P. tetraurelia and genetically identical symbiont-free cells confirmed altered gene expression in the symbiont-bearing line. Our results show up-regulation of specific metabolic and heat shock genes whereas down-regulated genes were involved in signaling pathways and cell cycle regulation. Functional analyses to validate the transcriptomics results demonstrated that the symbiont increases host density hence providing a fitness advantage. Comparative transcriptomics shows gene expression modulation of a ciliate caused by its bacterial endosymbiont thus revealing new adaptive advantages of the symbiosis. Caedibacter taeniospiralis apparently increases its host fitness via manipulation of metabolic pathways and cell cycle control. PMID- 29390089 TI - Physical activity behaviour in men with inflammatory joint disease: a cross sectional register-based study. AB - Objectives: Physical activity is recommended as an essential part of the non pharmacological management of inflammatory joint disease, but previous research in this area has predominantly included women. The aim of this study was to examine physical activity behaviour in men with inflammatory joint disease. Methods: The study was conducted as a cross-sectional register-based study. Data on physical activity behaviour in men with RA, PsA and AS were matched with sociodemographic and clinical variables extracted from the DANBIO registry. Logistic regression analyses using multiple imputations were performed to investigate demographic and clinical variables associated with regular engagement in physical activity (moderate-vigorous ?2 h/week). Descriptive statistics were applied to explore motivation, barriers and preferences for physical activity. Results: A total of 325 men were included of whom 129 (40%) engaged in regular physical activity. In univariate analyses, higher age, visual analogue scale (VAS) for pain, VAS fatigue, VAS patient's global, CRP level, disease activity, functional disability and current smoking were negatively associated with regular engagement in physical activity. In the final multivariable regression model only a high VAS fatigue score (?61 mm) (OR = 0.228; CI: 0.119, 0.436) remained significantly independently associated with regular physical activity. Conclusion: A majority of men with inflammatory joint disease do not meet the recommendations of regular physical activity. Both sociodemographic and clinical parameters were associated with engagement in physical activity, and fatigue especially seems to play a pivotal role in explaining suboptimal physical activity behaviour in this patient group. PMID- 29390090 TI - Codon Usage Bias in Animals: Disentangling the Effects of Natural Selection, Effective Population Size, and GC-Biased Gene Conversion. AB - Selection on codon usage bias is well documented in a number of microorganisms. Whether codon usage is also generally shaped by natural selection in large organisms, despite their relatively small effective population size (Ne), is unclear. In animals, the population genetics of codon usage bias has only been studied in a handful of model organisms so far, and can be affected by confounding, nonadaptive processes such as GC-biased gene conversion and experimental artefacts. Using population transcriptomics data, we analyzed the relationship between codon usage, gene expression, allele frequency distribution, and recombination rate in 30 nonmodel species of animals, each from a different family, covering a wide range of effective population sizes. We disentangled the effects of translational selection and GC-biased gene conversion on codon usage by separately analyzing GC-conservative and GC-changing mutations. We report evidence for effective translational selection on codon usage in large-Ne species of animals, but not in small-Ne ones, in agreement with the nearly neutral theory of molecular evolution. C- and T-ending codons tend to be preferred over synonymous G- and A-ending ones, for reasons that remain to be determined. In contrast, we uncovered a conspicuous effect of GC-biased gene conversion, which is widespread in animals and the main force determining the fate of AT<->GC mutations. Intriguingly, the strength of its effect was uncorrelated with Ne. PMID- 29390091 TI - Identification and Characterization at the Single-Cell Level of Cytokine Producing Circulating Cells in Children With Dengue. AB - In this study, we identified, at the single-cell level, naturally induced cytokine-producing circulating cells (CPCCs) in children with dengue virus (DENV) infection ranging clinically from mild to severe disease. Tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) CPCCs were detected in children with primary or secondary acute dengue virus (DENV) infection, and the pattern of these cytokines was similar to that seen in the supernatant of cultured peripheral blood mononuclear cells and partially comparable to that found in plasma. Monocytes, B cells, and myeloid dendritic cells (mDCs) were the primary CPCCs detected, and the frequency of mDCs was significantly higher in severe disease. B cells isolated from children with dengue spontaneously secreted TNF alpha, IL-6, and interleukin 10, and supernatants from cultures of purified B cells induced activation of allogeneic T cells, supporting an antibody independent function of these cells during DENV infection. Thus, CPCCs could be a new immune parameter with potential use to evaluate pathogenesis in this infection. PMID- 29390092 TI - Association of Degree of European Genetic Ancestry With Serum Vitamin D Levels in African Americans. AB - Circulating levels of vitamin D are generally lower in African Americans than in US whites, and 1 prior analysis carried out in a small number of African Americans suggested that, within this population, vitamin D levels may be related to the degree of genetic admixture. We assessed the association between percentage of European ancestry and serum vitamin D level (assessed in 2013-2015) among 2,183 African-American women from the Black Women's Health Study whose DNA had been genotyped for ancestry-informative markers. ADMIXMAP software was used to estimate the percentage of European ancestry versus African ancestry in each individual. In linear regression analyses with adjustment for genotype batch, age, body mass index, supplemental vitamin D use, ultraviolet B radiation flux in the participant's state of residence, and season of blood draw, each 10% increase in European ancestry was associated with a 0.67-ng/mL increase in serum vitamin D concentration (95% confidence interval: 0.17, 1.17). The association was statistically significant only among women who were not taking vitamin D supplements (for each 10% increase in European ancestry, beta = 0.86, 95% confidence interval: 0.14, 1.57). Among African Americans, use of vitamin D supplements may help to reduce vitamin D deficiency associated with genetic ancestry. PMID- 29390093 TI - Acute hepatotoxicity of 2' fluoro-modified 5-10-5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins. AB - We reported previously that a 2' fluoro-modified (2' F) phosphorothioate (PS) antisense oligonucleotides (ASOs) with 5-10-5 gapmer configuration interacted with proteins from Drosophila behavior/human splicing (DBHS) family with higher affinity than PS-ASOs modified with 2'-O-(2-methoxyethyl) (2' MOE) or 2',4' constrained 2'-O-ethyl (cEt) did. Rapid degradation of these proteins and cytotoxicity were observed in cells treated with 2' F PS-ASO. Here, we report that 2' F gapmer PS-ASOs of different sequences caused reduction in levels of DBHS proteins and hepatotoxicity in mice. 2' F PS-ASOs induced activation of the P53 pathway and downregulation of metabolic pathways. Altered levels of RNA and protein markers for hepatotoxicity, liver necrosis, and apoptosis were observed as early as 24 to 48 hours after a single administration of the 2' F PS-ASO. The observed effects were not likely due to the hybridization-dependent RNase H1 cleavage of on- or potential off-target RNAs, or due to potential toxicity of 2' F nucleoside metabolites. Instead, we found that 2' F PS-ASO associated with more intra-cellular proteins including proteins from DBHS family. Our results suggest that protein-binding correlates positively with the 2' F modification-dependent loss of DBHS proteins and the toxicity of gapmer 2' F PS-ASO in vivo. PMID- 29390095 TI - Small RNAs in cell-to-cell communications during bacterial infection. AB - Intercellular communication is a widespread phenomenon in all domains of life. Bacteria have developed many ways of communicating with one another and with other species, either prokaryotic or eukaryotic. RNA has been a key molecule since the beginning of life on Earth, and is one of the carriers of information. Given the current antibiotic crisis, understanding the way in which pathogens communicate can lead towards improved ways to control infections when antimicrobial therapy is not possible. Different subspecies of RNA, non-coding, and of small size, designated here as ncRNAs, have been in recent years the subject of a great research effort, and results have contributed to a growing field of knowledge. This review focuses on four different aspects of ncRNA involvement in cell-to-cell communications during bacterial infections: pathogen recognition by the host, alteration of host microRNA profiles, production of domestic and secreted forms of ncRNAs and subversion of the host responses. The current review article focuses on the most recent discoveries in the field and gives an integrative idea based on the discussed studies. PMID- 29390094 TI - Energy costs of feeding excess protein from corn-based by-products to finishing cattle. AB - The increased use of by-products in finishing diets for cattle leads to diets that contain greater concentrations of crude protein (CP) and metabolizable protein (MP) than required. The hypothesis was that excess dietary CP and MP would increase maintenance energy requirements because of the energy costs of removing excess N as urea in urine. To evaluate the potential efficiency lost, two experiments were performed to determine the effects of feeding excess CP and MP to calves fed a finishing diet at 1 * maintenance energy intake (Exp. 1) and at 2 * maintenance intake (Exp. 2). In each experiment, eight crossbred Angus based steers were assigned to two dietary treatments in a switchback design with three periods. Treatments were steam-flaked corn-based finishing diets with two dietary protein concentrations, 13.8% CP/9.63% MP (CON) or 19.5% CP/14.14% MP (dry matter basis; ECP), containing corn gluten meal to reflect a diet with excess CP and MP from corn by-products. Each period was 27 d in length with a 19 d dietary adaptation period in outdoor individual pens followed by a 4-d sample collection in one of four open circuit respiration chambers, 2-d fast in outdoor pen, and 2-d fast in one of four respiration chambers. Energy metabolism, diet digestibility, carbon (C) and nitrogen (N) balance, oxygen consumption, and carbon dioxide and methane production were measured. At both levels of intake, digestible energy as a proportion of gross energy (GE) tended to be greater (P < 0.06) in ECP than in CON steers. Metabolizable energy (ME) as a proportion of GE tended to be greater (P = 0.08) in the ECP steers than in the CON steers at 2 * maintenance intake. At 1 * and 2 * maintenance intake, urinary N excretion (g/d) was greater (P < 0.01) in the ECP steers than the CON steers. Heat production as a proportion of ME intake at 1 * maintenance tended (P = 0.06) to be greater for CON than for ECP (90.9% vs. 87.0% for CON and ECP, respectively); however, at 2 * maintenance energy intake, it was not different (63.9% vs. 63.8%, respectively). At 1 * maintenance intake, fasting heat production (FHP) was similar (P = 0.45) for both treatments, whereas at 2 * maintenance intake, FHP tended to be greater (P = 0.09) by 6% in ECP than in CON steers. Maintenance energy requirements estimated from linear and quadratic regression of energy retention on ME intake were 4% to 6% greater for ECP than for CON. Results of these studies suggest that feeding excess CP and MP from a protein source that is high in ruminally undegradable protein and low in protein quality will increase maintenance energy requirements of finishing steers. PMID- 29390096 TI - The Importance of Detecting Irritable Bowel-like Symptoms in Inflammatory Bowel Disease Patients. PMID- 29390097 TI - Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. PMID- 29390098 TI - Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma. PMID- 29390099 TI - MMP12 -82 A>G Promoter Polymorphism in Bronchial Asthma in a Population of Central Bulgaria. AB - A characteristic feature of inflamed lungs in bronchial asthma (BA) is airway remodeling. Due to limited information on this topic in the literature, we aimed to explore the possible role of polymorphisms in the promoter region of the macrophage elastase gene MMP12 82A>G (rs2276109) as a predisposing factor for BA in an ethnic Bulgarian population. Using restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments (PCR-RFLP), we performed genotype analysis of 58 patients and 119 control individuals. We found statistically significant differences in the distribution of genotypes (P = .008) and alleles (P = .004) between patients and nonaffected controls. In the dominant model, carriers of the G allele genotypes had 3.6-fold lower risk for BA, compared with those with the AA genotype, after adjustment for age and sex (odds ratio [OR], -0.277; 95% confidence interval [CI], .12-.65; P = .003). The results of our study suggest that the variant G allele of the MMP12 -82 A>G promoter polymorphism might be considered protective for development of BA in ethnic Bulgarian adults residing in central Bulgaria. PMID- 29390101 TI - Breastfeeding and Maternal Hypertension. AB - BACKGROUND: Little is known about the relationship between breastfeeding and hypertension. We performed this study to identify whether breastfeeding itself influenced maternal hypertension and whether degree of obesity or insulin sensitivity would contribute to the relationship between breastfeeding and hypertension in postmenopausal women. METHODS: Our study population comprised 3,119 nonsmoking postmenopausal women aged 50 years or above in the 2010-2011 Korea National Health and Nutrition Examination Survey. We performed logistic regression analyses to examine the relationship between breastfeeding and hypertension and mediation analyses to examine the contributions of obesity and insulin sensitivity to the breastfeeding-hypertension relationship. RESULTS: The odds ratios, with 95% confidence intervals, for hypertension among the highest quintile of number of breastfed children (5-11) and the highest quintile of duration of breastfeeding (96-324 months) were 0.49 (0.31-0.75) and 0.55 (0.37 0.82), respectively, compared to each of lowest quintile groups. The population attributable fractions of hypertension caused by breastfeeding 3 or fewer children and breastfeeding for 56 months or less were 10.2% (P < 0.001) and 6.5% (P = 0.017), respectively. In the mediation analysis, unexpectedly, increased insulin resistance significantly attenuated the protective effect on hypertension of having breastfed more children; additionally, greater obesity and insulin resistance significantly attenuated the protective effects on hypertension of having breastfed for longer. CONCLUSIONS: More children breastfed and longer duration of breastfeeding were associated with lower risk of hypertension in postmenopausal women, and degree of obesity and insulin resistance moderated the breastfeeding-hypertension association. PMID- 29390100 TI - Bacteria and fungi in day-old turkeys vary among companies, collection periods, and breeder flocks. AB - Microbial colonization of the intestinal tract of commercial poultry is highly variable, likely due to the fact that poults and chicks are hatched and raised without exposure to adult birds and their microbiota. In industrial poultry production, it is hypothesized that most of the microbiota is obtained through horizontal transmission from the environment and very little by maternal transmission. The initial gut microbiota will therefore differ between flocks and companies based on environmental conditions at the hatchery. Day-old poults were collected from the hatchery of 2 companies at 3 different time points to monitor the initial colonizing microbiota by sequencing amplicons of marker genes for bacteria, lactic acid bacteria (LAB), fungi, and archaea. Bacterial colonizers were distinct by company (pseudo-F 38.7, P <= 0.05) with the predominant bacteria at Company A being clostridia, specifically Clostridium celatum group, C. paraputrificum, and C. tertium. Predominant bacteria at Company B were Enterobacteriaceae, belonging to 2 different groups, one that included Escherichia; Shigella and Salmonella and the other Klebsiella; Enterobacter; and others. The predominant LAB at both companies were Enterococcus faecalis and E. gallinarum, confirmed by sequencing the 16S ribosomal RNA (rRNA) gene of colonies picked from lactobacilli agar plate counts. The predominant fungi were Aspergillus niger and Saccharomyces cerevisiae, with Candida sake or Alterneria sp. in some samples of Company A. Archaeal sequences were detected only in a single poult from Company B. The initial gastrointestinal colonizers of poults vary across company and time, signifying a strong environmental effect on microbiota acquisition. There was an indication of maternal effects in certain breeder flocks from Company B. Further work is necessary to determine how this variability affects microbiota succession and impacts growth and production of the birds. PMID- 29390102 TI - Extracellular Vesicles in Human Reproduction in Health and Disease. AB - Extensive evidence suggests that the release of membrane-enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communication both in normal physiology and in pathological conditions. This review presents evidence about the formation and release of different EVs, their definitive markers and cargo content in reproductive physiological processes, and their capacity to convey information between cells through the transfer of functional protein and genetic information to alter phenotype and function of recipient cells associated with reproductive biology. In the male reproductive tract, epididymosomes and prostasomes participate in regulating sperm motility activation, capacitation, and acrosome reaction. In the female reproductive tract, follicular fluid, oviduct/tube, and uterine cavity EVs are considered as vehicles to carry information during oocyte maturation, fertilization, and embryo-maternal crosstalk. EVs via their cargo might be also involved in the triggering, maintenance, and progression of reproductive- and obstetric-related pathologies such as endometriosis, polycystic ovarian syndrome, preeclampsia, gestational diabetes, and erectile dysfunction. In this review, we provide current knowledge on the present and future use of EVs not only as biomarkers, but also as therapeutic targeting agents, mainly as vectors for drug or compound delivery into target cells and tissues. PMID- 29390103 TI - Non-alcoholic fatty liver disease and clinical outcomes in chronic kidney disease. AB - Background: Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor associated with cardiovascular disease (CVD) and incidence of chronic kidney disease (CKD). NAFLD is threatening to become a major public health problem in association with the metabolic syndrome. The association of NAFLD with outcomes in patients with advanced CKD has not been evaluated. In this study, the prevalence of NAFLD and its impact on cardiovascular and renal outcomes and mortality were determined in a large secondary care CKD cohort. Methods: The study was conducted on 1148 CKD patients within a cohort of 3061 CKD patients, who had undergone ultrasound imaging of the liver over a 15-year period. A propensity-matched population from within the cohort was also included. Cox regression analysis was used to study the association of NAFLD with cardiovascular events, end-stage renal disease and mortality and linear regression analysis for CKD progression. Results: The prevalence of NAFLD was 17.9%. The median duration of follow-up after scanning was 5.4 years, with a median estimated glomerular filtration rate (eGFR) of 33.5 mL/min/1.73 m2 in this population. NAFLD proved to be a strong independent risk factor for cardiovascular events [hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.33 3.13; P < 0.01] but it was not associated with all-cause mortality (HR 0.79; 95% CI 0.58-1.08; P = 0.14) or CKD progression (P = 0.09 for rate of decline of eGFR slope). Patients with CKD are known to have high cardiovascular risk; the propensity-matched analysis showed that NAFLD increased this cardiovascular risk (HR 2.00; CI 1.10-3.66; P < 0.05). Conclusions: NAFLD has a strong independent association with cardiovascular events, even in an advanced CKD cohort with high comorbidity. The implication is that routine screening for NAFLD may be warranted in CKD populations to enable targeted interventions for CVD prevention in higher risk patients. PMID- 29390104 TI - Incidence of Colorectal Cancer and Extracolonic Cancers in Veteran Patients With Inflammatory Bowel Disease. AB - Background: The risk for colorectal cancer (CRC) and certain extracolonic cancers is thought to be increased in inflammatory bowel disease (IBD), but few recent US studies have evaluated this issue. We aimed to estimate the incidence of CRC and extracolonic cancers in IBD patients. Methods: In this case-control study, cases were all IBD patients treated in our Department of Veterans Affairs (VA) hospital who developed CRC or extracolonic cancers between 1996 and 2015. Controls were patients in the general VA population who developed these cancers during the same time. We compared cancer incidence rates (IRs) in cases and controls. Results: There was no significant difference between cases and controls in the 20-year IR for CRC (148/100 000 in IBD patients, 97/100 000 in controls; relative risk [RR], 1.53; 95% confidence interval [CI], 0.86-2.69). In contrast, IBD cases had a significantly higher 20-year IR for all extracolonic cancers than controls (2839/100 000 in IBD patients, 1960/100 000 in controls; RR, 1.45; 95% CI, 1.27 1.65). Site-specific analyses revealed that IBD patients had significantly elevated risks for nonmelanoma skin cancers (RR, 2.38; 95% CI, 1.99-2.85), melanoma skin cancers (RR, 2.85; 95% CI, 1.63-4.88), renal tumors (RR, 2.90; 95% CI, 1.46-5.84), prostate cancer (RR, 1.70; 95% CI, 1.28-2.27), and pancreatic cancer (RR, 4.23; 95% CI, 1.35-13.29). Conclusions: The incidence of CRC was not significantly higher in our veteran patients with IBD than in control patients in the general VA population. In contrast, our IBD patients had a significantly higher risk for extracolonic cancers than controls, including cancers of the skin, kidneys, prostate, and pancreas. 10.1093/ibd/izx046_video1Video 1.izx046_Mosher_Video5734484616001. PMID- 29390106 TI - Does provider advice to increase physical activity differ by activity level among US adults with cardiovascular disease risk factors? AB - Background: Regular physical activity (PA) lowers the risk of cardiovascular disease (CVD), but few US adults meet PA guidelines. The United States Preventive Services Task Force (USPSTF) recommends primary care providers offer PA counselling for CVD prevention. We examined the association between adherence to PA guidelines and reported provider advice to increase PA among US adults with overweight/obesity and >=1 additional CVD risk factor. Methods: Cross-sectional data from the National Health and Nutrition Examination Survey (2011-2014) on PA and provider advice to increase PA were analysed for 4158 adults (>=20 years old) with overweight/obesity who reported >=1 of hypertension, high cholesterol or impaired fasting glucose. Adherence to federal PA guidelines was determined using self-reported PA data from the Global Physical Activity Questionnaire. Meeting PA guidelines was defined as >=150 minutes/week moderate intensity PA, >=75 minutes/week vigorous intensity, or an equivalent combination. Participants self reported provider advice to increase PA. Results: In total, 57.7% of US adults with overweight/obesity and >=1 additional CVD risk factor who did not meet PA guidelines reported provider advice to increase PA compared to 49.7% of adults who met PA guidelines. Adults who did not meet PA guidelines were more likely to report provider PA advice (aOR = 1.21; 95% CI = 1.00-1.47). Conclusions: US adults with CVD risk factors who do not meet PA guidelines are more likely to receive provider advice to increase PA, but only half receive such advice. Strategies to increase provider advice are needed to improve adherence to USPSTF guidelines among US adults with overweight/obesity and additional CVD risk factors. PMID- 29390105 TI - Respiratory Syncytial Virus Seasonality: A Global Overview. AB - Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in children. By the age of 1 year, 60%-70% of children have been infected by RSV. In addition, early-life RSV infection is associated with the development of recurrent wheezing and asthma in infancy and childhood. The need for precise epidemiologic data regarding RSV as a worldwide pathogen has been growing steadily as novel RSV therapeutics are reaching the final stages of development. To optimize the prevention, diagnosis, and treatment of RSV infection in a timely manner, knowledge about the differences in the timing of the RSV epidemics worldwide is needed. Previous analyses, based on literature reviews of individual reports obtained from medical databases, have failed to provide global country seasonality patterns. Until recently, only certain countries have been recording RSV incidence through their own surveillance systems. This analysis was based on national RSV surveillance reports and medical databases from 27 countries worldwide. This is the first study to use original source, high-quality surveillance data to establish a global, robust, and homogeneous report on global country-specific RSV seasonality. PMID- 29390107 TI - Discerning autotrophy, mixotrophy and heterotrophy in marine TACK archaea from the North Atlantic. AB - DNA stable isotope probing (SIP) was used to track the uptake of organic and inorganic carbon sources for TACK archaea (Thaumarchaeota/Aigarchaeota/Crenarchaeota/Korarchaeota) on a cruise of opportunity in the North Atlantic. Due to water limitations, duplicate samples from the deep photic (60-115 m), the mesopelagic zones (local oxygen minimum; 215 835 m) and the bathypelagic zone (2085-2835 m) were amended with various combinations of 12C- or 13C-acetate/urea/bicarbonate to assess cellular carbon acquisition. The SIP results indicated the majority of TACK archaeal operational taxonomic units (OTUs) incorporated 13C from acetate and/or urea into newly synthesized DNA within 48 h. A small fraction (16%) of the OTUs, often representing the most dominant members of the archaeal community, were able to incorporate bicarbonate in addition to organic substrates. Only two TACK archaeal OTUs were found to incorporate bicarbonate but not urea or acetate. These results further demonstrate the utility of SIP to elucidate the metabolic capability of mesothermal archaea in distinct oceanic settings and suggest that TACK archaea play a role in organic carbon recycling in the mid-depth to deep ocean. PMID- 29390108 TI - Dural and pial pain-sensitive structures in humans: new inputs from awake craniotomies. AB - Our knowledge on intracranial pain-sensitive structures in humans comes essentially from observations during neurosurgical procedures performed in awake patients. It is currently accepted that intracranial pain-sensitive structures are limited to the dura mater and its feeding vessels and that small cerebral vessels and pia mater are insensitive to pain, which is inconsistent with some neurosurgical observations during awake craniotomy procedures. We prospectively collected observations of painful events evoked by mechanical stimulation (touching, stretching, pressure, or aspiration) of intracranial structures during awake craniotomies, routinely performed for intraoperative functional mapping to tailor brain tumour resection in the eloquent area. Intraoperatively, data concerning the locations of pain-sensitive structures were drawn by the surgeon on a template and their corresponding referred pain was indicated by the patient by drawing a cross on a diagram representing the head. Ninety-three painful events were observed and collected in 53 different patients (mean age 41.2 years, 25 males) operated on awake craniotomy for left (44 cases) or right (nine cases) supra-tentorial tumour resection in eloquent areas. On average, 1.8 painful events were observed per patient (range 1-5). All the painful events were referred ipsilaterally to the stimulus. In all cases, the evoked pain was sharp, intense and brief, stopped immediately after termination of the causing action, and did not interfere with the continuation of the surgery. In 30 events, pain was induced by stimulation of the dura mater of the skull base (23 events) or of the falx (seven events) and was referred predominantly in the V1 territory and in the temporal region. In 61 cases, pain was elicited by mechanical stimulation of the pia mater or small cerebral vessels of the temporal (19 events), frontal (25 events), parietal (four events) lobes and/or the peri-sylvian region, including the insular lobe (13 events), and referred in the V1 territory. In this observational study, we confirmed that dura of the skull base and dura of the falx cerebri are sensitive to pain and that their mechanical stimulation induced pain mainly referred in the sensory territories of the V1 and V3 divisions of the trigeminal nerve. Unlike earlier studies, we observed that the pia and the small cerebral vessels were also pain-sensitive, as their mechanical stimulation induced pain referred mainly in the V1 territory. These observations suggest that small pial cerebral vessels may also be involved in the pathophysiology of primary and secondary headaches.awy005media15756834882001. PMID- 29390109 TI - A low-complexity add-on score for protein remote homology search with COMER. AB - Motivation: Protein sequence alignment forms the basis for comparative modeling, the most reliable approach to protein structure prediction, among many other applications. Alignment between sequence families, or profile-profile alignment, represents one of the most, if not the most, sensitive means for homology detection but still necessitates improvement. We aim at improving the quality of profile-profile alignments and the sensitivity induced by them by refining profile-profile substitution scores. Results: We have developed a new score that represents an additional component of profile-profile substitution scores. A comprehensive evaluation shows that the new add-on score statistically significantly improves both the sensitivity and the alignment quality of the COMER method. We discuss why the score leads to the improvement and its almost optimal computational complexity that makes it easily implementable in any profile-profile alignment method. Availability and implementation: An implementation of the add-on score in the open-source COMER software and data are available at https://sourceforge.net/projects/comer. The COMER software is also available on Github at https://github.com/minmarg/comer and as a Docker image (minmar/comer). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29390110 TI - The Candida auris Alert: Facts and Perspectives. PMID- 29390111 TI - On the origins and domestication of the olive: a review and perspectives. PMID- 29390112 TI - Catch-Up Growth in Zebrafish Embryo Requires Neural Crest Cells Sustained by Irs1 Signaling. AB - Most animals display retarded growth in adverse conditions; however, upon the removal of unfavorable factors, they often show quick growth restoration, which is known as "catch-up" growth. In zebrafish embryos, hypoxia causes growth arrest, but subsequent reoxygenation induces catch-up growth. Here, we report the role of insulin receptor substrate (Irs)1-mediated insulin/insulinlike growth factor signaling (IIS) and the involvement of stem cells in catch-up growth in reoxygenated zebrafish embryos. Disturbed irs1 expression attenuated IIS, resulting in greater inhibition in catch-up growth than in normal growth and forced IIS activation-restored catch-up growth. The irs1 knockdown induced noticeable cell death in neural crest cells (NCCs; multipotent stem cells) under hypoxia, and the pharmacological/genetic ablation of NCCs hindered catch-up growth. Furthermore, inhibition of the apoptotic pathway by pan-caspase inhibition or forced activation of Akt signaling in irs1 knocked-down embryos blocked NCC cell death and rescued catch-up growth. Our data indicate that this multipotent stem cell is indispensable for embryonic catch-up growth and that Irs1-mediated IIS is a prerequisite for its survival under severe adverse environments such as prolonged hypoxia. PMID- 29390114 TI - Crosstalk between TGF-beta signaling and epigenome. PMID- 29390113 TI - Long-term Outcomes After Switching to CT-P13 in Pediatric-Onset Inflammatory Bowel Disease: A Single-Center Prospective Observational Study. AB - Background: The relatively high cost and patent expiry of infliximab, an anti tumor necrosis factor monoclonal antibody used in inflammatory bowel disease (IBD), has led to the development of biosimilar versions of the reference product (RP). This study investigated the long-term efficacy, safety, pharmacokinetics, and immunogenicity of CT-P13 after switching from infliximab RP in pediatric onset IBD patients. Methods: In this prospective observational study, patients with pediatric-onset IBD receiving maintenance infliximab RP were followed for 1 year after continuing infliximab RP (RP maintenance group) or switching to CT-P13 (CT-P13 switch group). Primary end points were the proportion of patients continuously receiving infliximab and the proportion achieving persistent remission-corticosteroid-free sustained clinical remission without dose intensification-at 1 year. Results: Thirty-six patients were recruited to the RP maintenance group and 38 to the CT-P13 switch group. At 1 year in the RP maintenance group and CT-P13 switch group, 86.1% (31/36) and 92.1% (35/38) patients had continuously received infliximab (P = 0.649), and 77.8% (28/36) and 78.9% (30/38) patients experienced persistent remission (P = 1.000), respectively. There were no statistically significant differences in any measures of disease activity, pharmacokinetics, or immunogenicity between the time of switch and 1-year postswitch in the CT-P13 switch group. Twenty-seven adverse events occurred in the maintenance group and 30 in the switch group. Conclusions: Switching from maintenance infliximab RP to CT-P13 did not result in any significant differences in efficacy, pharmacokinetics, or immunogenicity in patients with pediatric-onset IBD, and no unexpected safety issues occurred, supporting findings from randomized controlled trials. PMID- 29390115 TI - Inverse Probability Weights for the Analysis of Polytomous Outcomes. PMID- 29390116 TI - Safety and Effectiveness of Repeat Treatment With VYC-15L for Lip and Perioral Enhancement: Results From a Prospective Multicenter Study. AB - Background: VYC-15L (Juvederm Volbella XC) is a non-animal crosslinked hyaluronic acid (HA) gel with lidocaine. Objective: To evaluate safety and effectiveness of repeat treatment with VYC-15L administered 1 year after treatment for lip and perioral enhancement. Methods: In this prospective multicenter study, 124 subjects with minimal, mild, or moderate lip fullness on the validated 5-point Allergan Lip Fullness Scale (LFS) who received initial/touch-up treatment with VYC-15L received repeat treatment with VYC-15L 1 year after initial treatment. Effectiveness endpoints included LFS responder rates (>=1-point improvement from baseline) and scores on the FACE-Q Satisfaction With Lips and Appraisal of Lip Lines scales at 1 month after repeat treatment. Subjects completed safety diaries for 30 days after repeat treatment. Results: LFS responder rates were 86.2%, 80.3%, and 61.8% at months 1 and 3 and 1 year, respectively, after initial/touch up treatment. The responder rate improved to 94.3% 1 month after repeat treatment with VYC-15L and required less median volume vs initial/touchup treatment (1.5 vs 2.6 mL). FACE-Q scores doubled from baseline at 3 months, remained high through 1 year, and doubled from baseline after repeat treatment. At 1 month after repeat treatment, 96.7% and 89.3% of subjects showed improvement over baseline in FACE-Q Satisfaction With Lips and Appraisal of Lip Lines, respectively. Severe injection site responses were less frequent after repeat treatment than initial/touch-up treatment. Conclusion: Repeat treatment with VYC-15L at 1 year was safe and effective for lip and perioral enhancement, and required less product volume to achieve similar effectiveness to initial/touch-up treatment. PMID- 29390117 TI - Comment on: Reproducibility of the scleroderma pattern assessed by wide-field capillaroscopy in subjects suffering from Raynaud's phenomenon. PMID- 29390118 TI - Differences among Thai Agricultural Workers' Health, Working Conditions, and Pesticide Use by Farm Type. AB - More than 11 million Thai people (38%) work in agriculture, but since most are in the informal sector, government enforcement and support are very limited. As a result, working conditions on Thai farms vary greatly, putting the health of many agricultural workers at risk. A cross-sectional study in three Thai provinces collected information on the work activities and conditions of 424 farmers representing five farm types: rice, vegetable, flower, rice/vegetable, and flower/vegetable. The agricultural workers were mainly women (60%); their average age was 53 but ranged from 18 to 87 years. More than 64% worked more than 5 days/week. Seventy-four percent of them had only primary school education. A number of the health and hazardous working conditions surveyed were significantly different by farm type. Rice farmers were found to have the highest prevalence of allergies, nasal congestion, wheezing, and acute symptoms after pesticide use, while flower farmers had the lowest prevalence of these health outcomes. Rice farmers reported the highest prevalence of hazardous working conditions including high noise levels, working on slippery surfaces, sitting or standing on a vibrating machine, spills of chemicals/pesticides, and sharp injuries. The lowest prevalence of these working conditions (except noise) was reported by flower farmers. Vegetable farmers reported the highest prevalence knee problems, while rice farmers had the lowest prevalence. Among these farmers, more than 27 different types of pesticides were reported in use during the past year, with the majority reporting use once a month. The flower/vegetable farming group reported the highest frequency of good exposure prevention practices during pesticide use. They were the most likely to report using cotton or rubber gloves or a disposable paper masks during insecticide spraying. Those farmers who only grew vegetables had the lowest frequency of good exposure prevention practices, including use of personal protective equipment. The economic cost of work-related injuries and illnesses among informal sector agricultural workers in Thailand is unknown and in need of study. Gaps in the regulations covering pesticide sales allow farmers to purchase pesticides without adequate training in their safe use. Training targeted to farm type regarding safe pesticide use and the prevention of accidents and musculoskeletal disorders is needed. Studies of chronic health effects among Thai farmers are needed, with special emphasis on respiratory, metabolic disease and cancer. PMID- 29390119 TI - Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. AB - STUDY QUESTION: Can complete oocyte development be achieved from human ovarian tissue containing primordial/unilaminar follicles and grown in vitro in a multi step culture to meiotic maturation demonstrated by the formation of polar bodies and a Metaphase II spindle? SUMMARY ANSWER: Development of human oocytes from primordial/unilaminar stages to resumption of meiosis (Metaphase II) and emission of a polar body was achieved within a serum free multi-step culture system. WHAT IS KNOWN ALREADY: Complete development of oocytes in vitro has been achieved in mouse, where in vitro grown (IVG) oocytes from primordial follicles have resulted in the production of live offspring. Human oocytes have been grown in vitro from the secondary/multi-laminar stage to obtain fully grown oocytes capable of meiotic maturation. However, there are no reports of a culture system supporting complete growth from the earliest stages of human follicle development through to Metaphase II. STUDY DESIGN, SIZE, DURATION: Ovarian cortical biopsies were obtained with informed consent from women undergoing elective caesarean section (mean age: 30.7 +/- 1.7; range: 25-39 years, n = 10). PARTICIPANTS/MATERIALS, SETTING, METHODS: Laboratory setting. Ovarian biopsies were dissected into thin strips, and after removal of growing follicles were cultured in serum free medium for 8 days (Step 1). At the end of this period secondary/multi-laminar follicles were dissected from the strips and intact follicles 100-150 MUm in diameter were selected for further culture. Isolated follicles were cultured individually in serum free medium in the presence of 100 ng/ml of human recombinant Activin A (Step 2). Individual follicles were monitored and after 8 days, cumulus oocyte complexes (COCs) were retrieved by gentle pressure on the cultured follicles. Complexes with complete cumulus and adherent mural granulosa cells were selected and cultured in the presence of Activin A and FSH on membranes for a further 4 days (Step 3). At the end of Step 3, complexes containing oocytes >100 MUm diameter were selected for IVM in SAGE medium (Step 4) then fixed for analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Pieces of human ovarian cortex cultured in serum free medium for 8 days (Step 1) supported early follicle growth and 87 secondary follicles of diameter 120 +/- 6 MUm (mean +/- SEM) could be dissected for further culture. After a further 8 days, 54 of the 87 follicles had reached the antral stage of development. COCs were retrieved by gentle pressure from the cultured follicles and those with adherent mural granulosa cells (n = 48) were selected and cultured for a further 4 days (Step 3). At the end of Step 3, 32 complexes contained oocytes >100 MUm diameter were selected for IVM (Step 4). Nine of these complexes contained polar bodies within 24 h and all polar bodies were abnormally large. Confocal immuno-histochemical analysis showed the presence of a Metaphase II spindle confirming that these IVG oocytes had resumed meiosis but their developmental potential is unknown. LIMITATIONS, REASONS FOR CAUTION: This is a small number of samples but provides proof of concept that complete development of human oocytes can occur in vitro. Further optimization with morphological evaluation and fertilization potential of IVG oocytes is required to determine whether they are normal. WIDER IMPLICATIONS OF THE FINDINGS: The ability to develop human oocytes from the earliest follicular stages in vitro through to maturation and fertilization would benefit fertility preservation practice. STUDY FUNDING/COMPETING INTEREST(S): Funded by MRC Grants (G0901839 and MR/L00299X/1). No competing interests. PMID- 29390121 TI - Phenology of Brown Marmorated Stink Bug in a California Urban Landscape. AB - The brown marmorated stink bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae), is an invasive pest that has been resident in California since 2006. To better understand its seasonal phenology, we used baited traps to estimate nymph and adult population densities in midtown Sacramento, the focal area of the Northern California invasion. Adult H. halys populations were found soon after trapping began in February (2015-2016) or March (2014); the first egg masses for 2014, 2015, and 2016 were found on 5 May, 17 April, and 12 April, respectively, and the first nymphs were found 3 June, 19 May, and 9 May, respectively. There were two generations per year, with one peak in June and another in September. Summer temperatures above 36 degrees C in July and August were associated with reduced catches in traps of both nymphs and adults. This extreme heat may have helped to form two clear nymph peaks and suppressed egg deposition. In 2016, two trap types and four lures were also compared. Trap type influenced season-long nymph captures, with fewer nymphs in double cone traps than pyramid traps. Lure type influenced season-long trap catch, with more nymphs and adults trapped with the Rescue lure than the AgBio Combo lure, Alpha Scents, or Trece Pherocon Combo lures, although this difference was only associated with the capture of nymphs and we did not compare for longevity or seasonal variation. These data are discussed with respect to H. halys' phenology from the mid Atlantic region. PMID- 29390123 TI - Proteomics for synaptic markers of cognitive decline in neurodegenerative diseases. PMID- 29390120 TI - Development and validation of a small SNP panel for feed efficiency in beef cattle. AB - The objective of this study was to develop and validate a customized cost effective single nucleotide polymorphism (SNP) panel for genetic improvement of feed efficiency in beef cattle. The SNPs identified in previous association studies and through extensive analysis of candidate genomic regions and genes, were screened for their functional impact and allele frequency in Angus and Hereford breeds used as validation candidates for the panel. Association analyses were performed on genotypes of 159 SNPs from new samples of Angus (n = 160), Hereford (n = 329), and Angus-Hereford crossbred (n = 382) cattle using allele substitution and genotypic models in ASReml. Genomic heritabilities were estimated for feed efficiency traits using the full set of SNPs, SNPs associated with at least one of the traits (at P <= 0.05 and P < 0.10), as well as the Illumina bovine 50K representing a widely used commercial genotyping panel. A total of 63 SNPs within 43 genes showed association (P <= 0.05) with at least one trait. The minor alleles of SNPs located in the GHR and CAST genes were associated with decreasing effects on residual feed intake (RFI) and/or RFI adjusted for backfat (RFIf), whereas minor alleles of SNPs within MKI67 gene were associated with increasing effects on RFI and RFIf. Additionally, the minor allele of rs137400016 SNP within CNTFR was associated with increasing average daily gain (ADG). The SNPs genotypes within UMPS, SMARCAL, CCSER1, and LMCD1 genes showed significant over-dominance effects whereas other SNPs located in SMARCAL1, ANXA2, CACNA1G, and PHYHIPL genes showed additive effects on RFI and RFIf. Gene enrichment analysis indicated that gland development, as well as ion and cation transport are important physiological mechanisms contributing to variation in feed efficiency traits. The study revealed the effect of the Jak STAT signaling pathway on feed efficiency through the CNTFR, OSMR, and GHR genes. Genomic heritability using the 63 significant (P <= 0.05) SNPs was 0.09, 0.09, 0.13, 0.05, 0.05, and 0.07 for ADG, dry matter intake, midpoint metabolic weight, RFI, RFIf, and backfat, respectively. These SNPs contributed to genetic variation in the studied traits and thus can potentially be used or tested to generate cost effective molecular breeding values for feed efficiency in beef cattle. PMID- 29390122 TI - 14-3-3zeta is involved in the anticancer effect of metformin in colorectal carcinoma. AB - Metformin is a promising drug for cancer prevention and treatment, especially in the diabetic population. We aimed to test whether 14-3-3zeta affects the anticancer effect of metformin on colorectal carcinoma (CRC). In this study, we confirmed that higher 14-3-3zeta expression was found in CRC tissues than in pericarcinoma tissues, and in CRC tissue of patients with diabetes than in those without diabetes. A knockdown of 14-3-3zeta inhibited CRC proliferation and promoted apoptosis in vitro and in vivo. Then, we created stable cell lines with under-expressed 14-3-3zeta from SW480 and HCT15 cells after infection by a lentiviral vector carrying short hairpin RNA targeting 14-3-3zeta (named LV-sh14 3-3zeta). Of note, metformin induced apoptosis and retarded tumor growth in the CRCs with overexpressed 14-3-3zeta, whereas this action was attenuated when 14-3 3zeta was knocked down. Moreover, either metformin or downregulation of 14-3 3zeta noticeably activated AMP-dependent protein kinase (AMPK) signaling, whereas the effect of metformin was attenuated when the 14-3-3zeta expression was decreased. Taken together, our results suggest that 14-3-3zeta may be associated with carcinogenesis and poor prognosis of CRCs associated with diabetes, and metformin may reverse the AMPK inhibition caused by 14-3-3zeta in CRCs in the background of diabetes. Our study should lead to a better understanding of the anticancer activity of metformin and points to possible application of metformin to the treatment of cancers overexpressing 14-3-3zeta. PMID- 29390124 TI - Rest in peace FTDP-17. PMID- 29390125 TI - Editorial. PMID- 29390126 TI - Multimodal neuroimaging provides insights into the biology of Alzheimer's disease. PMID- 29390127 TI - Transcriptional response of Clostridium difficile to low iron conditions. AB - Clostridium difficile (Cd) is the leading cause of antibiotic-associated diarrhea. During an infection, Cd must compete with both the host and other commensal bacteria to acquire iron. Iron is essential for many cell processes, but it can also cause damage if allowed to form reactive hydroxyl radicals. In all organisms, levels of free iron are tightly regulated as are processes utilizing iron molecules. Genome-wide transcriptional analysis of Cd grown in iron-depleted conditions revealed significant changes in expression of genes involved in iron transport, metabolism and virulence. These data will aid future studies examining Cd colonization and the requirements for growth in vivo during an infection. PMID- 29390128 TI - The Effect of Workforce Mobility on Intervention Effectiveness Estimates. AB - Background: Little is known about how mobile populations of workers may influence the ability to implement, measure, and evaluate health and safety interventions delivered at worksites. Methods: A simulation study is used to objectively measure both precision and relative bias of six different analytic methods as a function of the amount of mobility observed in the workforce. Those six methods are then used to reanalyze a previously conducted cluster-randomized control trial involving a highly mobile workforce in the construction industry. Results: As workforce mobility increases, relative bias in treatment effects derived from standard models to analyze cluster-randomized trials also increases. Controlling for amount of time exposed to the intervention can greatly reduce this bias. Analyzing only subsets of workers who exhibit the least amount of mobility can result in decreased precision of treatment effect estimates. We demonstrate a 59% increase in the treatment effect size from the reanalysis of the previously conducted trial. Conclusions: When evaluating organizational interventions implemented at specific worksites by measuring perceptions and outcomes of workers present at those sites, researchers should consider the effects that the mobility of the workforce may have on the estimated treatment effects. The choice of analytic method can greatly affect both precision and accuracy of estimates. PMID- 29390129 TI - Direct visualization of the expression and localization of chlamydial effector proteins within infected host cells. AB - Chlamydia secrete into host cells a diverse array of effector proteins, but progress in characterizing the spatiotemporal localization of these proteins has been hindered by a paucity of genetic approaches in Chlamydia and also by the challenge of studying these proteins within the live cellular environment. We adapted a split-green fluorescent protein (GFP) system for use in Chlamydia to label chlamydial effector proteins and track their localization in host cells under native environment. The efficacy of this system was demonstrated by detecting several known Chlamydia proteins including IncA, CT005 and CT694. We further used this approach to detect two chlamydial deubiquitinases (CT867 and CT868) within live cells during the infection. CT868 localized only to the inclusion membrane at early and late developmental stages. CT867 localized to the chlamydial inclusion membrane at an early developmental stage and was concomitantly localized to the host plasma membrane at a late stage during the infection. These data suggest that chlamydial deubiquitinase play important roles for chlamydial pathogenesis by targeting proteins at both the plasma membrane and the chlamydial inclusion membrane. The split-GFP technology was demonstrated to be a robust and efficient approach to identify the secretion and cellular localization of important chlamydial virulence factors. PMID- 29390130 TI - Comment on: Reproducibility of the scleroderma pattern assessed by wide-field capillaroscopy in subjects suffering from Raynaud's phenomenon: reply. PMID- 29390131 TI - Comparative genomic survey of Bacillus cereus sensu stricto isolates from the dairy production chain in Brazil. AB - The genomes of 262 Bacillus cereus isolates were analyzed including 69 isolates sampled from equipment, raw milk and dairy products from Brazil. The population structure of isolates showed strains belonging to known phylogenetic groups II, III, IV, V and VI. Almost all the isolates obtained from dairy products belonged to group III. Investigation of specific alleles revealed high numbers of isolates carrying toxin-associated genes including cytK (53.62%), hblA (59.42%), hblC (44.93%), hblD (53.62%), nheA (84.06%), nheB (89.86%) and nheC (84.06%) with isolates belonging to groups IV and V having significant higher prevalence of hblACD and group IV of CytK genes. Strains from dairy products had significantly lower prevalence of CytK and hblACD genes compared to isolates from equipment and raw milk/bulk tanks. Genes related to sucrose metabolism were detected at higher frequency in isolates obtained from raw milk compared to strains from equipment and utensils. The population genomic analysis demonstrated the diversity of strains and variability of putative function among B. cereus group isolates in Brazilian dairy production, with large numbers of strains potentially able to cause foodborne illness. This detailed information will contribute to targeted interventions to reduce milk contamination and spoilage associated with B. cereus in Brazil. PMID- 29390132 TI - A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis. AB - Enterococci, one of the most common causes of hospital-associated infections, are responsible for substantial morbidity and mortality. Enterococcus faecalis, the more common and virulent species, causes serious high-inoculum infections, namely infective endocarditis, that are associated with cardiac surgery and mortality rates that remained unchanged for the last 30 years. The best cures for these infections are observed with combination antibiotic therapy; however, optimal treatment has not been fully elucidated. It is the purpose of this review to highlight treatment options and their limitations, and provide direction for future investigative efforts to aid in the treatment of these severe infections. While ampicillin plus ceftriaxone has emerged as a preferred treatment option, mortality rates continue to be high, and from a safety standpoint, ceftriaxone, unlike other cephalosporins, promotes colonization with vancomycin resistant enterococci due to high biliary concentrations. More research is needed to improve patient outcomes from this high-mortality disease. PMID- 29390133 TI - Commentary: Renewed controversy over cardiovascular risk with non-steroidal anti inflammatory drugs. PMID- 29390135 TI - Spotlight on... Emmanuelle Charpentier. PMID- 29390134 TI - The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA. AB - During amino acid starvation the Escherichia coli stringent response factor RelA recognizes deacylated tRNA in the ribosomal A-site. This interaction activates RelA-mediated synthesis of alarmone nucleotides pppGpp and ppGpp, collectively referred to as (p)ppGpp. These two alarmones are synthesized by addition of a pyrophosphate moiety to the 3' position of the abundant cellular nucleotide GTP and less abundant nucleotide GDP, respectively. Using untagged native RelA we show that allosteric activation of RelA by pppGpp increases the efficiency of GDP conversion to achieve the maximum rate of (p)ppGpp production. Using a panel of ribosomal RNA mutants, we show that the A-site finger structural element of 23S rRNA helix 38 is crucial for RelA binding to the ribosome and consequent activation, and deletion of the element severely compromises (p)ppGpp accumulation in E. coli upon amino acid starvation. Through binding assays and enzymology, we show that E. coli RelA does not form a stable complex with, and is not activated by, deacylated tRNA off the ribosome. This indicates that in the cell, RelA first binds the empty A-site and then recruits tRNA rather than first binding tRNA and then binding the ribosome. PMID- 29390136 TI - mir-374-5p, mir-379-5p, and mir-503-5p Regulate Proliferation and Hypertrophic Differentiation of Growth Plate Chondrocytes in Male Rats. AB - Growth plate chondrocytes undergo sequential differentiation to form the resting zone, the proliferative zone (PZ), and the hypertrophic zone (HZ). The important role of microRNAs (miRNAs) in the growth plate was previously revealed by cartilage-specific ablation of Dicer, an enzyme essential for biogenesis of many miRNAs. To identify specific miRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes, we microdissected individual growth plate zones from juvenile rats and performed miRNA profiling using a solution hybridization method and miRNA sequencing. Thirty-four miRNAs were differentially expressed between the PZ and the HZ, and we hypothesized that some of the miRNAs that are preferentially expressed in the PZ may promote proliferation and inhibit hypertrophic differentiation. Consistent with this hypothesis, transfection of inhibitors for four of these miRNAs (mir-369-3p, mir-374-5p, mir-379-5p, and mir 503-5p) decreased proliferation in primary epiphyseal chondrocytes. The inhibitors for three of these miRNAs (mir-374-5p, mir-379-5p, and mir-503-5p) also increased expression of multiple genes that are associated with chondrocyte hypertrophic differentiation. We next hypothesized that preferential expression of these miRNAs in the PZ is driven by the parathyroid hormone-related protein (PTHrP) concentration gradient across the growth plate. Consistent with this hypothesis, treatment of primary chondrocytes with a parathyroid hormone (PTH)/PTHrP receptor agonist, PTH1-34, increased expression of mir-374-5p, mir 379-5p, and mir-503-5p. Taken together, our findings suggest that the PTHrP concentration gradient across the growth plate induces differential expression of mir-374-5p, mir-379-5p, and mir-503-5p between the PZ and the HZ. In the PZ, the higher expression levels of these miRNAs promote proliferation and inhibit hypertrophic differentiation. In the HZ, downregulation of these miRNAs inhibits proliferation and promotes hypertrophic differentiation. PMID- 29390137 TI - In vitro activity of antimicrobial compounds against Xylella fastidiosa, the causal agent of the olive quick decline syndrome in Apulia (Italy). AB - Olive quick decline syndrome (OQDS) causes severe damages to the olive trees in Salento (Apulia, Italy) and poses a severe threat for the agriculture of Mediterranean countries. DNA-based typing methods have pointed out that OQDS is caused by a single outbreak strain of Xylella fastidiosa subsp. pauca referred to as CoDiRO or ST53. Since no effective control measures are currently available, the objective of this study was to evaluate in vitro antimicrobial activities of different classes of compounds against Salento-1 isolated by an OQDS affected plant and classified as ST53. A bioassay based on agar disk diffusion method revealed that 17 out of the 32 tested antibiotics did not affect bacterial growth at a dose of 5 MUg disk-1. When we assayed micro-, ultra- and nano-filtered fractions of olive mill wastewaters, we found that the micro-filtered fraction resulted to be the most effective against the bacterium. Moreover, some phenolics (4-methylcathecol, cathecol, veratric acid, caffeic acid, oleuropein) were active in their pure form. Noteworthy, also some fungal extracts and fungal toxins showed inhibitory effects on bacterial growth. Some of these compounds can be further explored as potential candidate in future applications for curative/preventive treating OQDS-affected or at-risk olive plants. PMID- 29390139 TI - Maintaining quality of life near the end of life: hospice in neuro-oncology. PMID- 29390138 TI - Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease. AB - Modified uridine containing taurine, 5-taurinomethyluridine (taum5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that taum5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of taum5U remained elusive. Here, we elucidated taum5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for taum5U formation catalyzed by MTO1 and GTPBP3. GTPBP3 knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little taum5U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of taum5U results in pathological consequences. Taurine starvation resulted in downregulation of taum5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5 carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of taum5U is replaced with glycine, was detected in mt-tRNAs from taurine-depleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition. PMID- 29390141 TI - Mosquito Species (Diptera: Culicidae) Diversity from Ovitraps in a Mesoamerican Tropical Rainforest. AB - Mosquito sampling using efficient traps that can assess species diversity and/or presence of dominant vectors is important for understanding the entomological risk of mosquito-borne disease transmission. Here, we present results from a survey of mosquito species sampled with ovitraps in a neotropical rainforest of Costa Rica. We found the method to be an efficient sampling tool. With a total sampling effort of 29 traps, we collected 157 fourth-instar larvae and three pupae belonging to eight mosquito taxonomic units (seven species and individuals from a homogenous taxonomic unit identified to the genus level). In our samples, we found two medically important species, Sabethes chloropterus (Humboldt) and Trichoprosopon digitatum (Rondani). The former is a proven vector of Yellow Fever in sylvatic environments and the later has been found infected with several arboviruses. We also found that mosquito species abundance and diversity increased with canopy cover and in environments where leaf litter dominated the ground cover. Finally, our results suggest that ovitraps have a great potential for systematic sampling in longitudinal and cross-sectional ecological "semi field" studies in neotropical settings. PMID- 29390142 TI - Endosymbiont diversity and prevalence in herbivorous spider mite populations in South-Western Europe. AB - Bacterial endosymbionts are known as important players of the evolutionary ecology of their hosts. However, their distribution, prevalence and diversity are still largely unexplored. To this aim, we investigated infections by the most common bacterial reproductive manipulators in herbivorous spider mites of South Western Europe. Across 16 populations belonging to three Tetranychus species, Wolbachia was the most prevalent (ca. 61%), followed by Cardinium (12%-15%), while only few individuals were infected by Rickettsia (0.9%-3%), and none carried Arsenophonus or Spiroplasma. These endosymbionts are here reported for the first time in Tetranychus evansi and Tetranychus ludeni, and showed variable infection frequencies between and within species, with several cases of coinfections. Moreover, Cardinium was more prevalent in Wolbachia-infected individuals, which suggests facilitation between these symbionts. Finally, sequence comparisons revealed no variation of the Wolbachia wsp and Rickettsia gtlA genes, but some diversity of the Cardinium 16S rRNA, both between and within populations of the three mite species. Some of the Cardinium sequences identified belonged to distantly-related clades, and the lack of association between these sequences and spider mite mitotypes suggests repeated host switching of Cardinium. Overall, our results reveal a complex community of symbionts in this system, opening the path for future studies. PMID- 29390140 TI - Positively Selected Effector Genes and Their Contribution to Virulence in the Smut Fungus Sporisorium reilianum. AB - Plants and fungi display a broad range of interactions in natural and agricultural ecosystems ranging from symbiosis to parasitism. These ecological interactions result in coevolution between genes belonging to different partners. A well-understood example is secreted fungal effector proteins and their host targets, which play an important role in pathogenic interactions. Biotrophic smut fungi (Basidiomycota) are well-suited to investigate the evolution of plant pathogens, because several reference genomes and genetic tools are available for these species. Here, we used the genomes of Sporisorium reilianum f. sp. zeae and S. reilianum f. sp. reilianum, two closely related formae speciales infecting maize and sorghum, respectively, together with the genomes of Ustilago hordei, Ustilago maydis, and Sporisorium scitamineum to identify and characterize genes displaying signatures of positive selection. We identified 154 gene families having undergone positive selection during species divergence in at least one lineage, among which 77% were identified in the two investigated formae speciales of S. reilianum. Remarkably, only 29% of positively selected genes encode predicted secreted proteins. We assessed the contribution to virulence of nine of these candidate effector genes in S. reilianum f. sp. zeae by deleting individual genes, including a homologue of the effector gene pit2 previously characterized in U. maydis. Only the pit2 deletion mutant was found to be strongly reduced in virulence. Additional experiments are required to understand the molecular mechanisms underlying the selection forces acting on the other candidate effector genes, as well as the large fraction of positively selected genes encoding predicted cytoplasmic proteins. PMID- 29390143 TI - Unusual Genomic Traits Suggest Methylocystis bryophila S285 to Be Well Adapted for Life in Peatlands. AB - The genus Methylocystis belongs to the class Alphaproteobacteria, the family Methylocystaceae, and encompasses aerobic methanotrophic bacteria with the serine pathway of carbon assimilation. All Methylocystis species are able to fix dinitrogen and several members of this genus are also capable of using acetate or ethanol in the absence of methane, which explains their wide distribution in various habitats. One additional trait that enables their survival in the environment is possession of two methane-oxidizing isozymes, the conventional particulate methane monooxygenase (pMMO) with low-affinity to substrate (pMMO1) and the high-affinity enzyme (pMMO2). Here, we report the finished genome sequence of Methylocystis bryophila S285, a pMMO2-possessing methanotroph from a Sphagnum-dominated wetland, and compare it to the genome of Methylocystis sp. strain SC2, which is the first methanotroph with confirmed high-affinity methane oxidation potential. The complete genome of Methylocystis bryophila S285 consists of a 4.53 Mb chromosome and one plasmid, 175 kb in size. The genome encodes two types of particulate MMO (pMMO1 and pMMO2), soluble MMO and, in addition, contains a pxmABC-like gene cluster similar to that present in some gammaproteobacterial methanotrophs. The full set of genes related to the serine pathway, the tricarboxylic acid cycle as well as the ethylmalonyl-CoA pathway is present. In contrast to most described methanotrophs including Methylocystis sp. strain SC2, two different types of nitrogenases, that is, molybdenum-iron and vanadium-iron types, are encoded in the genome of strain S285. This unique combination of genome-based traits makes Methylocystis bryophila well adapted to the fluctuation of carbon and nitrogen sources in wetlands. PMID- 29390144 TI - Clinical Predictors of Liver Fibrosis in Patients With Chronic Hepatitis B Virus Infection From Children to Adults. AB - Background: This study aimed to elucidate predictors of liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. Methods: Transient elastography was performed to define liver stiffness in 533 patients with chronic HBV infection (mean age +/- standard deviation, 30.72 +/- 0.57 years). Protein array was performed on serum samples and lysates of Huh7 cells transfected with HBV mutants; the results were confirmed by enzyme-linked immunosorbent assay. Single-nucleotide polymorphisms in the gene encoding interleukin 1beta (IL-1beta) were examined in patients with chronic HBV infection with and without liver fibrosis. Results: Male sex, age >=18 years, and serum alpha-fetoprotein level >3.6 ng/mL were independent predictors of a liver stiffness measurement of >=7 kPa (P = .005, .019, and <.001, respectively). HBV e antigen (HBeAg)-negative hepatitis is associated with increased liver stiffness (P < .001). Elevation of the serum IL-1beta level was demonstrated in subjects with liver fibrosis. IL 1beta was upregulated in Huh7 cells transfected with HBV mutants associated with HBeAg-negative hepatitis. The AA genotype at rs16944 and the CC genotype at rs1143627 in the gene encoding IL-1beta were associated with higher serum IL 1beta levels and liver fibrosis. Conclusions: Male sex, age >=18 years, elevated alpha-fetoprotein level, and HBeAg-negative hepatitis are risk factors for liver fibrosis. IL-1beta is involved in the progression of liver fibrosis in subjects with HBeAg-negative hepatitis. PMID- 29390145 TI - RecA requires two molecules of Mg2+ ions for its optimal strand exchange activity in vitro. AB - Mg2+ ion stimulates the DNA strand exchange reaction catalyzed by RecA, a key step in homologous recombination. To elucidate the molecular mechanisms underlying the role of Mg2+ and the strand exchange reaction itself, we investigated the interaction of RecA with Mg2+ and sought to determine which step of the reaction is affected. Thermal stability, intrinsic fluorescence, and native mass spectrometric analyses of RecA revealed that RecA binds at least two Mg2+ ions with KD ~ 2 mM and 5 mM. Deletion of the C-terminal acidic tail of RecA made its thermal stability and fluorescence characteristics insensitive to Mg2+ and similar to those of full-length RecA in the presence of saturating Mg2+. These observations, together with the results of a molecular dynamics simulation, support the idea that the acidic tail hampers the strand exchange reaction by interacting with other parts of RecA, and that binding of Mg2+ to the tail prevents these interactions and releases RecA from inhibition. We observed that binding of the first Mg2+ stimulated joint molecule formation, whereas binding of the second stimulated progression of the reaction. Thus, RecA is actively involved in the strand exchange step as well as bringing the two DNAs close to each other. PMID- 29390147 TI - Valid and efficient subgroup analyses using nested case-control data. AB - Background: It is not uncommon for investigators to conduct further analyses of subgroups, using data collected in a nested case-control design. Since the sampling of the participants is related to the outcome of interest, the data at hand are not a representative sample of the population, and subgroup analyses need to be carefully considered for their validity and interpretation. Methods: We performed simulation studies, generating cohorts within the proportional hazards model framework and with covariate coefficients chosen to mimic realistic data and more extreme situations. From the cohorts we sampled nested case-control data and analysed the effect of a binary exposure on a time-to-event outcome in subgroups defined by a covariate (an independent risk factor, a confounder or an effect modifier) and compared the estimates with the corresponding subcohort estimates. Cohort analyses were performed with Cox regression, and nested case control samples or restricted subsamples were analysed with both conditional logistic regression and weighted Cox regression. Results: For all studied scenarios, the subgroup analyses provided unbiased estimates of the exposure coefficients, with conditional logistic regression being less efficient than the weighted Cox regression. Conclusions: For the study of a subpopulation, analysis of the corresponding subgroup of individuals sampled in a nested case-control design provides an unbiased estimate of the effect of exposure, regardless of whether the variable used to define the subgroup is a confounder, effect modifier or independent risk factor. Weighted Cox regression provides more efficient estimates than conditional logistic regression. PMID- 29390146 TI - MiRNA160 is associated with local defense and systemic acquired resistance against Phytophthora infestans infection in potato. AB - To combat pathogen infection, plants employ local defenses in infected sites and elicit systemic acquired resistance (SAR) in distant tissues. MicroRNAs have been shown to play a significant role in local defense, but their association with SAR is unknown. In addition, no such studies of the interaction between potato and Phytophthora infestans have been reported. We investigated the role of miR160 in local and SAR responses to P. infestans infection in potato. Expression analysis revealed induced levels of miR160 in both local and systemic leaves of infected wild-type plants. miR160 overexpression and knockdown plants exhibited increased susceptibility to infection, suggesting that miR160 levels equivalent to those of wild-type plants may be necessary for mounting local defense responses. Additionally, miR160 knockdown lines failed to elicit SAR, and grafting assays indicated that miR160 is required in both local and systemic leaves to trigger SAR. Consistently, SAR-associated signals and genes were dysregulated in miR160 knockdown lines. Furthermore, analysis of the expression of defense and auxin pathway genes and direct regulation of StGH3.6, a mediator of salicylic acid auxin cross-talk, by the miR160 target StARF10 revealed the involvement of miR160 in antagonistic cross-talk between salicylic acid-mediated defense and auxin mediated growth pathways. Overall, our study demonstrates that miR160 plays a crucial role in local defense and SAR responses during the interaction between potato and P. infestans. PMID- 29390148 TI - Adherence to the Mediterranean diet and IVF success rate among non-obese women attempting fertility. AB - STUDY QUESTION: Is adherence to the Mediterranean diet (MedDiet) associated with better IVF performance in women attempting fertility? SUMMARY ANSWER: Greater adherence to the MedDiet, defined using the validated Mediterranean diet score (MedDietScore), was associated with a higher likelihood of achieving clinical pregnancy and live birth among non-obese women <35 years of age. WHAT IS KNOWN ALREADY: Diet impacts fertility and certain nutrients and food groups appear to have a greater effect on reproductive health, but there are relatively few published data on the role of dietary patterns, and the MedDiet in particular, on assisted reproductive performance. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 244 non-obese women (22-41 years of age; BMI < 30 kg/m2) who underwent a first IVF treatment in an Assisted Conception Unit in Athens, Greece, between November 2013 and September 2016. The study was designed to evaluate the influence of habitual dietary intake and lifestyle on fertility outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed before the IVF treatment via a validated food-frequency questionnaire. Adherence to the MedDiet was assessed through the MedDietScore (range: 0-55), with higher scores indicating greater adherence. Intermediate outcomes (oocyte yield, fertilization rate and embryo quality measures) and clinical endpoints (implantation, clinical pregnancy and live birth) were abstracted from electronic medical records. Associations between MedDietScore and IVF outcomes were analysed using generalized linear models adjusting for age, ovarian stimulation protocol, BMI, physical activity, anxiety levels, infertility diagnosis, caloric intake and supplements use. MAIN RESULTS AND THE ROLE OF CHANCE: No association of MedDietScore with any of the intermediate outcomes or with implantation was found. However, compared with women in the highest tertile of the MedDietScore (>=36, n = 86), women in the lowest tertile (<=30, n = 79) had significantly lower rates of clinical pregnancy (29.1 vs 50.0%, P = 0.01) and live birth (26.6 vs 48.8%, P = 0.01). The multivariable-adjusted relative risk (95% CI) for clinical pregnancy comparing women in the lowest with women in the highest tertile of the MedDietScore was 0.35 (0.16-0.78; P-trend=0.01), and for live birth it was 0.32 (0.14-0.71; P-trend = 0.01). These associations were significantly modified by women's age (P-interaction <0.01 for both outcomes). MedDietScore was positively related to clinical pregnancy and live birth among women <35 years old (P <= 0.01) but not among women >=35 years. Among women <35 years, a beneficial 5-point increase in the MedDietScore was associated with ~2.7 times higher likelihood of achieving clinical pregnancy and live birth. LIMITATIONS, REASONS FOR CAUTION: Our finding cannot be generalized to the whole reproductive population nor to obese women nor to women attending infertility clinics around the world. In addition, due to the observational study design, causal inference is limited. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that diet modifications and greater compliance to the Mediterranean diet may help increase the chances of a successful pregnancy and delivering a live baby for women undergoing IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was partially supported by a grand from Harokopio University (KE321). All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT03050944. PMID- 29390149 TI - Cord Blood Antiparasite Interleukin 10 as a Risk Marker for Compromised Vaccine Immunogenicity in Early Childhood. AB - Background: Antenatal exposure to parasites can affect infants' subsequent responses to vaccination. The present study investigated how maternal prenatal infections and newborns' antiparasite cytokine profiles relate to immunoglobulin G (IgG) responses to standard vaccination during infancy. Methods: A total of 450 Kenyan women were tested for parasitic infections during pregnancy. Their newborns' responses to Plasmodium falciparum, schistosome, and filaria antigens were assessed in cord blood lymphocytes. Following standard neonatal vaccination, this infant cohort was followed biannually to age 30 months for measurement of circulating IgG levels against Haemophilus influenzae b (Hib), diphtheria toxoid (DT), hepatitis B virus (HBV), and tetanus toxoid. Results: Trajectories of postvaccination IgG levels were classified by functional principal component (PC) analysis to assess each child's response profile. Two main components, PC1, reflecting height of response over time, and PC2, reflecting crossover from high to low responses or from low to high responses, were identified. Cord blood cytokine responses to schistosome and filarial antigens showed a significant association between augmented antihelminth interleukin 10 and reduced antibody levels, particularly to DT and HBV, and a more rapid postvaccination decline in circulating IgG levels against Hib. Conclusion: Antenatal sensitization to schistosomiasis or filariasis and related production of antiparasite interleukin 10 at birth are associated with reduced antivaccine IgG levels in infancy, with possibly impaired protection. PMID- 29390150 TI - Histo-Blood Group Antigen Phenotype Determines Susceptibility to Genotype Specific Rotavirus Infections and Impacts Measures of Rotavirus Vaccine Efficacy. AB - Background: Lewis and secretor histo-blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE. Methods: In infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD. Results: A vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36-.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort. Conclusions: Host HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status. Clinical Trials Registration: NCT01375647. PMID- 29390151 TI - A transcription factor network responsive to high CO2/hypoxia is involved in deastringency in persimmon fruit. AB - Plant responses to anaerobic environments are regulated by ethylene-response factors (ERFs) in both vegetative and productive organs, but the roles of other transcription factors (TFs) in hypoxia responses are poorly understood. In this study, eight TFs (DkbHLH1, DkMYB9/10/11, DkRH2-1, DkGT3-1, DkAN1-1, DkHSF1) were shown to be strongly up-regulated by an artificial high-CO2 atmosphere (1% O2 and 95% CO2). Dual-luciferase assays indicated that some TFs were activators of previously characterized DkERFs, including DkMYB10 for the DkERF9 promoter, DkERF18/19 and DkMYB6 for the DkERF19 promoter, and DkERF21/22 for the DkERF10 promoter. Yeast one-hybrid and cis-element mutagenesis confirmed these physical interactions with one exception. The potential roles of these TFs in persimmon fruit deastringency were analysed by investigating their transient over expression (TOX) in persimmon fruit discs, which indicated that DkMYB6TOX, DkMYB10TOX, DkERF18TOX, and DkERF19TOX were all effective in causing insolubilization of tannins, concomitantly with the up-regulation of the corresponding genes. These results indicated that multiple TFs of different classes are responsive to high-CO2/hypoxia in fruit tissues, and that a TF-TF regulatory cascade is involved in the hypoxia responses involving the Group VII DkERF10, and DkERFs and DkMYBs. PMID- 29390152 TI - Acute Liver Failure in an Adolescent Male Induced by Human Herpesvirus 6 (HHV-6): A Case Report With Literature Review. AB - A previously healthy 11-year-old Caucasian boy presented with a 2-week history of nonspecific symptoms of nausea and nonbilious, nonbloody emesis. He developed significant jaundice and hepatic encephalopathy within 1 week of beginning symptoms and was discovered to have fulminant liver failure. Extensive work-ups for underlying etiologies included serologic evaluation for underlying chronic liver diseases, toxicology screening, inborn errors of metabolism, and infectious diseases. The results of the entire assessment were negative except for human herpesvirus 6B, which was detected in the liver by quantitative real-time polymerase chain reaction and immunohistochemical analysis. The patient underwent ABO-compatible liver transplantation and has had clinically stable health, with no evidence to date of complications associated with HHV-6 or other members of the herpesvirus family. PMID- 29390153 TI - Interleukin-21 Regulates Natural Killer Cell Responses During Mycobacterium tuberculosis Infection. AB - Background: In the current study, we determined the effects of interleukin (IL) 21 on human natural killer (NK) cells and monocyte responses during Mycobacterium tuberculosis (Mtb) infection. Methods: We found that Mtb stimulated CD4+ and NK T cells from healthy individuals with latent tuberculosis infection (LTBI+) are major sources of IL-21. CD4+ cells from tuberculosis patients secreted less IL-21 than did CD4+ cells from healthy LTBI+ individuals. Interleukin-21 had no direct effect on Mtb-stimulated monocytes. Results: Interleukin-21-activated NK cells produced interferon (IFN)-gamma, perforin, granzyme B, and granulysin; lysed Mtb infected monocytes; and reduced Mtb growth. Interleukin-21-activated NK cells also enhanced IL-1beta, IL-18, and CCL4/macrophage-inflammatory protein (MIP) 1beta production and reduced IL-10 production by Mtb-stimulated monocytes. Recombinant IL-21 (1) inhibited Mtb growth, (2) enhanced IFN-gamma, IL-1beta, IL 18, and MIP-1beta, and (3) reduced IL-10 expression in the lungs of Mtb-infected Rag2 knockout mice. Conclusions: These findings suggest that activated T cells enhance NK cell responses to lyse Mtb-infected human monocytes and restrict Mtb growth in monocytes through IL-21 production. Interleukin-21-activated NK cells also enhance the immune response by augmenting IL-1beta, IL-18, and MIP-1beta production and reducing IL-10 production by monocytes in response to an intracellular pathogen. PMID- 29390154 TI - Bacterial gene control by DNA looping using engineered dimeric transcription activator like effector (TALE) proteins. AB - Genetic switches must alternate between states whose probabilities are dependent on regulatory signals. Classical examples of transcriptional control in bacteria depend on repressive DNA loops anchored by proteins whose structures are sensitive to small molecule inducers or co-repressors. We are interested in exploiting these natural principles to engineer artificial switches for transcriptional control of bacterial genes. Here, we implement designed homodimeric DNA looping proteins ('Transcription Activator-Like Effector Dimers'; TALEDs) for this purpose in living bacteria. Using well-studied FKBP dimerization domains, we build switches that mimic regulatory characteristics of classical Escherichia coli lactose, galactose and tryptophan operon promoters, including induction or co-repression by small molecules. Engineered DNA looping using TALEDs is thus a new approach to tuning gene expression in bacteria. Similar principles may also be applicable for gene control in eukaryotes. PMID- 29390155 TI - The S-Type Anion Channel ZmSLAC1 Plays Essential Roles in Stomatal Closure by Mediating Nitrate Efflux in Maize. AB - Diverse stimuli induce stomatal closure by triggering the efflux of osmotic anions, which is mainly mediated by the main anion channel SLAC1 in plants, and the anion permeability and selectivity of SLAC1 channels from several plant species have been reported to be variable. However, the genetic identity as well as the anion permeability and selectivity of the main S-type anion channel ZmSLAC1 in maize are still unknown. In this study, we identified GRMZM2G106921 as the gene encoding ZmSLAC1 in maize, and the maize mutants zmslac1-1 and zmslac1-2 harboring a mutator (Mu) transposon in ZmSLAC1 exhibited strong insensitive phenotypes of stomatal closure in response to diverse stimuli. We further found that ZmSLAC1 functions as a nitrate-selective anion channel without obvious permeability to chloride, sulfate and malate, clearly different from SLAC1 channels of Arabidopsis thaliana, Brassica rapa ssp. chinensis and Solanum lycopersicum L. Further experimental data show that the expression of ZmSLAC1 successfully rescued the stomatal movement phenotypes of the Arabidopsis double mutant atslac1-3atslah3-2 by mainly restoring nitrate-carried anion channel currents of guard cells. Together, these findings demonstrate that ZmSLAC1 is involved in stomatal closure mainly by mediating the efflux of nitrate in maize. PMID- 29390156 TI - The epidemiology and management of candidemia in Northern Ireland during 2002 2011, including a 12-month enhanced case review. AB - In Northern Ireland there are concerns about candidaemia, with rates higher than those reported in England and Wales. Our aim was to explore the epidemiology of candidaemia during a 10 year period and the clinical management upon suspicion of cases during a one year enhanced investigation in Northern Ireland.Candidaemia reports to the Public Health Agency were validated during 2002-2011 and used to examine incidence and antifungal sensitivity trends (during 2007-2011). A clinical proforma was used to collate information for all patients with candidaemia in 2011.The majority (96%) of isolates were captured through voluntary laboratory reporting. There was a year-on-year increase in candidaemia from 2002-2011, from 80 to 131 episodes (incidence rate ratio 1.09 95% CI 1.05 1.13). Rates were highest in males under 1 year and over 75 years. 83/98 (85%) of case notes were available from candidaemia patients during 2011. The most prevalent risk factors were patients on total parenteral nutrition (26 people, 31.3%), surgery in the two months prior to the candidaemia (25 people, 30.1%), significant steroid use in the previous 3 months (24 people, 28.9%) and active neoplastic disease (23 people, 27.7%),This study confirmed an increase in candidaemia rates over time, with the observed incidence in 2011 higher than England and Wales. We identified areas for improvement around the clinical management of candidaemia. We recommend raising the awareness of guidelines for fundoscopy, echocardiography and central venous catheter removal. PMID- 29390157 TI - Vacuolar Protein Degradation via Autophagy Provides Substrates to Amino Acid Catabolic Pathways as an Adaptive Response to Sugar Starvation in Arabidopsis thaliana. AB - The vacuolar lytic degradation of proteins releases free amino acids that plants can use instead of sugars for respiratory energy production. Autophagy is a major cellular process leading to the transport of proteins into the vacuole for degradation. Here, we examine the contribution of autophagy to the amino acid metabolism response to sugar starvation in mature leaves of Arabidopsis thaliana. During sugar starvation arising from the exposure of wild-type (WT) plants to darkness, autophagic transport of chloroplast stroma, which contains most of the proteins in a leaf, into the vacuolar lumen was induced within 2 d. During this time, the level of soluble proteins, primarily Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase), decreased and the amount of free amino acid increased. In dark-treated autophagy-defective (atg) mutants, the decrease of soluble proteins was suppressed, which resulted in the compromised release of basic amino acids, branched-chain amino acids (BCAAs) and aromatic amino acids. The impairment of BCAA catabolic pathways in the knockout mutants of the electron transfer flavoprotein (ETF)/ETF:ubiquinone oxidoreductase (etfqo) complex and the electron donor protein isovaleryl-CoA dehydrogenase (ivdh) caused a reduced tolerance to dark treatment similar to that in the atg mutants. The enhanced accumulation of BCAAs in the ivdh and etfqo mutants during the dark treatment was reduced by additional autophagy deficiency. These results indicate that vacuolar protein degradation via autophagy serves as an adaptive response to disrupted photosynthesis by providing substrates to amino acid catabolic pathways, including BCAA catabolism mediated by IVDH and ETFQO. PMID- 29390158 TI - Consumer acceptance of eggs from Hy-Line Brown layers fed soybean or soybean-free diets using cage or free-range rearing systems. AB - Consumers have begun to awaken to the food on their plates with respect to human health and the environment, as well as animal welfare. They have become more demanding about what they buy or prefer in their food, such as soy-free, gluten free, or organic products. The objective of this study was to evaluate consumer acceptance of eggs from hens fed soybean meal or soybean-free diets utilizing cottonseed meal and distillers' dried grains, using cage or free-range rearing systems. All eggs were stored at the sensory lab at Texas A&M University (TAMU) for a d prior to each test at 4 degrees C. A panel of consumers (n = 60) made up of TAMU students, faculty, and staff, ages 18 to 50, were recruited to evaluate consumer acceptance based on 2 tests using scrambled and hard cooked eggs. Samples were placed in separate weigh boats labeled with 3-digit codes to avoid visual bias. Sensory ballots were based on overall like or dislike of flavor, texture, odor, and color using the 9-point hedonic scales. For scrambled eggs, flavor did not differ (P > 0.05), but texture liking was higher (P = 0.064) for scrambled eggs from the soybean-free diet (7.08) vs. scrambled eggs from the soybean meal diet (6.65). With respect to the hard cooked eggs, the consumer panel preferred the flavor of the eggs from the caged rearing system (7.11) vs. eggs from the free-range system (6.60; P = 0.014). Consumers liked the texture (P = 0.018) for eggs collected from hens fed soybean meal (6.91) vs. eggs from hens fed the soybean-free diet (6.30). PMID- 29390159 TI - Improving shared decision-making in chronic lymphocytic leukemia through multidisciplinary education. AB - New treatments for chronic lymphocytic leukemia (CLL) with excellent response rates and varying toxicity profiles have emerged in recent years, creating an opportunity for a patient's personal preferences to contribute to treatment decisions. We conducted a prospective, quasi-experimental pre- and post evaluation of a multilevel educational program and its impact on knowledge of CLL and shared decision-making (SDM). We educated patients, lay navigators, nurses/advanced practice providers (APPs), and physicians. Patients were evaluated for change in patient activation, distress, desired role in decision making, perception of decision-making, satisfaction with oncologist explanation of treatment choice, and knowledge of CLL. Lay navigators, nurses/APPs, and physicians were evaluated for change in CLL knowledge and perception of decision making. Forty-four patients, 33 lay navigators, 27 nurses/APPs, and 27 physicians participated in the educational program. We observed trends toward improved patient activation, with 68% before education versus 76% after education reporting a Patient Activation Measure (PAM) score of 3 or 4. The percentage of patients desiring and perceiving SDM trended upward from 47% to 67% and from 35% to 49%, respectively. The percentage of patients understanding that CLL is incurable increased from 80% to 90%, as did reporting awareness of signs of progression (64% to 76%). Patients' satisfaction with their oncologists' explanations of therapy increased significantly from 83% to 95% (p = .03). CLL knowledge increased after education for lay navigators (36% vs 63%) and nurses/APPs (35% vs 69%), and remained high for physicians (85% vs 87%). Nurses/APPs and physicians perceived at least some patient involvement in decision-making at baseline, whereas 12% of patients and 23% of lay navigators perceived that physicians made decisions independently. This project demonstrated trends toward improvements in patient engagement, prognostic awareness, knowledge of signs of progression, and SDM. These promising findings should be tested in larger samples. There remains an opportunity for further improvement in SDM. PMID- 29390160 TI - Reagent Strips as an Aid to Diagnosis of Neonatal Meningitis in a Resource limited Setting. AB - Background: Without early recognition and treatment, neonatal meningitis (NM) has a high mortality and morbidity. Although some neonates have features of NM, many do not. In many low-resource settings, the laboratory support to diagnose NM is not available, and bedside diagnostics are needed. Methods: This retrospective study was conducted in a neonatal unit in Uganda. Clear cerebrospinal fluid samples were routinely screened for glucose, protein and leukocytes on a Combur(r)-10 urinalysis reagent strip. A definitive diagnosis was made using laboratory analysis. The results of the screening and definitive tests were compared. Results: The reagent strip showed moderate sensitivity and high specificity for leukocytes >=10*106 cells/l, high sensitivity for protein >=100 mg/dl and high specificity for glucose <50 mg/dl. Conclusion: The use of reagent strips has the potential to improve and hasten the diagnosis of probable NM in settings where adequate or timely laboratory support is not available. PMID- 29390161 TI - Working Health Services Scotland: a 4-year evaluation. AB - Background: Working Health Service Scotland (WHSS) supports the self-employed and employees of small and medium-sized enterprises (SMEs) in Scotland with a health condition affecting their ability to work, who are either absent or at risk of becoming absent due to it. Aims: To evaluate the impact on health and work outcomes of WHSS clients over a 4-year period. Methods: Data were collected at enrolment, entry, discharge and follow-up at 3 and 6 months after discharge. Clients completed up to three validated health questionnaires at entry and discharge-EuroQol five dimensions (EQ-5D) and visual analogue scale (VAS); Hospital Anxiety and Depression Scale (HADS); and Canadian Occupational Performance Measure (COPM). Results: A total of 13463 referrals occurred in the 4 year period; 11748 (87%) were eligible and completed entry assessment and 60% of the latter completed discharge paperwork. The majority of referrals were due to musculoskeletal conditions (84%) while 12% were referred with mental health conditions. Almost a fifth (18%) of cases were absent at entry and back at work at discharge. Work days lost while in WHSS was associated with age, length of absence prior to entering WHSS, primary health condition and time in programme. All health measures showed significant improvements from entry to discharge. Improvement in general health was sustained at 3- and 6-month follow-up. Conclusions: The WHSS evaluation findings indicate that participation was associated with positive changes to health and return-to-work. The extent of the positive change in health measures and work ability can be highly important economically for employees and employers. PMID- 29390162 TI - Androstadienone, a Chemosignal Found in Human Sweat, Increases Individualistic Behavior and Decreases Cooperative Responses in Men. AB - A growing body of evidence suggests that humans can communicate socially relevant information, such as aggression, dominance, and readiness for competition, through chemosensory signals. Androstadienone (androsta-4,16,-dien-3-one), a testosterone-derived compound found in men's axillary sweat, is a main candidate for a human pheromone that may convey such information. The current study aimed to investigate whether androstadienone serves as a chemosignaling threat cue to men, thus triggering avoidance behavior during competitive interaction with another man. In a double-blind, placebo-controlled, within-subject study design, 30 healthy, normosmic, heterosexual male participants completed the social orientation paradigm (SOP), a monetary game played against a fictitious partner that allows 3 types of responses to be measured in the context of provocation: an aggressive response, an individualistic withdrawal response, and a cooperative response. Participants completed the SOP task twice, once under exposure to androstadienone and once under exposure to a control solution. The results indicate that androstadienone increased individualistic responses while it decreased cooperative responses. These findings support the role of androstadienone as a threatening signal of dominance that elicits behavioral avoidance and social withdrawal tendencies, possibly as a submissive response. PMID- 29390163 TI - Identification of internally sialylated carbohydrate tumor marker candidates, including Sda/CAD antigens, by focused glycomic analyses utilizing the substrate specificity of neuraminidase. AB - In our previous study, 14 sulfated carbohydrate tumor marker candidates were identified by focused glycomic analyses. Here, glycomic analyses focused on internally sialylated glycans to identify novel marker candidates. Internally sialylated glycans were enriched by digestion of pyridylaminated glycans prepared from sera with alpha-neuraminidase from Salmonella typhimurium, which did not cleave sialic acids linked to internal residues, followed by anion-exchange chromatography. Next, internally sialylated O-glycan profiles were constructed using two types of high performance liquid chromatography, which were compared between 20 healthy controls and 11 patients with gastric cancer and 9 patients with pancreatic cancer. In all, 17 marker candidates were identified. The structures of glycan candidates were precisely analyzed using enzymatic digestion, glycan synthesis, 2D mapping and mass spectrometry. Among 17 candidates, one was STn, and the other 16 comprised 10 core1, 1 core2 and 5 core3 glycans. The various structures included a alpha2,6-sialylated reducing terminal GalNAc and alpha2,6-sialylated type1 N-acetyl-lactosamine. Eight candidates possessed the Sda/CAD antigen. The levels of these candidate glycans in sera from all 40 subjects were quantified using a selected reaction monitoring assay and found to be elevated in at least one or more patients. Although the serum levels of each candidate glycan varied between patients, those candidates having the same backbone or determinant, such as core3 backbone and core1 structures with extended type1 N-acetyl-lactosamine, displayed similar patterns of elevation. These results suggest that analysis of multiple markers may be an effective means of diagnosing various cancers. PMID- 29390164 TI - The effect of melatonin on antifungal susceptibility in planktonic and biofilm forms of Candida strains isolated from clinical samples. AB - In recent years, the significant increase in the isolation of antifungal resistant Candida species in presence of biofilm, have made it necessary to develop alternative agents for the treatment of these infections. In this study, the effect of antifungal susceptibility of melatonin were investigated in planktonic and biofilm forms of Candida strains isolated from the clinical samples sent to our laboratory. Biofilm formation was determined by modified microplate method. In order to determine antifungal susceptibility in biofilm forming strains, MIC was determined by broth microdilution method in planktonic form, and MBEC values by Calgary biofilm method in biofilm form. Susceptibility tests were repeated in the presence of melatonin. Antifungal susceptibility tests repeated with antifungals combined with melatonin showed a decrease in both MIC and MBEC values; melatonin was found to be more effective especially in planktonic forms. While the most effective combination was achieved with fluconazole in the planktonic form, no statistically significant difference was found between the combinations in biofilm form. As a result, melatonin was thought to be a new alternative in the treatment of Candida infections. PMID- 29390165 TI - Satisfaction with cancer care, self-efficacy, and health-related quality of life in Latino cancer survivors. AB - BACKGROUND: The objective of the current study was to examine how modifiable factors such as satisfaction with cancer care and self-efficacy impact health related quality of life (HRQOL) among Latino cancer survivors. METHODS: Latinos previously diagnosed with breast, prostate, or colorectal cancer (N = 288) completed questionnaires (Patient Satisfaction with Cancer Care Scale, Stanford Chronic Disease Self-Management Measures, Functional Assessment of Cancer Therapy General, and Short Acculturation Scale for Hispanics) within 2 years after receiving primary cancer treatment. RESULTS: Path model analyses demonstrated that satisfaction with cancer care was associated with greater HRQOL and that this relationship was explained by several facets of self-efficacy (ie, confidence in managing psychological distress [z = 3.81; P<.001], social support from close others [z = 2.46; P = .014], social/recreational activities [z = 3.30; P = .001], and patient-provider communication [z = -3.72; P<.001]). Importantly, foreign-born, less acculturated, and monolingual Spanish-speaking survivors reported lower self-efficacy in patient-provider communication; however, adjusting for acculturation, language, nativity, and other covariates did not alter these results. CONCLUSIONS: Factors that contribute to disparities in HRQOL among Latino cancer survivors compared with non-Latino whites, such as low income, less education, and a lack of health insurance, can be difficult to address. The findings of the current study emphasize the importance of self efficacy within the context of patient-centered cancer care practices (eg, patient inclusion in care decisions, sufficient time with provider, ready access to medical advice) and suggest that improving satisfaction with care may increase patients' confidence in managing important aspects of their cancer experience and, in turn, improve HRQOL among Latino cancer survivors. Cancer 2018. (c) 2018 American Cancer Society. Cancer 2018;124:1770-9. (c) 2018 American Cancer Society. PMID- 29390167 TI - An Unprecedented Pd-Catalyzed Carbonylative Route to Fused Furo[3,4-b]indol-1 ones. AB - A novel and efficient catalytic approach to functionalized furo[3,4-b]indol-1 ones is reported. It is based on a palladium-catalyzed sequential process involving an initial cyclization of 2-(hydroxypropyn-1-yl)anilines to form the indole moiety, followed by insertion of carbon monoxide and a second annulation step to build a lactone ring. In a single transformation, two fused heterocycles and three new bonds (C-N, C-C and C-O) are generated. The present methodology gives direct access to structurally complex molecules starting from readily available reagents. PMID- 29390166 TI - The diguanylate cyclase GcpA inhibits the production of pectate lyases via the H NS protein and RsmB regulatory RNA in Dickeya dadantii. AB - Dickeya dadantii 3937 secretes pectate lyases (Pels) to degrade plant cell walls. Previously, we have demonstrated that EGcpB and EcpC function as bis-(3',5') cyclic dimeric guanosine monophosphate (c-di-GMP)-specific phosphodiesterases (PDEs) to positively regulate Pel production. However, the diguanylate cyclase (DGC) responsible for the synthesis of c-di-GMP and the dichotomous regulation of Pel has remained a mystery. Here, we identified GcpA as the dominant DGC to negatively regulate Pel production by the specific repression of pelD gene expression. Quantitative reverse transcription-polymerase chain reaction (qRT PCR) assays revealed that the expression levels of histone-like, nucleoid structuring protein encoding gene hns and post-transcriptional regulator encoding genes rsmA and rsmB were significantly affected by GcpA. Deletion of hns or rsmB in the gcpAD418A site-directed mutant restored its Pel production and pelD expression, demonstrating that H-NS and RsmB contribute to the GcpA-dependent regulation of Pel in D. dadantii. In addition, RsmB expression was subject to positive regulation by H-NS. Thus, we propose a novel pathway consisting of GcpA H-NS-RsmB-RsmA-pelD that controls Pel production in D. dadantii. Furthermore, we showed that H-NS and RsmB are responsible for the GcpA-dependent regulation of motility and type III secretion system (T3SS) gene expression, respectively. Of the two PDEs involved in the regulation of Pels, only EGcpB regulates pelD expression through the same pathway as GcpA. PMID- 29390168 TI - Alkynyl Coinage Metal Clusters and Complexes-Syntheses, Structures, and Strategies. AB - In this Concept we discuss how the chemistry of coinage metal complexes based on alkynyl ligands has developed over the past decades. The rich coordination of alkynyl, that exhibit both eta1 (end-on) and eta2 (side on) modes, includes non bridged systems, as well as bridging of up to four (or six) metal centres. Resulting metal clusters often exhibit highly regular structures and typical coordination motifs forming fascinating assemblies exploiting this versatile coordination. Metallophilic interactions are often an important driving force for the formation of large clusters. In addition, the use of co-ligands as well the possibility to encapsulate counter ions greatly increases the chemical and structural diversity. Herein we attempt to summarize and highlight design principles towards multinuclear homo and hetero-bi-metallic coinage metal clusters of alkynyl ligands. PMID- 29390169 TI - Antibiotics for asymptomatic bacteriuria in kidney transplant recipients. AB - BACKGROUND: Asymptomatic bacteriuria, defined as bacteriuria without signs or symptoms of urinary tract infection (UTI), occurs in 17% to 51% of kidney transplant recipients and is thought to increase the risk for a subsequent UTI. No consensus exists on the role of antibiotics for asymptomatic bacteriuria in kidney transplantation. OBJECTIVES: To assess the benefits and harms of treating asymptomatic bacteriuria in kidney transplant recipients with antimicrobial agents to prevent symptomatic UTI, all-cause mortality and the indirect effects of UTI (acute rejection, graft loss, worsening of graft function). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 1 September 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs in any language assessing treatment of asymptomatic bacteriuria in kidney transplant recipients at any time-point after transplantation. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed quality and extracted data. Primary outcomes were incidence of symptomatic UTI and incidence of antimicrobial resistance. Other outcomes included incidences of all-cause mortality, graft loss, graft rejection, graft function, hospitalisation for UTI, adverse reactions to antimicrobial agents and relapse or persistence of asymptomatic bacteriuria. We expressed dichotomous outcomes as absolute risk difference (RD) or risk ratio (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) with 95% CI. Data were pooled using the random effects model. MAIN RESULTS: We included two studies (212 participants) comparing antibiotics versus no treatment, and identified three on-going studies. Overall, incidence of symptomatic UTI varied between 19% and 31% in the groups not treated for asymptomatic bacteriuria. Antibiotic treatment had uncertain effects on preventing symptomatic UTI (2 studies, 200 participants: RR 0.86, 95% CI 0.51 to 1.45). Risk for selecting multidrug resistant organisms was uncertain with antibiotic treatment (1 study, 112 participants: RR 1.21, 95% CI 0.60 to 2.41). Persistence of asymptomatic bacteriuria was high regardless of treatment. Antibiotics also have uncertain effects on other important patient and graft outcomes, for instance on all-cause mortality (1 study, 112 participants: RR 2.23, 95% CI 0.21 to 23.86), graft loss (1 study, 112 participants: RR 1.11, 95% CI 0.07 to 17.36), acute rejection (1 study, 112 participants: RR 0.93, 95% CI 0.44 to 1.97), hospitalisation for UTI (1 study, 112 participants: RR 0.74, 95% CI 0.13 to 4.27), graft function (2 studies, 200 participants, MD in serum creatinine concentration -0.06 mg/dL, 95% CI -0.19 to 0.08) and adverse reactions (1 study, 112 participants: no severe adverse event attributable to the antibiotic treatment). Evidence quality was low for all outcomes. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to support routinely treating kidney transplant recipients with antibiotics in case of asymptomatic bacteriuria after transplantation, but data are scarce. Further studies assessing routine antibiotic treatment would inform practice and we await the results of three ongoing randomised studies, which may help resolve existing uncertainties. PMID- 29390170 TI - Absorbable versus non-absorbable sutures for skin closure after carpal tunnel decompression surgery. AB - BACKGROUND: Carpal tunnel syndrome is a common problem and surgical decompression of the carpal tunnel is the most effective treatment. After surgical decompression, the palmar skin may be closed using either absorbable or non absorbable sutures. To date, there is conflicting evidence regarding the ideal suture material and this formed the rationale for our review. OBJECTIVES: To assess the effects of absorbable versus non-absorbable sutures for skin closure after elective carpal tunnel decompression surgery in adults on postoperative pain, hand function, scar satisfaction, wound inflammation and adverse events. SEARCH METHODS: We searched the following databases on 30 October 2017: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two clinical trials registries on 30 October 2017. SELECTION CRITERIA: We considered all randomised or quasi-randomised controlled trials comparing absorbable and non-absorbable sutures for skin closure after any form of carpal tunnel decompression surgery in adults. DATA COLLECTION AND ANALYSIS: The unit of analysis was the hand rather than the patient. We performed meta-analysis of direct comparisons to generate standardised mean differences (SMDs) with 95% confidence intervals (CIs) in pain scores and risk ratios (RRs) with 95% CIs for dichotomous outcomes, such as wound inflammation. The primary outcome was postoperative pain. Secondary outcomes included hand function, scar satisfaction, scar inflammation and adverse events (complications). We assessed the quality of evidence for key outcomes using GRADE. MAIN RESULTS: We included five randomised trials (255 participants). The trials were all European (UK, Republic of Ireland, Denmark and the Netherlands). Where quoted, the mean age of participants was between 48 and 53 years. The trials measured outcomes between one and 12 weeks postoperatively.Meta-analysis of postoperative pain scores for absorbable versus non-absorbable sutures at 10 days following open carpal tunnel decompression (OCTD) produced a SMD of 0.03 (95% CI -0.43 to 0.48; 3 studies, number of participants (N) = 137; I2 = 43%); the SMD suggests little or no difference, but with a high degree of uncertainty because of very low-quality evidence. At 10 days following endoscopic carpal tunnel decompression (ECTD), the SMD for postoperative pain with use of absorbable versus non-absorbable sutures was -0.81 (95% CI -1.36 to -0.25; 1 study; N = 54); although the SMD is consistent with a large effect, the very low-quality evidence means the results are very uncertain. Only the OCTD studies provided pain data at 6 weeks, when the SMD was 0.06 (95% CI -0.72 to 0.84; 4 studies; N = 175; I2 = 84%), which indicates little or no evidence of difference, but with a high degree of uncertainty (very low-quality evidence). The RR for wound inflammation using absorbable versus non-absorbable sutures after OCTD was 2.28 (95% CI 0.24 to 21.91; N = 95; I2 = 90%) and after ECTD 0.93 (95% CI 0.06 to 14.09; 1 study, N = 54). Any difference in effect on wound inflammation is uncertain because the quality of evidence is very low. One study reported postoperative hand function but found no evidence of a difference between suture types at two weeks (mean difference (MD) -0.10, 95% CI -0.53 to 0.33, N = 36), with similar findings at six and 12 weeks. Only the ECTD trial reported scar satisfaction, with 25 out of 28 people reporting a 'nice' result in the absorbable-suture group, versus 18 out of 26 in the group who received non absorbable sutures (RR 1.29, 95% CI 0.97 to 1.72, N = 54). These findings are also very uncertain as we judged the quality of the evidence to be very low. All studies were at high risk of bias for most domains. No trials reported adverse events. AUTHORS' CONCLUSIONS: It is uncertain whether absorbable sutures confer better, worse or equivalent outcomes compared to non-absorbable sutures following carpal tunnel decompression, because the quality of evidence is very low. Use of absorbable suture eliminates the need for suture removal, which could confer considerable savings to patients and healthcare providers alike. We need rigorously-performed, non-inferiority randomised trials with economic analyses to inform choice of suture. PMID- 29390171 TI - Direct Observation of an Imidoylnitrene: Photochemical Formation of PhC(=NMe)-N and Me-N from 1-Methyl-5-phenyltetrazole. AB - The imidoylnitrene 8, N-methyl-C-phenylimidoylnitrene, has been generated by laser photolysis of 1-methyl-5-phenyltetrazole 6 at 5 K and characterized by its ESR spectrum (|D/hc|=0.9602, |E/hc|=0.0144 cm-1 ). In addition, the triplet excited states of 6 and of 2-methyl-5-phenyltetrazole 11 were also observed by ESR spectroscopy in the 5 K matrices (6: |D/hc|=0.123 cm-1 , E/hc=0.0065 cm-1 , 11: |D/hc|=0.126 cm-1 , |E/hc|=0.0056 cm-1 ). The imidoylnitrene 8 is unstable both thermally (disappearing at 80 K) and photochemically (disappearing on continued irradiation at 266 nm). Methyl(phenyl)carbodiimide is the end product of photolysis. PMID- 29390172 TI - Orthodontic treatment for deep bite and retroclined upper front teeth in children. AB - BACKGROUND: A Class II division 2 malocclusion is characterised by upper front teeth that are retroclined (tilted toward the roof of the mouth) and an increased overbite (deep overbite), which can cause oral problems and may affect appearance.This problem can be corrected by the use of special dental braces (functional appliances) that move the upper front teeth forward and change the growth of the upper or lower jaws, or both. Most types of functional appliances are removable and this treatment approach does not usually require extraction of any permanent teeth. Additional treatment with fixed braces may be necessary to ensure the best result.An alternative approach is to provide space for the correction of the front teeth by moving the molar teeth backwards. This is done by applying a force to the teeth from the back of the head using a head brace (headgear) and transmitting this force to part of a fixed or removable dental brace that is attached to the back teeth. The treatment may be carried out with or without extraction of permanent teeth.If headgear use is not feasible, the back teeth may be held in place by bands connected to a fixed bar placed across the roof of the mouth or in contact with the front of the roof of the mouth. This treatment usually requires two permanent teeth to be taken out from the middle of the upper arch (one on each side). OBJECTIVES: To establish whether orthodontic treatment that does not involve extraction of permanent teeth produces a result that is any different from no orthodontic treatment or orthodontic treatment involving extraction of permanent teeth, in children with a Class II division 2 malocclusion. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (to 13 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 10), MEDLINE Ovid (1946 to 13 November 2017), and Embase Ovid (1980 to 13 November 2017). To identify any unpublished or ongoing trials, the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) were searched. We also contacted international researchers who were likely to be involved in any Class II division 2 clinical trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of orthodontic treatments to correct deep bite and retroclined upper front teeth in children. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results to find eligible studies, and would have extracted data and assessed the risk of bias from any included trials. We had planned to use random effects meta-analysis; to express effect estimates as mean differences for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals; and to investigate any clinical or methodological heterogeneity. MAIN RESULTS: We did not identify any RCTs or CCTs that assessed the treatment of Class II division 2 malocclusion in children. AUTHORS' CONCLUSIONS: There is no evidence from clinical trials to recommend or discourage any type of orthodontic treatment to correct Class II division 2 malocclusion in children. This situation seems unlikely to change as trials to evaluate the best management of Class II division 2 malocclusion are challenging to design and conduct due to low prevalence, difficulties with recruitment and ethical issues with randomisation. PMID- 29390173 TI - Accretion Product Formation from Self- and Cross-Reactions of RO2 Radicals in the Atmosphere. AB - Hydrocarbons are emitted into the Earth's atmosphere in very large quantities by human and biogenic activities. Their atmospheric oxidation processes almost exclusively yield RO2 radicals as reactive intermediates whose atmospheric fate is not yet fully unraveled. Herein, we show that gas-phase reactions of two RO2 radicals produce accretion products composed of the carbon backbone of both reactants. The rates for accretion product formation are very high for RO2 radicals bearing functional groups, competing with those of the corresponding reactions with NO and HO2 . This pathway, which has not yet been considered in the modelling of atmospheric processes, can be important, or even dominant, for the fate of RO2 radicals in all areas of the atmosphere. Moreover, the vapor pressure of the formed accretion products can be remarkably low, characterizing them as an effective source for the secondary organic aerosol. PMID- 29390175 TI - Amine Induced Retardation of the Radical-Mediated Thiol-Ene Reaction via the Formation of Metastable Disulfide Radical Anions. AB - The effect of amines on the kinetics and efficacy of radical-mediated thiol-ene coupling (TEC) reactions was investigated. By varying the thiol reactant and amine additive, it was shown that amines retard thiyl radical-mediated reactions when the amine is adequately basic enough to deprotonate the thiol affording the thiolate anion, e.g., when the weakly basic amine tetramethylethylenediamine was incorporated in the TEC reaction between butyl 2-mercaptoacetate and an allyl ether at 5 mol %, the final conversion was reduced from quantitative to <40%. Alternatively, no effect is observed when the less acidic thiol butyl 3 mercaptopropionate is employed. The thiolate anion was established as the retarding species through the introduction of ammonium and thiolate salt additives into TEC formulations. The formation of a two-sulfur three-electron bonded disulfide radical anion (DRA) species by the reaction of a thiyl radical with a thiolate anion was determined as the cause for the reduction in catalytic radicals and the TEC rate. Thermodynamic and kinetic trends in DRA formations were computed using density functional theory and by modeling the reaction as an associative electron transfer process. These trends correlate well with the experimental retardation trends of various thiolate anions in TEC reactions. PMID- 29390174 TI - Adapting the Elixhauser comorbidity index for cancer patients. AB - BACKGROUND: This study was designed to adapt the Elixhauser comorbidity index for 4 cancer-specific populations (breast, prostate, lung, and colorectal) and compare 3 versions of the Elixhauser comorbidity score (individual comorbidities, summary comorbidity score, and cancer-specific summary comorbidity score) with 3 versions of the Charlson comorbidity score for predicting 2-year survival with 4 types of cancer. METHODS: This cohort study used Texas Cancer Registry-linked Medicare data from 2005 to 2011 for older patients diagnosed with breast (n = 19,082), prostate (n = 23,044), lung (n = 26,047), or colorectal cancer (n = 16,693). For each cancer cohort, the data were split into training and validation cohorts. In the training cohort, competing risk regression was used to model the association of Elixhauser comorbidities with 2-year noncancer mortality, and cancer-specific weights were derived for each comorbidity. In the validation cohort, competing risk regression was used to compare 3 versions of the Elixhauser comorbidity score with 3 versions of the Charlson comorbidity score. Model performance was evaluated with c statistics. RESULTS: The 2-year noncancer mortality rates were 14.5% (lung cancer), 11.5% (colorectal cancer), 5.7% (breast cancer), and 4.1% (prostate cancer). Cancer-specific Elixhauser comorbidity scores (c = 0.773 for breast cancer, c = 0.772 for prostate cancer, c = 0.579 for lung cancer, and c = 0.680 for colorectal cancer) performed slightly better than cancer-specific Charlson comorbidity scores (ie, the National Cancer Institute combined index; c = 0.762 for breast cancer, c = 0.767 for prostate cancer, c = 0.578 for lung cancer, and c = 0.674 for colorectal cancer). Individual Elixhauser comorbidities performed best (c = 0.779 for breast cancer, c = 0.783 for prostate cancer, c = 0.587 for lung cancer, and c = 0.687 for colorectal cancer). CONCLUSIONS: The cancer-specific Elixhauser comorbidity score performed as well as or slightly better than the cancer-specific Charlson comorbidity score in predicting 2-year survival. If the sample size permits, using individual Elixhauser comorbidities may be the best way to control for confounding in cancer outcomes research. Cancer 2018;124:2018-25. (c) 2018 American Cancer Society. PMID- 29390176 TI - The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe infectious disease in need of new chemotherapies especially for drug-resistant cases. To meet the urgent requirement of new TB drugs with novel modes of action, the TB research community has been validating numerous targets from several biosynthetic pathways. The methylerythritol phosphate (MEP) pathway is utilized by Mtb for the biosynthesis of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), the universal five-carbon building blocks of isoprenoids. While being a common biosynthetic pathway in pathogens, the MEP pathway is completely absent in humans. Due to its unique presence in pathogens as well as the essentiality of the MEP pathway in Mtb, the enzymes in this pathway are promising targets for the development of new drugs against tuberculosis. In this Review, we discuss three enzymes in the MEP pathway: 1 deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (IspC/DXR), and 2 C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF), which appear to be the most promising antitubercular drug targets. Structural and mechanistic features of these enzymes are reviewed, as well as selected inhibitors that show promise as antitubercular agents. PMID- 29390177 TI - alpha-Helix Unwinding as Force Buffer in Spectrins. AB - Spectrins are cytoskeletal proteins located at the inner face of the plasma membrane, making connections between membrane anchors and the actin cortex, and between actin filaments. Spectrins share a common structure forming a bundle of 3 alpha-helices and play a major role during cell deformation. Here, we used high speed force spectroscopy and steered molecular dynamics simulations to understand the mechanical stability of spectrin, revealing a molecular force buffering function. We find that spectrin acts as a soft spring at short extensions (70-100 A). Under continuous external stretching, its alpha-helices unwind, leading to a viscous mechanical response over larger extensions (100-300 A), represented by a constant-force plateau in force/extension curves. This viscous force buffering emerges from a quasi-equilibrium competition between disruption and re-formation of alpha-helical hydrogen bonds. Our results suggest that, in contrast to beta sheet proteins, which unfold in a catastrophic event, alpha-helical spectrins dominantly unwind, providing a viscous force buffer over extensions about 5 times their folded length. PMID- 29390178 TI - Defect-Free Graphene Synthesized Directly at 150 degrees C via Chemical Vapor Deposition with No Transfer. AB - Direct graphene synthesis on substrates via chemical vapor deposition (CVD) is an attractive approach for manufacturing flexible electronic devices. The temperature for graphene synthesis must be below ~200 degrees C to prevent substrate deformation while fabricating flexible devices on plastic substrates. Herein, we report a process whereby defect-free graphene is directly synthesized on a variety of substrates via the introduction of an ultrathin Ti catalytic layer, due to the strong affinity of Ti to carbon. Ti with a thickness of 10 nm was naturally oxidized by exposure to air before and after the graphene synthesis, and the various functions of neither the substrates nor the graphene were influenced. This report offers experimental evidence of high-quality graphene synthesis on Ti-coated substrates at 150 degrees C via CVD. The proposed methodology was applied to the fabrication of flexible and transparent thin-film capacitors with top electrodes of high-quality graphene. PMID- 29390179 TI - Directed Self-Assembly of Asymmetric Block Copolymers in Thin Films Driven by Uniaxially Aligned Topographic Patterns. AB - We present a simple, versatile approach to generate highly ordered nanostructures of block copolymers (BCPs) using rubbed surfaces. A block of poly(tetrafluoroethylene) (PTFE) was dragged across a flat substrate surface above the melting point of PTFE transferring a highly aligned PTFE topographic pattern to the substrate. Si wafer, glass, and polyimide films were used as substrates. Thin films of cylinder-forming asymmetric polystyrene-block-poly(2 vinylpyridine) copolymers (S2VPs) were solvent annealed on the surfaces having the transferred surface pattern to induce their directed self-assembly. Cylinders of P2VP oriented normal to the surface are markedly aligned along the rubbing direction and used as templates to generate extremely uniform arrays of various metallic nanoparticles of gold, silver, and platinum over a large area. PMID- 29390181 TI - Competition between Naegleria fowleri and Free Living Amoeba Colonizing Laboratory Scale and Operational Drinking Water Distribution Systems. AB - Free living amoebae (FLA), including pathogenic Naegleria fowleri, can colonize and grow within pipe wall biofilms of drinking water distribution systems (DWDSs). Studies on the interactions between various FLA species in biofilms are limited. Understanding the interaction between FLA and the broader biofilm ecology could help better predict DWDS susceptibility to N. fowleri colonization. The aim of this study was to determine if N. fowleri and other FLAs ( Naegleria, Vermamoeba, Willaertia, and Vahlkampfia spp.) cocolonize DWDS biofilm. FLAs commonly isolated from DWDSs ( N. fowleri, V. vermiformis, and N. lovaniensis) were introduced into laboratory-scale biomonitors to determine the impact of these amoebae on N. fowleri's presence and viability. Over 18 months, a single viable amoebae ( N. fowleri, N. lovaniensis, or V. vermiformis) was detected in each biofilm sample, with the exception of N. lovaniensis and N. fowleri, which briefly cocolonized biofilm following their coinoculation. The analysis of biofilm and bulk water samples from operational DWDSs revealed a similar lack of cocolonization with a single FLA detected in 99% ( n = 242) of samples. Interestingly, various Naegleria spp. did colonize the same DWDS locations but at different times. This knowledge furthers the understanding of ecological factors which enable N. fowleri to colonize and survive within operational DWDSs and could aid water utilities to control its occurrence. PMID- 29390180 TI - Chemistry of a Unique Polyketide-like Synthase. AB - Like many complex natural products, the intricate architecture of saxitoxin (STX) has hindered full exploration of this scaffold's utility as a tool for studying voltage-gated sodium ion channels and as a pharmaceutical agent. Established chemical strategies can provide access to the natural product; however, a chemoenzymatic route to saxitoxin that could provide expedited access to related compounds has not been devised. The first step toward realizing a chemoenzymatic approach toward this class of molecules is the elucidation of the saxitoxin biosynthetic pathway. To date, a biochemical link between STX and its putative biosynthetic enzymes has not been demonstrated. Herein, we report the first biochemical characterization of any enzyme involved in STX biosynthesis. Specifically, the chemical functions of a polyketide-like synthase, SxtA, from the cyanobacteria Cylindrospermopsis raciborskii T3 are elucidated. This unique megasynthase is comprised of four domains: methyltransferase (MT), GCN5-related N acetyltransferase (GNAT), acyl carrier protein (ACP), and the first example of an 8-amino-7-oxononanoate synthase (AONS) associated with a multidomain synthase. We have established that this single polypeptide carries out the formation of two carbon-carbon bonds, two decarboxylation events and a stereospecific protonation to afford the linear biosynthetic precursor to STX (4). The synthetic utility of the SxtA AONS is demonstrated by the synthesis of a suite of alpha-amino ketones from the corresponding alpha-amino acid in a single step. PMID- 29390182 TI - Cost-Effective Design of High-Magnetic Moment Nanostructures for Biotechnological Applications. AB - Disk-shaped magnetic nanostructures present distinctive features for novel biomedical applications. Fine tuning of geometry and dimensions is demanded to evaluate efficiency and capability of such applications. This work addresses a cost-effective, versatile, and maskless design of biocompatible high-magnetic moment elements at the sub-micrometer scale. Advantages and disadvantages of two high throughput fabrication routes using interference lithography were evaluated. Detrimental steps such as the release process of nanodisks into aqueous solution were optimized to fully preserve the magnetic properties of the material. Then, cell viability of the nanostructures was assessed in primary melanoma cultures. No toxicity effects were observed, validating the potential of these nanostructures in biotechnological applications. The present methodology will allow the fabrication of magnetic nanoelements at the sub-micrometer scale with unique spin configurations, such as vortex state, synthetic antiferromagnets, or exchange-coupled heterostructures, and their use in biomedical techniques that require a remote actuation or a magneto-electric response. PMID- 29390183 TI - Coarse-Grained Molecular Simulation Model for Gecko Feet Keratin. AB - The mechanical properties of gecko setae and spatulae are investigated with a coarse-grained model having two bead types. The two-bead model is based on both experimental information of the internal structure of setae and the chemical amino acid composition. Because the seta is composed of a stiff fibril region and a soft matrix region, we model each of the regions separately. Our model is parameterized in a bottom-up way, and it successfully predicts essential mechanical properties without optimization against the macroscopic properties of keratin. Young's modulus of the fibril area (13.2 +/- 0.02 GPa) is 6 times stiffer than that of the pure matrix (2.13 +/- 0.059 GPa). Because the volume fraction of the matrix decreases toward the top of a seta, its distal area should be stiffer than its proximal area. The anisotropy of the fibrils is clearly confirmed by the comparison between Young's modulus and the shear modulus of the fibril region. Our model also lends some support to the notion that water uptake selectively weakens the axial cohesion of the fibrils, which leads to the experimentally observed plateau in the stress-strain curves beyond 2% strain for setae under high relative humidity. PMID- 29390184 TI - Progress and Challenges in the Diagnosis of Dementia: A Critical Review. AB - Longer life expectancies have led to an increased number of neurodegenerative disease cases globally. Accurate diagnosis of this devastating disorder is of crucial importance but is still feasible only by a brain biopsy after death. An enormous amount of attention and research has been in place over the years toward the better understanding of the mechanisms, as well as the early diagnosis, of neurodegeneration. However, numerous studies have been contradictory from time to time, while new diagnostic methods are constantly developed in a tireless effort to tackle the disease. Nonetheless, there is not yet a conclusive report covering a broader range of techniques for the diagnosis of different types of dementia. In this paper, we critically review current knowledge on the different hypotheses about the pathogenesis of distinct types of dementia, as well as risk factors and current diagnostic approaches in a clinical setting, including neuroimaging, cerebrospinal (CSF), and blood tests. Encouraging research results for the diagnosis and investigation of neurodegenerative disorders are also reported. Particular attention is given to the field of spectroscopy as an emerging tool to detect dementias, follow-up patients, and potentially monitor the patients' response to a therapeutic approach. Spectroscopic techniques, such as infrared and Raman spectroscopy, have facilitated numerous disease-related studies, including neurodegenerative disorders, and are currently undergoing trials for clinical implementation. This review constitutes a comprehensive report with an in-depth focus on promising imaging, molecular biomarker and spectroscopic tests in the field of dementive diseases. PMID- 29390185 TI - Rovibrational Resonances in H2He. AB - The nuclear dynamics of the metastable H2He+ complex is explored by symmetry considerations and angular momentum addition rules as well as by accurate quantum chemical computations with complex coordinate scaling, complex absorbing potential, and stabilization techniques. About 200 long-lived rovibrational resonance states of the complex are characterized and selected long-lived states are analyzed in detail. The stabilization mechanism of these long-lived resonance states is discussed on the basis of probability density plots of the wave functions. Overlaps of wave functions derived by a reduced-dimensional model with the full-dimensional wave functions reveal dissociation pathways for the long lived resonance states and allow the calculation of their branching ratios. PMID- 29390186 TI - Antimicrobial Metallopeptides. AB - Antimicrobial peptides are short amphipathic peptides that are produced by the innate immune system in order to protect a host from pathogens. They have been shown to have broad-spectrum antimicrobial activity toward Gram-positive and Gram negative bacteria, as well as antifungal, antiprotozoan, and antiviral activity. These peptides are able to exert their activity through a variety of mechanisms that include inhibiting DNA and RNA replication, inhibiting protein synthesis, permeabilizing the cell membrane, disrupting proton and ion transmembrane gradients, and inhibiting cell wall biosynthesis. Certain antimicrobial peptides are able to utilize metals to modulate their activity through structural changes upon metal binding, metal sequestration, and redox chemistry. This work aims to provide a review of the current literature regarding the influence of metals on the activity of antimicrobial metallopeptides and their uses in drug delivery and the treatment of implant-associated infections. PMID- 29390187 TI - Optoelectronic Properties of Self-Assembled Nanostructures of Polymer Functionalized Polythiophene and Graphene. AB - In this Feature Article, we discuss the variation of optoelectronic properties with the aggregation style of polythiophene (PT) graft copolymers and polymer modified graphene systems. Grafting of flexible polymers on a PT chain exhibits several self-organized patterns under various conditions, causing different optical and electronic properties, arising from the different conformational states of the conjugated chain. Graphene, a zero band gap material, is functionalized with polymers both covalently and noncovalently to create a finite band gap importing new optoelectronic properties. The polymer-triggered self assembled nanostructures of PT and graphene-based materials bring unique optical/electronic properties suitable for sensing toxic ions, nitroaromatics, and surfactants, for drug delivery, and also for fabricating molecular logic gates, electronic rectifiers, photocurrent devices, etc. PMID- 29390188 TI - Further Insight into the Formation and Oxidation of CaCr2O4 during Solid Fuel Combustion. AB - The control of toxic chromate (Cr6+) formation is still a significant challenge in solid fuel combustion. In particular, the mechanism of chromium transformation from Cr3+ to chromate or other unoxidized forms remains unclear. The present study confirms the formation of a significant unoxidized Cr-containing compound CaCr2O4(Cr3+) during solid fuel combustion. Experiments were conducted, for the first time, to clarify the mechanism of CaCr2O4 oxidation, which is quite different from Cr2O3 oxidation. The findings demonstrate that CaCr2O4 was formed at temperatures above 1200 K, through rapid decomposition of CaCrO4 or slow and direct interaction between CaO and Cr2O3. Compared to Cr2O3, CaCr2O4 could be oxidized at lower temperatures under the influence of free CaO. In the absence of free CaO, the oxidation of CaCr2O4 was minimal; however, in the presence of CaSO4, calcium in the form of CaCr2O4 participated in the oxidation of CaCr2O4. Thus, chromium in the form of CaCr2O4 was more likely to be oxidized when CaCr2O4 containing fly ash was reheated. Fortunately, CaCr2O4 showed slight basicity on the surface, allowing it to react with acidic gases. Accordingly, measures were proposed to suppress the oxidation of CaCr2O4 by stimulating the reactions between CaCr2O4 and acidic substances, like SO2 and Si/Al-compounds. These compounds competed with chromium at high temperatures to react with calcium in the fly ash and in CaCr2O4. As a result, the unoxidized chromium was transformed into highly stable Cr2O3 or Ca3Cr2 (SiO4)3. PMID- 29390189 TI - Grain-Size-Controlled Mechanical Properties of Polycrystalline Monolayer MoS2. AB - Pristine monocrystalline molybdenum disulfide (MoS2) possesses high mechanical strength comparable to that of stainless steel. Large-area chemical-vapor deposited monolayer MoS2 tends to be polycrystalline with intrinsic grain boundaries (GBs). Topological defects and grain size skillfully alter its physical properties in a variety of materials; however, the polycrystallinity and its role played in the mechanical performance of the emerging single-layer MoS2 remain largely unknown. Here, using large-scale atomistic simulations, GB structures and mechanical characteristics of realistic single-layered polycrystalline MoS2 of varying grain size prepared by confinement-quenched method are investigated. Depending on misorientation angle, structural energetics of polar-GBs in polycrystals favor diverse dislocation cores, consistent with experimental observations. Polycrystals exhibit grain-size-dependent thermally induced global out-of-plane deformation, although defective GBs in MoS2 show planar structures that are in contrast to the graphene. Tensile tests show that presence of cohesive GBs pronouncedly deteriorates the in-plane mechanical properties of MoS2. Both stiffness and strength follow an inverse pseudo Hall Petch relation to grain size, which is shown to be governed by the weakest link mechanism. Under uniaxial tension, transgranular crack propagates with small deflection, whereas upon biaxial stretching, the crack grows in a kinked manner with large deflection. These findings shed new light in GB-based engineering and control of mechanical properties of MoS2 crystals toward real-world applications in flexible electronics and nanoelectromechanical systems. PMID- 29390190 TI - Mixed Network Former Effect on Structure, Physical Properties, and Bioactivity of 45S5 Bioactive Glasses: An Integrated Experimental and Molecular Dynamics Simulation Study. AB - Boron-containing bioactive glasses display a strong potential in various biomedical applications lately due to their controllable dissolution rates. In this paper, we prepared a series of B2O3/SiO2-substituded 45S5 bioactive glasses and performed in vitro biomineralization tests with both simulated body fluid and K2HPO4 solutions to evaluate the bioactivities of these glasses as a function of boron oxide to silica substitution. The samples were examined with scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectrometry after immersing them in the two solutions (simulated body fluid and K2HPO4) up to 3 weeks. It was found that introduction of boron oxide delayed the formation of hydroxyapatite, but all the glasses were shown to be bioactive. Molecular dynamics (MD) simulations were used to complement the experimental efforts to understand the structural changes due to boron oxide to silica substitution by using newly developed partial charge composition-dependent potentials. Local structures around the glass network formers, medium-range structural information, network connectivity, and self-diffusion coefficients of ions were elucidated from MD simulation. Relationships between boron content and glass properties such as structure, density, glass transition temperature, and in vitro bioactivity were discussed in light of both experimental and simulation results. PMID- 29390191 TI - Inducible Knockdown of Endothelial Protein Tyrosine Phosphatase-1B Promotes Neointima Formation in Obese Mice by Enhancing Endothelial Senescence. AB - AIMS: Protein tyrosine phosphatase-1B (PTP1B) is a negative regulator of receptor tyrosine kinase signaling. In this study, we determined the importance of PTP1B expressed in endothelial cells for the vascular response to arterial injury in obesity. RESULTS: Morphometric analysis of vascular lesions generated by 10% ferric chloride (FeCl3) revealed that tamoxifen-inducible endothelial PTP1B deletion (Tie2.ERT2-Cre * PTP1Bfl/fl; End.PTP1B knockout, KO) significantly increased neointima formation, and reduced numbers of (endothelial lectin positive) luminal cells in End.PTP1B-KO mice suggested impaired lesion re endothelialization. Significantly higher numbers of proliferating cell nuclear antigen (PCNA)-positive proliferating cells as well as smooth muscle actin (SMA) positive or vascular cell adhesion molecule-1 (VCAM1)-positive activated smooth muscle cells or vimentin-positive myofibroblasts were detected in neointimal lesions of End.PTP1B-KO mice, whereas F4/80-positive macrophage numbers did not differ. Activated receptor tyrosine kinase and transforming growth factor-beta (TGFbeta) signaling and oxidative stress markers were also significantly more abundant in End.PTP1B-KO mouse lesions. Genetic knockdown or pharmacological inhibition of PTP1B in endothelial cells resulted in increased expression of caveolin-1 and oxidative stress, and distinct morphological changes, elevated numbers of senescence-associated beta-galactosidase-positive cells, and increased expression of tumor suppressor protein 53 (p53) or the cell cycle inhibitor cyclin-dependent kinase inhibitor-2A (p16INK4A) suggested senescence, all of which could be attenuated by small interfering RNA (siRNA)-mediated downregulation of caveolin-1. In vitro, senescence could be prevented and impaired re-endothelialization restored by preincubation with the antioxidant Trolox. INNOVATION: Our results reveal a previously unknown role of PTP1B in endothelial cells and provide mechanistic insights how PTP1B deletion or inhibition may promote endothelial senescence. CONCLUSION: Absence of PTP1B in endothelial cells impairs re-endothelialization, and the failure to induce smooth muscle cell quiescence or to protect from circulating growth factors may result in neointimal hyperplasia. Antioxid. Redox Signal. 00, 000-000. PMID- 29390192 TI - The Heterogeneity of Exercise-induced Laryngeal Obstruction. PMID- 29390193 TI - Knockdown of aquaporin-5 sensitizes colorectal cancer cells to 5-fluorouracil via inhibition of the Wnt-beta-catenin signaling pathway. AB - Aquaporin-5 (AQP5), a water channel protein, has been reported to possess oncogenic potential in multiple types of malignancies, including colorectal cancer (CRC). However, its effect on the chemosensitivity of CRC cells remains elusive. Hence, this study investigated the effect of AQP5 silencing in CRC cells on 5-fluorouracil (5-FU) sensitivity and attempted to elucidate the underlying mechanisms. A short hairpin RNA construct targeting AQP5 was transfected into HCT116 or HT29 cells to generate stable AQP5-silenced cell lines. The effects of AQP5 knockdown on cell viability, apoptosis, tumor growth, and 5-FU chemoresistance were evaluated. Relative protein levels of Wnt-beta-catenin pathway effectors were also measured. The results showed that silencing of AQP5 increased the chemosensitivity of CRC cells to 5-FU, facilitated 5-FU-mediated apoptosis, suppressed tumor growth, and reduced 5-FU chemoresistance in vivo. Furthermore, the effect of AQP5 on 5-FU chemosensitivity was mediated by the Wnt beta-catenin pathway. Silencing of AQP5 inhibited Wnt-beta-catenin signaling, whereas overexpression of the degradation-resistant mutant of beta-catenin (S33Y) reversed apoptosis induced by AQP5 silencing. Taken together, these results suggest that AQP5 silencing enhances the sensitivity of CRC cells to 5-FU, and the underlying mechanism is related to inhibition of the Wnt-beta-catenin pathway. AQP5 could be a useful therapeutic target for CRC treatment. PMID- 29390194 TI - Genotypic variation in the response of chickpea to arbuscular mycorrhizal fungi and non-mycorrhizal fungal endophytes. AB - Plant roots host symbiotic arbuscular mycorrhizal (AM) fungi and other fungal endophytes that can impact plant growth and health. The impact of microbial interactions in roots may depend on the genetic properties of the host plant and its interactions with root-associated fungi. We conducted a controlled condition experiment to investigate the effect of several chickpea (Cicer arietinum L.) genotypes on the efficiency of the symbiosis with AM fungi and non-AM fungal endophytes. Whereas the AM symbiosis increased the biomass of most of the chickpea cultivars, inoculation with non-AM fungal endophytes had a neutral effect. The chickpea cultivars responded differently to co-inoculation with AM fungi and non-AM fungal endophytes. Co-inoculation had additive effects on the biomass of some cultivars (CDC Corrine, CDC Anna, and CDC Cory), but non-AM fungal endophytes reduced the positive effect of AM fungi on Amit and CDC Vanguard. This study demonstrated that the response of plant genotypes to an AM symbiosis can be modified by the simultaneous colonization of the roots by non-AM fungal endophytes. Intraspecific variations in the response of chickpea to AM fungi and non-AM fungal endophytes indicate that the selection of suitable genotypes may improve the ability of crop plants to take advantage of soil ecosystem services. PMID- 29390195 TI - A U.S. Multicenter Study of Recorded Occupational Radiation Badge Doses in Nuclear Medicine. AB - Purpose To summarize occupational badge doses recorded for a sample of U.S. nuclear medicine technologists. Materials and Methods Nine large U.S. medical institutions identified 208 former and current nuclear medicine technologists certified after 1979 and linked these individuals to historic badge dose records maintained by a commercial dosimetry company (Landauer), yielding a total of 2618 annual dose records. The distributions of annual and cumulative occupational doses were described by using summary statistics. Results Between 1992 and 2015, the median annual personal dose equivalent per nuclear medicine technologist was 2.18 mSv (interquartile range [IQR], 1.25-3.47 mSv; mean, 2.69 mSv). Median annual personal dose equivalents remained relatively constant over this period (range, 1.40-3.30 mSv), while maximum values generally increased over time (from 8.00 mSv in 1992 to 13.9 mSv in 2015). The median cumulative personal dose equivalent was 32.9 mSv (IQR, 18.1-65.5 mSv; mean, 51.4 mSv) for 45 technologists who had complete information and remained employed through 2015. Conclusion Occupational radiation doses were well below the established occupational limits and were consistent with those observed for nuclear medicine technologists worldwide and were greater than those observed for nuclear and general medical workers in the United States These results should be informative for radiation monitoring and safety efforts in nuclear medicine departments. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29390196 TI - Diagnostic Performance and Interreader Agreement of a Standardized MR Imaging Approach in the Prediction of Small Renal Mass Histology. AB - Purpose To assess the diagnostic performance and interreader agreement of a standardized diagnostic algorithm in determining the histologic type of small (<=4 cm) renal masses (SRMs) with multiparametric magnetic resonance (MR) imaging. Materials and Methods This single-center retrospective HIPAA-compliant institutional review board-approved study included 103 patients with 109 SRMs resected between December 2011 and July 2015. The requirement for informed consent was waived. Presurgical renal MR images were reviewed by seven radiologists with diverse experience. Eleven MR imaging features were assessed, and a standardized diagnostic algorithm was used to determine the most likely histologic diagnosis, which was compared with histopathology results after surgery. Interreader variability was tested with the Cohen kappa statistic. Regression models using MR imaging features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear cell renal cell carcinoma (RCC) and papillary RCC were diagnosed, with sensitivities of 85% (47 of 55) and 80% (20 of 25), respectively, and specificities of 76% (41 of 54) and 94% (79 of 84), respectively. Interreader agreement was moderate to substantial (clear cell RCC, kappa = 0.58; papillary RCC, kappa = 0.73). Signal intensity (SI) of the lesion on T2-weighted MR images and degree of contrast enhancement (CE) during the corticomedullary phase were independent predictors of clear cell RCC (SI odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.4, 7.1; P = .003; CE OR, 4.45; 95% CI: 1.8, 10.8; P < .001) and papillary RCC (CE OR, 0.053; 95% CI: 0.02, 0.2; P < .001), and both had substantial interreader agreement (SI, kappa = 0.69; CE, kappa = 0.71). Poorer performance was observed for chromophobe histology, oncocytomas, and minimal fat angiomyolipomas, (sensitivity range, 14%-67%; specificity range, 97%-99%), with fair to moderate interreader agreement (kappa range = 0.23-0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR, 16.21; 95% CI: 1.0, 275.4; P = .049), with moderate interreader agreement (kappa = 0.49). Conclusion The proposed standardized MR imaging-based diagnostic algorithm had diagnostic accuracy of 81% (88 of 109) and 91% (99 of 109) in the diagnosis of clear cell RCC and papillary RCC, respectively, while achieving moderate to substantial interreader agreement among seven radiologists. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29390197 TI - Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation. AB - Purpose To retrospectively investigate the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, TACE-RFA) in the treatment of recurrent hepatocellular carcinoma (rHCC) with portal vein tumor thrombosis, extrahepatic metastases (advanced hepatocellular carcinoma), or both after initial hepatectomy. Materials and Methods The study was centrally approved by the ethics committee of three tertiary medical centers in China. From January 2010 to January 2015, 207 consecutive patients with advanced rHCC after initial hepatectomy received sorafenib combined with TACE-RFA (combination group, n = 106) or sorafenib alone (sorafenib group, n = 101) at the three medical centers. Overall survival (OS) and time to progression (TTP) were compared between the two groups. Complications were assessed. Survival curves were constructed with the Kaplan-Meier method and were compared with the log-rank test. Results Baseline characteristics were balanced between the two groups. No treatment-related death occurred in either group. The toxicity profile in the combination group was similar to that in the sorafenib group. After treatment, median OS (14.0 vs 9.0 months, respectively; P < .001) and TTP (7.0 vs 4.0 months, respectively; P < .001) were significantly longer in the combination group than in the sorafenib group. Multivariate analysis showed that treatment allocation was a significant predictor of OS and TTP, while the number of intrahepatic tumors was another prognostic factor of OS. Conclusion Sorafenib combined with TACE-RFA was well tolerated and safe and was superior to sorafenib alone in improving survival outcomes in patients with advanced rHCC after initial hepatectomy. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29390198 TI - [Enrichment of Claims Data with Official Causes of Death Using a Record Linkage with the Epidemiological Cancer Registry of North Rhine-Westphalia: Feasibility Study and Comparison of Procedures]. AB - BACKGROUND: Claims data of the statutory health insurance (SHI) are an important data source for the evaluation of cancer prevention programs. However, this source does not contain relevant information on cause of death. This study examined whether individual claims data can be enriched with data on the required cause of death using record linkage procedures with suitable external data sources. METHODS: In the German pharmacoepidemiologic research database (GePaRD) we identified a sample of 25,528 deceased female residents of North Rhine Westphalia (NRW) who, according to GePaRD information, died between 2006 and 2013. Date and cause of all deaths among inhabitants of NRW since 2005 were available in the epidemiological cancer registry of NRW. In cooperation with 2 SHI companies, we tried to match each individual of the sample with a case of death in NRW and the corresponding cause of death using a probabilistic and, alternatively, a deterministic linkage procedure. RESULTS: Of the study sample, 94.72% were successfully matched by the probabilistic and 93.36% by the deterministic method. CONCLUSIONS: The probabilistic and the deterministic record linkage approach produced comparably high matching rates. Cases without matches are probably due to errors occurring at the stage of personal data entry. Given the lower technical efforts, the deterministic approach appears to be the method of choice for the enrichment of claims data with cause of death information from suitable external data sources in Germany. PMID- 29390199 TI - Intramuscular Testosterone Supplementation Ameliorates Depression in Hypogonadal Men: A Retrospective Study in an Outpatient Department. AB - INTRODUCTION: Substantial evidence has indicated an association between hypogonadism and depressive symptoms, which led to the conduction of studies that found an ameliorating effect of testosterone (T) supplementation (S) upon depression in men. METHODS: Retrospective analysis of medical records identified 16 depressed, hypogonadal men who have not responded adequately to initial antidepressant therapy and subsequently received intramuscular T injections. Following the proposal of Button et al., a minimal clinically important difference was defined as an 18% reduction of the Beck Depression Inventory-II (BDI-II) score. RESULTS: After TS, the BDI-II score decreased by approximately 31% (p<0.01), from 27.2 (mean; standard deviation [SD] 11.8) to 18.8 (mean; SD 11.3). Patients with baseline BDI-II scores ranging from 29 to 63 (severe depression) showed a significantly higher absolute and relative reduction through TS. Also, men with a shorter depression duration (<2 years) demonstrated a greater benefit. CONCLUSIONS: The depressed, hypogonadal men generally benefited from TS given that the BDI-II score reduction was almost twice as much as needed for a minimal clinically important difference. PMID- 29390200 TI - Overview Tumour Disease and Oncologic Therapy During Pregnancy. AB - Newly diagnosed cancer in pregnancy is an issue with increasing importance, because fulfilling the wish to have a child is shifted later in life. Tumour disease is diagnosed in around 0.1% of all pregnancies in Germany. Most common tumour entities involve the breast, the cervix and the hematopoietic system. As tumour prognosis is not negatively affected by pregnancy and gestation does not disclude oncologic therapy it is important to plan treatment immediately. Oncologic surgery preserving the uterus is not at all limited. Chemotherapy with anthracyclines, taxanes or platinum derivates is possible from the second trimenon on. Only radiotherapy should be avoided during pregnancy. Before initiating therapy, fertility preserving methods like cryopreservation of oocytes and/or ovarian tissue should be offered to the patient. Preterm birth is more common in women with a first diagnosis of cancer during pregnancy. Other negative effects on the child's future are not yet known. Treatment of pregnant cancer patients should be handled by experienced centres with a multi-professional team. PMID- 29390201 TI - How Are Neonatology Fellows Trained for Antenatal Periviability Counseling? (Podcast). PMID- 29390202 TI - [Clinical trial: regeneration of skin perception after deep-degree burns in childhood]. AB - BACKGROUND: Cutaneous aesthesia is frequently impaired following thermal injury. The perception of pressure and touch is compromised. METHODS: We analysed 352 patient files retrospectively and tested the perception in deep burn-damaged skin of children. The skin regions examined were classified into groups according to treatment: group 1: necrosectomy + split-thickness skin graft; group 2: epifascial necrosectomy + split-thickness skin graft; group 3: epifascial necrosectomy + Integra(r) + split- thickness skin graft. We used clinically adequate test procedures. RESULTS: 31 children (3 to 16 years old) were included with a total of 228 areas of skin examined, 22 boys and 9 girls, mean total body surface area affected 17.6 %, mean age at time of accident 4.9 years. Perceived sensation in group 3: touching with sharp point = 34 out of 47 areas (6 patients), touching with blunt point = 47 out of 57 areas (6 patients), touching with soft tip = 37 out of 56 areas (7 patients), repositioning hair shafts = 9 out of 12 areas (4 patients), pressure of Frey hair = 40 out of 43 areas (7 patients). In group 1, differentiation of touch stimuli was possible in 7 out of 13 children (70 out of 94 skin areas). The simultaneous threshold was 1.8 cm (SD 1.4), compared with 1.2 cm (SD 1.1) in the control group. The successive threshold was 1.6 cm (SD 0.9) and 1.8 cm (SD 1.5) in the control group. In group 2, differentiation of touch stimuli was possible in 3 out of 6 children (27 out of 52 skin areas). The simultaneous threshold was 3.4 cm (SD 1.3) and 3.4 cm (SD 1.1) in the control group. The successive threshold was 2.4 (SD 1.0) and 1.7 (0.7) in the control group. One patient was examined in group 3. Differentiation of touch stimuli was possible in 4 out of 15 skin areas. The simultaneous threshold was 3.9 cm (SD 0.8) and 2.9 cm (SD 1.1) in the control group. The successive threshold was 2.7 (SD 1.4) and 2.1 (1.0) in the control group. In 93 % to 100 % of tested areas, vibration aesthesia was detectable. Vibration aesthesia did not differ between tune fork and biothesiometer. Four children with 11 different skin areas (group 3) were tested with sensory-evoked potentials. There was no significant difference between case group and control group. CONCLUSION: The sensory perception (receptors and nerve cells) of touch and pressure in deep burns suffered during childhood has an unexpected and high potential for regeneration. PMID- 29390203 TI - eNOS Uncoupling, A Therapeutic Target For Ischemic Foot of Diabetic Rat. AB - AIM: To determine the relationship between eNOS uncoupling and diabetic ischemic foot and whether reversing eNOS uncoupling by Dihydrofolate reductase (DHFR) transfection or folic acid (FA) supplementation can be beneficiary in diabetic ischemic foot. METHODS: The bilateral common iliac artery of diabetic rats were ligated to establish the diabetic ischemic foot animal model. DHFR transfection was implemented via femoral artery and muscle injection of in vivo transfection reagent mixture (GenEscortIII) every 4 days during the 2 weeks intervention. The color doppler flow imaging (CDFI) of femoral artery for RI measurement, triceps and quadriceps structure and histology, eNOS coupling status, DHFR expression level, superoxide, peroxynitrite (ONOO- ) and nitric oxide (NO) production in the presence or absence of L-NAME (eNOS inhibitor) were examined among wild type rats (WT), diabetic sham rats (DM), rats of diabetic ischemic foot (DF) or DF with DHFR transfection (DFT) or DF with FA supplementation (DFF). RESULTS: Dihydroethidium (DHE) fluorescence, as an index of superoxide production was enhanced in the femoral arteries of diabetic rats and even more in those of ischemic foot from diabetic rats. However, the DHE fluorescence was diminished in the presence of L-NAME suggesting eNOS uncoupling is the source of superoxide overproduction which further led to increased peroxynitrite production and decreased NO. bioavailability. Subsequently, the hind limb muscle became atrophic and the local collateral circulation was defective due to endothelial dysfunction related to eNOS uncoupling. However, all of the above and hemodynamic index (RI) of femoral artery were resumed via restoration of DHFR protein expression by folic acid treatment or DHFR transfection. CONCLUSIONS: eNOS uncoupling is involved in diabetic ischemic foot due to DHFR suppression. DHFR restoration can reverse eNOS uncoupling and resume the endothelial dysfunction and pathological changes (increased vasculature resistance, hind limb muscle atrophy and defective collateral circulation) associated with eNOS uncoupling in diabetic ischemic foot. All of which enlightens a novel therapeutic strategy for future diabetic ischemic foot treatments. PMID- 29390204 TI - Insights in Fungal Bioprospecting in Mexico. AB - Fungi have consistently been one of the richest sources of natural products, with unprecedented chemical scaffolds and potent biological activities. During the last 20 years, pharmacognosy researchers in Mexico, in collaboration with mycologists, have discovered many novel bioactive fungi natural products and new fungal species. To date, more than 100 bioactive secondary metabolites from 20 fungi from different ecosystems throughout Mexico have been documented in peer reviewed literature according to Scopus and SciFinder databases. These include compounds from different biosynthetic origins and structural cores with the potential for the development of anticancer, antidiabetic, and/or pesticide agents. PMID- 29390207 TI - ? PMID- 29390208 TI - ? PMID- 29390209 TI - ? PMID- 29390205 TI - Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. PMID- 29390210 TI - ? PMID- 29390211 TI - ? PMID- 29390212 TI - ? PMID- 29390213 TI - ? PMID- 29390214 TI - ? PMID- 29390215 TI - ? AB - In 2017, many new and promising therapeutic innovations entered uro-oncology. Immunotherapy was highly topical and was intensively discussed at the annual meetings. This review summarises the news, together with future developments in the diagnosis and treatment of prostate, bladder and kidney cancer. Within the last year, there have been major developments in the treatment of hormone sensitive metastastic prostate cancer, metastatic transitional cell carcinoma and metastastic renal cell cancer. Many new drugs will be added to our therapeutic arsenal during the upcoming months. PMID- 29390216 TI - ? PMID- 29390217 TI - [Female stress incontinence: aspects of pathogenesis and functional anatomy]. AB - This article focuses on female stress incontinence in the form of pelvic floor dysfunction and urethral sphincter deficiency, although isolated stress incontinence accounts for less than half of all incontinence cases. Especially in women of old age and those with neurological comorbidities, the causes of incontinence are mostly multifactorial. Also it has to be considered that the female bladder, urethra, uterus and rectum as well as the muscular and ligamentous structures of the female pelvis minor are affected by phases of fertility, possible pregnancies, births and menopause in addition to the normal ageing process. PMID- 29390218 TI - [Surgical treatment of pelvic organ prolapse]. AB - Female pelvic organ prolapse is a widely prevalent condition and is associated with variable morbidity. It encompasses a number of clinical conditions, including subvesical obstruction, overactive bladder symptoms, sexual dysfunction and urinary und fecal incontinence. The prevalence of pelvic insufficiency is estimated to be between 30 and 50 %. As life expectancy is increasing and the elderly population is growing, there will be an increased incidence of the condition and growing demand for pelvic floor treatment in the future. The incidence of recurrent pelvic floor prolapse is also growing. The goal of surgical management is the restoration of pelvic anatomy and bladder, vaginal and bowel function, resolution of patient symptoms and improvement in quality of life. The objective of this review is to present the main surgical procedures for different subtypes of genital prolapse and to evaluate their outcomes and complications. During the last ten years, technologies for the minimally invasive approach have advanced and robotic assisted sacrocolpopexy is now equivalent to classical vaginal and transabdominal procedures. PMID- 29390219 TI - [Combined treatment of endometriosis: radical yet gentle]. AB - Endometriosis is the second most common benign female genital disease after uterine myoma. This review discusses the management of individual patients. This should take into account the severity of the disease and whether the patient desires to have children. Particular emphasis is laid on the anatomical intersections which, when injured, can lead to persistent damage of the anterior, middle or posterior compartment and are not infrequently the cause of urological and urogynaecological follow-up measures. Typical symptoms of endometriosis include chronic pelvic pain, subfertility, dysmenorrhoea, deep dyspareunia, cyclical bowel or bladder symptoms (e. g. dyschezia, bloating, constipation, rectal bleeding, diarrhoea and haematuria), abnormal menstrual bleeding, chronic fatigue and low back pain. Approx. 50 % of all female teenagers and up to 32 % of all women of reproductive age who have been operated for chronic pelvic pain or dysmenorrhoea suffer from endometriosis. The time interval between the first unspecific symptoms and the medical diagnosis of endometriosis is about 7 years. This is caused not only by the non-specific nature of the symptoms but also by the frequent lack of awareness on the part of the cooperating disciplines with which the patients have first contact. As the pathogenesis of endometriosis is not clearly understood, causal treatment is still impossible. Treatment options include expectant management, analgesia, hormonal medical therapy, surgical intervention and the combination of medical treatment before and/or after surgery. The treatment should be as radical as necessary and as minimal as possible. The recurrence rate among treated patients lies between 5 % and > 60 % and is very much dependent on integrated management and surgical skills. Consequently, to optimise the individual patient's treatment, a high degree of interdisciplinary cooperation in diagnosis and treatment is crucial and should be reserved to appropriate centres - especially in the case of deep infiltrating endometriosis. PMID- 29390220 TI - [Surgical management of female stress urinary incontinence]. AB - Stress urinary incontinence in women is a common problem in Germany, with approx. 5 million women suffering from incontinence symptoms. These numbers are increasing, due to demographic changes; the suspected numbers are even higher. Prior to treatment, an extended diagnostic approach - including urodynamics and cystoscopy when necessary - is essential for optimal treatment selection.Primary treatment should be conservative, with pelvic floor training as an essential part of a multi-modal treatment concept. If conservative treatment fails, surgery is necessary and an increasing number of women are being treated with sub-urethral slings. The use of classical and well-known reconstructive surgeries - such as colposuspensions - is decreasing. An artificial urinary sphincter is a seldom indication in women, but a feasible option if the patient is physically and manually fit enough. The following article will summarise current diagnostic approaches and treatment options. PMID- 29390221 TI - [Diagnostic and therapeutic concepts for vesicovaginal and ureterovaginal fistulas]. AB - BACKGROUND: Vesico- and ureterovaginal fistulas are defined as abnormal connections between the urinary tract, on the one side, and the female genital system, on the other. Despite being highly prevalent as an acquired pathology of the urogenital system, there has as yet been no standardized protocol in place for diagnosing and treating these fistulas. This review analyses the current literature concerning vesico- and ureterovaginal fistulas in order to profile common diagnostic and therapeutic concepts. METHODS: Literature research was carried out using the data bases of Medline and PubMed. A general internet research was added as well as the subsequent analysis of textbooks. Subsequently 40 scientific publications, four textbooks and one internet source were consulted. RESULTS: In the diagnostic process of not only vesicovaginal, but also ureterovaginal fistulas a timely vaginal examination followed by a cystoscopy and further imaging by retrograde vaginal methylene blue instillation should be carried out. In order to further the differential diagnosis of ureterovaginal fistulas in particular, additional imaging techniques may be required. However, the therapies of both fistulas manifest essential differences. Ureterovaginal fistulas are closed in a two-stage procedure. At first, a percutaneous nephrostomy is placed to decompress the renal collecting system and further drain the urine, followed by a second intervention, which closes the fistula. The management of vesicovaginal fistulas includes both conservative and surgical concepts, the latter of which may in turn be divided into a transabdominal and/or a transvaginal approach. Essentially, transabdominal fistula surgery should, at first, include the identification of the orifices of both ureters to subsequently splint them as indicated. This should be followed by the excision of the fistula. In the case of large fistulas a flap reconstruction of the area may be considered after the mobilisation of the surrounding tissue. Despite almost all surgical techniques leading to successful outcomes, patients with radiogenic damage to the area might require an alternative form of urinary drainage. CONCLUSIONS: Industrial and developing countries continue to display significant differences in the etiology of fistulas as well as the operative treatment. The therapeutic concepts in place exhibit high success rates irrespecitve of the surgical approach and should be individually developed in accordance with the etiology, location and size of the fistula as well as the condition of the surrounding tissue. PMID- 29390222 TI - [Vesicouterine fistula after caesarean section]. AB - Vesicouterine fistulas (VUFs) are a pathological communication between uterus and urinary bladder, which are mainly related to iatrogenic lesions during caesarean sections or occur during vaginal deliveries after a previous caesarean section. The main symptoms are menstruation through the bladder (menouria), amenorrhea and urinary incontinence. Treatment can be conservative, hormonal or surgical; however, a spontaneous closure of the fistula is rare (5 %). We report a case of a female VUF with menouria after caesarean section with a successful surgical fistula excision. Based on this case report, we analyse the causes, symptoms, diagnostics and treatment of VUF as reported in the literature. PMID- 29390223 TI - ? PMID- 29390225 TI - Perturbation of Hemostatic Function by Nonbiologic Surfaces. PMID- 29390226 TI - Combination of Pulmonary Embolism Rule-out Criteria and YEARS Algorithm in a European Cohort of Patients with Suspected Pulmonary Embolism. AB - BACKGROUND: Both the YEARS algorithm and the pulmonary embolism (PE) rule-out criteria (PERC) were created to exclude PE with limited diagnostic tests. A diagnostic strategy combining both scores might save additional computed tomography pulmonary angiography (CTPA) scans, but they have never been evaluated in conjunction. AIM: The aim of this study was to determine the safety and efficiency of combining YEARS and PERC in a single diagnostic strategy for suspected PE. METHODS: The PERC rule was assessed in 1,316 consecutive patients with suspected PE who were managed according to YEARS. We calculated the absolute difference (with 95% confidence interval [CI]) in failure rate and the number of 'saved' CTPAs for the scenario that PE would have been ruled out without CTPA in the absence of all PERC items. RESULTS: Using the YEARS algorithm, PE was diagnosed in 189 patients (14%), 680 patients (52%) were managed without CTPA and the 3-month rate of venous thromboembolism in patients in whom PE was ruled out was 0.44% (95% CI: 0.19-1.0). Only 6 of 154 patients (3.9%; 95% CI: 1.4-8.2) with no YEARS items who were referred for CTPA would have been PERC negative, of whom none were diagnosed with PE at baseline or during follow-up (0%; 95% CI: 0-64). Applying PERC before YEARS in all patients would have led to a failure rate of 1.42% (95% CI: 0.87-2.3%), 0.98% (95% CI: 0.17-1.9) more than shown in patients managed by YEARS. CONCLUSION: Combining YEARS with PERC would have yielded only a modest improvement of efficiency in patients without a YEARS item and an unacceptable failure rate in patients with >= 1 YEARS item. PMID- 29390227 TI - Critical Analysis of an e-Learning and Interactive Teaching Module with Respect to the Interpretation of Emergency Computed Tomography of the Brain. AB - PURPOSE: To compare the learning benefit of three different teaching strategies on the interpretation of emergency cerebral computed tomography (CT) pathologies by medical students. MATERIALS AND METHODS: Three groups of students with different types of teaching (e-learning, interactive teaching, and standard curricular education in neuroradiology) were tested with respect to the detection of seven CT pathologies. The test results of each group were compared for each CT pathology using the chi-square test. A p-value <= 0.05 was considered to be significant. RESULTS: Opposed to the results of the comparison group (curricular education), the e-learning group and interactive teaching tutorial group both showed a significantly better performance in detecting hyperdense middle cerebral artery sign (p = 0.001 and p < 0.0001) as well as subarachnoid hemorrhage (p = 0.03 and p = 0.001) on CT. Moreover, an increase in performance for the detection of subdural hematoma and skull fracture could be observed for both the interactive teaching group and the e-learning group, with statistical significance in the latter (p = 0.03 and p < 0.0001, respectively). No statistically significant differences were found for the detection of intracranial and epidural hemorrhage, as well as midline shift, among the groups studied. CONCLUSION: Our study demonstrates potential learning benefits for both the interactive teaching tutorial and e-learning module group with respect to reading CT scans with slightly different advantages. Thus, the introduction of new learning methods in radiological education might be reasonable at an undergraduate stage but requires learning content-based considerations. KEY POINTS: . E-learning can offer benefits regarding the reading of cerebral CT scans by students. . Interactive tutorial can offer benefits regarding the reading of cerebral CT scans by students. . E-learning and interactive tutorial feature different strengths for student learning in radiology. . Application of interactive teaching methods in radiology requires learning content-based considerations. CITATION FORMAT: . Groth M, Barthe KG, Riemer M et al. Critical Analysis of an e-Learning and Interactive Teaching Module with Respect to the Interpretation of Emergency Computed Tomography of the Brain. Fortschr Rontgenstr 2017; 190: 334 - 340. PMID- 29390228 TI - Multiple Angulated Mammography Reconstructions in Digital Breast Tomosynthesis for the Diagnosis of Microcalcifications - Added Value to Standard Stack Reconstructions and Synthesized Mammography. AB - PURPOSE: To compare ratings regarding the depiction, diagnostic accuracy and lesion characterization of conventional synthesized mammography (SM), multiple angulated mammography reconstructions (INSIGHT3D), and standard stack reconstructions in digital breast tomosynthesis for microcalcifications. MATERIALS AND METHODS: This is a retrospective, multicase, multireader study. We included patients with digital breast tomosynthesis (DBT), microcalcifications and histology over a period of four months in our institution and the same number of normal cases. Three radiologists, who were blinded to patient data, independently rated the depiction, distribution, morphology and BI-RADS score of microcalcifications in SM, INSIGHT3D and standard stack reconstructions. Deidentified images were presented in random order. Reading time was measured. Friedman and post hoc Nemenyi tests, Cochrane's Q and post hoc Wilcoxon signed rank tests, Fleiss' kappa and receiver operating characteristics were used for statistical analysis. RESULTS: We included 41 histopathologically proven and 41 normal cases. Depiction of microcalcifications was rated better in INSIGHT3D than in SM and better in stack reconstructions than in INSIGHT3D and SM (P < 0.001). The reading time was lower in SM and INSIGHT3D compared to stack reconstructions (P < 0.001). The diagnostic accuracy and inter-rater correlation were comparable between all tested modes of reconstruction. CONCLUSIONS: INSIGHT3D has higher ratings regarding the depiction of microcalcifications compared to SM while maintaining a short reading time. Our preliminary assessment suggests that INSIGHT3D provides added value to SM. KEY POINTS: . INSIGHT3D depicts microcalcifications better than synthesized mammography while maintaining a low reading time.. . The diagnostic accuracy and inter-rater correlation were comparable between INSIGHT3D and synthesized mammography.. . INSIGHT3D may be a potential successor to synthesized mammography.. CITATION FORMAT: . Neubauer J, Neubauer C, Wicklein J et al. Multiple Angulated Mammography Reconstructions in Digital Breast Tomosynthesis for the Diagnosis of Microcalcifications - Added Value to Standard Stack Reconstructions and Synthesized Mammography. Fortschr Rontgenstr 2018; DOI: 10.1055/s-0044-100726. PMID- 29390230 TI - ? PMID- 29390231 TI - ? PMID- 29390232 TI - Topical Ascorbate Administration in Severe Ocular Burns. PMID- 29390229 TI - Feasibility of a Single Contrast Bolus High-Pitch Pulmonary CT Angiography Protocol Followed by Low-Dose Retrospectively ECG-Gated Cardiac CT in Patients with Suspected Pulmonary Embolism. AB - INTRODUCTION: To prospectively evaluate the feasibility of single contrast bolus high-pitch CT pulmonary angiography (CTPA) subsequently followed by low-dose retrospectively ECG-gated cardiac CT (4D-cCT) in patients with suspected pulmonary embolism (PE) to accurately evaluate right ventricular (RV) function. MATERIALS AND METHODS: 62 patients (33 female, age 65.1 +/- 17.5 years) underwent high-pitch CTPA examination with 80cc of iodinated contrast material. 5 s after the end of the high-pitch CTPA study, a low-dose retrospectively ECG gated cardiac CT examination was automatically started. The volume CT dose index (CTDI vol) and dose length product (DLP) were recorded in all patients and the effective dose was calculated. For the assessment of image quality, attenuation was measured as Hounsfield units (HUs) within various regions of interest (ROIs). These ROIs were used to calculate the signal-to-noise ratio (SNR) and contrast-to noise ratio (CNR). Subjective image quality was assessed using a five-point Likert scale. On 4D-cCT, the ejection fraction of both ventricles (RVEF, LVEF) as well as the ratio of RVEF and LVEF (RVEF/LVEF) was assessed. The statistical difference of all parameters between the PE and non-PE group was calculated. RESULTS: The mean effective radiation dose was 4.22 +/- 2.05 mSv. Attenuation measurements on CTPA showed the highest attenuation values in the main pulmonary artery (442.01 +/- 187.64). On 4D-cCT attenuation values were highest in the descending aorta (560.59 +/- 208.81). The CNR and SNR values on CTPA were highest within the main pulmonary artery (CNR = 12.43 +/- 4.57; SNR = 15.14 +/- 4.90). On 4D-cCT images, the highest SNR and CNR could be measured in the descending aorta (CNR = 10.26 +/- 5.57; SNR = 10.86 +/- 5.17). The mean LVEF was 60.73 %+/- 14.65 %, and the mean RVEF was 44.90 %+/- 9.54 %. The mean RVEF/LVEF was 0.79 +/- 0.29. There was no significant difference between the PE and non-PE group for either of the parameters. CONCLUSION: The investigated combined CTPA and 4D-cCT protocol is feasible using a single contrast bolus and allows the evaluation of RV function in patients with suspected PE. Further studies have to evaluate the additional value of this protocol regarding risk stratification in patients with PE. KEY POINTS: . High-pitch CTPA is fast enough to leave sufficient contrast material within the heart that can be used for an additional low-dose functional cardiac CT examination.. . The tube current of the evaluated 4D-cCT is reduced over the entire cardiac cycle without any full dose peak.. . Low-dose cardiac CT subsequently performed after high-pitch CTPA allows for detailed analysis of RV function.. CITATION FORMAT: . Schafer JC, Haubenreisser H, Meyer M et al. Feasibility of a Single Contrast Bolus High-Pitch Pulmonary CT Angiography Protocol Followed by Low-Dose Retrospectively ECG-Gated Cardiac CT in Patients with Suspected Pulmonary Embolism. Fortschr Rontgenstr 2018; 190: 542 - 550. PMID- 29390233 TI - OCT Angiography of the Central Macular Capillary Network in Glaucoma Patients and Healthy Controls. AB - PURPOSE: We aimed to investigate central macular microvasculature by optical coherence tomography angiography (OCTA) and to analyse its relation to alterations in classical parameters of optical coherence tomography (OCT) in glaucoma patients. METHODS: Using OCTA (Avanti incl. AngioVue; Optovue, Inc., Fremont, CA), the superficial flow (SF) and the superficial non-flow (SNF) area of the macula, as well as the S-ETDRS (based on Early Treatment Diabetic Retinopathy charts). and S-grid vessel density (zones 1 - 9) of the macula, were evaluated in 27 glaucoma patients (49 eyes) and compared to those of 27 age matched healthy controls (50 eyes; p = 0.253). The interactions between OCTA parameters representing macular microvasculature and classical OCT measurements of the circumpapillary retinal nerve fibre layer (RNFL) and macular ganglion cells (mGCC) were analysed within groups (linear mixed-effects model). RESULTS: SF, SNF, and S-ETDRS vessel density exhibited no significant difference between the glaucoma and control groups (all p >= 0.158). However, within the glaucoma group, decreased RNFL and mGCC thickness correlated significantly with decreased S-ETDRS density (zones 1; 2 - 9, p <= 0.033). The same held true for the interactions between the RNFL and mGCC thickness with S-grid density (zones 1 - 3; 6 - 9; p <= 0.033). For perimetric glaucoma patients, subgroup analyses demonstrated significantly reduced density maps of superficial foveal flow as well as significant interactions between OCT and OCTA parameters; this was not the case within the preperimetric group. CONCLUSIONS: Even if the central macular microvasculature, as measured by SF and SNF, is found preserved in glaucoma, the strong positive relation between the central microvascular and structural changes in OCTA and OCT indicates that there are alterations in central macular microvasculature in subclinical glaucoma. PMID- 29390234 TI - [Despite Challenges and Pitfalls: How Ophthalmology Benefits from the Use of Next Generation Sequencing]. AB - Within a few years, high-throughput sequencing (next-generation sequencing, NGS) has become a routine method in genetic diagnostics and has largely replaced conventional Sanger sequencing. The complexity of NGS data requires sound bioinformatic analysis: pinpointing the disease-causing variants may be difficult, and erroneous interpretations must be avoided. When looking at the group of retinal dystrophies as an example of eye disorders with extensive genetic heterogeneity, one can clearly say that NGS-based diagnostics yield important information for most patients and physicians, and that it has furthered our knowledge significantly. Furthermore, NGS has accelerated ophthalmogenetic research aimed at the identification of novel eye disease genes. PMID- 29390235 TI - [Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]. AB - Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field. PMID- 29390236 TI - [Questions unanswered and Answers unquestioned: what we do and do not know about women and kidney diseases. Reflection on World Kidney Day and International Women's Day]. AB - Chronic Kidney Disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and on the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29390237 TI - [Customization of hemodialysis therapy: dialysis is not a washing machine]. AB - In recent years, the population of chronic dialysis has grown in number but also in age and frequency of co-morbidies such as cardiac diseases, vascular pathologies, diabetes, etc. The majority of patients on chronic hemodialysis are over 70 years and, given the high number of comorbidities, they often exhibit poor tolerance to dialysis treatments. A non-tolerated dialytic treatment can have side-effects that would require an intensification of the dialysis sessions and many hospitalizations. Consequently, the problematic dialysis treatments, as well as harmful for the patient, become economically more detrimental than other treatments apparently more expensive but more tolerated ones In the current days we have, thanks to the huge developments in dialysis technology, powerful weapons to ensure effective and scarcely symptomatic dialysis treatments to the majority of the HD patients. New, highly biocompatible membranes with defined and modular cut-off and / or absorption capacity may allow us to provide adequate purification. Moreover the monitoring and biofeedback systems such as blood volume tracking, body temperature monitoring (BTM) and blood pressure (BPM) can be very useful in reducing the risk of intra-dialytic hypotension and symptoms. Therefore, the dialytic therapy, as well as all the pharmacological therapies for the chronic patient, must consider the specificity of the patient, basing on his metabolic problems, cardiovascular tolerance, residual renal function and on his dietary and general compliance. The central aim of the nephrologist is to formulate the better prescription for the individual patient, considering the dialysis modalities, the membrane type, the dry weight (ideal post-dialysis body weight), the frequency and the duration of the weekly sessions and the technological tools that can optimize the treatment. PMID- 29390238 TI - [Infrequent and incremental dialysis: differences and definitions]. AB - The purpose of this review is to give dignity at the Incremental Dialysis, which cannot be confused with the term and the therapeutic choice defined as Infrequent Dialysis. The Infrequent Dialysis is defined by each and every hemodialytic therapeutic choice like rhythms below thrice-weekly-hemodialytic treatments. Nonetheless, Infrequent Dialysis is a choice of replacement hemodialysis therapy with pays more special clinical attentions and nutritional monitoring and should also be accompanied by a slightly hypoproteic controlled nutrition. When talking about the Incremental Dialysis (CDDP) it is defined as a well-defined therapeutic program that requires a significant clinical attention. The CDDP begins with the pre-dialysis outpatient clinic in the short period of time when the patient passes, after a severe nutrition compliance assessment with a VFG of 5-10 mL / min / 1.73mq, from the conservative treatment to an hypoproteic diet composed of 0.6g/ Kg / day with or without essential amino acids and hyposaline diet supplemented by One-Weekly Dialysis. The Incremental Dialysis program is strictly tailored on the trend of Residual Renal Function (FRR). CDDP is a time variable therapeutic "bridge" that must provide a good metabolic status and a good quality of life of the treated patients. Recent studies have shown a lower mortality compared with thrice-weekly-dialysis and a neutral input/output balance of phosphorus pool due to the phosphaturia contribution compared to the thrice weekly-patients who lose early their FRR. Further studies are needed to confirm the safety and validity of this therapeutic choice. PMID- 29390239 TI - [Medicine and Nephrology from Social Networks]. PMID- 29390240 TI - [Hyperuricaemia and Chronic Kidney Disease]. AB - Hyperuricemia is defined as serum uric acid values greater than 6 mg/dl and could occur either due to hyperproduction or as a result of reduced renal excretion, which exceeds gut compensation. In Italy, prevalence is around 12% of the general population and increases in renal disease up to 60%. Recent experimental studies demonstrated a role of uric acid in the development of arterial hypertension and systemic arteriosclerosis, with an increase in cardiovascular risk. It also appears from observational studies that high uric acid is an independent risk factor associated with de novo onset of chronic kidney disease after adjustment of main confounding variables. Hyperuricemic subjects treated with febuxostat, a selective inhibitor of xantino-oxidase, showed in RCTs a better control of hyperuricaemia in comparison with those receiving allopurinol. Moreover, observational studies indicate that urate lowering treatment could be helpful in reducing cardiovascular events as well as in slowing the progression of chronic kidney disease; randomized controlled studies, designed to assess as primary outcome the nephroprotective effect of urate lowering treatment, are in progress. PMID- 29390241 TI - [Dystrophic Calcinosis Cutis: a rare fearsome issue of Chronic Kidney Disease]. AB - Disorders of calcium-phosphate-parathormone balance, are very important issues in ESRD patients, that may lead to severe complications, as dystrophic calcinosis cutis, a rare disease, caused by calcium salt deposits in cutaneous or subcutaneous tissues and many organs. We present the case of a 47 years old woman, in ESRD due to membranous glomerulopathy, treated by peritoneal dialysis, who, after 7 months of dialysis, developed painful masses on second finger and fifth metacarpus of the right hand. Laboratory and instrumental data showed hyperparathyroidism with a parathyroid mass consistent with adenoma. Increasing of therapy with phosphate binders and cinacalcet only, was not effective to solve cutaneous masses, that were biopsied. Histological exam revealed deposition of amorphic material with calcific component, consistent with cutaneous dystrophic calcinosis. We further increased dialysis and therapy and we observed complete regression of masses in 2 months. PMID- 29390242 TI - [Severe lactic acidosis requiring continuos haemodiafiltration in a young patient with unrecognized metabolic abnormality. Case report]. AB - BACKGROUND: Lactic acidosis (LA) is the most common form of metabolic acidosis, defined by lactate values greater than 5 mmol/L and pH<7.34. The pathogenesis of LA involves hypoxic causes (type A) and non-hypoxic (type B), often coexisting. Identification and removal of the trigger are mandatory in the therapeutic management of LA. The case: A 38 years-old male patient entered the Emergency Ward for dyspnea, fever, vomiting and hyporexia. An important respiratory distress with hyperventilation due to severe LA was found, together with severe hypoglicemia, without renal impairment. Past medical history unremarkable, except for reported episodic hypoglicemia in the childhood, with fructose "intolerance", without any other data. No evidence of intoxications, septic shock or significant cytolysis. No drugs causing LA. The patient underwent orotracheal intubation, glucose infusion, and continuous haemodiafiltration for 36-hrs. A rapid general improvement was obtained with stabilization of acid-base balance. A diagnosis of fructose-1,6-diphosphatase deficiency was made. It is an autosomical recessive gluconeogenesis abnormality, with recurrent episodes of hypoglicemia and lactic acidosis after fasting, potentially lethal. The therapy is based on avoiding prolonged fasts, glucose infusion, and a specific diet, rich in glucose without fructose intake. CONCLUSIONS: The presence of not-otherwise-explained lactic acidosis in young patients has to place the suspect of an underlying and unknown metabolic derangement; in these cases, the involvement of the nephrologist appears to be pivotal for the differential diagnosis of the abnormalities of the acid-base balance, and for setting the best treatment. PMID- 29390243 TI - [Bardet-Biedl syndrome and Kidney failure: a case report]. AB - Bardet-Biedl Syndrome (BBS) is a rare multi-systemic disease with autosomal recessive transmission. BBS was at first considered to be homogeneous as for its genetics, but subsequent studies have shown an extensive gene variability. Currently, 21 genes (BBS1-21) present on different chromosomes have been mapped: these genes are responsible for BBS phenotypes and they show a great heterogeneity of mutations.The most common genes are BBS1 (locus 11q13) and BBS10.We show here the case of a 50 year old patient with BBS. Medical History: retinitis pigmentosa at 4 years of age evolved to complete blindness, generalized epilepsy crises, poly-syndactyly, left-hand malformation. In April 1986 developed an epileptic episode: on that occasion Chronic Kidney Failure (CKF) diagnosis and starting of haemodialysis. In 1989, hospitalization for epileptic seizures. In 2009 the patient underwent kidney transplantation from deceased donor. Immunosuppressive initial protocol: Basiliximab, Azathioprine, Tacrolimus, Steroid, and Tacrolimus, Azathioprine, Steroid at hospital discharge. Post operative care complicated by respiratory failure with mechanical ventilation assistance. During hospitalization, the neurological picture remained stable. At hospital discharge Creatinine 1.8 mg/dl. Subsequently, immunosuppressant were gradually tapered until monotherapy with Tacrolimus. At present the patient's conditions appear to be good, renal function has remained substantially stable with Creatinine between 1.4-1.5 mg/dl and glomerular filtration rate (GFR) estimated at 39-42 mL/min/1.73 m 2 according to MDRD study Equation. This case shows the possibility to successfully manage a BBS-affected uremic patient, despite the complexity of the pathology and the aggravating factor of extreme rarity in diagnostic pathway. PMID- 29390244 TI - [Practical procedures to launch a once-weekly-dialysis program integrated into a personalized hypoproteic nutrition (CDDP)]. AB - This work is aimed for showing in detail to the nephrologists the methodology applied in the Combined Diet Dialysis Program (CDDP) in selected patients especially with the use of the Urea Nitrogen Appearance which allows to verify the sustainability and collaboration of patients on the 0.6 g/Kg/day hypoproteic diet by calculating the Protein Catabolic Rate in patients with metabolic steady state. It is also confirmed that the combined action of nutrition and the minimal contact with hemodialysis may allow a longer maintenance of the residual renal function with the further possibility of a greater excretion of Protein Bound Uremic Toxins and to obtain a phosphate balance thanks for a good maintenance of phosphaturia. In this paper are described in detail all the necessary steps and calculations. But it is mandatory a greater clinical commitment to achieve the achievement of a personalized therapeutic protocol like CDDP that is easily applicable in everyday clinical practice. PMID- 29390246 TI - [Errors in the medical report of urine cellular fraction]. AB - Urine examination guides doctors in formulating diagnosis and therapies or in excluding diseases, not only of the urinary tract. The research for urine cells has been and still is performed manually with manual optical microscopes. Recently, in the reading of cells found in the urine, various technologies such as automated microscopy and cytofluorometry are used. This change involved different preparation of the urine sample, microscope field diversity, sample volume diversity, different units of measurement, diversity of standard values. This change has not been accompanied by the change of terminology in urine examination reporting, resulting in conceptual errors, communication and interpretation by the clinicians. The job examines the errors and proposes the necessary changes. PMID- 29390245 TI - A strategy to reduce inflammation and anemia treatment's related costs in dialysis patients. AB - This is a post-hoc analysis evaluating erythropoiesis stimulating agents' (ESA) related costs while using an additional ultrafilter (Estorclean PLUS) to produce ultrapure dialysis water located within the fluid pathway after the treatment with reverse osmosis and before the dialysis machine. Twenty-nine patients (19 treated with epoetin alfa and 10 with darboepoetin alfa) were included in the analysis. We showed to gain savings of 210 ? per patient (35 ? per patient each month) with epoetin alfa during the experimental period of 6 months, compared to the control period and of 545 ? per patient (90 ? per patient each month) with darboepoetin alfa. Estorclean PLUS had a cost of 600 ? (25 ? per month per each patient) and was used for 6 months. Intravenous iron therapy with sodium ferrigluconate had a cost of 0,545 ?/62,5 mg. In conclusion, during the experimental period with the use of Estorclean, we obtained global savings of 11 ? per patient per month with epoetin alfa and 30 ? per patient per month with darboepoetin alfa to treat anemia in dialysis patients. PMID- 29390247 TI - [Technicity, ethics, significance of the limit and proximity]. PMID- 29390248 TI - [Data Protection Officer]. PMID- 29390250 TI - Endothelium Independent Effect of Pelargonidin on Vasoconstriction in Rat Aorta. AB - In this study, we investigated the effects of pelargonidin, an anthocyanidin found in many fruits and vegetables, on endothelium-independent vascular contractility to determine the underlying mechanism of relaxation. Isometric contractions of denuded aortic muscles from male rats were recorded, and the data were combined with those obtained in western blot analysis. Pelargonidin significantly inhibited fluoride-, thromboxane A2-, and phorbol ester-induced vascular contractions, regardless of the presence or absence of endothelium, suggesting a direct effect of the compound on vascular smooth muscles via a different pathway. Pelargonidin significantly inhibited the fluoride-dependent increase in the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation at Thr-855 and the phorbol 12,13-dibutyrate-dependent increase in the level of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at Thr202/Tyr204, suggesting the inhibition of Rho-kinase and mitogen-activated protein kinase kinase (MEK) activities and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxation effect of pelargonidin on agonist-dependent vascular contractions includes inhibition of Rho-kinase and MEK activities, independent of the endothelial function. PMID- 29390251 TI - A confused ECG with multiple rhythms caused by atrial premature contractions: A case report. AB - INTRODUCTION: Atrial premature contractions (APCs) are commonly encountered in clinical practice. The APCs may influence heart conduction system and induce other arrhythmia. The disorder of atrioventricular conduction is related to electrophysiological phenomena, difficult to understand and diagnose. CASE REPORT: We presented a 15-year-old male patient whose baseline electrocardiogram (ECG) was confused with multiple rhythms. Electrophysiological study results showed sinus rhythm with nonconducted APCs in bigeminal rhythm. Nonconducted APCs were blocked without H wave. Some APCs conducted to ventricle with longer AH interval and HV interval. When APCs were abolished by radiofrequency ablation, this patient was free from any arrhythmia during follow-up. CONCLUSION: We considered that the basic rhythm of the baseline ECG was sinus rhythm with atrial bigeminy rhythm and narrow QRS extrasystoles (junctional); some APCs were blocked and some APCs conducted to ventricle with aberrant QRS complexes. The phenomenon of baseline ECG was caused by the APCs. PMID- 29390252 TI - Correlation study of Framingham risk score and vascular dementia: An observational study. AB - Vascular dementia (VaD) is one of the most common forms of dementia, and second only to Alzheimer's disease. The purpose of this study was to evaluate the potential diagnostic value of Framingham risk score (FRS) in VaD by investigating the relationship among cardiovascular risks, FRS, and VaD.Data were collected from patients (n = 130) at Tongji Hospital in Wuhan, China. They were divided into 2 groups, including the control group (n = 70) and the VaD group (n = 60). Statistical methods including t-test, logistic regression model, multiple linear regression model, and receiver-operating characteristic (ROC) curve were adopted for the assessment.A significant difference (all P < .05) was observed in systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, total cholesterol (TC), homosysteine (HCY), glycosylated hemoglobin A1c (HbA1c), FRS, and cerebral white matter lesions (WMLs) between the 2 groups, even after adjusting for age (both P < .05). Age [odds ratio (OR) = 1.20; P = .002], FRS (OR = 1.55; P = .006), and WMLs (OR = 10.17; P = .011) were independent prognostic factors for VaD. The area under the ROC curve (AUC) of FRS for VaD diagnosis prediction was 0.830 (95% confidence interval, 95% CI: 0.730~ 0.929). There was a significant difference in the AUC between WMLs and WMLs combined with FRS (0.788 (95% CI: 0.667 ~ 0.880) versus 0.863 (95% CI: 0.754 ~ 0.936, P = .049). Age, HbA1c, and FRS were negatively correlated with the mini-mental state examination (MMSE) scores (all P < .05) in the VaD group. Moreover, multiple stepwise linear regression analysis showed that the age and FRS were independent predictors of MMSE scores.FRS has a moderate predictive value for the VaD diagnosis, and also increases the risk of cognitive decline. PMID- 29390253 TI - Factors associated with acute oral mucosal reaction induced by radiotherapy in head and neck squamous cell carcinoma: A retrospective single-center experience. AB - To investigate risk factors for acute oral mucosal reaction during head and neck squamous cell carcinoma radiotherapy.A retrospective study of patients with head and neck squamous cell carcinoma who underwent radiotherapy from November 2013 to May 2016 in Anhui Provincial Cancer Hospital was conducted. Data on the occurrence and severity of acute oral mucositis were extracted from clinical records. Based on the Radiation Therapy Oncology Group (RTOG) grading of acute radiation mucosal injury, the patients were assigned into acute reaction (grades 2-4) and minimum reaction (grades 0-1) groups. Preradiotherapy characteristics and treatment factors were compared between the 2 groups. Multivariate logistic regression analysis was used to detect the independent factors associated with acute oral mucosal reactions.Eighty patients completed radiotherapy during the study period. Oral mucosal reactions were recorded as 25, 31, and 24 cases of grades 1, 2, and 3 injuries, respectively. Significant differences between acute reaction and minimum reaction groups were detected in cancer lymph node (N) staging, smoking and diabetes history, pretreatment platelet count and T-Helper/T Suppressor lymphocyte (Th/Ts) ratio, concurrent chemotherapy, and total and single irradiation doses.Multivariate analysis showed that N stage, smoking history, single dose parapharyngeal irradiation, and pretreatment platelet count were independent risk factors for acute radiation induced oral mucosal reaction. Smoking history, higher grading of N stage, higher single dose irradiation, and lower preirradiation platelet count may increase the risk and severity of acute radiation oral mucosal reaction in radiotherapy of head and neck cancer patients. PMID- 29390254 TI - The association between ankylosing spondylitis and the risk of any, hip, or vertebral fracture: A meta-analysis. AB - BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease and strongly associated with an increased risk of fractures. A great proportion of patients with AS are suffering from sustaining fractures and the aim of this study is to evaluate and quantify the association between the site of the fracture and AS by performing a meta-analysis. METHODS: A systematic literature search was performed on Medline database from 1966 to August 15, 2016 and Embase database from 1980 to August 15, 2016. Studies were evaluated by 2 independent reviewers and quantitative estimates regarding the association between ankylosing spondylitis and the risk of any, hip, or vertebral fracture were presented. After the heterogeneity of selected studies was assessed by using Cochran I statistics, the random effect model was used to combine effect size. Publication bias was measured by Egger and Begg's regression tests. RESULTS: A total of 6 articles were involved in our study. The results of meta-analysis revealed that AS was strongly associated with the risk of vertebral fracture (odds ratio [OR] = 4.25, 95% confidence interval [CI] = 1.07-7.42) and was not significantly associated with the risk of any fracture (OR=2.00, 95%CI = 0.94-3.06) or hip fracture (OR=1.28, 95%CI =0.16-2.40). CONCLUSION: In the present study, a general knowledge of the association between AS and the risk of 3 kinds of fractures were presented, which could improve the ways of prevention of fracture in the patients with AS. PMID- 29390255 TI - Could late measurement of serum creatinine be missed for patients without early increase in serum creatinine following coronary angiography? AB - Most patients are discharged early (within 24 hours) after coronary angiography (CAG) and may miss identification the late (24-48 hours) increase in serum creatinine (SCr), whose characteristics and prognosis have been less intensively investigated.We prospectively recruited 3065 consecutive patients with SCr measurement, including only1344 patients with twice SCr measurement (both early and late). The late contrast-induced acute kidney injury (CI-AKI) was defined as significantly increase in SCr (>=0.3 mg/dL or >=50%) not in early phase, but only in late phase after the procedure, and the early CI-AKI experienced a significantly increase in early phase.Overall, CI-AKI developed in 134 patients (10%), and the incidence of late and early CI-AKI were 3.6% and 6.4%, respectively. There were no difference in age, renal, and heart function, contrast volume among patients with late and early CI-AKI. With mean follow-up period of 2.45 years, long-term mortality (3 years, 29.7% and 35.6%, respectively, P = .553) was similar for patients with late and early CI-AKI. Cox analysis showed that both late (adjusted HR 2.05; 95% CI, 1.02-4.15) and early (adjusted HR 2.68; 95% CI, 1.57-4.59) CI-AKI was significantly associated with long-term mortality (all P < .001).Only late increase in SCr, as late CI-AKI, accounted for about one-third of CI-AKI incidence and has similar good predictive value for long-term mortality with that of an early increase, early CI-AKI, among patients with SCr measured twice, supporting the importance of late repeating SCr measurement after CAG, even without an early significant increase in SCr. PMID- 29390256 TI - Sjogren's syndrome complicating pancytopenia, cerebral hemorrhage, and damage in nervous system: A case report and literature review. AB - RATIONALE: Sjogren's syndrome(SS) is a chronic autoimmune disease, which damages exocrine glands especially salivary and lacrimal glands, with xerostomia and xerophthalmia as common symptoms. PATIENT CONCERNS: We report a case of a 49-year old woman presented with pancytopenia. Her laboratory examinations lead us diagnose her as Sjogren's syndrome complicating pancytopenia. She had neurological symptoms during her treatment, which represent only 4.5% of Sjogren's syndrome complicating damage in nervous system. DIAGNOSES: Sjogren's syndrome complicating pancytopenia. INTERVENTIONS: Dexamethasone (40mg QD for 4 days) and immunoglobulin (25g QD for 2 days) were administered for intensive treatment followed by oral methylprednisolone 40mg QD as maintenance treatment. Total glucosides of paeony 0.6g TID and danazol 0.2g BID per os were given. We also gave her Piperacillin-tazobactam and moxifloxacin for anti-infection and Fluconazole for anti-fungal therapy, as well as other supportive treatments. OUTCOMES: Follow-up of the patient observed the normalization of peripheral blood cell count, immunity indices and neurological examinations 6 months after discharge. LESSONS: For patients presented with blood system abnormalities unilineage or multiple-lineage cytopenia in particular, history investigations and relevant examinations should be considered to exclude the existence of autoimmune diseases like Sjogren's syndrome. PMID- 29390257 TI - Community-onset extended-spectrum beta-lactamase producing Escherichia coli in urinary tract infections in children from 2015 to 2016: Prevalence, risk factors, and resistances. AB - Over the past 10 years, the resistances among microbes are increasing gradually in Europe and greater resistances are seen in southern countries. We studied the prevalence of community-onset ESBL-producing Escherichia coli urinary tract infections in children.As secondary objectives, we analyzed associated risk factors and the resistance patterns in ESBL-producing E coli isolates.Retrospective observational study in a tertiary care hospital about children <=14 years old with community-onset E coli urinary tract infection. The variables studied were age, sex, ESBL-producing, antibiotic therapy 7 to 30 days before the infection, hospitalization 7 to 30 days before the infection, nefrourologic pathology, and vesicoureteral reflux.Between January 1st, 2015 and December 31st, 2016, 229 isolates of E coli were obtained, of whom 21 (9.2%) where ESBL-producing E coli. Median age in non-ESBL-producing was 18 months versus 7 months in ESBL-producing group. Fourteen (66%) of the ESBL-producing group were men (P = .001), 5 (23.8%) were hospitalized 30 days before the infection (P = .001), 12 (57.1%) had nefrourological pathology (P = .003), 6 (28.5%) had vesicoureteral reflux (P = .032). Previous antibiotic therapy was not statistically significant. Multiple regression analyses between sex and 30 days previous hospitalization were r = 3.51 (P = .0001). Multidrug resistant isolates among ESBL-producing E coli was 12 (57%).The retrospective study allowed assessing the problem of ESBL-producing isolates in the outpatient settings. Some risk factors from past studies were confirmed and a combined risk is suggested. The resistant spectrum should be taken into account when choosing antibiotic regimens. PMID- 29390258 TI - Short-segment fixation with a cement-augmented pedicle screw for Kummell disease: Case report. AB - RATIONALE: Kummell disease is described as avascular necrosis of a vertebral body that occurred in a delayed fashion after a minor trauma. Anterior, posterior, and anterior-posterior approaches have been reported. Nevertheless, there is no standard treatment for patients with Kummell disease. PATIENT CONCERNS: We reported a successful cement-augmented pedicle screw placement in a patient with Kummell disease. A 63-year-old woman with serious osteoporosis complained persistent back pain with progressive lower extremities weakness for almost 2 years. DIAGNOSES: The diagnosis of Kummell disease was mainly depended on clinical symptoms and imaging examinations. INTERVENTIONS: The application of a cement-augmented pedicle screw was designed to treat this illness. OUTCOMES: The operation was successful without any complications. The patient stated that symptoms were obviously improved in 1 week after operation. LESSONS: The application of a cement-augmented pedicle screw is an effective treatment option for Kummell disease. PMID- 29390259 TI - Minimally invasive surgical approach versus open procedure for pancreaticoduodenectomy: A systematic review and meta-analysis. AB - BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) remains one of the most challenging abdominal procedures. Safety and feasibility remain controversial when comparing MIPD with open pancreaticoduodenectomy (OPD). The aim of this systematic review and meta-analysis was to evaluate the feasibility and safety of MIPD versus OPD. METHODS: A systematic review of the literature was performed to identify studies comparing MIPD and OPD. Postoperative complications, intraoperative outcomes and oncologic data, and postoperative recovery were compared. RESULTS: There were 27 studies that matched the selection criteria. Totally 1306 cases of MIPD and 5603 cases of OPD were included. MIPD was associated with a reduction in postoperative hemorrhage (odds ratio [OR] 1.60; 95% confidence interval [CI] 1.03-2.49; P = .04) and wound infection (OR 0.44, 95% CI 0.30-0.66, P < .0001). MIPD was also associated with less estimated blood loss (mean difference [MD] -300.14 mL, 95% CI -400.11 to -200.17 mL, P < .00001), a lower transfusion rate (OR 0.46, 95% CI 0.35-0.61; P < .00001) and a shorter length of hospital stay (MD -2.95 d, 95% CI -3.91 to -2.00 d, P < .00001) than OPD. Meanwhile, the MIPD group had a higher R0 resection rate (OR 1.45, 95% CI 1.18-1.78, P = .0003) and more lymph nodes harvested (MD 1.34, 95% CI 0.14 2.53, P = .03). However, the minimally invasive approach proved to have much longer operative time (MD 71.00 minutes; 95% CI 27.01-115.00 minutes; P = .002) than OPD. Finally, there were no significant differences between the 2 procedures in postoperative pancreatic fistula (P = .30), delayed gastric emptying (P = .07), bile leakage (P = .98), mortality (P = .88), tumor size (P = .15), vascular resection (P = .68), or reoperation rate (P = .11). CONCLUSIONS: Our results suggest that MIPD is currently safe, feasible, and worthwhile. Future large volume, well-designed randomized controlled trials (RCT) with extensive follow-up are awaited to further clarify this role. PMID- 29390260 TI - Paraproteinemic keratopathy in monoclonal gammopathy of undetermined significance treated with primary keratoprosthesis: Case report, histopathologic findings, and world literature review. AB - RATIONALE: We report a case of paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance, treated with keratoprosthesis as a primary penetrating procedure. Histopathological findings and a world literature review are presented. PATIENT CONCERNS: A 74 year old female recently diagnosed with monoclonal gammopathy undetermined significance presented with progressive blurry vision bilaterally. DIAGNOSES: Examination revealed corneal opacities consistent with paraproteinemic keratopathy. INTERVENTIONS: Corneal transplantation with the Boston Type I keratoprosthesis was performed on the right and, a year later, on the left. OUTCOMES: Visual outcomes were good. Histopathological staining of host corneal buttons were consistent with monoclonality, and electron microscopy revealed fibrillar extracellular aggregates within intervening normal stroma. LESSONS: Corneal deposits may be the only manifestation of monoclonal gammopathy of undetermined significance in patients who are otherwise systemically asymptomatic. Ophthalmologists who encounter corneal opacities may order the appropriate diagnostic studies to determine the presence of occult systemic disease. Risk of graft failure after penetrating keratoplasty from recurring opacities is high, so keratoprosthesis as a primary penetrating procedure may afford superior long-term outcomes. Host corneal buttons retrieved from penetrating keratoplasty or corneal biopsy may be sent for histopathological examination to confirm the diagnosis. PMID- 29390261 TI - Metabolic syndrome affects narrow-band UVB phototherapy response in patients with psoriasis. AB - Psoriasis is a chronic inflammatory skin disease. Metabolic syndrome (MS) is a combination of central obesity, dyslipidemia, glucose intolerance, and elevated blood pressure. Many epidemiological surveys have revealed the association of psoriasis with MS. Narrowband ultraviolet radiation b (NB-UVB) is an effective and widely used treatment for psoriasis. The purpose of this study was to investigate whether the presence of MS in patient with psoriasis affects NB-UVB treatment and whether this syndrome correlates with systemic inflammation.From June 2016 to December 2016, 243 adults with a diagnosis of psoriasis vulgaris eligible to treatment with NB-UVB were admitted to the phototherapy unit of Dermatology department, Chinese PLA General Hospital. Fifty-five included patients were grouped based on the presence of MS. They accepted the treatment of NB-UVB and the following data were collected: serum levels of IL-17 (interleukin), TNF-alpha (tumor necrosis factor) and IL-6, Psoriasis Area and Severity Index (PASI) scores before and after 10 sections of NB-UVB treatment.Significant PASI improvement was observed in psoriatic patients without MS after 10 sections of phototherapy, while patients with MS showed a less improvement (P < .001). There was statistically significant difference in percentage of patients achieving 50% reduction in PASI scores between the 2 groups (P < .05). Multivariate logistic regression analysis showed MS was an independent factor that affecting the treatment of NB-UVB (P < .05). Psoriatic patients with MS showed a much less reduction of IL-17 and IL-6 before and after 10 sections of NB-UVB treatment respectively than patients without MS (P < .05).Psoriatic patients with MS have poorer improvement in comparison those without MS using NB-UVB treatment. MS was an independent factor that affecting the treatment of NB-UVB. In addition, psoriatic patients with MS showed a much less reduction of systemic biomarkers (interleukin-IL-17, TNF-alpha, IL-6) than patients without MS. Namely, they may need a longer course of treatment to achieve improved skin lesions. PMID- 29390262 TI - Treatment of Bacillus cereus endophthalmitis with endoscopy-assisted vitrectomy. AB - To evaluate the use of endoscopy-assisted vitrectomy in patients with sight threatening Bacillus cereus endophthalmitis.A retrospective analysis was conducted in 15 eyes with Bacillus cereus endophthalmitis. Patients were divided into 2 groups: endoscopy-assisted vitrectomy (5 eyes) and conventional vitrectomy (10 eyes). The following clinical data were recorded and analyzed: sex, age, latent period, symptom duration, follow-up time, visual acuity pre- and postsurgery, recurrence of endophthalmitis, incidence of phithisis bulbi, and incidence of enucleation.In the conventional vitrectomy group, postoperative visual acuity ranged from no light perception in 5 patients (50%), light perception in 3 patients (30%), 20/1000 in 1 patient (10%), and 20/50 in 1 patient (10%). In the endoscopy-assisted vitrectomy group, postoperative visual acuity ranged from no light perception in 2 patients (40%), light perception in 1 patient (20%), and hand movements in 2 patients (40%). There was no statistically significant difference between the 2 groups in terms of the final postoperative visual acuity (F = 0.006, P = .937). There is no difference between the 2 groups in terms of the incidence of enucleation. The median symptom duration was 4 hours (range: 2-6 hours) in the conventional group and 9 hours (range: 7-11 hours) in the endoscopy-assisted vitrectomy group. The difference in the symptom duration between the 2 groups was statistically significant (P = .002).There is no statistical significant difference between the 2 groups in terms of visual acuity and incidence of enucleation. Therefore, endoscopy-assisted vitrectomy can be considered as an alternative treatment for treatment of B cereus endophthalmitis particularly for cases when symptom duration was more than 6 hours. PMID- 29390263 TI - Treatment of medullary thyroid carcinoma with apatinib: A case report and literature review. AB - RATIONALE: Medullary thyroid carcinoma (MTC) is a rare type thyroid carcinoma originating from the thyroid parafollicular cells (C cells). Chemotherapy has a limited efficacy for treating persistent or recurrent MTC. PATIENT CONCERNS: A 46 year-old woman who underwent thyroidectomy for MTC in December 2007. She began experience recurring diarrhea in January 2015 and started to cough and feel shortness of breath in March 2016. DIAGNOSES: A chestcomputed tomography (CT) scan showed metastases in the bilateral lungs, pulmonary hilum, and mediastinal lymph nodes. Percutaneous biopsy of the pulmonary occupying lesions performed on March 21, 2016 indicated medullary carcinoma metastases at the right pulmonary hilum. INTERVENTIONS: This patient was treated with oral apatinib (500 mg daily). OUTCOMES: The patient's symptoms of diarrhea, coughing, and shortness of breath disappeared. CT reexaminations for efficacy assessment at 1, 2, and 3 months after the treatment indicated partial remission. Systemic migrating bone and joint pains occurred during the treatment, which were considered to be adverse events of apatinib. LESSONS: Treatment of MTC with apatinib has been shown to be effective in our case. Tyrosine kinase inhibitors (TKIs) that suppress rearranged during transfection (RET) and vascular endothelial growth factor receptor (VEGFR) should be considered as a effective therapeutic approaches. PMID- 29390264 TI - Hereditary folate malabsorption with a novel mutation on SLC46A1: A case report. AB - RATIONALE: Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system. Its manifestations mainly include macrocytic anemia, recurrent infections, and neurological deficits. The neurological manifestations include progressive psychomotor retardation, behavioral disorders, and early-onset seizures. PATIENT CONCERNS: From early infancy, a Chinese boy had experienced macrocytic anemia, leukopenia, thrombocytopenia, recurrent pneumonia, diarrhea, and mouth ulcers. He also presented with progressive neurological symptoms. DIAGNOSIS: A novel mutation in the SLC46A1 gene was identified, and HFM was diagnosed at 18 months of age. INTERVENTIONS: After the HFM diagnosis, the boy was treated with folinic acid. LESSONS: Folinic acid supplementation is effective and may offer life-changing therapy for patients with HFM. PMID- 29390265 TI - Massive retroperitoneal hemorrhage secondary to femoral artery puncture: A case report and review of literature. AB - RATIONALE: A rare case of massive bleeding with rupture of the branch artery deriving from uterine artery was reported in the present study. PATIENT CONCERNS: A 29-year old female patient received embolism of malformed cerebral vessels. Ten hours after the operation, a sudden drop in blood pressure occurred. The patient developed coma and shock, and again underwent interventional angiography, which revealed bleeding at the right femoral artery puncture site of the first interventional procedure. The bleeding sign disappeared by pressure dressing. At 19 hours after stable condition, blood pressure fell again, and it was considered that recurrent bleeding occurred at the femoral artery puncture point. Therefore surgical suture of punctured blood vessel was performed. Then the condition was stabilized again. After another 20 hours, the third times blood pressure dropped. The third interventional angiography displayed a rupture of the branch artery deriving from the right uterine artery. Blood pressure of the patient elevated after embolism of right uterine artery, and the condition gradually stabilized. DIAGNOSES: The massive bleeding with rupture of the branch artery deriving from uterine artery seconded huge retroperitoneal hematoma after femoral artery puncture. INTERVENTIONS: The patient underwent three times interventional treatment including an embolism of malformed cerebral vessels, a right femoral artery interventional treatment, an embolism of the branch artery deriving from the right uterine artery and one time of surgical suture of punctured blood vessel. OUTCOMES: Half a month of comprehensive treatment later, the patient was discharged from the hospital. LESSONS: Massive bleeding with rupture of branch of artery deriving from the uterine artery following grain retroperitoneal hemorrhage is extremely rare, to the best of our knowledge, it has not been previously reported. The rupture of branch of artery deriving from the uterine artery should be considered as one the differential diagnosis in the retroperitoneal hemorrhage when the bleeding cause was not found. Endovascular trans-arterial embolism was a safe, effective, and minimally invasive therapeutic option. PMID- 29390266 TI - Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report. AB - RATIONALE: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by a mutation in the cathepsin K encoded by cathepsin K gene (CTSK). Medullary thyroid carcinoma (MTC) is also a relatively rare type of primary thyroid carcinoma. PATIENT CONCERNS: A 31-year-old woman presenting a short stature and a palpable nodule in the front of her neck that had gradually increased in size during the last 2 years was referred to our department. She has experienced multiple fractures at lower limbs in the last 2 decades. DIAGNOSES: The patient's clinical examination revealed short stature, underweight, a prominent forehead, stubby fingers, and a fixed nodule in the right thyroid lobe. Intraoral examination revealed multiple clinically malposed and missing teeth, as well as chronic periodontitis with a narrow and grooved palate. Radiographic examination revealed typical widely separated cranial sutures and an open anterior/posterior fontanel with an obtuse gonial angle, acroosteolysis, and osteosclerosis with narrowed medullary cavities. Ultrasonography of the thyroid gland showed a marked hypoechoic solid nodule in the right lobe in which tumor cell clusters were confirmed by ultrasound-guided fine needle aspiration biopsy and was suspected to be MTC. Laboratory tests revealed dramatically elevated serum calcitonin >2000 pg/L (reference range: 0-5 pg/L) and carcinoembryonic antigen (CEA) 134.37 ng/mL (reference range: 0-5 ng/mL). Genotypic screening revealed compound heterozygous mutations in the CTSK gene (c.158delA, P.Asn53Thr/c.C830T, P.Ala277Val) but no mutation associated with the familial forms of MTC. INTERVENTIONS: The patient underwent a total thyroidectomy with right-sided functional neck dissection. OUTCOMES: CEA and serum calcitonin decreased significantly postthyroidectomy, and no further fracture has been reported by the patient so far. LESSONS: The present study is the first to report a rare case of the coexistence of pycnodysostosis with a compound CTSK gene mutation and sporadic MTC. Radiological techniques and gene analysis play key roles in the definitive diagnosis. PMID- 29390267 TI - Rehabilitation program based on sensorimotor recovery improves the static and dynamic balance and modifies the basal ganglia neurochemistry: A pilot 1H-MRS study on Parkinson's disease patients. AB - Rehabilitation interventions represent an alternative strategy to pharmacological treatment in order to slow or reverse some functional aspects of disability in Parkinson's disease (PD). To date, the neurophysiological mechanisms underlying rehabilitation-mediated improvement in PD patients are still poorly understood. Interestingly, growing evidence has highlighted a key role of the glutamate in neurogenesis and brain plasticity. The brain levels of glutamate, and of its precursor glutamine, can be detected in vivo and noninvasively as "Glx" by means of proton magnetic resonance spectroscopy (H-MRS). In the present pilot study, 7 PD patients with frequent falls and axial dystonia underwent 8-week rehabilitative protocol focused on sensorimotor improvement. Clinical evaluation and Glx quantification were performed before and after rehabilitation. The Glx assessment was focused on the basal ganglia in agreement with their key role in the motor functions. We found that the rehabilitation program improves the static and dynamic balance in PD patients, promoting a better global motor performance. Moreover, we observed that the levels of Glx within the left basal ganglia were higher after rehabilitation as compared with baseline. Thus, we posit that our sensorimotor rehabilitative protocol could stimulate the glutamate metabolism in basal ganglia and, in turn, neuroplasticity processes. We also hypothesize that these mechanisms could prepare the ground to restore the functional interaction among brain areas deputed to motor controls, which are affected in PD. PMID- 29390268 TI - Case report: One case of primary AL amyloidosis repeatedly misdiagnosed as scleroderma. AB - INTRODUCTION: Amyloid light chain (AL) results from the deposition of immunoglobulin light chain fragments, and can affect multiple organs/systems. Our patient was diagnosed as scleroderma repeatedly because of extensive skin thickening and hardening, but the treatment was not effective. We did extensive laboratory examinations including serum/urine protein electrophoresis and flow cytometry assay of bone marrow aspiration. CONCLUSION: A diagnosis of primary AL amyloidosis was established. PMID- 29390269 TI - A new strategy to reconstruct type III acetabular bone defect associated with inflammatory pseudotumor: combined medial and lateral acetabular bone grafting: A case report. AB - RATIONALE: Inflammatory pseudotumor has been commonly reported in patients undergoing total hip arthroplasty (THA). PATIENT CONCERNS: We reported a patient who had a massive intra-pelvic pseudotumour and acetabular bone defect underwent two-stage revision THA. DIAGNOSES: A new surgical strategy for pseudotumor after THA is performed. INTERVENTIONS: Thorough debridement intra-pelvic pseudotumour via Smith-Petersen approach, bone grafting on iliac medial surface and plate screw internal fixation were performed in the first stage, followed by revision of the loosened prosthesis to a cementless primary prosthesis in the second stage. OUTCOMES: A follow-up for 5 years showed satisfactory recovery of function. LESSONS: This surgical revision is less invasive than conventional methods, resulting in a stable and well-functioning hip joint after mid-term follow-up for 5 years. PMID- 29390270 TI - Anesthetic management of off-pump simultaneous coronary artery bypass grafting and lobectomy: Case report and literature review. AB - RATIONALE: Survey data show approximately 10% patients with lung cancer may present concomitant coronary heart disease. Simultaneous surgery is a challenge for anesthetist. We review our experience in the anesthesia with 5 patients who required simultaneous off-pump coronary artery bypass grafting (OPCABG) and pulmonary resection for lung cancer. PATIENT CONCERNS: Between 2014 and 2016, 5 patients with ASA (American Society of Anesthesiologists) grade II or III, underwent combined OPCABG and lung resection in the first Affiliated Hospital, Zhejiang University School of Medicine. DIAGNOSES: All five patients were diagnosed with coronary heart disease and peripheral pulmonary carcinoma INTERVENTIONS:: Five patients received general anesthesia with double-lumen endobronchial tube for lung separation. The anesthetics were used, which caused slight hemodynamic fluctuations during induction of anesthesia; while during the maintenance of anesthesia, supplemented by Dexmedetomidine, the drug doses were titrated according to the depth of anesthesia. Guided by cardiac index (CI), stroke volume variation (SVV) and oxygen delivery (DO2), different strategies were taken at the different stage of surgery, during lung resection, SVV was kept about 13% to 15%, and less than 10% during OPCABG. OUTCOMES: Five patients were transferred to intensive care unit (ICU) with intubation after surgery, duration of ventilation was 10 to 18 hours, and length of ICU stay and hospital stay were 1.8 to 2.5 ds and 11 to 16 ds, respectively. All of patients were discharged with not any perioperative complication. LESSONS: In summary, anesthetists should focus on the maintenance of the balance between oxygen supply and demanding, which was achieved by close monitoring, titration of anesthetics and goal directed fluid therapy during surgical procedures. PMID- 29390271 TI - Prenatal diagnosis for a Chinese family with a de novo DMD gene mutation: A case report. AB - BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis. METHODS: First, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified. RESULTS: MLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient. CONCLUSION: The pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic. PMID- 29390272 TI - Efficacy and safety of SQJZ herbal mixtures on nonmotor symptoms in Parkinson disease patients: Protocol for a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: As a multisystemic neurodegenerative disorder, Parkinson disease (PD) has a broad spectrum of symptoms including motor and nonmotor symptoms (NMS). As shown in studies, NMS can also impact patient's quality of life, and many of them often go untreated. Chinese herbal medicines with multiconstituent may alleviate NMS in PD patients. This research is carried out to assess the efficacy and safety of a Chinese herbal formula for NMS, with its Chinese name acronym of SQJZ. METHODS/DESIGN: It will be a multicenter, randomized, double-blind, placebo controlled trial. Idiopathic PD with a Hoehn and Yahr scale score <=4, aged 18 to 80 years, will be involved. About 240 patients will be randomly assigned to either SQJZ or placebo in a 2:1 ratio. There is a 2-week run-in period before the randomization, and the follow-up will be 24 weeks, including 12-week treatment period, with visit once every 4 weeks and 12-week washout follow-up. All participants are asked to maintain the regular medication schedule. SQJZ formula will consist of Chinese herbs with effects for insomnia, constipation, anxiety, and so on. The primary outcome will be measured using NMS scale, and secondary outcomes will include unified PD rating scale, PD sleep scale, the Parkinson fatigue scale, the constipation severity instrument, and PD Questionnaire-39. The primary efficacy analysis will be based on the intention-to-treat method, and mixed-model repeated-measures analyses will be used. DISCUSSION: The findings from this research might provide evidence of the efficacy and safety of SQJZ Chinese herbal formula for treating NMS in PD patients. The results will sustain the broader use of SQJZ formula in PD. PMID- 29390273 TI - Evaluation of prognostic scoring systems in liver cirrhosis patients with bloodstream infection. AB - Patients with cirrhosis are at increased risk of developing bloodstream infections (BSIs), and the short-term mortality rate in those patients is high. The aim of this study was to compare the different scoring models to predict mortality in cirrhotic patients with BSIs.A total of 222 cirrhotic patients with BSIs were retrospectively included in the study. The demographic, clinical, and microbiologic data were collected and patients were followed for at least 28 days after blood cultures were established. A multivariable Cox proportional hazard model was used to identify independent risk factors for 28-day all-cause mortality. The prognostic accuracy of different scoring models (chronic liver failure-organ failure [CLIF-OF], model for end-stage liver disease [MELD], systemic inflammatory response syndrome [SIRS], and Pitt scores) were compared with the C-index and receiver operating characteristic curve (ROC).Forty deaths were recorded on day 28 after blood cultures were established. Male sex (hazard ratio [HR] = 2.75, 95% confidence interval [CI] = 1.10-6.86), international normalized ratio (INR) (HR = 1.76, 95% CI = 1.35-2.30), serum bilirubin (HR = 1.002, 95% CI = 1.000-1.003), circulation failure (HR = 3.56, 95% CI = 1.63 7.79), lung failure (HR = 2.23, 95% CI = 1.09-4.57), and non-primary BSI source (HR = 2.27, 95% CI = 1.09-4.73) were identified as independent risk factors for mortality in cirrhotic patients with BSIs. In predicting 28-day mortality, CLIF OF and MELD scores had significantly high C-indices (0.79 and 0.76, respectively) and ROC values (0.786 and 0.782, respectively) compared with Pitt and SIRS scores (C-indices: 0.61 and 0.57, respectively; ROC values: 0.591 and 0.637, respectively).Cirrhotic patients with BSIs had high short-term mortality rates. Our data suggested that both CLIF-OF and MELD scores can be used to predict the short-term prognosis of these patients. PMID- 29390274 TI - A highly malignant case of neuroblastoma with substantial increase of single nucleotide variants and normal mismatch repair system: A case report. AB - RATIONALE: Neuroblastoma is a common abdominal malignancy in children. The chemoresistant and relapsed cases have poor prognosis. The genetic background and the mechanism of resistance remain unelucidated. Next-generation sequence (NGS) is becoming a popular tool to unravel the genetic background and to guide precision medicine in oncology studies as well as in clinical practice. PATIENT CONCERNS: Here we report a neuroblastoma case of a boy aged 2 years and 8 months when first diagnosed, with multiple metastatic sites found in both lungs. The metastatic tumors were resistant to chemotherapy and the patient suffered from severe bone marrow suppression. NGS of the whole exon revealed somatic mutations including 9666 single-nucleotide variants (SNVs) from 5148 genes, 55 copy number variations (CNVs), and 140 insertion-deletion variations. The high frequency of SNVs makes it distinguished case. However, no mutation of key tumor driver genes with functional significance was identified. No abnormality was found in nucleic acid synthesis enzymes. No amplification of c-Myc and n-Myc was found by fluorescence in situ hybridization (FISH). Both NGS and immunohistochemistry (IHC) analysis indicated that DNA mismatch repair (MMR) system was intact. INTERVENTIONS: After initial diagnosis, the patient received combinational chemotherapy, which includes vindesine, an analogue of adriamycin suggested by NGS data, for 4 months. Radical section of the tumor together with the left kidney and the left adrenal gland was performed 5 months after diagnosis. Postsurgical chemotherapy protocols was similar with the previous. OUTCOMES: The patient died 2 years after initial diagnosis after 8 relapses following combinational chemotherapy. LESSONS: This case of neuroblastoma is with pronounced somatic mutations but unidentified driver gene and therapeutic target. Although NGS is a potentially powerful tool to guide precision medicine, at current stage, its application in the clinic certainly has its limits. The underlying mechanism of the substantially increased SNV number, as well as the malignant behaviors of the tumor, is yet to be revealed. PMID- 29390275 TI - Synchronous diffuse large B-cell lymphoma of the stomach and small cell lung carcinoma: A case report. AB - RATIONALE: The synchronous occurrence of lung cancer in patients with gastric neoplasms is relatively uncommon, especially the cases of synchronous coexistence of small cell lung carcinoma and diffuse large B-cell lymphoma of the stomach. PATIENT CONCERNS: We encountered a case of synchronous primary small cell lung carcinoma and diffuse large B-cell lymphoma of the stomach. A 63-year-old patient with a 7.5 * 5.09 cm mass in the superior lobe of the right lung diagnosed with small cell lung cancer and synchronous diffuse large B-cell lymphoma of the stomach. DIAGNOSES: The diseases were diagnosed by the pathological biopsy and immunohistochemical methods. INTERVENTIONS: As the patient received CHOP chemotherapy, pulmonary function deterioraed. Etoposide was added to the chemotherapy. OUTCOMES: However, after the first treatment, chest computed tomography showed that the mass in the superior lobe of the right lung had increased to 8.5 * 5.2 cm. LESSONS: This report draws attention to the fact that the treatment of synchronous tumors is a challenge. PMID- 29390276 TI - Could Chinese herbs accelerate the resolution of reversible bronchiectasis in adults?: A case report. AB - RATIONALE: The classic definition of bronchiectasis is of permanent bronchial dilatation. Therefore, bronchiectasis is generally considered irreversible in the adult population. PATIENT CONCERNS: A 27-year-old woman presented to an affiliated hospital with a 1-year history of productive cough. DIAGNOSIS: Bronchiectasis. INTERVENTIONS: The patient was treated with cephalosporin and a mucus clearance regimen for 6 days and then with Chinese herbs for 3 months. OUTCOMES: Reversible bronchial dilatation was evidenced by sequential chest high resolution computed tomography 6 months later. CONCLUSION: The current report demonstrated that, although rare in adult, bronchial dilatation might resolve completely in such a short period if receiving adequate regimens, for example, Chinese herbs. PMID- 29390277 TI - A rare case report of bilateral common and internal iliac arterial fibromuscular dysplasia: Coexisted dissection, aneurysm, and stenosis. AB - RATIONALE: Iliac arterial fibromuscular dysplasia (FMD) was rarely reported and its demographic, clinical, and imaging features have not been precisely described resulting in uncertain therapeutic methods. PATIENT CONCERNS: A 31-year-old man was referred because of 3-month-ago onset hypertension, low serum potassium, and a small-sized right kidney with normal renal artery under ultrasound examination. This patient was suspected of primary aldosteronism, whereas spirolactone was poorly effective. DIAGNOSIS: Contrast-enhanced computed tomographic angiography (CTA) and three-dimensional reconstruction of the whole aorta discovered an aneurysm from the right common iliac artery (CIA) to the internal iliac artery, consistent with a left CIA dissection and a remarkable right renal artery aneurysm before a stenosis. Iliac and renal arteries FMD were then confirmed through digital subtraction angiography (DSA). INTERVENTION: Percutaneous transluminal angioplasty (PTA) of right renal artery was operated and a stent was deployed in left CIA. OUTCOMES: This patient was normotensive, asymptomatic, and free from recurrence without any antihypertensive agents at an 8-month follow-up. LESSONS: To our knowledge, this is the first bilateral common and internal iliac arterial FMD case in China, with unique asymptomatic dissection, aneurysm, and renovascular hypertension. Screening for secondary hypertension in young population and for iliac or renal arterial FMD is therefore suggested with CTA and reconstruction from neck to pelvis and MRA in those with intracranial disorders. Among youth FMD, the potential of PTRA in renovascular hypertension out of antihypertensive drugs and stent in dissection is novelly indicated. PMID- 29390278 TI - Design of a school randomized trial for nudging students towards healthy diet and physical activity to prevent obesity: PAAPAS Nudge study protocol. AB - OBJECTIVE: To evaluate the effectiveness of nudge activities at school on the students' body mass index (BMI). DESIGN: School-based factorial randomized community trial. SETTING: Eighteen public schools in the municipality of Duque de Caxias, metropolitan area of Rio de Janeiro, Brazil. PARTICIPANTS AND INTERVENTION: The 18 schools will be randomized into 4 group arms: group 1 control (without any activity); group 2-will receive educational activities in the classroom; group 3-will receive changes in the school environment (nudge strategies); group 4-will receive educational activities and changes in the school environment. Activities will occur during the 2018 school-year. MAIN OUTCOME MEASURE(S): The primary (BMI) and secondary (body fat percentage) outcomes will be assessed at baseline and after the study using a portable electronic scale with a segmental body composition monitor. The height will be measured by a portable stadiometer. ANALYSIS: Statistical analyses for each outcome will be conducted through linear mixed models that took into account the missing data and cluster effect of the schools. PMID- 29390279 TI - Ectopic thyrotropin secreting pituitary adenoma concomitant with papillary thyroid carcinoma: Case report. AB - RATIONALE: Ectopic thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare. To date, there are only 6 cases reported. Here, we describe an even rarer ectopic TSH-secreting pituitary adenoma (TSH-oma) concomitant with papillary thyroid carcinoma. PATIENT CONCERNS: A 27-year-old female was admitted to the hospital in 2002 for neck enlargement and palpitation. Thyroid function test showed increased thyroid hormones and unrepressed TSH. Thyroid ultrasound examination displayed diffuse goiter. The patient was presumptively diagnosed as primary hyperthyroidism and treated with anti-thyroid drugs. Her condition was then improved, but the serum TSH was persistently unrepressed. Therefore, central hyperthyroidism due to TSH-oma or pituitary resistance to thyroid hormone (PRTH) was suspected. Pituitary magnetic resonance imaging (MRI) examination was deservedly performed to rule out TSH-oma, which turned out to be normal. In addition, T3 suppression test was negative. Thus, PRTH, as an uncommon cause of inappropriate TSH secretion, was regarded as the working diagnosis. Triiodothyroacetic acid, which was reported to be effective for PRTH, was then administrated. But it did not work well. To control the symptoms completely and normalize the level of thyroid hormones, radioiodine therapy was carried out in 2007, followed by levothyroxine replacement therapy. Consequently, the symptoms were relieved, whereas serum TSH remained at high levels even with adequate levothyroxine. Unexpected, thyroid papillary carcinoma and a neoplasm in her nasopharynx were successively detected in 2012, which were then removed by surgery. Somewhat interestingly, the serum TSH declined to normal after the operation. DIAGNOSES: The patient was ultimately diagnosed as an ectopic TSH secreting pituitary adenoma concomitant with papillary thyroid carcinoma. INTERVENTIONS: Thyroidectomy and removal of the ectopic TSH-secreting pituitary adenoma by surgery were carried out, followed by levothyroxine replacement therapy. OUTCOME: Three years after the surgery, the patient felt well with levothyroxine 125ug daily. Serum thyroid hormones and TSH kept in normal and no signs of neoplasm recurrence. LESSONS: Although extremely rare, ectopic TSH secreting pituitary adenoma, as an uncommon cause of thyrotoxicosis, should be taken into consideration among those who have a longstanding hyperthyroidism with unsuppressed TSH. PMID- 29390280 TI - Clinical and pathology analysis of 1 case of adult pleural pulmonary blastoma: A case report. AB - RATIONALE: Pulmonary blastoma is a rare primary lung cancer that can be categorized into adult type and child type. The clinical symptoms and imaging features of pulmonary blastoma are nonspecific, making it difficult to diagnose preoperatively. Postoperative pathology with immunohistochemical staining can help diagnosis. PATIENT CONCERNS: A 53-year-old male had chest tightness and shortness of breath. DIAGNOSES: The patient was diagnosed as pleural pulmonary blastoma based on computed tomography (CT) scan, pathology, immunohistochemistry, and molecular pathology. CT examination showed solid mass on the upper lobe of the left lung Intraoperative observation found that tumor tissue was gray with tough texture. The surrounding lung tissue showed AE1/AE3 (+), Vimentin (+), and CD34 (+) staining. No epidermal growth factor receptor gene mutation was detected. INTERVENTIONS: The left lobe resection plus mediastinal lymph node dissection were performed. After the operation, patient received paclitaxel combined with nedaplatin chemotherapy for 4 times. OUTCOMES: Four months later, left pleural metastasis, and mediastinal lymph node metastasis was found. The patient died 15 months later. LESSONS: Pleural pulmonary blastoma is a malignant tumor with rare pathological features that is easy to relapse and metastasis with poor prognosis. Surgical treatment preferably, lobectomy plus mediastinal lymph node dissection, is the first treatment option. The overall prognosis is poor. PMID- 29390281 TI - Comparison of safety and effectiveness between laparoscopic mini-gastric bypass and laparoscopic sleeve gastrectomy: A meta-analysis and systematic review. AB - BACKGROUND: The laparoscopic mini-gastric bypass is a newly emerged surgical procedure in recent years. Owe to safe and simple process and effective outcomes, laparoscopic mini-gastric bypass has quickly become one of the most popular procedures in some countries. The safety and effectiveness of laparoscopic mini gastric bypass versus laparoscopic sleeve gastrectomy remain unclear. METHODS: A systematic literature search was performed in PubMed, Embase, Cochrane library from inception to May 20, 2017. The methodological quality of Randomized Controlled Trials and non-Randomized Controlled Trials were, respectively, assessed by Cochrane Collaboration's tool for assessing risk of bias and Newcastle-Ottawa scale. The meta-analysis was performed by RevMan 5.3 software. RESULTS: Patients receiving mini-gastric bypass had a lot of advantageous indexes than patients receiving sleeve gastrectomy, such as higher 1-year EWL% (excess weight loss), higher 5-year EWL%, higher T2DM remission rate, higher hypertension remission rate, higher obstructive sleep apnea (OSA) remission rate, lower osteoarthritis remission rate, lower leakage rate, lower overall late complications rate, higher ulcer rate, lower gastroesophageal reflux disease (GERD) rate, shorter hospital stay and lower revision rate. No significant statistical difference was observed on overall early complications rate, bleed rate, vomiting rate, anemia rate, and operation time between mini-gastric bypass and sleeve gastrectomy. CONCLUSION: Mini-gastric bypass is a simpler, safer, and more effective bariatric procedure than laparoscopic sleeve gastrectomy. Due to the biased data, small sample size and short follow-up time, our results may be unreliable. Large sample and multicenter RCT is needed to compare the effectiveness and safety between mini-gastric bypass and sleeve gastrectomy. Future study should also focus on bile reflux, remnant gastric cancer, and long term effectiveness of mini-gastric bypass. PMID- 29390282 TI - Giant solitary fibrous tumor of the pleura with high-grade sarcomatous overgrowth accompanied by lipid-rich, rhabdomyosarcomatous, and pleomorphic components: A case report. AB - RATIONALE: Solitary fibrous tumors are mesenchymal tumors presenting as fibroblastic neoplasms with prominent branching vascular patterns, which are often generated from the pleura. Most solitary fibrous tumors are benign; however, some can turn malignant. High-grade sarcomas from solitary fibrous tumors include multidirectional histopathological components. PATIENT CONCERNS: We describe our experience of a giant high-grade sarcoma with mixed components generated from a solitary fibrous tumor of the pleura in a 67-year-old female patient presenting with cough and left-sided chest pain. The patient had been diagnosed with a pleural mass in the left chest by X-ray about 30 years earlier. However, the tumor was allowed to grow, without surgical intervention, for a long time. INTERVENTIONS: Thoracic surgeons performed the removal of the giant pleural tumor; the tumor measured 18.0 * 14.5 * 10 cm in size, and was considered a giant tumor generated from the pleura of the left chest cavity. DIAGNOSES: The surgically removed tumor was solid and light brownish, and included myxoid and arabesque pattern lesions. The tumor also showed hemorrhagic and necrotic lesions. Moreover, spindle cells with less atypia, resembling fibroblasts, were noted. These spindle tumor cells were CD34- and Stat6-positive, suggesting a solitary fibrous tumor. Some of the spindle tumor cells were surrounded by thick collagenous fibers. Considering that the tumor originated from the parietal pleura, the tumor was defined as a solitary fibrous tumor in origin. The tumor also comprised high-grade sarcomatous components; these included lipid-rich, rhabdomyosarcomatous, and pleomorphic components. The high-grade sarcoma component included bizarre tumor cells with severe atypia. OUTCOMES: Tumor recurrence occurred in the left chest about 4 months after the surgery, and the patient died 8 months postoperatively. LESSONS: The present case clearly demonstrates that a solitary fibrous tumor can develop into high-grade sarcomatous overgrowth, including lipid-rich, rhabdomyosarcoma, and pleomorphic sarcoma components, if left untreated for a prolonged period. This case provides profound insights about the natural history, histogenesis, differentiation, and malignant transformation of solitary fibrous tumors. PMID- 29390283 TI - A case report of gastric linitis plastica diagnosed by endoscopic ultrasound guided fine needle aspiration. AB - RATIONALE: There is currently no consensus on the ideal method for obtaining deep tissue biopsy material of advanced gastric LP. EUS-FNA has potential as a useful diagnostic method. Thus, we report the case of a 46-year-old male with advanced gastric linitis plastica (LP) who was diagnosed using endoscopic ultrasound guided fine needle aspiration (EUS-FNA). PATIENT CONCERNS: The patient underwent esophagogastroduodenoscopy (EGD) because of epigastric pain at a local clinic. The gastric fold swelling was pointed out by the EGD and despite the suspected advanced gastric LP, biopsy indicated Group 1. Repeat biopsy did not suggest malignancy. The patient was referred to our institution. DIAGNOSES: Endoscopic ultrasound indicated gastric wall thickening mainly in the greater curvature of the gastric corpus. Low-level echoes were detected throughout the entire gastric wall, and gastric wall layers had been disappeared. EUS-FNA of the gastric wall indicated signet ring cell carcinoma. INTERVENTIONS: As a result of EUS - FNA, it became a policy to administer chemotherapy. In accordance with the patient's wishes, he was referred to another institution for chemotherapy. OUTCOMES: Normal biopsy did not give a definitive pathological diagnosis, and final diagnosis of LP was obtained with EUS-FNA. LESSONS: We expect that EUS-FNA can be utilized as a relatively non-invasive, highly sensitive, and specific pathological diagnostic procedure for advanced gastric LP. EUS-FNA should be considered as one way to obtain a deep tissue biopsy of advanced gastric LP. PMID- 29390284 TI - The improvement of dry eye after cataract surgery by intraoperative using ophthalmic viscosurgical devices on the surface of cornea: The results of a consort-compliant randomized controlled trial. AB - BACKGROUD: This study aimed to investigate the protective effect of intraoperative used hydroxypropyl methylcellulose (HPMC 2%) on the ocular surface after cataract surgery. METHODS: A total of 149 eyes (149 patients) diagnosed with age-related cataract, age 69.19 +/- 9.74 years, were enrolled in this prospective, parallel-design, continuous, randomised controlled study. Patients were randomly assigned to receive HPMC 2% (study group) or balanced salt solution (control group) during the surgery to moisturize the cornea surface. The Ocular Surface Disease Index, Schirmer test without topical anesthetics, tear break-up time, and corneal fluorescein staining were assessed preoperatively, 1 day, 1 week, and 1 month after the surgery, respectively. RESULTS: The Schirmer test value of male patients in the study group at 1 week postoperation was higher than that of male patients in the control group (P = .019). For patients diagnosed with dry eye before the surgery, Schirmer test value in the male patients in the study group at 1 month after surgery was higher than that in the male patients in the control group (P = .037). Furthermore, for the cluster of preoperative dry eye patients whose surgical time was longer than median, corneal fluorescein staining of the patients in the study group was superior to that of the patients in the control group (P = .032). CONCLUSION: Intraoperative use of HPMC 2% on the cornea surface could improve clinical outcomes of tear film and ocular surface health to some degree, especially in the patients diagnosed with dry eye before the surgery, male patients, and patients whose surgical time was relatively longer. PMID- 29390285 TI - Use of Univent tube for intermittent lung isolation during thoracoscopic mediastinal tracheal resection and reconstruction: A case report. AB - RATIONALE: Primary tracheal adenoid cystic carcinoma of the trachea primary is a rare neoplasm and commonly misdiagnosed. Lung isolation during surgery and ventilation pose a tremendous challenge to anesthesiologists. PATIENT CONCERNS: The authors describe a novel technique of lung isolation and ventilation with a Univent tube during thoracoscopic mediastinal tracheal resection and reconstruction in a female patient. DIAGNOSES: Primary tracheal adenoid cystic carcinoma, nonsmall cell carcinoma. INTERVENTIONS: In this case, tracheal resection and reconstruction were performed. A bronchial blocker of the Univent tube was used as a guide to manipulate the depth of endotracheal tube. OUTCOMES: The intermittent 1-lung ventilation was established successfully. The patient recovered uneventfully and discharged after 10 days. LESSONS: The advantages of approach include a stable airway management without occupying the contracted space of thoracoscope and no potential risk of trapping or barotraumas. PMID- 29390286 TI - Purulent constrictive pericarditis caused by Salmonella enteritidis in a patient with adult-onset Still's disease: A case report. AB - RATIONALE: Purulent pericarditis is a rare and usually fatal disease. Immunodeficiency state and preexisting pericardial effusion can predispose patients to infections. However, we are not aware of similar cases in patients with adult-onset Still's disease (AOSD). In addition, it is seldom caused by Salmonella bacteria. PATIENT CONCERNS: We report a 30-year-old woman with dyspnea on exertion and epigastric fullness. She was newly diagnosed with AOSD 4 months previously and medicated with prednisolone. DIAGNOSES: Transthoracic echocardiography (TTE) and computed tomography revealed a thickened pericardium with loculations in the pericardial space, consistent with purulent constrictive pericarditis. Subsequent cultures of blood and pericardial fluid yielded S enteritidis. INTERVENTIONS: She underwent subtotal pericardiectomy through a limited median sternotomy, and antibiotic therapy (ceftriaxone) for 1 month. OUTCOMES: The New York Heart Association functional classification downgraded from class III to class I. There was no recurrence during the 1-year follow-up. LESSONS: This case presents an opportunity to highlight the importance of considering purulent pericarditis in patients previously diagnosed with AOSD. High clinical suspicion, early diagnosis, and prompt management can result in a better outcome in purulent pericarditis. PMID- 29390287 TI - The association between serum uric acid and blood pressure in different age groups in a healthy Chinese cohort. AB - High serum uric acid (sUA) has been reported to be a risk factor for hypertension however, whether this is the case for all age groups is not clear. We examined the association between sUA concentrations and systolic and diastolic blood pressure (SBP and DBP) in different age groups in a cohort of healthy Chinese participants.A total of 1082 healthy participants aged from 41 to 70 years were included. sUA concentration was measured by the uricase-peroxidase method. SBP and DBP were assessed using mercury sphygmomanometry. Hypertension was defined as SBP >=140 mm Hg or DBP >=90 mm Hg. Hyperuricemia (HUA) was defined as sUA concentration of >7 mg/dL in men and >6 mg/dL in women. The association between sUA concentration and SBP and DBP was examined using Pearson's correlation test, multivariate linear regression, and logistic regression analysis.The prevalence of hypertension and HUA increased with age (P < .001). Hypertension was more common in participants that had HUA than in those that did not (38.95% vs 30.16%, P = .02). Higher sUA was significantly associated with higher SBP and DBP in the 41- to 50-year-old participants (SBP, beta = 0.35, P < .001; DBP, beta = .29, P < .001; after adjustment for age, sex, total cholesterol, estimated glomerular filtration rate, and fasting plasma glucose). HUA was also a risk factor for hypertension in this age group (odds ratio 1.425, 95% confidence interval, 1.217 1.668, P < .001). There was no association between sUA concentration and SBP and DBP in the other age groups.In this population of healthy Chinese participants, sUA concentration was positively associated with hypertension only in the 41- to 50-year-old group. Lowering uric acid in this age group may help to reduce the incidence of hypertension. PMID- 29390288 TI - Intratympanic glucocorticosteroid therapy for idiopathic sudden hearing loss: Meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Glucocorticoids are the standard treatment for idiopathic sudden sensorineural hearing loss (ISSNHL), but whether intratympanic or systemic therapy is superior remains controversial. Previous meta-analyses of this question have omitted key clinical trials or included observational studies. METHODS: English-language randomized controlled trials in OvidSP, PubMed, Embase, CINAHL, and the Cochrane Library comparing intratympanic versus systemic glucocorticoid therapy for ISSNHL were meta-analyzed using RevMan 5.3. The primary outcome of interest was improvement in pure tone average (PTA) threshold. RESULTS: Six trials involving 248 patients receiving intratympanic steroids and 236 receiving systemic steroids were meta-analyzed. PTA thresholds were similar between the 2 groups at 3 months after therapy initiation (mean difference, 0.24; 95% confidence interval [CI] -2.43 to 2.91, P = .86; I = 54%, P = .07, random effects model). PTA thresholds were also similar at 6 months (mean difference, 4.69, 95% CI -5.84 to 15.22, P = .38), although the results showed extremely high heterogeneity (I = 98%). Sensitivity analysis indicated that a single trial containing 250 patients provided the strongest evidence for equivalence between the 2 types of therapy. Rates of recovery within 3 months (defined as PTA improvement >10 dB) were similar between the 2 types of therapy (odds ratio 0.92, 95% CI 0.59-1.43, P = .70), with no significant heterogeneity in the pooled data (I = 1%, P = .40). CONCLUSION: Intratympanic and systemic steroids' therapies appear to show similar short-term efficacy for restoring hearing in patients with ISSNHL. Intratympanic therapy may reduce systemic side effects associated with steroid use. PMID- 29390289 TI - Endovascular stent graft repair of aortogastric fistula caused by peptic ulcer after esophagectomy: A case report. AB - RATIONALE: Aortogastric fistula (AGF) is a rare but devastating clinical complication after esophagectomy. In a recent report, nearly all AGF patients died of massive hemorrhage or aspiration of massive hematemesis. Therefore, timely appropriate treatment of AGF remains a challenge.Herein, we report a case of AGF that resulted from peptic ulceration after esophagectomy and was successfully treated with endovascular stent graft placement. PATIENT CONCERNS: A 59-year-old man had undergone video-assisted thoracoscopic esophagectomy for squamous cell carcinoma and esophageal reconstruction using a gastric tube 14 months previously. He suddenly experienced massive hematemesis and unstable circulatory dynamics, Infusion was performed to treat critical hemorrhagic shock but was ineffective. We informed the patient and his family members of the situation, and once written informed consent to treatment was provided, we rushed him to the operating room. DIAGNOSES: Contrast medium permeated into the gastric cavity through a fistula between the abdominal aorta and gastric tube at the 11th thoracic level, Based on this, we made a diagnosis of AGF resulting from a peptic ulcer, and this diagnosis was further confirmed by high pressure angiography combined with computed tomography (CT) imaging. INTERVENTIONS: An endovascular stent graft was placed under the guidance of digital subtraction angiography and followed by antibiotic therapy to prevent infection and proton pump inhibitor therapy to inhibit gastric acid secretion. OUTCOMES: The patient recovered uneventfully after the procedure. Four months after surgery, the patient died of organ failure caused by retroperitoneal lymph node metastasis and multiple intrahepatic metastases, with no postoperative bleeding linked to the endovascular stent graft repair. LESSONS: Our case supports the notion that endovascular stent graft repair is a feasible alternative in treatment of AGF with several advantages in addition to surgical intervention, although more such cases should be collected and analyzed in the future to corroborate our observations. PMID- 29390290 TI - Association of apolipoprotein E genotype with outcome in hospitalized ischemic stroke patients. AB - The aim of this study was to study the ability of the genotype to predict impairment and disability in hospitalized ischemic stroke (IS) patients after hospital discharge and 6 months after the onset of stroke symptoms.A total of 786 patients with a first IS were enrolled. Apolipoprotein E (ApoE) polymorphism was examined using polymerase chain reaction. Stroke subtype was classified using the Oxfordshire Community Stroke Project classification scheme and the Trial of Org 10172 in Acute Stroke Treatment criteria. Impairment as assessed using the National Institutes of Health Stroke Scale (NIHSS), and disability as measured using the modified Rankin Scale (mRS), were compared against the ApoE genotype.There was no significant association between the type of ApoE allele present and the stroke subtype. On multivariate regression analysis, the apolipoprotein EE4 allele genotype did not predict poor outcome at discharge and or at 6 months after stroke onset. A higher NIHSS score on admission, older age, and higher fasting glucose levels did predict poor outcome at hospital discharge. Higher glucose levels and higher NIHSS scores on admission were independent risk factors predicting poor neurologic status at 6 months after stroke onset.The presence of the apolipoprotein EE4 and apolipoprotein EE2 genotypes, although related to cholesterol and triglyceride levels, do not affect recovery during rehabilitation. A higher NIHSS score on admission and a higher fasting glucose level predict poor neurologic status, both at hospital discharge and 6 months after onset. PMID- 29390291 TI - Are parents of children with Cockayne syndrome manifesting features of the disorder?: Case reports. AB - RATIONALE: Postnatal growth failure and progressive neurologic dysfunction and increasing multiorgan involvement are the main clinical features of Cockayne syndrome (CS). CS is a rare autosomal recessive disorder of the group of DNA repair diseases. Usually, genetic carriers, such as parents of patients, are not at risk for developing the disease. PATIENT CONCERNS: A series of 14 family subjects (6 children with age range from 6 months to 4 years with CS) and 9 parents (aged from 23 to 34 years) from consanguineous families is reported. DIAGNOSES: Ultraviolet irradiation studies were performed on these children and were indicative of CS. INTERVENTIONS: Cells of skin fibroblast from these children with the disease showed a symmetrical accumulation of chromosomal aberrations and the nuclear lamina aberrations. Our results showed a significant and simultaneous increase of percent of blebbs and invaginations of the nuclear lamina in all cases CS. The pronounced changes in 12.6 times at atypical form (girl); in 8.5 times at severe form (boy) and in 5.6 times at light form (boy). Percentage of metaphases with chromosomal aberration is significantly higher in CS cells: in 4 times at atypical form, in 3 times at hard form, and in 2 times at light form. The parents of these families (consanguineous families) were intellectually variable between normal/borderline intelligence, though most manifested a constellation of skeletal and extraskeletal abnormalities and notably, the characteristic cachectic facial appearance. The parents were considered as manifesting the mild type of CS, because they showed no abnormalities of DNA repair. OUTCOMES: Clinical manifestations in heterozygote carriers of an autosomal recessive disorders is a rare phenomenon as carriers are usually healthy. LESSONS: The interesting finding of the families studied is that there appeared to be a multitude of carriers manifesting with normal to borderline intelligence but with a wide spectrum of skeletal and extraskeletal abnormalities. PMID- 29390292 TI - Fatal cerebral hemorrhage associated with acute pancreatitis: A case report. AB - RATIONALE: Pancreatic encephalopathy (PE) refers to the abnormalities in mental status that complicate acute pancreatitis (AP). We report the case of a patient who developed AP that was complicated by PE and followed by fatal cerebral hemorrhage. PATIENT CONCERNS: A 41-year-old male patient with AP that initially manifested with PE and was subsequently complicated by fatal cerebral hemorrhage. DIAGNOSES: A head computed tomography (CT) scan showed a fatal intracerebral hemorrhage located in the occipital lobe, and an abdominal CT scan presented a large amount of peripancreatic fluid collections. INTERVENTIONS: The patient received a hematoma evacuation. The volume of the hematoma was approximately 15 mL. A consequent open pancreatic necrosectomy was performed to remove all necrotic tissues and to drain the peripancreatic fluid collections. OUTCOMES: The patient could perform his normal daily activities efficiently, and no abnormality was observed in the physical examination 3 months after his discharge. LESSONS: Although uncommon, PE should be properly monitored. Once the neurological symptoms of a patient dramatically worsen within a short time, the possibility of fatal cerebral hemorrhage should be considered. PMID- 29390293 TI - Prognostic utility of FDG PET/CT and bone scintigraphy in breast cancer patients with bone-only metastasis. AB - We performed this retrospective clinical study to examine the prognostic power of bone scintigraphy (BS) and F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in terms of overall survival (OS) of breast cancer with bone-only metastasis.We retrospectively evaluated 100 female invasive ductal breast cancer patients (mean age 48.1 years) with bone-only metastasis. Twenty-five patients had human epidermal growth factor receptor 2 (HER2)-positive tumors, 65 were estrogen receptor (ER) and/or progesterone receptor (PR)-positive, HER2-negative tumors, and 10 were triple negative tumors. The patients were treated properly with various treatments, including chemotherapy, radiotherapy, hormone, and bisphosphonate therapy, based on their clinical status. All patients underwent BS and FDG PET/CT at baseline and 1 year after treatment. The baseline and follow images were visually compared, and the patients were grouped as responders or nonresponders based on their images. OS was compared between the groups.The mean OS after the diagnosis of bone-only metastasis was 57.6 months. Fifty-one patients (51%) died within 5 years after diagnosis of metastasis. No difference in survival was evident between responders and nonresponders based on BS imaging data (P = .090). The response status based on PET imaging data waste only significant independent prognostic factor on multivariate analysis (P = .001). Survival was lower in nonresponders than in responders based on PET imaging (32.7% vs 66.4%; P < .001).Our findings suggest that the response status according to FDG PET imaging can be used to predict OS in breast cancer patients with bone-only metastasis. PMID- 29390294 TI - Primary vaginal squamous cell carcinoma with bladder involvement in uterine prolapsed patient: Case report. AB - RATIONALE: Primary vaginal squamous cell carcinoma (SCC) is a rare disease. Primary SCC in prolapsed vagina is extremely rare. In the presented case additional bladder involvement was found. PATIENTS CONCERNS: Primary vaginal SCC may be misinterpreted as decubitus in prolapsed vagina and it may delay proper diagnosis and treatment. DIAGNOSES: Diagnosis was confirmed by the vaginal ulceration biopsy and cystoscopic biopsy of the involved bladder. INTERVENTIONS: In the case presented percutaneous nephrostomy was the only possible treatment of hydronephrosis. OUTCOMES: In advanced primary SCC (Figo IVA) with nodal involvement palliative treatment is only option. LESSONS: Primary SCC mimicking decubitus which appeared in prolapsed vagina, may be accompanied by bladder involvement. PMID- 29390295 TI - Management of a neurotrophic deep corneal ulcer with amniotic membrane transplantation in a patient with functional monocular vision: A case report. AB - RATIONALE: Amniotic membrane transplantation (AMT) has been performed therapeutically in humans for over 100 years. In recent 2 decades AMTs have been used increasingly and successfully to treat various types of ophthalmic indications. PATIENT CONCERNS: An 83-year-old man was referred to our eye hospital with a refractory neurotrophic deep corneal ulcer of the left eye. DIAGNOSES: The best-corrected visual acuity of the left eye was 0.5 (0.3 logMAR) and of the right eye was 0.05 (1.3 logMAR), which was caused by a central retinal vein occlusion 5 years previously. In cases of binocular vision, a large amniotic membrane patch can cover the whole cornea, including the optical axis. However, in cases with functional monocular vision, as in the case reported here, the AMT has to be performed without the involvement of the optical axis to ensure vision for the patient. Otherwise the patient would have a massively restricted view like looking through waxed paper for at least 2-4 weeks until the overlay dissolved. INTERVENTIONS: For this case, an AMT using a modified sandwich technique was applied without involvement of the optic axis to ensure vision for the patient. This case report illustrates this eye's course of healing over time. OUTCOMES: A reduction in the inflammation and healing of the corneal ulcer could be seen. In addition, the corneal vascularization decreased. Six months after the AMT, a slit-lamp examination revealed stable findings. The best-corrected visual acuity of the left eye had increased to 0.8 (0.1 logMAR). LESSONS: To the best of our knowledge, a case report on the management of a neurotrophic deep corneal ulcer with AMT in a patient with functional monocular vision has never been undertaken before. PMID- 29390296 TI - Carney complex with PRKAR1A gene mutation: A case report and literature review. AB - RATIONALE: Carney complex (CNC) is a multiple neoplasia syndrome with autosomal dominant inheritance. CNC is characterized by the presence of myxomas, spotty skin pigmentation, and endocrine overactivity. No direct correlation has been established between disease-causing mutations and phenotype. PATIENT CONCERNS: A 16-year-old boy was admitted because of excessive weight gain over 3 years and purple striae for 1 year. Physical examination revealed Cushingoid features and spotty skin pigmentation on his face, lip, and sclera. DIAGNOSES: The patient was diagnosed as Carney complex. INTERVENTIONS: the patient underwent right adrenalectomy and partial adrenalectomy of the left adrenal gland. OUTCOME: Results of imaging showed bilateral adrenal nodular hyperplasia, multiple microcalcifications of the bilateral testes, and compression fracture of the thoracolumbar spine. Histopathological results confirmed multiple pigmented nodules in the adrenal glands. DNA sequencing revealed a nonsense mutation in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A; c.205C > T). After the second adrenalectomy, the Cushingoid features disappeared, and cortisol levels returned to normal. LESSONS: Carney complex is a rare disease that lacks consistent genotype-phenotype correlations. Our patient, who carried a germline PRKAR1A nonsense mutation (c.205C > T), clinical features included spotty skin pigmentation, osteoporosis, and primary pigmented nodular adrenal disease. Adrenalectomy is the preferred treatment for Cushing syndrome due to primary pigmented nodular adrenal disease. PMID- 29390297 TI - Prenatal diagnosis of sirenomelia with anencephaly and craniorachischisis totalis: A case report study. AB - RATIONALE: Sirenomelia and anencephaly are well-defined congenital malformations that usually occur independently. PATIENT CONCERNS: We report a case of combined sirenomelia, anencephaly and complete rachischisis, diagnosed in the 16th week of gestation. DIAGNOSES: To our knowledge, this is the 7th case in the literature and the first that is diagnosed so early in pregnancy. INTERVENTIONS: The final diagnosis is confirmed with radiological examination after the termination of pregnancy. OUTCOMES: Prenatal diagnosis of sirenomelia is difficult due to the presence of kidney agenesis and severe oligohydramnios. LESSONS: The combination of sirenomelia and craniorachischisis totalis is extremely rare and prenatal ultrasound scan are a challenge, even for experts in the field. PMID- 29390298 TI - Comparison of hemodynamic effects of sevoflurane and ketamine as basal anesthesia by a new and direct monitoring during induction in children with ventricular septal defect: A prospective, randomized research. AB - BACKGROUND: Sevoflurane and ketamine are commonly used to obtain sedation and facilitate intravenous anesthetic induction in children undergoing cardiac surgery who are uncooperative. We used a new and direct systemic hemodynamic monitoring technique pressure recording analytical method and compared the hemodynamic effects of sevoflurane and ketamine to facilitate intravenous anesthetic induction. METHODS: Forty-four children with ventricular septal defect (2.2 +/- 1.2 years) were enrolled and randomized to receive sevoflurane (Group S) or intramuscular ketamine (Group K) for sedation, followed by intravenous midazolam-sufentanil induction and tracheal intubation. Recorded parameters included heart rate (HR), arterial pressures, stroke volume index (SVI), cardiac index (CI), systemic vascular resistance index (SVRI), the maximal slope of systolic upstroke (dp/dtmax) after sedation obtained with sevoflurane or ketamine, 1, 2, 5 minutes after midazolam-sufentanil, 1, 2, 5, and 10 minutes after tracheal intubation. Rate-pressure product (RPP) and cardiac power output (CPO) were calculated. RESULTS: As compared with Group S, Group K had faster decreases during intravenous anesthetic induction in arterial pressures (P < .01 for all), higher HR, arterial pressures, SVRI, dp/dtmax, RPP, lower SVI, CI, CPO (P < .05 for all) during the study period. CONCLUSION: As compared with sevoflurane, ketamine facilitated intravenous anesthetic induction exerts unfavorable effects on systemic hemodynamic and myocardial energetic in children with ventricular septal defect. PMID- 29390299 TI - Black pleural effusion due to pancreatic pseudocyst: A case report. AB - RATIONALE: Black pleural effusion (BPE) is an extremely uncommon type of pleural fluid, which can be due to infection, primary or metastatic malignancy, and hemorrhage. As reported in previous studies, BPE is also observed in some patients with pancreatic pseudocyst. PATIENT CONCERNS: We herein reported a case of a 14-year-old female patient who was admitted to our center with a history of cough for 1 and a half months and right chest pain for 1 month. Before this, she was consecutively hospitalized in 3 different hospitals due to the same symptoms. However, the previous treatments were ineffective due to the lack of a definitive diagnosis. Laboratory examination of the pleural effusion showed BPE with a high amylase concentration. Chest x-ray and computed tomography (CT) showed massive pleural effusion, more prominent in the right chest. CT and MRCP of the abdomen showed a cystic lesion located in the tail of the pancreas, which entered the chest cavity via an esophageal hiatal hernia. DIAGNOSES:: pancreatic pseudocyst. INTERVENTIONS: After confirming that the tumor was a pancreatic pseudocyst by intraoperative biopsy, internal drainage to the jejunum was performed. OUTCOMES: The postoperative recovery was rapid and without complications, and the final discharge diagnosis was idiopathic pancreatic pseudocyst (without history of pancreatitis or pancreatic injuries) with BPE of the right chest. LESSONS: This case demonstrates that massive BPE could present as a rare complication of pancreatic pseudocyst, and surgery is a potential treatment for such patients. PMID- 29390300 TI - The effect of no drainage in patients who underwent thyroidectomy with neck dissection: A systematic review and meta-analysis. AB - BACKGROUND: To evaluate the effect of no drainage in patients who underwent thyroidectomy and neck lymph node dissection. METHODS: We followed the methodological standard expected by Cochrane. We searched the following databases by March 23, 2017: PubMed, The Cochrane Library, EMBASE via Ovid SP, and Medline via Ovid SP. Two reviewers screened the studies and extracted the data. Randomized controlled trials (RCTs) or nonrandomized interventional studies assessing the effect of no drainage following thyroidectomy with lymph node dissection were included. RESULTS: Three studies with 387 participants were included. There was no statistical difference between groups for the overall perioperative complications (2 RCTs, n = 234, RR 1.56, 95% CI 0.53-4.64), or specific complications such as seroma (2 RCTs, n = 234, RR 1.81, 95% CI 0.46 7.07), hematoma (2 RCTs, n = 234, RR 0.72, 95% CI 0.11-4.83) or hemorrhage (1 RCT, n = 69, RR 0.29, 95% CI 0.01-6.87). One case required reoperation due to hemorrhage in the drainage group was reported in 1 study (n = 32). No mortality was reported. Two studies (n = 234) stated a longer hospital stay in the drainage group than that in the group without drainage. There was moderate or serious bias for the risk of bias of included studies. CONCLUSION: The effect of no-drainage in patients with thyroid cancer who received thyroidectomy with neck dissections remains uncertain, since there are very few studies that addressed the question. Drainage may lead to longer hospital stay than nondrainage. More randomized or nonrandmized studies are required to address this issue. PMID- 29390301 TI - Contrast-enhanced ultrasound diagnosis of hepatic metastasis of concurrent medullary-papillary thyroid carcinoma: A case report. AB - RATIONALE: Co-occurrence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) in the same thyroid gland with liver metastasis is a rare condition. To our knowledge, the utility of contrast-enhanced ultrasound (CEUS) to diagnose it is much less. PATIENT CONCERNS: A 33-year-old female was referred to our hospital due to the increase in plasma calcitonin concentration and carcino-embryonic antigen 12 months after her total thyroidectomy. To find metastasis, she received laboratory tests, gray-scale US, and CEUS. In our paper, ethical approval was not necessary, as this article is a case report, which is based on the clinical information of the patient. Because our case does not refer to the patient's privacy, informed consent is not necessary. DIAGNOSES: Gray scale abdominal ultrasound image demonstrated a mildly hyperechoic nodule in the liver. In CEUS, the nodules were hyperenhanced in the arterial phase. In the late arterial phase, the enhancement was washed out quickly. The nodules presented hypoenhancement in the portal and parenchymal phase, which conformed to the hepatic metastasis. INTERVENTIONS: The patient received thyroid and liver surgery. OUTCOMES: She was free of disease for 10 months at the time of this report. LESSONS: In this case, liver metastases from MTC can be detected and characterized reliably as hypoenhancing lesions during the portal venous and late phases of CEUS, washing out starts early, and is marked. We suspect MTC is a kind of tumor that tends to have rich blood supply and consider contrast-enhanced ultrasound as a suitable method for the follow-up of patients with MTC. PMID- 29390302 TI - Gastrointestinal perforation secondary to accidental ingestion of toothpicks: A series case report. AB - RATIONALE: Toothpicks are widely used as a tooth cleaning tool after meals in China. Most of the Chinese toothpicks are made of wood or bamboo with a hard texture and sharp ends. This characteristic has proven to be potentially dangerous when toothpicks are accidentally ingested, as they can cause damage and perforation of the digestive tract and other subsequent complications. PATIENT CONCERNS: The main clinical complaints of 5 patients in this study were mainly acute or chronic abdominal pain, duration from 2 days to 2 months, 1 case with vomiting, 1 case with fever. DIAGNOSES: Four cases were initially diagnosed by computed tomography (CT) scan; However, the first case was misdiagnosed as appendicitis so the patient did not undertake a preoperative CT scan and it was diagnosed by laparoscopy. INTERVENTIONS: All the cases were treated by laparoscopy and the toothpicks were removed successfully. OUTCOMES: Toothpick caused digestive perforation was confirmed by laparoscopy in all this 5 cases, the perforation sites were 2 cases at the antrum of stomach, 1 case at the third part of duodenum, 1 case at the ileocecal junction and 1 case at the sigmoid colon. 4 cases had perforation repair . Operative time :48-67 min. Intraoperative bleeding: 25-80 ml. 1 patient had a secondary liver injury. No postoperative complications occurred in all cases. The length of hospital stay was between 4-25 days. LESSONS: Our case series study suggests that laparoscopy is a safe and feasible surgical procedure for definitive management of digestive tract perforation by toothpick ingestion. We also suggest all the people should have healthy life behaviors and use the toothpicks correctly. PMID- 29390303 TI - Angioplasty and stenting for the proximal anastomotic stenosis of a brachio axillary bypass graft using a helical interwoven nitinol stent: A case report. AB - RATIONALE: Thrombosis due to anastomotic site stenosis is the most common complication in patients with brachio-axillary arteriovenous graft (AVG). Intravascular stent placement may play a special role in the salvage of dialysis grafts that have been previously performed percutaneous angioplasty or surgical procedure on the graft. Herein, we applied a novel stent named Supera which has a high degree of flexibility and resistance to external compression for treating a patient with recurrent venous anastomotic stenosis of brachio-axillary AVG. PATIENTS CONCERNS AND DIAGNOSES: We report a case of the patient with end-stage renal disease who presented with brachio-axillary AVG malfunction. INTERVENTIONS: The patient underwent repeated percutaneous angioplasty with thrombectomy for total graft occlusion, and we placed the Supera stent to salvage the graft. OUTCOMES: Postprocedural Doppler ultrasonography did not show any restenosis on the 1- and 3-month follow-up periods, and average flow volume in the stent was >1000 mL/min. And he has been on dialysis for 6 months without any problems after stent placement. LESSONS: The Supera stent is a useful treatment option of interventional procedure for recurrent venous anastomotic stenosis of brachio axillary AVG in the clinical practice. PMID- 29390304 TI - Meningiomas with different histological grade in the same patient: Case report. AB - RATIONALE: Meningiomas are mostly regarded as benign tumors histologically,accounting for 13% to 26% of all primary intracranial tumors.It is testified that multiple meningiomas occur in <10% of cases.A case of concurrent grades I and II in the same patient in our hospital was described. PATIENT CONCERN: A 66-year-old man who was experiencing headache and weakening in the left limbs, which gradually improved.Then, the myodynamia of left limb was weakening to level 3 and the muscular tension of left limbwas too strong for 1 year. Finally the man was admitted to our department of neurosurgery. DIAGNOSES: According the symptoms, signs and imaging data the patient. The 2 masses was diagnosed as the meningioma.Finally the histological examination showed the meningioma located in the right parietal lobe was diagnosed as fibrous meningioma,WHOgrade I, whereas meningioma reaching to the skull as atypical meningioma, WHO grade II. INTERVENTIONS: The 2 masses including the invaded dura mater,parietal skull, and adjacent subcutaneous tissue were excised wholly In the process of surgery. OUTCOMES: There is no sign caused by recurrent tumor. within the half year.The physical of the patient is good LESSONS:: The patient with multicentric meningiomas should keep follow-up closely in case the meningiomas show the malignant characteristics. PMID- 29390305 TI - Intracameral air injection during Ahmed glaucoma valve implantation in neovascular glaucoma for the prevention of tube obstruction with blood clot: Case Report. AB - RATIONALE: Glaucoma drainage implant surgery is a treatment option for the management of neovascular glaucoma. However, tube obstruction by blood clot after Ahmed glaucoma valve (AGV) implantation is an unpredictable clinically challenging situation. PATIENT CONCERNS-DIAGNOSES-INTERVENTIONS: We report 4 cases using intracameral air injection for the prevention of the tube obstruction of AGV by blood clot. OUTCOMES: The first case was a 57-year-old female suffering from ocular pain because of a tube obstruction with blood clot after AGV implantation in neovascular glaucoma. Surgical blood clot removal was performed. However, intractable bleeding was noted during the removal of the blood clot, and so intracameral air injection was performed to prevent a recurrent tube obstruction. After the procedure, although blood clots formed around the tube, the tube opening where air could touch remained patent. In 3 cases of neovascular glaucoma with preoperative severe intraocular hemorrhages, intracameral air injection and AGV implantation were performed simultaneously. In all 3 cases, tube openings were patent. It appears that air impeded the blood clots formation in front of the tube opening. LESSONS: Intracameral air injection could be a feasible option to prevent tube obstruction of AGV implant with a blood clot in neovascular glaucoma with high risk of tube obstruction. PMID- 29390306 TI - Syphilis of the lumbar spine: A case report and review of the literature. AB - RATIONALE: Tertiary syphilis can manifest as gummatous disease, but gumma of the spine has been extremely rarely reported. PATIENT CONCERNS: A 61-year-old male complained of worsening pain and numbness in both lower legs for four weeks. DIAGNOSES: Syphilis of the Lumbar Spine. INTERVENTIONS: Pedicle screw fixation (L3-S1) and posterior decompression of the vertebral canal at L4-5 were performed. OUTCOMES: The postoperative VAS score of both lower extremities decline to 2 from 7 at admission. Dorsal thumb extensor motor power (left/right) at day 7 postoperatively was 3/3 (versus admission: 1/1). Laboratory examinations showed normal white blood cell count (versus admission: 13.8 * 10/L; reference value: 4.00-10.00 * 10/L) and decline in C-reactive protein (20.35 mg/L versus admission: 77.43 mg/L; reference value: 0.00-10.00 mg/mL) and ESR (58 mm versus admission: 73 mm; reference value: 0-15 mm). LESSONS: Our case illustrates that although gummatous disease of the spine may be extremely rare, it should be considered in the differential diagnosis of tuberculosis or malignancy of the spine so as to avoid a wrong diagnosis and incorrect treatment. PMID- 29390307 TI - Pulmonary resection in the treatment of multidrug-resistant tuberculosis: A case series. AB - Multidrug-resistant (MDR) and extensive drug-resistant (XDR) tuberculosis (TB) are significant health problems throughout the world. Although the main treatment is medical, adjunctive surgical resection may increase the chance of cure in selected patients with MDR-TB or XDR-TB. This study aimed to present a case series of patients who underwent surgical resection for MDR-TB.Between March 2008 and November 2011, surgical resection was performed on 54 patients including 34 with MDR-TB and 20 with XDR-TB at the Departments of Surgery of Shanghai Public Health Clinical Center (Shanghai), Henan Chest Hospital (Henan), and Anhui Chest Hospital (Henan). Preoperative sputum smear samples were positive for 28 patients and sputum quantitative polymerase chain reaction was positive for 32. Patients were treated according to a standard therapy protocol for a mean of 4.2 months before the operation. The variables that affected treatment outcomes were identified through multivariate regression analysis.Fifty-four patients were operated for MDR-TB with localized disease usually complicated by cavity formation or destroyed lung. Thirty-seven were males and 17 were females. Median age was 37.8 (range, 20-75) years. Lobectomy was performed in 46 patients and pneumonectomy in 8. Muscle flaps were used in 36 of the patients with lobectomy and 8 with pneumonectomy. Various complications occurred in 6 (11.1%) patients, including bronchopleural fistula in 1 patient, bleeding in 2 patients, and prolonged air leak in 2 patients. A favorable outcome was achieved in 47 patients (87%) who underwent surgical resection. Higher body mass index (BMI) was associated with better outcome (odds ratio = 0.537, 95% confidence interval: 0.310-0.928, P = .026).Patients with MDR-TB had good treatment outcomes after adjunctive pulmonary resection, and with few complications. Higher BMI was related to a favorable outcome. PMID- 29390308 TI - Utility and quality-adjusted life-years in coronary artery disease: Five-year follow-up of the MASS II trial. AB - OBJECTIVES: This study evaluated the utility and quality-of-life year measurements for patients with coronary artery disease who underwent any of 3 therapeutic strategies with a 5-year follow-up. METHODS: Quality-of-life data were obtained from the Medicine, Angioplasty, or Surgery Study II trial. To obtain utilities, the 36-Item Short-Form questionnaire was converted to a 6 Dimensional Health State Classification System. RESULTS: Of the 611 initial patients, 579 completed the questionnaire. In all, 188 patients received the surgical treatment-194 the percutaneous, and the remaining 197 the medical. The median utility scores for the 5 years analyzed were 0.809 (95% confidence interval [CI] 0.794-0.842) for patients assigned to percutaneous coronary intervention, 0.755 (95% CI 0.723-0.774) for medical treatment, and 0.780 (95% CI 0.761-0.809) for coronary artery bypass graft surgery. The difference between percutaneous coronary intervention and medical treatment was statistically significant (P < .05, Dunn test). The median cumulative quality-of-life years across the 5 years were 3.802 (95% CI 3.668-3.936) for percutaneous, 3.540 (95% CI 3.399-3.681) for medical, and 3.764 (95% CI 3.638-3.890) for surgery. Additionally, the median quality-of-life years between percutaneous and medical treatment was 0.262 (95% CI 0.068-0.456), between surgery and medical treatment it was 0.224 (95% CI 0.036-0.413), and between surgery and percutaneous coronary intervention it was -0.038 (95% CI -0.221 to -0.146). CONCLUSION: Coronary artery bypass surgery and percutaneous coronary intervention were similar regarding cumulative quality-of-life years; however, they were both superior to that of medical treatment. The results presented are valuable data for further cost utility studies. PMID- 29390309 TI - Recent changes in blood pressure levels, hypertension prevalence and treatment rates, and the rate of reaching target blood pressure in the elderly. AB - Antihypertensive treatment has beneficial effects in the elderly. Surveying the situation of blood pressure in the elderly is quite important for planning strategies to manage elderly hypertensives. The aim of the present study was to investigate changes in blood pressure in the elderly over the past 15 years.As part of a physical check-up program between 2001 and 2015, 29,363 elderly participants (>=65 years of age) attended and were enrolled in the present study. The characteristics of the participants in each year were analyzed cross sectionally and the results were compared over the 15 years. Changes in blood pressure, hypertension prevalence, and treatment rates, and the rate of reaching target blood pressure in the elderly were investigated.The prevalence of hypertension during the study period increased with increasing participant age. However, both the treatment rate and the rate of reaching target blood pressure in treated subjects improved. The blood pressure of treated hypertensive elderly subjects decreased from 146.1/83.0 to 130.6/75.4 mm Hg, and the reduction was most evident after revision of Japanese Society of Hypertension guidelines regarding target blood pressure in elderly hypertensives. Blood pressure in the entire cohort of elderly subjects decreased from 133.8/78.4 mm Hg in 2001 to 127.9/74.6 mm Hg in 2015.Blood pressure in elderly subjects had decreased over the 15-year study period primarily due to reductions in blood pressure in elderly hypertensive patients on medication. Guidelines for the treatment of hypertension have had a beneficial effect on the management of hypertension in the elderly. PMID- 29390310 TI - Recovery of akinetic mutism and injured prefronto-caudate tract following shunt operation for hydrocephalus and rehabilitation: A case report. AB - RATIONALE: A 76-year-old female patient was diagnosed with an aneurysmal subarachnoid hemorrhage following rupture of a right posterior communicating artery aneurysm. PATIENT CONCERNS: She was treated surgically with clipping of the aneurysmal neck. Six months after onset, when starting rehabilitation at our hospital, she showed no spontaneous movement or speech. DIAGNOSES:: aneurysmal subarachnoid hemorrhage following rupture of a right posterior communicating artery aneurysm. INTERVENTIONS: During 2 months' rehabilitation, her AM did not improve significantly. As there was no apparent change, she underwent a ventriculo-peritoneal shunt operation for hydrocephalus 8 months after her stroke. After the surgery, she remained in the AM state, but participated in a comprehensive rehabilitative management program similar to that before shunt operation. During 1 month's intensive rehabilitation, her AM gradually improved. At 9 months after onset, she became able to perform some daily activities by herself including eating, washing, and dressing. In addition, she could speak with some fluency. OUTCOMES: On 6-month DTT, the neural connectivity of the caudate nucleus (CN) to the medial prefrontal cortex (PFC, Broadmann area [BA]: 10 and 12) and orbito-frontal cortex (BA 11 and 13) was low in both hemispheres. However, the neural connectivity of the CN to the medial PFC increased on both sides on 9-month DTT. The integrity of the arcuate fasciculus (AF) was preserved in both hemispheres on both 6- and 9-month DTTs. LESSONS: Recovery of AM and injured PCTs was observed in a stroke patient. PMID- 29390311 TI - Systemic contact dermatitis due to corrosion of titanium-coated nickel and cobalt bone plate fixation: A case report. AB - RATIONALE: Corrosion refers to the degradation of a material that occurs following its interaction with other substances in the environment. Corrosion of metallic substances into tissues may lead to inflammatory responses such as systemic contact dermatitis (SCD), a skin condition where an individual who has previously been sensitized to a particular allergen via the cutaneous route will subsequently react to same allergen via the systemic route. This condition occurs following exposure to allergens such as metals, medications, and certain food substances. In recent years, the use of metal plates for internal fixation has become increasingly common in bone fracture repairs. PATIENT CONCERNS: A 34-year old Indonesian male presented with systemic erythema with itching 7 days following a bone plate fixation as a management for mandibular fracture. DIAGNOSES: Physical examination showed pruritic red macules, papules, and scales on almost his entire body, along with facial swelling. The patch test results revealed a positive reaction to nickel and cobalt. Therefore, the patient was diagnosed with SCD. INTERVENTIONS: The patient was treated with topical and systemic corticosteroids as well as bone plate removal. OUTCOME: After treatment, the eruption turned brown, the itching was resolved, and there were no facial swelling as well. LESSONS: This case report highlights the need to consider the occurrence of SCD in patients following bone plate fixation. PMID- 29390312 TI - Gait recovery by activation of the unaffected corticoreticulospinal tract in a stroke patient: A case report. AB - RATIONALE: A 50-year-old man presented with complete paralysis at the onset of a putaminal hemorrhage. PATIENT CONCERNS: The patient presented with complete paralysis of the left upper and lower extremities (Medical Research Council:0/5). DIAGNOSES: Spontaneous intra crebral hemorrhage on putamen. INTERVENTION: He underwent comprehensive rehabilitative therapy from 3 weeks after onset. At 3weeks after onset, he presented with severe weakness of the left extremities. The weakness of his left extremities had recovered as follows at 3 months after onset. Consequently, he was able to walk independently on an even floor. OUTCOMES: On 3-week and 3-month diffusion tensor tractography (DTTs), the right corticospinal tract (CST) and the corticoreticulospinal tract (CRT) showed discontinuations below the lesion. On 3-month DTT, the left CST had become thinner; however, the left CRT had become thicker compared with 3-week DTT (Fig. 1). LESSONS: To the best of our knowledge, this is the first study to demonstrate the activation process of the CRT in the unaffected hemisphere in relation to gait recovery from early to chronic stage of stroke. PMID- 29390313 TI - Disparities in quality of cancer care: The role of health insurance and population demographics. AB - Escalating costs and concerns about quality of cancer care have increased calls for quality measurement and performance accountability for providers and health plans. The purpose of the present cross-sectional study was to assess variability in the quality of cancer care by health insurance type in California.Persons with breast, ovary, endometrium, cervix, colon, lung, or gastric cancer during the period 2004 to 2014 were identified in the California Cancer Registry. Individuals were stratified into 5 health insurance categories: private insurance, Medicare, Medicaid, dual Medicare and Medicaid eligible, and uninsured. Quality of care was evaluated using Commission on Cancer quality measures. Logistic regression models were generated to assess the independent effect of health insurance type on stage at diagnosis, quality of care and survival after adjusting for age, sex, race/ethnicity, and socioeconomic status (SES).A total of 763,884 cancer cases were evaluated. Individuals with Medicaid or Medicare-Medicaid dual-eligible coverage and the uninsured had significantly lower odds of receiving recommended radiation and/or chemotherapy after diagnosis or surgery for breast, endometrial, and colon cancer, relative to those with private insurance. Dual eligible patients with gastric cancer had 21% lower odds of having the recommended number of lymph nodes removed and examined compared to privately insured patients.After adjusting for known demographic confounders, substantial and consistent disparities in quality of cancer care exist according to type of health insurance in California. Further study is needed to identify particular factors and mechanisms underlying the identified treatment disparities across sources of health insurance. PMID- 29390314 TI - Endoscopic ultrasound-guided transduodenal drainage of idiopathic retroperitoneal abscess in an immunocompromised patient: A case report. AB - RATIONALE: Idiopathic retroperitoneal abscesses are insidious, occult illnesses with high mortality if inadequately drained. Endoscopic ultrasound-guided drainage is an alternative to percutaneous or surgical drainage, it is not widely performed for retroperitoneal abscesses other than peripancreatic fluid collection. PATIENT CONCERNS: We present a 76-year-old Japanese woman with abdominal pain, high fever, and a history of rheumatism on treatment with immunosuppressants. DIAGNOSES: The patient was diagnosed with idiopathic retroperitoneal abscess based on results obtained from her clinical course and findings on computed tomography. INTERVENTIONS: We performed Endoscopic ultrasound-guided drainage. After we performed needle puncture via the descending portion of the duodenum, the fistula was expanded using a dilator, and a double pigtail stent and endoscopic nasobiliary drainage tube were inserted. OUTCOMES: The patient was kept nil by mouth, together with intravenous antibiotic therapy, and repeated washing of the abscess cavity with saline was performed. After that, we confirmed disappearance of the cavity, and, after removing the tubes, commenced oral feeding. We were able to avoid surgery in this immunosuppressed patient. LESSONS: Endoscopic ultrasound (EUS)-guided abscess drainage can be overall considered a safe and useful procedure. We also propose the double-stent method, with both internal and external stents, for the treatment of idiopathic retroperitoneal abscesses. PMID- 29390315 TI - Management strategy in patient with familial gigantiform cementoma: A case report and analysis of the literature. AB - RATIONALE: Familial gigantiform cementoma (FGC) is a rare benign autosomal dominant fibrocemento-osseous lesion generally limited to the facial bones, typically in the anterior portion of the mandible; it is often associated with abnormalities of the long bones and prepubertal pathologic fractures. Owing to the small number of such patients, a uniform treatment criterion has not been established. This paper presents a patient with FGC who was treated in our department, and offers a systematic review of the patients reported in the literature. Our aim was to explore the treatment strategy for patients with FGC. PATIENT CONCERNS: Our patient, a 13-year-old boy, presented with a painless enlargement of the mandible first noted 2 years earlier. It had grown rapidly over the preceding 8 months, affecting both his appearance and ability to chew. DIAGNOSIS: Based on the pathologic, clinical, and radiographic features, FGC was diagnosed. INTERVENTIONS: Mandibuloectomy was performed. The mandibular defect was immediately reconstructed with his right vascularized iliac crest flap. At the same time, a PubMed search was conducted to identify studies reporting on other patients with FGC. OUTCOMES: A 3-dimensional computed tomography (3D-CT) scan demonstrated appropriate height of the new alveolar bone. Follow-up results showed recovery of the patient's appearance and mandibular function. He was free of recurrence at 4-year follow-up. LESSONS: FGC is a rare benign fibrocemento osseous lesion of the jaws that can cause severe facial deformity. Incomplete removal leads to more rapid growth of the residual lesion. Therefore, extensive resection is a suitable strategy to avoid recurrence. Defects of the facial bones found intraoperatively should be repaired with resort to an appropriate donor site. However, it is important to be aware that patients with FGC always have concomitant abnormalities of skeletal metabolism and structure, as well as a vulnerability to fractures of the long bones of the lower extremity. Therefore, the optimal management strategy should include a review of treatment options for other patients as reported in the literature. An optimal protocol can not only provide sufficient high-quality bone suitable for the reconstruction of bone defects, but also minimize complications and maximize quality of life. PMID- 29390316 TI - Collision tumors composed of meningioma and growth hormone-secreting pituitary adenoma in the sellar region: Case reports and a literature review. AB - RATIONALE: Collision tumor is a rare disease that represents the coexistence of two histologically distinct neoplasms in the same area without histological admixture or an intermediate cell population zone. To our best knowledge, 13 cases besides our 2 cases have been reported till now, and our report represents the first publication regarding a collision tumor composed of growth hormone (GH) secreting pituitary adenoma and sellar meningioma. PATIENT CONCERNS: We collected two cases of collision tumors composed of meningioma and GH-secreting adenoma in the sellar region from 2014 to 2015 at Peking Union Medical College Hospital (PUMCH). DIAGNOSIS: Two cases were diagnosed with solid sellar tumors, and two tumor types were suspected with magnetic resonance imaging (MRI). Blood hormone tests revealed increased insulin-like growth factor 1 (IGF-1) and GH levels. INTERVENTIONS: Both cases underwent transsphenoidal microsurgical resection of pituitary adenoma. OUTCOMES: The tumor was completely resected, and the pathological examination after the operation revealed meningioma and GH-secreting pituitary adenoma. LESSONS: Collision tumors consisting of pituitary adenomas with other sellar neoplasms are rare. Histological examination is necessary because preoperative studies cannot guarantee an accurate diagnosis. If a collision tumor is suspected prior to operation, a craniotomy may need to be considered before other operation methods to avoid reoperation. PMID- 29390317 TI - Comparison of rigid and deformable registration through the respiratory phases of four-dimensional computed tomography image data sets for radiotherapy after breast-conserving surgery. AB - BACKGROUND: The aim of this study was to compare the geometric differences in gross tumor volume (GTV) and surgical clips propagated by rigid image registration (RIR) and deformable image registration (DIR) using a four dimensional computed tomography (4DCT) image data set for patients treated with boost irradiation or accelerated partial breast irradiation after breast conserving surgery (BCS). METHODS: The 4DCT data sets of 44 patients who had undergone BCS were acquired. GTV and selected clips were manually delineated on end-inhalation phase (CT0) and end-exhalation phase (CT50) images of 4DCT data sets. Subsequently, the GTV and selected clips from CT0 images were transformed and propagated to CT50 images using RIR and DIR, respectively. The geometric differences in GTV and surgical clips from DIR were compared with those of RIR. RESULTS: The mean Dice similarity coefficient (DSC) index was 0.860 +/- 0.042 for RIR and 0.870 +/- 0.040 for DIR for GTV (P = .000). The three-dimensional distance to the center of mass (COM) of the GTV from RIR was longer than that from DIR (1.22 mm and 1.10 mm, respectively, P = .000). Moreover, in the anterior posterior direction, displacements from RIR were significantly greater than those from DIR for both GTV (0.70 mm and 0.50 mm, respectively) and selected clips (upper clip, 0.45 mm vs 0.20 mm; inner clip, 0.55 mm vs 0.30 mm; outer clip, 0.40 mm vs 0.20 mm; lower clip, 0.50 mm vs 0.25 mm) (P = .000). However, in the left right and superior-inferior directions, there were no significant displacement differences between RIR and DIR for GTV and the selected clips (all P > .050). CONCLUSION: DIR can improve the overlap for GTV registration from CT0 to CT50 images from 4DCT scanning. Furthermore, DIR is superior to RIR in reflecting the displacement of GTV and selected clips in the anterior-posterior direction induced by respiratory movement. PMID- 29390318 TI - Hymenolepis nana: A case report of a perfect IBD camouflage warrior. AB - RATIONALE: There is evidence that parasitic helminths can ameliorate colitis in animal models and humans. Although infections with Hymenolepis sp. are clinically benign, the immunomodulatory interactions between host and parasite are largely unknown. PATIENT CONCERNS: In this study we examined the intestinal mucosa of an adult asymptomatic patient harboring adult and larval dwarf tapeworms (Hymenolepis nana) who underwent surgery for an unrelated reason. INTERVENTIONS: Routine histology and immunohistochemistry were performed to characterize the host's response to the parasite. Parasitic DNA was sequenced to identify the tapeworm species. DIAGNOSES: Morphological and immunohistochemical studies showed a nearly complete absence of an anti-parasite host immune response. The outer surface of the parasite also showed prominent cross-reactivity with various tested leukocyte antigens. Our findings closely resemble experimentally obtained data from the H. diminuta-infected rat at the state of persistent colonization. OUTCOMES: Cross-reactivity of parasite-borne molecules with anti-human-leukocyte antibodies indicates a potential functional role in active modulation of the host's immune response. LESSIONS: We believe that better understanding of the host-cestode interaction will certainly extend our knowledge on auto-aggressive disorders such as inflammatory bowel disease and might provide potential treatment options. PMID- 29390319 TI - The influence of artificial nucleus pulposus replacement on stress distribution in the cartilaginous endplate in a 3-dimensional finite element model of the lumbar intervertebral disc. AB - OBJECTIVE: This study aimed to investigate the effects involved with the artificial nucleus pulposus (NP) replacement on stress distribution of the cartilaginous endplate (CEP) in a 3-dimensional lumbar intervertebral disc (IVD) model using a finite element (FE) analysis. METHODS: A healthy male volunteer was recruited for the purposes of the study and a spiral computed tomography scan was subsequently conducted to obtain the data information in relation to the L4/5 motion segment. An FE model of the L4/5 motion segment constructed, on the basis of which degenerative IVD, IVD with NP removal, and IVD with NP replacement were in turn built. The stress distribution of the CEP and bulging of IVD were estimated using various motion states, including axial loading, forward flexion, backward extension, left axial rotation, and right axial rotation. RESULTS: Under different motion states, the vertebral stress was higher in the degenerative IVD, the IVD with NP removal, and the IVD with NP replacement, in comparison to that of the normal IVD. Furthermore, a higher vertebral stress was detected in the degenerative IVD than the IVD with NP removal and the IVD with NP replacement. An even distribution of vertebral stress was observed in the IVD model with an artificial NP replacement, while the vertebral stress and bulging displacement were lower than after NP removal. Our findings provided confirmation that stress of the CEP was consistent with the vertebral stress. CONCLUSION: This study provided evidence suggesting that NP replacement, vertebral stress, and bulging displacement are lower than that of degenerative IVD and IVD with NP removal under different motion states. PMID- 29390320 TI - Local resection of rectal neuroendocrine tumor with first clinical manifestation of giant liver metastasis by transanal endoscopic microsurgery: A case report. AB - RATIONALE: Rectal neuroendocrine tumor (NET) is a relatively rare tumor. Well differentiated NETs (G1 and G2) rarely display distant metastasis at initial diagnosis. Currently, treatment for the primary lesions of rectal NETs with liver metastasis remains controversial. The liver metastasis was resected in local hospital. Transanal endoscopic microsurgery (TEM) has emerged as an effective minimally invasive surgery for local resection of lower rectal lesions. Herein, we reported the initial application of TEM to remove the rectal primary lesion in patients with low rectal NETs (G2) with giant liver metastases. PATIENT CONCERNS: The patient, a 45-year-old woman, was primarily diagnosed with hepatocellular carcinoma and underwent curative resection of a giant liver lesion in a local hospital. Nevertheless, the postoperative pathologic examination revealed that the lesion was an NET (G2). The colonoscopy then showed a nodule 1.4 cm in diameter, 4 cm above the anal verge, located on the anterior wall of the rectum. The biopsy revealed that the nodule was also an NET (G2). However, the patient did not consent to abdominoperineal resection based on concerns for quality of life. DIAGNOSES: Rectal NET with liver metastasis. INTERVENTIONS: The patient underwent curative resection of liver metastasis. And, TEM was adopted to resect the primary tumor in rectum. OUTCOMES: The patient has been disease-free for 2 years with a good quality of life and presents no local recurrence in the rectum. LESSONS: TEM is an appropriate palliative operation for therapy of rectal NETs with distant metastases, especially for primary rectal NETs located in low rectal. PMID- 29390321 TI - Case report: Ribavirin and vitamin A in a severe case of measles. AB - RATIONALE: Despite a vaccine being widely available, measles continues to occur frequently, with sometimes lethal consequences. PATIENTS CONCERNS: The mortality rate reaches 35% and measles represents 44% of the 1.4 million deaths which are due to preventable diseases. Severe forms of measles are reported, mainly in young, unvaccinated adults, and in specific populations. The risk factors for severe measles include no or incomplete vaccination and vitamin A deficiency. Apart from secondary measles-related infections, severe measles is mainly represented by neurological, respiratory, and digestive symptoms. DIAGNOSES: Strengthening the hypothesis that there is a link between vitamin A deficiency and severe measles in this paper we report the case of a 25-year-old unvaccinated man hospitalized for severe and complicated measles. OUTCOMES: The evolution was good after administration of intramuscular vitamin A as well as intravenous ribavirin. LESSONS: Measles remains a fatal and serious disease. The early use of ribavirin and vitamin A shows significant improvements regarding morbimortality and should be systematic in severe cases. PMID- 29390322 TI - Intramural gastric pseudocyst: A case report and a comprehensive literature review. AB - RATIONALE: Intramural pseudocyst, although first reported several decades ago, is a rare entity. Scientific knowledge regarding its clinical management is sparse. PATIENT CONCERNS: We present three cases to show the diverse clinical patterns of patients diagnosed with an intramural gastric pseudocyst. DIAGNOSIS: A final diagnosis should rest on proper evaluation by cross sectional imaging, including computer tomography and magnetic resonance imaging. Endoscopic ultrasound adds to the work-up. INTERVENTIONS: Previously, identified "lesions of the gastric wall" were not well recognized as an intramural pseudocyst, and treatments including resectional surgery were employed. Contemporary proper diagnostics should provide support to a less aggressive treatment approach. OUTCOMES: While an indolent natural history without any clinical symptoms or discomfort could be expected in most cases, individual clinical evaluation should be applied. LESSONS: A heterogeneous information pattern from the limited number of cases in the literature makes it difficult to draw any firm conclusions. Attention to this rare condition should be increased to help clinicians arrive at a correct diagnosis and possibly prevent some patients from being over treated or from the use of unnecessary surgery. PMID- 29390323 TI - Liver transplantation for decompensated liver cirrhosis caused by progressive familial intrahepatic cholestasis type 3: A case report. AB - RATIONALE: Progressive familial intrahepatic cholestasis (PFIC) type 3, characterized by high gamma glutamyl transferase (GGT), is an autosomal recessive genetic disease. It often occurs in patients' first years of age. However, high GGT type PFIC is still rare. PATIENT CONCERNS: The present study reports a case of liver transplantation for decompensated liver cirrhosis caused by PFIC type 3. An 18-year-old male presented with a history of abdominal distension and jaundice for 2 months. He had abdominal tenderness but no rebounding pain. Moreover, his dullness was felt over the liver and the spleen was palpable 8 cm below the ribs. DIAGNOSES: Computed tomography and magnetic resonance cholangiopancreato graphy of the upper abdomen revealed cirrhosis, portal hypertension, collateral circulation formation, large spleen, and ascites. Blood biochemistry showed high alanine transaminase, aspartate transaminase, and GGT. The diagnosis of decompensated liver cirrhosis caused by PFIC-3 was finally confirmed by plasma gene detecting. INTERVENTIONS: The patient received an open surgery named allogeneic liver transplantation after successful matching of immune types between the recipient and donor. Peritoneal puncture and catheter drainage under B-ultrasound was performed when an encapsulated effusion between the liver and stomach arose. OUTCOMES: The patient was discharged without specific discomfort and was almost free of fluid accumulation 51 days after the surgery. At the 6 month follow-up, he had no discomfort and the blood routine, liver functions showed no abnormalities. LESSONS: We found a new mutant fragment of ABCB4 gene in the process of diagnosis. Liver transplantation remains the most definitive treatment for PFIC. Current medical therapies and surgical interventions such as biliary diversion have potentially created a synergistic outcome. PMID- 29390324 TI - Successful treatment with allogeneic stem cell transplantation followed by DLI and TKIs for e6a2 BCR-ABL-positive acute myeloid leukaemia: A case report and literature review. AB - RATIONALE: Patients with the e6a2 BCR-ABL transcript, 1 of the atypical transcripts, have been reported to have a poor prognosis, and allogeneic stem cell transplantation (ASCT) can be considered as additional therapy. However, long-term survival after ASCT for this disease is rare. PATIENT CONCERNS: This report concerns a 55-year-old female patient with e6a2 BCR-ABL-positive acute myeloid leukemia including the outcome of ASCT followed by donor lymphocyte infusion (DLI). DIAGNOSES: The breakpoint was confirmed by direct sequencing. Her minimal residual disease could be detected by nested reverse-transcription polymerase chain reaction using primers for the minor BCR-ABL (e1a2) transcript. INTERVENTIONS: Treatment with tyrosine kinase inhibitors (TKIs) and ASCT followed by DLI. OUTCOMES: Despite multiple cytogenetic and molecular relapses after ASCT, she remains in molecular remission at 46 months after ASCT. LESSONS: This case indicates the efficacy of the combination of the graft-versus-leukemia effect and TKIs for e6a2 BCR-ABL-positive acute leukemia. When the Philadelphia chromosome with an unusual chromosomal breakpoint is suggested, we should clarify the breakpoint because that information can aid molecular assessments and decisions to provide an additional or alternative therapy. PMID- 29390325 TI - Evaluation of tolerance to ambulatory blood pressure monitoring: Analysis of dipping profile in a large cohort of hypertensive patients. AB - Ambulatory blood pressure monitoring (ABPM) is a helpful tool to comprehensively identify and diagnose arterial hypertension. Moreover, it allows to better identify alterations in the circadian BP profile, as the nocturnal "nondipping" status, characterized by a lack of the physiological 10% night BP reduction and associated with a greater risk of target organ damage. However, ABPM has some limitations such as restricted availability, discomfort, particularly at night, cost implications, and reproducibility.Aim of the study was evaluate if the "nondipping" phenomenon may be related to low degree of tolerance to ABPM. Additionally, to determine whether self-reported events of sleep disorders and nighttime urinations may affect the "nondipping" status.From January 2013 to December 2015, we consecutively evaluated 1046 patients with arterial hypertension, performing ABPM, considering a tolerance index calculated on the basis of the patients' responses to a questionnaire.Thirty-eight out of 1046 patients showed complete lack of tolerance to the instrument during the day, whilst 126 during the night. There were no statistically significant differences in daytime and nighttime values of tolerance to the instrument between "dippers" and "nondippers," between "extreme-dippers" and the remaining patients or between "reverse-dippers" and the remaining patients. There were no statistically significant differences in the number of nocturnal awakenings between the groups. However, we found that the number of awakenings followed by urination was higher in "nondipping" patients and in "reverse-dipping" patients compared to the other groups.We found that the poor tolerance to the instrument does not seem to influence the BP "dipping" phenomenon among hypertensive individuals. Moreover, we think that in the evaluation of the ABPM data, factors, such as nocturnal urination and sleep disorders, need to be carefully taken into account, since may lead to a higher incidence of "nondipping" pattern. PMID- 29390326 TI - The application of 18F-FDG PET/CT in ovarian immature teratomas when pathological examination results contradict clinical observations: a case report. AB - RATIONALE: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) could reveal potential lymph node involvement and assisted locating sample sites for pathological examinations. PATIENT CONCERNS: Help choose the right treatment strategies for patients. To better stage immature ovarian teratomas with 18F-FDG PET/CT when lymphatic metastasis is suspected while lymph node biopsy results are negative. DIAGNOSES: The ultimate pathological diagnosis was left ovarian cancer, an immature teratoma (IMT) Grade 1. INTERVENTIONS: Surgery was the initial treatment option. Chemotherapy (BEP scheme: Bleomycin 30 mg d1, 7 + Etoposide 100mg d1-6 + Cisplatin 50mg d1-3) was then administered. OUTCOMES: The post-operational pathological examination additionally showed a small number of tumor cells in para-aortic lymph nodes. The end-of-treatment disclosed no recurrent tumors and serum levels of AFP (2.9 ng/mL), hCG (0.12 mIU/L), and CA-125 (11.4 IU/mL) were normal. LESSONS: 18F-FDG PET/CT successfully detected lymphatic metastasis when lymph node biopsy results were negative, which would be of great significance in detecting metastasis and monitoring reoccurrence of ovarian immature teratomas. PMID- 29390328 TI - Foregut duplication cyst: a novel computed tomography finding mimicking a small bowel hernia: A case report. AB - RATIONALE: A foregut duplication cyst (FDC) is an uncommon congenital disease. This report presents a case of mediastinal foregut duplication cyst that mimicked a diaphragmatic small bowel hernia. PATIENT CONCERN: A 27-month-old girl was first referred for a mediastinal lesion found incidentally on a chest radiograph. At that time, our impression was cystic lung lesion such as congenital pulmonary airway malformation or pulmonary sequestration. At the age 6 years, she presented with recurrent vomiting. The physical examination and laboratory studies were within normal limits. DIAGNOSES: Chest CT revealed a thin- and smooth-walled cystic mass containing an air-fluid level in the left paravertebral space. It had several inner circular folds and characteristic double-layer enhancement and inner circular fold. Our radiological impression was a type I congenital cystic adenomatoid malformation. INTERVENTIONS: The patients undergone video-assisted thoracoscopic surgery for excision. The operative finding was the cystic mass with smooth bowel-like outer surface and located between the aorta and heart. The cyst was excised and confirmed to be a foregut duplication cyst pathologically. OUTCOMES: The patient was doing well with no postoperative complications during follow-up. Recurrent vomiting was improved. This is the first case report describing foregut duplication cyst mimicking a small bowel hernia. LESSONS: Foregut duplication cysts are rare congenital anomalies of primitive foregut origin. They can occur at any level of the alimentary track and comprise approximately 10% of all mediastinal tumors. Its characteristic double-layered histopathological nature, an FDC can show a double-layered enhancement pattern, which is typical in the alimentary tract. PMID- 29390327 TI - Association between metabolic syndrome and bone fracture risk: A community-based study using a fracture risk assessment tool. AB - Osteoporosis and metabolic syndrome (MS) share similar risk factors. Previous studies of association between bone marrow density (BMD) and MS are controversial. Moreover, some studies revealed that MS is associated with BMD but not with bone fracture. In clinical practice, patients pay more attention to bone fracture risk than BMD values. Hence, this study aimed to evaluate the association between MS and the 10-year bone fracture risk probability using a fracture risk assessment tool (FRAX) from community-based data. From March 2014 to August 2015, 2689 participants (897 men and 1792 women) were enrolled in this study. Inflammatory cytokines, such as tumor necrosis factor alpha and C-reactive protein, and adipokines were included for analysis.The mean age was 60.2 +/- 10.7 years in men and 58.9 +/- 9.6 years in women. The percentage of MS was 27.6% in men and 27.9% in women. Participants were divided into 2 groups, those with or without MS. Compared with women without MS, women with MS had a higher rate of fracture risk (22.8% vs 16.3%, P = .001). In contrast, men with MS had a lower rate of fracture risk then men without MS (5.6% vs 12.3%, P = .004). However, MS loss the association with a high bone fracture risk in men based on multivariate logistical regression analysis, after adjusting for confounding factor of body mass index (BMI). Conclusively, the result of regression analysis between MS and the bone fracture risk may be different in men and women, and BMI was an important confounding factor to interfere with the regression analysis. PMID- 29390329 TI - Primary Sjogren syndrome that initially presented with repeated hypergammaglobulinemic purpura after prolonged sitting: A case report. AB - RATIONALE: Purpura is a common dermatologic manifestation in Sjogren syndrome (SS). When a patient presents with sicca symptoms, the diagnosis of SS is not difficult. PATIENT CONCERNS: Here, we reported a case of a 52-year-old Chinese woman who initially presented with nonpalpable purpura on both lower extremities, and these lesions had developed soon after prolonged sitting. In the past 2 years, she had repeated cutaneous nonpalpable purpura 4 times. She had no sicca symptoms, dry eyes, or dry mouth. DIAGNOSES: Combining the laboratory findings, Schirmer test, and labial gland biopsy, primary SS was confirmed. INTERVENTIONS: The patient was placed on a trial of hydroxychloroquine (200 mg once daily). OUTCOMES: The purpura on both lower extremities had faded at the sixth day after onset and at the third day after hydroxychloroquine treatment. LESSONS: These case was not easy to diagnosis primary SS because she had no sicca symptoms. A patient with primary SS who initially presented with recurrent purpura associated with prolonged sitting. Prolonged sitting had been a possible aggravating factor for the cutaneous purpura of this patient with primary SS. PMID- 29390330 TI - Musculoskeletal ultrasound-guided physical therapy in hemiplegic shoulder pain: A CARE-compliant case report. AB - RATIONALE: The use of musculoskeletal ultrasound (MU) method in the diagnosis of shoulder pain and injury and guidance of injection and pain blocking has been established. However, the treatment of posthemiplegic shoulder pain (HSP) with MU guided precise physical therapy has not been reported. PATIENT CONCERNS: Here, we present the first case report of a 64-year-old man with a right basal ganglia hemorrhage. Left side shoulder pain remained unbearable, which seriously affected sleep and shoulder-related activities. INTERVENTIONS: The patient received MU guided precise drug administration, laser, and other physical therapy in addition to exercise training for 2 months. OUTCOMES: The pain was significantly relieved and shoulder function was improved. Effusion extent and tendon thickness were reduced. LESSONS: MU-guided precise physical therapy can effectively reduce symptoms of HSP and improve inflammation and effusion absorption of lesioned tissue. PMID- 29390331 TI - Correlation of metastasis characteristics with prognosis in gastric mixed adenoneuroendocrine carcinoma: Two case reports. AB - RATIONALE: This article is aimed to retrospect the clinicopathological data of 2 cases of gastric MANENCs. MANEC is a rare biphasic tumor type that is coexistence of dual neuroendocrine and adenocarcinoma differentiation with each composing exceeding 30% volume. Gastric MANEC have just been reported anecdotally in the literature due to their rarity and heterogeneity. According to our study, these neoplasms have 3 different metastasis patterns: only adenocarcinomatous or neuroendocrine carcinoma and both of the 2 components. We first focus on the correlation of metastasis characteristics with prognosis in gastric MANEC, which may be potential implications for the choice of chemotherapy. PATIENT CONCERNS: The 2 cases of patient shared several symptoms: epigastric discomfort, weight loss, hematemesis, or melena. DIAGNOSIS: The 2 patients were diagnosis as MANEC based on the identification of histopathological analysis. In case 1, the poor differentiated adenocarcinoma accounted for 30%, the neuroendocrine part account for 70% and both of the 2 components metastasized to the lymph nodes, whereas in case 2, poorly differentiated adenocarcinoma accounted for 70%, the neuroendocrine part for 30% and only the glandular component invaded regional lymph nodes. INTERVENTIONS: The first patient underwent laparoscopic radical gastrectomy and underwent adjuvant chemotherapy, combination of cisplatin, and etoposide successfully. The second patient received radical gastronomy, and did not receive any chemotherapy due to general weakness. OUTCOMES: The first patient is alive with no evidence of recurrence, and the second patient died 6 months after the operation. LESSONS: The assessment of metastatic sites should be a routine pathological practice, which is crucial for clinical decision-making and the selection of management. PMID- 29390332 TI - Spontaneous rupture of the renal pelvis caused by upper urinary tract obstruction: A case report and review of the literature. AB - RATIONALE: Spontaneous renal rupture is rupture of the renal parenchyma, collecting system, or renal blood vessel, which often occurs in pathological kidney and is clinically less common. Postoperative long-term renal rupture is rarely reported in flexible ureteroscopy treatment of calculus in the upper urinary tract. PATIENT CONCERNS: A 58-year-old man complained of right lower abdominal pain with hematuria for 3 hours after flexible ureteroscopy, combined with holmium laser lithotripsy of right renal calculi was performed 1 month ago. The urinary B-mode ultrasonogram suggested calculi and dilatation at the end of the right ureter, and moderate hydronephrosis of the right kidney. On the second day, the urinary system computed tomography (CT) examination suggested right renal rupture. DIAGNOSIS: Spontaneous rupture of the right renal pelvis. INTERVENTION: The patient underwent conservative treatment after the optimal treatment strategy was reviewed and discussed. OUTCOMES: Urinary system CT re examination suggested complete absorption of the hematoma and urinary extravasation 3 months later. LESSONS: Calculi obstruction is the most important cause of spontaneous renal rupture. CT is a valuable diagnostic modality, and spontaneous renal rupture should receive tailored treatment. PMID- 29390333 TI - Atypical hemangioma mimicking mixed hepatocellular cholangiocarcinoma: Case report. AB - RATIONALE: Hemangioma of the liver is a benign hepatic tumor, more common in women than in men, which is typically asymptomatic, solitary, and incidentally discovered. Atypical hemangioma is a variant of hepatic hemangioma with atypical imaging finding features on CT and MRI that can be confused with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and mixed hepatocellular cholangiocarcinoma (HCC-CC). PATIENT CONCERNS: We report a case of atypical hepatic hemangioma mimicking HCC-CC: A 59-year-old man was referred to our hospital for a hepatic lesion that was 4.7*3.6 cm in size and located in segments 2 and 3 of the liver. Serum alpha-fetoprotein (AFP) level increased from 17.03 ng/mL to 374.9 ng/mL. The patient was positive for hepatitis B. DIAGNOSES: Atypical hepatic hemangioma. INTERVENTIONS: US, CT, MRI and Tc-99m RBC liver scans were performed. Dynamic contrast-enhanced MRI showed no uptake in the corresponding area during the arterial phase, peripheral nodular enhancement during the portal phase and delayed phase, and hypo-intensity in the central area. An initial diagnosis of HCC-CC was offered based on the history and imaging findings. Finally, percutaneous liver biopsy (PLB) was offered to the patient. Histopathologic examination of the liver lesions revealed nodular cirrhosis and atypical hyperplasia of liver cells with cavernous hemangioma, where numerous old Schistosoma japonicum eggs were found. OUTCOMES: Accurate diagnosis of the patient obviated the need for surgery. The patient's recovery after liver puncture was uneventful, and he was discharged on the seventh post-operative day. LESSONS: In some cases, accurate preoperative imaging of focal hepatic lesions is essential but insufficient for diagnosis. PLB and histopathological examination are important, especially in patients with suspected malignancy. PMID- 29390334 TI - Degeneration of the corticofugal tract from the secondary motor area in a Parkinson's disease patient with limb-kinetic apraxia: A case report. AB - RATIONALE: In this case report, we describe a Parkinson's disease (PD) patient with limb-kinetic apraxia (LKA) in whom degeneration of the corticofugal tract (CFT) from the supplementary motor area (SMA) was observed in diffusion tensor tractography (DTT). PATIENT CONCERNS: A 63-year-old woman presented with a loss of dexterity in both upper extremities, which indicated LKA, and typical PD related symptoms, including a gait disturbance with a short step, resting tremor in both upper extremities, and rigidity, and these symptoms had been present for 2 years. The F-florinated-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4 lodophenyl) nortropane positron emission tomography scanning findings were consistent with PD. Based on the clinical symptoms and imaging findings, we diagnosed the patient with PD. In a coin-rotation test that was used to evaluate the severity of the LKA, the patient's results significantly decreased compared to the results of the normal controls. DIAGNOSES: The DTT showed that the CFTs from the SMAs in both hemispheres were partially torn and thinned. The fractional anisotropy values and CFT volumes in both SMAs were >2 standard deviations lower than those of the normal controls. INTERVENTIONS: The patient was treated with an initial dose of 150/37.5 mg/day of levodopa/benserazide, and the dose was gradually increased to 400/100 mg/day. OUTCOMES: After treatment, although the bradykinesia, rigidity, and resting tremor of the patient significantly decreased, the dexterity of the patient's hands did not improve. LESSONS: These observations indicated degeneration of the CFTs from the SMAs in both hemispheres in the patient. This degeneration might have, at least in part, contributed to the patient's LKA. The results of this study suggest that CFT degeneration could be one of the pathological mechanisms underlying LKA in patients with PD. PMID- 29390335 TI - Fever of unknown origin and splenomegaly: A case report of blood culture negative endocarditis. AB - RATIONALE: Fever of unknown origin (FUO) can be determined by different conditions among which infectious diseases represent the main cause. PATIENT CONCERNS: A young woman, with a history of aortic stenosis, was admitted to our unit for a month of intermittent fever associated with a new diastolic heart murmur and splenomegaly. Laboratory tests were negative for infectious screening. The total body computed tomography (CT) scan excluded abscesses, occulted neoplasia, or lymphadenopathy. DIAGNOSES: The transthoracic and transesophageal echocardiogram showed an aortic valve vegetation. Three sets of blood cultures were negative for all microorganisms tested. According to these findings, Bartonella endocarditis was suspected and the serology tests performed were positive. Finally, real-time polymerase chain reaction (RT-PCR) detected Bartonella henselae DNA on tissue valve. INTERVENTIONS: The patient underwent heart valve surgery and a treatment of Ampicillin, Gentamicin, and oral Doxycycline was prescribed for 16 days and, successively, with Doxycycline and Ceftriaxone for 6 weeks. OUTCOMES: After surgery and antibiotic therapy, patient continued to do well. LESSONS: Bartonella species are frequently the cause of negative blood culture endocarditis. Molecular biology techniques are the only useful tool for diagnosis. Valvular replacement is often necessary and antibiotic regimen with Gentamicin and either Ceftriaxone or Doxycycline is suggested as treatment.Echocardiogram and blood cultures must be performed in all cases of FUO. When blood cultures are negative and echocardiographic tools are indicative, early use of Bartonella serology is recommended. PMID- 29390336 TI - Hemophagocytic lymphohistiocytosis complicated by multiorgan failure: A case report. AB - RATIONALE: We present a case of hemophagocytic lymphohistiocytosis (HLH) with severe pulmonary complication and acute respiratory distress syndrome (ARDS) hospitalized in our intensive care unit (ICU) in 2014; distinctive trait of this case has been the challenging diagnosis, with a bone marrow biopsy always negative, the severe pulmonary complication with ARDS and severe pulmonary hypertension, and the ferritin temporal kinetics that precisely followed the clinical course of disease. PATIENT CONCERNS: A 32-year-old woman from the Philippines first diagnosed with upper airway infection, was subsequently hospitalized in infectious disease department and treated for community acquired pneumonia. DIAGNOSES: After clinical picture worsened with a profound respiratory insufficiency, the patient was intubated and transferred to our ICU. During this hospitalization, the clinical picture of fever, cutaneous rashes, lymphadenitis, hepatitis, leukopenia, anemia, hyperferritinemia, hypertriglyceridemia, high level of auto-antibodies, and low NK activity suggested an hemophagocytic lymphohistiocytosis syndrome, even if bone marrow biopsy was negative for hemophagocytosis. INTERVENTIONS: Immunosuppressive therapy with dexamethasone and etoposide was started, and the patient was discharged from ICU 4 months after admission. LESSONS: HLH is a rare disorder of the mononuclear phagocytic system, characterized by systemic proliferation of non- neoplastic histiocytes. The diagnosis is often challenging and not all of the diagnostic criteria may be present at the same time; this case shows how complex the diagnosis could be, how hematic ferritin levels could help in following the course of the disease, and the possibility of severe pulmonary complication either due to the disease itself and to possible sovra infections. PMID- 29390337 TI - Linezolid-associated optic neuropathy in a pediatric patient with Mycobacterium nonchromogenicum: A case report. AB - BACKGROUND: Toxic optic neuropathies are alterations of the optic nerve and can be caused by environmental, pharmacological, or nutritional agents. CASE: It is about a 7-year-old male patient, a native of the State of Mexico, Mexico who was diagnosed with cervical mycobacterial lymphadenitis that required management with linezolid. OBSERVATIONS: After 7 months of treatment, visual acuity of the left eye decreased and was accompanied by headache. Neuroinfection and other central nervous system affections were discarded. An adverse effect related to treatment with linezolid was suspected, and linezolid was suspended. The symptoms subsided after discontinuation; however, the patient continued to show decreased visual acuity of the left eye, assessed by his ability to count 2 fingers. The right eye remained unaffected. CONCLUSIONS: Neurotoxicity can be decreased by reducing the total dose of linezolid or by administrating it in an intermittent form. To avoid progression and loss of vision, we suggest frequent periodic ophthalmological evaluation in patients treated with linezolid. PMID- 29390338 TI - Miller Fisher syndrome with acute angle-closure glaucoma as the first manifestation: A case report. AB - RATIONALE: There were no reports of Miller Fisher syndrome (MFS) with acute angle closure glaucoma as the first manifestation. PATIENT CONCERNS: A 78-year-old female patient was admitted to our hospital with pain in her left eye, blurred vision along with nausea, and vomiting for 2 days. It was extremely rare that ophthalmoplegia, loss of tendon reflexes, and ataxia, did not occur in the early stages of MFS, and initial presentation was only dilated pupis and an increase in intraocular pressure. DIAGNOSES: The final diagnosis of the patient was MFS. INTERVENTIONS: Intravenous immunoglobulins were administered. OUTCOMES: Ophthalmoplegia, walking instability, and ataxia gradually improved. At 3 months follow-up, there was no neurological deficit, and the patient could completely self-care. LESSONS: This is the first report of MFS patient with acute angle closure glaucoma as the first manifestation. Consideration should be given to the possibility of incorporating autonomic nervous system dysfunction, or even MFS, in patients with acute angle-closure glaucoma in order to reduce missed diagnosis rate. PMID- 29390339 TI - Infliximab associated with life-threatening lung infection in a patient with Behcet disease with intestinal and hematopoietic system involvement: A case report. AB - RATIONALE: Tumor necrosis factor (TNF-alpha) participates in the pathophysiology of Behcet's disease (BD) and myelodysplastic syndrome (MDS). Infliximab is recommaned for the most severe type of BD, however, there is little evidence for its effectiveness in BD associated MDS. PATIENT CONCERNS: A 46-year-old female, initially diagnosed with intestinal BD and leukopenia was later diagnosed as MDS. Treatement with infliximab and other immunoregulators lead to life-threatening pneumonia. DIAGNOSIS: Intestinal BD associated with MDS involving trisomy 8. INTERVENTIONS: The patient initially treated with methylprednisolone, thalidomide, cyclosporine A, and infliximab, which lead to severe lung infection. Therefore, the patient was transferred to Intensive Care Unit for life supportive, anti-infection and immune improving therapy. OUTCOMES: The patient survived from the lung infection. With combination of methylprednisolone, thalidomide and cyclosporine A, the patient recovered from her intestinal ulceration and MDS manifestations. LESSONS: Infliximab treatment may not benefit a patient with BD associated with MDS but place the patient at risk of infection. PMID- 29390340 TI - Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals. AB - Survival analysis methods have gained widespread use in the filed of oncology. For achievement of reliable results, the methodological process and report quality is crucial. This review provides the first examination of methodological characteristics and reporting quality of survival analysis in articles published in leading Chinese oncology journals.To examine methodological and reporting quality of survival analysis, to identify some common deficiencies, to desirable precautions in the analysis, and relate advice for authors, readers, and editors.A total of 242 survival analysis articles were included to be evaluated from 1492 articles published in 4 leading Chinese oncology journals in 2013. Articles were evaluated according to 16 established items for proper use and reporting of survival analysis.The application rates of Kaplan-Meier, life table, log-rank test, Breslow test, and Cox proportional hazards model (Cox model) were 91.74%, 3.72%, 78.51%, 0.41%, and 46.28%, respectively, no article used the parametric method for survival analysis. Multivariate Cox model was conducted in 112 articles (46.28%). Follow-up rates were mentioned in 155 articles (64.05%), of which 4 articles were under 80% and the lowest was 75.25%, 55 articles were100%. The report rates of all types of survival endpoint were lower than 10%. Eleven of 100 articles which reported a loss to follow-up had stated how to treat it in the analysis. One hundred thirty articles (53.72%) did not perform multivariate analysis. One hundred thirty-nine articles (57.44%) did not define the survival time. Violations and omissions of methodological guidelines included no mention of pertinent checks for proportional hazard assumption; no report of testing for interactions and collinearity between independent variables; no report of calculation method of sample size. Thirty-six articles (32.74%) reported the methods of independent variable selection. The above defects could make potentially inaccurate, misleading of the reported results, or difficult to interpret.There are gaps in the conduct and reporting of survival analysis in studies published in Chinese oncology journals, severe deficiencies were noted. More endorsement by journals of the report guideline for survival analysis may improve articles quality, and the dissemination of reliable evidence to oncology clinicians. We recommend authors, readers, reviewers, and editors to consider survival analysis more carefully and cooperate more closely with statisticians and epidemiologists. PMID- 29390341 TI - Accuracy of interleukin-27 assay for the diagnosis of tuberculous pleurisy: A PRISMA-compliant meta-analysis. AB - BACKGROUND: The concentration of interleukin-27 (IL-27) in pleural effusions was found to be increased in tuberculous pleurisy and several studies have investigated the diagnostic value of IL-27 for tuberculous pleural effusions (TPEs), but the results varied a lot. We conducted the present study to comprehensively evaluate the diagnostic value of IL-27 for TPE. METHODS: Primary diagnostic test studies of IL-27 for TPE was searched and identified from databases. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ration, diagnostic odds ratio, and receiver operating characteristic curves (SROCs) were computed or pooled to summarize the overall test performance. RESULTS: Nine studies with a total number of 1226 patients were identified in our research. The main pooled estimates were as follows: sensitivity 0.92 [95% confidence interval (CI), 0.90-0.95], specificity 0.90 (95% CI, 088-0.92), and area under the SROC 0.97. No evidence of publication bias was detected. CONCLUSION: Our research suggested the good diagnostic value of IL-27 for TPE and it could be used as a diagnostic biomarker. PMID- 29390342 TI - The predictive value of early oral motor assessments for neurodevelopmental outcomes of moderately and late preterm infants. AB - Oral motor assessment is used to identify abnormal sucking patterns which may reflect neurodevelopmental problems in preterm infants, but few studies have focused on moderately and late preterm infants. We enrolled 118 moderately and late preterm infants (mean gestational age, 35.04 weeks; mean birth weight, 2347.59 g) and analyzed the relationship between the Neonatal Oral-Motor Assessment Scale scores of these infants and the Chinese revision of Bayley Scales of Infant Development outcomes at 6 months corrected age. And the infants with abnormal sucking pattern had significantly lower Mental Development Index and Psychomotor Development Index and showed a higher rate of below average scores than control group (P = .003, P = .029, P = .022). The incoordination of suck-swallow-respiration was a risk factor for adverse neurodevelopment (RR = 3.67, 95% CI: 1.42-9.45). These indicate that abnormal sucking patterns in moderately and late preterm infants might provide some predictive value for short term neurodevelopmental outcomes, but the clinical predictive value for developmental delay need to be determined in a longer term follow-up. This finding may offer a basis for early intervention. PMID- 29390343 TI - Health-related quality of life and psychological status of women with primary Sjogren's syndrome: A cross-sectional study of 304 Chinese patients. AB - Patients with primary Sjogren syndrome (pSS) always suffer from dryness, pain, and fatigue caused by the involvement of multiple different systems or organs. The uncomfortable disease symptoms, the consequent disability, and the side effects of therapeutic drugs decrease the quality of life and lead to emotional problems. We investigated the health-related quality of life and psychological status of a large cohort of women patients with pSS and associated factors.A total of 304 women with pSS referred to Peking Union Medical College Hospital during 2011 and 2014 were included. The internationally recognized Short Form (36) Health Survey (SF-36) was used to assess patients' quality of life; a higher score indicated a better quality of life. Patients' psychological status was assessed by the Hospital Anxiety and Depression Scale (HADS), and higher scores predicted more anxiety or depression.Patients with pSS had remarkably lower SF-36 scores. The Hospital Anxiety Scale (HAS) and Hospital Depression Scale (HDS) scores of the pSS patients (7 [4,10] and 6 [3,10], respectively) were significantly higher than that of patients with other internal diseases (3.37 +/- 2.81 and 3.83 +/- 3.14; both P < .001). Negative predictors of quality of life were: pain (physical condition, beta = -0.225; P < .001); fatigue (physical condition, beta = -0.298; P < .001; and mental condition, beta = -0.319; P < .001). Risk factors for anxiety were: young age (beta = -0.059; P = .035); pain (beta = 0.025; P = .028); or fatigue (beta = 0.029; P = .004). Risk factors for depression were: xeroderma (beta = 0.030; P = .003); pain (beta = 0.022; P = .047); or fatigue (beta = 0.033; P = .001).Patients with pSS have a low quality of life with anxiety and depression. Pain and fatigue are primary factors for lower quality of life, which cause more anxiety and depression. PMID- 29390344 TI - Van Buchem disease: First case report in Taiwan. AB - RATIONALE: Van Buchem disease (VBD) is a very rare autosomal recessive disease. According to our review of the relevant literature, this article is the first case report of VBD in Taiwan. PATIENT CONCERNS: A 54-year-old woman developed a protruding chin, frontal bossing, and macrocephaly at the age of 40 years. She noted the onset of progressive bilateral visual and hearing impairment at the age of 40 and 45 years, respectively. Intermittent headaches, peripheral facial palsy, recurrent bilateral trigeminal neuralgia, and back pain were also observed since age 40. DIAGNOSES: She received a diagnosis of VBD based on the phenotypic abnormalities of the skull and mandible, facial nerve involvement, radiological images of the skeleton, and her family history. INTERVENTIONS: She received symptomatic treatment and surgical decompression for spinal stenosis. OUTCOMES: Her clinical condition did not improve satisfactorily. LESSONS: We hope to promote clinician awareness of this very rare disease and its symptoms and signs. A comprehensive understanding of VBD might lead to the development of a curative therapy in the future. PMID- 29390345 TI - A case of immunoglobulin G4-related lung disease with bilateral diffuse infiltration: A case report. AB - RATIONALE: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a rare and chronic progressive autoimmune disease. It is a novel clinical entity characterized by elevated serum IgG4 concentration and tissue infiltration by IgG4 plasma cells. IgG4-related lung disease (IgG4-RLD) has been described as interstitial pneumonia and inflammatory pseudotumor, with various abnormal radiographic patterns. We report a case of IgG4-related lung disease with bilateral diffuse infiltration. PATIENT CONCERNS: A 65-year-old woman was admitted to our hospital because of cough, sputum, and fever. Chest computed tomography (CT) revealed multifocal areas of consolidations, nodules, and ground glass opacities in both lungs. She still had fever after anti-infective therapy. DIAGNOSES: Bronchial bronchoscopy and percutaneous lung biopsy were performed, resulted in a pathological diagnosis of IgG4-RLD. INTERVENTIONS: The patient was started on oral prednisolone 30 mg/day for 28 days, and then was gradually tapered. OUTCOMES: After one week treatment, the temperature was stable, CT showed significant improvement in the areas of consolidations and nodules. LESSONS: It is a typical case of IgG4-RLD. This case indicated that suggestive evidence, radiological appearances, serum tests, pathological characteristics, and classic therapy IgG4-RLD. It is a rare disease that needs our more attention in future. PMID- 29390346 TI - Pipkin type III femoral head fracture-dislocation combined with complicated acetabular fracture: A rare case report and literature review. AB - RATIONALE: Pipkin III fracture, which is characterized by high risk of avascular necrosis of the femoral head, is extremely rare. It is more difficult to treat and has a worse prognosis when accompanied with severe acetabular fractures. Few studies show that both Pipkin type III femoral head fracture-dislocation and complicated acetabular fracture presented in one patient. PATIENT CONCERNS: A 34 year-old male suffered a terrible traffic accident with a serious damage to the left side when he was sitting in the car's cockpit. Pelvic radiograph and 3 dimensional reconstruction of computed tomography revealed characteristics of fractures before the emergency operation. DIAGNOSIS: Pipkin III fractures combined with complicated acetabular fracture. INTERVENTIONS: Firstly, we used combined anterior and posterior approach for treatment to fix the femoral head fractures. Then, we completed anatomical reduction of fractures with countersunk head screw, hollow screw, and reconstruction plate. OUTCOMES: At the 12-months follow-up, the patient could walk freely and perform activities of daily living without necrosis of femoral head and heterotopic ossification. LESSONS: Although there are serious complications in Pipkin III fractures combined with complicated acetabular fracture, early surgical treatment with appropriate approach and fixation could get satisfactory results. PMID- 29390347 TI - Transcatheter closure of a huge iatrogenic atrial septal defect: A case report. AB - RATIONALE: Iatrogenic atrial septal defects caused by cardiac surgery are rare complications that are traditionally repaired through reoperations; unfortunately, reoperations are accompanied by high risk and trauma. PATIENT CONCERNS: Herein, we report a rare case of a huge atrial septal defect after mitral and aortic mechanical valve replacement. DIAGNOSES: Transesophageal echocardiography revealed a 20 * 33 mm atrial septal defect with a mainly left-to right shunt and bidirectional shunt. INTERVENTIONS: The defect was successfully occluded using a Shape Memory septal occlude with a waist diameter of 42 mm. OUTCOMES: At follow-up 6 months after, the patient's symptoms were remarkably relieved and chest radiograph showed obvious improvement of the pulmonary congestion. LESSONS: Percutaneous device treatment can be used as an alternative to surgery in iatrogenic atrial septal defects if the anatomical condition of the septal defect is appropriate for transcatheter closure. PMID- 29390348 TI - Utility of KRAS mutational analysis in the preoperative diagnosis of synchronous pancreatic cancer and intrahepatic cholangiocarcinoma: A case report. AB - RATIONALE: It is often challenging to discriminate between intrahepatic cholangiocarcinoma (ICC) and metastatic liver tumors, especially when the hepatic tumor is small and of a mass-forming type. PATIENT CONCERNS: We report a 69-year old woman presented at our hospital with a small solid tumor in the head of the pancreas that was previously discovered during a medical checkup. DIAGNOSES: The patient was diagnosed with synchronous pancreatic cancer and ICC. INTERVENTIONS: The patient underwent clinical, histological, immunohistological, and KRAS mutational analysis. OUTCOMES: Computed tomography revealed poorly enhanced small nodules in both the pancreatic head and liver. Biopsies of both nodules revealed adenocarcinoma; however, it was unclear whether the hepatic lesion was a metastasis of the pancreatic tumor or primary ICC. KRAS mutational analysis from FFPE biopsy samples revealed a discordance of mutation status between the tumors. Therefore, the patient was diagnosed with synchronous pancreatic cancer and ICC, whereupon she underwent hepatopancreatoduodenectomy. LESSONS: KRAS mutational analysis of FFPE biopsy samples can be utilized for differentiating between ICC and metastatic liver tumor. PMID- 29390349 TI - Sjogren's syndrome manifesting as clinicopathological features of TAFRO syndrome: A case report. AB - RATIONALE: TAFRO syndrome is a newly proposed disorder that manifests as thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. In this report, we describe the development of severe TAFRO syndrome-like systemic symptoms during the clinical course of juvenile-onset Sjogren's syndrome in a 32-year-old woman. PATIENT CONCERNS: The patient was admitted due to dyspnea, fever, polyarthralgia, and generalized edema. She had been diagnosed with Sjogren's syndrome at the age of 14 years, based on histopathological examination of a biopsy of the minor salivary glands and the development of Raynaud's phenomenon, with no follow-up treatment required. On admission, she presented with anemia, elevated C-reactive protein levels, anasarca, and hepato-splenomegaly. A bone marrow examination revealed increased megakaryocytes with reticulin fibrosis, and the histopathology of an axillary lymph node was consistent with mixed-type Castleman disease. Eventually, she developed thrombocytopenia. INTERVENTIONS: Her symptoms fulfilled all of the major and minor categories of the diagnostic criteria for TAFRO syndrome. However, considering her prior diagnosis, we assumed that the clinical presentation was consistent with an acute exacerbation of Sjogren's syndrome. Unlike typical cases of TAFRO syndrome, the administration of relatively low-dose prednisolone relieved her symptoms. LESSONS: Differentiation between TAFRO syndrome and exacerbation of an autoimmune disease is clinically important, although this can be challenging. Identification of specific biomarkers for TAFRO syndrome would be clinically beneficial. PMID- 29390350 TI - Poorer prognosis in patients with advanced gastric squamous cell carcinoma compared with adenocarcinoma of the stomach: Case report. AB - RATIONALE: Primary squamous cell carcinoma (SCC) of the stomach is a rare disease. The pathogenesis and prognosis of advanced SCC remains to be elucidated. The aim of the current study was to investigate the prognosis of recurrent or metastatic SCC of the stomach. PATIENT CONCERNS: A retrospective study examined the clinical characteristics and survival outcomes of 14 patients diagnosed with recurrent or metastatic SCC of the stomach, including 7 patients followed up in the hospital and 7 patients selected from the PubMed and Chinese National Knowledge Infrastructure (CNKI) database with meta-analysis between January 2003 and January 2016. DIAGNOSES: All patients meet the following diagnoses criteria: histological diagnosis of gastric squamous cell carcinoma; the tumor must not be located in the cardia area or extend into the esophagus; presence of local relapse or distant metastases of gastric SCC in computed tomography (CT) images; and no evidence of secondary SCC in the body. Clinical pathological data and follow-up data were obtained from the medical record or case report of each patient. INTERVENTIONS: Palliative chemotherapy was administered in 14 patients diagnosed with recurrent or metastatic gastric SCC. OUTCOMES: The median age of 14 patients (10 males and 4 females) was 61 years old (range, 28-76). In total, 57% (8/14 cases) of tumors were located on the lesser curvature side of the stomach and 64% (9/14 cases) of metastatic sites were identified in the liver. All patients received systemic chemotherapy, and their median survival was 7.0 months (range, 2.0-22.3 months). LESSONS: The median survival of patients with advanced gastric SCC was shorter than the median survival (11 months) of advanced gastric adenocarcinoma, suggesting that advanced gastric SCC may have a poorer prognosis compared with adenocarcinoma of the stomach in recurrent or metastatic stage. PMID- 29390351 TI - Chinese herbal medicine for patients with atrial fibrillation: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Atrial fibrillation (AF) is the most clinically common cardiac arrhythmia. Chinese herbal medicine (CHM) has been widely applied in the treatment of AF, However, to our knowledge, there has been no systematic review and meta-analysis of randomized controlled trails (RCTs) regarding the effectiveness of this treatment. Therefore, we provide a protocol to evaluate the effectiveness and safety of CHM for AF. METHODS: The databases reviewed to collect RCTs related to CHM treatment for AF will be as follows: 3 English literature databases, which are PubMed, Embase, and Cochrane Library, and 3 Chinese literature databases, which are CBM, CNKI, and Wanfang. The data collection in the above-mentioned databases will be from the time when the respective databases were established to December 2017. The maintenance of sinus rhythm and p-wave dispersion will be accepted as the primary outcomes. Quality of life (QOL), such as QOL scale embolic events, bleeding events, and symptom improvement (such as chest distress, palpitations, etc) will be measured as secondary outcomes. Two reviewers will independently screen the titles, abstracts, or even full texts, and extract data. Methodological quality will be evaluated according to the Cochrane risk of bias. All analyses will be applied by RevMan (version 5.3). RESULTS: The results of study will be disseminated via both international conference and peer-review journal. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether CHM is an effective intervention for patient with AF. PMID- 29390352 TI - Coronary artery aneurysm combined with other multiple aneurysms at multiple locations: A case report and systematic review. AB - BACKGROUND: Coronary artery aneurysm (CAA) with concomitant aneurysms at multiple sites is quite unusual and rare. The characteristics and the etiology of this phenomenon are unknown. METHODS: Herein, we present a case with right coronary aneurysm with concomitant abdominal aorta as well as right renal artery aneurysm. A systematic review of the literatures regarding CAA with other coexisting aneurysms at multiple locations was also conducted on Medline and Embase databases. RESULTS: A total of 76 patients (male gender: 58; age: 37.4 +/- 26.5) including the present case were included in the final study. The most common etiology of CAA with multiple aneurysms was Kawasaki (43.3%) and atherosclerotic disease (16.4%). CAA was the most frequently found at the right coronary artery (62.7%), following, left anterior descending (51%), left main (43.1%), and left circumflex (35.3%). The most common concomitant aneurysms were abdominal aorta (52.6%) and iliac artery (50%). In addition, 60.5% of the patients had an involved bilateral peripheral artery. CONCLUSION: CAA with coexisting systemic aneurysms in multiple sites is quite rare. And it usually involves multiple aneurysms at the coronary and bilateral peripheral arteries simultaneously. Currently, there are no general consensus regarding the clinical characteristics, diagnostic method, and treatment of these cases. PMID- 29390353 TI - Associations between height and blood pressure in the United States population. AB - The mechanisms linking short stature with an increase in cardiovascular and cerebrovascular disease risk remain elusive. This study tested the hypothesis that significant associations are present between height and blood pressure in a representative sample of the US adult population.Participants were 12,988 men and women from a multiethnic sample (age >= 18 years) evaluated in the 1999 to 2006 National Health and Nutrition Examination Survey who were not taking antihypertensive medications and who had complete height, weight, % body fat, and systolic and diastolic arterial blood pressure (SBP and DBP) measurements; mean arterial blood pressure and pulse pressure (MBP and PP) were calculated. Multiple regression models for men and women were developed with each blood pressure as dependent variable and height, age, race/ethnicity, body mass index, % body fat, socioeconomic status, activity level, and smoking history as potential independent variables.Greater height was associated with significantly lower SBP and PP, and higher DBP (all P < .001) in combined race/ethnic-sex group models beginning in the 4th decade. Predicted blood pressure differences between people who are short and tall increased thereafter with greater age except for MBP. Socioeconomic status, activity level, and smoking history did not consistently contribute to blood pressure prediction models.Height-associated blood pressure effects were present in US adults who appeared in the 4th decade and increased in magnitude with greater age thereafter. These observations, in the largest and most diverse population sample evaluated to date, provide support for postulated mechanisms linking adult stature with cardiovascular and cerebrovascular disease risk. PMID- 29390354 TI - Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults. AB - Elevated serum fetuin-B is suggested to be associated with insulin resistance, but it is unknown if this association is causal. The aim of this study was to explore the potential causal relationship between fetuin-B and insulin resistance.We used Mendelian randomization analysis by incorporating information of genetic variants in FETUB and serum fetuin-B concentrations with insulin resistance in 1148 obese Chinese adults.Common genetic variants (FETUB rs4686434, rs6785067, and rs3733159) were significantly associated with serum fetuin-B concentrations but not with insulin resistance. Higher serum fetuin-B levels were significantly associated with increased homeostasis model assessment of insulin resistance (HOMA-IR) (0.17 [95%CI: 0.01 to 0.32, P = .037] 10 mol IU L higher per SD). However, Mendelian randomization analysis using 3 single-nucleotide polymorphisms as instrumental variables did not support a significant association between genetically predicted fetuin-B levels and HOMA-IR (-0.09 [95%CI: -0.62 to 0.44, P = .738] 10 mol IU L lower per SD). The regression coefficients for measured and genetically predicted fetuin-B concentrations on HOMA-IR were significantly different (P <.001).This study suggests the association between fetuin-B and insulin resistance may not be causal. Future studies on the nongenetic determinants of serum fetuin-B concentration to assess if such unmeasured factors may confound the association between fetuin-B and insulin resistance as well as more pathway analysis for this association are warranted. PMID- 29390355 TI - A case report of congenital scoliosis associated with situs inversus totalis. AB - RATIONALE: Situs inversus totalis is a rare anomaly disease in which the organs in the chest and abdomen are positioned in a mirror image reversal of normal positions. Although this has been confirmed to be associated with spinal abnormalities, reports about situs inversus totalis with congenital scoliosis remain limited. PATIENT CONCERNS: We present a 9-year-old girl having congenital scoliosis associated with situs inversus totalis. DIAGNOSES: She also had other associated anomalies: ventricular septal defect, mild restrictive ventilatory dysfunction, hydronephrosis, and syringomyelia. Her preoperative Cobb angle (T11 L3) was 78 degrees . INTERVENTIONS: She received single growing rods treatment and subsequent posterior spinal fusion correction surgery for her scoliosis. OUTCOMES: The coronal Cobb angle of the main curve was corrected to 20 degrees postoperatively and no obvious loss of spinal corrective angle was identified 1 year after the correction surgery. LESSONS: Growing rods technique could be a safe and effective alternative for the treatment of scoliosis associated with situs inversus totalis. In the correction of left-sided lumbar curve of this kind of patients, the risks of aorta impingements should not be neglected when placing pedicle screws on the concave sides. PMID- 29390356 TI - Risk factors for death in septic shock: A retrospective cohort study comparing trauma and non-trauma patients. AB - The aim of this study was to compare septic shock directly associated-mortality between severe trauma patients and nontrauma patients to assess the role of comorbidities and age. We conducted a retrospective study in an intensive care unit (ICU) (15 beds) of a university hospital (928 beds). From January 2009 to May 2015, we reviewed 2 anonymized databases including severe trauma patients and nontrauma patients. We selected the patients with a septic shock episode. Among 385 patients (318 nontrauma patients and 67 severe trauma patients), the ICU death rate was 43%. Septic shock was directly responsible for death among 35% of our cohort, representing 123 (39%) nontrauma patients and 10 (15%) trauma patients (P < 0.0). A sequential organ failure assessment score above 12 (odds ratio [OR]: 6.8; 95% confident interval (CI) [1.3-37], P = 0.025) was independently associated with septic shock associated-mortality, whereas severe trauma was a protective factor (OR: 0.26; 95% CI [0.08-0.78], P = 0.01). From these independent risk factors, we determined the probability of septic shock associated-mortality. The receiver-operating characteristics curve has an area under the curve at 0.76 with sensitivity of 55% and specificity of 86%. Trauma appears as a protective factor, whereas the severity of organ failure has a major role in the mortality of septic shock. However, because of the study's design, unmeasured confounding factors should be taken into account in our findings. PMID- 29390357 TI - Association between rs11200014, rs2981579, and rs1219648 polymorphism and breast cancer susceptibility: A meta-analysis. AB - BACKGROUND: Research on the polymorphism of breast cancer (BC) helps to search the BC susceptibility gene for mass screening, early diagnosis, and gene therapy, which has become a hotspot in BC research field. Previous studies have suggested associations between rs11200014, rs2981579, and rs1219648 polymorphisms and cancer risk. The aim of this study was to evaluate the relationship between rs11200014, rs2981579, and rs1219648 polymorphism and BC risk. METHODS: PubMed, Web of science, and the Cochrane Library databases were searched before October 11, 2015, to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Sensitivity and subgroup analyses were conducted. All included cases should have been diagnosed by a pathological examination. RESULTS: Twenty-six studies published from 2007 to 2015 were included in this meta-analysis. The pooled results showed that there was a significant association between all the 3 variants and BC risk in any genetic model. When stratified by Source of controls, the results showed the same association between rs2981579 polymorphism and BC susceptibility in hospital-based (HB) group, although there was not any genetic model attained statistical correlation in population-based (PB) group. Subgroup analysis was performed on rs1219648 by ethnicity and Source of controls, and the effects remained in Asians, Caucasians, HB, and PB groups. CONCLUSION: This meta-analysis of case-control studies provides strong evidence that fibroblast growth factor 2 (FGFR2; rs11200014, rs2981579, and rs1219648) polymorphisms are significantly associated with the BC risk. For rs2981579, the association remained in hospital populations, while not in general populations. For rs1219648, the association remained in Asians, Caucasians, hospital populations, and general populations. However, further large-scale multicenter epidemiological studies are warranted to confirm this finding and the molecular mechanism for the associations need to be elucidated in future studies. PMID- 29390358 TI - Prognostic value of postdiagnostic inflammation-based scores in short-term overall survival of advanced pancreatic ductal adenocarcinoma patients. AB - The prognostic relevance of commonly used composite inflammation-based scores remains severely underdiscussed in pancreatic cancer (PC), especially for advanced PC. In this retrospective cohort study, we aimed to discuss the association between multiple inflammatory scores and the short-term overall survival (OS) of advanced pancreatic ductal adenocarcinoma (PDAC) patients. A total of 66 histologically confirmed PDAC patients were retrospectively analyzed. A multivariate Cox proportional hazards model was used to explore the association between 6 commonly used inflammatory scores measured right after diagnosis, Glasgow Prognostic Score (GPS), Modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), prognostic nutritional index (PNI), and the short-term OS of advanced PDAC. Analytical results revealed that among GPS, mGPS, NLR, PLR, PI and PNI only PLR was significantly associated with short-term OS of PDAC. For both 1-year and 2-year OS, every 10 increase of PLR value resulted in 1.10 (95% CI: 1.04, 1.16) folds hazard ratio (HR). Further analysis identified a statistically significant dose-response relationship between PLR and HR. Our study results probably suggested that PLR is a promising prognostic factor of advanced PDAC; maintaining normally ranged platelet count may gain short-term survival benefit among such patients. PMID- 29390359 TI - Dietary patterns associated hyperuricemia among Chinese aged 45 to 59 years: An observational study. AB - In our literature research, we have not found any study reporting the association between the major dietary patterns and the risk of hyperuricemia in a middle-aged Chinese population. Herein, the present study aimed to evaluate the association of dietary patterns with the risk of hyperuricemia in the city of Hangzhou, Zhejiang Province, East China. We included 1204 participants (743 males and 461 females) aged 45 to 59 years in the present cross-sectional study. Dietary intake was assessed using a semiquantitative food frequency questionnaire in 2014 to 2016. All biochemical data and anthropometric measurements were collected following standardized procedures. Dietary patterns were determined by using factor analysis. We examined the associations between major dietary patterns and hyperuricemia risk by log-binominal regression analysis, and the results are presented as prevalence ratio (PR) and confidence interval (CI). Three major dietary patterns were identified by means of factor analysis: traditional Chinese, meat food, and mixed food patterns. After controlling for potential confounders, subjects in the highest quartile of the traditional Chinese pattern scores had a lower PR for hyperuricemia (PR = 0.82; 95%CI: 0.426-0.922), in comparison to those from the lowest quartile, while compared with the lowest quartile of the meat food pattern, the highest quartile had a greater PR for hyperuricemia (PR = 1.48; 95%CI: 1.120-2.097). Besides, no association was observed between mixed food pattern and the risk of hyperuricemia.Our findings indicate that the traditional Chinese pattern is associated with a decreased risk of hyperuricemia, and the meat food pattern is associated with an increased risk of hyperuricemia, whereas the mixed food pattern shows no association with the risk of hyperuricemia. Further large prospective studies are warranted to confirm our findings. PMID- 29390360 TI - Impact of tumor size on outcome after stereotactic body radiation therapy for inoperable hepatocellular carcinoma. AB - Stereotactic body radiation therapy (SBRT) for inoperable hepatocellular carcinoma (HCC) offers excellent local control rates. This study retrospectively analyzed the influence of different tumor size on treatment outcomes after SBRT.Between December 2008 and February 2014, 141 HCC patients were treated with Cyberknife SBRT. Patients were divided into 3 groups namely small tumors (<=4 cm), intermediate-sized (>4-<10 cm), and large (>=10 cm) tumors. Treatment outcomes, prognoses, and safety at each tumor size were compared and analyzed.A total of 52 patients with small tumors, 55 with intermediate tumors, and 34 patients with large tumors were retrospectively analyzed with a median follow-up of 16 months. Objective responses were achieved at 96.15%, 90.90%, and 76.47% for small, intermediate, and large tumors, respectively (P <= .0001) and the 3-year local control rates were 97.85%, 71.99%, and 82.14%, respectively (P = .0035). The 3-year overall survival rates were 50.26%, 45.29%, and 33.38% for small, intermediate, and large tumors, respectively (P = .3757). No significant differences were found in overall-survival, intra-hepatic recurrence free survival, disease-progression free survival, or distant metastasis-free survival.SBRT offers the best effective local control rate and response rate for small HCCs. However, tumor size did not significantly affect the overall survival rate, intra-hepatic recurrence free rate, or disease-progression free rate. PMID- 29390361 TI - Comparison of the efficacy of intravitreal ranibizumab for choroidal neovascularization due to pathological myopia with and without a dome-shaped macula. AB - Ranibizumab injection in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia (PM) with and without a dome-shaped macula (DSM).Prospective observational study.A total of 24 patients (24 eyes) with angiographic evidence of CNV secondary to PM were divided into 2 groups: eyes with a DSM and eyes without DSM. All patients received a baseline intravitreal ranibizumab injection. Additional injections were considered at each follow-up visit. Best-corrected visual acuity (BCVA) and optical coherence tomography were tested monthly through 12 months of follow-up. The mean changes in BCVA, central retinal thickness (CRT, including retinal and CNV thickness), and the number of injections were evaluated.There were no significant differences in visual outcomes between the groups over 12 months (P > .05). Patients with a DSM had a mean change in BCVA of +8.7 letters compared with +14.2 letters in patients without a DSM (P = .68). However, there were more patients without a DSM who gained at least 15 letters from baseline compared with patients with a DSM. By the end of the follow-up, there was no significant difference in the mean change in baseline CRT between patients with and without a DSM (-65.0 and -90.7, respectively, P = .42). The mean number of injections was 8.83 in the patients with DSM and 8.17 in the patients without a DSM (P > .05).For the pathological myopia patients who had CNV with a DSM, the DSM did not alter the effect of the ranibizumab treatment. There was no difference in the visual improvement, anatomic benefit and number of treatments between the 2 groups. PMID- 29390362 TI - Malignant transformation of glucagonoma with SPECT/CT In-111 OctreoScan features: A case report. AB - RATIONALE: Glucagonoma is an uncommon disease but it has been associated with a pattern of symptoms defined as glucagonoma syndrome. These symptoms, if promptly recognized, could help to speed up the diagnosing process. PATIENT CONCERNS: We report a case of a 68-year-old woman with a pancreatic glucagonoma. Her symptoms at the onset were typical of the glucagonoma syndrome. DIAGNOSES: After a significant weight loss, she underwent a computer tomography scan of the abdomen, which showed a hypervascular lesion of the tail of the pancreas and hypervascular lesions of the liver. An ultrasound guided biopsy was performed and pathology was consistent with glucagonoma. Her blood glucagon levels were elevated. OUTCOMES: She was treated with chemotherapy and somatostatin analogs. After 4 years, the disease had a malignant transformation, and metastases suddenly started to grow up. She stopped being responsive to treatment and eventually passed away. LESSONS: Due to its rarity, clinical diagnosis is challenging and generally it comes after a long interval since the onset of symptoms. Awareness of physicians and dermatologists of the characteristic necrolytic migratory erythema, and of the other symptoms, often leads to early diagnosis. PMID- 29390363 TI - Ruptured secondary abdominal pregnancy after primary laparoscopic treatment for tubal pregnancy: A case report. AB - INTRODUCTION: Most secondary abdominal pregnancies happen after spontaneous abortion of tubal pregnancy or ruptured intrauterine pregnancy. However, we presented a case of ruptured secondary abdominal pregnancy after primary laparoscopic treatment of tubal pregnancy. CASE REPORT: The ectopic pregnant lesion in the affected tube was thoroughly removed in the primary laparoscopy, and nothing abnormal was detected in abdomen or pelvis. Beta human chorionic gonadotropin levels dropped significantly after surgery, but the patient came back again for severe abdominal pain with beta human chorionic gonadotropin increasing, and free peritoneal fluid in the pouch of Douglas was detected at ultrasonography. The secondary laparoscopy was done according to the intraperitoneal hemorrhage and unstable vital signs. The secondary pregnancy was found ruptured in the splenic flexure of the colon. Although several cases of secondary abdominal pregnancies were reported in the literature, herein we describe a case secondary to the salpingotomy of the primary tubal pregnancy. CONCLUSION: After surgery for ectopic pregnancy, the patient's serum beta human chorionic gonadotropin levels should be closely followed until negative. When persistent ectopic pregnancy was suspected after surgery, physicians should keep in mind a rare possibility of secondary abdominal pregnancy. PMID- 29390364 TI - Silent aspiration in infants with Prader-Willi syndrome identified by videofluoroscopic swallow study. AB - Feeding intolerance in Prader-Willi syndrome (PWS) infants is well-recognized, but their swallow physiology is not well understood. Swallow dysfunction increases risks of respiratory compromise and choking, which have a high incidence in PWS. To investigate swallow pathology in PWS infants we undertook a retrospective review of videofluoroscopic swallow studies (VFSS) in infants with PWS seen at our institution. We hypothesize that VFSS will characterize swallow pathology suspected by clinical observation during a feeding evaluation and may help determine feeding safety in these infants.Retrospective review of 23 VFSS on 10 PWS infants (average age 9.7 +/- 8.4 months; range 3 weeks-29 months). Logistic regression models evaluated associations between gender, genetic subtype, and growth hormone (GH) use on aspiration incidence. Polysomnographic (PSG) studies conducted on the same participant +/-1 year from VFSS were examined to characterize respiratory abnormalities.There was a high rate of swallowing dysfunction (pharyngeal residue 71%, aspiration events 87%) and disordered sleep. All aspiration events were silent. There were no differences in rates of aspiration for gender, genetic subtype, or GH use.A high incidence of aspiration was identified indicating swallow dysfunction may frequently be present in infants with PWS. Comprehensive evaluation of feeding and swallowing is essential and requires a multidisciplinary approach. Providers should recognize risk factors for swallow dysfunction and consider a multidisciplinary approach to guide decision making and optimize feeding safety in PWS. PMID- 29390365 TI - Bilateral acute myopia and angle closure glaucoma induced by Ma-huang (Ephedra): A case report. AB - RATIONALE: Cases of bilateral acute angle closure have been reported after use of various drugs. PATIENT CONCERNS: A 52-year-old woman visited the emergency room and complained of acute bilateral ocular pain and decreased vision accompanied by headache, nausea, and vomiting. One day before, she had started a herbal medicine containing Ma-huang for weight loss. On examinations, myopic shift, edematous cornea, increased intraocular pressure, shallow anterior chamber, and thickened choroid on both eyes were observed. DIAGNOSES: Angle closure glaucoma induced by drug (Ma-huang). INTERVENTIONS: To promptly quit the offending drug and apply ocular hypotensives and cycloplegics. OUTCOMES: Her symptoms and signs were relieved after antiglaucoma medications and no significant recurrence has been occurred. LESSONS: Physicians prescribing weight loss medications containing Ma huang must be aware of the potentially sight-threatening adverse effect of bilateral acute angle closure. PMID- 29390366 TI - First case report of retroperitoneal metastasis of fascioliasis after surgery. AB - RATIONALE: Fascioliasis is a rare cause of liver abscesses, and its clinical course consists of hepatic phase and biliary phase. PATIENT CONCERNS: We describe a 58-year-old female patient who presented with a 2-month history of intermittent fever and abdominal pain. An abdominal computed tomography (CT) revealed confluent low-density lesions in the liver. Complete surgical resection of these abscesses was performed, and postoperative pathological examination and serological tests confirmed a diagnosis of fascioliasis. However, 4 months after the surgery, follow-up CT revealed a lesion in the retroperitoneal area. Meanwhile, ultrasonography-guided percutaneous needle biopsy of the retroperitoneal lesion was performed, and a parasitic infection was suspected. DIAGNOSES: Retroperitoneal metastasis of hepatic phase fascioliasis. INTERVENTIONS: The patient received parasitic resistance treatment with triclabendazole at a dose of 10 mg/kg/d for 2 consecutive days. OUTCOMES: After 2 courses of triclabendazole therapy, the retroperitoneal metastasis regressed to a minor lesion. LESSONS: To the best of our knowledge, this is the first case report of retroperitoneal metastasis of fascioliasis, aimed at helping recognize the clinical features and treatment options of this rare disease. PMID- 29390367 TI - Targeted therapy with apatinib in a patient with relapsed small cell lung cancer: A case report and literature review. AB - RATIONALE: Small cell lung cancer (SCLC) is a lethal malignancy. Once relapsed, the disease is irreversible and most of the patients will die of cancer aggravation in 1 to 2 months. In the past several decades, little progress has been made in the systemic treatment of SCLC. Apatinib, as a novel small-molecule tyrosine kinase inhibitor specifically targeting the vascular endothelial growth factor receptor 2 (VEGFR2), has achieved progress in treatment of a variety of cancers. However, there has been no report of the targeted therapy with apatinib in SCLC yet. PATIENT CONCERNS: A 63-year-old man, an ex-smoker, presented with a slight hoarseness and cough. The patient was admitted to our department with a primary diagnosis of SCLC at an extensive stage (ES-SCLC). After 17 months of successful first-, second-, and third-line chemotherapy, the disease eventually became relapsed. Then, apatinib treatment started promptly on demand by the patient and his family. INTERVENTION: After presenting an informed consent, the patient received apatinib treatment immediately at a dose of 250 mg/day orally. OUTCOMES: (1) On the 28th day of apatinib therapy, the symptoms of dyspnea and poor appetite of the patient were notably improved. (2) The CT scan taken on the 70th day showed that the pleural effusion in the left lung almost disappeared. (3) The elevated serum neuron-specific enolase (NSE) level was decreased. The patient died of acute respiratory failure on the 172nd day of apatinib treatment. Importantly, the tumor mass did not enlarge obviously during apatinib treatment. LESSONS: Here, we presented a case with relapsed SCLC who unexpectedly responded to single-agent apatinib treatment. Therefore, this report will shed light on future studies of targeted therapy with apatinib in SCLC at different stages. PMID- 29390368 TI - A case report of hepatic abscesses with soft tissue infection caused by methicillin resistant Staphylococcus aureus in a young child. AB - RATIONALE: Pyogenic hepatic abscess in children is a rare clinical condition. Hepatic abscesses caused by methicillin resistant Staphylococcus aureus are extremely rare. PATIENT CONCERNS: A 6-year-old boy was referred to a tertiary children's hospital for a 6-day history of right lower abdominal pain and fever. Radiographic findings showed hepatic abscesses and soft tissue abscesses around the left femur. DIAGNOSES: Bacteriology of blood, hepatic abscesses, and soft tissue abscesses showed methicillin resistant Staphylococcus aureus. INTERVENTIONS: Our patient received adequate drainage of MRSA abscesses and a complete course of antibiotics. OUTCOMES: The hepatic abscesses were healed and no recurrence has been founded until now. LESSONS: This report describes an extremely rare case of hepatic abscesses with soft tissue infection caused by MRSA. Adequate drainage and appropriate systemic antibiotics should be considered as a standard treatment of MRSA abscesses in order to reduce the mortality rate and improve the quality of life. PMID- 29390369 TI - Acupuncture for vertebrobasilar insufficiency vertigo: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Vertebrobasilar insufficiency vertebrobasilar (VBIV) is a serious nerve disease and many old people suffer from it. Acupuncture has been widely applied in the treatment of VBIV. However, to our knowledge, there has been no systematic review or meta-analysis of randomized controlled trails regarding the effectiveness of this treatment. Here, we provide a protocol to evaluate the effectiveness and safety of acupuncture for VBIV. METHODS: Relevant randomized controlled trials in 5 databases (EMBASE, PubMed, the Cochrane Central Register of Controlled Trials [Cochrane Library], Chinese Biomedical Literature Database [CBM], China National Knowledge Infrastructure [CNKI]) will be comprehensively searched by 2 researchers in December 2017. The clinical efficacy will be accepted as the primary outcomes. We will also use RevMan V.5.3 software to compute the data synthesis carefully when a meta-analysis is allowed. RESULTS: This study will provide a high-quality synthesis of current evidence of acupuncture for VBIV from several aspects including clinical efficacy, the blood flow velocity of the left vertebral artery (LVA), the right vertebral artery (RVA), the basilar artery (BA)and adverse events. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether acupuncture is an effective and safety intervention for patient with VBIV. PMID- 29390370 TI - Coexisting myasthenia gravis, myositis, and polyneuropathy induced by ipilimumab and nivolumab in a patient with non-small-cell lung cancer: A case report and literature review. AB - RATIONALE: Immune checkpoint inhibitors have led to the development of new approaches for cancer treatment with positive outcomes. However, checkpoint blockade is associated with a unique spectrum of immune-related adverse events (irAEs), which may cause irreversible neurological deficits and even death. PATIENT CONCERNS: We presented a case of a 57-year-old man with non-small-cell lung cancer.who developed ptosis, dyspnea, and muscle weakness as initial symptoms with progression after the treatment with ipilimumab and nivolumab. DIAGNOSES: Myasthenia gravis was confirmed by serum acetylcholine receptor antibody and single fiber electromyography. Myositis was identified by high level of serum creatine phosphokinase and electromyography. Polyneuropathy was identified by nerve conduction study. INTERVENTIONS: The patient underwent treatment with steroid and pyridostigmine. Respiratory rehabilitation was also performed. OUTCOMES: Dyspnea and muscle weakness improved gradually. Ipilimumab and nivolumab were permanently discontinued. LESSONS: This case has increased the clinical awareness by indicating that the checkpoint inhibitors-related neurological irAEs could be complicated and simultaneously involve multiple neurological systems. Early recognition and complete evaluation are critical in clinical practice. PMID- 29390371 TI - An intradural extramedullary bronchogenic cyst in the thoracolumbar spine: A case report. AB - RATIONALE: We report the symptoms beginning with weakness and the clinical courses of a patient who was diagnosed with an intradural extramedullary bronchogenic cyst. PATIENT CONCERNS: The patient was a 44-year-old man visited the Department of Physical Medicine and Rehabilitation for walking difficulties characterized by limping due to muscle weakness of left lower extremity for 5 months and atrophy in left calf muscle. DIAGNOSES: Lumbar spine MRI was repeated, since radiating pain in the left hip and posterior thigh with low back pain developed 16 months later. Intraspinal mass of T12 and L1 levels that was not found in the first MRI was newly found in the follow-up MRI. INTERVENTIONS: Total tumor removal was conducted with laminectomy. It was finally diagnosed as an intradural extramedullary bronchogenic cyst on the basis of the pathological analysis results. OUTCOMES: His left calf circumference was increased compared to before surgery the radiating pain also disappeared. LESSONS: If the patient's MRI findings are not correlated with the electrophysiologic and physical examination findings, additional MRI should be accompanied with other tests for an early detection. PMID- 29390372 TI - Dynamic paraspinal muscle impingement causing acute hemiplegia after C1 posterior arch laminectomy: A case report. AB - RATIONALE: Acute neurological deficits following spinal surgery commonly result from epidural hematoma, surgical trauma, vascular compromise, and graft or hardware impingement, with the cause identified by magnetic resonance imaging (MRI). We present a rare case of dynamic paraspinal muscle impingement after C1 posterior arch laminectomy, which was diagnosed by myelography, with no significant findings on MRI. PATIENT CONCERNS: An 81-year-old, severely obese male, was referred to our department for the treatment of vertebral disease of the lumbar spine. The patient presented with bilateral weakness and numbness of the upper extremities and gait disturbances. Based on MRI, a diagnosis of retro odontoid pseudotumor was made, and C1 posterior arch laminectomy, in combination with C4 partial laminectomy and C5 to C6 laminoplasty, was performed. On postoperative day 3, the patient's neurological status deteriorated, with right upper extremity and right lower extremity weakness increasing with neck extension. Although there was no evidence of epidural hematoma formation on MRI, obstruction of the flow of contrast medium by an external posterior compression in neck extension at the level of C1 was identified by myelography. Revision surgery was performed and local muscle swelling at the surgical site identified with no hematoma formation. Occiput to C3 fixation, with instrumentation, was performed. OUTCOMES: Muscle strength of the right upper extremity and lower extremities recovered postsurgery, and the patient has continued to improve function 3 years after surgery, with no further neurological episodes. LESSONS: Dynamic paraspinal muscle impingement following C1 laminectomy in a muscular man was diagnosed by myelography, with no significant findings on standard MRI. CONCLUSION: The possibility of dynamic paraspinal muscle impingement should be considered in patients developing acute, progressive, neurological deficits after posterior cervical decompression, with myelography being the imaging method of choice for diagnosis. PMID- 29390373 TI - Ozone therapy induced sinus arrest in a hypertensive patient with chronic kidney disease: A case report. AB - RATIONALE: Ozone autohemotherapy as an alternative treatment method has been applied to the treatment of several diseases. Here, we report a patient used ozone autohemotherapy to treat her hypertension and diabetes. Nevertheless, the patient occurred sudden dizziness and black haze due to hyperkalemia. PATIENT CONCERNS: A 54-year-old woman who was admitted to our emergency department complaining of sudden dizziness and black haze for 5 hours. DIAGNOSES: The blood potassium test showed hyperkalemia. Upon further inquiry of her medical history, the patient received ozone autohemotherapy to treat hypertension and diabetes for 9 days prior to admission. INTERVENTIONS: The ozone therapy had been asked to stop. Insulin, sodium bicarbonate, and sodium polystyrene sulfonate were administered to the patient. OUTCOMES: After treatment, blood potassium remained in the normal range. After 3 days of treatment, the 24-hour dynamic electrocardiogram revealed sinus rhythm with an average heart rate of 82 beats/min, occasional ventricular premature beats, occasional ventricular premature beats, and no ST segment depression. LESSONS: Although ozone therapy is widely used in the treatment of several diseases, adverse reactions should be given attention in clinical practice, especially in patients with chronic kidney disease. PMID- 29390374 TI - Use of small needle knife in autologous fat grafting for the treatment of depressed scar: A case report. AB - RATIONALE: Scars always related to functional limitations, cosmetic impairment, and social and emotional problems. Clinical improvements in scar characteristics after autologous fat grafting are well described. In this paper, we present an innovative approach to treat depressed scars. PATIENT CONCERNS: We presented a 29 year-old woman with multiple depressed scars in the left upper arm and near the elbow joint after trauma in childhood. DIAGNOSES: The patient was diagnosed as having multiple depressed scars accompanied with retraction and pain. INTERVENTIONS: We used small needle knife during fat grafting to treat the depressed scar. Vancouver Scar Scale was used to assess the effect. OUTCOMES: Aesthetic and functional improvements were observed. Resolution of pain and improvement in scar elasticity were objectively assessable. Improvement of both clinical evaluation and patient perception was obtained. LESSONS: Use of small needle knife during fat grafting is a good alternative for the treatment of depressed scars. PMID- 29390375 TI - Hepatic artery embolization cures the acute pancreatitis associated with a tiny arteriobiliary fistula after TIPS: A case report. AB - RATIONALE: Esophageal variceal bleeding caused by portal hypertension is massive and life-threatening to those patients with decompensated liver cirrhosis. A transjugular intrahepatic portosystemic shunt (TIPS) can effectively stop bleeding. But the process of puncture may lead to bile duct injury and even form fistulas between the hepatic artery and bile duct. PATIENT CONCERNS: The case report illustrated a 52-year-old Chinese female patient who underwent TIPS. DIAGNOSES: She suffered from acute upper gastrointestinal hemorrhage and acute pancreatitis because of the bile duct injury after TIPS. INTERVENTIONS: The fistulas between the hepatic artery and bile duct was embolized. OUTCOMES: The acute upper gastrointestinal hemorrhage and acute pancreatitis of the patient were cured. LESSONS: The arteriobiliary fistula should be paid more attention after TIPS while early-stage prevention should be carried out. PMID- 29390376 TI - Better clinical outcomes after unicompartmental knee arthroplasty when comparing with high tibial osteotomy. AB - BACKGROUND: Both high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) are well-established treatments for medial knee osteoarthritis (OA). However, it is unclear whether HTO or UKA leads to better clinical outcomes and lower complication rates. This meta-analysis compared the clinical outcomes and complications of HTO and UKA in patients with medial knee OA. METHODS: All studies comparing the functional outcome, postoperative pain, revision rate to total knee arthroplasty (TKA), postoperative complications, postoperative velocity, and postoperative range of motion (ROM) as assessed with various measurement tools in patients with medial knee OA treated with HTO or UKA were included. RESULTS: Sixteen studies were included in the meta-analysis. The proportion of patients who underwent revision to TKA (OR 1.56, 95% CI: 0.61-3.98; P = .35) did not differ significantly between HTO and UKA. In contrast, functional outcome (OR 0.47, 95% CI: 0.24 to 0.95; P = .04), postoperative pain (OR 0.28, 95% CI: 0.12 to 0.62; P = .002), postoperative complications (OR 2.48, 95% CI: 1.26 to 4.90; P = .009), postoperative velocity (95% CI: -0.11 to -0.00; P = .03), and postoperative ROM (95% CI: 2.02 to 15.23; P = .01) were significantly different between the 2 groups. CONCLUSIONS: There were no significant differences in the revision rate to TKA between HTO and UKA. However, results from subgroup analyses suggested that opening-wedge HTO resulted in a lower revision rate to TKA than did UKA, whereas closing-wedge HTO resulted in a higher revision rate to TKA than did UKA. In addition, UKA resulted in significantly better functional outcomes and postoperative velocity, along with less postoperative pain, fewer postoperative complications, and lower postoperative ROM. Based on the findings of current meta-analysis, UKA appears to be as efficacious and safe as HTO in the treatment of medial knee OA. PMID- 29390378 TI - Early onset epileptic encephalopathy with a novel GABRB3 mutation treated effectively with clonazepam: A case report. AB - RATIONALE: Early onset epileptic encephalopathy (EOEE) is one of the most serious early onset epilepsies. The etiopathology of this condition remains unclear, and recent evidence indicated that gamma-aminobutyric acid (GABA) A receptor, subunit beta 3 (GABRB3) gene mutations might be associated with EOEE. Furthermore, the therapeutic regimen for EOEE has yet to be well elucidated. Herein, we reported the clinical and genetic features of a case with GABRB3-related EOEE. PATIENT CONCERNS: A 6-year-old girl developed epileptic seizures 3 days after birth. She presented with multiple seizure types including myoclonic seizures, spasms, and absence seizures. Serial electroencephalographic examinations showed variable abnormalities, and intellectual evaluation revealed significant development retardation. Conventional antiepileptic drugs were ineffective for the seizure controlling. Genetic screening identified a novel nonsense mutation (C.5G > A, p.W2X) in the GABRB3 gene. DIAGNOSES: Early onset epileptic encephalopathy. INTERVENTIONS: We changed the antiepileptic strategy to oral clonazepam (0.5mg twice daily). The patient was followed up once a week and significant declining in the attack frequency was noted 1 week later (2-3 times daily). Subsequently, the dosage was doubled (1mg twice daily), and complete cessation of seizures was achieved 20 days later. OUTCOMES: Through a 9-month follow up,the girl remained seizure-free. LESSONS: This study identified a novel nonsensemutation (C.5G>A) in the exon 1 of GABRB3 Gene, which may be associated with EOEE. To our knowledge, this is the first report to use clonazepam in the patient with GABRB3-related EOEE with favorable outcome. Our finding suggested that clonazepam might be a choice for patient with GABRB3-related EOEE. The remarkable efficacy of clonazepam in the control of seizures indicated a potential GABRB3- or GABA related mechanism involved in the development of EOEE. PMID- 29390377 TI - Efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with ribavirin for the treatment of HCV genotype 1b compensated cirrhosis in patients aged 70 years or older. AB - Advanced age has been a major limitation of interferon-based treatment for chronic hepatitis C virus (HCV) infection because of its poor response and tolerability. Direct-acting antiviral (DAA) drug regimens are safe and highly effective, allowing administration of treatment also in elderly. This study aims to assess the efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with ribavirin for the treatment of patients aged >=70 years with HCV genotype 1b compensated cirrhosis.A total of 1008 patients with HCV genotype 1b compensated cirrhosis were prospectively treated with PrOD + ribavirin for 12 weeks, between December 2015 and July 2016. Sustained virologic response 12 weeks after the end of treatment (SVR12), adverse effects (AEs), comorbidities, discontinuation, and death rates were recorded. Efficacy and safety of therapy were assessed in patients aged >=70 years and compared with data from patients <70 years.There were 117 patients aged >=70 years, preponderantly females (58.9%), mean age 73.3 +/- 2.8 years (range 70-82), and 37 (31.6%) were treatment-experienced. Comorbidities were reported in 60.6% of patients >=70 years and in 39.8% of those <70 years (P < .001). SVR12 rates based on intention-to-treat and per-protocol analyses were 97.4% and 100%, respectively, in patients >=70 years, compared to 97.8% and 99.6%, respectively, in patients <70 years (P = ns and P = ns). Severe AEs were reported in 4 (3.4%) patients >=70 years, compared to 23 (2.6%) in those <70 years (P = ns). One death was recorded in a patient aged 79 years (0.9%) and 6 deaths (0.8%) in those <70 years (P = ns).Treatment with PrOD + ribavirin in patients 70 years of age or older with HCV genotype 1b compensated cirrhosis proved as effective, safe, and well tolerated, as it did in younger patients. PMID- 29390379 TI - Successful coronary stenting in a patient with factor V deficiency in the absence of fresh frozen plasma transfusion: Case report. AB - RATIONALE: Drug-eluting stent (DES) implantation in a patient with factor V deficiency (F5D) is very complex. No antithrombotic therapy study has been reported for F5D patients who undergo a coronary stenting procedure. PATIENT CONCERNS: A 73-year-old woman presented with chest discomfort and exertional dyspnea. Coronary stenting was performed successfully using DES stents. DIAGNOSES: The D-dimer, prothrombin time, and partial thromboplastin time prolongation persisted from admission until 24 hours after coronary stenting. Epistaxis and blood-tinged sputum occurred on day 3. The antiplatelet therapy measured using a Multiplate Analyzer was adequate, and other laboratory findings except factor V activity (14%) were within normal ranges; she was diagnosed with F5D based on low factor V activity. INTERVENTIONS: While taking 90 mg of ticagrelor and 100 mg of aspirin daily, the patient revisited due to recurrent epistaxis, hemoptysis, and coughing on day 26. Epistaxis and hemoptysis stopped after the aspirin was discontinued. Finally, the daily maintenance dose was reduced to 90 mg of ticagrelor once. OUTCOMES: She led healthy life for 9 months without any recurrent symptoms and the test results also were stabilized. LESSONS: We report a case of an F5D patient who underwent coronary stenting in the absence of frozen fresh plasma transfusion who received successful maintenance therapy using a single antiplatelet agent (90 mg of ticagrelor/day) with recurrent multiple mucosal bleeding events after coronary stenting. PMID- 29390380 TI - Significant efficacy and well safety of apatinib combined with radiotherapy in NSCLC: Case report. AB - RATIONALE: The outcomes of locally advanced non-small cell lung cancer (NSCLC) remain poor, in particular, the frail elderly patients cannot tolerate chemotherapy. The new efficient, safe, and more specific treatments are needed. Radiation combined with targeted therapy is the focus of research in recent years. Apatinib is highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, studies have revealed that apatinib inhibit the growth of solid tumors including NSCLC. However, there is no report to evaluate its efficacy and safety in combined with radiotherapy for the advanced NSCLC. Our original research about to explore the use of apatinib combined with radiotherapy in treatment of NSCLC and its side effects are as follows. PATIENT CONCERNS: Patient 1, man, 78-year old, admitted to hospital, due to "thoracalgia and dyspnea for 1 month." Chest and abdomen computed tomography (CT) scan showed that there was a huge mass at the left upper lobe and multiple lymph nodes metastasis in mediastinum and left hilus pulmonis, the diagnosis was left lung squamous cell carcinoma, however, the mass was huge and age of patient was elder, post chemotherapy the mass were bigger and more severe. Patient 2, man, 61-year old, the diagnosis was squamous carcinoma on left upper lobe with right mediastinum lymph notes metastases recrudescence post chemoradiotherapy. DIAGNOSES: Case 1 was diagnosed left lung huge squamous cell carcinoma and case 2 was left lung squamous carcinoma, the primary lesion and right mediastinum lymph notes metastases recrudescence after radiochemotherapy. INTERVENTIONS: Both patients who received local radiation therapy and concurrent apatinib. Apatinib 250 mg once daily in combination with thoracic radiotherapy (2 Gy/d, 5 fractions/wk) followed by Apatinib Maintenance Therapy. OUTCOMES: Favorable oncologic outcomes were achieved in the 2 cases after the treatment. The common side effects of apatinib were hypertension and hand-foot syndrome; however, the toxicity of was controllable and tolerable, no dyspnea, no hemoptysis, no thoracalgia. LESSONS: Apatinib combined with thoracic radiotherapy, may be an option for recurring or advanced NSCLC. But that still warrants further investigation in the prospective study. PMID- 29390381 TI - Mesalazine as a cause of fetal anemia and hydrops fetalis: A case report. AB - RATIONALE: Mesalazine and its prodrug sulfasalazine are both used for inflammatory bowel disease. Sulfasalazine has been associated with hematological side-effects such as aplastic and hemolytic anemia in patients, but also in fetuses after intrauterine exposure. To our knowledge, we describe the first case of a fetus with severe anemia, and subsequent hydrops, where this drug was found at concentrations in the fetus corresponding to those in the mother and most likely responsible for the fetal condition. PATIENT CONCERNS: A uniparous woman was referred at 31 weeks of gestation due to a hydropic fetus with massive ascites and cardiomegaly. DIAGNOSES: The patient had Crohn's disease and was thus treated with 4 g mesalazine daily. The fetus had severe anemia with an initial hemoglobin level of 51 g/L. INTERVENTIONS: The maternal medication was discontinued and four intrauterine erythrocyte transfusions were given during three weeks. Plasma samples were drawn from mother and fetus during cordocentesis for later analysis of mesalazine. OUTCOMES: A healthy baby was born after 37 full weeks of gestation. Plasma levels of mesalazine were non-conspicuous in neither mother nor fetus. The mesalazine half-life in the fetus (37 h) was half that of the mother (80 h), both considerably longer than previously reported (about 19 h). LESSONS: A causal relationship must be suspected between the fetal anemia and the maternal use of mesalazine. This fetal side-effect should be considered in pregnant women on mesalazine (and its prodrug sulfasalazine). PMID- 29390383 TI - Stop! Check your initial assumptions: Frozen patient management in obstetrical practice. AB - At times, leaping from one patient management routine to an alternative one may be required to mitigate medical errors. "Frozen patient management" is the resultant situation, when, in the face of an obvious gap between the expected and the actual phenomena, leaping from current patient management to an alternative one is not considered or done. Frozen patient management can lead to a significant delay of the correct definitive intervention, be it surgical or pharmacological. The significance of this delay is especially important in time dependent dynamic situations. In delivery ward, this may cost the life of either the fetus or the mother.In this study, we describe a sequence in which frozen patient management occurred in the delivery ward. Using "thinking protocol" (herein termed "de-freezing" questionnaire) made the team stop and consider a leap when gaps became apparent, and saved the mother's life.We believe that adopting the "de-freezing questionnaire" as a routine adjunct for all medical activities would lead to a timely change of treatment line, which, in turn, will save lives and unnecessary suffer. PMID- 29390382 TI - Brain metastasis in a patient with melanoma receiving Pembrolizumab therapy: A case report and review of the literature. AB - RATIONALE: Melanoma with brain metastasis is associated with a poor prognosis and high mortality rate. As patients with this condition have been excluded from most clinical trials, data on the use of anti-programmed death 1 therapy for these patients are limited. PATIENT CONCERNS: The patient was a 62-year-old man with a 10-year history of melanotic nevus in his right forearm. He was admitted to another hospital in August 2015 due to the growth of the melanotic nevus over 1 year and complaint of a mass in the right mid-axillary area. The patient had no relevant medical, surgical, or family history. DIAGNOSES: The biopsy of his right axillary lymph node showed malignant melanoma. INTERVENTIONS: He was subsequently treated with adjuvant high-dose interferon after dacarbazine. Numerous metastatic lesions were found in his lung, abdomen, pelvic cavity, and brain after five months later, and then Pembrolizumab was used for six cycles (2 mg/kg every 3 weeks). He experienced immunorelated adverse events and we gave him cortisol to treat immunorelated disease until pneumonia was found. OUTCOMES: We observed a delayed effect after three cycles of Pembrolizumab, the intracranial lesion presented clear margins and localization, while the other lesions became much smaller. A mixed response was observed after four cycles, with still stable extracranial metastases but growing a new lesion in brain. After two additional cycles of Pembrolizumab, the treatment was stopped due to the patient's inability to pay for it and a decline in his performance status. He then received palliative treatment at a local hospital and died for severe pulmonary infection, with an overall survival time of 7 months from metastasis. LESSONS: In the case reported here, a delayed and mixed response was observed after Pembrolizumab was used. Because of causing severe pulmonary infection, the use of steroids should be considered carefully when treating immunorelated adverse events. It seemed that the Pembrolizumab has a positive effect on melanoma brain metastases especially combined with other treatments. However, there are still some challenges including patient selection, predictors of response, drug tolerance, optimizing combination strategies and control of adverse effects. More carefully designed clinical trials are urgently needed. PMID- 29390384 TI - Migration of a stent from left main and its retrieval from femoral artery: A case report. AB - RATIONALE: Embolization of a deployed stent is a rare complication and its mechanism remains unclear in most cases. PATIENT CONCERNS: A 52-year-old man underwent coronary angiography for effort angina, revealing an 80% stenosis of the proximal left anterior descending (LAD) involving the distal left main (LM). After luminal sizing with intravascular ultrasound two drug-eluting stents were deployed (5.0 * 12 mm and 3.5 * 15 mm) to cover the LM-LAD lesion. After postdilatation, the proximal stent had disappeared from the LM. DIAGNOSES: The missing stent was found in the right deep femoral artery. INTERVENTIONS: A new 5.0 * 15 mm stent was deployed onto the LM-LAD ostium, in overlapping with the previously implanted. Then, the stent migrated to the deep femoral artery was successfully retieved through the contralateral femoral artery. OUTCOMES: The patient was discharged 2 days later, after an uneventful hospital stay. LESSONS: Stent deformation after postdilation is a possible causes of stent migration. PMID- 29390385 TI - Esophageal neuroendocrine tumor with initial presentation as painless forehead and neck masses: A case report. AB - RATIONALE: Esophageal neuroendocrine tumors (NETs) are a rare type of esophageal tumor which are usually positive for chromogranin A, synaptophysin, and CD56 in tumor immunohistochemical staining. The most common symptoms of esophageal NETs are gastrointestinal symptoms such as dysphagia and/or abdominal discomfort. While esophageal NETs have the potential for distant metastasis, there have only been a few reports of brain metastasis originating from esophageal NET. PATIENT CONCERNS: We report the case of a 60-year-old Taiwanese female who initially presented with a 1 month history of painless forehead and bilateral neck masses. She did not complain of any other symptoms, which complicated the diagnosis. DIAGNOSES: Chest and abdominal computed tomography were arranged for a thorough evaluation, and a paraesophageal lesion as well as multiple metastases in the liver, bilateral adrenal glands, and bone were found. Panendoscopy and pathology confirmed the diagnosis of an esophageal NET. INTERVENTIONS: Best supportive care. OUTCOMES: The clinical course of this case deteriorated drastically, and she died of tumor progression 10 days after the diagnosis had been made. LESSONS: To the best of our knowledge, this is the first article in the literature to report a case of esophageal NET whose initial presentation was painless forehead and bilateral neck masses. Clinicians should be aware of the early signs and symptoms of esophageal NET to allow for a prompt diagnosis. PMID- 29390387 TI - Distribution of hemoglobin and prevalence of anemia in 10 ethnic minorities in China: A population-based, cross-sectional study. AB - Racial differences have been reported in hemoglobin (Hb). However, distributions of Hb and anemia rate in ethnic minorities were rarely reported.We aimed to observe whether there are ethnic differences in Hb distributions and prevalence of anemia.The data included 480,699 women 20 to 49 years' old from 10 ethnic minorities in China in 2014. Analyses of variance were used to examine the differences of Hb distribution among the 10 ethnic groups, as well as the differences in Hb level between different ages, education levels, occupations, and non- or ethnic enclaves in each ethnic group. chi2-test was adopted to analyze the differences in anemia rate among the 10 ethnic groups and between different ages and nonethnic or ethnic enclaves in each ethnic group.The ethnic differences of the Hb distribution and anemia prevalence were observed in the 10 ethnic groups. The lowest mean Hb concentration was shown in Chuang (126.8 g/L), and the highest mean Hb concentration was in Tibetan (138.5 g/L). According to the World Health Organization criteria to define anemia, the highest prevalence was in Tibetan (46.9%) after the adjustment of Hb concentration for altitude, and the lowest prevalence was in Yi (10.6%). Furthermore, there were differences on mean Hb concentration or anemia rate in participants between ethnic enclaves and non-ethnic enclaves in most ethnic groups.The ethnic differences of the Hb distribution and anemia prevalence were observed in the 10 ethnic groups, which might be associated with geographic conditions, genetic background, and eating habits. PMID- 29390386 TI - Hemophagocytic lymphohistiocytosis in an adult kidney transplant recipient successfully treated by plasmapheresis: A case report and review of the literature. AB - RATIONALE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease entity primarily described in children, but not less relevant in adults. It is characterized by a misdirected activation of the immune system, resulting in an uncontrolled cytokine release from macrophages and cytotoxic T-cells (CTLs). Primary HLH relies on a genetic predisposition, whereas secondary HLH develops in the context of infections, malignancies or autoimmune diseases. However, the awareness and therapeutic knowledge for HLH in adulthood is limited. Most therapy protocols are almost exclusively validated in pediatric cohorts and for primary HLH. Their transferability to adult individuals with mostly secondary HLH is doubtful. Especially the high liver and bone marrow toxicity of applied etoposide based protocols is discussed controversially and connected to overwhelming infections and death. PATIENT CONCERN: A 51-year old, male, kidney transplant recipient was admitted to our center suffering from diarrhea, fever, nausea, hyponatremia, kidney graft failure, disorientation, progressive hemodynamic instability, and multiorgan failure. DIAGNOSES: Clinical and laboratory findings resembled those of a septic shock. Ferritin and soluble interleukin-2 receptor (sCD25) levels were disproportionally elevated. Only a mild hepatosplenomegaly was diagnosed in a CT scan. A T2-weighted, fluid-attenuated inversion recovery MRI showed marked, bilateral and periventricular white matter hyperintensities. The cerebrospinal fluid (CSF) analysis showed a moderately elevated protein content and cell count. There was no evidence of any bacterial, viral, or parasitic infection. The diagnosis of HLH was made. INTERVENTIONS & OUTCOMES: The patient was successfully treated by a combined approach consisting of plasma exchange (PE), corticosteroids, anakinra, and cyclosporine (CsA). LESSONS: HLH is an important differential diagnosis in critically ill patients. Its unspecific clinical picture complicates an early diagnosis and may be misclassified as sepsis. A combination of plasma exchange (PE), corticosteroids, anakinra, and cyclosporine (CsA) may be a promising and less toxic approach for HLH therapy in adults. PMID- 29390388 TI - Bladder cancer: detection and image quality compared among iShim, RESOLVE, and ss EPI diffusion-weighted MR imaging with high b value at 3.0 T MRI. AB - To compare the detection of bladder neoplasms and image quality among the diffusion-weighted imaging (DWI) acquired by the prototype single-shot echo planar-imaging (ss-EPI) sequence for integrated slice-specific dynamic shimming (iShim), readout segmentation of long variable echo trains (RESOLVE) and conventional ss-EPI sequences.Around 63 patients with 77 bladder lesions were enrolled. The MR protocol included T1WI, T2WI and 3 types of DWI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of each DWI for the detection of bladder tumor were computed. The subjective scores of imaging quality, diagnostic confidence, and detection of tumors of stage T2 or greater were recorded. The contrast-to-noise ratio (CNR), signal intensity ratios, and apparent diffusion coefficient (ADC) values were measured. The univariate analysis of variance technique, the Friedman test, and Bland-Altman plots were used in the statistical analysis. Observer performance of tumor T stage was tested using receiver operating characteristic (ROC) curve analysis.The sensitivity, NPV, and accuracy of iShim (92.75%; 61.54%; 93.51%) for detection of bladder tumor were superior to those of RESOLVE (84.06%; 42.11%; 85.71%) and ss-EPI (86.96%; 47.06%; 88.31%). All qualitative scores of iShim were higher than RESOLVE (all P < .05) and ss-EPI (all P < .05). The CNR, signal intensity ratios between bladder lesion and urine, lesion, and submucosal stalk (or nearby normal bladder wall), and between distal normal bladder wall and urine of iShim (39.84 +/- 12.11, 2.40 +/- 0.60, 1.98 +/- 0.43, 1.28 +/- 0.16) were higher than RESOLVE (16.97 +/- 7.08, 1.62 +/- 0.41, 1.52 +/- 0.42, 1.15 +/- 0.29, all P < .05) and ss-EPI (27.89 +/- 9.65, 1.66 +/- 0.46, 1.57 +/- 0.50, 0.99 +/- 0.22, all P < .05). No significant difference of ADC values were found for iShim and RESOLVE (P=0.46), iShim, and ss-EPI (P = 0.97), RESOLVE and ss-EPI (P = .48). The Az value for the detection of tumors of stage T2 or greater was slightly higher with the iShim DWI sequence (0.89) than with the RESOLVE (0.87, P = 0.72) or ss-EPI (0.85, P = .38) sequence.The iShim DWI has relatively better detection of bladder tumor and image quality without significant ADC value difference. PMID- 29390389 TI - Treatment-related acute granulocyte-monocytic leukemia from multiple myeloma: A case report and literature review. AB - RATIONALE: To investigate the clinical features of treatment-related acute granulocyte-monocytic leukemia (t-AML) from multiple myeloma (MM) thereby improving the understanding of this disease. PATIENT CONCERNS: A 72-year-old woman patient was initially diagnosed as MM. Two years and 7 months after treatment, this patient developed AML M4 as confirmed by the analyses from clinical features, bone marrow morphology, flow cytometry, and cytogenetic examination. DIAGNOSIS: Treatment-related acute myeloid leukaemia (t-AML). INTERVENTIONS: Due to lack of the ability to pay the cost, she declined our recommendation to accept therapy as an inpatient and was discharged. LESSONS: The reported case was a rare t-AML, which is resistant to currently available treatments and has a poor prognosis. PMID- 29390390 TI - Massive trapezial metastasis from gastric adenocarcinoma resected and reconstructed with a vascularized scapular bone graft: A case report. AB - RATIONALE: Isolated metastasis to the hand bones is very rare. Only seven cases of metastasis to the trapezium have been reported. To the best of our knowledge, this is the first report of a single metastasis to the trapezium from a gastric adenocarcinoma. PATIENT CONCERNS: A 62-year-old man presented with pain and massive swelling in the right carpometacarpal joint of the thumb. DIAGNOSES: The patient was diagnosed with trapezial metastasis of advanced gastric adenocarcinoma. INTERVENTIONS: The patient underwent systemic chemotherapy with cisplatin and S-1, radiotherapy to the metastatic bone, and treatment with denosumab. One year later, the huge metastatic tumor was resected, and the hand was reconstructed using vascularized scapular bone. OUTCOMES: Eighteen months postoperatively, the patient was satisfied with the appearance of the reconstructed hand and was able to use his right thumb in activities of daily living. LESSONS: Although rare, metastasis to the trapezium should be considered in patients with persistent and progressive thumb CMC joint pain. PMID- 29390392 TI - The treatment strategies for spine fractures in patients with ankylosing spondylitis: A case report: Erratum. PMID- 29390391 TI - The combination assessment of lipid pool and thrombus by optical coherence tomography can predict the filter no-reflow in primary PCI for ST elevated myocardial infarction. AB - The usefulness of distal protection devices is still controversial. Moreover, there is no report on thrombus evaluation by using optical coherence tomography (OCT) for determining whether to use a distal protection device. The aim of the present study was to investigate the predictor of filter no-reflow (FNR) by using OCT in primary percutaneous coronary intervention (PCI) for ST-elevated acute myocardial infarction (STEMI).We performed preinterventional OCT in 25 patients with STEMI who were undergoing primary PCI with Filtrap. FNR was defined as coronary flow decreasing to TIMI flow grade 0 after mechanical dilatation.FNR was observed in 13 cases (52%). In the comparisons between cases with or without the FNR, the stent length, lipid pool length, lipid pool + thrombus length, and lipid pool + thrombus index showed significant differences. In multivariate analysis, lipid pool + thrombus length was the only independent predictor of FNR (OR 1.438, 95% CI 1.001 - 2.064, P < .05). The optimal cut-off value of lipid pool + thrombus length for predicting FNR was 13.1 mm (AUC = 0.840, sensitivity 76.9%, specificity 75.0%). Moreover, when adding the evaluation of thrombus length to that of lipid pool length, the prediction accuracy of FNR further increased (IDI 0.14: 0.019-0.25, P = .023).The longitudinal length of the lipid pool plus thrombus was an independent predictor of FNR and the prediction accuracy improved by adding the thrombus to the lipid pool. These results might be useful for making intraoperative judgment about whether filter devices should be applied in primary PCI for STEMI. PMID- 29390393 TI - Quick needle insertion at pharyngeal acupoints for poststroke dysphagia: A case report. AB - RATIONALE: Dysphagia following stroke is a major complaint among patients, and effective treatment of post-stroke dysphagia can be difficult. We present a case report describing a new treatment for dysphagia, namely, quick needle insertion at pharyngeal acupoints. PATIENT CONCERNS: A 70-year-old man developed pharyngeal dysphagia after a stroke. Three months after the patient experienced a sudden stroke leading to liquid dysphagia, acupuncture, one of the most important therapies in Traditional Chinese Medicine, was used to treat the patient. DIAGNOSES: A diagnosis of cerebral infarction and bulbar paralysis was made. INTERVENTIONS: Quick needle insertion was performed at five pharyngeal acupoints, once a day, 6 times a week for 6 weeks. OUTCOMES: The patient subsequently showed significant improvement in the pharyngeal phase of swallowing. His performance in the drinking water test reduced to level 1 from level 4. The functional oral intake scale score changed from level 2 to level 7. In the video fluoroscopic swallowing study, no spillage occurred, but aspiration was present. The residue of the contrast agent was reduced. LESSONS: Quick needle insertion at pharyngeal acupoints can be an efficient way to treat post-stroke dysphagia. PMID- 29390394 TI - Recombinant human thrombopoietin improves the efficacy of intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor in mobilizing peripheral blood stem cells in patients with multiple myeloma: A cohort study. AB - The combination of intermediate-dose cyclophosphamide (ID-CTX) and granulocyte colony-stimulating factor (G-CSF) fails to mobilize peripheral blood stem cells (PBSCs) in approximately 20% of treated patients with multiple myeloma (MM).In this cohort study, patients with MM underwent PBSC mobilization with either an ID CTX plus G-CSF plus recombinant human thrombopoietin (rhTPO) regimen (72 patients; TPO group), or an ID-CTX plus G-CSF regimen (70 patients; non-TPO group).In the TPO group, the median CD34+ harvest was 5.36 * 10 per kg of body weight (0.50-22.39 * 10 per kg of body weight), with a harvest success rate of 91.7% (66/72), and an excellence rate of 55.6% (40/72). In the non-TPO group, the median CD34+ harvest was 3.30 * 10 per kg of body weight (0.20-21.14 * 10 per kg of body weight), with a harvest success rate of 75.7% (53/70), and an excellence rate of 25.7% (18/70). The median count of the CD34+ cells collected, success rate of collection, and excellence rate of collection were significantly higher in the TPO group than in the non-TPO group (P=.0001, P=.01, and P = .0001, respectively). Time to granulocyte and platelet engraftment was faster among patients in the TPO group than that in those from the non-TPO group. No platelet engraftment delay (>21 days) was observed among patients in the TPO group, while 3 patients in the non-TPO group displayed delayed platelet engraftment.Adding rhTPO to the ID-CTX chemotherapy plus G-CSF regimen improved treatment efficacy in mobilizing PBSCs for autologous hematopoietic stem cell transplantation. PMID- 29390395 TI - Estimation of ultrasound reference values for the upper limb peripheral nerves in adults: A cross-sectional study. AB - The objective of this study is to estimate the reference values for the upper limb peripheral nerves in adults.The demographics and physical characteristics of 69 adult healthy volunteers were evaluated and recorded. In addition, the side to side differences of the estimated reference values and their correlations with the age, weight, height, and body mass index (BMI) were evaluated.Cross-sectional area reference values of the upper limb nerves did not correlate with height; however, they correlated with age, weight, and BMI in some scanned sites.The data obtained in this study could be helpful in future diagnosis of peripheral nerve disorders of the upper limb. PMID- 29390397 TI - Effects of rational-emotive health education program on hiv risk perceptions among in-school adolescents in nigeria: Erratum. PMID- 29390398 TI - Advanced glycation end products promote ChREBP expression and cell proliferation in liver cancer cells by increasing reactive oxygen species: Erratum. PMID- 29390396 TI - Acute keratoconjunctivitis due to contamination of contact lens care solution with histamine-producing Raoultella species: A case report. AB - RATIONALE: Contact lens storage cases are known to be contaminated by a significant number of bacteria. However, histamine-producing Raoultella species has not been reported to contaminate contact lens storage case. PATIENT CONCERNS: A 27-year-old woman with keratoconjunctivitis that developed in the left eye owing to a cosmetic contact lens and poor hygiene was referred to our hospital. The corrected visual acuity was hand motion. DIAGNOSES: Corneal infection other than Acanthamoeba keratitis (AK) and corneal hypoxia were excluded. INTERVENTIONS: We initiated empirical therapy for AK, although no cysts or trophozoites were detected in the cornea and in the lens care solution. Analysis of 16S rDNA sequences from the lens care solution yielded the highest homology with Raoultella species, which are histamine-producing bacteria. Histamine was estimated to be 492 ng/mL in the lens care solution. OUTCOMES: Her clinical course was distinct from that of usual AK cases. The corrected visual acuity increased up to (1.2) only 5 days after initiating empirical therapy. LESSONS: To our knowledge, this is the first report to indicate an association between histamine-producing bacteria and keratoconjunctivitis. We should pay an attention to the microbial contamination of contact lens storage cases by histamine producing bacteria. PMID- 29390399 TI - Clinical characteristics and prognostic risk factors of healthcare-associated pneumonia in a Korean tertiary teaching hospital: Erratum. PMID- 29390401 TI - High dose of nimustine as an add-on treatment for small cell lung cancer with intracranial metastasis: A case report and literature review: Retraction. PMID- 29390400 TI - Hot food and beverage consumption and the risk of esophageal squamous cell carcinoma: A case-control study in a northwest area in China. AB - BACKGROUND: This study was trying to investigate the association of hot food and beverage consumption and the risk of esophageal squamous cell carcinoma in Hotan, a northwest area of China with high risk of esophageal squmous cell carcinoma. METHODS: A population-based case-control study was designed. For the study, 167 patients diagnosed with esophageal squamous cell carcinoma were selected from Hotan during 2014 to 2015, and 167 community-based controls were selected from the same area, matched with age and sex. Information involved of temperature of food and beverage intake was obtained by face-to-face interview. Logistic regression analyses were performed to investigate the association between temperature of food and beverage intake and the risk of esophageal squamous cell carcinoma. RESULTS: The temperature of the food and beverage consumed by the esophageal squamous cell carcinoma patients was significantly higher than the controls. High temperature of tea, water, and food intake significantly increased the risk of esophageal squamous cell carcinoma by more than 2-fold, with adjusted odds ratio 2.23 (1.45-2.90), 2.13 (1.53-2.66), and 2.98 (1.89-4.12). CONCLUSIONS: Intake of food and beverage with high temperature was positively associated with the incidence of esophageal squamous cell carcinoma in Northwestern China. PMID- 29390402 TI - Circulating microRNA expression and their target genes in deep vein thrombosis: A systematic review and bioinformatics analysis. AB - BACKGROUND: Clinically, D-dimer is the only established biomarker for the diagnosis of deep vein thrombosis (DVT). However, low specificity discounts its diagnostic value. Several publications have illustrated the differentially expressed circulating microRNAs (miRNAs) and their potential diagnostic values for DVT patients. Therefore, we systematically evaluated present researches and further performed bioinformatics analysis, to provide new insights into the diagnosis and underlying mechanisms of miRNAs in DVT. METHODS: Databases PubMed, Web of Science, and Embase were searched from January 2000 to April 2017. Articles on circulating miRNAs expression in DVT were retrieved and reference lists were handpicked. Bioinformatics analysis was conducted for further evaluation. RESULTS: Eventually, the eligibility criteria for inclusion in this study were met by 3 articles, which consisted of 13 specially expressed miRNAs and 149 putative target genes. Two representative KEGG pathways, vascular endothelial growth factor and phosphatidylinositol 3'-kinase (PI3K)-Akt signaling pathway, seemed to participate in the regulatory network of thrombosis. CONCLUSIONS: Despite the potential diagnostic value and regulation effect, the results of circulating miRNAs used as biomarkers for DVT are not so encouraging. More in-depth and larger sample investigations are needed to explore the diagnostic and therapeutic values of miRNAs for DVT. PMID- 29390404 TI - Primary extraskeletal myxoid chondrosarcoma in cerebellum: A case report with literature review: Erratum. PMID- 29390403 TI - Tumor recurrence versus treatment effects in glioma: A comparative study of three dimensional pseudo-continuous arterial spin labeling and dynamic susceptibility contrast imaging. AB - BACKGROUND: Gliomas constitute over 90% of primary brain tumors. Accurate identification of glioma recurrence and treatment effects is important, as it can help determine whether to continue with standard adjuvant chemotherapy or to switch to a second-line therapy for recurrence. Our purpose is to compare three dimensional pseudo-continuous arterial spin labeling (3D-pcASL) technique and dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC-MRI) for differentiation tumor recurrence from treatment-related effects in gliomas. METHODS: Twenty-nine patients with gliomas previously who showed enlarged, contrast-enhancing lesions within the radiation field after surgery and concurrent chemoradiotherapy (CCRT) were assessed with 3D-pcASL and DSC-MRI. These patients were classified into 2 groups, tumor recurrence group (n = 17) and treatment effects group (n = 12), based on pathologic analysis or clinical radiologic follow-up. The perfusion imaging quality was assessed using a 3-point scale (1 = poor imaging, 2 = moderate imaging, and 3 = good imaging). Comparison for perfusion imaging-quality score between the 2 techniques was performed with Wilcoxon one-sample test. Quantitative analyses were performed between the 2 groups with cerebral blood flow values (ASL-CBF), relative cerebral blood flow values (ASL-rCBF, DSC-rCBF), and relative cerebral blood volume values (DSC-rCBV) using Wilcoxon one-sample test. The intra-class correlation coefficient (ICC) statistics were calculated for testing intrareader variability in regions of interest (ROIs) measurement of all perfusion parameters. RESULTS: The imaging quality score of 3D-pcASL was higher than that of DSC-MRI (P = .01). The perfusion parameters between tumor recurrence group and treatment effects group had statistically significant differences. There was a significant correlation between ASL-rCBF and DSC-rCBF values (r = 0.803), between ASL-rCBF and DSC-rCBV values (r = 0.763), and between DSC-rCBF and DSC-rCBV (r = 0.907). A receiver operating characteristic (ROC) curve analysis was performed for significant results of perfusion parameters between the 2 groups. Using a cutoff value of 1.110, ASL-rCBF showed the maximum area under the ROC curve (AUC). However, there were no significant differences among different AUCs. The ICC demonstrated excellent agreement for ROIs measurements of ASL-CBF (ICC = 0.9636), dynamic susceptibility contrast- cerebral blood flow (DSC-CBF) (ICC = 0.8508), and dynamic susceptibility contrast-cerebral blood volume (DSC-CBV) (ICC = 0.8543). CONCLUSION: 3D-pcASL is an alternative perfusion method to DSC-MRI for the differentiation between tumor recurrence and treatment effects in gliomas. 3D pcASL is noninvasive and shows fewer susceptibility artifacts than DSC-MRI. PMID- 29390405 TI - Comparison of outcomes of surgeon-performed intraoperative ultrasonography-guided wire localization and preoperative wire localization in nonpalpable breast cancer patients undergoing breast-conserving surgery: A retrospective cohort study. AB - This study aimed to determine the efficacy of intraoperative ultrasonography guided wire localization guided breast-conserving surgery (BCS) for nonpalpable breast cancer and compare it to conventional preoperative wire localization (PWL) guided surgery.We retrospectively analyzed the medical charts of 214 consecutive nonpalpable breast cancer patients who underwent BCS using intraoperative ultrasonography-guided wire localization by a surgeon (IUWLS) and PWL, between April 2013 and March 2017. Positive surgical margins, reexcision rates, and resection volumes were investigated.Of the total cohort, 124 patients underwent BCS with IUWLS and 90 patients with PWL. The following did not differ between the IUWLS and PWL groups: positive margin status, re-excision rate, conversion rate, permanent positive margin status, reoperation rate, median optimal resection volume (ORV), median total resection volume (TRV), and median closest tumor-free margin. Rather, median (range) widest tumor-free margin was significantly smaller in the IUWLS group (9 mm [5-12]) than in the PWL group (14 mm [9-20]; P = .003]). Median (range) calculated resection ratio (CRR) was significantly lower in the IUWLS group (1.67 [0.87-9.38]) than in the PWL group (4.83 [1.63-21.04]; P = .02).In nonpalpable breast cancer patients undergoing BCS, IUWLS showed positive resection margins and reexcision rates equivalent to those of the conventional PWL method. Additionally, excision volume and widest tumor-free margin were smaller with IUWLS, confirming that healthy breast tissue is less likely to be resected with this method. Our results suggest that IUWLS offers an excellent alternative to PWL, while avoiding PWL-induced patient discomfort. PMID- 29390406 TI - Plasma endothelin-1-related peptides as the prognostic biomarkers for heart failure: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Most studies reported that high plasma endothelin-1 (ET-1), big ET-1, and C-terminal proET-1 (CT-proET-1) were correlated with poor prognosis of heart failure (HF). However, available evidence remains controversial. To help solve the debate, we collected all the available studies and performed a meta-analysis. METHODS: We searched the databases covering Embase, PubMed, Ovid, and Web of Science on June 28, 2017. The hazard ratio (HR) or risk ratio (RR) and its 95% confidence intervals (CIs) were collected and calculated by use of a random effect model. Heterogeneity was assessed by Cochran's Q test, and publication bias was assessed by funnel plots with Egger's and Begg's linear regression test. RESULTS: Thirty-two studies with 18,497 patients were included in the analysis. Results showed that circulating ET-1, big ET-1, and CT-proET-1 were positively correlated with high risk of adverse outcomes, with pooled RRs (95% CIs) of 2.22 (1.82-2.71, P < .001), 2.47 (1.93-3.17, P < .001), and 2.27 (1.57-3.29, P < .001), respectively. In the subgroup of death as primary outcome, the pooled RRs (95% CIs) were 2.13 (1.68-2.70, P < .001), 2.55 (1.82-3.57, P < .001), and 2.02 (1.39-2.92, P < .001) for ET-1, big ET-1, and CT-proET-1, respectively. No significant publication bias was observed in this study. CONCLUSION: Our meta analysis provided evidence that increased plasma levels of ET-1, big ET-1, and CT proET-1 were associated with poor prognosis or mortality for HF populations. PMID- 29390407 TI - Influence of vitreomacular interface on anti-vascular endothelial growth factor treatment outcomes in neovascular age-related macular degeneration: A MOOSE compliant meta-analysis. AB - The aim of the study was to evaluate the influence of vitreomacular interface configuration on treatment outcomes after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (AMD).The Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to identify relevant prospective or retrospective studies that evaluate the influence of vitreomacular adhesion (VMA) or vitreomacular traction (VMT) on functional and anatomical outcomes in neovascular AMD patients treated with anti-VEGF agents. The outcome measures were the mean change in best corrected visual acuity (BCVA) from baseline, the mean change in central macular thickness (CMT) from baseline, and the mean injection numbers of anti-VEGF treatment from baseline.In total, 9 studies were selected for this meta-analysis, including 2156 eyes (404 eyes in the VMA/VMT group and 1752 eyes in the non-VMA/VMT group). In neovascular AMD patients treated with anti-VEGF agents, the VMA/VMT group was associated with poorer visual acuity gains and CMT reductions at 1 year (WMD [95% CI], -6.17 [-11.91, -0.43] early treatment diabetic retinopathy study (ETDRS) letters, P = .04; WMD [95% CI], 22.19 [2.01, 42.38] MUm, P = .03, respectively). There was no significant difference between 2 groups in the mean BCVA change and the CMT change over 2 years (WMD [95% CI], -5.59 [-21.19, 10.01] ETDRS letters, P = .48; WMD [95% CI], 6.56 [-24.78, 37.90] MUm, P = .68, respectively). There was no significant difference in the mean injection numbers between 2 groups at 1 year (WMD [95% CI], 0.36 [-0.19, 0.90], P = .21), whereas the VMA/VMT group had a significantly higher mean injection numbers over 2 years (WMD [95% CI], 1.14 [0.11, 2.16], P = .03).The limited evidence suggests that vitreomacular interface configuration have a significant influence on the visual acuity gain and CMT reduction at 1 year, injection numbers at 2 years in neovascular AMD patients treated with anti VEGF agents. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs. Eyes with VMA/VMT on optical coherence tomography at baseline may require more intensive treatment with decreased response to anti-VEGF agents. PMID- 29390408 TI - Asymptomatic solitary bladder plasmocytoma: A case report and literature review. AB - RATIONALE: Solitary extramedullary plasmocytoma may arise in any organ, either as a primary tumor or as part of a systemic myeloma; if it rarely affects bladder, it presents with urinary symptoms. We describe the first case of asymptomatic BP occasionally diagnosed in a patient with ascites. PATIENT CONCERNS: A 74-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis presented with ascites and no urinary or other symptoms. DIAGNOSES: Routine blood tests were within normal ranges, except for mild elevation of transaminases due to chronic hepatitis. Abdominal ultrasound and computed tomography (CT) scanning showed multiple liver nodules suspected for carcinomas and, incidentally, a 18 mm solid lesion of right bladder wall. OUTCOMES: She underwent transurethral resection of the bladder tumor and percutaneous liver biopsies; final diagnosis was solitary bladder plasmocytoma (BP) and hepatocellular carcinoma (HCC), respectively. She was given chemoembolization of the main HCC nodule but no adjuvant treatment for BP. At 3-month follow-up, total-body CT showed no signs of bladder disease nor distant metastases; unfortunately, she died one month later due to liver failure. LESSONS: This is the first reported case of asymptomatic BP. This rare neoplasm may pose difficulties in differential diagnosis with both bladder metastases and the plasmocytoid variant of bladder transitional cell carcinoma. We also highlighted lack of factors predicting disease outcome as well as response to potential adjuvant treatments. PMID- 29390409 TI - Hepatic portal venous gas associated with colon cancer: A case report and literature review. AB - RATIONALE: Hepatic portal venous gas (HPVG) is a very rare radiological finding that occurs when gas enters the portal venous system. HGVG can be caused by various diseases, with the most common being intestinal ischemia or necrosis. While there are few reports of HPVG associated with colon cancer, we report a case of HPVG associated with advanced colon cancer. DIAGNOSIS: The diagnosis of this patient was HPVG caused by colon cancer. INTERVENTIONS: Left colon cancer resection, pancreatic tail resection, splenectomy, and transverse colostomy were performed. OUTCOMES: The patient recovered well, and postoperative paraffin pathology confirmed that the resected tumor was colon cancer. LESSONS: Abdominal computed tomography is an effective method for diagnosing and monitoring HPVG. Klebsiella pneumonia is a potential gas-producing microorganism associated with HPVG, which may be confirmed by Blood culture or drainage culture. The prognosis of HPVG is closely related to the underlying pathology. Surgery should be performed early when there are signs of intestinal ischemia, necrosis, or perforation. PMID- 29390410 TI - An ethmoid mucocele causing diplopia: A case report. AB - RATIONALE: Mucocele is a disease lined primarily by epithelium, and occurs mainly when the sinus ostium is obstructed. PATIENT CONCERNS: We report a case of a 37 year-old man who presented with painless proptosis of the right eye and diplopia. DIAGNOSES: The preoperative finding was mucocele of the ethmoid sinus. INTERVENTIONS: We performed endoscopic sinus surgery, which included uncapping of the anterior and superior wall of the mucocele. OUTCOMES: The mucocele was treated safely and effectively without touching the medial orbital wall. LESSONS: Clinicians should note that minimally invasive surgery to remove ethmoid mucoceles is relatively straightforward and can prevent the various complications associated with these lesions. PMID- 29390411 TI - Unexpected hemorrhage of a rare vessel, a pubic branch of the external iliac artery, after laparoscopic radical prostatectomy: Case report. AB - RATIONALE: Postoperative hemorrhage is a rare complication after laparoscopic radical prostatectomy (LRP), with no case reports of bleeding from the external iliac artery in the literature. PATIENT CONCERNS: A 73-year-old man diagnosed with clinical stage 2c prostate cancer underwent LRP successfully with only approximately 200 mL of intraoperative blood loss. However, his blood pressure dropped from 135/74 to 80/49 mm Hg and his hemoglobin decreased by 66 g/L compared with the preoperative level within 5 hours. DIAGNOSES: Active hemorrhage from a pubic branch of the external iliac artery was found by digital subtraction angiography (DSA). INTERVENTIONS: The patient was treated with superselective intraarterial embolization. OUTCOMES: The bleeding stopped and the patient recovered uneventfully with no further hemorrhage or other complications. LESSONS: Although postoperative hemorrhage after LRP is exceptionally rare, it can occur not only in the internal iliac artery but also in the external iliac artery. In addition, contracted pelvis cases should be addressed with more caution by the laparoscope holder in case external iliac artery is injured. PMID- 29390412 TI - Clinical evaluation of improved MyoSure hysteroscopic tissue removal system for the resection of type II submucosal myomas. AB - This study aims to determine whether clinical evaluation of improved MyoSure hysteroscopic tissue removal system can remove type II submucosal myomas with safety and high success rate of the first operation.Fifty-three patients with type II submucosal myomas hospitalized in the Huzhou Maternity and Child Care Hospital were enrolled in this study. The submucosal myomas were with the diameter of >2 cm and <=5 cm. All patients have surgical indications.Fifty-one of 53 hysteromyomas were successfully resected through 1-time operation. The average time was 37.92 +/- 18.57 minutes, average amount of bleeding: 24.80 +/- 12.12 mL, average length of stay: 2.02 +/- 0.14 days. One patient had a transient postoperative fever and one patient had slight fluid overload with hyponatremia.The success rate of the first operation for resecting type II submucosal myomas showed an increase using improved MyoSure hysteroscopic tissue removal system, which can be a new, safer, and more efficient operation for treating type II submucosal myomas. PMID- 29390413 TI - The early examination of combined serum and imaging data under flexible fiberoptic bronchoscopy as a novel predictor for refractory Mycoplasma pneumoniae pneumonia diagnosis. AB - The treatment role of flexible bronchoscopy (FOB) for pediatric refractory Mycoplasma pneumoniae pneumonia (RMPP) has been well documented. Besides, the application indication of FOB is also studied in patients with general MPP (GMPP), especially in those with large pulmonary lesions. This study was designed to examine the diagnostic value of bronchoscopic features for RMPP.The FOB and bronchoalveolar lavage (BAL) were adopted for pediatric patients who showed clinical and radiograph indications. On the basis of the final diagnosis on discharge, patients were divided into general and refractory MPP groups. The clinical, laboratory, and bronchoscopic imaging features were retrospectively investigated between these 2 groups.From June 2012 to May 2014, a total of 62 RMPP and 101 GMPP patients were treated with therapeutic bronchoscopy. The comparison analysis showed that the CRP, HBDH, LDH were significantly different between RMPP and GMPP groups (all P < .001). In the bronchoscopic imaging, the mucus plug was significantly more commonly seen in the RMPP group (P < .001). Receiver operating characteristic (ROC) analysis revealed that the combined serum, clinical, and FOB imaging data possessed greater specificity and sensitivity than serum and clinical data alone.Our data suggest that the combined serum, clinical, and bronchoscopic imaging data might serve as a promising predictor for early RMPP diagnosis for pediatric patients with large pulmonary lesions. PMID- 29390414 TI - Prenatal diagnosis of Joubert syndrome: A case report and literature review. AB - INTRODUCTION: Joubert syndrome (JS) is a rare autosomal recessive inherited disease belonging to ciliopathy with the causative mutation of genes. Except for X-linked inheritance, the high recurrence rate of a family is about 25%. After birth, it may cause a series of neurological symptoms, even with retina, kidney, liver, and other organ abnormalities, which is defined as Joubert syndrome and related disorders (JSRD). Molecular genetics research contributes to disease prediction and genetic counseling. Prenatal diagnosis is rare. Magnetic resonance imaging (MRI) is usually the first-choice diagnostic modality with typical brain images characterized by the molar tooth sign. We describe a case of JS prenatally and Dandy-Walker malformation for the differential diagnosis based on ultrasonograms. We also review the etiology, imaging features, clinical symptoms, and diagnosis of JSRD. CASE PRESENTATION: A 22-year-old woman was pregnant at 27 1/7 weeks' gestation with fetal cerebellar vermis hypoplasia. Fetal ultrasonography and MRI confirmed a diagnosis of JS at our center. The couple finally opted to terminate the fetus, which had a normal appearance and growth parameters. The couple also had an AHI1 gene mutation on chromosome 6. CONCLUSIONS: Currently, a diagnosis of JS is commonly made after birth. Fewer cases of prenatal diagnosis by ultrasonography have been made, and they are more liable to be misdirected because of some nonspecial features that also manifest in Dandy-Walker malformation, cranio-cerebello-cardiac syndrome, and so on. PMID- 29390415 TI - Is hemoglobin A1c and perioperative hyperglycemia predictive of periprosthetic joint infection following total joint arthroplasty?: A systematic review and meta analysis. AB - OBJECTIVE: This meta-analysis aims to determine whether hemoglobin A1c (HbA1c) and perioperative hyperglycemia are associated with the increased risk of periprosthetic joint infection following total knee and hip arthroplasty. METHODS: A systematic search is performed in Medline (1966-October 2017), PubMed (1966-October 2017), Embase (1980-October 2017), ScienceDirect (1985-October 2017), and the Cochrane Library. Only high-quality studies are selected. A meta analysis is performed using Stata 11.0 software. RESULTS: Six retrospective studies including 26,901 patients meet the inclusion criteria. The present meta analysis indicates that there are significant differences between groups in terms of perioperative random blood glucose level [weighted mean difference (WMD) = 2.365, 95% confidence interval (95% CI): 1.802-2.929, P = .000] and perioperative hemoglobin A1c level (WMD = 3.266, 95% CI: 2.858-3.674, P = .000). No significant difference is found regarding body mass index (BMI) condition between groups (WMD = 0.027, 95% CI: -0.487 to 0.541, P = .919). CONCLUSION: The present meta analysis shows that high HbA1c and perioperative hyperglycemia are associated with a higher risk of periprosthetic joint infection following total joint arthroplasty. Screening of HbA1c and perioperative blood glucose is therefore an effective method to predict deep infection. PMID- 29390416 TI - Southern Italian teenagers: the older they get, the unfit they become with girls worse than boys: a cohort epidemiological study: The adolescents surveillance system for the obesity prevention project (ASSO). AB - Italy comprises a high proportion of people who never exercised. Low physical activity levels in adolescents is a risk factor for several disorders. The aim of this cohort epidemiological study was to compare physical fitness profiles between boys and girls with regard to age and gender and to identify health and fitness-related markers that contribute to the make-up of Southern Italian teenagers.Eight hundred eleven teenagers were assessed for anthropometric measurements and completed the 5 ASSO-fitness tests battery. Data were analyzed with a 2-way analysis of variance (ANOVA) for repeated measures to compare the effect of both age and gender on the fitness components.The boys' anthropometric measurements were superior than the girls as expected [weight, height, body mass index (BMI), and waist circumference]; the overall BMI was found in the normality range. The overall teenagers' fitness markers were found to be quite poor with the boys outperforming the girls in all fitness tests. The weak cardiorespiratory performance of the female teenagers was remarkable. The under 16 years old (-16 yrs) girls outperformed the over 16 years old (+16yrs) girls. There were less significant differences when comparing (-16) and (+16) yrs old mixed-gender groups. There were no correlations between the (-16) and (+16) yrs when both genders were considered. The trend analysis showed the younger teenagers might be "catching up" the older ones in both contexts.Gender significantly influenced all variables. Although age did not influence cardiorespiratory fitness, the older the teenagers the worse their health and fitness markers become with the older girls worse than their younger peers. PMID- 29390417 TI - Diabetes mellitus is a risk factor for low bone mass-related fractures: A meta analysis of cohort studies. AB - BACKGROUND: Diabetes mellitus (DM) is inconsistently associated with the risk of low bone mass-related fractures (LBMF). This study aimed to summarize available cohort studies regarding the strength of association between type 2 diabetes mellitus (T2DM) and LBMF. METHODS: Electronic searches of PubMed, Embase, and the Cochrane Library were performed to identify studies through April 2016. Cohort studies that reported effect estimates with 95% confidence intervals (CIs) of LBMF for T2DM and control comparison were included. RESULTS: The summary relative risks (RRs) for T2DM versus non-T2DM were associated with a higher risk of LBMF (RR: 1.24; 95% CI: 1.09-1.41; P = .001). Further, women with T2DM showed a harmful impact on the incidence of LBMF (RR: 1.19; 95% CI: 1.04-1.36; P = .010). However, in men, T2DM showed no significant impact on the risk of LBMF (RR: 1.14; 95% CI: 0.93-1.39; P = .215). Furthermore, the summary results suggested an association between T2DM and LBMF in studies that reported hazard ratio (HR) as an effect estimate in total cohorts (HR: 1.31; 95% CI: 1.17-1.46; P < .001), men (HR: 1.26; 95% CI: 1.11-1.43; P < .001), and women (HR: 1.32; 95% CI: 1.16-1.50; P < .001). However, these significant associations were not observed in studies that reported RR/odds ratio as an effect estimate. CONCLUSIONS: The present meta analysis confirmed that T2DM was associated with an increased prevalence of LBMF compared with non-T2DM. PMID- 29390418 TI - Evaluation of carotid arterial elasticity in patients with obstructive sleep apnea hypopnea syndrome by two-dimensional speckle tracking imaging. AB - The objective is to evaluate carotid arterial elasticity in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) by two-dimensional speckle tracking imaging (2D-STI).Sixty-two hospitalized patients with OSAHS and 20 healthy subjects were studied. The OSAHS patients were divided into 3 subgroups: a mild group, a moderate group, and severe group. All subjects underwent complete left common carotid artery (LCCA) examination by echo-tacking technique and 2D STI. The stiffness parameter (beta), elastic modulus (Erho), stiffness beta single pulse wave velocity (PWVbeta), and arterial compliance (AC) were automatically calculated by echo-tracking technique. And the global and segmental peak systolic circumferential artery strain (CAS) values were made off-line using 2D-STI.The beta, Ep, and PWVbeta values of the carotid artery in the moderate and severe groups were greater than those in the control group (P < .05). In addition, the systolic peak global CAS and the segments between 5 and 7 o'clock in the moderate and severe groups were lower than those in the control group (P < .05). Compared with mild group, the beta, PWVp, and Ep values of the carotid artery in the moderate and severe groups were higher (P < .05) and the systolic peak global CAS lower than in the control group (P < .05). The systolic peak global CAS was significantly inversely correlated with stiffness (beta, r = - 0.61, P < .05) and stiffness beta single pulse wave velocity (PWVbeta, r = -0.59, P < .05). Through stepwise multiple linear regression analysis, age and SaO2 were the significant variables that determined the systolic peak global CAS2D-STI provides a new method to investigate carotid arterial elasticity in patients with OSAHS. PMID- 29390419 TI - Influencing factors on CPAP adherence and anatomic characteristics of upper airway in OSA subjects. AB - Although continuous positive airway pressure (CPAP) is the most effective treatment modality, poor adherence still remains a problem for obstructive sleep apnea (OSA) treatment and there is little evidence regarding how this might be improved. This study aims to analyze the anatomic and clinical factors of OSA subjects who failed to comply with CPAP therapy.The medical records of 47 OSA subjects who received CPAP therapy as a first-line treatment modality were retrospectively reviewed. The medical records were reviewed for demographic and polysomnographic data and anatomic findings of the nasal cavity and oropharynx.24 patients who adhered to CPAP therapy and 23 patients who were nonadherent were enrolled in the study. There were no statistically significant differences in sleep parameters between CPAP-adherent patients and CPAP nonadherent subjects. Mean body mass index of CPAP nonadherent group was significantly higher than CPAP adherent group. Higher grades of septal deviation and hypertrophic change of the inferior turbinate were observed more in the CPAP nonadherent group. In addition, CPAP nonadherent subjects showed considerably bigger tonsils and higher grade palatal position comparing with the CPAP adherent subjects. Subjective discomfort including inconvenience, mouth dryness, and chest discomfort were the main problems for OSA subjects who did not comply with CPAP therapy.Excessive upper airway blockage in the nasal cavity and oropharynx was predominant in CPAP nonadherent subjects, which might cause the reported subjective discomfort that reduces CPAP compliance. Therefore, resolution of these issues is needed to enhance CPAP compliance for control of OSA. PMID- 29390420 TI - Survival time and prognostic factors of patients with initial noncurative colorectal liver metastases. AB - The true survival benefit of different curative strategies involving type of operative procedure and timing for patients with initial noncurative colorectal liver metastases remains uncertain. The goal of this study was to examine the effect of primary tumor resection on patients' survival and to clarify the predictive factors related to overall survival (OS).This was a retrospective study that included 219 patients with initial noncurative colorectal liver metastases without extrahepatic disease. The clinicopathological characteristics of patients and their survival were examined. Survival analysis was performed using the Kaplan-Meier method. All variables associated with P <.05 in univariate analysis were included in multivariate analysis using a Cox proportional-hazard regression model.The 1-, 3-, 5-year OS rates of patients with simultaneous liver resection were 79.1%, 39.1%, and 28.4%, respectively, and those of patients with staged liver resection were 83.3%, 46.7%, and 36.8%, respectively (P = .380). The 1-, 3-, 5-year OS rates of patients with primary tumor resection were 57.0%, 18.2%, and 12.3%, respectively, while for the patients without primary tumor resection were 38.9%, 5.6%, and 0%, respectively (P = .012). Independent prognostic factors for OS were carbohydrate antigen19-9, primary tumor resection, tumor differentiation, and adjuvant chemotherapy.No difference in OS was observed between simultaneous liver resection and staged liver resection, while primary tumor resection was beneficial to noncurative colorectal liver metastases. PMID- 29390421 TI - Comprehensive evaluation of clinical efficacy and safety of celecoxib combined with chemotherapy in management of gastric cancer. AB - BACKGROUND: To evaluate the clinical efficacy and safety of celecoxib combined with chemotherapy in the treatment of gastric cancer. METHODS: In total, 240 gastric cancer patients undergoing radical gastrectomy followed by adjuvant chemotherapy were randomly assigned into 2 groups. In the experimental group (n = 120), patients were administered with celecoxib-based chemotherapy, and chemotherapy alone was performed in the control group. Disease-free survival (DFS) and progression-free survival (PFS) were considered as the primary efficacy parameters, and objective response rate (ORR), overall survival (OS), quality of life (QOL), and safety as the secondary efficacy parameters. RESULTS: The 3-year OS did not significantly differ between the experimental (72%) and control groups (68%, P = .67). The 3-year DFS in the experimental group was 64%, which did not significantly differ from 51% in the control group (P = .41). In patients with positive cyclooxygenase-2 (COX-2) from the experimental group, the 3-year OS was 78%, significantly higher compared with 66% in the control group (P = .02), and the 3-year DFS was 70%, considerably >50% in the control group (P = .01). No statistical significance was identified in the incidence of nausea, neutropenia, anorexia, peripheral neurotoxicity, diarrhea, vomiting, asthenia, and thrombocytopenia, etc. The EORTC quality of life questionnaire (QLQ)-C30 questionnaire revealed that the global QOL in the experimental group was significantly higher than that in the control group (P < .05). No statistical significance was noted in the scores of functioning scale between 2 groups, whereas the scores of the symptom scale, especially pain and fatigue in the experimental group were remarkably higher than that in the control group (P < .05). The global score of EORTC QLQ-STO22 in the experimental group was considerably higher compared with that in the control group (P < .05). No statistical significance was identified in term of the domains of restrictions on feeding, dysphagia, anxiety, reflux, sense of taste, dry mouth, hair loss, and body shape between groups (all P > .05). CONCLUSION: Celecoxib combined with chemotherapy yields clinical benefits for gastric cancer patients with positive COX-2, which not only enhances the OS, DFS, PFS, QOL, and short-term clinical efficacy, but also does not increase the risk of adverse events. PMID- 29390422 TI - Type V hypertriglyceridemia in children, a therapeutic challenge in pediatrics: A case report and a review of the literature. AB - RATIONALE: Hypertriglyceridemia is defined as a level of triglycerides above 150 mg/dL. The complex causes and classification of hypertriglyceridemia lead to difficulties in the diagnosis and management of this condition. PATIENT CONCERNS: We present the case of a 15 years and 6 months old female teenager, admitted in our clinic for the following complaints: severe abdominal pain predominantly in the lateral left quadrant, nausea, vomiting, and the lack of stools for 2 days. The clinical exam showed: impaired general status, painful abdomen at superficial and deep palpation in the left and upper abdominal quadrants, the absence of stools for 2 days. DIAGNOSES: The laboratory parameters revealed leukocytosis with neutrophilia, thrombocytopenia, high level of serum amylase and triglycerides, and increased inflammatory biomarkers. The imagistic investigations showed ascites and paralytic ileus. INTERVENTIONS: The management was burdened by the side-effects of hypolipidemic drugs impairing the liver function and leading to rhabdomyolysis, but eventually the patient's outcome was good. OUTCOMES: Type V hyperlipoproteinemia is a rare condition accounting for approximately 5% of the cases. The risk for acute pancreatitis is well-known to be associated with hypertriglyceridemia, even though in rare cases. LESSONS: The prognosis of hypertriglyceridemia is pediatrics is burdened not only by the long term risk factors associated to the diseases itself, but also by the negative effects of long-term hypolipidemic treatment. PMID- 29390424 TI - Adult hippocampal ganglioneuroblastoma: Case report and literature review. AB - RATIONALE: Intracranial ganglioneuroblastoma represents a rare subtype of primitive neuroectodermal tumor. Here, we report a hippocampal ganglioneuroblastoma and a literature review of cerebral anglioneuroblastoma is carried out. PATIENT CONCERNS: We report a 16-year-old male patient presenting with absence seizure and high-infiltration hippocampal ganglioneuroblastoma. INTERVENTIONS: Magnetic resonance imaging (MRI) indicates a space-occupying lesion with a well-defined margin in the right temporal lobe and hippocampus. However, hyper-signal on flair and diffusion-weighted imaging (DWI) with a low apparent diffusion coefficient (ADC) value is detected, which prompts high tumoral invasiveness. INTERVENTIONS: A total resection of tumor and subsequent chemotherapy combing with radiotherapy is performed. OUTCOMES: For a follow-up period of 60 months, no evidence of recurrence and further seizures are detected. LESSONS: High-infiltration hippocampal ganglioneuroblastoma is a rare event. MRI examination often showed features of low-grade gliomas, while hyper-signal lesion on DWI with a low ADC value can be detected. Complete resection combined with fractionated radiotherapy and chemotherapy was the optimal treatment for cerebral ganglioneuroblastoma. PMID- 29390423 TI - The use of sirolimus in the treatment of giant cystic lymphangioma: Four case reports and update of medical therapy. AB - RATIONALE: Lymphatic malformations (LMs) are rare and benign anomalies resulting from the defective embryological development of the primordial lymphatic structures. Due to their permeative growth throughout all tissue layers, treatment is often challenging. Small asymptomatic lesions can be conservatively managed, while symptomatic lesions require active management. Surgery has been historically considered the treatment of choice, but today less invasive therapeutic options are preferred (sclerotherapy, laser therapy, oral medications). However, there are not uniform therapeutic protocols. Sirolimus is an oral medication that has been reported to be effective in the recent literature. Here we present the case of 4 newborns with giant multicystic lymphangioma treated with oral sirolimus after surgical resection had failed. PATIENT CONCERNS: At birth the LMs were clinically appreciated as giant masses involving different organs and structures. DIAGNOSES: All patients had a prenatal diagnosis of giant multicystic lymphangioma confirmed at histological and cytological analysis. INTERVENTIONS: Patients were treated with oral sirolimus after unsuccessful surgical resection. OUTCOMES: In all patients, sirolimus determined an overall reduction of the mass and a global involution from the macro- to the microcystic composition. Sirolimus was safe and poor disadvantages had been observed. The main and isolated adverse effect at laboratory analysis was progressive dyslipidemia, with increasing levels of total cholesterol and triglycerides. LESSONS: To date, our experience with sirolimus in the management of LMs is favorable. We recommend the use of sirolimus after unsuccessful surgical excision have been tried or when the surgical approach is not feasible. A multidisciplinary follow-up is needed to monitor disease evolution. PMID- 29390425 TI - A "blind" vascular ring in association with congenital cystic adenomatoid malformation: A case report. AB - RATIONALE: The occurrence of congenital cystic adenomatoid malformation (CCAM) and vascular ring (VR) is extremely rare. PATIENT CONCERNS: We present a case of left CCAM with VR consisting of a left aortic arch and right descending aorta with left tracheal compression causing atelectasis. DIAGNOSES: A high-risk male neonate with the diagnosis of left CCAM was diagnosed at 20 weeks gestational age by antenatal ultrasound. Chest CT revealed multiple cysts in the left inferior lung. Cardiac CT showed VR consisting of a left aortic arch and right descending aorta with left tracheal compression causing atelectasis. INTERVENTIONS: left inferior lobectomy was performed. Cardiac CT showed VR consisting of a left aortic arch and right descending aorta with left tracheal compression causing atelectasis. Descending aorta transposition was performed. OUTCOMES: The patient recovered smoothly and remained asymptomatic during the 12-months of postoperative follow-up period. LESSONS: We report this rare case of CCAM with VR consisting of left aortic arch and right descending aorta with left tracheal compression causing atelectasis. From the findings of this report, early surgical treatment is recommended. Although the prognosis after surgery remained good, second surgery can be avoided if VR was detected early. PMID- 29390426 TI - Hepatic resection or transarterial chemoembolization for hepatocellular carcinoma within Milan criteria: A propensity score matching analysis. AB - This study aimed to compare the long-term survival of patients with hepatocellular carcinoma (HCC) within the Milan criteria who underwent hepatic resection (HR) or transarterial chemoembolization (TACE).Medical records were retrospectively analyzed for HCC patients within the Milan criteria treated at Affiliated Tumor Hospital of Guangxi Medical University between March 2003 and March 2008, 159 of whom underwent HR and 42 of whom underwent TACE. Long-term overall survival (OS) was evaluated using the Kaplan-Meier method before and after propensity score matching. Cox proportional hazard modeling was used to identify possible predictors of OS.Propensity score matching was used to generate 32 pairs of patients, for which OS was significantly higher after HR than TACE at 1 year, 96.6% versus 84.4%; 3 years, 75.4% versus 53.1%; 5 years, 48.8% versus 29.7%, respectively (P = .038). Among all patients with multinodular HCC (2-3 tumors <=3 cm), HR was also associated with significantly higher OS than TACE at 1 year, 95.2% versus 72.7%; 3 years, 71.4% versus 9.1%; 5 years, 35.1% versus 0%, respectively (P < .001). By contrast, among all patients with a single HCC tumor <=5 cm, HR and TACE were associated with similar OS at 1 year, 85.9% versus 90.3%; 3 years, 62.0% versus 61.3%; 5 years, 42.1% versus 33.2%, respectively (P = .332).HR provides survival benefit over TACE in HCC patients within the Milan criteria, especially patients with multinodular HCC involving 2 to 3 tumors <=3 cm. However, HR and TACE appear to be similarly effective for patients with single-tumor HCC <=5 cm. PMID- 29390427 TI - Primary adrenal malignant melanoma: A case report and review of literature. AB - RATIONALE: The primary adrenal melanoma (PAM) was an extremely rare occurrence, which was demonstrated as the few cases described in the medical literature. PATIENT CONCERNS: We reported a 58-year-old man who was admitted to hospital because of intermittent left flank pain which lasted for a month. The renal computed tomography (CT) scan showed that a large retroperitoneal tumor measuring 15.5 cm * 12.1 cm * 13.0 cm seemed to have its origin in the left adrenal gland. DIAGNOSES: According to clinical symptoms, previous history, physical examination, and postoperative pathology, the patient was diagnosed as PAM. INTERVENTIONS: The patient was treated with an open procedure for resection of retroperitoneal tumor. After the surgery, the patient participated in the clinical drug trial and received treatment with ipilimumab as adjuvant medical therapy. OUTCOMES: When this article was completed, the patient was still alive and the survival has been already up to 20 months. LESSONS: The PAM was extremely rare in clinic, and its diagnosis and differential diagnosis were difficult. Therefore, clinical physicians should attach great importance to this disease. PMID- 29390429 TI - New compound heterozygous variants of the cholinergic receptor nicotinic delta subunit gene in a Chinese male with congenital myasthenic syndrome: A case report. AB - INTRODUCTION: Congenital myasthenic syndromes (CMS) are a group of genetic disorders that stem mostly from molecular defects in nicotinic acetylcholine receptors (AChRs). Defects in the cholinergic receptor nicotinic delta subunit (CHRND) gene can cause a series of myasthenic syndromes. Here, we report 2 new compound heterozygous variants of the CHRND gene in a Chinese male with CMS. CASE PRESENTATION: A 43-year-old Chinese male presented with progressive muscle weakness, difficulty chewing, and an inability to lift his head from the time he was 8 years old. He was treated with pyridostigmine, which was partially effective. Two weeks prior, he was hospitalized for dyspnea. Upon examination, he was unable to drum his cheeks and exhibited fatigable muscle weakness and facial muscle atrophy. Sequencing of his exome revealed 2 previously unreported mutations in CHRND, c.59G>A (exon2) and c.423G>C (exon5). CONCLUSIONS: We identified a new mutational site that contributes to the onset of CMS. PMID- 29390430 TI - Congenital diaphragmatic hernia in association with congenital short esophagus: A case report. AB - RATIONALE: Congenital diaphragmatic hernia (CDH) associated congenital anomalies are present in about 25%. Congenital short esophagus (CSE) is a relatively rare condition. Both CDH and congenital intrathoracic stomach caused by CSE can be diagnosed in utero. However, CSE can be easily misdiagnosed in utero. PATIENT CONCERNS: We present a case of left CDH with CSE in a female neonate who was diagnosed at 24 weeks gestational age by antenatal ultrasound. DIAGNOSES: The neonate with CDH and congenital intrathoracic stomach due to CSE was confirmed by operation. Gastroesophageal reflux disease (GRED) occurred after operation. INTERVENTIONS: The left diaphragm was repaired, and gastric fixation by gastropexy, gastric folding anti-reflux procedure and operation of longitudinal incision and transverse suture for pyloroplasty procedure was underwent. Gastroesophageal reflux disease (GRED) occurred after operation and jejunal tube feeding was placed. OUTCOMES: This patient is currently alive 12 months post operation with GRED. LESSONS: To our knowledge, this is the first documented case of this rare type of CDH combined with congenital intrathoracic stomach caused by CSE. This condition could not be surgically repaired due to the extremely short esophagus. Early recognition of intrathoracic stomach associated with CSE is important as it is associated with difficult management and significant postnatal complications. The prognosis is cautiously guarded, and the parents should be appropriately counseled. PMID- 29390428 TI - Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database. AB - Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 +/- 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) <=50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry. PMID- 29390431 TI - Limb-kinetic apraxia in a patient with mild traumatic brain injury: A case report. AB - RATIONALE: We report on a patient who developed limb-kinetic apraxia (LKA) due to an injured corticofugal tract (CFT) from the secondary motor area following mild traumatic brain injury (TBI), demonstrated on diffusion tensor tractography (DTT). PATIENT CONCERNS: She was struck in the right leg by a sedan at a crosswalk and fell to the ground. She lost consciousness and experienced post traumatic amnesia for approximately ten minutes. She was obliged to wear a cast for a left humerus fracture for two months, and she found she could not move her left hand quickly with intention after removal of the cast; consequently her left hand was almost non-functional. When she visited the rehabilitation department of a university hospital two years after the crash, she had mild weakness of the left upper extremity (manual muscle test: 4/5). However, the movements of the left hand were slow, clumsy, and mutilated when executing grasp-release movements of her left hand. DIAGNOSES: A 44-year-old female suffered head trauma resulting from a pedestrian car accident. INTERVENTIONS: When she extended all her left fingers, it took approximately eight seconds at her fastest speed to perform the pattern extending from the thumb to little finger sequentially. OUTCOMES: On two year DTT, narrowing and partial tearing was observed in the right supplementary motor area (SMA)-CFT. LESSONS: Injury of the right SMA-CFT was demonstrated in a patient with LKA in a hand following mild TBI. Our results stress the need to evaluate the CFTs from the secondary motor area for patients with unexplained motor execution problems following mild TBI. PMID- 29390432 TI - The safety and effectiveness of 2-liter polyethylene glycol plus ascorbic acid in patients with liver cirrhosis: A retrospective observational study. AB - The safety of bowel-cleansing agents is an important issue in clinical practice, especially in patients with chronic diseases. Although the safety and efficacy of polyethylene glycol (PEG) has been investigated in many studies, few studies on PEG plus ascorbic acid exist. In this study, we compared the safety of 2 bowel cleansing agents for patients with liver cirrhosis: 2-liter PEG (2 L PEG) plus ascorbic acid versus 4-liter PEG (4 L PEG). We performed a retrospective study on colonoscopy in patients with liver cirrhosis. Patients referred for colonoscopy were divided into 2 groups: 2 L PEG plus ascorbic acid (n = 105) and 4 L PEG (n = 61). Safety was assessed by comparing the clinical factors and laboratory findings as follows: blood biochemistry, electrolytes, weight change, and bowel cleansing quality. Serum electrolytes, laboratory findings, and body weight showed no significant change between the 2 groups. There was no significant change in clinical factors before and after bowel preparation in the PEG group or the PEG plus ascorbic acid group. The acceptability and compliance of patients was better in the 2 L PEG plus ascorbic acid than the 4 L PEG group. In subgroup analysis, patients with compensated or decompensated cirrhosis showed no increased risk of electrolyte imbalances after bowel preparation. Child-Pugh scores did not influence the outcome after bowel cleansing. Successful cleansing was mostly achieved in both groups. Our analysis showed that of the use of 2 L PEG plus ascorbic acid could be a safe choice for colonoscopy in patients with liver cirrhosis. PMID- 29390433 TI - Effect of balance training with Pro-kin System on balance in patients with white matter lesions. AB - Patients with white matter lesions (WMLs) often present with problems of balance. The aim of this study was to verify the effects of combined Pro-kin system and conventional balance training to improve balance ability in WMLs patients.This is a randomized controlled study, and 40 participants were divided into 2 groups: the intervention group (n=18) received Pro-kin system with additional conventional balance training for 20 minutes per session, 5 times a week, for 2 weeks. The control group (n = 19) received only conventional balance training. Outcome measures were examined before and after the 2 weeks intervention using the Berg Balance Scale (BBS), Timed Up and Go (TUG) test, and Pro-kin system.After completion of the 2 weeks intervention, BBS, TUG, and Pro-kin system results significantly improved in the intervention group (P < .05). In the control group, BBS and Pro-kin system results significantly improved (P < .05). Changes in all outcomes but the ellipse area with eye closed (P < .05) were significantly higher in the intervention group than in the control group.The combination of Pro-kin system and conventional balance training is a potentially valuable treatment for patients with WMLs. PMID- 29390434 TI - Circulating miR-125b but not miR-125a correlates with acute exacerbations of chronic obstructive pulmonary disease and the expressions of inflammatory cytokines. AB - To investigate the correlation of miR-125a/b expression with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients and inflammatory cytokines.Eighty-seven AECOPD patients, 93 stable chronic obstructive pulmonary disease (COPD) patients and 100 health volunteers (HCs) were recruited. Plasma samples were collected from AECOPD patients at the day 1, day 7, day 14, and day 28 of admission and from stable COPD patients as well as HCs. Total RNA was extracted from plasma, and miR-125a/b relative expressions were determined by quantitative real time-polymerase chain reaction.MiR-125b had a great capacity for distinguishing AECOPD from stable COPD (AUC = 0.926, 95% CI: 0.884-0.967) and HCs (AUC = 0.923, 95% CI: 0.880-0.966), while miR-125a did not. There were associations between miR-125b expression with TNF-alpha, IL-8, and LTB-4 in AECOPD patients (P = .012, P = .032, and P = .047, respectively), while no correlation of miR-125a with inflammatory cytokines was found. MiR-125b expression gradually decreased at day 7, day 14, and day 28 compared with day 1 (all P < .05) on admission, while no difference in miR-125a was discovered between each visit compared to day 1. Besides, TNF-alpha, IL-1beta, IL-8, and LTB 4 were elevated in AECOPD patients compared with stable COPD patients (all P < .01).MiR-125b, but not miR-125a, was positively associated with inflammatory cytokines and could be a novel biomarker for distincting AECOPD from stable COPD patients and HCs. PMID- 29390435 TI - Early neurological deterioration during the acute phase as a predictor of long term outcome after first-ever ischemic stroke. AB - Early neurological deterioration (END) is associated with increased risk of functional disability and mortality. However, data are limited regarding the long term risk of poor functional outcomes. Thus we explored the association between END and long-term outcomes in patients with acute ischemic stroke.A total of 1064 patients were enrolled with acute ischemic stroke who were consecutively admitted to the 3 stroke units of Huai-He Hospital, Kaifeng, China. END was defined as an increment change of at least one point in motor power or total National Institute of Health Stroke Scale (NIHSS) score deterioration >=2 points within the first week after admission. We retrospectively assessed the risk factors of END and prospectively explored the relationship between END and the long-term outcomes by multivariable regression models after adjusting the potential confounding factors. Outcomes were evaluated at 18 months based on modified Rankin scale (MRS) scores.Approximately 32% of first-ever ischemic stroke patients experienced END during the acute phase. END was associated with diabetes (odds ratio [OR], 2.218; 95% confidence interval [CI] 1.619-3.037), NIHSS score at admission (OR, 1.052; 95% CI 1.023-1.082), C-reactive protein (CRP) levels (OR, 1.224; 95% CI 1.066-1.406]), and homocysteine (HCY) levels (OR, 1.203; 95% CI 1.061-1.365) after adjusting related factors, such as hypertension, diabetes, NIHSS at admission, and some blood laboratory values, including direct bilirubin, total cholesterol, low-density lipoprotein, glucose, CRP, HCY, and D-dimer levels. During the follow-up period, 52 (4.9%) patients died, 160 (15.0%) recrudesced, and 317 (29.8%) suffered poor outcomes. Multivariate logistic regression analyses revealed that poor outcome was associated with END (OR, 3.366; 95% CI 2.495 4.542), age (OR, 1.028; 95% CI 1.015-1.041), body mass index (OR, 1.096; 95% CI 1.051-1.144), coronary heart disease (OR, 1.637; 95% CI 1.108-2.416), and CRP (OR, 2.474; 95% CI 1.840-3.326).The risk factors of END are multifaceted. Diabetes, NIHSS score at admission, CRP, and HCY are independent predictors of END. In addition, the results of this study indicate that END is an important predictor of poor functional outcome. PMID- 29390436 TI - Endostar combined with chemotherapy in a pediatric osteosarcoma with pulmonary metastasis and malignant pleural effusion: A case report. AB - RATIONALE: Angiogenesis is a key factor for tumor growth and metastasis both in cancer and sarcoma. Endostar, a novel safe and well-tolerated recombinant human endostatin, can suppress the expression of VEGF and the activation of ERK, MAPK, and AKT, and then inhibit tumor progression. PATIENT CONCERNS: A pediatric osteosarcoma with pulmonary metastasis and malignant pleural effusion. DIAGNOSES: Osteosarcoma with pulmonary metastasis and malignant pleural effusion. INTERVENTIONS: Considering the physical condition of patient, the patient underwent surgical resection of the right lung lesion after receiving endostar combined with chemotherapy and maintained endostar alone for 47 cycles. OUTCOMES: The patient obtained pathologic complete remission and had been in progression free survival up to now. LESSONS: Our experience could provide a treatment strategy for pediatric osteosarcoma patients with pulmonary metastasis and malignant pleural effusion. PMID- 29390437 TI - Chronic primary adrenal insufficiency after unilateral adrenonephrectomy: A case report. AB - RATIONALE: Unilateral adrenalectomy as part of surgical resection of renal cell carcinoma (RCC) is not thought to increase the risk of chronic adrenal insufficiency, as the contralateral adrenal gland is assumed to be capable of compensating for the lost function of the resected gland. However, recent studies have indicated that adrenalectomy might cause irreversible impairment of the adrenocortical reserve. We describe a case of chronic primary adrenal insufficiency in a 68-year-old man who previously underwent unilateral adrenonephrectomy, which was complicated by severe postoperative adrenal stress that involved cardiopulmonary disturbance and systemic infection. PATIENT CONCERNS: A 68-year-old Japanese man presented with weight loss of 6 kg over a 4 month period, and renal biopsy confirmed a diagnosis of RCC. He underwent adrenonephrectomy for the RCC, but developed postoperative septic shock because of a retroperitoneal cystic infection and ventricular fibrillation that was induced by vasospastic angina. The patient was successfully treated using antibiotics and percutaneous coronary intervention, and was subsequently discharged with no apparent complications except decreased appetite and general fatigue. However, his appetite and fatigue did not improve over time and he was readmitted for an examination. DIAGNOSES: The workup revealed a markedly elevated adrenocorticotropic hormone (ACTH) level (151.4 pg/mL, normal: 7-50 pg/mL) and a mildly decreased morning serum cortisol level (6.4 mg/mL, normal: 7-28 mg/mL). In addition to the patient's clinical symptoms and laboratory results, the results from ACTH and corticotropin-releasing hormone stimulation tests were used to make a diagnosis of primary adrenal insufficiency. INTERVENTIONS: Treatment was initiated using oral prednisolone (20 mg), which rapidly resolved his symptoms. At the 1-year follow-up, the patient had a markedly decreased serum cortisol level (2.0 mg/mL) with an ACTH level that was within the normal range (44.1 pg/mL) before his morning dose of prednisolone, which confirmed the diagnosis of chronic primary adrenal insufficiency. LESSONS: Clinicians must be aware of chronic adrenal insufficiency as a possible complication of unilateral adrenalectomy, especially when patients who underwent unilateral adrenalectomy experience severe adrenal stress. PMID- 29390439 TI - Superior vena cava syndrome secondary to recurrent coronary artery fistula: A case report and literature review. AB - RATIONALE: Coronary artery fistula (CAF) is characterized by an abnormal communication of a coronary artery with a cardiac chamber or a great vessel bypassing the capillary bed. Surgical closure of large or symptomatic CAF is the gold standard treatment. However the previously closed CAF still has the possibility to reopen. Superior vena cava syndrome (SVCS) is defined as a condition that occurs when the obstruction of the superior vena cava interrupts blood flow from the head, upper extremities, and thorax to the right atrium and can present a life-threatening situation. In this report, we described a case of SVCS, which was secondary to the compression by a huge aneurysm formed in a recurrent CAF, as a long-term complication associated with surgical treatment of CAF. PATIENT CONCERNS: A 47-year-old woman presented with chief complaint of progressive exertional dyspnea for one month. DIAGNOSES: Superior vena cava syndrome and recurrent coronary artery fistula. INTERVENTIONS: Reoperation for ligation of the fistulous and excision of the aneurysm were performed. OUTCOMES: The patient made an uneventful recovery and her postoperative course through 1 year follow-up was uneventful. LESSONS: First, SVCS is a rare but clinically important postoperative complication of surgical ligation of CAF. Second, surgical ligation of the fistula alone is unlikely to prevent the ectatic course. Therefore, long-term follow-up is mandatory for patients with CAF undergoing surgical closure. PMID- 29390438 TI - Osteoporotic sacral insufficiency fracture: An easily neglected disease in elderly patients. AB - Sacral insufficiency fractures (SIFs) are easily neglected by clinical physicians.The incidence of SIFs remains unclear in patients with symptomatic osteoporotic compression fractures of the lumbar-sacral area.This retrospective study was conducted by reviewing the medical records and radiological reports and by reading magnetic resonance (MR) images from August 2013 to July 2016. We identified 1233 cases with symptomatic vertebral compression fractures for which surgical interventions were performed. A total of 1144 cases were eligible for this study. Neglected diagnoses by radiologists and clinical physicians were calculated, respectively.The MR imaging (MRI) findings of SIFs were divided into the body (S1, S2, S3, and S4 levels) and alar areas (unilateral, bilateral, transverse, and none).A total of 34 (3.00%) cases with SIFs were identified through MRI. A significant difference was observed between 19 (6.53%) patients aged >80 years and 15 (1.76%) aged <80 years (P < .0001). Eight (23.53%) and 26 (76.47%) cases of SIFs were neglected by radiologists and clinical physicians, respectively. The S2 and S3 levels were the predominantly involved area (23/34; 67.65%). Furthermore, the bilateral alar area was the most commonly involved (19/34; 55.88%), as observed in coronal views of MRI.While treating other levels of osteoporotic compression fractures, radiologists and clinical physicians should be aware of SIFs, particularly when the patients are aged >80 years. The coronal oblique MR images of the thoracolumbar region should be carefully read to avoid neglecting SIFs. PMID- 29390440 TI - Myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis developed from ANCA negative renal limited vasculitis: A case report. AB - RATIONALE: The relationship between antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and ANCA-negative vasculitis has not been elucidated. PATIENT CONCERNS: A 64-year-old female with edema and proteinuria was admitted. A kidney biopsy indicated focal proliferative nephritis with crescents in 25% of glomeruli. Serum ANCA was negative. Eighteen months later, systemic symptoms emerged and acute kidney injury occurred. Serum ANCA against myeloperoxidase (MPO) turned positive. Repeated kidney biopsy showed more severe lesion than last time. Immunoglobulin (Ig)G was purified from serum obtained before the first kidney biopsy. Weak ANCA which could not be detected in serum was found in IgG. DIAGNOSES: MPO-ANCA-associated AAV developed from ANCA-negative renal-limited AAV. INTERVENTIONS: The patient was treated with glucocorticoid. OUTCOMES: The serum creatinine decreased to 2.17 mg/dL a week later. MPO-ANCA turned negative when re-examined 3 weeks later. No relapse has been observed during follow-up for 6 months. LESSONS: This is the first reported case about the spontaneous transformation from ANCA-negative renal-limited AAV to ANCA-positive systemic vasculitis. There might be a slow process of epitope spreading in the pathogenesis of disease. Physicians should try their best to detect the ANCA in the diagnose and treatment of ANCA-negative AAV. PMID- 29390441 TI - Left renal failure caused by chronic obstructive uropathy due to a uretero inguinal hernia combined with contralateral renal pelvic carcinoma: A case report. AB - RATIONALE: Although rare, cases of renal failure secondary to a uretero-inguinal hernia have been reported. PATIENT CONCERNS: Here, we report a case of left renal failure caused by chronic obstructive uropathy due to a uretero-inguinal hernia combined with contralateral renal pelvic carcinoma. DIAGNOSES: The present case highly indicated that a comprehensive examination is very important when diagnosing an inguinal hernia. In particular, it is necessary to check whether the ureter is involved or not. INTERVENTIONS: A computed tomography scan should be performed to a uretero-inguinal hernia patient. OUTCOMES: Unfortunately, this patient was diagnosed too late to attempt surgical management to restore the left renal functions. LESSONS: In our opinion, a computed tomography scan is highly recommended for an accurate diagnosis. PMID- 29390442 TI - "Ancient" schwannoma of the submandibular gland: A case report and literature review. AB - RATIONALE: Schwannomas are solitary neurogenic tumors that arise from cells of the neural sheath. Ancient schwannoma is a relatively rare variant of schwannoma, characterized by increased cellularity and atypia. These cellular changes could be confusing and make the accurate pathologic diagnosis difficult. PATIENT CONCERNS AND DIAGNOSES: A 36-year-old man presented with painless swelling in left submandibular region for more than 2 years. The computed tomography confirmed a well-defined cystic lesion in the left submandibular space, which caused superior and posterior displacement of the left submandibular gland. Surgical excision was performed and the pathology confirmed the diagnosis of ancient schwannoma. To our knowledge, this patient is the second case of primary submandibular ancient schwannoma reported in the literatures. INTERVENTIONS AND OUTCOMES: The patient underwent tumor resection and postoperative recovery was uneventful. There were no nerve deficits after the operation. There was no recurrence within 1 year of follow-up. LESSONS: Schwannoma originated from the submandibular gland is extremely rare and only a few cases have been reported. Ancient schwannoma is an even more rare tumor. The increased cellularity and atypia of ancient schwannoma can resemble features of malignancy. Great care must be taken to make differential diagnosis with fibrosarcomas and malignant schwannoma. PMID- 29390443 TI - Effect of intravenous ketamine for postoperative analgesia in patients undergoing laparoscopic cholecystectomy: A meta-analysis. AB - BACKGROUND: We conducted a meta-analysis to assess the efficacy and safety of ketamine for reducing pain and narcotic use for patients undergoing laparoscopic cholecystectomy (LC). METHODS: PubMed, Embase, Web of science, Medline, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) were regarded as eligible in our study. After testing the heterogeneity across RCTs, data were aggregated for fixed/random effect model according to the I statistic. The meta-analysis was conducted using Stata 11.0 software. RESULTS: Five studies were included, with a total sample size of 212 patients. Current meta-analysis revealed that there were significant differences regarding postoperative pain score at 12 hours [standard mean difference (SMD) = 0.322, 95% confidence interval (95% CI): -0.594 to -0.050, P = .020], 24 hours (SMD = -0.332, 95% CI: -0.605 to -0.059, P = .017), and 48 hours (SMD = -0.340, 95% CI: -0.612 to -0.068, P = .014). Ketamine intervention was found to significantly decrease narcotic use at 12 hours (SMD = -0.296, 95% CI: -0.567 to 0.025, P = .033), 24 hours (SMD = -0.310, 95% CI: -0.581 to -0.039, P = .025), and 48 hours (SMD = -0.338, 95% CI: -0.609 to -0.066, P = .015). CONCLUSION: Ketamine appeared to significantly reduce postoperative pain and narcotic use following LC. On the basis of the current evidence available, higher quality RCTs are still required for further research. PMID- 29390444 TI - Family history and renin-angiotensin system gene polymorphisms in Chinese patients with type 2 diabetes mellitus. AB - A positive family history is recognized as an important risk factor for type 2 diabetes mellitus (T2DM), but the association of family history with rennin angiotensin system (RAS) gene polymorphisms has not been reported yet, thus we aim to investigate it.Family history records, clinical and biochemical data were obtained from 1239 T2DM patients. Polymerase chain reaction (PCR) was performed for angiotensin-converting enzyme (ACE) genotyping and PCR-restricted fragment length polymorphism was used for angiotensinogen (AGT) genotyping.Patients with a negative family history had higher level of triglyceride and blood pressure, whereas those with a positive family history showed younger onset age and lower body mass index value (All P < .05), these findings were age-dependent. The percentage of hypertension was lower with a higher percentage of overweight among the patients with a positive family history (All P < .05). Patients with a positive family history and those with a negative family history had comparable genotype and allele distribution of ACE gene insertion/deletion polymorphisms and AGT gene M/T polymorphisms.A positive family history of diabetes was not associated with the RAS gene polymorphisms. PMID- 29390445 TI - The comparison of acute toxicity in 2 treatment courses: Three-weekly and weekly cisplatin treatment administered with radiotherapy in patients with head and neck squamous cell carcinoma. AB - The most appropriate cisplatin treatment schedule delivered with radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) is unknown. The aim of this study was to compare the acute toxicity and its impact on the course of the treatment, administered cisplatin and radiation doses, the length of hospitalization and supportive drugs administration in patients with HNSCC receiving 2 different cisplatin treatment schedules administered with radiotherapy.In this retrospective analysis, 104 patients with HNSCC were enrolled. Patients received radiation concurrently with 100 mg/m cisplatin administered 3-weekly (n = 50; group A) or 35 to 40 mg/m cisplatin administered weekly (n = 54; group B). Chemoradiotherapy was performed in locally and/or regionally advanced disease (stage III-IV), in a definitive radical upfront setting (71.1%) or after surgical resection in patients with high-risk factors (28.8%).Both study groups were equally distributed in terms of age, gender, stage of the disease, Eastern Cooperative Oncology Group performance score, chronic diseases and primary tumor site. The schedule of cisplatin dosing did not influence the duration of hospitalization, the number of additional supportive drugs (antibiotics, opioids) administered or total doses of received radiotherapy. However, postponement of radiotherapy due to adverse events was significantly more frequent in patients treated with 35/40 mg/m (55.56% vs 32%; P = .015). Furthermore, patients treated with weekly treatment schedule received lower total cisplatin dose (160 mg/m) in comparison to those treated with the 3 weekly schedule (200 mg/m). Grade 3 and 4 mucositis occurred more frequently in patients treated in group A (70% vs 50%; P = .037). Leukopenia was also observed more frequently in group A (88% vs 72.2%; P = .04), however there was no difference in grade 3/4 leukopenia between both study arms. There was no statistically significant difference in any other adverse effects.These results do not demonstrate the advantage of modified weekly schedule over standard 3 weekly cisplatin treatment plan. However, severe mucositis occurred more frequently in patients receiving 3-weekly cisplatin, both chemotherapy schedules seemed to present similar toxicity. Due to conflicting efficacy and toxicity, the results and compliance of weekly and 3-weekly cisplatin schedules should be evaluated in further randomized, controlled trials and retrospective studies. PMID- 29390446 TI - Hepatic angiosarcomatous transformation of a mediastinal germinal cell tumor: A care case report. AB - RATIONALE: Mediastinal nonseminomatous germ cell tumor (NSGCT) is an uncommon entity. Metastatic hepatic sarcomatous transformation is rare. PATIENT CONCERNS: We report a 24-year-old man with no previous related medical history presented with chest pain and left arm numbness. DIAGNOSES: The x-ray showed an anterior mediastinal mass. The chest computed tomography (CT) confirmed the presence of a mildly enhancing mass in the same location, without invasion of any vascular structure. A CT-guided biopsy was performed, revealing a primary mediastinal nonseminomatous germ cell tumor (NSGCT), yolk sac histology, with areas of somatic transformation to malignant nerve sheath tumor. After surgery patient was followed-up with imaging. Two years later a CT scan showed a new hepatic hyper vascular lesion, confirmed by a subsequent magnetic resonance imaging (MRI) and positron emission tomography (PET) scan. A CT-guided biopsy revealed a hepatic metastatic transformation to angiosarcoma of the primitive NSGCT. INTERVENTIONS: The patient went on to received palliative chemotherapy. OUTCOMES: The patient is being followed-up regularly at the outpatient department. LESSONS: Because of the potential of metastatic sarcoma arising from germ cell tumors, these patients should undergo periodical follow-up, with periodical scans. PET?CT scan might have a role in the follow-up of these patients. PMID- 29390447 TI - Cervical myelopathy caused by invaginated laminae of the axis associated with occipitalizaion of the atlas: Case report and literature review. AB - RATIONALE: In previous studies, few cases of cervical myelopathy caused by invaginated anomalous laminae of the axis have been reported, and none of them was combined with occipitalization of the atlas. PATIENT CONCERNS: A 28-year-old male was brought to our hospital with motor and sensory impairments of the extremities after a car accident. DIAGNOSES: MRI showed the spinal cord was markedly compressed at the C2/3 level. Reconstructed CT scans revealed an invaginated laminae of axis into the spinal canal as well as atlas assimilation. INTERVENTIONS: The patient was successfully managed with surgical treatment by removal of the anomalous osseous structure as well as fixation and fusion. OUTCOMES: The patient had a rapid recovery after the operation. He regained the normal strength of his 4 extremities and the numbness of his extremities disappeared. He returned to his normal work 3 months after the surgery without any symptoms. LESSONS: Invaginated laminae of axis combined with occipitalization of the atlas is a rare deformity. MRI and reconstructed CT scans are useful for both diagnosing and surgical planning of this case. Surgical removal of the laminae results in a satisfactory outcome. The pathogenesis of this anomaly could be the fusion sequence error of the 4 chondrification centers in the embryological term. PMID- 29390448 TI - Systolic blood pressure decline in very old individuals is explained by deteriorating health: Longitudinal changes from Umea85+/GERDA. AB - Declining systolic blood pressure (SBP) is common in very old age and is associated with adverse events, such as dementia. Knowledge of factors associated with SBP changes could explain the etiology of this decline in SBP. This study investigated longitudinal changes in socioeconomic factors, medical conditions, drug prescriptions, and assessments and their associations with SBP changes among very old followed individuals.The study was based on data from the Umea85+/Gerontological Regional Database (GERDA) cohort study, which provided cross-sectional and longitudinal data on participants aged 85, 90, and >=95 years from 2000 to 2015. Follow-up assessments were conducted after 5 years. The main outcome was a change in SBP. Factors associated with SBP changes were assessed using multivariate linear regression models.In the Umea85+/GERDA study, 454 surviving individuals underwent follow-up assessment after 5 years. Of these, 297 had SBP measured at baseline and follow-up. The mean change +/- standard deviation in SBP was -12 +/- 25 mm Hg. SBP decline was associated independently with later investigation year (P = .009), higher baseline SBP (P < .001), baseline antidepressant prescription (P = .011), incident acute myocardial infarction during follow-up (P = .003), new diuretic prescription during follow up (P = .044), and a decline in the Barthel Activities of Daily Living index at follow-up (P < .001).In conclusion, SBP declines among very old individuals. This decline seems to be associated with initial SBP level, investigation year, and health-related factors. PMID- 29390449 TI - Predictive factors of in-hospital mortality in ventilated intensive care unit: A prospective cohort study. AB - Although it is clear that ventilated intensive care unit (ICU) patients have worse outcomes than those who are not, information about the risk factors of in hospital mortality remains important for medical groups to target interventions for these patients.The purpose of this study was to identify predictive factors of in-hospital mortality in ventilated ICU patients with an admission diagnosis of acute respiratory failure.We conducted a prospective cohort study in 3 medical ICUs in a 3600-bed university hospital. Consecutive patients with acute respiratory failure who received mechanical ventilation (MV) for at least 96 hours without evidence of pre-existing neuromuscular diseases were followed until discharge. Upon inclusion, the following parameters were collected or evaluated: demographics, clinical history (admission body mass index [BMI], etiology of acute respiratory failure, comorbidity, Charlson comorbidity index, laboratory data), Acute Physiology and Chronic Health Evaluation (APACHE) II, and right and left quadriceps femoris muscle force. The days of MV before extubation, ICU length of stay, survival status at discharge, and hospital length of stay were recorded from the hospital discharge summary. The primary endpoint was in hospital mortality.In all, 113 patients (65.49% males) were recruited with a mean age of 69.78 years and mean APACHE II score of 22.63. The mean ICU length of stay was 14.88 +/- 9.79 days. Overall in-hospital mortality was 25.66% (29 out of 113 patients). Multivariate analysis showed that the essential factors associated with increased in-hospital mortality were lower BMI (P = .013), and lower scores on the right or left quadriceps femoris muscle force (P = .002 and .010, respectively).Our study suggests that lower BMI and lower scores on lower limb muscle force may be associated with increased in-hospital mortality in ventilated ICU patients. PMID- 29390450 TI - Effect of probiotics on lipid profiles and blood pressure in patients with type 2 diabetes: A meta-analysis of RCTs. AB - BACKGROUND: This meta-analysis aimed to systematically evaluate the effects of probiotics on blood lipid and blood pressure among patients with type 2 diabetes mellitus (T2DM) based on the randomized controlled studies. METHODS: PubMed, Cochrane, Embase, Wanfang, China National Knowledge Infrastructure, and VIP database were searched by the index words to identify the qualified randomized control trial. The latest research was done in the January 2017. Mean difference (MD) along with 95% confidence interval (CI) was used to analyze the included outcomes. RESULTS: Ten trials were included at last with 297 patients in the treatment group and 294 patients in the control group. Probiotics significantly decreased the value of total cholesterol (SMD -0.57, 95% CI -0.92 to 0.21), triglyceride (SMD -0.66, 95% CI -0.93 to 0.39), low-density lipoprotein (SMD 0.40, 95% CI -0.79 to 0.01), systolic blood pressure (WMD -5.04, 95% CI -8.8 to 1.20), diastolic blood pressure (SMD -0.39, 95% CI -0.62 to 0.17), fasting blood glucose (FBG) (SMD 3.54, 95% CI 1.94-5.15) compared with the placebo treatment. Apart from this, probiotics could significantly improve the value of high-density lipoprotein (SMD 0.38, 95% CI 0.03-0.73). CONCLUSION: Probiotics may decrease the indexes of lipid profile, blood pressure, and FBG in patients with T2DM; application of probiotics might be a new method for lipid profiles and blood pressure management in T2DM. PMID- 29390451 TI - The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: A meta-analysis. AB - OBJECTIVE: This meta-analysis aimed to illustrate the efficacy and safety of preganalin for pain management in patients with postherpetic neuralgia (PHN). METHODS: In July 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, and Google database. Data on patients with PHN that compared pregabalin versus placebo were retrieved. The endpoints were the visual analog scale (VAS) at 8 weeks, the percentage of 30% and 50% pain responders; sleep interference score and improvement in patient global impression of change (PGIC). After testing for publication bias and heterogeneity between studies, data were aggregated for random-effects models when necessary. RESULTS: Seven clinical studies with 2192 patients (pregabalin group = 1381, control group = 811) were finally included in the meta-analysis. Pregabalin was associated with reduced pain scores at 8 weeks, corresponding to a reduction of 11.23 points (95% CI, -14.33, -8.13, P = .000) on a 100-point VAS. Pregabalin was also associated with a more percentage of 30% and 50% pain responders than controls (P < .05). Meanwhile, pregabalin can decrease sleep interference score and improvement in PGIC than control groups (P < .05). CONCLUSIONS: Pregabalin was efficacious in the reduction of postoperative pain and improvement the sleep quality in patients with PHN. PMID- 29390452 TI - Coexistence of t(2;14;11)(p16.1;q32;q23) and t(14;19)(q32;q13.3) chromosome translocations in a patient with chronic lymphocytic leukemia: A case report. AB - RATIONALE: With combination of multiple techniques, we have successfully characterized unique, complex chromosomal changes in a patient with chronic lymphocytic leukemia (CLL), a lymphoproliferative disorder. DIAGNOSES: The diagnosis was based on white blood cell, flow cytometry, and immunophenotypes and confirmed by karyotype, fluorescence in situ hybridization, and array comparative genomic hybridization from the patient's blood culture. INTERVENTIONS: The patient was given fludarabine, cyclophosphamide and rituximab (FCR) for 6 cycles. OUTCOMES: After completion of 6 cycles of FCR, the computed tomography scans of the neck/chest/abdomen/pelvic showed that the patient in CR. During the 10-month follow-up, the patient's clinical course remained uneventful. LESSONS: The translocation t(14;19) identified in this patient is a recurrent translocation found in patients with chronic B-cell lymphoproliferative disorders and the 3-way translocation involving chromosomes 2, 14, and 11 may play a role as an enhancer. PMID- 29390453 TI - Spontaneous rupture of the urinary bladder caused by eosinophilic cystitis in a male after binge drinking: A case report. AB - INTRODUCTION: Spontaneous rupture of the urinary bladder is a rare, difficult to diagnose surgical emergency with a high mortality, there are many causes for spontaneous rupture of the urinary bladder, but we only found 2 reports on this condition in our literature search. A 36-year-old male patient was admitted with "whole abdominal pain associated with hematuria for 5 hours." Our patient did not have a history of definite allergy, but a long-term history of alcohol abuse. This patient was followed up for 1 year, and the cystoscopy recheck showed that the bladder lesion had healed. CONCLUSIONS: Since eosinophilic cystitis is associated with long-term alcohol consumption, we recommended that the patient should stop drinking and taking antihistamines. PMID- 29390454 TI - Low-grade myofibroblastic sarcoma of the orbit: A case report and literature review. AB - RATIONALE: Low-grade myofibroblastic sarcoma (LGMS) is a malignant lesion composed of myofibroblasts. It is an uncommon tumor of unknown etiology that mainly develops in the bone or soft tissue and is most often reported in the head and neck, particularly in the tongue and oral cavity. PATIENT CONCERNS: A 2-year old girl, previously well and with no significant medical history or family history of other diseases, presented with a 2-week painless swelling of the right orbit. DIAGNOSES: Preoperative computed tomography (CT) revealed a large homogeneous enhanced mass, 21 * 13 mm in size, located on lateral wall of the right orbit with bone absorption. The mass was resected and histopathological examination revealed LGMS of the orbit. INTERVENTIONS: On May 2016, she underwent surgery without the additional postoperative treatment. OUTCOMES: The patient's postoperative course was uneventful, and was discharged on the 6th day after surgery. During a year follow-up period, there was no recurrence of the postoperative CT. The patient and her family were satisfied with the result of the surgery. LESSONS: Based on clinical characteristics and postoperative CT, we considered the mass may be a benign tumor. We completely resected along the capsule without an extensive surgical margin. However, postoperative histopathology diagnose LGMS, which shows a strong potential for local recurrence and vascular invasion. So we should close observation of the patient's symptoms and sign. If the tumor has invaded adjacent tissues, we will use adjuvant chemotherapy or radiotherapy. PMID- 29390455 TI - Cerebral injuries associated with Zika virus in utero exposure in children without birth defects in French Guiana: Case report. AB - RATIONALE: A major epidemic of Zika virus (ZIKV) infection occurred in French Guiana and West Indies. French national epidemiological surveillance estimated that 1650 pregnant women contracted the ZIKV during epidemic period from January 2016 to October 2016 in French Guiana. PATIENT CONCERNS: ZIKV infection during pregnancy is a cause of microcephaly and birth defects. DIAGNOSES: In this report, we describe 2 children with proven in utero ZIKV exposure. Their mothers were both symptomatic and ZIKV infection occurred early in pregnancy. Ultrasonography monitoring in utero did not show any abnormality for both patient. They were born at full-term, healthy, without any birth defects and no sign of congenital ZIKV infection. INTERVENTIONS: ZIKV was neither found on placenta fragments nor children blood and urine at birth. Their neurodevelopment outcomes in early-life fitted the expectations. As recommended in national guidelines, we performed cerebral MRIs at 2 months old, showing severe brain abnormalities, especially of white matter areas. After a large screening, we did not find any differential diagnosis for their brain lesions. OUTCOMES: We concluded it was due to their in utero ZIKV exposure. LESSONS: In this report, pathogenicity of ZIKV may involve mother's immunological response or metabolic disorder during the infection. PMID- 29390457 TI - Diagnostic ability of macular ganglion cell-inner plexiform layer thickness in glaucoma suspects. AB - The purpose is to assess the diagnostic ability for early glaucoma of macular ganglion cell-inner plexiform layer (GCIPL) thickness in a Chinese population including glaucoma suspects.A total of 367 eyes with primary open-angle glaucoma (168 early glaucoma, 78 moderate glaucoma, and 121 advanced glaucoma), 52 eyes with ocular hypertension (OHT), 59 eyes with enlarged cup-to-disc ratio (C/D), and 225 normal eyes were included. GCIPL thickness (average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal), retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) parameters were measured using Cirrus high-definition optical coherence tomography (OCT) and compared. The diagnostic ability of OCT parameters was assessed by area under receiver operating characteristic curve (AUROC) in 3 distinguishing groups: normal eyes and eyes with early glaucoma, normal eyes and eyes with glaucoma regardless of disease stage, and nonglaucomatous eyes (normal eyes, eyes with OHT, and enlarged C/D) and early glaucomatous eyes.Glaucomatous eyes showed a significant reduction in GCIPL thickness compared with nonglaucomatous eyes. In all 3 distinguishing groups, best-performing parameters of GCIPL thickness, RNFL thickness, and ONH parameters were minimum GCIPL thickness (expressed in AUROC, 0.899, 0.952, and 0.900, respectively), average RNFL thickness (0.904, 0.953, and 0.892, respectively), and rim area (0.861, 0.925, and 0.824, respectively). There was no statistical significance of AUROC between minimum GCIPL thickness and average RNFL thickness (all P > .05).GCIPL thickness could discriminate early glaucoma from normal and glaucoma suspects with good sensitivity and specificity. The glaucoma diagnostic ability of GCIPL thickness was comparable to that of RNFL thickness. PMID- 29390456 TI - NT-proBNP test with improved accuracy for the diagnosis of chronic heart failure. AB - The circulating concentration of N-terminal pro-brain natriuretic peptide (NT proBNP) has been shown to be a diagnostic tool for the detection of heart failure. Several factors influence NT-proBNP levels including age, sex, and body mass index (BMI). Therefore, the diagnostic sensitivity of NT-proBNP level for heart failure is relatively higher, but its specificity is low. This study aims to improve the diagnostic accuracy rate of this test by including multiple variables in the diagnostic test.The suspected chronic heart failure outpatients were divided into heart failure with reduced ejection fraction, heart failure with mid-range ejection fraction, heart failure with preserved ejection fraction, and normal heart function groups. Area under the receiver-operating characteristic (ROC) curve, cut-off value, and logistic regression analysis were used to select the model variables, sensitivity and specificity.In all, 436 subjects enrolled into this study were divided in 2 groups: model establishment (n = 300) and model validation (n = 136). In the model establishment group, the area under the curve (AUC) and cut-off value of NT-proBNP was 0.926 and 257.4 pg/mL, respectively. When age, glomerular filtration rate, BMI, atrial fibrillation, and sex were entered into the diagnosis model, AUC, sensitivity, and specificity further increased to 0.955 (95% confidence interval [CI] 0.934, 0.976), 94.2% (from 93.0%), and 86.7% (from 74.2%). The ROC curve of corrected NT proBNP diagnostic formula for heart failure was also significantly higher (P = .037).The corrected NT-proBNP diagnostic formula was found to improve the diagnostic accuracy of chronic heart failure. PMID- 29390458 TI - Recovery of injured Broca's portion of arcuate fasciculus in the dominant hemisphere in a patient with traumatic brain injury. AB - RATIONALE: Recovery of injured AF in patients with traumatic brain injury (TBI) has not been reported. In this study, we report on a patient with TBI who recovered from an injury to Broca's portion of AF in the dominant hemisphere, diagnosed by diffusion tensor tractography (DTT). PATIENT CONCERNS: A 28-year-old right-handed male patient suffered head trauma resulting from sliding while riding a motorcycle. DIAGNOSES: He was diagnosed with a traumatic contusional hemorrhage in the left frontal lobe, subarachnoid hemorrhage, and subdural hemorrhage in the left fronto-temporal lobe. INTERVENTIONS: He underwent craniectomy on the left fronto-temporal area, and hematoma removal for the subdural hemorrhage in the neurosurgery department of a university hospital. Two weeks after the injury, he was transferred to the rehabilitation department of another university hospital. He showed severe aphasia and brain MRI showed leukomalactic lesion in the left frontal lobe. OUTCOMES: The result WAB for the patient showed severe aphasia, with an aphasia quotient of 45.3 percentile. However, his aphasia improved rapidly by 9 months with an aphasia quotient at the 100.0 percentile. 2-week DTT detected discontinuity in the subcortical white matter at the branch to Broca's area of left AF. By contrast, on 9-month DTT, the discontinued portion of left AF was elongated to the left Broca's area. LESSONS: Recovery of injured Broca's portion of AF in the dominant hemisphere along with excellent improvement of aphasia was demonstrated in a patient with TBI. This study has important implications in brain rehabilitation because the mechanism of recovery from aphasia following TBI has not been elucidated. PMID- 29390459 TI - Successful treatment of an acute infective endocarditis secondary to fish bone penetrating into left atrium caused by Granulicatella adiacens and Candida albicans: A case report. AB - RATIONAL: Infective endocarditis caused by a foreign body of the upper digestive tract is rare. We report a rare case of Granulicatella adiacens and Candida albicans coinfection acute endocarditis combined with systematic embolization caused by a fish bone from the esophagus penetrating into the left atrium. PATIENT CONCERN: A 42-year-old woman was admitted to our hospital because of fever, abdominal pain, headache, and right limb weakness. DIAGNOSES: Clinical examination indicated endocarditis and systemic embolisms secondary to a fish bone from the esophagus penetrating into the left atrium. The emergency surgery confirmed the diagnosis. Cultures of blood and vegetation show G adiacens and C albicans. INTERVENTIONS: Antimicrobial therapy lasted 6 weeks after surgery. OUTCOMES: The patient was discharged with excellent condition7 weeks after hospitalization and was well when followed 6 months later. LESSONS: The successful treatment of this patient combines quick diagnosis, timely surgery, and effective antimicrobial regimen. This rare possibility should be kept up in mind in acute infective endocarditis cases. PMID- 29390460 TI - Infantile-onset Pompe disease with neonatal debut: A case report and literature review. AB - RATIONALE: Infantile-onset Pompe disease, also known as glycogen storage disease type II, is a progressive and fatal disorder without treatment. Enzyme replacement therapy with recombinant human acid alpha-glucosidase (GAA) enhances survival; however, the best outcomes have been achieved with early treatment. PATIENT CONCERNS: We report a case of a newborn with infantile-onset Pompe disease diagnosed in the first days of life who did not undergo universal neonatal screening. The patient was asymptomatic, with a general physical examination revealing only a murmur. The clinical presentation was dominated by the neonatal detection of hypertrophic cardiomyopathy, without hypotonia or macroglossia. DIAGNOSES: Pompe disease was confirmed in the first week of life by GAA activity in dried blood spots, and a GAA genetic study showed the homozygous mutation p.Arg854X. INTERVENTIONS: Parents initially refused replacement therapy. OUTCOMES: The patient experienced recurrent episodes of ventricular fibrillation during central line placement and could not be resuscitated. LESSONS: Although Pompe disease is rare, and universal screening has not been established, neonatologists should be alerted to the diagnosis of Pompe in the presence of hypertrophic cardiomyopathy. Diagnosis is achieved in a few days with the aid of dried blood spots. PMID- 29390461 TI - Immediate relief of herniated lumbar disc-related sciatica by ankle acupuncture: A study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Around 90% of sciatica cases are due to a herniated intervertebral disc in the lumbar region. Ankle acupuncture (AA) has been reported to be effective in the treatment of acute nonspecific low back pain. This study aims to evaluate the efficacy of a single session of ankle acupuncture for disc-related sciatica. METHOD: This will be a double-blinded, randomized controlled clinical trial. Patients diagnosed with disc-related sciatica will be randomly divided into 3 parallel groups. The treatment group (n = 30) will receive ankle acupuncture. The 2 control groups will either undergo traditional needle manipulation (n = 30) or sham acupuncture (n = 30) at the same point as the treatment group. The primary outcome will be pain intensity on a visual analog scale (VAS). The secondary outcomes will be paresthesia intensity on a VAS and the Abbreviated Acceptability Rating Profile (AAPR). The success of blinding will be evaluated, and the needle-induced sensation and adverse events will be recorded. All outcomes will be evaluated before, during, and after the treatment. DISCUSSION: This study will determine the immediate effect and specificity of ankle acupuncture for the treatment of disc-related sciatica. We anticipate that ankle acupuncture might be more effective than traditional needle manipulation or sham acupuncture. TRIAL REGISTRATION: ChiCTR-IPR-15007127 (http://www.chictr.org.cn/showprojen.aspx?proj=11989). PMID- 29390462 TI - Anaplastic astrocytoma with aquaporin-4 positive in CSF: A case report. AB - RATIONALE: An acute presentation with diffuse magnetic resonance imaging lesions can have a broad differential. Demyelination and malignancy are important considerations. Therefore, sometimes it is hard to differentiate glioma from some demyelinating diseases solely on imaging because of the similar clinical presentation and imaging features. Detection of highly specific serum autoantibody marker aquaporin-4 (AQP4)-IgG positivity has helped to define a category of neuromyelitis optica spectrum disorders (NMOSD), but the test of AQP4 antibody has not been reported in patients with glioma. PATIENTS CONCERNS AND DIAGNOSES: We report a case of a 56-year-old woman with cerebrospinal fluid (CSF) positive aquaporin-4 antibodies with initial response to immune therapy and secondary deterioration. A surgical biopsy revealed an anaplastic astrocytoma. INTERVENTIONS AND OUTCOMES: After the admission the patient was treated with a short course of intravenous steroid agents. After anaplastic astrocytoma was diagnosed, she began to receive a radiation treatment and soon later experienced a clinical deterioration with frequent epilepsy seizure and disturbance of consciousness within a few months. LESSON: This case indicates that tumors could lead to polyclonal antibody responses as in this case with aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies. The absence of a typical clinical phenotype and lack of sustained response to immunotherapy should alert the clinical suspicion of an alternative diagnosis. When AQP4 antibody was detected positive in CSF of a patient but negative in serum, differential diagnosis should especially be considered. PMID- 29390463 TI - A double-blinded, randomized, placebo-controlled trial assessing the effects of nifedipine on embryo transfer: Study protocol. AB - INTRODUCTION: Implantation failure is the main factor affecting the success rate of in vitro fertilization (IVF) procedures. Studies have reported that uterine contractions (UCs) at the time of embryo transfer (ET) were inversely related to implantation and pregnancy rate, hence reducing the success of IVF treatment. Various pharmacological agents, with the exception of calcium channel blocker (CCB), have been investigated to reduce UC. In this regard, we are presenting a proposal for a double-blind randomized placebo-controlled trial. The trial aims to determine whether nifedipine, a CCB with potent smooth muscle relaxing activity and an excellent safety profile, can improve the outcome of ET. METHODS AND ANALYSES: We will recruit 100 infertile women into one of 2 groups: placebo (n = 50) and nifedipine 20 mg (n = 50). Study participants will be admitted 30 minutes prior to ET and given either tablet after their baseline vital signs have been recorded. They will then undergo ET and be observed for adverse events for another 30 minutes post-ET. The primary outcome will be implantation rate and clinical pregnancy rate. Secondary outcomes include adverse events, miscarriage and pregnancy, and neonatal outcomes. Resulting data will then be analyzed using t test, Chi-square test, and multivariate test to compare outcomes between the 2 groups for any statistical significance. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines. PMID- 29390464 TI - Vascular spinal cord obstruction associated with superior vena cava syndrome: A case report and literature review. AB - RATIONALE: Superior vena cava syndrome (SVCS) is the obstruction of blood flow through the SVC, causing complete or partial blockade of the collateral circulation of returning venous blood. SVCS is frequently presented with facial, neck, trunk, and upper limbs swelling and so on. However, to the best of our knowledge, the obstruction of the venous return in the spinal veins is rarely a manifestation of SVCS. PATIENT CONCERNS: We presented a rare case of a 52-year old male patient with 2-month history of progressive right upper limb numbness and swelling and 10-day history of extremities malfunctioning. Cervical magnetic resonance imaging (MRI) detected obstruction of the spinal venous return. Lung computed tomography (CT) revealed lesions in the esophagus, which indicated esophageal cancer with mediastinal lymph nodes metastasis and signified SVCS. DIAGNOSES: With the results of laboratory findings, cervical MRI, lung CT findings, and physical examination, the patient was diagnosed with SVCS manifesting as spinal vein obstruction. INTERVENTIONS AND OUTCOMES: The family abandoned further treatment, and the patient passed away 2 months after discharge. LESSONS: The case indicates that SVCS can induce systemic and spinal cord diseases affecting the venous return. Further studies are necessary to reveal the mechanism for SVCS inducing spinal veins obstruction and to explore whether SVCS patients with and without vascular spinal cord obstruction have different prognoses. PMID- 29390465 TI - Interleukin-13 +2044 G/A and +1923C/T polymorphisms are associated with asthma susceptibility in Asians: A meta-analysis. AB - A number of studies have reported that the interleukin 13 (IL-13) gene is associated with asthma susceptibility. However, the reported relationships between the +2044G/A and +1923C/T polymorphisms and asthma susceptibility are inconsistent, especially in Asian adults and children with atopic status. Meta analysis was used to analyze combined data.The +2044G/A and +1923C/T polymorphisms were investigated using data from 18 and 11 studies, respectively. The results suggested that there was an association between asthma and the IL-13 +2044G/A polymorphisms: odds ratio (OR) 1.34, 95% confidence interval (CI) 1.03 1.75 for AA versus GG + GA and +1923C/T; OR 1.50, 95% CI 1.26-1.78 for TT versus CC; and OR 1.15, 95% CI 1.10-1.21 for TC versus CC. The subgroup meta-analysis demonstrated that IL-13 +2044G/A polymorphisms are associated with asthma: OR 1.47, 95% CI 1.06-2.04 for AA versus GG + GA and +1923C/T; OR 1.70, 95% CI 1.26 2.30 for TT versus CC; and OR 1.27, 95% CI 1.03-1.56 for TC versus CC. In particular, IL-13 +2044G/A polymorphisms are specifically associated with Asian ethnicity in both adults and children with atopic status. However, the 1923C/T polymorphisms were not significantly associated with age group or atopic status within the Asian subgroups. Further investigation using larger samples and meta analysis is required. No publication bias was detected.This meta-analysis indicates that the IL13 +2044G/A and +1923C/T polymorphisms are risk factors for asthma, especially among Asians. PMID- 29390466 TI - Iatrogenic acute aortic dissection induced by off-pump coronary artery bypass grifting: A case report and review of the literature. AB - RATIONALE: Iatrogenic acute aortic dissection (IAAD) induced by cardiac surgery is a fatal complication, with 0.04% of therapeutic procedures and worse outcomes than spontaneous aortic dissection. PATIENTS CONCERNS: A 64-year-old male complaining of intermittent chest tightness for 4 years received an off-pump coronary artery bypass grifting (OPCABG) and IAAD was found during surgery. DIAGNOSIS: Unstable angina, coronary artery triple vessel lesion, IAAD. INTERVENTIONS: An ascending aorta replacement surgery was implemented immediately and extracorporeal membrane oxygenation (ECMO) was applied during surgery. The patient suffered from oliguria symptoms and began to receive continuous renal replacement therapy (CRRT) after surgery. What was worse, osteofascial compartment syndrome (OCS) was also confirmed the day after surgery. OUTCOMES: The CRRT and ECMO were both removed and the condition of the right leg was also stable. But the patient passed away because of uncontrollable sepsis 18 days after the surgery. LESSONS: OPCABG is clearly the riskiest type of surgery associated with IAADs in cardiac surgical procedures, which should be considered with great concern. Whether ECMO should be used postoperatively in IAAD patients is still a controversial subject, due to some fatal complications linked with it. PMID- 29390467 TI - Role of serum TGF-beta1 level in atrial fibrosis and outcome after catheter ablation for paroxysmal atrial fibrillation. AB - This study aimed to evaluate the relationship between serum transforming growth factor-beta1 (TGF-beta1) concentration and atrial fibrosis and to determine whether plasma TGF-beta1 concentration is an independent predictor of atrial fibrillation (AF) recurrence after catheter ablation.We included 98 consecutive patients who underwent catheter ablation, including 38 with paroxysmal AF (AF group) and 60 with paroxysmal supraventricular tachycardia (control group). We compared their preablation serum concentration of biomarkers and clinical and echocardiographic findings.Serum TGF-beta1 concentrations, type-III procollagen N terminal peptides (PIIINP), type-IV procollagen (IV-C), and laminin (LN) were significantly higher in the AF group than in the control group; however, there was no correlation between their concentrations and left atrial diameter (LAD). The area of the low-voltage zone positively correlated with TGF-beta1 and PIIINP concentrations, but not with LAD. Atrial tachyarrhythmia (AF and AFL/AT) recurrence was observed in 15 patients (39.4%) at mean 241.4 +/- 68.5 days of follow-up 12 months after ablation. Regression analysis revealed that TGF-beta1 was a major risk factor for AF recurrence (odds ratio, 1.14; 95% confidence interval, 1.11-1.17; P = .02).Serum TGF-beta1 concentration is an independent predictor of AF recurrence in patients with paroxysmal AF and may help identify patients likely to have better outcomes after catheter ablation. PMID- 29390468 TI - Three-week topical treatment with placenta-derived mesenchymal stem cells hydrogel in a patient with diabetic foot ulcer: A case report. AB - RATIONALE: Diabetic foot ulcer (DFU) is a chronic complication of diabetes characterized by continuity, repeatability, and nonhealing. In recent years, mesenchymal stem cells hydrogel complex has been a new emerging technique in the treatment of DFU. The placenta-derived mesenchymal stem cells (PDMSCs) hydrogel is multipotent, and can secrete growth factors, cytokines, and immunomodulatory substances which could accelerate wound healing. PATIENT CONCERNS: In this case report, we present a 57-year-old female with type 2 diabetes mellitus and a 20 day DFU.A wound bed located at the dorsalis pedis of the right foot, and conventional therapies had no effect on the foot. DIAGNOSES: The patient was confirmed a diagnosis of type 2 DM with diabetic foot (Wagner classification III). INTERVENTIONS: To assess the efficacy and safety of PDMSCs hydrogel in wound repair and to improve the rate of wound healing, we administered PDMSCs hydrogel (cell number: 1 * 10/cells/cm) topically into the wound with the patient's permission. OUTCOMES: The patient's foot ulcer was almost healed, and foot function in walking was well preserved. No complications were observed. No recurrence occurred in the subsequent 6 months. LESSONS: To the best of our knowledge, this is the first patient globally to receive PDMSCs hydrogel to treat DFU. The present case study suggests that PDMSCs hydrogel may provide a new approach to DFU treatment. Clinical Trial Registration-URL: http://www.chictr.org.cn/searchproj.aspx:chiCRT-ONC-16008732. PMID- 29390469 TI - Insulin autoimmune syndrome in a pregnant female: A rare case report. AB - RATIONALE: Insulin autoimmune syndrome (IAS) is an uncommon disorder characterized by hyperinsulinemic hypoglycemia related to insulin-binding autoantibodies. To the best of our knowledge, we report the first case of a pregnant female with IAS. PATIENT CONCERNS: The 26-year-old patient with Graves disease and 10 weeks pregnant developed IAS after approximately 6 months treatment with methimazole. The patient exhibited recurrent spontaneous hypoglycemia. DIAGNOSES: On evaluation, laboratory findings detected both high fasting insulin (>1000 mIU/L) and insulin autoantibodies. An oral glucose tolerance test showed elevated insulin concentrations with disproportionately elevated C-peptide levels. The imaging study showed nomasslesionsinthepancreas,and the patient was clinically diagnosed with IAS. INTERVENTIONS: The patient had an abortion, discontinued methimazole and switched to oral prednisone (30 mg once daily) and propylth- iouracil (100 mg 3 times daily) for 3 months. OUTCOMES: At the 3-month follow-up visit, hypoglycemic episodes had disappeared and insulin antibody levels were no longer detectable. LESSONS: We have described this case and reviewed the relevant literature concerning diagnosis and treatment of IAS. Importantly, this case indicates that clinicians should view pregnancy as another factor of hypoglycemia in IAS. PMID- 29390470 TI - Delayed degeneration of the left fornical crus with verbal memory impairment in a patient with mild traumatic brain injury: A case report. AB - RATIONALE: We report on a patient who showed delayed degeneration of the left fornical crus with verbal memory impairment following mild traumatic brain injury (TBI), which was demonstrated by diffusion tensor tractography (DTT). PATIENT CONCERNS:: fter flexion and hyperextension of her head to the opposite side, the patient experienced a dazed feeling for a while at the time of head trauma. The patient's Glasgow Coma Scale score was 15, and mini-mental state examination score was 30. DIAGNOSES: A 50-year-old right-handed female with 12 years of education suffered from head trauma resulting from a car accident. INTERVENTIONS: A The patient showed normal memory function at one year after onset: the Memory Assessment Scale (global memory: 124 (95 percentile (%ile)), verbal memory: 111 (77%ile), and visual memory: 132 (98%ile) (A percentile is a measure used in statistics indicating the value below which a given percentage of observations in a group of observations fall). However, the patient began to experience decline of memory function such as forgetfulness at approximately 1.5 years after onset. On the 2-year evaluation, she showed decrement of memory function (global memory: 108 (70%ile), verbal memory: 86 (18%ile), and visual memory: 129 (97%ile). OUTCOMES: On 1-year DTT, the integrity of the fornix was well preserved between the fornical column and fornical crus. However, on 2-year DTT, a discontinuation was observed in the left fornical crus. LESSONS: Delayed degeneration of the left fornical crus was demonstrated in a patient who showed delayed onset of verbal memory impairment following mild TBI. PMID- 29390471 TI - Early pregnancy following multidrug regimen chemotherapy in a gestational trophoblastic neoplasia patient: A case report. AB - RATIONALE: Gestational trophoblastic neoplasia is a group of rare tumors that can be cured using chemotherapy. The use of artificial contraception for at least 1 year is recommended not only due to the high recurrence rate in the first year after treatment, but also because of the unclear genetic toxic effects of multidrug regimen chemotherapy on reproductive cells. There is no consensus about the contraception duration, but most patients want to have children. PATIENT CONCERNS: This case involved a 33-year-old female suffering from gestational trophoblastic neoplasia and 5-fluorouracil + actinomycin-D chemotherapy. She became pregnant 1 month after finishing the chemotherapy. DIAGNOSIS: Gestational trophoblastic neoplasia. INTERVENTIONS: No treatment during pregnancy. OUTCOMES: The patient had a full-term normal delivery, and the baby showed normal development and growth after a follow-up of 48 months. LESSONS: Pregnancy soon after chemotherapy can be viable with rigorous prenatal care. PMID- 29390472 TI - Upper extremity deep vein thrombosis after migration of peripherally inserted central catheter (PICC): A case report. AB - INTRODUCTION: Peripherally inserted central venous catheters (PICC) are widely used in cancer patients and ultrasound-guided PICC insertion could improve success rate. The tip position of the catheter should be located at the border of lower one-third of the superior vena cava (SVC) and cavo-atrial junction. The migration is malposition at the late stage after PICCs were inserted, and catheter malposition was associated with thrombosis and other complications.After patient's informed consent, we report a case of a 66-year-old male with twice catheter migrations resulting in thrombosis after being diagnosed with cardiac cancer. CONCLUSION: The correct position of the catheter tip can ensure the normal use of PICC and reduce the complications. For the migrated catheter, it should be removed as soon as possible, and when thrombosis has been developed, standard anticoagulant therapy should be given. PMID- 29390473 TI - Hormone therapy as a management strategy for lung metastasis after 5 years of endometrial cancer: A case report and literature review. AB - RATIONALE: Endometrial cancer patients with lung metastases are rare, and more rarely with long-term management of progesterone after recurrence. PATIENT CONCERNS: Informed consent of the patients and their families. DIAGNOSES: Endometrial cancer (IVB) (Refer to 2009 FIGO stag of endometrial cancer). INTERVENTIONS: the patient was treated with Megestrol Acetate Dispersible Tablets (trade name Yilizhi), 160 mg, orally, once daily, without interruption. OUTCOMES: The patient has been treated with progesterone therapy for stable conditions and her survival time is already roughly a decade (December 2006-October 2016). LESSONS: Hormone therapy may as a long-term management for hormone receptor positive patients with recurrent endometrial cancer. PMID- 29390474 TI - A successful insertion of PICC in patient with cardiac angiosarcoma and neoplasty of right atrium and pacemaker: A case report. AB - INTRODUCTION: Primary cardiac angiosarcoma is a rare tumor and the common treatment is surgical resection followed by chemotherapy. Peripherally inserted central venous catheters (PICCs) are widely used in cancer patients and ultrasound-guided PICC insertion could improve success rate especially in patient with abnormal anatomy structure. Reports about PICCs being placed in patient who had suffered from the cardiac angiosarcoma and neoplasty of right atrium with an ipsilateral cardiac permanent pacemaker are rarely.After patient's informed consent, we present a case of the successful insertion of PICC into a patient with the ipsilateral cardiac disease with a pacemaker placement, which has not been previously reported. CONCLUSIONS: This report highlights PICC could be used in patient with cardiac disease with a pacemaker placement for chemotherapy. PMID- 29390475 TI - Association of the insulin-like growth factor-1 single nucleotide polymorphisms rs35767, rs2288377, and rs5742612 with osteoporosis risk: A meta-analysis. AB - BACKGROUND: Insulin-like growth factor-1 (IGF-1) plays an important role in the regulation of bone formation and mineralization. We aimed to perform a meta analysis to assess the association of three IGF-1 single nucleotide polymorphisms (SNPs) rs35767, rs2288377, and rs5742612 with osteoporosis risk. METHODS: A systematic search of PubMed, Web of Science, Embase, Medline, Scopus, CNKI, and Wanfang databases was conducted. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a fixed effects model. RESULTS: Four Chinese case control studies with a total of 2807 participants were included in this meta analysis. The results revealed an association between rs35767 and osteoporosis risk in all study subjects (women and men) in dominant (OR 1.32, 95% CI 1.13 1.53, P < .001), recessive (OR 1.73, 95% CI 1.35-2.21, P < .001), homozygote (OR 1.89, 95% CI 1.46-2.45, P < .001), and allelic (OR 1.31, 95% CI 1.18-1.47, P < .001) models. Subgroup analysis according to gender showed that rs35767 was associated with osteoporosis risk in women under dominant (OR 1.29, 95% CI 1.08 1.54, P = .005), recessive (OR 1.59, 95% CI 1.19-2.12, P = .002), homozygote (OR 1.73, 95% CI 1.28-2.34, P < .001), and allelic (OR 1.28, 95% CI 1.12-1.47, P < .001) models. Meta-analysis did not find associations of rs2288377 and rs5742612 with osteoporosis risk. There was no evidence of between-study heterogeneity and publication bias. CONCLUSION: Our results suggest that rs35767 is associated with osteoporosis risk in Chinese, whereas there is no association of rs2288377 and rs5742612 with osteoporosis risk. PMID- 29390476 TI - Ultrasound-guided percutaneous nephrolithotomy for the treatment in patients with kidney stones. AB - BACKGROUND: In this study, we aimed to explore the effect of ultrasound-guided percutaneous nephrolithotomy (UGPN) for the treatment in patients with kidney stones (KS). METHODS: We randomly assigned 86 patients with KS to a UGPN group or a control group, each group comprising 43 patients. Patients from the UGPN group underwent UGPN whereas those from control group underwent fluoroscopic-guided percutaneous nephrolithotomy (FGPN). The primary outcome included the stone-free rate. Secondary outcomes included complication rates, operative time, and length of hospitalization. RESULTS: UGPN did not show better efficacy than the FGPN procedure in decreasing stone-free rate (UGPN group 79.1% vs control group 69.8%, P = .45), operative time (UGPN group 108.4 +/- 31.7 minute vs control group 113.2 +/- 34.5 minute, P = .50), and length of hospitalization (UGPN group 2.7 +/- 1.3 days vs control group 3.1 +/- 1.5 days, P = .19). Additionally, no complications, except fever (UGPN group 4.7% vs control group 9.3%, P = .41) and hemoglobin slightly reduced (UGPN group 7.0% vs control group 11.6%, P = .46) were noted in patients from both groups in this study. CONCLUSIONS: To summarize, we demonstrated that both UGPN and FGPN techniques showed similar efficacy and complications when used for the management of KS. PMID- 29390477 TI - Randomized controlled study of efficacy and safety of drotaverine hydrochloride in patients with irritable bowel syndrome. AB - BACKGROUND: This study aimed to assess the efficacy and safety of drotaverine hydrochloride (DHC) in Chinese patients with irritable bowel syndrome (IBS). METHODS: Totally, 144 patients with IBS were included and randomly divided into treatment group and placebo group in a 1:1 ratio. Patients received either DHC or placebo 80-mg tablet, 3 times daily for a total of 4 weeks. The primary outcome included abdominal pain, measured by the visual analog scale (VAS), and weekly stool frequency. The secondary outcomes were measured by the Bristol scale, and the 36-item short form health survey (SF-36), as well as the adverse events recorded during the treatment period. All those outcomes were measured at the end of 4-week treatment. RESULTS: The total and different types of IBS in VAS, stool frequency, and Bristol score were significantly better in the treatment group than those in the placebo group at the end of 4-week treatment. However, no significant difference was found in quality of life, measured by SF-36 scale between 2 groups. Additionally, no serious and significant differences in adverse events were found in and between both groups. CONCLUSION: The findings suggest that DHC has promising efficacy to enhance symptoms of IBS in Chinese population. PMID- 29390478 TI - Increased levels of prostaglandin E-major urinary metabolite (PGE-MUM) in active mesenteric panniculitis patients: A case report. AB - RATIONALE: Mesenteric panniculitis (MP) is a rare disease with abdominal and systemic symptoms and is characterized by nonspecific inflammation, fat necrosis, and fibrosis in mesenteric fat. Active inflammatory responses may increase levels of prostaglandin E-major urinary metabolite (PGE-MUM), which was reported to reflect the disease activity of ulcerative colitis and chronic fibrosing interstitial pneumonia. We recently experienced a case with elevated PGE-MUM at the time of diagnosis of MP and we investigated the potential of PGE-MUM as a biomarker. PATIENT CONCERN: In this report we described 2 active mesenteric panniculitis patients with high PGE-MUM levels. DIAGNOSES: Mesenteric panniculitis INTERVENTIONS:: Both MP patients were measured the levels of PGE MUM. OUTCOMES: Both MP patients exhibited high levels of PGE-MUM before treatment. In one, the levels were sensitively correlated with clinical symptoms and serological markers on steroids. LESSONS: The study observations suggest the potential of PGE-MUM to reflect the disease activity of MP. To verify its use, more findings based on clinical studies should be accumulated. PMID- 29390479 TI - Biaxial reduction technique for the medially displaced quadrilateral surface in acetabular fracture through the modified iliofemoral approach: An observational study. AB - Treatment of acetabular fractures is technically demanding injuries. The complex surgical approaches and special equipment have been introduced for achieving accurate anatomical reduction.The aim of the study was to present our experiences of using a newly operative technique to achieve accurate reduction of articular dome impaction and of the quadrilateral surface without special equipment or traction device in reference to fracture reduction and fixation, technical aspects, and the incidence of complications.Five acetabular fractures with involvement of the quadrilateral plate associated anterior column and posterior hemi-transverse fractures were treated with an anatomically curved reconstruction plate and 2 lag screws using a biaxial reduction technique with a modified iliofemoral approach. The impacted quadrilateral plate was reduced without special equipment with accurate reduction of the articular surface by direct digital palpation in an extensive working space.Fracture reduction was assessed by Matta radiographic scoring as anatomic (within 1 mm) or satisfactory reduction (between 1 and 3 mm) in all 5 cases. Functional outcomes, according to the Harris hip score system, were greater than 90 points in all 5 patients. No loss of reduction, joint penetration, or visceral and neurovascular injury was documented at 1-year follow-up.The biaxial reduction technique with a modified iliofemoral approach provides a versatile method for fracture fixation and greater surgical access in medial impacted dome injury with comminuted anterior AC fracture without special equipment or traction device.Observational study, level IV. PMID- 29390480 TI - Nutritional therapy and effect assessment of infants with primary intestinal lymphangiectasia: Case reports. AB - RATIONALE: Intestinal lymphangiectasia (IL) is a rare enteropathy involving the expansion and rupture of intestinal lymphatic channels. Although several reports have studied cases of primary IL (PIL), this condition is very rare, and is even less commonly encountered in infants. This study aimed to investigate the nutritional therapy and effect assessment of chylous reflux disorder caused by PIL in infants. PATIENT CONCERNS: Infantile patients were enrolled in the Affiliated Beijing Shijitan Hospital of the Capital Medical University between January 2012 and March 2014. The minimum age of onset was 4 months and the maximum age of onset was 16 months, with an average age of 4.9 months. DIAGNOSES: All children were inpatient who had been diagnosed with chylous reflux syndrome (chylothorax and/or chylic abdomen) caused by PIL. INTERVENTIONS: Retrospective analysis and individualized nutrition therapy of these cases were carried out. Finally, nutritional therapy and prognosis of PIL were assessed and summarized. OUTCOMES: All the children survived, showed improvement in the serum total protein, albumin, and HGB levels after nutritional therapy. After comprehensive nutritional therapy, we were able to achieve diarrhea control for all the 9 patients, and after treatment, the children passed soft, yellow stools 1 to 2 times/d. After treatment, the height and weight of all patients increased to within the normal ranges of the World Health Organization standard chart. The mean serum albumin level reached 41.3 g/L. All nutrition-related indicators were found to have significant improvement compared with the baseline levels. LESSONS: The results revealed that nutritional therapy for the 9 children with PIL was effective, and it may be able to improve the clinical syndromes and symptoms of children with PIL and promote recovery. PMID- 29390481 TI - Howell-Jolly bodies and liver-spleen scanning for assessment of splenic filtrative function yields discordant results in renal transplant recipients. AB - Given discrepancies between methods for diagnosing hyposplenism, the purpose of this study was to evaluate the effect of the spleen size on the correlation between the methods, and to propose a model for improving the interpretation. Patients with renal allografts were included, in whom the spleen was assessed using Doppler ultrasound, scintiscan, and the presence of Howell-Jolly bodies (HJBs) in peripheral smears. In 35 subjects, scintiscan and HJBs were normal (Group 0); 20 had an abnormal result in both methods (Group 1); 34 had discordant results with HJBs present (Group 2); and 14 had discordant results with decreased spleen uptake (Group 3). There was no association between HJBs and scintiscan. The patients of Groups 1 and 2 had smaller spleens. The patients with smaller spleen had more hematological evidence of hyposplenism and exhibit smaller discrepancies between the methods than patients with larger spleen. The spleen can tip the balance from a normal to impaired function provided that the spleen size is below the critical mass required to maintain splenic function. A mild impairment of phagocytic function and slight dyserythropoiesis along with a small spleen would result in decreased take up of radiocolloid or the appearance of HJBs in blood smears. PMID- 29390482 TI - Is peritoneal drainage essential after pancreatic surgery?: A meta-analysis and systematic review. AB - AIM: Our objective is to assess the function of peritoneal drainage, which is placed after pancreatic surgery. BACKGROUND: With the medical advancement some study put forward that peritoneal drainage is not the necessary after pancreatic surgery; it cannot improve the complications of postoperation even leading to more infection and so on. However, there is no one study can clear and definite whether omitting the drainage after surgery or not. METHOD: Searching databases consist of all kinds of searching tools, such as Medline, The Cochrane Library, Embase, PubMed, etc. All the included studies should meet our demand of this meta analysis. In the all interest outcomes blow we take the full advantage of RevMan5 to assess, the main measure is odds ratio (OR) with 95% confidence, the publication bias are assessed by Egger test and Begg test. RESULT: The rate of postoperative pancreatic fistula (POPF) in no drainage group is much lower than that in routine drainage group (OR = 0.47, I = 43%, P < .00001). The result of the 2 randomized controlled trials (RCTs) in this pool are almost accord with the former (OR = 0.57, I = 0%, P = .05). In subgroup the result suggest that the peritoneal drainage can increase the morbidity (OR = 0.71, I = 15%, P = .0002) after pancreaticoduodenectomy (PD), but reduce the mortality (OR = 1.92, I = 8%, P = .03) after PD. In distal pancreatectomy (DP) the rate of POPF and clinically relevant pancreatic fistula (CR-PF) is lower without drainage; there is no significant difference in the CR-PF, hospital stay, intra-abdominal abscess, radiologic invention, and the reoperation. CONCLUSION: In the current meta analysis, we cannot make a clear conclusion whether to abandon the routine drainage or not, but from the subgroup we can see something is safer than nothing to routine peritoneal drainage. And the patients who underwent DP can attempt to omit the drainage. But it still needs more RCTs to assess the necessity of drainage. PMID- 29390483 TI - Spontaneous peeled ileal giant lipoma caused by lower gastrointestinal bleeding: A case report. AB - RATIONALE: Gastrointestinal subepithelial tumors (SETs) with endoscopic features such as ulceration, a red color change, a peeled mucosal layer, and spontaneous bleeding could have malignant potential. However, we encountered a case of a lipoma that presented features different from the generally known features of gastrointestinal SETs. Therefore, we report an interesting rare case of a terminal ileal giant lipoma with a unique feature of spontaneous peeled ulceration on the surface on endoscopy that caused gastrointestinal bleeding. PATIENT: An 82-year-old woman with a 1-week history of abdominal pain and hematochezia presented to our hospital. DIAGNOSES: Ileocolonoscopy revealed a SET with a peeled surface and erythematous and ulcerative mucosal changes as well as exposed a submucosal mass at the terminal ileum. Macroscopically, the lesion appeared as a yellowish pedunculated polypoid mass measuring 3 * 2 cm with a peeled mucosal ulceration. Histopathological findings revealed a submucosal lipoma of the terminal ileum. INTERVENTION: We thought that the endoscopic finding indicated malignant SETs or those with malignant potential rather than benign SETs. Therefore, the patient underwent an elective laparoscopic ileocecectomy. LESSONS: We encountered a lipoma that did not present with the typical features of gastrointestinal SETs. Our findings suggest that clinicians should consider that benign SETs in the terminal ileum may present with various endoscopic findings similar to those of malignant SETs, which can cause fatal symptoms and signs. PMID- 29390484 TI - Predictor of abnormal gallbladder ejection fraction in patients with atypical biliary pain: Histopathological point of view. AB - Cholescintigraphy has traditionally been used as a tool to select patients with biliary pain for elective cholecystectomy. However, atypical biliary pain presents a clinical challenge and there is no literature evaluating the factors of the gallbladder (GB) wall related to abnormal ejection fraction of cholescintigraphy in such patients. Therefore, we aimed to evaluate characteristics of the GB wall in patients with abnormal gallbladder ejection fraction (GBEF) on cholescintigraphy and atypical biliary pain. Patients who underwent cholescintigraphy for atypical biliary pain and subsequent cholecystectomy were initially recruited for this study. Medical records and pathologic findings of these patients were retrospectively reviewed. Parameters that were significant on univariate analysis, including factors of GB wall and cholescintigraphy, were subsequently tested by multivariate analysis to identify independent predictors for abnormal GBEF. Abnormal or low GBEF was defined as GBEF <35%. A total of 41 adult patients were divided into a low GBEF (n = 15) and a high GBEF group (n = 26) based on the cutoff value of 35%. In univariate analysis mean muscle thickness, muscle to total layer ratio, and muscle to fibrosis layer ratio were significantly higher in the low GBEF group than in the high GBEF group. In multivariate analysis, the muscle to fibrosis layer ratio was found to be an independent risk factor for abnormal GBEF (odds ratio = 3.514, 95% confidence interval = 1.058-11.673, P = .04). The fibrosis to total layer ratio was negatively correlated with GBEF in the low GBEF group (r = -0.657, P < .01). Muscle to fibrosis layer ratio was significantly associated with decreased GBEF. The fibrosis thickness ratio also seems to play an important role in patients with decreased GBEF. PMID- 29390485 TI - Antiangiogenic therapy for primitive neuroectodermal tumor with thalidomide: A case report and review of literature. AB - RATIONALE: Peripheral primitive neuroectodermal tumor (PNET) is a kind of small round cell tumor derived from primitive neuroectodermal tumor. PATIENT CONCERNS: PNET is a highly malignant tumor that is subordinated to Ewing sarcoma. It occurs predominantly in soft tissue and bone and rarely in the bronchi and lung. Traditional surgery, radiotherapy, and chemotherapy are used for the treatment of PNET, but are usually ineffective. DIAGNOSES: There was a rare case of a 17 year old man diagnoses with primary pulmonary PNET. INTERVENTIONS: The patient was treated by the remedy treatment with thalidomide after the poor effect of conventional radiotherapy and chemotherapy. OUTCOMES: The patient survived without disease progression for 15 months and was in stable condition. LESSONS: Thalidomide provides a choice for maintenance therapy in PNET. PMID- 29390486 TI - Diagnostic value of thallium-201 myocardial perfusion IQ-SPECT without and with computed tomography-based attenuation correction to predict clinically significant and insignificant fractional flow reserve: A single-center prospective study. AB - The aim of this study was to clarify the predictive value of fractional flow reserve (FFR) determined by myocardial perfusion imaging (MPI) using thallium (Tl)-201 IQ-SPECT without and with computed tomography-based attenuation correction (CT-AC) for patients with stable coronary artery disease (CAD).We assessed 212 angiographically identified diseased vessels using adenosine-stress Tl-201 MPI-IQ-SPECT/CT in 84 consecutive, prospectively identified patients with stable CAD. We compared the FFR in 136 of the 212 diseased vessels using visual semiquantitative interpretations of corresponding territories on MPI-IQ-SPECT images without and with CT-AC.FFR inversely correlated most accurately with regional summed difference scores (rSDS) in images without and with CT-AC (r = 0.584 and r = -0.568, respectively, both P < .001). Receiver-operating characteristics analyses using rSDS revealed an optimal FFR cut-off of <0.80 without and with CT-AC. Although the diagnostic accuracy of FFR <0.80 did not significantly differ, FFR >=0.82 was significantly more accurate with, than without CT-AC. Regions with rSDS >=2 without or with CT-AC predicted FFR <0.80, and those with rSDS <=1 without and with CT-AC predicted FFR >=0.81, with 73% and 83% sensitivity, 84% and 67% specificity, and 79% and 75% accuracy, respectively.Although limited by the sample size and the single-center design, these findings showed that the IQ-SPECT system can predict FFR at an optimal cut off of <0.80, and we propose a novel application of CT-AC to MPI-IQ-SPECT for predicting clinically significant and insignificant FFR even in nonobese patients. PMID- 29390487 TI - The prognostic value of abnormally expressed lncRNAs in prostatic carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: Several long noncoding RNAs (lncRNAs) are abnormally expressed in prostate cancer (PCa), suggesting that they could serve as novel prognostic markers. The current meta-analysis was undertaken to better define the prognostic value of various lncRNAs in PCa. METHODS: The PubMed, Embase, Medline, and Cochrane Library databases were systematically searched up to February 19, 2017, to retrieve eligible articles. Outcomes analyzed were biochemical recurrence-free survival (BRFS), overall survival (OS), metastasis-free survival (MFS), and prostate cancer-specific survival (PCSS). Pooled hazard ratios (HRs) and 95% confidence intervals (95%CIs) were calculated using fixed-effects or random effects models. RESULTS: A total of 10 studies, evaluating 11 PCa-related lncRNAs, were included in the meta-analysis. Pooled results indicate that the abnormal expression of candidate lncRNAs in PCa samples predicted poor BRFS (HR: 1.67, 95%CI: 1.37-2.04, P < .05), without significant heterogeneity among studies (I = 44%, P = .06). Low PCAT14 expression was negatively associated with OS (HR: 0.66, 95%CI: 0.54-0.79, P < .05), MFS (HR: 0.59, 95%CI: 0.48-0.72, P < .05), and PCSS (HR: 0.50, 95%CI: 0.38-0.66, P < .05). Again, there was no significant heterogeneity among studies. The robustness of our results was confirmed by sensitivity and publication bias analyses. CONCLUSION: We conclude that expression analysis of selected lncRNAs may be of prognostic value in PCa patients. PMID- 29390488 TI - Evaluation of takayasu arteritis with delayed contrast-enhanced MR imaging by a free-breathing 3D IR turbo FLASH. AB - The primary aim of our case-control study was to observe delayed contrast enhanced magnetic resonance imaging (DCE-MRI) in patients with Takayasu arteritis (TA) in comparison with magnetic resonance angiography (MRA). Twenty-seven patients including 15 with active TA and 12 with stable TA who underwent both aortic MRA and DCE-MRI were included. A total of 27 sex- and age-matched healthy volunteers were enrolled as the control group. MRA were obtained with T1WI-volume interpolated breath-hold examination sequence or fast low-angle shot (FLASH) sequence. DCE-MRI was acquired with a free-breathing three-dimensional inversion recovery Turbo fast low-angle shot (3D IR Turbo FLASH). Neither stenosis nor delayed enhancement of arterial wall was shown in the control group. In patients with stable TA, arterial stenosis was observed on MRA. On DCE-MR, delayed enhancement of arterial walls could be observed in the active TA group but not in the stable TA group or the control group. Stenotic arteries on MRA were comparable in the active TA and stable TA (chi = 2.70, P = .259); however, delayed enhancement of arterial walls in the active-TA group were more than those in the stable group (chi = 27.00, P < .001). Our results suggest that DCE-MRI with the free-breathing 3D IR Turbo FLASH sequence could assess TA and delayed enhancement on DCE-MRI is one characteristics of the active TA. PMID- 29390490 TI - Ptosis induced by topical steroid eye drops: Two cases reports. AB - RATIONALE: Ptosis is a rare complication of periocular steroid use. Studies report that local injections of steroids produce ptosis. We describe the first 2 cases of ptosis because of long-term treatment with topical steroid eye drops. PATIENT CONCERNS: Two cases admitted to our hospital because of ptosis of their right eye after long-term treatment with topical steroid eye drops. Both of them had uncontrolled Posner-Schlossman syndrome. DIAGNOSIS: Two cases were diagnosed as steroid-related ptosis. INTERVENTIONS: Regulatory anti-inflammation therapy was prescribed for case 1, and after inflammation control, phacoemulsification was done for her. Six months after steroid withdrawal, the levator resection of the right eye was performed. Case 2 refused our advice of steroid reduction and ptosis surgery. OUTCOMES: After surgery, case 1 retained a symmetrical appearance during a 1-year follow-up. In the surgery, we found thin levator muscles and slack levator palpebrae superioris aponeurosis (LPSA) in the affected eye. Postoperative transmission electron microscopy revealed typical signs of apoptosis in levator muscle cells. LESSONS: We suggest topical application of steroids induces levator muscle apoptosis and LPSA weakness, and results in ptosis. PMID- 29390489 TI - Percutaneous kyphoplasty versus posterior spinal fixation with vertebroplasty for treatment of Kummell disease: A case-control study with minimal 2-year follow-up. AB - This is a retrospective case-control study.The aim of this study was to compare the surgical results of percutaneous kyphoplasty (KP) and posterior spinal fixation with vertebroplasty (PSF+VP) for treatment of Kummell disease (KD).KD is rare form of post-traumatic delayed avascular necrosis of the vertebral body. It is reported that KP is an effect measure for treatment of KD. Some studies have recommended posterior spinal fixation with vertebroplasty for KD.A total of 100 patients with KD who underwent spinal surgery at our hospital were enrolled from January 2008 to December 2013. The inclusion criteria were monosegment lesion without neurological deficit; the segments are restricted to T11-L2; conservative treatment is invalid. The exclusion criteria were metastatic spinal tumors, infection, primary bone tumor, and multiple myeloma; bisegments and multi segments; patients with neurological symptoms; the defect of posterior wall of vertebral body; the occupying of vertebral canal. The symptomatic vertebrae were restricted to T11-L2. Patients who were followed-up for less than 2 years after surgery were excluded. Finally, there are 25 patients in the KP group and 21 in the PSF+VP group. There were no significant differences in patient age, disease duration, or the length of follow-up between the 2 groups.Operative time (43.2 +/ 21.8 vs 230.6 +/- 87.1 minutes) was significantly longer and bleeding volume (5.3 +/- 3.1 vs 215.0 +/- 170.2 mL) significantly greater in the PSF+VP group. No significant difference between the 2 groups was observed in Visual analog scale score (VAS) (1.3 +/- 0.9 vs 1.2 +/- 0.9), Oswestry disability index score (ODI) (27.2 +/- 9.0 vs 26.0 +/- 6.3), and Cobb angle (17.0 +/- 7.2 vs 16.5 +/- 2.8). KP resulted in a shorter operation time, less bleeding volume, and fewer postoperative complications than PSF+VP.This study shows that both treatments KP and PSF+VP for KD can be safe and effective for the patients with monosegment lesion and without neurological deficit. However, KP show the advantages in a shorter surgical duration, less blood loss, and fewer postoperative complications. PMID- 29390491 TI - Absent-mindedness and injury of the ascending reticular activating system in a patient with mild traumatic brain injury: A case report. AB - RATIONALE: No study on the association of absent-mindedness and injury of the ascending reticular activating system (ARAS) has been reported. We report on a patient who showed absent-mindedness and injury of the ARAS following mild traumatic brain injury. PATIENT CONCERNS: The patient complained of absent mindedness since the head trauma, which was mainly observed while dining for several (5-10) minutes approximately 3 to 4 times a day: according to the patient's family, he usually stopped eating while holding the spoon in the air for approximately 5~10 minutes. DIAGNOSES: A 19-year-old man suffered from head trauma resulting from being hit on his head by a falling glass from a large window (1.5 * 2 m, approximately 100 kg) at a cafe. INTERVENTIONS: His absent mindedness showed slow improvement with the passage of time and had almost disappeared at seven months after onset. OUTCOMES: The lower portion of both lower dorsal ARAS and the upper portion of the left lower ventral ARAS of the patient were thinner, and partial tearing was observed in the right lower ventral ARAS. Decreased neural connectivity of the intralaminar thalamic nucleus to the prefrontal cortex, basal forebrain, parietal cortex, and occipital cortex was detected in both hemispheres. LESSONS: Injury of the ARAS and injury of the cerebral cortex was demonstrated in a patient with absent-mindedness following mild traumatic brain injury. The absent-mindedness in this patient might be related to the injury of the ARAS. PMID- 29390492 TI - The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children. AB - The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 +/- 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 +/- 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL. PMID- 29390493 TI - Traditional Chinese medicine as an adjunctive therapy to oral montelukast for treating patients with chronic asthma. AB - BACKGROUND: This study aimed to explore the efficacy and safety of Ping Chuan Ke Li (PCKL) as an adjunctive therapy to oral montelukast compared with placebo plus montelukast for treating patients with chronic asthma (CAS). METHODS: This randomized controlled trial involved 72 patients with CAS. They were randomly allocated to an intervention group or a control group, 36 subjects per group. Participants in the intervention group received PCKL and oral montelukast, while those in the control group received placebo and oral montelukast. The primary outcome was lung function, measured by forced expiratory volume in 1 second (FEV1). The secondary outcomes included quality of life, measured by St. George's Respiratory Questionnaire (SGRQ), and adverse events (AEs). RESULTS: Compared to placebo plus montelukast, PCKL and montelukast revealed greater efficacy in lung function, measured by FEV1 (P <.05), and quality of life, measured by the SGRQ scale (P <.05). Additionally, no significant differences were found in AEs between the 2 groups. CONCLUSION: Traditional Chinese medicine PCKL as an adjunctive therapy to oral montelukast alleviated the symptoms of CAS. Future studies with larger sample sizes are still needed to verify the efficacy and safety of PCKL plus montelukast in patients with CAS. PMID- 29390494 TI - A possible synergistic effect of MTHFR C677T polymorphism on homocysteine level variations increased risk for ischemic stroke. AB - BACKGROUND: Homocysteine (Hcy) plays an important role in vascular function and Hcy level contributes to pathogenesis of ischemic stroke (IS). MTHFR gene polymorphism may have effects on IS risks by influencing the Hcy metabolic pathway. In the present study, a case-control study was designed to evaluate the relationship among MTHFR C677Tpolymorphism, plasma Hcy level, and susceptibility of IS in Chinese population. METHODS: A total of 300 patients with IS and 261 matched control subjects were recruited. Plasma Hcy concentration was determined using enzymatic cycling assay. MTHFR C677T polymorphisms were genotyped by PCR RFLP. RESULTS: Compared with controls, the plasma Hcy level was significantly higher in the IS patients (P < .05). After adjusting for conventional risk factors, the T allele frequency of MTHFR C677T in IS group (54%) was significantly higher than that in the controls (38.3%) (P < .05; OR = 1.890, 95% CI: 1.489-2.399). Additionally, the plasma Hcy level of the TT genotype is significantly higher than that of the CC and CT genotypes (P < .05). CONCLUSION: Our study provided evidence that hyperhomocysteinemia (HHcy) and MTHFR C677T polymorphism were associated with IS. More importantly, suggesting that a possible synergistic effect of MTHFR C677T polymorphism on Hcy level variations increased risk for IS in Chinese population. PMID- 29390495 TI - A boy with 13.34-Mb interstitial deletion of chromosome 4p15: A new case report and review of the literature. AB - RATIONALE: To date, >40 cases have been described with interstitial deletions involving the 4p15 region. PATIENT CONCERNS AND DIAGNOSIS: We report a case of a 3-year-old boy with an interstitial de novo deletion of approximately 13.34 Mb in 4p15.1-15.31 having mild developmental delay and multiple minor congenital abnormalities. LESSONS: This case presents a clinical manifestation that is similar but not identical to other reported cases. In this report, we have provided a detailed description of a 3-year-old patient with an interstitial 4p deletion and mildly affected phenotype. We discuss the possible involvement of SLIT2, KCNIP4, and LGI2 in cortical development and RBPJ in skeletal abnormalities. PMID- 29390496 TI - A study on dynamic monitoring, components, and risk factors of embolism during total knee arthroplasty. AB - BACKGROUND: Fat embolism is a common complication of orthopedic surgery. However, the exact component and risk factor responsible for this complication remains unelucidated. This study aimed to detect the origin of the pulmonary embolus and identify relevant risk factors of pulmonary embolism in total knee replacement. METHODS: A total of 40 osteoarthritis patients who underwent primary unilateral TKA were recruited into this study. Transesophageal echocardiography (TEE) was utilized to dynamically monitor the embolism. Pulmonary arterial pressure was recorded and biopsies were obtained from the medullary cavity during surgery. RESULTS: After tourniquet release, the arterial embolism was observed by TEE to have a peak signal at 30 seconds when pulmonary arterial pressure was increased by 25% to 40% (P = .002). The pathology study of the embolism revealed its bone marrow origin. Total embolus quantity was positively correlated with age (P = .021), body mass index (BMI, P = .041), and fat content of the bone marrow (P = .003). Logistic regression analysis revealed that the fat content of the marrow (OR: 1.432, 95% CI: 1.335-1.592), age (OR: 1.632, 95% CI: 1.445-1.832), and BMI (OR: 1.231, 95% CI: 1.032-1.381) were risk factors for pulmonary hypertension. CONCLUSION: This study revealed that the embolus detected in the right atrium was derived from bone marrow tissues, and this led to pulmonary arterial pressure fluctuations after tourniquet release. Therefore, elderly patients who have high BMI or bone marrow fat content are at high-risk for pulmonary fat embolism during TKA. PMID- 29390497 TI - The short-term effectiveness of balance taping on acute nonspecific low-back pain: A case report. AB - RATIONALE: Low back pain has a significant socioeconomic impact. Repetitive lifting, with combined twisting and flexion motions of the lumbar spine, increases the risk for low-back pain and injury to the supporting tissues. PATIENT CONCERNS: A 60-year-old male who presented with acute low-back pain, with a pain intensity of 6/10 on the visual analog scale (VAS) and an Oswestry disability index (ODI) score of 70%. The range of motion (ROM) of the lumbar spine on initial examination, relative to the normal peak ROM, was as follows: extension, 12 degrees /30 degrees ; flexion, 15 degrees /80 degrees ; left rotation, 15 degrees /45 degrees ; and right rotation, 25 degrees /45 degrees . DIAGNOSES: He was diagnosed as acute nonspecific low-back pain sustained with repetitive lifting, combining motions of flexion and twisting. INTERVENTIONS: The balance taping was applied for 16 h/day, on average, for 3 consecutive days was used as the primary treatment to manage the patient's low-back pain. OUTCOMES: The application of balance taping increased the range of motion of the lumbar spine as follows: flexion, from 15 degrees to 77 degrees ; extension, from 12 degrees to 27 degrees ; right rotation, from 25 degrees to 45 degrees ; and left rotation, from 15 degrees to 45 degrees . The ODI score decreased from 70% to 0%, and the VAS score from 6/10 to 0. LESSONS: We propose that balance taping using kinesiology tape could serve as a complementary approach to other treatments for the treatment of acute nonspecific low-back pain. PMID- 29390498 TI - Assessment of radiation safety in cardiac CT angiography. AB - This study investigates the radiation dose and image quality of patients not receiving beta-blockers for cardiac CT angiography (CCTA) with or without the optimization of electrocardiographic (ECG) pulsing window. The differences in patient characteristics are also characterized.Normal-weight and obese patients (n = 154) with heart rates between 65 and 80 beats per minutes (bpm) during the prospective axial scanning were enrolled retrospectively. The ECG pulsing windows were set at 50% to 75% (Group A) or 60% to 75% (Group B) of the R-R interval for patients with heart rate variability higher than or not exceeding +/-5 bpm, respectively. The effective doses of individual patient were estimated from the dose length product of the CCTA scan. Two radiologists independently reviewed the images and applied a 4-point Likert scale for image quality assessment. The patients' characteristics were compared along with the patients' effective doses between groups.The optimized pulsing window significantly reduced the average radiation dose for normal-weight and obese patients by 33% and 27%, respectively. The CCTA image quality of patients in Group A was not different overall from those obtained from Group B. Nondiabetic obese patients were more likely to be accepted for the use of the optimized pulsing window. Unlike obese patients, normal-weight patients revealed no characteristic difference between Groups A and B.This study indicates an equivalent efficacy of using optimized pulsing windows for reducing the radiation dose for patients without beta-blocker administration between different body weight groups. Nevertheless, gender and diabetic status became prominent characteristics in the obese group when matching up with the optimized pulsing window. PMID- 29390499 TI - Rapid metastasis of mediastinal solitary fibrous tumor: Report a case. AB - RATIONALE: Mediastinal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms. Complete resection is considered as the effective treatment and the prognosis is quite good. Rapid metastasis after surgery is extremely rare. PATIENT CONCERNS: In this case report we describe a 42-year-old man who present with a mediastinal malignant SFTs. Enhanced computed tomography of chest revealed a 4.5 * 4.0-cm mass in the anterior mediastinum. DIAGNOSES: The tumor is composed of massive proliferation of atypical spindle cells. Immunohistochemical staining for cluster of differentiation (CD) 34, CD99, and vimentin were strongly positive. INTERVENTIONS: Due to the possibility that the tumor was malignant, a standard median sternotomy was performed under general anesthesia. The mediastinal tumor and the affected part of the pericardium and right upper lobe of the lung were completely resected. OUTCOMES: The patient underwent surgery and recovered uneventfully. After 2 months follow-up postoperation, there was recurrence in the chest wall and right middle lung. The patient refused any treatment and was dead after 2 months. LESSONS: The present cases indicate that mediastinal SFTs should always be kept in mind for rapid metastasis. Once found, surgical intervention should be performed promptly. Due to the rapid metastasis, radiotherapy, and chemotherapy may be needed after surgery and long-term follow up is required to monitor the metastasis of this type of tumor. PMID- 29390500 TI - Development of indicators for assessing rational drug use to treat community acquired pneumonia in children in hospitals and clinics: A modified Delphi study. AB - Community-acquired pneumonia (CAP) is a common infectious disease in children. Rational drug use (RDU) is an important approach to reducing the disease burden and mortality rate of CAP in children. There are no monitoring indicators for assessing RDU in children. This study aimed to develop a set of indicators to assess RDU to treat CAP in children in hospitals and clinics using a modified Delphi method.Initial indicators were generated based on a systematic review of guidelines and studies investigating CAP in children. A 3-round modified Delphi process in the form of an email survey combined with round-table discussion was then carried out, and an analytic hierarchy process (AHP) was applied to determine the weight of each indicator.A total of 24 and 8 experts were invited to participate in the email survey and round-table discussion, respectively. A consensus was reached after 3 rounds of the Delphi survey. Three first-rank indicators and 23 second-rank indicators were developed, and each indicator was weighted. The first-rank indicators comprised drug choice (45.5%), drug usage and dosage (36.4%), and the duration of drug therapy (18.2%); the second-rank indicators were indicators related to antibiotics (63.6%), antiviral agents (18.2%), traditional Chinese medicines (4.5%), and adjuvant drugs (13.6%). The weight value of drug selection was the highest, followed by the values of drug usage and dosage and the duration of drug therapy.The developed indicator set constitutes the first set intended to assess RDU to treat CAP in children in hospitals (including community hospitals) and clinics. The indicators were based on drug selection, drug usage and dosage and duration of drug therapy, which are associated with most therapeutic drugs for CAP in children. Monitoring these indicators will guide people towards the promotion of RDU in the absence of drug monitoring indicators for CAP. Furthermore, the indicator set constitutes a methodological reference for the development of other indicator sets. PMID- 29390501 TI - Space-time acupuncture for intractable cough after lupus nephropathy: A case report and literature review. AB - RATIONALE: Some intractable chronic cough remains a common complaint for seeking medical care. Unexplained cough in lupus nephropathy patient is rare and therapeutic options are limited. PATIENT CONCERNS: A 57 year-old woman with a 7 year history of lupus nephropathy. She has suffered from chronic cough for 3 years accompanied with chronic low back pain and fatigue, as the conventional therapy cannot relieve the symptoms. DIAGNOSES: The woman is diagnosed as intractable cough after lupus nephropathy. INTERVENTIONS: 9 times space-time acupuncture (STA) treatment was performed. OUTCOMES: The cough, as well as other uncomfortable symptoms like chronic low-back pain and fatigue have resolved, and no relapse for one year follow-up. LESSONS: STA may be an effective therapy to treat intractable chronic cough. PMID- 29390502 TI - Male occult breast cancer with axillary lymph node metastasis as the first manifestation: A case report and literature review. AB - RATIONALE: Occult breast cancer (OBC) is extremely rare in males with neither symptoms in the breast nor abnormalities upon imaging examination. PATIENT CONCERNS: This current case report presents a young male patient who was diagnosed with male OBC first manifesting as axillary lymph node metastasis. The physical and imaging examination showed no primary lesions in either breasts or in other organs. DIAGNOSES: The pathological results revealed infiltrating ductal carcinoma in the axillary lymph nodes. Immunohistochemical (IHC) staining was negative for estrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)20 and thyroid transcription factor-1 (TTF-1), positive for CK7, gross cystic disease fluid protein-15 (GCDFP-15), epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), and suspicious positive for human epidermal receptor-2 (Her-2). On basis of IHC markers, particularly such as CK7, CK20 and GCDFP-15, and eliminating other malignancies, male OBC was identified in spite of negativity for hormone receptors. INTERVENTIONS: The patient underwent left axillary lymph node dissection (ALND) but not mastectomy. After the surgery, the patient subsequently underwent chemotherapy and radiotherapy. OUTCOMES: The patient is currently being followed up without any signs of recurrence. LESSONS: Carefully imaging examination and pathological analysis were particularly essential in the diagnosis of male OBC. The guidelines for managing male OBC default to those of female OBC and male breast cancer. PMID- 29390503 TI - Extramedullary plasmacytoma occuring in ileocecum: A case report and literature review. AB - RATIONALE: Gastrointestinal solitary extramedullary plasmacytoma (EMP) is rare, just occupies about 5% of all EMPs. The most common site is small intestine followed by stomach. The colorectal incidence is much rare. PATIENT CONCERNS: A 63-year-old female had an episodic pain around the umbilicus for about one week. The hyperemia and edema in the ileocecal mucosa were found in colonoscopy, and the endoscopy could not cross the ileocecal valve. The pathology specimens showed a high index suspicion of plasmacytoma. DIAGNOSES: The patient was diagnosed with extramedullary plasmacytoma. INTERVENTIONS: A right hemicolectomy surgery was performed to treat the disease. OUTCOMES: Post surgery pathologic report showed low grade malignant mucosa associated marginal zone B cell lymphoma. LESSONS: We report a case of an extramedullary plasmacytoma in ileocecum with abdominal pain and a review of extramedullary plasmacytoma. PMID- 29390504 TI - Relationship between general anesthesia and Alzheimer disease: A protocol for a systematic review and meta-analysis. AB - BACKGROUND: Alzheimer disease (AD) entails a long-term progressive decline in the cognitive ability to think and remember, and it has become a major concern for patients receiving surgery and anesthesia. However, studies investigating the relationship between general anesthesia and AD have yielded inconsistent results. Therefore, we plan to perform a systematic review and meta-analysis to determine the relationship between general anesthesia and AD, and to verify whether general anesthesia is an independent risk factor for AD. METHODS: A systematic and comprehensive search will be performed using MEDLINE, EMBASE, and Google scholar from their inception to August 2017. Peer-reviewed cohort and case-control studies including nested case-control studies reporting the relationship between general anesthesia and AD will be eligible for inclusion. The quality of included studies will be assessed using the Newcastle-Ottawa scale. Heterogeneity of estimates across studies as well as publication bias will be assessed. This systematic review and meta-analysis will be performed according to the Meta analysis of Observational Studies in Epidemiology (MOOSE) guidelines and reported according to the Preferred Reporting Items for Systematic reviews and Meta Analysis (PRISMA) guidelines. All statistical analyses will be conducted using the Stata SE version 15.0. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: Our study will provide the evidence for the relationship between general anesthesia and dementia. The review will benefit patients and anesthesiologists, surgeons, and policymakers. ETHICS AND DISSEMINATION: Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. TRIAL REGISTRATION: The protocol for this review has been registered in the PROSPERO network (registration number: CRD42017073790). PMID- 29390505 TI - Blood-letting therapy for the common cold: A protocol for a systematic review of controlled trials. AB - BACKGROUND: Many people experience the common cold, but there is currently no special treatment. For this reason, complementary and alternative medicine (CAM) therapies are used to improve the symptoms of the common cold. Blood-letting therapy (BL) is a CAM therapy that has been used for over 2000 years to treat various diseases. However, few studies have provided evidence for the efficacy and safety of BL for the common cold. This study aims to assess the effectiveness and safety of BL for the common cold. METHODS AND ANALYSIS: A total of 11 databases will be searched for studies conducted through June 2017. We will include randomized controlled trials assessing BL for the common cold. All randomized controlled trials on BL or related interventions will be included. Risk of bias will be assessed using the Cochrane Risk of Bias Assessment Tool, while confidence in the accumulated evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to inform and guide healthcare practices. PMID- 29390506 TI - Efficacy and safety of nanoparticle albumin-bound paclitaxel monotherapy as second-line therapy of cytotoxic anticancer drugs in patients with advanced non small cell lung cancer. AB - BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), which avoids toxicities associated with a vehicle used in solvent-based PTX, has already shown safety and efficacy in patients with non-small cell lung cancer (NSCLC). METHODS: A phase II study was performed to assess the safety and efficacy of nab-PTX monotherapy as second-line chemotherapy after cytotoxic anticancer drugs for previously treated advanced NSCLC. Thirty-two patients with advanced NSCLC who had previously undergone 1 regimen of cytotoxic anticancer drugs were enrolled. Nab-PTX was administered intravenously at a dose of 100 mg/m on days 1, 8, and 15 of a 28-day cycle. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile were evaluated. RESULTS: The ORR was 28.1%, the DCR was 71.9%, median PFS was 3.9 months (95% confidence interval [CI] 2.7-5.1 months), and median OS was 10.9 months (95% CI 9.5-12.3 months). The mean relative dose intensity of nab-PTX was 77%. Grade 3 or 4 neutropenia, and grade 3 febrile neutropenia were observed in 11 and 1 of 32 patients, respectively. As nonhematologic toxicities, grade 3 peripheral sensory neuropathy and pneumonitis were each observed in 2 of 32 patients. CONCLUSION: Nab-PTX is an active and well-tolerated regimen in patients with previously treated NSCLC. PMID- 29390507 TI - Arterial stiffness assessment in patients with phenylketonuria. AB - In patients with phenylketonuria (PKU) compliant to diet greater tendency to overweight and higher inflammatory biomarkers levels than controls were reported. Although this could lead to atherogenesis, the elastic properties of large arteries in PKU patients have never been assessed. The aim of this study was to assess arterial stiffness measured by applanation tonometry in PKU patients compared to healthy controls.We carried out a cross-sectional study in 41 PKU patients (range age: 6-50 years old) and 41 age- and gender-matched healthy controls. Evaluated data included pharmacological treatment with sapropterin, clinical, and biochemical parameters. Aortic stiffness was assessed noninvasively by applanation tonometry measuring central blood pressure, aortic augmentation index (Aix@HR75), augmentation pressure (AP), and pulse wave velocity (PWV).We found higher PWV in classic PKU patients (6.60 m/second vs 5.26 m/second; P: .044). Percentage of PKU patients with PWV above 90 percentile was higher than controls (14.63% vs 2.32%; P: .048). A positive relationship was observed between the annual Phe median and PWV (r: 0.496; P: .012). PKU subjects with lower Phe tolerance showed more body weight (67.6 kg vs 56.8 kg; P: .012) and more PWV than those with higher Phe tolerance (6.55 m/second vs 5.42 m/second; P: .044).Our data show increased aortic stiffness in PKU patients, measured by applanation tonometry, when compared to healthy controls. Higher Phe levels are associated with a bigger PWV increase, which is not present in those subjects compliant to diet or under sapropterin treatment. These results could have marked effects in both research and clinical daily practice for a proper evaluation of cardiovascular risk in PKU subjects. PMID- 29390508 TI - Analysis of early death in newly diagnosed acute promyelocytic leukemia patients. AB - The aim of this study was to identify risk factors for early death (ED) in acute promyelocitic leukemia (APL) patients.Clinical records of 49 APL patients who suffered ED were divided into 4 groups: death before treatment or within the first 3 days (immediate death; iED group), death during treatment at least 3 days after commencement (ED after treatment), low/intermediate risk, and high-risk groups.White blood cell (WBC) count, high-risk cases, prothrombin time (PT) prolongation, international society on thrombosis and hemostasis (ISTH) scores (P < .05), bleeding (P = .05), and death due to severe hemorrhage (P = .010) were higher in iED group than ED after treatment. And the time from onset to initial hospitalization or death was significantly shorter (P < .05) in iED patients. LDH level (P = .002), PT prolongation (P = .014), and incidence of grades 3 or 4 bleeding (P = .049) were higher in high-risk group than in ED and low/intermediate-risk groups, while the times from onset to the initial hospitalization or death were lower for ED patients in high-risk group (P = .037).We found that different types of EDs have different clinical features. A high WBC count contributes to the occurrence of more ED, which is usually not associated with delay of diagnosis and hospitalization. Current therapeutic strategies to reduce the incidence of ED in these cases are not adequate and will benefit from focused research attention. PMID- 29390509 TI - Skeletal-related events and overall survival of patients with bone metastasis from nonsmall cell lung cancer - A retrospective analysis. AB - Because of improving treatments and survival, 40% to 58% of patients with bone metastases from nonsmall cell lung cancer (NSCLC) will suffer from at least one skeletal-related event (SRE), affecting their quality of life, but the natural history of SRE is poorly understood. The study aimed to examine the factors involved in SRE-free survival (SRS) and overall survival (OS) of patients with NSCLC and bone metastases.This was a retrospective study of 211 patients with bone metastasis from NSCLC and treated at the Tumor Hospital Affiliated to Harbin Medical University between January 2007 and January 2012. OS and SRS were evaluated by the Kaplan-Meier method. The factors associated with SRS and OS were examined using multivariate Cox analyses.The 1 year OS was 55.9% and the median OS was 30 months (range, 1-98 months). Multivariate analyses showed that clinical staging at initial diagnosis (P < .001) and SRE (P = .033) were independently associated with OS, and clinical staging at initial diagnosis (P = .009), bone pain (P = .008), primary tumor radiotherapy (P < .001), and chemotherapy (P = .031) were independently associated with SRS. Stage I, II, and III patients under biphosphonate therapy fared better than those without biphosphonate treatment, but there was no difference for stage IV patients.The identification of factors associated with OS and SRS of patients with NSCLC and bone metastases should provide new clues for a better management of these patients. PMID- 29390510 TI - Differentiation of direct and indirect socioeconomic effects on suicide attempts in South Korea. AB - Despite the wide recognition of the inverse association between socioeconomic position (SEP) and suicidal behaviors, its underlying process and potential mediators are little known. This study investigated the pathway from SEP to suicide attempts with attention to potential mediators.From the Korean Health and Nutrition Examination Survey 2007-2013, which is a nationwide cross-sectional survey of the health and nutritional status, a total of 34,565 participants (>=30 years) were included in the analysis. To unfold the pathways linking SEP to suicide attempts, the direct and indirect effects of 3 SEP measures (educational attainment, household income, and occupational group) and 3 mediators (physical illness, mental health problems, and problematic drinking) were differentiated using structured equation model (SEM).Most of direct and indirect effects of educational attainment, household income, and occupational group on suicide attempts were significant; Nonemployment status had the largest total (beta = 0.291, P < .01) and direct effects (beta = 0.212, P < .01), while educational attainment had the largest indirect effect (beta = -0.124, P < .01). Educational attainment was mainly mediated by physical illness and problem drinking, whereas household income and occupational group were mainly mediated by anxious or depressed mood and problem drinking. Physical illness played a major role in explaining suicide attempts, compared to mental health problem and problem drinking.Overall, experience of socioeconomic disadvantage increased suicide attempts independently of mental and physical problems. An extension of suicide prevention program is required for comprehensively targeting people with general problems such as physical illness and low SEP, complemented to narrowly targeting high risk group with, such as mental health problem. PMID- 29390511 TI - Mandibular Fracture Patterns at a Medical Center in Central Taiwan: A 3-Year Epidemiological Review. AB - Mandibular fractures constitute a major portion of maxillofacial trauma and may lead to considerable functional and aesthetic sequelae if treatment is inadequate or delayed. An epidemiology study on mandibular fractures may guide the preventive efforts of the Taiwan public health care system. Therefore, a retrospective review was conducted at a medical center in central Taiwan to evaluate the current mandibular fracture epidemiology.The medical records and digitized radiographs of 198 patients who received treatment for mandibular fractures during a 3-year period (from October 2010 to September 2013) at a medical center in central Taiwan were reviewed to obtain demographic and injury data.The average age was 29.4 years (3-82 years). Patients aged 21 to 30 years sustained the most mandibular fractures (62 patients, 31.3%). The overall sex distribution (male to female) ratio was 1.8. Motor-vehicle accidents (MVAs) were the most common mechanism of injury (162 patients, 82%), and scooter and motorcycle riders wearing partial-coverage helmets constituted the majority of patients. A chart review identified 198 patients with 335 mandibular fractures; 113 patients (57.1%) had multiple mandibular fractures. The most common fracture sites were the symphysis and parasymphysis regions (38.9%), followed by the condyle (26.0%), angle (14.3%), body (14.3%), and ramus (6.6%).MVAs are the major cause of mandibular fractures in central Taiwan, and patients aged <30 years sustained the most mandibular fractures. Compared with previous studies, the present study has a higher percentage of women with mandibular fractures. In addition, inadequate mandibular protection by partial-coverage helmets may be a major reason for mandibular fractures most commonly localized in the symphysis and parasymphysis regions. The incidence and causes of mandibular fractures may reflect the trauma patterns within the community, thus facilitating the development of a preventive strategy for the socioeconomic and environmental background of central Taiwan. PMID- 29390512 TI - Venous thromboembolism related to cytomegalovirus infection: A case report and literature review. AB - RATIONALE: Herein, we present a case of seemingly unprovoked portal vein thrombosis (PVT) occurring in the context of an acute cytomegalovirus (CMV) infection and prolonged debilitating fatigue. PATIENT CONCERNS: A 46-year-old male airline pilot presented with a 2 week history of abdominal pain, nausea, vomiting, watery diarrhea, and daily recurrent fevers. This was in the context of progressive, debilitating fatigue for 3 months forcing the patient to leave his job. DIAGNOSES: Computed tomography of the abdomen revealed PVT, which was managed initially by heparin infusion. Cefepime was ordered for broad-spectrum antibiotic management of sepsis and possible septic thrombosis. Further workup exposed elevated transaminases consistent with mild hepatitis without synthetic dysfunction and colonoscopy revealed colitis. A comprehensive evaluation for liver disease was notable for a markedly elevated ferritin level. Spiking fevers and neutrophilia persisted for several days despite empiric antimicrobial treatment, but eventually resolved. The remainder of the workup was negative except for positive CMV IgM titer and viral load. This raised suspicion for a hypercoagulable state caused by CMV hepatitis with CMV-induced PVT. Heparin was transitioned to warfarin at the time of discharge. INTERVENTIONS: Given the patient's immunocompetent state and resolution of fevers, antiviral therapy for CMV infection was not initiated. OUTCOMES: The patient continued to improve with a normalization of the serum ferritin level and anticoagulation therapy was stopped after 6 months. LESSONS: There is mounting support for infectious causes of venous thromboembolism (VTE) based on existing molecular biology and clinical research. Meta-analysis of existing data showed that between 1.9% and 9.1% of patients hospitalized with VTE had concurrent acute CMV infection. Theoretical mechanisms for this association include transient formation of antiphospholipid antibodies, transient formation of antibodies targeting CMV capsule phospholipids with procoagulant properties, and direct infection of the endothelial cells. We hope this case will serve as a reminder to consider CMV as a transient cause of PVT and VTE, particularly in light of 2016 guidelines for unprovoked VTE recommending lifelong anticoagulation. We also plan to prospectively study the association of unprovoked VTE and acute CMV infection in our own hospital system. PMID- 29390513 TI - Concomitant systemic lupus erythematosus and HIV infection: A rare case report and literature review. AB - RATIONALE: Coexisting systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection cases are rare worldwide. Great challenges are posed on the diagnosis and treatment of such concurrent cases. PATIENT CONCERN: We report the case of a 44-year-old Chinese man with edema, hematuria, and fever who presented at West China Hospital, Sichuan University, Chengdu, Sichuan, China, in 2013. DIAGNOSES: An initial diagnosis of SLE was made from the clinical manifestations and laboratory findings based on the Systemic Lupus International Collaborating Clinics classification criteria. Immunosuppressant therapy relieved him of the edema and hematuria, but he regained the symptoms after a cold. Workup, including electrochemiluminescence immunoassay, western blot, and polymerase chain reaction analysis, revealed that he was concurrently infected with HIV after hospitalization. INTERVENTIONS: The treatment plan included methylprednisolone and cyclophosphamide, with gastroprotective and hepatoprotective agents, simultaneously aiming to reduce urinary protein. After HIV infection confirmed, cyclophosphamide was stopped. He was referred to the local Centers for Disease Control and Prevention for combination antiretroviral therapy (ART). He was suggested to continue monitoring CD4 T-cell count for an appropriate dose of immunosuppressive drugs. OUTCOMES: In the last follow-up in May 2017, he had been stable in terms of both SLE and HIV infection. LESSONS: The case highlights the presence of concurrent SLE and HIV infection. Laboratory technicians and clinicians should be cautious on diagnosis, especially in eliminating the false-positive results. Attention should be paid to the dose of immunosuppressants and the ART procedure. PMID- 29390514 TI - Successful gamma knife radiosurgery combined with S-1 in an elderly man with local recurrent pancreatic cancer: A case report. AB - RATIONALE: Pancreatic cancer is common in people older than 40 years, and the incidence peaks at the age of 70 years and older. Chemoradiotherapy has been generally considered a high-risk procedure in elderly patients with local recurrent pancreatic cancer. Gamma knife stereotactic radiosurgery has the advantage in protecting the surrounding tissues, and providing short-term effects. It has been successfully used in patients with brain metastases.The efficacy of GKSRS in other malignancies has barely been studied.S-1 is one of the key drug against metastatic and local advanced pancreatic cancer. The combination of GKSRS and S-1 in local recurrent pancreatic cancer has hardly been reported. PATIENT CONCERNS: We present a rare case of a 76-year-old man with pancreatic cancer. He complained of recurrent abdominal pain and chronic pain in the right shoulder for more than 3 years. DIAGNOSES: After several examinations, the diagnosis was carcinoma of the pancreas. INTERVENTIONS: A resection of the pancreatic neoplasm was performed on June 21, 2011; he did not receive adjuvant chemotherapy. In April 2014, postoperative recurrence was confirmed in the head of the pancreas. The patient received gamma knife stereotactic radiosurgery (GKSRS) combined with S-1 treatment. OUTCOMES: The patient showed complete response after 2 months. He has achieved an overall survival of 76 months with a very good performance status. LESSONS: GKSRS applied to other malignancies has rarely been reported. S-1 is the key drug for adjuvant chemotherapy in resected pancreatic cancer. There are a few studies on this combination in local recurrent pancreatic cancer. GKSRS combined with S-1 seems to be a good option in improving efficacy and prolonging life in elderly patients with locally recurrent pancreatic cancer. PMID- 29390515 TI - Application of failure mode and effect analysis in managing catheter-related blood stream infection in intensive care unit. AB - In this study, failure mode and effect analysis (FMEA), a proactive tool, was applied to reduce errors associated with the process which begins with assessment of patient and ends with treatment of complications. The aim of this study is to assess whether FMEA implementation will significantly reduce the incidence of catheter-related bloodstream infections (CRBSIs) in intensive care unit.The FMEA team was constructed. A team of 15 medical staff from different departments were recruited and trained. Their main responsibility was to analyze and score all possible processes of central venous catheterization failures. Failure modes with risk priority number (RPN) >=100 (top 10 RPN scores) were deemed as high-priority risks, meaning that they needed immediate corrective action. After modifications were put, the resulting RPN was compared with the previous one. A centralized nursing care system was designed.A total of 25 failure modes were identified. High-priority risks were "Unqualified medical device sterilization" (RPN, 337), "leukopenia, very low immunity" (RPN, 222), and "Poor hand hygiene Basic diseases" (RPN, 160). The corrective measures that we took allowed a decrease in the RPNs, especially for the high-priority risks. The maximum reduction was approximately 80%, as observed for the failure mode "Not creating the maximal barrier for patient." The averaged incidence of CRBSIs was reduced from 5.19% to 1.45%, with 3 months of 0 infection rate.The FMEA can effectively reduce incidence of CRBSIs, improve the security of central venous catheterization technology, decrease overall medical expenses, and improve nursing quality. PMID- 29390516 TI - Analysis of hospitalization expenditures and influencing factors for inpatients with coronary heart disease in a tier-3 hospital in Xi'an, China: A retrospective study. AB - BACKGROUND: The medical costs for inpatients with coronary heart disease (CHD) have risen to unprecedented levels, putting tremendous financial pressure on their families and the entire society. The objective of this study was to examine the actual direct medical costs of inpatients with CHD and to analyze the influencing factors of those costs, to provide advice on the prevention and control of high medical costs of patients with CHD. METHODS: A retrospective descriptive analysis of hospitalization expenditures data examined 10,301 inpatients with coronary heart disease of a tier-3 hospital in Xi'an from January 1, 2015 to December 31, 2015. The data included demographic information, the average length of stay, and different types of expenses incurred during the hospitalization period. The difference between different groups was analyzed using a univariate analysis, and the influencing factors of hospitalization expenditures were explored by the multiple linear stepwise regression analysis. RESULTS: The average age of these patients was 60.0 years old, the average length of stay was 4.0 days, and the majority were males (7172, 69.6%). The average hospitalization expenses were $6791.38 (3294.16-9, 732.59), and the top 3 expenses were medical consumables, operation fees, and drugs. The influencing factors of hospitalization expenditures included the length of stay, the number of times of admission, the type of medical insurance schemes, whether have a surgery or not, the gender, the age, and the marriage status. CONCLUSION: The inpatients with CHD in this tier-3 hospital were mostly over 45 years old. The average medical cost of males was much higher than that of females. Our findings suggest that the solution for tremendous hospitalization expenditures should be that more attention is paid to controlling the high expense of medical consumables and that the traditional method of reducing medical expenses by shortening the length of stay is still important in nowadays. Furthermore, the type of medical insurance schemes has different impacts on medical expenses. Reducing or controlling high hospitalization expenditures is a complicated process that needs multifaceted cooperation. PMID- 29390517 TI - Cervical digit in a child: A case report. AB - BACKGROUND: A "digit-like" bone is a rare developmental anomaly that is usually seen in the pelvic or thoracic regions. Such an anomaly in the cervical spine is extremely rare and few cases have been reported. We present a patient with an anomalous bone posterior to a cervical vertebra. The patient was admitted to our hospital with a gradually growing hard neck mass and esthetic complaints. Physical examination, radiographs, reconstructed computed tomography, and magnetic resonance imaging revealed a digit-like bone posterior to the cervical spine. The patient was diagnosed with a "cervical digit." Through a posterior midline approach, the anomalous bone was excised because of its gradually increasing size and esthetic complaints. RESULTS: Intraoperatively, the bony mass was found to have a pseudoarticulation with the spinous process of C5 (the fifth cervical vertebra). The specimen consisted of normal bone and cartilage. The child returned to a normal life postoperatively with no symptoms. There was no recurrence at the 2-year follow-up. CONCLUSION: A congenital cervical digit is a rare deformity. A detailed clinical workup and advanced imaging examinations are useful for diagnosing such conditions. Esthetic complaints contribute to surgical indications. This is the first cervical digit managed with surgical excision of the anomalous bone and had a favorable outcome. PMID- 29390518 TI - Central vestibular disorder due to ischemic injury on the parieto-insular vestibular cortex in patients with middle cerebral artery territory infarction: Observational study. AB - Central vestibular disorder is common after middle cerebral artery (MCA) territory infarction. The MCA supplies blood to the parieto-insular vestibular cortex (PIVC), a core region of central vestibular symptoms. We report on patients that sustained injuries of the core vestibular pathway to the PIVC with central vestibular disorder following MCA territory infarction, demonstrated on diffusion tensor imaging (DTI). Nineteen patients with MCA territory infarction and 12 control subjects were recruited. To reconstruct the core vestibular pathway to the PIVC, we defined seed region of interest (ROI) as vestibular nuclei of pons and target ROI as the PIVC. Fractional anisotropy (FA), mean diffusivity, and tract volume were measured. In the affected hemisphere, FA value of the core vestibular pathway to the PIVC revealed significant difference between all patient groups and the control group (P < .05). In contrast, patients with symptoms of ataxia only revealed significant decrement of tract volume compared with the control group (P < .05). Additionally, subgroup B revealed significant decrement of tract volume compared with that of subgroup A and the control group (P < .05). In the unaffected hemisphere, there was no significant difference in all DTI parameters between all patient groups and the control group (P < .05). Injury to the core vestibular pathway to the PIVC was demonstrated in patients that revealed typical central vestibular disorder following MCA territory infarction. Analysis of the core vestibular pathway to the PIVC using DTI would be beneficial in clinical evaluation and management of patients with MCA territory infarction. PMID- 29390519 TI - Preparation of immunochromatographic strips for rapid detection of early secreted protein ESAT-6 and culture filtrate protein CFP-10 from Mycobacterium tuberculosis. AB - The early secreted protein early secretory antigenic target 6(ESAT-6) and the culture filtrate protein 10 (CFP-10) are 2 antigens that are specific to Mycobacterium tuberculosis. These 2 antigens are good targets for tuberculosis (TB) detection.To rapidly diagnose TB across a variety of samples, we developed colloidal gold immunochromatographic strips (ICSs) based on ESAT-6 and CFP-10.The strips were evaluated using 233 samples, including sputum, plasma, and pleural effusion samples.The positive detection rates for ICSs for ESAT-6 and CFP-10 in sputum (culture-positive for M tuberculosis) were 100% and 91.2%, respectively. The positive detection rates for ICSs for ESAT-6 and CFP-10 in plasma were 34.1% and 29.4%, respectively. The positive detection rates for ICSs for ESAT-6 and CFP 10 in pleural effusion were 64.7% and 55.9%, respectively. Experimental analysis of culture supernatant showing that the ICS developed for ESAT-6 had a sensitivity of 100% and a specificity of 91.2%. While the ICS developed for CFP 10 had a sensitivity of 91.2% and a specificity of 88.2%.The validity of the test is limited by source of sample. The technique is sensitive and specific for samples in sputum and culture media but not for plasma or pleural effusion samples. Detection of M tuberculosis using ICSs is rapid, simple, and relatively effective; thus, ICSs are a potential screening tool for TB. PMID- 29390520 TI - Advanced gastrointestinal carcinoma with massive ascites and hydrothorax during pregnancy: A case report and review of the literature. AB - RATIONALE: Gastrointestinal carcinoma is rare during pregnancy. It is usually diagnosed at an advanced stage because special gastrointestinal symptoms are generally overlooked during pregnancy, and there are many limitations and contraindications for using diagnostic tools during pregnancy. PATIENT CONCERNS: We present a case of a 29-year-old patient with 27 weeks and 5 days of gestation due to massive ascites and hydrothorax. DIAGNOSES: The patient was diagnosed with an advanced gastrointestinal cancer. Pathological report showed poorly differentiated tumor with the signet ring cell component. INTERVENTIONS: Caesarean section was performed. At the same time, an abdominal exploration showed that the omentum was like biscuits . There were extensive and firm intestinal adhesions, and many tumor lesions were found on the surface of greater curvature of stomach, spleen, intestine, peritoneum, ascending colon and descending colon. OUTCOMES: Gastrointestinal surgeon was invited during operation, and palliative gastrectomy was not performed because of extensive metastases. The patient died 30 days after caesarean section. LESSONS: This study present a case with advanced gastrointestinal cancer during pregnancy. We suggest that endoscopic exam is recommended if the patient is highly suspicious. PMID- 29390521 TI - Solitary fibrous tumor of the ilium: A case report. AB - RATIONALE: Solitary fibrous tumors (SFTs) are rare spindle cell tumors that are most commonly found in the mediastinal pleura. Although there are increasingly more reports of extra-pleural SFTs, reports of SFTs in bone are very rare. To our knowledge, a SFT of the ilium has not yet been reported. With low specificity on computer tomograpy and magnetic resonance imaging, SFTs are easily misdiagnosed. PATIENT CONCERNS: A 33-year-old man visited our hospital due to repeated right ilium pain for 3 months. The pain was dull and bearable, with no hip joint dyskinesia. The relevant physical examinations are negative. The patient was healthy before and had a negative family history. Radiologically, a large mass with inhomogeneous attenuation and intensity and obvious heterogeneous enhancement was misdiagnosed as a giant cell tumor of ilium. DIAGNOSES: The man was diagnosed as the solitary fibrous tumor of right ilium. INTERVENTIONS: The patient was performed an "incision biopsy of the right ilium" and "extended resection of tumor". OUTCOMES: The pathology and immunohistochemistry was confirmed as the solitary fibrous tumors. The patient was followed-up by computed tomography of pelvis in local hospital every 6 mouths, and there is no recurrence and any symptoms. LESSONS: We learned that the solitary fibrous tumor could locate in the ilium, and when we see imaging manifestations like this case, we should think it may be SFT. PMID- 29390523 TI - Efficacy of eculizumab in an adult patient with HIV-associated hemolytic uremic syndrome: A case report. AB - INTRODUCTION: Hemolytic uremic syndrome (HUS) in Human Immunodeficiency Virus (HIV)-positive patients has become a rare cause of kidney injury since the era of highly active antiretroviral therapy (HAART). Plasma exchange and antiretroviral therapy were previously recommended but often failed to achieve remission. We report a case of HUS in a HIV-positive patient treated successfully with eculizumab. CASE SUMMARY: A 52-year-old woman presented to hospital with acute renal failure, thrombocytopenia, anemia, and hypoxemia. She had been diagnosed with HIV infection in 1997. Kidney biopsy showed several fibrinous microthrombi in the glomerular capillaries, formation of thrombi in arterioles, moderate parietal and mesangial deposits of C3 and Immunoglobulin M, and intense glomerular and arterial deposits of Complement component 5b9 complement component. Serum HIV viral load was 227,848 copies/mL, and CD4 lymphocyte count was 120 cells/MUL. A diagnosis of HIV-associated HUS was made. The patient had no confounding cause of HUS. Initiation of eculizumab and HAART resulted in complete hematological remission on day 32 and dialysis withdrawal on day 110. The patient has not relapsed during long-term follow-up (M17). CONCLUSION: This observation suggests that eculizumab can achieve remission in HIV patients with HUS. PMID- 29390522 TI - Delayed onset Mycobacterium intracellulare keratitis after laser in situ keratomileusis: A case report and literature review. AB - RATIONALE: Infectious keratitis is a relatively uncommon but potentially sight threatening complication of laser in situ keratomileusis (LASIK). Mycobacterial keratitis is usually regarded as late onset keratitis among post-LASIK keratitis. There has been no documented case of Mycobacterium intracellulare post-LASIK keratitis of a long-latent period. PATIENT CONCERNS: A 36-year-old man was referred to our out-patient clinic, for persistent corneal epithelial defect with intrastromal infiltration. He had undergone uneventful bilateral LASIK procedure 4 years before. He complained decreased vision, accompanied by ocular pain, photophobia, and redness in his left eye for 7 months. DIAGNOSIS: Lamellar keratectomy was taken using femtosecond laser. Bacterial culture with sequenced bacterial 16s ribosomal DNA confirmed the organism to be M intracellulare. INTERVENTIONS: After 3 months of administration of topical clarithromycin, amikacin, and moxifloxacin, the corneal epithelial defect was resolved and the infiltration was much improved. However, newly developed diffuse haziness with surrounding granular infiltration in the central cornea was noted. Drug toxicity was suspected and topical moxifloxacin was discontinued, resulting in resolution of the diffuse haze with infiltration. OUTCOME: The patient was followed up regularly without medication thereafter and recurrence was not found for 7 years. LESSONS: This case presents the first case of M intracellulare keratitis after LASIK. LASIK surgeons should aware that post-LASIK keratitis can develop long after the operation and careful suspicion of infectious disease with meticulous diagnostic test is needed. PMID- 29390524 TI - The effectiveness, safety, and economic evaluation of Korean medicine for unexplained infertile women: A multi-center, prospective, observational study protocol. AB - : Infertility is a condition in which a woman has not been pregnant despite having had normal intercourse for 1 year. The number of unexplained infertile females is increasing because of late marriage customs, as well as environmental and lifestyle habits. In Korea, infertile females have been treated with Korean medicine (KM). However, these effects have not been objectively confirmed through clinical trials. Therefore, this study was conducted to demonstrate the effectiveness of herbal medicine treatment in infertile patients and to demonstrate the economic feasibility through economical evaluation with assisted reproductive technology.This study is designed as a multicenter, single-arm clinical trial. All participants included will be from 3 Korean Medicine hospitals in Korea and will voluntarily sign an informed consent agreement. All recruited patients will conduct related surveys and tests, and be provided with treatment according to their menstrual cycle. Patients will take herbal medicines for 4 menstruation cycles and receive acupuncture and moxibustion treatment at 3 times (menstrual cycle day 3, 8, 14) during 4 menstruation cycles. They will also undergo an approximately 4 menstrual cycle treatment period, and 3 menstrual cycle observation period. If pregnant during the study, participants will take the herbal medicine for implantation for about 15 days. In this study, the primary outcome will be the clinical pregnancy rate, whereas the secondary outcome will include the implantation rate, ongoing pregnancy rate, and live birth rate.Ultimately, this study will provide clinical data regarding the effectiveness and safety of KM treatment for females with unexplained infertility and important evidence for establishing standard KM treatments for unexplained infertility. Moreover, we will identify the most cost-effective way to treat unexplained infertility. TRIAL REGISTRATION IDENTIFIER: Korean Clinical Trial Registry (CRIS), Republic of Korea: KCT0002235. Date: February 21, 2017 (retrospectively registered). PMID- 29390525 TI - Renal cyst masses (Bosniak category II-III) may be over evaluated by the Bosniak criteria based on MR findings. AB - A classification system of renal cysts developed by Bosniak is based on computed tomography (CT) findings and has been applied to deal with the complex cystic renal masses. Magnetic resonance (MR) has excellent soft-tissue resolution, it has been used to further evaluate some complex renal lesions, especially those suspected of containing soft tissue components and hyperattenuating cystic lesions seen on CT. Compared with CT, MR images may find additional information, which may lead to inconsistent classification. However, at present, there is no consensus on the treatment of these inconsistent lesions. This study aimed to investigate the value of MR in the evaluation of renal cystic masses by using the Bosniak classification system and improve understanding of the MR features of renal cyst masses.The present study retrospectively analyzed 35 renal cyst masses in 34 patients (10 men and 24 women with age from 20 to 65 years old, with an average of 49 +/- 12.08), who underwent both MR and computed tomography (CT) examinations within 6 months (range from 1 to 135 days with an average of 11 +/- 24.16 days). Twenty-four lesions (9 category III and 15 category IV on CT) received surgical treatment, 4 category IIF lesions on CT were upgraded to category III on MR, which were finally accepted operative resection. The remaining 7 lesions (category II-IIF on both CT and MR) were followed up for at least 3 years. For each lesion, size of both cyst and solid component, presence of calcification, number of septa, thickness of wall and septa, and appearance of enhancement were analyzed. Each lesion was categorized by using Bosniak criteria on CT and MR, respectively. The MR findings were compared with CT and pathology or follow-up results.On MR, categories of the lesions were as follows: category IIF (n = 7), III (n = 12), IV (n = 16). On CT, categories of the lesions were as follows: II (n = 3), IIF (n = 8), III (n = 9), and IV (n = 15). Findings on MR and CT images were inconsistent in 8 (23%) lesions. Among them, 3 category II lesions on CT were classified as category IIF on MR images, 4 category IIF lesions on CT were upgraded to category III on MR, and 1 category III lesions to category IV. In these lesions, MR detected more increased wall/septa thickness (n = 8) and septa number (n = 3) than CT, resulting in an upgrade in classification. Based on the pathological results, 5 of category III (5/9, 56%) and all category IV (15/15, 100%) lesions on CT images were malignant. On MR, 4 of category III (4/12, 33%) and all category IV (16/16, 100%) lesions were malignant.The renal cyst masses in some cases, especially category II to III lesions, may be over evaluated by the Bosniak criteria based on MR findings. It is necessary to combine MR features with CT findings in evaluation and management of these cases with renal cystic masses. PMID- 29390526 TI - Genetic variation in bone morphogenetic proteins family members (BMPs 2 and 4) and hypertension risk in middle-aged men: The TAMRISK study. AB - Bone morphogenetic proteins (BMPs) are important regulators of iron metabolism affecting hepcidin expression. We have previously shown that 2 genetic polymorphisms in different genes (histocompatibility complex class I-like transmembrane protein, hemojuvelin) involved in the regulation of hepcidin expression pathways are associated with hypertension. In this study, we analyzed genetic variation sites in BMP2 (rs235756, rs235768) and BMP4 (rs4901474) to get more evidence linking iron metabolism to hypertension risk in the Finnish population.The study included 321 hypertensive cases and 463 controls from the Tampere Adult Population Cardiovascular Risk study cohort. Genotyping of polymorphisms was done by polymerase chain reaction using DNAs extracted from buccal swabs.We found that men carrying the GG genotype of BMP2 rs235756 (A>G) polymorphic site had a 4.09-fold risk (confidence interval [CI] 1.61-10.39, P = .003) for hypertension at the age of 50 years compared with A-allele carriers. The risk was significant in the age groups of 45 and 40 years as well. In addition, the 15-year follow-up period of the same individuals showed that carriers of the GG-genotype had also significantly higher readings of both systolic (P < .001) and diastolic (P = .01) blood pressure during the follow-up time. No significant association between BMP2 rs235768 (A>T) and hypertension was found. BMP4 polymorphic site rs4901474 (T>C) also had an effect on hypertension. CC genotype carriers had a 1.48-fold risk (CI 1.03-2.13, P = .033) for hypertension at the age of 50 years when compared with T-allele carriers.In conclusion, BMP2 polymorphic site rs235756 was associated with hypertension in Finnish men. An effect of BMP4 polymorphic site on hypertension was also found. PMID- 29390527 TI - Comparison of different automated lesion delineation methods for metabolic tumor volume of 18F-FDG PET/CT in patients with stage I lung adenocarcinoma. AB - The aim of the study was to investigate the suitable segmentation method in small, low uptake and heterogeneous nodules of stage I lung adenocarcinoma.133 stage I lung adenocarcinoma patients with F-FDG PET/CT scans were enrolled in this retrospective study. All lesions were divided into different groups according to nodule density, nodule size, and the maximum standard uptake value (SUVmax) level. Four different PET segmentation methods were performed, including percentage threshold of SUVmax (T42% and T42% * RC), gradient-based threshold (adaptive iterative algorithm, AT-AIA), and background-related threshold (adaptive thresholding at 40% SUVmax, AT40%) approaches. The MTVs were evaluated and compared with CT volume (CTV). Percentage volume error (%VE) compared to CTV was calculated and the correlations between MTVs and CTV were analyzed.AT-AIA had the highest accuracy in large, high uptake, and solid nodules (72.5%, 72.4%, and 65.6%, respectively). AT40% had the highest accuracy in small, low uptake and nonsolid nodules (56.6%, 56.1%, and 62.6%, respectively). In part-solid nodules, the accuracy of AT-AIA (60.0%) and AT40% (56.7%) were higher than that of T42% and T42% * RC. The MTV of AT-AIA was in excellent correlation with the CTV in solid nodules (R = 0.831, P < .001) and in high uptake nodules (R = 0.830, P < .001). The MTV of AT40% was in good correlation with the CTV in nonsolid nodules (R = 0.686, P = .003) and in part-solid nodules (R = 0.731, P < .001).AT40% showed best performance in small, low uptake, nonsolid and part-solid lesions. AT AIA was suitable for large, high uptake, and solid lesions. PMID- 29390528 TI - Efficacy of photodynamic therapy combined with minocycline for treatment of moderate to severe facial acne vulgaris and influence on quality of life. AB - BACKGROUND: Acne vulgaris is a prevalent skin disorder impairing both physical and psychosocial health. This study was designed to investigate the effectiveness of photodynamic therapy (PDT) combined with minocycline in moderate to severe facial acne and influence on quality of life (QOL). METHODS: Ninety-five patients with moderate to severe facial acne (Investigator Global Assessment [IGA] score 3 4) were randomly treated with PDT and minocycline (n = 48) or minocycline alone (n = 47). All patients took minocycline hydrochloride 100 mg/d for 4 weeks, whereas patients in the minocycline plus PDT group also received 4 times PDT treatment 1 week apart. IGA score, lesion counts, Dermatology Life Quality Index (DLQI), and safety evaluation were performed before treatment and at 2, 4, 6, and 8 weeks after enrolment. RESULTS: There were no statistically significant differences in characteristics between 2 treatment groups at baseline. Minocycline plus PDT treatment led to a greater mean percentage reduction from baseline in lesion counts versus minocycline alone at 8 weeks for both inflammatory (-74.4% vs -53.3%; P < .001) and noninflammatory lesions (-61.7% vs 42.4%; P < .001). More patients treated with minocycline plus PDT achieved IGA score <2 at study end (week 8: 30/48 vs 20/47; P < .05). Patients treated with minocycline plus PDT got significant lower DLQI at 8 weeks (4.4 vs 6.3; P < .001). Adverse events were mild and manageable. CONCLUSIONS: Compared with minocycline alone, the combination of PDT with minocycline significantly improved clinical efficacy and QOL in moderate to severe facial acne patients. PMID- 29390529 TI - Comparison of clinical parameters, microbiological effects and calprotectin counts in gingival crevicular fluid between Er: YAG laser and conventional periodontal therapies: A split-mouth, single-blinded, randomized controlled trial. AB - BACKGROUND: The erbium-doped yttrium, aluminum, and garnet (Er:YAG) laser is thought to be the most promising laser for periodontal treatment; however, its application is still under consideration. The aim of this study was to compare Er:YAG laser monotherapy with conventional scaling and root planing (SRP) for chronic periodontitis using clinical parameters, the detection rate of periodontal pathogens, and the calprotectin level in gingival crevicular fluid. METHODS: Twenty-seven participants with moderate-to-advanced chronic periodontitis were included. In a split-mouth design, the 2 half-mouths of each participant were randomly assigned to Er:YAG laser or SRP (combination of ultrasonic and manual instruments) treatment. Clinical parameters were recorded at baseline, 6 weeks, and 3 and 6 months after treatment. At the same time points, gingival crevicular fluid was collected to analyze the detection rate of 6 periodontal pathogens by polymerase chain reaction and the levels of calprotectin by enzyme-linked immunosorbent assay. RESULTS: Both treatment groups showed significant reductions in probing depth (PD), bleeding index (BI), and clinical attachment level (CAL) from baseline to 6 months. For sites with 4 mm <= PD <= 6 mm at baseline, SRP resulted in a greater reduction in PD and CAL than Er:YAG laser treatment, and the difference remained at 6 months post-treatment (P = .01 and P < .01, respectively). For sites with PD >=7 mm at baseline, the clinical parameters showed similar results between the 2 groups. SRP resulted in a lower detection rate of Porphyromonas gingivalis at 6 months post-treatment. The levels of calprotectin were significantly decreased from baseline to 6 months in both groups, without a significant difference between the groups. CONCLUSION: For mild pockets, conventional SRP may still be the preferred choice. For deep pockets, Er:YAG laser treatment could be an effective alternative. Studies are needed to explore more advanced instruments and new application methods for the Er:YAG laser for periodontal treatment in deep pockets. PMID- 29390530 TI - Nonsurgical management of an extensive spontaneous spinal epidural hematoma causing quadriplegia and respiratory distress in a choledocholithiasis patient: A case report. AB - RATIONALE: Spontaneous spinal epidural hematoma (SSEH) manifests from blood accumulating in the epidural space, compressing the spinal cord, and leading to acute neurological deficits. The disease's cloudy etiology and rarity contribute to dangerously suboptimal therapeutic principles. These neural deficits can be permanent, even fatal, if the SSEH is not treated in a timely and appropriate manner. Standard therapy is decompressive laminectomy, though nonsurgical management is a viable course of action for patients who meet a criterion that is continuously being refined. PATIENT CONCERNS: A 76-year-old woman on warfarin for a past pulmonary embolism presented to the emergency room with jaundice, myalgia, hematuria, neck pain, and an International Normalized Ratio (INR) of 14. Upon admission, she rapidly developed quadriplegia and respiratory distress that necessitated intubation. DIAGNOSES: T2-weighted magnetic resonance imaging (MRI) revealed an epidural space-occupying hyperintensity from C2 to S5 consistent with a spinal epidural hematoma. An incidental finding of dilated intrahepatic and common bile ducts prompted an endoscopic retrograde cholangiopancreatography, which demonstrated choledocholithiasis. INTERVENTIONS: The patient's INR was normalized with Vitamin K and Beriplex. Upon transfer to the surgical spine team for assessment of a possible intervention, the patient began to demonstrate recovery of neural functions. The ensuing sustained motor improvement motivated the team's preference for close neurologic monitoring and continued medical therapy over surgery. Thirteen hours after the onset of her symptoms, the patient was extubated. A sphincterotomy was later performed, removing 81 common bile duct stones. OUTCOMES: MRI demonstrated complete resorption of the SSEH and the patient maintained full neurological function at final follow-up. LESSONS: Nonsurgical management of SSEH should be considered in the context of early and sustained recovery. Severe initial neural deficit does not necessitate surgical decompression. Choledocholithiasis and subsequent Vitamin K deficiency, particularly when coupled with anticoagulant use, can increase INR and is a novel proposed risk factor for SSEH. Furthermore, coagulopathies should be medically corrected before surgical intervention within a given timeframe, as spontaneous recovery may manifest. This should be favored over surgery in patients demonstrating early and sustained recovery, as nonsurgical management is 25% more effective in achieving full recovery. PMID- 29390531 TI - Dexmedetomidine-based monitored conscious sedation combined local anesthesia for levator resection in a 10-year-old child with Marcus Gunn jaw-winking synkinesis: A case report. AB - RATIONALE: Levator resection has become a routine procedure for patients with severe Marcus Gunn jaw-winking synkinesis (MGJWS). To optimize the surgical outcome, adult patients need to be kept awake, or easily aroused and responsive to verbal commands during the operation. However, levator resection is commonly performed under general anesthesia in pediatric patients. In the present case, we described a successful anesthetic protocol of conscious sedation with local anesthesia for levator resection in a child. PATIENT CONCERNS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The patient was born through a normal delivery and had no previous history of allergy, no comorbidity, and no history of receiving anesthesia or operation. The laboratory tests of the patient were unremarkable. DIAGNOSES: The diagnosis of MGJWS was made by two experienced ophthalmologists. INTERVENTIONS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The levator resection was performed under monitored conscious sedation with dexmedetomidine and local anesthesia. OUTCOMES: Patient with spontaneous breathing responded normally to verbal commands throughout the operation, and no adverse events occurred. The patient and ophthalmologist reported high satisfaction with anesthesia management. LESSONS: Dexmedetomidine-based monitored conscious sedation with local anesthesia is a feasible alternative to general anesthesia for levator resection in collaborative patients. PMID- 29390532 TI - Comparison of surgical results in patients with hypertrophic obstructive cardiomyopathy after classic or modified morrow septal myectomy. AB - The study was conducted to evaluate the surgical results in patients with hypertrophic obstructive cardiomyopathy (HOCM) who underwent either classic Morrow septal myectomy or modified procedure.The modified Morrow septal myectomy has gained interest as a new treatment for patients with drug-refractory symptoms of HOCM; however, its benefits in comparison to the classic procedure are unknown.In all, 236 symptomatic HOCM patients underwent surgical treatment from January 2006 to January 2015. Among them, 86 patients were treated by the classic Morrow myectomy and 150 patients via the modified procedure. Septal thickness, maximal left ventricular outflow tract (LVOT) pressure gradient (PG), and the presence of a permanent pacemaker were recorded after operation and follow-upThe left ventricular septal thickness (22.1 +/- 11.9 vs 17.1 +/- 4.0 mm for classic procedure, and 22.3 +/- 4.4 vs 16.1 +/- 3.5 mm for modified procedure; P < .001), LVOT velocity (410.6 +/- 134.0 vs 210.5 +/- 81.4 mm/s for classic procedure, and 432.7 +/- 119.3 vs 167.7 +/- 50.1 mm/s for modified procedure; P < .001), LVOT PG (76.0 +/- 43.5 vs 19.8 +/- 16.7 mm Hg for classic procedure, and 80.8 +/- 40.7 vs 12.3 +/- 8.5 mm Hg for modified procedure; P < .001) were significantly decreased after the operation in both groups. The modified group, however, showed significantly greater reduction in these echocardiographic parameters than the classic group. PG was completely eliminated in 142 (94.7%) patients receiving the modified myectomy, and a resting PG over 30 mm Hg was demonstrated in 16 (18.6%) patients in the classic group at follow-up (P = .001). Thirty-two (37.2%) patients in the classic groups had a mitral valve replacement, which is significant more than 14 (9.3%) in the modified group (P < .001).Both the classic procedure and the modified procedure can reduce LVOT obstruction and alleviate symptoms in patients with HOCM. The modified Morrow septal myectomy is superior to the classic procedure in reducing the LVOT gradient with a lower incidence of mitral valve replacement. PMID- 29390533 TI - Multimodality imaging-based evaluation of Rosai-Dorfman disease in the head and neck: A retrospective observational study. AB - Rosai-Dorfman disease (RDD) is an uncommon benign entity characterized histologically by lymphatic sinus dilatation due to histiocyte proliferation. This study was performed to delineate its imaging features, reviewed retrospectively in 12 patients (8 women and 4 men, mean age 58.2 years [range 27 84]) with pathologically confirmed RDD in the head and neck. The location, involvement, and imaging characteristics (CT, magnetic resonance imaging (MRI), and PET/CT) of all lesions were evaluated. Signal intensity on MRI images was compared to gray matter (orbital RDD) and adjacent muscle (sinonasal and cervical RDD). RDD in the head and neck involved multiple sites, primarily the sinonasal cavity (n = 7), neck (n = 3), and orbit (n = 1), with one case of simultaneous involvement of the sinonasal cavity, orbit, and neck. With sinonasal involvement, MRI signal intensity of the involved areas was isointense or slightly hyperintense relative to adjacent muscle on T1WI images and heterogeneous on T2WI images; with lacrimal involvement, it was isointense relative to gray matter on T1- and T2-weighted images; and with neck involvement, it was isointense relative to muscle on T1WI images and relatively hyperintense on T2WI images, with homogenous postcontrast enhancement in all sites of involvement. The lesions on CT were observed as enhancing masses with or without bony destruction. PET/CT showed hypermetabolism in one lesion in the neck. RDD is a rare disorder with multiple sites of involvement in the head and neck. Concomitant cervical lymphadenopathy with extranodal masses assisted by multimodal imaging may be useful in the diagnosis of RDD. PMID- 29390534 TI - Toe keloid after nail extraction treated with surgical excision: A case report. AB - RATIONALE: In this study, a case of toe keloid after nail extraction is presented, in which the keloids on both toes were resected by surgical excision. Keloids (from the Greek word meaning "crab's claw") are fibrous growths that extend beyond the original area of injury to involve the adjacent normal skin. In general, keloid tendencies appear to be regionally isolated to keloid-prone areas, such as the chest, ears, and deltoid regions, whereas the hands and feet are usually spared, which is why this case is meaningful. PATIENT CONCERNS: A 20 year-old Chinese man had paronychia on both halluxes when he was 16 years old. He underwent a nail extraction at the age of 17. The nails of both halluxes were removed by nail extraction. This operation was successful, and the postoperative course was uneventful. After 6 months, the scars of the nail extraction on both sides began to exhibit hyperplasia and became red and swollen with itching. Later, the scar expanded and eroded the tissue beyond the matrix unguis. The whole matrix unguis was destroyed, and the nails were distorted. The scars began to ulcerate after 2 years. The patient used potassium permanganate to clean his wounds, but the keloid scars did not improve. DIAGNOSES: The patient was diagnosed as toe keloid based on his history and symptoms. The biopsy result supported our diagnoses. INTERVENTIONS: The toe keloids were effectively cured by surgical excision and skin flap transplantation combined with postoperative irradiation and hyperbaric oxygen (HBO) treatment. OUTCOMES: No recurrence was detected during the period from 6 to 24 months of follow-up after the surgery. LESSONS: In this case, the trauma of the nail extraction was likely the key cause of the keloid. However, the patient was also predisposed to keloids, as we observed keloids on his chest. In general, keloid tendencies appear to be regionally isolated to keloid-prone areas such as the chest, ears, and deltoid regions, whereas the hands and feet are usually spared, which is why this case is meaningful. PMID- 29390536 TI - Osteoma with actinomycosis in a nasal cavity: A case report. AB - RATIONALE: Osteoma with actinomycosis is a very rare disease in the nasal cavity. PATIENT CONCERNS: We report a case of a 17-year-old female student who presented with nasal obstruction and rhinorrhea for 6 months. DIAGNOSES: The preoperative finding was osteoma covered with yellowish polypoid material. INTERVENTIONS: We performed endoscopic sinus surgery, which included excision of the tumor and medication with oral penicillin for 8 weeks. OUTCOMES: Postoperative recovery was uneventful. There was no evidence of tumor recurrence during the 1-year period after surgery. CONCLUSION: Anaerobic conditions as a result of allergic rhinitis and narrowed nasal cavity because of osteoma can be the cause of formation of actinomycosis. Clinicians should note that osteoma with actinomycosis can be treated with surgical removal of the tumor and short-term antibiotic therapy. PMID- 29390535 TI - Efficacy of Lactobacillus reuteri DSM 17938 for infantile colic: Systematic review with network meta-analysis. AB - BACKGROUND: 5% to 40% of infants cry excessively, usually accompanied by fussiness and excessive of gas. There are no uniform criteria for treatment of infantile colic. Lactobacillus reuteri DSM 17938 has been used with promising results. The objective of this network-meta-analysis (NMA) is to compare the efficacy of L reuteri DSM 17938 with other interventions for infantile colic. METHODS: RCTs, published between 1960 and 2015 for the treatment of infantile colic were included. Primary outcome was duration of crying after 21 to 28 days of treatment. Different databases were searched. Information was analyzed using control group as central axis. A random effect model was used. Hedges standard mean difference (SMD) and odds ratio (OR) were calculated. A SUCRA analysis was performed to evaluate superiority for each intervention. RESULTS: 32 RCTs were analyzed, including 2242 patients. Studies with L reuteri DSM 17938 versus Ctrl., Diet versus Ctrl. and Acupuncture versus Ctrl. were the most influential studies in the NMA. L reuteri DSM 17938 [WMD -51.3 h (CI95% -72.2 to -30.5 h), P .0001] and dietetic approaches [WMD -37.4 h (CI95% -56.1 to -18.7 h), P .0001] were superior compared to the other treatments. CONCLUSIONS: L reuteri DSM 17938 and some dietetic approaches are better to other interventions for treatment of infantile colic. PMID- 29390537 TI - ANCA positive relapsing polychondritis, Graves disease, and suspected moyamoya disease: A case report. AB - RATIOINALE: Relapsing polychondritis (RP) is a rare and heterogeneous disease complex of unknown origin which basically affects cartilaginous structures, 40% of which accompanied by rheumatic, hematologic, and endocrine disease. Among them, vasculitis is the most common accompanying type and usually presented with positive antineutrophilic cytoplasmic antibody (ANCA). The presence of ANCA could be primary or drug-induced like propylthiouracil (PTU). Central involvement of RP is very rare, and there is almost no report of cerebral vasculopathy manifested as moyamoya. PATIENT CONCERNS: A 26-year-old woman complained about recurrent fever, auricular chondritis, ocular inflammation, and arthritis. She had an 8 year drug intake of PTU for Graves disease. Myeloperoxidase antineutrophilc cytoplasmic antibodies (MPO-ANCA) were found positive. Magnetic resonance angiography (MRA) detected multiple intracranial vasculopathy which we highly suspected it as moyamoya disease. DIAGNOSES: Relapsing polychondritis, Graves disease and suspected moyamoya disease were clinically diagnosed. INTERVENTIONS AND OUTCOMES: In case of possible PTU-induced vasculitis and the aggravation of vasculopathy, PTU was replaced by Iodine-131 (I) therapy. Induction treatment included oral prednisone 30 mg daily and oral cyclophosphamide 100 mg daily. Symptoms rapidly relieved before discharge. Inflammation markers were normal and MPO-ANCA decreased in 3 weeks after admission. Prednisone was gradually tapered to 7.5 mg daily and at month 10 azathioprine was continued for maintenance. LESSONS: RP can overlap with Graves disease and moyamoya disease; comprehensive tests should be performed when admission. When relapsing polychondritis is accompanied with Graves disease, especially when ANCA is positive, PTU should be avoided. PMID- 29390538 TI - The clinical efficacy of reminiscence therapy in patients with mild-to-moderate Alzheimer disease: Study protocol for a randomized parallel-design controlled trial. AB - INTRODUCTION: Alzheimer disease (AD) is one of the most common diseases among the older adults. Currently, various nonpharmacological interventions are used for the treatment of AD. Such as reminiscence therapy is being widely used in Western countries. However, it is often used as an empirical application in China; the evidence-based efficacy of reminiscence therapy in AD patients remains to be determined. Therefore, the aim of this research is to assess the effectives of reminiscence therapy for Chinese elderly. METHODS AND ANALYSIS: This is a randomized parallel-design controlled trial. Mild and moderate AD patients who are in the Beijing Geriatric Hospital, China will be randomized into control and intervention groups (n = 45 for each group). For the intervention group, along with conventional drug therapy, participants will be exposed to a reminiscence therapy of 35 to 45 minutes, 2 times/wk for 12 consecutive weeks. Patients in the control group will undergo conventional drug therapy only. The primary outcome measure will be the differences in Alzheimer disease Assessment Scale-Cognitive Section Score. The secondary outcome measures will be the differences in the Cornell scale for depression in dementia, Neuropsychiatric Inventory score, and Barthel Index scores at baseline, at 4 and 12 weeks of treatment, and 12 weeks after treatment. ETHICS AND DISSEMINATION: The protocols have been approved by the ethics committee of Beijing Geriatric Hospital of China (approval no. 2015 010). Findings will be disseminated through presentation at scientific conferences and in academic journals. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier ChiCTR-INR-16009505. PMID- 29390539 TI - Oral contraceptives caused venous sinus thrombosis complicated with cerebral artery infarction and secondary epileptic seizures: A case report and literature review. AB - RATIONALE: Venous sinus thrombosis is a special type of cerebrovascular disease. Its incidence is low and its symptoms are lack of specificity. And its early diagnosis and treatment are very difficult. PATIENT CONCERNS: This paper reported a rare case of a 43-year-old female who presented with cerebral venous thrombosis (CVT) complicated with cerebral artery infarction and secondary epileptic seizures due to oral contraceptives. DIAGNOSES: The final diagnosis was intracranial venous sinus thrombosis, acute cerebral infarction in the left parietal lobe, intracranial hypertension syndrome, and continuous epilepsy. INTERVENTIONS: The patient recovered well after active treatment. OUTCOMES: Three months after discharge, the muscle strength of the right limb of the patient was significantly increased, and no recurrence of neurological symptoms occurred. LESSONS: In conclusion, early diagnosis, correct evaluation, and standard treatment are still important challenges for CVT. Active treatment is recommended. PMID- 29390540 TI - Ki-67 labeling index is a predictive marker for a pathological complete response to neoadjuvant chemotherapy in breast cancer: A meta-analysis. AB - BACKGROUND: A pathological complete response (pCR) after neoadjuvant chemotherapy (NCT) is a strong indicator of the benefit of therapy and presents an early surrogate for a favorable long-term outcome. It remains unclear whether Ki-67, a marker for tumor proliferation, can function as a predictor of the response to NCT in breast cancer. The objective of this meta-analysis was to compare the pCR rate and clinical outcomes in breast cancer patients with different Ki-67 labeling indexes (Ki-67 LI) who received NCT. METHODS: Clinical studies were retrieved from the electronic databases of PubMed, Embase, Clinical Trials, Wanfang, and the Chinese National Knowledge Infrastructure, from their inception to July 31, 2017. Meta-analysis was performed on pool eligible studies to determine whether Ki-67 LI was associated with the pCR rate and clinical outcomes of breast cancer patients who were treated with NCT. Pooled analyses were performed using fixed effects models. Two reviewers screened all titles and abstracts and independently assessed all articles. RESULTS: A total of 36 studies involving 6793 patients were included in the meta-analysis. Pooled analysis results revealed that patients with high Ki-67 LI exhibited significantly higher pCR rates (odds ratio [OR] = 3.94, 95% confidence interval [CI]: 3.33-4.67, P <.001) but poorer relapse-free survival (OR = 1.99, 95% CI: 1.39-2.85, P <.001) than those with low Ki-67 LI, but there was no significant difference in objective tumor response rate. CONCLUSION: The meta-analysis reported here demonstrates that pretherapeutic Ki-67 LI is associated with pCR in breast cancer patients undergoing NCT. More phase III randomized clinical trials will be required to confirm our findings. PMID- 29390541 TI - Mucoepidermoid carcinoma of the breast: Four case reports and review of the literature. AB - RATIONALE: Mucoepidermoid carcinoma (MEC) of the breast is a rare entity comprising specific morphological and immunohistochemical features, and has been previously only reported in 33 cases. PATIENT CONCERNS: Four cases of MEC of the breast are reported in this study. All patients were women with ages ranging from 39 to 66 years. The lesions consisted of neoplastic solid nests and cystic spaces sometimes filled with mucoid material. DIAGNOSES: At high power, the tumors were composed of various proportions of basaloid, intermediate, epidermoid, and mucinous cells in different cases. All cases were classified as low-grade MEC of the breast. Tumor cells exhibited low levels of hormonal receptor expression in two cases (cases 1 and 3), and immunonegativity in one case (case 2). On the contrary, estrogen receptors (ER) were positively expressed in 60% of tumor cells in case 4. Tumor cells did not express human epidermal growth factor receptor 2 (HER-2)/neu protein in all the cases. INTERVENTIONS: Modified radical mastectomy (Auchincloss) was performed in the first two cases, while the remaining two patients underwent mastectomy plus sentinel lymph node biopsy. OUTCOMES: All patients were alive and well without evidence of recurrent disease after a period ranging from 4 months to 156 months. LESSONS: MEC of the breast is a rare primary carcinoma that is difficult to diagnose. Multiple tissue blocks are necessary before obtaining all cell types. Special stains for mucin and electron microscopy would be helpful in suspected cases. Hormonal factors might have an impact on the biological behavior of tumors, but further studies are needed to draw conclusions. PMID- 29390542 TI - Particularities of the management and the treatment in a rare sepsis with Candida tropicalis of a Collodion baby: Case report. AB - RATIONALE: Collodion baby is a rare autosomal recessive disorder. It can be the first expression of some forms of ichthyosis. PATIENT CONCERNS: The authors present the case of a newborn diagnosed with severe Collodion baby syndrome who required prolonged hospitalization in the intensive care unit because of infectious complications like the fungal sepsis and other bacterial superinfections. DIAGNOSES: The case has many diagnostic and therapeutic particularities and management difficulties. Skin culture, dermatological and genetic exam were required. INTERVENTIONS: The treatment required multidisciplinary involvement: neonatologist, pediatrician, geneticist, dermatologist, psychologist, ophthalmologist, audiologist. OUTCOMES: The evolution during hospitalization was slowly favorable, but later, after a few months, it developed some complications. LESSONS: In our case, skin injuries, total parenteral nutrition, aggressive and prolonged antibiotic therapy, intravenous devices, high hospitalization duration were risk factors for colonization and sepsis with fungi, especially in the neonatal period, sometimes with severe evolution and prognosis. PMID- 29390543 TI - The risk of missed abortion associated with the levels of tobacco, heavy metals and phthalate in hair of pregnant woman: A case control study in Chinese women. AB - To assess the association between exposure to the tobacco, heavy metals and phthalate on early pregnancy and missed abortion.42 women with missed abortion and 57 matched controls (women with normal pregnancies) were recruited between March and May 2012, from the Department of Gynecology and Obstetrics, First Affiliated Hospital of Guangxi Medical University and the People Hospital of Guangxi Zhuang Autonomous Region. The questionnaire survey was carried on to learn about the basic conditions, as well as smoking history of all participants. The levels of tobacco, heavy metal, and phthalate exposure were compared between the 2 groups by measuring nicotine, cocaine, cadmium (Cd), manganese (Mn), plumbum (Pb) and dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di-2-ethyl hexyl phthalate (DEHP) in the hair samples.Out results showed that significant differences in age (P = .042), premarital examination (P = .041), passive smoking (P = .021), and heavy metal exposure (P = .022) were found in the case group compared to the control. In addition, the concentration of nicotine (P = .037), cotinine (P = .018), Cd (P = .01), Pb (P = .038) and DEHP (P = .001) in the hair were significantly higher in the case group. Furthermore, logistic analysis revealed that age [Odds Ratio (OR) 1.172, 95% confidence interval (CI) 1.036-1.327], Cd (OR 8.931, 95% CI 2.003 39.811), Cotinine (OR 4.376, 95% CI 1.159-16.531), DEHP (OR 1.863, 95% CI 1.103 3.146) were important factors contributing to the missed abortion (P < .05).It was demonstrated that high gestational age, passive smoking, heavy metals, and the phthalate exposure were the risk factors for missed abortion, while the premarital health examination was a protective factor. Avoiding these harmful substances before getting pregnant and during the early stages of pregnancy, might help prevent missed abortions. PMID- 29390544 TI - Anesthetic management of primary hyperparathyroidism during pregnancy: A case report. AB - RATIONALE: Primary hyperparathyroidism (PHPT) during pregnancy is rare. Nevertheless, hypercalcemia secondary to gestational PHPT may be masked by physiological changes in calcium homeostasis during pregnancy. Gestational PHPT constitutes a serious danger to mother and fetus. Surgery is the only curative treatment when conservative treatment could not control the condition. Due to the lack of guidelines concerning PHPT during pregnancy, the optimal anesthetic management of PHPT during pregnancy needs to be individualized. Patient concerns: We report a case of PHPT with successful surgical treatment under combined cervical plexus block and general anesthesia. DIAGNOSIS: She was diagnosed with hypercalcemia, PHPT, a possible parathyroid adenoma, and a 19-week intrauterine pregnancy. INTERVENTIONS: The patient underwent heparin-free hemodialysis before the surgery in the nephrology department in the presence of a cardiologist. She then received a successful parathyroidectomy under combined bilateral superficial cervical plexus block and general anesthesia in her 19th week of pregnancy. OUTCOMES: She was released from the hospital with no maternal or fetal complications on postoperative day 9. A healthy baby boy was uneventfully born at 37 weeks of gestation. LESSONS: We suggest that surgical removal of the lesion after lowering the blood calcium concentration in mid-pregnancy is currently the optimal treatment option for pregnant patients with PHPT. Furthermore, multidisciplinary perioperative management is particularly important. PMID- 29390545 TI - Rare upper gastrointestinal hemorrhage of cetuximab: A case report. AB - RATIONALE: cetuximab, an epidermal growth factor receptor inhibitor, is a targeted therapeutic regimen of colorectal cancers. Several common adverse effects have been found, such as cutaneous or gastrointestinal toxicity. However, according to the articles had been published, upper gastrointestinal bleeding (UGIB) is considered to be rare and its mechanism remains unclear. PATIENT CONCERNS: In this report, we presented a 42-year-old male patient with advanced recto-sigmoid cancer. After palliative operation, the patient suffered from complete upper gastrointestinal (GI) obstruction, which was induced by extensive abdominal metastasis of the tumor. Considering his poor condition, we chose the targeted drug, cetuximab, as his further treatment. But after the application of cetuximab, the UGIB immediately happened twice in this patient. DIAGNOSIS: UGIB, as a rare complication of cetuximab, occured to the patient. INTERVENTIONS: We stopped the bleeding with thrombin, hemocoagulase and somatostatin and suspended the subsequent treatment plan of cetuximab. At the same time, anti-shock treatment was given immediately. OUTCOMES: He was died of respiratory and circulatory failure caused by UGIB and advanced tumor eventually. LESSONS: UGIB should be considered as a rare but severe complication of cetuximab. When cetuximab is applied for patients with advanced colon tumors, more cautions should be required if the patients are accompanied by upper gastrointestinal obstruction. In addition, for those patients who suffered from UGIB recently, cetuximab should be prohibited if the Rockall score ranged > 5 points. PMID- 29390546 TI - Primary osteosarcoma of frontal bone: A case report and review of literature. AB - RATIONALE: Primary osteosarcomas of the skull and skull base are rare, comprising <2% of all skull tumors. Primary osteosarcomas of the skull are aggressive neoplasms composed of spindle cells producing osteoid which have poor outcome. PATIENT CONCERNS: A 33-year-old woman was admitted to our hospital with a major complaint of a growing mass on her left frontal region of the skull for 10 months. Prior to the accurate diagnosis, the mass on her skull was considered to be eosinophilic granuloma. DIAGNOSES: Computerized tomogram (CT) scan of skull revealed a lytic lesion causing destruction of left frontal bone with surrounding soft tissue mass. The histological examination of the lesion showed typical features of osteosarcoma. INTERVENTIONS: The patient received 3 surgeries and adjuvant chemotherapy and radiotherapy for the frontal bone lesion. OUTCOMES: At the last follow-up, after 4 years, the patient was free of disease both clinically and on imaging by magnetic resonance imaging (MRI) scan after 4 years. LESSONS: Because osteosarcoma of skull is a rare disease, the early recognition and correct diagnosis are very important for a better prognosis. It is therefore imperative that clinicians recognize osteosarcoma early to make an accurate diagnosis and complete surgical resection followed by combined chemo-radiation is proved to be one of the most optimal treatment regimens. PMID- 29390547 TI - Quantitative evaluation of lumbar intervertebral disc degeneration by axial T2* mapping. AB - To quantitatively evaluate the clinical value and demonstrate the potential benefits of biochemical axial T2* mapping-based grading of early stages of degenerative disc disease (DDD) using 3.0-T magnetic resonance imaging (MRI) in a clinical setting.Fifty patients with low back pain and 20 healthy volunteers (control) underwent standard MRI protocols including axial T2* mapping. All the intervertebral discs (IVDs) were classified morphologically. Lumbar IVDs were graded using Pfirrmann score (I to IV). The T2* values of the anterior annulus fibrosus (AF), posterior AF, and nucleus pulposus (NP) of each lumbar IVD were measured. The differences between groups were analyzed regarding specific T2* pattern at different regions of interest.The T2* values of the NP and posterior AF in the patient group were significantly lower than those in the control group (P < .01). The T2* value of the anterior AF was not significantly different between the patients and the controls (P > .05). The mean T2*values of the lumbar IVD in the patient group were significantly lower, especially the posterior AF, followed by the NP, and finally, the anterior AF. In the anterior AF, comparison of grade I with grade III and grade I with grade IV showed statistically significant differences (P = .07 and P = .08, respectively). Similarly, in the NP, comparison of grade I with grade III, grade I with grade IV, grade II with grade III, and grade II with grade IV showed statistically significant differences (P < .001). In the posterior AF, comparison of grade II with grade IV showed a statistically significant difference (P = .032). T2 values decreased linearly with increasing degeneration based on the Pfirrmann scoring system (rho < -0.5, P < .001).Changes in the T2* value can signify early degenerative IVD diseases. Hence, T2* mapping can be used as a diagnostic tool for quantitative assessment of IVD degeneration. PMID- 29390548 TI - Short-course neoadjuvant chemoradiotherapy and surgery are beneficial in Chinese patients: A retrospective study. AB - Preoperative neoadjuvant chemoradiotherapy (NACR) is used to reduce tumor size for easier resection or improved resectability rates. Considering the difficulties regarding health insurance and health resources in China, an evidence-based short-course neoadjuvant chemoradiotherapy with surgery to cure patients was performed. This study compared the postoperative effects between short-course neoadjuvant chemoradiotherapy and surgery and surgery without neoadjuvant chemoradiotherapy.The current retrospective study was based on a rectal cancer database, including 274 patients diagnosed with rectal cancer between January 2014 and October 2016. Data were analyzed with respect to curative rate, postoperative recovery indicators (times to nasogastric tube, urinary catheter, and drainage tube removal and times to first oral feeding and passing of flatus postsurgery), chemoradiotherapy-related indicators [white blood cell count (WBC) and carcinoembryonic antigen (CEA) levels], and adverse effects indicators, evaluated according to Common Terminology Criteria for Adverse Events Version 4.0.There was no significant difference between the combined therapy and surgery groups (P > .05) in terms of radical resection rates and the times to urinary catheter removal and passing flatus (P > .05). Statistically significant differences (P < .05) in terms of earlier time for removal of the nasogastric and drainage tubes and time to first oral feeding were observed in the combined therapy group. The decreases in WBC and CEA levels in the combined therapy group were significantly greater than those in the surgery group 1 week after surgery (P < .05); after 1 month, the CEA decrease in the combined therapy group was significantly greater than that in the surgery group (P < .05). More patients in the combined therapy group experienced vomiting, indigestion, dehydration, oral mucositis, sensory neuritis, and alopecia compared with those in the surgery group 1 week after surgery (P < .05); after 1 month, only the incidence of alopecia was higher in the combined therapy group (P < .05).The combined therapy group demonstrated earlier postoperative recovery compared with the surgery group. Short-course neoadjuvant chemoradiotherapy with surgery may lead to postoperative treatment-related adverse effects of varying degrees; however, these adverse effects eventually improve with time. PMID- 29390549 TI - Five-year follow up results of posterior decompression and fixation surgery for delayed neural disorder associated with osteoporotic vertebral fracture. AB - Usually, after osteoporotic vertebral fracture (OVF), bone healing follows a normal clinical course leading to bone union with conservative treatment using a brace. However, some patients with OVF do not undergo the normal fracture healing process for a few months, possibly leading to delayed union and/or pseudoarthrosis. In these cases, we performed posterior surgery with combined decompression, vertebroplasty, and posterior spinal fusion with spinal instrumentation. This study aimed to determine the clinical results of posterior surgery for delayed neural disorder secondary to OVF over a 5-year follow up.Forty-one Japanese patients who had posterior surgery for delayed paralysis secondary to OVF were enrolled in this study. All patients were followed for >=5 years (mean, 67 months; range, 61-86 months). Patients comprised 12 men and 29 women with an average age of 76.3 +/- 6.2 years (range 63-87 years) at the time of operation. We performed posterior fixation from 2 levels above to 1 level below the decompression and vertebroplasty as an all in one procedure. Vertebral height index (VHI) and kyphotic angle (KA) were evaluated on radiogram. For clinical symptoms, a visual analog scale of back and leg pain and the Frankel classification and Japanese Orthopaedic Association scores were used.During the operation and perioperative period, no serious complications occurred. In all patients, symptoms improved within 1 month and were maintained for 5 years postoperatively. In all patients, VHI and KA improved after surgery; however, reduction losses of 7.7% of VHI and 23% of KA were recognized. Five of 41 patients required reoperation due to adjacent vertebral fracture (AVF) and recollapse of the vertebral body.Operation time and blood loss were acceptable, even for elderly patients. In all patients, alignment and subjective symptoms improved. However, reoperation owing to AVF and recollapse was necessary within 1 year in 5 of 41 (12%) patients. Careful follow-up is required within 1 year after surgery for OVF. PMID- 29390550 TI - Successful treatment of sudden sensorineural hearing loss by means of pharmacotherapy combined with early hyperbaric oxygen therapy: Case report. AB - RATIONALE: According to the World Health Organization reports, adult-onset hearing loss is the 15th leading cause of burden of disease, and is projected to move up to 7th by the year 2030, especially in high-income countries. Sudden sensorineural hearing loss is considered by otologists as a true otologic emergency. The current standard treatment for sudden hearing loss is a tapered course of oral high-dose corticosteroids. The described clinical case points to the validity of undertaking early hyperbaric oxygenation (HBO) therapy together with corticosteroids for full recovery of adult onset idiopathic sudden sensorineural hearing loss. PATIENT CONCERNS: A 44-year-old woman complained of an abrupt hearing deterioration in the left ear with the sensation of aural fullness and loud tinnitus presented for 48 hours. The patient was admitted to the Department of Otolaryngology of Public Hospital for diagnosis and treatment. DIAGNOSES: The patient was diagnosed with unilateral sudden idiopathic sensorineural hearing loss, assessed by measuring the tonal audiograms. INTERVENTIONS: The patient received treatment including oral high-dose corticosteroids combined with HBO protocol including 15 daily 1-hour exposures to 100% oxygen at 2.5 atmosphere absolute. OUTCOMES: A pharmacotherapy combined with early HBO resulted in full recovery of hearing. LESSONS: Early implementation of HBO to the pharmacotherapy in sudden sensorineural hearing loss may lead to full recovery of hearing. There is a need for systematic research to establish guidelines for optimal number of HBO sessions in relation to the timeframe from hearing loss symptoms onset to implementation of HBO therapy. PMID- 29390551 TI - Xanthomatosis in bilateral hands mimicking rheumatoid arthritis: A case report. AB - RATIONALE: Xanthomatosis often accompanies familial hypercholesterolemia. This disease usually occurs in tendons, most commonly located in the Achilles tendon; occasionally it can also be seen in other systems. Although there are previous reports for bilateral hand extensor tendon involvement, to our knowledge there is no report in English literature regarding bilateral hands with small joint synovium presenting as rheumatoid arthritis. Therefore, the case that is presented in this report is unique. PATIENT CONCERNS: An 18-year-old woman was admitted to our department because she presented with morning stiffness, joint deformation, and swelling in both hands. Computed tomography of the right hand showed soft tissue swelling on multiple small joints, including metacarpophalangeal and proximal interphalangeal joints, but without obvious bone destruction. There was soft tissue swelling around the small joints, which were hypointensities on T1-weighted and hyperintensities on T2-weighted images, not uniformly enhanced appearances on magnetic resonance imaging. DIAGNOSES: Biopsy from the 3rd metacarpophalangeal joint capsule of the left hand confirmed xanthoma. INTERVENTIONS: She was treated with statin drugs to reduce blood fat. OUTCOMES: After 3 months of follow-up, no recurrence or complications were detected regarding a full range of motion remaining of the affected joints. LESSONS: The young patient with symptoms of small joint synovium involved in both hands and the performance of magnetic resonance imaging similar to rheumatoid arthritis may be suffering from xanthomatosis. PMID- 29390552 TI - Monocyte chemoattractant protein-1 (MCP-1)-2518 A/G polymorphism and lupus nephritis risk: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the development of allergic inflammatory reactions by recruiting various immune cells, which is associated with many autoimmune diseases, but the association with the MCP-1-2518A/G gene polymorphism and lupus nephritis (LN) was still controversial in previous studies. Thus, we performed a meta-analysis to derive a more precise evaluation of the association between MCP-1 -2518A/G polymorphism and LN risk and evaluated influence of ethnicity and source of controls. METHODS: A systematic review and meta-analysis that will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Relevant literatures dated to September 2016 were acquired from the PubMed, EMBASE, Cochran Library databases. A total of 961 LN cases and 1867 controls were extracted from 10 published case-control studies. We used odds ratios (OR) with 95% confidence intervals (CI) to assess the risk of LN with MCP-1-2518A/G. RESULTS: Our meta-analysis suggested that MCP-1-2518A/G polymorphism was associated with the risk of LN (GG vs AG+AA: P < .01, OR = 1.42, 95% CI: 1.13 1.79 and A vs G P = .02, OR = 0.74, 95% CI: 0.58-0.95). Then the subgroup analysis showed MCP-1 -2518 A/G gene has a certain correlation with LN susceptibility in the American population (GG vs AA: P < .01, OR = 5.70, 95% CI: 2.09-15.50, GG vs AG+AA: P < .01, OR = 3.31, 95% CI: 1.97-5.54, GG+AG vs AA: P < .01, OR = 2.86, 95% CI: 1.14-7.18, and A vs G: P < .01, OR = 0.43, 95% CI: 0.24 0.79), while no significant risk in Europeans and Asians. CONCLUSION: The current meta-analysis suggests that the MCP-1-2518A/G polymorphism is associated with an increased risk of LN, especially in the American population. However, better designed studies with larger sample sizes are needed to validate the results. PMID- 29390553 TI - ERCC1 expression status predicts the response and survival of patients with metastatic or recurrent cervical cancer treated via platinum-based chemotherapy. AB - The deoxyribonucleic acid (DNA) repair gene encoding the excision-repair cross complementation group 1 (ERCC1) protein is known to predict the response to platinum-based chemotherapy. Our aim was to explore whether ERCC1 expression predicted tumor response and survival in patients with recurrent or metastatic cervical cancer treated via platinum-based chemotherapy. We analyzed 32 such patients. ERCC1 expression was assessed immunohistochemically in pretreatment biopsy samples. Of the 32 patients, 13 (40.6%) were ERCC1 high. ERCC1-low patients exhibited a significantly higher response rate (73.7%) than did others (15.4%). The median progression-free survival differed significantly by ERCC1 status, being 135 days in ERCC1-high and 242 days in ERCC1-low patients (hazard ratio, 2.428; 95% confidence interval, 1.145-5.148, P = .032). Overall survival was significantly longer in ERCC1-low (617 days) than in ERCC1-high (320 days) patients (hazard ratio, 2.322; 95% confidence interval, 1.051-5.29; P = .037). Thus, pretreatment ERCC1 expression status can be used to predict tumor response and survival of patients with recurrent or metastatic uterine cervical cancer receiving platinum-based chemotherapy. PMID- 29390554 TI - Association between serum ferritin and hemoglobin levels and bone health in Korean adolescents: A nationwide population-based study. AB - It is important to identify risk factors for low bone mass at a young age. An influence of iron store on bone health in the general population has been reported but has not been studied in adolescents. This study aimed to investigate the relationship between hemoglobin and serum ferritin levels and bone mineral content (BMC) in South Korean adolescents.This study was based on data collected during the 2009to 2010 Korea National Health and Nutrition Examination Survey. We included 1321 participants aged 10 to 18 years. BMC was measured at the femur and lumbar spine using dual-energy x-ray absorptiometry, and hemoglobin and serum ferritin levels were examined.In boys, hemoglobin and serum ferritin levels were positively associated with BMC of the total femur and lumbar spine after adjusting for confounders, and hemoglobin levels significantly increased as BMC increased at all sites (P for trend = .001 for total femur, .01 for femur neck, and <.001 for lumbar spine). Likewise, serum ferritin levels showed increasing trends according to increasing BMC of the total femur and lumbar spine in boys (P for trend = .04 for total femur; and <.001 for lumbar spine). However, these associations were not observed in girls.This study suggests a positive relationship between serum ferritin and hemoglobin levels and BMC in South Korean adolescent boys. PMID- 29390555 TI - Predicting new-onset diabetes after minimally invasive subtotal distal pancreatectomy in benign and borderline malignant lesions of the pancreas. AB - The purpose of this study was to evaluate the time-dependent probability and risk factors of pancreatogenic diabetes mellitus (PDM) in patients who underwent minimally invasive subtotal distal pancreatectomy.Changes in glucose metabolic consequence of 34 patients (laparoscopic: 31, robotic: 3) who underwent surgery from December 2005 to December 2014 were estimated by assessing impaired fasting glucose, PDM, and PDM-free time analysis.A total of 22 patients showed glucose intolerance, including 13 (38.2%) with impaired fasting glucose and 9 (26.5%) with PDM. The median onset time of PDM was 6.8 months (range 5.3-13.2 months). The PDM-free time probability according to time interval was 94.1% (6 months), 75.9% (12 months), and 72.6% (18 months). It was shown that body mass index>23 kg/m (49.9 vs 87.9 months, P = .020) and preoperative cholesterol >200 mg/dL (40.9 vs 85.2 months, P = .003) adversely influenced PDM-free time. Preoperative cholesterol >200 mg/dL (hazard ratio = 6.172; 95% confidence interval, 1.532 24.865; P = .010) was significantly associated with short PDM-free time in Cox proportional hazards model.Patients with high cholesterol levels and high BMI should be closely monitored for the development of PDM. PMID- 29390556 TI - Treatment of longitudinal stent compression under intravenous ultrasound guidance: A case report. AB - RATIONALE: Longitudinal stent compression is a rare phenomenon, which has been increasingly reported in recent years. PATIENT CONCERNS: Following 2 stents implanted into the middle and proximal segments of the left anterior descending (LAD) artery, longitudinal stent compression occurred when a post-dilation balloon was introduced into the proximal stent opening. DIAGNOSE: The intravenous ultrasound (IVUS) examination revealed overlapping at the opening of the proximal stent and poor stent adherence. INTERVENTIONS: Another balloon was carefully inserted into the opening for post-dilation, followed by angiography and IVUS examination. OUTCOMES: The IVUS examination indicated that the overlapping at the opening of the proximal stent was improved and the stents were well adhered. LESSONS: Such compression may be prevented by gentle and careful balloon maneuverability and improved with the use of additional balloon angioplasty or stent implantation. PMID- 29390557 TI - Evaluating the clinical application of a leaflet for clinical practice guideline in patients with lumbar herniated intervertebral discs: Randomized controlled trial. AB - BACKGROUND: This study aims to demonstrate the effectiveness of using clinical practice guideline (CPG) leaflets as a communication tool between doctors and patients. We evaluated the leaflets as a communication tool in the treatment of lumbar herniated intervertebral discs (HIVDs) in terms of patient and physician satisfaction and ease of treatment. METHODS: This study is a 2-parallel-arm, assessor-blinded, randomized controlled trial at Jaseng Hospital, Seoul, South Korea. We evaluated efficacy through a comparison of satisfaction and clinical outcomes in randomly allocated groups of HIVD lumbar patients visiting Jaseng Hospital of Korean Medicine. We used leaflets on the basis of Korean medicine CPG recommendations as an intervention. The intervention group received treatment and diagnosis using the leaflet, and the control group received the typical intervention, which was provided without the leaflet. RESULTS: The levels of patient satisfaction with and understanding of the doctors' explanation was 92% in the leaflet group and 64% in the nonleaflet group, which showed that, compared with patient satisfaction in the nonleaflet group, patient satisfaction was considerably higher by 28% in the leaflet group. In addition, the level of the reliability with treatment was 92% in the leaflet group and 64% in the control group. However, there were no significant differences in statistical analyses. The level of doctors' satisfaction with communicating with patients using the leaflet was 100% in the leaflet group. Given this satisfaction, the ease of persuasion of treatment was highest (84%) and followed the improvement in the patient's understanding of the treatment (16%) in the leaflet group. In addition, in the nonleaflet user group, almost all doctors thought that having a leaflet would be a more effective treatment. CONCLUSION: Although this study failed to show significant differences between the intervention and control groups, the leaflet, which included CPG information in the treatment of HIVD patients, was an effective communication tool between patients and doctors. However, further studies with larger samples should be conducted to investigate the effectiveness of the communication tool based on the CPG. TRIAL REGISTRATION NUMBER: Clinical Research Information Service: KCT0001762. PMID- 29390558 TI - Course of hepatitis E infection in a patient with rheumatoid arthritis and autoimmune hepatitis: A case report. AB - RATIONALE: A 62-year-old male patient was admitted to our clinic in February 2016 with persistently elevated liver enzymes. PATIENT CONCERNS: Clinical history involved a long time of poly-autoimmunity with a rheumatoid arthritis (in remission under tocilizumab therapy), an autoimmune thyroiditis, an eosinophilia as well as a hyper-immunoglobulin (IgG) 4-syndrome. DIAGNOSES: Laboratory studies revealed a significant increase in liver enzymes with an alanine aminotransferase (ALT) level of 574 U/L and an aspartate aminotransferase (AST) level of 864 U/L (normal <50 U/L). Furthermore, the patient was positive for anti-nuclear autoantibodies (ANA) with a titer of 1:320 (normal upper limit: 1:80). INTERVENTIONS: Liver histology, obtained via mini-laparoscopy, demonstrated lobular hepatitis with markedly increased hepatocyte apoptosis, lymphoplasmatic cell infiltration, and 20% microvascular fat without significant fibrosis, which strengthened the diagnosis of autoimmune hepatitis (AIH). Pulse steroid treatment with 100 mg prednisolone for 3 days followed by a tapering down was initiated. Follow-up laboratory analysis demonstrated a decrease in liver enzymes and also of the ANA-titer. OUTCOMES: At that point, hepatitis E virus (HEV) infection was diagnosed with a positive anti-HEV immunoglobulin M (IgM) antibody and HEV ribonucleotide acid (RNA) of 6280 copies/mL. LESSONS: Despite the HEV infection and due to the strength of autoimmunity, we decided to continue immunosuppressive therapy and monitored HEV-PCR regularly. However, HEV-RNA became negative after 2 months and HEV-IgM turned negative after 13 months. PMID- 29390559 TI - Systematic evaluation of different doses of cyclophosphamide induction therapy for lupus nephritis. AB - OBJECTIVE: This study systemically evaluated the efficacy and safety of intermittent intravenous pulse therapy with different doses of cyclophosphamide (CTX) for the treatment of lupus nephritis (LN). METHODS: We screened the Chinese Journal Full-text Database (CNKI, 1994-present), China Biology Medicine (CBMdisc, 1978-present), VIP Database for Chinese Technical Periodicals (1989-present), PubMed (1948-present), MEDLINE (Ovid SP, 1946-present), Embase (1947-present), and the Cochrane controlled trials register (13, 2017). Literature reports were selected according to the inclusion and exclusion criteria, effective data were extracted, research quality was evaluated, and RevMan5.2 was used for meta analysis. RESULTS: Seven randomized controlled studies were included, consisting of 655 patients. The meta-analysis results showed no significant differences between the low- and high-dose cyclophosphamide groups in partial, complete, and total remission rates as well Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Furthermore, there were no significant differences between the 2 groups in hematologic toxicity and gastrointestinal reaction, but the risk of infection (risk ratio [RR] = 0.74, 95% confidence interval [CI], 0.56-0.98, total effect inspection Z = 2.12, P = .03), and menstrual disorder (RR = 0.46, 95% CI, 0.31 0.69, total effect inspection Z = 3.83, P = .0001) decreased in the low-dose cyclophosphamide group. CONCLUSIONS: There was no obvious difference between the low- and high-dose cyclophosphamide groups in efficacy in the treatment of lupus nephritis, but the risk of infection and menstrual disorder significantly decreased in the low-dose group. PMID- 29390560 TI - Fibromyxoid sarcoma in the retroperitoneum: A case report. AB - RATIONALE: Low-grade fibromyxoid sarcoma (LGFMS) is a pathological type of fibrosing fibrosarcoma that appears as a distinctive soft tissue masse with bland histological features. It is mostly located in the deep soft tissues of the extremities. Computed tomography (CT) plays an important role in diagnosing fibrosing fibrosarcoma in the abdomen. To date, several studies in the literature have reported on CT features of LGFMS. PATIENT CONCERNS AND DIAGNOSES: We report another case of LGFMS, which presented with certain unique CT feature. The anterolateral region and the wall of the cystic nodules showed gradual enhancement and several nourishing vessels were seen after contrast administration. These imaging features were consistent with the histologic findings of LGFMS. INTERVENTIONS AND OUTCOMES: The patient underwent tumorectomy and implantation of radioactive implants. Two years after the operation, 1 metastasis mass occur in the right psoas major. LESSONS: These CT features in LGFMS may be useful to assess the histological characteristics of LGFMS to facilitate preoperative diagnosis in the clinical setting and provide the supplemental imaging knowledge for future studies. PMID- 29390561 TI - Gastrointestinal malignant neoplasms disguised as pneumatosis cystoids intestinalis: A case report and literature review. AB - RATIONALE: Pneumatosis cystoids intestinalis (PCI) is a rare disease in which gas develops in the mucosa or submucosa of the digestive tract. The etiology and pathogenesis of this disease, at present, remain unclear, and gastrointestinal malignant neoplasms may be a potentially important cause. Herein, we report a case of mantle cell lymphoma presenting as PCI as well as present a literature review of cases of suspect PCI that was definitively diagnosed as gastrointestinal neoplasms. In doing so, we highlighted cases of neoplastic pathogenesis that present as PCI. PATIENT CONCERNS: A 55-year-old man was referred to our gastrointestinal department with complaints of intermittent abdominal pain, distention, diarrhea, and occasional melena that persisted for 2 months. He has a history of nasopharyngeal carcinoma. DIAGNOSES: Intensive, translucent, grape-like cystoids of the whole colon and small intestine were disguised as PCI upon colonoscopy and capsule endoscopy. INTERVENTIONS: Right hemicolectomy and ileocecectomy were performed for intussusception and to confirm the diagnosis. Final pathology indicated that the mass was mantle cell lymphoma. OUTCOMES: After surgery and subsequent chemotherapy, the patient showed good recovery and no abnormal lesions were detected on colonoscopy. LESSONS: As shown through this case and a literature review of similar cases of apparent PCI that was definitively diagnosed as gastrointestinal neoplasm, gastrointestinal malignant neoplasms might rarely present as PCI and neoplastic etiologies should also be considered once PCI is detected. Because most patients with malignant PCIs might inevitably experience severe complications, abdominal surgery should be considered and applied timely after unsuccessful resolution by conservative medical therapies and symptomatic treatments. PMID- 29390562 TI - Specialized second-opinion radiology review of PET/CT examinations for patients with diffuse large B-cell lymphoma impacts patient care and management. AB - To identify discrepancies in fludeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) reports generated by general radiologists and subspecialized oncological radiologists for patients with diffuse large B-cell lymphoma (DLBCL), and to assess if such discrepancies impact patient management.Two radiologists retrospectively reviewed 72 PET/CT scans of patients with DLBCL referred to our institutions between 2009 and 2011, and recorded the discrepancies between the outside and second-opinion reports regarding multiple preset criteria using kappa statistic (Kappa), including the disease stage. A multidisciplinary staging that considered all patient clinical data, pathology, and follow up radiological scans, was considered as standard of reference. A hemato-oncologist, blinded to the reports' origin, subjectively graded the quality and structure of these reports for each patient to determine if clinical stage and disease activity could be derived accurately from these reports.Agreement was not, or slightly, achieved between the reports regarding the binary and multilevel criteria (Kappa < 0-0.2 and weighted Kappa = 0.082, respectively). Second-opinion reviews of PET/CT scans were concordant with the multidisciplinary staging in 78% of cases with an almost perfect agreement (Kappa = 0.860). A change in staging was demonstrated in 36% of cases. In addition, 68% of second-opinion reports were assigned the highest grades on quality (grades 4 and 5) by the hemato-oncologist, compared with 15% of outside reports, with no noted agreement (weighted Kappa = -0.007).Second-opinion review of PET/CT scans by sub-specialized oncological radiologists increases accuracy of initial staging, posttreatment evaluation and also the clinical relevance of the radiology reports. PMID- 29390563 TI - Thin-slice brain CT with iterative model reconstruction algorithm for small lacunar lesions detection: Image quality and diagnostic accuracy evaluation. AB - This study was aimed to evaluate the image quality and lacunar lesion detection of thin-slice brain computed tomography (CT) images with different reconstruction algorithms, including filtered back projection (FBP), hybrid iterative reconstruction (HIR), and iterative model reconstruction (IMR) by comparison of routine slice images with FBP reconstruction. Sixty-one patients underwent noncontrast brain CT and images were reconstructed with a routine slice of 5.0 mm by FBP and thin slice of 1.0 mm by IMR, HIR, and FBP algorithms, respectively. Objective analyses included CT attenuation, noise, artifacts index of posterior cranial fossa, and contrast-to-noise ratio (CNR). Subjective analyses were performed according to overall image quality using a 5-point scale [1 (unacceptable) to 5 (excellent)]. In addition, lacunar lesion detection was compared in images with different reconstruction settings among 26 patients with lacunar lesions, with magnetic resonance imaging (MRI) as reference.Thin-slice IMR images enabled the lowest noise, artifacts index, and the best CNR. Both IMR and HIR thin-slice images enabled better scores in subjective image quality than routine slice FBP images. Moreover, both thin-slice IMR and HIR images enabled higher sensitivity and positive predictive value (PPV) in lesion detection of 35 mm lacunar lesions compared with routine slice FBP images.Thin-slice IMR images improve image quality, meanwhile yield better detection of small lacunar lesions in brain CT compared with routine slice FBP images. PMID- 29390564 TI - The associations of stroke, transient ischemic attack, and/or stroke-related recurrent vascular events with Lipoprotein-associated phospholipase A2: A systematic review and meta-analysis. AB - BACKGROUND: Studies on stroke and lipoprotein-associated phospholipase A2 (Lp PLA2) have produced conflicting results. OBJECTIVE: The aim of the study was to assess the associations of Lp-PLA2 levels (mass and activity) with recurrent vascular events in patients with transient ischemic attack (TIA) and/or first ischemic stroke and with stroke in the general population. METHODS: The MEDLINE, Embase, the Cochrane Library, Web of Science, Science Direct, China National Knowledge Infrastructure, China Biology Medical Disc (CBMdisc), and WanFang were searched for prospective observational studies reported until January 2017. Eligible studies reported Lp-PLA2 levels and adjusted risk estimates of recurrent vascular events and/or stroke. Risk ratio (RR) with corresponding 95% confidence intervals (CIs) were used to express the pooled data in a random-effects model. RESULTS: A total of 11 studies that comprised 20,284 participants (4,045 were TIA and/or first ischemic stroke patients and 16,239 were residents in general population) were identified, which reported either Lp-PLA2 mass levels (4 studies) or Lp-PLA2 activity levels (10 studies). The pooled RR of recurrent vascular events (467 cases) in TIA and/or first ischemic group was 2.24 (95% CI, 1.33-3.78), whereas the pooled RR of stroke (1604 cases) in the general population was 1.47 (95% CI, 1.10-1.97). The pooled RRs of Lp-PLA2 mass and activity levels with the risk of stroke in the general population were 1.69 (95% CI, 1.03-2.79) and 1.28 (95% CI, 0.88-1.85), respectively. CONCLUSIONS: In patients with TIA and first ischemic stroke, elevated Lp-PLA2 activity levels were associated with recurrent vascular events. And in the general population elevated Lp-PLA2 levels were associated with the risk of stroke, although the association between Lp-PLA2 activity levels and the risk of stroke was less profound compared with the corresponding association of stroke risk with the Lp PLA2 mass levels. PMID- 29390565 TI - Lymphoepithelioma-like hepatocellular carcinoma: A case report and brief review of literature. AB - RATIONAL: Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a rare variant of hepatocellular carcinoma (HCC). To date, few cases have been reported in the literature, and almost no report in analyzing the different features of LEL-HCC. PATIENT CONCERNS: We describe a 37-year-old female patient with a 32 * 30 mm mass in the right liver. INTERVENTIONS: Complete surgical resection of the lesion was performed. DIAGNOSES: Histopathological examination of the resected tumor revealed undifferentiated HCC cells with significant lymphocytes infiltration. Immunohistochemically, the tumor cells were positive for AFP (alpha fetoprotein), hepatocyte, CK8, and glypican-3. The patient was diagnosed with LEL HCC. OUTCOMES: The patient had a favorable clinical outcome, and was free from tumor recurrence after a 52-months follow-up. LESSONS: Our case was the youngest patient of all the reported cases, and the third case who was infected with both hepatitis B virus (HBV) and hepatitis C virus (HCV). LEL-HCC is a rare variant of HCC, with a relatively favorable prognosis. Further research recruiting more patients is required to determine the accurate causes and mechanism of LEL-HCC. PMID- 29390566 TI - Clinical features and outcomes of blunt splenic injury in children: A retrospective study in a single institution in China. AB - Although the spleen is the most commonly injured intra-abdominal organ after blunt trauma, there are limited data available in China. The objectives of this study were to investigate the clinical features and determine the risk factors for operative management (OM) in children with blunt splenic injury (BSI).A review of the medical records of children diagnosed with BSI between January 2010 and September 2016 at West China Hospital of Sichuan University was performed.A total of 101 patients diagnosed with BSI were recruited, including 76 patients transferred from other hospitals. The male-to-female ratio was 2.06:1, with a mean age of 7.8 years old. The most common injury season was summer and the most common injury mechanism was road traffic accidents. Sixty-eight patients suffered multiple injuries. Thirty-four patients received blood transfusions. Two patients died from multiple organ failure or hemorrhagic shock. Significant differences were observed in the injury season, injury mechanism, injury date, and hemoglobin levels between the isolated injury group and the multiple injuries group. The overall operative rate was 29.7%. Multivariate regression analysis revealed that age, blood transfusion, and grade of injury were independent risk factors for OM.Our study provided evidence that the management of pediatric BSI was variable. The operative rate in pediatric BSI may be higher in certain patient groups. Although nonoperative management is one of the standard treatment options, our data suggest that OM is an appropriate way to treat patients who are hemodynamically unstable. PMID- 29390567 TI - Comparison of long-term benefits of organ-preserving pancreatectomy techniques for benign or low-grade malignant tumors at the pancreatic head. AB - The aim of this article was to investigate and emphasize the clinical benefits of organ-preserving surgeries by comparing the pancreatic head resection with segmental duodenectomy (PHRSD), pylorus-preserving pancreatoduodenectomy (PPPD), and classic pancreatoduodenectomy (PD).A retrospective analysis of PHRSD (20 patients), PPPD (42 patients), and PD (92 patients) with benign lesions, low grade malignancies, or early-stage carcinomas at the pancreatic head was performed since 2008. The intraoperative and postoperative courses and a long term statuses were compared.The overall average age of the patients in 3 groups was 48.82 years old (range 12-76). The mean operative time and the blood loss were significantly less in the PHRSD and PPPD groups than that in the PD group (P < .05), but there were no differences between the PHRSD and PPPD groups. The possibilities of postoperative complications were equivalent in all 3 groups. During an average follow-up time of 61.1 months, there were no recurrence or distant metastasis happened. Patients in the PHRSD and PPPD groups had a better long-term nutritional status because they had less body weight loss (P < .01), and suffered less from long-term diarrhea (P < .001) than that in the PD group. However, the results in the PPPD group seemed to be better than that in the PHRSD group.PHRSD and PPPD are ideal procedures of organ-preserving pancreatectomy to fulfill the curative goals of benign lesions, low-grade malignancies, or early stage carcinomas at the pancreatic head. It was proved to be operative safe and could bring patients with a better nutritional status and quality of life after surgery. However, PHRSD was more difficult with no better long-term benefits than PPPD, which asked a comprehensive consideration when made the surgical choice. PMID- 29390568 TI - Uterine fibroids with positive 18F-FDG PET/CT image and significantly increased CA19-9: A case report. AB - RATIONALE: Uterine fibroids are the most common pelvic solid tumors and common to 25% of women. F-fluorodexyglucose (F-FDG) is an energy metabolism tracer. Although FDG is generally concentrated in malignant lesions with high glucose metabolism, it can also accumulate in normal tissues, benign lesions, and inflammatory sites. The exact mechanism of FDG uptake by uterine fibroids is not clear. Here, we report a case of uterine fibroids with positive F-FDG positron emission tomography/computed tomography (PET/CT) imaging and significantly increased CA19-9. PATIENTS CONCERNS: The patient was a 43-year-old woman and admitted to our hospital because of "1-year-extended menstrual periods." At admission, she had normal CA125, AFP, and CEA level and CA19-9>1000.00 U/mL. Gynecological transvaginal ultrasound found enlarged uterus with an anterior hypoechoic area of 3.9 * 4.2 cm. CT and contrast-enhanced CT showed significantly enhanced mass shadow on the left anterior wall of uterus. F-FDG PET/CT showed increased FDG metabolism of tumor in the anterior wall of the uterus. INTERVENTIONS: Laparoscopic hysterectomy was performed. DIAGNOSIS: Pathological examination demonstrated subserosal leiomyoma. OUTCOMES: Her CA19-9 level dropped to 91.50 U/mL 1 day after surgery. LESSONS: Significantly elevated CA19-9 was positioned in the uterus by PET/CT imaging, which not only avoided unnecessary gastrointestinal endoscopy and reduced the suffering of patients, but also strengthened the operation confidence in gynecologists. PMID- 29390569 TI - Intracranial squamous cell carcinoma arising in a cerebellopontine angle epidermoid cyst: A case report and literature review. AB - RATIONALE: Most of the intracranial epidermoid cysts are benign, but malignant lesions are occasionally reported. These lesions appear as squamous cell carcinoma and carry a dismal prognosis. Here, we report a case of a primary intracranial squamous cell carcinoma arising in a cerebellopontine epidermoid cyst. The relevant literatures were also reviewed. PATIENT CONCERNS: A 53-year old woman presented with dizziness and diplopia 9 months in duration. Magnetic resonance imaging revealed an epidermoid cyst in the left cerebellopontine angle and prepontine region with a focal enhancing lesion on T1-weighted gadolinium enhanced images. DIAGNOSES: Histopathologic diagnosis revealed squamous cell carcinoma on a background of epidermoid cyst. Imaging studies excluded metastases. INTERVENTIONS: The tumor was removed subtotally through a lateral suboccipital approach. The patient received intensity modulated radiation therapy (6720 cGy total) postoperatively. OUTCOMES: The patient was free from recurrence of the tumor until 3 years after surgery, at which point she was lost to follow up. The patient died 4 years after the surgery. LESSONS: The epidermoid cyst may occasionally become malignant. Finding an area of enhancement through preoperative magnetic resonance imaging can help to make a correct diagnosis. Based on the review of previous reports, surgical removal followed by radiotherapy shows the best result to treat malignant epidermoid cysts. PMID- 29390570 TI - Impact of metformin on serum prostate-specific antigen levels: Data from the national health and nutrition examination survey 2007 to 2008. AB - PURPOSE: A possible association between metformin use and the development of prostate cancer (PCa) has been reported. However, there is limited information on the impact of long-term metformin use on serum prostate-specific antigen (PSA) levels. We investigated the association between exposure to metformin and PSA levels among diabetic patients who were not previously diagnosed with PCa. METHODS: The analytic sample consisted of 1363 US men aged above 40 in the National Health and Nutrition Examination Survey 2007 to 2008 cycle. Men who had previous diagnoses of PCa or prostatitis and men exposed to manipulations that might have affected PSA levels were excluded. Multivariate logistic regression analyses were used to evaluate the association between PSA levels and metformin use by adjusting for potential confounders. RESULTS: The mean PSA level of the overall population was 1.8 (standard deviation = 3.1) ng/mL. There were no differences in PSA levels according to the presence of diabetes (P = .517). Among patients with diabetes, metformin users exhibited significantly lower PSA levels compared with nonmetformin users (odds ratio = 0.790; 95% confidence interval 0.666-0.938; P = .007). However, no significant difference was found in PSA levels among men over duration of metformin use when levels were stratified by either 1 year or 5 years by Pearson's coefficient. CONCLUSION: A negative association between serum PSA levels and metformin use was observed in patients with diabetes. Duration of metformin use did not influence PSA levels. Further studies are warranted to elucidate whether the reduction in PSA level with metformin truly reflects reduced risk of PCa development and progression. PMID- 29390571 TI - Association between MDR1 C3435T polymorphism and colorectal cancer risk: A meta analysis. AB - BACKGROUND: The multidrug resistance gene 1(MDR1) C3435T polymorphism has been reported to be associated with colorectal cancer (CRC) risk in Asians, however the results were inconsistent. Thus, we performed a meta-analysis to generate large-scale evidence on the association between C3435T polymorphism and CRC risk in Asian populations. METHODS: The PubMed, Web of Science, Embase, CNKI, and Chinese Biomedicine databases were searched up to January 15, 2017. The odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by a fixed effects or random-effects model. Sensitivity and cumulative meta-analysis were also performed. RESULTS: A total of 7 studies involving 4818 individuals were included in this pooled-analysis. The results suggested that persons carrying a T allele at the C3435T polymorphism had a significantly decreased risk of CRC in Asian population (T vs C: OR = 0.897, 95%CI = 0.826-0.975, P = .01), and the significant association was also observed in another 2 genetic models (TT vs CC: OR = 0.721, 95%CI = 0.605-0.861, P < .001; TT vs TC+CC: OR = 0.679, 95%CI = 0.579 0.795, P < .001). Moreover, the results of sensitivity and cumulative meta analysis indicated the stable of our results. Finally, funnel plot and Egger's test showed no evidence of publication bias. CONCLUSIONS: In summary, this meta analysis provided evidence that MDR1 C3435T polymorphism is associated with a decreased risk of CRC in Asian population. PMID- 29390572 TI - Acute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer: A case report. AB - RATIONALE: Keytruda (pembrolizumab) is an inhibitor of programmed cell death receptor-1 (PD-1), which was approved to treat advanced melanoma and nonsmall cell lung cancer patients who do not respond to other treatment. However, its efficacy and security in the treatment of advanced liver cancer is still under investigation. PATIENT CONCERNS: A 60-year-old man was diagnosed with pulmonary metastatic liver cancer who accepted pembrolizumab treatment after the failure of sorafenib. When injected pembrolizumab, in spite of pulmonary metastatic lesion shrink, the patient experienced severe liver dysfunction. DIAGNOSES: Based on the features of the clinical signs and laboratory examination,the patient was diagnosed with pembrolizumab-induced immune-related hepatitis by excluding other etiologies and drug-induced side effects. INTERVENTIONS: The patient received glucocorticoid and artificial liver (plasma exchange) therapy after failed conservative liver protection treatment. OUTCOMES: The patient's liver dysfunction continuously progressed and he finally died of liver failure and its complications during his hospitalization. LESSONS: Pembrolizumab showed efficacy in an advanced hepatocellular carcinoma patient with lung metastases. However, it can generate immune-related adverse events such as immune-related hepatitis which can be lethal. PMID- 29390573 TI - Totally laparoscopic radiofrequency-assisted liver partition with portal vein ligation for hepatocellular carcinoma in cirrhotic liver. AB - RATIONALE: Adequate future liver remnant (FLR) volume is often a concern for patients with hepatocellular carcinoma (HCC). Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure can rapidly lead to impressive growth of FLR. We describe the technique of an entirely laparoscopic radiofrequency-assisted liver partition with portal vein ligation for staged hepatectomy (RALPP) in a cirrhotic patient with HCC. PATIENT CONCERNS: A 33 year old female cirrhotic patient with HCC in the right liver was indicated for RALPP as the predicted future liver remnant (FLR) was 21%. DIAGNOSES: HCC with liver cirrhosis. INTERVENTIONS: The first surgery consisted of ligation of the right portal vein and radiofrequency ablation of the liver without parenchymal transection. Three weeks postoperatively, FLR reached 42%, and the patient underwent right hepatectomy. OUTCOMES: Operative times for the both surgeries were 60 and 240 minutes respectively, with negligeable blood loss. The patient had an uneventful postoperative course, and the FLR reached 53% 1 week after the second procedure. No recurrence occurred at 10 months. LESSONS: Laparoscopic RALPP is feasible in some cirrhotic patients with liver cancer that in line with the indications and this method may be a superior choice for selected cirrhotic patients with HCC, as it decreases potential morbidity associated with open surgery. PMID- 29390574 TI - A case report of parenchymal hematoma after intravenous thrombolysis in a rivaroxaban-treated patient: Is it a true rivaroxaban hemorrhagic complication? AB - RATIONALE: To date, the only treatment approved for acute ischemic strokes is thrombolysis. Whether intravenous thrombolysis may be safe in patients taking direct oral anticoagulants (DOACs) is currently a matter of debate. PATIENT CONCERNS: A 74-year-old woman, who was on rivaroxaban 20 mg/d for nonvalvular atrial fibrillation, was admitted to our stroke unit with left-sided hemiparesis and aphasia. The onset of neurologic deficits had occurred 5 hours after the last rivaroxaban dose. DIAGNOSIS: An acute ischemic stroke was diagnosed. INTERVENTIONS: The patient was administered thrombolytic treatment with intravenous recombinant tissue plasminogen activator (r-TPA) 3 hours and 20 minutes after symptoms onset. Seven hours post-r-TPA treatment, the neurological deficit had worsened, and a type I intraparenchymal hematoma was detected on a computed tomography brain scan. OUTCOMES: The clinical/neuroradiological picture improved significantly in the following days. The patient was discharged to a rehabilitation facility after 3 weeks. LESSONS: In this case, factor ten activated (Xa) inhibitor, rivaroxaban might have increased the risk of hemorrhagic transformation of the ischemic stroke. However, this risk was overweighed by the benefit of thrombolysis, as the patient's clinical condition had improved significantly in the following weeks. The current guidelines discourage the use of thrombolytic treatment in patients with DOACs administered within the last 24(48) hours. However, the case reported herein and other world experiences, even though limited, suggest that an ongoing DOAC medication could no longer be considered a barrier to r-TPA treatment which may be a reasonable and valuable option, at least in selected acute stroke patients taking factor Xa inhibitors. PMID- 29390575 TI - Evaluation of a commercial quantitative Aspergillus fumigatus-specific IgM assay for the diagnosis of invasive pulmonary aspergillosis. AB - Invasive pulmonary aspergillosis (IPA) is a common fungal infection with high mortality rates in immunocompromised patients. Early diagnosis of IPA is still challenging because of its nonspecific clinical symptoms and radiological presentations.To evaluate the clinical value of a commercial Aspergillus fumigates-specific IgM antibody assay in diagnosis of IPA, a multicenter prospective study was performed in 12 hospitals in Zhejiang Province, China, from January 1 to December 31, 2016.A total of 59 patients were enrolled in this study, including 30 IPA and 29 non-IPA patients. The sensitivities of IgM assay were 30.0%, 26.7%, 23.3%, and 20.0%, and the specificities were 79.3%, 86.2%, 86.2%, and 96.6% at the cutoff values of 50, 60, 70 and 80 AU/mL, respectively. The area under the curve of the IgM assay revealed by the receiver-operating characteristic analysis was 0.511 in the IPA cases. This study is the first to evaluate the clinical performance of a commercial A. fumigatus-specific IgM antibody assay that uses envelopes galactomannan extracted from A. fumigatus as the sole antigen in diagnosis of IPA.In conclusion, the A. fumigatus-specific IgM antibody assay has limited value and should not be a prior recommendation for IPA diagnosis. PMID- 29390576 TI - Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma: Is it a significant prognostic factor? AB - The purpose of this study was to evaluate the prognostic impact of endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma.This retrospective study was based on medical records from a single tertiary medical center. The records of 317 patients with esophageal squamous cell carcinoma treated with surgery or definitive chemoradiotherapy (CRT) between January 2009 and March 2016 were reviewed. Finally, we retrieved the data on 168 consecutive patients. These 168 patients were divided into 2 groups based on their endoscopic traversability findings: Group A (the endoscope traversable group), and Group B (the endoscope non-traversable group). We then retrospectively compared the clinical characteristics of these 2 groups.The endoscope non-traversable group (Group B) revealed an advanced clinical stage, a poor Eastern Cooperative Oncology Group (ECOG) score, a lower serum albumin level, a higher rate of requirement for esophageal stent insertion and definitive CRT as initial treatment than the endoscope traversable group (Group A). Patients with endoscope traversable cancer showed a significantly higher 3-year overall survival and 3-year relapse-free survival than patients who were endoscope non traversable (53.8% vs 17.3%, P < .001 and 71.1% vs 45.3%, P = .003, respectively). Upon multivariate analysis of patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT, the serum albumin level <3.5 g/dL and endoscopic non-traversability were significant negative factors of survival.Endoscopic traversability in patients with locally advanced esophageal squamous cell carcinoma treated with definitive CRT is a significant prognostic factor. PMID- 29390577 TI - 24-month HIV-free survival among infants born to HIV-positive women enrolled in Option B+ program in Kigali, Rwanda: The Kabeho Study. AB - Lifelong antiretroviral therapy (ART) provision to all pregnant HIV-positive women ("Option B+") has been recommended by the World Health Organization since 2013, but there remain limited data on the effects of Option B+ on long-term HIV free survival in breastfeeding HIV-exposed infants. The Kigali Antiretroviral and Breastfeeding Assessment for the Elimination of HIV (Kabeho) study enrolled HIV positive women from the third trimester of pregnancy to 2 weeks postpartum in 14 heath facilities implementing Option B+ in Kigali, Rwanda. Mother-child pairs in the longitudinal observational cohort were followed until 24 months postpartum, with HIV diagnostic testing at 6 weeks, and 9, 18 and 24 months. The Kaplan-Meier method was used to estimate HIV transmission, survival, and HIV-free survival through 24 months. We enrolled 608 HIV-positive women in 2013-2014; birth outcome data were available for 600 women and 597 live-born infants. By 6 weeks, 11 infants had died and 3 infants had confirmed HIV infection (0.5% transmission; 95% confidence interval [CI] 0.2-1.6). At 9 months, there were 9 additional deaths and 2 new infections (cumulative transmission 0.9%, 95% CI 0.4-2.2). At 18 months, there were 6 additional deaths and no new infant infections. At 24 months, there were no additional child deaths and 1 new infection (cumulative 2.2%, 95% CI 0.7-7.0), for an overall 24-month HIV-free survival of 93.2% (95% CI 89.5-95.6). Low transmission rates and high HIV-free survival at 24 months were achieved in breastfeeding infants of HIV-positive mothers receiving universal ART in urban health facilities in Rwanda, though vigilance on maintaining viral suppression for ART-experienced women is needed. PMID- 29390578 TI - Analysis of quality of life and influencing factors in 197 Chinese patients with port-wine stains. AB - Port-wine stains (PWS) are congenital capillary malformations, usually occurring on the face, neck, and other exposed parts of the skin, that have serious psychological and social impact on the patient. Most researchers focus on the treatment of PWS, but the quality of life (QoL) of PWS patients is seldom researched. The objective of this study is to evaluate the QoL of patients with PWS on exposed parts and explore the factors influencing the QoL of PWS patients. The QoL of 197 cases with PWS on exposed parts were prospectively studied using the Dermatology Life Quality Index questionnaire (DLQI), and the factors influencing the patients' QoL were analyzed by single-factor analysis and multiple-factor logistic regression analysis. The reliability and validity of the QoL of PWS patients were then assessed by DLQI. A total of 197 valid questionnaires were collected. The DLQI scores in PWS cases ranged from 2 to 16, with 2 to 5 in 52.29% (103/197), 6 to 10 in 42.13% (83/197), and 11 to 20 in 5.58% (11/197). The main score elements of the DLQI focused on symptoms and feelings, daily activities, and social entertainment. Single-factor analysis and multiple-factor logistic regression analysis showed that the main influencing factors were female sex, skin hypertrophy, and lesion area >30 cm. The inter-item correlation averaged 47.46% and the Cronbach alpha was 0.740, indicating high internal consistency. Correlation of the 6 dimensions of the DLQI questionnaires with the total scores showed that the Spearman correlation coefficient r ranged from 0.550 to 0.782 (P < .001), with symptoms and feelings having a correlation coefficient of 0.782 and a high correlation with total scores. This study shows that PWS has mild to moderate influence on the QoL of most patients, mainly on daily activities, social entertainment, and feelings. PMID- 29390579 TI - Single posterior surgical management for lumbosacral tuberculosis: titanium mesh versus iliac bone graft: A retrospective case-control study. AB - Recently, the one-stage posterior approach for treating spinal tuberculosis (TB) has gained popularity. However, large bony defects after debridement remain a major challenge in posterior surgery. The present retrospective study aims to compare the clinical outcomes of posterior-only surgical management by titanium mesh versus iliac bone grafts for treating lumbosacral TB. This was a retrospective cohort study. From January 2006 to April 2012, 36 patients with lumbosacral TB were treated at our department. The 36 cases were divided into 2 groups: 17 patients in Group A (titanium mesh) underwent one-stage posterior internal fixation, debridement, and titanium mesh bone fusion. The 19 patients in Group B (iliac bone graft) underwent posterior instrumentation, debridement, and iliac bone graft in a single procedure. The clinical and radiographic results for the 2 groups were analyzed and compared. The mean year of patients was 49.9 +/- 15.4 months in group A and 55.5 +/- 12.6 months in group B. All patients were followed up for an average of 47.3 +/- 8.1 months (range 36-60 months). Spinal TB was completely cured and no intraspinal infection and central nervous system complications of TB infection occurred. Bone fusion was achieved 6.4 +/- 1.9 months in group A and 7.8 +/- 2.1 months in group B. There was no significant statistical difference in bone fusion between the 2 groups (P > .05). The Oswestry Disability Index score (ODI) significantly improved between the preoperative and the last visit in either group. However, no significant difference was observed between the 2 groups at last visit (P > .05). There were significant differences between groups regarding the postoperative lumbosacral angle and angle correction loss at the final follow-up (P < .05). The average operative complication rate of Group A was less than that of Group B. Both iliac bone and titanium mesh can effectively construct anterior column defects in posterior surgery. The titanium mesh has the advantage of minor surgical invasion, effective reconstruction of large defects, and ideal sagittal alignment in lumbosacral TB for patients with osteoporosis and poor iliac bone quality. PMID- 29390580 TI - Successful management of a complicated clinical crisis: A patient with left-sided endocarditis and secondary hemophagocytic lymphohistiocytosis: a rare case report and literature review. AB - RATIONALE: Hemophagocytic lymphohistiocytosis (HLH) secondary to methicillin resistant Staphylococcus epidermidis (MRSE)-related left-sided infectious endocarditis had never been reported before. In the last decade, daptomycin, a novel lipopeptide antibiotic, showed its excellent role in anti-Gram-positive bacteria, including soft tissue infection, bloodstream and deep tissueinfection. PATIENT CONCERNS: An Asian women under sever condition due to the cooccurrence of HLH and MRSE-related endocarditis while also be allergic to vancomycin. The patient was cured by high-dose daptomycin monotheraphy, HLH-2004 protocol and cardiothoracic surgery to remove the valve at last, and was obviously benefit from the endeavor of a multidisciplinary team (MDT) strategy. DIAGNOSES: IE was made on March 27according to the modified Duke criteria. HLH was diagnosed too. INTERVENTIONS: The patient was cured by high-dose daptomycin monotheraphy, HLH 2004 protocol and cardiothoracic surgery to remove the valve at last, and was obviously benefit from the endeavor of a multidisciplinary team (MDT) strategy. OUTCOMES: The patient was healthy andstable when we published this case. LESSONS: This case proves high-dose daptomycin monotheraphy could be used as an effective alternative regimen for vancomycin in treating MRSE-related left-sided endocarditis and highlight the importance of early diagnosis and appropriate management for HLH. Furthermore, our work suggests an MDT model as a practical strategy in managing similar clinical situation. PMID- 29390581 TI - Novel treatment of blastic plasmacytoid dendritic cell neoplasm: A case report. AB - RATIONALE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN), derived from precursors of plasmacytoid dendritic cells, is a rare and aggressive malignancy with frequent cutaneous involvement. Although cutaneous lesions are often chemosensitive, BPDCN portends a poor prognosis as most patients relapse after developing drug resistance. PATIENT CONCERNS: We report a case of a 65-year-old man who presented with a rapidly enlarging hyperpigmented plaque on his shoulder with subsequent similarly appearing macules and plaques on his chest, back, and neck. DIAGNOSIS: Skin biopsy revealed a dense adnexocentric dermal infiltrate of immature blastoid cells without epidermal involvement. The infiltrate was immunoreactive for CD4, CD56, CD123, and Bcl-2, but negative for CD3, CD8, CD30, MPO, EBER, and ISH. The patient was diagnosed with BPDCN based on these cell markers. INTERVENTION: Bone marrow biopsy and radiologic work-up showed no evidence of extracutaneous involvement. The patient attained partial remission after undergoing 2 rounds of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP regimen) before autologous stem cell transplantation, however, he quickly relapsed and developed new cutaneous lesions. OUTCOMES: The patient was treated with venetoclax, a Bcl-2 inhibitor, and exhibits complete resolution of prior skin findings and continues to remain free of new cutaneous lesions 10 months posttreatment initiation with venetoclax. LESSONS: Herein, we present a case that supports the use of venetoclax, a Bcl-2 inhibitor, in the off-label treatment of BPDCN with Bcl-2 overexpression. Only 1 prior case has reported the off-label use of venetoclax for the treatment of BPDCN. This case highlights a novel therapeutic option for BPDCN patients unresponsive to traditional treatment. PMID- 29390582 TI - A Klebsiella pneumoniae liver abscess presenting with myasthenia and tea-colored urine: A case report and review of 77 cases of bacterial rhabdomyolysis. AB - RATIONALE: Rhabdomyolysis is a well-known syndrome in clinical practice, although rhabdomyolysis caused by a liver abscess is rarely reported and the patient may lack symptoms that are associated with a primary site of infection. Early recognition of this possibility is needed to avoid diagnostic delay and facilitate treatment. We report the case of a 71-year-old woman with a Klebsiella pneumoniae (KP) pyogenic liver abscess who presented with myasthenia and tea colored urine and also review the 77 reported cases of bacterial rhabdomyolysis. PATIENT CONCERNS: The patient was 71 years old and presenting with a 7-day history of myasthenia and a 3-day history of tea-colored urine, but without fever or abdominal pain. DIAGNOSES: Laboratory testing in our case revealed rhabdomyolysis, and blood culture revealed KP. Abdominal ultrasonography revealed a hypoechoic enclosed mass, and computed tomography (CT) revealed an enclosed low density mass (8.3 * 6.6 * 6.1 cm). The main diagnoses were a pyogenic liver abscess with rhabdomyolysis. INTERVENTIONS: Empirically intravenous piperacillin sulbactam and intravenous potassium treatment, as well as fluid infusions and other supportive treatments were provided after admission. After the diagnosis was confirmed and susceptibility test results were available, we adjusted the antibiotics to cefoperazone and sulbactam, which were maintained for 6 weeks. OUTCOMES: The patient's symptoms relieved and the abnormal laboratory parameters corrected. Follow-up abdominal ultrasonography at 24 months after her discharge revealed that the abscess had disappeared. LESSONS: Early recognition and careful consideration of the underlying cause of rhabdomyolysis are critical to improving the patient's prognosis. Thus, physicians should carefully consider the underlying cause in elderly patients who present with rhabdomyolysis, as they may lack symptoms of a primary infection. PMID- 29390583 TI - A rare diagnosis of abdominal pain presentation in the emergency department: Idiopathic omental bleeding: A case report. AB - RATIONALE: Idiopathic omental bleeding is a rare cause of acute abdomen, with only a few reported cases. It usually presents with abdominal pain and may be life-threatening. As it rarely occurs, it may not be considered initially during patient presentation. PATIENT CONCERNS: A 35-year-old male came to our emergency department with abdominal pain present for around 5 to 6 hours. The patient complained of left upper quadrant abdominal pain after eating breakfast. The only associated symptom was 3 episodes of vomiting up food. Physical examination revealed mild left upper quadrant abdominal tenderness without muscle guarding or rebounding pain. Blood examination showed leukocytosis with neutrophil predominance and C reactive protein elevation. The pain was persistent and relief was not obtained by medication. DIAGNOSES: Computed tomography showed a large lobular-contour homogenous slightly hyperdense lesion without enhancement along the greater curvature of the stomach in the lesser sac. A surgeon was consulted and laparotomy was suggested. Hematoma was found at Morrison pouch, subsplenic fossa, and lesser sac under operation. INTERVENTION: Laparotomy and ligation for hemostasis. OUTCOMES: The patient was discharged with stable condition after 7 days of hospitalization. LESSONS: This diagnosis should be considered in patients presenting with epigastric pain and vomiting after eating while in the emergency department because this disease might be life-threatening. This case highlights 2 important learning points. First, idiopathic omental bleeding could occur after eating in patients without underlying disease or trauma history, and this disease should be taken into consideration when acute abdomen occurs. Second, emergent laparotomy is indicated if the cause of acute abdomen is not clear. PMID- 29390584 TI - An intracardiac accessory thyroid gland mimicking cardiac tumor: A case report and literature review. AB - RATIONALE: An accessory thyroid gland (ATG) in the right ventricle is an extremely rare condition. Described herein are histological findings of ATG in the right ventricle found in a patient with a normal cervical thyroid gland. PATIENT CONCERNS: A 53-year-old woman was referred to our hospital after experiencing intermittent precordial pain for 2 years. DIAGNOSES: The mass in the right ventricle was diagnosed pathologically as ATG. INTERVENTIONS: Complete excision was performed because of the patient's intermittent precordial pain and to exclude the possibility of malignancy. OUTCOME: The patient's pain was resolved. No recurrence was observed during the 6-month follow-up. LESSONS: After review and analysis of the case, we found that plain and contrast-enhanced computed tomography scans showed that the mass had a similar intensity and enhancement to a cervical thyroid gland, which we think may be a useful clue for making a preoperative diagnosis of ATG. PMID- 29390585 TI - Combined treatment of botulinumtoxin and robot-assisted rehabilitation therapy on poststroke, upper limb spasticity: A case report. AB - RATIONALE: Spasticity is a major complication after stroke, and botulinumtoxin A (BoNT-A) injection is commonly used to manage focal spasticity. However, it is uncertain whether BoNT-A can improve voluntary motor control or activities of daily living function of paretic upper limbs. This study investigated whether BoNT-A injection combined with robot-assisted upper limb therapy improves voluntary motor control or functions of upper limbs after stroke. PATIENT CONCERNS: Two subacute stroke patients were transferred to the Department of Rehabilitation. DIAGNOSES: Patients demonstrated spasticity in the upper extremity on the affected side. INTERVENTIONS: BoNT-A was injected into the paretic muscles of the shoulder, arm, and forearm of the 2 patients at the subacute stage. Conventional rehabilitation therapy and robot-assisted upper limb training were performed during the rehabilitation period. OUTCOMES: Manual dexterity, grip strength, muscle tone, and activities of daily living function were improved after multidisciplinary rehabilitation treatment. LESSONS: BoNT-A injection in combination with multidisciplinary rehabilitation treatment, including robot-assisted arm training, should be recommended for subacute spastic stroke patients to enhance appropriate motor recovery. PMID- 29390586 TI - A case report of phosphaturic mesenchymal tumor-induced osteomalacia. AB - RATIONALE: Tumor-induced osteomalacia (TIO) is a rare and often misdiagnosed syndrome. Surgical resection is currently the first line treatment for TIO. PATIENT CONCERNS: Here we report the case of a 49-year-old woman presented with intermittent pain in the right chest and bilateral hip that had persisted for over two years. DIAGNOSES: She was diagnosed of TIO caused by a phosphaturic mesenchymal tumor based on the following examinations. Laboratory tests revealed high serum alkaline phosphatase, high urinary phosphorus, hypophosphatemia and normal serum calcium levels. 18-FDG PET/CT indicated a systemic multi-site symmetrical pseudo fracture and a tumor in the 7th right rib. INTERVENTIONS: Curettage of the tumor was performed, and pathological analysis also confirmed our diagnoses as a phosphaturic mesenchymal tumor. OUTCOMES: At seven months post surgery, the symptoms were relieved, proximal muscle strength was improved and serum levels of phosphorus and alkaline phosphatase normalized. The bilateral femoral neck and bilateral pubic bone fractures were blurred in the pelvic plain X-ray, suggesting that the fracture was healing. LESSONS: This case report strengthened the importance of recognition of this rare disease to avoid delay of diagnosis and surgical removal of the causative tumor is recommended. PMID- 29390587 TI - Prospective association of a genetic risk score with major adverse cardiovascular events in patients with coronary artery disease. AB - Many susceptibility loci associated with coronary artery disease (CAD) have been identified using genome-wide association studies (GWAS). This study aimed to examine whether a composite of single nucleotide polymorphisms (SNPs) derived from GWAS could identify the risk of major adverse cardiovascular events (MACEs) in patients with established CAD. There were 1059 patients with CAD were included in the analysis. Of the participants, 686 were on statin treatment at the start of follow-up. A weighted genetic risk score (wGRS) was calculated as the sum of risk alleles multiplied by the hazard ratio for a particular SNP. In single variant analyses, rs579459, rs4420638, and rs2107595 were associated with an increased risk of MACE. A wGRS was further constructed to evaluate the cumulative effect of the 3 SNPs on the prognosis of CAD. The risk of MACE among patients with high and intermediate wGRS was 1.968- and 1.838-fold, respectively, higher than those with low wGRS. This effect was more evident in patients using lipid lowering medication and with hypertension. Furthermore, the interaction analysis revealed that lipid-lowering medication and hypertension interacted with the genetic effect off wGRS on the risk of MACE in patients using lipid-lowering medication or with hypertension (Pinteraction < .001). We further analyzed the follow-up change in low-density lipoprotein cholesterol (LDL-C) level at 6 months after CAD disclosure and evaluated whether that was due to wGRS or statin use. The lowest reduction in LDL-C was observed in patients with high GRS who received statin treatment. Furthermore, LDL-C reduction of patients with intermediate wGRS was less than those with low wGRS in patients treated with statin. Taken together, a wGRS comprised of SNPs significantly predicts MACE in CAD patients receiving statin treatment and hypertension. PMID- 29390588 TI - Identification of SEPP1 polymorphisms is not a genetic risk factor for preeclampsia in Chinese Han women: A clinical trial and experimental study: Erratum. PMID- 29390589 TI - Multiple aneurysms and gastrointestinal involvement in Behcet's disease: A case report: Erratum. PMID- 29390590 TI - Correlation of volumetric flow rate and skin blood flow with cold intolerance in digital replantation. AB - Cold intolerance is a common complication of digital replantation. The exact etiology is unclear, but it is considered to be multifactorial, including nonsurgical characteristics, vascular, and neurologic conditions. Blood flow may play a significant role in cold intolerance. This study was designed to evaluate the correlation of digital blood flow, including volumetric flow rate (VFR) and skin blood flow (SkBF), with cold intolerance in replanted fingers.A retrospective study was conducted among patients who underwent digital replantation between 2010 and 2013. Patients were selected into study cohort based on the inclusion criteria. Surgical data was collected on each patient, including age, sex, injury mechanism, amputation level, ischemia time, number of arteries repaired, and whether or not vascular crisis occurred. Patients were included as study cohort with both nerves repaired and without chronic disease. Cold intolerance was defined as a Cold Intolerance Symptom Severity (CISS) score over 30. The arterial flow velocity and caliber were measured by Color Doppler Ultrasound and the digital VFR was calculated. The SkBF was measured by Laser Speckle Imager. Both VFR and SkBF were calculated as a percentage of the contralateral fingers. Comparative study of surgical data and blood flow was performed between the patient with and without cold intolerance. Correlation between VFR and SkBF was also analyzed.A total of 93 patients met inclusion criteria for the study. Approximately, 42 patients were identified as having cold intolerance. Fingers that survived vascular crisis had a higher incidence of cold intolerance with a lower VFR and SkBF. The VFR was higher in 2-artery replantation, but the SkBF and incidence of cold intolerance did not differ significantly. No differences were found in age, sex, injury mechanism, amputation level, or ischemia time. Furthermore, no correlation was found between VFR and SkBF.Cold intolerance of digital replantation is associated with decreased SkBF and VFR in the replanted fingers, which survived vascular crisis. Further work will be focused on how vascular crisis cause the decreasing of SkBF and VFR and the increasing chance of cold intolerance. PMID- 29390591 TI - Robot-assisted laparoendoscopic single site adrenalectomy: A comparison of 3 different port platforms with 3 case reports. AB - RATIONALE: Laparoscopic adrenalectomy is currently the standard of care for adrenal lesion. Minimal invasive laparoscopic surgery such as laparoendoscopic single site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES) have been developed to improve cosmetic outcomes and reduce postoperative pain. However, there are still some problems related to instruments and port limitation during LESS surgery. Robot-assisted laparoscopic surgery may help to overcome these problems, and port platforms selection is an important issue. PATIENT CONCERNS: Three cases received robot-assisted LESS adrenalectomy due to adrenal tumor were enrolled. Blood loss, hospital stay, and analgesia injection were compared. DIAGNOSES: Preoperative evaluations were done in a usual manner. Benign tumors were suspect for two patients, while metastatic tumor could not be excluded for the other patient with prior malignancy history. The pathology reports were all benign adrenal cortical adenoma after operation. INTERVENTIONS: Three different port platforms, Da Vinci Single-Site Surgical Platform, GelPOINT, and homemade glove port were used. Trans-peritoneal approach was used for two patients, while the other one received trans-retroperitoneal approach. The advantage and disadvantage of different port platforms were discussed. OUTCOMES: All patients underwent the operation smoothly without major complications or conversion to open surgery. Blood loss amount was small, hospital stay was short, and only one patient received one single dose of opioid analgesia injection after the surgery. LESSONS: The main problems of LESS are the loss of a working triangle and the limitations of the instruments. Robot-assisted LESS may help surgeons overcome part of these problems. Many different port platforms are available, and based on our initial experience, we believe that the GelPoint may be a more suitable platform, for it maintains the endo-wrist function of the Da Vinci instruments, and allows the surgeon to design the position of ports freely to minimize external and internal collision. PMID- 29390592 TI - Unusual brain images of a boy with adolescent cerebral X-linked adrenoleukodystrophy presenting with exhibitionism: A CARE-compliant case report. AB - RATIONALE: The respective involvements of both the thalamus and exhibitionism in cerebral X-linked adrenoleukodystrophy (X-ALD) have not been reported. PATIENT CONCERNS: An 11-year-old boy initially presented with exhibitionism and progressive neurobehavioral symptoms. He subsequently developed transient urinary and fecal incontinence, and an unwillingness to eat or communicate. DIAGNOSES: We conducted contrast-enhanced brain magnetic resonance imaging (MRI), which revealed symmetrical altered signal intensities in bilateral frontal white matter, the basal ganglia, and dorsal thalami, as well as a peripheral rim of contrast enhancement. Diagnosis of adolescent cerebral X-ALD was confirmed on the basis of next generation genetic sequencing analysis. INTERVENTIONS: We initiated the patient on hormonal replacement therapy. OUTCOMES: We observed rapidly progressive neurologic deterioration in this patient, and the boy fell into a vegetative state 10 months after discharge. LESSONS: We recommend that physicians should not disregard X-ALD in patients with isolated psychiatric symptoms, including hypersexual behavior. The combination of detailed clinical evaluation, MRI, and next generation genetic sequencing can expedite the diagnostic process of atypical variant of X-ALD. PMID- 29390593 TI - Esophageal diverticulum serves as a unique cause of bronchoesophageal fistula in children: A case report. AB - RATIONALE: Most of the esophageal diverticulums are congenital traction instead of in childhood. In most conditions, esophageal diverticulums are free of any symptoms. As one of the rare entity, esophageal diverticulum can also result in bronchoesophageal fistula. PATIENT CONCERNS: A 10-year-old girl was admitted due to a 2-month history of cough and choking after drinking, and fever for 3 days. No symptoms when taking solid food were found. DIAGNOSES: By esophagogram, 3 dimensional computed tomography and esophagoscopy, an esophageal diverticulum was demonstrated in the middle esophagus with a bronchoesophageal fistula visualized. Then the diagnoses of esophageal diverticulum and bronchoesophageal fistula were established. INTERVENTIONS: A regular trans-anterolateral thoracotomy was carried out under general anesthesia with patient lying on the right side. The diverticulum was then removed and the fistulous tract was closed. OUTCOMES: The girl discharged on the 14th postoperative day and received a regular monthly follow-up, at present, no recurrence was found. LESSONS: Bronchoesophageal fistula may be a complication of esophageal diverticula, and should be considered in cases of unexplained cough or recurrent pneumonia. PMID- 29390595 TI - The humanities and its relevance to the practice of medicine PMID- 29390594 TI - Hybrid repair of pectus excavatum and congenital heart disease: A case report. AB - RATIONALE: Pectus excavatum (PE) in the setting of congenital heart disease is not uncommon. The surgical strategy has evolved over the last 20 years from a staged approach to simultaneous repair of both defects. PATIENT CONCERNS: A 3 year-old boy was admitted for elective repair of PE and atrial septal defect (ASD). DIAGNOSES: Clinically, there were obvious features of PE and a grade 2 systolic murmur heard loudest at the 2nd intercostal space abutting the left sternal border. Echocardiography confirmed the presence of a secundum-type ASD. Following discussions with the family, consent was obtained and the patient underwent concomitant surgery for both defects. The ASD was first device-closed under the guidance of transesophageal echocardiography (TEE) and then a standard Nuss procedure was performed with an 8-inch bar. OUTCOMES: Postoperative echocardiography confirmed a satisfactory device closure of the ASD. The repair of PE was considered satisfactory on physical examination and with chest radiography. The postoperative course was uneventful except for atelectasis of the right upper lobe. The patient was discharged 10 days postoperatively. LESSONS: This case suggests that in carefully selected cases with concomitant PE and ASD, a combination of Nuss procedure and TEE-guided transcatheter device closure can be safely performed with less physical and no radiation trauma and theoretically better aesthetic effects and surgical outcome. PMID- 29390596 TI - Novel urinary biomarkers and their association with urinary heavy metals in chronic kidney disease of unknown aetiology in Sri Lanka: a pilot study AB - Introduction: Chronic kidney disease of unknown etiology(CKDu) has emerged as a significant public healthproblem in Sri Lanka. The role of environmental exposureto cadmium and arsenic in the aetiology of CKDu is stillunclear. Identification of a panel of novel urinary biomarkerswould be invaluable in the study of toxin mediated damagepostulated to be the aetiology of CKDu. Objectives: The aims of this study were to evaluate theprofile of novel urinary biomarkers in CKDu patients andidentify any association with environmental exposure toheavy metals. Methods: Thirty seven randomly selected CKDu patientsattending a renal clinic in the North Central Province andtwo control groups namely a farmer group (n=39) and anon-farmer group (n=40) from a non-endemic area wereincluded in this comparative cross sectional study. Urinesamples were analyzed for heavy metals and five urinarybiomarkers. Results: CKDu patients had significantly elevated urinarylevels of fibrinogen (198.2 ng/mg creatinine p<0.001),clusterin (3479 ng/mg creatinine p<0.001), cystatin-C(5124.8 ng/mg creatinine p<0.001) and beta2 microglobulin(9913.4 ng/mg creatinine p<0.001) compared to the controlgroups. Fibrinogen and beta2-microglobulin were the best todiscriminate CKDu patients from normal individuals with thereceiver operator areas under the curve being 0.867 and0.853, respectively. Urinary fibrinogen and KIM-1 levelscorrelated positively with urinary arsenic levels. KIM-1 levelscorrelated positively with urinary mercury and lead levelsbut no correlation was seen with urinary cadmium levels. Conclusions: Fibrinogen and beta2-microglobulin have thepotential of being a screening tool for detection of CKDu andmay aid the early diagnosis of toxin mediated tubular injuryin CKDu. Their usefulness need to be further validated in alarger epidemiological study of patients with early stagesof CKDu. PMID- 29390597 TI - High prevalence of dental fluorosis among schoolchildren in three villages in Vavuniya District: an observational study AB - Background: Studies of groundwater sources in Sri Lankashow that in the entire Northern, North Central, Uva andEastern Provinces, and also in a large area of the NorthWestern Province, groundwater fluoride content is withinthe range 1.0 mg/l and 3.0 mg/l. The WHO recommendedsafe upper limit of fluoride for drinking water is 1.5 mg/l. Objective: Our objective was to determine the prevalenceand degree of dental fluorosis in a cohort of schoolchildrenin Sinnasippikulam in Vavuniya District, the fluoride contentin their serum and urine, and fluoride levels in drinkingwater in dug wells of the area. Methods: Invitations in Tamil and Sinhala were sent to allhouseholds by courier. Demographic information and oralhygiene practices of 307 responsive children were recordedby interviewing children and their mothers. Detailed clinicalexaminations were performed according to WHO basicmethods, with some modifications. Assessment of dentalfluorosis in the children was done according to Dean'sIndex codes and criteria. Results: We found drinking water sources (dug wells) inSinnasippikulam (n= 82) to have a high mean concentrationof fluoride ( x 1.58+ 0.69 mg/l). Of 307 children examined,224 (72.9%) had clinical evidence of dental fluorosis ofvarying degrees of severity. The mean fluoride level inserum of schoolchildren was 0.198 mg/l (SD + 0.074;S.E.M. 0.013), and in their urine, 1.44 mg/l (SD + 0.59;SEM 0.11). Conclusions: Our results show that harmful levels of fluorideare extremely common in groundwater sources in the studyarea, and consequently, dental fluorosis is highly endemic(72.9%) among resident schoolchildren. PMID- 29390598 TI - Help-seeking behaviour and its impact on patients attending a psychiatry clinic at National Hospital of Sri Lanka AB - Background: Mental illness contributes significantly to the global disease burden. There is great diversity in the manner in which mentally ill patients seek help as this is influenced by their beliefs and the opinion of the family social support unit. The stigma associated with mental illness is a barrier to effective therapy in Sri Lanka where systematic public awareness programmes are minimal. Objective: To study the help-seeking behaviour and its impact on patients attending a psychiatry clinic of the National Hospital of Sri Lanka. Methods: A cross sectional study was carried out among 120 attendees of the psychiatry clinic of the National Hospital of Sri Lanka. Sample was selected using systematic sampling. Data was collected using an interviewer administered questionnaire. Results: More than half the participants sought psychiatric care as their first help-seeking behaviour and found it significantly more useful than non-psychiatric care alternatives. The average time to seek psychiatric care, irrespective of the pathway to care, was less than one month. The recommendation of the family and the social support unit and perceiving that the symptoms were due to a mental illness were the key factors in determining help-seeking behaviour. The average expense on alternative care was zero. There was no significant difference on the impact to employment among those that chose psychiatry care initially from those that did not. Conclusions: Our findings suggest that mentally ill patients presenting to a tertiary care hospital in Colombo, are likely to seek psychiatric care early. This is probably due to better recognition and knowledge regarding available treatment. PMID- 29390599 TI - [Antibiotic diffusion to central nervous system]. AB - Central nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. Transport of fluid and solutes is tightly controlled within CNS, where vasculature exhibits a blood-brain barrier (BBB).The entry of drugs, including antibiotics, into the cerebro-spinal fluid (CSF) is governed by molecular size, lipophilicity, plasma protein binding and their affinity to transport systems at the BBB. The ratio of the AUCCSF (Area under the curve in CSF)/AUCS (Area under the curve in serum) is the most accurate parameter to characterize drug penetration into the CSF. Linezolid, some fluoroquinolones and metronidazole get high CSF concentrations and are useful for treating susceptible pathogens. Some highly active antibiotic compounds with low BBB permeability can be directly administered into the ventricles together with concomitant intravenous therapy. The ideal antibiotic to treat CNS infections should be that with a small moderately lipophilic molecule, low plasma protein binding and low affinity to efflux pumps at BBB. Knowledge of the pharmacokinetics and pharmacodynamics of antibiotics at the BBB will assist to optimize antibiotic treatment in CNS infections. This article reviews the physicochemical properties of the main groups of antibiotics to assess which compounds are most promising for the treatment of CNS infections and how to use them in the daily clinical practice. PMID- 29390600 TI - Prosthetic hip joint infection caused by Campylobacter fetus: A case report and literature review. PMID- 29390601 TI - [Undiagnosed arterial hypertension in HIV-infected patients on antiretroviral therapy]. PMID- 29390602 TI - [Antimicrobial susceptibility in urinary tract infections caused by ESBL- and non ESBL-producing Enterobacteriaceae in hospitalized/outpatient-, sex-, age-matched patients]. PMID- 29390603 TI - [Capnocytophaga canimorsus as a cause of sepsis and meningitis in immunosuppressed patient]. PMID- 29390604 TI - [Antipseudomonic effect of macrolides. Experience in a case of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa without response to antibiotic therapy]. PMID- 29390605 TI - Infective endocarditis in a patient with metastatic colorectal cancer. PMID- 29390606 TI - Morphogenesis of Metal-Organic Mesocrystals Mediated by Double Hydrophilic Block Copolymers. AB - Mesocrystals-superstructures of crystalline nanoparticles that are aligned in a crystallographic fashion-are of increasing interest for formation of inorganic materials with complex and sophisticated morphologies to tailor properties without changing chemical composition. Here we report morphogenesis of a novel mesocrystal consisting of nanoscale metal-organic frameworks (MOF) by using double hydrophilic block copolymer (DHBC) as a crystal modulator. DHBC selectively prefers the metastable hexagonal kinetic polymorph and promotes anisotropic crystal growth to generate hexagonal rod mesocrystals via oriented attachment and mesoscale assembly. The metastable nature of hexagonal mesocrystals enables further hierarchical morphogenesis by a solvent-mediated polymorphic transformation toward stable tetragonal mesocrystals that retain the outer hexagonal particle morphology. Furthermore, synthesis of hybrid MOFs, where hexagonal mesocrystals are vertically aligned on specific surfaces of cubic MOFs, is demonstrated. The present strategy opens a new avenue to create MOF mesocrystals and their hybrids with controlled size and morphology that can be designed for various potential applications. PMID- 29390607 TI - Aziridinium Lead Iodide: A Stable, Low-Band-Gap Hybrid Halide Perovskite for Photovoltaics. AB - The low ionization energy of an A site molecule is a very important factor, which determines the thermodynamical stability of APbI3 hybrid halide perovskites, while the size of the molecule governs the stable phase at room temperature and, eventually, the band gap. It is challenging to achieve both a low ionization energy and the reasonable size for the PbI3 cage to circumvent the stability issue inherent to hybrid halide perovskites. Here we propose a new three-membered charged ring radical, which demonstrates a low ionization energy that renders a good stability for its corresponding perovskite and a reasonable cation size that translates into a suitable band gap for the photovoltaic application. We use ab initio calculations to evaluate a polymorphism of the crystal structure of the proposed hybrid halide perovskite, its stability, and electronic properties in comparison with the mainstream perovskites, such as the methylammonium and formamidinium lead iodide. PMID- 29390608 TI - Exploring Polaronic, Excitonic Structures and Luminescence in Cs4PbBr6/CsPbBr3. AB - Among the important family of halide perovskites, one particular case of all inorganic, 0-D Cs4PbBr6 and 3-D CsPbBr3-based nanostructures and thin films is witnessing intense activity due to ultrafast luminescence with high quantum yield. To understand their emissive behavior, we use hybrid density functional calculations to first compare the ground-state electronic structure of the two prospective compounds. The dispersive band edges of CsPbBr3 do not support self trapped carriers, which agrees with reports of weak exciton binding energy and high photocurrent. The larger gap 0-D material Cs4PbBr6, however, reveals polaronic and excitonic features. We show that those lattice-coupled carriers are likely responsible for observed ultraviolet emission around ~375 nm, reported in bulk Cs4PbBr6 and Cs4PbBr6/CsPbBr3 composites. Ionization potential calculations and estimates of type-I band alignment support the notion of quantum confinement leading to fast, green emission from CsPbBr3 nanostructures embedded in Cs4PbBr6. PMID- 29390609 TI - Direct Detection of S(3P) and S(1D) Generated in the O(1D) + OCS Reaction: Mechanism of the Formation of S2(X3Sigmag- and a1Deltag). AB - Highly vibrationally excited disulfur S2 in the X3Sigmag- and a1Deltag states has been detected in the gaseous mixture of O3 and OCS irradiated with light at 266 nm. Generation of CO2 in the reaction system has been reported; however, no direct detection of sulfur atoms (S(3P) and S(1D)) has been made. In the present study, we have employed the two-photon laser-induced fluorescence (2P-LIF) technique to detect S(3P) and S(1D) directly and recorded the time profiles of the atoms at varying pressures of OCS. Kinetic analyses of the profiles show that (i) S(1D) is generated in the O(1D) + OCS reaction and consumed by the S(1D) + OCS reaction, and (ii) S(3P) is mainly generated in the O(1D) + OCS reaction instead of quenching of S(1D) by collisions with OCS and ambient gases. The vibrational levels v = 19 and 10 of the respective electronic states X3Sigmag- and a1Deltag of S2 were detected in the O3/OCS/266 nm system. The two vibrational levels cannot be generated by the available energy of the S(3P) + OCS reaction, giving evidence that S2 in the X3Sigmag- and a1Deltag states are generated by the S(1D) + OCS reaction. PMID- 29390610 TI - Grotthuss versus Vehicular Transport of Hydroxide in Anion-Exchange Membranes: Insight from Combined Reactive and Nonreactive Molecular Simulations. AB - Combined reactive and nonreactive polarizable molecular dynamics simulations were used to probe the transport mechanisms of hydroxide in hydrated anion-exchange membranes (AEMs) composed of poly(p-phenylene oxide) functionalized with the quaternary ammonium cationic groups. The direct mapping of membrane morphologies between two models allowed us to investigate the contributions of vehicular and Grotthuss mechanisms in hydroxide motion and correlate these mechanisms with the details of local structure. In AEMs with nonblocky polymer structure, where anion transport occurs through narrow (subnanometer size) percolating water channels, simulations indicate the importance of the Grotthuss mechanism. In nonreactive simulations, in order to diffuse through bottlenecks in the water channels, the hydroxide anion has to lose part of its hydration structure, therefore creating a large kinetic barrier for such events. However, when the Grotthuss mechanism is involved, the hydroxide transport through these bottlenecks can easily occur without loss of anion hydration structure and with a much lower barrier. PMID- 29390611 TI - Soft depth-profiling of mixed peptide/lipid samples by means of cluster induced desorption/ionization mass spectrometry-High depth resolution and low matrix effect. AB - Mixed peptide/lipid samples were analyzed with respect to their chemical composition by means of desorption/ionization induced by neutral SO2 clusters (DINeC) in combination with mass spectrometry (MS). Depth profiles of the mixed films indicated a segregation layer of lipid on top of all samples. The thickness of this layer as obtained by DINeC-MS was in the order of one nanometer what can be seen as an upper limit for the depth resolution of DINeC-MS. The relative amounts of the substance of peptide and lipid derived for the bulk material of mixed samples with different compositions were found to be close to the nominal values indicating a low matrix effect. Throughout the depth profiles, only intact molecular ions [M+H]+ as well as dimers of peptides and lipids were detectable, indicating the soft nature of DINeC even when used for depth profiling of biomolecular samples. PMID- 29390612 TI - Mode-locking in advection-reaction-diffusion systems: An invariant manifold perspective. AB - Fronts propagating in two-dimensional advection-reaction-diffusion systems exhibit a rich topological structure. When the underlying fluid flow is periodic in space and time, the reaction front can lock to the driving frequency. We explain this mode-locking phenomenon using the so-called burning invariant manifolds (BIMs). In fact, the mode-locked profile is delineated by a BIM attached to a relative periodic orbit (RPO) of the front element dynamics. Changes in the type (and loss) of mode-locking can be understood in terms of local and global bifurcations of the RPOs and their BIMs. We illustrate these concepts numerically using a chain of alternating vortices in a channel geometry. PMID- 29390613 TI - Likelihood for transcriptions in a genetic regulatory system under asymmetric stable Levy noise. AB - This work is devoted to investigating the evolution of concentration in a genetic regulation system, when the synthesis reaction rate is under additive and multiplicative asymmetric stable Levy fluctuations. By focusing on the impact of skewness (i.e., non-symmetry) in the probability distributions of noise, we find that via examining the mean first exit time (MFET) and the first escape probability (FEP), the asymmetric fluctuations, interacting with nonlinearity in the system, lead to peculiar likelihood for transcription. This includes, in the additive noise case, realizing higher likelihood of transcription for larger positive skewness (i.e., asymmetry) index beta, causing a stochastic bifurcation at the non-Gaussianity index value alpha = 1 (i.e., it is a separating point or line for the likelihood for transcription), and achieving a turning point at the threshold value beta~-0.5 (i.e., beyond which the likelihood for transcription suddenly reversed for alpha values). The stochastic bifurcation and turning point phenomena do not occur in the symmetric noise case (beta = 0). While in the multiplicative noise case, non-Gaussianity index value alpha = 1 is a separating point or line for both the MFET and the FEP. We also investigate the noise enhanced stability phenomenon. Additionally, we are able to specify the regions in the whole parameter space for the asymmetric noise, in which we attain desired likelihood for transcription. We have conducted a series of numerical experiments in "regulating" the likelihood of gene transcription by tuning asymmetric stable Levy noise indexes. This work offers insights for possible ways of achieving gene regulation in experimental research. PMID- 29390614 TI - Prediction of flow dynamics using point processes. AB - Describing a time series parsimoniously is the first step to study the underlying dynamics. For a time-discrete system, a generating partition provides a compact description such that a time series and a symbolic sequence are one-to-one. But, for a time-continuous system, such a compact description does not have a solid basis. Here, we propose to describe a time-continuous time series using a local cross section and the times when the orbit crosses the local cross section. We show that if such a series of crossing times and some past observations are given, we can predict the system's dynamics with fine accuracy. This reconstructability neither depends strongly on the size nor the placement of the local cross section if we have a sufficiently long database. We demonstrate the proposed method using the Lorenz model as well as the actual measurement of wind speed. PMID- 29390615 TI - Lateral movements in Rayleigh-Taylor instabilities due to frontiers. Experimental study. AB - Lateral movements of the fingers in Rayleigh-Taylor hydrodynamic instabilities at the interface between two fluids are studied. We show that transverse movements appear when a physical boundary is present; these phenomena have not been explained until now. The boundary prevents one of the fluids from crossing it. Such frontiers can be buoyancy driven as, for example, the frontier to the passage of a less dense solution through a denser solution or when different aggregation states coexist (liquid and gaseous phases). An experimental study of the lateral movement velocity of the fingers was performed for different Rayleigh numbers (Ra), and when oscillations were detected, their amplitudes were studied. Liquid-liquid (L-L) and gas-liquid (G-L) systems were analysed. Aqueous HCl and Bromocresol Green (sodium salt, NaBCG) solutions were used in L-L experiments, and CO2 (gas) and aqueous NaOH, NaHCO3, and CaCl2 solutions were employed for the G-L studies. We observed that the lateral movement of the fingers and finger collapses near the interface are more notorious when Ra increases. The consequences of this, for each experience, are a decrease in the number of fingers and an increase in the velocity of the lateral finger movement close to the interface as time evolves. We found that the amplitude of the oscillations did not vary significantly within the considered Ra range. These results have an important implication when determining the wave number of instabilities in an evolving system. The wave number could be strongly diminished if there is a boundary. PMID- 29390616 TI - The role of conductivity discontinuities in design of cardiac defibrillation. AB - Fibrillation is an erratic electrical state of the heart, of rapid twitching rather than organized contractions. Ventricular fibrillation is fatal if not treated promptly. The standard treatment, defibrillation, is a strong electrical shock to reinitialize the electrical dynamics and allow a normal heart beat. Both the normal and the fibrillatory electrical dynamics of the heart are organized into moving wave fronts of changing electrical signals, especially in the transmembrane voltage, which is the potential difference between the cardiac cellular interior and the intracellular region of the heart. In a normal heart beat, the wave front motion is from bottom to top and is accompanied by the release of Ca ions to induce contractions and pump the blood. In a fibrillatory state, these wave fronts are organized into rotating scroll waves, with a centerline known as a filament. Treatment requires altering the electrical state of the heart through an externally applied electrical shock, in a manner that precludes the existence of the filaments and scroll waves. Detailed mechanisms for the success of this treatment are partially understood, and involve local shock-induced changes in the transmembrane potential, known as virtual electrode alterations. These transmembrane alterations are located at boundaries of the cardiac tissue, including blood vessels and the heart chamber wall, where discontinuities in electrical conductivity occur. The primary focus of this paper is the defibrillation shock and the subsequent electrical phenomena it induces. Six partially overlapping causal factors for defibrillation success are identified from the literature. We present evidence in favor of five of these and against one of them. A major conclusion is that a dynamically growing wave front starting at the heart surface appears to play a primary role during defibrillation by critically reducing the volume available to sustain the dynamic motion of scroll waves; in contrast, virtual electrodes occurring at the boundaries of small, isolated blood vessels only cause minor effects. As a consequence, we suggest that the size of the heart (specifically, the surface to volume ratio) is an important defibrillation variable. PMID- 29390617 TI - Estimating epidemic arrival times using linear spreading theory. AB - We study the dynamics of a spatially structured model of worldwide epidemics and formulate predictions for arrival times of the disease at any city in the network. The model is composed of a system of ordinary differential equations describing a meta-population susceptible-infected-recovered compartmental model defined on a network where each node represents a city and the edges represent the flight paths connecting cities. Making use of the linear determinacy of the system, we consider spreading speeds and arrival times in the system linearized about the unstable disease free state and compare these to arrival times in the nonlinear system. Two predictions are presented. The first is based upon expansion of the heat kernel for the linearized system. The second assumes that the dominant transmission pathway between any two cities can be approximated by a one dimensional lattice or a homogeneous tree and gives a uniform prediction for arrival times independent of the specific network features. We test these predictions on a real network describing worldwide airline traffic. PMID- 29390618 TI - Dirac light bullets in nonlinear binary waveguide arrays. AB - We investigate the formation and dynamics of spatially broad Dirac light bullets in nonlinear binary waveguide arrays. We show that a Dirac light bullet can be formed during propagation when a pulse with an initial profile slightly different from the one of the Dirac light bullet is launched into the system. We also reveal that these Dirac light bullets are metastable and can propagate without significant distortion for hundreds of dispersion lengths even in the presence of the Raman effect, group velocity mismatch, and group velocity dispersion difference between adjacent waveguides. PMID- 29390619 TI - Solitary states for coupled oscillators with inertia. AB - Networks of identical oscillators with inertia can display remarkable spatiotemporal patterns in which one or a few oscillators split off from the main synchronized cluster and oscillate with different averaged frequency. Such "solitary states" are impossible for the classical Kuramoto model with sinusoidal coupling. However, if inertia is introduced, these states represent a solid part of the system dynamics, where each solitary state is characterized by the number of isolated oscillators and their disposition in space. We present system parameter regions for the existence of solitary states in the case of local, non local, and global network couplings and show that they preserve in both thermodynamic and conservative limits. We give evidence that solitary states arise in a homoclinic bifurcation of a saddle-type synchronized state and die eventually in a crisis bifurcation after essential variation of the parameters. PMID- 29390620 TI - Efficiency of quarantine and self-protection processes in epidemic spreading control on scale-free networks. AB - One of the most effective mechanisms to contain the spread of an infectious disease through a population is the implementation of quarantine policies. However, its efficiency is affected by different aspects, for example, the structure of the underlining social network where highly connected individuals are more likely to become infected; therefore, the speed of the transmission of the decease is directly determined by the degree distribution of the network. Another aspect that influences the effectiveness of the quarantine is the self protection processes of the individuals in the population, that is, they try to avoid contact with potentially infected individuals. In this paper, we investigate the efficiency of quarantine and self-protection processes in preventing the spreading of infectious diseases over complex networks with a power-law degree distribution [ P(k)~k-nu] for different nu values. We propose two alternative scale-free models that result in power-law degree distributions above and below the exponent nu = 3 associated with the conventional Barabasi Albert model. Our results show that the exponent nu determines the effectiveness of these policies in controlling the spreading process. More precisely, we show that for the nu exponent below three, the quarantine mechanism loses effectiveness. However, the efficiency is improved if the quarantine is jointly implemented with a self-protection process driving the number of infected individuals significantly lower. PMID- 29390621 TI - Generating one to four-wing hidden attractors in a novel 4D no-equilibrium chaotic system with extreme multistability. AB - By using a simple state feedback controller in a three-dimensional chaotic system, a novel 4D chaotic system is derived in this paper. The system state equations are composed of nine terms including only one constant term. Depending on the different values of the constant term, this new proposed system has a line of equilibrium points or no equilibrium points. Compared with other similar chaotic systems, the newly presented system owns more abundant and complicated dynamic properties. What interests us is the observation that if the value of the constant term of the system is nonzero, it has no equilibria, and therefore, the Shil'nikov theorem is not suitable to verify the existence of chaos for the lack of heteroclinic or homoclinic trajectory. However, one-wing, two-wing, three wing, and four-wing hidden attractors can be obtained from this new system. In addition, various coexisting hidden attractors are obtained and the complex transient transition behaviors are also observed. More interestingly, the unusual and striking dynamic behavior of the coexistence of infinitely many hidden attractors is revealed by selecting the different initial values of the system, which means that extreme multistability arises. The rich and complex hidden dynamic characteristics of this system are investigated by phase portraits, bifurcation diagrams, Lyapunov exponents, and so on. Finally, the new system is implemented by an electronic circuit. A very good agreement is observed between the experimental results and the numerical simulations of the same system on the Matlab platform. PMID- 29390622 TI - Analysis of chaos in high-dimensional wind power system. AB - A comprehensive analysis on the chaos of a high-dimensional wind power system is performed in this study. A high-dimensional wind power system is more complex than most power systems. An 11-dimensional wind power system proposed by Huang, which has not been analyzed in previous studies, is investigated. When the systems are affected by external disturbances including single parameter and periodic disturbance, or its parameters changed, chaotic dynamics of the wind power system is analyzed and chaotic parameters ranges are obtained. Chaos existence is confirmed by calculation and analysis of all state variables' Lyapunov exponents and the state variable sequence diagram. Theoretical analysis and numerical simulations show that the wind power system chaos will occur when parameter variations and external disturbances change to a certain degree. PMID- 29390623 TI - Characterizing scaling properties of complex signals with missed data segments using the multifractal analysis. AB - The scaling properties of complex processes may be highly influenced by the presence of various artifacts in experimental recordings. Their removal produces changes in the singularity spectra and the Holder exponents as compared with the original artifacts-free data, and these changes are significantly different for positively correlated and anti-correlated signals. While signals with power-law correlations are nearly insensitive to the loss of significant parts of data, the removal of fragments of anti-correlated signals is more crucial for further data analysis. In this work, we study the ability of characterizing scaling features of chaotic and stochastic processes with distinct correlation properties using a wavelet-based multifractal analysis, and discuss differences between the effect of missed data for synchronous and asynchronous oscillatory regimes. We show that even an extreme data loss allows characterizing physiological processes such as the cerebral blood flow dynamics. PMID- 29390624 TI - Prediction and generation of binary Markov processes: Can a finite-state fox catch a Markov mouse? AB - Understanding the generative mechanism of a natural system is a vital component of the scientific method. Here, we investigate one of the fundamental steps toward this goal by presenting the minimal generator of an arbitrary binary Markov process. This is a class of processes whose predictive model is well known. Surprisingly, the generative model requires three distinct topologies for different regions of parameter space. We show that a previously proposed generator for a particular set of binary Markov processes is, in fact, not minimal. Our results shed the first quantitative light on the relative (minimal) costs of prediction and generation. We find, for instance, that the difference between prediction and generation is maximized when the process is approximately independently, identically distributed. PMID- 29390626 TI - On system behaviour using complex networks of a compression algorithm. AB - We construct complex networks of scalar time series using a data compression algorithm. The structure and statistics of the resulting networks can be used to help characterize complex systems, and one property, in particular, appears to be a useful discriminating statistic in surrogate data hypothesis tests. We demonstrate these ideas on systems with known dynamical behaviour and also show that our approach is capable of identifying behavioural transitions within electroencephalogram recordings as well as changes due to a bifurcation parameter of a chaotic system. The technique we propose is dependent on a coarse grained quantization of the original time series and therefore provides potential for a spatial scale-dependent characterization of the data. Finally the method is as computationally efficient as the underlying compression algorithm and provides a compression of the salient features of long time series. PMID- 29390625 TI - Causality analysis of leading singular value decomposition modes identifies rotor as the dominant driving normal mode in fibrillation. AB - Cardiac fibrillation is a major clinical and societal burden. Rotors may drive fibrillation in many cases, but their role and patterns are often masked by complex propagation. We used Singular Value Decomposition (SVD), which ranks patterns of activation hierarchically, together with Wiener-Granger causality analysis (WGCA), which analyses direction of information among observations, to investigate the role of rotors in cardiac fibrillation. We hypothesized that combining SVD analysis with WGCA should reveal whether rotor activity is the dominant driving force of fibrillation even in cases of high complexity. Optical mapping experiments were conducted in neonatal rat cardiomyocyte monolayers (diameter, 35 mm), which were genetically modified to overexpress the delayed rectifier K+ channel IKr only in one half of the monolayer. Such monolayers have been shown previously to sustain fast rotors confined to the IKr overexpressing half and driving fibrillatory-like activity in the other half. SVD analysis of the optical mapping movies revealed a hierarchical pattern in which the primary modes corresponded to rotor activity in the IKr overexpressing region and the secondary modes corresponded to fibrillatory activity elsewhere. We then applied WGCA to evaluate the directionality of influence between modes in the entire monolayer using clear and noisy movies of activity. We demonstrated that the rotor modes influence the secondary fibrillatory modes, but influence was detected also in the opposite direction. To more specifically delineate the role of the rotor in fibrillation, we decomposed separately the respective SVD modes of the rotor and fibrillatory domains. In this case, WGCA yielded more information from the rotor to the fibrillatory domains than in the opposite direction. In conclusion, SVD analysis reveals that rotors can be the dominant modes of an experimental model of fibrillation. Wiener-Granger causality on modes of the rotor domains confirms their preferential driving influence on fibrillatory modes. PMID- 29390627 TI - Maximizing synchronizability of duplex networks. AB - We study the synchronizability of duplex networks formed by two randomly generated network layers with different patterns of interlayer node connections. According to the master stability function, we use the smallest nonzero eigenvalue and the eigenratio between the largest and the second smallest eigenvalues of supra-Laplacian matrices to characterize synchronizability on various duplexes. We find that the interlayer linking weight and linking fraction have a profound impact on synchronizability of duplex networks. The increasingly large inter-layer coupling weight is found to cause either decreasing or constant synchronizability for different classes of network dynamics. In addition, negative node degree correlation across interlayer links outperforms positive degree correlation when most interlayer links are present. The reverse is true when a few interlayer links are present. The numerical results and understanding based on these representative duplex networks are illustrative and instructive for building insights into maximizing synchronizability of more realistic multiplex networks. PMID- 29390628 TI - Dynamic range maximization in excitable networks. AB - We study the strategy to optimally maximize the dynamic range of excitable networks by removing the minimal number of links. A network of excitable elements can distinguish a broad range of stimulus intensities and has its dynamic range maximized at criticality. In this study, we formulate the activation propagation in excitable networks as a message passing process in which a critical state is reached when the largest eigenvalue of the weighted non-backtracking matrix is close to one. By considering the impact of single link removal on the largest eigenvalue, we develop an efficient algorithm that aims to identify the optimal set of links whose removal will drive the system to the critical state. Comparisons with other competing heuristics on both synthetic and real-world networks indicate that the proposed method can maximize the dynamic range by removing the smallest number of links, and at the same time maintaining the largest size of the giant connected component. PMID- 29390629 TI - Interactive social contagions and co-infections on complex networks. AB - What we are learning about the ubiquitous interactions among multiple social contagion processes on complex networks challenges existing theoretical methods. We propose an interactive social behavior spreading model, in which two behaviors sequentially spread on a complex network, one following the other. Adopting the first behavior has either a synergistic or an inhibiting effect on the spread of the second behavior. We find that the inhibiting effect of the first behavior can cause the continuous phase transition of the second behavior spreading to become discontinuous. This discontinuous phase transition of the second behavior can also become a continuous one when the effect of adopting the first behavior becomes synergistic. This synergy allows the second behavior to be more easily adopted and enlarges the co-existence region of both behaviors. We establish an edge-based compartmental method, and our theoretical predictions match well with the simulation results. Our findings provide helpful insights into better understanding the spread of interactive social behavior in human society. PMID- 29390630 TI - Nonlinear resonances in the ABC-flow. AB - In this paper, we study resonances of the ABC-flow in the near integrable case ( C?1). This is an interesting example of a Hamiltonian system with 3/2 degrees of freedom in which simultaneous existence of two resonances of the same order is possible. Analytical conditions of the resonance existence are received. It is shown numerically that the largest n:1 (n = 1, 2, 3) resonances exist, and their energies are equal to theoretical energies in the near integrable case. We provide analytical and numerical evidences for existence of two branches of the two largest n:1 (n = 1, 2) resonances in the region of finite motion. PMID- 29390631 TI - Approximating hidden chaotic attractors via parameter switching. AB - In this paper, the problem of approximating hidden chaotic attractors of a general class of nonlinear systems is investigated. The parameter switching (PS) algorithm is utilized, which switches the control parameter within a given set of values with the initial value problem numerically solved. The PS-generated attractor approximates the attractor obtained by averaging the control parameter with the switched values, which represents the hidden chaotic attractor. The hidden chaotic attractors of a generalized Lorenz system and the Rabinovich Fabrikant system are simulated for illustration. PMID- 29390632 TI - The response analysis of fractional-order stochastic system via generalized cell mapping method. AB - This paper is concerned with the response of a fractional-order stochastic system. The short memory principle is introduced to ensure that the response of the system is a Markov process. The generalized cell mapping method is applied to display the global dynamics of the noise-free system, such as attractors, basins of attraction, basin boundary, saddle, and invariant manifolds. The stochastic generalized cell mapping method is employed to obtain the evolutionary process of probability density functions of the response. The fractional-order phi6 oscillator and the fractional-order smooth and discontinuous oscillator are taken as examples to give the implementations of our strategies. Studies have shown that the evolutionary direction of the probability density function of the fractional-order stochastic system is consistent with the unstable manifold. The effectiveness of the method is confirmed using Monte Carlo results. PMID- 29390633 TI - Lateral movements in Rayleigh-Taylor instabilities due to frontiers. Numerical analysis. AB - Numerical simulations were performed for Rayleigh-Taylor (RT) hydrodynamic instabilities when a frontier is present. The frontier formed by the interface between two fluids prevents the free movement of the fingers created by the instability. As a consequence, transversal movements at the rear of the fingers are observed in this area. These movements produce collapse of the fingers (two or more fingers join in one finger) or oscillations in the case that there is no collapse. The transversal velocity of the fingers, the amplitude of the oscillations, and the wave number of the RT instabilities as a function of the Rayleigh number (Ra) were studied near the frontier. We verified numerically that in classical RT instabilities, without a frontier, these lateral movements do not occur; only with a physical frontier, the transversal displacements of the fingers appear. The transverse displacement velocity and the initial wave number increase with Ra. This leads to the collapse of the fingers, diminishing the wave number of the instabilities at the interface. Instead, no significant changes in the amplitude of the oscillations are observed modifying Ra. The numerical results are independent of the type or origin of the frontier (gas-liquid, liquid liquid, or solid-liquid). The numerical results are in good agreement with the experimental results reported by Binda et al. [Chaos 28, 013107 (2018)]. Based on these results, it was possible to determine the cause of the transverse displacements, which had not been explained until now. PMID- 29390634 TI - Induced waveform transitions of dissipative solitons. AB - The effect of an externally applied force upon the dynamics of dissipative solitons is analyzed in the framework of the one-dimensional cubic-quintic complex Ginzburg-Landau equation supplemented by a potential term with an explicit coordinate dependence. The potential accounts for the external force manipulations and consists of three symmetrically arranged potential wells whose depth varies along the longitudinal coordinate. It is found out that under an influence of such potential a transition between different soliton waveforms coexisting under the same physical conditions can be achieved. A low-dimensional phase-space analysis is applied in order to demonstrate that by only changing the potential profile, transitions between different soliton waveforms can be performed in a controllable way. In particular, it is shown that by means of a selected potential, stationary dissipative soliton can be transformed into another stationary soliton as well as into periodic, quasi-periodic, and chaotic spatiotemporal dissipative structures. PMID- 29390635 TI - Coexisting multiple attractors and riddled basins of a memristive system. AB - In this paper, a new memristor-based chaotic system is designed, analyzed, and implemented. Multistability, multiple attractors, and complex riddled basins are observed from the system, which are investigated along with other dynamical behaviors such as equilibrium points and their stabilities, symmetrical bifurcation diagrams, and sustained chaotic states. With different sets of system parameters, the system can also generate various multi-scroll attractors. Finally, the system is realized by experimental circuits. PMID- 29390636 TI - Several localized waves induced by linear interference between a nonlinear plane wave and bright solitons. AB - We investigate linear interference effects between a nonlinear plane wave and bright solitons, which are admitted by a pair-transition coupled two-component Bose-Einstein condensate. We demonstrate that the interference effects can induce several localized waves possessing distinctive wave structures, mainly including anti-dark solitons, W-shaped solitons, multi-peak solitons, Kuznetsov-Ma like breathers, and multi-peak breathers. Specifically, the explicit conditions for them are clarified by a phase diagram based on the linear interference properties. Furthermore, the interactions between these localized waves are discussed. The detailed analysis indicates that the soliton-soliton interaction induced phase shift brings the collision between these localized waves which can be inelastic for solitons involving collision and can be elastic for breathers. These characters come from the fact that the profile of solitons depends on the relative phase between bright solitons and a plane wave, and the profile of breathers does not depend on the relative phase. These results would motivate more discussions on linear interference between other nonlinear waves. Specifically, the solitons or breathers obtained here are not related to modulational instability. The underlying reasons are discussed in detail. In addition, possibilities to observe these localized waves are discussed in a two species Bose-Einstein condensate. PMID- 29390637 TI - Analytic methods to find beating transitions of asymmetric Gaussian beams in GNLS equations. AB - In a simple model of propagation of asymmetric Gaussian beams in nonlinear waveguides, described by a reduction to ordinary differential equations of generalized nonlinear Schrodinger equations with cubic-quintic (CQ) and saturable (SAT) nonlinearities and a graded-index profile, the beam widths exhibit two different types of beating behavior, with transitions between them. We present an analytic model to explain these phenomena, which originate in a 1:1 resonance in a 2 degree-of-freedom Hamiltonian system. We show how small oscillations near a fixed point close to 1:1 resonance in such a system can be approximated using an integrable Hamiltonian and, ultimately, a single first order differential equation. In particular, the beating transitions can be located from coincidences of roots of a pair of quadratic equations, with coefficients determined (in a highly complex manner) by the internal parameters and initial conditions of the original system. The results of the analytic model agree with the numerics of the original system over large parameter ranges, and allow new predictions that can be verified directly. In the CQ case, we identify a band of beam energies for which there is only a single beating transition (as opposed to 0 or 2) as the eccentricity is increased. In the SAT case, we explain the sudden (dis)appearance of beating transitions for certain values of the other parameters as the grade index is changed. PMID- 29390638 TI - Multistate intermittency on the route to chaos of a semiconductor laser subjected to optical feedback from a long external cavity. AB - We observe experimentally two regimes of intermittency on the route to chaos of a semiconductor laser subjected to optical feedback from a long external cavity as the feedback level is increased. The first regime encountered corresponds to multistate intermittency involving two or three states composed of several combinations of periodic, quasiperiodic, and subharmonic dynamics. The second regime is observed for larger feedback levels and involves intermittency between period-doubled and chaotic regimes. This latter type of intermittency displays statistical properties similar to those of on-off intermittency. PMID- 29390639 TI - Influence of external extrusion on stability of hydrogen molecule and its chaotic behavior. AB - We have determined the stability conditions of the hydrogen molecule under the influence of an external force of harmonic-type explicitly dependent on the amplitude (A) and frequency (Omega). The ground state of the molecule has been determined in the framework of the Born-Oppenheimer approximation, whereas the energy of the electronic subsystem has been calculated using the Hubbard model including all two-site electron interactions. The diagram of RT0 (A,Omega), where RT0 denotes the distance between protons after the fixed initial time T0, allowed us to visualize the area of the instability with the complicated structure. We have shown that the vibrations of the hydrogen molecule have a chaotic nature for some points of the instability region. In addition to the amplitude and frequency of the extrusion, the control parameter of the stability of the molecule is the external force associated with pressure. The increase in its value causes the disappearance of the area of the instability and chaotic vibrations. PMID- 29390640 TI - Dual-induced multifractality in online viewing activity. AB - Although recent studies have found that the long-term correlations relating to the fat-tailed distribution of inter-event times exist in human activity and that these correlations indicate the presence of fractality, the property of fractality and its origin have not been analyzed. We use both detrended fluctuation analysis and multifractal detrended fluctuation analysis to analyze the time series in online viewing activity separating from Movielens and Netflix. We find long-term correlations at both the individual and communal levels and that the extent of correlation at the individual level is determined by the activity level. These long-term correlations also indicate that there is fractality in the pattern of online viewing. We first find a multifractality that results from the combined effect of the fat-tailed distribution of inter-event times (i.e., the times between successive viewing actions of individuals) and the long-term correlations in online viewing activity and verify this finding using three synthesized series. Therefore, it can be concluded that the multifractality in online viewing activity is caused by both the fat-tailed distribution of inter event times and the long-term correlations and that this enlarges the generic property of human activity to include not just physical space but also cyberspace. PMID- 29390641 TI - Synergistic effects in threshold models on networks. AB - Network structure can have a significant impact on the propagation of diseases, memes, and information on social networks. Different types of spreading processes (and other dynamical processes) are affected by network architecture in different ways, and it is important to develop tractable models of spreading processes on networks to explore such issues. In this paper, we incorporate the idea of synergy into a two-state ("active" or "passive") threshold model of social influence on networks. Our model's update rule is deterministic, and the influence of each meme-carrying (i.e., active) neighbor can-depending on a parameter-either be enhanced or inhibited by an amount that depends on the number of active neighbors of a node. Such a synergistic system models social behavior in which the willingness to adopt either accelerates or saturates in a way that depends on the number of neighbors who have adopted that behavior. We illustrate that our model's synergy parameter has a crucial effect on system dynamics, as it determines whether degree-k nodes are possible or impossible to activate. We simulate synergistic meme spreading on both random-graph models and networks constructed from empirical data. Using a heterogeneous mean-field approximation, which we derive under the assumption that a network is locally tree-like, we are able to determine which synergy-parameter values allow degree-k nodes to be activated for many networks and for a broad family of synergistic models. PMID- 29390642 TI - Effects of topologies on signal propagation in feedforward networks. AB - We systematically investigate the effects of topologies on signal propagation in feedforward networks (FFNs) based on the FitzHugh-Nagumo neuron model. FFNs with different topological structures are constructed with same number of both in degrees and out-degrees in each layer and given the same input signal. The propagation of firing patterns and firing rates are found to be affected by the distribution of neuron connections in the FFNs. Synchronous firing patterns emerge in the later layers of FFNs with identical, uniform, and exponential degree distributions, but the number of synchronous spike trains in the output layers of the three topologies obviously differs from one another. The firing rates in the output layers of the three FFNs can be ordered from high to low according to their topological structures as exponential, uniform, and identical distributions, respectively. Interestingly, the sequence of spiking regularity in the output layers of the three FFNs is consistent with the firing rates, but their firing synchronization is in the opposite order. In summary, the node degree is an important factor that can dramatically influence the neuronal network activity. PMID- 29390643 TI - A unified method of detecting core-periphery structure and community structure in networks. AB - The core-periphery structure and the community structure are two typical meso scale structures in complex networks. Although community detection has been extensively investigated from different perspectives, the definition and the detection of the core-periphery structure have not received much attention. Furthermore, the detection problems of the core-periphery and community structure were separately investigated. In this paper, we develop a unified framework to simultaneously detect the core-periphery structure and community structure in complex networks. Moreover, there are several extra advantages of our algorithm: our method can detect not only single but also multiple pairs of core-periphery structures; the overlapping nodes belonging to different communities can be identified; different scales of core-periphery structures can be detected by adjusting the size of the core. The good performance of the method has been validated on synthetic and real complex networks. So, we provide a basic framework to detect the two typical meso-scale structures: the core-periphery structure and the community structure. PMID- 29390644 TI - Dynamics of delay-coupled FitzHugh-Nagumo neural rings. AB - This paper studies the dynamical behaviors of a pair of FitzHugh-Nagumo neural networks with bidirectional delayed couplings. It presents a detailed analysis of delay-independent and delay-dependent stabilities and the existence of bifurcated oscillations. Illustrative examples are performed to validate the analytical results and to discover interesting phenomena. It is shown that the network exhibits a variety of complicated activities, such as multiple stability switches, the coexistence of periodic and quasi-periodic oscillations, the coexistence of periodic and chaotic orbits, and the coexisting chaotic attractors. PMID- 29390645 TI - A novel L-shaped linear ultrasonic motor operating in a single resonance mode. AB - In this study, a large thrust linear ultrasonic motor using an L-shaped stator is described. The stator is constructed by two mutually perpendicular rectangular plate vibrators, one of which is mounted in parallel with the slider to make the motor structure to be more compact. The symmetric and antisymmetric modes of the stator based on the first order bending vibration of two vibrators are adopted, in which each resonance mode is assigned to drive the slider in one direction. The placement of piezoelectric ceramics in a stator could be determined by finite element analysis, and the influence of slots in the head block on the vibration amplitudes of driving foot was studied as well. Three types of prototypes (non slotted, dual-slot, and single-slot) were fabricated and experimentally investigated. Experimental results demonstrated that the prototype with one slot exhibited the best mechanical output performance. The maximum loads under the excitation of symmetric mode and antisymmetric mode were 65 and 90 N, respectively. PMID- 29390646 TI - Graphical method for analyzing wide-angle x-ray diffraction. AB - Wide-angle X-ray diffraction on large-scale laser facility is a well-established experimental method, which is used to study the shock response of single crystal materials by recording X-rays diffracted from numerous lattice planes. We present a three-dimensional graphical method for extracting physical understanding from the raw diffraction data in shocked experiments. This method advances beyond the previous iterative process by turning abstract diffraction theories in shock physics into mathematic issues, providing three-dimensional visualization and quick extraction of data characteristics. The capability and versatility of the method are exhibited by identifying lattice planes for single crystal samples with different orientations and quantitatively measuring the lattice compression and rotation under dynamic loading. PMID- 29390647 TI - Simultaneous measurement of triboelectrification and triboluminescence of crystalline materials. AB - Triboelectrification has been studied for over 2500 years, yet there is still a lack of fundamental understanding as to its origin. Given its utility in areas such as xerography, powder spray painting, and energy harvesting, many devices have been made to investigate triboelectrification at many length-scales, though few seek to additionally make use of triboluminescence: the emission of electromagnetic radiation immediately following a charge separation event. As devices for measuring triboelectrification became smaller and smaller, now measuring down to the atomic scale with atomic force microscope based designs, an appreciation for the collective and multi-scale nature of triboelectrification has perhaps abated. Consider that the energy required to move a unit charge is very large compared to a van der Waals interaction, yet peeling Scotch tape (whose adhesion is derived from van der Waals forces) can provide strong enough energy-focusing to generate X-ray emission. This paper presents a device to press approximately cm-sized materials together in a vacuum, with in situ alignment. Residual surface charge, force, and position and X-ray, visible light, and RF emission are measured for single crystal samples. Charge is therefore tracked throughout the charging and discharging processes, resulting in a more complete picture of triboelectrification, with controllable and measurable environmental influence. Macroscale charging is directly measured, whilst triboluminescence, originating in atomic-scale processes, probes the microscale. The apparatus was built with the goal of obtaining an ab initio-level explanation of triboelectrification for well-defined materials, at the micro- and macro-scale, which has eluded scientists for millennia. PMID- 29390648 TI - A parallel input composite transimpedance amplifier. AB - A new approach to high performance current to voltage preamplifier design is presented. The design using multiple operational amplifiers (op-amps) has a parasitic capacitance compensation network and a composite amplifier topology for fast, precision, and low noise performance. The input stage consisting of a parallel linked JFET op-amps and a high-speed bipolar junction transistor (BJT) gain stage driving the output in the composite amplifier topology, cooperating with the capacitance compensation feedback network, ensures wide bandwidth stability in the presence of input capacitance above 40 nF. The design is ideal for any two-probe measurement, including high impedance transport and scanning tunneling microscopy measurements. PMID- 29390649 TI - Impulse excitation scanning acoustic microscopy for local quantification of Rayleigh surface wave velocity using B-scan analysis. AB - A new technique for performing quantitative scanning acoustic microscopy imaging of Rayleigh surface wave (RSW) velocity was developed based on b-scan processing. In this technique, the focused acoustic beam is moved through many defocus distances over the sample and excited with an impulse excitation, and advanced algorithms based on frequency filtering and the Hilbert transform are used to post-process the b-scans to estimate the Rayleigh surface wave velocity. The new method was used to estimate the RSW velocity on an optically flat E6 glass sample, and the velocity was measured at +/-2 m/s and the scanning time per point was on the order of 1.0 s, which are both improvement from the previous two-point defocus method. The new method was also applied to the analysis of two titanium samples, and the velocity was estimated with very low standard deviation in certain large grains on the sample. A new behavior was observed with the b-scan analysis technique where the amplitude of the surface wave decayed dramatically on certain crystallographic orientations. The new technique was also compared with previous results, and the new technique has been found to be much more reliable and to have higher contrast than previously possible with impulse excitation. PMID- 29390650 TI - Design of a facility for the in situ measurement of catalytic reaction by neutron scattering spectroscopy. AB - Catalysis is a critical enabling science for future energy needs. The next frontier of catalysis is to evolve from catalyst discovery to catalyst design, and for this next step to be realized, we must develop new techniques to better understand reaction mechanisms. To do this, we must connect catalytic reaction rates and selectivities to the kinetics, energetics, and dynamics of individual elementary steps and relate these to the structure and dynamics of the catalytic sites involved. Neutron scattering spectroscopies offer unique capabilities that are difficult or impossible to match by other techniques. The current study presents the development of a compact and portable instrumental design that enables the in situ investigation of catalytic samples by neutron scattering techniques. The developed apparatus was tested at the Spallation Neutron Source (SNS) in Oak Ridge National Laboratory and includes a gas handling panel that allows for computer hookups to control the panel externally and online measurement equipment such as coupled GC-FID/TCD (Gas Chromatography-Flame Ionization Detector/Thermal Conductivity Detector) and MS (Mass Spectrometry) to characterize offgassing while the sample is in the neutron scattering spectrometer. This system is flexible, modular, compact, and portable enabling its use for many types of gas-solid and liquid-solid reactions at the various beamlines housed at the SNS. PMID- 29390651 TI - Development of a high current 60 keV neutral lithium beam injector for beam emission spectroscopy measurements on fusion experiments. AB - A 60 keV neutral lithium beam system was designed and built up for beam emission spectroscopy measurement of edge plasma on the KSTAR and EAST tokamaks. The electron density profile and its fluctuation can be measured using the accelerated lithium beam-based emission spectroscopy system. A thermionic ion source was developed with a SiC heater to emit around 4-5 mA ion current from a 14 mm diameter surface. The ion optic is following the 2 step design used on other devices with small modifications to reach about 2-3 cm beam diameter in the plasma at about 4 m from the ion source. A newly developed recirculating sodium vapour neutralizer neutralizes the accelerated ion beam at around 260-280 degrees C even during long (<20 s) discharges. A set of new beam diagnostic and manipulation techniques are applied to allow optimization, aiming, cleaning, and beam modulation. The maximum 60 keV beam energy with 4 mA ion current was successfully reached at KSTAR and at EAST. Combined with an efficient observation system, the Li-beam diagnostic enables the measurement of the density profile and fluctuations on the plasma turbulence time scale. PMID- 29390652 TI - A low energy ion beam facility for mass spectrometer calibration: First results. AB - The exploration of habitable environments around the gas giants in the Solar System is of major interest in upcoming planetary missions. Exactly this theme is addressed by the Jupiter Icy Moons Explorer (JUICE) mission of the European Space Agency (ESA), which will characterise Ganymede, Europa, and Callisto as planetary objects and potential habitats. The NIM, Neutral gas and Ion Mass spectrometer, is part of the PEP experiment and will be used to measure the chemical composition of the exospheres of the icy Jovian moons. We designed and developed a calibration facility (SATANS, Supersonic cATion and ANion Source), especially for use with the NIM instrument. In a first step, we established a low energy ion beam for positive ions in the range of 0.01-30 eV. Then we conducted beam velocity calibrations with a velocity uncertainty <5%, which provided exact settings and formulas for the cation beam velocity of different gas mixtures in the range of 1-15 km/s. In addition, first results are obtained by using the NIM prototype for direct ion beam measurements under realistic JUICE mission conditions, i.e., for velocities from 1 up to 7 km/s and even more. PMID- 29390653 TI - Development of sub-100 femtosecond timing and synchronization system. AB - The precise timing and synchronization system is an essential part for the ultra fast electron and X-ray sources based on the photocathode injector where strict synchronization among RF, laser, and beams are required. In this paper, we present an integrated sub-100 femtosecond timing and synchronization system developed and demonstrated recently in Tsinghua University based on the collaboration with Lawrence Berkeley National Lab. The timing and synchronization system includes the fiber-based CW carrier phase reference distribution system for delivering stabilized RF phase reference to multiple receiver clients, the Low Level RF (LLRF) control system to monitor and generate the phase and amplitude controllable pulse RF signal, and the laser-RF synchronization system for high precision synchronization between optical and RF signals. Each subsystem is characterized by its blocking structure and is also expansible. A novel asymmetric calibration sideband signal method was proposed for eliminating the non-linear distortion in the optical synchronization process. According to offline and online tests, the system can deliver a stable signal to each client and suppress the drift and jitter of the RF signal for the accelerator and the laser oscillator to less than 100 fs RMS (~0.1 degrees in 2856 MHz frequency). Moreover, a demo system with a LLRF client and a laser-RF synchronization client is deployed and operated successfully at the Tsinghua Thomson scattering X-ray source. The beam-based jitter measurement experiments have been conducted to evaluate the overall performance of the system, and the jitter sources are discussed. PMID- 29390654 TI - In-depth study of in-trap high-resolution mass separation by transversal ion ejection from a multi-reflection time-of-flight device. AB - The recently introduced method of ion separation by transversal ejection of unwanted species in electrostatic ion-beam traps and multi-reflection time-of flight devices has been further studied in detail. As this separation is performed during the ion storage itself, there is no need for additional external devices such as ion gates or traps for either pre- or postselection of the ions of interest. The ejection of unwanted contaminant ions is performed by appropriate pulses of the potentials of deflector electrodes. These segmented ring electrodes are located off-center in the trap, i.e., between one of the two ion mirrors and the central drift tube, which also serves as a potential lift for capturing incoming ions and axially ejecting ions of interest after their selection. The various parameters affecting the selection effectivity and resolving power are illustrated with tin-cluster measurements, where isotopologue ion species provide mass differences down to a single atomic mass unit at ion masses of several hundred. Symmetric deflection voltages of only 10 V were found sufficient for the transversal ejection of ion species with as few as three deflection pulses. The duty cycle, i.e., the pulse duration with respect to the period of ion revolution, has been varied, resulting in resolving powers of up to several tens of thousands for this selection technique. PMID- 29390656 TI - A novel approach to electron data background treatment in an online wide-angle spectrometer for laser-accelerated ion and electron bunches. AB - Laser-based ion acceleration is driven by electrical fields emerging when target electrons absorb laser energy and consecutively leave the target material. A direct correlation between these electrons and the accelerated ions is thus to be expected and predicted by theoretical models. We report on a modified wide-angle spectrometer, allowing the simultaneous characterization of angularly resolved energy distributions of both ions and electrons. Equipped with online pixel detectors, the RadEye1 detectors, the investigation of this correlation gets attainable on a single shot basis. In addition to first insights, we present a novel approach for reliably extracting the primary electron energy distribution from the interfering secondary radiation background. This proves vitally important for quantitative extraction of average electron energies (temperatures) and emitted total charge. PMID- 29390657 TI - Phase noise reduction by optical phase-locked loop for a coherent bichromatic laser based on the injection-locking technique. AB - We present a coherent bichromatic laser system with low phase noise. An optical injection process is used to generate coherent laser beams with a frequency difference of 9.192 631 77 GHz using an electro-optical modulator. An optical phase-locked loop is then applied to reduce the phase noise. The phase noise of the beat note is -41, -81, -98, -83, and -95 dBrad2/Hz at the offset frequencies of 1 Hz, 100 Hz, 1 kHz, 10 kHz, and 1 MHz, respectively. Compared to a system that uses optical injection alone, the phase noise is reduced by up to 20-30 dB in the low-frequency range, and the intermodulation effect on the continuous atomic clock is reduced by an order of magnitude. This configuration can adjust the intensities and polarizations of the laser beams independently and reduce the phase noise caused by environmental disturbances and optical injection, which may be useful for application to atomic coherence experiments. PMID- 29390658 TI - Design of a cathodoluminescence image generator using a Raspberry Pi coupled to a scanning electron microscope. AB - In this work, an innovative cathodoluminescence (CL) system is coupled to a scanning electron microscope and synchronized with a Raspberry Pi computer integrated with an innovative processing signal. The post-processing signal is based on a Python algorithm that correlates the CL and secondary electron (SE) images with a precise dwell time correction. For CL imaging, the emission signal is collected through an optical fiber and transduced to an electrical signal via a photomultiplier tube (PMT). CL Images are registered in a panchromatic mode and can be filtered using a monochromator connected between the optical fiber and the PMT to produce monochromatic CL images. The designed system has been employed to study ZnO samples prepared by electrical arc discharge and microwave methods. CL images are compared with SE images and chemical elemental mapping images to correlate the emission regions of the sample. PMID- 29390659 TI - Direct intensity calibration of X-ray grazing-incidence microscopes with home-lab source. AB - Direct intensity calibration of X-ray grazing-incidence microscopes is urgently needed in quantitative studies of X-ray emission from laser plasma sources in inertial confinement fusion. The existing calibration methods for single reflecting mirrors, crystals, gratings, filters, and X-ray detectors are not applicable for such X-ray microscopes due to the specific optical structure and the restrictions of object-image relation. This article presents a reliable and efficient method that can be performed using a divergent X-ray source and an energy dispersive Si-PIN (silicon positive-intrinsic-negative) detector in an ordinary X-ray laboratory. The transmission theory of X-ray flux in imaging diagnostics is introduced, and the quantities to be measured are defined. The calibration method is verified by a W/Si multilayer-coated Kirkpatrick-Baez microscope with a field of view of ~95 MUm at 17.48 keV. The mirror reflectance curve in the 1D coordinate is drawn with a peak value of 20.9% and an uncertainty of ~6.0%. PMID- 29390660 TI - A new ultrasonic transducer sample cell for in situ small-angle scattering experiments. AB - Ultrasound irradiation is a commonly used technique for nondestructive diagnostics or targeted destruction. We report on a new versatile sonication device that fits in a variety of standard sample environments for neutron and X ray scattering instruments. A piezoelectric transducer permits measuring of the time-dependent response of the sample in situ during or after sonication. We use small-angle neutron scattering (SANS) to demonstrate the effect of a time dependent perturbation on the structure factor of micelles formed from sodium dodecyl sulfate surfactant molecules. We observe a substantial change in the micellar structure during and after exposure to ultrasonic irradiation. We also observe a time-dependent relaxation to the equilibrium values of the unperturbed system. The strength of the perturbation of the structure factor depends systematically on the duration of sonication. The relaxation behavior can be well reproduced after multiple times of sonication. Accumulation of the recorded intensities of the different sonication cycles improves the signal-to-noise ratio and permits reaching very short relaxation times. In addition, we present SANS data for the micellar form factor on alkyl-poly (ethylene oxide) surfactant molecules irradiated by ultrasound. Due to the flexibility of our new in situ sonication device, different experiments can be performed, e.g., to explore molecular potentials in more detail by introducing a systematic time-dependent perturbation. PMID- 29390661 TI - Simultaneous 3D coincidence imaging of cationic, anionic, and neutral photo fragments. AB - We present the design and simulations of a 3D coincidence imaging spectrometer for fast beam photofragmentation experiments. Coincidence detection of cationic, neutral, and anionic fragments involves spectrometer aberrations that are successfully corrected by an analytical model combined with exact numerical simulations. The spectrometer performance is experimentally demonstrated by characterization of four different channels of intense 800 nm pulse interaction with F2-: F- + F photodissociation, F + F dissociative photodetachment, F+ + F dissociative ionization, and F+ + F+ coulomb explosion. Improved measurement of F2- photodissociation with a 400 nm photon allows a better determination of the F2- anion dissociation energy, 1.256 +/- 0.005 eV. PMID- 29390662 TI - A local sensor for joint temperature and velocity measurements in turbulent flows. AB - We present the principle for a micro-sensor aimed at measuring local correlations of turbulent velocity and temperature. The operating principle is versatile and can be adapted for various types of flow. It is based on a micro-machined cantilever, on the tip of which a platinum resistor is patterned. The deflection of the cantilever yields an estimate for the local velocity, and the impedance of the platinum yields an estimate for the local temperature. The velocity measurement is tested in two turbulent jets: one with air at room temperature which allows us to compare with well-known calibrated reference anemometers, and another one in the GReC jet at CERN with cryogenic gaseous helium which allows a much larger range of resolved turbulent scales. The recording of temperature fluctuations is tested in the Barrel of Ilmenau which provides a controlled turbulent thermal flow in air. Measurements in the wake of a heated or cooled cylinder demonstrate the capability of the sensor to display the cross correlation between temperature and velocity correctly. PMID- 29390663 TI - Research on the honeycomb restrain layer application to the high power microwave dielectric window. AB - Dielectric window breakdown is an important problem of high power microwave radiation. A honeycomb layer can suppress the multipactor in two directions to restrain dielectric window breakdown. This paper studies the effect of the honeycomb restrain layer on improving the dielectric window power capability. It also studies the multipactor suppression mechanism by using the electromagnetic particle-in-cell software, gives the design method, and accomplishes the test experiment. The experimental results indicated that the honeycomb restrain layer can effectively improve the power capability twice. PMID- 29390664 TI - Note: An innovative method for 12C4+ suppression in 18O6+ beam production in an electron cyclotron resonance ion source. AB - It is a major and complex task to accelerate an ion which has the same charge to mass ratio with strong contaminant ions, such as 12C4+ in the 18O6+ beam. An innovative method has been developed to suppress the contaminant ions in the Electron Cyclotron Resonance (ECR) ion source by introducing Li vapor. The ion distribution inside the ECR zone was obtained by the optical analysis of ions inside the ECR ion source. The 12C4+ ions were suppressed as much as by a factor of 10, whereas the 18O6+ beam changed little with the use of this technique. PMID- 29390665 TI - Efficient design and verification of diagnostics for impurity transport experiments. AB - Recent attempts to measure impurity transport in Alcator C-Mod using an x-ray imaging crystal spectrometer and laser blow-off impurity injector have failed to yield unique reconstructions of the transport coefficient profiles. This paper presents a fast, linearized model which was constructed to estimate diagnostic requirements for impurity transport experiments. The analysis shows that the spectroscopic diagnostics on Alcator C-Mod should be capable of inferring simple profiles of impurity diffusion DZ and convection VZ accurate to better than +/ 10% uncertainty, suggesting that the failure to infer unique DZ and VZ from experimental data is attributable to an inadequate analysis procedure rather than the result of insufficient diagnostics. Furthermore, the analysis reveals that even a modest spatial resolution can overcome a low time resolution. This approach can be adapted to design and verify diagnostics for transport experiments on any magnetic confinement device. PMID- 29390666 TI - Measurement and control from frequency to phase based on virtual signal reconstruction. AB - A virtual reconstruction method of directly capturing phase information between different nominal frequency signals, without frequency transformation, is proposed in this paper, building a virtual standard frequency signal whose frequency equals the measured nominal frequency and then making continuous comparison in the measuring gate which is synchronous with multiple periods between the measured signal and the reference frequency signal. Phase variations of the measured signal in every continuous gate are determined, and continuous phase-measuring is implemented. The experimental result verifies this special method for directly processing the phase difference between different nominal frequency signals and realizes a comparison precision of 10-17/day in a wide range. PMID- 29390667 TI - Instrumentation for low noise nanopore-based ionic current recording under laser illumination. AB - We describe a nanopore-based optofluidic instrument capable of performing low noise ionic current recordings of individual biomolecules under laser illumination. In such systems, simultaneous optical measurements generally introduce significant parasitic noise in the electrical signal, which can severely reduce the instrument sensitivity, critically hindering the monitoring of single-molecule events in the ionic current traces. Here, we present design rules and describe simple adjustments to the experimental setup to mitigate the different noise sources encountered when integrating optical components to an electrical nanopore system. In particular, we address the contributions to the electrical noise spectra from illuminating the nanopore during ionic current recording and mitigate those effects through control of the illumination source and the use of a PDMS layer on the SiNx membrane. We demonstrate the effectiveness of our noise minimization strategies by showing the detection of DNA translocation events during membrane illumination with a signal-to-noise ratio of ~10 at 10 kHz bandwidth. The instrumental guidelines for noise minimization that we report are applicable to a wide range of nanopore-based optofluidic systems and offer the possibility of enhancing the quality of synchronous optical and electrical signals obtained during single-molecule nanopore-based analysis. PMID- 29390668 TI - Measurement of pre-bunched beam's longitudinal form factor based on radiation from a tunable-gap undulator. AB - The form factor, representing the statistical characteristics of a bunch's longitudinal distribution, is one of the most essential properties of a pre bunched electron beam and is used for many types of frontier accelerator applications. We demonstrated the measurement of a pre-bunched beam's longitudinal form factor component based on coherent radiation from a widely tunable-gap undulator. The radiation energy from bunches with different longitudinal properties was measured as a function of undulator gap. The root mean-square length of a 60 pC ultrashort quasi-Gaussian bunch generated by linac and chicane compression ranged from 75 fs to 240 fs, as obtained by fitting the radiation energy curve. Furthermore, the form factor component of the bunch train based on nonlinear longitudinal space charge oscillation was measured, and a higher-order harmonic component was observed with the proposed method than with the widely used coherent transition radiation method. The proposed method may satisfy the requirements of sub-fs bunch length measurement with proper undulator design. PMID- 29390669 TI - Low Rm magnetohydrodynamics as a means of measuring the surface shear viscosity of a liquid metal: A first attempt on Galinstan. AB - This paper introduces an experimental apparatus which generates the end-driven annular flow of a liquid metal pervaded by a uniform magnetic field. Unlike past viscometers involving an annular channel with particular values of the depth-to width ratio, the present experiment enables us to drive the viscous shear at the surface of an annular liquid metal bath put in rotation. The magnetic interaction parameter N and the Boussinesq number related to the surface shear viscosity can be monitored from the magnitude of the applied magnetic field; the latter being set large enough for avoiding artefacts related to centrifugation and surface dilatation. This essential feature is obtained due to the ability of the magnetic field to set dimensionality of the annular flow in the channel between 2D-1/2 (swirling flow) and 2D axisymmetric (extinction of the overturning flow if N is large enough). By tracking the azimuthal velocity of tracers seeded along the oxidised surface of liquid Galinstan, an estimate for the surface shear viscosity of a liquid metal can be given. PMID- 29390670 TI - Critical current measurements of high-temperature superconducting short samples at a wide range of temperatures and magnetic fields. AB - High-Temperature Superconductors (HTS) are potential materials for high-field magnets, low-loss transmission cables, and Superconducting Magnetic Energy Storage (SMES) due to their high upper critical magnetic field (Hc2) and critical temperature (Tc). The critical current (Ic) of HTS, which is one of the most important parameters for superconductor application, depends strongly on the magnetic fields and temperatures. A new Ic measurement system that can carry out accurate Ic measurement for HTS short samples with various temperatures (4.2-80 K), magnetic fields (0-14 T), and angles of the magnetic field (0 degrees -90 degrees ) has been developed. The Ic measurement system mainly consists of a measurement holder, temperature-control system, background magnet, test cryostat, data acquisition system, and DC power supply. The accuracy of temperature control is better than +/-0.1 K over the 20-80 K range and +/-0.05 K when measured below 20 K. The maximum current is over 1000 A with a measurement uncertainty of 1%. The system had been successfully used for YBa2Cu3O7-x(YBCO) tapes Ic determination with different temperatures and magnetic fields. PMID- 29390671 TI - A laser heating facility for energy-dispersive X-ray absorption spectroscopy. AB - A double-sided laser heating setup for diamond anvil cells installed on the ID24 beamline of the ESRF is presented here. The setup geometry is specially adopted for the needs of energy-dispersive X-ray absorption spectroscopic (XAS) studies of materials under extreme pressure and temperature conditions. We illustrate the performance of the facility with a study on metallic nickel at 60 GPa. The XAS data provide the temperature of the melting onset and quantitative information on the structural parameters of the first coordination shell in the hot solid up to melting. PMID- 29390672 TI - Diagnostics of microwave assisted electron cyclotron resonance plasma source for surface modification of nylon 6. AB - Looking at the increasing scope of plasma processing of materials surface, here we present the development and diagnostics of a microwave assisted Electron Cyclotron Resonance (ECR) plasma system suitable for surface modification of polymers. Prior to the surface-treatment, a detailed diagnostic mapping of the plasma parameters throughout the reactor chamber was carried out by using single and double Langmuir probe measurements in Ar plasma. Conventional analysis of I-V curves as well as the elucidation form of the Electron Energy Distribution Function (EEDF) has become the source of calibration of plasma parameters in the reaction chamber. The high energy tail in the EEDF of electron temperature is seen to extend beyond 60 eV, at much larger distances from the ECR zone. This proves the suitability of the rector for plasma processing, since the electron energy is much beyond the threshold energy of bond breaking in most of the polymers. Nylon 6 is used as a representative candidate for surface processing in the presence of Ar, H2 + N2, and O2 plasma, treated at different locations inside the plasma chamber. In a typical case, the work of adhesion is seen to almost get doubled when treated with oxygen plasma. Morphology of the plasma treated surface and its hydrophilicity are discussed in view of the variation in electron density and electron temperature at these locations. Nano-protrusions arising from plasma treatment are set to be responsible for the hydrophobicity. Chemical sputtering and physical sputtering are seen to influence the surface morphology on account of sufficient electron energies and increased plasma potential. PMID- 29390673 TI - Vision sensor and dual MEMS gyroscope integrated system for attitude determination on moving base. AB - To determine the relative attitude between the objects on a moving base and the base reference system by a MEMS (Micro-Electro-Mechanical Systems) gyroscope, the motion information of the base is redundant, which must be removed from the gyroscope. Our strategy is to add an auxiliary gyroscope attached to the reference system. The master gyroscope is to sense the total motion, and the auxiliary gyroscope is to sense the motion of the moving base. By a generalized difference method, relative attitude in a non-inertial frame can be determined by dual gyroscopes. With the vision sensor suppressing accumulative drift of the MEMS gyroscope, the vision and dual MEMS gyroscope integration system is formed. Coordinate system definitions and spatial transform are executed in order to fuse inertial and visual data from different coordinate systems together. And a nonlinear filter algorithm, Cubature Kalman filter, is used to fuse slow visual data and fast inertial data together. A practical experimental setup is built up and used to validate feasibility and effectiveness of our proposed attitude determination system in the non-inertial frame on the moving base. PMID- 29390674 TI - A compact design of a characterization station for far UV photodetectors. AB - A newly fabricated characterization station is presented. It is a compact, cost effective, and easily adjustable apparatus. Each part including 4-pin probe, manipulators, operating temperature, and applied bias can be independently controlled. The station can provide highly reliable, reproducible, and economical methods to quickly conduct and complete the characterizations of a large amount of sensing materials within a short period of time. It is particularly suitable for studies of various nanostructured materials and their related thermal effect, polarization effect, sensitivity, and electrical and electronic properties. PMID- 29390675 TI - Opto-acoustic microscopy reveals adhesion mechanics of single cells. AB - Laser-generated GHz-ultrasonic-based technologies have shown the ability to image single cell adhesion and stiffness simultaneously. Using this new modality, we here demonstrate quantitative indicators to investigate contact mechanics and adhesion processes of the cell. We cultured human cells on a rigid substrate, and we used an inverted pulsed opto-acoustic microscope to generate acoustic pulses containing frequencies up to 100 GHz in the substrate. We map the reflection of the acoustic pulses at the cell-substrate interface to obtain images of the acoustic impedance of the cell, Zc, as well as of the stiffness of the interface, K, with 1 MUm lateral resolution. Our results show that the standard deviation DeltaZc reveals differences between different cell types arising from the multiplicity of local conformations within the nucleus. From the distribution of K-values within the nuclear region, we extract a mean interfacial stiffness, Km, that quantifies the average contact force in areas of the cell displaying weak bonding. By analogy with classical contact mechanics, we also define the ratio of the real to nominal contact areas, Sr/St. We show that Km can be interpreted as a quantitative indicator of passive contact at metal-cell interfaces, while Sr/St is sensitive to active adhesive processes in the nuclear region. The ability to separate the contributions of passive and active adhesion processes should allow gaining insight into cell-substrate interactions, with important applications in tissue engineering. PMID- 29390676 TI - Note: Motor-piezoelectricity coupling driven high temperature fatigue device. AB - The design and performance evaluation of a novel high temperature fatigue device simultaneously driven by servo motor and piezoelectric actuator is our focus. The device integrates monotonic and cyclic loading functions with a maximum tensile load of 1800 N, driving frequency of 50 Hz, alternating load of 95 N, and maximum service temperature of 1200 degrees C. Multimodal fatigue tests with arbitrary combinations of static and dynamic loads are achieved. At temperatures that range from RT to 1100 degrees C, the tensile and tensile-fatigue coupling mechanical behaviors of UM Co50 alloys are investigated to verify the feasibility of the device. PMID- 29390677 TI - Prototype of the novel CAMEA concept-A backend for neutron spectrometers. AB - The continuous angle multiple energy analysis concept is a backend for both time of-flight and analyzer-based neutron spectrometers optimized for neutron spectroscopy with highly efficient mapping in the horizontal scattering plane. The design employs a series of several upward scattering analyzer arcs placed behind each other, which are set to different final energies allowing a wide angular coverage with multiple energies recorded simultaneously. For validation of the concept and the model calculations, a prototype was installed at the Swiss neutron source SINQ, Paul Scherrer Institut. The design of the prototype, alignment and calibration procedures, experimental results of background measurements, and proof-of-concept inelastic measurements on LiHoF4 and h-YMnO3 are presented here. PMID- 29390678 TI - Reflector automatic acquisition and pointing based on auto-collimation theodolite. AB - An auto-collimation theodolite (ACT) for reflector automatic acquisition and pointing is designed based on the principle of autocollimators and theodolites. First, the principle of auto-collimation and theodolites is reviewed, and then the coaxial ACT structure is developed. Subsequently, the acquisition and pointing strategies for reflector measurements are presented, which first quickly acquires the target over a wide range and then points the laser spot to the charge coupled device zero position. Finally, experiments are conducted to verify the acquisition and pointing performance, including the calibration of the ACT, the comparison of the acquisition mode and pointing mode, and the accuracy measurement in horizontal and vertical directions. In both directions, a measurement accuracy of +/-3" is achieved. The presented ACT is suitable for automatic pointing and monitoring the reflector over a small scanning area and can be used in a wide range of applications such as bridge structure monitoring and cooperative target aiming. PMID- 29390679 TI - Accounting for Debye sheath expansion for proud Langmuir probes in magnetic confinement fusion plasmas. AB - A Child-Langmuir law-based method for accounting for Debye sheath expansion while fitting the current-voltage I-V characteristic of proud Langmuir probes (electrodes that extend into the volume of the plasma) is described. For Langmuir probes of a typical size used in tokamak plasmas, these new estimates of electron temperature and ion saturation current density values decreased by up to 60% compared to methods that did not account for sheath expansion. Changes to the collection area are modeled using the Child-Langmuir law and effective expansion perimeter lp, and the model is thus referred to as the "perimeter sheath expansion method." lp is determined solely from electrode geometry, so the method may be employed without prior measurement of the magnitude of the sheath expansion effects for a given Langmuir probe and can be used for electrodes of different geometries. This method correctly predicts the non-saturating DeltaI/DeltaV slope for cold, low-density plasmas where sheath-expansion effects are strong, as well as for hot plasmas where DeltaI/DeltaV ~ 0, though it is shown that the sheath can still significantly affect the collection area in these hot conditions. The perimeter sheath expansion method has several advantages compared to methods where the non-saturating current is fitted: (1) It is more resilient to scatter in the I-V characteristics observed in turbulent plasmas. (2) It is able to separate the contributions to the DeltaI/DeltaV slope from sheath expansion to that of the high energy electron tail in high Te conditions. (3) It calculates the change in the collection area due to the Debye sheath for conditions where DeltaI/DeltaV ~ 0 and for V = Vf. PMID- 29390680 TI - Comparing the ISO-recommended and the cumulative data-reduction algorithms in S on-1 laser damage test by a reverse approach method. AB - We compare the ISO-recommended (the standard) data-reduction algorithm used to determine the surface laser-induced damage threshold of optical materials by the S-on-1 test with two newly suggested algorithms, both named "cumulative" algorithms/methods, a regular one and a limit-case one, intended to perform in some respects better than the standard one. To avoid additional errors due to real experiments, a simulated test is performed, named the reverse approach. This approach simulates the real damage experiments, by generating artificial test data of damaged and non-damaged sites, based on an assumed, known damage threshold fluence of the target and on a given probability distribution function to induce the damage. In this work, a database of 12 sets of test-data containing both damaged and non-damaged sites was generated by using four different reverse techniques and by assuming three specific damage probability distribution functions. The same value for the threshold fluence was assumed, and a Gaussian fluence distribution on each irradiated site was considered, as usual for the S on-1 test. Each of the test-data was independently processed by the standard and by the two cumulative data-reduction algorithms, the resulting fitted probability distributions were compared with the initially assumed probability distribution functions, and the quantities used to compare these algorithms were determined. These quantities characterize the accuracy and the precision in determining the damage threshold and the goodness of fit of the damage probability curves. The results indicate that the accuracy in determining the absolute damage threshold is best for the ISO-recommended method, the precision is best for the limit-case of the cumulative method, and the goodness of fit estimator (adjusted R-squared) is almost the same for all three algorithms. PMID- 29390681 TI - Application of time-resolved shadowgraph imaging and computer analysis to study micrometer-scale response of superfluid helium. AB - Application of inexpensive light emitting diodes as backlight sources for time resolved shadowgraph imaging is demonstrated. The two light sources tested are able to produce light pulse sequences in the nanosecond and microsecond time regimes. After determining their time response characteristics, the diodes were applied to study the gas bubble formation around laser-heated copper nanoparticles in superfluid helium at 1.7 K and to determine the local cavitation bubble dynamics around fast moving metal micro-particles in the liquid. A convolutional neural network algorithm for analyzing the shadowgraph images by a computer is presented and the method is validated against the results from manual image analysis. The second application employed the red-green-blue light emitting diode source that produces light pulse sequences of the individual colors such that three separate shadowgraph frames can be recorded onto the color pixels of a charge-coupled device camera. Such an image sequence can be used to determine the moving object geometry, local velocity, and acceleration/deceleration. These data can be used to calculate, for example, the instantaneous Reynolds number for the liquid flow around the particle. Although specifically demonstrated for superfluid helium, the technique can be used to study the dynamic response of any medium that exhibits spatial variations in the index of refraction. PMID- 29390682 TI - Backscatter spectra measurements of the two beams on the same cone on Shenguang III laser facility. AB - In laser driven hohlraums, laser beams on the same incident cone may have different beam and plasma conditions, causing beam-to-beam backscatter difference and subsequent azimuthal variations in the x-ray drive on the capsule. To elucidate the large variation of backscatter proportion from beam to beam in some gas-filled hohlraum shots on Shenguang-III, two 28.5 degrees beams have been measured with the Stimulated Raman Scattering (SRS) time-resolved spectra. A bifurcated fiber is used to sample two beams and then coupled to a spectrometer and streak camera combination to reduce the cost. The SRS spectra, characterized by a broad wavelength, were further corrected considering the temporal distortion and intensity modulation caused by components along the light path. This measurement will improve the understanding of the beam propagation inside the hohlraum and related laser plasma instabilities. PMID- 29390683 TI - A transportable Paul-trap for levitation and accurate positioning of micron-scale particles in vacuum for laser-plasma experiments. AB - We report on a Paul-trap system with large access angles that allows positioning of fully isolated micrometer-scale particles with micrometer precision as targets in high-intensity laser-plasma interactions. This paper summarizes theoretical and experimental concepts of the apparatus as well as supporting measurements that were performed for the trapping process of single particles. PMID- 29390684 TI - Cryogenic positioning and alignment with micrometer precision in a magnetic resonance force microscope. AB - Aligning a microcantilever to an area of interest on a sample is a critical step in many scanning probe microscopy experiments, particularly those carried out on devices and rare, precious samples. We report a series of protocols that rapidly and reproducibly align a high-compliance microcantilever to a <10 MUm sample feature under high vacuum and at cryogenic temperatures. The first set of protocols, applicable to a cantilever oscillating parallel to the sample surface, involve monitoring the cantilever resonance frequency while laterally scanning the tip to map the sample substrate through electrostatic interactions of the substrate with the cantilever. We demonstrate that when operating a cantilever a few micrometers from the sample surface, large shifts in the cantilever resonance frequency are present near the edges of a voltage-biased sample electrode. Surprisingly, these "edge-finder" frequency shifts are retained when the electrode is coated with a polymer film and a ~10 nm thick metallic ground plane. The second series of methods, applicable to any scanning probe microscopy experiment, integrate a single-optical fiber to image line scans of the sample surface. The microscope modifications required for these methods are straightforward to implement, provide reliable micrometer-scale positioning, and decrease the experimental setup time from days to hours in a vacuum, cryogenic magnetic resonance force microscope. PMID- 29390685 TI - Measurement of shape and deformation of insect wing. AB - To measure the shape and deformation of an insect wing, a scanning setup adopting laser triangulation and image matching was developed. Only one industry camera with two light sources was employed to scan the transparent insect wings. 3D shape and point to point full field deformation of the wings could be obtained even when the wingspan is less than 3 mm. The venation and corrugation could be significantly identified from the results. The deformation of the wing under pin loading could be seen clearly from the results as well. Calibration shows that the shape and deformation measurement accuracies are no lower than 0.01 mm. Laser triangulation and image matching were combined dexterously to adapt wings' complex shape, size, and transparency. It is suitable for insect flight research or flapping wing micro-air vehicle development. PMID- 29390686 TI - An experimental platform for real-time measurement of the deformation of nuclear fuel rod claddings submitted to thermal transients. AB - We report on experimental development and qualification of a system developed to detect and quantify the deformations of the cladding surface of nuclear fuel pellet assemblies submitted to heat transient conditions. The system consists of an optical instrument, based on 2 wavelengths speckle interferometry, associated with an induction furnace and a model pellet assembly used to simulate the radial thermal gradient experienced by fuel pellets in pressurized water reactors. We describe the concept, implementation, and first results obtained with this system. We particularly demonstrate that the optical system is able to provide real time measurements of the cladding surface shape during the heat transients from ambient to high temperatures (up to a cladding surface temperature of 600 degrees C) with micrometric resolution. PMID- 29390687 TI - Soft x-ray spectroscopy of high pressure liquid. AB - We describe a new experimental technique that allows for soft x-ray spectroscopy studies (~100-1000 eV) of high pressure liquid (~100 bars). We achieve this through a liquid cell with a 100 nm-thick Si3N4 membrane window, which is sandwiched by two identical O-rings for vacuum sealing. The thin Si3N4 membrane allows soft x-rays to penetrate, while separating the high-pressure liquid under investigation from the vacuum required for soft x-ray transmission and detection. The burst pressure of the Si3N4 membrane increases with decreasing size and more specifically is inversely proportional to the side length of the square window. It also increases proportionally with the membrane thickness. Pressures > 60 bars could be achieved for 100 nm-thick square Si3N4 windows that are smaller than 65 MUm. However, above a certain pressure, the failure of the Si wafer becomes the limiting factor. The failure pressure of the Si wafer is sensitive to the wafer thickness. Moreover, the deformation of the Si3N4 membrane is quantified using vertical scanning interferometry. As an example of the performance of the high pressure liquid cell optimized for total-fluorescence detected soft x-ray absorption spectroscopy (sXAS), the sXAS spectra at the Ca L edge (~350 eV) of a CaCl2 aqueous solution are collected under different pressures up to 41 bars. PMID- 29390688 TI - Simultaneous measurement of surface tension and viscosity using freely decaying oscillations of acoustically levitated droplets. AB - Oscillations of small liquid drops around a spherical shape have been of great interest to scientists measuring physical properties such as interfacial tension and viscosity, over the last few decades. A powerful tool for contactless positioning is acoustic levitation, which has been used to simultaneously determine the surface tension and viscosity of liquids at ambient pressure. In order to extend this acoustic levitation measurement method to high pressure systems, the method is first evaluated under ambient pressure. To measure surface tension and viscosity using acoustically levitated oscillating drops, an image analysis method has to be developed and factors which may affect measurement, such as sound field or oscillation amplitude, have to be analyzed. In this paper, we describe the simultaneous measurement of surface tension and viscosity using freely decaying shape oscillations of acoustically levitated droplets of different liquids (silicone oils AK 5 and AK 10, squalane, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, and 1-octanol) in air. These liquids vary in viscosity from 2 to about 30 mPa s. An acoustic levitation system, including an optimized standing wave acoustic levitator and a high-speed camera, was used for this study. An image analysis was performed with a self-written Matlab(r) code. The frequency of oscillation and the damping constant, required for the determination of surface tension and viscosity, respectively, were calculated from the evolution of the equatorial and polar radii. The results and observations are compared to data from the literature in order to analyze the accuracy of surface tension and viscosity determination, as well as the effect of non-spherical drop shape or amplitude of oscillation on measurement. PMID- 29390689 TI - Design and testing of a coil-unit barrel for helical coil electromagnetic launcher. AB - A coil-unit barrel for a helical coil electromagnetic launcher is described. It provides better features of high structural strength and flexible adjustability. It is convenient to replace the damaged coil units and easy to adjust the number of turns in the stator coils due to the modular design. In our experiments, the highest velocity measured for a 4.5-kg projectile is 47.3 m/s and the mechanical reinforcement of the launcher could bear 35 kA peak current. The relationship between the energy conversion efficiency and the inductance gradient of the launcher is also studied. In the region of low inductance gradient, the efficiency is positively correlated with the inductance gradient. However, in the region of high inductance gradient, the inter-turn arc erosion becomes a major problem of limiting the efficiency and velocity of the launcher. This modular barrel allows further studies in the inter-turn arc and the variable inductance gradient helical coil launcher. PMID- 29390690 TI - Thermal stability control system of photo-elastic interferometer in the PEM-FTs. AB - A drifting model for the resonant frequency and retardation amplitude of a photo elastic modulator (PEM) in the photo-elastic modulated Fourier transform spectrometer (PEM-FTs) is presented. A multi-parameter broadband-matching driving control method is proposed to improve the thermal stability of the PEM interferometer. The automatically frequency-modulated technology of the driving signal based on digital phase-locked technology is used to track the PEM's changing resonant frequency. Simultaneously the maximum optical-path-difference of a laser's interferogram is measured to adjust the amplitude of the PEM's driving signal so that the spectral resolution is stable. In the experiment, the multi-parameter broadband-matching control method is applied to the driving control system of the PEM-FTs. Control of resonant frequency and retardation amplitude stabilizes the maximum optical-path-difference to approximately 236 MUm and results in a spectral resolution of 42 cm-1. This corresponds to a relative error smaller than 2.16% (4.28 standard deviation). The experiment shows that the method can effectively stabilize the spectral resolution of the PEM-FTs. PMID- 29390691 TI - In situ magnetometry for experiments with atomic quantum gases. AB - Precise control of magnetic fields is a frequent challenge encountered in experiments with atomic quantum gases. Here we present a simple method for performing in situ monitoring of magnetic fields that can readily be implemented in any quantum-gas apparatus in which a dedicated field-stabilization approach is not feasible. The method, which works by sampling several Rabi resonances between magnetically field sensitive internal states that are not otherwise used in a given experiment, can be integrated with standard measurement sequences at arbitrary fields. For a condensate of 87Rb atoms, we demonstrate the reconstruction of Gauss-level bias fields with an accuracy of tens of microgauss and with millisecond time resolution. We test the performance of the method using measurements of slow resonant Rabi oscillations on a magnetic-field sensitive transition and give an example for its use in experiments with state-selective optical potentials. PMID- 29390692 TI - Correlated ion and neutral time of flight technique combined with velocity map imaging: Quantitative measurements for dissociation processes in excited molecular nano-systems. AB - The combination of the Dispositif d'Irradiation d'Agregats Moleculaire with the correlated ion and neutral time of flight-velocity map imaging technique provides a new way to explore processes occurring subsequent to the excitation of charged nano-systems. The present contribution describes in detail the methods developed for the quantitative measurement of branching ratios and cross sections for collision-induced dissociation processes of water cluster nano-systems. These methods are based on measurements of the detection efficiency of neutral fragments produced in these dissociation reactions. Moreover, measured detection efficiencies are used here to extract the number of neutral fragments produced for a given charged fragment. PMID- 29390693 TI - Effects of stray lights on Faraday rotation measurement for polarimeter interferometer system on EAST. AB - A double-pass radially view 11 chords polarimeter-interferometer system has been operated on the experimental advanced superconducting tokamak and provides important current profile information for plasma control. Stray light originating from spurious reflections along the optical path (unwanted reflections from various optical components/mounts and transmissive optical elements such as windows, waveplates, and lens as well as the detectors) and also direct feedback from the retro-reflector used to realize the double-pass configuration can both contribute to contamination of the Faraday rotation measurement accuracy. Modulation of the Faraday rotation signal due to the interference from multiple reflections is observable when the interferometer phase (plasma density) varies with time. Direct reflection from the detector itself can be suppressed by employing an optical isolator consisting of a lambda/4-waveplate and polarizer positioned in front of the mixer. A Faraday angle oscillation during the density ramping up (or down) can be reduced from 5 degrees -10 degrees to 1 degrees -2 degrees by eliminating reflections from the detector. Residual modulation arising from misalignment and stray light from other sources must be minimized to achieve accurate measurements of Faraday rotation. PMID- 29390694 TI - Temperature dependence of reduced offset in double Hall sensor structure reducing voltage offset. AB - We have recently described the principle of operation of a double Hall sensor structure (DHSS) reducing the voltage offset [M. Oszwaldowski and S. El-Ahmar, Rev. Sci. Instrum. 88, 075005 (2017)]. The correctness of operation of the structure and its characteristic features were checked and clarified experimentally using the structures made of InSb thin films. In the present paper, we investigate the very important problem of the temperature dependence of the reduced offset in the DHSS. We show that the reduced voltage temperature dependence is entirely governed by the temperature dependence of the resistance of the component Hall sensors. If the averaged temperature dependence of the resistance of both the component Hall sensors were the same in a given temperature range, the reduced offset of the DHSS can be virtually independent of temperature in that temperature range. This behavior is confirmed by experimental investigations performed on DHSSs made of InSb thin films. PMID- 29390695 TI - Design techniques for a stable operation of cryogenic field-programmable gate arrays. AB - In this paper, we show how a deep-submicron field-programmable gate array (FPGA) can be operated more stably at extremely low temperatures through special firmware design techniques. Stability at low temperatures is limited through long power supply wires and reduced performance of various printed circuit board components commonly employed at room temperature. Extensive characterization of these components shows that the majority of decoupling capacitor types and voltage regulators are not well behaved at cryogenic temperatures, asking for an ad hoc solution to stabilize the FPGA supply voltage, especially for sensitive applications. Therefore, we have designed a firmware that enforces a constant power consumption, so as to stabilize the supply voltage in the interior of the FPGA. The FPGA is powered with a supply at several meters distance, causing significant resistive voltage drop and thus fluctuations on the local supply voltage. To achieve the stabilization, the variation in digital logic speed, which directly corresponds to changes in supply voltage, is constantly measured and corrected for through a tunable oscillator farm, implemented on the FPGA. The impact of the stabilization technique is demonstrated together with a reconfigurable analog-to-digital converter (ADC), completely implemented in the FPGA fabric and operating at 15 K. The ADC performance can be improved by at most 1.5 bits (effective number of bits) thanks to the more stable supply voltage. The method is versatile and robust, enabling seamless porting to other FPGA families and configurations. PMID- 29390696 TI - On the effect of local barrier height in scanning tunneling microscopy: Measurement methods and control implications. AB - A common cause of tip-sample crashes in a Scanning Tunneling Microscope (STM) operating in constant current mode is the poor performance of its feedback control system. We show that there is a direct link between the Local Barrier Height (LBH) and robustness of the feedback control loop. A method known as the "gap modulation method" was proposed in the early STM studies for estimating the LBH. We show that the obtained measurements are affected by controller parameters and propose an alternative method which we prove to produce LBH measurements independent of the controller dynamics. We use the obtained LBH estimation to continuously update the gains of a STM proportional-integral (PI) controller and show that while tuning the PI gains, the closed-loop system tolerates larger variations of LBH without experiencing instability. We report experimental results, conducted on two STM scanners, to establish the efficiency of the proposed PI tuning approach. Improved feedback stability is believed to help in avoiding the tip/sample crash in STMs. PMID- 29390697 TI - Attosecond transient absorption instrumentation for thin film materials: Phase transitions, heat dissipation, signal stabilization, timing correction, and rapid sample rotation. AB - We present an extreme ultraviolet (XUV) transient absorption apparatus tailored to attosecond and femtosecond measurements on bulk solid-state thin-film samples, specifically when the sample dynamics are sensitive to heating effects. The setup combines methodology for stabilizing sub-femtosecond time-resolution measurements over 48 h and techniques for mitigating heat buildup in temperature-dependent samples. Single-point beam stabilization in pump and probe arms and periodic time zero reference measurements are described for accurate timing and stabilization. A hollow-shaft motor configuration for rapid sample rotation, raster scanning capability, and additional diagnostics are described for heat mitigation. Heat transfer simulations performed using a finite element analysis allow comparison of sample rotation and traditional raster scanning techniques for 100 Hz pulsed laser measurements on vanadium dioxide, a material that undergoes an insulator-to metal transition at a modest temperature of 340 K. Experimental results are presented confirming that the vanadium dioxide (VO2) sample cannot cool below its phase transition temperature between laser pulses without rapid rotation, in agreement with the simulations. The findings indicate the stringent conditions required to perform rigorous broadband XUV time-resolved absorption measurements on bulk solid-state samples, particularly those with temperature sensitivity, and elucidate a clear methodology to perform them. PMID- 29390698 TI - Median filters as a tool to determine dark noise thresholds in high resolution smartphone image sensors for scientific imaging. AB - An evaluation of the use of median filters in the reduction of dark noise in smartphone high resolution image sensors is presented. The Sony Xperia Z1 employed has a maximum image sensor resolution of 20.7 Mpixels, with each pixel having a side length of just over 1 MUm. Due to the large number of photosites, this provides an image sensor with very high sensitivity but also makes them prone to noise effects such as hot-pixels. Similar to earlier research with older models of smartphone, no appreciable temperature effects were observed in the overall average pixel values for images taken in ambient temperatures between 5 degrees C and 25 degrees C. In this research, hot-pixels are defined as pixels with intensities above a specific threshold. The threshold is determined using the distribution of pixel values of a set of images with uniform statistical properties associated with the application of median-filters of increasing size. An image with uniform statistics was employed as a training set from 124 dark images, and the threshold was determined to be 9 digital numbers (DN). The threshold remained constant for multiple resolutions and did not appreciably change even after a year of extensive field use and exposure to solar ultraviolet radiation. Although the temperature effects' uniformity masked an increase in hot pixel occurrences, the total number of occurrences represented less than 0.1% of the total image. Hot-pixels were removed by applying a median filter, with an optimum filter size of 7 * 7; similar trends were observed for four additional smartphone image sensors used for validation. Hot-pixels were also reduced by decreasing image resolution. The method outlined in this research provides a methodology to characterise the dark noise behavior of high resolution image sensors for use in scientific investigations, especially as pixel sizes decrease. PMID- 29390699 TI - Advanced platform for the in-plane ZT measurement of thin films. AB - The characterization of nanostructured samples with at least one restricted dimension like thin films or nanowires is challenging, but important to understand their structure and transport mechanism, and to improve current industrial products and production processes. We report on the 2nd generation of a measurement chip, which allows for a simplified sample preparation process, and the measurement of samples deposited from the liquid phase using techniques like spin coating and drop casting. The new design enables us to apply much higher temperature gradients for the Seebeck coefficient measurement in a shorter time, without influencing the sample holder's temperature distribution. Furthermore, a two membrane correction method for the 3omega thermal conductivity measurement will be presented, which takes the heat loss due to radiation into account and increases the accuracy of the measurement results significantly. Errors caused by different sample compositions, varying sample geometries, and different heat profiles are avoided with the presented measurement method. As a showcase study displaying the validity and accuracy of our platform, we present temperature dependent measurements of the thermoelectric properties of an 84 nm Bi87Sb13 thin film and a 15 MUm PEDOT:PSS thin film. PMID- 29390700 TI - Improving the magnetic field homogeneity by varying magnetic field structure in a geophone. AB - The magnetic field structure is a key factor that affects performance of the magneto-electric geophone. In order to enhance the magnetic field homogeneity and magnetic induction intensity of the magnetic field structure, this paper proposes a new magnetic field structure. It consists of two cylindrical permanent magnets: an H-type magnetic boot and an external magnetic yoke. The proposed magnetic field structure can broaden the range of a uniform magnetic field and increase the magnetic field intensity of working air-gap. To confirm the validity of the design, the finite element analysis and real measurement experiments were conducted. The finite element simulations using the ANASYS Electromagnetics Suite 17.2.0 showed that the air-gap magnetic induction intensity is increased and the work space with a uniform magnetic field is broadened. Meanwhile, the output voltage of the coil is increased, and the harmonic distortion rate of output voltage is reduced. According to the real measurement experimental results, compared with the traditional magnetic field structure, the uniform range of the magnetic field is improved 23% in the entire air-gap path, and the magnetic induction intensity enhances 24% over the proposed new magnetic field structure. PMID- 29390701 TI - A highly stable monolithic enhancement cavity for second harmonic generation in the ultraviolet. AB - We present a highly stable bow-tie power enhancement cavity for critical second harmonic generation (SHG) into the UV using a Brewster-cut beta-BaB2O4 (BBO) nonlinear crystal. The cavity geometry is suitable for all UV wavelengths reachable with BBO and can be modified to accommodate anti-reflection coated crystals, extending its applicability to the entire wavelength range accessible with non-linear frequency conversion. The cavity is length-stabilized using a fast general purpose digital PI controller based on the open source STEMlab 125 14 (formerly Red Pitaya) system acting on a mirror mounted on a fast piezo actuator. We observe 130 h uninterrupted operation without decay in output power at 313 nm. The robustness of the system has been confirmed by exposing it to accelerations of up to 1 g with less than 10% in-lock output power variations. Furthermore, the cavity can withstand 30 min of acceleration exposure at a level of 3 grms without substantial change in the SHG output power, demonstrating that the design is suitable for transportable setups. PMID- 29390702 TI - A high throughput spectral image microscopy system. AB - A high throughput spectral image microscopy system is configured for rapid detection of rare cells in large populations. To overcome flow cytometry rates and use of fluorophore tags, a system architecture integrates sample mechanical handling, signal processors, and optics in a non-confocal version of light absorption and scattering spectroscopic microscopy. Spectral images with native contrast do not require the use of exogeneous stain to render cells with submicron resolution. Structure may be characterized without restriction to cell clusters of differentiation. PMID- 29390703 TI - Erratum: "Low vibration laboratory with a single-stage vibration isolation for microscopy applications" [Rev. Sci. Instrum. 88, 023703 (2017)]. PMID- 29390704 TI - Simultaneous high-pressure high-temperature elastic velocity measurement system up to 27 GPa and 1873 K using ultrasonic and synchrotron X-ray techniques. AB - A new pulse-echo interferometry system has been developed for measurements of sound velocity at simultaneous high pressure and temperature corresponding to those of the Earth's lower mantle, using synchrotron X-ray techniques at SPring 8. A combination of a low-noise high-frequency amplifier and a high-speed solid state relay system allowed us to clearly detect the ultrasonic echoes of a small sample (<1.0 mm in diameter and length) in multi-anvil apparatus. A new high pressure cell has also been introduced for precise measurement of the length of the tiny sample by X-ray radiography imaging under very high pressure and temperature. The new system was tested by measuring elastic velocities of alpha Al2O3 over wide pressure and temperature ranges of up to 27 GPa and 1873 K, respectively. The resultant adiabatic bulk modulus, shear modulus, and pressure and temperature derivatives of alpha-Al2O3 are K0S = 251.2 (18) GPa, ?KS/?P = 4.21 (10), ?KS/?T = -0.025 (1), G = 164.1 (7), ?G/?P = 1.59 (3), ?G/?T = -0.021 (1). These values are consistent with those previously reported based on experiments at high temperatures at ambient pressure and high pressures at room temperature. The present system allows precise measurements of the elastic velocities of minerals under the pressures and temperatures corresponding to the lower mantle for the first time, which should greatly contribute to our understanding of mineralogy of the whole mantle. PMID- 29390705 TI - A new apparatus for on-site calibration of gamma dose rate monitors. AB - In order to carry out on-site calibrations of environmental gamma dose rate monitors, a new irradiation apparatus was developed in this study. The apparatus mainly consists of a piece of 137Cs source, a set of beam attenuators, and 3 built-in laser rangefinders, and it can be remotely controlled by using a laptop through WiFi network. With an activity of 4.6 * 108 Bq of 137Cs source, the reference air kerma rate could be adjusted from 0.26 MUGy h-1 to 140 MUGy h-1 by changing the calibration distance from 0.5 m to 5 m and using different beam attenuators (or none), and both the reproducibility and the homogeneity of reference radiation were better than 97%. The overall uncertainty of the calibration was estimated to be 6.5% (k = 2). Both the laboratory and field experiments confirmed that the calibration method met the requirements of ISO 4037-1. As the advantages of portability and simplicity, it is considered that the new irradiation apparatus is applicable to stationary gamma radiation monitors for on-site calibration. PMID- 29390706 TI - Development of a multistage compliant mechanism with new boundary constraint. AB - This paper presents a piezo-actuated compliant mechanism with a new boundary constraint to provide concurrent large workspace and high dynamic frequency for precision positioning or other flexible manipulation applications. A two-stage rhombus-type displacement amplifier with the "sliding-sliding" boundary constraint is presented to maximize the dynamic frequency while retaining a large output displacement. The vibration mode is also improved by the designed boundary constraint. A theoretical kinematic model of the compliant mechanism is established to optimize the geometric parameters, and a prototype is fabricated with a compact dimension of 60 mm * 60 mm * 12 mm. The experimental testing shows that the maximum stroke is approximately 0.6 mm and the output stiffness is 1.1 N/MUm with the fundamental frequency of larger than 2.2 kHz. Lastly, the excellent performance of the presented compliant mechanism is compared with several mechanisms in the previous literature. As a conclusion, the presented boundary constraint strategy provides a new way to balance the trade-off between the frequency response and the stroke range widely existed in compliant mechanisms. PMID- 29390707 TI - Note: Low temperature calibration of a commercial differential scanning calorimeter. AB - A method for a direct calibration of temperature for a commercial differential scanning calorimeter is presented. The advantage of this calibration method is that it can be done for any number of selected temperatures and is not dependent on standards of known melting points in the temperature range of interest. The calibration presented in this note is for the temperature range from 91 K to 273 K, the temperature range of interest, but the range can easily be extended. PMID- 29390708 TI - Measuring the lateral charge-carrier mobility in metal-insulator-semiconductor capacitors via Kelvin-probe. AB - We report a Kelvin-probe method to investigate the lateral charge-transport properties of semiconductors, most notably the charge-carrier mobility. The method is based on successive charging and discharging of a pre-biased metal insulator-semiconductor stack by an alternating voltage applied to one edge of a laterally confined semiconductor layer. The charge carriers spreading along the insulator-semiconductor interface are directly measured by a Kelvin-probe, following the time evolution of the surface potential. A model is presented, describing the device response for arbitrary applied biases allowing the extraction of the lateral charge-carrier mobility from experimentally measured surface potentials. The method is tested using the organic semiconductor poly(3 hexylthiophene), and the extracted mobilities are validated through current voltage measurements on respective field-effect transistors. Our widely applicable approach enables robust measurements of the lateral charge-carrier mobility in semiconductors with weak impact from the utilized contact materials. PMID- 29390709 TI - New algorithms for motion error detection of numerical control machine tool by laser tracking measurement on the basis of GPS principle. AB - As a three-dimensional measuring instrument, the laser tracker is widely used in industrial measurement. To avoid the influence of angle measurement error on the overall measurement accuracy, the multi-station and time-sharing measurement with a laser tracker is introduced on the basis of the global positioning system (GPS) principle in this paper. For the proposed method, how to accurately determine the coordinates of each measuring point by using a large amount of measured data is a critical issue. Taking detecting motion error of a numerical control machine tool, for example, the corresponding measurement algorithms are investigated thoroughly. By establishing the mathematical model of detecting motion error of a machine tool with this method, the analytical algorithm concerning on base station calibration and measuring point determination is deduced without selecting the initial iterative value in calculation. However, when the motion area of the machine tool is in a 2D plane, the coefficient matrix of base station calibration is singular, which generates a distortion result. In order to overcome the limitation of the original algorithm, an improved analytical algorithm is also derived. Meanwhile, the calibration accuracy of the base station with the improved algorithm is compared with that with the original analytical algorithm and some iterative algorithms, such as the Gauss-Newton algorithm and Levenberg-Marquardt algorithm. The experiment further verifies the feasibility and effectiveness of the improved algorithm. In addition, the different motion areas of the machine tool have certain influence on the calibration accuracy of the base station, and the corresponding influence of measurement error on the calibration result of the base station depending on the condition number of coefficient matrix are analyzed. PMID- 29390710 TI - Thickness measurement by two-sided step-heating thermal imaging. AB - Infrared thermal imaging is a promising nondestructive technique for thickness prediction. However, it is usually thought to be only appropriate for testing the thickness of thin objects or near-surface structures. In this study, we present a new two-sided step-heating thermal imaging method which employed a low-cost portable halogen lamp as the heating source and verified it with two stainless steel step wedges with thicknesses ranging from 5 mm to 24 mm. We first derived the one-dimensional step-heating thermography theory with the consideration of warm-up time of the lamp, and then applied the nonlinear regression method to fit the experimental data by the derived function to determine the thickness. After evaluating the reliability and accuracy of the experimental results, we concluded that this method is capable of testing thick objects. In addition, we provided the criterions for both the required data length and the applicable thickness range of the testing material. It is evident that this method will broaden the thermal imaging application for thickness measurement. PMID- 29390711 TI - Image quality assessment metric for frame accumulated image. AB - The medical image quality determines the accuracy of diagnosis, and the gray scale resolution is an important parameter to measure image quality. But current objective metrics are not very suitable for assessing medical images obtained by frame accumulation technology. Little attention was paid to the gray-scale resolution, basically based on spatial resolution and limited to the 256 level gray scale of the existing display device. Thus, this paper proposes a metric, "mean signal-to-noise ratio" (MSNR) based on signal-to-noise in order to be more reasonable to evaluate frame accumulated medical image quality. We demonstrate its potential application through a series of images under a constant illumination signal. Here, the mean image of enough images was regarded as the reference image. Several groups of images by different frame accumulation and their MSNR were calculated. The results of the experiment show that, compared with other quality assessment methods, the metric is simpler, more effective, and more suitable for assessing frame accumulated images that surpass the gray scale and precision of the original image. PMID- 29390712 TI - An electron beam linear scanning mode for industrial limited-angle nano-computed tomography. AB - Nano-computed tomography (nano-CT), which utilizes X-rays to research the inner structure of some small objects and has been widely utilized in biomedical research, electronic technology, geology, material sciences, etc., is a high spatial resolution and non-destructive research technique. A traditional nano-CT scanning model with a very high mechanical precision and stability of object manipulator, which is difficult to reach when the scanned object is continuously rotated, is required for high resolution imaging. To reduce the scanning time and attain a stable and high resolution imaging in industrial non-destructive testing, we study an electron beam linear scanning mode of nano-CT system that can avoid mechanical vibration and object movement caused by the continuously rotated object. Furthermore, to further save the scanning time and study how small the scanning range could be considered with acceptable spatial resolution, an alternating iterative algorithm based on l0 minimization is utilized to limited-angle nano-CT reconstruction problem with the electron beam linear scanning mode. The experimental results confirm the feasibility of the electron beam linear scanning mode of nano-CT system. PMID- 29390713 TI - Real-time and high accuracy frequency measurements for intermediate frequency narrowband signals. AB - Real-time and accurate measurements of intermediate frequency signals based on microprocessors are difficult due to the computational complexity and limited time constraints. In this paper, a fast and precise methodology based on the sigma-delta modulator is designed and implemented by first generating the twiddle factors using the designed recursive scheme. This scheme requires zero times of multiplications and only half amounts of addition operations by using the discrete Fourier transform (DFT) and the combination of the Rife algorithm and Fourier coefficient interpolation as compared with conventional methods such as DFT and Fast Fourier Transform. Experimentally, when the sampling frequency is 10 MHz, the real-time frequency measurements with intermediate frequency and narrowband signals have a measurement mean squared error of +/-2.4 Hz. Furthermore, a single measurement of the whole system only requires approximately 0.3 s to achieve fast iteration, high precision, and less calculation time. PMID- 29390714 TI - An apparatus for generation and quantitative measurement of homogeneous isotropic turbulence in He ii. AB - The superfluid phase of helium-4, known as He ii, exhibits extremely small kinematic viscosity and may be a useful tool for economically producing and studying high Reynolds number turbulent flow. Such applications are not currently possible because a comprehensive understanding of the complex two-fluid behavior of He ii is lacking. This situation could be remedied by a systematic investigation of simple, well controlled turbulence that can be directly compared with theoretical models. To this end, we have developed a new apparatus that combines flow visualization with second sound attenuation to study turbulence in the wake of a mesh grid towed through a He ii filled channel. One of three mesh grids (mesh number M = 3, 3.75, or 5 mm) can be pulled at speeds between 0.1 and 60 cm/s through a cast acrylic flow channel which has a 16 mm * 16 mm cross section and measures 330 mm long. The motion of solidified deuterium tracer particles, with diameter of the order 1 MUm, in the resulting flow is captured by a high speed camera, and a particle tracking velocimetry algorithm resolves the Lagrangian particle trajectories through the turbulent flow field. A pair of oscillating superleak second sound transducers installed in the channel allows complementary measurement of vortex line density in the superfluid throughout the turbulent decay process. Success in early experiments demonstrates the effectiveness of both probes, and preliminary analysis of the data shows that both measurements strongly correlate with each other. Further investigations will provide comprehensive information that can be used to address open questions about turbulence in He ii and move toward the application of this fluid to high Reynolds number fluid research. PMID- 29390715 TI - General-purpose readout electronics for white neutron source at China Spallation Neutron Source. AB - The under-construction White Neutron Source (WNS) at China Spallation Neutron Source is a facility for accurate measurements of neutron-induced cross section. Seven spectrometers are planned at WNS. As the physical objectives of each spectrometer are different, the requirements for readout electronics are not the same. In order to simplify the development of the readout electronics, this paper presents a general method for detector signal readout. This method has advantages of expansibility and flexibility, which makes it adaptable to most detectors at WNS. In the WNS general-purpose readout electronics, signals from any kinds of detectors are conditioned by a dedicated signal conditioning module corresponding to this detector, and then digitized by a common waveform digitizer with high speed and high precision (1 GSPS at 12-bit) to obtain the full waveform data. The waveform digitizer uses a field programmable gate array chip to process the data stream and trigger information in real time. PXI Express platform is used to support the functionalities of data readout, clock distribution, and trigger information exchange between digitizers and trigger modules. Test results show that the performance of the WNS general-purpose readout electronics can meet the requirements of the WNS spectrometers. PMID- 29390716 TI - Characterization of a commercial software defined radio as high frequency lock-in amplifier for FM spectroscopy. AB - A commercial software defined radio based on a Rafael Micro R820T2 tuner is characterized for the use as a high-frequency lock-in amplifier for frequency modulation spectroscopy. The sensitivity limit of the receiver is 1.6 nV/Hz. Frequency modulation spectroscopy is demonstrated on the 6406.69 cm-1 absorption line of carbon monoxide. PMID- 29390717 TI - Note: Contrast enhancement and artifact suppression in computed tomography using sinogram normalization. AB - The intensity and direction of the incident beam at the sample position in synchrotron full-field transmission X-ray microscopy is subject to change. Incident-beam fluctuation in computed tomography results in significant contrast degradation of the reconstructed image. In the present study, we devised a simple method by which that problem could be corrected using sinogram normalization. According to our results, the image contrast was improved by 13%, and the artifacts were suppressed. PMID- 29390718 TI - First results of the multi-purpose real-time processing video camera system on the Wendelstein 7-X stellarator and implications for future devices. AB - A special video camera has been developed for the 10-camera overview video system of the Wendelstein 7-X (W7-X) stellarator considering multiple application needs and limitations resulting from this complex long-pulse superconducting stellarator experiment. The event detection intelligent camera (EDICAM) uses a special 1.3 Mpixel CMOS sensor with non-destructive read capability which enables fast monitoring of smaller Regions of Interest (ROIs) even during long exposures. The camera can perform simple data evaluation algorithms (minimum/maximum, mean comparison to levels) on the ROI data which can dynamically change the readout process and generate output signals. Multiple EDICAM cameras were operated in the first campaign of W7-X and capabilities were explored in the real environment. Data prove that the camera can be used for taking long exposure (10-100 ms) overview images of the plasma while sub-ms monitoring and even multi-camera correlated edge plasma turbulence measurements of smaller areas can be done in parallel. These latter revealed that filamentary turbulence structures extend between neighboring modules of the stellarator. Considerations emerging for future upgrades of this system and similar setups on future long-pulse fusion experiments such as ITER are discussed. PMID- 29390719 TI - A sample holder for simultaneous Raman and neutron vibrational spectroscopy. AB - We have built a sample holder (called a center stick or sample stick) for performing simultaneous Raman and neutron vibrational spectroscopy on samples of material at the VISION neutron vibrational spectrometer of the Spallation Neutron Source at Oak Ridge National Laboratory. This equipment holds material samples in the neutron beam within the cryogenic environment of the VISION spectrometer, allowing for samples to be studied at temperatures as low as 5 K. It also provides the capability for gas to be loaded to or evacuated from the sample while it is loaded at VISION. The optical components for directing and filtering light are located within the cryogenic volume, in physical proximity to the sample. We describe the construction of this sample holder and discuss our first measurements of simultaneous Raman and neutron vibrational spectra. The samples that we report on were of 4-nitrophenol at a temperature of 20 K and of cryogenic hydrogen of a number of different orthohydrogen fractions. PMID- 29390720 TI - High resolution Thomson scattering system for steady-state linear plasma sources. AB - The high resolution Thomson scattering system with 63 points along a 25 mm line measures the radial electron temperature (Te) and its density (ne) in an argon plasma. By using a DC arc source with lanthanum hexaboride (LaB6) electrode, plasmas with electron temperature of over 5 eV and densities of 1.5 * 1019 m-3 have been measured. The system uses a frequency doubled (532 nm) Nd:YAG laser with 0.25 J/pulse at 20 Hz. The scattered light is collected and sent to a triple grating spectrometer via optical-fibers, where images are recorded by an intensified charge coupled device (ICCD) camera. Although excellent in stray light reduction, a disadvantage comes with its relatively low optical transmission and in sampling a tiny scattering volume. Thus requires accumulating multitude of images. In order to improve photon statistics, pixel binning in the ICCD camera as well as enlarging the intermediate slit-width inside the triple grating spectrometer has been exploited. In addition, the ICCD camera capture images at 40 Hz while the laser is at 20 Hz. This operation mode allows us to alternate between background and scattering shot images. By image subtraction, influences from the plasma background are effectively taken out. Maximum likelihood estimation that uses a parameter sweep finds best fitting parameters Te and ne with the incoherent scattering spectrum. PMID- 29390721 TI - Modular portable unit for thermal conductivity measurements in multiple cryogenic/magnetic field environments. AB - A modular design for a miniature thermal conductivity cell suitable for a dilution refrigerator and other sample-in-vacuum cryogenic environments with different magnet options is described. The sample is mounted once and the contacts remain in place when the unit is repositioned or transported between different magnets and cryostats. This mobility enables comprehensive measurements with access to specific options, such as vector magnet in one lab and ultra-high field in another. This design enables significant expansion of the temperature range by using not only dilution refrigerators but also 3He, 4He cryostats and even ubiquitous Quantum Design Physical Property Measurement System. PMID- 29390722 TI - A mini-photofragment translational spectrometer with ion velocity map imaging using low voltage acceleration. AB - A mini time-sliced ion velocity map imaging photofragment translational spectrometer using low voltage acceleration has been constructed. The innovation of this apparatus adopts a relative low voltage (30-150 V) to substitute the traditional high voltage (650-4000 V) to accelerate and focus the fragment ions. The overall length of the flight path is merely 12 cm. There are many advantages for this instrument, such as compact structure, less interference, and easy to operate and control. Low voltage acceleration gives a longer turn-around time to the photofragment ions forming a thicker Newton sphere, which provides sufficient time for slicing. Ion trajectory simulation has been performed for determining the structure dimensions and the operating voltages. The photodissociation and multiphoton ionization of O2 at 224.999 nm is used to calibrate the ion images and examine the overall performance of the new spectrometer. The velocity resolution (Deltanu/nu) of this spectrometer from O2 photodissociation is about 0.8%, which is better than most previous results using high acceleration voltage. For the case of CF3I dissociation at 277.38 nm, many CF3 vibrational states have been resolved, and the anisotropy parameter has been measured. The application of low voltage acceleration has shown its advantages on the ion velocity map imaging (VMI) apparatus. The miniaturization of the VMI instruments can be realized on the premise of high resolution. PMID- 29390723 TI - A velocity map imaging mass spectrometer for photofragments of fast ion beams. AB - We present the details of a fast ion velocity map imaging mass spectrometer that is capable of imaging the photofragments of trap-cooled (>=7 K) ions produced in a versatile ion source. The new instrument has been used to study the predissociation of N2O+ produced by electric discharge and the direct dissociation of Al2+ formed by laser ablation. The instrument's resolution is currently limited by the diameter of the collimating iris to a value of Deltav/v = 7.6%. Photofragment images of N2O+ show that when the predissociative state is changed from 2Sigma+(200) to 2Sigma+(300) the dominant product channel shifts from a spin-forbidden ground state, N (4S) + NO+(v = 5), to a spin-allowed pathway, N*(2D) + NO+. The first photofragment images of Al2+ confirm the existence of a directly dissociative parallel transition (2Sigma+u <- 2Sigma+g) that yields products with a large amount of kinetic energy. D0 of ground state Al2+ (2Sigma+g) measured from these images is 138 +/- 5 kJ/mol, which is consistent with the published literature. PMID- 29390724 TI - Super-Alfvenic translation of a field-reversed configuration into a large-bore dielectric chamber. AB - An experimental device to demonstrate additional heating and control methods for a field-reversed configuration (FRC) has been developed. The newly developed device, named FRC Amplification via Translation (FAT), has a field-reversed theta pinch plasma source and a low-elongation dielectric (transparent quartz) confinement chamber with quasi-static confinement field. In the initial experiments on the FAT device, FRC translation and trapping were successfully demonstrated. Although the typical elongation of the trapped FRC in the confinement region was roughly three, no disruptive global instability, such as tilt, was observed. The FAT device increases the latitude to perform translation related experiments, such as those concerning inductive current drive, equivalent neutral beam injection effects, and wave applications. PMID- 29390725 TI - Web-based interactive drone control using hand gesture. AB - This paper develops a drone control prototype based on web technology with the aid of hand gesture. The uplink control command and downlink data (e.g., video) are transmitted by WiFi communication, and all the information exchange is realized on web. The control command is translated from various predetermined hand gestures. Specifically, the hardware of this friendly interactive control system is composed by a quadrotor drone, a computer vision-based hand gesture sensor, and a cost-effective computer. The software is simplified as a web-based user interface program. Aided by natural hand gestures, this system significantly reduces the complexity of traditional human-computer interaction, making remote drone operation more intuitive. Meanwhile, a web-based automatic control mode is provided in addition to the hand gesture control mode. For both operation modes, no extra application program is needed to be installed on the computer. Experimental results demonstrate the effectiveness and efficiency of the proposed system, including control accuracy, operation latency, etc. This system can be used in many applications such as controlling a drone in global positioning system denied environment or by handlers without professional drone control knowledge since it is easy to get started. PMID- 29390726 TI - Note: An approach to 1000 T using the electro-magnetic flux compression. AB - The maximum magnetic field obtained by the electro-magnetic flux compression technique was investigated with respect to the initial seed magnetic field. It was found that the reduction in the seed magnetic field from 3.8 T to 3.0 T led to a substantial increase in the final peak magnetic field. The optical Faraday rotation method with a minimal size probe evades disturbances from electromagnetic noise and shockwave effects to detect such final peak fields in a reduced space of an inner wall of the imploding liner. The Faraday rotation signal recorded the maximum magnetic field increased significantly to the highest magnetic field of 985 T approaching 1000 T, ever achieved by the electro-magnetic flux compression technique as an indoor experiment. PMID- 29390727 TI - EUV polarimetry for thin film and surface characterization and EUV phase retarder reflector development. AB - The knowledge and the manipulation of light polarization state in the vacuum ultraviolet and extreme ultraviolet (EUV) spectral regions play a crucial role from materials science analysis to optical component improvements. In this paper, we present an EUV spectroscopic ellipsometer facility for polarimetry in the 90 160 nm spectral range. A single layer aluminum mirror to be used as a quarter wave retarder has been fully characterized by deriving the optical and structural properties from the amplitude component and phase difference delta measurements. The system can be suitable to investigate the properties of thin films and optical coatings and optics in the EUV region. PMID- 29390728 TI - Spatially resolved single crystal x-ray spectropolarimetry of wire array z-pinch plasmas. AB - A recently developed single-crystal x-ray spectropolarimeter has been used to record paired sets of polarization-dependent and axially resolved x-ray spectra emitted by wire array z-pinches. In this measurement, two internal planes inside a suitable crystal diffract the x-rays into two perpendicular directions that are normal to each other, thereby separating incident x-rays into their linearly polarized components. This paper gives considerations for fielding the instrument on extended sources. Results from extended sources are difficult to interpret because generally the incident x-rays are not separated properly by the crystal. This difficulty is mitigated by using a series of collimating slits to select incident x-rays that propagate in a plane of symmetry between the polarization splitting planes. The resulting instrument and some of the spatially resolved polarized x-ray spectra recorded for a 1-MA aluminum wire array z-pinch at the Nevada Terawatt Facility at the University of Nevada, Reno will be presented. PMID- 29390729 TI - Note: Improvement of the 3omega thermal conductivity measurement technique for its application at the nanoscale. AB - Conventional techniques for thermal conductivity measurements can lead to unreliable results when applied to nanostructures because heaters and temperature sensors needed for the measurement cannot have a negligible size and therefore perturb the result. In this paper, we focus on the 3omega technique, applied to the evaluation of the thermal conductivity of suspended silicon nanoribbons. We introduce a numerical approach based on the finite element solution of the electrical and thermal transport equations and compare its results with those of conventional methods. We show that with our approach we achieve an excellent fit of the experimental data, in particular, for nanostructured materials. PMID- 29390730 TI - Paradigmatic variation of vowels in expressive speech: Acoustic description and dimensional analysis. AB - Acoustic variation in expressive speech at the syllable level is studied. As emotions or attitudes can be conveyed by short spoken words, analysis of paradigmatic variations in vowels is an important issue to characterize the expressive content of such speech segments. The corpus contains 160 sentences produced under seven expressive conditions (Neutral, Anger, Fear, Surprise, Sensuality, Joy, Sadness) acted by a French female speaker (a total of 1120 sentences, 13 140 vowels). Eleven base acoustic parameters are selected for voice source and vocal tract related feature analysis. An acoustic description of the expressions is drawn, using the dimensions of melodic range, intensity, noise, spectral tilt, vocalic space, and dynamic features. The first three functions of a discriminant analysis explain 95% of the variance in the data. These statistical dimensions are consistently associated with acoustic dimensions. Covariation of intensity and F0 explains over 80% of the variance, followed by noise features (8%), covariation of spectral tilt, and F0 (7%). On the basis of isolated vowels alone, expressions are classified with a mean accuracy of 78%. PMID- 29390731 TI - Dependence of the subharmonic signal from contrast agent microbubbles on ambient pressure: A theoretical analysis. AB - This paper investigates the dependence of the subharmonic response in a signal scattered by contrast agent microbubbles on ambient pressure to provide quantitative estimations of local blood pressure. The problem is formulated by assuming a gas bubble encapsulated by a shell of finite thickness with dynamic behavior modeled by a nonlinear viscoelastic constitutive equation. For ambient overpressure compatible with the clinical range, the acoustic pressure intervals where the subharmonic signal may be detected (above the threshold for the onset and below the limit value for the first chaotic transition) are determined. The analysis shows that as the overpressure is increased, all harmonic components are displaced to higher frequencies. This displacement is significant for the subharmonic of order 1/2 and explains the increase or decrease in the subharmonic amplitude with ambient pressure described in previous works. Thus, some questions related to the monotonic dependence of the subharmonic amplitude on ambient pressure are clarified. For different acoustic pressures, quantitative conditions for determining the intervals where the subharmonic amplitude is a monotonic or non-monotonic function of the ambient pressure are provided. Finally, the influence of the ambient pressure on the subharmonic resonance frequency is analyzed. PMID- 29390732 TI - Comments on "Killer whale (Orcinus orca) behavioral audiograms" [J. Acoust. Soc. Am. 141, 2387-2398 (2017)]. AB - Branstetter and his colleagues present the audiograms of eight killer whales and provide a comprehensive review of previous killer whale audiograms. In their paper, they say that the present authors have reported a relationship between size and high-frequency hearing but that echolocating cetaceans might be a special case. The purpose of these comments is to clarify that the relationship of a species' high-frequency hearing is not to its size (mass) but to its "functional interaural distance" (a measure of the availability of sound localization cues). Moreover, it has previously been noted that echolocating animals, cetaceans as well as bats, have extended their high-frequency hearing somewhat beyond the frequencies used by comparable non-echolocators for passive localization. PMID- 29390733 TI - Semi-analytical discontinuous Galerkin finite element method for the calculation of dispersion properties of guided waves in plates. AB - The development of reliable guided waves inspection systems is conditioned by an accurate knowledge of their dispersive properties. The semi-analytical finite element method has been proven to be very practical for modeling wave propagation in arbitrary cross-section waveguides. However, when it comes to computations on complex geometries to a given accuracy, it still has a major drawback: the high consumption of resources. Recently, discontinuous Galerkin finite element method (DG-FEM) has been found advantageous over the standard finite element method when applied as well in the frequency domain. In this work, a high-order method for the computation of Lamb mode characteristics in plates is proposed. The problem is discretised using a class of DG-FEM, namely, the interior penalty methods family. The analytical validation is performed through the homogeneous isotropic case with traction-free boundary conditions. Afterwards, functionally graded material plates are analysed and a numerical example is presented. It was found that the obtained results are in good agreement with those found in the literature. PMID- 29390735 TI - Training candidate selection for effective out-of-set rejection in robust open set language identification. AB - Research in open-set language identification (LID) generally focuses on in-set language modeling versus out-of-set (OOS) language rejection. However, unknown/OOS language rejection is essential for effective speech and language pre processing. To address this, an approach for OOS language selection is proposed. Using probe OOS data, three effective OOS candidate selection methods are developed for universal OOS language coverage. The selected OOS candidates are expected to reflect the entire OOS language space for the state-of-the-art i vector LID system followed by a Gaussian back-end. Two front-end feature selection strategies are proposed: (i) unsupervised k-means clustering and (ii) complementary candidate selection. Also, (iii) general candidate selection is proposed according to language relationship explored at the score level. All methods are evaluated on a large-scale corpus (LRE-09) containing 40 languages. The proposed selection methods reduce OOS training data diversity by 86% while achieving performance similar to closed-set using all probe OOS for training. The proposed methods also show clear benefits versus random candidate selection (i.e., the proposed solutions achieve sustained performance while employing a minimum number of effective OOS language candidates). To the best of our knowledge, this is the first major effort on effective OOS language selection and enhancement for improved OOS rejection in open-set LID. PMID- 29390734 TI - Swept-tone stimulus-frequency otoacoustic emissions: Normative data and methodological considerations. AB - Stimulus-frequency otoacoustic emissions (SFOAEs) are reflection-source emissions, and are the least familiar and perhaps most underutilized otoacoustic emission. Here, normative SFOAE data are presented from a large group of 48 young adults at probe levels from 20 to 60 dB sound pressure level (SPL) across a four octave frequency range to characterize the typical SFOAE and describe recent methodological advances that have made its measurement more efficient. In young adult ears, SFOAE levels peaked in the low-to-mid frequencies at mean levels of ~6-7 dB SPL while signal-to-noise ranged from 23 to 34 dB SPL and test-retest reliability was +/-4 dB for 90% of the SFOAE data. On average, females had ~2.5 dB higher SFOAE levels than males. SFOAE input/output functions showed near linear growth at low levels and a compression threshold averaging 35 dB SPL across frequency. SFOAE phase accumulated ~32-36 cycles across four octaves on average, and showed level effects when converted to group delay: low-level probes produced longer SFOAE delays. A "break" in the normalized SFOAE delay was observed at 1.1 kHz on average, elucidating the location of the putative apical basal transition. Technical innovations such as the concurrent sweeping of multiple frequency segments, post hoc suppressor decontamination, and a post hoc artifact-rejection technique were tested. PMID- 29390736 TI - Effects of vibratory pile driver noise on echolocation and vigilance in bottlenose dolphins (Tursiops truncatus). AB - Vibratory pile drivers, used for marine construction, can produce sustained, high sound pressure levels (SPLs) in areas that overlap with dolphin habitats. Dolphins rely on echolocation for navigation, detecting predators and prey, and to coordinate group behavior. This study examined the effects of vibratory pile driver noise on dolphin sustained target detection capabilities through echolocation. Five dolphins were required to scan their enclosure and indicate the occurrences of phantom echoes during five different source levels of vibratory pile driver playback sound (no-playback control, 110, 120, 130, and 140 dB re 1 MUPa). Three of the dolphins demonstrated a significant decrease in target detection performance at 140 dB playback level that was associated with an almost complete secession of echolocation activity. The performance of two dolphins was not affected. All dolphins rapidly returned to baseline levels of target detection performance by their second replication. However, an increased number of clicks was produced at the highest playback SPL. The data suggest that the decrease in vigilant behavior was due to the vibratory pile driver noise distracting the dolphins and decreasing their motivation to perform the task. PMID- 29390737 TI - An investigation of infrasound propagation over mountain ranges. AB - Linear theory is used to analyze trapping of infrasound within the lower tropospheric waveguide during propagation above a mountain range. Atmospheric flow produced by the mountains is predicted by a nonlinear mountain gravity wave model. For the infrasound component, this paper solves the wave equation under the effective sound speed approximation using both a finite difference method and a Wentzel-Kramers-Brillouin approach. It is shown that in realistic configurations, the mountain waves can deeply perturb the low-level waveguide, which leads to significant acoustic dispersion. To interpret these results, each acoustic mode is tracked separately as the horizontal distance increases. It is shown that during statically stable situations, situations that are common during night over land in winter, the mountain waves induce a strong Foehn effect downstream, which shrinks the waveguide significantly. This yields a new form of infrasound absorption that can largely outweigh the direct effect the mountain induces on the low-level waveguide. For the opposite case, when the low-level flow is less statically stable (situations that are more common during day in summer), mountain wave dynamics do not produce dramatic responses downstream. It may even favor the passage of infrasound and mitigate the direct effect of the obstacle. PMID- 29390738 TI - How does the perceptual organization of a multi-tone mixture interact with partial and global loudness judgments? AB - Two experiments were conducted to investigate how the perceptual organization of a multi-tone mixture interacts with global and partial loudness judgments. Grouping (single-object) and segregating (two-object) conditions were created using frequency modulation by applying the same or different modulation frequencies to the odd- and even-rank harmonics. While in Experiment 1 (Exp. 1) the two objects had the same loudness, in Experiment 2 (Exp. 2), loudness level differences (LLD) were introduced (LLD = 6, 12, 18, or 24 phons). In the two object condition, the loudness of each object was not affected by the mixture when LLD = 0 (Exp. 1), otherwise (Exp. 2), the loudness of the softest object was modulated by LLD, and the loudness of the loudest object was the same regardless of whether it was presented in or out of the mixture. In the single- and the two object conditions, the global loudness of the mixture was close to the loudness of the loudest object. Taken together, these results suggest that while partial loudness judgments are dependent on the perceptual organization of the scene, global loudness is not. Yet, both partial and global loudness computations are governed by relative "saliences" between different auditory objects (in the segregating condition) or within a single object (in the grouping condition). PMID- 29390739 TI - Ultrasonic defect characterisation-Use of amplitude, phase, and frequency information. AB - This paper studies ultrasonic defect characterisation with the aim of reducing the characterisation uncertainty. Ultrasonic array data contain a mixture of responses from all reflecting features, and the scattering matrix for each defect can be extracted in post-processing, which describes how ultrasonic waves at a given incident angle are scattered by a defect. In this paper, it is shown that defect characterisation performance can be improved by the inclusion of phase and frequency information relative to current single-frequency-amplitude approaches. This superior characterisation performance is due to the increased number of informative principal components (PCs) and higher signal-to-noise ratios in the PC directions. Scattering matrix phase measurement is very sensitive to localisation errors, and an effective approach is proposed, which can be used to reliably extract phase from experimental data. Nine elliptical defects having different aspect ratios and orientation angles are characterised experimentally. The complex multi-frequency defect database has achieved up to 90.60% reduction in the quantified sizing uncertainty compared to the results obtained using only the amplitude at a single frequency. PMID- 29390740 TI - Seismoelectric interface electromagnetic wave characteristics for the finite offset Vertical Seismoelectric Profiling configuration: Theoretical modeling and experiment verification. AB - The seismoelectric interface electromagnetic characteristics have been studied for the finite offset Vertical Seismoelectric Profiling (VSEP) configuration. The approach consists of theoretical modeling and laboratory verification. The results show that the wave variation characteristics along the finite offset measurement line are markedly different from those along the zero-offset line. More interestingly, the wave characteristics for both configurations can be satisfactorily explained by the electric dipole model for the seismoelectric interface wave radiation. Besides, the experiment confirms the modeling result based on the seismoelectric coupling theory and validates the VSEP technique as an effective method for subsurface interface delineation. PMID- 29390742 TI - Comment on "Temporal and spatial variation in harbor seal (Phoca vitulina L.) roar calls from southern Scandinavia" [J. Acoust. Soc. Am. 141, 1824-1834 (2017)]. AB - In their recent article, Sabinsky and colleagues investigated heterogeneity in harbor seals' vocalizations. The authors found seasonal and geographical variation in acoustic parameters, warning readers that recording conditions might account for some of their results. This paper expands on the temporal aspect of the encountered heterogeneity in harbor seals' vocalizations. Temporal information is the least susceptible to variable recording conditions. Hence geographical and seasonal variability in roar timing constitutes the most robust finding in the target article. In pinnipeds, evidence of timing and rhythm in the millisecond range-as opposed to circadian and seasonal rhythms-has theoretical and interdisciplinary relevance. In fact, the study of rhythm and timing in harbor seals is particularly decisive to support or confute a cross-species hypothesis, causally linking the evolution of vocal production learning and rhythm. The results by Sabinsky and colleagues can shed light on current scientific questions beyond pinniped bioacoustics, and help formulate empirically testable predictions. PMID- 29390744 TI - Acoustic nonreciprocity in Coriolis mean flow systems. AB - One way to break acoustic reciprocity is to have a moving wave propagation medium. If the acoustic wave vector and the moving fluid velocity are collinear, the wave vector shift caused by the fluid flow can be used to break. In this paper, an alternative approach is investigated in which the fluid velocity enters the differential equation of the system as a cross product term with the wave vector. A circular field where the fluid velocity increases radially has a Coriolis acceleration term. In such a system, the acoustic wave enters from the central wall and exits from the perimeter wall. In this paper, the differential equation is solved numerically and the effect of fluid velocity on the nonreciprocity factor is examined. PMID- 29390743 TI - Auditory stream segregation of iterated rippled noises by normal-hearing and hearing-impaired listeners. AB - Individuals with hearing loss are thought to be less sensitive to the often subtle variations of acoustic information that support auditory stream segregation. Perceptual segregation can be influenced by differences in both the spectral and temporal characteristics of interleaved stimuli. The purpose of this study was to determine what stimulus characteristics support sequential stream segregation by normal-hearing and hearing-impaired listeners. Iterated rippled noises (IRNs) were used to assess the effects of tonality, spectral resolvability, and hearing loss on the perception of auditory streams in two pitch regions, corresponding to 250 and 1000 Hz. Overall, listeners with hearing loss were significantly less likely to segregate alternating IRNs into two auditory streams than were normally hearing listeners. Low pitched IRNs were generally less likely to segregate into two streams than were higher pitched IRNs. High-pass filtering was a strong contributor to reduced segregation for both groups. The tonality, or pitch strength, of the IRNs had a significant effect on streaming, but the effect was similar for both groups of subjects. These data demonstrate that stream segregation is influenced by many factors including pitch differences, pitch region, spectral resolution, and degree of stimulus tonality, in addition to the loss of auditory sensitivity. PMID- 29390745 TI - Underwater noise from pile driving of conductor casing at a deep-water oil platform. AB - Underwater noise from impact pile driving of 512 -m-long conductor casings was measured at a deep-water offshore oil platform in the Santa Barbara Channel. Beamforming measurements, obtained with a vertical array, confirmed that the primary wave front generated by hammering the conductor casing was a Mach cone propagating at an angle of 17.6 degrees below the horizontal. Analysis of the processed array data also revealed the presence of high-frequency secondary waves at angles steeper than 45 degrees below the horizontal. These secondary waves, which appeared to be generated near the sea-surface, dominated the acoustic spectrum of the pulses at frequencies above 1 kHz. Shallow hydrophone measurements outside the Mach cone showed clear evidence of a surface shadow zone, which was caused by the strong downward directivity of the source. Although reflected waves, diffraction, and secondary waves still produced sound inside the surface shadow zone, sound levels were 10-15 dB lower in this region. Long-term hydrophone measurements showed that there was little difference (+/-1 dB) in mean sound levels from impact hammering of different conductors installed at the same platform over three months. PMID- 29390746 TI - Stability-controlled hybrid adaptive feedback cancellation scheme for hearing aids. AB - Adaptive feedback cancellation (AFC) techniques are common in modern hearing aid devices (HADs) since these techniques have been successful in increasing the stable gain. Accordingly, there has been a significant effort to improve AFC technology, especially for open-fitting and in-ear HADs, for which howling is more prevalent due to the large acoustic coupling between the loudspeaker and the microphone. In this paper, the authors propose a hybrid AFC (H-AFC) scheme that is able to shorten the time it takes to recover from howling. The proposed H-AFC scheme consists of a switched combination adaptive filter, which is controlled by a soft-clipping-based stability detector to select either the standard normalized least mean squares (NLMS) algorithm or the prediction-error-method (PEM) NLMS algorithm to update the adaptive filter. The standard NLMS algorithm is used to obtain fast convergence, while the PEM-NLMS algorithm is used to provide a low bias solution. This stability-controlled adaptation is hence the means to improve performance in terms of both convergence rate as well as misalignment, while only slightly increasing computational complexity. The proposed H-AFC scheme has been evaluated for both speech and music signals, resulting in a significantly improved convergence and re-convergence rate, i.e., a shorter howling period, as well as a lower average misalignment and a larger added stable gain compared to using either the NLMS or the PEM-NLMS algorithm alone. An objective evaluation using the perceptual evaluation of speech quality and the perceptual evaluation of audio quality measures shows that the proposed H-AFC scheme provides very high quality speech and music signals. This has also been verified through a subjective listening experiment with N = 15 normal-hearing subjects using a multi stimulus test with hidden reference and anchor, showing that the proposed H-AFC scheme results in a better perceptual quality than the state-of-the-art PEM-NLMS algorithm. PMID- 29390747 TI - The importance of particle motion to fishes and invertebrates. AB - This paper considers the importance of particle motion to fishes and invertebrates and the steps that need to be taken to improve knowledge of its effects. It is aimed at scientists investigating the impacts of sounds on fishes and invertebrates but it is also relevant to regulators, those preparing environmental impact assessments, and to industries creating underwater sounds. The overall aim of this paper is to ensure that proper attention is paid to particle motion as a stimulus when evaluating the effects of sound upon aquatic life. Directions are suggested for future research and planning that, if implemented, will provide a better scientific basis for dealing with the impact of underwater sounds on marine ecosystems and for regulating those human activities that generate such sounds. The paper includes background material on underwater acoustics, focusing on particle motion; the importance of particle motion to fishes and invertebrates; and sound propagation through both water and the substrate. Consideration is then given to the data gaps that must be filled in order to better understand the interactions between particle motion and aquatic animals. Finally, suggestions are provided on how to increase the understanding of particle motion and its relevance to aquatic animals. PMID- 29390748 TI - Acoustofluidic particle dynamics: Beyond the Rayleigh limit. AB - In this work a numerical model to calculate the trajectories of multiple acoustically and hydrodynamically interacting spherical particles is presented. The acoustic forces are calculated by solving the fully coupled three-dimensional scattering problem using finite element software. The method is not restricted to single re-scattering events, mono- and dipole radiation, and long wavelengths with respect to the particle diameter, thus expanding current models. High frequency surface acoustic waves have been used in the one cell per well technology to focus individual cells in a two-dimensional wave-field. Sometimes the cells started forming clumps and it was not possible to focus on individual cells. Due to a lack of existing theory, this could not be fully investigated. Here, the authors use the full dynamic simulations to identify limiting factors of the one-cell-per-well technology. At first, the authors demonstrate good agreement of the numerical model with analytical results in the Rayleigh limiting case. A frequency dependent stability exchange between the pressure and velocity was then demonstrated. The numerical formulation presented in this work is relatively general and can be used for a multitude of different high frequency applications. It is a powerful tool in the analysis of microscale acoustofluidic devices and processes. PMID- 29390749 TI - Phonological feature-based speech recognition system for pronunciation training in non-native language learning. AB - The authors address the question whether phonological features can be used effectively in an automatic speech recognition (ASR) system for pronunciation training in non-native language (L2) learning. Computer-aided pronunciation training consists of two essential tasks-detecting mispronunciations and providing corrective feedback, usually either on the basis of full words or phonemes. Phonemes, however, can be further disassembled into phonological features, which in turn define groups of phonemes. A phonological feature-based ASR system allows the authors to perform a sub-phonemic analysis at feature level, providing a more effective feedback to reach the acoustic goal and perceptual constancy. Furthermore, phonological features provide a structured way for analysing the types of errors a learner makes, and can readily convey which pronunciations need improvement. This paper presents the authors implementation of such an ASR system using deep neural networks as an acoustic model, and its use for detecting mispronunciations, analysing errors, and rendering corrective feedback. Quantitative as well as qualitative evaluations are carried out for German and Italian learners of English. In addition to achieving high accuracy of mispronunciation detection, the system also provides accurate diagnosis of errors. PMID- 29390750 TI - Striation-based source depth estimation with a vertical line array in the deep ocean. AB - A striation-based method with a vertical line array is proposed for source depth estimation. Broadband striation structures of direct and surface-reflected arrivals after propagating to receivers near the ocean bottom are applied. A tracking algorithm for the striation structures is proposed based on the extended Kalman filter. A cost function for source depth estimation is presented by matching the traces of the measured striations with a library of model-based traces under different source depths. The method is demonstrated on array data collected during an acoustic research experiment in the South China Sea in 2016. PMID- 29390751 TI - Binaural detection of a Gaussian noise target in the presence of a lead/lag masker. AB - Masked detection thresholds were measured for a noise target in the presence of a masker composed of (1) a lead/lag noise pair with the lead interaural time difference (ITD) set the same or opposite to the target, (2) a diotic masker, and (3) a dichotic pair of decorrelated noises. If the precedence effect actually eliminates a second, later arriving stimulus, a spatial release from masking would be expected when the lead ITD is opposite that of the target. Results for a range of lead/lag delays suggest that the precedence effect is not the result of a perceptual removal of the lag. PMID- 29390752 TI - Variability of phase and amplitude fronts due to horizontal refraction in shallow water. AB - The variability of the interference pattern of a narrow-band sound signal in a shallow water waveguide in the horizontal plane in the presence of horizontal stratification, in particular due to linear internal waves, is studied. It is shown that lines of constant phase (a phase front) and lines of constant amplitude/envelope (an amplitude front) for each waveguide mode may have different directions in the spatial vicinity of the point of reception. The angle between them depends on the waveguide's parameters, the mode number, and the sound frequency. Theoretical estimates and data processing methodology for obtaining these angles from experimental data recorded by a horizontal line array are proposed. The behavior of the angles, which are obtained for two episodes from the Shallow Water 2006 (SW06) experiment, show agreement with the theory presented. PMID- 29390753 TI - Erratum: Oestreicher and elastography [J. Acoust. Soc. Am. 138, 2317-2325 (2015)]. PMID- 29390754 TI - Acoustic radiation force on a parametrically distorted bubble. AB - The subject of acoustic radiation pressure on a gas bubble is important in many applications because it controls how bubbles are moved by acoustic fields to target locations, and often how they act upon the target. Previous theoretical treatments assume a spherical bubble undergoing linear pulsations, but some (such as cleaning using Faraday waves on the bubble wall) require that the bubble be aspherical. Therefore, this paper derives ways to calculate the variation in the radiation pressure due to the non-spherical bubble oscillations. The magnitude and direction of the radiation force are determined by two factors: the amplitude of volume oscillations, Vm, and the phase relationship between those oscillations and the acoustic field which drives them. There are two key findings that correct for the predictions of a model accounting for only linear pulsations. First, the growth of the radiation force slows down as Vm ceases to increase linearly with increasing amplitude of the acoustic wave above the threshold. Second, although both models show that the direction of the force relative of the standing wave antinode can be attractive or repulsive depending on frequency, when distortion modes are included the frequency at which this force changes its sign is shifted. PMID- 29390755 TI - Bayesian inference of elastic properties with resonant ultrasound spectroscopy. AB - Bayesian modeling and Hamiltonian Monte Carlo (HMC) are utilized to formulate a robust algorithm capable of simultaneously estimating anisotropic elastic properties and crystallographic orientation of a specimen from a list of measured resonance frequencies collected via Resonance Ultrasound Spectroscopy (RUS). Unlike typical optimization procedures which yield point estimates of the unknown parameters, computing a Bayesian posterior yields probability distributions for the unknown parameters, and HMC is an efficient way to compute this posterior. The algorithms described are demonstrated on RUS data collected from two parallelepiped specimens of structural metal alloys. First, the elastic constants for a specimen of fine-grain polycrystalline Ti-6Al-4 V with random crystallographic texture and isotropic elastic symmetry are estimated. Second, the elastic constants and crystallographic orientation for a single crystal Ni based superalloy CMSX-4 specimen are accurately determined, using only measurements of the specimen geometry, mass, and resonance frequencies. The unique contributions of this paper are as follows: the application of HMC for sampling the Bayesian posterior of a probabilistic RUS model, and the procedure for simultaneous estimation of elastic constants and lattice-specimen misorientation. Compared to previous approaches these algorithms demonstrate superior convergence behavior, particularly when the initial parameterization is unknown, and enable substantially simplified experimental procedures. PMID- 29390756 TI - Assessing the shielding of engine noise by the wings for current aircraft using model predictions and measurements. AB - Reducing aircraft noise is a major issue to be dealt with by the aerospace industry. In addition to lowering noise emissions from the engine and airframe, also the shielding of engine noise by the aircraft is considered as a promising means for reducing the perceived noise on the ground. In literature, noise shielding predictions indicate significant reductions in received noise levels for blended wing body configurations, but also for conventional aircraft with the engines placed above the wings. Little work has been done in assessing these potential shielding effects for full aircraft under real operational conditions. Therefore, in this work, noise shielding for current aircraft is investigated using both measurements and model predictions. The predictions are based on the Kirchhoff integral theory and the Modified Theory of Physical Optics. For the comparison between the predictions and measurements, Twenty Fokker 70 flyovers are considered. The data analysis approach for the extraction of shielding levels for aircraft under these operational conditions is presented. Directly under the flight path, the simulations predict an engine noise shielding of 6 dB overall sound pressure level. This is confirmed by some of the flyover data. On average, the measurements show somewhat lower shielding levels. PMID- 29390757 TI - Experimental investigation of the influence of natural convection and end-effects on Rayleigh streaming in a thermoacoustic engine. AB - The influence of both the natural convection and end-effects on Rayleigh streaming pattern in a simple standing-wave thermoacoustic engine is investigated experimentally at different acoustic levels. The axial mean velocity inside the engine is measured using both Laser Doppler Velocimetry and Particle Image Velocimetry. The mean flow patterns are categorized in three different regions referred to as "cold streaming" region, "hot streaming" region, and "end-effects" region. In the cold streaming region, the dominant phenomenon is Rayleigh streaming and the mean velocity measurements correspond well with the theoretical expectations of Rayleigh streaming at low acoustic levels. At higher acoustic levels, the measurements deviate from the theoretical expectations which complies with the literature. In the hot streaming region, temperature measurements reveal that the non-uniformity of the resonator wall temperature is the origin of natural convection flow. Velocity measurements show that natural convection flow superimposes on the Rayleigh streaming flow so that the measured mean velocity deviates from the theoretical expectations of Rayleigh streaming. In the last region, the measured mean velocity is very different from Rayleigh streaming due to the combined effects of both the flow disturbances generated near the extremity of the stack and the natural convection flow. PMID- 29390758 TI - An equivalent fluid model based finite-difference time-domain algorithm for sound propagation in porous material with rigid frame. AB - An equivalent fluid model based finite-difference time-domain algorithm is proposed to simulate the frequency characteristic of porous material with rigid frame. The rigid-frame porous material is replaced by an equivalent fluid characterized by the effective density and the effective bulk modulus, which reflect the viscous effects and thermal effects in the porous material, respectively. The effective density and the effective bulk modulus are frequency dependent complex values, which are designed in the form of infinite impulse response filters in the frequency domain. The Z transform theory is used to discretize the frequency-domain wave equations. The accuracy of the proposed algorithm is preliminarily validated by good agreement between the calculated and measured normal-incidence sound absorption coefficients of two samples composed of different multiple-layered materials in a wide frequency range. PMID- 29390759 TI - Presenting and processing information in background noise: A combined speaker listener perspective. AB - Transferring information orally in background noise is challenging, for both speaker and listener. Successful transfer depends on complex interaction between characteristics related to listener, speaker, task, background noise, and context. To fully assess the underlying real-life mechanisms, experimental design has to mimic this complex reality. In the current study, the effects of different types of background noise have been studied in an ecologically valid test design. Documentary-style information had to be presented by the speaker and simultaneously acquired by the listener in four conditions: quiet, unintelligible multitalker babble, fluctuating city street noise, and little varying highway noise. For both speaker and listener, the primary task was to focus on the content that had to be transferred. In addition, for the speakers, the occurrence of hesitation phenomena was assessed. The listener had to perform an additional secondary task to address listening effort. For the listener the condition with the most eventful background noise, i.e., fluctuating city street noise, appeared to be the most difficult with markedly longer duration of the secondary task. In the same fluctuating background noise, speech appeared to be less disfluent, suggesting a higher level of concentration from the speaker's side. PMID- 29390760 TI - A comparison between directly measured and inferred wave speeds from an acoustic propagation experiment in Currituck Sound. AB - An acoustic propagation experiment was conducted in Currituck Sound to characterize low-frequency propagation in a very-shallow-water estuarine environment. The water column properties were homogeneous over the study area, and the emphasis of this work is on understanding the propagation effects induced by the estuarine bed. During the experiment, low-frequency sound propagation measurements of waterborne sound and interface waves were acquired, and direct measurements of the compressional and shear wave properties were obtained at high frequencies. The propagation data consist of signals from a Combustive Sound Source recorded on bottom mounted geophones and a vertical line array of hydrophones. A statistical inference method was applied to obtain an estimate of the sediment compressional and shear wave speed profiles as a function of depth within the estuarine bed. The direct measurements were obtained in situ by inserting probes 30 cm into the sediment. Sediment acoustics models were fit to the high-frequency in situ data to enable comparison with the inferred low frequency wave speeds. Overall, good agreement was found between the directly measured and inferred wave speeds for both the compressional and shear wave data. PMID- 29390762 TI - Children's early bilingualism and musical training influence prosodic discrimination of sentences in an unknown language. AB - This study investigated whether early bilingualism and early musical training positively influence the ability to discriminate between prosodic patterns corresponding to different syntactic structures in otherwise phonetically identical sentences in an unknown language. In a same-different discrimination task, participants (N = 108) divided into four groups (monolingual non-musicians, monolingual musicians, bilingual non-musicians, and bilingual musicians) listened to pairs of short sentences in a language unknown to them (French). In discriminating phonetically identical but prosodically different sentences, musicians, bilinguals, and bilingual musicians outperformed the controls. However, there was no interaction between bilingualism and musical training to suggest an additive effect. These results underscore the significant role of both types of experience in enhancing the listeners' sensitivity to prosodic information. PMID- 29390763 TI - Active control of simply supported cylindrical shells using the weighted sum of spatial gradients control metric. AB - It is often desired to reduce sound radiated from cylindrical shells. Active structural acoustic control (ASAC) provides a means of controlling the structural vibration in a manner to efficiently reduce the radiated sound. Previous work has often required a large number of error sensors to reduce the radiated sound power, and the control performance has been sensitive to the location of error sensors. The ultimate objective is to provide global sound power reduction using a minimal number of local error measurements, while also minimizing any dependence on error sensor locations. Recently, a control metric referred to as weighted sum of spatial gradients (WSSG) was developed for ASAC. Specific features associated with WSSG make this method robust under a variety of conditions. In this work, the WSSG control metric is extended to curved structures, specifically a simply supported cylindrical shell. It is shown that global attenuation of the radiated sound power is possible using only one local error measurement. It is shown that the WSSG control metric provides a solution approximating the optimal solution of attenuating the radiated sound power, with minimal dependence on the error sensor location. Numerical and experimental results are presented to demonstrate the effectiveness of the method. PMID- 29390764 TI - Acoustic inversion method for parameters of sediments based on adaptive predatory genetic algorithm. AB - Acoustic inversion for the physical parameters of seafloor sediments is an important and difficult aspect of sediment acoustic research. Submarine surface sediments are typical porous media, which involve many parameters. Thus, the optimization of high-dimensional inversion represents one of the difficulties. An acoustic inversion method to obtain the physical parameters of seafloor sediments is constructed based on the adaptive predatory genetic algorithm and effective density fluid model derived from Biot theory. The method introduces the adaptive process and predatory strategy into the genetic algorithm and uses the norm of the relative difference between the predicted wave number and the measured wave number as the objective function. The method is confirmed to be stable and efficient by simulated data and is also applied to invert porosity, tortuosity, and permeability of the sediments in Hangzhou Bay of China using acoustic data measured by an in situ acoustic measurement system. PMID- 29390765 TI - Impact of loudspeaker nonlinear distortion on personal sound zones. AB - Personal sound zone systems aim at creating multiple listening zones within a shared space with minimum interference between zones, but the performance is often poorer than simulations predict and effects of nonlinear distortion are sometimes audible. This paper assesses the impact of nonlinear distortion on sound zones through simulations and measurements performed under anechoic conditions. Two sound zones, one bright and one dark, are created with acoustic contrast control using two loudspeaker arrays driven at 250 Hz. Nonlinear distortion is modelled using second or third order nonlinearities. Simulations show that nonlinear distortion degrades the acoustic contrast, which is confirmed by experimental measurements. The harmonic distortion is audible in the dark zone. Frequency resolved measurements reveal that harmonic distortion contributes to contrast loss, but nonlinear effects on the fundamental component are the main cause. Nonlinear distortion can be controlled through regularization of the loudspeaker control effort. Simulations and experiments show an optimum regularization range where contrast is optimized by balancing linear performance and nonlinear distortion. PMID- 29390766 TI - Pile driving acoustics made simple: Damped cylindrical spreading model. AB - Sound produced by marine pile driving activities poses a possible risk to marine life. The assessment and mitigation of this risk requires a precise prediction of the expected levels. An analytical approach to estimate the radiated sound exposure levels is presented, based on the axial symmetry of the problem, resulting in damped cylindrical spreading. The approach is verified against numerical results from the recently held COMPILE benchmark workshop and validated with data from three different wind farm construction sites in the North Sea. In addition, found to yield more accurate estimates of the sound exposure level than an empirical decay formula sometimes used to evaluate the impact of marine pile driving. PMID- 29390767 TI - The violin bridge-island input filter. AB - The influence on the acoustics of the violin of the bridge and the island area between the f-holes is demonstrated by treating the body as a thin-walled shell structure. COMSOL finite element software is used as a quasi-experimental tool to identify and understand the coupling of the bridge, island area, offset soundpost, and bassbar to the radiating surfaces of the body shell by varying their properties, often over a wide range. The frequency dependence of the resulting input filter between the vibrating strings and body shell modes is derived using a quasi-statistical averaging approach involving the strong damping of the body shell modes. The bridge-island filter response over the whole playing range of the violin is shown to be strongly dependent on the properties of the bridge, island area, soundpost, and bassbar. Their properties influence both the intensity and tonal balance of the radiated sound and the broad Bridge-Hill feature in the vibro-acoustic response of many fine instruments. PMID- 29390769 TI - Off-axis targets maximize bearing Fisher Information in broadband active sonar. AB - Broadband active sonar systems estimate range from time delay and velocity from Doppler shift. Relatively little attention has been paid to how the received echo spectrum encodes information about the bearing of an object. This letter derives the bearing Fisher Information encoded in the frequency dependent transmitter beampattern. This leads to a counter-intuitive result: directing the sonar beam so that a target of interest is slightly off-axis maximizes the bearing information about the target. Beam aim data from a dolphin biosonar experiment agree closely with the angle predicted to maximize bearing information. PMID- 29390768 TI - Age effects on perceptual restoration of degraded interrupted sentences. AB - Adult cochlear-implant (CI) users show small or non-existent perceptual restoration effects when listening to interrupted speech. Perceptual restoration is believed to be a top-down mechanism that enhances speech perception in adverse listening conditions, and appears to be particularly utilized by older normal hearing participants. Whether older normal-hearing participants can derive any restoration benefits from degraded speech (as would be presented through a CI speech processor) is the focus of this study. Two groups of normal-hearing participants (younger: age <=30 yrs; older: age >=60 yrs) were tested for perceptual restoration effects in the context of interrupted sentences. Speech signal degradations were controlled by manipulating parameters of a noise vocoder and were used to analyze effects of spectral resolution and noise burst spectral content on perceptual restoration. Older normal-hearing participants generally showed larger and more consistent perceptual restoration benefits for vocoded speech than did younger normal-hearing participants, even in the lowest spectral resolution conditions. Reduced restoration in CI users thus may be caused by factors like noise reduction strategies or small dynamic ranges rather than an interaction of aging effects and low spectral resolution. PMID- 29390770 TI - ACOUSTICAL NEWS. AB - Editor's Note: Readers of this journal are encouraged to submit news items on awards, appointments, and other activities about themselves or their colleagues. Deadline dates for news and notices are 2 months prior to publication. PMID- 29390771 TI - Evaluation of speech improvement following obturator prostheses for patients with palatal defect. AB - Palatal defect is a common maxillofacial defect after maxillectomy that can be repaired by obturator prostheses, which can effectively improve patients' speech. However, comprehensive evaluation methods for speech recovery are still controversial and remain undefined. A prospective cohort study on 34 patients with palatal defect and 34 healthy controls was performed. Patients received obturator prostheses and their speech was recorded without and then with obturators. Participants pronounced six Chinese vowels and 100 syllables for recording. This paper evaluated the recovery of speech function of patients through the combination of subjective and objective assessment methods. Recruited listeners evaluated the speech intelligibility (SI) of 100 syllables. Vowel formant frequency and quantified vowel nasalization were measured using analysis software. The SI of patients improved significantly after wearing obturators. F2 values of six vowels in patients with obturators were higher than patients without obturators and close to the corresponding values in normal controls. The differences in F2 of /i/ and /u/, (A1-P1) of /i/ and /u/ for patients without and with obturator use were significant. Patients' ability to control the pronunciation of /i/ and /u/ improved greatly with obturators. These provide clinical evidence of the treatment outcomes in patients with palatal defect who received obturators. PMID- 29390772 TI - Rapid calculation of acoustic fields from arbitrary continuous-wave sources. AB - A Green's function solution is derived for calculating the acoustic field generated by phased array transducers of arbitrary shape when driven by a single frequency continuous wave excitation with spatially varying amplitude and phase. The solution is based on the Green's function for the homogeneous wave equation expressed in the spatial frequency domain or k-space. The temporal convolution integral is solved analytically, and the remaining integrals are expressed in the form of the spatial Fourier transform. This allows the acoustic pressure for all spatial positions to be calculated in a single step using two fast Fourier transforms. The model is demonstrated through several numerical examples, including single element rectangular and spherically focused bowl transducers, and multi-element linear and hemispherical arrays. PMID- 29390773 TI - Reflection and transmission of thermo-elastic waves without energy dissipation at the interface of two dipolar gradient elastic solids. AB - The reflection and transmission of thermal elastic waves at the interface between two different dipolar gradient elastic solids are studied based on the generalized thermo-elastic theory of Green and Naghdi [(1993). J. Elasticity 31, 189-208] (type II of no energy dissipation). First, some thermodynamic formulas are generalized to a dipolar gradient elastic solid and the function of free energy density is postulated. Second, equations of thermal motion and constitutive relations in a dipolar gradient elasticity are derived. Then the nontraditional interfacial conditions are used to determine the amplitude ratio of the reflection and transmission waves with respect to the incident wave. Some numerical results of the reflection and transmission coefficients in the form of an energy flux ratio are given for different microstructure parameters while thermal parameters are fixed. The numerical results are validated by the consideration of energy conservation. It is found that there are a total of five modes of dispersive waves, namely, coupled MT1 wave, coupled MT2 wave, coupled MT3 wave, SV wave, and one evanescent wave which reduces to the surface waves at an interface, namely, SS wave. The thermal parameters mainly affect the coupled MT2 wave while the microstructure parameters affect not only the coupled waves but also the SS surface waves. PMID- 29390774 TI - ACOUSTICAL STANDARDS NEWS. AB - American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, S3/SC 1, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, animal bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes a catalog of Acoustical American National Standards. To receive a copy of the latest Standards catalog, please contact Neil Stremmel.Comments are welcomed on all material in Acoustical Standards News.This Acoustical Standards News section in JASA and other information on the Standards Program of the Acoustical Society of America are available via the ASA home page: http://acousticalsociety.org. PMID- 29390775 TI - Uncovering mental representations of smiled speech using reverse correlation. AB - Which spectral cues underlie the perceptual processing of smiles in speech? Here, the question was addressed using reverse-correlation in the case of the isolated vowel [a]. Listeners were presented with hundreds of pairs of utterances with randomly manipulated spectral characteristics and were asked to indicate, in each pair, which was the most smiling. The analyses revealed that they relied on robust spectral representations that specifically encoded vowel's formants. These findings demonstrate the causal role played by formants in the perception of smile. Overall, this paper suggests a general method to estimate the spectral bases of high-level (e.g., emotional/social/paralinguistic) speech representations. PMID- 29390776 TI - Generic uniform search grid generation algorithm for far-field source localization. AB - In this letter, a generic search grid generation algorithm for far-field source localization (SL) is proposed. Since conventional uniform regular grid structures only consider the resolution of the distribution, it is difficult to control the number of grid points to be distributed. The proposed algorithm generates a search grid by distributing a desired number of points evenly, depending on the target criterion, in either direction of arrival or time difference of arrival domain. The experimental results show that the proposed algorithm provides optimally distributed grid points given the number of desired points and the corresponding domain for SL processing. PMID- 29390777 TI - Prediction of flow induced sound generated by cross flow past finite length circular cylinders. AB - The paper presents aeroacoustic results for the flow around finite-length circular cylinders at Reynolds number 84 770 for various length-to-diameter (L/D) ratios (= 3, 9, 20, 25, 30, and 35). The incompressible Navier-Stokes equations are solved using the large eddy simulation model of turbulence followed by acoustic predictions in the far field using Ffwocs Williams and Hawkings method. The comparisons of numerical and anechoic wind tunnel measurements show good agreement in terms of the aerodynamic forces and acoustic parameters such as tonal frequency, tonal sound pressure level, and overall sound pressure level. The cylinder L/D ratio was observed to be a significant parameter that controls vortex shedding and consequently the flow induced sound generation. PMID- 29390778 TI - Effects of chair vibration on indoor annoyance ratings of sonic booms. AB - The effects of perceptible whole-body vibrations on annoyance ratings of sonic booms and other impulsive environmental sounds experienced indoors were studied. Fifteen pairs of test subjects made annoyance ratings while seated in a living room environment. There were two chairs, one isolated from floor vibrations and the other not isolated, and every test subject rated all signals in both chairs. Halfway through each test session, subjects changed seats. Subjects who sat in the isolated chair first gave lower mean annoyance ratings in both halves of the test than subjects who sat in the non-isolated chair first. Annoyance predictions from models using both sound and vibration measures were closer to average annoyance ratings than predictions from a model using sound measures alone. Reformulation of the annoyance model revealed that the presence of perceptible vibration is equivalent to increasing acoustic metric Perceived Level by 4.8 dB when calculated on exterior signals and by 5.6 dB when calculated on interior signals. PMID- 29390779 TI - Erratum: Velocity and attenuation of scalar and elastic waves in random media: A spectral function approach [J. Acoust. Soc. Am. 131(3), 1843-1862 (2012)]. PMID- 29390780 TI - Influence of grain morphology on ultrasonic wave attenuation in polycrystalline media with statistically equiaxed grains. AB - The influence of a polycrystals' grain structure on elastic wave scattering is studied with analytical and numerical methods in a broad frequency range. A semi analytical attenuation model, based on an established scattering theory, is presented. This technique accurately accounts for the grain morphology without prior assumptions on grain statistics. This is achieved by incorporating a samples' exact spatial two-point correlation function into the theory. The approach is verified by using a finite element method (FEM) to simulate P-wave propagation in 3D Voronoi crystals with equal mean grain diameter, but different grain shape uniformity. Aluminum and Inconel serve as representatives for weak and strong scattering cubic class materials for simulations and analytical calculations. It was found that the shape of the grains has a strong influence on the attenuation curve progression in the Rayleigh-stochastic transition region, which was attributed to mode conversion scattering. Comparisons between simulations and theory show excellent agreement for both materials. This demonstrates the need for accurately taking the microstructure of heterogeneous materials into account, to get precise analytical predictions for their scattering behaviour. It also demonstrates the impressive accuracy and flexibility of the scattering theory which was used. PMID- 29390781 TI - A model for acoustic vaporization dynamics of a bubble/droplet system encapsulated within a hyperelastic shell. AB - Nanodroplets have great, promising medical applications such as contrast imaging, embolotherapy, or targeted drug delivery. Their functions can be mechanically activated by means of focused ultrasound inducing a phase change of the inner liquid known as the acoustic droplet vaporization (ADV) process. In this context, a four-phases (vapor + liquid + shell + surrounding environment) model of ADV is proposed. Attention is especially devoted to the mechanical properties of the encapsulating shell, incorporating the well-known strain-softening behavior of Mooney-Rivlin material adapted to very large deformations of soft, nearly incompressible materials. Various responses to ultrasound excitation are illustrated, depending on linear and nonlinear mechanical shell properties and acoustical excitation parameters. Different classes of ADV outcomes are exhibited, and a relevant threshold ensuring complete vaporization of the inner liquid layer is defined. The dependence of this threshold with acoustical, geometrical, and mechanical parameters is also provided. PMID- 29390782 TI - Features of acoustic wave propagation in the Me/ZnO/Me/diamond waveguide structure. AB - The effect of mass loading on the phase velocities of the surface acoustic wave dispersion modes in the Me/ZnO/Me/diamond piezoelectric layered structure as a function of frequency, metallic, and piezoelectric layer thickness has been investigated. Aluminum, molybdenum, and platinum were considered as the metallic layer materials. It has been demonstrated that the change in the phase velocities substantially depends on the acoustic impedance of the metal layer and its thickness. Results obtained can be useful in the development of controlled acoustoelectronic devices and sensors operating on the Rayleigh and Love waves. PMID- 29390783 TI - Spatial decorrelation of wind noise with porous microphone windscreens. AB - This paper explores the wind noise reduction mechanism of porous microphone windscreens by investigating the spatial correlation of wind noise. First, the spatial structure of the wind noise signal is studied by simulating the magnitude squared coherence of the pressure measured with two microphones at various separation distances, and it is found that the coherence of the two signals decreases with the separation distance and the wind noise is spatially correlated only within a certain distance less than the turbulence wavelength. Then, the wind noise reduction of the porous microphone windscreen is investigated, and the porous windscreen is found to be the most effective in attenuating wind noise in a certain frequency range, where the windscreen diameter is approximately 2 to 4 times the turbulence wavelengths (2 < D0/xi < 4), regardless of the wind speed and windscreen diameter. The spatial coherence between the wind noise outside and inside a porous microphone windscreen is compared with that without the windscreen, and the coherence is found to decrease significantly when the windscreen diameter is approximately 2 to 4 times the turbulence wavelengths, corresponding to the most effective wind noise reduction frequency range of the windscreen. Experimental results with a fan are presented to support the simulations. It is concluded that the wind noise reduction mechanism of porous microphone windscreens is related to the spatial decorrelation effect on the wind noise signals provided by the porous material and structure. PMID- 29390784 TI - Physical modeling of a conical lip reed instrument. AB - A model of a brass instrument is described in which the air flow and pressure inside the instrument are computed with the Navier-Stokes equations and the motion of the player's lips are described using the swinging lip model of Adachi and Sato [J. Acoust. Soc. Am. 99, 1200-1209 (1996)]. Using the Navier-Stokes equations to treat the air motion allows the calculation of the spatial variations and time dependences of the pressure and velocity near the lips, which has not been possible with previous modeling approaches. Detailed results for these quantities and for the lip motion are presented, and compared with the results of previous modeling of lip reed instruments and with available experimental results. Shortcomings are found in previous treatments of the aerodynamic force on the lips, and the implications of this result for first principles modeling of brass instruments are discussed. PMID- 29390785 TI - Distribution of spectral modulation transfer functions in a young, normal-hearing population. AB - Spectral modulation transfer functions (SMTFs) were measured in 49 young (18-35 years of age) normal-hearing listeners. Noise carriers spanned six octaves from 200 to 12 800 Hz. Sinusoidal (on a log-amplitude scale) spectral modulation with random starting phase was superimposed on the carrier at spectral modulation frequencies of 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 cycles/octave. Modulation detection thresholds (in dB) yielded SMTFs that were bandpass in nature, consistent with previous investigations reporting data for only a few subjects. Thresholds were notably consistent across subjects despite minimal practice. Population statistics are reported that may serve as reference data for future studies. PMID- 29390786 TI - Design of continuously graded elastic acoustic cloaks. AB - This letter demonstrates the design of continuously graded elastic cylinders to achieve passive cloaking from harmonic acoustic excitation, both at single frequencies and over extended bandwidths. The constitutive parameters in a multilayered, constant-density cylinder are selected in a partial differential equation-constrained optimization problem, such that the residual between the pressure field from an unobstructed spreading wave in a fluid and the pressure field produced by the cylindrical inclusion is minimized. The radial variation in bulk modulus appears fundamental to the cloaking behavior, while the shear modulus distribution plays a secondary role. Such structures could be realized with functionally-graded elastic materials. PMID- 29390787 TI - Soundscape expectations of rural tourism: A comparison between Chinese and English potential tourists. AB - A questionnaire survey was carried out for a comparative study between Chinese and English potential tourists to examine their soundscape expectation. The results show that while both groups prefer natural sounds most, compared to the English, the Chinese expect natural, livestock, melodic sounds more, and traffic and industrial sounds less. The sound categories related to the interactions between human activities and nature play a more dominant role for the English than the Chinese, in terms of preference of sound sources. On the expectation of a holistic soundscape, function is the most important aspect for the Chinese, while that for the English is sound characteristics; the expected psychological perception for the English is associated with emotional response rather than basic ecology consciousness, as for the Chinese. PMID- 29390788 TI - Impact of temporal Doppler on synthetic aperture sonar imagery. AB - Synthetic Aperture Sonar (SAS) coherently processes the acoustic data acquired along a linear trajectory. The imaging process is in essence an inverse problem where the reflectivity of the seafloor has to be estimated. Several imaging algorithms have been proposed over the years including back-projection algorithms. One commonly assumed hypothesis, however, is that the antenna is motionless during transmission and reception. This hypothesis is known as the start-stop assumption. This paper questions the validity of this assumption, and proposes a full derivation of the SAS processing taking into account the vehicle motion by using the Lorentz transformation. The cell migration for the SAS system is computed and the validity limit of the stop-start assumption depending on the SAS system parameters is derived. Numerical examples of start-stop assumption violations are given and the Doppler cell migration correction on real SAS data are presented and discussed. PMID- 29390790 TI - Effects of background noises on nonlinear dynamics of a modelled thermoacoustic combustor. AB - In this work, the effects of background noises on nonlinear dynamics of a modelled standing-wave thermoacoustic system with subcritical Hopf bifurcation behaviors are studied. These noises include (1) pressure-coupled (acoustic), (2) velocity-coupled (flow), and (3) external combustion noise. It is found that these three types of background noises play important, but different roles in changing the hysteresis width and stability boundary. In addition, the stochastic transition from stability to instability is investigated, as the noise intensity is varied. Two different stochastic P-bifurcations are identified. One is related to a craterlike probability density distribution. The other is associated with a probability density distribution characterized with two peaks and one trough. With each type of noise affecting the system's stochastic behaviors being evaluated, the effect of two different types of noises is then studied. It is shown that the combined noises (types 1 and 2) cannot only destabilize global stable thermoacoustic system, but also stabilize linearly unstable system. This depends strongly on the superimposition form of the two types of noises. In addition, when the thermoacoustic system is disturbed by the combined noise (types 3 and 1 or types 3 and 2), the transition process is dominated by the combustion noise. PMID- 29390789 TI - Pressurized transient otoacoustic emissions measured using click and chirp stimuli. AB - Transient-evoked otoacoustic emission (TEOAE) responses were measured in normal hearing adult ears over frequencies from 0.7 to 8 kHz, and analyzed with reflectance/admittance data to measure absorbed sound power and the tympanometric peak pressure (TPP). The mean TPP was close to ambient. TEOAEs were measured in the ear canal at ambient pressure, TPP, and fixed air pressures from 150 to -200 daPa. Both click and chirp stimuli were used to elicit TEOAEs, in which the incident sound pressure level was constant across frequency. TEOAE levels were similar at ambient and TPP, and for frequencies from 0.7 to 2.8 kHz decreased with increasing positive and negative pressures. At 4-8 kHz, TEOAE levels were larger at positive pressures. This asymmetry is possibly related to changes in mechanical transmission through the ossicular chain. The mean TEOAE group delay did not change with pressure, although small changes were observed in the mean instantaneous frequency and group spread. Chirp TEOAEs measured in an adult ear with Eustachian tube dysfunction and TPP of -165 daPa were more robust at TPP than at ambient. Overall, results demonstrate the feasibility and clinical potential of measuring TEOAEs at fixed pressures in the ear canal, which provide additional information relative to TEOAEs measured at ambient pressure. PMID- 29390791 TI - The impact of exploiting spectro-temporal context in computational speech segregation. AB - Computational speech segregation aims to automatically segregate speech from interfering noise, often by employing ideal binary mask estimation. Several studies have tried to exploit contextual information in speech to improve mask estimation accuracy by using two frequently-used strategies that (1) incorporate delta features and (2) employ support vector machine (SVM) based integration. In this study, two experiments were conducted. In Experiment I, the impact of exploiting spectro-temporal context using these strategies was investigated in stationary and six-talker noise. In Experiment II, the delta features were explored in detail and tested in a setup that considered novel noise segments of the six-talker noise. Computing delta features led to higher intelligibility than employing SVM based integration and intelligibility increased with the amount of spectral information exploited via the delta features. The system did not, however, generalize well to novel segments of this noise type. Measured intelligibility was subsequently compared to extended short-term objective intelligibility, hit-false alarm rate, and the amount of mask clustering. None of these objective measures alone could account for measured intelligibility. The findings may have implications for the design of speech segregation systems, and for the selection of a cost function that correlates with intelligibility. PMID- 29390792 TI - Lamb wave propagation in monocrystalline silicon wafers. AB - Monocrystalline silicon wafers are widely used in the photovoltaic industry for solar panels with high conversion efficiency. Guided ultrasonic waves offer the potential to efficiently detect micro-cracks in the thin wafers. Previous studies of ultrasonic wave propagation in silicon focused on effects of material anisotropy on bulk ultrasonic waves, but the dependence of the wave propagation characteristics on the material anisotropy is not well understood for Lamb waves. The phase slowness and beam skewing of the two fundamental Lamb wave modes A0 and S0 were investigated. Experimental measurements using contact wedge transducer excitation and laser measurement were conducted. Good agreement was found between the theoretically calculated angular dependency of the phase slowness and measurements for different propagation directions relative to the crystal orientation. Significant wave skew and beam widening was observed experimentally due to the anisotropy, especially for the S0 mode. Explicit finite element simulations were conducted to visualize and quantify the guided wave beam skew. Good agreement was found for the A0 mode, but a systematic discrepancy was observed for the S0 mode. These effects need to be considered for the non destructive testing of wafers using guided waves. PMID- 29390793 TI - Acoustic behaviors of the microperforated panel absorber array in nonlinear regime under moderate acoustic pressure excitation. AB - The acoustic performance of a microperforated panel (MPP) absorber array in the nonlinear regime is investigated both numerically and experimentally. The MPP absorber array is constructed by three parallel-arranged MPP absorbers with different cavity depths. A finite element model is used to simulate the acoustic response of the MPP absorber array by adopting the nonlinear impedance model. The results show that the absorption of the MPP absorber array is affected by the incident sound pressure when it is beyond around 100 dB. With appropriate structural and perforation property of MPP, the MPP absorber array in non-linear regime outperforms that in linear regime due to the improvement of equivalent acoustic impedance matching with ambient air over wide frequency range. However, when the sound pressure excitation is too high, the local resonance effect of the resonating component MPP absorber is diminished and the sound absorption is decreased. With the carefully chosen properties of MPP, the performance degradation induced by panel vibration can be avoided. An optimal set of MPP properties to avoid the performance degradation induced by panel vibration is determined. The measured normal absorption coefficients of a prototype MPP absorber array compare well with the numerical prediction in both linear and nonlinear regimes. PMID- 29390794 TI - Estimating drift of directional sonobuoys from acoustic bearings. AB - A maximum likelihood method is presented for estimating drift direction and speed of a directional sonobuoy given the deployment location and a time series of acoustic bearings to a sound source at known position. The viability of this method is demonstrated by applying it to two real-world scenarios: (1) during a calibration trial where buoys were independently tracked via satellite, and (2) by applying the technique to sonobuoy recordings of a vocalising Antarctic blue whale that was simultaneously tracked by photogrammetric methods. In both test cases, correcting for sonobuoy drift substantially increased the accuracy of acoustic locations. PMID- 29390795 TI - Modeling the level-dependent changes of concurrent vowel scores. AB - The difference in fundamental frequency (F0) between talkers is an important cue for speaker segregation. To understand how this cue varies across sound level, Chintanpalli, Ahlstrom, and Dubno [(2014). J. Assoc. Res. Otolaryngol. 15, 823 837] collected level-dependent changes in concurrent-vowel identification scores for same- and different-F0 conditions in younger adults with normal hearing. Modeling suggested that level-dependent changes in phase locking of auditory nerve (AN) fibers to formants and F0s may contribute to concurrent-vowel identification scores; however, identification scores were not predicted to test this suggestion directly. The current study predicts these identification scores using the temporal responses of a computational AN model and a modified version of Meddis and Hewitt's [(1992). J. Acoust. Soc. Am. 91, 233-245] F0-based segregation algorithm. The model successfully captured the level-dependent changes in identification scores of both vowels with and without F0 difference, as well as identification scores for one vowel correct. The model's F0-based vowel segregation was controlled using the actual F0-benefit across levels such that the predicted F0-benefit matched qualitatively with the actual F0-benefit as a function of level. The quantitative predictions from this F0-based segregation algorithm demonstrate that temporal responses of AN fibers to vowel formants and F0s can account for variations in identification scores across sound level and F0 difference conditions in a concurrent-vowel task. PMID- 29390797 TI - Combining degradations: The effect of background noise on intelligibility of disordered speech. AB - The effect of background noise on intelligibility of disordered speech was assessed. Speech-shaped noise was mixed with neurologically healthy (control) and disordered (dysarthric) speech at a series of signal-to-noise ratios. In addition, bandpass filtered control and dysarthric speech conditions were assessed to determine the effect of noise on both naturally and artificially degraded speech. While significant effects of both the amount of noise and the type of speech were revealed, no interaction between the two factors was observed, in either the broadband or filtered testing conditions. Thus, it appears that there is no multiplicative effect of the presence of background noise on intelligibility of disordered speech relative to control speech. That is, the decrease in intelligibility due to increasing levels of noise is similar for both types of speech, and both types of testing conditions, and the function for dysarthric speech is simply shifted downward due to the inherent source degradations of the speech itself. Last, large-scale online crowdsourcing via Amazon Mechanical Turk was utilized to collect data for the current study. Findings and implications for this data and data collection approach are discussed. PMID- 29390798 TI - Deciphering complex dynamics of water counteraction around secondary structural elements of allosteric protein complex: Case study of SAP-SLAM system in signal transduction cascade. AB - The first hydration shell of a protein exhibits heterogeneous behavior owing to several attributes, majorly local polarity and structural flexibility as revealed by solvation dynamics of secondary structural elements. We attempt to recognize the change in complex water counteraction generated due to substantial alteration in flexibility during protein complex formation. The investigation is carried out with the signaling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, and interacting with SLAM-associated protein (SAP), composed of one SH2 domain. All atom molecular dynamics simulations are employed to the aqueous solutions of free SAP and SLAM-peptide bound SAP. We observed that water dynamics around different secondary structural elements became highly affected as well as nicely correlated with the SLAM peptide induced change in structural rigidity obtained by thermodynamic quantification. A few instances of contradictory dynamic features of water to the change in structural flexibility are explained by means of occluded polar residues by the peptide. For betaD, EFloop, and BGloop, both structural flexibility and solvent accessibility of the residues confirm the obvious contribution. Most importantly, we have quantified enhanced restriction in water dynamics around the second Fyn-binding site of the SAP due to SAP-SLAM complexation, even prior to the presence of Fyn. This observation leads to a novel argument that SLAM induced more restricted water molecules could offer more water entropic contribution during the subsequent Fyn binding and provide enhanced stability to the SAP-Fyn complex in the signaling cascade. Finally, SLAM induced water counteraction around the second binding site of the SAP sheds light on the allosteric property of the SAP, which becomes an integral part of the underlying signal transduction mechanism. PMID- 29390799 TI - Non-adiabatic quantum reactive scattering in hyperspherical coordinates. AB - A new electronically non-adiabatic quantum reactive scattering methodology is presented based on a time-independent coupled channel formalism and the adiabatically adjusting principal axis hyperspherical coordinates of T Pack and Parker [J. Chem. Phys. 87, 3888 (1987)]. The methodology computes the full state to-state scattering matrix for A + B2(v, j) <-> AB(v', j') + B and A + AB(v, j) > A + AB(v', j') reactions that involve two coupled electronic states which exhibit a conical intersection. The methodology accurately treats all six degrees of freedom relative to the center-of-mass which includes non-zero total angular momentum J and identical particle exchange symmetry. The new methodology is applied to the ultracold hydrogen exchange reaction for which large geometric phase effects have been recently reported [B. K. Kendrick et al., Phys. Rev. Lett. 115, 153201 (2015)]. Rate coefficients for the H/D + HD(v = 4, j = 0) -> H/D + HD(v', j') reactions are reported for collision energies between 1 MUK and 100 K (total energy ~1.9 eV). A new diabatic potential energy matrix is developed based on the Boothroyd, Keogh, Martin, and Peterson (BKMP2) and double many body expansion plus single-polynomial (DSP) adiabatic potential energy surfaces for the ground and first excited electronic states of H3, respectively. The rate coefficients computed using the new non-adiabatic methodology and diabatic potential matrix reproduce the recently reported rates that include the geometric phase and are computed using a single adiabatic ground electronic state potential energy surface (BKMP2). The dramatic enhancement and suppression of the ultracold rates due to the geometric phase are confirmed as well as its effects on several shape resonances near 1 K. The results reported here represent the first fully non-adiabatic quantum reactive scattering calculation for an ultracold reaction and validate the importance of the geometric phase on the Wigner threshold behavior. PMID- 29390800 TI - Particle-based membrane model for mesoscopic simulation of cellular dynamics. AB - We present a simple and computationally efficient coarse-grained and solvent-free model for simulating lipid bilayer membranes. In order to be used in concert with particle-based reaction-diffusion simulations, the model is purely based on interacting and reacting particles, each representing a coarse patch of a lipid monolayer. Particle interactions include nearest-neighbor bond-stretching and angle-bending and are parameterized so as to reproduce the local membrane mechanics given by the Helfrich energy density over a range of relevant curvatures. In-plane fluidity is implemented with Monte Carlo bond-flipping moves. The physical accuracy of the model is verified by five tests: (i) Power spectrum analysis of equilibrium thermal undulations is used to verify that the particle-based representation correctly captures the dynamics predicted by the continuum model of fluid membranes. (ii) It is verified that the input bending stiffness, against which the potential parameters are optimized, is accurately recovered. (iii) Isothermal area compressibility modulus of the membrane is calculated and is shown to be tunable to reproduce available values for different lipid bilayers, independent of the bending rigidity. (iv) Simulation of two dimensional shear flow under a gravity force is employed to measure the effective in-plane viscosity of the membrane model and show the possibility of modeling membranes with specified viscosities. (v) Interaction of the bilayer membrane with a spherical nanoparticle is modeled as a test case for large membrane deformations and budding involved in cellular processes such as endocytosis. The results are shown to coincide well with the predicted behavior of continuum models, and the membrane model successfully mimics the expected budding behavior. We expect our model to be of high practical usability for ultra coarse-grained molecular dynamics or particle-based reaction-diffusion simulations of biological systems. PMID- 29390801 TI - Vibrationally resolved photoelectron spectra of lower diamondoids: A time dependent approach. AB - Vibrationally resolved lowest-energy bands of the photoelectron spectra (PES) of adamantane, diamantane, and urotropine were simulated by a time-dependent correlation function approach within the harmonic approximation. Geometries and normal modes for neutral and cationic molecules were obtained from B3LYP hybrid density functional theory (DFT). It is shown that the simulated spectra reproduce the experimentally observed vibrational finestructure (or its absence) quite well. Origins of the finestructure are discussed and related to recurrences of autocorrelation functions and dominant vibrations. Remaining quantitative and qualitative errors of the DFT-derived PES spectra refer to (i) an overall redshift by ~0.5 eV and (ii) the absence of satellites in the high-energy region of the spectra. The former error is shown to be due to the neglect of many-body corrections to ordinary Kohn-Sham methods, while the latter has been argued to be due to electron-nuclear couplings beyond the Born-Oppenheimer approximation [Gali et al., Nat. Commun. 7, 11327 (2016)]. PMID- 29390802 TI - Dynamic coarse-graining fills the gap between atomistic simulations and experimental investigations of mechanical unfolding. AB - We present a dynamic coarse-graining technique that allows one to simulate the mechanical unfolding of biomolecules or molecular complexes on experimentally relevant time scales. It is based on Markov state models (MSMs), which we construct from molecular dynamics simulations using the pulling coordinate as an order parameter. We obtain a sequence of MSMs as a function of the discretized pulling coordinate, and the pulling process is modeled by switching among the MSMs according to the protocol applied to unfold the complex. This way we cover seven orders of magnitude in pulling speed. In the region of rapid pulling, we additionally perform steered molecular dynamics simulations and find excellent agreement between the results of the fully atomistic and the dynamically coarse grained simulations. Our technique allows the determination of the rates of mechanical unfolding in a dynamical range from approximately 10-8/ns to 1/ns thus reaching experimentally accessible time regimes without abandoning atomistic resolution. PMID- 29390803 TI - Communication: Modeling electrolyte mixtures with concentration dependent dielectric permittivity. AB - We report a new implicit-solvent simulation model for electrolyte mixtures based on the concept of concentration dependent dielectric permittivity. A combining rule is found to predict the dielectric permittivity of electrolyte mixtures based on the experimentally measured dielectric permittivity for pure electrolytes as well as the mole fractions of the electrolytes in mixtures. Using grand canonical Monte Carlo simulations, we demonstrate that this approach allows us to accurately reproduce the mean ionic activity coefficients of NaCl in NaCl CaCl2 mixtures at ionic strengths up to I = 3M. These results are important for thermodynamic studies of geologically relevant brines and physiological fluids. PMID- 29390804 TI - Perspective: Quantum Hamiltonians for optical interactions. AB - The multipolar Hamiltonian of quantum electrodynamics is extensively employed in chemical and optical physics to treat rigorously the interaction of electromagnetic fields with matter. It is also widely used to evaluate intermolecular interactions. The multipolar version of the Hamiltonian is commonly obtained by carrying out a unitary transformation of the Coulomb gauge Hamiltonian that goes by the name of Power-Zienau-Woolley (PZW). Not only does the formulation provide excellent agreement with experiment, and versatility in its predictive ability, but also superior physical insight. Recently, the foundations and validity of the PZW Hamiltonian have been questioned, raising a concern over issues of gauge transformation and invariance, and whether observable quantities obtained from unitarily equivalent Hamiltonians are identical. Here, an in-depth analysis of theoretical foundations clarifies the issues and enables misconceptions to be identified. Claims of non-physicality are refuted: the PZW transformation and ensuing Hamiltonian are shown to rest on solid physical principles and secure theoretical ground. PMID- 29390805 TI - Behavior of intermolecular interactions in alpha-glycine under high pressure. AB - Pressure-response on the crystal structure of deuterated alpha-glycine was investigated at room temperature, using powder and single-crystal X-ray diffraction, and powder neutron diffraction measurements under high pressure. No phase change was observed up to 8.7 GPa, although anisotropy of the lattice compressibility was found. No significant changes in the compressibility and the intramolecular distance between non-deuterated alpha-glycine and deuterated alpha glycine were observed. Neutron diffraction measurements indicated the distance of the intermolecular D?O bond along with the c-axis increased with compression up to 6.4 GPa. The distance of another D?O bond along with the a-axis decreased with increasing pressure and became the shortest intermolecular hydrogen bond above 3 GPa. In contrast, the lengths of the bifurcated N-D?O and C-D?O hydrogen bonds, which are formed between the layers of the alpha-glycine molecules along the b axis, decreased significantly with increasing pressure. The decrease of the intermolecular distances resulted in the largest compressibility of the b-axis, compared to the other two axes. The Hirshfeld analysis suggested that the reduction of the void region size, rather than shrinkage of the strong N-D?O hydrogen bonds, occurred with compression. PMID- 29390806 TI - Theoretical restrictions on longest implicit time scales in Markov state models of biomolecular dynamics. AB - Markov state models (MSMs) have been widely used to analyze computer simulations of various biomolecular systems. They can capture conformational transitions much slower than an average or maximal length of a single molecular dynamics (MD) trajectory from the set of trajectories used to build the MSM. A rule of thumb claiming that the slowest implicit time scale captured by an MSM should be comparable by the order of magnitude to the aggregate duration of all MD trajectories used to build this MSM has been known in the field. However, this rule has never been formally proved. In this work, we present analytical results for the slowest time scale in several types of MSMs, supporting the above rule. We conclude that the slowest implicit time scale equals the product of the aggregate sampling and four factors that quantify: (1) how much statistics on the conformational transitions corresponding to the longest implicit time scale is available, (2) how good the sampling of the destination Markov state is, (3) the gain in statistics from using a sliding window for counting transitions between Markov states, and (4) a bias in the estimate of the implicit time scale arising from finite sampling of the conformational transitions. We demonstrate that in many practically important cases all these four factors are on the order of unity, and we analyze possible scenarios that could lead to their significant deviation from unity. Overall, we provide for the first time analytical results on the slowest time scales captured by MSMs. These results can guide further practical applications of MSMs to biomolecular dynamics and allow for higher computational efficiency of simulations. PMID- 29390807 TI - Near-infrared in situ generation of the higher-energy trans conformer of tribromoacetic acid: Observation of a large-scale matrix-site changing mediated by conformational conversion. AB - The first observation of the higher-energy conformer of tribromoacetic acid (trans-TBAA) is reported. The conformer was produced in cryogenic matrices (Ar, Kr, and N2) by in situ selective narrowband near-infrared excitation of the lower energy cis-TBAA conformer and characterized both structurally and vibrationally. The novel trans-TBAA conformer is shown to spontaneously decay to the most stable cis-TBAA form in all studied matrix media, by tunneling, and the measured decay rates in the different matrices were compared with those of the trans conformers of other carboxylic acids in similar experimental conditions. In the N2 matrix, where trans-TBAA establishes a specific stabilizing intermolecular interaction with the host N2 molecules via its OH group and is about 11 times more stable than in rare gas matrices, the effect of changing the irradiation wavenumber within the 2nuOH absorption profile was investigated in detail. An interesting phenomenon of matrix-site changing mediated by conformational conversion was observed in the N2 matrix: vibrational excitation of cis-TBAA in the 2nuOH wavenumber range predominantly converts the molecules located in a specific "matrix site" into trans-TBAA; then, relaxation (by tunneling) of the produced higher-energy conformer back to the cis form populates almost exclusively another "matrix site." The experimental studies received support from quantum chemistry calculations, which allowed a detailed characterization of the relevant regions of the potential energy surface of the molecule and the detailed assignment of the infrared spectra of the two conformers in the various matrices. PMID- 29390808 TI - Active vs. spectator modes in nonadiabatic photodissociation dynamics of the hydroxymethyl radical via the 22A(3s) Rydberg state. AB - The choice of the active degrees of freedom (DOFs) is a pivotal issue in a reduced-dimensional model of quantum dynamics when a full-dimensional one is not feasible. Here, several five-dimensional (5D) models are used to investigate the nonadiabatic photodissociation dynamics of the hydroxymethyl (CH2OH) radical, which possesses nine internal DOFs, in its lowest absorption band. A normal-mode based scheme is used to identify the active and spectator modes, and its predictions are confirmed by 5D quantum dynamical calculations. Our results underscore the important role of the CO stretching mode in the photodissociation dynamics of CH2OH, originating from the photo-induced promotion of an electron from the half-occupied pi*CO antibonding orbital to a carbon Rydberg orbital. PMID- 29390809 TI - Oscillator strengths and integral cross sections for the valence-shell excitations of nitric oxide studied by fast electron impact. AB - The generalized oscillator strengths for the valence-shell excitations of A2Sigma+, C2Pi, and D2Sigma+ electronic-states of nitric oxide have been determined at an incident electron energy of 1500 eV with an energy resolution of 70 meV. The optical oscillator strengths for these transitions have been obtained by extrapolating the generalized oscillator strengths to the limit that the squared momentum transfer approaches to zero, which give an independent cross check to the previous experimental and theoretical results. The integral cross sections for the valence-shell excitations of nitric oxide have been determined systematically from the threshold to 2500 eV with the aid of the newly developed BE-scaling method for the first time. The present optical oscillator strengths and integral cross sections of the valence-shell excitations of nitric oxide play an important role in understanding many physics and chemistry of the Earth's upper atmosphere such as the radiative cooling, ozone destruction, day glow, aurora, and so on. PMID- 29390810 TI - Rapid sampling of stochastic displacements in Brownian dynamics simulations with stresslet constraints. AB - Brownian Dynamics simulations are an important tool for modeling the dynamics of soft matter. However, accurate and rapid computations of the hydrodynamic interactions between suspended, microscopic components in a soft material are a significant computational challenge. Here, we present a new method for Brownian dynamics simulations of suspended colloidal scale particles such as colloids, polymers, surfactants, and proteins subject to a particular and important class of hydrodynamic constraints. The total computational cost of the algorithm is practically linear with the number of particles modeled and can be further optimized when the characteristic mass fractal dimension of the suspended particles is known. Specifically, we consider the so-called "stresslet" constraint for which suspended particles resist local deformation. This acts to produce a symmetric force dipole in the fluid and imparts rigidity to the particles. The presented method is an extension of the recently reported positively split formulation for Ewald summation of the Rotne-Prager-Yamakawa mobility tensor to higher order terms in the hydrodynamic scattering series accounting for force dipoles [A. M. Fiore et al., J. Chem. Phys. 146(12), 124116 (2017)]. The hydrodynamic mobility tensor, which is proportional to the covariance of particle Brownian displacements, is constructed as an Ewald sum in a novel way which guarantees that the real-space and wave-space contributions to the sum are independently symmetric and positive-definite for all possible particle configurations. This property of the Ewald sum is leveraged to rapidly sample the Brownian displacements from a superposition of statistically independent processes with the wave-space and real-space contributions as respective covariances. The cost of computing the Brownian displacements in this way is comparable to the cost of computing the deterministic displacements. The addition of a stresslet constraint to the over-damped particle equations of motion leads to a stochastic differential algebraic equation (SDAE) of index 1, which is integrated forward in time using a mid-point integration scheme that implicitly produces stochastic displacements consistent with the fluctuation dissipation theorem for the constrained system. Calculations for hard sphere dispersions are illustrated and used to explore the performance of the algorithm. An open source, high-performance implementation on graphics processing units capable of dynamic simulations of millions of particles and integrated with the software package HOOMD-blue is used for benchmarking and made freely available in the supplementary material. PMID- 29390811 TI - Microwave spectroscopy of 2-(trifluoromethyl)pyridine?water complex: Molecular structure and hydrogen bond. AB - In order to explore the -CF3 substitution effect on the complexation of pyridine, we investigated the 2-(trifluoromethyl)pyridine?water complex by using pulsed jet Fourier transform microwave spectroscopy complemented with quantum chemical calculations. Experimental assignment and ab initio calculations confirmed that the observed complex is stabilized through N?H-O and O?H-C hydrogen bonds forming a five-membered ring structure. The bonding distance in N?H-O is determined to be 2.027(2) A, whilst that in O?H-C interaction is 2.728(2) A. The quantum theory of atoms in molecules analysis indicates that the interaction energy of N?H-O hydrogen bond is ~22 kJ mol-1 and that for O?H-C hydrogen bond is ~5 kJ mol-1. The water molecule lies almost in the plane of the aromatic ring in the complex. The -CF3 substitution to pyridine quenches the tunneling splitting path of the internal motion of water molecule. PMID- 29390812 TI - Vitrification and gelation in sticky spheres. AB - Glasses and gels are the two dynamically arrested, disordered states of matter. Despite their importance, their similarities and differences remain elusive, especially at high density, where until now it has been impossible to distinguish them. We identify dynamical and structural signatures which distinguish the gel and glass transitions in a colloidal model system of hard and "sticky" spheres. It has been suggested that "spinodal" gelation is initiated by gas-liquid viscoelastic phase separation to a bicontinuous network and the resulting densification leads to vitrification of the colloid-rich phase, but whether this phase has sufficient density for arrest is unclear [M. A. Miller and D. Frenkel, Phys. Rev. Lett. 90, 135702 (2003) and P. J. Lu et al., Nature 435, 499-504 (2008)]. Moreover alternative mechanisms for arrest involving percolation have been proposed [A. P. R. Eberle et al., Phys. Rev. Lett. 106, 105704 (2011)]. Here we resolve these outstanding questions, beginning by determining the phase diagram. This, along with demonstrating that percolation plays no role in controlling the dynamics of our system, enables us to confirm spinodal decomposition as the mechanism for gelation. We are then able to show that gels can be formed even at much higher densities than previously supposed, at least to a volume fraction of phi = 0.59. Far from being networks, these gels apparently resemble glasses but are still clearly distinguished by the "discontinuous" nature of the transition and the resulting rapid solidification, which leads to the formation of inhomogeneous (with small voids) and far-from-equilibrium local structures. This is markedly different from the glass transition, whose continuous nature leads to the formation of homogeneous and locally equilibrated structures. We further reveal that the onset of the attractive glass transition in the form of a supercooled liquid is in fact interrupted by gelation. Our findings provide a general thermodynamic, dynamic, and structural basis upon which we can distinguish gelation from vitrification. PMID- 29390813 TI - Influence of electric field on the amyloid-beta(29-42) peptides embedded in a membrane bilayer. AB - Alzheimer's disease is linked to various types of aggregates of amyloid-beta (Abeta) peptide and their interactions with protein receptors and neuronal cell membranes. Little is known on the impact of the electric field on membrane embedded Abeta. Here we use atomistic molecular dynamics simulations to study the effects of a constant electric field on the conformations of Abeta29-42 dimer inside a membrane, where the electric field has a strength of 20 mV/nm which exists across the membrane of a human neuron. Starting from alpha-helix peptides, the transmembrane electric field (TMEF) accelerates the conversion from the Gly out substate to the Gly-side and Gly-in substates. Starting from beta-sheet peptides, TMEF induces changes of the kink and tilt angles at Gly33 and Gly37. Overall, in the simulations totaling 10 MUs, TMEF establishes new ground states for the dimer, similar to induced-fit in ligand binding. Our findings indicate that TMEF can stabilize rare conformations of amyloid peptides, and this could influence the cleavage of the amyloid precursor protein and the formation of beta sheet oligomers in membrane bilayers. PMID- 29390814 TI - Publisher's Note: "Construction of non-Markovian coarse-grained models employing the Mori-Zwanzig formalism and iterative Boltzmann inversion" [J. Chem. Phys. 147, 244110 (2017)]. PMID- 29390815 TI - Kinetic boundaries and phase transformations of ice i at high pressure. AB - Raman spectroscopy in diamond anvil cells has been employed to study phase boundaries and transformation kinetics of H2O ice at high pressures up to 16 GPa and temperatures down to 15 K. Ice i formed at nearly isobaric cooling of liquid water transforms on compression to high-density amorphous (HDA) ice at 1.1-3 GPa at 15-100 K and then crystallizes in ice vii with the frozen-in disorder (ice vii') which remains stable up to 14.1 GPa at 80 K and 15.9 GPa at 100 K. Unexpectedly, on decompression of ice vii', it transforms to ice viii in its domain of metastability, and then it relaxes into low-density amorphous (LDA) ice on a subsequent pressure release and warming up. On compression of ice i at 150 170 K, ice ix is crystallized and no HDA ice is found; further compression of ice ix results in the sequential phase transitions to stable ices vi and viii. Cooling ice i to 210 K at 0.3 GPa transforms it to a stable ice ii. Our extensive investigations provide previously missing information on the phase diagram of water, especially on the kinetic paths that result in formation of phases which otherwise are not accessible; these results are keys for understanding the phase relations including the formation of metastable phases. Our observations inform on the ice modifications that can occur naturally in planetary environments and are not accessible for direct observations. PMID- 29390816 TI - Adsorption of hairy particles with mobile ligands: Molecular dynamics and density functional study. AB - We study models of hairy nanoparticles in contact with a hard wall. Each particle is built of a spherical core with a number of ligands attached to it and each ligand is composed of several spherical, tangentially jointed segments. The number of segments is the same for all ligands. Particular models differ by the numbers of ligands and of segments per ligand, but the total number of segments is constant. Moreover, our model assumes that the ligands are tethered to the core in such a manner that they can "slide" over the core surface. Using molecular dynamics simulations we investigate the differences in the structure of a system close to the wall. In order to characterize the distribution of the ligands around the core, we have calculated the end-to-end distances of the ligands and the lengths and orientation of the mass dipoles. Additionally, we also employed a density functional approach to obtain the density profiles. We have found that if the number of ligands is not too high, the proposed version of the theory is capable to predict the structure of the system with a reasonable accuracy. PMID- 29390817 TI - On the difference between variational and unitary coupled cluster theories. AB - There have been assertions in the literature that the variational and unitary forms of coupled cluster theory lead to the same energy functional. Numerical evidence from previous authors was inconsistent with this claim, yet the small energy differences found between the two methods and the relatively large number of variational parameters precluded an unequivocal conclusion. Using the Lipkin Hamiltonian, we here present conclusive numerical evidence that the two theories yield different energies. The ambiguities arising from the size of the cluster parameter space are absent in the Lipkin model, particularly when truncating to double excitations. We show that in the symmetry adapted basis under strong correlation, the differences between the variational and unitary models are large, whereas they yield quite similar energies in the weakly correlated regime previously explored. We also provide a qualitative argument rationalizing why these two models cannot be the same. Additionally, we study a generalized non unitary and non-hermitian variant that contains excitation, de-excitation, and mixed operators with different amplitudes and show that it works best when compared to the traditional, variational, unitary, and extended forms of coupled cluster doubles theories. PMID- 29390818 TI - High pressure luminescence of Nd3+ in YAlO3 perovskite nanocrystals: A crystal field analysis. AB - Pressure-induced energy blue- and red-shifts of the 4F3/2 -> 4I9/2,11/2 near infrared emission lines of Nd3+ ions in YAlO3 perovskite nano-particles have been measured from ambient conditions up to 29 GPa. Different positive and negative linear pressure coefficients have been calibrated for the emission lines and related to pressure-induced changes in the interactions between those Nd3+ ions and their twelve oxygen ligands at the yttrium site. Potentiality of the simple overlap model, combined with ab initio structural calculations, in the description of the effects of these interactions on the energy levels and luminescence properties of the optically active Nd3+ ion is emphasized. Simulations show how the energies of the 4f3 ground configuration and the barycenters of the multiplets increase with pressure, whereas the Coulomb interaction between f-electrons decreases and the crystal-field strength increases. All these effects combined explain the wavelength blue-shifts of some near-infrared emission lines of Nd3+ ions. Large pressure rates of various emission lines suggest that a YAlO3 perovskite nano-crystal can be a potential candidate for near-infrared optical pressure sensors. PMID- 29390819 TI - A high-resolution photoelectron imaging and theoretical study of CP- and C2P. AB - The discovery of interstellar anions has been a milestone in astrochemistry. In the search for new interstellar anions, CP- and C2P- are viable candidates since their corresponding neutrals have already been detected astronomically. However, scarce data exist for these negatively charged species. Here we report the electron affinities of CP and C2P along with the vibrational frequencies of their anions using high-resolution photoelectron imaging. These results along with previous spectroscopic data of the neutral species are used further to benchmark very accurate quartic force field quantum chemical methods that are applied to CP, CP-, C2P, and two electronic states of C2P-. The predicted electron affinities, vibrational frequencies, and rotational constants are in excellent agreement with the experimental data. The electron affinities of CP (2.8508 +/- 0.0007 eV) and C2P (2.6328 +/- 0.0006 eV) are measured accurately and found to be quite high, suggesting that the CP- and C2P- anions are thermodynamically stable and possibly observable. The current study suggests that the combination of high resolution photoelectron imaging and quantum chemistry can be used to determine accurate molecular constants for exotic radical species of astronomical interest. PMID- 29390820 TI - Forward flux sampling calculation of homogeneous nucleation rates from aqueous NaCl solutions. AB - We used molecular dynamics simulations and the path sampling technique known as forward flux sampling to study homogeneous nucleation of NaCl crystals from supersaturated aqueous solutions at 298 K and 1 bar. Nucleation rates were obtained for a range of salt concentrations for the Joung-Cheatham NaCl force field combined with the Extended Simple Point Charge (SPC/E) water model. The calculated nucleation rates are significantly lower than the available experimental measurements. The estimates for the nucleation rates in this work do not rely on classical nucleation theory, but the pathways observed in the simulations suggest that the nucleation process is better described by classical nucleation theory than an alternative interpretation based on Ostwald's step rule, in contrast to some prior simulations of related models. In addition to the size of NaCl nucleus, we find that the crystallinity of a nascent cluster plays an important role in the nucleation process. Nuclei with high crystallinity were found to have higher growth probability and longer lifetimes, possibly because they are less exposed to hydration water. PMID- 29390822 TI - Electro-suppression of water nano-droplets' solidification in no man's land: Electromagnetic fields' entropic trapping of supercooled water. AB - Understanding water solidification, especially in "No Man's Land" (NML) (150 K < T < 235 K) is crucially important (e.g., upper-troposphere cloud processes) and challenging. A rather neglected aspect of tropospheric ice-crystallite formation is inevitably present electromagnetic fields' role. Here, we employ non equilibrium molecular dynamics of aggressively quenched supercooled water nano droplets in the gas phase under NML conditions, in externally applied electromagnetic (e/m) fields, elucidating significant differences between effects of static and oscillating fields: although static fields induce "electro freezing," e/m fields exhibit the contrary - solidification inhibition. This anti freeze action extends not only to crystal-ice formation but also restricts amorphisation, i.e., suppression of low-density amorphous ice which forms otherwise in zero-field NML environments. E/m-field applications maintain water in the deeply supercooled state in an "entropic trap," which is ripe for industrial impacts in cryo-freezing, etc. PMID- 29390821 TI - Conversion between parallel and antiparallel beta-sheets in wild-type and Iowa mutant Abeta40 fibrils. AB - Using a variant of Hamilton-replica-exchange, we study for wild type and Iowa mutant Abeta40 the conversion between fibrils with antiparallel beta-sheets and such with parallel beta-sheets. We show that wild type and mutant form distinct salt bridges that in turn stabilize different fibril organizations. The conversion between the two fibril forms leads to the release of small aggregates that in the Iowa mutant may shift the equilibrium from fibrils to more toxic oligomers. PMID- 29390823 TI - Energetics of charged metal clusters containing vacancies. AB - We study theoretically large metal clusters containing vacancies. We propose an approach, which combines the Kohn-Sham results for monovacancy in a bulk of metal and analytical expansions in small parameters cv (relative concentration of vacancies) and RN,v-1, RN,v being cluster radii. We obtain expressions of the ionization potential and electron affinity in the form of corrections to electron work function, which require only the characteristics of 3D defect-free metal. The Kohn-Sham method is used to calculate the electron profiles, ionization potential, electron affinity, electrical capacitance; dissociation, cohesion, and monovacancy-formation energies of the small perfect clusters NaN, MgN, AlN (N <= 270) and the clusters containing a monovacancy (N >= 12) in the stabilized jellium model. The quantum-sized dependences for monovacancy-formation energies are calculated for the Schottky scenario and the "bubble blowing" scenario, and their asymptotic behavior is also determined. It is shown that the asymptotical behaviors of size dependences for these two mechanisms differ from each other and weakly depend on the number of atoms in the cluster. The contribution of monovacancy to energetics of charged clusters and the size dependences of their characteristics and asymptotics are discussed. It is shown that the difference between the characteristics for the neutral and charged clusters is entirely determined by size dependences of ionization potential and electron affinity. Obtained analytical dependences may be useful for the analysis of the results of photoionization experiments and for the estimation of the size dependences of the vacancy concentration including the vicinity of the melting point. PMID- 29390824 TI - Communication: Evaluating non-empirical double hybrid functionals for spin-state energetics in transition-metal complexes. AB - The computationally assisted, accelerated design of inorganic functional materials often relies on the ability of a given electronic structure method to return the correct electronic ground state of the material in question. Outlining difficulties with current density functionals and wave function-based approaches, we highlight why double hybrid density functionals represent promising candidates for this purpose. In turn, we show that PBE0-DH (and PBE-QIDH) offers a significant improvement over its hybrid parent functional PBE0 [as well as B3LYP* and coupled cluster singles and doubles with perturbative triples (CCSD(T))] when computing spin-state splitting energies, using high-level diffusion Monte Carlo calculations as a reference. We refer to the opposing influence of Hartree-Fock (HF) exchange and MP2, which permits higher levels of HF exchange and a concomitant reduction in electronic density error, as the reason for the improved performance of double-hybrid functionals relative to hybrid functionals. Additionally, using 16 transition metal (Fe and Co) complexes, we show that low spin states are stabilised by increasing contributions from MP2 within the double hybrid formulation. Furthermore, this stabilisation effect is more prominent for high field strength ligands than low field strength ligands. PMID- 29390825 TI - Electronic excitations of manganese phthalocyanine molecules. AB - We have investigated the electronic excitation spectrum of individual manganese phthalocyanine (MnPc) molecules in a coronene matrix. Our results corroborate that the observed excitation spectrum is rather sensitive to oxygen contamination of the respective samples. Annealing in vacuum allowed the determination of the electronic excitations of individual MnPc molecules. These results confirm previous data from the literature and, in addition, we have identified a low energy excitation at about 0.8 eV, which had not been reported before. PMID- 29390826 TI - Driving spin transition at interface: Role of adsorption configurations. AB - A clear insight into the electrical manipulation of molecular spins at interface is crucial to the design of molecule-based spintronic devices. Here we report on the electrically driven spin transition in manganocene physisorbed on a metallic surface in two different adsorption configurations predicted by ab initio techniques, including a Hubbard-U correction at the manganese site and accounting for the long-range van der Waals interactions. We show that the application of an electric field at the interface induces a high-spin to low-spin transition in the flat-lying manganocene, while it could hardly alter the high-spin ground state of the standing-up molecule. This phenomenon cannot be explained by either the molecule-metal charge transfer or the local electron correlation effects. We demonstrate a linear dependence of the intra-molecular spin-state splitting on the energy difference between crystal-field splitting and on-site Coulomb repulsion. After considering the molecule-surface binding energy shifts upon spin transition, we reproduce the obtained spin-state energetics. We find that the configuration-dependent responses of the spin-transition originate from the binding energy shifts instead of the variation of the local ligand field. Through these analyses, we obtain an intuitive understanding of the effects of molecule surface contact on spin-crossover under electrical bias. PMID- 29390827 TI - Quantum cascade laser spectroscopy of OCS isotopologues in 4He nanodroplets: A test of adiabatic following for a heavy rotor. AB - We report high-resolution infrared spectra of OCS isotopologues embedded in helium nanodroplets that were recorded with a newly built spectrometer. For the normal isotopologue, we observed the relatively weak third bending overtone band, in addition to new high J transitions in the C-O stretching fundamental, which has previously been investigated by diode laser spectroscopy [S. Grebenev et al., J. Chem. Phys. 112, 4485 (2000)]. Similar to the gas phase, the overtone band is (only) 45 cm-1 higher in energy than the fundamental, and this leads to additional broadening due to rapid vibrational relaxation that is accompanied by the creation of real/virtual phonon excitations. We also observed spectra in the C-O stretching fundamental for several minor isotopologues of OCS, including 18OCS, O13CS, and OC33S, in addition to some new peaks for OC34S. A rovibrational analysis allowed for determination of the moment of inertia of helium (DeltaIHe) that couples to the rotation of OCS for each isotopologue. In the context of the adiabatic following approximation, the helium density structure that follows the rotation of OCS should essentially remain unchanged between the isotopologues, i.e., there should be no dependence of DeltaIHe on the gas phase moment of inertia of OCS (IG). While this behavior was expected for the "heavy" OCS rotor investigated here, we instead found an approximately linear 1:1 relation between DeltaIHe and IG, which suggests partial breakdown of the adiabatic following approximation, making OCS the heaviest molecule for which evidence for this effect has been obtained. PMID- 29390828 TI - Calculation of the orientational linear and nonlinear correlation factors of polar liquids from the rotational Dean-Kawasaki equation. AB - A calculation of the Kirkwood and Piekara-Kielich correlation factors of polar liquids is presented using the forced rotational diffusion theory of Cugliandolo et al. [Phys. Rev. E 91, 032139 (2015)]. These correlation factors are obtained as a function of density and temperature. Our results compare reasonably well with the experimental temperature dependence of the linear dielectric constant of some simple polar liquids across a wide temperature range. A comparison of our results for the linear dielectric constant and the Kirkwood correlation factor with relevant numerical simulations of liquid water and methanol is given. PMID- 29390829 TI - A new collocation-based multi-configuration time-dependent Hartree (MCTDH) approach for solving the Schrodinger equation with a general potential energy surface. AB - We present a new collocation-based multi-configuration time-dependent Hartree (MCTDH) approach for solving the Schrodinger equation required to compute (ro )vibrational spectra, photodissociation cross sections, reaction rate constants, etc., that can be used with general potential energy surfaces. Collocation obviates the need for quadrature and facilitates using complicated kinetic energy operators. When the basis is good, the accuracy of collocation solutions to the Schrodinger equation is not sensitive to the choice of the collocation points. We test the collocation MCTDH equations we derive by showing that they can be used to compute accurate vibrational energy levels of CH3. It is possible to choose (imaginary) time-independent collocation points with which collocation-based MCTDH energies are accurate. It is therefore not necessary to calculate potential values many times during the propagation. PMID- 29390830 TI - SSAGES: Software Suite for Advanced General Ensemble Simulations. AB - Molecular simulation has emerged as an essential tool for modern-day research, but obtaining proper results and making reliable conclusions from simulations requires adequate sampling of the system under consideration. To this end, a variety of methods exist in the literature that can enhance sampling considerably, and increasingly sophisticated, effective algorithms continue to be developed at a rapid pace. Implementation of these techniques, however, can be challenging for experts and non-experts alike. There is a clear need for software that provides rapid, reliable, and easy access to a wide range of advanced sampling methods and that facilitates implementation of new techniques as they emerge. Here we present SSAGES, a publicly available Software Suite for Advanced General Ensemble Simulations designed to interface with multiple widely used molecular dynamics simulations packages. SSAGES allows facile application of a variety of enhanced sampling techniques-including adaptive biasing force, string methods, and forward flux sampling-that extract meaningful free energy and transition path data from all-atom and coarse-grained simulations. A noteworthy feature of SSAGES is a user-friendly framework that facilitates further development and implementation of new methods and collective variables. In this work, the use of SSAGES is illustrated in the context of simple representative applications involving distinct methods and different collective variables that are available in the current release of the suite. The code may be found at: https://github.com/MICCoM/SSAGES-public. PMID- 29390831 TI - Efficiency-limiting processes in cyclopentadithiophene-bridged donor-acceptor type dyes for solid-state dye-sensitized solar cells. AB - The charge generation and recombination processes in three novel push-pull photosensitizers for dye-sensitized solar cells (DSSCs) are studied by ps-MUs transient absorption (TA) and quasi-steady-state photoinduced absorption (PIA) spectroscopy. The three cyclopentadithiophene-based photosensitizer dye molecules exhibit comparably low power conversion efficiencies ranging from 0.8% to 1.7% in solid-state DSSCs. We find that the photocurrents increase in the presence of Li salt additives. Both TA and PIA measurements observe long-lived dye cations created by electron injection from the dyes' excited state for two dyes from the series. However, the third dye shows significantly lower performance as a consequence of the less efficient electron injection even after the addition of Li-salts and faster electron-hole recombination on the ns-MUs time scale. In essence, the prerequisites for this class of donor-pi bridge-acceptor photosensitizers to reach higher charge generation efficiencies are a combination of strong dipole moments and fine tuning of the electronic landscape at the titania-dye interface by Li-salt addition. PMID- 29390832 TI - Photodissociation dynamics of the simplest alkyl peroxy radicals, CH3OO and C2H5OO, at 248 nm. AB - The photodissociation dynamics of the simplest alkyl peroxy radicals, methyl peroxy (CH3OO) and ethyl peroxy (C2H5OO), are investigated using fast beam photofragment translational spectroscopy. A fast beam of CH3OO- or C2H5OO- anions is photodetached to generate neutral radicals that are subsequently dissociated using 248 nm photons. The coincident detection of the photofragment positions and arrival times allows for the determination of mass, translational energy, and angular distributions for both two-body and three-body dissociation events. CH3OO exhibits repulsive O loss resulting in the formation of O(1D) + CH3O with high translational energy release. Minor two-body channels leading to OH + CH2O and CH3O + O(3P) formation are also detected. In addition, small amounts of H + O(3P) + CH2O are observed and attributed to O loss followed by CH3O dissociation. C2H5OO exhibits more complex dissociation dynamics, in which O loss and OH loss occur in roughly equivalent amounts with O(1D) formed as the dominant O atom electronic state via dissociation on a repulsive surface. Minor two-body channels leading to the formation of O2 + C2H5 and HO2 + C2H4 are also observed and attributed to a ground state dissociation pathway following internal conversion. Additionally, C2H5OO dissociation yields a three-body product channel, CH3 + O(3P) + CH2O, for which the proposed mechanism is repulsive O loss followed by the dissociation of C2H5O over a barrier. These results are compared to a recent study of tert-butyl peroxy (t-BuOO) in which 248 nm excitation results in three body dissociation and ground state two-body dissociation but no O(1D) production. PMID- 29390833 TI - Solvophilic and solvophobic surfaces and non-Coulombic surface interactions in charge regulating electric double layers. AB - The properties of electric double layers are governed by the interface between the substrate and the adjacent electrolyte solution. This interface is involved in chemical, Coulombic, and non-Coulombic (e.g., van der Waals or Lennard-Jones) interactions with all components of the fluid phase. We present a detailed study of these interactions using a classical density functional approach. A particular focus is placed on the non-Coulombic interactions and their effect on the surface chemistry and charge regulation. The solution structure near the charged interface is also analyzed and used to offer a thorough interpretation of established concepts such as the Stern and diffuse ionic layers. PMID- 29390834 TI - Self-consistent predictor/corrector algorithms for stable and efficient integration of the time-dependent Kohn-Sham equation. AB - The "real time" formulation of time-dependent density functional theory (TDDFT) involves integration of the time-dependent Kohn-Sham (TDKS) equation in order to describe the time evolution of the electron density following a perturbation. This approach, which is complementary to the more traditional linear-response formulation of TDDFT, is more efficient for computation of broad-band spectra (including core-excited states) and for systems where the density of states is large. Integration of the TDKS equation is complicated by the time-dependent nature of the effective Hamiltonian, and we introduce several predictor/corrector algorithms to propagate the density matrix, one of which can be viewed as a self consistent extension of the widely used modified-midpoint algorithm. The predictor/corrector algorithms facilitate larger time steps and are shown to be more efficient despite requiring more than one Fock build per time step, and furthermore can be used to detect a divergent simulation on-the-fly, which can then be halted or else the time step modified. PMID- 29390835 TI - Phase transitions in single macromolecules: Loop-stretch transition versus loop adsorption transition in end-grafted polymer chains. AB - We use Brownian dynamics simulations and analytical theory to compare two prominent types of single molecule transitions. One is the adsorption transition of a loop (a chain with two ends bound to an attractive substrate) driven by an attraction parameter epsilon and the other is the loop-stretch transition in a chain with one end attached to a repulsive substrate, driven by an external end force F applied to the free end. Specifically, we compare the behavior of the respective order parameters of the transitions, i.e., the mean number of surface contacts in the case of the adsorption transition and the mean position of the chain end in the case of the loop-stretch transition. Close to the transition points, both the static behavior and the dynamic behavior of chains with different length N are very well described by a scaling ansatz with the scaling parameters (epsilon - epsilon*)Nphi (adsorption transition) and (F - F*)Nnu (loop stretch transition), respectively, where phi is the crossover exponent of the adsorption transition and nu is the Flory exponent. We show that both the loop stretch and the loop adsorption transitions provide an exceptional opportunity to construct explicit analytical expressions for the crossover functions which perfectly describe all simulation results on static properties in the finite-size scaling regime. Explicit crossover functions are based on the ansatz for the analytical form of the order parameter distributions at the respective transition points. In contrast to the close similarity in equilibrium static behavior, the dynamic relaxation at the two transitions shows qualitative differences, especially in the strongly ordered regimes. This is attributed to the fact that the surface contact dynamics in a strongly adsorbed chain is governed by local processes, whereas the end height relaxation of a strongly stretched chain involves the full spectrum of Rouse modes. PMID- 29390836 TI - Power functional theory for Newtonian many-body dynamics. AB - We construct a variational theory for the inertial dynamics of classical many body systems out of equilibrium. The governing (power rate) functional depends on three time- and space-dependent one-body distributions, namely, the density, the particle current, and the time derivative of the particle current. The functional is minimized by the true time derivative of the current. Together with the continuity equation, the corresponding Euler-Lagrange equation uniquely determines the time evolution of the system. An adiabatic approximation introduces both the free energy functional and the Brownian free power functional, as is relevant for liquids governed by molecular dynamics at constant temperature. The forces beyond the Brownian power functional are generated from a superpower (above the overdamped Brownian) functional. PMID- 29390837 TI - Chemical ordering and crystal nucleation at the liquid surface: A comparison of Cu50Zr50 and Ni50Al50 alloys. AB - We study the influence of the liquid-vapor surface on the crystallization kinetics of supercooled metal alloys. While a good glass former, Cu50Zr50, shows no evidence of surface enhancement of crystallization, Ni50Al50 exhibits an increased rate of crystallization due to heterogeneous nucleation at the free liquid surface. The difference in the compositional fluctuations at the interface is proposed as the explanation of the distinction between the two alloys. Specifically, we observe compositional ordering at the surface of Ni50Al50, while the Cu50Zr50 alloy only exhibits a diffuse adsorption of the Cu at the interface. We argue that the general difference in composition susceptibilities at planar surfaces represents an important factor in understanding the difference in the glass forming ability of the two alloys. PMID- 29390838 TI - Ab initio potential and rotational spectra of the CO-N2 complex. AB - Ab initio calculations of the intermolecular potential energy surface (PES) of CO N2 have been carried out using the closed-shell single- and double-excitation coupled cluster approach with a non-iterative perturbative treatment of triple excitations method and the augmented correlation-consistent quadruple-zeta (aug cc-pVQZ) basis set supplemented with midbond functions. The global minimum (De = 117.35 cm-1) of the four-dimensional PES corresponds to an approximately T-shaped structure with the N2 subunit forming the leg and CO the top. The bound rovibrational levels of the CO-N2 complex were calculated for total angular momenta J = 0-8 on this intermolecular potential surface. The calculated dissociation energies D0 are 75.60 and 76.79 cm-1 for the ortho-N2 (A-symmetry) and para-N2 (B-symmetry) nuclear spin modifications of CO-N2, respectively. Guided by these bound state calculations, a new millimeter-wave survey for the CO N2 complex in the frequency range of 110-145 GHz was performed using the intracavity OROTRON jet spectrometer. Transitions not previously observed were detected and assigned to the subbands connecting the K = 0 and 1, (jCO, jN2 ) = (1, 0) states with a new K = 1, (jCO, jN2 ) = (2, 0) state. Finally, the measured rotational energy levels of the CO-N2 complex were compared to the theoretical bound state results, thus providing a critical test of the quality of the PES presented. The computed rovibrational wave functions were analyzed to characterize the nature of the different bound states observed for the two nuclear spin species of CO-N2. PMID- 29390839 TI - Double layer of platinum electrodes: Non-monotonic surface charging phenomena and negative double layer capacitance. AB - In this study, a refined double layer model of platinum electrodes accounting for chemisorbed oxygen species, oriented interfacial water molecules, and ion size effects in solution is presented. It results in a non-monotonic surface charging relation and a peculiar capacitance vs. potential curve with a maximum and possibly negative values in the potential regime of oxide-formation. PMID- 29390840 TI - Perturbative treatment of spin-orbit-coupling within spin-free exact two component theory using equation-of-motion coupled-cluster methods. AB - A scheme is reported for the perturbative calculation of spin-orbit coupling (SOC) within the spin-free exact two-component theory in its one-electron variant (SFX2C-1e) in combination with the equation-of-motion coupled-cluster singles and doubles method. Benchmark calculations of the spin-orbit splittings in 2Pi and 2P radicals show that the accurate inclusion of scalar-relativistic effects using the SFX2C-1e scheme extends the applicability of the perturbative treatment of SOC to molecules that contain heavy elements. The contributions from relaxation of the coupled-cluster amplitudes are shown to be relatively small; significant contributions from correlating the inner-core orbitals are observed in calculations involving third-row and heavier elements. The calculation of term energies for the low-lying electronic states of the PtH radical, which serves to exemplify heavy transition-metal containing systems, further demonstrates the quality that can be achieved with the pragmatic approach presented here. PMID- 29390841 TI - Effects of temperature and mass conservation on the typical chemical sequences of hydrogen oxidation. AB - Macroscopic properties of reacting mixtures are necessary to design synthetic strategies, determine yield, and improve the energy and atom efficiency of many chemical processes. The set of time-ordered sequences of chemical species are one representation of the evolution from reactants to products. However, only a fraction of the possible sequences is typical, having the majority of the joint probability and characterizing the succession of chemical nonequilibrium states. Here, we extend a variational measure of typicality and apply it to atomistic simulations of a model for hydrogen oxidation over a range of temperatures. We demonstrate an information-theoretic methodology to identify typical sequences under the constraints of mass conservation. Including these constraints leads to an improved ability to learn the chemical sequence mechanism from experimentally accessible data. From these typical sequences, we show that two quantities defining the variational typical set of sequences-the joint entropy rate and the topological entropy rate-increase linearly with temperature. These results suggest that, away from explosion limits, data over a narrow range of thermodynamic parameters could be sufficient to extrapolate these typical features of combustion chemistry to other conditions. PMID- 29390842 TI - Surface damage in cystine, an amino acid dimer, induced by keV ions. AB - We have studied the interaction of an ion beam (17.6 keV F-) with cystine, a dimer formed by the binding of two cysteine residues. Cystine can be considered as an ideal prototype for the study of the relevance of the disulfide (-S-S-) chemical bond in biomolecules. For the sake of comparison, the amino acid cysteine has also been subjected to the same experimental conditions. Characterization of the samples by XPS and NEXAFS shows that both pristine cystine and pristine cysteine are found as a dipolar ion (zwitterion). Following irradiation, the dimer and the amino acid show a tendency to change from the dipole ion form to the normal uncharged form. The largest spectral modification was observed in the high resolution XPS spectra obtained at around the N 1s core level for the two biomolecules. The 2p sulfur edge spectra of cysteine and cystine were much less sensitive to radiation effects. We suggest that the disulfide bond (-S-S-) remains stable before and after irradiation, contributing to the larger radiation stability of cystine as compared to the amino acid cysteine. PMID- 29390843 TI - Measurement of Soret coefficients in a ternary mixture of toluene-methanol cyclohexane in convection-free environment. AB - We report on the measurement of Soret (ST) coefficients in the ternary system toluene (T)-methanol (M)-cyclohexane (Ch) onboard the International Space Station in the experiment selectable optical diagnostic instrument/DCMIX2 (Diffusion Coefficients Measurement in ternary mIXtures). Nine experiments were conducted in the range of mean temperatures between 298.15 K and 306.15 K in the mixture with composition 0.62 (T)-0.31 (M)-0.07 (Ch) in mass fractions. A linear dependence of the Soret coefficients on temperature was established for the ternary mixture. It has also been found that, over considered range of mean temperatures, the Soret coefficients of toluene are small and positive, while the Soret coefficients for methanol are negative and, at least, two times larger. The present work also presents a comprehensive study of possible methodologies to process raw data from the Soret experiment in ternary mixtures. All the experiments were processed by seven different schemes and two of them were identified as the most reliable. We also investigate the error propagation and explain the reasons for the discrepancy of the results obtained by different schemes. PMID- 29390844 TI - Breit corrections to individual atomic and molecular orbital energies. AB - Several issues concerning Breit correction to electron-electron interaction in many-electron systems, which are important in precise atomic and molecular calculations, are presented. At first, perturbative versus self-consistent calculations of Breit correction were studied in selected cases. Second, the Z dependence of Breit contribution per subshell is shown, based on values calculated for selected atoms with 30 <= Z <= 118. Third, the relations between magnetic and retardation parts of Breit interaction are analyzed. Finally, Gaunt contribution calculated for Kr, Xe, and Rn noble gas atoms and its iso-electronic HBr, HI, and HAt diatomic molecules has been compared to full-Breit atomic calculations. We found that Breit corrections should be treated by self consistent calculations and that there is a functional dependence of those corrections for subshells as epsilonnlBreit(Z)?a*Zb. We also found that molecular Gaunt corrections are close to their atomic counterparts for inner electrons though they are not for outer orbitals. In any case, accurate calculations must include retardation correction in addition to Gaunt. PMID- 29390845 TI - Singlet-triplet splittings from the virial theorem and single-particle excitation energies. AB - The zeroth-order (uncorrelated) singlet-triplet energy difference in single particle excited configurations is 2Kif, where Kif is the Coulomb self-energy of the product of the transition orbitals. Here we present a non-empirical, virial theorem argument that the correlated singlet-triplet energy difference should be half of this, namely, Kif. This incredibly simple result gives vertical HOMO-LUMO excitation energies in small-molecule benchmarks as good as the popular TD-B3LYP time-dependent approach to excited states. For linear acenes and nonlinear polycyclic aromatic hydrocarbons, the performance is significantly better than TD B3LYP. In addition to the virial theorem, the derivation borrows intuitive pair density concepts from density-functional theory. PMID- 29390846 TI - Magnetic properties and core electron binding energies of liquid water. AB - The magnetic properties and the core and inner valence electron binding energies of liquid water are investigated. The adopted methodology relies on the combination of molecular dynamics and electronic structure calculations. Born Oppenheimer molecular dynamics with the Becke and Lee-Yang-Parr functionals for exchange and correlation, respectively, and includes an empirical correction (BLYP-D3) functional and classical molecular dynamics with the TIP4P/2005-F model were carried out. The Keal-Tozer functional was applied for predicting magnetic shielding and spin-spin coupling constants. Core and inner valence electron binding energies in liquid water were calculated with symmetry adapted cluster configuration interaction. The relationship between the magnetic shielding constant sigma(17O), the role played by the oxygen atom as a proton acceptor and donor, and the tetrahedral organisation of liquid water are investigated. The results indicate that the deshielding of the oxygen atom in water is very dependent on the order parameter (q) describing the tetrahedral organisation of the hydrogen bond network. The strong sensitivity of magnetic properties on changes of the electronic density in the nuclei environment is illustrated by a correlation between sigma(17O) and the energy gap between the 1a1[O1s] (core) and the 2a1 (inner valence) orbitals of water. Although several studies discussed the eventual connection between magnetic properties and core electron binding energies, such a correlation could not be clearly established. Here, we demonstrate that for liquid water this correlation exists although involving the gap between electron binding energies of core and inner valence orbitals. PMID- 29390847 TI - The nearest neighbor and next nearest neighbor effects on the thermodynamic and kinetic properties of RNA base pair. AB - The thermodynamic and kinetic parameters of an RNA base pair with different nearest and next nearest neighbors were obtained through long-time molecular dynamics simulation of the opening-closing switch process of the base pair near its melting temperature. The results indicate that thermodynamic parameters of GC base pair are dependent on the nearest neighbor base pair, and the next nearest neighbor base pair has little effect, which validated the nearest-neighbor model. The closing and opening rates of the GC base pair also showed nearest neighbor dependences. At certain temperature, the closing and opening rates of the GC pair with nearest neighbor AU is larger than that with the nearest neighbor GC, and the next nearest neighbor plays little role. The free energy landscape of the GC base pair with the nearest neighbor GC is rougher than that with nearest neighbor AU. PMID- 29390848 TI - Optimized "detectors" for dynamics analysis in solid-state NMR. AB - Relaxation in nuclear magnetic resonance (NMR) results from stochastic motions that modulate anisotropic NMR interactions. Therefore, measurement of relaxation rate constants can be used to characterize molecular-dynamic processes. The motion is often characterized by Markov processes using an auto-correlation function, which is assumed to be a sum of multiple decaying exponentials. We have recently shown that such a model can lead to severe misrepresentation of the real motion, when the real correlation function is more complex than the model. Furthermore, multiple distributions of motion may yield the same set of dynamics data. Therefore, we introduce optimized dynamics "detectors" to characterize motions which are linear combinations of relaxation-rate constants. A detector estimates the average or total amplitude of motion for a range of motional correlation times. The information obtained through the detectors is less specific than information obtained using an explicit model, but this is necessary because the information contained in the relaxation data is ambiguous, if one does not know the correct motional model. On the other hand, if one has a molecular dynamics trajectory, one may calculate the corresponding detector responses, allowing direct comparison to experimental NMR dynamics analysis. We describe how to construct a set of optimized detectors for a given set of relaxation measurements. We then investigate the properties of detectors for a number of different data sets, thus gaining an insight into the actual information content of the NMR data. Finally, we show an example analysis of ubiquitin dynamics data using detectors, using the DIFRATE software. PMID- 29390849 TI - Enhanced gel formation in binary mixtures of nanocolloids with short-range attraction. AB - Colloidal suspensions transform between fluid and disordered solid states as parameters such as the colloid volume fraction and the strength and nature of the colloidal interactions are varied. Seemingly subtle changes in the characteristics of the colloids can markedly alter the mechanical rigidity and flow behavior of these soft composite materials. This sensitivity creates both a scientific challenge and an opportunity for designing suspensions for specific applications. In this paper, we report a novel mechanism of gel formation in mixtures of weakly attractive nanocolloids with modest size ratio. Employing a combination of x-ray photon correlation spectroscopy, rheometry, and molecular dynamics simulations, we find that gels are stable at remarkably weaker attraction in mixtures with size ratio near two than in the corresponding monodisperse suspensions. In contrast with depletion-driven gelation at larger size ratio, gel formation in the mixtures is triggered by microphase demixing of the species into dense regions of immobile smaller colloids surrounded by clusters of mobile larger colloids that is not predicted by mean-field thermodynamic considerations. These results point to a new route for tailoring nanostructured colloidal solids through judicious combination of interparticle interaction and size distribution. PMID- 29390850 TI - Kinetic energy classification and smoothing for compact B-spline basis sets in quantum Monte Carlo. AB - Quantum Monte Carlo calculations of defect properties of transition metal oxides have become feasible in recent years due to increases in computing power. As the system size has grown, availability of on-node memory has become a limiting factor. Saving memory while minimizing computational cost is now a priority. The main growth in memory demand stems from the B-spline representation of the single particle orbitals, especially for heavier elements such as transition metals where semi-core states are present. Despite the associated memory costs, splines are computationally efficient. In this work, we explore alternatives to reduce the memory usage of splined orbitals without significantly affecting numerical fidelity or computational efficiency. We make use of the kinetic energy operator to both classify and smooth the occupied set of orbitals prior to splining. By using a partitioning scheme based on the per-orbital kinetic energy distributions, we show that memory savings of about 50% is possible for select transition metal oxide systems. For production supercells of practical interest, our scheme incurs a performance penalty of less than 5%. PMID- 29390851 TI - Calculations of non-adiabatic couplings within equation-of-motion coupled-cluster framework: Theory, implementation, and validation against multi-reference methods. AB - We report an implementation of non-adiabatic coupling (NAC) forces within the equation-of-motion coupled-cluster with single and double excitations (EOM-CCSD) framework via the summed-state approach. Using illustrative examples, we compare NAC forces computed with EOM-CCSD and multi-reference (MR) wave functions (for selected cases, we also consider configuration interaction singles). In addition to the magnitude of the NAC vectors, we analyze their direction, which is important for the calculations of the rate of non-adiabatic transitions. Our benchmark set comprises three doublet radical-cations (hexatriene, cyclohexadiene, and uracil), neutral uracil, and sodium-doped ammonia clusters. When the characters of the states agree among different methods, we observe good agreement between the respective NAC vectors, both in the Franck-Condon region and away. In the cases of large discrepancies between the methods, the disagreement can be attributed to the difference in the states' character, which, in some cases, is very sensitive to electron correlation, both within single reference and multi-reference frameworks. The numeric results confirm that the accuracy of NAC vectors depends critically on the quality of the underlying wave functions. Within their domain of applicability, EOM-CC methods provide a viable alternative to MR approaches. PMID- 29390852 TI - Structures of the dehydrogenation products of methane activation by 5d transition metal cations revisited: Deuterium labeling and rotational contours. AB - A previous infrared multiple photon dissociation (IRMPD) action spectroscopy and density functional theory (DFT) study explored the structures of the [M,C,2H]+ products formed by dehydrogenation of methane by four, gas-phase 5d transition metal cations (M+ = Ta+, W+, Ir+, and Pt+). Complicating the analysis of these spectra for Ir and Pt was observation of an extra band in both spectra, not readily identified as a fundamental vibration. In an attempt to validate the assignment of these additional peaks, the present work examines the gas phase [M,C,2D]+ products of the same four metal ions formed by reaction with perdeuterated methane (CD4). As before, metal cations are formed in a laser ablation source and react with methane pulsed into a reaction channel downstream, and the resulting products are spectroscopically characterized through photofragmentation using the free-electron laser for intracavity experiments in the 350-1800 cm-1 range. Photofragmentation was monitored by the loss of D for [Ta,C,2D]+ and [W,C,2D]+ and of D2 in the case of [Pt,C,2D]+ and [Ir,C,2D]+. Comparison of the experimental spectra and DFT calculated spectra leads to structural assignments for all [M,C,2H/2D]+ systems that are consistent with previous identifications and allows a full description of the systematic spectroscopic shifts observed for deuterium labeling of these complexes, some of the smallest systems to be studied using IRMPD action spectroscopy. Further, full rotational contours are simulated for each vibrational band and explain several observations in the present spectra, such as doublet structures in several bands as well as the observed linewidths. The prominent extra bands in the [Pt,C,2D/2H]+ spectra appear to be most consistent with an overtone of the out-of plane bending vibration of the metal carbene cation structure. PMID- 29390853 TI - Properties of closed-shell superheavy element hydrides and halides using coupled cluster method and density functional theory with spin-orbit coupling. AB - We report bond lengths, force constants, and dissociation energies for a series of closed-shell superheavy element monohydrides and halides at the singles and doubles level with perturbative triples (CCSD(T)) using recently developed relativistic effective core potentials in this work. CCSD(T) results with spin orbit coupling (SOC) included in self-consistent field (SCF) calculations provide highly accurate estimates for properties of these molecules. Trends as well as SOC effects on properties of these molecules are presented. Performance of the coupled-cluster (CC) approach with SOC included in post-SCF calculations (SOC-CC) on these superheavy element molecules is evaluated. Our results show that SOC CCSD results are in excellent agreement with those of KR-CCSD, while the error of SOC-CCSD(T) is larger, particularly for molecules containing element 114. Density functional theory results with various exchange-correlation (XC) functionals for these superheavy element molecules are also compared with those of CCSD(T). PBE0 is shown to be able to give rise to results that agree best with those of CCSD(T) in scalar-relativistic calculations among the investigated XC functionals. On the other hand, B97-3 is the best XC functional when SOC is considered in calculations. PMID- 29390854 TI - Lanthanum-mediated dehydrogenation of butenes: Spectroscopy and formation of La(C4H6) isomers. AB - La atom reactions with 1-butene, 2-butene, and isobutene are carried out in a laser-vaporization molecular beam source. The three reactions yield the same La hydrocarbon products from the dehydrogenation and carbon-carbon bond cleavage and coupling of the butenes. The dehydrogenated species La(C4H6) is the major product, which is characterized with mass-analyzed threshold ionization (MATI) spectroscopy and quantum chemical computations. The MATI spectrum of La(C4H6) produced from the La+1-butene reaction exhibits two band systems, whereas the MATI spectra produced from the La+2-butene and isobutene reactions display only a single band system. Each of these spectra shows a strong origin band and several vibrational progressions. The two band systems from the spectrum of the 1-butene reaction are assigned to the ionization of two isomers: La[C(CH2)3] (Iso A) and La(CH2CHCHCH2) (Iso B), and the single band system from the spectra of the 2 butene and isobutene reactions is attributed to Iso B and Iso A, respectively. The ground electronic states are 2A1 (C3v) for Iso A and 2A' (Cs) for Iso B. The ionization of the doublet state of each isomer removes a La 6s-based electron and leads to the 1A1 ion of Iso A and the 1A' ion of Iso B. The formation of both isomers consists of La addition to the C=C double bond, La insertion into two C(sp3)-H bonds, and H2 elimination. In addition to these steps, the formation of Iso A from the La+1-butene reaction may involve the isomerization of 1-butene to isobutene prior to the C-H bond activation, whereas the formation of Iso B from the La+trans-2-butene reaction may include the trans- to cis-butene isomerization after the C-H bond activation. PMID- 29390855 TI - Upside/Downside statistical mechanics of nonequilibrium Brownian motion. I. Distributions, moments, and correlation functions of a free particle. AB - Statistical properties of Brownian motion that arise by analyzing, separately, trajectories over which the system energy increases (upside) or decreases (downside) with respect to a threshold energy level are derived. This selective analysis is applied to examine transport properties of a nonequilibrium Brownian process that is coupled to multiple thermal sources characterized by different temperatures. Distributions, moments, and correlation functions of a free particle that occur during upside and downside events are investigated for energy activation and energy relaxation processes and also for positive and negative energy fluctuations from the average energy. The presented results are sufficiently general and can be applied without modification to the standard Brownian motion. This article focuses on the mathematical basis of this selective analysis. In subsequent articles in this series, we apply this general formalism to processes in which heat transfer between thermal reservoirs is mediated by activated rate processes that take place in a system bridging them. PMID- 29390856 TI - Formation of He4+ via electron impact of helium droplets. AB - Electron impact ionization of superfluid helium droplets containing several thousand atoms produces a broad distribution of Hen+ ions that peaks at n = 2 and decreases monotonically toward larger n. In larger droplets (say 105 or more atoms), however, the He4+ signal intensity is anomalously large. We have studied the mechanism for the formation of He4+ ions in large helium droplets by varying the duration of the electron impact excitation pulse. Droplets of different average sizes were generated using the expansion of helium at 20 bars and 9-20 K through a pulsed valve nozzle. The resulting ions were analyzed by time-of-flight mass spectroscopy (TOFMS) and quadrupole mass spectroscopy (QMS). The intensity distributions obtained with the TOFMS technique initially showed much smaller He4+ signals than those obtained using QMS. However, we discovered that the intensity anomaly is associated with the duration of the electron bombardment pulse in the TOFMS instrument. Measurements with different electron bombardment pulse durations enabled us to discern a characteristic time of ~10 MUs for enhanced He4+ production in large droplets under our experimental conditions. A qualitative model is presented in which metastables interact on droplet surfaces, yielding two He2+ cores that share a Rydberg electron while minimizing repulsion between the cores. This is the He4+(4A2) state suggested by Knowles and Murrell. PMID- 29390857 TI - Lowering of the complexity of quantum chemistry methods by choice of representation. AB - The complexity of the standard hierarchy of quantum chemistry methods is not invariant to the choice of representation. This work explores how the scaling of common quantum chemistry methods can be reduced using real-space, momentum-space, and time-dependent intermediate representations without introducing approximations. We find the scalings of exact Gaussian basis Hartree-Fock theory, second-order Moller-Plesset perturbation theory, and coupled cluster theory (specifically, linearized coupled cluster doubles and the distinguishable cluster approximation with doubles) to be O(N3), O(N3), and O(N5), respectively, where N denotes the system size. These scalings are not asymptotic and hold over all ranges of N. PMID- 29390858 TI - Communication: Electronic flux induced by crossing the transition state. AB - We present a new effect of chemical reactions, e.g., isomerizations, that occurs when the reactants pass along the transition state, on the way to products. It is based on the well-known fact that at the transition state, the electronic structure of one isomer changes to the other. We discover that this switch of electronic structure causes a strong electronic flux that is well distinguishable from the usual flux of electrons that travel with the nuclei. As a simple but clear example, the effect is demonstrated here for bond length isomerization of Na2 (21Sigmau+), with adiabatic crossing the barrier between the inner and outer wells of the double minimum potential that support different "Rydberg" and "ionic" type electronic structures, respectively. PMID- 29390859 TI - Early stage aggregation of a coarse-grained model of polyglutamine. AB - In this paper, we study the early stages of aggregation of a model of polyglutamine (polyQ) for different repeat lengths (number of glutamine amino acid groups in the chain). In particular, we use the Large-scale Atomic/Molecular Massively Parallel Simulator to study a generic coarse-grained model proposed by Bereau and Deserno. We focus on the primary nucleation mechanism involved and find that our results for the initial self-assembly process are consistent with the two-dimensional classical nucleation theory of Kashchiev and Auer. More specifically, we find that with decreasing supersaturation, the oligomer fibril (protofibril) transforms from a one-dimensional beta sheet to two-, three-, and higher layer beta sheets as the critical nucleus size increases. We also show that the results are consistent with several predictions of their theory, including the dependence of the critical nucleus size on the supersaturation. Our results for the time dependence of the mass aggregation are in reasonable agreement with an approximate analytical solution of the filament theory by Knowles and collaborators that corresponds to an additional secondary nucleation arising from filament fragmentation. Finally, we study the dependence of the critical nucleus size on the repeat length of polyQ. We find that for the larger length polyglutamine chain that we study, the critical nucleus is a monomer, in agreement with experiment and in contrast to the case for the smaller chain, for which the smallest critical nucleus size is four. PMID- 29390860 TI - Healthcare resource utilization and costs in amyloid light-chain amyloidosis: a real-world study using US claims data. AB - AIM: To estimate healthcare utilization and costs in amyloid light-chain (AL) amyloidosis. PATIENTS & METHODS: AL amyloidosis patients were identified in 2007 2015 claims databases if they had >=1 inpatient/>=2 outpatient claims consistent with AL amyloidosis and received >=1 AL-specific treatment. Descriptive statistics were reported. RESULTS: 50.1% (n = 3670) were admitted >=1 time during the year, 11.3% (n = 827) >=3 times. From 2007 to 2015, bortezomib use increased from 4.6 to 25.3%; melphalan use decreased from 18.9 to 2.0%; costs increased from 92,866 to $114,030. Among incident patients with at least 2 years of follow up, healthcare utilization and costs decreased from first to second year post diagnosis. CONCLUSION: AL chemotherapy-based prescribing practices changed. Total annual healthcare costs increased over time among AL amyloidosis patients. PMID- 29390862 TI - Financial Incentives for Chronic Disease Management: Results and Limitations of 2 Randomized Clinical Trials With New York Medicaid Patients. AB - PURPOSE: To identify whether financial incentives promote improved disease management in Medicaid recipients diagnosed with hypertension or diabetes, respectively. DESIGN: Four-group, multicenter, randomized clinical trials. SETTING AND PARTICIPANTS: Between 2013 and 2016, New York State Medicaid managed care members diagnosed with hypertension (N = 920) or with diabetes (N = 959). INTERVENTION: Participants in each 6-month trial were randomly assigned to 1 of 4 arms: (1) process incentives-earned by attending primary care visits and/or receiving prescription medication refills, (2) outcome incentives-earned by reducing systolic blood pressure (hypertension) or hemoglobin A1c (HbA1c; diabetes) levels, (3) combined process and outcome incentives, and (4) control (no incentives). MEASURES: Systolic blood pressure (hypertension) and HbA1c (diabetes) levels, primary care visits, and medication prescription refills. Analysis and Results: At 6 months, there were no statistically significant differences between intervention arms and the control arm in the change in systolic blood pressure, P = .531. Similarly, there were no significant differences in blood glucose control (HbA1c) between the intervention arms and control after 6 months, P = .939. The majority of participants had acceptable systolic blood pressure (<140 mm Hg) or blood glucose (<8.0%) levels at baseline and throughout the study. CONCLUSION: Financial incentives-regardless of whether they were delivered based on disease-relevant outcomes, process activities, or a combination of the two-have a negligible impact on health outcomes for Medicaid recipients diagnosed with either hypertension or diabetes in 2 studies in which, among other design and operational limitations, the majority of recipients had relatively well-controlled diseases at the time of enrollment. PMID- 29390861 TI - Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox Active Compounds That Cycle with Ascorbate. AB - AIMS: We aim here to demonstrate that radiation (RT) enhances tumor sensitization by only those Mn complexes that are redox active and cycle with ascorbate (Asc), thereby producing H2O2 and utilizing it subsequently in protein S glutathionylation in a glutathione peroxidase (GPx)-like manner. In turn, such compounds affect cellular redox environment, described by glutathione disulfide (GSSG)/glutathione (GSH) ratio, and tumor growth. To achieve our goal, we tested several Mn complexes of different chemical and physical properties in cellular and animal flank models of 4T1 breast cancer cell. Four other cancer cell lines were used to substantiate key findings. RESULTS: Joint administration of cationic Mn porphyrin (MnP)-based redox active compounds, MnTE-2-PyP5+ or MnTnBuOE-2-PyP5+ with RT and Asc contributes to high H2O2 production in cancer cells and tumor, which along with high MnP accumulation in cancer cells and tumor induces the largest suppression of cell viability and tumor growth, while increasing GSSG/GSH ratio and levels of total S-glutathionylated proteins. Redox-inert MnP, MnTBAP3- and two other different types of redox-active Mn complexes (EUK-8 and M40403) were neither efficacious in the cellular nor in the animal model. Such outcome is in accordance with their inability to catalyze Asc oxidation and mimic GPx. INNOVATION: We provided here the first evidence how structure-activity relationship between the catalytic potency and the redox properties of Mn complexes controls their ability to impact cellular redox environment and thus enhance the radiation and ascorbate-mediated tumor suppression. CONCLUSIONS: The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects. PMID- 29390863 TI - A Civic Engagement Approach to Encourage Healthy Eating and Active Living in Rural Towns: The HEART Club Pilot Project. AB - PURPOSE: To assess the feasibility and effectiveness of a civic engagement curriculum (encouraging Healthy Eating and Activity in Rural Towns [HEART] Club) designed to engage rural residents in improving their local food or physical activity environment. DESIGN: Pre-post surveys and focus groups. SETTING: Three rural Northeastern towns in the United States. PARTICIPANTS: Twenty-six rural residents (7-12 per town) recruited by local extension educators. MEASURES: Online surveys were used to assess outcomes related to feasibility (satisfaction) and effectiveness (knowledge, awareness, motivation, self-efficacy, and group efficacy for community change). Feasibility was also assessed through attendance logs, benchmark achievement records, and post-implementation focus groups. ANALYSIS: Participant characteristics and feasibility measures were summarized using descriptive statistics. Pre-post changes in effectiveness outcomes were assessed using Wilcoxon signed rank tests. Focus group data were thematically examined to identify barriers to and facilitators of HEART Club progress. RESULTS: Meeting attendance and program satisfaction were high (88% and 91%). Participants reported improvements in awareness; however, no other significant changes were observed. All HEART Clubs accomplished 3 or more project benchmarks after 6 months of implementation. Despite competing priorities and limited finances, groups effectively leveraged existing resources to achieve their goals. Important facilitators of success included stakeholder support, effective leadership, and positive group dynamics. CONCLUSION: These findings suggest that resident-driven initiatives that build upon local resources and establish feasible goals can successfully foster environmental change in rural communities. PMID- 29390865 TI - Holocord oligodendroglioma with intracranial extension in a young adult: a case report and review of literature. AB - Widespread primary spinal oligodendrogliomas are a rare variety of tumors that usually affect children. Currently, there are only two adult cases reported worldwide. We report the first case of primary holocord oligodendroglioma with intracranial extension in a young adult female. The patient presented with a 4 month history of fluctuating hemiparesis of the left upper extremity eventually becoming quadriplegic after 1 month. Imaging findings revealed a contrast enhancing holocord neoplasm spanning from the cervical region to the conus medullaris and with extension to the lower medulla. The patient succumbed to severe pneumonia after 1 month of admission. An autopsy was done and the histopathologic findings were consistent with oligodendroglioma. PMID- 29390866 TI - Carotid Artery Stenting Has a Role in the Management of Asymptomatic Carotid Stenosis, but This Is Currently Small. PMID- 29390867 TI - The Incidence, Risk Factors, and Outcomes of Contrast-Induced Nephropathy In Patients With Critical Limb Ischemia Following Lower Limb Angiography. AB - Intra-arterial digital subtraction angiography (DSA) is commonly used for the diagnosis and treatment of patients with critical limb ischemia (CLI). The aim of this study was to analyze the incidence of contrast-induced nephropathy (CIN) in patients with CLI and to assess their outcomes. Between May 2013 and May 2014, a prospective and observational study was conducted with 107 patients admitted exclusively for CLI treatment. The main outcomes included hemodialysis independence (HI) and overall survival (OS), as assessed by Kaplan-Meier curves. Overall, there was a predominance of males (57%), with a mean age of 70.5 (10.7) years. The incidence of CIN was 35.5%, and chronic kidney failure was the only factor associated with elevated risk of this condition (relative risk [RR] = 1.9; 95% confidence interval = 1.17-3.09; P = .017). The median follow-up was 645 days, and in 720-day analyses, patients who experienced CIN had worse HI (81.2% vs 96.3%; P = .0107) and OS (49.5% vs 66.3%; P = .0463). The current study found a high incidence of CIN in patients with CLI after DSA. This renal impairment was associated with a worse prognosis in terms of survival. PMID- 29390868 TI - Selected Parameters of Angiogenesis and the JAK2, CALR, and MPL Mutations in Patients With Essential Thrombocythemia. AB - The aim of the study was to evaluate selected angiogenic factors in patients with essential thrombocythemia (ET) depending on JAK2V617F, calreticulin gene (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations. Sixty ET patients and 20 healthy volunteers were enrolled in the study. The following tests were performed: vascular endothelial growth factor- A (VEGF-A), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1),soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), platelet-derived growth factor( PDGF-BB), and stromal-derived factor-1alpha (SDF-1alpha). We observed an increased PDGF-BB level in patients with ET compared to the controls. Patients with CALR mutation had significantly higher concentration of PDGF-BB and lower concentration of SDF 1alpha than patients with JAK2V617F mutation. High concentration of PDGF-BB and low concentration of SDF-1alpha in patients with CALR(+) ET may indicate a contribution of these chemokines in disturbed Ca2+ metabolism in platelets. PMID- 29390869 TI - Sleep Pattern and Predictors of Sleep Disturbance Among Family Caregivers of Terminal Ill Patients With Cancer in Taiwan: A Longitudinal Study. AB - BACKGROUND: Sleep disturbance commonly has a negative impact on the well-being of family caregivers (FCs) of terminally ill patients with cancer. The effect of sleep disturbance on FCs has not been explored through long-term follow-up studies in Taiwan. OBJECTIVE: The purposes of this study were to (1) identify the trajectory of sleep quality of FCs of terminally ill patients with cancer in Taiwan and (2) examine the determinants of sleep disturbance through a longitudinal follow-up until patient death. METHODS: A prospective, longitudinal study was conducted among 95 FCs of terminally ill patients with cancer. The FCs' sleep quality was measured subjectively by using the Pittsburgh Sleep Quality Index and objectively by wearing a wrist actigraphy for 48 hours each month during the 6-month follow-up assessments. The trajectory and determinants of sleep quality were identified using a generalized estimation equation approach. RESULTS: The FCs' sleep quality significantly decreased as the patient's death approached. Family caregivers who were women or older, had a relative with a longer survival period after diagnosis, reported higher levels of depression and fatigue, and provided lower levels of assistance to their relatives experienced more sleep disturbance. CONCLUSION: The sleep quality of Taiwanese FCs significantly deteriorated as the death of the terminally ill patients with cancer approached. Early detection of the FCs' sleep disturbance, increasing their self-awareness of sleep problems, and providing nonpharmacological interventions and psychosocial support may be helpful for FCs to improve their quantity and quality of sleep. PMID- 29390870 TI - Medical Decision-Making for Adults Who Lack Decision-Making Capacity and a Surrogate: State of the Science. AB - BACKGROUND: Adults who lack decision-making capacity and a surrogate ("unbefriended" adults) are a vulnerable, voiceless population in health care. But little is known about this population, including how medical decisions are made for these individuals. OBJECTIVE: This integrative review was to examine what is known about unbefriended adults and identify gaps in the literature. METHODS: Six electronic databases were searched using 4 keywords: "unbefriended," "unrepresented patients," "adult orphans," and "incapacitated patients without surrogates." After screening, the final sample included 10 data-based articles for synthesis. RESULTS: Main findings include the following: (1) various terms were used to refer to adults who lack decision-making capacity and a surrogate; (2) the number of unbefriended adults was sizable and likely to grow; (3) approaches to medical decision-making for this population in health-care settings varied; and (4) professional guidelines and laws to address the issues related to this population were inconsistent. There have been no studies regarding the quality of medical decision-making and its outcomes for this population or societal impact. CONCLUSION: Extremely limited empirical data exist on unbefriended adults to develop strategies to improve how medical decisions are made for this population. There is an urgent need for research to examine the quality of medical decision-making and its outcomes for this vulnerable population. PMID- 29390871 TI - Factors associated with DSM-5 severity level ratings for autism spectrum disorder. AB - The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) introduced substantial changes to the diagnostic criteria for autism spectrum disorder, including new severity level ratings for social communication and restricted and repetitive behavior domains. The purpose of this study was to evaluate the use of these new severity ratings and to examine their relation to other measures of severity and clinical features. Participants included 248 children with autism spectrum disorder who received diagnostic evaluations at one of six Autism Treatment Network sites. Higher severity ratings in both domains were associated with younger age, lower intelligence quotient, and greater Autism Diagnostic Observation Schedule-Second Edition domain-specific symptom severity. Greater restricted and repetitive behavior severity was associated with higher parent-reported stereotyped behaviors. Severity ratings were not associated with emotional or behavioral problems. The new DSM-5 severity ratings in both domains were significantly associated with behavioral observations of autism severity but not with measures of other behavioral or emotional symptoms. However, the strong associations between intelligence quotient and DSM-5 severity ratings in both domains suggest that clinicians may be including cognitive functioning in their overall determination of severity. Further research is needed to examine clinician decision-making and interpretation of these specifiers. PMID- 29390872 TI - The potassium channel blocker, dalfampridine diminishes ouabain-induced arrhythmia in isolated rat atria. AB - The aim of the present experiment was to investigate the possible antiarrhythmic effects of dalfampridine in ouabain-induced arrhythmia in rats. Twenty-four male rats including the control and dalfampridine-incubated (100 uM to 10 mM) ouabain stimulated (40 uM) groups were used. After induction of anesthesia, the atria were isolated and the time of onset of arrhythmia and asystole were recorded. The contractile force of atria was also measured. Dalfampridine at concentration of 1 mM significantly postponed the onset of arrhythmia and asystole compared to control group (p <= .05). Ouabain significantly increased the atrial beating rate in control group (p <= .05), while pretreatment of isolated atria with dalfampridine reversed this effect. Incubation of isolated atria with ouabain did not alter the contractile force in both control- and dalfampridine-treated groups (p > .05). It is concluded that dalfampridine might possess antiarrhythmic properties in reducing the atrial arrhythmias. PMID- 29390873 TI - Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy. AB - Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients. PMID- 29390874 TI - Optimized Longitudinal Monitoring of Stem Cell Grafts in Mouse Brain Using a Novel Bioluminescent/Near Infrared Fluorescent Fusion Reporter. AB - Biodistribution and fate of transplanted stem cells via longitudinal monitoring has been successfully achieved in the last decade using optical imaging. However, sensitive longitudinal imaging of transplanted stem cells in deep tissue like the brain remains challenging not only due to low light penetration but because of other factors such as low or inferior expression levels of optical reporters in stem cells and stem cell death after transplantation. Here we describe an optimized imaging protocol for sensitive long-term monitoring of bone marrow derived human mesenchymal stem cells (hMSCs) expressing a novel bioluminescent/near infrared fluorescent (NIRF) fusion reporter transplanted in mouse brain cortex. Lentivirus expressing the luc2-iRFP720 reporter, a fusion between luc2 codon-optimized firefly luciferase (luc2) and the gene encoding NIRF protein iRFP720, was generated to transduce hMSCs. These cells were analyzed for their fluorescent and bioluminescent emission and checked for their differentiation potential. In vivo experiments were performed by transplanting decreasing amounts of luc2-iRFP720 expressing hMSCs in mouse brain, followed by fluorescence and bioluminescence imaging (BLI) starting 1 wk after cell injection when the blood-brain barrier was restored. Bioluminescent images were acquired when signals peaked and used to compare different luc2 substrate performances, that is, D-luciferin (D-Luc; 25 MUM/kg or 943 MUM/kg) or CycLuc1 (25 MUM/kg). Results showed that luc2-iRFP720 expressing hMSCs maintained a good in vitro differentiation potential toward adipocytes, chondrocytes, and osteocytes, suggesting that lentiviral transduction did not affect cell behavior. Moreover, in vivo experiments allowed us to image as low as 1 * 105 cells using both fluorescence and BLI. The highest bioluminescent signals (~1 * 107 photons per second) were achieved 15 min after the injection of D-Luc (943 MUM/kg). This allowed us to monitor as low as 1 * 105 hMSCs for the subsequent 7 wk without a significant drop in bioluminescent signals, suggesting the sustained viability of hMSCs transplanted into the cortex. PMID- 29390875 TI - Defined Culture Conditions Accelerate Small-molecule-assisted Neural Induction for the Production of Neural Progenitors from Human-induced Pluripotent Stem Cells. AB - The use of defined conditions for derivation, maintenance, and differentiation of human-induced pluripotent stem cells (hiPSCs) provides a superior experimental platform to discover culture responses to differentiation cues and elucidate the basic requirements for cell differentiation and fate restriction. Adoption of defined systems for reprogramming, undifferentiated growth, and differentiation of hiPSCs was found to significantly influence early stage differentiation signaling requirements and temporal kinetics for the production of primitive neuroectoderm. The bone morphogenic protein receptor agonist LDN-193189 was found to be necessary and sufficient for neural induction in a monolayer system with landmark antigens paired box 6 and sex-determining region Y-box 1 appearing within 72 h. Preliminary evidence suggests this neuroepithelium was further differentiated to generate ventral spinal neural progenitors that produced electrophysiologically active neurons in vitro, maintaining viability posttransplantation in an immunocompromised host. Our findings support current developments in the field, demonstrating that adoption of defined reagents for the culture and manipulation of pluripotent stem cells is advantages in terms of simplification and acceleration of differentiation protocols, which will be critical for future clinical translation. PMID- 29390876 TI - Decellularization and Solubilization of Porcine Liver for Use as a Substrate for Porcine Hepatocyte Culture: Method Optimization and Comparison. AB - Biologic substrates, prepared by decellularizing and solubilizing tissues, have been of great interest in the tissue engineering field because of the preservation of complex biochemical constituents found in the native extracellular matrix (ECM). The integrity of the ECM is critical for cell behavior, adhesion, migration, differentiation, and proliferation that in turn affect homeostasis and tissue regeneration. Previous studies have shown that various processing methods have a distinctive way of affecting the composition of the decellularized ECM. In this study, we developed a bioactive substrate for hepatocytes in vitro, made of decellularized and solubilized liver tissue. The present work is a comparative approach of 2 different methods. First, we decellularized porcine liver tissue with ammonium hydroxide versus a sodium deoxycholate method, then characterized the decellularized tissue using various methods including double stranded DNA (dsDNA) content, DNA size, immunogenicity, and mass spectrometry. Second, we solubilized the decellularized porcine liver with hydrochloric acid versus acetic acid (AA) and characterized the resultant solubilized tissues using relevant methodologies including protein yield, immunogenicity, and bioactivity. Finally, we isolated primary porcine hepatocytes, cultured, and evaluated their bioactivity on the optimized decellularized-solubilized liver substrate. The decellularized porcine liver ECM processed by the ammonium hydroxide method and solubilized with AA displayed higher ECM integrity, low dsDNA, no evidence of intact nuclei, low human monocyte chemoattraction, and the presence of key molecules typically found in the native liver, a very important element for normal cell function. In addition, primary porcine hepatocytes showed enhanced functionality including albumin and urea production and bile canaliculi formation when cultured on the developed liver substrate compared to type I collagen. PMID- 29390877 TI - Adipose-Derived Mesenchymal Stromal Cells Improve the Healing of Colonic Anastomoses Following High Dose of Irradiation Through Anti-Inflammatory and Angiogenic Processes. AB - Cancer patients treated with radiotherapy (RT) could develop severe late side effects that affect their quality of life. Long-term bowel complications after RT are mainly characterized by a transmural fibrosis that could lead to intestinal obstruction. Today, surgical resection is the only effective treatment. However, preoperative RT increases the risk of anastomotic leakage. In this study, we attempted to use mesenchymal stromal cells from adipose tissue (Ad-MSCs) to improve colonic anastomosis after high-dose irradiation. MSCs were isolated from the subcutaneous fat of rats, amplified in vitro, and characterized by flow cytometry. An animal model of late radiation side effects was induced by local irradiation of the colon. Colonic anastomosis was performed 4 wk after irradiation. It was analyzed another 4 wk later (i.e., 8 wk after irradiation). The Ad-MSC-treated group received injections several times before and after the surgical procedure. The therapeutic benefit of the Ad-MSC treatment was determined by colonoscopy and histology. The inflammatory process was investigated using Fluorine-182-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography and Computed Tomography (18F-FDG-PET/CT) imaging and macrophage infiltrate analyses. Vascular density was assessed using immunohistochemistry. Results show that Ad-MSC treatment reduces ulcer size, increases mucosal vascular density, and limits hemorrhage. We also determined that 1 Ad-MSC injection limits the inflammatory process, as evaluated through 18F-FDG-PET-CT (at 4 wk), with a greater proportion of type 2 macrophages after iterative cell injections (8 wk). In conclusion, Ad-MSC injections promote anastomotic healing in an irradiated colon through enhanced vessel formation and reduced inflammation. This study also determined parameters that could be improved in further investigations. PMID- 29390878 TI - Neuroprotective Effects of Betulin in Pharmacological and Transgenic Caenorhabditis elegans Models of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system in the elderly. It is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, as well as by motor dysfunction. Although the causes of PD are not well understood, aggregation of alpha-synuclein (alpha-syn) in neurons contributes to this disease. Current therapeutics for PD provides satisfactory symptom relief but not a cure. Treatment strategies include attempts to identify new drugs that will prevent or arrest the progressive course of PD by correcting disease-specific pathogenic process. Betulin is derived from the bark of birch trees and possesses anticancer, antimicrobial, and anti-inflammatory properties. The aim of the present study was to evaluate the potential for betulin to ameliorate PD features in Caenorhabditis elegans ( C. elegans) models. We demonstrated that betulin diminished alpha-syn accumulation in the transgenic C. elegans model. Betulin also reduced 6-hydroxydopamine-induced dopaminergic neuron degeneration, reduced food-sensing behavioral abnormalities, and reversed life-span decreases in a pharmacological C. elegans model. Moreover, we found that the enhancement of proteasomes activity by promoting rpn1 expression and downregulation of the apoptosis pathway gene, egl-1, may be the molecular mechanism for betulin mediated protection against PD pathology. Together, these findings support betulin as a possible treatment for PD and encourage further investigations of betulin as an antineurodegenerative agent. PMID- 29390879 TI - Circumferential Esophageal Replacement by a Tissue-engineered Substitute Using Mesenchymal Stem Cells: An Experimental Study in Mini Pigs. AB - Tissue engineering appears promising as an alternative technique for esophageal replacement. Mesenchymal stem cells (MSCs) could be of interest for esophageal regeneration. Evaluation of the ability of an acellular matrix seeded with autologous MSCs to promote tissue remodeling toward an esophageal phenotype after circumferential replacement of the esophagus in a mini pig model. A 3 cm long circumferential replacement of the abdominal esophagus was performed with an MSC seeded matrix (MSC group, n = 10) versus a matrix alone (control group, n = 10), which has previously been matured into the great omentum. The graft area was covered with an esophageal removable stent. A comparative histological analysis of the graft area after animals were euthanized sequentially is the primary outcome of the study. Histological findings after maturation, overall animal survival, and postoperative morbidity were also compared between groups. At postoperative day 45 (POD 45), a mature squamous epithelium covering the entire surface of the graft area was observed in all the MSC group specimens but in none of the control group before POD 95. Starting at POD 45, desmin positive cells were seen in the graft area in the MSC group but never in the control group. There were no differences between groups in the incidence of surgical complications and postoperative death. In this model, MSCs accelerate the mature re-epitheliazation and early initiation of muscle cell colonization. Further studies will focus on the use of cell tracking tools in order to analyze the becoming of these cells and the mechanisms involved in this tissue regeneration. PMID- 29390880 TI - Magnetic Targeting of Stem Cell Derivatives Enhances Hepatic Engraftment into Structurally Normal Liver. AB - Attaining consistent robust engraftment in the structurally normal liver is an obstacle for cellular transplantation. Most experimental approaches to increase transplanted cells' engraftment involve recipient-centered deleterious methods such as partial hepatectomy or irradiation which may be unsuitable in the clinic. Here, we present a cell-based strategy that increases engraftment into the structurally normal liver using a combination of magnetic targeting and proliferative endoderm progenitor (EPs) cells. Magnetic labeling has little effect on cell viability and differentiation, but in the presence of magnetic targeting, it increases the initial dwell time of transplanted EPs into the undamaged liver parenchyma. Consequently, greater cell retention in the liver is observed concomitantly with fewer transplanted cells in the lungs. These highly proliferative cells then significantly increase their biomass over time in the liver parenchyma, approaching nearly 4% of total liver cells 30 d after transplant. Therefore, the cell-based mechanisms of increased initial dwell time through magnetic targeting combined with high rate of proliferation in situ yield significant engraftment in the undamaged liver. PMID- 29390881 TI - Efficacy of Cellular Therapy for Diabetic Foot Ulcer: A Meta-Analysis of Randomized Controlled Clinical Trials. AB - Diabetes mellitus is a widely spread chronic disease with growing incidence worldwide, and diabetic foot ulcer is one of the most serious complications of diabetes. Cellular therapy has shown promise in the management of diabetic foot ulcer in many preclinical experiments and clinical researches. Here, we performed a meta-analysis to evaluate the efficacy and safety of cellular therapy in the management of diabetic foot ulcer. We systematically searched PubMed, MEDLINE, EMBASE, and Cochrane Library databases from inception to May 2017 for randomized controlled trials assessing the efficacy of cellular therapy in diabetic foot ulcer, and a meta-analysis was conducted. A total of 6 randomized controlled clinical trials involving 241 individuals were included in this meta-analysis. The results suggested that cellular therapy could help accelerating the healing of diabetic foot ulcer, presented as higher ankle-brachial index (mean difference = 0.17, 95% confidence interval [CI] = 0.11 to 0.23), higher transcutaneous oxygen pressure (standardized mean difference [SMD] = 1.43; 95% CI, 1.09- to 1.78), higher ulcer healing rate (relative risk [RR] = 1.78; 95% CI, 1.41 to 2.25), higher amputation-free survival (RR = 1.25; 95% CI, 1.11 to 1.40), and lower scale of pain (SMD = -1.69; 95% CI, -2.05 to -1.33). Furthermore, cellular therapy seemed to be safe, with no serious complications and low risk of short term slight complications. Cellular therapy could accelerate the rate of diabetic foot ulcer healing and may be more efficient than standard therapy for diabetic foot treatment. PMID- 29390882 TI - Mitochondrial Impairment as a Key Factor for the Lack of Attachment after Cold Storage of Hepatocyte Suspensions. AB - Isolated primary hepatocytes, which are widely used for pharmacological and clinical purposes, usually undergo certain periods of cold storage in suspension during processing. While adherent hepatocytes were shown previously to suffer iron-dependent cell death during cold (4 degrees C) storage and early rewarming, we previously found little iron-dependent hepatocyte death in suspension but severely decreased attachment ability unless iron chelators were added. Here, we focus on the role of mitochondrial impairment in this nonattachment of hepatocyte suspensions. Rat hepatocyte suspensions were stored in a chloride-poor, glycine containing cold storage solution with and without iron chelators at 4 degrees C. After 1 wk of cold storage in the basic cold storage solution, cell viability in suspension was unchanged, while cell attachment was decreased by >80%. In the stored cells, a loss of mitochondrial membrane potential (MMP), a decrease in adenosine triphosphate (ATP) content (2 +/- 2 nmol/106 cells after cold storage, 5 +/- 3 nmol/106 cells after rewarming vs. control 29 +/- 6 nmol/106 cells), and a decrease in oxygen consumption (101 +/- 59 pmol sec-1 per 106 cells after rewarming vs. control 232 +/- 83 pmol sec-1 per 106 cells) were observed. Addition of iron chelators to the cold storage solution increased cell attachment to 53% +/- 20% and protected against loss of MMP, and cells were able to partially regenerate ATP during rewarming (15 +/- 10 nmol/106 cells). Increased attachment could also be achieved by addition of the inhibitor combination of mitochondrial permeability transition, trifluoperazine + fructose. Attached hepatocytes displayed normal MMP and mitochondrial morphology. Additional experiments with freshly isolated hepatocytes confirmed that impaired energy production-as elicited by an inhibitor of the respiratory chain, antimycin A-can decrease cell attachment without decreasing viability. Taken together, these results suggest that mitochondrial impairment with subsequent energy deficiency is a key factor for the lack of attachment of cold-stored hepatocyte suspensions. PMID- 29390883 TI - Mutational spectrum of the phenylalanine hydroxylase gene in patients with phenylketonuria in the central region of China. AB - Phenylketonuria (PKU, OMIM 261600) caused by phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disease that is characterized by abnormalities of phenylalanine metabolism. In this study, a total of 77 patients, originating from the central region of China and who were diagnosed with PAH deficiency at the third affiliated hospital of Zhengzhou University, were enrolled in this study. The 13 exons and 12 flanking introns of the PAH gene were analyzed by Sanger sequencing and next generation sequencing. The sequencing data were aligned to the hg19, PAHvdb and HGMD databases to characterize the genotypes of PKU patients, and genotype-phenotype correlations and BH4 responsiveness predictions were performed using BIOPKUdb. In total, 149 alleles were characterized among the 154 PKU alleles. These mutations were located in exons 2 13, and intron 12 of the PAH gene, with a relative frequency of >=5%, for EX6 96A>G, p.R241C, p.R243Q, p.V399V and p.R53H. Additionally, a novel variant, p.D84G, was identified. The genotype correlated with clinical symptoms in 33.3 100% of the cases, depending on the disease severity, and BH4 responsiveness predictions show that only five patients with MHP-PKU and one patient with Mild PKU were predicted to be BH4 responsive. In conclusion, we have characterized the mutational spectrum of PAH in the central region of China and have identified a novel mutation. The hotspot mutation information might be useful for screening, diagnosis and treatment of PKU. PMID- 29390884 TI - Does Medical Expansion Improve Population Health? AB - Medical expansion has become a prominent dynamic in today's societies as the biomedical model becomes increasingly dominant in the explanation of health, illness, and other human problems and behavior. Medical expansion is multidimensional and represented by expansions in three major components of the healthcare system: increasing medical investment, medical professionalization/specialization, and the relative size of the pharmaceutical industry. Using Organisation for Economic Co-operation and Development health data and World Development Indicators 1981 to 2007, we find medical investment and medical professionalization/specialization significantly improve all three measures of life expectancy and decrease mortality rate even after controlling for endogeneity problems. In contrast, an expanded pharmaceutical industry is negatively associated with female life expectancy at age 65 and positively associated with the all-cause mortality rate. It further compromises the beneficial effect of medical professionalization/specialization on population health. In general, medical professionalization/specialization and gross domestic product per capita have similar and stronger effects than medical investment. PMID- 29390885 TI - Multi-targeted directed ligands for Alzheimer's disease: design of novel lead coumarin conjugates. AB - Alzheimer's Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin-morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin-piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 MUM and 1 MUM, respectively. Molecular modelling studies were conducted with Accelrys(r) Discovery Studio(r) V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design. PMID- 29390886 TI - Molecular activity prediction by means of supervised subspace projection based ensembles of classifiers. AB - This paper proposes a method for molecular activity prediction in QSAR studies using ensembles of classifiers constructed by means of two supervised subspace projection methods, namely nonparametric discriminant analysis (NDA) and hybrid discriminant analysis (HDA). We studied the performance of the proposed ensembles compared to classical ensemble methods using four molecular datasets and eight different models for the representation of the molecular structure. Using several measures and statistical tests for classifier comparison, we observe that our proposal improves the classification results with respect to classical ensemble methods. Therefore, we show that ensembles constructed using supervised subspace projections offer an effective way of creating classifiers in cheminformatics. PMID- 29390887 TI - Prediction of therapeutic potency of tacrine derivatives as BuChE inhibitors from quantitative structure-activity relationship modelling. AB - Numerous studies show that tacrine derivatives exhibit increased inhibitory activity against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). However, the screening assays for currently available BuChE inhibitors are expensive, time consuming and dependent on the inhibitory compound. It is therefore desirable to develop alternative methods to facilitate the screening of these derivatives in the early phase of drug discovery. In order to develop robust predictive models, three regression methods were chosen in this study: multiple linear regression (MLR), support vector regression (SVR) and multilayer perceptron network (MLP). Eight relevant descriptors were selected on a dataset of 151 molecules using a method based on genetic algorithms. Internal and external validation strategies play an important role. Also, to check the robustness of the selected models, all available validation strategies were used, and all criteria used to validate these models revealed the superiority of the SVR model. The statistical parameters obtained with the SVR model were RMSE = 0.197, r2 = 0.969 and Q2 = 0.964 for the training set, and r2 = 0.906 and Q2 = 0.891 for the test set. Therefore, the model developed in this study provides an excellent prediction of the inhibitory concentration of tacrine derivatives. PMID- 29390888 TI - Why some patients who do not need hospitalization cannot leave: A case study of reviews in 6 Canadian hospitals. AB - In an optimal healthcare system, patients receive care in the most appropriate, least expensive setting. In Canada, too many patients remain in hospital well after they no longer require hospital-based care. This study examines the observations on this problem by a team with a home and community lens in six cases. The underlying issues across the six are the insufficiency of home and community supports before hospitalization, the routine underestimation of these patients' potential for independence, the deconditioning of patients while in hospital, and hospital staff's lack of understanding of home care. Addressing these issues would help many of these patients transition from hospital to less costly, more fitting settings. PMID- 29390889 TI - Engaging patients as partners in health research: Lessons from BC, Canada. AB - Canada is seeing increased interest in engaging patients in health research, recognizing the potential to improve its relevance and quality. The momentum is promising, but there may be a tendency to ignore the challenges inherent when lay people and professionals collaborate. We address some of these challenges as they relate to recruitment, training, and support for patients at the British Columbia (BC) Support for People and Patient-Oriented Research Unit, part of Canada's Strategy for Patient-Oriented Research. A retrospective review of a telehealth project demonstrates that, as well as the practical elements of recruitment, training, and support, attention must be paid to issues of credibility, legitimacy, and power when engaging patients. We propose that all patient oriented research projects would benefit from using a similar framework to guide patient engagement planning and implementation, helping to anticipate and mitigate challenges from the outset. Projects would ideally also include the study of patient engagement methods, to add to this important body of knowledge. PMID- 29390890 TI - The ethics of silence: Does conflict of interest explain employee silence? AB - Employee silence constitutes a significant threat to organizational success. This article argues that silence is a by-product of a structural Conflict of Interest (COI) between employees and their employers. This argument turns on the claim, also defended here, that employees are in a privileged position vis-a-vis knowledge of their work and that leaders-whether they recognize it or not-are dependent on their employees for reliable information about the work they are doing. Employee voice, therefore, is an organizational necessity. It is also a moral achievement as it involves risking one's personal interests for the sake of the organization. Leaders must take steps to mitigate COI and encourage employee voice; this article provides several strategies for doing exactly that. PMID- 29390891 TI - Improving Access to Psychological Therapies (IAPT) - The Need for Radical Reform. AB - Improving Access to Psychological Therapies is a UK government-funded initiative to widen access to the psychological treatment of depression and anxiety disorders. The author has had the opportunity to independently assess 90 Improving Access to Psychological Therapies clients, using a standardised semi structured interview, the Structured Clinical Diagnostic Interview for DSM Disorders (SCID) and to listen to their account of interaction with the service. The results suggest that only the tip of the iceberg fully recovers from their disorder (9.2%) whether or not they were treated before or after a personal injury claim. There is a pressing need to re-examine the modus operandi of the service. PMID- 29390892 TI - Pregnancy and subsequent uterine rupture in a 72-year-old gravida: medical tourism versus procreative freedom. PMID- 29390893 TI - Association of body composition with menopausal symptoms in (peri-)menopausal women. AB - OBJECTIVE: To explore the correlation of body composition with the severity of menopausal symptoms, as well as each classic menopausal symptom. METHODS: A total of 758 (peri-)menopausal women were recruited (aged from 40 to 67 years) from the Menopause Clinic in the Shanghai Sixth People's Hospital. Different regions of fat mass, lean mass and fat-free mass were measured by bioelectrical impedance analysis, while menopausal symptoms were evaluated by valid modified Kupperman's index (KMI) in the Chinese version. RESULTS: After adjusting for potential confounders, logistic regression revealed that trunk lean mass (odds ratio 0.29, 95% confidence interval 0.09-0.99) was the independent determinant of moderate to severe menopausal symptoms (KMI >= 16). In multiple regression analysis, significant relationships were found between body mass index and hot flushes/sweating and diabetes (p < 0.05). There was a significant relationship between lean mass and muscle/joint pain and sexual problems (p < 0.05). We also observed significant relationships between fat mass and hot flushes/sweating and muscle/joint pain. CONCLUSIONS: Our findings indicated that trunk lean mass was an independent protective factor for moderate to severe menopausal symptoms. Strengthening the trunk lean mass may alleviate menopausal symptoms. PMID- 29390894 TI - Difference and alteration in pharmacokinetic and metabolic characteristics of low solubility natural medicines. AB - Drug metabolism plays vital roles in the absorption and pharmacological activity of poorly soluble natural medicines. It is important to choose suitable delivery systems to increase the bioavailability and bioactivity of natural medicines with low solubility by regulating their metabolism and pharmacokinetics. This review investigates recent developments about the metabolic and pharmacokinetic behavior of poorly soluble natural medicines and their delivery systems. Delivery systems, dosage, administration route and drug-drug interactions alter the metabolic pathway, and bioavailability of low-solubility natural medicines to different degrees. Influencing factors such as formulation, dosage, and administration route are discussed. The metabolic reactions, metabolic enzymes, metabolites and pharmacokinetic behaviors of low-solubility natural medicines, and their delivery systems are systematically reviewed. There are various metabolic situations in the case of low-solubility natural medicines. CYP3A4 and CYP2C are the most common metabolic enzymes, and hydroxylation is the most common metabolic reaction of low solubility natural medicines. The stereo isomeric configuration can have a large influence on metabolism. This review will be useful for physicians and pharmacists to guide more accurate treatment with low-solubility natural medicines by increasing drug efficacies and protecting patients from toxic side effects. PMID- 29390895 TI - Correction to: Fischer et al., Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-beta related to anticancer drug resistance. PMID- 29390896 TI - Targeting the endocannabinoid system as a potential anticancer approach. AB - The endocannabinoid system is currently under intense investigation due to the therapeutic potential of cannabinoid-based drugs as treatment options for a broad variety of diseases including cancer. Besides the canonical endocannabinoid system that includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2 arachidonoylglycerol, recent investigations suggest that other fatty acid derivatives, receptors, enzymes, and lipid transporters likewise orchestrate this system as components of the endocannabinoid system when defined as an extended signaling network. As such, fatty acids acting at cannabinoid receptors (e.g. 2 arachidonoyl glyceryl ether [noladin ether], N-arachidonoyldopamine) as well as endocannabinoid-like substances that do not elicit cannabinoid receptor activation (e.g. N-palmitoylethanolamine, N-oleoylethanolamine) have raised interest as anticancerogenic substances. Furthermore, the endocannabinoid degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid binding protein family, additional cannabinoid-activated G protein-coupled receptors, members of the transient receptor potential family as well as peroxisome proliferator-activated receptors have been considered as targets of antitumoral cannabinoid activity. Therefore, this review focused on the antitumorigenic effects induced upon modulation of this extended endocannabinoid network. PMID- 29390897 TI - A method for determining precise electrical hearing thresholds in cochlear implant users. AB - OBJECTIVE: A psychoacoustic procedure designed for the precise assessment of perceptional threshold (T-level) in cochlear implant (CI) users is presented. The impact of this procedure on speech perception was investigated. DESIGN: Individual T-level measurements were obtained with the proposed procedure and three different speech processor fitting conditions were applied: (1) fitting familiar to the subject, T-levels unchanged, (2) T-level set to thresholds determined with the new procedure, (3) T-level set to thresholds determined with the new procedure, but T-level is decreased by 10 clinical units (CU). The impact of the different fitting conditions was measured by means of categorical loudness scaling (CLS) and speech perception tests in quiet and noise. STUDY SAMPLE: A prospective study at a tertiary referral university hospital. 18 experienced postlingually deafened cochlear implanted adult subjects. RESULTS: Average sound field thresholds obtained by CLS were lowest in condition using the new procedure yielding a larger dynamic range with significantly higher speech scores in quiet compared to those with a subject's commonly used programme, and significantly improved in noise even after reducing T-levels by 10 CU. CONCLUSION: The precise determination of T-levels by means of the proposed procedure improved performance in several speech recognition tasks. Compared to the default behavioural setting, T-level increased on median by 9 CU. Average speech reception threshold in noise for soft speech levels (50 dB sound pressure level) decreased by 1 dB. PMID- 29390898 TI - Design and synthesis of naphthalimide group-bearing thioglycosides as novel beta N-acetylhexosaminidases inhibitors. AB - GH20 human beta-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these beta-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 uM against hsHexB; Ki > 100 uM against hOGA) and compound 15b (Ki = 3.76 uM against hOGA; Ki = 30.42 uM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific beta-N-acetylhexosaminidase inhibitors. PMID- 29390899 TI - Vasomotor symptoms: natural history, physiology, and links with cardiovascular health. AB - Vasomotor symptoms (VMS), or hot flushes and night sweats, are the classic symptom of menopause. Recent years have brought key advances in the knowledge about VMS. VMS last longer than previously thought, on average 7-10 years for frequent or moderate to severe VMS. Although VMS have long been understood to be important to women's quality of life, research has also linked VMS to indicators of cardiovascular disease (CVD) risk, such as an adverse CVD risk factor profile, greater subclinical CVD and, in emerging work, CVD events. Relations between VMS and CVD are not typically accounted for by CVD risk factors. In newer work, VMS CVD risk relations are demonstrated with state-of-the-art subjective and objective measures of VMS. Some research indicates that VMS-CVD risk relations may be sensitive to the timing or duration of VMS. Thus, research collectively supports relations between VMS and CVD risk independent of known CVD risk factors. Next steps include identifying the mechanisms linking VMS and CVD risk indicators, understanding any timing effects, and clarifying the precise nature of relations between VMS and CVD risk. Clinical implications are discussed. PMID- 29390900 TI - Anticancer Activity in Honeybee Propolis: Functional Insights to the Role of Caffeic Acid Phenethyl Ester and Its Complex With gamma-Cyclodextrin. AB - Besides honey, honeybees make a sticky substance (called propolis/bee glue) by mixing saliva with poplar tree resin and other botanical sources. It is known to be rich in bioactivities of which the anticancer activity is most studied. Caffeic acid phenethyl ester (CAPE) is a key anticancer component in New Zealand propolis. We have earlier investigated the molecular mechanism of anticancer activity in CAPE and reported that it activates DNA damage signaling in cancer cells. CAPE-induced growth arrest of cells was mediated by downregulation of mortalin and activation of p53 tumor suppressor protein. When antitumor and antimetastasis activities of CAPE were examined in vitro and in vivo, we failed to find significant activities, which was contrary to our expectations. On careful examination, it was revealed that CAPE is unstable and rather gets easily degraded into caffeic acid by secreted esterases. Interestingly, when CAPE was complexed with gamma-cyclodextrin (gammaCD) the activities were significantly enhanced. In the present study, we report that the CAPE-gammaCD complex with higher cytotoxicity to a wide range of cancer cells is stable in acidic milieu and therefore recommended as an anticancer amalgam. We also report a method for preparation of stable and less-pungent powder of propolis that could be conveniently used for health and therapeutic benefits. PMID- 29390901 TI - Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies. AB - Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 +/- 0.01 MUM) was found to be the most active h-TNAP inhibitor. Another 4 fluorobenzenesulphonate derivative 1i (IC50 = 0.45 +/- 0.02 MUM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes. PMID- 29390902 TI - Factorial structure of the Persian version of Childbearing Questionnaire in first time engaged couples in Iran. AB - The primary aim of this study was to assess the factorial structure of a Childbearing Questionnaire (CBQ). Using confirmatory factor analysis, it examined modified eight-factor models on a sample of 448 couples. Cronbach's alpha coefficients were 0.90 and 0.83 for positive and negative childbearing motivation, respectively, and the intra-class correlation coefficient (ICC) was in the range of 0.81-0.86, which indicated that the reliability of the questionnaire was high. The modified model was found to have 'adequate' fitness based on the Root Mean Square Error of Approximation (RMSEA), but other indicators such as the Tucker-Lewis Index (TLI) and Comparative Fit Index (CFI) did not show any 'acceptable' fitness. In the eight-factor model, three factors with low loading were removed to achieve adequate fitness. Also, 13 correlated error terms were added to the modified model. The confirmatory factor analysis of the modified model showed 'adequate' fitness (CFI = 0.91, TLI =0.9, RMSEA = 0.06 and Chi-square to a degree of freedom ratio (chi2/df) = 3.49). This study supported the use of CBQ as a valid and reliable instrument of childbearing in engaged couples. Impact statement Current research on the subject: Some studies have suggested that the construct validity, internal consistency and the test retest reliability of a Childbearing Questionnaire (CBQ) are high. The contribution made by the results of this study: It determined the reliability (internal consistency and test-retest reliability), the content validity and construct validity (confirmatory factor analysis) of the Persian version of the Childbearing Questionnaire. The implications of findings for clinical practice and further research: This reliable and valid instrument can be used for measuring the factors affecting childbearing motivations among engaged couples. PMID- 29390903 TI - Juggling identities of rheumatoid arthritis, motherhood and paid work - a grounded theory study. AB - PURPOSE: To explore how women with rheumatoid arthritis manage their illness, motherhood, and work life. METHODS: A constructivist, grounded theory approach based on individual interviews and participant observations with 20 women with rheumatoid arthritis who participated in work life and had children living at home or were pregnant. After initial and focused coding Goffman's concepts of social identity were applied. RESULTS: A core category: "Juggling meaningful identities" and three conceptual categories were developed: (1) Work life as the strongest identity marker; (2) Motherhood: a two-sided act; (3) Living with rheumatoid arthritis as an identity? Paid work, motherhood, and illness are linked to the women's social identities. The women construct and change their identities in interactions with children, partners, other parents, colleagues, and employers. CONCLUSION: The women attribute the highest priority to their professional identity, spending the majority of their time and energy in an effort to appear as "good stable workers". The disease is seen as a hindrance in this regard, and the illness identity is almost completely rejected. In motherhood, the women prioritize close interaction with their children, and deprioritize external activities. Extended outbreaks of the disease and issues regarding the children force the women to deprioritize working life. Implications for rehabilitation Juggling meaningful identities of rheumatoid arthritis, motherhood, and paid work challenge women in managing their everyday lives. Therefore, rehabilitation professionals should support individuals to develop new strategies to manage the challenges they experience regarding juggling motherhood and work ability. Work is a dominant identity marker for women with rheumatoid arthritis therefore, rehabilitation professionals have an important role to play in investigating possible ways for the individual to maintain employment or return to work. Living with rheumatoid arthritis and being a paid worker challenge women's role performance and thereby their identification as mothers. Therefore, rehabilitation professionals have to support the women and their families. PMID- 29390904 TI - Meta-analysis of Exercise Training on Vascular Endothelial Function in Cancer Survivors. AB - Cancer and cardiovascular disease (CVD) are leading causes of morbidity and mortality in the United States. Vascular endothelial dysfunction, an important contributor in the development of CVD, improves with exercise training in patients with CVD. However, the role of regular exercise to improve vascular function in cancer survivors remains equivocal. We performed a meta-analysis to determine the effect of exercise training on vascular endothelial function in cancer survivors. We searched PubMed (1975 to 2016), EMBASE CINAHL (1937 to 2016), OVID MEDLINE (1948 to 2016), and Cochrane Central Registry of Controlled Trials (1991 to 2016) using search terms: vascular function, endothelial function, flow-mediated dilation [FMD], reactive hyperemia, exercise, and cancer. Studies selected were randomized controlled trials of exercise training on vascular endothelial function in cancer survivors. We calculated pooled effect sizes and performed a meta-analysis. We identified 4 randomized controlled trials (breast cancer, n=2; prostate cancer, n=2) measuring vascular endothelial function by FMD (n=3) or reactive hyperemia index (n=1), including 163 cancer survivors (exercise training, n=82; control, n=81). Aerobic exercise training improved vascular function (n=4 studies; standardized mean difference [95% CI]=0.65 [0.33, 0.96], I2=0%; FMD, weighted mean difference [WMD]=1.28 [0.22, 2.34], I2=23.2%) and peak exercise oxygen uptake (3 trials; WMD [95% CI]=2.22 [0.83, 3.61] mL/kg/min; I2=0%). Our findings indicate that exercise training improves vascular endothelial function and exercise capacity in breast and prostate cancer survivors. PMID- 29390905 TI - Elevated circulating nitric oxide levels correlates with enhanced oxidative stress in patients with hyperemesis gravidarum. AB - Since the biochemical and molecular mechanisms responsible for ongoing oxidative stress in hyperemesis gravidarum (HEG) patients have not yet been fully elucidated, the aim of this study was to evaluate the possible role of nitric oxide (NO), malondialdehyde (MDA) and other oxidative stress markers in the disease pathophysiology. Moreover, the relation between oxidative stress markers and Helicobacter pylori (H. pylori) infection was also investigated. Women with pregnancies complicated by HEG (n = 33) were compared with pregnant women without HEG (n = 30) and with healthy non-pregnant women (n = 31). Serum NO, MDA, total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and H. pylori infection status were determined for each subject. Serum NO levels and OSI index were found to be increased (p = .001 and .013, respectively) and TAS levels were decreased (p < .001) in HEG patients compared with both controls regardless of H. pylori infection status. Serum MDA and TOS levels were not different between the study groups. Helicobacter pylori infection rates were similar in each group. The reduced antioxidant activities, as well as the increased OSI and NO levels in HEG patients indicate possible oxidative stress conditions in HEG patients. Moreover, serum NO levels may be used as an adjunctive marker to distinguish HEG patients from other causes of emesis during pregnancy. Impact statement What is already known on this subject? Current evidence suggests that oxidative stress is a significant factor responsible for a number of complications during pregnancy. What do the results of this study add? Hyperemesis gravidarum is an oxidative stress condition, as reflected by increased nitric oxide (NO) and decreased total antioxidant status activity, regardless of H. Pylori infection. What are the implications for clinical practice and/or further research? Full disclosure of the association between circulating NO and hyperemesis gravidarum would shed light on underlying biological mechanisms and could help clinical management of similar pregnancy associated morbidity states. PMID- 29390906 TI - Comparison of the symptoms and localisation of endometriosis involvement according to fertility status of endometriosis patients. AB - This cross-sectional study aimed to assess the prevalence of endometriosis in women who were referred for Diagnostic Laparoscopy Unit due to infertility or pelvic pain between January 2012 and January 2013 and compare the symptoms and laparoscopic signs among the three groups according to the fertility status. Four hundred and thirteen women were evaluated; of these, 383 patients for infertility and 30 patients for pelvic pain and/or cyst. Endometriosis symptoms were compared between fertile and infertile women with primary and secondary infertility. There was no statistically significant difference in the overall prevalence of endometriosis between the three study groups (52.9%, 45% and 40.7%, respectively, in primary, secondary infertile and fertile women). The endometriosis stage was categorised as early- (I and II) or late- (III and IV) stages and the extent of endometriosis was divided into peritoneal, ovarian and ovarian coexisting with peritoneal. There is no relationship between the frequency of dysmenorrhoea or non-cyclic pelvic pain and the disease stage; although these pain symptoms are significantly more prevalent in cases with both ovarian and peritoneal endometriotic implants. Infertility was more prevalent among the patients with peritoneal endometriosis in comparison to the ones with ovarian endometriosis. Further studies with a larger sample size are required to confirm these findings. Impact statement What is already known on this subject? Few studies have been done in this area and only one study compared the localisation of endometriosis lesions between fertile and infertile endometriosis cases; however, more study is needed to confirm their results. What the results of this study add? A possible relationship between localisation of endometriosis involvement and infertility was found in the present study in agreement to result of a previous study performance in this area. Although the present study includes a greater number of cases than that of the previous reported study, further studies with a larger sample size are required for the confirmation or refusal of this finding. What are the implications of these findings for clinical practice and/or further research? The results of this study could have clinical application in the consultation and decision-making in infertile women with an endometriosis diagnosis. PMID- 29390907 TI - Impact of late pregnancy haemoglobin A1c at 29-30 weeks' gestation on adverse pregnancy outcomes among women with pre-existing diabetes: a retrospective analysis. AB - This study was to assess the relationship between late pregnancy haemoglobin A1C (HbA1C) at 29-30 weeks of gestation and adverse pregnancy outcomes (APOs) in 272 pregnant women with pre-existing diabetes. HbA1C >=6.1% was associated with significantly increased risk of preterm delivery, Caesarean section, large for gestational age (LGA), neonatal respiratory distress, neonatal hypoglycaemia, and composite adverse neonatal outcome (p < .05). The risk of pre-eclampsia increased significantly at the lower HbA1C cut-off of > 5.6% (p = .039). Reduction of HbA1C cut-off from 6.1% to 5.6% improved the sensitivity but reduced the specificity for prediction of APOs. Overall, the receiver operating characteristic (ROC) curves demonstrated the moderate predictive value of late pregnancy HbA1C for APOs. In conclusion, elevated late pregnancy HbA1C levels at 29-30 gestational weeks had a negative impact on APOs in pregnant women with pre-existing diabetes. However, HbA1C cut-off levels of neither >=6.1% nor >5.6% were ideal for predicting APOs. Impact statement What is already known on this subject: Poorly controlled diabetes is associated with adverse pregnancy outcomes (APOs). Periconceptual haemoglobin A1C (HbA1C) correlates well with the risk of foetal anomaly but is not predictive of APOs at time of delivery. New evidence suggested that late pregnancy HbA1C is predictive of APOs but the definitions of a late pregnancy gestational week and target HbA1C cutpoint remain in doubt. What the results of this study add: This study investigated the relationship between late pregnancy HbA1C levels at 29-30 weeks of gestation and the APOs among pregnant women with pre-existing diabetes. Late pregnancy HbA1C >= 6.1% correlated with the risk of APOs but the increased risk of pre-eclampsia only became significant at the lower cut-off of >5.6%. Reducing HbA1C cut-off from 6.1% to 5.6% improved the sensitivity but reduced the specificity for prediction of APOs. Overall, late pregnancy HbA1C had a moderate predictive value for APOs. What the implications are of these findings for clinical practice and/or further research: HbA1C cut off levels of neither >=6.1% nor >5.6% were ideal in predicting APOs among pregnant women with pre-existing diabetes. As HbA1C levels tend to drop in pregnancy, caution should be taken when interpreting HbA1C in pregnancy. More multi-centred studies are required to explore the respective glycaemic target for each APO and to determine the ideal timing for late pregnancy HbA1C measurement. PMID- 29390910 TI - Evolving the concept of APD. AB - OBJECTIVE: To consider the evolving concept of auditory processing disorder (APD). DESIGN: Narrative review and opinion piece. STUDY SAMPLE: Eight approaches to APD described in the literature and its definitions by ten societies or groups from around the world. RESULTS: The dominant conceptualisation of APD remains one of disorders (or at least deficits) in the bottom-up processing of sound in the primary auditory nervous system that are not due to higher order (top-down) language or cognitive deficits. Challenges to this conceptualisation question the relevance of (bottom-up) AP to listening, learning and language. These challenges are rejected by some groups who maintain the dominant bottom-up conceptualisation of APD, but accepted by others who suggest APD be reconceptualised to include top down processing of sound or attempts to define APD be de-emphasised in favour of a hierarchical approach to listening difficulties. CONCLUSIONS: To reconcile these challenges, the concept of APD could be better evolved by considering it as a spectrum disorder spanning from bottom-up AP to the top-down cognitive processes (particularly attention) that affect it. PMID- 29390909 TI - Colpocytological abnormalities in HIV infected and uninfected pregnant women: prevalence, persistence and progression. AB - In this retrospective case-control study, we analyse data of 48 HIV-positive pregnant patients, versus a control group of 99 HIV-negative pregnant women, followed as outpatients by our department from 2009 to 2014. The aims of the study were to investigate the prevalence, persistence and progression of cervical squamous intraepithelial lesions (SIL) in each group and to correlate colpo cytological lesions to the socio-demographic and clinical-laboratory findings in the HIV + pregnant women. In our study we observed that immunosuppression, HPV infection and vaginal coinfections were predictive of cervical lesions. Pap smear and colposcopy should be part of routine care for HIV-infected pregnant women because these lesions behave aggressively in these patients. Success of prevention depends on massive access of patients to screening. HAART reduces viral load and maintains CD4 count and can affect progression of SIL. Multidisciplinary services on the same site appear to be one promising strategy to improve compliance in patients. Impact Statement What is already known on this subject: Our study provided novel information on a highly vulnerable population of young HIV + pregnant women. What the results of this study add: We observed that immunosuppression, HPV infection and vaginal coinfections were predictive of cervical lesions remarkable with colposcopy. We could consider these important risk factors to evaluate to establish an appropriate strategy of management for these patients. What the implications are of these findings for clinical practice and/or further research: Association of the risk between SIL presence and HIV and HPV infection also deserves additional investigation. We believe that Pap smears and colposcopies should be part of the routine care for HIV-infected women because these lesions behave particularly aggressively in these patients. PMID- 29390908 TI - Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12. AB - GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer's disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets. PMID- 29390911 TI - Social, obstetric and environmental determinants of low Apgar score among infants born in four selected hospitals in Ibadan, Nigeria. AB - Little information exists about socio-economic, environmental or occupational determinants of low Apgar scores among Nigerian neonates. Mothers in lying-in wards of four hospitals in Ibadan were interviewed on socio-demographic characteristics, obstetric history and work activities during index pregnancy. Apgar scores and clinical data were extracted from case notes. Of the 1349 respondents, 20% had Apgar score <7 at one minute, 4% at five minutes. Lower education, cooking with kerosene, physical exertion at work, nulliparity, hypertension in pregnancy, prolonged rupture of membranes, breech presentation and caesarean section were predictors for low Apgar scores at one minute; nulliparity, male infant and breech presentation at five minutes. Occupations with lower socio-economic status or those requiring physical exertion; tailoring, catering and hairdressing recorded higher rates of low Apgar scores at one minute (p = .08). Physical exertion at work and cooking with kerosene may be predictive of low Apgar scores and require further study. PMID- 29390912 TI - Carbon- versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? AB - A set of compounds incorporating carbon-based zinc-binding groups (ZBGs), of the type PhX (X = COOH, CONH2, CONHNH2, CONHOH, CONHOMe), and the corresponding derivatives with sulphur(VI)-based ZBGs (X = SO3H, SO2NH2, SO2NHNH2, SO2NHOH, SO2NHOMe) were tested as inhibitors of all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1), CA I-XV. Three factors connected with the ZBG influenced the efficacy as CA inhibitor (CAI) of the investigated compounds: (i) the pKa of the ZBG; (ii) its geometry (tetrahedral, i.e. sulphur-based, versus trigonal, i.e. carbon-based ZBGs), and (iii) orientation of the organic scaffold induced by the nature of the ZBG. Benzenesulphonamide was the best inhibitor of all isoforms, but other ZBGs led to interesting inhibition profiles, although with an efficacy generally reduced when compared to the sulphonamide. The nature of the ZBG also influenced the CA inhibition mechanism. Most of these derivatives were zinc binders, but some of them (sulfonates, carboxylates) may interact with the enzyme by anchoring to the zinc-coordinated water molecule or by other inhibition mechanisms (occlusion of the active site entrance, out of the active site binding, etc.). Exploring structurally diverse ZBGs may lead to interesting new developments in the field of CAIs. PMID- 29390913 TI - A new flavonol glycoside from the flowers of Hosta plantaginea with cyclooxygenases-1/2 inhibitory and antioxidant activities. AB - Hosta plantaginea was a traditional Chinese medicinal plants used to treat inflammatory and painful diseases with partial scientific validation. Solvent extractions followed by repeated chromatographic purification of the H. plantaginea flowers led to the isolation of one new flavonoid glycoside, hostaflavone A (1), together with one related known compound, kaempferol-3-O sophoroside-7-O-glucoside (2), and their structures were elucidated on the basis of chemical and spectral evidence, as well as by comparison with literature data. Compounds 1 and 2 were evaluated for the anti-inflammatory activites against cyclooxygenases (COX-1 and COX-2) and DPPH free radical-scavenging activities in vitro. The results revealed that 1 and 2 exhibited significant COX-1 inhibition and moderate COX-2 inhibition compared to the reference celecoxib. Additionally, 1 and 2 displayed insignificant antioxidant activities compared to the positive control L-ascorbic acid. PMID- 29390914 TI - Acceptance or decline of requests to review manuscripts: A gender-based approach from a public health journal. AB - Peer review in the scientific publication is widely used as a method to identify valuable knowledge. Editors have the task of selecting appropriate reviewers. We assessed the reasons given by potential reviewers for declining a request to review, and the factors associated with acceptance, taking into account the difference in the sex of the reviewer. This is a descriptive study of the review requests from a public health journal (Gaceta Sanitaria) with an enforced gender policy. The dependent variables were requests, response to requests, reasons potential reviewers gave for declining requests and time to review. We carried out a descriptive analysis of these indicators and applied logistic regression to analyze factors (professional and research/review experience) associated with having done at least one review in 2014-2015. Results were stratified by sex. Journal editors sent 1,775 requests to 773 potential reviewers; 52.3% of whom reviewed at least one manuscript. Of the 396 declined requests (22.3%), the most common reasons were lack of time and of experience (88.1%). No differences were observed by sex. In the multivariate analysis, having reviewed for the journal in previous years showed the strongest association with acceptance. Specific analyses of data on requests reviewers may be useful for improving the acceptance rates to review. This study did not show gender differences in several indicators of the reviewing process. PMID- 29390916 TI - Saponin-rich fraction from Agave sisalana: effect against malignant astrocytic cells and its chemical characterisation by ESI-MS/MS. AB - Astrocytic tumour cells derived from human (GL-15) and rat (C6) gliomas, as well as non-tumoural astrocytic cells, were exposed to the saponin-rich fraction (SF) from Agave sisalana waste and the cytotoxic effects were evaluated. Cytotoxicity assays revealed a reduction of cell viability that was more intensive in glioma than in non-tumoural cells. The SF induced morphological changes in C6 cells. They were characterised by cytoplasmic vacuole formation associated with increase in the formation of acidic lysosomes. The SF was subjected to purification on Sephadex LH-20, which characterised three probable steroidal saponins (sisalins) by electrospray ionisation mass spectrometry multistage (ESI-MSn). Sisalins from sisal may be responsible for the cytotoxicity, which involves cytoplasmatic vacuole formation and selective action for glioma cells. PMID- 29390915 TI - Real-Time Detection of Infusion Site Failures in a Closed-Loop Artificial Pancreas. AB - BACKGROUND: As evidence emerges that artificial pancreas systems improve clinical outcomes for patients with type 1 diabetes, the burden of this disease will hopefully begin to be alleviated for many patients and caregivers. However, reliance on automated insulin delivery potentially means patients will be slower to act when devices stop functioning appropriately. One such scenario involves an insulin infusion site failure, where the insulin that is recorded as delivered fails to affect the patient's glucose as expected. Alerting patients to these events in real time would potentially reduce hyperglycemia and ketosis associated with infusion site failures. METHODS: An infusion site failure detection algorithm was deployed in a randomized crossover study with artificial pancreas and sensor-augmented pump arms in an outpatient setting. Each arm lasted two weeks. Nineteen participants wore infusion sets for up to 7 days. Clinicians contacted patients to confirm infusion site failures detected by the algorithm and instructed on set replacement if failure was confirmed. RESULTS: In real time and under zone model predictive control, the infusion site failure detection algorithm achieved a sensitivity of 88.0% (n = 25) while issuing only 0.22 false positives per day, compared with a sensitivity of 73.3% (n = 15) and 0.27 false positives per day in the SAP arm (as indicated by retrospective analysis). No association between intervention strategy and duration of infusion sets was observed ( P = .58). CONCLUSIONS: As patient burden is reduced by each generation of advanced diabetes technology, fault detection algorithms will help ensure that patients are alerted when they need to manually intervene. Clinical Trial Identifier: www.clinicaltrials.gov,NCT02773875. PMID- 29390918 TI - A novel natural source Vicia faba L. membranes as colourant: development and optimisation of the extraction process using response surface methodology (RSM). AB - In this research paper, an eco-friendly extraction process of dyes from Vicia faba L. membranes was developed. In this regard, the influence of independent process factors like the weight of material, the extraction time, the temperature and the sodium hydroxide concentration on the natural dye extraction from Vicia faba membranes was investigated. The optimisation of the extraction conditions and the effect evaluation of the different operating parameters were carried out using a Box-Behnken design under response surface methodology. The optimum conditions were found to be 66 degrees C, 90 min, 5 g and 0.1628 mol.L-1 for extraction temperature, time, mass of the material and sodium hydroxide concentration, respectively. The efficiency of this extraction process under these optimum conditions was evaluated by measuring the total phenolic content (TPC), the total flavonoid content and the relative colour yield (K/S). In these operating conditions, good fastness ratios were observed for the dyed fabrics. PMID- 29390917 TI - An Analysis of Diabetes Mobile Applications Features Compared to AADE7TM: Addressing Self-Management Behaviors in People With Diabetes. AB - BACKGROUND: Diabetes self-management (DSM) applications (apps) have been designed to improve knowledge of diabetes and self-management behaviors. However, few studies have systematically examined if diabetes apps followed the American Association of Diabetes Educators (AADE) Self-Care BehaviorsTM guidelines. The purpose of this study was to compare the features of current DSM apps to the AADE7TM guidelines. METHODS: In two major app stores (iTunes and Google Play), we used three search terms "diabetes," "blood sugar," and "glucose" to capture a wide range of diabetes apps. Apps were excluded based on five exclusion criteria. A multidisciplinary team analyzed and classified the features of each app based on the AADE7TM. We conducted interviews with six diabetes physicians and educators for their opinions on the distribution of the features of DSM apps. RESULTS: Out of 1050 apps retrieved, 173 apps were identified as eligible during November 2015 and 137 apps during December 2017. We found an unbalanced DSM app development trend based on AADE7TM guidelines. Many apps were designed to support the behaviors of Healthy Eating (77%), Monitoring (76%), Taking Medication (58%), and Being Active (45%). On the other hand, few apps explored the behaviors of Problem Solving (31%), Healthy Coping (10%), and Reducing Risks (5%). From interviews, we identified the main reasons why only a few apps support the features related to Problem Solving, Healthy Coping, and Reducing Risks. CONCLUSIONS: Future diabetes apps should attempt to incorporate features under evidence-based guidelines such as AADE7TM to better support the self-management behavior changes of people with diabetes. PMID- 29390919 TI - Consensus QSAR modelling of SIRT1 activators using simplex representation of molecular structure. AB - Hierarchical QSAR technology (HiT QSAR) was used for consensus QSAR modelling of 65 SIRT1 activators. Simplex representation of molecular structure (SiRMS) has been used for descriptor generation. The predictive QSAR models were developed using the partial least squares (PLS) method. The QSAR models were built up according to OECD principles. One hundred rounds of Y-scrambling were performed for each selected model to exclude chance correlations. A successful consensus model (r2 = 0.830, [Formula: see text] = 0.754) was obtained from the five best QSAR models. Leverage, ellipsoid and local tree domain of applicability (DA) approaches have been used for evaluation of the quality of predictions. Molecular fragments responsible for an increase and decrease of the activation properties have been determined by mechanistic interpretation of the developed QSAR model. PMID- 29390920 TI - Utility of Additional Tissue Sections in Surgical Pathology. AB - BACKGROUND: To avoid diagnostic errors such as missed diagnosis and errors in staging tumors due to inadequate tissue sampling, pathologists submit additional sections (AS). OBJECTIVE: This study assessed frequency, diagnostic yield, distribution, and cost of AS. METHOD: Among 1542 AS cases, we calculated mean AS per case; fraction of AS that altered diagnosis or stage; AS variation by tissue, malignant versus benign lesions, presence or absence of neoadjuvant therapy, mass, margin, lymph nodes, or other source, resident versus pathologist assistant (PA) dissector; and AS cost per case. RESULTS: Overall 9.2 +/- 8.8 AS were collected per case. In only 3.8% (58/1542) of cases AS altered diagnosis or stage. Urinary bladder cases provoked the most AS: 19.5 +/- 15.1 per case. Significantly more AS came from malignant versus benign lesions (10.8 +/- 9.7 vs 7.6 +/- 7.5, P = <.0001) and from specimens treated with neoadjuvant therapy versus malignant lesions not so treated (12.3 +/- 9.4 vs 10.3 +/- 9.8, P = .02). Lymph nodes were sampled more heavily compared with mass, margin, and other sites combined (11.8 +/- 11.4 vs 8.9 +/- 8.4, P = .003), but in 78.4% (1209/1542) of cases, AS were from mass. Of diagnosis or stage altering AS cases, two thirds (38/58) were from masses, one fifth (11/58) from lymph nodes, a 10th (6/58) from margins, and a 20th (3/58) from other specimen sites. Resident versus pathologist assistant dissection caused no significant AS difference. AS contributed 40% cost per case. CONCLUSIONS: AS per case ranged widely; their diagnostic yield was low; they were highest in urinary bladder specimens, in malignant and particularly neoadjuvant-treated lesions. Although lymph nodes were most heavily sampled, most AS were from masses. Resident dissection did not increase AS and cost of AS was high. PMID- 29390921 TI - Ovulation induction and oocyte retrieval for fertility preservation in young adolescents newly diagnosed with medulloblastoma: a case series. PMID- 29390922 TI - Age-based normative data for a computerized dynamic posturography system that uses a virtual visual surround environment. AB - BACKGROUND: Computerized dynamic posturography (CDP) is the gold standard to differentiate between sensory, motor, and central adaptive impairments to postural control. OBJECTIVE: To obtain normative values in healthy adults age 20 69 for a CDP system that uses a full-field dynamic visual surround. This is in contrast to the mechanically movable visual surround used in traditional CDP systems. METHODS: Fifty healthy adults divided into five age groups were tested during the three test protocols for CDP: sensory organization test (SOT), motor control test (MCT), and adaptation test (ADT). Outcomes were compared across age groups and to published normative CDP values. Repeatability was assessed in five different subjects (23-30 years old) on 2 days, 1 week apart. RESULTS: Most outcomes were comparable to published norms with notable differences in SOT condition 4 and ADT. SOT composite and conditions 4-6, all MCT translations, and ADT toes up showed moderate to good repeatability (r = 0.60 to 0.99). Age group and gender differences were not substantial. CONCLUSIONS: Some but not all CDP outcomes with a virtual visual environment were comparable to published norms. The differences are likely related to the virtual surround having a more compelling effect on balance even in conditions with a stationary surround. PMID- 29390923 TI - Maternal overnutrition leads to cognitive and neurochemical abnormalities in C57BL/6 mice. AB - OBJECTIVES: Epidemiological studies have linked maternal obesity with metabolic as well as psychiatric disorders in the progeny. However, very little is known how maternal overnutrition may affect the cognitive abilities of the offspring. METHODS: Here, we tested the hypothesis whether maternal high-fat diet (HFD) exposure in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the offspring during different age trajectories. RESULTS: We found that maternal HFD led to cognitive disabilities in adult offspring compared to controls. It was mostly evident in a reference memory and in an associative learning paradigm. More severe and pervasive impairments were evident in the aged adult group across multiple cognitive domains. In addition, adult and aged adult HFD offspring showed potentiation of prepulse inhibition. The cognitive impairments observed at adulthood were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions. DISCUSSION: Our results suggest that HFD offspring are at an increased risk to develop cognitive deficits, affecting learning and memory processes in adulthood. Furthermore, maternal HFD exposure may facilitate or even drive pathological brain aging mainly in the hippocampal and prefrontal cortex structures that may explain the cognitive deficits observed in the offspring. PMID- 29390924 TI - A 4-gene expression prognostic signature might guide post-remission therapy in patients with intermediate-risk cytogenetic acute myeloid leukemia. AB - In intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) patients, novel biomarkers to guide post-remission therapy are needed. We analyzed with high density arrays 40 IRC-AML patients who received a non-allogeneic hematopoietic stem-cell transplantation-based post-remission therapy, and identified a signature that correlated with early relapse. Subsequently, we analyzed selected 187 genes in 49 additional IRC-AML patients by RT-PCR. BAALC, MN1, SPARC and HOPX overexpression correlated to refractoriness. BAALC or ALDH2 overexpression correlated to shorter overall survival (OS) (5-year OS: 33 +/- 8.6% vs. 73.7 +/- 10.1%, p = .006; 32 +/- 9.3% vs. 66.4 +/- 9.7%, p = .016), whereas GPR44 or TP53INP1 overexpression correlated to longer survival (5-year OS: 66.7 +/- 10.3% vs. 35.4 +/- 9.1%, p = .04; 58.3 +/- 8.2% vs. 23.1 +/- 11.7%, p = .029). A risk score combining these four genes expression distinguished low-risk and high-risk patients (5-year OS: 79 +/- 9% vs. 30 +/- 8%, respectively; p = .001) in our cohort and in an independent set of patients from a public repository. Our 4-gene signature may add prognostic information and guide post-remission treatment in IRC-AML patients. PMID- 29390925 TI - Diagnostic criteria and contributors to Gilbert's syndrome. AB - Hyperbilirubinemia is a well-known condition in the clinical setting; however, the causes of elevated serum bilirubin are diverse, as are the clinical ramifications of this condition. For example, diagnoses of individuals vary depending on whether they exhibit an unconjugated or conjugated hyperbilirubinemia. Diagnoses can include conditions of disordered bilirubin metabolism (Gilbert's, Crigler-Najjar, Rotor, or Dubin-Johnson syndromes) or an acquired disease, including alcoholic/non-alcoholic fatty liver disease, hepatotropic hepatitis, cirrhosis, or hepato-biliary malignancy. Assessment of bilirubin concentrations is typically conducted as part of routine liver function testing. Mildly elevated total bilirubin with normal serum activities of liver transaminases, biliary damage markers, and red blood cell counts, however, may indicate the presence of Gilbert's syndrome (GS), a benign condition that is present in ~5-10% of the population. In this case, mildly elevated unconjugated bilirubin in GS is strongly associated with "reduced" prevalence of chronic diseases, particularly cardiovascular diseases (CVD) and type 2 diabetes mellitus (and associated risk factors), as well as CVD-related and all-cause mortality. These reports challenge the dogma that bilirubin is simply a potentially neurotoxic by-product of heme catabolism and emphasize the importance of understanding its potential beneficial physiologic and detrimental pathophysiologic effects, in order to appropriately consider bilirubin test results within the clinical laboratory setting. With this information, we hope to improve the understanding of disorders of bilirubin metabolism, emphasize the diagnostic importance of these conditions, and outline the potential impact GS may have on resistance to disease. PMID- 29390926 TI - Twelve tips for crossborder curriculum partnerships in medical education. AB - Crossborder curriculum partnerships are a relatively new and fast-growing form of internationalization in which the curriculum that has been developed by one institution (the home institution) crosses borders and is implemented in another institution (the host institution). These partnerships aim to provide comparable learning experiences to the students in both institutions and are driven by a variety of motives, such as strengthening international networks, increasing financial gains, and stimulating research spinoffs. Although popular, crossborder curriculum partnerships are also criticized for their potentially low educational quality, failing to address fundamental differences in teaching and learning between the home and host institutions, and not addressing the educational needs of the host country's health care system. Our aim is to provide guidance to those considering or engaged in designing, developing, managing, and reviewing a crossborder curriculum partnership or other forms of international educational partnerships in medical education. Drawing from research, personal, and institutional experiences in this area, we listed twelve tips categorized into four themes, which contribute to the establishment of sustainable partnerships that can withstand the aforementioned criticism. PMID- 29390927 TI - Malignant Ewing-Like Neoplasm With an EWSR1-KLF15 Fusion: At the Crossroads of a Myoepithelial Carcinoma and a Ewing-Like Sarcoma. A Case Report With Treatment Options. AB - We present a case of a malignant Ewing-like neoplasm of the parotid gland in a 20 year-old woman with an EWSR1-KLF15 gene fusion that presented with pulmonary metastasis. Despite the fact that the tumor was essentially immunohistochemically negative for keratins, p63, and p40, we interpret this neoplasm as an unusual form of a high-grade myoepithelial carcinoma based on its focal plasmacytoid cytology, chondromyxoid matrix, SOX10, S100 protein, and calponin expression, and the knowledge that the EWSR1-KLF15 gene fusion has, to date, only been identified in 2 tumors, both myoepithelial carcinomas of the kidney. We also present a cytogenetic analysis of this unusual tumor. This "Ewing-like myoepithelial carcinoma" initially did not respond to 2 cycles of ifosfamide and etoposide alternated with a cycle of cytoxan, adriamycin, and vincristine, a standard regimen for Ewing sarcoma. Subsequent oral pazopanib therapy did result in a reduction of the patient's pulmonary and nodal disease. PMID- 29390928 TI - Association of Vascular Endothelial Growth Factor ( VEGF) Gene Polymorphisms With Gastric Cancer and Its Development, Prognosis, and Survival. AB - The relationship between vascular endothelial growth factor gene polymorphism and gastric cancer risk and its development, prognosis, and survival are still being debated. This meta-analysis was performed to assess these relationships. The association reports were identified from PubMed, Embase, Cochrane Library, and CBM-disc (China Biological Medicine Database), and eligible studies were included and calculated using the meta-analysis method. VEGF+936C/T, VEGF+405 G>C, VEGF 460 T>C, VEGF-1498 T>C, and VEGF-2578 C>A gene polymorphisms were found to be unassociated with gastric cancer risk for the overall population in this meta analysis, whereas the VEGF-634 G>C GG genotype was associated with gastric cancer risk in the overall population. Furthermore, VEGF-634 G>C C allele and the GG genotype were associated with gastric cancer risk in Caucasians, and VEGF+1612G/A gene polymorphism was associated with gastric cancer risk for the Asian population. VEGF+936C/T gene polymorphism was not associated with the stage of cancer, lymph node metastasis, Lauren classification, or survival of gastric cancer. However, VEGF+936C/T T allele and TT genotype were associated with the tumor size of gastric cancer. In conclusion, the VEGF-634 G>C GG genotype was associated with gastric cancer risk in the overall population with the VEGF-634 G>C C allele and GG genotype being associated with risk in Caucasians and VEGF+1612G/A in the Asian population. PMID- 29390929 TI - Use and impact of herpes zoster prophylaxis in myeloma patients treated with proteasome inhibitors. PMID- 29390930 TI - Blue Beads on the Duodenal Surface: Cause of Diarrhea in a Renal Transplant Recipient. PMID- 29390931 TI - Correction to: Chamoun et al., Bacterial pathogenesis and interleukin-17: interconnecting mechanisms of immune regulation, host genetics, and microbial virulence that influence severity of infection. PMID- 29390932 TI - Recent advances in the management of multiple myeloma: clinical impact based on resource-stratification. Consensus statement of the Asian Myeloma Network at the 16th international myeloma workshop. AB - Predicated on our improved understanding of the disease biology, we have seen remarkable advances in the management of multiple myeloma over the past few years. Recently approved drugs have radically transformed the treatment paradigm and improved survivals of myeloma patients. The progress has necessitated revision of the diagnostic criteria, risk-stratification and response definition. The huge disparities in economy, healthcare infrastructure and access to novel drugs among different Asian countries will hinder the delivery of optimum myeloma care to patients managed in resource-constrained environments. In the light of the tremendous recent changes and evolution in myeloma management, it is timely that the resource-stratified guidelines from the Asian Myeloma Network be revised to provide updated recommendations for Asia physicians practicing under various healthcare reimbursement systems. This review will highlight the most recent advances and our recommendations on how they could be integrated in both resource abundant and resource-constrained facilities. PMID- 29390933 TI - Coupling model of aerobic waste degradation considering temperature, initial moisture content and air injection volume. AB - A quantitative description of aerobic waste degradation is important in evaluating landfill waste stability and economic management. This research aimed to develop a coupling model to predict the degree of aerobic waste degradation. On the basis of the first-order kinetic equation and the law of conservation of mass, we first developed the coupling model of aerobic waste degradation that considered temperature, initial moisture content and air injection volume to simulate and predict the chemical oxygen demand in the leachate. Three different laboratory experiments on aerobic waste degradation were simulated to test the model applicability. Parameter sensitivity analyses were conducted to evaluate the reliability of parameters. The coupling model can simulate aerobic waste degradation, and the obtained simulation agreed with the corresponding results of the experiment. Comparison of the experiment and simulation demonstrated that the coupling model is a new approach to predict aerobic waste degradation and can be considered as the basis for selecting the economic air injection volume and appropriate management in the future. PMID- 29390934 TI - Interpregnancy interval and subsequent pregnancy outcomes after dilation and evacuation. AB - We conducted this study to compare outcomes for pregnancies conceived <=6 months after dilation and evacuation (D&E) with those conceived >6 months after D&E. This retrospective cohort study included women who underwent D&E (14-26 weeks) and were readmitted with a subsequent pregnancy. The primary outcome was the rate of preterm birth (<37 weeks). We identified 737 D&Es with 214 subsequent pregnancies. Outcomes were available for 85.5% of these pregnancies. Preterm birth <37 weeks occurred in 9.4% (3/32) of patients with an interpregnancy interval <=6 months and 20.7% (12/58) of patients with an interpregnancy interval >6 months (p = .17). No differences in preterm birth <34 weeks, postpartum haemorrhage, placentation abnormalities, intrauterine growth restriction, cervical insufficiency or mode of delivery were noted. Adverse pregnancy outcomes were not higher in the group of women who conceived <=6 months after D&E compared to those who waited longer than 6 months. IMPACT STATEMENT What is already known on this subject: A small number of studies have noted an increased risk of adverse pregnancy outcomes with an interpregnancy interval of 6 months or fewer after a spontaneous or an induced abortion. What the results of this study add: We present the first study exploring pregnancy outcomes after dilation and evacuation for termination of pregnancy at 14 weeks or greater. Our results do not support an increased rate of adverse events with an interpregnancy interval of 6 months or fewer following dilation and evacuation. What the implications are of these findings for clinical practice and/or further research: Because of limitations in sample size, our results should be interpreted in the context of other studies. PMID- 29390935 TI - Revisiting DNA barcoding of true bugs of the infraorder Pentatomomorpha (Hemiptera: Heteroptera) from India. AB - Cytochrome c oxidase subunit I gene (COI) sequences of roughly 509 bp length for various species of the Infraorder Pentatomomorpha were generated. K2P divergences within and between species and genera were calculated and compared using newly generated sequences and the ones available on online portals. Mean interspecific (within-genus) genetic divergence (14.23%) was ~ eight times greater than mean intraspecific (within-species) divergence (1.79%). Distance-based as well as character-based approaches were used towards constructing (COI) trees. In total, 20 sequences were of the species that were previously not part of the Barcode Of Life Database (BOLD), hence representing additions to the barcode library of Indian Heteroptera. Some of the analyzed species are well-known agricultural pests. All the COI sequences and the associated specimen data have been deposited on BOLD. PMID- 29390936 TI - Comparison of biliary brush biopsy and fine needle biopsy in the diagnosis of biliary strictures. AB - PURPOSE: The purpose of this study is to evaluate the accuracy of percutaneous fine needle biopsy (FNB) and brush biopsy (BB) at a cancer center. MATERIAL AND METHODS: Retrospective analysis of all bile duct biopsies performed in Interventional Radiology between January 2000 and January 2015 was performed. FNB was performed under real-time cholangiographic guidance using a notched needle directed at the bile duct stricture. BB was performed by advancing a brush across the stricture and moving it back and forth to scrape the stricture. Biopsy results were categorized as true positive (TP), true negative (TN), false positive (FP) and false negative (FN) based on pathology reports and confirmed by surgical specimens or clinical follow-up of at least six months. Fisher's exact test was used to compare the rate of TP in FNB and BB. RESULTS: One-hundred and nineteen patients underwent FNB or BB. Fifteen were censored because of lack of follow-up. The remaining 104 patients underwent a total of 117 bile duct biopsies during the study period: 34 FNB and 83 BB. There were no complications in either group. In the FNB group 22/34 (64%) biopsies were TP, 4/34(12%) were TN and there were 8(24%) FN biopsies. In the BB group, 20/83 (24%) were TP, 38/83 (46%) TN and 25/83 (30%) FN biopsies. There were no FP biopsies in either group. The sensitivity of detecting malignancy by FNB was significantly higher than that by BB (73% vs 44%, p < .0005). There were no complications associated with FNB or BB. CONCLUSIONS: FNB of bile duct strictures is safe and has a higher sensitivity for detecting malignancy than BB. PMID- 29390937 TI - Pregnancy and iron status in beta-thalassaemia major and intermedia: six years' experience in a North London Hospital. PMID- 29390938 TI - Comparative values of medical school assessments in the prediction of internship performance. AB - BACKGROUND: Multiple undergraduate achievements have been used for graduate admission consideration. Their relative values in the prediction of residency performance are not clear. This study compared the contributions of major undergraduate assessments to the prediction of internship performance. METHODS: Internship performance ratings of the graduates of a medical school were collected from 2012 to 2015. Hierarchical multiple regression analyses were used to examine the predictive values of undergraduate measures assessing basic and clinical sciences knowledge and clinical performances, after controlling for differences in the Medical College Admission Test (MCAT). RESULTS: Four hundred eighty (75%) graduates' archived data were used in the study. Analyses revealed that clinical competencies, assessed by the USMLE Step 2 CK, NBME medicine exam, and an eight-station objective structured clinical examination (OSCE), were strong predictors of internship performance. Neither the USMLE Step 1 nor the inpatient internal medicine clerkship evaluation predicted internship performance. The undergraduate assessments as a whole showed a significant collective relationship with internship performance (DeltaR2 = 0.12, p < 0.001). CONCLUSIONS: The study supports the use of clinical competency assessments, instead of pre-clinical measures, in graduate admission consideration. It also provides validity evidence for OSCE scores in the prediction of workplace performance. PMID- 29390939 TI - Multipronged ethanol ablation combined with TACE for intermediate hepatocellular carcinoma. AB - PURPOSE: To retrospectively investigate the efficacy of multipronged ethanol ablation with or without transarterial chemoembolization (TACE) in the treatment of intermediate hepatocellular carcinoma (HCC) (3.1-5.0 cm in diameter) at high risk locations . MATERIAL AND METHODS: From March 2009 to April 2014, 25 consecutive patients with intermediate HCC who underwent multipronged ethanol ablation combined with TACE were included in the combination treatment group, while 50 patients who underwent multipronged ethanol ablation alone were included in the control group. RESULTS: Primary technique effectiveness was achieved in 70 patients (25/25, 100% in the combination treatment group; 45/50, 90% in the control group; p = .162). The local tumor progression (LTP) rates at 1, 3, 5, and 7 years were 8.0%, 24.0%, 24.0%, and 24.0% in the combination treatment group, respectively, which were significantly lower than those in the control group (24.4%, 44.1%, 66.5% and 66.5%, respectively; p = .043). However, no significant differences of overall survival and disease-free survival were found between the two groups (p = .996 and .974, respectively). CONCLUSION: Multipronged ethanol ablation combined with TACE could improve local tumor control for patients with intermediate HCC at high-risk locations when compared with multipronged ethanol ablation alone, although the survival outcomes were comparable. PMID- 29390941 TI - A cross-sectional study on teaching pelvic examination in medical schools in the UK (the COTES study). AB - Gynaecological teaching associates (GTAs) appear to be effective in aiding medical students to acquire core skills in female pelvic examination (FPE). The aim was to explore the current provision for teaching and assessment of FPE in Obstetric and Gynaecological (O&G) placements across UK medical schools and in particular, the use of GTAs. An online survey was sent to undergraduate academic leads for O&G, representing 29 of the 30 UK medical schools. The response rate was 21/29 (72%). The average placement was 6.7 weeks and teaching of FPE varied including training on manikins (20/21, 95%), instruction in outpatient clinics (17/21, 81%) and instruction on anaesthetised patients (17/21, 81%). The survey revealed that anatomic pelvic models are combined with supervised instruction in outpatient clinics and operating theatres. GTAs are used by less than a third of medical schools, and where used are thought to enhance teaching in this core skill in contrast to those universities not using GTAs. Short placements, a reluctance to use GTAs and a lack of formal assessment may adversely impact upon the competency of newly qualifying medical students in FPE. Impact statement What is already known on this subject: Experience of female pelvic examination intimate is limited. Expert patients, known as Gynaecological Teaching Associates (GTAs), have been suggested as a potential solution to improve teaching of gynaecological examination, but the last survey of medical schools in the United Kingdom (UK) conducted in 1989 reported that only two were using GTAs in an average clinical placement length of 11.5 weeks. What the results of this study add: Twenty-five years after the last survey, Obstetrics and Gynaecology (O&G) clinical placements have been reduced to an average of 6 weeks with one-third requiring only an informal impression of competence in female pelvic examination. Despite published evidence since 1989 supporting the effectiveness of GTAs, just six medical schools are using GTAs for teaching and assessment with all believing them to be effective. What the implications are of these findings for clinical practice and/or further research: A combination of short placements, an apparent reluctance to use GTAs and a lack of uniform formal assessment may mean that the competency of newly qualifying medical students in basic gynaecological examination is compromised. PMID- 29390940 TI - Metastasis to the F344 Rat Pancreas from Lung Cancer Induced by 4 (Methylnitrosamino)- 1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4 (Methylnitrosamino)-1-(3-pyridyl)- 1-butanol, Constituents of Tobacco Products. AB - Lung cancer is the most common cause of cancer-related deaths in humans worldwide. There is strong evidence that the tobacco-specific nitrosamine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) play an important role in carcinogenesis caused by tobacco products. NNK and racemic NNAL are reported to induce lung and pancreatic tumors in rats. The carcinogenicity in Fischer 344 rats of NNK, NNAL, and its enantiomers ( R)-NNAL and ( S)-NNAL has been studied recently, and all test compounds induced significant numbers of lung tumors. We report here the detailed histopathological and immunohistochemical characterization of these tumors and their aggressive nature as shown by their metastasis locally and to the pancreas. The spectrum of treatment-related histopathological findings comprised pulmonary alveolar/bronchiolar (A/B) epithelial hyperplasia, A/B adenomas, and A/B carcinomas. A/B carcinomas frequently exhibited local invasion/metastasis within the mediastinum and thoracic cavity and distant metastasis to the pancreas that was confirmed by immunohistochemistry using the lung-specific markers prosurfactant protein-C and club (Clara) cell-10. Our observation regarding metastasis to the pancreas was an important, and unexpected, finding in this study both for the experimental animal model and potential human relevance. PMID- 29390942 TI - Assessment of total sialic acid levels in patients with hyperemesis gravidarum: a preliminary study. AB - To determine the levels of serum total sialic acid (TSA) in patients with hyperemesis gravidarum (HG) and their gestational age-matched controls. Thirty pregnant women with HG, and 30 healthy pregnant women at up to 14 weeks of gestation were enrolled in this preliminary study. Total sialic acid levels in maternal serum were measured using the quantitative sandwich ELISA method. We observed statistically significant difference in TSA levels between HG and the control groups (p = .003). The identification of the role of SA in the prediction, diagnosis and follow-up of HG warrants more comprehensive studies in the future. Impact Statement What is already known on this subject? The derivatives of neuraminic acid are collectively referred to as sialic acid (SA). Changes in SA levels are known to trigger various conditions and disorders, including inflammatory, cardiovascular, neurological and endocrine diseases. Although a sensitive test capable of identifying hyperemesis gravidarum (HG) would be useful for diagnosis purposes, such a test is currently not available. Studies focussing on identifying new potential indicators and biomarkers for HG - as well as identifying their relevance in establishing diagnosis and assessing disease severity - would not only assist in elucidating the underlying causes of this condition but would also contribute to the development of new diagnostic tests for HG. What the results of this study add? Total sialic acid levels are significantly higher in sera of the patients with HG. The present study is the first in the literature to assess total sialic acid levels in patients with HG and healthy pregnant women before 14 weeks of gestation. What the implications are of these findings for clinical practice and/or further research? Total sialic acid levels could give an idea to clinicians in the etiopathogenesis of HG. The identification of the role of sialic acid in the prediction, diagnosis and follow up of HG warrants more comprehensive studies in the future. PMID- 29390944 TI - Goofy vs. Regular: Laterality effects in surfing. AB - The aim of the present study was to test if lateral preferences of surfers are associated with behaviour and performance depending on the direction of a breaking wave. We hypothesized that wave direction and surf stance interact in creating favourable or debilitative performance demands as surfers are either facing the wave (frontside) or the wave is breaking in the back of the surfers (backside). Study 1 was an online survey collecting self-report data of recreational surfers (n = 394). In Study 2, we analysed all wave scores (n = 2,552) and laterality of professional surfers during the season of 2014. Study 1 demonstrated that recreational surfers preferred surfing frontside and described themselves as more skilful when surfing frontside as this is facilitative for picking up visual information. Study 2 did not provide clear evidence that professional surfers on average scored higher during contests when surfing frontside, but when professional surfers had a choice of surfing frontside vs. backside, they were more likely to surf frontside. We discuss the diverging findings between Study 1 and Study 2 from the "circumvention-of-limits" argumentation within the expertise literature as professional surfers most likely have acquired skills allowing them to compensate for debilitative individual and environmental circumstances. PMID- 29390943 TI - Transient Receptor Potential Melastatin 4 Induces Astrocyte Swelling But Not Death after Diffuse Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a prevalent disease with significant costs. Although progress has been made in understanding the complex pathobiology of focal lesions associated with TBI, questions remain regarding the diffuse responses to injury. Expression of the transient receptor potential melastatin 4 (Trpm4) channel is linked to cytotoxic edema during hemorrhagic contusion expansion. However, little is known about Trpm4 following diffuse TBI. To explore Trpm4 expression in diffuse TBI, rats were subjected to a diffuse central fluid percussion injury (CFPI) and survived for 1.5 h to 8 weeks. The total number of Trpm4+ cells, as well as individual cellular intensity/expression of Trpm4, were assessed. Hemotoxylin and eosin (H&E) labeling was performed to evaluate cell damage/death potentially associated with Trpm4 expression following diffuse TBI. Finally, ultrastructural assessments were performed to evaluate the integrity of Trpm4+ cells and the potential for swelling associated with Trpm4 expression. Trpm4 was primarily restricted to astrocytes within the hippocampus and peaked at 6 h post-injury. While the number of Trpm4+ astrocytes returned to sham levels by 8 weeks post-CFPI, cellular intensity occurred in region-specific waves following injury. Correlative H&E assessments demonstrated little evidence of hippocampal damage, suggesting that Trpm4 expression by astrocytes does not precipitate cell death following diffuse TBI. Additionally, ultrastructural assessments showed Trpm4+ astrocytes exhibited twice the soma size compared with Trpm4- astrocytes, indicating that astrocyte swelling is associated with Trpm4 expression. This study provides a foundation for future investigations into the role of Trpm4 in astrocyte swelling and edema following diffuse TBI. PMID- 29390945 TI - Validated Living Worldwide Supercentenarians, Living and Recently Deceased: February 2018. PMID- 29390946 TI - Successful Phenobarbital Desensitization After DRESS Reaction in the Management of Refractory Status Epilepticus. AB - PURPOSE: Drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with antiepileptic drug use and is a rare but life-threatening side effect. We present a case of phenobarbital-induced DRESS in a patient who subsequently required phenobarbital and was successfully desensitized. SUMMARY: A 5-year-old male presented with medically refractory status epilepticus (SE). He had been trialed on several antiepileptic medications without achieving burst suppression. Burst suppression was achieved with a pentobarbital infusion, and thus, phenobarbital was initiated as the pentobarbital was weaned. After five days of phenobarbital, the patient developed signs and symptoms concerning for DRESS; a punch biopsy confirmed the drug reaction. Two months later, he again developed SE unresponsive to antiepileptic infusions. Burst suppression was achieved with pentobarbital, and it was decided to transition the patient to phenobarbital. Due to concerns of phenobarbital-induced DRESS, the patient underwent a phenobarbital desensitization consisting of 6 doses sequentially administered in 10-fold increasing concentrations before achieving therapeutic dosing. Three days later, the patient achieved therapeutic phenobarbital levels, was weaned off of pentobarbital, and remained seizure-free without recurrence of DRESS. CONCLUSIONS: Graded desensitization may be an option to minimize recurrence of DRESS in patients where avoidance of the offending agent is not possible. PMID- 29390947 TI - Broad Consent for Research on Biospecimens: The Views of Actual Donors at Four U.S. Medical Centers. AB - Commentators are concerned that broad consent may not provide biospecimen donors with sufficient information regarding possible future research uses of their tissue. We surveyed with interviews 302 cancer patients who had recently provided broad consent at four diverse academic medical centers. The majority of donors believed that the consent form provided them with sufficient information regarding future possible uses of their biospecimens. Donors expressed very positive views regarding tissue donation in general and endorsed the use of their biospecimens in future research across a wide range of contexts. Concerns regarding future uses were limited to for-profit research and research by investigators in other countries. These results support the use of broad consent to store and use biological samples in future research. PMID- 29390948 TI - Limberg flap in management of pilonidal sinus disease: systematic review and a local experience. AB - OBJECTIVES: To review published evidence of Limberg flap (LF) use in pilonidal sinus disease (PSD). We also included our local experience of LF. METHODS: Medline and Embase database were searched for the words 'pilonidal, sinus, Limberg, flap'. Non-English articles and those not-related to our scope of search were omitted. We included a retrospective study of patients underwent LF in our district hospital. Data including length of hospital stay, post-operative complications and recurrence were collected. RESULTS: Literature review revealed 68 studies (22 case series, 35 comparative studies, nine RCTs and two meta analyses). Recurrence rate was 0-7.4% in case series. Recurrence rate in comparative studies was 0-8.3%, compared to 4-37.7% for primary closure and 0-11% for Karydakis flap. RCTs showed that LF or its modification is superior to primary closure, with comparable results to Karydakis flap. About 26 patients included in the cohort study (16 male, average age 27 years). Six patients presented with recurrent disease. Post-operative length of hospital stay was four to seven days. Post-operative complication rate was 11.5% - [two partial wound dehiscence, one wound infection]. Recurrence rate was 7.7%. Average follow-up was 18 months. CONCLUSIONS: Limberg flap presents a safe and effective method that can be offered for patients with primary or recurrent PSD. PMID- 29390949 TI - Test-enhanced learning in health professions education: A systematic review: BEME Guide No. 48. AB - BACKGROUND: Cognitive psychology studies demonstrate that subjects who attempt to recall information show better learning, retention, and transfer than subjects who spend the same time studying the same material (test-enhanced learning, TEL). We systematically reviewed TEL interventions in health professions education. METHODS: We searched 13 databases, 14 medical education journals, and reference lists. Inclusion criteria included controlled studies of TEL that compared TEL to studying the same material or to a different TEL strategy. Two raters screened articles for inclusion, abstracted information, determined quality scores, and calculated the standardized mean difference (SMD) for the learning outcomes. RESULTS: Inter-rater agreement was excellent for all comparisons. The 19 included studies reported 41 outcomes with data sufficient to determine a SMD. TEL interventions included short answer questions, multiple choice questions, simulation, and standardized patients. Five of six immediate learning outcomes (SMD 0.09-0.44), 21 of 23 retention outcomes (SMD 0.12-2.5), and all seven transfer outcomes (SMD 0.33-1.1) favored TEL over studying. CONCLUSIONS: TEL demonstrates robust effects across health professions, learners, TEL formats, and learning outcomes. The effectiveness of TEL extends beyond knowledge assessed by examinations to clinical applications. Educators should include TEL in health professions curricula to enhance recall, retention, and transfer. PMID- 29390951 TI - The death of the Byzantine Emperor John II Komnenos (1087-1143). AB - INTRODUCTION: The purpose of this study is to give a brief account of the life of John II Komnenos, his reign and to clarify the events and causes surrounding his death. METHODS: A thorough search of the literature was undertaken in PubMed and Google Scholar as well as in history books through the internet and in History and Medical University libraries. RESULTS: The death of the king cannot be attributed to poisoning from an injured hand by arrow poison. The long period of time before the presentation of symptoms should be attributed to their being caused by an infection. The failure of both conservative anti-inflammatory treatment and surgical drainage point towards an anaerobic infection or a septic inflammation. CONCLUSION: The death of the emperor John Komnenos was caused by a severe infection of the hand of unknown agent leading to septicaemia. This conclusion is based on the fact that death came a week or more after the injury of the hand and it was not caused by the poison of the arrow which would have been fatal within several hours. PMID- 29390953 TI - Midwest Nursing Research Society News. PMID- 29390955 TI - Genomic prediction of piglet response to infection with one of two porcine reproductive and respiratory syndrome virus isolates. AB - BACKGROUND: Genomic prediction of the pig's response to the porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) would be a useful tool in the swine industry. This study investigated the accuracy of genomic prediction based on porcine SNP60 Beadchip data using training and validation datasets from populations with different genetic backgrounds that were challenged with different PRRSV isolates. RESULTS: Genomic prediction accuracy averaged 0.34 for viral load (VL) and 0.23 for weight gain (WG) following experimental PRRSV challenge, which demonstrates that genomic selection could be used to improve response to PRRSV infection. Training on WG data during infection with a less virulent PRRSV, KS06, resulted in poor accuracy of prediction for WG during infection with a more virulent PRRSV, NVSL. Inclusion of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with a major quantitative trait locus (QTL) on chromosome 4 was vital for accurate prediction of VL. Overall, SNPs that were significantly associated with either trait in single SNP genome-wide association analysis were unable to predict the phenotypes with an accuracy as high as that obtained by using all genotyped SNPs across the genome. Inclusion of data from close relatives into the training population increased whole genome prediction accuracy by 33% for VL and by 37% for WG but did not affect the accuracy of prediction when using only SNPs in the major QTL region. CONCLUSIONS: Results show that genomic prediction of response to PRRSV infection is moderately accurate and, when using all SNPs on the porcine SNP60 Beadchip, is not very sensitive to differences in virulence of the PRRSV in training and validation populations. Including close relatives in the training population increased prediction accuracy when using the whole genome or SNPs other than those near a major QTL. PMID- 29390956 TI - Social genetic effects for growth in pigs differ between boars and gilts. AB - BACKGROUND: Average daily gain (ADG) in pigs is affected by the so-called social (or indirect) genetic effects (SGE). However, SGE may differ between sexes because boars grow faster than gilts and their social behaviours differ. We hypothesized that direct genetic effects (DGE) and SGE for ADG in pigs differ between boars and gilts and that accounting for these differences will improve the predictive ability of a social genetic effects model (SGM). Our data consisted of ADG from 30 to 94 kg for 32,212 uncastrated males (boars) and 48,252 gilts that were raised in sex-specific pens. Data were analyzed using a univariate model with sex as a fixed effect and a bivariate model with ADG in boars and gilts as separate traits using both a classical animal model (CM) and a SGM. RESULTS: With the univariate model, the heritability for ADG was 0.22 +/- 0.01 for the CM, while the estimate of the total heritable variance (T2) was 0.23 +/- 0.01 with the SGM. With the bivariate model, the genetic variance for SGE was higher for boars (13.8 +/- 5.8) than for gilts (9.3 +/- 3.9). For the bivariate model, T2 was 0.32 +/- 0.02 for boars and 0.27 +/- 0.01 for gilts. Estimates of the genetic correlations between DGE (0.88 +/- 0.02) and SGE (0.30 +/- 0.30) for boars versus gilts indicated that ADG in boars and gilts are different traits. Moreover, the estimate of the genetic correlation between DGE and SGE indicated presence of genetic effects of competition among gilts but not among boars. Compared to a CM, the univariate SGM improved predictive ability significantly only for gilts and the bivariate SGM improved predictive ability significantly for both boars and gilts. CONCLUSIONS: We found significant genetic variances of SGE for ADG. The covariance between DGE and SGE was much more negative for gilts than for boars when applying the bivariate model. Because the estimate of the genetic correlation for ADG between gilts and boars differed significantly from 1 and the predictive ability for boars and gilts was improved significantly with the bivariate model, we recommend the use of a bivariate model to estimate both SGE and DGE for ADG in pigs. PMID- 29390957 TI - Streptococcus agalactiae meningoencephalitis associated with gastroesophageal reflux disease and chronic proton pump inhibitors use, in a 9 month-old infant: a case report. AB - BACKGROUND: Streptococcus agalactiae (Group B Streptococcus) is recognized as the etiologic agent of newborn and infant meningitis, aged up to 90 days, starting from the colonization of the maternal genital or gastrointestinal tract, but it is rarely responsible for meningitis in old infants. CASE PRESENTATION: We present the case of a 9 month-old infant diagnosed with S. agalactiae meningoencephalitis associated with chronic gastroesophageal reflux disease treated with a proton pump inhibitor (PPI). CONCLUSION: The use of a PPI is a risk factor for ultra-late onset of Group B Streptococcus meningitis. The use of PPI in infants should be closely monitored in the light of changes in the gut microbiota, in the oropharyngeal and of the respiratory tract colonization, potentially with pathogenic flora. PMID- 29390958 TI - Grid-based prediction of torsion angle probabilities of protein backbone and its application to discrimination of protein intrinsic disorder regions and selection of model structures. AB - BACKGROUND: Protein structure can be described by backbone torsion angles: rotational angles about the N-Calpha bond (phi) and the Calpha-C bond (psi) or the angle between Calphai-1-Calphai-Calphai + 1 (theta) and the rotational angle about the Calphai-Calphai + 1 bond (tau). Thus, their accurate prediction is useful for structure prediction and model refinement. Early methods predicted torsion angles in a few discrete bins whereas most recent methods have focused on prediction of angles in real, continuous values. Real value prediction, however, is unable to provide the information on probabilities of predicted angles. RESULTS: Here, we propose to predict angles in fine grids of 5 degrees by using deep learning neural networks. We found that this grid-based technique can yield 2-6% higher accuracy in predicting angles in the same 5 degrees bin than existing prediction techniques compared. We further demonstrate the usefulness of predicted probabilities at given angle bins in discrimination of intrinsically disorder regions and in selection of protein models. CONCLUSIONS: The proposed method may be useful for characterizing protein structure and disorder. The method is available at http://sparks-lab.org/server/SPIDER2/ as a part of SPIDER2 package. PMID- 29390959 TI - Feruloyl esterase immobilization in mesoporous silica particles and characterization in hydrolysis and transesterification. AB - BACKGROUND: Enzymes display high reactivity and selectivity under natural conditions, but may suffer from decreased efficiency in industrial applications. A strategy to address this limitation is to immobilize the enzyme. Mesoporous silica materials offer unique properties as an immobilization support, such as high surface area and tunable pore size. RESULTS: The performance of a commercially available feruloyl esterase, E-FAERU, immobilized on mesoporous silica by physical adsorption was evaluated for its transesterification ability. We optimized the immobilization conditions by varying the support pore size, the immobilization buffer and its pH. Maximum loading and maximum activity were achieved at different pHs (4.0 and 6.0 respectively). Selectivity, shown by the transesterification/hydrolysis products molar ratio, varied more than 3-fold depending on the reaction buffer used and its pH. Under all conditions studied, hydrolysis was the dominant activity of the enzyme. pH and water content had the greatest influence on the enzyme selectivity and activity. Determined kinetic parameters of the enzyme were obtained and showed that Km was not affected by the immobilization but kcat was reduced 10-fold when comparing the free and immobilized enzymes. Thermal and pH stabilities as well as the reusability were investigated. The immobilized biocatalyst retained more than 20% of its activity after ten cycles of transesterification reaction. CONCLUSIONS: These results indicate that this enzyme is more suited for hydrolysis reactions than transesterification despite good reusability. Furthermore, it was found that the immobilization conditions are crucial for optimal enzyme activity as they can alter the enzyme performance. PMID- 29390960 TI - A high throughput screen for active human transposable elements. AB - BACKGROUND: Transposable elements (TEs) are mobile genetic sequences that randomly propagate within their host's genome. This mobility has the potential to affect gene transcription and cause disease. However, TEs are technically challenging to identify, which complicates efforts to assess the impact of TE insertions on disease. Here we present a targeted sequencing protocol and computational pipeline to identify polymorphic and novel TE insertions using next generation sequencing: TE-NGS. The method simultaneously targets the three subfamilies that are responsible for the majority of recent TE activity (L1HS, AluYa5/8, and AluYb8/9) thereby obviating the need for multiple experiments and reducing the amount of input material required. RESULTS: Here we describe the laboratory protocol and detection algorithm, and a benchmark experiment for the reference genome NA12878. We demonstrate a substantial enrichment for on-target fragments, and high sensitivity and precision to both reference and NA12878 specific insertions. We report 17 previously unreported loci for this individual which are supported by orthogonal long-read evidence, and we identify 1470 polymorphic and novel TEs in 12 additional samples that were previously undocumented in databases of insertion polymorphisms. CONCLUSIONS: We anticipate that future applications of TE-NGS alongside exome sequencing of patients with sporadic disease will reduce the number of unresolved cases, and improve estimates of the contribution of TEs to human genetic disease. PMID- 29390961 TI - Fractures among patients with dizziness - a ten-year follow-up. AB - BACKGROUND: The number of elderly people persons suffering from dizziness is substantial, and dizziness is a risk factor for falls and fractures. Fall-related fractures represent a major public health issue. Longitudinal studies can help find ways of predicting fall-related fractures among frail elderly persons with multisensory dizziness. The aim of the present study was therefore to investigate whether different measures of balance, being male/female or admission to hospital, could predict fracture at a ten-year follow-up in patients suffering from multisensory dizziness. METHODS: Patients who had participated in two earlier (ten years previous) dizziness studies were sought in the local health authority's patient administrative system. Information was extracted regarding patient hospitalization, for fractures or for any other reason, during the ten year period. Logistic regression was used to analyse the relations between clinical balance measures, vestibular rehabilitation, admission to hospital, sex, and fracture. RESULTS: There was no difference between the group of patients with fracture and the group of patients without fracture, regarding balance measures at baseline or admission to hospital for reasons other than fracture. There was no difference between men and women in any of the measures. CONCLUSIONS: This study did not identify any predictors of fracture. Thus, among frail elderly, attention to fall risk should be equally high regardless of patient history. PMID- 29390962 TI - Al Kharj diabetic patients' perception about diabetes mellitus using revised illness perception questionnaire (IPQ-R). AB - BACKGROUND: Illness perception questionnaires for various medical conditions have become more useful in recent years. However, very few have addressed this issue for Type 2 diabetes in Saudi Arabia. METHODS: A self-administered questionnaire was distributed to Type 2 diabetic patients attendees of primary health care centers and Al Kharj Military Industries Corporation Hospital in Al Kharj, Saudi Arabia, from November 24th 2016 to April 24th, 2017. RESULTS: Overall, 383 of the 500 distributed questionnaires were returned, and 187 were males (48.8). Most participants understood that what led to diabetes was hereditary, including diet or eating habits. The Cronbach's alpha value for identity, timeline (cyclical), and emotional factors were relatively high, showing that these scales had a strong level of internal consistency; it also showed that the timeline (acute/chronic) and treatment control scales were low, thus showing internal consistency of these scales. Cronbach's value of coherence and consequences scales were low. CONCLUSION: Saudis with type 2 diabetes mellitus had appropriate knowledge of their disease. They agreed that diabetes was likely to be permanent and would have major consequences on their lives. PMID- 29390963 TI - Evaluation of reference genes for gene expression studies in mouse and N2a cell ischemic stroke models using quantitative real-time PCR. AB - BACKGROUND: Real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a critical tool for evaluating the levels of mRNA transcribed from genes. Reliable RT-qPCR results largely depend on normalization to suitable reference genes. Middle cerebral artery occlusion (MCAO) and oxygen glucose deprivation/reoxygenation (OGD/R) are models that are commonly used to study ischemic stroke. However, the proper reference genes for RNA analysis in these two models have not yet been determined. RESULTS: In this study, we evaluated the expression levels of six candidate housekeeping genes and selected the most suitable reference genes for RT-qPCR analyses of the cortices of MCAO mice and OGD/R-injured N2a cells. Four software programs, geNorm, NormFinder, BestKeeper and RefFinder, were used to validate the stabilities of the candidate reference genes. The results revealed that HPRT and 18S were the most stable reference genes in the cortices of MCAO mice and that beta-actin and cyclophilin were the most stable reference genes in the OGD/R-injured N2a cells; in contrast, GAPDH and Sdha were the least stable genes in the cortices of MCAO mice and the OGD/R-injured N2a cells, respectively. Moreover, a combination of HPRT, 18S and cyclophilin was most suitable for normalization in analyses of the cortices of MCAO mice, and a combination of beta-actin, cyclophilin, GAPDH, and 18S was most suitable for analyses of the OGD/R-injured N2a cells. CONCLUSIONS: This study provides appropriate reference genes for further RT-qPCR analyses of in vivo and in vitro ischemic stroke and demonstrates the necessity of validating reference genes for RNA analyses under variable conditions. PMID- 29390964 TI - Evolutionary fates of universal stress protein paralogs in Platyhelminthes. AB - BACKGROUND: Universal stress proteins (USPs) are present in all domains of life. Their expression is upregulated in response to a large variety of stress conditions. The functional diversity found in this protein family, paired with the sequence degeneration of the characteristic ATP-binding motif, suggests a complex evolutionary pattern for the paralogous USP-encoding genes. In this work, we investigated the origin, genomic organization, expression patterns and evolutionary history of the USP gene family in species of the phylum Platyhelminthes. RESULTS: Our data showed a cluster organization, a lineage specific distribution, and the presence of several pseudogenes among the USP gene copies identified. The absence of a well conserved -CCAATCA- motif in the promoter region was positively correlated with low or null levels of gene expression, and with amino acid changes within the ligand binding motifs. Despite evidence of the pseudogenization of various USP genes, we detected an important functional divergence at several residues, mostly located near sites that are critical for ligand interaction. CONCLUSIONS: Our results provide a broad framework for the evolution of the USP gene family, based on the emergence of new paralogs that face very contrasting fates, including pseudogenization, subfunctionalization or neofunctionalization. This framework aims to explain the sequence and functional diversity of this gene family, providing a foundation for future studies in other taxa in which USPs occur. PMID- 29390965 TI - Breed-dependent microRNA expression in the primary culture of skeletal muscle cells subjected to myogenic differentiation. AB - BACKGROUND: Skeletal muscle in livestock develops into meat, an important source of protein and other nutrients for human consumption. The muscle is largely composed of a fixed number of multinucleated myofibers determined during late gestation and remains constant postnatally. A population of postnatal muscle stem cells, called satellite cells, gives rise to myoblast cells that can fuse with the existing myofibers, thus increasing their size. This requires a delicate balance of transcription and growth factors and specific microRNA (miRNA) expressed by satellite cells and their supporting cells from the muscle stem cell niche. The role of transcription and growth factors in bovine myogenesis is well characterized; however, very little is known about the miRNA activity during this process. We have hypothesized that the expression of miRNA can vary between primary cultures of skeletal muscle cells isolated from the semitendinosus muscles of different cattle breeds and subjected to myogenic differentiation. RESULTS: After a 6-day myogenic differentiation of cells isolated from the muscles of the examined cattle breeds, we found statistically significant differences in the number of myotubes between Hereford (HER)/Limousine (LIM) beef breeds and the Holstein-Friesian (HF) dairy breed (p <= 0.001). The microarray analysis revealed differences in the expression of 23 miRNA among the aforementioned primary cultures. On the basis of a functional analysis, we assigned 9 miRNA as molecules responsible for differentiation progression (miR-1, -128a, -133a, -133b, -139, -206, -222, -486, and -503). The target gene prediction and functional analysis revealed 59 miRNA-related genes belonging to the muscle organ development process. CONCLUSION: The number of myotubes and the miRNA expression in the primary cultures of skeletal muscle cells derived from the semitendinosus muscles of the HER/LIM beef cattle breeds and the HF dairy breed vary when cells are subjected to myogenic differentiation. The net effect of the identified miRNA and their target gene action should be considered the result of the breed-dependent activity of satellite cells and muscle stem cell niche cells and their mutual interactions, which putatively can be engaged in the formation of a larger number of myotubes in beef cattle-related cells (HER/LIM) during in vitro myogenesis. PMID- 29390967 TI - Cross-linking BioThings APIs through JSON-LD to facilitate knowledge exploration. AB - BACKGROUND: Application Programming Interfaces (APIs) are now widely used to distribute biological data. And many popular biological APIs developed by many different research teams have adopted Javascript Object Notation (JSON) as their primary data format. While usage of a common data format offers significant advantages, that alone is not sufficient for rich integrative queries across APIs. RESULTS: Here, we have implemented JSON for Linking Data (JSON-LD) technology on the BioThings APIs that we have developed, MyGene.info , MyVariant.info and MyChem.info . JSON-LD provides a standard way to add semantic context to the existing JSON data structure, for the purpose of enhancing the interoperability between APIs. We demonstrated several use cases that were facilitated by semantic annotations using JSON-LD, including simpler and more precise query capabilities as well as API cross-linking. CONCLUSIONS: We believe that this pattern offers a generalizable solution for interoperability of APIs in the life sciences. PMID- 29390966 TI - Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (Th1, Th2) to immune-mediated tumour cell death induced by NAC. AB - BACKGROUND: The tumour microenvironment consists of malignant cells, stroma and immune cells. In women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC), tumour-infiltrating lymphocytes (TILs), various subsets (effector, regulatory) and cytokines in the primary tumour play a key role in the induction of tumour cell death and a pathological complete response (pCR) with NAC. Their contribution to a pCR in nodal metastases, however, is poorly studied and was investigated. METHODS: Axillary lymph nodes (ALNs) (24 with and 9 without metastases) from women with LLABCs undergoing NAC were immunohistochemically assessed for TILs, T effector and regulatory cell subsets, NK cells and cytokine expression using labelled antibodies, employing established semi-quantitative methods. IBM SPSS statistical package (21v) was used. Non-parametric (paired and unpaired) statistical analyses were performed. Univariate and multivariate regression analyses were carried out to establish the prediction of a pCR and Spearman's Correlation Coefficient was used to determine the correlation of immune cell infiltrates in ALN metastatic and primary breast tumours. RESULTS: In ALN metastases high levels of TILs, CD4+ and CD8+ T and CD56+ NK cells were significantly associated with pCRs.. Significantly higher levels of Tregs (FOXP3+, CTLA-4+) and CD56+ NK cells were documented in ALN metastases than in the corresponding primary breast tumours. CD8+ T and CD56+ NK cells showed a positive correlation between metastatic and primary tumours. A high % CD8+ and low % FOXP3+ T cells and high CD8+: FOXP3+ ratio in metastatic ALNs (tumour-free para-cortex) were associated with pCRs. Metastatic ALNs expressed high IL-10, low IL-2 and IFN-Upsilon. CONCLUSIONS: Our study has provided new data characterising the possible contribution of T effector and regulatory cells and NK cells and T helper1 and 2 cytokines to tumour cell death associated with NAC in ALNs. TRIAL REGISTRATION: The Trial was retrospectively registered. Study Registration Number is ISRCTN00407556 . PMID- 29390968 TI - General practitioner contributions to achieving sustained healthcare for offenders: a qualitative study. AB - BACKGROUND: Offenders frequently have substantial healthcare needs and, like many other socially marginalised groups, often receive healthcare in inverse proportion to their needs. Improved continuity of healthcare over time could contribute to addressing these needs. General Practitioners need to be able to support people with complex social and medical problems, even in systems that are not specifically designed to manage individuals with such degrees of complexity. We aimed to examine offenders' perspectives on factors that contributed to, or worked against, creating and sustaining their access to healthcare. METHODS: From a sample of 200 participants serving community or prison sentences in South West (SW) and South East (SE) England, who were interviewed about their health care experiences as part of the Care for Offenders: Continuity of Access (COCOA) study, we purposively sampled 22 participants for this sub-study, based on service use. These interviews were transcribed verbatim. A thematic analytic approach initially applied 5 a priori codes based on access and different components of continuity. Data were then examined for factors that contributed to achieving and disrupting access and continuity. RESULTS: Participants described how their own life situations and behaviours contributed to their problems in accessing healthcare and also identified barriers created by existing access arrangements. They also highlighted how some General Practitioners used their initiative and skills to 'workaround' the system, and build positive relationships with them; feeling listened to and building trust were particularly valued, as was clear communication. Limitations faced by General Practitioners included a lack of appropriate services to refer people to, where the offender patients would meet the access criteria, and disagreements regarding medication prescriptions. CONCLUSIONS: General Practitioners can make a positive contribution to supporting access to healthcare for an under-served population by facilitating more flexible and less formal access arrangements, by using their relationship skills, and by problem-solving. General Practitioners should recognise their potential to transform people's experience of healthcare whilst working in imperfect systems, particularly with vulnerable and marginalised groups who have complex medical and social needs. PMID- 29390969 TI - Hypertension, mitral valve disease, atrial fibrillation and low education level predict delirium and worst outcome after cardiac surgery in older adults. AB - BACKGROUND: Delirium is a common complication after cardiac surgery in older adult patients. However, risk factors and the influence of delirium on patient outcomes are not well established. We aimed to determine the incidence, predisposing and triggering factors of delirium following cardiac surgery. METHODS: One hundred seventy-three consecutive patients aged >=60 years were studied. Patients' characteristics and two cognitive function assessment tests were recorded preoperatively. Perioperative variables were blood transfusion, orotracheal intubation time (OIT), renal dysfunction, and hypoxemia. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit. The composite outcome consisted of death, infection, and perioperative myocardial infarction until hospital discharge or 30 days after surgery, and for up to 18 months. RESULTS: One hundred six patients (61.27%) were men and the age was 69.5 +/- 5.8 years. EuroSCORE II index was 4.06 +/- 3.86. Hypertension was present in 75.14%, diabetes in 39.88%, and 30.06% were illiterate. Delirium occurred in 59 patients (34.1%). Education level (OR 0.81, 0.71-0.92), hypertension (OR 2.73, 1.16-6.40), and mitral valve disease (OR 2.93, 1.32-6.50) were independent predisposing factors for delirium, and atrial fibrillation after surgery (OR 2.49, 1.20-5.20) represented the potential triggering factor. Delirium (OR 2.35, 1.20-4.58) and OIT >= 900 min (OR 2.50; 1.30-4.80) were independently associated with the composite outcome. CONCLUSIONS: In older adult patients submitted to cardiac surgery, delirium is a frequent complication that is associated with worst outcome. Independent risk factors for delirium included education level, hypertension, mitral valve disease, and atrial fibrillation after cardiac surgery. PMID- 29390970 TI - The experience of lived space in persons with dementia: a systematic meta synthesis. AB - BACKGROUND: Identifying how persons with dementia experience lived space is important for enabling supportive living environments and creating communities that compensate for the fading capabilities of these persons. Several single studies have explored this topic; however, few studies have attempted to explicitly review and synthesize this research literature. The aim of this systematic meta-synthesis was therefore to interpret and synthesize knowledge regarding persons with dementia's experience of space. METHODS: A systematic, computerized search of AgeLine, CINAHL Complete, Embase, Medline and PsycINFO was conducted using a search strategy that combined MeSH terms and text words for different types of dementia with different descriptions of experience. Studies with 1) a sample of persons with dementia, 2) qualitative interviews as a research method and 3) a description of experiences of lived space were included. The search resulted in 1386 articles, of which 136 were identified as eligible and were read and assessed using the CASP criteria. The analysis was inspired by qualitative content analyses. RESULTS: This interpretative qualitative meta synthesis included 45 articles encompassing interviews with 672 persons with dementia. The analysis showed that living in one's own home and living in long term care established different settings and posed diverse challenges for the experience of lived space in persons with dementia. The material revealed four main categories that described the experience of lived space: (1) belonging; (2) meaningfulness; (3) safety and security; and (4) autonomy. It showed how persons with dementia experienced a reduction in their lived space due to the progression of dementia. A comprehensive understanding of the categories led to the latent theme: "Living with dementia is like living in a space where the walls keep closing in". CONCLUSION: This meta-synthesis reveals a process whereby lived space gradually becomes smaller for persons with dementia. This underscores the importance of being aware of the experiences of persons with dementia and the spatial dimensions of their life-world. To sustain person-centred care and support the preservation of continuity and identity, one must acknowledge not only the physical and social environment but also space as an existential experience for persons with dementia. PMID- 29390971 TI - Is small size at birth associated with early childhood morbidity in white British and Pakistani origin UK children aged 0-3? Findings from the born in Bradford cohort study. PMID- 29390972 TI - Establishment of malignantly transformed dendritic cell line SU3-ihDCTC induced by Glioma stem cells and study on its sensitivity to resveratrol. AB - BACKGROUND: As a factor contributing to the tumor cell drug resistance, tumor microenvironment (TME) is being paid increasingly attention. However, the drug resistance of malignantly transformed cells in TME has rarely been revealed. This paper is designed to investigate the sensitivity of malignantly transformed cell line (ihDCTC) induced by glioma stem cells (GSCs) in TME to chemotherapeutic drugs. METHODS: (1) Establishment of ihDCTC cell line,The bone marrow cells from enhanced green fluorescent protein (EGFP) transgenic nude mice were employed to culture the dendritic cells (DCs) in vitro, which were then co-cultured with red fluorescence protein (RFP) transgenic GSCs (SU3) to obtain ihDCTC (2) Res and Cis were used to intervene in the growth of abovemetioned cell lines in vitro and Res treated in bearing ihDCTC tumor mice, followed by evaluating their drug sensitivity and changes in key signaling proteins via half maximal inhibitory concentration (IC50), tumor mass and immunostaining method. RESULTS: (1) ihDCTC could express CD11c and CD80 as well as possessed immortalized potential, heteroploid chromosomes and high tumorigenicity in nude mice in vivo. (2) At 24 h, 48 h and 72 h, the IC50 value of ihDCTC treated with Cis was 3.62, 3.25 and 2.10 times higher than that of SU3, while the IC50 value of ihDCTC treated with Res was 0.03, 0.47 and 1.19 times as much as that of SU3; (3) The xenograft mass (g) in vivo in the control, Res, Cis and Res + Cis groups were 1.44 +/- 0.19, 0.45 +/- 0.12, 0.94 +/- 0.80 and 0.68 +/- 0.35(x +/- s) respectively. The expression levels of IL-6, p-STAT3 and NF-kappaB proteins in the xenograft tissue were significantly reduced only in the Res treatment group. CONCLUSION: In vitro co-culture with GSC can induce the malignant transformation of bone marrow derived dendritic cells, on the one hand, ihDCTC shows higher drug resistance to the traditional chemotherapeutic drug Cis than GSCs, but, on the other hand, appears to be more sensitive to Res than GSCs. Therefore, our findings provide a broader vision not only for the further study on the correlation between TME and tumor drug resistance but also for the exploration of Res anti-cancer value. PMID- 29390973 TI - MPBoot: fast phylogenetic maximum parsimony tree inference and bootstrap approximation. AB - BACKGROUND: The nonparametric bootstrap is widely used to measure the branch support of phylogenetic trees. However, bootstrapping is computationally expensive and remains a bottleneck in phylogenetic analyses. Recently, an ultrafast bootstrap approximation (UFBoot) approach was proposed for maximum likelihood analyses. However, such an approach is still missing for maximum parsimony. RESULTS: To close this gap we present MPBoot, an adaptation and extension of UFBoot to compute branch supports under the maximum parsimony principle. MPBoot works for both uniform and non-uniform cost matrices. Our analyses on biological DNA and protein showed that under uniform cost matrices, MPBoot runs on average 4.7 (DNA) to 7 times (protein data) (range: 1.2-20.7) faster than the standard parsimony bootstrap implemented in PAUP*; but 1.6 (DNA) to 4.1 times (protein data) slower than the standard bootstrap with a fast search routine in TNT (fast-TNT). However, for non-uniform cost matrices MPBoot is 5 (DNA) to 13 times (protein data) (range:0.3-63.9) faster than fast-TNT. We note that MPBoot achieves better scores more frequently than PAUP* and fast-TNT. However, this effect is less pronounced if an intensive but slower search in TNT is invoked. Moreover, experiments on large-scale simulated data show that while both PAUP* and TNT bootstrap estimates are too conservative, MPBoot bootstrap estimates appear more unbiased. CONCLUSIONS: MPBoot provides an efficient alternative to the standard maximum parsimony bootstrap procedure. It shows favorable performance in terms of run time, the capability of finding a maximum parsimony tree, and high bootstrap accuracy on simulated as well as empirical data sets. MPBoot is easy-to-use, open-source and available at http://www.cibiv.at/software/mpboot . PMID- 29390974 TI - Burden of Ischaemic heart disease and attributable risk factors in China from 1990 to 2015: findings from the global burden of disease 2015 study. AB - BACKGROUND: Ischaemic heart disease (IHD) is a major barrier to sustainable human development, but its health burden and geographic distribution among provinces of China remain unclear. This study aimed to estimate IHD burden in provinces of China, and attributable to risk factors from 1990 to 2015. METHODS: Data were collected from the Global Burden of Disease 2015 Study, which evaluated IHD burden and attributable risk factors using deaths and disability-adjusted life years (DALYs). Statistical models including cause of death ensemble modelling, Bayesian meta-regression analysis, and comparative risk assessment approaches were applied to reduce bias and produce comprehensive results of IHD deaths, DALYs and attributable risks. The 95% uncertainty intervals (UIs) were calculated and reported for mortality and DALYs. RESULTS: The age-standardised death rate per 100,000 people increased by 13.3% from 101.3 (95%UI: 95.3-107.5) to 114.8 (95%UI: 109.8-120.1) from 1990 to 2015 in China, whereas the age-standardised DALY rate declined 3.9% to 1760.2 per 100,000 people (95%UI: 1671.6-1864.3). In 2015, the age-standardised death rate per 100,000 people was the highest in Heilongjiang (187.4, 95%UI: 161.6-217.5) and the lowest in Shanghai (44.2, 95%UI: 37.0-53.1), and the age-standardised DALY rate per 100,000 people was the highest in Xinjiang (3040.8, 95%UI: 2488.8-3735.4) and the lowest in Shanghai (524.4, 95%UI: 434.7-638.4). Geographically, the age-standardised death and DALY rates for southern provinces were lower than northern provinces, especially in southeastern coastal provinces. 95.3% of the IHD burden in China was attributable to environmental, behavioural and metabolic risk factors. The five leading IHD risks in 2015 were high systolic blood pressure, high total cholesterol, diet high in sodium, diet low in whole grains, and smoking. CONCLUSIONS: Population growth and ageing has led to a steady increase in the IHD burden. Regional disparities in IHD burden were observed in provinces of China. The distribution characteristics of IHD burden provide guidance for decision makers to formulate targeted preventive policies and interventions. PMID- 29390975 TI - Social-economic analysis of patients with Sjogren's syndrome dry eye in East China: a cross-sectional study. AB - BACKGROUND: Sjogren's syndrome is the leading cause for aqueous tear-deficiency dry eye. Little is known regarding the relationship between Sjogren's syndrome dry eye (SSDE) and patients' medical expenditure, clinical severity and psychological status changes. METHODS: Thirty-four SSDE patients and thirty non Sjogren's syndrome dry eye (non-SSDE) subjects were enrolled. They were required to complete three self-report questionnaires: Ocular Surface Disease Index, Zung Self Rating Anxiety Scales, and a questionnaire designed by the researchers to study the patients' treatment, medical expenditure and income. The correlations between expenditures and these parameters were analyzed. RESULTS: The annual total expenditure on the treatment of SSDE was Chinese Yuan 7637.2 (approximately US$1173.8) on average, and the expense paid by SSDE patients themselves was Chinese Yuan 2627.8 (approximately US$403.9), which were 5.5 and 4.5 times higher than non-SSDE patients (both P < 0.001). The annual total expense on Chinese medicine and western medicine were 35.6 times and 78.4% higher in SSDE group than in non-SSDE group (both P < 0.001). Moreover, indirect costs associated with the treatment were 70.0% higher in SSDE group. In SSDE group, the score of Zung Self Rating Anxiety Scales had significantly positive correlation with total medical expenditure and the expense on Chinese medicine (rho = 0.399 and rho = 0.400,both P = 0.019). Nevertheless, total medical expenditure paid by the patients in non SSDE group positively correlated with the score of Ocular Surface Disease Index (rho = 0.386, P = 0.035). CONCLUSIONS: Medication expenditures and associated costs is an unignorable economic burden to the patients with SSDE. The medical expense had a significantly correlation with clinical severity of SSDE and the patients' psychological status. PMID- 29390976 TI - Probiotics and infective endocarditis in patients with hereditary hemorrhagic telangiectasia: a clinical case and a review of the literature. AB - BACKGROUND: In the last decades, probiotics have been widely used as food supplements because of their putative beneficial health effects. They are generally considered safe but rare reports of serious infections caused by bacteria included in the definition of probiotics raise concerns on their potential pathogenic role in patients with particular predisposing factors. Patients with hereditary hemorrhagic telangiectasia (HHT) are exposed to infections because of telangiectasias and arteriovenous malformations (AVMs). We describe what is, to our knowledge, the first case of infective endocarditis (IE) caused by Lactobacillus rhamnosus in a patient with HHT. A systematic review of the relevant medical literature is presented. CASE PRESENTATION: A patient with HHT and an aortic bioprosthesis was admitted because of prolonged fever not responding to antibiotics. The patient had a history of repeated serious infections with hospitalizations and prolonged use of antibiotics, and used to assume large amounts of different commercial products containing probiotics. Weeks before the onset of symptoms the patient had been treated with nasal packings and with surgical closure of a nasal bleeding site because of recurrent epistaxis. A diagnosis of IE of the aortic bioprosthesis was made. All blood coltures were positive for L. rhamnosus. The patients responded to a cycle of 6 weeks of amoxicillin/clavulanate plus gentamicin. A systematic review of IE linked to consumption of probiotics, and of infective endocarditis in patients with HHT was conducted. 10 cases of IE linked to probiotics consumption and 6 cases of IE in patients with HHT were found. CONCLUSIONS: Consumption of probiotics can pose a risk of serious infections in patients with particular predisposing factors. Patients with HHT can be considered at risk because of their predisposition to infections. Prophylaxis with antibiotics before nasal packings in patients with HHT can be considered. PMID- 29390977 TI - Acute biliary events during anti-tuberculosis treatment: hospital case series and a nationwide cohort study. AB - BACKGROUND: Tuberculosis (TB) remains one of the major infectious diseases worldwide. Adverse reactions are common during TB treatment. Few reports, however, are available on treatment-related acute biliary events (ABEs), such as cholelithiasis, biliary obstruction, acute cholecystitis, and cholangitis. METHODS: We first report four pulmonary TB patients who developed ABEs during anti-TB treatment. Abdominal sonography revealed multiple gall stones with dilated intrahepatic ducts in three patients and cholecystitis in one patient. To investigate the incidence of and risk factors for ABEs during anti-TB treatment, we subsequently conducted a nationwide cohort study using the National Health Insurance Research Database of Taiwan. RESULTS: A total of 159,566 pulmonary TB patients were identified from the database between 1996 and 2010, and among them, 195 (0.12%) developed ABEs within 180 days after beginning anti-TB treatment. Logistic regression analysis revealed that the risk factors associated with ABEs are older age (relative risk [RR]: 1.32 [1.21-1.44] per 10-year increment) and diabetes mellitus (RR: 1.59 [1.19-2.13]). CONCLUSIONS: Although infrequently encountered, ABEs should be considered among patients with TB who experience abdominal discomfort with hyperbilirubinemia, especially patients who have older age or diabetes. PMID- 29390978 TI - Perioperative risk assessment for successful kidney transplant in leigh syndrome: a case report. AB - BACKGROUND: Leigh syndrome (LS) is a rare neurodegenerative mitochondrial disorder which typically presents in childhood but has a varied clinical course. Renal involvement such as proximal tubulopathy in patients with mitochondrial disorders has been described. However, end stage renal disease (ESRD) is uncommon and literature regarding patients undergoing kidney transplantation is limited. Successful deceased donor renal transplant has not been previously described in a patient with Leigh Syndrome. CASE PRESENTATION: We report a 21-year-old Han Chinese man who presented with limb weakness and unsteady gait, which progressed rapidly over a period of months until he was wheelchair-bound. He subsequently developed ESRD and was commenced on hemodialysis. Investigations revealed a m.13513G > A mutation with clinical and radiological features consistent with LS. His mitochondrial disease stabilised and he underwent a multidisciplinary assessment for deceased donor kidney transplantation to identify and minimise the LS-associated perioperative risks and potential negative effects of immunosuppressants on his LS. Successful kidney transplantation followed with excellent graft function three and a half years post-transplant and improvement in the patient's physical function. CONCLUSION: This case highlights the importance of careful pre-transplant perioperative risk assessment and post transplant care in a rare and heterogeneous neurological disease to achieve an ultimately excellent clinical outcome. To our knowledge, this is the first report of successful deceased donor kidney transplant in a patient with known LS. PMID- 29390979 TI - Reduction in HIV community viral loads following the implementation of a "Treatment as Prevention" strategy over 2 years at a population-level among men who have sex with men in Hangzhou, China. AB - BACKGROUND: Previous studies have shown that the increased coverage of antiretroviral therapy (ART) could reduce the community viral load (CVL) and reduce the occurrence of new HIV infections. However, the impact on the reduction of HIV transmission among men who have sex with men (MSM) is much less certain. The frequency of HIV infections in MSM have been rapidly increasing in recent years in Hangzhou, China. The "Treatment as Prevention" strategy was implemented at a population-level for HIV-infected MSM from January 2014 to June 2016 in Hangzhou; it aimed to increase the ART coverage, reduce the CVL, and reduce HIV transmission. METHODS: We investigated a subset of MSM diagnosed with HIV pre- and post-implementation of the strategy, using random sampling methods. Viral load (VL) testing was performed for all enrolled individuals; the lower limits of detection were 20 and 50 copies/mL. The data on infections were collected from the national epidemiology database of Hangzhou. Logistic regression analyses were conducted to identify factors associated with the differences in social demographic characteristics and available VL data. RESULTS: The ART coverage increased from 60.7% (839/1383) during the pre-implementation period to 92.3% (2183/2365) during the post-implementation period in Hangzhou. A total of 940 HIV infected MSM were selected for inclusion in this study: 490 (52.1%) and 450 (47.9%) MSM in the pre- and post-implementation periods, respectively. In total, 89.5% (841/940) of patients had data available on VL rates. The mean CVL was 579 copies/mL pre-implementation and this decreased to 33 copies/mL post implementation (Kruskal-Wallis < 0.001). The mean CVL decreased for all variables investigated post-implementation of the treatment strategy (P < 0.05). The undetectable VL (<=400 copies/mL) rate pre-implementation period was 50.0% which increased to 84.7% post-implementation (P < 0.001). The mean CVL at the county level significantly decreased in each county post-implementation (Kruskal-Wallis < 0.05). CONCLUSION: Our study confirmed a population-level association between increased ART coverage and decreased mean CVL; overall 84.7% of HIV infected MSM had an undetectable VL and were no longer infectious. PMID- 29390980 TI - Existing creatinine-based equations overestimate glomerular filtration rate in Indians. AB - BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians. METHODS: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations. RESULTS: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 +/- 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 +/- 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 +/- 20.19 (range: 41.90-134.50) ml/min/1.73m2. CONCLUSION: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population. PMID- 29390981 TI - Selective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro. AB - BACKGROUND: Oestrogen receptors (ER) have a well-established role to the initiation, progression and regulation of responses to treatment of breast, prostate, and lung cancers. Previous data indicates altered ER expression in oesophageal cancers (OC). However the role of ER subtypes and ER specific inhibitors in the regulation of OC progression remains unclear. This study sought to assess levels of ERalpha and ERbeta in OC. The effects of highly selective ER antagonists on cell proliferation and apoptosis in two OC adenocarcinoma cell lines was also studied. METHODS: ERalpha and ERbeta expression profiling in paired normal oesophageal mucosa and tumour tissues (n = 34; adenocarcinoma n = 28; squamous cell carcinoma n = 6) was performed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Correlation between levels of ER with the clinico-pathological features for OC was determined. The effect of selective ER antagonists on proliferation of OE33 and OE19 OC cell lines was studied. RESULTS: ERalpha and ERbeta mRNA expression was significantly higher (p < 0.05) in tumour tissues relative to their paired normal mucosa and correlated inversely with survival outcome (p < 0.05). Upregulation of ERalpha mRNA correlated with higher pathological T-stage (p < 0.05) and lymph node metastasis (p < 0.05) while ERbeta mRNA upregulation correlated with positive vascular invasion (p < 0.05). A significant concentration-dependent inhibition of proliferation in OE33 and OE19 cell lines was induced by a highly-selective ERalpha antagonist (MPP) and an ERbeta specific antagonist (PHTPP) (p < 0.05). Moreover, anti-oestrogens induced cell death through stimulation of apoptotic caspase activity. CONCLUSION: These findings indicate that the ER system is involved in OC progression and thus may provide a novel target for the treatment of OC. PMID- 29390982 TI - Characteristics of diarrheagenic Escherichia coli among children under 5 years of age with acute diarrhea: a hospital based study. AB - BACKGROUND: Diarrhea is the leading infectious cause of childhood morbidity and mortality. Among bacterial agents, diarrheagenic Escherichia coli (DEC) is the major causal agent of childhood diarrhea in developing countries, particularly in children under the age of 5 years. Here, we performed a hospital-based prospective study to explore the pathotype distribution, epidemiological characteristics and antibiotic resistance patterns of DEC from < 5-year-old diarrheal children. METHODS: Between August 2015 and September 2016, 684 stool samples were collected from children (< 5 years old) with acute diarrhea. All samples were cultured and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and biochemical tests. PCR was used for subtyping, and enteropathogenic E. coli (EPEC) isolates were identified simultaneously with serology. Furthermore, antimicrobial sensitivity tests and sequencing of antibiotic resistance-related genes were conducted. RESULTS: DEC strains were identified in 7.9% of the 684 stool samples. Among them, the most commonly detected pathotype was EPEC (50.0% of DEC), of which 77.8% were classified as atypical EPEC (aEPEC). Age and seasonal distribution revealed that DEC tended to infect younger children and to occur in summer/autumn periods. Multidrug-resistant DEC isolates were 66.7%; resistance rates to ampicillin, co-trimoxazole, cefazolin, cefuroxime, cefotaxime, and ciprofloxacin were >= 50%. Among 5 carbapenem-resistant DEC, 60.0% were positive for carbapenemase genes (2 blaNDM-1 and 1 blaKPC-2). Among 30 cephalosporin-resistant DEC, 93.3% were positive for extended-spectrum beta-lactamase (ESBL) genes, with blaTEM-1 and blaCTX-M-55 being the most common types. However, no gyrA or gyrB genes were detected in 16 quinolone-resistant isolates. Notably, aEPEC, which has not received much attention before, also exhibited high rates of drug resistance (81.0%, 66.7%, and 14.3% for ampicillin, co-trimoxazole , and carbapenem resistance, respectively). CONCLUSIONS: EPEC was the most frequent DEC pathotype in acute diarrheal children, with aEPEC emerging as a dominant diarrheal agent in central China. Most DEC strains were multidrug-resistant, making even ciprofloxacin unsuitable for empiric treatment against DEC infection. Among carbapenem-resistant DEC strains, those harboring blaNDM-1 and blaKPC-2 were the main causal agents. blaTEM-1 and blaCTX-M-55 were the major genetic determinants associated with high levels of cephalosporin resistance. PMID- 29390983 TI - Community service provider perceptions of implementing older adult fall prevention in Ontario, Canada: a qualitative study. AB - BACKGROUND: Despite evidence for effective fall prevention interventions, measurable reductions in older adult (>= 65 years) fall rates remain unrealized. This study aimed to describe the perceived barriers to and effective strategies for the implementation of evidence-based fall prevention practices within and across diverse community organizations. This study is unique in that it included community service providers who are not generally thought to provide fall prevention services to older adults, such as retail business, community support, volunteer services, community foundations, recreation centres, and various emergency services. METHODS: Interviews and focus groups were conducted with a purposive sampling of providers (n = 84) in varied roles within diverse community based organizations across disparate geographical settings. RESULTS: Community service providers experience significant multi-level barriers to fall prevention within and across organizations and settings. The overall challenge of serving dispersed populations in adverse environmental conditions was heightened in northern rural areas. Barriers across the system, within organizations and among providers themselves emerged along themes of Limited Coordination of Communication, Restrictive Organizational Mandates and Policies, Insufficient Resources, and Beliefs about Aging and Falls. Participants perceived that Educating Providers, Working Together, and Changing Policies and Legislation were strategies that have worked or would work well in implementing fall prevention. An unintentional observation was made that several participants in this extremely varied sample identified expanded roles in fall prevention for themselves during the interview process. CONCLUSIONS: Community service providers experience disabling contexts for implementing fall prevention on many levels: their specific geography, their service systems, their organizations and themselves. A systemic lack of fit between the older adult and fall prevention services limits access, making fall prevention inaccessible, unaccommodating, unavailable, unaffordable, and unacceptable. Educating Providers, Working Together, and Changing Policies and Legislation offers promise to create more enabling contexts for community stakeholders, including those who do not initially see their work as preventing falls. PMID- 29390984 TI - Phase I clinical study of brentuximab vedotin (SGN-35) involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma: rationale, design and methods of BV-HLALCL study: study protocol. AB - BACKGROUND: Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) are the two most common tumors expressing CD30. Internationally, a clinical study that is being conducted involving adults with recurrent or refractory HL or ALCL suggests efficacy of brentuximab vedotin (SGN-35). Pediatric patients should be given medicines that have been appropriately evaluated for their use. In the past, however, new approved drugs have been used for pediatric patients without the confirmation of safety and efficacy in pediatric patients. Therefore, it is important to examine the safety and efficacy of SGN-35 in Japanese children. METHODS: Phase I clinical study of SGN-35 involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma (BV-HLALCL study) is being conducted for pediatric patients in order to evaluate the safety, feasibility and preliminary clinical effectiveness of brentuximab vedotin. SGN-35 is intravenously administered on Day 1 of each cycle (21 days/cycle). The dose of SGN-35 is calculated based on the body weight at the baseline. The primary endpoint is dose limiting toxicity and incidence of adverse events. The secondary endpoints are pharmacokinetics, response rate, complete remission rate, response duration, progression-free survival and event-free survival. The reduction rate of tumor will be calculated according to revised response criteria for malignant lymphoma for measurable tumor. Six pediatric patients will be enrolled in this study. DISCUSSION: This study aims to expand indication of SGN-35 in Japan by assessing its safety and efficacy in pediatric patients. TRIAL REGISTRATION: JMACCT ID: JMA-IIA00229 . Registered on 17 Nov 2015. PMID- 29390985 TI - Seasonality and determinants of child growth velocity and growth deficit in rural southwest Ethiopia. AB - BACKGROUND: Ethiopia faces cyclic food insecurity that alternates between pre- and post- harvest seasons. Whether seasonal variation in access to food is associated with child growth has not been assessed empirically. Understanding seasonality of child growth velocity and growth deficit helps to improve efforts to track population interventions against malnutrition. The aim of this study was assess child growth velocity, growth deficit, and their determinants in rural southwest Ethiopia. METHOD: Data were obtained from four rounds of a longitudinal household survey conducted in ten districts in Oromiya Region and Southern Nations, Nationality and Peoples Region of Ethiopia, in which 1200 households were selected using multi-stage cluster sampling. Households with a child under 5 years were included in the present analyses (round 1 n = 579, round 2 n = 674, round 3 n = 674 and round 4 n = 680). The hierarchical nature of the data was taken into account during the statistical analyses by fitting a linear mixed effects model. A restricted maximum likelihood estimation method was employed in the analyses. RESULT: Compared to the post-harvest season, a higher length and weight velocity were observed in pre-harvest season with an average difference of 6.4 cm/year and 0.6 kg/year compared to the post-harvest season. The mean height of children in post-harvest seasons was 5.7 cm below the WHO median reference height. The mean height of children increased an additional 3.3 cm [95% CI (2.94, 3.73)] per year in pre-harvest season compared to the post-harvest season. Similarly, the mean weight of children increased 1.0 kg [95% CI (0.91, 1.11)] per year more in the pre-harvest season compared to the post-harvest season. Children who had a low dietary diversity and were born during the lean season in both seasons had a higher linear growth deficit. Being member of a highly food insecure household was negatively associated with higher weight gain. Having experienced no illness during the previous 2 weeks was positively associated with linear growth and weight gain. CONCLUSION: Child growth velocities and child growth deficits were higher in the pre-harvest season and post- harvest season respectively. Low dietary diversity and being part of a highly food insecure household were significantly risk factors for decreased linear growth and weight gain respectively. PMID- 29390986 TI - The prevalence of malocclusion and the need for orthodontic treatment among adolescents in the northern border region of Saudi Arabia: an epidemiological study. AB - BACKGROUND: To assess the prevalence of malocclusion and orthodontic treatment need among adolescents using the dental health component (DHC) of the index of orthodontic treatment need (IOTN). METHODS: A descriptive cross-sectional study was conducted among 500 (mean age 16.25 +/- 1.09) adolescents randomly selected from the northern border region of Saudi Arabia (KSA). The northern border region is sub-divided into three governorates: Ar'ar (186), Rafha (142) and Turayf (172). The data were recorded in questionnaires to assess the prevalence of malocclusion and estimate of DHC of the IOTN index. RESULTS: The most common malocclusions in order of prevalence were Angle's Class I (52.8%), Angle's Class II (31.8%), Angle's Class III (15.4%), crowding (47.2%), excessive overjet (> 2 mm) (22.2%), reduced overjet (< 1 mm) (11.4%), excessive overbite (> 2 mm) (23.4%), reduced overbite (< 1 mm) (12.2%), anterior crossbite (4.8%), posterior crossbite (9.4%) and open bite (4.6%). The most common facial profiles determined in the sagittal plane, were the straight facial profile (49.2%), convex (42.6%) and concave (8.2%). The prevalence of Grade 1 and 2 DHC was 49.4%, Grade 3 was 29.6%, Grade 4 and 5 was 21%. The grades of DHC of IOTN index were as follows: 48.73% of males and 50.22% of females showed grades 1 and 2. Grade 3 was observed in 30.32% of males and 28.69% of females. Grades 4 and 5 were recorded in 20.93% of males and 21.07% of females. CONCLUSIONS: The prevalence of malocclusion and orthodontic treatment need among the north border region of KSA is comparable with that of other regional studies. PMID- 29390987 TI - CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study. AB - BACKGROUND: CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy. METHODS: The prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28-180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at <= 1 (gPM, gIM and gNM-S phenotypes) and >= 1.5 (gNM-F and gUM phenotypes). RESULTS: Genotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01-3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of <= 1 versus >= 1.5 (p = 0.917). CONCLUSIONS: The results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine-primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity. PMID- 29390988 TI - Effectiveness of active school transport interventions: a systematic review and update. AB - BACKGROUND: Active school transport (AST) is a promising strategy to increase children's physical activity. A systematic review published in 2011 found large heterogeneity in the effectiveness of interventions in increasing AST and highlighted several limitations of previous research. We provide a comprehensive update of that review. METHODS: Replicating the search of the previous review, we screened the PubMed, Web of Science, Cochrane, Sport Discus and National Transportation Library databases for articles published between February 1, 2010 and October 15, 2016. To be eligible, studies had to focus on school-aged children and adolescents, include an intervention related to school travel, and report a measure of travel behaviors. We assessed quality of individual studies with the Effective Public Health Practice Project quality assessment tool, and overall quality of evidence with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. We calculated Cohen's d as a measure of effect size. RESULTS: Out of 6318 potentially relevant articles, 27 articles reporting 30 interventions met our inclusion criteria. Thirteen interventions resulted in an increase in AST, 8 found no changes, 4 reported inconsistent results, and 5 did not report inferential statistics. Cohen's d ranged from -0.61 to 0.75, with most studies reporting "trivial-to-small" positive effect sizes. Three studies reported greater increases in AST over longer follow-up periods and two Safe Routes to School studies noted that multi level interventions were more effective. Study quality was rated as weak for 27/30 interventions (due notably to lack of blinding of outcome assessors, unknown psychometric properties of measurement tools, and limited control for confounders), and overall quality of evidence was rated as low. Evaluations of implementation suggested that interventions were limited by insufficient follow up duration, incomplete implementation of planned interventions, and limited access to resources for low-income communities. CONCLUSIONS: Interventions may increase AST among children; however, there was substantial heterogeneity across studies and quality of evidence remains low. Future studies should include longer follow-ups, use standardized outcome measures (to allow for meta-analyses), and examine potential moderators and mediators of travel behavior change to help refine current interventions. TRIAL REGISTRATION: Registered in PROSPERO: CRD42016033252. PMID- 29390989 TI - Gender-specific differences in high-risk sexual behaviors among methamphetamine users in Myanmar-China border city, Muse, Myanmar: who is at risk? AB - BACKGROUND: Methamphetamine (MA) use is a significant public health concern due to its negative effects on health. However, to date, no epidemiological research has examined high-risk sexual behaviors (inconsistent condom use, having multiple sexual partners and having a history of sexually transmitted infections) among MA users. This topic is particularly important in Myanmar, which is recognized as one of the key MA production countries in the Southeast Asia region. Therefore, this study examined factors associated with high-risk sexual behaviors among MA users in Muse city, Myanmar. METHODS: A community-based cross-sectional study was conducted from January to March 2013 in Muse city, Northern Shan State, Myanmar. In total, 1183 MA users (772 male; 411 female) were recruited using respondent driven sampling and a computer assisted self-interviewing method. Generalized estimating equation models were used to examine factors associated with high-risk sexual behaviors. RESULTS: A large proportion of MA users engaged in high-risk sexual behaviors (inconsistent condom use: males, 90.7%, females, 85.2%; multiple sexual partners: males, 94.2%, females, 47.2%; and history of STIs: males, 55.7%, females, 56.0%). Among males, being a multiple stimulants drug user (adjusted odds ratio [AOR] =1.77; 95% confidence interval [CI] =1.30-2.41) and being a client of sex workers (AOR = 1.41; 95% CI = 1.08-1.83) were risk factors for engaging in high-risk sexual behaviors. Among females, being a migrant worker (AOR = 2.70; 95% CI = 1.86-3.93) and being employed (AOR = 1.57; 95% CI = 1.13 2.18) were risk factors for engaging in high-risk sexual behaviors as well. CONCLUSIONS: High-risk sexual behaviors were particularly pronounced among both male and female MA users. MA prevention programs that reflect gender considerations should be developed to pay more attention to vulnerable populations such as migrants, clients of sex workers, and less educated female MA users. PMID- 29390990 TI - First molecular characterization of Echinococcus granulosus (sensu stricto) genotype 1 among cattle in Sudan. AB - BACKGROUND: Echinococcus granulosus sensu lato (s.l.) is the causative agent of cystic echinococcosis (CE), which is a cosmopolitan zoonotic parasitic disease infecting humans and a wide range of mammalian species including cattle. Currently, little information is available on the genetic diversity of Echinococcus species among livestock in Sudan. In the present study, fifty (n = 50) hydatid cysts were collected from cattle carcasses (one cyst sample per animal) at Al-kadarou slaughterhouse, Khartoum North, Sudan. DNA was extracted from protoscolices and the germinal layer of each cyst and subsequently amplified by PCR targeting the mitochondrial NADH dehydrogenase subunit 1 (NADH-1) gene. The amplified PCR products were purified and subjected to direct sequencing for subsequent construction of phylogenetic tree and net work analysis. RESULTS: The phylogenetic tree revealed the presence of Echinococcus canadenesis genotype 6 (G6) in 44 cysts (88.0%), Echinococcus ortleppi genotype 5 (G5) in 4 cysts (8.0%) and Echinococcus granulosus sensu stricto (s.s) genotype 1 (G1) in 2 cysts (4.0%). The phylogenetic network analysis revealed genetic variation among the different haplotypes/genotypes. This report has provided, for the first time, an insight of the role of cattle in the transmission of the zoonotic G1 echinococosis. CONCLUSIONS: The results of the study illustrate that Sudanese breeds of cattle may play an important role in the transmission dynamics and the epidemiology of cystic echinococcosis in Sudan. This study reports the first molecular identification of E. granulosus s.s. in cattle in Central Sudan. PMID- 29390991 TI - Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. AB - BACKGROUND: Although numerous studies have shown that perineural invasion (PNI) is linked to prostate cancer (PCa) risk, the results have been inconsistent. This study aimed to explore the association between PNI and biochemical recurrence (BCR) in patients with PCa following radical prostatectomy (RP) or radiotherapy (RT). METHODS: According to the PRISMA statement, we searched the PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wan Fang databases from inception to May 2017. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted from eligible studies. Fixed or random effects model were used to calculate pooled HRs and 95% CIs according to heterogeneity. Publication bias was calculated by Begg's test. RESULTS: Ultimately, 19 cohort studies that met the eligibility criteria and that involved 13,412 patients (82-2,316 per study) were included in this meta-analysis. The results showed that PNI was associated with higher BCR rates in patients with PCa after RP (HR=1.23, 95% CI: 1.11, 1.36, p<0.001) or RT (HR=1.22, 95% CI: 1.12, 1.34, p<0.001). No potential publication bias was found among the included studies in the RP group (p-Begg = 0.124) or the RT group (p-Begg = 0.081). CONCLUSIONS: This study suggests that the presence of PNI by histopathology is associated with higher risk of BCR in PCa following RP or RT, and could serve as an independent prognostic factor in patients with PCa. PMID- 29390992 TI - Traumatic events: exploring associations with maternal depression, infant bonding, and oxytocin in Latina mothers. AB - BACKGROUND: Childhood and adulthood traumatic experiences negatively impact maternal-infant bonding and increase risk of postpartum depression (PPD). Lower oxytocin levels have also been associated with PPD and compromised mother-infant bonding. Despite advances in these areas of investigation, much of the research has not included Latinas, who are important because they have high rates of fertility, traumatic events, and PPD. METHODS: To address gaps identified in the literature, we explored associations between traumatic life events, PPD, and bonding subscale scores (e.g., Impaired Bonding, Rejection and Anger, Anxiety about Care) in a sample of 28 Latinas. We also examined associations between these factors and oxytocin (OT). Wilcoxon signed-rank tests were employed to examine differences in subscale scores over time. Kruskal-Wallis one-way analysis of variance was used to examine differences in bonding subscale scores and OT by maternal depression status and traumatic events. We also explored interaction effects of traumatic events and OT AUC on bonding subscale scores. RESULTS: Women with PPD at 8 weeks had significantly higher Rejection and Anger subscale scores (p = 0.054) than non-PPD women, where higher scores represent more compromised bonding. Significant differences in Rejection and Anger (p = 0.042) and Anxiety about Care (p = 0.005) by adulthood traumatic histories were observed at 8 weeks postpartum. There was also a significant difference in Anxiety about Care scores at 4 weeks postpartum (p = 0.024) and Impaired Bonding at 8 weeks postpartum (p = 0.041) by trauma events involving an infant. There was a significant interaction between OT and childhood sexual abuse on Impaired Bonding (p = 0.038). CONCLUSION: We observed differential responses in bonding subscale scores by traumatic histories. Women who experienced a trauma involving an infant had higher compromised bonding scores, whereas those with adulthood traumatic histories, such as intimate partner violence, had lower scores. We also found an interaction between childhood trauma and oxytocin levels on bonding scores, suggesting a physiological response to early abuse that can have implications on mothers' bonding perceptions. These preliminary results suggest the need for additional research on the long-term emotional and physiological effects of traumatic events occurring prior to parturition. PMID- 29390993 TI - Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. AB - BACKGROUND: We intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate. METHODS: We assessed 74 patients with EOE whose seizures started before 3 years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software. Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Each case was further discussed in a monthly consensus meeting that included the participation of all laboratory personnel, bioinformaticians, geneticists, and clinicians. RESULTS: The NGS panel identified 28 patients (37.8%) with genetic abnormalities; 25 patients had pathogenic or likely pathogenic SNVs in 17 genes including SXTBP1 (n = 3), CDKL5 (n = 2), KCNQ2 (n = 2), SCN1A (n = 2), SYNGAP1 (n = 2), GNAO1 (n = 2), KCNT1 (n = 2), BRAT1, WWOX, ZEB2, CHD2, PRICKLE2, COL4A1, DNM1, SCN8A, MECP2, SLC9A6 (n = 1). The other 3 patients had pathogenic CNVs (2 duplications and 1 deletion) with varying sizes (from 2.5 Mb to 12 Mb). The overall diagnostic yield was 37.8% after following our step-by-step approach for clinical consensus. CONCLUSIONS: NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach. PMID- 29390994 TI - Characteristics of cervical sagittal parameters in healthy cervical spine adults and patients with cervical disc degeneration. AB - BACKGROUND: The cervical sagittal parameters of the normal population and the impact of disc degeneration on cervical sagittal alignment have not been clearly defined yet. This study is applied to investigate the characteristics and relationships of cervical sagittal parameters in normal adults and patients with cervical disc degeneration. METHODS: We reviewed 50 normal control subjects (normal group, NG) and 50 patients with cervical disc degeneration (degeneration group, DG), who had both cervical MRI and radiographs obtained together, between January 2010 and September 2015. Data including C2-7 lordosis (CL), T1 slope (T1S), thoracic inlet angle (TIA), neck tilt (NT), C2-7 sagittal vertical axis (C2-7 SVA), cervical tilting, and cranial tilting on cervical radiographs were collected and analyzed. RESULTS: T1S in the NG was significantly greater than in the DG (P < 0.05), while NT and C2-7 SVA in the NG were significantly lower than in the DG (P < 0.01 and P < 0.05, respectively). T1S positively correlated with CL in both groups (Pearson correlation coefficients of 0.588 in the NG and 0.504 in the DG). No significant difference was seen in TIA between the NG and DG. CONCLUSIONS: T1S was involved in the occurrence and development of cervical disc degeneration, and TIA could be considered as a constant morphological parameter in both the normal population and cervical disc degeneration patients. PMID- 29390995 TI - A self-harm series and its relationship with childhood adversity among adolescents in mainland China: a cross-sectional study. AB - BACKGROUND: Self-harm (SH) is an emerging problem among Chinese adolescents. The present study aimed to measure the prevalence of SH behaviours and to explore the relationship between childhood adversity and different SH subtypes among Chinese adolescents. METHODS: A total of 5726 middle school students were randomly selected in three cities of Anhui province, China, using a stratified cluster sampling method. SH was categorized into five subtypes (highly lethal self-harm, less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self harm). Multivariate logistic regression was used to explore the relationships between childhood adversity and different subtypes of adolescent SH. RESULTS: The prevalence rates of highly lethal self-harm, less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self-harm were 6.1, 20.4, 32.0, 20.0 and 23.0%, respectively. Childhood sexual abuse and physical peer victimization were associated with each SH subtype with adjusted odds ratios (AORs) ranging from 1.23 to 1.76. Highly lethal self-harm was associated with childhood physical peer victimization, sexual abuse, emotional abuse, and emotional neglect. The less lethal SH subtypes (i.e., less lethal self-harm with visible tissue damage, self harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self-harm) were associated with childhood peer victimization, family life stress event scores and childhood sexual abuse. CONCLUSIONS: A high prevalence of SH exists among Chinese adolescents. The association of childhood adversity with SH merits serious attention in both future research and preventive interventions. PMID- 29390996 TI - Realising the right to sexual and reproductive health: access to essential medicines for medical abortion as a core obligation. AB - BACKGROUND: WHO has a pivotal role to play as the leading international agency promoting good practices in health and human rights. In 2005, mifepristone and misoprostol were added to WHO's Model List of Essential Medicines for combined use to terminate unwanted pregnancies. However, these drugs were considered 'complementary' and qualified for use when in line with national legislation and where 'culturally acceptable'. DISCUSSION: This article argues that these qualifications, while perhaps appropriate at the time, must now be removed. First, compelling medical evidence justifies their reclassification as a 'core' essential medicine. Second, continuing to subjugate essential medicines for medical abortion to domestic law and cultural practices is incoherent with today's human rights standards in which universal access to these medicines is an inextricable part of the right to sexual and reproductive health, which should be supported and realised through domestic legislation. CONCLUSION: This article shows that removing such limitations will align WHO's Model List of Essential Medicines with the mounting scientific evidence, human rights standards, and its own more recently developed policy guidance. This measure will send a strong normative message to governments that these medicines should be readily available in a functioning and human-rights-abiding health system. PMID- 29390997 TI - Normal/high-fat milk consumption is associated with higher lean body and muscle mass in Japanese women aged between 40 and 60 years: a cross-sectional study. AB - BACKGROUND: Milk is known to contain various nutrients that may have health benefits for postmenopausal women who are at an increased risk of cardiovascular and musculoskeletal diseases. We investigated the association between normal/high and low-fat milk consumption and body composition in Japanese women aged 40 to 60 years. METHODS: This cross-sectional study used the baseline data collected in a previous study that examined the effects of a dietary supplement on a variety of health parameters in 85 Japanese women aged 40 to 60 years. Participants had been assessed for age, menopausal status, lifestyle factors, and body composition. We estimated the consumption of normal/high- and low-fat milk using a brief-type self-administered diet history questionnaire (BDHQ). Normal/high- and low-fat milk intake were classified as consumer (drank milk at least twice a week) or non-consumer (drank milk at most once a week), in order to identify the parameters that were independently associated with the consumption of normal/high and low-fat milk. RESULTS: Of the 85 participants who completed the BDHQ, 27 were categorized as non-consumers, 18 as exclusive low-fat milk consumers, and 29 as exclusive normal/high-fat milk consumers. 11 women who consumed both low-fat and normal/high-fat milk were excluded from the analysis. Compared with non consumers and exclusive low-fat milk consumers, exclusive high-fat milk consumers had significantly higher lean body mass (mean +/- standard deviation [SD], 39.4 +/- 2.7 kg vs. 37.9 +/- 2.2 kg and 37.6 +/- 2.9 kg, P < 0.05) and muscle mass (mean +/- SD, 37.2 +/- 2.5 kg vs. 35.8 +/- 2.0 kg and 35.5 +/- 2.7 kg, P < 0.05). Both lean body and muscle masses were significantly correlated with vitamin D intake from milk (Pearson r = 0.29, P = 0.008, and Pearson r = 0.29, P = 0.008, respectively). CONCLUSION: Normal/high-fat milk consumption was associated with higher lean body and muscle mass in middle-aged Japanese women presumably through high vitamin D intake. PMID- 29390998 TI - Mixed-method tutoring support improves learning outcomes of veterinary students in basic subjects. AB - BACKGROUND: Tutoring is a useful tool in the university teaching-learning binomial, although its development is impaired in large classes. Recent improvements in information and communication technologies have made tutoring possible via the Internet. The aim of this study was to evaluate the efficacy of mixed-method academic tutoring in two basic subjects in Veterinary Science studies at the University of Leon (Spain) to optimize the usefulness of tutoring support in the college environment. This quasi-experimental study was firstly carried out as a pilot study in a small group of tutored students of "Cytology and Histology" (CH) (47/186; 25.3%) and "Veterinary Pharmacology" (VP) (33/141; 23.4%) subjects, and was implemented in a large class of CH the next academic year (150 students) while comparing the results with those obtained in a previous tutorless course (162 students). Tutored students were given access to online questionnaires with electronic feedback on each subject. In addition to traditional tutoring carried out in both tutored and tutorless students, the pilot study included three sessions of face-to-face tutoring in order to monitor the progress of students. Its efficacy was assessed by monitoring students' examination scores and attendance as well as a satisfaction survey. RESULTS: Although the examination attendance rate in the pilot study was not significantly different between tutored and tutorless groups in both subjects, an increase for numerical scores in tutored groups was observed, with a significant higher final score in VP (p = 0.001) and in the CH practice exams (first term, p = 0.009; final, p = 0.023). Good and merit scores were also better in tutored students with significant differences in VP (p = 0.005). Students felt comfortable with the tutoring service (100% in CH; 91.7% in VP). Implementation of this additional support in CH also resulted in a significant increase of attendance at the final exam in tutored courses (87.3% versus 77.2%; p = 0.026), scaled (p = 0.001) and numerical scores (final score, p = 0.001). CONCLUSIONS: Online tutoring support, together with conventional teaching methods, may be a useful method to incorporate student-centered learning in basic subjects in Veterinary Science. PMID- 29390999 TI - Organizational factors associated with readiness for change in residential aged care settings. AB - BACKGROUND: Organizational change is inevitable in any workplace. Previous research has shown that leadership and a number of organizational climate and contextual variables can affect the adoption of change initiatives. The effect of these workplace variables is particularly important in stressful work sectors such as aged care where employees work with challenging older clients who frequently exhibit dementia and depression. METHODS: This study sought to examine the effect of organizational climate and leadership variables on organizational readiness for change across 21 residential aged care facilities. Staff from each facility (N = 255) completed a self-report measure assessing organizational factors including organizational climate, leadership and readiness for change. RESULTS: A hierarchical regression model revealed that the organizational climate variables of work pressure, innovation, and transformational leadership were predictive of employee perceptions of organizational readiness for change. CONCLUSION: These findings suggest that within aged care facilities an organization's capacity to change their organizational climate and leadership practices may enhance an organization's readiness for change. PMID- 29391000 TI - Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2). AB - BACKGROUND: Betulinic acid (BA) is a natural triterpenoid compound and exhibits a wide range of biological and medicinal properties including anti-inflammatory activity. Therefore, this theoretical investigation is performed to evaluate (a) physicochemical properties such as acid dissociation constant (pKa), distribution coefficient (logD), partition coefficient (logP), aqueous solubility (logS), solvation free energy, dipole moment, polarizability, hyperpolarizability and different reactivity descriptors, (b) pharmacokinetic properties like human intestinal absorption (HIA), cellular permeability, skin permeability (PSkin), plasma protein binding (PPB), penetration of the blood brain barrier (BBB), (c) toxicological properties including mutagenicity, carcinogenicity, risk of inhibition of hERG gene and (d) molecular mechanism of anti-inflammatory action which will aid the development of analytical method and the synthesis of BA derivatives. METHODS: The physicochemical properties were calculated using MarvinSketch 15.6.29 and Gaussian 09 software package. The pharmacokinetic and toxicological properties were calculated on online server PreADMET. Further, the molecular docking study was conducted on AutoDock vina in PyRx 0.8. RESULTS: The aqueous solubility increased with increasing pH due to the ionization of BA leading to decrease in distribution coefficient. The solvation energies in water, dimethyl sulfoxide (DMSO), acetonitrile, n-octanol, chloroform and carbon tetrachloride were - 41.74 kJ/mol, - 53.80 kJ/mol, - 66.27 kJ/mol, - 69.64 kJ/mol, - 65.96 kJ/mol and - 60.13 kJ/mol, respectively. From the results of polarizability and softness, it was clear that BA is less stable and hence, kinetically more reactive in water. BA demonstrated good human intestinal absorption (HIA) and moderate cellular permeability. Further, BA also exhibited positive CNS activity due to high permeability through BBB. The toxicological study revealed that BA was a mutagenic compound but noncarcinogenic in mice model. Moreover, molecular docking study of BA with PLA2 revealed that BA interacts with GLY22 & GLY29 through hydrogen bond formation and LEU2, PHE5, HIS6, ALA17, ALA18, HIS47 and TYR51 through different types of hydrophobic interactions. The binding affinity of BA was - 41.00 kJ/mol which is comparable to the binding affinity of potent inhibitor 6-Phenyl-4(R)-(7-Phenyl heptanoylamino)-hexanoic acid (BR4) (- 33.89 kJ/mol). CONCLUSIONS: Our computed properties may assist the development of analytical method to assay BA or to develop BA derivatives with better pharmacokinetic and toxicological profile. PMID- 29391001 TI - Detection of persistent pestivirus infection in pudu (Pudu puda) in a captive population of artiodactyls in Chile. AB - BACKGROUND: Bovine Viral Diarrhea Virus (BVDV) is the viral agent causing the most important economic losses in livestock throughout the world. Infection of fetuses before their immunological maturity causes the birth of animals persistently infected with BVDV (PI), which are the main source of infection and maintenance of this pathogen in a herd. There is evidence of susceptibility to infection with BVDV in more than 50 species of the order Artiodactyla, and the ability to establish persistent infection in wild cervid species of South America could represent an important risk in control and eradication programs of BVDV in cattle, and a threat to conservation of these wild species. In this study, a serological and virological study was performed to detect BVDV infection in a captive population of non-bovine artiodactyl species in a Chilean zoo with antecedents of abortions whose pathology suggests an infectious etiology. RESULTS: Detection of neutralizing antibodies against BVDV was performed in 112 artiodactyl animals from a zoo in Chile. Three alpacas (Vicugna pacos), one guanaco (Lama guanicoe) and seven pudus (Pudu puda) resulted seropositive, and the only seronegative pudu was suspected to be persistently infected with BVDV. Then two blood samples nine months apart were analyzed by a viral neutralization test and RT-PCR. Non-cytopathogenic BVDVs were isolated in both samples. A phylogenetic analysis showed that the virus was highly related to BVDV-1b strains circulating among Chilean cattle. CONCLUSIONS: This is the first report of a South American deer persistently infected with Bovine Viral Diarrhea Virus. Further studies are needed to determine the possible role of BVDV as a pathogen in pudus and as a threat to their conservation. PMID- 29391002 TI - Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells. AB - BACKGROUND: Most of herbal medicines are used without any standard safety and toxicological trials although common assumption is that these products are nontoxic. However, this assumption is incorrect and dangerous, so toxicological studies should be done for herbal drugs. Although Pterolobium stellatum, Otostegia integrifolia and Vernonia amygdalina root extracts are frequently used in Ethiopian traditional medicine, there are no evidences of their active toxic compounds. Therefore, we made an effort to assess probable genotoxic effect of these plant extracts on DNA of human hematoma (HepG2) cells using alkaline comet assay. METHODS: Genotoxic effects of extracts were evaluated using single cell gel electrophoresis (SCGE) method on HepG2 cell. Regarding comet data, the average mean tail intensities (TI) from each individual experiment and treatment (usually at least 3 cultures/treatment) were pooled and the average mean TI was used as an indicator of DNA damage and the standard error of mean (SEM) as the measure of variance. RESULTS: DNA damage in the form of comet tail has been observed for 1 and 0.5 mg/ml P. stellatum chloroform and 80% methanol extracts on HepG2 cells, respectively. The chloroform extract of P. stellatum showed increased tail DNA percentage in a concentration dependent manner. Comet tail length in the chloroform P. stellatum extract treated cells (1 mg/ml) was significantly higher by 89% (p < 0.05) compared to vehicle treated controls. The rest of test extracts seemed to be without genotoxic effect up to a concentration of 0.5 mg/ml. CONCLUSIONS: Our findings show that two extracts from one plant evaluated have a genotoxic potential in vitro which calls for a more thorough safety evaluation. Such evaluation should include other end-points of genotoxicity apart from DNA damage, and possibly also pure compounds. PMID- 29391003 TI - Qualitative assessment of the primary care outcomes questionnaire: a cognitive interview study. AB - BACKGROUND: The Primary Care Outcomes Questionnaire (PCOQ) is a new patient reported outcome measure designed specifically for primary care. This paper describes the developmental process of improving the item quality and testing the face validity of the PCOQ through cognitive interviews with primary care patients. METHODS: Two formats of the PCOQ were developed and assessed: the PCOQ Status (which has an adjectival scale) and the PCOQ-Change (which has the same items as the PCOQ-Status, but a transitional scale). Three rounds of cognitive interviews were held with twenty patients from four health centres in Bristol. Patients seeking healthcare were recruited directly by their GP or practice nurse, and others not currently seeking healthcare were recruited from patient participation groups. An adjusted form of Tourangeau's model of cognitive processing was used to identify problems. This contained four categories: general comprehension, temporal comprehension, decision process, and response process. The resultant pattern of problems was used to assess whether the items and scales were working as intended, and to make improvements to the questionnaires. RESULTS: The problems identified in the PCOQ-Status reduced from 41 in round one to seven in round three. It was noted that the PCOQ-Status seemed to be capturing a subjective view of health which might not vary with age or long-term conditions. However, as it is designed to be evaluative (measuring change over time) as opposed to discriminative (measuring change between different groups of people), this does not present a problem for validity. The PCOQ-Status was both understood by patients and was face valid. The PCOQ-Change had less face validity, and was misunderstood by three out of six patients in round 1. It was not taken forward after this round. CONCLUSIONS: The cognitive interviews successfully contributed to the development of the PCOQ. Through this study, the PCOQ-Status was found to be well understood by patients, and it was possible to improve comprehension through each round of interviews. The PCOQ-Change was poorly understood and, given that this corroborates existing research, this may call into question the use of transitional questionnaires generally. PMID- 29391005 TI - Parents' knowledge, attitudes and beliefs regarding sun protection in children: a qualitative study. AB - BACKGROUND: Childhood is a critical period for sun protection, when the skin is particularly susceptible to the carcinogenic effects of ultraviolet radiation. Children are dependent upon parents to implement sun protective measures. Existing qualitative research exploring parents' attitudes and beliefs underpinning children's sun protection is from Australia, which has the highest melanoma incidence rates globally, and thus benefits from widespread sun protection awareness campaigns. Parents' sun protective behaviour may, therefore, differ between Australia and the UK. This study investigates the topic in a UK context, using qualitative methodology to gain detailed insights into a relatively under-researched area. The aim of the study was to explore parents' knowledge and understanding of sun protection in children, and factors that motivate and challenge them in this area. Finally, it aimed to determine if and how ethnicity and skin type influence these attitudes and beliefs. METHODS: Twenty-two semi-structured individual interviews were carried out with parents of children aged 5 years or younger, recruited from local nurseries. Transcripts were analysed using thematic analysis. RESULTS: Four overarching themes emerged, each incorporating two to three sub-themes. 'Attitudes towards children's sun protection' refers to the fact that parents considered sun protection to be important for children, a finding which was consistent between different skin types. 'Sun protection practices' brings together several protective behaviours adopted in children and, to a lesser degree, in parents, and their associated disadvantages. 'Sun safety knowledge' refers to parents' awareness of the risks of sun exposure and the need for protection, and illustrates where gaps in knowledge exist, such as regarding the need for vitamin D, and the importance of vigilant sun protection even in the UK. Finally, 'motivating and facilitating factors' highlights motivations for sun protection in children, and factors that facilitate it in practice. CONCLUSION: This study found parents to be motivated and concerned about children's sun protection, irrespective of children's ethnicity, and aware of appropriate protective behaviours. It indicates key challenges which could be targeted in future campaigns in order to improve sun protection in children and reduce uncertainty and anxiety regarding sun safety amongst parents. PMID- 29391004 TI - Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review. AB - BACKGROUND: Although acute diarrhea often leads to acute dehydration and electrolyte imbalance, children with diarrhea also suffer long term morbidity, including recurrent or prolonged diarrhea, loss of weight, and linear growth faltering. They are also at increased risk of post-acute mortality. The objective of this systematic review was to identify interventions that address these longer term consequences of diarrhea. METHODS: We searched Medline for randomized controlled trials (RCTs) of interventions conducted in low- and middle-income countries, published between 1980 and 2016 that included children under 15 years of age with diarrhea and follow-up of at least 7 days. Effect measures were summarized by intervention. PRISMA guidelines were followed. RESULTS: Among 314 otherwise eligible RCTs, 65% were excluded because follow-up did not extend beyond 7 days. Forty-six trials were included, the majority of which (59%) were conducted in Southeast Asia (41% in Bangladesh alone). Most studies were small, 76% included less than 200 participants. Interventions included: therapeutic zinc alone (28.3%) or in combination with vitamin A (4.3%), high protein diets (19.6%), probiotics (10.9%), lactose free diets (10.9%), oral rehydration solution (ORS) formulations (8.7%), dietary supplements (6.5%), other dietary interventions (6.5%), and antimicrobials (4.3%). Prolonged or recurrent diarrhea was the most commonly reported outcome, and was assessed in ORS, probiotic, vitamin A, and zinc trials with no consistent benefit observed. Seven trials evaluated mortality, with follow-up times ranging from 8 days to 2 years. Only a single trial found a mortality benefit (therapeutic zinc). There were mixed results for dietary interventions affecting growth and diarrhea outcomes in the post-acute period. CONCLUSION: Despite the significant post-acute mortality and morbidity associated with diarrheal episodes, there is sparse evidence evaluating the effects of interventions to decrease these sequelae. Adequately powered trials with extended follow-up are needed to identify effective interventions to prevent post-acute diarrhea outcomes. PMID- 29391006 TI - Two approaches for estimating the lower limit of quantitation (LLOQ) of microRNA levels assayed as exploratory biomarkers by RT-qPCR. AB - BACKGROUND: Circulating microRNAs are undergoing exploratory use as safety biomarkers in drug development. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is one common approach used to quantitate levels of microRNAs in samples that includes the use of a standard curve of calibrators fit to a regression model. Guidelines are needed for setting assay quantitation thresholds that are appropriate for this method and to biomarker pre-validation. RESULTS: In this report, we develop two workflows for determining a lower limit of quantitation (LLOQ) for RT-qPCR assays of microRNAs in exploratory studies. One workflow is based on an error threshold calculated by a logistic model of the calibration curve data. The second workflow is based on a threshold set by the sample blank, which is the no template control for RT-qPCR. The two workflows are used to set lower thresholds of reportable microRNA levels for an example dataset in which miR-208a levels in biofluids are quantitated in a cardiac injury model. LLOQ thresholds set by either workflow are effective in filtering out microRNA values with large uncertainty estimates. CONCLUSIONS: Two workflows for LLOQ determinations are presented in this report that provide methods that are easy to implement in investigational studies of microRNA safety biomarkers and offer choices in levels of conservatism in setting lower limits of acceptable values that facilitate interpretation of results. PMID- 29391007 TI - Marked differences in tight junction composition and macromolecular permeability among different intestinal cell types. AB - BACKGROUND: Mammalian small intestinal tight junctions (TJ) link epithelial cells to one another and function as a permselective barrier, strictly modulating the passage of ions and macromolecules through the pore and leak pathways, respectively, thereby preventing the absorption of harmful compounds and microbes while allowing regulated transport of nutrients and electrolytes. Small intestinal epithelial permeability is ascribed primarily to the properties of TJs between adjoining enterocytes (ENTs), because there is almost no information on TJ composition and the paracellular permeability of nonenterocyte cell types that constitute a small but significant fraction of the intestinal epithelia. RESULTS: Here we directed murine intestinal crypts to form specialized organoids highly enriched in intestinal stem cells (ISCs), absorptive ENTs, secretory goblet cells, or Paneth cells. The morphological and morphometric characteristics of these cells in organoids were similar to those in vivo. The expression of certain TJ proteins varied with cell type: occludin and tricellulin levels were high in both ISCs and Paneth cells, while claudin-1, -2, and -7 expression was greatest in Paneth cells, ISCs, and ENTs, respectively. In contrast, the distribution of claudin-15, zonula occludens 1 (ZO-1), and E-cadherin was relatively homogeneous. E-cadherin and claudin-7 marked mainly the basolateral membrane, while claudin-2, ZO-1, and occludin resided in the apical membrane. Remarkably, organoids enriched in ENTs or goblet cells were over threefold more permeable to 4 and 10 kDa dextran compared to those containing stem and Paneth cells. The TJ-regulator larazotide prevented the approximately tenfold increases in dextran flux induced by the TJ-disrupter AT1002 into organoids of different cell types, indicating that this ZO toxin nonselectively increases permeability. Forced dedifferentiation of mature ENTs results in the reacquisition of ISC-like characteristics in TJ composition and dextran permeability, suggesting that the post-differentiation properties of TJs are not hardwired. CONCLUSIONS: Differentiation of adult intestinal stem cells into mature secretory and absorptive cell types causes marked, but potentially reversible, changes in TJ composition, resulting in enhanced macromolecular permeability of the TJ leak pathway between ENTs and between goblet cells. This work advances our understanding of how cell differentiation affects the paracellular pathway of epithelia. PMID- 29391008 TI - Adherence to home fortification with micronutrient powders in Kenyan pre-school children: self-reporting and sachet counts compared to an electronic monitoring device. AB - BACKGROUND: The efficacy of home fortification with iron-containing micronutrient powders varies between trials, perhaps in part due to population differences in adherence. We aimed to assess to what extent adherence measured by sachet count or self-reporting forms is in agreement with adherence measured by electronic device. In addition, we explored how each method of adherence assessment (electronic device, sachet count, self-reporting forms) is associated with haemoglobin concentration measured at the end of intervention; and to what extent baseline factors were associated with adherence as measured by electronic device. METHODS: Three hundred thirty-eight rural Kenyan children aged 12-36 months were randomly allocated to three treatment arms (home fortification with two different iron formulations or placebo). Home fortificants were administered daily by parents or guardians over a 30 day-intervention period. We assessed adherence using an electronic device that stores and provides information of the time and day of opening of the container that was used to store the fortificants sachets in each child's residence. In addition, we assessed adherence by self-reporting and sachet counts. We also measured haemoglobin concentration at the end of intervention. RESULTS: Adherence, defined as having received at least 24 sachets (>= 80%), during the 30-day intervention period was attained by only 60.6% of children as assessed by the electronic device. The corresponding values were higher when adherence was assessed by self-report (83.9%; difference: 23.3%, 95% CI: 18.8% to 27.8%) or sachet count (86.3%; difference: 25.7%, 95% CI: 21.0% to 30.4%). Among children who received iron, each 10 openings of the electronic cap of the sachet storage container were associated with an increase in haemoglobin concentration at the end of intervention by 1.2 g/L (95% CI: 0.0 to 1.9 g/L). Adherence was associated with the age of the parent but not with intervention group; with age, sex or anthropometric indices of the child; or with age or sex of the parent or guardian. CONCLUSIONS: The use of self -reporting and sachet count may lead to overestimates of adherence to home fortification. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov ( NCT02073149 ) on 25 February 2014. PMID- 29391009 TI - Anti-inflammatory activities of Guang-Pheretima extract in lipopolysaccharide stimulated RAW 264.7 murine macrophages. AB - BACKGROUND: Guang-Pheretima, which is originated from Pheretima aspergillum, has been documented in academic Chinese herbal studies for nearly 2000 years for its prominent treating effects of various inflammatory diseases such as asthma, cough and fever. However, the anti-inflammatory activity and mechanism of Guang Pheretima has been rarely reported. Hence, we investigated the inhibitory effect and the underlying mechanism of Guang-Pheretima aqueous extracts on inflammatory response in RAW 264.7 cells. METHOD: RAW 264.7 macrophages were pretreated with various concentrations of Guang-Pheretima decoction (GPD) or protein-free Guang Pheretima decoction (PF-GPD) and subsequently stimulated with lipopolysaccharide (LPS) to trigger the inflammatory response. Productions of nitric oxide (NO) were determined by Griess reaction, and prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 were measured by enzyme-linked immunosorbent assays (ELISA). The protein expressions and messenger ribonucleic acid (mRNA) amounts of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were analyzed by Western Blot and Real-Time polymerase chain reaction (PCR), respectively. Finally, the translocation of nuclear factor (NF)-kappaB was observed by Western Blot. RESULTS: GPD of the experimental concentrations showed no anti-inflammatory activity. In contrast, PF-GPD at concentrations of 40-320 MUg/mL significantly inhibited NF-kappaB activation and reduced the production of inflammatory mediators, such as NO, PGE2, TNF-alpha, as well as the related key synthases including iNOS and COX-2. Moreover, PF-GPD markedly suppressed the release of inflammatory cytokines, such as IL-1beta and IL-6. CONCLUSION: These results demonstrate the excellent anti-inflammatory properties of PF-GPD, and suggest that Guang-Pheretima may be used to treat and prevent certain inflammatory diseases. PMID- 29391010 TI - A multicenter, prospective study evaluating the impact of the clinical pharmacist physician counselling on warfarin therapy management in Lebanon. AB - BACKGROUND: Health care professionals (HCP) are known key elements of effective patient's counselling and education. For patients taking warfarin, education about the dose, side effects, and toxicity is clearly identified as a cornerstone of achieving improved health and quality of life. The study objective was to evaluate the patients' knowledge about warfarin and assess the impact of the health care professionals' counselling in enhancing patients' knowledge in achieving warfarin therapeutic outcomes. METHOD: A six-month prospective multicentered study was conducted in three hospitals, enrolling 300 patients admitted to the cardiac care unit and internal medicine departments. Patients' warfarin knowledge and INR levels were assessed before and after the clinical pharmacist counselling. The main therapeutic outcome was the impact of the clinical pharmacist-physician counselling on improving patient's education and achieving therapeutic INR level. RESULTS: A higher mean knowledge about warfarin score was found after counselling as compared to before counselling (4.82 vs 13.2; p < 0.001). Likewise, the drug dose (1.05 vs 1.88), drug toxicity (0.41 vs 1.92), drug-drug and food-drug interactions (0.02 vs 1.89), therapeutic INR and general drug knowledge scores (2.66 vs 4.68) were significantly higher after as compared to before counselling (p < 0.001 for all variables). The percentages of patients who achieved therapeutic INR levels pre/post counselling was 37.2% and 74.4% respectively (p < 0.001). CONCLUSION: Based on the study findings, HCP play a major role in enhancing patients' knowledge about the factors that affect warfarin therapeutic outcomes. This study highlights the need to establish and develop strategies for appropriate warfarin utilization in Lebanon. PMID- 29391011 TI - Caprine herpesvirus 2-associated malignant catarrhal fever of captive sika deer (Cervus nippon) in an intensive management system. AB - BACKGROUND: Caprine herpesvirus 2 (CpHV-2) infection usually induces chronic malignant catarrhal fever (MCF) in sika deer (Cervus nippon), with the primary signs of weight loss, dermatitis and alopecia. CASE PRESENTATION: Here, we report a case of CpHV-2-associated acute MCF in a sika deer herd raised in an intensive management system distant to the reservoir goats. Affected deer developed clinical signs of high fever (41 degrees C) followed by nasal discharge and lameness. Severe lesions of hemorrhage, necrosis and infiltration of lymphoid cells could readily be observed in the lung, kidney, heart valves and subcutaneous tissue surrounding a tendon. Etiologically, identical CpHV-2 specific DNA sequences were detected in peripheral blood lymphocyte (PBL) from the affected deer and reservoir goats. CONCLUSION: In summary, domestic goats were the reservoir of the CpHV-2, which is the causative agent of the outbreak of MCF in the three hinds. The disease was probably transmitted via aerosol infection. In addition, necrosis and inflammation in subcutaneous tissue surrounding a tendon was the reason for lameness. Therefore, MCF should be put into a differential diagnostic list when similar disease occurs in sika deer herds. PMID- 29391012 TI - Near-death experiences, attacks by family members, and absence of health care in their home countries affect the quality of life of refugee women in Germany: a multi-region, cross-sectional, gender-sensitive study. AB - BACKGROUND: The year 2016 has marked the highest number of displaced people worldwide on record. A large number of these refugees are women, yet little is known about their specific situation and the hurdles they have to face during their journey. Herein, we investigated whether sociodemographic characteristics and traumatic experiences in the home country and during the flight affected the quality of life of refugee women arriving in Germany in 2015-2016. METHODS: Six hundred sixty-three women from six countries (Afghanistan, Syria, Iran, Iraq, Somalia, and Eritrea) living in shared reception facilities in five distinct German regions were interviewed by native speakers using a structured questionnaire. Sociodemographic data and information about reasons for fleeing, traumatic experiences, symptoms, quality of life, and expectations towards their future were elicited. All information was stored in a central database in Berlin. Descriptive analyses, correlations, and multivariate analyses were performed. RESULTS: The most frequent reasons cited for fleeing were war, terror, and threat to one's life or the life of a family member. Eighty-seven percent of women resorted to smugglers to make the journey to Europe, and this significantly correlated to residence in a war zone (odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.4-4.6, p = 0.003) and homelessness prior to fleeing (OR = 2.1, 95% CI = 1-4.3, p = 0.04). Overall the described quality of life by the women was moderate (overall mean = 3.23, range of 1-5) and slightly worse than that of European populations (overall mean = 3.68, p < 0.0001). The main reasons correlating with lower quality of life were older age, having had a near-death experience, having been attacked by a family member, and absence of health care in case of illness. CONCLUSIONS: Refugee women experience multiple traumatic experiences before and/or during their journey, some of which are gender specific. These experiences affect the quality of life in their current country of residence and might impact their integration. We encourage the early investigation of these traumatic experiences to rapidly identify women at higher risk and to improve health care for somatic and mental illness. PMID- 29391013 TI - Impact of high-density lipoprotein 3 cholesterol subfraction on periprocedural myocardial injury in patients who underwent elective percutaneous coronary intervention. AB - BACKGROUND: Periprocedural myocardial injury (PMI) is a major complication of percutaneous coronary intervention (PCI) and is associated with atherosclerotic coronary plaque and worse clinical outcomes. High-density lipoprotein cholesterol (HDL-C) is a protective factor for cardiovascular disease. However, the role of HDL-C subfractions, such as HDL2 cholesterol (HDL2-C) or HDL3 cholesterol (HDL3 C), in cardiovascular disease remains unclear. The purpose of the study was to investigate the relationship between HDL2-C and HDL3-C subfractions and the incidence of PMI in patients who underwent elective PCI. METHODS: We enrolled 129 patients who underwent elective PCI for stable angina pectoris. PMI was defined as an increase in high-sensitivity troponin T levels > 5 times the upper normal limit (> 0.070 ng/mL) at 24 h after PCI. Serum HDL-C subfractions (HDL2-C and HDL3-C) were assessed using ultracentrifugation in patients with and those without PMI. RESULTS: HDL3-C levels were significantly lower in patients with PMI than in those without (15.1 +/- 3.0 mg/dL vs. 16.4 +/- 2.9 mg/dL, p = 0.016) and had an independent and inverse association with PMI (odds ratio, 0.86; 95% confidence interval, 0.74-0.99; p = 0.038). When divided by the cut-off value of HDL3-C for PMI (14.3 mg/dL), the incidence of PMI was significantly higher in low HDL3-C patients than in high HDL3-C patients (51.2% vs. 30.2%, p = 0.020). CONCLUSIONS: HDL3-C was an independent inverse predictor of PMI in patients who underwent elective PCI. PMID- 29391014 TI - alpha-Tocopherol and beta-carotene concentrations in feed, colostrum, cow and calf serum in Swedish dairy herds with high or low calf mortality. AB - BACKGROUND: A study of herd-level risk factors for calf mortality in large Swedish dairy herds showed low serum concentrations of alpha-tocopherol and beta carotene in 1-7 day old calves to be more common in high mortality herds. Therefore, we aimed to investigate if calf mortality risk at herd level is associated with concentrations of alpha-tocopherol and/or beta-carotene at individual level in feed, colostrum, cow and calf serum, while controlling for herd level covariates. Inclusion criteria were affiliation to the Swedish official milk recording scheme, herd size of >= 120 milking cows/year, calf mortality risk (day 1-90) of at least 6% (high mortality; HM) or less than 1% (low mortality; LM) and located within one of two regions in southern Sweden. This cross-sectional study was performed in 2010 in 19 (nHM = 9; nLM = 10) dairy herds. Questionnaires were used to collect information about feed and routines for colostrum feeding. Feed (n = 57), colostrum (n = 162), cow serum (n = 189) and calf serum samples (n = 187) were collected and analysed for alpha-tocopherol and beta-carotene. Other analyses e.g. total serum protein, fat content, and total solids in colostrum were also performed. Linear regression models with vitamin concentrations in feed, colostrum, cow and calf serum as outcome were performed. RESULTS: Calves in HM herds had lower concentrations of alpha tocopherol in serum than calves in LM herds, but the effect depended on total protein status in serum of the calf (P = 0.036). Calves from herds that fed transition milk for 3 days or more had higher alpha-tocopherol concentrations in serum than calves from herds feeding transition milk up to 2 days (P = 0.013). Fat percentage in colostrum was positively associated with alpha-tocopherol (P < 0.001) and beta-carotene concentrations in colostrum (P < 0.001). A diet containing >= 20% (in kg dry matter) maize silage of the total ration was negatively associated with beta-carotene concentration in cow serum (P = 0.001). CONCLUSIONS: High calf mortality risks were associated with lower concentrations of alpha-tocopherol in calf serum for calves with failure of passive transfer. Feeding transition milk longer was associated with higher concentrations of alpha tocopherol in calf serum. In HM herds, evaluation of the calves' alpha-tocopherol status is recommended. PMID- 29391015 TI - Bisphenol a increases risk for presumed non-alcoholic fatty liver disease in Hispanic adolescents in NHANES 2003-2010. AB - BACKGROUND: Bisphenol-A (BPA) is a ubiquitous chemical and recognized endocrine disruptor associated with obesity and related disorders. We explored the association between BPA levels and suspected non-alcoholic fatty liver disease (NAFLD). METHODS: Unweighted analyses were used to study the relationship between urinary BPA levels and suspected NAFLD (alanine aminotransferase (ALT). > 30 U/L, body mass index (BMI) Z-score > 1.064 and evidence of insulin resistance) using National Health and Nutrition Examination Survey (NHANES) data (2003-2010) on 12 19 year olds. Unweighted and weighted analyses were used to evaluate the risk with only elevated ALT. RESULTS: We included 944 adolescents with urinary BPA and fasting laboratory tests from a total of 7168 adolescents. Risk of suspected NAFLD was increased in the second quartile of BPA levels (1.4-2.7 ng/mL) when compared to the first (< 1.4 ng/mL) (Odds Ratio (OR) 4.23, 95% Confidence Interval (CI) 1.44-12.41). The ORs for the third and second quartiles were positive but did not reach statistical significance. The association was stronger in Hispanics (n = 344) with BPA levels in the second (OR 6.12, 95% C.I. 1.62 23.15) quartile and when limiting the analyses to overweight/obese adolescents (n = 332), in the second (OR 5.56, 95% C.I. 1.28-24.06) and fourth BPA quartiles (OR 6.85, 95% C.I. 1.02-46.22) compared to the first quartile. BPA levels were not associated with ALT elevation. CONCLUSIONS: The risk of suspected NAFLD is increased in participants in higher quartiles of BPA exposure, particularly in those of Hispanic ethnicity. Further studies are required to fully understand the potential role of BPA in non-alcoholic fatty liver disease. PMID- 29391016 TI - Measuring social exclusion in healthcare settings: a scoping review. AB - BACKGROUND: Social exclusion is a concept that has been widely debated in recent years; a particular focus of the discussion has been its significance in relation to health. The meanings of the phrase "social exclusion", and the closely associated term "social inclusion", are contested in the literature. Both of these concepts are important in relation to health and the area of primary healthcare in particular. Thus, several tools for the measurement of social exclusion or social inclusion status in health care settings have been developed. METHODS: A scoping review of the peer-reviewed and grey literature was conducted to examine tools developed since 2000 that measure social exclusion or social inclusion. We focused on those measurement tools developed for use with individual patients in healthcare settings. Efforts were made to obtain a copy of each of the original tools, and all relevant background literature. All tools retrieved were compared in tables, and the specific domains that were included in each measure were tabulated. RESULTS: Twenty-two measurement tools were included in the final scoping review. The majority of these had been specifically developed for the measurement of social inclusion or social exclusion, but a small number were created for the measurement of other closely aligned concepts. The majority of the tools included were constructed for engaging with patients in mental health settings. The tools varied greatly in their design, the scoring systems and the ways they were administered. The domains covered by these tools varied widely and some of the tools were quite narrow in the areas of focus. A review of the definitions of both social inclusion and social exclusion also revealed the variations among the explanations of these complex concepts. CONCLUSIONS: There are several definitions of both social inclusion and social exclusion in use and they differ greatly in scope. While there are many tools that have been developed for measuring these concepts in healthcare settings, these do not have a primary healthcare focus. There is a need for the development of a tool for measuring social inclusion or social exclusion in primary healthcare settings. PMID- 29391017 TI - Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. AB - BACKGROUND: Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. FINDINGS: Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. CONCLUSION: This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes. PMID- 29391018 TI - The impact of nursing students on the health-related quality of life and perceived social support of a rural population in Ecuador: effects of a service based learning course. AB - BACKGROUND: Students seeking degrees in healthcare in Ecuador participate in community improvement projects and provide free health services under the supervision of faculty health professionals. The aim of this study is to determine the impact of a community-based intervention delivered by nursing students on health-related quality of life (HRQoL) and perceived social support of a rural population in Ecuador. METHODS: A quasi-experimental non-equivalent control group design study was conducted in two rural communities in Tumbaco, Ecuador. Families from one rural community were invited to participate in the intervention, receiving 8 weekly home visits from nursing students. Families from a neighboring community were similarly recruited as wait-list controls. One member of each family was consented into the study; the final sample included 43 intervention participants and 55 control participants. HRQoL and perceived social support were assessed before and after the intervention in both groups. The SF-12 was used to measure HRQoL, including eight domain scores and two composite scores, and the Interpersonal Support Evaluation List was used as an indicator of perceived social support. Difference-in-differences (DD) analyses were conducted to mitigate the effects of any baseline differences in the non- equivalent control group design. RESULTS: When compared to the control group, the intervention group realized significant improvements in the physical component summary score of the SF-12 (4.20, p < 0.05) and the physical function domain of the SF-12 (4.92, p < 0.05). There were no statistically significant differences for any other components of the SF-12 or in the measure of perceived social support. CONCLUSIONS: Nursing students completing their rural service rotation have the potential to improve the health-related quality of life of rural residents in Ecuador. Future research should continue to examine the impact of service-based learning on recipient populations. PMID- 29391019 TI - Evaluation of the Deadly Liver Mob program: insights for roll-out and scale-up of a pilot program to engage Aboriginal Australians in hepatitis C and sexual health education, screening, and care. AB - BACKGROUND: Deadly Liver Mob (DLM) is a peer-driven, incentivised health promotion program aimed at increasing understanding of hepatitis C, promoting harm reduction in relation to injecting drug use, and linking participants to screening for hepatitis C, other blood borne viruses and sexually transmissible infections among Aboriginal people in Western Sydney, NSW. This paper presents the evaluation of a pilot study examining the acceptability of the program as a first step of a scalability assessment. METHODS: Deadly Liver Mob operated in co located needle and syringe programs and sexual health clinics in two sites: (Site 1: two and a half years for 2 days/week; Site 2: 1 year for 1 day per week). Comparisons were made of the proportion of Aboriginal clients (Site 1) and occasions of service provided to Aboriginal clients (Site 2) in the 12 months prior and post-introduction of DLM. Interviews were conducted with 13 staff involved in delivery of DLM and with 19 clients. RESULTS: A total of 655 and 55 Aboriginal clients, respectively, attended Site 1 and Site 2 for health education. The proportion of Aboriginal clients attending both sites was significantly higher during the DLM compared with prior to its implementation. Of those attending for health education, 79 and 73%, respectively, attended screening following education. DLM clients strongly endorsed the program. Some staff were concerned about workforce capacity to effectively engage Aboriginal clients with multiple and complex needs, managing the differing aims of the participating services involved, and about offering of incentives for attendance at health services. CONCLUSION: While acceptability was high among staff and clients and preliminary results show high engagement with Aboriginal communities, this evaluation of a pilot program raises some issues to consider in scale up of DLM to other sites. The initiation of additional DLM sites should address issues of alignment with governing strategies and workforce capacity. PMID- 29391021 TI - Involvement of community pharmacists in continuing professional development (CPD): a baseline survey in Gondar, Northwest Ethiopia. AB - BACKGROUND: Health care professionals have been striving to maintain their competence to deliver the best quality of service. This study intended to determine involvement in continuing professional development of community pharmacists in Gondar, Northwest Ethiopia. METHODS: About 46 community pharmacists, each from a different setting, were interviewed using structured questionnaire. Data were analyzed using Pearson's Chi-square test of independence and Mann-Whitney U test with p < 0.05 taken as statistically significant. RESULTS: The majority (n = 26, 56.5%) reported of being unaware of the CPD concept. The mean hour spent per week on CPD is 4.1 +/- 4.0. Most (n = 34, 73.9%) were engaged in self directed learning and expressed an interest to be more involved in CPD activities (N = 39, 84.8%). Interactive workshops were the most preferred modality. However they seek further support in the process of identifying learning needs (N = 34, 73.9%). The main barriers for CPD engagement include lack of (N = 36, 78.3%) and inaccessibility (N = 34, 73.9%) of CPD opportunities as well as time shortage (N = 33, 71.7%). CONCLUSIONS: The community pharmacists in Gondar, Northwest Ethiopia lack awareness of CPD concept but engaged in various types of CPD activities. They demonstrated good attitude and seek more support. The main barrier was lack of opportunities related to CPD. PMID- 29391020 TI - Suppressive regulatory T cells and latent transforming growth factor-beta expressing macrophages are altered in the peritoneal fluid of patients with endometriosis. AB - BACKGROUND: Endometriosis is a known cause of infertility. Differences in immune tolerance caused by regulatory T cells (Tregs) and transforming growth factor beta (TGF-beta) are thought to be involved in the pathology of endometriosis. Evidence has indicated that Tregs can be separated into three functionally and phenotypically distinct subpopulations and that activated TGF-beta is released from latency-associated peptide (LAP) on the surfaces of specific cells. The aim of this study was to examine differences in Treg subpopulations and LAP in the peripheral blood (PB) and peritoneal fluid (PF) of patients with and without endometriosis. METHODS: PB and PF were collected from 28 women with laparoscopically and histopathologically diagnosed endometriosis and 20 disease free women who were subjected to laparoscopic surgery. Three subpopulations of CD4+ T lymphocytes (CD45RA+FoxP3low resting Tregs, CD45RA-FoxP3high effector Tregs, and CD45RA-FoxP3low non-Tregs) and CD11b+ mononuclear cells expressing LAP were analyzed by flow cytometry using specific monoclonal antibodies. RESULTS: Proportions of suppressive Tregs (resting and effector Tregs) were significantly higher in the PF samples of patients with endometriosis than in those of control women (P = 0.02 and P < 0.01, respectively) but did not differ between the PB samples of patients and controls. The percentage of CD11b+LAP+ macrophages was significantly lower in PF samples of patients with endometriosis than in those of controls (P < 0.01) but was not altered in the PB samples. CONCLUSION: Proportions of suppressive Tregs and LAP+ macrophages are altered locally in the PF of endometriosis patients. PMID- 29391022 TI - An automated haematology analyzer XN-30 distinguishes developmental stages of falciparum malaria parasite cultured in vitro. AB - BACKGROUND: The automated haematology analyzer XN-30 (Sysmex, Kobe, Japan) easily and rapidly detects malarial parasites in clinical blood samples using flow cytometry. The XN-30 analyzer is able to distinguish each developmental stage by measuring DNA content and cell size. Thus, it was expected to be capable of quantifying the developmental stages of cultured falciparum parasite. To achieve this requirement, a modified algorithm was tested for its validity and reliability using in vitro cultured falciparum parasite. RESULTS: The XN-30 analyzer automatically measured each developmental stage as well as total parasitaemia. Comparison of the parasitaemia obtained using the XN-30 analyzer equipped with the modified algorithm with that obtained using microscopy examination of Giemsa-stained smears revealed the greater sensitivity and reproducibility of the former. The XN-30 analyzer also detected free merozoites and purified gametocytes. CONCLUSIONS: The XN-30 analyzer allows the precise recognition and enumeration of total and each developmental stages of cultured falciparum parasites, and permits the sensitive and reproducible calculation of parasitaemia. The results indicate the potential of the XN-30 analyzer for basic research on malarial biology, anti-malarial drug discovery, and evaluation of drug efficacy. PMID- 29391023 TI - Spatial and temporal dynamics of malaria in Madagascar. AB - BACKGROUND: Malaria is one of the primary health concerns in Madagascar. Based on the duration and intensity of transmission, Madagascar is divided into five epidemiological strata that range from low to mesoendemic transmission. In this study, the spatial and temporal dynamics of malaria within each epidemiological zone were studied. METHODS: The number of reported cases of uncomplicated malaria from 112 health districts between 2010 and 2014 were compiled and analysed. First, a Standardized Incidence Ratio was calculated to detect districts with anomalous incidence compared to the stratum-level incidence. Building on this, spatial and temporal malaria clusters were identified throughout the country and their variability across zones and over time was analysed. RESULTS: The incidence of malaria increased from 2010 to 2014 within each stratum. A basic analysis showed that districts with more than 50 cases per 1000 inhabitants are mainly located in two strata: East and West. Lower incidence values were found in the Highlands and Fringe zones. The standardization method revealed that the number of districts with a higher than expected numbers of cases increased through time and expanded into the Highlands and Fringe zones. The cluster analysis showed that for the endemic coastal region, clusters of districts migrated southward and the incidence of malaria was the highest between January and July with some variation within strata. CONCLUSION: This study identified critical districts with low incidence that shifted to high incidence and district that were consistent clusters across each year. The current study provided a detailed description of changes in malaria epidemiology and can aid the national malaria programme to reduce and prevent the expansion of the disease by targeting the appropriate areas. PMID- 29391024 TI - Chi3l3: a potential key orchestrator of eosinophil recruitment in meningitis induced by Angiostrongylus cantonensis. AB - BACKGROUND: Angiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human. However, the characteristics and mechanisms of the infection are still poorly understood. This study sought to determine the key molecules and its underlying mechanism in inducing brain eosinophilic infiltration caused by Angiostrongylus cantonensis. METHODS: Mathematical models were established for prediction of significantly changing genes and the functional associated protein with RNA-seq data in Angiostrongylus cantonensis infection. The expression level of Chi3l3, the predicted key molecule, was verified using Western blotting and real-time quantitative PCR. Critical cell source of Chi3l3 and its relationship with eosinophils were identified with flow cytometry, immunohistochemistry, and further verified by macrophage depletion using liposomal clodronate. The role of soluble antigens of Angiostrongylus cantonensis in eosinophilic response was identified with mice airway allergy model by intranasal administration of Alternaria alternate. The relationship between Chi3l3 and IL-13 was identified with flow cytometry, Western blotting, and Seahorse Bioscience extracellular flux analyzer. RESULTS: We analyzed the skewed cytokine pattern in brains of Angiostrongylus cantonensis-infected mice and found Chi3l3 to be an important molecule, which increased sharply during the infection. The percentage of inflammatory macrophages, the main source of Chi3l3, also increased, in line with eosinophils percentage in the brain. Network analysis and mathematical modeling predirect a functional association between Chi3l3 and IL-13. Further experiments verified that the soluble antigen of Angiostrongylus cantonensis induce brain eosinophilic meningitis via aggravating a positive feedback loop between IL-13 and Chi3l3. CONCLUSIONS: We present evidences in favor of a key role for macrophave-derived Chi3l3 molecule in the infection of Angiostrongylus cantonensis, which aggravates eosinophilic meningitis induced by Angiostrongylus cantonensis via a IL-13-mediated positive feedback loop. These reported results constitute a starting point for future research of angiostrongyliasis pathogenesis and imply that targeting chitinases and chitinase-like-proteins may be clinically beneficial in Angiostrongylus cantonensis-induced eosinophilic meningitis. PMID- 29391025 TI - Detection of sleep disordered breathing severity using acoustic biomarker and machine learning techniques. AB - PURPOSE: Breathing sounds during sleep are altered and characterized by various acoustic specificities in patients with sleep disordered breathing (SDB). This study aimed to identify acoustic biomarkers indicative of the severity of SDB by analyzing the breathing sounds collected from a large number of subjects during entire overnight sleep. METHODS: The participants were patients who presented at a sleep center with snoring or cessation of breathing during sleep. They were subjected to full-night polysomnography (PSG) during which the breathing sound was recorded using a microphone. Then, audio features were extracted and a group of features differing significantly between different SDB severity groups was selected as a potential acoustic biomarker. To assess the validity of the acoustic biomarker, classification tasks were performed using several machine learning techniques. Based on the apnea-hypopnea index of the subjects, four group classification and binary classification were performed. RESULTS: Using tenfold cross validation, we achieved an accuracy of 88.3% in the four-group classification and an accuracy of 92.5% in the binary classification. Experimental evaluation demonstrated that the models trained on the proposed acoustic biomarkers can be used to estimate the severity of SDB. CONCLUSIONS: Acoustic biomarkers may be useful to accurately predict the severity of SDB based on the patient's breathing sounds during sleep, without conducting attended full night PSG. This study implies that any device with a microphone, such as a smartphone, could be potentially utilized outside specialized facilities as a screening tool for detecting SDB. PMID- 29391026 TI - Machine learning and medicine: book review and commentary. AB - This article is a review of the book "Master machine learning algorithms, discover how they work and implement them from scratch" (ISBN: not available, 37 USD, 163 pages) edited by Jason Brownlee published by the Author, edition, v1.10 http://MachineLearningMastery.com . An accompanying commentary discusses some of the issues that are involved with use of machine learning and data mining techniques to develop predictive models for diagnosis or prognosis of disease, and to call attention to additional requirements for developing diagnostic and prognostic algorithms that are generally useful in medicine. Appendix provides examples that illustrate potential problems with machine learning that are not addressed in the reviewed book. PMID- 29391028 TI - Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis. AB - BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a potentially disabling disorder. Little is known about the contributors to severe forms of the illness. We describe three consecutive patients with severe ME/CFS whose symptoms improved after recognition and surgical management of their cervical spinal stenosis. METHODS: All patients satisfied clinical criteria for ME/CFS and orthostatic intolerance, and were later found to have cervical spinal stenosis. Overall function was assessed before and after surgery using the Karnofsky score and the SF-36 physical function subscale score. RESULTS: Neurological findings included > 3+ deep tendon reflexes in 2 of 3, a positive Hoffman sign in 2 of 3, tremor in 2 of 3, and absent gag reflex in 1 of 3. The cervical spine canal diameter in the three patients ranged from 6 to 8.5 mm. One had congenital cervical stenosis with superimposed spondylosis, and two had single- or two-level spondylosis. Anterior cervical disc replacement surgery in two patients and a hybrid anterior cervical disc fusion and disc replacement in the third was associated with a marked improvement in myelopathic symptoms, resolution of lightheadedness and hemodynamic dysfunction, improvement in activity levels, and improvement in global ME/CFS symptoms. CONCLUSIONS: The prompt post-surgical restoration of more normal function suggests that cervical spine stenosis contributed to the pathogenesis of refractory ME/CFS and orthostatic symptoms. The improvements following surgery emphasize the importance of a careful search for myelopathic examination findings in those with ME/CFS, especially when individuals with severe impairment are not responding to treatment. PMID- 29391027 TI - BACE1 elevation engendered by GGA3 deletion increases beta-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice. AB - BACKGROUND: beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Abeta), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized gamma-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo. Moreover, levels of GGA3 are reduced and inversely related to BACE1 levels in post-mortem brains of AD patients. METHOD: In order to assess the effect of GGA3 deletion on AD-like phenotypes, we crossed GGA3 -/- mice with 5XFAD mice. BACE1-mediated processing of APP and the cell adhesion molecule L1 like protein (CHL1) was measured as well as levels of Abeta42 and amyloid burden. RESULTS: In 5XFAD mice, we found that hippocampal and cortical levels of GGA3 decreased while BACE1 levels increased with age, similar to what is observed in human AD brains. GGA3 deletion prevented age-dependent elevation of BACE1 in GGA3KO;5XFAD mice. We also found that GGA3 deletion resulted in increased hippocampal levels of Abeta42 and amyloid burden in 5XFAD mice at 12 months of age. While levels of BACE1 did not change with age and gender in GGAKO;5XFAD mice, amyloid precursor protein (APP) levels increased with age and were higher in female mice. Moreover, elevation of APP was associated with a decreased BACE1-mediated processing of CHL1 not only in 12 months old 5XFAD mice but also in human brains from subjects affected by Down syndrome, most likely due to substrate competition. CONCLUSION: This study demonstrates that GGA3 depletion is a leading candidate mechanism underlying elevation of BACE1 in AD. Furthermore, our findings suggest that BACE1 inhibition could exacerbate mechanism-based side effects in conditions associated with APP elevation (e.g. Down syndrome) owing to impairment of BACE1-mediated processing of CHL1. Therefore, therapeutic approaches aimed to restore GGA3 function and to prevent the down stream effects of its depletion (e.g. BACE1 elevation) represent an attractive alternative to BACE inhibition for the prevention/treatment of AD. PMID- 29391029 TI - Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. AB - BACKGROUND: Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease. METHODS: To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD. RESULTS: Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size. CONCLUSIONS: Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD. PMID- 29391030 TI - Patients want more information after surgery: a prospective audit of satisfaction with perioperative information in lung cancer surgery. AB - BACKGROUND: Receiving information about their disease and treatment is very important to patients with cancer. There is an association between feeling appropriately informed and better quality of life. This audit aimed to estimate patient satisfaction with perioperative information in those undergoing surgery for lung cancer and any change in satisfaction over time. METHODS: A questionnaire (EORTC-Info-25) was administered prospectively to patients preoperatively and up to six months postoperatively. The preoperative questionnaire was completed by 292 patients and 88 free text comments were completed. Intrapersonal responses were compared over time. RESULTS: Patients were highly satisfied with information prior to surgery. The overall helpfulness of information did not change over time but satisfaction with the amount of information decreased. Patients who received more information about 'the disease' and 'things you can do to help yourself get well' were less likely to report a drop in satisfaction (Odds Ratio 0.858, 95% Confidence interval 0.765 to 0.961, p = 0.008 and OR 0.102, 95% CI 0.018 to 0.590, p = 0.011 respectively). Free text responses revealed patients most frequently wanted more information on the disease, aftercare and self-care. Suffering complications from surgery was not associated with a change in satisfaction with information postoperatively. CONCLUSIONS: Patients want to know more about their diagnosis, but also how to recover and cope with issues once they have gone home after surgery. Postoperative satisfaction with information may improve if patients are given more information on these topics. PMID- 29391032 TI - Adolescence/adult onset MTHFR deficiency may manifest as isolated and treatable distinct neuro-psychiatric syndromes. AB - 5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a genetic disorder that can occur at any age and can be easily detected by increased homocysteinemia. In adolescence/adult onset forms, the clinical picture is often complex with association of various neurological features and thrombosis.Here we report the cases of two adult siblings who experienced focal epilepsy at 18 years old as a first disease manifestation, without other symptom during several years. Upon diagnosis, both patients received metabolic treatment comprising B9, B12 and betaine which has stopped the occurrence of seizures, allowing discontinuation of anti-epileptic drugs.Among 24 reviewed adolescent/adult onset patients with MTHFR deficiency in the literature, clinical manifestations included gait disorder (96%, from motor central or peripheral origin), cognitive decline (74%), epileptic syndromes (50%), encephalopathy (30%), psychotic symptoms (17%), and thrombotic events (21%). A total of 41% presented a single neurological manifestation that could stay isolated during at least 3 years, delaying achievement of the diagnosis. Brain MRI showed a mostly periventricular white matter changes in 71% of cases. All patients stabilized or improved following metabolic treatment.Despite being rare, adolescence/adult onset MTHFR deficiency can nevertheless be successfully treated. Therefore, homocysteinemia should be tested in various unexplained neuro-psychiatric syndromes like epilepsy or spastic paraparesis, even if isolated, since waiting for completion of the clinical picture is likely to increase the risk of irreversible neurological damage. PMID- 29391031 TI - Progress in brain barriers and brain fluid research in 2017. AB - The past year, 2017, has seen many important papers published in the fields covered by Fluids and Barriers of the CNS. This article from the Editors highlights some. PMID- 29391033 TI - Alcohol-impaired driving in US counties, 2002-2012. AB - BACKGROUND: Excessive alcohol consumption and alcohol-impaired driving remain significant public health problems, leading to considerable morbidity and mortality, particularly among younger populations. METHODS: Using data from the Behavioral Risk Factor Surveillance System (BRFSS), we employed a small areas modeling strategy to estimate the county-level annual prevalence of alcohol impaired driving in every United States county for the years 2002 through 2012, the latest year in which county identifiers were publicly available. RESULTS: Alcohol-impaired driving episodes declined from 157.0 million in 2002 (prevalence 3.8%: 95% uncertainty interval [UI], 3.7%-4.0%) to 129.7 million in 2012 (prevalence 3.7%: 95% UI, 3.5%-3.8%), a 17.4% decline. There is considerable variation in the prevalence of alcohol-impaired driving at the county level, ranging from 2.0% in the Sitka City Borough of Alaska to 9.3% in Nance County, Nebraska. Clusters of increased alcohol-impaired driving were observed in Northern Wisconsin (Marinette, Florence, Forest, Vilas, Oneida, Iron counties), North Dakota (Cavalier, Pembina, Walsh, Ramsey, Nelson, Benson, Eddy counties) and Montana (Sheridan, Daniels, Roosevelt, Valley, Phillips, Petroleum, Garfield counties). CONCLUSIONS: This study showed guarded progress with respect to the occurrence of alcohol-impaired driving episodes in the US from 2002 to 2012. Because these data rely on self-report, this likely represents an underestimate of the true prevalence of alcohol-impaired driving in the US. As the US continues to have several million episodes of alcohol-impaired driving each month, renewed efforts are needed to mitigate this high-risk health behavior. PMID- 29391034 TI - Vena cava anomalies in thoracic surgery. AB - BACKGROUND: Vena cava anomalies are a rare group of anatomical variations due to an incorrect development of the superior or inferior vena cava during fetal life. They generally show no clinical relevance and the diagnosis is done due to the association with congenital heart diseases in most of cases. However, preoperative identification of these anomalies is mandatory for surgeons to proper surgical planning. If not recognized, lethal complications may occur, as already reported in literature. CASE PRESENTATION: We report a case series of three different unidentified vena cava anomalies in patients undergoing lung resection. These unrecognized anomalies led to minor complications in two cases and required an accurate intraoperative evaluation in another. A careful retrospective evaluation of preoperative radiological images showed the anomalies. CONCLUSIONS: A careful evaluation of the vena cava anatomy at pre operative imaging is mandatory for thoracic surgeons to properly plan the surgery and avoid complications. PMID- 29391035 TI - Comparative genetic analysis and pathological characteristics of goose parvovirus isolated in Heilongjiang, China. AB - BACKGROUND: Goose parvovirus (GPV) causes acute enteritis, hepatitis, myocarditis and high morbidity and mortality in geese and ducks. GPV H strain was isolated from a Heilongjiang goose farm where the geese were showing signs of hemorrhage in the brain, liver, and intestinal tract. In this study, we explored the genetic diversity among waterfowl parvovirus isolates and the pathological characteristics of GPV H in Shaoxing ducklings. METHODS: The complete capsid protein (VP) and non-structural (NS) sequences of the isolated H strain were sequenced, and phylogenetic trees of VP and NS were constructed in MEGA version 5.05 using the neighbor-joining method. Three-day-old Shaoxing ducklings were inoculated with GPV and were euthanized at 1, 2, 4, 6, and 8 days post inoculation (PI), and their organs were removed and collected. The organs of 6 day PI ducklings were fixed in formalin, embedded in paraffin, sectioned for histology, stained with HE and analyzed for pathological lesions. The distribution of the GPV H strain in the tissues of the inoculated ducklings was detected using the polymerase chain reaction (PCR) method. RESULTS: Genetic analysis of the NS and VP genes indicated that the H strain was closely related to strains circulating in China during 1999-2014, and the nucleic acid identity of those strains was 98%-99%. Classical symptoms were observed in the inoculated ducklings. GPV remained in many tissues and replicated in a majority of the tissues, leading to histopathological lesions in four tissues. CONCLUSIONS: We first reported the distribution and histopathological lesions of a Chinese strain of GPV in infected shaoxing ducklings. This H strain was moderate pathogenic for Shaoxing ducklings. PMID- 29391036 TI - Modified minimally invasive approach and intra-osseous portal for three-part proximal humeral fractures: a comparative study. AB - BACKGROUND: Proximal humeral fracture is a common fracture. Different approaches have been utilized in the surgical intervention of three-part fractures. Our study is to evaluate the clinical outcomes and effectiveness of a modified anterolateral approach and intra-osseous portal in minimally invasive treatment for three-part proximal humeral fractures in comparison to the traditional deltopectoral approach. METHODS: From March 2015 to September 2016, 13 patients with three-part proximal humeral fractures were treated with internal fixation through the modified anterolateral minimally invasive approach (MIPO). These cases were compared to 20 additional cases using the deltopectoral approach (DP). Clinical and radiographic evaluations were performed, including the constant score (CS) and range of motion in abduction, flexion/extension and external/internal rotation. Complications were recorded as well. RESULTS: All patients were followed up for a mean time of 12.12 +/- 4.01 months. At the latest follow-up, no significant differences (p < 0.05) were observed in terms of length of stay, range of motion for abduction, flexion or internal/external rotation of the shoulder, Constant score or visual analog scors (VAS) for pain. Elbow flexion (142.31 +/- 8.32 vs. 123.00 +/- 10.18), posterior shoulder extension (41.92 +/- 5.22 vs. 35.50 +/- 5.83) and postoperative VAS (4.38 +/- 1.04 vs. 6.15 +/- 0.99) were significantly better in the MIPO group than in the DP group (p < 0.05). No significant differences were detected in the radiographic evaluation, and complications including axillary nerve injury were not present. CONCLUSION: The use of the modified anterolateral approach and intra-osseous portal is safe and effective for minimally invasive reduction and plating treatment for three-part proximal humeral fractures. PMID- 29391037 TI - Effect of pulsatile flow perfusion on decellularization. AB - BACKGROUND: Decellularized animal organs have been used as scaffolds for tissue engineering. To make a properly functioning scaffolds, the extracellular matrix (ECM) components must be preserved after decellularization. Because pulsatile flow is known to be beneficial for tissue perfusion, pulsatile perfusion of a detergent might decrease the exposure time of the tissues to the detergent used for decellularization. Using Energy Equivalent Pressure (EEP) as a pulsatility parameter, the effect of pulsatile flow in decellularization process is studied. RESULTS: Twelve rat hearts were decellularization with 1% sodium dodecyl sulfate (SDS) solution for 2 h. They are divided into two groups, one with pulsatile perfusion (n = 6), the other with non-pulsatile perfusion (n = 6) of SDS. The initial mean perfusion pressures were same in both group. The result indicated that the EEP and the perfusion flow were increased significantly in the pulsatile group compared to the non-pulsatile group. Photographs taken during the decellularization showed more profound decellularization in the pulsatile group. The residual DNA content in the scaffolds was significantly lower in the pulsatile group. However, the level of ECM components, collagen and GAG showed no significant differences between the groups. CONCLUSIONS: Decellularization is more efficient in pulsatile flow than in non-pulsatile flow but still preserves the ECM molecules. PMID- 29391038 TI - Collecting verbal autopsies: improving and streamlining data collection processes using electronic tablets. AB - BACKGROUND: There is increasing interest in using verbal autopsy to produce nationally representative population-level estimates of causes of death. However, the burden of processing a large quantity of surveys collected with paper and pencil has been a barrier to scaling up verbal autopsy surveillance. Direct electronic data capture has been used in other large-scale surveys and can be used in verbal autopsy as well, to reduce time and cost of going from collected data to actionable information. METHODS: We collected verbal autopsy interviews using paper and pencil and using electronic tablets at two sites, and measured the cost and time required to process the surveys for analysis. From these cost and time data, we extrapolated costs associated with conducting large-scale surveillance with verbal autopsy. RESULTS: We found that the median time between data collection and data entry for surveys collected on paper and pencil was approximately 3 months. For surveys collected on electronic tablets, this was less than 2 days. For small-scale surveys, we found that the upfront costs of purchasing electronic tablets was the primary cost and resulted in a higher total cost. For large-scale surveys, the costs associated with data entry exceeded the cost of the tablets, so electronic data capture provides both a quicker and cheaper method of data collection. CONCLUSIONS: As countries increase verbal autopsy surveillance, it is important to consider the best way to design sustainable systems for data collection. Electronic data capture has the potential to greatly reduce the time and costs associated with data collection. For long-term, large-scale surveillance required by national vital statistical systems, electronic data capture reduces costs and allows data to be available sooner. PMID- 29391039 TI - Incidence of diabetes mellitus-related comorbidities among patients attending two major HIV clinics in Botswana: a 12-year retrospective cohort study. AB - OBJECTIVES: Exposure to combination antiretroviral therapy (cART) is associated with the development of diabetes mellitus related comorbidities (DRCs). This study aims to: (i) estimate the incidence of DRCs among cART recipients, (ii) assess the time-to-event (development of DRC) and, (iii) compare survival function between recipients on first-line regimen and those on second-, third line cART regimen. RESULTS: The incidence of DRCs was 26.8/1000 person-years, with total time of exposure of 3316 person-years. The average time to event for all the three regimens was 11.72 +/- 0.20 years. The first-line cART regimen had a shorter mean +/- SE of 10.59 +/- 0.26 years to the event compared to 12.69 +/- 0.24 years for the second-, third-line cART regimen. Recipients on the first-line had a shorter survival than recipients on second-, third-line cART (Log-rank X2 = 8.98, p < 0.003). Data from this study showed that the risk of developing DRCs per year of exposure was significantly greater for patients on first-line compared to those who were on second-, third-line regimen; which, suggests that monitoring of cART long-term side effects and regular reviewing of cART regimens is important. Meticulous selection of drug combinations is a key to improving recipients' survival. PMID- 29391040 TI - Antimicrobial susceptibility pattern, and associated factors of Salmonella and Shigella infections among under five children in Arba Minch, South Ethiopia. AB - BACKGROUND: Diarrheal diseases continue to be the major cause of morbidity and mortality among children under 5 years. Salmonella and Shigella specious are the major enteric pathogen causing diarrhea among children worldwide. Examination of stool sample is the most sensitive method to diagnose diarrheal disease in children. This study aimed to determining the prevalence, antimicrobial susceptibility pattern and associated factor of Salmonella and Shigella infection among under five children. METHODS: A cross sectional study was conducted on under 5 years children attending Arba Minch town. Pre-tested and structured questionnaire was used for collecting data about socio-demographic characteristics and associated factors. Stool sample was used to isolate and identified the pathogen. Antimicrobial susceptibility test was performed for isolated Salmonella and Shigella specious. A logistic regression analysis was used to see the association between different variables and outcome variable. Odds ratio with 95% CI was computed to determine the presence and strength of the association. RESULTS: A total of 167 under five children were included in the study. About 57% of participants were males with the mean age of 32 months. The overall prevalence of Salmonella and Shigella species infection was 17.45% with 12.6% Salmonella species. The isolates were resistant to common antibiotics such as Amoxicillin, Erythromycin, Chloramphenicol, Clindamycin, Norfloxacin, Ciprofloxacin, Cotrimoxazole, and Gentamycin. Urban resident [AOR = 7.11; 95% CI (2.3, 22.2)], month income < 1000 Ethiopian birr [AOR = 6.5; 95% CI (2.0, 21.4)], absence of waste disposal system [AOR = 3.3; 95% CI (1.2, 9.3)], poor hand washing habit [AOR = 6.0; 95% CI (2.0, 18.2)], untrimmed finger nail [AOR = 3.7; 95% CI (1.4, 10.6)], and use of napkin [AOR = 3.2; 95% CI (1.1, 9.3)] had significant association with Salmonella and Shigella infection. CONCLUSION: Salmonella and Shigella species infections were higher as compared the national prevalence. This study also revealed that the enteric infection were significantly associated with finger nail status, residence, hand washing practice, month income of parents, usage of napkin after toilet, and absence of waste disposal system. Therefore, working on identified associated factors and regular drug susceptibility test is mandatory to reduce the problem. PMID- 29391041 TI - Would the control of invasive alien plants reduce malaria transmission? A review. AB - Vector control has been the most effective preventive measure against malaria and other vector-borne diseases. However, due to concerns such as insecticide resistance and budget shortfalls, an integrated control approach will be required to ensure sustainable, long-term effectiveness. An integrated management strategy should entail some aspects of environmental management, relying on coordination between various scientific disciplines. Here, we review one such environmental control tactic: invasive alien plant management. This covers salient plant mosquito interactions for both terrestrial and aquatic invasive plants and how these affect a vector's ability to transmit malaria. Invasive plants tend to have longer flowering durations, more vigorous growth, and their spread can result in an increase in biomass, particularly in areas where previously little vegetation existed. Some invasive alien plants provide shelter or resting sites for adult mosquitoes and are also attractive nectar-producing hosts, enhancing their vectorial capacity. We conclude that these plants may increase malaria transmission rates in certain environments, though many questions still need to be answered, to determine how often this conclusion holds. However, in the case of aquatic invasive plants, available evidence suggests that the management of these plants would contribute to malaria control. We also examine and review the opportunities for large-scale invasive alien plant management, including options for biological control. Finally, we highlight the research priorities that must be addressed in order to ensure that integrated vector and invasive alien plant management operate in a synergistic fashion. PMID- 29391042 TI - Economic evaluations of lymphatic filariasis interventions: a systematic review and research needs. AB - In 2000, the World Health Organization established the Global Programme to Eliminate Lymphatic Filariasis (GPELF), with the goal of eliminating the disease as a public health problem by 2020. Since the start of the programme, a cumulative total of 6.2 billion treatments have been delivered to affected populations - with more than 556 million people treated in 2015 alone. In this paper, we perform a rigorous systematic review of the economic evaluations of lymphatic filariasis interventions have been conducted. We demonstrate that the standard interventions to control lymphatic filariasis are consistently found to be highly cost-effective. This finding has important implications for advocacy groups and potential funders. However, there are several important inconsistencies and research gaps that need to be addressed as we move forward towards the 2020 elimination goals. One of the most important identified research gaps was a lack of evaluation of new interventions specifically targeting areas co-endemic with onchocerciasis and Loa loa - which could become a major barrier to achieving elimination. PMID- 29391043 TI - Precise preoperative diagnosis of struma ovarii with pseudo-Meigs' syndrome mimicking ovarian cancer with the combination of 131I scintigraphy and 18F-FDG PET: case report and review of the literature. AB - BACKGROUND: Struma ovarii is a rare ovarian neoplasm that often appears malignant on conventional imaging. Pseudo-Meigs' syndrome with ascites, pleural effusion, and elevated serum CA 125 levels is much rarer and leads to misdiagnosis of ovarian cancer and unnecessary extended surgery. CASE PRESENTATION: A 50-year-old woman with abdominal distention and dyspnoea was referred to our hospital. Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed a polycystic ovarian tumor with a solid component, pleural effusion, and massive ascites with negative cytology. Her serum CA 125 level was 1237 U/ml, indicating the presence of ovarian cancer. Based on increased uptake of 131I but no uptake of 18F-FDG in the tumor, the preoperative diagnosis was struma ovarii with pseudo Meigs' syndrome, which was confirmed histologically. She had no evidence of ascites and pleural effusion six months after surgery. CONCLUSIONS: To date, there have been no systematic reviews focused on preoperative diagnosis with imaging modalities. The combination of 131I scintigraphy and 18F-FDG PET/CT in addition to conventional imaging modalities can provide the precise preoperative diagnosis of struma ovarii with pseudo-Meigs' syndrome mimicking ovarian cancer, leading to the appropriate treatment strategy. PMID- 29391044 TI - DeepARG: a deep learning approach for predicting antibiotic resistance genes from metagenomic data. AB - BACKGROUND: Growing concerns about increasing rates of antibiotic resistance call for expanded and comprehensive global monitoring. Advancing methods for monitoring of environmental media (e.g., wastewater, agricultural waste, food, and water) is especially needed for identifying potential resources of novel antibiotic resistance genes (ARGs), hot spots for gene exchange, and as pathways for the spread of ARGs and human exposure. Next-generation sequencing now enables direct access and profiling of the total metagenomic DNA pool, where ARGs are typically identified or predicted based on the "best hits" of sequence searches against existing databases. Unfortunately, this approach produces a high rate of false negatives. To address such limitations, we propose here a deep learning approach, taking into account a dissimilarity matrix created using all known categories of ARGs. Two deep learning models, DeepARG-SS and DeepARG-LS, were constructed for short read sequences and full gene length sequences, respectively. RESULTS: Evaluation of the deep learning models over 30 antibiotic resistance categories demonstrates that the DeepARG models can predict ARGs with both high precision (> 0.97) and recall (> 0.90). The models displayed an advantage over the typical best hit approach, yielding consistently lower false negative rates and thus higher overall recall (> 0.9). As more data become available for under-represented ARG categories, the DeepARG models' performance can be expected to be further enhanced due to the nature of the underlying neural networks. Our newly developed ARG database, DeepARG-DB, encompasses ARGs predicted with a high degree of confidence and extensive manual inspection, greatly expanding current ARG repositories. CONCLUSIONS: The deep learning models developed here offer more accurate antimicrobial resistance annotation relative to current bioinformatics practice. DeepARG does not require strict cutoffs, which enables identification of a much broader diversity of ARGs. The DeepARG models and database are available as a command line version and as a Web service at http://bench.cs.vt.edu/deeparg . PMID- 29391045 TI - Automated cell cycle and cell size measurements for single-cell gene expression studies. AB - OBJECTIVES: Recent rise of single-cell studies revealed the importance of understanding the role of cell-to-cell variability, especially at the transcriptomic level. One of the numerous sources of cell-to-cell variation in gene expression is the heterogeneity in cell proliferation state. In order to identify how cell cycle and cell size influences gene expression variability at the single-cell level, we provide an universal and automatic toxic-free label method, compatible with single-cell high-throughput RT-qPCR. The method consists of isolating cells after a double-stained, analyzing their morphological parameters and performing a transcriptomic analysis on the same identified cells. RESULTS: This led to an unbiased gene expression analysis and could be also used for improving single-cell tracking and imaging when combined with cell isolation. As an application for this technique, we showed that cell-to-cell variability in chicken erythroid progenitors was negligibly influenced by cell size nor cell cycle. PMID- 29391046 TI - Maternal and neonatal characteristics that influence very early neonatal mortality in the Eastern Regional Hospital of Ghana, Koforidua: a retrospective review. AB - OBJECTIVE: This study was conducted to determine the maternal and neonatal characteristics that influence very early neonatal mortality using 811 delivery records at the Eastern Regional Hospital of Ghana. RESULTS: The very early neonatal mortality rate was 9 per 1000 live births. Multi-parity reduced the odds of very early neonatal death by 30%. Mothers with a previous neonatal death had about 8 times the odds of having a very early neonatal death as compared to those without a history of neonatal death. PMID- 29391047 TI - Regulatory role of microRNA in mesenteric lymph nodes after Salmonella Typhimurium infection. AB - Salmonellosis is a gastrointestinal disease caused by non-typhoidal Salmonella serovars such as Salmonella Typhimurium. This pathology is a zoonosis, and food animals with subclinical infection constitute a vast reservoir for disease. After intestinal colonization, Salmonella Typhimurium reaches mesenteric lymph nodes (MLN), where infection is controlled avoiding systemic spread. Although the molecular basis of this infection has been extensively studied, little is known about how microRNA (miRNA) regulate the expression of proteins involved in the Salmonella-host interaction. Using small RNA-seq, we examined expression profiles of MLN 2 days after infection with Salmonella Typhimurium, and we found 110 dysregulated miRNA. Among them, we found upregulated miR-21, miR-155, miR-150, and miR-221, as well as downregulated miR-143 and miR-125, all of them previously linked to other bacterial infections. Integration with proteomic data revealed 30 miRNA potentially regulating the expression of 15 proteins involved in biological functions such as cell death and survival, inflammatory response and antigenic presentation. The inflammatory response was found increased via upregulation of miRNA such as miR-21 and miR-155. Downregulation of miR-125a/b, miR-148 and miR-1 were identified as potential regulators of MHC-class I components PSMB8, HSP90B1 and PDIA3, respectively. Furthermore, we confirmed that miR-125a is a direct target of immunoproteasome component PSMB8. Since we also found miR-130 downregulation, which is associated with upregulation of HSPA8, we suggest induction of both MHC-I and MHC-II antigen presentation pathways. In conclusion, our study identifies miRNA that could regulate critical networks for antigenic presentation, inflammatory response and cytoskeletal rearrangements. PMID- 29391048 TI - miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development. AB - BACKGROUND: Metastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs) are powerful posttranscriptional regulators of HMGA2. METHODS: The binding sites of miR-302a-5p and miR-367-3p on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-302a-5p and miR-367-3p were detected using quantitative real-time PCR and in situ hybridization. Western blotting and immunohistochemistry were used to detect the levels of HMGA2 and epithelial-mesenchymal transition pathway related proteins. Co-immunoprecipitation was used to detect protein interactions. The roles of miR-302a-5p and miR-367-3p in the regulation of HMGA2 during the progression of endometrial cancer were investigated using both in vitro and in vivo assays. RESULTS: In the present study, high HMGA2 expression was correlated with poor clinical outcomes in endometrial cancer. The binding sites of miRNAs on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. In the endometrial cancer cell lines Ishikawa and HEC-1A, the overexpression of miR-302a-5p/367-3p significantly inhibited the expression of HMGA2 mRNA. In endometrial cancer tissues, we showed that miR-302a 5p and miR-367-3p were significantly downregulated and thus inversely correlated with HMGA2. The miR-302a-5p and miR-367-3p expression levels were closely correlated with FIGO stage and lymph node metastasis. High expression of miR-302a 5p/367-3p was correlated with high survival rates in endometrial cancer. In addition, miR-302a-5p/367-3p suppressed the malignant behaviour of endometrial carcinoma cells via the inhibition of HMGA2 expression. CONCLUSION: Our findings indicate that miR-302a-5p/367-3p-mediated expression of HMGA2 regulates the malignant behaviour of endometrial carcinoma cells, which suggests that the miR 302a-5p/367-3p-HMGA2 axis may be a predictive biomarker of endometrial cancer metastasis and patient survival and a potential therapeutic target in metastatic endometrial cancer. PMID- 29391049 TI - Bone regeneration by human dental pulp stem cells using a helioxanthin derivative and cell-sheet technology. AB - BACKGROUND: Human dental pulp stem cells (DPSCs), which have the ability to differentiate into multiple lineages, were recently identified. DPSCs can be collected readily from extracted teeth and are now considered to be a type of mesenchymal stem cell with higher clonogenic and proliferative potential than bone marrow stem cells (BMSCs). Meanwhile, the treatment of severe bone defects, such as fractures, cancers, and congenital abnormalities, remains a great challenge, and novel bone regenerative techniques are highly anticipated. Several studies have previously shown that 4-(4-methoxyphenyl)pyrido[40,30:4,5]thieno[2,3 b]pyridine-2-carboxamide (TH), a helioxanthin derivative, induces osteogenic differentiation of preosteoblastic and mesenchymal cells. However, the osteogenic differentiation activities of TH have only been confirmed in some mouse cell lines. Therefore, in this study, toward the clinical use of TH in humans, we analyzed the effect of TH on the osteogenic differentiation of DPSCs, and the in vivo osteogenesis ability of TH-induced DPSCs, taking advantage of the simple transplantation system using cell-sheet technology. METHODS: DPSCs were obtained from dental pulp of the wisdom teeth of five healthy patients (18-22 years old) and cultured in regular medium and osteogenic medium with or without TH. To evaluate osteogenesis of TH-induced DPSCs in vivo, we transplanted DPSC sheets into mouse calvaria defects. RESULTS: We demonstrated that osteogenic conditions with TH induce the osteogenic differentiation of DPSCs more efficiently than those without TH and those with bone morphogenetic protein-2. However, regular medium with TH did not induce the osteogenic differentiation of DPSCs. TH induced osteogenesis in both DPSCs and BMSCs, although the gene expression pattern in DPSCs differed from that in BMSCs up to 14 days after induction with TH. Furthermore, we succeeded in bone regeneration in vivo using DPSC sheets with TH treatment, without using any scaffolds or growth factors. CONCLUSIONS: Our results demonstrate that TH-induced DPSCs are a useful cell source for bone regenerative medicine, and the transplantation of DPSC sheets treated with TH is a convenient scaffold-free method of bone healing. PMID- 29391050 TI - Hypoglycaemia without diabetes encountered by emergency medical services: a retrospective cohort study. AB - BACKGROUND: The current study investigates the incidence, aetiology, and outcome of hypoglycaemia of patients without diabetes in the EMS. METHODS: The study was a retrospective cohort study that utilized electronic EMS patient record system (population of one million). All patients encountered by EMS with plasma glucose <=3.9 mmol/l from 2009 to 2015 were included in the study and hospital records were screened manually to detect possible reasons for hypoglycaemia. Data from the governmental health insurance agency for all residents in Finland was used to reveal the diabetes status of the patients. Survival of the patients was followed from Population register centre up to six years. Serious hypoglycaemia was defined as plasma glucose <=3.0 mmol/l. RESULTS: From EMS cases with a plasma glucose measurement a total of 5467 hypoglycaemic patients without diabetes were encountered by EMS during the study period with an incidence of 1082 (CI95% 1019 1148) per 100,000 inhabitants per year, corresponding 41.6%, (CI95% 40.8-42.3) of all hypoglycaemic patients. Of those patients, 3856 [71.6%, (CI95% 70.4-72.8)] were transported to hospital and 910 [23.2%, (CI95% 22.0-24.6)] had serious hypoglycaemia. The three main diagnosis groups that appeared in the subsequent hospital treatment associated with hypoglycaemia in all transported cases without diabetes as well with serious hypoglycaemia cases were: alcohol abuse [41.2%, (CI95% 39.7-42.8) and 42.2%, (CI95% 39.0-45.4)], hypothermia [17.2%, (CI95% 16.0 18.4) and 27.4%, (CI95% 24.6-30.4)], and malnutrition [16.9%, (CI95% 15.8-18.1) and 25.1%, (CI95% 22.4-28.0)]. Mortality ranged from 0.6-65.4% depending of admission reason and increased significantly at long-term. Non-Diabetics survival was less than with diabetics, when serious hypoglycaemia was present. DISCUSSION: The most common possible hypoglycaemia related aetiological causes encountered in the EMS, alcohol abuse, hypothermia, and malnutrition, although frequent are often relatively benign conditions. These possible causes of hypoglycaemia can often be treated at scene or need only short hospital admissions. Hence they are not so prevalent in hospital studies. CONCLUSIONS: Hypoglycaemia without diabetes is commonly observed among the hypoglycaemic EMS cases. Main causes for it are alcohol abuse, hypothermia, and malnutrition. Mortality correlated with age, higher priority dispatch codes, and plasma glucose rate in multivariate logistic regression analysis. Some of the etiological subgroups carry a markedly high mortality rate. PMID- 29391052 TI - Loop-mediated isothermal amplification (LAMP) shield for Arduino DNA detection. AB - OBJECTIVE: Loop-mediated isothermal amplification (LAMP) of DNA is gaining relevance as a method to detect nucleic acids, as it is easier, faster, and more powerful than conventional Polymerase Chain Reaction. However, LAMP is still mostly used in laboratory settings, because of the lack of a cheap and easy, one button device that can perform LAMP experiments. RESULTS: Here we show how to build and program an Arduino shield for a LAMP and detection of DNA. The here described Arduino Shield is cheap, easy to assemble, to program and use, it is battery operated and the detection of DNA is done by naked-eye so that it can be used in field. PMID- 29391051 TI - Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial. AB - BACKGROUND: Community-acquired pneumonia (CAP) is commonly diagnosed in children. The Infectious Disease Society of America guidelines recommend 10 days of high dose amoxicillin for the treatment of non-severe CAP but 5-day "short course" therapy may be just as effective. Randomized trials in adults have already demonstrated non-inferiority of 5-day short-course treatment for adults hospitalized with severe CAP and for adults with mild CAP treated as outpatients. Minimizing exposure to antimicrobials is desirable to avoid harms including diarrhoea, rashes, severe allergic reactions, increased circulating antimicrobial resistance, and microbiome disruption. METHODS: The objective of this multicentre, randomized, non-inferiority, controlled trial is to investigate whether 5 days of high-dose amoxicillin is associated with lower rates of clinical cure 14-21 days later as compared to 10 days of high-dose amoxicillin, the reference standard. Recruitment and enrolment will occur in the emergency departments of McMaster Children's Hospital and the Children's Hospital of Eastern Ontario. All children in the study will receive 5 days of amoxicillin after which point they will receive either 5 days of a different formulation of amoxicillin or a placebo. Assuming a clinical failure rate of 5% in the reference arm, a non-inferiority margin of 7.5%, one-sided alpha set at 0.025 and power of 0.80, 270 participants will be required. Participants from a previous feasibility study (n = 60) will be rolled over into the current study. We will be performing multiplex respiratory virus molecular testing, quantification of nasopharyngeal pneumococcal genomic loads, salivary inflammatory marker testing, and faecal microbiome profiling on participants. DISCUSSION: This is a pragmatic study seeking to provide high-quality evidence for front-line physicians evaluating children presenting with mild CAP in North American emergency departments in the post-13-valent pneumococcal, conjugate vaccine era. High-quality evidence supporting the non-inferiority of short-course therapy for non-severe paediatric CAP should be generated prior to making changes to established guidelines. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02380352 . Registered on 2 March 2015. PMID- 29391053 TI - Oral immunization with a novel attenuated Salmonella Typhimurium encoding influenza HA, M2e and NA antigens protects chickens against H7N9 infection. AB - Attenuated Salmonella strains constitute a promising technology for the development of efficient protein-based influenza vaccines. H7N9, a low pathogenic avian influenza (LPAI) virus, is a major public health concern and currently there are no effective vaccines against this subtype. Herein, we constructed a novel attenuated Salmonella Typhimurium strain for the delivery and expression of H7N9 hemagglutinin (HA), neuraminidase (NA) or the conserved extracellular domain of the matrix protein 2 (M2e). We demonstrated that the constructed Salmonella strains exhibited efficient HA, NA and M2e expressions, respectively, and the constructs were safe and immunogenic in chickens. Our results showed that chickens immunized once orally with Salmonella (Sal) mutants encoding HA (Sal HA), M2e (Sal-M2e) or NA (Sal-NA), administered either alone or in combination, induced both antigen-specific humoral and cell mediated immune (CMI) responses, and protected chickens against the lethal H7N9 challenge. However, chickens immunized with Sal-HA+Sal-M2e+Sal-NA vaccine constructs exhibited efficient mucosal and CMI responses compared to the chickens that received only Sal-HA, Sal M2e or Sal-M2e+Sal-NA vaccine. Further, chickens immunized with Sal-HA+Sal M2e+Sal-NA constructs cleared H7N9 infection at a faster rate compared to the chickens that were vaccinated with Sal-HA, Sal-M2e or Sal-M2e+Sal-NA, as indicated by the reduced viral shedding in cloacal swabs of the immunized chickens. We conclude that this vaccination strategy, based on HA, M2e and NA, stimulated efficient induction of immune protection against the lethal H7N9 LPAI virus and, therefore, further studies are warranted to develop this approach as a potential prophylaxis against LPAI viruses affecting poultry birds. PMID- 29391054 TI - suPAR is associated with risk of future acute surgery and post-operative mortality in acutely admitted medical patients. AB - BACKGROUND: Acutely admitted medical patients are often fragile and in risk of future surgery. The biomarker soluble urokinase plasminogen activator receptor (suPAR) is a predictor of readmission and mortality in the acute care setting. We aimed to investigate if suPAR also predicts acute surgery, which is associated with higher mortality than elective surgery, and if it predicts post-operative mortality. METHODS: A retrospective registry-based cohort study of 17,312 patients admitted to an acute medical unit in Denmark, from 18 November 2013 until 30 September 2015. The first admission with available suPAR was defined as the index admission, and patients were followed via national registries until 1 January 2016. The risk of acute surgery during the entire follow-up period as well as the 90-day post-operative mortality risk was modeled by Cox regression analyses adjusted for sex, age, C-reactive protein, and Charlson Comorbidity Index (Charlson Score). RESULTS: Acute surgery was carried out on 2404 patients (13.9%) after a median of 45 days (interquartile range 5-186) following the index admission. Patients receiving acute surgery had higher baseline suPAR compared with patients receiving elective- or no surgery (p < 0.0001). The hazard ratio (HR) for acute surgery was 1.50 (95% confidence interval (CI): 1.42-1.59) for every doubling of the suPAR level in the adjusted Cox regression analysis. Death within 90 days occurred in 439 (18.3%) patients receiving acute surgery, and the adjusted HR for post-operative mortality was 1.73 (95% CI: 1.52-1.95). DISCUSSION: Elevated levels of suPAR in acutely admitted medical patients were independently associated with increased risk of future acute surgery as well as with 90-day post-operative mortality. TRIAL REGISTRATION: This retrospective registry-based cohort study was approved by the Danish Health and Medicines authority (reference no. 3-3013-1061/1). All processing of personal data followed national guidelines, and the project was approved by the Danish Data Protection Agency (reference no. HVH-2014-018, 02767). PMID- 29391056 TI - Geo-statistical analysis of Culicoides spp. distribution and abundance in Sicily, Italy. AB - BACKGROUND: Biting midges belonging to Culicoides imicola, Culicoides obsoletus complex and Culicoides pulicaris complex (Diptera: Ceratopogonidae) are increasingly implicated as vectors of bluetongue virus in Palaearctic regions. Culicoides obsoletus complex includes C. obsoletus (sensu stricto), C. scoticus, C. dewulfi and C. chiopterus. Culicoides pulicaris and C. lupicaris belong to the Culicoides pulicaris complex. The aim of this study was a geo-statistical analysis of the abundance and spatial distribution of Culicoides spp. involved in bluetongue virus transmission. As part of the national bluetongue surveillance plan 7081 catches were collected in 897 Sicilian farms from 2000 to 2013. METHODS: Onderstepoort-type blacklight traps were used for sample collection and each catch was analysed for the presence of Culicoides spp. and for the presence and abundance of Culicoides vector species (C. imicola, C. pulicaris / C. obsoletus complexes). A geo-statistical analysis was carried out monthly via the interpolation of measured values based on the Inverse Distance Weighted method, using a GIS tool. Raster maps were reclassified into seven classes according to the presence and abundance of Culicoides, in order to obtain suitable maps for Map Algebra operations. RESULTS: Sicilian provinces showing a very high abundance of Culicoides vector species were Messina (80% of the whole area), Palermo (20%) and Catania (12%). A total of 5654 farms fell within the very high risk area for bluetongue (21% of the 26,676 farms active in Sicily); of these, 3483 farms were in Messina, 1567 in Palermo and 604 in Catania. Culicoides imicola was prevalent in Palermo, C. pulicaris in Messina and C. obsoletus complex was very abundant over the whole island with the highest abundance value in Messina. CONCLUSIONS: Our study reports the results of a geo-statistical analysis concerning the abundance and spatial distribution of Culicoides spp. in Sicily throughout the fourteen year study. It provides useful decision support in the field of epidemiology, allowing the identification of areas to be monitored as bases for improved surveillance plans. Moreover, this knowledge can become a tool for the evaluation of virus transmission risks, especially if related to vector competence. PMID- 29391055 TI - She knows that she will not come back: tracing patients and new thresholds of collective surveillance in PMTCT Option B. AB - BACKGROUND: Malawi, Uganda, and Zimbabwe have recently adopted a universal 'test and-treat' approach to the prevention of mother-to-child transmission of HIV (Option B+). Amongst a largely asymptomatic population of women tested for HIV and immediately started on antiretroviral treatment (ART), a relatively high number are not retained in care; they are labelled 'defaulters' or 'lost-to follow-up' patients. METHODS: We draw on data collected as part of a study looking at ART decentralization (Lablite) to reflect on the spaces created through the instrumentalization of community health workers (CHWs) for the purpose of bringing women who default from Option B+ back into care. Data were collected through semi-structured interviews with CHWs who are designated to trace Option B+ patients in Uganda, Malawi and Zimbabwe. FINDINGS: Lost to follow up women give a range of reasons for not coming back to health facilities and often implicitly choose not to be traced by providing a false address at enrolment. New strategies have sought to utilize CHWs' liminal positionality - situated between the experience of living with HIV, having established local social ties, and being a caretaker - in order to track 'defaulters'. CHWs are often deployed without adequate guidance or training to protect confidentiality and respect patients' choice. CONCLUSIONS: CHWs provide essential linkages between health services and patients; they embody the role of 'extension workers', a bridge between a novel health policy and 'non-compliant patients'. Option B+ offers a powerful narrative of the construction of a unilateral 'moral economy', which requires the full compliance of patients newly initiated on treatment. PMID- 29391057 TI - A human gut phage catalog correlates the gut phageome with type 2 diabetes. AB - BACKGROUND: Substantial efforts have been made to link the gut bacterial community to many complex human diseases. Nevertheless, the gut phages are often neglected. RESULTS: In this study, we used multiple bioinformatic methods to catalog gut phages from whole-community metagenomic sequencing data of fecal samples collected from both type II diabetes (T2D) patients (n = 71) and normal Chinese adults (n = 74). The definition of phage operational taxonomic units (pOTUs) and identification of large phage scaffolds (n = 2567, >= 10 k) revealed a comprehensive human gut phageome with a substantial number of novel sequences encoding genes that were unrelated to those in known phages. Interestingly, we observed a significant increase in the number of gut phages in the T2D group and, in particular, identified 7 pOTUs specific to T2D. This finding was further validated in an independent dataset of 116 T2D and 109 control samples. Co occurrence/exclusion analysis of the bacterial genera and pOTUs identified a complex core interaction between bacteria and phages in the human gut ecosystem, suggesting that the significant alterations of the gut phageome cannot be explained simply by co-variation with the altered bacterial hosts. CONCLUSIONS: Alterations in the gut bacterial community have been linked to the chronic disease T2D, but the role of gut phages therein is not well understood. This is the first study to identify a T2D-specific gut phageome, indicating the existence of other mechanisms that might govern the gut phageome in T2D patients. These findings suggest the importance of the phageome in T2D risk, which warrants further investigation. PMID- 29391058 TI - Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations. AB - OBJECTIVE: Marijuana (Cannabis spp.) growing operations (MGO) in California have increased substantially since the mid-1990s. One environmental side-effect of MGOs is the extensive use of anticoagulant rodenticides (AR) to prevent damage to marijuana plants caused by wild rodents. In association with a long-term demographic study, we report on an observation of brodifacoum AR exposure in a threatened species, the northern spotted owl (Strix occidentalis caurina), found freshly dead within 669-1347 m of at least seven active MGOs. RESULTS: Liver and blood samples from the dead northern spotted owl were tested for 12 rodenticides. Brodifacoum was the only rodenticide detected in the liver (33.3-36.3 ng/g) and blood (0.48-0.54 ng/ml). Based on necropsy results, it was unclear what role brodifacoum had in the death of this bird. However, fatal AR poisoning has been previously reported in owls with relatively low levels of brodifacoum residues in the liver. One likely mechanism of AR transmission from MGOs to northern spotted owls in California is through ingestion of AR contaminated prey that frequent MGOs. The proliferation of MGOs with their use of ARs in forested landscapes used by northern spotted owls may pose an additional stressor for this threatened species. PMID- 29391059 TI - Strategies for improving the lives of US women aged 40 and above living with HIV/AIDS: an evidence map. AB - BACKGROUND: While in its early years the HIV epidemic affected primarily the male and the young, nowadays, the population living with HIV/AIDS is approximately 24% women, and its age composition has shifted towards older ages. Many of the older women who live with HIV/AIDS also live with the medical and social conditions that accompany aging. This work aims to identify and characterize empirical studies of strategies for the comprehensive management of women over 40, including transgender women, who live with HIV/AIDS. Forty was chosen as an operational age cutoff to identify premenopausal women who are less likely to bear children, as well as peri- and postmenopausal women. METHODS: We conducted a literature search after discussions with a diverse panel of content experts and other stakeholders and developed an evidence map that identified 890 citations that address questions having to do with programs and barriers to engaging with programs, as well as the role of insurance and comorbidities, and have enrolled older women who live with HIV/AIDS. RESULTS: Of these, only 37 (4%) reported results of interest for women over 40 who live with HIV/AIDS, or examined interactions between gender and older age that would allow predictions in this subgroup. Few of the 37 eligible studies focused on women facing obvious challenges, such as immigrants, transgender, physically abused, or those recently released from prison. No studies focused on women caring for dependents, including children and grandchildren, or those diagnosed after age 40. CONCLUSION: The evidence base that is directly applicable to women over 40 who live with HIV/AIDS in the USA is limited, and the research need is broad. We propose research prioritization strategies for this population. PMID- 29391060 TI - Inferring ecological explanations for biogeographic boundaries of parapatric Asian mountain frogs. AB - BACKGROUND: Identifying and understanding the mechanisms that shape barriers to dispersal and resulting biogeographic boundaries has been a longstanding, yet challenging, goal in ecology, evolution and biogeography. Characterized by stable, adjacent ranges, without any intervening physical barriers, and limited, if any, range overlap in a narrow contact zone, parapatric species are an interesting system for studying biogeographic boundaries. The geographic ranges of two parapatric frog species, Feirana quadranus and F. taihangnica, meet in a contact zone within the Qinling Mountains, an important watershed for East Asia. To identify possible ecological determinants of the parapatric range boundaries for two closely related frog species, we quantified the extent of their niche differentiation in both geographical and environmental space combining ecological niche models with an ordination technique. We tested two alternative null hypotheses (sharp environmental gradients versus a ribbon of unsuitable habitat dividing two highly suitable regions) for biogeographic boundaries, against the null expectation that environmental variation across a given boundary is no greater than expected by chance. RESULTS: We found that the niches of these two parapatric species are more similar than expected by chance, but not equivalent. No sharp environmental gradient was found, while a ribbon of unsuitable habitat did act as a barrier for F. quadranus, but not for F. taihangnica. CONCLUSIONS: Integrating our findings with historical biogeographic information, our results suggest that at a contact zone, environmental tolerance restricted F. quadranus from dispersing further north, while interspecific competition most likely prevented the southward expansion of F. taihangnica. This study highlights the importance of both climate and competition in exploring ecological explanations for parapatric range boundaries between ecologically similar frog species, in particular under the effects of changing climate. PMID- 29391061 TI - The role of HFE genotype in macrophage phenotype. AB - BACKGROUND: Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein alters cellular iron homeostasis and is associated with a number of neurological diseases and cancer. In the brain, microglial and infiltrating macrophages are critical to maintaining iron homeostasis and modulating inflammation associated with the pathogenic process in multiple diseases. This study addresses whether HFE genotype affects macrophage function and the implications of these findings for disease processes. METHODS: Bone marrow macrophages were isolated from wildtype and H67D HFE knock in mice. The H67D gene variant in mice is the human equivalent of the H63D variant. Upon differentiation, the macrophages were used to analyze iron regulatory proteins, cellular iron release, migration, phagocytosis, and cytokine expression. RESULTS: The results of this study demonstrate that the H67D HFE genotype significantly impacts a number of critical macrophage functions. Specifically, fundamental activities such as proliferation in response to iron exposure, L-ferritin expression in response to iron loading, secretion of BMP6 and cytokines, and migration and phagocytic activity were all found to be impacted by genotype. Furthermore, we demonstrated that exposure to apo-Tf (iron poor transferrin) can increase the release of iron from macrophages. In normal conditions, 70% of circulating transferrin is unsaturated. Therefore, the ability of apo-Tf to induce iron release could be a major regulatory mechanism for iron release from macrophages. CONCLUSIONS: These studies demonstrate that the HFE genotype impacts fundamental components of macrophage phenotype that could alter their role in degenerative and reparative processes in neurodegenerative disorders. PMID- 29391062 TI - Genotoxicity evaluation of So-ochim-tang-gamibang (SOCG), a herbal medicine. AB - BACKGROUND: So-ochim-tang-gamibang (SOCG) is a traditional Korean medicine frequently used for depression in the clinical field. In this study, we evaluated the potential genotoxicity of SOCG using three standard batteries of tests as part of a safety evaluation. METHODS: SOCG was evaluated for potential genotoxic effects using the standard three tests recommended by the Ministry of Food and Drug Safety (MFDS) of Korea. These tests were the bacterial reverse mutation test (Ames test), in vitro mammalian chromosomal aberration test using Chinese hamster lung cells, and in vivo micronucleus test using ICR mice. RESULTS: The Ames test with Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 and the Escherichia coli strain WP2uvrA(pKM101) showed that SOCG did not induce gene mutations at any dose level in all of the strains. SOCG did not induce any chromosomal aberrations in the in vitro chromosomal aberration test (for both the 6 and 24 h test) and the in vivo micronucleus test. CONCLUSIONS: Based on the results of these tests, it was concluded that SOCG does not exhibit any genotoxic risk under the experimental conditions of this study. PMID- 29391063 TI - Permissive weight bearing in trauma patients with fracture of the lower extremities: prospective multicenter comparative cohort study. AB - BACKGROUND: The standard aftercare treatment in surgically treated trauma patients with fractures around or in a joint, known as (peri)- or intra-articular fractures of the lower extremities, is either non-weight bearing or partial weight bearing. We have developed an early permissive weight bearing post-surgery rehabilitation protocol in surgically treated patients with fractures of the lower extremities. In this proposal we want to compare our early permissive weight bearing protocol to the existing current non-weight bearing guidelines in a prospective comparative cohort study. METHODS/DESIGN: The study is a prospective multicenter comparative cohort study in which two rehabilitation aftercare treatments will be contrasted, i.e. permissive weight bearing and non weight bearing according to the AO-guideline. The study population consists of patients with a surgically treated fracture of the pelvis/acetabulum or a surgically treated (peri)- or intra-articular fracture of the lower extremities. The inclusion period is 12 months. The duration of follow up is 6 months, with measurements taken at baseline, 2,6,12 and 26 weeks post-surgery. PRIMARY OUTCOME MEASURE: ADL with Lower Extremity Functional Scale. Outcome variables for compliance, as measured with an insole pressure measurement system, encompass peak load and step duration. DISCUSSION: This study will investigate the (cost-) effectiveness of a permissive weight bearing aftercare protocol. The results will provide evidence whether a permissive weight bearing protocol is more effective than the current non-weight bearing protocol. TRIAL REGISTRATION: The study is registered in the Dutch Trial Register ( NTR6077 ). Date of registration: 01-09 2016. PMID- 29391064 TI - Cost-effectiveness analysis of metformin+dipeptidyl peptidase-4 inhibitors compared to metformin+sulfonylureas for treatment of type 2 diabetes. AB - BACKGROUND: Patients with type 2 diabetes (T2D) typically use several drug treatments during their lifetime. There is a debate about the best second-line therapy after metformin monotherapy failure due to the increasing number of available antidiabetic drugs and the lack of comparative clinical trials of secondary treatment regimens. While prior research compared the cost effectiveness of two alternative drugs, the literature assessing T2D treatment pathways is scarce. The purpose of this study was to evaluate the long-term cost effectiveness of dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) as second-line therapy in combination with metformin in patients with T2D. METHODS: A Markov model was developed with four health states, 1 year cycle, and a 25-year time horizon. Clinical and cost data were collected from previous studies and other readily available secondary data sources. The incremental cost-effectiveness ratio (ICER) was estimated from the US third party payer perspective. Both, costs and outcomes, were discounted at a 3% annual discount rate. One way and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainty on the base-case results. RESULTS: The discounted incremental cost of metformin+DPP-4i compared to metformin+SU was $11,849 and the incremental life-years gained were 0.61, resulting in an ICER of $19,420 per life-year gained for patients in the metformin+DPP-4i treatment pathway. The ICER estimated in the probabilistic sensitivity analysis was $19,980 per life-year gained. Sensitivity analyses showed that the results of the study were not sensitive to changes in the parameters used in base-case. CONCLUSIONS: The metformin+DPP-4i treatment pathway was cost-effective compared to metformin+SU as a long-term second-line therapy in the treatment of T2D from the US health care payer perspective. Study findings have the potential to provide clinicians and third party payers valuable evidence for the prescription and utilization of cost-effective second-line therapy after metformin monotherapy failure in the treatment of T2D. PMID- 29391065 TI - Comparison of lipid profiles and inflammation in pre- and post-menopausal women with cerebral infarction and the role of atorvastatin in such populations. AB - BACKGROUND: The risks of atherosclerotic cardiovascular and cerebrovascular diseases in women rapidly increase with age in post-menopausal women. We aimed to investigate the lipid profiles in peri-menopausal women with cerebral infarction and to explore the effects of atorvastatin intervention. METHODS: We collected women aged 40-60 with cerebral infarction between January 2013 and December 2016. Atorvastatin was applied for 6 months in all included patients. Blood lipid profiles, serum pro-inflammation cytokines, intracranial plaque and NIH stroke scale (NIHSS) scores were evaluated before and after atorvastatin treatment. RESULTS: Totally 210 patients were included. Before atorvastatin treatment, post menopausal patients had significantly higher levels of triglyceride, cholesterol, low-density lipoprotein and a reduced level of high-density lipoprotein than those in pre-menopausal patients. Blood levels of pro-inflammatory cytokines including interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha were higher in post-menopausal patients, who had larger intracranial plaques than pre-menopausal patients. Consistently, post-menopausal patients had higher NIHSS scores than pre menopausal ones. Atorvastatin reduced NIHSS scores and improved dyslipidemia in patients and eliminated the differences of these parameters between pre- and post menopausal patients. CONCLUSIONS: Post-menopausal patients were severer than pre menopausal patients in terms of dyslipidemia, systemic inflammation and NIHSS scores. Atorvastatin may be beneficial for women with cerebral infarction. PMID- 29391066 TI - Recombinant chicken interleukin-7 as a potent adjuvant increases the immunogenicity and protection of inactivated infectious bursal disease vaccine. AB - Our previous work showed that a plasmid-based chicken interleukin-7 (chIL-7) gene expression vector possessed potent adjuvant activity for a VP2 DNA vaccine against chicken infectious bursal disease virus (IBDV). Whether recombinant chIL 7 prepared in procaryotic expression system has the adjuvant activity for inactivated IBDV vaccine remains unknown. Here, we prepared recombinant chIL-7 using an E. coli expression system and analyzed its adjuvant activity for the inactivated IBDV vaccine. The results show that the recombinant chIL-7 was successfully prepared in E. coli using the pET20b vector, which possessed biological activity to stimulate mouse B lymphocyte proliferation. Co administration of the chIL-7 with inactivated IBDV vaccine significantly increased specific serum antibody titers against IBDV, enhanced lymphocyte proliferation and IFN-gamma and IL-4 productions, and increased protection against virulent IBDV infection. PMID- 29391067 TI - LncRNA HOTAIR promotes cell migration and invasion by regulating MKL1 via inhibition miR206 expression in HeLa cells. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a new and crucial layer of gene regulation in recent years and regulate various biological processes such as carcinogenesis and metastasis. LncRNA HOTAIR, an oncogenic lncRNA, is involved in human tumorigenesis and dysregulated in cervical cancer. Megakaryoblastic leukemia 1 (MKL1), as a transcription coactivity factor, involved in cancer metastasis and cell differentiation. However, the precise mechanism of biological roles of HOTAIR and MKL1 in cancer cells remain unclear. METHODS: The expression levels of HOTAIR and MKL1 were measured by quantitative PCR (qPCR), immunoblotting, in situ hybridization (ISH) and immunohistochemistry (IHC). Wound-healing and transwell assays were used to examine the invasive abilities of HeLa cells. Luciferase reporter assays and CHIP were used to determine how MKL1 regulates HOTAIR. Tissue microarray and immunohistochemical staining were used to assess the correlation between HOTAIR and MKL1 in Cervical cancer tissues in vivo. RESULT: In this study, we have identified that MKL1 had a role in the induction of migration and invasion in cervical cancer cells. Moreover, the expression level of MKL1, as the targeting gene of miR206, was decreased after HOTAIR inhibition in HeLa cells. Agreement with it, Highly level of MKL1 correlation with HOTAIR is validated in cervical cancer tissues. Importantly, HOTAIR is observed to participate in the silencing of miR206 expression. Interestingly, HOTAIR inhibition could also accelerate the expression of MKL1 in cytoplasm. What is more, MKL1 can activate the transcription of HOTAIR through binding the CArG box in the promoter of HOTAIR. CONCLUSION: These elucidates that the phenotypic effects of migration and invasion observed after HOTAIR inhibition, at least in part, through the regulation of MKL1 via inhibition of miR206 expression in HeLa cells. These data indicate the existence of a positive feedback loop between HOTAIR and MKL1. Together, these findings suggest that MKL1 is an important player in the functions of HOTAIR in the migration and invasion of cancer cells. PMID- 29391068 TI - Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources? AB - BACKGROUND: Humans are exposed to poly- and perfluoroalkyl substances (PFASs) from diverse sources and this has been associated with negative health impacts. Advances in analytical methods have enabled routine detection of more than 15 PFASs in human sera, allowing better profiling of PFAS exposures. The composition of PFASs in human sera reflects the complexity of exposure sources but source identification can be confounded by differences in toxicokinetics affecting uptake, distribution, and elimination. Common PFASs, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and their precursors are ubiquitous in multiple exposure sources. However, their composition varies among sources, which may impact associated adverse health effects. METHODS: We use available PFAS concentrations from several demographic groups in a North Atlantic seafood consuming population (Faroe Islands) to explore whether chemical fingerprints in human sera provide insights into predominant exposure sources. We compare serum PFAS profiles from Faroese individuals to other North American populations to investigate commonalities in potential exposure sources. We compare individuals with similar demographic and physiological characteristics and samples from the same years to reduce confounding by toxicokinetic differences and changing environmental releases. RESULTS: Using principal components analysis (PCA) confirmed by hierarchical clustering, we assess variability in serum PFAS concentrations across three Faroese groups. The first principal component (PC)/cluster consists of C9-C12 perfluoroalkyl carboxylates (PFCAs) and is consistent with measured PFAS profiles in consumed seafood. The second PC/cluster includes perfluorohexanesulfonic acid (PFHxS) and the PFOS precursor N-ethyl perfluorooctane sulfonamidoacetate (N-EtFOSAA), which are directly used or metabolized from fluorochemicals in consumer products such as carpet and food packaging. We find that the same compounds are associated with the same exposure sources in two North American populations, suggesting generalizability of results from the Faroese population. CONCLUSIONS: We conclude that PFAS homologue profiles in serum provide valuable information on major exposure sources. It is essential to compare samples collected at similar time periods and to correct for demographic groups that are highly affected by differences in physiological processes (e.g., pregnancy). Information on PFAS homologue profiles is crucial for attributing adverse health effects to the proper mixtures or individual PFASs. PMID- 29391070 TI - Impact of meteorological factors on the incidence of childhood hand, foot, and mouth disease (HFMD) analyzed by DLNMs-based time series approach. AB - BACKGROUND: Hand, foot, and mouth disease (HFMD) has become an emerging infectious disease in China in the last decade. There has been evidence that meteorological factors can influence the HFMD incidence, and understanding the mechanisms can help prevent and control HFMD. METHODS: HFMD incidence data and meteorological data in Minhang District, Shanghai were obtained for the period between 2009 and 2015. Distributed lag non-linear models (DLNMs) were utilized to investigate the impact of meteorological factors on HFMD incidence after adjusting for potential confounders of long time trend, weekdays and holidays. RESULTS: There was a non-linear relationship between temperature and HFMD incidence, the RR of 5th percentile compared to the median is 0.836 (95% CI: 0.671-1.042) and the RR of 95th percentile is 2.225 (95% CI: 1.774-2.792), and the effect of temperature varied across age groups. HFMD incidence increased with increasing average relative humidity (%) (RR = 1.009, 95% CI: 1.005-1.015) and wind speed (m/s) (RR = 1.197, 95% CI: 1.118-1.282), and with decreasing daily rainfall (mm) (RR = 0.992, 95% CI: 0.987-0.997) and sunshine hours (h) (RR = 0.966, 95% CI: 0.951-0.980). CONCLUSIONS: There were significant relationships between meteorological factors and childhood HFMD incidence in Minhang District, Shanghai. This information can help local health agencies develop strategies for the control and prevention of HFMD under specific climatic conditions. PMID- 29391069 TI - Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment. AB - BACKGROUND: Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7-24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. RESULTS: Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-alpha are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. CONCLUSIONS: Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis. PMID- 29391072 TI - Endoscopic examination of labial fusion in a postmenopausal woman: a case report. AB - BACKGROUND: Labial fusion is defined as adhesions of the labia minora or majora. Labial fusion may cause urinary retention. Surgical treatment based on an accurate anatomic assessment may be needed, but the usefulness of endoscopic examination for this disease has not been reported. CASE PRESENTATION: A 76-year old Japanese woman undergoing chemoradiation treatment for esophageal cancer was referred to our department for evaluation of high accumulation in the vagina on a positron emission tomography scan. On physical examination, her labia were noted to be extensively fused with a pinhole opening at the midline. Endoscopic examination revealed that her vagina was filled with urine and there were no abnormalities in her urethral meatus and cervix. The adhesions were separated under anesthesia and there has been no recurrence during follow-up. CONCLUSIONS: We present a case of a postmenopausal patient with labial fusion who underwent successful surgical management. An endoscopic examination enabled us to determine the precise anatomic position and adopt a safe surgical procedure. PMID- 29391071 TI - Natural vertical transmission of dengue virus in Aedes aegypti and Aedes albopictus: a systematic review. AB - Dengue is of great concern in various parts of the world, especially in tropical and subtropical countries where the mosquito vectors Aedes aegypti and Aedes albopictus are present. The transmission of this virus to humans, by what is known as horizontal transmission, occurs through the bite of infected females of one or other of the two mosquito species. Furthermore, an infected female or male parent, by what is known as vertical transmission, can transfer this arbovirus to some part of their offspring. Considering that vertical transmission may represent an important strategy for maintaining the circulation of arboviruses in nature, the verification of this phenomenon worldwide is extremely important and necessary to better understand its dynamic. In the present study, we conducted a literature review of the presence of natural vertical transmission of dengue virus in Ae. aegypti and Ae. albopictus worldwide. Searches were conducted in MEDLINE, sciELO and Lilacs and all the studies published in Portuguese, English and Spanish were read, evaluated and organized by mosquito species, serotype and the location at which the samples were collected. Forty-two studies were included in accordance with the exclusion criteria and methodology. The presence of natural vertical transmission in Ae. aegypti and Ae. albopictus was most clearly evidenced by dengue virus in endemic countries, especially in those in South America and Asia. Despite several African countries being considered endemic for dengue, there is a lack of publications on this subject on that continent, which highlights the importance of conducting studies there. Furthermore, the finding of natural vertical transmission in Ae. albopictus in countries where this species is not yet incriminated as a vector is of great concern as it demonstrates the circulation of this virus in populations of Ae. albopictus and alerts to the possibility of some other mosquito species playing a role in the transmission dynamics of this arbovirus. Parallel to this, the small number of studies of natural vertical transmission of chikungunya and Zika virus in the world may be explained by the recent entry of these arboviruses into most of the countries concerned. PMID- 29391074 TI - Seizures and Choice of Antiepileptic Drugs Following Subarachnoid Hemorrhage: A Review. AB - Seizures are important complications following a subarachnoid hemorrhage (SAH). The evidence for the use of antiepileptic drugs (AEDs) in treatment and prevention of those seizures is conflicting. The purpose of this review is to provide an up-to-date evidence summary of the incidence and outcomes of seizures following an SAH as well as the use of different AEDs post-SAH in order to evaluate the need for seizure prophylaxis, the choice of AEDs, and their dosing considerations in SAH patients. A literature search of PubMed, Medline, Embase, and the Cochrane Library was performed. A total of 37 studies were reviewed, mostly observational. Definitions of seizures in temporal relation to initial hemorrhage were variable. Similarly, the rates of seizures varied in the literature, ranging from 0 to 31%. Given the reported adverse outcomes associated with AED usage, seizure prophylaxis is not warranted. Levetiracetam appears to be better tolerated than phenytoin in SAH patients, though further research is needed. Higher initial dosing of levetiracetam might be required due to its enhanced clearance in SAH patients. In conclusion, there is a lack of quality evidence to definitively recommend the use of one AED over another. Further prospective research comparing the use of different AEDs in patients with an SAH is needed. PMID- 29391073 TI - Effects of temperature on Veronaea botryosa infections in white sturgeon Acipenser transmontanus and fungal induced cytotoxicity of fish cell lines. AB - Veronaea botryosa is a melanized mold and cause of systemic fungal infections in cultured sturgeon (Acipenser spp.). Mortality in adult female sturgeon caused by this emergent pathogen results in significant economic losses for the caviar industry. Little is known regarding environmental conditions conducive to V. botryosa infection. This study evaluated the effect of temperature on V. botryosa infectivity and dissemination following intramuscular injection challenge of white sturgeon maintained at 13 or 18 degrees C for 40 days. Daily mortality was recorded and persistence of the fungus in the livers of moribund and surviving fish was investigated using culture and histopathological analysis. Fish maintained at 18 degrees C developed systemic phaeohyphomycosis and had significantly greater mortality than controls and fish maintained at 13 degrees C (p < 0.05). Challenged fish, regardless of temperature, exhibited lesions in multiple organs. However, muscle lesions, angioinvasion, and systemic dissemination were more severe and widespread in fish challenged at the higher temperature. In vitro cytotoxicity of V. botryosa was evaluated in white sturgeon skin (WSSK-1) and epithelioma papulosum cyprini (EPC) cell lines inoculated at spore:cell ratios of 1:10, 1:1 and 10:1, then incubated 15, 20 and 25 degrees C. Cytotoxicity, as indicated by quantifying the release of lactate dehydrogenase into culture supernatants, increased with increasing spore dose and incubation temperature in both fish cell lines. Findings suggest that temperature significantly influences the development of systemic V. botryosa infection in white sturgeon and that WSSK-1 and EPC cells are suitable in vitro models for the study of host-pathogen interactions between V. botryosa and fish epithelial cells. PMID- 29391075 TI - Health and Community-Based Services for Individuals with Neurological Conditions. AB - BACKGROUND: The current study involves a national survey of healthcare providers who offer services for individuals with a variety of neurological conditions. It aims to describe the provision of health and community-based services as well as the admission criteria, waitlist practices, and referral sources of these services. METHODS: An online survey was directed at administrators/managers from publicly funded hospital programs, long-term care homes, and community-based healthcare provider agencies that were believed to be providing information and/or services to patients with a variety of neurological conditions. RESULTS: Approximately 60% (n=254) of respondents reported providing services in either urban/suburban areas or rural/remote areas only, whereas the remaining 40% (n=172) provided services regardless of patient location. A small proportion of respondents reported providing services for individuals with dystonia (28%), Tourette syndrome (17%), and Rett syndrome (13%). There was also a paucity of diverse healthcare professionals across all institutions, but particularly mental healthcare professionals in hospitals. Lastly, the majority of respondents reported numerous exclusion criteria with regard to service provision, including prevalent comorbid conditions. CONCLUSIONS: If the few services provided for these neurological patient populations exclude common comorbidities, it is likely that there will be no other place for these individuals to seek care. PMID- 29391076 TI - Gamunex(r) in Guillain-Barre Syndrome: A Postmarketing, Retrospective, Observational Study. AB - BACKGROUND: The objective of this retrospective study was to evaluate the effectiveness and safety of Gamunex(r) (immune globulin [human] 10%; hereinafter "Gamunex") when administered intravenously in the initial treatment of Guillain Barre syndrome (GBS). The study was conducted as a postapproval commitment for Health Canada. METHODS: A medical chart review for hospitalized patients diagnosed with GBS and treated with Gamunex (Gamunex 10% and IGIVnex(r) 10%; N=109; n=69 evaluable) was conducted at seven Canadian study centers in reverse chronological order. The primary endpoint for assessing effectiveness was the proportion of patients with treatment success compared with a prospectively defined historical effectiveness threshold for plasma exchange (PE) treatment (55.05%). Treatment success was assessed as >=1 point improvement from baseline on the GBS Disability Scale or abbreviated GBS Disability Scale. Cases were not evaluable if treatment success, relapse, or treatment failure could not be determined by the available chart data. RESULTS: Applying a conservative estimate with all nonevaluable patients (n= 40) classified as treatment failures, Gamunex treatment success was estimated at 57.8% (63 of 109 patients), which exceeded the predefined historical PE effectiveness threshold. In the evaluable population of this study, Gamunex treatment was successful in 91.3% of patients (63/69). Some 23 (21.1%) of 109 Gamunex-treated patients experienced >=1 adverse event; the profile and frequency were consistent with the adverse events reported for Gamunex in the product's labeling and with the natural clinical course of GBS. CONCLUSIONS: The effectiveness of Gamunex for treatment of GBS was comparable to PE therapy. Gamunex was observed to have an acceptable safety profile in this study population. PMID- 29391077 TI - Cerebral Manifestations of Mitochondrial Disorders. AB - This review aims at summarizing and discussing previous and recent findings concerning the cerebral manifestations of mitochondrial disorders (MIDs). MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) either already at onset or later in the course. After the muscle, the brain is the organ second most frequently affected in MIMODS. Cerebral manifestations of MIDs are variable and may present with or without a lesion on imaging or functional studies, but there can be imaging/functional lesions without clinical manifestations. The most well-known cerebral manifestations of MIDs include stroke-like episodes, epilepsy, headache, ataxia, movement disorders, hypopituitarism, muscle weakness, psychiatric abnormalities, nystagmus, white and gray matter lesions, atrophy, basal ganglia calcification, and hypometabolism on 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron-emission tomography. For most MIDs, only symptomatic therapy is currently available. Symptomatic treatment should be supplemented by vitamins, cofactors, and antioxidants. In conclusion, cerebral manifestations of MIDs need to be recognized and appropriately managed because they strongly determine the outcome of MID patients. PMID- 29391078 TI - Prescribing Pattern for Parkinson's Disease in Indian Community before Referral to Tertiary Center. AB - BACKGROUND: Several factors determine the choice of medications in patients with Parkinson's disease (PD). We aimed to analyze the pattern of prescription of drugs in patients with PD before attending a tertiary-care center. METHODS: The study included chart review of 800 PD patients attending the Department of Neurology of the National Institute of Mental Health and Neurosciences in Bangalore, India. RESULTS: The mean age at onset was 51.1+/-11.8 years. The mean duration of illness was 41.7+/-43.6 months. At first visit, 79.4% (group 1, n=635) of patients were on medications, 10% (group 2, n=80) were on medications but later discontinued, and 10.6% (group 3, n=85) were drug-naive. Overall, levodopa was prescribed in 94.8%, trihexyphenidyl in 40.4%, dopamine agonists in 23.2%, and amantadine in 17.2% either as monotherapy or in combination. In group 1, 37.8% were on monotherapy, with levodopa being the most commonly used agent (33.1%), followed by trihexyphenidyl (2.2%), dopamine agonists (1.6%), and amantadine (0.6%). Among those on polytherapy, levodopa plus trihexyphenidyl was the preferred combination (23.9%). In group 2, levodopa monotherapy was also most common (72.5%), followed by trihexyphenidyl monotherapy (7.5%). CONCLUSIONS: Levodopa and trihexyphenidyl were the most commonly prescribed drugs in our patients. A higher use of trihexyphenidyl could be due to its easy availability, low cost, and better tolerability in our patients, who were relatively young at the time of onset of their disease. The choice of antiparkinsonian medications at the primary and secondary care levels in India may be inappropriate, and newer guidelines tailored to the Indian context are warranted. PMID- 29391080 TI - Hirayama Disease: A Diagnostic and Therapeutic Challenge. PMID- 29391079 TI - Update on Minimal Standards for Electroencephalography in Canada: A Review by the Canadian Society of Clinical Neurophysiologists. AB - Surface electroencephalogram (EEG) recording remains the gold standard for noninvasive assessment of electrical brain activity. It is the most efficient way to diagnose and classify epilepsy syndromes as well as define the localization of the epileptogenic zone. The EEG is useful for management decisions and for establishing prognosis in some types of epilepsy. Electroencephalography is an evolving field in which new methods are being introduced. The Canadian Society of Clinical Neurophysiologists convened an expert panel to develop new national minimal guidelines. A comprehensive evidence review was conducted. This document is organized into 10 sections, including indications, recommendations for trained personnel, EEG yield, paediatric and neonatal EEGs, laboratory minimal standards, requisitions, reports, storage, safety measures, and quality assurance. PMID- 29391081 TI - Glioblastoma Following Ischemic Stroke. PMID- 29391082 TI - Common Data Elements for Concussion in Tertiary Care: Phase One in Ontario. AB - BACKGROUND: Standardized data collection for traumatic brain injury (TBI) (including concussion) using common data elements (CDEs) has strengthened clinical care and research capacity in the United States and Europe. Currently, Ontario healthcare providers do not collect uniform data on adult patients diagnosed with concussion. OBJECTIVE: The Ontario Concussion Care Strategy (OCCS) is a collaborative network of multidisciplinary healthcare providers, brain injury advocacy groups, patient representatives, and researchers with a shared vision to improve concussion care across the province, starting with the collection of standardized data. METHODS: The International Framework of Functioning Disability and Health was selected as the conceptual framework to inform the selection of CDEs. The CDEs recommended by the OCCS were identified using key literature, including the National Institute of Neurological Disorders and Stroke-Zurich Consensus Statements for concussion in sport and the Ontario Neurotrauma Foundation Concussion/mTBI clinical guidelines. RESULTS: The OCCS has recommended and piloted CDEs for Ontario that are readily available at no cost, clinically relevant, patient friendly, easy to interpret, and recognized by the international scientific community. CONCLUSIONS: The implementation of CDEs can help to shift Ontario toward internationally recognized standard data collection, and in so doing yield a more comprehensive evidence-based approach to care while also supporting rigorous research. PMID- 29391083 TI - Corpus Callosum Impingement Syndrome: A Callosal or Colossal Problem? PMID- 29391084 TI - Complications and Caveats of Burst Spinal Cord Stimulation. PMID- 29391085 TI - Rapid Development of Intracranial Aneurysm Associated with Tuberculous Meningitis. PMID- 29391086 TI - B7-Homolog 4 Promotes Epithelial-Mesenchymal Transition and Invasion of Bladder Cancer Cells via Activation of Nuclear Factor-kappaB. AB - B7-homolog 4 (B7-H4), a member of the B7 family of costimulatory molecules, has been reported to be upregulated in urothelial cell carcinoma. This study was conducted to explore the biological role of B7-H4 in the aggressiveness of bladder cancer and the associated molecular mechanism. We found that the mRNA and protein levels of B7-H4 were significantly greater in bladder cancer cell lines than in SV-HUC-1 (normal human urothelial cells). Overexpression of B7-H4 significantly promoted bladder cancer cell migration and invasion, whereas knockdown of B7-H4 exerted an opposite effect. However, the growth of bladder cancer cells was not altered by B7-H4 overexpression or knockdown. Overexpression of B7-H4 promoted epithelial-mesenchymal transition (EMT), as evidenced by decreased E-cadherin and increased vimentin expression. The EMT inducers Twist1 and Snail were upregulated by B7-H4 overexpression and downregulated by B7-H4 silencing. Mechanistically, overexpression of B7-H4 induced the activation of NF kappaB signaling. Pharmacological inhibition of NF-kappaB partially prevented B7 H4-mediated bladder cancer cell invasion. Taken together, B7-H4/NF-kappaB signaling is involved in the EMT and invasion of bladder cancer cells and represents a new candidate target for the treatment of bladder cancer. PMID- 29391087 TI - Percutaneous Needle Biopsies of the Breast in Women Younger than 35 Years: Minimally or Excessively Invasive? AB - Percutaneous needle biopsy (PNB) of the breast is commonly used for diagnosis of breast pathology, but has been less studied in young women. We sought to determine the effectiveness and necessity of PNB in patients younger than 35 years of age. The charts of sequential patients <35 years who underwent PNB between February 2013 and May 2016 were reviewed; 181 PNB were performed in 127 patients. Median age was 30 years (13-34). Indications for PNB were Breast Imaging Reporting and Data System (BIRADS) >=4 in 137 (75.7%) cases, with mass on imaging in 139 (76.8%). Carcinoma was diagnosed in 12 (6.6%), PNB in eight unique patients (6.3%). Other PNB pathology included atypia in four (2.2%) patients; papillary lesion, five (2.8%); benign lymph node, 10 (5.5%); fibroepithelial lesion, 15 (8.3%); benign breast tissue, 63 (34.8%); and fibroadenoma, 72 (39.8%). Women with atypia or malignancy were older than those with benign findings (30.9 vs 28.0 years, P = 0.002). No other patient or imaging factors were significantly associated with pathologic diagnosis on PNB. Routine PNB for all BIRADS 4 findings may be over-used in young women as most results are benign and subsequent surgical findings are concordant. Improved diagnostic accuracy of breast imaging is warranted to reduce unnecessary procedures. PMID- 29391088 TI - Concurrent Biliary Disease Increases the Risk for Conversion and Bile Duct Injury in Laparoscopic Cholecystectomy: A Retrospective Analysis at a County Teaching Hospital. AB - Biliary tract disease remains a common indication for operative intervention. The incidence of concurrent biliary tract disease (>2 biliary tract disease processes) is unknown and the impact of more than one biliary tract diagnosis on outcomes remains to be defined. The objective of this study was to determine the effect of concurrent biliary tract disease on conversion rate and outcomes after laparoscopic cholecystectomy. A 5-year retrospective analysis of all patients who underwent a laparoscopic cholecystectomy was performed comparing those with a single biliary diagnosis to patients with concurrent biliary tract disease. Variables analyzed were conversion to open cholecystectomy, incidence of bile duct injury, use of endoscopic retrograde cholangiopancreatography and/or intraoperative cholangiogram, length of surgery, and duration of hospitalization. The incidence of concurrent biliary tract disease was 9 per cent and a conversion to open cholecystectomy was performed in 16 per cent of patients. After adjusting for confounding factors, concurrent biliary tract disease was predictive of conversion (odds ratio 1.6, 95% confidence interval 1.1-2.3, P = 0.03) and bile duct injury (odds ratio 2.5, 95% confidence interval 0.8-5, P = 0.01). Concurrent biliary tract disease patients were more likely to undergo intraoperative cholangiogram or endoscopic retrograde cholangiopancreatography, as well as longer operation and length of stay. PMID- 29391089 TI - Abdominal Visceral Fat Area and Chronic Pouchitis after Ileal Pouch-Anal Anastomosis. AB - Chronic pouchitis (CP) after ileal pouch-anal anastomosis is a significant clinical problem. Adipose tissues produce antiinflammatory cytokines and chemokines. We evaluated the association between abdominal visceral fat area (VFA) and CP. Patients with a preoperative CT evaluation were included. The diagnosis of CP was confirmed in all cases by endoscopy with afferent ileal limb intubation. Patients were allocated into groups of high VFA and low VFA. The study cohort of 52 patients had a median body mass index of 22 (range, 14-32). Indications for surgery were medically refractory disease in 46 (88%) patients and cancer/dysplasia in six (12%) patients. Median VFA was 27.1 (range, 1-144). Six (12%) patients developed CP. Low VFA patients were significantly younger (29 vs 45 years; P < 0.0001), had lower body mass index (20.4 vs 24.7; P < 0.0001), had surgery more commonly for medically refractory disease than for cancer or dysplasia (100 vs 77%; P = 0.02), and had a higher incidence of CP than high VFA patients (23 vs 0%; P = 0.02). Multiple linear regression analysis demonstrated that only low VFA was associated with CP (P = 0.009). An association is present between VFA and CP after ileal pouch-anal anastomosis, implicating adipocytes in the pathogenesis of inflammatory bowel disease. PMID- 29391090 TI - Extreme Interventions for Trauma Patients in Extremis: Variations among Trauma Centers. AB - Although guidelines for the performance of an emergency department thoracotomy (EDT) are available, high level evidence remains scarce potentially leading to variation in decisions and practices among trauma surgeons. The National Trauma Databank was queried for all subjects who died in the emergency department (ED) between 2007 and 2011. Trauma centers were divided into four quartiles based on the rate of EDT among ED deaths. A total of 31,623 subjects admitted to 729 trauma centers met inclusion criteria. Most of of these centers (n = 328, 53%) never performed an EDT during the study period. Very few outlier centers (1.1%) performed this procedure in 50.0 per cent or more of all patients who died in the ED. Trauma centers in the highest quartiles in performing EDT were more likely to intervene with both surgical and nonsurgical procedures in patients who died in the ED, independent of the performance of an EDT. There are significant variations among trauma centers in the management of trauma patients who expire in the ED. Further research at a national level toward standardizing the management of the trauma patient in extremis and the decision to perform an EDT is necessary, given the extremely low survival associated with this procedure. PMID- 29391091 TI - Lobular Carcinoma In Situ: A 15-Year Single Institution Review. AB - The optimal management of lobular carcinoma In Situ (LCIS) has largely been debated. This study evaluated practice patterns and outcomes in women diagnosed with LCIS at a single institution from 2000 to 2014. Patient characteristics, histology, method of diagnosis, and management were examined in relation to disease-free survival, and overall survival (OS). A total of 209 patients were identified. Surgical management in the majority of patients was excisional biopsy or local excision. Patients diagnosed with LCIS by core biopsy were less likely to have mastectomy as compared with other methods of initial diagnosis (P = 0.01). A total of 108 (90.8%) patients received chemoprevention (CP) counseling, and 47 (43.5%) used chemoprevention. Estimated five-year disease-free survival rate was 96.3 per cent (95% confidence interval (CI): 92.0-98.3%) and OS rate was 98.6 per cent (95% CI: 94.6-99.7%). Older age was associated with a higher risk of subsequent breast cancer (hazard ratio (HR): 1.04; 95% CI: 1.01-1.07; P = 0.01). Older age (HR: 1.06; 95% CI: 1.02-1.11; P = 0.004) and diagnosis in the earlier years of the study period (HR: 0.65; 95% CI: 0.48-0.89; P = 0.007) were significantly associated with worse OS in multivariate analysis. LCIS has a favorable prognosis and is most commonly managed conservatively. PMID- 29391092 TI - Outcomes of Unroofing with Limited Excision and Structured Postoperative Care for Pilonidal Disease. AB - Despite a wide variety of surgical techniques to treat chronic pilonidal disease, high rates of recurrence are common. The current study analyzes the outcome of unroofing with limited excision combined with structured postoperative wound care for pilonidal disease. We performed a retrospective review of all patients who were treated with this technique over a seven year period. Ninety-four patients aged 11 to 63 (mean age 26) received this treatment for pilonidal disease. Eighty nine patients were treated for primary pilonidal disease and five were treated for recurrent disease after procedures such as flaps. There were 66 males (70%) and 28 females (30%). The operation was performed by unroofing the entire pilonidal sinus along with its pits and area of chronic abscess cavity. All granulation tissue was removed and the base of the sinus was completely cauterized. No wide local excisions were performed. The cavity was packed with dry gauze and the dressing was changed twice daily. Patients were seen postoperatively on a weekly basis in clinic. The area was shaved; the cavity was cleaned and often treated with silver nitrate. In the event of premature skin closure starting to form, unroofing was easily performed in the office. The median time to achieve complete healing was 53 days requiring, on average, seven visits. With a mean follow-up of 40 months, there were two recurrences (2.1%) and reoperation for two (2.1%) inappropriately healing wounds. This study demonstrates that unroofing with limited excision and structured postoperative care for pilonidal disease is a safe and effective treatment approach with a very low recurrence and complication rate. PMID- 29391093 TI - Development of Postoperative Diabetes Mellitus in Patients Undergoing Distal Pancreatectomy versus Whipple Procedure. AB - Because the islets of Langerhans are more prevalent in the body and tail of the pancreas, distal pancreatectomy (DP) is believed to increase the likelihood of developing new onset diabetes mellitus (NODM). To determine whether the development of postoperative diabetes was more prevalent in patients undergoing DP or Whipple procedure, 472 patients undergoing either a DP (n = 122) or Whipple (n = 350), regardless of underlying pathology, were analyzed at one month postoperatively. Insulin or oral hypoglycemic requirements were assessed and patients were stratified into preoperative diabetic status: NODM or preexisting diabetes. A retrospective chart review of the 472 patients between 1996 and 2014 showed that the total rate of NODM after Whipple procedure was 43 per cent, which was not different from patients undergoing DP (45%). The incidence of preoperative diabetes was 12 per cent in patients undergoing the Whipple procedure and 17 per cent in the DP cohort. Thus, the overall incidence of diabetes after Whipple procedure was 54 and 49 per cent in the DP group. The development of diabetes was unrelated to the type of resection performed. Age more than 65 and Caucasian ethnicity were associated with postoperative diabetes regardless of the type of resection performed. PMID- 29391094 TI - A Comparative Analysis of Open versus Endovascular Techniques for Management of Non-Aortic Cervicothoracic Arterial Injuries. AB - The objective of this study is to describe the contemporary management of proximal upper extremity and neck arterial injuries by comparing open and endovascular repair at a single institution. This is a retrospective study of 22 patients that sustained subclavian, axillary, and carotid artery injuries from 2011 to 2016 that were managed with open or endovascular repair. There were nine subclavian, eight axillary, and five carotid artery injuries of which 10 (45.5%) underwent endovascular repair and 12 (54.5%) underwent open repair. There was no statistically significant difference between the groups including injury severity score or preoperative hypotension. There were no deaths in the endovascular group, and three (25.0%) deaths in the open group. All patients in the endovascular group were discharged home. In the open group, seven (58.3%) patients had at least one inpatient complication with a mean of 1.1 (standard deviation 1.4) complications per patient. In the endovascular group, there were three (30.0%) patients with inpatient complications and a mean of 0.4 (standard deviation 0.7) complications per patient (P = 0.18). Endovascular management of nonaortic cervicothoracic arterial injuries was successfully performed in hypotensive patients and patients with other life threatening traumatic injuries. Further studies are warranted to look at long-term patency of these repairs and to help develop a protocol to guide decision-making in the management of cervicothoracic injuries. PMID- 29391095 TI - Delta Shock Index in the Emergency Department Predicts Mortality and Need for Blood Transfusion in Trauma Patients. AB - Shock Index (SI = heart rate/systolic blood pressure) predicts outcomes among trauma patients. Studies have also shown that the change in SI between the field and Emergency Department (ED) arrival (Delta SI) predicts mortality in trauma. Given the lack of reliable prehospital data, Delta SI may more accurately prognosticate if used within the ED. All trauma patients arriving to our Level I trauma center in 2014 were reviewed. Patients were matched for age, gender, mechanism of injury, and injury severity score. SI and ED Delta SI were calculated. ED Delta SI >0.1 and <=0.1 defined the study groups. Pregnant patients, pediatric patients, and patients with incomplete data were excluded. Outcomes included intensive care unit (ICU) length of stay, blood products, and mortality. A total of 2591 patients were identified (n = 1294 patients analyzed). After matching, patients with ED Delta SI >0.1 had greater mortality (6.6 vs 2.6%, P = 0.010), need for blood transfusion (1764 vs 565 cc, P < 0.001), and ICU length of stay (5.6 vs 3.8 days, P = 0.014) compared with patients with ED Delta SI <=0.1. In conclusion, ED Delta SI >0.1 is associated with increased mortality, need for blood transfusion, and ICU length of stay. Delta SI may be superior to traditional SI for trauma outcome prognostication. PMID- 29391096 TI - Ultrasound Accuracy in Diagnosing Appendicitis in Obese Pediatric Patients. AB - The use of ultrasound to diagnose appendicitis in pediatric patients has been growing with the improvement of ultrasound technology and operator skills, but its utility in the increasingly obese pediatric population has not been thoroughly investigated. A retrospective review of all pediatric (<=18 years old) patients with appendicitis who were admitted at a single hospital from 2014 to 2016 was conducted. Patients were stratified into body mass index (BMI) percentile categories based on the centers for disease control guidelines. Comparisons were then made. There were 231 patients with an average BMI percentile of 72.6; 99 (42.9%) who had an ultrasound, of which 54 (54.5%) were positive for acute appendicitis, whereas 43 (43.4%) were nondiagnostic. In patients who had a nondiagnostic ultrasound, 37 had a CT demonstrating acute appendicitis. These were compared with 123 patients who had CT alone demonstrating acute appendicitis. The CT-only group was older (12 vs 9, P < 0.005), tended to be male (78 (63%) vs 15 (41%), P = 0.019), had fewer operations performed (81 (66%) vs 30 (81%), P = 0.048) but had no significant difference in BMI percentile (75.8 vs 71.7, P = 0.465). Ultrasound had a 100 per cent positive predictive value in obese and overweight children. Ultrasound is a reliable study in obese and overweight pediatric patients with acute appendicitis. PMID- 29391097 TI - The Growing Utilization of Laparoscopy in Emergent Colonic Disease. AB - Emergent colonic disease has traditionally been managed with open procedures. Evaluation of recent trends suggests a shift toward minimally invasive techniques in this disease setting. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) targeted colectomy database from 2012 to 2014 was used to examine clinical data from patients who emergently underwent open colectomy (OC) and laparoscopic colectomy (LC). Multivariate regression was utilized to analyze preoperative characteristics and determine risk-adjusted outcomes with intent-to-treat and as-treated approach. Of 10,018 patients with emergent colonic operation, 90 per cent (9023) underwent OC whereas 10 per cent (995) underwent LC. Laparoscopic utilization increased annually, with LC composing 10.9 per cent of emergent colonic operations in 2014 compared with 9.3 per cent in 2012. Compared with LC, patients treated with OC had higher rates of overall morbidity (odds ratio 2.01, 95% confidence interval 1.74-2.34, P < 0.01) and 30-day mortality (odds ratio 1.79, 95% confidence interval 1.30-2.46, P < 0.01). Subset analysis of emergent patients without preoperative septic shock revealed consistent benefits with laparoscopy in overall morbidity, 30-day mortality, ileus, and surgical site infection. In select patients with hemodynamic stability, emergent LC appears to be a safe and beneficial operation. This study reflects the growing preference and utilization of minimally invasive techniques in emergent colonic operations. PMID- 29391098 TI - Survival Analysis with Extended Lymphadenectomy for Gastric Cancer: Removing Stage Migration from the Equation. AB - The survival benefit of an extended versus standard lymphadenectomy for gastric cancer (GC) is often attributed to upstaging when more lymph nodes (LNs) are removed, i.e., stage migration. An extended lymphadenectomy is defined as 30 or more LNs examined, a surrogate for a D2 dissection. The aim of this study is to examine whether the survival benefit of extended lymphadenectomy persists when stage migration is not possible. The National Cancer Data Base was queried to identify patients with pathologic N3 (pN3, >=7 positive LNs) gastric adenocarcinoma. Overall survival (OS) was compared by extent of lymphadenectomy (7-14, 15-29, and >=30 LN) and stratified by T stage. Of 2101 pN3 patients, 419 (19.9%) had 7 to 14 LNs examined, 1164 (55.4%) had 15 to 29 LNs examined, and 518 (24.7%) had >=30 LNs examined. Unadjusted three-year OS in the entire cohort was 24.6, 27.3, 30.5 per cent for 7 to 14 LNs, 15 to 29 LNs, and >=30 LNs, respectively (P = 0.003). On adjusted survival analysis by stage for patients with pT1-T2N3 disease, removing >=30 LNs significantly improved OS compared with removing 7 to 14 LNs (hazard ratio [HR] 2.45, 95% confidence interval = 1.25 4.82, P = 0.009). Extended lymphadenectomy may confer a survival benefit in select patients with pT1N3 and pT2N3 GC, highlighting the importance of the number of LNs examined rather than stage migration on survival. For the majority of the N3 population, pT3-pT4, the extent of lymphadenectomy did not significantly improve the OS. PMID- 29391099 TI - High-Risk Prehospital Mechanisms in Tier II Trauma Codes: An Analysis of Under Triage at a Level II Trauma Center. AB - Under-triage is used as a surrogate for trauma quality. We sought to analyze factors that may impact under-triage at our institution by a detailed analysis of prehospital mechanisms and patient factors that were associated with the need for invasive intervention, intensive care unit monitoring, or death. Patients admitted to our Level II trauma center who met the criteria for under-triage using the Cribari method were studied, n = 160, and prominent mechanisms were motor vehicle collisions (MVCs). Patient demographics, detailed mechanism characteristics, ED vital signs, operative intervention, and outcomes were studied. The age of the study group and injury severity score were 42 +/- 20 and 22 +/- 6, respectively. Alcohol or drug use was common as were high-speed frontal collisions. Overall, 38 per cent of patients required surgery, and a monitored bed was required in 60 per cent of patients. Logistic regression identified drug use as predictive of mortality and MVC speeds >=40 mph as predictive of intensive care unit admission. Patients requiring surgery had a high incidence of frontal collisions, 40 per cent. MVCs were predominant in under-triaged trauma patients. Operative intervention, intensive care unit monitoring, and deaths were associated with frontal impacts, high speeds, and drug use. Further study is warranted to assess the incorporation of high-risk injury patterns in triage algorithms aimed at enhancing trauma quality. PMID- 29391100 TI - Robotic Minor Hepatectomy Offers a Favorable Learning Curve and May Result in Superior Perioperative Outcomes Compared with Laparoscopic Approach. AB - Minorhepatectomy (MH) is a common type of robotic-assisted liver resection, but few studies compared it with laparoscopic. We compared the perioperative outcomes of patients who underwent robotic (RH) or laparoscopic (LH) minor hepatectomy and evaluated the effect of surgeon's experience on outcomes. A prospective database was used to identify patients from 2009 through 2016 who underwent RH or LH. Two surgeons performed RH starting in 2014, whereas LH had been established before that. Of the 93 patients, 42 were in RH and 51 in LH group. The mean patient age, gender, race, American Society of Anesthesiologists score, proportion of patients with cirrhosis and hepatocellular carcinoma were similar. Operative time, estimated blood loss (EBL), conversion to open, 30-day complication rate, Clavien Dindo grade >= 3 complications, and length of hospital stay (LOS) were similar. There was no difference in average tumor size, specimen volume, or achievement of R0 margin. In RH group, after completing 15 cases, there were no conversions to open. After 25 cases, EBL, LOS, and 30-day complication rate were improved as compared with LH. Perioperative outcomes of robotic MH are equivalent to laparoscopic. After approximately 25 cases, robotic-assisted MH may result in superior outcomes compared with laparoscopic. PMID- 29391101 TI - Comparative Analysis of Laparoscopic and Open Approaches in Emergency Abdominal Surgery. AB - The objective of this study was to evaluate usage and outcomes of emergency laparoscopic versus open surgery at a single tertiary academic center. Over a three-year period 165 patients were identified retrospectively using National Surgical Quality Improvement Program results. Appendectomies and cholecystectomies were excluded. Open and laparoscopic approaches were compared regarding preoperative and operative characteristics, the development of postoperative complications, 30-day mortality, and length of hospital stay. Indications for operation were similar between groups. Patients who underwent open surgery had more severe comorbidities and higher ASA class. Laparoscopy was associated with reduced complication rates, operative time, length of stay, and discharges to skilled nursing facilities on univariate analysis. In a multivariate model, surgical approach was not associated with the development of complications. Older age, dependent status, and dyspnea were predictors of conversion from attempted laparoscopic to open approaches. PMID- 29391102 TI - The Burden of Tunneled Central Venous Catheters for Hemodialysis in a County Hospital. AB - Prolonged use of central venous catheters (CVCs) for hemodialysis (HD) is associated with greater morbidity and mortality when compared with autogenous arteriovenous fistulas (AVF). The objective was to assess compliance with CVC guidelines in adults referred for hemoaccess at a county teaching hospital. Out of 256 patients, 172 (67.2%) were male, with a mean age of 50.0 +/- 12.4 years. Overall 62.5 per cent initiated dialysis via CVC. Patients were divided into two groups (those with CVC (62.5%) and those without (37.5%)). Male gender was associated with initiation of dialysis via CVC versus no CVC (72.5 vs 58.3%, P = 0.02), as was a history of prior vascular access (P < 0.01). There were no significant differences between the groups regarding age, diabetes, smoking, ambulatory status, or insurance status. There were no differences in gender, age, insurance status, or prior vascular access between prolonged CVC use (>=90 days) and short-term CVC use (<90 days). We conclude that most patients initiated HD with CVC and exceed the recommended CVC duration. Men are more likely to initiate HD via CVC. Insurance status was not associated with CVC use. Multidisciplinary action may address barriers to reducing CVC duration. PMID- 29391103 TI - Predictors of Steal in Hemodialysis Access. AB - Pathological steal is an uncommon but devastating complication after the creation of arteriovenous access for hemodialysis. In this study, we sought to assess predictors of clinically significant steal syndrome and to further evaluate the outcome of differing surgical treatment approaches. A retrospective analysis was performed of 282 consecutive patients undergoing hemodialysis access at a single center from November 2014 to April 2016. Adequate follow-up to assess for the development of steal was obtained in 237 patients. One hundred and fifty-seven (66%) patients were male, 152 (64%) Hispanic, and 164 (69%) had diabetes. Forty three (18%) had prior access procedures. Autologous fistula was created in 218 patients (92%). Pathologic steal occurred in 15 patients (6.7%). On univariate analysis, significant predictors of steal included female sex [P = 0.03, odds ratio (OR) = 3.3, CI [1.1-9]), no systemic heparin at operation (P = 0.02, OR = 5.0, CI [1.4-10]), use of angiotensin-converting enzyme inhibitor (P = 0.003, OR = 5.6, CI [1.7-18.6]), and increased vein size (3.1 vs 4.1 mm P = 0.01). Twelve patients had steal managed with an intervention, but only one patient received distal revascularization. Furthermore, we identify key predictors of clinically significant steal syndrome while demonstrating that distal revascularization and/or fistula ligation are rarely indicated treatment modalities. PMID- 29391104 TI - Management and Outcomes of Appendectomy during Pregnancy. AB - Acute appendicitis is a common nonobstetric indication for surgical intervention during pregnancy with serious potential complications for the mother and fetus. The aim of this study was to evaluate the presentation, management practices, outcomes, and costs of appendectomy during pregnancy. We did a retrospective analysis of 62,118 nonincidental appendectomies performed in women (age 15-45 years) identified from the California State Inpatient Database (2005-2011). Primary outcomes included diagnosis or type of appendicitis, use of laparoscopy, morbidity, length of stay, and cost. Pregnant women were less likely to undergo laparoscopy (OR = 0.51, P < 0.01). Pregnancy had no effect on perforation rates, but was associated with higher rates of negative appendectomy (OR = 9.29, P < 0.01). Pregnancy was not associated with nonpregnancy-related complications after appendectomy. Pregnant women had longer length of stay (RR = 1.07, P < 0.01) but similar costs. Appendectomy did increase risk of preterm delivery at the time of surgical admission (19.5 vs 8.8%, P < 0.01). However, once discharged, there was no difference in rates of preterm delivery (9.1 vs 8.9%, P = 0.23). Pregnant women had higher rates of negative appendectomy with lower rates of laparoscopy. Despite these differences, there was no difference in nonpregnancy-related morbidity and cost. Appendectomy did increase risk of preterm birth, but the increased risk normalized over time. PMID- 29391105 TI - Hyperglycemia Is Associated with Surgical Site Infections among General and Vascular Surgery Patients. AB - Surgical site infection (SSI) is a common cause of morbidity in general and vascular surgery patients. There is inconsistent evidence on the association of glycemic status with SSI, and its utility in predicting and mitigating SSI. General and vascular surgery patients at a public teaching hospital had the following markers of glycemic status prospectively collected: preoperative hemoglobin A1c (HbA1c) and capillary blood glucose (cBG, within six months before surgery), perioperative cBG (within 24 hours before surgery), and postoperative cBG (peak value up to 48 hours after surgery). Patient records were assessed for SSI within 30 days of surgery. Over a two-month period, 229 patients underwent surgery. The overall SSI rate was 9.6 per cent. Preoperative HbA1c >7 per cent and postoperative cBG >=180 mL/dL occurred in 25.9 and 27.0 per cent of patients, respectively. Preoperative HbA1c >7 per cent was significantly associated with SSI [odds ratio (OR) 2.26, 80 per cent confidence interval (CI) 1.01-5.07], as was postoperative cBG >=180 mg/dL (OR 2.12, 80 per cent CI 1.02-4.41). There was no significant correlation between preoperative or perioperative cBG and SSI. In conclusion, SSI and hyperglycemia were frequent among the study population, and positively associated. Glycemic status may be used for improved preoperative risk assessment, and as it is potentially mutable, to reduce SSI. PMID- 29391106 TI - Evaluation of Preoperative Weight Loss for Elective Hernia Repair in the Veteran Population. AB - The safety and efficacy of preoperative weight loss before elective nonbariatric surgery is controversial. We evaluated the effect of planned surgical delay for a preoperative weight loss trial in hernia repairs. Four hundred and fourteen patients undergoing elective hernia repair between July 2008 and May 2012 at a Level 1B VA Medical Center were identified. Included patients were divided into two groups: those who underwent immediate hernia repair (nontrial) and those who underwent weight loss trial before hernia repair (TRIAL). Twenty-two patients were categorized in the TRIAL group, and 392 in nontrial. Time from surgical evaluation to operation was longer in the TRIAL vs nontrial group (226 days vs 113 days, P = 0.001). Outcome measures were similar between groups. Net change in body mass index (BMI) was -2.2 per cent in TRIAL vs -0.86 per cent in nontrial patients (P = 0.440). Of the TRIAL patients, ten obtained a poor result (<3% decreased BMI), nine a moderate result (3-10% decreased BMI), and three a good result (>10% decreased BMI). Weight loss trials in elective hernia patients appear to be safe, although they result in significant delay to surgery and confer no difference in postoperative outcomes. Thus, efficacy of preoperative weight loss trials may be limited. PMID- 29391107 TI - Mandatory Operative Re-Exploration after Initial Debridement of Necrotizing Soft Tissue Infections: Is it Mandatory? AB - Necrotizing soft tissue infections (NSTIs) are aggressive infections requiring prompt diagnosis and extensive surgical debridement. Traditionally, patients undergo mandatory re-exploration to ensure adequacy of source control. The purpose of this study is to determine if re-exploration in the operating room is mandatory for all patients with NSTIs. An eight-year retrospective analysis of adult patients with NSTIs was performed comparing two groups: mandatory operative re-exploration versus operative re-exploration based on clinical examination findings. Outcomes measured included mortality, number of debridements, and length of stay (LOS). Twenty-two per cent of patients underwent a mandatory re exploration. These patients were older, had a higher incidence of diabetes, and a longer duration of symptoms. There were no significant differences between groups with regard to the physical examination, severity of sepsis, time to repeat debridements, or in-hospital mortality, whereas LOS and the total number of debridements were increased in mandatory re-exploration. Bacteremia and septic shock were predictive of the need for further debridement in patients in the operative re-exploration based on clinical examination findings group. Mandatory re-exploration after initial debridement may not be necessary in all patients with NSTIs. Instead, bedside wound checks may be a safe strategy to determine the need for further operative debridement. PMID- 29391108 TI - Application of a Geriatric Injury Protocol Demonstrates High Survival Rates for Geriatric Trauma Patients with High Injury Acuity. AB - Geriatric trauma has historically been associated with poor outcomes, particularly in the setting of severe polytrauma. Although geriatric trauma protocols are common, there are limited data on their impact in patients with high injury severity. In this study, we sought to investigate the impact of a geriatric injury protocol on outcomes in patients with severe trauma acuity. Ninety-eight geriatric patients (age >=65) admitted to our trauma center with injury severity scores (ISS) >=15 comprised the study cohort. The mean age was 75 +/- 7.7 yrs. The mean ISS was 25 +/- 9.2, and the mean geriatric trauma outcome score was 150 +/- 3. Mortality was 17 per cent and 70 per cent were due to central nervous system injury. When patients with nonsurvivable injuries or advanced directives resulting in early care withdrawal were excluded, the mortality was 6 per cent. Extremes of age did not impact mortality[ (>80 years, 21%) vs (65-79, 16%, P = 0.5)]. Most patients (53%) were discharged home. The application of our geriatric trauma protocol led to favorable results despite high injury acuity. These data suggest that even at the extremes of age, a large percentage of patients can be expected to survive. A prospective validation of these findings is warranted. PMID- 29391109 TI - The Dangers of Equivocal FAST in Trauma Resuscitation. AB - Equivocal focused abdominal sonography for trauma (FAST) examinations confound decision-making for trauma surgeons. We sought to determine whether the equivocal FAST (defined as any nonconcordant result) has a deleterious effect on trauma outcomes. A 2-year review (2014-2015) of all trauma activations at our Level I trauma center was performed. Patients were matched at baseline and FAST results were compared. Outcomes included resuscitation time (h), ventilation days (d), hospital length of stay (HLOS-d), ICU length-of-stay, and survival (%). In addition, skill level of the sonographer was stratified by novice (postgraduate year (PGY) years 1-3) or expert skill levels (PGY-4/fellow or attending). A total of 1,027 patients were included. Compared with concordant FAST examinations, equivocal FASTs were associated with increased HLOS (14.1 vs 10.6, P = 0.05), higher mortality (9.8 vs 3.7%, P = 0.02), decreased positive predictive value in the right upper quadrant (RUQ) (55 vs 79%, P = 0.02) and left upper quadrant (LUQ) (50 vs 83%, P < 0.01) and significantly decreased specificity in the thoracic (83 vs 98%), RUQ (80 vs 98%), LUQ (86 vs 99%), and pelvic (88 vs 98%) windows (P < 0.01 for all). A trend of greater positive predictive value in the thoracic window (100 vs 81%, P = 0.09) among PGY-4/fellow and attending providers compared with PGY levels 1-3 was observed. Equivocal FASTs portend worse outcomes than concordant FASTs because of high false-negative rates, specifically in the thoracic region and the upper quadrants. Lower thresholds for intervention are recommended. PMID- 29391110 TI - Anatomic Location Is the Primary Determinant of Survival for Paragangliomas. AB - Paragangliomas (PGL) are rare neuroendocrine tumors. This study describes the largest collection of PGLs and evaluates factors that impact survival. Patients with PGL from 1998 to 2013 in the NCDB were reviewed. Independent predictors of overall survival (OS) were identified for patients with non-central nervous system (CNS) tumors. Of 867 PGLs, the primary site was CNS (39.9%), abdomen/pelvis (A&P) (21.0%), head and neck (H&N) (17.5%), thoracic (15.1%), bladder (3%), or unspecified (3.5%). Of 521 non-central nervous system (CNS) PGLs, there were differences in sex, comorbidities, treatment facility, tumor size, treatment modality (P < 0.001). Five-year OS for this cohort was 66 per cent and 10-year OS was 51 per cent. Median OS differed significantly between primary sites (H&N 106.0 months, thoracic 89.0 months, A&P 81.7 months, bladder 69.7 months, and unspecified 27.2, P < 0.001). After controlling for multiple factors, age greater than 50 (HR 1.97; CI 1.38-2.81), primary site A&P (HR 2.01; CI) 1.17-3.48) or bladder (HR 4.03; CI 1.64-9.89) as compared with H&N, distant metastasis (HR 2.25; CI 1.44-3.53) and those who did not receive surgery (HR 2.85; CI 1.89-4.31) all exhibited decreased OS. This is the largest series of PGLs and the first to demonstrate significant survival differences based on PGL site. Abdominal/pelvic and bladder PGLs had the lowest survival in addition to patients that did not have a surgical resection, those with distant metastases, and >50 years of age. PMID- 29391111 TI - Current Methods and Advances in Simulation of Hemorrhage after Trauma. AB - As animal models fall out of favor, there is demand for simulators to train medical personnel in the management of trauma and hemorrhage. Realism is essential to the development of simulators for training in the management of trauma and hemorrhage, but is difficult to achieve because it is difficult to create models that accurately represent bleeding organs. We present a simulation platform that uses real-time mathematical modeling of hemodynamics after hemorrhage and trauma and visually represents the injury described by the model. Using patient-specific imaging, 3D-mesh representations of the liver were created and merged with an anatomically accurate vascular tree. By using anatomically accurate representations of the vasculature, we were able to model the cardiovascular response to hemorrhage in a specific artery. The incorporation of autonomic tone allowed for the calculation of bleeding rate and aortic pressures. The 3D-mesh representation of the liver allowed us to simulate blood flow from the liver after trauma. For the first time, we have successfully incorporated tissue modeling and fluid dynamics with a model of the cardiovascular system to create a simulator. These simulations may aid in the creation of realistic virtual environments for training. PMID- 29391112 TI - Evaluation of Single- versus Dual-Tube Thoracostomy after Thoracotomy for Trauma. AB - Draining the chest cavity with two chest tubes after thoracotomy for trauma is controversial. This article aims to determine whether using two tubes after thoracotomy for trauma is more effective than using a single tube. A 9-year retrospective review (2007-2015) was performed at our academic level I trauma center. All patients who underwent trauma thoracotomy (unilateral and bilateral) were included for analysis (n = 99). Patients with incomplete data, pediatric patients (age < 18), pregnant patients, and early deaths (<24 hours) were excluded. When analyzed by chest cavity, dual tubes have increased drainage bilaterally (P = 0.008) and require more days to clear the right chest (P = 0.002). Patients with dual tubes bilaterally are associated with increased intensive care unit length of stay (P = 0.05) and ventilator days (P = 0.04). Although dual chest tube insertion achieves greater drainage, it comes at the cost of increased time to clear the chest and is associated with worse outcomes in bilateral injuries. One chest tube may be sufficient post-trauma thoracotomy; routine placement of two chest tubes is not recommended. PMID- 29391113 TI - Surgical Site Infection Reduction Bundle: Implementation and Challenges at Ventura County Medical Center. AB - Surgical Site Infections (SSIs) are a significant cause of morbidity and increased cost in the postoperative patient occurring in 2-5 per cent of those undergoing inpatient surgery. Ventura County Medical Center (VCMC) initiated an SSI reduction bundle in 2013, to try to reduce the incidence of SSI. The bundle is a series of best practices including preoperative, perioperative, intraoperative, and postoperative components, as well as items focused on the staff and electronic medical record. VCMC started with a 6.1 per cent SSI rate in 2013. A consistent reduction in SSI rate followed each quarter after that for a rate of less than 2.0 per cent in early 2016. The most critical aspect of this process was the necessary collaboration between disparate departments and the ongoing investment of the staff to this challenging process; the people at the heart of the collaborative process were the key to its success. PMID- 29391114 TI - Optimizing the Management of Abnormal Liver Function Tests after Orthotopic Liver Transplant: A Systems-Based Analysis of Health Care Utilization. AB - Elevated liver function tests (eLFTs) are a major cause of unplanned readmissions (UR) after orthotopic liver transplantation. Diagnostic workup for eLFTs requires multiple invasive and noninvasive procedures, often done in the inpatient setting to expedite diagnosis, yet consequently resulting in increased costs. In this study, we evaluated eLFT readmissions at a single institution with respect to resource utilization. From 3/2013 to 12/2015, 388 patients underwent orthotopic liver transplantation, resulting in 463 UR totaling 5833 bed days; 87 (18.8%) UR and 929 (15.9%) bed days were for eLFTs. During eLFT-UR all patients underwent repeat laboratory testing, 75 (86.2%) liver ultrasound, 66 (75.8%) liver biopsy, and 17 (19.5%) endoscopic retrograde cholangiopancreatography. Discharge diagnoses were acute cellular rejection (40.2%), transaminitis not otherwise specified (17.2%), biliary complications (16.1%), recurrent hepatitis (11.5%), vascular complications (5.8%), viral hepatitis (5.8%), and steatohepatitis (3.5%). The greatest bed-day utilization was secondary to acute cellular rejection (60.8%) and biliary complications (13.7%). More than 35 per cent of eLFT-UR were due to transaminitis not otherwise specified, steatohepatitis, recurrent or viral hepatitis, none of which necessitate inpatient treatment. In addition, >25 per cent of eLFT-UR bed days were attributed to diagnostic workup. Identifying patients who can undergo expedited outpatient workup and require only outpatient management will result in significantly decreased readmissions, bed days, and hospital costs. PMID- 29391115 TI - Early Contact after Hospital Discharge Does Not Prevent Readmission in Patients Undergoing Pancreaticoduodenectomy. AB - Studies suggest that early contact (EC) after hospital discharge may help reduce hospital readmissions among medical patients. The objective of this study is to determine if EC after hospital discharge in patients undergoing a pancreaticoduodenectomy (PD) can reduce readmission. We performed a retrospective study of 35 patients who underwent PD over 18 months. Early, focused contact after hospital discharge was either a telephone call by a registered nurse or a clinic visit with a provider within four days of discharge. Hospital readmission rates were analyzed between the EC and no-early contact (NC) cohorts. Nineteen patients received EC after hospital discharge and 16 were in the NC group. Fourteen patients (40%) were readmitted, with postoperative pancreatic fistula and delayed gastric emptying as the most common indications for readmission (71.4%). Overall readmission rates were not significantly different between the EC and NC groups (31.6 vs 50.0%, respectively, P = 0.27). EC after hospital discharge in patients undergoing PD does not prevent readmission. This is likely due to the high incidence of postoperative pancreatic fistula or delayed gastric emptying that clinically manifests after hospital discharge and EC and requires readmission for management. PMID- 29391116 TI - Outcomes of Soft Tissue Reconstruction for Traumatic Lower Extremity Fractures with Compromised Vascularity. AB - Traumatic lower extremity fractures with compromised arterial flow are limb threatening injuries. A retrospective review of 158 lower extremities with traumatic fractures, including 26 extremities with arterial injuries, was performed to determine the effects of vascular compromise on flap survival, successful limb salvage and complication rates. Patients with arterial injuries had a larger average flap surface area (255.1 vs 144.6 cm2, P = 0.02) and a greater number of operations (4.7 vs 3.8, P = 0.01) than patients without vascular compromise. Patients presenting with vascular injury were also more likely to require fasciotomy [odds ratio (OR): 6.5, confidence interval (CI): 2.3 18.2] and to have a nerve deficit (OR: 16.6, CI: 3.9-70.0), fracture of the distal third of the leg (OR: 2.9, CI: 1.15-7.1) and intracranial hemorrhage (OR: 3.84, CI: 1.1-12.9). After soft tissue reconstruction, patients with arterial injuries had a higher rate of amputation (OR: 8.5, CI: 1.3-53.6) and flap failure requiring a return to the operating room (OR: 4.5, CI: 1.5-13.2). Arterial injury did not correlate with infection or overall complication rate. In conclusion, arterial injuries resulted in significant complications for patients with lower extremity fractures requiring flap coverage, although limb salvage was still effective in most cases. PMID- 29391117 TI - Efficacy of Negative Pressure Wound Treatment in Preventing Surgical Site Infections after Whipple Procedures. AB - Surgical site infections (SSIs) occur at an average rate of 21.1 per cent after Whipple procedures per NSQIP data. In the setting of adherence to standard National Surgery Quality Improvement Program (NSQIP) Hepatopancreatobiliary recommendations including wound protector use and glove change before closing, this study seeks to evaluate the efficacy of using negative pressure wound treatment (NPWT) over closed incision sites after a Whipple procedure to prevent SSI formation. We retrospectively examined consecutive patients from January 2014 to July 2016 who met criteria of completing Whipple procedures with full primary incision closure performed by a single surgeon at a single institution. Sixty-one patients were included in the study between two cohorts: traditional dressing (TD) (n = 36) and NPWT dressing (n = 25). There was a statistically significant difference (P = 0.01) in SSI formation between the TD cohort (n = 15, SSI rate = 0.41) and the NPWT cohort (n = 3, SSI rate = 0.12). The adjusted odds ratio (OR) of SSI formation was significant for NPWT use [OR = 0.15, P = 0.036] and for hospital length of stay [OR = 1.21, P = 0.024]. Operative length, operative blood loss, units of perioperative blood transfusion, intraoperative gastrojejunal tube placement, preoperative stent placement, and postoperative antibiotic duration did not significantly impact SSI formation (P > 0.05). PMID- 29391118 TI - Does Travel Distance Affect Readmission Rates after Cardiac Surgery? AB - With emphasis on value-based health care, empiric models are used to estimate expected readmission rates for individual institutions. The aim of this study was to determine the relationship between distance traveled to seek surgical care and likelihood of readmission in adult patients undergoing cardiac operations at a single medical center. All adults undergoing major cardiac surgeries from 2008 to 2015 were included. Patients were stratified by travel distance into regional and distant travel groups. Multivariable logistic regression models were developed to assess the impact of distance traveled on odds of readmission. Of the 4232 patients analyzed, 29 per cent were in the regional group and 71 per cent in the distant. Baseline characteristics between the two groups were comparable except mean age (62 vs 61 years, P < 0.01) and Caucasian race (59 vs 73%, P < 0.01). Distant travel was associated with a significantly longer hospital length of stay (11.8 vs 10.5 days, P < 0.01) and lower risk of readmission (9.5 vs 13.4%, P < 0.01). Odds of readmission was inversely associated with logarithm of distance traveled (odds ratio 0.75). Travel distance in patients undergoing major cardiac surgeries was inversely associated with odds of readmission. PMID- 29391119 TI - Prognostic Factors Associated with Outcomes in Small Bowel Neuroendocrine Tumors. AB - Small bowel neuroendocrine tumors (SBNET) account for most gastrointestinal neuroendocrine tumors. Patients often present with late-stage disease; however, there is little information regarding factors that contribute to recurrence. Database review identified 301 patients diagnosed with SBNET between 1990 and 2013. Univariate analysis included patients who underwent complete resection. Survival was estimated by the Kaplan-Meier method. A total of 147 patients met study criteria. Average age was 60 years (range 21-91); 49 per cent were male. Thirty-seven (25.3%) patients had laparoscopic resection, and 29 (19.9%) patients had only small bowel disease, whereas 108 (72.6%) had nodal metastasis. Five-year overall and disease-free survival were 97.5 and 73.5 per cent. Forty-seven (32%) patients had recurrence. The recurrence group was more likely to have an open operation (59.6 vs 32%, P < 0.01), mesenteric invasion, or lymphatic metastasis (87.2 vs 67%, P < 0.01) compared with the no-recurrence group. Cox regression analysis showed that variables associated with recurrence included nodal disease (HR 9.06, P = 0.03), lymphovascular invasion (LVI) (3.95, P < 0.01), perineural invasion (PNI) (3.48, P < 0.01), and mesenteric involvement (3.77, P = 0.03). Patients with SBNET presenting with nodal metastasis, mesenteric involvement, LVI, or PNI have a higher risk of recurrence. Closer surveillance should be considered after operative resection. PMID- 29391120 TI - Laparoscopy Can Safely Be Performed in Frail Patients Undergoing Colon Resection for Cancer. AB - The present study aims to evaluate the role of laparoscopy in frail patients undergoing colorectal surgery for colorectal cancer. A review of the 2011 to 2014 American College of Surgeons National Surgical Quality Improvement Program database was performed to identify frail patients (using a frailty index), who underwent resection for colorectal cancer. Univariable and multivariable analyses were performed to evaluate 30-day mortality and Clavien-Dindo grade IV (CD-IV) complications. A total of 52,087 patients with colorectal cancer were identified, of which frailty accounted for 2.63 per cent (index score >=5). Patients above the age 85 were considered frail 6.8 per cent of the time and accounted for 24.5 per cent of patients with frailty. Laparoscopic surgery was performed in 32.9 and 53.1 per cent of patients with and without frailty (P < 0.001). Patients with frailty were less likely to die within 30 days of surgery if younger (P = 0.004), performed electively (P < 0.001), or laparoscopically (P < 0.001). On multivariate analysis, laparoscopy and elective surgery were associated with better perioperative survival; whereas, older age, male sex, and tobacco use were associated with 30-day mortality. Laparoscopy and lower body mass index were associated with fewer Clavien-Dindo grade IV complications. Although laparoscopy is performed less commonly in the frail, this study indicated better perioperative outcomes for patients undergoing elective surgery who were <85 years old. PMID- 29391121 TI - Safety and Efficacy of Electromagnetic-Guided Bedside Placement of Nasoenteral Feeding Tubes versus Standard Placement. AB - Although enteral feeding in critically ill patients has been shown to be beneficial, reliable postpyloric placement of feeding tubes remains a challenge. The standard of care involves blind placement, frequently requiring multiple attempts, and radiographs. To evaluate the effect of electromagnetic-guided bedside placement in reducing time to establishment of feeding, lung placement, use of radiography, and cost, we initiated a prospective trial using electromagnetic-guided bedside placement and compared them to a retrospective cohort. Fifty-three consecutive placements of nasoenteral feeding tubes were made using electromagnetic-guidance on patients requiring enteral nutrition in a surgical intensive care unit at a tertiary care center. Sixty-three placement attempts in the preceding seven months served as controls. There were no significant differences between the two groups in terms of age, sex, weight, body mass index, hiatal or ventral hernias, or previous esophageal/gastric operations. The number of radiographs needed per patient, need for fluoroscopy, radiology charge per patient for the tube placement, and time from first attempt at placement to confirmation of postpyloric location were lower for the electromagnetic-guided group. Use of electromagnetic guidance allows reliable and cost-effective postpyloric enteral feeding tube placement compared with blind insertion. PMID- 29391122 TI - Geographic and Institutional Trends in Ambulatory Surgery in the State of California, 2012-2014. AB - Although geographic variation in health care services is well established, relatively less is known about ambulatory surgical procedures in California. Thus, we sought to describe statewide trends according to geographic and institutional factors. Using the California Office of State Health Planning and Development Ambulatory Surgery and Hospital Utilization datasets, overall and per capita procedure rates by county and institution were calculated and compared across 2012 to 2014. There was substantial variation in services provided at the county level (Range: 49-382,142 cases/county). Among the 10 largest counties, there was a more than 2-fold difference in case volume per capita; across all counties, a 50-fold variation was observed. Changes in county population size and surgical case volume were correlated only if Los Angeles, the most populous and highest-volume county in the state, was excluded as an outlier. In the first year of California's full Medicaid expansion, Medicaid ambulatory surgery cases increased 29 per cent and self-pay cases decreased 16 per cent. The top 10 facilities by volume experienced substantial volatility in case volume over two years, ranging from -19.6 to +11.5 per cent. Geographic differences in rates of ambulatory surgery may be related to population shifts, but this was not uniformly true. The factors driving this variation and its impact on patient care warrant further investigation. PMID- 29391124 TI - Eye Drop Dispenser Type and Medication Possession Ratio in Patients With Glaucoma: Single-Use Containers Versus Multiple-Use Bottles. AB - PURPOSE: To determine whether the consumption of topical glaucoma medication is influenced by the type of eye drop dispenser. DESIGN: Retrospective cohort study. METHODS: We examined 366 patients with open-angle glaucoma or ocular hypertension who were bilaterally treated with 0.0015% tafluprost or 2% dorzolamide/0.5% timolol fixed combination (DTFC). The patients were grouped by the type of dispenser and content of eye drops used: (1) tafluprost in bottles (T-Bottle group); (2) tafluprost in unit-dose pipettes (T-Unit group); (3) DTFC in bottles (C-Bottle group); and (4) DTFC in unit-dose pipettes (C-Unit group). We evaluated the medication possession ratio (MPR) among groups, and factors associated with over-consumption (MPR > 1.2) or under-consumption (MPR < 0.8) in multinomial logistic regression. RESULTS: The mean MPR was 1.49 (range, 0.69-2.91) in the T Bottle group, 0.91 (range, 0.32-1.27) in the T-Unit group, 1.25 (range, 0.51 2.60) in the C-Bottle group, and 0.96 (range, 0.36-1.60) in the C-Unit group. The Bottle groups demonstrated higher mean values and wider ranges of MPR compared to the Unit groups. The MPR interval at which the largest number of patients were found was 1.0-1.4 in the Bottle groups and 0.8-1.2 in the Unit groups. Bottle type dispenser (odds ratio [OR] 64.02), tafluprost medication (OR 2.84), and older age (OR 1.03) were associated with over-consumption, whereas no factor was correlated with under-consumption. CONCLUSIONS: The type of eye drop dispenser affects the consumption of glaucoma medication. Physicians should consider the type of eye drop dispenser when assessing glaucoma medication adherence. PMID- 29391123 TI - Phycobilisomes from the mutant cyanobacterium Synechocystis sp. PCC 6803 missing chromophore domain of ApcE. AB - Phycobilisome (PBS) is a giant photosynthetic antenna associated with the thylakoid membranes of cyanobacteria and red algae. PBS consists of two domains: central core and peripheral rods assembled of disc-shaped phycobiliprotein aggregates and linker polypeptides. The study of the PBS architecture is hindered due to the lack of the data on the structure of the large ApcE-linker also called LCM. ApcE participates in the PBS core stabilization, PBS anchoring to the photosynthetic membrane, transfer of the light energy to chlorophyll, and, very probably, the interaction with the orange carotenoid protein (OCP) during the non photochemical PBS quenching. We have constructed the cyanobacterium Synechocystis sp. PCC 6803 mutant lacking 235 N-terminal amino acids of the chromophorylated PBLCM domain of ApcE. The altered fluorescence characteristics of the mutant PBSs indicate that the energy transfer to the terminal emitters within the mutant PBS is largely disturbed. The PBSs of the mutant become unable to attach to the thylakoid membrane, which correlates with the identified absence of the energy transfer from the PBSs to the photosystem II. At the same time, the energy transfer from the PBS to the photosystem I was registered in the mutant cells and seems to occur due to the small cylindrical CpcG2-PBSs formation in addition to the conventional PBSs. In contrast to the wild type Synechocystis, the OCP mediated non-photochemical PBS quenching was not registered in the mutant cells. Thus, the PBLCM domain takes part in formation of the OCP binding site in the PBS. PMID- 29391125 TI - Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases. AB - INTRODUCTION: Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown. METHODS: Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182). RESULTS: The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99-1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87-0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations. DISCUSSION: Increased NFL levels are a common feature in neurodegenerative dementias. PMID- 29391126 TI - Research of novel anticancer agents targeting arginase inhibition. AB - Arginase plays an important part in l-arginine metabolism. This metalloenzyme also regulates polyamine biosynthesis, nitric oxide production and the T-cell mediated immune response, which are all involved in the growth and control of cancer. Research over the past decades has reported arginase as an attractive target for cancer treatment, and inhibition of arginase could be a promising strategy for cancer therapy. Herein, we present the available data on the role of arginase in cancer development. The principal synthetic and natural arginase inhibitors are outlined and followed by their mechanism of action. Among them, some molecules have shown their anticancer effects. The perspectives of arginase inhibitors as new anticancer agents will be discussed. PMID- 29391127 TI - Knowledge, attitudes and practices regarding malaria in people living with HIV in rural and urban Ghana. AB - BACKGROUND: One of the malaria vulnerable groups is people living with HIV. This study investigated knowledge, attitude and practices (KAP) towards malaria in people living with HIV attending anti-retroviral therapy (ART) clinics in rural and urban Ghana. METHODS: In this descriptive cross-sectional study patients attending the ART clinics in Atibie (rural area) and Accra (urban area) were interviewed on their knowledge, attitude and practices regarding malaria. Finger prick capillary blood was tested for Plasmodium spp. with rapid diagnostic tests. Multivariate regression analysis was used to determine the influence of KAP on malaria prevalence. RESULTS: Parasitemia was generally more frequent among HIV positive individuals in the rural area (29/116; 25%) in the rural area than in the urban area (35/350; 10%). Inaccurate knowledge of cause of malaria and prevention methods were associated with increased odds of malaria parasitemia; [OR = 1.51 (CI: 1.29-5.12); p < .05] and [OR = 2.59 (CI: 2.53-4.75); p < .05], respectively. There were disparities in socio-economic factors. For instance, low level of education was higher in the rural area (45/116; 38.8%) compared to the urban area (121/350; 34.6%). CONCLUSIONS: Malaria control efforts may yield further results when the knowledge and socio-economic gap between rural and urban areas is closed. PMID- 29391128 TI - Rift Valley Fever in Egypt and other African countries: Historical review, recent outbreaks and possibility of disease occurrence in Egypt. AB - This article reviews and discusses the historical and recent status of Rift Valley Fever (RVF) in Egypt and the other African countries based on the available and scattered reports. The recent outbreaks in African countries were reviewed and mapped out. Four major epidemics have been recorded in Egypt (1977, 1978, 1993 and 2003). The outbreak resulted in unpredicted human disease with severe clinical manifestations and heavy mortality as well as many abortions and deaths in sheep, goats, cattle, water buffalo and camels. Of the 18 culicine mosquito species that occur in Egypt, Culex pipiens and Cx. antennatus were implicated as vectors of RVF in Egypt based on their natural infection with RVF virus. Aedes caspius was also suspected of disseminating the virus among livestock based on host feeding and vector competence studies. The epidemiological factors related to the introduction and spread of RVF in Egypt are discussed. The study concluded that due to the availability and abundance of the potential vectors, suitability of environmental conditions, continuous importation of livestock's from Sudan, and the close association of susceptible domestic animals with humans, the RVF virus could possibly occur and circulate in Egypt. PMID- 29391129 TI - When Biochemical Phenotype Predicts Genotype: Pheochromocytoma and Paraganglioma. PMID- 29391130 TI - Mortal Portal: Left Ventricular Free Wall Rupture. PMID- 29391131 TI - Telehealth in Inflammatory Bowel Disease: Every Patient May Need a Coach! PMID- 29391133 TI - Dynamics of Stability of Orientation Maps Recorded with Optical Imaging. AB - Orientation selectivity is an important feature of visual cortical neurons. Optical imaging of the visual cortex allows for the generation of maps of orientation selectivity that reflect the activity of large populations of neurons. To estimate the statistical significance of effects of experimental manipulations, evaluation of the stability of cortical maps over time is required. Here, we performed optical imaging recordings of the visual cortex of anesthetized adult cats. Monocular stimulation with moving clockwise square-wave gratings that continuously changed orientation and direction was used as the mapping stimulus. Recordings were repeated at various time intervals, from 15 min to 16 h. Quantification of map stability was performed on a pixel-by-pixel basis using several techniques. Map reproducibility showed clear dynamics over time. The highest degree of stability was seen in maps recorded 15-45 min apart. Averaging across all time intervals and all stimulus orientations revealed a mean shift of 2.2 +/- 0.1 degrees . There was a significant tendency for larger shifts to occur at longer time intervals. Shifts between 2.8 degrees (mean +/- 2SD) and 5 degrees were observed more frequently at oblique orientations, while shifts greater than 5 degrees appeared more frequently at cardinal orientations. Shifts greater than 5 degrees occurred rarely overall (5.4% of cases) and never exceeded 11 degrees . Shifts of 10-10.6 degrees (0.7%) were seen occasionally at time intervals of more than 4 h. Our findings should be considered when evaluating the potential effect of experimental manipulations on orientation selectivity mapping studies. PMID- 29391134 TI - Lipemic interference of ceruloplasmin assays - An evaluation of lipid removal methods. AB - BACKGROUND: The present studies were conducted to characterize lipemic interference across three FDA-cleared ceruloplasmin (CERU) assays and to evaluate procedures designed to remove lipemic interference. METHODS: CERU assays on the Abbott ARCHITECT ci8200, Beckman AU5800, and Roche cobas Integra 400 Plus were evaluated. Precision, linearity with dilution, lipemic interference, and three methods for removing lipemia were assessed on each platform: ultracentrifugation (UC), lipemia-clearing reagent LipoClear (LC), and 1:5 dilution (DIL). Lipemia index (L-index) thresholds were established using endogenously lipemic specimens and sera spiked with human-derived triglyceride-rich lipoproteins. RESULTS: The ci8200 showed greater susceptibility to endogenous lipemic interference than would be expected based on vendor-derived limits established with Intralipid. Endogenous lipemia causes a negative interference on the ci8200 and a positive interference on the Integra. UC was generally the most reliable method of removing lipemic interference without impacting baseline CERU results. CONCLUSIONS: CERU assays on different platforms have varying susceptibility to lipemic interference. L-index thresholds derived using Intralipid may not accurately represent interference caused by endogenous lipemia. PMID- 29391132 TI - Neonatal Ethanol and Choline Treatments Alter the Morphology of Developing Rat Hippocampal Pyramidal Neurons in Opposite Directions. AB - Some of the neurobehavioral deficits identified in children with Fetal Alcohol Spectrum Disorders (FASDs) have been recapitulated in a binge model of gestational third trimester-equivalent ethanol (EtOH) exposure, in which Sprague Dawley rats are intragastrically intubated between post-natal day (PD) 4 and PD9 with high doses of EtOH. In this model, the ameliorating effects of choline (Chol) administration on hippocampus-dependent behaviors altered by EtOH have also been extensively documented. In the present study, we investigated the effects of EtOH (5 g/kg/day) and/or Chol (100 mg/kg/day) on morphometric parameters of CA1 pyramidal neurons by Golgi-Cox staining followed by Neurolucida tracing and analysis. We found that EtOH increased apical dendrite complexity in male and female pups neonatally exposed to EtOH. EtOH did not significantly affect basal dendrite parameters in female and male rats. Interestingly, Chol treatments decreased basal dendrites' length, number, and maximal terminal distance in male pups. When pups were co-treated with EtOH and Chol, Chol did not rescue the effect of EtOH. In conclusion, EtOH increases while Chol decreases dendritic length and arborization of hippocampal CA1 neurons in PD9 rats. We hypothesize that developmental EtOH exposure induces a premature maturation of neurons, leading to early restriction of neuronal plasticity while Chol treatments delay the normal program of neuronal maturation and therefore prolong the window of maximal plasticity. Chol does not prevent the effects of developmental alcohol exposure on hippocampal pyramidal neurons' morphology characterized in the present study, although whether prolonged Chol administration after developmental EtOH exposure rectifies EtOH damage remains to be assessed. PMID- 29391135 TI - Cyclosporin A inhibits mitochondrial biogenesis in Hep G2 cells. AB - Dysregulation of mitochondrial biogenesis is associated with pathogenesis in many diseases, including liver diseases. Cyclosporine A (CsA), one of the most commonly used drug to treat many autoimmune diseases and to prevent allograft rejection after organ transplantation, has been reported to cause mitochondrial dysfunction. However, the cellular mechanisms underlying CsA on mitochondrial dysfunction remain at present not completely elucidated. In this study, we found that CsA reduced the expression of PGC-1alpha at both the mRNA and protein levels in HepG2 cells. Correspondingly, the expressions of its target genes NRF 1 and TFAM were reduced in response to CsA treatment. In addition, mtDNA/nDNA, mitochondria mass, ATP production, and cytochrome C oxidase activity were significantly reduced by treatment with CsA. Over-expression of PGC-1alpha was found to rescue the negative effect of CsA administration on mitochondrial biogenesis. Mechanistically, CREB was involved in the inhibitory effects of CsA in mitochondrial biogenesis. PMID- 29391136 TI - Editorial Comment. PMID- 29391137 TI - Editorial Comment. PMID- 29391139 TI - Reply by Authors. PMID- 29391138 TI - Erratum. PMID- 29391140 TI - Radiation Exposure in the Medical ICU: Predictors and Characteristics. AB - BACKGROUND: Patients admitted to the medical ICU (MICU) are often subjected to multiple radiologic studies. We hypothesized that some endure radiation dose exposure (cumulative effective dose [CED]) in excess of annual US federal occupational health standard limits (CED >= 50 mSv) and 5-year cumulative limit (CED >= 100 mSv). We also evaluated the correlation of CED with Acute Physiology and Chronic Health Evaluation (APACHE) III score and other clinical variables. METHODS: Retrospective observational study conducted in an academic medical center involving all adult admissions (N = 4,155) to the MICU between January 2013 and December 2013. Radiation doses from ionizing radiologic studies were calculated from reference values to determine the CED. RESULTS: Three percent of admissions (n = 131) accrued CED >= 50 mSv (1% [n = 47] accrued CED >= 100 mSv). The median CED was 0.72 mSv (interquartile range, 0.02-5.23 mSv), with a range of 0.00 to 323 mSv. Higher APACHE III scores (P = .003), longer length of MICU stay (P < .0001), sepsis (P = .03), and gastrointestinal disorders and bleeding (P < .0001) predicted higher CED in a multivariable linear regression model. Patients with gastrointestinal bleeding and disorders had an odds ratio of 21.05 (95% CI, 13.54-32.72; P < .0001) and 6.94 (95% CI, 3.88-12.38; P < .0001), respectively, of accruing CED >= 50 mSv in a multivariable logistic regression model. CT scan and interventional radiology accounted for 49% and 38% of the total CED, respectively. CONCLUSIONS: Patients in the MICU are exposed to radiation doses that can be substantial, exceeding federal annual occupational limits, and in a select subset, are > 100 mSv. Efforts to justify, restrict, and optimize the use of radiologic resources when feasible are warranted. PMID- 29391141 TI - Spontaneous Intrahepatic Portal Systemic Venous Shunt: It Can Happen! PMID- 29391142 TI - Enteritis and Rapid-Onset Renal Dysfunction in a Previously Healthy Adult. PMID- 29391143 TI - TGF-beta/Smad signaling pathway positively up-regulates the differentiation of Interleukin-9-producing CD4+ T cells in human Echinococcus granulosus infection. AB - OBJECTIVES: Cystic echinococcosis (CE) is a zoonotic disease caused by Echinococcus granulosus (Eg) infection. Th9 cells are reported to be involved in the immune responses in CE patients. This study aims to investigate the role of TGF-beta/Smad pathway in the regulation of Th9 cells in CE patients. METHODS: Using Western blot analysis, flow cytometry, qPCR, immunohistochemistry, ELISA and MTT assay, we measured the expression levels of TGF-beta/Smad, PU.1, IRF-4, and IL-9 in CE patients. RESULTS: The levels of TGF-beta, p-Samd3, PU.1 and IL-9 were elevated in the liver of CE patients. IL-9 and IL-9R expressions were also elevated in the infected liver tissue, and IL-9 level was positively correlated with the liver inflammation. The levels of IL-9, IL-4, TGF-beta and IL-10 in the supernatant were also significantly increased after stimulating hepatic lymphocytes of CE patients with Eg antigen B. After blocking the TGF-beta pathway signaling in vitro, PU.1 and IL-9 were obviously reduced. CONCLUSIONS: IL-9 may aggravate the inflammatory response in the liver of CE patients. The TGF beta/Smad signaling pathway is activated, and the signaling pathway may promote the differentiation of Th9 cells and IL-9 expression in active CE patients. PMID- 29391144 TI - Predicting Distal Aortic Remodeling After Endovascular Repair for Chronic DeBakey III Aortic Dissection. AB - BACKGROUND: Chronic DeBakey III aortic dissection is typically managed with open aortic reconstruction. Thoracic endovascular aortic grafting (TEVAR) has been attempted in patients with chronic DeBakey III with improved outcomes over medical management, however with frequent failures. This study investigates factors associated with positive aortic remodeling from a large aortic center. METHODS: Three-dimensional reconstructions (M2S, West Lebanon, NH) of computed tomography angiography scans of 48 patients who underwent TEVAR from 2005 to 2015 were analyzed. The dissection was characterized, and measurements were obtained from preoperative and postoperative scans at four time points. Standard univariate Wilcoxon rank sum and Fisher's exact tests were used to analyze continuous and ordinal/nominal data, respectively. Multivariable logistic regression was performed. RESULTS: In a multivariate logistic model, having fewer than two visceral vessels off the true lumen was a negative predictor of total thrombosis (odd ratio [OR] 0.01, 95% confidence interval [CI]: <0.01 to 0.84, p = 0.04). In a logistic model that predicted total thrombosis in zones 3 and 4, maximum diameter 2 cm above the celiac axis was a significant negative predictor (OR 0.75, 95% CI: 0.57 to 0.99, p = 0.05). In a model that predicted failure of the maximum overall diameter of the descending aorta to regress within 1 year after TEVAR, maximum overall diameter preoperatively (OR 1.19, 95% CI: 1.02 to 1.29, p = 0.03) and tear location on the greater curve (OR 18.1, 95% CI: 1.3 to 243, p = 0.03) were significant positive predictors. CONCLUSIONS: TEVAR is feasible in chronic dissection but is limited by complex dissection-related anatomy. Increasing number of visceral vessels off the false lumen, maximum preoperative aortic size, and location of the primary tear on the greater curve were associated with poorer remodeling. PMID- 29391145 TI - Associations Between Surgical Ablation and Operative Mortality After Mitral Valve Procedures. AB - BACKGROUND: Surgical ablation (SA) for atrial fibrillation (AF) concomitant to mitral valve repair/replacement (MVRR) improves longitudinal sinus rhythm. However, the risk of adding SA remains a clinical question. This study examined whether the addition of contemporary SA for AF has an impact on operative outcomes. METHODS: The study cohort included 88,765 MVRR patients with or without SA, coronary artery bypass grafting (CABG), septal defect, and tricuspid repair in The Society of Thoracic Surgeons Database between 2011 and 2014. Group 1 did not have AF (No-AF) and did not receive SA (No-SA); group 2 had No-AF immediately preoperatively but received SA; group 3 had AF but No-SA; and group 4 had AF with SA. Groups 3 and 4 were stratified into paroxysmal versus nonparoxysmal AF. With the use of logistic regression, with group 1 as reference, risk-adjusted odds ratios (OR) for mortality were compared for SA performance, AF type, and SA technique. RESULTS: Group 3 had higher age, New York Heart Association class, redo operations, and unadjusted mortality than group 4. Relative to group 1, group 3 had an OR for mortality of 1.15 (95% confidence interval: 1.04 to 1.27, p < 0.01). OR increments were similar for paroxysmal and nonparoxysmal AF. In group 4, concomitant SA was independently associated with lower AF-related relative risk (OR 1.08), to a level that was not different from group 1 (p = 0.13). Observed treatment effects were equivalent for paroxysmal and nonparoxysmal AF and across all levels of baseline risk. CONCLUSIONS: For patients with AF at the time of mitral operation, the performance of SA seems associated with a lower risk-adjusted operative mortality compared with patients who do not undergo ablation. PMID- 29391147 TI - Aortic Valve Repair of a Stenotic Unicuspid Aortic Valve in Young Patients. AB - BACKGROUND: The unicuspid aortic valve (UAV) is a well-described pediatric congenital abnormality, with incidence of 0.02% in the general population. Bicuspidization has been described as a potential surgical option to repair this defect. METHODS: Seventeen symptomatic young patients with a unicuspid valve combined with either valve insufficiency or valve stenosis underwent aortic valve (AV) bicuspidization procedure by using an equine pericardium. In addition to bicuspidization, 8 patients underwent aortic ring implantation and 5 patients underwent supracoronary replacement of the aorta. RESULTS: Our results show safety of the bicuspidization procedure. No deaths occurred during our average follow-up period of 26 months. Freedom from reoperation for any valve-related reason was 100% during this follow-up period. We observed a statistically significant increase in the AV area from 0.8 +/- 0.1 cm2 to 2.8 +/- 0.7 cm2 (p < 0.01), a statistically significant decrease in the mean systolic pressure gradient from 36 +/- 13.3 mm Hg to 9 +/- 4 mm Hg (p < 0.001), a statistically significant decrease in aortic insufficiency grade from 2.1 +/- 1.0 to 0.6 +/- 0.7 (p < 0.01) before and after bicuspidization, respectively, and a statistically significant decrease in the left ventricular end-diastolic diameter from 49.88 +/- 5.11 mm to 40.46 +/- 7.20 mm (p < 0.0005) and a statistically significant increase of the left ventricular ejection fraction from 56% +/- 8.20% to 64% +/- 7.83% at the time of follow-up. CONCLUSIONS: From our study, bicuspidization is an attractive surgical option to repair UAV, particularly in young patients who do not want to be subjected to long-term anticoagulation therapy or who refuse a more traditional surgical approach, such as Ross procedure, for reasons described previously. PMID- 29391146 TI - Ischemic Mitral Regurgitation: Abnormal Strain Overestimates Nonviable Myocardium. AB - BACKGROUND: Therapy for moderate ischemic mitral regurgitation remains unclear. Determination of myocardial viability, a necessary prerequisite for an improvement in regional contractility, is a likely key factor in determining response to revascularization alone. Myocardial strain has been proposed as a viability measure but has not been compared with late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We hypothesized that abnormal strain overestimates nonviable left ventricular (LV) segments measured with LGE and that ischemia and mechanical tethering by adjacent transmural myocardial infarction (TMI) also decreases strain in viable segments. METHODS: Sixteen patients with mild or greater ischemic mitral regurgitation and 7 healthy volunteers underwent cardiac magnetic resonance imaging with noninvasive tags (complementary spatial modulation of magnetization [CSPAMM]), LGE, and stress perfusion. CSPAMM images were post-processed with harmonic phase and circumferential and longitudinal strains were calculated. Viability was defined as the absence of TMI on LGE (hyperenhancement >50% of wall thickness). The borderzone was defined as any segment bordering TMI. Abnormal strain thresholds (+/-1 to 2.5 SDs from normal mean) were compared with TMI, ischemia, and borderzone. RESULTS: 7.4% of LV segments had TMI on LGE, and more than 14.5% of LV segments were nonviable by strain thresholds (p < 0.005). In viable segments, ischemia impaired longitudinal strain (least perfused one-third of LV segments: -0.18 +/- 0.08 versus most perfused: -0.22 +/- 0.1, p = 0.01) and circumferential strain (-0.12 +/- 0.1 versus -0.16 +/- 0.08, p < 0.05). In addition, infarct proximity impaired longitudinal strain (-0.16 +/- 0.11 borderzone versus -0.18 +/- 0.09 remote, p = 0.05). CONCLUSIONS: Impaired LV strain overestimates nonviable myocardium compared with TMI on LGE. Ischemia and infarct proximity also decrease strain in viable segments. PMID- 29391148 TI - Lean, Efficient, and Profitable Operating Rooms: How I Teach It. PMID- 29391149 TI - Surgical Treatment of Multifocal Pulmonary Mucormycosis. AB - Mucormycosis is a devastating opportunistic fungal infection to which the immunosuppressed are particularly vulnerable. We report the case of a 60-year-old man who was found to have multifocal pulmonary mucormycosis 10 weeks after concomitant heart and kidney transplantation. Despite appropriate antifungal therapy, the infection progressed rapidly and soon involved critical pulmonary vasculature. He successfully underwent staged operative resection of his pulmonary mucormycosis without recurrence of infection. Although surgical debridement of pulmonary mucormycosis is typically reserved for localized disease, this case demonstrates that surgical intervention should be considered as an adjunct to antifungal therapy in multifocal disease. PMID- 29391150 TI - Microvascular Responsiveness to Pulsatile and Nonpulsatile Flow During Cardiopulmonary Bypass. AB - BACKGROUND: Pulsatile perfusion may offer microcirculatory advantages over conventional nonpulsatile perfusion during cardiopulmonary bypass (CPB). Here, we present direct visual evidence of microvascular perfusion and vasoreactivity between perfusion modalities. METHODS: A prospective, randomized cohort study of 20 high-risk cardiac surgical patients undergoing pulsatile (n = 10) or nonpulsatile (n = 10) flow during CPB was conducted. Changes in sublingual mucosal microcirculation were assessed with orthogonal polarization spectral imaging along with near-infrared spectroscopic indices of thenar muscle tissue oxygen saturation (StO2) and its recovery during a vascular occlusion test at the following time points: baseline (T0), 30 minutes on CPB (T1), 90 minutes on CPB (T2), 1 hour after CPB (T3), and 24 hours after CPB (T4). RESULTS: On the basis of our scoring scale, a shift in microcirculatory blood flow occurred over time. The pulsatile group maintained normal perfusion characteristics, whereas the nonpulsatile group exhibited deterioration in perfusion during CPB (T2: 74.0% +/- 5.6% versus 57.6% +/- 5.0%) and after CPB (T3: 76.2% +/- 2.7% versus 58.9% +/- 5.2%, T4: 85.7% +/- 2.6% versus 69.8% +/- 5.9%). Concurrently, no important differences were found between groups in baseline StO2 and consumption slope at all time points. Reperfusion slope was substantially different between groups 24 hours after CPB (T4: 6.1% +/- 0.6% versus 3.7% +/- 0.5%), indicating improved microvascular responsiveness in the pulsatile group versus the nonpulsatile group. CONCLUSIONS: Pulsatility generated by the roller pump during CPB improves microcirculatory blood flow and tissue oxygen saturation compared with nonpulsatile flow in high-risk cardiac surgical patients, which may reflect attenuation of the systemic inflammatory response and ischemia-reperfusion injury. PMID- 29391151 TI - Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction. AB - Diabetic vascular complications are often defined by vascular endothelial lesions. However, as a plastic cell type, whether endothelial cells could transit from quiescence to hyper-active status and hamper vascular stability upon hyperglycemia stimulation and whether this process is involved in diabetic vascular complications remain obscure. Survivin has been identified as an anti apoptotic protein in tumor or epithelial cells by either promoting proliferation or inhibiting apoptosis. Therefore, this study aims at investigating the effects of hyperglycemia on endothelial cell status and the potential involvement of survivin. We found that high glucose (25 mM) did not cause endothelial injuries, instead, it evidently promotes endothelial proliferation and tube formation capacity indicating endothelial cell dysfunction upon hyperglycemia characterized by its preference to hyper-active status. Concomitantly, an upregulation of survivin was detected accompanied by the key component elevations of autophagy pathway including LC3, Beclin1, and p62. YM155, a specific inhibitor of survivin, could abrogate hyperglycemia-induced endothelial hyper-activation. Application of the autophagy inhibitor (3MA) and agonist (rapamycin) supported that survivin could be as a downstream effect or of autophagy. Thus, our results suggested that survivin/autophagy axis a potential therapeutic target in treatment of diabetic vascular complications. PMID- 29391152 TI - LZ205, a newly synthesized flavonoid compound, exerts anti-inflammatory effect by inhibiting M1 macrophage polarization through regulating PI3K/AKT/mTOR signaling pathway. AB - Macrophage polarization is involved in the process of inflammation. Regulation of macrophage polarization is considered to be an effective method for the treatment of various inflammatory diseases. In our study, we investigated the potential molecular mechanism of the flavonoid compound LZ205, which exhibits anti inflammatory property. Results showed that LZ205 significantly reduced M1 macrophage-associated proinflammatory cytokines secretion by regulating PI3K/AKT/mTOR signaling pathway without affecting M2 macrophage-associated cytokines mRNA levels. In vivo studies showed that LZ205 significantly inhibited M1 macrophages polarization in DSS-induced colitis and alum-induced murine peritonitis. Consistent with in vitro studies, LZ205 significantly blocked expression of PI3K, p-AKT and p-mTOR in colon tissues and peritoneal macrophages. Taken together, LZ205 exerts anti-inflammatory effect by inhibiting M1 macrophage polarization via regulating PI3K/AKT/mTOR signaling pathway. PMID- 29391153 TI - An historical note on the cell theory. AB - The development of the microscope was a precondition for the discovery of cells. This instrument magnifies objects too small to be seen by the naked eye. In 1673, the Dutch botanist, Anton van Leeuwenhoek, made a more advanced microscope and reported seeing a myriad of microscopic "animalcules" in water. He also made further studies of red blood cells and sperm cells. Most studies that followed were done on the easily studied plant tissues. Plant cells, rigidly encased in their cell walls, were ideal to study in situ. The cell theory proposes that nucleated cells are the basic structure of plants and animals. This concept was observed and published separately, first by the botanist, Matthias Schleiden, in 1838, and then by the zoologist, Theodor Schwann, in 1839. Their work demonstrated that cells form the basic unit of life of plants and animals. Rudolf Virchow concluded that all living organisms are the sum of single cellular units and that cells multiply. PMID- 29391154 TI - O-GlcNAcylation affects beta-catenin and E-cadherin expression, cell motility and tumorigenicity of colorectal cancer. AB - O-GlcNAcylation, the addition of beta-N-acetylglucosamine (O-GlcNAc) moiety to Ser/Thr residues, is a sensor of the cell metabolic state. Cancer diseases such as colon, lung and breast cancer, possess deregulated O-GlcNAcylation. Studies during the last decade revealed that O-GlcNAcylation is implicated in cancer tumorigenesis and proliferation. The Wnt/beta-catenin signaling pathway and cadherin-mediated adhesion are also implicated in epithelial-mesenchymal transition (EMT), a key cellular process in invasion and cancer metastasis. Often, deregulation of the Wnt pathway is caused by altered phosphorylation of its components. Specifically, phosphorylation of Ser or Thr residues of beta catenin affects its location and interaction with E-cadherin, thus facilitating cell-cell adhesion. Consistent with previous studies, the current study indicates that beta-catenin is O-GlcNAcylated. To test the effect of O-GlcNAcylation on cell motility and how O-GlcNAcylation might affect beta-catenin and E-cadherin functions, the enzyme machinery of O-GlcNAcylation was modulated either with chemical inhibitors or by gene silencing. When O-GlcNAcase (OGA) was inhibited, a global elevation of protein O-GlcNAcylation and increase in the expression of E cadherin and beta-catenin were noted. Concomitantly with enhanced O GlcNAcylation, beta-catenin transcriptional activity were elevated. Additionally, fibroblast cell motility was enhanced. Stable silenced cell lines with adenoviral OGA or adenoviral O-GlcNAc transferase (OGT) were established. Consistent with the results obtained by OGA chemical inhibition by TMG, OGT-silencing led to a significant reduction in beta-catenin level. In vivo, murine orthotropic colorectal cancer model indicates that elevated O-GlcNAcylation leads to increased mortality rate, tumor and metastasis development. However, reduction in O-GlcNAcylation promoted survival that could be attributed to attenuated tumor and metastasis development. The results described herein provide circumstantial clues that O-GlcNAcylation deregulates beta-catenin and E-cadherin expression and activity in fibroblast cell lines and this might influence EMT and cell motility, which may further influence tumor development and metastasis. PMID- 29391155 TI - Antagonism of corticotropin-releasing factor CRF1 receptors blocks the enhanced response to cocaine after social stress. AB - Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526, or 15 or 30 ug/kg of the peptidic corticotropin-releasing factor CRF2 receptor antagonist Astressin2-B. Three weeks after the last defeat, conditioned place preference (CPP) induced by 1 mg/kg of cocaine was evaluated. Motor response to 10 mg/kg of cocaine was also studied after a sensitization induction. Blockade of corticotropin-releasing factor CRF1 receptor reversed the increase in cocaine CPP induced by social defeat. Conversely, peripheral corticotropin-releasing factor CRF2 receptor blockade produced similar effects to those observed in socially stressed animals. The effect of RSD on cocaine sensitization was again blocked by the corticotropin-releasing factor CRF1 receptor antagonist, while peripheral CRF2 receptor antagonist did not show effect. Acute administration of Astressin2 B induced an anxiogenic response. Our results confirm that CRF modulates the effects of social stress on reinforcement and sensitization induced by cocaine in contrasting ways. These findings highlight CRF receptors as potential therapeutic targets to be explored by research about stress-related addiction problems. PMID- 29391156 TI - Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses. AB - Experimental colitis studies, including T cell-mediated colitis, indicate that IL 23 rather than IL-12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL-12 and IL-23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL-12 and IL-23, especially since the discovery of novel IL-12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL 12 and IL-23 in T cell-mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL-23-specific receptor subunit with that of an anti-IL 12/23p40 mAb in a naive CD4+ T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti-IL-23 receptor mAb inhibited not only the systemic Th17-response but also the Th1-response, both of which were up regulated in this model. These results suggest that IL-23, but not IL-12, signaling is critical for the development of colitis. Blockade of IL-23 signaling is a promising therapeutic approach for IBD. PMID- 29391157 TI - Ethyl rosmarinate inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in alveolar macrophages. AB - In this study, a series of rosmarinic acid and analogs were investigated for their anti-inflammatory potential against LPS-induced alveolar macrophages (MH S). Our results showed that, among the test compounds, ethyl rosmarinate (3) exhibited the most potent inhibitory effect on NO production in LPS-induced MH-S cells, with low cytotoxicity. Compound 3 exhibited remarkable inhibition of the production of PGE2 in LPS-induced MH-S cells. The inhibitory potency of compound 3 against LPS-induced NO and PGE2 release was approximately two-fold higher than that of dexamethasone. Compound 3 significantly decreased the mRNA and protein expression of iNOS and COX-2 and suppressed p65 expression in the nucleus in LPS induced MH-S cells. These results suggested that compound 3 inhibited NO and PGE2 production, at least in part, through the down-regulation of NF-kappaB activation. Analysis of structure-activity relationship revealed that the free carboxylic group did not contribute to inhibitory activity and that the alkyl group of the corresponding alkyl ester analogs produced a strong inhibitory effect. We concluded that compound 3, a structurally modified rosmarinic acid, possessed potent inhibitory activity against lung inflammation, which strongly supported the development of this compound as a novel therapeutic agent for the treatment of macrophage-mediated lung inflammatory diseases, such as COPD. PMID- 29391158 TI - GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet. AB - Skeletal muscle, hepatic insulin resistance, and beta cell dysfunction are the characteristic pathophysiological features of type 2 diabetes mellitus. GABA has an important role in pancreatic islet cells. The present study attempted to clarify the possible mechanism of GABA to improve glucose tolerance in a model of type 2 diabetes mellitus in rats. Fifty Wistar rats were divided into five groups: NDC that was fed the normal diet, CD which received a high-fat diet with streptozotocin, CD-GABA animals that received GABA via intraperitoneal injection, plus CD-Ins1 and CD-Ins2 groups which were treated with low and high doses of insulin, respectively. Body weight and blood glucose were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), urine volume, amount of water drinking, and food intake assessments were performed monthly. The hyperinsulinemic euglycemic clamp was done for assessing insulin resistance. Plasma insulin and glucagon were measured. Abdominal fat was measured. Glucagon receptor, Glucose 6 phosphatase, Phosphoenolpyruvate carboxykinase genes expression were evaluated in liver and Glucose transporter 4 (GLUT4) genes expression and protein translocation were evaluated in the muscle. GABA or insulin therapy improved blood glucose, insulin level, IPGTT, ITT, gluconeogenesis pathway, Glucagon receptor, body weight and body fat in diabetic rats. GLUT4 gene and protein expression increased. GABA whose beneficial effect was comparable to that of insulin, also increased glucose infusion rate during an euglycemic clamp. GABA could improve insulin resistance via rising GLUT4 and also decreasing the gluconeogenesis pathway and Glucagon receptor gene expression. PMID- 29391159 TI - Cricothyroid Membrane Puncture-Guided Tracheostomy: A New Technique for Emergency Airway Access. AB - PURPOSE: We sought to compare cricothyroid membrane puncture-guided tracheostomy (CMPGT) with surgical cricothyroidotomy (SC) and percutaneous tracheostomy with Griggs' guidewire dilating forceps (GWDF) for establishing an emergency airway in a porcine model. We hypothesized that CMPGT would be associated with a shorter time to ventilation and more rapid restoration of oxygenation. MATERIALS AND METHODS: We implemented a small pilot animal study. Eighteen miniature pigs were randomly assigned to undergo CMPGT, SC, or GWDF. The predictor variable was the technique used. The primary outcome variable was time to ventilation. Other outcome variables were efficiency of oxygenation restoration, procedure duration, and procedure-related complications. The data were assessed using 1-way analysis of variance and Bonferroni correction. The oxygen saturation (SpO2) changes over time were graphed using a time-series line plot. Statistical significance was set at P < .05. RESULTS: Airways were successfully established in all 18 pigs. SC (68 +/- 4 seconds) showed the shortest procedure duration compared with GWDF (95 +/- 3 seconds) and CMPGT (96 +/- 4 seconds); however, the time to ventilation using CMPGT (21 +/- 2 seconds) was significantly shorter than that with SC (68 +/- 4 seconds) and GWDF (95 +/- 3 seconds) (P < .01). Spo2 in each group increased postoperatively, reaching 95% at 120 seconds, 131 seconds, and 144 seconds in the CMPGT, SC, and GWDF groups, respectively. The slope of the ascending phase of the Spo2 curve was 0.38 for CMPGT, 0.42 for SC, and 0.53 for GWDF (P < .05). Two pigs in each group had minor intraoperative bleeding, and 1 pig in the SC group had moderate bleeding. CONCLUSIONS: The results of this animal study suggest that CMPGT is a time-efficient and safe technique for emergency airway access that allows for a more rapid return of ventilation and obviates conversion to definitive tracheostomy. Further cadaveric study is ongoing. PMID- 29391160 TI - Identification of Independent Risk Factors for Complications: A Retrospective Analysis of 163 Fibular Free Flaps for Mandibulofacial Reconstruction. AB - PURPOSE: Fibular free flap transfer is a powerful tool available to the reconstructive surgeon when treating oral and maxillofacial defects, but complications still occasionally occur and predictive analysis focusing on this specific flap is limited in terms of risk factors for complication. The purpose of this study was to identify key variables associated with complications in patients undergoing fibular free flap transfer. PATIENTS AND METHODS: The data of 163 consecutive patients who underwent fibular free flap surgery at the Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, between 2012 and 2015 were reviewed retrospectively. Patient demographic data, laboratory data, surgical data, and fluid infusion related data that may have an influence on free flap outcomes were recorded. Univariate and multivariate logistic regression analyses were used to identify relevant risk factors. RESULTS: A total of 163 fibular free flaps were transferred for mandibulofacial reconstruction in 163 patients with a mean age of 50.9 years. Postoperative complications developed in 33 (20.2%). Multivariate analysis showed that free flap complications were significantly associated with radiotherapy history (odds ratio [OR], 5.12; P = .001), postoperative anemia (OR, 1.048; P = .041), postoperative hypoalbuminemia (OR, 0.844; P = .002), and prolonged operative time (OR, 1.005; P = .004). CONCLUSIONS: Radiotherapy history, decreased postoperative hemoglobin and albumin levels, and prolonged operative time are potential predictors of postoperative complications after fibular free flap reconstruction for mandibulofacial defects. PMID- 29391161 TI - Benefit of Temporomandibular Joint Lavage With Intra-Articular Steroids Versus Lavage Alone in the Management of Temporomandibular Joint Involvement in Juvenile Idiopathic Arthritis. AB - PURPOSE: The aim of the present investigation was to evaluate, in patients with juvenile idiopathic arthritis, the effect of lavage with or without intra articular corticosteroid (IACS) injection on clinical temporomandibular joint (TMJ) signs and symptoms of inflammation and changes in acute inflammation as assessed using magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-one patients (mean age, 13.6 +/- 4.0 yr) with juvenile idiopathic arthritis participating in a large prospective juvenile inflammatory rheumatism cohort study (JIRcohorte) were included in this study. Clinical history, examination, and MRI were carried out at baseline and 6 months after intervention, if any. Twenty-one patients underwent lavage and IACS injection in at least 1 TMJ, 8 patients underwent lavage of at least 1 TMJ, and 12 patients were followed with no intervention. Outcomes measured were maximal mouth opening, Helkimo dysfunction index scores, pain intensity, and acute inflammation as assessed using MRI. RESULTS: All groups showed a mean increase in mouth opening and mean decrease in pain intensity. The mean Helkimo clinical dysfunction score decreased for the 2 intervention groups but not for the control group. The mean Helkimo anamnestic dysfunction score decreased for the lavage with IACS group but not for the lavage-only group. The only statistically relevant difference was found for the Helkimo anamnestic dysfunction score comparing the lavage-only with the lavage with IACS group, with a more positive effect found in the lavage with IACS group. More than 50% of joints in each group showed no change at MRI examination. Joints with lavage and ICAS injection showed better improvement than joints that had lavage only or no intervention. CONCLUSION: TMJ lavage with or without IACS injection cannot be claimed to systematically decrease pain, increase mouth opening, or resolve acute inflammation. Despite a tendency for improvement, response to this treatment is very patient dependent and can be determined by an array of other variables. PMID- 29391162 TI - Resection of the Posterior, Middle, and Anterior Superior Alveolar Nerves and Infraorbital Nerve Neurolysis for Refractory Maxillary Pain. AB - Trigeminal injury can cause intractable facial pain. However, surgical approaches to the superior alveolar nerves have not been widely described. We report resection of the anterior superior alveolar nerve (ASAN), middle superior alveolar nerve (MSAN), and posterior superior alveolar nerve (PSAN) in a patient with refractory facial pain and outline an algorithmic approach to the treatment of trigeminal nerve injury. A 56-year-old woman presented with a 3-year history of refractory facial pain in the distribution of the right superior alveolar nerves after dental trauma. As a comorbidity, central sensitization developed in the patient, manifesting in the uninjured oral areas being painful. After several temporary nerve blocks and medical management, the patient underwent resection of the ASAN, MSAN, and PSAN, as well as neurolysis of the infraorbital nerve, through a Caldwell-Luc approach. One week postoperatively, she reported substantial improvement in pain symptoms, including burning and temperature sensitivity, in the right maxilla. These findings were maintained at 7 months, without any maxillary sinus complications. Central sensitization caused continued intraoral symptoms. The ASAN, MSAN, and PSAN can be surgically resected within the maxillary sinus to treat refractory neuropathic pain. An etiology-based approach can guide successful treatment of trigeminal neuropathy. Central sensitization as a comorbidity must be addressed medically. PMID- 29391163 TI - Biologic Rationale of a Surgical Procedure: Bone Augmentation. PMID- 29391164 TI - Molecular specification of facial branchial motor neurons in vertebrates. AB - Orofacial muscles are critical for life-sustaining behaviors, such as feeding and breathing. Centuries of work by neuroanatomists and surgeons resulted in the mapping of bulbar motor neurons in the brainstem and the course of the cranial nerves that carry their axons. Despite the sophisticated understanding of the anatomy of the region, the molecular mechanisms that dictate the development and maturation of facial motor neurons remain poorly understood. This fundamental problem has been recently revisited by physiologists with novel techniques of studying the rhythmic contraction of orofacial muscles in relationship to breathing. The molecular understanding of facial motor neuron development will not only lead to the comprehension of the neural basis of facial expression but may also unlock new avenues to generate stem cell-derived replacements. This review summarizes the current understanding of molecular programs involved in facial motor neuron generation, migration, and maturation, including neural circuit assembly. PMID- 29391165 TI - Stochastic clonal expansion of "superstars" enhances the reserve capacity of enteric nervous system precursor cells. AB - We quantified cell population increase in the quail embryo enteric nervous system (ENS) from E2.5 (about 1500 cells) to E12 (about 8 million cells). We then probed ENS proliferative capacity by grafting to the chorio-allantoic membrane large (600 cells) and small (40 cells) populations of enteric neural crest (ENC) cells with aneural gut. This demonstrated that ENC cells show an extremely high capacity to regulate their proliferation while forming the ENS. Previous mathematical models and clonal label experiments revealed that a few dominant ENS "superstar" cell clones emerge but most clones are small. The model implied that "superstars" arise stochastically, but the same outcome could arise if "superstars" were pre-determined. We investigated these two modes mathematically and by grafting experiments with large and small numbers of ENCs, each including one EGFP-labelled ENC cell. The stochastic model predicts that the frequency of "superstar" detection increases as the ENC population decreases, the pre determined model does not. Experimentally, as predicted by the stochastic model, the frequency of "superstar" detection increased with small ENC cell number. We conclude that ENS "superstar" clones achieve this status stochastically. Clonal dominance implies that clonal diversity is greatly reduced and in this case, somatic mutations may affect the phenotype. We suggest that somatic mutations coupled with loss of clonal diversity may contribute to variable penetrance and expressivity in individuals with genetically identical ENS pathologies. PMID- 29391166 TI - A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved? AB - The journey of embryonic development starts at oocyte fertilization, which triggers a complex cascade of events and cellular pathways that guide early embryogenesis. Recent technological advances have greatly expanded our knowledge of cleavage-stage embryo development, which is characterized by an increased rate of whole-chromosome losses and gains, mixoploidy, and atypical cleavage morphokinetics. Embryonic aneuploidy significantly contributes to implantation failure, spontaneous miscarriage, stillbirth or congenital birth defects in both natural and assisted human reproduction. Essentially, early embryo development is strongly determined by maternal factors. Owing to considerable limitations associated with human oocyte and embryo research, the use of animal models is inevitable. However, cellular and molecular mechanisms driving the error-prone early stages of development are still poorly described. In this review, we describe known events that lead to aneuploidy in mammalian oocytes and preimplantation embryos. As the processes of oocyte and embryo development are rigorously regulated by multiple signal-transduction pathways, we explore the putative role of signaling pathways in genomic integrity maintenance. Based on the existing evidence from human and animal data, we investigate whether critical early developmental pathways, like Wnt, Hippo and MAPK, together with distinct DNA damage response and DNA repair pathways can be associated with embryo genomic instability, a question that has, so far, remained largely unexplored. PMID- 29391168 TI - Mapping diet-induced alternative polyadenylation of hypothalamic transcripts in the obese rat. AB - RNA biogenesis has emerged as a powerful biological event that regulates energy homeostasis. In this context insertion of alternative polyadenylation sites (APSs) dictate the fate of newly synthesized RNA molecules and direct alternative splicing of nascent transcripts. Thus APSs serve a mechanistic function by regulating transcriptome expression and function. In this study we employed a novel RNA-Seq Next Generation Sequencing (NGS) approach that utilized the power of Whole Transcriptome Termini Site Sequencing (WTTS-Seq) to simultaneously measure APS events on multiple RNA biotypes. We used this technique to measure APS events in the hypothalamus of adult male Long Evans rats exposed to a palatable high fat diet (HFD) or chow. Rats maintained on HFD displayed typical hyperphagic feeding and ensuing body weight gain over the one-month manipulation period. Our WTTS-Seq analysis mapped approximately 89,000 unique hypothalamic APSs induced by HFD relative to chow fed controls. HFD exposure produced APSs on multiple RNA biotypes in the hypothalamus. The majority of detected APSs occur on mRNA transcripts that encode functional proteins. Notably we find APSs on micro (miRNA) and long non-coding RNAs (lncRNA), newly recognized transcription factors that regulate body weight in rodents. In addition we detect APSs on protein encoding mRNAs that control neuron projection development and synapse organization and glutamate signaling, key events hypothesized to maintain excess food intake. Importantly, quantitative real time PCR indicated that APS insertion led to increased hypothalamic expression of multiple RNA biotypes. Collectively these data highlight APS events as a novel genetic mechanism that directs hypothalamic RNA biogenesis stimulated by diet-induced obesity. PMID- 29391167 TI - Structural basis for the interaction of the beta-secretase with copper. AB - The beta-secretase (BACE1) features a unique sulfur rich motif (M462xxxC466xxxM470xxxC474xxxC478) in its transmembrane helix (BACE1-TM) which is characteristic for proteins involved in copper ion storage and transport. While this motif has been shown to promote BACE1-TM trimerization and binding of copper ions in vitro, the structural basis for the interaction of copper ions with the BACE1-TM is still not well understood. Using molecular dynamics (MD) simulations, we show that membrane embedded BACE1-TMs adopt a flexible trimeric structure that binds and conducts copper ions through variable coordination. In coarse-grained (CG) MD simulations, the spontaneous assembly of BACE1-TMs trimers results in a right-handed helix packing arrangement. In subsequent atomistic MD simulations the sulfur rich motif defines characteristic copper ion coordination sites along a constricted partially solvated axial pore. Sliding and tilting of BACE1-TMs along smooth A459xxxA463/464xxA467 surfaces, facilitated by a central P472 induced kink, enables copper ions to alternate between different coordination sites, including the prominent C466 and M470. We shed light into the structural arrangement of BACE1-TM trimers and propose a mechanism for copper ion conduction that might also apply to other proteins involved in metal ion transport. PMID- 29391169 TI - New triterpenoids with diverse side-chains from the barks of Melia Toosendan. AB - Nine new euphane- and apotirucallane-type triterpenoids (Toosendines A-I; 1-9), along with three known tirucallane-type compounds were isolated from the barks of Melia toosendan. Their structures were elucidated based on detailed spectroscopic analyses (HRESIMS, 1D/2D-NMR) and circular dichroism spectra. Results of bioactivities screening exhibited that compounds 1, 4 and 5 showed remarkable NO inhibitory activities in LPS-activated RAW 264.7 macrophages, meanwhile, compounds 1 and 4 showed moderate cytotoxicities against U2OS human cancer cell line. PMID- 29391170 TI - EzMol: A Web Server Wizard for the Rapid Visualization and Image Production of Protein and Nucleic Acid Structures. AB - EzMol is a molecular visualization Web server in the form of a software wizard, located at http://www.sbg.bio.ic.ac.uk/ezmol/. It is designed for easy and rapid image manipulation and display of protein molecules, and is intended for users who need to quickly produce high-resolution images of protein molecules but do not have the time or inclination to use a software molecular visualization system. EzMol allows the upload of molecular structure files in PDB format to generate a Web page including a representation of the structure that the user can manipulate. EzMol provides intuitive options for chain display, adjusting the color/transparency of residues, side chains and protein surfaces, and for adding labels to residues. The final adjusted protein image can then be downloaded as a high-resolution image. There are a range of applications for rapid protein display, including the illustration of specific areas of a protein structure and the rapid prototyping of images. PMID- 29391171 TI - Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues. AB - The growth and dynamics of epithelial tissues govern many morphogenetic processes in embryonic development. A recent quantitative transition in data acquisition, facilitated by advances in genetic and live-imaging techniques, is paving the way for new insights to these processes. Computational models can help us understand and interpret observations, and then make predictions for future experiments that can distinguish between hypothesised mechanisms. Increasingly, cell-based modelling approaches such as vertex models are being used to help understand the mechanics underlying epithelial morphogenesis. These models typically seek to reproduce qualitative phenomena, such as cell sorting or tissue buckling. However, it remains unclear to what extent quantitative data can be used to constrain these models so that they can then be used to make quantitative, experimentally testable predictions. To address this issue, we perform an in silico study to investigate whether vertex model parameters can be inferred from imaging data, and explore methods to quantify the uncertainty of such estimates. Our approach requires the use of summary statistics to estimate parameters. Here, we focus on summary statistics of cellular packing and of laser ablation experiments, as are commonly reported from imaging studies. We find that including data from repeated experiments is necessary to generate reliable parameter estimates that can facilitate quantitative model predictions. PMID- 29391172 TI - Within-host dynamics and random duration of pathogen infection: Implications for between-host transmission. AB - Taking an ecological perspective, this paper reports theoretical and empirical results concerning fatal bacterial infections of adult insects. Two models, each combining deterministic and stochastic elements, characterize how the pathogen's dynamics might govern an infected host's mortality rate. We analyze the models in detail for exponential pathogen growth, and apply them to observed insect mortality when the pathogen's growth is unregulated. We then allow bacteriophage to generate fluctuations in the within-host pathogen density; we demonstrate that only one of our models matches host mortality rates when pathogen growth is regulated by phage. We generalize our results on mortality hazard of individual hosts to analyze how random duration of the infectious period can combine with probabilistic transmission events to affect between-host transmission. PMID- 29391173 TI - Generation of Pax6-IRES-EGFP knock-in mouse via the cloning-free CRISPR/Cas9 system to reliably visualize neurodevelopmental dynamics. AB - Pax6 encodes a transcription factor that plays pivotal roles in eye development, early brain patterning, neocortical arealization, and so forth. Visualization of Pax6 expression dynamics in these events could offer numerous advantages to neurodevelopmental studies. While CRISPR/Cas9 system has dramatically accelerated one-step generation of knock-out mouse, establishment of gene-cassette knock-in mouse via zygote injection has been considered insufficient due to its low efficiency. Recently, an improved CRISPR/Cas9 system for effective gene-cassette knock-in has been reported, where the native form of guide RNAs (crRNA and tracrRNA) assembled with recombinant Cas9 protein are directly delivered into mouse fertilized eggs. Here we apply this strategy to insert IRES-EGFP-pA cassette into Pax6 locus and achieve efficient targeted insertions of the 1.8 kb reporter gene. In Pax6-IRES-EGFP mouse we have generated, EGFP-positive cells reside in the eyes and cerebellum as endogenous Pax6 expressing cells at postnatal day 2. At the early embryonic stages when the embryos are transparent, EGFP-positive regions can be easily identified without PCR-based genotyping, precisely recapitulating the endogenous Pax6 expression patterns. Remarkably, at E12.5, the graded expression patterns of Pax6 in the developing neocortex now become recognizable in our knock-in mice, serving a sufficiently sensitive and useful tool to precisely visualize neurodevelopmental processes. PMID- 29391174 TI - DNA extracellular traps are part of the immune repertoire of Periplaneta americana. AB - Extracellular traps (ETs), web-like structures composed of DNA and histones, are released by innate immune cells in a wide range of organisms. ETs capture microorganisms, thereby avoiding their spread, and also concentrate antimicrobial molecules, which helps to kill microbes. Although vertebrate innate immune systems share homology with the insect immune system, ETosis have yet to be characterized in insects. Here, we report that the hemocytes of the hemimetabolous insect Periplaneta americana release ETs upon in vitro stimulation. We further discuss the relationship between ETs and nodulation and in controlling bacterial spread in vivo. PMID- 29391175 TI - A protocolized approach to veno-arterial extracorporeal membrane oxygenation for massive pulmonary embolism. PMID- 29391176 TI - Intake of Trace Metals and the Risk of Incident Kidney Stones. AB - PURPOSE: The association between the intake of trace metals and the risk of incident stones has not been longitudinally investigated. MATERIALS AND METHODS: We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study, and the Nurses' Health Study I and II. During a followup of 3,316,580 person-years there was a total of 6,576 incident stones. We used multivariate regression models to identify associations of the intake of zinc, iron, copper and manganese with the risk of stones. In a subset of participants with 24-hour urine collections we examined the association between the intake of trace metals and urine composition. RESULTS: After multivariate adjustment total and dietary intakes of zinc and iron were not significantly associated with incident stones. A higher intake of manganese was associated with a lower risk of stones. The pooled HR of the highest quintile of total manganese intake compared with the lowest intake was 0.82 (95% CI 0.68-0.98, p = 0.02). Total but not dietary copper intake was marginally associated with a higher risk of stones (pooled HR 1.14, 95% CI 1.02-1.28, p = 0.01). There were no statistically significant associations of the total intake of manganese and copper with urinary supersaturation. CONCLUSIONS: Zinc and iron intake was not associated with a risk of stones. Copper intake may be associated with a higher risk in some individuals. Higher total manganese intake was associated with a lower risk of stones but not with traditional 24-hour urinary composite markers of stone risk. Further research is needed to elucidate the mechanisms by which manganese may reduce kidney stone formation. PMID- 29391177 TI - Usefulness of Preoperative Ultrasound for the Evaluation of Testicular Rupture in the Setting of Scrotal Gunshot Wounds. AB - PURPOSE: A scrotal gunshot wound may result in testicular injury, necessitating urgent scrotal exploration and attempted testicular salvage. Scrotal ultrasound is highly sensitive and specific for testicular rupture in the setting of blunt scrotal trauma but it has been poorly studied in the setting of scrotal gunshot wounds. Our objective was to determine the accuracy of scrotal ultrasound to identify testicular rupture following a scrotal gunshot wound. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with a scrotal gunshot wound from 2003 to 2014 in whom preoperative ultrasound was done prior to scrotal exploration. A heterogeneous echo pattern of testicular parenchyma with contour loss was considered a positive examination for testicular rupture. Patients underwent scrotal exploration within 24 hours of presentation. The sensitivity and specificity of ultrasound were estimated and compared to operative findings. ROC curve analysis was done. RESULTS: Of 75 patients who sustained a scrotal gunshot wound ultrasound was positive in 30 and negative in 45. No ultrasound revealed bilateral injuries. Scrotal exploration demonstrated a total of 40 testicular ruptures in 35 patients, of which 30 testicles were salvaged. Ten orchiectomies were performed. The sensitivity and specificity of ultrasound were 60% and 95%, respectively, with 16 missed injuries and 6 false positive findings. Positive predictive value was 80% and negative predictive value was 87%. The ROC AUC was 0.79. In 6 of the 16 missed injuries there was an ipsilateral hematocele or hematoma. CONCLUSIONS: The sensitivity of scrotal ultrasound is limited for evaluating testicular rupture after a scrotal gunshot wound. Large coincident hematoceles or hematomas may obscure the diagnosis of testicular rupture. Negative ultrasound should not preclude scrotal exploration after a scrotal gunshot wound is sustained. PMID- 29391178 TI - Triplex real-time PCR method for the qualitative detection of European and American foulbrood in honeybee. AB - The bacteria Melissococcus plutonius and Paenibacillus larvae, causative agents of respectively European and American foulbrood, damage honeybee health worldwide. Here, we present a specific and sensitive qualitative triplex real time PCR method to detect simultaneously those microbial agents and a honeybee gene, validated through a study involving 7 laboratories through Europe. PMID- 29391179 TI - The role of emotions and physiological arousal in modulating impulsive behaviour. AB - Impulsivity received considerable attention in the context of drug misuse and certain neuropsychiatric conditions. Because of its great health and well-being importance, it is crucial to understand factors which modulate impulsive behaviour. As a growing body of literature indicates the role of emotional and physiological states in guiding our actions and decisions, we argue that current affective state and physiological arousal exert a significant influence on behavioural impulsivity. As 'impulsivity' is a heterogeneous concept, in this paper, we review key theories of the topic and summarise information about distinct impulsivity subtypes and their methods of assessment, pointing out to the differences between the various components of the construct. Moreover, we review existing literature on the relationship between emotional states, arousal and impulsive behaviour and suggest directions for future research. PMID- 29391180 TI - The late posterior negativity in episodic memory: A correlate of stimulus retrieval? AB - We investigated whether the late posterior negativity (LPN) is a component linked to stimulus retrieval or rather to complex, higher-order stimulus evaluation processes or response preparation processes. Participants performed three separate tasks across separate sessions: an encoding task, a memory recognition task, and a visual discrimination task. In the visual discrimination task, the difficulty of stimulus evaluation was manipulated via stimuli varying in complexity (easy vs. moderately difficult) and duration of stimulus presentation (short vs. long). Three indices of the LPN peak were examined: amplitude, latency, and width. The LPN was present in all three tasks, with maximum amplitudes at occipital sites. Results of the visual discrimination task showed that the LPN amplitude is modulated by task difficulty. No latency differences were observed between short and long presentations, suggesting that the LPN is not related to response preparation. Consequently, we compared the LPN associated with short presentations of easy and difficult stimuli with the LPN of the encoding and memory task. The LPN amplitude was more negative in the memory task compared to the other tasks. Latency and width of the LPN were modulated by stimulus complexity, with increased latency and width in the encoding and memory task relative to the visual discrimination task. Overall, these findings suggest that the LPN is not a component linked to stimulus retrieval and response preparation, but rather to complex, higher-order stimulus evaluation processes, which are modulated by task difficulty. PMID- 29391181 TI - Secondary caries development and the role of a matrix metalloproteinase inhibitor: A clinical in situ study. AB - OBJECTIVES: This in situ study aimed to investigate whether the dentin treatment with MMPs inhibitor (CHX 2%) could influence the development of secondary caries wall lesions in different dentin-composite interfaces. MATERIAL AND METHODS: For 21 days, 15 volunteers wore a modified-occlusal splint loaded with dentin composite samples treated or not with CHX and restored according 4 different interface conditions: Bonding (B = samples restored with complete adhesive procedure), no bonding (NB = restored with composite resin without adhesive procedure), 100 MUm (no adhesive procedure and with intentional gap) and 100 MUm + B (adhesive material on composite side and intentional gap). Eight times per day, the splint with samples was dipped in a 20% sucrose solution for 10 min. Before and after caries development, samples were imaged with T-WIM and lesion depth (LD) and mineral loss (ML) were calculated. RESULTS: Linear mixed effect analysis showed that dentin treatment with CHX did not significantly affect the caries lesion progression (LD and ML; p <= 0.797). Dentin wall lesions were observed in the 100 MUm and 100 MUm + B groups independently of MMP inhibitor treatment. CONCLUSION: The treatment of dentin with MMP inhibitor was not able to slow down the secondary caries wall lesion development in this in situ study. SIGNIFICANCE: The dentin treatment with 2% CHX did not prevent secondary caries wall lesion initiation. PMID- 29391182 TI - Application of electrophoretic deposition to occlude dentinal tubules in vitro. AB - OBJECTIVES: This study aims to apply electrophoretic deposition (EPD) for occlusion of dentinal tubules in vitro and investigate its effect on tubule occlusion and shear bond strength (SBS). METHODS: Charged mesoporous silica nanoparticles (MSNs) were synthesized and characterized through field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier transform infrared (FT-IR) spectroscopy analyses. Thirty-nine sensitive dentin specimens were modeled and assigned randomly to three groups with different treatments (n = 13 each): group 1, immersion in the MSN suspension; and groups 2 and 3, anodic EPD with the specimen on the negative and positive electrode respectively. The effect of dentinal tubule occlusion was evaluated by dentin permeability test (n = 10 each) and FESEM examination (n = 3 each). Moreover, 18 specimens were grouped (n = 6 each) and treated in the same method. A resin stick was bonded onto each of the specimen using a self-etch adhesive (single bond universal) for SBS testing. RESULTS: Negatively-charged MSNs were synthesized and characterized as small and well-dispersed particles. After the EPD treatment (group 3), the dentinal tubules were effectively occluded by MSNs, which infiltrated into the tubules at a depth of approximately 7-8 MUm and tightly associated with the tubular inwalls. SBS was not significantly different among the three groups (P > 0.05). CONCLUSIONS: Synthesized MSNs were deposited into dentinal tubules by EPD treatment without compromising dentin bond strength. CLINICAL SIGNIFICANCE: Application of EPD is a new approach for occlusion of dentinal tubules and exhibits potential in the study of dentin hypersensitivity. PMID- 29391184 TI - Repint of "Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity". AB - Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. PMID- 29391186 TI - Non-random mating and information theory. AB - In this work, mate choice is modeled by means of the abstract concept of mutual mating propensity. This only assumes that different types of couples can have different mating success. The model is adequate for any population where mating occurs among distinct types. There is no extra assumption about particular mating scheme or preference model. The concept of mutual mating propensity permits to express the observed change in the mating phenotypes as the gain in information with respect to random mating. The obtained expression is a form of the Price equation in which the mapping between ancestral and descendant population is substituted by a mapping between random mating and non random mating population. At the same time, this framework provides the connection between mate choice and the exact mathematical partition of the choice effects, namely sexual isolation, sexual selection and a mixed effect. The sexual selection component is the sum of the intra-sexual male and female selection. The proposed framework helps to unveil previously hidden invariants. For example, if the mutual preference between partner types is multiplicative there is no sexual isolation (inter sexual selection) effect on the frequencies, i.e. the only possible effect of mate choice is intra-sexual selection. On the contrary, whatever the contribution of each partner to the mutual preference, if it comes as a non-multiplicative factor, there is at least an inter-sexual selection detectable effect. This new view over the mate choice problem, permits to develop general mating propensity models and to make predictions of the mate choice effects that may emerge from such models. This possibility opens up the way for setting a general theory of model fitting and multimodel inference for mate choice. Thus, it is suggested that the proposed framework, by describing mate choice as the flow of information due to non-random mating, provides a new important setting for exploring different mating models and their consequences. PMID- 29391187 TI - Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity. AB - In the course of our search for new GLP-1 analogs, we screened a number of [Ser8] GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser8]-GLP-1 (7-35)-GVKALIDEILAA-NH2, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4 h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs. PMID- 29391183 TI - The neurobiological basis of sleep: Insights from Drosophila. AB - Sleep is a biological enigma that has raised numerous questions about the inner workings of the brain. The fundamental question of why our nervous systems have evolved to require sleep remains a topic of ongoing scientific deliberation. This question is largely being addressed by research using animal models of sleep. Drosophila melanogaster, also known as the common fruit fly, exhibits a sleep state that shares common features with many other species. Drosophila sleep studies have unearthed an immense wealth of knowledge about the neuroscience of sleep. Given the breadth of findings published on Drosophila sleep, it is important to consider how all of this information might come together to generate a more holistic understanding of sleep. This review provides a comprehensive summary of the neurobiology of Drosophila sleep and explores the broader insights and implications of how sleep is regulated across species and why it is necessary for the brain. PMID- 29391188 TI - Maternal Separation Induces Different Autophagic Responses in the Hippocampus and Prefrontal Cortex of Adult Rats. AB - Our previous study has reported that maternal separation (MS) results in abnormal behaviors such as depressive-like and anxious-like behaviors in adult rats. However, the underlying mechanism remains unclear. In this study, we focused on the relationship between MS and autophagy in an effort to explain potential mechanisms. Pups experienced MS from postnatal days 7 to 21 and were randomly divided into the control (CON) group and MS group. Data showed that MS induced depressive-like and anxious-like behaviors in adult rats. Compared with the CON group, the glutamate level was obviously increased in the hippocampus (HP) and prefrontal cortex (PFC) of rats in the MS group. Interestingly, both beclin-1 expression and ratio of LC3II/LC3I were decreased in the HP, but they were increased in the PFC. Furthermore, N-methyl-d-aspartate receptor subunit 2B (NR2B) expression was significantly increased in the HP and PFC. Additionally, postsynaptic density-95 was increased in the HP; however, it was unchanged in the PFC. Moreover, the expression of synaptophysin was obviously decreased in both the HP and PFC. In conclusion, these findings suggest that MS induces different autophagic responses in the HP and PFC (i.e., the inhibition of autophagy in the HP and the activation of autophagy in the PFC), which can be related to the NR2B signaling pathway. PMID- 29391189 TI - Eosinophilic Solid and Cystic Renal Cell Carcinoma: Imaging Features of a Novel Neoplasm. AB - Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a recently described entity with distinct clinical, pathologic, and molecular features. However, the radiological aspects of ESC RCC have not been characterized. In this report, we describe the imaging findings of 2 ESC RCCs. We found 2 distinct imaging patterns that varied depending on histopathologic features (solid or cystic predominance). In conclusion, it is important to know the imaging characteristics and pathologic correlation of this novel neoplasm to increase its recognition and to improve the decision-making process. PMID- 29391185 TI - Colorectal cancer prevention: Immune modulation taking the stage. AB - Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention. PMID- 29391190 TI - Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization. AB - Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of "MR-associated hypertension", in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events. PMID- 29391191 TI - Proliferation of cells with aggregation and communication. AB - Cell proliferation is often considered to occur via front propagation with constant velocity. This scenario proposed by Fisher, Kolmogorov, Petrovsky, and Piskunov is based on the solution of the corresponding mean-field reaction diffusion equations and does not take into account that due to adhesion the cells have tendency to aggregate and that the rate of cell division may depend on the cell-cell communication. Herein, the author presents extensive Monte Carlo simulations taking both these factors into account and illustrating that the former factor can dramatically modify the spatio-temporal kinetics of cell proliferation. In particular, the conventional relation between the front velocity and diffusion coefficient may fail, the front velocity may appreciably increase with increasing time, and/or the front may be partly or fully smeared on the realistic length scales. PMID- 29391193 TI - Cloning and sequencing of three-finger toxins from the venom glands of four Micrurus species from Mexico and heterologous expression of an alpha-neurotoxin from Micrurus diastema. AB - The three-finger toxins (3FTxs) represent an extremely diverse protein family in elapid venoms, where the short chain alpha-neurotoxins are the most relevant toxin group from the clinical point of view. Essentially, the 3FTxs variability and the low proportions of alpha-neurotoxins in the venoms of North American coral snakes make it difficult to obtain effective elapid antivenoms against the envenomation symptoms caused mainly by these alpha-neurotoxins. In this work, thirty 3FTx transcript sequences were obtained from the venom glands of four coral snake species from Mexico (M. diastema, M. laticollaris, M. browni and M. tener). The transcripts were mined using a forward oligonucleotide based on the highly conserved signal peptide from the 3FTxs, and four of these transcripts, named MlatA1, B.D, B.E and D.H, encoded for short-chain alpha-neurotoxins. Additionally, one isoform of the D.H alpha-neurotoxin transcript was identified in the venom of M. diastema. The mature alpha-neurotoxin coded in the D.H transcript was heterologously expressed, and it was found soluble (4.2 mg/l) in the cytoplasm of a bacterial system. The recombinant D.H (rD.H) had an IC50 value of 31.5 +/- 4.4 nM on nicotinic acetylcholine receptors of the muscular type expressed in rhabdomyosarcoma cells (TE671). The rDH also had an LD50 of 0.15 mg/kg mice, and it was evaluated as a potential immunogen in New Zealand rabbits. The protective capacity of rabbit sera was tested against two native coral snake alpha-neurotoxins, and against rD.H. One of the anti-rD.H rabbit sera was able to neutralize the lethality of all three neurotoxins when tested in groups of CD1 mice. This work contributes to the increasing understanding of the high diversity of 3FTxs, and shows that recombinant coral snake alpha-neurotoxins are promising supplements for hyperimmunization protocols for coral snake antivenom production. PMID- 29391192 TI - Comparative study of the antioxidant properties of monocarbonyl curcumin analogues C66 and B2BrBC in isoproteranol induced cardiac damage. AB - AIM: To test the antioxidant properties of the newly synthesized (2E,6E)-2,6 bis(2-bromobenzylidene)cyclohexanone (B2BrBC) in parallel with C66 in rats with cardiac hypertrophy. MATERIALS AND METHODS: The protective effects of both C66 and B2BrBC against oxidative stress in rats with cardiac hypertrophy, was studied by evaluating the activity of antioxidant enzymes, the relationship between the ratio of the activities of the antioxidant enzymes R = SOD/(GPx + CAT) and levels of thiols and lipid peroxidation in the heart. In order to gain better understanding of the antioxidant properties of the studied compounds, computational methods were utilized. The properties of selected structurally related derivatives were obtained on optimized geometries for ground states, using semi-empirical PM3 quantum mechanical calculations. KEY FINDINGS: The ratio R shows disequilibrium in rats with induced hypertrophy (p < 0.001). Coextending changes were detected in total and free sulfhydryl group content (p = 0.011 for t SH and p = 0.008, for free SH, respectively). The results with the B2BrBC, indicated strong thiol prevention reflected in the levels of both t-SH and f-SH. Taking into account the HOMO energies of B2BrBC (-9.398 eV) and C66 (-9.667), it can be concluded that B2BrBC has lower HOMO energy, which makes it a better electron donor and a better antioxidant. SIGNIFICANCE: The obtained results indicated that the antioxidant ability of B2BrBC is positively associated with the catalytic SOD and GPx activities expressed through preserved t-SH levels. It seems plausible that for a compound to exhibit antioxidant activity, as most of the 2,6-bis(benzylidene)cyclohexanones do, they should be good electron donors. IMPACT STATEMENT: Understanding the relationship between cardiac hypertrophy induced oxidative injuries and supporters of endogenous reparatory machinery will help in establishing the beneficial role of adequate antioxidant supplementation. In this study reliable data on the preventive effects of newly synthesized symmetric monocarbonyl curcumin analogue B2BrBC and its role in the prevention of oxidative injuries on three levels (enzymatic, protein and lipid), in the heart hypertrophic onset, were obtained. PMID- 29391194 TI - Contrasting consequences of different defence strategies in a natural multihost parasite system. AB - Hosts counteract infections using two distinct defence strategies, resistance (reduction in pathogen fitness) and tolerance (limitation of infection damage). These strategies have been minimally investigated in multi-host systems, where they may vary across host species, entailing consequences both for hosts (virulence) and parasites (transmission). Comprehending the interplay among resistance, tolerance, virulence and parasite success is highly relevant for our understanding of the ecology and evolution of infectious and parasitic diseases. Our work investigated the interaction between an insect parasite and its most common bird host species, focusing on two relevant questions: (i) are defence strategies different between main and alternative hosts and, (ii) what are the consequences (virulence and parasite success) of different defence strategies? We conducted a matched field experiment and longitudinal studies at the host and the parasite levels under natural conditions, using a system comprising Philornis torquans flies and three bird hosts - the main host and two of the most frequently used alternative hosts. We found that main and alternative hosts have contrasting defence strategies, which gave rise in turn to contrasting virulence and parasite success. In the main bird host, minor loss of fitness, no detectable immune response, and high parasite success suggest a strategy of high tolerance and negligible resistance. Alternative hosts, on the contrary, resisted by mounting inflammatory responses, although with very different efficiency, which resulted in highly dissimilar parasite success and virulence. These results show clearly distinct defence strategies between main and alternative hosts in a natural multi-host system. They also highlight the importance of defence strategies in determining virulence and infection dynamics, and hint that defence efficiency is a crucial intervening element in these processes. PMID- 29391196 TI - Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury. AB - Traumatic brain injury (TBI) contributes to over 30% of injury-related deaths and is a major cause of disability without effective clinical therapies. Oxidative stress contributes to neurodegeneration, neuroinflammation, and neuronal death to amplify the primary injury after TBI. NADPH oxidase (NOX) is a major source of reactive oxygen species following brain injury. Our current study addresses the functional role of the NOX4 isoform in the damaged cortex following TBI. Adult male C57BL/6 J and NOX4-/- mice received a controlled cortical impact and lesion size, NOX4 expression, oxidative stress, neurodegeneration, and cell death were assessed in the injured cerebral cortex. The results revealed that NOX4 mRNA and protein expression were significantly upregulated at 1-7 days post-TBI in the injured cerebral cortex. Expression of the oxidative stress markers, 8-OHdG, 4 HNE, and nitrotyrosine was upregulated at 2 and 4 days post-TBI in the WT injured cerebral cortex, and nitrotyrosine primarily colocalized with neurons. In the NOX4-/- mice, expression of these oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine were significantly attenuated at both timepoints. In addition, examination of NOX4-/- mice revealed a reduced number of apoptotic (TUNEL+) and degenerating (FJB+) cells in the perilesional cortex after TBI, as well as a smaller lesion size compared with the WT group. The results of this study implicate a functional role for NOX4 in TBI induced oxidative damage and neurodegeneration and raise the possibility that targeting NOX4 may have therapeutic efficacy in TBI. PMID- 29391197 TI - Ocular injury during fetal endoscopy surgery. AB - A premature infant born at 31 weeks' gestational age was evaluated for periocular laceration and retrobulbar hematoma secondary to injury during a percutaneous fetal procedure. He later developed optic nerve atrophy. PMID- 29391195 TI - PID1 in adipocytes modulates whole-body glucose homeostasis. AB - The novel obesity-associated protein Phosphotyrosine Interaction Domain containing 1 (PID1) inhibits insulin-PI3K/Akt signaling pathway and insulin stimulated glucose uptake in vitro. In this study, we generated fat tissue specific aP2-PID1 transgenic (aP2-PID1tg) mice and PID1 knockout (PID1-/-) mice to explore how PID1 affects glucose metabolism in vivo. We observed insulin resistance and impaired insulin-PI3K/Akt signaling in aP2-PID1tg mice. Consistent with these data, the PID1-/- mice displayed improved glucose tolerance and insulin sensitivity under chow diet, with increased Akt phosphorylation in white adipose tissue (WAT). We further demonstrated that PID1 could interact with low density lipoprotein receptor-related protein 1 (LRP1) but not the insulin receptor (IR) in adipocytes, and its overexpression could lead to decreased GLUT4 level. Our results thus indentify PID1 as a critical regulator of glucose metabolism in adipocytes. PMID- 29391198 TI - A high expression of cell adhesion molecule 1 (CADM1) is an unfavorable prognostic factor in mycosis fungoides. PMID- 29391200 TI - The importance of food allergy to the practicing clinician. PMID- 29391199 TI - Leishmanicidal and cytotoxic activity from plants used in Tacana traditional medicine (Bolivia). AB - ETNOPHARMACOLOGICAL RELEVANCE: Thirty-eight Tacana medicinal plant species used to treat skin problems, including leishmania ulcers, skin infections, inflammation and wound healing, were collected in the community of Buena Vista, Bolivia, with the Tacana people. Twenty two species are documented for the first time as medicinal plants for this ethnic group living in the northern area of the Department of La Paz. AIM OF THE STUDY: To evaluate the leishmanicidal effect (IC50) and cytotoxicity (LD50) of the selected plants. To carry out bioguided studies on the active extracts. To assess the potential of Bolivian plant biodiversity associated with traditional knowledge in the discovery of alternative sources to fight leishmaniasis. MATERIALS AND METHODS: Seventy three ethanol extracts were prepared from 38 species by maceration and were evaluated in vitro against promastigotes of Leishmania amazonensis and L. braziliensis. Active extracts (IC50 <= 50 MUg/mL) were fractionated by chromatography on Silica gel column and the fractions were assessed against the two Leishmania strains. The most active fractions and the crude extracts were evaluated against reference strains of L. amazonensis, L. braziliensis, L. aethiopica, two native strains (L. Lainsoni and L. braziliensis) and for cytotoxicity against HeLa cells. The chromatographic profile of the active fractions was obtained by reverse phase chromatography using HPLC. RESULTS: From the 73 extracts, 39 extracts (53.4%) were inactive and 34 showed activity. Thirteen species were sselected for bioguided studies. The crude extracts and their 36 fractions were evaluated against two Leishmania strains. The most active fraction were tested in a panel of five leishmania strains and for cytotoxicity. The Selective Index (SI = LD50/IC50) was calculated, and were generally low. Retention time and UV spectra were recorded for the active fractions by HPLC-DAD using a reverse phase column. Profiles were very different from each other, showing the presence of different compounds. CONCLUSION: Bolivian traditional knowledge from the Tacanba was useful to identify plants with effect on Leishmania promastigotes. Chromatographic bioguided studies showed stronger leishmanicidal and cytotoxic activity for the medium polar fraction. HPLC analysis showed different chromatographic profiles of the active fractions. PMID- 29391201 TI - Balancing the risks and burdens of food allergen avoidance. PMID- 29391202 TI - Phylogenetic analysis, structure modeling and docking study of HCV NS3 protease for the identification of potent inhibitors. AB - The nonstructural protein 3 (NS3) helicase of HCV is believed to be a plausible target for the identification and designing of potent antiviral drugs. NS3 protein is involved in a positive sense single-stranded viral replication as well as it also cleaves viral poly protein into diverse mature proteins at different time spans. Structural exploration of NS3 revealed that HCV helicase could also act as translocase. In order to identify potential inhibitors for HCV-3a, the current study has been designed. Serum samples from the Pakistani HCV positive patients were collected, sequenced and after purification included in the present study. Phylogenetic analysis on the samples clustered around it in the same group with those from India. Using homology modeling technique, we determined 3D structure of NS3 gene of HCV-3a and employed further in docking studies to discover potent inhibitor against it. As a result of docking Compound 1, with IC50 value of 0.015 and -14.4 kcal/mol energy, ranked as a most pungent inhibitor among all the studied inhibitors. Compound 1 also exhibited good hydrogen bond interactions with the modeled protein. The finding of present study could be used as a lead in future to design an effective dual inhibitor against HCV-3a. PMID- 29391203 TI - Analysis of genetic diversity and population structure of gene encoding cell traversal protein for ookinetes and sporozoites (CelTOS) vaccine candidate antigen in global Plasmodium falciparum populations. AB - Plasmodium falciparum cell-traversal protein for ookinetes and sporozoites (PfCelTOS) has been reported as one of the most attractive malaria vaccine candidate antigens. To design a broadly effective malaria vaccine based on this antigen, it is crucial to have adequate information on genetic diversity in global PfCelTOS. Therefore, the extent of sequence diversity at the full-length of the pfceltos was assessed among both natural P. falciparum isolates collected from Iran (n = 93) and from available global pfceltos sequence data retrieved from PlasmoDB database (n = 159). Also, recombination, natural selection, the degree of genetic differentiation as well as the predicted immunodominant regions in PfCelTOS were analyzed. In total, 40 SNPs (including 1 synonymous and 39 non synonymous) were detected in 34 positions, as compared to 3D7 sequence, which led to 66 distinct haplotypes with different frequencies. Among those haplotypes, 34 (51.5%, excluded from further analysis) were singleton haplotype and mostly detected among Senegalese parasite isolates. PfCelt-1 was found as predominant haplotype (32.6% total frequency) that was only detected in Iranian P. falciparum isolates. Nucleotide diversity was low in French Guiana (0.00236 +/- 0.00203) and Iranian (0.00259 +/- 0.00048) P. falciparum isolates in comparison with African populations. Evidence for positive selection by host immunity and intragenic recombination were detected that are two key factors responsible for gene evolution and genetic diversity of pfceltos gene. The results of Fst analysis and haplotype network revealed that PfCelTOS antigen displayed evident genetic structure between geographical parasite populations. In conclusion, the present analysis demonstrates that there is a limited antigenic diversity and geographic variation in global PfCelTOS, and this finding may be associated with the critical function of this antigen in cell traversal of the parasite in sporozoite and ookinete. Besides, most of the predicted B- and T-cell epitopes were located in the conserved region of the gene, but most of the amino acid replacements were located at the C-terminal region of PfCelTOS. The obtained results in this investigation could provide knowledge for better design of PfCelTOS-based malaria vaccine. PMID- 29391204 TI - Spontaneous Mycobacterium bolletti skin abscesses - An underrecognized zoonosis from raw bovine milk. PMID- 29391205 TI - Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment. AB - Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' microenvironment in order to predict the potential activity of immunomodulatory agents. This review briefly summarizes the basis of the brain immunogenicity, providing the most updated clinical evidences in terms of immune-checkpoint inhibitors efficacy and toxicity in both primary and metastatic brain tumors with the final aim of defining potential biomarkers for immunomodulatory cancer treatment. PMID- 29391206 TI - Long-term outcomes of a large, prospective observational cohort of older adults with back pain. AB - BACKGROUND CONTEXT: Although back pain is common among older adults, there is relatively little research on the course of back pain in this age group. PURPOSE: Our primary goals were to report 2-year outcomes of older adults initiating primary care for back pain and to examine the relative importance of patient factors versus medical interventions in predicting 2-year disability and pain. STUDY DESIGN/SETTING: This study used a predictive model using data from a prospective, observational cohort from a primary care setting. PATIENT SAMPLE: The study included patients aged >=65 years at the time of new primary care visits for back pain. OUTCOME MEASURES: Self-reported 2-year disability (Roland Morris Disability Questionnaire [RDQ]) and back pain (0-10 numerical rating scale [NRS]). METHODS: We developed our models using a machine learning least absolute shrinkage and selection operator approach. We evaluated the predictive value of baseline characteristics and the incremental value of interventions that occurred between 0 and 90 days, and the change in patient disability and pain from 0 to 90 days. Limitations included confounding by indication and unmeasured confounding. RESULTS: Of 4,665 patients (89%) with follow-up, both RDQ (from mean 9.6 [95% confidence interval {CI} 9.4-9.7] to mean 8.3 [95% CI 8.0-8.5]) and back pain NRS (from mean 5.0 [95% CI 4.9-5.1] to mean 3.5 [95% CI 3.4-3.6]) scores improved slightly. Only 16% (15%-18%) reported no back pain-related disability or back pain at 2 years after initial visits. Regression model parameters explained 40% of the variation (R2) in 2-year RDQ scores, and the addition of 0- to 3-month change in RDQ score and pain improved prediction (R2=51%). The most consistent predictors of 2-year RDQ scores and back pain NRS scores were 0- to 90-day change in each respective outcome and patient confidence in improvement. Patients experienced 50% and 43% improvement in back pain and disability, respectively, 2 years after their initial visit. However, fewer than 20% of patients had complete resolution of their back pain and disability at that time. CONCLUSIONS: Baseline patient factors were more important than early interventions in explaining disability and pain after 2 years. PMID- 29391207 TI - Diversity of transcripts emanating from protein-coding genes. PMID- 29391208 TI - Isocitrate dehydrogenase 2 deficiency exacerbates dermis damage by ultraviolet-B via DeltaNp63 downregulation. AB - Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains the balance of mitochondrial redox status by generating NADPH as a reducing factor, which is used to reduce oxidized antioxidant proteins and oxidized glutathione. Therefore, the role of IDH2 is crucial in organs that are easily influenced by reactive oxygen species (ROS) or mechanical damage. Humans are constantly exposed to ultraviolet (UV) radiation throughout their lifetime, which can cause various cutaneous diseases, such skin carcinoma, dermatitis, and sunburn. ROS play an important role in the initial step of these diseases; therefore, IDH2 deficient mice (Idh2-/-) could be a useful model to investigate UV-mediated skin damage. When we exposed the dorsal skin of Idh2-/- mice to UVB, pyrimidine dimers and (6 4) photoproducts (6-4PPs), marker of photoproducts generated by UVB, were found in the dermis of the knockout mice. Increased collagen degradation, apoptosis, inflammation, and ROS levels in the dermis were also observed. These results indicated that UVB could reach the dermis by penetrating the epidermis. We then attempted to determine how the epidermis was breached, and observed a decrease in the expression level of DeltaNp63, a major protein required for epidermis generation, in the Idh2-/- mice. The mito-TEMPO supplement significantly ameliorates UVB-induced damage in the skin of Idh2-/- mice. In the present study, we provided a role for IDH2 in protection against UVB-induced skin damage and a new connection between IDH2 and DeltaNp63. PMID- 29391209 TI - Cardiac adaptations to obesity, diabetes and insulin resistance. PMID- 29391210 TI - Proteomic analysis of the promotive effect of plant-derived smoke on plant growth of chickpea. AB - : Plant-derived smoke plays a key role in seed germination and plant growth. To investigate the effect of plant-derived smoke on chickpea, a gel-free/label-free proteomic technique was used. Germination percentage, root/shoot length, and fresh biomass were increased in chickpea treated with 2000 ppm plant-derived smoke within 6 days. On treatment with 2000 ppm plant-derived smoke for 6 days, the abundance of 90 proteins including glycolysis-related proteins significantly changed in chickpea root. Proteins related to signaling and transport were increased; however, protein metabolism, cell, and cell wall were decreased. The sucrose synthase for starch degradation was increased and total soluble sugar was induced. The proteins for nitrate pathway were increased and nitrate content was improved. On the other hand, although secondary metabolism related proteins were decreased, flavonoid contents were increased. Based on proteomic and immuno-blot analyses, proteins related to redox homeostasis were decreased and increased in root and shoot, respectively. Furthermore, fructose-bisphosphate aldolase was increased; while, phosphotransferase and phosphoglycero mutase were decreased in glycolysis. In addition, phosphoglyceraldehyde-3-phosphate dehydrogenase and glutamine synthetase related genes were up-regulated. These results suggest that plant-derived smoke improves early stage of growth in chickpea with the balance of many cascades such as glycolysis, redox homeostasis, and secondary metabolism. BIOLOGICAL SIGNIFICANCE: The current study examined the effects of plant-derived smoke on root of chickpea seedlings using a gel-free/label-free proteomic technique. Based on functional categorization of results from proteomics, proteins related to glycolysis, signaling, transport, protein metabolism, cell wall, and cell were predominantly changed in chickpea. The proteins related to carbohydrate and nitrate pathways were increased, while, those of secondary metabolism were decreased. Physiological analysis indicated that flavonoid, total soluble sugar, and nitrate content were increased in root of chickpea treated with plant-derived smoke for 6 days. Moreover, accumulated protein abundance of glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase was in agreement with immuno-blot results, which suggests that glycolysis process might be enhanced in root of chickpea in response to plant-derived smoke. PMID- 29391211 TI - Physiological uptake and retention of radiolabeled resveratrol loaded gold nanoparticles (99mTc-Res-AuNP) in colon cancer tissue. AB - When tagged with a suitable radionuclide, the cancer targeting properties of trans-resveratrol could be utilized to locate cancerous sites in the body using radionuclide imaging technique. However, the polyphenol due to its rapid and extensive metabolism exhibits low bioavailability in vivo. The study was designed to enhance the cancer targeting efficacy of radiolabeled resveratrol using nano based technology. Technetium-99m labeled resveratrol loaded gold nanoparticles (Res-AuNP) were synthesized, characterized and evaluated for their cancer targeting efficacy in HT29 colon cancer cells and in animal cancer model. Results of various investigations were compared to corresponding results obtained for 99mTc-AuNP and 99mTc-resveratrol. Cancer cell internalization observed for 99mTc Res-AuNP was significantly higher than that of 99mTc-AuNP and 99mTc-resveratrol. Also, a gradual rise in target to nontarget uptake with time was observed following i.v. administration of 99mTc-Res-AuNP to colon tumor bearing rats, demonstrating better in vivo targeting of colon adenocarcinoma with 99mTc-Res AuNP when compared to 99mTc-resveratrol. PMID- 29391212 TI - Assessing the selective therapeutic efficacy of superparamagnetic erlotinib nanoparticles in lung cancer by using quantitative magnetic resonance imaging and a nuclear factor kappa-B reporter gene system. AB - Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used as the first-line treatment for advanced NSCLC; however, the efficacy of drug delivery remains unknown. Hence, we successfully developed erlotinib conjugated iron oxide nanoparticles (FeDC-E NPs) as theranostic probe that can potentially provide a new avenue for monitoring drug delivering through noninvasive magnetic resonance imaging. MRI DeltaR2* relaxivity measurements offer an opportunity to quantitatively evaluate the uptake of FeDC-E NPs at cellular and tumoral levels. Additionally, NF-kappaB reporter gene system provides NF-kappaB activation status monitoring to validate the therapeutic efficiency of FeDC-E NPs. FeDC-E NPs not only inhibit the tumor growth and NF kappaB-modulated antiapoptotic mechanism but also trigger extrinsic and intrinsic apoptotic pathways. Taken together, dual functional FeDC-E NPs offer diagnostic and therapeutic benefits against lung cancers, indicating that our presented probe could be applied in clinical. PMID- 29391214 TI - Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery. AB - Pre-clinical research often uses rodents as animal models to guide the selection of appropriate oral drug and dose selection in humans. However, traditionally, such research fails to consider the gastrointestinal differences between the sexes of rats and the impact on oral drug delivery. This study aimed to identify and characterise the potential sex-related differences in the gastrointestinal environment of sacrificed male and female Wistar rats. Their gastrointestinal tracts were excised and segmented into the stomach, duodenum, jejunum, ileum, caecum and colon. The respective contents and tissue sections were collected and analysed for pH, buffer capacity, surface tension, osmolality and relative P glycoprotein (P-gp) expression. The pH in the stomach of females was found to be lower than in males. Female rats also exhibited a higher buffer capacity in the caecum and colon when compared with their male counterparts. Males were found to have a higher osmolality than females in the duodenum, ileum and colon. Significant sex differences (p < 0.05) in surface tension were observed in the ileum, where females exhibited a higher surface tension. Interestingly, female rats displayed significantly higher relative P-gp expression levels (p < 0.05) when compared with male rats in the duodenum (1.24 +/- 0.85 vs. 0.36 +/- 0.26), jejunum (1.45 +/- 0.88 vs. 0.38 +/- 0.26) and ileum (0.92 +/- 0.43 vs. 0.40 +/- 0.18) but not in the colon (0.5 +/- 0.32 vs. 0.33 +/- 0.16) segments. The work reported has demonstrated the stark physiological differences between male and female rats at a physiological level, indicating how the 'sex of the gut' could influence oral drug delivery. These findings, therefore, are of critical importance in pre-clinical research and drug development. PMID- 29391215 TI - Stability of motor bias in the domestic dog, Canis familiaris. AB - This study explored the relationship between four measures of canine paw preference to establish whether the distribution, direction or strength of motor bias was consistent between tasks. Thirty-two dogs had their paw preferences tested using the Kong ball, tape, lift paw and First-stepping tests. A smaller sample were re-tested 6 months later. The distribution of the dogs' paw preferences was not significantly different from that expected by chance for the Kong ball and lift paw tests; dogs were significantly more inclined towards ambilaterality on the tape and First-stepping tests. More female dogs employed their right paw on the lift paw test; males were more likely to be ambilateral or left-pawed. There was no significant correlation in the direction of dogs' paw use for any tests. The First-stepping and lift paw tests were positively correlated for strength of paw use. Analysis revealed a significant correlation in direction and strength of dogs' paw use between the first and second attempts of all measures, except the tape test. Findings suggest that paw preference in the dog is not consistent between tasks, although stable over time. The study raises questions as to which test of paw preference is the most appropriate to employ. PMID- 29391216 TI - Early detection of a hypervirulent KPC-2-producing Pseudomonas aeruginosa ST235 in Brazil. PMID- 29391213 TI - Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia. AB - : Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. PERSPECTIVE: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system. PMID- 29391217 TI - Electrophysiological characterization of Muller cells from the ischemic retina of mice deficient in the leukemia inhibitory factor. AB - Leukemia inhibitory factor (LIF) is a cytokine that exerts different effects in the nervous system. It is involved in neuronal injuries and diseases and is assumed to be neuroprotective and to regulate reactive gliosis. In LIF-deficient (LIF-/-) mice, expression of glial fibrillary acidic protein in retinal Muller glial cells as a hallmark of reactive gliosis is suppressed during retinal degenerations. Here, we detected expression of LIF and its receptors in Muller cells of the murine retina. Moreover, electrophysiological alterations of Muller cells 7 days after transient retinal ischemia were studied by the patch-clamp technique. The amplitude of inward currents in Muller cells from the postischemic retina was reduced to 51% in wild type and to 70% in LIF-/- mice. This demonstrates that decrease of inward currents takes place in reactive Muller cells even in the absence of LIF. PMID- 29391218 TI - Event-related brain potential correlates of words' emotional valence irrespective of arousal and type of task. AB - Many Event-Related brain Potential (ERP) experiments have explored how the two main dimensions of emotion, arousal and valence, affect linguistic processing. However, the heterogeneity of experimental paradigms and materials has led to mixed results. In the present study, we aim to clarify words' emotional valence effects on ERP when arousal is controlled, and determine whether these effects may vary as a function of the type of task performed. For these purposes, we designed an ERP experiment with the valence of words manipulated, and arousal equated across valences. The participants performed two types of task: in one, they had to read aloud each word, written in black on a white background; in the other, they had to name the color of the ink in which each word was written. The results showed the main effects of valence irrespective of task, and no interaction between valence and task. The most marked effects of valence were in response to negative words, which elicited an Early Posterior Negativity (EPN) and a Late Positive Complex (LPC). Our results suggest that, when arousal is controlled, the cognitive information in negative words triggers a 'negativity bias', these being the only words able to elicit emotion-related ERP modulations. Moreover, these modulations are largely unaffected by the types of task explored here. PMID- 29391219 TI - Spinal cord neuronal components involved in the reflex activity of female rat pubococcygeus motoneurons. AB - Evoked EMG reflex activity from the pubococcygeus muscle of female Wistar rats has been reported, but has not been carefully analyzed. Here, we studied this reflex activity through mechanical stimulation of the clitoris, perigenital skin, caudal vagina and foot, all of which produced bilateral reflex multiunit electromyographic (MEMG) tonic "on" activity and displayed a rapid adaptation. However, deep vagina and cervical stimulation did not modify MEMG baseline activity even if it was combined with clitoris, perigenital skin and foot stimulation. Electrical stimulation of the dorsal nerve of the clitoris produced bilateral MEMG activity that when recorded at fast sweep speed, it was possible to observe that the ipsilateral response had an 8 ms latency, while the contralateral response had a 10 ms latency. These data suggest that bilateral reflex activation of pubococcygeus muscle motoneurons is produced by several sensory sources in which a specialized neural circuitry of afferent and efferent components and several spinal cord interneurons are involved. This is in accordance with the multi functionality of this muscle in reproductive and behavioral processes. PMID- 29391220 TI - Cholinergic responses of satellite glial cells in the superior cervical ganglia. AB - Satellite glial cells (SGCs) surround the neurons in sympathetic ganglia and are believed to make important contributions to the function of the ganglia under normal and pathological conditions. It has been proposed that SGCs communicate chemically with the neurons, but little is known about their pharmacological properties and there is no information on whether they respond to acetylcholine (ACh), which is the major neurotransmitter in these ganglia. We used calcium imaging to examine responses of SGCs in the mouse superior cervical ganglion to ACh. The SGCs responded to ACh (0.01-2 mM) with an elevation of intracellular Ca2+, which appeared to be due to direct action on these cells, as the response persisted in the presence of the nerve blocker tetrodotoxin (1 MUM). The response was largely inhibited by atropine, indicating an action on muscarinic ACh receptors. In contrast to this, sensory ganglia (nodose and trigeminal) were not sensitive to ACh. Incubation of the ganglia in ACh (0.5 or 1 mM) increased the expression of glial fibrillay acidic protein, which is a marker for glial activation. Such incubation also increased the electrical coupling of SGCs, which is known to occur in sensory ganglia following injury. We conclude that SGCs in the superior cervical ganglia display muscarinic ACh receptors, which enable them to communicate chemically with the sympathetic neurons. PMID- 29391222 TI - MicroRNAs in the pathogenesis and treatment of progressive liver injury in NAFLD and liver fibrosis. AB - Non-alcoholic fatty liver disease (NAFLD) increases the risk of various liver injuries, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and ultimately hepatocellular carcinoma (HCC). Ample evidence has suggested that aberrant expression of microRNAs (miRNAs) is functionally involved in the activation of cellular stress, inflammation and fibrogenesis in hepatic cells, including hepatocytes, Kupffer and hepatic stellate cells (HSCs), at different pathological stages of NAFLD and liver fibrosis. Here, we overview recent findings on the potential role of miRNAs in the pathogenesis of NAFLD, including lipotoxicity, oxidative stress, metabolic inflammation and fibrogenesis. We critically assess the literatures on both human subjects and animal models of NAFLD and liver fibrosis with miRNA dysregulation and their mechanisms of actions in liver damage. We further highlight the potential use of miRNA mimics or antimiRNAs as therapeutic approaches for the prevention and treatment of NAFLD and liver fibrosis. PMID- 29391223 TI - Intrinsic and extrinsic carbohydrates in the vagina: A short review on vaginal glycogen. AB - The reasons for (i) the presence and (ii) mechanisms of utilisation of glycogen by the lactic acid bacteria in the human vaginal tract are not well understood. It is probable that the vaginal epithelia produce both glycogen and alpha-amylase where the enzyme depolymerises the polysaccharide within the vagina itself. Only these depolymerised residues are then utilised for growth by the lactic acid bacteria. The lactic acid bacteria cannot metabolise the glycogen directly due to their incapacity to produce the alpha-amylase enzyme. These bacteria may, however, metabolise exogenous carbohydrates (such as prebiotics) selectively for growth effectively. These carbohydrate utilisation issues within the vagina are considered in this short review. PMID- 29391221 TI - Improving long-term subcutaneous drug delivery by regulating material bioenvironment interaction. AB - Subcutaneous long-acting release (LAR) formulations have been extensively developed in the clinic to increase patient compliance and reduce treatment cost. Despite preliminary success for some LAR systems, a major obstacle limiting the therapeutic effect remains on their interaction with surrounding tissues. In this review, we summarize how living bodies respond to injected or implanted materials, and highlight some typical strategies based on smart material design, which may significantly improve long-term subcutaneous drug delivery. Moreover, possible strategies to achieve ultra-long (months, years) subcutaneous drug delivery systems are proposed. Based on these discussions, we believe the well designed subcutaneous long-acting formulations will hold great promise to improve patient quality of life in the clinic. PMID- 29391224 TI - Study on structure, mechanical property and cell cytocompatibility of electrospun collagen nanofibers crosslinked by common agents. AB - Collagen electrospun scaffolds properly reproduce the framework of the extracellular matrix (ECM) of tissues that are natural with the fibrous morphology of the protein by coupling large biomimetism of the biological material. However, traditional solvents employed for collagen electrospinning lead to poor mechanical attributes and bad hydro-stability. In this work, by N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride with N hydroxysulfosuccinimide (EDC-NHS), glutaraldehyde (GTA) and genipin (GP) respectively, electrospun collagen fibers cross-linked, effectively stabilized the fiber morphology over 2months and improved the mechanical properties in both dry and wet state, especially EDC-NHS with large ultimate tensile stress and epsilonb. The secondary structure of collagen structure still remained and had no obvious difference among various crosslinked samples according to FTIR. On the cell assessment, electrospun collagen fibers crosslinked by EDC-NHS, GTA and GP, were found to support cell adhesion, spreading and proliferation of MC3T3-E1. By contrast, GTA was more effective in preserving explicit fibrous morphology with a relatively lower cell viability both in FBS and BSA soaked mats. Interestingly, GP also had the similar cytocompatibility of MC3T3-E1 as EDC-NHS did. The study proved the feasibility of chemical crosslinker to electrospun collagen for biomedical application. PMID- 29391225 TI - Carboxymethyl cellulose-rosin gum hybrid nanoparticles: An efficient drug carrier. AB - Adequate release of 5-ASA in colon is challenging as it easily permeates at the acidic pH of the upper gastrointestinal tract. Targeting delayed release of 5-ASA at acidic pH, Carboxymethyl cellulose-rosin gum hybrid nanoparticles (CRNP3) with an average size of 267nm have been crafted through nanoprecipitation method. CRNP3 was extensively characterized using Fourier Transform Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), and particle size analysis based on dynamic light scattering. Colon specific targeted in-vitro release of 5-Aminosalicylic acid from CRNPs was monitored in simulated gastric (SGF) and intestinal (SIF) fluids. The release rate was very slow in first 2h in SGF, while in SIF, it was greater and 72% drug was released in a controlled manner during the time span of 12h in contrast to native carboxymethyl cellulose or rosin gum for which 100% release was accomplished within 5h or 8h respectively. The delayed release from CRNPs is attractive for enhancing the bioavailability of drug in colon. The drug release followed zero-order kinetics and non-Fickian diffusion mechanism. PMID- 29391226 TI - Antiparasitic effects induced by polyclonal IgY antibodies anti-phospholipase A2 from Bothrops pauloensis venom. AB - Activities of phospholipases (PLAs) have been linked to pathogenesis in various microorganisms, and implicated in cell invasion and so the interest in these enzymes as potential targets that could contribute to the control of parasite survival and proliferation. Chicken eggs immunized with BnSP-7, a Lys49 phospholipase A2 (PLA2) homologue from Bothrops pauloensis snake venom, represent an excellent source of polyclonal antibodies with potential inhibitory activity on parasite PLAs. Herein, we report the production, characterization and anti parasitic effect of IgY antibodies from egg yolks of hens immunized with BnSP-7. Produced antibodies presented increasing avidity and affinity for antigenic toxin epitopes throughout immunization, attaining a plateau after 4weeks. Pooled egg yolks-purified anti-BnSP-7 IgY antibodies were able to specifically recognize different PLA2s from Bothrops pauloensis and Bothrops jararacussu venom. Antibodies also neutralized BnSP-7 cytotoxic activity in C2C12 cells. Also, the antibodies recognized targets in Leishmania (Leishmania) amazonensis and Toxoplasma gondii extracts by ELISA and immunofluorescence assays. Anti-BnSP-7 IgY antibodies were cytotoxic to T. gondii tachyzoite and L. (L.) amazonensis promastigotes, and were able to decrease proliferation of both parasites treated before infection. These data suggest that the anti-BnSP-7 IgY is an important tool for discovering new parasite targets and blocking parasitic effects. PMID- 29391227 TI - Comparison of yields and properties of microbial polyhydroxyalkanoates generated from waste glycerol based substrates. AB - The accumulation efficiency and the properties of polyhydroxyalkanoates (PHAs) produced from acidified waste glycerol (AWG) and its derivatives via an enriched microbial consortium derived from soil, were investigated in this study. AWG consisted mainly from short chain fatty acids, 1,3 propanediol and residual glycerol, which were also evaluated individually as substrates. Accumulation capacity and yields were estimated after solvent extraction and purification and PHAs were further analyzed in terms of their chemical structure, thermal properties, molecular masses and mechanical properties. The lowest accumulation capacity was noticed for non-acidified waste glycerol as carbon source which led to the generation of P(3HB), whereas for the other carbon sources co-polymers of 3HB with 3HV or 3HHx were produced. Average molecular mass weights were quite high in all cases reaching ~1.8*106Da. The thermal properties and the mechanical behavior of PHAs were shown to be highly affected by their monomeric composition, whereas it was also concluded that DSC and DMA results were in good agreement. PMID- 29391228 TI - Development of functional antimicrobial papers using chitosan/starch-silver nanoparticles. AB - In the present work, we report the synthesis of chitosan:starch-silver nanoparticle (Cht:St-AgNPs) coated papers for antimicrobial packaging applications. The starch-assisted synthesized St-AgNPs are spherical in shape with an average particle size of 7 nm. Chitosan was mixed into the synthesized St AgNPs solution with different ratios of 9:1, 8:2, 7:3, and 5:5 by weight. Further, the influence of different ratios of Cht:St-AgNPs on the various paper properties such as mechanical properties, water and oil resistance, and antimicrobial activities was investigated. It was observed that the properties of the coated papers were strongly dependent on the composition of Cht:St-AgNPs. The Cht:St-AgNPs-coated paper prepared with the ratio of 9:1 showed excellent mechanical properties and good resistance properties against water and oil. The Cht:St-AgNPs coated papers showed a remarkable enhancement in mechanical strength, oil and water resistance, and antibacterial and antifungal activity, which can make them a potential candidate for functional antimicrobial packaging applications. PMID- 29391229 TI - Antitumor activity and underlying mechanism of Sargassum fusiforme polysaccharides in CNE-bearing mice. AB - This study was designed to investigate the antitumor effects of Sargassum fusiforme polysaccharides (SFPS) on nasopharyngeal carcinoma (NPC) and the underlying mechanism of its effect on splenic lymphocytes. As a result, SFPS significantly inhibited the growth of nasopharyngeal carcinoma CNE in vivo, and remarkably increased the serum cytokines and IgM levels in CNE-bearing mice. Meanwhile, SFPS stimulated the peritoneal macrophages to secrete the cytokines, exerted a stimulatory effect on splenic lymphocytes proliferation, and increased the expression of IgM from splenic lymphocytes. The pretreatment of splenic lymphocytes with special antibodies (anti-TLR4 and anti-TLR2) significantly suppressed the proliferation of splenic lymphocytes and blocked SFPS-induced IgM production. SB203580, a specific inhibitor of p38 MAPK, effectively suppressed SFPS-induced IgM secretion in splenic lymphocytes. Taken together, SFPS has antitumor and immunomodulatory activities in NPC, and its activity is mediated, at least in part, by TLR2/TLR4 receptors and p38 MAPK signaling pathway. PMID- 29391230 TI - Interactions of hyaluronan with oppositely charged surfactants in very diluted solutions in water. AB - The phase behavior of aqueous systems containing hyaluronan, at concentrations between 2 and 100 mg/L, and oppositely charged surfactants was investigated. A fluorescence probe technique revealed the formation of micellar structures on the hyaluronan in homogeneous systems well below the surfactant standard, critical, micellar concentration. Moreover, regions of gel-phase separation were revealed. A detailed phase diagram was, thus, constructed in the very diluted region and the hyaluronan concentration was found to be the main parameter controlling the phase behavior, in contrast to the charge ratio. The stability of hyaluronan surfactant aggregates in the homogeneous systems while in storage at 4 degrees C (up to three months), against dilution, salt addition and on heating-cooling (between 10 and 50 degrees C) was also investigated. The aggregates were stable while in storage or upon increasing and decreasing the temperature. The dilution of hyaluronan-surfactant complexes or the addition of 0.15 M NaCl led to their disintegration. Finally, systems prepared in a 0.15 M NaCl solution showed that interactions are suppressed and no aggregation below the standard critical micellar concentration was observed. PMID- 29391231 TI - Inhibiting intimal hyperplasia in prosthetic vascular grafts via immobilized all trans retinoic acid. AB - Peripheral arterial disease is a leading cause of morbidity and mortality. The most commonly utilized prosthetic material for peripheral bypass grafting is expanded polytetrafluoroethylene (ePTFE) yet it continues to exhibit poor performance from restenosis due to neointimal hyperplasia, especially in femoral distal bypass procedures. Recently, we demonstrated that periadventitial delivery of all-trans retinoic acid (atRA) immobilized throughout porous poly(1,8 octamethylene citrate) (POC) membranes inhibited neointimal formation in a rat arterial injury model. Thus, the objective of this study was to investigate whether atRA immobilized throughout the lumen of ePTFE vascular grafts would inhibit intimal formation following arterial bypass grafting. Utilizing standard ePTFE, two types of atRA-containing ePTFE vascular grafts were fabricated and evaluated: grafts whereby all-trans retinoic acid was directly immobilized on ePTFE (atRA-ePTFE) and grafts where all-trans retinoic acid was immobilized onto ePTFE grafts coated with POC (atRA-POC-ePTFE). All grafts were characterized by SEM, HPLC, and FTIR and physical characteristics were evaluated in vitro. Modification of these grafts, did not significantly alter their physical characteristics or biocompatibility, and resulted in inhibition of intimal formation in a rat aortic bypass model, with atRA-POC-ePTFE inhibiting intimal formation at both the proximal and distal graft sections. In addition, treatment with atRA-POC-ePTFE resulted in increased graft endothelialization and decreased inflammation when compared to the other treatment groups. This work further confirms the biocompatibility and efficacy of locally delivered atRA to inhibit intimal formation in a bypass setting. Thus, atRA-POC-ePTFE grafts have the potential to improve patency rates in small diameter bypass grafts and warrant further investigation. PMID- 29391233 TI - Effects of Qijian mixture on type 2 diabetes assessed by metabonomics, gut microbiota and network pharmacology. AB - Qijian mixture, a new traditional Chinese medicine (TCM) formula comprising of Astragalus membranaceus, Ramulus euonymi, Coptis chinensis and Pueraria lobata, was designed to ameliorate the type 2 diabetes (T2D), and its safety and efficacy were evaluated in the research by metabonomics, gut microbiota and system pharmacology. To study the hypoglycemic effect of Qijian mixture, male KKay mice (28-30 g, 8-9 week) and C57/BL6 mice (18-19 g, 8-9 week) were used. Thirty KKay diabetic mice were randomly distributed into 5 groups, abbreviated as Model group (Model), Low Qijian Mixture group (QJM(L)), High Qijian Mixture group (QJM(H)), Chinese Medicine (Gegen Qinlian Decoction) Positive group (GGQL), and Western Medicine (Metformin hydrochloride) Positive group (Metformin). C57/BL6 was considered as the healthy control group (Control). Moreover, a system pharmacology approach was utilized to assess the physiological targets involved in the action of Qijian mixture. There was no adverse drug reaction of Qijian mixture in the acute toxicity study and HE result, and, compared with Model group, Qijian mixture could modulate blood glycemic level safely and effectively. Qijian Mixture was lesser effective than metformin hydrochloride; however, both showed similar hypoglycemic trend. Based on 1H NMR based metabonomics study, the profoundly altered metabolites in Qijian mixture treatment group were identified. Qijian mixture-related 55 proteins and 4 signaling pathways, including galactose metabolism, valine, leucine and isoleucine degradation metabolism, aminoacyl-tRNA biosynthesis metabolism and alanine, aspartate and glutamate metabolism pathways, were explored. The PCoA analysis of gut microbiota revealed that Qijian mixture treatment profoundly enriched bacteroidetes. In addition, the system pharmacology paradigm revealed that Qijian mixture acted through TP53, AKT1 and PPARA proteins. It was concluded that Qijian mixture effectively alleviated T2D, and this effect was linked with the altered features of the metabolite profiles and the gut microbiota. PMID- 29391234 TI - The role of dopaminergic midbrain in Alzheimer's disease: Translating basic science into clinical practice. AB - Mammalian brain cortical functions, from executive and motor functioning to memory and emotional regulation, are strictly regulated by subcortical projections. These projections terminate in cortical areas that are continuously influenced by released neurotransmitters and neuromodulators. Among the subcortical structures, the dopaminergic midbrain plays a pivotal role in tuning cortical functions that commonly result altered in many neurological and psychiatric disorders. Incidentally, extensive neuropathological observations support a strong link between structural alterations of the dopaminergic midbrain and significant behavioural symptomatology observed in patients suffering from Alzheimer 's disease(AD). Here, we will review recent progress on the involvement of the dopaminergic system in the pathophysiology of AD as well as the current therapeutic strategies targeting this system. PMID- 29391232 TI - Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment. AB - Several cancer immunotherapy approaches have been recently introduced into the clinics and they have shown remarkable therapeutic potentials. The groundbreaking cancer immunotherapeutic agents function as a stimulant or modulator of the body immune system to fight against or kill cancers. Although targeted immunotherapies such as immune check point inhibitors (CTLA-4 or PD-1/PD-L1), DNA vaccination and CAR-T therapy are revolutionizing cancer treatment, the delivery efficacy can be further improved while their off-target toxicity can be mitigated through nanotechnology approaches. Recent research has demonstrated that nanotechnology has multifaceted role for (i) reeducating tumor associated macrophages (TAM) to function as tumor suppressor agent, (ii) serving as an efficient alternative for Chimeric Antigen Receptor (CAR)-T cell generation and transduction, and (iii) selective knockdown of Kras oncogene addiction by nano-Crisper-Cas9 delivery system. The function of host immune stimulatory signals and tumor immunotherapies can further be improved by repurposing of nanomedicine platform. This review summarizes the role of multifunctional polymeric, lipid, metallic and cell based nanoparticles for improving current immunotherapy. PMID- 29391235 TI - Novel targets in Alzheimer's disease: A special focus on microglia. AB - Several years after the intriguing novelty in the beta-amyloid (Abeta) cascade hypothesis, where the Abeta oligomers emerged as the most detrimental species in the neuropathogenic process of Alzheimer's disease (AD) in place of fibrillar plaques, more recently innate immune system have come on stage as the other prominent factor. Neuroinflammation apparently contributes to AD eziopathogenesis, in large part through overactivation of microglia cells. Genetic and experimental studies strongly support the contribution of the immune system to increasing the risk of AD and participating in its progression. Besides the central immune response mediated by resident microglial cells, peripheral immune challenges may have profound negative effects on brain physiology as well, such as those originating from the gut microbiota. Despite the initial immune response to defend the organism, perpetuation seemingly turns into a chronic detrimental phenomenon that contributes to neuronal dysfunction and exacerbation of the disease. Several new immune-druggable targets are now under investigation, but much still remains to be defined about their precise role and whether and how their physiological activity changes in the injurious context of AD. From a therapeutic perspective, we can undoubtedly consider that AD is no longer solely an Abeta pathology, but rather a multifaceted disorder calling for multi-target therapies. New therapies fighting AD must still counteract Abeta but must also restore appropriate immune defences by tempering maladaptive factors and enabling beneficial responses. PMID- 29391236 TI - The role of gut microbiota in the pharmacokinetics of antihypertensive drugs. AB - The intestine is one of the most important sites for the metabolism of several xenobiotic compounds. In addition to intestinal drug-metabolizing enzymes and drug transporters, gut microbial enzymes modulate the biotransformation of orally administered drugs in the gastrointestinal tract. Antihypertensive drugs such as amlodipine and nifedipine could be metabolized by gut microbial enzymes, which may influence drug absorption, leading to changes in pharmacological potency of the drug and eventual failure of the appropriate blood pressure control or unexpected side effects. This may suggest that there are additional mechanisms that can alter the therapeutic efficacy of antihypertensive drugs, especially in certain pathological conditions of the gastrointestinal tract or with concomitant use of substances such as antibiotics and probiotics that might alter the gut microbial composition. This review describes the metabolism of antihypertensive drugs by hepatic and intestinal microbial enzymes in an attempt to understand the potential effects of gut microbiota on their pharmacokinetics. PMID- 29391237 TI - Sulforaphane attenuates microglia-mediated neuronal necroptosis through down regulation of MAPK/NF-kappaB signaling pathways in LPS-activated BV-2 microglia. AB - Sulforaphane (SFN), a natural dietary isothiocyanate in cruciferous vegetables such as broccoli and cabbage, has very strong anti-inflammatory activity. Activation of microglia leads to overexpression of a series of pro-inflammatory mediators, which play a vital role in neuronal damage. SFN may have neuroprotective effects in different neurodegenerative diseases related to inflammation. However, the mechanisms underlying SFN's protection of neurons against microglia-mediated neuronal damage are not fully understood. Here, we investigated how SFN attenuated microglia-mediated neuronal damage. Our results showed that SFN could not directly protect the viability of neurons following pro inflammatory mediators, but increased the viability of BV-2 microglia and down regulated the mRNA and protein levels of pro-inflammatory mediators including TNF alpha, IL-1beta, IL-6 and iNOS in a concentration-dependent manner in BV-2 cells. SFN also significantly blocked the phosphorylation of MAPKs (p38, JNK, and ERK1/2) and NF-kappaB p65, both by itself and with MAPK inhibitors (SB203580, SP 600125, and U0126) or an NF-kappaB inhibitor (PDTC). The expression of pro inflammatory proteins was also blocked by SFN with or without inhibitors. Further, SFN indirectly increased the viability and maintained the morphology of neurons, and the protein expression of RIPK3 and MLKL was significantly suppressed by SFN in neuronal necroptosis through p38, JNK, and NF-kappaB p65 but not ERK1/2 signaling pathways. Together, our results demonstrate that SFN attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-kappaB signaling pathway in BV-2 microglia and thus indirectly suppresses microglia-mediated neuronal damage. PMID- 29391239 TI - Ozone modifies the metabolic and endocrine response to glucose: Reproduction of effects with the stress hormone corticosterone. AB - Air pollution is associated with increased incidence of metabolic disease (e.g. metabolic syndrome, obesity, diabetes); however, underlying mechanisms are poorly understood. Air pollutants increase the release of stress hormones (human cortisol, rodent corticosterone), which could contribute to metabolic dysregulation. We assessed acute effects of ozone, and stress axis involvement, on glucose tolerance and on the metabolic (triglyceride), endocrine/energy regulation (insulin, glucagon, GLP-1, leptin, ghrelin, corticosterone), and inflammatory/endothelial (TNF, IL-6, VEGF, PAI-1) response to exogenous glucose. Male Fischer-344 rats were exposed to clean air or 0.8 ppm ozone for 4 h in whole body chambers. Hypothalamic-pituitary-adrenal (HPA) axis involvement in ozone effects was tested through subcutaneous administration of the glucocorticoid synthesis inhibitor metyrapone (50 mg/kg body weight), corticosterone (10 mg/kg body weight), or vehicle (40% propylene glycol) prior to exposure. A glucose tolerance test (2 g/kg body weight glucose) was conducted immediately after exposure, with blood samples collected at 0, 30, 60, 90, and 120 min. Ozone exposure impaired glucose tolerance, an effect accompanied by increased plasma triglycerides but no impairment of insulin release. Ozone diminished glucagon, GLP-1, and ghrelin responses to glucose, but did not significantly impact inflammatory/endothelial analytes. Metyrapone reduced corticosterone but increased glucose and triglycerides, complicating evaluation of the impact of glucocorticoid inhibition. However, administration of corticosterone reproduced the profile of ozone effects, supporting a role for the HPA axis. The results show that ozone-dependent changes in glucose tolerance are accompanied by altered metabolic and endocrine responses to glucose challenge that are reproduced by exogenous stress hormone. PMID- 29391238 TI - Upregulation of histone-lysine methyltransferases plays a causal role in hexavalent chromium-induced cancer stem cell-like property and cell transformation. AB - While hexavalent chromium [Cr(VI)] is generally considered as a genotoxic environmental carcinogen, studies showed that Cr(VI) exposure also causes epigenetic changes. However, whether Cr(VI)-caused epigenetic dysregulations plays an important role in Cr(VI) carcinogenicity remain largely unknown. The aim of this study was to determine if chronic low dose Cr(VI) exposure causes epigenetic changes, the underlying mechanism and whether chronic low dose Cr(VI) exposure-caused epigenetic dysregulation contributes causally to Cr(VI)-induced cancer stem cell (CSC)-like property and cell transformation. Two immortalized human bronchial epithelial cell lines (BEAS-2B and 16HBE) were exposed to 0.25 MUM of K2Cr2O7 for 20 and 40 weeks to induce cell transformation, respectively. Cr(VI)-induced epigenetic changes were examined in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Pharmacological inhibitors and gene knockdown experiments were used to determine the role of epigenetic dysregulation in Cr(VI) carcinogenicity. We found that chronic Cr(VI) exposure causes epigenetic dysregulation as evidenced by the increased levels of histone H3 repressive methylation marks (H3K9me2 and H3K27me3) and the related histone lysing methyltransferases (HMTases). Pharmacological inhibition or knockdown of HMTases reduces H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in parental cells significantly reduces chronic Cr(VI) exposure-induced CSC-like property and cell transformation. Further mechanistic study revealed that knockdown of HMTases decreases Cr(VI) exposure-caused DNA damage. Our findings indicate that chronic Cr(VI) exposure increases H3 repressive methylation marks by increasing the related HMTases expression; and that increased expression of HMTases plays a causal role in Cr(VI)-induced CSC-like property and cell transformation. PMID- 29391240 TI - Atorvastatin and insulin equally mitigate brain pathology in diabetic rats. AB - Although insulin and atorvastatin have been shown to exert glycemic control and could improve brain function, the effects of atorvastatin or insulin as well as the combination of atorvastatin plus insulin on brain pathology in diabetes mellitus type 1 (T1DM) are unclear. Therefore, this study investigated the effect of atorvastatin, insulin or combined drugs on brain pathology in streptozotocin induced diabetic rats. Thirty-six male rats were divided into two groups, a control group (n = 12) and a diabetic or experimental group (n = 24). Diabetic rats were further divided into four groups (n = 6/group) and the groups received either a vehicle (normal saline), atorvastatin (10 mg/kg/day), insulin (4 U/day) or a combination of the drugs for 4 weeks. The control group rats were divided into two groups (n = 6/group) to receive either just the vehicle or atorvastatin for 4 weeks. We found that streptozotocin-induced diabetic rats developed hyperglycemia, showing evidence of increased brain oxidative stress, impaired brain mitochondrial function, increased brain apoptosis, increased tau protein expression, increased phosphorylation of tau protein expression and amyloid beta levels, and decreased dendritic spine density. Although atorvastatin and insulin therapies led to an equal reduction in plasma glucose level in these diabetic rats, the combined drug therapy showed the greatest efficacy in decreasing plasma glucose level. Interestingly, atorvastatin, insulin and the combined drugs equally mitigated brain pathology. Our findings indicate that the combined drug therapy showed the greatest efficacy in improving metabolic parameters. However, atorvastatin, insulin and the combined drug therapy shared a similar efficacy in preventing brain damage in T1DM rats. PMID- 29391241 TI - Improved estimation of subject-level functional connectivity using full and partial correlation with empirical Bayes shrinkage. AB - Reliability of subject-level resting-state functional connectivity (FC) is determined in part by the statistical techniques employed in its estimation. Methods that pool information across subjects to inform estimation of subject level effects (e.g., Bayesian approaches) have been shown to enhance reliability of subject-level FC. However, fully Bayesian approaches are computationally demanding, while empirical Bayesian approaches typically rely on using repeated measures to estimate the variance components in the model. Here, we avoid the need for repeated measures by proposing a novel measurement error model for FC describing the different sources of variance and error, which we use to perform empirical Bayes shrinkage of subject-level FC towards the group average. In addition, since the traditional intra-class correlation coefficient (ICC) is inappropriate for biased estimates, we propose a new reliability measure denoted the mean squared error intra-class correlation coefficient (ICCMSE) to properly assess the reliability of the resulting (biased) estimates. We apply the proposed techniques to test-retest resting-state fMRI data on 461 subjects from the Human Connectome Project to estimate connectivity between 100 regions identified through independent components analysis (ICA). We consider both correlation and partial correlation as the measure of FC and assess the benefit of shrinkage for each measure, as well as the effects of scan duration. We find that shrinkage estimates of subject-level FC exhibit substantially greater reliability than traditional estimates across various scan durations, even for the most reliable connections and regardless of connectivity measure. Additionally, we find partial correlation reliability to be highly sensitive to the choice of penalty term, and to be generally worse than that of full correlations except for certain connections and a narrow range of penalty values. This suggests that the penalty needs to be chosen carefully when using partial correlations. PMID- 29391242 TI - Sex- and sex hormone-related variations in energy-metabolic frontal brain asymmetries: A magnetic resonance spectroscopy study. AB - Creatine is a key regulator of brain energy homeostasis, and well-balanced creatine metabolism is central in healthy brain functioning. Still, the variability of brain creatine metabolism is largely unattended in magnetic resonance spectroscopy (MRS) research. In the human brain, marginal sex differences in creatine levels have been found in the prefrontal cortex. It is however not known to what degree these sex differences are stable or change with varying gonadal hormone levels. The current study therefore investigated creatine in the prefrontal cortex across the menstrual cycle. In addition, we explored cerebral asymmetries. Creatine, Choline (Cho), N-acetylaspartate (NAA), Myo inositol (mI), and glutamate + glutamine (Glx) were assessed three times in 15 women and 14 men using MRS. Women were tested in cycle phases of varying hormone levels (menstrual, follicular, and luteal phase). Prefrontal creatine was found to change across the menstrual cycle, in a hemisphere-specific manner. Women in the follicular phase showed increased left prefrontal creatine accompanied with reduced right prefrontal creatine, while this asymmetry was not present in the luteal phase. In men, the creatine levels remained stable across three testing sessions. In general, both men and women were found to have higher creatine levels in the left as compared to the right prefrontal cortex. Exploratory analyses of other metabolites showed similar asymmetries in NAA, Cho, and mI, while Cho also showed a menstrual cycle effect. This is the first time that sex hormone-related changes in creatine metabolism have been demonstrated in the human brain. These findings may have important methodological implications for MRS research, as it supports previous concerns against uncritical usage of creatine as a reference measure for other metabolites, assumed to be invariant across individuals and conditions. PMID- 29391244 TI - Role of PCR method using IS6110 primer in detecting Mycobacterium tuberculosis among the clinically diagnosed childhood tuberculosis patients at an urban hospital in Dhaka, Bangladesh. AB - OBJECTIVE: Better methods are needed for the accurate detection of child tuberculosis (TB). This study compared different laboratory tests and evaluated IS6110 PCR for the detection of Mycobacterium tuberculosis (MTB) among clinically diagnosed child TB patients. METHODS: A total of 102 paediatric patients (<15 years old) with clinically diagnosed TB were enrolled in this study. The patients were admitted to the icddr,b hospital in Dhaka between 2003 and 2005. Sputum/gastric lavage samples were collected for smear microscopy, culture (solid/Lowenstein-Jensen medium and liquid/MGIT), and IS6110 PCR testing. The sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of smear microscopy and PCR were compared to the two culture methods. RESULTS: Three patients were positive on smear microscopy (2.9%). MTB was detected by conventional culture in 15.7% (16/102), liquid culture in 14% (14/100), and IS6110 PCR in 61.8% (63/102). PCR detected an additional 45 patients who were undetected with the three other tests. Compared to conventional and liquid culture, respectively, smear microscopy showed sensitivity of 18.8% and 21.4%, specificity of 100% individually, PPV of 100% individually, and NPV of 86.9% and 88.7%, whereas PCR had sensitivity of 87.5% and 92.9%, specificity of 43% individually, PPV of 22.2% and 21%, and NPV of 94.9% and 97.4%. CONCLUSIONS: PCR can be useful compared to smear microscopy and culture methods and is applicable as a rapid screening test for child TB. A larger scale study is required to determine its diagnostic efficacy in improving the detection of child TB in the presence and absence of severe malnutrition. PMID- 29391243 TI - Incentives facilitate developmental improvement in inhibitory control by modulating control-related networks. AB - Adolescence is a period of heightened sensitivity to incentives and relatively weak cognitive control, which may contribute to risky behaviors. Studies of brain activity have generally identified greater activation of the ventral striatum to rewards and less activation of prefrontal regions during control tasks in adolescents compared to adults. Little is known, however, about age-related changes in the functional brain networks underlying incentive processing and cognitive control. This cross-sectional study characterized the effects of incentives on inhibitory control during an oculomotor task using whole-brain functional connectivity analyses. During an fMRI scan, one hundred forty typically developing individuals completed an incentivized antisaccade task consisting of incentive cue, preparation, and response phases. We found that task modulation of control networks increased gradually from childhood to adulthood, whereas a network including ventral striatum and ventromedial prefrontal cortex displayed an adolescent-specific peak in response to the receipt of outcomes, consistent with dual-systems models. Notably, however, greater modulation of salience and motor networks during the preparation phase mediated age-related improvements in antisaccade accuracy, whereas adolescent enhancement of value related circuitry did not. Relative to neutral cues, both reward and loss cues enhanced task-related connectivity of the salience network when preparing to inhibit a saccade. Altogether, our findings suggest that incentives facilitate inhibitory control by enhancing the salience of one's responses and that over development, the recruitment of functional networks involved in saliency and motor preparation supports better performance. PMID- 29391245 TI - Absence of cerebrospinal fluid pleocytosis in tuberculous meningitis is a common occurrence in HIV co-infection and a predictor of poor outcomes. PMID- 29391247 TI - Saccade latency bias toward temporal hemifield: Evidence for role of retinotectal tract in mediating reflexive saccades. AB - The superior colliculus (SC) plays a critical role in mediating reflexive eye movements. Under optimal conditions, for example including a temporal 'gap' of 200 ms after fixation offset and prior to target onset, it is possible to isolate a population of 'express saccades' with very short latencies between 80 and 120 ms. Ablation of the SC abolishes express saccades in monkeys. However, it remains to be established whether express saccade generation is dependent upon visual afferents transmitting direct retinal projections to SC via the retinotectal tract (RTT). In nineteen healthy human participants, we used a gap paradigm to investigate whether express saccades demonstrate shorter latencies to targets in the temporal hemifield, a marker for RTT function. A population of predominantly reflexive saccades (with latencies between 70 and 150 ms) was isolated in which latencies toward temporal hemifield targets were shown to be shorter than toward nasal hemifield targets. The advantages for reflexive saccades toward temporal hemifield targets suggest that visual efferents from the retina to the superior colliculus contribute to generating reflexively triggered saccades. PMID- 29391246 TI - Respiratory infections in elderly people: Viral role in a resident population of elderly care centers in Lisbon, winter 2013-2014. AB - OBJECTIVE: The aim of this study was to analyze the etiology and clinical consequences of viral respiratory infections in 18 elderly care centers (ECC) in Lisbon, which housed a total of 1022 residents. METHODS: Nasopharyngeal swabs were collected whenever an elderly had symptoms of acute respiratory infections (ARI). PCR and RT-PCR were performed for influenza A/B, human parainfluenza virus 1-4, adenovirus, human metapneumovirus (HMPV), respiratory syncytial virus (RSV), rhinovirus, enterovirus, human coronavirus and human Bocavirus (HBoV). Array cards for atypical bacteria were also used in severe cases. RESULTS: In total, 188 episodes of ARI were reported, being rhinovirus the most frequently detected (n=53), followed by influenza A(H3) (n=19) and HBoV (n=14). Severe infections were reported in 19 patients, 11 of which were fatal, Legionela pneumophila, rhinovirus, HMPV and RSV associated with these fatalities. Nine influenza strains were analyzed, all antigenically dissimilar from vaccine strain 2013/14. "Age", "HMPV" and "Respiratory disease" showed an association with severe infection. CONCLUSIONS: In this study an etiologic agent could be found in 60% of the acute respiratory episodes. These data provides information about the circulating viruses in ECC and highlights the importance of searching both viruses and atypical bacteria in severe ARI. PMID- 29391248 TI - Knowledge supports memory retrieval through familiarity, not recollection. AB - Semantic memory, or general knowledge of the world, guides learning and supports the formation and retrieval of new episodic memories. Behavioral evidence suggests that this knowledge effect is supported by recollection-a more controlled form of memory retrieval generally accompanied by contextual details to a greater degree than familiarity-a more automatic form of memory retrieval generally absent of contextual details. In the current study, we used functional magnetic resonance imaging (fMRI) to investigate the role that regions associated with recollection and familiarity play in retrieving recent instances of known (e.g., The Summer Olympic Games are held four years apart) and unknown (e.g., A flaky deposit found in port bottles is beeswing) statements. Our results revealed a surprising pattern: Episodic retrieval of known statements recruited regions associated with familiarity, but not recollection. Instead, retrieval of unknown statements recruited regions associated with recollection. These data, in combination with quicker reaction times for the retrieval of known than unknown statements, suggest that known statements can be successfully retrieved on the basis of familiarity, whereas unknown statements were retrieved on the basis of recollection. Our results provide insight into how knowledge influences episodic retrieval and demonstrate the role of neuroimaging in providing insights into cognitive processes in the absence of explicit behavioral responses. PMID- 29391250 TI - Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models. AB - Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production. PMID- 29391251 TI - EB2017-Progress in Epidermolysis Bullosa Research toward Treatment and Cure. AB - Epidermolysis bullosa, a group of heritable blistering disorders, shows extensive phenotypic variability due to mutations in as many as 20 distinct genes. There is no cure for this devastating group of disorders; however, a number of preclinical developments show promise, and some approaches have already reached the stage of early clinical trials. Dystrophic Epidermolysis Bullosa Research Association (DEBRA) International, a global coalition of national patient organizations advocating on behalf of the patients and families with epidermolysis bullosa, supports research and organizes periodic scientific and clinical meetings on this disease. The most recent meeting, EB2017, was held in Salzburg in September 2017. This report summarizes some of the recent research and clinical developments that have identified promising avenues toward treatment and perhaps eventual cure, with improved quality of life for patients with epidermolysis bullosa. PMID- 29391249 TI - Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations. AB - Previous studies have shown that mouse dermis is composed of functionally distinct fibroblast lineages. To explore the extent of fibroblast heterogeneity in human skin, we used a combination of comparative spatial transcriptional profiling of human and mouse dermis and single-cell transcriptional profiling of human dermal fibroblasts. We show that there are at least four distinct fibroblast populations in adult human skin, not all of which are spatially segregated. We define markers permitting their isolation and show that although marker expression is lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signaling, responsiveness to IFN-gamma, and ability to support human epidermal reconstitution when introduced into decellularized dermis. These findings suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications in wound healing and diseases characterized by excessive fibrosis. PMID- 29391252 TI - Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin. AB - Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed >=24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2. PMID- 29391253 TI - ADA2 deficiency: Clonal lymphoproliferation in a subset of patients. PMID- 29391254 TI - Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome. AB - BACKGROUND: Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome. OBJECTIVE: We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder. METHODS: We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages. RESULTS: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B cell activating factor availability, development past this B-cell activating factor-dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased alpha-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively. CONCLUSION: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome. PMID- 29391255 TI - An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcgammaRIIb. AB - BACKGROUND: Induction of allergen-specific IgG antibodies is a critical parameter for successful allergen-specific immunotherapy. IgG antibodies can inhibit IgE mediated mast cell activation through direct allergen neutralization or through the inhibitory receptor FcgammaRIIb. The affinity of IgE antibodies to the allergen has been shown to be critical for cellular activation. OBJECTIVE: Here we addressed the question of affinity thresholds of allergen-specific IgG antibodies for inhibition of mast cell activation using 2 different mAbs against the major cat allergen Fel d 1 both in vitro and in vivo in mice. METHODS: Sequences of the 2 high-affinity mAbs were back-mutated to germline, resulting in low-affinity (10-7 mol/L) antibodies of the exact same specificity. RESULTS: Using these newly generated recombinant antibodies, we demonstrate that low affinity antibodies are still able to inhibit mast cell activation through FcgammaRIIb but do not neutralize the allergen. CONCLUSION: Antibody affinity dictates the mechanism of mast cell inhibition, and IgG antibodies triggering the inhibitory FcgammaRIIb pathway can show a broader cross-reactivity pattern than previously thought. This indicates that allergen-specific immunotherapy generates a larger protective umbrella of inhibitory IgG antibodies than previously appreciated. PMID- 29391256 TI - Human TH17 cell development requires processing of dendritic cell-derived CXCL8 by neutrophil elastase. PMID- 29391257 TI - CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses. AB - BACKGROUND: A particular characteristic of non-small cell lung cancer is the composition of the tumor microenvironment with a very high proportion of fibroblastic stromal cells (FSCs). OBJECTIVE: Lapses in our basic knowledge of fibroblast phenotype and function in the tumor microenvironment make it difficult to define whether FSC subsets exist that exhibit either tumor-promoting or tumor suppressive properties. METHODS: We used gene expression profiling of lung versus tumor FSCs from patients with non-small cell lung cancer. Moreover, CCL19 expressing FSCs were studied in transgenic mouse models by using a lung cancer metastasis model. RESULTS: CCL19 mRNA expression in human tumor FSCs correlates with immune cell infiltration and intratumoral accumulation of CD8+ T cells. Mechanistic dissection in murine lung carcinoma models revealed that CCL19 expressing FSCs form perivascular niches to promote accumulation of CD8+ T cells in the tumor. Targeted ablation of CCL19-expressing tumor FSCs reduced immune cell recruitment and resulted in unleashed tumor growth. CONCLUSION: These data suggest that a distinct population of CCL19-producing FSCs fosters the development of an immune-stimulating intratumoral niche for immune cells to control cancer growth. PMID- 29391258 TI - Identification of Clostridium species using the VITEK(r) MS. AB - The genus Clostridium is of high clinical relevance, as some species may cause rapid and even lethal infections. Thus, a timely identification of these anaerobic bacteria is desirable. Conventional identification methods rely on biochemical properties of these organisms, however, establishing these is time consuming and not always reliable. Alternatively, 16S rRNA gene sequence based diagnostic methods may be used, but they are expensive and not ubiquitously available. This study was designed to assess the possibility to identify Clostridium species employing the matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). For this purpose, 848 Clostridium strains representing 42 species were analyzed with the VITEK(r) MS instrument (bioMerieux, Marcy l'Etoile, France), comparing mass spectra derived from these organisms with the spectra provided in the available database. 90.3% of the strains were correctly identified at species level and another 3.6% at genus level. Since the number of Clostridium species included in the database was rather limited (21 altogether), the spectra obtained were also analyzed employing the Shimadzu Pro Series software. Thus, it became possible to create a dendrogram of the species included in this study. PMID- 29391259 TI - Comparative genomics analysis of Clostridium difficile epidemic strain DH/NAP11/106. AB - Clostridium difficile PCR ribotype 106 (also identified as restriction endonuclease analysis [REA] group DH) recently emerged as the most common strain causing C. difficile infection (CDI) among US adults. We previously identified this strain predominating our pediatric cohort. Pediatric clinical CDI isolates previously characterized by REA underwent antibiotic resistance testing and whole genome sequencing. Of 134 isolates collected from children, 31 (23%) were REA group DH. We performed a comparative genomics analysis to identify DH-associated accessory genes. We identified five DH-associated genes that are associated with virulence in other bacterial species but not previously known to contribute to CDI. These genes are associated with intestinal mucosal adhesion (collagen binding surface protein), sporulation (sporulation integral membrane protein YtvI), and protection from oxidative stress and foreign DNA (DNA phosphorothioation-dependent restriction proteins, sulfurtransferase, and DNA sulfur modification proteins). The association of these genes was validated in a cohort of 623 publicly available C. difficile sequences, 10 (1.6%) of which were monophyletic to REA group DH through in silico multilocus sequence typing and core genome phylogenetic analysis. Further investigation is required to determine the contribution of these genes to the emergence and virulence of this epidemic strain. PMID- 29391260 TI - Professional medical associations and the opportunity to promote breakthrough biomedical innovation. PMID- 29391261 TI - Nanomedicine as a potential approach to empower the new strategies for the treatment of preeclampsia. AB - Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta. PMID- 29391262 TI - Quercetogetin protects against cigarette smoke extract-induced apoptosis in epithelial cells by inhibiting mitophagy. AB - Recent studies demonstrate that the autophagy-dependent turnover of mitochondria (mitophagy) mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure, and contributes to emphysema development in vivo during chronic cigarette smoke (CS)-exposure, although the underlying mechanisms remain unclear. Here, we investigated the role of mitophagy in regulating apoptosis in CSE-exposed human lung bronchial epithelial cells. Furthermore, we investigated the potential of the polymethoxylated flavone antioxidant quercetogetin (QUE) to inhibit CSE-induced mitophagy-dependent apoptosis. Our results demonstrate that CSE induces mitophagy in epithelial cells via mitochondrial dysfunction, and causes increased expression levels of the mitophagy-regulator protein PTEN-induced putative kinase-1 (PINK1) and the mitochondrial fission protein dynamin-1-like protein (DRP-1). CSE induced epithelial cell death and increased the expression of the apoptosis-related proteins cleaved caspase-3, -8 and -9. Caspase-3 activity was significantly increased in Beas-2B cells exposed to CSE, and decreased by siRNA-dependent knockdown of DRP-1. Treatment of epithelial cells with QUE inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting phospho (p)-DRP-1 and PINK1 expression. QUE suppressed mitophagy-dependent apoptosis by inhibiting the expression of cleaved caspase-3, -8 and -9 and downregulating caspase activity in human bronchial epithelial cells. These findings suggest that QUE may serve as a potential therapeutic in CS-induced pulmonary diseases. PMID- 29391263 TI - Evaluating opportunities for advancing the use of alternative methods in risk assessment through the development of fit-for-purpose in vitro assays. AB - An evolving regulatory, scientific, and legislative landscape is driving a fundamental change in how chemical safety decisions are made. As we move to implement changes, regulatory agencies and industry are beginning to adopt tiered approaches, which leverage high-throughput screening technologies for prioritization and read across, followed by interrogation of "hit chemicals" with more rigorous dose-response assessment either in fit-for-purpose human cell-based assays or with traditional in vivo tests. However, to date, suitable in vitro alternatives do not exist for the vast majority of the organ toxicities that form the basis of current regulatory decisions. To successfully support safety decisions, biologically relevant, quantitative, cell-based assays that evaluate dose-response and identify regions of safety for chemical exposure are required. This review evaluates the current state of the science in the development of such assays, identifies key gaps in the current tests, and recommends areas where research efforts may be focused to help move the risk assessment community towards more wide-spread use of in vitro methods. Our analysis suggests that a key shortcoming in the current efforts is the ability to test volatile compounds and to predict pulmonary toxicity. We present a mechanistically-based path forward for the development of a fit-for-purpose lung toxicity assay. PMID- 29391264 TI - Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan. AB - Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. PMID- 29391265 TI - Efficacy of Granulocyte Colony-Stimulating Factor and N-Acetylcysteine Therapies in Patients With Severe Alcoholic Hepatitis. AB - BACKGROUND & AIMS: Patients with alcoholic hepatitis (AH) have high mortality, so new therapies are needed. Administration of granulocyte colony stimulating factor (G-CSF) increases survival times of patients with AH. It is not known whether addition of N-acetyl cysteine (NAC) to G-CSF could further increase survival time. We performed a randomized controlled pilot study to compare the efficacy of standard medical therapy with pentoxifylline to treatment with a combination of G CSF and standard medical therapy as well as to the combination of NAC, G-CSF, and standard medical therapy in patients with severe AH. METHODS: We performed an open-label, single-center study of 57 patients with severe AH admitted to a Liver Intensive Care unit in India from October 2014 through March 2017. Patients were randomly assigned to groups that received standard medical therapy (with pentoxifylline) plus G-CSF for 5 days (G-CSF group; n = 18), standard medical therapy plus G-CSF and intravenous NAC for 5 days (combination group; n = 19), or standard medical therapy alone (n = 20). Clinical data and blood samples were collected at baseline; on day 6; and 1, 2, and 3 months after the study began. CD34+ cells were measured in blood samples collected on days 0 and 6. The primary outcome was proportion of patients surviving for 90 days. Secondary outcomes were mobilization of CD34+ cells at day 6, as well as Child Turcotte Pugh, model for end-stage liver disease, and modified discriminant function scores until day 90. RESULTS: Significantly higher proportions of patients in the G-CSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20) (P = .0001 for G-CSF group and P = .037 and combination group). The GGSF and combination groups each had increased numbers of CD34+ cells from baseline until day 6, compared with the standard medical therapy group. The G-CSF group (but not the combination group) had significantly larger median reductions in modified discriminant function scores at study months 1 (reduction of 60.36%), 2 (reduction of 75.36%), and 3 (reduction of 88.73%) vs the standard medical therapy group (P = .02; P = .05; and P = .00, respectively). The G-CSF group had a significantly larger median reduction in model for end stage liver disease score at 3 months (reduction of 55.77%; P = .01), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications. CONCLUSION: In a pilot randomized controlled trial, we found administration of G-CSF to improve liver function and increase survival times in patients with severe AH, compared with standard therapy. We found no evidence for benefit of adding NAC to G-CSF. These findings require confirmation in larger trials. ClincialTrials.gov, number: NCT02971306. PMID- 29391266 TI - Lack of Association Between Proton Pump Inhibitor Use and Cognitive Decline. AB - BACKGROUND & AIMS: Studies of association between use of proton pump inhibitors (PPI) and dementia have yielded conflicting results. We investigated the effects of PPIs on cognitive decline in a study of middle-aged and elderly twins in Denmark. METHODS: In a prospective study, we collected data from surveys of middle-aged individuals (46-67 years old; the Middle Aged Danish Twin study) and older individuals (the Longitudinal Study of Aging Danish Twins) who underwent cognitive assessments (a 5-component test battery) over a 10-year period (middle age study, n = 2346) or a 2-year period (longitudinal study of aging: n = 2475). We determined cumulative use of PPIs 2 years prior study enrollment and during follow up, in defined daily doses (DDDs) of PPIs, using data from a nationwide prescription register. Multi-variable linear regression models were used to examine associations between cumulative PPI use and a composite score of cognitive function at baseline and decreases in scores during the follow-up periods. RESULTS: Use of PPIs before study enrollment was associated with a slightly lower mean cognitive score at baseline in the middle age study. The adjusted difference in mean score of individuals with high consumption of PPIs (>=400 DDD) was lower than that of non-users in the middle-age study (mean crude score for high PPI use, 43.4 +/- 13.1 vs for non-use, 46.8 +/- 10.2; adjusted difference of 0.69 points; 95% CI, -4.98 to 3.61). In the longitudinal study of aging twins, individuals with high consumption of PPI had higher adjusted scores than non-users (mean crude score for high PPI use, 35.2 +/- 10.8 vs for non-use, 36.2 +/- 11.1; adjusted difference of 0.95 points; 95% CI, -1.88 to 3.79). In analyses of cognitive decline, among individuals with high consumption of PPIs in the longitudinal study of aging, the adjusted mean difference between baseline score and follow-up score was lower than that of non-users (mean crude score for high PPI use at baseline, 36.6 +/- 10.1 and at follow up, 34.3 +/- 12.3 vs for non-use at baseline, 38.1 +/- 10.5 and at follow up, 37.6 +/- 11.3; adjusted difference of -1.22 points; 95% CI, -3.73 to 1.29). In the middle-age study, users with the highest consumption of PPIs (>=1600 DDD) had slightly less cognitive decline than non-users (baseline mean crude score for high PPI use, 43.4 +/- 10.1 and follow-up mean crude score, 41.3 +/- 9.7 vs baseline score of 49.1 +/- 10.2 for non-users and follow-up score of 46.3 +/- 9.9 for non-users; adjusted difference of 0.94 points; 95% CI, -1.63 to 3.50). No stated differences in scores between PPI users and non-users were significant. CONCLUSIONS: In analyzing data from 2 large population-based studies of twins in Denmark, we found no association between PPI use and cognitive decline. PMID- 29391267 TI - Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome. AB - BACKGROUND & AIMS: Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality). METHODS: We performed a retrospective analysis of 4 different cohorts of consecutive patients with HRS treated with terlipressin and albumin from February 2007 through January 2016 at medical centers in Europe (total, 298 patients). We analyzed demographic, clinical, and laboratory data collected before and during treatment; patients were followed until death, liver transplantation, or 90 days after HRS diagnosis. RESULTS: Response to treatment was observed in 53% of patients. Of patients with grade 1 ACLF, 60% responded to treatment; among those with grade 2 ACLF, 48% responded, and among those with grade 3 ACLF, 29% responded (P < .001 for comparison between grades). In multivariate analysis, baseline serum level of creatinine (odds ratio, 0.23; P = .001) and ACLF grade (odds ratio, 0.63; P = .01) were independently associated with response to treatment. Patient age (hazard ratio [HR], 1.05; P < .001), white blood cell count (HR, 1.51; P = .006), ACLF grade (HR, 2.06; P < .001), and no response to treatment (HR, 0.41; P < .001) associated with 90-day mortality. CONCLUSION: In a retrospective analysis of data from 4 cohorts of patients treated for type 1 HRS, we found ACLF grade to be the largest determinant of response to terlipressin and albumin. ACLF grade affects survival independently of response to treatment. New therapeutic strategies should be developed for patients with type 1 HRS and extrarenal organ failure. PMID- 29391268 TI - Novel Computer-enhanced Visualization of Volumetric Laser Endomicroscopy Correlates Endoscopic and Pathological Images. PMID- 29391269 TI - Functional Gastrointestinal Disorders: All Roads Lead to Prevention. PMID- 29391270 TI - A Never Ending STORI. PMID- 29391271 TI - Eicosapentaenoic Acid Reduces Fecal Levels of Calprotectin and Prevents Relapse in Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: High fecal levels of calprotectin indicate mucosal inflammation and have been shown to predict relapse in patients with ulcerative colitis (UC). Eicosapentaenoic acid (EPA), the major component of n-3 fish oil, has anti-inflammatory properties in patients with chronic inflammatory disorders. We performed a placebo-controlled trial of patients with UC at risk of relapse to determine the ability of the free fatty acid form of EPA (EPA-FFA) to reduce intestinal inflammation, using fecal level of calprotectin as a marker. METHODS: From June 2014 to May 2016, 60 patients with UC with a partial Mayo score < 2 and fecal calprotectin >=150 MUg/g, in stable therapy for at least the 3 previous months, were randomly assigned to groups (1:1) given either EPA-FFA (500 mg, twice daily) or placebo for 6 months. A colonoscopy was performed at baseline. Clinical assessments and measurements of fecal calprotectin were made at baseline, at study months 3 and 6, or the time of clinical relapse. Patients with a relapse of UC underwent a second colonoscopy. The primary end point was a 100 point reduction in fecal levels of calprotectin at 6 months from the baseline value; the secondary end point was maintenance of clinical remission at 6 months. RESULTS: The primary end point was achieved by 19 of 30 patients (63.3%) in the EPA-FFA group vs 4 of 30 patients (13.3%) in the placebo group (odds ratio, 12.0; 95% CI, 3.12-46.24; P < .001). The secondary end point was achieved by 23 of 30 patients (76.7%) in the EPA-FFA group vs 15 of 30 (50%) patients in the placebo group (OR, 3.29; 95% CI, 1.08-9.95; P = .035). No serious adverse events were observed. CONCLUSIONS: In a placebo-controlled trial of 60 patients with UC, we found 6 months' administration of EPA-FFA to reduce fecal levels of calprotectin with no serious adverse events. This agent might be used to induce and maintain symptom-free remission in patients with UC. ClinicalTrials.gov number: NCT02179372. PMID- 29391272 TI - Identification of co-occurrence in a patient with Dent's disease and ADA2 deficiency by exome sequencing. AB - Patients with co-occurrence of two independent pathologies pose a challenge for clinicians as the phenotype often presents as an unclear syndrome. In these cases, exome sequencing serves as a powerful instrument to determine the underlying genetic causes. Here, we present the case of a 4-year old boy with proteinuria, microhematuria, hypercalciuria, nephrocalcinosis, livedo-like rash, recurrent abdominal pain, anemia and continuously elevated CRP. Single exome sequencing revealed the pathogenic nonsense mutation p.(Arg98*) in the CLCN5 gene causing the X-linked inherited, renal tubular disorder Dent's disease. Furthermore, the two pathogenic and compound heterozygous missense variants p.(Gly47Ala) and p.(Pro251Leu) in the CECR1 gene could be identified. Mutations in the CECR1 gene are associated with a hereditary form of polyarteritis nodosa, called ADA2-deficiency. Both parents were carriers of a single heterozygous variant in CECR1 and the mother was carrier of the CLCN5 variant. This case evidently demonstrates the advantage of whole exome sequencing compared to single gene testing as the pathology in the CECR1 gene might have only been diagnosed after the occurrence of signs of systemic vasculitis like strokes or hemorrhages. Therefore, treatment and prevention can now start early to improve the outcome of these patients. PMID- 29391273 TI - Knockdown of long noncoding RNA MEG3 impairs VEGF-stimulated endothelial sprouting angiogenesis via modulating VEGFR2 expression in human umbilical vein endothelial cells. AB - Long noncoding RNAs is a novel class of RNA molecules, which is closely related to the occurrence and development of human disease. Recent studies have highlighted the importance of MEG3 in angiogenesis and the maintenance of normal function of vascular endothelial cells. However, whether MEG3 contributes to human endothelial cell angiogenesis as well as potential mechanisms are largely unknown. In this work, we found that the high expression level of MEG3 in primary HUVEC was controlled by DNA methylation, and its expression in HUVEC was regulated by HIF-1alpha under hypoxia condition. Meanwhile, we discovered that knockdown of MEG3 significantly suppressed VEGFR2 mRNA level, but had no influence on gene expression of VEGFR1, Notch1, DLL4 and Hes1. MEG3 reduction also suppressed VEGF-induced endothelial migration and angiogenesis. Furthermore, MEG3 knockdown reduced the tube formation and the spheroid sprouting of primary HUVEC under normoxic and hypoxic conditions. Altogether, MEG3 regulated by HIF 1alpha is required to maintain VEGFR2 expression in endothelial cells and plays a vital role for VEGFA-mediated endothelial angiogenesis. PMID- 29391274 TI - Association of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population: A case-control study. AB - Corins are membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. These pro-atrial natriuretic peptide convertases are essential for sodium homeostasis and normal blood pressure. CORIN variants have been identified in humans and other animals, but no studies of CORIN polymorphisms have been conducted in northeastern China. This study aims to investigate the association of 2 single nucleotide polymorphisms (SNPs) in CORIN (rs2271037 and rs3749585) with hypertension, as well as their potential interactions with some risk factors of hypertension in a Han population of northeastern China. A case-control study, including 402 patients with hypertension and 406 participants with normal blood pressure, was conducted in Liaoning province. SNP genotyping was carried out by high resolution melting (HRM) after polymerase chain reaction amplifications. Since rs3749585 is located in 3' untranslated region (UTR) of CORIN, in silico analysis was used to predict target micro RNAs on TargetScan, miRanda, and DIANA-microT. As a result, mutant T allele in rs2271037 (odds ratio [OR], 1.693; 95% confidence [CI], 1.528-1.877; p < 0.001) and C allele in rs3749585 (OR, 1.114; 95% CI 1.011-1.227; p = 0.029) increased the risk of hypertension, comparing with wild G allele and T allele, respectively. Patients with genotype TT (OR, 10.209; 95% CI, 6.414-16.250; p < 0.001) and GT (OR, 1.730; 95% CI, 1.226-2.443; p = 0.002) have higher risk of hypertension than those with genotype GG. SNP rs2271037 was significantly associated with susceptibility to hypertension in all genetic models (dominant model: OR, 2.879; 95% CI, 2.080-3.986; p < 0.001; recessive model: OR, 7.159; 95% CI, 4.779-10.724; p < 0.001; additive model: OR, 1.535; 95% CI, 1.163-2.027; p = 0.002). SNP rs3749585 was significantly correlated with hypertension susceptibility only in dominant model (OR, 1.533; 95% CI, 1.073-2.189; p = 0.019), but not in recessive model (OR, 1.220; 95% CI, 0.906-1.644; p = 0.191) or additive model (OR, 0.915; 95% CI, 0.694-1.205; p = 0.527). After adjusting for age, gender, body mass index (BMI), smoking, low-density lipoprotein cholesterol, and serum sodium level in logistic models, the same statistical results were obtained. Interaction study showed the association between CORIN polymorphisms and hypertension could be changed by overweight (BMI >= 25 kg/m2). In silico analyses implicated hsa-miR-495 as a target miRNA that potentially interacts with the 3' UTR of CORIN. In conclusion, polymorphisms of rs2271037 and rs3749585 in CORIN were significantly associated with hypertension in a Han population of northeastern China. The mutant-type T allele of rs2271037 and C allele of rs3749585 might increase the susceptibility to hypertension in this population. PMID- 29391275 TI - Ortholog-based screening and identification of genes related to intracellular survival. AB - Bioinformatics and comparative genomics analysis methods were used to predict unknown pathogen genes based on homology with identified or functionally clustered genes. In this study, the genes of common pathogens were analyzed to screen and identify genes associated with intracellular survival through sequence similarity, phylogenetic tree analysis and the lambda-Red recombination system test method. The total 38,952 protein-coding genes of common pathogens were divided into 19,775 clusters. As demonstrated through a COG analysis, information storage and processing genes might play an important role intracellular survival. Only 19 clusters were present in facultative intracellular pathogens, and not all were present in extracellular pathogens. Construction of a phylogenetic tree selected 18 of these 19 clusters. Comparisons with the DEG database and previous research revealed that seven other clusters are considered essential gene clusters and that seven other clusters are associated with intracellular survival. Moreover, this study confirmed that clusters screened by orthologs with similar function could be replaced with an approved uvrY gene and its orthologs, and the results revealed that the usg gene is associated with intracellular survival. The study improves the current understanding of intracellular pathogens characteristics and allows further exploration of the intracellular survival related gene modules in these pathogens. PMID- 29391276 TI - Molecular influence of anterior cruciate ligament tear remnants on chondrocytes: a biologic connection between injury and osteoarthritis. AB - OBJECTIVE: Anterior cruciate ligament (ACL) injury initiates a cascade of events often leading to osteoarthritis (OA). ACL reconstruction does not alter the course of OA, suggesting that heightened OA risk is likely due to factors in addition to the joint instability. We showed that torn ACL remnants express periostin (POSTN) in the acute phase of injury. Considering that ACL injury predisposes to OA and that POSTN is associated with cartilage metabolism, we hypothesize that ACL injury affects chondrocytes via POSTN. DESIGN: Cartilage was obtained from osteoarthritic patients and ACL remnants were collected from patients undergoing ACL reconstruction. Crosstalk between ACL remnants and chondrocytes was studied in a transwell co-culture system. Expression of POSTN and other anabolic and catabolic genes was assessed via real-time polymerase chain reaction (PCR). Immunostaining for periostin was performed in human and mouse cartilage. The impact of exogenous periostin and siRNA-mediated ablation of periostin on matrix metabolism and cell migration was examined. Furthermore, the effect of anabolic (transforming growth factor beta 1 [TGF-beta1]) and catabolic (interleukin 1 beta [IL-1beta]) factors on POSTN expression was investigated. RESULTS: ACL remnants induced expression of POSTN, MMP13 and ADAMTS4. Periostin levels were significantly higher in osteoarthritic compared to normal cartilage. Exogenous periostin induced MMP13 expression and cell migration, and repressed COL1A1 expression while POSTN knockdown inhibited expression of both anabolic and catabolic genes and impeded cell migration. TGF-beta1 and IL-1beta treatment did not alter POSTN expression but influenced chondrocyte metabolism as determined by quantification of anabolic and catabolic genes via real-time PCR. CONCLUSIONS: ACL remnants can exert paracrine effects on cartilage, altering cellular homeostasis. Over time, this metabolic imbalance could contribute to OA development. PMID- 29391277 TI - Pain and functional trajectories in symptomatic knee osteoarthritis over up to 12 weeks of exercise exposure. AB - OBJECTIVE: Exercise is the recommended treatment for knee osteoarthritis (OA). However, heterogeneous patterns in treatment response are poorly understood. Our purpose was to identify pain and functional trajectories from exercise interventions in knee OA, and to determine their association with baseline factors. METHODS: Prospective cohort of 171 participants (mean age 61 years; BMI 32 kg/m2, 71% female; 57% white) with symptomatic knee OA from a randomized trial comparing 12-week Tai Chi and Physical Therapy. We analyzed weekly Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain (0-500) and function (0 1700) scores using group-based trajectory models. Associations between baseline factors and trajectories were examined using multinomial logistic regression. RESULTS: We identified four pain trajectories: Lower-Early Improvement (43%), Moderate-Early Improvement (32%), Higher-Delayed Improvement (15%), and Higher-No Improvement (10%). We found similar trajectories for function, except that the lower function trajectories diverged into gradual (12%) or delayed-improvement (15%). Compared with the Lower-Early Improvement pain trajectory, moderate and higher trajectories were associated with poorer physical and psychosocial health. A similar pattern of associations were found among the function trajectories. CONCLUSIONS: We found four distinct trajectories for pain and function over up to 12-weeks of exercise interventions. While most participants experienced improvements over a short-term exposure, subgroups with greater baseline pain/physical disability had either gradual, delayed, or no improvements. These findings help disentangle the heterogeneity of treatment response and may advance patient-centered care in knee OA. PMID- 29391278 TI - Human umbilical cord Wharton's jelly mesenchymal stem cells combined with an acellular cartilage extracellular matrix scaffold improve cartilage repair compared with microfracture in a caprine model. AB - OBJECTIVE: As a novel and promising seed cell, human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) are widely applied in tissue engineering. However, whether hWJMSCs can better repair and regenerate the articular cartilage in big animals than microfracture (MF, a predominant clinical treatment strategy for damaged cartilage) is unclear. Evaluation of the validity, and safety of hWJMSCs in a caprine model with a full-thickness femoral condyle articular cartilage defect, compared with MF is required. METHODS: After cultivation and identification, hWJMSCs were seeded in an acellular cartilage extracellular matrix (ACECM)-oriented scaffold to construct cell-scaffold complex. Six goats with full-thickness femoral condyle articular cartilage defects were randomized to MF (microfracture group, MFG) and cell-scaffold complexes (experimental group, EG). At 2 and 4 weeks, joint fluid was used to assess immuno-inflammatory responses. At 6 and 9 months, all goats were euthanized for assessment of morphology, and magnetic resonance imaging (MRI), histology staining, and evaluation of the elasticity modulus and glycosaminoglycan (GAG) contents of the repaired regions. RESULTS: There were no significant differences between the two groups in immuno-inflammatory parameters. MRI demonstrated higher-quality cartilage and complete subchondral bone at defect sites in the EG at 9 months. Histological staining showed that extracellular cartilage, cartilage lacuna and collagen type II levels were higher in the EG compared to the MFG, while the EG exhibited a higher elasticity modulus. CONCLUSIONS: The hWJMSCs-ACECM scaffold complex achieved better quality repair and regeneration of hyaline cartilage without cartilage-inducing factor, while retaining the structure and functional integrity of the subchondral bone, compared with MF. PMID- 29391280 TI - Injury- and inflammation-driven skin fibrosis: The paradigm of epidermolysis bullosa. AB - Genetic or acquired destabilization of the dermal extracellular matrix evokes injury- and inflammation-driven progressive soft tissue fibrosis. Dystrophic epidermolysis bullosa (DEB), a heritable human skin fragility disorder, is a paradigmatic disease to investigate these processes. Studies of DEB have generated abundant new information on cellular and molecular mechanisms at play in skin fibrosis which are not only limited to intractable diseases, but also applicable to some of the most common acquired conditions. Here, we discuss recent advances in understanding the biological and mechanical mechanisms driving the dermal fibrosis in DEB. Much of this progress is owed to the implementation of cell and tissue omics studies, which we pay special attention to. Based on the novel findings and increased understanding of the disease mechanisms in DEB, translational aspects and future therapeutic perspectives are emerging. PMID- 29391281 TI - Appendicitis Grade, Operative Duration, and Hospital Cost. AB - BACKGROUND: The American Association for the Surgery of Trauma (AAST) established a grading system for appendicitis to allow prediction of risk and outcomes, to assist in quality improvement and resource management, and to provide a framework for research. Grading is determined in clinical, imaging, operative, and pathologic categories, but has not been completely validated. Our aim was to validate appendicitis grade with respect to duration of symptoms, operative duration, and hospital costs. STUDY DESIGN: We performed a retrospective medical record review, working backward until at least 40 of each grade of appendicitis were reviewed. Patients 8 years old and younger and those treated nonoperatively were excluded. Appendicitis severity was determined using the AAST grading scale (I to V), with V being the most severe. Statistical comparisons were made between increased grade and duration of symptoms, operative duration, hospital costs, and revenue. Data were analyzed using ANOVA or chi-square tests as appropriate. RESULTS: A total of 1,099 appendectomies performed between August 2013 and December 2016 were analyzed. Most were low grade. Median age was 18 years old, and 44.4% were female. Patients with increasing AAST grade had a longer symptom duration (p < 0.001), longer operative duration (p < 0.001), increased direct costs (p < 0.001) in every category measured (operating room, pharmacy, imaging, lab), and contribution margin (p < 0.001). CONCLUSION: The AAST appendicitis grade is a valid predictor of disease severity as defined by operative duration, hospital cost, and revenue. Duration of symptoms predicts severity. Appendicitis grade can be used in clinical care, residency training, and resource allocation. PMID- 29391279 TI - Gut microbiota modulates alcohol withdrawal-induced anxiety in mice. AB - Excessive alcohol consumption remains a major public health problem that affects millions of people worldwide. Accumulative experimental evidence has suggested an important involvement of gut microbiota in the modulation of host's immunological and neurological functions. However, it is previously unknown whether enteric microbiota is implicated in the formation of alcohol withdrawal-induced anxiety. Using a murine model of chronic alcoholism and withdrawal, we examined the impact of alcohol consumption on the possible alterations of gut microbiota as well as alcohol withdrawal-induced anxiety and behavior changes. The 16S rRNA sequencing revealed that alcohol consumption did not alter the abundance of bacteria, but markedly changed the composition of gut microbiota. Moreover, the transplantation of enteric microbes from alcohol-fed mice to normal healthy controls remarkably shaped the composition of gut bacteria, and elicited behavioral signs of alcohol withdrawal-induced anxiety. Using quantitative real-time polymerase chain reaction, we further confirmed that the expression of genes implicated in alcohol addiction, BDNF, CRHR1 and OPRM1, was also altered by transplantation of gut microbes from alcohol-exposed donors. Collectively, our findings suggested a possibility that the alterations of gut microbiota composition might contribute to the development of alcohol withdrawal-induced anxiety, and reveal potentially new etiologies for treating alcohol addiction. PMID- 29391282 TI - Expression and purification of high sulfur and high glycine-tyrosine keratin associated proteins (KAPs) for biochemical and biophysical characterization. AB - Keratin-associated proteins (KAPs) were identified 70 years ago in wool follicles. KAPs are encoded by several multi-gene families and are classified into three different groups: ultra-high sulfur (UHS), high sulfur (HS) and high glycine-tyrosine (HGT). KAPs are the major constituent of the matrix between the hair keratin intermediate filaments (IFs), and stabilise hair structure by extensive disulfide bonding. However, detailed molecular structural information is lacking for KAPs and for KAP interactions with IFs. As a preliminary step towards their biophysical and structural characterization, we have expressed and purified a HS KAP (KAP11.1) and a HGT KAP (KAP6.1). The expression and purification of KAPs is challenging because they are cysteine-rich proteins with unusual amino acid compositions, they tend to be insoluble in isolation and are prone to forming aggregates in solution. Here we describe the high yield production of pure, soluble KAPs in a chaotrope- and detergent-free buffer. This method has the potential to be used for the overproduction of other KAPs and similar cysteine-rich proteins with high isoelectric points. PMID- 29391283 TI - Can You See the Gorilla? PMID- 29391284 TI - Unexplained Practice Variation in Primary Care Providers' Concern for Pediatric Obstructive Sleep Apnea. AB - OBJECTIVE: To examine primary care provider (PCP) screening practice for obstructive sleep apnea (OSA) and predictive factors for screening habits. A secondary objective was to describe the polysomnography completion proportion and outcome. We hypothesized that both provider and child health factors would predict PCP suspicion of OSA. METHODS: A computer decision support system that automated screening for snoring was implemented in 5 urban primary care clinics in Indianapolis, Indiana. We studied 1086 snoring children aged 1 to 11 years seen by 26 PCPs. We used logistic regression to examine the association between PCP suspicion of OSA and child demographics, child health characteristics, provider characteristics, and clinic site. RESULTS: PCPs suspected OSA in 20% of snoring children. Factors predicting PCP concern for OSA included clinic site (P < .01; odds ratio [OR] = 0.13), Spanish language (P < .01; OR = 0.53), provider training (P = .01; OR = 10.19), number of training years (P = .01; OR = 4.26) and child age (P < .01), with the youngest children least likely to elicit PCP concern for OSA (OR = 0.20). No patient health factors (eg, obesity) were significantly predictive. Proportions of OSA suspicion were variable between clinic sites (range, 6-28%) and between specific providers (range, 0-63%). Of children referred for polysomnography (n = 100), 61% completed the study. Of these, 67% had OSA. CONCLUSIONS: Results suggest unexplained small area practice variation in PCP concern for OSA among snoring children. It is likely that many children at risk for OSA remain unidentified. An important next step is to evaluate interventions to support PCPs in evidence-based OSA identification. PMID- 29391285 TI - Quality Improvement to Immunization Coverage in Primary Care Measured in Medical Record and Population-Based Registry Data. AB - OBJECTIVES: Despite the proven benefits of immunizations, coverage remains low in many states, including Vermont. This study measured the impact of a quality improvement (QI) project on immunization coverage in childhood, school-age, and adolescent groups. METHODS: In 2013, a total of 20 primary care practices completed a 7-month QI project aimed to increase immunization coverage among early childhood (29-33 months), school-age (6 years), and adolescent (13 years) age groups. For this study, we examined random cross-sectional medical record reviews from 12 of the 20 practices within each age group in 2012, 2013, and 2014 to measure improvement in immunization coverage over time using chi-squared tests. We repeated these analyses on population-level data from Vermont's immunization registry for the 12 practices in each age group each year. We used difference-in-differences regressions in the immunization registry data to compare improvements over time between the 12 practices and those not participating in QI. RESULTS: Immunization coverage increased over 3 years for all ages and all immunization series (P <= .009) except one, as measured by medical record review. Registry results aligned partially with medical record review with increases in early childhood and adolescent series over time (P <= .012). Notably, the adolescent immunization series completion, including human papillomavirus, increased more than in the comparison practices (P = .037). CONCLUSIONS: Medical record review indicated that QI efforts led to increases in immunization coverage in pediatric primary care. Results were partially validated in the immunization registry particularly among early childhood and adolescent groups, with a population-level impact of the intervention among adolescents. PMID- 29391286 TI - Health-Related Quality of Life with Subcutaneous C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema. AB - BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1 INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks. METHODS: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1 INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1 INH(SC) treatment compared with placebo. CONCLUSIONS: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on demand treatment alone (placebo prophylaxis). PMID- 29391287 TI - The Role of Systemic Therapy in the Management of Stage I Large Cell Neuroendocrine Carcinoma of the Lung. AB - INTRODUCTION: The optimal treatment strategy for resected stage I large cell neuroendocrine carcinoma of the lung (LCNEC) remains unknown. In this analysis, we evaluate the impact of systemic chemotherapy on patients with stage I LCNEC who have undergone surgical resection. METHODS: The study population included patients who underwent surgical resection for LCNEC and had pathologic stage I disease. We compared overall survival between patients who underwent surgical resection alone and those who underwent surgical resection plus chemotherapy. Overall survival was estimated by the Kaplan-Meier method, and comparisons were analyzed by using multivariable Cox models and propensity score-matched analyses. RESULTS: From 2004 to 2013, 1232 patients underwent surgical resection for stage I LCNEC in the National Cancer Database, including 957 patients (77.7%) who underwent surgical resection alone and 275 (22.3%) who received both surgery and systemic chemotherapy. Five-year survival was significantly improved in patients who received chemotherapy (64.5% versus 48.4% [hazard ratio =0.54, 95% confidence interval: 0.43-0.68, p < 0.001]). Multivariable Cox modeling confirmed the survival benefit from chemotherapy for patients with resected stage I LCNEC (hazard ratio = 0.54, 95% confidence interval: 0.43-0.68, p <0.0001). The survival benefit was further confirmed by propensity-matched analysis. In addition, older (age >70 years), comorbid white patients who underwent sublobar resections for tumors larger than 20 mm had worse survival outcomes. CONCLUSION: In this largest-reported retrospective study of patients with resected stage I LCNEC, survival was improved in patients who received chemotherapy in both stage IA and stage IB LCNEC. PMID- 29391288 TI - Differences in Longitudinal Health Utility between Stereotactic Body Radiation Therapy and Surgery in Stage I Non-Small Cell Lung Cancer. AB - INTRODUCTION: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. METHODS: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire-Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five Dimension questionnaire) was calculated from the Quality of Life Questionnaire Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach. RESULTS: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028-0.080). Differences in health utility decreased over time. CONCLUSIONS: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined. PMID- 29391289 TI - Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review. AB - In cryoimmunotherapy, target tumors are treated with cryoablation to generate antitumor immune responses. Because immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy-responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review preclinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation-induced antitumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation. PMID- 29391290 TI - Ureteral obstruction and ruptured kidney following ovarian hyperstimulation syndrome. AB - In vitro fertilization (IVF) is nowadays a reliable and common method for couple who need medically assisted procreation. Complications are rare. We report in this paper, the case of a woman with severe endometriosis who developed ureteral obstruction complicated by a renal rupture of the fornix due to ovarian hyperstimulation during an IVF attempt. The condition was diagnosed by CT scan and resolved with insertion of double-J catheter in the left ureter. PMID- 29391291 TI - Can hospital discharge data be used for monitoring indicators associated with postpartum hemorrhages? The HERA multicenter observational study. AB - OBJECTIVES: The principal objective of this study was to assess the reliability of measuring the incidence of postpartum hemorrhages (PPH) from the national hospital discharge summary database (PMSI). The secondary objectives were to assess this reliability according to the maternity unit level and status and to assess the measurement of second-line procedures for PPH. MATERIALS AND METHODS: This study compared PPH incidence rates from February through July 2011 in 131 maternity units, as measured in the PMSI and the prospective HERA study cohort, considered as the reference standard. RESULTS: Compared with the cohort, PPH incidence was over-reported in the PMSI among vaginal deliveries (4.0% vs. 3.5; P<0.0001), but not cesareans (3.2 vs. 2.9%; P=0.1). For the second-line curative procedures, PMSI data underestimated the incidence of vessel embolization and transfusion (P<0.0001) among vaginal deliveries and of hypogastric ligation (P=0.002), other vessel ligation (P=0.005), and transfusion (P<0.0001) among cesareans. CONCLUSION: Despite some coding inaccuracy in the PMSI, routinely collected data can provide acceptable estimates for maternity units and perinatal networks to use to improve quality of care through the monitoring of quality indicators. Improvements are nonetheless needed for international comparisons and other epidemiologic purposes. PMID- 29391292 TI - Effect of the use of a video tutorial in addition to simulation in learning the maneuvers for shoulder dystocia. AB - The development of video tutorials is flourishing and may make it possible to maintain knowledge learned during instruction with simulation. The aim of this study was to assess the effect of adding a video tutorial to a lecture and simulation for learning the maneuvers and protocol for the management of shoulder dystocia. Student midwives and medical students attended a lecture class including instruction about maneuvers and a presentation of an algorithm for the management of shoulder dystocia. They were randomized into two groups. The video group was reminded every two weeks to watch a short tutorial. The control group was reminded to consult the slide show. At the end of two months, they were evaluated by graders. The practice, theory, and global scores of the students in the video group were significantly higher than those of the students in the control group (14.8 vs. 10.4; 5.6 vs. 3.4; and 9.3 vs. 7.0, P<0.001). The scores for the video group improved at the second simulation session, compared with the first (14.8 vs. 9.9; 5.6 vs. 2.9; and 9.3 vs. 7, P<0.001). The addition of a video tutorial improved learning compared to a standard lecture and simulation session alone. PMID- 29391293 TI - A case of non-treated Trichomonas vaginalis infection and severe preterm labor with positive obstetrical outcome. AB - Trichomonas vaginalis is a very common, sexually transmitted, infection that may sometimes be asymptomatic or cause vaginitis and urethritis. Recently, it has been associated with adverse obstetric outcomes such as preterm delivery, low birth weight and premature rupture of membranes. Trichomonas vaginalis can be vertically transmitted at birth. It has been found in pharynx and low respiratory tract of neonates with respiratory disease. It has also been involved in some cases of intellectual disability. The recommended treatment is a 2g metronidazole oral single dose, even for asymptomatic patients. This treatment is effective against Trichomonas and its use is safe during pregnancy. We report here a case of Trichomonas vaginalis infection diagnosed during pregnancy in a patient with severe preterm labor. The patient being allergic to nitroimidazole antibiotics, she did not receive any treatment. She finally gave birth at 34 weeks of gestation (WG) and 5 days, with no other adverse outcome than small prematurity. PMID- 29391294 TI - Which neovagina reconstruction procedure for women with Mayer-Rokitansky-Kuster Hauser syndrome in the uterus transplantation era? Editorial from the French Uterus Transplantation Committee (CETUF) of CNGOF. PMID- 29391295 TI - Is Eighty the New Sixty? Outcomes and Complications after Lumbar Decompression Surgery in Elderly Patients over 80 Years of Age. AB - OBJECTIVE: An increasing demographic aging of the general population results in a rising incidence of octogenarians and nonagenarians with spine disease. Patients older than 65 years represent the majority of patients with degenerative lumbar spine disease in our daily clinical routine. Surgical treatment is undertaken reluctantly because of an increased rate of comorbidities. We therefore assessed complication rates of lumbar decompression in regard to neurological outcome and medical conditions in patients age 80 years or older in a retrospective single center series. METHODS: Data for 244 patients (124 female, 120 male; mean age, 83.1 +/- 3 years; age range, 80-95 years) who underwent decompressive surgery for lumbar spinal stenosis or disc herniation between April 2007 and February 2016 were assessed retrospectively. Age at surgery, neurologic deficits (preoperative and postoperative), relevant medical comorbidities and previous lumbar decompression, intraoperative and postoperative complications (e.g., surgery related, medical), duration of surgery, length of hospital stay, and rate of revision surgeries were recorded. RESULTS: Surgery was performed for lumbar stenosis (184 patients; 75.4%), lumbar disc herniation (13 patients; 5.3%) or both (47 patients; 19.3%). Seventy-six patients (31.3%) patients experienced preoperative neurologic deficits; 48 (63.2%) of these patients improved, 28 (36.8%) of them were unchanged after surgery, and none deteriorated. New transient, postoperative, neurologic deficits occurred in 6 patients (2.5%). All 55 (22.5%) intraoperative complications were mild to moderate, and no severe surgical complications occurred. Two hundred fifteen patients (88%) had relevant medical disorders. Nineteen (7.7%) postoperative medical complications were reported in 17 patients (7%), of which 14 (73.7%) were severe and 5 (26.3%) were mild (4 pulmonary embolisms, 6 pneumonias, 3 myocardial infarctions, 1 postoperative renal failure, 5 urinary tract infections). Medical complications that necessitated intensive care unit treatment and resulted in lethal outcome were seen in 2 patients (0.8%). CONCLUSION: Despite their age, the vast majority of octogenarians and nonagenarians benefited from lumbar decompression surgery. Mild to moderate intraoperative complications were relatively frequent, whereas severe intraoperative complications did not occur. The majority of medical complications was severe, but the incidence was acceptable, and the postoperative outcome was still favorable in most patients. PMID- 29391296 TI - Using the Reversed Temporal Island Flap to Cover Small Forehead Defects from Titanium Mesh Exposure After Cranial Reconstruction. AB - BACKGROUND: Skin ulcers and alloplastic implant exposure are intractable complications that arise after cranial defect reconstruction. Many methods have been used to repair these defects, including skin grafting, local flaps, and free flaps; however, in most cases, alloplastic implants must be removed to control infections. Here, we describe the use of a reversed temporal island flap to repair exposed titanium mesh without removing it. METHODS: Eight cases of skin and titanium mesh exposure were included from 2010 to 2015. A preauricular flap pedicled on the reversed superficial temporal artery was designed to repair forehead defects. The titanium mesh was retained, resterilized, and reimplanted. RESULTS: Flaps were survived completely, and the titanium meshes were reimplanted with no complications. The results were aesthetically and functionally sufficient, with minimal donor-site morbidity in all cases during the 10- to 24 month follow-up period. CONCLUSIONS: The described method is easy to design and perform. The flap has a reliable blood supply to help fight infection. The titanium mesh is preserved completely, avoiding a second cranioplasty. PMID- 29391297 TI - Minimally Invasive Lateral Endoscopic Multiport Approach to the Infratemporal Fossa: A Cadaveric Study. AB - BACKGROUND: Expanded endoscopic endonasal approaches to the infratemporal fossa (ITF) are increasingly performed owing to improved visualization and less morbidity compared with classic open approaches. Only a few studies in the literature investigated lateral endoscopic access to the ITF. The aim of this study was to examine the ITF with the minimally invasive endoscopically assisted Gillies approach with a trial of its expansion through a double port technique. METHODS: The ITF was examined in 10 sides of 5 cadaveric heads using a lateral endoscopic assisted approach. A double portal technique was developed to allow bimanual dissection. Specific long angled skull base instruments were used for dissection under stereotactic guidance. RESULTS: The endoscopic assisted Gillies approach permitted minimally invasive access to the complete anteroposterior extension of the ITF with sufficient mobility of surgical instruments. A new anatomic classification for the ITF from a lateral endoscopic perspective was introduced. The addition of the second port allowed bimanual dissection. CONCLUSIONS: This cadaveric study shows the feasibility of an endoscopically assisted lateral approach to the ITF. The addition of a posterior port expands the approach through increasing the working area and enabling a bimanual dissection technique. Performed alone or combined with an anterior endoscopic transnasal approach, this technique offers minimally invasive access to the ITF. The development of specifically designed instruments would further improve this promising approach. PMID- 29391298 TI - Pseudoaneurysm of Posterior Ascending Branch of Vertebral Artery: Previously Unreported Case. AB - BACKGROUND: Pseudoaneurysms are less common than true aneurysms. Herein, we present a rare case of a mass of the right posterior ascending artery. CASE DESCRIPTION: This was identified during routine dissection of an adult female cadaver. Histology demonstrated that the mass was a pseudoaneurysm. The mass was located posterior to the right alar ligament superior to the right portion of the transverse ligament and measured 7.37 mm and 2.97 mm. CONCLUSIONS: To our knowledge, such a case has not previously been reported. Epidural masses anterior to the cervical dura mater at the craniocervical junction should consider such a pathology in the differential diagnosis. PMID- 29391299 TI - Prohibited Arc Angles During Leksell Frame-Based Stereotaxy. AB - BACKGROUND: During Leksell frame-based stereotaxy the lateral trajectory can be obstructed by the arc supports at certain combinations of the X-coordinate and arc angle. OBJECTIVE: To provide a matrix with usable and prohibited combinations of the X-coordinate and arc angle to faciliate finding lateral stereotactic trajectories with the Leksell frame in standard configuration. METHODS: Various combination settings of the X-coordinate and arc angle were tested for a Leksell Multi-Purpose Stereotactic Arc mounted on a Leksell Coordinate Frame G. RESULTS: A matrix of usable and prohibited combinations of the X-coordinate and arc angle is provided. CONCLUSIONS: The matrix will help to facilitate surgical work flow during stereotactic procedures involving the Leksell frame. PMID- 29391301 TI - COVERING THE COVER. PMID- 29391300 TI - Incidence and Risk Factors for Facet Joint Violation in Open Versus Minimally Invasive Procedures During Pedicle Screw Placement in Patients with Trauma. AB - OBJECTIVE: A possible risk factor for premature facet joint degeneration or adjacent segment degeneration after surgical treatment of spine fractures is facet joint violation (FV) during insertion of pedicle screws. The aim of this study was to determine risk factors for FV in the thoracic and lumbar spine after minimally invasive screw insertion or open instrumentation (OI). METHODS: A retrospective analysis of all patients with spine fractures requiring posterior stabilization was performed. After patients were allocated to the thoracic/lumbar group, FV was defined as an involvement caused by the positioning of a pedicle screw and its severity as determined by computed tomography was assessed by using a customized scoring system. Gender, age, and body mass index as well as segmental facet joint angle and the instrumentation system used (side-loading [SL] vs. top-loading) were considered as individual factors. RESULTS: In total, 1099 pedicle screws were evaluated and an FV was identified in 433 instrumentations (39.0%). OI was used in 61.1% (n = 671) and an SL system was inserted in 45.0% (n = 494). In both, the thoracic (odds ratio [OR], 1.663; 95% confidence interval [CI], 1.119-2.472; P = 0.012) and the lumbar spine (OR, 0.494; 95% CI, 0.317-0.771; P = 0.002), OI was associated with a lower risk of FV. The violation rate was significantly higher when using a SL system (thoracic spine: OR, 1.822; 95% CI, 1.163-2.854; P = 0.009; lumbar spine: OR, 0.311; 95% CI, 0.203-0.477; P <= 0.001). CONCLUSIONS: FV is a common complication after thoracic and lumbar spine surgery. Although both, the SL instrumentation and a minimally invasive procedure increases its occurrence, the patient characteristics do not affect the rate of FV. PMID- 29391302 TI - Improving the quality of colonoscopy: Impact of efficient and safer preparation protocols and shorter waiting times. PMID- 29391303 TI - Liver fibrosis. AB - Liver fibrosis is a wound-healing response generated against an insult to the liver that causes liver injury. It has the potential to progress into cirrhosis, and if not prevented, it may lead to liver cancer and liver failure. The activation of hepatic stellate cells (HSCs) is the central event underlying liver fibrosis. In addition to HSCs, numerous studies have supported the potential contribution of bone marrow-derived cells and myofibroblasts to liver fibrosis. The liver is a heterogeneous organ; thus, molecular and cellular events that underlie liver fibrogenesis are complex. This review aims to focus on major events that occur during liver fibrogenesis. In addition, important antifibrotic therapeutic approaches and experimental liver fibrosis models will be discussed. PMID- 29391304 TI - High-dose vs. Low-dose Proton Pump Inhibitors post-endoscopic hemostasis in patients with bleeding peptic ulcer. A meta-analysis and meta-regression analysis. AB - BACKGROUND/AIMS: Present meta-analysis aims to evaluate studies of low- versus high-dose proton pump Inhibitors (PPI) post-endoscopic hemostasis, including the newly published randomized controlled trials (RCTs) and to conclude whether low dose PPI can generate the comparable results as high-dose PPI. MATERIALS AND METHODS: To identify suitable trials, the electronic databases PubMed, Medline, Cochrane Library, and the Embase were used. All RCTs concerning low- versus high dose PPI administration post-endoscopic hemostasis published until December 2016 were identified. Primary outcomes were rebleeding rates, need for surgical intervention, and mortality. RESULTS: Studies included a total of 1.651 participants. There were significantly less cases of rebleeding in the low-dose PPI treatment arm (p=0.003). All but one study provided data concerning need for Surgical Intervention and Mortality. The respective effect sizes were [odds ratio (OR), 95% confidence intervals (CI): 1.35, 0.72-2.53] and [OR, 95% CI: 1.20, 0.70 2.05]. Both treatment arms were comparable considering the aforementioned outcomes (p=0.35 and p=0.51, respectively). Meta-regression analysis likewise unveiled comparable outcomes between studies using pantoprazole versus lansoprazole concerning all three outcomes [rebleeding (p=0.944), surgical intervention (p=0.884), and mortality (p=0.961)]. CONCLUSION: A low-dose PPI treatment is equally effective as a high-dose PPI treatment following endoscopic arresting of bleeding. However, we anticipate the completion of more high-quality RCTs that will embrace distinct ethnicities, standardized endoscopic diagnosis and management, double-blind strategies, and appraisal of results working specific standards over clear-cut follow-up periods. PMID- 29391305 TI - Utility of a laboratory score in the prediction of altered autonomic nervous system function in autoimmune gastritis. AB - BACKGROUND/AIMS: Autoimmune gastritis patients may have autonomic nerve dysfunction. The goal of our study was to explore the predictive value of two scoring systems in the differentiation of altered autonomic nerve function in autoimmune gastritis patients. MATERIALS AND METHODS: Seventy-five patients with autoimmune gastritis were evaluated by using cardiovascular reflex tests in order to delineate autonomic nerve function. Data were analyzed by using two laboratory based scoring systems: "global score" (hemoglobin, mean corpuscular volume, gastrin, vitamin B12, and chromogranin A) and "simple score" (hemoglobin, mean corpuscular volume, gastrin) in order to discriminate deranged and normal autonomic nerve function. RESULTS: Mean "simple" and "global" scores were significantly higher in subjects with altered autonomic dysfunction than in subjects with normal autonomic function (3.55+/-1.88 vs. 0.908+/-0.409, p<0.001 and 5.95+/-2.07 vs 2.46+/-1.28, p<0.001, respectively). Receiver operator characteristic (ROC) analysis revealed that the optimum "simple score" cutoff point was 0.75 with a sensitivity of 86.7% and specificity of 92.3% for discriminating autoimmune gastritis patients with autonomic nerve dysfunction from patients with normal autonomic nerve function [area under the curve (AUC): 88.3, positive predictive value (PPV): 97.5% and negative predictive value (NPV): 66.6%; 95% confidence interval (CI), 88.4-99.7]. CONCLUSION: Simple score and global score have a high predictive value in the assessment of autoimmune gastritis patients with autonomic nerve dysfunction. These scoring systems may help physicians while evaluating autoimmune gastritis patients for the existence of autonomic nerve dysfunction instead of complex cardiovascular reflex tests. PMID- 29391306 TI - Incidence patterns of colorectal cancers in four countries of the Middle East Cancer Consortium (Cyprus, Jordan, Israel, and Izmir, Turkey) compared with those in the United States Surveillance, Epidemiology, and End Results Program. AB - BACKGROUND/AIMS: There are wide variations in colorectal cancer (CRC) incidence across the world. Historically, the highest incidence rates have been reported historically in more developed countries; however, increasing trends have been seen in developing countries. Here, we present the CRC incidence pattern in Cyprus, Israel, Jordan, and Izmir, Turkey, which are countries of the Middle East Cancer Consortium (MECC). MATERIALS AND METHODS: We analyzed 2005-2010 CRC data from population-based registries and calculated crude and age standardized rates for CRC, colon and rectum subsites, and annual percent changes (APCs) for trends. RESULTS: The age-adjusted incidence rates (AAIRs) for CRC were the highest in Israeli Jews (IJ) (46.7 for males and 35.5 for females), which exceeded those of the USA Surveillance, Epidemiology, and End Result (SEER) program registries. In both sexes, AAIRs in Cyprus and Israeli Arabs (IA) were close to those in SEER registries. For both sexes, AAIRs in Izmir and Jordan were substantially lower than those in other registries. Statistically significant decreasing trends over time were observed in AAIRs for both sexes in the SEER program (APCs: males, 3.24% and females, -2.54%), whereas the trends varied within the MECC registries. There were decreasing AAIR trends for males in IJ and IA and for females in Cyprus and IJ; APC for females in IJ (-4.29%) was significant. Conversely, increasing trends with the significant APCs were observed in males in Izmir (2.43%) and Jordan (7.57%). CONCLUSION: MECC countries comprise both high- and low-risk populations for CRCs. However, increasing trends in low-risk populations have been alarming. Thus, the need for implementing tailored primary and secondary prevention programs in the region is essential. PMID- 29391307 TI - Expression of Th17/Treg related molecules in gastric cancer tissues. AB - BACKGROUND/AIMS: The function of regulatory T cells (Treg) and helper T cells 17 (Th17) related indexes, such as interleukin (IL)-6, IL-17, transforming growth factor (TGF)-beta1, and forkhead box protein 3(FoxP3) in gastric adenocarcinoma tissues remains undefined. We investigated and analyzed the relevance of the proteins with the clinicopathological characteristics and the interactions among them in gastric cancer. MATERIALS AND METHODS: A total 68 gastric cancer patients and 40 healthy controls were enrolled. Immunohistochemistry (IHC) as well as quantitative real-time reverse transcription- polymerase chain reaction (RT-PCR) was used to determine the expression levels of IL-6, TGF-beta1, IL-17, and FoxP3 in the prepared tissues. Statistical analysis included ANOVA and chi-square test. RESULTS: The expression levels of IL-6, IL-17, FoxP3, and TGF-beta1 had significantly increased in cancer tissues compared to controls. Clinical staging of gastric cancer were correlated with the rise of IL-6, IL-17, FoxP3, and TGF beta1 levels expressed in cancer tissues. The expression level of TGF-beta1 and IL-6 was positively related to that of IL-17 and FoxP3, similar to FoxP3 and IL 17 in gastric cancer tissues. CONCLUSION: IL-6, TGF-beta1, FoxP3, and IL-17 may promote the progression of gastric cancer individually or jointly and have complex interactions. PMID- 29391308 TI - The relationship of alanine aminotransferase to metabolic syndrome in a Korean population. AB - BACKGROUND/AIMS: Although associations between serum alanine aminotransferase and metabolic syndrome are well-recognized in Western countries, only a limited number of prospective studies have been performed in Asian populations. The aim of the study was to cross-sectionally and longitudinally examine whether serum alanine aminotransferase levels are associated with metabolic syndrome and its associated components in a Korean population. MATERIALS AND METHODS: A total of 31,832 subjects who received health screenings were included in cross-sectional analyses; a subgroup of 4.070 subjects without metabolic syndrome at baseline was included in the longitudinal analyses. The metabolic syndrome definition was based on the National Cholesterol Education Program Third Adult Treatment Panel criteria with modification on waist circumference cut-off to be more appropriate for an Asian population. RESULTS: In the cross-sectional analyses, serum alanine aminotransferase is positively associated with metabolic syndrome and its components. In the longitudinal analyses, the prevalence of metabolic syndrome increased across serum alanine aminotransferase quartiles in a dose-dependent manner after extensive adjustments (hazard ratios were 1.000, 1.609, 2.601, and 3.015 for quartiles, 1 through quartile 4; P for trend<0.001). CONCLUSION: Our study confirmed a positive association between components of metabolic syndrome and elevated serum alanine aminotransferase in a Korean population. PMID- 29391309 TI - Role of nucleoside/nucleotide analogues and low-dose hepatitis B immune globulin in prophylaxis of hepatitis B recurrence among cadaveric liver transplant recipients. AB - BACKGROUND/AIMS: Hepatitis B core antibody (HBcAb) positivity of the donor or the recipient may pose a risk of hepatitis B virus (HBV) reactivation following liver transplantation (LT). We retrospectively investigated patient survival and reactivation among recipients who were given low-dose Hepatitis B Immune Globulin (HBIG) plus antiviral agent (AV) versus AV only. MATERIALS AND METHODS: Records of cadaveric LT recipients, between 2013 and 2016, with positive Hepatitis B surface Antigen (HBsAg) and/or HBcAb and recipients who had received LT from HBcAb-positive donors were reviewed. Patient characteristics and clinical data were extracted. Donor variables were retrieved from the United Network of Organ Sharing (UNOS) database. HBIG (1560 IU/mL) Intravenous (IV) was intraoperatively administered with three daily doses. Entecavir 1 mg daily was also given. STATA was used for statistical analysis. RESULTS: There were 53 recipients; 39 (73.6%) were male with a median age of 59 y. HCV was the major indication in 30 (55.6%) patients. There were 28 recipients (52.8%) who received HBIG plus AV and 25 (47.2%) received AV only. The Model of End Stage Liver Disease (MELD) score between the groups were similar. Survival rates at 6, 12, and 24 months were 100% (n=53), 93.2% (n=44), and 100.0% (n=26), respectively. There was no reactivation; two recipients in the AV group and one in the HBIG plus AV group died within 12 months. CONCLUSION: This study supports the use of low-dose HBIG and AV for post LT prophylaxis to be as effective as conventionally used high-dose HBIG (9600 IU) plus AV. Future prospective larger studies are warranted to examine the potential benefits of using AV alone without HBIG. PMID- 29391310 TI - Polyethylene Glycol-3350 (Miralax(r))+1.9-L sports drink (Gatorade(r))+2 tablets of bisacodyl results in inferior bowel preparation for colonoscopy compared with Polyethylene Glycol-Ascorbic Acid (MoviPrep(r)). AB - BACKGROUND/AIMS: Polyethylene glycol (PEG)-3350, approved by Food and Drug Administration (FDA) only for constipation, combined with 1.9 L of sports drink (SD) (GatoradeR) and bisacodyl (B) is commonly used in outpatient practice for bowel preparation due to cited patient satisfaction and tolerability of this specific regimen. We aim to compare PEG-3350 (MiralaxR) with PEG-AA-based (MoviPrepR) in terms of efficacy, patient satisfaction, and the effects of these two regimen on serum electrolytes. MATERIALS AND METHODS: This study is a prospective, single-blinded, block randomized trial comparing single-dose PEG 3350+SD+B to split-dose 2-L PEG-AA in the outpatient endoscopy unit in patients undergoing colonoscopy. Basic metabolic profiles were checked on the day of randomization and on the day of procedure. Patients completed a survey on the day of procedure. Bowel preparation quality was assessed using the Boston Bowel Preparation Scale (BBPS) by two endoscopists and a nurse present during the procedure. RESULTS: We randomized 150 patients (74 PEG-3350+SD+B and 76 PEG-AA). The PEG-AA group had significantly higher BBPS scores in the right colon by Endoscopist 1, Nurse, and Endoscopist 2 (p 0.005, <0.000, 0.001) and in the left and transverse colon by Nurse and Endoscopist 2 (p 0.004, 0.26, 0.000, 0.006). There was no statistically significant difference in patient satisfaction or change in serum electrolytes between the two groups. CONCLUSION: Use of single dose PEG-3350+SD+B results in inferior bowel preparation for colonoscopy compared with split-dose PEGAA and does not provide any advantage in regards to patient satisfaction. We therefore recommend discontinuing the use of PEG 3350 for bowel preparation. PMID- 29391311 TI - Shorter waiting times from education to colonoscopy can improve the quality of bowel preparation: A randomized controlled trial. AB - BACKGROUND/AIMS: Adequate bowel preparation is essential for an effective and safe colonoscopy. This study aimed to evaluate the quality of bowel preparation according to waiting times from education to colonoscopy. MATERIALS AND METHODS: A prospective, investigator-blinded, randomized study was performed from December 2016 to March 2017. Patients were divided into two groups: within 2 weeks (group A, n=64) or more than 2 weeks (group B, n=66) from education about bowel preparation to colonoscopy. The primary outcome was the quality of bowel preparation as assessed by the Boston Bowel Preparation Scale (BBPS). The secondary outcome was the polyp and adenoma detection rate. RESULTS: A total of 130 patients were enrolled. The total BBPS score was significantly higher in group A (within 2 weeks from education to colonoscopy) than in group B (more than 2 weeks). Total BBPS scores were 8.25?}0.97 in group A and 7.75?}1.32 in group B (P=.017). The rate of good preparation (BBPS>=8) was higher in group A than in group B (78.1% vs. 59.1%, P=.020). The rates of polyp and adenoma detection were both slightly higher in group A (polyps, 42.2% vs. 38.5%, P=.667; adenoma, 31.2% vs. 22.7%, P=.275). A numerical trend was observed for the slightly superior polyp and adenoma detection rate in group A, but it was not statistically significant. CONCLUSION: This study demonstrated that shorter waiting times from education to colonoscopy can improve the quality of bowel preparation. Ensuring sufficient staff and equipment for endoscopy is one approach to reducing waiting times to colonoscopy. If waiting times can not be reduced, more contact through telephone, e-mail, and text messaging could be used to remind patients about information regarding bowel preparation. PMID- 29391312 TI - A simplified technique of esophageal self-expandable metallic stent placement without fluoroscopic and endoscopic guidance for treating esophageal carcinoma. AB - BACKGROUND/AIMS: Self-expandable metallic stent (SEMS) placement with fluoroscopic guidance is a commonly used technique to relieve obstruction in patients with esophageal carcinoma. However, it has disadvantages such as radiation exposure. SEMS placement with endoscopic guidance also has the disadvantages of causing discomfort to patients as the endoscope and SEMS assembly are simultaneously used and it needs two experts for the procedure to be performed. To overcome these disadvantages, a simplified technique for SEMS placement was developed that does not require fluoroscopic or endoscopic guidance. Our objective was to compare the efficacy and safety of this simplified technique with the conventional SEMS placement method. MATERIALS AND METHODS: This is a retrospective study including patients with esophageal carcinoma who underwent SEMS placement for the palliation of dysphagia. RESULTS: Sixty-two patients were placed on stents for the palliation for esophageal carcinoma, with 46 patients in the conventional technique group (group A) and 16 in the simplified technique group (group B). The duration of the procedure was considerably lesser in group B than in group A (2 min 53 s vs. 15 min 4 s, p=0.001). The technical success rate achieved in groups A and B were 97.82% and 100%, respectively. SEMS placement required two experts in the conventional technique whereas the simplified technique required only one expert. CONCLUSION: The advantages of the simplified technique are as follows: technical ease, cost effectiveness, no exposure to radiation, requirement of minimal manpower, and less time-consuming; these advantages make it the technique day-care procedure. PMID- 29391313 TI - Post-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey. AB - BACKGROUND/AIMS: A liver transplant is the preferred treatment for patients with end-stage liver disease, as it usually results in longterm survival. However, due to the use of chronic immunosuppressive therapy, which is necessary to prevent rejection, de novo cancer is a major risk after transplantation. The aim of this study was to assess the incidence of post-transplant malignancies in children after liver transplantations. MATERIALS AND METHODS: The study group consisted of 206 liver transplant recipients, with no history of cancer, including hepatocellular carcinoma, in two liver transplantation centers in Turkey between 1997 and 2015. Data were obtained from patient's data chart. RESULTS: In the study group, de novo cancer was diagnosed in 13 of the 206 patients. Post transplant lymphoproliferative disease (PTLD) occurred in seven (53.8%) patients and other malignancies in six of the 13 patients. The types of PTLD were as follows: B-cell origin (n=2), Epstein-Barr virus (EBV)-related (n=2), T-cell origin (n=1), and Hodgkin's lymphoma (n=2). EBV DNA was isolated from seven patients, three of whom developed PTLD. The others developed Kaposi's sarcomas, Burkitt's lymphomas, cutaneous large-cell lymphomas, Hodgkin's lymphomas, and liver sarcomas. CONCLUSION: After transplantation, immunosuppressive treatment is unavoidable, increasing the risk of malignancies. However, a close follow-up and periodic screening can reduce cancer-related mortality and morbidity. PMID- 29391314 TI - A case of multiple myeloma initially presenting as hematemesis. AB - A few cases of multiple myeloma with gastrointestinal bleeding have been reported, but hematemesis is rarely encountered as an initial symptom of multiple myeloma. Here we report a case of multiple myeloma with an initial symptom of hematemesis. Gastroscopy revealed ulceration in the angulus of the stomach. Colonoscopy revealed many ulcers in the ascending colon. A definite diagnosis of gastrointestinal amyloidosis was made using tissue biopsy. A definite diagnosis of multiple myeloma was made using bone marrow puncture. Hematemesis may be an initial symptom of multiple myeloma. A diagnosis of amyloidosis-induced hematemesis should be considered in patients with multiple myeloma. PMID- 29391316 TI - Patulous upper esophageal sphincter - an unusual endoscopic finding. AB - The upper esophageal sphincter (UES) has various important functions, such as protection of the airway from aspiration and conduct of bolus into esophagus, which are controlled by complex neuronal mechanisms. The functions will be affected when there is malfunction of the UES due to various etiologies. Here we present an 80-year-old male with non-progressive dysphagia and patulous UES incidentally found on esophagoduodenoscopy. There are no documented cases of idiopathic patulous UES in literature. Endoscopists must be aware of this rare condition while evaluating a patient presenting with oropharyngeal dysphagia. PMID- 29391315 TI - A rare cause of multiple small bowel ulcers and strictures in a 10-year-old child. AB - Enteritis and small bowel ulcers can be caused by inflammatory bowel disease, drug-induced enteritis, cytomegalovirus, tuberculosis, or intestinal lymphoma. Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is an uncommon idiopathic cause of ulceration and stricture of the small bowel. CMUSE can occur in adults, but only few pediatric cases have been reported. Inflammatory bowel disease and other causes should be carefully sought first before the diagnosis of CMUSE can be made. Previous reports demonstrated that surgical intervention may be necessary for both diagnostic and therapeutic purposes. With regard to the management, systemic corticosteroids may help, and surgery plays a role in patients present with signs of intestinal obstruction. We report a young girl who presented with a prolonged history of refractory iron deficiency anemia with protein-losing enteropathy without other obvious gastrointestinal symptoms. She underwent several laboratory and endoscopic investigations as well as histopathology of the resected full-thickness small bowel area before a proposed diagnosis of CMUSE was made. A trial of immunosuppression (both prednisolone and azathioprine) was initiated that provided a relatively satisfactory result. PMID- 29391317 TI - Multiple liver masses mimicking metastatic liver disease in an elderly patient. PMID- 29391318 TI - A tough scope to swallow: endoscopic retrograde cholangiopancreatography through percutaneous endoscopic gastrostomy. PMID- 29391319 TI - Rectal pyogenic granulomas: an uncommon cause of gastrointestinal bleeding. PMID- 29391320 TI - Inflammatory pseudotumor-like follicular dendritic cell tumor of the spleen. PMID- 29391321 TI - Surgical treatment of pneumatosis cystoides intestinalis with pneumoperitoneum secondary. PMID- 29391322 TI - Laparoscopic splenectomy and subsequent oncologic gastric surgery in cirrhotic patients with portal hypertension and hypersplenism. PMID- 29391323 TI - An unusual case of duodenal metastasis of pulmonary pleomorphic carcinoma. PMID- 29391324 TI - Unusual self-healing of a traumatic pancreatic fistula that persisted for 16 months. PMID- 29391325 TI - Idiopathic mesenteric phlebosclerosis associated with long-term use of Chinese herbal medicine. PMID- 29391326 TI - Use of Proton Pump Inhibitors and risk of gastric cancer. PMID- 29391327 TI - Spurious Thrombocytosis in the Setting of Hemolytic Anemia and Microcytosis Secondary to Extensive Burn Injury PMID- 29391328 TI - First Report of an SH2D1A Mutation Associated with X-Linked Lymphoproliferative Disease in Turkey PMID- 29391329 TI - Association between fok1 polymorphism of vitamin D receptor gene with uterine leiomyoma in Turkish populations AB - Objective: The aim of this research was to determine the association between the fok1 polymorphism and uterine leiomyomas. Material and Methods: For genotyping the fok1 polymorphism of the vitamin D receptor, real-time polymerase chain reaction was performed on blood samples of uterine leiomyoma (n=27) and control (n=33) groups. For statistical analyses, SPSS v.23 software (SPSS Inc., Chicago, IL, USA) was used. Results: A statistically significant difference was observed for the frequency of the CC genotype between the uterine leiomyoma and control groups, and the frequencies of the T allele in the uterine leiomyoma groups were significantly higher than in the control group. CONCLUSION: The presence of the fok1 CC genotype may be a risk-reducing factor and the T allele may be a potential risk factor for developing uterine leiomyoma. PMID- 29391330 TI - Successful Treatment of Chronic Lymphocytic Leukemia Multifocal Central Nervous System Involvement with Ibrutinib. PMID- 29391331 TI - Improvement of Cutaneous Anaplastic Large Cell Lymphoma by Brentuximab Vedotin Monotherapy. PMID- 29391332 TI - Intravascular Large B-Cell Lymphoma of the Gallbladder. PMID- 29391333 TI - t(9;19)(q22;p13) in Acute Myelomonocytic Leukemia. PMID- 29391335 TI - Use of Plerixafor to Mobilize a Healthy Donor Infected with Influenza A. PMID- 29391336 TI - Sclerosing Extramedullary Hematopoietic Tumor PMID- 29391334 TI - Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies. AB - Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods may offer better predictive values in certain cases. Treatment options for resistant fungal infections are limited and new drugs with novel mechanisms of actions are needed. Prevention of resistance through antifungal stewardship programs is of paramount importance. PMID- 29391337 TI - Intracranial Bleeding in a Female Hemophilia Patient: Molecular Analysis of the Factor 8 Gene and Determination of a Novel Mutation PMID- 29391338 TI - Expansion of a Myeloma-associated Lesion from Orbita to the Cerebrum. PMID- 29391339 TI - Kasabach-Merritt Syndrome in an Adult PMID- 29391340 TI - Effectiveness of Ankaferd BloodStopper in Prophylaxis and Treatment of Oral Mucositis in Childhood Cancers Evaluated with Plasma Citrulline Levels. PMID- 29391341 TI - Objectively Measured Baseline Physical Activity Patterns in Women in the mPED Trial: Cluster Analysis. AB - BACKGROUND: Determining patterns of physical activity throughout the day could assist in developing more personalized interventions or physical activity guidelines in general and, in particular, for women who are less likely to be physically active than men. OBJECTIVE: The aims of this report are to identify clusters of women based on accelerometer-measured baseline raw metabolic equivalent of task (MET) values and a normalized version of the METs >=3 data, and to compare sociodemographic and cardiometabolic risks among these identified clusters. METHODS: A total of 215 women who were enrolled in the Mobile Phone Based Physical Activity Education (mPED) trial and wore an accelerometer for at least 8 hours per day for the 7 days prior to the randomization visit were analyzed. The k-means clustering method and the Lloyd algorithm were used on the data. We used the elbow method to choose the number of clusters, looking at the percentage of variance explained as a function of the number of clusters. RESULTS: The results of the k-means cluster analyses of raw METs revealed three different clusters. The unengaged group (n=102) had the highest depressive symptoms score compared with the afternoon engaged (n=65) and morning engaged (n=48) groups (overall P<.001). Based on a normalized version of the METs >=3 data, the moderate-to-vigorous physical activity (MVPA) evening peak group (n=108) had a higher body mass index (P=.03), waist circumference (P=.02), and hip circumference (P=.03) than the MVPA noon peak group (n=61). CONCLUSIONS: Categorizing physically inactive individuals into more specific activity patterns could aid in creating timing, frequency, duration, and intensity of physical activity interventions for women. Further research is needed to confirm these cluster groups using a large national dataset. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280812; https://clinicaltrials.gov/ct2/show/NCT01280812 (Archived by WebCite at http://www.webcitation.org/6vVyLzwft). PMID- 29391342 TI - Activity Monitors as Support for Older Persons' Physical Activity in Daily Life: Qualitative Study of the Users' Experiences. AB - BACKGROUND: Falls are a major threat to the health and independence of seniors. Regular physical activity (PA) can prevent 40% of all fall injuries. The challenge is to motivate and support seniors to be physically active. Persuasive systems can constitute valuable support for persons aiming at establishing and maintaining healthy habits. However, these systems need to support effective behavior change techniques (BCTs) for increasing older adults' PA and meet the senior users' requirements and preferences. Therefore, involving users as codesigners of new systems can be fruitful. Prestudies of the user's experience with similar solutions can facilitate future user-centered design of novel persuasive systems. OBJECTIVE: The aim of this study was to investigate how seniors experience using activity monitors (AMs) as support for PA in daily life. The addressed research questions are as follows: (1) What are the overall experiences of senior persons, of different age and balance function, in using wearable AMs in daily life?; (2) Which aspects did the users perceive relevant to make the measurements as meaningful and useful in the long-term perspective?; and (3) What needs and requirements did the users perceive as more relevant for the activity monitors to be useful in a long-term perspective? METHODS: This qualitative interview study included 8 community-dwelling older adults (median age: 83 years). The participants' experiences in using two commercial AMs together with tablet-based apps for 9 days were investigated. Activity diaries during the usage and interviews after the usage were exploited to gather user experience. Comments in diaries were summarized, and interviews were analyzed by inductive content analysis. RESULTS: The users (n=8) perceived that, by using the AMs, their awareness of own PA had increased. However, the AMs' impact on the users' motivation for PA and activity behavior varied between participants. The diaries showed that self-estimated physical effort varied between participants and varied for each individual over time. Additionally, participants reported different types of accomplished activities; talking walks was most frequently reported. To be meaningful, measurements need to provide the user with a reliable receipt of whether his or her current activity behavior is sufficient for reaching an activity goal. Moreover, praise when reaching a goal was described as motivating feedback. To be useful, the devices must be easy to handle. In this study, the users perceived wearables as easy to handle, whereas tablets were perceived difficult to maneuver. Users reported in the diaries that the devices had been functional 78% (58/74) of the total test days. CONCLUSIONS: Activity monitors can be valuable for supporting seniors' PA. However, the potential of the solutions for a broader group of seniors can significantly be increased. Areas of improvement include reliability, usability, and content supporting effective BCTs with respect to increasing older adults' PA. PMID- 29391343 TI - Substance Use Prevention Programs for Indigenous Adolescents in the United States of America, Canada, Australia and New Zealand: Protocol for a Systematic Review. AB - BACKGROUND: Indigenous adolescents are at a higher risk of experiencing harms related to substance use compared with their non-Indigenous counterparts as a consequence of earlier onset and higher rates of substance use. Early onset of substance use has been identified as a risk factor for future substance use problems and other health, social, and family outcomes. Therefore, prevention of substance use among adolescents has been identified as a key area to improve health of Indigenous Peoples. Evidence exists for the effectiveness of prevention approaches for adolescents in mainstream populations and, most recently, for the use of computer- and Internet-delivered interventions to overcome barriers to implementation. However, there is currently no conclusive evidence about the effectiveness of these approaches for Indigenous adolescents. OBJECTIVE: The purpose of this review is to synthesize the international evidence regarding the effectiveness of substance use prevention programs for Indigenous adolescents in the United States, Canada, Australia, and New Zealand. METHODS: A total of 8 peer reviewed databases and 20 gray literature databases will be searched, using search terms in line with the aims of this review and based on previous relevant reviews of substance use prevention. Studies will be included if they evaluate a substance use prevention program with Indigenous adolescents (aged 10 to 19 years) as the primary participant group and are published between January 1, 1990 and August 31, 2017. RESULTS: A narrative synthesis will be provided about the effectiveness of the programs, the type of program (whether culture-based, adapted, or unadapted), delivery of the program (computer- and Internet-delivered or traditional), and the setting in which the programs are delivered (community, school, family, clinical, or a combination). CONCLUSIONS: The study will identify core elements of effective substance use prevention programs among Indigenous adolescents and appraise the methodological quality of the studies. This review will provide researchers, policy makers, and program developers with evidence about the potential use of prevention approaches for Indigenous adolescents. PMID- 29391344 TI - Clinical Validity, Understandability, and Actionability of Online Cardiovascular Disease Risk Calculators: Systematic Review. AB - BACKGROUND: Online health information is particularly important for cardiovascular disease (CVD) prevention, where lifestyle changes are recommended until risk becomes high enough to warrant pharmacological intervention. Online information is abundant, but the quality is often poor and many people do not have adequate health literacy to access, understand, and use it effectively. OBJECTIVE: This project aimed to review and evaluate the suitability of online CVD risk calculators for use by low health literate consumers in terms of clinical validity, understandability, and actionability. METHODS: This systematic review of public websites from August to November 2016 used evaluation of clinical validity based on a high-risk patient profile and assessment of understandability and actionability using Patient Education Material Evaluation Tool for Print Materials. RESULTS: A total of 67 unique webpages and 73 unique CVD risk calculators were identified. The same high-risk patient profile produced widely variable CVD risk estimates, ranging from as little as 3% to as high as a 43% risk of a CVD event over the next 10 years. One-quarter (25%) of risk calculators did not specify what model these estimates were based on. The most common clinical model was Framingham (44%), and most calculators (77%) provided a 10-year CVD risk estimate. The calculators scored moderately on understandability (mean score 64%) and poorly on actionability (mean score 19%). The absolute percentage risk was stated in most (but not all) calculators (79%), and only 18% included graphical formats consistent with recommended risk communication guidelines. CONCLUSIONS: There is a plethora of online CVD risk calculators available, but they are not readily understandable and their actionability is poor. Entering the same clinical information produces widely varying results with little explanation. Developers need to address actionability as well as clinical validity and understandability to improve usefulness to consumers with low health literacy. PMID- 29391345 TI - Automated Information Extraction on Treatment and Prognosis for Non-Small Cell Lung Cancer Radiotherapy Patients: Clinical Study. AB - BACKGROUND: In outcome studies of oncology patients undergoing radiation, researchers extract valuable information from medical records generated before, during, and after radiotherapy visits, such as survival data, toxicities, and complications. Clinical studies rely heavily on these data to correlate the treatment regimen with the prognosis to develop evidence-based radiation therapy paradigms. These data are available mainly in forms of narrative texts or table formats with heterogeneous vocabularies. Manual extraction of the related information from these data can be time consuming and labor intensive, which is not ideal for large studies. OBJECTIVE: The objective of this study was to adapt the interactive information extraction platform Information and Data Extraction using Adaptive Learning (IDEAL-X) to extract treatment and prognosis data for patients with locally advanced or inoperable non-small cell lung cancer (NSCLC). METHODS: We transformed patient treatment and prognosis documents into normalized structured forms using the IDEAL-X system for easy data navigation. The adaptive learning and user-customized controlled toxicity vocabularies were applied to extract categorized treatment and prognosis data, so as to generate structured output. RESULTS: In total, we extracted data from 261 treatment and prognosis documents relating to 50 patients, with overall precision and recall more than 93% and 83%, respectively. For toxicity information extractions, which are important to study patient posttreatment side effects and quality of life, the precision and recall achieved 95.7% and 94.5% respectively. CONCLUSIONS: The IDEAL-X system is capable of extracting study data regarding NSCLC chemoradiation patients with significant accuracy and effectiveness, and therefore can be used in large-scale radiotherapy clinical data studies. PMID- 29391346 TI - Impact of Atrial Fibrillation During ST-Segment-Elevation Myocardial Infarction on Infarct Characteristics and Prognosis. AB - BACKGROUND: Atrial fibrillation (AF) is frequently observed in patients with ST segment-elevation myocardial infarction and associated with worse clinical outcome. However, the mechanisms for this increased risk are not fully understood. The purpose of this study was to investigate the relationship of the presence of AF to cardiac magnetic resonance (CMR) derived myocardial salvage and damage as well as clinical outcomes. METHODS AND RESULTS: This multicenter CMR study enrolled 786 patients with ST-segment-elevation myocardial infarction. CMR parameters (infarct size, myocardial salvage index, microvascular obstruction, and myocardial function) were assessed 3 (interquartile range [IQR], 2-4) days post-ST-segment-elevation myocardial infarction and compared between patients with or without AF during hospitalization. Major adverse cardiac events were assessed as a composite of all-cause death, reinfarction, and new congestive heart failure at 12 months. AF was documented in 48 (6.1%) patients. There was no significant difference in infarct size (18 [IQR, 9-29]% versus 17 [IQR, 9-25]% of left ventricular mass; P=0.340), myocardial salvage index (51 [IQR, 34-69] versus 51 [IQR, 33-69]; P=0.830), or microvascular obstruction (0.6 [IQR, 0-2.0]% versus 0.0 [IQR, 0-1.8]% of left ventricular mass; P=0.340) between groups. Patients with AF had significantly lower left ventricular (47 [IQR, 34-54]% versus 51 [IQR, 44-58]%; P=0.003) and left atrial (42 [IQR, 17-57]% versus 53 [IQR, 45 59]%; P<0.001) ejection fraction. AF was associated with major adverse cardiac events, even when adjusting for clinical risk factors (odds ratio, 2.48 [95% confidence interval, 1.22-5.03]; P=0.0120) or CMR prognosis markers (odds ratio, 3.77 [95% confidence interval, 1.83-7.79]; P=0.001). CONCLUSIONS: This CMR study found no major differences in myocardial salvage, infarct size, or microvascular damage in patients with ST-segment-elevation myocardial infarction or without AF. AF was, however, associated with cardiac dysfunction and independently related to major adverse cardiac events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00712101. PMID- 29391347 TI - Atrial Fibrillation and Worse Outcomes in ST-Segment-Elevation Myocardial Infarction: Is It All About Infarct Size, or Do We Need to Look Elsewhere? PMID- 29391349 TI - Correction: Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression. PMID- 29391350 TI - Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors. AB - Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA-damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release SLFN11 and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here.Experimental Design:SLFN11 expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on SLFN11 expression and sensitivity to DNA-damaging agents.Results:SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11, transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea, and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested.Conclusions: This study reports the prevalent epigenetic regulation of SLFN11 and the dominant stimulatory effect of HDAC inhibitors on SLFN11 expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA-damaging agents to overcome epigenetic inactivation of SLFN11-mediated resistance to DNA-targeted agents. Clin Cancer Res; 24(8); 1944-53. (c)2018 AACR. PMID- 29391352 TI - PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer. AB - Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer.Experimental design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data.Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case-control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival.Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. Clin Cancer Res; 24(8); 1974-86. (c)2018 AACR. PMID- 29391351 TI - T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T cell Function in Large Solid Tumors. AB - Purpose: Infused autologous tumor-infiltrating lymphocytes (TIL) and tumor targeted chimeric antigen receptor (CAR) T cells typically surround malignant lesions or penetrate small tumor nodules but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required.Experimental Design: We tested the effects of IL12 plus doxorubicin on T-cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model, and two human xenograft tumor models bearing large tumors (>10 mm).Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR T cells. This combined treatment halted tumor progression and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immunosuppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL12-induced IFNgamma accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells.Conclusions: The deep penetration of infused T cells associated with combined IL12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T cell therapy to a wider range of solid tumors. Clin Cancer Res; 24(12); 2920-34. (c)2018 AACRSee related commentary by Berraondo et al., p. 2716. PMID- 29391353 TI - HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. AB - Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) was an attractive therapeutic target for myeloma due to its direct regulation of transcriptional programs implicated in both protein homeostasis and the oncogenic phenotype. Here, we interrogate HSF1 as a therapeutic target in myeloma using bioinformatic, genetic, and pharmacologic means.Experimental Design: To assess the clinical relevance of HSF1, we analyzed publicly available patient myeloma gene expression datasets. Validation of this novel target was conducted in in vitro experiments using shRNA or inhibitors of the HSF1 pathway in human myeloma cell lines and primary cells as well as in in vivo human myeloma xenograft models.Results: Expression of HSF1 and its target genes were associated with poorer myeloma patient survival. ShRNA-mediated knockdown or pharmacologic inhibition of the HSF1 pathway with a novel chemical probe, CCT251236, or with KRIBB11, led to caspase-mediated cell death that was associated with an increase in EIF2alpha phosphorylation, CHOP expression and a decrease in overall protein synthesis. Importantly, both CCT251236 and KRIBB11 induced cytotoxicity in human myeloma cell lines and patient-derived primary myeloma cells with a therapeutic window over normal cells. Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.Conclusions: Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma. Clin Cancer Res; 24(10); 2395-407. (c)2018 AACRSee related commentary by Parekh, p. 2237. PMID- 29391354 TI - Metformin-associated lactic acidosis mimicking ischaemic bowel. AB - Metformin-associated lactic acidosis (MALA) is a rare complication among patients who are diabetic, commonly presenting with non-specific findings, and developing mostly among those with other risk factors for lactic acidosis. We report the development of MALA in a 67-year-old man with diabetes who presented with progressive abdominal pain and bloody diarrhoea. On presentation the patient was in shock, with signs suggestive of peritonitis, and with severe lactic acidosis, renal failure and non-specific findings on abdominal CT. Neither the patient nor family could provide details of his home pharmaceuticals. Circulatory resuscitation with intravenous crystalloids and vasopressors was commenced, along with empiric broad-spectrum antibiotics. Emergent laparotomy did not show pathological findings. Emergent haemodialysis, initiated postoperatively, resulted in rapid resolution of shock and lactic acidosis. A list of patient's medications, provided afterwards by the family, included metformin. Microbiological studies remained negative and renal function normalised by the time of patient's hospital discharge after 9 days. PMID- 29391355 TI - Simultaneous endoscopic full-thickness resection of two synchronous colonic granular cell tumours. AB - Granular cell tumours (GCTs) are rare soft tissue tumours originating from Schwann cells. Due to potential malignant transformation, complete endoscopic resection should be aimed for. We report on a 49-year-old patient with two synchronous GCTs found in the caecum and the ascending colon, respectively. Synchronous endoscopic full-thickness resection (EFTR) using an all-in-one full thickness resection device (FTRD) was performed under propofol sedation. Completeness of resection was proven histologically. No adverse events occurred. We report safe and complete simultaneous EFTR of two synchronous colonic GCTs. PMID- 29391356 TI - Oral condyloma acuminatum in a 75-year-old geriatric patient. AB - Condyloma acuminatum (CA) is a human papillomavirus-induced sexually transmitted disease which is characterised by epithelial proliferation in the genital region, perianal region, oral cavity and larynx. It was first reported by Knapp and Uohara in 1967. The disease is more common in children and teenagers and appears as solitary or multiple, pinkish, sessile papules or plaques with pebbled surface or as pedunculated papillary lesions. Oral lesions commonly affect the lips, floor of the mouth, lateral and ventral surfaces of tongue, buccal mucosa, soft palate and rarely gingiva. The present report deals with a case of CA affecting a 75-year-old male patient with emphasis on clinical presentation, histological features and importance of PCR for establishment of definitive diagnosis. This case is unique because CA is extremely rare in geriatric age group. PMID- 29391357 TI - Prostatic abscess: a rare complication of staghorn calculi. AB - A staghorn calculus is a calculus accommodating the majority of a renal calyx extending into the renal pelvis. A conservative approach to its treatment may lead to high morbidity and mortality rates. Such morbidity usually manifests with renal failure, obstructed upper urinary tractand/or life-threatening sepsis. Prostatic abscesses have never been associated with staghorn calculi in the literature. We report a case of a 70-year-old man who presented with sepsis, which was found to originate from a complex prostatic abscess. The patient had no history of urinary tract infections or risk factors. The authors believe that the incidentally identified staghorn calculi promoted the growth of Proteus mirabilis which led to the development of the prostatic abscess. The patient underwent a transurethral resection and drainage of the abscess following a failed course of antibiotic therapy. This case also highlights the paucity of guidelines available in treating prostatic abscesses. PMID- 29391358 TI - Wave of renal impairment. AB - We present a case of a 51-year-old man who went to the emergency department after an almost-drowning episode, presenting with muscular weakness, myalgia and dark urine. Laboratory data showed a severe rhabdomyolysis (creatine kinase 497 510 U/L). Despite aggressive fluid therapy, an oliguric acute kidney injury was established with temporary need of haemodialysis. The patient had a longtime history of exercise intolerance and family history of a metabolic myopathy, namely a sister with McArdle's disease. The genetic test was positive. McArdle's disease is an autosomal recessive disorder caused by mutations in the muscle glycogen phosphorylase gene that encodes the myophosphorylase. The main symptom consists in exercise intolerance and the most severe complication is rhabdomyolysis with acute renal failure. Metabolic myopathies, such as McArdle's disease, should be considered in patients with acute renal failure due to unexplained severe rhabdomyolysis, especially if there are chronic complaints of exercise intolerance and positive family history. PMID- 29391359 TI - Treating chronic hepatitis E: when is enough enough? AB - We present a 38-year-old white British man who was taking long-term immunosuppressive medication following kidney transplantation. On routine review, he was noted to have an isolated and asymptomatic rise in alanine aminotransferase. After thorough investigation, he was found to have positive IgM and IgG serology to hepatitis E virus-and given the duration of his transaminitis, he was determined to have chronic hepatitis E infection. Treatment options were complicated by the presence of his kidney transplant, by chronic anaemia and by his wish for concomitant fertility treatment. Ribavirin therapy was instituted with a dramatic and immediate drop in serum viral load, although stool viraemia persisted. No clear protocols guide duration of treatment in chronic hepatitis E infection, but protracted faecal virus shedding predicts viral recrudescence, and treatment should continue at least until the stool is clear of virus. PMID- 29391360 TI - GaPP2, a multicentre randomised controlled trial of the efficacy of gabapentin for the management of chronic pelvic pain in women: study protocol. AB - INTRODUCTION: Chronic pelvic pain (CPP) affects more than 1 million UK women with associated healthcare costs of L158 million annually. Current evidence supporting interventions when no underlying pathology is identified is very limited and treatment is frequently inadequate. Gabapentin (a GABA analogue) is efficacious and often well tolerated in other chronic pain conditions. We have completed a successful pilot randomised controlled trial Gabapentin for Pelvic Pain 1 (GaPP1) and here describe the protocol for our definitive multicentre trial to assess the efficacy of gabapentin in the management of CPP in women Gabapentin for Pelvic Pain 2 (GaPP2). METHODS AND ANALYSIS: We plan to perform a double-blind placebo controlled randomised multicentre clinical trial, recruiting 300 women with CPP from up to 40 National Health Service hospitals within the UK. After randomisation, women will titrate their medication (gabapentin or placebo) over a 4-week period to a maximum of 2700 mg or placebo equivalent and will then maintain a stable dose for a 12-week period. Response to treatment will be monitored with validated questionnaires and coprimary outcome measures of average and worst pain scores will be employed. The primary objective is to test the hypothesis that treatment with gabapentin has the potential to provide an effective oral treatment to alleviate pain in women with CPP in the absence of any obvious pelvic pathology. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Coventry and Warwick Research Ethics Committee (REC 15/WM/0036). Data will be presented at international conferences and published in peer-reviewed journals. We will make the information obtained from the study available to the public through national bodies and charities. TRIAL REGISTRATION NUMBER: ISRCTN77451762; Pre-results. PMID- 29391361 TI - Effect of spinal orthoses and postural taping on balance, gait and quality of life in older people with thoracic hyperkyphosis: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Thoracic hyperkyphosis is one of the most common spinal disorders in older people, creating impairment, postural instability, gait disorders and a reduced quality of life. The use of spinal orthoses and/or postural taping may be feasible conservative interventions, but their efficacy is uncertain. The aim of this review is therefore to investigate the effectiveness of spinal orthoses and taping on the balance and gait of older people with hyperkyphosis. METHODS AND ANALYSIS: We will include randomised controlled trials and clinical trial studies which assess the efficacy of spinal orthoses and taping using the WHO International Classification of Functioning, Disability and Health (ICF) outcome measures in older people with hyperkyphosis of the thoracic spine. A search will be performed in PubMed, SCOPUS, ISI Web of Knowledge, CENTRAL, EMBASE, CINAHL, AMED, PEDro, REHAB DATA and RECAL databases with no restriction of language. Two independent reviewers will perform the study selection and data extraction. Quality assessment will be implemented using modified Down and Black checklists. Publication bias and data synthesis will be assessed by funnel plots, Begg's and Egger's tests, and plots using STATA software V.12.1 version. ETHICS AND DISSEMINATION: No ethical issues are predicted. These findings will be published in a peer reviewed journal and presented at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42016045880. PMID- 29391362 TI - Associations between introduction and withdrawal of a financial incentive and timing of attendance for antenatal care and incidence of small for gestational age: natural experimental evaluation using interrupted time series methods. AB - OBJECTIVES: To determine whether introduction or withdrawal of a maternal financial incentive was associated with changes in timing of first attendance for antenatal care ('booking'), or incidence of small for gestational age. DESIGN: A natural experimental evaluation using interrupted time series analysis. SETTING: A hospital-based maternity unit in the north of England. PARTICIPANTS: 34 589 women (and their live-born babies) who delivered at the study hospital and completed the 25th week of pregnancy in the 75 months before (January 2003 to March 2009), 21 months during (April 2009 to December 2010) and 36 months after (January 2011 to December 2013) the incentive was available. INTERVENTION: The Health in Pregnancy Grant was a financial incentive of L190 ($235; ?211) payable to pregnant women in the UK from the 25th week of pregnancy, contingent on them receiving routine antenatal care. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was mean gestational age at booking. Secondary outcomes were proportion of women booking by 10, 18 and 25 weeks' gestation; and proportion of babies that were small for gestational age. RESULTS: By 21 months after introduction of the grant (ie, immediately prior to withdrawal), compared with what was predicted given prior trends, there was an reduction in mean gestational age at booking of 4.8 days (95% CI 2.3 to 8.2). The comparable figure for 24 months after withdrawal was an increase of 14.0 days (95% CI 2.8 to 16.8). No changes in incidence of small for gestational age babies were seen. CONCLUSIONS: The introduction of a universal financial incentive for timely attendance at antenatal care was associated with a reduction in mean gestational age at first attendance, but not the proportion of babies that were small for gestational age. Future research should explore the effects of incentives offered at different times in pregnancy and of differing values; and how stakeholders view such incentives. PMID- 29391363 TI - Patient safety in transitional care of the elderly: effects of a quasi experimental interorganisational educational intervention. AB - OBJECTIVE: The study objective was to assess the effects of an interorganisational educational intervention called the 'Meeting Point' on patient safety culture among staff in hospital and nursing home wards. DESIGN: The study employs a quasi-experimental, non-randomised design with a hospital and nursing home intervention group and a hospital and nursing home control group. The study uses one preintervention and two postintervention survey measurements. The intervention group participated in an educational programme 'The Meeting Point' including interorganisational staff meetings combining educational sessions with a discussion platform focusing on quality and safety in transitional care of the elderly. RESULTS: The results show a stable development over time for the patient safety culture factor 'Handoff and transitions', and small improvements for 'Overall perceptions of patient safety culture' and 'Organisational learning - continuous improvement' for the hospital intervention group. No similar development was reported in the nursing home intervention group, which is most likely explained by ongoing organisational changes. Qualitative data show the existence of ongoing initiatives in the hospital to improve transitional care, but not all were connected to the 'Meeting Point'. CONCLUSION: The 'Meeting Point' has the potential to be a useful measure for healthcare professionals when aiming to improve patient safety culture in transitional care. Further refinement of the key components and testing with a more robust study design will be beneficial. PMID- 29391364 TI - Overuse of diagnostic tools and medications in acute rhinosinusitis in Spain: a population-based study (the PROSINUS study). AB - OBJECTIVES: Acute rhinosinusitis (ARS) has a high incidence. Diagnosis is clinical, and evolution is mostly self-limited. The aim of this study was to describe the sociodemographic characteristics and use of diagnostic tools and medications in patients with ARS. DESIGN: This is a prospective observational study in real-life clinical practice. SETTING: Patients with clinical diagnosis of ARS (n=2610) were included from ear, nose and throat clinics in Spain. A second visit at resolution was done. PARTICIPANTS: Patients were classified according to the duration of symptoms: viral ARS (<=10 days), postviral ARS (>10 days, <=12 weeks) and chronic rhinosinusitis (>12 weeks). MAIN OUTCOME MEASURES: Sociodemographic characteristics, symptoms, disease severity, quality of life (Sino-Nasal Outcome Test-16), used diagnostic tools and medications, and the management performed by primary care physicians (PCPs) and by otorhinolaryngologists (ORLs) were assessed. RESULTS: Of the patients 36% were classified as having viral ARS, 63% postviral ARS and 1% as chronic rhinosinusitis. Working in a poorly air-conditioned environment was a risk factor (OR: 2.26, 95% CI 1.27 to 4.04) in developing postviral ARS. A higher number of diagnostic tools (rhinoscopy/endoscopy: 80% vs 70%; plain X-ray: 70% vs 55%; CT scan: 22% vs 12%; P<0.0001) were performed in postviral than viral cases. PCPs performed more X-rays than ORLs (P<0.0001). Patients, more those with postviral than viral ARS, received a high number of medications (oral antibiotics: 76% vs 62%; intranasal corticosteroids: 54% vs 38%; antihistamines: 46% vs 31%; mucolytic: 48% vs 60%; P<0.0001). PCPs prescribed more antibiotics, antihistamines and mucolytics than ORLs (P<0.0068). More patients with postviral than viral ARS reported symptoms of potential complications (1.5% vs 0.4%; P=0.0603). Independently of prescribed medications, quality of life was more affected in patients with postviral (38.7+/-14.2 vs 36.0+/-15.3; P=0.0031) than those with viral ARS. ARS resolution was obtained after 6.04 (viral) and 16.55 (postviral) days, with intranasal corticosteroids being associated with longer (OR: 1.07, 95% 1.02 to 1.12) and phytotherapy with shorter (OR: 0.95, 95% CI 0.91 to 1.00) duration. CONCLUSIONS: There is a significant overuse of diagnostic tools and prescribed medications, predominantly oral antibiotics, by PCPs and ORLs, for viral and postviral ARS. PMID- 29391365 TI - Social and structural conditions for the avoidance of advance care planning in neuro-oncology: a qualitative study. AB - BACKGROUND: Primary brain tumours newly affect >260 000 people each year worldwide. In the UK, every year >10 000 people are diagnosed with a brain tumour while >5000 die annually from the disease. Prognoses are poor, cognitive deterioration common and patients have prolonged palliative needs. Advance care planning (ACP) may enable early discussion of future care decisions. Although a core commitment in the UK healthcare strategy, and the shared responsibility of clinical teams, ACP appears uncommon in practice. Evidence around ACP practice in neuro-oncology is limited. OBJECTIVES: We aimed to elicit key social and structural conditions contributing to the avoidance of ACP in neuro-oncology. DESIGN: A cross-sectional qualitative study design was used. SETTING: One tertiary care hospital in the UK. PARTICIPANTS: Fifteen healthcare professionals working in neuro-oncology participated in this study, including neuro oncologists, neurosurgeons, clinical nurse specialists, allied healthcare professionals and a neurologist. METHOD: Semi-structured interviews were conducted with participants to explore their assumptions and experiences of ACP. Data were analysed thematically using the well-established framework method. RESULTS: Participants recognised the importance of ACP but few had ever completed formal ACP documentation. We identified eight key factors, which we suggest comprise three main conditions for avoidance: (1) difficulties being a highly emotive, time-intensive practice requiring the right 'window of opportunity' and (2) presence and availability of others; (3) ambiguities in ACP definition, purpose and practice. Combined, these created a 'culture of shared avoidance'. CONCLUSION: In busy clinical environments, 'shared responsibility' is interpreted as 'others' responsibility' laying the basis for a culture of avoidance. To address this, we suggest a 'generalists and specialists' model of ACP, wherein healthcare professionals undertake particular responsibilities. Healthcare professionals are already adopting this model informally, but without formalised structure it is likely to fail given a tendency for people to assume a generalist role. PMID- 29391366 TI - Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. AB - INTRODUCTION: Improving accessible, acceptable recovery-oriented service provision for people with bipolar disorder (BD) is an important priority. Mindfulness and acceptance-based cognitive and behavioural therapies (or 'third wave' CBT) may prove fruitful due to the considerable overlap between these approaches and key features of personal recovery. Groups also confer therapeutic benefits consistent with personal recovery and may improve recovery-oriented service provision by adding another modality for accessing support. The primary objective of this trial is to explore the feasibility and acceptability of a new recovery-focused group therapy (RfGT) intervention for adults with BD. This is the first published feasibility assessment of a time-limited RfGTrecovery-focused group therapy intervention for BD. METHODS/ ANALYSIS: This protocol describes an open feasibility study, utilising a pre-treatment design versus post- treatment design and nested qualitative evaluation. Participants will be recruited from the Central Coast region of New South Wales, Australia, from primary care providers, specialist mental health services, non-government organisations and via self referral. The primary outcomes are feasibility and acceptability as indexed by recruitment, retention, intervention adherence, adverse events (if any) and detailed consumer feedback. Clinical outcomes and process measures will be assessed to inform future research. Primary outcome data will utiliseuse descriptive statistics (eg, summarizingsummarising recruitment, demographics, attendance, attrition and intervention adherence). Secondary outcomes will be assessed using repeated-measures analysis of covariance across all time points (including change, effect size and variability). ETHICS AND DISSEMINATION: Ethical approval has been granted by the Northern Sydney Local Health District HREChuman research ethics committee (HREC) (HREC/16/HAWKE/69) and The University of Newcastle HREC (H-2016-0107). The Ffindings will be used to improve the intervention per user needs and preferences, and inform what amendments and/or information are required before a follow-on trial would be possible. This study contributes to a growing body of innovative, recovery-oriented innovations of psychological treatments for adults with BD. TRIAL REGISTRATION NUMBER: ACTRN12616000887471; Pre-results. PMID- 29391367 TI - Impact of sex work on risk behaviours and their association with HIV positivity among people who inject drugs in Eastern Central Canada: cross-sectional results from an open cohort study. AB - OBJECTIVES: The objectives of this study were: (1) to examine the correlates of HIV positivity among participants who injected drugs and engaged in sex work (PWID-SWs) in the SurvUDI network between 2004 and 2016, after stratification by sex, and (2) to compare these correlates with those of sexually active participants who did not engage in sex work (PWID non-SWs). DESIGN AND SETTING: This biobehavioural survey is an open cohort of services where participants who had injected in the past 6 months were recruited mainly through harm reduction programmes in Eastern Central Canada. PARTICIPANTS: Data from 5476 participants (9223 visits in total; 785 not included in multivariate analyses due to missing values) were included. METHODS: Participants completed an interviewer administered questionnaire and provided saliva samples for anti-HIV antibody testing. Generalised estimating equations taking into account multiple participations were used. RESULTS: Baseline HIV prevalence was higher among SWs compared with non-SWs (women: 13.0% vs 7.7%; P<0.001, and men: 17.4% vs 10.8%; P<0.001). PWID-SWs were particularly susceptible to HIV infection as a result of higher levels of vulnerability factors and injection risk behaviours. They also presented different risk-taking patterns than their non-SWs counterparts, as shown by differences in correlates of HIV positivity. Additionally, the importance of sex work for HIV infection varies according to gender, as suggested by a large proportion of injection risk behaviours associated with HIV among women and, conversely, a stronger association between sexual behaviours and HIV positivity observed among men. CONCLUSION: These results suggest that sex work has an impact on the risk of HIV acquisition and that risk behaviours vary according to gender. Public health practitioners should take those specificities into account when designing HIV prevention interventions aimed at PWIDs. PMID- 29391368 TI - Predicting prostate cancer progression: protocol for a retrospective cohort study to identify prognostic factors for prostate cancer outcomes using routine primary care data. AB - INTRODUCTION: Prostate cancer is the most common cancer in men in the UK, with nearly 40 000 diagnosed in 2014; and it is the second most common cause of male cancer-related mortality. The clinical conundrum is that most men live with prostate cancer rather than die from it, while existing treatments have significant associated morbidity. Recent studies have shown very low mortality rates (1% after a median of 10-year follow-up) and no treatment-related reductions in mortality, in men with localised prostate cancer. This study will identify prognostic factors associated with prostate cancer progression to help differentiate aggressive from more indolent tumours in men with localised disease at diagnosis, and so inform the decision to adopt conservative (active surveillance) or radical (surgery or radiotherapy) management strategies. METHODS AND ANALYSIS: The Clinical Practice Research Datalink (CPRD) contains 57 318 men who were diagnosed with prostate cancer between 1 January 1987 and 31 December 2016. These men will be linked to the Office for National Statistics (ONS) and the National Cancer Registration and Analysis Service registry databases for mortality, TNM stage, Gleason grade and treatment data. Men with a diagnosis date prior to 1 January 1987 and men with lymph node or distant metastases at diagnosis will be excluded. A priori determined prognostic factors potentially associated with prostate cancer mortality, the end point of cancer progression, will be measured at baseline, and the participants followed through to development of cancer progression, death or the end of the follow-up period (31 December 2016). Cox proportional hazards regression will be used to estimate crude and mutually adjusted HRs. Mortality risk will be predicted using flexible parametric survival models that can accurately fit the shape of the hazard function. ETHICS AND DISSEMINATION: This study protocol has approval from the Independent Scientific Advisory Committee for the UK Medicines and Healthcare products Regulatory Agency Database Research (protocol 17_041). The findings will be presented in peer-reviewed journals and local CPRD researcher meetings. PMID- 29391369 TI - Are self-reported telemonitored blood pressure readings affected by end-digit preference: a prospective cohort study in Scotland. AB - OBJECTIVE: Simple forms of blood pressure (BP) telemonitoring require patients to text readings to central servers creating an opportunity for both entry error and manipulation. We wished to determine if there was an apparent preference for particular end digits and entries which were just below target BPs which might suggest evidence of data manipulation. DESIGN: Prospective cohort study SETTING: 37 socioeconomically diverse primary care practices from South East Scotland. PARTICIPANTS: Patients were recruited with hypertension to a telemonitoring service in which patients submitted home BP readings by manually transcribing the measurements into text messages for transmission ('patient-texted system'). These readings were compared with those from primary care patients with uncontrolled hypertension using a system in which readings were automatically transmitted, eliminating the possibility of manipulation of values ('automatic-transmission system'). METHODS: A generalised estimating equations method was used to compare BP readings between the patient-texted and automatic-transmission systems, while taking into account clustering of readings within patients. RESULTS: A total of 44 150 BP readings were analysed on 1068 patients using the patient-texted system compared with 20 705 readings on 199 patients using the automatic-transmission system. Compared with the automatic-transmission data, the patient-texted data showed a significantly higher proportion of occurrences of both systolic and diastolic BP having a zero end digit (OR 2.1, 95% CI 1.7 to 2.6) although incidence was <2% of readings. Similarly, there was a preference for systolic 134 and diastolic 84 (the threshold for alerts was 135/85) (134 systolic BP OR 1.5, 95% CI 1.3 to 1.8; 84 diastolic BP OR 1.5, 95% CI 1.3 to 1.9). CONCLUSION: End digit preference for zero numbers and specific-value preference for readings just below the alert threshold exist among patients in self-reporting their BP using telemonitoring. However, the proportion of readings affected is small and unlikely to be clinically important. TRIAL REGISTRATION NUMBER: ISRCTN72614272; Post-results. PMID- 29391370 TI - CODIFI (Concordance in Diabetic Foot Ulcer Infection): a cross-sectional study of wound swab versus tissue sampling in infected diabetic foot ulcers in England. AB - OBJECTIVE: To determine the extent of agreement and patterns of disagreement between wound swab and tissue samples in patients with an infected diabetic foot ulcer (DFU). DESIGN: Multicentre, prospective, cross-sectional study. SETTING: Primary and secondary care foot ulcer/diabetic outpatient clinics and hospital wards across England. PARTICIPANTS: Inclusion criteria: consenting patients aged >=18 years; diabetes mellitus; suspected infected DFU. EXCLUSION CRITERIA: clinically inappropriate to take either sample. INTERVENTIONS: Wound swab obtained using Levine's technique; tissue samples collected using a sterile dermal curette or scalpel. OUTCOME MEASURES: Coprimary: reported presence, and number, of pathogens per sample; prevalence of resistance to antimicrobials among likely pathogens. Secondary: recommended change in antibiotic therapy based on blinded clinical review; adverse events; sampling costs. RESULTS: 400 consenting patients (79% male) from 25 centres.Most prevalent reported pathogens were Staphylococcus aureus (43.8%), Streptococcus (16.7%) and other aerobic Gram positive cocci (70.6%). At least one potential pathogen was reported from 70.1% of wound swab and 86.1% of tissue samples. Pathogen results differed between sampling methods in 58% of patients, with more pathogens and fewer contaminants reported from tissue specimens.The majority of pathogens were reported significantly more frequently in tissue than wound swab samples (P<0.01), with equal disagreement for S. aureus and Pseudomonas aeruginosa. Blinded clinicians more often recommended a change in antibiotic regimen based on tissue compared with wound swab results (increase of 8.9%, 95% CI 2.65% to 15.3%). Ulcer pain and bleeding occurred more often after tissue collection versus wound swabs (pain: 9.3%, 1.3%; bleeding: 6.8%, 1.5%, respectively). CONCLUSION: Reports of tissue samples more frequently identified pathogens, and less frequently identified non pathogens compared with wound swab samples. Blinded clinicians more often recommended changes in antibiotic therapy based on tissue compared with wound swab specimens. Further research is needed to determine the effect of the additional information provided by tissue samples. TRIAL REGISTRATION NUMBER: ISRCTN52608451. PMID- 29391371 TI - The unmet needs of informal carers of stroke survivors: a protocol for a systematic review of quantitative and qualitative studies. AB - INTRODUCTION: Stroke events deeply affect not only the stroke survivor but also often the quality of life and physical and psychological health of the family and friends who care for them. There is a need for further information about the unmet needs of these informal carers in order to develop support services and interventions. The primary objective of this review is to report and synthesise the research describing the unmet needs of carers of stroke survivors. METHODS AND ANALYSIS: A systematic review of quantitative and qualitative studies that report on the unmet needs of carers will be conducted. The following databases will be searched for relevant articles: MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, EMBASE, Allied and Complementary Medicine Database and Scopus. No publication date constraints will be applied. Studies will be limited to those published in English and conducted among humans. Eligible studies will report on the unmet needs of informal carers of stroke survivors, defined as family members, friends and other unpaid caregivers. Studies which focus on formal, clinical or medical caregivers will be excluded. A narrative synthesis and pooled analysis of the main outcomes will be reported. ETHICS AND DISSEMINATION: This review will be submitted to a peer-reviewed journal. Our findings are expected to provide new insights into the unmet needs of stroke survivors' carers. Knowledge about the unmet needs of carers will inform the development and refinement of interventions and services to address these needs and better support carers of stroke survivors. The findings of this systematic review will be disseminated publicly and in peer-reviewed journals and may be the topic of research presentations. TRIAL REGISTRATION NUMBER: CRD42017067391. PMID- 29391372 TI - Normal saline instillation versus no normal saline instillation And lung Recruitment versus no lung recruitment with paediatric Endotracheal Suction: the NARES trial. A study protocol for a pilot, factorial randomised controlled trial. AB - INTRODUCTION: Endotracheal suction (ETS) is a frequent and necessary airway intervention for the intubated child. The aim of ETS is to clear the endotracheal tube and airways of respiratory secretions; however, the methods of performing ETS are varied. Internationally a number of ETS treatments are in use. Many have not been rigorously evaluated in a randomised controlled trial setting, and it is uncertain whether any are associated with better outcomes for the critically ill child. With approximately 50% of paediatric intensive care admissions requiring intubation, ETS interventions that maximise the efficacy and minimise the complications of ETS could translate to improved health for substantial numbers of critically ill children, and significant cost savings. The primary aim of the study is to examine two ETS interventions, normal saline instillation and lung recruitment, to determine if it is feasible to conduct a full efficacy trial. METHODS AND ANALYSIS: NARES (Normal saline instillation versus no normal saline instillation And lung Recruitment versus no lung recruitment with paediatric Endotracheal Suction) is a single-centre, pilot, factorial randomised controlled trial conducted in a tertiary referral paediatric centre in Brisbane, Australia. Children (aged 0-16 years) are eligible if they are intubated with an endotracheal tube and mechanically ventilated. Two intervention pairs will be compared using a 2*2 factorial design: (1) normal saline instillation versus no normal saline instillation; and (2) lung recruitment versus no lung recruitment. The primary outcome is study feasibility measured by a composite analysis of eligibility, recruitment, retention, protocol adherence and missing data. Secondary outcomes are ventilator-associated pneumonia, SpO2/FiO2 ratio, lung compliance, end expiratory level and regional tidal volume. ETHICS AND DISSEMINATION: Ethical approval to conduct the research has been obtained. Dissemination of the research findings will be untaken, guided by the Consolidated Standards of Reporting Trials statement recommendations. Protocol content was guided by the Standard Protocol Items: Recommendations for Interventional Trials 2013 statement. TRIAL REGISTRATION NUMBER: ACTRN12617000609358; Pre-results. PMID- 29391373 TI - Do police officers and firefighters have a higher risk of disease than other public officers? A 13-year nationwide cohort study in South Korea. AB - OBJECTIVES: The work of public officers involves repeated and long-term exposure to heavy workloads, high job strain and workplace violence, all of which negatively impact physical and mental health. This study aimed to evaluate and compare the incidences of diseases among different categories of public officers in Korea, in order to further understand the health risks associated with these occupations. DESIGN: A cohort study using the National Health Insurance data. PARTICIPANTS: We collated claims data between 2002 and 2014 for 860 221 public officers. PRIMARY AND SECONDARY OUTCOME MEASURES: Age-standardised rates were calculated using the direct standardisation method, and HRs were calculated using the Cox proportional hazard regression models. RESULTS: Overall, we found that police officers and firefighters had a higher incidence of a range of diseases when compared with national and regional government officers (NRG). The most prominent HRs were observed among police officers for angina pectoris (HR: 1.52, 95% CI 1.49 to 1.54), acute myocardial infarction (HR: 1.84, 95% CI 1.77 to 1.92) and cerebrovascular disease (HR: 1.36, 95% CI 1.31 to 1.40). Firefighters were more susceptible to physical ailments and were at a significantly higher risk for traumatic stress disorders (HR: 1.40, 95% CI 1.26 to 1.56) than NRGs. CONCLUSION: Compared withNRGs, police officers had higher HRs for all measured diseases, except for traumatic stress disorders. While firefighters had higher HRs for almost all diseases examined, public education officers had a higher HR for traumatic stress disorders, when compared with NRGs. PMID- 29391374 TI - Protocol for Pertussis Immunisation and Food Allergy (PIFA): a case-control study of the association between pertussis vaccination in infancy and the risk of IgE mediated food allergy among Australian children. AB - INTRODUCTION: Atopic diseases, including food allergy, have become a predominant cause of chronic illness among children in developed countries. In Australia, a rise in hospitalisations among infants coded as anaphylaxis to foods coincided with the replacement of whole-cell pertussis (wP) vaccine with subunit acellular pertussis (aP) vaccine on the national immunisation schedule in the late 1990s. Atopy is characterised by a tendency to mount T helper type 2 (Th2) responses to otherwise innocuous environmental antigens. Compared with infants who receive aP as their first pertussis vaccine, those who receive wP appear less likely to mount Th2 immune responses to either vaccine or extraneous antigens. We therefore speculate that removal of wP from the vaccine schedule contributed to the observed rise in IgE-mediated food allergy among Australian infants. METHODS AND ANALYSIS: This is a retrospective individually matched case-control study among a cohort of Australian children born from 1997 to 1999, the period of transition from wP to aP vaccines; we include in the cohort children listed on Australia's comprehensive population-based immunisation register as having received a first dose of either pertussis vaccine by 16 weeks old. 500 cohort children diagnosed as having IgE-mediated food allergy at specialist allergy clinics will be included as cases. Controls matched to each case by date and jurisdiction of birth and regional socioeconomic index will be sampled from the immunisation register. Conditional logistic regression will be used to estimate OR (+/-95% CI) of receipt of wP (vs aP) as the first vaccine dose among cases compared with controls. ETHICS AND DISSEMINATION: The study is approved by all relevant human research ethics committees: Western Australia Child and Adolescent Health Services (2015052EP), Women's and Children's Hospital (HREC/15/WCHN/162), Royal Children's Hospital (35230A) and Sydney Children's Hospital Network (HREC/15/SCHN/405). Outcomes will be disseminated through publication and scientific presentation. TRIAL REGISTRATION NUMBER: NCT02490007. PMID- 29391375 TI - Investigating the long-term impact of a childhood sun-exposure intervention, with a focus on eye health: protocol for the Kidskin-Young Adult Myopia Study. AB - INTRODUCTION: Excessive and insufficient sun exposure during childhood have been linked to serious diseases in later life; for example, insufficient sun exposure during childhood may increase the risk of developing myopia. The Kidskin-Young Adult Myopia Study (K-YAMS) is a follow-up of participants in the Kidskin Study, a non-randomised controlled trial that evaluated the effect of a 4-year educational intervention on sun-protection behaviours among primary school children in the late 1990s. Children who received the Kidskin intervention had lower levels of sun exposure compared with peers in the control group after 2 and 4 years of the intervention, but this was not maintained 2 years after the intervention had ceased. Thus, a follow-up of Kidskin Study participants provides a novel opportunity to investigate the associations between a childhood sun exposure intervention and potentially related conditions in adulthood. METHODS AND ANALYSIS: The K-YAMS contacts Kidskin Study participants and invites them to participate using a variety of methods, such as prior contact details, the Australian Electoral Roll and social media. Self-reported and objective measures of sun-exposure and sun-protection behaviours are collected as well as a number of eye measurements including cycloplegic autorefraction and ocular biometry. Data will be analysed to investigate a possible association between myopic refractive error and Kidskin intervention group or measured sun exposure. ETHICS AND DISSEMINATION: The K-YAMS is approved by the Human Research Ethics Committee of the University of Western Australia (RA/4/1/6807). Findings will be disseminated via scientific journals and conferences. TRIAL REGISTRATION NUMBER: ACTRN12616000812392; Pre-results. PMID- 29391376 TI - Did case-based payment influence surgical readmission rates in France? A retrospective study. AB - OBJECTIVES: To determine whether implementation of a case-based payment system changed all-cause readmission rates in the 30 days following discharge after surgery, we analysed all surgical procedures performed in all hospitals in France before (2002-2004), during (2005-2008) and after (2009-2012) its implementation. SETTING: Our study is based on claims data for all surgical procedures performed in all acute care hospitals with >300 surgical admissions per year (740 hospitals) in France over 11 years (2002-2012; n=51.6 million admissions). INTERVENTIONS: We analysed all-cause 30-day readmission rates after surgery using a logistic regression model and an interrupted time series analysis. RESULTS: The overall 30-day all-cause readmission rate following discharge after surgery increased from 8.8% to 10.0% (P<0.001) for the public sector and from 5.9% to 8.6% (P<0.001) for the private sector. Interrupted time series models revealed a significant linear increase in readmission rates over the study period in all types of hospitals. However, the implementation of case-based payment was only associated with a significant increase in rehospitalisation rates for private hospitals (P<0.001). CONCLUSION: In France, the increase in the readmission rate appears to be relatively steady in both the private and public sector but appears not to have been affected by the introduction of a case-based payment system after accounting for changes in care practices in the public sector. PMID- 29391377 TI - Prevalence of tobacco consumption among young physicians at a regional university hospital in southern Spain: a cross-sectional study. AB - INTRODUCTION: The aim of the study is to analyse the prevalence of smoking among resident physicians at a regional university hospital. In addition, we examined the trends in the smoking behaviour of physicians in relation to results obtained in other studies carried out previously at this hospital, as well as those published nationally and internationally METHOD: A cross-sectional observational study evaluating tobacco consumption in young physicians was carried out at the level of secondary healthcare in a regional university hospital in Cordoba, Spain. All the study subjects were resident physicians who underwent a mandatory preliminary occupational health examination between 2012 and 2016. There was no sampling selection as anyone who took this examination was considered to be within the target population. We calculated the proportions of smokers, former smokers and non-smokers, with 95% CIs. Univariate and multivariate analyses (binary logistic regression) were used to analyse the results (P<0.05). RESULTS: The response rate was 99.4%, with a sample size of 324 out of a possible 326 physicians. The average age was 28.6+/-3.7-DT-(95% CI 28.2 to 29.0), and 62.3% (202/324; 95% CI 57.3 to 67.2) were women. Smoking prevalence was 6.5% (21/324; 95% CI 3.5 to 9.3) with a further 5.2% (17/324; 95% CI 2.7 to 7.8) being ex smokers. There were no significant differences in the prevalence of tobacco consumption according to age (P=0.266), sex (9.0% for men and 5.0% for women; P=0.128), medical specialty (P=0.651) or year of residency (P=0.975). A 52.7% decline in the number of young physician smokers was noted between 1986 and 2016 (95% CI -44.0 to -63.5), together with a 64.4% increase in non-smokers (95% CI 55.2 to 77.3). CONCLUSIONS: We observed a significantly low prevalence of tobacco use among trainee physicians in the cohort, an effect of new antismoking laws, with positive role model implications for new physicians and medical students. PMID- 29391378 TI - The cost of mental and physical health disability in childhood and adolescence to families in the UK: findings from a repeated cross-sectional survey using propensity score matching. AB - OBJECTIVE: In the UK, families of disabled children are entitled to receive disability benefits to help meet costs associated with caring for their child. Evidence of actual costs incurred is scant, especially for mental health disability. In this study, we aimed to quantify the cost of mental and physical health disability in childhood and adolescence to families in the UK using the concept of compensating variation (CV). DESIGN: Repeated cross-sectional survey. SETTING: The UK general population PARTICIPANTS: 85 212 children drawn from 8 waves of the Family Resources Survey. OUTCOMES: Using propensity score matching we matched families with a disabled child to similar families without a disabled child and calculated the extra income the former require to achieve the same living standards as the latter, that is, their CV. We calculated the additional costs specifically associated with several definitions of mental health and physical health disability. RESULTS: Families of a child with any mental health disability, regardless of the presence of physical health comorbidity, needed an additional L49.31 (95% CI: 21.95 to 76.67) and, for more severe disabilities, an additional L57.56 (95% CI: 17.69 to 97.44) per week to achieve the same living standards of families without a disabled child. This difference was greater for more deprived families, who needed between L59.28 (95% CI: 41.38 to 77.18) and L81.26 (95% CI: 53.35 to 109.38) more per week depending on the extent of mental health disability. Families of children with physical health disabilities, with or without mental health disabilities, required an additional L35.86 (95% CI: 13.77 to 57.96) per week, with economically deprived families requiring an extra L42.18 (95% CI: 26.38 to 57.97) per week. CONCLUSIONS: Mental and physical health disabilities among children and adolescents were associated with high additional costs for the family, especially for those from deprived economic backgrounds. Means testing could help achieve a more equitable redistribution of disability benefit. PMID- 29391379 TI - Training approaches for the deployment of a mechanical chest compression device: a randomised controlled manikin study. AB - OBJECTIVES: To evaluate the effect of training strategy on team deployment of a mechanical chest compression device. DESIGN: Randomised controlled manikin trial. SETTING: Large teaching hospital in the UK. PARTICIPANTS: Twenty teams, each comprising three clinicians. Participating individuals were health professionals with intermediate or advanced resuscitation training. INTERVENTIONS: Teams were randomised in a 1:1 ratio to receive either standard mechanical chest compression device training or pit-crew device training. Training interventions lasted up to 1 h. Performance was measured immediately after training in a standardised simulated cardiac arrest scenario in which teams were required to deploy a mechanical chest compression device. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was chest compression flow fraction in the minute preceding the first mechanical chest compression. Secondary outcomes included cardiopulmonary resuscitation quality and mechanical device deployment metrics, and non-technical skill performance. Outcomes were assessed using video recordings of the test scenario. RESULTS: In relation to the primary outcome of chest compression flow fraction in the minute preceding the first mechanical chest compression, we found that pit-crew training was not superior to standard training (0.76 (95% CI 0.73 to 0.79) vs 0.77 (95% CI 0.73 to 0.82), mean difference -0.01 (95% CI -0.06 to 0.03), P=0.572). There was also no difference between groups in performance in relation to any secondary outcome. CONCLUSIONS: Pit-crew training, compared with standard training, did not improve team deployment of a mechanical chest device in a simulated cardiac arrest scenario. TRIAL REGISTRATION NUMBER: ISRCTN43049287; Pre-results. PMID- 29391380 TI - Protein-enriched, milk-based supplement to counteract sarcopenia in acutely ill geriatric patients offered resistance exercise training during and after hospitalisation: study protocol for a randomised, double-blind, multicentre trial. AB - INTRODUCTION: Age-related loss of muscle mass and strength, sarcopaenia, burdens many older adults. The process is accelerated with bed rest, protein intakes below requirements and the catabolic effect of certain illnesses. Thus, acutely ill, hospitalised older adults are particularly vulnerable. Protein supplementation can preserve muscle mass and/or strength and, combining this with resistance exercise training (RT), may have additional benefits. Therefore, this study investigates the effect of protein supplementation as an addition to offering RT among older adults while admitted to the geriatric ward and after discharge. This has not previously been investigated. METHODS AND ANALYSIS: In a block-randomised, double-blind, multicentre intervention study, 165 older adults above 70 years, fulfilling the eligibility criteria, will be included consecutively from three medical departments (blocks of n=20, stratified by recruitment site). After inclusion, participants will be randomly allocated (1:1) to receive either ready-to-drink, protein-enriched, milk-based supplements (a total of 27.5 g whey protein/day) or isoenergetic placebo products (<1.5 g protein/day), twice daily as a supplement to their habitual diet. Both groups will be offered a standardised RT programme for lower extremity muscle strength (daily while hospitalised and 4*/week after discharge). The study period starts during their hospital stay and continues 12 weeks after discharge. The primary endpoint is lower extremity muscle strength and function (30 s chair-stand-test). Secondary endpoints include muscle mass, measures of physical function and measures related to cost-effectiveness. ETHICS AND DISSEMINATION: Approval is given by the Research Ethic Committee of the Capital Region of Denmark (reference no. H-16018240) and the Danish Data Protection Agency (reference no. HGH-2016 050). There are no expected risks associated with participation, and each participant is expected to benefit from the RT. Results will be published in peer reviewed international journals and presented at national and international congresses and symposiums. TRIAL REGISTRATION NUMBER: NCT02717819 (9 March 2016). PMID- 29391381 TI - Investigation of the conditions affecting the joining of Hungarian hospitals to an accreditation programme: a cross-sectional study. AB - OBJECTIVE: Quantitative studies have shown the various benefits for having accreditation in hospitals. However, neither of these explored the general conditions before applying for an accreditation. To close this gap, this study aimed to investigate the possible association between joining an accreditation programme with various hospital characteristics. DESIGN: A cross-sectional study was implemented using the databases of the 2013 Hungarian hospital survey and of the Hungarian State Treasury. SETTING: Public general hospitals in Hungary. PARTICIPANTS: The analysis involved 44 public general hospitals, 14 of which joined the preparatory project for a newly developed accreditation programme. MAIN OUTCOME MEASURES: The outcomes included the percentage of compliance in quality management, patient information and identification, internal professional regulation, safe surgery, pressure sore prevention, infection control, the opinions of the heads of quality management regarding the usefulness of quality management and clinical audits, and finally, the total debt of the hospital per bed and per discharged patient. RESULTS: According to our findings, the general hospitals joining the preparatory project of the accreditation programme performed better in four of the six investigated activities, the head of quality management had a better opinion on the usefulness of quality management, and both the debt per bed number and the debt per discharged patient were lower than those who did not join. However, no statistically significant differences between the two groups were found in any of the examined outcomes. CONCLUSIONS: The findings suggest that hospitals applying for an accreditation programme do not differ significantly in characteristics from those which did not apply. This means that if in the future the accredited hospitals become better than other hospitals, then the improvement could be solely contributed to the accreditation. PMID- 29391383 TI - Feasibility study to assess the impact of a lifestyle intervention ('LivingWELL') in people having an assessment of their family history of colorectal or breast cancer. AB - OBJECTIVES: To assess the feasibility of delivering and evaluating a weight management (WM) programme for overweight patients with a family history (FH) of breast cancer (BC) or colorectal cancer (CRC). STUDY DESIGN: A two-arm (intervention vs usual care) randomised controlled trial. SETTING: National Health Service (NHS) Tayside and NHS Grampian. PARTICIPANTS: People with a FH of BC or CRC aged>=18 years and body mass index of >=25 kg/m2 referred to NHS genetic services. INTERVENTION: Participants were randomised to a control (lifestyle booklet) or 12-week intervention arm where they were given one face-to face counselling session, four telephone consultations and web-based support. A goal of 5% reduction in body weight was set, and a personalised diet and physical activity (PA) programme was provided. Behavioural change techniques (motivational interviewing, action and coping plans and implementation intentions) were used. PRIMARY OUTCOME: Feasibility measures: recruitment, programme implementation, fidelity measures, achieved measurements and retention, participant satisfaction assessed by questionnaire and qualitative interviews. SECONDARY OUTCOMES: Measured changes in weight and PA and reported diet and psychosocial measures between baseline and 12-week follow-up. RESULTS: Of 480 patients approached, 196 (41%) expressed interest in the study, and of those, 78 (40%) patients were randomised. Implementation of the programme was challenging within the time allotted and fidelity to the intervention modest (62%). Qualitative findings indicated the programme was well received. Questionnaires and anthropometric data were completed by >98%. Accelerometer data were attained by 84% and 54% at baseline and follow-up, respectively. Retention at 12 weeks was 76%. Overall, 36% of the intervention group (vs 0% in control) achieved 5% weight loss. Favourable increases in PA and reduction in dietary fat were also reported. CONCLUSIONS: A lifestyle programme for people with a family history of cancer is feasible to conduct and acceptable to participants, and indicative results suggest favourable outcomes. TRIAL REGISTRATION NUMBER: ISRCTN13123470; Pre-results. PMID- 29391382 TI - Identification of new biomarkers to promote personalised treatment of patients with inflammatory rheumatic disease: protocol for an open cohort study. AB - INTRODUCTION: The introduction of biological disease-modifying antirheumatic drugs (bDMARDs) has improved the treatment of inflammatory rheumatic diseases dramatically. However, bDMARD treatment failure occurs in 30%-40% of patients due to lack of effect or adverse events, and the tools to predict treatment outcomes in individual patients are currently limited. The objective of the present study is to identify diagnostic, prognostic and predictive biomarkers, which can be used to (1) diagnose inflammatory rheumatic diseases early in the disease course with high sensitivity and specificity, (2) improve prognostication or (3) predict and monitor treatment effectiveness and tolerability for the individual patient. METHODS AND ANALYSIS: The present study is an observational and translational open cohort study with prospective collection of clinical data and biological materials (primarily blood) in patients with inflammatory rheumatic diseases treated in routine care. Patients contribute with one cross-sectional blood sample and/or are enrolled for longitudinal follow-up on initiation of a new DMARD (blood sampling after 0, 3, 6, 12, 24, 36, 48, 60 months of treatment). Other biological materials will be collected when accessible and relevant. Demographics, disease characteristics, comorbidities and lifestyle factors are registered at inclusion; DMARD treatment and outcomes are collected repeatedly during follow-up. Currently (July 2017), >5000 samples from approximately 3000 patients have been collected. Data will be analysed using appropriate statistical analyses. ETHICS AND DISSEMINATION: The protocol is approved by the Danish Ethics Committee and the Danish Data Protection Agency. Participants give written and oral informed consent. Biomarkers will be evaluated and published according to the Reporting Recommendations for Tumour Marker (REMARK) prognostic studies, Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. Results will be published in peer-reviewed scientific journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03214263. PMID- 29391384 TI - Socioeconomic differences in hearing among middle-aged and older adults: cross sectional analyses using the Health Survey for England. AB - BACKGROUND: Hearing loss impacts on cognitive, social and physical functioning. Both hearing loss and hearing aid use vary across population subgroups. We examined whether hearing loss, and reported current hearing aid use among persons with hearing loss, were associated with different markers of socioeconomic status (SES) in a nationally representative sample of community-dwelling middle-aged and older adults. METHODS: Hearing was measured using an audiometric screening device in the Health Survey for England 2014 (3292 participants aged 45 years and over). Hearing loss was defined as >35 dB HL at 3.0 kHz in the better-hearing ear. Using sex-specific logistic regression modelling, we evaluated the associations between SES and hearing after adjustment for potential confounders. RESULTS: 26% of men and 20% of women aged 45 years and over had hearing loss. Hearing loss was higher among men in the lowest SES groups. For example, the multivariable-adjusted odds of hearing loss were almost two times as high for those in the lowest versus the highest income tertile (OR 1.77, 95% CI 1.15 to 2.74). Among those with hearing loss, 30% of men and 27% of women were currently using a hearing aid. Compared with men in the highest income tertile, the multivariable-adjusted odds of using a hearing aid nowadays were lower for men in the middle (OR 0.50, 95% CI 0.25 to 0.99) and the lowest (OR 0.47, 95% CI 0.23 to 0.97) income tertiles. Associations between SES and hearing were weaker or null among women. CONCLUSIONS: While the burden of hearing loss fell highest among men in the lowest SES groups, current hearing aid use was demonstrably lower. Initiatives to detect hearing loss early and increase the uptake and the use of hearing aids may provide substantial public health benefits and reduce socioeconomic inequalities in health. PMID- 29391385 TI - The NICE-GUT trial protocol: a randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children. AB - INTRODUCTION: Diarrhoeal disease is the second leading cause of death in children under 5 years globally, killing 525 000 annually. Australian Aboriginal and Torres Strait Islander (hereafter Aboriginal) children suffer a high burden of disease. Randomised trials in other populations suggest nitazoxanide accelerates recovery for children with Giardia, amoebiasis, Cryptosporidium, Rotavirus and Norovirus gastroenteritis, as well as in cases where no enteropathogens are found. METHODS AND ANALYSIS: This double blind, 1:1 randomised, placebo controlled trial is investigating the impact of oral nitazoxanide on acute gastroenteritis in hospitalised Australian Aboriginal children aged 3 months to <5 years. Dosing is based on age-based dosing. The primary endpoint is the time to resolution of 'significant illness' defined as the time from randomisation to the time of clinical assessment as medically ready for discharge, or to the time of actual discharge from hospital, whichever occurs first. Secondary endpoints include duration of hospitalisation, symptom severity during the period of significant illness and following treatment, duration of rehydration and drug safety. Patients will be followed for medically significant events for 60 days. Analysis is based on Bayesian inference. Subgroup analysis will occur by pathogen type (bacteria, virus or parasite), rotavirus vaccination status, age and illness severity. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Central Australian Human Research Ethics Committee (HREC-14-221) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC2014-2172). Study investigators will ensure that the trial is conducted in accordance with the principles of the Declaration of Helsinki. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. TRIAL REGISTRATION NUMBER: ACTRN12614000381684. PMID- 29391388 TI - A Patient with Left Bundle Branch Block and Persistent Atrial Fibrillation Treated with Cardiac Catheter Ablation and Pharmacologic Cardiac Resynchronization Therapy without the Use of an Implantable Cardiac Device. AB - BACKGROUND Left bundle branch block (LBBB) is associated with atrial fibrillation (AF) and systolic heart failure, which can be treated with cardiac resynchronization therapy (CRT) that includes an implantable cardiac device (ICD). However, in some patients, LBBB may vary with heart rate, and during episodes of AF in LBBB, aberrant ventricular conduction, or wide QRS complex tachycardia (Ashman beats) can occur. This report is a case of LBBB treated with pharmacologic CRT, without the use of an ICD. CASE REPORT A 68-year-old man presented with persistent AF and systolic heart failure. Serial electrocardiograms (ECGs) showed AF and mixed narrow (116 ms) and wide (152 ms) QRS duration of LBBB. Echocardiography showed a left ventricular ejection fraction (LVEF) of 30%. Catheter ablation for AF resulted in the restoration of sinus rhythm. The patient was treated with step-wise decreasing doses of amiodarone, from 200 mg to 75 mg daily, and step-wise increasing doses of bisoprolol, from 3.75 mg to 5.0 mg daily, which effectively slowed heart rate, inhibited aberrant cardiac conduction due to LBBB, reduced the symptoms of heart failure, and improved LVEF to 60%, despite persistent sinus bradycardia and the inability of the heart rate to increase during activity (chronotropic incompetence). CONCLUSIONS This report of a case of AF associated with LBBB shows that pharmacologic CRT can restore sinus rhythm following catheter ablation and can reduce heart rate and treat heart failure without the use of an ICD. PMID- 29391387 TI - The Preciseness in Diagnosing Thyroid Malignant Nodules Using Shear-Wave Elastography. AB - Our study aimed to identify more accurate results about the diagnostic role of shear-wave elastography (SWE) for thyroid malignant nodules through a meta analysis. Potential articles were searched in PubMed, Embase, and the Cochrane Library databases. Overall sensitivity and specificity with 95% confidence intervals (CIs) was used to represent the diagnostic accuracy of SWE. Summary receiver operating characteristic (ROC) curve was constructed to illustrate the results. In addition, chi2 and I2 tests were performed to assess heterogeneity. A value of p<=0.05 indicated significant heterogeneity. All the analysis was conducted in Meta-DiSc version 1.4 software. Twenty studies were included in the analysis. There were a total of 2,907 patients and 3,397 thyroid nodules included in the meta-analysis. Overall sensitivity and specificity were 0.68 (95% CI: 0.66 0.70) and 0.85 (95% CI: 0.84-0.87), respectively. The results showed the area under curve (AUC) was 0.9041, suggesting high accuracy of SWE for differentiating benign and malignant thyroid nodules. SWE showed high accuracy in identifying thyroid malignant nodules, suggesting it could serve as a diagnostic biomarker in thyroid nodules. PMID- 29391389 TI - Does Enteric Conversion Affect Graft Survival After Pancreas Transplantation with Bladder Drainage? AB - BACKGROUND Although bladder drainage is effective for monitoring urine amylase levels to detect graft rejection, enteric drainage is performed more frequently. The optimal method for monitoring pancreatic enzyme secretions remains unclear. We investigated graft survival in recipients of bladder drainage and assessed the risk of graft rejection and failure after enteric conversion. MATERIAL AND METHODS From January 1999 to October 2015, we performed 318 pancreas transplantations at our institution. We enrolled 180 recipients who underwent pancreas transplantation with bladder drainage (82 underwent enteric conversion and the rest did not). RESULTS The mean interval between pancreas transplantation and enteric conversion was 20+/-24 months. The graft survival rate was significantly higher in the enteric conversion group for 10 years after pancreas transplantation than in the maintain bladder drainage group. After enteric conversion, 14 recipients lost graft function. The interval between enteric conversion and graft failure was 43+/-26 months. In the enteric conversion group, immediate postoperative thromboembolectomy (HR=12.729, p=0.000), renal failure (HR=5.710, p=0.005), pancreas graft rejection after EC (HR=19.006, p=0.000), and delayed graft function (HR=7.021, p=0.001) had a significant relationship with graft failure. CONCLUSIONS Enteric conversion can be safe and effective for improving short- and long-term graft survival if performed after approximately 9 months. Caution should be exercised with enteric conversion if recipients have a history of thromboembolectomy, delayed graft function, or renal failure. PMID- 29391390 TI - Ulk4 regulates GABAergic signaling and anxiety-related behavior. AB - Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4 +/tm1a mice, demonstrating that Ulk4 +/tm1a mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4 +/tm1a mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67+ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4 +/tm1a mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments. PMID- 29391391 TI - A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. AB - Schizophrenia is a debilitating neuropsychiatric illness that is characterized by positive, negative, and cognitive symptoms. Research over the past two decades suggests that the nociceptin receptor system may be involved in domains affected in schizophrenia, based on evidence aligning it with hallmark features of the disorder. First, aberrant glutamatergic and striatal dopaminergic function are associated with psychotic symptoms, and the nociceptin receptor system has been shown to regulate dopamine and glutamate transmission. Second, stress is a critical risk factor for first break and relapse in schizophrenia, and evidence suggests that the nociceptin receptor system is also directly involved in stress modulation. Third, cognitive deficits are prevalent in schizophrenia, and the nociceptin receptor system has significant impact on learning and working memory. Last, reward processing is disrupted in schizophrenia, and nociceptin signaling has been shown to regulate reward cue salience. These findings provide the foundation for the involvement of the nociceptin receptor system in the pathophysiology of schizophrenia and outline the need for future research into this system. PMID- 29391393 TI - Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma. AB - Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) -rs11706832-in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression. PMID- 29391392 TI - A cerebellar mechanism for learning prior distributions of time intervals. AB - Knowledge about the statistical regularities of the world is essential for cognitive and sensorimotor function. In the domain of timing, prior statistics are crucial for optimal prediction, adaptation and planning. Where and how the nervous system encodes temporal statistics is, however, not known. Based on physiological and anatomical evidence for cerebellar learning, we develop a computational model that demonstrates how the cerebellum could learn prior distributions of time intervals and support Bayesian temporal estimation. The model shows that salient features observed in human Bayesian time interval estimates can be readily captured by learning in the cerebellar cortex and circuit level computations in the cerebellar deep nuclei. We test human behavior in two cerebellar timing tasks and find prior-dependent biases in timing that are consistent with the predictions of the cerebellar model. PMID- 29391394 TI - Testing frameworks for personalizing bipolar disorder. AB - The hallmark of bipolar disorder is a clinical course of recurrent manic and depressive symptoms of varying severity and duration. Mathematical modeling of bipolar disorder holds the promise of an ability to personalize diagnoses, to predict future mood episodes, to directly compare diverse datasets, and to link basic mechanisms to behavioral data. Several modeling frameworks have been proposed for bipolar disorder, which represent competing hypothesis about the basic framework of the disorder. Here, we test these hypotheses with self-report assessments of mania and depression symptoms from 178 bipolar patients followed prospectively for 4 or more years. Statistical analysis of the data did not support the hypotheses that mood arises from a rhythmic process or multiple stable states (e.g., mania or depression) or that manic and depressive symptoms are highly anti-correlated. Alternatively, it is shown that bipolar disorder could arise from an inability for mood to quickly return to normal when perturbed. This latter concept is embodied by an affective instability model that can be personalized to the clinical course of any individual with chronic disorders that have an affective component. PMID- 29391395 TI - Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort. AB - Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question "Would you consider yourself a risk taker?" Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders. PMID- 29391396 TI - Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8. AB - Bipolar disorder (BD) is associated with binge eating behavior (BE), and both conditions are heritable. Previously, using data from the Genetic Association Information Network (GAIN) study of BD, we performed genome-wide association (GWA) analyses of BD with BE comorbidity. Here, utilizing data from the Mayo Clinic BD Biobank (969 BD cases, 777 controls), we performed a GWA analysis of a BD subtype defined by BE, and case-only analysis comparing BD subjects with and without BE. We then performed a meta-analysis of the Mayo and GAIN results. The meta-analysis provided genome-wide significant evidence of association between single nucleotide polymorphisms (SNPs) in PRR5-ARHGAP8 and BE in BD cases (rs726170 OR = 1.91, P = 3.05E-08). In the meta-analysis comparing cases with BD with comorbid BE vs. non-BD controls, a genome-wide significant association was observed at SNP rs111940429 in an intergenic region near PPP1R2P5 (p = 1.21E-08). PRR5-ARHGAP8 is a read-through transcript resulting in a fusion protein of PRR5 and ARHGAP8. PRR5 encodes a subunit of mTORC2, a serine/threonine kinase that participates in food intake regulation, while ARHGAP8 encodes a member of the RhoGAP family of proteins that mediate cross-talk between Rho GTPases and other signaling pathways. Without BE information in controls, it is not possible to determine whether the observed association reflects a risk factor for BE in general, risk for BE in individuals with BD, or risk of a subtype of BD with BE. The effect of PRR5-ARHGAP8 on BE risk thus warrants further investigation. PMID- 29391398 TI - Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease. AB - Schizophrenia (SCZ) is a neuropsychiatric disorder with a complex genetic etiology. The redundancy of the gene networks underlying SCZ indicates that many gene combinations have the potential to cause a system dysfunction that can manifest as SCZ or a related neurodevelopmental disorder. Recent studies show that small non-coding microRNA (miRNA) and long non-coding RNA (lncRNA) are important factors in shaping these networks and are dynamically regulated by neuronal activation. We investigated the genome-wide transcription profiles of 46 human amygdala samples obtained from 22 SCZ patients and 24 healthy controls. Using RNA sequencing (RNA-seq), we determined lncRNA expression levels in all samples and generated miRNA profiles for 27 individuals (13 cases and 14 controls). Previous studies have identified differentially expressed miRNAs in SCZ, including miR-132, miR-212, and miR-34a/miR-34c. Here we report differential expression of a novel miRNA, miR1307, in SCZ. Notably, miR1307 maps to a locus previously associated with SCZ through GWAS. Additionally, one lncRNA that was overexpressed in SCZ, AC005009.2, also maps to a region previously associated with SCZ based on GWAS and overlapped SCZ-related genes. The results were replicated in a large independent data set of 254 dorsolateral prefrontal cortex samples from the CommonMind consortium. Taken together, these results suggest that miRNA and lncRNAs are important contributors to the pathogenesis of SCZ. PMID- 29391397 TI - Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. AB - Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative phosphorylation and beta-oxidation and has been proposed as a neuroprotectant. BT and other SCFAs have also been associated with autism spectrum disorders (ASD), a condition associated with mitochondrial dysfunction. We have developed a lymphoblastoid cell line (LCL) model of ASD, with a subset of LCLs demonstrating mitochondrial dysfunction (AD-A) and another subset of LCLs demonstrating normal mitochondrial function (AD-N). Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. To this end, we measured mitochondrial function in ASD and age-matched control (CNT) LCLs, all derived from boys, following 24 and 48 h exposure to BT (0, 0.1, 0.5, and 1 mM) both with and without an in vitro increase in reactive oxygen species (ROS). We also examined the expression of key genes involved in cellular and mitochondrial response to stress. In CNT LCLs, respiratory parameters linked to adenosine triphosphate (ATP) production were attenuated by 1 mM BT. In contrast, BT significantly increased respiratory parameters linked to ATP production in AD-A LCLs but not in AD-N LCLs. In the context of ROS exposure, BT increased respiratory parameters linked to ATP production for all groups. BT was found to modulate individual LCL mitochondrial respiration to a common set-point, with this set-point slightly higher for the AD-A LCLs as compared to the other groups. The highest concentration of BT (1 mM) increased the expression of genes involved in mitochondrial fission (PINK1, DRP1, FIS1) and physiological stress (UCP2, mTOR, HIF1alpha, PGC1alpha) as well as genes thought to be linked to cognition and behavior (CREB1, CamKinase II). These data show that the enteric microbiome derived SCFA BT modulates mitochondrial activity, with this modulation dependent on concentration, microenvironment redox state, and the underlying mitochondrial function of the cell. In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings. PMID- 29391399 TI - Stress hormone response to the DEX-CRH test and its relation to psychotherapy outcome in panic disorder patients with and without agoraphobia. AB - This study tested whether the hormonal stress response to the DEX-CRH test may be predictive of the psychotherapy success for panic disorder (PD). Thirty-four patients diagnosed either with agoraphobia with PD or PD without agoraphobia were subjected to cognitive behavioural therapy (CBT). Patients (pre-therapy) and healthy volunteers were exposed to the DEX-CRH test. Blood samples were taken for cortisol and adrenocorticotropic hormone (ACTH) assessment. Established panic specific questionnaires were handed out for the pre-therapy and post-therapy evaluation of disease severity (with reference to panic beliefs and agoraphobic cognitions, fear of bodily sensations, agoraphobic avoidance behaviour). Repeated measures ANCOVA were conducted for the analysis of the pre-therapy hormonal response, and Pearson's correlation analysis to test for associations with the psychotherapy outcome. Data analyses revealed large effect sizes for CBT in the clinical measures (eta2 >= 0.321), main effects of time for cortisol and ACTH with no differences between both groups, and significant associations between cortisol release and agoraphobic cognitions for the patients. PD diagnosis had no impact on the hormonal response. However, those patients with higher cortisol release showed less improvement after CBT (significantly for agoraphobic cognitions). Clinical implications of these findings are the prediction of the therapy success from a potential endocrine correlate whose persistency (if assessed repeatedly) during the treatment may predict (non-)response to the current treatment, possibly representing a decision support for a change in treatment to avoid the continuation of an inefficient treatment. PMID- 29391400 TI - Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder. AB - Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene. PMID- 29391401 TI - Silicon based mid-IR super absorber using hyperbolic metamaterial. AB - Perfect absorbers are indispensable components for energy harvesting applications. While many absorbers have been proposed, they encounter inevitable drawbacks including bulkiness or instability over time. The urge for CMOS compatible absorber that can be integrated for on chip applications requires further investigation. We theoretically demonstrate Silicon (Si) based mid IR super absorber with absorption (A) reaching 0.948. Our structure is composed of multilayered N-doped Si/ Si hyperbolic metamaterial (HMM) integrated with sub hole Si grating. Our proposed structure has tunable absorption peak that can be tuned from 4.5 um to 11 um through changing the grating parameters. We also propose two grating designs integrated with N-doped Si/ Si HMM that can achieve wide band absorption. The first grating design is based on Si grating incorporating different holes' height with (A) varying between 0.83 and 0.97 for wavelength from 5 um to 7 um. The second grating design is based on Si grating with variable holes' diameter; the latter shows broad band absorption with the maximum (A) reaching 0.97. We also show that our structure is omnidirectional. We propose an all Si based absorber which demonstrates a good candidate for thermal harvesting application. PMID- 29391402 TI - Differentiated surface fungal communities at point of harvest on apple fruits from rural and peri-urban orchards. AB - The diverse fungal communities that colonize fruit surfaces are closely associated with fruit development, preservation and quality control. However, the overall fungi adhering to the fruit surface and the inference of environmental factors are still unknown. Here, we characterized the fungal signatures on apple surfaces by sequencing internal transcribed spacer 1 (ITS1) region. We collected the surface fungal communities from apple fruits cultivated in rural and peri urban orchards. A total of 111 fungal genera belonging to 4 phyla were identified, showing remarkable fungal diversity on the apple surface. Comparative analysis of rural samples harboured higher fungal diversity than those from peri urban orchards. In addition, fungal composition varied significantly across apple samples. At the genus level, the protective genera Coniothyrium, Paraphaeosphaeria and Periconia were enriched in rural samples. The pathogenic genera Acremonium, Aspergillus, Penicillium and Tilletiposis were enriched in peri-urban samples. Our findings indicate that rural samples maintained more diverse fungal communities on apple surfaces, whereas peri-urban-planted apple carried potential pathogenic risks. This study sheds light on ways to improve fruit cultivation and disease prevention practices. PMID- 29391403 TI - The membrane tethered transcription factor EcbZIP17 from finger millet promotes plant growth and enhances tolerance to abiotic stresses. AB - The occurrence of various stresses, as the outcome of global climate change, results in the yield losses of crop plants. Prospecting of genes in stress tolerant plant species may help to protect and improve their agronomic performance. Finger millet (Eleusine coracana L.) is a valuable source of superior genes and alleles for stress tolerance. In this study, we isolated a novel endoplasmic reticulum (ER) membrane tethered bZIP transcription factor from finger millet, EcbZIP17. Transgenic tobacco plants overexpressing this gene showed better vegetative growth and seed yield compared with wild type (WT) plants under optimal growth conditions and confirmed upregulation of brassinosteroid signalling genes. Under various abiotic stresses, such as 250 mM NaCl, 10% PEG6000, 400 mM mannitol, water withdrawal, and heat stress, the transgenic plants showed higher germination rate, biomass, primary and secondary root formation, and recovery rate, compared with WT plants. The transgenic plants exposed to an ER stress inducer resulted in greater leaf diameter and plant height as well as higher expression of the ER stress-responsive genes BiP, PDIL, and CRT1. Overall, our results indicated that EcbZIP17 improves plant growth at optimal conditions through brassinosteroid signalling and provide tolerance to various environmental stresses via ER signalling pathways. PMID- 29391404 TI - Perivascular Spaces Segmentation in Brain MRI Using Optimal 3D Filtering. AB - Perivascular Spaces (PVS) are a feature of Small Vessel Disease (SVD), and are an important part of the brain's circulation and glymphatic drainage system. Quantitative analysis of PVS on Magnetic Resonance Images (MRI) is important for understanding their relationship with neurological diseases. In this work, we propose a segmentation technique based on the 3D Frangi filtering for extraction of PVS from MRI. We used ordered logit models and visual rating scales as alternative ground truth for Frangi filter parameter optimization and evaluation. We optimized and validated our proposed models on two independent cohorts, a dementia sample (N = 20) and patients who previously had mild to moderate stroke (N = 48). Results demonstrate the robustness and generalisability of our segmentation method. Segmentation-based PVS burden estimates correlated well with neuroradiological assessments (Spearman's rho = 0.74, p < 0.001), supporting the potential of our proposed method. PMID- 29391405 TI - Impact of thickness variation on structural, dielectric and piezoelectric properties of (Ba,Ca)(Ti,Zr)O3 epitaxial thin films. AB - It is shown that the dielectric and piezoelectric properties of Ba(Ti0.8Zr0.2)O3 x(Ba0.7Ca0.3)TiO3 (x = 0.45) (BCTZ 45) epitaxial thin films have a nontrivial dependence on film thickness. BCTZ 45 epitaxial films with different thicknesses (up to 400 nm) have been deposited on SrTiO3 by pulsed laser deposition and investigated by different combined techniques: conventional and off-axis X-ray diffraction, high resolution transmission electron microscopy and dielectric and piezoforce microscopy. The changes occurring in epitaxial films when their thickness increases have been attributed to a partial relaxation of misfit strain, driving the induced tetragonal symmetry in very thin films to the original rhombohedral symmetry of the bulk material in the thickest film, which influences directly and indirectly the dielectric and piezoelectric properties. PMID- 29391406 TI - Advanced Steel Microstructural Classification by Deep Learning Methods. AB - The inner structure of a material is called microstructure. It stores the genesis of a material and determines all its physical and chemical properties. While microstructural characterization is widely spread and well known, the microstructural classification is mostly done manually by human experts, which gives rise to uncertainties due to subjectivity. Since the microstructure could be a combination of different phases or constituents with complex substructures its automatic classification is very challenging and only a few prior studies exist. Prior works focused on designed and engineered features by experts and classified microstructures separately from the feature extraction step. Recently, Deep Learning methods have shown strong performance in vision applications by learning the features from data together with the classification step. In this work, we propose a Deep Learning method for microstructural classification in the examples of certain microstructural constituents of low carbon steel. This novel method employs pixel-wise segmentation via Fully Convolutional Neural Network (FCNN) accompanied by a max-voting scheme. Our system achieves 93.94% classification accuracy, drastically outperforming the state-of-the-art method of 48.89% accuracy. Beyond the strong performance of our method, this line of research offers a more robust and first of all objective way for the difficult task of steel quality appreciation. PMID- 29391407 TI - Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion. AB - The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa. PMID- 29391409 TI - A Neuro-Musculo-Skeletal Model for Insects With Data-driven Optimization. AB - Simulating the locomotion of insects is beneficial to many areas such as experimental biology, computer animation and robotics. This work proposes a neuro musculo-skeletal model, which integrates the biological inspirations from real insects and reproduces the gait pattern on virtual insects. The neural system is a network of spiking neurons, whose spiking patterns are controlled by the input currents. The spiking pattern provides a uniform representation of sensory information, high-level commands and control strategy. The muscle models are designed following the characteristic Hill-type muscle with customized force length and force-velocity relationships. The model parameters, including both the neural and muscular components, are optimized via an approach of evolutionary optimization, with the data captured from real insects. The results show that the simulated gait pattern, including joint trajectories, matches the experimental data collected from real ants walking in the free mode. The simulated character is capable of moving at different directions and traversing uneven terrains. PMID- 29391408 TI - Grey matter OPCs are less mature and less sensitive to IFNgamma than white matter OPCs: consequences for remyelination. AB - Multiple sclerosis (MS) is a chronic inflammatory disease characterized by the formation of demyelinated lesions in the central nervous system. At later stages of the disease repair in the form of remyelination often fails, which leads to axonal degeneration and neurological disability. For the regeneration of myelin, oligodendrocyte progenitor cells (OPCs) have to migrate, proliferate and differentiate into remyelinating oligodendrocytes. Remyelination occurs faster and is more extensive in grey matter (GM) lesions than in white matter (WM) lesions. Here, we examined differences in neonatal OPCs from GM (gmOPCs) and WM (wmOPCs), both intrinsically and in response to environmental (injury) signals. We show that gmOPCs are less mature than wmOPCs, both on morphological and on gene-expression level. Additionally, gmOPCs proliferate more and differentiate slower than wmOPCs. When exposed to astrocyte-secreted signals wmOPC, but not gmOPC, migration decreases. In addition, wmOPCs are more sensitive to the detrimental effects of IFNgamma treatment on proliferation, differentiation, and process arborisation, which is potentiated by TNFalpha. Our results demonstrate that OPCs from GM and WM differ both intrinsically and in response to their environment, which may contribute to the difference in remyelination efficiency between GM and WM MS lesions. PMID- 29391410 TI - Magnesium prevents vascular calcification in vitro by inhibition of hydroxyapatite crystal formation. AB - Magnesium has been shown to effectively prevent vascular calcification associated with chronic kidney disease. Magnesium has been hypothesized to prevent the upregulation of osteoblastic genes that potentially drives calcification. However, extracellular effects of magnesium on hydroxyapatite formation are largely neglected. This study investigated the effects of magnesium on intracellular changes associated with transdifferentiation and extracellular crystal formation. Bovine vascular smooth muscle cells were calcified using beta glycerophosphate. Transcriptional analysis, alkaline phosphatase activity and detection of apoptosis were used to identify transdifferentiation. Using X-ray diffraction and energy dispersive spectroscopy extracellular crystal composition was investigated. Magnesium prevented calcification in vascular smooth muscle cells. beta-glycerophosphate increased expression of osteopontin but no other genes related to calcification. Alkaline phosphatase activity was stable and apoptosis was only detected after calcification independent of magnesium. Blocking of the magnesium channel TRPM7 using 2-APB did not abrogate the protective effects of magnesium. Magnesium prevented the formation of hydroxyapatite, which formed extensively during beta-glycerophosphate treatment. Magnesium reduced calcium and phosphate fractions of 68% and 41% extracellular crystals, respectively, without affecting the fraction of magnesium. This study demonstrates that magnesium inhibits hydroxyapatite formation in the extracellular space, thereby preventing calcification of vascular smooth muscle cells. PMID- 29391411 TI - The "weak" interdependence of infrastructure systems produces mixed percolation transitions in multilayer networks. AB - Previous studies of multilayer network robustness model cascading failures via a node-to-node percolation process that assumes "strong" interdependence across layers-once a node in any layer fails, its neighbors in other layers fail immediately and completely with all links removed. This assumption is not true of real interdependent infrastructures that have emergency procedures to buffer against cascades. In this work, we consider a node-to-link failure propagation mechanism and establish "weak" interdependence across layers via a tolerance parameter alpha which quantifies the likelihood that a node survives when one of its interdependent neighbors fails. Analytical and numerical results show that weak interdependence produces a striking phenomenon: layers at different positions within the multilayer system experience distinct percolation transitions. Especially, layers with high super degree values percolate in an abrupt manner, while those with low super degree values exhibit both continuous and discontinuous transitions. This novel phenomenon we call mixed percolation transitions has significant implications for network robustness. Previous results that do not consider cascade tolerance and layer super degree may be under- or over-estimating the vulnerability of real systems. Moreover, our model reveals how nodal protection activities influence failure dynamics in interdependent, multilayer systems. PMID- 29391412 TI - The paxillin-plectin-EPLIN complex promotes apical elimination of RasV12 transformed cells by modulating HDAC6-regulated tubulin acetylation. AB - Recent studies have revealed that newly emerging RasV12-transformed cells are often apically extruded from the epithelial layer. During this cancer preventive process, cytoskeletal proteins plectin and Epithelial Protein Lost In Neoplasm (EPLIN) are accumulated in RasV12 cells that are surrounded by normal cells, which positively regulate the apical elimination of transformed cells. However, the downstream regulators of the plectin-EPLIN complex remain to be identified. In this study, we have found that paxillin binds to EPLIN specifically in the mix culture of normal and RasV12-transformed cells. In addition, paxillin is accumulated in RasV12 cells surrounded by normal cells. Paxillin, plectin and EPLIN mutually influence their non-cell-autonomous accumulation, and paxillin plays a crucial role in apical extrusion of RasV12 cells. We also demonstrate that in RasV12 cells surrounded by normal cells, acetylated tubulin is accumulated. Furthermore, acetylation of tubulin is promoted by paxillin that suppresses the activity of histone deacetylase (HDAC) 6. Collectively, these results indicate that in concert with plectin and EPLIN, paxillin positively regulates apical extrusion of RasV12-transformed cells by promoting microtubule acetylation. This study shed light on the unexplored events occurring at the initial stage of carcinogenesis and would potentially lead to a novel type of cancer preventive medicine. PMID- 29391413 TI - The Effect of a Slowly Rocking Bed on Sleep. AB - Rocking movements appear to affect human sleep. Recent research suggested a facilitated transition from wake to sleep and a boosting of slow oscillations and sleep spindles due to lateral rocking movements during an afternoon nap. This study aimed at investigating the effect of vestibular stimulation on sleep onset, nocturnal sleep and its potential to increase sleep spindles and slow waves, which could influence memory performance. Polysomnography was recorded in 18 males (age: 20-28 years) during three nights: movement until sleep onset (C1), movement for 2 hours (C2), and one baseline (B) without motion. Sleep dependent changes in memory performance were assessed with a word-pair learning task. Although subjects preferred nights with vestibular stimulation, a facilitated sleep onset or a boost in slow oscillations was not observed. N2 sleep and the total number of sleep spindles increased during the 2 h with vestibular stimulation (C2) but not over the entire night. Memory performance increased over night but did not differ between conditions. The lack of an effect might be due to the already high sleep efficiency (96%) and sleep quality of our subjects during baseline. Nocturnal sleep in good sleepers might not benefit from the potential facilitating effects of vestibular stimulation. PMID- 29391414 TI - Design and synthesis of coumarin-based organoselenium as a new hit for myeloprotection and synergistic therapeutic efficacy in adjuvant therapy. AB - A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.o. in concomitant and pretreatment schedules with carboplatin (12 mg/kg b.wt, i.p. for 10 days) in female Swiss albino mouse. MUS treatment reduced (P < 0.001) the percentage of chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in murine bone marrow cells and also enhanced (P < 0.001) the bone marrow cell proliferation of the carboplatin-treated mice. These activities cumulatively restored the viable bone marrow cell count towards normalcy. Myeloprotection by MUS was achieved, in part, due to a significant reduction in the ROS/RNS formation and restoration of glutathione redox pool. Additionally, MUS synergistically enhanced the cytotoxicity of carboplatin against two human cancer cell lines (MCF-7 and Colo-205). Furthermore, MUS can effectively potentiate the antitumour activity of carboplatin against two murine cancers (Dalton's Lymphoma and Sarcoma-180) in vivo. These preclinical findings clearly indicate that MUS can improve the therapeutic index of carboplatin and ensures more effective therapeutic strategy against cancer for clinical development. PMID- 29391415 TI - Expression and specificity of a chitin deacetylase from the nematophagous fungus Pochonia chlamydosporia potentially involved in pathogenicity. AB - Chitin deacetylases (CDAs) act on chitin polymers and low molecular weight oligomers producing chitosans and chitosan oligosaccharides. Structurally defined, partially deacetylated chitooligosaccharides produced by enzymatic methods are of current interest as bioactive molecules for a variety of applications. Among Pochonia chlamydosporia (Pc) annotated CDAs, gene pc_2566 was predicted to encode for an extracellular CE4 deacetylase with two CBM18 chitin binding modules. Chitosan formation during nematode egg infection by this nematophagous fungus suggests a role for their CDAs in pathogenicity. The P. chlamydosporia CDA catalytic domain (PcCDA) was expressed in E. coli BL21, recovered from inclusion bodies, and purified by affinity chromatography. It displays deacetylase activity on chitooligosaccharides with a degree of polymerization (DP) larger than 3, generating mono- and di-deacetylated products with a pattern different from those of closely related fungal CDAs. This is the first report of a CDA from a nematophagous fungus. On a DP5 substrate, PcCDA gave a single mono-deacetylated product in the penultimate position from the non reducing end (ADAAA) which was then transformed into a di-deacetylated product (ADDAA). This novel deacetylation pattern expands our toolbox of specific CDAs for biotechnological applications, and will provide further insights into the determinants of substrate specificity in this family of enzymes. PMID- 29391416 TI - Comparative transcriptome analysis reveals molecular response to salinity stress of salt-tolerant and sensitive genotypes of indica rice at seedling stage. AB - Abiotic stresses, such as salinity, greatly threaten the growth and productivity of plants. Rice (Oryza sativa L.) is one of the most important food crops, as well as a monocot model for genomic research. To obtain a global view of the molecular response to salinity stress, we conducted a leaf transcriptome analysis on rice seedlings. Two cultivars of rice subspecies indica, including the salt tolerant genotype Xian156 and the salt-sensitive genotype IR28, were used in the present study. Eighteen RNA libraries were obtained from these two genotypes at three timepoints (0 h, 48 h and 72 h) after applying salinity stress. We obtained the reference-guided assembly of the rice transcriptome, which resulted in 1,375 novel genes, including 1,371 annotated genes. A comparative analysis between genotypes and time points showed 5,273 differentially expressed genes (DEGs), of which 286 DEGs were only found in the tolerant genotype. The Disease resistance response protein 206 and TIFY 10 A were differentially expressed, which were validated by quantitative real-time PCR. The differentially expressed genes identified through the mRNA transcriptome, along with the structure, provide a revealing insight into rice molecular response to salinity stress and underlie the salinity tolerance mechanism between genotypes. PMID- 29391417 TI - Terahertz Dispersion Characteristics of Super-aligned Multi-walled Carbon Nanotubes and Enhanced Transmission through Subwavelength Apertures. AB - The terahertz (THz) dielectric properties of super-aligned multi-walled carbon nanotube (MWCNT) films were characterized in the frequency range from 0.1 to 2.5 THz with terahertz time-domain spectroscopy. The refractive index, effective permittivity, and conductivity were retrieved from the measured transmission spectra with THz incident wave polarized parallel and perpendicular to the orientation of carbon nanotubes (CNTs), and a high degree of polarization dependence was observed. The Drude-Lorentz model combined with Maxwell-Garnett effective medium theory was employed to explain the experimental results, revealing an obvious metallic behavior of the MWCNT films. Moreover, rectangular aperture arrays were patterned on the super-aligned MWCNT films with laser machining techniques, and the transmission measurement demonstrated an extraordinarily enhanced transmission characteristic of the samples with incident wave polarized parallel to the orientation of the CNTs. Surface plasmon polaritons were employed to explain the extraordinarily enhanced transmission with high accuracy, and multi-order Fano profile was applied to model the transmission spectra. A high degree of agreement was exhibited among the experimental, numerical, and theoretical results. PMID- 29391418 TI - Hypomagnesemia and clinical benefits of anti-EGFR monoclonal antibodies in wild type KRAS metastatic colorectal cancer: a systematic review and meta-analysis. AB - Hypomagnesemia is a recognized side-effect of cetuximab- or panitumumab-based chemotherapy for metastatic colorectal cancer (mCRC). The clinical relevance of hypomagnesemia is under debate. Thus, a systematic review and meta-analysis of retrospective studies and randomized clinical trials (RCTs) comparing hypomagnesemia with normal magnesium levels in wild-type KRAS mCRC was performed. One RCT, two retrospective studies, and two American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) conference presentations from phase III RCTs involving 1723 patients were included in this study. Patients with hypomagnesemia demonstrated better progression-free survival (PFS) (Hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.47-0.88), overall survival (OS) (HR: 0.72; 95% CI: 0.53-0.92), and objective response rate (ORR) (Risk ratio [RR]: 1.81; 95% confidence interval [CI]: 1.30-2.52). By subgroup analysis, frontline, later lines or combination therapy with hypomagnesemia were associated with PFS benefits (HR: 0.78; 95% CI: 0.62-0.98; HR: 0.60; 95% CI: 0.40-0.90; HR: 0.62; 95% CI: 0.41-0.94, respectively). In patients with wild-type KRAS mCRC, hypomagnesemia is associated with better clinical benefits of PFS, OS and ORR when treated with cetuximab- or panitumumab-based chemotherapy. Future clinical trials should corroborate its predictive role. PMID- 29391419 TI - Thermally-triggered Dual In-situ Self-healing Metallic Materials. AB - The microstructural evolution and crack filling phenomena of (Al81Cu13Si6)100 x(Sn57Bi43) x (x = 0, 1, and 3 at.%) composites was investigated. The Sn and Bi elements were selected by considering the ability for liquid phase separation when combined with Al, Cu, and Si. Because of liquid phase separation, both Al-Cu Si-rich L1 and Sn-Bi-rich L2 phases separately solidified at different temperatures yielding a trimodal eutectic structure in the cast alloys. The Sn and Bi elements have high mobilities due to the large interface of the eutectic microstructure and tend to strongly diffuse towards higher strained region during heat treatment. Furthermore, the mobile Sn and Bi elements in the Al-Cu-Si-based bimodal eutectic structure evidently fill cracks during warm rolling at 423 K. These results reveal that the developed alloy system has simultaneously dual self healing characteristics, derived from the both precipitated Sn-Bi-rich particles and low melting agent, and the proposed alloy design based on liquid phase separation provides a novel strategy for creating self-crack filling metallic materials. PMID- 29391420 TI - Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression. AB - One of the causal genes for holoprosencephaly (HPE) is ZIC2 (HPE5). It belongs to the zinc finger protein of the cerebellum (Zic) family of genes that share a C2H2 type zinc finger domain, similar to the GLI family of genes. In order to clarify the role of Zic2 in gene regulation, we searched for its direct target genes using chromatin immunoprecipitation (ChIP). We identified TGIF1 (HPE4), another holoprosencephaly-causative gene in humans. We identified Zic2-binding sites (ZBS) on the 5' flanking region of Tgif1 by in vitro DNA binding assays. ZBS were essential for Zic2-dependent transcriptional activation in reporter gene assays. Zic2 showed a higher affinity to ZBS than GLI-binding sequences. Zic2-binding to the cis-regulatory element near the Tgif1 promoter may be involved in the mechanism underlying forebrain development and incidences of HPE. PMID- 29391421 TI - Mapping Monthly Water Scarcity in Global Transboundary Basins at Country-Basin Mesh Based Spatial Resolution. AB - Currently fresh water scarcity is an issue with huge socio-economic and environmental impacts. Transboundary river and lake basins are among the sources of fresh water facing this challenge. Previous studies measured blue water scarcity at different spatial and temporal resolutions. But there is no global water availability and footprint assessment done at country-basin mesh based spatial and monthly temporal resolutions. In this study we assessed water scarcity at these spatial and temporal resolutions. Our results showed that around 1.6 billion people living within the 328 country-basin units out of the 560 we assessed in this study endures severe water scarcity at least for a month within the year. In addition, 175 country-basin units goes through severe water scarcity for 3-12 months in the year. These sub-basins include nearly a billion people. Generally, the results of this study provide insights regarding the number of people and country-basin units experiencing low, moderate, significant and severe water scarcity at a monthly temporal resolution. These insights might help these basins' sharing countries to design and implement sustainable water management and sharing schemes. PMID- 29391422 TI - Toxicity assessment of chlorpyrifos-degrading fungal bio-composites and their environmental risks. AB - Bioremediation techniques coupling with functional microorganisms have emerged as the most promising approaches for in-situ elimination of pesticide residue. However, the environmental safety of bio-products based on microorganisms or engineered enzymes was rarely known. Here, we described the toxicity assessment of two previously fabricated fungal bio-composites which were used for the biodegradation of chlorpyrifos, to clarify their potential risks on the environment and non-target organisms. Firstly, the acute and chronic toxicity of prepared bio-composites were evaluated using mice and rabbits, indicating neither acute nor chronic effect was induced via short-term or continuous exposure. Then, the acute mortality on zebrafish was investigated, which implied the application of fungal bio-composites had no lethal risk on aquatic organisms. Meanwhile, the assessment on soil organic matters suggested that no threat was posed to soil quality. Finally, by monitoring, the germination of cabbage was not affected by the exposure to two bio-products. Therefore, the application of fungal bio composites for chlorpyrifos elimination cannot induce toxic risk to the environment and non-target organisms, which insured the safety of these engineered bio-products for realistic management of pesticide residue, and provided new insights for further development of bioremediation techniques based on functional microorganisms. PMID- 29391423 TI - All Sequential Dip-Coating Processed Perovskite Layers from an Aqueous Lead Precursor for High Efficiency Perovskite Solar Cells. AB - A novel, sequential method of dip-coating a ZnO covered mesoporous TiO2 electrode was performed using a non-halide lead precursor in an aqueous system to form a nanoscale perovskite film. The introduction of a ZnO interfacial layer induced significant adsorption in the non-halide lead precursor system. An efficient successive solid-state ion exchange and reaction process improved the morphology, crystallinity, and stability of perovskite solar cells. Improved surface coverage was achieved using successive ionic layer adsorption and reaction processes. When all sequential dipping conditions were controlled, a notable power conversion efficiency of 12.41% under standard conditions (AM 1.5, 100 mW.cm-2) was achieved for the perovskite solar cells fabricated from an aqueous non-halide lead precursor solution without spin-casting, which is an environmentally benign and low-cost manufacturing processes. PMID- 29391424 TI - Large-scale intact glycopeptide identification by Mascot database search. AB - Workflows capable of determining glycopeptides in large-scale are missing in the field of glycoproteomics. We present an approach for automated annotation of intact glycopeptide mass spectra. The steps in adopting the Mascot search engine for intact glycopeptide analysis included: (i) assigning one letter codes for monosaccharides, (ii) linearizing glycan sequences and (iii) preparing custom glycoprotein databases. Automated annotation of both N- and O-linked glycopeptides was proven using standard glycoproteins. In a large-scale study, a total of 257 glycoproteins containing 970 unique glycosylation sites and 3447 non redundant N-linked glycopeptide variants were identified in 24 serum samples. Thus, a single tool was developed that collectively allows the (i) elucidation of N- and O-linked glycopeptide spectra, (ii) matching glycopeptides to known protein sequences, and (iii) high-throughput, batch-wise analysis of large-scale glycoproteomics data sets. PMID- 29391425 TI - Spatial and temporal evolution of natural and anthropogenic dust events over northern China. AB - Mineral dust interacts with radiation and cloud microphysics in East Asia can affect local and regional climate. In this study, we found that the occurrences of dust storms, blowing dust, and floating dust over northern China has decreased 76.7%, 68.5%, and 64.5% considerably since the beginning of this century. Based on a multi-dimensional ensemble empirical mode decomposition (MEEMD) method, a steady decrease in zonal maximum wind speed (up to -0.95 m/s) in the Northern Hemisphere was largely responsible for this recent decline in dust event occurrences. Then, a new detection technique that combines multi-satellite datasets with surface observations of dust events is developed to estimate the contribution of anthropogenic dust column burden from disturbed soils to the observed total dust. It is found that the percentage of the anthropogenic dust column burdens to total mineral dust is up to 76.8% by human activities during 2007-2014 in eastern China, but only less than 9.2% near desert source regions in northwestern China. However, we note that the anthropogenic effects on the dust loading for both regions are non-negligible. PMID- 29391426 TI - Prevalence and Risk Factors of self-reported dry eye in Brazil using a short symptom questionnaire. AB - To evaluate dry eye prevalence and investigate associated risk factors in Brazil by applying a short questionnaire of symptoms and risk factors. A cross-sectional study of 3,107 participants from all the five different geopolitical regions of Brazil. Overall prevalence of dry eye in this study population was 12.8%. Dry eye previous diagnosis was reported by 10.2% and presence of severe symptoms in 4.9%. Logistic regression analysis confirmed some significantly risk factors, such as female sex (Odds Ratio (OR) 1.74; 95% Confidence Interval (CI): 1.12-1.93), age >=60 year-old (OR 2.00; 95%CI: 1.44-2.77), history of ocular surgery (OR 1.84; 95%CI: 1.30-2.60), contact lens wear (OR 1.93; 95%CI: 1.36-2.73), cancer treatment (OR 3.03; 95%CI: 1.36-6.59), computer use >6 hours per day (OR 1.77; 95%CI: 1.36-2.31), antidepressants (OR 1.61; 95%CI: 1.12-2.31) and anti-allergy (OR 2.11; 95%CI: 1.54-2.89) medications. Nevertheless, when stratified by regions, each one had its own significant factors and inherent characteristics. This is the first study about prevalence and risk factors of dry eye in a large population sample from all regions of Brazil. Dry eye is a common condition in the Brazilian population and prevalence rates varies substantially in the different geographic regions of the country, possibly reflecting climate and socioeconomic discrepancies. PMID- 29391427 TI - Identification of coffee bean varieties using hyperspectral imaging: influence of preprocessing methods and pixel-wise spectra analysis. AB - Hyperspectral imaging was used to identify and to visualize the coffee bean varieties. Spectral preprocessing of pixel-wise spectra was conducted by different methods, including moving average smoothing (MA), wavelet transform (WT) and empirical mode decomposition (EMD). Meanwhile, spatial preprocessing of the gray-scale image at each wavelength was conducted by median filter (MF). Support vector machine (SVM) models using full sample average spectra and pixel wise spectra, and the selected optimal wavelengths by second derivative spectra all achieved classification accuracy over 80%. Primarily, the SVM models using pixel-wise spectra were used to predict the sample average spectra, and these models obtained over 80% of the classification accuracy. Secondly, the SVM models using sample average spectra were used to predict pixel-wise spectra, but achieved with lower than 50% of classification accuracy. The results indicated that WT and EMD were suitable for pixel-wise spectra preprocessing. The use of pixel-wise spectra could extend the calibration set, and resulted in the good prediction results for pixel-wise spectra and sample average spectra. The overall results indicated the effectiveness of using spectral preprocessing and the adoption of pixel-wise spectra. The results provided an alternative way of data processing for applications of hyperspectral imaging in food industry. PMID- 29391428 TI - beta-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation. AB - beta-Sitosterol (BS), a major bioactive constituent present in plants and vegetables has shown potent anticancer effect against many human cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered apoptosis via ROS mediated mitochondrial dysregulation as evidenced by caspase-3 & 9 activation, Annexin V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-alpha, BS induced apoptosis was reduced in A549 cells. Furthermore, BS induced apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers. PMID- 29391430 TI - Historical ecology reveals landscape transformation coincident with cultural development in central Italy since the Roman Period. AB - Knowledge of the direct role humans have had in changing the landscape requires the perspective of historical and archaeological sources, as well as climatic and ecologic processes, when interpreting paleoecological records. People directly impact land at the local scale and land use decisions are strongly influenced by local sociopolitical priorities that change through time. A complete picture of the potential drivers of past environmental change must include a detailed and integrated analysis of evolving sociopolitical priorities, climatic change and ecological processes. However, there are surprisingly few localities that possess high-quality historical, archeological and high-resolution paleoecologic datasets. We present a high resolution 2700-year pollen record from central Italy and interpret it in relation to archival documents and archaeological data to reconstruct the relationship between changing sociopolitical conditions, and their effect on the landscape. We found that: (1) abrupt environmental change was more closely linked to sociopolitical and demographic transformation than climate change; (2) landscape changes reflected the new sociopolitical priorities and persisted until the sociopolitical conditions shifted; (3) reorganization of new plant communities was very rapid, on the order of decades not centuries; and (4) legacies of forest management adopted by earlier societies continue to influence ecosystem services today. PMID- 29391429 TI - Non-invasive detection of divergent metabolic signals in insulin deficiency vs. insulin resistance in vivo. AB - The type 2 diabetic phenotype results from mixed effects of insulin deficiency and insulin resistance, but the relative contributions of these two distinct factors remain poorly characterized, as do the respective roles of the gluconeogenic organs. The purpose of this study was to investigate localized in vivo metabolic changes in liver and kidneys of contrasting models of diabetes mellitus (DM): streptozotocin (STZ)-treated wild-type Zucker rats (T1DM) and Zucker diabetic fatty (ZDF) rats (T2DM). Intermediary metabolism was probed using hyperpolarized (HP) [1-13C]pyruvate MRI of the liver and kidneys. These data were correlated with gene expression data for key mediators, assessed using rtPCR. Increased HP [1-13C]lactate was detected in both models, in association with elevated gluconeogenesis as reflected by increased expression of phosphoenolpyruvate carboxykinase. In contrast, HP [1-13C]alanine diverged between the two models, increasing in ZDF rats, while decreasing in the STZ treated rats. The differences in liver alanine paralleled differences in key lipogenic mediators. Thus, HP [1-13C]alanine is a marker that can identify phenotypic differences in kidneys and liver of rats with T1DM vs. T2DM, non invasively in vivo. This approach could provide a powerful diagnostic tool for characterizing tissue metabolic defects and responses to treatment in diabetic patients with ambiguous systemic manifestations. PMID- 29391431 TI - Orbital-anisotropic electronic structure in the nonmagnetic state of BaFe2(As1-xP x )2 superconductors. AB - High-temperature superconductivity in iron-pnictides/chalcogenides arises in balance with several electronic and lattice instabilities. Beside the antiferromagnetic order, the orbital anisotropy between Fe 3d xz and 3d yz occurs near the orthorhombic structural transition in several parent compounds. However, the extent of the survival of orbital anisotropy against the ion-substitution remains to be established. Here we report the composition (x) and temperature (T) dependences of the orbital anisotropy in the electronic structure of a BaFe2(As1 xP x )2 system by using angle-resolved photoemission spectroscopy. In the low-x regime, the orbital anisotropy starts to evolve on cooling from high temperatures above both antiferromagnetic and orthorhombic transitions. By increasing x, it is gradually suppressed and survives in the optimally doped regime. We find that the in-plane orbital anisotropy persists in a large area of the nonmagnetic phase, including the superconducting dome. These results suggest that the rotational symmetry-broken electronic state acts as the stage for superconductivity in BaFe2(As1-xP x )2. PMID- 29391432 TI - Systems Analysis of the Liver Transcriptome in Adult Male Zebrafish Exposed to the Plasticizer (2-Ethylhexyl) Phthalate (DEHP). AB - The organic compound diethylhexyl phthalate (DEHP) represents a high production volume chemical found in cosmetics, personal care products, laundry detergents, and household items. DEHP, along with other phthalates causes endocrine disruption in males. Exposure to endocrine disrupting chemicals has been linked to the development of several adverse health outcomes with apical end points including Non-Alcoholic Fatty Liver Disease (NAFLD). This study examined the adult male zebrafish (Danio rerio) transcriptome after exposure to environmental levels of DEHP and 17alpha-ethinylestradiol (EE2) using both DNA microarray and RNA-sequencing technologies. Our results show that exposure to DEHP is associated with differentially expressed (DE) transcripts associated with the disruption of metabolic processes in the liver, including perturbation of five biological pathways: 'FOXA2 and FOXA3 transcription factor networks', 'Metabolic pathways', 'metabolism of amino acids and derivatives', 'metabolism of lipids and lipoproteins', and 'fatty acid, triacylglycerol, and ketone body metabolism'. DE transcripts unique to DEHP exposure, not observed with EE2 (i.e. non-estrogenic effects) exhibited a signature related to the regulation of transcription and translation, and ruffle assembly and organization. Collectively our results indicate that exposure to low DEHP levels modulates the expression of liver genes related to fatty acid metabolism and the development of NAFLD. PMID- 29391433 TI - Comparison of plants with C3 and C4 carbon fixation pathways for remediation of polycyclic aromatic hydrocarbon contaminated soils. AB - The phytoremediation technique has been demonstrated to be a viable option for the remediation of polycyclic aromatic hydrocarbons (PAHs) contaminated sites. This study evaluated the potential applicability of plants with C3 and C4 carbon fixation pathways for the phytoremediation of recalcitrant high molecular weight (HMW) PAHs contaminated soil. A 60 and 120-day greenhouse study was conducted which showed higher degradation of HMW PAHs in soil grown with C4 plants when compared to C3 plants. Also, no PAHs were detected in the maize cobs, sunflower, wallaby, and Sudan grass seeds at the end of the experiment. The effect of plants in modifying the microbial community and dynamics in the rhizosphere was also examined by measuring soil biochemical properties such as dehydrogenase activity and water-soluble phenols. The results demonstrate a substantial difference in the microbial populations between planted and unplanted soils, which in turn facilitate the degradation of PAHs. To the best of our knowledge, this study for the first time evaluated the phytoremediation efficacy through the A. cepa cyto- and genotoxicity assay which should be considered as an integral part of all remediation experiments. PMID- 29391434 TI - Diverse patterns of molecular changes in the mechano-responsiveness of focal adhesions. AB - Focal adhesions anchor contractile actin fibers with the extracellular matrix, sense the generated tension and respond to it by changing their morphology and composition. Here we ask how this mechanosensing is enabled at the protein network level, given the modular assembly and multitasking of focal adhesions. To address this, we applied a sensitive 4-color live cell imaging approach, enabling monitoring patterns of molecular changes in single focal adhesions. Co-imaging zyxin, FAK, vinculin and paxillin revealed heterogeneities in their responses to Rho-associated kinase (ROCK)-mediated perturbations of actomyosin contractility. These responses were rather weakly correlated between the proteins, reflecting diverse compositional changes in different focal adhesions. This diversity is partially attributable to the location of focal adhesions, their area, molecular content and previous contractility perturbations, suggesting that integration of multiple local cues shapes differentially focal adhesion mechano-responsiveness. Importantly, the compositional changes upon ROCK perturbations exhibited distinct paths in different focal adhesions. Moreover, the protein exhibiting the strongest response to ROCK perturbations varied among different focal adhesions. The diversity in response patterns is plausibly enabled by the modular mode of focal adhesions assembly and can provide them the needed flexibility to perform multiple tasks by combining optimally a common set of multifunctional components. PMID- 29391435 TI - The activity of the C4-dicarboxylic acid chemoreceptor of Pseudomonas aeruginosa is controlled by chemoattractants and antagonists. AB - Chemotaxis toward organic acids has been associated with colonization fitness and virulence and the opportunistic pathogen Pseudomonas aeruginosa exhibits taxis toward several tricarboxylic acid intermediates. In this study, we used high throughput ligand screening and isothermal titration calorimetry to demonstrate that the ligand binding domain (LBD) of the chemoreceptor PA2652 directly recognizes five C4-dicarboxylic acids with KD values ranging from 23 uM to 1.24 mM. In vivo experimentation showed that three of the identified ligands act as chemoattractants whereas two of them behave as antagonists by inhibiting the downstream chemotaxis signalling cascade. In vitro and in vivo competition assays showed that antagonists compete with chemoattractants for binding to PA2652-LBD, thereby decreasing the affinity for chemoattractants and the subsequent chemotactic response. Two chemosensory pathways encoded in the genome of P. aeruginosa, che and che2, have been associated to chemotaxis but we found that only the che pathway is involved in PA2652-mediated taxis. The receptor PA2652 is predicted to contain a sCACHE LBD and analytical ultracentrifugation analyses showed that PA2652-LBD is dimeric in the presence and the absence of ligands. Our results indicate the feasibility of using antagonists to interfere specifically with chemotaxis, which may be an alternative strategy to fight bacterial pathogens. PMID- 29391436 TI - Continuous cropping of endangered therapeutic plants via electron beam soil treatment and neutron tomography. AB - Various medicinal plants are threatened with extinction owing to their over exploitation and the prevalence of soil borne pathogens. In this study, soils infected with root-rot pathogens, which prevent continuous-cropping, were treated with an electron beam. The level of soil-borne fungus was reduced to <=0.01% by soil electron beam treatment without appreciable effects on the levels of antagonistic microorganism or on the physicochemical properties of the soil. The survival rate of 4-year-old plant was higher in electron beam-treated soil (81.0%) than in fumigated (62.5%), virgin (78%), or untreated-replanting soil (0%). Additionally, under various soils conditions, neutron tomography permitted the monitoring of plant health and the detection of root pathological changes over a period of 4-6 years by quantitatively measuring root water content in situ. These methods allow continual cropping on the same soil without pesticide treatment. This is a major step toward the environmentally friendly production of endangered therapeutic herbs. PMID- 29391437 TI - Differential abundance and transcription of 14-3-3 proteins during vegetative growth and sexual reproduction in budding yeast. AB - 14-3-3 is a family of relatively low molecular weight, acidic, dimeric proteins, conserved from yeast to metazoans including humans. Apart from their role in diverse cellular processes, these proteins are also known for their role in several clinical implications. Present proteomic and biochemical comparison showed increased abundance and differential phosphorylation of these proteins in meiotic cells. Double deletion of bmh1-/-bmh2-/- leads to complete absence of sporulation with cells arrested at G1/S phase while further incubation of cells in sporulating media leads to cell death. In silico analysis showed the presence of 14-3-3 interacting motifs in bonafide members of kinetochore complex (KC) and spindle pole body (SPB), while present cell biological data pointed towards the possible role of yeast Bmh1/2 in regulating the behaviour of KC and SPB. We further showed the involvement of 14-3-3 in segregation of genetic material and expression of human 14-3-3beta/alpha was able to complement the function of endogenous 14-3-3 protein even in the complex cellular process like meiosis. Our present data also established haplosufficient nature of BMH1/2. We further showed that proteins synthesized during mitotic growth enter meiotic cells without de novo synthesis except for meiotic-specific proteins required for induction and meiotic progression in Saccharomyces cerevisiae. PMID- 29391438 TI - Obtaining high-quality draft genomes from uncultured microbes by cleaning and co assembly of single-cell amplified genomes. AB - Single-cell genomics is a straightforward approach to obtain genomes from uncultured microbes. However, sequence reads from a single-cell amplified genome (SAG) contain significant bias and chimeric sequences. Here, we describe Cleaning and Co-assembly of a Single-Cell Amplified Genome (ccSAG), a novel analytical workflow to obtain composite single-cell genomes with elimination of sequence errors. By the integration of ccSAG with a massively parallel single-cell genome amplification platform based on droplet microfluidics, we can generate multiple SAGs and effectively integrate them into the composite genomes quality equivalent to the data obtained from bulk DNA. We obtained two novel draft genomes from single gut microbial cells with high completeness (>96.6%) and extremely low contamination (<1.25%). Moreover, we revealed the presence of single nucleotide polymorphisms in the specific gene by sequence comparison at the single-cell level. Thus, the workflow yields near-complete genomes from uncultured microbes, and enables analyses of genetic heterogeneity within identical strains. PMID- 29391439 TI - Stacking change in MoS2 bilayers induced by interstitial Mo impurities. AB - We use a theoretical approach to reveal the electronic and structural properties of molybdenum impurities between MoS2 bilayers. We find that interstitial Mo impurities are able to reverse the well-known stability order of the pristine bilayer, because the most stable form of stacking changes from AA' (undoped) into AB' (doped). The occurrence of Mo impurities in different positions shows their split electronic levels in the energy gap, following octahedral and tetrahedral crystal fields. The energy stability is related to the accommodation of Mo impurities compacted in hollow sites between layers. Other less stable configurations for Mo dopants have larger interlayer distances and band gaps than those for the most stable stacking. Our findings suggest possible applications such as exciton trapping in layers around impurities, and the control of bilayer stacking by Mo impurities in the growth process. PMID- 29391440 TI - First in situ evidence of wakes in the far field behind offshore wind farms. AB - More than 12 GW of offshore wind turbines are currently in operation in European waters. To optimise the use of the marine areas, wind farms are typically clustered in units of several hundred turbines. Understanding wakes of wind farms, which is the region of momentum and energy deficit downwind, is important for optimising the wind farm layouts and operation to minimize costs. While in most weather situations (unstable atmospheric stratification), the wakes of wind turbines are only a local effect within the wind farm, satellite imagery reveals wind-farm wakes to be several tens of kilometres in length under certain conditions (stable atmospheric stratification), which is also predicted by numerical models. The first direct in situ measurements of the existence and shape of large wind farm wakes by a specially equipped research aircraft in 2016 and 2017 confirm wake lengths of more than tens of kilometres under stable atmospheric conditions, with maximum wind speed deficits of 40%, and enhanced turbulence. These measurements were the first step in a large research project to describe and understand the physics of large offshore wakes using direct measurements, together with the assessment of satellite imagery and models. PMID- 29391441 TI - miR-539 acts as a tumor suppressor by targeting epidermal growth factor receptor in breast cancer. AB - Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-associated death in women worldwide. microRNAs (miRNAs) play critical roles in the cellular processes of breast cancer. However, the crucial roles and underlying mechanisms of miR-539 in breast cancer remain unclear. By RT-qPCR, we found that expression of miR-539 was markedly down-regulated in breast cancer tissues and cell lines compared with that in paired adjacent normal tissues and normal cell lines. The low level of miR-539 expression was positively associated with lymph node metastasis. Furthermore, forced expression of miR-539 inhibited proliferation and migration of breast cancer MDA-MB-231 and MCF7 cells in vitro and suppressed tumor growth in vivo. Moreover, bioinformatics analysis and luciferase reporter assays indicated that epidermal growth factor receptor (EGFR) was a direct target of miR-539. Over-expression of miR-539 decreased the EGFR mRNA and protein levels in MDA-MB-231 and MCF7 cells. In addition, ectopic over expression of EGFR partly reversed miR-539-inhibited proliferation as well as migration of MDA-MB-231 and MCF7 cells. Taken together, our results demonstrate that miR-539 functions as a tumor suppressor in breast cancer by downregulating EGFR, supporting the targeting of the novel miR-539/EGFR axis as a potentially effective therapeutic approach for breast cancer. PMID- 29391442 TI - Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA. AB - Venous thromboembolic (VTE) disease, consisting of deep venous thrombosis (DVT) and pulmonary embolism (PE) is a leading cause of morbidity and mortality. Current prophylactic measures are insufficient to prevent all occurrence in part due to an incomplete understanding of the underlying pathophysiology. Mounting evidence describes interplay between activation of the innate immune system and thrombus development. Recent work has demonstrated that platelet release of HMGB1 leads to increased microvascular complications following injury. Additionally, platelet HMGB1 was found to enhance DVT and increase the formation of neutrophil extracellular traps (NETs), although the role of HMGB1 induced NET release in thrombosis remains unexplored. Utilizing a transgenic mouse lacking HMGB1 specifically from platelets and megakaryocytes we now demonstrate the specific role of platelet-derived HMGB1 in acute and subacute/chronic venous thrombosis. Platelets account for the majority of circulating HMGB1 and HMGB1 deposition within the developing clot. The pro-thrombotic effect of platelet-derived HMGB1 is mediated through enhanced neutrophil recruitment, NET formation and specifically release of extracellular DNA during NET formation. Taken together, these data suggest that platelet HMGB1 mediated NET release is a primary regulator of DVT formation in mice. PMID- 29391443 TI - Precipitation of string-shaped morphologies consisting of aligned alpha phase in a metastable beta titanium alloy. AB - String-shaped morphologies consisting of preferentially aligned lath-shaped alpha precipitates were observed in the metastable beta Ti-6Cr-5Mo-5V-4Al alloy after deformations at high strain rates and elevated temperatures. The morphology and 3 dimentional arrangement of this feature have been elaborated based on the characterizations via a combination of transmission electron microscopy, transmission kikuchi diffraction and atom probe tomography. The 2D projected morphology of the coalescent alpha laths observed in the etched samples by SEM depends on the metallographic section. All the microstructural observations indicate that dislocation structures are most likely the nucleation sites for the aligned alpha laths. In addition, an appropriate testing temperature, which can ensure a relatively high diffusion rate of solutes without inducing strong recovery of dislocation structures, is necessary for the occurrence of the string shaped morphologies. PMID- 29391444 TI - Recent intensification of winter haze in China linked to foreign emissions and meteorology. AB - Wintertime aerosol pollution in the North China Plain has increased over the past several decades as anthropogenic emissions in China have increased, and has dramatically escalated since the beginning of the 21st century, but the causes and their quantitative attributions remain unclear. Here we use an aerosol source tagging capability implemented in a global aerosol-climate model to assess long term trends of PM2.5 (particulate matter less than 2.5 MUm in diameter) in the North China Plain. Our analysis suggests that the impact of China's increasing domestic emissions on PM2.5 concentrations over the last two decades of 20th century was partially offset (13%) by decreasing foreign emission over this period. As foreign emissions stabilized after 2000, their counteracting effect almost disappeared, uncovering the impact of China's increasing domestic emissions that had been partially offset in previous years by reductions in foreign emissions. A slowdown in the impact from foreign emission reductions together with weakening winds explain 25% of the increased PM2.5 trend over 2000 2014 as compared to 1980-2000. Further reductions in foreign emissions are not expected to relieve China's pollution in the future. Reducing local emissions is the most certain way to improve future air quality in the North China Plain. PMID- 29391445 TI - The fossil teeth of the Peking Man. AB - This study provides new original data, including the endostructure of most Zhoukoudian H. erectus teeth preserved to date, since the publication of Black in 1927 and Weidenreich in 1937. The new evidence ratifies the similarities of Zhoukoudian with other East Asian mid-Middle Pleistocene hominins such as Hexian and Yiyuan, and allows defining a dental pattern potentially characteristic of this population commonly referred to as classic H. erectus. Given the possible chronological overlaps of classic H. erectus with other archaic Homo, the characterization of this group becomes a key issue when deciphering the taxonomy and evolutionary scenario of the Middle Pleistocene hominins in East Asia. Internally, the most remarkable feature of Zhoukoudian teeth is the highly crenulated enamel-dentine junction (EDJ) and its imprint on the roof of the pulp cavity. So far, this "dendrite-like" EDJ has been found only in East Asia Middle Pleistocene hominins although a large group of samples were assessed, and it could be useful to dentally define classic H. erectus in China. The crenulated EDJ surface, together with the stout roots and the taurodontism could be a mechanism to withstand high biomechanical demand despite a general dentognathic reduction, particularly of the crowns, in these populations. PMID- 29391446 TI - VOC emissions influence intra- and interspecific interactions among stored product Coleoptera in paddy rice. AB - Olfaction is a pivotal sense for insects and granivorous pests may exploit grain volatiles for food selection. Tribolium confusum, is a secondary pest of stored cereals that benefits from primary pests' infestation, as other secondary feeders, triggering competition. This study aimed to evaluate the preferences of T. confusum females toward different-infested paddy rice, highlighting the impact of intra- and interspecific competition. Tribolium confusum showed positive chemotaxis toward rice infested by larvae of a primary pest (Sitophilus zeamais), but not for grain attacked by adults alone. Furthermore, kernels concurrently infested by a primary (S. zeamais) and a secondary pest (T. confusum or Cryptolestes ferrugineus) were evaluated in Y-tube bioassays, highlighting that both food-sources were innately attractive for T. confusum females. Moreover, females positively oriented toward rice infested by conspecifics, while they avoided grain infested by C. ferrugineus, averting an extremely competitive habitat. Behavioural responses of T. confusum females and volatile emissions of different-infested rice highlighted the occurrence of plant-mediated interactions among insects from the same trophic guild. Seventy volatiles were identified and significant differences among the tested food-sources were recorded, emphasizing the presence of 6 putative attractants and 6 repellents, which may be useful biocontrol tools. PMID- 29391447 TI - Aminergic Signaling Controls Ovarian Dormancy in Drosophila. AB - In response to adverse environmental conditions many organisms from nematodes to mammals deploy a dormancy strategy, causing states of developmental or reproductive arrest that enhance somatic maintenance and survival ability at the expense of growth or reproduction. Dormancy regulation has been studied in C. elegans and in several insects, but how neurosensory mechanisms act to relay environmental cues to the endocrine system in order to induce dormancy remains unclear. Here we examine this fundamental question by genetically manipulating aminergic neurotransmitter signaling in Drosophila melanogaster. We find that both serotonin and dopamine enhance adult ovarian dormancy, while the downregulation of their respective signaling pathways in endocrine cells or tissues (insulin producing cells, fat body, corpus allatum) reduces dormancy. In contrast, octopamine signaling antagonizes dormancy. Our findings enhance our understanding of the ability of organisms to cope with unfavorable environments and illuminate some of the relevant signaling pathways. PMID- 29391448 TI - Vasoactive intestinal peptide gene polymorphisms, associated with its serum levels, predict treatment requirements in early rheumatoid arthritis. AB - We previously reported that early arthritis (EA) patients with low vasoactive intestinal peptide (VIP) serum levels demonstrate a worse clinical disease course. In this study, we analysed whether variants in the VIP gene correlated with its serum levels and clinical EA parameters. The VIP gene was sequenced in patients with extremely high/low VIP levels, measured by enzyme immunoassay. Sixteen single nucleotide polymorphisms (SNPs) were differentially distributed between both groups, which were subsequently genotyped in two patients' sets. We observed that patients with rs688136 CC genotype showed higher VIP levels in both discovery (n = 91; p = 0.033) and validation populations (n = 131; p = 0.007). This effect was attenuated by the presence of minor alleles rs35643203 and rs12201140, which showed a clear trend towards low VIP level association (p = 0.118 and p = 0.049, respectively). Functional studies with miR-205-5p, which has a target site in the 3' UTR close to rs688136, revealed a miRNA-mediated regulatory mechanism explaining the higher VIP gene expression in homozygous patients. Moreover, patients with an rs688136 CC genotype and no minor alleles of the other polymorphisms required less treatment (p = 0.009). We concluded that the identification of polymorphisms associated with VIP serum levels would complement the clinical assessment of the disease severity in rheumatoid arthritis patients. PMID- 29391450 TI - Roles of different types of oxalate surface complexes in dissolution process of ferrihydrite aggregates. AB - The dissolution of ferrihydrite induced by low molar mass (LMM) organics is an important process that provides bioavailable iron for organisms. Here, ATR-FTIR analysis was combined with characterization of ferrihydrite nanoparticles and kinetic modeling to investigate the roles of different oxalate surface complex species in the dissolution of ferrihydrite aggregates. ATR-FTIR results revealed that at least four different species were present at or near the ferrihydrite surface in the process of ferrihydrite aggregate dissolution. At a relatively low addition of oxalate (oxalate/Fe < 0.1), oxalate was dominantly present as binuclear bidentate surface complexes and aqueous species. The binuclear bidentate complexes mainly caused electrostatic repulsion between particles, resulting in the disaggregation of large ferrihydrite aggregates into colloidal particles with hydrodynamic diameters of 116-174 nm. Kinetic modeling showed that these colloidal particles were stable at the oxalate/Fe ratio of 0.1. With increasing addition of oxalate (oxalate/Fe >= 0.1), mononuclear bidentate oxalate complexes and hydrogen-bonded surface complex replaced the binuclear bidentate complexes and aqueous species. The aggregates or larger colloidal particles were further disaggregated into smaller colloidal particles with hydrodynamic diameters of 35-64 nm. Additionally, the mononuclear bidentate oxalate complexes promoted the dissolution of ferrihydrite colloids into dissolved Fe. PMID- 29391449 TI - Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression. AB - Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells. PMID- 29391451 TI - ATP12A promotes mucus dysfunction during Type 2 airway inflammation. AB - Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport properties of airway epithelium. However, these electrophysiological changes cannot explain the thick, tenacious airway mucus that characterizes the clinical phenotype. Here we report that IL-13 dramatically increases the airway surface liquid (ASL) viscosity in cultured primary human bronchial epithelial cells and thereby inhibits mucus clearance. These detrimental rheological changes require ATP12A, a non-gastric H+/K+-ATPase that secretes protons into the ASL. ATP12A knockdown or inhibition prevented the IL-13 dependent increase in ASL viscosity but did not alter the ASL pH. We propose that ATP12A promotes airway mucus dysfunction in individuals with T2 inflammatory airway diseases and that ATP12A may be a novel therapeutic target to improve mucus clearance. PMID- 29391452 TI - Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling. AB - ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is anti-inflammatory by virtue of covalently attached phosphorylcholine. Previously we have reported that drug-like Small Molecule Analogues (SMAs) of its phosphorylcholine moiety can mimic ES-62 in protecting against disease development in certain mouse models of autoimmune and allergic conditions, due to them causing partial degradation of the TLR/IL-1R adaptor MyD88. We have now taken a molecular modelling approach to investigating the mechanism underlying this effect and this predicts that the SMAs interact directly with the MyD88 TIR domain. Further support for this is provided by assay of LPS-induced MyD88/NF kappaB-driven secreted alkaline phosphatase (SEAP) reporter activity in commercially-available stably transfected (TLR4-MD2-NF-kappaB-SEAP) HEK293 cells, as SMA12b-mediated inhibition of such SEAP activity is blocked by its pre incubation with recombinant MyD88-TIR domain. Direct binding of SMA12b to the TIR domain is also shown to inhibit homo-dimerization of the adaptor, an event that can explain the observed degradation of the adaptor and inhibition of subsequent downstream signalling. Thus, these new data identify initial events by which drug like ES-62 SMAs, which we also demonstrate are able to inhibit cytokine production by human cells, homeostatically maintain "safe" levels of MyD88 signalling. PMID- 29391453 TI - Predicting phase behavior of grain boundaries with evolutionary search and machine learning. AB - The study of grain boundary phase transitions is an emerging field until recently dominated by experiments. The major bottleneck in the exploration of this phenomenon with atomistic modeling has been the lack of a robust computational tool that can predict interface structure. Here we develop a computational tool based on evolutionary algorithms that performs efficient grand-canonical grain boundary structure search and we design a clustering analysis that automatically identifies different grain boundary phases. Its application to a model system of symmetric tilt boundaries in Cu uncovers an unexpected rich polymorphism in the grain boundary structures. We find new ground and metastable states by exploring structures with different atomic densities. Our results demonstrate that the grain boundaries within the entire misorientation range have multiple phases and exhibit structural transitions, suggesting that phase behavior of interfaces is likely a general phenomenon. PMID- 29391454 TI - Synthesis of organic aerogels with tailorable morphology and strength by controlled solvent swelling following Hansen solubility. AB - We introduce a generalized approach to synthesize aerogels that allows remarkable control over its mechanical properties. The Hansen solubility parameters are used to predict and regulate the swelling properties of the precursor gels and, consequently, to achieve aerogels with tailored density and mechanical properties. As a demonstration, crosslinked organogels were synthesized from cellulose esters to generate aerogels. By determination of Hansen's Relative Energy Difference, it was possible to overcome the limitations of current approaches that solely rely on the choice of precursor polymer concentration to achieve a set of aerogel properties. Hence, from a given concentration, aerogels were produced in a range of mass densities, from 25 to 113 mg/cm3. Consequently, it was possible to tailor the stiffness, toughness and compressive strength of the aerogels, in the ranges between 14-340, 4-103 and 22-373 kPa, respectively. Additionally, unidirectional freeze-drying introduced pore alignment in aerogels with honeycomb morphologies and anisotropy. Interestingly, when the swelling of the polymeric gel was arrested in a non-equilibrium state, it was possible to gain additional control of the property space. The proposed method is a novel and generic solution to achieving full control of aerogel development, which up to now has been an intractable challenge. PMID- 29391455 TI - Accuracy of fetal fibronectin for the prediction of preterm birth in symptomatic twin pregnancies: a pilot study. AB - Our goal was to evaluate the performance of fetal fibronectin (fFN) test alone or combined with cervical length (CL), to predict spontaneous preterm birth (PTB) in symptomatic twin pregnancies. We carry out a short pilot study including all uncomplicated diamniotic twin pregnancies with symptoms of preterm labor (PTL) and intact membranes at 24-33 weeks + 6 days of gestation. Studied outcome were spontaneous delivery within 7 and 14 days of testing and spontaneous PTB at <34 and <37 weeks of gestation. Among 40 women, fFN test was positive in 3 of them (7.5%). Regardless of the outcome studied CL did not significantly predict PTB. Performance of fFN was sensitivity (66.7%), specificity (97.2%), positive predictive value (66.7%), negative predictive value (97.2%), positive likelihood ratio (LR) (24.0), and negative LR (0.3) to predict spontaneous PTB within 7 days (p = 0.01). Thus, 66.1% of patients with a positive fFN test would deliver within 7 days versus 2.4% if negative testing; starting with a pre-test probability of 7.5%. Combining CL and fFN did not enable to increase enough positive LR or decrease significantly negative LR. In conclusion, fFN test alone might have a better ability to detect spontaneous delivery within 7 days among symptomatic twin pregnancies. PMID- 29391457 TI - The mechanistic link between health and gut microbiota diversity. AB - Although numerous reports link a decreased diversity of the gut microbiota to a declined health status, to date no mechanistic motivation for this exists. Here, we show by applying first principles basic graph theory on small networks that higher diversity within such a network indeed leads to more efficient systems and redundancy. Our results quantitatively support earlier hypothetical considerations on gut microbiota richness with respect to these parameters. Our simulations show that higher species diversity leads to higher resilience within small microbiological ecosystems, like being present in the gut microbiota. This notion should provide an ingredient when developing new interventional strategies within the domain of microbiota management. PMID- 29391456 TI - Gene silencing in Tribolium castaneum as a tool for the targeted identification of candidate RNAi targets in crop pests. AB - RNAi shows potential as an agricultural technology for insect control, yet, a relatively low number of robust lethal RNAi targets have been demonstrated to control insects of agricultural interest. In the current study, a selection of lethal RNAi target genes from the iBeetle (Tribolium castaneum) screen were used to demonstrate efficacy of orthologous targets in the economically important coleopteran pests Diabrotica virgifera virgifera and Meligethes aeneus. Transcript orthologs of 50 selected genes were analyzed in D. v. virgifera diet based RNAi bioassays; 21 of these RNAi targets showed mortality and 36 showed growth inhibition. Low dose injection- and diet-based dsRNA assays in T. castaneum and D. v. virgifera, respectively, enabled the identification of the four highly potent RNAi target genes: Rop, dre4, ncm, and RpII140. Maize was genetically engineered to express dsRNA directed against these prioritized candidate target genes. T0 plants expressing Rop, dre4, or RpII140 RNA hairpins showed protection from D. v. virgifera larval feeding damage. dsRNA targeting Rop, dre4, ncm, and RpII140 in M. aeneus also caused high levels of mortality both by injection and feeding. In summary, high throughput systems for model organisms can be successfully used to identify potent RNA targets for difficult to-work with agricultural insect pests. PMID- 29391458 TI - Early Cambrian fuxianhuiids from China reveal origin of the gnathobasic protopodite in euarthropods. AB - Euarthropods owe their evolutionary and ecological success to the morphological plasticity of their appendages. Although this variability is partly expressed in the specialization of the protopodite for a feeding function in the post deutocerebral limbs, the origin of the former structure among Cambrian representatives remains uncertain. Here, we describe Alacaris mirabilis gen. et sp. nov. from the early Cambrian Xiaoshiba Lagerstatte in China, which reveals the proximal organization of fuxianhuiid appendages in exceptional detail. Proximally, the post-deutocerebral limbs possess an antero-posteriorly compressed protopodite with robust spines. The protopodite is attached to an endopod with more than a dozen podomeres, and an oval flap-shaped exopod. The gnathal edges of the protopodites form an axial food groove along the ventral side of the body, indicating a predatory/scavenging autecology. A cladistic analysis indicates that the fuxianhuiid protopodite represents the phylogenetically earliest occurrence of substantial proximal differentiation within stem-group Euarthropoda illuminating the origin of gnathobasic feeding. PMID- 29391459 TI - Optimising the glaucoma signal/noise ratio by mapping changes in spatial summation with area-modulated perimetric stimuli. AB - Identification of glaucomatous damage and progression by perimetry are limited by measurement and response variability. This study tested the hypothesis that the glaucoma damage signal/noise ratio is greater with stimuli varying in area, either solely, or simultaneously with contrast, than with conventional stimuli varying in contrast only (Goldmann III, GIII). Thirty glaucoma patients and 20 age-similar healthy controls were tested with the Method of Constant Stimuli (MOCS). One stimulus modulated in area (A), one modulated in contrast within Ricco's area (CR), one modulated in both area and contrast simultaneously (AC), and the reference stimulus was a GIII, modulating in contrast. Stimuli were presented on a common platform with a common scale (energy). A three-stage protocol minimised artefactual MOCS slope bias that can occur due to differences in psychometric function sampling between conditions. Threshold difference from age-matched normal (total deviation), response variability, and signal/noise ratio were compared between stimuli. Total deviation was greater with, and response variability less dependent on defect depth with A, AC, and CR stimuli, compared with GIII. Both A and AC stimuli showed a significantly greater signal/noise ratio than the GIII, indicating that area-modulated stimuli offer benefits over the GIII for identifying early glaucoma and measuring progression. PMID- 29391460 TI - Genetic interaction involving photoperiod-responsive Hd1 promotes early flowering under long-day conditions in rice. AB - Although flowering in rice has been extensively investigated, few studies focused on genetic interactions. Flowering evaluation of two recombinant inbred line (RIL) populations involving photo-insensitive rice cultivars, Bengal and Cypress, and a weedy rice accession, PSRR-1, under natural long-day (LD) conditions, revealed six to ten quantitative trait loci (QTLs) and a major QTL interaction. In addition to the validation of several previously cloned genes using an introgression lines (IL) population of PSRR-1, a few novel QTLs were also discovered. Analysis of the marker profiles of the advanced backcross lines revealed that Hd1 allele of PSRR-1 was responsible for the photoperiodic response in the near-isogenic lines (NILs) developed in both cultivar backgrounds. Based on the phenotypic and genotypic data of the NILs, and NIL mapping population and the transcript abundance of key flowering pathway genes, we conclude that Hd1 and its interaction with a novel gene other than Ghd7 play an important role in controlling flowering under LD conditions. Our study demonstrates the important role of genetic interaction that regulates flowering time in rice and the need for further investigation to exploit it for breeding adaptable rice varieties. PMID- 29391461 TI - Internet Communication Disorder and the structure of the human brain: initial insights on WeChat addiction. AB - WeChat represents one of the most popular smartphone-based applications for communication. Although the application provides several useful features that simplify daily life, a growing number of users spend excessive amounts of time on the application. This may lead to interferences with everyday life and even to addictive patterns of use. In the context of the ongoing discussion on Internet Communication Disorder (ICD), the present study aimed to better characterize the addictive potential of communication applications, using WeChat as an example, by examining associations between individual variations in tendencies towards WeChat addiction and brain structural variations in fronto-striatal-limbic brain regions. To this end levels of addictive tendencies, frequency of use and structural MRI data were assessed in n = 61 healthy participants. Higher tendencies towards WeChat addiction were associated with smaller gray matter volumes of the subgenual anterior cingulate cortex, a key region for monitoring and regulatory control in neural networks underlying addictive behaviors. Moreover, a higher frequency of the paying function was associated with smaller nucleus accumbens volumes. Findings were robust after controlling for levels of anxiety and depression. The present results are in line with previous findings in substance and behavioral addictions, and suggest a similar neurobiological basis in ICD. PMID- 29391462 TI - The effects of pressure on the energy landscape of proteins. AB - Protein dynamics is characterized by fluctuations among different conformational substates, i.e. the different minima of their energy landscape. At temperatures above ~200 K, these fluctuations lead to a steep increase in the thermal dependence of all dynamical properties, phenomenon known as Protein Dynamical Transition. In spite of the intense studies, little is known about the effects of pressure on these processes, investigated mostly near room temperature. We studied by neutron scattering the dynamics of myoglobin in a wide temperature and pressure range. Our results show that high pressure reduces protein motions, but does not affect the onset temperature for the Protein Dynamical Transition, indicating that the energy differences and barriers among conformational substates do not change with pressure. Instead, high pressure values strongly reduce the average structural differences between the accessible conformational substates, thus increasing the roughness of the free energy landscape of the system. PMID- 29391463 TI - A joint matrix minimization approach for seismic wavefield recovery. AB - Reconstruction of the seismic wavefield from sub-sampled data is important and necessary in seismic image processing; this is partly due to limitations of the observations which usually yield incomplete data. To make the best of the observed seismic signals, we propose a joint matrix minimization model to recover the seismic wavefield. Employing matrix instead of vector as weight variable can express all the sub-sampled traces simultaneously. This scheme utilizes the collective representation rather than an individual one to recover a given set of sub-samples. The matrix model takes the interrelation of the multiple observations into account to facilitate recovery, for example, the similarity of the same seismic trace and distinctions of different ones. Hence an l2, p(0 < p <= 1)-regularized joint matrix minimization is formulated which has some computational challenges especially when p is in (0, 1). For solving the involved matrix optimization problem, a unified algorithm is developed and the convergence analysis is accordingly demonstrated for a range of parameters. Numerical experiments on synthetic and field data examples exhibit the efficient performance of the joint technique. Both reconstruction accuracy and computational cost indicate that the new strategy achieves good performance in seismic wavefield recovery and has potential for practical applications. PMID- 29391464 TI - Cholesterol-like effects of a fluorotelomer alcohol incorporated in phospholipid membranes. AB - Fluorocarbon amphiphiles are anthropogenic substances widely used in diverse applications such as food packaging, clothing or cookware. Due to their widespread use and non-biodegradability, these chemicals are now ubiquitous in the natural world with high propensity to bioaccumulate in biological membranes, wherein they may affect microscopic properties. Here, we test the hypothesis that a typical fluorocarbon amphiphile can affect lipid membranes similarly to cholesterol by investigating the effect of 1H,1H,2H,2H-perfluoro-1-decanol (8:2 FTOH) on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membranes. Using solid-state nuclear magnetic resonance spectroscopy, differential scanning calorimetry and confocal microscopy, we present a consistent set of independent experimental evidences supporting this hypothesis, namely that upon incorporation of 8:2 FTOH, (i) a condensing effect on the acyl chains occurs in the fluid phase, (ii) coexistence of two membrane phases is observed below melting, and (iii) the melting temperature of DPPC varies no more than approximately +/-1 degrees C up to a concentration of 40 mol% of 8:2 FTOH. The condensing effect is quantified by means of advanced dipolar recoupling solid-state NMR experiments and is found to be of approximately half the magnitude of the cholesterol effect at the same concentration. PMID- 29391465 TI - Solitons in a modified discrete nonlinear Schrodinger equation. AB - We study the bulk and surface nonlinear modes of a modified one-dimensional discrete nonlinear Schrodinger (mDNLS) equation. A linear and a modulational stability analysis of the lowest-order modes is carried out. While for the fundamental bulk mode there is no power threshold, the fundamental surface mode needs a minimum power level to exist. Examination of the time evolution of discrete solitons in the limit of strongly localized modes, suggests ways to manage the Peierls-Nabarro barrier, facilitating in this way a degree of soliton steering. The long-time propagation of an initially localized excitation shows that, at long evolution times, nonlinear effects become negligible and as a result, the propagation becomes ballistic. The qualitative similarity of the results for the mDNLS to the ones obtained for the standard DNLS, suggests that this kind of discrete soliton is an robust entity capable of transporting an excitation across a generic discrete medium that models several systems of interest. PMID- 29391466 TI - Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke. AB - The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced prominent atrophic changes in the striatum and led to proliferation of neural progenitor cells in the subventricular zone (SVZ) and the surrounding areas of the striatum (SVZ + striatum) of MCAO mice. The mBMSC and EA treatment markedly enhanced mature brain-derived neurotrophic factor (mBDNF) expression in the SVZ + striatum and hippocampus of mice with MCAO, and combined treatment enhanced neurotrophin-4 (NT4) expression. The number of mBDNF- and NT4 positive neurons in the SVZ + striatum and hippocampus increased following EA treatment. Combined treatment led to an increase in the expression levels of phosphorylated cAMP response element binding protein in the neuroblasts of the striatum. Our results indicate that combined MSC and EA treatment may lead to a better therapeutic effect via co-regulation of neurotrophic factors in the brain, by regulating neurogenesis more than single therapy. PMID- 29391467 TI - Improvement in bladder dysfunction after bladder transplantation of amniotic fluid stem cells in diabetic rats. AB - To examine the effects of human amniotic fluid stem cells (hAFSCs) transplantation on bladder function and molecular changes in diabetic rats, 60 female Sprague-Dawley rats were used for study. Three groups were assigned including sham control rats, streptozotocin (STZ, 60 mg/kg)-induced diabetic rats and STZ-induced diabetic rats plus bladder hAFSCs transplantation. Compared to controls, diabetic rats had decreased body weight but increased bladder weight. Cystometries showed non-voiding contraction, residual volume, voided volume and intercontraction interval increased significantly in diabetic rats at week 4 and 12 after DM induction, but improved after hAFSCs transplantation. The immunoreactivities and mRNAs of nerve growth factor (NGF) decreased significantly in diabetic bladder at week 4 and 12 after DM induction, but recovered after hAFSCs transplantation. The immunoreactivities and mRNAs of M2 and M3 muscarinic receptor increased significantly in diabetic bladder at week 4 after DM induction but recovered after hAFSCs transplantation. The immunoreactivity of 8-hydroxy-20 deoxyguanosine increased significantly in diabetic bladder at week 4 and 12 after DM induction but reduced after hAFSCs transplantation. The present study showed bladder dysfunction in STZ-induced diabetic rats could be improved by hAFSCs transplantation into bladder, which may be related to the recovery of bladder NGF and muscarinic receptors. PMID- 29391468 TI - Deep brain stimulation induces sparse distributions of locally modulated neuronal activity. AB - Deep brain stimulation (DBS) therapy is a potent tool for treating a range of brain disorders. High frequency stimulation (HFS) patterns used in DBS therapy are known to modulate neuronal spike rates and patterns in the stimulated nucleus; however, the spatial distribution of these modulated responses are not well understood. Computational models suggest that HFS modulates a volume of tissue spatially concentrated around the active electrode. Here, we tested this theory by investigating modulation of spike rates and patterns in non-human primate motor thalamus while stimulating the cerebellar-receiving area of motor thalamus, the primary DBS target for treating Essential Tremor. HFS inhibited spike activity in the majority of recorded cells, but increasing stimulation amplitude also shifted the response to a greater degree of spike pattern modulation. Modulated responses in both categories exhibited a sparse and long range spatial distribution within motor thalamus, suggesting that stimulation preferentially affects afferent and efferent axonal processes traversing near the active electrode and that the resulting modulated volume strongly depends on the local connectome of these axonal processes. Such findings have important implications for current clinical efforts building predictive computational models of DBS therapy, developing directional DBS lead technology, and formulating closed-loop DBS strategies. PMID- 29391470 TI - High Energy electron and proton acceleration by circularly polarized laser pulse from near critical density hydrogen gas target. AB - Relativistic electron rings hold the possibility of very high accelerating rates, and hopefully a relatively cheap and compact accelerator/collimator for ultrahigh energy proton source. In this work, we investigate the generation of helical shaped quasi-monoenergetic relativistic electron beam and high-energy proton beam from near critical density plasmas driven by petawatt-circularly polarized-short laser pulses. We numerically observe the efficient proton acceleration from magnetic vortex acceleration mechanism by using the three dimensional particle-in cell simulations; proton beam with peak energy 350 MeV, charge ~10nC and conversion efficiency more than 6% (which implies 2.4 J proton beam out of the 40 J incident laser energy) is reported. We detailed the microphysics involved in the ion acceleration mechanism, which requires investigating the role of self generated plasma electric and magnetic fields. The concept of efficient generation of quasi-monoenergetic electron and proton beam from near critical density gas targets may be verified experimentally at advanced high power - high repetition rate laser facilities e.g. ELI-ALPS. Such study should be an important step towards the development of high quality electron and proton beam. PMID- 29391469 TI - KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE epsilon4-positive cognitively normal adults with high Abeta-amyloid burden. AB - A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer's disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Abeta-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Abeta-amyloid levels across study duration. In comparison to APOE epsilon4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE epsilon4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Abeta-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Abeta-amyloid and APOE epsilon4. PMID- 29391471 TI - Detection of 16S rRNA and KPC Genes from Complex Matrix Utilizing a Molecular Inversion Probe Assay for Next-Generation Sequencing. AB - Targeted sequencing promises to bring next-generation sequencing (NGS) into routine clinical use for infectious disease diagnostics. In this context, upfront processing techniques, including pathogen signature enrichment, must amplify multiple targets of interest for NGS to be relevant when applied to patient samples with limited volumes. Here, we demonstrate an optimized molecular inversion probe (MIP) assay targeting multiple variable regions within the 16S ribosomal gene for the identification of biothreat and ESKAPE pathogens in a process that significantly reduces complexity, labor, and processing time. Probes targeting the Klebsiella pneumoniae carbapenemase (KPC) antibiotic resistance (AR) gene were also included to demonstrate the ability to concurrently identify etiologic agent and ascertain valuable secondary genetic information. Our assay captured gene sequences in 100% of mock clinical samples prepared from flagged positive blood culture bottles. Using a simplified processing and adjudication method for mapped sequencing reads, genus and species level concordance was 100% and 80%, respectively. In addition, sensitivity and specificity for KPC gene detection was 100%. Our MIP assay produced sequenceable amplicons for the identification of etiologic agents and the detection of AR genes directly from blood culture bottles in a simplified single tube assay. PMID- 29391472 TI - On the Defect Structure of Biaxial Nematic Droplets. AB - We present a detailed Monte Carlo study of the effects of molecular biaxiality on the defect created at the centre of a nematic droplet with radial anchoring at the surface. We have studied a lattice model based on a dispersive potential for biaxial mesogens [Luckhurst et al., Mol. Phys. 30, 1345 (1975)] to investigate how increasing the biaxiality influences the molecular organisation inside the confined system. The results are compared with those obtained from a continuum theory approach. We find from both approaches that the defect core size increases by increasing the molecular biaxiality, hinting at a non universal behaviour previously not reported. PMID- 29391473 TI - Duplicated RGS (Regulator of G-protein signaling) proteins exhibit conserved biochemical but differential transcriptional regulation of heterotrimeric G protein signaling in Brassica species. AB - G-alpha (Galpha) and 'Regulator of G-protein Signaling (RGS)' proteins are the two key components primarily involved in regulation of heterotrimeric G-proteins signaling across phyla. Unlike Arabidopsis thaliana, our knowledge about G protein regulation in polyploid Brassica species is sparse. In this study, we identified one Galpha and two RGS genes each from three species of Brassica 'U' triangle and assessed the effects of whole genome triplication on the divergence of gene sequence and structure, protein-protein interaction, biochemical activities, and gene expression. Sequence and phylogenetic analysis revealed that the deduced Galpha and RGS proteins are evolutionarily conserved across Brassica species. The duplicated RGS proteins of each Brassica species interacted with their cognate Galpha but displayed varying levels of interaction strength. The Galpha and the duplicated RGS proteins of Brassica species exhibited highly conserved G-protein activities when tested under in-vitro conditions. Expression analysis of the B. rapa RGS genes revealed a high degree of transcriptional differentiation across the tested tissue types and in response to various elicitors, particularly under D-glucose, salt and phytohormone treatments. Taken together, our results suggest that the RGS-mediated regulation of G-protein signaling in Brassica species is predominantly governed by stage and condition specific expression differentiation of the duplicated RGS genes. PMID- 29391474 TI - Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization. AB - Erythropoietin (EPO) is recognized for neuroprotective and angiogenic effects and has been associated with aging and neovascular age-related macular degeneration (AMD). We hypothesized that systemic EPO facilitates the development of choroidal neovascularization (CNV). Wild type mice expressed murine EPOR (mWtEPOR) in RPE/choroids at baseline and had significantly increased serum EPO after laser treatment. To test the role of EPO signaling, we used human EPOR knock-in mice with the mWtEPOR gene replaced by either the human EPOR gene (hWtEPOR) or a mutated human EPOR gene (hMtEPOR) in a laser-induced choroidal neovascularization (LCNV) model. Loss-of-function hWtEPOR mice have reduced downstream activation, whereas gain-of-function hMtEPOR mice have increased EPOR signaling. Compared to littermate controls (mWtEPOR), hMtEPOR with increased EPOR signaling developed larger CNV lesions. At baseline, hMtEPOR mice had increased numbers of macrophages, greater expression of macrophage markers F4/80 and CD206, and following laser injury, had greater expression of cytokines CCL2, CXCL10, CCL22, IL-6, and IL-10 than mWtEPOR controls. These data support a hypothesis that injury from age- and AMD-related changes in the RPE/choroid leads to choroidal neovascularization through EPOR-mediated cytokine production. PMID- 29391475 TI - Periconception onset diabetes is associated with embryopathy and fetal growth retardation, reproductive tract hyperglycosylation and impaired immune adaptation to pregnancy. AB - Diabetes has been linked with impaired fertility but the underlying mechanisms are not well defined. Here we use a streptozotocin-induced diabetes mouse model to investigate the cellular and biochemical changes in conceptus and maternal tissues that accompany hyperglycaemia. We report that streptozotocin treatment before conception induces profound intra-cellular protein beta-O-glycosylation (O GlcNAc) in the oviduct and uterine epithelium, prominent in early pregnancy. Diabetic mice have impaired blastocyst development and reduced embryo implantation rates, and delayed mid-gestation growth and development. Peri conception changes are accompanied by increased expression of pro-inflammatory cytokine Trail, and a trend towards increased Il1a, Tnf and Ifng in the uterus, and changes in local T-cell dynamics that skew the adaptive immune response to pregnancy, resulting in 60% fewer anti-inflammatory regulatory T-cells within the uterus-draining lymph nodes. Activation of the heat shock chaperones, a mechanism for stress deflection, was evident in the reproductive tract. Additionally, we show that the embryo exhibits elevated hyper-O-GlcNAcylation of both cytoplasmic and nuclear proteins, associated with activation of DNA damage (gammaH2AX) pathways. These results advance understanding of the impact of peri-conception diabetes, and provide a foundation for designing interventions to support healthy conception without propagation of disease legacy to offspring. PMID- 29391476 TI - The risk of cognitive impairment associated with hearing function in older adults: a pooled analysis of data from eleven studies. AB - Impaired hearing and cognition are disabling conditions among older adults. Research has presented inconsistent conclusions regarding hearing impairment posing a risk for cognitive impairment. We aimed to assess this from published evidence via searching PubMed and Embase, from the inception of the databases indexed to December 2, 2016. For those high-quality studies retrieved, relative risk (RR) and 95% confidence intervals (CIs) were combined to estimate the risk of cognitive impairment. Eleven cohort studies were included in the present study. Pooled results found that elderly people with disabled peripheral and central hearing function had a higher risk of cognitive impairment (for moderate/severe peripheral hearing impairment: RR = 1.29, 95% CI: 1.04-1.59 during a follow-up <=6 years. RR = 1.57, 95% CI: 1.13-2.20 during a follow-up >6 years; for severe central hearing impairment, RR = 3.21, 95% CI: 1.19-8.69) compared to those with normal hearing function. We also recorded a dose-response trend for cognitive impairment as hearing thresholds rose. No evident bias from potential confounding factors was found with one exception: the length for clinical follow-up. Although results are preliminary because qualifying studies were few, statistical findings were consistent with older people identified as having greater levels of hearing loss, having a corresponding higher risk of cognitive impairment. PMID- 29391477 TI - Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. AB - Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues were relatively slow (>2 weeks). Among them, 10 nm PEGylated IONPs achieved the highest tumor uptake. No obvious toxicity was found for PEGylated IONPs in BALB/c mice, whereas PEI-coated IONPs exhibited dose-dependent lethal toxicity. Therefore, it is crucial to consider the size and coating properties of IONPs in their applications. PMID- 29391478 TI - Disrupted Resting State Network of Fibromyalgia in Theta frequency. AB - Fibromyalgia (FM), chronic widespread pain, exhibits spontaneous pain without external stimuli and is associated with altered brain activities during resting state. To understand the topological features of brain network in FM, we employed persistent homology which is a multiple scale network modeling framework not requiring thresholding. Spontaneous magnetoencephalography (MEG) activity was recorded in 19 healthy controls (HCs) and 18 FM patients. Barcode, single linkage dendrogram and single linkage matrix were generated based on the proposed modeling framework. In theta band, the slope of decrease in the number of connected components in barcodes showed steeper in HC, suggesting FM patients had decreased global connectivity. FM patients had reduced connectivity within default mode network, between middle/inferior temporal gyrus and visual cortex. The longer pain duration was correlated with reduced connectivity between inferior temporal gyrus and visual cortex. Our findings demonstrated that the aberrant resting state network could be associated with dysfunction of sensory processing in chronic pain. The spontaneous nature of FM pain may accrue to disruption of resting state network. PMID- 29391479 TI - Expression of steroidogenic enzymes and metabolism of steroids in COS-7 cells known as non-steroidogenic cells. AB - The COS-7 (CV-1 in Origin with SV40 genes) cells are known as non-steroidogenic cells because they are derived from kidney cells and the kidney is defined as a non-steroidogenic organ. Therefore, COS-7 cells are used for transfection experiments to analyze the actions of functional molecules including steroids. However, a preliminary study suggested that COS-7 cells metabolize [3H]testosterone to [3H]androstenedione. These results suggest that COS-7 cells are able to metabolize steroids. Therefore, the present study investigated the expression of steroidogenic enzymes and the metabolism of steroids in COS-7 cells. RT-PCR analyses demonstrated the expressions of several kinds of steroidogenic enzymes, such as cytochrome P450 side-chain cleavage enzyme, 3beta hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase, cytochrome P450 7alpha hydroxylase, cytochrome P450 17alpha-hydroxylase/17,20-lyase, 17beta hydroxysteroid dehydrogenase, 5alpha-reductase, cytochrome P450 21-hydroxylase, cytochrome P450 11beta-hydroxylase, and cytochrome P450 aromatase in COS-7 cells. In addition, steroidogenic enzymes 3beta-HSD, P4507alpha, 5alpha-reductase, P450c17, P450c21, P450c11beta, and 17beta-HSD actively metabolized various steroids in cultured COS-7 cells. Finally, we demonstrated that 17beta-HSD activity toward androstenedione formation was greater than other steroidogenic enzyme activities. Our results provide new evidence that COS-7 cells express a series of steroidogenic enzyme mRNAs and actively metabolize a variety of steroids. PMID- 29391480 TI - Subclinical and overt hypothyroidism is associated with reduced glomerular filtration rate and proteinuria: a large cross-sectional population study. AB - Subclinical hypothyroidism has been associated with dyslipidemia, hypertension, and increased risk of coronary artery disease. However, limited is known for its effect on renal function. Here we aimed to investigate whether subclinical hypothyroidism is associated with reduced estimated glomerular filtration rate (eGFR) and proteinuria in the general population. A cross-sectional cohort of 74,356 adults aged >=20 year participating in voluntary health examinations without previous thyroid diseases were recruited in Taiwan. The mean eGFR of persons with euthyroidism, subclinical, and overt hypothyroidism are 87.99, 83.46, and 72.22 mL/min/1.73 m2, respectively (P-for- trend < 0.001). The proportion of proteinuria in persons with euthyroidism, subclinical and overt hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively (P-for-trend: 0.001). The odds ratio of CKD for subclinical, clinical, and all hypothyroidism is 2.04 (95% confidence interval (CI): 1.67-2.50) and 7.61 (95% CI: 4.92-11.77), and 2.41 (95% CI: 2.01-2.89), respectively as compared to euthyroidism. These odd ratios remained significant after further adjustments. The odds ratios for proteinuria is 2.04 (95% CI: 1.67-2.50), 7.61 (95% CI: 4.92-11.77), and 2.41 (95% CI: 2.01 2.89) for subclinical, clinical, and total hypothyroidism, respectively, although the odds ratios were attenuated after further adjustment. Our results suggest subclinical hypothyroidism is a novel risk factor of reduced renal function but not proteinuria. PMID- 29391481 TI - Neurophysiological mechanisms of interval timing dissociate inattentive and combined ADHD subtypes. AB - It is far from conclusive what distinguishes the inattentive (ADD) and the combined (ADHD-C) subtype of ADHD on the neuronal level. Theoretical considerations suggest that especially interval timing processes may dissociate these subtypes from each other. Combining high-density EEG recordings with source localization analyses, we examine whether there are ADHD-subtype specific modulations of neurophysiological processes subserving interval timing in matched groups of ADD (n = 16), ADHD-C (n = 16) and controls (n = 16). Patients with ADD and ADHD-C show deficits in interval timing, which was correlated with the degree of inattention in ADD patients. Compared to healthy controls, patients with ADHD C display a somewhat weaker, yet consistent response preparation process (contingent negative variation, CNV). In patients with ADD, the early CNV is interrupted, indicating an oscillatory disruption of the interval timing process. This is associated with activations in the supplemental motor areas and the middle frontal gyrus. Patients with ADD display adequate feedback learning mechanisms (feedback-related negativity, FRN), which is not the case in patients with ADHD-C. The results suggest that altered pacemaker-accumulation processes in medial frontal structures distinguish the ADD from the ADHD-C subtype. Particularly in patients with ADD phasic interruptions of preparatory neurophysiological processes are evident, making this a possible diagnostic feature. PMID- 29391482 TI - 5-HT1A receptor-dependent modulation of emotional and neurogenic deficits elicited by prolonged consumption of alcohol. AB - Repeated episodes of binge-like alcohol consumption produce anxiety, depression and various deleterious effects including alterations in neurogenesis. While the involvement of the serotonin receptor 1 A (5-HT1A) in the regulation of anxiety like behavior and neurogenesis is well documented, its contribution to alcohol withdrawal-induced anxiety and alcohol-induced deficits in neurogenesis is less documented. Using the Drinking-In-the-Dark (DID) paradigm to model chronic long term (12 weeks) binge-like voluntary alcohol consumption in mice, we show that the selective partial activation of 5-HT1A receptors by tandospirone (3 mg/kg) prevents alcohol withdrawal-induced anxiety in a battery of behavioral tests (marble burying, elevated-plus-maze, open-field), which is accompanied by a robust decrease in binge-like ethanol intake (1 and 3 mg/kg). Furthermore, using triple immunolabelling of proliferation and neuronal differentiation markers, we show that long-term DID elicits profound deficits in neurogenesis and neuronal fate specification in the dorsal hippocampus that are entirely reversed by a 2 week chronic treatment with the 5-HT1A partial agonist tandospirone (3 mg/kg/day). Together, our results confirm previous observations that 5-HT1A receptors play a pivotal role in alcohol drinking behavior and the associated emotional and neurogenic impairments, and suggest that 5-HT1A partial agonists represent a promising treatment strategy for alcohol abuse. PMID- 29391483 TI - Pattern recognition with machine learning on optical microscopy images of typical metallurgical microstructures. AB - For advanced materials characterization, a novel and extremely effective approach of pattern recognition in optical microscopic images of steels is demonstrated. It is based on fast Random Forest statistical algorithm of machine learning for reliable and automated segmentation of typical steel microstructures. Their percentage and location areas excellently agreed between machine learning and manual examination results. The accurate microstructure pattern recognition/segmentation technique in combination with other suitable mathematical methods of image processing and analysis can help to handle the large volumes of image data in a short time for quality control and for the quest of new steels with desirable properties. PMID- 29391484 TI - A highly efficient murine model of experimental myopia. AB - Despite the global pandemic of myopia, the precise molecular mechanism of the onset of myopia remains largely unknown. This is partially because of the lack of efficient murine myopic models that allow genetic manipulation at low cost. Here we report a highly practical and reproducible lens-induced myopia model by specially designed frames and lenses for mice. A lens power dependent myopic induction in mice was shown until minus 30 diopter lenses. The phenotype was significantly stronger than form-deprivation myopia. We presented the protocol for precise evaluations of the state of myopia, including refraction, corneal curvature and axial length using up-to-date devices. We also found that myopic mouse eyes showed decreased visual acuity on optokinetic response examination. Finally, we confirmed the anti-myopic effect of 1% atropine using this model, which showed its potential in drug screening. The strong phenotype, stable evaluation and the potential for gene manipulation utilizing the presented method in mice will accelerate the translational research of myopia. PMID- 29391486 TI - Author Correction: Interrogation of gamma-tubulin alleles using high-resolution fitness measurements reveals a distinct cytoplasmic function in spindle alignment. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29391485 TI - Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression. AB - There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression. PMID- 29391487 TI - Probing the folding pathway of a consensus serpin using single tryptophan mutants. AB - Conserpin is an engineered protein that represents the consensus of a sequence alignment of eukaryotic serpins: protease inhibitors typified by a metastable native state and a structurally well-conserved scaffold. Previously, this protein has been found to adopt a native inhibitory conformation, possess an atypical reversible folding pathway and exhibit pronounced resistance to inactivation. Here we have designed a version of conserpin, cAT, with the inhibitory specificity of alpha1-antitrypsin, and generated single-tryptophan variants to probe its folding pathway in more detail. cAT exhibited similar thermal stability to the parental protein, an inactivation associated with oligomerisation rather a transition to the latent conformation, and a native state with pronounced kinetic stability. The tryptophan variants reveal the unfolding intermediate ensemble to consist of an intact helix H, a distorted helix F and 'breach' region structurally similar to that of a mesophilic serpin intermediate. A combination of intrinsic fluorescence, circular dichroism, and analytical gel filtration provide insight into a highly cooperative folding pathway with concerted changes in secondary and tertiary structure, which minimises the accumulation of two directly-observed aggregation-prone intermediate species. This functional conserpin variant represents a basis for further studies of the relationship between structure and stability in the serpin superfamily. PMID- 29391488 TI - Age-associated microbiome shows the giant panda lives on hemicelluloses, not on cellulose. AB - The giant panda feeds almost exclusively on bamboo, a diet highly enriched in lignin and cellulose, but is characterized by a digestive tract similar to carnivores. It is still large unknown if and how the giant panda gut microbiota contributes to lignin and cellulose degradation. Here we show the giant pandas' gut microbiota does not significantly contribute to cellulose and lignin degradation. We found that no operational taxonomic unit had a nearest neighbor identified as a cellulolytic species or strain with a significant higher abundance in juvenile than cubs, a very low abundance of putative lignin and cellulose genes existed in part of analyzing samples but a significant higher abundance of genes involved in starch and hemicellulose degradation in juveniles than cubs. Moreover, a significant lower abundance of putative cellulolytic genes and a significant higher abundance of putative alpha-amylase and hemicellulase gene families were present in giant pandas than in omnivores or herbivores. PMID- 29391489 TI - Objective Assessment of Patient Inhaler User Technique Using an Audio-Based Classification Approach. AB - Many patients make critical user technique errors when using pressurised metered dose inhalers (pMDIs) which reduce the clinical efficacy of respiratory medication. Such critical errors include poor actuation coordination (poor timing of medication release during inhalation) and inhaling too fast (peak inspiratory flow rate over 90 L/min). Here, we present a novel audio-based method that objectively assesses patient pMDI user technique. The Inhaler Compliance Assessment device was employed to record inhaler audio signals from 62 respiratory patients as they used a pMDI with an In-Check Flo-Tone device attached to the inhaler mouthpiece. Using a quadratic discriminant analysis approach, the audio-based method generated a total frame-by-frame accuracy of 88.2% in classifying sound events (actuation, inhalation and exhalation). The audio-based method estimated the peak inspiratory flow rate and volume of inhalations with an accuracy of 88.2% and 83.94% respectively. It was detected that 89% of patients made at least one critical user technique error even after tuition from an expert clinical reviewer. This method provides a more clinically accurate assessment of patient inhaler user technique than standard checklist methods. PMID- 29391490 TI - msgbsR: An R package for analysing methylation-sensitive restriction enzyme sequencing data. AB - Genotyping-by-sequencing (GBS) or restriction-site associated DNA marker sequencing (RAD-seq) is a practical and cost-effective method for analysing large genomes from high diversity species. This method of sequencing, coupled with methylation-sensitive enzymes (often referred to as methylation-sensitive restriction enzyme sequencing or MRE-seq), is an effective tool to study DNA methylation in parts of the genome that are inaccessible in other sequencing techniques or are not annotated in microarray technologies. Current software tools do not fulfil all methylation-sensitive restriction sequencing assays for determining differences in DNA methylation between samples. To fill this computational need, we present msgbsR, an R package that contains tools for the analysis of methylation-sensitive restriction enzyme sequencing experiments. msgbsR can be used to identify and quantify read counts at methylated sites directly from alignment files (BAM files) and enables verification of restriction enzyme cut sites with the correct recognition sequence of the individual enzyme. In addition, msgbsR assesses DNA methylation based on read coverage, similar to RNA sequencing experiments, rather than methylation proportion and is a useful tool in analysing differential methylation on large populations. The package is fully documented and available freely online as a Bioconductor package ( https://bioconductor.org/packages/release/bioc/html/msgbsR.html ). PMID- 29391491 TI - MiR-26a-5p regulates cardiac fibroblasts collagen expression by targeting ULK1. AB - MiRNA is a class of small non-coding RNA which has an important effect on posttranscriptional gene regulation. It can regulate the expression of the target gene at the mRNA level and further influence the protein level of the target gene. We found that ULK1 may be the target gene of miR-26a-5p, and ULK1 (unc-51 like autophagy activating kinase 1) is a key component in autophagy pathway. In this study, we overexpressed miR-26a-5p by transfecting miR-26a-5p mimic into cells and simultaneously inhibited miR-26a-5p by transfecting miR-26a-5p inhibitor into cells. We demonstrated that overexpression of miR-26a-5p can reduce the expression of ULK1 and collagen I, and decrease the activation of LC3 I to LC3-II. In contrast, inhibition of miR-26a-5p can increase the expression of ULK1 and collagen I, and increase the activation of LC3-I to LC3-II. The Dual luciferase reporter assay showed that miR-26a-5p directly acted on the 3'UTR of ULK1 and thus affected the expression of ULK1. As such, our study demonstrated that miR-26a-5p might regulate the autophagy in cardiac fibroblasts by targeting ULK1, which may have an effect on cardiac fibrosis. To our knowledge, this is the first study that shows miR-26a-5p regulates the autophagic pathway in cardiac fibroblasts. PMID- 29391492 TI - Comparison of proximal versus distal upper-limb robotic rehabilitation on motor performance after stroke: a cluster controlled trial. AB - This study examined the treatment efficacy of proximal-emphasized robotic rehabilitation by using the InMotion ARM (P-IMT) versus distal-emphasized robotic rehabilitation by using the InMotion WRIST (D-IMT) in patients with stroke. A total of 40 patients with stroke completed the study. They received P-IMT, D-IMT, or control treatment (CT) for 20 training sessions. Primary outcomes were the Fugl-Meyer Assessment (FMA) and Medical Research Council (MRC) scale. Secondary outcomes were the Motor Activity Log (MAL) and wrist-worn accelerometers. The differences on the distal FMA, total MRC, distal MRC, and MAL quality of movement scores among the 3 groups were statistically significant (P = 0.02 to 0.05). Post hoc comparisons revealed that the D-IMT group significantly improved more than the P-IMT group on the total MRC and distal MRC. Furthermore, the distal FMA and distal MRC improved more in the D-IMT group than in the CT group. Our findings suggest that distal upper-limb robotic rehabilitation using the InMotion WRIST system had superior effects on distal muscle strength. Further research based on a larger sample is needed to confirm long-term treatment effects of proximal versus distal upper-limb robotic rehabilitation. PMID- 29391493 TI - The effects of glyphosate, glufosinate, paraquat and paraquat-diquat on soil microbial activity and bacterial, archaeal and nematode diversity. AB - In this study, we investigated the effects of one-off applications of glyphosate, glufosinate, paraquat, and paraquat-diquat on soil microbial diversity and function. All herbicides were added to soil as pure compounds at recommended dose and were incubated under laboratory conditions for 60 days. High-throughput phylogenetic marker gene sequencing revealed that none of the herbicides significantly influenced the richness, evenness and composition of bacterial and archaeal communities. Likewise, the diversity, composition and size of nematode communities were not significantly influenced by any of the herbicides. From a functional perspective, herbicides did not significantly affect fluorescein diacetate hydrolysis (FDA) and beta-glucosidase activities. Furthermore, the ability of soil organisms to utilise 15 substrates was generally unaffected by herbicide application. The only exception to this was a temporary impairment in the ability of soil organisms to utilise three organic acids and an amino acid. Given the global and frequent use of these herbicides, it is important that future studies evaluate their potential impacts on microbial communities in a wider-range of soils and environmental conditions. PMID- 29391494 TI - Spatiotemporal summation and correlation mimicked in a four-emitter light-induced artificial synapse. AB - In the brain, each postsynaptic neuron interconnects many presynaptic neurons and performs functions that are related to summation and recognition as well as correlation. Based on a convolution operation and nonlinear distortion function, we propose a mathematical model to explore the elementary synaptic mechanism. A four-emitter light-induced artificial synapse is implemented on an III-nitride-on silicon platform to validate the device concept for emulating the synaptic behaviors of a biological synapse with multiple presynaptic inputs. In addition to a progressive increase in the amplitude of successive spatiotemporal excitatory postsynaptic voltages, the differences in the stimulations are remembered for signal recognition. When repetitive stimulations are simultaneously applied and last over a long period of time, resonant spatiotemporal correlation occurs because an association is formed between the presynaptic stimulations. Four resonant spatiotemporal correlations of each triple-stimulation combination are experimentally demonstrated and agree well with the simulation results. The repetitive stimulation combinations with prime number-based periods inherently exhibit the maximum capacity of resonant spatiotemporal correlation. Our work offers a new approach to building artificial synapse networks. PMID- 29391495 TI - Author Correction: NaAlTi3O8, A Novel Anode Material for Sodium Ion Battery. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29391496 TI - ATP-dependent conformational change in ABC-ATPase RecF serves as a switch in DNA repair. AB - RecF is a principal member of the RecF pathway. It interacts with RecO and RecR to initiate homologous recombination by loading RecA recombinases on single stranded DNA and displacing single-stranded DNA-binding proteins. As an ATP binding cassette ATPase, RecF exhibits ATP-dependent dimerization and structural homology with Rad50 and SMC proteins. However, the mechanism and action pattern of RecF ATP-dependent dimerization remains unclear. Here, We determined three crystal structures of TTERecF, TTERecF-ATP and TTERecF-ATP?S from Thermoanaerobacter tengcongensis that reveal a novel ATP-driven RecF dimerization. RecF contains a positively charged tunnel on its dimer interface that is essential to ATP binding. Our structural and biochemical data indicate that the Walker A motif serves as a switch and plays a key role in ATP binding and RecF dimerization. Furthermore, Biolayer interferometry assay results showed that the TTERecF interacted with ATP and formed a dimer, displaying a higher affinity for DNA than that of the TTERecF monomer. Overall, our results provide a solid structural basis for understanding the process of RecF binding with ATP and the functional mechanism of ATP-dependent RecF dimerization. PMID- 29391497 TI - Elevated particulate organic carbon export flux induced by internal waves in the oligotrophic northern South China Sea. AB - To understand the biogeochemical response to internal waves in the deep basin of the northern South China Sea (NSCS), particulate organic carbon (POC) export fluxes were quantified for the first time during the passage of large internal waves using drifting sediment traps attached with hydrographic sensors. Results revealed large variations in temperature, nitrate and chlorophyll a (Chl a) concentrations during and after internal waves, suggesting that cold nutrient replete waters may be brought to the euphotic zone in the dissipation zone during and after the passage of internal wave packets, resulted in phytoplankton flourished. Most importantly, POC export fluxes (110.9 +/- 10.7 mg C m-2 d-1) were significantly enhanced after internal waves compared to non-internal wave area (32.6-73.0 mg C m-2 d-1) in the NSCS. Such elevated POC fluxes may be induced by downward flourished biogenic particles, particle aggregation or converged particles from mixed layer triggered by internal waves. PMID- 29391498 TI - COMSOL-Based Modeling and Simulation of SnO2/rGO Gas Sensor for Detection of NO2. AB - Despite SIESTA and COMSOL being increasingly used for the simulation of the sensing mechanism in the gas sensors, there are no modeling and simulation reports in literature for detection of NO2 based rGO/SnO2 sensors. In the present study, we model, simulate, and characterize an NO2 based rGO/SnO2 gas sensor using COMSOL by solving the Poisson's equations under associated boundary conditions of mass, heat and electrical transitions. To perform the simulation, we use an exposure model for presenting the required NO2, a heat transfer model to obtain a reaction temperature, and an electrical model to characterize the sensor's response in the presence of the gas. We characterize the sensor's response in the presence of different concentrations of NO2 at different working temperatures and compare the results with the experimental data, reported by Zhang et al. The results from the simulated sensor show a good agreement with the real sensor with some inconsistencies due to differences between the practical conditions in the real chamber and applied conditions to the analytical equations. The results also show that the method can be used to define and predict the behavior of the rGO-based gas sensors before undergoing the fabrication process. PMID- 29391499 TI - Chaos and dynamical complexity in the quantum to classical transition. AB - We study the largest Lyapunov exponents lambda and dynamical complexity for an open quantum driven double-well oscillator, mapping its dependence on coupling to the environment Gamma as well as effective Planck's constant beta2. We show that in general lambda increases with effective Hilbert space size (as beta decreases, or the system becomes larger and closer to the classical limit). However, if the classical limit is regular, there is always a quantum system with lambda greater than the classical lambda, with several examples where the quantum system is chaotic even though the classical system is regular. While the quantum chaotic attractors are generally of the same family as the classical attractors, we also find quantum attractors with no classical counterpart. Contrary to the standard wisdom, the correspondence limit can thus be the most difficult to achieve for certain classically chaotic systems. These phenomena occur in experimentally accessible regimes. PMID- 29391500 TI - Resistance Switching and Memristive Hysteresis in Visible-Light-Activated Adsorbed ZnO Thin Films. AB - The discovery of resistance switching memristors marks a paradigm shift in the search for alternative non-volatile memory components in the semiconductor industry. Normally a dielectric in these bistable memory cells changes its resistance with an applied electric field or current, albeit retaining the resistive state based on the history of the applied field. Despite showing immense potential, sustainable growth of this new memory technology is bogged down by several factors including cost, intricacies of design, lack of efficient tunability, and issues with scalability and eco-friendliness. Here, we demonstrate a simple arrangement wherein an ethanol-adsorbed ZnO thin film exhibits orders of magnitude change in resistance when activated by visible light. We show that there exists two stable ohmic states, one in the dark and the other in the illuminated regime, as well as a significant delay in the transition between these saturated states. We also demonstrate that visible light acts as a non-invasive tuning parameter for the bistable resistive states. Furthermore, a pinched hysteresis I-V response observed in these devices indicate what seems to be a new type of memristive behaviour. PMID- 29391501 TI - Using Transfer Function Analysis to develop biologically and economically efficient restoration strategies. AB - Rare species across taxonomic groups and biomes commonly suffer from multiple threats and require intensive restoration, including population reintroduction and threat control. Following reintroduction, it is necessary to identify what level of threat control is needed for species to persist over time. Population reintroduction and threat control are time intensive and costly. Thus, it is pragmatic to develop economically efficient restoration strategies. We combined transfer function analysis and economic cost analysis to evaluate the effects of biologically meaningful increases in demographic processes on the persistence of a reintroduced population of a Hawaii endemic long-lived shrub, Delissea waianaeensis. We show that an increase in fertility by 0.419 following the suppression of non-native rodents or an increase by 0.098 in seedling growth following the suppression of invasive molluscs would stabilize the population (i.e., lambda = 1). Though a greater increase in fertility than seedling growth was needed for the reintroduced population to persist over time, increasing fertility by suppressing rodents was the most cost effective restoration strategy. Our study emphasizes the importance of considering the effects of large increases in plant vital rates in population projections and incorporating the economic cost of management actions in demographic models when developing restoration plans for endangered species. PMID- 29391502 TI - Effects of pulsing of light on the dentinogenesis of dental pulp stem cells in vitro. AB - Low power light (LPL) treatment has been widely used in various clinical trials, which has been known to reduce pain and inflammation and to promote wound healing. LPL was also shown to enhance differentiation of stem cells into specific lineages. However, most studies have used high power light in mW order, and there was lack of studies about the effects of very low power light in MUW. In this study, we applied 810 nm LPL of 128 MUW/cm2 energy density in vitro. Upon this value, continuous wave (CW) irradiation did not induce any significant changes for differentiation of human dental pulp stem cells (hDPSCs). However, the membrane hyperpolarization, alkaline phosphatase activity, and intracellular oxidative stress were largely enhanced in the pulsed wave (PW) with 30% of duty cycle and 300-3000 Hz frequencies-LPL in which LED driver work in the form of square wave. After 21 days of daily LPL treatment, Western blot revealed the dentinogenesis in this condition in vitro. This study demonstrates that the very low power light at 810 nm enhanced significant differentiation of hDPSCs in the PW mode and there were duty cycle dependency as well as pulsing frequency dependency in the efficiency. PMID- 29391503 TI - A Wearable High-Resolution Facial Electromyography for Long Term Recordings in Freely Behaving Humans. AB - Human facial expressions are a complex capacity, carrying important psychological and neurological information. Facial expressions typically involve the co activation of several muscles; they vary between individuals, between voluntary versus spontaneous expressions, and depend strongly on personal interpretation. Accordingly, while high-resolution recording of muscle activation in a non laboratory setting offers exciting opportunities, it remains a major challenge. This paper describes a wearable and non-invasive method for objective mapping of facial muscle activation and demonstrates its application in a natural setting. We focus on muscle activation associated with "enjoyment", "social" and "masked" smiles; three categories with distinct social meanings. We use an innovative, dry, soft electrode array designed specifically for facial surface electromyography recording, a customized independent component analysis algorithm, and a short training procedure to achieve the desired mapping. First, identification of the orbicularis oculi and the levator labii superioris was demonstrated from voluntary expressions. Second, the zygomaticus major was identified from voluntary and spontaneous Duchenne and non-Duchenne smiles. Finally, using a wireless device in an unmodified work environment revealed expressions of diverse emotions in face-to-face interaction. Our high-resolution and crosstalk-free mapping, along with excellent user-convenience, opens new opportunities in gaming, virtual-reality, bio-feedback and objective psychological and neurological assessment. PMID- 29391504 TI - Mapping the interaction site and effect of the Siglec-9 inflammatory biomarker on human primary amine oxidase. AB - Human primary amine oxidase (hAOC3), also known as vascular adhesion protein 1, mediates leukocyte rolling and trafficking to sites of inflammation by a multistep adhesion cascade. hAOC3 is absent on the endothelium of normal tissues and is kept upregulated during inflammatory conditions, which is an applicable advantage for imaging inflammatory diseases. Sialic acid binding immunoglobulin like-lectin 9 (Siglec-9) is a leukocyte ligand for hAOC3. The peptide (CARLSLSWRGLTLCPSK) based on the region of Siglec-9 that interacts with hAOC3, can be used as a specific tracer for hAOC3-targeted imaging of inflammation using Positron Emission Tomography (PET). In the present study, we show that the Siglec 9 peptide binds to hAOC3 and triggers its amine oxidase activity towards benzylamine. Furthermore, the hAOC3 inhibitors semicarbazide and imidazole reduce the binding of wild type and Arg/Ala mutated Siglec-9 peptides to hAOC3. Molecular docking of the Siglec-9 peptide is in accordance with the experimental results and predicts that the R3 residue in the peptide interacts in the catalytic site of hAOC3 when the topaquinone cofactor is in the non-catalytic on copper conformation. The predicted binding mode of Siglec-9 peptide to hAOC3 is supported by the PET studies using rodent, rabbit and pig AOC3 proteins. PMID- 29391505 TI - Body ownership and the four-hand illusion. AB - Recent studies of the rubber hand illusion (RHI) have shown that the sense of body ownership is constrained by several factors and yet is still very flexible. However, exactly how flexible is our sense of body ownership? In this study, we address this issue by investigating the following question: is it possible that one may have the illusory experience of owning four hands? Under visual manipulation, the participant adopted the experimenter's first-person perspective (1PP) as if it was his/her own. Sitting face to face, the participant saw four hands-the experimenter's two hands from the adopted 1PP together with the subject's own two hands from the adopted third-person perspective (3PP). We found that: (1) the four-hand illusion did not occur in the passive four-hand condition. (2) In the active four-hand condition, the participants tapped their index fingers, imitated by the experimenter. When tactile stimulations were not provided, the key illusion was not induced, either. (3) Strikingly, once all four hands began to act with the same pattern and received synchronous tactile stimulations at the same time, many participants felt as if they had two more hands. These results show that the sense of body ownership is much more flexible than most researchers have suggested. PMID- 29391506 TI - Therapeutic effects of anti-CD154 antibody in cynomolgus monkeys with advanced rheumatoid arthritis. AB - Rheumatoid arthritis is one major chronic inflammatory systemic autoimmune disease. The CD154-CD40 interactions play a critical role in the regulation of immune responses and the maintenance of autoimmunity. Therefore, we aimed to determine whether anti-CD154 antibody treatment show positive effects on immunomodulation and clinical improvement of sustained severe rheumatoid arthritis in cynomolgus monkeys. Arthritis was induced using chicken type II collagen (CII) and arthritic monkey were divided into control and anti-CD154 treatment groups based on their concentrations of anti-CII antibodies on week 7 post-immunization. Blood and tissue samples were collected on week 16 post immunization. Anti-CD154 antibody treatment improved arthritis and movement, and significantly decreased the numbers of proliferating B cells and the serum levels of anti-type II collagen antibody and sCD154 compared with non-treatment group. Further anti-CD154 antibody treatment significantly decreased the percentage of CD4+ cells and the ratio of CD4+ to CD8+ T cells and significantly increased the percentage of CD8+ cells and effector memory CD8+ cells in peripheral blood. We have shown for the first time in a nonhuman primate model of RA that CD154 blockade has beneficial effects. This study might be valuable as preclinical data of CD154 blockade in nonhuman primate models of severe rheumatoid arthritis. PMID- 29391507 TI - Kisspeptin-10 (KP-10) stimulates osteoblast differentiation through GPR54 mediated regulation of BMP2 expression and activation. AB - Kisspeptin-10 (KP-10) acts as a tumor metastasis suppressor via its receptor, G protein-coupled receptor 54 (GPR54). The KP-10-GPR54 system plays an important role in embryonic kidney development. However, its function in osteoblast differentiation is unknown. Osteoblast differentiation is controlled by a range of hormones and cytokines, such as bone morphogenetic protein (BMPs), and multiple transcription factors, such as Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Distal-less homeobox 5 (Dlx5). In the present study, KP-10-treatment significantly increased the expression of osteogenic genes, including mRNA and protein levels of BMP2, in C3H10T1/2 cells. Moreover, KP-10 induced BMP2-luc activity and increased phosphorylation of Smad1/5/9. In addition, NFATc4 specifically mediated KP-10-induced BMP2 gene expression. However, KP-10 treatment did not induce expression of the BMP2 and Runx2 genes in GPR54-/- cells. To examine whether KP-10 induced secretion of BMP2 to the culture medium, we used the conditioned-medium (C.M) of KP-10 treated medium on C3H10T1/2 cells. Dlx5 and Runx2 expressions were higher in GPR54-/- cells treated with C.M than in those treated with KP-10. These results demonstrate that BMP2 protein has an autocrine effect upon KP-10 treatment. Taken together, these findings suggest that KP-10/GPR54 signaling induces osteoblast differentiation via NFATc4-mediated BMP2 expression. PMID- 29391508 TI - The effects of scaling on age, sex and size relationships in Red-legged Partridges. AB - Wild birds differ in size according to their age and sex, adult birds being larger than juveniles. In the galliforms, males are larger than females, in contrast to some groups, such as the raptors, in which the females are larger. Size generally influences the rank hierarchy within a group of birds, although the age, sex, temperament and behaviour of an individual may override its size related rank order. The scaled size of birds according to age and sex affects their physiology and behaviour. Precise details of body-size differences by age and sex are poorly known in most partridge species. We measured 13,814 wild partridges in a homogenous population over 14 years of study to evaluate size differences within a uniform habitat and population management regime. We show that wild Red-legged Partridges have scaled mass, and body- and wing-lengths consistent with age/sex classes. Power functions between mass and body-length (as a proxy for walking efficiency), and between mass and wing-length (for flight efficiency) differ between juvenile females and males, and adult females and males. We discuss these findings and their physiological, behavioural and ecological implications. PMID- 29391509 TI - Synergistic Anti-tumour Effects of Quercetin and Oncolytic Adenovirus expressing TRAIL in Human Hepatocellular Carcinoma. AB - The combination of oncolytic adenoviruses and specific chemotherapy agents is fast emerging as a novel therapeutic approach for resistan the patocellular carcinoma (HCC) cells. A detailed analysis of the network between adenovirus and chemotherapeutic agents can help design an effective strategy to combat HCC. We sought to investigate whether a combined treatment of ZD55-TRAIL and quercetin can have an enhanced cell-killing effect on HCC cells. In-vitro experiments showed that quercetin can enhance ZD55-TRAIL mediated growth inhibition and apoptosis in HCC cells. In addition, we showed that quercetin reduced ZD55-TRAIL mediated NF-kappaB activation and down-regulated its downstream targets, which in turn promoted the pro-apoptotic action of ZD55-TRAIL. Furthermore, in-vivo experiments in mice injected with HuH-7 cells resulted in significantly greater reduction in tumour growth and volume following combined ZD55-TRAIL and quercetin treatment. In conclusion, we demonstrated that quercetin could sensitize human HCC cells to apoptosis via ZD55-TRAIL in-vitro and in-vivo and presented ZD55 TRAIL and quercetin combination as a suitable anti-HCC therapy. PMID- 29391510 TI - Visual impairment and risk of depression: A longitudinal follow-up study using a national sample cohort. AB - The association of visual impairment and depression has been investigated in several studies based on a cross-sectional design, which cannot delineate temporal relationships. In the present study, we evaluated the influence of visual impairment on depression in all age groups using a longitudinal database of a national sample cohort from 2002 to 2013 provided by the Korean National Health Insurance Service. Of a total of 1,025,340 subjects, 5,846 participants who were registered as visually impaired persons without a previous diagnosis of depression were enrolled at a 1:4 ratio with 23,384 control participants matched for age, sex, income, and region of residence. The crude and adjusted (age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia) hazard ratios (HRs) for the development of depression between the visually impaired and control groups were analyzed using a Cox proportional hazards model. Visual impairment increased the risk of depression after adjusting for age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia (adjusted HR = 1.19, P = 0.002). The risk of depression increased significantly in both the non blindness visual impairment (adjusted HR = 1.15, P = 0.036) and blindness subgroups (adjusted HR = 1.31, P = 0.016), with a higher HR in the blindness subgroup. PMID- 29391511 TI - 'Photonic Hook' based optomechanical nanoparticle manipulator. AB - Specialized electromagnetic fields can be used for nanoparticle manipulation along a specific path, allowing enhanced transport and control over the particle's motion. In this paper, we investigate the optical forces produced by a curved photonic jet, otherwise known as the "photonic hook", created using an asymmetric cuboid. In our case, this cuboid is formed by appending a triangular prism to one side of a cube. A gold nanoparticle immersed in the cuboid's transmitted field moves in a curved trajectory. This result could be used for moving nanoparticles around obstacles; hence we also consider the changes in the photonic hook's forces when relatively large glass and gold obstacles are introduced at the region where the curved photonic jet is created. We show, that despite the obstacles, perturbing the field distribution, a particle can move around glass obstacles of a certain thickness. For larger glass slabs, the particle will be trapped stably near it. Moreover, we noticed that a partial obstruction of the photonic jet's field using the gold obstacle results in a complete disruption of the particle's trajectory. PMID- 29391512 TI - Phenome of pearl quality traits in the mollusc transplant model Pinctada margaritifera. AB - The bivalve Pinctada margaritifera exhibits three main transplant phenotypes derived from the donor (from which a mantle graft tissue, the saibo, is excised), the recipient (into which the saibo is implanted with a nucleus, leading to the formation of a pearl sac "chimera") and the cultured pearls themselves. This first phenome study on the species derived from a large experimental graft. Transplant phenotype was assessed at three scales: 1) macro, pearl size, colour, grade, 2) micro, pearl surface microstructure, and 3) molecular, biomineralisation gene expression level in saibo and pearl sac tissues. From donor to pearl, the phenome revealed fine variations of quality traits dependent on the position on the mantle where the saibo was cut, whose variation could overlap with inter-individual donor phenotype differences. A single donor phenotype could therefore produce multiple pearl phenotypes at the scale of the saibo position, mirroring its original activity at the mantle position level and the colour and shape of the shell. This phenome study provides essential information on phenotypic trait architecture enabling us to explore and explain the main biological functions and pave the way for a phenomic project on P. margaritifera that could benefit the pearl industry. PMID- 29391513 TI - A Systematic Machine Learning Based Approach for the Diagnosis of Non-Alcoholic Fatty Liver Disease Risk and Progression. AB - Prevention and diagnosis of NAFLD is an ongoing area of interest in the healthcare community. Screening is complicated by the fact that the accuracy of noninvasive testing lacks specificity and sensitivity to make and stage the diagnosis. Currently no non-invasive ATP III criteria based prediction method is available to diagnose NAFLD risk. Firstly, the objective of this research is to develop machine learning based method in order to identify individuals at an increased risk of developing NAFLD using risk factors of ATP III clinical criteria updated in 2005 for Metabolic Syndrome (MetS). Secondly, to validate the relative ability of quantitative score defined by Italian Association for the Study of the Liver (IASF) and guideline explicitly defined for the Canadian population based on triglyceride thresholds to predict NAFLD risk. We proposed a Decision Tree based method to evaluate the risk of developing NAFLD and its progression in the Canadian population, using Electronic Medical Records (EMRs) by exploring novel risk factors for NAFLD. Our results show proposed method could potentially help physicians make more informed choices about their management of patients with NAFLD. Employing the proposed application in ordinary medical checkup is expected to lessen healthcare expenditures compared with administering additional complicated test. PMID- 29391514 TI - X-Ray Dark-field Imaging to Depict Acute Lung Inflammation in Mice. AB - The aim of this study was to evaluate the feasibility of early stage imaging of acute lung inflammation in mice using grating-based X-ray dark-field imaging in vivo. Acute lung inflammation was induced in mice by orotracheal instillation of porcine pancreatic elastase. Control mice received orotracheal instillation of PBS. Mice were imaged immediately before and 1 day after the application of elastase or PBS to assess acute changes in pulmonary structure due to lung inflammation. Subsequently, 6 mice from each group were sacrificed and their lungs were lavaged and explanted for histological analysis. A further 7, 14 and 21 days later the remaining mice were imaged again. All images were acquired with a prototype grating-based small-animal scanner to generate dark-field and transmission radiographs. Lavage confirmed that mice in the experimental group had developed acute lung inflammation one day after administration of elastase. Acute lung inflammation was visible as a striking decrease in signal intensity of the pulmonary parenchyma on dark-field images at day 1. Quantitative analysis confirmed that dark-field signal intensity at day 1 was significantly lower than signal intensities measured at the remaining timepoints, confirming that acute lung inflammation can be depicted in vivo with dark-field radiography. PMID- 29391515 TI - Heterologous pathway assembly reveals molecular steps of fungal terreic acid biosynthesis. AB - Terreic acid is a potential anticancer drug as it inhibits Bruton's tyrosine kinase; however, its biosynthetic molecular steps remain unclear. In this work, the individual reactions of terreic acid biosynthesis were determined by stepwise pathway assembly in a heterologous host, Pichia pastoris, on the basis of previous knockout studies in a native host, Aspergillus terreus. Polyketide synthase AtX was found to catalyze the formation of partially reduced polyketide 6-methylsalicylic acid, followed by 3-methylcatechol synthesis by salicylate 1 monooxygenase AtA-mediated decarboxylative hydroxylation of 6-methylsalicylic acid. Our results show that cytochrome P450 monooxygenase AtE hydroxylates 3 methylcatechol, thus producing the next product, 3-methyl-1,2,4-benzenetriol. A smaller putative cytochrome P450 monooxygenase, AtG, assists with this step. Then, AtD causes epoxidation and hydroxyl oxidation of 3-methyl-1,2,4 benzenetriol and produces a compound terremutin, via which the previously unknown function of AtD was identified as cyclooxygenation. The final step involves an oxidation reaction of a hydroxyl group by a glucose-methanol-choline oxidoreductase, AtC, which leads to the final product: terreic acid. Functions of AtD and AtG were determined for the first time. All the genes were reanalyzed and all intermediates and final products were isolated and identified. Our model fully defines the molecular steps and corrects previous results from the literature. PMID- 29391516 TI - The characterization, renoprotection and antioxidation of enzymatic and acidic exopolysaccharides from Hypsizigus marmoreus. AB - The present work was designed to investigate the characterization, as well as the antioxidation and renoprotection in streptozocin (STZ)-induced diabetic mice, of exopolysaccharides (EPS) and the enzymatic-EPS (EEPS) and acidic-EPS (AEPS) hydrolysates, which were separated from the fermentation liquor of Hypsizigus marmoreus. Animal results demonstrated that EPS, EEPS and AEPS had potential antioxidant and renoprotective effects, especially EEPS. Additionally, they were the most effective, reflecting increases in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), total antioxidant capacity (T AOC), and albumin (ALB) of 168.33%, 124.8%, 268.17% 179.49%, and 68.71%, respectively, and decreases in the contents of malondialdehyde (MDA), lipid peroxide (LPO) and levels of serum urea nitrogen (BUN) and creatinine (CRE) by 70.58%, 58.43%, 23.97% and 29.60%, respectively, at a dose of 800 mg/kg compared to those of model mice. Three polysaccharides ameliorated the histopathological alterations which were observed in the kidney of diabetic mice. Furthermore, the characterization of polysaccharides had been expressed. These findings indicated that the EEPS from H. marmoreus possesses more effective renoprotection and antioxidation effects and provided insight into its potential clinical values on preventing diabetes. PMID- 29391517 TI - Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. AB - Curcumin has been reported to exhibit anti-tumorigenic activity; however, since its precise actions remain unclear, its effects are considered to be deceptive. In the present study, we confirmed the anti-tumorigenic effects of curcumin on CML-derived leukemic cells in a xenograft model and in vitro culture system. In vitro pull-down and mass analyses revealed a series of enzymes (carbonyl reductase, glutathione-S-transferase, glyoxalase, etc.) that function in a reactive oxygen species (ROS) metabolic pathway as curcumin-binding targets, the expression of which was up-regulated in human leukemia. Curcumin increased ROS levels over the threshold in leukemic cells, and the antioxidant, glutathione (GSH) and overexpression of curcumin-binding enzymes partially mitigated the up regulation of ROS and growth inhibition caused by curcumin. These results show that curcumin specifically inhibits tumor growth by increasing ROS levels over the threshold through the miscellaneous inhibition of ROS metabolic enzymes. Curcumin has potential in therapy to regulate ROS levels in tumor cells, thereby controlling tumor growth. PMID- 29391518 TI - Age-related changes in function and gene expression of the male and female mouse bladder. AB - We investigated age-related changes in in vivo and in vitro functions and gene expression of the bladder of male and female mice. Mature and aged (12 and 27-30 month old) C57BL/6 mice of both sexes were used. Frequency volume, conscious free moving cystometry and detrusor contractile and relaxant properties in in vitro organ bath were evaluated. mRNA expression level of muscarinic, purinergic, and beta-adrenergic receptors and gene expression changes by cDNA microarray analysis of the bladder were determined. Cystometry demonstrated storage and voiding dysfunctions with ageing in both sexes. Detrusor strips from aged mice showed weaker contractile responses particularly in the cholinergic component and weaker relaxant responses to isoproterenol. These age-related impairments were generally severer in males. mRNA expression of bladder tissue was decreased for M3 muscarinic receptors in aged males and beta2-adrenoceptors in aged females. cDNA microarray analysis results, albeit substantial sex difference, indicated "cell to-cell signaling and interaction" as the most common feature of age-related gene expression. In summary, aged mice demonstrated voiding and storage dysfunctions resembling to detrusor hyperactivity with impaired contractility (DHIC), which were more pronounced in males. Genomic changes associated with aging may contribute to the age-related bladder functional deterioration in mice. PMID- 29391519 TI - Author Correction: Characterization of slow cycling corneal limbal epithelial cells identifies putative stem cell markers. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29391520 TI - Evaluating upper limb impairments in multiple sclerosis by exposure to different mechanical environments. AB - Multiple sclerosis is a chronic, autoimmune and neurodegenerative disease affecting multiple functional systems and resulting in motor impairments associated with muscle weakness and lack of movement coordination. We quantified upper limb motor deficits with a robot-based assessment including behavioral and muscle synergy analysis in 11 multiple sclerosis subjects with mild to moderate upper limb impairment (9 female; 50 +/- 10 years) compared to 11 age- and gender- matched controls (9 female; 50 +/- 9 years). All subjects performed planar reaching tasks by moving their upper limb or applying force while grasping the handle of a robotic manipulandum that generated four different environments: free space, assistive or resistive forces, and rigid constraint. We recorded the activity of 15 upper body muscles. Multiple sclerosis subjects generated irregular trajectories. While activities in isolated arm muscles appeared generally normal, shoulder muscle coordination with arm motions was impaired and there was a marked co-activation of the biceps and triceps in extension movements. Systematic differences in timing and organization of muscle synergies have also been observed. This study supports the definition of new biomarkers and rehabilitative treatments for improving upper limb motor coordination in multiple sclerosis. PMID- 29391521 TI - A clinical and molecular characterisation of CRB1-associated maculopathy. AB - To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date. PMID- 29391523 TI - Observation of Time Reversed Light Propagation by an Exchange of Eigenstates. AB - As time flow dictates all evolution, its effective reversal is a topic of active research in a broad range of disciplines, including acoustics, hydrodynamics and optics. This multifarious set of environments is reflected by a great diversity of approaches to observe various echoes of wave functions. Here, we experimentally demonstrate time reversal of a pulse sequence propagating through a photonic mesh lattice realized by two coupled loops of telecommunication fibres. Our system features a symmetric band structure, which allows for almost perfect reversal of its evolution by exchanging the population between two opposing bands. The protocol applied is based on a non-adiabatic and instantaneous exchange of eigenstates resulting in highly efficient time reversal of a pulse chain. PMID- 29391522 TI - Cultural effects on computational metrics of spatial and temporal context. AB - The concept of "prediction error" - the difference between what occurred and was expected - is key to understanding the cognitive processes of human decision making. Expectations have to be learned so the concept of prediction error critically depends on context, specifically the temporal context of probabilistically related events and their changes across time (i.e. volatility). While past research suggests context differently affects some cognitive processes in East Asian and Western individuals, it is currently unknown whether this extends to computationally-grounded measures of learning and prediction error. Here we compared Chinese and British nationals in an associative learning task that quantifies behavioural effects of prediction error, and-through a hierarchical Bayesian learning model-also captures how individuals learn about probabilistic relationships and their volatility. For comparison, we also administered a psychophysical task, the tilt illusion, to assess cultural differences in susceptibility to spatial context. We found no cultural differences in the effect of spatial context on perception. In the domain of temporal context there was no effect of culture on sensitivity to prediction error, or learning about volatility, but some suggestion that Chinese individuals may learn more readily about probabilistic relationships. PMID- 29391524 TI - Evaluation of infliximab as second-line treatment of acute graft versus host disease -validating response on day 7 and 28 as predictors of survival. AB - Several immunosuppressive drugs have been proposed for second-line treatment of steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation. However, the studies on these drugs are small, retrospective, uncontrolled and use different endpoints. Therefore, it remains unknown which treatment is superior. We retrospectively evaluated 68 consecutive patients treated with infliximab for aGvHD. We adhered to recently proposed guidelines for aGvHD trials and thus evaluated response on day 7 and 28. Furthermore, we assessed the composite endpoint 6 months freedom from treatment failure (6MFTF). The majority of patients had grade III-IV aGvHD. We found that 41 patients (60%) responded on day 7 and 31 patients (46%) on day 28. Twenty-four patients (35%) achieved 6MFTF. The main reasons for failure within 6 months were death (n = 31) or additional immunosuppression (n = 16). By six and 24 months, 44 and 34% of the patients were alive respectively. Patients with response to infliximab on day 7 and 28 had significantly higher overall survival (OS) probability than non-responders. We show that response on day 7 and 28 identifies high and low risk groups. Patients who fail to respond should be identified early and offered alternative therapy. PMID- 29391525 TI - Rituximab for second desensitization in patients with rebound of donor-specific anti-HLA antibodies before T-replete haplo-transplant using high-dose post transplant cyclophosphamide. PMID- 29391526 TI - Whole metagenome sequencing reveals links between mosquito microbiota and insecticide resistance in malaria vectors. AB - In light of the declining global malaria burden attained largely due to insecticides, a deeper understanding of the factors driving insecticide resistance is needed to mitigate its growing threat to malaria vector control programs. Following evidence of microbiota-mediated insecticide resistance in agricultural pests, we undertook a comparative study of the microbiota in mosquitoes of differing insecticide resistance status. The microbiota of wild caught Anopheles albimanus, an important Latin American malaria vector, that were resistant (FEN_Res) or susceptible (FEN_Sus) to the organophosphate (OP) insecticide fenitrothion were characterized and compared using whole metagenome sequencing. Results showed differing composition of the microbiota and its functions between FEN_Res and FEN_Sus, with significant enrichment of OP degrading bacteria and enzymes in FEN_Res compared to FEN_Sus. Lower bacterial diversity was observed in FEN_Res compared to FEN_Sus, suggesting the enrichment of bacterial taxa with a competitive advantage in response to insecticide selection pressure. We report and characterize for the first time whole metagenomes of An. albimanus, revealing associations between the microbiota and phenotypic resistance to the insecticide fenitrothion. This study lays the groundwork for further investigation of the role of the mosquito microbiota in insecticide resistance. PMID- 29391527 TI - High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer. AB - The gene encoding the ATPase of the chromatin remodeling SWI/SNF complexes SMARCA4 (BRG1) is often mutated or silenced in tumors, suggesting a role as tumor suppressor. Nonetheless, recent reports show requirement of SMARCA4 for tumor cells growth. Here, we performed a computational meta-analysis using gene expression, prognosis, and clinicopathological data to clarify the role of SMARCA4 and the alternative SWI/SNF ATPase SMARCA2 (BRM) in cancer. We show that while the SMARCA4 gene is mostly overexpressed in tumors, SMARCA2 is almost invariably downexpressed in tumors. High SMARCA4 expression was associated with poor prognosis in many types of tumors, including liver hepatocellular carcinoma (LIHC), and kidney renal clear cell carcinoma (KIRC). In contrast, high SMARCA2 expression was associated with good prognosis. We compared tumors with high versus low expression of SMARCA4 or SMARCA2 in LIHC and KIRC cohorts from The Cancer Genome Atlas. While a high expression of SMARCA4 is associated with aggressive tumors, a high expression of SMARCA2 is associated with benign differentiated tumors, suggesting that SMARCA4 and SMARCA2 play opposite roles in cancer. Our results demonstrate that expression of SMARCA4 and SMARCA2 have a high prognostic value and challenge the broadly accepted general role of SMARCA4 as a tumor suppressor. PMID- 29391528 TI - Unravelling genetic variation underlying de novo-synthesis of bovine milk fatty acids. AB - The relative abundance of specific fatty acids in milk can be important for consumer health and manufacturing properties of dairy products. Understanding of genes controlling milk fat synthesis may contribute to the development of dairy products with high quality and nutritional value. This study aims to identify key genes and genetic variants affecting de novo synthesis of the short- and medium chained fatty acids C4:0 to C14:0. A genome-wide association study using 609,361 SNP markers and 1,811 animals was performed to detect genomic regions affecting fatty acid levels. These regions were further refined using sequencing data to impute millions of additional genetic variants. Results suggest associations of PAEP with the content of C4:0, AACS with the content of fatty acids C4:0-C6:0, NCOA6 or ACSS2 with the longer chain fatty acids C6:0-C14:0, and FASN mainly associated with content of C14:0. None of the top-ranking markers caused amino acid shifts but were mostly situated in putatively regulating regions and suggested a regulatory role of the QTLs. Sequencing mRNA from bovine milk confirmed the expression of all candidate genes which, combined with knowledge of their roles in fat biosynthesis, supports their potential role in de novo synthesis of bovine milk fatty acids. PMID- 29391529 TI - Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy. AB - The hereditary neurodegenerative disorder spinal muscular atrophy (SMA) is characterized by the loss of spinal cord motor neurons and skeletal muscle atrophy. SMA is caused by mutations of the survival motor neuron (SMN) gene leading to a decrease in SMN protein levels. The SMN deficiency alters nuclear body formation and whether it can contribute to the disease remains unclear. Here we screen a series of small-molecules on SMA patient fibroblasts and identify flunarizine that accumulates SMN into Cajal bodies, the nuclear bodies important for the spliceosomal small nuclear RNA (snRNA)-ribonucleoprotein biogenesis. Using histochemistry, real-time RT-PCR and behavioural analyses in a mouse model of SMA, we show that along with the accumulation of SMN into Cajal bodies of spinal cord motor neurons, flunarizine treatment modulates the relative abundance of specific spliceosomal snRNAs in a tissue-dependent manner and can improve the synaptic connections and survival of spinal cord motor neurons. The treatment also protects skeletal muscles from cell death and atrophy, raises the neuromuscular junction maturation and prolongs life span by as much as 40 percent (p < 0.001). Our findings provide a functional link between flunarizine and SMA pathology, highlighting the potential benefits of flunarizine in a novel therapeutic perspective against neurodegenerative diseases. PMID- 29391530 TI - Inferring genetic origins and phenotypic traits of George Bahr, the architect of the Dresden Frauenkirche. AB - For historic individuals, the outward appearance and other phenotypic characteristics remain often non-resolved. Unfortunately, images or detailed written sources are only scarcely available in many cases. Attempts to study historic individuals with genetic data so far focused on hypervariable regions of mitochondrial DNA and to some extent on complete mitochondrial genomes. To elucidate the potential of in-solution based genome-wide SNP capture methods - as now widely applied in population genetics - we extracted DNA from the 17th century remains of George Bahr, the architect of the Dresdner Frauenkirche. We were able to identify the remains to be of male origin, showing sufficient DNA damage, deriving from a single person and being thus likely authentic. Furthermore, we were able to show that George Bahr had light skin pigmentation and most likely brown eyes. His genomic DNA furthermore points to a Central European origin. We see this analysis as an example to demonstrate the prospects that new in-solution SNP capture methods can provide for historic cases of forensic interest, using methods well established in ancient DNA (aDNA) research and population genetics. PMID- 29391532 TI - Bafilomycin C1 exert antifungal effect through disturbing sterol biosynthesis in Candida albicans. AB - In a previous study on discovering new antimicrobial agents from microbial sources, nine bafilomycins were isolated from the fermentation broth of Streptomyces albolongus. Among them, bafilomycin C1 (Baf C1) showed strong antifungal activity against Candida albicans, with MIC value of 1.56 MUg/mL. The aim of this study was to evaluate the action mechanism of Baf C1 against C. albicans. Quantitative PCR analysis revealed that ergosterol biosynthesis-related genes of C. albicans ACS1, HMG1, IDI1, ERG1, ERG2, ERG6, ERG7, ERG8, ERG9, ERG12, ERG13, ERG20, ERG24, ERG251, ERG252, ERG26, ERG27, and ERG28 were all down regulated (Log2fold change < -1) after Baf C1(4 MUg/mL) exposure. Moreover, the expression of MET6 gene, encoded methionine synthase, was also down-regulated (2.7-fold). It is corresponding with the quantitative PCR result, the content of ergosterol has dropped about 41% compared with the control. Transmission electron microscope examination also revealed that the Baf C1 strongly destroyed the cell membrane of C. albicans. In addition, the content of farnesol was significantly increased, about 2.1-fold compared with the control. The results indicated Baf C1 caused aberrations in sterol biosynthesis, leaded to the lack of ergosterol of the fungal membrane. PMID- 29391531 TI - Molecular identification, transcript expression, and functional deorphanization of the adipokinetic hormone/corazonin-related peptide receptor in the disease vector, Aedes aegypti. AB - The recently discovered adipokinetic hormone/corazonin-related peptide (ACP) is an insect neuropeptide structurally intermediate between corazonin (CRZ) and adipokinetic (AKH) hormones, which all demonstrate homology to the vertebrate gonadotropin-releasing hormone (GnRH). To date, the function of the ACP signaling system remains unclear. In the present study, we molecularly identified the complete open reading frame encoding the Aedes aegypti ACP receptor (ACPR), which spans nine exons and undergoes alternative splicing giving rise to three transcript variants. Only a single variant, AedaeACPR-I, yielding a deduced 577 residue protein, contains all seven transmembrane domains characteristic of rhodopsin-like G protein-coupled receptors. Functional deorphanization of AedaeACPR-I using a heterologous cell culture-based system revealed highly selective and dose-dependent receptor activation by AedaeACP (EC50 = 10.25 nM). Analysis of the AedaeACPR-I and AedaeACP transcript levels in all post-embryonic developmental stages using quantitative RT-PCR identified enrichment of both transcripts after adult eclosion. Tissue-specific expression profiling in adult mosquitoes reveals expression of the AedaeACPR-I receptor transcript in the central nervous system, including significant enrichment within the abdominal ganglia. Further, the AedaeACP transcript is prominently detected within the brain and thoracic ganglia. Collectively, these results indicate a neuromodulator or neurotransmitter role for ACP and suggest this neuropeptide may function in regulation of post-ecdysis activities. PMID- 29391533 TI - 'Cold shock' increases the frequency of homology directed repair gene editing in induced pluripotent stem cells. AB - Using CRISPR/Cas9 delivered as a RNA modality in conjunction with a lipid specifically formulated for large RNA molecules, we demonstrate that homology directed repair (HDR) rates between 20-40% can be achieved in induced pluripotent stem cells (iPSC). Furthermore, low HDR rates (between 1-20%) can be enhanced two to ten-fold in both iPSCs and HEK293 cells by 'cold shocking' cells at 32 degrees C for 24-48 hours following transfection. This method can also increases the proportion of loci that have undergone complete sequence conversion across the donor sequence, or 'perfect HDR', as opposed to partial sequence conversion where nucleotides more distal to the CRISPR cut site are less efficiently incorporated ('partial HDR'). We demonstrate that the structure of the single stranded DNA oligo donor can influence the fidelity of HDR, with oligos symmetric with respect to the CRISPR cleavage site and complementary to the target strand being more efficient at directing 'perfect HDR' compared to asymmetric non-target strand complementary oligos. Our protocol represents an efficient method for making CRISPR-mediated, specific DNA sequence changes within the genome that will facilitate the rapid generation of genetic models of human disease in iPSCs as well as other genome engineered cell lines. PMID- 29391534 TI - Strain-engineered two-dimensional MoS2 as anode material for performance enhancement of Li/Na-ion batteries. AB - Recent years have witnessed a surge of research in two-dimensional (2D) nanostructures for development of new rechargeable Li/Na-ion battery systems. Herein, via first-principles calculations we demonstrate strain-engineered Li/Na adsorption and storage in 2D MoS2 as anode material, aiming to enhance the operating performance of Li/Na-ion batteries. Our results show that tensile strain greatly increases the adsorption of Li/Na atoms on MoS2, and a modest strain of 6% increases Li (Na) adsorption energy by over 70%, which originates from the strain-induced upshift of Mo d states towards Fermi level that interact strongly with Li/Na s states, in analogy with the d-band model in metal catalyst. Significant narrowing of the n-doped semiconducting gap of MoS2 suggests the improved electric conductivity that may benefit charge carrier transport. By mapping out the potential energy surfaces, we show shallow energy barriers of ion diffusion with ~0.2 eV for Li and 0.1 eV for Na. Furthermore, the strain-steered competition between chemical bonding and coulomb repulsion results in high Li/Na storage capability and relatively low average operating voltage. We believe that the fundamental principle underlying the use of strain to enhance performance of renewable ion battery is applicable to other stretchable low-dimensional nanomaterials. PMID- 29391535 TI - Kaempferol mitigates Endoplasmic Reticulum Stress Induced Cell Death by targeting caspase 3/7. AB - The Endoplasmic Reticulum (ER) plays a fundamental role in executing multiple cellular processes required for normal cellular function. Accumulation of misfolded/unfolded proteins in the ER triggers ER stress which contributes to progression of multiple diseases including neurodegenerative disorders. Recent reports have shown that ER stress inhibition could provide positive response against neuronal injury, ischemia and obesity in in vivo models. Our search towards finding an ER stress inhibitor has led to the functional discovery of kaempferol, a phytoestrogen possessing ER stress inhibitory activity in cultured mammalian cells. We have shown that kaempferol pre-incubation significantly inhibits the expression of GRP78 (a chaperone) and CHOP (ER stress associated pro apoptotic transcription factor) under stressed condition. Also, our investigation in the inhibitory specificity of kaempferol has revealed that it inhibits cell death induced by diverse stimuli. Further study on exploring the molecular mechanism implied that kaempferol renders protection by targeting caspases. Both the in silico docking and in vitro assay using recombinant caspase-3 enzyme confirmed the binding of kaempferol to caspases, through an allosteric mode of competitive inhibition. Altogether, we have demonstrated the ability of kaempferol to alleviate ER stress in in vitro model. PMID- 29391536 TI - A practical solution for preserving single cells for RNA sequencing. AB - The design and implementation of single-cell experiments is often limited by their requirement for fresh starting material. We have adapted a method for histological tissue fixation using dithio-bis(succinimidyl propionate) (DSP), or Lomant's Reagent, to stabilise cell samples for single-cell transcriptomic applications. DSP is a reversible cross-linker of free amine groups that has previously been shown to preserve tissue integrity for histology while maintaining RNA integrity and yield in bulk RNA extractions. Although RNA-seq data from DSP-fixed single cells appears to be prone to characteristic artefacts, such as slightly reduced yield of cDNA and a detectable 3' bias in comparison with fresh cells, cell preservation using DSP does not appear to substantially reduce RNA complexity at the gene level. In addition, there is evidence that instantaneous fixation of cells can reduce inter-cell technical variability. The ability of DSP-fixed cells to retain commonly used dyes, such as propidium iodide, enables the tracking of experimental sub-populations and the recording of cell viability at the point of fixation. Preserving cells using DSP will remove several barriers in the staging of single-cell experiments, including the transport of samples and the scheduling of shared equipment for downstream single cell isolation and processing. PMID- 29391537 TI - Targeting histone deacetylase and NFkappaB signaling as a novel therapy for Mucoepidermoid Carcinomas. AB - Malignancies from the salivary glands are rare and represent 11% of all cancers from the oropharyngeal anatomical area. Mucoepidermoid Carcinomas (MEC) is the most common malignancy from the salivary glands. Low survival rates of high-grade Mucoepidermoid Carcinomas (MEC) are particularly associated with the presence of positive lymph nodes, extracapsular lymph node spread, and perineural invasion. Most recently, the presence of cancer stem cells (CSC), and the activation of the NFkappaB signaling pathway have been suggested as cues for an acquired resistance phenotype. We have previously shown that NFkappaB signaling is very active in MEC tumors. Herein, we explore the efficacy of NFkappaB inhibition in combination with class I and II HDAC inhibitor to deplete the population of CSC and to destroy MEC tumor cells. Our finding suggests that disruption of NFkappaB signaling along with the administration of HDAC inhibitors constitute an effective strategy to manage MEC tumors. PMID- 29391538 TI - Chitosan nanoparticles functionalized with beta-cyclodextrin: a promising carrier for botanical pesticides. AB - Carvacrol and linalool are natural compounds extracted from plants and are known for their insecticidal and repellent activities, respectively. However, their low aqueous solubility, high photosensitivity, and high volatility restrict their application in the control of agricultural pests. The encapsulation of volatile compounds can be an effective way of overcoming such problems. Inclusion complexes between beta-cyclodextrin (beta-CD) and carvacrol (CVC) or linalool (LNL) were investigated. Inclusion complexes were prepared by the kneading method. Both complexes presented 1:1 host:guest stoichiometry and the highest affinity constants were observed at 20 degrees C for both molecules. The nanoparticles containing carvacrol and linalool had mean diameters of 175.2 and 245.8 nm, respectively and high encapsulation efficiencies (<90%) were achieved for both compounds. Biological assays with mites (Tetranychus urticae) showed that the nanoparticles possessed repellency, acaricidal, and oviposition activities against this organism. Nanoencapsulated carvacrol and linalool were significantly more effective in terms of acaricidal and oviposition activities, while the unencapsulated compounds showed better repellency activity. The nanoformulations prepared in this study are good candidates for the sustainable and effective use of botanical compounds in agriculture, contributing to the reduction of environmental contamination, as well as promoting the effective control of pests in agriculture. PMID- 29391540 TI - 4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1. AB - 4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA. In mice, FA protected against high-fat diet-induced weight gain, reduced food intake and exhibited an overall improved metabolic phenotype. The food intake suppression by FA was accompanied by a specific reduction in hypothalamic orexigenic neuropeptides, including agouti-related protein and neuropeptide Y, with no significant changes in the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-regulated transcript. FA treatment also inhibited fat accumulation in the liver and white adipose tissue and suppressed the expression of gluconeogenic genes, including phosphoenolpyruvate carboxylase and glucose-6 phosphatase. Furthermore, we show that FA phosphorylated and inactivated the transcription factor FoxO1, which positively regulates the expression of gluconeogenic and orexigenic genes, providing evidence that FA might exert its beneficial metabolic effects through inhibition of FoxO1 function in the periphery and the hypothalamus. PMID- 29391539 TI - Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. AB - Hepcidin is a crucial peptide for regulating cellular iron efflux. Because iron is essential for cell survival, especially for highly active cells, such as tumor cells, it is imperative to understand how tumor cells manipulate hepcidin expression for their own metabolic needs. Studies suggest that hepcidin expression and regulation in tumor cells show important differences in comparison with those in non-tumorous cells. These differences should be investigated to develop new strategies to fight cancer cells. Manipulating hepcidin expression to starve cancer cells for iron may prove to be a new therapy in the anticancer arsenal. PMID- 29391541 TI - Arginase II inhibition prevents interleukin-8 production through regulation of p38 MAPK phosphorylation activated by loss of mitochondrial membrane potential in nLDL-stimulated hAoSMCs. AB - Arginase inhibition exhibits beneficial effects in vascular endothelial and smooth muscle cells. In human aortic smooth muscle cells (hAoSMCs), native low density lipoprotein (nLDL) induced the production of interleukin-8 (IL-8) that is involved in the pathogenesis of cardiovascular diseases. Therefore, we examined the effect of arginase inhibition on IL-8 production and the underlying mechanism. In hAoSMCs, reverse transcription-PCR, western blotting and immunocytochemistry with MitoTracker confirmed that arginase II was confined predominantly to mitochondria. The mitochondrial membrane potential (MMP) was assessed using tetramethylrhodamine ethyl ester. The MMP decreased upon nLDL stimulation but was restored upon arginase inhibition. MMP loss caused by nLDL was prevented by treatment with the intracellular Ca2+ chelator BAPTA-AM. In mitochondrial Ca2+ measurements using Rhod-2 AM, increased mitochondrial Ca2+ levels by nLDL were inhibited upon preincubation with an arginase inhibitor. Among the polyamines, spermine, an arginase activity-dependent product, caused mitochondrial Ca2+ movement. The nLDL-induced MMP change resulted in p38 mitogen activated protein kinase (MAPK) phosphorylation and IL-8 production and was prevented by the arginase inhibitors BAPTA and ruthenium 360. In isolated AoSMCs from ApoE-/- mice fed a high-cholesterol diet, arginase activity, p38 MAPK phosphorylation, spermine and mitochondrial Ca2+ levels and keratinocyte-derived chemokine (KC) production were increased compared with wild-type (WT) mice. However, in AoSMCs isolated from arginase II-null mice, increases in MMP and decreases in mitochondrial Ca2+ levels were noted compared with WT and were associated with p38 MAPK activation and IL-8 production. These data suggest that arginase activity regulates the change in MMP through Ca2+ uptake that is essential for p38 MAPK phosphorylation and IL-8 production. PMID- 29391542 TI - Multi-radial LBP Features as a Tool for Rapid Glomerular Detection and Assessment in Whole Slide Histopathology Images. AB - We demonstrate a simple and effective automated method for the localization of glomeruli in large (~1 gigapixel) histopathological whole-slide images (WSIs) of thin renal tissue sections and biopsies, using an adaptation of the well-known local binary patterns (LBP) image feature vector to train a support vector machine (SVM) model. Our method offers high precision (>90%) and reasonable recall (>70%) for glomeruli from WSIs, is readily adaptable to glomeruli from multiple species, including mouse, rat, and human, and is robust to diverse slide staining methods. Using 5 Intel(R) Core(TM) i7-4790 CPUs with 40 GB RAM, our method typically requires ~15 sec for training and ~2 min to extract glomeruli reproducibly from a WSI. Deploying a deep convolutional neural network trained for glomerular recognition in tandem with the SVM suffices to reduce false positives to below 3%. We also apply our LBP-based descriptor to successfully detect pathologic changes in a mouse model of diabetic nephropathy. We envision potential clinical and laboratory applications for this approach in the study and diagnosis of glomerular disease, and as a means of greatly accelerating the construction of feature sets to fuel deep learning studies into tissue structure and pathology. PMID- 29391543 TI - MtNRLK1, a CLAVATA1-like leucine-rich repeat receptor-like kinase upregulated during nodulation in Medicago truncatula. AB - Peptides are signaling molecules regulating various aspects of plant development, including the balance between cell division and differentiation in different meristems. Among those, CLAVATA3/Embryo Surrounding Region-related (CLE-ESR) peptide activity depends on leucine-rich-repeat receptor-like-kinases (LRR-RLK) belonging to the subclass XI. In legume plants, such as the Medicago truncatula model, specific CLE peptides were shown to regulate root symbiotic nodulation depending on the LRR-RLK SUNN (Super Numeric Nodules). Amongst the ten M. truncatula LRR-RLK most closely related to SUNN, only one showed a nodule-induced expression, and was so-called MtNRLK1 (Nodule-induced Receptor-Like Kinase 1). MtNRLK1 expression is associated to root and nodule vasculature as well as to the proximal meristem and rhizobial infection zone in the nodule apex. Except for the root vasculature, the MtNRLK1 symbiotic expression pattern is different than the one of MtSUNN. Functional analyses either based on RNA interference, insertional mutagenesis, and overexpression of MtNRLK1 however failed to identify a significant nodulation phenotype, either regarding the number, size, organization or nitrogen fixation capacity of the symbiotic organs formed. PMID- 29391544 TI - Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet. AB - C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP-VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid beta-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity. PMID- 29391545 TI - Effects of the floral phytochemical eugenol on parasite evolution and bumble bee infection and preference. AB - Ecological and evolutionary pressures on hosts and parasites jointly determine infection success. In pollinators, parasite exposure to floral phytochemicals may influence between-host transmission and within-host replication. In the bumble bee parasite Crithidia bombi, strains vary in phytochemical resistance, and resistance increases under in vitro selection, implying that resistance/infectivity trade-offs could maintain intraspecific variation in resistance. We assessed costs and benefits of in vitro selection for resistance to the floral phytochemical eugenol on C. bombi infection in Bombus impatiens fed eugenol-rich and eugenol-free diets. We also assessed infection-induced changes in host preferences for eugenol. In vitro, eugenol-exposed cells initially increased in size, but normalized during adaptation. Selection for eugenol resistance resulted in considerable (55%) but non-significant reductions in infection intensity; bee colony and body size were the strongest predictors of infection. Dietary eugenol did not alter infection, and infected bees preferred eugenol-free over eugenol-containing solutions. Although direct effects of eugenol exposure could influence between-host transmission at flowers, dietary eugenol did not ameliorate infection in bees. Limited within-host benefits of resistance, and possible trade-offs between resistance and infectivity, may relax selection for eugenol resistance and promote inter-strain variation in resistance. However, infection-induced dietary shifts could influence pollinator mediated selection on floral traits. PMID- 29391547 TI - Identification and whole-genome characterization of a recombinant Enterovirus B69 isolated from a patient with Acute Flaccid Paralysis in Niger, 2015. AB - Enterovirus B69 (EV-B69) is a rarely reported type and till date, only the full length genome sequence of the prototype strain is available. Besides the prototype strain, only limited VP1 sequences of this virus from Africa and India are available in GenBank. In this study, we analyzed the full-length genome sequence of an EV-B69 strain recovered from a patient with acute flaccid paralysis in Niger. Compared with the EV-B69 prototype strain, it had 79.6% and 76.3% nucleotide identity in the complete genome and VP1 coding region, respectively. VP1 sequence analyses revealed also high variation in nucleotide similarity (68.9%-82.8%) with previously isolated EV-B69 strains in India and Africa. The great genetic divergence among EV-B69 strains indicates that this type is not a newly emergent virus, but has circulated for many years at low epidemic strength. Phylogenetic incongruity between structural and non-structural regions and similarity plot analyses revealed that multiple recombination events occurred during its evolution. This study expands the number of EV-B69 whole genome sequences which would help genomic comparison for future studies to understand the biological and pathogenic properties of this virus, assess its potential public health impact and comprehend the role of recombination in the evolution of enteroviruses. PMID- 29391546 TI - The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice. AB - Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9-10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and stem cell functions. The GI-protective effects are associated with rapid and selective induction of tight junction proteins and cytokines including TGF-beta, IL-10, IL-17a, IL-22 and Notch signaling long before bone marrow depletion. However, no change was observed in crypt death or the expression of prototypic pro-inflammatory cytokines such as TNF-alpha, IL-6 or IL-1beta. Surprisingly, bone marrow transplantation (BMT) performed 24 hours after TBI improves intestinal barrier and stem cell recovery with induction of IL-10, IL-17a, IL-22, and Notch signaling. Further, BMT-rescued TBI survivors display increased intestinal permeability, impaired ISC function and proliferation, but not obvious intestinal inflammation or increased epithelial death. These findings identify intestinal epithelium as a novel target of radiation mitigation, and potential strategies to enhance ISC recovery and regeneration after accidental or medical exposures. PMID- 29391548 TI - Arrhythmogenicity of fibro-fatty infiltrations. AB - The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset. PMID- 29391549 TI - Growth and structural characterisation of Sr-doped Bi2Se3 thin films. AB - We grew Sr-doped Bi2Se3 thin films using molecular beam epitaxy, and their high quality was verified using transmission electron microscopy. The thin films exhibited weak antilocalisation behaviours in magneto-resistance measurements, a typical transport signature of topological insulators, but were not superconducting. In addition, the carrier densities of the non-superconducting thin-film samples were similar to those of their superconducting bulk counterparts. Atom-by-atom energy-dispersive X-ray mapping also revealed similar Sr doping structures in the bulk and thin-film samples. Because no qualitative distinction between non-superconducting thin-film and superconducting bulk samples had been found, we turned to a quantitative statistical analysis, which uncovered a key structural difference between the bulk and thin-film samples. The separation between Bi layers in the same quintuple layer was compressed whereas that between the closest Bi layers in two neighbouring quintuple layers was expanded in the thin-film samples compared with the separations in pristine bulk Bi2Se3. In marked contrast, the corresponding changes in the bulk doped samples showed opposite trends. These differences may provide insight into the absence of superconductivity in doped topological insulator thin films. PMID- 29391550 TI - Understanding non-linear effects from Hill-type dynamics with application to decoding of p53 signaling. AB - Analytical equations are derived depicting four possible scenarios resulting from pulsed signaling of a system subject to Hill-type dynamics. Pulsed Hill-type dynamics involves the binding of multiple signal molecules to a receptor and occurs e.g., when transcription factor p53 orchestrates cancer prevention, during calcium signaling, and during circadian rhythms. The scenarios involve: (i) enhancement of high-affinity binders compared to low-affinity ones, (ii) slowing reactions involving high-affinity binders, (iii) transfer of the clocking of low affinity binders from the signal molecule to the products, and (iv) a unique clocking process that produces incremental increases in the activity of high affinity binders with each signal pulse. In principle, these mostly non-linear effects could control cellular outcomes. An applications to p53 signaling is developed, with binding to most gene promoters identified as category (iii) responses. However, currently unexplained enhancement of high-affinity promoters such as CDKN1a (p21) by pulsed signaling could be an example of (i). In general, provision for all possible scenarios is required in the design of mathematical models incorporating pulsed Hill-type signaling as some aspect. PMID- 29391551 TI - A conserved motif within cox 2 allows broad detection of economically important fruit flies (Diptera: Tephritidae). AB - The genera Anastrepha, Bactrocera, Ceratitis, Dacus and Rhagoletis in the family Tephritidae order Diptera are economically important, worldwide distributed and cause damage to a large number of commercially produced fruits and vegetables. China had regulated these five genera as quarantine pests, including the species Carpomya vesuviana. An accurate molecular method not depending on morphology able to detect all the quarantine fruit flies simultaneously is required for quarantine monitoring. This study contributes a comparative analysis of 146 mitochondrial genomes of Diptera species and found variable sites at the mt DNA cox2 gene only conserved in economically important fruit flies species. Degenerate primers (TephFdeg/TephR) were designed specific for the economically important fruit flies. A 603 bp fragment was amplified after testing each of the 40 selected representative species belonging to each economically important Tephritid genera, no diagnostic fragments were detected/amplified in any of the other Tephritidae and Diptera species examined. PCR sensitivity assays demonstrated the limit of detection of targeted DNA was 0.1 ng/MUl. This work contributes an innovative approach for detecting all reported economically important fruit flies in a single-step PCR specific for reported fruit fly species of quarantine concern in China. PMID- 29391552 TI - Reducing acquisition time for MRI-based forensic age estimation. AB - Radiology-based estimation of a living person's unknown age has recently attracted increasing attention due to large numbers of undocumented immigrants entering Europe. To avoid the application of X-ray-based imaging techniques, magnetic resonance imaging (MRI) has been suggested as an alternative imaging modality. Unfortunately, MRI requires prolonged acquisition times, which potentially represents an additional stressor for young refugees. To eliminate this shortcoming, we investigated the degree of reduction in acquisition time that still led to reliable age estimates. Two radiologists randomly assessed original images and two sets of retrospectively undersampled data of 15 volunteers (N = 45 data sets) applying an established radiological age estimation method to images of the hand and wrist. Additionally, a neural network-based age estimation method analyzed four sets of further undersampled images from the 15 volunteers (N = 105 data sets). Furthermore, we compared retrospectively undersampled and acquired undersampled data for three volunteers. To assess reliability with increasing degree of undersampling, intra-rater and inter-rater agreement were analyzed computing signed differences and intra-class correlation. While our findings have to be confirmed by a larger prospective study, the results from both radiological and automatic age estimation showed that reliable age estimation was still possible for acquisition times of 15 seconds. PMID- 29391553 TI - Development and performance of prototype serologic and molecular tests for hepatitis delta infection. AB - Worldwide, an estimated 5% of hepatitis B virus (HBV) infected people are coinfected with hepatitis delta virus (HDV). HDV infection leads to increased mortality over HBV mono-infection, yet HDV diagnostics are not widely available. Prototype molecular (RNA) and serologic (IgG) assays were developed for high throughput testing on the Abbott m2000 and ARCHITECT systems, respectively. RNA detection was achieved through amplification of a ribozyme region target, with a limit of detection of 5 IU/ml. The prototype serology assay (IgG) was developed using peptides derived from HDV large antigen (HDAg), and linear epitopes were further identified by peptide scan. Specificity of an HBV negative population was 100% for both assays. A panel of 145 HBsAg positive samples from Cameroon with unknown HDV status was tested using both assays: 16 (11.0%) had detectable HDV RNA, and 23 (15.7%) were sero-positive including the 16 HDV RNA positive samples. Additionally, an archival serial bleed panel from an HDV superinfected chimpanzee was tested with both prototypes; data was consistent with historic testing data using a commercial total anti-Delta test. Overall, the two prototype assays provide sensitive and specific methods for HDV detection using high throughput automated platforms, allowing opportunity for improved diagnosis of HDV infected patients. PMID- 29391554 TI - Maximum field emission current density of CuO nanowires: theoretical study using a defect-related semiconductor field emission model and in situ measurements. AB - In this study, we proposed a theoretical model for one-dimensional semiconductor nanowires (NWs), taking account of the defect-related electrical transport process. The maximum emission current density was calculated by considering the influence of Joule heating, using a one-dimensional heat equation. The field emission properties of individual CuO NWs with different electrical properties were studied using an in situ experimental technique. The experimental results for maximum emission current density agreed well with the theoretical predictions and suggested that multiple conduction mechanisms were active. These may be induced by the concentration of defects in the CuO NW. The concentration of defects and the transport mechanisms were found to be key factors influencing the maximum field emission current density of the semiconductor NW. As is limited by the change of resistivity with temperature, only thermal runaway can trigger breakdown in CuO NWs. PMID- 29391555 TI - Effects of blood glucose level on 18F fluorodeoxyglucose (18F-FDG) uptake for PET/CT in normal organs: an analysis on 5623 patients. AB - Our purpose was to evaluate the effect of glycemia on 18F-FDG uptake in normal organs of interest. The influences of other confounding factors, such as body mass index (BMI), diabetes, age, and sex, on the relationships between glycemia and organ-specific standardized uptake values (SUVs) were also investigated. We retrospectively identified 5623 consecutive patients who had undergone clinical PET/CT for oncological indications. Patients were stratified into groups based on glucose levels, measured immediately before 18F-FDG injection. Differences in mean SUVmax values among glycemic ranges were clinically significant only when >10% variation was observed. The brain was the only organ that presented a significant inverse relationship between SUVmax and glycemia (p < 0.001), even after controlling for diabetic status. No such difference was observed for the liver or lung. After adjustment for sex, age, and BMI, the association of glycemia with SUVmax was significant for the brain and liver, but not for the lung. In conclusion, the brain was the only organ analyzed showing a clinically significant relationship to glycemia after adjustment for potentially confounding variables. The lung was least affected by the variables in our model, and may serve as an alternative background tissue to the liver. PMID- 29391556 TI - Expression analysis of candidate genes for fatty acid composition in adipose tissue and identification of regulatory regions. AB - The aim of this work was to study the genetic basis of the backfat expression of lipid-related genes associated with meat quality traits in pigs. We performed a genome-wide association study with the backfat gene expression measured in 44 genes by qPCR and the PorcineSNP60 BeadChip genotypes in 115 Iberian x Landrace backcross animals. A total of 193 expression-associated SNPs located in 19 chromosomal regions were associated with expression levels of ACSM5, ELOVL6, FABP4, FADS2, and SLC27A4 genes. Three expression quantitative trail loci (eQTLs) corresponding to ACSM5, FABP4, and FADS2 were classified as cis-acting eQTLs, whereas the remaining 16 eQTLs have trans-regulatory effects. Remarkably, a SNP in the ACSM5 promoter region and a SNP in the 3'UTR region of FABP4 were the most associated polymorphisms with the ACSM5 and FABP4 expression levels, respectively. Moreover, relevant lipid-related genes mapped in the trans-eQTLs regions associated with the ACSM5, FABP4, FADS2, and SLC27A4 genes. Interestingly, a trans-eQTL hotspot on SSC13 regulating the gene expression of ELOVL6, ELOLV5, and SCD, three important genes implicated in the elongation and desaturation of fatty acids, was identified. These findings provide new data to further understand the functional regulatory mechanisms implicated in the variation of fatty acid composition in pigs. PMID- 29391558 TI - Polyoxygenated cyathane diterpenoids from the mushroom Cyathus africanus, and their neurotrophic and anti-neuroinflammatory activities. AB - In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A-J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K-R (1-8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9-11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1-25 MUM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein. PMID- 29391557 TI - SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses. AB - The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV. PMID- 29391559 TI - Substitutions of the S4DIV R2 residue (R1451) in NaV1.4 lead to complex forms of paramyotonia congenita and periodic paralyses. AB - Mutations in NaV1.4, the skeletal muscle voltage-gated Na+ channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L. PMID- 29391560 TI - Pharmaceutical compounding of aflibercept in prefilled syringes does not affect structural integrity, stability or VEGF and Fc binding properties. AB - Macular edema due to neovascular age-related macular degeneration, diabetes or retinal vein occlusion can cause central vision loss. Intravitreal treatment with antibody-based biopharmaceutical compounds designed to neutralize vascular endothelial growth factor (VEGF) has proven to be an efficient strategy to ameliorate macular edema and restore visual acuity. At the same time, the use of anti-VEGF drugs places an economic burden on the health care system; the drugs are expensive, and repeated injections are usually required to maintain the therapeutic effect. Thus, there is an unmet need for more cost-effective procedures. We here describe how the most recently approved anti-VEGF drug, aflibercept, can be compounded into prefilled sterile syringes and stored for up to 4 weeks without compromising its quality, stability or functional properties, including VEGF and neonatal Fc receptor (FcRn) binding. The novel compounding method for repackaging of aflibercept in sterile plastic syringes can greatly reduce both cost and time spent per patient in the injection room. PMID- 29391561 TI - Asymmetric dimethylarginine (ADMA) is identified as a potential biomarker of insulin resistance in skeletal muscle. AB - To unravel metabolic determinats of insulin resistance, we performed a targeted metabolomics analysis in Korean Children-Adolescent Cohort Study (KoCAS, n = 430). Sixty-seven metabolites were associated with insulin resistance in adolescents and the association also found in an adult population (KoGES, n = 2,485). Functional interactions of metabolites with gene/proteins using biological pathway with insulin resistance were not identified biological significance and regulatory effects of asymmetric dimethylarginine (ADMA). However, ADMA showed a higher association with adolescent obesity (P < 0.001) and adult diabetes (P = 0.007) and decreased after obesity intervention program. Functional studies in cellular and mouse models demonstrated that an accumulation of ADMA is associated with the regulation of obesity-induced insulin resistance in skeletal muscle. ADMA treatment inhibited dimethylarginine dimethylaminohydrolase (DDAH) activity and mRNA expression in insulin resistance muscle cell. Moreover, the treatment led to decrease of phosphorylation of insulin receptor (IR), AKT, and GLUT4 but increase of protein-tyrosine phosphatase 1B (PTP1B). Accordingly, increased ADMA significantly inhibited glucose uptake in myotube cell. We suggest that accumulation of ADMA is associated with modulation of insulin signaling and insulin resistance. ADMA might expand the possibilities of new therapeutic target for functional and clinical implications in the control of energy and metabolic homeostasis in humans. PMID- 29391562 TI - Electron irradiation induced amorphous SiO2 formation at metal oxide/Si interface at room temperature; electron beam writing on interfaces. AB - Al2O3 (5 nm)/Si (bulk) sample was subjected to irradiation of 5 keV electrons at room temperature, in a vacuum chamber (pressure 1 * 10-9 mbar) and formation of amorphous SiO2 around the interface was observed. The oxygen for the silicon dioxide growth was provided by the electron bombardment induced bond breaking in Al2O3 and the subsequent production of neutral and/or charged oxygen. The amorphous SiO2 rich layer has grown into the Al2O3 layer showing that oxygen as well as silicon transport occurred during irradiation at room temperature. We propose that both transports are mediated by local electric field and charged and/or uncharged defects created by the electron irradiation. The direct modification of metal oxide/silicon interface by electron-beam irradiation is a promising method of accomplishing direct write electron-beam lithography at buried interfaces. PMID- 29391563 TI - Association of estimated glomerular filtration rate and proteinuria with all cause mortality in community-based population in China: A Result from Kailuan Study. AB - This study was based on 95391 participants (18-98 years old) from the Kailuan study, which assessed all-cause mortality in a community-based population in northern China according to estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and proteinuria estimated from urine dipstick results. Data were analysed based on Cox proportional hazards models with adjustment for relevant confounders, and the results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). During eight years of follow-up, a total of 6024 participants died. The two indicators, eGFR < 45 ml/min/1.73 m2 and the presence of proteinuria, were independently associated with all-cause mortality. Compared with eGFR >=45 ml/min/1.73 m2 with negative proteinuria, HRs of all-cause mortality were 1.26 (95% CI 1.10-1.44) for eGFR < 45 ml/min/1.73 m2 without proteinuria, 1.95 (1.78 2.14) for eGFR >=45 ml/min/1.73 m2 with proteinuria, and 2.63 (2.14-3.23) for eGFR < 45 ml/min/1.73 m2 with proteinuria. The all-cause mortality risk of eGFR and/or proteinuria was much higher in females than in males (P for interaction < 0.01). In conclusion, both severely decreased eGFR and proteinuria are independent predictors of all-cause mortality in the general northern Chinese population. A combination of severely decreased eGFR and proteinuria increases the risk of all-cause mortality, which is even over 5-fold higher in females. PMID- 29391564 TI - Multi-slice ptychographic tomography. AB - Ptychography is a form of Coherent Diffractive Imaging, where diffraction patterns are processed by iterative algorithms to recover an image of a specimen. Although mostly applied in two dimensions, ptychography can be extended to produce three dimensional images in two ways: via multi-slice ptychography or ptychographic tomography. Ptychographic tomography relies on 2D ptychography to supply projections to conventional tomographic algorithms, whilst multi-slice ptychography uses the redundancy in ptychographic data to split the reconstruction into a series of axial slices. Whilst multi-slice ptychography can handle multiple-scattering thick specimens and has a much smaller data requirement than ptychographic tomography, its depth resolution is relatively poor. Here we propose an imaging modality that combines the benefits of the two approaches, enabling isotropic 3D resolution imaging of thick specimens with a small number of angular measurements. Optical experiments validate our proposed method. PMID- 29391565 TI - Origin and transition of sex determination mechanisms in a gynogenetic hexaploid fish. AB - Most vertebrates reproduce sexually, and plastic sex determination mechanisms including genotypic sex determination (GSD) and environmental sex determination (ESD) have been extensively revealed. However, why sex determination mechanisms evolve diversely and how they correlate with diverse reproduction strategies remain largely unclear. Here, we utilize the superiority of a hexaploid gibel carp (Carassius gibelio) that is able to reproduce by unisexual gynogenesis and contains a rare but diverse proportion of males to investigate these puzzles. A total of 2248 hexaploid specimens were collected from 34 geographic wild populations throughout mainland China, in which 24 populations were revealed to contain 186 males with various incidences ranging from 1.2 to 26.5%. Subsequently, the proportion of temperature-dependent sex determination (TSD) was revealed to be positively correlated to average annual temperature in wild populations, and male incidence in lab gynogenetic progenies was demonstrated to increase with the increasing of larval rearing temperature. Meanwhile, extra microchromosomes were confirmed to play genotypic male determination role as previously reported. Thereby, GSD and TSD were found to coexist in gibel carp, and the proportions of GSD were observed to be much higher than that of TSD in sympatric wild populations. Our findings uncover a potential new mechanism in the evolution of sex determination system in polyploid vertebrates with unisexual gynogenesis ability, and also reveal a possible association of sex determination mechanism transition between TSD and GSD and reproduction mode transition between unisexual gynogenesis and bisexual reproduction. PMID- 29391566 TI - Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract. AB - Oral delivery, a patient-friendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Lipidoid nanoparticles, which have been previously shown to deliver siRNA to intestinal epithelial cells, have potential to treat intestinal disease. It is unknown, however, whether the oral delivery of these particles is possible. To better understand the fate of lipid nanoparticles in the gastrointestinal (GI) tract, we studied delivery under deconstructed stomach and intestinal conditions in vitro. Lipid nanoparticles remained potent and stable following exposure to solutions with pH values as low as 1.2. Efficacy decreased following exposure to "fed", but not "fasting" concentrations of pepsin and bile salts. The presence of mucin on Caco-2 cells also reduced potency, although this effect was mitigated slightly by increasing the percentage of PEG in the lipid nanoparticle. Mouse biodistribution studies indicated that siRNA-loaded nanoparticles were retained in the GI tract for at least 8 hours. Although gene silencing was not initially observed following oral LNP delivery, confocal microscopy confirmed that nanoparticles entered the epithelial cells of the mouse small intestine and colon. Together, these data suggest that orally-delivered LNPs should be protected in the stomach and upper intestine to promote siRNA delivery to intestinal epithelial cells. PMID- 29391567 TI - Cinacalcet use and the risk of cardiovascular events, fractures and mortality in chronic kidney disease patients with secondary hyperparathyroidism. AB - With the aim to expand the randomized controlled trial evidence of cinacalcet treatment to the unselected, general chronic kidney disease (CKD) population we analysed a large inception cohort of CKD patients in the region of Stockholm, Sweden 2006-2012 (both non-dialysis, dialysis and transplanted) with evidence of secondary hyperparathyroidism (SHPT). We used marginal structural models to account for both confounding by indication and time-dependent confounding. Over 37 months, 435/3,526 (12%) initiated cinacalcet de novo. Before cinacalcet initiation, parathyroid hormone (PTH) had increased progressively to a median of 636ng/L. After cinacalcet initiation, PTH declined, as did serum calcium and phosphate. In total, 42% of patients experienced a fatal/non-fatal cardiovascular event, 32% died and 9% had a new fracture. The unadjusted cardiovascular odds ratio (OR) associated with cinacalcet treatment was 1.01 (95% confidence interval: 0.83, 1.22). In the fully weighted model, the cardiovascular odds was lower in cinacalcet treated patients (OR 0.67: 0.48, 0.93). The adjusted ORs for all-cause mortality and for fractures were 0.79 (0.56, 1.11) and 1.08 (0.59, 1.98) respectively. Our study suggests cinacalcet treatment improves biochemical abnormalities in the wider CKD population, and adds real-world support that treating SHPT with cinacalcet may have beneficial effects on cardiovascular outcomes. PMID- 29391568 TI - Dual-functional tunable coding metasurface based on saline water substrate. AB - In this paper, a dual-functional tunable coding metasurface is presented at X band based on water substrate, which can realize two different functions of specific scattering pattern and absorption at two different frequency ranges. Besides, by changing the salinity of the saline water substrate, the absorption performance in high frequency can be tuned, while the scattering pattern in low frequency remains unchanged. A coding element is designed with small water cavity in it. Three coding sequences with different radiation patterns are designed to verify these functions, and one of them is fabricated and measured. Experimental results have good accordance with our simulations, which demonstrates our schemes. We believe this work can not only broaden our design manner of metasurfaces, but also have plenty potential applications in biological and medical detection domain. PMID- 29391569 TI - Dynamic single-cell NAD(P)H measurement reveals oscillatory metabolism throughout the E. coli cell division cycle. AB - Recent work has shown that metabolism between individual bacterial cells in an otherwise isogenetic population can be different. To investigate such heterogeneity, experimental methods to zoom into the metabolism of individual cells are required. To this end, the autofluoresence of the redox cofactors NADH and NADPH offers great potential for single-cell dynamic NAD(P)H measurements. However, NAD(P)H excitation requires UV light, which can cause cell damage. In this work, we developed a method for time-lapse NAD(P)H imaging in single E. coli cells. Our method combines a setup with reduced background emission, UV-enhanced microscopy equipment and optimized exposure settings, overall generating acceptable NAD(P)H signals from single cells, with minimal negative effect on cell growth. Through different experiments, in which we perturb E. coli's redox metabolism, we demonstrated that the acquired fluorescence signal indeed corresponds to NAD(P)H. Using this new method, for the first time, we report that intracellular NAD(P)H levels oscillate along the bacterial cell division cycle. The developed method for dynamic measurement of NAD(P)H in single bacterial cells will be an important tool to zoom into metabolism of individual cells. PMID- 29391570 TI - Flexible spectral manipulation property of a high power linearly polarized random fiber laser. AB - Fiber lasers with flexible spectral manipulation property could provide a flexible tool for scenes where the temporal coherence property accounts, for example, coherent sensing/communication and nonlinear frequency conversion. Due to the good laser performance and relative simplicity of implementation, random fiber lasers (RFLs) based on random distributed feedback and Raman gain have earned more and more attention in the past few years, and a variety of RFLs with substantially different spectral properties have been developed. In this presentation, we demonstrate a high power linearly polarized RFL with flexible spectral manipulation property, in which the central wavelength and the linewidth of the spectrum can be tuned independently through a bandwidth-adjustable tunable optical filter (BA-TOF). The central wavelength of the RFL can be continuously tuned from 1095 to 1115 nm, while the full width at half-maximum (FWHM) linewidth has a maximal tuning range from ~0.6 to more than 2 nm. Moreover, the output power of 1102.5-1112.5 nm reaches ~23 W with polarization extinction ratio (PER) value > 20 dB. To the best of our knowledge, this is the first demonstration of a powerful linearly polarized RFL with both wavelength and linewidth tunability. PMID- 29391571 TI - Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation. AB - Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 (Sfi1) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood. PMID- 29391572 TI - Obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is increasing in prevalence due to rising obesity. While OSA is a disorder primarily of the upper airway during sleep, its pathophysiological impact on other body systems is increasingly recognised. There has been interest in the prevalence of OSA in different ophthalmic conditions and possible causation has been postulated. As OSA is common, it can be expected that people with co-existent OSA will be found in any ophthalmic disease population studied. To determine with confidence the significance of finding patients with OSA in a particular cohort requires a well matched control group, ideally matched for age, obesity, gender and co-morbidities. Only if one can say with certainty that the prevalence of OSA is higher in a group with a particular co-existent ophthalmic disease can we begin to speculate about possible mechanisms for the overlap in these conditions. Possible mechanisms for how OSA might affect the eye are discussed in this review. The current literature is reviewed with respect to diabetic retinopathy, glaucoma, floppy eyelid syndrome, non-arteritic ischaemic optic neuropathy, keratoconus and AMD. Associations with OSA have been found, but robust prospective studies using multi-channel sleep studies to diagnose OSA are lacking. Gaps remain in the evidence and in our knowledge. It is hoped that this review will highlight the need for ophthalmologists to consider OSA in their patients. It also makes recommendations for future research, especially to consider whether therapies for OSA can also be effective for ophthalmic disorders. PMID- 29391573 TI - Myopia prevalence in Canadian school children: a pilot study. AB - PURPOSE: A pilot study to determine the prevalence of myopia, proportion of uncorrected myopia and pertinent environmental factors among children in a suburban region in Canada. METHODS: Refraction with cycloplegia and ocular biometry were measured in children of two age groups. Myopia was considered at a spherical equivalent refraction (SER) <=-0.50 D in at least one eye. Parents completed a questionnaire that captured the child's daily activities. RESULTS: A total of 166 children completed the study (83 aged 6-8 and 83 aged 11-13). Myopia prevalence was 17.5% among the overall group, 6.0% among ages 6-8 and 28.9% among ages 11-13. Mean subjective SER in myopic children was -1.10 D (95% confidence interval (CI), -0.34 to -1.86 D) at ages 6-8 and -2.44 D (95% CI, -1.71 to -3.18 D) at ages 11-13. In this study, 34.5% of the myopic children were uncorrected, which represented 6.0% of the entire group of children. Mean axial length (AL) increased by 1.03 mm from ages 6-8 (mean 22.62 mm; 95% CI, 22.45 to 22.79 mm) to ages 11-13 (mean 23.65 mm; 95% CI, 23.45 to 23.84 mm; p < 0.01). The correlation coefficient between AL and SER was -0.618 (p < 0.01). Binary logistic regression between outdoor time and the prevalence of myopia showed that one additional hour of outdoor time per week lowered the odds of a child having myopia by 14.3% (p = 0.007). CONCLUSION: Myopia prevalence increased from 6% at ages 6-8 to 29% at ages 11-13. Thirty-five per cent of the myopes in this study were uncorrected. More time outdoors may be beneficial to protect against myopia onset. PMID- 29391575 TI - The effect of the timing of the cessation of contact lens use on the results of biometry. AB - BACKGROUND: Current guidelines vary regarding when to remove contact lenses prior to performing biometry, and there is no clear evidence behind these guidelines. This study aimed to determine the effect of soft contact lens wear on biometric measurements by examining the change in predicted lens power for emmetropia at several time points following removal of soft contact lenses. METHODS: A prospective, controlled study of healthy soft contact lens wearers. Biometry was performed immediately after removing contact lenses and then after 2, 4 and 7 days of no contact lens use. Healthy non-contact lens wearers were used as controls. All measurements were taken with the Zeiss IOLMaster. RESULTS: In all, 14 subjects and 13 controls were recruited. There was no significant difference in age or gender between groups. Eight of the fourteen subjects wore daily disposable CLs, two wore 2-weekly and four wore monthly soft CLs. Measurements from controls and contact lens-wearing subjects showed similar degrees of variation over time. The within-subject SD in predicted intraocular lens (IOL) power for emmetropia for contact lens wearers was 0.20 D (95% CI 0.16-0.25 D) compared to 0.18 D (95% CI 0.12-0.26 D) for controls. CONCLUSIONS: There is a significant variation in UK practice regarding advice on the timing of cessation of contact lens wear prior to having biometry performed. Our study suggests that it is likely that soft contact lens wearers are currently being advised to remove their contact lenses for an unnecessarily long period of time prior to having biometry performed. PMID- 29391574 TI - Optical coherence tomography in multiple sclerosis. AB - To summarize recent findings regarding the utility of optical coherence tomography in multiple sclerosis. We searched PubMed for relevant articles using the keywords 'optical coherence tomography multiple sclerosis'. Additional articles were found via references in these articles. We selected articles based on relevance. Optical coherence tomography has contributed to greater insights into the pathophysiology of multiple sclerosis. Loss of retinal nerve fibre layer and ganglion cell layer thickness correlate with clinical and paraclinical parameters such as visual function, disability and magnetic resonance imaging. Some studies indicate that OCT parameters may be able to predict disability progression and visual function in MS. OCT angiography has recently emerged as a novel technique to study MS. OCT has proven very useful with regards to research, monitoring and predicting disability in multiple sclerosis. It will be interesting to see how OCT angiography will contribute to this field. PMID- 29391576 TI - Change in eyelid parameters after orbital decompression in thyroid-associated orbitopathy. AB - PURPOSE: To investigate quantitative changes in eyelid parameters after orbital decompression surgery in thyroid-associated orbitopathy using the PC-based program, Eyelid Analysis Software (EAS). METHODS: This study included 202 eyes of 109 thyroid-associated orbitopathy patients. Digital photographs of the patients in primary gaze were taken just before and after orbital decompression surgery, and exophthalmos degree was measured by Hertel exophthalmometry (Hertel Exophthalmometer SKU:52400; Oculus, Arlington, VA, USA). The custom-made PC-based software EAS (Biomedical Research Institute, Seoul, Korea) was used to analyze eyelid parameters. The 11 parameters included pupil to inferior eyebrow distance (PBD), margin reflex distance 1 (MRD1), margin reflex distance 2 (MRD2), palpebral fissure (PF), total lid length, upper and lower lid length, area, medial area, center area, and lateral area. RESULTS: Univariate linear regression analysis showed a significant positive association between amount of exophthalmos reduction and the following parameters: area (p = 0.007); MRD2 (p = 0.043); upper lid length (p = 0.045); lower lid length (p = 0.006); medial area (p = 0.045); and lateral area (p = 0.005). Multivariate linear regression analysis showed only two parameters, lower lid length (p = 0.022) and lateral area (p = 0.019) were associated with exophthalmos reduction. CONCLUSIONS: A reduction in the inferior lateral part of the eyelid (lateral area + lower lid length) occurred after orbital decompression surgery in patients with thyroid-associated orbitopathy. PMID- 29391577 TI - Double MgO-based Perpendicular Magnetic-Tunnel-Junction Spin-valve Structure with a Top Co2Fe6B2 Free Layer using a Single SyAF [Co/Pt]n Layer. AB - A new perpendicular spin-transfer-torque magnetic-tunnel-junction (p-MTJ) spin valve was developed to achieve a high tunneling magnetoresistance (TMR) ratio. It had a double MgO-based spin-valve structure with a top Co2Fe6B2 free layer and incorporated a single SyAF [Co(0.4 nm)/Pt(0.3 nm)]3 layer and a new buffer layer of Co(0.6)/Pt(0.3)/Co(0.4). It had a TMR ratio of 180% and anisotropy exchange field (H ex ) of 3.44 kOe after ex-situ annealing of 350 degrees C for 30 min under a vacuum below 10-6 torr and a perpendicular magnetic field of 3 tesla, thereby ensuring a memory margin and avoiding read disturbance failures. Its high level of performance was due to the face-center-cubic crystallinity of the MgO tunneling barrier being significantly improved by decreasing its surface roughness (i.e., peak-to-valley length of 1.4 nm). PMID- 29391579 TI - A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. AB - Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities. PMID- 29391578 TI - Possible role of chondroitin sulphate and glucosamine for primary prevention of colorectal cancer. Results from the MCC-Spain study. AB - A safe and effective colorectal cancer (CRC) chemoprevention agent remains to be discovered. We aim to evaluate the association between the use of glucosamine and/or chondroitin sulphate and risk of colorectal cancer (CRC) in the MCC-Spain study, a case-control study performed in Spain that included 2140 cases of CRC and 3950 population controls. Subjects were interviewed on sociodemographic factors, lifestyle, family and medical history and regular drug use. Adjusted odds ratios and their 95% confidence intervals were estimated. The reported frequency of chondroitin and/or glucosamine use was 2.03% in controls and 0.89% in cases. Users had a reduced risk of CRC (OR: 0.47; 95% CI: 0.28-0.79), but it was no longer significant when adjusted for NSAID (nonsteroidal anti-inflammatory drugs) use (OR: 0.82; 95% CI: 0.47-1.40). A meta-analysis with previous studies suggested a protective effect, overall and stratified by NSAID use (OR: 0.77; 95% CI: 0.62-0.97). We have not found strong evidence of an independent preventive effect of CG on CRC in our population because the observed effects of our study could be attributed to NSAIDs concurrent use. These results merit further research due to the safety profile of these drugs. PMID- 29391580 TI - Structural and mechanistic divergence of the small (p)ppGpp synthetases RelP and RelQ. AB - The nutritional alarmones ppGpp and pppGpp (collectively: (p)ppGpp) are nucleotide-based second messengers enabling bacteria to respond to environmental and stress conditions. Several bacterial species contain two highly homologous (p)ppGpp synthetases named RelP (SAS2, YwaC) and RelQ (SAS1, YjbM). It is established that RelQ forms homotetramers that are subject to positive allosteric regulation by pppGpp, but structural and mechanistic insights into RelP lack behind. Here we present a structural and mechanistic characterization of RelP. In stark contrast to RelQ, RelP is not allosterically regulated by pppGpp and displays a different enzyme kinetic behavior. This discrepancy is evoked by different conformational properties of the guanosine-substrate binding site (G Loop) of both proteins. Our study shows how minor structural divergences between close homologues result in new functional features during the course of molecular evolution. PMID- 29391583 TI - Alzheimer disease: Risk variants associated with amyloid deposition in Alzheimer disease. PMID- 29391582 TI - Saline Accelerates Oxime Reaction with Aldehyde and Keto Substrates at Physiological pH. AB - We have discovered a simple and versatile reaction condition for oxime mediated bioconjugation reaction that could be adapted for both aldehyde and keto substrates. We found that saline accelerated the oxime kinetics in a concentration-dependent manner under physiological conditions. The reaction mechanism is validated by computational studies, and the versatility of the reaction is demonstrated by cell-surface labeling experiments. Saline offers an efficient and non-toxic catalytic option for performing the bioorthogonal coupling reaction of biomolecules at the physiological pH. This saline mediated bioconjugation reaction represents the most biofriendly, mild and versatile approach for conjugating sensitive biomolecules and does not require any extensive purification step. PMID- 29391581 TI - Panton-Valentine Leukocidin associated with S. aureus osteomyelitis activates platelets via neutrophil secretion products. AB - Globalization and migration promote the spread of Panton-Valentine leukocidin (PVL)-positive Staphylococcus aureus strains. The toxin PVL is linked to the development of thrombosis in association with osteomyelitis. The mechanisms by which PVL drives thrombosis development are however still unknown. We demonstrate that PVL-damaged neutrophils activate platelets via neutrophil secretion products, such as alpha-defensins and the myeloperoxidase product HOCl, as well as the formation of HOCl-modified proteins. Neutrophil damage by PVL is blocked by anti-PVL-antibodies, explaining why especially young osteomyelitis patients with a low antibody titre against PVL suffer from thrombotic complications. Platelet activation in the presence of PVL-damaged neutrophils is prevented by alpha-defensin inhibitors and by glutathione and resveratrol, which are both inhibitors of HOCl-modified protein-induced platelet activation. Remarkably, intravenously infused glutathione also prevents activation of human platelets in an ex vivo assay. We here describe a new mechanism of PVL-neutrophil-platelet interactions, which might be extrapolated to other toxins that act on neutrophils. Our observations may make us think about new approaches to treat and/or prevent thrombotic complications in the course of infections with PVL producing S. aureus strains. PMID- 29391584 TI - Demyelinating disease: Cholesterol crystals thwart repair in old CNS. PMID- 29391585 TI - Parkinson disease: LRRK2 variants linked to PD and Crohn's disease. PMID- 29391586 TI - Alzheimer disease: BACE1 inhibitors block new Abeta plaque formation. PMID- 29391588 TI - Toward reliable population estimates of wolves by combining spatial capture recapture models and non-invasive DNA monitoring. AB - Decision-makers in wildlife policy require reliable population size estimates to justify interventions, to build acceptance and support in their decisions and, ultimately, to build trust in managing authorities. Traditional capture-recapture approaches present two main shortcomings, namely, the uncertainty in defining the effective sampling area, and the spatially-induced heterogeneity in encounter probabilities. These limitations are overcome using spatially explicit capture recapture approaches (SCR). Using wolves as case study, and non-invasive DNA monitoring (faeces), we implemented a SCR with a Poisson observation model in a single survey to estimate wolf density and population size, and identify the locations of individual activity centres, in NW Iberia over 4,378 km2. During the breeding period, posterior mean wolf density was 2.55 wolves/100 km2 (95%BCI = 1.87-3.51), and the posterior mean population size was 111.6 +/- 18.8 wolves (95%BCI = 81.8-153.6). From simulation studies, addressing different scenarios of non-independence and spatial aggregation of individuals, we only found a slight underestimation in population size estimates, supporting the reliability of SCR for social species. The strategy used here (DNA monitoring combined with SCR) may be a cost-effective way to generate reliable population estimates for large carnivores at regional scales, especially for endangered species or populations under game management. PMID- 29391589 TI - Upfront surgery and pathological stage-based adjuvant chemoradiation strategy in locally advanced esophageal squamous cell carcinoma. AB - Adjuvant chemoradiation is reported to have a survival benefit for esophageal squamous cell carcinoma (ESCC). We evaluated the "upfront surgery and pathological stage-based adjuvant chemoradiation" strategy, in which adjuvant therapy is guided by pathological stage, in locally advanced ESCC. Data from 2976 clinical stage II/III ESCC patients, including 1735 in neoadjuvant chemoradiation and 1241 in upfront surgery groups, were obtained from a nationwide database. Patients in the upfront surgery group were further categorized into the "upfront surgery and pathological stage-based adjuvant chemoradiation" and "upfront surgery only" groups. The 3-year overall survival (OS) rates in the "neoadjuvant chemoradiation", "upfront surgery and pathological stage-based adjuvant chemoradiation", and "upfront surgery only" groups were 41.5%, 45.8%, and 28.5%, respectively. In propensity score matched patients, the 3-year OS rate was 41.7% in the neoadjuvant chemoradiation group, compared to 35.6% in the "upfront surgery and pathological stage-based adjuvant chemoradiation" group (p = 0.147), and 20.3% in the "upfront surgery only" group (p < 0.001). No survival difference was observed between the "neoadjuvant chemoradiation followed by surgery" protocol and the "upfront surgery and pathological stage-based adjuvant chemoradiation" strategy. PMID- 29391590 TI - Measures of low food variety and poor dietary quality in a cross-sectional study of London school children. AB - BACKGROUND/OBJECTIVES: The use of simple screening tools to measure nutritional adequacy in a public health context in developed countries are currently lacking. We explore the relationship between food variety and nutrient intake of London school children using a simple tool with potential use for screening for inadequate diets. SUBJECTS/METHODS: A cross-sectional survey was carried out in 2010. The survey included 2579 children aged 7-10 years in 52 primary schools in East London in the United Kingdom. The analysis included 2392 children (93% of the original sample). Food variety was assessed as the total number of listed foods recorded over 24 h using the validated Child and Diet Assessment Tool (CADET) comprising 115 listed foods divided into 16 food categories. Dietary quality was determined by the proportion of children meeting recommended intakes of individual micronutrients, namely, calcium, iron, zinc, folate, vitamin A and vitamin C. RESULTS: The mean number of CADET-listed foods consumed daily by children was 17.1 (95% CI: 16.8, 17.5). Children who consumed fewer than 11 foods on the collection day had particularly low nutrient intakes. Children consuming three different vegetables and two different fruits on average consumed 19-20 listed foods. It was estimated between 4 and 20% of children did not meet the recommended levels for individual micronutrients during the period of data collection. CONCLUSIONS: A simple method using food counts to assess daily food variety may help public health nutritionists identify groups of children at risk of inadequate diets. PMID- 29391591 TI - A-mode and B-mode ultrasound measurement of fat thickness: a cadaver validation study. AB - BACKGROUND/OBJECTIVES: With technological advances, there has been a resurgence in ultrasound as a method to measure subcutaneous fat thickness. Despite the increased interest in this methodology, research comparing A-mode and B-mode ultrasound devices is lacking. Subcutaneous fat thickness measured by a low resolution (2.5 MHz) A-mode ultrasound and a high resolution (12 MHz) B-mode ultrasound were compared to the actual fat thickness in dissected cadavers. SUBJECTS/METHODS: Subcutaneous fat thickness of six cadavers was measured at the abdomen, thigh, triceps, and calf (plus chest for males and suprailiac for females) with both ultrasound devices before the cadavers were dissected and site specific thickness was measured. RESULTS: Correlations between both ultrasounds and the dissected measurement exceeded 0.90 at all sites with a few exceptions. At the abdomen, the relationship between the ultrasounds was 0.76, and the B-mode and dissected measurement was also 0.76. The correlation between dissection and A mode was 0.75 for the suprailiac site, but it was not possible to discern the separation of tissue at this site when using the B-mode device. There were no significant differences (P > 0.05) between the devices and the dissected measurement at any of the six sites. The mean difference in fat thickness between A-mode and B-mode was <0.7 mm at all sites except the calf (1.2 mm) CONCLUSION: With the exception of the suprailiac site, both A-mode and B-mode ultrasound are equally capable of providing measurements of subcutaneous fat thickness with an accuracy of <1 mm at most sites. PMID- 29391592 TI - Development and validation of bioelectrical impedance analysis equations for prediction total body water and fat-free mass using D2O technique in Moroccan children aged between 8 and 11 years old. AB - BACKGROUND/OBJECTIVES: Estimating body composition using bioelectric impedance analysis (BIA) requires specific prediction equations. The purpose of our study was to examine the validity of published BIA equations for assessing total body water (TBW) and fat-free mass (FFM) using deuterium oxide dilution (D2O) as a reference method and to develop new FFM and TBW BIA equations if needed for Moroccan pre-pubertal children. SUBJECTS/METHODS: Data were collected from 247 schoolchildren aged 8-11 years old. Children were sorted by gender and age group and assigned in development and validation groups. D2O dilution was used as reference method for estimating TBW and FFM. Bland and Altman test, effect size, pure error, and proportional bias were used to assess the reliability of previous published equations. Cross-validation was performed by Bland and Altman test and BIA new equations were developed by linear regression. RESULTS: Previously published equations were tested and showed significant bias values indicating that if used they would provide biased values of TBW and FFM. The new prediction equations developed were: [Formula: see text] (l) = 0.269 + 0.292 Ht2/R (cm2/Omega) + 0.221 weight (kg) + 0.824 sex (boys = 1, girls = 0) + 0.291 age (years) (R2 = 0.91, RMSE = 1.54 kg); [Formula: see text] (kg) = -0.450 + 0.380 Ht2/R (cm2/Omega) + 0.291 weight (kg) + 1.294 sex (boys = 1, girls = 0) + 0.446 age (years) (R2 = 0.91, RMSE = 1.97 kg). These equations provide better values of proportional bias, agreement, and pure error than the other tested equations. CONCLUSIONS: The new BIA prediction equations seem to be the most accurate for Moroccan pre-pubertal children. PMID- 29391587 TI - Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction. AB - The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage. PMID- 29391593 TI - Vitamin D status and risk for sarcopenia in youth with inflammatory bowel diseases. AB - Suboptimal vitamin D (vitD) status and reduced lean body mass are highly prevalent in pediatric inflammatory bowel diseases (IBD). The study objective was to determine sarcopenia prevalence and associations with vitD status in newly diagnosed pediatric IBD. Children with Crohn's disease (CD; n = 58) and ulcerative colitis (UC; n = 27) were included. Primary outcomes included body composition (total/regional/percent fat mass (FM), fat-free mass (FFM), skeletal muscle mass (SMM)), and vitD status (serum 25(OH)D). Sarcopenia was defined as SMM-z < -2. Additional variables measured included serum CRP, ESR, anthropometric, Pediatric Crohn's Disease Activity Index (PCDAI), and the Pediatric Ulcerative Colitis Disease Activity index (PUCAI). Sarcopenia and suboptimal 25(OH)D levels (< 50 nmol/l) were found in 23.5% (n = 20) and 52% (n = 44) of children, respectively. Younger children (< 13 years) with CD with suboptimal 25(OH)vitD (< 50 nmol/l) had the greatest frequency of sarcopenia (57.1%) (p = 0.004). Sarcopenia was prevalent in newly diagnosed, young children with CD with vitD deficiency. PMID- 29391594 TI - Contraction of T cell richness in lung cancer brain metastases. AB - Very little is known about how the adaptive immune system responds to clonal evolution and tumor heterogeneity in non-small cell lung cancer. We profiled the T-cell receptor beta complementarity determining region 3 in 20 patients with fully resected non-small cell lung cancer primary lesions and paired brain metastases. We characterized the richness, abundance and overlap of T cell clones between pairs, in addition to the tumor mutation burden and predicted neoantigens. We found a significant contraction in the number of unique T cell clones in brain metastases compared to paired primary cancers. The vast majority of T cell clones were specific to a single lesion, and there was minimal overlap in T cell clones between paired lesions. Despite the contraction in the number of T cell clones, brain metastases had higher non-synonymous mutation burdens than primary lesions. Our results suggest that there is greater richness of T cell clones in primary lung cancers than their paired metastases despite the higher mutation burden observed in metastatic lesions. These results may have implications for immunotherapy. PMID- 29391595 TI - The Molecular Basis of the Sodium Dodecyl Sulfate Effect on Human Ubiquitin Structure: A Molecular Dynamics Simulation Study. AB - To investigate the molecular interactions of sodium dodecyl sulfate (SDS) with human ubiquitin and its unfolding mechanisms, a comparative study was conducted on the interactions of the protein in the presence and absence of SDS at different temperatures using six independent 500 ns atomistic molecular dynamics (MD) simulations. Moreover, the effects of partial atomic charges on SDS aggregation and micellar structures were investigated at high SDS concentrations. The results demonstrated that human ubiquitin retains its native-like structure in the presence of SDS and pure water at 300 K, while the conformation adopts an unfolded state at a high temperature. In addition, it was found that both SDS self-assembly and the conformation of the resulting protein may have a significant effect of reducing the partial atomic charges. The simulations at 370 K provided evidence that the SDS molecules disrupted the first hydration shell and expanded the hydrophobic core of ubiquitin, resulting in complete protein unfolding. According to these results, SDS and temperature are both required to induce a completely unfolded state under ambient conditions. We believe that these findings could be useful in protein folding/unfolding studies and structural biology. PMID- 29391596 TI - Superficial Slow Rhythms Integrate Cortical Processing in Humans. AB - The neocortex is composed of six anatomically and physiologically specialized layers. It has been proposed that integration of activity across cortical areas is mediated anatomically by associative connections terminating in superficial layers, and physiologically by slow cortical rhythms. However, the means through which neocortical anatomy and physiology interact to coordinate neural activity remains obscure. Using laminar microelectrode arrays in 19 human participants, we found that most EEG activity is below 10-Hz (delta/theta) and generated by superficial cortical layers during both wakefulness and sleep. Cortical surface grid, grid-laminar, and dual-laminar recordings demonstrate that these slow rhythms are synchronous within upper layers across broad cortical areas. The phase of this superficial slow activity is reset by infrequent stimuli and coupled to the amplitude of faster oscillations and neuronal firing across all layers. These findings support a primary role of superficial slow rhythms in generating the EEG and integrating cortical activity. PMID- 29391597 TI - IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades. AB - Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF 1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system. PMID- 29391598 TI - Decreased TGFBR3/betaglycan expression enhances the metastatic abilities of renal cell carcinoma cells through TGF-beta-dependent and -independent mechanisms. AB - TGF-beta regulates both the tumor-forming and migratory abilities of various types of cancer cells. However, it is unclear how the loss of TGF-beta signaling components affects these abilities in clear-cell renal cell carcinoma (ccRCC). In this study, we investigated the role of TGFBR3 (TGF-beta type III receptor, also known as betaglycan) in ccRCC. Database analysis revealed decreased expression of TGFBR3 in ccRCC tissues, which correlated with poor prognosis in patients. Orthotopic inoculation experiments using immunocompromised mice indicated that low TGFBR3 expression in ccRCC cells enhanced primary tumor formation and lung metastasis. In the presence of TGFBR3, TGF-beta2 decreased the aldehyde dehydrogenase (ALDH)-positive ccRCC cell population, in which renal cancer initiating cells are enriched. Loss of TGFBR3 also enhanced cell migration in cell culture and induced expression of several mesenchymal markers in a TGF-beta independent manner. Increased lamellipodium formation by FAK-PI3K signaling was observed with TGFBR3 downregulation, and this contributed to TGF-beta-independent cell migration in ccRCC cells. Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-beta dependent and independent pathways. PMID- 29391599 TI - Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer. AB - Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2 overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available. PMID- 29391600 TI - PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation. AB - PI3K/AKT pathway activation is thought to be a driving force in metastatic melanomas. Members of the pleckstrin homology (PH) domain leucine-rich repeat protein Ser/Thr specific phosphatase family (PHLPP1 and PHLPP2) can regulate AKT activation. By dephosphorylating specific serine residues in the hydrophobic motif, PHLPP1 and PHLPP2 restrain AKT signalings, thereby regulating cell proliferation and survival. We here show that PHLPP1 expression was significantly downregulated or lost and correlated with metastatic potential in melanoma. Forcing expression of either PHLPP1 or PHLPP2 in melanoma cells inhibited cell proliferation, migration, and colony formation in soft agar; but PHLPP1 had the most profound inhibitory effect on metastasis. Moreover, expression of PH mutant forms of PHLPP1 continued to inhibit metastasis, whereas a phosphatase-dead C terminal mutant did not. The introduction of activated PHLPP1-specific targets AKT2 or AKT3 also promoted melanoma metastasis, while the non-PHLPP1 target AKT1 did not. AKT2 and AKT3 could even rescue the PHLPP1-mediated inhibition of metastasis. An AKT inhibitor blocked the activity of AKT2 and inhibited AKT2 mediated tumor growth and metastasis in a preclinical mouse model. Our data demonstrate that PHLPP1 functions as a metastasis suppressor through its phosphatase activity, and suggest that PHLPP1 represents a novel diagnostic and therapeutic marker for metastatic melanoma. PMID- 29391601 TI - The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim. AB - Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lyn, which results in an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptotic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells. PMID- 29391602 TI - Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis. AB - Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinases are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma, and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using DNA microarray and RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that upregulated genes by EN were mainly associated with cell motion, membrane invagination, and cell proliferation, while downregulated genes were involved in cell adhesion, which correlated with the transforming potential and increased proliferation in EN-transduced cells. KEGG pathway analysis identified the JAK STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the STAT1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, eventually inhibiting the interaction between the NF-kappaB p65 subunit and acetylated STAT1. Consequently, nuclear translocation of NF-kappaB p65 and subsequent NF-kappaB activity were increased by EN. Notably, inhibition of STAT1 phosphorylation attenuated tumorigenic ability of EN in vitro and in vivo. Taken together, here we report, for the first time, STAT1 as a significant EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis. PMID- 29391603 TI - Determination of Ochratoxin A contamination in grapes, processed grape products and animal-derived products using ultra-performance liquid chromatography-tandem mass spectroscopy system. AB - We developed a sensitive and rapid analytical method to determine the level of Ochratoxin A contamination in grapes, processed grape products and in foods of animal origin (a total of 11 different food matrices). A pretreatment that followed a "quick, easy, cheap, effective, rugged, and safe" protocol was optimized to extract Ochratoxin A from the matrices, and the extracted Ochratoxin A was then detected with the use of a highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry system. Good linearities of Ochratoxin A were obtained in the range of 0.1-500 ug L-1 (correlation coefficient (R2) > 0.9994 in each case). Mean recovery from the 11 matrices ranged from 70.3 to 114.7%, with a relative standard deviation <=19.2%. The method is easy to use and yields reliable results for routine determination of Ochratoxin A in food products of grape and animal origin. In store-purchased foods and foods obtained from the field and wholesale suppliers, the Ochratoxin A concentration ranged from undetectable to 10.14 ug kg-1, with the more contaminated samples being mainly those of processed grape products. Our results indicate that the necessity for regulation of and supervision during the processing of grape products. PMID- 29391605 TI - The knowledge mobilisation challenge: does producing evidence lead to its adoption within dentistry? AB - The transfer of evidence into clinical practice is the ultimate aim of those engaged in health research. But is this a process that occurs naturally? Can health researchers take it for granted that the evidence they produce will be embraced by clinicians and incorporated into their everyday practice? In this article, we use the example of oral healthcare in dependent older people and the issue of antibiotic prescribing by GDPs to illustrate the fact that successful knowledge transfer between researchers and practitioners cannot be automatically assumed. What is needed, so we argue, are certain tools to facilitate the knowledge transfer, exchange and implementation process. These tools may take the form of human intermediaries, who can occupy the space in between the worlds of research and practice, acting as brokers to mobilise knowledge, or through the establishment of communities of practice. We outline both of these approaches here as a potential solution to the problem of knowledge mobilisation in dentistry. PMID- 29391606 TI - Maximum likelihood estimation for semiparametric regression models with multivariate interval-censored data. AB - Interval-censored multivariate failure time data arise when there are multiple types of failure or there is clustering of study subjects and each failure time is known only to lie in a certain interval. We investigate the effects of possibly time-dependent covariates on multivariate failure times by considering a broad class of semiparametric transformation models with random effects, and we study nonparametric maximum likelihood estimation under general interval censoring schemes. We show that the proposed estimators for the finite dimensional parameters are consistent and asymptotically normal, with a limiting covariance matrix that attains the semiparametric efficiency bound and can be consistently estimated through profile likelihood. In addition, we develop an EM algorithm that converges stably for arbitrary datasets. Finally, we assess the performance of the proposed methods in extensive simulation studies and illustrate their application using data derived from the Atherosclerosis Risk in Communities Study. PMID- 29391604 TI - Free-living greylag geese adjust their heart rates and body core temperatures to season and reproductive context. AB - Animals adaptively regulate their metabolic rate and hence energy expenditure over the annual cycle to cope with energetic challenges. We studied energy management in greylag geese. In all geese, profound seasonal changes of heart rate (fH) and body temperature (Tb) showed peaks in summer and troughs during winter, and also daily modulation of fH and Tb. Daily mean fH was on average 22% lower at the winter trough than at the summer peak, whereas daily mean Tb at the winter trough was only about 1 degrees C below the summer peak. Daily means of Tb together with those of air temperature and day length were the most important predictors of daily mean fH, which was further modulated by precipitation, reproductive state, and, to a minor degree, social rank. Peaks of fH and Tb occurred earlier in incubating females compared to males. Leading goslings increased daily mean fH. Our results suggest that in greylag geese, pronounced changes of fH over the year are caused by photoperiod-induced changes of endogenous heat production. Similar to large non-hibernating mammals, tolerance of lower Tb during winter seems the major factor permitting this. On top of these major seasonal changes, fH and Tb are elevated in incubating females. PMID- 29391607 TI - From Near-Neutral to Strongly Stratified: Adequately Modelling the Clear-Sky Nocturnal Boundary Layer at Cabauw. AB - The performance of an atmospheric single-column model (SCM) is studied systematically for stably-stratified conditions. To this end, 11 years (2005 2015) of daily SCM simulations were compared to observations from the Cabauw observatory, The Netherlands. Each individual clear-sky night was classified in terms of the ambient geostrophic wind speed with a [Formula: see text] bin-width. Nights with overcast conditions were filtered out by selecting only those nights with an average net radiation of less than [Formula: see text]. A similar procedure was applied to the observational dataset. A comparison of observed and modelled ensemble-averaged profiles of wind speed and potential temperature and time series of turbulent fluxes showed that the model represents the dynamics of the nocturnal boundary layer (NBL) at Cabauw very well for a broad range of mechanical forcing conditions. No obvious difference in model performance was found between near-neutral and strongly-stratified conditions. Furthermore, observed NBL regime transitions are represented in a natural way. The reference model version performs much better than a model version that applies excessive vertical mixing as is done in several (global) operational models. Model sensitivity runs showed that for weak-wind conditions the inversion strength depends much more on details of the land-atmosphere coupling than on the turbulent mixing. The presented results indicate that in principle the physical parametrizations of large-scale atmospheric models are sufficiently equipped for modelling stably-stratified conditions for a wide range of forcing conditions. PMID- 29391608 TI - Chemical stability of rainbow trout in icing medium containing pistachio (Pistachia vera) green hull extract during chilled storage. AB - In this study, the effect of icing medium containing different concentration of pistachio (Pistacia vera L. cv. Akbari) green hull extract (PHE) was investigated on the chemical stability of rainbow trout. The fishes were stored for 12 days in flaked ice containing 0, 0.1, 0.2 and 0.3% PHE and the parameters of pH, total volatile base nitrogen (TVB-N), histamine, free fatty acids, peroxide and thiobarbituric acid index (TBA-i) were periodically evaluated. In all experiments, a significant difference was evident between control and fish muscles stored in ice containing PHE. Fish icing with 0.3% PHE could considerably retard the oxidative and hydrolytic rancidity. In addition, it had significant effect on prevention of pH increase and production of volatile basic nitrogen during 12 days storage. PHE could diminish histamine accumulation in fish muscle and improve safety of rainbow trout. Consequently, PHE could have potential of application in icing medium for preservation of fish quality especially fatty ones. PMID- 29391609 TI - Cold extraction method of chia seed mucilage (Salvia hispanica L.): effect on yield and rheological behavior. AB - Chia seeds (Salvia hispanica L.) when immersed in water, produce a highly viscous solution due to the release of mucilage, high molecular weight complex carbohydrates with wide application in the food industry. Thus, this study involve development of method for extracting mucilage from chia seed based on mechanical process and low temperature. The method involve extraction by cold pressing and drying by freeze-drying, which was compared to the traditional hot extraction method. The chia seed mucilage cultivated in Brazil was extracted successfully using the previously mentioned extraction method. Rheological analysis including thixotropy, flow curve and frequency sweep of mucilage was done. Microstructure was examined by scanning electron microscopy. The optimal process at 27 degrees C gave yield of 8.46%. The rheograms showed that the apparent viscosity decreased with increase in shear rate and this effect was most notable in the dispersions obtained by cold extraction and with high concentrations. The gum obtained using CE presented higher values for thixotropic behavior. The storage modulus (G') was consistently higher than the loss modulus (G") and the data indicated formation of 'weak gel' structure of the dispersions. SEM indicated macroscopic fibrous structure of mucilage obtained through cold extraction process, indicating that the macromolecular network formed by fibrous material contained in mucilage maintained its structure in the process of deep freezing and freeze-drying. PMID- 29391610 TI - Morphological, mechanical and antioxidant properties of Portuguese almond cultivars. AB - The aim of this study was to evaluate morphological (of fruit and kernel), mechanical (namely shell rupture force) and antioxidant properties (including phenolics and flavonoid content) of five Portuguese almond cultivars, comparing them with two commercial cultivars (Glorieta and Ferragnes). Of the analyzed traits, nut and kernel dimensions varied substantially and were used to describe cultivars. However, some traditional cultivars recorded similar (Pegarinhos), or even higher (Amendoao, Casanova and Refego) nut and kernel weight than commercial cultivars. Furthermore, shelling percentage of traditional cultivar (Bonita) was higher than commercial cultivars. Rupture force necessary to break fruits of all traditional cultivars was higher than commercial ones, and was correlated to nut weight cultivars. The phenolics, flavonoids content and antioxidants were higher for Casanova. Parameters like high kernel weight, low percentages of double kernels or losses during shelling and considerable higher phenolics and flavonoids content may be considered by industry during selection of almond. PMID- 29391611 TI - Changes in nutritional and bio-functional compounds and antioxidant capacity during black garlic processing. AB - This study aimed to explore ideal processing condition for black garlic based on the change of nutritional and active components and antioxidant capacity. Fresh garlic was processed under the condition of constant temperature (65, 75 and 85 degrees C) and relative humidity (70, 75, 80 and 85%) for 16 days. The sensory scores, contents of nutritional and active components, and antioxidant capacity were monitored. The sensory scores reached the maximum on the 8th day at 85% humidity and 75 degrees C. The contents of nutritional components were significantly affected by humidity and temperature, and 85% humidity and 75 degrees C were appropriate. The polyphenol content increased with increase in temperature and decrease in humidity. The reducing sugars and total sugars, total acids and 5-HMF were higher at 75 degrees C than at 65 and 85 degrees C. Reducing sugar and protein contents and sensory scores decreased on the 8th day. Maintaining the temperature of 75 degrees C and relative humidity of 85% for 8 days were ideal for black garlic to retain antioxidant capacity and abundant nutrients. PMID- 29391612 TI - Preparation and physicochemical properties of protein concentrate and isolate produced from Acacia tortilis (Forssk.) Hayne ssp. raddiana. AB - The composition and physicochemical properties of defatted acacia flour (DFAF), acacia protein concentrate (APC) and acacia protein isolate (API) were evaluated. The results indicated that API had lower, ash and fat content, than DFAF and APC. Also, significant difference in protein content was noticed among DFAF, APC and API (37.5, 63.7 and 91.8%, respectively). Acacia protein concentrate and isolates were good sources of essential amino acids except cystine and methionine. The physicochemical and functional properties of acacia protein improved with the processing of acacia into protein concentrate and protein isolate. The results of scanning electron micrographs showed that DFAF had a compact structure; protein concentrate were, flaky, and porous type, and protein isolate had intact flakes morphology. PMID- 29391613 TI - Effect of virgin coconut oil on properties of surimi gel. AB - Effects of virgin coconut oil (VCO) at various levels (0-25%) on the properties of croaker surimi gels were studied. As the levels of VCO increased up to 15%, breaking force continuously decreased. No differences in breaking force, deformation and fracture constant were noticeable when VCO of 15-25% was incorporated. Based on texture profile analysis, hardness and chewiness decreased as the level of added VCO increased up to 10%, while no marked changes were observed with the addition of 10-25% VCO. Addition of VCO had no profound impact on springiness, cohesiveness and resilience. No remarkable change in protein pattern among all surimi gel samples was noticed, regardless of VCO levels. Lower elastic (G') as well as loss moduli (G") of surimi paste were observed when VCO was added, compared to the control. Nevertheless, there was no marked difference in the moduli among samples containing VCO at all levels. Whiteness of surimi gel increased, whereas expressible moisture content decreased as VCO levels increased. Microstructure study revealed that VCO droplets were distributed uniformly in gel network. Overall likeness of surimi gel was also increased for gel added with VCO. Therefore, VCO addition directly affected textural properties and improved the whiteness as well as sensory property of surimi gel. PMID- 29391614 TI - Predictive growth model of the effects of temperature on the growth kinetics of generic Escherichia coli in the Korean traditional rice cake product "Garaetteok". AB - In this study, a predictive growth model of generic Escherichia coli in Garaetteok at a range of storage temperatures (T, 10-40 degrees C) was developed. The primary models of specific growth rate (SGR) and lag time (LT) fit well (R2 >= 0.985) using a Gompertz equation. Secondary polynomial models were obtained by non-linear regression and calculated as SGR = - 0.01,570 + 0.0183T + 0.000008T2; LT = 43.2064 - 2.4824T + 0.0355T2. The appropriateness of the secondary models was verified by mean square error (MSE; 0.0006 for SGR, 0.282 for LT), bias factor (B f ; 0.948 for SGR, 0.942 for LT), accuracy factor (A f ; 1.163 for SGR, 1.355 for LT), and coefficient of determination (r2; 0.986 for SGR, 0.996 for LT), and these models were found to be in good agreement with the experimental values used for validation. The secondary models developed in this study may thus be used as practical prediction models for generic E. coli growth in Garaetteok. These newly developed secondary models of SGR and LT for generic E. coli in Garaetteok may thus be incorporated into tertiary modeling programs such as the Korea Pathogen Modeling Program, in which they can easily be used to predict the growth kinetics of E. coli as a function of storage temperature. Ultimately, model developed in this study may be a vital tool for the reduction of E. coli levels in food production, processing, and distribution processes, which in turn will lead to enhanced safety of rice products. PMID- 29391615 TI - Quality, protease inhibitor and gelling property of duck egg albumen as affected by storage conditions. AB - Physicochemical properties, trypsin inhibitory activity, and gelling properties of albumen from duck egg during 15 days of storage at 4 degrees C and room temperature (28-30 degrees C) were studied. As the storage time increased, Haugh unit and moisture content decreased, while the pH value increased (P < 0.05). The rate of changes was lower at 4 degrees C. Trypsin inhibitory activity in albumen from egg stored at 4 degrees C was higher than that kept at room temperature throughout the storage time (P < 0.05). Nevertheless, no differences in protein patterns were observed during the storage. Based on texture profile analysis, the highest hardness, gumminess, and chewiness were found at day 3 for room temperature and at day 6 for 4 degrees C. Higher values were attained for eggs kept at 4 degrees C. Conversely, albumen gels made from eggs stored at room temperature exhibited higher cohesiveness, adhesiveness, springiness, resilience than those kept at 4 degrees C. The gels had the lowered whiteness when eggs were stored for a longer time, particularly at room temperature. Thus, storage condition directly affected the quality of albumen from duck egg. PMID- 29391616 TI - Enrichment of rice-based extrudates with Cactus Opuntia dillenii seed powder: a novel source of fiber and antioxidants. AB - The present study investigated the effects of adding the powder of cactus Opuntia dillenii (O. dillenii) seeds on the functional properties, fiber, antioxidants and acceptability of rice-based extrudates. The control blend consisting basically of rice flour was replaced with O. dillenii seed powder at 2, 4, 6, 8, 10, 15 and 20% then extruded at the optimum processing conditions. The extruded products were evaluated for their chemical composition, functional properties, color attributes, antioxidant activity and sensory characteristics. The results revealed that adding O. dillenii seeds powder enhanced the fiber, phenolics, flavonoid contents and antioxidant activity of extrudates. Expansion, bulk density and breaking strength were significantly decreased, while water absorption index, water solubility index and oil absorption index were significantly increased compared to the control. Furthermore, the mean scores of sensory evaluation indicated clear improvements in all tested sensory attributes, which significantly increased by increasing the level of O. dillenii seed powder up to 15%. The results confirmed that O. dillenii seed powder could be incorporated in rice to develop snack products of acceptable functional, nutritional and sensory properties. PMID- 29391617 TI - Edible films developed from carboxylic acid cross-linked sesame protein isolate: barrier, mechanical, thermal, crystalline and morphological properties. AB - Films were developed from sesame protein crosslinked with three different carboxylic acids (malic acid, citric acid and succinic acid) at 1, 3 and 5% (w/w, on protein isolate basis). The effect of crosslinking on physical, mechanical, thermal and morphological properties was studied. Succinic acid crosslinked films exhibited least water vapor permeability the highest tensile strength and overall showed superlative properties among other films. X-ray diffraction showed single main crystalline reflection at 20 degrees indicating amorphous structure of films. DSC curves of films indicated single melting peak in the range of 103-161 degrees C. All films exhibited weight loss in three stages. FTIR exhibited peak at 1700 cm-1 confirming crosslinking reaction between carboxylic acids and protein. Crosslinked films were compact, nonporous and smooth as compared to film from native sesame protein isolate. PMID- 29391618 TI - Hygroscopic properties and glass transition of dehydrated mango, apple and banana. AB - An undesirable crispiness loss occurs when some dry fruits reach a critical moisture content (Xc ) and their glass transition temperature (Tg ) matches the storage temperature. Models for sorption isotherms and onset Tg values for dry mango, apple, and banana were used to estimate Xc values at 25 and 32 degrees C. All models yielded R2 > 0.97 but information theory criteria strongly supported GAB in all but one case (40 degrees C, mango). The Gordon-Taylor Tg model (GT) yielded high R2 values for apple and banana but resulted in R2 = 0.834 for mango. As moisture approached zero, mango Tg estimates displayed a downward concavity contrasting with a rapidly increasing trend for apple and banana. The Khalloufi Maslouhi-Ratti (KMR) model for Tg as a function of aw showed a linear behavior. Although the KMR model fitted data with R2 > 0.996, it requires more parameters and when aw approached 0, estimated Tg values increased at a slower rate than for the GT model. In the case of banana and mango, both models predicted approximately the same Xc at 25 degrees C but not at 32 degrees C. Finally, all Xc values estimated based on Tg were lower than the monolayer values obtained with the GAB (apple and banana) and BET (mango) models. These results indicate that the glass transition induced by moisture uptake dominates the quality degradation of these dry fruits. PMID- 29391619 TI - Bacteriophage application for biocontrolling Shigella flexneri in contaminated foods. AB - Shigellosis (bacillary dysentery) is an acute enteric infection caused by members of Shigella genus. It causes annual deaths of approximately five million children in developing countries. Among Shigella spp., S. flexneri causes more serious forms of dysentery than other Shigella species. Due to the appearance of multidrug-resistant strains of Shigella spp., it is necessary to find alternative antimicrobial agents. The aims of this study were the isolation of a novel species-specific phage against S. flexneri and to evaluate its potential and efficacy for biocontrolling of S. flexneri in foods. Shigella flexneri PTCC 1234 was used as the host strain for bacteriophage isolation from waste water. A lytic phage of the Siphoviridae family was isolated and designated as vB_SflS-ISF001. The phage activity remained at high levels after 1 h of incubation at - 20 to 50 degrees C and was fairly stable for 1 h at pH values ranging from 7 to 9. The latent period and burst size were approximately 20 min and 53 +/- 4 phages per host cell, respectively. Raw and cooked chicken breast were inoculated with a predetermined amount of S. flexneri and subjected to biocontrol test. The results showed that using vB_SflS-ISF001 phage led to more than two logs reduction in the count of viable S. flexneri. It was demonstrated that using vB_SflS-ISF001 phage is of high potential for developing an alternative strategy against S. flexneri contamination in foodstuffs. PMID- 29391620 TI - Potential use of deodorised water extracts: polyphenol-rich extract of Thymus pannonicus All. as a chemopreventive agent. AB - Deodorised water extracts of aromatic plants are obtained as by-products of essential oil isolation and usually discarded as waste. However, phytochemical composition of these extracts encourages their further utilization as food additives or functional food ingredients. In this study we investigated phytochemical composition, antioxidant and in vivo antiproliferative activity of deodorised water extract of Thymus pannonicus All. (DWE). HPLC analysis revealed rosmarinic acid (RA) (71.11 +/- 1.54 mg/g) as the most abundant constituent of the extract, followed by salvianolic acid H (14.83 +/- 0.79 mg/g, calculated as RA). DWE exhibited pronounced antioxidant activity in vitro, in FRAP and DPPH tests (FRAP value: 7.41 mmol Fe/g and SC50: 3.80 MUg/g, respectively). Using the model of Ehrlich carcinoma cells in mice that were treated with DWE prior, at the time, and after tumour cells implantation, the tumour growth suppression and redox status of malignant cells (i.e., activities of antioxidant enzymes, level of glutathione and intensity of lipid peroxidation) were followed. DWE applied as pretreatment caused disturbance of antioxidant equilibrium as well as apoptosis/necrosis of up to 90% EAC cells. Results obtained in the present study revealed chemopreventive potential and possibility of T. pannonicus DWE usage. High content of RA and other phenolic compounds explains, at least in part, the observed effects. PMID- 29391621 TI - Effect of thermal and high pressure processing on stability of betalain extracted from red beet stalks. AB - Red beet stalks are a potential source of betalain, but their pigments are not widely used because of their instability. In the present work, the applicability of high pressure processing (HPP) and high temperature short time (HTST) thermal treatment was investigated to improve betalain stability in extracts with low and high concentrations. The HPP was applied at 6000 bar for 10, 20 and 30 min and HTST treatment was applied at 75.7 degrees C for 80 s, 81.1 degrees C for 100 s and 85.7 degrees C for 120 s, HPP treatment did not show any improvement in the betalain stability. In turn, the degradation rate of the control and the HTST thermal treatment at 85.7 degrees C for 120 s of the sample with high initial betalain concentration were 1.2 and 0.4 mg of betanin/100 ml of extract per day respectively. Among the treatments studied, HTST was considered the most suitable to maintain betalain stability from red beet stalks. PMID- 29391622 TI - Influence of the growth phenophases on the phenolic composition and anti-oxidant properties of Roscoea procera Wall. in western Himalaya. AB - Roscoea procera Wall. is one of the important Himalayan medicinal plant used in traditional as well as in modern health care system. The present study aimed to find out the influence of different phenophases on the phenolic compounds and anti-oxidant properties by analysing after every week for over 4 months from shoot bud initiation to the preparation of senescence. Concentration of total phenolic content were found to be about 1.5 times higher in preparation of senescence phase (6.10 mg GAE/g dry weight or dw) as compared to vegetative growth phase. Similarly, total flavonoid concentration ranged from 4.36 to 5.65 mg querectin equivalents/g dw. The concentration of selected phenolic compounds, i.e., gallic acid, catechin and p-coumaric acid was quantified by reverse phase high performance liquid chromatography and varied significantly among the different phenophases. While, anti-oxidant activity was found 2-3 times higher in preparation of senescence phase as compared to vegetative phase. Thus, these results concluded that in R. procera, November month (preparation of senescence phase) could be recommended for extracting optimum level of total phenolics, flavonoids and anti-oxidant activity. These results will be further helpful for obtaining maximum benefits from the species and to reduce pressure on reproductive phase while ensuring its conservation. PMID- 29391623 TI - Chemical properties of commercially available honey species and the functional properties of caramelization and Maillard reaction products derived from these honey species. AB - The chemical parameters and the functionalities of six monofloral honeys of different botanical and geographical origins were investigated. Vitamins B1, B2, and C and the protein content of majority of honeys were distinguishable from general honey. Honeys not only were rich in a variety of functional components like flavonoids but also had strong anti-oxidant activities, scavenging activities against ROS, and anti-hypertensive and anti-allergic activities. Honeys were heated at 100 degrees C for 24 h and their browning intensity during heating process was observed to vary with botanical origin. The functional properties of caramelization and maillard reaction (MR) products derived from honeys during heating were evaluated. The browning of honeys progressed regardless of honey species. Anti-oxidant activities and scavenging activities against superoxide and DPPH radicals of products drastically increased, but ACE and hyaluronidase activities gradually decreased with passage of heating time. It concluded that the products, mainly melanoidins, produced simultaneously to browning process in caramelization and MR contributed to the expression of its useful function. PMID- 29391624 TI - Optimization of low-fat meat hamburger formulation containing quince seed gum using response surface methodology. AB - In the present study, feasibility of low-fat hamburger production by partial replacement with quince seed gum (QSG) was investigated. The effects of different QSG levels (1.2, 2.4, 3.6, and 4.8 wt%) on cooking loss, water holding capacity, lipid oxidation, antioxidant activity, and hardness of hamburger were investigated during a period of 9 days. The optimization was carried out based on minimum cooking loss, lipid oxidation, and maximum water holding capacity, antioxidant activity, and tissue hardness. Optimum conditions were achieved as 3.26% oil, 4.73% QSG, and 8.25th day of storagability. According to the optimum conditions, values for cooking loss, water holding capacity, lipid oxidation, free radical scavenging, raw hamburger hardness, and fried hamburger hardness were as 13.80%, 55.61%, 0.59 mg MDA/Kg, 48.12%, 2.99 N, and 8.66 N, respectively. Overall acceptability of optimized hamburgers was better and more acceptable than control ones. PMID- 29391625 TI - Bioefficacy potential of different genotypes of walnut Juglans regia L. AB - The purpose of investigation was to assess the phytochemical and nutraceutical of walnut in leaf extracts through diverse quantitative and qualitative phytochemical tests followed by array of assays. The screening of 50 elite walnut genotypes which exhibited wide range of discrepancy in terms of phytochemicals as well as their anti-oxidant potential was done. Walnut genotypes displayed maximum divergence in quercetin content (2.86-5.78 mg/100 g) as represented by cluster analysis. The phenolic rich genotypes exhibiting total phenols (37.61-46.47 mg/g GAE) having higher DPPH potential (IP of 32.82-73.50) where as genotypes that accumulate flavonoids/flavanols (5.52-28.48 mg/g QE and 4.11-21.76 mg/g QE showed immense FRAP activity (418.92-1067.94 uM Fe2+/g FW). There was positive correlation between the phenolics content and anti-oxidant potential. The results showed oil content of 50.1-85.08% and kernel percentage 25.21-81.92% of all walnut genotypes. To evaluate the anti-proliferative potential of walnut genotypes, Trypan blue exclusion test, MTT assay and Griess assay was used. Each assay was repeated with different positive controls against a panel of human cancer cell lines viz THP-1, U2OS, IMR-32 and HBL-100 and then compared with the walnut extracts for their efficiency in anti-proliferative activity. The SPS 1 walnut extract at concentration of 500 ug/ml exhibited 10% cell viability and with 1000 ug/ml walnut extract there was consequent decline towards (6.25%) viability. The results indicated that walnut leaf constitutes an excellent source of effective natural antioxidants and chemo-preventive agents that can act as anti cancer agents. PMID- 29391626 TI - Development of lotus root fermented sugar syrup as a functional food supplement/condiment and evaluation of its physicochemical, nutritional and microbiological properties. AB - Lotus (Nelumbo nucifera) root has been used as an edible vegetable in East Asia for thousands of years. The present research was aimed to explore the physicochemical, nutritional and microbiological safety of lotus root fermented sugar syrup as a fermented food supplement or condiment for human health benefits. In this study, the physicochemical, nutritional and microbiological safety properties of lotus root syrup fermented with 57 degrees Brix brown sugar at different time periods until 6 months (180 days) was investigated. There was a significant improvement as compared to 57 degrees Brix brown sugar broth (as a control) in the total acceptability and physicochemical properties of lotus root sugar syrup samples such as pH and color improvement. The red color values of 180 days lotus root fermented sugar syrup samples were significantly enhanced (6.85 +/- 0.58) when compared with the control (0.20 +/- 0.15). In addition, the total protein content was increased from 8.27 +/- 0.86 to 392.33 +/- 7.19 MUg/mL, along with the increase in fermentation time reaching to the level of consumption acceptability. All the lotus root fermented sugar syrup samples were subjected to microbiological analysis. It was found that the coliform, Bacillus cereus, Escherichia coli, Salmonella and Staphylococcus aureus counts were not detected in majority of the samples, confirming the high degree of hygiene processing of lotus root fermented sugar syrup samples for its use as a food supplement or condiment. PMID- 29391627 TI - High hydrostatic pressure (HHP) effects on antigenicity and structural properties of soybean beta-conglycinin. AB - In this study, the effect of high hydrostatic pressure (HHP) on antigenicity, free sulfhydryl group (SH) content, hydrophobicity (Ho), fluorescence intensity and circular dichroism data of soybean beta-conglycinin was studied. The antigenicity of soybean beta-conglycinin was decreased significantly at pressures 200-400 MPa. The antigenicity inhibition rate of beta-conglycinin declined from 92.72 to 55.15%, after being treated at 400 MPa for 15 min. Results indicated that free sulphydryl (SH) groups and surface Ho of beta-conglycinin were significantly increased at pressures 200-400 MPa and 5-15 min, whereas these properties decreased at the treatments above 400 MPa and 15 min. The maximum fluorescence intensity was noticed at 400 MPa and 15 min. The circular dichroism data analysis revealed that the amount of beta-turns and unordered structure significantly increased, while the content of alpha-helix1 and beta-strand1 noticeably decreased. These results provide evidence that HHP-induced the structural modification of beta-conglycinin and could alter the antigenicity of beta-conglycinin. PMID- 29391628 TI - Optimal germination condition impacts on the antioxidant activity and phenolic acids profile in pigmented desi chickpea (Cicer arietinum L.) seeds. AB - Legume sprouts are considered natural, healthy products that provide a source of bioactive compounds to fight against chronic diseases. This study aims to identify the optimal germination temperature (GT) and germination time (Gt) to maximize total phenolic and flavonoid contents (TPC, FC), and antioxidant activity (AoxA) of desi chickpea. Response surface methodology was used as an optimization tool. An experimental design with two factors (GT and Gt) and five levels was used (13 treatments). The sprouts from each treatment were lyophilized, tempered, and milled to obtain germinated chickpea flours (GCF). To predict the phytochemicals composition and AoxA in GCF, regression models were developed. Maximum TPC, FC, and AoxA were attained during germination 33.7 degrees C for 171 h. Optimized germinated chickpea flour produced applying the optimal germination conditions resulted in an increase of protein and total dietary fibre content, TPC, FC, phenolic acids profile, and AoxA. Germination at optimal conditions also increased the level of coumaric, ferulic, synapic, ellagic, and syringic acids. This study demonstrated that germination carried out under optimal conditions enhanced the nutraceutical value of desi chickpea seeds. PMID- 29391629 TI - Electrically induced changes in amaranth seed enzymatic activity and their effect on bioactive compounds content after germination. AB - Electric treatment applied to seeds and sprouts can change their phytochemical composition. However, only a handful of studies have investigated the effects of treating seeds with electric current prior to their germination on the enzymatic antioxidant system of their sprouts. The aim of this study was to determine the changes in bioactive compounds and the enzymatic antioxidant activities in seeds and amaranth sprouts under direct electric current (DC) treatments. Amaranth seeds were treated with DC at 500 mA for different periods of time (0, 2, 5, 10 and 30 min) and let sprout (85% RH, 25 +/- 2 degrees C) for 6 days. Significant changes were found in the antioxidant enzymatic activities and in the total content of flavonoids (15.44 +/- 0.56 mg RE/gDW) and phenolic compounds (35.87 +/ 0.17 mg GAE/gDW) in 6-day-old sprouts from DC-treated seeds in comparison to sprouts form non-treated seeds. The results suggested that DC treatment for short period (5 min) can induce quantitative changes to the enzymatic antioxidant system of amaranth sprouts, thus representing a relatively cost-effective method for enhancing health-improving properties of sprouts. PMID- 29391630 TI - Extraction and characterization of proteins from banana (Musa Sapientum L) flower and evaluation of antimicrobial activities. AB - Ultrasonic assisted alkaline extraction of protein from banana flower was optimized using response surface methodology. The extracted proteins were characterized by Fourier transform infrared spectroscopy and molecular weight distribution was determined by gel electrophoresis. The maximum protein yield of 252.25 mg/g was obtained under optimized extraction conditions: temperature 50 degrees C, 30 min extraction time and 1 M NaOH concentration. The alkaline extraction produced a significantly high protein yield compared to enzymatic extraction of banana flower. Chemical finger printing of proteins showed the presence of tyrosine, tryptophan and amide bonds in extracted protein. Alkaline and pepsin assisted extracted banana flower proteins showed characteristic bands at 40 and 10 kDA, respectively. The extracted proteins showed antibacterial effects against both gram positive and gram negative bacteria. The high protein content and antimicrobial activity indicate the potential applications of banana flower in the food and feed industry. PMID- 29391631 TI - Effects of addition of different fibers on rheological characteristics of cake batter and quality of cakes. AB - The aim of this study was to investigate the effects of addition of dietary fibers on rheological properties of batter and cake quality. Wheat flour was replaced by 5 and 10% (wt%) oat, pea, apple and lemon fibers. All cake batters showed shear thinning behavior. Incorporation of fibers increased consistency index (k), storage modulus (G') and loss modulus (G"). As quality parameters, specific volume, hardness, weight loss, color and microstructure of cakes were investigated. Cakes containing oat and pea fibers (5%) had similar specific volume and texture with control cakes which contained no fiber. As fiber concentration increased, specific volume decreased but hardness increased. No significant difference was found between weight loss of control cake and cakes with oat, pea and apple fibers. Lemon fiber enriched cakes had the lowest specific volume, weight loss and color difference. When microstructural images were examined, it was seen that control cake had more porous structure than fiber enriched cakes. In addition, lemon and apple fiber containing cakes had less porous crumb structure as compared to oat and pea containing ones. Oat and pea fiber (5%) enriched cakes had similar physical properties (volume, texture and color) with control cakes. PMID- 29391632 TI - Modeling sorption phenomena and moisture migration rates in paprika (Capsicum annuum L.) using physicochemical characteristics. AB - In the present study, the GAB and moisture migration rate models were used to predict the shelf life of paprika under domestic (40 degrees C and 90% RH) and industrial (5, 10, 15 and 20 degrees C with 70% RH) storage conditions. The correlations between physicochemical characteristics and moisture content of paprika were developed to estimate the stability of the paprika. The estimated shelf life of low moisture paprika (4.40% dry basis) was found to be 101 and 31 days in HDPE and LDPE packages, respectively when stored in domestic condition. In industrial storage condition, the shelf life prediction was 5.47 years in HDPE and 1.68 years in LDPE packages. The first order kinetic models of extractable color (ASTA) and degree of caking described the quality degradation of paprika during storage. The relative humidity and temperature of the storage environment were significant parameters affecting the stability of paprika. The shelf life of paprika can be extended by storage at or below monolayer moisture content and low temperature. PMID- 29391633 TI - Antilisterial efficacy of Lactobacillus bacteriocins and organic acids on frankfurters. Impact on sensory characteristics. AB - Dipping solutions containing bacteriocins produced by Lactobacillus curvatus CRL705 and Lactobacillus sakei CRL1862 (Bact705/1862), nisin and organic acids (lactic acid, LA; acetic acid, AA) were tested alone or in combination against Listeria monocytogenes inoculated by immersion on vacuum-packaged frankfurters stored at 10 degrees C during 36 days. LA/AA solution (2.5% v/v each) reduced pathogen population by 1.50 log10 CFU/ml during storage. Semi-purified Bact705/1862 prevented L. monocytogenes growth, while nisin was not able to avoid its regrowth after 20 days. The combined addition of Bact705/1862 + LA/AA was the most effective approach for pathogen reduction below detection level from day 6 to final storage. Frankfurters treated with Bact705/1862 + LA/AA compared to fresh-purchased samples did not show significant differences in flavor, juiciness, color intensity and overall preference at 22 days-storage at 5 degrees C. Meat processors should not only validate the antimicrobial efficacy of combined treatments but also their sensory impact on the product, which is directly related to consumer acceptability. PMID- 29391634 TI - Simple and fast multiplex PCR method for detection of species origin in meat products. AB - Identification of animal species is one of the major concerns in food regulatory control and quality assurance system. Different approaches have been used for species identification in animal origin of feedstuff. This study aimed to develop a multiplex PCR approach to detect the origin of meat and meat products. Specific primers were designed based on the conserved region of mitochondrial Cytochrome C Oxidase subunit I (COX1) gene. This method could successfully distinguish the origin of the pig, camel, sheep, donkey, goat, cow, and chicken in one single reaction. Since PCR products derived from each species represent unique molecular weight, the amplified products could be identified by electrophoresis and analyzed based on their size. Due to the synchronized amplification of segments within a single PCR reaction, multiplex PCR is considered to be a simple, fast, and inexpensive technique that can be applied for identification of meat products in food industries. Nowadays, this technique has been considered as a practical method to identify the species origin, which could further applied for animal feedstuffs identification. PMID- 29391635 TI - Assessment of malting characteristics of different Indian barley cultivars. AB - The impact of malting on composition and malt quality parameters such as diastatic power, alpha-amylase activity, beta-amylase activity, hot water extract and beta-glucan content were investigated in five different Indian barley cultivars. Protein content of grains increased significantly after malting. Soluble protein content of unmalted grain, which ranged from 3.20-3.93% increased after malting to 4.26-4.85%. Diastatic power of mature grain varied across genotype and their level increased (58.98-81.05 to 115.93-142.45 DP degrees ) after malting. Diastatic power correlated very strongly with protein content (r = 0.90) and strongly with beta-amylase activity (r = 0.74). alpha-amylase, which was low (0.042-0.189 Ceralpha Unit/g) initially in unmalted grain, was synthesized during germination to the range of 149.42-223.78 Ceralpha Unit/g. The correlation between diastatic power and alpha-amylase was very weak (r = - 0.04). The levels of beta-amylase in unmalted grain was in the range of 13.97-18.26; that amount got reduced after malting to 12.55-15.97 Betamyl-3 U/g. beta-amylase had a strong positive correlation (r = 0.85) with grain protein. Malted grain which had higher protein content showed very strong negative correlation (r = - 0.86) with hot water extract value. beta-glucan content reduced 70-80% from the initial level, across genotypes. PMID- 29391636 TI - Optimized preparation, characterization, and antioxidant activity of chitooligosaccharide-glycine Maillard reaction products. AB - In this study, chitooligosaccharide (COS) and glycine (Gly) were selected to prepare Maillard reaction products, which were designated COS-Gly-MRPs. Changes in the FTIR and fluorescence spectra confirmed the formation of the COS-Gly-MRPs. Using ferric reducing antioxidant power (FRAP) as a response, the optimal reaction conditions, i.e., a time of 107 min, temperature of 121 degrees C, pH of 6.0, and nCOS:nGly = 2.5:1, were obtained by one-variable-at-a-time method and by response surface methodology. The resulting COS-Gly-MRPs exhibited much stronger antioxidant activity than their substrates. The FRAP of COS-Gly-MRPs was 32.14 mmol Fe2+/L, and the radical scavenging activity of COS-Gly-MRPs reached 78.6, 89.0, 92.3, and 86.0% for ABTS, superoxide, DPPH, and hydroxyl radicals, respectively. After 7 days of storage, COS-Gly-MRPs-treated fruit juices showed higher antioxidant capacity than those treated with a mixture of COS and Gly. PMID- 29391637 TI - Functional and antioxidant properties of protein hydrolysates obtained from white shrimp (Litopenaeus vannamei). AB - Protein hydrolysates from white shrimp (Litopenaeus vannamei) with different degrees of hydrolysis (DH-10 and 20%) were prepared using the enzymes Alcalase 2.4 L and Protamex. The hydrolysates were evaluated for amino acid composition, solubility, foaming properties, emulsifying and antioxidant activity. All the hydrolysates showed high concentrations of Glutamic Acid, Aspartic acid, Arginine, Glycine, Lysine, Proline. It was found that the increase in the production of negatively charged amino acids was related to increase in DH. The hydrophobic amino acids were higher for hydrolysates obtained with Alcalase (10% DH) and Protamex (20% DH). The results indicated that higher degree of hydrolysis showed positive relation with the protein solubility of the hydrolysates, while negatively influenced foam and emulsification properties. The antioxidant properties presented by the white shrimp protein hydrolysates were influenced by the composition and peptides size. Hydrolysates with higher peptide chain showed the highest antioxidant power for the 2,2-Diphenyl-1-picrylhydrazyl radical scavenging and reducing power, while hydrolysates with lower peptide chain showed higher antioxidant power for 2,2'-azinobis (3-ethylbenzothiazoline sulfonic acid) radical scavenging. All hydrolysates showed dose-dependent antioxidant activities. Therefore, the results of the present study suggest that white shrimp is a potential source of protein hydrolysates as bioactive ingredients for the use in the formulation of functional foods as well as natural antioxidants in lipid food systems. PMID- 29391638 TI - Nutritional profile and molecular fingerprints of indigenous black jamun (Syzygium cumini L.) landraces. AB - The indigenous black jamun landraces (Syzygium Cumini L.), found in western Gujarat of Gir forest region (India), produced fruits with different size and shape. Fruit morphology like shape, volume, weight, length, girth were examined and black jamun categorized into six landraces viz., BJLR 1 (big fruit, > 11 g); BJLR 2 (medium to big fruit, 8-11 g); BJLR 3 (medium fruit, 6-8 g); BJLR 4 (medium to small fruit, 5-6 g); BJLR 5 (small fruit, 3-5 g) and BJLR 6 (very small fruit, < 3 g fruit weight). The landraces (BJLR 1 and 2) with larger size fruits were accumulated higher amount of moisture, total fat content, sugars, total protein, starch, free amino acid contents. Smaller fruits (BJLR 6) contained higher amount of ascorbic acid-137 and 132 mg%; anthocynin-47.7 and 2.35 mg%; crude fibre 3.05 and 10.5 g%; and total phenol-21.7 and 45.0 mg g-1 in their fruit pulp and seed part, respectively with better nutritional profile compared with big and moderate fruited landraces. Nutritional profile of six landraces indicated that fruit pulp accumulated higher amount of soluble sugars (6.51-17.6 mg g-1), anthocyanins (29.7-47.7 mg%) and free amino acids (7.54-18.9 mg%) while that of seeds exhibited higher amount of crude fibre (6017-10.5 g%), ascorbic acid (90-137 mg%), starch (22.8-29.4 g%), total protein (4.72-7.17 mg%), phenols (45-56.7 mg g-1). The black jamun landraces were subjected to ISSR based polymorphic finger prints and genetic diversity analysis. Total 144 bands were amplified across six landraces by 18 UBC primers, of which 94 were polymorphic with 64.2% average polymorphism. Cluster analysis demonstrates the BJLR 6 landraces distinguished from other landraces with 53% similarity. PMID- 29391639 TI - Blanching and antimicrobial mixture (potassium sorbate-sodium benzoate) impact on the stability of a tamarillo (Cyphomandra betacea) sweet product preserved by hurdle technology. AB - In a previous study, a stable tamarillo sweet product (TSP) was obtained by applying hurdle technology (low pH, reduction of water activity, sodium benzoate addition and stored at 4 degrees C, with oxygen and light protection). In order to improve the TSP shelf life, it was decided to employ a mixture of antimicrobial agents (sodium benzoate and potassium sorbate 50-50%) and fruit blanching. The phenolic compounds content, total monomeric anthocyanins of TSP, antioxidant capacity, microbial growth (aerobic mesophilic bacteria, molds and yeasts) and net color change were evaluated, during 63 days. The results showed that the use of blanched tamarillo and the addition of the antimicrobial mixture increased the TSP stability, in which the microbial counts were maintained below the limits established by the official food safety norms, without effects the antioxidant compounds and color. PMID- 29391641 TI - Preparation of omega 3 rich oral supplement using dairy and non-dairy based ingredients. AB - Fish oil is a rich source of omega 3 fatty acids, an essential fatty acid, vital for the functioning of the human body. But the undesirable flavour is an inherent limitation of fish oil which reduces its acceptability. Masking its fish flavour can increase acceptability of fish oil. The present study was focused on double encapsulation of fish oil to mask its distinct flavour. Fish oil was emulsified using soya lecithin where emulsifier to fat ratio was kept 1:4. The emulsion droplets were in the size range of 172.9 +/- 1.7 to 238.2 +/- 33.8 nm. The emulsion was mixed with whey protein-sodium alginate solution and converted to beads by dropwise extrusion in calcium chloride solution. Droplets were converted to soft gel beads containing fish oil. The encapsulation efficiency was 89.3%. Fish oil flavour was perceived from the dried beads. Hence, beads were further coated with high melting fat using pan coater and flavoured for making beads palatable to use as an oral supplement. Beads were free-flowing and light yellowish in colour. Beads coated with high melting fat and vanilla flavour scored more in the sensory evaluation by panelists. Beads were kept in airtight pack and stored under refrigeration. PMID- 29391640 TI - Development of a rapid PCR protocol to detect Vibrio parahaemolyticus in clams. AB - Vibrio parahaemolyticus is part of the natural microflora of estuarine and coastal marine waters and can be also present in seafood, especially shellfish and bivalve molluscs. In this study we compared the reference cultural method ISO 6887-3 with two molecular methods, multiplex PCR and real-time PCR, for the detection of two distinct genetic markers (tlh species-specific gene and tdh virulence gene) of V. parahaemolyticus in bivalve mollusc. The analyses were performed on clams inoculated with V. parahaemolyticus ATCC 43996 at T0 and after a 3 and 6 h of pre-enrichment in alkaline saline peptone water. Counts on agar plates were largely inaccurate, probably due to other Vibrio species grown on the TCBS selective agar. Multiplex PCR assays, performed using primers pairs for tdh and tlh genes, showed a detection limit of 104 CFU/g of shell stock within 6 h of pre-enrichment, respecting however the action level indicated by the National Seafood Sanitation Program guideline. Detection by tdh gene in real-time PCR reached the definitely highest sensitivity in shorter times, 101 CFU/g after 3 h of pre-enrichment, while the sensitivity for the tlh gene was not promising, detecting between 105 and 106 CFU/g after 6 h of pre-enrichment. Our findings provide a rapid routine method of detection of V. parahaemolyticus based on tdh gene by real-time PCR for commercial seafood analysis to identify the risk of gastrointestinal diseases. PMID- 29391642 TI - Impact of the addition of cocoa butter equivalent on the volatile compounds profile of dark chocolate. AB - The effect of the partial replacement of cocoa butter (CB) by cocoa butter equivalent (CBE) in the release of volatile compounds in dark chocolate was studied. The fatty acid profile, triacylglyceride composition, solid fat content (SFC) and melting point were determined in CB and CBE. Chocolate with CB (F1) and with different content of CBE (5 and 10%-F2 and F3, respectively) were prepared. Plastic viscosity and Casson flow limit, particle size distribution and release of volatile compounds using a solid phase microextraction with gas chromatography (SMPE-GC) were determined in the chocolate samples. The melting point was similar for the studied samples but SFC indicated different melting behavior. CBE showed a higher saturated fatty acid content when compared to CB. The samples showed similar SOS triglyceride content (21 and 23.7% for CB and CBE, respectively). Higher levels of POS and lower POP were observed for CB when compared to CBE (44.8 and 19.7 and 19 and 41.1%, respectively). The flow limit and plastic viscosity were similar for the studied chocolates samples, as well as the particle size distribution. Among the 27 volatile compounds identified in the samples studied, 12 were detected in significantly higher concentrations in sample F1 (phenylacetaldehyde, methylpyrazine, 2,6-dimethylpyrazine, 2-ethyl-5 methylpyrazine, 2-ethyl-3,5-dimethylpyrazine, tetramethylpyrazine, trimethylpyrazine, 3-ethyl-2,5-dimethylpyrazine, phenethyl alcohol, 2 acetylpyrrole, acetophenone and isovaleric acid). The highest changes were observed in the pyrazines group, which presented a decrease of more than half in the formulations where part of the CB was replaced by the CBE. PMID- 29391643 TI - Application of 1-methylcyclopropene on mango fruit (Cv. Kesar): potential for shelf life enhancement and retention of quality. AB - The present investigation was carried out to study the effect of gaseous application of 1-methylcyclopropene (1-MCP) on quality and shelf life of mango fruits of Cv. Kesar. The freshly harvested matured mango fruits were washed, cleaned and treated with fungicide at 500 ppm concentration for 10 min. The fruits were then subjected to 1-MCP treatment at different concentrations (500, 1000, 1500, 2000 ppb) and exposed for 18 and 24 h at 20 degrees C temperature in an air tight chamber along with control sample. The results indicated that the ripening in the early stages of mango was delayed by 1-MCP and shelf life of the fruits was increased with increase in the concentration of 1-MCP, also the physico-chemical changes such as percent physiological loss in weight of fruit, total soluble solids and colour was slowly increased and ascorbic acid content was effectively reduced. 1-MCP treatment of 2000 ppb for 24 h exposure time gave the best results for percent physiological loss in weight of fruit from 6.1 to 13% and ascorbic acid content from 80.28 to 22.34 mg/100 g, total soluble solids increased from 7.3 to 16.23 degrees Brix and the colour was improved from 50.9 to 68.6 h with shelf life of 20 days. PMID- 29391644 TI - Physicochemical and microstructural characterisation of green gram and foxtail millet starch gels. AB - The starch and starch gels from green gram (GG) and foxtail millet (FM) were characterised for their physicochemical, thermal and microstructural characteristics; the features of shape and size were determined by image analysis. Both GG and FM formed well-set gels at 9% concentration of starch. The fracture strain of the gels was between 78 and 80% indicating non-brittle gels. The peak temperatures of the native flour of GG (74.9 degrees C) and FM (75.7 degrees C) were significantly higher than their corresponding starch samples (72.2 and 75.0 degrees C). The conclusion temperatures of the FM native flour (81.2 degrees C) and starch (79.4 degrees C) samples were higher than the native GG flour (79.9 degrees C) and GG starch (77.1 degrees C) samples. Starches were nearly spherical as the roundness values were between 0.88 and 0.95. Green gram starch was pentagonal having an average diameter of 3.9-9.2 um while foxtail millet starch was spherical with a diameter of 4.9-10.1 um. The freeze-dried GG and FM starch gels showed cellular structure containing organised hexagonal pores, bound by thin pore walls; the GG starch gels deviated from the circular shape as they had the highest elongation value of 4.21. The thicker pore walls were observed for GG starch gels (0.88 MUm) compared to that of FM samples (0.57 MUm). The higher pore wall thickness in the case of GG gel showed the formation of junction zones. PMID- 29391645 TI - Comparison of physicochemical properties and antioxidant activities of fermented soybean-based red pepper paste, Gochujang, prepared with five different red pepper (Capsicum annuum L.) varieties. AB - The purposes of this study were to identify physicochemical properties and evaluate bioactive compound levels and antioxidant characteristics at 30 day intervals during the 90 days of fermentation of gochujang fortified with five different varieties of red pepper: Juktoma pepper (RP1), facing heaven pepper (RP2), Thai chili pepper (RP3), bird's eye pepper (RP4), and red bell pepper (RP5). Physicochemicals properties, including reducing sugar, capsaicin, pH, beta carotene, and color parameters, of gochujang were evaluated. Antioxidant compounds of total polyphenols and total flavonoids were analyzed with antioxidant activities of DPPH and FRAP assays. The results showed that gochujangs (GRP1, GRP5) fortified with RP1, and RP5, had consistently higher values of reducing sugars, total polyphenols, and total flavonoids with antioxidant activities, but lower values of capsaicin, pH, beta-carotene, and color parameters as compared to GRP2, GRP3, GRP4 during 90 days of fermentation. GRP5 especially had the highest reducing sugar, amino acid contents, total polyphenols, and total flavonoids with antioxidant activities and the lowest value of capsaicin during the 90 days of fermentation. PMID- 29391646 TI - Physico-chemical, hydration, cooking, textural and pasting properties of different adzuki bean (Vigna angularis) accessions. AB - Physico-chemical, hydration, cooking, textural and pasting properties of thirteen adzuki bean (Vigna angularis) accessions were studied. Protein and ash content ranged from 18.82 to 24.52% and 2.02 to 7.03%, respectively. Bulk density and seed weight of the adzuki seed ranged from 0.76 to 1.00 g/mL and 74.87 to 148.20 g/1000 seeds, respectively. Hydration capacity, swelling capacity and cooking time ranged from 0.05 to 0.12 g/seed, 0.04 to 0.15 mL/seed and 48.67 to 74.33 min, respectively. Different accessions showed significant variations in their physicochemical, cooking, hydration and texture properties. Swelling capacity showed significantly positive correlation with L* value. Hardness of soaked grain varied ranged between 68.67 and 120.25 N and had significant positive correlation with gumminess and chewiness. The springiness and chewiness of cooked seeds showed highly significant positive correlation. Peak viscosity, breakdown viscosity, final viscosity, setback viscosity and pasting temperature of adzuki bean flour ranged from 1979 to 2373 cP, 45 to 183 cP, 2954 to 4004 cP, 931 to 1666 cP and 75.02 to 78.27 degrees C, respectively. Peak viscosity and breakdown viscosity were negatively correlated to amylose content while setback viscosity showed positive correlation. PMID- 29391647 TI - Optimization of lipid profile and hardness of low-fat mortadella following a sequential strategy of experimental design. AB - This study aims to optimize simultaneously the lipid profile and instrumental hardness of low-fat mortadella. For lipid mixture optimization, the overlapping of surface boundaries was used to select the quantities of canola, olive, and fish oils, in order to maximize PUFAs, specifically the long-chain n-3 fatty acids (eicosapentaenoic-EPA, docosahexaenoic acids-DHA) using the minimum content of fish oil. Increased quantities of canola oil were associated with higher PUFA/SFA ratios. The presence of fish oil, even in small amounts, was effective in improving the nutritional quality of the mixture, showing lower n-6/n-3 ratios and significant levels of EPA and DHA. Thus, the optimal lipid mixture comprised of 20, 30 and 50% fish, olive and canola oils, respectively, which present PUFA/SFA (2.28) and n-6/n-3 (2.30) ratios within the recommendations of a healthy diet. Once the lipid mixture was optimized, components of the pre-emulsion used as fat replacer in the mortadella, such as lipid mixture (LM), sodium alginate (SA), and milk protein concentrate (PC), were studied to optimize hardness and springiness to target ranges of 13-16 N and 0.86-0.87, respectively. Results showed that springiness was not significantly affected by these variables. However, as the concentration of the three components increased, hardness decreased. Through the desirability function, the optimal proportions were 30% LM, 0.5% SA, and 0.5% PC. This study showed that the pre-emulsion decreases hardness of mortadella. In addition, response surface methodology was efficient to model lipid mixture and hardness, resulting in a product with improved texture and lipid quality. PMID- 29391648 TI - Anti-oxidant and anti-microbial properties of mutton nuggets incorporated with blends of essential oils. AB - The present study was carried out to evaluate effect of natural anti-oxidants on the quality of mutton nuggets. Different blends of essential oil were evaluated for incorporation in mutton nuggets and it was found that Blend-1 had significantly higher sensory scores. Then, Blend-1 was tried at 0.25, 0.5 and 0.75% levels and product containing 0.25% level received significantly higher sensory scores. Thereafter, two combinations of flaxseed flour and 0.25% Blend-1 were tried viz., 4% flaxseed flour + 0.25% Blend-1 and 8% flaxseed flour + 0.25% Blend-1. Evaluation of sensory and physico-chemical properties were done in mutton nuggets incorporated with 0.25% Blend-1 (T-1) and selected combination (4% flaxseed flour + 0.25% Blend-1) (T-2). T-2 had significantly higher dietary fiber and crude fiber than T-1 products. These products were then assessed for quality changes during storage at refrigerated temperature for 30 days at 5 days interval. Significantly lower TBARS values were recorded for treatment products than control at each interval of storage period. T-2 product showed significantly higher DPPH value than other products. Microbial count remained within the permissible limit of log104 cfu/g for TPC, PC, yeast and mould count up to 15th day, 25th day and 30th day for control, T-1 and T-2 products, respectively. Essential oil and their combination incorporated mutton nuggets had about 10 days longer shelf life than control. PMID- 29391649 TI - Life-history responses to changing temperature and salinity of the Baltic Sea copepod Eurytemora affinis. AB - To understand the effects of predicted warming and changing salinity of marine ecosystems, it is important to have a good knowledge of species vulnerability and their capacity to adapt to environmental changes. In spring and autumn of 2014, we conducted common garden experiments to investigate how different populations of the copepod Eurytemora affinis from the Baltic Sea respond to varying temperatures and salinity conditions. Copepods were collected in the Stockholm archipelago, Bothnian Bay, and Gulf of Riga (latitude, longitude: 58 degrees 48.19', 17 degrees 37.52'; 65 degrees 10.14', 23 degrees 14.41'; 58 degrees 21.67', 24 degrees 30.83'). Using individuals with known family structure, we investigated within population variation of the reaction norm (genotype and salinity interaction) as a means to measure adaptive capacity. Our main finding was that low salinity has a detrimental effect on development time, the additive effects of high temperature and low salinity have a negative effect on survival, and their interaction has a negative effect on hatching success. We observed no variation in survival and development within populations, and all genotypes had similar reaction norms with higher survival and faster development in higher salinities. This suggests that there is no single genotype that performs better in low salinity or high salinity; instead, the best genotype in any given salinity is best in all salinities. Genotypes with fast development time also had higher survival compared to slow developing genotypes at all salinities. Our results suggest that E. affinis can tolerate close to freshwater conditions also in high temperatures, but with a significant reduction in fitness. PMID- 29391650 TI - RADI: a low-rank ADI-type algorithm for large scale algebraic Riccati equations. AB - This paper introduces a new algorithm for solving large-scale continuous-time algebraic Riccati equations (CARE). The advantage of the new algorithm is in its immediate and efficient low-rank formulation, which is a generalization of the Cholesky-factored variant of the Lyapunov ADI method. We discuss important implementation aspects of the algorithm, such as reducing the use of complex arithmetic and shift selection strategies. We show that there is a very tight relation between the new algorithm and three other algorithms for CARE previously known in the literature-all of these seemingly different methods in fact produce exactly the same iterates when used with the same parameters: they are algorithmically different descriptions of the same approximation sequence to the Riccati solution. PMID- 29391651 TI - Refined saddle-point preconditioners for discretized Stokes problems. AB - This paper is concerned with the implementation of efficient solution algorithms for elliptic problems with constraints. We establish theory which shows that including a simple scaling within well-established block diagonal preconditioners for Stokes problems can result in significantly faster convergence when applying the preconditioned MINRES method. The codes used in the numerical studies are available online. PMID- 29391652 TI - Stationary Schrodinger equation in the semi-classical limit: numerical coupling of oscillatory and evanescent regions. AB - This paper is concerned with a 1D Schrodinger scattering problem involving both oscillatory and evanescent regimes, separated by jump discontinuities in the potential function, to avoid "turning points". We derive a non-overlapping domain decomposition method to split the original problem into sub-problems on these regions, both for the continuous and afterwards for the discrete problem. Further, a hybrid WKB-based numerical method is designed for its efficient and accurate solution in the semi-classical limit: a WKB-marching method for the oscillatory regions and a FEM with WKB-basis functions in the evanescent regions. We provide a complete error analysis of this hybrid method and illustrate our convergence results by numerical tests. PMID- 29391653 TI - Reading-Related Causal Attributions for Success and Failure: Dynamic Links With Reading Skill. AB - The present study investigated the relation among reading skills and attributions, naming speed, and phonological awareness across a wide range of reading skill. Participants were 1,105 school-age children and youths from two understudied populations: African Americans and Hispanic Americans. Individual assessments of children ranging in age from 8 to 15 years were conducted for reading outcomes, cognitive and linguistic predictors of reading, and attributions for success and failure in reading situations. Quantile regressions were formulated to estimate these relations across the full skill span of each outcome. Reading-related attributions predicted contextual word recognition, sight word and decoding fluency, and comprehension skills. Attributions to ability in success situations were positively related to each outcome across the full span. On three reading outcomes, this relation strengthened at higher skill levels. Attributions to effort in success situations were consistently and negatively related to all reading outcomes. The results provide evidence that the strength of the relation between reading and attributions varies according to reading skill levels, with the strongest evidence for ability-based attributions in situations of reading success. PMID- 29391654 TI - Estimating Moderated Causal Effects with Time-varying Treatments and Time-varying Moderators: Structural Nested Mean Models and Regression with Residuals. AB - Individuals differ in how they respond to a particular treatment or exposure, and social scientists are often interested in understanding how treatment effects are moderated by observed characteristics of individuals. Effect moderation occurs when individual covariates dampen or amplify the effect of some exposure. This article focuses on estimating moderated causal effects in longitudinal settings where both the treatment and effect moderator vary over time. Effect moderation is typically examined using covariate by treatment interactions in regression analyses, but in the longitudinal setting, this approach may be problematic because time-varying moderators of future treatment may be affected by prior treatment-for example, moderators may also be mediators-and naively conditioning on an outcome of treatment in a conventional regression model can lead to bias. This article introduces to sociology moderated intermediate causal effects and the structural nested mean model for analyzing effect moderation in the longitudinal setting. It discusses problems with conventional regression and presents a new approach to estimation that avoids these problems (regression-with residuals). The method is illustrated using longitudinal data from the PSID to examine whether the effects of time-varying exposures to poor neighborhoods on the risk of adolescent childbearing are moderated by time-varying family income. PMID- 29391656 TI - Fret not thyself: The persuasive effect of anger expression and the role of perceived appropriateness. AB - Anger expression is increasingly prevalent in Western mass media, particularly in messages that aim to persuade the audience of a certain point of view. There is a dearth of research, however, investigating whether expressing anger in mediated messages is indeed effective as a persuasive strategy. In the present research, the results of four experiments showed that expressing anger in a persuasive message was perceived as less socially appropriate than expressing non-emotional disagreement. There was also evidence that perceived appropriateness mediated a negative persuasive effect of anger expression (Study 2-4) and that anger expression resulted in perceptions of the persuasive source as unfriendly and incompetent (Studies 1 and 2). In all, the findings suggest that politicians and other public figures should be cautious in using anger as a persuasive instrument. PMID- 29391655 TI - Linking psychological need experiences to daily and recurring dreams. AB - The satisfaction of individuals' psychological needs for autonomy, competence, and relatedness, as conceived from a self-determination theory perspective, is said to be conducive to personal growth and well-being. What has been unexamined is whether psychological need-based experiences, either their satisfaction or frustration, manifests in people's self-reported dream themes as well as their emotional interpretation of their dreams. A cross-sectional study (N = 200; M age = 21.09) focusing on individuals' recurrent dreams and a three-day diary study (N = 110; M age = 25.09) focusing on daily dreams indicated that individuals experiencing psychological need frustration, either more enduringly or on a day to-day basis, reported more negative dream themes and interpreted their dreams more negatively. The contribution of psychological need satisfaction was more modest, although it related to more positive interpretation of dreams. The discussion focuses on the role of dreams in the processing and integration of psychological need-frustrating experiences. PMID- 29391657 TI - The Influence of Classmates on Adolescent Criminal Activities in the United States. AB - This article examines the effect of delinquent peers on an individual's criminal activity by leveraging quasi-experimental variation in exposure to peers, separating confounding and causal effects. In particular, we examine the role of wider peer networks (i.e., classmates) as a critical source of influence on adolescents' delinquent behavior. Using a combined instrumental variables/fixed effects methodology, we address important methodological challenges in estimating peer effects. Results suggest that increasing the proportion of peers who engage in criminal activities by 5 percent will increase the likelihood an individual engages in criminal activities by 3 percentage points. PMID- 29391658 TI - Stochastic Forecasting of Labor Supply and Population: An Integrated Model. AB - This paper presents a stochastic model to forecast the German population and labor supply until 2060. Within a cohort-component approach, our population forecast applies principal components analysis to birth, mortality, emigration, and immigration rates, which allows for the reduction of dimensionality and accounts for correlation of the rates. Labor force participation rates are estimated by means of an econometric time series approach. All time series are forecast by stochastic simulation using the bootstrap method. As our model also distinguishes between German and foreign nationals, different developments in fertility, migration, and labor participation could be predicted. The results show that even rising birth rates and high levels of immigration cannot break the basic demographic trend in the long run. An important finding from an endogenous modeling of emigration rates is that high net migration in the long run will be difficult to achieve. Our stochastic perspective suggests therefore a high probability of substantially decreasing the labor supply in Germany. PMID- 29391659 TI - An M-estimator for reduced-rank system identification. AB - High-dimensional time-series data from a wide variety of domains, such as neuroscience, are being generated every day. Fitting statistical models to such data, to enable parameter estimation and time-series prediction, is an important computational primitive. Existing methods, however, are unable to cope with the high-dimensional nature of these data, due to both computational and statistical reasons. We mitigate both kinds of issues by proposing an M-estimator for Reduced rank System IDentification ( MR. SID). A combination of low-rank approximations, l1 and l2 penalties, and some numerical linear algebra tricks, yields an estimator that is computationally efficient and numerically stable. Simulations and real data examples demonstrate the usefulness of this approach in a variety of problems. In particular, we demonstrate that MR. SID can accurately estimate spatial filters, connectivity graphs, and time-courses from native resolution functional magnetic resonance imaging data. MR. SID therefore enables big time series data to be analyzed using standard methods, readying the field for further generalizations including non-linear and non-Gaussian state-space models. PMID- 29391660 TI - Spectral signatures of charge transfer in assemblies of molecularly-linked plasmonic nanoparticles. AB - Self-assembly of functionalized nanoparticles (NPs) provides a unique class of nanomaterials for exploring and utilizing quantum-plasmonic effects that occur if the interparticle separation between NPs approaches a few nanometers and below. We review recent theoretical and experimental studies of plasmon coupling in self assembled NP structures that contain molecular linkers between the NPs. Charge transfer through the interparticle gap of an NP dimer results in a significant blue-shift of the bonding dipolar plasmon (BDP) mode relative to classical electromagnetic predictions, and gives rise to new coupled plasmon modes, the so called charge transfer plasmon (CTP) modes. The blue-shift of the plasmon spectrum is accompanied by a weakening of the electromagnetic field in the gap of the NPs. Due to an optical far-field signature that is sensitive to charge transfer across the gap, plasmonic molecules represent a sensor platform for detecting and characterizing gap conductivity in an optical fashion and for characterizing the role of molecules in facilitating the charge transfer across the gap. PMID- 29391661 TI - Multi-scale surface topography to minimize adherence and viability of nosocomial drug-resistant bacteria. AB - Toward minimizing bacterial colonization of surfaces, we present a one-step etching technique that renders aluminum alloys with micro- and nano-scale roughness. Such a multi-scale surface topography exhibited enhanced antibacterial effect against a wide range of pathogens. Multi-scale topography of commercially grade pure aluminum killed 97% of Escherichia coli and 28% of Staphylococcus aureus cells in comparison to 7% and 3%, respectively, on the smooth surfaces. Multi-scale topography on Al 5052 surface was shown to kill 94% of adhered E. coli cells. The microscale features on the etched Al 1200 alloy were not found to be significantly bactericidal, but shown to decrease the adherence of S. aureus cells by one-third. The fabrication method is easily scalable for industrial applications. Analysis of roughness parameters determined by atomic force microscopy revealed a set of significant parameters that can yield a highly bactericidal surface; thereby providing the design to make any surface bactericidal irrespective of the method of fabrication. The multi-scale roughness of Al 5052 alloy was also highly bactericidal to nosocomial isolates of E. coli, K. pneumoniae and P. aeruginosa. We envisage the potential application of engineered surfaces with multi-scale topography to minimize the spread of nosocomial infections. PMID- 29391662 TI - Failing to progress or progressing to fail? Age-for-grade heterogeneity and grade repetition in primary schools in Karonga district, northern Malawi. AB - Timely progression through school is an important measure for school performance, completion and the onset of other life transitions for adolescents. This study examines the risk factors for grade repetition and establishes the extent to which age-for-grade heterogeneity contributes to subsequent grade repetition at early and later stages of school. Using data from a demographic surveillance site in Karonga district, northern Malawi, a cohort of 8174 respondents (ages 5-24 years) in primary school was followed in 2010 and subsequent grade repetition observed in 2011. Grade repetition was more common among those at early (grades 1 3) and later (grades 7-8) stages of school, with little variation by sex. Being under-age or over-age in school has different implications on schooling outcomes, depending on the stage of schooling. After adjusting for other risk factors, boys and girls who were under-age at early stages were at least twice as likely to repeat a grade as those at the official age-for-grade (girls: adjusted OR 2.06 p < 0.01; boys: adjusted OR 2.37 p < 0.01); while those over-age at early stages were about 30% less likely to repeat (girls: adjusted OR 0.65 p < 0.01; boys: adjusted OR 0.72 p < 0.01). Being under/over-age at later grades (4-8) was not associated with subsequent repetition but being over-age was associated with dropout. Other risk factors identified that were associated with repetition included both family-level factors (living away from their mother, having young children in the household, lower paternal education) and school-level factors (higher student-teacher ratio, proportion of female teachers and schools without access to water). Reducing direct and indirect costs of schooling for households; and improving school quality and resources at early stages of school may enable timely progression at early stages for greater retention at later stages. PMID- 29391663 TI - Using the Early Childhood Environment Rating Scale-Revised in High Stakes Contexts: Does Evidence Warrant the Practice? AB - Increasingly, states establish different thresholds on the Early Childhood Environment Rating Scale-Revised (ECERS-R), and use these thresholds to inform high-stakes decisions. However, the validity of the ECERS-R for these purposes is not well established. The objective of this study is to identify thresholds on the ECERS-R that are associated with preschool-aged children's social and cognitive development. Applying non-parametric modeling to the nationally representative Early Childhood Longitudinal Study Birth Cohort (ECLS-B) dataset, we found that once classrooms achieved a score of 3.4 on the overall ECERS-R composite score, there was a leveling-off effect, such that no additional improvements to children's social, cognitive, or language outcomes were observed. Additional analyses found that ECERS-R subscales that focused on teaching and caregiving processes, as opposed to the physical environment, did not show leveling-off effects. The findings suggest that the usefulness of the ECERS-R for discerning associations with children's outcome may be limited to certain score ranges or subscales. PMID- 29391665 TI - Determination of Carbon Chain Lengths of Fatty Acid Mixtures by Time Domain NMR. AB - Average carbon chain length is a key parameter that defines the quality of liquid biofuels. In this paper, a method for the determination of carbon chain lengths of fatty acid mixtures is presented. The approach is based on proton relaxation rates measured by time domain nuclear magnetic resonance. The spin-spin relaxation rates R2 were used for the estimation of the carbon chain lengths. The method was examined for the set of samples with different mean lengths of the main linear carbon chain. Samples were prepared using four different fatty acids and mixtures of two, three or four of these fatty acids. The correlation coefficient between the known and measured values was equal to 0.994. Based on the relaxation theory, a linear-like dependence between the relaxation rate and carbon chain length was briefly shown, which endorses the experimental results. The developed methodology for determining carbon chain lengths offers robustness and rapidity, which are significant advantages when it comes to online use of the method in real industrial environments. PMID- 29391664 TI - Resonators for In Vivo Imaging: Practical Experience. AB - Resonators for preclinical electron paramagnetic resonance imaging have been designed primarily for rodents and rabbits and have internal diameters between 16 and 51 mm. Lumped circuit resonators include loop-gap, Alderman-Grant, and saddle coil topologies and surface coils. Bimodal resonators are useful for isolating the detected signal from incident power and reducing dead time in pulse experiments. Resonators for continuous wave, rapid scan, and pulse experiments are described. Experience at the University of Chicago and University of Denver in design of resonators for in vivo imaging is summarized. PMID- 29391666 TI - Towards Determination of Distances Between Nanoparticles and Grafted Paramagnetic Ions by NMR Relaxation. AB - We developed an approach for determining distances between carbon nanoparticles and grafted paramagnetic ions and molecules by means of nuclear spin-lattice relaxation data. The approach was applied to copper-, cobalt- and gadolinium grafted nanodiamonds, iron-grafted graphenes, manganese-grafted graphene oxide and activated carbon fibers that adsorb paramagnetic oxygen molecules. Our findings show that the aforementioned distances vary in the range of 2.7-5.4 A and that the fixation of paramagnetic ions to nanoparticles is most likely implemented by means of the surface functional groups. The nuclear magnetic resonance data data are compared with the results of electron paramagnetic resonance measurements and density functional theory calculations. PMID- 29391668 TI - Change of Guard. PMID- 29391667 TI - HaCaT Cells as a Reliable In Vitro Differentiation Model to Dissect the Inflammatory/Repair Response of Human Keratinocytes. AB - Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFalpha or IL-1beta. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti inflammatory interventions/therapies on skin diseases. PMID- 29391669 TI - The Partograph in Childbirth: An Absolute Essentiality or a Mere Exercise? AB - WHO has recommended use of the partograph, a low-tech paper form that has been hailed as an effective tool for the early detection of maternal and fetal complications during childbirth. Yet despite decades of training and investment, implementation rates and capacity to correctly use the partograph remain low in resource-limited settings. Nevertheless, competent use of the partograph, especially using newer technologies, can save maternal and fetal lives by ensuring that labor is closely monitored and that life-threatening complications such as obstructed labor are identified and treated. To address the challenges for using partograph among health workers, health-care systems must establish an environment that supports its correct use. Health-care staff should be updated by providing training and asking them about the difficulties faced at their health center. Then only the real potential of this wonderful tool will be maximally utilized. PMID- 29391670 TI - Amniotic Fluid Stem Cells: A New Era in Regenerative Medicine. AB - Regenerative medicine has become an emerging field which focuses on repair, replacement or regeneration of cells, tissues and the entire organs. The regeneration may occur in patient's own body by using their system as a bioreactor, e.g., cell therapy that involves transplantation of stem cells capable of proliferating, differentiating and replacing damaged host cells. As the field of regenerative medicine advances, and sources of stem cells has been intensified. Though embryonic and adult tissues can be used for isolation of pluripotent stem cells, the amniotic fluid (AF) has been proposed as an alternative source of stem cells for tissue regeneration. AF cells could be banked and used for either allogeneic or autologous transplantation. PMID- 29391671 TI - Decision Delivery Interval in Emergency and Urgent Caesarean Sections: Need to Reconsider the Recommendations? AB - Introduction: The timeline between a decision made and delivery of the baby is termed decision delivery interval (DDI). According to current recommendations, an emergency caesarean section must be performed within 30 min of the decision. The present study was conducted with an objective to assess DDI in a busy obstetric unit in India and its impact on obstetric outcome. Material and Method: A total of 480 women with indications of category I (emergency): Immediate threat to life of woman or foetus (n = 66), and category II (urgent): Maternal or foetal compromise but not immediately life-threatening (n = 414), were studied in the context of DDI and composite adverse perinatal outcomes including fresh stillbirth, 5-min Apgar score <7 and NICU admission. Result: Recommended DDI of <30 min could be achieved in 30% cases of emergency CS only. Sixty-three per cent with prolapsed cord could be delivered within 30 min. The composite neonatal outcomes were not significantly increased up to DDI of 60 min for category I (emergency) (except in prolapsed cord) and up to 90 min in category II (urgent) caesarean sections. Conclusion: Authors propose reconsideration of the present recommendations of DDI in categories I and II, while Crash CS (cord prolapse or catastrophic antepartum haemorrhage) should be a separate group with recommended DDI of 30 min. For the remaining cases in the present emergency CS group, the suggested DDI of 60 and, for urgent group, 90 min may be made following further studies to prevent this DDI yardstick from becoming a rod at our back. PMID- 29391672 TI - First-Trimester Inflammatory Markers for Risk Evaluation of Pregnancy Hypertension. AB - Introduction: Hypertension in pregnancy is one of the potential causes of maternal and fetal morbidity and mortality. It complicates 7-10% of pregnancies. As of today, prediction of pregnancy hypertension is not possible. Aim and Objectives: Evaluation of pregnancy associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin, tumor necrosis factor-alpha (TNF-alpha) and interferon gamma (INF-gamma) in establishing a biomarker or combination of biomarkers for the early identification of pregnancy hypertension. Methodology: This prospective study was carried out in two phases. Phase I was a cohort study in which 2000 pregnant women were enrolled in their first trimester (11 + 0 to 13 + 6 weeks of gestation) and followed till delivery. Women who developed hypertension were compared with normotensive cohort (women who remained normotensive till term). Phase II was a case-control study. The women who were diagnosed with hypertension in phase I were cases and their controls were matched for gestational age and sample storage time from normotensive cohort population. Two additional proinflammatory markers TNF-alpha and INF-gamma were evaluated in this case-control population. Results: Out of 2000 women, 199 women developed hypertension and 1454 women remained normotensive throughout their pregnancy. Among 199 hypertensive women, 151 (9.13%) cases had gestational hypertension, 45 (2.72%) had preeclampsia (PE) and 3 (0.18%) had eclampsia (E). First trimester mean arterial pressure (MAP) (p < 0.001) and body mass index (BMI) (p < 0.001) were found significantly higher in hypertensive women when compared with normotensive women. Maternal serum levels of PAPP-A (p < 0.001) were significantly low in hypertensive women as compared to normotensive women, while free beta-hCG (p = 0.59) was high, but the difference was not statistically significant. TNF-alpha (p < 0.001) and INF-gamma (p = 0.014) both were high in hypertensive women. When all biomarkers were combined we found the positive predictive value (PPV) of 51.6% an negative predictive value (NPV) of 71.4%. Conclusion: Increased levels of proinflammatory cytokines suggest the role of underlying inflammation in pathogenesis of pregnancy hypertension, and low PAPP-A may be attributed to impaired implantation. Combining biomarkers may improve the prediction of pregnancy hypertension in the early stages of gestation. NPV of 71.4% depicts that if woman has all biomarkers in normal ranges during first trimester, she will have 71.4% chances of remaining normotensive during pregnancy. PMID- 29391673 TI - Salivary and Serum Antioxidants in Women with Preeclampsia with or Without Periodontal Disease. AB - Background and Objectives: Preeclampsia is a challenging disease of human pregnancy that affects the mother and her foetus. It is a common obstetric syndrome of undefined aetiology affecting 7-10% of pregnant women. This study aimed to investigate the total antioxidant capacity (TAC), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, malondialdehyde levels, uric acid, vitamin C, and vitamin E levels in serum and saliva of preeclamptic and normotensive pregnant women with and without periodontitis. Methods: Sixty pregnant women, divided into four groups, preeclamptic women with and without periodontitis, and normotensive pregnant women with and without periodontitis, were recruited between 26 and 36 weeks of gestation from the Outpatient Department of Obstetrics and Gynaecology, KS Hedge Hospital, Mangalore. Pocket depth, clinical attachment loss, and gingival index were measured in all subjects. Saliva and serum levels of TAC, SOD, and GPx activities, malondialdehyde levels, vitamin C, vitamin E, uric acid were determined using spectrophotometer. Results: Comparison of sociodemographic variables among the study groups showed no significant differences. Salivary malondialdehyde levels were highest (p = 0.025), levels of antioxidants vitamin C (p = 0.027) and uric acid (p = 0.013) being significantly lower in preeclamptic women with periodontitis. This group also had significantly lower serum levels of vitamin C (p = 0.041) and SOD (p = 0.004). Conclusions: The results of our study show that periodontal disease may be potential risk factor for severity, progression, and even initiation of preeclampsia because of reduced antioxidant capacity or increased oxidative stress. PMID- 29391674 TI - Comparison of Mifepristone Followed by Misoprostol with Misoprostol Alone for Treatment of Early Pregnancy Failure: A Randomized Double-Blind Placebo Controlled Trial. AB - Objective: To compare the efficacy and safety of mifepristone followed by misoprostol with misoprostol alone in the management of early pregnancy failure (EPF). Study Design: A randomized double-blind placebo-controlled clinical trial. Methods: Ninety-two women with EPF <=12 weeks were recruited and randomly allocated to receive either mifepristone 200 mg (n = 46) or placebo (n = 46). Forty-eight hours later, patients in both the groups were given 800 ug misoprostol per-vaginum. If no expulsion occurred within 4 h, repeat doses of 400 ug misoprostol were given orally at 3-hourly interval to a maximum of 2 doses in women <=9 weeks by scan and 4 doses in women >9 weeks by scan. Results: Pre treatment of misoprostol with mifepristone significantly increased the complete abortion rate (86.7 vs. 57.8%, p = 0.009) and, hence, reduced the need for surgical evacuation (13.3 vs. 42.2%, p = 0.002), induction to expulsion interval (4.74 +/- 2.24 vs. 8.03 +/- 2.77 h, p = 0.000), mean number of additional doses of misoprostol required (0.68 vs. 1.91, p = 0.000), and side effects. Conclusion: Use of mifepristone prior to misoprostol in EPF significantly improves the efficacy and reduces the side effects of misoprostol alone. PMID- 29391675 TI - Use of Hysteroscopy in Abnormal Uterine Bleeding: An Edge Over Histopathological Examination. AB - Purpose of the Study: To assess the efficacy of hysteroscopy in diagnosis of AUB. Method: A total of 56 women in reproductive and peri-menopausal age group (20-50 years) with complaints of abnormal uterine bleeding were enrolled in the study. All the patients underwent hysteroscopic examination followed by biopsy/histopathological evaluation. Hysteroscopic findings were compared against histopathological findings. Sensitivity, specificity, PPV, NPV and accuracy of hysteroscopy were calculated. Results: Mean age of patients was 36.4 +/- 7.6. Majority (60.7%) presented within 6 months of complaints. Clinically, 66.1% were diagnosed as menorrhagia, 30.4% polymenorrhoea and 3.6% intermenstrual bleeding. Hysteroscopically 53.6% presented with abnormal pathology, it diagnosed polyps in 16.1%, calcification in 12.5%, submucous fibroma in 10.7%, necrotic mass in 7.1%, adhesion and forgotten IUCD in 5.4% cases each. However, on histopathology, 33 (58.9%) cases had normal/proliferative/atrophic endometrium, 12 (21.4%) had hyperplasia, 7 (12.5%) had calcified endometrium, and 12 (21.4%) had polyp. No significant difference between two modalities was observed with respect to number of normal/proliferative/atrophic endometrium (p = 0.185). Histopathology diagnosed hyperplasia in significantly higher proportion of patients as compared to hysteroscopy (p = 0.042). Hysteroscopy diagnosed significantly higher proportion of patients with submucous myoma (p = 0.012) and necrotic mass (p = 0.042). Statistically, no significant difference between two modalities was observed with respect to other pathologies (p > 0.05). Overall agreement between two modalities was 62.5%. For pathological abnormalities in general, hysteroscopy had sensitivity, specificity, PPV, NPV and accuracy values of 78.3, 63.6, 60, 80.8 and 69.6%, respectively. Conclusion: Hysteroscopy provided additional information for some of the pathologies, otherwise remaining undiagnosed by HPE. PMID- 29391676 TI - Comparison of Cervical Length Measured by Transvaginal Ultrasonography and Bishop Score in Predicting Response to Labor Induction. AB - Background: This study aims to compare the value of the Bishop score and cervical length measurement by transvaginal ultrasonography in predicting active labor within 6 h, induction-to-delivery interval, and the duration of active labor and to estimate the most useful cutoff points for the two methods. Methods: This is a prospective comparative study of Bishop score and cervical length measured by transvaginal sonography on 62 nulliparous subjects who underwent induction of labor. Results: The Bishop score of the subjects ranged from two to seven (2-7). The mean Bishop in this study population was 4.37 + 1.23. The mean cervical length in this study was 25.59 + 6.07. Bishop score was highly significant (P value < 0.0001) in predicting active phase of labor as compared to cervical length (P = 0.004). The best cutoff value for Bishop score to predict induction of labor within 6 h was more than 4 with sensitivity of 69% and specificity of 79%. Similarly, best cutoff value for cervical length to predict induction of labor within 6 h was less than or equal to 25 mm with sensitivity of 51% and specificity of 70%. Bishop score was more significant (P = 0.001) in predicting induction-to-delivery interval within 12 h as compared to cervical length (P = 0.01). Conclusion: The Bishop score was superior in predicting the response to induction as compared to the cervical length measured by transvaginal ultrasonography. PMID- 29391677 TI - Endocrine Abnormalities in Adolescents with Menstrual Disorders. AB - Purpose: To look for endocrine abnormalities like thyroid disorders, hyperprolactinemia, hyperandrogenism and PCOS among adolescents with menstrual disorders and to compare the above endocrine status with those without menstrual disorders. Methods: This was a case-control study carried out in adolescent girls aged 10-19 years in gynecology outpatient department of a tertiary care hospital. Sample of venous blood (5 ml) was taken for hormonal studies as clinically indicated-thyroid function test, serum prolactin, total testosterone, which were analyzed by chemiluminescence system. Results: Oligomenorrhea was the most common menstrual abnormality in our study, the prevalence being 61.0% in cases followed by primary amenorrhea (16.4%). Thyroid dysfunction was found in 13.6% girls with menstrual disorders compared to 3.5% in those without menstrual disorders, and this was statistically significant (p = 0.006). Biochemical hyperandrogenism was seen in 9.04% cases compared to 0.7% controls (p = 0.001). The overall prevalence of hyperprolactinemia was 0.94%, and there was no statistically significant difference in girls with and without menstrual disorders. The prevalence of PCOS was 12.4% in the study population and 22.6% cases. Oligomenorrhea and PCOS were the most prevalent phenotypes in 52.5% of PCOS girls. No endocrine abnormality was detected in cases of polymenorrhea, hypomenorrhea and intermenstrual bleeding. Conclusions: Although immaturity of hypothalamic pituitary ovarian axis is considered to be the most common cause of menstrual irregularities in adolescent girls, endocrine abnormalities, namely thyroid dysfunction and hyperandrogenism, may be responsible in some cases, thus warranting further evaluation. PMID- 29391678 TI - Comparison of Effectiveness of Different Protocols Used for Controlled Ovarian Hyperstimulation in Intrauterine Insemination Cycle. AB - Introduction: Intrauterine insemination (IUI) is one of the most commonly performed procedure of assisted reproductive technology, for the treatment of infertility. Controlled ovarian hyperstimulation is an important first step while performing IUI. This study aims at establishing a relationship between stimulation protocol and pregnancy outcome following IUI. Methods: This is a retrospective study of 1001 cycles of IUI in which the patients were divided into two groups: Group A Clomiphene citrate (CC only) and Group B Clomiphene citrate and Gonadotropin or Gonadotropin alone(CC+GN OR GN alone). The primary outcome assessed was clinical pregnancy rates (CPRs), and the secondary outcomes were miscarriage rate (MR), multiple pregnancy rates (MPRs), follicle numbers and endometrial thickness (ET). Results: Significantly, higher CPR was observed in Group B in comparison with Group A (14.55 vs. 7.82%; p = 0.05). MR was much higher in Group A in comparison with Group B, (14.29 vs. 5.43%; p = 0.94), but it was non-significant. The follicle number and the ET of the Group A versus Group B are (1.54 +/- 0.69 vs. 1.90 +/- 1.04; p = 0.0003) and (8.56 +/- 1.33 vs. 8.39 +/- 1.29; p = 0.1784), respectively; and for subgroups, Group B1 and Group B2 are 1.92 +/- 0.99 versus 1.65 +/- 0.92; p = 0.0008 and 8.32 +/- 1.27 vs. 8.69 +/- 1.24; p = 0.0004, respectively. Conclusion: GN, either alone or the combination with CC, gives a higher CPR and a lower abortion rate following IUI, thus increasing the multiple pregnancy rate. PMID- 29391679 TI - Rare Presentation of Catastrophic Antiphospholipid Syndrome with Myocarditis in Post-partum Period: Case Report and Review of Literature. PMID- 29391680 TI - Effect of feed supplement and additives on stress mitigation in Karan Fries heifers. AB - Aim: The objective of this study was to evaluate the effects of protected fat plus yeast, niacin, zinc, and chromium dietary supplementation on the reduction of heat stress in Karan Fries (KF) heifers during hot humid months. Materials and Methods: The basal ration for both the control and treatment groups was the same, containing maize as green fodder and concentrate mixture. However, the treatment group was supplemented with protected fat (2.5% of dry matter intake [DMI]), yeast (10 g/animal/day), niacin (6 g/animal/day), zinc (40 mg/kg DMI), and chromium (1.5 mg/kg DMI). Result: The overall mean value of afternoon rectal temperature for control and treatment group was 103.17+/-0.09 and 102.72+/-0.10 degrees F, respectively, and was significantly (p<0.01) lower in the treatment group. The overall mean value of afternoon respiration rate for control and treatment group was 76.35+/-0.56 and 73.13+/-0.58 breaths/min, respectively, and was also significantly (p<0.01) lower in the treatment group. The overall mean value of afternoon pulse rate for control and treatment group was 97.09+/-0.63 and 94.67+/-0.67 beats/minute, respectively, and was also significantly (p<0.01) lower in the treatment group. Finally, the mean cortisol concentration for control and treatment group was 3.94+/-0.05 ng/ml and 3.70+/-0.06 ng/ml, respectively, and was significantly (p<0.01) lower in the treatment group. Conclusion: The present study shows that supplementation with the above feed additives could serve as a heat stress abatement strategy in growing KF heifers during extreme conditions in summer months. PMID- 29391681 TI - Ocular squamous cell carcinoma in Holstein cows from the South of Brazil. AB - Aim: The aim of this study was to investigate 10 cases of bovine ocular squamous cell carcinoma (OSCC) diagnosed in Holstein or Holstein-crosses cows. Materials and Methods: The investigation was performed exclusively in OSCC cases diagnosed in the State of Parana and Santa Catarina. A combination of two previously existing histopathological classifications systems was used. The tissue samples were tested for immunoexpression of p53 and p16 and polymerase chain reaction (PCR) for bovine herpesvirus and papillomavirus. Results: A positive correlation between number of mitotic figures and tissue invasion was found. Anaplasia parameters did not correlate well with tumor invasion of deeper tissues and mitotic counts. Six of 10 OSCC cases were in animals with heavily pigmented eyes. Immunoexpression of p53 and p16 was observed in 3 cases each. Bovine herpesvirus and papillomavirus were not detected by PCR. Conclusions: Our results indicate that OSCC occurrence is most likely multifactorial with genetic, phenotypic, and environmental influences contributing to the pathogenesis of the disease. PMID- 29391682 TI - Seroprevalence of viral and bacterial diseases among the bovines in Himachal Pradesh, India. AB - Aim: The study was designed to measure the seroprevalence of viral and bacterial diseases: Infectious bovine rhinotracheitis, bovine viral diarrhea, bovine leukemia, bovine parainfluenza, bovine respiratory syncytial disease, brucellosis, and paratuberculosis among bovine of Himachal Pradesh during the year 2013-2015. Materials and Methods: The serum samples were collected from seven districts of state, namely, Bilaspur, Kangra, Kinnaur, Lahul and Spiti, Mandi, Sirmour, and Solan. The samples were screened using indirect ELISA kits to measure the seroprevalence of viral and bacterial diseases. Results: The overall seroprevalence of infectious bovine rhinotracheitis was 24.24%, bovine viral diarrhea 1.52%, bovine leukemia 9.09%, bovine parainfluenza 57.58%, bovine respiratory syncytial disease 50%, brucellosis 19.69%, and paratuberculosis 9.09% in Himachal Pradesh. The seroprevalence of bovine rhinotracheitis, bovine leukemia, bovine parainfluenza, bovine respiratory syncytial disease, and paratuberculosis in the state varied significantly (p<0.01) while was insignificant for bovine viral diarrhea and brucellosis (p>0.01). Multiple seropositivity has been observed in this study. Bovine parainfluenza virus 3 was observed commonly in mixed infection with almost all viruses and bacteria under study. Conclusion: The viral and bacterial diseases are prevalent in the seven districts of Himachal Pradesh investigated in the study. Therefore, appropriate management practices and routine vaccination programs should be adopted to reduce the prevalence of these diseases. PMID- 29391684 TI - Use of black soldier fly larvae (Hermetia illucens) to substitute soybean meal in ruminant diet: An in vitro rumen fermentation study. AB - Aim: This experiment aimed to evaluate substitution of soybean meal (SBM) by black soldier fly (BSF) larvae meal in a napier grass diet as performed by an in vitro rumen fermentation system. Materials and Methods: Samples of napier grass, SBM, and BSF larvae age 1 week (BSF1) and 2 weeks (BSF2) were arranged according to the following dietary treatments (dry matter [DM] basis): T1, 100% napier grass; T2, 60% napier grass + 40% SBM; T3, 60% napier grass + 40% BSF1; T4, 60% napier grass + 40% BSF2; T5, 60% napier grass + 20% SBM + 20% BSF1; and T6, 60% napier grass + 20% SBM + 20% BSF2. The samples were determined for their chemical composition and were incubated in vitro using buffered rumen fluid for 48 h at 39 degrees C. In vitro incubation was carried out in three runs and represented by two incubation bottles per run. Results: Supplementation of BSF, both BSF1 and BSF2, increased ether extract, neutral- and acid-detergent insoluble crude protein contents of T3-T6 diets. The T3 or T4 diet resulted in lower ruminal ammonia concentration, in vitro DM digestibility, and in vitro organic matter (OM) digestibility as compared to those in T2 (p<0.05). Diet supplemented with BSF produced lower methane emission in comparison to that of supplemented with SBM (p<0.05). Diet containing BSF2 produced lower methane and methane per digestible OM than that containing BSF1 (p<0.05). Conclusion: Substitution of SBM by BSF in ruminant diet results in a lower nutritional value in vitro but with an advantage of lowering ruminal methane emission. PMID- 29391683 TI - Cryptic etiopathological conditions of equine nervous system with special emphasis on viral diseases. AB - The importance of horse (Equus caballus) to equine practitioners and researchers cannot be ignored. An unevenly distributed population of equids harbors numerous diseases, which can affect horses of any age and breed. Among these, the affections of nervous system are potent reason for death and euthanasia in equids. Many episodes associated with the emergence of equine encephalitic conditions have also pose a threat to human population as well, which signifies their pathogenic zoonotic potential. Intensification of most of the arboviruses is associated with sophisticated interaction between vectors and hosts, which supports their transmission. The alphaviruses, bunyaviruses, and flaviviruses are the major implicated groups of viruses involved with equines/humans epizootic/epidemic. In recent years, many outbreaks of deadly zoonotic diseases such as Nipah virus, Hendra virus, and Japanese encephalitis in many parts of the globe addresses their alarming significance. The equine encephalitic viruses differ in their global distribution, transmission and main vector species involved, as discussed in this article. The current review summarizes the status, pathogenesis, pathology, and impact of equine neuro-invasive conditions of viral origin. A greater understanding of these aspects might be able to provide development of advances in neuro-protective strategies in equine population. PMID- 29391685 TI - Prophylactic and immune modulatory influences of Nigella sativa Linn. in broilers exposed to biological challenge. AB - Background and Aim: Prophylaxis and disease prevention is an essential strategy among biorisk management in poultry farms that stimulate and maintain the birds' immunity. The aim of this study was to investigate the prophylactic, and immune stimulant influence of Nigella sativa Linn. in broilers under biological stress. Materials and Methods: A total of 250 1-day-old (ross) chicks were divided into 5 groups; four of which were supplemented with 1.4%, 2.8%, 4.2%, and 5.6% N. sativa Linn., respectively. The four supplemented groups were challenged with Escherichia coli O157:H7 1.5*108 at a 14th day old. A total of 1050 samples (150 serum, 150 swab, and 750 organ samples) were collected and examined. Results: A highly significant increase (p<0.01) in 5.6% N. sativa Linn. supplemented group in performance traits (body weight, weight gain, and performance index), biochemical parameters (proteinogram, liver enzymes, and creatinine), immunoglobulins concentration, and immune organs' weight. Meanwile, liver showed improvement of histoarchitecture without fibrosis. Heart showed a mild pericarditis with a mild degree of hydropic degeneration. Bursa, thymus, and spleen showed lymphoid hyperplasia. Conclusion: A concentration of 5.6% N. sativa Linn. in broiler's feed can improve the immune response and subsequent resistance of broilers against diseases. PMID- 29391686 TI - Effects of incorporating agro-industrial by-products into diet of New Zealand rabbits: Case of rebus of date and apricot kernel meal. AB - Aim: The aim of this study was to determine the effects of incorporating the by products complex of date and apricot on the fattening performance of the New Zealand breed of rabbits, to reduce the economic costs of the food formula. Materials and Methods: A total of 288 young New Zealand rabbits aged 35 days were divided into four equal groups each containing 72 animals and into sub-groups of 6 rabbits per cage, depending on the rate of substitution of corn by date rebus and of soybean meal by apricot kernel meal (0%, 10%, 20%, and 30%). Results: The change in weight from day 35 to 77 and the average daily gain are not significantly different, regardless of the diet. The pH and water content are proportional to the substitution rates (6.4-6.6% and 66.5-68.8%). Meat protein levels increased significantly, in particular for the 10% and 30% groups (+8.1% and 6%) while the fat and mineral content levels decreased significantly, in particular for the 30% group displaying -16% and -17%, respectively. Incorporation of dates and apricot kernel meal into the ration of rabbits reduces the cost of the kilogram of food produced of -9%, with an opportunity cost of 165 Algerian dinars (DZD). Conclusion: The date rebus/apricot kernel meal complex can be used as an alternative to the corn/soybean meal complex at substitution rates of up to 30% without adverse effects on growth rates, feed contribution, or slaughter yield. It improves the chemical composition of the meat and reduces the cost price of the quintal of feed produced. PMID- 29391687 TI - A comprehensive study on seroprevalence of bluetongue virus in Haryana state of India. AB - Aim: The aim of present study was to determine seroprevalence of bluetongue virus (BTV) in Haryana state of India. Materials and Methods: A total of 803 serum samples, 408 of cattle and 395 of buffalo origin, respectively, were collected from different villages of Haryana. Sampling was done randomly to obtain unbiased results. The samples were evaluated by a competitive enzyme-linked immunosorbent assay for the presence of BTV antibodies. Results: Overall seroprevalence of BTV antibody in cattle and buffaloes for all 21 districts of Haryana state was found to be 75.49% and 92.91%, respectively. The prevalence of BTV in different agroclimatic zones ranged between 72-77% and 90-94% for cattle and buffalo, respectively. In buffaloes, the BTV seroprevalence was comparatively higher than in cattle. Conclusion: The study showed that BTV is circulating in cattle and buffalo populations in the Northern part of India. PMID- 29391689 TI - Prevalence of Theileria annulata in dairy cattle in Nyala, South Darfur State, Sudan. AB - Aim: This study was conducted in dairy cattle in Nyala, South Darfur State, during the period from June to September 2015, to study the prevalence of bovine tropical theileriosis. Materials and Methods: Apparently, healthy cattle of different age groups, different breeds, and from both sexes were randomly selected from seven locations. Three age groups of cattle were selected, group one <1 year old, group two 1-3 years old, and group three older than 3 years. These cattle were indigenous and cross (Friesian X zebu). A total of 150 blood samples were collected for blood smears, blood in EDTA tubes, and serum samples as well as ticks infesting cattle. Three diagnostic techniques were used such as blood smear, indirect fluorescent antibody test (IFAT), and polymerase chain reaction (PCR). Results: Of 150 samples, 11 (7.3%, 95% confidence interval [CI]: 9.1-5.5) were positive for Theileria spp. piroplasms in the blood smears, 70 (46.7%, 95% CI: 35.7-57.7) were positive for Theileriaannulata antibodies in the IFAT, and of 100 samples, 39 (39%, 95% CI: 46.6-31.4) were positive for T. annulata using PCR. The prevalence of T. annulata was higher in indigenous breed than cross cattle by the three diagnostic techniques. The highest prevalence of T. annulata was recorded among cattle older than 3 years old. There were three genera and ten species of ticks found feeding on cattle. These were Rhipicephalus evertsi evertsi, Rhipicephalus decoloratus, Rhipicephalus annulatus, Hyalomma dromedrii, Hyalomma impeltatum, Hyalomma rufipes, Hyalomma anatolicum, Hyalomma truncatum, Amblyomma variegatum, and Amblyomma lepidum. Conclusion: The study concluded that tropical theileriosis is prevalent among dairy cattle in Nyala. H. anatolicum was found in very low numbers, suggesting other ticks may play a role in the transmission of the disease. Molecular characterization of T. annulata is recommended for accurate mapping of the disease and evaluates the magnitude problem of tropical theileriosis in South Darfur region. PMID- 29391688 TI - Prevalence of carrier state theileriosis in lactating cows. AB - Aim: The objective of this study was to examine the carrier status of theileriosis among apparently healthy cross-bred jersey cattle population of Odisha using conventional blood smear examination and polymerase chain reaction (PCR). Materials and Methods: A total of 34 apparently healthy cross-bred Jersey lactating cows were considered in this study. Blood samples were subjected to microscopic examination after staining with Giemsa stain and PCR based molecular diagnosis using two sets of primer, i.e., N516/N517 and TorF1/TorF2 specific for Theileria annulata and Theileriaorientalis, respectively. Results: Examination of blood samples revealed presence of theileria parasites to a magnitude of 20.59% for T. annulata, 8.82% for T. orientalis, and 2.94% for both. Conclusion: Molecular diagnosis was found to be much more sensitive than conventional method for diagnosis of theileriosis. T. annulata was found to be the predominant species affecting the exotic cattle. T. orientalis was detected in apparently healthy cows. PMID- 29391690 TI - The role of staphylococci in subclinical mastitis of cows and lytic phage isolation against to Staphylococcus aureus. AB - Aim: This study was conducted to determine the role of Staphylococcus in the formation of subclinical mastitis in cows and to isolate the phage against isolated Staphylococcus aureus strains. Materials and Methods: In this study, 400 milk cows were screened by California Mastitis Test (CMT) for subclinical mastitis and 235 udders of 96 cows, which were determined to be positive, were evaluated for Staphylococcus. Milk samples were evaluated using conventional and molecular methods. In addition, phage isolation studies were performed against S. aureus strains causing mastitis. Results: At the result of cultural examination, of 235 milk samples that were found as positive for mastitis by CMT, a total of 117 (49.7%) Staphylococcus spp. were isolated as a distribution of 74 (63.24%) coagulase-positive staphylococci and 43 (36.75%) coagulase-negative staphylococci. Of these isolates, 76 (64.95%) were characterized as S. aureus both conventional and molecular techniques. Lytic bacteriophages against two S. aureus strains which were isolated from mastitic milk samples were obtained from wastewater samples. Conclusion: The results of this study show that a significant portion of subclinical mastitis was formed by staphylococci. In addition, phage isolation against S. aureus strains isolated can be considered as one of the steps to be applied in the prophylaxis and treatment of such infections. PMID- 29391691 TI - Seasonal influence on sperm parameters, scrotal measurements, and serum testosterone in Ouled Djellal breed rams in Algeria. AB - Aim: This study was conducted to determine the effect of seasonal variations on testosterone serum concentration, body weight, scrotal circumference, and some sperm parameters in rams living in a semi-arid region of eastern part of Algeria. Materials and Methods: Blood samples were taken monthly from eight Ouled Djellal rams, aged between 3 and 4 years, in the Technical Institute of Breeding "ITELV" located at Ain M'lila City. Sperm were collected by an electro-ejaculator once a month for 1 year (spring, summer, autumn, and winter: 3 times/season). Results: Mean values of volume, mass motility, live sperm, and scrotal circumference were higher during spring (p<0.05) with 1.23+/-0.26 mL, 3.39+/-1.07, 79.16+/-15.82%, and 36.29+/-1.91 cm, respectively; whereas, the sperm concentration was higher during autumn with 1.19+/-0.56*109 spz/ml compared to 0.46+/-0.13*109 spz/mL to spring. The season influenced significantly the percentage of abnormal sperm (p<0.05), especially during winter (6.47+/-2.12%), but had no influence on the weight of rams. Seasonal hormonal activity was high with 4.89+/-2.06 ng/mL and 3.09+/-1.35 ng/mL of testosterone in mating seasons (spring and autumn, respectively), knowing that the sexual season is not marked too much in these latitude. Conclusion: We can conclude that testosterone concentration is strongly correlated with the scrotal circumference and that the season has a significant influence on spermatic parameters, and that despite the large variations in sperm production, the rams can be used throughout the year. PMID- 29391692 TI - Partial purification and characterization of glutathione S-transferase from the somatic tissue of Gastrothylax crumenifer (Trematoda: Digenea). AB - Aim: Aim of the present study was to carry out the partial purification and biochemical characterization of glutathione S-transferase (GST) from the somatic tissue of ruminal amphistome parasite, Gastrothylax crumenifer (Gc) infecting Indian water buffalo (Bubalus bubalis). Materials and Methods: The crude somatic homogenate of Gc was subjected to progressive ammonium sulfate precipitation followed by size exclusion chromatography in a Sephacryl S 100-HR column. The partially purified GST was assayed spectrophotometrically, and the corresponding enzyme activity was also recorded in polyacrylamide gel. GST isolated from the amphistome parasite was also exposed to variable changes in temperature and the pH gradient of the assay mixture. Results: The precipitated amphistome GST molecules showed maximum activity in the sixth elution fraction. The GST subunit appeared as a single band in the reducing polyacrylamide gel electrophoresis with an apparent molecular weight of 26 kDa. The GST proteins were found to be fairly stable up to 37 degrees C, beyond this the activity got heavily impaired. Further, the GST obtained showed a pH optima of 7.5. Conclusion: Present findings showed that GST from Gc could be conveniently purified using gel filtration chromatography. The purified enzyme showed maximum stability and activity at 4 degrees C. PMID- 29391693 TI - Isolation, molecular characterization and prevalence of Clostridium perfringens in sheep and goats of Kashmir Himalayas, India. AB - Aim: The study was conducted to report the occurrence of the Clostridium perfringens in sheep and goats of the Kashmir valley for the 1st time and to characterize them molecularly with respect to toxin genes to determine the prevalence of the various toxinotypes. Materials and Methods: A total of 177 samples (152 from sheep and 25 from goats) collected from healthy, diarrheic animals, and morbid material of animals suspected to have died of enterotoxaemia were screened for C. perfringens toxinotypes. The presumptive positive isolates were confirmed using 16S rRNA gene-based polymerase chain reaction (PCR). All the confirmed isolates were screened for six toxin genes, namely; cpa, cpb, etx, cpi, cpb2, and cpe using a multiplex PCR. Results: The PCR amplification of 16S rRNA gene revealed that out of 177 samples collected, 125 (70.62%) were found positive for C. perfringens, of which 110 (72.36%) were from sheep and 15 (60%) were from goats. The highest prevalence of C. perfringens toxinotype D was observed in lambs (56.16%) and kids (46.16%) followed by 3.84% in adult sheep while it was absent in samples obtained from adult goats. The multiplex PCR revealed that 67 (60.90%) isolates from sheep and 8 (53.33%) isolates from goats belonged to toxinotype A, while 43 (39.09%) isolates from sheep and 7 (46.66%) isolates from goats were detected as toxinotype D. None of the isolates was found to be toxinotype B, C, or E. All the C. perfringens toxinotype A isolates from sheep were negative for both cpb2 and cpe genes, however, 27.90% toxinotype D isolates from sheep carried cpb2 gene, and 6.97% possessed cpe gene. In contrast, 12.50% C. perfringens toxinotype A isolates from goats harbored cpb2 and cpe genes while 14.28% isolates belonging to toxinotype D carried cpb2 and cpe genes, respectively. Conclusion: The high prevalence of C. perfringens was observed, even in day-old lambs. The toxinotypes A and D are prevalent in both sheep and goats. The severity of disease and mortality may be associated with the presence of minor toxins in both the detected toxinotypes. PMID- 29391694 TI - Effect of probiotic supplementation on organic feed to alternative antibiotic growth promoter on production performance and economics analysis of quail. AB - Aim: The purpose of this study was to know the production performance and economic analysis in quail which use probiotic supplementation to alternate antibiotic growth promoter (AGP) to feed consumption, water consumption, egg production, egg mass, feed conversion, and feed efficiency. Materials and Methods: About 240 quails (Coturnix coturnix japonica) at 14 weeks of age were completely randomized into four treatments, each treatment consisted of six replications and each replication consisted by 10 heads. The treatment was T0 (organic feed without AGP and without probiotic), T1 (organic feed + 0.001% AGP), T2 (organic feed + 0.005% probiotic in feed), and T3 (organic feed + 0.005% probiotic in drinking water). The probiotic consist of 1.2*105 CFU/g of Lactobacillus casei and Lactobacillus rhamnosus. Results: The results showed that the probiotic supplementation both in feed and water give a significant impact to feed consumption, water intake, feed conversion, feed efficiency, and quail day production, but no statistical difference of egg mass. The T3 also show the most profitable business analysis, which has the best result in income, profit, break even point, return cost ratio, benefit-cost ratio, and return on investment. Conclusion: It can be concluded that giving 0.005% probiotic in drinking water to get the best egg production and profit. PMID- 29391695 TI - Isolation and identification of a cellulolytic Enterobacter from rumen of Aceh cattle. AB - Aims: The aim of this study was to isolate and identify a cellulolytic bacterium from the rumen fluid of Aceh's cattle. Biodegradation by cellulolytic rumen bacteria can be used as a source of cellulolytic bacteria that act to degrade feed fibrous material so as to improve the quality of nutrients and digestibility of feed ingredients at a cheaper price than the use of commercial cellulase enzymes. Materials and Methods: Samples were collected from rumen fluid of Aceh's cattle in Abattoirs (RPH) of Banda Aceh city, Indonesia, isolation, and screening of cellulolytic bacteria were done in Microbiology Laboratory, Faculty of Veterinary Medicine, Syiah Kuala University, Banda Aceh, Indonesia. Results: The S1 isolates showed +/-2.5 cm of clear zone diameter. Microscopically, this strain was found to be a Gram-negative, Bacillus. Homology and phylogenetic tree analysis of 16S rRNA showed that S1 isolate has 91% of sequence similarity with that of Enterobacter cloacae. 91% sequence homology shown in this study proved that the S1 isolate is probably either a new species or another genus of Enterobacteriaceae. Conclusion: Current study suggests that cellulose hydrolytic bacteria isolated from rumen fluid of Aceh cattle on Bushnell Haas medium carboxymethylcellulose agar, and some potent cellulose degrading bacteria have been identified. PMID- 29391696 TI - Studies on reconstruction of large skin defects following mammary tumor excision in dogs. AB - Aim: The main objective of the study was to describe the use of skin fold advancement flaps (SFAFs) and other reconstructive techniques for closure of large skin defects following mammary tumor excision in dogs. Materials and Methods: Twelve dogs underwent reconstruction of large ventral skin defects following mammary tumor excision with wide margins. Skin fold flaps (flank fold flap and elbow fold flap) were elevated from the flank and elbow region, respectively, and transposed and sutured onto the large ventral skin defect following mastectomy in all the dogs. In addition to the skin fold flaps, other reconstructive techniques such as undermining, walking sutures, and tension relieving suture techniques were followed during surgery in the closure of large skin defects without skin tension and compromising limb mobility. The skin flap viability was assessed subjectively by gross observation of the flap such as color, temperature, capillary perfusion, and cosmetic appearance, and scoring (1 4) was done. Tissue samples were collected from a surgical site on days 3, 6, and 12 post-operatively for histopathological evaluation and healing status of the skin flap. Results: All the surgical wounds healed primarily, without any major complications and the skin flap remained healthy throughout the healing process post-operatively. Distal flap necrosis was noticed in one case and necrosis of skin flap between two suture lines was noticed in another case in which the necrotized distal portion healed by secondary intention after 7 days. The mean survival of subdermal plexus flap in the above cases was 98% which was a subjective evaluation based on surface area of the skin defect measured by Image' J software and the flap dimensions. The average healing of skin flap in days was 14.91+/-0.86. Conclusion: The SFAFs along with other reconstructive techniques help in the reconstruction of large ventral skin defects following mastectomy in dogs without much compromising limb mobility. PMID- 29391697 TI - Insights into bovine endometritis with special reference to phytotherapy. AB - Postpartum reproductive disorders cause heavy economic losses in dairy sector. Uterine infections include endometritis, metritis, mucometra, and pyometra. Postpartum endometritis in dairy cows has been defined as inflammation of endometrium occurring 21 days or more after parturition without systemic signs of illness. The treatment of endometritis with antimicrobials has met with varying degrees of success, inconsistent recovery rate, high cost of treatment, milk disposal, emergence of microbial resistance, and reduced phagocytic activity of polymorphonuclear leukocytes In our country, around 20,000 medicinal plant species have been recorded, but more than 500 traditional communities use about 800 plant species for curing different diseases. Many herbs such as garlic, neem, ashwagandha, and turmeric have been tried for the treatment of endometritis in cows with a good success. PMID- 29391698 TI - Isolation, culture, characterization, and osteogenic differentiation of canine endometrial mesenchymal stem cell. AB - Aim: In this study, the canine endometrium tissue is characterized for its stem cell properties such as adherence to tissue culture plate (plasticity), short population doubling time, serial clonal passaging, long-term culturing properties, stem cell marker expression, and multilineage differentiation potential. Materials and Methods: The present work describes a novel isolation protocol for obtaining mesenchymal stem cells from the uterine endometrium and is compared with cells derived from umbilical cord matrix as a positive control. These cells are clonogenic, can undergo several population doublings in vitro, and can be differentiated to the osteocytes in mature mesenchymal tissues when grown in osteogenic differentiation media as detected by Alizarin Red-S staining. Results: It is reported for the first time that the cells derived from the canine endometrium (e-multipotent stem cells [MSCs]) were able to differentiate into a heterologous cell type: Osteocytes, thus demonstrating the presence of MSCs. Thus, the endometrium may be told as a potential source of MSCs which can be used for various therapeutic purposes. Conclusion: The endometrium can be used as a potential source of MSCs, which can be used for various therapeutic purposes. PMID- 29391699 TI - From the Editor's Desk. PMID- 29391700 TI - Oral potentially malignant disorders: Revisited. PMID- 29391701 TI - Dr. H. M. Dholakia. PMID- 29391702 TI - Oral submucous fibrosis: An update. PMID- 29391703 TI - Natural killer cell: An immuno-oncology novel target for cancer therapy? PMID- 29391704 TI - Correlation of salivary glucose level with blood glucose level in diabetes mellitus. AB - Background: Saliva is a unique fluid, which is important for normal functioning of the oral cavity. Diabetes mellitus (DM) is a disease of absolute or relative insulin deficiency characterized by insufficient secretion of insulin by pancreatic beta-cells. The diagnosis of diabetes through blood is difficult in children, older adults, debilitated and chronically ill patients, so diagnosis by analysis of saliva can be potentially valuable as collection of saliva is noninvasive, easier and technically insensitive, unlike blood. The aim of the study was to correlate blood glucose level (BGL) and salivary glucose level (SGL) in DM patients. Methodology: A cross-sectional study was conducted in 120 patients, who were categorized as 40 controlled diabetics, 40 uncontrolled diabetics and 40 healthy, age- and sex-matched individuals constituted the controls. The blood and unstimulated saliva samples were collected from the patients at the different intervals for fasting, random and postprandial levels. These samples were then subjected for analysis of glucose in blood and saliva using glucose oxidase/peroxidase reagent in HITACHI 902(R) Automatic analyzer, and the results were recorded. Results: The mean SGLs were higher in uncontrolled and controlled diabetic groups than in nondiabetic group. A highly statistically significant correlation was found between fasting saliva glucose and fasting blood glucose in all the groups. Conclusion: With increase in BGL, increase in SGL was observed in patients with diabetes suggesting that SGL can be used for monitoring glycemic level in DM. PMID- 29391705 TI - Curcuma longa extract - Haldi: A safe, eco-friendly natural cytoplasmic stain. AB - Background: Eosin is most widely used synthetic dye belonging to the xanthene group. These dyes are efficient but are hazardous to human and animal health. With the increasing awareness of a green earth, it is advisable to use more of eco-friendly and biodegradable material which can be effectively achieved by the use of natural dyes obtained from plants and other natural sources. Turmeric, available as Curcuma longa (domestic), has long been in use in the subcontinent as a spice and flavoring agent in most food preparations. Its health benefit as a natural antibiotic and anti-inflammatory has been successfully established by several researchers. The intense yellow color imparted by turmeric inspired us to explore its efficacy as a potential alternative for eosin in routine histopathological procedures. Aim: The aim of this was to explore the efficacy of turmeric extract as a stand-alone counterstain for hematoxylin and its comparative assessment with routine H and E staining. Materials and Methods: The rhizomes of C. longa were cut into small pieces, dried and milled. This powder was dissolved into alcohol and centrifuged using a centrifugal machine. The supernatant was then collected with the help of micropipette. This supernatant was used as a counterstain for hematoxylin. Results: The data were analyzed using Mann-Whitney U test with Statistical Package for the Social Sciences version 15.0 (SPSS Inc.,). The P value obtained was statistically insignificant (P > 0.05). Conclusion: Although eosin is the most efficient counterstain for hematoxylin, turmeric can also be used as an alternative for eosin. PMID- 29391706 TI - The effect of fluorosis on human teeth under light microscopy: A cross-sectional study. AB - Background: Fluoride is needed for the normal development of bone and teeth; in high levels, it affects developing teeth and bone. Dental fluorosis (DF) is caused by ingestion of excess fluoride mainly through drinking water. Aim: The present study aims to observe and understand the histological changes of fluorosed teeth under light microscope (LM). Materials and Methods: Teeth which were indicated for extractions for orthodontic or periodontal problems were selected. Thirty extracted teeth were selected with varying degrees of DF based on modified Dean's fluorosis index. Ground sections of these teeth were prepared and the sections were studied under binocular LM. Photomicrographs were taken under high power objective using 15 megapixels Nikon camera. Results and Conclusion: Qualitative histologic changes in different grades of fluorosed teeth were evaluated in enamel, dentin, cementum and between their junctions. Fluoride interacts with enamel in both mineral phases and organic macromolecules by strong ionic and hydrogen bonds resulting in incomplete crystal growth at prism peripheries. This presents as hypomineralization of enamel and dentin, increased interglobular dentin, increased secondary curvatures and changes in cementum such as diffuse cementodentinal junction and increased thickness of Tomes' granular layer. Changes in the structure of the teeth with Dean's index below 2 and teeth with Dean's index of 2 and above were compared using Chi-square test. P value was found to be highly significant being 0.00047. Many of the features of dental fluorosis seen in the present study under light microscope are comparable to those results studied under specialized microscopes. PMID- 29391707 TI - Oral candidiasis: A retrospective study of 276 Brazilian patients. AB - Background: Although oral candidiasis (OC) is a very common fungal infection of oral cavity, clinical features of affected patients and their demographic profile are not well documented. Objective: The objective of the study was to assess the demographic profile of patients diagnosed with OC and its clinical features in an import Brazilian center of oral and maxillofacial pathology. Materials and Methods: A retrospective study consisted of 276 patients diagnosed with OC by cytopathology Periodic Acid-Schiff (PAS) staining, during the period of 20 years. The variables related to patients were gender, age and skin color. Regarding infection, the data collected were location, color, symptoms, early manifestation, or recurrent and associated factors. Results: Male and female were equally affected, and the median age was 43 years. The majority of lesions were of primitive origin, asymptomatic and affecting only one site of oral cavity. The most affected site was the palate followed by tongue. More than a half of the patients (56.2%) had red lesions. The main associated factors related were the use of removable prostheses, bone marrow transplantation and AIDS. Conclusions: OC affects predominantly adults and elderly, without difference between sex and skin color. Although clinical findings are crucial, cytopathology tests are important complementary examinations to reach a definitive diagnosis. PAS staining seems to be more used in cases of erythematous candidiasis since white lesions are easier to diagnose clinically. PMID- 29391708 TI - Prevalence of nasal carriers of methicillin-resistant Staphylococcus aureus among dental students: An in vivo study. AB - Aim: The aim of this study is to evaluate the prevalence of nasal carriage of coagulase positive methicillin-resistant Staphylococcus aureus (MRSA) among dental students. Materials and Methods: Four hundred dental students, divided into two groups - undergraduates (200) and postgraduates (200), were screened using sterile cotton swabs for carriage of MRSA in anterior nares. The samples were inoculated on HiCrome MeReSa Agar Base-with cefoxitin supplement. Further confirmatory tests were done by Gram-staining, Tube coagulase and Cefoxitin disc diffusion test on Mueller-Hinton agar. Results: MRSA was positive among 25 (12.50%) undergraduates and 49 (24.50%) postgraduates students. Further confirmatory test also showed the same results. MRSA colonization was significantly more in postgraduate students, who are exposed to more number of patients and have put in more clinical hours as compared to undergraduate students who have just entered clinics and have limited clinical exposure. Conclusion: The present study concluded that rate of MRSA colonization was 18.5% in the dental school population. The colonization rate was significantly (P = 0.002%) higher in postgraduate students as compared to undergraduate students emphasizing the need to follow infection control protocols stringently. Clinical Significance: Awareness about MRSA among dental doctors is mandatory so as to prevent transmission of MRSA in dental settings. PMID- 29391709 TI - Quantitative and qualitative assessment of argyrophilic nucleolar organizer regions in normal, premalignant and malignant oral lesions. AB - Aim: The aim of the study was to assess the cell proliferation and biologic aggressiveness of the lesions by evaluating the significance of number and dispersal pattern of Argyrophillic Nucleolar organizing Regions (AgNORs) using silver colloid technique in normal mucosa, premalignant and malignant lesions. Settings and Design: In-vitro study, lab setting. Methods and Material: The study sample consisted of five groups each with a sample size of 10 and a control group. Group I (Control), Group II (Oral Submucous Fibrosis - Mild dysplasia), Group III (Oral Submucous Fibrosis - Moderate dysplasia), Group IV (Leukoplakia - Mild dysplasia), Group V (Leukoplakia - Moderate dysplasia) and Group VI (Squamous cell carcinoma). Two sections were cut, of which one was stained with H/E stain for histopathological analysis and the second one with Silver nitrate for AgNOR counting and grading. The data obtained were analyzed both qualitatively and qualititavely. Statistical Analysis Used: Student's Unpaired T test and One- way ANOVA. Results: The Mean AgNOR count increased in the following ascending order: i.e OSMF with mild dysplasia, leukoplakia with mild dysplasia, OSMF with moderate dysplasia, leukoplakia with moderate dysplasia and squamous cell carcinoma. Qualititatively, Type II AgNOR pattern was found to be the predominant one in all the samples. Type III AgNOR pattern was found to be increasing with the increase in the grade of dysplasia. Conclusions: AgNOR quantity is proportional to the proliferative activity of the cell and does not necessarily always indicate malignancy. It is the qualitative characteristics of AgNOR that help to differentiate the premalignant and malignant lesions. PMID- 29391710 TI - Kerosene: Contributing agent to xylene as a clearing agent in tissue processing. AB - Background: Research methodology in oral and maxillofacial pathology has illimitable potential. The tissue processing involves many steps of which one of the most important step is "Clearing," which is a process of replacing dehydrant with a substance which is miscible with embedding medium or paraffin wax. Xylene is one of the common clearing agents used in laboratory, but it is also hazardous. The main aim of this study is to substitute conventionally used xylene by a mixture of kerosene and xylene in clearing steps without altering the morphology and staining characteristics of tissue sections. This will also minimize the toxic effects and tend to be more economical. Materials and Methods: One hundred and twenty bits of tissue samples were collected, each randomly separated into 4 groups (A, B, C and D) and kept for routine tissue processing till the step of clearing; during the step of clearing instead of conventional xylene, we used mixture of xylene and kerosene in 4 ratios ([A-K:X - 50:50]; [B K:X - 70:30]; [C - Ab. Kerosene]; [D - Ab. Xylene - as control]) and observed for the light microscopic study adopting H and E staining, IHC (D2-40), Special stains (periodic acid-Schiff and congo red) procedure. The result was subjected to statistical analysis by using Fisher's exact test. Results: The results obtained from the present study were compared with control group, i.e., D and it was observed that Groups A and B were absolutely cleared without altering the morphology of tissue and cellular details; optimum embedding characteristics and better staining characteristics were also noted, whereas Group C presents poor staining characteristics with reduced cellular details. Embedded tissues in Group C presented with rough, irregular surface and also appeared shrunken. Conclusion: Combined mixture of xylene and kerosene as a clearing agent in different ratio, i.e., Group A (K:X - 50:50) and B (K:X - 70:30) can be used without posing any health risk or compromising the cellular integrity. PMID- 29391711 TI - Immunohistochemical evaluation of inducible nitric oxide synthase in the epithelial lining of odontogenic cysts: A qualitative and quantitative analysis. AB - Introduction: The three common odontogenic cysts include radicular cysts (RCs), dentigerous cysts (DCs), and odontogenic keratocysts (OKCs). Among these 3 cysts, OKC is recently been classified as benign keratocystic odontogenic tumor attributing to its aggressive behavior, recurrence rate, and malignant potential. The present study involved qualitative and quantitative analysis of inducible nitric oxide synthase (iNOS) expression in epithelial lining of RCs, DCs, and OKCs, compare iNOS expression in epithelial linings of all the 3 cysts and determined overexpression of iNOS in OKCs which might contribute to its aggressive behavior and malignant potential. Aims: The present study is to investigate the role of iNOS in the pathogenesis of OKCs, DCs, and RCs by evaluating the iNOS expression in the epithelial lining of these cysts. Subjects and Methods: Analysis of iNOS expression in epithelial lining cells of 20 RCs, 20 DCs, and 20 OKCs using immunohistochemistry done. Statistical Analysis Used: The percentage of positive cells and intensity of stain was assessed and compared among all the 3 cysts using contingency coefficient. Kappa statistics for the two observers were computed for finding interobserver agreement. Results: The percentage of iNOS-positive cells was found to be remarkably high in OKCs (12/20) -57.1% as compared to RCs (6/20) - 28.6% and DCs (3/20) - 14.3%. The interobserver agreement for iNOS-positive percentage cells was arrived with kappa values with OKCs -> Statistically significant (P > 0.000), RCs -> statistically significant (P > 0.001) with no significant values for DCs. No statistical difference exists among 3 study samples in regard to the intensity of staining with iNOS. Conclusions: Increased iNOS expression in OKCs may contribute to bone resorption and accumulation of wild-type p53, hence, making OKCs more aggressive. PMID- 29391712 TI - Osteopontin expression and clinicopathologic correlation of oral hyperplastic reactive lesions: An institutional 6-year retrospective study. AB - Background and Objective: Reactive proliferations of oral cavity comprise pyogenic granuloma (PG), fibrous hyperplasia (FH), peripheral ossifying fibroma (POF), and peripheral giant-cell granuloma (PGCG). They often pose diagnostic challenges due to their overlapping clinical and histopathological features. This study was conducted to determine the frequency and clinicopathological correlation of reactive hyperplastic lesions in the oral cavity reported in our institute and compared it with other previous studies. Further evaluation of osteopontin (OPN) expression in normal gingival tissue and different types of focal reactive lesions was also done. Materials and Methods: Data of all reactive hyperplasias were retrieved, reviewed, and analyzed for age, gender, clinical presentation, and site of location. Presence and distribution of OPN were assessed using immunohistochemistry in these reactive lesions. Results: Two hundred and forty-eight reactive lesions were comprised of FH (38%), PG (23%), POF (13%), and PGCG (7%). FH was more common in males (55%) whereas other reactive lesions were more in females (68%-73%). The most frequently involved site was gingiva (59%), and most common clinical presentation was sessile growth on gingiva. OPN expression was minimal in normal gingiva. Few cases of FH, PG, and all cases of POF showed positivity for OPN in inflammatory cells, stromal cells, extracellular matrix, and in calcifications. Conclusion: Reactive hyperplastic lesions of oral cavity are mucosal responses to chronic low-grade irritation caused by plaque, calculus, and any other irritant. It is helpful to know their frequency and presentation as their early identification enables accurate patient evaluation and management. PMID- 29391713 TI - Evaluation of oxidative stress markers in oral lichen planus. AB - Background: Lichen planus (LP) is a chronic, inflammatory disease that affects the skin, mucous membrane, scalp and nails that frequently involves the oral mucosa. Oxidative stress reflects an imbalance between the production of reactive oxygen species and the biological system's ability to readily detoxify the reactive intermediates or repair the resulting damage. It has been suggested that oxidative stress may play a role in the pathogenesis of LP. Aim and Objectives: To evaluate the role of oxidative parameters in the pathogenesis of oral LP, estimate the levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx) and uric acid (UA) in saliva of oral LP patients and to compare the levels of SOD, MDA, GP and UA in oral LP patients with healthy controls. Methodology: In this cross-sectional study, 1.5 ml of fasting saliva sample was collected using passive drool method from the study group (30 patients diagnosed as having oral LP) and the control group (30 age-matched healthy volunteers). The unstimulated saliva was collected were analyzed by spectrophotometry. Statistical analysis was done to evaluate and compare the values between groups. Results: The mean values of SOD and MDA in saliva in the study group showed a significant increase in amount when compared with the control group whereas GPx showed a significant decrease in the study group. UA value showed an insignificant difference in the same comparison. Interpretation and Conclusion: Oxidative stress markers as MDA and SOD are elevated, and GPx is decreased in the saliva of oral LP patients. PMID- 29391714 TI - Comparative analysis of the oxidative stress and antioxidant status in type II diabetics and nondiabetics: A biochemical study. AB - Background: Diabetes mellitus is a metabolic disorder characterized by hyperglycemia along with biochemical alterations of glucose and lipid peroxidation. It produces free radicals that induce lipid peroxidation which acts as an indicator for oxidative stress in the body. The widely used assay for lipid peroxidation involves measurement of malondialdehyde (MDA). Defensive system in the body consists of antioxidant enzymes which help in scavenging free radicals. Two such antioxidant enzymes are reduced glutathione (GSH) and superoxide dismutase (SOD). In this study MDA, GSH and SOD are assessed in serum and saliva of age- and sex-matched 33 diabetics and nondiabetics. Objective: (1) To estimate the levels of MDA, GSH and SOD in saliva and serum of both diabetics and nondiabetics. (2) To correlate the levels of MDA, GSH and SOD in saliva and serum of both diabetics and nondiabetics. (3) To find if serum levels of MDA, GSH and SOD can be predicted from values of the same in saliva, in both groups. Materials and Methods: Whole unstimulated saliva and venous blood samples obtained after 12 h of overnight fast were transported to the designated laboratory chosen for the study. Supernatants of the centrifuged samples were used for the assays of MDA, GSH and SOD. Results: A significant correlation was obtained between serum and saliva values of MDA and GSH, hence the prediction of serum MDA and GSH was possible from their subsequent saliva values. Although the levels of serum and salivary SOD showed a weak positive correlation, prediction of SOD was not possible. Conclusion: Saliva can be used as a diagnostic tool for the estimation of MDA, GSH and SOD. PMID- 29391715 TI - Immunofluorescence in oral lesions. AB - Immunofluorescence is an immunohistochemical method used to demonstrate the presence of antigen and antibodies in the tissues or serum. It is an auxiliary diagnostic tool for the autoimmune bullous and inflammatory disorders. It detects the in situ and circulating immune deposits that are involved in the pathogenesis of immunobullous diseases. PMID- 29391717 TI - Hemangioendothelioma of palate: A case report with review of literature. AB - Hemangioendothelioma commonly occurs in the superficial or deep soft tissue of the extremities, lungs, liver, bone and lymph nodes, with oral cavity being a rare location. It is usually benign but can show variable grades of malignancy. According to the histological presentation, hemangioendothelioma has been classified as epithelioid, Kaposiform, hobnail (Dabska-Retiform), epithelioid sarcoma like and composite. We present a case of ulcerated swelling of palate clinically diagnosed as pyogenic granuloma which presented a diagnostically challenging histological picture. We discuss the differential diagnoses obtained from various oral pathologists and general pathologists and substantiate the diagnosis of hemangioendothelioma based on its clinical behavior, histological features and immunohistochemical findings. In addition, we attempt to highlight the diagnostic dilemma that such cases can pose to the attending pathologists. PMID- 29391716 TI - Nanotechnology in oral cancer: A comprehensive review. AB - Oral health could be maintained by application of this technology in prevention, diagnosis and treatment. Oral cancer is a debilitating disease, and numerous research activities are being pursued worldwide to combat this deleterious process. Nanotechnology is very diverse field that has revolutionized the industry and is setting new trends in the management of oral cancer. Hence, we performed a PubMed search on nanotechnology in oral cancer and found 211 articles related to this search. We have reviewed the reported literature to the best of our abilities and summarized the various aspects of nanotechnology, its role in diagnosis - nanodiagnostics and treatment of oral cancer - nanotherapeutics in this article. PMID- 29391718 TI - Early diagnosis of an isolated primary peripheral T-cell lymphoma masquerading as massive gingival enlargement in a pediatric patient. AB - Lymphomas are malignant neoplasm of the lymphocyte cell lines, classified as either Hodgkin's or non-Hodgkin's lymphoma (NHL). NHL comprises a heterogeneous group of lymphoid neoplasm arising from B-cell, T-cell or natural killer cell with a spectrum of behavior ranging from relatively indolent to highly aggressive and potentially fatal. Peripheral T-cell lymphoma, a variant of NHL, is a disease characterized by the presence of diffuse lymphadenopathy, extranodal involvement, classical B symptoms such as fever (>100.4 degrees F) for 3 consecutive days, weight loss exceeding 10% of body weight in 6 months and drenching night sweats with a tendency for recurrence. Among NHLs, extranodal presentations are relatively common. Extranodal presentation particularly in the oral cavity is very rare and may misinterpret the diagnosis. Lesions of this type should be cautiously dealt especially in pediatric patients and young adolescents. The present case report is about an atypical presentation of disease process in a 15 year-old male patient, which was diagnosed early with the help of a combination of histopathology and immunohistochemistry techniques. PMID- 29391719 TI - Clear-cell variant of squamous cell carcinoma in maxilla as primary lesion: A rare case. AB - Oral squamous cell carcinoma with prominent clear-cell differentiation is a rare occurrence with incompletely understood etiology. We report a case of a 55-year old male working in a steel factory presented with an ulcerated swelling on maxillary alveolar ridge, a rare site. Histopathology showed sheets of squamous cells with clear cell differentiation and features of malignancy. Periodic acid Schiff and mucicarmine stains showed negative reaction. Immunohistochemical study using antibody for cytokeratin and epithelial membrane antigen revealed diffuse and intense positivity. The neoplastic cells showed complete negative reaction with antibodies for S-100 and vimentin. PMID- 29391720 TI - Giant-cell fibroma: Understanding the nature of the melanin-laden cells. AB - Giant-cell fibroma is a localized, benign fibrous mucosal mass, which clinically mimics any other fibroepithelial growth, and its distinction from other lesions is on the basis of its peculiar histopathology. A case of giant-cell fibroma with stroma strewn with brown pigment-laden cells is presented herewith. Immunohistochemical staining aided with histochemical reaction to understand the origin of these cells was carried out. Various mechanisms that explain the presence of melanin granules in reactive lesions of giant-cell fibroma is discussed in the present report. PMID- 29391721 TI - Xanthomatous sialadenitis: Autoimmune- or treatment-induced lesions? AB - Xanthomatous sialadenitis (XS) is rarely reported. Here we report XS in a case of HLA-B27-positive ankylosing spondylitis showing also anti-MAG-positive polyneuropathy with IgM-kappa dysimmunoglobulinemia/paraproteinemia, lung small cell carcinoma and buccal squamous cell carcinoma (SCC). The lesions were identified in submandibular and labial minor salivary glands of a neck dissection specimen (made during a buccal 1.7 cm large SCC resection procedure). The oral SCC was resected at 8 months after the diagnosis of the lung small cell carcinoma (with skull dome metastases, revealed by a superior cava syndrome) and at 2 months after radiotherapy. The microscopic XS-lesions consisted in multifocal accumulations of CD68-positive macrophages. Plasmocyte-abundant foci (CD138 positive) were extra-xanthomatous (atrophic parenchyma, zones of adipose involution). CD138 was also expressed in ductal cells and in acini (focally). In conclusion, we report XS of submandibular and labial minor salivary glands, occurring in the context of a HLA-B27-positive ankylosing spondylitis, polyneuropathy with IgM-kappa dysimmunoglobulinemia and anti-MAG antibodies in a case of small cell lung carcinoma (treated by radio-chemotherapy) and oral SCC. PMID- 29391722 TI - Screening of oral potentially malignant disorders: Need of the hour. AB - Oral potentially malignant disorders (OPMDs) include a variety of lesions and conditions which display an increased risk for malignant transformation to oral cancer. As the incidence and prevalence of OPMD are highly increasing in India, its early detection and prevention is the need of the hour. Early diagnosis of such disorders is necessary to prevent the malignant transformation. Many advanced diagnostic techniques are used to predict their progression and to assess the risk of malignant transformation. Management of symptoms of OPMDs is necessary for the overall well-being of the patient. This short communication provides an overview and the importance of early diagnosis and prevention of OPMDs. PMID- 29391723 TI - Post extraction foreign body reaction in mandibular third molar region: An uncommon presentation. PMID- 29391724 TI - A comparative study of three commonly used two-dimensional overlay generation methods in bite mark analysis. AB - Aim: The present study attempts to compare the bite mark overlays generated by three different methods. The objectives of the study were to compare the three commonly used techniques for overlay generation and to evaluate the interobserver reliability in assessing bite marks by these methods. Materials and Methods: Overlays were produced from the biting surfaces of six upper and six lower anterior teeth of 30 dental study models using the following three methods: (a) Hand tracing from wax impressions, (b) radiopaque impression method and (c) computer-based method. Results: The computer-based method was found to be the most accurate method. Of the two hand tracing methods, radiopaque wax impression method was better than the wax impression method for overlay generation. Conclusions: It is recommended that forensic odontologists use computerized method, but the use of hand tracing overlays in bite mark comparison cases using radiopaque wax impression method can also be done where sophisticated software and trained persons in forensic odontology are not available. PMID- 29391725 TI - Assessment of the most reliable sites in mandibular bone for the best deoxyribonucleic acid yield for expeditive human identification in forensics. AB - Background: In recent years, the techniques used to identify human remains post accidents, trauma or in case of criminal investigation have been expanded, improved and rendered more complex by the emergence of technologies based on deoxyribonucleic acid (DNA) analysis. In the head and neck area, tooth has been proven to be the best quantitative source for DNA but in certain cases where the mandible specimen is edentulous or the tooth is extensively destroyed with caries, large dental restorations, mobile, or if they show any perimortem or postmortem fractures, sampling of such tooth specimen is usually avoided. In such situations, bone is considered the next best site for DNA analysis. Mandible being the largest, strongest and dense cortical bone is the most prominent facial bone that can be easily disarticulated. It can be analyzed for the best short tandem repeat (STR) segment qualitative amplification using polymerase chain reaction (PCR) technique for forensic analysis which can be used for gender and age determination. Aim: The aim of this study is to determine the best site for optimum quantitative and qualitative yield of DNA for amplification using specific and standard STR segment by conventional PCR technique. Methodology: Fifteen mandibular samples exposed to different environmental conditions were collected. Bone pieces of 1 cm * 1 cm were cut from each mandible from three sites, i.e., the ramus, angle and body, wherein the genomic DNA was isolated and was subjected to PCR using restricted number of 25 cycles. Results: The STR segment D3S1358 from clone RP11-438F9 used for the study showed very good amplification in restricted number of PCR cycles in the ramus region with number of repeats in every 15th genomic region. Conclusion: This study highlights the use of mandibular bone for the expeditive human identification. As per the study, the ramus of the mandible gave high quantitative and qualitative yield of DNA with thick amplification band of the STR segment as compared to the body and angle of the mandible. Thus ramus of the mandible can be preferred over other sites for molecular forensic investigations. PMID- 29391726 TI - Estimation of silver nucleolar organizer regions in oral lichen planus, oral lichenoid reactions and oral lichenoid dysplasia. AB - Aims and Objective: (1) To study the clinical and histological features of oral lichen planus, oral lichenoid reaction (OLR) and oral lichenoid dysplasia (OLD). (2) To estimate and compare the silver nucleolar organizer regions in OLR and OLD. Materials and Methods: A total of 40 biopsies were studied; sections were divided as study group, which consists of OLP, OLR and OLD each of 10 cases and 10 biopsies of normal oral mucosa as control group. Sections were stained by silver staining technique and total number of silver stained nucleolar organizer regions (AgNORs) were counted in nucleoli of 100 cells in each section under x100 objective (oil immersion). Results: Our study revealed that the difference between the (AgNOR) count of OLP (2.272 +/- 0.09) and OLR (2.27 +/- 0.073) is not statistically significant (P = 0.81). The mean AgNOR count of OLD (2.388 +/- 0.043) compared to that of OLP (2.272 +/- 0.09) and OLR (2.27 +/- 0.073) showed an increase and it is statistically highly significant (P = 0.002 and P = 0.003, respectively). Conclusion: AgNOR count is an objective test, which has stronger biological basis for diagnosing epithelial dysplasia. It is easy to perform, inexpensive and is performed on biopsied specimen. However, this technique cannot differentiate OLP and OLR, as there is no much difference in the proliferative activity of cells in these two lesions. It is reasonable to suggest that all biopsy tissues from lichenoid lesions where dysplastic features are observed in routine histopathological sections should be additionally stained by silver technique to ascertain dysplastic status of the lesion. Clinical Significance: This is an improved diagnostic parameter, which will help pathologists to formulate more definitive final histopathological diagnosis and will in turn facilitate the formulation of patient treatment and follow-up care by clinicians. PMID- 29391727 TI - Evaluation of role of trace elements in oral submucous fibrosis patients: A study on Gujarati population. AB - Introduction: Oral submucous fibrosis (OSMF), a precancerous condition, is highly prevalent in the Indian subcontinent. Among many trace elements, copper and iron are required for the functioning of numerous enzymes. The biochemical alterations of these trace elements in the serum of patients with premalignant conditions can help in determining the staging of the disease, its appropriate treatment and as an indicator for prognosis. Aims and Objectives: The objective of the study was to evaluate the role of iron and copper as well as to identify the better predictor of the two in the diagnosis and progression of OSMF. Materials and Methods: The study sample consisted of 150 patients, out of which the cases group consisting of 100 OSMF patients and control group consisting of 50 individuals. All the cases were confirmed of having OSMF by histopathological examination. The blood sample was obtained from all 150 patients and evaluated by digital autoanalyzer photometer for serum level of copper and iron by the colorimetric method. The results obtained for cases and controls were compared by statistical analysis. Results: The mean serum copper level increases while the mean serum iron level decreases with the advancement in the severity of clinical and histological stages of OSMF. Conclusion: Biopsy is the gold standard to diagnose OSMF, but it is an invasive and time-consuming technique. However, nowadays, many recent advances are used to diagnose OSMF at an early stage and reduce its progression into late and reversible stages. The trace elements serve as potential prognostic and diagnostic markers for OSMF patients. PMID- 29391728 TI - Influence of risk factors on patients suffering from potentially malignant disorders and oral cancer: A case-control study. AB - Background: Tobacco use can alone lead to death worldwide, especially in developing and underdeveloped countries. China and Brazil are the world's largest producer of tobacco. India holds the third place in producing, and it is the fourth largest consumer of tobacco and its products in the world. Objectives: A case-control study was carried out to assess the influence of risk factors on patients with potentially malignant disorders (PMD) and oral cancer. Materials and Methods: Fifty cases diagnosed with PMD and oral cancer patients were selected for the study. An equal number 50 healthy controls who were also selected after age and gender matching. Multivariate logistic regression analysis was used to estimate the suspected risk factors for PMD and oral cancers. Chi square test, Adjusted odd's ratios with 95% confidence interval were also used for the statistical analysis. Results: There is a statistically significant difference between the different age group, duration, frequency, exposure time, and synergistic effect of tobacco chewing, smoking and alcohol drinking. Conclusions: Chewing tobacco is one of the major risk factors in the initiation of PMD which can lead to oral cancer. PMID- 29391729 TI - Expression of survivin and p53 in oral lichen planus, lichenoid reaction and lichenoid dysplasia: An immunohistochemical study. AB - Context: The malignant transformation potential of oral lichen planus (OLP) and related lesions is a subject of great controversy. Aim: The aim of this study was to compare the expression of proteins related to apoptosis and tumour suppressor gene processes in OLP, oral lichenoid reaction (OLR) and oral lichenoid dysplasia (OLD). Materials and Methods: The immunohistochemical study was carried out to investigate the expressions of survivin and p53 in a total of 30 lesional biopsy specimens - 10 cases each of OLP, OLR and OLD. The expression rates were further compared with 10 control specimens of normal oral mucosa (NORM). Results: Immunoreactivity for p53 was seen in 7 cases (70%) of OLD, 4 cases (40%) of OLP and 2 cases (20%) of OLR and none of NORM. We obtained a significant difference (P = 0.01) in mean p53 expression between the different entities. The positive staining rate of survivin was found to be significantly different between OLD (50%), OLP (10%), OLR (0%), and normal mucosa (0%) (P = 0.004). There was a positive correlation between p53 and survivin expression in OLP and OLD using Pearson's correlation coefficient. Conclusion: Lichenoid dysplasia has shown p53 and survivin expression in the range of not OLP, but leukoplakia. On the other hand, OLR seems to be an innocuous lesion. The study results with OLP are inconclusive but points toward a small but important malignant potential in OLP. This kind of comparative study highlights the importance of biopsying OLP and related lesions for proper diagnosis and appropriate management. PMID- 29391730 TI - Odontogenic tumors: Review of 127 cases in Marathwada region of Maharashtra. AB - Introduction: Odontogenic tumors (OTs) are a group of heterogeneous lesions derived from epithelial or ectomesenchymal tissues or both, which are part of the tooth-forming apparatus. They range from hamartomatous or nonneoplastic tissue proliferations to malignant neoplasms with metastatic capacity. OTs are comparatively rare, comprising about 4.79% of all oral and maxillofacial biopsy specimens diagnosed. Several retrospective studies carried out in Africa, Asia, Europe and America, show that differences exist in the relative frequency of the various histologic types. Very few studies are reported among Asians, especially from the Indian subcontinent. Hence, the present study is designed to determine the frequency of the OTs and compare them with reports of various other part of the world. Study Design: A retrospective study was carried out with the ethical clearance and permission from the authority. The histopathology records from the Department of Oral Pathology and Microbiology, within the period from January 1992 to June 2012 were obtained. A total number of OTs were analyzed for age, gender, site of the tumor and histopathological type. The odontogenic keratocyst now considered as kerato cysticodontogenic tumor (KCOT) was also included in the present study. Results: Totally, 2652 tissue specimens were received for histopathologic examination out of which 127 were OTs. All these reported cases were benign except two cases of malignancy. Among these male: female ratio of 1.04:1 with an overall mandible: maxilla ratio of 1.01:1. The most common benign odontogenic tumor was KCOT (44.9%). Ameloblastomas were the second most common benign tumors (35.43%), followed by odontome (7.08%) and adenomatoid odontogenic tumor (4.72%). Age distribution showed a peak occurrence of the odontogenic tumor in the fourth decade (31.49%). Conclusion: OTs are rare lesions in the studied population and are represented mainly by the KCOT, ameloblastoma and odontoma. Data from the reviewed cases have shown a possible geographic variation of OTs. With the introduction of the KCOT in the 2005 WHO classification, this neoplasm is now one of the most prevalent OT types. PMID- 29391731 TI - Comparitive efficacies of a natural fixative with a conventional fixative. AB - Introduction: The quest for formalin substitutes has long been going on due to its health hazards. Honey has been recognized as a safe substitute for formalin. However, we explored jaggery as a natural substitute for formalin. The aim of this study was to compare the tissue fixation abilities of jaggery syrup (30%) with that of 10% neutral-buffered formalin (NBF) and to determine the best fixative among both. Materials and Methods: A study was conducted with 65 pathological tissues. Each specimen was divided into two equal parts. One part was fixed in 30% jaggery solution (Group A), while the other half was fixed in 10% NBF solution (Group B). 24 h tissue fixation was attained at room temperature followed by evaluation of pre- and post-fixation, tissue shrinkage, weight difference and ease of sectioning, followed by evaluation of conventional processing and staining. The histomorphological assessment for each slide was made based on evaluation of cellular outline, cytoplasmic details, nuclear details, staining quality and overall morphology under light microscopy. Each criterion was rated on a scale of 1-4. Nominal categorical data between the groups were compared using Chi-squared test. Results: The preservation of tissue specimen by jaggery syrup was comparable to that of formalin and surprisingly overall nuclear detail of the tissue was better than conventional formalin fixative. Conclusion: Jaggery can be successfully adopted in routine histopathology laboratories in place of formalin. PMID- 29391732 TI - A comparative study of odontogenic keratocyst and orthokeratinized odontogenic cyst using Ki67 and alpha smooth muscle actin. AB - Aim: This study aimed to demonstrate and evaluate the expression of stromal myofibroblasts (MFs) and epithelial cell proliferation using alpha-smooth muscle actin (alpha-SMA) and Ki67 markers, respectively, in odontogenic keratocyst (OKC) and orthokeratinized odontogenic cyst (OOC) to correlate their aggressive behavior. Materials and Methods: Twenty cases of OKC and twenty cases of OOC were stained with alpha-SMA and Ki67 markers for demonstration of stromal MFs and epithelial cell proliferation, respectively, and ten cases of well-differentiated squamous cell carcinoma were used as positive control. Assessment of the number of alpha-SMA-positive stromal cells and Ki67-positive epithelial cells determined by MFs and proliferative epithelial cell frequency in 10 high-power fields (*400) was presented as the mean number of positive cells per field. Statistical Analysis: Kruskal-Wallis and Mann-Whitney test were used to analyze the difference in the mean number of alpha-SMA- and Ki67-positive cells per field between OKC and OOC. Results: The mean number of positively stained cells for alpha-SMA and Ki67 is significantly higher in OKC compared to OOC. Conclusion: Impression is that, the different behaviors of these two entities are compatible with their immunohistochemical view. The high value of stromal MFs and proliferative epithelial cells in OKC in comparison to OOC indicates its aggressiveness and potential for recurrence. PMID- 29391733 TI - A study on Evaluation of efficacy of bethanechol in the management of chemoradiation-induced xerostomia in oral cancer patients. AB - Objectives: Squamous cell carcinoma is the most common oral cancer. Radiotherapy with concomitant chemotherapy is an ideal treatment modality largely used for oral cancers, which precipitates many side effects, of which the most challenging and debilitating side effect is xerostomia. This study aimed to evaluate the efficacy of bethanechol in patients with xerostomia following chemoradiation therapy for oral cancer. Materials and Methods: Fifty patients with xerostomia postchemoradiation therapy, aged between 30 and 65 years, were selected based on selection criteria. Thirty patients in the study group were administered 25 mg bethanechol three times daily (TDS) and 20 patients in the control group with placebo capsules. The subjective symptoms of oral dryness were periodically evaluated at baseline, at the end of 1st, 2nd and 3rd weeks using a self-reported questionnaire. Salivary analysis such as whole resting saliva and whole stimulated saliva (WSS) volumes, amylase, pH and sodium potassium ratio were evaluated before and 3 weeks after bethanechol and placebo therapy. Results: Twenty-four (80%) patients in bethanechol group and only 2 (10%) patients in control group showed subjective improvement in oral dryness at the end of 3rd week. A significant difference was found between two groups in whole resting and stimulated saliva volume, pH and amylase. However, there was no statistically significant difference in sodium potassium ratio with insignificant adverse effects after 3 weeks of bethanechol therapy. Conclusions: 25 mg bethanechol (TDS) has shown subjective improvement in oral dryness in 24 (80%) patients with significant improvement in whole resting and WSS volumes, pH and salivary amylase with insignificant adverse effects. PMID- 29391734 TI - Quantitative assessment of silver-stained nucleolar organizer region in odontogenic cysts to correlate the growth and malignant potentiality. AB - Context: The most common and important odontogenic cyst involving jaws is the odontogenic keratocyst (OKC) or primordial cyst, the dentigerous cyst and the radicular cyst. These cysts all though do not show similar behavior, they all have the potentiality to recur. Silver nitrate staining of the nucleolar organizer regions (AgNORs) of the benign and malignant lesions is becoming very useful as a diagnostic indicator. Thus, the aim of this study is to assess the diagnostic potential of AgNORs in the cystic epithelium of common odontogenic cysts. Materials and Methods: Archived specimens of odontogenic cysts were stained with hematoxylin and eosin stain and AgNOR stain. Results: The comparative evaluation of the AgNOR counts was done among the three varieties of odontogenic cysts, i.e., radicular cysts, dentigerous cysts and OKC and were observed that the mean for OKC was significantly higher than that of radicular cyst. Conclusion: Therefore, AgNor could be used as an efficient tool for comparative evaluation of microscopic features such as epithelial thickness, surface keratinization and mural proliferation in dentigerous cyst to that of the AgNOR count. PMID- 29391735 TI - The relationship between histological differentiation and disease recurrence of primary oral squamous cell carcinoma. AB - Background: Although advance techniques were available for diagnosis and prognosis of oral cancer, histopathology was used as major method in clinical routine. Of all oral subsites, buccal mucosa squamous cell carcinoma is aggressive in nature with poor survival. Therefore, the aim of the present study was to evaluate the relation of tumor histopathological grade with disease recurrence of buccal squamous cell mucosa carcinoma. Materials and Methods: A retrospective study was carried out in regional cancer research institute, Tamil Nadu. Demographic, histopathological and participant's follow-up details were collected from medical records. Results: Of 198 participants, high frequently encountered with well-differentiated squamous cell carcinoma (n = 98, 49.5%). The clinical characteristics of lymphovascular invasion (P = 0.031), perineural invasion (P = 0.019), tumor stage (P = 0.004), tumor depth (P = 0.048), lymph node (P = 0.02) and metastasis (P = 0.043) had significant association with histopathological grade. In addition, the treatment strategies (P = 0.014) also showed significance at P < 0.05. Further, multivariate revealed cell differentiation (P = 0.048), tumor size (P = 0.037) and depth (P = 0.021) as independent hazard risk of the development of disease using recurrence-free survival of participants at P < 0.05. Of 198 participants, 24 (12.1%) recurrences reported during 34-month follow-up period and the overall estimated recurrence free survival was 52%. The high frequency of recurrence, 12 (50%), was identified with moderately differentiated tumor cells. However, poorly differentiated tumor showed significantly lower survival (28%) than moderate (54%) and well differentiated (81%) by Kaplan-Meier analysis using log-rank test (P = 0.004, P < 0.05). Conclusions: The present study concludes high frequency of recurrence observed in moderately differentiated and also revealed lower survival in poorly differentiated tumor. Hence, further treatment plans should focus on moderate and poorly differentiated tumors to improve survival outcome. PMID- 29391736 TI - Immunoexpression of programmed cell death 4 protein in normal oral mucosa, oral epithelial dysplasia and oral squamous cell carcinoma. AB - Background: Oral squamous cell carcinoma (OSCC) is the frequently reported cancer of the head and neck. Recent studies are being conducted to evaluate the role of potential markers for diagnosing the stages of development of OSCC from normal cells. Aim: The aim of this study is to evaluate and compare the immunoexpression of programmed cell death 4 (PDCD4) protein in normal oral mucosa, oral epithelial dysplasia (OED) and OSCC. Materials and Methods: Histologically diagnosed, formalin-fixed paraffin-embedded archived cases (n = 100) of normal mucosa (n = 10), OED (n = 60) and OSCC (n = 30) were analyzed immunohistochemically in the present retrospective study using monoclonal rabbit antihuman PDCD4. OED and squamous cell carcinoma were graded according to the World Health Organization and Broder's histological grading criteria, respectively. Clinical parameters and immunohistochemical results were analyzed by Fisher exact test using SPSS software. P <0.05 was indicative of significant differences. Results: PDCD4 expression was observed in the normal oral mucosa, OED and OSCC. The maximum expression was observed in the normal oral mucosa, which reduced significantly in OED and OSCC (P = 0.017). With the increase in the transformation from normal cells to cancer cells, a shift from nuclear to cytoplasmic staining was observed indicating predominant cytoplasmic localization of stain as a feature of altered cells. Conclusion: The present study delineates the molecular difference between the normal, dysplastic and carcinomatous cells; and points toward the role of PDCD4 localization in the proliferation of cells. This study thus highlights the need for further research with inclusion of long follow-up period and other pathological criteria such as inflammation and microenvironment, immune status of patient and tumor stage, which could aid in the development of prospective diagnostic options. PMID- 29391737 TI - Myofibroblasts: Master of disguise. AB - Myofibroblasts are the unique population of smooth muscle-like fibroblasts. These cells have a role in growth factors secretion, matrix deposition and degradation. Thereby, myofibroblast contributes in both human physiology and pathology. This review explains the myofibroblastic lesions, imperative role of myofibroblasts in organogenesis, repair, regeneration, inflammation and tumorigenesis. PMID- 29391738 TI - Cancer stem cells: An insight. AB - Cancer stem cells (CSCs) have the ability to self-renew and are present in most tissues including breast, brain, lung, head and neck, prostates, testis, ovary, esophagus, colon and liver. Their origin is yet to be discovered though a series of hypotheses have been proposed in this regard. CSCs play a role in not only the creation of cancer but also its evolution, metastasis and recurrence. CSCs have an important role in cancer therapy and the resistance toward chemotherapeutic agents. This article reviews the characteristics of CSCs in terms of origin, methods of isolation and cancer therapy. PMID- 29391740 TI - Occupational Health Index: Assessing Occupational Health Performance. PMID- 29391739 TI - Metastasis: To and fro. AB - Cancer is one of the most life threatening diseases afflicting mankind. Oral carcinogenesis is a multifactorial process involving numerous genetic events that alter normal functions of oncogenes and tumour suppressor genes. These changes lead to a cell phenotype with increased cell proliferation, with loss of cell cohesion, and infiltration of adjacent tissue thus causing distant metastasis. The fact that cancer patients might develop metastasis after years or even decades from diagnosis of the primary tumor makes the metastatic process even more complex and the disease more deadly. The promise of this article is to enhance the understanding on molecular mechanisms underlying metastasis and provide a better approach towards development of novel therapeutic treatment modalities. PMID- 29391741 TI - Healthy Worker Effect Phenomenon: Revisited with Emphasis on Statistical Methods A Review. AB - Known since 1885 but studied systematically only in the past four decades, the healthy worker effect (HWE) is a special form of selection bias common to occupational cohort studies. The phenomenon has been under debate for many years with respect to its impact, conceptual approach (confounding, selection bias, or both), and ways to resolve or account for its effect. The effect is not uniform across age groups, gender, race, and types of occupations and nor is it constant over time. Hence, assessing HWE and accounting for it in statistical analyses is complicated and requires sophisticated methods. Here, we review the HWE, factors affecting it, and methods developed so far to deal with it. PMID- 29391743 TI - Web-based KAP Intervention on Office Ergonomics: A Unique Technique for Prevention of Musculoskeletal Discomfort in Global Corporate Offices. AB - Aims: The purpose of this study was to evaluate web-based Knowledge, Attitude and Practice (KAP) intervention on office ergonomics - a unique method for prevention of musculoskeletal discomfort (MSD) - in corporate offices that influences behavior modification. Background: With the increasing use of computers, laptops and hand-held communication devices globally among office employees, creating awareness on office ergonomics has become a top priority. Emphasis needs to be given on maintaining ideal work postures, ergonomic arrangement of workstations, optimizing chair functions, as well as performing desk stretches to reduce MSD arising from the use of these equipment, thereby promoting safe work practices at offices and home, as in the current scenario many employees work from home with flexible work hours. Hence, this justifies the importance of our study. Objective: To promote safe working by exploring cost-effective communication methods to achieve behavior change at distant sites when an on-site visit may not be feasible. Materials and Methods: An invitation was sent by the Medical and Occupational Health Team of a multinational corporation to all employees at their offices in Sri Lanka, Singapore, and Malaysia to take up an online Nordic questionnaire, a screening tool for musculoskeletal symptoms, shared in local languages on two occasions - baseline evaluation (n = 240) and a follow-up evaluation after 3 months (n = 203). After completing the baseline questionnaire, employees were immediately trained on correct postures and office ergonomics with animation graphics. The same questionnaire was sent again after a 12-week gap only to those employees who responded to the baseline questionnaire on initial assessment. Statistical Analysis Used: Data collected were analyzed using the Statistical Package for the Social Sciences (SPSS) version 20.0 software and variables were compared using odds ratio as well as Chi-square test. Results: Of the 203 employees who responded, 47.35% had some musculoskeletal symptoms. Among them 58.7% had lower back pain, 46.9% had upper back pain, 44.1% had wrist pain, 39.5% had shoulder pain, and 37% had knee pain. The percentages are high as some participants had multiple complaints i.e. 2 or 3 complaints. However, only 40% of these employees had ongoing symptoms at the time of evaluation (past 7 days). A subsequent 3-month evaluation after web-based intervention showed a significant 41-50% decline in ongoing symptoms. Conclusions: We conclude that newer technology using web-based animation graphics is a highly efficient technique to create office ergonomics awareness and has the potential to become a best practice in countries where language is a communication barrier and an on-site visit may not be feasible due to meagre resources. PMID- 29391742 TI - Occupational, Environmental, and Lifestyle Factors and their Contribution to Preterm Birth - An Overview. AB - Preterm birth (PTB) is a significant public health concern and a leading cause of infant mortality and morbidity worldwide and often contributes to various health complications later in life. More than 60% of PTBs occur in Africa and south Asia. This overview discusses the available information on occupational, environmental, and lifestyle factors and their contribution to PTB and proposes new etiological explanations that underlie this devastating pregnancy complication. Several factors such as emotional, stress, social, racial, maternal anxiety, multiple pregnancies, infections during pregnancy, diabetes and high blood pressure, and in-vitro fertilization pregnancy have been shown to be associated with PTB. Data are emerging that occupational, environmental exposure and lifestyle factors might also be associated in part with PTB, however, they are at best limited and inconclusive. Nevertheless, data on heavy metals such as lead, air pollutants and particulate matters, bisphenol A, phthalate compounds, and environmental tobacco smoke (ETS) are promising and point to higher incidence of PTB associated with exposure to them. Thus, these observations can be used to advise pregnant women or women of reproductive age to avoid such exposures and adopt positive lifestyle to protect pregnancy and normal fetal development. There is a need to conduct well-planned epidemiological studies that include all the pathology causing factors that may contribute to adverse pregnancy outcomes, including PTB. PMID- 29391744 TI - Occupational Stress and Hypertension among Railway Loco Pilots and Section Controllers. AB - Introduction: A cross-sectional study on occupational stress was conducted on loco pilots in 2008, in view of loco pilots being one of the high strain jobs in Indian Railways. Subsequently, a comparative cross-sectional study on occupational stress was conducted among section controllers in 2011, which is another high strain job of Indian Railways. Objective: The studies were conducted to analyze and compare occupational stress and hypertension. Setting and Design: A cross-sectional study on occupational stress and hypertension was conducted among 230 loco pilots in 2008, and subsequently, a comparative cross-sectional study was conducted among 82 section controllers in 2011. Materials and Methods: A closed end 24 item questionnaire on occupational stress was administered. Systolic blood pressure above 140 mmHg and diastolic blood pressure above 90 mmHg were considered as hypertension as per the VII Joint National Committee. Chi square test and t-test were used for testing significance at P < 0.05. Results: The mean stress score was 8.56 in loco pilots and 7.32 in section controllers. The number of loco pilots with more than 12 stress factors was 49 (21.3%) and the number of section controllers with more than 12 stress factors was 7 (8.5%). The number employees with more than 12 stress factors in different categories of loco pilots were 30 (32%) in the goods category, 12 (12%) in the mail/passenger category, and 7 (19%) in the shunter category, and 3 (11%) in the supervisory category and 4 (7%) in the on-board category of section controllers. The prevalence of hypertension in loco pilots was 36.52% (84) and in the section controllers was 53.66% (44). The prevalence of hypertension in the category with more than 12 stress factors was 30.61% (15) in the loco pilots and 28.57% (2) in the section controllers. The prevalence of hypertension in the both the study groups were higher in the older age, with a family history of hypertension, and with a body mass index of more than 25 kg/m2. The mean occupational stress and employees with more than 12 stress factors were higher in the loco pilots group. The goods category of loco pilots had highest stress factors. The prevalence of hypertension was high in the category with risk factors such as older age, family history of hypertension and BMI above 25 kg/m2. PMID- 29391745 TI - Assessment of Effectiveness of Cool Coat in Reducing Heat Strain among Workers in Steel Industry. AB - A research study was conducted to assess the effectiveness of cool coat in reducing heat strain among workers exposed to heat in a steel plant located in south India. The study consists of assessing heat strain of workers exposed to heat in a steel plant by measuring physiological reactions of workers such as pulse rate and core body temperature with and without cool coat. The coal coat taken for this study was procured from M/s Yamuna Industries, Noida. Out of 140 employees exposed to heat hazard, 101 employees were examined in this study. Study was done in important production units in steel plant having heat hazard. Workers were interviewed and examined and information regarding thermal comfort was collected. First, the heat strain was assessed when the workers were not using cool coats. The air temperature was measured at all hot zone workplaces and found in the range of 34 0 C to 39.4 0 C (Mean: 36.54 0 C & S.D: 1.54). Physiological response such as core body temperature, pulse rate and blood pressure of workers exposed to heat hazard were measured before & after work to know the heat strain sustained by workers when they were working. Maximum core body temperature after work was found to be 39.3 0 C (Mean; 38.52 & S.D; 0.7). Maximum pulse rate of workers after work was found to be 120 beats/minute (Mean; 94.96 beats/minute, S.D: 13.11). The study indicate core body temperature of workers was found more than the permissible exposure limit prescribed by ACGIH, indicating the heat strain sustained by workers is significant, whereas the pulse rate and blood pressure was found normal & not exceeded the limits. Second, with cool coat, the heat strain was assessed among 10 workers selected from the 101 employees. Core body temperature was measured before and soon after work, The core body temperature recorded soon after work was in the range of 35.5 - 37.20C (Mean 36.36, SD= 0.52), indicating a drop in the core body temperature. In this study, a core body temperature rise in the range of 1 0 -1.4 0 C was noticed when the employees were not wearing cool coats. Whereas, with the usage of cool coat a rise in core body temperature was not found and in many coat wearing workers a drop in core body temperature (0.2 to 0.9 0 C) was noticed. Employees revealed that the cool coats was comfortable to use and provided the thermal comforts. The study concluded that the cool coat taken for this study was found effective in reducing the heat strain. PMID- 29391746 TI - Factors Influencing Employment and Employability for Persons with Disability: Insights from a City in South India. AB - Background: There is a lack of evidence on barriers faced by persons with disability in accessing employment opportunities in India. Aim: This study was undertaken to ascertain both employee and employer perceptions on barriers existing among Information Technology (IT) and IT-enabled sectors to employ persons with disabilities. Materials and Methods: Two hundred participants from six IT/IT-enabled sector organizations were included in the study; study was conducted at Hyderabad, India. A semi-structured questionnaire was administered to the participants. Results: Physical access to and within the worksite was highlighted as a concern by 95% of respondents. Majority perceived that communication, attitude of people, discrimination, harassment at work place, and information were critical barriers. Only 3.8% of employers were aware that their company had a written policy on employing persons with disabilities. Employers stated that commitment and perseverance were important facilitators among persons with disabilities. Conclusions: Evidence from this study will help in planning need-based employment for persons with disabilities. PMID- 29391747 TI - Biomimicry in mending the broken heart; Will hypoxia and pulsatile flow play Cupids? PMID- 29391748 TI - Comparing the in vivo and in vitro effects of hypoxia (3% O2) on directly derived cells from murine cardiac explants versus murine cardiosphere derived cells. AB - Coronary heart disease (CHD) is still one of the main causes of death in the world, despite significant advances in clinical treatments. Stem cell transplantation methods have the potential to improve cardiac function and patients' outcome following heart attack, but optimal cell types, cell preparation methods and cell delivery routes are yet to be developed. Mammalian hearts contain a small fraction of progenitor cells which, in culture, migrate out of the cardiac explants, known as explant-derived cell (EDCs) and contribute to spheroids known as cardiospheres (Csphs). Following further culture and cell passaging, Csphs give rise to cardiosphere-derived cells (CDCs). EDCs, Csphs and CDCs show in vitro and in vivo angiogenesis and tissue regeneration in myocardial ischemia. However, CDC and Csph formation is time consuming, expensive and not always successful. Therefore, this study aims to compare EDCs with CDCs and assess the effect of hypoxic preconditioning on their pro-angiogenic potential. The data showed that preconditioning EDCs in hypoxic cell culture enhances cell growth, viability and expression of stem cell and pro-angiogenic markers more than CDCs. In vivo experiments using a sub-dermal matrigel plug assay showed that EDCs and CDCs alone have limited pro-angiogenic potential; however, hypoxic preconditioning of EDCs and CDCs significantly enhances this process. Further research will increase our understanding of cardiac stem cell mediated angiogenesis and improve clinical therapies for myocardial infarction (MI) patients. PMID- 29391749 TI - Cathepsin K Localizes to Equine Bone In Vivo and Inhibits Bone Marrow Stem and Progenitor Cells Differentiation In Vitro. AB - Selective inhibition of Cathepsin K (CatK) has a promising therapeutic potential for diseases associated with bone loss and osseous inflammation, such as osteoarthritis, periodontitis, and osteoporosis. In horses, stress-related bone injuries are common and accompanied by bone pain and inflammation resulting in excessive bone resorption and periostitis. VEL-0230 is a highly selective inhibitor of CatK that significantly decreased bone resorption and increased bone formation biomarkers. The goal of this study was to demonstrate the presence of CatK in equine bone and a simultaneous influence on the bone marrow cellular components including function and differentiation. Our objectives were: 1) to investigate the tissue localization of CatK protein in equine bone using immunohistochemistry, and 2) to determine the effect of CatK inhibition on osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine stem and progenitor cells in vitro using histochemical staining and differentiation-related gene expression analyses. Bone biopsies, harvested from the tuber coxae and proximal phalanx of six healthy horses, were processed for immunostaining against CatK. Sternal bone marrow aspirates were cultured in 0, 1, 10, or 100 MUM of VEL-0230 and subsequent staining scoring and gene expression analyses performed. All cells morphologically characterized as osteoclasts and moderate number of active bone lining osteoblasts stained positive for CatK. Histochemical staining and gene expression analyses revealed a significant increase in the osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine bone marrow cells, which was VEL-0230-concentration dependent for the latter two. These results suggested that CatK inhibition may have anabolic effects on bone and cartilage regeneration that may be explained as a feedback response to CatK depletion. In conclusion, the use of CatK inhibition to reduce inflammation and associated bone resorption in equine osseous disorders may offer advantages to other therapeutics that would require further study. PMID- 29391750 TI - Neural stem/progenitor cells maintained in vitro under different culture conditions alter differentiation capacity of monocytes to generate dendritic cells. AB - Cell therapy of the nervous system disorders using neural stem/progenitor cells (NSPCs) proved its efficacy in preclinical and pilot clinical studies. The mechanisms of the beneficial effects of NSPCs transplantation include replacement of damaged cells, paracrine activation of the regeneration, and immunomodulation. Detailed assessment of NSPCs-induced immunomodulation can contribute to better control of autoimmune reactions and inflammation in patients with neurodegenerative diseases. Interactions of NSPCs with dendritic cells (DCs), the key players in the induction of the immune system response to antigens are of particular interest. Here, we demonstrate that co-culturing of monocytes with NSPCs obtained and grown utilizing serum-containing medium instead of growth factor-containing serum-free medium, results in total suppression of monocyte differentiation into DCs. The effect is similar to the action of mesenchymal stem cells (MSCs). No significant effect on DCs maturation was observed. Cultures of NSPCs set up and maintained in serum-free medium have no influence on monocyte differentiation and DCs maturation. Therefore, the effects of NSPCs upon DC differentiation from monocytes strongly depend on culture conditions, whereas the molecular marker expression patterns are similar in both types of NSPCs cultures. In broader prospective, it means that cells with almost identical phenotypes can display opposite immunological properties depending upon culture conditions. It should be taken into account when developing NSPCs-based cell products for regenerative medicine. PMID- 29391751 TI - Increased motility of mesenchymal stem cells is correlated with inhibition of stimulated peripheral blood mononuclear cells in vitro. AB - Immunomodulatory properties of mesenchymal stem cells (MSC) are key components of their successful applications in clinical setting. However, treatments based on MSC immunomodulation need understanding of cell characteristics before cell transplantation. We used live-imaging to test the suitability of the MSC motility as a parameter for quick prediction of the immunomodulatory potential of human MSC in regulating the activity of stimulated peripheral blood mononuclear cells (PBMC) in vitro. Bone marrow MSC, from various donors and in vitro passages, were cultured with or without stimulated PBMC. After seven days, immunomodulation was assessed by measuring PBMC proliferation, IgG production and cytokine secretion in MSC and PBMC monocultures and co-cultures, and results were correlated to MSC motility. In co-culture, we observed that MSC successfully inhibited PBMC activity, reducing PBMC proliferation and IgG production compared to PBMC monoculture. MSC modulated PBMC to reduce the secretion of TNFalpha and IL-10, increase IL-6, G-CSF and MCP-1, while GM-CSF was not affected. By live-imaging tracking of cell trajectories, we observed that fast moving MSC were inhibiting more efficiently stimulated PBMC compared to slow ones. In co-culture, fast MSC were more effective in inhibiting IgG production (~30% less IgG), and secreted higher levels of IL-10 (~10% increase) and GM-CSF (~20% increase) compared to slower cells. Furthermore, fast MSC in monocultures produced 2.3-fold more IL-6, 1.5-fold MCP-1 and 1.2-fold G-CSF in comparison to slower cells. In conclusion, live-imaging cell tracking allowed us to develop an indicative assay of the immune-regulatory potential of MSC prior to in vivo administration. Key Words: Human mesenchymal stem cells, Immunomodulatory potential, In vitro cell motility, Stem cell transplantation. PMID- 29391752 TI - StemRegenin 1 selectively promotes expansion of Multipotent Hematopoietic Progenitors derived from Human Embryonic Stem Cells. AB - Human embryonic stem cell (hESC)-derived hematopoietic stem/progenitor cells hold tremendous potential as alternative cell sources for the treatment of various hematological diseases, drug discovery and toxicological screening. However, limited number of hematopoietic stem/progenitor cells generated from the differentiation of hESCs hinders their downstream applications. Here, we show that aryl hydrocarbon receptor antagonist StemRegenin 1 (SR1) selectively promotes expansion of hESC-derived lin-CD34+ hematopoietic progenitors in a concentration-dependent manner. The colony-forming cell (CFC) activity was found to be enriched in the CD34+ cells that were expanded with SR1; however, these cells have less colony-forming activity as compared to unexpanded cells (1,338 vs. 7 of CD34+ cells to form 1 colony, respectively). Interestingly, SR1 showed a bipotential effect on the proliferation of CD34 negative population, that is low dose of SR1 (1 uM) enhanced cell proliferation, whereas it was repressed at higher doses (>5 uM). In summary, our results suggest that SR1 has the potential to facilitate expansion of hESC-derived lin-CD34+ hematopoietic progenitors, which further retain the potential to form multilineage hematopoietic colonies. PMID- 29391753 TI - Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee- Letter to the Editor & Author Response. PMID- 29391754 TI - Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates. AB - Since the advent of direct acting antiviral (DAA) agents, chronic hepatitis C virus (HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant (LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response (SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period. PMID- 29391755 TI - circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling. AB - AIM: To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that underlies hepatocellular steatosis. METHODS: The effect of circRNA on miR-34a was recognized by the miRNA response element (MRE), and validated by the dual luciferase reporter assay. Its association with hepatocellular steatosis was investigated in HepG2-based hepatocellular steatosis induced by free fatty acids (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis related circRNA by expression vector, analysis of miR-34a activity, peroxisome proliferator-activated receptor (PPAR)alpha level, and expression of downstream genes were carried out so as to reveal its impact on the miR-34a/PPARalpha regulatory system. Both triglyceride (TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34a-dependent hepatosteatogenesis. RESULTS: Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of miR-34a via MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circRNA_0046366 up-regulation abolished the miR-34a dependent inhibition of PPARalpha that played a critical role in metabolic signaling pathways. PPARalpha restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TG-specific lipolytic genes [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A (SLC27A)] among these showed significant increase in their expression levels. The circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular steatosis. CONCLUSION: Dysregulation of circRNA_0046366/miR 34a/PPARalpha signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target for the treatment of hepatic steatosis. PMID- 29391756 TI - Effect of Lactobacillus rhamnosus GG supernatant on serotonin transporter expression in rats with post-infectious irritable bowel syndrome. AB - AIM: To evaluate the effect of Lactobacillus rhamnosus GG supernatant (LGG-s) on the expression of serotonin transporter (SERT) in rats with post-infectious irritable bowel syndrome (PI-IBS). METHODS: Campylobacter jejuni 81-176 (1010 CFU/mL) was used to induce intestinal infection to develop a PI-IBS model. After evaluation of the post-infectious phase by biochemical tests, DNA agarose gel electrophoresis, abdominal withdrawal reflex (AWR) test, and the intestinal motility test, four PI-IBS groups received different concentrations of LGG-s for 4 wk. The treatments were maintained for 1.0, 2.0, 3.0 or 4.0 wk during the experiment, and the colons and brains were removed for later use each week. SERT mRNA and protein levels were detected by real-time PCR and Western blot, respectively. RESULTS: The levels of SERT mRNA and protein in intestinal tissue were higher in rats treated with LGG-s than in control rats and PI-IBS rats gavaged with PBS during the whole study. Undiluted LGG-s up-regulated SERT mRNA level by 2.67 times compared with the control group by week 2, and SERT mRNA expression kept increasing later. Double-diluted LGG-s was similar to undiluted LGG-s, resulting in high levels of SERT mRNA. Triple-diluted LGG-s up-regulated SERT mRNA expression level by 6.9-times compared with the control group, but SERT mRNA expression decreased rapidly at the end of the second week. At the first week, SERT protein levels were basically comparable in rats treated with undiluted LGG-s, double-diluted LGG-s, and triple-diluted LGG-s, which were higher than those in the control group and PBS-treated PI-IBS group. SERT protein levels in the intestine were also comparable in rats treated with undiluted LGG s, double-diluted LGG-s, and triple-diluted LGG-s by the second and third weeks. SERT mRNA and protein levels in the brain had no statistical difference in the groups during the experiment. CONCLUSION: LGG-s can up-regulate SERT mRNA and protein levels in intestinal tissue but has no influence in brain tissue in rats with PI-IBS. PMID- 29391757 TI - Epidermal growth factor receptor-targeted immune magnetic liposomes capture circulating colorectal tumor cells efficiently. AB - AIM: To compare the capacity of newly developed epidermal growth factor receptor (EGFR)-targeted immune magnetic liposomes (EILs) vs epithelial cell adhesion molecule (EpCAM) immunomagnetic beads to capture colorectal circulating tumor cells (CTCs). METHODS: EILs were prepared using a two-step method, and the magnetic and surface characteristics were confirmed. The efficiency of capturing colorectal CTCs as well as the specificity were compared between EILs and EpCAM magnetic beads. RESULTS: The obtained EILs had a lipid nanoparticle structure similar to cell membrane. Improved binding with cancer cells was seen in EILs compared with the method of coupling nano/microspheres with antibody. The binding increased as the contact time extended. Compared with EpCAM immunomagnetic beads, EILs captured more CTCs in peripheral blood from colorectal cancer patients. The captured cells showed consistency with clinical diagnosis and pathology. Mutation analysis showed same results between captured CTCs and cancer tissues. CONCLUSION: EGFR antibody-coated magnetic liposomes show high efficiency and specificity in capturing colorectal CTCs. PMID- 29391758 TI - Hypoxia preconditioning protects Ca2+-ATPase activation of intestinal mucosal cells against R/I injury in a rat liver transplantation model. AB - AIM: To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1alpha to protect rat intestinal tissue against I/R injury. METHODS: Rats received non-lethal hypoxic preconditioning therapy to induce HIF 1alpha expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively. RESULTS: HIF-1alpha expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-alpha was significantly lower in the HP group than in the AT group. CONCLUSION: Hypoxia-induced HIF-1alpha could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure. PMID- 29391759 TI - Multi-parameter gene expression profiling of peripheral blood for early detection of hepatocellular carcinoma. AB - AIM: In our previous study, we have built a nine-gene (GPC3, HGF, ANXA1, FOS, SPAG9, HSPA1B, CXCR4, PFN1, and CALR) expression detection system based on the GeXP system. Based on peripheral blood and GeXP, we aimed to analyze the results of genes expression by different multi-parameter analysis methods and build a diagnostic model to classify hepatocellular carcinoma (HCC) patients and healthy people. METHODS: Logistic regression analysis, discriminant analysis, classification tree analysis, and artificial neural network were used for the multi-parameter gene expression analysis method. One hundred and three patients with early HCC and 54 age-matched healthy normal controls were used to build a diagnostic model. Fifty-two patients with early HCC and 34 healthy people were used for validation. The area under the curve, sensitivity, and specificity were used as diagnostic indicators. RESULTS: Artificial neural network of the total nine genes had the best diagnostic value, and the AUC, sensitivity, and specificity were 0.943, 98%, and 85%, respectively. At last, 52 HCC patients and 34 healthy normal controls were used for validation. The sensitivity and specificity were 96% and 86%, respectively. CONCLUSION: Multi-parameter analysis methods may increase the diagnostic value compared to single factor analysis and they may be a trend of the clinical diagnosis in the future. PMID- 29391760 TI - Clinical advantages of single port laparoscopic hepatectomy. AB - AIM: To evaluate the clinical advantages of single-port laparoscopic hepatectomy (SPLH) compare to multi-port laparoscopic hepatectomy (MPLH). METHODS: We retrospectively reviewed the medical records of 246 patients who underwent laparoscopic liver resection between January 2008 and December 2015 at our hospital. We divided the surgical technique into two groups; SPLH and MPLH. We performed laparoscopic liver resection for both benign and malignant disease. Major hepatectomy such as right and left hepatectomy was also done with sufficient disease-free margin. The operative time, the volume of blood loss, transfusion rate, and the conversion rate to MPLH or open surgery was evaluated. The post-operative parameters included the meal start date after operation, the number of postoperative days spent in the hospital, and surgical complications was also evaluated. RESULTS: Of the 246 patients, 155 patients underwent SPLH and 91 patients underwent MPLH. Conversion rate was 22.6% in SPLH and 19.8% in MPLH (P = 0.358). We performed major hepatectomy, which was defined as resection of more than 2 sections, in 13.5% of patients in the SPLH group and in 13.3% of patients in the MPLH group (P = 0.962). Mean operative time was 136.9 +/- 89.2 min in the SPLH group and 231.2 +/- 149.7 min in the MPLH group (P < 0.001). The amount of blood loss was 385.1 +/- 409.3 mL in the SPLH group and 559.9 +/- 624.9 mL in the MPLH group (P = 0.016). The safety resection margin did not show a significant difference (0.84 +/- 0.84 cm in SPLH vs 1.04 +/- 1.22 cm in MPLH, P = 0.704). Enteral feeding was started earlier in the SPLH group (1.06 +/- 0.27 d after operation) than in the MPLH group (1.63 +/- 1.27 d) (P < 0.001). The mean hospital stay after operation was non-significantly shorter in the SPLH group than in the MPLH group (7.82 +/- 2.79 d vs 7.97 +/- 3.69 d, P = 0.744). The complication rate was not significantly different (P = 0.397) and there was no major perioperative complication or mortality case in both groups. CONCLUSION: Single-port laparoscopic liver surgery seems to be a feasible approach for various kinds of liver diseases. PMID- 29391761 TI - Autoimmune liver disease-related autoantibodies in patients with biliary atresia. AB - AIM: To investigate the prevalence and clinical significance of autoimmune liver disease (ALD)-related autoantibodies in patients with biliary atresia (BA). METHODS: Sera of 124 BA patients and 140 age-matched non-BA controls were assayed for detection of the following autoantibodies: ALD profile and specific anti nuclear antibodies (ANAs), by line-blot assay; ANA and anti-neutrophil cytoplasmic antibody (ANCA), by indirect immunofluorescence assay; specific ANCAs and anti-M2-3E, by enzyme linked immunosorbent assay. Associations of these autoantibodies with the clinical features of BA (i.e., cytomegalovirus infection, degree of liver fibrosis, and short-term prognosis of Kasai procedure) were evaluated by Spearman's correlation coefficient. RESULTS: The overall positive rate of serum autoantibodies in preoperative BA patients was 56.5%. ALD profile assay showed that the positive reaction to primary biliary cholangitis-related autoantibodies in BA patients was higher than that to autoimmune hepatitis related autoantibodies. Among these autoantibodies, anti-BPO was detected more frequently in the BA patients than in the controls (14.8% vs 2.2%, P < 0.05). Accordingly, 32 (25.8%) of the 124 BA patients also showed a high positive reaction for anti-M2-3E. By comparison, the controls had a remarkably lower frequency of anti-M2-3E (P < 0.05), with 6/92 (8.6%) of patients with other liver diseases and 2/48 (4.2%) of healthy controls. The prevalence of ANA in BA patients was 11.3%, which was higher than that in disease controls (3.3%, P < 0.05), but the reactivity to specific ANAs was only 8.2%. The prevalence of ANCAs (ANCA or specific ANCAs) in BA patients was also remarkably higher than that in the healthy controls (37.9% vs 6.3%, P < 0.05), but showed no difference from that in patients with other cholestasis. ANCA positivity was closely associated with the occurrence of postoperative cholangitis (r = 0.61, P < 0.05), whereas none of the autoantibodies showed a correlation to cytomegalovirus infection or the stages of liver fibrosis. CONCLUSION: High prevalence of autoantibodies in the BA developmental process strongly reveals the autoimmune-mediated pathogenesis. Serological ANCA positivity may be a useful predictive biomarker of postoperative cholangitis. PMID- 29391762 TI - Helicobacter pylori and corpus gastric pathology are associated with lower serum ghrelin. AB - AIM: To evaluate the association of Helicobacter pylori (H. pylori), cagA genotype, and type of gastric pathology with ghrelin, leptin and nutritional status. METHODS: Fasted dyspeptic adults (18-70 years) referred for an upper digestive endoscopy were enrolled in this cross-sectional study. Height and weight were assessed for body mass index (BMI) calculation. A sociodemographic survey was administered and nutrient intake was evaluated with 24 h dietary recalls. Serum total ghrelin and leptin levels were analyzed by enzyme-linked immunosorbent assay. 13C-Urea Breath Test was performed and four gastric biopsies were obtained during endoscopy for histopathology and H. pylori DNA amplification and genotyping. Data analysis was performed using chi2, Mann-Whitney U, Kruskal Wallis tests, Spearman's correlation and linear regression. RESULTS: One hundred and sixty-three patients (40.8 +/- 14.0 years), 98/65 females/males, were included. Overall, persistent H. pylori prevalence was 53.4% (95%CI: 45.7% 65.8%). Neither nutrient intake nor BMI differed significantly between H. pylori positive and negative groups. Serum ghrelin was significantly lower in infected patients [median 311.0 pg/mL (IQR 230.0-385.5)] than in uninfected ones [median 355.0 pg/mL (IQR 253.8-547.8)] (P = 0.025), even after adjusting for BMI and gender (P = 0.03). Ghrelin levels tended to be lower in patients carrying cagA positive strains both in the antrum and the corpus; however, differences with those carrying cagA negative strains did not reach statistical significance (P = 0.50 and P = 0.49, respectively). In addition, the type and severity of gastric pathology in the corpus was associated with lower serum ghrelin (P = 0.04), independently of H. pylori status. Conversely, leptin levels did not differ significantly between infected and uninfected patients [median 1.84 ng/mL (0.80 4.85) vs 1.84 ng/mL (0.50-5.09), (P = 0.51)]. CONCLUSION: H. pylori infection and severity of gastric corpus pathology are associated with lower serum ghrelin. Further studies could confirm a lower ghrelin prevalence in cagA-positive patients. PMID- 29391763 TI - Metal stents placement for refractory pancreatic duct stricture in children. AB - AIM: To evaluate the use of fully covered self-expandable metal stents (FCSEMSs) for pancreatic duct strictures in children with chronic pancreatitis. METHODS: Eight patients with refractory benign dominant stricture of the main pancreatic duct (MPD) were enrolled through chart reviews between December 2014 and June 2017 in a single center. Endoscopic retrograde cholangiopancreatography (ERCP) with placement of a 6-mm FCSEMS with dual flaps was performed. Endoscopic removal of FCSEMSs was performed with a snare or rat-tooth forceps. All procedures were performed by a pediatric gastroenterologist. For the assessment of outcomes, technical and clinical success, adverse events, and stent patency were evaluated retrospectively. RESULTS: The placement and removal of the FCSEMSs were successful in all 8 patients. Five patients were boys and 3 were girls. The median age at initial FCSEMS placement was 12 years (range, 5-18 years). The diameters of all the inserted stents were 6 mm, and the lengths were 4-7 cm. The median indwelling time was 6 mo (range, 3-10 mo). No pancreatic sepsis, pancreatitis, cholestasis, or mortality occurred. There was no proximal and distal migration. All subjects showed a patent stent. On follow-up ERCP, the mean diameter of the stricture improved from 1.1 mm to 2.8 mm (P < 0.05), whereas that of upstream dilation improved from 8.4 mm to 6.3 mm (P < 0.05). CONCLUSION: This initial experience showed that temporary FCSEMS placement is feasible and safe for the management of refractory benign MPD stricture in children. PMID- 29391764 TI - Optimization of hepatobiliary phase delay time of Gd-EOB-DTPA-enhanced magnetic resonance imaging for identification of hepatocellular carcinoma in patients with cirrhosis of different degrees of severity. AB - AIM: To optimize the hepatobiliary phase delay time (HBP-DT) of Gd-EOB-DTPA enhanced magnetic resonance imaging (GED-MRI) for more efficient identification of hepatocellular carcinoma (HCC) occurring in different degrees of cirrhosis assessed by Child-Pugh (CP) score. METHODS: The liver parenchyma signal intensity (LPSI), the liver parenchyma (LP)/HCC signal ratios, and the visibility of HCC at HBP-DT of 5, 10, 15, 20, and 25 min (i.e., DT-5, DT-10, DT-15, DT-20, and DT-25 ) after injection of Gd-EOB-DTPA were collected and analyzed in 73 patients with cirrhosis of different degrees of severity (including 42 patients suffering from HCC) and 18 healthy adult controls. RESULTS: The LPSI increased with HBP-DT more significantly in the healthy group than in the cirrhosis group (F = 17.361, P < 0.001). The LP/HCC signal ratios had a significant difference (F = 12.453, P < 0.001) among various HBP-DT points, as well as between CP-A and CP-B/C subgroups (F = 9.761, P < 0.001). The constituent ratios of HCC foci identified as obvious hypointensity (+++), moderate hypointensity (++), and mild hypointensity or isointensity (+/-) kept stable from DT-10 to DT-25: 90.6%, 9.4%, and 0.0% in the CP-A subgroup; 50.0%, 50.0%, and 0.0% in the CP-B subgroup; and 0.0%, 0.0%, and 100.0% in the CP-C subgroup, respectively. CONCLUSION: The severity of liver cirrhosis has significant negative influence on the HCC visualization by GED-MRI. DT-10 is more efficient and practical than other HBP-DT points to identify most of HCC foci emerging in CP-A cirrhosis, as well as in CP-B cirrhosis; but an HBP DT of 15 min or longer seems more appropriate than DT-10 for visualization of HCC in patients with CP-C cirrhosis. PMID- 29391765 TI - Epidemiology of inflammatory bowel disease in racial and ethnic migrant groups. AB - AIM: To summarise the current literature and define patterns of disease in migrant and racial groups. METHODS: A structured key word search in Ovid Medline and EMBASE was undertaken in accordance with PRISMA guidelines. Studies on incidence, prevalence and disease phenotype of migrants and races compared with indigenous groups were eligible for inclusion. RESULTS: Thirty-three studies met the inclusion criteria. Individual studies showed significant differences in incidence, prevalence and disease phenotype between migrants or race and indigenous groups. Pooled analysis could only be undertaken for incidence studies on South Asians where there was significant heterogeneity between the studies [95% for ulcerative colitis (UC), 83% for Crohn's disease (CD)]. The difference between incidence rates was not significant with a rate ratio South Asian: Caucasian of 0.78 (95%CI: 0.22-2.78) for CD and 1.39 (95%CI: 0.84-2.32) for UC. South Asians showed consistently higher incidence and more extensive UC than the indigenous population in five countries. A similar pattern was observed for Hispanics in the United States. Bangladeshis and African Americans showed an increased risk of CD with perianal disease. CONCLUSION: This review suggests that migration and race influence the risk of developing inflammatory bowel disease. This may be due to different inherent responses upon exposure to an environmental trigger in the adopted country. Further prospective studies on homogenous migrant populations are needed to validate these observations, with a parallel arm for in depth investigation of putative drivers. PMID- 29391766 TI - Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up. AB - Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5 inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis. PMID- 29391768 TI - Robust optimization model for uncertain multiobjective linear programs. AB - In this paper, we consider the multiobjective linear programs where coefficients in the objective function belong to uncertainty sets. We introduce the concept of robust efficient solutions to uncertain multiobjective linear programming problems. By using two scalarization methods, the weighted sum method and the epsilon-constraint method, we obtain that the robust efficient solutions for uncertain multiobjective linear programs with ellipsoidal uncertainty sets and general norm uncertainty sets can be computed by some deterministic optimization problems. PMID- 29391767 TI - Frequency Diffeomorphisms for Efficient Image Registration. AB - This paper presents an efficient algorithm for large deformation diffeomorphic metric mapping (LDDMM) with geodesic shooting for image registration. We introduce a novel finite dimensional Fourier representation of diffeomorphic deformations based on the key fact that the high frequency components of a diffeomorphism remain stationary throughout the integration process when computing the deformation associated with smooth velocity fields. We show that manipulating high dimensional diffeomorphisms can be carried out entirely in the bandlimited space by integrating the nonstationary low frequency components of the displacement field. This insight substantially reduces the computational cost of the registration problem. Experimental results show that our method is significantly faster than the state-of-the-art diffeomorphic image registration methods while producing equally accurate alignment. We demonstrate our algorithm in two different applications of image registration: neuroimaging and in-utero imaging. PMID- 29391769 TI - Inferring Generative Model Structure with Static Analysis. AB - Obtaining enough labeled data to robustly train complex discriminative models is a major bottleneck in the machine learning pipeline. A popular solution is combining multiple sources of weak supervision using generative models. The structure of these models affects training label quality, but is difficult to learn without any ground truth labels. We instead rely on these weak supervision sources having some structure by virtue of being encoded programmatically. We present Coral, a paradigm that infers generative model structure by statically analyzing the code for these heuristics, thus reducing the data required to learn structure significantly. We prove that Coral's sample complexity scales quasilinearly with the number of heuristics and number of relations found, improving over the standard sample complexity, which is exponential in n for identifying nth degree relations. Experimentally, Coral matches or outperforms traditional structure learning approaches by up to 3.81 F1 points. Using Coral to model dependencies instead of assuming independence results in better performance than a fully supervised model by 3.07 accuracy points when heuristics are used to label radiology data without ground truth labels. PMID- 29391770 TI - Understanding and Optimizing Asynchronous Low-Precision Stochastic Gradient Descent. AB - Stochastic gradient descent (SGD) is one of the most popular numerical algorithms used in machine learning and other domains. Since this is likely to continue for the foreseeable future, it is important to study techniques that can make it run fast on parallel hardware. In this paper, we provide the first analysis of a technique called Buckwild! that uses both asynchronous execution and low precision computation. We introduce the DMGC model, the first conceptualization of the parameter space that exists when implementing low-precision SGD, and show that it provides a way to both classify these algorithms and model their performance. We leverage this insight to propose and analyze techniques to improve the speed of low-precision SGD. First, we propose software optimizations that can increase throughput on existing CPUs by up to 11*. Second, we propose architectural changes, including a new cache technique we call an obstinate cache, that increase throughput beyond the limits of current-generation hardware. We also implement and analyze low-precision SGD on the FPGA, which is a promising alternative to the CPU for future SGD systems. PMID- 29391771 TI - Does herpes zoster predispose to giant cell arteritis: a geo-epidemiologic study. AB - Purpose: Giant cell arteritis (GCA) is the most common systemic vasculitis in the elderly and can cause irreversible blindness and aortitis. Varicella zoster (VZ), which is potentially preventable by vaccination, has been proposed as a possible immune trigger for GCA, but this is controversial. The incidence of GCA varies widely by country. If VZ virus contributes to the immunopathogenesis of GCA we hypothesized that nations with increased incidence of GCA would also have increased incidence of herpes zoster (HZ). We conducted an ecologic analysis to determine the relationship between the incidence of HZ and GCA in different countries. Methods: A literature search for the incidence rates (IRs) of GCA and HZ from different countries was conducted. Correlation and linear regression was performed comparing the disease IR of each country for subjects 50 years of age or older. Results: We found the IR for GCA and HZ from 14 countries. Comparing the IRs for GCA and HZ in 50-year-olds, the Pearson product-moment correlation (r) was -0.51, with linear regression coefficient (beta) -2.92 (95% CI -5.41, 0.43; p=0.025) using robust standard errors. Comparing the IRs for GCA and HZ in 70-year-olds, r was -0.40, with beta -1.78, which was not statistically significant (95% CI -4.10, 0.53; p=0.12). Conclusion: Although this geo epidemiologic study has potential for aggregation and selection biases, there was no positive biologic gradient between the incidence of clinically evident HZ and GCA. PMID- 29391772 TI - Vernal keratoconjunctivitis. AB - Vernal keratoconjunctivitis (VKC) is a chronic allergic conjunctivitis that is most often seen in young, males. Although most types of allergic conjunctivitis do not affect vision, VKC is unusual in that damage to the cornea from the condition can result in vision loss. Although it is typically seasonal, year round symptoms can be seen, which can lead to uncertain diagnoses being made. Although the pathophysiology of VKC is better understood in recent years, allowing more targeted therapies, management of these patients can still be very challenging, and complications can occur. As such, aggressive management of VKC is necessary, especially since vision loss in the amblyogenic age range can be permanent. PMID- 29391774 TI - Subthreshold microsecond laser for proliferative diabetic retinopathy: a randomized pilot study. AB - Aim: To compare the outcomes of subthreshold microsecond (STM) and continuous wave laser (CWL) panretinal photocoagulation (PRP). Methods: In this randomized, prospective, pilot study, 20 eyes of 10 subjects with symmetric severe non proliferative (NPDR) or low-risk proliferative diabetic retinopathy (PDR) were included. Each eye of the subject was randomized into either CWL or STM PRP group. Patients were evaluated at baseline and at months 3, 6, and 9 with color fundus photographs and visual field tests at each visit; however, electroretinography (ERG) was conducted at baseline and at month 9. The primary outcome measure was the difference in disease progression between the groups. Secondary outcome measures included change in visual acuity, contrast visual acuity, retinal sensitivity on visual field test, and change in ERG parameters. Results: During the 9-month follow-up, one eye of the STM group progressed to vitreous hemorrhage at the month 6 follow-up and required rescue conventional laser. The CWL group showed a drop in low-contrast visual acuity, visual field index, and scotopic b/a ratio in comparison to the STM group, although the difference was statistically insignificant (p>0.05). Conclusion: This prospective pilot study proposes microsecond PRP is non-inferior to CWL PRP and could be an alternative to CWL PRP to avoid associated complications in cases of severe NPDR and early PDR. PMID- 29391773 TI - Dry eye syndrome: developments and lifitegrast in perspective. AB - Dry eye (DE) is a chronic ocular condition with high prevalence and morbidity. It has a complex pathophysiology and is multifactorial in nature. Chronic ocular surface inflammation has emerged as a key component of DE that is capable of perpetuating ocular surface damage and leading to symptoms of ocular pain, discomfort, and visual phenomena. It begins with stress to the ocular surface leading to the production of proinflammatory mediators that induce maturation of resident antigen-presenting cells which then migrate to the lymph nodes to activate CD4 T cells. The specific antigen(s) targeted by these pathogenic CD4+ T cells remains unknown. Two emerging theories include self-antigens by autoreactive CD4 T cells or harmless exogenous antigens in the setting of mucosal immunotolerance loss. These CD4 T cells migrate to the ocular surface causing additional inflammation and damage. Lifitegrast is the second topical anti inflammatory agent to be approved by the US Food and Drug Administration for the treatment of DE and the first to show improvement in DE symptoms. Lifitegrast works by blocking the interaction between intercellular adhesion molecule-1 and lymphocyte functional associated antigen-1, which has been shown to be critical for the migration of antigen-presenting cells to the lymph nodes as well as CD4+ T cell activation and migration to the ocular surface. In four large multicenter, randomized controlled trials, lifitegrast has proven to be effective in controlling both the signs and symptoms of DE with minimal side effects. Further research should include comparative and combination studies with other anti inflammatory therapies used for DE. PMID- 29391775 TI - Tuberculosis and viral hepatitis infection in Eastern Europe, Asia, and Latin America: impact of tumor necrosis factor-alpha inhibitors in clinical practice. AB - Tumor necrosis factor-alpha (TNF-alpha) inhibitors are increasingly becoming the standard of care for treating a number of inflammatory diseases. However, treatment with TNF-alpha inhibitors carries an inherent risk of compromising the immune system, resulting in an increased susceptibility to infections and malignancies. This increased risk of infection is of particular concern in Asia, Eastern Europe, and Latin America where tuberculosis (TB) and viral hepatitis are endemic. In this brief review, we examine the literature and review the impact of TNF-alpha inhibitors on the incidence and the reactivation of latent disease with respect to TB, hepatitis C infection, and hepatitis B infection. Our findings show that TNF-alpha inhibitors are generally safe, if used with caution. Patients should be screened prior to the initiation of TNF-alpha inhibitor treatment and given prophylactic treatment if needed. In addition, patients should be monitored during treatment with TNF-alpha inhibitors and after treatment has stopped to ensure that infections, if detected, are treated promptly and effectively. Our analysis is consistent with other reports and guidelines. PMID- 29391776 TI - Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis. AB - Background and objective: Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner's formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma. We aimed to quantify the usefulness and side effects of theophylline with or without ethylene diamine (aminophylline) in acute asthma, with particular emphasis on patient subgroups, such as children, adults, and concomitant medications. Methods: We searched PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, and the WHO Clinical Trials Registry for randomized, controlled clinical trials. We planned a priori subgroup analyses by time post medication, concomitant medication, control type, and age. Results: We included 52 study arms from 42 individual trials. Of these, 29 study arms included an active control, such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, and 23 study arms compared theophylline (with or without ethylene diamine) with placebo or no drug. Theophylline significantly reduced heart rate when compared with active control (p=0.01) and overall duration of stay (p=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) (p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. Closer examination of the data revealed that the medications given in addition to theophylline or control significantly changed the effectiveness of theophylline (subgroup difference: p<0.00001). Conclusion: Given the low cost of theophylline, and its similar efficacy and rate of side effects compared with other drugs, we suggest that theophylline, when given with bronchodilators with or without steroids, is a cost effective and safe choice for acute asthma exacerbations. PMID- 29391778 TI - Ipriflavone promotes proliferation and osteogenic differentiation of periodontal ligament cells by activating GPR30/PI3K/AKT signaling pathway. AB - Objectives: This study was performed to investigate the effects and mechanism of ipriflavone (IP) on the proliferation and osteoblastic differentiation of periodontal ligament cells in vitro and periodontal tissue remodeling following orthodontic tooth movement (OTM) in vivo. Materials and methods: Human periodontal ligament cells (hPDLCs) were cultured in vitro and cell counting kit 8, alkaline phosphatase (ALP) activity assay, plate clone formation assay, and alizarin red staining were used to test proliferation and osteogenic differentiation of hPDLCs. What is more, the expression of ALP, Runx2, and GPR30 was examined by real-time polymerase chain reaction and Western blot. To find out if PI3K/AKT signaling pathway was involved in the process, AKT and p-AKT were examined by Western blot. LY294002 (PI3K signaling pathway inhibitor) and small interfering RNA targeting GPR30 mRNA (siGPR30) were used to verify the function of GPR30-mediated PI3K/AKT pathway in this process. Twenty-four male Wistar rats were randomized into 2 groups, the control group with force application and the IP group with force application plus IP. Morphological changes in the periodontal tissue between roots of teeth were investigated using hematoxylin and eosin (HE) staining and bone morphogenetic protein-2 was detected to assess bone remodeling by immunohistochemical staining. Results: In vitro, 10-7 M IP was selected significantly promoting proliferation, ALP activity, colony forming efficiency, and mineral deposition (P<0.05) on hPDLCs. Gene expressions of ALP, Runx2, GPR30, and p-AKT were all upregulated than the control group (P<0.05). According to the mechanism, promotion of ALP and Runx2 interdicted by LY294002 and siGPR30 reduced the activation of PI3K/AKT signaling pathway. In addition, HE staining and immunohistochemical staining results showed that the IP group had more new bone formation in the periodontal tissue compared to the control group in vivo. Conclusion: IP can promote the expression of ALP and Runx2 which was probably related to the GPR30-mediated PI3K/AKT signaling pathway. Moreover, IP coordination seemed to have the potential to prevent relapsing following OTM. PMID- 29391777 TI - Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism. AB - Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound-multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs. PMID- 29391779 TI - Biological activity, quantitative structure-activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs. AB - Background: Xanthone derivatives have a wide range of pharmacological activities, such as those involving antibacterial, antiviral, antimalarial, anthelmintic, anti-inflammatory, antiprotozoal, and anticancer properties. Among these, we investigated the anticancer properties of xanthone. This research aimed to analyze the biological activity of ten novel xanthone derivatives, to investigate the most contributing-descriptors for their cytotoxic activities, and to examine the possible mechanism of actions of xanthone compound through molecular docking. Materials and methods: The cytotoxic tests were carried out on WiDR and Vero cell lines, by a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay method. The structural features required for xanthone's anticancer activity were conducted by using the semi-empirical Austin Model-1 method, and continued with quantitative structure-activity relationship (QSAR) analysis using BuildQSAR program. The study of the possible mechanism of actions of the selected xanthone compound was done through molecular docking with PLANTS. Results: The three novel xanthone derivatives (compounds 5, 7, and 8) exhibited cytotoxic activity with compound 5 showed the highest degree of cytotoxicity at concentration 9.23 ug/mL (37.8 uM). The following best equation model was obtained from the BuildQSAR calculation: log 1/IC50 = -8.124 qC1 -35.088 qC2 -6.008 qC3 + 1.831 u + 0.540 logP -9.115 (n = 10, r = 0.976, s = 0.144, F = 15.920, Q2 = 0.651, SPRESS = 0.390). This equation model generated 15 proposed new xanthone compounds with better-predicted anticancer activities. A molecular docking study of compound 5 showed that xanthone formed binding interactions with some receptors involved in cancer pathology, including telomerase, tumor-promoting inflammation (COX-2), and cyclin-dependent kinase-2 (CDK2) inhibitor. Conclusion: The results suggested that compound 5 showed the best cytotoxic activity among the xanthone derivatives tested. QSAR analysis showed that the descriptors contributed to xanthone's cytotoxic activity were the net atomic charge at qC1, qC2, and qC3 positions, also dipole moment and logP. Compound 5 was suspected to be cytotoxic by its inhibition of telomerase, COX-2, and CDK2 receptors. PMID- 29391780 TI - Diminishing the side effect of mitomycin C by using pH-sensitive liposomes: in vitro characterization and in vivo pharmacokinetics. AB - Introduction: Mitomycin C is an anticancer antibiotic agent that has the potential for broad-spectrum use against several cancers, including mammary cancers. Because its half-life is 17 min after a 30 mg intravenous bolus administration, the suitability of mitomycin C for wide use in the clinical setting is limited. Based on tumor pathophysiology, pH-sensitive liposomes could provide better tumor-targeted effects. The aim of this study was to investigate the possibility of diminishing the side effect of mitomycin C by using pH sensitive liposomes. Materials and methods: pH-sensitive liposomes was employed to deliver mitomycin C and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay. Results: The results demonstrated that mitomycin C-loaded pH-sensitive liposomes had a particle diameter of 144.5+/-2.8 nm and an entrapment efficiency of 66.5%. The in vitro release study showed that the pH-sensitive liposome release percentages at pH 7.4 and pH 5.5 were approximately 47% and 93%, respectively. The cell viability of MCF-7 cells showed that both the solution and liposome group exhibited a concentration-dependent effect on cell viability. The MCF-7 cell uptake of pH-sensitive liposomes with a folate modification was higher which was indicated by an increased fluorescence intensity compared to that without a folate modification. The area under the concentration-time curve of mitomycin C loaded pH-sensitive liposomes (18.82+/-0.51 ug.h/L) was significantly higher than that of the mitomycin C solution group (10.07+/-0.31 ug.h/L). The mean residence times of the mitomycin C-loaded and mitomycin C solution groups were 1.53+/-0.16 and 0.05 h, respectively. In addition, there was no significant difference in terms of Vss (p>0.05). Moreover, the half-life of pH-sensitive liposomes and the mitomycin C solution was 1.35+/-0.15 and 1.60+/-0.04 h, respectively. In terms of safety, mitomycin C-loaded pH-sensitive liposomes did not affect the platelet count and the levels of blood urea nitrogen and aspartate aminotransferase. Conclusion: The positive results of pH-sensitive liposomes demonstrated maintained the cytotoxicity and decrease the side effect. PMID- 29391781 TI - A new pulmonary rehabilitation maintenance strategy through home-visiting and phone contact in COPD. AB - Background: The benefit of pulmonary rehabilitation (PR) for patients with COPD diminishes over time. We investigated a new strategy involving home-visit and phone contact and compared this to usual care in maintenance of PR benefits. Methods: A total of 172 stable COPD patients receiving 8-week PR program were recruited for this prospective study. Patients were allocated into usual care group (UC) and PR maintenance group (PRMG) randomly. Patients in PRMG participated in maintenance strategy at home under supervision through home-visit and phone contact. The 6-minute walking test (6MWT), COPD assessment test (CAT), and modified Medical Research Council scale (mMRC) scores were evaluated every 3 months. Results: Of the total, 151 patients completed 8-week PR program with satisfactory PR results (p<0.001), and 104 patients finished the follow-up. The clinical improvements in 6MWT, CAT, and mMRC scores were maintained (p<0.001) in PRMG. In comparison, the benefit of PR diminished gradually in UC. The differences in 6MWT, CAT, and mMRC scores between groups were observed 6, 9, and 6 months after PR, respectively (p<0.05). Total frequency of exacerbations in PRMG was lower than UC (p=0.021). Conclusion: Maintenance strategy involving home visit and phone contact is superior to usual care to preserve PR benefits, and reduces the acute COPD exacerbation rate. PMID- 29391782 TI - Comparison of claims vs patient-reported adherence measures and associated outcomes among patients with nonvalvular atrial fibrillation using oral anticoagulant therapy. AB - Objective: To compare oral anticoagulant (OAC) adherence among patients with nonvalvular atrial fibrillation (NVAF) using patient-reported and claims-based measures, and to evaluate the effect of OAC adherence on health care costs and patient satisfaction with OAC therapy. Methods: This was a hybrid US observational study consisting of a longitudinal cohort survey followed by linkage and analysis of respondents' administrative claims data. Patients with NVAF receiving warfarin, dabigatran, rivaroxaban, or apixaban completed an initial survey and follow-up surveys at 4, 8, and 12 months. Patient-reported adherence was measured at each survey by Morisky Medication Adherence Scale (MMAS 8) and pharmacy claims-determined adherence by the proportion of days covered (PDC) for the 12-month period following the initial survey date; adherence was defined as MMAS-8 score =8 and PDC >=80%. Patient satisfaction with OAC therapy was assessed by the Duke Anticoagulation Satisfaction Scale (DASS). Results: Overall, 675 patients completed at least the initial survey (warfarin, n=271; dabigatran, n=266; rivaroxaban, n=128; apixaban, n=10). Fewer than half (47.9%) were PDC adherent, 37.2% were MMAS-8 adherent, and 19.4% were adherent by both measures. Total medical costs of PDC-adherent patients were significantly lower vs PDC-nonadherent patients (US$640 vs $993 per-patient per-month, respectively, p<0.05). MMAS-8-adherent patients reported higher treatment satisfaction; total DASS score was significantly lower among MMAS-8-adherent than MMAS-8-nonadherent patients (37.3 vs 42.9, respectively, p<0.001). Conclusion: Using claims-based or patient-reported methods to measure OAC adherence may lead to different results when assessing impact on health care costs and satisfaction with anticoagulation medication. These results underscore the importance of considering both claims based and patient-reported measures when evaluating treatment adherence in real world settings. PMID- 29391783 TI - Comparisons of predictive values of sarcopenia with different muscle mass indices in Korean rural older adults: a longitudinal analysis of the Aging Study of PyeongChang Rural Area. AB - Purpose: It is important to define lean muscle mass when diagnosing sarcopenia, but there is still controversy on the clinical implication of sarcopenia derived by height, weight, and body mass index (BMI) adjusted muscle mass indices. We aimed to evaluate the longitudinal clinical relevance of 3 sarcopenia definitions in the Korean population. Patients and methods: We conducted comprehensive geriatric assessments for 1,379 community-dwelling older participants in the Aging Study of PyeongChang Rural Area (ASPRA) cohort and followed them up prospectively for death, institutionalization, and disability every 3 months. Sarcopenia was defined using the Asian Working Group consensus algorithm, combining grip strength, gait speed, and muscle mass. Results: Among 1,343 participants (mean age: 76 years, 741 women) analyzed, there were 29 deaths and 89 institutionalizations during 22.0 +/- 8.3 months follow-up (mean +/- SD). All three muscle indices correlated to age and sex. All sarcopenia criteria with muscle mass indices of height, weight, and body mass index (BMI) adjustment significantly predicted death or institutionalization. However, when adjusted for age and sex, only the sarcopenia criteria with muscle mass index of height adjustment were significantly associated with major adverse health outcomes. Conclusion: Adjusting age and gender, the sarcopenia definition from the quintile based muscle index of height adjustment could predict death or institutionalization in Korean community-dwelling older adults. PMID- 29391784 TI - Efficacy of supervised maintenance exercise following pulmonary rehabilitation on health care use: a systematic review and meta-analysis. AB - Introduction: The clinical benefit of continued supervised maintenance exercise programs following pulmonary rehabilitation in COPD remains unclear. This systematic review aimed to synthesize the available evidence on the efficacy of supervised maintenance exercise programs compared to usual care following pulmonary rehabilitation completion on health care use and mortality. Methods: Electronic databases (MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, Web of Science, and PEDro) and trial registers (ClinicalTrials.gov and Current Controlled Trials) were searched for randomized trials comparing supervised maintenance exercise programs with usual care following pulmonary rehabilitation completion. Primary outcomes were respiratory cause hospital admissions, exacerbations requiring treatment with antibiotics and/or systemic corticosteroids, and mortality. Results: Eight trials (790 COPD patients) met the inclusion criteria, six providing data for meta-analysis. Continued supervised maintenance exercise compared to usual care following pulmonary rehabilitation completion significantly reduced the risk of experiencing at least one respiratory-cause hospital admission (risk ratio 0.62, 95% confidence interval [CI] 0.47-0.81, P<0.001). Meta-analyses also suggested that supervised maintenance exercise leads to a clinically important reduction in the rate of respiratory-cause hospital admissions (rate ratio 0.72, 95% CI 0.50 1.05, P=0.09), overall risk of an exacerbation (risk ratio 0.79, 95% CI 0.52 1.19, P=0.25), and mortality (risk ratio 0.57, 95% CI 0.17-1.92, P=0.37). Conclusion: In the first systematic review of the area, current evidence demonstrates that continued supervised maintenance exercise compared to usual care following pulmonary rehabilitation reduces health care use in COPD. The variance in the quality of the evidence included in this review highlights the need for this evidence to be followed up with further high-quality randomized trials. PMID- 29391785 TI - Economic burden of COPD in a Swedish cohort: the ARCTIC study. AB - Background: We assessed direct and indirect costs associated with COPD in Sweden and examined how these costs vary across time, age, and disease stage in a cohort of patients with COPD and matched controls in a real-world, primary care (PC) setting. Patients and methods: Data from electronic medical records linked to the mandatory national health registers were collected for COPD patients and a matched reference population in 52 PC centers from 2000 to 2014. Direct health care costs (drug, outpatient or inpatient, PC, both COPD related and not COPD related) and indirect health care costs (loss of income, absenteeism, loss of productivity) were assessed. Results: A total of 17,479 patients with COPD and 84,514 reference controls were analyzed. During 2013, direct costs were considerably higher among the COPD patient population (?13,179) versus the reference population (?2,716), largely due to hospital nights unrelated to COPD. Direct costs increased with increasing disease severity and increasing age and were driven by higher respiratory drug costs and non-COPD-related hospital nights. Indirect costs (~?28,000 per patient) were the largest economic burden in COPD patients of working age during 2013. Conclusion: As non-COPD-related hospital nights represent the largest direct cost, management of comorbidities in COPD would offer clinical benefits and relieve the financial burden of disease. PMID- 29391786 TI - Narrative medicine to improve the management and quality of life of patients with COPD: the first experience applying parallel chart in Italy. AB - Purpose: Poor adherence to therapy and the failure of current smoking cessation programs demonstrate that the current management of COPD can be improved, and it is necessary to educate physicians about new approaches for taking care of patients. Parallel chart is a narrative medicine tool that improves the doctor patient relationship by asking physicians to write about their patients' lives, thereby encouraging reflective thoughts on care. Patients and methods: Between October 2015 and March 2016, 50 Italian pulmonologists were involved in the collection of parallel charts of anonymous patients with COPD. The narratives were analyzed according to the Grounded Theory methodology. Results: In the 243 parallel charts collected, the patients (mean age 69 years, 68% men) are described as still active and as a resource for their families (71%). The doctor patient relationship started as difficult in 50% of cases, and younger age and smoking were the main risk factors. The conversations turned positive in 78% of narratives, displaying deeper mutual knowledge, trust for the clinicians' ability to establish effective therapy (92%), support efforts to quit smoking (63%), or restore patients' activities (78%). Conclusion: All the physicians concurred that the adoption of innovative parallel charts was useful for improving clinical care and worthy of official inclusion in protocols for the management of COPD. PMID- 29391787 TI - Epidemiological study of PM2.5 and risk of COPD-related hospital visits in association with particle constituents in Chuncheon, Korea. AB - Background and objective: Aside from smoking, which is already recognized as a strong risk factor for COPD, interest in the impact of particulate matter (PM) on COPD is increasing. This study aimed to investigate the effect of PM, especially with an aerodynamic diameter <=2.5 um (PM2.5), and its chemical constituents on the exacerbation of COPD. Methods: Data on hospital visits including admission and outpatient clinic visits for exacerbation of COPD in Chuncheon, Korea, between 2006 and 2012 were extracted from the National Health Insurance Service database. PM2.5 and its chemical constituents were measured on the roof of the four-story Kangwon National University Natural Sciences building once every 3 days. Meteorological data were provided by the Korean Meteorological Administration. Results: During the study period, the mean level of PM2.5 was 35.0+/-25.2 ug/m3, and the number of daily hospital visits were 6.42+/-4.28 and 2.07+/-1.93 for males and females, respectively. The number of COPD-related hospital visits increased with increasing PM2.5 after adjusting for meteorological covariates and females tended to be more affected sooner than males. Among the PM2.5 constituents, Al, Si, and elemental carbon were associated with increased hospital visits and there was a difference according to sex. In males, some constituents of PM2.5 were related to an increased risk of a hospital visit, mainly on the first and second days of measurement (Lag1 and Lag2). In contrast, there was no significant increase in the risk of hospital visits due to any of the PM2.5 constituents in females. Conclusion: Concentrations of PM2.5 mass and some of the PM2.5 constituents were associated with increased COPD related hospital visits in Chuncheon. PMID- 29391788 TI - Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects. AB - Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6 hydroxydopamine model of PD. Materials and methods: The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results: Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (P<0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Conclusion: Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD. PMID- 29391789 TI - Effect of zirconium oxide nanoparticles addition on the optical and tensile properties of polymethyl methacrylate denture base material. AB - Background: Polymethyl methacrylate (PMMA) is widely used for the fabrication of removable prostheses. Recently, zirconium oxide nanoparticles (nano-ZrO2) have been added to improve some properties of PMMA, but their effect on the optical properties and tensile strength are neglected. Objective: The aim of this study was to investigate the effect of nano-ZrO2 addition on the translucency and tensile strength of the PMMA denture base material. Materials and methods: Eighty specimens (40 dumbbell-shaped and 40 discs) were prepared out of heat-polymerized acrylic resin and divided into four groups per test (n=10). The control group for each test included unreinforced acrylic, while the test groups were reinforced with 2.5, 5, and 7.5 wt% nano-ZrO2. Acrylic resin was mixed according to manufacturer's instructions, packed, and processed by conventional method. After polymerization, all specimens were finished, polished, and stored in distilled water at 37 degrees C for 48+/-2 hours. Tensile strength (MPa) was evaluated using the universal testing machine while the specimens' translucency was examined using a spectrophotometer. Statistical analysis was carried out by SPSS using the paired sample t-test (p<=0.05). A scanning electron microscope was used to analyze the morphological changes and topography of the fractured surfaces. Results: This study showed that the mean tensile strength of the PMMA in the test groups of 2.5%NZ, 5%NZ, and 7.5%NZ was significantly higher than the control group. The tensile strength increased significantly after nano-ZrO2 addition, and the maximum increase seen was in the 7.5%NZ group. The translucency values of the experimental groups were significantly lower than those of the control group. Within the reinforced groups, the 2.5%NZ group had significantly higher translucency values when compared to the 5%NZ and 7.5%NZ groups. Conclusion: The addition of nano-ZrO2 increased the tensile strength of the denture base acrylic. The increase was directly proportional to the nano-ZrO2 concentration. The translucency of the PMMA was reduced as the nano-ZrO2 increased. Clinical significance: Based on the results of the current study, the tensile strength was improved with different percentages of nano-ZrO2 additions. However, translucency was adversely affected. Therefore, it is important to determine the appropriate amount of reinforcing nano-ZrO2 that will create a balance between achieved properties - mechanical and optical. PMID- 29391790 TI - Targeting prostate cancer cells with hybrid elastin-like polypeptide/liposome nanoparticles. AB - Prostate cancer cells frequently overexpress the gastrin-releasing peptide receptor, and various strategies have been applied in preclinical settings to target this receptor for the specific delivery of anticancer compounds. Recently, elastin-like polypeptide (ELP)-based self-assembling micelles with tethered GRP on the surface have been suggested to actively target prostate cancer cells. Poorly soluble chemotherapeutics such as docetaxel (DTX) can be loaded into the hydrophobic cores of ELP micelles, but only limited drug retention times have been achieved. Herein, we report the generation of hybrid ELP/liposome nanoparticles which self-assembled rapidly in response to temperature change, encapsulated DTX at high concentrations with slow release, displayed the GRP ligand on the surface, and specifically bound to GRP receptor expressing PC-3 cells as demonstrated by flow cytometry. This novel type of drug nanocarrier was successfully used to reduce cell viability of prostate cancer cells in vitro through the specific delivery of DTX. PMID- 29391791 TI - Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: an approach for acceptable level of evidence of an effective novel herbal weight loss product. AB - Purpose: Herbal supplements are currently available as a safer alternative to manage obesity, which has become a rising problem over the recent years. Many chemical drugs on the market are designed to prevent or manage obesity but high cost, low efficacy, and multiple side effects limit its use. Nano lipo-vesicles phytosomal thermogel of Soybean, Glycine max (L.) Merrill, was formulated and evaluated in an attempt to investigate its anti-obesity action on body weight gain, adipose tissue size, and lipid profile data. Methods: Three different techniques were used to prepare phytosome formulations including solvent evaporation, cosolvency, and salting out. The optimized phytosome formulation was then selected using Design Expert(r) (version 7.0.0) depending on the highest entrapment efficiency, minimum particle size (PS), and maximum drug release within 2 hours as responses for further evaluation. The successful phytosome complex formation was investigated by means of Fourier-transform infrared spec troscopy and determination of PS and zeta potential. Phytosome vesicles' shape was evaluated using transmission electron microscope to ensure its spherical shape. After characterization of the optimized phytosome formulation, it was incorporated into a thermogel formulation. The obtained phytosomal thermogel formulation was evaluated for its clarity, homogeneity, pH, and gel transformation temperature besides rheology behavior and permeation study. An in vivo study was done to investigate the anti-weight-gain effect of soy phytosomal ther mogel. Results: EE was found to be >99% for all formulations, PS ranging from 51.66-650.67 while drug release was found to be (77.61-99.78) in range. FTIR and TEM results confirmed the formation of phytosome complex. In vivo study showed a marked reduction in body weight, adipose tissue weight and lipid profile. Conclusion: Concisely, soy phytosomal thermogel was found to have a local anti-obesity effect on the abdomen of experimental male albino rats with a slight systemic effect on the lipid profile data. PMID- 29391793 TI - Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines. AB - The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature. However, there is a risk that such stimuli may disrupt the structure and thereby diminish the activity of the delivered drugs, especially complex antibody and viral-based nanomedicines. In this study, we characterize the impact of cavitation on four different agents, doxorubicin (Dox), cetuximab, adenovirus (Ad) and vaccinia virus (VV), representing a scale of sophistication from a simple small-molecule drug to complex biological agents. To achieve tight regulation of the level and duration of cavitation exposure, a "cavitation test rig" was designed and built. The activity of each agent was assessed with and without exposure to a defined cavitation regime which has previously been shown to provide effective and safe delivery of agents to tumors in preclinical studies. The fluorescence profile of Dox remained unchanged after exposure to cavitation, and the efficacy of this drug in killing a cancer cell line remained the same. Similarly, the ability of cetuximab to bind its epidermal growth factor receptor target was not diminished following exposure to cavitation. The encoding of the reporter gene luciferase within the Ad and VV constructs tested here allowed the infectivity of these viruses to be easily quantified. Exposure to cavitation did not impact on the activity of either virus. These data provide compelling evidence that the US parameters used to safely and successfully delivery nanomedicines to tumors in preclinical models do not detrimentally impact on the structure or activity of these nanomedicines. PMID- 29391794 TI - Micelle-templated, poly(lactic-co-glycolic acid) nanoparticles for hydrophobic drug delivery. AB - Purpose: Poly(lactic-co-glycolic acid) (PLGA) is widely used for drug delivery because of its biocompatibility, ability to solubilize a wide variety of drugs, and tunable degradation. However, achieving sub-100 nm nanoparticles (NPs), as might be desired for delivery via the enhanced permeability and retention effect, is extremely difficult via typical top-down emulsion approaches. Methods: Here, we present a bottom-up synthesis method yielding PLGA/block copolymer hybrids (ie, "PolyDots"), consisting of hydrophobic PLGA chains entrapped within self assembling poly(styrene-b-ethylene oxide) (PS-b-PEO) micelles. Results: PolyDots exhibit average diameters <50 nm and lower polydispersity than conventional PLGA NPs. Drug encapsulation efficiencies of PolyDots match conventional PLGA NPs (ie, ~30%) and are greater than those obtained from PS-b-PEO micelles (ie, ~7%). Increasing the PLGA:PS-b-PEO weight ratio alters the drug release mechanism from chain relaxation to erosion controlled. PolyDots are taken up by model glioma cells via endocytotic mechanisms within 24 hours, providing a potential means for delivery to cytoplasm. PolyDots can be lyophilized with minimal change in morphology and encapsulant functionality, and can be produced at scale using electrospray. Conclusion: Encapsulation of PLGA within micelles provides a bottom up route for the synthesis of sub-100 nm PLGA-based nanocarriers with enhanced stability and drug-loading capacity, and tunable drug release, suitable for potential clinical applications. PMID- 29391792 TI - Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles. AB - Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine. PMID- 29391795 TI - Design and immunological evaluation of anti-CD205-tailored PLGA-based nanoparticulate cancer vaccine. AB - The aim of this research was to develop a targeted antigen-adjuvant assembled delivery system that will enable dendritic cells (DCs) to efficiently mature to recognize antigens released from tumor cells. It is important to target the DCs with greater efficiency to prime T cell immune responses. In brief, model antigen, ovalbumin (OV), and monophosphoryl lipid A adjuvant were encapsulated within the nanoparticle (NP) by double emulsification solvent evaporation method. Targeted NPs were obtained through ligand incorporation via physical adsorption or chemical conjugation process. Intracellular uptake of the NPs and the maturation of DCs were evaluated with flow cytometry. Remarkably, the developed delivery system had suitable physicochemical properties, such as particle size, surface charge, OV encapsulation efficiency, biphasic OV release pattern, and safety profile. The ligand modified formulations had higher targeting efficiency than the non-tailored NPs. This was also evident when the targeted formulations expressed comparatively higher fold increase in surface activation markers such as CD40, CD86, and major histocompatibility complex class II molecules. The maturation of DCs was further confirmed through secretion of extracellular cytokines compared to control cells in the DC microenvironment. Physicochemical characterization of NPs was performed based on the polymer end groups, their viscosities, and ligand-NP bonding type. In conclusion, the DC stimulatory response was integrated to develop a relationship between the NP structure and desired immune response. Therefore, the present study narrates a comparative evaluation of some selected parameters to choose a suitable formulation useful for in vivo cancer immunotherapy. PMID- 29391796 TI - In vivo therapeutic efficacy of TNFalpha silencing by folate-PEG-chitosan DEAE/siRNA nanoparticles in arthritic mice. AB - Background: Tumor necrosis factor-alpha (TNFalpha), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNFalpha expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. Methods: Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-DEAE15). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNFalpha, DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNFalpha-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNFalpha expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. Results: We demonstrated that folate-PEG-CH-DEAE15/siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNFalpha protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. Conclusion: The results indicate that folate-PEG-CH-DEAE15 nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation. PMID- 29391797 TI - Dose reduction of bone morphogenetic protein-2 for bone regeneration using a delivery system based on lyophilization with trehalose. AB - Introduction: To induce sufficient new bone formation, high doses of bone morphogenetic protein-2 (BMP-2) are applied in regenerative medicine that often induce serious side effects. Therefore, improved treatment strategies are required. Here, we investigate whether the delivery of BMP-2 lyophilized in the presence of trehalose reduced the dose of BMP-2 required for bone regeneration. Materials and methods: A new growth factor delivery system was fabricated using BMP-2-loaded TiO2 nanotubes by lyophilization with trehalose (TiO2-Lyo-Tre-BMP 2). We measured BMP-2 release characteristics, bioactivity, and stability, and determined the effects on the osteogenic differentiation of bone marrow stromal cells in vitro. Additionally, we evaluated the ability of this formulation to regenerate new bone around implants in rat femur defects by micro-computed tomography (micro-CT), sequential fluorescent labelling, and histological analysis. Results: Compared with absorbed BMP-2-loaded TiO2 nanotubes (TiO2-BMP 2), TiO2-Lyo-Tre-BMP-2 exhibited sustained release, consistent bioactivity, and higher stability of BMP-2, and resulted in greater osteogenic differentiation of BMSCs. Eight weeks post-operation, TiO2-Lyo-Tre-BMP-2 nanotubes, with various dosages of BMP-2, regenerated larger amounts of new bone than TiO2-BMP-2 nanotubes. Conclusion: Our findings indicate that delivery of BMP-2 lyophilized with trehalose may be a promising method to reduce the dose of BMP-2 and avoid the associated side effects. PMID- 29391799 TI - Safety and effectiveness of rapid-acting intra-muscular olanzapine for agitation associated with schizophrenia - Japan postmarketing surveillance study. AB - Objective: The objective of this study was to evaluate the safety and effectiveness of rapid-acting intramuscular (IM) olanzapine in the treatment of acute agitation associated with schizophrenia in real-world clinical settings in Japan. Methods: In this multicenter, postmarketing surveillance (PMS) study, patients with acute agitation associated with schizophrenia were treated with IM olanzapine daily in a daily clinical setting. The observational period ranged from 1 to 7 days, including the day of initial administration. Safety was assessed by reporting treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs). The Positive and Negative Syndrome Scale - Excited Component (PANSS-EC) score was used to evaluate effectiveness at baseline and at 2 hours (after each administration), 2 days, and 3 days (end of the observational period) from the last administration of the IM olanzapine injection. Results: The safety analysis set included 999 patients, and the initial dose of 10 mg was administered to 955 patients. TEAEs were reported in 28 patients (36 events), the most common of which were dyslalia (5 patients), akathisia and somno lence (4 patients each), hepatic function abnormal (3 patients), and constipation and dehydration (2 patients each). One serious adverse event of akathisia occurred during the observation period. The PANSS-EC score (mean +/- standard deviation) was 23.3+/-6.4 (n=625) at baseline, 16.9+/-7.0 (n=522) at 2 hours after initial injection, and 14.9+/-6.5 (n=650) at the last observation carried forward. Conclusion: The results of this Japanese PMS study demonstrated that IM olanzapine is safe and has a favorable effectiveness profile in the treatment of schizophrenia patients with acute agitation. PMID- 29391798 TI - Controlled drug delivery for glaucoma therapy using montmorillonite/Eudragit microspheres as an ion-exchange carrier. AB - Background: Glaucoma is a serious eye disease that can lead to loss of vision. Unfortunately, effective treatments are limited by poor bioavailability of antiglaucoma medicine due to short residence time on the preocular surface. Materials and methods: To solve this, we successfully prepared novel controlled release ion-exchange microparticles to deliver betaxolol hydrochloride (BH). Montmorillonite/BH complex (Mt-BH) was prepared by acidification-intercalation, and this complex was encapsulated in microspheres (Mt-BH encapsulated microspheres [BMEMs]) by oil-in-oil emulsion-solvent evaporation method. The BH loaded into ion-exchange Mt was 47.45%+/-0.54%. After the encapsulation of Mt-BH into Eudragit microspheres, the encapsulation efficiency of BH into Eudragit microspheres was 94.35%+/-1.01% and BH loaded into Eudragit microspheres was 14.31%+/-0.47%. Results: Both Fourier transform infrared spectra and X-ray diffraction patterns indicated that BH was successfully intercalated into acid-Mt to form Mt-BH and then Mt-BH was encapsulated into Eudragit microspheres to obtain BMEMs. Interestingly, in vitro release duration of the prepared BMEMs was extended to 12 hours, which is longer than both of the BH solution (2.5 hours) and the conventional BH microspheres (5 hours). Moreover, BMEM exhibited lower toxicity than that of BH solution as shown by the results of cytotoxicity tests, chorioallantoic membrane-trypan blue staining, and Draize rabbit eye test. In addition, both in vivo and in vitro preocular retention capacity study of BMEMs showed a prolonged retention time. The pharmacodynamics showed that BMEMs could extend the drug duration of action. Conclusion: The developed BMEMs have the potential to be further applied as ocular drug delivery systems for the treatment of glaucoma. PMID- 29391800 TI - Effectiveness of high-frequency repetitive transcranial magnetic stimulation in patients with depression and Parkinson's disease: a meta-analysis of randomized, controlled clinical trials. AB - Aim: This meta-analysis aimed to assess the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) for the treatment of depression in patients with Parkinson's disease (PD). Methods: The design was a meta-analysis of randomized controlled trials (RCTs). The participants were patients with PD who suffered from depression. The interventions were HF-rTMS alone or in combination with other treatments compared with sham-rTMS, placebo, and anti depressant treatments. The primary outcome measure was changes in depressive symptoms, defined as the mean change in the total depression score. The secondary outcome was changes in motor symptoms, defined by Unified Parkinson's Disease Rating Scale part III scores, and the acceptability, defined as the risk of all cause discontinuation. These were expressed as mean differences (MDs), standardized mean differences (SMDs), or risk ratios (RRs) with 95% confidence intervals (CIs). Results: We identified nine suitable trials, with data from 332 participants. For the patients with depression in PD, HF-rTMS was not better than sham-rTMS (SMD =-0.33, 95% CI -0.83 to 0.17) or selective serotonin re-uptake inhibitors (SSRIs) (SMD =0.07, 95% CI -0.52 to 0.18) for the treatment of depressive symptoms. However, the motor benefits after treatment with HF-rTMS might be better than sham-rTMS (MD =-2.80, 95% CI -5.45 to -0.15) and SSRIs (MD = 2.70, 95% CI -4.51 to -0.90). Conclusion: This meta-analysis provides some evidence that in patients with PD with depression, HF-rTMS may lead to improvement in motor function but not in depression compared with sham-rTMS or SSRIs. PMID- 29391801 TI - Spotlight on once-monthly long-acting injectable aripiprazole and its potential as maintenance treatment for bipolar I disorder in adult patients. AB - The lack of long-term medication adherence is a challenge in the treatment of bipolar disorder, particularly during the maintenance phase when symptoms are less prominent. The rate of nonadherence is ~20%-60% depending on how strict a definition is used. Nonadherence worsens the course of bipolar disorder and can add hundreds of thousands of dollars to the lifetime cost of treating the illness. Long-acting injectable (LAI) medication is an attractive alternative to daily dosing of oral medication, especially among patients who are ambivalent about treatment. The purpose of this paper is to review the evidence for the safety and efficacy of LAI aripiprazole, which was recently approved for the treatment of bipolar disorder. The approval was based on a single double-blind, placebo-controlled, multisite trial that recruited participants from 103 sites in 7 countries. A total of 731 participants with bipolar disorder were enrolled in the study. Out of that total, 266 were successfully stabilized on LAI aripiprazole and entered the randomization phase. Treatment-emergent adverse events were, for the most part, mild to moderate. Akathisia was the most common adverse event, which, combined with restlessness, was experienced by 23% of the sample. At the end of the 52-week study period, nearly twice as many LAI-treated participants remained stable compared to those treated with placebo. Stability during the maintenance phase is arguably the most important goal of treatment. It is during this period of relative freedom from symptoms that patients are able to build a meaningful and satisfying life. The availability of a new treatment agent, particularly one that has the potential to enhance long-term adherence, is a welcome development. PMID- 29391802 TI - ADHD and lifestyle habits in Czech adults, a national sample. AB - Background: Adult attention-deficit/hyperactivity disorder (ADHD) has been added as a diagnosis to the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM5) in 2013, thus making ADHD, which has been classically known as a childhood disorder, a life-long disorder. Those suffering from the condition show very specific behavioral traits, which manifest as lifestyle habits; they also show comorbidities that can be the symptoms and/or consequences of certain lifestyles. Materials and methods: The targeted population was adults aged 18-65 years. The total sample was 1,012 (507 males and 505 females). The Adult ADHD Self-Report Scale (ASRS V. 1.1) was administered to evaluate the current symptoms of ADHD and a questionnaire regarding lifestyles that are pertinent to ADHD, exercise, drug use, and diet. Results: An ASRS score of 4-6 points was found in 11.4% of the male population and 9.7% of the female population (5-6 points indicate very high-intensity symptoms). A score of 6, the highest intensity of symptomatology, was found in 1.18% of males and 0.99% of females. Gender differences in scores were not statistically significant. In terms of self reported lifestyles, we calculated an ordered logistic regression and the odds ratios of those with ASRS scores >4. Those with higher ASRS scores had higher rates of self-reported unhealthy lifestyles and poor diets with high consumption of sweets. We also ascertained a paradoxical finding that is not in line with the current literature on the disorder - lower rates of cigarette smoking among people with higher ADHD symptomatology. Conclusion: Several specific lifestyles were found to be associated with higher ADHD symptoms such as poor diet and cannabis use. Other factors classically associated with the disorder such as cocaine addiction and nicotinism were either insignificant or surprisingly less prominent among the Czech sample. However, ADHD-prone respondents reported to be more physically active, which fits the clinical picture of hyperactivity but contrasts with literature that reports sedentary ADHD lifestyle. PMID- 29391803 TI - Acute pulmonary embolism in a patient with cesarean scar pregnancy after receiving uterine artery embolization: a case report. AB - Uterine artery embolization (UAE) is considered to be an effective treatment for patients with cesarean scar pregnancy, especially for those presenting uncontrollable hemorrhage. However, it can also cause some potential complications. Pulmonary embolism is a rare but fatal complication in patients treated with UAE. Here, we report a case of a woman who was diagnosed with cesarean scar pregnancy presenting with pulmonary embolism during the operation of dilation and curettage after UAE treatment. Prompt resuscitation was carried out and the patient received anticoagulant treatment immediately. During the follow-up, she recovered well without any complications. We present the clinical details and imaging findings, followed by discussions of the etiology, treatments, and prevention strategies. PMID- 29391804 TI - Impact of depression on change in coronary heart disease risk status: the Korean Genome and Epidemiology Study (KoGES). AB - Purpose: The objective of this study was to evaluate the association between depression and change in coronary heart disease (CHD) risk status by an analysis of examination data in the general Korean population. Patients and methods: We examined 1,851 men and 1,689 women (aged 43-73 years) for the Korean Genome and Epidemiology Study Ansan between 2005 and 2012. The estimated CHD risk score of participants was calculated using the Framingham CHD risk score in baseline and after 8-year follow-up period. Among them, population with low Framingham CHD risk score (<10%) in baseline (n=1,582) was used for further analyses. The low Framingham CHD risk score participants were assigned to one of two groups based on the Beck depression inventory (BDI) score: no depression (BDI <10) and depression (BDI >=10). Multivariate logistic regression was performed to test whether depression was associated with participants' status change to intermediate or high CHD risk score (>=10%) in men and women, respectively, after 8-year follow-up period. Results: Women with depression showed significant higher rates of changing to intermediate or high CHD risk score status when compared with women without depression even after adjusting for age, systolic blood pressure, high-density lipoprotein, and smoking (adjusted odds ratio [OR], 1.54; 95% CI, 1.08-2.03). However, depression was not associated with intermediate or high CHD risk score status in men (adjusted OR, 1.38; 95% CI, 0.95-1.82). Conclusion: This general population-based cohort study provides evidence that depression can affect the risk of changing CHD risk score status in women. PMID- 29391806 TI - Comparative study of clinical efficacy using three-dimensional and two dimensional laparoscopies in the treatment of distal gastric cancer. AB - Background: Three-dimensional (3D) laparoscopy has the advantages and characteristics of more radical procedures in the treatment of gastric cancer. The objective of this research was to investigate the short-term efficacy and safety of 3D laparoscopic procedures in the treatment of advanced distal gastric cancer. Methods: We retrospectively analyzed the clinical data of 124 patients treated with 3D and two-dimensional (2D) laparoscopic D2 lymphadenectomy for distal gastric cancer at the China Academy of Medical Sciences Cancer Hospital and the Affiliated Cancer Hospital of Guangxi Medical University from January 2014 to January 2015. The effects on operative time, bleeding, hospitalization time, complications, and the number of lymph nodes removed were analyzed. Results: The difference between the general data of the two groups was not statistically significant (P>0.05). In analysis of the subgroups, the number of lymph nodes removed in the 3D laparoscopic group was significantly higher than in the 2D laparoscopic group ([2.52+/-1.88] vs [2.22+/-1.80], P=0.001; [2.22+/-1.80] vs [1.47+/-1.99], P=0.019). However, the differences among the total number of lymph nodes removed, operative time, intraoperative blood loss, intraoperative complications, postoperative complications, postoperative recovery time, and postoperative hospital stay were not statistically significant. Conclusion: 3D laparoscopic-assisted radical gastrectomy for distal advanced gastric cancer is safe and feasible. PMID- 29391805 TI - Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes. PMID- 29391807 TI - A novel tumor suppressor gene NCOA5 is correlated with progression in papillary thyroid carcinoma. AB - Background: In contrast to the excellent prognosis for papillary thyroid carcinoma (PTC), the high incidence of lymph node metastasis (LNM) markedly increases the risk of recurrence and secondary surgery. Thus, novel biomarkers must be urgently identified to assess LNM for patients with PTC. NCOA5 is deeply involved in the progression of human cancer; however, its role in thyroid cancer remains unknown. Patients and methods: Quantitative real-time polymerase chain reaction was conducted to investigate the expression of NCOA5 in PTC. RNA-seq data from The Cancer Genome Atlas (TCGA) database were downloaded to further understand the role of NCOA5 in PTC and its relationship with LNM. Results: NCOA5 was significantly downregulated in PTC tissues when compared with that in adjacent noncancerous thyroid tissues both in our local cohort and TCGA database. Reduced expression of NCOA5 was significantly associated with aggressive clinicopathological features, including histological type, tumor stage, BRAF V600E mutation, LNM, extrathyroid extension, and clinical stage. Moreover, logistic analysis indicated that reduced expression of NCOA5, age, histological type, and clinical stage are independent high-risk factors for LNM in PTC. Conclusion: Our study provides new insights and evidence that NOCA5 was significantly correlated with the progression of PTC and was particularly involved in LNM. PMID- 29391808 TI - The silencing of LncRNA-H19 decreases chemoresistance of human glioma cells to temozolomide by suppressing epithelial-mesenchymal transition via the Wnt/beta Catenin pathway. AB - Introduction: Temozolomide (TMZ) is commonly used for glioma chemotherapy. However, TMZ resistance limits the therapeutic effect of TMZ in glioma treatment. LncRNA-H19 acts as an oncogenic LncRNA in some types of cancers and has been reported to be up-regulated in glioma. Materials and methods: In our present study, we established TMZ-resistant glioma cells (U-251TMZ and M059JTMZ) to explore the effect of H19 on the chemoresistance of glioma cells. Results: We observed that the expression of H19 was significantly increased in U-251TMZ and M059JTMZ cells. Knockdown of H19 expression using specific shRNA in U-251TMZ and M059JTMZ led to decreased half maximal inhibitory concentration (IC50) values for TMZ and increased cell apoptosis rates, indicating that the silencing of H19 decreased chemoresistance of glioma cells to TMZ. In addition, silencing of H19 suppressed epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin and decreasing the expression of mesenchymal marker Vimentin and ZEB1. Moreover, inducing EMT by TGF-beta1 treatment led to increased IC50 values for TMZ and decreased cell apoptosis rates compared with TMZ+H19 shRNA group, suggesting that the induction of EMT counteracted the inhibitory effect of H19 shRNA on chemoresistance of glioma cells to TMZ. Furthermore, the reduced expression of H19 down-regulated the expression of beta Catenin and its downstream targets c-myc and Survivin in TMZ-treated glioma cells. Activation of Wnt/beta-Catenin pathway by Licl treatment promoted EMT and enhanced chemoresistance to TMZ compared with TMZ+H19 shRNA group. Conclusion: Taken together, our data suggest that H19 decreased chemoresistance of glioma cells to TMZ by suppressing EMT via the inhibition of Wnt/beta-Catenin pathway. Our study might represent a novel therapeutic target for TMZ-resistant glioma. PMID- 29391810 TI - The clinical characteristics and prognostic analysis of Chinese advanced NSCLC patients based on circulating tumor DNA sequencing. AB - Purpose: Circulating tumor DNA (ctDNA) is a noninvasive and real-time marker for tumor diagnosis, prognosis, and prediction. However, further investigations about ctDNA prognostic and predictive value are still needed, and conclusions from several studies were inconsistent. Experimental design: We performed capture based targeted ultradeep sequencing on liquid biopsies from a cohort of 34 advanced Chinese non-small-cell lung cancer (NSCLC) patients and analyzed the clinical use of ctDNA in this study. Results: On the basis of clinical characteristics of the 34 NSCLC patients, we found that brain metastasis correlated with shorter progression-free survival (PFS) and is more prone to happen in younger patients. After ctDNA sequencing, we analyzed the prognostic value of baseline ctDNA. In osimertinib-treated group, high max allelic fraction (maxAF) correlated with shorter PFS. But for the cohort of 34 patients, no correlation can be observed between maxAF and PFS. We also presented two cases to demonstrate the value of disease progression prediction by ctDNA, which can be detected earlier than clinical response. Conclusion: In this study, we demonstrated that ctDNA is a prognostic marker for evaluating treatment response and predicting recurrence in advanced NSCLC. Further investigations with larger cohort and uniformed patient background are still needed to validate our findings. PMID- 29391809 TI - High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas. AB - Purpose: Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients. Materials and methods: We immunohistochemically examined various components of Wnt signaling pathway including beta-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women. Results: Cytoplasmic beta-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of beta-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic beta-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers. Conclusions: High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs targeting this pathway. PMID- 29391811 TI - Safety and efficacy of transarterial chemoembolization with degradable starch microspheres (DSM-TACE) in the treatment of secondary liver malignancies. AB - Purpose: To evaluate the safety and efficacy of degradable starch microspheres (DSM) as embolic agents in transarterial chemoembolization (TACE) in the treatment of secondary liver metastases. Methods: This was a national, multicenter observational study. Primary endpoints were safety and treatment response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Results: A total of 77 DSM-TACE procedures were performed in 20 patients. Minor immediate adverse events (AEs) were epigastric pain with an incidence of 45.5% (35/77), and nausea and vomiting at an incidence of 23.4% (18/77). Delayed minor AEs were epigastric pain in 13/77 (16.9%) treatments and nausea and vomiting in 10 (13.0%) treatments. No severe AEs were documented. Therapeutic efficacy of DSM-TACE procedures according to mRECIST was as follows: complete response 0/77, partial response 17/77, stable disease 33/77 and progressive disease 6/77, no data was available for 21/77 treatments. Overall, objective response was achieved in 8 of 20 patients (40.0%). Conclusion: DSM as embolic agent for TACE is safe in the treatment of liver metastases. An objective response in 40.0% of patients and disease control in 64.9% of procedures was achieved, and this should lead to further evaluation of DSM-TACE as treatment option for nonresectable liver metastases. PMID- 29391812 TI - Prognostic role of HSPs in human gastrointestinal cancer: a systematic review and meta-analysis. AB - Background: Heat shock proteins (HSPs) have been reported to be overexpressed in a wide range of human tumors. It has been shown that HSPs act as an oncogenic regulator and are involved in tumorigenesis. The clinical and prognostic significance of HSPs in gastrointestinal cancers (GICs) remains controversial. The aim of this study was to conduct a meta-analysis to assess the prognostic value of HSPs in GICs. Materials and methods: A literature search was performed in PubMed, Cochrane Library, Web of Science, and Embase databases. Data on the relationship between expression of HSPs and survival outcomes were extracted. Pooled hazard ratios (HRs) with 95% CI were calculated. Results: The expression of HSPs was not associated with the overall survival (OS) of GIC patients; however, it was significantly associated with worse OS for gastric cancer (GC) and colorectal cancer (CRC) patients. Conclusion: Current evidence suggests that a high level of HSPs may not be a potential marker to predict the survival rate for every type of GICs. However, the expression of HSPs may predict a poor prognosis for GC and CRC patients. PMID- 29391813 TI - Combination of betulinic acid with diazen-1-ium-1,2-diolate nitric oxide moiety donating a novel anticancer candidate. AB - Background: Betulinic acid (BA) is a complex lupane triterpenoid with unique antineoplastic activity. However, its antiproliferative activity is far from satisfaction. In order to improve its anticancer efficacy, betulinic acid was conjugated with a nitric oxide (NO)-releasing moiety to get a novel hybrid, BA 78. Methods: The antiproliferative activity of BA-78 against 6 cell lines and the ability of releasing nitric oxide were determined. The pro-apoptosis mechanism of BA-78 was investigated as well. Results: BA-78 exhibited time-dependent release of NO, and it displayed higher antiproliferative potential than BA through increasing apoptosis and inducing cell cycle arrest at G1 phase. Western blotting results showed that BA-78 increased the expression of Bax, Bid, Bad and cytochrome C and reduced the level of anti-apoptosis proteins including Bcl-2 and Bcl-xl. Conclusion: Our study revealed that novel compound BA-78, possessing betulinic acid and nitric oxide (NO)-releasing moiety, could be developed as an antitumor agent. PMID- 29391814 TI - Targeting polyelectrolyte networks in purulent body fluids to modulate bactericidal properties of some antibiotics. AB - The response of the human immune system to most bacterial infections results in accumulation of neutrophils at infection sites that release a significant quantity of DNA and F-actin. Both are negatively charged polyelectrolytes that can interact with positively charged host defense molecules such as cathelicidin delivered LL-37 peptide or other cationic antibiotic agents. Evaluation of the ability of bacterial outgrowth (using luminescence measurements or counting colony-forming units) to form a biofilm (quantified by crystal violet staining) and analysis of the structure of DNA/F-actin network by optical microscopy in human pus samples treated with different antibiotics in combination with plasma gelsolin, DNAse 1, and/or poly-aspartic acid revealed that bactericidal activity of most tested antibacterial agents increases in the presence of DNA/F-actin depolymerizing factors. PMID- 29391815 TI - Molecular analysis of multidrug resistance in clinical isolates of Shigella spp. from 2001-2010 in Kolkata, India: role of integrons, plasmids, and topoisomerase mutations. AB - To understand the genetic basis of high drug resistance in Shigella, 95 clinical isolates of Shigella spp. (2001-2010) were obtained from the Infectious Diseases Hospital, Kolkata, India. Ninety-three isolates were resistant to three or more antibiotics. Resistance to nalidixic acid, trimethoprim, streptomycin, and co trimoxazole was most common in this population. Dendrogram analysis showed that S. sonnei strains were more clonally related when compared to the other Shigella species. The role of mobile genetic elements and chromosome-borne resistance factors was analyzed in detail. Integron analysis indicated the preponderance of class 2 and atypical class 1 integrons in that population. Typical class 1 integron was present in only one S. sonnei isolate and harbored trimethoprim resistance-encoding gene dfrV, while atypical class 1 integrons harbored dfrA1 aadA or blaOXA-aadA gene cassettes responsible for resistance to trimethoprim, aminoglycosides, and beta-lactams. Class 2 integrons harbored either dfrA1-sat aadA or dfrA1-sat gene cassettes. Most importantly, a novel gene cassette array InsE-InsO-dfrA1-sat was found in class 2 integron of S. sonnei NK4846. Many of the resistance traits for antibiotics such as trimethoprim, co-trimoxazole, kanamycin, ampicillin, and tetracycline were transferred from parent Shigella isolates to recipient Escherichia coli during conjugation, establishing the role of plasmids in horizontal transfer of resistance genes. Multiple mutations such as S80->I, S83->L, and D87->G/N/Y in quinolone resistance determining regions of topoisomerases from the representative quinolone-resistant isolates could explain the spectrum of minimal inhibitory concentration values for various quinolones. To the best of our knowledge, this is the first comprehensive report that describes the contribution of mobile (plasmids, integrons, and quinolone resistance genes named qnr) and innate genetic elements (mutations in topoisomerases) in determining the resistance phenotype of all the four species of Shigella over a span of ten years. PMID- 29391816 TI - Antibacterial effect evaluation of moxalactam against extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae with in vitro pharmacokinetics/pharmacodynamics simulation. AB - Objectives: The aim of this study was to evaluate the bactericidal effects of moxalactam (MOX), cefotaxime (CTX), and cefoperazone/sulbactam (CFZ/SBT) against extended-spectrum beta-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae, using an in vitro pharmacokinetics (PK)/pharmacodynamics model. Methods: Two clinical ESBL-producing strains (blaCTX-M-15 positive E. coli 3376 and blaCTX-M-14 positive K. pneumoniae 2689) and E. coli American Type Culture Collection (ATCC)25922 were used in the study. The PK Auto Simulation System 400 was used to simulate the human PK procedures after intravenous administration of different doses of MOX, CTX, and CFZ/SBT. Bacterial growth recovery time (RT) and the area between the control growth curve and bactericidal curves (IE) were employed to assess the antibacterial efficacies of all the agents. Results: The minimum inhibitory concentrations of MOX, CTX, and CFZ/SBT against E. coli ATCC25922, 3376, and 2689 strains were 0.5, 0.5, 0.25; 0.06, >256, 256; and 0.5/0.5, 16/16, 32/32 mg/L. All the agents demonstrated outstanding bactericidal effects against E. coli ATCC25922 (RT >24 h and IE >120 log10 CFU/mL.h-1) with simulating PK procedures, especially in the multiple dose administration models. Against ESBL producers, CTX and CFZ/SBT displayed only weak bactericidal effects, and subsequent regrowth was evident. MOX exhibited potent antibacterial activity against all the strains tested. The values of effective parameters of MOX were much higher than those of CTX and CFZ/SBT (the bacterial RTs with the 3 agents were >24, <4, and <13 h, and the IEs were >110, <10, and <60 log10 CFU/mL.h-1, respectively). Conclusion: MOX demonstrated excellent bactericidal effect, which is worthy of further exploration to serve as an alternative therapeutic agent against ESBL-producing Enterobacteriaceae. PMID- 29391817 TI - Economic evaluation of spondyloarthritis: economic impact of diagnostic delay in Italy. AB - Background and aim: Spondyloarthritis (SpA) is a disease that normally affects the axial skeleton. It progressively leads to overall stiffness up to severe postural deformity of rachis and functional impotence. The objective of the study was to quantify, through an economic model, the impact of specialized testing and pharmacological treatments carried out by the National Health Service (NHS) in normal clinical practice, before the patient is diagnosed with SpA in Italy. In line with the analysis objective, the chosen perspective is that of the NHS. Method: The study was conducted by analyzing the Health Search Database - IMS Health Longitudinal Patient Database, from which newly diagnosed SpA patients were identified over the period 1 January 2007 to 31 December 2013. The use of specialist health care services and pharmacological treatments provided to the patients before the final SpA diagnosis were estimated. Results: Through a retrospective analysis of the Health Search Database, 1,084 subjects (aged 25-45 years) were identified. These patients produced an expense of approximately ?153,000 in the 3 years prior to a confirmed SpA diagnosis, in terms of specialist check-ups and drugs, presumably not appropriately used due to a lack of diagnosis. If we assume that the Health Search Database is a representative sample of the Italian population, it may be estimated that, in the 3 years prior to SpA diagnosis, over ?5.4 million was largely unduly spent in Italy to examine and manage 38,232 newly diagnosed SpA patients, between 2010 and 2013. Conclusion: The costs due to the delay in SpA diagnosis were quantified for the first time in Italy. For this reason, this work represents a contribution for national and regional decision makers to understand the current clinical practice and the economic consequences of a diagnostic delay in the short and medium term. PMID- 29391818 TI - Calcium hydroxylapatite treatment of human skin: evidence of collagen turnover through picrosirius red staining and circularly polarized microscopy. AB - Background: Calcium hydroxylapatite (CaHA, Radiesse(r)) is a biocompatible, injectable filler for facial soft-tissue augmentation that provides volume to tissues, followed by a process of neocollagenesis for improved skin quality. Objective: To examine the effects of CaHA treatment on the molecular organization of collagen using a combination of picrosirius red staining and circularly polarized light microscopy. Methods: Five subjects received subdermal injection of 0.3 mL of CaHA in tissues scheduled for removal during abdominoplasty 2 months later. Tissue specimens from the CaHA injection site and a control untreated area were obtained from excised skin at the time of surgery. Processed tissue sections were stained with picrosirius red solution 0.1% and visualized under circularly polarized light microscopy for identification of thick mature (type I) and thin newly formed (type III) collagen fibers. Pixel signals from both the control and CaHA-treated areas were extracted from the images, and morphometric computerized hue analysis was performed to provide a quantitative evaluation of mature and newly formed collagen fibers. Results: Under picrosirius red staining and circularly polarized light microscopy, green/yellow areas (thin newly formed collagen type III) were visible among the collagen fibers in tissue sections from the area of CaHA injection. In contrast, the majority of the collagen fibers appeared red (thick mature collagen type I) in control tissues. Morphometric analysis confirmed that, following CaHA treatment, the proportion of fibers represented by thin newly formed collagen type III increased significantly (p<0.01) in comparison with the proportion of thick mature collagen type I fibers. In contrast, collagen content of control tissues consisted almost exclusively of thick mature collagen type I fibers. Conclusion: The use of picrosirius red staining and circularly polarized light microscopy provides evidence that subdermal injection of CaHA stimulates the formation of new collagen and dermal remodeling. PMID- 29391819 TI - Endoscope-connected water pump with high flow rates improves the unsedated colonoscopy performance by water immersion method. AB - Objectives: The aim of this study was to determine if different water pump flow rates influence the insertion time of water immersion method in unsedated patients. We tested the hypothesis that high flow rate (HFR) is more effective than low flow rate (LFR) in facilitating insertion. Clinical registration number: NCT01869296. Methods: Consecutive symptomatic patients without prior abdominal surgery were consented and enrolled. They were randomized to an HFR (10.4 mL/s) or LFR (1.7 mL/s) group. The patients were not informed about the flow rate of the water pump (single blinded). Patients underwent unsedated colonoscopy examination with standard colonoscope. Demographic and procedural parameters were recorded. Data were analyzed with Student's t-test or Chi-square test as appropriate. Results: A total of 132 patients (66 in HFR and 66 in LFR group) were recruited. The HFR group showed significantly shorter cecal intubation time (12.5+/-6.2 min in HFR vs 16.3+/-7.3 min in LFR, p=0.004), shorter time to pass rectosigmoid (3.6+/-2.2 min in HFR vs 6.2+/-4.6 min in LFR, p<0.001), and lower pain score (4.2+/-2.8 in HFR vs 5.3+/-2.6 in LFR, p=0.024). The cecal intubation rate was not significantly different (87.9% in HFR vs 80.3% in LFR, p=0.34), and 29 (14 in HFR and 15 in LFR) patients with signs of colon redundancy were successfully intubated to the cecum after repeated loop reduction and position changes. Conclusion: Compared to LFR, HFR of the water infusion pump significantly reduced colonoscopy insertion time and pain score in unsedated patients. Significantly shorter time to pass the rectosigmoid appeared to play a contributory role. PMID- 29391820 TI - Relationship of vitamin D receptor gene polymorphisms in Helicobacter pylori gastric patients. AB - Purpose: The present study aimed to investigate the association between the human VDR gene and Helicobacter pylori infection. Patients and methods: A cross sectional study was conducted on 208 adult patients with upper gastrointestinal symptoms. Gastric biopsy specimens were obtained from each patient for molecular DNA and histological examination. Patients were genotyped for VDR gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism analysis. Results: The allelic and genotypic distribution analyses of the FokI, ApaI and TaqI polymorphisms of the VDR gene did not show distribution differences between H. pylori-positive and -negative groups. The genotype distribution observed for polymorphism BsmI deviated significantly from what was expected in a Hardy-Weinberg equilibrium test in the H. pylori-positive group (chi2=29.048, p<0.001). The distribution of BsmI genotypes differed significantly between the H. pylori-negative and H. pylori-positive groups (p=0.0034), where the frequency of the bb genotype increased among H. pylori positive individuals compared with those without infection (63.25% versus 50.55%, respectively). Conversely, the H. pylori-negative group showed a Bb frequency that was 20.27% higher than in the infected group. Conclusion: We identified a possible association between the BsmI polymorphism and infection by H. pylori. However, further research is required to clarify this relationship. PMID- 29391821 TI - Isolation and gene expression profiling of intestinal epithelial cells: crypt isolation by calcium chelation from in vivo samples. AB - Aim: The epithelial layer within the colon represents a physical barrier between the luminal contents and its underlying mucosa. It plays a pivotal role in mucosal homeostasis, and both tolerance and anti-pathogenic immune responses. Identifying signals of inflammation initiation and responses to stimuli from within the epithelial layer is critical to understanding the molecular pathways underlying disease pathology. This study validated a method to isolate and analyze epithelial populations, enabling investigations of epithelial function and response in a variety of disease setting. Materials and methods: Epithelial cells were isolated from whole mucosal biopsies harvested from healthy controls and patients with active ulcerative colitis by calcium chelation. The purity of isolated cells was assessed by flow cytometry. The expression profiles of a panel of epithelial functional genes were investigated by reverse transcription polymerase chain reaction (PCR) in isolated epithelial cells and corresponding mucosal biopsies. The expression profiles of isolated cells and corresponding mucosal biopsies were evaluated and compared between healthy and inflamed colonic tissue. Results: Flow cytometry identified 97% of cells isolated as intestinal epithelial cells (IECs). Comparisons of gene expression profiles between the mucosal biopsies and isolated IECs demonstrated clear differences in the gene expression signatures. Sixty percent of the examined genes showed contrasting trends of expression between sample types. Conclusion: The calcium chelation isolation method provided a reliable method for the isolation of a pure population of cells with preservation of epithelial cell-specific gene expression. This demonstrates the importance of sample choice when investigating functions directly affecting the colonic epithelial layer. PMID- 29391822 TI - Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch(r) capsules 2.5 MUg) in 3,762 hemodialysis patients with intractable pruritus. AB - Background: Intractable pruritus in hemodialysis patients can significantly decrease their quality of life and is also associated with poor vital prognosis. Although combined multiple causes of intractable pruritus in these patients have been identified, no existing treatments are proven to be sufficiently effective. We conducted a post-marketing surveillance to follow-up and assess the safety and efficacy of nalfurafine, a selective kappa-opioid receptor agonist, for the treatment of intractable pruritus in patients undergoing hemodialysis. Patients and methods: Hemodialysis patients with intractable pruritus from institutions in Japan who received oral nalfurafine hydrochloride between January 2010 and December 2013 were enrolled in the surveillance. Surveillance was completed in July 2015. Safety data during 1 year after nalfurafine treatment onset, and efficacy data of nalfurafine evaluating the first 12-week treatment period and the following period until 1 year after the initial dose of nalfurafine (using global assessment of the itch improvement by the physician, Visual Analog Scale, and the Shiratori's severity scores) were collected and analyzed. Results: In total, 3,762 patients were analyzed for safety. Adverse drug reactions were experienced by 402/3,762 (10.69%) patients. The most frequent adverse drug reactions were insomnia (127/3,762 [3.38%] patients), constipation (34 [0.90%]), somnolence (32 [0.85%]), dizziness (23 [0.61%]), nausea (13 [0.35%]), and malaise (9 [0.24%]). No patients developed dependence on nalfurafine. Nalfurafine was effective in 82.50% (2,880/3,491) of patients during the first 12 weeks and in 84.95% (2,167/2,551) on treatment during the subsequent period until 1 year after nalfurafine treatment initiation. Statistically significant decreases were reported in the Visual Analog Scale and the Shiratori's severity scores (p<0.001). Conclusion: Oral nalfurafine hydrochloride (from 2.5 MUg/day to a maximum of 5.0 MUg/day) continues to be safe and effective for the treatment of intractable pruritus in hemodialysis patients in real-world clinical settings. PMID- 29391823 TI - Pulse versus daily oral Alfacalcidol treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized controlled trial. AB - Background: Secondary hyperparathyroidism is a common complication of chronic kidney disease and is managed using vitamin D replacement therapy. Very few studies have examined the effectiveness of pulse alfacalcidol therapy in comparison to daily oral alfacalcidol therapy in suppressing serum parathyroid hormone (PTH) levels in hemodialysis patients. The aim of this randomized controlled trial was to replicate the findings of prior studies comparing effectiveness of pulse oral alfacalcidol therapy versus daily oral alfacalcidol therapy in suppressing PTH after 13 weeks of therapy using a Palestinian sample of hemodialysis patients, and to identify demographic and biomedical characteristics of patients that are independently associated with PTH levels. Methods: One hundred and sixty-seven patients completed the study, 88 in the daily group and 79 in the pulse group. The pulse group had more clinically significant reduction in mean PTH level by 75 pg/dL at 13 weeks than the daily group, but this was not statistically significant. Results: The effect of alfacalcidol therapy on metabolism of phosphate and corrected calcium levels was comparable in both groups, and pulse therapy was not associated with increased risk of hypercalcemia and hyperphosphatemia. Serum PTH levels were independently and inversely associated with older age and diabetes. Conclusion: Switching daily alfacalcidol therapy to thrice-weekly alfacalcidol pulse therapy seems safe and convenient, especially for hemodialysis patients with poor compliance with treatment. This study also highlights the importance of monitoring and preventing malnutrition in hemodialysis patients and maintaining optimal glycemic control in diabetic hemodialysis patients. PMID- 29391825 TI - Tramadol use in a patient with Brugada syndrome and morphine allergy: a case report. AB - Brugada syndrome is a rare syndrome characterized by arrhythmias and sudden death, particularly in younger individuals. A mutation in a gene encoding the human cardiac sodium channels is responsible for this syndrome. In the literature, there are several case reports of Brugada syndrome in association with the use of several anesthetic agents. Herein, we present our anesthetic practice and the use of tramadol in a 75-year-old female patient who underwent pulmonary lobectomy under general anesthesia and was diagnosed with Brugada syndrome. PMID- 29391824 TI - Altered perfusion of the sensorimotor cortex in patients with cervical spondylotic myelopathy: an arterial spin labeling study. AB - Objective: Advanced magnetic resonance imaging studies have shown functional plasticity or reorganization and metabolite alterations of N-acetyl aspartate in the sensorimotor cortex (SMC), a hallmark region and key brain network, in patients with cervical spondylotic myelopathy (CSM). However, the nature of perfusion in the SMC and the relationship between regional cerebral blood flow (CBF), motor function scores, and structural damage of the cervical cord in patients with CSM are not fully understood. Materials and methods: All right handed participants underwent pseudo-continuous arterial spin labeling pulse sequence scanning, and CBF was then calculated and compared between CSM and healthy groups. Clinical and structural associations were assessed in the SMC. Receiver operating characteristic (ROC) and leave-one-out cross-validation analyses were used to estimate the sensitivity and specificity of the significantly altered CBF in the SMC to distinguish myelopathy-related impairment. Results: A total of 18 pairs of CSM patients and well-matched healthy subjects were included in the analyses. Compared with healthy subjects, CSM patients exhibited significantly decreased CBF in the left premotor ventral/precentral operculum (PMv/PrCO) and the bilateral dorsal anterior cingulate cortex (dACC); and increased CBF in the left paracentral lobule (PCL), the right PCL/supplementary motor area (PCL/SMA), and the right postcentral gyrus (PoCG; Gaussian random field correction at P<0.01). In the CSM group, the CBF values in the right PoCG were negatively correlated with Japanese Orthopaedic Association scores, and the CBF values in several regions were negatively correlated with Neck Disability Index scores. Finally, the ROC analysis revealed that significantly increased CBF in the left PCL, the right PCL/SMA, and the right PoCG discriminated patients with myelopathy-related impairment from healthy subjects. Conclusion: Regional CBF was reduced in operculum-integrated (PMv/PrCO) and motor control (dACC) regions but increased in sensory (PoCG) and motor sensory processing (PCL/SMA) regions in patients with CSM. PMID- 29391826 TI - Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy. AB - Opioid-induced constipation (OIC) is an increasingly prevalent problem in the USA due to the growing use of opioids. A novel class of therapeutics, the peripherally acting MU-opioid receptor antagonists (PAMORAs), has been developed to mitigate the deleterious effects of opioids in the gastrointestinal tract while maintaining central analgesia and minimizing opioid withdrawal. This review aimed to summarize the literature on naldemedine, the third PAMORA to gain US Food and Drug Administration (FDA) approval for the treatment of OIC in adults with chronic noncancer pain-related syndromes. Naldemedine has a chemical structure similar to naltrexone, an opioid receptor antagonist, with chemical modifications that limit its ability to cross the blood-brain barrier. Naldemedine was evaluated in two Phase II and three Phase III clinical trials prior to gaining FDA approval. In two pivotal identical Phase III trials, COMPOSE I (NCT 01965158) and COMPOSE-II (NCT 01993940), patients receiving naldemedine were significantly more likely to respond when compared with placebo (COMPOSE-I: 47.6 vs 34.6%, P=0.002 and COMPOSE-II: 52.5 vs 33.6%, P<0.0001). The most frequent adverse events were abdominal pain (8%) and diarrhea (7%) - rates similar to the other PAMORAs. Based on the available data, naldemedine appears to be an effective and safe drug for the treatment of OIC in adults with chronic noncancer pain. PMID- 29391827 TI - Development and implementation of an inpatient multidisciplinary pain management program for patients with intractable chronic musculoskeletal pain in Japan: preliminary report. AB - Introduction: Multidisciplinary pain management is a useful method to treat chronic musculoskeletal pain. Few facilities in Japan administer a multidisciplinary pain management program, especially an inpatient program. Therefore, we implemented a multidisciplinary pain management program in our hospital based on biopsychosocial factors guided by the recommendations of the International Association for the Study of Pain. The purpose of this study is to describe our inpatient pain management program for Japanese patients, which uses the biopsychosocial method of pain self-management. Materials and methods: Fourteen patients with intractable chronic musculoskeletal pain, who were implemented a multidisciplinary pain management program in our hospital, were studied using the evaluation of the pain and associated factors and physical function. Results: Significant improvement in outcomes were seen in the brief pain inventory, the pain catastrophizing scale (rumination, magnification, and helplessness), the pain disability assessment scale, the hospital anxiety and depression scale (anxiety and depression), the pain self-efficacy questionnaire, the EuroQol five dimensions questionnaire, and muscle endurance and physical fitness. We found no statistically significant differences in static flexibility or walking ability. Conclusion: We developed an inpatient chronic pain management program for Japanese patients. Our results suggest that our program improves chronic musculoskeletal pain coping mechanisms, and that the program can improve patients' quality of life and some physical function. This inpatient pain management program is being expanded to better help intractable chronic musculoskeletal pain patients. PMID- 29391828 TI - Toxic elements as biomarkers for breast cancer: a meta-analysis study. AB - Aims and background: Breast cancer (BC) is responsible for a large proportion of incidence of cancer in the world. Identifying the risk factors contributing to the incidence of BC is crucial to find efficient preventive and management strategies for this disease. Several studies have examined Arsenic (As), Cadmium (Cd), and Nickel (Ni) as risk factors for BC. The present study aimed at studying the link between As, Cd, and Ni concentrations and BC by using a meta-analysis. Materials and methods: All case-control studies addressing the relationship between As, Cd, and Ni concentrations with BC were identified through electronic search databases (Scopus, ISI Web of Science, PubMed, EmBase, and Cochrane Library). The relevant data obtained from these papers were analyzed by a random effects model. The heterogeneity of studies was secured by using I2 index. Funnel plots and Egger's test were used to examine publication bias. Results: In the present study, due to different measurement methods used for measuring As, Cd, and Ni, the concentration of these elements was measured in various subgroups (1: plasma, 2: breast tissue, and 3: scalp hair and nail) of individuals with BC and healthy subjects. The overall integration of data from the 3 groups led to the conclusion that there was a significant difference in Cd and Ni statuses between healthy and BC patients; the standard mean difference was 2.65 (95% CI: 1.57 3.73; P=0.000) and 2.06 (95% CI: 1.20-3.32; P=0.000), respectively. Whereas, there was no significant statistical difference in As status between healthy subjects and BC patients; the standard mean difference between them being 0.52 (95% CI: -0.12-1.16; P=0.114). Conclusion: The present study indicates that there is a direct and positive association between Cd and Ni concentrations and BC risk. It is a warning to health care providers and policy makers to find viable solutions and take requisite measures to reduce BC risk in the society. PMID- 29391829 TI - The potential role of angiogenesis in the development of shoulder pain, shoulder dysfunction, and lymphedema after breast cancer treatment. AB - Shoulder morbidity is a well-documented sequela of breast cancer treatment, which includes various manifestations such as pain, reduced range of motion, and lymphedema, among others. The multifactorial nature of such morbidities has long been appreciated, and research on reliable risk predictors of development thereof still continues. Previous studies have demonstrated the potential of different types of physical therapy to treat such shoulder problems, and the integration of such interventions into routine care for breast cancer survivors is a requirement in most high-income countries. Although patients at risk for developing shoulder problems would most likely benefit from posttreatment physical therapy, currently, there is no gold standard for identifying this patient group. This is particularly important in low- and middle-income countries where scarce monetary resources need to be directed specifically to those most in need. Modulators of the angiogenesis pathway have been implicated in noncancer shoulder conditions such as rotator cuff disease, adhesive capsulitis, and tendon injuries. The present review summarizes the role of angiogenesis in the development of shoulder morbidity among breast cancer survivors and sets forth the rationale for our belief that angiogenesis signaling may help explain a proportion of the reported clinical variability noted in the development of shoulder pain and dysfunction and upper-limb lymphedema after breast cancer treatment. PMID- 29391830 TI - Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going. AB - Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer (BC) subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile. PMID- 29391831 TI - Metabolic syndrome as a risk factor for total hip or knee replacement due to primary osteoarthritis: a prospective cohort study (the HUNT study and the Norwegian Arthroplasty Register). AB - Objective: Biochemical changes associated with obesity may accelerate osteoarthritis beyond the effect of mechanical factors. This study investigated whether metabolic syndrome and its components (visceral obesity, hypertension, dyslipidemia and insulin resistance) were risk factors for subsequent total hip replacement (THR) or total knee replacement (TKR) due to primary osteoarthritis. Design: In this prospective cohort study, data from the second survey of the Nord Trondelag Health Study 2 (HUNT2) were linked to the Norwegian Arthroplasty Register for identification of the outcome of THR or TKR. The analyses were stratified by age (<50, 50-69.9 and >=70 years) and adjusted for gender, body mass index, smoking, physical activity and education. Results: Of the 62,661 participants, 12,593 (20.1%) were identified as having metabolic syndrome, and we recorded 1,840 (2.9%) THRs and 1,111 (1.8%) TKRs during a mean follow-up time of 15.4 years. Cox regression analyses did not show any association between full metabolic syndrome and THR or TKR, except in persons <50 years with metabolic syndrome who had a decreased risk of THR (hazard ratio [HR] 0.58, 95% CI 0.40 0.83). However, when including only participants whose exposure status did not change during follow-up, this protective association was no longer significant. Increased waist circumference was associated with increased risk of TKR in participants <50 years (HR 1.62, 95% CI 1.10-2.39) and 50-69.9 years (HR 1.43, 95% CI 1.14-1.80). Hypertension significantly increased the risk of TKR in participants <50 years (HR 1.38, 95% CI 1.05-1.81), and this risk was greater for men. Conclusion: This study found an increased risk of TKR in men <50 years with hypertension and persons <70 years with increased waist circumference. Apart from this, neither metabolic syndrome nor its components were associated with increased risk of THR or TKR due to primary osteoarthritis. PMID- 29391832 TI - Familial aggregation of tonsillectomy in early childhood and adolescence. AB - Background: The tonsils are immunological gatekeepers against pathogens. Immunological response to tonsillitis may vary clinically from no enlargement of the tonsils to nearly obstructive conditions. In this investigation, we studied the familial aggregation of tonsillectomy, as an indicator of the extent to which tonsillar immune responses to infections might be genetically controlled. Methods: Data on kinship relations and vital status from the Danish Civil Registration System were used to establish a cohort of Danes with relatives born since 1977. Tonsillectomies in all hospitals and clinics from 1977 to 2013 were identified in national registers together with the indication for tonsillectomy. Rate ratios (RRs) for tonsillectomy >1 year after tonsillectomy in specific types of relatives (first to fourth degree) were estimated in Poisson regression models with adjustment for calendar period, sex, age, and total number of specified relatives. Results: A cohort of 2.4 million persons was followed for 44,100,697 million person-years (mean 18.4 years/person), and included 148,190 tonsillectomies. RRs of tonsillectomy were consistently higher when the relatedness and the number of tonsillectomized relatives were higher. RRs were similar in boys and girls, but were larger in early childhood. Additional analyses suggested that this relatively higher RR at younger ages was due to a larger influence of shared environment at younger ages, whereas the genetic influence was similar at all ages. Results were similar for tonsillectomies performed strictly due to tonsillitis. Conclusions: Genetic factors appear to predispose to severe tonsillitis underlying tonsillectomies, regardless of age and sex. Further studies are needed to understand how genes regulate the tonsils' immune response against infections. PMID- 29391833 TI - A validation study of the CirCom comorbidity score in an English cirrhosis population using the Clinical Practice Research Datalink. AB - Purpose: The CirCom score has been developed from Danish data as a specific measure of comorbidity for cirrhosis to predict all-cause mortality. We compared its performance with the Charlson Comorbidity Index (CCI) in an English cirrhosis population. Patients and methods: We used comorbidity scores in a survival model to predict mortality in a cirrhosis cohort in the Clinical Practice Research Datalink. The discrimination of each score was compared by age, gender, socioeconomic status, cirrhosis etiology, cirrhosis stage, and year after cirrhosis diagnosis. We also measured their ability to predict liver-related versus non-liver-related death. Results: There was a small improvement in the C statistic from the model using the CirCom score (C=0.63) compared to the CCI (C=0.62), and there was an overall improvement in the net reclassification index of 1.5%. The improvement was more notable in younger patients, those with an alcohol etiology, and those with compensated cirrhosis. Both scores performed better (C statistic >0.7) for non-liver-related deaths than liver-related deaths (C statistic <0.6), as comorbidity was only weakly predictive of liver-related death. Conclusion: The CirCom score provided a small improvement in performance over the CCI in the prediction of all-cause and non-liver mortality, but not liver-related mortality. Therefore, it is important to include a measure of comorbidity in studies of cirrhosis survival, alongside a measure of cirrhosis severity. PMID- 29391834 TI - Independent and combined effect of bilirubin and smoking on the progression of chronic kidney disease. AB - Objective: Whether serum bilirubin and cigarette smoking affect the risk of renal function decline remains inconclusive. We aimed to test the independent and combined effects of bilirubin and cigarette smoking on the progression of chronic kidney disease (CKD) in hypertensive adults. Methods: The study population consisted of 12,633 patients in the renal sub-study of the China Stroke Primary Prevention Trial. The primary outcome was progression of CKD, defined as a decrease in estimated glomerular filtration rate (eGFR) of >=30% and to a level of <60 mL/min/1.73 m2 if baseline eGFR was >=60 mL/min/1.73 m2, or a decrease in eGFR of >=50% if baseline eGFR was <60 mL/min/1.73 m2, or end-stage renal disease. The secondary outcomes included 1) rapid decline in renal function and 2) annual rate of eGFR decline. Results: The median follow-up duration was 4.4 years. Cigarette smoking had no significant effect on the progression of CKD (odds ratio [OR]: 1.11, 95% confidence interval [95% CI]: 0.78-1.57). However, a significantly lower risk of the primary event (OR: 0.72, 95% CI: 0.55-0.95) was found in participants in tertile 3 compared to those in tertiles 1-2 for total bilirubin (TBiL) levels. More importantly, there was an interaction between TBiL and smoking status on the primary outcome (P for interaction =0.013). Among ever smokers, TBiL levels had no significant effect on the primary outcome. However, among never smokers, higher TBiL levels were significantly associated with a lower risk of the primary outcome (tertile 3 vs 1-2; OR: 0.53, 95% CI: 0.36 0.78). Similar trends were observed for direct bilirubin and secondary outcomes. Conclusion: Among hypertensive patients, bilirubin was inversely associated with the progression of CKD in never smokers, but not in ever smokers. PMID- 29391835 TI - Cardiovascular medication changes over 5 years in a national data linkage study: implications for risk prediction models. AB - Background: Despite widespread use of cardiovascular disease (CVD) preventive medications in cohorts used to develop CVD risk prediction models, only some incorporate baseline CVD pharmacotherapy and none account for treatment changes during study follow-up. Therefore, current risk prediction scores may underestimate the true CVD event risk. We examined changes in CVD pharmacotherapy over 5 years in preparation for developing new 5-year risk prediction models. Methods: Anonymized individual-level linkage of eight national administrative health datasets enabled identification of all New Zealanders aged 30-74 years, without prior hospitalization for CVD or heart failure, who utilized publicly funded health services during 2006. We determined proportions of participants dispensed blood pressure lowering, lipid lowering, and antiplatelet/anticoagulant pharmacotherapy at baseline in 2006, and the proportion of person years of follow up (2007-2011) where dispensing occurred. Results: The study population comprised of 1,766,584 individuals, representing85% of all New Zealanders aged 30-74 years without prior CVD or heart failure in 2006, with mean follow-up of 4.9 years (standard deviation 0.6 years; 8,589,931 total person years). CVD medications were dispensed to 21% of people at baseline, with most single or combination pharmacotherapies continuing for >=80% of follow-up. Complete discontinuation of baseline treatment accounted for 2% of follow-up time while CVD pharmacotherapy that commenced after baseline accounted for 7% of total follow-up time. Conclusion: In a national primary prevention cohort of 30-74 year olds, one in five received baseline CVD primary preventive pharmacotherapy and medication changes over the subsequent 5 years were modest. Baseline medication use is an important consideration when estimating CVD risk from modern cohorts. It is currently unclear how to incorporate available methods to account for treatment changes during follow-up into risk prediction scores, but this study demonstrates that baseline therapy captures most of the effect of treatment in 5-year risk models. However, the impact of treatment changes on the more common 10-year risk models requires further investigation. PMID- 29391836 TI - Physician preference items: what factors matter to surgeons? Does the vendor matter? AB - Background: The USA devotes roughly $200 billion (6%) of annual national health expenditures to medical devices. A substantial proportion of this spending occurs during orthopedic (eg, hip and knee) arthroplasties - two high-volume hospital procedures. The implants used in these procedures are commonly known as physician preference items (PPIs), reflecting the physician's choice of implant and vendor used. The foundations for this preference are not entirely clear. This study examines what implant and vendor characteristics, as evaluated by orthopedic surgeons, are associated with their preference. It also examines other factors (eg, financial relationships and vendor tenure) that may contribute to implant preference. Methods: We surveyed all practicing orthopedic surgeons performing 12 or more implant procedures annually in the Commonwealth of Pennsylvania. The survey identified each surgeon's preferred hip/knee vendor as well as the factors that surgeons state they use in selecting that primary vendor. We compared the surgeons' evaluation of multiple characteristics of implants and vendors using analysis of variance techniques, controlling for surgeon characteristics, hospital characteristics, and surgeon-vendor ties that might influence these evaluations. Results: Physician's preference is heavily influenced by technology/implant factors and sales/service factors. Other considerations such as vendor reputation, financial relationships with the vendor, and implant cost seem less important. These findings hold regardless of implant type (hip vs knee) and specific vendor. Conclusion: Our results suggest that there is a great deal of consistency in the factors that surgeons state they use to evaluate PPIs such as hip and knee implants. The findings offer an empirically derived definition of PPIs that is consistent with the product and nonproduct strategies pursued by medical device companies. PPIs are products that surgeons rate favorably on the twin dimensions of technology and sales/service. PMID- 29391837 TI - Refractory relapsing polychondritis: challenges and solutions. AB - Relapsing polychondritis is a severe systemic immune-mediated disease characterized by an episodic and progressive inflammatory condition with progressive destruction of cartilaginous structures. This disease has for nearly a century kept secrets not yet explained. The real incidence and prevalence of this rare disease are unknown. The multiple clinical presentations and episodic nature of relapsing polychondritis cause a significant diagnosis delay. No guidelines for the management of patients with relapsing polychondritis have been validated to date. The challenges remain, both in the understanding of its pathophysiology and diagnosis, evaluation of its activity and prognosis, and its treatment. Possible solutions involve the sharing of data for relapsing polychondritis from worldwide reference centers. Thus, we would be able to evolve toward a better knowledge of its pathophysiology, the publication of new diagnosis criteria, which will include biological markers and imaging findings, the prediction of life-threatening or organ-threatening situations, and the publication of therapeutic evidence-based guidelines after performing at randomized controlled trials. PMID- 29391839 TI - Impact of siltuximab on patient-related outcomes in multicentric Castleman's disease. AB - Multicentric Castleman's disease (MCD) is a rare, widespread lymphoproliferative disorder and a life-threatening disease involving hyperactivity of the immune system, excessive proinflammatory cytokine release, immune cell proliferation, and organ system dysfunction. Interleukin-6 (IL-6) is a cytokine that plays a key role in the pathogenesis of MCD, as it is involved in the synthesis of acute phase reactants and aids in the induction of B-cell proliferation. Siltuximab is an anti-IL-6 chimeric monoclonal antibody that acts as a novel treatment modality to bind to IL-6 with high affinity, thus neutralizing the cytokine bioactivity and inhibiting B-cell proliferation. Clinical trials with siltuximab have shown early clinical promise for patients with MCD for many years, leading to recent US Food and Drug Administration approval as a novel agent for the treatment of MCD. Here, a systematic review was conducted to include 171 cases of MCD patients treated with siltuximab. While traditional treatment methods were able to achieve a 5-year survival rate of only 55%-77%, results of siltuximab treatment demonstrated 5-year survival rates of nearly 96.4% (only 2 deaths reported out of 55 patients with follow-up data). Ultimately, the results from multiple clinical trials have demonstrated that siltuximab is extremely efficacious in alleviating disease symptoms (fatigue, pain, and lymphadenopathy) while simultaneously achieving disease remission, thus extending progression-free survival for years longer than the average 5-year survival rates for MCD. PMID- 29391838 TI - Spotlight on dream recall: the ages of dreams. AB - Brain and sleep maturation covary across different stages of life. At the same time, dream generation and dream recall are intrinsically dependent on the development of neural systems. The aim of this paper is to review the existing studies about dreaming in infancy, adulthood, and the elderly stage of life, assessing whether dream mentation may reflect changes of the underlying cerebral activity and cognitive processes. It should be mentioned that some evidence from childhood investigations, albeit still weak and contrasting, revealed a certain correlation between cognitive skills and specific features of dream reports. In this respect, infantile amnesia, confabulatory reports, dream-reality discerning, and limitation in language production and emotional comprehension should be considered as important confounding factors. Differently, growing evidence in adults suggests that the neurophysiological mechanisms underlying the encoding and retrieval of episodic memories may remain the same across different states of consciousness. More directly, some studies on adults point to shared neural mechanisms between waking cognition and corresponding dream features. A general decline in the dream recall frequency is commonly reported in the elderly, and it is explained in terms of a diminished interest in dreaming and in its emotional salience. Although empirical evidence is not yet available, an alternative hypothesis associates this reduction to an age-related cognitive decline. The state of the art of the existing knowledge is partially due to the variety of methods used to investigate dream experience. Very few studies in elderly and no investigations in childhood have been performed to understand whether dream recall is related to specific electrophysiological pattern at different ages. Most of all, the lack of longitudinal psychophysiological studies seems to be the main issue. As a main message, we suggest that future longitudinal studies should collect dream reports upon awakening from different sleep states and include neurobiological measures with cognitive performances. PMID- 29391840 TI - Medical students' experiences of resuscitation and discussions surrounding resuscitation status. AB - Objectives: In the UK, cardiopulmonary resuscitation (CPR) should be undertaken in the event of cardiac arrest unless a patient has a "Do Not Attempt CPR" document. Doctors have a legal duty to discuss CPR with patients or inform them that CPR would be futile. In this study, final-year medical students were interviewed about their experiences of resuscitation on the wards and of observing conversations about resuscitation status to explore whether they would be equipped to have an informed discussion about resuscitation in the future. Methods: Twenty final-year medical students from two medical schools were interviewed about their experiences on the wards. Interviews were transcribed verbatim, and thematic analysis was undertaken. Results: Students who had witnessed CPR on the wards found that aspects of it were distressing. A significant minority had never seen resuscitation status being discussed with a patient. No students reported seeing a difficult conversation. Half of the students interviewed reported being turned away from difficult conversations by clinicians. Only two of the twenty students would feel comfortable raising the issue of resuscitation with a patient. Conclusion: It is vital that doctors are comfortable talking to patients about resuscitation. Given the increasing importance of this aspect of communication, it should be considered for inclusion in the formal communication skills teaching during medical school. PMID- 29391841 TI - Relationships of demographic variables to USMLE physician licensing exam scores: a statistical analysis on five years of medical student data. AB - Introduction: The purpose of this study was to determine the associations of the demographic variables of gender, state of legal residency, student age, and undergraduate major with scores on the Medical College Admissions Test (MCAT) and the United States Medical Licensing Exam (USMLE) Step 1 and Step 2 Clinical Knowledge. Methods: The researchers collected and analyzed exam scores and demographic student data from participants of five graduating classes of students at the University of Minnesota Medical School (N = 1,067). Results: Significant differences (p < 0.05) were found for traditional-aged (defined as < 25 years old at matriculation) versus nontraditional-aged students on USMLE Step 1 scores (t[1065] = 2.91, p = 0.004) and USMLE Step 2 scores (t[1061] = 4.39, p < 0.001), both in favor of traditional-aged students. Significant differences were found for males versus females on MCAT Composite scores (t[1063] = 6.53, p < 0.001) and USMLE Step 1 scores (t[1065] = 5.14, p < 0.001), both in favor of males. There were no significant differences between science and nonscience majors or between Minnesota legal residents and nonresidents. Conclusion: Traditional age and male gender were associated with higher exam scores, although patterns differed between tests, whereas undergraduate major and state of legal residency were not associated with higher exam scores. PMID- 29391842 TI - Utilizing the principles of Gagne's nine events of instruction in the teaching of Goldmann Applanation Tonometry. AB - Intraocular pressure measurement is important to identify people who are at risk of glaucoma. Goldmann Applanation Tonometry is considered the gold standard with regards to evaluating patients with glaucoma, a sight-threatening condition. The professional execution of this evaluation is critical in the reduction of associated complication rates. This article seeks to put forward a structured lesson plan for ophthalmology trainees, specialist nurses, and optometrists, which integrates Gagne's nine events of instruction to accomplish this objective. PMID- 29391843 TI - Associations between substance use and type of crime in prisoners with substance use problems - a focus on violence and fatal violence. AB - Aim: The present study aimed to study the associations between substance use patterns and types of crimes in prisoners with substance use problems, and specifically whether substance use patterns were different in violent offenders. Methods: Interview data of prisoners with substance use problems (N=4,202, mean age 33.5 years, SD 9.8), derived from the Addiction Severity Index, were run against criminal register data on main types of crimes in the verdict. Results: In binary analyses, compared to those with acquisitive and drug crimes, violent offenders had lower prevalence of illicit drugs and homelessness, but higher prevalence of binge drinking, and higher prevalence of sedative use than clients sentenced with drug crimes. Clients with violent crime had lower prevalence of injecting drug use, compared to all other crimes. In logistic regression, binge drinking and sedatives were positively associated with violent crime (as opposed to non-violent crime), whereas heroin, amphetamine, cocaine, and injecting drug use were negatively associated with violent crime. Among violent offenders only, sedatives tended to be associated with fatal violence (p=0.06), whereas amphetamine, homelessness, age, and (marginally significant, p=0.05) heroin were negatively associated with fatal violence, as opposed to non-fatal violence. Conclusion: Treatment and risk assessment in violent perpetrators with substance use may need to address sedatives and alcohol specifically. Limitations of the study are due to self-reported and cross-sectional data and because a large majority of the prison sample studied here are men. PMID- 29391844 TI - Investigation on Risk Factors of Ventilator-Associated Pneumonia in Acute Cerebral Hemorrhage Patients in Intensive Care Unit. AB - Ventilator-associated pneumonia (VAP) is a predominant factor of pulmonary infection. We analyzed the risk factors of VAP with acute cerebral hemorrhage in intensive care unit (ICU) by univariate and multivariate logistic regression analyses. After comparison of 197 cases of the VAP and non-VAP patients, we found that age > 65 years (P = 0.003), smoke (P = 0.003), coronary heart disease (P = 0.005), diabetes (P = 0.001), chronic obstructive pulmonary disease (COPD) (P = 0.002), ICU and hospital stay (P = 0.01), and days on mechanical ventilation (P = 0.01) were significantly different, indicating that they are risk factors of VAP. All the age > 65 years (OR = 3.350, 95% CI = 1.936-5.796, P <= 0.001), smoke (OR = 3.206, 95% CI = 1.909-5.385, P <= 0.001), coronary heart disease (OR = 3.179, 95% CI = 1.015-4.130, P = 0.017), diabetes (OR = 5.042, 95% CI = 3.518-7.342, P <= 0.001), COPD (OR = 1.942, 95% CI = 1.258-2.843, P = 0.012), ICU and hospital stay (OR = 2.34, 95% CI = 1.145-3.892, P = 0.038), and days on mechanical ventilation (OR = 1.992, 95% CI = 1.107-3.287, P = 0.007) are independent risk factors of VAP. After observation of patients with 6 months of follow-up, the BI score was significantly lower in VAP than that in non-VAP, and the rebleeding rate and mortality rate were significantly higher in VAP than those in non-VAP. Thus, the prognosis of the patients with acute cerebral hemorrhage and VAP in ICU is poor. PMID- 29391845 TI - Metabolomics in COPD Acute Respiratory Failure Requiring Noninvasive Positive Pressure Ventilation. AB - We aimed to investigate whether metabolomic analysis can discriminate acute respiratory failure due to COPD exacerbation from respiratory failure due to heart failure and pneumonia. Since COPD exacerbation is often overdiagnosed, we focused on those COPD exacerbations that were severe enough to require noninvasive mechanical ventilation. We enrolled stable COPD subjects and patients with acute respiratory failure requiring noninvasive mechanical ventilation due to COPD, heart failure, and pneumonia. We excluded subjects with history of both COPD and heart failure and patients with obstructive sleep apnea and obstructive lung disease other than COPD. We performed metabolomics analysis using NMR. We constructed partial least squares discriminant analysis (PLS-DA) models to distinguish metabolic profiles. Serum (p=0.001, R2 = 0.397, Q2 = 0.058) and urine metabolic profiles (p < 0.001, R2 = 0.419, Q2 = 0.142) were significantly different between the four diagnosis groups by PLS-DA. After excluding stable COPD patients, the metabolomes of the various respiratory failure groups did not cluster separately in serum (p=0.2, R2 = 0.631, Q2 = 0.246) or urine (p=0.065, R2 = 0.602, Q2 = -0.134). However, several metabolites in the serum were reduced in patients with COPD exacerbation and pneumonia. We did not find a metabolic profile unique to COPD exacerbation, but we were able to clearly and reliably distinguish stable COPD patients from patients with respiratory failure in both serum and urine. PMID- 29391846 TI - A new species of the genus Teloganopsis with setaceous mouthparts and forelegs from southern China (Ephemeroptera, Ephemerellidae). AB - The nymph and reared male and female of a new ephemerellid species, which was collected from southern China and named Teloganopsis setosa Zhou, sp. n., are described. The nymph is unique because of its long and dense setae on labrum, mandibles, maxillae, labium, and forelegs as well as the elongated segments II of labial palpi and expanded paraglossae. The male can be differentiated from close relatives by its larger penis lobes with dorsolateral projections, and the more pigmented tergum IV and caudal filaments. The nymph described in this paper represents a new adaptive and ecological type in the family Ephemerellidae. PMID- 29391847 TI - Morphological anomalies of endangered Korean relict long-horned beetle Callipogon relictus (Cerambycidae, Coleoptera) during ontogenesis and possible causes of their occurrence. AB - This paper describes for the first time cases of exogenous morphological anomalies that occur during rearing of Callipogon relictus Semenov, 1899 in a laboratory setting. The highest frequency of the anomalies has been observed during pupation. It can be assumed that in beetles of this group, at final stages of ontogenesis, some abiotic factors such as humidity and temperature play an important role. PMID- 29391849 TI - Chrysomelinae species (Coleoptera, Chrysomelidae) and new biological data from Rio de Janeiro, Brazil. AB - Chrysomelinae is one of the largest subfamilies in Chrysomelidae, yet much basic information remains unknown for Neotropical species. The present study aims to compile the first regional list of Chrysomelinae for the State of Rio de Janeiro, Brazil, and assemble natural history traits obtained from our fieldwork from 2005 to 2010 in Serra dos Orgaos National Park, a mountainous area of Atlantic forest. The species list was compiled from data from field work, collections, and literature, and recorded a total of 100 species, belonging to 21 genera in one tribe (Chrysomelini) and three subtribes: Chrysolinina (91 species), Chrysomelina (eight species) and Entomoscelina (one species). Of these, 91 species are new records for the state. Serra dos Orgaos National Park holds records of 43 species, with Platyphora being the most species-rich genus, and Solanaceae the most common host plant family. Some new records of reproductive mode (larviparous vs. oviparous) and larval behavior are also given. These Brazil Chrysomelinae species exhibited a clear seasonal pattern, with more species recorded in the hot and rainy season from October to January, and considerably fewer species from June to August, during the drier and colder months. The fraction of new records in comparison with published species and natural history information illustrates how little we know of Chrysomelinae in the state and in the country. PMID- 29391848 TI - Polyphyly of the traditional family Flabellinidae affects a major group of Nudibranchia: aeolidacean taxonomic reassessment with descriptions of several new families, genera, and species (Mollusca, Gastropoda). AB - The Flabellinidae, a heterogeneous assembly of supposedly plesiomorphic to very derived sea slug groups, have not yet been addressed by integrative studies. Here novel material of rarely seen Arctic taxa as well as North Atlantic, North and South Pacific, and tropical Indo-West Pacific flabellinid species is investigated morpho-anatomically and with multi-locus markers (partial COI, 16S rDNA, 28S rDNA and H3) which were generated and analysed in a comprehensive aeolid taxon sampling. It was found that the current family Flabellinidae is polyphyletic and its phylogeny and taxonomic patterns cannot be understood without considering members from all the Aeolidacean families and, based on a robust phylogenetic hypothesis, morpho-anatomical evolution of aeolids is more complex than suspected in earlier works and requires reclassification of the taxon. Morphological diversity of Flabellinidae is corroborated by molecular divergence rates and supports establishing three new families (Apataidae fam. n., Flabellinopsidae fam. n., Samlidae fam. n.), 16 new genera, 13 new species, and two new subspecies among the former Flabellinidae. Two families, namely Coryphellidae and Paracoryphellidae, are restored and traditional Flabellinidae is considerably restricted. The distinctness of the recently described family Unidentiidae is confirmed by both morphological and molecular data. Several species complexes among all ex-"Flabellinidae" lineages are recognised using both morphological and molecular data. The present study shows that Facelinidae and Aeolidiidae, together with traditional "Tergipedidae", deeply divide traditional "Flabellinidae." Diagnoses for all aeolidacean families are therefore provided and additionally two new non-flabellinid families (Abronicidae fam. n. and Murmaniidae fam. n.) within traditional tergipedids are established to accommodate molecular and morphological disparity. To address relationships and disparity, we propose a new family system for aeolids. Here the aeolidacean species are classified into at least 102 genera and 24 families. Operational rules for integration of morphological and molecular data for taxonomy are suggested. PMID- 29391850 TI - New contributions to the leafhopper genus Gladkara from Thailand (Hemiptera, Cicadellidae, Typhlocybinae, Erythroneurini). AB - General characteristics of Gladkara Dworakowska and a checklist to all the known species of this genus are provided. A new species Gladkara klongensis Song & Dietrich, sp. n. from Thailand is added. PMID- 29391851 TI - A Nomenclator of Croton (Euphorbiaceae) in Madagascar, the Comoros Archipelago, and the Mascarene Islands. AB - All published names of Croton from Madagascar, the Comoros, and the Mascarenes are treated here. We indicate which names are currently accepted (123 native species and 1 introduced), which ones we consider to be heterotypic synonyms (188), which ones are doubtful (25), and which ones should be excluded (5). We newly designate lectotypes for 108 names, and epitypes for C. anisatus Baill., C. nobilis Baill., and C. submetallicus Baill. A total of 133 names are newly treated as synonyms. One new combination is made, Croton basaltorum (Leandri) P.E.Berry for C. antanosiensis var. basaltorum Leandri, and one new name is proposed, Croton toliarensis B.W.vanEe & Kainul. for C. tranomarensis var. rosmarinifolius Radcl.-Sm. PMID- 29391852 TI - The systematic position of Dryopteris blanfordii subsp. nigrosquamosa (Ching) Fraser-Jenkins within the genus Dryopteris Adans. AB - Dryopteris blanfordii (C.Hope) C.Chr. is a member of the Dryopteridaceae, growing in high altitude Picea or Abies forests (2900-3500 m) in China and India. Phylogenetic relationships between D. blanfordii subsp. nigrosquamosa and closely related species of Dryopteris were investigated using a combined analysis of multiple molecular data sets (the protein-coding region of rbcL and matK genes and intergenic spacers psbA-trnH, trnP-petG, rps4-trnS, trnL-trnF and rbcL-accD). An assumption about the position of D. blanfordii subsp. nigrosquamosa within Dryopteris was made by using the Maximum Likelihood and Bayesian Inference approach and chloroplast marker sequences of Dryopteris species from GenBank. The results demonstrated that Asian taxa D. blanfordii subsp. nigrosquamosa and D. laeta as well as two American species D. arguta and D. marginalis belong to the same clade, all four of them being part of Dryopteris section Dryopteris. PMID- 29391854 TI - Insect biodiversity of the Algodones Dunes of California. AB - Over a nine year period beginning in 2007 we surveyed the insects of the Algodones Dunes, Imperial Count, California, as part of a study undertaken for the U.S. Bureau of Land Management. In a series of 22 collecting trips ranging in duration from 2 to 8 days we thus far have accumulated records of 1,840 species, 21 orders and 244 families from the dunes. Hymenoptera constituted the most diverse order, comprising about 45% of all the species recovered. Insect diversity and abundance peaked during the hottest part of the year between the months of May and September. Life history traits of the insects sampled included herbivores (29.6%), parasitoids (28.7%), predators (18.1%), pollen/nectar feeders (10.9%), detritivores (6.2%) and scavengers (2.4%). Seventy-nine or 4% of the insect species collected in the dunes have been solely recorded from there, and 3% of the species almost certainly derive from adjacent aquatic habitats or agricultural ecosystems, as their life histories could not be completed in Algodones Dunes habitat. The insect fauna of the Algodones Dunes is unexpectedly rich and diverse. PMID- 29391853 TI - A new species of Voria Robineau-Desvoidy (Diptera: Tachinidae) from Area de Conservacion Guanacaste in northwestern Costa Rica. AB - Background: We describe a new species in the genus Voria Robineau-Desvoidy, 1830 (Diptera: Tachinidae: Voriini) from Area de Conservacion Guanacaste (ACG) in northwestern Costa Rica. It was reared as part of an ongoing inventory of wild caught caterpillars spanning a variety of moth and butterfly families (Lepidoptera). Our study provides a concise description of the new species using morphology, life history, molecular data, and photographic documentation. In addition to the new species, we provide a diagnosis of the genus as well as new data relating to host use. New information: The following new species of Voria is described: Voriaerasmocoronadoi Fleming & Wood sp. n.The following are proposed by Fleming & Wood as new synonyms of Voria: Xenoplagia Townsend, 1914 syn. n., Hystricovoria Townsend, 1928 syn. n., Afrovoria Curran, 1938 syn. n., and Anavoria Mesnil, 1953 syn. n., and Itavoria Townsend, 1931 syn. n.The following new combinations are proposed as a result of the new synonymies: Voria bakeri (Townsend, 1928), comb. n. and Voria setosa (Townsend, 1914), comb. n. The authors also propose Voria pollyclari (Rocha-e-Silva, Lopes & Della Lucia, 1999), comb. n. based on the morphology of the holotype. PMID- 29391855 TI - Biological control of human disease vectors: a perspective on challenges and opportunities. AB - Chemical insecticides are the mainstay of contemporary control of human disease vectors. However, the spread of insecticide resistance and the emergence of new disease threats are creating an urgent need for alternative tools. This perspective paper explores whether biological control might be able to make a greater contribution to vector control in the future, and highlights some of the challenges in taking a technology from initial concept through to operational use. The aim is to stimulate a dialogue within biocontrol and vector control communities, in order to make sure that biological control tools can realize their full potential. PMID- 29391856 TI - Turning points and advanced family cycles: aging effect in Mexican homes. AB - Aging in Mexico is a process with several effects in the families and homes. However, the presence of older members in Mexican families has been scarcely analyzed. In this paper we reflect on the experiences of homes with advanced life cycles when turning points happen, such as widowhood, retirement, empty nest stage and when chronic diseases appear, as well as caring processes and family and social networks weakening, and social and institutional support diminution. We analyze some data from the National Survey on Health and Aging in Mexico (Enasem, 2001) considering the gender differences and, specially, health condition of elder people. PMID- 29391858 TI - Multi-grade Kindergarten Classrooms and Children's Academic Achievement, Executive Function, and Socio-Emotional Development. AB - Using data from the Early Childhood Longitudinal Study Kindergarten Class of 2010 2011 (ECLS-K: 2011; n = 11,000), this study examined the developmental outcomes of 5-year-old children in multi-grade classrooms (combined pre-kindergarten and kindergarten classrooms serving 3-, 4-, and 5-year-olds) compared with 5-year olds attending kindergarten-only classrooms serving primarily 5-year-olds. Results from regression and propensity score analyses revealed that 5-year-old children who attended multi-grade classrooms with pre-kindergarteners made smaller gains in math and literacy skills and demonstrated less optimal executive function at the end of the school year as compared with children who attended kindergarten-only classrooms. Classroom-level factors largely explained the differences in children's academic achievement but did not consistently explain differences in their executive functioning. No consistent differences emerged for children's social-behavioral development. PMID- 29391857 TI - Community and Proteomic Analysis of Anaerobic Consortia Converting Tetramethylammonium to Methane. AB - Tetramethylammonium-degrading methanogenic consortia from a complete-mixing suspended sludge (CMSS) and an upflow anaerobic sludge blanket (UASB) reactors were studied using multiple PCR-based molecular techniques and shotgun proteomic approach. The prokaryotic 16S rRNA genes of the consortia were analyzed by quantitative PCR, high-throughput sequencing, and DGGE-cloning methods. The results showed that methanogenic archaea were highly predominant in both reactors but differed markedly according to community structure. Community and proteomic analysis revealed that Methanomethylovorans and Methanosarcina were the major players for the demethylation of methylated substrates and methane formation through the reduction pathway of methyl-S-CoM and possibly, acetyl-CoA synthase/decarbonylase-related pathways. Unlike high dominance of one Methanomethylovorans population in the CMSS reactor, diverse methylotrophic Methanosarcina species inhabited in syntrophy-like association with hydrogenotrophic Methanobacterium in the granular sludge of UASB reactor. The overall findings indicated the reactor-dependent community structures of quaternary amines degradation and provided microbial insight for the improved understanding of engineering application. PMID- 29391859 TI - MOCCA: Mirrored Convex/Concave Optimization for Nonconvex Composite Functions. AB - Many optimization problems arising in high-dimensional statistics decompose naturally into a sum of several terms, where the individual terms are relatively simple but the composite objective function can only be optimized with iterative algorithms. In this paper, we are interested in optimization problems of the form F(Kx) + G(x), where K is a fixed linear transformation, while F and G are functions that may be nonconvex and/or nondifferentiable. In particular, if either of the terms are nonconvex, existing alternating minimization techniques may fail to converge; other types of existing approaches may instead be unable to handle nondifferentiability. We propose the MOCCA (mirrored convex/concave) algorithm, a primal/dual optimization approach that takes a local convex approximation to each term at every iteration. Inspired by optimization problems arising in computed tomography (CT) imaging, this algorithm can handle a range of nonconvex composite optimization problems, and offers theoretical guarantees for convergence when the overall problem is approximately convex (that is, any concavity in one term is balanced out by convexity in the other term). Empirical results show fast convergence for several structured signal recovery problems. PMID- 29391860 TI - The Relationship Between Ocular Itch, Ocular Pain, and Dry Eye Symptoms (An American Ophthalmological Society Thesis). AB - Purpose: To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs. Methods: A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch. Results: The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms. Conclusions: Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity. PMID- 29391861 TI - Noninvasive Assessment of Fibrosis Regression in Hepatitis C Virus Sustained Virologic Responders. AB - The emergence of direct-acting antiviral (DAA) therapies and noninvasive measures of liver fibrosis has streamlined the management of patients with chronic hepatitis C virus (HCV) infection. DAA therapy is associated with a significantly higher rate of sustained virologic response (SVR) compared to interferon-based therapies. Concomitantly, validated noninvasive measures of fibrosis allow evaluation of patients for therapy without an invasive liver biopsy. Noninvasive measures of fibrosis can be classified as serologic tests or imaging modalities. Several serologic tests have shown robust reliability and clinical applicability. Similarly, imaging modalities such as vibration-controlled transient elastography and magnetic resonance elastography can be used to assess liver stiffness and correlate with fibrosis. Combinations of serologic and imaging tests further improve accuracy compared to an individual modality. The availability of noninvasive fibrosis measures coupled with high SVR rates has shifted the paradigm in the management of HCV infection in the DAA era. Although these noninvasive tests are valuable in evaluating hepatic fibrosis prior to HCV therapy, use of these measures in monitoring fibrosis regression after HCV eradication is currently limited. Furthermore, for patients with pretreatment cirrhosis, the association between fibrosis regression after successful therapy and the risk of hepatocellular carcinoma (HCC) over time is unclear. There are no guidelines on long-term fibrosis monitoring and HCC surveillance after SVR is achieved. This article summarizes the current data on the applications of noninvasive methods to measure hepatic fibrosis and portal hypertension in HCV. In addition, a road map is provided for monitoring patients with advanced fibrosis after HCV eradication. PMID- 29391863 TI - Occlusion of left atrial appendage affects metabolomic profile: focus on glycolysis, tricarboxylic acid and urea metabolism. AB - Background: Left atrial appendage (LAA) closure (LAAC) by implantation of an occlusion device is an established cardiac intervention to reduce risk of stroke while avoiding intake of oral anticoagulation medication during atrial fibrillation. Cardiac interventions can alter local or systemic gene and protein expression. Effects of LAAC on systemic metabolism have not been studied yet. Objectives: We aimed to study the effects of interventional LAAC on systemic metabolism. Methods: Products of glycolysis, tricarboxylic acid and urea metabolism were analyzed by ESI-LC-MS/MS and MS/MS using the AbsoluteIDQTM p180 Kit in plasma of 44 patients undergoing successful interventional LAAC at baseline (T0) and after 6 months (T1). Results: During follow up, plasma concentrations of several parameters of glycolysis and tricarboxylic acid cycle (TCA) and urea metabolism increased (alanine, hexose, proline, sarcosine), while others decreased (aspartate, glycine, SDMA, serine). Multivariate linear regression analysis showed that time after interventional LAAC was an independent predictor for metabolite changes, including the decrease of SDMA (beta -0.19, p < 0.01) and the increase of sarcosine (beta 0.16, p < 0.01). Conclusions: Successful interventional LAAC affects different pathways of the metabolome, which are probably related to cardiac remodeling. The underlying mechanisms as well as the long term effects have to be studied in the future. PMID- 29391862 TI - The Spatial Relationship between Apparent Diffusion Coefficient and Standardized Uptake Value of 18F-Fluorodeoxyglucose Has a Crucial Influence on the Numeric Correlation of Both Parameters in PET/MRI of Lung Tumors. AB - The minimum apparent diffusion coefficient (ADCmin) derived from diffusion weighted MRI (DW-MRI) and the maximum standardized uptake value (SUVmax) of FDG PET are markers of aggressiveness in lung cancer. The numeric correlation of the two parameters has been extensively studied, but their spatial interplay is not well understood. After FDG-PET and DW-MRI coregistration, values and location of ADCmin- and SUVmax-voxels were analyzed. The upper limit of the 95% confidence interval for registration accuracy of sequential PET/MRI was 12 mm, and the mean distance (D) between ADCmin- and SUVmax-voxels was 14.0 mm (average of two readers). Spatial mismatch (D > 12 mm) between ADCmin and SUVmax was found in 9/25 patients. A considerable number of mismatch cases (65%) was also seen in a control group that underwent simultaneous PET/MRI. In the entire patient cohort, no statistically significant correlation between SUVmax and ADCmin was seen, while a moderate negative linear relationship (r = -0.5) between SUVmax and ADCmin was observed in tumors with a spatial match (D <= 12 mm). In conclusion, spatial mismatch between ADCmin and SUVmax is found in a considerable percentage of patients. The spatial connection of the two parameters SUVmax and ADCmin has a crucial influence on their numeric correlation. PMID- 29391864 TI - Robust and Adaptive Online Time Series Prediction with Long Short-Term Memory. AB - Online time series prediction is the mainstream method in a wide range of fields, ranging from speech analysis and noise cancelation to stock market analysis. However, the data often contains many outliers with the increasing length of time series in real world. These outliers can mislead the learned model if treated as normal points in the process of prediction. To address this issue, in this paper, we propose a robust and adaptive online gradient learning method, RoAdam (Robust Adam), for long short-term memory (LSTM) to predict time series with outliers. This method tunes the learning rate of the stochastic gradient algorithm adaptively in the process of prediction, which reduces the adverse effect of outliers. It tracks the relative prediction error of the loss function with a weighted average through modifying Adam, a popular stochastic gradient method algorithm for training deep neural networks. In our algorithm, the large value of the relative prediction error corresponds to a small learning rate, and vice versa. The experiments on both synthetic data and real time series show that our method achieves better performance compared to the existing methods based on LSTM. PMID- 29391865 TI - Proinflammatory Cytokine IL-17 Shows a Significant Association with Helicobacter pylori Infection and Disease Severity. AB - Background: The pro- and anti-inflammatory cytokines play an important role in the immune response against H. pylori infection. The proinflammatory cytokines of Th17 cells have been suggested to play a major role in H. pylori infection and resulting gastric inflammation. Objective: The objective of this study was to compare the expression of selected inflammatory cytokines (IL-10, IL-17, IL-21, IL-23, and TNF-alpha) in H. pylori-infected patients and healthy controls and to understand their association with H. pylori infection and disease severity. Results: The expression levels of IL-17 and IL-23 were significantly higher in H. pylori-infected patients. The expression of IL-21 was also higher in H. pylori positive patients but there was no significant association with infection. IL-17 expression showed a significant increase with the severity of chronic gastritis. Conclusion: The proinflammatory cytokine, IL-17, shows a significant association with H. pylori infection and disease severity in a Sri Lankan dyspeptic patient population. PMID- 29391867 TI - ANA-Negative Hydralazine-Induced Pericardial Effusion. AB - This case describes a patient with pericardial effusion as a phenomenon of the drug-induced lupus erythematosus (DILE) syndrome due to hydralazine. The relevance of this case report lies in the fact that although hydralazine has been a known causative agent of DILE, its presentation may involve a negative anti nuclear antibody (ANA) study. Pericardial effusion is a documented adverse effect as a result of hydralazine use. It is typically common to screen for DILE with the serum ANA test prior to proceeding to more costly and specific tests (i.e., anti-histone antibody). As per our literature review, this is the second case of hydralazine causing DILE with a negative ANA. As in our case, although the screening serum ANA is the initial next best step for suspicion of DILE by hydralazine, it is important to consider the diagnosis without ANA positivity. PMID- 29391866 TI - Pigmented Cells in the Pineal Gland of Female Viscacha (Lagostomus maximus maximus): A Histochemical and Ultrastructural Study. AB - The presence of pigment has been demonstrated in different nervous structures such as those of retina, substantia nigra, and locus coeruleus. These pigments have also been described in the pineal gland of different mammal species. Histochemical and ultrastructural studies of the pineal gland of female viscacha (Lagostomus maximus maximus) were performed to analyze the presence of pigmented cells under natural conditions and to evaluate a probable relation between pigment content and glandular activity during pregnancy. The following techniques were applied: hematoxylin-eosin, phosphotungstic acid-hematoxylin, Masson-Fontana silver, DOPA histochemistry, Schmorl's reaction and toluidine blue. Estradiol and progesterone serum levels were determined by RIA. The ultrastructural features of the pineal pigment granules were also analyzed. Pigment granules were observed in a random distribution, but the pigmented cells were frequently found near blood vessels. The pineal pigment was histochemically identified as melanin. Differences in the amount of pigmented cells were found between pregnant and nonpregnant viscachas. The ultrastructural analysis revealed the presence of premelanosomes and melanosomes. Estradiol and progesterone levels vary during pregnancy. In conclusion, the changes in the amount of pigment content and hormone levels may indicate that the pineal gland of female viscacha is susceptible to endocrine variations during pregnancy. PMID- 29391868 TI - Tuberculous Spondylitis: A Report of Different Clinical Scenarios and Literature Update. AB - Tuberculosis is still one of the most important health problems in the world. In developed countries, the proportion of extrapulmonary tuberculosis cases is increasing. Nowadays tuberculous spondylitis, also known as Pott disease, is a rare clinical condition but can cause severe vertebral and neurological sequelae that can be prevented with an early correct diagnosis. The aim of this paper is to increase awareness of tuberculous spondylitis in modern times, describing three different cases and discussing its best diagnostic and therapeutic approach based on the current literature. PMID- 29391869 TI - Severe Cholestasis and Bile Cast Nephropathy Induced by Anabolic Steroids Successfully Treated with Plasma Exchange. AB - We report a case of a bodybuilder who took a regimen of anabolic steroids containing stanozolol and testosterone propionate for 8 weeks which led to the development of jaundice and severe pruritus with serum total bilirubin reaching 41.22 mg/dL. Despite supportive care with fluid and albumin therapy, serum creatinine was progressively increasing. He underwent 6 successful sessions of plasma exchange (PE) with marked improvement at the end of the sessions. Three months after discharge, the patient's creatinine and total bilirubin levels were 1.08 mg/dL and 1.2 mg/dL, respectively. PMID- 29391870 TI - Platelet Lysate: The Better Choice for Jaw Periosteal Cell Mineralization. AB - Previously, we demonstrated a high quality of minerals formed by serum-free cultured jaw periosteal cells (JPCs) by Raman spectroscopy but the mineralization extent was not satisfactory. In the present study, we analyzed the proliferation and mineralization potential of human platelet lysate- (hPL-) cultured JPCs in comparison to that of FCS-cultured JPCs. By cell impedance measurements, we detected significantly higher population doubling times of PL-cultured JPCs in comparison to FCS-cultured JPCs. However, this result was not based on lower proliferation activities but on diminished cell sizes which JPCs develop under PL cultivation. The measurements of the metabolic activities clearly showed significantly higher cell proliferation rates under PL culturing. Equivalent levels of the mesenchymal cell markers CD29, CD45, CD73, CD90, and CD105 were detected, but there were significantly increased MSCA-1 levels under PL cultivation. While JPCs only occasionally mineralize under FCS culture conditions, the mineralization potential was significantly stronger under PL cultivation. Moreover, in 4 of 5 analyzed patient cells, the addition of dexamethasone was proved no longer necessary for strong mineralization of PL cultured JPCs. We conclude that in vitro cultivation of JPCs with platelet lysate is a suitable alternative to FCS culture conditions and a powerful tool for the development of high-quality TE constructs using jaw periosteal cells. PMID- 29391872 TI - In Vitro Assessment of Antifungal Caspofungin on Leishmania donovani Culture Isolation. AB - Leishmania parasite isolation from the human aspirates is always challenging due to most probability of the fungal contamination and the use of antifungal drug which could support the selective growth of the Leishmania parasite. In this study, we examine the effect of antifungal drug caspofungin on the promastigote stage of Leishmania donovani. Promastigote parasite was cultivated in M199 + 20% heat-inactivated fetal calf serum and plated in 96-well plates. Seven different concentrations of caspofungin (512 ug/ml to 8 ug/ml) were exposed to parasites, and 50% inhibitory concentration (IC50) was calculated. Candida spp. was used in the experiments to know the efficacy of caspofungin to inhibit fungal growth. The IC50 values of Leishmania strains ranged from 23.02 to 155.80 ug/ml (mean 90.25 +/- 39.01 ug/ml), and it was significantly higher (P value = 0.02) than IC50 values of Candida spp. (ranged from 0.001 to 0.12 ug/ml, mean = 0.05 +/- 0.05 ug/ml). The reduced growth rate of the parasite was found with exposure to 50 ug/ml of caspofungin. Growth inhibition of Leishmania donovani is significantly lower with caspofungin and could be used to protect the parasite cultivation from fungal contamination. PMID- 29391871 TI - Cellular Therapeutics for Heart Failure: Focus on Mesenchymal Stem Cells. AB - Resulting from a various etiologies, the most notable remains ischemia; heart failure (HF) manifests as the common end pathway of many cardiovascular processes and remains among the top causes for hospitalization and a major cause of morbidity and mortality worldwide. Current pharmacologic treatment for HF utilizes pharmacologic agents to control symptoms and slow further deterioration; however, on a cellular level, in a patient with progressive disease, fibrosis and cardiac remodeling can continue leading to end-stage heart failure. Cellular therapeutics have risen as the new hope for an improvement in the treatment of HF. Mesenchymal stem cells (MSCs) have gained popularity given their propensity of promoting endogenous cellular repair of a myriad of disease processes via paracrine signaling through expression of various cytokines, chemokines, and adhesion molecules resulting in activation of signal transduction pathways. While the exact mechanism remains to be completely elucidated, this remains the primary mechanism identified to date. Recently, MSCs have been incorporated as the central focus in clinical trials investigating the role how MSCs can play in the treatment of HF. In this review, we focus on the characteristics of MSCs that give them a distinct edge as cellular therapeutics and present results of clinical trials investigating MSCs in the setting of ischemic HF. PMID- 29391873 TI - Quantitative Analysis and Biological Efficacies regarding the Neuroprotective and Antineuroinflammatory Actions of the Herbal Formula Jodeungsan in HT22 Hippocampal Cells and BV-2 Microglia. AB - Jodeungsan (JDS) is a traditional herbal formula that comprises seven medicinal herbs and is broadly utilized to treat hypertension, dementia, and headache. However, the effects of JDS and its herbal components on neurodegenerative diseases have not been reported. We examined the inhibitory effects of JDS and its seven components on neuronal cell death and inflammation using HT22 hippocampal cells and BV-2 microglia, respectively. Among its seven herbal components, Uncaria sinensis (US), Chrysanthemum morifolium (CM), Zingiber officinale (ZO), Pinellia ternata (PT), Citrus unshiu (CU), and Poria cocos (PC) exhibited significant neuroprotective effects in HT22 cells. In BV-2 cells, JDS significantly suppressed the production of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), indicating the antineuroinflammatory activity of JDS. In addition, the herbal extracts from ZO, Panax ginseng (PG), PT, CU, and PC exhibited inhibitory effects on the inflammatory response in microglia. These data imply that the JDS effect on neurodegeneration occurs via coordination among its seven components. To establish a quality control for JDS, a simultaneous analysis using five standard compounds identified hesperidin (37.892 +/- 1.228 mg/g) as the most abundant phytochemical of JDS. Further investigation of the combinatorial activities of two or more standard compounds will be necessary to verify their antineurodegenerative regulatory mechanisms. PMID- 29391875 TI - Change in the magnitude and mechanisms of global temperature variability with warming. AB - Natural unforced variability in global mean surface air temperature (GMST) can mask or exaggerate human-caused global warming, and thus a complete understanding of this variability is highly desirable. Significant progress has been made in elucidating the magnitude and physical origins of present-day unforced GMST variability, but it has remained unclear how such variability may change as the climate warms. Here we present modeling evidence that indicates that the magnitude of low-frequency GMST variability is likely to decline in a warmer climate and that its generating mechanisms may be fundamentally altered. In particular, a warmer climate results in lower albedo at high latitudes, which yields a weaker albedo feedback on unforced GMST variability. These results imply that unforced GMST variability is dependent on the background climatological conditions, and thus climate model control simulations run under perpetual preindustrial conditions may have only limited relevance for understanding the unforced GMST variability of the future. PMID- 29391874 TI - Regulating the Balance of Th17/Treg via Electroacupuncture and Moxibustion: An Ulcerative Colitis Mice Model Based Study. AB - Aim: To investigate the relationship between the effects of electroacupuncture/moxibustion and the balance of Th17/Treg in treating ulcerative colitis (UC) and to preliminary compare the effects of the above two methods. Methods: DSS-induced UC mice were treated by electroacupuncture and moxibustion. Disease activity index (DAI) was scored; intestinal pathological structure and ultrastructure were observed. The levels of IL-2, IL-6, IL-10, IL 17A, IL-17F, and TGF-beta in plasma were measured by ELISA. The percentages of Treg and Th17 in spleen lymphocytes were analyzed by flow cytometry. Also, the expressions of TLR2, TLR4, RORgammat, and FOXP3 in the distal colon were detected by immunohistochemistry or western blot. Results: Both electroacupuncture and moxibustion can relieve UC. These effects are further supported by ELISA results. In addition, the ratio of Treg and Th17 in spleen lymphocytes and the expression of TLR2 and TLR4 are significantly improved. Also, the expression of RORgammat and FOXP3 in distal colon were improved. Besides, the effect of moxibustion is better than that of electroacupuncture on TLR2, TLR4, and FOXP3 expression (P < 0.05). Conclusion: Both electroacupuncture and moxibustion may ameliorate UC by regulating the balance of Th17/Treg. Whether moxibustion has better efficacy than electroacupuncture needs further study. PMID- 29391876 TI - Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity. AB - The crosstalk of multiple cellular signaling pathways is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation and metastasis. The Hedgehog (Hh) and Wnt signaling pathways are both considered to be essential regulators of cell proliferation, differentiation and oncogenesis. Recent studies have indicated that the Hh and Wnt signaling pathways are closely associated and involved in regulating embryogenesis and cellular differentiation. Hh signaling acts upstream of the Wnt signaling pathway, and negative regulates Wnt activity via secreted frizzled-related protein 1 (SFRP1), and the Wnt/beta-catenin pathway downregulates Hh activity through glioma associated oncogene homolog 3 transcriptional regulation. This evidence suggests that the imbalance of Hh and Wnt regulation serves a crucial role in cancer associated processes. The activation of SFRP1, which inhibits Wnt, has been demonstrated to be an important cross-point between the two signaling pathways. The present study reviews the complex interaction between the Hh and Wnt signaling pathways in embryogenesis and tumorigenicity, and the role of SFRP1 as an important mediator associated with the dysregulation of the Hh and Wnt signaling pathways. PMID- 29391877 TI - Low-level miR-646 in colorectal cancer inhibits cell proliferation and migration by targeting NOB1 expression. AB - Aberrant expression of microRNA (miRNA) is important in the progression of various human cancers, however further investigation is required in order to fully elucidate mechanisms of and validate actions of endogenous non-coding RNAs. The present study demonstrated that the expression of miR-646 was downregulated in colorectal cancer tissues and cell lines. Notably, it was observed that miR 646, a tumor suppressor, inhibited colorectal cancer cell progression through directly targeting Nin one binding protein (NOB1) expression, which possesses anti-tumor properties in colorectal cancer. Furthermore, knockdown of NOB1 expression was responsible for the tumor-suppressive effect of miR-646. The findings suggest that miR-646 may act as a therapeutic target for the treatment of colorectal cancer. PMID- 29391878 TI - Podoplanin is an important stromal prognostic marker in perihilar cholangiocarcinoma. AB - Cancer-associated fibroblasts (CAFs) exhibit various phenotypes and serve an important role in tumor progression. However, research on podoplanin expression in CAFs is limited, and its role in the cholangiocarcinoma microenvironment remains unclear. The present study analyzed the clinical and pathological records of 42 patients diagnosed with perihilar cholangiocarcinoma (pCCA) in The Affiliated Drum Tower Hospital of Nanjing University Medical School (Nanjing, China). Immunohistochemical staining was performed to evaluate the expression of podoplanin in CAFs in order to determine its association with clinicopathological parameters and survival rate. Podoplanin expression in the CAFs was associated with the tumor-node-metastasis staging system, and lymph node metastasis in pCCA. Tumor tissue demonstrated an increase in lymphatic vessel density (LVD) compared with para-tumor tissue. Podoplanin expression in CAFs was associated with LVD in tumor and para-tumor tissues. To examine the effect of podoplanin expression in CAFs on tumor progression, CAFs were isolated from tumor xenografts. Following transfection with an expression plasmid encoding podoplanin, the migratory ability of CAFs was significantly increased. Therefore, CAF-associated podoplanin expression in pCCA may serve as a potential biomarker to evaluate prognosis and provide a valuable target for anticancer therapy. PMID- 29391879 TI - Combined acupuncture and general anesthesia on immune and cognitive function in elderly patients following subtotal gastrectomy for gastric cancer. AB - This study investigated the effects of acupuncture combined with general anesthesia on postoperative immune and cognitive functions in elderly patients undergoing subtotal gastrectomy. We recruited 96 elderly patients who received anesthesia for subtotal gastrectomy and randomly divided them into control (n=48) and experimental (n=48) groups. The control group received general anesthesia and the experimental group received combined acupuncture and general anesthesia. We measured hemodynamic immediately before and after anesthesia induction, and immune observations before and after surgery. We found no significant differences in mean heart rate (HR), mean oxygen saturation (SpO2), and partial pressure of end-tidal carbon dioxide (PETCO2) in the perioperative period between the two groups. Mean arterial pressure (MAP) was lower in the experimental group than that in the control group (P<0.05). The levels of cluster of differentiation 3 (CD3+), CD4+ and CD4+/CD8+ in both groups were significantly lower after surgery in both groups (P<0.05). We also found some time-points in which the immune markers where significantly higher in the experimental group. In terms of adverse reactions, there were no differences in nausea, vomiting, and hypoxemia between the two groups (P>0.05), but the incidence of delayed recovery and postoperative agitation were significantly lower in the experimental group compared with those in the control group (P<0.05). One day after surgery, the experimental group showed better protection of cognitive function than the control group (P<0.05). Overall, combined acupuncture and general anesthesia in elderly gastric cancer patients receiving subtotal gastrectomy showed more stable hemodynamics and fewer stress responses during surgery. Thus, combined acupuncture and general anesthesia can shorten the recovery time from anesthesia, have less negative effects on immune function and decrease the incidence of postoperative cognitive impairment. PMID- 29391880 TI - Downregulation of regulator of G protein signaling 2 expression in breast invasive carcinoma of no special type: Clinicopathological associations and prognostic relevance. AB - Changes in the expression of regulator of G protein signaling 2 (RGS2) are involved in the genesis and development of a number of malignancies. However, the association between changes in the expression of RGS2 and breast invasive carcinoma of no special type (BIC-NST) remains unknown. The present study found that, in comparison to normal breast tissue, BIC-NST exhibited low expression of RGS2 mRNA and protein, as detected using data mining and immunohistochemical analysis. The low expression of RGS2 was associated with the positive status of hormone receptor expression in BIC-NST. Kaplan-Meier analysis revealed that patients with low RGS2 expression had a significantly poorer overall survival rate. Furthermore, multivariate Cox regression analysis demonstrated that the RGS2 low expression was an independent high-risk factor. Gene set enrichment analysis using data from The Cancer Genome Atlas supported these results. In summary, the results of the current study indicate that RGS2 acts as a suppressor gene in the progression of BIC-NST. To the best of our knowledge, the present study is the first concerning the association between RGS2 and hormone receptors in BIC-NST, as well as that between RGS2 expression and the prognosis of patients with BIC-NST. However, the effect of RGS2 in breast cancer requires further investigation. PMID- 29391881 TI - Sialyl Lewisx expression at the invasive front as a predictive marker of liver recurrence in stage II colorectal cancer. AB - Sialyl Lewisx (SLX) is a carbohydrate ligand for endothelial selectin that participates in cell adhesion, proliferation and scattering. It plays an important role in cancer cell adhesion to vascular endothelial cells, leading to hematogenous metastasis. The prognostic significance of SLX expression level at the invasive front in patients with stage II colorectal cancer (CRC) was examined. A total of 209 patients with stage II CRC curatively resected between 1997 and 2000 were enrolled. The preoperative serum SLX levels measured by radioimmunoassay and SLX immunoexpression levels at the invasive front, and at the non-invasive frontal region determined by tissue microarray were analyzed. SLX expression at the invasive front was positively associated with tumor invasion depth (P=0.007) and tumor budding grade (P=0.038). Disease-free survival curves differed between the high and low SLX-expression groups (5-year survival rates, 77.0 and 89.7%, respectively; P=0.036). Liver cancer recurrence was more frequent in the high-expression group than in the low-expression group (15.9 and 2.4%; P=0.002). Multivariate analysis revealed that its expression (hazard ratio, 5.26; P=0.015) and venous invasion (hazard ratio, 4.14; P=0.040) were independent predictive markers of liver cancer recurrence. Neither the preoperative serum SLX level nor SLX expression at the non-invasive frontal region showed any association with histopathological features or disease-free survival. SLX expression level at the invasive front is a promising marker for identifying patients with stage II CRC with a high risk of liver cancer recurrence. PMID- 29391882 TI - Roles of circulating endothelial progenitor cells and endothelial cells in gastric carcinoma. AB - The present study aimed to investigate the role of endothelial progenitor cells (EPCs) and endothelial cells (ECs) in the peripheral blood of patients with gastric cancer (GC), and to investigate vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in GC tissues. First, 6 ml peripheral blood with added anticoagulant was collected from each of the 42 patients with GC, followed by determination of the number of EPCs and ECs by flow cytometry using the surface markers cluster of differentiation (CD)34brightCD133+CD31+CD45dim and CD34dimCD133-CD31brightCD45-, respectively. VEGF expression in patients with GC was detected by the streptomycin avidin peroxidase immunohistochemical method, and MVD was calculated using the marker CD34. EPC and EC levels were positively associated with VEGF expression level, as well as with MVD. VEGF expression was positive in 66.67% GC cases, and its level was significantly associated with tumor-node-metastasis (TNM) stage, invasion depth and lymph-node metastasis (P<0.05). VEGF expression level was also positively associated with MVD. MVD in GC was significantly larger than that in normal tissue (P<0.01), and it was significantly associated with TNM stage (P<0.05), invasion depth (P<0.01) and lymph-node metastasis (P<0.01). EPCs in the peripheral blood have an important role in GC development, and may be a promising indicator of GC diagnosis and prognosis. PMID- 29391883 TI - Modified vs. standard D2 lymphadenectomy in distal subtotal gastrectomy for locally advanced gastric cancer patients under 70 years of age. AB - The present study was conducted to investigate the prognosis and survival of patients with locally advanced gastric cancer who underwent distal subtotal gastrectomy with modified D2 (D1+) and D2 lymphadenectomy, under 70 years of age. The five-year overall survival rates of 390 patients were compared between those receiving D1+ and D2 lymphadenectomy. Univariate and multivariate analyses were used to identify factors that correlated with prognosis and lymph node metastasis. Tumor size (P=0.039), pT stage (P=0.011), pN stage (P<0.001), and lymphadenectomy (P=0.004) were identified as independent prognostic factors. Furthermore, tumor size (P=0.022), pT stage (P=0.012), and lymphadenectomy (P=0.028) were proven as independent factors predicting lymph node metastasis. In conclusion, cancers of larger size, higher pT stage, and with D1+ lymphadenectomy had a higher risk of lymph node metastasis. Standard D2 lymphadenectomy removes sufficient lymph nodes to improve staging accuracy and survival. Therefore, D2 lymphanectomy is recommended in distal subtotal gastrectomy for locally advanced gastric cancer, especially for cancers of larger size and higher pT stage. PMID- 29391884 TI - Impact of endoscopic stent insertion on detection of viable circulating tumor cells from obstructive colorectal cancer. AB - The placement of a self-expanding metallic stent (SEMS) in obstructive colorectal cancer (OCRC) is acknowledged to be a safe and effective procedure for the relief of obstruction. However, there is concern that shear forces acting on the tumor during stent expansion may release cancer cells into the circulation, resulting in a poor prognosis. The aim of the present study was to determine whether colonic stent insertion increases viable circulating tumor cells (v-CTCs). A telomerase-specific replication-selective adenovirus-expressing GFP (TelomeScanF35) detection system was used to detect v-CTCs in 8 OCRC patients with a SEMS before and after stent insertion and after surgical resection. In 7 patients, a SEMS was inserted as a bridge to surgery (BTS), and in one patient, a SEMS was inserted for palliation. Surgical resection (R0) was performed in 7 patients. Four patients had no v-CTCs before SEMS placement, two of four measurable patients had an increased number of v-CTCs after SEMS placement (1-3 v CTCs), and one of two patients with increased v-CTCs developed distant lymphatic metastasis despite curative resection. Four patients had v-CTCs (1-19 cells) before SEMS placement, and two of these four patients had an increase in the number of v-CTCs (20-21 cells) after SEMS placement, while one of the four patients died early with distant metastasis. The present study demonstrated that endoscopic stent insertion for OCRC may result in tumor cell dissemination into the peripheral circulation and may induce distant metastases. PMID- 29391885 TI - Sperm-associated antigen 9 is upregulated in hepatocellular carcinoma tissue and enhances QGY cell proliferation and invasion in vitro. AB - The incidence and mortality rates of hepatocellular carcinoma (HCC) are higher in China compared with in other countries. Further research is required in order to improve the diagnosis and treatment of HCC. Sperm-associated antigen 9 (SPAG9) protein has been revealed to serve an important function in cancer progression; however, the underlying mechanisms remain to be elucidated. The present study investigated the expression level of SPAG9 in HCC tissues using quantitative polymerase chain reaction, immunohistochemistry and western blotting, and the results demonstrated that SPAG9 was overexpressed in HCC tissues compared with the adjacent non-cancerous tissues. To explore the potential mechanisms underlying SPAG9 in HCC, the effect of SPAG9 on cell proliferation, cell cycle, migration and invasion capacities were investigated in the QGY HCC cell line by RNA interference. It was revealed that inhibition of SPAG9 mRNA in QGY cells significantly inhibited the expression level of SPAG9 compared with the control. Depletion of SPAG9 expression decreased cell proliferation (P<0.01) and increased the percentage of cells in the G1/G2 cell cycle phase. The percentage of cells in the S phase was decreased, and cell migration and invasion capabilities in vitro were reduced (P<0.01). In summary, the results of the present study suggested that SPAG9 was upregulated in HCC and may serve an important function in cancer cell proliferation, differentiation and invasion. Whether SPAG9 is a potential diagnostic marker and therapeutic target of human HCC requires additional study. PMID- 29391886 TI - Silencing of ECHDC1 inhibits growth of gemcitabine-resistant bladder cancer cells. AB - Combined gemcitabine and cisplatin (GC) treatment is a first line chemotherapy for bladder cancer. However, acquired resistance to GC has been a major problem. To address the mechanism of gemcitabine resistance, and to identify potential biomarkers or target proteins for its therapy, we aimed to identify candidate proteins associated with gemcitabine resistance using proteomic analysis. We established gemcitabine-resistant human bladder cancer cell lines (UMUC3GR and HT1376GR) from gemcitabine-sensitive human bladder cancer cell lines (UMUC3 and HT1376). We compared the protein expression of parental and gemcitabine-resistant cell lines using isobaric tags for relative and absolute quantification (iTRAQ) and liquid chromatography tandem mass spectrometry. Among the identified proteins, ethylmalonyl-CoA decarboxylase (ECHDC1) expression was significantly increased in both of the gemcitabine-resistant cell lines compared to the respective parental cell lines. Silencing of ECHDC1 reduced ECHDC1 expression and significantly inhibited the proliferation of UMUC3GR cells. Furthermore, silencing of ECHDC1 induced upregulation of p27, which is critical for cell cycle arrest in the G1 phase, and induced G1 arrest. In conclusion, ECHDC1 expression is increased in gemcitabine-resistant bladder cancer cells, and is involved in their cell growth. ECHDC1, which is a metabolite proofreading enzyme, may be a novel potential target for gemcitabine-resistant bladder cancer therapy. PMID- 29391887 TI - Targeted sequencing of cancer-associated genes in hepatocellular carcinoma using next-generation sequencing. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Although the clinical success rate for the treatment of early-stage HCC has improved, the prognosis of advanced HCC remains poor owing to the high recurrence rate and the refractory nature of HCC for various anticancer drugs. A better understanding of the pathogenesis of HCC is therefore critically needed in order to treat HCC, including its genetic alterations. Next-generation sequencing (NGS) has provided an unbiased platform to systematically identify gene mutations and reveal the pathogenesis of various cancers. In the present study, a total of 118 samples (59 liver tissues including cancer and adjacent normal tissues) were sequenced using the AmpliSeq Hotspot Cancer Panel (version 2). The most common somatic mutations identified were tumor protein 53 (TP53; 35.6%) and beta-catenin 1 (CTNNB1; 30.5%), and the most frequent variants of those genes were missense variants. In addition, somatic mutations including those in genes encoding colony stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), RET proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (ERBB4; 1.7%) and serine/threonine kinase 11 (STK11, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC. A frameshift variant in STK11, a splice acceptor variant in TP53, a splice region variant in ERBB4 and a stop-gained variant in TP53 were also specifically determined. The most abundant alteration was a C:G>T:A transition (50%) and other transversions, i.e., C:G>G:C (19.6%), T:A>C:G (19.6%), C:G>A:T (12.5%), T:A>G:C (12.5%) and T:A>A:T (5.4%). This spectrum pattern differs from that in other solid tumors. TP53 mutations in the tumors at advanced stages were significantly more frequent compared with those in early-stage tumors. Additionally, age (<70 vs. >=70 years) was significantly associated with CTNNB1 mutations. Using NGS, a number of novel gene mutations were identified in HCC, including established mutations and disproved mutations. The results of the present study offer new insight and improved understanding of the etiology and the development of HCC. PMID- 29391888 TI - Expression of nerve growth factor and brain-derived neurotrophic factor in astrocytomas. AB - Neurotrophic factors (NTFs) are well known to serve critical functions in neural survival, neurite growth and cell differentiation in vivo and in vitro. Previous progress has indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two NTF family members, may be involved in the process of tumor progression. In the present study, the expression of NGF and BDNF was detected using immunohistochemistry on 70 adult astrocytoma samples collected from distinct locations as well as of various pathological grades, with an additional 15 samples being collected from normal adult brain tissue to be used as controls. NGF and BDNF were identified to be expressed in all samples, and their positive cell expression rates in astrocytomas demonstrated a significant increase compared with that in the normal controls (P<0.05), particularly in grade III (P<0.05). In addition, the expression of NGF and BDNF exhibited a gradual decrease ranging from the temporal lobe, parietal lobe and cerebellum to the frontal lobe (P<0.05). The results of the present study suggest that the expression of NGF and BDNF is increased in astrocytomas, which is associated with the pathological grade and the astrocytoma location. PMID- 29391889 TI - Significant expression of CHK1 and p53 in bladder urothelial carcinoma as potential therapeutic targets and prognosis. AB - Checkpoint kinase 1 (CHK1) and p53 are involved in cell-cycle checkpoint, and cellular response to DNA damage. CHK1 and p53 are overexpressed in bladder urothelial carcinoma (BUC); however, a clear elucidation on their interaction and influence in the progress of BUC is absent. The aim of the present study was to examine the correlation between CHK1 and p53 in BUC, and analyze their value as therapeutic targets and prognostic indicators in BUC. A clinically annotated cohort of 110 patients with BUC was identified retrospectively. EnVision-based immunohistochemistry and western blot analysis of the aforementioned DNA repair proteins were conducted on formalin-fixed-paraffin-embedded or frozen tissues from the primary tumor. A total of 45 peritumoral tissue cases were assessed similarly as the control group. In the cohort of 110 patients with BUC, a significant overexpression of CHK1 and p53 was observed in primary compared with the peritumoral tissues (P<0.05). CHK1 and p53 demonstrated a positive correlation in BUC, and both were positively associated with the histological grade, clinical pathological staging, lymphatic metastasis and the 5-year survival rate (P<0.05). However, CHK1 and p53 were not associated with sex, age, tumor diameter, single/multiple sites or incipient/recurrence. The overexpression of CHK1 and p53, and their synergistic interaction were putatively correlated with the physiology of BUC that may be deemed as potential therapeutic targets and prognostic indicators. PMID- 29391890 TI - Identification of proteins with the CDw75 epitope in human colorectal cancer. AB - The CDw75 epitope is an alpha(2,6) sialylated antigen overexpressed in colorectal cancer (CRC), where its expression correlates with the progression of the disease. The CDw75 epitope is located mainly in N-glycoproteins, whose identity remains unknown. The aim of the present study was to identify proteins with the CDw75 epitope as a strategy to deepen the understanding of molecular pathogenesis of CRC and to identify novel biomarkers for this disease. For this purpose, a two dimensional electrophoresis approach was employed. Protein spots in the gels were matched to the corresponding CDw75 positive spots in the immunoblotted polyvinylidene difluoride membranes, and further identification of the protein species was performed by mass spectrometry. Additionally, one-dimensional western blotting experiments were performed to verify the expression of these candidate proteins in the colorectal tissue and their coincidence in molecular mass with the CDw75-positive bands. The findings of the present study indicate that haptoglobin and the keratins 8 (K8) and 18 (K18) are proteins with the CDw75 epitope in the colorectal tissue from CRC patients and also suggest novel functions and cellular locations for these proteins in the colorectal tissue and in relation to CRC. PMID- 29391891 TI - Efficacy of second-line treatment and importance of comorbidity scores and clinical parameters affecting prognosis in elderly patients with non-small cell lung cancer without epidermal growth factor receptor mutations. AB - The present study investigated the importance of comorbidity scores and clinical parameters in elderly patients with non-small cell lung cancer (NSCLC) not harboring epidermal growth factor receptor (EGFR) mutations who received second line chemotherapy. The present study also compared the efficacy of tyrosine kinase inhibitor and cytotoxic chemotherapy as second-line treatment in elderly patients. The present study retrospectively reviewed the treatment of elderly patients with NSCLC (>=70 years old) who received second-line chemotherapy at Korea University Guro Hospital. Patients who had an EGFR mutation were excluded from the analysis. Between 2005 and 2013, 126 patients were included in the present study. The median progression-free survival (PFS) and overall survival (OS) for all patients who received second-line treatment were 2.47 months [95% confidence interval (CI), 2.08-2.86] and 8.63 months (95% CI, 5.99-11.28), respectively. A total of 52 patients (41.3%) were treated with tyrosine kinase inhibitor (TKI) and 74 (58.7%) were treated with chemotherapy. No difference was observed in the median PFS and OS between the TKI and chemotherapy groups (P=0.287 for PFS and P=0.374 for OS). The Charlson comorbidity index was not associated with survival, whereas a simplified comorbidity score and clinical factors, including poor performance status, short PFS of first-line chemotherapy, presence of brain metastasis and low serum albumin and sodium levels were significant prognostic factors in these elderly patients. Second-line chemotherapy was not beneficial to patients who had at least 3 of these factors and a median OS of 1.73 months, whereas patients who had less than 2 of these factors had a median OS of 11.50 months. For elderly lung cancer patients without EGFR mutations, clinical parameters were the most important factors affecting survival, rather than the types of drugs. PMID- 29391892 TI - Influence of magnesium and parathyroid hormone on cisplatin-induced nephrotoxicity in esophageal squamous cell carcinoma. AB - Magnesium (Mg) supplementation has previously been demonstrated to confer protective effects against nephrotoxicity induced by cisplatin. Parathyroid hormone (PTH) regulates Mg homeostasis. The aim of present study was to determine the protective effects of Mg supplementation against cisplatin-induced nephrotoxicity and its association with PTH levels in patients with esophageal squamous cell carcinoma (ESCC). A total of 55 patients with primary ESCC who received chemotherapy with high-dose cisplatin were examined. Mg was administered intravenously, and serum concentrations of PTH, parathyroid hormone-related protein (PTH-rP), creatinine and Mg were prospectively measured. Of the 55 patients, 37 received Mg supplementation. Post-chemotherapeutic creatinine concentrations were significantly increased in patients without Mg supplementation (P=0.01), with grade 1 and 2 increases of 22.2 and 5.6%, respectively, whereas these increases were suppressed by Mg supplementation (change in creatinine, P=0.21), with grade 1 and 2 increases of 8.1 and 0%, respectively. In addition, PTH and PTH-rP concentrations were high in 8 (14.5%) and 6 (10.9%) of all 55 patients, respectively. Alterations in creatinine concentrations (post-/pre-chemotherapy) due to chemotherapy were higher in patients with high levels of PTH regardless of Mg supplementation (P<0.01). Pre therapeutic creatinine concentrations did not correlate with the alterations in creatinine concentrations due to chemotherapy. Intravenous Mg supplementation therefore conferred protective effects against cisplatin-induced nephrotoxicity in patients with ESCC. Furthermore, increases in PTH or PTH-rP may have influenced the extent of nephrotoxicity. PMID- 29391893 TI - Expression levels of UL16 binding protein 1 and natural killer group 2 member D affect overall survival in patients with gastric cancer following gastrectomy. AB - UL16 binding protein 1 (ULBP1) expressed on the tumor cell surface binds to the natural killer group 2 member D (NKG2D) receptor presenting on natural killer (NK), cluster of differentiation (CD)8+ T, and gamma delta T cells. However, the roles of ULBP1 and NKG2D expression and associated immune responses in gastric cancer are unclear. The present study investigated the associations between ULBP1 and NKG2D expression and clinical outcomes in patients with gastric cancer. The levels of ULBP1 and NKG2D expression were examined in human gastric cancer cell lines and gastric cancer tissues from 98 patients who underwent surgery from 2004 to 2008. MKN-74 cells expressed ULBP1 with ULBP2, -5, or -6. NKG2D was expressed at a higher level following activation of T cells and NK cells. Among the tissue sections positive for NKG2D expression, 6 patients were positive for CD8 and CD56. In all tissues, NKG2D-expressing cells were typically aCD8+ T cells. Patients with NKG2D expression in tumors exhibited significantly longer overall survival (OS) compared with patients without NKG2D expression in tumors (P=0.0217). The longest OS was observed in patients positive for ULBP1 and NKG2D, whereas the shortest OS was observed in patients negative for ULBP1 and NKG2D. The interaction between ULBP1 and NKG2D may improve OS in patients with gastric cancer, and may have applications in immunotherapy for the induction of adaptive immunity in patients with cancer. Additionally, ULBP1 and NKG2D may be useful as prognostic biomarkers in gastric cancer. PMID- 29391894 TI - Correlation between chemotherapy resistance in osteosarcoma patients and PAK5 and Ezrin gene expression. AB - The correlation between PAK5 (P21-activated kinase 5) and Ezrin gene expression and chemotherapy resistance of osteosarcoma patients was investigated. The cisplatin (CDDP)-resistance model of osteosarcoma cells SOSP-9607/CDDP was established to detect the cell growth curve. Methyl thiazolyl tetrazolium (MTT) assay was used to detect the drug resistance of cells to chemotherapy drugs. Transwell assay was used to detect the invasive capacity of cells. Semi quantitative PCR (qPCR) was used to detect the mRNA expression levels in the drug resistance-related genes PAK5 and Ezrin. Western blot analysis was used to detect the protein expression levels in PAK5 and Ezrin. Tumor tissues were taken from the osteosarcoma patients with chemotherapy resistance to detect the expression levels of PAK5 and Ezrin via immunohistochemical detection, and the correlation between PAK5 and Ezrin expressions was studied. The results of MTT assay showed that the growth rate of SOSP-9607 was similar to that of SOSP-9607/CDDP, and the difference was not statistically significant (P>0.05). The sensitivity of SOSP 9607 to CDDP was significantly higher than that of SOSP-9607/CDDP, and the difference was statistically significant (P<0.01). Transwell assay showed that the migration capacity of SOSP-9607/CDDP was significantly better than that of SOSP-9607 (P<0.01), indicating that the drug resistance cell lines of osteosarcoma were constructed successfully. Semi-qPCR and western blot analysis showed that the protein expression levels in PAK5 and Ezrin in SOSP-9607/CDDP were significantly higher than those in SOSP-9607 (P<0.01). The results of immunohistochemistry showed that the expression quantities of PAK5 and Ezrin in osteosarcoma tissues were significantly higher than those in para-tumor tissues (P<0.01). Pearson's correlation analysis showed that expression of PAK5 and Ezrin was positively correlated (r=0.197, P=0.023). The osteosarcoma resistance is closely related to the expression levels of PAK5 and Ezrin genes. Thus, PAK5 and Ezrin genes may affect the tolerance of osteosarcoma patients to chemotherapy drugs during treatment via the synergistic effect. PMID- 29391895 TI - High expression of c-Met and EGFR is associated with poor survival of patients with glottic laryngeal squamous cell carcinoma. AB - The present study was undertaken to explore the association between the expression of hepatocyte growth factor receptor (c-Met) and epidermal growth factor receptor (EGFR) with clinicopathological factors and survival status, to obtain prognostic biomarkers in patients with glottis laryngeal squamous cell carcinoma (GLSCC). The expression status of c-Met and EGFR protein was analyzed in 71 archival laryngeal cancer samples by immunohistochemistry. Statistical methods, including univariate and multivariate Cox regression analysis, were used to determine risk factors of progression. In addition, survival analysis was performed by the Kaplan-Meier method. The present study detected positive expression of c-Met and EGFR in 69.0 and 91.5% of GLSCC samples, respectively. The median disease-free survival (DFS) and overall survival (OS) times of all patients were 42.4 and 81.8 months, respectively, and the 2-year DFS and OS rates were 60.1 and 84.91%, respectively. Univariate Cox regression analysis revealed that patients with high expression of EGFR or c-Met had a predisposition for tumor recurrence. The expression of c-Met expression was significantly associated with that of EGFR (P=0.001). High expression of c-Met or EGFR was associated with shorter DFS and OS times. Findings of the multivariate Cox regression analysis indicated that c-Met-expression may be used as an independent predictor of DFS and OS (P=0.002 and P=0.008, respectively). However, EGFR expression was not an independent predictor for DFS and OS (P=0.352 and P=0.24, respectively). The high expression of c-Met and EGFR was associated with poor survival and are important predictors for prognosis of patients with GLSCC. PMID- 29391896 TI - Perfused hypertonic-saline-augmented needle enlarges ablation zones in ex vivo porcine livers. AB - There is a great clinical requirement to improve radiofrequency ablation (RFA) efficacy and create larger coagulation necrotic areas. The aim of the present study was to assess the ability of a hypertonic-saline (HS)-enhanced multipolar RFA technique using a perfused electrode to increase RF-created coagulation necrosis, and to compare that technique with natural saline-augmented needle and conventional multipolar RFA. A total of 18 ablations were performed in explanted porcine livers. A total of 6 thermal ablation zones were created in each of 3 groups treated with the conventional multipolar mode, the multipolar mode with 0.9% NaCl and the multipolar mode with 6% NaCl, respectively. During RFA, the dimensions and volumes of the ablation zones were compared, and gross and microscopic pathological evaluations were performed. Multipolar RFA with 6% NaCl created the largest short-axis diameters and volumes of coagulation necrosis (3.89+/-0.09 mm and 40.01+/-2.86 mm3, respectively) among the three groups (conventional group: 2.31+/-0.04 mm and 8.99+/-0.52 mm3, respectively; 0.9% NaCl solution group: 3.17+/-0.05 mm and 21.79+/-1.05 mm3, respectively). Overall, multipolar RFA with the instillation of 6% NaCl solution through an open perfusion system created a larger ablation zone compared with the conventional and 0.9% NaCl modes. Therefore, HS-enhanced multipolar RFA may be a promising approach for treating large liver tumors. PMID- 29391897 TI - Evaluation of VEGF and PEDF in prostate cancer: A preliminary study in serum and biopsies. AB - Vascular endothelial growth factor (VEGF) and the pigment epithelium-derived factor (PEDF) serve an important role in prostate cancer (PCa). The aim of the present study was to evaluate whether the levels of VEGF and PEDF in serum are associated with the severity of PCa, and whether they can differentiate from patients with benign prostatic hyperplasia (BPH). Two groups of patients were recruited, patients with PCa or BPH that were newly diagnosed without other comorbidities, and were compared with healthy individuals. The levels of VEGF and PEDF were measured by ELISA in serum, and by immunohistochemistry in biopsies. A correlation analysis was performed for the values in biopsies and serum, comparing the VEGF/PEDF ratio, total-prostate-specific antigen (t-PSA) levels and the status of each sample as acinar Ad (Gleason score) or as benign hyperplasia. The results demonstrated that serum levels of VEGF, PEDF, and t-PSA between PCa and BPH were similar to each other, but different to healthy individuals (P<0.05). The VEGF/PEDF ratio in serum had a significant difference between acinar Ad with Gleason score 8-10 and BPH groups (P<0.05). The VEGF and PEDF immunostaining intensities were correlated with its circulating levels in all cases of PCa, but not in BPH. These preliminary results suggest that VEGF and PEDF levels by themselves or in combination with t-PSA did not differentiate between malignant, and benign prostate diseases. However, there was a significant difference observed in the VEGF/PEDF ratio in serum between the groups, suggesting that it may be used as an index for diagnosis and prognosis in a personalized manner, although more studies are necessary. PMID- 29391898 TI - Stewart-Treves syndrome: Magnetic resonance imaging data compared with pathological results from a single center. AB - The aim of the present study was to evaluate the magnetic resonance imaging (MRI) data of patients with Stewart-Treves Syndrome (STS), and to compare them with the corresponding pathological data. A total of 4,289 cases of secondary upper limb lymphedema (LE) from a single center, including 5 female cases of STS who underwent modified-radical post mastectomy, were included in the study. All cases were diagnosed pathologically, and by conventional and contrast-enhanced (ce)MRI scans. A total of 43 tumor nodules (Phi >=4 mm) were examined. According to the immunohistochemical results, the 5 cases of STS were divided into 2 types; 4 patients exhibited STS type I [angiosarcoma (AS)] and 1 patient exhibited STS type 2 [mixed lymphangiosarcoma (mLAS)]. The MRI signal intensity (SI) of all the nodules was compared with the pathological results. In the T1WI sequences, all nodules showed isointensity compared with normal muscle tissues in the same image. However, in the T2WI sequences, there were the visually recognizable differences in the SI compared with the LE tissues in the two STS types. The SI of mLAS was more markedly decreased compared with that of AS. The SI of mLAS was closer to that of normal muscle tissues compared with the SI of AS. In the ceMRI, the SI of the tumor nodules was markedly increased in the two STS types, compared with non-enhancement imaging. Overall, MRI is a useful tool for the evaluation and diagnosis of STS. A chronic case of LE, in which MRI examination demonstrates nodules within the LE, may suggest a diagnosis of STS. PMID- 29391899 TI - CoCl2 increases the expression of hypoxic markers HIF-1alpha, VEGF and CXCR4 in breast cancer MCF-7 cells. AB - The aim of the present study was to investigate the effect of a hypoxic environment on the biological behavior of breast cancer MCF-7 cells, using CoCl2 to mimic the hypoxia model in breast cancer cells. Using 50, 100, 150 and 200 uM CoCl2 as a hypoxic inducer, a hypoxic model was established in MCF-7 cells in vitro. MTT, reverse transcription-quantitative polymerase chain reaction (RT qPCR), terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and western blotting assays were performed to detect MCF-7 cell proliferation under hypoxic conditions and the expression of the hypoxic markers hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and C-X-C motif chemokine receptor 4 (CXCR4) mRNA and that of the associated proteins. The RT-qPCR results revealed that there were no obvious changes in the expression of HIF-1alpha mRNA; however, the expression of CXCR4 and VEGF mRNA increased significantly following treatment with different CoCl2 concentrations (P<0.05). The results of western blotting identified that CoCl2 significantly induced the expression of HIF-1alpha, CXCR4 and VEGF proteins (P<0.05). The MTT assay revealed that different concentrations of CoCl2 inhibited the proliferation of MCF-7 cells. The TUNEL assay demonstrated that CoCl2 was able to trigger apoptosis of MCF-7 cells. Therefore, the results of the present study identified that CoCl2 is able to control MCF-7 cell proliferation and apoptosis, also increasing the expression of HIF-1alpha, CXCR4 and VEGF. The present study may aid the discovery of a novel method to prevent cell damage and decrease cell proliferation in order to prevent the occurrence and development of breast cancer. PMID- 29391900 TI - Network analysis revealed aurora kinase dysregulation in five gynecological types of cancer. AB - Gene markers are crucial for cancer prognosis and treatment. Previous studies have placed greater emphasis on individual diagnostic genes, thereby ignoring systemic-level attributes across diseases. Female-specific cells namely, breast, endometrium, cervical, ovarian and vulvar cells are highly susceptible to cancer. To date, a limited number of molecular studies have been performed that evaluate common biological processes across gynecological types of cancer. Differentially expressed genes in breast, cervical, endometrial, vulvar and ovarian cancer were utilized to construct protein-protein interaction networks, and to identify a common module across the five cancer types. A single common module with 8 nodes and 26 edges was mined among the five cancer systems. In total, four hub genes were present across the five cancer gene sets. Genes in the common module were enriched for the common pathways and associated diseases. The aurora kinase pathway was revealed to be conserved across the five cancer types surveyed. The present study, therefore, revealed that the aurora kinase pathway has a crucial function in the pathogenesis of the five aforementioned gynecological types of cancer through cross-tumor conservation. PMID- 29391901 TI - Expression of cluster of differentiation 151 prior to and following transcatheter arterial chemoembolization therapy in patients with hepatocellular carcinoma and its association with clinicopathological characteristics. AB - Cluster of differentiation (CD)151, a member of tetraspanin family, is considered to be the first tetraspanin to be associated with tumor metastasis. Previous studies in vivo, in vitro and in the clinic have demonstrated that CD151 is involved in tumor progression at different levels through interaction with integrins, growth factor receptors and matrix metalloproteinases. Transcatheter arterial chemoembolization (TACE) is widely recommended for the treatment of patients with advanced hepatocellular carcinoma (HCC) worldwide. It has been hypothesized that TACE may create a hypoxic-ischemic environment that increases the expression of tumor progression-associated factors, promotes the angiogenesis of HCC, and initiates the recurrence and metastasis of HCC. Whether TACE promotes HCC progression remains controversial and numerous studies have focused on the influence of TACE on a number of tumor progression-associated factors. In the present study, the expression of serum CD151 in patients with HCC prior to and following TACE and its association with clinicopathological characteristics was investigated. It was revealed that the expression level of CD151 at 5-7 days post TACE was significantly increased compared with pre-TACE levels. Risk factors and protective factors associated with tumor progression following a single TACE procedure and 18 months of follow-up were also identified. Furthermore, the present study revealed that a pre-TACE CD151 level of >0.3247 ng/ml and a 5-7 days post-TACE CD151 level of >0.3146 ng/ml revealed moderate sensitivity and specificity for predicting HCC progression following a single TACE procedure. The present study highlights CD151 as a useful marker in predicting the response to treatment and monitoring the disease course following TACE. PMID- 29391902 TI - Metformin use and its effect on gastric cancer in patients with type 2 diabetes: A systematic review of observational studies. AB - Increasing evidence suggests that metformin use is associated with a decreased risk of cancer. The traditional therapies for gastric cancer (GC) are gastrectomy and chemoradiotherapy; however, these therapies may cause certain adverse effects, which affect a patient's quality of life, and the overall survival rate is low. At present, little is known about whether the use of metformin decreases the risk of GC in patients with type 2 diabetes. Therefore, in the present study, a systematic review was performed to analyze the effect of metformin on GC. A literature search was conducted in PubMed, EMBASE, and the Cochrane Library databases for articles published up to June 30th, 2016. The studies that evaluated GC patients treated with metformin and compared them with GC patients treated with other antidiabetic drugs were reviewed. Eligible studies were evaluated using the Newcastle-Ottawa Scale. Adjusted hazard ratio and 95% confidence intervals were determined to evaluate the effect of metformin on GC. From the 422 articles evaluated, 5 studies involving a total of 1,804,479 patients met the inclusion criteria and were qualitatively analyzed. The quality of all selected articles was classified as moderate. These studies reported that the long-term use of metformin was associated with a lower risk of GC compared with the lack of use of metformin or the use of other hypoglycemic drugs. In GC patients with diabetes who were subjected to gastrectomy, the cumulative use of metformin reduced the rates of disease recurrence and of all-cause and cancer specific mortality. Despite the limited number of studies on this subject, currently available evidence indicates that metformin is associated with a decreased risk of GC and improves survival in patients with type 2 diabetes. However, more well-designed trials are required to elucidate this association. PMID- 29391903 TI - Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma. AB - It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6 methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM. PMID- 29391904 TI - Hemacytotoxicity and natural killer lytic index: New parameters to evaluate natural killer cell immunity for clinical use in cancer. AB - Cytotoxicity assays with patient peripheral blood mononuclear cell (PBMC)-derived natural killer (NK) cells are useful in evaluating the innate immunity of patients with cancer. However, the size of the NK cell population in PBMC preparations may have significant effects on the assay outcome. Therefore, the present study examined the effect of NK cell frequency in a cytotoxicity system to investigate NK cell immunity in post-surgical colorectal cancer patients. For this, hemacytotoxicity was assessed using PBMC preparations, and lymphocyte subset populations were analyzed in samples obtained from 47 patients and 45 healthy volunteers. In addition, a new theoretical parameter, the 'NK lytic index', was termed to represent the per-cell cytotoxicity and compensate for the NK cell frequency effect during PBMC preparations. Notably, the patterns of hemacytotoxicity and NK lytic index did not coincide in follow-up studies with consecutive patients following surgical intervention. In addition, it was determined that NK cell NKG2D expression influences NK lytic index, but not hemacytotoxicity. Transforming growth factor (TGF)-beta-bound lymphocytes influenced hemacytotoxicity and NK lytic index. These findings indicate that total cell activity (hemacytotoxicity) is not a sum of per-cell activities (NK lytic indexes), suggesting that clinicians should employ NK lytic index in addition to hemacytotoxicity in order to precisely determine how to enhance NK cell immunity in patients with cancer, either focusing on recovering the number of NK cells or boosting NK cell activity in single cell levels, or both. PMID- 29391905 TI - TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells. AB - Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3-mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L-02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3-shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER stress and AKT signaling pathways. PMID- 29391906 TI - PERCIST in Perspective. AB - Positron Emission tomography Response Criteria In Solid Tumors (PERCIST) version 1.0 was introduced in 2009 for objective assessment of tumor metabolic response using 18F-FDG PET/CT. Practical PERCIST: A Simplified Guide to PET Response Criteria in Solid Tumors 1.0 was published in 2016 to review and clarify some of the issues with the PERCIST. In this article, we reflect on the benefits and challenges of implementing PERCIST, and speculate on topics that could be discussed in PERCIST 1.1 in the future. PMID- 29391907 TI - Current Methods to Define Metabolic Tumor Volume in Positron Emission Tomography: Which One is Better? AB - Numerous methods to segment tumors using 18F-fluorodeoxyglucose positron emission tomography (FDG PET) have been introduced. Metabolic tumor volume (MTV) refers to the metabolically active volume of the tumor segmented using FDG PET, and has been shown to be useful in predicting patient outcome and in assessing treatment response. Also, tumor segmentation using FDG PET has useful applications in radiotherapy treatment planning. Despite extensive research on MTV showing promising results, MTV is not used in standard clinical practice yet, mainly because there is no consensus on the optimal method to segment tumors in FDG PET images. In this review, we discuss currently available methods to measure MTV using FDG PET, and assess the advantages and disadvantages of the methods. PMID- 29391908 TI - Obesity and Brain Positron Emission Tomography. AB - Obesity, an increasingly common problem in modern societies, results from energy intake chronically exceeding energy expenditure. This imbalance of energy can be triggered by the internal state of the caloric equation (homeostasis) and non homeostatic factors, such as social, cultural, psychological, environmental factors or food itself. Nowadays, positron emission tomography (PET) radiopharmaceuticals have been examined to understand the cerebral control of food intake in humans. Using 15O-H2 PET, changes in regional cerebral blood flow (rCBF) coupled to neuronal activity were reported in states of fasting, satiation after feeding, and sensory stimulation. In addition, rCBF in obese subjects showed a greater increase in insula, the primary gustatory cortex. 18F fluorodeoxyglucose PET showed higher metabolic activity in postcentral gyrus of the parietal cortex and lower in prefrontal cortex and anterior cingulate cortex in obese subjects. In addition, dopamine receptor (DR) PET demonstrated lower DR availability in obese subjects, which might lead to overeating to compensate. Brain PET has been utilized to reveal the connectivity between obesity and brain. This could improve understanding of obesity and help develop a new treatment for obesity. PMID- 29391909 TI - Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies. AB - The pathological features of Alzheimer's disease are senile plaques which are aggregates of beta-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease. PMID- 29391910 TI - Prognostic Value of Pre- and Post-Treatment FDG PET/CT Parameters in Small Cell Lung Cancer Patients. AB - Purpose: To evaluate the prognostic value of PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC. Methods: Fifty nine patients with initially diagnosed SCLC from 2009 to 2014 were included and had chemotherapy and/or concurrent chemoradiotherapy. FDG PET/CT examinations were performed before (PET1) and after (PET2) treatment to evaluate treatment response. A region of interest was placed over the primary lesion and metastatic lymph nodes within the thoracic cavity. PET parameters including change from PET1 to PET2 (Delta in %) were acquired: SUVmax, SUVpeak, MTV2.5, TLG, DeltaSUVmax, DeltaSUVpeak, DeltaMTV and DeltaTLG. Patient characteristics including staging, age, sex, LDH and response evaluation by RECIST were surveyed. Statistical analysis was done using Kaplan-Meier method and Cox regression analysis with respect to OS and PFS. Results: The median follow-up was 9.6 months (2.5-80.5 months). 27 patients were LD and 32 were ED. Forty-six patients (78.0%) had died, and median OS was 8.6 months; 51 patients (86%) showed disease progression, and median PFS was 2.5 months. On univariate analysis, patients with ED, high interval change (DeltaSUVmax and DeltaSUVpeak) and low PET2 parameters showed longer OS and PFS. Multivariate analyses demonstrated that DeltaSUVpeak (HR 2.6, P = 0.002) was an independent prognostic factors for OS, and MTV2.5 of PET2 (HR 2.8, P = 0.001), disease stage (HR 2.7, P = 0.003) and RECIST (HR 2.0, P = 0.023) were independent prognostic factors for PFS. Conclusions: Metabolic and volumetric PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC have significant prognostic information. PMID- 29391911 TI - Evaluation of 18F-FDG PET/CT Parameters for Detection of Lymph Node Metastasis in Cutaneous Melanoma. AB - Purpose: The purpose of this study was to investigate the value of 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in the detection of regional lymph node (LN) metastasis in patients with cutaneous melanoma. Methods: We evaluated patients with cutaneous melanoma who underwent FDG PET/CT for initial staging or recurrence evaluation. A total of 103 patients were enrolled, and 165 LNs were evaluated. LNs that were confirmed pathologically or by follow-up imaging were included in this study. PET parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis and tumour-to-liver ratio, were used to determine the presence of metastases, and the results were compared with CT-determined LN metastasis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the FDG PET parameters. Results: A total of 93 LNs were malignant, and 84 LNs were smaller than 10 mm. In all 165 LNs, an SUVmax of >2.51 showed a sensitivity of 73.1%, a specificity of 88.9%, and an accuracy of 80.0% in detecting metastatic LNs. CT showed a higher specificity (87.3%) and lower accuracy (65.5%). For non-enlarged regional LNs (<10 mm), an SUVmax cut-off value of 1.4 showed the highest negative predictive value (81.3%). For enlarged LNs (>=10 mm), an SUVmax cut-off value of 2.4 showed the highest sensitivity (90.7%) and accuracy (88.9%) in detecting metastatic LNs. Conclusions: In patients with cutaneous melanoma, an SUVmax of >2.4 showed a high sensitivity (91%) and accuracy (89%) in detecting metastasis in LNs >=1 cm, and LNs <1 cm with an SUVmax <1.4 were likely to be benign. PMID- 29391912 TI - Correlation of FDG PET/CT Findings with Long-Term Growth and Clinical Course of Abdominal Aortic Aneurysm. AB - Purpose: Herein, we report characteristics of 18F-fluorodeoxyglucose (FDG) uptake in abdominal aortic aneurysms (AAAs) during a long-term follow-up. In addition, we investigated the association between FDG uptake and the physician decision to perform an intervention. Methods: We performed a retrospective review of 42 patients with AAAs who underwent FDG positron emission tomography (PET)/computed tomography (CT). The size of the AAA was measured in serial CT or PET/CT images. The long-term growth rate of AAAs was calculated by linear regression of the size change. Maximal SUV of the AAA (SUVAAA) and mean SUV of the blood pool (SUVBlood) were measured in PET/CT fusion images. To assess the FDG uptake of AAAs, the target-to-background ratio (TBR) was defined as the ratio of SUVAAA to SUVBlood. We compared FDG uptake of AAAs with the long-term growth rate of AAAs and clinical data. Results: TBR was not significantly different between patients with and without significant growth (1.55 +/- 0.20 vs. 1.57 +/- 0.14; P = 0.5599). However, in patients with significant growth, TBR exhibited a significant positive correlation with the growth rate (r2 = 0.2601, P = 0.0306). TBR also exhibited a significant difference between patients with and without intervention (P = 0.0228). Conclusion: FDG uptake of AAA is associated with long-term growth of AAAs in a specified group that exhibits growth. FDG PET/CT may only be effective in predicting the long-term growth of AAAs in specific subgroups of patients. It is also suggested that FDG PET is potentially related to the clinical conditions of AAA patients who need surgical or interventional treatment. PMID- 29391913 TI - The Utility of FDG PET/CT in IgG4-Related Disease with a Focus on Coronary Artery Involvement. AB - Purpose: Our case series aims to study the growing use of FDG PET/CT in diagnostic evaluation and follow up of IgG4-RD with emphasis on patients presenting with coronary artery involvement. Methods: We conducted a search on the nuclear medicine and rheumatology service databases and identified patients with histologically proven IgG4-RD with FDG PET/CT performed at the Singapore General Hospital. The radiological, clinical, and laboratory findings of these patients were analyzed retrospectively. Results: The series included ten male and two female patients. The commonest organ involved (five patients) was the pancreas. In three patients, coronary artery involvement manifested as soft tissue masses surrounding the arterial lumens. In these patients, histological diagnosis was established from alternative biopsy sites with abnormal metabolic activity on FDG PET/CT.Correlation between laboratory and metabolic imaging findings was not statistically significant in our series.Four patients had follow up FDG PET/CT; three showed interval reduction in metabolic activity to baseline. One showed persistent abnormal metabolic activity before a rise in IgG4 levels. The metabolic imaging response was used to guide steroid dose. Conclusions: FDG PET/CT is a useful tool in evaluation and follow-up of IgG4-RD, particularly in identifying alternative biopsy sites in patients who present with coronary artery involvement. Hypermetabolic coronary artery masses on FDG PET/CT should raise clinical suspicion of IgG4-RD. As the coronary artery masses may not show decrease in size after treatment, FDG PET/CT is also useful for metabolic response assessment. PMID- 29391914 TI - Multiple Regression Analysis of Predictors of Bone Scintigraphy Positivity in Patients with Head and Neck Cancers. AB - Purpose: The value of bone scintigraphy (BS) in patients with head and neck cancers (HNCs) has been questioned, with conflicting findings regarding positivity yield with some reports recommending BS be omitted from work-up of HNC patients since it rarely yields positive results. This study aims to determine the positivity yield of BS in HNCs and to determine predictors for BS positivity to help tailor appropriate BS utilization. Methods: BS studies of HNC patients were reviewed, the positivity yield was determined. Clinical predictors for BS positivity including age, sex, site of cancer, staging, histological grading were analyzed using univariable and multivariable logistic regression. Results: Among the 259 BS studies included, 35 (13.5%), 194 (74.9%), and 30 (11.6%) were positive, negative, and equivocal for bone metastasis, respectively. After exclusion of equivocal cases, 229 were analyzed in the regression models. Independent predictors of BS positivity include site of tumor at the nasopharynx (OR 4.37, 95% C.I. 1.04-18.41, p = 0.044), age less than 45 years (OR 3.01, 95% C.I. 1.24-7.33, p = 0.015), and presence of distant metastasis to other organs (OR 3.84, 95% C.I. 1.19-12.43, p = 0.025). Conclusions: In contrast to several studies, bone metastasis as detected by BS was found in a relatively high proportion of patients with HNCs. Independent predictors of BS positivity include the age of less than 45 years, tumor site at the nasopharynx, and the presence of extraskeletal distant metastasis. BS could be useful in patients with these characteristics which enhance the pretest probability of bone metastasis. PMID- 29391915 TI - Primary Renal Leiomyosarcoma Presenting with Subcutaneous and Osseous Metastases: Staging and Follow-Up with 18F-FDG PET/CT. AB - A 60 year old woman who presented with multiple small subcutaneous nodules in the upper back and arms, was referred for an [18F] fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) after histological evaluation revealed metastatic leiomyosarcoma of unknown origin. The PET/CT showed multiple 18F-FDG-avid subcutaneous nodules, bone lesions, as well as a large left renal mass, which was biopsied to confirm a primary renal leiomyosarcoma arising from the renal parenchyma. A post therapy PET/CT showed overall progression of disease. The use of 18F-FDG PET/CT in the staging and evaluation of response to therapy of a renal leiomyosarcoma has not been previously described in the literature. PMID- 29391916 TI - Systemic Lupus Erythematosus Associated Pitfalls on 18F-FDG PET/CT: Reactive Follicular Hyperplasia, Kikuchi-Fujimoto Disease, Inflammation and Lymphoid Hyperplasia of the Spleen Mimicking Lymphoma. AB - Systemic lupus erythematosus (SLE) is associated with a variety of inflammatory processes that can affect the lymph nodes, brain, kidneys, and spleen. We present two patients with SLE in whom SLE-associated conditions complicated interpretation of 18F-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging of the lymph nodes and the spleen. The imaging findings mimicked lymphoma, but histopathological evaluation showed benign processes including reactive follicular hyperplasia in the lymph nodes, Kikuchi-Fujimoto disease in perisplenic lymph nodes, and inflammatory changes and lymphoid hyperplasia in the spleen. PMID- 29391917 TI - Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an Empirical Proof of a Promising Concept. AB - The dose-limiting salivary gland toxicity of 225Ac-labelled PSMA for treatment of metastatic, castration-resistant prostate cancer remains unresolved. Suppressing the metabolism of the gland by intraparenchymal injections of botulinum toxin appears to be a promising method to reduce off-target uptake. A 68Ga-PSMA PET/CT scan performed 45 days after injection of 80 units of botulinum toxin A into the right parotid gland in a 63-year-old patient showed a decrease in the SUVmean in the right parotid gland of up to 64% as compared with baseline. This approach could be a significant breakthrough for radioprotection of the salivary glands during PSMA radioligand therapy. PMID- 29391918 TI - Transiently Altered Distribution of F-18 FDG in a Patient with Subacute Thyroiditis. AB - F-18 fluorodeoxyglucose (FDG) is a highly influential radiotracer that provides valuable information in many cancer types. However, the normal biodistribution of F-18 FDG is often variable and can be altered by intrinsic or iatrogenic factors. We report a case of diffuse symmetrically increased skeletal muscle uptake and relatively decreased hepatic uptake on F-18 FDG PET/CT in a 57-year-old female with pulmonary adenocarcinoma. Detailed clinical evaluation and retrospective radiologic evaluation revealed that she had been diagnosed with subacute thyroiditis 2 weeks ago. After 6 weeks, F-18 FDG distribution was normalized at the follow-up PET/CT study. PMID- 29391920 TI - High-Dimensional Bayesian Geostatistics. AB - With the growing capabilities of Geographic Information Systems (GIS) and user friendly software, statisticians today routinely encounter geographically referenced data containing observations from a large number of spatial locations and time points. Over the last decade, hierarchical spatiotemporal process models have become widely deployed statistical tools for researchers to better understand the complex nature of spatial and temporal variability. However, fitting hierarchical spatiotemporal models often involves expensive matrix computations with complexity increasing in cubic order for the number of spatial locations and temporal points. This renders such models unfeasible for large data sets. This article offers a focused review of two methods for constructing well defined highly scalable spatiotemporal stochastic processes. Both these processes can be used as "priors" for spatiotemporal random fields. The first approach constructs a low-rank process operating on a lower-dimensional subspace. The second approach constructs a Nearest-Neighbor Gaussian Process (NNGP) that ensures sparse precision matrices for its finite realizations. Both processes can be exploited as a scalable prior embedded within a rich hierarchical modeling framework to deliver full Bayesian inference. These approaches can be described as model-based solutions for big spatiotemporal datasets. The models ensure that the algorithmic complexity has ~ n floating point operations (flops), where n the number of spatial locations (per iteration). We compare these methods and provide some insight into their methodological underpinnings. PMID- 29391921 TI - Intracranial Migration of Hardware 16 Years Following Craniosynostosis Repair. AB - Introduction: The techniques used to fixate osteotomized segments of bone have evolved alongside the treatment of craniosynostosis. The use of nonresorbable metal plates and screws offered a method of rigidly stabilizing repositioned segments of bone. Several reports specify the tendency for these fixation systems to "migrate" transcranially. Methods: We present a unique case of a patient who initially underwent treatment of multisuture craniosynostosis utilizing titanium miniplates at 6 months of age. At 16 years of age, the patient was returned to the operating room with complaints of pain and contour irregularities, and intracranial migration of the screws and plates was observed. Results: The hardware was extracted and the cranium reconstructed. Symptoms resolved and bony contour was improved. Conclusion: The craniofacial surgeon considering metal plate fixation in the pediatric population should be aware of the possibility for transcranial plate and screw migration. PMID- 29391919 TI - Fragranced consumer products: effects on asthmatics. AB - Fragranced consumer products, such as cleaning supplies, air fresheners, and personal care products, can emit a range of air pollutants and trigger adverse health effects. This study investigates the prevalence and types of effects of fragranced products on asthmatics in the American population. Using a nationally representative sample (n = 1137), data were collected with an on-line survey of adults in the USA, of which 26.8% responded as being medically diagnosed with asthma or an asthma-like condition. Results indicate that 64.3% of asthmatics report one or more types of adverse health effects from fragranced products, including respiratory problems (43.3%), migraine headaches (28.2%), and asthma attacks (27.9%). Overall, asthmatics were more likely to experience adverse health effects from fragranced products than non-asthmatics (prevalence odds ratio [POR] 5.76; 95% confidence interval [CI] 4.34-7.64). In particular, 41.0% of asthmatics report health problems from air fresheners or deodorizers, 28.9% from scented laundry products coming from a dryer vent, 42.3% from being in a room cleaned with scented products, and 46.2% from being near someone wearing a fragranced product. Of these effects, 62.8% would be considered disabling under the definition of the Americans with Disabilities Act. Yet 99.3% of asthmatics are exposed to fragranced products at least once a week. Also, 36.7% cannot use a public restroom if it has an air freshener or deodorizer, and 39.7% would enter a business but then leave as quickly as possible due to air fresheners or some fragranced product. Further, 35.4% of asthmatics have lost workdays or a job, in the past year, due to fragranced product exposure in the workplace. More than twice as many asthmatics would prefer that workplaces, health care facilities and health care professionals, hotels, and airplanes were fragrance-free rather than fragranced. Results from this study point to relatively simple and cost-effective ways to reduce exposure to air pollutants and health risks for asthmatics by reducing their exposure to fragranced products. PMID- 29391922 TI - Heterotopic Ossification: A Late Complication From a Chemical Burn. PMID- 29391923 TI - Roles of Endoplasmic Reticulum Stress in NECA-Induced Cardioprotection against Ischemia/Reperfusion Injury. AB - Objective: This study aimed to investigate whether the nonselective A2 adenosine receptor agonist NECA induces cardioprotection against myocardial ischemia/reperfusion (I/R) injury via glycogen synthase kinase 3beta (GSK-3beta) and the mitochondrial permeability transition pore (mPTP) through inhibition of endoplasmic reticulum stress (ERS). Methods and Results: H9c2 cells were exposed to H2O2 for 20 minutes. NECA significantly prevented H2O2-induced TMRE fluorescence reduction, indicating that NECA inhibited the mPTP opening. NECA blocked H2O2-induced GSK-3beta phosphorylation and GRP94 expression. NECA increased GSK-3beta phosphorylation and decreased GRP94 expression, which were prevented by both ERS inductor 2-DG and PKG inhibitor KT5823, suggesting that NECA may induce cardioprotection through GSK-3beta and cGMP/PKG via ERS. In isolated rat hearts, both NECA and the ERS inhibitor TUDCA decreased myocardial infarction, increased GSK-3beta phosphorylation, and reversed GRP94 expression at reperfusion, suggesting that NECA protected the heart by inhibiting GSK-3beta and ERS. Transmission electron microscopy showed that NECA and TUDCA reduced mitochondrial swelling and endoplasmic reticulum expansion, further supporting that NECA protected the heart by preventing the mPTP opening and ERS. Conclusion: These data suggest that NECA prevents the mPTP opening through inactivation of GSK-3beta via ERS inhibition. The cGMP/PKG signaling pathway is responsible for GSK-3beta inactivation by NECA. PMID- 29391925 TI - Modulation of Oxidative Stress: Pharmaceutical and Pharmacological Aspects 2017. PMID- 29391924 TI - How AMPK and PKA Interplay to Regulate Mitochondrial Function and Survival in Models of Ischemia and Diabetes. AB - Adenosine monophosphate-activated protein kinase (AMPK) is a conserved, redox activated master regulator of cell metabolism. In the presence of oxidative stress, AMPK promotes cytoprotection by enhancing the conservation of energy by suppressing protein translation and by stimulating autophagy. AMPK interplays with protein kinase A (PKA) to regulate oxidative stress, mitochondrial function, and cell survival. AMPK and dual-specificity A-kinase anchoring protein 1 (D AKAP1), a mitochondrial-directed scaffold of PKA, interact to regulate mitochondrial function and oxidative stress in cardiac and endothelial cells. Ischemia and diabetes, a chronic disease that increases the onset of cardiovascular diseases, suppress the cardioprotective effects of AMPK and PKA. Here, we review the molecular mechanisms by which AMPK and D-AKAP1/PKA interplay to regulate mitochondrial function, oxidative stress, and signaling pathways that prime endothelial cells, cardiac cells, and neurons for cytoprotection against oxidative stress. We discuss recent literature showing how temporal dynamics and localization of activated AMPK and PKA holoenzymes play a crucial role in governing cellular bioenergetics and cell survival in models of ischemia, cardiovascular diseases, and diabetes. Finally, we propose therapeutic strategies that tout localized PKA and AMPK signaling to reverse mitochondrial dysfunction, oxidative stress, and death of neurons and cardiac and endothelial cells during ischemia and diabetes. PMID- 29391927 TI - Rat model of anal sphincter injury and two approaches for stem cell administration. AB - AIM: To establish a rat model of anal sphincter injury and test different systems to provide stem cells to injured area. METHODS: Adipose-derived stem cells (ASCs) were isolated from BDIX rats and were transfected with green fluorescent protein (GFP) for cell tracking. Biosutures (sutures covered with ASCs) were prepared with 1.5 x 106 GFP-ASCs, and solutions of 106 GFP-ASCs in normal saline were prepared for injection. Anorectal normal anatomy was studied on Wistar and BDIX female rats. Then, we designed an anal sphincter injury model consisting of a 1 cm extra-mucosal miotomy beginning at the anal verge in the anterior middle line. The sphincter lesion was confirmed with conventional histology (hematoxylin and eosin) and immunofluorescence with 4', 6-diamidino-2-phenylindole (commonly known as DAPI), GFP and alpha-actin. Functional effect was assessed with basal anal manometry, prior to and after injury. After sphincter damage, 36 BDIX rats were randomized to three groups for: (1) Cell injection without repair; (2) biosuture repair; and (3) conventional suture repair and cell injection. Functional and safety studies were conducted on all the animals. Rats were sacrificed after 1, 4 or 7 d. Then, histological and immunofluorescence studies were performed on the surgical area. RESULTS: With the described protocol, biosutures had been covered with at least 820000-860000 ASCs, with 100% viability. Our studies demonstrated that some ASCs remained adhered after suture passage through the muscle. Morphological assessment showed that the rat anal anatomy is comparable with human anatomy; two sphincters are present, but the external sphincter is poorly developed. Anal sphincter pressure data showed spontaneous, consistent, rhythmic anal contractions, taking the form of "plateaus" with multiple twitches (peaks) in each pressure wave. These basal contractions were very heterogeneous; their frequency was 0.91-4.17 per min (mean 1.6980, SD 0.57698), their mean duration was 26.67 s and mean number of peaks was 12.53. Our morphological assessment revealed that with the aforementioned surgical procedure, both sphincters were completely sectioned. In manometry, the described activity disappeared and was replaced by a gentle oscillation of basal line, without a recognizable pattern. Surprisingly, these findings appeared irrespective of injury repair or not. ASCs survived in this potentially septic area for 7 d, at least. We were able to identify them in 84% of animals, mainly in the muscular section area or in the tissue between the muscular endings. ASCs formed a kind of "conglomerate" in rats treated with injections, while in the biosuture group, they wrapped the suture. ASCs were also able to migrate to the damaged zone. No relevant adverse events or mortality could be related to the stem cells in our study. We also did not find unexpected tissue growths. CONCLUSION: The proposed procedure produces a consistent sphincter lesion. Biosutures and injections are suitable for cell delivery. ASCs survive and are completely safe in this clinical setting. PMID- 29391928 TI - Associating liver partition and portal vein ligation for staged hepatectomy for extensive alveolar echinococcosis: First case report in the literature. AB - Alveolar echinococcosis (AE) is a zoonotic disease that is caused by Echinococcus multilocularis that affects liver and a variety of organs and tissues. It differs from other echinococcal disease because it shows tumor like behavior in the affected organ and tissues. The treatment of choice is concomitant medical therapy and resection with negative margins. Nevertheless, resection with the intent of negative margins (R0) may lead to serious complications such as liver failure. In the present case report, we used Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure, which was defined in 2012 by Schnitzbauer et al, in a 28-year-old male patient to avoid complications of major liver resection in order to treat alveolar echinococcosis. Until now, we have not encountered any study using ALPPS procedure for the treatment of alveolar echinococcosis. In the present case report we aimed to show that ALPPS procedure can be safely performed for margin-negative resection of primary or recurrent AE that shows a tumor like behavior. It is our opinion that this procedure should be performed in centers that have expertise and sufficient technical capacity to perform liver transplantation and advanced liver surgery. PMID- 29391929 TI - Transcatheter aortic valve replacement in membranous interventricular septum aneurysm with left ventricular outflow tract extension. AB - We report a challenging case of a 81-year-old male with history of severe calcific aortic valve stenosis and aneurysmal membranous interventricular septum. The presence of anomalies in the sub-annular area can lead to valve malpositioning and its consequences. transcatheter aortic valve implantation (TAVR) in patients with aneurysm of the perimembranous interventricular septum extending into the left ventricular outflow tract has not been previously reported. This case describes a successful transfemoral TAVR with an Edwards SAPIEN XT valve (Edwards Lifesciences, Irvine, CA, United States) with such anomaly. PMID- 29391926 TI - The Interrelation between Reactive Oxygen Species and Autophagy in Neurological Disorders. AB - Neurological function deficits due to cerebral ischemia or neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have long been considered a thorny issue in clinical treatment. Recovery after neurologic impairment is fairly limited, which poses a major threat to health and quality of life. Accumulating evidences support that ROS and autophagy are both implicated in the onset and development of neurological disorders. Notably, oxidative stress triggered by excess of ROS not only puts the brain in a vulnerable state but also enhances the virulence of other pathogenic factors, just like mitochondrial dysfunction, which is described as the culprit of nerve cell damage. Nevertheless, autophagy is proposed as a subtle cellular defense mode against destructive stimulus by timely removal of damaged and cytotoxic substance. Emerging evidence suggests that the interplay of ROS and autophagy may establish a determinant role in the modulation of neuronal homeostasis. However, the underlying regulatory mechanisms are still largely unexplored. This review sets out to afford an overview of the crosstalk between ROS and autophagy and discusses relevant molecular mechanisms in cerebral ischemia, AD, and PD, so as to provide new insights into promising therapeutic targets for the abovementioned neurological conditions. PMID- 29391930 TI - The effects of sodium butyrate and inulin supplementation on angiotensin signaling pathway via promotion of Akkermansia muciniphila abundance in type 2 diabetes; A randomized, double-blind, placebo-controlled trial. AB - Introduction: Inflammation has a crucial role in the progression of cardiovascular disease in diabetes. Tumour necrosis factor-alpha (TNF-alpha) as an inflammatory marker induces angiotensin II (Ang II) related hypertension pathway in diabetic patients. Gut modulation via prebiotics may ameliorate hypertension caused by inflammation. The aim of this study was to investigate the role of sodium butyrate (NaBut) and inulin supplements on inflammatory and oxidative stress parameters in type 2 diabetic patients. Methods: In this clinical trial, 60 overweight and obese diabetic patients were recruited and randomly allocated into four groups. The groups received, respectively, 600 mg/d NaBut (group A), 10 g/d inulin powder (group B), both inulin and NaBut (group C), or placebo (group D) for 45 consecutive days. Blood and stool samples were collected at baseline and after intervention. Quantitative real-time PCR analysis targeting the 16S rRNA gene of Akkermansia muciniphila was done. We assessed the TNF-alpha mRNA expression and the serum levels of the high sensitive C-reactive protein (hs-CRP) and malondialdehyde (MDA). Results: There was a significant increase in A. muciniphila percent change in inulin and butyrate supplemented groups (P < 0.05). Furthermore, significant decrease was seen in TNF-alpha mRNA expression in group A (fold change 0.88 +/- 0.16, P< 0.05), group B (fold change 0.75 +/- 0.18, P < 0.05) and group C (fold change 0.91 +/- 0.32, P < 0.05). Also hs-CRP, MDA and diastolic blood pressure levels decreased significantly in these groups (P < 0.05). Conclusion: Intervention had significant effects on inflammatory and oxidative stress parameters and led to improvement of hypertension. However, further investigations are needed to make concise conclusions. PMID- 29391931 TI - In vitro inhibition of platelets aggregation with generic form of clopidogrel versus branded in patients with stable angina pectoris. AB - Introduction: Clopidogrel is a potent platelet activation and aggregation inhibitor that prevents thrombosis in coronary artery diseases (CADs). In comparison to locally produced generic one (Osvix(r)), original brand of clopidogrel (Plavix(r)) is expensive. This study was designed to evaluate the effectiveness and uniformity of Osvix(r) versus Plavix(r) in patients with percutaneous coronary intervention (PCI) by means of platelet aggregation indexes. Methods: This randomized, double blind clinical study was conducted at Shahid Madani heart hospital, Tabriz, Iran, and 129 patients with previous PCI were enrolled in two independent treatment groups. All patients participated in this study were on dual antiplatelet therapy at least for 30 days. ASA 80 mg/d and clopidogrel 75 mg/d and a stat dose of 300 mg of clopidogrel before PCI were administered for all patients. To evaluate the anti-platelet activity, blood samples were taken from the patients and platelet aggregation test was performed. Results: The total study population represents a group of 129 patients (99 men and 30 women) with mean age of 57.7 +/- 9.7 years with stable angina pectoris. The baseline characteristics and laboratory findings of two groups (except mean platelet volume [MPV]) were not different statistically. The mean platelets aggregation at 30th day was 13.7+/-7.0 in Plavix(r) group and 14.8+/-5.8 in Osvix(r) group (P value = 0.35). Conclusion: This study showed that Osvix(r) as a generic form of clopidogrel was not significantly different from the original brand (Plavix) in terms of in vitro platelet inhibition. PMID- 29391932 TI - Comparison of tracheal tube cuff pressure with two techniques: fixed volume versus pilot balloon palpation. AB - Introduction: Filling tracheal tube cuff (TTC) after intubation is necessary to provide a safe airway in intubated patients. On the other hand, excessive increase or decrease in the pressure of TTC's balloon leads into the dangerous complications such as necrosis and/or aspiration. Accordingly, in the present study, we tried to evaluate the most two common fixed volume and pilot balloon palpitation methods to control TTC pressure. Methods: In a prospective cross sectional study that was carried out in the emergency department of Tabriz Imam Reza hospital upon 194 patients who needed intubation and from April 2015 to June 2016. The patients were randomly allocated into two equal groups. For the first the Pilot Balloon Palpation technique and for the second group 10 cc fixed volume cuff filling technique was assigned. After that, the pressure was checked with manometer and data were analyzed using SPSS software. Results: TTC pressure average in fixed volume group was 44.96+/-21.77 cmH2O and for palpation group, it was 118.15+/-22.15 cmH2O. There was a meaningful difference between two groups in terms of cuff inside pressure (P value <0.001) and it was meaningfully lower in fixed volume group than the first one. Conclusion: The present study showed that pilot balloon palpation or fixed volume method was not appropriate methods to assess cuff pressure during intubation and the cuff pressure must be controlled by the manometer. PMID- 29391933 TI - Saffron and crocin improved appetite, dietary intakes and body composition in patients with coronary artery disease. AB - Introduction: Central obesity is an independent risk factor for coronary artery disease (CAD). It can increase cardio-metabolic risks through hypertension, hyperlipidemia and insulin resistance. Saffron and its bioactive compounds (crocin and crocetin) can modify some of metabolic disorders through multiple mechanisms. The aim of this study was to assess the efficacy of saffron and crocin on lipid profile, appetite, dietary intakes, anthropometric indices and body composition in patients with CAD. Methods: This 8 weeks randomized, double blind, and placebo-controlled trial was conducted on 84 patients with CAD between the ages of 40 and 65 years old. Participants were randomly divided into groups to receive a daily supplement of 30 mg saffron aqueous extract (SAE) or 30 mg crocin or placebo. Appetite, dietary intake, anthropometry, body composition, biochemical analysis were assessed before and after the study. Results: In SAE and crocin group, anthropometric and some body composition variables revealed a pattern of improvement after intervention. Decrease in body mass index (BMI), waist circumference and fat mass values in SAE group was significantly more than crocin group (P < 0.001). There was no significant difference at the end of study in lipid profile parameters. Both SAE and crocin yielded significant decrease in energy and dietary intake mean values (P < 0.001 and P = 0.046), while it remained unchanged in the placebo group, also the appetite decreased significantly in SAE and crocin group (P < 0.001 and P = 0.029, respectively). Conclusion: The results of present study regarding anti-obesity feature of SAE and crocin in patients with CAD was promising. However the SAE was better in appetite suppressing, dietary intake and central obesity reduction. PMID- 29391934 TI - Fibrinolytic therapy in patients with ST-segment elevation myocardial infarction: Accelerated versus standard Streptokinase infusion regimen. AB - Introduction: Timely fibrinolysis for acute ST-segment elevation myocardial infarction (STEMI) reduces infarct size and hence preserves LV function and reduces mortality. Optimal regimen of streptokinase (SK) infusion in such patients is a matter of interest. The current study aimed to compare efficacy and safety of accelerated SK infusion regimen in patients with STEMI versus the standard one. Methods: One hundred consecutive STEMI patients were randomly allocated into one of 2 groups: group I (50 patients) who received accelerated SK regimen (1.5 million units over 30 minutes) and group II (50 patients) received standard SK regimen (1.5 million units over 60 minutes). Efficacy was evaluated non-invasively using clinical (chest pain), ECG (resolution of ST segment) and laboratory tests (earlier and higher peaking of cardiac troponin I). Safety was evaluated by assessment of multiple in-hospital adverse events. Results: Both groups were statistically matched in all baseline criteria. There was a significant difference between both groups regarding each parameter of successful reperfusion in favor of accelerated regimen. When all these parameters were combined, 31 patients (62%) had successful reperfusion in group I versus 19 patients (38%) in group II (P = 0.016). We did not report any significant difference between both groups regarding in-hospital mortality, in-hospital heart failure, major bleeding, hypotension or allergic reaction to SK. Mean pre discharge ejection fraction was higher in group I than group II (50.9 +/- 6.6% versus 47.3 +/- 4.6%, P = 0.002). Conclusion: Accelerated regimen of SK infusion is safe and effective method of reperfusion in patients with STEMI. PMID- 29391935 TI - The frequency and importance of chest pain in midterm follow up of transcatheter closure of interatrial septal defect. AB - Introduction: We evaluated chest pain alongside other midterm subjective and objective complications of the transcatheter closure of atrial septal defects (ASDs) and patent foramen ovales (PFOs) with various closure devices. Methods: This cross-sectional study, performed from March 2010 to October 2015 in Rajaie Cardiovascular, Medical, and Research Center, evaluated 313 patients (mean age = 29.12 +/- 10 years, 32.9% male) for probable complications associated with the transcatheter occlusion of secundum ASDs (n = 289, mean age = 30.5 +/- 11.4 years, 28% male) or PFOs (n = 24, mean age = 42.8 +/- 10.2 years). ASD closure was performed under sedation and transesophageal echocardiography (TEE) guidance. Duration of follow-up was 12 +/- 3 months (mean follow-up = 11.52 months). Results: Among the subjective complications, chest pain was the most frequent complaint during the follow-up period and although it was common (7.3%), a clear cardiac etiology was rare. Thirteen (4.2%) patients reported palpitation during the follow-up period, and 4 had documented arrhythmias-including atrial flutter, atrial fibrillation, and 2:1 atrioventricular block. Migraine with or without aura occurred in 1.6% of the patients. Objective complications comprising tamponade, device embolization, and thrombus formation occurred in 6 (1.9%) patients. There was no procedure-related mortality in our patients. Conclusion: Transcatheter closure of PFOs and secundum-type ASDs in our adult patients using ASD septal occluders was associated with a high degree of success, minimal procedural subjective and objective complication rates, and excellent short- and midterm results. Although chest pain was common after the first month following ASD closure, there was no cardiac death or aortic erosion in 11.52 months follow up. PMID- 29391936 TI - The effect of intraoperative lung protective ventilation vs conventional ventilation, on postoperative pulmonary complications after cardiopulmonary bypass. AB - Introduction: This study aimed to evaluate the effects of high positive-end expiratory pressure (PEEP) and low tidal volume (TV) and recruitment maneuver, on postoperative pulmonary complications (PPCs) after coronary artery bypass grafting (CABG) surgery. Methods: This study is a randomized double blind clinical trial on 64 patients who were undergoing CABG surgery, and were randomly divided into two groups of conventional ventilation (C-Vent) with TV of 9 mL/kg and PEEP=0 cm H2O, and lung protective ventilation (P-Vent), with 6 mL/kg TV and PEEP=10 cm H2O with recruitment maneuver every 30 minutes. Measures of PPCs and modified clinical pulmonary infection score (mCPIS), were assessed for the first 24 hours of postoperative time in order to evaluate the pulmonary complications. Results: P-Vent with 31 patients and C-Vent with 30 patients, participated in the stage of data analysis. Demographic, and preoperative laboratory results showed no significant difference between two groups. During surgery, cardiovascular complications were higher in P-Vent group (P = 0.61) but pulmonary complications were higher in C-Vent group (P = 0.26). Extubation time was not significantly different between two groups, and also components of arterial blood gases (ABG) of 24 hours after surgery showed no significant difference between the two groups. Pathologic changes in the chest X-ray (CXR) of 24 hours after surgery, were lower in P-Vent group, but the difference was not significant (P = 0.22). The PPC criteria was less positive in P-Vent (2 patients) vs 9 patients in C-Vent group (P = 0.02) and mCPIS score was significantly lower in P-Vent group (1.2 +/- 1.4) than C-Vent group (2 +/- 1.6) (P = 0.048). Conclusion: Lung protective strategy during and after cardiac surgery, reduces the postoperative mCPIS in patients undergoing open heart surgery for CABG. PMID- 29391937 TI - Foreign body associated non-ST elevation myocardial infarction: a case report. AB - The incidence of guiding catheter tip fracture, is quite rare during percutaneous coronary interventions (PCI). Retained broken catheter tip in coronary artery and circulation can result in serious complications such as thrombosis, embolism, acute occlusion and myocardial infarction, arrhythmias and sepsis. It is mandatory to remove the fractured catheter as soon as possible to avoid these complications. Transcatheter removal is the treatment of choice. If percutaneous removal is failed, surgical intervention is advised. PMID- 29391938 TI - Variation of the cephalic and basilic veins: A case report. AB - Cephalic and basilic veins begin their path from around the wrist and continue towards the area above the forearm. The basilic vein becomes deep around the mid arm, while the cephalic vein becomes deep around the upper forearm, in deltopectoral groove. The superficial veins are most commonly used for vein puncture, transfusion, bypass graft, and cardiac catheterization. In renal patients, the basilic vein use as an arteriovenous graft or fistula for haemodialysis access. During a routine dissection in the department of anatomy in Isfahan, we observed a variation in the left arm of an infant boy (six months old). The cephalic and basilic veins directly joined together in the middle of the cubital fossa. The brachial vein began from this point and, unlike the normal anatomy location, there was no paired brachial vein; rather, it was one unpaired brachial vein. PMID- 29391939 TI - Design, Synthesis and Structure-Activity Relationships of (+/-)-Isochaihulactone Derivatives. AB - Z-K8 (2), the racemic form of isochaihulactone (1), previously showed significant antitumor effects in A549 and LNCaP tumor-bearing mice. In the present study, 17 derivatives of 2, were designed, synthesized and evaluated for anti-proliferative activity against four human tumor cell lines. All new derivatives exhibited high potency against A549 and P-glycoprotein (P-gp)-overexpressing KBvin. One of our new derivative exhibited greater activity against three tested tumor cells (A549, KB, and KB-VIN) than 2, and induced cell cycle arrest in the G2/M phase. Moreover, SAR conclusions were first established for this series of compounds. Our study clearly identified a structural feature that should be retained for good activity and also a moiety that can tolerate various modifications and, thus, is ideal for further changes. PMID- 29375811 TI - Initial study of three different pathogenic microorganisms by gas chromatography mass spectrometry. AB - Background: Diagnoses of respiratory tract infections usually happen in the late phase of the disease and usually result in reduction of the pathogen load after broad-spectrum antibiotic therapy, but not in eradication of the pathogen. The development of a non-invasive, fast, and accurate method to detect pathogens has always been of interest to researchers and clinicians alike. Previous studies have shown that bacteria produce organic gases. The current study aimed to identify the volatile organic compounds (VOCs) produced by three respiratory tract pathogens, including Staphylococcus aureus, Escherichia coli and Candida albicans.Methods: The VOCs produced were identified by gas chromatography-mass spectrometry (GC-MS), with prior collection of microbial volatile compounds using solid phase microextraction (SPME) fiber. The volatile compounds were collected by obtaining bacterial headspace samples. Results: Results showed that these three organisms have various VOCs, which were analyzed under different conditions. By ignoring common VOCs, some species-specific VOCs could be detected. The most important VOC of E. coli was indole, also some important VOCs produced by S. aureus were 2,3-pentandione, cis-dihydro-alpha terpinyl acetate, 1-decyne, 1,3-heptadiene, 2,5-dimethyl pyrazine, ethyl butanoate and cyclohexene,4-ethenyl. Furthermore, most of the identified compounds by C. albicans are alcohols. Conclusions: The detection of VOCs produced by infectious agents maybe the key to make a rapid and precise diagnosis of infection, but more comprehensive studies must be conducted in this regard. PMID- 29259772 TI - Genetics in the 21st Century: Implications for patients, consumers and citizens. AB - The first human genome project, completed in 2003, uncovered the genetic building blocks of humankind. Painstakingly cataloguing the basic constituents of our DNA ('genome sequencing') took ten years, over three billion dollars and was a multinational collaboration. Since then, our ability to sequence genomes has been finessed so much that by 2018 it is possible to explore the 20,000 or so human genes for under L1000, in a matter of days. Such testing offers clues to our past, present and future health, as well as information about how we respond to medications so that truly 'personalised medicine' is now moving closer to a reality. The impact of such a 'genomic era' is likely to have some level of impact on an increasingly large number of us, even if we are not directly using healthcare services ourselves. We explore how advancements in genetics are likely to be experienced by people, as patients, consumers and citizens; and urge policy makers to take stock of the pervasive nature of the technology as well as the human response to it. PMID- 29259773 TI - Identification of organic pigments in tattoo inks and permanent make-up using laser desorption ionisation mass spectrometry. AB - Nowadays, about 12% of the European and 20% of the US population are tattooed. Rising concerns regarding consumer safety, led to legal restrictions on tattoo and permanent make-up (PMU) inks. Restrictions also include bans on certain colourants. Both ink types use organic pigments for colour-giving, plus inorganic pigments for white and black and colour tones. Pigments are only sparingly soluble in common solvents and occur as suspended particles in the ink matrix. Their detection and identification therefore pose a major challenge for laboratories involved in monitoring the legal compliance of tattoo inks and PMU. We overcame this challenge by developing a direct laser desorption ionisation time-of-flight mass spectrometry method, which included an easy sample clean up. The method proved to be capable of detecting and identifying organic pigments in almost all of the tested ink samples. Method validation and routine deployment during market surveys showed the method to be fit for purpose. Pigment screening of 396 tattoo inks and 55 PMU taken from the Swiss market between 2009 and 2017 lead to the following conclusions: Pigment variety is much greater in tattoo inks (18) than in PMU (10); four prohibited pigments (Pigment Green 7, Pigment Red 122, Pigment Violet 19 and 23) were found in both ink types; for PMU, these four pigments made up 12% of the pigment findings, compared to 32% for tattoo inks. Therefore, legal compliance of PMU was at a higher level. A comparison of pigments found with those declared on tattoo ink labels clearly showed that banned pigments are rarely declared, but rather masked by listing non present legal pigments and label forging; therefore, highlighting the urgency of widespread market controls. PMID- 29391944 TI - Transitioning financial responsibility for health programs from external donors to developing countries: Key issues and recommendations for policy and research. PMID- 29391943 TI - Layer-by-layer Assembled Membranes with Immobilized Porins. AB - With the synthesis and functionalization of membranes for selective separations, reactivity, and stimuli responsive behavior arises new and advanced opportunities. The integration of bio-based channels is one of these advancements in membrane technologies. By a layer-by-layer (LbL) assembly of polyelectrolytes, outer membrane protein F trimers (OmpF) or "porins" from Escherichia coli with a central pore of ~2 nm diameter at its opening and ~0.7 * 1.1 nm at its constricted region are immobilized within the pores of poly(vinylidene fluoride) microfiltration membranes, as opposed to traditional ruptured lipid bilayer or vesicles processes. These OmpF-membranes demonstrate selective rejections of non charged organics over ionic solutes, allowing the passage of salts up to 2 times higher than traditional nanofiltration membranes starting with rejections of 84% for 0.4-1.0 kDa organics. The presence of charged groups in OmpF membranes also leads to pH-dependent salt rejection through Donnan exclusion. These OmpF membranes also show exceptional durability and stability, delivering consistent and constant permeability and recovery for over 160 h of operation. Characterization of solutions containing OmpF, and membranes were conducted during each stage of the process, including detection by fluorescence labelling (FITC), zeta potential, pH responsiveness, flux changes, and rejections of organic-inorganic solutions. PMID- 29391945 TI - A public health approach to pediatric hearing impairment in the Pacific Islands. PMID- 29391946 TI - Stability of Spline-Type Systems in the Abelian Case. AB - In this paper, the stability of translation-invariant spaces of distributions over locally compact groups is stated as boundedness of synthesis and projection operators. At first, a characterization of the stability of spline-type spaces is given, in the standard sense of the stability for shift-invariant spaces, that is, linear independence characterizes lower boundedness of the synthesis operator in Banach spaces of distributions. The constructive nature of the proof for Theorem 2 enabled us to constructively realize the biorthogonal system of a given one. Then, inspired by the multiresolution analysis and the Lax equivalence for general discretization schemes, we approached the stability of a sequence of spline-type spaces as uniform boundedness of projection operators. Through Theorem 3, we characterize stable sequences of stable spline-type spaces. PMID- 29391947 TI - In Vivo Antimalarial Activity of the Solvent Fractions of Fruit Rind and Root of Carica papaya Linn (Caricaceae) against Plasmodium berghei in Mice. AB - Background: Currently, antimalarial drug resistance poses a serious challenge. This stresses the need for newer antimalarial compounds. Carica papaya is used traditionally and showed in vitro antimalarial activity. This study attempted to evaluate in vivo antimalarial activity of C. papaya in mice. Methods: In vivo antimalarial activity of solvent fractions of the plant was carried out against early P. berghei infection in mice. Parasitemia, temperature, PCV, and body weight of mice were recorded. Windows SPSS version 16 (one-way ANOVA followed by Tukey's post hoc test) was used for data analysis. Results: The pet ether and chloroform fractions of C. papaya fruit rind and root produced a significant (p < 0.001) chemosuppressive effect. A maximum parasite suppression of 61.78% was produced by pet ether fraction of C. papaya fruit rind in the highest dose (400 mg/kg/day). Only 400 mg/kg/day dose of chloroform fraction of C. papaya root exhibited a parasite suppression effect (48.11%). But, methanol fraction of the plant parts produced less chemosuppressive effect. Conclusion: Pet ether fraction of C. papaya fruit rind had the highest antimalarial activity and could be a potential source of lead compound. Further study should be done to show the chemical and metabolomic profile of active ingredients. PMID- 29391948 TI - Minimally Invasive Repetitive UVA Irradiation along with Riboflavin Treatment Increased the Strength of Sclera Collagen Cross-Linking. AB - Objective: This study aimed to investigate the efficacy of minimally invasive repetitive UVA irradiation along with riboflavin treatment on sclera collagen cross-linking in rabbits. Method: Forty-eight healthy adult New Zealand white rabbits were randomly divided into four groups: pseudosurgery group (group I), single-irradiation group (group II), duplicate-irradiation group (group III), and triplicate-irradiation group (group IV), with 12 rabbits in each group. For the single-irradiation group, a specially made LED light source was inserted through a minimally invasive conjunctival incision to gain close contact with the sclera for irradiation, and for the repetitive irradiation groups, the above experimental procedure was repeated once or twice every other week. Biomechanical parameters of the sclera including ultimate stress (sigma) and 8% Young's modulus (E) were compared among the groups. Results: In comparison with control group I, the ultimate stress of group II, group III, and group IV increased by 80.1%, 107.9%, and 182.1%, respectively, and their 8% Young's modulus increased by 106.1%, 159.5%, and 208.5%, respectively, one day after surgery (P < 0.01). Conclusion: Repetitive minimally invasive UVA irradiation with riboflavin significantly increased biomechanical strength of the sclera in the irradiated area, and biomechanical strength increased with repeated times of irradiation. PMID- 29391949 TI - Multicomponent Lifestyle Interventions for Treating Overweight and Obesity in Children and Adolescents: A Systematic Review and Meta-Analyses. AB - Background: Treatment of childhood obesity is important in preventing development of obesity-related diseases later in life. This systematic review evaluates the effect of multicomponent lifestyle interventions for children and adolescents from 2 to 18 years. Methods and Results: We performed systematic searches in nine databases. Thirty-nine studies met the criteria for meta-analyses. We found a significant difference in body mass index (BMI) after 6 months (MD -0.99 (95% CI 1.36 to -0.61)), 12 months (MD -0.67 (95% CI -1.01 to -0.32)), and 24 months (MD 0.96 (95% CI -1.63 to -0.29)) in favour of multicomponent lifestyle interventions compared to standard, minimal, and no treatment. We also found a significant difference in BMI Z scores after 6 months (MD -0.12 (95% CI -0.17 to -0.06)), 12 months (MD -0.16 (95% CI -0.21 to -0.11)), and 24 months (MD -0.16 (95% CI -0.21 to -0.10)) in favour of multicomponent lifestyle interventions. Subgroup analyses suggested an increased effect in specialist health care with a group treatment component included in the intervention. Conclusion: Multicomponent lifestyle interventions have a moderate effect on change in BMI and BMI Z score after 6, 12, and 24 months compared with standard, minimal, and no treatment. PMID- 29391950 TI - Hypovitaminosis D and Its Associated Factors in North Algerian Postmenopausal Women: Results of a Cross-Sectional Study. AB - Purpose: As the vitamin D status of Algerian postmenopausal women was poorly described, this cross-sectional study investigated the prevalence of low vitamin D status in a sample population. Secondarily, predictive factors of this hypovitaminosis D were explored. Methods: All the 336 selected women >= 45 years from Douera were interviewed to get anthropometric and lifestyle data, reproductive and medical history, medications, and calcium/vitamin D intakes. A blood sample was collected to measure 25-hydroxyvitamin D (25(OH)D) concentrations. Results: Approximately 86% of subjects had low vitamin D status (<20 ng/mL). Mean 25(OH)D level was 14.4 +/- 5.3 ng/mL with a clear seasonal dynamic and a significant negative correlation with PTH levels (r = -0.15, p=0.006). A multiple regression analysis using the 25(OH)D cutoff value of 17 ng/mL instead of the generally admitted level of 20 ng/mL was performed to increase statistical power. Other seasons than summer (OR 4.159 and 95% CI 2.456 7.043), obesity (>=30 kg/m2, OR 1.826, 95% CI 1.081-3.083), and veiling (OR 3.526, 95% CI 1.090-11.400) were significantly associated with 25(OH)D concentrations <17 ng/mL. Conclusions: In North Algeria, the abundant sunlight appears insufficient to fully offset hypovitaminosis D risk factors in postmenopausal women, especially obesity and veiling. It suggests the major need to increase vitamin D supplementation in this subpopulation. PMID- 29391951 TI - Enhancing Plasticity of the Central Nervous System: Drugs, Stem Cell Therapy, and Neuro-Implants. AB - Stroke represents the first cause of adult acquired disability. Spontaneous recovery, dependent on endogenous neurogenesis, allows for limited recovery in 50% of patients who remain functionally dependent despite physiotherapy. Here, we propose a review of novel drug therapies with strong potential in the clinic. We will also discuss new avenues of stem cell therapy in patients with a cerebral lesion. A promising future for the development of efficient drugs to enhance functional recovery after stroke seems evident. These drugs will have to prove their efficacy also in severely affected patients. The efficacy of stem cell engraftment has been demonstrated but will have to prove its potential in restoring tissue function for the massive brain lesions that are most debilitating. New answers may lay in biomaterials, a steadily growing field. Biomaterials should ideally resemble lesioned brain structures in architecture and must be proven to increase functional reconnections within host tissue before clinical testing. PMID- 29391953 TI - Comparison of Adult Hippocampal Neurogenesis and Susceptibility to Treadmill Exercise in Nine Mouse Strains. AB - The genetic background of mice has various influences on the efficacy of physical exercise, as well as adult neurogenesis in the hippocampus. In this study, we investigated the basal level of hippocampal neurogenesis, as well as the effects of treadmill exercise on adult hippocampal neurogenesis in 9 mouse strains: 8 very commonly used laboratory inbred mouse strains (C57BL/6, BALB/c, A/J, C3H/HeJ, DBA/1, DBA/2, 129/SvJ, and FVB) and 1 outbred mouse strain (ICR). All 9 strains showed diverse basal levels of cell proliferation, neuroblast differentiation, and integration into granule cells in the sedentary group. C57BL/6 mice showed the highest levels of cell proliferation, neuroblast differentiation, and integration into granule cells at basal levels, and the DBA/2 mice showed the lowest levels. The efficacy of integration into granule cells was maximal in ICR mice. Treadmill exercise increased adult hippocampal neurogenesis in all 9 mouse strains. These results suggest that the genetic background of mice affects hippocampal neurogenesis and C57BL/6 mice are the most useful strain to assess basal levels of cell proliferation and neuroblast differentiation, but not maturation into granule cells. In addition, the DBA/2 strain is not suitable for studying hippocampal neurogenesis. PMID- 29391955 TI - Ticagrelor-Induced Angioedema: A Rare and Unexpected Phenomenon. AB - Angioedema can cause potentially life-threatening airway obstruction. This case report describes an exceedingly rare episode of ticagrelor-induced hypersensitivity reaction, manifesting as angioedema with periorbital and likely respiratory involvement. The heart team should be vigilant for this precarious condition which may require emergent airway management. Desensitization protocols and alternative regimens (e.g., clopidogrel, prasugrel, and addition of an adjunctive anticoagulant) should be considered when there is an absolute indication for antiplatelet therapy. PMID- 29391954 TI - Activation State-Dependent Substrate Gating in Ca2+/Calmodulin-Dependent Protein Kinase II. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) is highly concentrated in the brain where its activation by the Ca2+ sensor CaM, multivalent structure, and complex autoregulatory features make it an ideal translator of Ca2+ signals created by different patterns of neuronal activity. We provide direct evidence that graded levels of kinase activity and extent of T287 (T286alpha isoform) autophosphorylation drive changes in catalytic output and substrate selectivity. The catalytic domains of CaMKII phosphorylate purified PSDs much more effectively when tethered together in the holoenzyme versus individual subunits. Using multisubstrate SPOT arrays, high-affinity substrates are preferentially phosphorylated with limited subunit activity per holoenzyme, whereas multiple subunits or maximal subunit activation is required for intermediate- and low affinity, weak substrates, respectively. Using a monomeric form of CaMKII to control T287 autophosphorylation, we demonstrate that increased Ca2+/CaM dependent activity for all substrates tested, with the extent of weak, low affinity substrate phosphorylation governed by the extent of T287 autophosphorylation. Our data suggest T287 autophosphorylation regulates substrate gating, an intrinsic property of the catalytic domain, which is amplified within the multivalent architecture of the CaMKII holoenzyme. PMID- 29391956 TI - Treatment of Extensively Comminuted Mandibular Fracture with the Aid of a Condylar Positioning Device. AB - We describe a case of extensively comminuted mandibular fracture that extends bilaterally to the angle of mandible successfully treated with the use of condylar positioning device (CPD). This simple, yet effective, technique that almost exclusively described in orthognathic surgery is useful when advance surgical techniques such as pre- or intraoperative landmark identification may not be readily available. CPD technique optimizes the manual manipulations of the comminuted distal segments during fracture reduction and internal fixation. At the same time, it allows greater control of the proximal segments to avoid further surgical complication. PMID- 29391957 TI - Sequential Use of Second-Generation Tyrosine Kinase Inhibitor Treatment and Intensive Chemotherapy Induced Long-Term Complete Molecular Response in Imatinib Resistant CML Patient Presenting as a Myeloid Blast Crisis. AB - Myeloid blast crisis of chronic myeloid leukemia (CML-MBC) is rarely seen at presentation and has a poor prognosis. There is no standard therapy for CML-MBC. It is often difficult to distinguish CML-MBC from acute myeloid leukemia expressing the Philadelphia chromosome (Ph+ AML). We present a case in which CML MBC was seen at the initial presentation in a 75-year-old male. He was treated with conventional AML-directed chemotherapy followed by imatinib mesylate monotherapy, which failed to induce response. However, he achieved long-term complete molecular response after combination therapy involving dasatinib, a second-generation tyrosine kinase inhibitor, and conventional chemotherapy. PMID- 29391959 TI - Erroneously Suspected Ovarian Cancer in a 38-Year-Old Woman with Pelvic Inflammatory Disease and Chlamydia. AB - Chlamydia trachomatis is the most common bacterial cause of sexually transmitted disease and can cause pelvic inflammatory disease (PID), leading to severe outcomes such as ectopic pregnancy, infertility, or pelvic pain. We report a case of a 38-year-old patient with abdominal pain and dyspareunia. Clinical examination revealed diffuse abdominal tenderness. Vaginal and abdominal sonography showed substantial ascites and CA-125 level was elevated. Therefore, the attendant physician performed an abdominal CT scan for further diagnosis. Radiographically diffuse peritoneal enhancement, consistent with peritoneal carcinomatosis, 4-quadrant ascites, and slightly enlarged ovaries with solid and cystic structures were diagnosed, leading to the suspicion of ovarian cancer. In addition, the results of the cervical smear PCR for chlamydia were positive. Due to the positive chlamydia result, the suspicious CT scan, and the young age, we decided to perform a diagnostic laparoscopy as a first step. Intraoperatively, the ovaries were of normal aspect without any cancerous lesions. However, the ascites and the yellow-reddish jelly-like deposits were consistent with acute PID. Thus, chlamydia infection may simulate the presentation of ovarian cancer. Therefore, especially in young patients, we recommend careful scrutiny of every diagnosis of ovarian cancer even if its presentation seems to be typical. PMID- 29391958 TI - Emergence of Lassa Fever Disease in Northern Togo: Report of Two Cases in Oti District in 2016. AB - Background: Lassa fever belongs to the group of potentially fatal hemorrhagic fevers, never reported in Togo. The aim of this paper is to report the first two cases of Lassa fever infection in Togo. Case Presentation: The two first Lassa fever cases occurred in two expatriate's health professionals working in Togo for more than two years. The symptoms appeared among two health professionals of a clinic located in Oti district in the north of the country. The absence of clinical improvement after antimalarial treatment and the worsening of clinical symptoms led to the medical evacuation. The delayed diagnosis of the first case led to a fatal outcome. The second case recovered under ribavirin treatment. Conclusion: The emergence of this hemorrhagic fever confirms the existence of Lassa fever virus in Togo. After a period of intensive Ebola virus transmission from 2013 to 2015, this is an additional call for the establishment and enhancement of infection prevention and control measures in the health care setting in West Africa. PMID- 29391960 TI - C2 Solitary Bone Plasmacytoma Curettage and Vertebral Augmentation in an 83-Year Old Female: Case Report and Review of Surgical Treatment Approaches in the Spine. AB - Surgically, solitary bone plasmacytoma (SBP) of the craniocervical junction (CCJ) is typically treated with cement augmentation and occipital-cervical stabilization (OCS). In the orthopedic spine literature, various surgical treatment options have been described for SBP, but only a few studies exist describing SBP of the CCJ with treatment involving cement augmentation alone. We report the case of an 83-year-old female found to have C2 SBP that was successfully treated with curettage and cement augmentation alone. PMID- 29391961 TI - Chiari 1 Malformation in a Child with Febrile Seizures, Parasomnias, and Sleep Apnea Syndrome. AB - Introduction: The type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to disturbances in cerebrospinal fluid circulation and to direct compression of nervous tissue. Case report: We describe a 4-year-old Caucasian female child with febrile seizures, headache, parasomnias, and a delay of speech. The child underwent a magnetic resonance imaging to investigate these neurological signs, disclosing a Chiari malformation type 1. The polysomnography showed a mild-moderate sleep-disordered breathing, increased number of central sleep apneas, and generalized spike waves at sleep onset. Conclusions: Seizures have been seldom described in CM1 patients. The main reasons for performing MRI in this case were frequent seizures, a delay of speech, and headache, leading to an unexpected diagnosis of CM1. Polysomnography detected a discrete SDB. PMID- 29391962 TI - Seizure and Pulmonary Embolism: A Differential That Can Save a Life. AB - Seizures is a relatively common presentation with a wide differential diagnosis. However, seizures presenting secondary to underlying pulmonary emboli are rare and, without prompt recognition and management, this easily treatable condition can be potentially fatal. The few available case reports discussing seizures and PE reveal a high mortality rate which underscores the importance of prompt diagnosis. A 38-year-old woman presented to the emergency room having experienced loss of consciousness and a generalized tonic-clonic seizure at home. In the emergency room, her presenting signs and symptoms included tachycardia, worsening dyspnea, mild hypoxemia, and elevated D-dimer. Pertinent history findings revealed she recently received depot hormonal contraceptive treatments. Her initial workup included an EKG which showed sinus tachycardia without evidence of right heart strain. Subsequently a chest CT with angiography revealed massive bilateral pulmonary emboli. DVT studies also revealed a unilateral acute DVT. The patient was promptly started on therapeutic anticoagulation and stabilized. Fortunately, the patient remained symptom-free and eventually was discharged with close follow-up. The goal of this report is to make clinicians more aware of the possibility that seizures, along with the appropriate clinical findings, can be caused by acute PE. PMID- 29391963 TI - Extraosseous Multiple Myeloma: Case Report of Presentation in the Lower Extremity Soft Tissues with Literature Review. AB - A rare presentation of extramedullary multiple myeloma in the soft tissues of the bilateral thighs prompted a literature review of published cases of extramedullary multiple myeloma (EM-MM) and solitary plasmacytomas to determine the relative anatomic distribution of these lesions. All available published cases in English were included in the analysis, dating back to 1966 and including 2,538 extramedullary myeloma or solitary plasmacytoma lesions. Analysis of the anatomic location of EM-MM lesions demonstrates the majority being in the upper airway (33.8%), soft tissues including retroperitoneum and abdomen (14.1%), gastrointestinal tract (10.3%), central nervous system, head and neck (16.0%), and GU (2.4%). We were able to find only 44 documented cases of extremity soft tissue lesions, comprising 1.7% of all lesions. PMID- 29391964 TI - Large Enterolith Complicating a Meckel Diverticulum Causing Obstructive Ileus in an Adolescent Male Patient. AB - We present a unique case of a 16-year-old male patient who was eventually diagnosed with a large enterolith arising from a Meckel's diverticulum. The enterolith had caused intermittent intestinal symptoms for three years before resulting in small bowel obstruction requiring surgical intervention. Meckel's enterolith ileus is very rare with only few cases described in the literature. To our knowledge, this is only the second case of Meckel's enterolith which had caused intermittent symptoms over a period of time, before resulting in ileus, and the first case where the intermittent symptoms lasted several years before bowel obstruction. The patient had been evaluated with colonoscopy, computerized tomography (CT), and magnetic resonance imaging enterography (MRIE); a calcified pelvic mass had been found, but no further diagnosis other than calcification was established. The patient presented at our emergency department, with symptoms of obstructive ileus and underwent exploratory laparotomy, where a large enterolith arising from a Meckel's diverticulum (MD) was identified, causing the obstruction. A successful partial enterectomy, enterolith removal, and primary end-to-end anastomosis took place; the patient was permanently relieved from his long-standing symptoms. Consequently, complications of Meckel's diverticulum and enterolithiasis have to be included in the differential diagnosis of abdominal complaints. PMID- 29391965 TI - Unusual Case of Severe Lactic Acidosis in a Liver Transplant Patient. AB - Lactic acidosis is a standard indicator for oxygen debt and some other very significant causes. We describe a case of liver transplant patient presenting with vague abdominal pain and lactic acidosis without any liver dysfunction/failure/ischemia/rejection or sepsis. The imaging studies showed vague bowel edema and normal hepatic perfusion. The patient continued to deteriorate with rising lactic acidosis when a repeat CT abdomen eventually showed signs of lymphomatosis peritonei. Biopsy revealed the unusual diagnosis of posttransplant lymphoproliferative disorder. Immediate discontinuation of immunosuppression and initiation of chemotherapy led to clinical improvement. Our intention of presenting this case is to increase awareness of posttransplant lymphoma and propose lactic acidosis as not only an indicator of liver dysfunction or rejection but also an aid for diagnosis of this unusual but fatal and potentially curable condition. PMID- 29391967 TI - Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study. AB - A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40 degrees C under 75% relative humidity and dry conditions. For this study, a method based on high performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD) and charged aerosol detector (CAD). The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 MUg mL-1 for amlodipine and from 25 to 500 MUg mL-1 for olmesartan with coefficient of determination (R2 >= 0.9908) while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing. PMID- 29391966 TI - Age-Dependent Susceptibility to Alcohol-Induced Cerebral Artery Constriction. AB - Background: Age has been recognized as an important contributor into susceptibility to alcohol-driven pathology. Purpose: We aimed at determining whether alcohol-induced constriction of cerebral arteries was age-dependent. Study design: We used rat middle cerebral artery (MCA) in vitro diameter monitoring, patch-clamping and fluorescence labeling of myocytes to study an age dependent increase in the susceptibility to alcohol in 3 (50 g), 8 (250 g), and 15 (440 g) weeks-old rats. Results: An age-dependent increase in alcohol-induced constriction of MCA could be observed in absence of endothelium, which is paralleled by an age-dependent increase in both protein level of the calcium /voltage-gated potassium channel of large conductance (BK) accessory beta1 subunit and basal BK channel activity. Ethanol-induced BK channel inhibition is increased with age. Conclusions: We demonstrate an increased susceptibility of MCA to ethanol-induced constriction in a period equivalent to adolescence and early adulthood when compared to pre-adolescence. Our work suggests that BK beta1 constitutes a significant contributor to age-dependent changes in the susceptibility of cerebral arteries to ethanol. PMID- 29391968 TI - The Foundation Story of Turkish Archives of Otorhinolaryngology. PMID- 29391969 TI - Effect of Septorhinoplasty on Olfactory Function: Assessment Using the Brief Smell Identification Test. AB - Objective: Septorhinoplasty (SRP), one of the most commonly performed rhinologic surgery procedures, can affect olfactory function; however, the findings of studies investigating smell following SRP are controversial. We used a culturally adapted modified Brief Smell Identification Test (B-SIT) to investigate the long- and short-term effects of SRP on olfactory function. Methods: We enrolled 59 patients admitted to the Ear-Nose-Throat Clinic, who were complaining of external nasal deformity and nasal obstruction. Functional SRP was performed on all cases. The B-SIT was administered prior to surgery and at 4 and 12 weeks post-surgery. The smell identification score (SIS) reflected the number of correct answers. In addition, we investigated the effects of gender and smoking on olfactory function and whether the SRP procedure changed these associations. Results: The mean preoperative, 4-week, and 12-week postoperative SISs were 10.15+/-1.30, 10.21+/ 1.52, and 10.92+/-0.95, respectively. The difference between the preoperative and 4-week postoperative SISs was not statistically significant; however, the 12-week postoperative score was significantly different from the preoperative and 4-week postoperative scores. Furthermore, the repeated measures analysis according to gender and smoking habit revealed a significant difference between the 4-and 12 week postoperative SISs. One patient developed postoperative anosmia; however, the patient recovered in the 12-week postoperative period. Conclusion: SRP surgery is a safe procedure in terms of olfactory function. In addition, olfactory function may increase following surgery as a result of improved nasal airflow. PMID- 29391970 TI - Infectious and Noninfectious Causes of Epiglottitis in Adults, Review of 24 Patients. AB - Objective: The present study reports the etiological differences, clinical features, management, and patient outcomes between infectious and noninfectious causes of epiglottitis in adult patients. Methods: The medical records of 24 patients with infectious and noninfectious epiglottitis were investigated. Diagnosis was made by anamnesis and endoscopic examination. On admission, respiratory distress of patients was classified according to Freidman's classification. Results: Fifteen patients were male, and nine patients were female. Their ages ranged between 24 and 69 years of age (mean, 43.4+/-11.6). In total, 16 patients were diagnosed with infectious epiglottitis, and eight patients were diagnosed with noninfectious epiglottitis. Of patients with noninfectious epiglottitis, two had angioedema, two had experienced organophosphate ingestion, one had experienced hot water aspiration, one had experienced hot milk aspiration, one had experienced foreign body aspiration (fishbone), and one had epiglottitis due to Behcet's disease. Sore throat was the most common symptoms of infectious and noninfectious epiglottitis in our patients. Odynophagia was the second most common symptom of infectious epiglottitis, and muffled voice was the second most common symptom in noninfectious patients. Conclusion: Epiglottit is an emergency situation; when a patient is diagnosed with epiglottitis, close follow-up should be performed, and airway support should properly be maintained according to the degree of respiratory distress. Tracheostomy should be performed without hesitation, as needed. PMID- 29391971 TI - Titanium versus Hydroxyapatite Prostheses: Comparison of Hearing and Anatomical Outcomes after Ossicular Chain Reconstruction. AB - Objective: This study aimed to compare hearing and anatomical outcomes after ossicular chain reconstruction with titanium or hydroxyapatite prostheses. Methods: In this study, patients who underwent tympanoplasty and ossicular chain reconstruction with titanium or hydroxyapatite prostheses at a university hospital from January 2007 to February 2013 were retrospectively reviewed; they had a minimum follow-up period of 6 months. Patients were divided into 4 groups according to the type of prostheses. The surgical procedure, follow-up examinations, preoperative, and postoperative audiometry results were noted and evaluated for partial and total prostheses. The results were compared both for titanium and hydroxyapatite prostheses. Results: The study subjects included 51 patients. Titanium had better hearing results in partial prostheses (p<0.05), while the anatomical outcomes were similar. Nevertheless, both types had similar results in total prostheses (p>0.05). The extrusion rate was 5.8% for all patients. Conclusion: Both types of prostheses had satisfactory functional and anatomical results and no preponderance could be stated, except for the hearing results of partial titanium prostheses. PMID- 29391972 TI - Tularemia: A Rare Cause of Neck Mass. AB - Objective: Tularemia is a bacterial zoonosis caused by Francisella tularensis. In this study, we aimed to retrospectively evaluate the documents of patients who had a diagnosis of tularemia in our hospital and discuss this condition with a literature review. Methods: Twenty-five patients who had a diagnosis of tularemia between 2010 and 2013 were included in the study. The patients were assessed with respect to their demographic data; presenting complaints; leukocyte, sedimentation, and C-reactive protein (CRP) values; applied treatment protocols; duration of stay in the hospital; and histopathological examinations. Results: Fifty-seven patients were admitted to the health department of our clinic with a preliminary diagnosis of tularemia, and the diagnosis of tularemia was serologically confirmed for 25 patients. Pharyngeal mucosa cultures, centrifuged serum samples, and abscess and/or pathological samples were collected from all the patients. Thirteen patients were female, and 12 were male. The ages of the patients were between 10 and 75 (average 33.12+/-15.53) years. The most frequent (100%) symptom among the patients was swelling in the neck. While abscess drainage was performed in 12 patients (48%), the neck mass was excised in 3 patients (12%), and 10 patients (40%) were given only medical treatment. According to the guide of tularemia management by the Ministry of Health, treatment using suitable doses of streptomycin was started for all the patients; in addition, for 8 (32%) patients, doxycycline treatment was added. Conclusion: In recent years, tularemia in our country has been increasing at some specific locations, and those patients are frequently admitted to polyclinics with a complaint of swelling in the neck. In endemic areas in particular, tularemia should also be considered in the differential diagnosis of patients who present with abscess in the neck. PMID- 29391952 TI - Drosophila: An Emergent Model for Delineating Interactions between the Circadian Clock and Drugs of Abuse. AB - Endogenous circadian oscillators orchestrate rhythms at the cellular, physiological, and behavioral levels across species to coordinate activity, for example, sleep/wake cycles, metabolism, and learning and memory, with predictable environmental cycles. The 21st century has seen a dramatic rise in the incidence of circadian and sleep disorders with globalization, technological advances, and the use of personal electronics. The circadian clock modulates alcohol- and drug induced behaviors with circadian misalignment contributing to increased substance use and abuse. Invertebrate models, such as Drosophila melanogaster, have proven invaluable for the identification of genetic and molecular mechanisms underlying highly conserved processes including the circadian clock, drug tolerance, and reward systems. In this review, we highlight the contributions of Drosophila as a model system for understanding the bidirectional interactions between the circadian system and the drugs of abuse, alcohol and cocaine, and illustrate the highly conserved nature of these interactions between Drosophila and mammalian systems. Research in Drosophila provides mechanistic insights into the corresponding behaviors in higher organisms and can be used as a guide for targeted inquiries in mammals. PMID- 29391973 TI - Role of Elective Neck Dissection in Early Stage Lip Cancers. AB - Objective: To date, the management of the neck in early stage lower lip cancers remains controversial. The aim of this study is to investigate if prophylactic neck dissection is necessary in early stage lower lip cancers. Methods: Charts of 11 patients who underwent surgery of the primary site and neck because of T1-2N0 lower lip cancer between 1997 and 2011 were retrospectively examined. Clinical stages, surgeries, histopatological examination results, and loco-regional recurrences were evaluated. Results: Of the 11 patients, 10 were male (90.9%) and 1 was female (9.09%). The follow-up time of these patients was between 24-168 months (mean, 56.6 months). There were 5 patients with clinically diagnosed T1N0 tumors and 6 patients with clinically diagnosed T2N0 tumors. Suprahyoid neck dissection was performed in 4/5 T1N0 patients and supraomohyoid neck dissection was performed in the remaining 1 patient. For T2N0 tumors, 4 suprahyoid, 1 supraomohyoid, and 1 comprehensive neck dissection was performed. Histopathological examination revealed no occult metastasis in any of the patients. In 1 patient who had lower lip resection and suprahyoid neck dissection for T1N0 lower lip cancer, a contralateral neck metastasis was detected 22 months postsurgery, and a comprehensive neck dissection was performed. Conclusion: Our results show that in patients with T1N0 lower lip tumors, neck dissection may not be necessary; however, close follow-up is mandatory. Further researches with larger series dividing T2N0 tumors into subgroups for tumor size and thickness are necessary to determine neck treatment in these tumors. PMID- 29391974 TI - Recent Landmark Studies on Head and Neck Cancers: Evidence-Based Fundamentals of Modern Therapeutic Approaches. AB - Evidence-based medicine, established on prospective studies and related algorithms is living its golden age in recent years. Within the last few decades, medical knowledge has been systematically produced, categorized, and spread in a way never seen before. One of the most important factors in realizing this situation is the expansion of the communication facilities. The area of the management of head and neck cancers was also affected by these advances, and studies with high-level evidence became the mainstay in the determination of the management strategies. However, probably almost all of these studies are about non-surgical modalities, and studies with high-level evidence regarding the surgical treatment of head and neck cancers are scarce. In this paper, important studies on head and neck cancers and their results will be reviewed. PMID- 29391975 TI - A Rare Variation of Inferior Laryngeal Nerve: Nonrecurrent Laryngeal Nerve. AB - A nonrecurrent laryngeal nerve variant of the inferior laryngeal nerve is very rarely seen, and surgeons should keep it in mind during thyroid surgery. Preoperative findings, like situs invertus and dysphagia lusoria, may be suggestive of a nonrecurrent laryngeal nerve. However, these findings always have not to be together with nonrecurrent laryngeal nerve, like our case. PMID- 29391976 TI - Submandibular Sialolithiasis Perforating the Floor of Mouth: A Case Report. AB - Calculus formation in salivary glands (sialolithiasis) is one of the most common diseases of the salivary glands and is most commonly seen in the submandibular gland. Not only can the stones be small and inside the duct, they may also get larger and reside inside the gland. We can easily see submandibular sialolithiasis perforating the floor of the mouth in cases having sialolithiasis for decades and not having any treatment and its transoral removal as we look in the medical literature. A 52-year-old lady who had rejected surgical treatment for submandibular sialolithiasis for 25 years is presented as a case in this study. Treatment of the case was performed effectively by taking out the calculus transorally with a simple intervention whose examination revealed that the calculus was seen to perforate the floor of the mouth. It is aimed to stress with this case that transoral removal of submandibular sialolithiasis that perforates the floor of the mouth without performing external approaches is a method that has to be thought in the first step. PMID- 29391977 TI - Lemierre's Syndrome Case Secondary to Otitis Media. AB - Lemierre's syndrome is a rare but fatal thrombophlebitis of the internal jugular vein (IJV). It usually follows acute oropharyngeal infections in healthy, young adults. Fusobacterium necrophorum is the most common bacteria that causes Lemierre's syndrome, whereas various microorganisms are reported. We are reporting a case with Lemierre's syndrome secondary to otitis media, which is a rare occurrence of a rare disease. PMID- 29391978 TI - Dermoid Cyst Arising from the Epiglottis. AB - Dermoid cysts arising from the head and neck region are rare, slow-growing, and well-circumscribed neoplasms. Symptoms are non-specific and usually related to the size and the location of the lesion. A dermoid cyst of the epiglottis is extremely rare. To the best of our knowledge, only one case has been previously reported in the English literature. In this study, a case of a dermoid cyst arising from the epiglottis was presented as an extremely rare clinical condition. The characteristics, differential diagnosis, and treatment of the disease are summarized. PMID- 29391979 TI - Assessment of Subepithelial Angiogenesis in Acquired Cholesteatoma between Pediatric and Adult Patients. AB - Objective: The aim of this study was to compare subepithelial angiogenesis developing within the perimatrix of the cholesteatoma between pediatric and adult patients. Methods: Sixty-one patients who underwent mastoidectomy for the first intent because of chronic otitis media with cholesteatoma between 1993 and 2013 and from whom appropriate tissue specimens were taken were included in the study. The patients were classified in the pediatric patient group if they were under the age of 18 years and the adult patient group if they were 18 years and older. Immunohistochemical staining for CD-31 was performed on new sections taken during surgery and sections prepared from archived tissues in paraffin blocks. Results were compared between the groups. Results: A total of 61 patients, of whom 25 were pediatric and 36 were adult patients, were included in the study. The mean CD-31 immunopositive microvessel rates were 8.8 (3-15) and 6.61 (2-14) for the pediatric and adult patient groups, respectively. The difference between the groups was statistically significant (p=0.037). Correlation analysis showed a statistically significant negative correlation between the CD-31 immunopositive microvessel rates and age (p=0.036). Conclusion: Subepithelial angiogenesis developing within the perimatrix of the cholesteatoma of the pediatric patients was more expressed than that of the adult patients. PMID- 29391980 TI - Reliability of Frozen Section Pathology in Transoral Laser Laryngectomy. AB - Objective: To evaluate the reliability of frozen section analysis in transoral laser laryngectomy (TOLL). Methods: A retrospective analysis was conducted for patients who underwent TOLL in a university hospital between January 2012 and February 2014. The grade of the tumor and the histopathological diagnosis were noted. The results of frozen section pathologies and routine histological examinations were compared. Results: A total number of 84 sections from 21 patients with a mean age of 57.3 years were included in the study. All the patients were operated with superpulse continuous mode carbon dioxide laser with a power of 5-8 watts. Squamous cell carcinoma was histologically diagnosed in all patients. The tumor was grade 1 in 80.95% of the patients, grade 2 in 9.52%, and grade 3 in 9.52%. A routine histopathological examination confirmed the frozen section in 94.04% of the patients. Conclusion: Laser surgery is a commonly preferred treatment modality in early-stage laryngeal carcinomas, in particular. However, a safe surgical margin is a debate in transoral laser surgery. In light of our results, we can conclude that frozen section pathology is a reliable method to achieve safe surgical margins in TOLL. PMID- 29391981 TI - Evaluation of bcl-2, bax and c-erbB-2 Levels in Chronic Otitis Patients with or without Cholesteatoma. AB - Objective: The aim of this study was to evaluate bcl-2, bax, and c-erbB-2 expressions in primary and secondary acquired cholesteatoma and to indicate the role of apoptosis and accompanying increased cellular proliferation in the pathogenesis of cholesteatoma. Methods: Samples obtained from the skin of the external ear canal (EEC) of patients operated for chronic otitis media (COM) without cholesteatoma constituted Group 1; samples from the EEC skin of patients in Group 3 operated for COM with cholesteatoma and from the EEC skin of patients in Group 4 constituted Group 2; samples obtained from the cholesteatoma matrix of patients operated for COM with primary acquired cholesteatoma constituted Group 3; and samples obtained from the cholesteatoma matrix of patients operated for COM with secondary acquired cholesteatoma constituted Group 4. The assessment of the positive cell ratio was based on the presence of the following findings and was semiquantitatively classified into four groups: 0, no staining; + cell staining (weak positive staining: 1%-33%); ++ cell staining (moderately positive staining: 34%-66%); and +++ cell staining (strong positive staining: 67%-100%). Results: Comparison of the staining scores of bcl-2, bax, and c-erbB-2 revealed a statistically insignificant difference in the staining of samples obtained from the EEC skin (p>0.05). Decreased bcl-2 expression and increased bax and c-erbB-2 expressions were determined in primary and secondary acquired cholesteatoma epithelium compared with the EEC skin of patients operated for COM with or without cholesteatoma, and the differences were found to be statistically significant (p<0.05). Conclusion: In acquired cholesteatoma epithelium, the finding of decreased bcl-2 expression as well as increased bax and c-erbB-2 expressions compared with the EEC skin is an indicator of the increase in both cellular proliferation and apoptosis. PMID- 29391982 TI - The Value of Sentinel Lymph Node Biopsy in Oral Cavity Cancers. AB - Objective: The aim of this study was to establish the effectiveness of sentinel lymph node biopsy in the detection of metastasis in N0 necks of T1-T2 early-stage oral cavity cancers. Materials and Methods: Twenty neck dissections were performed in 18 patients diagnosed with T1 and T2 oral cavity cancer, with an indication for elective neck dissection between November 2007 and January 2011. The male to female ratio was 12:8, with a mean age of 54.5 years (range 28-76). Eight of the dissections were performed for lower lip cancer, 7 for tongue cancer, and 5 for floor of the mouth cancer. Sentinel lymph node biopsy was used to detect metastatic lymph nodes. Tc99m radionuclide injection was administered to the periphery of the tumor 24 h before the operation, and a lymphoscintigraphy image was obtained 30 min after the injection. Sentinel lymph nodes were localized and excised on the day of surgery using static lymphoscintigraphy images and a gamma probe. Sentinel lymph nodes were sent for a frozen section examination, and either a selective or a comprehensive neck dissection was performed for each neck according to the results. Results: After the final histopathological examination of the specimens, the negative predictive value, the positive predictive value, the accuracy of the sentinel lymph node biopsy, and frozen section accuracy were found to be 100%. Conclusion: Sentinel lymph node biopsy was found to be an efficient method in the pathological staging and management of the N0 neck in early T-stage oral cavity cancers. PMID- 29391983 TI - The Role of PET-CT in Evaluation of Cervical Lymph Node Metastases in Oral Cavity Squamous Cell Carcinomas. AB - Objective: The aim of this study is to determine the sensitivity and specificity of positron emission tomography-computed tomography (PET-CT) in the evaluation of cervical lymph node metastasis in oral cavity squamous cell cancers (SCCs) and to determine the SUV-max values in differentiating reactive and metastatic lymph nodes as a supportive parameter. Methods: In this study, 23 patients were included who were diagnosed with oral cavity SCC and treated with surgery between 2006 and 2013 in our department. All the patients were scanned with PET-CT during the pretreatment evaluation. Detailed pretreatment PET-CT (retention sites and SUV-max values) and histopathological examination results were obtained. SPSS 17.0 software package was used for statistical analysis of the data. Categorical measurement was summarized as number and percentage and continuous measurements as mean and standard deviation (median and minimum-maximum where necessary). Chi square test or Fisher's test were used in the comparison of categorical variables. Compliance of methods was assessed by Kappa coefficient analysis. In this study, the advantages of PET-CT were determined by the calculation of sensitivity and specificity values with histopathological examination results considered as the gold standard, and SUV-max value was assessed by examining the area under the ROC curve. In all tests, the level of statistical significance was accepted as 0.05. Results: The threshold value for SUV-max depending on the data of the histopathological examination and results of PET-CT of the 23 patients was 2.50. The reliability of this threshold was determined as AUC=0.819. In demonstrating neck metastasis in patients with cancer of the oral cavity, PET-CT has a sensitivity of 89% and specificity of 98%. Compliance between the histopathological examination and PET-CT for metastatic cervical lymph nodes was determined to be 0.416 by kappa coefficient analysis. Conclusion: There was FDG uptake on PET-CT in the cervical lymph node regions of all patients with metastatic cervical lymph nodes. There were no metastases in any of the patients with no FDG retention. The sensitivity and specificity of PET-CT in determining cervical lymph node metastasis were 89% and 98%, respectively, with a threshold SUV-max value considered as 2.50 in patients with FDG retention. PMID- 29391984 TI - Use of PET in Head and Neck Cancers. AB - Head and neck cancer imaging is especially necessary for staging. Computed tomography and magnetic resonance imaging are the techniques frequently used for this purpose. These methods are valuable for displaying detailed anatomical structures; however, they may be inadequate for making the distinction between recurrence, residual tumor, fibrosis, and normal tissues with an altered anatomy after treatments such as surgery, radiotherapy, and chemotherapy and for the detection of metastases. From this point, positron emission tomography may be a promising imaging method. Scanning the entire body with a single method is an important advantage of positron emission tomography. It may be useful in the detection of synchronous tumors, which are a serious problem in head and neck cancers. Positron emission tomography may provide additional contribution for neck metastases, where the primary site is unknown and is undetectable by other imaging techniques. PMID- 29391985 TI - A Rare Tumor of the Retropharyngeal Area: Solitary Fibrous Tumor. AB - We describe a case of retropharyngeal solitary fibrous tumor (SFT) in a 46-year old female patient. Total removal of the tumor without any complications was performed by transoral surgery. Intraoral resection of retropharyngeal SFT can be preoperatively performed by meticulous assessment of the extent and vasculature of the tumor with radiological guidance. PMID- 29391986 TI - Obliteration of a Large Mandibular Arterio-Venous Malformation with Polymethyl Methacrylate Bone Cement. AB - Mandibular arteriovenous malformations (AVMs) are rare and potentially life threatening vascular lesions. Surgery, embolization, or bone cement implantation is an option for the treatment of mandibular AVMs. We present a case of huge mandibular AVM refractory to multiple embolizations of the supplying arteries, which was treated with polymethylmethacrylate (PMMA) bone cement implantation after the extraction of a molar tooth. PMID- 29391987 TI - Bilateral Sigmoid Sinus Thrombosis and Otitis Media. AB - Sigmoid sinus thrombosis is a rare complication of otitis media and is known to be unilateral. In this report, we present a case of bilateral sigmoid sinus thrombosis secondary to bilateral otitis. To the best of our knowledge, there are no bilateral-simultaneous cases reported in literature to date. Here, the diagnosis of and treatment for the disease as well as predisposing factors are discussed. PMID- 29391988 TI - A Case of Cranial Meningioma with Symptoms Similar to Nasopharyngeal Mass. AB - Meningiomas are generally slow-growing benign tumors associated with the dura. They form lumps that mostly grow extra-axially, by repulsing, rather than infiltrating the surrounding neural parenchyma. Majority of meningiomas are intracranial. However, although rare, meningioma formation has been reported in almost all other organs. We report the case of a patient with an extra-neuraxial meningioma presenting as a nasopharyngeal mass. PMID- 29391989 TI - Evaluation of Inner Ear Damage by Using Otoacoustic Emissions in Patients Who Underwent Mastoidectomy and Tympanoplasty Operations in the Early Period. AB - Objective: We aim to demonstrate inner ear damage caused by drilling in the early period. Healthy contralateral ears of patients who underwent mastoidectomy using drill or tympanoplasty without using drill were compared. Methods: A total of 38 patients (mastoidectomy: 22, tympanoplasty: 16) who were diagnosed as chronic otitis media and were scheduled for surgery were included. Distortion product (dp) otoacoustic emissions measurements were performed on healthy contralateral ears of patients on pre- and post-operative 1. hour, 1. day, 2. day, 3. day, and 4. day. Results: In mastoidectomy group, dp otoacoustic emission values on post operative 1. hour, 1. day, 2. day, 3. day, and 4. day at a frequency of 4000 Hz were significantly lower than in tympanoplasty group (p<0.05). In mastoidectomy group, dp values on post-operative 1. hour, 1. day, 2. day, 3. day, and 4. day at 4000 Hz significantly decreased in comparison with pre-operative period (p<0.05). In comparison with pre-operative period, decrease in dp values on post-operative 1. hour, 1. day, and 2. day at 4000 Hz in mastoidectomy group is significantly higher than those in tympanoplasty group (p<0.05). In tympanoplasty group, dp values on post-operative 1. hour at 4000 Hz significantly decreased in comparison with pre-operative period (p<0.05). Conclusion: Drilling used in mastoidectomy operation damage healthy contralateral ears by causing acoustic trauma. This damage can be determined by otoacoustic emissions in the early period. According to our study, hearing loss is temporary and more distinct at higher frequencies. PMID- 29391990 TI - Opinions of Otorhinolaryngology Residents about Their Education Process. AB - Objective: Our study was planned to get the views of residents about the Otorhinolaryngology (ORL) education process and to enlighten the studies to make this process more effective. Methods: A questionnaire was sent to the residents who were still in the residency program in all education clinics via "Google Drive". Seventy-four of 354 residents responded and the answers were evaluated electronically. Results: Fifty residents (67.56%) gave an affirmative answer to the question about the use of "Resident Log Book" and no difference was seen among the clinics. While 9 residents (12.16%) were reporting that they did not read any scientific papers, 43 (58.1%) reported they read less than three per month. Forty-one residents thougt that they were having a good and sufficient education. Seventeen residents (51.51%) who thought they were not having a sufficient education reported that the education period should be longer. When they were wanted to evaluate the education process, while 66 of them (89.18%) said "Exhausting", 52 (70.27%) said "Stressful", it was seen that the ones who said "Instructive" and "Rewarding" were 26 (35.13%) and 17 (22.97%) respectively. Further, 43 of 48 residents (89.58%) who were over the third year of their residency program indicated that they were unable to perform at least one procedure listed in the questionnaire after finishing their education. Conclusion: This study is important because it is the first study about the opinion of ORL residents and will help determine the current status in Turkey. This study will be useful for the preparation of educational programs and guides in the future. PMID- 29391991 TI - Pediatric Tracheotomy: A 5-Year Experience in Duzce University Medical Faculty. AB - Objective: Tracheotomy is one of the oldest surgical procedures. Pediatric tracheotomy indications have changed in recent decades. Currently, tracheotomy is performed because of prolonged intubation, upper airway obstruction, neuromuscular, and craniofacial anomalies instead of acute airway infections. This study aims to present our experience regarding indications and complications of tracheotomy in pediatric patients. Methods: We retrospectively evaluated 17 pediatric patients who underwent tracheotomy because of prolonged intubation, increased pulmonary secretions, and upper respiratory tract obstruction from June 2010 to June 2015. The patients' age, gender, tracheotomy indications, duration of intubation, complications, and actual clinical condition were recorded. Results: Tracheotomy was performed on 17 pediatric patients in our clinic. Discharged patients were followed with a 3-month routine check. Six patients (35.29%) had died because of a primary disease during follow-up, and one (5.88%) of them was a one-day-old newborn who had anomalies that were incompatible with life. In one patient, emergency tracheotomy was performed because of a tracheal trauma. None of the patients has been decannulated except one (5.88%). One (5.88%) patient had an accidental decannulation, while another had bleeding in the operation field. The total minor complication rate was 11.76%, and no major complication was observed. Two (11.76%) of the discharged patients underwent re operation for widening of the tracheotomy stoma during their routine visit. Conclusion: Currently, tracheotomy in pediatric patients is mostly performed for prolonged intubation and upper respiratory tract obstruction for which intubation is not possible. Tracheotomy enables the discharge of these patients after training their families. PMID- 29391993 TI - Tumor Microenvironment in Head and Neck Squamous Cell Carcinomas. AB - Recent studies about solid tumors demonstrated that tumor microenvironment has an important role in tumor progression, aggressivity, and metastasis process, in addition to genetic aberrations and molecular alterations of cancer cells. Therefore, the crosstalks between cancerous and noncancerous cells and metabolic changes in tumor microenvironment cause significant detrimental effects. The purpose of this review is to present the role and effect of noncancerous cells and their crosstalks with cancer cells, metabolic changes in tumor microenvironment, and to discuss the clinical significance of all these factors with respect to the current literature. PMID- 29391994 TI - Laryngeal Transplantation. AB - Patients who require laryngectomy usually do not want to completely or partially lose their larynx. Laryngeal transplantation (LT) is a composite tissue transplantation from a cadaver to an alive recipient and requires lifelong immunosuppression in postoperative term. The aims of LT are breathing without tracheostoma, normal swallowing, and voice production. To date, only two successful complete LT have been performed in human despite many researches. The requirement of post-transplant immunosuppressive treatment has ethical concern for the larynx, which is a non-vital organ. However, LT may be an option for improving the quality of life of patients undergoing laryngectomy. In this study, we discussed the LT procedure and researches with the literature. PMID- 29391992 TI - The 100 Most Cited Turkish Papers in the Otorhinolaryngology Journals of Web of Science. AB - Objective: The aim of the study was to analyze the 100 most cited publications with Turkish origin in the Web of Science Otorhinolaryngology (ORL) journals. Methods: The Web of Science database was searched in terms of citations for publications originating from Turkey in ORL journals since 1983. After the identification of the 100 most cited articles, analysis was performed for the first author, institution, city, publication type, subject related to subspecialty, and journals having the most cited articles. Moreover, the number of ORL publications and citations of countries was determined in descending order using the same database. Results: A total of 3948 ORL articles with Turkish origin was identified. The number of citations was 181 for the first and 28 for the last in the 100 most cited articles. As there was more than one article with 28 citations, 101 articles were analyzed. The number of the articles was 76, 22, and 3 for the university, education/research, and state hospitals, respectively. Hacettepe University, Ankara Numune Hospital, and Gazi University were the three leading institutions having the most cited articles, and Ankara was the first city. While 98 of 101 articles were original research, the number of case reports and review articles were 2 and 1, respectively. Thirty-five articles were related to otology, 23 to pediatric ORL, 20 to rhinology and head and neck surgery, and 3 to facial plastic surgery. Laryngoscope, Otolaryngology-Head and Neck Surgery, and International Journal of Pediatric Otorhinolaryngology were the leading 3 journals with the most cited articles coming from Turkey. The evaluation of countries revealed that Turkey was among the first 10 countries in terms of number of ORL articles but fell behind for the number of citations. Conclusion: This bibliometric study is the first one regarding the contribution of Turkish authors and institutions to ORL literature. Similar studies might be periodically repeated to determine national development in the field of ORL and place of Turkey in the world. PMID- 29391995 TI - A Rare Cause of Acute Respiratory Distress: Cervical Ranula. AB - Plunging or cervical ranula is a mucus extravasation pseudocyst arising from the sublingual gland that is located below the mylohyoid muscle. Clinically, if large enough, cervical ranulas can affect swallowing, speech, chewing, and even breathing. The acute presentation of ranulas, which are clinically known as slow growing, painless masses, is rare. In this study, we present a case of cervical ranula that grew in a short period of 3 days and resulted in respiratory distress and that was operated in our clinic. PMID- 29391996 TI - Human Immunodeficiency Virus (HIV) Positive Case with Squamous Cell Larynx Cancer: Difficulties in the Choice of Treatment. AB - Squamous cell carcinoma of the larynx is rarely encountered in HIV (human immunodeficiency virus)-positive patients compared with HIV-associated malignancies. Standard protocols are absent for the management of laryngeal carcinoma in HIV-positive patients. HIV infection-associated immune suppression increases the mortality and morbidity of laryngeal carcinoma treatment. In the management of laryngeal carcinoma in HIV-positive patients, beside the clinical staging, the detection of CD4+ cell count is important. Regular antiretroviral treatment may have favorable effects in the management of laryngeal carcinoma. The treatment modality in the presented HIV-positive case with the diagnosis of laryngeal cancer was determined with a multidisciplinary approach. PMID- 29391997 TI - The Relationship between Th1/Th2 Balance and 1alpha, 25-Dihydroxyvitamin D3 in Patients with Allergic Rhinitis. AB - Objective: With regard to the correlation between T helper1/T helper2 (Th1/Th2) cell balance and 1alpha,25-dihydroxyvitamin D3, active metabolite of vitamin D, we studied Th1/Th2 cell balance by measuring levels of the cytokines interleukin (IL)-4, IL-10 and interferon-gamma (IFN-gamma), which are important for immune response of patients with allergic rhinitis. Methods: Thirty adult patients diagnosed with allergic rhinitis (study group) and 40 healthy volunteers (control group) are examined in the research. IFN-gamma, IL-4, IL-10, and total immunoglobulin E (IgE) levels from serum samples and vitamin D3 levels from plasma were determined in all patients. Results: In IgE, IL-4, IL-10, IFN-gamma, and 1alpha,25-dihydroxyvitamin D3 levels (p<0.05), a statistically noticeable difference was observed between the study and control group. The 1alpha,25 dihydroxyvitamin D3 levels in both groups were compared and a statistically significant difference between the 1alpha,25-dihydroxyvitamin D3 levels in the study group and that in the control group (p<0.05) was observed. There was a positive correlation between IFN-gamma and vitamin D levels (p<0.05) in the study group, whereas IgE, IL-4, and IL-10 levels showed a negative correlation with vitamin D3 levels (p<0.05). Conclusion: In our study, 1alpha,25-dihydroxyvitamin D3 levels were associated with Th1/Th2 balance in allergic rhinitis, and a remarkable correlation was observed among vitamin D deficiency and allergy. These findings show that 1alpha,25-dihydroxyvitamin D3 may have a remarkable role in the severity and control of allergic disorders. In addition, further investigations are required to confirm how vitamin D should be used in allergic diseases. Furthermore, to reveal the exact mechanism of vitamin D on allergic diseases, further studies are required. PMID- 29391998 TI - The Analysis of Patients Operated for Frontal Sinus Osteomas. AB - Objective: Paranasal sinus osteomas are benign tumors that are smooth-walled, slow-growing, and induced by bone tissue. Although their most common localization is the frontal sinus, some osteomas are seen in the ethmoid, maxillary, and sphenoid sinuses. Frontal sinus osteomas are often asymptomatic; however, when they become symptomatic, headache is the most common complaint. In this study, we aimed to analyze the postoperative results of patients who were diagnosed with frontal sinus osteoma and were operated with appropriate surgical techniques. Methods: We retrospectively evaluated 14 patients who were diagnosed with frontal sinus osteoma and were operated in our department between March 2009 and July 2014. The following parameters were analyzed: patients' age and gender, complaints at the time of admission to our clinic, pathological findings from physically examination, tumor features observed in preoperative paranasal sinus computed tomography (size and localization), surgical methods applied, intra- and postoperative complications, and recurrence rates. All patients preoperatively provided informed consent. Results: Of the 14 patients, 7 were males and 7 were females, with a mean age of 40.57 years. A total of 11 (79%) osteomas were located within the frontal sinus and 3 (21%) within the frontal recess. External surgical approach was performed to 11 patients, endoscopic approach was performed to 2 patients and external and endoscopic approach was performed to 1 patient together. Conclusion: Although the preferred surgical method in frontal sinus osteoma depends depended on size and localization of tumors, experience of surgeon is also important. Although the external surgical approach is appropriate for large and laterally localized osteomas, the endoscopic approach is appropriate for small and inferomedially localized osteomas. In both surgical approaches the site of origin should be drilled. PMID- 29391999 TI - Evaluation of Articles on Rhinology Published in National Otorhinolaryngology Journals between 2010-2015. AB - Objective: This study aimed to investigate the articles regarding rhinology published in national otorhinolaryngology journals between 2010 and 2015 according to the manuscript type, headline, citation city, and institution, as a reference for studies that will be designed in the future. Methods: Articles published on rhinology between 2010 and 2015 in national otorhinolaryngology journals were searched through websites of journals. The names of the journals, subjects of the manuscripts, manuscript type, citation city and institution, and manuscript language were recorded. Results: In this study, 890 articles were reviewed in 6 national otorhinolaryngology journals. Of these, 274 were regarding rhinology and 129 (47%) and 117 (42.7%) were original articles and case reports, respectively. Of the 274 articles, 21 (7.7%) and 5 (1.9%) were review and animal studies, respectively, and 2 (0.7%) articles defined surgical technique. Most frequently studied topics were benign tumors and inflammatory diseases of the paranasal sinuses. Conclusion: The ratio of case reports was relatively high in national rhinology publications. In future, smell and taste disorders, skull base surgery, and nasal physiology-related to Rhinology may be innovative research areas. PMID- 29392000 TI - Evaluation of Hearing Loss in Pilots. AB - Objective: High-intensity noise sources with an increase in air traffic and sudden changes in atmospheric pressure can cause hearing loss in pilots. The main goal of this research is to examine hearing loss due to age, the total flight hours and aircraft types and to evaluate the effects of personal conditions that can influence the hearing level. Methods: We examined the data of 234 Turkish pilots aged between 25 and 54 years who were examined due to the aviation Law for annual control from January 2005 to January 2014 at Baskent University Medical Faculty, Ankara Hospital. The audiometric results of the pilots were used. While 1, 2, 3, 4, 6, and 8 KHz were used for the airway threshold, 1, 2, and 4 KHz were used for the bone conduction threshold. Results: According to the data of the 234 pilots, there was a significant correlation between high-frequency hearing loss and the total flight hours and pilots' ages. The average hearing loss was higher, particularly in the left ear, in pilots using helicopters than in those using other aircraft types. There was no statistically significant correlation between hearing loss and diabetes, hypercholesterolemia, high blood pressure, anemia, obesity, and smoking. Conclusion: A significant correlation was observed between high frequency hearing loss and the total flight hours, pilots' age, and aircraft types in our study. PMID- 29392001 TI - The Importance and Place of Adenotonsillectomy in Syndromic Children. AB - Objective: Upper airway obstruction and sleeping disorders are important issues in syndromic children, including mouth, lower-upper jaw, or all facial abnormalities. Tonsillectomy and/or adenoidectomy is required because of systemic problems and upper airway obstruction that increase the existing systemic problems, except those anomalies. However, tonsillectomy and/or adenoidectomy are mostly avoided because of the tendency to cause both intubation/perioperative systemic problems and respiratory complications in the postoperative period and in delays in the oral intake. However, these surgeries are sometimes required. In this context, we present our experience related with performing tonsillectomy and/or adenoidectomy in syndromic children admitted to our hospital. Methods: We retrospectively examined the data on tonsillectomy and/or adenoidectomy performed in syndromic patients in our clinic between 2001 and 2011. Results: We did not observe any postoperative complications in adenoidectomy and/or tonsillectomy performed by the same surgeon in 14 syndromic cases. Conclusion: It should be noted that respiratory problems may arise from many different anatomical regions in syndromic patients. Therefore, surgery should be performed taking into consideration all of these factors in these patients. These patients must be hospitalized in the postoperative period. PMID- 29392002 TI - Adenoid Vegetation in Children with Allergic Rhinitis. AB - Objective: Pediatric patients with nasal obstruction due to adenoid vegetation (AV) can also encounter allergic rhinitis (AR) as a comorbidity. The aim of the study was to estimate the incidence of mite sensitization and its effect on adenoid size in children who underwent adenoidectomy. Methods: This prospective randomized study conducted between August and September 2014 included 84 children. Skin Prick Test (SPT) for inhalant allergens was preoperatively applied to all children who underwent adenoidectomy for nasal obstruction. Children were divided into two study groups: AV only (Group I) (n=52) and AV with Dermatophagoides Pteronyssinus and/or D. farinae allergy (Group II) (n=32). Postoperative specimen volumes, visual analogue scale (VAS) scores, and adenoid volumes measured using flexible fiberoptic nasopharyngolaryngoscopy were compared between the two groups. Results: Postoperative specimen volume measures were higher in Group II compared with those in Group I (p<0.05). Furthermore, in preoperative endoscopic examination, adenoid volume measures were higher in Group II compared with those in Group I (p<0.05). Pre and postoperative VAS scores in SPT+ group were higher in the Group II (p<0.05) than those in Group I. Conclusion: We observed that children with AR tend to have an early onset of symptoms of adenoid hypertrophy. We believe that focusing on the management of role of allergy regarding these early symptoms will reduce the need for surgery in a large number of cases. We suggest that SPT must be performed in all children with AV and adenoid examination should not be neglected in children with AR. PMID- 29392003 TI - The Management of Thyroid Nodules. AB - Thyroid nodules are extremely common and are detected in 3%-7% of the general population by palpation and in 70% of the population by ultrasonography (USG). Approximately 5%-15% of these nodules are malignant. Therefore, in nodule examination, our primary aim is to detect malignant nodules. Besides the medical history and the findings of the physical examination, USG and fine-needle aspiration biopsy (FNAB) are the most commonly used methods to examine these nodules. Ultrasound-guided FNAB and on-site assessment of FNA specimens are suggested to decrease false negative and non-diagnostic test results. FNAB results in the "atypia of undetermined significance" group is challenging in the follow-up or treatment of the nodule. In this group, to differentiate the malignant nodules, other developing methods, such as analyzing molecular genetic markers, protein markers, and elastography, are generally studied. However, these methods are not used in a routine nodule examination because of cost-benefit analysis. PMID- 29392004 TI - Reconstruction of Orbital Walls with Bone Cement in a Maxillectomy Patient. AB - Orbital wall defects occur because of trauma and secondary to oncologic surgery. Reconstruction of orbital bones is of most importance to ensure normal eye functions and cosmesis. Acrylic resin materials can be used instead of a bone in orbital wall defects that are secondary to the resection of tumors invading the orbita. Polymethyl methacrylate is one of the acrylic resin materials. In this study, the orbital wall reconstruction technique with bone cement after maxillectomy and results are reported. PMID- 29392005 TI - Oropharyngeal Hairy Polyp Causing Dysphagia. AB - Hairy polyp is a rare, benign tumor that comprises ectodermal and mesodermal germ layers. The embryogenesis of hairy polyp is precisely unknown, and concurrently, it has a female predominance. Although hairy polyp is observed in every part of the body; it is frequently located in the nasopharynx and oropharynx. Respiratory distress and feeding difficulties are the most related symptoms. Differential diagnoses comprise hemangioma, teratoma, epidermoid cyst, neuroblastoma, and meningocele. In this report, a seven-year-old patient who was admitted to our clinic with swallowing difficulty because of an oropharyngeal hairy polyp was described. PMID- 29392006 TI - An Unusual Cause of Dysphagia: Live Leech in the Tongue Base. AB - Inhaled or ingested foreign bodies are relatively common causes of airway obstructions. They can be associated with significant morbidity and even mortality. Although various foreign bodies are aspirated or ingested, live leeches are rarely encountered. We reported a case of a live leech at the base of the tongue in an 18-year-old female patient with a history of unfiltered spring water drinking. We discussed the surgical technique and importance of anesthesia with this brief study. PMID- 29392007 TI - Izmir School for the Deaf. PMID- 29392008 TI - Retrospective Analysis of Surgically Managed Maxillofacial Fractures in Kayseri Training and Research Hospital. AB - Objective: To retrospectively evaluate the clinical and surgical data of patients with maxillofacial fracture (MFF) who were surgically treated at the Department of ENT and Head Neck Surgery in the Kayseri Training and Research Hospital and to compare and discuss the results with relevant literature, including that from Turkey. Methods: Data concerning the age, gender, etiology, type and site of injury, treatment modality, and postoperative complications were collected and analyzed from medical records of patients who underwent maxillofacial surgery for MFF at the Department of ENT and Head Neck Surgery in the Kayseri Training and Research Hospital between January 2013 and March 2015. Results: A total of 35 patients were surgically treated because of MFF between January 2013 and March 2015. Of the 35 patients, 28 (80%) were male, whereas seven (20%) were female. Traffic accidents (40%) were the most frequent cause of MFFs. Mandibular fractures (49.1%) were the most common fractures, followed by zygomatic fractures (31.6%). Surgical management of MFFs was performed via closed reduction (17.5%) and/or open reduction with internal fixation by miniplates (82.5%). A total of five complications were observed in the present study: malunion (n=2), removal of fixation plate because of infection (n=2), and permanent infraorbital nerve injury (n=1). Conclusion: Based on the experience from the close proximity of the area, we think that surgeries for MFFs should be in the surgical repertoire of ENT surgeons. PMID- 29392009 TI - Evaluation of Acoustic Reflex and Reflex Decay Tests in Geriatric Group. AB - Objective: To determine average acoustic reflex thresholds in geriatric groups by assessing ipsilateral and contralateral acoustic reflex and reflex decay tests. Methods: A total of 25 elders between ages 65-84 years (74.3+/-5.4) and 25 individuals between ages 18-45 years (30.4+/-4.2) were recruited for the study. After ear, nose, and throat examination, ipsilateral and contralateral acoustic reflex thresholds at 500, 1000, 2000, and 4000 Hertz (Hz) were determined and a reflex decay test at contralateral 500 Hz was conducted. Ipsilateral acoustic reflex thresholds were obtained with high-frequency band, low-frequency band, and wide band noise, and the results were compared with ipsilateral acoustic reflexes at 500, 1000, 2000, and 4000 Hz. Results: There was no statistically significant difference between the two groups in ipsilateral and contralateral acoustic reflex measurements at 500, 1000, 2000, and 4000 Hz (p>0.05). Negative reflex decay was obtained in all participants and no statistically significant difference between the two groups was observed in terms of reflex decay thresholds (p>0.05). Acoustic reflex with high-frequency band noise was observed in five of nine elders whose acoustic reflexes were not obtained at 2000 and 4000 Hz, whereas acoustic reflex with low-frequency band noise was observed in one of six elders who did not show reflexes at 500 and 1000 Hz. Conclusion: It was concluded that although some changes were observed due to age, middle ear and stapes muscles work normally in geriatric group. In the reflex decay test, reliable results were obtained at contralateral 500 Hz. Acoustic reflex measurements with low- and high-frequency band noise may also be used to assess middle ear functions. PMID- 29392010 TI - Submandibular Gland Surgery: Our Clinical Experience. AB - Objective: The aim of this study was to assess the demographic findings and surgical results of patients who underwent submandibular gland excision at a tertiary care center. Methods: The clinical characteristics and histopathological results of 45 patients who had undergone submandibular gland excision between 1997 and 2014 were evaluated in detail. Results: Twenty-eight (62.2%) and 17 (37.8%) patients presented with a complaint of a painful mass and painless mass, respectively. Histopathologic investigation of the surgical specimens revealed sialolithiasis in 14 patients (31.1%), chronic sialadenitis in 16 (35.6%), benign tumor in 12 (26.7%), malignant tumor in two (4.4%), and mucocele extravasation in one. As complications, permanent paralysis of the marginal mandibular branch of the facial nerve was seen in one patient (2.2%), temporary paralysis of the marginal mandibular branch of the facial nerve was seen in seven (15.6%), orocutaneous fistula was seen in one (2.2%), and temporary paralysis of the hypoglossal nerve was seen in one (2.2%). Conclusion: This study revealed that in patients presenting with complaints of a submandibular gland mass, sialolithiasis, sialadenitis, and benign masses were the mostly diagnosed disorders. Transcervical submandibular gland excision is a satisfactory procedure with low complication and recurrence rates when it is performed on selected patients and obeyed to surgical techniques. PMID- 29392011 TI - Prevalence of Allergic Rhinitis in Children in the Trabzon Province of the Black Sea Region of Turkey. AB - Objective: We aimed to determine the prevalence of allergic rhinitis in children aged 12-15 years who lived in the Trabzon Province, specify possible risk factors, and compare the data obtained with those of the other studies conducted in our country and in other countries. Methods: First, 1372 students from nine primary schools determined according to the recommendations of Department of Public Health and approval of The Provincial Directorate of Health were screened in their schools with questionnaire forms. Second, students providing the response "yes" to the first and/or second questions in the questionnaire forms were considered as possible allergic rhinitis patients and invited to our clinic. Then, 246 students were subjected to a skin prick test. Data were collected with the evalution of questionnaire and skin prick test results together. Results: The prevalance of allergic rhinitis in children between 12 and 15 years age was found to be 14.5% in Trabzon. Female gender was found to be a relative a risk factor for allergic rhinitis (p=0.015). The prevalence of allergic rhinitis in children whose both parents were smoking was significantly higher than that in children whose only one parent was smoking or both parents were nonsmokers (p=0.0024). In addition, living in an apartment flat (p=0.015) and owing pets (p=0.04) were detected to be other risk factors for allergic rhinitis. Conclusion: According to our investigations, this is the first prevalence study in Trabzon, which is the largest settlement in the Eastern Black Sea Region. The prevalence of allergic rhinitis in children was found to be 14.5%. Female gender, smoking habits of the parents, owing pets, and living in an apartment flat are risk factors for allergic rhinitis. PMID- 29392012 TI - Pediatric Mass Lesions of the Head and Neck Region and Fine-Needle Aspiration Biopsy Results. AB - Objective: 1. To provide a classification of pediatric mass of the head and neck region and evaluate their frequency. 2. To examine the findings of fine-needle aspiration biopsy (FNAB) in pediatric patients along with its contribution to diagnosis. Methods: Totally, 233 pediatric patients (125 boys and 108 girls) operated at Baskent University for head and neck mass were included. Clinical, radiological, and histopathological data were retrieved from medical records. Results: The mean age was 119+/-65 months, and the mean duration of follow-up was 75+/-49 months. Localization of the masses was as follows: 208 (89%) in the neck, 21 (9%) in the oral cavity, 2 (1%) in the neck and nasopharynx, and two (1%) in the larynx. The most common surgical procedure was open excisional biopsy (n=105, 45%) followed by cystic mass excision (n=72, 31%) and salivary gland excision (n=33, 14%). Based on histopathological findings, benign cystic lesions were the most common disease group (n=77, 33.1%), whereas reactive lymphadenopathy was the most common condition (n=36, 15%) when a single disease was considered. Infectious/inflammatory diseases, malignancies, and benign salivary gland diseases were present in 49 (21%), 24 (10.3%), and 22 (9.4%) patients, respectively. FNAB was performed in 29.8% of the patients with an accuracy of 90.3% (95% CI, 80.1-96.4). Conclusion: The differential diagnosis of head and neck masses during childhood includes a wide spectrum with the different conditions being benign cystic diseases of congenital origin and reactive lymphadenopathies. Owing to its high predictive value, FNAB represents a rapid and reliable method that can be commonly used in both adult and pediatric patients. PMID- 29392013 TI - The Role of Sentinel Lymph Node Biopsy in Head and Neck Cancers and Its Application Areas. AB - The management of the clinically N0 neck in patients with head and neck cancers still remains controversial. Elective neck dissection is traditionally recommended when the subside of the head and neck, such as the oral cavity and supraglottic area, confers at least a 15-20% risk of lymphatic spread. However, elective neck dissection may cause an increase in patient morbidity and mortality rates. The emergence of sentinel lymph biopsy provides the possibility of accurate pathological staging of the cervical node with a less invasive procedure. The present review will summarize the role of sentinel lymph node biopsy and its application areas when evaluating occult metastases in patients with head and neck cancers. PMID- 29392014 TI - Metastatic Papillary Thyroid Cancer Diagnosed and Treated during Pregnancy. AB - Physiological changes of the thyroid gland encountered during pregnancy can cause previously diagnosed thyroid nodules to grow or new nodules to form. Surgery of the slowly growing, localized, non-metastatic, well-differentiated, thyroid cancers diagnosed during pregnancy can be delayed to after delivery, whereas rapidly growing and metastatic cancers with compressive symptoms may be a candidate for surgery during pregnancy. In this case report, we present a case of cervical metastatic papillary thyroid cancer diagnosed and treated by total thyroidectomy and right functional neck dissection during pregnancy in a 22-year old pregnant woman at 23-week pregnancy. In this case report, the optimal treatment for papillary thyroid cancer diagnosed during pregnancy is discussed under the light of current endocrine guidelines and previous case reports and series. PMID- 29392015 TI - Recurrent Pleomorphic Adenoma of the Submandibular Gland. AB - Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. Most PAs occur in the parotid (80%), followed by the submandibular gland (10%) and minor salivary and sublingual glands (10%). Submandibular gland PAs usually manifest in the submandibular area as a painless hard mass. Although several recurrent parotid gland PA cases have been reported in the literature, recurrent submandibular gland PA is quite rare. Complete surgical removal of tumor of the submandibular gland and keeping the capsule intact are important to prevent recurrence. Here we present a rare case of submandibular gland PA recurrence that occurred 5 years after the first surgery and methods to prevent recurrence. PMID- 29392016 TI - Endoscopic Sphenopalatine Artery Ligation in Posterior Epistaxis: Retrospective Analysis of 30 Patients. AB - Objective: Although posterior epistaxis is rarely seen, it is an important medical problem that both decreases the quality of life of the patient and causes difficulties in the management for otorhinolaryngologists. In this study, we aimed to present the results of 30 patients who underwent transnasal endoscopic sphenopalatine artery ligation (TESPAL) for posterior epistaxis in our department. Methods: The records of 30 patients who underwent TESPAL from January 2014 to April 2016 were analyzed retrospectively, and the relationship between perioperative factors and need for revision surgery was assessed. Results: The success rate of TESPAL in posterior epistaxis was 90%. There was no relationship between surgical failure and antiaggregant use (p=0.224), anticoagulant use (p=0.534), hypertension (p=0.564), previous nasal surgery (p=0.279), and bilateral TESPAL application (p=0.279). TESPAL was seen to be effective in cases with Osler-Weber-Rendu disease, pregnancy, and uncontrollable epistaxis after rhinoplasty surgery. Mortality was seen in one of our patients not related to endoscopic ligation in the follow-up period. Conclusion: TESPAL is an effective method in the treatment of posterior epistaxis. Hypertension, antiaggregant or anticoagulant use, bilateral sphenopalatine artery ligation, and previous nasal surgery do not seem to be factors leading to surgical failure. PMID- 29392017 TI - Histopathological Effects of Parylene C (poly-chloro-p-xylylene) in the Inner Ear. AB - Objective: To assess the histopathological effects of parylene C (PC) (poly chloro-p-xylylene) in the inner ear. Methods: Nine adult Dunkin Hartley guinea pigs (500-600 g) were included in the study. PC pieces were inserted into the cochlea in the right ear of the animals (study group). The round windows were punctured in the left ears comprised the control group. After three months, the animals were sacrificed, and the dissected temporal bones were examined under a light microscope. Results: No significant difference was revealed between the study and control groups regarding histopathological findings such as perineural congestion, perineural inflammation, neural fibrosis, number of ganglion cells, edema, and degeneration of ganglion cells (p>0.05). Conclusion: PC did not cause any additional histopathologic damage in the cochlea. This finding may be promising regarding the use of PC in cochlear implant electrodes as an alternative to silicon materials in the future. PMID- 29392018 TI - Evaluation of Cases Who Underwent Reconstruction Through Pectoralis Major Myocutaneous Flap after Laryngopharyngectomy. AB - Objective: In this retrospective study, we discussed the results of patients who underwent hypopharynx reconstruction through a pectoralis major myocutaneous flap (PMMF) after laryngopharyngectomy. Methods: Twenty-three patients who underwent total laryngectomy, subtotal pharyngectomy, and/or esophagus upper segment resection due to advanced-stage (T3 and T4) laryngeal, hypopharyngeal, and esophagus upper segment-located squamous cell carcinoma and subsequent reconstruction with PMMF were retrospectively evaluated. While the minor complications were determined to be wound site infection, hemorrhage, and disruption of suture at the donor site, major complications were determined to be anastomotic line disruption, fistula, and dysphagia. Results: Eighteen (78.2%) patients were male and five (21.7%) were female; their ages varied between 33 and 72 years (mean: 60.1). According to lesion localization, 11 patients were evaluated as having laryngeal cancer, seven as having hypopharyngeal cancer, and five as having esophagus upper segment-located cancer. The rate of minor complications was 30.4%: fistula was observed in 11 (47.8%) patients and 13 (56.5%) patients mentioned difficulty swallowing only solid foods. The total follow-up period ranged from 4 to 60 (mean: 31.6) months. Conclusion: PMMF is continuing to be a good alternative reconstruction method for the reconstruction of partial hypopharyngeal defects because it is easily obtainable, one surgical team is sufficient when using the flap, and it is associated with low morbidity and mortality rates. PMID- 29392019 TI - Histopathological Effects of Fibrin Glue and Cyanoacrylate on the Maxillary Sinus. AB - Objective: To compare the histopathological effects of fibrin glue (FbGl) and cyanoacrylate (CyAc) on the maxillary sinus mucosa. Methods: Twenty rabbits were divided into two groups of 10, and surgical defects were created in the maxillary sinuses. The right maxillary sinus was treated with FbGl in one group and with CyAc in the other group. As a control, the left maxillary sinuses of all rabbits were treated with sterile saline solution. One rabbit treated with CyAc died during the study and was excluded. On postoperative day 21, all animals were sacrificed. Maxillary sinus mucosa samples were studied to determine the extent of inflammation and fibrosis, foreign body reaction, cilia loss, increased osteogenesis in bony structures under the mucosa, and loss of serous glands. Results: The FbGl group differed significantly from the CyAc and control groups in terms of a high degree of inflammation (p<0.001), fibrosis (p<0.001), foreign body reaction (p<0.001), cilia loss (p<0.001), and serous gland loss (p<0.001). In terms of osteogenesis, there were no significant differences between the FbGl and CyAc groups (p=0.650), while there was a significant (p=0.002) difference between these two groups and the control group. Conclusion: Histopathologically, CyAc had fewer side effects than FbGl. Further clinical studies are needed to demonstrate the validity of these results in humans. PMID- 29392020 TI - Re-Evaluation of Open Partial Horizontal Laryngectomies at Our Institution According to the New Classification Recommended by the European Laryngological Society. AB - Objective: The aim of this study was to re-evaluate the open partial horizontal laryngectomies (OPHLs) performed at our institution in terms of the new classification of the European Laryngological Society and compare the differences with the new classification system. Methods: A retrospective analysis of 45 patients diagnosed with T1b, T2, and T3 laryngeal carcinoma who were treated with OPHLs in our department between 2010 and 2016 were conducted. Results: All supraglottic laryngectomies (31 operations) were classified as OPHL Type 1. Among these, 11 operations required a resection of an additional structure including arytenoid (ARY) in five operations, piriform sinus (PIR) in four operations, the base of tongue (BOT) in one surgery, and ARY + PIR in one patient. Five supracricoid laryngectomies with cricohyoidoepiglottopexy (CHEP), five supracricoid laryngectomies with cricohyoidopexy (CHP), and four near-total laryngectomy operations constituted Type 2 OPHL (7 operations) and Type 3 OPHL (7 operations). Among these operations, two were classified into Type 2b OPHL and four into Type 3b OPHL as the superior margin of incision included epiglottis. Conclusion: We consider that, this new classification, because it allows understanding the content of the surgery from the related title, will be useful in comparing different series and techniques. PMID- 29392021 TI - The Role and Importance of Molecular Tests in Approach to Thyroid Nodules. AB - Although there is a significant increase in the detection of thyroid cancer because of the widespread utilization of ultrasound and fine needle aspiration biopsy, sometimes these techniques prove inefficient for diagnosis. Therefore, improved diagnostic tools are required. Increasing knowledge regarding thyroid cancer genetics has revived molecular testing. The possibility of thyroid malignancy can be considered or ruled out because of the high accuracy of results, such as 90% positive predictive value (PPV) and 96% negative predictive value (NPV), obtained from the molecular tests. Although the molecular biology of all thyroid cancers has not been completely understood, the remarkable progress done in this domain has widened the horizon of their diagnosis, prognosis and treatment. PMID- 29392022 TI - Bilateral Nasolabial Cyst as a Rare Case Report. AB - The etiology, clinical features, and treatment of an extremely rare case of a bilateral nasolabial cyst have been evaluated in this report. A 60-year-old female presented to our clinic with a pain-free swelling above the upper lip for a year and obstruction of the left nasal cavity for two months. On undergoing a physical ENT examination, she showed bulging of both nasal fossae and effacement of the bilateral nasolabial groove with a fluctuating smooth mass. A paranasal sinus CT scan showed a smooth, ovoid mass of 20*13 mm at the right side and 26*22 mm at the left side occupying the floor of the nasal fossa and restricted to the soft parts of the premaxillary region, without any bony destruction. The patient underwent surgical excision under general anesthesia via sublabial approach. Histopathology confirmed the diagnosis of bilateral nasolabial cyst. The patient was asymptomatic during 18-month of postoperative follow-up. Bilateral nasolabial cysts should be considered in the differential diagnosis of cystic masses of the nasal vestibule and deformities of the premaxillary region. Although endonasal endoscopic cyst marsupialization is a relatively new treatment, surgical resection with the sublabial approach is the treatment of choice. PMID- 29392023 TI - Cervico-Thoracic Giant Lipoma in a Child. AB - Lipomas are benign mesenchymal tumors that can be observed all over the body. In total, 25% of lipomas are observed in the head and neck region, and most of them are located in the posterior cervical triangle. Lipomas that are greater than 10 cm in width or more than 1000 g in weight are called giant tumors. Cervico thoracic lipomas are extremely rare, and only four cases have been reported in the English literature. We report successful surgical excision of a giant lipoma, which started from middle-anterior cervical region covered the anterior cervical triangle, and extended to the mediastinum, without thoracotomy. PMID- 29392024 TI - Lingual Osseous Choristoma. AB - An osseous choristoma is a rare benign lesion consisting of normal bone tissue; it is seen in abnormal locations. It is most often seen in the posterior 1/3 of the tongue in the head. Its etiopatogenesis is controversial, and till date, less than 100 cases have been reported in the literature. Although a lingual osseous choristoma is asymptomatic, in some patients, symptoms such as swelling sensation in the throat, globus pharyngeus, dysphagia, retching, nausea, and sore throat have been reported. In this article, a 41-year-old female patient admitted to our clinic with throat pain and globus pharyngeus who underwent an excision from the region of radix lingua and the result of histopathological examination was reported as "osseous choristoma" was presented and related literature is reviewed. PMID- 29392025 TI - Being an Associate Professor. PMID- 29392026 TI - Pharyngocutaneous Fistula after Total Laryngectomy: Risk Factors with Emphasis on Previous Radiotherapy and Heavy Smoking. AB - Objective: In this retrospective cohort study, we aimed to determine the incidence of pharyngocutaneous fistula (PCF) after total laryngectomy (TL) and to define the possible predictors for PCF formation. Methods: The medical records of 198 patients with laryngeal squamous cell carcinoma who underwent TL were reviewed. After the exclusion of patients with history of free flap reconstruction, previous laryngeal surgery, and previous radiotherapy (RT) for other primary cancers, the risk factors for PCF were analyzed in 183 patients who were included in the study. Results: The overall incidence of PCF was 20.2%. A history of heavy smoking and previous RT were detected as independent risk factors in both univariate (p=0.004 and p=0.007, respectively) and multivariate (p=0.005) analyses. Preoperative tracheotomy (PT) longer than 14 days was a risk factor for PCF among patients with PT in the univariate analysis (p=0.031). Overall three- and five-year survival rates were statistically indifferent between the PCF and non-PCF groups (p>0.05). However, the overall five-year survival rate was lesser in the persistent PCF group (47%) than in the non persistent PCF group (83%) (p=0.038). Conclusion: Heavy smoking and previous RT are independent risk factors for PCF, and the persistence of PCF decreases survival rates. Preventable measures should be taken to decrease the incidence and persistence of this complication of TL in the management of patients with possible risk factors. PMID- 29392027 TI - Comparison of Endoscopic and External Dacryocystorhinostomy Results and Analysis of Patients' Satisfaction. AB - Objective: Comparison of endoscopic and external dacryocystorhinostomy (DCR) results and evaluation of patients' satisfaction. Methods: Forty six (35 females and 11 males) patients who underwent endoscopic DCR and 43 (37 females and six males) who underwent external DCR were included. Surgical success was objectively and subjectively assessed. The nasolacrimal duct was irrigated by a saline solution, and the saline solution was objectively visualized by endoscopy from the nose. Subjective assessment was performed asking the patients' epiphora. In addition to evaluating the success of the operation, satisfaction and result surveys were administered to the two groups. Results: There was no statistically significant difference between the two groups in terms of age and sex (respectively p=0.486, p=0.23). However, the number of females was higher than the number of males in the two groups, and the difference was statistically significant (endoscopic-DCR p=0.01, external-DCR p=0.001). There was no statistically significant difference between the two groups in terms of postoperative bleeding and punctum damage. The success rate was 84.7% in the endoscopic DCR group and 90.6% in the external DCR group. There was no statistically significant difference in the success rate between the two groups (p=0.397). The survey results revealed that there was no statistically significant difference between the two groups in terms of patient satisfaction (p=0.397). Conclusion: The results of many studies in the literature show operation success rates between the two groups that are similar to ours. Both techniques have advantages and disadvantages. Independent of the preferred procedure, our results show that functional success mainly determines patient satisfaction. PMID- 29392028 TI - Role of Fine-Needle Aspiration Biopsy in the Management of Salivary Gland Masses. AB - Objective: Fine-needle aspiration biopsy (FNAB) is widely used in the management of salivary gland masses. Its main advantage is its ability to differentiate benign from malignant disease. In this study, we aimed to evaluate the diagnostic ability of FNAB in salivary gland masses. Methods: The records of patients who had undergone FNAB before parotidectomy or submandibular gland excision between 2005 and 2013 were retrospectively analyzed. FNAB results were classified as negative, positive, suspicious for malignancy, and non-diagnostic. Preoperative FNAB results were compared with definitive histopathological results. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FNAB results were calculated. Results: A total of 285 patients were enrolled. Among them, 230 (80.7%) had parotid gland and 55 (19.3%) had submandibular gland masses. Following a definitive histopathological examination, the most common benign tumor was pleomorphic adenoma (52.6%), whereas malignant tumors were mucoepidermoid carcinoma (2%) and squamous cell carcinoma (2%). The sensitivity, specificity, PPV, NPV and accuracy of FNAB results were 76.9%, 95.4%, 75%, 95.9%, and 92.6%, respectively. The rate of a suspicious cytology was 5.2% (15 patients) and that of a non-diagnostic cytology was 8.8% (25 patients). Conclusion: FNAB is a safe and simple diagnostic tool for the diagnosis of salivary gland masses and has a relatively high sensitivity and specificity. It may provide valuable information for patient counselling and surgical planning. The major drawbacks include a lower sensitivity than specificity and a relatively high rate of non-diagnostic results. PMID- 29392029 TI - Recurrent Parotid Pleomorphic Adenomas: Our Clinical Experience. AB - Objective: The aim of our study was to present our findings in a series of patients who were treated for recurrent parotid pleomorphic adenoma with their clinical, surgical, and follow-up information and to discuss them in light of the recent literature. Methods: Eleven patients who had revision surgery for recurrent pleomorphic adenoma at our institution were retrospectively analyzed for the clinical and radiological features of their lesions, surgery type, facial nerve management, and follow-up period. Results: Seven patients were females and four were males with an average age of 45 years. All patients underwent previous surgeries at other institutions. Revision surgery was performed with superficial parotidectomy in six patients and total conservative parotidectomy with preservation of the facial nerve in five patients. Two patients had lesions involving the facial nerve branches necessitating sacrifice of involved branches. One patient was given adjuvant radiotherapy because of adjacent lymphatic vessel involvement with tumor cells. During the mean follow-up period of 9.1 years, there were no recurrences in any of the patients. Conclusion: Management of patients with recurrent parotid pleomorphic adenomas must be carefully planned according to the size, location, and multicentricity of the tumor and involvement of the facial nerve. Surgery should aim at reaching tumor-free surgical margins. Sacrifice of the facial nerve should be considered only in cases with direct involvement. In the postoperative period, patients must be followed up regularly for early diagnosis of recurrences. PMID- 29392030 TI - Comparison of Radiofrequency Thermal Ablation and Microdebrider-Assisted Turbinoplasty in Inferior Turbinate Hypertrophy: A Prospective, Randomized, and Clinical Study. AB - Objective: To compare the effectiveness of radiofrequency thermal ablation with those of microdebrider-assisted turbinoplasty, we designed a prospective, randomized clinical study. Methods: Forty patients suffering from nasal obstruction due to bilateral inferior turbinate hypertrophy were enrolled. Half of the patients were operated by radiofrequency thermal ablation, while the other half underwent microdebrider-assisted turbinoplasty. The outcomes of both techniques were compared in terms of symptomatology, nasal patency, and mucociliary transport. Results: A statistically significant difference existed between the two groups with respect to nasal obstruction and the frequency of obstruction at the first post-operative week and first and third post-operative months (p<0.05). Rhinomanometry detected a significant decrease in nasal resistance values in both surgical groups compared to the preoperative values. The mucociliary transport time was significantly prolonged in the first postoperative week and first postoperative month in microdebrider-assisted inferior turbinoplasty group. Conclusion: Both radiofrequency thermal ablation and microdebrider-assisted turbinoplasty are effective techniques for treating inferior turbinate hypertrophy. The treatment modality should be individually determined, and parameters such as tissue healing, volume reduction, and mucociliary activity must be taken into account. PMID- 29392032 TI - Life-Threatening Respiratory Distress in a Total Laryngectomy Patient: Aspirated Voice Prosthesis or Lung Tumor? AB - Laryngectomy patients usually have poor pulmonary functions due to long-term smoking. Their lungs can easily be decompensated. Hence, meticulous evaluation and timely management of severe respiratory distress in laryngectomy patients can be life savers. Here we present an interesting case of a laryngectomy patient with two different clinical presentations of life-threatening respiratory distress at the same time (aspiration of voice prosthesis and a second primary lung cancer). Marked or persistent respiratory distress in a laryngectomy patient deserves thorough clinical evaluation and may require urgent intervention. We consider that the presentation and course of respiratory distress in our laryngectomy patient will provide an additional aspect for emergency room doctors and airway specialists dealing with such a patient. PMID- 29392031 TI - Validity and Reliability of the Diagnostic Tests for Meniere's Disease. AB - Meniere's disease is defined as an idiopathic syndrome characterized by endolymphatic hydrops. Various tests and measurement methods have been employed for the diagnosis of Meniere's disease. These include audiological, vestibular, radiological, clinical, and biochemical tests. However, the lack of a definitive or gold standard diagnostic test sometimes complicates the process of diagnosis. Hence, the clinician should be well-experienced in deciding when to perform a test and how to interpret the results of the test. Furthermore, having the knowledge of the validity and reliability of these tests plays a critical role. This review particularly emphasizes on remarking the validity and reliability of each test performed for the diagnosis of Meniere's disease and discussing the results according to the up-to-date literature. PMID- 29392033 TI - Hemorrhagic Bullous Angina: A Case Report and Review of the Literature. AB - Hemorrhagic bullous angina (HBA) is described as the sudden onset of one or more bullous lesions in the oral cavity, not attributable to other vesiculobullous diseases, blood dyscrasias, or autoimmune and vascular diseases. These lesions occur almost exclusively in the oral cavity, particularly in the soft palate, and do not affect the masticatory mucosa. Here we present the case of a 57-year-old male who had a spontaneously ruptured hemorrhagic bulging in his soft palate diagnosed as HBA, along with discussion of the literature. In conclusion, HBA is a rare, benign, oral disease with low complication rates. Diagnosis is essentially clinical, and treatment consists of local hygiene and prevention of oral trauma. PMID- 29392034 TI - Thyroglossal Duct Cyst in a 3-Month-Old Infant: A Rare Case. AB - Thyroglossal duct cyst (TGDC) is the most common congenital midline neck mass in children. It usually becomes symptomatic following a respiratory tract infection and is usually diagnosed at 5 years of age. Thyroglossal duct cyst is rarely observed in less than 1-year-old infants. In this study, we present a 3-month-old infant with TGDC, who was administered multiple courses of antibiotic therapy for the hyperemic, draining, midline neck mass that had existed since he was 15 days old. Physical examination revealed an infrahyoid midline neck mass measuring 3*3 cm, which moved while swallowing and had a sinus opening in the overlying skin. The patient underwent Sistrunk operation under general anesthesia. Histopathologic examination revealed TGDC. One-year follow-up revealed no recurrence. PMID- 29392035 TI - Effect of Ecklonia Cava Polyphenol Extract in House Ear Institute-Organ of Corti 1 Cells Against Cisplatin Ototoxicity: A Preliminary Study. AB - Objective: Cisplatin is a widely used agent for the treatment of adult and childhood malignancies. Side effects such as nephrotoxicity, neurotoxicity, and ototoxicity lead to dose limitations. Ecklonia cava polyphenol extract (ECP) is a molecule obtained from algae that live in seawater in the Far East. ECP has recently been shown to have protective effects against oxidative stress. The aim of this study was to evaluate the possible protective effects of ECP on cisplatin ototoxicity. Methods: In this study, we investigated the protective effects of ECP against cisplatin-induced cell death in mouse-derived House Ear Institute Organ of Corti (HEI-OC1) cochlear cells. Cisplatin (100 MUM) and 1, 10, and 25 MUM doses of ECP were administered to the cells, and the protective effects of ECP at 24 and 72 hours were investigated. Cell viability was evaluated by the WST 1 (water soluble tetrazolium salt). Results: Cisplatin (100 MUM) reduced cell viability in both the 24th and 72nd hour evaluation. Although the 25 MUM dose of ECP showed otoprotective effects in the 24th hour, in the 72nd hour this effect disappeared. Other doses of ECP showed no otoprotective effects in the 24th and 72nd hours. Conclusion: Although ECP showed some protective effects in the 24th hour against cisplatin ototoxicity, these effects disappeared by the 72nd hour. Further studies using recurrent and higher doses of ECP are required. PMID- 29392037 TI - Laryngomalacia: Our Clinical Experience. AB - Objective: The aim of this study is to analyse the clinical symptoms, follow-up and treatment properties of the laryngomalacia patients that we encountered between 2009 and 2014. Methods: Records of 81 laryngomalacia patients who were followed up in our clinic between 2009 and 2014 were retrospectively analysed. Patients' gender, age, time of onset of the symptoms, chief complaints, other co existing congenital laryngeal anomalies and treatment and follow-up properties were evaluated. Results: Of the 81 patients, 48 were male and 33 were female, and the mean age was 4.9 months. The average period of follow-up was 12.1 months. The chief complaints at the time of admission were stridor (100%) and episodic cyanosis with feeding (27.16%). Symptoms of 75 patients were resolved at an average of 8.2 months with conservative treatment. Three patients underwent supraglottoplasty. Tracheotomy and posterior cordotomy was performed for a patient with co-existing vocal cord paralysis. Additional tracheotomy was necessary for a patient with pulmonary co-morbidities and for another with co existing subglottic stenosis. Conclusion: Laryngomalacia is the most common cause of stridor in infants. The majority of laryngomalacia patients can be managed conservatively by close follow-up. For patients in whom respiratory and feeding problems persist or growth retardation develops, surgical treatment is performed. Tracheotomy may be necessary for a small group of patients with additional diseases. PMID- 29392036 TI - Assessment of Effects of Septoplasty on Acoustic Parameters of Voice: A Prospective Clinical Study. AB - Objective: To investigate the effects of septoplasty on the acoustic parameters of voice. Methods: In total, 23 patients (seven females and 16 males; average age, 32.13+/-9.67 years; age range: 19-56 years) with a diagnosis of nasal septal deviation and who underwent septoplasty were included. Preoperative and on postoperative 30th day, acoustic analysis of voice was conducted for all patients. The recordings of /mana/ vowel were used to evaluate average fundamental frequency (F0), jitter, shimmer, and noise-to-harmony ratio (NHR). F0, shimmer percent, jitter percent, and NHR of two terms were compared. A p value<0.05 was considered to indicate statistical significance. Results: A statistically significant change was not observed in F0 (p=0.741), jitter (p=0.930), and shimmer (p=0.128) measured preoperatively and on postoperative day 30. However, the increase in NHR measured on postoperative day 30 were statistically significant compared with preoperative NHR (p=0.017). Conclusion: According to the findings of this study, except NHR value, no statistically significant changes on F0, jitter and shimmer were detected after septoplasty. PMID- 29392038 TI - Patient Characteristics and Frequent Localizations of Rhinoliths. AB - Objective: A rhinolith is a rare entity affecting all people in all age groups. It is defined as a mineralized foreign body. The purpose of the present study was to reveal the distribution in age and gender and the localization, side, and prominent symptoms of rhinoliths to identify the risk groups and characteristics of the rhinoliths in a large case series. Methods: A retrospective review was performed from the medical charts of 28 patients who were diagnosed with rhinolith and underwent surgery between May 2011 and January 2015 in Ankara Research and Training Hospital. All data, including age, gender, duration of symptoms, localization of the lesion and accompanying pathologies, were documented. Results: In total, 28 patients (18 females and 10 males) with a mean age of 26.2+/-16.6 (5-62) years who were diagnosed with rhinolithiasis were reviewed. Nasal obstruction (71.4%) and nasal discharge (64.3%) were the most common complaints. The rhinolith was located in the right nasal cavity in 24 patients and in the left in four; this difference was statistically significant (p<0.001). There were 11 accompanying pathologies including nasal septal deviation (n=6), nasal polyposis (n=2), concha bullosa (n=2), and adenoid vegetation (n=1). In 21 (75%) patients, the most common site was the nasal base of the cavity between the inferior turbinate and the nasal septum. Conclusion: If unilateral right-sided nasal obstruction with foul-smelling purulent discharge is detected in a young adult and a nasal examination reveals a mass in the floor of the cavity, a rhinolith should be strongly considered in the differential diagnosis. PMID- 29392039 TI - The Effects of Superficial Musculoaponeurotic System Flap on the Development of Frey's Syndrome and Cosmetic Outcomes After Superficial Parotidectomy. AB - Objective: To investigate the outcomes of superficial musculoaponeurotic system (SMAS) flap and classic techniques in superficial parotidectomy in terms of Frey's syndrome (FS) and cosmetic satisfaction. Methods: In this study, a retrospective chart review of patients that underwent superficial parotidectomy was performed. These patients were divided into two subgroups: group 1 included patients in which the SMAS flap was harvested and group 2 comprised the remaining patients on whom classic superficial parotidectomy was performed. All the patients were evaluated clinically and with Minor's starch-iodine test for FS. For the evaluation of the cosmetic results, the patient's satisfaction was queried according to the incision scar and surgical field skin retraction/facial symmetry. Both groups were compared in terms of complications and numbness of surgical area. Results: Fifty-five patients (31 male and 24 female) with a mean age of 50.19 years were included in the study. Thirty-two patients were in group 1 and 23 in group 2. Thirteen patients (23.7%) described as having FS and six of them were in group 1, while seven were in group 2. Minor's starch-iodine test was positive in nine patients in group 1 (28.1%) and six patients in group 2 (26.1%) (p=1.000). With regard to cosmetic satisfaction, eight patients (25%) stated mild discomfort from the incision scar and two patients (6.3%) stated cosmetic dissatisfaction for facial asymmetry in group 1. In group 2 for the same factors the number of patients were 11 (47.8%) and 2 two (8.7%), respectively (p=0.027). There were no statistically significant differences in means of complication and numbness (p>0.05). Conclusion: According to our study results, there was no superiority between both the groups in terms of FS and incision scar satisfaction. We determined that there was a significant benefit of SMAS flap application in the prevention of volume loss and surgical area retraction. PMID- 29392040 TI - Coincidental Killian-Jamieson Diverticulum During Thyroid Surgery: A Rare Cause of Dysphagia. AB - The aim of this case report is to demonstrate a very rare coincidental existence and management of the Killian-Jamieson diverticulum during thyroid surgery in a patient with dysphagia. An 18-year-old female patient with the complaints of progressive dysphagia and a rapidly growing mass at the anterior cervical region was undergone thyroid lobectomy. Coincidentally, a 2*2 cm Killian-Jamieson diverticulum was observed and simultaneously excised with the thyroid lobe, preserving the recurrent laryngeal nerve. Dysphagia is a frequent symptom, especially in patients with a rapidly growing thyroid mass. Thyroid surgeons should keep in mind that hypopharyngeal and upper esophageal pathologies can mimic the symptoms of a thyroid mass; therefore, detailed imaging techniques should be used for the differential diagnosis. PMID- 29392041 TI - Facial Palsy due to Parotid Abscess: An Unusual Complication. AB - Facial nerve palsy is usually associated with a malignant parotid neoplasm; it is highly unusual for it to result from a benign situation, such as inflammation or infection of the parotid gland. Surgery along with prompt medical treatment is the mainstay, and in the majority of the patients, nerve paralysis recovers in the follow-up period. We report a case of a 50-year-old non-diabetic non hypertensive female who presented with odynophagia, left-sided parotid swelling, and left facial nerve palsy. The diagnosis of facial nerve palsy due to a parotid abscess extending to the parapharyngeal space was made. Facial palsy fully recovered within 2 months. PMID- 29392042 TI - A Rare Complication of Tonsillectomy: Subcutaneous Emphysema. AB - Tonsillectomy is one of the surgical procedures that are frequently performed by ear, nose, and throat surgeons. The procedure is associated with many intraoperative and postoperative complications, and the nature of the operation site hampers surgical interventions. Cervicofacial subcutaneous emphysema is characterized by the presence of air within the fascial planes of the head-neck region because of various reasons. It may develop iatrogenically or spontaneously because of trauma. Herein, we report a 4-year-old male patient who presented to our clinic with complaints of frequent tonsillitis and snoring and who developed subcutaneous emphysema involving only the maxillofacial region following tonsillectomy. In addition, treatment strategies have been discussed, taking current literature into account. PMID- 29392043 TI - Do Case Reports Still Have a Place in Turkish Archives of Otorhinolaryngology? PMID- 29392044 TI - Effect of Topical Dexamethasone for Preventing Experimentally Induced Myringosclerosis. AB - Objective: We aimed to examine the effect of topical dexamethasone by otomicroscopic and histologic examinations for preventing myringosclerosis induced by myringotomy in rat tympanic membranes. Methods: Twenty-one Sprague Dawley rats (42 ears) were randomly divided into the following three groups after otomicroscopic examinations: experimental surgical group (5 rats), control group (8 rats), and study group (8 rats). The rats of all the groups underwent myringotomy in both tympanic membranes. Other than myringotomy, no additional procedure was performed for the rats in the experimental surgical group. In the control group, 0.9% NaCl was applied to the ears, whereas in the study groups, topical dexamethasone was applied to the ears. These applications in the control and study groups were repeated for nine days. On the 10th day of the study, the rat ears of all groups underwent otomicroscopic and histologic examinations. The prevalence and process of myringosclerosis were evaluated by otomicroscopic examination, whereas inflammation, membrane thickness, and myringosclerosis intensity were evaluated by histologic examination. Results: The growth of myringosclerosis with otomicroscopic examination was lesser in the study group in which topical dexamethasone was applied than the control and the experimental surgical groups. Moreover, it was observed that myringosclerosis effected fewer quadrants in the study group.Histologic examinations revealed that inflammation was significantly lesser in the study group than in the experimental surgical and control groups. The average membrane thickness values were significantly lesser in the study group than in the experimental surgical group. With respect to myringosclerosis growth, no statistically significant difference was observed among all groups, whereas with respect to myringosclerosis intensity, the rat ears in the study group were less severely affected. Conclusion: Thus, our study results suggest that applying topical dexamethasone after myringotomy has positive effects on limiting the intensity and prevalence of myringosclerosis. PMID- 29392045 TI - Importance of Sonoelastography in Assessing Non-Thyroid Neck Masses. AB - Objective: To evaluate the feasibility and value of sonoelastography in assessing non-thyroid neck masses. Methods: Non-thyroid neck masses requiring surgical interventions were evaluated using conventional B-mode ultrasonography (US) (size, short/long axis rate, shape, hilum, echogenity, calcification, necrosis, and peripheral edema) and sonoelastograpy (SE) with strain ratio (SR) and elasticity score (ES) before surgery. These parameters were compared with the histopathological examination. Results: In total, 116 non-thyroid neck masses (66 lymph node, 35 parotid gland, eight submandibular gland, and seven cervical mass) of 89 patients (51 men, 38 women) with a mean age of 50.3+/-15.1 (19-79) years were evaluated. Thirty-seven malignant lymph nodes (23 metastatic and 14 lymphoma), seven malignant parotid tumors, two malignant submandibular tumors, 29 benign lymph nodes, 28 benign parotid lesions, and six benign submandibular lesions were evaluated. Mean SR and ES values of malignant masses were 6.3/3.2 for lymph nodes, 5.5/3.3 for the parotid gland, and 4.2/3 for the submandibular gland. Mean SR and ES values of benign lesions were 2.0/2.1 for lymph nodes, 4.4/3.2 for the parotid gland, and 3.2/3 for the submandibular gland. SR and ES were significantly higher for malignant masses compared with those for benign ones. SR was more predictive than ES in evaluating malignant lymph nodes. The area under the curve was 0.917(0.827-1.00) (p<0.05) for SR in differentiating benign-malignant lymph nodes, and the upper cut-off value was two. SR and ES were higher in the malign parotid and submandibular gland lesions than the benign ones, but the difference was not statistically significant. Conclusion: Strain ratio value could be a useful parameter in differentiating benign-malignant lymph nodes. More studies are necessary for differentiating benign-malignant parotid and submandibular lesions using SE. PMID- 29392046 TI - Relation of Actinomyces with Tonsillar Hypertrophy and Antibiotic Use. AB - Objective: This study aimed to investigate the incidence of Actinomyces in tonsillar tissues of patients undergoing tonsillectomy and to determine the association among tonsillar volume, preoperative antibiotic use, and presence of Actinomyces in tonsil tissues. Methods: In this study, 142 patients who underwent tonsillectomy in last four years were included. Of the total patients, 97 (66.9%) were children and 47 (33.1%) were adults. The patients' age, sex, preoperative antibiotic use, tonsillar volume, and presence of actinomyces in tonsillar tissues were recorded. Results: Actinomyces was identified in tonsillar tissues of 16 (16.4%) pediatric and 21 (44.6%) adult patients. Of all pediatric patients positive for Actinomyces, 13 were males and three were females whereas of all adult patients positive for actinomyces, 14 were males and seven were females. Tonsillar tissue volumes in both pediatric and adult patients positive for Actinomyces were statistically higher than the Actinomyces negative ones. Antibiotic use was higher and the incidence of Actinomyces was lower in pediatric patients than in adult patients positive for Actinomyces. Conclusion: Our study results revealed that Actinomyces was prominent in adult patients with tonsillar hypertrophy. In addition, the frequent use of antibiotic decreased the incidence of Actinomyces in tonsillar tissues. PMID- 29392047 TI - Vidian Canal Types and Dehiscence of the Bony Roof of the Canal: An Anatomical Study. AB - Objective: To determine the prevalence of Vidian canal types and dehiscence of the bony roof of the canal. Methods: This study included 594 patients (391 males and 203 females; average age, 32.43+/-11.98 years; range, 18-65 years). Computed tomography (CT) images were analyzed in terms of the prevalence of Vidian canal types and dehiscence of the bony roof of the canal. Results: Vidian canal types 1, 2, and 3 based on the sphenoid sinus body were found on the right side in 33.8%, 29.7%, and 6.5%, and on the left side in 36.4%, 27.4%, and 36.2% of the patients, respectively. Dehiscence of the bony roof of the canal was found on the right side in 22.2% of the patients and on the left side in 26.6%. In terms of Vidian canal types based on the sphenoid sinus floor, types 1, 2, 3, and 4 were found on the right side in 53.5%, 27.4%, 7.6%, and 11.5%, and on the left side in 54.9%, 26.6%, 6.6%, and 11.9% of the patients, respectively. On the right side, Vidian canal type 2 was significantly (p=0.002) more frequent in males than in females. Conclusion: When studying the complex anatomy of the sphenoid sinus, it is essential to consider Vidian canal types. Before endoscopic sinus surgery the Vidian canal and other anatomical structures should be carefully evaluated in all patients during preoperative paranasal sinus CT imaging to avoid complications. PMID- 29392048 TI - Analysis of Recurrence after Frontolateral Laryngectomy. AB - Objective: This study aimed to evaluate the recurrence and survival of patients treated with frontolateral laryngectomy for T1 and T2 glottic laryngeal carcinoma. Methods: Patients who underwent frontolateral laryngectomy for glottic laryngeal carcinoma at a tertiary hospital between March 2009 and June 2014 were included. Patient demographics, tumor stage, treatment and histopathological examination data, and adjuvant therapy details were evaluated. Results: Thirty patients with T1aN0, T1bN0, and T2N0 vocal fold carcinoma were examined. The mean follow-up duration was 40 months. Of the 30 patients, nine (30%) were stage T1 and 21 (70%) were in stage T2. Twenty-nine patients were males and one was female, and the mean age was 59 (range, 42-81) years. During follow-up, local recurrence was observed in four patients following frontolateral laryngectomy. Six patients continued smoking after frontolateral laryngectomy, of which three developed tumor recurrence. The local control rate was poor in patients with anterior commissure involvement (66.6%) compared with those with no involvement (95.2%). Two of four patients with local recurrence were treated with salvage total laryngectomy and adjuvant postoperative radiotherapy; the remaining two were treated with only radiotherapy. One patient who was treated with only radiotherapy developed lung metastasis during follow-up and died because of distant metastasis. Conclusion: Frontolateral laryngectomy is an efficient choice of treatment for selected cases of T1 and T2 glottic laryngeal carcinoma. PMID- 29392049 TI - Sensorineural Hearing Loss in Selective Immunglobulin A Deficiency. AB - Objective: To assess hearing functions in pediatric patients with selective immunoglobulin A (IgA) deficiency (SIGAD). Methods: Pure-tone audiometry, acoustic impedance, otoacoustic emission, and brainstem audiometric measurements were taken during a non-infectious period in 28 patients with SIGAD and 28 healthy children with normal otoscopic examination. The results of the hearing tests were compared between the two groups. Results: Two male patients and one female patient in the SIGAD group were found to have sensorineural hearing loss (SNHL). However, a comparison of the average pure tone cut-off values at 0.5, 1, 2, and 4 kHz did not reveal any statistically significant difference between the groups (p>0.05). Conclusion: Pediatric patients with SIGAD may exhibit SNHL at certain frequencies and require follow-up for the potential development of hearing loss. PMID- 29392051 TI - Dyspnea Associated with Henna Stone: A Rare Cause of Pediatric Tracheotomy. AB - Tracheotomy is one of the oldest surgical procedures, and it is a life-saving procedure to overcome upper airway obstructions. While congenital causes play an important role in pediatric tracheotomy indications, upper airway edema and obstruction due to anaphylaxis rarely require tracheotomy. Allergy can cause life threatening acute edema by anaphylactic reactions in the respiratory tract. Henna stone is the material for dyeing hair with henna and making a temporary tattoo. It contains high proportions of paraphenylendiamine. In this study, the case of a 3-year-old boy who had accidentally drunk some henna stone solution that was prepared for hair dyeing at home and who had to undergo emergency tracheotomy because of upper airway obstruction is presented. The potential dangerous effects of this material and the importance of emergency tracheotomy as a life-saving procedure are emphasized. PMID- 29392050 TI - Minimally Invasive Procedures for Laryngeal Carcinoma: Transoral Endoscopic Laser and Transoral Robotic Surgery. AB - Open partial or total laryngectomies with or without radiotherapy (RT) or chemoradiotherapy (CRT) are the only mainstays in the treatment of laryngeal carcinomas. However, minimally invasive procedures such as transoral endoscopic carbondioxide laser microsurgery (TLM) or transoral robotic surgeries (TRS) are now being increasingly used in selected patients. The laryngeal framework is not disturbed in these procedures; therefore, the postoperative swallowing function improves more rapidly, and routine tracheotomy is not usually required. Moreover, they have oncological results comparable with open procedures. PMID- 29392052 TI - Septal Schwannoma of the Nose: A Rare Case. AB - A schwannoma is a benign tumor arising from Schwann cells present in the nerve sheath of myelinated nerves.It is rarely seen in the nose and paranasal sinuses, and it very rarely originates from the nasal septum. A 40-year-old female presented to our outpatient department with a gradual onset, progressive, left nasal obstruction since the last 4 years. On performing a local examination, a soft tissue mass occupying the left nasal cavity was seen. Surgery via the external approach was performed; the mass was found to arise from the nasal septum and was totally excised. Histopathologic examination revealed a schwannoma. Nasal septal schwannoma along with review of the literature is a rare entity. It should be considered in the differential diagnosis of benign tumors of the nasal cavity. PMID- 29392053 TI - Retrotracheal Extraskeletal Ewing's Sarcoma: Case Report and Discussion on Airway Management. AB - Extraskeletal Ewing's sarcoma is a rare tumor, and the management of airway compromise in case of cervical Ewing's sarcoma has not been established. This report describes the case of a patient with retrotracheal Ewing's sarcoma and discusses a successful approach to airway management. A 12-year-old male presented with a 2-week history of sore throat and sleep-disordered breathing and 48 hours of stridor. Imaging confirmed a retrotracheal soft tissue mass with airway compromise. A planned and controlled approach to his airway management resulted in a secure airway prior to definitive treatment. PMID- 29392054 TI - Osteoma Originating from Mastoid Cortex. AB - Mastoid osteomas are very rare and defined as benign masses growing gradually in size. Temporal bone computed tomography is the examination of choice for their diagnosis and differentiation. Surgical resection is used to treat mastoid osteomas causing cosmetic deformity. Prognosis is good in cosmetic and curative aspects, and recurrences are very rare. No case of malign transformation has been reported. In this study, an adult patient who was treated because of a mastoid osteoma is presented with review of the current literature. PMID- 29392055 TI - TNF-alpha and IL-1 beta Cytokine Gene Polymorphism in Patients with Nasal Polyposis. AB - Objective: Nasal Polyp (NP) is a benign mass of the paranasal sinuses that protrudes into the nasal cavity. The exact underlying pathogenesis is not known. In this study we aimed to determine the genetic susceptibility of NP formation in relation to TNF-alpha-308 and IL-1beta-511 promoter region gene polymorphisms. Methods: A total of 71 patients with NP with asthma (n=21) or without asthma (n=50) were taken as the study group, and 91 healthy volunteers were taken as the control group. Blood was gathered into EDTA-containing tubes, and patient DNA was extracted. The polymorphisms of the IL-beta and TNF-alpha cytokine genes were analyzed using real time polymerase chain reaction. Results: The GG genotype in the TNF-alpha-308 region and the CC genotype in the IL-1beta-511 region were found to be risk factors for NP formation (OR: 9.2, p=0.007 and OR: 33.3, p=0.001, respectively). Regarding allelic frequencies, the G allele at the TNF alpha-308 promoter region was a risk factor for NP formation (OR: 6.06, p<0.001). Conclusion: TNF-alpha GG genotype in the -308 promoter region and the IL-1beta CC genotype in the -511 region are genetic risk factors for NP formation. PMID- 29392056 TI - A New Trend in the Management of Pediatric Deep Neck Abscess: Achievement of the Medical Treatment Alone. AB - Objective: Albeit the traditional opinion that advocates a routine surgical drainage for the treatment of an abscess, the case series presenting high success rates of the medical therapy alone is increasing in deep neck abscesses of childhood. This research focuses on children whose deep neck abscess fully disappeared after only medical treatment. Methods: In a retrospective study, we evaluated medical records of 12 pediatric (<18 years old) cases diagnosed with deep neck abscess or abscess containing suppurative lymphadenitis and treated with only medical therapy between 2010 and 2015 for age, gender, treatment modality, parameters related to antimicrobial agents, location of the infection, etiology, symptoms, duration of hospital stay, characteristics of the radiological and biochemical examination findings, and complications. Results: The mean age of 10 male and two female children was 5.9 years (range, 1-17 years). Baseline and the last control's mean values of white blood cell (WBC), C reactive protein, and erythrocyte sedimentation rate were 18,050/MUL, 99.8 mg/L, 73.1 mm/h, and 8,166/MUL, 34.1 mg/L, 35.3 mm/h, respectively. Contrast-enhanced neck computed tomography demonstrated an abscess in seven cases and an abscess containing suppurative lymphadenitis in five cases. The largest diameter of the abscess was 41 mm. All cases were given broad-spectrum empirical antibiotherapy (penicillin+metronidazole, ceftriaxone+metronidazole, or clindamycin). No medical treatment failure was experienced. Conclusion: Independent of age and abscess size, if the baseline WBC is <=25.200/MUL, if only two or less than two cervical compartments are involved, if there are no complications in the admission, and if the etiological reason is not a previous history of trauma, surgery, foreign body, and malignancy, pediatric deep neck abscess can be treated successfully with parenteral empirical wide-spectrum antibiotherapy. PMID- 29392057 TI - Analysis of Otologic Injuries Due to Blast Trauma by Handmade Explosives. AB - Objective: The aim of this study is to identify the otologic injuries due to handmade explosive-welded blast travma in the law enforcement officers during the combat operations in the curfew security region and to specify the disorders that Otolaryngology and Head Neck Surgery (OHNS) physicians can face during such operations. Methods: Medical records of patients in law enforcement who were initially treated by OHNS physicians of Silopi State Hospital during combat operations, between December 14, 2015 and January 15, 2016 were reviewed. Twenty five patients with otologic injuries due to blast trauma were included in the study. Trauma characteristics, physical examination findings, and beginning treatments were identified. Results: Primary blast injury (PBI) was identified as the major disorder in all 24 cases. Tinnitus and hearing loss were the most frequent complaints. In physical examination, tympanic membrane perforations were found in four ears of three patients. Oral methylprednisolone in decreasing doses for 10 days was commenced as an initial treatment in patients with PBI. Secondary blast injury presented in the form of soft tissue damage in the auricular helix due to shrapnel pieces in one patient and a minor surgery was performed. Conclusion: Otologic injuries due to blast trauma may often develop during this type of combat operations. Otologic symptoms should be checked, otoscopic examination should be performed, and patients should consult OHNS physicians as soon as possible after trauma. PMID- 29392058 TI - Comparison of Hydroxyapatite Prosthesis and Incus Interposition in Incus Defects. AB - Objective: Chronic otitis media most commonly causes an ossicular chain defect in incus. Different materials can be used for repair of this defect. In this study, the hydroxyapatite prosthesis, used for repair of the incus defect, was compared with the incus interposition. Methods: Between 2010 and 2016, 27 female and 16 male patients who underwent ossiculoplasty due to an incus defect were studied retrospectively. Patients' hearing results at the sixth month were compared. The hydroxyapatite prosthesis was used in 24 patients (group 1) and incus interposition was used in 19 patients (group 2) for the ossicular chain repair. Hearing gain at 500, 1000, 2000, and 4000 Hz between the two groups and the success rates in the two groups were compared. Results: Successful hearing reconstruction was performed on 10 patients in each group (group 1, 41.6% and group 2, 52.9%). There was no statistically significant difference between groups both in terms of successful hearing and hearing gain at 500, 1000, 2000, and 4000 Hz. There was no extrusion of the materials used in both groups. Conclusion: As it does not have any additional cost and is easily shaped and biocompatibility problem is not encountered; we recommend using incus interposition primarily in incus defects. PMID- 29392059 TI - Examination of the Relationship between Umbilical Cord Blood Gas Values and Hearing Function in Neonates. AB - Objective: The aim of the present study was to examine the relationship between the results of the transient otoacoustic emission (TEOAE) test used in neonatal hearing screening and the results of the umbilical cord blood (UCB) analysis in neonates. Methods: This retrospective study included 209 neonates born in the obstetric unit at the 37th gestational week. Based on the results of the TEOAE test, the neonates included in the study were divided into two groups as the study group composed of those "REFER" (n=141) and the control group consisting those "PASS" (n=68) the test. The UCB sampling procedure was performed on all neonates. In the blood samples, the pH parameters were evaluated by using glass electrodes, and the pCO2 and pO2 parameters were evaluated directly by using sensitive electrodes. Results: When the additional maternal diseases were compared with the TEOAE results, the ratio of hypothyroidism was found to be statistically higher in the study group (p<0.05). In terms of the pO2, pCO2, HCO3, and pH values obtained as a result of analyzing the UCB samples, there was no statistically significant difference between the groups (p>0.05). Conclusion: The results of the present study showed that there was no statistically significant difference between the results of UCB analysis and the TEOAE test. However, we believe that conducting a larger study evaluating other parameters and employing UCB analysis would be useful, and UCB evaluation, which is an inexpensive, easy and effective method in determining hypoxia in neonates, might be a significant marker in cases at risk of hearing loss. PMID- 29392060 TI - Three Cases of Relapsing Polycondritis with Isolated Laryngotracheal Stenosis. AB - Relapsing polychondritis (RP) is a rare autoimmune and inflammatory disease, particularly characterized by recurrent inflammation of the hyaline cartilage. Laryngotracheal involvement in RP is the most serious complication that is observed in 50% of the patients and may lead to a life-threatening condition. The most common cause of death is laryngotracheal stenosis associated with lung infections or severe respiratory insufficiency that may be observed in 10%-50% of the patients. In this study, three RP patients comprising a child with isolated laryngotracheal stenosis have been presented. PMID- 29392061 TI - Benign Paroxysmal Positional Vertigo in Pregnancy. AB - Benign paroxysmal positional vertigo (BPPV) is a clinical entity characterized by acute, brief paroxysmal attacks of rotational vertigo induced by head position changes. It is the most common peripheral vestibular pathology and is seen more frequently in women. However, to our knowledge, there is very limited data on the association between BPPV and pregnancy in both English and Turkish literature. We present four pregnant women diagnosed with BPPV for the first time during gestation and revise the etiological factors of BPPV and the role of pregnancy related changes in BPPV. PMID- 29392062 TI - Posttraumatic Intramuscular Hemangioma Arising from Scalene Muscles in Supraclavicular Region. AB - Intramuscular hemangiomas (IMH) account for <%1 of all hemangiomas and are rarely located in the head and neck region. The most common site of origin in the head and neck is the masseter muscle, whereas IMH originating from the scalene muscles are rarely seen. Surgical excision of intramuscular hemangioma is considered the main treatment modality. Here we present the case of a male patient aged 17 with IMH that occured after blunt trauma in the supraclavicular region, fed by the thyrocervical and costocervical trunks, and with an arteriovenous shunt. PMID- 29392063 TI - Unilateral Pedunculated Lymphangiectatic Fibrolipomatous Polyp of the Palatine Tonsil: A Rare Case. AB - Lymphangiomatous polyps are rare benign hamartomatous tumors of the palatine tonsils that can cause significant distress to the patients such as sore throat, foreign body sensation, a lumpy feeling in the throat region, dysphagia, and eventual suffocation. In this paper, the case of a 17-year-old male who came to the outpatient clinic with a complaint of difficulty in swallowing, eventual vomiting, and occasions of hematemesis is presented. On physical examination, the patient had a smooth-surface, polypoid, pedunculated tumoral lesion originating from the middle pole of the left palatine tonsil and protruding into the oropharyngeal isthmus. The patient underwent left tonsillectomy. Histopathological examination of the surgical specimen showed typical features of a lymphangiectatic fibrolipomatous polyp. The case reported herein with the brief literature review points out the clinical and the benign, non-neoplastic characteristics of the lymphangiectatic fibrolipomatous polyp, which can be cured by surgical excision along with tonsillectomy. PMID- 29392064 TI - Are We as Otorhinolaryngologists Aware of the Danger of Predatory Journals? PMID- 29392065 TI - Possible Ototoxic Effects of Topical Rifamycin Application: An Electrophysiological and Ultrastructural Study. AB - Objective: This study aimed to investigate possible ototoxicity associated with topical rifamycin application via electrophysiological tests and ultrastructural examinations. Methods: Electrophysiological assessment was performed with tympanometry, auditory brainstem response (ABR), and distortion product otoacoustic emission (DPOAE) measurements. This study was conducted on 40 ears of 20 guinea pigs that were detected to have normal hearing thresholds. The animals were randomly assigned to three groups: Group 1 (n=12) received 0.1 mL rifamycin, Group 2 (n=8) received 0.1 ml gentamycin, and Group 3 (n=20) received 0.1 mL physiological saline. The antibiotics and saline solutions were administered via intratympanic injections. After five injections every other day, electrophysiological tests were performed again on the 15th day. After electrophysiological measurements, the temporal bones of all guinea pigs were prepared for ultrastructural examinations and the cochlear surface morphology was examined by scanning electron microscopy (SEM). Results: The animals in group 3 did not show a statistically significant change in their DPOAE signal/noise ratio (SNR) or ABR thresholds (p>0.05). In groups 1 and 2, the reduction in the DPOAE SNR and the increase in the ABR threshold were statistically significant (p<0.05). Regarding SEM examination results, the animals in groups 1 and 2 showed statistically significant outer hair cell damage and cochlear degeneration due to the ototoxic effect of the drugs (p<0.05), whereas the animals in group 3 showed no significant damage (p>0.05). Conclusion: The results indicate that rifamycin application to the middle ears of guinea pigs has mild ototoxic effects on their inner ears. PMID- 29392067 TI - Defect Reconstruction of the Nose After Surgery for Nonmelanoma Skin Cancer: Our Clinical Experience. AB - Objective: This study aimed to investigate reconstruction methods according to nasal subunits in patients who were surgically treated with diagnosis of non melanoma skin cancer of the nose. Methods: All patients were retrospectively investigated. This study was conducted between April 2004 and December 2010; 180 patients who were surgically treated with diagnoses of skin basal cell carcinoma, squamous cell carcinoma, cancer of skin appendages, and precancerous lesions and 194 lesions were included. The types of repair performed were divided into seven main groups: Secondary healing, primary closure, skin graft, local flap, auricular composite graft, subtotal reconstruction and prosthesis application. Results: Among the 180 patients, 110 (61.1%) were males and 70 (38.9%) were females. The mean duration of follow-up was 39.8 (range, 32-81) months. Repair was by a local flap, a primary suture, a skin graft, and an auricular composite graft in 133, 16, 38, and 2 defects, respectively. Four defects were left for secondary healing. A prosthesis was applied to one patient. Totally, 194 defects were treated by surgery. Conclusion: Although nonsurgical treatment options such as radiotherapy or cryotherapy may be effectively used, surgery is the main treatment option for cancer of the nasal skin. Nasal subunits have distinct characteristics; thus, optimal reconstruction should be preferred for each subunit. The objective of the reconstruction is not only closing the defect. Closing the defect appropriately with the optimal flap and in proper with the aesthetic subunits is the most important point in reconstruction of the nose. PMID- 29392066 TI - Pretreatment Prediction of the Outcomes of Intranasal Steroid Sprays in Cases with Inferior Turbinate Hypertrophy. AB - Objective: Intranasal steroid sprays (INSS) are frequently prescribed for treating inferior turbinate hypertrophy (ITH). Complications due to the long-term application of INSS such as crusting, epistaxis, nasal mucosa dryness, and septal perforation may occur. Predicting patients who would benefit from INSS early might lower treatment costs and complication rates. We examined the predictive value of nasal decongestant response rates for the outcomes of INSS in ITH. Methods: Fifty patients with bilateral ITH were included in two groups: patients benefiting from INSS and those not benefiting. Nasal airflow was assessed by peak nasal inspiratory flow (PNIF) measurement in all cases. Measurements were taken three times: before and after the application of nasal decongestant sprays and after the application of INSS. Results: In both groups, the nasal air flow rates significantly increased after the application of nasal decongestant sprays; however, the nasal decongestant response rates were higher in the group with patients benefiting from INSS. There was a strong correlation between the nasal air flow rates measured after the application of nasal decongestant sprays and after the application of INSS. The cut-off value for the relationship between increased nasal air flow rates after the application of nasal decongestant sprays and outcomes of INSS was 23%. Conclusion: Measurement of nasal airflow increase rate after the application of nasal decongestant sprays is a simple and easy method for the early prediction of the outcomes of INSS in ITH. A higher than 23% increase in nasal air flow rates after the application of nasal decongestant sprays indicates much better outcomes of INSS for patients. PMID- 29392068 TI - Through-and-Through Mattress Suturing Versus Tie-Over Dressing in Full-Thickness Skin Graft Reconstruction. AB - Objective: To compare the outcomes of securing full-thickness skin grafting (FTSG) with through-and-through mattress suturing versus the classic tie-over and pressure dressing and identify the associated risk factors of graft failure. Methods: A single-institution, retrospective case series of patients who had undergone excision of head and neck skin lesions requiring FTSG over a 10-year period was reviewed. Results: In total, 128 FTSG reconstructions were performed. The follow-up period ranged from 1 to 192 weeks. The observed graft take rate was 86.4%. There was no significant difference in the outcome when the surgical fixation technique was compared. Age, sex, or defect area did not affect the graft take rate. Smoking and the use of anticoagulants were not found to be contributory factors to graft failure. Conclusion: Simple through-and-through mattress suturing provides adequate graft take, while minimizing tissue handling of the graft and reducing surgical time in comparison to the traditional tie-over and pressure technique. PMID- 29392069 TI - Serum Oxidative Stress Levels in Patients with Nasal Septal Deviation. AB - Objective: Comparison of the total oxidant status (TOS), total antioxidant status (TAS) and paraoxonase (PON1) serum levels in patients with nasal septum deviation (NSD) and healthy subjects. Methods: The TAS, TOS, and PON1 serum levels of 47 patients with NSD (mean age 35.3) and 50 healthy subjects (mean age 37.8) were compared in this study. Results: We found significantly higher TAS levels in the control group (p<0.001). The mean TAS value was 1.196 mmoL/L in the control group, whereas it was 1.046 mmoL/L in the NSD group. On the other hand, TOS was significantly higher in the NSD group (p<0.001). We found that the mean TOS value was 6.600 mmoL/L in the control group, and 20.194 mmoL/L in the NSD group. The NSD and control groups had similar PON1 levels (p=0.446). The mean PON1 value was 279.64 U/L in the control group, and 324.21 U/L in the NSD group. Conclusion: We detected higher TOS and lower TAS levels in patients with NSD compared to healthy subjects. These results indicate that patients with NSD are exposed to oxidative stress. PMID- 29392070 TI - Assessment of Approaches of Otorhinolaryngologists in Facial Plastic and Nasal Surgery: A Survey Study. AB - Objective: To assess approaches and experiences of otorhinolaryngologists in facial plastic and nasal surgery. Methods: In total, 234 surgeons (191 males and 43 females; average age, 37.22+/-8.4 years; age range, 26-63 years) were included. All participants were given a questionnaire comprising 22 multiple choice and closed-ended questions. All responses to the questionnaires were analyzed. Results: Of 234 participants, 42 (17.9%) were residents and 192 (82.1%) were specialists in otorhinolaryngology. The most challenging cases in rhinoplasty were crooked nose (33.8%), ideal nasal dorsum (18.8%), revision cases (13.2%), and skin deformities (11.1%). The photodocumentation rate by surgeons before and after procedures of facial plastic surgery was 86.3%, whereas the intraoperative photodocumentation rate by surgeons was 47%. The most common facial plastic surgery procedures other than rhinoplasty were otoplasty (68.4%), filler-Botox-fat injections (20.5%), and mentoplasty (18.4%). Conclusion: This survey study is quite important because it assesses approaches of otorhinolaryngologists in facial plastic surgery. Although this study provides more valuable data for determining the current status, further studies with larger number of surgeons are required. PMID- 29392071 TI - Comparison of Early-period Results of Nasal Splint and Merocel Nasal Packs in Septoplasty. AB - Objective: Several types of nasal packs are used postoperatively in septoplasty. In this study, we compared two commonly used nasal packing materials, the intranasal septal splint with airway and Merocel tampon, in terms of pain, bleeding, nasal obstruction, eating difficulties, discomfort in sleep, and pain and bleeding during removal of packing in the early period. Methods: The study group included 60 patients undergoing septoplasty. Patients were divided into two groups (n=30 in each group). An intranasal splint with airway was used for the patients in the first group after septoplasty, while Merocel nasal packing was used for the second group. Patients were investigated in terms of seven different factors - pain, bleeding while the tampon was in place, nasal obstruction, eating difficulties, night sleep, pain during removal of the nasal packing, and bleeding after removal of packing. Results: There was no statistically significant difference between the groups in terms of pain 24 hours after operation (p=0.05), while visual analog scale (VAS) scores for nasal obstruction, night sleep, eating difficulties, and pain during packing removal were lower in the nasal splint group with a statistically significant difference (p<0.05). There was no statistically significant difference between the groups in terms of postoperative bleeding (p=0.23). Significantly less bleeding occurred during removal of the packing in the nasal splint group (p<0.05). Conclusion: Our study indicates that the nasal splint was more comfortable and effective in terms of causing lesser bleeding and pain during removal of packing. PMID- 29392072 TI - A Rare Complication of Chronic Otitis Media: Cerebellar Abscess. AB - Chronic otitis media (COM) and its associated complications are currently less common because of the popularity of imaging modalities such as computed tomography and magnetic resonance imaging and the increased use of antibiotics. Patients can be treated without any complications owing to early diagnosis. Despite all these new developments and opportunities, complications of autogenous cerebellar abscess may develop and be fatal. In this case report, we present our own clinical experience regarding a patient with cerebellar abscess as a complication of COM. PMID- 29392073 TI - Transverse Cervicothoracic Stabbing: Multidisciplinary Management of a Surgical Emergency. AB - Tracheobronchial injuries are closely related to orotracheal intubations and chest traumas. Stabbing injuries are very rare and often life threatening because of the damage to vital structures such as the respiratory tract and large arterial or venous vessels. Early diagnosis and treatment of penetrating neck injuries increase survival rates. We report a case of the tracheobronchial section with a penetrating stabbing wound on the left laterocervical area associated with contralateral pneumothorax, requiring urgent surgical pulmonary repair, tracheal suture, and tracheotomy. Prompt action with a multidisciplinary approach resulted in a favorable outcome. PMID- 29392074 TI - A Rare Cause of Positional Dyspnea: Hypopharyngeal Hamartoma. AB - Hypopharyngeal hamartomas are quite rare tumors that may cause nutritional or respiratory problems in neonates and infants. They may be confused with other benign laryngeal lesions. In this study a 7-month-old infant with congenital stridor and positional dyspnea caused by a hypopharyngeal hamartoma was reported with review of the literature. Hypopharyngeal hamartomas should be considered in the differential diagnosis of pathologies that cause respiratory or feeding problems in neonates or infants. PMID- 29392075 TI - Ectopic Tooth in the Maxillary Sinus. PMID- 29392076 TI - The Study of Rhabdomyolysis in the Elderly: An Epidemiological Study and Single Center Experience. AB - Rhabdomyolysis is a syndrome caused by injury to skeletal muscle. There is limited data of rhabdomyolysis in the elderly. The objective of this study is to investigate demographic data, etiologies, laboratory values, prognostic factors, and mortality of rhabdomyolysis in the geriatric population. A 4-years retrospective chart review study was conducted. Our inclusion criteria were age above 65 years and creatinine kinase level excess five times of normal upper limit. Among 167 patients, 47.3% were male. The median age at diagnosis was 80.11 (66-101) years. The duration of follow up in the study ranged from 0 to 48 months. Fall (with or without immobilization) was the most frequent cause of rhabdomyolysis in 56.9%. The mean baseline glomerular filtration rate (GFR), GFR at diagnosis, and peak decline in GFR was 76.94, 48.96, and 54.41 cc/min respectively. The mean CK at diagnosis and peak CK was 5097.22 and 6320.07. There were 45 deaths (21%) over the span of 4 years. Multivariate analysis demonstrated that number of medications pre-admission (Meds No.), peak decline in GFR, and acute kidney injury (AKI) are independent predictors for overall survival for rhabdomyolysis in the elderly. To our knowledge, this is the first epidemiological study of rhabdomyolysis in the elderly. Falls (with and without immobilization) were the most common etiology. Meds No. (>8), peak decline in GFR (<30 cc/min), and evidence of AKI are associated with shorter overall survival and can serve as potential independent prognostic markers for rhabdomyolysis in elderly patients. PMID- 29392077 TI - Clinical Profile of Chinese Long-Term Parkinson's Disease Survivors With 10 Years of Disease Duration and Beyond. AB - Background: Parkinson's disease (PD) patients with 10 years or more survival (PD 10) are not well characterized. The aim of this study was to evaluate the main issues facing PD-10 patients and identify factors that independently contributed to quality of life (QoL). Methods: A group of 121 PD-10 patients recruited from outpatient clinics participated in this cross-sectional study. Data on demographic and clinical factors were collected. Multiple linear regression analyses were conducted to identify determinants of poor QoL. Results: The entire PD-10 patients had disease duration ranging from 10 to 23 years, with 84.2% of the total cohort skewed to between 10 and 15 years' duration. The PD-10 patients had great frequency of left-sided onset, increased motor and non-motor symptoms as well as inferior QoL. The more advanced stage of disease in PD-10 patients was associated with motor phenotype, freezing of gait, higher UPDRS sub-scores and levodopa equivalent dose, less balanced confidence, fatigue, anxiety, depression, reduced quality of life and worse Timed Up & Go performance. Self-reported mood symptoms, decreased balance confidence and reduced daily activities were the three factors most closely associated with poorer QoL, but excessive daytime sleepiness and long disease duration additionally contributed to the explanatory power. Conclusions: This is the first report to investigate the clinical characteristics of Chinese PD-10 patients. Our study may elucidate an important clue for understanding PD-10 patients in clinical practice and identifying patients with PD at risk for reduced QoL. PMID- 29392078 TI - PARP-1 Inhibition Rescues Short Lifespan in Hyperglycemic C. Elegans And Improves GLP-1 Secretion in Human Cells. AB - TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C. elegans, in part by impacting key well-conserved insulin-modulated signaling pathways, we investigated the effect of PARP-1 inhibition with Olaparib on the lifespan of C. elegans nematodes under varying hyperglycemic conditions. Subsequently, we investigated whether Olaparib treatment had any effect on glucose-stimulated GLP-1 secretion in the human NCI-H716 intestinal cell line, a model system for the investigation of enteroendocrine function. Treatment with 100uM Olaparib in nematodes exposed to high concentrations of glucose led to significant lifespan rescue. The beneficial lifespan effect of Olaparib appeared to require both PARP-1 and TCF7L2, since treatment had no effect in hyperglycemic conditions in knock-out worm strains for either of these homologs. Further investigation using the NCI-H716 cells revealed that Olaparib significantly enhanced secretion of the incretin, GLP-1, plus the gene expression of TCF7L2, GCG and PC1. These data from studies in both C. elegans and a human cell line suggest that PARP-1 inhibition offers a novel therapeutic avenue to treat type 2 diabetes. PMID- 29392079 TI - Novel Modification of Potassium Chloride Induced Cardiac Arrest Model for Aged Mice. AB - Experimental cardiac arrest (CA) in aging research is infrequently studied in part due to the limitation of animal models. We aimed to develop an easily performed mouse CA model to meet this need. A standard mouse KCl-induced CA model using chest compressions and intravenous epinephrine for resuscitation was modified by blood withdrawal prior to CA onset, so as to decrease the requisite KCl dose to induce CA by decreasing the circulating blood volume. The modification was then compared to the standard model in young adult mice subjected to 8 min CA. 22-month old mice were then subjected to 8 min CA, resuscitated, and compared to young adult mice. Post-CA functional recovery was evaluated by measuring spontaneous locomotor activity pre-injury, and on post-CA days 1, 2, and 3. Neurological score and brain histology were examined on day 3. Brain elF2alpha phosphorylation levels were measured at 1 h to verify tissue stress. Compared to the standard model, the modification decreased cardiopulmonary resuscitation duration and increased 3-day survival in young mice. For aged mice, survival was 100 % at 24 h and 54% at 72 h. Neurological deficit was present 3 days post-CA, although more severe versus young mice. Mild neuronal necrosis was present in the cortex and hippocampus. The modified model markedly induced elF2alpha phosphorylation in both age groups. This modified procedure makes the CA model feasible in aged mice and provides a practical platform for understanding injury mechanisms and developing therapeutics for elderly patients. PMID- 29392080 TI - Identification of MAVS as a Novel Risk Factor for the Development of Osteoarthritis. AB - Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIG-I, rs17857295 (P allele: 0.073518) and rs7262903 (P-allele: 0.054052, P-genotype: 0.067930) in MAVS were marginally associated with OA. Rs7269320 (P-allele: 0.014783, P genotype: 0.03272) in MAVS was significant associated with OA. Further analyses in different genders indicated that rs7262903 (P-allele: 0.017256, P-genotype: 0.045683) and rs7269320 (P-allele: 0.013073, P-genotype: 0.038881) are significantly associated with OA in female group. Haplotype analyses indicated G C-G (chi2: 4.328, P-value: 0.037503) in rs10813821-rs11795343-rs659527 block of RIG-I, G-C-A-T (chi2: 4.056, P-value: 0.044028) and G-C-C-C (chi2: 14.295, P value: 0.000158) in rs17857295-rs2326369-rs7262903-rs7269320 block of MAVS were significantly associated with OA. Furthermore, forced expression of MAVS could suppress the viability and promote the apoptosis of ATDC5 chondrogenic cells. In conclusion, this study indicated that RIG-I and MAVS are probably associated with OA in the females of Chinese Han population. And MAVS might be a novel risk factor for OA which may involve in growth of chondrocytes and cartilage homeostasis. PMID- 29392082 TI - Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK Dependent Pathway in Neonatal Rat Cardiomyocytes. AB - Diabetes Mellitus is a common disorder, with increasing risk of cardiac arrhythmias. Studies have shown that altered connexin expression and gap junction remodeling under hyperglycemia contribute to the high prevalence of cardiac arrhythmias and even sudden death. Connexin 43 (Cx43), a major protein that assembles to form cardiac gap junctions, has been found to be downregulated under high glucose conditions, along with inhibition of gap junctional intercellular communication (GJIC). While, apelin, a beneficial adipokine, increases Cx43 protein expression in mouse and human embryonic stem cells during cardiac differentiation. However, it remains unknown whether apelin influences GJIC capacity in cardiomyocytes. Here, using Western blotting and dye transfer assays, we found that Cx43 protein expression was reduced and GJIC was impaired after treatment with high glucose, which, however, could be abrogated after apelin treatment for 48 h. We also found that apelin increased Cx43 expression under normal glucose. Real-time PCR showed that the Cx43 mRNA was not significantly affected under high glucose conditions in the presence of apelin or high glucose and apelin. High glucose decreased the phosphorylation of AMPKalpha; however, apelin activated AMPKalpha. Interestingly, we found that Cx43 expression was increased after treatment with AICAR, an activator of AMPK signaling. AMPKalpha inhibition mediated with transfection of siRNA-AMPKalpha1 and siRNA-AMPKalpha2 abolished the protective effect of apelin on Cx43 expression. Our data suggest that apelin attenuates high glucose-induced Cx43 downregulation and improves the loss of functional gap junctions partly through the AMPK pathway. PMID- 29392081 TI - Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson's Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage. AB - : Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson's disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores' distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD. PMID- 29392083 TI - Short Telomere Length is Associated with Aging, Central Obesity, Poor Sleep and Hypertension in Lebanese Individuals. AB - In Lebanon, data stemming from national cross-sectional surveys indicated significant increasing trends in the prevalence of cardiovascular diseases and associated behavioral and age-related risk factors. To our knowledge, no data are available on relative telomere length (RTL) as a potential biomarker for age related diseases in a Lebanese population. The aim of this study was to evaluate whether there is an association between RTL and demographic characteristics, lifestyle habits and diseases in the Lebanese. This was a cross-sectional study of 497 Lebanese subjects. Peripheral blood RTL was measured by amplifying telomere and single copy gene using real-time PCR. Mean +/- SD RTL was 1.42 +/- 0.83, and it was categorized into 3 tertiles. Older age (P=0.002) and wider waist circumference (WC) (P=0.001) were statistically significantly associated with shorter RTL. Multinomial logistic regression showed that subjects who had some level of sleeping difficulty had a statistically significantly shorter RTL when compared to those with no sleeping difficulties at all [OR (95% CI): 2.01 (1.11 3.62) in the first RTL tertile]. Importantly, statistically significantly shorter RTL was found with every additional 10 cm of WC [OR (95% CI): 1.30 (1.11-1.52) for first RTL tertile]. In addition, and after performing the multivariate logistic regression and adjusting for "predictors" of RTL, the odds of having hypertension or being treated for hypertension were higher in patients who had shorter RTL: OR (95% CI): 2.45 (1.36-4.44) and 2.28 (1.22-4.26) in the first RTL tertiles respectively with a similar trend, though not statistically significant, in the second RTL tertiles. This is the first study in Lebanon to show an association between age, central obesity, poor sleep and hypertension and RTL. It is hoped that telomere length measurement be potentially used as a biomarker for biological age and age-related diseases and progression in the Lebanese. PMID- 29392084 TI - Cardiovascular Risk Factors Are Correlated with Low Cognitive Function among Older Adults Across Europe Based on The SHARE Database. AB - Increased life expectancy is associated with a high prevalence of chronic, non communicable diseases including cognitive decline and dementia. The purpose of this study was to evaluate the prevalence of cognitive impairment using three cognitive abilities (verbal fluency, numeracy and perceived memory) and their association with cardiovascular risk factors in seniors across Europe. Data from participants in wave 4 of the SHARE (Survey of Health, Ageing, and Retirement in Europe) database was used. Cognitive performance in perceived memory, verbal fluency and numeracy was evaluated using simple tests and a memory complaints questionnaire. Clinical and sociodemographic variables were also studied for potential associations. Standardised prevalence rates of cognitive impairment based on age and gender were calculated by country. The prevalence of cognitive impairment was 28.02% for perceived memory, 27.89% for verbal fluency and 20.75% for numeracy throughout the 16 evaluated countries. Years of education, being a current or former smoker, number of chronic diseases, diabetes or hyperglycemia, heart attack and stroke were all independent variables associated with impairment in the three studied cognitive abilities. We also found independent associations between physical inactivity and verbal fluency and numeracy impairment, as well as hypertension and perceived memory impairment. Lower performance in the evaluated cognitive abilities and higher memory complaints are highly prevalent, have a heterogeneous distribution across Europe, and are associated with multiple factors, most of which are potentially preventable or treatable, especially cardiovascular risk factors. PMID- 29392085 TI - Causes of Death in Chinese Patients with Multiple System Atrophy. AB - The objective of this study was to explore the causes of death in Chinese patients with multiple system atrophy (MSA) as well as differences in the cause of death according to sex, subtype, disease onset, and whether the disease was accompanied by nocturnal stridor. A total of 131 MSA patients were enrolled and followed up once every year until their deaths. Clinical information was collected by neurologists, and the cause of death of the MSA patients was obtained from the patients' relatives or caregivers. The current study included 62 MSA with predominant parkinsonism (MSA-P) and 69 MSA with predominant cerebellar ataxia (MSA-C) patients. Median survival time from disease onset to death of the MSA patients was 5.59 years. The most common cause of death was respiratory infection (65.6%). The second most common cause of death was sudden death (14.5%). Other causes included nutritional disorder due to dysphagia (9.2%), urinary tract infection (3.1%), suicide (2.3%), choking (1.5%), cerebrovascular accident (1.5%), myocardial infarction (1.5%), and lymphoma (0.8%). We found that sudden death was more likely to occur in patients with nocturnal stridor than in those without (P<0.001). There were no significant differences in the cause of death according to subtype, sex, or onset symptoms (autonomic failure or motor symptoms). Sudden death is a relatively common cause of death in MSA patients, second only to respiratory infection, especially in patients with nocturnal stridor. The information provided by our study may help to provide better medical care to MSA patients. PMID- 29392086 TI - Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT. AB - Brain aging is associated with changes of various metabolic pathways. Copper is required for brain development and function, but little is known about changes in copper metabolism during brain aging. The objective of this study was to investigate alteration of copper fluxes in the aging mouse brain with positron emission tomography/computed tomography using 64CuCl2 as a radiotracer (64CuCl2 PET/CT). A longitudinal study was conducted in C57BL/6 mice (n = 5) to measure age-dependent brain and whole-body changes of 64Cu radioactivity using PET/CT after oral administration of 64CuCl2 as a radiotracer. Cerebral 64Cu uptake at 13 months of age (0.17 +/- 0.05 %ID/g) was higher than the cerebral 64Cu uptake at 5 months of age (0.11 +/- 0.06 %ID/g, p < 0.001), followed by decrease to (0.14 +/- 0.04 %ID/g, p = 0.02) at 26 months of age. In contrast, cerebral 18F-FDG uptake was highest at 5 months of age (7.8 +/- 1.2 %ID/g) and decreased to similar values at 12 (5.2 +/- 1.1 %ID/g, p < 0.001) and 22 (5.6 +/- 1.1 %ID/g, p < 0.001) months of age. The findings demonstrated alteration of copper fluxes associated with brain aging and the time course of brain changes in copper fluxes differed from changes in brain glucose metabolism across time, suggesting independent underlying physiological processes. Hence, age-dependent changes of cerebral copper fluxes might represent a novel metabolic biomarker for assessment of human brain aging process with PET/CT using 64CuCl2 as a radiotracer. PMID- 29392087 TI - Role of Dietary Protein and Muscular Fitness on Longevity and Aging. AB - Muscle atrophy is an unfortunate effect of aging and many diseases and can compromise physical function and impair vital metabolic processes. Low levels of muscular fitness together with insufficient dietary intake are major risk factors for illness and mortality from all causes. Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence. However, the extent of muscle wasting differs greatly between individuals due to differences in the aging process per se as well as physical activity levels. Interventions for sarcopenia include exercise and nutrition because both have a positive impact on protein anabolism but also enhance other aspects that contribute to well-being in sarcopenic older adults, such as physical function, quality of life, and anti-inflammatory state. The process of aging is accompanied by chronic immune activation, and sarcopenia may represent a consequence of a counter-regulatory strategy of the immune system. Thereby, the kynurenine pathway is induced, and elevation in the ratio of kynurenine to tryptophan concentrations, which estimates the tryptophan breakdown rate, is often linked with inflammatory conditions and neuropsychiatric symptoms. A combined exercise program consisting of both resistance-type and endurance-type exercise may best help to ameliorate the loss of skeletal muscle mass and function, to prevent muscle aging comorbidities, and to improve physical performance and quality of life. In addition, the use of dietary protein supplementation can further augment protein anabolism but can also contribute to a more active lifestyle, thereby supporting well-being and active aging in the older population. PMID- 29392088 TI - MicroRNAs and Presbycusis. AB - Presbycusis (age-related hearing loss) is the most universal sensory degenerative disease in elderly people caused by the degeneration of cochlear cells. Non coding microRNAs (miRNAs) play a fundamental role in gene regulation in almost every multicellular organism, and control the aging processes. It has been identified that various miRNAs are up- or down-regulated during mammalian aging processes in tissue-specific manners. Most miRNAs bind to specific sites on their target messenger-RNAs (mRNAs) and decrease their expression. Germline mutation may lead to dysregulation of potential miRNAs expression, causing progressive hair cell degeneration and age-related hearing loss. Therapeutic innovations could emerge from a better understanding of diverse function of miRNAs in presbycusis. This review summarizes the relationship between miRNAs and presbycusis, and presents novel miRNAs-targeted strategies against presbycusis. PMID- 29392089 TI - A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. AB - NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly. PMID- 29392091 TI - Chronic Remote Ischemic Conditioning May Mimic Regular Exercise:Perspective from Clinical Studies. AB - Chronic remote ischemic conditioning (RIC), particularly long-term repeated RIC, has been applied in clinical trials with the expectation that it could play its protective roles for protracted periods. In sports medicine, chronic RIC has also been demonstrated to improve exercise performance, akin to improvements seen with regular exercise training. Therefore, chronic RIC may mimic regular exercise, and they may have similar underlying mechanisms. In this study, we explored the common underlying mechanisms of chronic RIC and physical exercise in protecting multiple organs and benefiting various populations, the advantages of chronic RIC, and the challenges for its popularization. Intriguingly, several underlying mechanisms of RIC and exercise have been shown to overlap. These include the production of many autacoids, enhanced ability for antioxidant activity, modulating immune and inflammatory responses. Therefore, it appears that chronic RIC, just like regular exercise, has beneficial effects in unhealthy, sub-healthy and healthy individuals. Compared with regular exercise, chronic RIC has several advantages, which may provide novel insights into the area of exercise and health. Chronic RIC may enrich the modes of exercise, and benefit individuals with severe diseases. Also, the disabled, and sub-healthy individuals are likely to benefit from chronic RIC either as an alternative to exercise or an adjunct to pharmacological or non-pharmacological therapy. PMID- 29392090 TI - Acute Sarcopenia Secondary to Hospitalisation - An Emerging Condition Affecting Older Adults. AB - There has been increasing interest and research into sarcopenia in community dwelling older adults since the European Working Group on Sarcopenia in Older People (EWGSOP) agreed a consensus definition in 2010. Sarcopenia has been defined as loss of muscle mass with loss of muscle function (strength or physical performance), with measurements two Standard Deviations (SDs) below the mean of a young reference population. This definition does not necessitate longitudinal measurements, or the absence of acute illness and diagnosis can be made from single measurements. We hypothesise that hospitalisation, due to a combination of acute inflammatory burden and muscle disuse, leads to an acute decline in muscle mass and function and may lead to some individuals meeting criteria for sarcopenia, acutely, based on the EWGSOP definition. This may be partially recoverable or may lead to increased risk of developing sarcopenia long-term. We have denoted the term "acute sarcopenia" to refer to acute loss of muscle mass and function associated with hospitalisation. This review discusses some of the current available research in this context and also identifies some of the knowledge gaps and potential areas for future research. PMID- 29392092 TI - Cutaneous Scarring: Basic Science, Current Treatments, and Future Directions. AB - Significance: Scarring of the skin from burns, surgery, and injury constitutes a major burden on the healthcare system. Patients affected by major scars, particularly children, suffer from long-term functional and psychological problems. Recent Advances: Scarring in humans is the end result of the wound healing process, which has evolved to rapidly repair injuries. Wound healing and scar formation are well described on the cellular and molecular levels, but truly effective molecular or cell-based antiscarring treatments still do not exist. Recent discoveries have clarified the role of skin stem cells and fibroblasts in the regeneration of injuries and formation of scar. Critical Issues: It will be important to show that new advances in the stem cell and fibroblast biology of scarring can be translated into therapies that prevent and reduce scarring in humans without major side effects. Future Directions: Novel therapies involving the use of purified human cells as well as agents that target specific cells and modulate the immune response to injury are currently undergoing testing. In the basic science realm, researchers continue to refine our understanding of the role that particular cell types play in the development of scar. PMID- 29392093 TI - Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation. AB - Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed. PMID- 29392094 TI - Review of the Current Management of Pressure Ulcers. AB - Significance: The incidence of pressure ulcers is increasing due to our aging population and the increase in the elderly living with disability. Learning how to manage pressure ulcers appropriately is increasingly important for all professionals in wound care. Recent Advances: Many new dressings and treatment modalities have been developed over the recent years and the goal of this review is to highlight their benefits and drawbacks to help providers choose their tools appropriately. Critical Issues: Despite an increased number of therapies available on the market, none has demonstrated any clear benefit over the others and pressure ulcer treatment remains frustrating and time-consuming. Future Directions: Additional research is needed to develop products more effective in prevention and treatment of pressure ulcers. PMID- 29392095 TI - Rethinking childhood adversity in chronic fatigue syndrome. AB - Background: Previous studies have consistently shown increased rates of childhood adversity in chronic fatigue syndrome (CFS). However, such aetiopathogenic studies of CFS are potentially confounded by co-morbidity and misdiagnosis particularly with depression. Purpose: We examined the relationship between rates of childhood adversity using two complimentary approaches (1) a sample of CFS patients who had no lifetime history of depression and (2) a modelling approach. Methods: Childhood trauma questionnaire (CTQ) administered to a sample of 52 participants with chronic fatigue syndrome and 19 controls who did not meet criteria for a psychiatric disorder (confirmed using the Structured Clinical Interview for DSM-IV). Subsequently, Mediation Analysis (Baye's Rules) was used to establish the risk childhood adversity poses for CFS with and without depression. Results: In a cohort of CFS patients with depression comprehensively excluded, CTQ scores were markedly lower than in all previous studies and, in contrast to these previous studies, not increased compared with healthy controls. Post-hoc analysis showed that CTQ scores correlated with the number of depressive symptoms during the lifetime worst period of low mood. The probability of developing CFS given a history of childhood trauma is 4%, a two-fold increased risk compared to the general population. However, much of this risk is mediated by the concomitant development of major depression. Conclusions: The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder. Abbreviations: CFS: Chronic fatigue syndrome; CTQ: Childhood trauma questionnaire; MDD: Major depressive disorder; CA: Childhood adversity; P: Probability. PMID- 29392096 TI - Breast Imaging of Transgender Individuals: A Review. AB - Purpose: This review will inform radiologists about the evidence base regarding radiographic imaging for transgender individuals and considerations for providing culturally sensitive care for this population. Findings: Transgender individuals are increasingly referred for both screening and diagnostic breast imaging. It is important that the clinic environment is welcoming, the medical staff utilize accepted terminology and patients are able to designate their gender and personal history to ensure appropriate care. Hormone and surgical treatments used for transition by many transgender women and men may change the approach to imaging. Summary: Although not yet evidence-based, screening mammography is currently suggested for transgender women with risk factors, including those receiving hormone treatment over 5 years. The risk for breast cancer in transgender individuals is still being defined. PMID- 29392097 TI - Functionalization of flat sheet and hollow fiber microfiltration membranes for water applications. AB - Functionalized membranes containing nanoparticles provide a novel platform for organic pollutant degradation reactions and for selective removal of contaminants without the drawback of potential nanoparticle loss to the environment. These eco friendly and sustainable technology approaches allow various water treatment applications through enhanced water transport through the membrane pores. This paper presents "green" techniques to create nanocomposite materials based on sponge-like membranes for water remediation applications involving chlorinated organic compounds. First, hydrophobic hollow fiber microfiltration membranes (HF) of polyvinylidene fluoride were hydrophilized using a water-based green chemistry process with polyvinylpyrrolidone and persulfate. HF and flat sheet membrane pores were then functionalized with poly(acrylic acid) and synthesized Fe/Pd nanoparticles. Surface modifications were determined by contact angle, surface free energy and infrared spectroscopy. The synthesized nanoparticles were characterized by electronic microscopy, X-ray spectrometry and image analysis. Nanoparticle sizes of 193 and 301 nm were obtained for each of the membranes. Depending on the concentration of the dopant (Pd) in the membrane, catalytic activity (established by trichloroethylene (TCE) reduction), was enhanced up to tenfold compared to other reported results. Chloride produced in reduction was close to the stoichiometric 3/1 (Cl-/TCE), indicating complete absence of reaction intermediates. PMID- 29392098 TI - Patient-specific coronary blood supply territories for quantitative perfusion analysis. AB - Myocardial perfusion imaging, coupled with quantitative perfusion analysis, provides an important diagnostic tool for the identification of ischaemic heart disease caused by coronary stenoses. The accurate mapping between coronary anatomy and under-perfused areas of the myocardium is important for diagnosis and treatment. However, in the absence of the actual coronary anatomy during the reporting of perfusion images, areas of ischaemia are allocated to a coronary territory based on a population-derived 17-segment (American Heart Association) AHA model of coronary blood supply. This work presents a solution for the fusion of 2D Magnetic Resonance (MR) myocardial perfusion images and 3D MR angiography data with the aim to improve the detection of ischaemic heart disease. The key contribution of this work is a novel method for the mediated spatiotemporal registration of perfusion and angiography data and a novel method for the calculation of patient-specific coronary supply territories. The registration method uses 4D cardiac MR cine series spanning the complete cardiac cycle in order to overcome the under-constrained nature of non-rigid slice-to-volume perfusion-to-angiography registration. This is achieved by separating out the deformable registration problem and solving it through phase-to-phase registration of the cine series. The use of patient-specific blood supply territories in quantitative perfusion analysis (instead of the population-based model of coronary blood supply) has the potential of increasing the accuracy of perfusion analysis. Quantitative perfusion analysis diagnostic accuracy evaluation with patient-specific territories against the AHA model demonstrates the value of the mediated spatiotemporal registration in the context of ischaemic heart disease diagnosis. PMID- 29392100 TI - Use of N-Acetylcysteine in Psychiatric Conditions among Children and Adolescents: A Scoping Review. AB - N-acetylcysteine (NAC) is a well-known antidote for acetaminophen toxicity and is easily available over the counter. It has antioxidant and anti-inflammatory properties and an established tolerance and safety profile. Owing to its neuroprotective effects, its clinical use has recently expanded to include the treatment of different psychiatric and non-psychiatric disorders. Although a number of randomized controlled trials have documented the clinical evidence for NAC, there are no reviews that summarize the evidence. The present scoping review summarizes the study designs, the patient characteristics, the evidence and the limitations in randomized controlled trials designed to explore the efficacy of NAC for psychiatric conditions in the pediatric population. PMID- 29392102 TI - An Orthopaedic Fracture Clinic Service Audit: A Complete Loop. AB - Introduction The British Orthopaedic Association Standards for Trauma (BOAST) Guideline 7 informs the standard of care patients should expect when they come to orthopaedic fracture clinics in the United Kingdom (UK). Objectives We compared our fracture clinic's practice against the standards set by BOAST Guideline 7 to make changes for aligning with the standard of care. We aimed to then re-audit our practice for further evaluation against the guidelines. Material and methods We prospectively collected data from 100 patients presenting to the fracture clinics of different orthopaedic consultants working in our hospital, using the Royal College of Surgeons in Ireland's (RCSI's) satisfaction with outpatients services (SWOPS) questionnaire. We made some improvements, recommended changes to the hospital management, and conducted a re-audit, collecting data from another 100 patients. Results With reference to improvements, we were only able to make them on behalf of the doctors and clinical auxiliary staff. We were able to decrease the waiting time from a patient's initial presentation in the accident and emergency (A&E) department to an appointment at the fracture clinic. A few improvements were made to the waiting area facilities. However, the cumulative changes resulted in a positive attitude in patient satisfaction levels. Conclusion Considering our complete audit loop, we found gaps and enabled improvements, but areas of concern remain, which will need to be addressed in the future. PMID- 29392101 TI - Radiosurgical Treatment Verification Using Removable Megavoltage Radiation Detectors. AB - Introduction Accurate dose delivery is critical to the success of stereotactic radiosurgery. Unfortunately, verification of the accuracy of treatment delivery remains a challenging problem. Existing radiosurgery delivery paradigms are limited in their ability to verify the accurate delivery of radiation beams using data sampled from the beam after it has traversed the patient. The Zap-X Radiosurgery System (Zap Surgical Systems, San Carlos, CA) addresses this issue by implementing a fully integrated treatment delivery system that utilizes a factory commissioned megavoltage (MV) imager to measure the transmitted beam. The measured intensity is then compared with an expected value in order to confirm that treatment is proceeding as expected. The purpose of this study was to evaluate a prototype system and investigate the accuracy of an attenuation model used in generating the expected transmitted intensity values. Methods A prototype MV imager was used to measure transmitted beam intensities at various exposure levels and through several thicknesses of solid water. The data were used to evaluate imager linearity and model accuracy. Results Experimental results indicate that a quadratic attenuation model is appropriate for predicting beam attenuation and that the imager exhibits excellent dose linearity. Conclusions The MV imager system is shown to be capable of accurately acquiring the data needed to confirm treatment validity. PMID- 29392099 TI - Improving C1-C2 Complex Fusion Rates: An Alternate Approach. AB - The surgical repair of atlantoaxial instabilities (AAI) presents complex and unique challenges, originating from abnormalities and/or trauma within the junction regions of the C1-C2 atlas-axis, to surgeons. When this region is destabilized, surgical fusion becomes of key importance in order to prevent spinal cord injury. Several techniques can be utilized to provide for the adequate fusion of the atlantoaxial construct. Nevertheless, many individuals have less than ideal rates of fusion, below 35%-40%, which also involves the C2 nerve root being sacrificed. This suboptimal and unavoidable iatrogenic complication results in the elevated probability of complications typically composed of vertebral artery injury. This review is a retrospective analysis of 87 patients from Cedars Sinai Medical Center in Los Angeles, California, who had the C1-C2 surgical fusion procedure performed within the time frame from 2001 to 2008, with a mean follow-up period of three years. These patients had presented with typical AAI symptoms of fatigability, limited mobility, and clumsiness. Diagnosis of C1-C2 instability was documented via radiographic studies, typically utilizing computed tomography (CT) scans or x-rays. All patients had bilateral C1 lateral masses and C2 pedicle screws. In addition, the C1-C2 joint was accessed by retracting the C2 nerve root superiorly and exposing the joint by utilizing a high-speed burr. The cavity that is developed within the joint is packed with local autologous bone from the cephalad resection of the C2 laminae. Fusion of the C1-C2 joint was achieved in all patients and a final follow-up was conducted approximately three years postoperative. Of the 87 patients, two presented with occipital headaches resulting from the C1 screws impinging on the C2 nerve root. The issue was rectified by removing instrumentation in both patients after documenting complete fusion via radiographic studies, with complete resolution of symptoms. No vertebral artery or spinal cord injuries were reported as a result of the minor complication. Overall, we aim to describe a safe and reliable alternative technique to fuse C1-C2 instability by focusing on intra-articular arthrodesis complementing instrumentation fixation. This methodology is advantageous from a biomechanical standpoint secondary to axial loading, as well as the large surface area available for arthrodesis. Additionally, this technique does not involve the resection of the C2 nerve root, resulting in low risk for vertebral artery or spinal cord injury. PMID- 29392103 TI - Occipital Neuralgia in Chiari I Malformation: Two Different Events or Two Different Faces of the Same Event? AB - Occipital neuralgia (ON) is characterized by severe pain in the occipital region due to an irritation of the occipital nerves. Traumatic injuries, mass or vascular compression, and infective and inflammatory processes could cause ON. The dislocation of a nerve/muscle/tendon, as can happen in malformations such as the Chiari I malformation (CIM), also can be responsible. Usually, headaches associated with CIM and ON are distinguishable based on specific features of pain. However, the diagnosis is not easy in some cases, especially if a clear medical history cannot be accurately collected. Determining if the pain is related to ON rather than to CIM is important because the treatments may be different. PMID- 29392104 TI - Conjunctival Capillary Hemangioma. AB - Conjunctival hemangioma over the age of 60 is rare, with few cases reported in the literature. We present a unique case of a conjunctival capillary hemangioma, adding to the sparse literature of this uncommon vascular tumor. Here, we present an interesting case of spontaneous development of this tumor at age 68, without associated systemic disease process or cutaneous manifestations. PMID- 29392105 TI - Physician's Perception Versus Patient's Actual Incidence of Drug Non-adherence in Chronic Illnesses. AB - Objectives Treatment adherence is crucial to the success of a management plan. The objectives of this study are (i) to assess medication adherence in patients with chronic diseases, (ii) to assess if physicians correctly perceive medication adherence among said patients, and (iii) to investigate the factors associated with low drug adherence. Materials & methods This observational cross-sectional study included 283 patients and 208 physicians from various hospitals in Karachi, Pakistan. The participants in the "patient group" completed the eight-item Morisky Medication Adherence Scale form. The participants in the "physician group" completed a questionnaire with questions related to their perception of their patients' characteristics of adherence to medical prescriptions. Data were entered and analyzed using the Statistical Package for Social Sciences (SPSS) for Windows, Version 22.0. (IBM Corp., Armonk, NY). Results The actual incidence of low drug adherence among patients with chronic diseases is 85%. However, the perceived incidence by physicians is 40%. Low adherence was common in women, individuals aged 35 to 50 years, and individuals who were single and illiterate. Adherence decreased with an increasing number of pills, duration of treatment, and increasing average expense of medications. The actual most common barrier to adherence among patients is medication cost; however, physicians perceive forgetfulness to be the more common barrier. Conclusion Patients with chronic illnesses have low medication adherence levels. Physicians, however, misinterpret the frequency of low adherence. Our findings will help physicians have a more real and accurate understanding of the challenges their patients face in long term adherence to treatment regimens. It may ultimately lead to improved treatment adherence and quality of management once patients' actual challenges are addressed and necessary steps are taken. PMID- 29392106 TI - Environmental risk assessment of biocidal products: identification of relevant components and reliability of a component-based mixture assessment. AB - Background: Biocidal products are mixtures of one or more active substances (a.s.) and a broad range of formulation additives. There is regulatory guidance currently under development that will specify how the combined effects of the a.s. and any relevant formulation additives shall be considered in the environmental risk assessment of biocidal products. The default option is a component-based approach (CBA) by which the toxicity of the product is predicted from the toxicity of 'relevant' components using concentration addition. Hence, unequivocal and practicable criteria are required for identifying the 'relevant' components to ensure protectiveness of the CBA, while avoiding unnecessary workload resulting from including by default components that do not significantly contribute to the product toxicity. The present study evaluated a set of different criteria for identifying 'relevant' components using confidential information on the composition of 21 wood preservative products. Theoretical approaches were complemented by experimentally testing the aquatic toxicity of seven selected products. Results: For three of the seven tested products, the toxicity was underestimated for the most sensitive endpoint (green algae) by more than factor 2 if only the a.s. were considered in the CBA. This illustrated the necessity of including at least some additives along with the a.s. Considering additives that were deemed 'relevant' by the tentatively established criteria reduced the underestimation of toxicity for two of the three products. A lack of data for one specific additive was identified as the most likely reason for the remaining toxicity underestimation of the third product. In three other products, toxicity was overestimated by more than factor 2, while prediction and observation fitted well for the seventh product. Considering all additives in the prediction increased only the degree of overestimation. Conclusions: Supported by theoretical calculations and experimental verifications, the present study developed criteria for the identification of CBA-relevant components in a biocidal product. These criteria are based on existing criteria stated in the regulation for classification, labelling and packaging of substances. The CBA was found sufficiently protective and reliable for the tested products when applying the here recommended criteria. The lack of available aquatic toxicity data for some of the identified relevant components was the main reason for underestimation of product toxicity. PMID- 29392107 TI - In vivo MRI features of spinal muscles in the ovine model. AB - Muscle fatty infiltration (MFI) has been identified in patients with spinal pain using magnetic resonance imaging (MRI). Even though sheep are a commonly used animal model for the human spine, comparative sheep MFI data from MRI is not available. Determining MFI in sheep spinal muscles using acquisition protocols commonly used in man will identify the applicability of this approach in future sheep model studies, such that the effects of spinal interventions on muscle can be assessed prior to their use in a human (clinical) population. Therefore, the purpose of this study was to quantify ovine lumbar spine MFI using 3D 2-point Dixon and T1-weighted sequences. T1-weighted and Dixon lumbar spine axial sequences were collected in 14 healthy Austrian mountain sheep using a 1.5T MRI. At each vertebrae, the region of interest of psoas major and minor (PS), multifidus (M) and longissimus (L) were identified. To determine MFI from the T1 weighted images, mean pixel intensity (MPI) was calculated as a percentage of subcutaneous or intermuscular fat. For the Dixon images, fat sequence MPI was calculated as a percentage of the summed fat and water sequence MPIs. Spinal degeneration was graded and correlated to MFI. Dixon MFI was compared to T1 weighted MFI obtained from subcutaneous and intermuscular fat. For every muscle, T1-weighted MFI calculated using subcutaneous fat scored significantly lower than Dixon MFI and T1-weighted MFI calculated using intermuscular fat (p<0.001). There were no significant MFI differences between T1-weighted images calculated using intermuscular fat and Dixon images for M and L (p>0.05), although significant differences were found for PS. In sheep, Dixon sequences provide an acceptable comparison to T1-weighted sequences for lumbar extensor MFI based on intermuscular fat. However, compared to human literature, ovine lumbar musculature contains greater MFI, making interspecies comparisons more complex. PMID- 29392108 TI - Extracorporeal shock wave therapy for avulsion fractures of the sublime tubercle of the ulna in high school baseball players: A report of two cases. PMID- 29392109 TI - Clinical outcome of meniscus repair for isolated meniscus tear in athletes. AB - Objective: To examine the clinical and functional outcomes for a series of patients who underwent meniscal repair for isolated meniscal tears focusing the study population on athletes. Methods: This study represents a case series of 46 athletes who underwent repair of isolated meniscal lesions of the knee from 2010 to 2015. Cases of discoid meniscal lesions and combined ligament injuries were excluded. The mean age of the patients was 22.9 years ranging from 12 to 50 years. Arthroscopic inside-out repair was primarily a procedure of option. For repair of tears with degeneration and inferior vascularity, autogenous fibrin clot was implanted to the repair site for healing enhancement. The mean follow-up period of all patients was 19.8 +/- 6.8 months (range; 12 months-33 months). Results: In total, 37 of 46 patients (80%) could go back to their original sports activities. During the follow-up period, re-tear was encountered in 4 of 46 knees (8.7%). No significant differences in clinical/functional outcomes and re-tear rate were detected between the medial and lateral meniscal repairs. Conclusion: In our expanded repair indication for isolated meniscus repair for athletes, the rate of satisfactory return to sports was 91.3% in total (88.9% for the medial meniscus group; 92.9% for the lateral meniscus group). During the follow-up period ranging from 12 to 33 months (mean, 19.8 months), re-tear of the repaired site was encountered in 4 of the 46 knees (8.7%). PMID- 29392110 TI - Construct and criterion validity of the Malaysia version of Lower Extremity Functional Scale (LEFS). AB - Objective: The objective of this study is to translate the Lower Extremity Functional Scale (LEFS) into the Malay language and to validate the resulting version. Methods: A two-stage observational study was conducted. The LEFS was initially cross-culturally adapted to Malay language through double forward and backward translation. The finalized version of Malay LEFS (M-LEFS) was subsequently validated for both construct validity and criterion validity. Participants (n = 208) with normal lower limb condition and various lower limb conditions completed the M-LEFS. Results: Reliability of M-LEFS revealed excellent Cronbach's alpha value of 0.98. Construct validity, evaluated using exploratory factor analysis, exhibited good factor loadings (>0.6) of all 20 items. Interestingly, we extracted 2 components which was not reported elsewhere. With a cut-off point of 60, the sensitivity of the scale was 99% and the specificity was 81%. Conclusions: The M-LEFS had very good psychometric properties among the studied population. Further studies are needed to enhance these preliminary outcomes in Malaysia. PMID- 29392111 TI - Stress fracture of the second proximal phalanx of the foot in teenage athletes: Unrecognized location of stress fracture. AB - Background: Adolescent athletes are a high-risk population for stress fractures. We report four cases of stress fractures of the second proximal phalanx, which had not been previously diagnosed as the location of the stress fracture of the foot, in teenage athletes. Case report: All fractures were on the plantar side of the proximal phalangeal base, and the oblique images of the plain radiograph clearly depicted the fractures. Notably, three out of the four patients had histories of stress fracture of other locations. While three athletes with acute cases were able to make an early return to play with simple conservative management, the chronic case required surgical treatment for this rare injury. Conclusion: Although a rare injury, it is important that clinicians be aware of this type of stress fracture, as a timely diagnosis can avoid the need for surgical treatment and allow an early return to play. PMID- 29392112 TI - Social psychological aspects of ACL injury prevention and rehabilitation: An integrated model for behavioral adherence. AB - Managing rehabilitation for ACL injury is dependent on uptake of, and compliance with, medical and safety recommendations. In this paper, we propose a multi theory model that integrates self-determination theory and the theory of planned behavior to identify the motivational determinants ACL injury prevention and management behaviors and the processes involved. PMID- 29392113 TI - Femoral attachment of anterior cruciate ligament remnant tissue influences the stability of the anterior cruciate ligament-injured knee in patients over 40 years old. PMID- 29392114 TI - An Ecuadorian in Asia: Learn, live, laugh, share, SLARD-APKASS 2016. PMID- 29392115 TI - Dutch version of the Victorian Institute of Sports Assessment-Achilles questionnaire for Achilles tendinopathy: Reliability, validity and applicability to non-athletes. AB - AIM: To translate the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire into the Dutch language (VISA-A-NL), and to assess its reliability, validity, and applicability to non-athletes. METHODS: After translation according to a forward-backward protocol, 101 patients with complaints of Achilles tendinopathy were asked to fill out the VISA-A-NL at two time points together with visual analogue scale, the Foot and Ankle Outcome Score, and the Short Form 36 questionnaires. Reliability, internal consistency, construct validity, and content validity were tested. RESULTS: The VISA-A-NL showed high reliability (0.97, 95%CI: 0.95-0.98). Cronbach's alpha (internal consistency) was 0.80. It increased to 0.88 without activity domain. Correlation with other questionnaires was moderate or poorer. CONCLUSION: The VISA-A-NL proved to be an excellent evaluation instrument for the Dutch physician. If applied to non-athletes, using a modified score (questions 1-6) should be considered. PMID- 29392116 TI - Analysis of serum magnesium ions in dogs exposed to external stress: A pilot study. AB - Magnesium ions (Mg2+) are essential for various enzymatic reactions in the body associated with energy production and activation of the muscles and nerves. Mg2+ is also involved in blood pressure regulation, maintenance of body temperature, and glucose metabolism. Although various factors including foods and physical conditions have been reported to change serum Mg2+ status in humans, serum Mg2+ in dogs exposed to external stress has been unclear. In this study, we examined serum levels of Mg2+ in dogs at different conditions using the guide dog candidates for the blind. Serum Mg2+ was decreased in winter and increased in summer. Guide dog candidates in an elementary class of the training showed markedly lower levels of serum Mg2+, compared with that of dogs in an advanced class. When healthy adult dogs were subjected to forced exercise using a treadmill, a significant reduction in serum Mg2+ levels was observed, particularly in winter. These findings suggest that serum levels of Mg2+ may be influenced by weather fluctuation such as air temperature, nervousness in unaccustomed situations, age, and physical stress induced by exercise. The results indicate that Mg2+ supplementation should be considered for working dogs, dogs moving or traveling to a new environment, and dogs during winter. PMID- 29392117 TI - Long-term follow-up of surgical resection alone for primary intracranial rostrotentorial tumors in dogs: 29 cases (2002-2013). AB - Intracranial neoplasia is frequently encountered in dogs. After a presumptive diagnosis of intracranial neoplasia is established based on history, clinical signs and advanced imaging characteristics, the decision to treat and which treatment to choose must be considered. The objective of this study is to report survival times (ST) for dogs with intracranial meningiomas and gliomas treated with surgical resection alone (SRA), to identify potential prognostic factors affecting survival, and to compare the results with the available literature. Medical records of 29 dogs with histopathologic confirmation of intracranial meningiomas and gliomas treated with SRA were retrospectively reviewed. For each dog, signalment, clinical signs, imaging findings, type of surgery, treatment, histological evaluation, and ST were obtained. Twenty-nine dogs with a histological diagnosis who survived >7 days after surgery were included. There were 15 (52%) meningiomas and 14 (48%) gliomas. All tumors had a rostrotentorial location. At the time of the statistical analysis, only two dogs were alive. Median ST for meningiomas was 422 days (mean, 731 days; range, 10-2735 days). Median ST for gliomas was 66 days (mean, 117 days; range, 10-730 days). Kaplan Meier analysis indicated that ST was significantly longer for meningiomas than for gliomas (P<0.05). A negative correlation between the presence of a midline shift and ST (P=0.037) and ventricular compression and ST (P=0.038) was observed for meningiomas. For gliomas, there were no significant associations between ST and any of the variables evaluated. In conclusion, the results of this study suggest that, for dogs that survived >7 days postoperatively, SRA might be an appropriate treatment, particularly for meningiomas, when radiation therapy is not readily available. Also, the presence of midline shift and ventricular compression might be negative prognostic factors for dogs with meningiomas. PMID- 29392118 TI - The diagnostic activity on wild animals through the description of a model case report (caseous lymphadenitis by Corynebacterium pseudotuberculosis associated with Pasteurella spp and parasites infection in an alpine ibex - Capra ibex). AB - The diagnostic activity on wild animals implies a hard laboratory protocol where multiple disciplines, from biology to pathological anatomy until the biotechnological techniques, must be integrated to establish the causes of death. To demonstrate these concepts, the analytical approach adopted for an alpine ibex (Capra ibex) found dead in a mountain area of North Western Italy was described. The animal showed sub-costal and lymph nodes collections of green-yellow pus, fibrinous pleuropneumonia and catarrhal-hemorrhagic enteritis. Purulent process was ascribed to Corynebacterium pseudotuberculosis, the causative agent of caseous lymphadenitis or pseudotuberculosis, pleuropneumonia to Pasteurella multocida and Mannheimia haemolytica and enteritis to Mannheimia haemolytica. Parasitic bronchopneumonia in the caudal lobes of the lung, a severe enteric infestation by gastro-intestinal and pulmonary strongyles and coccidia were found. The cause of death in the studied ibex appeared to be a consequence of an association between various pathological processes, with bacteriological and parasitic etiology. PMID- 29392119 TI - Cloacal impaction with cloacolith in a black-legged seriema (Chunga burmeisteri). AB - A 5-year-old intact female black-legged seriema (Chunga burmeisteri) was presented for behavioral changes and slight decrease in activity (minor vocalization and less mobility in enclosure). Physical examination revealed a firm, moderate dilation in the caudal coelom. A semi-spherical mass of greater radiodensity than soft tissues was observed in the region of the cloaca on radiographs. A cloacolith measuring approximately 4x3.7x3 cm was extracted manually. Cloacoliths are uncommon conditions in birds, and this case is the first record of cloacolith in Chunga burmeisteri. PMID- 29392120 TI - Comparative Analysis of Wavelet-based Feature Extraction for Intramuscular EMG Signal Decomposition. AB - Background: Electromyographic (EMG) signal decomposition is the process by which an EMG signal is decomposed into its constituent motor unit potential trains (MUPTs). A major step in EMG decomposition is feature extraction in which each detected motor unit potential (MUP) is represented by a feature vector. As with any other pattern recognition system, feature extraction has a significant impact on the performance of a decomposition system. EMG decomposition has been studied well and several systems were proposed, but feature extraction step has not been investigated in detail. Objective: Several EMG signals were generated using a physiologically-based EMG signal simulation algorithm. For each signal, the firing patterns of motor units (MUs) provided by the simulator were used to extract MUPs of each MU. For feature extraction, different wavelet families including Daubechies (db), Symlets, Coiflets, bi-orthogonal, reverse bi orthogonal and discrete Meyer were investigated. Moreover, the possibility of reducing the dimensionality of MUP feature vector is explored in this work. The MUPs represented using wavelet-domain features are transformed into a new coordinate system using Principal Component Analysis (PCA). The features were evaluated regarding their capability in discriminating MUPs of individual MUs. Results: Extensive studies on different mother wavelet functions revealed that db2, coif1, sym5, bior2.2, bior4.4, and rbior2.2 are the best ones in differentiating MUPs of different MUs. The best results were achieved at the 4th detail coefficient. Overall, rbior2.2 outperformed all wavelet functions studied; nevertheless for EMG signals composed of more than 12 MUPTs, syms5 wavelet function is the best function. Applying PCA slightly enhanced the results. PMID- 29392121 TI - Incidental prostate cancer: a 10-year review of a tertiary center, Tehran, Iran. AB - Objective: Incidental prostate cancer (IPCa) is defined as a symptom-free cancer unexpectedly discovered upon microscopic examination of resected tissue. The aim of this study was to report the correlation between some specific clinical criteria in patients incidentally diagnosed with prostate cancer (PCa) during transurethral resection of the prostate (TURP) or open prostatectomy (OP) after clinically suspected benign prostatic hyperplasia. Patients and methods: This was a cross-sectional, retrospective study. Data were collected from Shohada-e Tajrish Hospital database during November 2006 to October 2016. Four hundred and twenty three men suffering from symptomatic benign prostatic hyperplasia who underwent either TURP or OP that provided a prostate specimen were evaluated. The data analysis was performed using Pearson correlation test and independent t-test using SPSS version 20 software. Results: The mean age of subjects was 68.74+/ 9.87 years old (45-93 years). The mean prostate specific antigen (PSA) level was 21.47+/-13.44 ng/mL (0.6-47.1 ng/mL). Results showed that 84 patients (19.9%) had PCa (40 patients who underwent TURP [12.6%] and 44 patients who underwent OP [40.7%] groups). Cut-off point of PSA for detecting IPCa was 3.8 ng/mL in our study, and this showed sensitivity, specificity, negative predictive value, and positive predictive value of 26.08%, 100%, 100%, and 29.79%, respectively. Twenty two patients with cancer had a positive family history for PCa; thus, a significant relationship between familial history of PCa and its occurrence was shown (p=0.0001). Conclusion: According to the results of this study, the cut-off point for PSA levels in detecting PCa was 3.8 ng/mL, which is similar to that reported by other studies. Familial history of PCa and PSA levels were two predictors in determining the PCa. PMID- 29392122 TI - Liver resection versus radiofrequency ablation for hepatitis B virus-related small hepatocellular carcinoma. AB - Background: To compare the outcomes of liver resection (LR) with radiofrequency ablation (RFA) for patients with hepatitis B virus (HBV)-related small hepatocellular carcinoma (HCC). Methods: A total of 122 HBV-related small HCC patients who underwent LR (n=64) or RFA (n=58) were involved in this retrospective study. Their basic clinical data, postoperative complications, survival outcomes, and prognostic factors were compared and analyzed. Results: Patients in the LR group had more serious complications (11 versus 0) and longer postoperative hospital stays (11.3 versus 6.0 days) than those in the RFA group (all P<0.05). LR was associated with better recurrence-free survival (RFS) rates at 1, 3, and 5 years compared with RFA (90.4%, 65.9%, and 49.5% versus 79.3%, 50.3%, and 35.6%, P=0.037), but there was no significant difference in overall survival (OS) (95.2%, 78.1%, 58.6% versus 93.1%, 71.3%, 52.9%, P=0.309). Multivariate Cox analysis showed that the hepatic cirrhosis (hazard ratio [HR]: 2.13), tumor number (HR: 3.73), tumor diameter (HR: 1.92), and postoperative anti HBV therapy (HR: 0.53) had predictive values for RFS, and the latter three (HR: 4.34, 2.30, and 0.44) were independent predictors of OS (all P<0.05). Conclusion: LR might be considered the preferred method for patients with HBV-related small HCC, while RFA could apply to selective cases. Anti-HBV therapy after treatment was recommended. PMID- 29392124 TI - Reviewers do matter. PMID- 29392123 TI - Phase II trial of SOM230 (pasireotide LAR) in patients with unresectable hepatocellular carcinoma. AB - Background: A phase II trial of pasireotide was performed to assess its efficacy and safety in advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods: Patients with advanced HCC and Child-Pugh score <=7 received pasireotide LAR 60 mg intramuscularly every 28 days. Primary endpoint was disease control rate. Secondary endpoints were time to tumor progression, response rate, treatment-related adverse events, and overall survival. Serum insulin growth factor-1 was measured before and after pasireotide. Results: Twenty patients were treated and evaluable. Eighteen patients (90%) had prior therapy; 16 patients (80%) had multiple therapies. Median age was 65, 75% had Barcelona Clinic Liver Cancer stage C, and 55% had metastatic disease. The main toxicity was hyperglycemia. Rare adverse effects included reversible grade 4 elevation in alanina transaminase/aspartate transaminase in one patient. The best response was stable disease in 9 patients (45%). Median time to tumor progression for the 20 patients was 3 months, and median survival was 9 months. Conclusion: Pasireotide had limited clinical benefit as second-line or third-line treatment in patients with advanced or metastatic HCC. Low baseline insulin growth factor-1 level may be indicative when SOM230 treatment may be ineffective, and decreasing levels after treatment may be indicative of disease control. PMID- 29392125 TI - Detailed Histologic Evaluation of Eosinophilic Esophagitis in Pediatric Patients Presenting with Dysphagia or Abdominal Pain and Comparison of the Histology between the Two Groups. AB - EoE in children presents with four main symptoms. Most common symptoms exhibited by our clinic population are dysphagia (D) and abdominal pain (AP). Despite similar treatments, we found in an earlier study that the outcomes between these two groups were different. Therefore, we investigated if there exist any histological differences between these groups that could further our knowledge of EoE. Aim. To compare esophageal histology in detail, apart from the eosinophil count, between EoE-D and EoE-AP. Method. Biopsies of patients with EoE-D and EoE AP were reevaluated for 10 additional histological criteria, in addition to the eosinophil count. Results. Both groups had 67 patients; peak mean eosinophil was 33.9 and 31.55 for EoE-D and EoE-AP (p < 0.05). Eosinophilic microabscesses, superficial layering of eosinophils, and epithelial desquamation were twice as common and significant in EoE-D group than EoE-AP. Eosinophil distribution around rete pegs was also significantly higher in EoE-D group. The remaining criteria were numerically higher in EoE-D, but not significant, with the exception of rete peg elongation. Conclusion. EoE-D patients have significantly higher eosinophils compared to EoE-AP, and the level of inflammation as seen from eosinophil microabscesses, superficial layering, desquamation, and the distribution around rete pegs is significantly higher. PMID- 29392126 TI - Helicobacter pylori Pathogenicity Factors Related to Gastric Cancer. AB - Background: Although the causal relationship between Helicobacter pylori infection and the development of gastric cancer is firmly established, the exact nature of the pathogenicity factors of H. pylori that predispose to gastric oncogenesis remains incompletely characterized. We investigated the association between H. pylori virulence genotypes and disease in a well-characterized cohort consisting of 109 H. pylori isolates from gastric biopsies originating from patients. Methods: The prevalence of genotype was assessed by PCR and related to clinical histopathological parameters. Results: The relation of babA2 and babB negative and iceA1 positive genotype as a single genotype and the development of cases to GC was statistically significant (P < 0.001). The cagE, cagA, and iceA1 were found more commonly in patients with GC as compared with the other groups. The relation of the presence of iceA1 and the development of cases to GC was statistically significant (P = 0.008), but babA2 and babB alleles were not detected in these patients. These apparent negative associations were still statically significant (P = 0 and 0.005). Conclusion: Our results show an elevated prevalence of infection with H. pylori strains carrying known virulence genotypes with high genetic diversity. This highlights the importance of identifying gene variants for an early detection of virulent genotypes. PMID- 29392127 TI - Epidemiology of Respiratory Pathogens among Elderly Nursing Home Residents with Acute Respiratory Infections in Corsica, France, 2013-2017. AB - Background: The current study aims to describe the demographical and clinical characteristics of elderly nursing home (NH) residents with acute respiratory infections (ARIs) during four winter seasons (2013/2014-2016/2017), as well as the microbiological etiology of these infections. Methods: Seventeen NHs with at least one ARI resident in Corsica, France, were included. An ARI resident was defined as a resident developing a sudden onset of any constitutional symptoms in addition to any respiratory signs. Nasopharyngeal swabs from ARI residents were screened for the presence of 21 respiratory agents, including seasonal influenza viruses. Results: Of the 107 ARI residents enrolled from NHs, 61 (57%) were positive for at least one of the 21 respiratory pathogens. Forty-one (38.3%) of the 107 ARI residents had influenza: 38 (92%) were positive for influenza A (100% A(H3N2)) and three (8%) for influenza B/Victoria. Axillary fever (>=38 degrees C) was significantly more common among patients infected with influenza A(H3N2). Conclusion: The circulation of seasonal respiratory viruses other than influenza A(H3N2) seems to be sporadic among elderly NH residents. Investigating the circulation of respiratory viruses in nonwinter seasons seems to be important in order to understand better the dynamic of their year-round circulation in NHs. PMID- 29392128 TI - Effect of Airborne Particle Abrasion on Microtensile Bond Strength of Total-Etch Adhesives to Human Dentin. AB - Aim of this study was to investigate a specific airborne particle abrasion pretreatment on dentin and its effects on microtensile bond strengths of four commercial total-etch adhesives. Midcoronal occlusal dentin of extracted human molars was used. Teeth were randomly assigned to 4 groups according to the adhesive system used: OptiBond FL (FL), OptiBond Solo Plus (SO), Prime & Bond (PB), and Riva Bond LC (RB). Specimens from each group were further divided into two subgroups: control specimens were treated with adhesive procedures; abraded specimens were pretreated with airborne particle abrasion using 50 MUm Al2O3 before adhesion. After bonding procedures, composite crowns were incrementally built up. Specimens were sectioned perpendicular to adhesive interface to produce multiple beams, which were tested under tension until failure. Data were statistically analysed. Failure mode analysis was performed. Overall comparison showed significant increase in bond strength (p < 0.001) between abraded and no abraded specimens, independently of brand. Intrabrand comparison showed statistical increase when abraded specimens were tested compared to no-abraded ones, with the exception of PB that did not show such difference. Distribution of failure mode was relatively uniform among all subgroups. Surface treatment by airborne particle abrasion with Al2O3 particles can increase the bond strength of total-etch adhesives. PMID- 29392129 TI - Analysis of the Metabolites of Indole Degraded by an Isolated Acinetobacter pittii L1. AB - Indole and its derivatives are typical nitrogen heterocyclic compounds and have been of immense concern since they are known for the risk of their toxic, recalcitrant, and carcinogenic properties for human and ecological environment. In this study, a Gram-negative bacterial strain of eliminating indole was isolated from a coking wastewater. The strain was confirmed as Acinetobacter pittii L1 based on the physiological and biochemical characterization and 16S ribosomal DNA (rDNA) gene sequence homology. 400 mg/L indole could be completely removed within 48 h by the strain on the optimum condition of 37 degrees C, pH 7.4, and 150 rpm. The organic nitrogen was converted to NH3-N and then to NO3- and the organic carbon was partially transferred to CO2 during the indole biodegradation. The metabolic pathways were proposed to explain the indole degradation based on the liquid chromatography tandem mass spectrometry (LC MS/MS) analysis of indigo, 4-(3-Hydroxy-1H-pyrrol-2-yl)-2-oxo-but-3-enoic acid, and isatin. The toxicity of the biodegradation products was evaluated using the Microtox test, which revealed that the metabolites were more toxic than indole. Our research holds promise for the potential application of Acinetobacter pittii L1 for NHCs degradation, production of indigoids, and soil remediation as well as treatment of indole containing wastewater. PMID- 29392130 TI - Curcuma longa Is Able to Induce Apoptotic Cell Death of Pterygium-Derived Human Keratinocytes. AB - Pterygium is a relatively common eye disease that can display an aggressive clinical behaviour. To evaluate the in vitro effects of Curcuma longa on human pterygium-derived keratinocytes, specimens of pterygium from 20 patients undergoing pterygium surgical excision were collected. Pterygium explants were put into culture and derived keratinocytes were treated with an alcoholic extract of 1.3% Curcuma longa in 0.001% Benzalkonium Chloride for 3, 6, and 24 h. Cultured cells were examined for CAM5.2 (anti-cytokeratin antibody) and CD140 (anti-fibroblast transmembrane glycoprotein antibody) expression between 3th and 16th passage to assess cell homogeneity. TUNEL technique and Annexin-V/PI staining in flow cytometry were used to detect keratinocyte apoptosis. We showed that Curcuma longa exerts a proapoptotic effect on pterygium-derived keratinocytes already after 3 h treatment. Moreover, after 24 h treatment, Curcuma longa induces a significant increase in TUNEL as well as Annexin-V/PI positive cells in comparison to untreated samples. Our study confirms previous observations highlighting the expression, in pterygium keratinocytes, of nuclear VEGF and gives evidence for the first time to the expression of nuclear and cytoplasmic VEGF-R1. All in all, these findings suggest that Curcuma longa could have some therapeutic potential in the treatment and prevention of human pterygium. PMID- 29392131 TI - Foveal Avascular Zone in Normal Tension Glaucoma Measured by Optical Coherence Tomography Angiography. AB - Aim: To measure diameter of foveal avascular zone (FAZ), FAZ area, and vessel density using Optical Coherence Tomography Angiography (OCT-A) in patients with normal tension glaucoma (NTG) and to establish the possible role of OCT-A in diagnosis and follow-up of patients with NTG. Methods: Twenty-one eyes of 21 patients with NTG and 30 eyes of 30 healthy subjects underwent complete ophthalmic examination as well as OCT-A on ZEISS AngioPlex. 3 * 3 macula scans were used to measure vertical, horizontal, and maximum diameter of FAZ by two graders. Mean values and interobserver variability were analyzed. Image J was used for analysis of FAZ area and vessel density. Results: Mean vertical diameter (t = 5.58, p < 0.001), horizontal diameter (t = 3.59, p < 0.001), maximum diameter (t = 5.94, p < 0.001), and FAZ area (t = 5.76, p < 0.001) were statistically significantly enlarged in the NTG group compared to those in the control group. Vessel density (t = -5.80, p < 0.001) was statistically significantly decreased in the NTG group compared to that in the control group. Conclusion: OCT-A could have an important role in the future in diagnosis of patients with NTG. In patients with NTG, there is larger FAZ area, while the vessel density is reduced in comparison to the control group. PMID- 29392132 TI - Antimicrobial Natural Product Berberine Is Efficacious for the Treatment of Atrial Fibrillation. AB - The purpose of this study is to test the efficacy of bioactive natural product berberine in the treatment of patients with atrial fibrillation (AF). Data of 45 paroxysmal AF patients treated with berberine and 43 age, gender, New York Heart Association functional classification score, and concomitant cardiovascular disease matched patients treated with amiodarone were analyzed retrospectively to examine conversion rate, average conversion time, average heart rate, and echocardiographic parameters. There was no statistical difference between berberine and amiodarone on conversion rate or echocardiographic parameters. Berberine treatment showed a significantly longer average time to conversion and higher heart rate during sinus rhythm (SR) than amiodarone. Echocardiographic parameters showed that E/A ratio and left atrial diameter were significantly improved after 6- and 12-month berberine treatment, but only E/A ratio improved significantly at the same time points after amiodarone treatment. This is the first report to specifically compare efficacy of berberine and amiodarone in the treatment of patients with AF. We find that berberine and amiodarone are equally effective for conversion of AF and maintenance of normal SR. PMID- 29392133 TI - Shape Optimization of Bone-Bonding Subperiosteal Devices with Finite Element Analysis. AB - Subperiosteal bone-bonding devices have been proposed for less invasive treatments in orthodontics. The device is osseointegrated onto a bone surface without fixation screws and is expected to rapidly attain a bone-bonding strength that successfully meets clinical performance. Hence, the device's optimum shape for rapid and strong bone bonding was examined in this study by finite element analyses. First, a stress analysis was performed for a circular rod device with an orthodontic force parallel to the bone surface, and the estimate of the bone bonding strength based on the bone fracture criterion was verified with the results of an animal experiment. In total, four cross-sectional rod geometries were investigated: circular (Cr), elliptical (El), semicircular (Sc), and rectangular (Rc). By changing the height of the newly formed bone to mimic the progression of new bone formation, the estimation of the bone-bonding strength was repeated for each geometry. The rod with the Rc cross section exhibited the best performance, followed by those with the Sc, El, and Cr cross sections, from the aspects of the rapid acquisition of strength and the strength itself. Thus, the rectangular cross section is the best for rod-like subperiosteal devices for rapid bone bonding. PMID- 29392135 TI - miRNAs in Prediction of Prognosis in Clear Cell Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) is the most common type of urinary malignancy. Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, accounting for 70-80% of RCC. In recent years, miRNAs have been found to be closely associated with the outcome of the patients with ccRCC. In this review, we summarize recent advances in research exploring the role of miRNAs in predicting prognosis in patients with ccRCC. PMID- 29392134 TI - The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis. AB - Objective: To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion. Methods: In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria. Results: The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; P = 0.001; I2, 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups. Conclusion: Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion. PMID- 29392136 TI - Angiotensin Converting Enzyme Inhibitory and Antioxidant Activities of Enzymatic Hydrolysates of Korean Native Cattle (Hanwoo) Myofibrillar Protein. AB - The purpose of this study was to determine the angiotensin converting enzyme (ACE) inhibitory and antioxidant activities of myofibrillar protein hydrolysates (HMPHs) of different molecular weights (<3 and <10 kDa) derived from Korean native cattle (Hanwoo breed) using a commercially available and inexpensive enzyme (Alkaline-AK). HMPH of both tested molecular weights had ACE inhibitory activity. Among the antioxidant activities, iron chelation and nitrite scavenging activities were higher in low-molecular-weight peptide of HMPH (<3 kDa), whereas 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was higher in high-molecular-weight peptide of HMPH (<10 kDa). HMPH did not induce cytotoxicity in RAW 264.7 cells at concentrations of 5-20 mg/mL. These results indicate that HMPH can be cheaply produced using Alkaline-AK and applied as a potential ACE inhibitor and antioxidant. PMID- 29392137 TI - Corpuls CPR Generates Higher Mean Arterial Pressure Than LUCAS II in a Pig Model of Cardiac Arrest. AB - According to the European Resuscitation Council guidelines, the use of mechanical chest compression devices is a reasonable alternative in situations where manual chest compression is impractical or compromises provider safety. The aim of this study is to compare the performance of a recently developed chest compression device (Corpuls CPR) with an established system (LUCAS II) in a pig model. Methods. Pigs (n = 5/group) in provoked ventricular fibrillation were left untreated for 5 minutes, after which 15 min of cardiopulmonary resuscitation was performed with chest compressions. After 15 min, defibrillation was performed every 2 min if necessary, and up to 3 doses of adrenaline were given. If there was no return of spontaneous circulation after 25 min, the experiment was terminated. Coronary perfusion pressure, carotid blood flow, end-expiratory CO2, regional oxygen saturation by near infrared spectroscopy, blood gas, and local organ perfusion with fluorescent labelled microspheres were measured at baseline and during resuscitation. Results. Animals treated with Corpuls CPR had significantly higher mean arterial pressures during resuscitation, along with a detectable trend of greater carotid blood flow and organ perfusion. Conclusion. Chest compressions with the Corpuls CPR device generated significantly higher mean arterial pressures than compressions performed with the LUCAS II device. PMID- 29392138 TI - Optimization, Purification, and Starch Stain Wash Application of Two New alpha Amylases Extracted from Leaves and Stems of Pergularia tomentosa. AB - A continuous research is attempted to fulfil the highest industrial demands of natural amylases presenting special properties. New alpha-amylases extracted from stems and leaves of Pergularia tomentosa, which is widespread and growing spontaneously in Tunisia, were studied by the means of their activities optimization and purification. Some similarities were recorded for the two identified enzymes: (i) the highest amylase activity showed a promoted thermal stability at 50 degrees C; (ii) the starch substrate at 1% enhanced the enzyme activity; (iii) the two alpha-amylases seem to be calcium-independent; (iv) Zn2+, Cu2+, and Ag2+ were considered as important inhibitors of the enzyme activity. Following the increased gradient of elution on Mono Q-Sepharose column, an increase in the specific activity of 11.82-fold and 10.92-fold was recorded, respectively, for leaves and stems with the presence of different peaks on the purification profiles. Pergularia amylases activities were stable and compatible with the tested commercial detergents. The combination of plant amylase and detergent allowed us to enhance the wash performance with an increase of 35.24 and 42.56%, respectively, for stems and leaves amylases. Characterized amylases were reported to have a promoted potential for their implication notably in detergent industry as well as biotechnological sector. PMID- 29392139 TI - Integrative Analysis of miRNA and mRNA Expression Profiles in Calcium Oxalate Nephrolithiasis Rat Model. AB - The microRNA (miRNA) expression profiles and their biological functions in calcium oxalate nephrolithiasis remain unclear. In this study, we investigate the miRNA and mRNA expression profiles of kidney tissues in calcium oxalate stone rats. 16 Sprague Dawley rats were divided into control group and stone-forming group. 24-hour urine samples and kidney tissues were collected for biochemical and histological determination after 4 weeks. MiRNA and mRNA microarray were applied to evaluate the miRNA and mRNA expression profiles. To validate the microarray results, the quantitative real-time PCR (qRT-PCR) was performed. A total of 38 miRNAs and 2728 mRNAs were significantly and differentially expressed in kidney tissues of stone-forming group versus control group. Gene Ontology (GO) analysis revealed that most of the target genes were enriched in terms of oxidation reduction, ion transport, inflammatory response, and response to wounding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these targets highlights their critical role in cytokine-cytokine receptor interaction, gap junction, and chemokine signaling pathway. Furthermore, the reliability of the microarray-based results was confirmed by using qRT-PCR determination. The miRNA and mRNA expressions in calcium oxalate stone rat kidneys might provide a basis for further research on urolithiasis mechanism. PMID- 29392141 TI - Comparison between the HLA-B*58 : 01 Allele and Single-Nucleotide Polymorphisms in Chromosome 6 for Prediction of Allopurinol-Induced Severe Cutaneous Adverse Reactions. AB - Severe cutaneous adverse drug reactions (SCARs) are life-threatening reactions. The strong association between the HLA-B*58 : 01 allele and allopurinol-induced SCARs is well recognized. Screening for HLA-B*58 : 01 allele before prescribing allopurinol in some populations has been recommended. Several single-nucleotide polymorphisms (SNPs) in chromosome 6 have been found to be tightly linked with the HLA allele, and these SNPs have been proposed as surrogate markers of the HLA B*58 : 01 allele. This study aimed to evaluate the association between three SNPs in chromosome 6 and allopurinol-induced SCARs in a Thai population. The linkage disequilibrium between the HLA-B*58 : 01 allele and these SNPs was also evaluated. Results showed that three SNPs including rs9263726, rs2734583, and rs3099844 were significantly associated with allopurinol-induced SCARs but with a lower degree of association when compared with the HLA-B*58 : 01 allele. The sensitivity, specificity, PPV, and NPV of these SNPs were comparable to those of the HLA-B*58 : 01 allele. Although detection of the SNP is simpler and less expensive compared with that of the HLA-B*58 : 01 allele, these SNPs were not perfectly linked with the HLA-B*58 : 01 allele. Screening using these SNPs as surrogate markers of the HLA-B*58 : 01 allele to avoid SCARs prior to allopurinol administration needs caution because of their imperfect linkage with the HLA-B*58 : 01 allele. PMID- 29392142 TI - Hydroxychloroquine Use in Lupus Patients during Pregnancy Is Associated with Longer Pregnancy Duration in Preterm Births. AB - Objective: To investigate the effect of hydroxychloroquine (HCQ) in pregnant women with systemic lupus erythematosus (SLE). Methods: In SLE pregnancies of a single Dutch center (2000-2015), lupus activity and flares before and during pregnancy and postpartum were assessed using the SLE Disease Activity Index (SLEDAI)/SLEPDAI (SLEDAI adjusted for pregnancy). The association between HCQ use and pregnancy outcomes (early spontaneous abortion, fetal death, and preterm and term live birth) was analyzed using generalized estimating equations (GEE) accounting for the occurrence of multiple pregnancies per patient. Analyses were adjusted for antiphospholipid antibody (aPL) status. Results: 110 pregnancies (63 mostly Caucasian patients) were included, of which, in 30, HCQ was used; overall occurrence of flares was low (non-HCQ group: 5 mild (6.4%) and 2 severe (2.6%); HCQ group: 2 mild (6.7%) and no severe flares). The HCQ group showed a trend towards lower dosage of prednisone (OR 0.2 (95% CI 0.0-1.4); p = 0.10). Pregnancy outcomes were comparable between groups. Among preterm live births, pregnancy duration was significantly longer in HCQ users (2.4 weeks (95% CI 1.0-3.8; p <= 0.001)). Conclusion: HCQ use was associated with longer pregnancy duration in the vulnerable preterm birth population, underscoring the beneficial effect of HCQ use during pregnancy. PMID- 29392140 TI - A Fatty Acids Mixture Reduces Anxiety-Like Behaviors in Infant Rats Mediated by GABAA Receptors. AB - Fatty acids (C6-C18) found in human amniotic fluid, colostrum, and maternal milk reduce behavioral indicators of experimental anxiety in adult Wistar rats. Unknown, however, is whether the anxiolytic-like effects of fatty acids provide a natural mechanism against anxiety in young offspring. The present study assessed the anxiolytic-like effect of a mixture of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, and linoleic acid in Wistar rats on postnatal day 28. Infant rats were subjected to the elevated plus maze, defensive burying test, and locomotor activity test. Diazepam was used as a reference anxiolytic drug. A group that was pretreated with picrotoxin was used to explore the participation of gamma-aminobutyric acid-A (GABAA) receptors in the anxiolytic-like effects. Similar to diazepam, the fatty acid mixture significantly increased the frequency of entries into and time spent on the open arms of the elevated plus maze and decreased burying behavior in the defensive burying test, without producing significant changes in spontaneous locomotor activity. These anxiolytic-like effects were blocked by picrotoxin. Results suggest that these fatty acids that are contained in maternal fluid may reduce anxiety-like behavior by modulating GABAergic neurotransmission in infant 28-day old rats. PMID- 29392144 TI - Serum Vitamin A Levels in Patients with Chalazion. AB - Chalazion is a chronic, localized lipogranulomatous inflammation of the sebaceous glands of the lids. Chalazion occurs often secondary to blockage of the sebaceous gland ducts. Some studies have reported vitamin A deficiency as a risk factor for chalazion. In this study, we determined the serum levels of vitamin A in patients with chalazion. The study involved a total of 107 subjects (52 patients with chalazion and 55 control healthy subjects). The study was conducted at the Ophthalmology Clinics of Imam Khomeini Hospital, Ahwaz Jundishapur University of Medical Sciences, Ahwaz, Iran between September 2014 and February 2015. The subjects were divided into three groups according to age: 7-12 years old, 13-19 years old, and more than 19 years old. Patients were further divided into four subgroups based on the type of chalazion: single, multiple, primary, and recurrent. Blood samples were collected and the serum was tested for levels of vitamin A using high-performance liquid chromatography (HPLC). The average serum vitamin A levels in patients with chalazion in the age groups of 7-12 and 13-19 years were significantly lower than in their control counterparts. Serum vitamin A levels in patients with recurrent, multiple chalazia were significantly lower than in patients with primary, multiple chalazia (P = 0.026) and patients with a recurrent, single chalazion (P = 0.029). In conclusion, chalazion could be one of the ocular presentations of vitamin A deficiency. PMID- 29392143 TI - Antibodies against Pneumococcal Capsular Polysaccharides and Natural Anti Galactosyl (Alpha-Gal) in Patients with Humoral Immunodeficiencies. AB - Humoral deficiencies represent a broad group of disorders. The aim of the study was to compare the levels of antibodies against pneumococcal capsular polysaccharides (anti-PCP) and natural anti-galactosyl (anti-Gal) antibodies in (1) patients with chronic lymphocytic leukaemia (CLL), (2) patients with common variable immunodeficiency (CVID), and (3) a healthy population and to explore their diagnostic and prognostic potential. Serum immunoglobulin levels and levels of anti-Gal IgG, IgA, and IgM and anti-PCP IgG and IgG2 were determined in 59 CLL patients, 30 CVID patients, and 67 healthy controls. Levels of IgG, IgA, IgM, anti-Gal IgA, anti-Gal IgM, and anti-PCP IgA were lower in CLL and CVID patients than in healthy controls (p value for all parameters < 0.0001). Decrease in the levels of IgA, IgM, anti-Gal IgA, and anti-PCP IgA was less pronounced in the CLL group than in the CVID group. IgA decline, anti-Gal IgA, anti-PCP IgA, and anti PCP IgG2 were negatively correlated with CLL stage. We devise the evaluation of anti-Gal antibodies to be a routine test in humoral immunodeficiency diagnostics, even in cases of immunoglobulin substitution therapy. Significant reductions, mainly in anti-Gal IgA, IgM, and anti-PCP IgA levels, may have prognostic importance in CLL patients. PMID- 29392145 TI - Comparison of Intravitreal Bevacizumab and Intravitreal Diclofenac in the Treatment of Diabetic Macular Edema: a 6-month Follow-up. AB - The aim of this study was to compare the effect of intravitreal diclofenac, a non steroidal anti-inflammatory drug (NSAID), with that of bevacizumab, a well-known anti-vascular endothelial growth factor (VEGF) drug, in the treatment of diabetic macular edema (DME). Diclofenac was chosen in this study because it has both features of NSAIDs and corticosteroids by inhibiting the cyclooxygenase (COX) and lipoxygenase pathways, respectively. In this non-randomized comparative interventional case series, 64 eyes from 32 patients with bilateral naive DME were selected and every eye was randomly assigned to intravitreal injection of bevacizumab (IVB) or diclofenac (IVD). After exclusion of some patients because of short follow-up duration or less than two intravitreal injections, finally, 52 eyes from 26 patients were analyzed. Of those, 26 eyes received 500 ug/0.1 mL IVD and 26 eyes received 1.25 mg IVB. After 6 months of follow-up, the results indicated that visual acuity was significantly improved from 0.50 +/- 0.13 in IVB and 0.52 +/- 0.12 LogMAR in IVD at baseline to 0.2 +/- 0.1 and 0.29 +/- 0.07, respectively. Central macular thickness (CMT) and macular volume were measured based on spectral-domain optical coherence tomography (OCT) at month 1, 3, and 6. Both groups showed a significant reduction in CMT and macular volume from baseline but there was no significant difference between the IVB and IVD groups. Interestingly, IVD, but not IVB, decreased intraocular pressure (IOP), which is a desirable effect. There was no serious complication due to injections. This study sheds light into the long-term effects of NSAIDs and may support the idea that inflammation suppression by NSAIDs may have the same results as anti-VEGF administration. PMID- 29392147 TI - Measurement of the Inner Retinal Layers of Megalopapilla by Optical Coherence Tomography. AB - The main purpose of this study was to assess the differences in the peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses between subjects with megalopapilla (MP) and those with large (physiological) cup discs (LCD) measured by spectral-domain optical coherence tomography. The secondary purpose was to determine whether pRNFL and GCIPL thicknesses increase with the optic nerve head (ONH) area. This cross-sectional study included 184 eyes (92 eyes with MP and 92 eyes with LCD). The subjects with LCD were used as sex-and-age-matched controls. All subjects were imaged using the Cirrus HD-OCT system. Macula and pRNFL thickness maps were obtained for all subjects. The inferior quadrant pRNFL thickness was higher in the MP group than in the LCD group (P < 0.05). There were no differences in the GCIPL thickness between the two groups. A positive correlation was found between average, superior, and inferior quadrant pRNFL thicknesses and the ONH area (P < 0.05). The slope of the correlation curve was higher for the inferior quadrant. No correlation was found between the GCIPL thickness and the ONH area. In comparison to patients with LCD, the inferior quadrant pRNFL thickness of patients with MP was higher. As the ONH area increased, the average, superior, and inferior quadrant pRNFL thicknesses also increased. In patients with MP, the assessment of a glaucomatous lesion based on pRNFL thickness measurements may not be reliable. It is recommended that in these patients, the evaluation of glaucomatous damage be based on the GCIPL thickness map analysis rather than on the pRNFL thickness. PMID- 29392146 TI - Single-dose Intravitreal Bevacizumab after Complete Panretinal Photocoagulation in Proliferative Diabetic Retinopathy: an Effective Adjunctive Treatment. AB - Patients with proliferative diabetic retinopathy (PDR) who are refractory to complete panretinal photocoagulation (PRP) have a high risk of severe vision loss. The aim of this study was to evaluate the effectiveness of single-dose intravitreal bevacizumab (IVB) after complete PRP in patients with refractory PDR. Patients with retinal neovascularization (NV) secondary to diabetes mellitus and refractory to complete PRP were enrolled in this study. All patients received a single dose of 1.25 mg IVB at 3 months after completing the PRP. Patients underwent complete ophthalmic evaluation and fluorescein angiography (FA) at baseline and 1 month after injection. The main outcome measure was a reduction in the areas of leakage (mm2) on FA. All patients were evaluated at baseline and on every visit at 1 day, 1 week, and 1 month after the injection. A total of 21 consecutive patients (32 eyes) with PDR completed this study. Thirteen (61.9%) patients were female. The mean +/- standard deviation (SD) age was 64.1 +/- 5.6 years. Complete and partial response of angiographic leakage of NV was noted in 7 (21.9%) and 18 (56.2%) of 32 eyes after a single IVB injection, respectively. No satisfactory response of retinal NV was observed in 7 eyes (21.9%) at 1 month after the injection. No significant ocular or systemic adverse events were observed. A single-dose of IVB could be associated with a satisfactory response of retinal NV, secondary to PDR, in patients who are refractory to complete PRP. PMID- 29392148 TI - The Relationship of Body Mass Index and Blood Pressure with Corneal Biomechanical Parameters in Healthy Subjects. AB - This study aimed to assess the possible relationship of body mass index (BMI) and blood pressure (BP) with corneal biomechanical parameters in healthy subjects. The study included 88 eyes of 88 healthy subjects aged 20-40 years. After a thorough medical history, a digital sphygmomanometer was used to measure the systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, several hematological and biochemical parameters were determined to assess general health. Prior the ophthalmic examination, the body height and weight were measured; then, the BMI was calculated. Finally, after comprehensive ophthalmic examination, all cases were evaluated with Pentacam (Oculus) in order to rule out corneal ectasia; then, the corneal biomechanical parameters of all individuals were measured using the Scheimpflug-based Corvis ST (Oculus Optikgerate GmbH, Wetzlar, Germany). If the measurements of the hematological and biochemical parameters were within normal range, the results of the Corvis ST, BMI, and BP were included in the analysis carried out with SPSS software. The mean (+/- standard deviation [SD]) BMI, SBP, DBP, intraocular pressure (IOP), central corneal thickness (CCT), deformation amplitude, radius, and peak distance was 27.24 +/- 4.80 kg/m2, 116.47 +/- 11.21 mmHg, 80.51 +/- 5.68 mmHg, 15.10 +/- 1.70 mmHg, 533.10 +/- 30.97 micrometer, 1.03 +/- 0.11 mm, 7.51 +/- 0.86 mm, and 5.03 +/- 0.30 mm, respectively. Results showed no significant difference in IOP, CCT, peak distance, radius, and deformation amplitude between different BMI subcategories defined by World Health Organization (all P > 0.05). The results of the Corvis ST showed that corneal biomechanical parameters had no significant correlation with BMI, SBP, and DBP in three subgroups of BMI and all participants (all P > 0.05) but the results showed a positive correlation between CCT and IOP (P < 0.001, r = 0.504) in all participants. CCT and IOP had no correlation with BMI, SBP, and DBP (P > 0.05). This study showed that BMI and BP had no correlation with corneal biomechanical parameters in healthy subjects using the Corvis ST. PMID- 29392149 TI - Comparison of Matrix Frequency-Doubling Technology (FDT) Perimetry with the SWEDISH Interactive Thresholding Algorithm (SITA) Standard Automated Perimetry (SAP) in Mild Glaucoma. AB - This study aimed to compare second-generation frequency-doubling technology (FDT) perimetry with standard automated perimetry (SAP) in mild glaucoma. Forty-seven eyes of 47 participants who had mild visual field defect by SAP were included in this study. All participants were examined using SITA 24-2 (SITA-SAP) and matrix 24-2 (Matrix-FDT). The correlations of global indices and the number of defects on pattern deviation (PD) plots were determined. Agreement between two sets regarding the stage of visual field damage was assessed. Pearson's correlation, intra-cluster comparison, paired t-test, and 95% limit of agreement were calculated. Although there was no significant difference between global indices, the agreement between the two devices regarding the global indices was weak (the limit of agreement for mean deviation was -6.08 to 6.08 and that for pattern standard deviation was -4.42 to 3.42). The agreement between SITA-SAP and Matrix FDT regarding the Glaucoma Hemifield Test (GHT) and the number of defective points in each quadrant and staging of the visual field damage was also weak. Because the correlation between SITA-SAP and Matrix-FDT regarding global indices, GHT, number of defective points, and stage of the visual field damage in mild glaucoma is weak, Matrix-FDT cannot be used interchangeably with SITA-SAP in the early stages of glaucoma. PMID- 29392150 TI - A multichannel computer-driven system to raise aquatic embryos under selectable hypoxic conditions. AB - The formation of a functional cardiovascular system is an essential step in the early vertebrate embryo. Nevertheless, the effect of hypoxia on the developmental program of organisms was studied rarely. In particular, this holds true for vertebrate embryos that depend on a functional placenta for proper development and had not been studied in this respect due to the obvious limitation. We established a protocol to culture aquatic embryos, which enabled us to culture a high number of Xenopus embryos until tadpole stage under defined hypoxic conditions in four hypoxia chambers simultaneously, employing a computerized system. In general, our results show that hypoxia results in delayed development and, in particular, we could show that oxygen availability was most crucial during gastrulation and organogenesis (early tailbud) phases during embryonic development of Xenopus laevis. PMID- 29392151 TI - Pearl-White Gallstones Causing Choledocholithiasis. PMID- 29392152 TI - Small Bowel Diverticulosis and Jejunal Perforation in Marfan Syndrome. AB - Marfan syndrome is an autosomal dominant disorder involving mutation in the FBN1 gene, which encodes fibrillin-1, a protein critical to maintain the integrity of connective tissue. A mutation in this gene can affect multiple organ systems, but it is not classically associated with gastrointestinal complications. We describe a man with Marfan syndrome with multiple small bowel diverticula leading to small intestinal bacterial overgrowth and recurrent small bowel perforations. PMID- 29392153 TI - Hepatic Failure Due to Cholestatic Hepatitis C in an Immunosuppressed Patient Treated With Elbasvir and Grazeprevir. AB - Hepatitis C-induced cholestatic hepatitis is a well-known fatal complication of postorthotropic liver transplantation and prolonged immunosuppression. Recent studies on direct-acting antiviral agents have shown promising results in terms of morbidity and mortality of this condition in postorthotropic liver, heart, and renal transplant patients. However, hepatitis C-induced cholestatic hepatitis remains a highly fatal condition in non-transplant patients. We report the first ever use of the oral direct-acting antiviral combination, elbasvir and grazeprevir, in the treatment of a non-liver transplant patient with cholestatic hepatitis. PMID- 29392154 TI - Chronic Diarrhea as the Only Symptom in a Patient With Duodenal-Colo-Renal Primary Fistula. PMID- 29392155 TI - Bayesian Modeling and Analysis of Geostatistical Data. AB - The most prevalent spatial data setting is, arguably, that of so-called geostatistical data, data that arise as random variables observed at fixed spatial locations. Collection of such data in space and in time has grown enormously in the past two decades. With it has grown a substantial array of methods to analyze such data. Here, we attempt a review of a fully model-based perspective for such data analysis, the approach of hierarchical modeling fitted within a Bayesian framework. The benefit, as with hierarchical Bayesian modeling in general, is full and exact inference, with proper assessment of uncertainty. Geostatistical modeling includes univariate and multivariate data collection at sites, continuous and categorical data at sites, static and dynamic data at sites, and datasets over very large numbers of sites and long periods of time. Within the hierarchical modeling framework, we offer a review of the current state of the art in these settings. PMID- 29392156 TI - Concurrent measurement of cerebral hemodynamics and electroencephalography during transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is currently being used for research and treatment of some neurological and neuropsychiatric disorders, as well as for improvement of cognitive functions. In order to better understand cerebral response to the stimulation and to redefine protocols and dosage, its effects must be monitored. To this end, we have used functional diffuse correlation spectroscopy (fDCS) and time-resolved functional near-infrared spectroscopy (TR-fNIRS) together with electroencephalography (EEG) during and after stimulation of the frontal cortex. Twenty subjects participated in two sessions of stimulation with two different polarity montages and twelve also underwent a sham session. Cerebral blood flow and oxyhemoglobin concentration increased during and after active stimulation in the region under the stimulation electrode while deoxyhemoglobin concentration decreased. The EEG spectrum displayed statistically significant power changes across different stimulation sessions in delta (2 to 4 Hz), theta (4 to 8 Hz), and beta (12 to 18 Hz) bands. Results suggest that fDCS and TR-fNIRS can be employed as neuromonitors of the effects of transcranial electrical stimulation and can be used together with EEG. PMID- 29392157 TI - Prefrontal hemodynamic changes measured using near-infrared spectroscopy during the Valsalva maneuver in patients with orthostatic intolerance. AB - The Valsalva maneuver (VM) with beat-to-beat blood pressure and heart rate monitoring are used to evaluate orthostatic intolerance (OI). However, they lack the ability to detect cerebral hemodynamic changes, which may be a cause of OI symptoms. Therefore, we utilized near-infrared spectroscopy during VM. Patients with OI symptoms and normal healthy subjects were recruited. Patients were subgrouped according to VM results: patients with normal VM (NVM) and abnormal VM (AbVM). Oxyhemoglobin (HbO), deoxyhemoglobin, and total hemoglobin changes were measured at four different source-detector distances (SD) (15, 30, 36, and 45 mm), and latency, amplitude, duration, and integrated total signal were calculated. Those parameters were compared between a normal healthy control (HC) group and the two OI patient subgroups. We found that HbO increment latency at 30 mm SD in the HC, NVM, and AbVM groups was as follows: [Formula: see text], [Formula: see text], and [Formula: see text], respectively ([Formula: see text]). Among the four parameters we evaluated, latency of HbO increment was the best marker for differentiating OI. PMID- 29392159 TI - Navigation of guidewires and catheters in the body during intervention procedures: a review of computer-based models. AB - Guidewires and catheters are used during minimally invasive interventional procedures to traverse in vascular system and access the desired position. Computer models are increasingly being used to predict the behavior of these instruments. This information can be used to choose the right instrument for each case and increase the success rate of the procedure. Moreover, a designer can test the performance of instruments before the manufacturing phase. A precise model of the instrument is also useful for a training simulator. Therefore, to identify the strengths and weaknesses of different approaches used to model guidewires and catheters, a literature review of the existing techniques has been performed. The literature search was carried out in Google Scholar and Web of Science and limited to English for the period 1960 to 2017. For a computer model to be used in practice, it should be sufficiently realistic and, for some applications, real time. Therefore, we compared different modeling techniques with regard to these requirements, and the purposes of these models are reviewed. Important factors that influence the interaction between the instruments and the vascular wall are discussed. Finally, different ways used to evaluate and validate the models are described. We classified the developed models based on their formulation into finite-element method (FEM), mass-spring model (MSM), and rigid multibody links. Despite its numerical stability, FEM requires a very high computational effort. On the other hand, MSM is faster but there is a risk of numerical instability. The rigid multibody links method has a simple structure and is easy to implement. However, as the length of the instrument is increased, the model becomes slower. For the level of realism of the simulation, friction and collision were incorporated as the most influential forces applied to the instrument during the propagation within a vascular system. To evaluate the accuracy, most of the studies compared the simulation results with the outcome of physical experiments on a variety of phantom models, and only a limited number of studies have done face validity. Although a subset of the validated models is considered to be sufficiently accurate for the specific task for which they were developed and, therefore, are already being used in practice, these models are still under an ongoing development for improvement. Realism and computation time are two important requirements in catheter and guidewire modeling; however, the reviewed studies made a trade-off depending on the purpose of their model. Moreover, due to the complexity of the interaction with the vascular system, some assumptions have been made regarding the properties of both instruments and vascular system. Some validation studies have been reported but without a consistent experimental methodology. PMID- 29392160 TI - Distinguishing benign and malignant breast tumors: preliminary comparison of kinetic modeling approaches using multi-institutional dynamic contrast-enhanced MRI data from the International Breast MR Consortium 6883 trial. AB - Comparative preliminary analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data collected in the International Breast MR Consortium 6883 multicenter trial was performed to distinguish benign and malignant breast tumors. Prebiopsy DCE-MRI data from 45 patients with suspicious breast lesions were obtained. Semiquantitative mean signal-enhancement ratio ([Formula: see text]) was calculated for all lesions, and quantitative pharmacokinetic, parameters [Formula: see text], [Formula: see text], and [Formula: see text], were calculated for the subset with available [Formula: see text] maps ([Formula: see text]). Diagnostic performance was estimated for DCE-MRI parameters and compared to standard clinical MRI assessment. Quantitative and semiquantitative metrics discriminated benign and malignant lesions, with receiver operating characteristic area under the curve (AUC) values of 0.71, 0.70, and 0.82 for [Formula: see text], [Formula: see text], and [Formula: see text], respectively ([Formula: see text]). At equal 94% sensitivity, the specificity and positive predictive value of [Formula: see text] (53% and 63%, respectively) and Ktrans (42% and 58%) were higher than clinical MRI assessment (32% and 54%). A multivariable model combining [Formula: see text] and clinical MRI assessment had an AUC value of 0.87. Quantitative pharmacokinetic and semiquantitative analyses of DCE-MRI improves discrimination of benign and malignant breast tumors, with our findings suggesting higher diagnostic accuracy using [Formula: see text]. [Formula: see text] has potential to help reduce unnecessary biopsies resulting from routine breast imaging. PMID- 29392161 TI - On-the-fly augmented reality for orthopedic surgery using a multimodal fiducial. AB - Fluoroscopic x-ray guidance is a cornerstone for percutaneous orthopedic surgical procedures. However, two-dimensional (2-D) observations of the three-dimensional (3-D) anatomy suffer from the effects of projective simplification. Consequently, many x-ray images from various orientations need to be acquired for the surgeon to accurately assess the spatial relations between the patient's anatomy and the surgical tools. We present an on-the-fly surgical support system that provides guidance using augmented reality and can be used in quasiunprepared operating rooms. The proposed system builds upon a multimodality marker and simultaneous localization and mapping technique to cocalibrate an optical see-through head mounted display to a C-arm fluoroscopy system. Then, annotations on the 2-D x-ray images can be rendered as virtual objects in 3-D providing surgical guidance. We quantitatively evaluate the components of the proposed system and, finally, design a feasibility study on a semianthropomorphic phantom. The accuracy of our system was comparable to the traditional image-guided technique while substantially reducing the number of acquired x-ray images as well as procedure time. Our promising results encourage further research on the interaction between virtual and real objects that we believe will directly benefit the proposed method. Further, we would like to explore the capabilities of our on-the-fly augmented reality support system in a larger study directed toward common orthopedic interventions. PMID- 29392162 TI - Combining intraoperative ultrasound brain shift correction and augmented reality visualizations: a pilot study of eight cases. AB - We present our work investigating the feasibility of combining intraoperative ultrasound for brain shift correction and augmented reality (AR) visualization for intraoperative interpretation of patient-specific models in image-guided neurosurgery (IGNS) of brain tumors. We combine two imaging technologies for image-guided brain tumor neurosurgery. Throughout surgical interventions, AR was used to assess different surgical strategies using three-dimensional (3-D) patient-specific models of the patient's cortex, vasculature, and lesion. Ultrasound imaging was acquired intraoperatively, and preoperative images and models were registered to the intraoperative data. The quality and reliability of the AR views were evaluated with both qualitative and quantitative metrics. A pilot study of eight patients demonstrates the feasible combination of these two technologies and their complementary features. In each case, the AR visualizations enabled the surgeon to accurately visualize the anatomy and pathology of interest for an extended period of the intervention. Inaccuracies associated with misregistration, brain shift, and AR were improved in all cases. These results demonstrate the potential of combining ultrasound-based registration with AR to become a useful tool for neurosurgeons to improve intraoperative patient-specific planning by improving the understanding of complex 3-D medical imaging data and prolonging the reliable use of IGNS. PMID- 29392158 TI - Review of quantitative multiscale imaging of breast cancer. AB - Breast cancer is the most common cancer among women worldwide and ranks second in terms of overall cancer deaths. One of the difficulties associated with treating breast cancer is that it is a heterogeneous disease with variations in benign and pathologic tissue composition, which contributes to disease development, progression, and treatment response. Many of these phenotypes are uncharacterized and their presence is difficult to detect, in part due to the sparsity of methods to correlate information between the cellular microscale and the whole-breast macroscale. Quantitative multiscale imaging of the breast is an emerging field concerned with the development of imaging technology that can characterize anatomic, functional, and molecular information across different resolutions and fields of view. It involves a diverse collection of imaging modalities, which touch large sections of the breast imaging research community. Prospective studies have shown promising results, but there are several challenges, ranging from basic physics and engineering to data processing and quantification, that must be met to bring the field to maturity. This paper presents some of the challenges that investigators face, reviews currently used multiscale imaging methods for preclinical imaging, and discusses the potential of these methods for clinical breast imaging. PMID- 29392164 TI - gamma-Secretase Epsilon-cleavage Assay. AB - gamma-Secretase epsilon-cleavage assay is derived from the cell-based Tango assay (Kang et al., 2015), and is a fast and sensitive method to determine the initial cleavage of C99 by gamma-secretase. In this protocol, we use HTL cells, which are HEK293 cells with a stably integrated luciferase reporter under the control of the bacterial tetO operator element, in which C99 C terminally fused to a reversed tetracyclin-inducible activator (rTA) transcriptional activator is expressed. Endogenous or transfected gamma-secretase cleaves a C terminally fused rTA transcriptional activator from C99, allowing rTA to move to the nucleus to activate a luciferase reporter gene as a measurement for gamma-secretase cleavage activity. PMID- 29392163 TI - Ascending the PEAK1 toward targeting TGFbeta during cancer progression: Recent advances and future perspectives. AB - Cancer is the second leading cause of death in the United States. Mortality in patients with solid, epithelial-derived tumors strongly correlates with disease stage and the systemic metastatic load. In such cancers, notable morphological and molecular changes have been attributed to cells as they pass through a continuum of epithelial-mesenchymal transition (EMT) states and many of these changes are essential for metastasis. While cancer metastasis is a complex cascade that is regulated by cell-autonomous and microenvironmental influences, it is well-accepted that understanding and controlling metastatic disease is a viable method for increasing patient survival. In the past 5 years, the novel non receptor tyrosine kinase PEAK1 has surfaced as a central regulator of tumor progression and metastasis in the context of solid, epithelial cancers. Here, we review this literature with a special focus on our recent work demonstrating that PEAK1 mediates non-canonical pro-tumorigenic TGFbeta signaling and is an intracellular control point between tumor cells and their extracellular microenvironment. We conclude with a brief discussion of potential applications derived from our current understanding of PEAK1 biology. PMID- 29392166 TI - Streptavidin Bead Pulldown Assay to Determine Protein Homooligomerization. AB - Pulldown assay is a conventional method to determine protein-protein interactions in vitro. Expressing a protein of interest with two different tags allows testing whether both versions can be captured via one of the two tags as homooligomeric complex. This protocol is based on streptavidin bead capture of a biotinylated protein and co-associated Flag-tagged protein using Streptavidin MagBeads. PMID- 29392165 TI - Detection of Membrane Protein Interactions by Cell-based Tango Assays. AB - The Tango assay is a protein-protein interaction assay, in which a transcription factor (rTA) is fused to a membrane-bound protein via a linker that contains a cleavage site for TEV protease, whereas a soluble interaction partner is fused to TEV protease (Barnea et al., 2008). Association between the two interaction partners leads to an efficient cleavage of the transcription factor, allowing it to translocate to the nucleus and activate a luciferase reporter gene as measurement of the interactions. In this modified assay, we fused one copy of the membrane-spanning amyloid precursor protein (APP) C99 region to TEV site-rTA (C99 TEV site-rTA) and a second copy to TEV protease (C99-TEV) to analyze intramembrane C99-C99 interaction in live cells. PMID- 29392170 TI - A Conversation with Natia Frank. PMID- 29392167 TI - The Advertising Strategies of Early E-cigarette Brand Leaders in the United States. AB - Objectives: We examined differential advertising strategies used by 4 major United States e-cigarette companies with differential affiliations with the traditional tobacco industry (ie, Njoy - independent, Blu - acquired, Vuse and MarkTen - launched by cigarette companies) over time. Methods: We conducted a mixed-methods study regarding e-cigarette adspend, adspend per media channel (eg, TV, print), and advertising messaging strategies among these 4 top e-cigarette brands from January 2013 through December 2015. Results: E-cigarette adspend increased from $59 million in 2013 to $91 million in 2014, followed by a sharp decline to $37 million in 2015. These companies showed distinct spending trajectories overall and across media channels, with Njoy and Vuse spending a higher proportion of their dollars on TV and Blu and MarkTen spending more on print. Marketing messages were also different by company. Key themes included switching from cigarettes (particularly by Njoy and Blu), circumventing smoke free policies (particularly by Blu), and technological advancement (particularly by Vuse and MarkTen). Conclusions: These e-cigarette brands have shifted their adspend, use of media channels, and advertising messaging strategies over time. Some differing strategies may reflect the different affiliations of each brand to the traditional cigarette industry. PMID- 29392168 TI - Near-common-path interferometer for imaging Fourier-transform spectroscopy in wide-field microscopy. AB - Imaging Fourier-transform spectroscopy (IFTS) is a powerful method for biological hyperspectral analysis based on various imaging modalities, such as fluorescence or Raman. Since the measurements are taken in the Fourier space of the spectrum, it can also take advantage of compressed sensing strategies. IFTS has been readily implemented in high-throughput, high-content microscope systems based on wide-field imaging modalities. However, there are limitations in existing wide field IFTS designs. Non-common-path approaches are less phase-stable. Alternatively, designs based on the common-path Sagnac interferometer are stable, but incompatible with high-throughput imaging. They require exhaustive sequential scanning over large interferometric path delays, making compressive strategic data acquisition impossible. In this paper, we present a novel phase-stable, near common-path interferometer enabling high-throughput hyperspectral imaging based on strategic data acquisition. Our results suggest that this approach can improve throughput over those of many other wide-field spectral techniques by more than an order of magnitude without compromising phase stability. PMID- 29392169 TI - Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli-Triggered siRNA Release from Lipid-Polymer Nanocomplexes. AB - Lipid-siRNA assemblies are modified with photo-responsive polymers to enable spatiotemporally-controlled silencing of interleukin 1 beta (IL1beta) and cadherin 11 (CDH11), two genes that are essential drivers of maladaptive responses in human aortic adventitial fibroblasts (AoAFs). These hybrid nanocomplexes address the critical challenge of locally mitigating fibrotic actions that lead to the high rates of vascular graft failures. In particular, the lipid-polymer formulations provide potent silencing of IL1beta and CDH11 that is precisely modulated by a photo-release stimulus. Moreover, a dynamic modeling framework is used to design a multi-dose siRNA regimen that sustains knockdown of both genes over clinically-relevant timescales. Multi-dose suppression illuminates a cooperative role for IL1beta and CDH11 in pathogenic adventitial remodeling and is directly linked to desirable functional outcomes. Specifically, myofibroblast differentiation and cellular proliferation, two of the primary hallmarks of fibrosis, are significantly attenuated by IL1beta silencing. Meanwhile, the effects of CDH11 siRNA treatment on differentiation become more pronounced at higher cell densities characteristic of constrictive adventitial remodeling in vivo. Thus, this work offers a unique formulation design for photo responsive gene suppression in human primary cells and establishes a new dosing method to satisfy the critical need for local attenuation of fibrotic responses in the adventitium surrounding vascular grafts. PMID- 29392171 TI - Cellular Service for Drug Delivery. PMID- 29392172 TI - Computational Design of Functionalized Metal-Organic Framework Nodes for Catalysis. AB - Recent progress in the synthesis and characterization of metal-organic frameworks (MOFs) has opened the door to an increasing number of possible catalytic applications. The great versatility of MOFs creates a large chemical space, whose thorough experimental examination becomes practically impossible. Therefore, computational modeling is a key tool to support, rationalize, and guide experimental efforts. In this outlook we survey the main methodologies employed to model MOFs for catalysis, and we review selected recent studies on the functionalization of their nodes. We pay special attention to catalytic applications involving natural gas conversion. PMID- 29392174 TI - Toward Green Acylation of (Hetero)arenes: Palladium-Catalyzed Carbonylation of Olefins to Ketones. AB - Green Friedel-Crafts acylation reactions belong to the most desired transformations in organic chemistry. The resulting ketones constitute important intermediates, building blocks, and functional molecules in organic synthesis as well as for the chemical industry. Over the past 60 years, advances in this topic have focused on how to make this reaction more economically and environmentally friendly by using green acylating conditions, such as stoichiometric acylations and catalytic homogeneous and heterogeneous acylations. However, currently well established methodologies for their synthesis either produce significant amounts of waste or proceed under harsh conditions, limiting applications. Here, we present a new protocol for the straightforward and selective introduction of acyl groups into (hetero)arenes without directing groups by using available olefins with inexpensive CO. In the presence of commercial palladium catalysts, inter- and intramolecular carbonylative C-H functionalizations take place with good regio- and chemoselectivity. Compared to classical Friedel-Crafts chemistry, this novel methodology proceeds under mild reaction conditions. The general applicability of this methodology is demonstrated by the direct carbonylation of industrial feedstocks (ethylene and diisobutene) as well as of natural products (eugenol and safrole). Furthermore, synthetic applications to drug molecules are showcased. PMID- 29392173 TI - Nanopore Electrochemistry: A Nexus for Molecular Control of Electron Transfer Reactions. AB - Pore-based structures occur widely in living organisms. Ion channels embedded in cell membranes, for example, provide pathways, where electron and proton transfer are coupled to the exchange of vital molecules. Learning from mother nature, a recent surge in activity has focused on artificial nanopore architectures to effect electrochemical transformations not accessible in larger structures. Here, we highlight these exciting advances. Starting with a brief overview of nanopore electrodes, including the early history and development of nanopore sensing based on nanopore-confined electrochemistry, we address the core concepts and special characteristics of nanopores in electron transfer. We describe nanopore-based electrochemical sensing and processing, discuss performance limits and challenges, and conclude with an outlook for next-generation nanopore electrode sensing platforms and the opportunities they present. PMID- 29392175 TI - Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis. AB - Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models. PMID- 29392176 TI - Learning a Local-Variable Model of Aromatic and Conjugated Systems. AB - A collection of new approaches to building and training neural networks, collectively referred to as deep learning, are attracting attention in theoretical chemistry. Several groups aim to replace computationally expensive ab initio quantum mechanics calculations with learned estimators. This raises questions about the representability of complex quantum chemical systems with neural networks. Can local-variable models efficiently approximate nonlocal quantum chemical features? Here, we find that convolutional architectures, those that only aggregate information locally, cannot efficiently represent aromaticity and conjugation in large systems. They cannot represent long-range nonlocality known to be important in quantum chemistry. This study uses aromatic and conjugated systems computed from molecule graphs, though reproducing quantum simulations is the ultimate goal. This task, by definition, is both computable and known to be important to chemistry. The failure of convolutional architectures on this focused task calls into question their use in modeling quantum mechanics. To remedy this heretofore unrecognized deficiency, we introduce a new architecture that propagates information back and forth in waves of nonlinear computation. This architecture is still a local-variable model, and it is both computationally and representationally efficient, processing molecules in sublinear time with far fewer parameters than convolutional networks. Wave like propagation models aromatic and conjugated systems with high accuracy, and even models the impact of small structural changes on large molecules. This new architecture demonstrates that some nonlocal features of quantum chemistry can be efficiently represented in local variable models. PMID- 29392177 TI - Controlling the Size of Two-Dimensional Polymer Platelets for Water-in-Water Emulsifiers. AB - A wide range of biorelevant applications, particularly in pharmaceutical formulations and the food and cosmetic industries, require the stabilization of two water-soluble blended components which would otherwise form incompatible biphasic mixtures. Such water-in-water emulsions can be achieved using Pickering stabilization, where two-dimensional (2D) nanomaterials are particularly effective due to their high surface area. However, control over the shape and size of the 2D nanomaterials is challenging, where it has not yet been possible to examine chemically identical nanostructures with the same thickness but different surface areas to probe the size-effect on emulsion stabilization ability. Hence, the rationale design and realization of the full potential of Pickering water-in-water emulsion stabilization have not yet been achieved. Herein, we report for the first time 2D poly(lactide) platelets with tunable sizes (with varying coronal chemistry) and of uniform shape using a crystallization-driven self-assembly methodology. We have used this series of nanostructures to explore the effect of 2D platelet size and chemistry on the stabilization of a water-in-water emulsion of a poly(ethylene glycol) (PEG)/dextran mixture. We have demonstrated that cationic, zwitterionic, and neutral large platelets (ca. 3.7 * 106 nm2) all attain smaller droplet sizes and more stable emulsions than their respective smaller platelets (ca. 1.2 * 105 nm2). This series of 2D platelets of controlled dimensions provides an excellent exemplar system for the investigation of the effect of just the surface area on the potential effectiveness in a particular application. PMID- 29392178 TI - Comparative Nucleotide-Dependent Interactome Analysis Reveals Shared and Differential Properties of KRas4a and KRas4b. AB - The KRAS gene encodes two isoforms, KRas4a and KRas4b. Differences in the signaling functions of the two KRas proteins are poorly understood. Here we report the comparative and nucleotide-dependent interactomes of KRas4a and KRas4b. Many previously unknown interacting proteins were identified, with some interacting with both isoforms while others prefer only one. For example, v ATPase a2 and eIF2Bdelta interact with only KRas4b. Consistent with the v-ATPase interaction, KRas4b has a significant lysosomal localization. Comparing WT and constitutively active G12D mutant KRas, we examined differences in the effector proteins of the KRas4a and KRas4b. Interestingly, KRas4a binds RAF1 stronger than KRas4b. Correspondingly, KRas4a can better promote ERK phosphorylation and anchorage-independent growth than KRas4b. The interactome data represent a useful resource to understand the differences between KRas4a and KRas4b and to discover new function or regulation for them. A similar proteomic approach would be useful for studying numerous other small GTPases. PMID- 29392179 TI - Exploiting Anti-T-shaped Graphene Architecture to Form Low Tortuosity, Sieve-like Interfaces for High-Performance Anodes for Li-Based Cells. AB - Graphitic carbon anodes have long been used in Li ion batteries due to their combination of attractive properties, such as low cost, high gravimetric energy density, and good rate capability. However, one significant challenge is controlling, and optimizing, the nature and formation of the solid electrolyte interphase (SEI). Here it is demonstrated that carbon coating via chemical vapor deposition (CVD) facilitates high electrochemical performance of carbon anodes. We examine and characterize the substrate/vertical graphene interface (multilayer graphene nanowalls coated onto carbon paper via plasma enhanced CVD), revealing that these low-tortuosity and high-selection graphene nanowalls act as fast Li ion transport channels. Moreover, we determine that the hitherto neglected parallel layer acts as a protective surface at the interface, enhancing the anode performance. In summary, these findings not only clarify the synergistic role of the parallel functional interface when combined with vertical graphene nanowalls but also have facilitated the development of design principles for future high rate, high performance batteries. PMID- 29392180 TI - REDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment. AB - Bryostatin 1 (henceforth bryostatin) is in clinical trials for the treatment of Alzheimer's disease and for HIV/AIDS eradication. It is also a preclinical lead for cancer immunotherapy and other therapeutic indications. Yet nothing is known about the conformation of bryostatin bound to its protein kinase C (PKC) target in a membrane microenvironment. As a result, efforts to design more efficacious, better tolerated, or more synthetically accessible ligands have been limited to structures that do not include PKC or membrane effects known to influence PKC ligand binding. This problem extends more generally to many membrane-associated proteins in the human proteome. Here, we use rotational-echo double-resonance (REDOR) solid-state NMR to determine the conformations of PKC modulators bound to the PKCdelta-C1b domain in the presence of phospholipid vesicles. The conformationally limited PKC modulator phorbol diacetate (PDAc) is used as an initial test substrate. While unanticipated partitioning of PDAc between an immobilized protein-bound state and a mobile state in the phospholipid assembly was observed, a single conformation in the bound state was identified. In striking contrast, a bryostatin analogue (bryolog) was found to exist exclusively in a protein-bound state, but adopts a distribution of conformations as defined by three independent distance measurements. The detection of multiple PKCdelta C1b-bound bryolog conformers in a functionally relevant phospholipid complex reveals the inherent dynamic nature of cellular systems that is not captured with single-conformation static structures. These results indicate that binding, selectivity, and function of PKC modulators, as well as the design of new modulators, are best addressed using a dynamic multistate model, an analysis potentially applicable to other membrane-associated proteins. PMID- 29392181 TI - Robust Pinhole-free Li3N Solid Electrolyte Grown from Molten Lithium. AB - Lithium metal is the ultimate anode choice for high energy density rechargeable lithium batteries. However, it suffers from inferior electrochemical performance and safety issues due to its high reactivity and the growth of lithium dendrites. It has long been desired to develop a materials coating on Li metal, which is pinhole-free, mechanically robust without fracture during Li metal deposition and stripping, and chemically stable against Li metal and liquid electrolytes, all while maintaining adequate ionic conductivity. However, such an ideal material coating has yet to be found. Here we report a novel synthesis method by reacting clean molten lithium foil directly with pure nitrogen gas to generate instantaneously a pinhole-free and ionically conductive alpha-Li3N film directly bonded onto Li metal foil. The film consists of highly textured large Li3N grains (tens of MUm) with (001) crystalline planes parallel to the Li metal surface. The bonding between textured grains is strong, resulting in a mechanically robust film which does not crack even when bent to a 0.8 cm curvature radius and is found to maintain pinhole-free coverage during Li metal deposition and stripping. The measured ionic conductivity is up to 5.2 * 10-4 S cm-1, sufficient for maintaining regular current densities for controllable film thicknesses ranging from 2 to 30 MUm. This Li3N coating is chemically stable, isolating the reactive metallic lithium from liquid electrolyte, prevents continuous electrolyte consumption during battery cycling, and promotes dendrite-free uniform lithium plating/stripping underneath. We demonstrated Li|Li4Ti5O12 cells with stable and flat potential profiles for 500 cycles without capacity decay or an increase in potential hysteresis. PMID- 29392182 TI - [Ti8Zr2O12(COO)16] Cluster: An Ideal Inorganic Building Unit for Photoactive Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) based on Ti-oxo clusters (Ti-MOFs) represent a naturally self-assembled superlattice of TiO2 nanoparticles separated by designable organic linkers as antenna chromophores, epitomizing a promising platform for solar energy conversion. However, despite the vast, diverse, and well-developed Ti-cluster chemistry, only a scarce number of Ti-MOFs have been documented. The synthetic conditions of most Ti-based clusters are incompatible with those required for MOF crystallization, which has severely limited the development of Ti-MOFs. This challenge has been met herein by the discovery of the [Ti8Zr2O12(COO)16] cluster as a nearly ideal building unit for photoactive MOFs. A family of isoreticular photoactive MOFs were assembled, and their orbital alignments were fine-tuned by rational functionalization of organic linkers under computational guidance. These MOFs demonstrate high porosity, excellent chemical stability, tunable photoresponse, and good activity toward photocatalytic hydrogen evolution reactions. The discovery of the [Ti8Zr2O12(COO)16] cluster and the facile construction of photoactive MOFs from this cluster shall pave the way for the development of future Ti-MOF-based photocatalysts. PMID- 29392183 TI - When NiO@Ni Meets WS2 Nanosheet Array: A Highly Efficient and Ultrastable Electrocatalyst for Overall Water Splitting. AB - The development of low-cost, high-efficiency, and stable bifunctional electrocatalysts toward the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is of paramount importance for large-scale water splitting. Here, we develop a new strategy for the first design and synthesis of a NiO@Ni decorated WS2 nanosheet array on carbon cloth (NiO@Ni/WS2/CC) composite. This composite serves as a unique three-dimensional (3D) synergistic electrocatalyst that not only combines the intrinsic properties of individual NiO@Ni and WS2, but also exhibits significantly improved HER and OER activities when compared to that of pure NiO@Ni and WS2. This electrocatalyst possesses Pt like activity for HER and exhibits better OER performance than that for commercial RuO2, as well as demonstrating superior long-term durability in alkaline media. Furthermore, it enables an alkaline electrolyzer with a current density of 10 mA cm-2 at a cell voltage as 1.42 V, which is the lowest one among all reported values to date. The excellent performance is mainly attributed to the unique 3D configuration and multicomponent synergies among NiO, Ni, and WS2. Our findings provide a new idea to design advanced bifunctional catalysts for water splitting. PMID- 29392184 TI - Generating Focused Molecule Libraries for Drug Discovery with Recurrent Neural Networks. AB - In de novo drug design, computational strategies are used to generate novel molecules with good affinity to the desired biological target. In this work, we show that recurrent neural networks can be trained as generative models for molecular structures, similar to statistical language models in natural language processing. We demonstrate that the properties of the generated molecules correlate very well with the properties of the molecules used to train the model. In order to enrich libraries with molecules active toward a given biological target, we propose to fine-tune the model with small sets of molecules, which are known to be active against that target. Against Staphylococcus aureus, the model reproduced 14% of 6051 hold-out test molecules that medicinal chemists designed, whereas against Plasmodium falciparum (Malaria), it reproduced 28% of 1240 test molecules. When coupled with a scoring function, our model can perform the complete de novo drug design cycle to generate large sets of novel molecules for drug discovery. PMID- 29392185 TI - Loss of Renal Function After Retrograde Ureteral Placement of an Allium Stent for Severe Ureteral Stricture. AB - Background: Ureteral strictures are a recurrent chronic condition that leads to severe side effects and poor quality of life. Management of ureteral stricture is a great challenge for urologists and no specific guidelines exist. Retrograde Allium(r) ureteral stent (AUS) is a newly developed ureteral stent to treat either bulbar urethral or ureteral stenosis. Case Presentation: We describe a case of a 74-year-old Caucasian adult male presenting with a severe ureteral stricture secondary to an ureteroscopy for stone disease. Treatment with retrograde AUS placement produced a complete loss of renal function after 36 months, probably because of the development of a long achalasic stretch of the ureter. Conclusions: AUS is a new and promising device for the treatment of ureteral stenosis. However, a lack of standardization of the technique recommends a close instrumental follow-up after the procedure to decide the optimal time for stent removal. PMID- 29392187 TI - Regeneration mechanism for skin and peripheral nerves clarified at the organ and molecular scales. AB - This article is a review of current research on the mechanism of regeneration of skin and peripheral nerves based on use of collagen scaffolds, particularly the dermis regeneration template (DRT), which is widely used clinically. DRT modifies the normal wound healing process, converting it from wound closure by contraction and scar formation to closure by regeneration. DRT achieves this modification by blocking wound contraction, which spontaneously leads to cancellation of scar formation, a process secondary to contraction. Contraction blocking by DRT is the result of a dramatic phenotype change in contractile cells (myofibroblasts, MFB) which follows specific binding of integrins alpha1beta1 and alpha2beta1 onto hexapeptide ligands, probably GFOGER and GLOGER, that are naturally present on the surface of collagen fibers in DRT. The methodology of organ regeneration based on use of DRT has been recently extended from traumatized skin to diseased skin. Successful extension of the method to other organs in which wounds heal by contraction is highly likely though not yet attempted. This regenerative paradigm is much more advanced both in basic mechanistic understanding and clinical use than methods based on tissue culture or stem cells. It is also largely free of risk and has shown decisively lower morbidity and lower cost than organ transplantation. PMID- 29392186 TI - Environmental Toxicant Exposures and Type 2 Diabetes Mellitus: Two Interrelated Public Health Problems on the Rise. AB - Rates of type 2 diabetes mellitus (T2DM) are rising rapidly across the globe and the impact of this devastating disease threatens to plague the 21st century. While some contributing factors are well-recognized (e.g. sedentary lifestyles and caloric excess), others diabetes-promoting risk factors are less established or poorly appreciated. The latter category includes environmental exposures to diabetogenic contaminants. Herein we review some of the latest concepts and mechanisms by which environmental exposures may contribute to rising rates of T2DM with a particular focus on mechanisms involving mitochondrial dysfunction and imbalances in reactive oxygen species (ROS). Furthermore, while the pathogenesis of diabetes includes impairments in insulin sensitivity as well as insulin secretion, we will specifically delve into the links between environmental exposures to toxicants such as arsenic and disruptions in insulin release from pancreatic beta-cells. Since beta-cell death or dysfunction lies at the heart of both T2DM as well as type 1 diabetes mellitus (T1DM), environmental endocrine disrupting chemicals (EDCs) that disrupt the production or regulated release of the glucose-lowering hormone insulin are likely contributors to diabetes risk. Importantly, understanding the contribution of toxicants to diabetes risk as well as improved understanding of their mechanisms of action offer unique opportunities to modulate diabetes risk via targeted therapeutics or public policy interventions to reduce and remediate exposures. PMID- 29392188 TI - Access to PAIN Reports is now open: IASP inaugurates a new journal. PMID- 29392189 TI - Voluntary and evoked behavioral correlates in inflammatory pain conditions under different social housing conditions. AB - Most preclinical pain models rely on short-duration stimulus-evoked hind paw measurements even though chronic pain is usually a day and night experience. Pain is a debilitating condition that influences the sociability and the ability for voluntary tasks, but the relevant behavioral readouts for these aspects are mostly underrepresented in the literature. Moreover, we lack standardization in most behavioral paradigms. Important aspects are herewith the combination and duration of particular behavioral tasks and the effects of social environment. We aimed at thoroughly investigating stimulus-evoked and voluntary behavioral parameters in the Complete Freund's Adjuvant model of unilateral hind paw inflammation in male mice. Moreover, we analyzed the impact of different social housing conditions. We used a portfolio of classical response measurements, detailed gait analysis, using 2 different measuring systems (Dynamic weight bearing and CatWalk), as well as observer-independent voluntary wheel running and homecage monitoring in a longitudinal time frame. The impact of grouped or isolated housing was investigated in all behavioral paradigms. We observed that unilateral hind paw inflammation provoked changes in several behaviors. Among these were wheel running activity and different homecage activity parameters. Stimulus-evoked hypersensitivity lasted much longer than gait abnormalities and decreased voluntary wheel running activity. Similar effects were monitored in both social housing conditions. This is the first longitudinal study providing detailed insights into various voluntary behavioral parameters related to pain in a unilateral inflammatory model. Stimulus-evoked behavioral changes lasted longer than changes in voluntary behavioral parameters, and the social environment hardly affects these changes. PMID- 29392191 TI - Abstracts from FEDELAT 2016 meeting: Latin American Federation of IASP chapters. PMID- 29392190 TI - Targeting the innate repair receptor to treat neuropathy. AB - The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the beta-common (CD131) receptor, which simultaneously activates anti inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a beta-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D) mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies. PMID- 29392192 TI - Catastrophizing and pain-related fear predict failure to maintain treatment gains following participation in a pain rehabilitation program. AB - The present study explored whether pain-related psychosocial risk factors played a role in determining whether treatment gains were maintained following participation in a rehabilitation intervention for musculoskeletal injury. The study sample consisted of 310 individuals (163 women, 147 men) with work-related musculoskeletal conditions who were enrolled in a physical rehabilitation program. Measures of pain severity, pain catastrophizing and pain-related fear were completed at the time of admission and at the time of discharge. Pain severity was assessed again at 1-year postdischarge. Participants were classified as "recovered" if they showed a decrease in pain of at least 2 points and rated their pain at discharge as less than 4/10. Recovered participants were considered to have failed to maintain treatment gains if their pain ratings increased by at least 2 points from discharge assessment to 1-year follow-up, and they rated their pain as 4/10 or greater at 1-year follow-up. The results of a logistic regression revealed that participants with high posttreatment scores on measures of catastrophizing and fear of pain were at increased risk of failing to maintain treatment gains. The findings suggest that unless end-of-treatment scores on catastrophizing and fear of pain fall below the risk range, treatment-related reductions in pain severity may not be maintained in the long term. The clinical and theoretical implications of the findings are discussed. PMID- 29392194 TI - A novel lozenge containing bupivacaine as topical alleviation of oral mucositis pain in patients with head and neck cancer: a pilot study. AB - Introduction: Oral mucositis induces severe oral pain in head and neck cancer patients. There is at this point no effective pain treatment without considerable side effects. Objective: The aim of this pilot study was to investigate pain reduction in oral cavity and pharynx in patients with head and neck cancer (HNC) with oral mucositis, the location of anesthetic effect, and duration of pain relief, after a single-dose administration of a 25 mg bupivacaine lozenge. Methods: Ten patients with HNC suffering from oral mucositis pain were included. The patients assessed pain in the oral cavity and pharynx on a visual analogue scale (from 0 to 100 mm) at baseline and up to 3 hours after the lozenge was dissolved. Possible adverse events were registered. Results: The baseline pain was 51 mm (range: 30-73 mm) in the oral cavity and 58 mm (range: 35-70 mm) in the pharynx. When the lozenge was dissolved, both oral (-27 mm; range: -3 to -52 mm; P = 0.0003) and pharynx pain (-20 mm; range: -3 to -45 mm; P = 0.008) were significantly reduced. After 180 minutes, the mean reduction in pain was significant in the oral cavity (-18 mm; range: -8 to -30 mm; P < 0.0001) but not in the pharynx (-8 mm; range: +4 to -23 mm; P = 0.12). No adverse events were observed. Conclusion: The results indicate that the bupivacaine lozenge has a clinically significant and long-lasting pain-relieving effect on pain because of oral mucositis in patients with HNC. PMID- 29392195 TI - Advances in multivariate pattern analysis for chronic pain: an emerging, but imperfect method. PMID- 29392193 TI - The dark side of opioids in pain management: basic science explains clinical observation. AB - Introduction: In the past 2 decades, opioids have been used increasingly for the treatment of persistent pain, and doses have tended to creep up. As basic science elucidates mechanisms of pain and analgesia, the cross talk between central pain and opioid actions becomes clearer. Objectives: We aimed to examine the published literature on basic science explaining pronociceptive opioid actions, and apply this knowledge to clinical observation. Methods: We reviewed the existing literature on the pronociceptive actions of opioids, both preclinical and clinical studies. Results: Basic science provides a rationale for the clinical observation that opioids sometimes increase rather than decrease pain. Central sensitization (hyperalgesia) underlies pain chronification, but can also be produced by high dose and high potency opioids. Many of the same mechanisms account for both central pain and opioid hyperalgesia. Conclusion: Newly revealed basic mechanisms suggest possible avenues for drug development and new drug therapies that could alter pain sensitization through endogenous and exogenous opioid mechanisms. Recent changes in practice such as the introduction of titration-to-effect for opioids have resulted in higher doses used in the clinic setting than ever seen previously. New basic science knowledge hints that these newer dosing practices may need to be reexamined. When pain worsens in a patient taking opioids, can we be assured that this is not because of the opioids, and can we alter this negative effect of opioids through different dosing strategies or new drug intervention? PMID- 29392196 TI - TRPV1 antagonist JNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study. AB - This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ 39439335 on capsaicin-induced flare and sensory testing on naive and UVB sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ 39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development. PMID- 29392197 TI - Legal and ethical issues of using brain imaging to diagnose pain. AB - Pain, by definition, is a subjective experience, and as such its presence has usually been based on a self-report. However, limitations of self-reports for pain diagnostics, particularly for legal and insurance purposes, has led some to consider a brain-imaging-based objective measure of pain. This review will provide an overview of (1) differences between pain and nociception, (2) intersubject variability in pain perception and the associated brain structures and functional circuits, and (3) capabilities and limitations of current brain imaging technologies. I then discuss how these factors impact objective proxies of pain. Finally, the ethical, privacy, and legal implications of a brain-imaging based objective measure of pain are considered as potential future technological developments necessary to create a so-called "painometer test." PMID- 29392199 TI - Discrete hypo/de-pigmented spots as an early, prodromal, objective sign of somatic origin pain. PMID- 29392201 TI - Summary of the Fibromyalgia Research Symposium 2016 in Nagasaki. PMID- 29392198 TI - Spontaneous recurrent episodes of wrist pain in a 16-year-old girl: a case of complex regional pain syndrome. AB - Introduction: Complex regional pain syndromes (CRPS) are disabling pain syndromes that can develop after minor tissue injury or trauma and are characterized by sensory, motor, and autonomic abnormalities distributed in a glove-like or stocking-like manner. Complex regional pain syndrome is well known in adults, but is relatively rare in children. Most of the reported cases of CRPS in children are clinical diagnoses that are not supported by examinations such as three-phase bone scintigraphy. Furthermore, different centres often use different diagnostic criteria for CRPS, which sometimes questions the diagnosis of CRPS. Objective/Methods: Although, recurrences and in particular relapses of CRPS have been observed, a periodically, nearly self-limiting course of disease without any residues in pain-free episodes and without any new obvious injury in CRPS is rather unusual. We present the case of a 16-year-old girl who reported recurrent spontaneous pain which lasted for 2 to 3 weeks and occurred approximately 2 times a year after the patient had experienced a mild trauma 3 years ago. Results: The pain was accompanied by swelling, temperature asymmetry, and decreased range of motion of the right hand without any complains in pain-free episodes. Recurrent symptoms occurred without any obvious trauma. Diagnosis of CRPS was made from clinical findings including quantitative sensory testing, increased periarticular radioisotope uptake in the delayed phase of three-phase bone scintigraphy and examination during anaesthesia. Multimodal inpatient pain treatment resolved her symptoms substantially. Conclusion: Complex regional pain syndrome in children may imitate rheumatologic diseases, and the course is different from adults despite similar clinical findings. PMID- 29392202 TI - The 2nd Pain Science in Motion Colloquium at a glance. PMID- 29392203 TI - Methodology for self-report of rest pain (or spontaneous pain) vs evoked pain in chronic neuropathic conditions: a prospective observational pilot study. AB - Introduction: The distinction between pain at rest and pain evoked by touch or movement has important clinical implications and may be associated with different mechanisms. However, current methods of clinical pain assessment pay little attention to directly distinguishing between these contrasting components of symptom burden. Objectives: We developed the 10-item "Functional Impact of Neuropathic Evoked and Spontaneous Symptom Evaluation" questionnaire designed to distinguish between rest and evoked pain. Methods: A prospective observational pilot study of this questionnaire was conducted in 78 participants with neuropathic pain diagnoses. Other study measures included the self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs questionnaire and a modified Brief Pain Inventory. Exploratory analyses were conducted to evaluate the validity of the Functional Impact of Neuropathic Evoked and Spontaneous Symptom Evaluation questionnaire. Results: Pain symptoms often/very often/always (1) evoked by touch or movement, and (2) occurring at rest without tactile stimulation were reported by 81% and 65%, respectively. Evoked pain was associated with walking (64%) and standing (35%); and rest pain was associated with watching television (47%), reading (37%), and sitting (36%). Participants reporting both rest and evoked pain tended to report higher levels of pain interference compared to those reporting evoked pain only. Discussion: These results provide support for the feasibility and validity of new patient-report methods to distinguish between rest pain and evoked pain in chronic neuropathic conditions. Future studies are needed to confirm the reliability and validity of these methods, which may facilitate important improvements in the research and development of new treatments for chronic pain. PMID- 29392205 TI - Influence of opioid-related side effects on disability, mood, and opioid misuse risk among patients with chronic pain in primary care. AB - Background: There is increasing concern among primary care practitioners about the use of opioids for chronic pain, including their adverse effects, but little attention has been given to how reports of side effects from prescription medication can contribute to outcomes among patients with chronic pain. The aim of this study was to investigate the impact of frequently reported side effects on mood, disability, and opioid misuse in patients with chronic pain prescribed opioids within primary care. Methods: Two hundred (N = 200) patients with chronic pain taking opioids for pain were recruited into the study. All patients completed baseline measures and a monthly side effects checklist once a month for 6 months. Patients were divided evenly based on a median split of the number of endorsed side effects over 6 months. The subjects repeated the baseline measures at the end of the study period. Results: Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up (6-month time) were not significant, and the order of the frequency of the reported side effects remained similar. Patients who reported significant medication-related adverse effects reported significantly greater activity interference, negative affect, and catastrophizing compared with those with fewer side effects (P < 0.01). In addition, those patients with pain who reported more side effects showed significantly higher scores on opioid misuse risk (P < 0.001). Discussion: This study demonstrates the important role of monitoring medication-related side effects among patients with chronic pain who are prescribed opioid medication for pain within primary care. PMID- 29392206 TI - Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia. AB - Introduction: Neuroimaging reveals increased glutamate within the insula of patients with fibromyalgia (FM), suggesting a link between FM symptoms and increased central excitatory neurotransmission. Many patients with FM also present with decreased intraepidermal nerve fiber density (IENFD), consistent with small fiber pathology. It remains unknown, however, whether either of these mechanistic findings represent a cause or a consequence of the other. This study tests the hypothesis that an excitatory imbalance within the insula leads to small fiber pathology. Objectives: This is a proof-of-concept study to examine whether a chronic, bilateral increase in insular glutamate can be a causal factor in the development of small fiber neuropathy in FM. Methods: The glutamate transport inhibitor l-trans-Pyrrolidine-2,4-dicarboxylic acid (PDC), which increases endogenous levels of glutamate, was dissolved in Ringer solution and bilaterally delivered into the insula of rats for 6 weeks. Naive rats that did not undergo any surgery or treatment and rats administered Ringer vehicle solution into the insula served as controls. Multimodal nociceptive sensitivity was assessed weekly. Hind paw tissue biopsies were collected for IENFD assessment, at the end of the experiment. Results: Compared with controls, increasing endogenous glutamate in the insula with PDC caused sustained decreases in mechanical paw withdrawal threshold and thermal paw withdrawal latency, increased aversion to noxious mechanical stimulation, and a decrease in IENFD. Cold reactivity was not altered by PDC administration. Conclusion: Bilateral insular PDC administration produced a persistent increase in multimodal pain behaviors and a decrease in peripheral nerve fibers in rat. These preclinical findings offer preliminary support that insular hyperactivity may be a casual factor in the development of small fiber pathology in FM. PMID- 29392204 TI - Postoperative pain-from mechanisms to treatment. AB - Introduction: Pain management after surgery continues to be suboptimal; there are several reasons including lack of translation of results from basic science studies and scientific clinical evidence into clinical praxis. Objectives: This review presents and discusses basic science findings and scientific evidence generated within the last 2 decades in the field of acute postoperative pain. Methods: In the first part of the review, we give an overview about studies that have investigated the pathophysiology of postoperative pain by using rodent models of incisional pain up to July 2016. The second focus of the review lies on treatment recommendations based on guidelines and clinical evidence, eg, by using the fourth edition of the "Acute Pain Management: Scientific Evidence" of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Results: Preclinical studies in rodent models characterized responses of primary afferent nociceptors and dorsal horn neurons as one neural basis for pain behavior including resting pain, hyperalgesia, movement-evoked pain or anxiety- and depression-like behaviors after surgery. Furthermore, the role of certain receptors, mediators, and neurotransmitters involved in peripheral and central sensitization after incision were identified; many of these are very specific, relate to some modalities only, and are unique for incisional pain. Future treatment should focus on these targets to develop therapeutic agents that are effective for the treatment of postoperative pain as well as have few side effects. Furthermore, basic science findings translate well into results from clinical studies. Scientific evidence is able to point towards useful (and less useful) elements of multimodal analgesia able to reduce opioid consumption, improve pain management, and enhance recovery. Conclusion: Understanding basic mechanisms of postoperative pain to identify effective treatment strategies may improve patients' outcome after surgery. PMID- 29392207 TI - Accelerated aging in adults with knee osteoarthritis pain: consideration for frequency, intensity, time, and total pain sites. AB - Introduction: Individuals with osteoarthritis (OA) show increased morbidity and mortality. Telomere length, a measure of cellular aging, predicts increased morbidity and mortality. Telomeres shorten with persisting biological and psychosocial stress. Living with chronic OA pain is stressful. Previous research exploring telomere length in people with OA has produced inconsistent results. Considering pain severity may clarify the relationship between OA and telomeres. Objectives: We hypothesized that individuals with high OA chronic pain severity would have shorter telomeres than those with no or low chronic pain severity. Methods: One hundred thirty-six adults, ages 45 to 85 years old, with and without symptomatic knee OA were included in the analysis. Peripheral blood leukocyte telomere length was measured, and demographic, clinical, and functional data were collected. Participants were categorized into 5 pain severity groups based on an additive index of frequency, intensity, time or duration, and total number of pain sites (FITT). Covariates included age, sex, race or ethnicity, study site, and knee pain status. Results: The no or low chronic pain severity group had significantly longer telomeres compared with the high pain severity group, P = 0.025. A significant chronic pain severity dose response emerged for telomere length, P = 0.034. The FITT chronic pain severity index was highly correlated with the clinical and functional OA pain measures. However, individual clinical and functional measures were not associated with telomere length. Conclusion: Results demonstrate accelerated cellular aging with high knee OA chronic pain severity and provide evidence for the potential utility of the FITT chronic pain severity index in capturing the biological burden of chronic pain. PMID- 29392208 TI - Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy. AB - Introduction: Alleviation of pain, by either medical or surgical therapy, is accompanied by transition from less efficient, or pro-nociceptive, to efficient conditioned pain modulation (CPM). Spontaneous decrease or resolution of pain with disease progression is reported for some patients with painful diabetic neuropathy (PDN). Objectives: To explore whether CPM changes similarly in parallel to spontaneous resolution of pain in PDN patients. Methods: In this cross-sectional study, thirty-three patients with PDN underwent psychophysical assessment of pain modulation on the forearm, remote from the clinical pain. Results: Pain duration was not correlated with neuropathic pain intensity, yet, it correlated with CPM efficiency; patients with longer pain duration had same pain level, but more efficient CPM than those with short-pain duration (rho = 0.417; P = 0.025, Spearman correlation). Patients with pain more than 2 years (median split) expressed efficient CPM that was not different from that of healthy controls. These patients also had lower temporal summation of pain than the short-pain duration patients group (P < 0.05). The 2 patient groups did not differ in clinical pain characteristics or use of analgesics. Conclusion: Pro nociception, expressed by less efficient CPM and high temporal summation that usually accompanies clinical painful conditions, seems to "normalize" with chronicity of the pain syndrome. This is despite continuing pain, suggesting that pro-nociceptivity in pain syndromes is multifactorial. Because the pain modulation profile affects success of therapy, this suggests that different drugs might express different efficacy pending on duration of the pain in patients with PDN. PMID- 29392209 TI - Methylphenidate attenuates the response to cold pain but not to aversive auditory stimuli in healthy human: a double-blind randomized controlled study. AB - Introduction: We recently showed that the psycho-stimulant norepinephrine dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD). Objectives: The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MP's effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities. Methods: This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo. Results: Forty men, 26.1 +/- 4.0 (mean +/- SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 +/- 2.6 to 5.4 +/- 3.1 seconds, P = 0.001 and from 4.5 +/- 2.6 to 4.3 +/- 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 +/- 54.0 to 73.8 +/- 61.8 seconds, P = 0.001 and from 52.5 +/- 53.7 sec to 57.0 +/- 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters. Conclusion: These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli. PMID- 29392210 TI - Corticospinal excitability as a biomarker of myofascial pain syndrome. AB - Introduction: Myofascial pain syndrome (MPS) is a common chronic pain disorder that lacks effective diagnostic criteria. To better understand neurophysiological changes in chronic pain, several trials exploring corticospinal excitability in different populations of patients with chronic pain have been performed. Objectives: In this systematic review, we aimed to investigate the current literature on MPS and intracortical disinhibition, by means of increased intracortical facilitation and decreased intracortical inhibition (ICI). Methods: We performed a search on PubMed to identify clinical trials on MPS and transcranial magnetic stimulation measurements. We then applied the Harford Hill criteria to the identified studies to assess the possible causal relationship between intracortical disinhibition measurements and MPS. Finally, we compared our findings on MPS with other chronic pain conditions. Results: Four studies assessing corticospinal excitability in patients with MPS were found. Although the amount of trials available is limited, all the reported studies indicated an increased intracortical disinhibition in patients with MPS. Importantly, these measurements were also correlated with psychological factors, such as pain catastrophism, or anxiety. However, based on the Harford Hill criteria, we could not assert a strong causal relationship between these markers and MPS. Although intracortical disinhibition has been consistently found in patients having MPS, this lack of cortical inhibition was not only observed in this specific chronic pain syndrome but also in fibromyalgia and neuropathic pain conditions. Conclusion: Intracortical disinhibition seems to be a marker that has been consistently observed in MPS. Future prospective cohort studies could provide new insights in the development of neoplastic and maladaptive changes occurring in chronic pain syndromes and help the development of new therapeutic options. PMID- 29392211 TI - Women report higher pain intensity at a lower level of inflammation after knee surgery compared with men. AB - Introduction and Objectives: We previously found that women report more pain after knee arthroscopic procedures than men. It remains unclear whether this is due to different biochemical responses or nociceptive mechanisms. Methods: We analyzed acute pain-related inflammatory markers in a clinical model of patient self-reported pain immediately after knee surgery. To simultaneously measure 92 inflammatory biomarkers, we used the proximity extension assay with the Proseek Multiplex Inflammation I panel (Olink Bioscience, Uppsala, Sweden). Knee surgery was performed under general anesthesia with propofol and remifentanil. Analgesic drugs were only administered on patient request. Results: Women were 4.9 times more likely to report moderate or severe pain than men (95% confidence interval, 1.2-19.6, P = 0.024). Patient age, preoperative pain, and surgery duration were not significant factors. We analyzed synovial fluids from 44 patients (23 women, 21 men). After false discovery rate correction, MMP-10 was the only biomarker that was higher among men (P = 0.01). Linear discriminant analysis showed that 3 proteins (IL-8, CCL-4, and MCP-2) were expressed at higher levels in men, with differences of >1 normalized protein expression. No proteins were overexpressed by >1 normalized protein expression in women. Conclusion: Acute pain after knee arthroscopy was more intense in women, but pro-inflammatory biomarkers and MMP-10 were higher in men. Further knowledge of cytokine function is required before concluding that the disparities in biomarker expression are clinically unimportant. The similar biochemical signaling between sexes suggests that central mechanisms are of greater importance in sex-specific joint pain perception. PMID- 29392212 TI - Effect of gastroretentive gabapentin (Gralise) on postmastectomy pain syndrome: a proof-of-principle open-label study. AB - Introduction: Chronic pain is a common and debilitating complication following breast surgery. One of the most challenging for treatment is the neuropathic pain condition, postmastectomy pain syndrome (PMPS). Gabapentin is a pharmacotherapy for neuropathic pain disorders; however, its once-daily, gastroretentive formulation, Gralise, has not been evaluated in PMPS. Objective: To evaluate the safety and effectiveness of Gralise in patients with moderate-to-severe PMPS. Methods: The primary effectiveness endpoint was a change in the worst pain intensity score from baseline to completion of 8 weeks of Gralise therapy. The secondary endpoints included the change in mood, coping behavior, sleep, and function. Sensitivity to experimental stimuli was tested before and after treatment via quantitative sensory testing. The incidence and type of adverse event were used to evaluate the safety and tolerability of Gralise. Results: Twenty-one patients with confirmed moderate-to-severe PMPS were enrolled. Nineteen of 21 (90.5%) patients completed the 8-week treatment with Gralise. A significant positive change was found in pain intensity, pain impact, and sleep. There was no change in sensory testing scores. Of total, 63.16% of patients reported reduction in present pain, 78.95% in average pain, 89.47% in worst pain, and 84.21% in overall pain severity at posttreatment visit. No significant adverse effects were noted in the study. Limitations: Variation in type of breast surgery, small sample size, lack of placebo control. Conclusion: There was a significant improvement in pain and sleep, and Gralise was well tolerated in patients with PMPS. Further investigation is warranted. PMID- 29392214 TI - The opioid epidemic and national guidelines for opioid therapy for chronic noncancer pain: a perspective from different continents. AB - Introduction: A marked rise in opioid prescriptions for patients with chronic noncancer pain (CNCP) with a parallel increase in opioid abuse/misuse, and resulting deaths was noted in the Unites states in the past decade (opioid epidemic). In response, the US Center of Diseases Control (CDC) developed a guideline for prescribing of opioids for patients with CNCP. Objectives: To assess (1) if there is an opioid epidemic in Australia, Canada, and Germany (2) to compare Australian, Canadian, German, and Center of Diseases Control guidelines recommendations for long-term opioid therapy for CNCP. Methods: National evidence-based guidelines and PubMed were searched for recommendations for opioid prescriptions for CNCP. Results: There are signs of an opioid epidemic in Australia and Canada, but not in Germany. Guidelines in all 4 countries provide similar recommendations: opioids are not the first-line therapy for patients with CNCP; regular clinical assessments of benefits and harms are necessary; excessive doses should be avoided (recommended morphine equivalent daily doses range from 50 to 200 mg/d); stopping rules should be followed. All guidelines do not recommend the use of opioids in chronic pain conditions without an established nociceptive or neuropathic cause such as fibromyalgia and primary headache. Conclusion: Implementation of opioid prescribing guidelines should ensure that physicians prescribe opioids only for appropriate indications in limited doses for selected patients and advice patients on their safe use. These measures could contribute to reduce prescription opioid misuse/abuse and deaths. PMID- 29392213 TI - Diagnostic confounders of chronic widespread pain: not always fibromyalgia. AB - Introduction: Chronic widespread pain (CWP) is the defining feature of fibromyalgia (FM), a worldwide prevalent condition. Chronic widespread pain is, however, not pathognomonic of FM, and other conditions may present similarly with CWP, requiring consideration of a differential diagnosis. Objectives: To conduct a literature search to identify medical conditions that may mimic FM and have highlighted features that may differentiate these various conditions from FM. Methods: A comprehensive literature search from 1990 through September 2016 was conducted to identify conditions characterized by CWP. Results: Conditions that may mimic FM may be categorized as musculoskeletal, neurological, endocrine/metabolic, psychiatric/psychological, and medication related. Characteristics pertaining to the most commonly identified confounding diagnoses within each category are discussed; clues to enable clinical differentiation from FM are presented; and steps towards a diagnostic algorithm for mimicking conditions are presented. Conclusion: Although the most likely reason for a complaint of CWP is FM, this pain complaint can be a harbinger of illness other than FM, prompting consideration of a differential diagnosis. This review should sensitize physicians to a broad spectrum of conditions that can mimic FM. PMID- 29392215 TI - Can training in empathetic validation improve medical students' communication with patients suffering pain? A test of concept. AB - Introduction: Patient-centered, empathetic communication has been recommended as a means for improving the health care of patients suffering pain. However, a problem has been training health care providers since programs may be time consuming and difficult to learn. Validation, a form of empathetic response that communicates that what a patient experiences is accepted as true, has been suggested as an appropriate method for improving communication with patients suffering pain. Objectives: We study the immediate effects of providing medical students with a 2-session (45-minute duration each) program in validation skills on communication. Methods: A one group, pretest vs posttest design was employed with 22 volunteer medical students. To control patient variables, actors simulated 1 of 2 patient scenarios (randomly provided at pretest and posttest). Video recordings were blindly evaluated. Self-ratings of validation and satisfaction were also employed. Results: Observed validation responses increased significantly after training and corresponded to significant reductions in invalidating responses. Both the patient simulators and the medical students were significantly more satisfied after the training. Conclusions: We demonstrated that training empathetic validation results in improved communication thus extending previous findings to a medical setting with patients suffering pain. Our results suggest that it would be feasible to provide validation training for health care providers and this warrants further investigation in controlled studies. PMID- 29392216 TI - The impact of pain-related fear on neural pathways of pain modulation in chronic low back pain. AB - Introduction: Pain-related fear plays a substantial role in chronic low back pain (LBP) by amplifying the experienced disability. Related dysfunctional emotions and cognitions may also affect sensory aspects of pain through a modulatory pathway in which the periaqueductal gray (PAG) and the amygdala play key roles. Objectives: We therefore hypothesized a differential amygdala-PAG functional connectivity (FC) in patients with chronic LBP that is modulated by the degree of pain-related fear. Methods: We used data of a previously reported fMRI study where 20 chronic LBP patients (7 females, mean age = 39.35) and 20 healthy controls (12 females, mean age = 32.10) were asked to observe video clips showing potentially harmful and neutral activities for the back. Pain-related fear was assessed using the Tampa Scale of kinesiophobia (TSK) and Fear Avoidance Beliefs questionnaires (FABQ). Generalized psychophysiological interactions were used to reveal task-based FC. Results: Compared to controls, patients exhibited a significant decrease in amygdala-PAG-FC (P = 0.022) during observation of harmful activities, but not of neutral activities. Furthermore, amygdala-PAG-FC correlated negatively with Tampa Scale of kinesiophobia scores in patients (R2 = 0.28, P = 0.01) but not with Fear Avoidance Beliefs questionnaires scores. Discussion: Our findings might indicate a maladaptive psychobiological interaction in chronic LBP patients characterized by a disrupted amygdala-PAG-FC that is modulated by the degree of pain-related fear. These results shed new light on brain mechanisms underlying psychological factors that may have pronociceptive effects in chronic LBP. PMID- 29392217 TI - Psychosocial factors and their influence on the experience of pain. AB - Over the past 20 years, our understanding of social factors on pain experience has increased. Edwards et al observed that the presence of a friend resulted in an increased pain threshold and tolerance to experimentally induced pain (cold pressor test and pressure algometry). Having a male friend present had the most prominent effect on male participants' reporting of pain. However, the effects of psychosocial traits known to effect pain experience (eg, catastrophising) were not considered. PMID- 29392219 TI - "Are perioperative opioids obsolete?" Proceedings of an IASP Acute Pain Special Interest Group Satellite Symposium September 25, 2016 Yokohama, Japan. AB - This IASP Satellite Symposium surveyed opioid adverse effects upon patients and society, current and future drug and nondrug alternatives, and strategies to optimize postoperative outcomes through quality improvement. PMID- 29392218 TI - Rat model of cancer-induced bone pain: changes in nonnociceptive sensory neurons in vivo. AB - Introduction: Clinical data on cancer-induced bone pain (CIBP) suggest extensive changes in sensory function. In a previous investigation of an animal model of CIBP, we have observed that changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) nociceptive neurons correspond to mechanical allodynia and hyperalgesia. Objectives: To investigate the mechanisms underlying changes in nonnociceptive sensory neurons in this model, we have compared the electrophysiological properties of primary nonnociceptive sensory neurons at <1 and >2 weeks after CIBP model induction with properties in sham control animals. Methods: Copenhagen rats were injected with 106 MAT-LyLu rat prostate cancer cells into the distal femur epiphysis to generate a model of CIBP. After von Frey tactile measurement of mechanical withdrawal thresholds, the animals were prepared for acute electrophysiological recordings of mechanically sensitive neurons in the DRG in vivo. Results: The mechanical withdrawal threshold progressively decreased in CIBP model rats. At <1 week after model induction, there were no changes observed in nonnociceptive Abeta-fiber DRG neurons between CIBP model rats and sham rats. However, at >2 weeks, the Abeta fiber low-threshold mechanoreceptors (LTMs) in CIBP model rats exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and lower AP amplitude compared with sham rats. Furthermore, enhanced excitability of Abeta-fiber LTM neurons was observed as an excitatory discharge in response to intracellular injection of depolarizing current into the soma. Conclusion: After induction of the CIBP model, Abeta-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Abeta-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP. PMID- 29392220 TI - Interpersonal behavior in anticipation of pain: a naturalistic study of behavioral mimicry prior to surgery. AB - Introduction: Social relationships facilitate coping with pain, but research suggests that it may be difficult to galvanize social support during an episode of acute pain. Objectives: The current research examined whether social connections are optimized in the anticipation of pain by observing patients' mimicry of an interaction partner prior to surgery. We hypothesized that when controlling for their current experience of pain, patients' anticipation of pain would be associated with greater mimicry of an interaction partner. Methods: Sixty-five patients were interviewed in the waiting room of a maxillofacial surgery unit prior to the removal of an impacted wisdom tooth. Patients' spontaneous mimicry of an interviewer was observed. Patients then rated the quality and intensity of their anticipated pain, as well as the intensity of their current pain and their affective distress. Results: Anticipated pain, current pain, and affective distress were positively correlated. Current pain was associated with less frequent mimicry of an interaction partner. The zero-order correlation between anticipated pain and mimicry did not reach conventional levels of significance; however, when controlling for current pain, anticipated pain predicted more frequent mimicry of an interaction partner. The relationship between anticipated pain and mimicry was not explained by affective distress. Conclusion: This is the first study to demonstrate that anticipated and current pain relate to behavioral mimicry in divergent ways. Further research is needed to investigate whether the current pattern of results generalizes to other interpersonal behaviors that facilitate social bonds. PMID- 29392221 TI - Differences in opioid prescribing in low back pain patients with and without depression: a cross-sectional study of a national sample from the United States. AB - Introduction: Low back pain (LBP) is among the leading indications for the prescription of opioid analgesics in clinical practice. There is increasing evidence suggesting that these agents may have diminished efficacy in the treatment of LBP. Objectives: We evaluated the relationship between depression, the probability of receiving an opioid prescription, and the amount of morphine equivalent amounts prescribed per year among patients with LBP using nationwide data. Methods: A cross-sectional analysis was performed on existing data from the Medical Expenditure Panel Survey data set from the period 2004 to 2009. Demographic, medical condition, Patient Health Questionnaire-2 responses, and prescription drug information were obtained on 56,811,864 weighted person-years of data from individuals aged 18 to 65 with an ICD-9 code specific to LBP. Results: Increases in PHQ-2 score, as well a positive screen for depression, were associated with an increased probability of being prescribed opioid therapy and more morphine equivalents per year. Conclusion: Analysis of a nationwide sample of patients with LBP shows an association between depression and higher rates of opioid prescribing after controlling for several known cofounders. Clinicians prescribing opioids in LBP populations that rely on clinical trial results that exclude depressed patients may misjudge the risks and benefits of this class of therapy. PMID- 29392222 TI - Psychosocial factors and their influence on the experience of pain: response to commentary. PMID- 29392223 TI - A new role of growth hormone and insulin growth factor receptor type 1 in neonatal inflammatory nociception. AB - Growth hormone (GH) and insulin growth factor 1 (IGF1) are implicated in nociceptive processing; it has been reported that the latter participates in neonatal inflammatory nociception. In the target article, the authors propose that local inflammation evoked by carrageenan administration in mice produces a decrease in the local GH levels and an increment of IGF1 receptors type 1 expression, this produces behavioral nociception and peripheral sensitization that can be prevented by GH systemic administration pretreatment. PMID- 29392224 TI - A new role of growth hormone and insulin-like growth factor receptor type 1 in neonatal inflammatory nociception: response to commentary. PMID- 29392226 TI - Acute pain management in patients with drug dependence syndrome. AB - Managing patients with dependence requires knowledge of pharmacology; an understanding of the diagnosis of dependence and recognition of withdrawal; skills in communication and collaborative working; and a nonjudgmental, empathic attitude. PMID- 29392225 TI - Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study. AB - Introduction: Drugs that counteract nociceptive transmission in the spinal dorsal horn preferentially after nerve injury are being pursued as possible neuropathic pain treatments. In a previous behavioural study, the peptide toxin Tx3-3, which blocks P/Q- and R-type voltage-gated calcium channels, was effective in neuropathic pain models. Objectives: In the present study, we aimed to investigate the effect of Tx3-3 on dorsal horn neuronal responses in rats under physiological conditions and neuropathic pain condition induced by spinal nerve ligation (SNL). Methods: In vivo electrophysiological recordings of dorsal horn neuronal response to electrical and natural (mechanical and thermal) stimuli were made in rats under normal physiological state (naive rats) or after the SNL model of neuropathic pain. Results: Tx3-3 (0.3-100 pmol/site) exhibited greater inhibitory effect on electrical-evoked neuronal response of SNL rats than naive rats, inhibiting nociceptive C-fibre and Adelta-fibre responses only in SNL rats. The wind-up of neurones, a measurement of spinal cord hyperexcitability, was also more susceptible to a dose-related inhibition by Tx3-3 after nerve injury. Moreover, Tx3-3 exhibited higher potency to inhibit mechanical- and thermal evoked neuronal response in conditions of neuropathy. Conclusion: Tx3-3 mediated differential inhibitory effect under physiological and neuropathic conditions, exhibiting greater potency in conditions of neuropathic pain. PMID- 29392227 TI - Preventing and treating medication overuse headache. AB - Medication overuse headache is a secondary headache-a worsening of a pre-existing headache (usually a primary headache) owing to overuse of one or more attack aborting or pain-relieving medications. PMID- 29392228 TI - Pediatric chronic pain programs: current and ideal practice. AB - Introduction: The treatment of youth with chronic pain has improved in recent years. However, because pediatric chronic pain programs are not governed by international standards, the development and implementation of new initiatives may be limited. Objectives: The objectives of this study were to identify the features of programs as they exist at present and to determine what features they should have in an ideal state. Methods: A web-based international survey was used to collect information. The survey contained 86 questions seeking respondent professional demographic data and information about the pain program with which the respondent was affiliated at the time (program organization, types of pain problem treated, professionals involved, services provided, size of the program, research, professional training, public education and advocacy, and funding sources). Results: Respondents were 136 pediatric pain experts representing different specialties located in 12 countries. Most respondents indicated that ideal programs would have a multidisciplinary staff; provide a wide range of treatments for different chronic pain problems; integrate research, formal clinical training of specialists, and public education and advocacy into their activities; and be an accredited part of the public health system. Conclusions: The results of this survey may be useful for health care professionals interested in treating chronic pain in children and adolescents and for policy makers concerned with improving the care given to these children and their families. PMID- 29392230 TI - Pharmacoeconomics of genotyping-based treatment decisions in patients with chronic pain. AB - Introduction: Genotyping-based treatment decisions may optimize treatment response and minimize adverse drug events (ADEs) in patients with chronic pain. Objectives: To estimate the financial impact of genotyping-based treatment decisions in patients with moderate to severe chronic pain in a managed care setting. Methods: A budget impact model was built with a 1-year time horizon to estimate costs of genotyping-based treatment decisions in a 1000-patient cohort. The model includes drug costs, type and cost of ADEs, distribution of treatments used, and genotyping costs. Event rates and health care costs were derived from primary literature. Three patient cohorts were assessed with and without genotyping-based treatment decisions: no genetic testing; 50% genetic testing; and 100% genetic testing. Sensitivity analysis was performed varying costs, adherence, and the percentage of patients treated according to genotyping results. Results: Medical and ADE costs varied by patient severity and genotyping rates. Without genotyping, drug and ADE costs ranged from $1,544,377 to $24,313,844. With genotyping-based treatment, total costs ranged from $1,780,922 to $18,868,032. Sensitivity analysis, varying costs, adherence, and genotyping rates suggested genotyping improves outcomes and is cost saving in patients with chronic pain. Conclusion: Genotyping-based treatment costs are offset by reduced medication utilization and adverse event costs. Genotyping should be considered for patients with chronic pain in clinical practice and within clinical trials. PMID- 29392229 TI - Mice with cancer-induced bone pain show a marked decline in day/night activity. AB - Introduction: Cancer-induced bone pain (CIBP) is the most common type of pain with cancer. In humans, this pain can be difficult to control and highly disabling. A major problem with CIBP in humans is that it increases on weight bearing and/or movement of a tumor-bearing bone limiting the activity and functional status of the patient. Currently, there is less data concerning whether similar negative changes in activity occur in rodent models of CIBP. Objectives: To determine whether there are marked changes in activity in a rodent model of CIBP and compare this to changes in skin hypersensitivity. Methods: Osteosarcoma cells were injected and confined to 1 femur of the adult male mouse. Every 7 days, spontaneous horizontal and vertical activities were assessed over a 20-hour day and night period using automated activity boxes. Mechanical hypersensitivity of the hind paw skin was assessed using von Frey testing. Results: As the tumor cells grew within the femur, there was a significant decline in horizontal and vertical activity during the times of the day/night when the mice are normally most active. Mice also developed significant hypersensitivity in the skin of the hind paw in the tumor-bearing limb. Conclusion: Even when the tumor is confined to a single load-bearing bone, CIBP drives a significant loss of activity, which increases with disease progression. Understanding the mechanisms that drive this reduction in activity may allow the development of therapies that allow CIBP patients to better maintain their activity and functional status. PMID- 29392231 TI - Persistent postsurgical pain in children and young people: prediction, prevention, and management. AB - Ensuring optimum preoperative and postoperative pain management should always be a priority in children. PMID- 29392232 TI - Gray matter alteration associated with pain catastrophizing in patients 6 months after lumbar disk surgery: a voxel-based morphometry study. AB - Introduction: Pain catastrophizing (PC), the increased attention to harmful aspects of pain (magnification), and the belief of low controllability (helplessness) has been shown to be important in the maintenance of pain. A growing research on structural alterations in chronic pain revealed an association between PC and brain areas that are involved in affective and cognitive pain processing. However, little is known about a differential effect of the components magnification and helplessness. Objective: The aim of this study was to identify brain regions associated with overall PC and with the single components of magnification and helplessness. Methods: We investigated 29 patients 6 months after lumbar disk surgery using voxel-based morphometry. Magnification and helplessness were assessed with subscales of the Avoidance Endurance Questionnaire (AEQ); overall PC was computed using the sum score. The structural brain imaging data were preprocessed and analyzed using SPM8 and VBM8. Multiple regression analyses were performed with PC scales as predictors and depression as covariate. Results: Pain catastrophizing was significantly associated with cortical gray matter in brain areas involved in processing attentional, sensory, and affective aspects of pain, including the left posterior cingulate cortex, supplementary motor area, and medial frontal gyrus. In addition, we provide preliminary evidence for brain structure association related to magnification and helplessness. Conclusion: This study provides evidence for PC-related structural alterations in patients with low back pain, which are consistent with findings from previous research in different chronic pain disorders. This study is the first to evaluate brain changes related to differential domains of PC. PMID- 29392234 TI - Effect of bupivacaine lozenges on oral mucositis pain: a randomized controlled multicenter phase II study. AB - Introduction: A nonblinded parallel-group randomized controlled study investigated the efficacy and tolerability of repeated administration of a bupivacaine lozenge (25 mg) as pain management for oral mucositis pain in head and neck cancer patients as add-on to standard systemic pain management. Objective: The primary end point was the difference between the intervention group (Lozenge group) and the Control group in daily mean pain scores in the oral cavity or pharynx (whichever was higher). Method: Fifty patients from 2 hospitals in Denmark were randomized 1:1 to 7 days of treatment with bupivacaine lozenges (taken up to every 2 hours) plus standard pain treatment minus topical lidocaine (Lozenge group) or standard pain treatment including topical lidocaine (Control group). The efficacy analysis included 38 patients, as 12 patients were excluded because of changes in study design and missing data. Results: Mean pain in the oral cavity or pharynx (whichever was higher) was significantly lower 60 minutes after taking lozenges (35 mm [n = 22]) than for the Control group (51 mm [n = 16]) (difference between groups -16 mm, 95% confidence interval: -26 to -6, P = 0.0032). Pain in the oral cavity was also significantly lower in the Lozenge group (18 mm) vs the Control group (36 mm, P = 0.0002). Pharyngeal mucositis pain did not differ significantly (37 mm [Lozenge group] vs 48 mm [Control group], P = 0.0630). No serious adverse events were reported. Conclusion: These results show that the bupivacaine lozenge as an add-on to standard pain treatment had a clinically significant pain-relieving effect in patients with oral mucositis. ClinicalTrialsgov: NCT02252926. PMID- 29392233 TI - Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms. AB - Introduction: It is generally believed that exercise produces its effects by activating central opioid receptors; there are little data that support this claim. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are key nuclei in opioid-induced analgesia, and opioids interact with serotonin to produce analgesia. Objectives: The purpose was to examine central inhibitory mechanisms involved in analgesia produced by wheel running. Methods: C57/Black6 mice were given access to running wheels in their home cages before induction of chronic muscle hyperalgesia and compared with those without running wheels. Systemic, intra-PAG, and intra-RVM naloxone tested the role of central opioid receptors in the antinociceptive effects of wheel running in animals with muscle insult. Immunohistochemistry for the serotonin transporter (SERT) in the spinal cord and RVM, and pharmacological blockade of SERT, tested whether the serotonin system was modulated by muscle insult and wheel running. Results: Wheel running prevented the development of muscle hyperalgesia. Systemic naloxone, intra-PAG naloxone, and intra-RVM naloxone reversed the antinociceptive effect of wheel running in animals that had received muscle insult. Induction of chronic muscle hyperalgesia increased SERT in the RVM, and blockade of SERT reversed the hyperalgesia in sedentary animals. Wheel running reduced SERT expression in animals with muscle insult. The serotonin transporter in the superficial dorsal horn of the spinal cord was unchanged after muscle insult, but increased after wheel running. Conclusion: These data support the hypothesis that wheel running produced analgesia through central inhibitory mechanisms involving opioidergic and serotonergic systems. PMID- 29392235 TI - Co-occurrence of posttraumatic stress symptoms, pain, and disability 12 months after traumatic injury. AB - Introduction: Chronic pain is common after traumatic injury and frequently co occurs with posttraumatic stress disorder (PTSD) and PTSD symptoms (PTSS). Objectives: This study sought to understand the association between probable PTSD, PTSS, and pain. Methods: Four hundred thirty-three participants were recruited from the Victorian Orthopaedic Trauma Outcomes Registry and Victorian State Trauma Registry and completed outcome measures. Participants were predominantly male (n = 324, 74.8%) and aged 17-75 years at the time of their injury (M = 44.83 years, SD = 14.16). Participants completed the Posttraumatic Stress Disorder Checklist, Brief Pain Inventory, Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire, Tampa Scale of Kinesiophobia, EQ-5D-3L and Roland Morris Disability Questionnaire 12 months after hospitalization for traumatic injury. Data were linked with injury and hospital admission data from the trauma registries. Results: Those who reported having current problems with pain were 3 times more likely to have probable PTSD than those without pain. Canonical correlation showed that pain outcomes (pain severity, interference, catastrophizing, kinesiophobia, self-efficacy, and disability) were associated with all PTSSs, but especially symptoms of cognition and affect, hyperarousal, and avoidance. Posttraumatic stress disorder symptoms, on the contrary, were predominantly associated with high catastrophizing and low self-efficacy. When controlling for demographics, pain and injury severity, depression, and self efficacy explained the greatest proportion of the total relationship between PTSS and pain-related disability. Conclusion: Persons with both PTSS and chronic pain after injury may need tailored interventions to overcome fear-related beliefs and to increase their perception that they can engage in everyday activities, despite their pain. PMID- 29392236 TI - Impact of patient information leaflets on pain medication intake behavior: a pilot study. AB - Introduction: Patient information leaflets on pain medication primarily list side effects while positive effects and action mechanisms remain underrepresented. Nocebo research has shown that negative instructions can lower analgesic effects. Objectives: Research on information leaflets and their influence on mood, memory of side effects, and intake behavior of healthy participants is needed. Methods: To determine the ratio of positive to negative phrases, 18 information leaflets of common, over-the-market analgesics were examined of which 1 was selected. In a randomized, controlled study design, 18 healthy participants read this leaflet while 18 control group participants read a matched, neutral leaflet of an electrical device. Collected data concerned the recall of positive and negative contents, mood, anxiety, and the willingness to buy and take the drug. Results: All examined leaflets listed significantly more side effects than positive effects (t17 = 5.82, P < 0.01). After reading the analgesic leaflet, participants showed a trend towards more negative mood (F1,34 = 3.78, P = 0.06, etap2 = 0.1), a lower intention to buy [chi2 (1, n = 36) = 12.5, P < 0.01], a higher unwillingness to take the medication [chi2 (1, n = 36) = 7.2, P < 0.01], and even a greater recall for side effects than positive effects (t17 = 7.47, P < 0.01). Conclusion: Reading the patient information leaflets can increase fear and lower the intention to buy and the willingness to take a pain medication. PMID- 29392237 TI - Development of a risk stratification and prevention index for stratified care in chronic low back pain. Focus: yellow flags (MiSpEx network). AB - Introduction: Chronic low back pain (LBP) is a major cause of disability; early diagnosis and stratification of care remain challenges. Objectives: This article describes the development of a screening tool for the 1-year prognosis of patients with high chronic LBP risk (risk stratification index) and for treatment allocation according to treatment-modifiable yellow flag indicators (risk prevention indices, RPI-S). Methods: Screening tools were derived from a multicentre longitudinal study (n = 1071, age >18, intermittent LBP). The greatest prognostic predictors of 4 flag domains ("pain," "distress," "social environment," "medical care-environment") were determined using least absolute shrinkage and selection operator regression analysis. Internal validity and prognosis error were evaluated after 1-year follow-up. Receiver operating characteristic curves for discrimination (area under the curve) and cutoff values were determined. Results: The risk stratification index identified persons with increased risk of chronic LBP and accurately estimated expected pain intensity and disability on the Pain Grade Questionnaire (0-100 points) up to 1 year later with an average prognosis error of 15 points. In addition, 3-risk classes were discerned with an accuracy of area under the curve = 0.74 (95% confidence interval 0.63-0.85). The RPI-S also distinguished persons with potentially modifiable prognostic indicators from 4 flag domains and stratified allocation to biopsychosocial treatments accordingly. Conclusion: The screening tools, developed in compliance with the PROGRESS and TRIPOD statements, revealed good validation and prognostic strength. These tools improve on existing screening tools because of their utility for secondary preventions, incorporation of exercise effect modifiers, exact pain estimations, and personalized allocation to multimodal treatments. PMID- 29392238 TI - Complex regional pain syndrome-up-to-date. AB - Complex regional pain syndrome (CRPS) was described for the first time in the 19th century by Silas Weir Mitchell. After the exclusion of other causes, CRPS is characterised by a typical clinical constellation of pain, sensory, autonomic, motor, or trophic symptoms which can no longer be explained by the initial trauma. These symptoms spread distally and are not limited to innervation territories. If CRPS is not improved in the acute phase and becomes chronic, the visible symptoms change throughout because of the changing pathophysiology; the pain, however, remains. The diagnosis is primarily clinical, although in complex cases further technical examination mainly for exclusion of alternative diagnoses is warranted. In the initial phase, the pathophysiology is dominated by a posttraumatic inflammatory reaction by the activation of the innate and adaptive immune system. In particular, without adequate treatment, central nociceptive sensitization, reorganisation, and implicit learning processes develop, whereas the inflammation moderates. The main symptoms then include movement disorders, alternating skin temperature, sensory loss, hyperalgesia, and body perception disturbances. Psychological factors such as posttraumatic stress or pain-related fear may impact the course and the treatability of CRPS. The treatment should be ideally adjusted to the pathophysiology. Pharmacological treatment maybe particularly effective in acute stages and includes steroids, bisphosphonates, and dimethylsulfoxide cream. Common anti-neuropathic pain drugs can be recommended empirically. Intravenous long-term ketamine administration has shown efficacy in randomised controlled trials, but its repeated application is demanding and has side effects. Important components of the treatment include physio- and occupational therapy including behavioural therapy (eg, graded exposure in vivo and graded motor imaging). If psychosocial comorbidities exist, patients should be appropriately treated and supported. Invasive methods should only be used in specialised centres and in carefully evaluated cases. Considering these fundamentals, CRPS often remains a chronic pain disorder but the devastating cases should become rare. PMID- 29392240 TI - A tonic heat test stimulus yields a larger and more reliable conditioned pain modulation effect compared to a phasic heat test stimulus. AB - Introduction: The interest in conditioned pain modulation (CPM) as a clinical tool for measuring endogenously induced analgesia is increasing. There is, however, large variation in the CPM methodology, hindering comparison of results across studies. Research comparing different CPM protocols is needed in order to obtain a standardized test paradigm. Objectives: The aim of the study was to assess whether a protocol with phasic heat stimuli as test-stimulus is preferable to a protocol with tonic heat stimulus as test-stimulus. Methods: In this experimental crossover study, we compared 2 CPM protocols with different test stimulus; one with tonic test-stimulus (constant heat stimulus of 120-second duration) and one with phasic test-stimuli (3 heat stimulations of 5 seconds duration separated by 10 seconds). Conditioning stimulus was a 7 degrees C water bath in parallel with the test-stimulus. Twenty-four healthy volunteers were assessed on 2 occasions with minimum 1 week apart. Differences in the magnitude and test-retest reliability of the CPM effect in the 2 protocols were investigated with repeated-measures analysis of variance and by relative and absolute reliability indices. Results: The protocol with tonic test-stimulus induced a significantly larger CPM effect compared to the protocol with phasic test-stimuli (P < 0.001). Fair and good relative reliability was found with the phasic and tonic test-stimuli, respectively. Absolute reliability indices showed large intraindividual variability from session to session in both protocols. Conclusion: The present study shows that a CPM protocol with a tonic test stimulus is preferable to a protocol with phasic test-stimuli. However, we emphasize that one should be cautious to use the CPM effect as biomarker or in clinical decision making on an individual level due to large intraindividual variability. PMID- 29392241 TI - Risk stratification for the development of chronic postsurgical pain. AB - Risk stratification for the development chronic postsurgical pain is an important tool, which may permit preventive measures or appropriate advice for patients at high risk. PMID- 29392239 TI - Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment. AB - Introduction: Chronic pancreatitis (CP) is a disease characterized by inflammation of the pancreas resulting in replacement of the normal functioning parenchyma by fibrotic connective tissue. This process leads to progressively impairment of exocrine and endocrine function and many patients develop a chronic pain syndrome. Objectives: We aimed to characterize the neurobiological signature of pain associated with CP and to discuss its implications for treatment strategies. Methods: Relevant basic and clinical articles were selected for review following an extensive search of the literature. Results: Pathophysiological changes in the peripheral (pancreatic gland) and central nervous system characterize the pain syndrome associated with CP; involved mechanisms can be broken down to 3 main branches: (1) peripheral sensitization, (2) pancreatic neuropathy, and (3) neuroplastic changes in the central pain pathways. Disease flares (recurrent pancreatitis) may accelerate the pathophysiological process and further sensitize the pain system, which ultimately results in an autonomous and self-perpetuating pain state that may become independent of the peripheral nociceptive drive. These findings share many similarities with those observed in neuropathic pain disorders and have important implications for treatment; adjuvant analgesics are effective in a subset of patients, and neuromodulation and neuropsychological interventions may prove useful in the future. Conclusion: Chronic pancreatitis is associated with abnormal processing of pain at the peripheral and central level of the pain system. This neurobiological understanding of pain has important clinical implications for treatment and prevention of pain chronification. PMID- 29392242 TI - Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine. AB - Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odors can act as a trigger to initiate an attack in sensitized individuals. Although noninvasive vagus nerve stimulation (nVNS) is now an approved treatment for chronic migraine, how it functions to inhibit trigeminal nociception in an episodic migraine model is not known. Objectives: The objectives of this study were to determine if nVNS could inhibit trigeminal nociception in a novel model of episodic migraine and investigate changes in the expression of proteins implicated in peripheral and central sensitization. Methods: Sprague-Dawley male rats were injected with an inflammatory agent in the trapezius muscle before exposure to pungent volatile compounds, which was used to initiate trigeminal nociceptor activation. The vagus nerve was stimulated transdermally by a 1-ms pulse of 5 kHz sine waves, repeated at 25 Hz for 2 minutes. Nocifensive head withdrawal response to von Frey filaments was determined and immunoreactive protein levels in the spinal cord and trigeminal ganglion (TG) were investigated. Results: Exposure to the pungent odor significantly increased the number of nocifensive withdrawals in response to mechanical stimulation of sensitized TG neurons mediated by neck muscle inflammation. Noninvasive vagus nerve stimulation inhibited nociception and repressed elevated levels of P-ERK in TG, Iba1 in microglia, and GFAP in astrocytes from sensitized animals exposed to the pungent odor. Conclusion: Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine. PMID- 29392243 TI - Evidence that dry eye is a comorbid pain condition in a U.S. veteran population. AB - Introduction: Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions. Objectives: To evaluate DE as a comorbid condition in the U.S. veteran population. Methods: Retrospective review of veterans seen in the Veterans Administration Healthcare System (Veteran Affairs) between January 1, 2010, and December 31, 2014. Dry eye and nonocular pain disorders were ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes. Dry eye was further separated into ICD-9 codes representing tear film dysfunction or ocular pain. chi2 and logistic regression analyses were used to examine frequency and risk of DE, ocular pain, and tear film dysfunction by pain disorders. Results: Of 3,265,894 veterans, 959,881 had a DE diagnosis (29.4%). Dry eye frequency increased with the number of pain conditions reported (P < 0.0005). Ocular pain was most strongly associated with headache (odds ratio [OR] 2.98; 95% confidence interval [CI] 2.95-3.01), tension headache (OR 2.64; 95% CI 2.58-2.71), migraine (OR 2.58; 95% CI 2.54-2.61), temporomandibular joint dysfunction (OR 2.39; 95% CI 2.34-2.44), pelvic pain (OR 2.30; 95% CI 2.24-2.37), central pain syndrome (OR 2.24; 95% CI 1.94-2.60), and fibromyalgia/muscle pain (OR 2.23; 95% CI 2.20-2.26), all P < 0.0005. Tear film dysfunction was most closely associated with osteoarthritis (OR 1.97; 95% CI 1.96-1.98) and postherpetic neuralgia (OR 1.95; 95% CI 1.90-2.00), both P < 0.0005. Conclusions: Dry eye, including both ocular pain and tear film dysfunction, is comorbid with pain conditions in this nationwide population, implying common mechanisms. PMID- 29392244 TI - Post-traumatic stress symptom clusters in acute whiplash associated disorder and their prediction of chronic pain-related disability. AB - Introduction: The presence of post-traumatic stress disorder (PTSD) symptoms has been found to be associated with an increased risk of persisting neck pain and disability in motor vehicle crash (MVC) survivors with whiplash injuries. The findings are mixed as to which PTSD symptom(s) best predicts recovery in this population. Objectives: The aims were (1) to explore the factor structure of the Post-traumatic Stress Diagnostic Scale (PDS) in a sample of acute whiplash injured individuals following a MVC and (2) to identify the PTSD-symptom clusters that best predict long-term neck pain-related disability in this population as measured by the Neck Pain Disability Index (NDI). Methods: A sample (N = 146) of whiplash-injured individuals completed the NDI and the PDS at baseline (<1 month) and at 6 months follow-up. Results: Principal component analyses generated 2 symptom clusters: re-experiencing/avoidance and hyperarousal/numbing. Nine trauma related PTSD symptoms loaded exclusively on the re-experiencing/avoidance cluster and 7 nonspecific PTSD symptoms loaded exclusively on the hyperarousal/numbing cluster. One PTSD symptom (ie, inability to recall an important aspect of the trauma) had no salient loading on either clusters. Structural equation modelling analysis indicated that there was a significant positive relationship between the hyperarousal/numbing symptom cluster and long-term neck pain-related disability, while no significant relationship was found between the re-experiencing/avoidance symptom cluster and long-term neck pain-related disability. Conclusion: Given that only the hyperarousal/numbing symptom cluster predicted long-term neck pain related disability, this finding may have implications in terms of diagnosis, assessment, and management of the psychological impact of whiplash-injured individuals following a MVC. PMID- 29392245 TI - EMR-Radiological Phenotypes in Diseases of the Optic Nerve and their Association with Visual Function. AB - Multi-modal analyses of diseases of the optic nerve, that combine radiological imaging with other electronic medical records (EMR), improve understanding of visual function. We conducted a study of 55 patients with glaucoma and 32 patients with thyroid eye disease (TED). We collected their visual assessments, orbital CT imaging, and EMR data. We developed an image-processing pipeline that segmented and extracted structural metrics from CT images. We derive EMR phenotype vectors with the help of PheWAS (from diagnostic codes) and ProWAS (from treatment codes). Next, we performed a principal component analysis and multiple-correspondence analysis to identify their association with visual function scores. We find that structural metrics derived from CT imaging are significantly associated with functional visual score for both glaucoma (R2=0.32) and TED (R2=0.4). Addition of EMR phenotype vectors to the model significantly improved (p<1E-04) the R2 to 0.4 for glaucoma and 0.54 for TED. PMID- 29392246 TI - Maximum Mean Discrepancy Based Multiple Kernel Learning for Incomplete Multimodality Neuroimaging Data. AB - It is challenging to use incomplete multimodality data for Alzheimer's Disease (AD) diagnosis. The current methods to address this challenge, such as low-rank matrix completion (i.e., imputing the missing values and unknown labels simultaneously) and multi-task learning (i.e., defining one regression task for each combination of modalities and then learning them jointly), are unable to model the complex data-to-label relationship in AD diagnosis and also ignore the heterogeneity among the modalities. In light of this, we propose a new Maximum Mean Discrepancy (MMD) based Multiple Kernel Learning (MKL) method for AD diagnosis using incomplete multimodality data. Specifically, we map all the samples from different modalities into a Reproducing Kernel Hilbert Space (RKHS), by devising a new MMD algorithm. The proposed MMD method incorporates data distribution matching, pair-wise sample matching and feature selection in an unified formulation, thus alleviating the modality heterogeneity issue and making all the samples comparable to share a common classifier in the RKHS. The resulting classifier obviously captures the nonlinear data-to-label relationship. We have tested our method using MRI and PET data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset for AD diagnosis. The experimental results show that our method outperforms other methods. PMID- 29392247 TI - Novel conformationally constrained 2'-C-methylribonucleosides: synthesis and incorporation into oligonucleotides. AB - Synthesis of two novel conformationally constrained bicyclic ribonucleoside phosphoramidites bearing a 2'-C-methyl substituent has been accomplished. These phosphoramidites were used to incorporate the corresponding 2'-C-methyl nucleotides into oligonucleotides and to study their effects on duplex thermal stability. Whereas the C2'-O4'-linked LNA-type derivative induced severe destabilization of duplexes formed with complementary DNA and RNA, the C3'-O4' linked derivative induced RNA-selective hybridization with increased affinity relative to that of the unmodified DNA-based probe. PMID- 29392248 TI - Selective and sensitive detection of lysozyme based on plasmon resonance light scattering of hydrolyzed peptidoglycan stabilized-gold nanoparticles. AB - The simple, economic, rapid, and sensitive detection of lysozyme has an important significance for disease diagnosis since it is a potential biomarker. In this work, a new detection strategy for lysozyme was developed based on the change of the plasmon resonance light scattering (PRLS) signal of peptidoglycan stabilized gold nanoparticles (PGN-AuNPs). Peptidoglycan (PGN) was employed as a stabilizer to prepare PGN-AuNPs which have the properties of a uniform particle size, good stability, and a specific biological function. Due to the specific cleavage of lysozyme to PGN, a very simple specific and sensitive detection method for lysozyme was developed based on the PRLS signal of PGN-AuNPs after mixing with lysozyme for 1.5 h. The enhanced PRLS signals (DeltaIPRLS, at 560 nm) increased linearly with increasing lysozyme in the range 5 nM to 1600 nM with the detection limit down to 2.32 nM (DeltaIPRLS = 41.6397 + 0.5332c, R = 0.9961). When the PGN AuNP based method was applied to assay lysozyme in authentic human serum samples, the recovery efficiency was 106.76-119.32% with the relative standard deviations in the range of 0.14-3.11%, showing good feasibility. The PGN-AuNP based method for lysozyme assay developed here is simple, rapid, selective, and sensitive, which is expected to provide a feasible new method for the diagnosis or prognosis of lysozyme-related diseases in a clinical setting. PMID- 29392249 TI - Cryofocus fast gas chromatography combustion isotope ratio mass spectrometry for rapid detection of synthetic steroid use in sport doping. AB - Sports doping requires high precision carbon isotope ratio (CIR) analysis of endogenous steroids using gas chromatography-combustion isotope ratio mass spectrometry (GCC-IRMS), however methods are relatively slow and cumbersome. A cryofocusing fast GCC-IRMS (Cryofocus Fast GCC-IRMS) was developed and optimized with minimal peak broadening using a programmable temperature vaporization (PTV) inlet and a low dead volume narrow-bore continuous capillary combustion interface to an IRMS. PTV injection, followed with cryofocusing before steroid analytes were volatilized by a hot jet, was used to initiate chromatography. Compared to ramping temperature using a conventional GC oven, cryofocusing with hot jet volatilization reduced analysis time by a factor of 3 to 4 and reduced peak widths to ~800 ms. Well separated peak isotope ratios were measured with SD(delta13C) < 0.50/00 over a range of 10-50 ng of each steroid on column and were accurate from 2 ng to 100 ng. Characterization of the current experimental system with well characterized pure steroid isotopic standards demonstrates how the technique can be applied to steroid mixtures derived from real urine samples. Cryofocus Fast GCC-IRMS advances toward the goal of routine CIR testing of steroids in all urine samples for doping control. PMID- 29392250 TI - A gold nanoparticle-based four-color proximity immunoassay for one-step, multiplexed detection of protein biomarkers using ribonuclease H signal amplification. AB - A novel gold nanoparticle-based four-color fluorescence proximity immunoassay is developed for one-step, multiplexed detection of protein biomarkers using ribonuclease H signal amplification. This assay could detect proteins with detection limits down to pg mL-1 and a 5-log dynamic range. Furthermore, it is suitable for rapid, direct quantification of multiple proteins in biological samples. PMID- 29392251 TI - Synthesis, structure and N-N bonding character of 1,1-disubstituted indazolium hexafluorophosphate. AB - 1,1-Disubstituted indazolium hexafluorophosphates were synthesized via intramolecular electrophilic amination reactions under mild conditions. The crystal structures were determined and are consistent with the presence of a stable N-N bond, which can be cleaved by hydrogenation. Both experimental and computational studies suggest a covalent bonding character of the N-N bond, with diminished aromaticity of the newly formed pyrazolium ring due to the quaternary ammonium atom (N1), in contrast to the aromatic character of the parent indazole. PMID- 29392252 TI - Foam flow in a model porous medium: I. The effect of foam coarsening. AB - Foam structure evolves with time due to gas diffusion between bubbles (coarsening). In a bulk foam, coarsening behaviour is well defined, but there is less understanding of coarsening in confined geometries such as porous media. Previous predictions suggest that coarsening will cause foam lamellae to move to low energy configurations in the pore throats, resulting in greater capillary resistance when restarting flow. Foam coarsening experiments were conducted in both a model-porous-media micromodel and in a sandstone core. In both cases, foam was generated by coinjecting surfactant solution and nitrogen. Once steady state flow had been achieved, the injection was stopped and the system sealed off. In the micromodel, the foam coarsening was recorded using time-lapse photography. In the core flood, the additional driving pressure required to reinitiate flow after coarsening was measured. In the micromodel the bubbles coarsened rapidly to the pore size. At the completion of coarsening the lamellae were located in minimum energy configurations in the pore throats. The wall effect meant that the coarsening did not conform to the unconstricted growth laws. The coreflood tests also showed coarsening to be a rapid process. The additional driving pressure to restart flow reached a maximum after just 2 minutes. PMID- 29392253 TI - Polysubstituted 3-trifluoromethylpyrazoles: regioselective (3 + 2)-cycloaddition of trifluoroacetonitrile imines with enol ethers and functional group transformations. AB - Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Bronsted acid-induced elimination of ROH molecules led to the formation of 3 trifluoromethylated pyrazoles. In the case of 2,3-dihydrofuran, the respective bicyclic intermediate was isolated and its structure was confirmed by X-ray analysis. Using the developed protocol the synthesis of a known antitumor compound SC-560 was performed in 45% yield. Subsequent functionalisations of selected 4-(omega-hydroxyalkyl)pyrazoles at C(5) through lithiation/addition, cross-coupling reactions or via intramolecular Pd-catalysed C-H arylations opened up an access to polysubstituted pyrazoles including unusual tricyclic systems comprising 7-membered rings (oxepane, thiepane and azepane) as the central unit. PMID- 29392254 TI - A conductive hydrogel based on alginate and carbon nanotubes for probing microbial electroactivity. AB - Some bacteria can act as catalysts to oxidize (or reduce) organic or inorganic matter with the potential of generating electrical current. Despite their high value for sustainable energy, organic compound production and bioremediation, a tool to probe the natural biodiversity and to select most efficient microbes is still lacking. Compartmentalized cell culture is an ideal strategy for achieving such a goal but the appropriate compartment allowing cell growth and electron exchange must be tailored. Here, we develop a conductive composite hydrogel made of a double network of alginate and carbon nanotubes. Homogeneous mixing of carbon nanotubes within the polyelectrolyte is obtained by a surfactant assisted dispersion followed by a desorption step for triggering electrical conductivity. Dripping the mixture in a gelling bath through simple extrusion or a double one allows the formation of either plain hydrogel beads or liquid core hydrogel capsules. The process is shown to be compatible with the bacterial culture (Geobacter sulfurreducens). Bacteria can indeed colonize the outer wall of plain beads or the inner wall of the conductive capsules' shell that function as an anode from which electrons produced by the cells are collected. PMID- 29392255 TI - Neglected nano-effects of nanoparticles in the interpretation of their toxicity. AB - Nanoparticles with smaller diameters have larger surface areas. Unfortunately, this fact is often neglected in their biomedical characterization, e.g. in the evaluation of their toxicity with cell viability tests. We here point out the different scientific conclusions drawn in such tests when considering the traditional mass or concentration of nanoparticles, or their surface areas. PMID- 29392256 TI - Immobilization of membrane proteins on solid supports using functionalized beta sheet peptides and click chemistry. AB - We have developed two functionalized beta-sheet peptides (FBPs) and demonstrated that they can stabilize a variety of integral membrane proteins (IMPs), and most importantly allow covalent crosslinking of the IMPs onto solid supports via the highly selective click chemistry. The FBPs are promising tools for the preparation of IMP-based biomaterials or biosensors. PMID- 29392257 TI - Zn-Porphyrin propped with hydantoin anchor: synthesis, photophysics and electron injection/recombination dynamics. AB - In this work, Zn-porphyrin with a hydantoin anchor (ZnPHy) was designed and synthesized for dye-sensitized solar cell (DSC) applications. The synthesized ZnPHy was well characterized using IR, NMR and mass spectral techniques, and satisfactory results were obtained. Cyclic voltammetry, UV-visible absorption, steady-state fluorescence, time-resolved fluorescence and transient absorption spectroscopic techniques were employed to elucidate the electrochemical and photophysical properties of ZnPHy. The obtained properties revealed that the synthesized ZnPHy can be used as a photosensitizer for DSC applications. The nature of ZnPHy binding onto the TiO2 surface was investigated using ATR-FTIR and UV-Vis absorption measurements. The amount of adsorbed ZnPHy on TiO2 surface was reasonably fit using the Langmuir adsorption isotherm, with a binding constant value of 1.03 * 105 M-1. Time-resolved measurements were used to elucidate the rate of electron injection and the regeneration and recombination kinetics for ZnPHy/TiO2 film. The ZnPHy showed a high electron injection rate with a phiinj of 99%. Intriguingly, the rate of electron recombination is much slower than the rates reported for carboxyl-based Zn-porphyrins. Such a high electron injection and slow electron recombination rate are beneficial to produce long-lived electrical current in a photovoltaic device. Thus, the ZnPHy-sensitized TiO2 electrode showed the best photovoltaic performance, with the short-circuit photocurrent density (JSC), open-circuit voltage (VOC) and fill factor (ff) of 3.49 mA cm-2, 0.6 V and 0.52, respectively, yielding an overall conversion efficiency (eta) of 1.01%. For comparison, the ZnCOOH-sensitized electrode was also fabricated under the same conditions and yielded the eta value of 0.84%. Hence, the hydantoin moiety could be a potential alternative anchoring group for DSC applications. PMID- 29392258 TI - Investigating low-valent compositions in the Na3V2O2x(PO4)2F3-2x family: structural transitions and their consequences. AB - A member of the family of compounds with the formula Na3V2O2x(PO4)2F3-2x is synthesized by carbothermal reduction and 2 consecutive hydrothermal processes. The initial structural and spectroscopic characterization indicates that there are two phases in the as-synthesized material, a mixed valent phase with an intermediate V oxidation state adopting a P42/mnm space group at about 66%, and another phase with a V oxidation state close to V3+ adopting an Amam space group at about 33%. The role of each species in the electrode function is interrogated using in situ synchrotron X-ray diffraction and these data indicate that soon after charge begins, the Amam phase transforms into the P42/mnm phase. Further structural evolution of the material shows a prevailing two-phase reaction at lower potentials and a significant solid solution region during the high potential feature in the electrochemical curve with a final two-phase region at the end of charge. The conversion of the Amam component into P42/mnm showed no reversibility upon discharge. This phase-mixed electrode appears to illustrate that the mixed valent P42/mnm phase dominates electrochemical behavior during cycling and this may prove vital when preparing members in the sodium vanadium fluorophosphate family, especially if there is an energetically preferred phase for cycling. PMID- 29392259 TI - A general strategy for diverse syntheses of anhydrolandomycinone, tetrangulol, and landomycinone. AB - A general synthetic strategy based on a protecting group-promoted CH arylation method was developed for total syntheses of anhydrolandomycinone (1), tetrangulol (2), and landomycinone (3) from the same set of starting materials. PMID- 29392260 TI - Topological behaviour of ternary non-symmorphic crystals KZnX (X = P, As, Sb) under pressure and strain: a first principles study. AB - An ab initio study on the impact of hydrostatic pressure and strain on the electronic properties of an unexplored class of ternary Zintl phases KZnX (X = P, As, Sb) is reported. Density functional theory (DFT) based studies revealed that all the three materials are direct band gap semiconductors under ambient conditions. We have theoretically demonstrated that KZnX can be driven into different metallic phases under pressure. In contrast, by applying strain the compounds can be realized as topological insulators. This is confirmed by the observed non-trivial topological character in the electronic band structure of the present ternary systems. For the precise determination of low energy band topology, the Tran Blaha modified Becke-Johnson (TBmBJ) exchange potential was used by incorporating spin-orbit coupling. The concomitant change of electronic band shapes as a function of pressure indicates a semi-metallic nature in KZnX (X = P, As, Sb) at 30 GPa, 21 GPa and 11 GPa respectively. Based on an analysis of the parity eigenvalues, we anticipate that a band inversion occurs between the Zn s and X-p states, thus demonstrating a weak topological behaviour in semi metallic states. Also, a weak non-trivial topologically insulating phase is realized in strained KZnAs (18%) and KZnSb (10%) which appears to be due to overlapping of the Zn-s and X-p orbitals. The calculated surface spectral functions further validate the non-triviality of strained KZnX (X = As, Sb), whereas strained KZnP is found to be a trivial insulator. We confirm the topological behaviour of these materials by calculating topological surface states and defining a Z2 topological invariant. Our work based on sophisticated first-principles calculations highlights that both pressure and strain can trigger topological phases in non-symmorphic trivial band insulators even with a weak spin orbit interaction. This study paves the way for realizing semi-metallic and topological insulating states in non-symmorphic ternary semiconductors, which have not been experimentally demonstrated so far. PMID- 29392261 TI - Non-linear and non-local behaviour in spontaneously electrical solids. AB - Using reflection-absorption infrared spectroscopy (RAIRS), we show that solids displaying spontaneous dipole orientation possess quite general non-local and non linear characteristics, exemplified through their internal electric fields. The most graphic illustration of this, uncovered originally through electron beam studies, may be found in films of cis-methyl formate (cis-MF), for which data demonstrated the counter-intuitive property that the degree of dipole order in the film does not monotonically decrease as the temperature of deposition rises, but rather increases sharply above ~77 K. Here we show how RAIRS provides independent evidence to support this conclusion. These new data confirm (i) that the behaviour of spontelectrics is governed by an expression for the degree of dipole orientation, which is continuous in temperature, but with a discontinuity in the derivative, and (ii) that the temperature of deposition associated with this discontinuity matches the temperature above which dipole order switches from the expected reduction with temperature to an increase with temperature. PMID- 29392263 TI - Construction of unprecedented pillar-layered metal organic frameworks via a dual ligand strategy for dye degradation. AB - A dual-ligand strategy is used to construct two pillar-layered metal organic frameworks (MOFs) with [Zn2(COO)3]+ subunits (SBUs) and [ZnxCo3 x(ethanol)2(COO)4]2+ SBUs, respectively. Remarkably, the Zn/Co mixed compound 2 exhibits excellent and adjustable photocatalytic activity to degrade crystal violet (CV) in water under visible light. PMID- 29392264 TI - Dean flow assisted cell ordering system for lipid profiling in single-cells using mass spectrometry. AB - This study describes a novel Dean flow assisted cell ordering system which is connected to an electrospray ionization-mass spectrometer for the detection of lipids in a single-cell. This platform provides a facile method for direct analysis of label-free lipids in single-cells and significantly improves the efficiency of single-cell mass spectrometry. PMID- 29392265 TI - Super-resolution optical microscopy resolves network morphology of smart colloidal microgels. AB - We present a new method to resolve the network morphology of colloidal particles in an aqueous environment via super-resolution microscopy. By localization of freely diffusing fluorophores inside the particle network we can resolve the three dimensional structure of one species of colloidal particles (thermoresponsive microgels) without altering their chemical composition through copolymerization with fluorescent monomers. Our approach utilizes the interaction of the fluorescent dye rhodamine 6G with the polymer network to achieve an indirect labeling. We calculate the 3D structure from the 2D images and compare the structure to previously published models for the microgel morphology, e.g. the fuzzy sphere model. To describe the differences in the data an extension of this model is suggested. Our method enables the tailor-made fabrication of colloidal particles which are used in various applications, such as paints or cosmetics, and are promising candidates for drug delivery, smart surface coatings, and nanocatalysis. With the precise knowledge of the particle morphology an understanding of the underlying structure-property relationships for various colloidal systems is possible. PMID- 29392266 TI - Influences of the molecular fuel structure on combustion reactions towards soot precursors in selected alkane and alkene flames. AB - In this study, we experimentally investigate the high-temperature oxidation kinetics of n-pentane, 1-pentene and 2-methyl-2-butene (2M2B) in a combustion environment using flame-sampling molecular beam mass spectrometry. The selected C5 fuels are prototypes for linear and branched, saturated and unsaturated fuel components, featuring different C-C and C-H bond structures. It is shown that the formation tendency of species, such as polycyclic aromatic hydrocarbons (PAHs), yielded through mass growth reactions increases drastically in the sequence n pentane < 1-pentene < 2M2B. This comparative study enables valuable insights into fuel-dependent reaction sequences of the gas-phase combustion mechanism that provide explanations for the observed difference in the PAH formation tendency. First, we investigate the fuel-structure-dependent formation of small hydrocarbon species that are yielded as intermediate species during the fuel decomposition, because these species are at the origin of the subsequent mass growth reaction pathways. Second, we review typical PAH formation reactions inspecting repetitive growth sequences in dependence of the molecular fuel structure. Third, we discuss how differences in the intermediate species pool influence the formation reactions of key aromatic ring species that are important for the PAH growth process underlying soot formation. As a main result it was found that for the fuels featuring a C[double bond, length as m-dash]C double bond, the chemistry of their allylic fuel radicals and their decomposition products strongly influences the combination reactions to the initially formed aromatic ring species and as a consequence, the PAH formation tendency. PMID- 29392267 TI - Virus-like particles as crosslinkers in fibrous biomimetic hydrogels: approaches towards capsid rupture and gel repair. AB - Biological hydrogels can become many times stiffer under deformation. This unique ability has only recently been realised in fully synthetic gels. Typically, these networks are composed of semi-flexible polymers and bundles and show such large mechanical responses at very small strains, which makes them particularly suitable for application as strain-responsive materials. In this work, we introduced strain-responsiveness by crosslinking the architecture with a multi functional virus-like particle. At high stresses, we find that the virus particles disintegrate, which creates an (irreversible) mechanical energy dissipation pathway, analogous to the high stress response of fibrin networks. A cooling-heating cycle allows for re-crosslinking at the damaged site, which gives rise to much stronger hydrogels. Virus particles and capsids are promising drug delivery vehicles and our approach offers an effective strategy to trigger the release mechanically without compromising the mechanical integrity of the host material. PMID- 29392268 TI - Bimetallic Rh-Fe catalysts for N2O decomposition: effects of surface structures on catalytic activity. AB - Well-homogenized RhFe alloy nanoparticles and core-shell structured Fe@Rh nanoparticles were highly dispersed on SBA-15 and then applied to N2O catalytic conversion. Compared to RhFe/SBA-15, Fe@Rh/SBA-15 showed a higher catalytic activity for N2O decomposition. This is because the Rh layers covering the Fe core were able to protect against oxidization and so Fe@Rh/SBA-15 was prevented from deactivating. DFT calculations were performed to study the reaction mechanism of N2O decomposition. The rate-determining step, which was found to be the formation of O2 from adsorbed oxygen atoms on the surfaces of RhFe and Fe@Rh, revealed that O atoms prefer to be adsorbed on exposed Fe atoms on the surface of RhFe rather than that of Fe@Rh. The calculation results indicate that the exposed Fe atoms tend to be oxidized on the surface of RhFe, resulting in the deactivation of RhFe/SBA-15 during the experiment. PMID- 29392269 TI - Homogeneous and heterogeneous dynamics in native and denatured bovine serum albumin. AB - A characteristic property of unfolded and disordered proteins is their high molecular flexibility, which enables the exploration of a large conformational space. We present neutron scattering experiments on the dynamics of denatured and native folded bovine serum albumin (BSA) in solution. Global protein diffusion and internal macromolecular dynamics were measured using quasielastic neutron time-of-flight and backscattering spectroscopy on the picosecond to nanosecond time- and Angstrom length-scale. Internal protein dynamics were analysed in a first approach using stretched exponential functions. In denatured BSA predominantly slow heterogeneous dynamics dominates the observed macromolecular motions. Reduction of disulphide bridges in denatured BSA does not significantly alter the visible motions. In native folded BSA fast homogeneous dynamics and slow heterogeneous dynamics were observed. In an alternative data analysis approach, internal protein dynamics was interpreted using the analytical model of the overdamped Brownian oscillator, which allowed us to extract mean square displacements of protein internal dynamics and the fraction of hydrogen atoms participating in the observed motions. Our results demonstrate that denaturation modifies the physical nature of internal protein dynamics significantly as compared to the native folded structure. PMID- 29392270 TI - Multi-fuel surrogate chemical kinetic mechanisms for real world applications. AB - The most important driving force for development of detailed chemical kinetic reaction mechanisms in combustion is the desire by researchers to simulate practical systems. This paper reviews the parallel evolution of kinetic reaction mechanisms and applications of those models to practical, real engines. Early, quite simple, kinetic models for small fuel molecules were extremely valuable in analyzing long-standing, poorly understood applied ignition and flame quenching problems, and later kinetic models have been applied to much more complex flame propagation, problems including autoignition in spark-ignition engines and issues related to octane numbers and knock in modern, high compression ratio and other engines. The recent emergence of very large, multi-fuel surrogate kinetic mechanisms that can address many different fuel types and real engine applications is discussed as a modern analytical tool that can be used for a wide variety of practical applications. PMID- 29392271 TI - Not Just Digital Pathology, Intelligent Digital Pathology. PMID- 29392272 TI - Pink Papules in a Patient With Salivary Duct Carcinoma. PMID- 29392273 TI - Tumor-Treating Fields: Answering the Concern About Quality of Life. PMID- 29392274 TI - Fitting mSMART Into the Current Clinical Management of Waldenstrom Macroglobulinemia. PMID- 29392275 TI - Patient and Physician Assessment of Surgical Scars: A Systematic Review. AB - Importance: Surgical scarring affects patients by distracting the gaze of onlookers, disrupting social interactions, and impairing psychosocial health. Patient and physician agreement regarding ideal scar characteristics is important in developing congruent expectations after surgery. Objective: To summarize published studies assessing patient and physician ratings of surgical scars, rates of patient and physician agreement in scar assessment, and elements of cutaneous scar assessment that differ between patients and physicians. Evidence Review: A literature search of Ovid/Medline, PubMed, and EMBASE was conducted from January 1, 1972, to August 1, 2015. Prospective studies comparing scars from different surgical techniques using at least 1 physician-reported and patient reported scar measure were included. Strength of studies was graded according to the Oxford Centre for Evidence-Based Medicine guidelines. Findings: The review identified 29 studies comprising 4485 patients. Of the 29 included studies, 20 (69%) were randomized clinical trials (RCTs), 5 (17%) were prospective, nonrandomized studies, and 4 (14%) were descriptive studies. Disagreement between patients and physician evaluation of scars occurred in 28% (8 of 29) studies, with only patients rating scar difference in 75% (6 of 8) of these cases. Patients were more likely to value scar depth while physicians were more likely to value scar pigmentation and relief. Conclusions and Relevance: Methodologically rigorous studies that include clinician- and patient-reported scar outcomes are uncommon. Studies that incorporate subjective and objective scar grading reveal disagreement between patients and clinicians. Of the incision and wound closure techniques assessed, few affected patient- and clinician reported outcomes, but the evidence remains weak and future studies are recommended. PMID- 29392276 TI - Psychometric functions of uncertain template matching observers. AB - This theoretical note describes a simple equation that closely approximates the psychometric functions of template-matching observers with arbitrary levels of position and orientation uncertainty. We show that the approximation is accurate for detection of targets in white noise, 1/f noise, and natural backgrounds. In its simplest form, this equation, which we call the uncertain normal integral (UNI) function, has two parameters: one that varies only with the level of uncertainty and one that varies only with the other properties of the stimuli. The UNI function is useful for understanding and generating predictions of uncertain template matching (UTM) observers. For example, we use the UNI function to derive a closed-form expression for the detectability (d') of UTM observers in 1/f noise, as a function of target amplitude, background contrast, and position uncertainty. As a descriptive function, the UNI function is just as flexible and simple as other common descriptive functions, such as the Weibull function, and it avoids some of their undesirable properties. In addition, the estimated parameters have a clear interpretation within the family of UTM observers. Thus, the UNI function may be the better default descriptive formula for psychometric functions in detection and discrimination tasks. PMID- 29392277 TI - Visual search reveals a critical component to shape. AB - Objects are often identified by the shape of their contours. In this study, visual search tasks were used to reveal a visual dimension critical to the analysis of the shape of a boundary-defined area. Points of maximum curvature on closed paths are important for shape coding and it was shown here that target patterns are readily identified among distractors if the angle subtended by adjacent curvature maxima at the target pattern's center differs from that created in the distractors. A search asymmetry, indicated by a difference in performance in the visual search task when the roles of target and distractor patterns are reversed, was found when the critical subtended angle was only present in one of the patterns. Performance for patterns with the same subtended angle but differing local orientation and curvature was poor, demonstrating insensitivity to differences in these local features of the patterns. These results imply that the discrimination of objects by the shape of their boundaries relies on the relative positions of their curvature maxima rather than the local properties of the boundary from which these positions are derived. PMID- 29392279 TI - Erratum. PMID- 29392278 TI - The relative contributions of various viewpoint oscillation frequencies to the perception of distance traveled. AB - Humans and most animals are able to navigate in their environment, which generates sensorial information of various kinds, such as proprioceptive cues and optic flow. Previous research focusing on the visual effects of walking (bob, sway, and lunge head motion) has shown that the perception of forward self-motion experienced by static observers can be modulated by adding simulated viewpoint oscillations to the radial flow. In three experimental studies, we examined the effects of several viewpoint oscillation frequencies on static observers' perception of the distance traveled, assuming the assessment of distance traveled to be part of the path integration process. Experiment 1 showed that observers' estimates depended on the frequency of the viewpoint oscillations. In Experiment 2, increasing the viewpoint oscillation frequency actually led to an increase in the global retinal flow. It also emerged that simulated viewpoint oscillations enhance the sensation of self-motion: In a specific low-frequency range (<4 Hz), they improved subjects' estimates of the distances traveled. Lastly, in Experiment 3, observers were presented with two different simulated viewpoint oscillation patterns, both involving the same amount of global retinal motion, but in one case, the pattern simulated the visual effects of natural walking, and in the other case, the pattern was not biologically realistic. Contrary to the predictions of a previous ecological hypothesis, the subjects gave similar responses under both conditions. The global retinal motion may be mainly responsible for these effects, which were found to be optimal in a specific fairly low-oscillation frequency range. PMID- 29392281 TI - Error Consistency in Acquired Apraxia of Speech With Aphasia: Effects of the Analysis Unit. AB - Purpose: Diagnostic recommendations for acquired apraxia of speech (AOS) have been contradictory concerning whether speech sound errors are consistent or variable. Studies have reported divergent findings that, on face value, could argue either for or against error consistency as a diagnostic criterion. The purpose of this study was to explain discrepancies in error consistency results based on the unit of analysis (segment, syllable, or word) to help determine which diagnostic recommendation is most appropriate. Method: We analyzed speech samples from 14 left-hemisphere stroke survivors with clinical diagnoses of AOS and aphasia. Each participant produced 3 multisyllabic words 5 times in succession. Broad phonetic transcriptions of these productions were coded for consistency of error location and type using the word and its constituent syllables and sound segments as units of analysis. Results: Consistency of error type varied systematically with the unit of analysis, showing progressively greater consistency as the analysis unit changed from the word to the syllable and then to the sound segment. Consistency of error location varied considerably across participants and correlated positively with error frequency. Conclusions: Low to moderate consistency of error type at the word level confirms original diagnostic accounts of speech output and sound errors in AOS as variable in form. Moderate to high error type consistency at the syllable and sound levels indicate that phonetic error patterns are present. The results are complementary and logically compatible with each other and with the literature. PMID- 29392280 TI - Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Tumor-treating fields (TTFields) therapy improves both progression free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients' health-related quality of life (HRQoL). Objective: To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma. Design, Setting, and Participants: This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016. Interventions: Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device. Main Outcomes and Measures: Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items. Results: Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months; P < .01); physical (5.1 vs 3.7 months; P < .01) and emotional functioning (5.3 vs 3.9 months; P < .01); pain (5.6 vs 3.6 months; P < .01); and leg weakness (5.6 vs 3.9 months; P < .01), likely related to improved progression-free survival. Time to deterioration, reflecting the influence of treatment, did not differ significantly except for itchy skin (TTFields worse; 8.2 vs 14.4 months; P < .001) and pain (TTFields improved; 13.4 vs 12.1 months; P < .01). Role, social, and physical functioning were not affected by TTFields. Conclusions and Relevance: The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays. Trial Registration: clinicaltrials.gov Identifier: NCT00916409. PMID- 29392282 TI - Primary Palate Trauma in Patients Presenting to US Emergency Departments, 2006 2010. AB - Importance: The sequelae of palate trauma vary from minimal discomfort to major neurovascular injury. Infrequency of palate trauma and clinician unfamiliarity with the disease process may lead to variation in evaluation, treatment, and disposition in the emergency department (ED). Objectives: To measure the incidence of primary palate trauma visits to US emergency departments with analysis of demographics, disposition, and repair and to determine frequency and factors associated with head and neck imaging. Design, Setting, and Participants: A retrospective analysis using the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample was performed of 22 094 patients presenting to US emergency departments from 2006 to 2010 with a primary diagnosis of palate trauma. Data analysis was conducted from March 29, 2016, to November 18, 2017. Main Outcomes and Measures: National estimates of palate trauma were calculated from weights available within the database. Palate repair was identified by International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. Imaging was calculated from reliable Current Procedural Terminology coding facilities identified using a previously published method. Logistic models were calculated to identify clinical associations for admission, imaging, and palate repair. Results: A total of 22 094 patients (13 967 male and 8121 female patients, 6 missing data on sex; median age, 2.8 years [interquartile range, 1.1-6.1 years]) with primary palate trauma presented to US emergency departments during the study period. Total hospital visits decreased from 4715 (1.58 per 100 000 people) to 3915 (1.26 per 100 000 people) during the 5-year study period. A total of 19 819 patients (89.7%) had routine discharge from the hospital, while palate repair (965 [4.4%]) and mortality (34 [0.2%]) were rare. Complicated palate trauma (odds ratio [OR], 5.32; 95% CI, 3.10-9.15), male sex (OR, 1.57; 95% CI, 1.11-2.21), codiagnosis status (OR, 2.75; 95% CI, 1.84-4.12), and residence in the Northeast vs South (OR, 2.73; 95% CI, 1.11-6.71) increased the likelihood of admission, which was infrequent (1027 patients [4.6%]). After restriction to reliable Current Procedural Terminology coding facilities, head and neck imaging occurred in 823 of 6897 patients (11.9%). Factors associated with head and neck imaging included living in a medium vs large metropolitan area (OR 1.62; 95% CI, 1.04-2.55), while living in the Midwest vs South region (OR, 0.43; 95% CI, 0.25-0.74) had a negative association with imaging. Conclusions and Relevance: Although it is often suggested in the otolaryngology literature to perform imaging, primary palate trauma usually results in a routine discharge home without imaging or repair. Imaging frequency should be noted since palate trauma could have life-threatening neurovascular sequelae, which presents an opportunity to define and promote optimal management for potential neurologic sequelae in the patients who were not imaged. PMID- 29392284 TI - Cataract, Vitritis, and Diffuse Hypofluorescent Retinal Dots on Fluorescein Angiography. PMID- 29392285 TI - Diagnostic Accuracy of Parallel vs Perpendicular Orientation of the Tuning Fork in the Identification of Conductive Hearing Loss. PMID- 29392283 TI - Comparison of the Hemostatic Efficacy of Pathogen-Reduced Platelets vs Untreated Platelets in Patients With Thrombocytopenia and Malignant Hematologic Diseases: A Randomized Clinical Trial. AB - Importance: Pathogen reduction of platelet concentrates may reduce transfusion transmitted infections but is associated with qualitative impairment, which could have clinical significance with regard to platelet hemostatic capacity. Objective: To compare the effectiveness of platelets in additive solution treated with amotosalen-UV-A vs untreated platelets in plasma or in additive solution in patients with thrombocytopenia and hematologic malignancies. Design, Setting, and Participants: The Evaluation of the Efficacy of Platelets Treated With Pathogen Reduction Process (EFFIPAP) study was a randomized, noninferiority, 3-arm clinical trial performed from May 16, 2013, through January 21, 2016, at 13 French tertiary university hospitals. Clinical signs of bleeding were assessed daily until the end of aplasia, transfer to another department, need for a specific platelet product, or 30 days after enrollment. Consecutive adult patients with bone marrow aplasia, expected hospital stay of more than 10 days, and expected need of platelet transfusions were included. Interventions: At least 1 transfusion of platelets in additive solution with amotosalen-UV-A treatment, in plasma, or in additive solution. Main Outcomes and Measures: The proportion of patients with grade 2 or higher bleeding as defined by World Health Organization criteria. Results: Among 790 evaluable patients (mean [SD] age, 55 [13.4] years; 458 men [58.0%]), the primary end point was observed in 126 receiving pathogen reduced platelets in additive solution (47.9%; 95% CI, 41.9%-54.0%), 114 receiving platelets in plasma (43.5%; 95% CI, 37.5%-49.5%), and 120 receiving platelets in additive solution (45.3%; 95% CI, 39.3%-51.3%). With a per-protocol population with a prespecified margin of 12.5%, noninferiority was not achieved when pathogen-reduced platelets in additive solution were compared with platelets in plasma (4.4%; 95% CI, -4.1% to 12.9%) but was achieved when the pathogen reduced platelets were compared with platelets in additive solution (2.6%; 95% CI, -5.9% to 11.1%). The proportion of patients with grade 3 or 4 bleeding was not different among treatment arms. Conclusions and Relevance: Although the hemostatic efficacy of pathogen-reduced platelets in thrombopenic patients with hematologic malignancies was noninferior to platelets in additive solution, such noninferiority was not achieved when comparing pathogen-reduced platelets with platelets in plasma. Trial Registration: clinicaltrials.gov Identifier: NCT01789762. PMID- 29392286 TI - Mechanisms of Vowel Variation in African American English. AB - Purpose: This research explored mechanisms of vowel variation in African American English by comparing 2 geographically distant groups of African American and White American English speakers for participation in the African American Shift and the Southern Vowel Shift. Method: Thirty-two male (African American: n = 16, White American controls: n = 16) lifelong residents of cities in eastern and western North Carolina produced heed,hid,heyd,head,had,hod,hawed,whod,hood,hoed,hide,howed,hoyd, and heard 3 times each in random order. Formant frequency, duration, and acoustic analyses were completed for the vowels /i, i, e, E, ae, alpha, o, u, upsilon, o, ai, aupsilon, oi, ?/ produced in the listed words. Results: African American English speakers show vowel variation. In the west, the African American English speakers are participating in the Southern Vowel Shift and hod fronting of the African American Shift. In the east, neither the African American English speakers nor their White peers are participating in the Southern Vowel Shift. The African American English speakers show limited participation in the African American Shift. Conclusion: The results provide evidence of regional and socio-ethnic variation in African American English in North Carolina. PMID- 29392287 TI - Comparative Evaluation of Clinical Methods of Tear Film Stability Assessment: A Randomized Crossover Trial. AB - Importance: Tear film breakup time assessment is an integral component of dry eye evaluation. To our knowledge, the comparative discriminative ability of the noninvasive Keratograph (Oculus) vs conventional fluorescein method in detecting dry eye is unknown. Objective: To compare tear film stability measurements obtained with an automated noninvasive corneal topographer vs conventional fluorescein methods and evaluate their respective discriminative ability in detecting dry eye. Design, Setting, and Participants: This investigator-masked randomized crossover trial was conducted at a single-center university clinic between May 26, 2016, and October 3, 2016, and included 74 participants 18 years or older. Participants were recruited into 2 equally sized age, sex, and race/ethnicity-matched groups, with and without symptomatic dry eye (Ocular Surface Disease Index >=13). Interventions: Participants were assigned to receive a noninvasive keratograph evaluation and topical fluorescein instillation in a randomized order. Main Outcomes and Measures: Noninvasive keratograph breakup time (NIKBUT) and fluorescein breakup time (TBUT). Area under the receiver operating characteristic curve, Youden-optimal diagnostic cutoff sensitivity, and specificity of NIKBUT and TBUT in detecting dry eye. Results: Seventy-four participants (74 eyes; 43 women [58.1%]) with a mean (SD) age of 24 (4) years were randomized. Noninvasive keratograph breakup time was significantly longer than TBUT in participants with dry eye (median, 6.3 seconds vs 4.3 seconds [difference, 2.0 seconds]; 95% CI, 1.1-3.4 seconds; P = .003), and healthy participants (median, 11.9 seconds vs 5.0 seconds [difference, 6.9 seconds]; 95% CI, 4.7-7.6 seconds; P < .001). Fluorescein breakup time measurements were more narrowly distributed in both the dry eye (variance, 188 seconds2 vs 27.9 seconds2; P < .001) and control groups (variance, 113 seconds2 vs 13.4 seconds2; P < .001). The discriminative ability of NIKBUT in detecting dry eye (area under the receiver operating characteristic curve, 0.68; 95% CI, 0.56-0.81; P = .007) was greater than that of TBUT (area under the receiver operating characteristic curve, 0.57; 95% CI, 0.44-0.70; P = .31). The optimal diagnostic cutoff for NIKBUT was 9 seconds or less with a sensitivity of 68% (95% CI, 50%-82%), specificity of 70% (95% CI, 53%-84%), positive likelihood ratio of 2.27 (95% CI, 1.32-3.91), and negative likelihood ratio of 0.46 (95% CI, 0.28-0.77). The optimal threshold for TBUT was 5 seconds or less with a sensitivity of 54% (95% CI, 37%-71%), specificity of 68% (95% CI, 50%-82%), positive likelihood ratio of 1.67 (95% CI, 0.96-2.89), and negative likelihood ratio of 0.68 (95% CI, 0.45 1.03). Conclusions and Relevance: Conventional fluorescein tear film breakup time measurements were significantly shorter with narrower distributions, while automated noninvasive keratograph readings displayed superior discriminative ability in detecting dry eye. Trial Registration: anzctr.org.au Identifier: ACTRN12617001428358. PMID- 29392289 TI - Finite Element Study to Evaluate the Biomechanical Performance of the Spine After Augmenting Percutaneous Pedicle Screw Fixation With Kyphoplasty in the Treatment of Burst Fractures. AB - Percutaneous pedicle screw fixation (PPSF) is a well-known minimally invasive surgery (MIS) employed in the treatment of thoracolumbar burst fractures (TBF). However, hardware failure and loss of angular correction are common limitations caused by the poor support of the anterior column of the spine. Balloon kyphoplasty (KP) is another MIS that was successfully used in the treatment of compression fractures by augmenting the injured vertebral body with cement. To overcome the limitations of stand-alone PPSF, it was suggested to augment PPSF with KP as a surgical treatment of TBF. Yet, little is known about the biomechanical alteration occurred to the spine after performing such procedure. The objective of this study was to evaluate and compare the immediate post operative biomechanical performance of stand-alone PPSF, stand-alone-KP, and KP augmented PPSF procedures. Novel three-dimensional (3D) finite element (FE) models of the thoracolumbar junction that describes the fractured spine and the three investigated procedures were developed and tested under mechanical loading conditions. The spinal stiffness, stresses at the implanted hardware, and the intradiscal pressure at the upper and lower segments were measured and compared. The results showed no major differences in the measured parameters between stand alone PPSF and KP-augmented PPSF procedures, and demonstrated that the stand alone KP may restore the stiffness of the intact spine. Accordingly, there was no immediate post-operative biomechanical advantage in augmenting PPSF with KP when compared to stand-alone PPSF, and fatigue testing may be required to evaluate the long-term biomechanical performance of such procedures. PMID- 29392288 TI - Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema With Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Prevalence of persistent central-involved diabetic macular edema (DME) through 24 weeks of anti-vascular endothelial growth factor therapy and its longer-term outcomes may be relevant to treatment. Objective: To assess outcomes of DME persisting at least 24 weeks after randomization to treatment with 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab. Design, Setting, and Participants: Post hoc analyses of a clinical trial, the DRCR.net Protocol T among 546 of 660 participants (82.7%) meeting inclusion criteria for this investigation. Interventions: Six monthly intravitreous anti-vascular endothelial growth factor injections (unless success after 3 to 5 injections); subsequent injections or focal/grid laser as needed per protocol to achieve stability. Main Outcomes and Measures: Persistent DME through 24 weeks, probability of chronic persistent DME through 2 years, and at least 10-letter (>= 2-line) gain or loss of visual acuity. Results: The mean age of participants was 60 years, 363 (66.5%) were white, and 251 (46.0%) were women. Persistent DME through 24 weeks was more frequent with bevacizumab (118 of 180 [65.6%]) than aflibercept (60 of 190 [31.6%]) or ranibizumab (73 of 176 [41.5%]) (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; and aflibercept vs ranibizumab, P = .05). Among eyes with persistent DME through 24 weeks (n = 251), rates of chronic persistent DME through 2 years were 44.2% with aflibercept, 68.2% with bevacizumab (aflibercept vs bevacizumab, P = .03), and 54.5% with ranibizumab (aflibercept vs ranibizumab, P = .41; bevacizumab vs ranibizumab, P = .16). Among eyes with persistent DME through 24 weeks, proportions with vs without chronic persistent DME through 2 years gaining at least 10 letters from baseline were 62% of 29 eyes vs 63% of 30 eyes (P = .88) with aflibercept, 51% of 70 vs 54% of 31 (P = .96) with bevacizumab, and 44% of 38 vs 65% of 29 (P = .10) with ranibizumab. Only 3 eyes with chronic persistent DME lost at least 10 letters. Conclusions and Relevance: Persistent DME was more likely with bevacizumab than with aflibercept or ranibizumab. Among eyes with persistent DME, eyes assigned to bevacizumab were more likely to have chronic persistent DME than eyes assigned to aflibercept. These results suggest meaningful gains in vision with little risk of vision loss, regardless of anti-vascular endothelial growth factor agent given or persistence of DME through 2 years. Caution is warranted when considering switching therapies for persistent DME following 3 or more injections; improvements could be owing to continued treatment rather than switching therapies. Trial Registration: clinicaltrials.gov Identifier: NCT01627249. PMID- 29392290 TI - Voice, Articulation, and Prosody Contribute to Listener Perceptions of Speaker Gender: A Systematic Review and Meta-Analysis. AB - Purpose: The aim of this study was to provide a systematic review of the aspects of verbal communication contributing to listener perceptions of speaker gender with a view to providing clinicians with guidance for the selection of the training goals when working with transsexual individuals. Method: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guidelines were adopted in this systematic review. Studies evaluating the contribution of aspects of verbal communication to listener perceptions of speaker gender were rated against a new risk of bias assessment tool. Relevant data were extracted, and narrative synthesis was then conducted. Meta-analyses were conducted when appropriate data were available. Results: Thirty-eight articles met the eligibility criteria. Meta-analysis showed speaking fundamental frequency contributing to 41.6% of the variance in gender perception. Auditory perceptual and acoustic measures of pitch, resonance, loudness, articulation, and intonation were found to be associated with listeners' perceptions of speaker gender. Tempo and stress were not significantly associated. Mixed findings were found as to the contribution of a breathy voice quality to gender perception. Nonetheless, there exists significant risk of bias in this body of research. Conclusions: Speech and language clinicians working with transsexual individuals may use the results of this review for goal setting. Further research is required to redress the significant risk of bias. PMID- 29392291 TI - Clinicians' Guide to Obtaining a Valid Auditory Brainstem Response to Determine Hearing Status: Signal, Noise, and Cross-Checks. AB - Purpose: The auditory brainstem response (ABR) is a powerful tool for making clinical decisions about the presence, degree, and type of hearing loss in individuals in whom behavioral hearing thresholds cannot be obtained or are not reliable. Although the test is objective, interpretation of the results is subjective. Method: This review provides information about evidence-based criteria, suggested by the 2013 Newborn Hearing Screening Program guidelines, and the use of cross-check methods for making valid interpretations about hearing status from ABR recordings. Results: The use of an appropriate display scale setting, templates of expected response properties, and objective criteria to estimate the residual noise, signal level, and signal-to-noise ratio will provide quality data for determining ABR thresholds. Cross-checks (e.g., immittance measures, otoacoustic emissions testing, functional indications of a child's hearing) are also needed to accurately interpret the ABR. Conclusions: Using evidence-based ABR signal detection criteria and considering the results within the context of other physiologic tests and assessments of hearing function will improve the clinician's accuracy for detecting hearing loss and, when present, the degree of hearing loss. Diagnostic accuracy will ensure that appropriate remediation is initiated and that children or infants with normal hearing are not subjected to unnecessary intervention. PMID- 29392292 TI - Sport-Related Concussion. PMID- 29392293 TI - Fitting mSMART Into the Current Clinical Management of Waldenstrom Macroglobulinemia-Reply. PMID- 29392294 TI - A Pediatric Nasopharyngeal Mass. PMID- 29392295 TI - A Meta-Analysis: Acoustic Measurement of Roughness and Breathiness. AB - Purpose: Over the last 5 decades, many acoustic measures have been created to measure roughness and breathiness. The aim of this study is to present a meta analysis of correlation coefficients (r) between auditory-perceptual judgment of roughness and breathiness and various acoustic measures in both sustained vowels and continuous speech. Method: Scientific literature reporting perceptual acoustic correlations on roughness and breathiness were sought in 28 databases. Weighted average correlation coefficients (rw) were calculated when multiple r values were available for a specific acoustic marker. An rw >= .60 was the threshold for an acoustic measure to be considered acceptable. Results: From 103 studies of roughness and 107 studies of breathiness that were investigated, only 33 studies and 34 studies, respectively, met the inclusion criteria of the meta analysis on sustained vowels. Eighty-six acoustic measures were identified for roughness and 85 acoustic measures for breathiness on sustained vowels, in which 43 and 39 measures, respectively, yielded multiple r-values. Finally, only 14 measures for roughness and 12 measures for breathiness produced rw >= .60. On continuous speech, 4 measures for roughness and 21 measures for breathiness were identified, yielding 3 and 6 measures, respectively, with multiple r-values in which only 1 and 2, respectively, had rw >= .60. Conclusion: This meta-analysis showed that only a few acoustic parameters were determined as the best estimators for roughness and breathiness. PMID- 29392296 TI - Correlation Between Noninvasive Ultrasonography and Dynamically Monitored Intracranial Pressure. PMID- 29392299 TI - Validating Fatigue Safety Factor Calculation Methods for Cardiovascular Stents. PMID- 29392297 TI - Long-term Mortality in NFL Professional Football Players: No Significant Increase, but Questions Remain. PMID- 29392298 TI - Eliciting the Language Sample for Developmental Sentence Scoring: A Comparison of Play With Toys and Elicited Picture Description. AB - Purpose: This study investigated whether language samples elicited during play and description of pictured events would yield the same results for developmental sentence scoring (DSS). Method: Two language samples were elicited from 58 three year-olds. One sample was elicited during play with a parent, and the other sample was elicited by an examiner asking children to talk about pictured events in response to elicitation questions. Results: DSS scores were not significantly different between the play and event description samples. However, sentence points were significantly higher for the play sample than for the event description sample. Although there was a correlation between sample types for both DSS and sentence points, the correlation for DSS (r = .52) was below an acceptable level, and the correlation for sentence points (r = .71) was at a minimally acceptable level. Agreement between sample types for pass-fail decisions on the DSS scores using the 10th percentile cutoff recommended by Lee (1974) was only moderate (78%). Conclusion: The current study shows that type of language samples could affect DSS and sentence point scores of 3-year-olds and, hence, the passing and failing decisions for their performance on DSS. PMID- 29392300 TI - Effects of Increased Arterial Stiffness on Atherosclerotic Plaque Amounts. AB - Increased arterial stiffness is associated with atherosclerosis in humans, but there have been limited animal studies investigating the relationship between these factors. We bred elastin wildtype (Eln+/+) and heterozygous (Eln+/-) mice to apolipoprotein E wildtype (Apoe+/+) and knockout (Apoe-/-) mice and fed them normal diet (ND) or Western diet (WD) for 12 weeks. Eln+/- mice have increased arterial stiffness. Apoe-/- mice develop atherosclerosis on ND that is accelerated by WD. It has been reported that Apoe-/- mice have increased arterial stiffness and that the increased stiffness may play a role in atherosclerotic plaque progression. We found that Eln+/+Apoe-/- arterial stiffness is similar to Eln+/+Apoe+/+ mice at physiologic pressures, suggesting that changes in stiffness do not play a role in atherosclerotic plaque progression in Apoe-/- mice. We found that Eln+/-Apoe-/- mice have increased structural arterial stiffness compared to Eln+/+Apoe-/- mice, but they only have increased amounts of ascending aortic plaque on ND, not WD. The results suggest a change in atherosclerosis progression but not end stage disease in Eln+/-Apoe-/- mice due to increased arterial stiffness. Possible contributing factors include increased blood pressure and changes in circulating levels of interleukin-6 (IL6) and transforming growth factor beta 1 (TGF-beta1) that are also associated with Eln+/ genotype. PMID- 29392302 TI - Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Does Flavor Matter? PMID- 29392301 TI - Ultrasonography Assessments of Optic Nerve Sheath Diameter as a Noninvasive and Dynamic Method of Detecting Changes in Intracranial Pressure. AB - Importance: The crtierion standard method for monitoring intracranial pressure (ICP) can result in complications and pain. Hence, noninvasive, repeatable methods would be valuable. Objective: To examine how ultrasonographic optic nerve sheath diameter (ONSD) correlated with noninvasive and dynamically monitored ICP changes. Design, Setting, and Participants: The ONSD was measured before the lumbar puncture (LP) in 60 patients on admission. Patients with elevated ICP were divided into group 1 (200 < LP <= 300 mm H2O) and group 2 (LP > 300 mm H2O). Patients underwent follow-up ONSD and LP measurements within 1 month. We analyzed the correlations between the ONSD and ICP on admission and between the changes in ONSD and ICP, which were the respective changes in ONSD and ICP from admission to follow-up. Main Outcomes and Measures: The ultrasonographic ONSD and ICP were measured on admission and follow-up. The correlations between the ONSD and ICP on admission and between the changes in ONSD and ICP were analyzed using Pearson correlation analyses. Results: For 60 patients (Han nationality; mean [SD] age, 36.2 [12.04] years; 29 [48%] female) on admission, the ONSD and ICP values were strongly correlated, with an r of 0.798 (95% CI, 0.709-0.867; P < .001). Twenty five patients with elevated ICP who completed the follow-up were included. The mean (SD) ONSD and ICP on admission were 4.50 (0.54) mm and 302.40 (54.26) mm H2O, respectively. The ONSD and ICP values obtained on admission were strongly correlated , with an r of 0.724 (95% CI, 0.470-0.876; P < .001). The mean (SD, range) changes in ICP and ONSD were 126.64 (52.51 mm H2O, 20-210 mm H2O) (95% CI, 106.24-146.07) and 1.00 (0.512 mm, 0.418-2.37 mm) (95% CI, 0.83-1.20), respectively. The change in ONSD was strongly correlated with the change in ICP, with an r of 0.702 (95% CI, 0.425-0.870; P < .001). The follow-up evaluations revealed that the elevated ICP and dilated ONSD had returned to normal, and no evidence of difference was found in the mean ONSDs between group 1 (3.49 mm; 95% CI, 3.34-3.62 mm) and group 2 (3.51 mm; 95% CI, 3.44-3.59 mm) (P = .778) at follow-up. Conclusions and Relevance: The dilated ONSDs decreased along with the elevated ICP reduction. Ultrasonographic ONSD measurements may be a useful, noninvasive tool for dynamically evaluating ICP. PMID- 29392303 TI - Pathogen Inactivation Strategies to Improve Blood Safety: Let's Not Throw Pathogen-Reduced Platelets Out With Their Bath Water. PMID- 29392304 TI - Association Between Playing American Football in the National Football League and Long-term Mortality. AB - Importance: Studies of the longevity of professional American football players have demonstrated lower mortality relative to the general population but they may have been susceptible to selection bias. Objective: To examine the association between career participation in professional American football and mortality risk in retirement. Design, Setting, and Participants: Retrospective cohort study involving 3812 retired US National Football League (NFL) players who debuted in the NFL between 1982 and 1992, including regular NFL players (n = 2933) and NFL "replacement players" (n = 879) who were temporarily hired to play during a 3 game league-wide player strike in 1987. Follow-up ended on December 31, 2016. Exposures: NFL participation as a career player or as a replacement player. Main Outcomes and Measures: The primary outcome was all-cause mortality by December 31, 2016. Cox proportional hazards models were estimated to compare the observed number of years from age 22 years until death (or censoring), adjusted for birth year, body mass index, height, and position played. Information on player death and cause of death was ascertained from a search of the National Death Index and web-based sources. Results: Of the 3812 men included in this study (mean [SD] age at first NFL activity, 23.4 [1.5] years), there were 2933 career NFL players (median NFL tenure, 5 seasons [interquartile range {IQR}, 2-8]; median follow-up, 30 years [IQR, 27-33]) and 879 replacement players (median NFL tenure, 1 season [IQR, 1-1]; median follow-up, 31 years [IQR, 30-33]). At the end of follow-up, 144 NFL players (4.9%) and 37 replacement players (4.2%) were deceased (adjusted absolute risk difference, 1.0% [95% CI, -0.7% to 2.7%]; P = .25). The adjusted mortality hazard ratio for NFL players relative to replacements was 1.38 (95% CI, 0.95 to 1.99; P = .09). Among career NFL players, the most common causes of death were cardiometabolic disease (n = 51; 35.4%), transportation injuries (n = 20; 13.9%), unintentional injuries (n = 15; 10.4%), and neoplasms (n = 15; 10.4%). Among NFL replacement players, the leading causes of death were cardiometabolic diseases (n = 19; 51.4%), self-harm and interpersonal violence (n = 5; 13.5%), and neoplasms (n = 4; 10.8%). Conclusions and Relevance: Among NFL football players who began their careers between 1982 and 1992, career participation in the NFL, compared with limited NFL exposure obtained primarily as an NFL replacement player during a league-wide strike, was not associated with a statistically significant difference in long-term all-cause mortality. Given the small number of events, analysis of longer periods of follow-up may be informative. PMID- 29392305 TI - Temporal Ventriloquism Reveals Intact Audiovisual Temporal Integration in Amblyopia. AB - Purpose: We have shown previously that amblyopia involves impaired detection of asynchrony between auditory and visual events. To distinguish whether this impairment represents a defect in temporal integration or nonintegrative multisensory processing (e.g., cross-modal matching), we used the temporal ventriloquism effect in which visual temporal order judgment (TOJ) is normally enhanced by a lagging auditory click. Methods: Participants with amblyopia (n = 9) and normally sighted controls (n = 9) performed a visual TOJ task. Pairs of clicks accompanied the two lights such that the first click preceded the first light, or second click lagged the second light by 100, 200, or 450 ms. Baseline audiovisual synchrony and visual-only conditions also were tested. Results: Within both groups, just noticeable differences for the visual TOJ task were significantly reduced compared with baseline in the 100- and 200-ms click lag conditions. Within the amblyopia group, poorer stereo acuity and poorer visual acuity in the amblyopic eye were significantly associated with greater enhancement in visual TOJ performance in the 200-ms click lag condition. Conclusions: Audiovisual temporal integration is intact in amblyopia, as indicated by perceptual enhancement in the temporal ventriloquism effect. Furthermore, poorer stereo acuity and poorer visual acuity in the amblyopic eye are associated with a widened temporal binding window for the effect. These findings suggest that previously reported abnormalities in audiovisual multisensory processing may result from impaired cross-modal matching rather than a diminished capacity for temporal audiovisual integration. PMID- 29392306 TI - Deep Defects Seen on Visual Fields Spatially Correspond Well to Loss of Retinal Nerve Fiber Layer Seen on Circumpapillary OCT Scans. AB - Purpose: To examine the structure-function relationship in glaucoma between deep defects on visual fields (VF) and deep losses in the circumpapillary retinal nerve fiber layer (cpRNFL) on optical coherence tomography (OCT) circle scans. Methods: Thirty two glaucomatous eyes with deep VF defects, as defined by at least one test location worse than <= -15 dB on the 10-2 and/or 24-2 VF pattern deviation (PD) plots, were included from 87 eyes with "early" glaucoma (i.e., 24 2 mean deviation better than -6 dB). Using the location of the deep VF points and a schematic model, the location of local damage on an OCT circle scan was predicted. The thinnest location of cpRNFL (i.e., deepest loss) was also determined. Results: In 19 of 32 eyes, a region of complete or near complete cpRNFL loss was observed. All 19 of these had deep VF defects on the 24-2 and/or 10-2. All of the 32 eyes with deep VF defects had abnormal cpRNFL regions (red, 1%) and all but 2 had a region of cpRNFL thickness <21 MUm. The midpoint of the VF defect and the location of deepest cpRNFL had a 95% limit of agreement within approximately two-thirds of a clock-hour (or 30 degrees ) sector (between -22.1 degrees to 25.2 degrees ). Individual fovea-to-disc angle (FtoDa) adjustment improved agreement in one eye with an extreme FtoDa. Conclusions: Although studies relating local structural (OCT) and functional (VF) measures typically show poor to moderate correlations, there is good qualitative agreement between the location of deep cpRNFL loss and deep defects on VFs. PMID- 29392308 TI - Pharmacokinetic and Safety Evaluation of a Transscleral Sustained Unoprostone Release Device in Monkey Eyes. AB - Purpose: We evaluate the ocular tissue distribution and retinal toxicity of unoprostone (UNO) during 12 months, after transscleral sustained-UNO administration using a drug delivery device in monkey eyes. Methods: The device consisted of a reservoir, controlled-release cover, and a drug formulation of photopolymerized polyethylene glycol dimethacrylate. Six mg UNO was loaded into the device (length, 17 mm; width, 4.4 mm; height, 1 mm). The concentrations of M1, a primary metabolite of UNO, in the retina, choroid, vitreous, lens, aqueous humor, iris, ciliary body, and plasma were determined by liquid chromatography tandem mass spectrometry at 3, 6, and 12 months after implantation. Retinal toxicity was evaluated by electroretinography (ERG), optical coherence tomography (OCT), and IOP at preimplantation, and at 6, 9, and 12 months after implantation. Focal ERGs were performed at 9 and 12 months after implantation. Results: M1 was detected in the choroid and retina with maximum peaks of 243.2 and 8.41 ng/g at 6 months, respectively. M1 in the ciliary body and iris was detected with maximum peaks of 7.66 and 10.4 ng/g at 6 and 12 months, respectively. Less than 1 ng/mL or ng/g of M1 was detected in the aqueous humor, vitreous, and lens. No changes were observed in retinal function as assessed by ERG, IOP, or macula thickness and retinal histology by OCT examinations during the 12-month period. No differences in focal ERG amplitudes, especially in the macula, were observed. Conclusions: The device provided intraocular sustained delivery of UNO for 12 months without producing severe retinal toxicity. PMID- 29392309 TI - Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy. AB - Purpose: Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). Methods: Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2-/ ) mice were used in the OIR model, exposed to 75% O2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR. Results: tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor alpha (VEGFalpha), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2-/- displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFalpha and angiopoietin expression. Conclusions: Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies. PMID- 29392310 TI - Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty. AB - Purpose: To evaluate the association between endothelial cell density (ECD) after Descemet's stripping automated endothelial keratoplasty (DSAEK) and preoperative cytokine levels in the aqueous humor (AqH). Methods: This prospective consecutive case series included 97 consecutive patients who underwent DSAEK (64 eyes) or cataract surgery (33 eyes). AqH samples were collected at the beginning of each surgery. The levels of cytokines (IL-1alpha, IL-1beta, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN-alpha, IFN-gamma, monocyte chemotactic protein [MCP] 1, E-selectin, P-selectin, and soluble intercellular adhesion molecule [sICAM]-1) in the AqH were measured by multiplex beads immunoassay. The correlations between preoperative aqueous cytokine levels and the ECD at 12 months after DSAEK were analyzed. Results: The ECD decreased from 2747 +/- 259 cells/mm2 in the donor graft to 1235 +/- 607 cells/mm2 at 12 months after DSAEK. In all subjects undergoing DSAEK, the postoperative ECD at 12 months was significantly correlated with the preoperative levels of MCP-1 (r = -0.467, 95% confidence interval [CI]: 0.650 to -0.222, P = 0.0003). In an analysis excluding Fuchs endothelial corneal dystrophy (11 eyes), the ECD at 12 months after DSAEK was significantly correlated with preoperative levels of IL-17A (r = -0.635, 95% CI: -0.819 to 0.319, P = 0.0004), MCP-1 (r = -0.605, 95% CI: -0.779 to -0.345, P < 0.0001), IFN gamma (r = -0.633, 95% CI: -0.796 to -0.385, P < 0.0001), E-selectin (r = -0.516, 95% CI: -0.756 to -0.276, P = 0.0004), and sICAM-1 (r = -0.537, 95% CI: -0.735 to -0.253, P = 0.0005). Conclusions: Higher preoperative levels of IL-17A, MCP-1, IFN-gamma, E-selectin, and sICAM-1 in the AqH were associated with lower ECD after DSAEK for bullous keratopathy. PMID- 29392307 TI - Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. AB - Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P <= 0.033) and not women (permuted P >= 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P <= 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets. PMID- 29392312 TI - Erratum. PMID- 29392311 TI - Effect of Anti-C5a Therapy in a Murine Model of Early/Intermediate Dry Age Related Macular Degeneration. AB - Purpose: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. Methods: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-~HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. Results: Aged Cfh+/- mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. Conclusions: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD like pathologies observed in Cfh+/-~HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies. PMID- 29392313 TI - A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model. AB - Purpose: To investigate the drug release profiles of a tacrolimus-loaded poly(D,L lactide-co-epsilon-caprolactone) (PLC) microfilm, and to evaluate its efficacy on the treatment of allergic conjunctivitis using a mouse model. Methods: The in vitro and in vivo drug release profiles were first characterized. Balb/c mice were immunized with short ragweed (SRW) injection followed by re-challenges with topical SRW solution. The mice were divided into six groups (n = 12 in each): negative control (NC); positive control (PC); tacrolimus eye drops (Te); subconjunctival tacrolimus microfilm (Tm); dexamethasone eye drops (De); and tacrolimus + dexamethasone eye drops (Te+De). The mice were evaluated for 28 days by a scoring system for allergic conjunctivitis. Histopathologic and immunohistochemical staining with CD11c, CD4, and IL-4 were performed. Results: The microfilms were biocompatible and delivered clinically sufficient dose in a sustained manner, with a steady rate of 0.212 to 0.243 MUg/day in vivo. Compared to the PC groups, the Te, Tm, De, and Te+De groups significantly reduced the allergic clinical scores throughout the study period (all P < 0.01; 0.0 +/- 0.0, 5.6 +/- 0.9, 3.3 +/- 0.9, 3.2 +/- 0.9, 1.9 +/- 0.4 and 1.7 +/- 0.8 for the NC, PC, Tm, Te, De, and Te+De groups, respectively, at 4 weeks after treatment). The suppressed eosinophils, CD11c, CD4, and IL-4 expression were also observed in all treatment groups, with more reduction in the Te+De group. Conclusions: Tacrolimus loaded microfilms display good biocompatibility and desirable sustained drug release. It was as effective as conventional tacrolimus eye drops on the treatment of allergic conjunctivitis, providing a promising clinically applicable alternative for controlling allergic disease activity, or other immune-mediated ocular diseases. PMID- 29392314 TI - Leucine-Rich alpha-2-Glycoprotein-1 (LRG-1) Expression in Retinoblastoma. AB - Purpose: Retinoblastomas' growth rate is dependent on their ability to induce neovascularization. Leucine-rich alpha-2-glycoprotein-1 (LRG-1) was recently reported to be upregulated in human retinal disease with neovascular pathology. The purpose of the study was to determine LRG-1 expression in human retinoblastoma and to correlate it with clinical and histopathologic parameters and to assess how its expression correlates with vascular endothelial growth factor (VEGF) expression. Methods: LRG-1 expression was immunohistochemically evaluated in 34 retinoblastoma sections. Immunofluorescence for LRG-1/VEGF-A, LRG 1/TGF-beta1/CD31, and LRG-1/Ki67 was performed. Quantitative RT-PCR analysis for the expression of LRG-1 was also done. Results: LRG-1 was found to be extensively and robustly expressed in retinoblastoma tumors (88%) irrespective of the degree of invasiveness, differentiation, iris neovascularization, and anterior segment involvement. LRG-1 immunoreactivity was predominantly observed in the central tumor vasculature and in the surrounding rim of ischemia. The higher frequency of LRG-1 expression in the presence of optic nerve infiltration, vitreous seeding, and necrosis was not statistically significant. Colocalization was observed between LRG-1 and VEGF-A staining, and no difference in their counts was detected. Quantitative RT-PCR analysis showed that LRG-1 gene expression was significantly upregulated (4.8-fold increase, P = 0.01). Conclusions: LRG-1 was highly expressed in human retinoblastoma sections, thus providing new insights into the molecular mechanism of retinoblastoma pathogenesis, and suggests a possible new therapeutic target. LRG-1 is a novel oncogene-associated protein shown to be vital to the progression of human cancers. Inhibiting tumor vasculature is progressively evolving as a target in anticancer therapy. PMID- 29392315 TI - Autotaxin-Lysophosphatidic Acid Pathway in Intraocular Pressure Regulation and Glaucoma Subtypes. AB - Purpose: To compare the levels of autotaxin (ATX), lysophosphatidic acid (LPA), and lysophosphatidylcholine (LPC) in the aqueous humor (AH) of healthy control subjects with those of patients with different subtypes of glaucoma, and also to investigate the relationship of the ATX-LPA pathway with IOP and subtype of glaucoma. Methods: This study included 164 eyes of 164 consecutive cases of cataract and glaucoma surgery (37 healthy, 31 normal tension glaucoma, 49 primary open angle glaucoma, 28 secondary open angle glaucoma, and 19 exfoliation glaucoma). Aqueous levels of LPA, LPC, and ATX were quantified using liquid chromatography-tandem mass spectrometry and a two-site immunoenzymetric assay. The association between aqueous levels of ATX/LPA/LPC and IOP elevation in different glaucoma subtypes was investigated. The diagnostic values of indices of the ATX-LPA pathway were compared using receiver operating characteristic curve analysis. Results: Notable increases in ATX/LPA/LPC levels in glaucoma patients were observed. The ATX-LPA pathway was significantly related to IOP elevation and the subtype of glaucoma, especially in SOAG and XFG patients, and the area under the curve was significant for discriminating glaucoma eyes from healthy eyes. Conclusions: Bioactive ATX/LPA/LPC concentrations were present in aqueous humor, and higher ATX and LPA concentrations were significantly correlated with IOP in all study subjects. Furthermore, the ATX-LPA pathway was significantly related to glaucoma subtype. These results reveal the potentially important role of the ATX LPA pathway for IOP regulation in healthy subjects and glaucoma patients. PMID- 29392317 TI - Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients With Diabetic Macular Edema. AB - Purpose: To investigate the associations between soluble CD14 (sCD14), a cytokine released by microglia and macrophages, and hyperreflective foci (HF) and various characteristics of spectral-domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME). Methods: Sixty-nine eyes from 51 patients with DME and 28 eyes from 28 control subjects were studied. sCD14 levels in the aqueous humor (AH) were measured using ELISA before bevacizumab injection (IVB), and the associations between sCD14 and visual acuity, the number of HF, retinal volume, and the DME pattern were assessed. Results: sCD14 levels were higher in DME patients than in the control subjects (29.9 +/- 41.6 pg/mL versus 8.1 +/- 3.6 pg/mL, P < 0.001). sCD14 levels in diffuse edema were higher than those in focal edema (50.0 +/- 65.3 pg/mL versus 19.8 +/- 14.7 pg/mL, P = 0.039). The number of HF in the inner retina of patients with diffuse edema was significantly higher than that in patients with focal edema (4.4 +/- 2.3 vs. 2.6 +/- 2.1, P = 0.001), but no difference was found in the outer retina (5.8 +/- 3.4 vs. 5.0 +/- 3.9, P = 0.25). According to multivariate analyses, elevated sCD14 levels were associated with an increased inner nuclear layer volume and the total number of HF in all retinal layers on SD-OCT. Reduction of DME following IVB was correlated with reduction in the number of HF in a subset of eyes followed longitudinally in the study (n = 30). Conclusions: DME patients with diffuse edema exhibit higher sCD14 levels in the AH and more HF in the inner retina than patients with focal edema, indicating severe inflammation. The strong correlation between sCD14 and HF in the inner retina suggests that the HF observed on SD-OCT may be due to activated microglia in DME. PMID- 29392316 TI - Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. AB - Purpose: To investigate the benefit of bone marrow mesenchymal stem cell (BMSC) derived small extracellular vesicles (sEV) as an intravitreal (ivit) therapy in two rat models of glaucoma and to determine and identify candidate miRNA involved in the mechanism. Methods: sEV were isolated from human BMSC and fibroblasts and ivit injected into adult rats after induction of elevated IOP. IOP was elevated using either intracameral injection of microbeads or laser photocoagulation of circumferential limbal vessels and the trabecular meshwork. Retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography, positive scotopic threshold response (pSTR) recorded using ERG, and RNA binding protein with multiple splicing (RBPMS+) retinal ganglion cell (RGC) counted using retinal wholemounts. sEV miRNA were sequenced using RNAseq. Results: sEV isolated from BMSC promoted significant neuroprotection of RGC while preventing RNFL degenerative thinning and loss of pSTR. sEV proved therapeutically efficacious when ivit injected every week or every month, but ineffective with longer delays between treatments. Knockdown of Argonaute2 (AGO2), a protein critical for miRNA function and packing into sEV prior to sEV isolation, significantly attenuated the above effects. Addition of BMSC sEV (but not fibroblast sEV) reduced death of cultured purified RGC. RNAseq identified 43 miRNA upregulated in BMSC sEV in comparison to fibroblast sEV, which yielded no neuroprotective effects. Conclusions: Injection of BMSC-derived sEV into the vitreous provided significant therapeutic benefit to glaucomatous eyes. The neuroprotective effect of sEV, at least partially, may be explained by direct action on RGC through miRNA-dependent mechanisms. PMID- 29392318 TI - A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age Related Macular Degeneration-Associated Complement Factor H Variant 402H. AB - Purpose: Choroidal endothelial cells play a central role in the pathogenesis of age-related macular degeneration (AMD). Protocols for isolating primary choroidal endothelial cells have been described but require access to human donor eyes, which is a limiting factor. Therefore, a conditionally immortalized choroidal endothelial cell (ciChEnC) line has been established. Methods: Choroidal endothelial cells were selected by magnetic-activated cell sorting and conditionally immortalized using temperature-sensitive simian virus 40 large T antigen and human telomerase. The cell line obtained was characterized based on expression of endothelial marker proteins and endothelial cell-specific responses to various stimuli. Binding of AMD-associated and non-AMD variants of complement factor H in the context of a recombinant CCP6-8 (complement control protein domains 6-8) construct was determined using ELISA. Results: ciChEnCs maintained morphology and von Willebrand factor and vascular endothelial cadherin expression for up to 27 passages. The cells internalized acetylated low-density lipoprotein, formed tubes on Matrigel, and increased intercellular adhesion molecule-1 expression in response to tumor necrosis factor-alpha. Cells grew into dense monolayers with barrier function and showed characteristics of choriocapillary cells, such as expression of plasmalemma vesicle-associated protein, human leukocyte antigen ABC, carbonic anhydrase IV, and membrane indentations reflecting fenestrations. ciChEnCs synthesized glycosaminoglycans chondroitin sulfate and the complement factor H ligand heparan sulfate. Interestingly, binding of the AMD-associated 402H variant of factor H to ciChEnC was significantly decreased compared to the 402Y variant. Conclusions: A novel ciChEnC cell line with choriocapillary characteristics has been established and should greatly facilitate investigation of the pathogenesis of AMD in the context of the choriocapillary microenvironment. PMID- 29392319 TI - Nanosecond Laser Treatment for Age-Related Macular Degeneration Does Not Induce Focal Vision Loss or New Vessel Growth in the Retina. AB - Purpose: Subthreshold, nanosecond pulsed laser treatment shows promise as a treatment for age-related macular degeneration (AMD); however, the safety profile needs to be robustly examined. The aim of this study was to investigate the effects of laser treatment in humans and mice. Methods: Patients with AMD were treated with nanosecond pulsed laser at subthreshold (no visible retinal effect) energy doses (0.15-0.45 mJ) and retinal sensitivity was assessed with microperimetry. Adult C57BL6J mice were treated at subthreshold (0.065 mJ) and suprathreshold (photoreceptor loss, 0.5 mJ) energy settings. The retinal and vascular responses were analyzed by fundus imaging, histologic assessment, and quantitative PCR. Results: Microperimetry analysis showed laser treatment had no effect on retinal sensitivity under treated areas in patients 6 months to 7 years after treatment. In mice, subthreshold laser treatment induced RPE loss at 5 hours, and by 7 days the RPE had retiled. Fundus imaging showed reduced RPE pigmentation but no change in retinal thickness up to 3 months. Electron microscopy revealed changes in melanosomes in the RPE, but Bruch's membrane was intact across the laser regions. Histologic analysis showed normal vasculature and no neovascularization. Suprathreshold laser treatment did not induce changes in angiogenic genes associated with neovascularization. Instead pigment epithelium-derived factor, an antiangiogenic factor, was upregulated. Conclusions: In humans, low-energy, nanosecond pulsed laser treatment is not damaging to local retinal sensitivity. In mice, treatment does not damage Bruch's membrane or induce neovascularization, highlighting a reduced side effect profile of this nanosecond laser when used in a subthreshold manner. PMID- 29392320 TI - A Naturally Fluorescent Mgp Transgenic Mouse for Angiogenesis and Glaucoma Longitudinal Studies. AB - Purpose: Our goal was to generate and characterize a new mouse model in which only angiogenesis- and glaucoma-relevant tissues would be naturally fluorescent. The Matrix Gla (MGP) gene is highly expressed in vascular smooth muscle cells (VSMC) and trabecular meshwork (TM). We sought to direct our Mgp-Cre.KI mouse recombinase to VSMC/TM cells to produce their longitudinal fluorescent profiles. Methods: Homozygous Mgp-Cre.KI mice were crossed with Ai9 homozygous reporter mice harboring a loxP-flanked STOP cassette preventing transcription of a DsRed fluorescent protein (tdTomato). The F1 double-heterozygous (Mgp-tdTomato) was examined by direct fluorescence, whole mount, histology, and fundus photography. Custom-made filters had 554/23 emission and 609/54 exciter nanometer wavelengths. Proof of concept of the model's usefulness was conducted by inducing guided imaging laser burns. Evaluation of a vessel's leakage and proliferation was followed by noninvasive angiography. Results: The Mgp-tdTomato mouse was viable, fertile, with normal IOP and ERG. Its phenotype exhibited red paws and snout (cartilage expression), which precluded genotyping. A fluorescent red ring was seen at the limbus and confirmed to be TM expression by histology. The entire retinal vasculature was red fluorescent (VSMC) and directly visualized by fundus photography. Laser burns on the Mgp-tdTomato allowed separation of leakiness and neovascularization evaluation parameters. Conclusions: The availability of a transgenic mouse naturally fluorescent in glaucoma-relevant tissues and retinal vasculature brings the unique opportunity to study a wide spectrum of single and combined glaucomatous conditions in vivo. Moreover, the Mgp-tdTomato mouse provides a new tool to study mechanisms and therapeutics of retinal angiogenesis longitudinally. PMID- 29392321 TI - Retinopathy of Prematurity Among Very Low-Birth-Weight Infants in China: Incidence and Perinatal Risk Factors. AB - Purpose: Retinopathy of prematurity (ROP) is the leading cause of blindness in children worldwide. This study aimed to determine the incidence and perinatal risk factors for ROP in very low-birth-weight (VLBW) Chinese infants. Methods: A retrospective study of the medical records of 504 VLBW infants screened for ROP from 2012 to 2015 was performed in West China Second University Hospital. VLBW infants were examined according to the Royal College of Ophthalmologists ROP guideline and retinopathy was graded following the International Classification of ROP. Perinatal risk factors for ROP were assessed using univariate and multivariate analyses. Results: The overall incidence of ROP in our study was 26.0% (131/504). Stage 1 ROP, stage 2 ROP, and stage >=3 ROP were detected in 17.5%, 5.4%, and 3.2% of the infants screened, respectively. In the univariate analysis, many perinatal risk factors were found to have a significant association with ROP. In the subsequent multivariate analysis, in vitro fertilization (IVF) (odds ratio [OR] = 1.896; 95% confidence interval [CI] 1.031 3.486), gestational age (GA) < 32 weeks (OR = 2.171; 95% CI 1.085-4.346), apnea (OR = 2.001; 95% CI 1.224-3.272), bronchopulmonary dysplasia (BPD) (OR = 5.098; 95% CI 2.307-11.265), sepsis (OR = 2.212; 95% CI 1.070-4.576), patent ductus arteriosus (PDA) (OR = 1.675; 95% CI 1.011-2.774), and blood transfusion (OR = 1.819; 95% CI 1.046-3.163) were independently associated with the development of ROP (all P < 0.05). Conclusions: In VLBW Chinese infants, IVF, GA < 32 weeks, apnea, BPD, sepsis, PDA, and blood transfusion were independent perinatal risk factors for ROP. PMID- 29392323 TI - Association Between Ocular Surface Temperature and Tear Film Stability in Soft Contact Lens Wearers. AB - Purpose: To investigate the correlation between the changes in the ocular surface temperature (OST) and tear film stability over soft contact lenses (SCLs). Methods: We enrolled 20 eyes of 20 normal SCL wearers (20 men; 24.4 +/- 4.1 years). We used four different daily disposable SCLs: one silicone hydrogel lens (delefilcon A) and three hydrogel lenses (etafilcon A with polyvinylpyrrolidone [PVP], etafilcon A, and polymacon). OST was measured every second during 10 seconds without blinking. We defined the difference in the OST from 0 to 10 seconds as DeltaOST. To evaluate tear film stability, we measured noninvasive tear break-up time (NIBUT) and tear interference patterns on the contact lenses (TIPCL) using tear film interferometry. The parameters were measured before and 15 minutes after wearing each SCL. Results: DeltaOST was correlated significantly with NIBUT without (r = 0.411, P < 0.01) and with SCL (r = 0.642, P < 0.01). TIPCL grade was correlated significantly with DeltaOST over SCLs (r = -0.636, P < 0.01). DeltaOST was significantly smaller with silicone hydrogel delefilcon A than hydrogel etafilcon A and polymacon lenses (P < 0.05 and P < 0.01, respectively). Delefilcon A and etafilcon A with PVP lenses had significantly smaller NIBUT than etafilcon A (P < 0.05 for both comparisons). TIPCL grade of delefilcon A lens was significantly smaller than those of etafilcon A and polymacon (P < 0.01 for both comparisons). Conclusions: The changes in OST over SCLs are related to tear film stability. Measurements of OST can be used to evaluate tear film stability for SCL wearers. PMID- 29392322 TI - Effect of UVA/Riboflavin Collagen Crosslinking on Biomechanics of Artificially Swollen Corneas. AB - Purpose: The purpose of this study was to characterize the relation between corneal hydration and stiffening effects of the UVA/riboflavin collagen crosslinking treatment and to investigate how artificially swelling the cornea prior to this treatment procedure affects tensile property improvement. Methods: Porcine corneas were collagen crosslinked in vitro at different hydration levels using a number of hypoosmolar and isoosmolar riboflavin solutions. Thickness of the specimens prior to crosslinking was taken as a proxy for their hydration and was used to divide them into different thickness groups. A Dynamic Mechanical Analysis (DMA) machine was used to perform mechanical tensile tests. The hydration of specimens during the mechanical tests was kept similar to the hydration at which they were crosslinked. The recorded force was used to calculate the maximum tensile stress and tangent modulus as a function of thickness (hydration) prior to collagen crosslinking treatment. Results: Collagen crosslinking with either a hypoosmolar or isoosmolar solution significantly increased corneal tensile modulus (P < 0.05). Corneas that were swollen prior to crosslinking showed significantly softer tensile properties compared with those that were crosslinked at lower hydration (P < 0.05). Although the degree of tensile property improvement was hydration dependent, the stiffness of samples crosslinked at higher hydration was not significantly different than the stiffness of those crosslinked at lower hydration when the hydration was kept similar in the mechanical experiments. Conclusions: Swelling porcine corneas to the different extents prior to collagen crosslinking treatment does not significantly change the amount of biomechanical improvement if tensile properties are measured at similar hydration. PMID- 29392324 TI - Eye Movement Control in the Argus II Retinal-Prosthesis Enables Reduced Head Movement and Better Localization Precision. AB - Purpose: Visual scanning by sighted individuals is done using eye and head movements. In contrast, scanning using the Argus II is solely done by head movement, since eye movements can introduce localization errors. Here, we tested if a scanning mode utilizing eye movements increases visual stability and reduces head movements in Argus II users. Methods: Eye positions were measured in real time and were used to shift the region of interest (ROI) that is sent to the implant within the wide field of view (FOV) of the scene camera. Participants were able to use combined eye-head scanning: shifting the camera by moving their head and shifting the ROI within the FOV by eye movement. Eight blind individuals implanted with the Argus II retinal prosthesis participated in the study. A white target appeared on a touchscreen monitor and the participants were instructed to report the location of the target by touching the monitor. We compared the spread of the responses, the time to complete the task, and the amount of head movements between combined eye-head and head-only scanning. Results: All participants benefited from the combined eye-head scanning mode. Better precision (i.e., narrower spread of the perceived location) was observed in six out of eight participants. Seven of eight participants were able to adopt a scanning strategy that enabled them to perform the task with significantly less head movement. Conclusions: Integrating an eye tracker into the Argus II is feasible, reduces head movements in a seated localization task, and improves pointing precision. PMID- 29392325 TI - Challenges to the Common Clinical Paradigm for Diagnosis of Glaucomatous Damage With OCT and Visual Fields. AB - The most common clinical paradigm (CCP) for diagnosing glaucoma includes a visual field (VF) with a 6 degrees test grid (e.g., the 24-2 or 30-2 test pattern) and an optical coherence tomography (OCT) scan of the optic disc. Furthermore, these tests are assessed based upon quantitative metrics (e.g., the pattern standard deviation [PSD] of the VF and the global retinal nerve fiber thickness of the OCT disc scan). This CCP is facing three challenges. First, the macular region (i.e., +/-8 degrees from fixation) is affected early in the glaucomatous process, and the CCP can miss and/or underestimate the damage. Second, use of the typical VF and OCT metrics underestimates the degree of agreement between structural (OCT) and functional (VF) damage. Third, resolution of the OCT scan has improved, and local glaucomatous damage can be visualized like never before. However, the clinician often does not look at the OCT scan image. Together these challenges argue for a modification of the VF test pattern and OCT protocol, replacement of metrics with a comparison of abnormal regions on VF and OCT, and careful inspection of actual OCT scan images. In principle, the CCP could be modified easily. In practice, change is facing a number of impediments. PMID- 29392326 TI - Culture Systems of Dissociated Mouse and Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells Purified by Two-Step Immunopanning. AB - Purpose: We aimed to establish purification and culture systems for retinal ganglion cells (RGCs) differentiated from mouse and human pluripotent stem cells (PSC) for in vitro and regenerative medicine studies. Methods: We used a two-step immunopanning method to purify RGCs from mouse and human PSC-derived three dimensional (3D) retinal organoids. To assess the method, we purified RGCs from 3D retinal organoids derived from embryonic stem cells (ESCs) generated from Thy1 EGFP transgenic (TG) mice. In addition, 3D retinal organoids differentiated from human induced PSCs (iPSCs) were cultured for up to differentiation day (DD) 120, and RGCs were purified by immunopanning. RGC marker expressions were confirmed by immunostaining and reverse transcription-quantitative PCR. The purified RGCs were cultured, and neurite outgrowth was measured and analyzed using an IncuCyte Zoom system. Results: Mouse RGCs purified from Thy1-EGFP TG mouse retinas and the ESC derived 3D retinas could be maintained for approximately 2 to 3 weeks, expressing the markers BRN3B and SMI-312. Purified RGCs from human iPSC-derived retinal organoids expressed RGC markers and could be maintained for up to 4 weeks. The RGCs collected at DD 90 to 110 extended longer neurites than those collected at younger stages. Conclusions: We successfully purified RGCs from mouse and human PSC-derived 3D retinal organoids cultured for approximately 120 days. RGCs from older retinal organoids would be useful for neurite tracking. This method would be effective not only for studying the pathology of human RGC diseases but also for therapeutic drug studies and RGC transplantation. PMID- 29392327 TI - Increased Substrate Stiffness Elicits a Myofibroblastic Phenotype in Human Lamina Cribrosa Cells. AB - Purpose: Alteration in the extracellular matrix (ECM) of the optic nerve head (ONH) causes lamina cribrosa (LC) fibrosis and affects the mechanical integrity of the ONH. Increased ECM tissue stiffness drives myofibroblast activation leading to tissue fibrosis throughout the body. Here using primary human LC cells, we investigate the effect of substrate stiffness on profibrotic changes, which might be a key molecular mechanism driving ECM remodeling of the LC in primary open-angle glaucoma (POAG) glaucoma. Methods: Primary human LC cells from normal and age-matched POAG glaucoma donors were cultured on substrates with defined mechanical properties of 5 and 100 kPa to replicate the range of mechanical microenvironments that cells may experience in vivo. Cell morphology, spread area, actin stress fibers, vinculin-focal adhesion formation, and alpha smooth muscle actin (alpha-SMA) signal were examined using immunofluorescence staining. The elastic modulus of cells was measured using atomic force microscopy (AFM). Results: Significantly greater cell spread area along with increased actin filament development, and vinculin-focal adhesion formation (number and size) were found in both normal and glaucoma LC cells cultured on stiff substrates. These changes were positively associated with elevated cell stiffness measured by AFM. Changes in spreading and cytoskeleton organization of glaucoma LC cells were significantly more pronounced than those in normal cells. The transformation to a myofibroblast-like cell phenotype was identified in both LC cells exposed to stiffer substrates, as indicated by an increased alpha-SMA signal and its colocalization with the actin stress fibers. Conclusions: These findings demonstrated that a stiffer cell microenvironment activates a myofibroblastic transformation in human LC cells, and therefore contributes to LC remodelling and fibrosis in glaucoma. PMID- 29392328 TI - Relationship between parents' occupational characteristics and untreated dental caries in offspring: A population-based study of data from the Korean National Health and Nutrition Examination Survey, 2008-2015. AB - Objectives We investigated the association between parents' occupational characteristics and untreated dental caries in their children. Methods We analyzed the data of 4764 and 5862 children merged with data of their mothers and fathers, respectively, derived from the Korean National Health and Nutrition Examination Survey, 2008-2015. Dentists assessed untreated dental caries, and occupational characteristics were self-reported. The associations between untreated dental caries in children and their parents' occupational characteristics were assessed with logistic regression analysis. Results The prevalence of untreated dental caries was 18.58% and 16.39% in the mother- and father-matched data, respectively. Compared to children whose mothers worked regular hours, those whose mothers worked overtime had increased odds of untreated dental caries [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.02 1.39]. Children of female self-employed workers/employers/unpaid family workers had higher odds of untreated dental caries than those of wage earners (OR 1.18, 95% CI 1.00-1.39). The OR of untreated dental caries was higher among children with shift-working parents than those whose parents worked daytime hours (mother: OR 1.29, 95% CI 1.11-1.51; father: OR 1.36, 95% CI 1.18-1.58). Conclusions The children of non-white-collar workers, non-wage earners, and workers working overtime or doing shift work had higher odds of untreated dental caries. The effects of parental occupational characteristics on untreated dental caries differed by sex (mother versus father). Public health programs targeting the prevention of dental caries among children should consider parental occupational characteristics. PMID- 29392329 TI - Effectiveness of conservative treatment for patellofemoral pain syndrome: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the evidence regarding the effectiveness of conservative treatment in reducing patellofemoral pain. DATA SOURCES: CENTRAL, MEDLINE, CINAHL, and PEDro databases. STUDY SELECTION: Adults with patellofemoral pain, randomized controlled trials only, any conservative treatment compared with placebo, sham, other conservative treatment, or no treatment. Two independent reviewers. DATA EXTRACTION: Data were extracted from the full-text of the articles, based on Cochrane Collaboration recommendations. The outcome of interest was the difference between groups regarding change in pain severity. DATA SYNTHESIS: The majority of studies were underpowered. More than 80% of the 37 trials did not show a clinically significant benefit. Clinically significant effects of different sizes were found for 7 trials (6 studies out of 7 had short follow-ups). These effects were found for: (i) pulsed electromagnetic fields combined with home exercise -33.0 (95% CI -45.2 to -20.8); (ii) hip muscle strengthening -65.0 (95% CI -87.7 to -48.3) and -32.0 (-37.0 to -27.0); (iii) weight-bearing exercise -40.0 (95% CI -49.4 to -30.6); (iv) neuromuscular facilitation combined with aerobic exercise and stretching -60.1 (95% CI -66.9 to -54.5); (v) postural stabilization -24.4 (95% CI -33.5 to -15.3); and (vi) patellar bracing -31.6 (95% CI -35.2 to -28.0). CONCLUSION: There is no evidence that a single treat-ment modality works for all patients with patellofemoral pain. There is limited evidence that some treatment modalities may be beneficial for some subgroups of patients with patellofemoral pain. PMID- 29392330 TI - Responding to the World Health Organization Global Disability Action Plan in Egypt: A Technical Consultancy to develop a National Disability, Health and Rehabilitation Plan. AB - OBJECTIVE: A technical consultation to develop a National Disability, Health and Rehabilitation Plan (NDHRP) for Egypt was carried out in 2015. Its overall goal was to improve health, functioning, well-being, quality of life, and participation of persons with disability in Egypt by supporting the Ministry of Health and Population and other stakeholders to improve access to health services and strengthen health-related rehabilitation services for all persons in need. METHODS: The methodological steps of the technical consultation were as follows: collecting and reviewing accessible documents and data; site visits to state institutions, health and rehabilitation services; discussions with relevant stakeholders in rehabilitation, including persons with disability; drafting recommendations based on the principles of the World Report on Disability and the World Health Organization Global Disability Action Plan and the information collected; discussion with stakeholders in a workshop; and preparation of a final report. RESULTS AND DISCUSSION: The development of a NDHRP was successful and led to recommendations with a good level of consensus among stakeholders in Egypt. The authors hope that the NDHRP will lead to improved rehabilitation service provision, and health and quality of life of persons with disability and chronic health conditions living in Egypt. PMID- 29392331 TI - Relationships between internal and external handcycle training load in people with spinal cord injury training for the handbikebattle. AB - OBJECTIVE: To establish the relationship between internal and external handcycling training load for monitoring training in people with paraplegia. DESIGN: Observational study. SUBJECTS: Ten people with paraplegia. METHODS: All participants performed a graded peak exercise test. Power output and heart rate (HR) were measured and the session rating of perceived exertion (sRPE) was determined during a 12-week training period. Training Stress Score (TSS) was calculated from power output data, and TRaining IMPuls (TRIMP) was determined, based on HR, HRzones and sRPE. Partial correlations (for all training sessions of all participants) and Pearson's correlations (for all training sessions of an individual participant) were performed to determine the relationship between external (TSS) and internal (TRIMPHR, TRIMPHRzones and TRIMPsRPE) training loads. RESULTS: Partial correlations between measures of internal and external loads (r = 0.81-0.85) and correlations between TRIMPsRPE and TRIMP scores based on HR (r = 0.77-0.78) were very large. At the individual level, Pearson's correlations varied from moderate (r=0.48) to nearly perfect (r = 0.99). CONCLUSION: TRIMPsRPE and TRIMPHR showed very large correlations with external training load, and thus appear appropriate for use in monitoring handcycling training load in people with paraplegia. How-ever, it is recommended that both measures are used in combination, when possible, since some individuals showed weaker relationships. PMID- 29392332 TI - Effect of high-frequency repetitive transcranial magnetic stimulation on chronic central pain after mild traumatic brain injury: A pilot study. AB - OBJECTIVE: Central pain can occur following traumatic brain injury, leading to poor functional recovery, limitation of activities of daily living, and decreased quality of life. The aim of this study was to determine whether high-frequency (10 Hz) repetitive transcranial magnetic stimulation, applied over the primary motor cortex of the affected hemisphere, can be used to manage chronic central pain after mild traumatic brain injury. DESIGN: Prospective randomized feasibility study. METHODS: Twelve patients with mild traumatic brain injury and chronic central pain were randomly assigned to transcranial magnetic stimulation (high-frequency stimulation, 10 sessions) or sham groups. Diffuse tensor tractography revealed partially injured spinothalamocortical tracts in all recruited patients. A numerical rating scale (NRS) was used to evaluate pain intensity during pre-treatment and immediately after the 5th transcranial magnetic stimulation session (post1), 10th transcranial magnetic stimulation session (post2), and 1 (post3), 2 (post4), and 4 weeks (post 5) after finishing treatment. Physical and mental health status were evaluated using the Short Form 36 Health Survey (SF-36), including physical and mental component scores (PCS, MCS). RESULTS: The NRS score of the repetitive transcranial magnetic stimulation group was significantly lower than the sham group score at all clinical evaluation time-points during and after transcranial magnetic stimulation sessions. The transcranial magnetic stimulation group's SF-36 PCS score was significantly higher at post2, post3, post4, and post5 compared with the sham group. CONCLUSION: High-frequency transcranial magnetic stimulation may be used to manage chronic central pain and improve quality of life in patients with mild traumatic brain injury. However, this is a pilot study and further research is needed. PMID- 29392333 TI - Comparison of the de Morton Mobility Index and Hierarchical Assessment of Balance and Mobility in older acute medical patients. AB - OBJECTIVE: To compare the measurement properties of the de Morton Mobility Index (DEMMI) and the Hierarchical Assessment of Balance and Mobility (HABAM) in an older acute medical inpatient population. DESIGN: Cross-sectional. SUBJECTS: Older acute medical inpatients. METHODS: The DEMMI, HABAM and further assessments were performed after hospital admission. Construct validity was assessed by testing 13 hypotheses on convergent and known-groups validity. Test-retest reliability and minimal detectable change were estimated based on a re-assessment of unchanged patients. Floor and ceiling effects were used to indicate adequacy of scale width. RESULTS: For both the DEMMI and HABAM, 11 (85%) hypotheses regarding construct validity were confirmed (n = 158). Both scales showed strong correlations with other multi-component mobility scales (Spearman's rho 0.75 0.92). Neither floor nor ceiling effects were evident. The intraclass correlation coefficient was 0.98 (95% confidence interval (95% CI) 0.96-0.99) for the DEMMI and 0.99 (95% CI 0.99-0.99) for the HABAM, respectively (n = 30). The minimal detectable change with 90% confidence was 6 points on the 100-point DEMMI scale and 1 point on the 26-point HABAM scale. CONCLUSION: The DEMMI and the HABAM appear to be suitable for measuring mobility in older acute medical patients. PMID- 29392334 TI - Effect of postsurgical rehabilitation programmes in patients operated for lung cancer: A systematic review and meta-analysis. AB - OBJECTIVE: To review the evidence concerning the effects of postoperative exercise interventions on exercise capacity and health-related quality of life following resection for non-small cell lung cancer, and to review whether different initiation times of exercise produce different effects on exercise capacity. DATA SOURCES: Comprehensive literature search of MEDLINE, Embase, CENTRAL, CINAHL and PEDro. STUDY SELECTION: Randomized controlled trials examining the effects of exercise interventions were eligible for inclusion. DATA EXTRACTION: Postoperative outcome measurements were extracted and the quality of evidence was graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. DATA SYNTHESIS: Four randomized controlled trials were identified involving 262 participants. Short-term follow-up (12-20 weeks) showed significantly higher exercise capacity and physical component of health-related quality of life in the intervention group (standardized mean difference (SMD) 0.48; 95% confidence interval (CI) 0.04-0.93) compared with the control group (SMD 0.50; 95% CI 0.19-0.82). There was no difference between the effect of late- and early-initiated exercise intervention. CONCLUSION: Exercise has a small-to-moderate effect at short-term follow-up on exercise capacity and the physical component of health-related quality of life in patients operated for lung cancer. The long-term effects of exercise capacity are unknown. Early initiated exercise programmes (2 weeks post-operation) did not show an effect on exercise capacity. These findings should be interpreted with caution. PMID- 29392335 TI - Interposition of the transverse ligament of the knee into a fracture of the tibial plateau: a case report. AB - Interposition of the transverse ligament of the knee between fragments of an intercondylar eminence fracture was diagnosed using magnetic resonance imaging (MRI) in a 11-year-old boy after a sports injury. The interposition was confirmed and corrected during arthroscopy. We report what we believe to be the first published case of isolated interposition of the transverse ligament in a minimally displaced fracture of the tibial eminence. PMID- 29392336 TI - An IL-15 superagonist/IL-15Ralpha fusion complex protects and rescues NK cell cytotoxic function from TGF-beta1-mediated immunosuppression. AB - Natural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF) beta1. An interleukin (IL)-15 superagonist/IL-15 receptor alpha fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies. This in vitro study investigated the efficacy of IL-15SA/IL-15RA on TGF-beta1 induced suppression of NK cell-cytotoxic function. IL-15SA/IL-15RA inhibited TGF beta1 from decreasing NK cell lysis of four of four tumor cell lines (H460, LNCap, MCF7, MDA-MB-231). IL-15SA/IL-15RA rescued healthy donor and cancer patient NK cell-cytotoxicity, which had previously been suppressed by culture with TGF-beta1. TGF-beta1 downregulated expression of NK cell-activating markers and cytotoxic granules, such as CD226, NKG2D, NKp30, granzyme B, and perforin. Smad2/3 signaling was responsible for this TGF-beta1-induced downregulation of NK cell-activating markers and cytotoxic granules. IL-15SA/IL-15RA blocked Smad2/3 induced transcription, resulting in the rescue of NK cell-cytotoxic function from TGF-beta1-induced suppression. These findings suggest that in addition to increasing NK cell function via promoting the IL-15 signaling pathway, IL-15SA/IL 15RA can function as an inhibitor of TGF-beta1 signaling, providing a potential remedy for NK cell dysfunction in the immunosuppressive tumor microenvironment. PMID- 29392337 TI - An image-processing method to detect sub-optical features based on understanding noise in intensity measurements. AB - Accurate quantitative analysis of image data requires that we distinguish between fluorescence intensity (true signal) and the noise inherent to its measurements to the extent possible. We image multilamellar membrane tubes and beads that grow from defects in the fluid lamellar phase of the lipid 1,2-dioleoyl-sn-glycero-3 phosphocholine dissolved in water and water-glycerol mixtures by using fluorescence confocal polarizing microscope. We quantify image noise and determine the noise statistics. Understanding the nature of image noise also helps in optimizing image processing to detect sub-optical features, which would otherwise remain hidden. We use an image-processing technique "optimum smoothening" to improve the signal-to-noise ratio of features of interest without smearing their structural details. A high SNR renders desired positional accuracy with which it is possible to resolve features of interest with width below optical resolution. Using optimum smoothening, the smallest and the largest core diameter detected is of width [Formula: see text] and [Formula: see text] nm, respectively, discussed in this paper. The image-processing and analysis techniques and the noise modeling discussed in this paper can be used for detailed morphological analysis of features down to sub-optical length scales that are obtained by any kind of fluorescence intensity imaging in the raster mode. PMID- 29392339 TI - [Posttraumatic torsional deformities of the forearm : Methods of measurement and decision guidelines for correction]. AB - Forearm fractures are common in all age groups. Even if the adjacent joints are not directly involved, these fractures have an intra-articular character. One of the most common complications of these injuries is a painful limitation of the range of motion and especially of pronation and supination. This is often due to an underdiagnosed torsional deformity; however, in recent years new methods have been developed to make these torsional differences visible and quantifiable through the use of sectional imaging. The principle of measurement corresponds to that of the torsion measurement of the lower limbs. Computed tomography (CT) or magnetic resonance imaging (MRI) scans are created at defined heights. By searching for certain landmarks, torsional angles are measured in relation to a defined reference line. A new alternative is the use of 3D reformation models. The presence of a torsional deformity, especial of the radius, leads to an impairment of the pronation and supination of the forearm. In the presence of torsional deformities, radiological measurements can help to decide if an operation is needed or not. Unlike the lower limbs, there are still no uniform cut-off values as to when a correction is indicated. Decisions must be made together with the patient by taking the clinical and radiological results into account. PMID- 29392338 TI - Recurrence rates of urinary calculi according to stone composition and morphology. AB - Few studies have examined the relative risk of recurrence of different stone types. The object of the present study was to evaluate the tendency for stone recurrence as a function of major mineral composition of the stones and morphological characteristics of the stones. This study was carried out using 38,274 stones for which we had data available to specify if the stone was from the first or a subsequent urinary stone episode. Stones were analyzed for morphology by stereomicroscope and for composition by infrared spectroscopy. Overall, 42.7% of stones were from patients who had had a previous stone event, with these being more frequent in men (44.4%) than in women (38.9%, p < 0.0001). Age of first stone occurrence was lowest for dihydroxyadenine (15.7 +/- 16.6 years) and highest for anhydrous uric acid (62.5 +/- 14.9 years), with the average age of first stones of calcium oxalate falling in the middle (40.7 +/- 14.6 years for calcium oxalate dihydrate, and 48.4 +/- 15.1 years for calcium oxalate monohydrate, COM). By composition alone, COM was among the least recurrent of stones, with only 38.0% of COM stones coming from patients who had had a previous episode; however, when the different morphological types of COM were considered, type Ic-which displays a light color, budding surface and unorganized section-had a significantly greater rate of recurrence, at 82.4% (p < 0.0001), than did other morphologies of COM. Similarly, for stones composed of apatite, morphological type IVa2-a unique form with cracks visible beneath a glossy surface-had a higher rate of recurrence than other apatite morphologies (78.8 vs. 39-42%, p < 0.0001). Stone mineral type alone is insufficient for identifying the potential of recurrence of the stones. Instead, the addition of stone morphology may allow the diagnosis of highly recurrent stones, even among common mineral types (e.g., COM) that in general are less recurrent. PMID- 29392340 TI - Decompression for cervical disc herniation using the full-endoscopic anterior technique. AB - OBJECTIVE: Resection of a cervical disc herniation using a full-endoscopic technique with an anterior approach. INDICATION: Fresh disc herniation with monoradicular symptoms in the upper extremity. CONTRAINDICATIONS: Pure neck pain, cervical myelopathy, older and calcified disc herniations, higher grade of instability and deformity. SURGICAL TECHNIQUE: Introduction of a guidewire and dilatator to a cervical disc using an anterior approach. Under full-endoscopic view, preparation of the posterior parts of the annulus, opening of the annulus and posterior longitudinal ligament and resection of the herniated fragment from the epidural space. POSTOPERATIVE MANAGEMENT: Immediate mobilisation, isometric/coordinative exercises, functional exercises from week 3, building up strength from week 6. RESULTS: A total of 120 patients were operated using the full-endoscopic or microsurgically assisted technique and were followed up for 24 months. Significant improvement was achieved in both groups. The group of full endoscopic operated patients returned to work significantly earlier and 89% of all patients would undergo the operation again. PMID- 29392341 TI - Hyperacusis: major research questions. AB - BACKGROUND: Hyperacusis is a troublesome symptom that can have a marked negative impact on quality of life. OBJECTIVES: To identify major research questions in hyperacusis. MATERIALS AND METHODS: Review of gaps in knowledge regarding hyperacusis, and where opportunities may lie to address these. RESULTS: Eight major research questions were identified as priorities for future research. These were: What is the prevalence of hyperacusis in adults and children? What are the risk factors associated with hyperacusis? What is the natural history of hyperacusis? How is 'pain hyperacusis' perceived? What mechanisms are involved in hyperacusis? What is the relationship between hyperacusis and tinnitus? Can a questionnaire be developed that accurately measures the impact of hyperacusis and can be used as a treatment outcome measure? What treatments, alone or in combination, are effective for hyperacusis? CONCLUSION: This clinical/researcher led project identified major research questions in hyperacusis. A further development to identify patient-prioritized research will follow. PMID- 29392342 TI - [Surgical strategy for early stage carcinoma of the esophagus]. AB - Early stage carcinomas of the esophagus are histologically differentiated into adenocarcinomas and squamous cell carcinomas and subdivided into mucosal (m1-3) and submucosal (sm1-3) carcinomas depending on the infiltration depth. While the prevalence of lymph node metastases in mucosal carcinomas is very low, the probability of lymph node metastases increases from submucosal infiltration with increasing depth. According to the current German S3 guidelines endoscopic resection is the recommended treatment strategy for mucosal adenocarcinoma without histological risk factors (lymphatic invasion [L1], venous invasion [V1], poorly differentiated [>G2], microscopic residual disease [R1] at the deep resection margin). For superficial submucosal infiltration (sm1) without histological risk factors endoscopic resection can also be carried out, whereby in this case the guidelines make a stronger recommendation for esophagectomy. For squamous cell carcinoma endoscopic resection is indicated for an infiltration depth up to middle layer mucosal carcinoma (m2) without histological risk factors. Outside of these criteria an esophageal resection should always be carried out. The surgical gold standard is a subtotal abdominothoracic esophagectomy with two-field lymphadenectomy. Alternative procedures are total esophagectomy in proximal esophageal carcinoma and transhiatal extended gastrectomy for carcinoma of the cardia. Limited proximal or distal esophageal resections can be performed in proximal or distal mucosal carcinoma without the possibility of endoscopic resection; however, partial resections are not superior in terms of functional results and are not oncologically equivalent due to limited lymphadenectomy. Minimally invasive procedures show good oncological results and reduce the morbidity of radical esophagectomy. Reduced morbidity might be an argument for surgical resection in borderline cases between endoscopic and surgical resection. PMID- 29392343 TI - [Drug-induced angioedema : Focus on bradykinin]. AB - On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated. PMID- 29392344 TI - Soil commensal rhizobia promote Rhizobium etli nodulation efficiency through CinR mediated quorum sensing. AB - The rhizosphere microbiome is composed of diverse microorganisms directly interacting with plants and each other. We sought to achieve a better understanding of how rhizobia interact with other soil bacteria during the initial symbiosis period. In this study, we investigated how soil commensals, particularly other rhizobia, affect Rhizobium etli-Phaseolus vulgaris interactions. We found that R. etli formed significantly more nodules on beans grown in unsterilized soil than those in sterilized soil. Furthermore, a strain identified as Rhizobium fabae, isolated from unsterilized soil, was found to affect R. etli nodulation. Interestingly, we found that the key quorum sensing regulator CinR is important for R. etli nodulation efficiency when it is co inoculated with R. fabae. Moreover, we found that quorum sensing signals produced by R. fabae promoted CinR-mediated gene expression in R. etli. These data suggest that the effects of R. fabae on R. etli symbiosis may act through multispecies bacterial cell-cell communication. PMID- 29392345 TI - Albumin infusion improves endothelial function in septic shock patients: a pilot study. PMID- 29392346 TI - Freiburg Neuropathology Case Conference : Tumor Located in the Anterior Portion of the Third Ventricle. PMID- 29392347 TI - Diffusion Tensor Imaging of Dystrophic Skeletal Muscle : Comparison of Two Segmentation Methods Adapted to Chemical-shift-encoded Water-fat MRI. AB - PURPOSE: To compare the influence of two different regions of interest (ROIs) on diffusion tensor metrics in dystrophic thigh muscles using a custom-made (whole muscle) ROI including and a selective ROI excluding areas of fatty replacement. METHODS: Diffusion tensor imaging (DTI) and chemical-shift-encoded water-fat magnetic resonance imaging (MRI) of the thigh was conducted on a 3-Tesla system in 15 cases with muscular dystrophy and controls. The ROIs were chosen according to patterns of fatty replacement on co-registered axial DTI and gradient echo sequence (GRE) images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), fiber track length (FTL), and muscle fat fractions (MFF) were compared between both ROI segmentations. These comparisons, muscle-specific correlation coefficients, and the influence of ROI localization on tensor metrics were derived based on linear mixed effects regression models. RESULTS: In the cases a high correlation was observed for ADC and FA with MFF using a custom ROI. The correlation was weaker but still significant with a selective ROI method. Using the custom ROI, FTL correlated significantly with MFF in 3 out of 4 muscles (r <= -0.51). A correlation was not found for the selective ROI method. Interaction analysis revealed that the association of ADC and FA with MFF was not significantly influenced by the ROI localization. For FTL the ROI localization significantly reduced the negative association with MFF. CONCLUSION: The DTI metrics and FTL of custom ROI segmentation are significantly influenced by MFF. Contrary to ADC and FA, the effect of MFF on FTL is significantly reduced when applying selective ROI segmentation, which could therefore be a better option for MR tractography. PMID- 29392348 TI - Determinants of Increased Aortic Diameters in Young Normotensive Patients With Turner Syndrome Without Structural Heart Disease. AB - Factors associated with aortic dilation and dissection in patients with Turner syndrome (TS) remain unclear. We assessed magnetic resonance imaging-based aortic diameters at nine predefined anatomic positions and examined associations of increased aortic diameters with B-type natriuretic peptide (BNP), A-type NP (ANP), growth hormone treatment, insulin-like growth factor 1 (IGF1), and estrogen status. Forty-seven patients with TS aged 7.3-21 years and 34 healthy peers were enrolled in this study. Aortic diameters were higher in patients with TS at three positions than in controls (p < 0.05). History of GH treatment, pubertal status, and serum estradiol levels were not associated with increased aortic diameters. Patients with TS had higher plasma BNP and ANP levels than controls. BNP and IGF1 were independently associated with the increase in aortic diameters in TS at three positions of the ascending aorta (R2 = 0.361-0.458, p < 0.05 for all). At two positions of the descending aorta, only BNP emerged as an independent variable (R2 = 0.130-0.139, p < 0.05). We conclude that young, normotensive patients with TS had greater aortic diameters at several positions than healthy controls. BNP and IGF1 were independently associated with increased aortic diameters in TS. PMID- 29392349 TI - Necrotizing Enterocolitis in Infants with Hypoplastic Left Heart Syndrome Following Stage 1 Palliation or Heart Transplant. AB - Previous studies of necrotizing enterocolitis (NEC) among infants with hypoplastic left heart syndrome (HLHS) were conducted in single centers or had small sample sizes. This study aimed to determine the mortality rate and the risk factors for NEC among infants with HLHS who were discharged over a 10-year period (2004-2013) from 41 Pediatric Health Information System affiliated children's hospitals. Either stage 1 palliation and/or heart transplant were completed prior to patient's death or hospital discharge. We compared the characteristics of infants with HLHS who did not develop NEC and those who developed medical or surgical NEC and of patients who had medical vs. surgical NEC. The primary outcome was mortality over time and by birth weight category (low birth weight [LBW], birth weight < 2500 vs. >= 2500 g). Multivariable analyses were performed to identify the risk factors for developing NEC and for mortality among infants with HLHS. The study evaluated 5720 infants with HLHS including 349 patients (6.1%) with medical or surgical NEC. Fifty-two patients (0.9%) required laparotomy or percutaneous abdominal drainage. On univariable analysis, the overall mortality rate for infants who developed NEC was significantly higher than infants who did not develop NEC (23.5 vs. 13.9%, P < 0.001). On multivariable analysis, neither medical nor surgical NEC was a significant predictor of mortality in the study population. LBW infants were at higher risk for mortality in both the univariable and the multivariable models. Nevertheless, LBW did not significantly predispose infants with HLHS to develop NEC. Our results provide a national benchmark incidence of NEC, its risk factors, and outcomes among a large cohort of infants with HLHS and establish that NEC is not a significant risk factor for mortality in this population. PMID- 29392350 TI - Evaluation of the efficiency of the Cheneau brace on scoliosis deformity : A systematic review of the literature. AB - BACKGROUND: Scoliosis is a three-dimensional deformity of the spine and rib cage. Depending on the severity of this disease, various kinds of treatment methods have been used and bracing is among the most common. One of the braces which has been used for subjects with scoliosis is the Cheneau brace. The aim of this review was to evaluate the efficiency of the Cheneau brace on the scoliosis curve progression and control based on the available literature. METHOD: We conducted a Medline search via PubMed, Google Scholar, ISI Web of Sciences, Ebsco and Scopus. Keywords such as Cheneau brace, Cheneau light and CAD/CAM spinal brace were used in combination with scoliosis. The quality of the studies was evaluated by the Down and Black tool. RESULTS: Based on the aforementioned keywords, 55 papers were found. Finally based on the mentioned criteria 14 papers were selected for final analysis. The quality of the studies varied between scores of 13 and 25 using the Down and Black tool. The results of the selected studies confirmed that a good scoliotic curve correction can be achieved with the Cheneau brace. CONCLUSION: The Cheneau brace provides a 3-dimensional correction of the spinal deformity which not only influences the progression of scoliotic curve but also influences its natural history. It cannot be concluded that the Cheneau brace is superior to other available braces; however, it has been shown that this brace is effective to control the scoliotic curve progression especially in the lumbar and thoracolumbar regions. PMID- 29392351 TI - Determination of plasma concentration reference ranges for oral aripiprazole, olanzapine, and quetiapine. AB - BACKGROUND: Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. AIMS: The aim of this study was to develop "reference ranges" for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. METHODS: Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. RESULTS: Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7-41.6 ng/mL 0-4 h post dose and 10.6-37.1 ng/mL 20-24 h post dose. These ranges increased to 221-624 ng/mL 0-4 h post dose following administration of a 30-mg dose, and 159-557 ng/mL 20-24 h post dose. The 80% reference range 0-4 h post dose was 22.5-67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179-768 ng/mL following a 150-mg dose once daily of oral quetiapine. CONCLUSIONS: Comparing individual patients' APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy. PMID- 29392353 TI - [Nivolumab for pretreated metastatic anal cancer : Immune checkpoint blockade is also advised in combination with radiochemotherapy]. PMID- 29392354 TI - Advances in Transcriptomics of Plants. AB - The current global population of 7.3 billion is estimated to reach 9.7 billion in the year 2050. Rapid population growth is driving up global food demand. Additionally, global climate change, environmental degradation, drought, emerging diseases, and salty soils are the current threats to global food security. In order to mitigate the adverse effects of these diverse agricultural productivity constraints and enhance crop yield and stress-tolerance in plants, we need to go beyond traditional and molecular plant breeding. The powerful new tools for genome editing, Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR)/Cas systems (CRISPR-Cas9), have been hailed as a quantum leap forward in the development of stress-resistant plants. Plant breeding techniques, however, have several drawbacks. Hence, identification of transcriptional regulatory elements and deciphering mechanisms underlying transcriptional regulation are crucial to avoiding unintended consequences in modified crop plants, which could ultimately have negative impacts on human health. RNA splicing as an essential regulated post-transcriptional process, alternative polyadenylation as an RNA-processing mechanism, along with non-coding RNAs (microRNAs, small interfering RNAs and long non-coding RNAs) have been identified as major players in gene regulation. In this chapter, we highlight new findings on the essential roles of alternative splicing and alternative polyadenylation in plant development and response to biotic and abiotic stresses. We also discuss biogenesis and the functions of microRNAs (miRNAs) and small interfering RNAs (siRNAs) in plants and recent advances in our knowledge of the roles of miRNAs and siRNAs in plant stress response. Graphical Abstract. PMID- 29392352 TI - Epidemiology of diabetes and diabetic complications in China. AB - The People's Republic of China (herein referred to as China) has witnessed one of the most dramatic rises in diabetes prevalence anywhere in the world. The latest epidemiological study suggests that approximately 11% of the population has diabetes, with a significant proportion remaining undiagnosed. Risk factors for diabetes in the Chinese population are similar to those in other populations, though gestational diabetes and young-onset diabetes is becoming increasingly common. Data on the prevalence of diabetic complications remain limited, though cardio-renal complications account for significant morbidity and mortality. Other diabetes-related comorbidities are becoming increasingly common, with cancer emerging as a major cause of mortality among individuals with diabetes. There are many challenges and obstacles that impede effective diabetes prevention and the delivery of care, though much progress has occurred over recent years. Lessons learnt from how China has responded to the challenges posed by the diabetes epidemic will be invaluable for other countries facing the many threats of diabetes and its complications. PMID- 29392355 TI - Risk-equivalent T-score adjustment for using lumbar spine trabecular bone score (TBS): the Manitoba BMD registry. AB - : Lumbar spine trabecular bone score (TBS) can be used to modify the output from the fracture risk assessment tool, FRAX, to enhance fracture prediction. An alternative approach for using TBS in clinical practice, based upon an adjustment to the bone mineral density (BMD) T-score, may be helpful in regions where intervention guidelines and/or reimbursement are primarily based on BMD T-score. INTRODUCTION: The aim of this study is to develop an approach for using TBS in clinical practice based upon a "risk-equivalent" adjustment to the BMD T-score. METHODS: We identified 45,185 women age 40 years and older with baseline spine and hip DXA, TBS, and FRAX probabilities including femoral neck BMD. Incident major osteoporotic fractures (MOF, n = 3925) were identified from population based health services data (mean follow-up 7.4 years comprising 335,910 person years). Cox proportional hazards models adjusted for age and BMI were first used to estimate the risk for MOF from BMD T-score alone, then after including TBS and a multiplicative age interaction term. From the parameter estimates, we developed a TBS offset to the BMD T-score based upon change in TBS that would give the same risk as a unit change in BMD T-score for the femoral neck, total hip, and lumbar spine. RESULTS: All BMD measurements, TBS, and the age interaction term independently predicted MOF (p < 0.001). Measures of risk stratification and model fit were improved for the TBS-adjusted BMD T-score versus the unadjusted BMD T-score (p < 0.001). There was a high level of agreement between MOF probability estimated from TBS-adjusted MOF FRAX probability and FRAX probability using the "risk-equivalent" femoral BMD T-score: MOF probability r2 = 0.98, slope = 1.02, intercept = - 0.3; hip probability r2 = 0.95, slope = 1.07, intercept = 0.0. CONCLUSIONS: The BMD-independent effect of lumbar spine TBS on fracture risk can be estimated as a simple offset to the BMD T-score. PMID- 29392356 TI - Efficacy of external nasal nerve block following nasal surgery : A randomized, controlled trial. AB - BACKGROUND: Pain is the major determinant factor which affects the quality of recovery and postoperative agitation following nasal surgery with the patient under general anesthesia. Our objectives were to test the hypothesis that an external nasal nerve block will decrease pain intensity, decrease drug consumption, decrease the incidence of postoperative emergence agitation and improve quality of recovery. MATERIAL AND METHODS: In this study 100 adult patients who were scheduled for elective external nasal surgery with the patient under general anesthesia and nasal packing on each side, received external nasal nerve blocks postoperatively for 24 h with saline (group I) or 2% xylocaine (group II) with 1:200,000 epinephrine. Postoperative pain was measured at the postanesthesia care unit (PACU) utilizing a visual analog scale (VAS). Narcotics consumption was also measured. Emergence agitation and quality of recovery were also assessed. RESULTS: Pain scores were statistically significant between both groups. Requirements of equivalent morphine doses in the PACU were lower in group II (block) than group I (control) with a significant P value <0.001. Group II (block) patients required significantly less intraoperative fentanyl than group I (control) patients (p = 0.001). Group II (block) showed higher scores in pain dimension of QoR-40 in comparison with group I (P <0.001). The incidence of emergence agitation was lower in group II (block) than in group I (control, 24% vs. 48%, P = 0.012). CONCLUSION: External nasal nerve block is an effective technique for reducing postoperative pain, drug consumption and quality of recovery. It also reduces emergence agitation. The effects are mainly due to profound analgesia and effective pain control that lead to decreased drug usage and reduced discomfort. PMID- 29392358 TI - Response to Comments Made on "Alternative Rhinoplasty Technique: Rotational Spreader Flap (Rabbit Flap)". PMID- 29392357 TI - Thyromental distance ("Patil") revisited : Knowledge and performance of a basic airway screening tool among European anesthetists. AB - Predicting and managing the difficult airway is a lifesaving and vital basic task for the anesthetist. Current guidelines of all important societies include thyromental distance (TMD, "Patil") as a possible predictor for a difficult airway and includes two important aspects for airway management: the mandibular space and the flexibility of the cervical spine. We evaluated knowledge and execution regarding TMD for predicting a difficult airway on participants at the Euroanaesthesia (ESA) congress and German Anaesthesia Congress (DAC) in 2014. Our evaluation consisted of a theoretical part with questions regarding general knowledge and a practical evaluation with anesthetists performing on a human airway model. Practical evaluations were performed separately from other participants. During the DAC 245 (ESA 230) physicians participated, of which 64% were male (ESA 58%). At the DAC 182 (74.3%) and ESA 82 (35.6%) participants knew about Patil/TMD. Its use as a predictive score for a difficult airway was known by 122 (49.8%; DAC) and 79 (34.4%; ESA) participants. The correct definition for intubation was given by 45 (25.7%) at the DAC and 56 (24.3%) at ESA. Only 40-41% of the participants measured the correct distance for TMD. Only 6.1-6.5% completed both the theoretical and practical parts correctly. As non-invasive TMD includes two different aspects of patient airways and is part of current guidelines, education and training must be extended to assure adequate evaluation in the future. PMID- 29392359 TI - The Use of Meshed Dermal Autograft in Breast Reconstruction. AB - The advantages and disadvantages of acellular dermal matrix (ADM) in breast reconstruction have been well documented. ADM is commonly used in breast reconstruction, but it adds cost to the procedure and has been associated with an increased risk of seroma, flap necrosis and infectious complications. A dermal autograft may be a useful alternative to matrices, and it has a lot of advantages: more biocompatible and more likely to be retained as a free graft, low cost, well tolerated, readily available and integrated. This report discusses a new surgical technique that uses an autologous dermis, which was harvested from the controlateral breast in patients having simultaneous breast reduction/mastopexy. Before the insertion, the autologous dermal matrix was meshed at a ratio of 3:1 to increase the graft surface area, to provide additional draining and to improve the engraftment of the autologous dermal matrix. Consequently, the resulting meshed graft allows for the cover of the inferior pole of a larger breast size implant and decreases the complication rate. In our clinic, this method was used on five women; there was one limited necrosis of the mastectomy flaps. The described technique is straightforward and reliable, it adds minimally to the operative time, and it eliminates costs and covers a bigger part of the prosthesis and promises good results. No Level Assigned This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29392360 TI - Hepatic sinusoidal dilatation. AB - Hepatic sinusoidal dilatation refers to the enlargement of the hepatic capillaries. Most of the time this condition is caused by hepatic venous outflow obstruction, which results in vascular stasis and congestion of hepatic parenchyma. In this setting, hepatic sinusoidal dilatation can be related to pericardial disease, heart failure, compression or thrombosis of the hepatic veins or inferior vena cava (i.e., Budd-Chiari syndrome) or central veins/sinusoids involvement (i.e., sinusoidal obstruction syndrome). Nevertheless, some extrahepatic inflammatory conditions (such as pyelonephritis, cholecystitis, pneumonia, pancreatitis, intestinal bowel disease, and others) may be associated with hepatic sinusoidal dilatation without concurrent venous outflow obstruction. On contrast-enhanced cross-sectional imaging, hepatic sinusoidal dilatation is typically characterized by a mottled, reticular enhancement of the liver, usually referred to as "mosaic" pattern. Other hepatic and extrahepatic imaging features, such us the dilatation of the hepatic veins or the presence of ascites, can help in identifying the cause of sinusoidal dilatation. PMID- 29392361 TI - Hepatic pseudolymphoma: imaging features on dynamic contrast-enhanced MRI and diffusion-weighted imaging. AB - PURPOSE: To investigate dynamic contrast-enhanced (DCE) MR findings and diffusion weighted imaging (DWI) characteristics of hepatic pseudolymphoma. MATERIALS AND METHODS: The MR data of 20 lesions in 14 patients with histopathologically proven hepatic pseudolymphoma were retrospectively analyzed. All patients underwent dynamic gadopentetate dimeglumine-enhanced MR imaging and DWI. Morphologic characteristics and signal features on T1- and T2-weighted images (T1WI, T2WI), and DCE pattern were qualitatively evaluated. The quantitative analysis was performed for the size, the degree of enhancement on arterial phase, signal intensity (SI) of DWI, and apparent diffusion coefficient (ADC) values. The Wilcoxon signed ranks test was used for statistical analysis. RESULTS: The contour of all lesions was round. The lesion size was 0.7-2.8 cm (mean 1.3 +/- 0.5 cm). All lesions manifested as homogeneous hypointensity on T1WI and hyperintensity on T2WI. All lesions were shown as hypervascular with various enhancement patterns on DCE MR imaging. The presence of peripheral enhancement and pseudocapsule was observed in 7 and 4 lesions, respectively. SI of the hepatic pseudolymphoma was significantly lower than that of portal vein on arterial phase (P < 0.001) and the ADC was significantly lower than that of spleen (P = 0.012). CONCLUSION: A homogeneous nodule with small size (<2 cm), manifestation of hypervascular with lower SI than that of portal vein on arterial phase and lower ADC values than that of spleen are the common MR features of hepatic pseudolymphoma. PMID- 29392362 TI - Diagnostic performance of diffusion-weighted MR imaging at 3.0 T in predicting muscle invasion in urinary bladder cancer: utility of evaluating the morphology of the reactive tumor stalk. AB - PURPOSE: To evaluate the diagnostic performance of stalk morphology on diffusion weighted imaging (DWI) in comparison with conventional MRI in predicting muscle invasion in urinary bladder cancer. METHODS: The study was prospective and approved by the institutional ethics committee. A written informed consent was obtained from all the patients. The study included 56 patients who presented with bladder mass between January 2014 and November 2015. After excluding 16 patients, 40 patients with 92 tumors were assessed. All the 40 patients underwent MRI at 3.0 Tesla (Achieva, Philips) inclusive of DWI (b0, 500, 1000 and 1500). Two radiologists evaluated the images independently, and disparities were resolved through consensus. For predicting muscle invasion on T2-weighted images, tumor morphology (papillary versus non-papillary), distensibility of the underlying bladder wall, and perivesical fat infiltration were evaluated. On DWI, the criterion used in a previous study (Takeuchi et al.) was used along with tumor stalk morphology. Findings were compared with histopathology using Pearson's chi2 test, and diagnostic performance indices were calculated. RESULTS: All the evaluated features were present with significantly higher frequency in muscle invasive tumors (p < 0.001). The finding of absent or distorted stalk on DWI had the highest sensitivity (87.5%) and specificity (97.6%). Conventional imaging features of non-papillary stalk morphology, restricted distension of underlying bladder wall, perivesical fat infiltration, as well as the previous DWI criterion were less sensitive (56.3%, 68.8%, 56.3% and 56.3%, respectively) in predicting muscle invasion. CONCLUSIONS: Assessment of the morphology of the reactive tumor stalk on DWI has better diagnostic performance in predicting muscle invasion than conventional MRI. PMID- 29392363 TI - Structured reporting and quality control in CT colonography. AB - Standardized recommended techniques for performing and reporting CT colonography (CTC) examinations were developed by a consensus of experts. Published reporting guidelines, known as the CT colonography reporting and data system supplemented by recently updated comprehensive recommendations were incorporated into the American College of Radiology (ACR) practice guidelines. The application of continuous quality improvement to the practice of CT was aided by the development of an ACR national data registry (NRDR) for CTC that addressed both process and outcome quality measures. These measures can be used to benchmark an institution's CTC practice as compared to all participants. This article will discuss the best practices for reporting CTC and describe the use of NRDR to foster quality CTC performance. PMID- 29392364 TI - Pharyngeal manifestations of gastroesophageal reflux disease. AB - This article discusses the extraesophageal manifestations of gastroesophageal reflux disease, focusing primarily on the gamut of pharyngeal abnormalities that can be detected on barium swallows. Abnormalities of pharyngeal swallowing caused by gastroesophageal reflux are illustrated. We particularly emphasize how pharyngoesophageal relationships can guide the radiologist for performing tailored barium swallows to optimally evaluate pharyngeal abnormalities in patients with underlying gastroesophageal reflux disease. PMID- 29392365 TI - ADC similarity predicts microvascular invasion of bifocal hepatocellular carcinoma. AB - PURPOSE: This study aimed to investigate whether ADC similarity can predict microvascular invasion (MVI) in patients with bifocal hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between January 2015 and September 2015, 51 patients with two HCC lesions were included. All patients underwent conventional magnetic resonance imaging including diffusion-weighted imaging (DWI) before the HCC lesions were surgically resected; the tumor specimens were examined histopathologically. Similarity between two HCC lesions regarding DWI signal intensity (SI) and ADC value was calculated as the difference between the two lesions: Value Similarity = [1-(|valuelarge lesion-valuesmall lesion|)/(valuelarge lesion + valuesmall lesion)] * 100%. Univariate and multivariate logistic regression analyses were performed to assess the presence of MVI. RESULTS: Risk factors significantly related to MVI of bifocal HCC in univariate analysis were cirrhosis (P = 0.010), histological grade (P = 0.040), DWI SI similarity (P = 0.027) and ADC similarity (P = 0.003). In multivariate analysis, cirrhosis (odds ratio 0.068, P = 0.022) and ADC similarity (odds ratio 1.204, P = 0.008) were independent risk factors for MVI of bifocal HCC. CONCLUSION: In patients with two HCC lesions, highly similar ADC values for the two HCC lesions may be a preoperative predictor of MVI. PMID- 29392366 TI - Keyhole sign in posterior urethral valve. PMID- 29392367 TI - Abdominal radiograph usage trends in the setting of constipation: a 10-year experience. AB - PURPOSE: Limited data are available to guide the use of abdominal radiographs in the setting of constipation, especially in adults. Anecdotally, there has been a recent increase in such examinations. We sought to determine ordering trends for abdominal radiographs ordered to assess constipation, as well as to better understand referring clinician and radiologist opinion on such examinations. METHODS: We conducted a retrospective review of all abdominal radiographs performed between 2004 and 2014 at our institution with a primary indication of constipation. We also surveyed clinicians and radiologists regarding their opinions and practices involving such examinations. RESULTS: Constipation radiograph volume increased by approximately 56% over the 10-year period, while volume of all other abdominal radiographs decreased. Growth was greatest in adult females. Both radiologists and clinicians agree that constipation is a clinical diagnosis and are neutral as to whether radiographs help make the diagnosis. Clinicians somewhat agree that radiographs are helpful in determining management and find quantitation of stool burden within the radiology report helpful. Radiologists tend to find radiographs inaccurate at quantifying stool burden. Clinicians tend to agree that the increasing use of radiographs for constipation is appropriate while radiologists disagree. Education on these trends did not affect the intended future ordering practice of referring clinicians. CONCLUSIONS: Constipation abdominal radiograph volume has disproportionately increased, especially in adult women. Clinicians and radiologists agree that constipation is a clinical diagnosis. Otherwise, the groups tend to have differing opinions on the utility of such examinations. Clinicians indicated no intention to change their ordering practices. Further investigation is needed to better define the role of imaging for this indication, including how the radiologist may best interpret and report such examinations. PMID- 29392368 TI - Normal reference values for bladder wall thickness on CT in a healthy population. AB - PURPOSE: To determine normal bladder wall thickness on CT in patients without bladder disease. MATERIALS AND METHODS: Four hundred and nineteen patients presenting for trauma with normal CTs of the abdomen and pelvis were included in our retrospective study. Bladder wall thickness was assessed, and bladder volume was measured using both the ellipsoid formula and an automated technique. Patient age, gender, and body mass index were recorded. Linear regression models were created to account for bladder volume, age, gender, and body mass index, and the multiple correlation coefficient with bladder wall thickness was computed. Bladder volume and bladder wall thickness were log-transformed to achieve approximate normality and homogeneity of variance. Variables that did not contribute substantively to the model were excluded, and a parsimonious model was created and the multiple correlation coefficient was calculated. Expected bladder wall thickness was estimated for different bladder volumes, and 1.96 standard deviation above expected provided the upper limit of normal on the log scale. RESULTS: Age, gender, and bladder volume were associated with bladder wall thickness (p = 0.049, 0.024, and < 0.001, respectively). The linear regression model had an R2 of 0.52. Age and gender were negligible in contribution to the model, and a parsimonious model using only volume was created for both the ellipsoid and automated volumes (R2 = 0.52 and 0.51, respectively). CONCLUSION: Bladder wall thickness correlates with bladder wall volume. The study provides reference bladder wall thicknesses on CT utilizing both the ellipsoid formula and automated bladder volumes. PMID- 29392369 TI - Cecal arrowhead sign. PMID- 29392370 TI - Applicability of current NCCN Guidelines for pancreatic adenocarcinoma resectability: analysis and pitfalls. AB - PURPOSE: To test the applicability of National Comprehensive Cancer Network (NCCN v 3.2017) resectability criteria for pancreatic ductal adenocarcinoma (PDAC) in clinical practice, at a high-volume tertiary referral center. MATERIALS AND METHODS: 102 consecutive patients (53 female; mean age 66.2 years, range 34-90 years) with biopsy proven, non-metastatic PDAC were evaluated by our multidisciplinary pancreatic cancer program between July 2013 and February 2016. Retrospective review of staging pancreatic CT angiography was performed, and radiographic features were categorized as conforming to or non-conforming to existing v 3.2017 definitions. RESULTS: Among 102 patients, 10 (10%) had CTA evidence of vascular involvement that did not conform to existing NCCN Guidelines. Six new scenarios of vascular involvement were identified. The remaining 92 patients presented with resectable (n = 20 [22%]), borderline resectable (n = 42 [45.6%]), or unresectable (n = 30 [33%]) PDAC. Approximately half (n = 21 [51%]) of borderline resectable patients' tumors demonstrated isolated venous involvement, whereas 39% had both arterial and venous involvement. A minority (11%) demonstrated only major arterial involvement. Assignment to unresectable status reflected both arterial and venous involvement (11, 37%), arterial involvement only (10, 33%) patients, and unreconstructible venous involvement in 9 (30%). CONCLUSION: In our experience, current NCCN resectability guidelines for PDAC do not accurately classify vascular involvement identified in approximately 10% of patients. Revision of the current guidelines could be helpful to clinical practice. PMID- 29392372 TI - Inhibiting automatic negative social responses in alcohol intoxication: interactions with theory of mind ability and level of task guidance. AB - RATIONALE: Alcohol intoxication is associated with socially disinhibited behaviours that may reflect impaired social cognitive abilities that guide social behaviour. The effects of alcohol on social cognition and how this may contribute to disinhibited behaviour are poorly understood. The aim of this study was to examine whether intoxicated individuals could inhibit automatic negative responses to negative social information, whether these difficulties were reliant on theory of mind (ToM) ability and whether intoxicated individuals were able to adjust verbal responses when provided with guidelines about how to respond. METHODS: Sixty-four participants aged between 18 and 34 (balanced for gender) consumed a beverage containing either placebo or alcohol calculated to achieve a target BrAC of 0.080%, before completing a Flanker task, a go/no-go task and a novel measure of social disinhibition, the social disinhibition task. RESULTS: Results indicate that alcohol-intoxicated individuals can inhibit negative responses to negative social information, but display difficulty inhibiting negative responses to social information that requires ToM. They also suggest that people under the influence of moderate-to-high-dose alcohol can adjust their responses when provided with specific guidelines on how to respond. CONCLUSIONS: These findings may have important implications for understanding negative alcohol related behaviours and promote the consideration of social context, social pressure and social cognitive abilities in the development of public policy and targeted interventions to prevent alcohol-related antisocial behaviours. PMID- 29392371 TI - Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. METHODS: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two period crossover design. Primary measures included five tests of Cogstate(r) computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. RESULTS: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate(r) tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. CONCLUSIONS: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo comparable levels by 2 h postdose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094378. PMID- 29392373 TI - Brain-derived neurotrophic factor as a biomarker for cognitive recovery in acute schizophrenia: 12-week results from a prospective longitudinal study. AB - RATIONALE: It is generally accepted that impaired cognitive function is a core feature of schizophrenia. There is evidence for the role of brain-derived neurotrophic factor (BDNF) in cognitive function. Olanzapine was reported to yield cognitive improvement in patients with schizophrenia. OBJECTIVES: In this study, we performed a prospective, open-label, 12-week observation trial to investigate whether peripheral BDNF may represent a potential biomarker for the effect of cognitive improvement induced by olanzapine in patients with schizophrenia. METHODS: In total, 95 patients with acute schizophrenia were enrolled in the study. We also recruited 72 healthy individuals for a control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate symptom severity and treatment response. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma BDNF levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Of the 95 patients consented into the study, 68 completed the 12-week follow up. Our results showed that schizophrenia patients with acute exacerbation had significantly poorer performance than that of the controls (Ps < 0.01). A significantly decreased plasma level of BDNF in patients was observed compared with the controls (F = 7.77, P = 0.006). A significant improvement in each PANSS subscore and total score was observed when the patients completed this study (Ps < 0.01). Additionally, 12-week olanzapine treatment exhibited significant improvements in RBANS immediate memory, attention, and total scores (P = 0.018, 0.001, and 0.007, respectively). Along with the clinical improvement, plasma BDNF levels after 12-week olanzapine monotherapy (4.67 +/- 1.74 ng/ml) were also significantly increased compared with those at baseline (3.38 +/- 2.11 ng/ml) (P < 0.01). Spearman's correlation analysis showed that the increase in plasma levels of BDNF is significantly correlated with the change in the RBANS total scores (r = 0.28, P = 0.02) but not with the change in the PANSS total scores (r = - 0.18, P = 0.13). There is a significant correlation of BDNF increase with the change of RBANS attention subscore (r = 0.27, P = 0.028). CONCLUSIONS: Our findings suggest that olanzapine improves psychiatric symptoms and cognitive dysfunction, particularly attention and immediate memory, in patients with acute schizophrenia, in parallel with increased plasma BDNF levels. Plasma BDNF levels may be a potential biomarker for cognitive recovery in acute schizophrenia. PMID- 29392374 TI - Mapping and validation of a new QTL for adult-plant resistance to powdery mildew in Chinese elite bread wheat line Zhou8425B. AB - KEY MESSAGE: Four QTLs for adult-plant resistance to powdery mildew were mapped in the Zhou8425B/Chinese Spring population, and a new QTL on chromosome 3B was validated in 103 wheat cultivars derived from Zhou8425B. Zhou8425B is an elite wheat (Triticum aestivum L.) line widely used as a parent in Chinese wheat breeding programs. Identification of genes for adult-plant resistance (APR) to powdery mildew in Zhou8425B is of high importance for continued controlling the disease. In the current study, the high-density Illumina iSelect 90K single nucleotide polymorphism (SNP) array was used to map quantitative trait loci (QTL) for APR to powdery mildew in 244 recombinant inbred lines derived from the cross Zhou8425B/Chinese Spring. Inclusive composite interval mapping identified QTL on chromosomes 1B, 3B, 4B, and 7D, designated as QPm.caas-1BL.1, QPm.caas-3BS, QPm.caas-4BL.2, and QPm.caas-7DS, respectively. Resistance alleles at the QPm.caas-1BL.1, QPm.caas-3BS, and QPm.caas-4BL.2 loci were contributed by Zhou8425B, whereas that at QPm.caas-7DS was from Chinese Spring. QPm.caas-3BS, likely to be a new APR gene for powdery mildew resistance, was detected in all four environments. One SNP marker closely linked to QPm.caas-3BS was transferred into a semi-thermal asymmetric reverse PCR (STARP) marker and tested on 103 commercial wheat cultivars derived from Zhou8425B. Cultivars with the resistance allele at the QPm.caas-3BS locus had averaged maximum disease severity reduced by 5.3%. This STARP marker can be used for marker-assisted selection in improvement of the level of powdery mildew resistance in wheat breeding. PMID- 29392377 TI - Sample pretreatment and SERS-based detection of ceftriaxone in urine. AB - The aim of the work is the development of the procedure for ceftriaxone (antibiotic drug of cephalosporin class) detection in urine using surface enhanced Raman spectroscopy (SERS). Hydroxylamine stabilized silver nanoparticles were used as SERS-active material. Additional urine pretreatment steps were developed in order to eliminate the influence of creatinine on the ceftriaxone SERS signal. These steps include adjusting of the sample pH to alkaline value (pH 13) and purification of the sample using silica gel column chromatography. Alkali pH increases SERS signal of ceftriaxone, while silica gel separates the analyte from creatinine-the main admixture in urine which provides inappropriate SERS signal background. Additionally, it was found that total protein content up to 0.2 mg/mL (upper level for urine of healthy person) and pH deviation of initial urine do not influence on SERS signal of ceftriaxone. The proposed detection procedure enables fast (~ 10 min) determination of ceftriaxone in artificially spiked urine samples within 5 to 500 MUg/mL range of concentrations which matches the range of the drug concentrations in urine after injection of therapeutically required dosages. Limits of detection (3sigma) and quantification (10sigma) were found to be 0.4 and 2.0 MUg/mL, correspondingly. Graphical abstract Application of urine pretreatment enables the purification of target analyte from intrinsic urine components and improves SERS-based detection of ceftriaxone (antibiotic drug). PMID- 29392378 TI - Fabrication and application of noble metal nanoclusters as optical sensors for toxic metal ions. AB - Atomically precise noble metal nanoclusters with ultrasmall physical sizes in the subnanometer range have emerged as a new class of probing fluorophores and have attracted considerable research interest because of their intrinsic physical, chemical, optical, biological, and electrical properties, such as stability, biocompatibility, and molecule-like photoluminescence. In comparison with traditional fluorophores such as organic dyes and quantum dots, noble metal nanoclusters have significant advantages, including low toxicity toward the environment and biological tissues, high stability when exposed to irradiation, and small size, that make them more suitable for biological sensing or biological labeling applications. Several reviews have summarized the fabrication of noble metal nanoclusters, including gold, silver, copper, and bimetallic nanoclusters. However, these reviews focused either on various facile preparation methods or multidisciplinary application areas. Here, we focus on the application of noble metal nanoclusters as optical sensing materials for toxic metal ions, including new synthetic approaches and discussion of the detection mechanism. We briefly summarize the development of metal cation monitoring technology that uses ultrasmall nanoclusters as the sensing probes. We also provide a fresh opinion on research expectations in the field of inorganic nanoscience and nanotechnology Finally, perspectives for future research hot topics are discussed. PMID- 29392379 TI - Multiresidue analysis of oestrogenic compounds in cow, goat, sheep and human milk using core-shell polydopamine coated magnetic nanoparticles as extraction sorbent in micro-dispersive solid-phase extraction followed by ultra-high-performance liquid chromatography tandem mass spectrometry. AB - In this work, the suitability of Fe3O4 nanoparticles coated with polydopamine was evaluated as sorbent for the extraction of a group of 21 compounds with oestrogenic activity including seven phytoestrogens, six mycotoxins as well as four synthetic and four natural oestrogens from different types of milk, including sheep milk, in which the evaluation of oestrogenic compounds have never been developed before. Extraction was carried out using magnetic micro-dispersive solid-phase extraction after a previous deproteinisation step. Separation, determination and quantification of the target analytes were achieved by ultra high-performance liquid chromatography coupled to triple quadrupole-tandem mass spectrometry. The methodology was validated for five milk samples using 17beta estradiol-2,4,16,16,17-d5 as internal standard for natural and synthetic oestrogens, beta-zearalanol-10,10,11,12,12-d5 for mycotoxins and prunetin for phytoestrogens. Recovery values ranged from 70 to 120% for the five types of matrices with relative standard deviation values lower than 18%. Limits of quantification of the method were in the range 0.55-11.8 MUg L-1 for all samples. Graphical abstract General scheme of the multiresidue analysis of oestrogenic compounds in milk using core-shell polydopamine coated magnetic nanoparticles as extraction sorbent in MU-dSPE. PMID- 29392380 TI - High-performance non-enzymatic catalysts based on 3D hierarchical hollow porous Co3O4 nanododecahedras in situ decorated on carbon nanotubes for glucose detection and biofuel cell application. AB - In this work, high-performance non-enzymatic catalysts based on 3D hierarchical hollow porous Co3O4 nanododecahedras in situ decorated on carbon nanotubes (3D Co3O4-HPND/CNTs) were successfully prepared via direct carbonizing metal-organic framework-67 in situ grown on carbon nanotubes. The morphology, microstructure, and composite of 3D Co3O4-HPND/CNTs were characterized by scanning electron microscopy, transmission electron microscopy, micropore and chemisorption analyzer, and X-ray diffraction. The electrochemical characterizations indicated that 3D Co3O4-HPND/CNTs present considerably catalytic activity toward glucose oxidation and could be promising for constructing high-performance electrochemical non-enzymatic glucose sensors and glucose/O2 biofuel cell. When used for non-enzymatic glucose detection, the 3D Co3O4-HPND/CNTs modified glassy carbon electrode (3D Co3O4-HPND/CNTs/GCE) exhibited excellent analytical performance with high sensitivity (22.21 mA mM-1 cm-2), low detection limit of 0.35 MUM (S/N = 3), fast response (less than 5 s) and good stability. On the other hand, when the 3D Co3O4-HPND/CNTs/GCE worked as an anode of a biofuel cell, a maximum power density of 210 MUW cm-2 at 0.15 V could be obtained, and the open circuit potential was 0.68 V. The attractive 3D hierarchical porous structural features, the large surface area, and the excellent conductivity based on the continuous and effective electron transport network in 3D Co3O4-HPND/CNTs endow 3D Co3O4-HPND/CNTs with the enhanced electrochemical performance and promising applications in electrochemical sensing, biofuel cell, and other energy storage and conversion devices such as supercapacitor. Graphical abstract High performance non-enzymatic catalysts for enzymeless glucose sensing and biofuel cell based on 3D hierarchical hollow porous Co3O4 nanododecahedras anchored on carbon nanotubes were successfully prepared via direct carbonizing metal-organic framework-67 in situ grown on carbon nanotubes. PMID- 29392381 TI - Trace analysis of pesticide residues in sediments using liquid chromatography high-resolution Orbitrap mass spectrometry. AB - The present study describes the optimization and validation of an analytical method based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction and purification with dispersive solid-phase extraction (dSPE) before analysis, followed by ultrahigh-performance liquid chromatography-high-resolution linear ion trap/Orbitrap (LTQ Orbitrap) mass spectrometry for the determination of 18 pesticides in sediment. To optimize process efficiency, parameters such as pH, extraction salts, sediment amount, and cleanup sorbents were evaluated. Identification was based on both accurate mass and retention time, and further confirmation was achieved by mass spectrometry fragmentation. The optimized analytical method demonstrated good validation characteristics, such as accuracy (recoveries from 70.8% to 106.2%), method quantification limits (below 10 ng g-1 for 89% of the pesticides selected), linearity (coefficient of determination greater than 0.9921 in all cases), precision (repeatability and reproducibility with standard deviations below 18% and 21%, respectively), and matrix effect (signal suppression was exhibited for almost all analytes). The overall method performance, expressed as process efficiency, ranged from 58.8% to 102.1%. The validated method was successfully applied to real samples collected along two rivers in northwestern Greece, revealing the presence of three selected pesticides but at levels below the method quantification limit. PMID- 29392382 TI - Construction of Effective Minimal Active Microbial Consortia for Lignocellulose Degradation. AB - Enriched microbial communities, obtained from environmental samples through selective processes, can effectively contribute to lignocellulose degradation. Unfortunately, fully controlled industrial degradation processes are difficult to reach given the intrinsically dynamic nature and complexity of the microbial communities, composed of a large number of culturable and unculturable species. The use of less complex but equally effective microbial consortia could improve their applications by allowing for more controlled industrial processes. Here, we combined ecological theory and enrichment principles to develop an effective lignocellulose-degrading minimal active microbial Consortia (MAMC). Following an enrichment of soil bacteria capable of degrading lignocellulose material from sugarcane origin, we applied a reductive-screening approach based on molecular phenotyping, identification, and metabolic characterization to obtain a selection of 18 lignocellulose-degrading strains representing four metabolic functional groups. We then generated 65 compositional replicates of MAMC containing five species each, which vary in the number of functional groups, metabolic potential, and degradation capacity. The characterization of the MAMC according to their degradation capacities and functional diversity measurements revealed that functional diversity positively correlated with the degradation of the most complex lignocellulosic fraction (lignin), indicating the importance of metabolic complementarity, whereas cellulose and hemicellulose degradation were either negatively or not affected by functional diversity. The screening method described here successfully led to the selection of effective MAMC, whose degradation potential reached up 96.5% of the degradation rates when all 18 species were present. A total of seven assembled synthetic communities were identified as the most effective MAMC. A consortium containing Stenotrophomonas maltophilia, Paenibacillus sp., Microbacterium sp., Chryseobacterium taiwanense, and Brevundimonas sp. was found to be the most effective degrading synthetic community. PMID- 29392383 TI - Intramedullary nailing in opening wedge high tibial osteotomy-in vitro test for validation of a method of fixation. AB - PURPOSE: Opening wedge high tibial osteotomy (HTO) as a treatment in unicompartimental osteoarthritis of the knee can significantly relieve pain and prevent or at least delay an early joint replacement. The fixation of the osteotomy has undergone development and refinements during the last years. The angle-stable plate fixator is currently one of the most commonly used plates in HTOs. The angular stable fixation between screws and the plate offers a high primary stability to retain the correction with early weight-bearing protocols. This surgical technique is performed as a standard of care and generally well tolerated by the patients. Nevertheless, some studies observed that many patients complained about discomfort related to the implant. METHODS: Therefore, the stability of two different intramedullary nails, a short implant used in humeral fractures and a long device used in tibial fractures for stabilization in valgus HTOs, was investigated as an alternative fixation technique. The plate fixator was defined as reference standard. Nine synthetic tibia models were standardly osteotomized and stabilized by one of the fixation devices. Axial compression was realized using a special testing machine and two protocols were performed: a multi-step fatigue test and a load-to-failure test. RESULTS: Overall motion, medial, and lateral displacements were documented. Fractures always occurred at the lateral cortex. Axial cyclic loading up to 800 N was tolerated by all implants without failure. The tibia nail provided highest fatigue strength under the load-to-failure conditions. CONCLUSIONS: The results suggest that intramedullary nailing might be used as an alternative concept in HTO. PMID- 29392384 TI - Comparative study of lateral condyle fracture with or without posteromedial elbow dislocation in children. AB - PURPOSE: The purpose of this study was to compare the surgical findings and clinical outcomes of the lateral condylar fractures of the humerus with or without posteromedial elbow dislocation in children. METHODS: Between January 2013 and June 2016, a total of 21 Milch type II humeral condylar fractures were treated with open reduction and internal fixation. The average follow-up was 2.8 years (range, 1 to 4 years). There were 8 patients in group A with posteromedial elbow dislocation and 13 patients in group B without dislocation. The surgical findings, bone union time, the recovery of function, and the time needed to regain full range of elbow movement were all compared. The complications encountered during operation and follow-up were documented. RESULTS: Surgical findings showed that all the fracture lines in group A extended to the lower medial part of the trochlea. The fracture lines in group B only involved the lateral and middle part of the trochlea. There were no significant differences in bone union time between the two groups. The time needed to regain full range of elbow movement after operation in group A (21 +/- 4.0 weeks) was significantly longer in group B (17.85 +/- 2.51 weeks; P < 0.05). There were no significant differences in MEPS, the flexion-extension arc, and the total range of flexion and extension between the two groups (P < 0.05).There was no difference in complications between the two groups (P < 0.05). CONCLUSION: The fracture lines in Milch type II fractures of lateral humeral condyle with concomitant posteromedial elbow dislocation extend to the lower medial part of the trochlea. The soft tissue injuries are more badly so that longer time needed to regain full range of elbow movement. Initial recognition of this rare injury is essential to regain satisfactory functional outcomes. PMID- 29392385 TI - Evaluation of risk factors for stiffness after distal humerus plating. AB - PURPOSE: In distal humerus fractures, the goal is to achieve a functional range of motion of 30 degrees -130 degrees which is not always possible. The aims of the study were to evaluate the functional results after distal humerus fracture operation and to investigate the risk factors for stiffness. METHODS: Between 2005 and 2014, 75 patients with the mean age of 37.8 years (17-80) underwent open reduction and plate fixation for distal humerus fractures. Range of motion (ROM), Mayo elbow performance scores, and quick DASH scores were used for functional evaluation. Patients were divided into two groups according their ROM. Group 1 had > 100 degrees of extension-flexion ROM and group 2 had < 100 degrees . Older age (> 60), AO type C2-3 fracture, open fracture, longer injury-surgery interval, type of plating, and presence of olecranon osteotomy were investigated as risk factors for poor outcome. RESULTS: At a mean follow-up of 25 months (6-80), 40 patients were in group 1 and 35 patients were in group 2. Group 1 had significantly better functional scores than group 2. AO type C2 and C3 fracture (odds ratio (OR) 16.6, p < 0.0001) and injury-surgery interval longer than 7 days (OR 2.59, p 0.047) were found as significant risk factors for stiffness. CONCLUSIONS: Patients who had distal humerus fracture should be informed about the risk of elbow stiffness especially in AO type C2-C3 fractures and surgical treatment should be planned without any delay. PMID- 29392387 TI - D-lyxose isomerase and its application for functional sugar production. AB - Functional sugars have attracted attention because of their wide application prospects in the food, cosmetics, and pharmaceutical industries in recent decades. Compared with complex chemical synthesis, enzymatic methods of creating functional sugars, characterized by high specificity, moderate reaction conditions, and sustainability, are favored. D-lyxose isomerase (D-LI, EC 5.3.1.15), an important aldose-ketose isomerase, catalyzes the reverse isomerization reaction between D-xylulose and D-lyxose, as well as D-fructose and D-mannose. D-LI has drawn researchers' attention due to its broad substrate specificity and high potential for enzymatic production of some functional sugars such as D-xylulose, D-mannose, and D-ribose. In this article, an overview of recent advances in the biochemical properties of various D-LIs is explored in detail. Structural analysis, active site identification, and catalytic mechanisms are also provided. Additionally, the applications of D-LIs for functional sugar production, including D-lyxose, D-mannose, and L-ribose, are reviewed in detail in this paper. PMID- 29392386 TI - Mu-driven transposition of recombinant mini-Mu unit DNA in the Corynebacterium glutamicum chromosome. AB - A dual-component Mu-transposition system was modified for the integration/amplification of genes in Corynebacterium. The system consists of two types of plasmids: (i) a non-replicative integrative plasmid that contains the transposing mini-Mu(LR) unit bracketed by the L/R Mu ends or the mini-Mu(LER) unit, which additionally contains the enhancer element, E, and (ii) an integration helper plasmid that expresses the transposition factor genes for MuA and MuB. Efficient transposition in the C. glutamicum chromosome (~ 2 * 10-4 per cell) occurred mainly through the replicative pathway via cointegrate formation followed by possible resolution. Optimizing the E location in the mini-Mu unit significantly increased the efficiency of Mu-driven intramolecular transposition amplification in C. glutamicum as well as in gram-negative bacteria. The new C. glutamicum genome modification strategy that was developed allows the consequent independent integration/amplification/fixation of target genes at high copy numbers. After integration/amplification of the first mini-Mu(LER) unit in the C. glutamicum chromosome, the E-element, which is bracketed by lox-like sites, is excised by Cre-mediated fashion, thereby fixing the truncated mini-Mu(LR) unit in its position for the subsequent integration/amplification of new mini-Mu(LER) units. This strategy was demonstrated using the genes for the citrine and green fluorescent proteins, yECitrine and yEGFP, respectively. PMID- 29392388 TI - Engineering Escherichia coli for glycolic acid production from D-xylose through the Dahms pathway and glyoxylate bypass. AB - Glycolic acid (GA) is an ?-hydroxy acid used in cosmetics, packaging, and medical industries due to its excellent properties, especially in its polymeric form. In this study, Escherichia coli was engineered to produce GA from D-xylose by linking the Dahms pathway, the glyoxylate bypass, and the partial reverse glyoxylate pathway (RGP). Initially, a GA-producing strain was constructed by disrupting the xylAB and glcD genes in the E. coli genome and overexpressing the xdh(Cc) from Caulobacter crescentus. This strain was further improved through modular optimization of the Dahms pathway and the glyoxylate bypass. Results for module 1 showed that the rate-limiting step of the Dahms pathway was the xylonate dehydratase reaction, and the overexpression of yagF was sufficient to overcome this bottleneck. Furthermore, the appropriate aldolase gene for module 1 was proven to be yagE. The results also show that overexpression of the lactaldehyde dehydrogenase gene, aldA, is needed to increase the GA production while the overexpression of glyoxylate reductase gene, ycdW, was only essential when the glyoxylate bypass was active. On the other hand, the module 2 enzymes AceA and AceK were vital in activating the glyoxylate bypass, while the RGP enzymes were dispensable. The final strain (GA19) produced 4.57 g/L GA with a yield of 0.46 g/g from D-xylose. So far, this is the highest value achieved for GA production in engineered E. coli through the Dahms pathway. PMID- 29392390 TI - Strategies to prevent the occurrence of resistance against antibiotics by using advanced materials. AB - Drug resistance occurrence is a global healthcare concern responsible for the increased morbidity and mortality in hospitals, time of hospitalisation and huge financial loss. The failure of the most antibiotics to kill "superbugs" poses the urgent need to develop innovative strategies aimed at not only controlling bacterial infection but also the spread of resistance. The prevention of pathogen host invasion by inhibiting bacterial virulence and biofilm formation, and the utilisation of bactericidal agents with different mode of action than classic antibiotics are the two most promising new alternative strategies to overcome antibiotic resistance. Based on these novel approaches, researchers are developing different advanced materials (nanoparticles, hydrogels and surface coatings) with novel antimicrobial properties. In this review, we summarise the recent advances in terms of engineered materials to prevent bacteria-resistant infections according to the antimicrobial strategies underlying their design. PMID- 29392391 TI - Normalized gait analysis parameters are closely related to patient-reported outcome measures after total knee arthroplasty. AB - Up till now, only a weak connection could be shown between patient-related outcome measures (PROMs) and measurements obtained by gait analysis (e.g. speed, step length, cadence, ground reaction force, joint moments and ranges of motion) after total knee arthroplasty (TKA). This may result from the methodical problem that regression analyses are performed using data that are not normalized against a healthy population. It does appear reasonable to assume that patients presenting a physiological gait pattern are content with their joint. The more the gait parameters differ from a normal gait pattern the worse the clinical outcome measured by PROMs should be expected to be. In this retrospective study, 40 patients were enrolled who had received a gait analysis after TKA, and whose PROMs had been evaluated. A gender- and age-matched control group was formed out of a group of test persons who had already undergone gait analysis. Gait analysis was undertaken using the motion analysis system 3D Vicon with ten infrared cameras and three strength measuring force plates. The physiological gait analysis parameters were deduced from arithmetic mean values taken from all control patients. The deviances of the operated patients' gait analysis parameters from the arithmetic mean values were squared. From these values, the Pearson correlation coefficients for different PROMs were then calculated, and regression analyses were performed to elucidate the correlation between the different PROMs and gait parameters. In the regression analysis, the normalized cadence, relative gait speed of the non-operated side, and range of the relative knee moment of the operated side could be identified as factors which influence the Forgotten Joint Score (FJS-12). The explanation model showed an increase of the FJS-12 with minimisation of these normalized values corresponding to an approximation of the gait pattern seen in the healthy control group. The connection was strong, having a correlation coefficient of 0.708. A physiological gait pattern after TKA results in better PROMs, especially the FJS-12, than a non physiological gait pattern does. PMID- 29392389 TI - Coumarin: a novel player in microbial quorum sensing and biofilm formation inhibition. AB - Antibiotic resistance is a growing threat worldwide, causing serious problems in the treatment of microbial infections. The discovery and development of new drugs is urgently needed to overcome this problem which has greatly undermined the clinical effectiveness of conventional antibiotics. An intricate cell-cell communication system termed quorum sensing (QS) and the coordinated multicellular behaviour of biofilm formation have both been identified as promising targets for the treatment and clinical management of microbial infections. QS systems allow bacteria to adapt rapidly to harsh conditions, and are known to promote the formation of antibiotic tolerant biofilm communities. It is well known that biofilm is a recalcitrant mode of growth and it also increases bacterial resistance to conventional antibiotics. The pharmacological properties of coumarins have been well described, and these have included several that possess antimicrobial properties. More recently, reports have highlighted the potential role of coumarins as alternative therapeutic strategies based on their ability to block the QS signalling systems and to inhibit the formation of biofilms in clinically relevant pathogens. In addition to human infections, coumarins have also been found to be effective in controlling plant pathogens, infections in aquaculture, food spoilage and in reducing biofouling caused by eukaryotic organisms. Thus, the coumarin class of small molecule natural product are emerging as a promising strategy to combat bacterial infections in the new era of antimicrobial resistance. PMID- 29392392 TI - Renal trematode infection in wild birds: histopathological, morphological, and molecular aspects. AB - Paratanaisia are eucotylidae digeneans that affect the upper urinary tract of birds. This genus contains three species (Paratanaisia bragai, P. robusta, and P. confusa) with similar morphological features. Macroscopic and microscopic damage caused by these parasites ranges from the irrelevant to significant lesions. This study aimed to describe the histological, morphological, and molecular features of the renal tissues and parasite specimens obtained from naturally infected free ranging and captive wild birds in Brazil. Histopathological evaluations were performed on 103 slides containing kidney tissue sections from parasitized birds. Parasites were observed inside the collecting ducts, causing the dilation and destruction of the lining epithelial cells and alterations in other structures of the renal parenchyma. Such findings indicate that Paratanaisia have pathogenic potential in a wide range of hosts, suggesting low host specificity. The parasites recovered from the kidneys of 10 birds, including Columbiformes, Galliformes, Strigiformes, and Cuculiformes, were morphologically evaluated and identified as Paratanaisia sp. Formalin-fixed paraffin-embedded kidney fragments were subjected to conventional PCR assays targeting the 18S and 28S rDNA genes. A Bayesian inference analysis based on an 800-bp 18S rDNA gene fragment separated the trematode genus accurately, clustering all of the parasites tested with a previously described P. bragai specimen. Analyses on a small fragment of the 28S rDNA gene did not allow for accurately differentiating the Paratanaisia species. Therefore, further morphological studies with additional molecular markers are necessary to improve our understanding of the alpha-taxonomy of this group. PMID- 29392393 TI - Early identification of autism spectrum disorders using the two-step Modified Checklist for Autism: experience in Southern Switzerland. PMID- 29392394 TI - Clinical spectrum of paediatric coeliac disease: a 10-year single-centre experience. AB - : This study was undertaken to gain insight in the clinical spectrum of paediatric coeliac disease (CD) in a Dutch teaching hospital. We retrospectively compared the frequency of CD in children with a wide spectrum of complaints with and without CD antibodies in serum and were interested if certain complaints are more pathognomonic for CD. Furthermore, we expected that over a period of 10-year incidence rates of CD would have increased and shifted towards an atypical presentation with more non-gastrointestinal symptoms with increasing age. A retrospective, single-centre, case-control study was performed. All patients who presented at the Department of Paediatrics, Tergooi Hospital, with symptoms suspected for CD were eligible for inclusion during the study period from 1 January 2007 till 31 December 2016. Children were diagnosed with CD according to the 2005 and 2012 ESPGHAN guideline between 2007 and 2016, respectively. Demographic data, presenting symptoms, prevalence of associated conditions and serology results were examined. A total of 105 new cases of paediatric CD were observed, with an average of 10 new cases each year. The calculated incidence was 21.09 (CI 17.49-25.22)/100,000 under 18 years of age. About 40% were infants and toddlers, predominantly presenting with gastrointestinal symptoms. Primary and high school children had more display of atypical symptoms (p = 0.001, p = 0.017) and non-gastrointestinal symptoms (p = 0.009, p = 0.009) than infants and toddlers. In 8.6% of the CD patients, mostly primary school aged female patients, the serology was repeated at least once in time to become positive. The median time for serology to become positive was 609 days (range 140-1054). CONCLUSION: As it is well known, our study supports the increasing notion of a shift in the clinical spectrum of presenting symptoms in paediatric CD towards an atypical presentation, with more non-gastrointestinal symptoms and a diagnosis at a later age in a Dutch population, whereas the number of new cases did not increase over the years. What is Known: * The clinical spectrum of paediatric coeliac disease is shifting towards a presentation with more atypical and non-GI symptoms. * The incidence of paediatric coeliac disease is still increasing as is the age at which it is diagnosed. What is New: * An average of 10 paediatric CD cases are diagnosed per year in our general teaching hospital. * The calculated (gender specific) incidence rates are higher than previously reported. PMID- 29392396 TI - FlowerMorphology: fully automatic flower morphometry software. AB - MAIN CONCLUSION: The software FlowerMorphology is designed for automatic morphometry of actinomorphic flowers. The novel complex parameters of flowers calculated by FlowerMorphology allowed us to quantitatively characterize a polyploid series of tobacco. Morphological differences of plants representing closely related lineages or mutants are mostly quantitative. Very often, there are only very fine variations in plant morphology. Therefore, accurate and high throughput methods are needed for their quantification. In addition, new characteristics are necessary for reliable detection of subtle changes in morphology. FlowerMorphology is an all-in-one software package to automatically image and analyze five-petal actinomorphic flowers of the dicotyledonous plants. Sixteen directly measured parameters and ten calculated complex parameters of a flower allow us to characterize variations with high accuracy. The program was developed for the needs of automatic characterization of Nicotiana tabacum flowers, but is applicable to many other plants with five-petal actinomorphic flowers and can be adopted for flowers of other merosity. A genetically similar polyploid series of N. tabacum plants was used to investigate differences in flower morphology. For the first time, we could quantify the dependence between ploidy and size and form of the tobacco flowers. We found that the radius of inner petal incisions shows a persistent positive correlation with the chromosome number. In contrast, a commonly used parameter-radius of outer corolla-does not discriminate 2n and 4n plants. Other parameters show that polyploidy leads to significant aberrations in flower symmetry and are also positively correlated with chromosome number. Executables of FlowerMorphology, source code, documentation, and examples are available at the program website: https://github.com/Deyneko/FlowerMorphology . PMID- 29392397 TI - Efficiency and measurements agreement between swept-source OCT and low-coherence interferometry biometry systems. AB - PURPOSE: To compare and evaluate the agreement between the measurements obtained with a swept-source optical coherence tomography (OCT)-based biometer, the IOLMaster(r) 700 (IOLM), and those obtained by an optical biometer based on optical low-coherence interferometry (OLCI), the Aladdin (ALD); To evaluate the ability to perform biometric measurements in those eyes with transparency alterations. METHODS: Fifty-five eyes of 55 subjects were included in this study. Axial length (AL), corneal power (K, in diopters) and its astigmatism, anterior chamber depth (ACD), central corneal thickness (CCT), and lens thickness (LT) measures were obtained within both biometers, Zeiss IOLMaster 700 and Topcon Aladdin. Results were analyzed and compared using the Student's paired samples t test, Bland-Altman analysis and intraclass correlation coefficient (ICC). RESULTS: Mean age was 73.12 +/- 2.63 (62-89 years). The IOLM mean AL, K, and LT values did not show a statistically significant difference from ALD values and showed excellent agreement and correlation (ICC = 1.000, 0.970, 0.952). IOLM measured a lower mean ACD (-0.036 mm) and higher CCT measurements (9.296 MUm). Those results were statistically different (p < 0.001 in both cases) but showed an excellent correlation coefficients (ICC = 0.994, 0.938). IOLM was able to obtain measures from all the eyes examined, while ALD did not measure in two cases with dense nuclear cataract. ALD showed spherical K measures in 7.27% of cases. CONCLUSION: Overall a quite good agreement between IOLM and ALD was found. ALD showed spherical keratometry measures in 7.27% of cases. IOLMaster 700 was more effective in obtaining AL measurements in eyes with dense cataracts. PMID- 29392395 TI - Recent advances in osteoclast biology. AB - The bone is an essential organ for locomotion and protection of the body, as well as hematopoiesis and mineral homeostasis. In order to exert these functions throughout life, bone tissue undergoes a repeating cycle of osteoclastic bone resorption and osteoblastic bone formation. The osteoclast is a large, multinucleated cell that is differentiated from monocyte/macrophage lineage cells by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL). RANKL transduces its signal through the signaling receptor, RANK. RANKL/RANK signaling activates NFATc1, the master regulator of osteoclastogenesis, to induce osteoclastogenic gene expression. Many types of cells express RANKL to support osteoclastogenesis depending on the biological context and the dysregulation of RANKL signaling leads to bone diseases such as osteoporosis and osteopetrosis. This review outlines the findings on osteoclast and RANKL/RANK signaling that have accumulated to date. PMID- 29392398 TI - Generation and characterisation of decellularised human corneal limbus. AB - PURPOSE: Limbal epithelial stem cells (LESC) reside in a niche in the corneo scleral transition zone. Deficiency leads to pain, corneal opacity, and eventually blindness. LESC transplantation of ex-vivo expanded human LESC on a carrier such as human amniotic membrane is a current treatment option. We evaluated decellularised human limbus (DHL) as a potential carrier matrix for the transplantation of LESC. METHODS: Human corneas were obtained from the local eye bank. The limbal tissue was decellularised by sodium desoxychelate and DNase solution and sterilised by gamma-irradiation. Native limbus- and DHL-surface structures were assessed by scanning electron microscopy and collagen ultrastructure using transmission electron microscopy. Presence and preservation of limbal basement membrane proteins in native limbus and DHL were analysed immunohistochemically. Absence of DNA after decellularisation was assessed by Feulgen staining and DNA quantification. Presence of immune cells was explored by CD45 staining, and potential cytotoxicity was tested using a cell viability assay. RESULTS: In the DHL, the DNA content was reduced from 1.5 +/- 0.3 MUg/mg to 0.15 +/- 0.01 MUg/mg; the three-dimensional structure and the arrangement of the collagen fibrils were preserved. Main basement membrane proteins such as collagen IV, laminin, and fibronectin were still present after decellularisation and gamma-irradiation. CD45-expressing cells were evident neither in the native limbus nor in the DHL. DHL did not convey cytotoxicity. CONCLUSIONS: The extracellular matrix (ECM) of the limbus provides a tissue specific morphology and three-dimensionality consisting of particular ECM proteins. It therefore represents a substantial component of the stem cell niche. The DHL provides a specific limbal niche surrounding, and might serve as an easily producible carrier matrix for LESC transplantation. PMID- 29392399 TI - Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis. AB - The adult mammalian kidney has a complex, highly-branched collecting duct epithelium that arises as a ureteric bud sidebranch from an epithelial tube known as the nephric duct. Subsequent branching of the ureteric bud to form the collecting duct tree is regulated by subcellular interactions between the epithelium and a population of mesenchymal cells that surround the tips of outgrowing branches. The mesenchymal cells produce glial cell-line derived neurotrophic factor (GDNF), that binds with RET receptors on the surface of the epithelial cells to stimulate several subcellular pathways in the epithelium. Such interactions are known to be a prerequisite for normal branching development, although competing theories exist for their role in morphogenesis. Here we introduce the first agent-based model of ex vivo kidney uretic branching. Through comparison with experimental data, we show that growth factor-regulated growth mechanisms can explain early epithelial cell branching, but only if epithelial cell division depends in a switch-like way on the local growth factor concentration; cell division occurring only if the driving growth factor level exceeds a threshold. We also show how a recently-developed method, "Approximate Approximate Bayesian Computation", can be used to infer key model parameters, and reveal the dependency between the parameters controlling a growth factor dependent growth switch. These results are consistent with a requirement for signals controlling proliferation and chemotaxis, both of which are previously identified roles for GDNF. PMID- 29392400 TI - Extranodal extension of nodal metastases is a poor prognostic moderator in non small cell lung cancer: a meta-analysis. AB - Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta analysis, we weighted the prognostic role of ENE in patients with lymph node positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60 months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2 = 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2 = 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2 = 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2 = 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter. PMID- 29392402 TI - Presence of micropapillary and solid patterns are associated with nodal upstaging and unfavorable prognosis among patient with cT1N0M0 lung adenocarcinoma: a large scale analysis. AB - PURPOSE: To investigate whether the presence of micropapillary and solid patterns are associated with nodal upstaging and survival patterns in patients with cT1N0M0 lung adenocarcinoma. METHOD: We retrospectively analyzed the clinicopathologic data of 2571 patients undergoing lobectomy and lymph node dissection or sampling. Logistic and Cox regression analysis were applied to determine the association between histological patterns and nodal upstaging and survival. RESULTS: Nodal upstaging was detected in 115 patients (4.5%) through postoperative pathologic examination. Tumors absent of lepidic pattern, and present with acinar, micropapillary and solid patterns had significantly higher nodal upstaging rate (all P < 0.001). Presence of micropapillary [odds ratios (ORs) = 3.51; 95% confidence intervals (CI) = 2.09-5.89; P < 0.001] and solid (OR 2.28; 95% CI 1.42-3.64; P = 0.001) patterns were independent predictors for nodal upstaging. Presence of micropapillary and solid patterns also significantly deteriorated the recurrence-free survival (RFS) (both log-rank P < 0.001), and were independently associated with unfavorable RFS in multivariable Cox analysis RFS [micropapillary: hazard ratios (HR) = 1.41; 95% CI 1.04-1.99; P = 0.041; solid: HR 2.05; 95% CI 1.56-2.70; P < 0.001]. CONCLUSION: The analysis of a large scale cohort demonstrated that the presence of micropapillary and solid patterns significantly increase the risk of nodal upstaging and are independently associated with unfavorable prognosis. PMID- 29392401 TI - DDM1 guards against telomere truncation in Arabidopsis. AB - KEY MESSAGE: Prolonged hypomethylation of DNA leads to telomere truncation correlated with increased telomere recombination, transposon mobilization and stem cell death. Epigenetic pathways, including DNA methylation, are crucial for telomere maintenance. Deficient in DNA Methylation 1 (DDM1) encodes a nucleosome remodeling protein, required to maintain DNA methylation in Arabidopsis thaliana. Plants lacking DDM1 can be self-propagated, but in the sixth generation (G6) hypomethylation leads to rampant transposon activation and infertility. Here we examine the role of DDM1 in telomere length homeostasis through a longitudinal study of successive generations of ddm1-2 mutants. We report that bulk telomere length remains within the wild-type range for the first five generations (G1-G5), and then precipitously drops in G6. While telomerase activity becomes more variable in later generation ddm1-2 mutants, there is no correlation between enzyme activity and telomere length. Plants lacking DDM1 also exhibit no dysregulation of several known telomere-associated transcripts, including TERRA. Instead, telomere shortening coincides with increased G-overhangs and extra chromosomal circles, consistent with deletional recombination. Telomere shortening also correlates with transcriptional activation of retrotransposons, and a hypersensitive DNA damage response in root apical meristems. Since abiotic stresses, including DNA damage, stimulate homologous recombination, we hypothesize that telomere deletion in G6 ddm1-2 mutants is a by-product of elevated genome-wide recombination in response to transposon mobilization. Further, we speculate that telomere truncation may be beneficial in adverse environmental conditions by accelerating the elimination of stem cells with aberrant genomes. PMID- 29392403 TI - Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma. AB - PURPOSE: We researched into the effect and mechanism of AC0010, a novel BTK inhibitor, in MCL, and compared its efficacy and safety with Ibrutinib to develop a preclinical study for the future therapy of MCL. METHODS: MTS assay was used to detect the growth inhibition caused by AC0010 and Ibrutinib, respectively, in MCL cell lines (Jeko-1 and JVM-2), primary MCL cells, and normal peripheral lymphocytes. Apoptosis of Jeko-1 and JVM-2 after exposure into AC0010 and Ibrutinib was conducted by flow cytometry; the expression of apoptosis-related proteins was checked by Western blot. q-PCR and Western blot were applied to examine the expression of BTK and p-BTK at mRNA and protein level as well as the BTK-ralated signaling pathways. MCL xenograft was developed to testify the efficacy and safety of AC0010 in vivo. RESULTS: In contrast with Ibrutinib, AC0010 proved to be more toxic to MCL cells in vitro (p < 0.01) with no augment in cytotoxicity to normal peripheral lymphocytes, and it can induce obvious apoptosis in MCL cell lines (p < 0.01) through caspase family and Bcl-2 family. AC0010 at 300 mg/kg can prolong the survival rate in MCL xenograft (p < 0.01). The phosphorylation of BTK is inhibited by AC0010 following simultaneously inhibition of BCR-BTK and PI3K/AKT signaling pathway in MCL cells. CONCLUSION: AC0010 is a novel BTK inhibitor of great efficacy and safety in MCL. PMID- 29392404 TI - [Neuroendocrine neoplasms of the auditory, olfactory, and visual sensory organs]. AB - Neuroendocrine neoplasms (NENs) are infrequent in sensory organs. There are well differentiated neuroendocrine neoplasms that should be classified as neuroendocrine tumors, in analogy to their gastrointestinal counterparts, however the nomenclature is inconsistent. The best defined entities are neuroendocrine tumors in the middle ear and ectopic pituitary adenoma in the sphenoid region. Poorly differentiated NENs most often arise in the olfactory organ and nasal cavity that are represented by olfactory neuroblastomas and poorly differentiated neuroendocrine carcinomas. They have several mimickers such as the sinonasal undifferentiated carcinoma, poorly differentiated squamous cell carcinoma, mucosal malignant melanoma, rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor and non-Hodgkin lymphoma. PMID- 29392405 TI - Correction to: Total analysis of clinical factors for surgical success of adenotonsillectomy in pediatric OSAS. AB - The authors would like to publish this erratum to indicate Dr Rayleigh Ping-Ying Chiang as the corresponding author of this article. PMID- 29392406 TI - Importance of complete phenotyping in prenatal whole exome sequencing. AB - Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects. Re analysis of WES variants and combination of prenatal and postnatal phenotyping yielded pathogenic variants in at least 20% of cases including PORCN gene in a fetus with split-hand/foot malformation, as well as variants of uncertain significance in NEB and NOTCH1 in fetuses with postnatal muscle weakness and Adams-Oliver syndrome, respectively. Furthermore, Sanger sequencing in a patient with holoprosencephaly, elucidated by postnatal MRI, revealed a pathogenic 47 base pairs deletion in ZIC2 which was missed by prenatal WES. This study suggests that incomplete prenatal phenotyping and lack of prenatal ultrasound-genotype databases are the limiting factors for current interpretation of WES data in prenatal diagnosis. Development of prenatal phenotype-genotype databases would significantly help WES interpretation in this setting. Patients who underwent prenatal clinical WES may benefit from the re-analysis based on detailed postnatal findings. PMID- 29392407 TI - SSR-based association mapping of fiber quality in upland cotton using an eight way MAGIC population. AB - The quality of fiber is significant in the upland cotton industry. As complex quantitative traits, fiber quality traits are worth studying at a genetic level. To investigate the genetic architecture of fiber quality traits, we conducted an association analysis using a multi-parent advanced generation inter-cross (MAGIC) population developed from eight parents and comprised of 960 lines. The reliable phenotypic data for six major fiber traits of the MAGIC population were collected from five environments in three locations. Phenotypic analysis showed that the MAGIC lines have a wider variation amplitude and coefficient than the founders. A total of 284 polymorphic SSR markers among eight parents screened from a high density genetic map were used to genotype the MAGIC population. The MAGIC population showed abundant genetic variation and fast linkage disequilibrium (LD) decay (0.76 cM, r2 > 0.1), which revealed the advantages of high efficiency and power in QTL exploration. Association mapping via a mixed linear model identified 52 significant loci associated with six fiber quality traits; 14 of them were mapped in reported QTL regions with fiber-related or other agronomic traits. Nine markers demonstrated the pleiotropism that controls more than two fiber traits. Furthermore, two SSR markers, BNL1231 and BNL3452, were authenticated as hotspots that were mapped with multi-traits. In addition, we provided candidate regions and screened six candidate genes for identified loci according to the LD decay distance. Our results provide valuable QTL for further genetic mapping and will facilitate marker-based breeding for fiber quality in cotton. PMID- 29392408 TI - Genome-wide DNA methylation analysis in jejunum of Sus scrofa with intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) may elicit a series of postnatal body developmental and metabolic diseases due to their impaired growth and development in the mammalian embryo/fetus during pregnancy. In the present study, we hypothesized that IUGR may lead to abnormally regulated DNA methylation in the intestine, causing intestinal dysfunctions. We applied reduced representation bisulfite sequencing (RRBS) technology to study the jejunum tissues from four newborn IUGR piglets and their normal body weight (NBW) littermates. The results revealed extensively regional DNA methylation changes between IUGR/NBW pairs from different gilts, affecting dozens of genes. Hiseq-based bisulfite sequencing PCR (Hiseq-BSP) was used for validations of 19 genes with epigenetic abnormality, confirming three genes (AIFM1, MTMR1, and TWIST2) in extra samples. Furthermore, integrated analysis of these 19 genes with proteome data indicated that there were three main genes (BCAP31, IRAK1, and AIFM1) interacting with important immunity- or metabolism-related proteins, which could explain the potential intestinal dysfunctions of IUGR piglets. We conclude that IUGR can lead to disparate DNA methylation in the intestine and these changes may affect several important biological processes such as cell apoptosis, cell differentiation, and immunity, which provides more clues linking IUGR and its long-term complications. PMID- 29392409 TI - Concordance of Gleason grading with three-dimensional ultrasound systematic biopsy and biopsy core pre-embedding. AB - PURPOSE: To determine the value of a three-dimensional (3D) greyscale transrectal ultrasound (TRUS)-guided prostate biopsy system and biopsy core pre-embedding method on concordance between Gleason scores of needle biopsies and radical prostatectomy (RP) specimens. METHODS: Retrospective analysis of prostate biopsies and subsequent RP for PCa in the Jeroen Bosch Hospital, the Netherlands, from 2007 to 2016. Two cohorts were analysed: conventional 2D TRUS-guided biopsies and RP (2007-2013, n = 266) versus 3D TRUS-guided biopsies with pre embedding (2013-2016, n = 129). The impact of 3D TRUS-guidance with pre-embedding on Gleason score (GS) concordance between biopsy and RP was evaluated using the kappa-coefficient. Predictors of biopsy GS 6 upgrading were assessed using logistic regression models. RESULTS: Gleason concordance was comparable between the two cohorts with a kappa = 0.44 for the 3D cohort, compared to kappa = 0.42 for the 2D cohort. 3D TRUS-guidance with pre-embedding, did not significantly affect the risk of biopsy GS 6 upgrading in univariate and multivariate analysis. CONCLUSIONS: 3D TRUS-guidance with biopsy core pre-embedding did not improve Gleason concordance. Improved detection techniques are needed for recognition of low-grade disease upgrading. PMID- 29392410 TI - STEEx, a boundary between the world of quiescence and the vegetative cycle. AB - Telomere maintenance mechanism is poorly studied in quiescence, a reversible non proliferative state. We previously described in fission yeast a new mode of repair of telomeres named STEEx, that specifically operates in post-mitotic cells harboring eroded telomeres. This mechanism, promoted by transcription-induced telomeric recombination, prevents cells to exit properly from quiescence, suggesting that STEEx act as an anti-proliferative barrier. Here, we further showed that STEEx are genetically controlled by the Tel1ATM- and Rad3ATR- dependent DDR pathways. We discussed the possibility that STEEx represent a boundary between quiescence and vegetative cycle. PMID- 29392411 TI - Investigating the roles of regulatory T cells, mast cells and interleukin-9 in the control of skin inflammation by vitamin D. AB - Topical application of biologically active vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D)], or low-calcemic analogues, curb skin inflammation through mechanisms that involve migratory dendritic cells (DCs) and regulatory T (TReg) cells. 1,25(OH)2D also promotes immunoregulation by mast cells, and inhibits the development of T helper type-9 (Th9) cells that secrete interleukin-9 (IL-9). Here, we investigated the ability of topical 1,25(OH)2D to suppress contact dermatitis through an IL-9-dependent process, examining mast cells and IL-9 secreting T cells. Contact dermatitis was modelled in adult BALB/c female mice by initiating a "biphasic ear swelling response" following a single application of 2,4-dinitrofluorobenzene (DNFB). Topical 1,25(OH)2D (125 ng) applied to ear pinnae prior to (but not after) DNFB sensitisation suppressed the efferent phase of the ear swelling response. This dose of 1,25(OH)2D did not cause hypercalcemia. At the peak of the efferent ear swelling response, proportions of TReg (CD3 + Foxp3+) cells and numbers of mast cells were increased in ear skin of 1,25(OH)2D-treated mice. Topical 1,25(OH)2D increased the proportion of Foxp3 + IL-9 + TReg cells and the capacity of TReg cells to secrete IL-9 ex vivo. However, the proportion of the IL-9 + cells of the total TReg cell population was small (< 1%), and the amount of IL-9 secreted by TReg cells from mice treated with IL-9 was low (< 50 pg/ml). Furthermore, injection of anti-IL-9 neutralising antibody (100 ug, intraperitoneally) prior to sensitisation did not significantly reverse the suppressive effects of 1,25(OH)2D. In conclusion, topically applied 1,25(OH)2D suppressed the efferent phase of a biphasic cutaneous ear swelling response through mechanism(s) that may be dependent on mast cells and TReg cells; however, the role of IL-9 in mediating these responses is uncertain. More studies are needed to further characterise the mechanisms by which topical 1,25(OH)2D modulates cell-mediated immune responses central to its suppressive effects upon contact dermatitis. PMID- 29392412 TI - Cardiac fibroblasts : Active players in (atrial) electrophysiology? AB - Fibrotic areas in cardiac muscle-be it in ventricular or atrial tissue-are considered as obstacles for conduction of the excitatory wave and can therefore facilitate re-entry, which may contribute to the sustenance of cardiac arrhythmias. Persistence of one of the most frequent arrhythmias, atrial fibrillation (AF), is accompanied by enhanced atrial fibrosis. Any kind of myocardial perturbation, whether via mechanical stress or ischemic damage, inflammation, or irregular and high-frequency electrical activity, activates fibroblasts. This leads to the secretion of paracrine factors and extracellular matrix proteins, especially collagen, and to the differentiation of fibroblasts into myofibroblasts. Excessive collagen production is the hallmark of fibrosis and impairs regular impulse propagation. In addition, direct electrical coupling between cardiomyocytes and nonmyocytes, such as fibroblasts and macrophages, via gap junctions affects conduction. Although fibroblasts are not electrically excitable, they express functional ion channels, in particular K+ channels and mechanosensitive channels, some of which could be involved in tissue remodeling. Here, we briefly review these aspects with special reference to AF. PMID- 29392413 TI - Impacted and transmigrated mandibular canines: an analysis of 3D radiographic imaging data. AB - OBJECTIVES: Impacted and transmigrated mandibular canines differ greatly in incidence, etiopathology, associated anomalies, and treatment prospects, when compared to their maxillary counterparts. The aim of this study was to provide a detailed analysis of 3D radiographic imaging data of impacted mandibular canines. MATERIALS AND METHODS: In a retrospective cross-sectional study, CT/CBCT data of 88 patients with a total of 94 impacted mandibular canines were analysed. Evaluated parameters included location, morphology, neighbouring structures, associated anomalies, the influence of those factors on mandibular canine transmigration, as well as applied treatment. RESULTS: Transmigration was found to occur in 40.4% of impacted mandibular canines. Transmigrated canines were located significantly more basally and horizontally angulated. Further, transmigration was significantly associated with a lack of contact to adjacent teeth and the canine's apex not contacting the mandibular cortical bone. The overall incidence of root resorptions of adjacent teeth related to impacted mandibular canines was 7.3% and was more likely, if the canine was lingually impacted. While about half of the non-transmigrated impacted canines were orthodontically aligned, half of the transmigrated canines were surgically removed. Monitoring was the second most applied treatment strategy for both groups, and no canines were autotransplantated. CONCLUSIONS: Root resorption of adjacent teeth and transmigration are commonly occurring phenomena related to impacted mandibular canines. CLINICAL RELEVANCE: Treatment often entails the surgical removal of the canine-especially in cases of transmigration. The findings emphasise the importance of early diagnosis and CT/CBCT imaging for further diagnostics and future research of impacted mandibular canines. PMID- 29392414 TI - Cyclic fatigue using severely curved canals and torsional resistance of thermally treated reciprocating instruments. AB - OBJECTIVES: To evaluate the cyclic fatigue using severely curved canals and torsional resistance of ProDesign R (Easy Equipamentos Odontologicos, Belo Horizonte, MG, Brazil), Reciproc Blue (VDW, Munich, Germany), and WaveOne Gold (Dentsply Maillefer, Ballaigues, Switzerland) reciprocating instruments MATERIALS AND METHODS: Twenty instruments of the ProDesign R (25/0.06) system, 20 instruments of the Reciproc Blue (25/0.08v) system, and 20 instrument of the WaveOne Gold (25/0.07v) system were used. Cyclic fatigue resistance was tested measuring the time to fracture and the number of cycles to fracture in an artificial stainless steel severely curved canal with 80 degrees angle and a 3 mm radius of curvature (n = 10). Torque and angle of rotation at failure of new instruments (n = 10) were measured according to ISO 3630-1. The fracture surfaces of all fragments were examined with a scanning electron microscope. Results were statistically analyzed using one-way ANOVA and Tukey's test at a significance level of p < 0.05. RESULTS: ProDesign R instruments showed a significantly longer cyclic fatigue life than the other tested instruments (p < 0.05). Reciproc Blue showed longer cyclic life than WaveOne Gold (p < 0.05). Reciproc Blue showed the higher torsional strength, followed by WaveOne Gold and ProDesign R instruments (p < 0.05). Moreover, Reciproc Blue showed significantly higher angular rotation to fracture than ProDesign R (p < 0.05). WaveOne Gold showed intermediary results regarding angular rotation to fracture with no differences when compared to Reciproc Blue or ProDesign R instruments (p < 0.05). CONCLUSIONS: ProDesign R presented the highest cyclic fatigue resistance in severely curved canals when compared with Reciproc Blue and WaveOne Gold. However, Reciproc Blue showed the higher torsional strength overall and higher angular rotation to fracture when compared to ProDesign R. CLINICAL RELEVANCE: Despite the numerous advantages of reciprocating instruments, these instruments still have some risk of fracture during its use, especially in severely curved canals. The present study evaluated the cyclic fatigue and torsional resistance of thermally treated reciprocating instruments. PMID- 29392415 TI - Fair weather voters: do Canadians stay at home when the weather is bad? AB - What is the relationship between precipitation and the temperature on turnout? Using data on the 2004, 2006, 2008, 2011, and 2015 Canadian federal elections, we try to answer this question. Through bivariate and multi-variate statistics, we find that each millimeter of precipitation decreases turnout by more than 0.1 percentage points. When it comes to the temperature, our results indicate that higher temperatures trigger higher turnout. However, we also find that these relationships are influenced by season and only apply to spring, summer, and fall elections. In the winter 2006 elections, the association was inversed; warmer temperatures in this election triggered lower turnout, in particular when it was combined with precipitation. PMID- 29392416 TI - Within-clutch variability in gamete size arises from the size variation in gametangia in the marine green alga Monostroma angicava. AB - KEY MESSAGE: Within-clutch gamete size variability in Monostroma angicava. In many organisms, it is unclear how the size variation in gametes is generated in each clutch (i.e., total gametes produced by a gametophyte for a single spawning) or how gamete size is adjusted. Within-clutch variation in gamete size has been explained as a result of either physiological/developmental constraints or bet hedging during gametogenesis. These two explanations have been assumed to be mutually exclusive, and related observations are conflicting. The slightly anisogamous dioecious green alga Monostroma angicava employs a simple mechanism to produce gametes of each sex: each vegetative cell becomes a single gametangium cell, which synchronously divides to form equally sized gametes. The number of such cell divisions has several variations, which might vary gamete size. We measured the volume of gametangia in each clutch, counted the number of cell divisions in each gametangium and estimated the size of the gametes. We found that larger gametangia divided more times than smaller gametangia in both sexes, although male gametangia were smaller than female gametangia when they underwent the same number of cell divisions. Therefore, the variation in the number of cell divisions during gametogenesis serves to adjust gamete size in each sex rather than to vary it. Within-clutch gamete size variability originates in within clutch variation in gametangium size: any factors that increase the variation in the size of gametangia can increase the within-clutch variation in gamete size. PMID- 29392417 TI - Great trochanter bursitis vs sciatica, a diagnostic-anatomic trap: differential diagnosis and brief review of the literature. AB - PURPOSE: The purpose of this study is to point out the difficulty of differentiating great trochanter bursitis (GTB) from sciatica and estimating the prevalence of GTBeta, in patients poorly diagnosed with sciatica in their first visit to the general practitioner and referred to a spine infirmary. METHODS: The diagnosis of GTBeta was made based on history and physical examination, and was confirmed by ultrasonography and/or response to an anesthetic plus corticosteroid injection to the trochanteric bursa. Demographic and clinical characteristics of the study group were evaluated. The statistical analysis was held with the SPSS pc package (version 24.0). RESULTS: In a total of 657 referrals for sciatica, 72 patients (10.95%) were incorrectly diagnosed as suffering from sciatica, whereas, in fact, they were suffering from GTBeta. In addition, 18 patients (2.74%) were diagnosed as suffering from persistent sciatica with coexisting GTBeta. More women than men had GTBeta (79-11). Mean age for patients with sciatica diagnosis but suffering from GTBeta was 60 years. Mean age for patients with both sciatica and GTBeta was 61 years. CONCLUSIONS: The GTB is a common clinical entity in middle-aged women, which can escape from the physician in cases of incomplete medical history and clinical examination, leading to unnecessary imaging tests and treatment approaches, burdening both the patient and the health system. Early diagnosis of GTB may dramatically reduce cost, prevent unwanted and inappropriate imaging exams and treatment, and make the patient free of symptoms immediately. These slides can be retrieved under Electronic Supplementary Material. PMID- 29392418 TI - Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls. AB - In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442). PMID- 29392419 TI - Hepatic glutamate transport and glutamine synthesis capacities are decreased in finished vs. growing beef steers, concomitant with increased GTRAP3-18 content. AB - Hepatic glutamate uptake and conversion to glutamine is critical for whole-body N metabolism, but how this process is regulated during growth is poorly described. The hepatic glutamate uptake activities, protein content of system [Formula: see text] transporters (EAAC1, GLT-1) and regulatory proteins (GTRAP3-18, ARL6IP1), glutamine synthetase (GS) activity and content, and glutathione (GSH) content, were compared in liver tissue of weaned Angus steers randomly assigned (n = 8) to predominantly lean (growing) or predominantly lipid (finished) growth regimens. Steers were fed a cotton seed hull-based diet to achieve final body weights of 301 or 576 kg, respectively, at a constant rate of growth. Liver tissue was collected at slaughter and hepatic membranes fractionated. Total (75%), Na+ dependent (90%), system [Formula: see text]-dependent (abolished) glutamate uptake activity, and EAAC1 content (36%) in canalicular membrane-enriched vesicles decreased as steers developed from growing (n = 6) to finished (n = 4) stages, whereas Na+-independent uptake did not change. In basolateral membrane enriched vesicles, total (60%), Na+-dependent (60%), and Na+-independent (56%) activities decreased, whereas neither system [Formula: see text]-dependent uptake nor protein content changed. EAAC1 protein content in liver homogenates (n = 8) decreased in finished vs. growing steers, whereas GTRAP3-18 and ARL6IP1 content increased and GLT-1 content did not change. Concomitantly, hepatic GS activity decreased (32%) as steers fattened, whereas GS and GSH contents did not differ. We conclude that hepatic glutamate uptake and GS synthesis capacities are reduced in livers of finished versus growing beef steers, and that hepatic system [Formula: see text] transporter activity/EAAC1 content is inversely proportional to GTRAP3-18 content. PMID- 29392420 TI - Cardioprotective effect of ghrelin against myocardial infarction-induced left ventricular injury via inhibition of SOCS3 and activation of JAK2/STAT3 signaling. AB - The molecular mechanisms through which ghrelin exerts its cardioprotective effects during cardiac remodeling post-myocardial infarction (MI) are poorly understood. The aim of this study was to investigate whether the cardioprotection mechanisms are mediated by modulation of JAK/STAT signaling and what triggers this modulation. Rats were divided into six groups (n = 12/group): control, sham, sham + ghrelin (100 ug/kg, s.c., daily, starting 1 day post-MI), MI, MI+ ghrelin, and MI+ ghrelin+ AG490, a potent JAK2 inhibitor (5 mg/kg, i.p., daily). All treatments were administered for 3 weeks. Administration of ghrelin to MI rats improved left ventricle (LV) architecture and restored cardiac contraction. In remote non-infarcted areas of MI rats, ghrelin reduced cardiac inflammation and lipid peroxidation and enhanced antioxidant enzymatic activity. In addition, independent of the growth factor/insulin growth factor-1 (GF/IGF-1) axis, ghrelin significantly increased the phosphorylation of JAK2 and Tyr702 and Ser727 residues of STAT3 and inhibited the phosphorylation of JAK1 and Tyr701 and Ser727 residues of STAT1, simultaneously increasing the expression of BCL-2 and decreasing in the expression of BAX, cleaved CASP3, and FAS. This effect coincided with decreased expression of SOCS3. All these beneficial effects of ghrelin, except its inhibitory action on IL-6 expression, were partially and significantly abolished by the co-administration of AG490. In conclusion, the cardioprotective effect of ghrelin against MI-induced LV injury is exerted via activation of JAK2/STAT3 signaling and inhibition of STAT1 signaling. These effects were independent of the GF/IGF-1 axis and could be partially mediated via inhibition of cardiac IL-6. PMID- 29392421 TI - The effect of magnetic resonance imaging on neural tube development in an early chicken embryo model. AB - PURPOSE: We aimed to determine whether varying the magnetic field during magnetic resonance imaging would affect the development of chicken embryos and neural tube defects. METHODS: Following incubation for 24 h, we exposed chicken embryos to varying magnetic fields for 10 min to assess the impact on development. Three magnetic resonance imaging devices were used, and the eggs were divided into four groups: group 1 is exposed to 1 T, group 2 is exposed to 1.5 T, group 3 is exposed to 3 T, and group 4, control group, was not exposed to magnetic field. After MRI exposure, all embryos were again put inside incubator to complete 48 h. "The new technique" was used to open eggs, a stereomicroscope was used for the examination of magnified external morphology, and each embryo was examined according to the Hamburger and Hamilton chicken embryo stages. Embryos who had delayed stages of development are considered growth retarded. Growth retardation criteria do not include small for stage. RESULTS: Compared with embryos not exposed to a magnetic field, there was a statistically significant increase in the incidence of neural tube closure defects and growth retardation in the embryos exposed to magnetic fields (p < 0.05). However, although the incidence of neural tube closure defects was expected to increase as exposure (tesla level) increased, we found a higher rate of defects in the 1.5-T group compared with the 3-T group. By contrast, the highest incidence of growth retardation was in the 3 T group, which was consistent with our expectation that growth retardation would be more likely as tesla level increased. CONCLUSIONS: We therefore conclude that the use of magnetic resonance imaging as a diagnostic tool can result in midline closure defects and growth retardation in chicken embryos. We hypothesize that this may also be true for human embryos exposed to MRI. If a pregnant individual is to take an MRI scan, as for lumbar disc disease or any other any other reason, our results indicate that consideration should be given to an avoidance of MRI during pregnancy. PMID- 29392422 TI - Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China. AB - PURPOSE: Neural tube defects (NTDs) are one of the most prevalent and the most severe congenital malformations worldwide. Studies have confirmed that folic acid supplementation could effectively reduce NTDs risk, but the genetic mechanism remains unclear. In this study, we explored association of single nucleotide polymorphisms (SNP) within folate metabolic pathway genes with NTDs in Han population of Northern China. METHODS: We performed a case-control study to compare genotype and allele distributions of SNPs in 152 patients with NTDs and 169 controls. A total of 16 SNPs within five genes were genotyped by the Sequenom MassARRAY assay. RESULTS: Our results indicated that three SNPs associated significantly with NTDs (P<0.05). For rs2236225 within MTHFD1, children with allele A or genotype AA had a high NTDs risk (OR=1.500, 95%CI=1.061~2.120; OR=2.862, 95%CI=1.022~8.015, respectively). For rs1801133 within MTHFR, NTDs risk markedly increased in patients with allele T or genotype TT (OR=1.552, 95%CI=1.130~2.131; OR=2.344, 95%CI=1.233~4.457, respectively). For rs1801394 within MTRR, children carrying allele G and genotype GG had a higher NTDs risk (OR=1.533, 95%CI=1.102~2.188; OR=2.355, 95%CI=1.044~5.312, respectively). CONCLUSIONS: Our results suggest that rs2236225 of MTHFD1 gene, rs1801133 of MTHFR gene and rs1801394 of MTRR gene were associated with NTDs in Han population of Northern China. PMID- 29392423 TI - Marked functional recovery and imaging response of refractory optic pathway glioma to BRAFV600E inhibitor therapy: a report of two cases. AB - BACKGROUND: Despite appropriate therapeutic interventions, progressive optic pathway glioma (OPG) in children may result in loss of vision and other neurologic morbidities. Molecularly targeted therapy against the MAP kinase pathway holds promise in improving outcomes while resulting in lower treatment related toxicities. We report two children with refractory OPG who had a substantial and early reversal of their neurologic deficits and an impressive imaging response of their tumor to BRAFV600E inhibition therapy. METHODS: Two children with OPG (BRAFV600E-mutated pilocytic astrocytoma) who did not respond to at least one frontline therapy were treated with the oral BRAFV600E inhibitor vemurafenib. RESULTS: Both children had substantial visual compromise before start of therapy, with one child additionally having motor deficits. Both had an early improvement in their vision, and the second child showed a demonstrable improvement in motor weakness. This was accompanied by a decrease in tumor size, which was sustained at 6 months from therapy. Neither child had significant toxicities except for mild skin sensitivity to vemurafenib. CONCLUSIONS: BRAFV600E inhibitor therapy can potentially reverse visual and neurologic decline associated with progressive OPG. The clinico-radiologic response appears to be prompt and marked. Ongoing clinical trials using BRAFV600E inhibitors can help confirm these early promising findings. PMID- 29392424 TI - Minimal residual disease (MRD) detection using rearrangement of immunoglobulin/T cell receptor genes in adult patients with acute lymphoblastic leukemia (ALL). AB - MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage. An ASO qPCR technique was then applied for 2.5-year monthly MRD quantification for detection of patient-specific Ig/TCR receptor rearrangements as a molecular target. From 98 patients who were diagnosed as ALL, 72 (73.5%) were enrolled in the present study for MRD detection. MRD was successfully quantified in patients with 1-month interval time. MRD level at the end of induction therapy up to day 88 was the only significant prognostic factor. Regarding MRD level, patients were categorized into two groups of low and high-risk. 2.5-year OS in all three time points (days 28, 58 and 88) were significantly lower in high-risk group (P < 0.008). The results of the 2.5-year MRD detection indicate that MRD level at the end of induction up to about 6 months after the first diagnosis was associated with clinical outcome. This study may highlight the usefulness of PB and the definitions of cut-off level for early prediction of relapse and for stratifying ALL patients. Short-interval time points and frequent PB sampling to monitor MRD level is suggested for early clinical relapse prediction and clinical management of the disease. PMID- 29392426 TI - Assessing effectiveness of long-term forestry best management practices on stream water quality at a basin scale-a case study in Southern USA. AB - Forestry best management practices (BMPs) have proven to be very effective in protecting adjacent stream water quality at the plot scale. However, our knowledge is incomplete about the effectiveness of forestry BMPs in large watersheds where industrial forests are intensively managed. In this study, we compared long-term concentrations and loadings of total suspended solids (TSS), nitrate/nitrite nitrogen (NO3NO2-N), total Kjeldahl nitrogen (TKN), and total phosphorus (TP) before (1978-1988) and after extensive implementation of forestry BMPs (1994-2008) at the outlet of a 5000-km2 river basin that is predominately covered by intensively managed pine forests in Central Louisiana, USA. Our study shows that after extensive BMP implementation, both concentrations and loads of TSS in the basin outlet decreased significantly from 34 to 25 mg L-1 and from 55,000 to 36,700 t year-1, respectively. However, no significant difference was found in NO3NO2-N, TKN, and TP concentrations between the two periods. The results of nutrient loadings varied, whereby the annual nitrogen loading declined without significant differences (from 1790 to 1600 t year-1 for TKN and from 176 to 158 t year-1 for NO3NO2-N, respectively) but the annual TP loading increased significantly (from 152 to 192 t year-1) after BMP implementation. The increase in TP loading is likely due to an increased application of phosphorus fertilizer, which offset BMPs' effects especially during high-flow conditions. These results strongly suggest that current forestry BMPs in this region are effective in reducing sediment loading, but current BMP guidelines for fertilization and nutrient management need to be reviewed and improved. PMID- 29392425 TI - A phase I-II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia. AB - Clinical outcomes of patients with acute myeloid leukemia (AML) showing the first primary refractory or early-relapsed disease remain very poor. The Programa Espanol de Tratamientos en Hematologia (PETHEMA) group designed a phase I-II trial using FLAG-Ida (fludarabine, idarubicin, cytarabine, and G-CSF) plus high dose intravenous plerixafor, a molecule inducing mobilization of blasts through the SDF-1alpha-CXCR4 axis blockade and potentially leading to chemosensitization of the leukemic cells. We aimed to establish a recommended phase 2 dose (RP2D) of plerixafor plus FLAG-Ida, as well as the efficacy and safety of this combination for early-relapsed (first complete remission (CR/CRi) < 12 months) or primary refractory AML. Between 2012 and 2015, 57 patients were enrolled, and 41 received the RP2D (median age 52 years [range, 18-64]). Among these patients, 20 (49%) achieved CR/CRi, and 3 (7%) died during induction. CR/CRi rate was 50% (13/26) among primary refractory and 47% (7/15) among early relapse. Overall, 25 patients (61%) were allografted. Median overall and disease-free survivals were 9.9 and 13 months, respectively. In summary, the combination of plerixafor plus FLAG-Ida resulted in a relatively high CR/CRi rate in adult patients with primary refractory or early relapsed AML, with an acceptable toxicity profile and induction mortality rate, bridging the majority of patients to allogeneic stem cell transplantation. ClinicalTrials.gov Identifier: NCT01435343. PMID- 29392428 TI - Biologically important conformational features of DNA as interpreted by quantum mechanics and molecular mechanics computations of its simple fragments. AB - Deciphering the mechanism of functioning of DNA as the carrier of genetic information requires identifying inherent factors determining its structure and function. Following this path, our previous DFT studies attributed the origin of unique conformational characteristics of right-handed Watson-Crick duplexes (WCDs) to the conformational profile of deoxydinucleoside monophosphates (dDMPs) serving as the minimal repeating units of DNA strand. According to those findings, the directionality of the sugar-phosphate chain and the characteristic ranges of dihedral angles of energy minima combined with the geometric differences between purines and pyrimidines determine the dependence on base sequence of the three-dimensional (3D) structure of WCDs. This work extends our computational study to complementary deoxydinucleotide-monophosphates (cdDMPs) of non-standard conformation, including those of Z-family, Hoogsteen duplexes, parallel-stranded structures, and duplexes with mispaired bases. For most of these systems, except Z-conformation, computations closely reproduce experimental data within the tolerance of characteristic limits of dihedral parameters for each conformation family. Computation of cdDMPs with Z-conformation reveals that their experimental structures do not correspond to the internal energy minimum. This finding establishes the leading role of external factors in formation of the Z-conformation. Energy minima of cdDMPs of non-Watson-Crick duplexes demonstrate different sequence-dependence features than those known for WCDs. The obtained results provide evidence that the biologically important regularities of 3D structure distinguish WCDs from duplexes having non-Watson-Crick nucleotide pairing. PMID- 29392427 TI - Dry versus hydrated collagen scaffolds: are dry states representative of hydrated states? AB - Collagen composite scaffolds have been used for a number of studies in tissue engineering. The hydration of such highly porous and hydrophilic structures may influence mechanical behaviour and porosity due to swelling. The differences in physical properties following hydration would represent a significant limiting factor for the seeding, growth and differentiation of cells in vitro and the overall applicability of such hydrophilic materials in vivo. Scaffolds based on collagen matrix, poly(DL-lactide) nanofibers, calcium phosphate particles and sodium hyaluronate with 8 different material compositions were characterised in the dry and hydrated states using X-ray microcomputed tomography, compression tests, hydraulic permeability measurement, degradation tests and infrared spectrometry. Hydration, simulating the conditions of cell seeding and cultivation up to 48 h and 576 h, was found to exert a minor effect on the morphological parameters and permeability. Conversely, hydration had a major statistically significant effect on the mechanical behaviour of all the tested scaffolds. The elastic modulus and compressive strength of all the scaffolds decreased by ~95%. The quantitative results provided confirm the importance of analysing scaffolds in the hydrated rather than the dry state since the former more precisely simulates the real environment for which such materials are designed. PMID- 29392429 TI - Minimally Invasive Surgery (MIS) in Children and Adolescents with Pheochromocytomas and Retroperitoneal Paragangliomas: Experiences in 42 Patients. AB - BACKGROUND: Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access. MATERIALS: In the setting of a prospective study (1/2001-12/2016), 42 consecutive children and adolescents (33 m, 9 f) were operated on. Thirty-seven patients (88%) suffered from inherited diseases. Twenty six patients had PH, 11 presented retroperitoneal PGL, and five patients suffered from both. Altogether, 70 tumours (mean size 2.7 cm) were removed (45 PH, 25 PGL). All operations were performed by a minimally invasive access (retroperitoneoscopic, laparoscopic, extraperitoneal). Partial adrenalectomy was the preferred procedure for PH (31 out of 39 patients). Twenty patients received alpha-receptor blockade preoperatively. RESULTS: One patient died after induction of anaesthesia due to cardiac arrest. All other complications were minor. Conversion to open surgery was necessary in two cases with PGL. Median operating time for unilateral PH was 55 min, in bilateral cases 125, 143 min in PGs, and 180 min in combined cases. Median blood loss was 20 ml (range 0-1000). Blood transfusion was necessary in two cases. Intraoperative, systolic peak pressure was 170 +/- 39 mmHg with alpha-receptor blockade and 191 +/- 33 mmHg without alpha-receptor blockade (p = 0.41). The median post-operative hospital stay was 3 days. After a mean follow-up of 8.5 years, two patients presented ipsilateral recurrence (after partial adrenalectomy). All patients with bilateral PH (n = 13) are steroid independent post-operatively. CONCLUSIONS: PH and PGL in children and adolescents should preferably be removed by minimally invasive surgery. Partial adrenalectomy provides long-term steroid independence in bilateral PH and a low rate of (ipsilateral) recurrence. alpha-Receptor blockade may not be necessary in these patients. PMID- 29392430 TI - Comprehensive Analysis of the Neutrophil-to-Lymphocyte Ratio for Preoperative Prognostic Prediction Nomogram in Gastric Cancer. AB - BACKGROUND: The role of neutrophil-to-lymphocyte ratio (NLR) and preoperative prediction model in gastric cancer is controversial, while postoperative prognostic models are available. This study investigated NLR as a preoperative prognostic indicator in gastric cancer. METHODS: We reviewed patients with primary gastric cancer who underwent surgery during 2007-2010. Preoperative clinicopathologic factors were analyzed with their interaction and used to develop a prognosis prediction nomogram. That preoperative prediction nomogram was compared to a nomogram using pTNM or a historical postoperative prediction nomogram. The contribution of NLR to a preoperative nomogram was evaluated with integrated discrimination improvement (IDI). RESULTS: Using 2539 records, multivariable analysis revealed that NLR was one of the independent prognostic factors and had a significant interaction with only age among other preoperative factors (especially significant in patients < 50 years old). NLR was constantly significant between 1.1 and 3.1 without any distinctive cutoff value. Preoperative prediction nomogram using NLR showed a Harrell's C-index of 0.79 and an R2 of 25.2%, which was comparable to the C-index of 0.78 and 0.82 and R2 of 26.6 and 25.8% from nomogram using pTNM and a historical postoperative prediction nomogram, respectively. IDI of NLR to nomogram in the overall population was 0.65%, and that of patients < 50 years old was 2.72%. CONCLUSIONS: NLR is an independent prognostic factor for gastric cancer, especially in patients < 50 years old. A preoperative prediction nomogram using NLR can predict prognosis of gastric cancer as effectively as pTNM and a historical postoperative prediction nomogram. PMID- 29392431 TI - Assessing Risk Factors for Intubation Difficulty in Thyroid Surgical Patients. PMID- 29392432 TI - Safe Surgery for All: Early Lessons from Implementing a National Government Driven Surgical Plan in Ethiopia. PMID- 29392433 TI - Impact of 3D Printing Technology on Comprehension of Surgical Anatomy of Retroperitoneal Tumor. AB - OBJECTIVES: To investigate the impact of 3D printed model on understanding of surgical anatomy of retroperitoneal tumor. MATERIALS AND METHODS: Three dimensional model was printed, based on multi-detectors computed tomography (MDCT) of a retroperitoneal tumor. Participants (10 students, 10 residents and 10 surgeons) were asked to identify vasculatures which were important in resection of the tumor, after viewing MDCT images, 3D visualization model and 3D printed model, respectively. Regarding this tumor, left renal vein (LRV), right renal pedicles (RRP) and inferior vena cava (IVC) were chosen as indicators to assess participants' performances. Identification of vasculatures was evaluated and a score was given (1 point = success; 0 point = failure). The total number and percentage of correct identification were used to measure how these three types of anatomic presentation were able to transfer in terms of anatomical recognition. Recorded data were analyzed both pooling together data from three groups of participants and separately for each group. RESULTS: In analysis of overall comparison among 3D printing, 3D visualization and MDCT, recognition of all three vasculatures simultaneously was 83.33, 73.33 and 46.67%, respectively (P = 0.007); recognition of LRV was 90, 80 and 63.33% (P = 0.043), respectively; recognition of RRP was 96.67, 83.33 and 73.33% (P = 0.035), respectively; recognition of IVC was 93.33, 90 and 80% (P = 0.366), respectively. In subgroup analysis of performances of three groups of participants, no significant differences regarding anatomic recognition were observed among MDCT, 3D visualization and 3D printed model for each group of participants. CONCLUSION: Three-dimensional printed model improved the understanding of surgical anatomy of retroperitoneal tumor. PMID- 29392434 TI - Classic Primary Hyperparathyroidism Versus Normocalcemic and Normohormonal Variants: Do They Really Differ? AB - BACKGROUND: Normocalcemic (NCpHPT) and normohormonal (NHpHPT) variants have been recognized primary hyperparathyroidism entities that pose serious challenges. We sought to define the differences among them in a series of surgically treated patients. PATIENTS AND METHODS: Between 2011 and 2015, 149 patients were enrolled into three groups: CpHPT (Ca > 10.2 mg/dL, PTH > 65 pg/mL), NCpHPT (normal Ca, PTH > 65 pg/mL) and NHpHPT (Ca > 10.2 mg/dL, normal PTH). Descriptive statistics and inter-group differences were computed, whereas multiple logistic/linear regression tests were used for further analysis. RESULTS: Of these patients 125 were female and 24 male, mean age 56.3 years (range 8-83). A total of 115 (77.2%) patients presented with CpHPT, 23 (15.4%) with NCpHPT and 11 (7.4%) with NHpHPT. MGD was found in 25 (16.8%) patients and SGD in 124 (83.2%); multivariate analysis failed to reveal statistically significant association of MGD with any pHPT variant (CpHPT 16.5% vs NCpHPT 21.7% vs NHpHPT 9.1%, p = 0.726). Conversely, NCpHPT patients exhibited statistically significant smaller adenoma weight (p = 0.023). Moreover, U/S in these patients had smaller positive predictive value (p = 0.278), whereas concordance between U/S and MIBI was also lower (p = 0.669). The utility of MIBI and U/S differed significantly (p < 0.001); more frequent use of U/S was observed for all groups. However, their predictive values did not differ significantly (p = 0.832). CONCLUSIONS: NCpHPT is more similar than different to CpHPT. NCpHPT constitutes the most challenging entity: it is associated with smaller adenoma weight, whereas U/S exhibited lower positive predictive value and lower concordance rate with MIBI. A trend for higher MGD presence in this group of patients was observed, though without statistical significance. PMID- 29392435 TI - Neonatal Gastric Perforation: Case Series and Literature Review. AB - PURPOSE: We reported clinical findings of neonatal gastric perforation in a tertiary children's hospital. PATIENTS AND METHODS: Retrospective chart reviews were conducted for neonatal gastric perforation between 1980 and 2016. Factors including sex, gestational age, birth weight, age, main symptoms and signs, white blood cell count (WBC), surgical intervention time (time between development of main symptom and surgical intervention), surgical findings, pathologic results, clinical outcomes, and causes of death were collected. RESULTS: Sixty-eight patients were identified. In total, 76.5% were male infants, the median age was 4 days, median birth weight was 2500 g, and 42.6% were premature. Abdominal distention and vomiting were the most common symptoms, and pneumoperitoneum was the most common radiographic finding. The median surgical intervention time was 51 h (range 8-312). In total, 73.5% of perforations occurred in the great curvature, 17.6% in the lesser curvature, and 8.9% unspecified. The median perforation size was 4 cm (range 0.2-16). Associated gastrointestinal anomalies were found in 20.6% of patients, and the most common anomaly was intestinal malrotation. Of the 51 patients with pathologic results, 11 showed the presence of musculature in the perforated gastric wall, while 40 showed the absence of musculature. Of the 66 patients with known clinical outcomes, 26 (39.4%) died, 23 of who died of infection. Among those aforementioned factors, WBC has a significant impact on survival. The mortality for four arbitrary divided year groups (1980-1989, 1990-1999, 2000-2009, and 2010-2016) was 100, 50, 31.6, and 16.7%, respectively. CONCLUSIONS: The mortality of neonatal gastric perforation is constantly decreasing. Associated gastrointestinal anomalies and the presence of musculature are found in a minority of this condition. PMID- 29392437 TI - Independent association between uterine malformations and cervical insufficiency: a retrospective population-based cohort study. AB - OBJECTIVE: The purpose of our study was to explore maternal and fetal outcomes in the second and third trimester in women with uterine malformations. STUDY DESIGN: This was a retrospective population-based cohort study including women with a diagnosis of uterine malformation arised from workup for infertility or recurrent pregnancy loss, was accidental during pregnancy, or was noticed at the time of cesarean delivery. RESULTS: A total of 280,721 pregnancies met the inclusion criteria and were divided into two study groups: (1) pregnancies in women with uterine malformations (n = 1099); and (2) controls (n = 279,662). The rate of women presenting uterine malformations was 0.39%. The prevalence of cervical os insufficiency was significantly higher in women with a uterine malformation than in the control group (3.6 vs. 0.4%, p < 0.001). A multivariate analysis, performed to evaluate risk factors for cervical insufficiency in women with uterine malformations. Mullerian anomalies (OR 6.19, 95% CI 4.41-8.70, p < 0.001), maternal age (OR 1.05, 95% CI 1.04-1.06, p < 0.001), recurrent abortions (OR 12.93, 95% CI 11.43-14.62, p < 0.001), and ethnicity (OR 2.86, 95% CI 2.454 3.34, p < 0.001) were found to be independently associated with the development of cervical insufficiency. CONCLUSION: Uterine anomalies have a strong association with cervical insufficiency. Women with uterine anomalies have an increased risk to develop pregnancy complications that arise from a loss in cervical function during the midtrimester or early third trimester. PMID- 29392436 TI - Prothrombin Complex Concentrate Reversal of Coagulopathy in Emergency General Surgery Patients. AB - BACKGROUND: Coagulopathy can delay or complicate surgical diseases that require emergent surgical treatment. Prothrombin complex concentrates (PCC) provide concentrated coagulation factors which may reverse coagulopathy more quickly than plasma (FFP) alone. We aimed to determine the time to operative intervention in coagulopathic emergency general surgery patients receiving either PCC or FFP. We hypothesize that PCC administration more rapidly normalizes coagulopathy and that the time to operation is diminished compared to FFP alone. METHODS: Single institution retrospective review was performed for coagulopathic EGS patients during 2/1/2008 to 8/1/2016. Patients were divided into three groups (1) PCC alone (2) FFP alone and (3) PCC and FFP. The primary outcome was the duration from clinical decision to operate to the time of incision. Summary and univariate analyses were performed. RESULTS: Coagulopathic EGS patients (n = 183) received the following blood products: PCC (n = 20, 11%), FFP alone (n = 119, 65%) and PCC/FFP (n = 44, 24%). The mean (+/- SD) patient age was 71 +/- 13 years; 60% were male. The median (IQR) Charlson comorbidity index was similar in all three groups (PCC = 5(4-6), FFP = 5(4-7), PCC/FFP = 5(4-6), p = 0.33). The mean (+/- SD) dose of PCC administered was similar in the PCC/FFP group and the PCC alone group (2539 +/- 1454 units vs. 3232 +/- 1684, p = .09). The mean (+/-SD) time to incision in the PCC alone group was significantly lower than the FFP alone group (6.0 +/- 3.6 vs. 8.8 +/- 5.0 h, p = 0.01). The mean time to incision in the PCC + FFP group was also significantly lower than the FFP alone group (7.1 +/- 3.6 vs. 8.8 +/- 5.0, p = 0.03). The incidence of thromboembolic complications was similar in all three groups. CONCLUSIONS: PCC, alone or in combination with FFP, reduced INR and time to surgery effectively and safely in coagulopathic EGS patients without an apparent increased risk of thromboembolic events, when compared to FFP use alone. LEVEL OF EVIDENCE: IV single institutional retrospective review. PMID- 29392438 TI - Letrozole versus clomiphene citrate in polycystic ovary syndrome: a meta-analysis of randomized controlled trials. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is a common endocrine disturbance affecting women in the reproductive age group. The present study aimed to compare the effects of letrozole (LE) and clomiphene citrate (CC) for ovulation induction in women with PCOS. METHODS: The PUBMED, Web of Science, and EMBASE databases were screened systematically for randomized controlled trials (RCTs) published from database inception to July 2017. RESULTS: Eleven RCTs involving 2255 patients were included, and data were independently extracted and analyzed using 95% risk ratios (RRs) and confidence intervals (CIs) based on a random- or fixed effect model (as appropriate). Meta-analyses of nine RCTs comparing LE and CC ovulation induction, followed by timed intercourse, indicated that the former significantly increased the ovulation rate (RR = 1.18; 95% CI 1.03-1.36, P = 0.01), pregnancy rate (RR = 1.34; 95% CI 1.09-1.64, P = 0.006), and live birth rate (RR = 1.55; 95% CI 1.28-1.88, P < 0.00001). However, LE and CC did not differ significantly in terms of the multiple pregnancy and abortion rates. Furthermore, LE for ovulation induction significantly improved the pregnancy rate after IUI. CONCLUSION: LE is superior to CC for ovulation induction in patients with PCOS. PMID- 29392439 TI - Mode of delivery, childbirth experience and postpartum sexuality. AB - PURPOSE: Although childbirth has been studied extensively with regard to postpartum sexuality, the association between the psychological aspects of childbirth and postpartum sexuality has rarely been examined. This research is aimed at studying the possible association of mode of delivery, childbirth experience, sexual functioning, and sexual satisfaction. METHODS: Three hundred seventy-six primiparous and nulliparous women completed this web-based survey 100 390 days postpartum. The participants completed a socio-demographic and delivery details questionnaire, the Childbirth Perception Questionnaire (CPQ), the Index of Sexual Satisfaction (ISS) and the Sexual Function Questionnaire's Medical Impact Scale (SFQ-MIS). RESULTS: Structural equation modeling showed that there are indirect effects of mode of delivery on sexual functioning and sexual satisfaction through childbirth experience. Specific significant indirect paths were found: mode of delivery to sexual functioning through childbirth experience [B = - 0.26, p = 0.023, 95% CI = (- 0.40, - 0.10)] and from mode of delivery to sexual satisfaction through childbirth experience [B = 0.11, p = 0.013, 95% CI = (0.05, 0.21)]. No significant direct effects were found between mode of delivery and sexual functioning or sexual satisfaction. CONCLUSIONS: The results point to the association of the psychological experience of childbirth, sexual functioning and sexual satisfaction. In addition, we found a possible indirect link between mode of delivery and postpartum sexuality. It can be concluded that the psychological factors associated with childbirth are important to the understanding of postpartum sexuality. PMID- 29392441 TI - Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Diagnosis and Management. AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors represent a major step forward in the field of oncologic immunotherapy these last years and have significantly increased survival of cancer patients in an ever-growing number of indications. These agents block specific immune checkpoint molecules (programmed cell death protein 1 and its ligand as well as cytotoxic T-lymphocyte-associated antigen 4) that normally downregulate the immune response. These new agents show a specific range of adverse effects induced by abnormal immunologic activation. RECENT FINDINGS: Many different neurologic adverse events have been described, including encephalitis, myelopathy, aseptic meningitis, meningoradiculitis, Guillain-Barre like syndrome, peripheral neuropathy (including mononeuropathy, mononeuritis multiplex, and polyneuropathy) as well as myasthenic syndrome. Immune checkpoint inhibitors have shown promising results in cancer but can possibly induce autoimmune disorders. Although rare, neurological adverse events require prompt recognition and treatment to avoid substantial morbidity. PMID- 29392442 TI - Risk of herbivore attack and heritability of ontogenetic trajectories in plant defense. AB - Ontogeny has been identified as a main source of variation in the expression of plant phenotypes. However, there is limited information on the mechanisms behind the evolution of ontogenetic trajectories in plant defense. We explored if risk of attack, herbivore damage, heritability, and phenotypic plasticity can promote or constrain the evolutionary potential of ontogenetic trajectories in three defensive traits. We exposed 20 genotypes of Turnera velutina to contrasting environments (shadehouse and field plots), and measured the cyanogenic potential, trichome density, and sugar content in extrafloral nectar in seedlings, juveniles and reproductive plants. We also assessed risk of attack through oviposition preferences, and quantified herbivore damage in the field. We estimated genetic variance, broad sense heritability, and evolvability of the defensive traits at each ontogenetic stage, and of the ontogenetic trajectories themselves. For plants growing in the shadehouse, we found genetic variation and broad sense heritability for cyanogenic potential in seedlings, and for trichome density at all ontogenetic stages. Genetic variation and heritability of ontogenetic trajectories was detected for trichome density only. These genetic pre-requisites for evolution, however, were not detected in the field, suggesting that environmental variation and phenotypic plastic responses mask any heritable variation. Finally, ontogenetic trajectories were found to be plastic, differing between shadehouse and field conditions for the same genetic families. Overall, we provide support for the idea that changes in herbivore pressure can be a mechanism behind the evolution of ontogenetic trajectories. This evolutionary potential, however, can be constrained by phenotypic plasticity expressed in heterogeneous environments. PMID- 29392440 TI - Cannabinoids and glial cells: possible mechanism to understand schizophrenia. AB - Clinical and neurobiological findings have reported the involvement of endocannabinoid signaling in the pathophysiology of schizophrenia. This system modulates dopaminergic and glutamatergic neurotransmission that is associated with positive, negative, and cognitive symptoms of schizophrenia. Despite neurotransmitter impairments, increasing evidence points to a role of glial cells in schizophrenia pathobiology. Glial cells encompass three main groups: oligodendrocytes, microglia, and astrocytes. These cells promote several neurobiological functions, such as myelination of axons, metabolic and structural support, and immune response in the central nervous system. Impairments in glial cells lead to disruptions in communication and in the homeostasis of neurons that play role in pathobiology of disorders such as schizophrenia. Therefore, data suggest that glial cells may be a potential pharmacological tool to treat schizophrenia and other brain disorders. In this regard, glial cells express cannabinoid receptors and synthesize endocannabinoids, and cannabinoid drugs affect some functions of these cells that can be implicated in schizophrenia pathobiology. Thus, the aim of this review is to provide data about the glial changes observed in schizophrenia, and how cannabinoids could modulate these alterations. PMID- 29392443 TI - Geographical co-occurrence of butterfly species: the importance of niche filtering by host plant species. AB - The relevance of interspecific resource competition in the context of community assembly by herbivorous insects is a well-known topic in ecology. Most previous studies focused on local species assemblies that shared host plants. Few studies evaluated species pairs within a single taxon when investigating the effects of host plant sharing at the regional scale. Herein, we explore the effect of plant sharing on the geographical co-occurrence patterns of 232 butterflies distributed across the Japanese archipelago; we use two spatial scales (10 * 10 and 1 * 1 km grids) to this end. We considered that we might encounter one of two predictable patterns in terms of the relationship between co-occurrence and host sharing among butterflies. On the one hand, host sharing might promote distributional exclusivity attributable to interspecific resource competition. On the other hand, sharing of host plants may promote co-occurrence attributable to filtering by resource niche. At both grid scales, we found significant negative correlations between host use similarity and distributional exclusivity. Our results support the hypothesis that the butterfly co-occurrence pattern across the Japanese archipelago is better explained by filtering via resource niche rather than interspecific resource competition. PMID- 29392444 TI - Plasmid to generate Mycobacteria mutants. AB - The generation of conditional mutants has been an effective approach to studying bacteria and validating drug targets, and mutants of Mycobacteria are no exception. However unlike other bacteria, there is still a paucity of available tools for Mycobacteria. We constructed a new plasmid containing tetracycline repressive expression system (TetRr1.7) and Xer Site-Specific recombinase system to generate label-free controllable expression strains. The plasmid was subsequently used to construct a strain of M. tuberculosis expressing the only copy of D-alanine:D-alanine ligase under the control of the tetracycline repressive promoter. The results showed that the mutant strain lost the ability of colony formation, became more sensitive to D-cycloserine and the cell wall of the mutant strain was disrupted when anhydrotetracycline was added to the medium. Taken together these observations, confirmed that the expression of D-alanine:D alanine ligase was tightly controlled by the promoter. In conclusion, the new plasmid is a convenient tool for constructing stable conditional mutant strains in Mycobacteria and can be used for future target identification. PMID- 29392445 TI - Correction to: Paragangliomas arise through an autonomous vasculo-angio neurogenic program inhibited by imatinib. AB - The given and family names of two co-authors were incorrect in the published article. The correct spelling should read as: Sampath Chandra Prasad and Vinagolu K Rajasekhar. PMID- 29392446 TI - Psychiatric Aspects of Acute Porphyria: a Comprehensive Review. AB - PURPOSE OF REVIEW: The aim of this paper is to review psychiatric manifestations, comorbidities, and psychopharmacological management in individuals with acute porphyria (AP). RECENT FINDINGS: Recent literature begins to clarify associations between AP, schizophrenia, bipolar disorder, and other psychopathology. Broad psychiatric symptoms have been associated to acute porphyria (AP) and correspond to a spectrum of heterogeneous manifestations such as anxiety, affective alterations, behavioral changes, personality, and psychotic symptoms. These symptoms may be difficult to identify as being related to porphyria since symptoms may arise at any time during the disease process. In addition, these patients may present psychiatric conditions secondary to the disease, such as adjustment disorder and substance use disorders. Timely diagnosis and appropriate treatment of psychiatric manifestations positively impact the course of the disease. PMID- 29392447 TI - TiO2 and its composites as promising biomaterials: a review. AB - TiO2 is a well-known material and has remarkable physical, chemical and biocompatible properties which have made it a suitable material in the biological world. The development of new TiO2-based materials is strongly required to achieve desired properties and applications. A large number of TiO2 composites have been synthesized and applied in various fields. The present review reports the utility of TiO2 and its composites in biosensing, in Photodynamic Therapy, as an antimicrobial agent and as a nanodrug carrier. The aim of this review is to discuss the biological application of the TiO2 based materials and some recent advancement in TiO2 to enhance its application in the biological world. PMID- 29392448 TI - Effect of zinc intake on hepatic autophagy during acute alcohol intoxication. AB - Autophagy is a conserved mechanism that plays a housekeeping role by eliminating protein aggregates and damaged organelles. Recent studies have demonstrated that acute ethanol intoxication induces hepatic autophagy in mice. The effect of dietary zinc intake on hepatic autophagic flux during ethanol intoxication has not been evaluated using animal models. Herein, we investigated whether zinc deficiency and excess can affect autophagic flux in the liver in mice and in human hepatoma cells acutely exposed to ethanol. A mouse model of binge ethanol feeding was utilized to analyze the effect of low, adequate, and high zinc intake on hepatic autophagic flux during ethanol intoxication. Autophagic flux was inferred by analyzing LC3II/LC3I ratio, protein levels of p62/SQSTM1, Beclin1 and Atg7, and phosphorylation of 4EBP1. In addition, the degradation of the fusion protein LC3-GFP and the formation of autophagosomes and autolysosomes were evaluated in cells. Ethanol treatment stimulated autophagy in mice and cells. High zinc intake resulted in enhanced autophagy in mice exposed to ethanol. Conversely, zinc deficiency was consistently associated with impaired ethanol induced autophagy in mice and cells. Zinc-deficient mice exhibited a high degree of ethanol-driven steatosis. Furthermore, zinc depletion increased apoptosis in cells exposed to ethanol. The results of this study suggest that adequate zinc intake is necessary for proper stimulation of autophagy by ethanol. Poor zinc status is commonly found among alcoholics and could likely contribute to faulty autophagy. PMID- 29392449 TI - Essentials from clinical practice guidelines for CKD stage G3b-5 2017. PMID- 29392450 TI - A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. AB - PURPOSE: The artemisinin class of anti-malarial drugs has shown significant anti cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS). METHODS: Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1. RESULTS: A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose. CONCLUSION: The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population. CLINICALTRIALS. GOV IDENTIFIER: NCT02353026. PMID- 29392451 TI - Phase 1 summary of plasma concentration-QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML. AB - PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. METHOD: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Delta) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. RESULTS: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or DeltaQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. CONCLUSION: The concentration-QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development. PMID- 29392452 TI - YSA-conjugated mesoporous silica nanoparticles effectively target EphA2 overexpressing breast cancer cells. AB - PURPOSE: Neoadjuvant chemotherapy is commonly used to treat patients with locally advanced breast cancer and a common option for primary operable disease. However, systemic toxicity including cardiotoxicity and inefficient delivery are significant challenges form any chemotherapeutics. The development of targeted treatments that lower the risk of toxicity has, therefore, become an active area of research in the field of novel cancer therapeutics. Mesoporous silica nanoparticles (MSNs) have attracted significant attention as efficient drug delivery carriers, due to their high surface area and tailorable mesoporous structures. Eph receptors are the largest receptor tyrosine kinase family, which are divided into the A- and the B-type. Eph receptors play critical roles in embryonic development and human diseases including cancer. EphA2 is expressed in breast cancer cells and has roles in carcinogenesis, progression and prognosis of breast cancer. METHODS: A homing peptide with the sequence YSAYPDSVPMMSK (YSA) that binds specifically to EphA2 was used to functionalize MSN. We focus on a novel EphA2-targeted delivery MSN system for breast cancer cells. RESULTS: We show that the EphA2 receptor is differentially expressed in breast cancer cells and highly expressed in the HER2-negative breast cancer cell line MCF7. Our results suggest that EphA2-targeted MSN for doxorubicin delivery (MSN-YSA-DOX) are more effective than MSN-DOX in treating breast cancer cell lines in vitro. CONCLUSIONS: Our preliminary observations suggest that the EphA2-targeted MSN delivery system may provide a strategy for enhancing delivery of therapeutic agents to breast cancer cells expressing EphA2, and potentially reduce toxicity while enhancing therapeutic efficacy. PMID- 29392453 TI - Properties important for solid-liquid separations change during the enzymatic hydrolysis of pretreated wheat straw. AB - OBJECTIVES: The biochemical conversion of lignocellulosic biomass into renewable fuels and chemicals provides new challenges for industrial scale processes. One such process, which has received little attention, but is of great importance for efficient product recovery, is solid-liquid separations, which may occur both after pretreatment and after the enzymatic hydrolysis steps. Due to the changing nature of the solid biomass during processing, the solid-liquid separation properties of the biomass can also change. The objective of this study was to show the effect of enzymatic hydrolysis of cellulose upon the water retention properties of pretreated biomass over the course of the hydrolysis reaction. RESULTS: Water retention value measurements, coupled with 1H NMR T2 relaxometry data, showed an increase in water retention and constraint of water by the biomass with increasing levels of cellulose hydrolysis. This correlated with an increase in the fines fraction and a decrease in particle size, suggesting that structural decomposition rather than changes in chemical composition was the most dominant characteristic. CONCLUSIONS: With increased water retained by the insoluble fraction as cellulose hydrolysis proceeds, it may prove more difficult to efficiently separate hydrolysis residues from the liquid fraction with improved hydrolysis. PMID- 29392454 TI - Engineering phytosterol transport system in Mycobacterium sp. strain MS136 enhances production of 9alpha-hydroxy-4-androstene-3,17-dione. AB - OBJECTIVES: To enhance the yield of 9alpha-hydroxy-4-androstene-3,17-dione (9 OHAD) from phytosterols, a phytosterol transport system was constructed in Mycobacterium sp. strain MS136. RESULTS: 9-OHAD can be produced via the controlled degradation of phytosterols by mycobacteria. This involves an active transport process that requires trans-membrane proteins and ATP. A phytosterol transport system from Mycobacterium tuberculosis H37Rv was constructed in Mycobacterium sp. strain MS136 by co-expression of an energy-related gene, mceG, and two integrated membrane protein genes, yrbE4A and yrbE4B. The resultant of the Mycobacterium sp. strain MS136-GAB gave 5.7 g 9-OHAD l-1, which was a 20% increase over 4.7 g l-1 by the wild-type strain. The yield of 9-OHAD was increased to 6.0 g l-1 by optimization of fermentation conditions, when 13 g phytosterols l-1 were fermented for 84 h in 30 ml biotransformation medium in shake flasks. CONCLUSIONS: Phytosterol transport system plays an active role in the uptake and transport of sterols, cloning of the system improved the mass transfer of phytosterols and increased the production of 9-OHAD. PMID- 29392455 TI - The MOVES (Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey): cross-cultural evaluation of the French version and additional psychometric assessment. AB - INTRODUCTION: The Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES) is a self-report scale suggested as a severity scale for tics and related sensory phenomena observed in Gilles de la Tourette syndrome (GTS) and recommended as a screening instrument by the Committee on Rating Scale Development of the International Parkinson's Disease and Movement Disorder Society. OBJECTIVES: To cross-culturally adapt a French version of the MOVES and to evaluate its psychometric properties. METHODS: After the cross-cultural adaptation of the MOVES, we assessed its psychometric properties in 53 patients aged 12-16 years and in 54 patients aged 16 years and above: reliability and construct validity (relationships between items and scales), internal consistency and concurrent validity with the Yale Global Tic Severity Scale (YGTSS) and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) or the auto-Yale-Brown scale. RESULTS: The results showed very good acceptability with response rates greater than 92%, good internal consistency (Cronbach's alpha ranging from 0.62 and 0.89) and good test-retest reliability (ICCs ranging from 0.59 to 0.91). Concurrent validity with the YGTSS, CY-BOCS and auto-Yale-Brown scales showed strong expected correlations. The cut-off points tested for diagnostic performance gave satisfactory values of sensitivity, specificity, and positive and negative predictive values. DISCUSSION: Our study provides evidence of the good psychometric properties of the French version of the MOVES. The cross cultural adaptation of this specific instrument will allow investigators to include French-speaking persons with GTS aged 12 years and over in national and international collaboration research projects. PMID- 29392456 TI - Distinct manifestation of cognitive deficits associate with different resting state network disruptions in non-demented patients with Parkinson's disease. AB - Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, but a relationship between the heterogeneity of cognitive deficits and resting-state network (RSN) changes remains elusive. In this study, we examined five sub-domain scores according to Addenbrooke's Cognitive Examination-Revised (ACE-R) for the cognitive evaluation and classification of 72 non-demented patients with PD. Twenty-eight patients were classified as PD with normal cognition (PD-NC). The remaining 44 were subdivided into the following 2 groups using a hierarchical cluster analysis: 20 with a predominant decrease in memory (PD with amnestic cognitive deficits: PD-A) and 24 with good memory who exhibited a decrease in other sub-domains (PD with non-amnestic cognitive deficits: PD-NA). We used an independent component analysis of RS-fMRI data to investigate the inter-group differences of RSN. Compared to the controls, the PD-A showed lower FC within the ventral default mode network (vDMN) and the visuospatial network. On the other hand, the PD-NA showed lower FC within the visual networks and the cerebellum brainstem network. Significant differences in the FC within the vDMN and cerebellum-brainstem network were observed between the PD-A and PD-NA, which provided a good discrimination between PD-A and PD-NA using a support vector machine. Distinct patterns of cognitive deficits correspond to different RSN changes. PMID- 29392457 TI - The long-term impact of early treatment of multiple sclerosis on the risk of disability pension. AB - OBJECTIVE: The objective of this retrospective, observational study was to estimate the long-term impact of early treatment of multiple sclerosis (MS) on the risk of disability pension. METHODS: Our cohort comprised patients with MS in Sweden, identified in a nationwide disease-specific register (the Swedish Multiple Sclerosis Registry), who started treatment with a disease-modifying drug (DMD) between January 1, 2002, and December 31, 2012. We analyzed the association between time from onset of MS to treatment initiation and full-time disability pension using survival analysis. RESULTS: Our sample comprised 2477 patients. Unadjusted Kaplan-Meier failure functions showed that patients who started treatment within six months after onset had a lower risk of disability pension across follow-up compared with patients initiating therapy after 12 months. Outcomes from the univariate Cox proportional hazards model showed that time from onset to treatment initiation (in years) was significantly associated with disability pension (HR 1.03, p < 0.001). Outcomes from the multivariable Cox proportional hazards model showed that patients who started treatment within 6 months after onset had, on average, a 36% lower risk (HR 0.74, p = 0.010) of full time disability pension during follow-up compared with patients starting treatment after 18 months when controlling for age, sex, marital status, university education, and prevalent comorbidities. CONCLUSIONS: We show that early treatment with DMDs of MS is associated with a significantly reduced risk of disability pension. Our findings highlight the potential long-term benefits of early treatment of MS and should be helpful to inform ongoing discussion on the optimum medical management of the disease. PMID- 29392458 TI - Cerebrovascular events in Takayasu arteritis: a multicenter case-controlled study. AB - OBJECTIVES: Takayasu arteritis (TA) is a giant cell arteritis usually affecting young women and characterized by inflammatory and ischemic signs of large vessel involvement, including extracranial cerebral arteries. The impact of stroke on TA prognosis has not been well evaluated. METHODS: We performed a retrospective multicenter review of patients with definite TA who experienced at least one stroke and compared the findings to 17 matched patients with TA diagnosis without neurological involvement. RESULTS: Seventeen patients (15 women, median age at stroke diagnosis 44 years) receiving a diagnosis of TA and stroke between 2002 and 2016 in our institution were included, from a cohort of 126 patients suffering from TA (13.5%). At diagnosis, patients from both groups had comparable cardiovascular risk factors. The first cerebrovascular event was ischemic stroke (n = 15) or transient ischemic attack (n = 2). In eight patients, stroke occurred after the TA diagnosis was made. In four patients, stroke occurred after carotid surgery. At the end of follow-up, 59% of patients had a neurological impairment, 35% had a recurrence of stroke, and 24% suffered from epilepsy. CONCLUSIONS: Stroke is a major cause of disability in TA patients. Internal carotid surgery may be performed with caution because of the risk of stroke after the procedure. PMID- 29392459 TI - Patient-centered integrated healthcare improves quality of life in Parkinson's disease patients: a randomized controlled trial. AB - INTRODUCTION: Improving quality of life (QoL) is a key issue when dealing with Parkinson's disease (PD). Integrative care shows potential to achieve improvements in QoL. Here, we analyzed whether a community-based, open-label, integrated approach improves QoL in PD patients. METHODS: PD patients were screened for eligibility and evaluated by a university-based PD specialist, a PD nurse, and a general neurologist at a local practice. Patients were randomly assigned to a control group (CG), receiving standard German neurological treatment including a baseline assessment and follow-up visit at 6 months, or an interventional group (IG) who received an individually tailored therapy plan and additional home visits. Patients and investigators were not blinded for either intervention. Primary outcome analysis compared the differential change of PDQ-39 from baseline to 6-month follow-up between CG and IG. Between-group changes in mood, motor/non-motor functioning, and cognition were secondary outcomes. RESULTS: 300 patients were included and randomized equally to IG and CG. 132 IG and 125 CG patients had a valid PDQ-39 at follow-up and qualified for the modified ITT analysis. PDQ-39 improved more in IG compared to CG [2.2 points (95% CI - 4.4 to 0.1); p = 0.044]. Likewise, change scores between IG and CG favored IG for UPDRS III (p < 0.001, mean change 3.3, 95% CI - 4.9 to - 1.7) and PD-NMS (p < 0.001, mean change 11.3, 95% CI - 17.1 to - 5.5). CONCLUSIONS: Data show that an integrated approach, compared to regular PD care, improves QoL as well as motor and nonmotor PD symptoms over 6 months. Future studies need to address the cost-benefit ratio and whether positive effects can be maintained beyond intervention. PMID- 29392460 TI - Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review. AB - BACKGROUND AND AIMS: Due to common pathophysiological findings of Alzheimer's disease (AD) with diabetes mellitus (DM), insulin has been suggested as a possible treatment of AD or mild cognitive impairment (MCI). A safe alternative of IV insulin is intranasal (IN) insulin. The aim of this systematic review is to investigate the effects of IN insulin on cognitive function of patients with either AD or MCI. METHODS: A literature search of the electronic databases Medline, Scopus and CENTRAL was performed to identify RCTs investigating the effect of IN insulin administration on cognitive tasks, in patients with AD or MCI. RESULTS: Seven studies (293 patients) met our inclusion criteria. Most studies showed that verbal memory and especially story recall was improved after IN insulin administration. Sometimes the effect was restricted for apoe4 (-) patients. Intranasal insulin did not affect other cognitive functions. However, there were some positive results in functional status and daily activity. Data suggested that different insulin types and doses may have different effects on different apoe4 groups. In addition, the effects of treatment on Alphabeta levels differed from study to study. Finally, IN insulin resulted in minor adverse effects. CONCLUSIONS: Intranasal insulin improved story recall performance of apoe4 (-) patients with AD or MCI. Other cognitive functions were not affected, but there were some positive results in functional status and daily activity. Since IN insulin is a safe intervention, future studies should be conducted with larger doses and after proper selection of patients and insulin types. PMID- 29392462 TI - A systematic review of economic evaluations on stent-retriever thrombectomy for acute ischemic stroke. AB - BACKGROUND: Our objective was to review economic evaluations on stent-retriever thrombectomy (SRT) added/not added to intravenous (IV) tissue plasminogen activator (t-PA) in acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). METHODS: We conducted a systematic review using several electronic databases and searching for studies published from January 2009 to September 2017. INCLUSION CRITERIA: any publication type reporting the incremental cost effectiveness ratio of SRT in people with AIS secondary to LVO. Quality assessment was undertaken with the CHEERS and the Philips' checklists. RESULTS: Eight original articles (four from North America/four from Europe) were included; of these, seven were model-based cost-effectiveness studies and one was a study conducted alongside a clinical trial. The perspective was the healthcare system in seven studies, and societal in one. The time horizon was lifetime (minimum 20 years) in all but two studies where it was 1 and 5 years. Overall, studies were rated of good quality (mean score 79%; range 70-90). Data sources, effectiveness outcomes and other input parameters were heterogeneous across studies. In three studies, SRT was dominant (less expensive and more effective). In five studies, SRT was more expensive and generated more quality-adjusted life years but had a high probability (79-100%) to be cost-effective at conventional thresholds. CONCLUSION: This review shows that SRT added/not added to IV t-PA is likely to be cost-effective or even dominant, which is consistent with the opinion from several Health Technology Assessment bodies recommending SRT. However, our findings are supported by primary studies with substantial methodological heterogeneity. PMID- 29392461 TI - Phenotypic differences of amyotrophic lateral sclerosis (ALS) in China and Germany. AB - OBJECTIVE: The aim of this study is to explore phenotypical differences of amyotrophic lateral sclerosis (ALS) between two cohorts from Germany and China. METHODS: Registry-based studies of ALS were conducted in South-West Germany from 2010 to 2014 and an ALS clinic in Beijing from 2013 to 2016, respectively. Demographic and clinical features of 663 German and 276 Chinese ALS patients were collected and compared. RESULTS: Mean age-at-onset was higher in German than in Chinese ALS patients [66.6 years (95% CI 65.7, 67.5) vs. 53.2 years (95% CI 52.0, 54.5)]. Age distribution of ALS patients peaked around 70-74 years in Germany and 50-54 years in China. Bulbar onset was more prevalent among German than among Chinese patients (35.9 vs. 22.8%). Diagnostic delay was higher in the Chinese than in the German study sample (12 vs. 5 months). Cognitive deficits were more pronounced in the Chinese cohort. Both cohorts differed in smoking habits, prevalence of diabetes and in body mass index (BMI). CONCLUSIONS: The apparent discrepancies between German and Chinese ALS patients (age at onset, gender distribution, bulbar forms, cognitive dysfunction, risk factors) reveal a quite different clinical phenotype in China, maybe due to socioeconomic status, environmental factors or genetic background. The observed differences in phenotype need to be pursued by further epidemiological studies on environmental and genetic risk factors. PMID- 29392463 TI - Insular multiple sclerosis lesions are associated with erectile dysfunction. AB - Erectile function (EF) is frequently compromised in men with multiple sclerosis (MS). Functional neuroimaging in healthy men identified a network of brain areas, such as the insula, visual and somatosensory association areas, cingulate gyrus, prefrontal cortex, as well as subcortical regions, contributing to EF. This study intended to determine associations between EF deterioration during MS and cerebral MS-associated lesion sites. In 31 men with MS (mean age 38.2 +/- 11.2 years), we evaluated MS-related EF deterioration by comparing scores of the 5 item International Index of Erectile Function-5 questionnaire (IIEF5) at the time of study and retrospectively, 3 months prior to MS diagnosis, by calculating score differences as DeltaIIEF5 (DeltaIIEF5 score < 0 indicated EF deterioration). To assess the impact of confounding factors of EF, patient age, disease duration, disease severity, depressiveness, bladder and bowel symptoms, and total cerebral MS lesion volume were correlated with DeltaIIEF5 scores (Spearman rank correlation) and compared between patients with and without EF deterioration (t tests or Mann-Whitney U test). MS lesions were assessed on T2 weighted magnetic resonance imaging (MRI; 1.5 or 3 T). We determined the lesion overlap (prevalence of identical lesion sites among patients), subtracted lesion overlaps in patients without EF deterioration from overlaps in patients with EF deterioration, and compared DeltaIIEF5 scores voxel-wise between patients with and without lesions in a given voxel (t test; significance: p < 0.05). In 14 patients (45.2%), DeltaIIEF5 scores indicated EF deterioration. DeltaIIEF5 scores were not associated with age (rho = 0.06; p = 0.74), disease duration (rho = 0.26; p = 0.15), disease severity (rho = - 0.19; p = 0.31), depressiveness (rho = 0.07; p = 0.72), bladder symptoms (rho = - 0.11; p = 0.57), bowel symptoms (rho = 0.17; p = 0.37), and total lesion volume (rho = - 0.13; p = 0.47). The voxel-wise analysis showed associations between EF deterioration and MS lesions primarily in the bilateral, and predominantly left juxtacortical insular region. In conclusion, MS lesions particularly in the left insular region, which is activated with sexual arousal, contribute to erectile dysfunction. PMID- 29392465 TI - Molecular characterization of hard tick Haemaphysalis longicornis from China by sequences of the internal transcribed spacers of ribosomal DNA. AB - In the present study, the entire first and second internal transcribed spacer (ITS-1 and ITS-2) regions of nuclear ribosomal DNA (rDNA) of Haemaphysalis longicornis from China were amplified by polymerase chain reaction. The 45 representative amplicons were sequenced, and sequence variation in the ITS was examined. The ITS sequences of H. longicornis were 3644 bp in size, including the part of 18S rDNA, 28S rDNA sequences and the complete ITS-1, 5.8S rDNA and ITS-2 sequences. Sequence analysis revealed that the ITS-1, 5.8S rDNA and ITS-2 of this hard tick were 1582, 152, and 1610 bp in size, respectively. The intra-specific sequence variations of ITS-1 and ITS-2 within H. longicornis were 0-2 and 0-2.2%; however, the inter-specific sequence differences among members of the genus Haemaphysalis were significantly higher, being 35.1-55.2 and 37-52% for ITS-1 and ITS-2, respectively. The molecular approach employed in this study provides the foundation for further studies of the genetic variation of H. longicornis from different hosts and geographical origins in China. PMID- 29392466 TI - Spermatozoa production in male Varroa destructor and its impact on reproduction in worker brood of Apis mellifera. AB - Reproduction in Varroa destructor exclusively takes place within the sealed honey bee brood cell and is, therefore, limited by the duration of the postcapping period. Oogenesis, ontogenetic development and mating must be optimized to ensure the production of as many mated daughter mites as possible. One adult male mite has to mate with up to five sister mites and transfer 30-40 spermatozoa to each female. We analyzed the production and transfer of male spermatozoa during a reproductive cycle by counting all spermatozoa in the genital tracts of the male and daughter mites in 80 worker brood cells at defined times after cell capping. We could show that spermatozoa production in male mites is an ongoing process throughout their adult lifetime starting after the adult molt. The spermatozoa are transferred to the females in an early non-capacitated stage and require further maturation within the female's genital tract. Our study points out that a Varroa male has at any time in the brood cell enough spermatozoa to inseminate all daughter mites but does not waste energy in producing a big surplus. In total one male produced, on average, 125 spermatozoa during a reproductive cycle in worker brood which is sufficient for successful matings with at least three daughter mites. Spermiogenesis in Varroa males represents therefore a further adaptation to the limited time available for reproduction. PMID- 29392464 TI - Primary progressive aphasia: a clinical approach. AB - The primary progressive aphasias are a heterogeneous group of focal 'language led' dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap'. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers. PMID- 29392467 TI - The introduction and subsequent extinction of the camel tick Hyalomma (Euhyalomma) dromedarii (Acari, Ixodidae) in Australia, with a review of the introduction of foreign ticks to Australia. AB - Historically, several tick taxonomists have reported Hyalomma aegyptium within Australia due to misidentifications. This has resulted in confusion relating to the occurrence of the genus Hyalomma within Australia. Based on the recent discovery of museum specimens of Hyalomma dromedarii, misidentified as H. aegyptium, the historical occurrence of H. dromedarii is reported for the first time within Australia, along with its apparent subsequent extinction. The introduction and naturalisation of foreign tick species into Australia is also reviewed. PMID- 29392468 TI - Neutrophils: multitasking first responders of immunity and tissue homeostasis. PMID- 29392469 TI - Endoscopic and surgical management of nonampullary duodenal neoplasms. AB - BACKGROUND: Sporadic nonampullary duodenal neoplasms (SNADN) can have malignant potential for which endoscopic and surgical resections are offered. We report combined gastroenterologic and surgical experience for treatment of SNADN, including endoscopic mucosal resection (EMR) and pancreas-preserving partial duodenectomy (PPPD). METHODS: We retrospectively reviewed 121 consecutive patients, who underwent 30 PPPDs and 91 EMRs for mucosal and submucosal SNADN. Decision to undergo EMR or surgical resection was based on expert endoscopist and surgeon discretion including multidisciplinary tumor board review. Main outcomes were recurrence rate of neoplasia and adverse events requiring hospital admission or prolonged care. EMRs were performed with submucosal lifting followed by snare resection. PPPD included total duodenectomy, supra-ampullary PPPD for neoplasms proximal to the ampulla, and infra-ampullary PPPD for lesions distal to the ampulla. Follow-up data were available for 65% of EMR and 73% of surgical patients. RESULTS: Surgically resected neoplasia was larger with more advanced neoplasia and submucosal lesions. En bloc resection was achieved in all surgical resections and in 53% of EMRs. Post-EMR, mucosal and submucosal neoplasia recurred in 32 and 0%, respectively, including five neoplasms (26%) after an initial negative esophagogastroduodenoscopy. All recurrences were treated endoscopically. Complications occurred in 14 endoscopically and eight surgically treated patients, none requiring surgical intervention. CONCLUSIONS: Post-EMR patients had higher recurrence of mucosal neoplasia, whereas submucosal neoplasms, mainly carcinoid, did not recur. Polyp size and positive resection margin were not associated with neoplasia recurrence. Patients with SNADN could benefit from a multidisciplinary approach to stratify the optimal treatment based on local expertise. PMID- 29392470 TI - Heart failure with preserved vs reduced ejection fraction following cardiac rehabilitation: impact of endothelial function. AB - There is no proven therapy for heart failure with preserved ejection fraction (HFpEF). Research has shown beneficial responses to cardiac rehabilitation (CR) among HF patients. To date, there are no reports comparing those responses between patients with HFpEF and those with reduced ejection fraction (HFrEF). The purpose of this study was to compare responses to CR in patients with HFpEF versus those with HFrEF. We included 78 consecutive patients (mean age 69 +/- 15 years; 80% male) with HF in our CR unit who underwent cardiopulmonary exercise testing and brachial artery flow-mediated dilation (FMD) testing pre- and 5 months post-CR. Patients were judged as HFpEF (n = 40) or HFrEF (n = 38) using a left ventricular ejection fraction (LVEF) cut-off of 50%, and endothelial dysfunction was defined as FMD <= 5.0%. Following 155 +/- 11 days and 44 +/- 8 sessions, peak oxygen uptake ([Formula: see text]) and plasma B-type natriuretic peptide concentrations improved significantly in both groups. The percentage change in peak [Formula: see text] of HFrEF patients was significantly greater than compared with the HFpEF patients (P < 0.01). To further investigate whether a combination of LVEF and FMD values predicts the effect of CR, we divided patients into four groups according to LVEF of 50% and FMD of 50%. Post hoc analysis showed a significant difference between HFrEF patients without endothelial dysfunction and HFpEF patients with endothelial dysfunction (P = 0.01). In conclusion, although CR improves prognosis in HF patients, a larger effect can be expected in HFrEF patients than in HFpEF patients, and endothelial function may enhance the effect. PMID- 29392471 TI - GRASE Revisited: breath-hold three-dimensional (3D) magnetic resonance cholangiopancreatography using a Gradient and Spin Echo (GRASE) technique at 3T. AB - OBJECTIVE: To evaluate the clinical feasibility and image quality of breath-hold (BH) three-dimensional (3D) magnetic resonance cholangiopancreatography (MRCP) using a gradient and spin-echo (GRASE) technique compared to the conventional 3D respiratory-triggered (RT)-MRCP using a turbo spin-echo (TSE) sequence at 3 T. METHODS: Sixty-six patients underwent both 3D RT-TSE-MRCP and 3D BH-GRASE-MRCP at 3 T. Three radiologists independently reviewed the visualisation of biliary and pancreatic ducts, image blurring, and overall image quality of the two data sets using four- or five-point scales. The numbers of scans with non-diagnostic or poor image quality were compared between the two scans. RESULTS: The 3D BH-GRASE MRCP had a significantly better image quality (3.69 +/- 0.77 vs. 3.30 +/- 1.18, p = 0.005) and less image blurring (3.23 +/- 0.94 vs. 3.65 +/- 0.57, p = 0.0003) than the 3D RT-TSE-MRCP. In detail, 3D BH-GRASE-MRCP better depicted the common bile duct, cystic duct, and bilateral first intrahepatic duct (all ps < 0.05). The number of scans with non-diagnostic or poor image quality significantly decreased with 3D BH-GRASE-MRCP compared with 3D RT-TSE-MRCP [19.7% (13/66) vs. 1.5% (1/66), p = 0.002]. CONCLUSION: The 3D BH-GRASE-MRCP provided better image quality and a reduced number of non-diagnostic images compared to 3D RT-TSE-MRCP. KEY POINTS: * The GRASE technique enabled 3D MRCP acquisition within a single breath-hold. * The short acquisition time of 3D BH-GRASE-MRCP significantly reduced image blurring. * The 3D BH-GRASE-MRCP had a better image quality than 3D RT-TSE-MRCP. * The number of non-diagnostic scans was reduced with 3D BH-GRASE MRCP. PMID- 29392472 TI - Single-dose local administration of parathyroid hormone (1-34, PTH) with beta tricalcium phosphate/collagen (beta-TCP/COL) enhances bone defect healing in ovariectomized rats. AB - Parathyroid hormone (1-34, PTH) combined beta-tricalcium phosphate (beta-TCP) achieves stable bone regeneration without cell transplantation in previous studies. Recently, with the development of tissue engineering slow release technology, PTH used locally to promote bone defect healing become possible. This study by virtue of collagen with a combination of drugs and has a slow release properties, and investigated bone regeneration by beta-TCP/collagen (beta TCP/COL) with the single local administration of PTH. After the creation of a rodent critical-sized femoral metaphyseal bone defect, beta-TCP/COL was prepared by mixing sieved granules of beta-TCP and atelocollagen for medical use, then beta-TCP/COL with dripped PTH solution (1.0 ug) was implanted into the defect of OVX rats until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that single-dose local administration of PTH combined local usage of beta-TCP/COL can increase the healing of defects in OVX rats. Furthermore, treatments with single-dose local administration of PTH and beta TCP/COL showed a stronger effect on accelerating the local bone formation than beta-TCP/COL used alone. The results from our study demonstrate that combination of single-dose local administration of PTH and beta-TCP/COL had an additive effect on local bone formation in osteoporosis rats. PMID- 29392474 TI - Using Rasch Analysis to Evaluate the Reliability and Validity of the Swallowing Quality of Life Questionnaire: An Item Response Theory Approach. AB - The Swallowing Quality of Life questionnaire (SWAL-QOL) is widely used clinically and in research to evaluate quality of life related to swallowing difficulties. It has been described as a valid and reliable tool, but was developed and tested using classic test theory. This study describes the reliability and validity of the SWAL-QOL using item response theory (IRT; Rasch analysis). SWAL-QOL data were gathered from 507 participants at risk of oropharyngeal dysphagia (OD) across four European countries. OD was confirmed in 75.7% of participants via videofluoroscopy and/or fiberoptic endoscopic evaluation, or a clinical diagnosis based on meeting selected criteria. Patients with esophageal dysphagia were excluded. Data were analysed using Rasch analysis. Item and person reliability was good for all the items combined. However, person reliability was poor for 8 subscales and item reliability was poor for one subscale. Eight subscales exhibited poor person separation and two exhibited poor item separation. Overall item and person fit statistics were acceptable. However, at an individual item fit level results indicated unpredictable item responses for 28 items, and item redundancy for 10 items. The item-person dimensionality map confirmed these findings. Results from the overall Rasch model fit and Principal Component Analysis were suggestive of a second dimension. For all the items combined, none of the item categories were 'category', 'threshold' or 'step' disordered; however, all subscales demonstrated category disordered functioning. Findings suggest an urgent need to further investigate the underlying structure of the SWAL-QOL and its psychometric characteristics using IRT. PMID- 29392475 TI - Inclusion of Whole Flour from Latin-American Crops into Bread Formulations as Substitute of Wheat Delays Glucose Release and Uptake. AB - Bakery formulations limiting glucose availability for uptake without compromising product quality are required. Herein, bread formulations containing whole flour from Amaranthus hypochondriacus (AB), Chenopodium quinoa (QB), Salvia hispanica L (ChB) or wheat (WWB) were compared to white bread (WB) for glycaemic index (GI) in fasted animals. The hepatic expression (mRNA) of PPAR-gamma receptor as key regulator in substrate fractionation towards energy expenditure was monitored. GIs were associated to fluxes of glucose release (FGluc) and metabolic response (MTT assay) of HepG2 cells. ChB (19.7%) and AB (13.5%) decreased GI to a higher extent than QB (2.7%), but all increased expression of PPARgamma in relation to WB. FGluc (AB> > ChB, WWB, WB > QB) showed a reciprocal relationship with the area under curve (AUC) in vivo, and decreased MTT conversion values (WB > WWB, ChB, AB, QB) by HepG2 cells. Thus, inclusion of latin-american crops (LAcs) reducing GI, without compromising bread quality, could help preventing metabolic diseases. PMID- 29392473 TI - Mammalian transposable elements and their impacts on genome evolution. AB - Transposable elements (TEs) are genetic elements with the ability to mobilize and replicate themselves in a genome. Mammalian genomes are dominated by TEs, which can reach copy numbers in the hundreds of thousands. As a result, TEs have had significant impacts on mammalian evolution. Here we summarize the current understanding of TE content in mammal genomes and find that, with a few exceptions, most fall within a predictable range of observations. First, one third to one half of the genome is derived from TEs. Second, most mammalian genomes are dominated by LINE and SINE retrotransposons, more limited LTR retrotransposons, and minimal DNA transposon accumulation. Third, most mammal genome contains at least one family of actively accumulating retrotransposon. Finally, horizontal transfer of TEs among lineages is rare. TE exaptation events are being recognized with increasing frequency. Despite these beneficial aspects of TE content and activity, the majority of TE insertions are neutral or deleterious. To limit the deleterious effects of TE proliferation, the genome has evolved several defense mechanisms that act at the epigenetic, transcriptional, and post-transcriptional levels. The interaction between TEs and these defense mechanisms has led to an evolutionary arms race where TEs are suppressed, evolve to escape suppression, then are suppressed again as the defense mechanisms undergo compensatory change. The result is complex and constantly evolving interactions between TEs and host genomes. PMID- 29392476 TI - UMP kinase activity is involved in proper chloroplast development in rice. AB - Isolation of leaf-color mutants is important in understanding the mechanisms of chloroplast biogenesis and development. In this study, we identified and characterized a rice (Oryza sativa) mutant, yellow leaf 2 (yl2), exhibiting pale yellow leaves with a few longitudinal white stripes at the early seedling stage then gradually turning yellow. Genetic analyses revealed that YL2 encodes a thylakoid membrane-localized protein with significant sequence similarity to UMP kinase proteins in prokaryotes and eukaryotes. Prokaryotic UMP kinase activity was subsequently confirmed, with YL2 deficiency causing a significant reduction in chlorophyll accumulation and photochemical efficiency. Moreover, YL2 is also light dependent and preferentially expressed in green tissues. Chloroplast development was abnormal in the yl2 mutant, possibly due to reduced accumulation of thylakoid membranes and a lack of normal stroma lamellae. 2D Blue-Native SDS PAGE and immunoblot analyses revealed a reduction in several subunits of photosynthetic complexes, in particular, the AtpB subunit of ATP synthase, while mRNA levels of corresponding genes were unchanged or increased compared with the wild type. In addition, we observed a significant decrease (ca. 36.3%) in cpATPase activity in the yl2 mutant compared with the wild type. Taken together, our results suggest that UMP kinase activity plays an essential role in chloroplast development and regulating cpATPase biogenesis in rice. PMID- 29392477 TI - Antihypertensive-related adverse drug reactions among older hospitalized adults. AB - Background Antihypertensive medications are commonly used for a wide range of indications, yet it is unknown to what extent older adults are at risk of adverse drug reactions (ADRs) associated with their antihypertensive medication use. Objective The aim of this study was to determine the prevalence and characteristics of antihypertensive-related ADRs on hospital admission. Setting Metropolitan teaching hospital in Sydney, Australia. Method A retrospective cross sectional audit of 503 older patients (>= 65 years) admitted to hospital was conducted. Potential ADRS were identified from the medical record. Two independent clinical pharmacists reviewed each potential ADR using validated tools for causality, severity, preventability and contribution to hospitalization. Characteristics associated with an increased ADR risk among antihypertensive users were identified via logistic regression. Main outcome measure Antihypertensive related ADRs. Results Antihypertensives were used on admission by 68% of the cohort and the prevalence of 'definite/probable' antihypertensive-related ADRs among antihypertensive users was 16.4%. Antihypertensive medications were associated with a threefold ADR risk (OR = 3.09, 95% CI 1.85-5.16). Angiotensin II Receptor Blockers (ARB), impaired renal function, recent medication changes and previous history of allergy or ADR were all associated with an increased risk of experiencing an ADR. Conclusions ADRS associated with antihypertensive medicines were relatively common among older adults admitted to hospital. Increased awareness of those older persons who are most at risk of experiencing an antihypertensive-related ADR in the clinical setting may lead to early detection and minimization of ADR associated harms. PMID- 29392478 TI - The TEACHH model to predict life expectancy in patients presenting for palliative spine radiotherapy: external validation and comparison with alternate models. AB - INTRODUCTION: The TEACHH score was developed to identify patients with predicted short (< 3 months) and long (> 1 year) life expectancy. We aimed to validate this model in an independent group of patients presenting for palliative spine radiotherapy and to compare it to alternate prognostic models. METHODS: We retrospectively reviewed charts of 195 consecutive patients referred for palliative spine radiotherapy. Patients were grouped according to the number of risk factors from the TEACHH model, Chow model, and Oswestry Risk Index. RESULTS: One hundred and eighty patients with a median age of 65 years were included. Follow-up was 5.8 months in all patients and 31.8 months in living patients. For the TEACHH model, patients in groups 1, 2, and 3 had a median (95% CI) overall survival (OS) of 22.3 (15.7-36.1), 4.9 (3.8-6.6), and 1.5 (0.8-5.4) months, respectively. Wilcoxon pairwise comparisons showed statistically different survival between groups 1 and 2, and 1 and 3. In the Chow model, patients in groups 1, 2, and 3 had a median (95% CI) OS of 16.1 (10.0-22.3), 5.9 (3.8-9.2), and 1.9 (1.2-2.5) months, respectively. There was a significant difference between all groups. The Oswestry Risk Index identified five prognostic groups with median OS (95% CI) ranging from 22.2 (12.9-30.2) to 2.1 (0.8-4.0) months. Only group 1 was statistically different from the others. Although the effect of age was small, the TEACHH model performed best with the inclusion of all parameters. CONCLUSIONS: The TEACHH model is useful to identify patients with spinal metastases with predicted short, intermediate, and long LE. Its prognostic ability is similar to the Chow model. PMID- 29392479 TI - Assessment of content validity for patient-reported outcome measures used in patients with non-muscle invasive bladder cancer: a systematic review. AB - OBJECTIVE: Non-muscle invasive bladder cancer (NMIBC) is a chronic condition requiring ongoing treatment and endoscopic examinations that are frequent and can be life-long. To ensure the comprehensive assessment of the benefits and harms of treatments for NMIBC, the impact on important and relevant patient-reported outcomes (PROs) should be determined. We systematically reviewed the NMIBC PRO literature to determine the suitability of available PRO measures (PROMs) for use in evaluating patient outcomes in NMIBC research. METHODS: We searched six electronic databases, reference lists, and key authors. Two reviewers independently applied inclusion and quality criteria and extracted findings. PROM domains, item content, and content coverage and relevance were determined for identified PROMs. Content validity was assessed against an empirically derived NMIBC-specific conceptual framework that includes 11 PRO domains and 19 sub domains. RESULTS: Seventeen studies assessed PROs related to NMIBC and treatment impact. From these studies, 11 PROMs were identified, including three generic, three cancer-specific, and five symptom-specific. None of the PROMs cover all PRO domains important in NMIBC as assessed against our conceptual framework. The EORTC QLQ-C30 plus the NMIBC24 module was best aligned to the conceptual model, but failed to represent six outcomes important to NMIBC patients. CONCLUSIONS: Currently, some outcomes important in NMIBC are inadequately covered by generic and cancer-specific measures despite similar conceptual models. This review identified gaps in the literature regarding assessment of symptoms and other PROs considered important by NMIBC patients. Careful consideration of PROM item content is required when selecting outcome measures for use in future NMIBC clinical trials to ensure that appropriate measures are used to assess outcomes that matter to patients. PMID- 29392480 TI - Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients. AB - PURPOSE: Obtaining qualitative data directly from the patient perspective enhances the content validity of patient-reported outcome (PRO) instruments. The objective of this qualitative study was to evaluate the content validity of the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) and its usability on an electronic device. METHODS: A cross-sectional methodological study, using a qualitative approach, was conducted among patients recruited from four clinical sites. The primary target population included patients with pleural mesothelioma; data were also collected from patients with peritoneal mesothelioma on an exploratory basis. Semi-structured interviews were conducted consisting of concept elicitation, cognitive interviewing, and evaluation of electronic patient reported outcome (ePRO) usability. RESULTS: Participants (n = 21) were interviewed in person (n = 9) or by telephone (n = 12); 71% were male with a mean age of 69 years (SD = 14). The most common signs and symptoms experienced by participants with pleural mesothelioma (n = 18) were shortness of breath, fluid build-up, pain, fatigue, coughing, and appetite loss. The most commonly described symptoms for those with peritoneal mesothelioma (n = 4) were bloating, changes in appetite, fatigue, fluid build-up, shortness of breath, and pain. Participants with pleural mesothelioma commonly described symptoms assessed by the LCSS-Meso in language consistent with the questionnaire and a majority understood and easily completed each of the items. The ePRO version was easy to use, and there was no evidence that the electronic formatting changed the way participants responded to the questions. CONCLUSIONS: Results support the content validity of the LCSS-Meso and the usability of the electronic format for use in assessing symptoms among patients with pleural mesothelioma. PMID- 29392481 TI - Health-related quality of life and pelvic floor dysfunction in advanced-stage ovarian cancer survivors: associations with objective activity behaviors and physiological characteristics. AB - PURPOSE: Little is known about the relationship between health-related quality of life (HRQoL), pelvic floor dysfunction (PFD), and modifiable lifestyle and physiological factors for ovarian cancer survivors (OCS). The primary aim of the study was to compare post-treatment advanced-stage OCS with age-matched controls on measures of HRQoL and PFD. The secondary aim was to examine associations between HRQoL, PFD, objective activity behaviors, physical function, and body composition in OCS. METHODS: Twenty advanced-stage OCS and 20 controls completed questionnaires assessing HRQoL (SF-36) and PFD (Australian Pelvic Floor Questionnaire), and underwent objective assessments of activity behavior (7-day accelerometry), physical function (400-m walk, repeated chair rise, 6-m usual pace walk, one-repetition maximum chest press, and single-leg extension), and body composition (dual-energy x-ray absorptiometry). RESULTS: Compared to controls, OCS had worse physical HRQoL (- 4.3 median difference, p = 0.013), but equivalent self-reported PFD, indicated by combined bladder, bowel, and pelvic organ prolapse symptoms (0.89 mean difference, p = 0.277). In OCS, physical HRQoL was significantly negatively associated with PFD (r = 0.468, p = 0.043). Decreased physical HRQoL and increased PFD were significantly associated with less moderate-to-vigorous physical activity in >= 10-min bouts (rho = 0.627, p = 0.003; rho = - 0.457, p = 0.049), more sedentary time (r = - 0.449, p = 0.047; r = 0.479, p = 0.038), and slower 400-m walk time (rho = - 0.565, p = 0.022; rho = 0.504, p = 0.028). CONCLUSIONS: Post-treatment advanced-stage OCS have decreased physical HRQoL, which is associated with modifiable factors such as worse PFD, less moderate-to-vigorous physical activity, more sedentary time, and decreased objective physical function. This highlights the need for ongoing supportive care and multidisciplinary interventions after first-line ovarian cancer treatment. PMID- 29392482 TI - Ixazomib-induced cutaneous necrotizing vasculitis. AB - Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life. PMID- 29392483 TI - Crossing the death threshold: experiencing multi-disciplinary end-of-life integrative oncology training. AB - OBJECTIVE: Complementary and integrative medicine (CIM) is acknowledged in more and more oncology-care centers as part of supportive and palliative cancer care. However, only limited research is available on medical training of CIM practitioners regarding end-of-life (EOL) care. In this study, we assess the impact of multi-disciplinary EOL training on cultural-diverse groups of CIM trained healthcare practitioners (HCPs) working in integrative oncology care settings in Germany and Israel. METHODS: The authors co-designed an evidence based patient-centered EOL-training curriculum incorporating palliative and CIM concepts of care. Afterwards, a 3-day course was designed for 25 HCPs working in three anthroposophic-medicine-oriented medical centers in Germany and 14 CIM trained HCPs from one oncology center in Israel. Qualitative assessment of the EOL-training impact on trainees was assessed 4-month post-intervention. Narratives were analyzed using ATLAS.ti software for systematic coding. RESULTS: Post-training narrative assessment was reported by 18 German and 14 Israeli HCPs comprising 10 physicians, 12 nurses and paramedical practitioners, and 10 CIM therapists and spiritual care-providers. Content analysis of post-training outcomes suggested participants' attitude-change regarding their professional role in EOL care as individuals and as members of a team. Participants acquired practical clinical tools to enhance EOL care and to better communicate with patients about death, implementing a patient-centered, cultural-sensitive approach. CONCLUSIONS: EOL training of CIM-trained HCPs enhances communication and palliative clinical skills. Multidisciplinary and international training settings emphasize a cross-cultural perspective and enrich the bio-psycho-social spiritual model of palliative care. PMID- 29392484 TI - Correction to: Associations Between Croatian Adolescents' Use of Sexually Explicit Material and Sexual Behavior: Does Parental Monitoring Play a Role? AB - The versions of Figures 2-4 presented in the original version of this article were incomplete. In all three figures, structural paths were omitted. The article has been updated to provide the correct figures, which are also presented here. PMID- 29392485 TI - Is Viewing Sexually Explicit Material Cheating on Your Partner? A Comparison Between the United States and Spain. AB - This cross-sectional study examined whether university students from the U.S. (n = 392) and Spain (n = 200) considered the viewing of sexually explicit material (SEM) to be tantamount to committing infidelity. Participants' ages ranged from 18 to 36 (U.S. sample) and 18 to 35 (Spain sample), respectively. At both universities, the study was made available to students via a computer program that allows recruitment and completion of the questionnaires online. It was found that the majority of U.S. and Spanish participants (73 and 77%, respectively) indicated that they did not consider viewing SEM as an act of infidelity. Also, overall, U.S. participants, those who were not currently in a relationship, and those who do not view SEM, were significantly more likely to believe that viewing SEM constituted infidelity compared to Spanish participants, those currently in a relationship, and those who view SEM. Finally, it was found that among U.S. and Spanish participants, intolerance of infidelity in general, negative attitudes toward SEM, and the proclivity for jealousy significantly correlated with believing that viewing SEM was tantamount to infidelity. For U.S. participants only, religiosity and (low) self-esteem also correlated with the belief that viewing SEM was infidelity. Implications of the findings are discussed. PMID- 29392486 TI - Validation of an Event-Level, Male Sexual Pleasure Scale (EMSEXpleasure) Among Condom-Using Men in the U.S. AB - Sexual pleasure is a key determinant of condom use. We developed and validated a male, event-level sexual pleasure scale (EMSEXpleasure) among a sample of condom using men in the U.S. in order to facilitate improved measurement of sexual pleasure. Based on an expert panel process, a 12-item scale was developed. An online sample of 169 men who have sex with men and 162 men who have sex with women were recruited. Factor analysis yielded a two-factor solution that matched domains identified a priori by the expert panel, general pleasure and condom specific pleasure, indicating internal validity of the instrument. One item was deleted from the scale due to poor validity performance. The overall EMSEXpleasure scale, and each subscale, had high (> 0.8) Cronbach's alpha coefficients, indicating internal reliability. The scale demonstrated convergent validity, with theoretically related constructs associated both with individual scale items and with scale totals. Overall relationship quality (b 3.0, 95% CI 2.0, 4.0), sexual relationship quality (b 2.9, 95% CI 2.0, 4.0), foreplay quality (b 7.5, 95% CI 2, 13), positive feelings about condoms (b 18.8, 95% CI 15, 23), and erection problems while using condoms (b - 17.9, 95% CI - 22, - 14) were associated with the EMSEXpleasure scale in expected directions. The validated EMSEXpleasure event-level scale may be advantageous for future assessments of the ephemeral experience of sexual pleasure, including clinical trials of condoms and other interventions, because it can be used immediately after sex, potentially limiting recall error. PMID- 29392487 TI - Nature-Inspired Algorithm for Training Multilayer Perceptron Networks in e-health Environments for High-Risk Pregnancy Care. AB - Nature presents an infinite source of inspiration for computational models and paradigms, in particular for researchers associated with the area known as natural computing. The simultaneous optimization of the architectures and weights of artificial neural networks (ANNs) through biologically inspired algorithms is an interesting approach for obtaining efficient networks with relatively good generalization capabilities. This methodology constitutes a concordance between a low structural complexity model and low training error rates. Currently, complexity and high error rates are the leading issues faced in the development of clinical decision support systems (CDSSs) for pregnancy care. Hence, in this paper the use of a biologically inspired technique, known as particle swarm optimization (PSO), is proposed for reducing the computational cost of the ANN based method referred to as the multilayer perceptron (MLP), without reducing its precision rate. The results show that the PSO algorithm is able to improve computational model performance, showing lower validation error rates than the conventional approach. This technique can select the best parameters and provide an efficient solution for training the MLP algorithm. The proposed nature inspired algorithm and its parameter adjustment method improve the performance and precision of CDSSs. This technique can be applied in electronic health (e health) systems as a useful tool for handling uncertainty in the decision-making process related to high-risk pregnancy. The proposed method outperformed, on average, other approaches by 26.4% in terms of precision and 14.9% in terms of the true positive ratio (TPR), and showed a reduction of 35.4% in the false positive ratio (FPR). Furthermore, this method was superior to the MLP algorithm in terms of precision and area under the receiver operating characteristic curve by 2.3 and 10.2%, respectively, when applied to the delivery outcome for pregnant women. PMID- 29392488 TI - Novel contrast mixture achieves contrast resolution of human bladder wall suitable for T1 mapping: applications in interstitial cystitis and beyond. AB - PURPOSE: Instillation of novel contrast mixture (NCM) was recently shown to improve the contrast resolution of rat bladder wall with high contrast-to-noise ratio (CNR). Here, the clinical safety and the feasibility of NCM-enhanced MRI to achieve artifact-free visualization of human bladder wall suitable for quantitative measurement of the magnetic resonance (MR) longitudinal relaxation time (T1) was assessed. METHODS: Six female subjects [two controls and two with Hunner-type interstitial cystitis IC and two with non-Hunner-type IC] consented for MRI at 3 T before and after instillation of NCM [4 mM gadobutrol and 5 mM ferumoxytol in 50 mL of sterile water for injection]. Single breath-hold fast MR acquisition in large readout bandwidth for 5-mm-thick single slice with variable flip angle was applied to minimize the motion and chemical shift artifacts in measurements of bladder wall thickness (BWT), CNR and T1 from 20 pixels. RESULTS: NCM instillation in subjects did not evoke pain or discomfort. Fourfold increase in bladder wall CNR (*p < 0.02) and pixel size of 0.35 mm with minimal influence of artifacts allowed accurate determination of bladder wall thinning ~ 0.46 mm from 50 mL NCM (*p < 0.05). Pre-contrast bladder wall T1 of 1544 +/- 34.2 ms was shortened to 860.09 +/- 13.95 ms in Hunner-type IC (*p < 0.0001) relative to only 1257.42 +/- 20.59 and 1258.16 +/- 6.16 ms in non-Hunner-type IC and controls, respectively. CONCLUSION: Findings demonstrate the safety and feasibility of NCM enhanced MRI to achieve artifact-free differential contrast and spatial resolution of human bladder wall, which is suitable for measuring BWT and pixel wise measurement of T1 in post-contrast setting. PMID- 29392489 TI - Surgical management of renal cell carcinoma with levels III and IV tumor thrombus using the " flush " technique. AB - OBJECTIVE: To determinate feasibility and results of the flush technique by hands for the surgical management of renal cell carcinoma (RCC) with levels III and IV inferior vena cava thrombus (VCT). MATERIALS AND METHODS: We conducted a retrospective study for all patients who underwent a surgical treatment for RCC with levels III and IV VCT in our department between June 2010 and July 2017. Sixteen patients were identified. RESULTS: All tumors were resected using a subcostal incision for right RCC and a chevron incision for the left RCC. Vena cava control was performed only on its subhepatic portion. After renal artery ligature, anesthesiologists were asked to generate a positive pressure in the small circulation. Subsequently, the vena cava was incised longitudinally to the orifice of the renal vein and the thrombus dissected and extracted of the upper part of the vena cava. Only once the supra-renal part of the vena cava was free of thrombus, the supra-renal portion of the vena cava could be clamped. We never had to perform neither thoracotomy nor hepatic mobilization. Therefore, support of a hepatic, vascular or cardiac surgeon was not necessary. The mean operative time was 201 min. The mean estimated blood loss was 2040 ml. No patient died during hospitalization, and mean hospitalization stay duration was 16.6 days. CONCLUSION: The flush technique allows a limitation of the dissection extent. It requires neither hepatic mobilization nor thoracotomy. This results in a decrease in the operative time and blood loss. PMID- 29392490 TI - Isolation and genomic characterization of a novel avian orthoreovirus strain in Korea, 2014. AB - In this study, we isolated a novel avian reovirus (ARV) strain, K738/14, from a broiler chicken with viral arthritis in South Korea. Genome sequence comparisons showed relatively low nucleotide identity with previously identified ARV strains. Phylogenetic analyses suggested multiple reassortment events between reovirus strain S1133 and reoviruses of Hungarian, Chinese, and US origin had occurred. In addition, recombination analyses showed evidence of intra-segmental recombination in the M2 and S2 genes. Based on our genetic analyses, multiple reassortment events, intra-segmental recombination, and accumulation of point mutations have possibly contributed to the emergence of this novel genotype of ARV, identified in Korea. PMID- 29392491 TI - Targeting of rice grassy stunt virus pc6 protein to plasmodesmata requires the ER to-Golgi secretory pathway and an actin-myosin VIII motility system. AB - The nonstructural protein pc6 encoded by rice grassy stunt virus (RGSV) plays a significant role in viral cell-to-cell movement, presumably by transport through plasmodesmata (PD). We confirmed the association of pc6 with PD, and also elucidated the mechanisms of protein targeting to PD. Several inhibitor treatments showed conclusively that pc6 is targeted to PD via the ER-to-Golgi secretory system and actin filaments. In addition, VIII-1 myosin was also found to be involved in pc6 PD targeting. Deletion mutants demonstrated that C-terminal amino acid residues 209-229 (transmembrane domain 2; TM2) are essential for pc6 to move through PD. PMID- 29392492 TI - Human bocavirus in hospitalized children under 5 years with acute respiratory infection, Sao Paulo, Brazil, 2010. AB - The aims of this study were to investigate the human bocavirus (HBoV) frequency and genotypes in hospitalized children <5 years presenting acute respiratory infections (ARI) within the Sao Paulo metropolitan area. Nasopharyngeal samples from 300 patients, previously screened for common respiratory viruses, were tested by qPCR for the NSP1 and NP-1 genes. The VP1/2 gene in positive samples was then amplified by PCR and sequenced. A total of 49 positive HBoV cases (16.3%; mean Ct value of 34.41) were detected with the mean age being 18.1 months (range 1 month to 5 years) and the median age being 1 year of age. Children aged between 0 and 12 months had higher detection rates of HBoV (69.4%; 34/49; mean Ct = 34.45) than children from other age groups (30.6%; 15/49; mean Ct = 34.34). No significant differences were observed between HBoV Ct levels and clinical illness. The occurrence was more frequently associated with fall (38.8%; 19/49) and spring (36.7%; 18/49). All 12 sequenced isolates were identified as HBoV-1, displaying minor genetic variation compared to the Swedish reference strains ST1 and ST2 (99.1-99.7% nt). The sole identification of HBoV-1 supports the hypothesis that this particular genotype is strongly related to ARI, and contributes to the role of this virus in the aetiology of respiratory diseases. PMID- 29392493 TI - Grapevine virus I, a putative new vitivirus detected in co-infection with grapevine virus G in New Zealand. AB - A novel virus, with characteristics of viruses classified within the genus Vitivirus, was identified from a sample of Vitis vinifera cv. Chardonnay in New Zealand. The virus was detected with high throughput sequencing (small RNA and total RNA) and its sequence was confirmed by Sanger sequencing. Its genome is 7507 nt long (excluding the polyA tail) with an organisation similar to that described for other classifiable members of the genus Vitivirus. The closest relative of the virus is grapevine virus E (GVE) with 65% aa identity in ORF1 (65% nt identity) and 63% aa identity in the coat protein (66% nt identity). The relationship with GVE was confirmed with phylogenetic analysis, showing the new virus branching with GVE, Agave tequilina leaf virus and grapevine virus G (GVG). A limited survey revealed the presence of this virus in multiple plants from the same location where the newly described GVG was discovered, and in most cases both viruses were detected as co-infections. The genetic characteristics of this virus suggest it represents an isolate of a new species within the genus Vitivirus and following the current nomenclature, we propose the name "Grapevine virus I". PMID- 29392494 TI - Molecular characterization of a divergent strain of calla lily chlorotic spot virus infecting celtuce (Lactuca sativa var. augustana) in China. AB - Through sequencing and assembly of small RNAs, an orthotospovirus was identified from a celtuce plant (Lactuca sativa var. augustana) showing vein clearing and chlorotic spots in the Zhejiang province of China. The S, M, and L RNAs of this orthotospovirus were determined to be 3146, 4734, and 8934 nt, respectively, and shared 30.4-72.5%, 43.4-80.8%, and 29.84-82.9% nucleotide sequence identities with that of known orthotospoviruses. The full length nucleoprotein (N) of this orthotospovirus shared highest amino acid sequence identity (90.25%) with that of calla lily chlorotic spot virus isolated from calla lily (CCSV-calla) [China: Taiwan: 2001] and tobacco (CCSV-LJ1) [China: Lijiang: 2014]. Phylogenetic analyses showed that this orthotospovirus is phylogenetically associated with CCSV isolates and clustered with CCSV, tomato zonate spot virus (TZSV), and tomato necrotic spot-associated virus (TNSaV) in a separate sub-branch. These results suggest that this orthotospovirus is a divergent isolate of CCSV and was thus named CCSV-Cel [China: Zhejiang: 2017]. PMID- 29392495 TI - Spatial transmission of H5N6 highly pathogenic avian influenza viruses among wild birds in Ibaraki Prefecture, Japan, 2016-2017. AB - From 29 November 2016 to 24 January 2017, sixty-three cases of H5N6 highly pathogenic avian influenza virus (HPAIV) infections were detected in wild birds in Ibaraki Prefecture, Japan. Here, we analyzed the genetic, temporal, and geographic correlations of these 63 HPAIVs to elucidate their dissemination throughout the prefecture. Full-genome sequence analysis of the Ibaraki isolates showed that 7 segments (PB2, PB1, PA, HA, NP, NA, NS) were derived from G1.1.9 strains while the M segment was from G1.1 strains; both groups of strains circulated in south China. Pathological studies revealed severe systemic infection in dead swans (the majority of dead birds and the only species necropsied), thus indicating high susceptibility to H5N6 HPAIVs. Coalescent phylogenetic analysis using the 7 G1.1.9-derived segments enabled detailed analysis of the short-term evolution of these highly homologous HPAIVs. This analysis revealed that the H5N6 HPAIVs isolated from wild birds in Ibaraki Prefecture were divided into 7 groups. Spatial analysis demonstrated that most of the cases concentrated around Senba Lake originated from a single source, and progeny viruses were transmitted to other locations after the infection expanded in mute swans. In contrast, within just a 5-km radius of the area in which cases were concentrated, three different intrusions of H5N6 HPAIVs were evident. Multi segment analysis of short-term evolution showed that not only was the invading virus spread throughout Ibaraki Prefecture but also that, despite the small size of this region, multiple invasions had occurred during winter 2016-2017. PMID- 29392496 TI - Respiratory syncytial virus infection up-regulates TLR7 expression by inducing oxidative stress via the Nrf2/ARE pathway in A549 cells. AB - In order to better understand the early pathways of the pathogenesis of, and immune response to, RSV, herein, we explored the relationship between TLR7 expression and oxidative stress induction following RSV infection in A549 cells. We studied the intervening effects of the Nrf2/ARE pathway agonist butylated hydroxyanisole (BHA) and inhibitor trigonelline (TRI) on TLR7 modulation or oxidative stress induction. For comparison purposes, we set up seven treatment groups in this study, including RSV-treated cells, BHA + RSV-treated cells, TRI + RSV-treated cells, normal cell controls, inactivated RSV controls, BHA controls and TRI controls. We measured changes in TLR7, IL-6, TNF-alpha mRNA using RT-PCR and IL-6, TNF-alpha and IL-1beta protein using ELISA as well as TLR7, Nrf2 and HO 1 protein using Western blot in A549 cells from the different treatment groups. We also assessed changes in cell proliferation and measured changes in .OH and NO in A549 cells from the different treatment groups. The results indicate that TLR7 up-regulation is related to RSV infection and the induction of oxidative stress and that TLR7 expression was mediated by the anti-inflammatory effects of Nrf2/ARE pathway inhibitors or agonists. Our experiments may help elucidate the underlying pathology of RSV infection and suggest potential therapeutic targets for drug development and the prevention of RSV-induced human diseases. PMID- 29392497 TI - Inhibition of dengue virus infection by small interfering RNAs that target highly conserved sequences in the NS4B or NS5 coding regions. AB - Dengue fever is one of the most common viral infections in the world. Although a vaccine against dengue virus (DENV) has been approved in several countries, this disease is still considered a public health priority worldwide. The ability of three small interfering RNAs (FG-siRNAs) targeting conserved sequences in the NS4B and NS5 regions of the DENV genome to inhibit DENV replication was tested in vitro in both Vero and C6/36 cells. The FG-siRNAs were effective against DENV-1, 3, and -4, but not DENV-2. A fourth siRNA specifically targeting the NS5 region of the DENV-2 genome (SG-siRNA) was designed and tested against two different DENV-2 strains, showing high levels of inhibition in both mammalian and insect cells. PMID- 29392498 TI - Full genome sequence of the first bluetongue virus serotype 21 (BTV-21) isolated from China: evidence for genetic reassortment between BTV-21 and bluetongue virus serotype 16 (BTV-16). AB - Bluetongue (BT) is one of the most important insect-borne, non-contagious viral diseases of ruminants and can cause severe disease and death in sheep. Its pathogen, bluetongue virus (BTV) has a double-stranded RNA genome consisting of 10 segments that provides an opportunity for field and vaccine strains of different serotypes to reassort whilst simultaneously infecting the same animal. For the first time, we report the full-length genome sequence of a BTV strain of serotype 21 (5149E) isolated from sentinel cattle in Guangxi Province in China in 2015. Sequence analysis suggested that the isolate 5149E had undergone a reassortment incident and acquired seg-6 from an isolate of BTV-16 which originated from Japan. This study aims to provide more understanding as to the origin and epidemiology of BTV. PMID- 29392499 TI - Comparative genomic analysis of novel bacteriophages infecting Vibrio parahaemolyticus isolated from western and southern coastal areas of Korea. AB - Vibrio parahaemolyticus, a foodborne pathogen, has become resistant to antibiotics. Therefore, alternative bio-control agents such bacteriophage are urgently needed for its control. Six novel bacteriophages specific to V. parahaemolyticus (vB_VpaP_KF1~2, vB_VpaS_KF3~6) were characterized at the molecular level in this study. Genomic similarity analysis revealed that these six bacteriophages could be divided into two groups with different genomic features, phylogenetic grouping, and morphologies. Two groups of bacteriophages had their own genes with different mechanisms for infection, assembly, and metabolism. Our results could be used as a future reference to study phage genomics or apply phages in future bio-control studies. PMID- 29392500 TI - The first complete genome sequence of narcissus latent virus from Narcissus. AB - The complete sequence of a narcissus virus isolated from the Netherlands (Narv NL) was determined to be 8172 nucleotides in length with an open reading frame encoding for 2624 amino acids. Phylogenetic analysis indicates that Narv-NL is clustered with high confidence among representative members from the genus Macluravirus, including artichoke latent virus (ArLV) and Chinese yam necrotic mosaic virus (CYNMV). Sequence analyses indicated Narv-NL shares 67%-69% nucleotide and 51%-68% amino acid sequence identity with ArLV and CYNMV either in the complete ORF or the coat protein (CP) gene, whereas it had 81%-99 % nucleotide and 80%-99 % amino acid sequence identity with the corresponding CP sequences of narcissus latent virus (NLV) isolates, suggesting that Narv-NL is a member of NLV. To our knowledge, this is the first report of the complete sequence of a NLV isolate. PMID- 29392502 TI - Mosaic capillaroscopic findings in systemic sclerosis. AB - A 67-year-old woman with triphasic Raynaud's phenomenon since 2 years was diagnosed as having limited cutaneous systemic sclerosis (SSc) 1 year ago based on puffy fingers, positive antinuclear and anti-Scl-70 autoantibodies, and initial pulmonary fibrosis. Capillaroscopic examination revealed "mosaic" capillaroscopic findings that included normal pattern; "scleroderma"-type capillaroscopic pattern "early" phase, with single giant capillaries and haemorrhages, preserved capillary distribution; and "scleroderma"-type capillaroscopic pattern "active" phase, with high number of giant capillary loops and haemorrhages, moderately disturbed distribution. Nailfold capillaroscopy is an established non-invasive imaging technique for morphologic evaluation of the capillaries in the nail-fold area that reveals diagnostic changes in the majority of SSc patients. It has been included in the recently published EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria for SSc (2013). The generalized microangiopathy is a cardinal feature of SSc, but the underlying endothelial damage of the capillaries varies in the different compartments of the body, sometimes even within the same organ. As typical capillaroscopic findings are diagnostic in clinical context, this case of a "mosaic" pattern should remind the clinicians that the capillaroscopic examination should be performed for the eight fingers bilaterally (excluding the thumbs because of poor visibility), in order to detect the presence of all types and grades of pathological microvascular changes to facilitate the highest diagnostic accuracy. PMID- 29392501 TI - Osteoblastic cell response on high-rough titanium coatings by cold spray. AB - Highly rough and porous commercially pure titanium coatings have been directly produced for first time by the cold spray technology, which is a promising technology in front of the vacuum plasma spray for oxygen sensitive materials. The wettability properties as well as the biocompatibility evaluation have been compared to a simply sand blasted Ti6Al4V alloy substrate. Surface topographies were analysed using confocal microscopy. Next, osteoblast morphology (Phalloidin staining), proliferation (MTS assay), and differentiation (alkaline phosphatase activity) were examined along 1, 7 and 14 days of cell culture on the different surfaces. Finally, mineralization by alizarin red staining was quantified at 28 days of cell culture. The contact angle values showed an increased hydrophilic behaviour on the as-sprayed surface with a good correlation to the biological response. A higher cell viability, proliferation and differentiation were obtained for highly rough commercial pure titanium coatings in comparison with sand blasted substrates. Cell morphology was similar in all coatings tested; at 14 days both samples showed extended filopodia. A higher amount of calcium-rich deposits was detected on highly rough surfaces. In summary, in-vitro results showed an increase of biological properties when surface roughness increases. PMID- 29392503 TI - A comparative brief on conducted electrical weapon safety. AB - The variety and high number of published research articles on conducted electrical weapons (CEW) provides a detailed, yet in some parts inconclusive overview of medical aspects of CEW. Due to different research approaches and the use of dissimilar test subjects, an assessment of possible health risks of CEW is limited. The present work provides a brief on CEW safety based on currently available animal, computer and human research data. Using the medical database PubMed, articles published on this topic are critically evaluated and compared with each other. Special focuses are the differences and similarities of human and animal research as well as computer simulation programs. The authors explain why some studies are more reliable than others and give their expert opinion on the safety of CEW. The body of data that have been reviewed provides reasonable support for the safety of CEW. PMID- 29392505 TI - Laparoscopic repair is a treatment of choice for selected patients with incarcerated obturator hernia. AB - PURPOSE: The feasibility and potential advantages of laparoscopic diagnosis and repair of incarcerated obturator hernia (OH) is debated. The aim of this retrospective study was to compare short-term complications comparing laparoscopic to open repair of OH. METHODS: A total of 29 preoperatively diagnosed patients underwent surgery for a preoperatively diagnosed OH between January 2006 and July 2017. The patients were divided into a laparoscopic group (11 patients underwent laparoscopic repair; 8 without and 3 with intestinal resection) and an open group (18 patients who underwent open repair; 9 without and 9 with intestinal resection).The outcomes were compared between groups. A risk factor analysis for postoperative complications was performed. RESULTS: The incidence of postoperative complications was fewer in the laparoscopic group [9.0% vs. 61.1%; (p < 0.001)]. The bleeding amount [1.2 g vs. 40.4 g; (p = 0.087)] and postoperative length of stay [13.3 days vs. 17.1 days; (p = 0.072)] showed a tendency to be favorable in the laparoscopic group. Occult contralateral OH was detected in three patients (27.7%) in the laparoscopic group and one patient (5.5%) in the open group (p = 0.099). Open surgery and intestinal resection were independent risk factors for a postoperative complication. One patient in the open group developed an incarcerated OH on the contralateral side 1 year after the first surgery. CONCLUSIONS: Laparoscopic repair for incarcerated obturator hernia demonstrated more favorable short-term outcomes compared with open repair in terms of a lower incidence of postoperative complications and it was potentially beneficial for detecting and repairing an occult OH on the contralateral side. PMID- 29392506 TI - Benefits of laparoscopic posterior wall suture repair in treating adolescent indirect inguinal hernias. AB - PURPOSE: Adolescent inguinal hernias are treated using high ligation or posterior wall suture repair with laparoscopic mesh implantation. This study aimed to evaluate the efficacy of laparoscopic intracorporeal posterior wall suture repair without mesh implantation for treating adolescent indirect inguinal hernias. METHODS: Laparoscopic herniorrhaphy was performed between September 2012 and April 2015 in 244 patients aged 11-18 years who were diagnosed with indirect inguinal hernias at Damsoyu Hospital, Seoul, Korea. The patients were stratified by surgical procedure into the high-ligation (115 patients) and wall suture (129 patients) groups. RESULTS: Four (3.5%) of the 115 patients in the high-ligation group experienced recurrence, but those in the wall suture group did not. The difference in recurrence rates between these groups was significant (p < 0.001). The wall suture procedures were longer (mean 28.2 min) than the high-ligation procedures (mean 17.4 min) (p < 0.001). The lengths of postoperative hospital stays were similar in both groups. Few complications were observed: one patient developed hematoma and one developed seroma in the high-ligation group; two patients developed inguinal hematomas and one developed seroma in the wall suture group. Visual analog scale scores at 1 week after surgery and the mean times to return to normal activities were similar in both groups. No chronic inguinodynia after the operation in either group was observed. CONCLUSIONS: Laparoscopic intracorporeal posterior wall suture repair without mesh implantation was effective for treating adolescent indirect inguinal hernias and resulted in fewer recurrences than those with high ligation. PMID- 29392507 TI - Do we really need a renaissance of pure tissue repair? Invited comment to: Desarda's technique versus Lichtenstein technique for the treatment of primary inguinal hernia: a systematic review and meta-analysis of randomized controlled trials. Emile S, Elfeki H. PMID- 29392504 TI - Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. AB - The molecular chaperone Hsp90 is one component of a highly complex and interactive cellular proteostasis network (PN) that participates in protein folding, directs misfolded and damaged proteins for destruction, and participates in regulating cellular transcriptional responses to environmental stress, thus promoting cell and organismal survival. Over the last 20 years, it has become clear that various disease states, including cancer, neurodegeneration, metabolic disorders, and infection by diverse microbes, impact the PN. Among PN components, Hsp90 was among the first to be pharmacologically targeted with small molecules. While the number of Hsp90 inhibitors described in the literature has dramatically increased since the first such small molecule was described in 1994, it has become increasingly apparent that not all of these agents have been sufficiently validated for specificity, mechanism of action, and lack of off-target effects. Given the less than expected activity of Hsp90 inhibitors in cancer-related human clinical trials, a re-evaluation of potentially confounding off-target effects, as well as confidence in target specificity and mechanism of action, is warranted. In this commentary, we provide feasible approaches to achieve these goals and we discuss additional considerations to improve the clinical efficacy of Hsp90 inhibitors in treating cancer and other diseases. PMID- 29392508 TI - Fukuoka-Negative Branch-Duct IPMNs: When to Worry? A Study from the French Surgical Association (AFC). AB - BACKGROUND: This study analyzed the pathologic findings for patients with Fukuoka negative branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) who theoretically were eligible for surveillance care with follow-up assessment, but instead underwent resection. METHODS: From January 2005 to December 2012, 820 patients underwent evaluation for IPMN. At initial staging, 319 patients had BD IPMN, and 89 of these patients presented with Fukuoka-negative criteria. These 89 patients were included in this study. RESULTS: Of the 89 patients, 55 (62%) underwent pancreatectomy. After pathologic examination, the ultimate diagnosis was MT-IPMN for 20 (36%) of these patients (the MT group) and BD-IPMN for 35 (64%) of these patients (the BD group). The remaining 34 patients (38%) underwent enucleation. The patients in the MT group were more likely to be male (P = 0.01) and to have a higher rate of recent (< 1 year) diabetes mellitus diagnosis (P = 0.007) than the patients in the BD group. In the multivariate analysis, diabetes mellitus was independently associated with involvement of the main pancreatic duct (P = 0.05). Malignancy was diagnosed for 14 (16%) of the 89 patients. The rate of invasive IPMN was higher in the MT group than in the BD group (20% vs. 0%, P = 0.02). The 5-year overall survival rate was 100% for the BD group and 84% for the MT group (P = 0.02). For the male patients with diabetes mellitus, the rate of malignancy rose to 67%. CONCLUSIONS: For patients with a diagnosis of Fukuoka-negative BD-IPMN, resection should be considered primarily for male patients with a recent diabetes mellitus diagnosis. PMID- 29392509 TI - Anti-inflammatory effects of sinapic acid on 2,4,6-trinitrobenzenesulfonic acid induced colitis in mice. AB - This study was conducted to evaluate the effect of sinapic acid, a cinnamic acid derivative, on inflammatory changes in a mouse model of colitis. Colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Sinapic acid (10, 30, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered to Balb/c female mice after TNBS instillation. The anti inflammatory effect of sinapic acid on colonic injury or damage was assessed by clinical, macroscopic, microscopic, and biochemical analyses. Compared with TNBS control, treatment with sinapic acid significantly improved colonic weight and length and decreased the macroscopic and microscopic changes in TNBS-induced colitis. Furthermore, myeloperoxidase activity and the colonic tissue levels of malondialdehyde and tumor necrosis factor alpha were decreased by administration of sinapic acid. The findings of this study suggest that sinapic acid exerts anti inflammatory effects on intestinal inflammation and can be selected as a novel therapeutic candidate in the treatment of inflammatory bowel disease. PMID- 29392510 TI - The use of SLICC and ACR criteria to correctly label patients with cutaneous lupus and systemic lupus erythematosus. AB - The American College of Rheumatology (ACR) classification criteria for lupus and Systemic Lupus International Collaborating Clinics (SLICC) criteria are designed to classify disease. However, they have become widely used as diagnostic criteria in clinical situations. Patients may be labelled as systemic lupus erythematosus (SLE) in their medical records, when in fact they have cutaneous lupus erythematosus (CLE) without systemic symptoms. We sought to investigate how many of our cutaneous lupus patients attending a dermatology lupus clinic were mislabelled as either CLE or SLE using the ACR and SLICC criteria. Thirty-six patients with biopsy-proven cutaneous lupus were identified. Fourteen (39%) of the patients were labelled as 'SLE' in their medical notes, either by dermatology or another medical team. Of these 14 patients, 12 (86%) fulfilled the ACR and SLICC criteria; however, two (14%) did not meet the criteria for SLE. Of the remaining 22 patients who were not labelled as having SLE, four (18%) met both the SLICC and ACR criteria, one (5%) met the ACR criteria and one (5%) met the SLICC criteria. These patients had a history of discoid or subacute lupus, with very few systemic symptoms. They met the criteria for SLE primarily on their cutaneous signs and positive serology. It is important to screen patients with CLE routinely for SLE. Although the ACR and SLICC criteria can be helpful as they have a high sensitivity for systemic lupus, their use needs to be paired with the clinical context and patient evolution. We found patients were labelled as SLE when in fact they had no evidence of systemic involvement, as well as patients labelled as cutaneous lupus who fulfilled the criteria for SLE, although unlikely having any systemic involvement. It is important to correctly identify patients as 'cutaneous lupus' or 'systemic lupus erythematosus' and documentation in clinical notes should be accurate to avoid confusion and allow appropriate treatment. PMID- 29392511 TI - Comparative efficacy and safety of biosimilar adalimumab and originator adalimumab in combination with methotrexate in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. AB - We aimed to assess the relative efficacy and safety of biosimilar adalimumab and originator adalimumab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA) who showed an inadequate response to MTX. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of biosimilar + MTX and adalimumab + MTX versus placebo + MTX (MTX group) in patients with active RA despite treatment with MTX. A total of eight RCTs involving 2543 patients met the inclusion criteria. The ACR20 response rate was significantly higher in the biosimilar + MTX (odds ratio [OR] 2.91, 95% credible interval [CrI] 1.57-5.74) and adalimumab + MTX (OR 2.80, 95% CrI 1.81 4.46) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar + MTX and adalimumab + MTX groups. Biosimilar + MTX had the highest probability of being the best treatment in terms of the ACR20 response rate (surface under the cumulative ranking curve [SUCRA] = 0.7896), followed by adalimumab + MTX (SUCRA = 0.7082) and MTX (SUCRA = 0.0022). The ACR50 and ACR70 response rates showed a distribution pattern similar to that of the ACR20 response rate. Safety based on the number of serious adverse events did not differ significantly among the three interventions in the follow-up period of 12 to 24 weeks. Biosimilar and originator adalimumab, in combination with MTX, represent an effective intervention for active RA despite treatment with MTX. No significant difference was found between biosimilar and originator adalimumab in terms of efficacy and safety. However, follow-up in RCTs is short and not all safety outcomes can be assessed in RCTs. Thus, additional long-term evaluations are needed. PMID- 29392512 TI - Different ethnic background is associated with distinct clinical profiles in the spondyloarthritides in the North and South of Brazil. AB - The objective of this study was to analyze the clinical profile of the spondyloarthritides (SpA) in distinct Brazilian regions. A common protocol of investigation was prospectively applied to 202 SpA patients, including 138 patients from the South and 64 patients from the North. All the patients were classified as axial or peripheral SpA. Clinical and demographic variables and disease indexes were analyzed. Bonferroni correction was used to adjust the level of significance of each test; results with p value < 0.003 were considered statistically relevant. White ethnicity was associated with positive HLA-B27, while non-Whites presented higher frequency of peripheral arthritis, although not statistically significant. When comparing non-White patients from the North with those from the South, the Southerners presented significantly higher scores of Ankylosing Spondylitis Disease Activity Score using C-reactive protein (p = 0.001) and Health Assessment Questionnaire (p = 0.001). Although not statistically significant, Northern non-White patients were more frequently males, while Southerners had higher frequency of anterior uveitis and higher Bath Ankylosing Spondylitis Disease Activity Index and Ankylosing Spondylitis Quality of Life. Brazilian SpA patients present distinct patterns of disease according to the geographic region, especially regarding the non-White populations. PMID- 29392513 TI - Polymorphic and Covalent Transformations of Gabapentin in Binary Excipient Mixtures after Milling-Induced Stress. AB - PURPOSE: The purpose of the research described herein was to develop a kinetic model for quantifying the effects of conditional and compositional variations on non-covalent polymorphic and covalent chemical transformations of gabapentin. METHODS: Kinetic models that describe the relationship between polymorphs and degradation product in a series of sequential or parallel steps were devised based on analysis of the resultant concentration time profiles. Model parameters were estimated using non-linear regression and Bayesian methods and evaluated in terms of their quantitative relationship to compositional and conditional variations. RESULTS: The model was constructed in which co-milling gabapentin with excipients determined three physically-initial concentrations (II0*, II0 and III0) and one chemically-initial concentration (lactam0). For chemical transitions, no humidity effect was present but the catalytic effects of excipients on the conversion of II and III?lactam were observed. For physical transition, excipient primarily influenced the physical state transition of III?II through its ability to interact with humidity. CONCLUSIONS: This model was shown to be robust to quantitatively account for the effects of temperature, humidity and excipient on rate constants associated with kinetics for each physical and chemical transition. PMID- 29392514 TI - Letter to the editor. PMID- 29392515 TI - Obstetric and neonatal outcome following ICSI with assisted oocyte activation by calcium ionophore treatment. AB - PURPOSE: Calcium ionophore treatment is being used in assisted reproductive technology (ART) for cases with previous low fertilization rate or total absence of fertilization after insemination by intracytoplasmic sperm injection or when a specific indication such as globozoospermia is present. As this technique is more invasive and differs from the physiological process of fertilization, a thorough investigation of the health of the children born following this procedure is required. We intent to report the medical outcome of all children conceived following calcium ionophore treatment in our IVF center. METHODS: One-armed descriptive study is performed to report the obstetrical and neonatal outcome of children born after using calcium ionophore treatment during the intracytoplasmic sperm injection procedure in our center. RESULTS: A number of 237 cycles were included in this study, with 74 pregnancies reported, from which 47 children (31 singletons and 16 twin children) were born. No major malformations were detected in singletons. In twins, three children were diagnosed with major malformations. Minor malformations were present in seven singletons and in one twin. CONCLUSIONS: In conclusion, our results regarding birth characteristics and congenital malformations are within the expected range but, although reassuring, should be interpreted with caution due to the small number of children included. PMID- 29392516 TI - Ovarian tissue cryopreservation (OTC) in prepubertal girls and young women: an analysis of parents' and patients' decision-making. AB - PURPOSE: The purpose of this study was to explore the decision-making influences, perceived level of control over decision-making, and mood states of parents and patients who were offered OTC prior to gonadotoxic therapy. METHODS: Parents and patients, at least 12 years old, who required gonadotoxic therapy and were offered OTC prior to therapy, were asked to complete questionnaires. Two validated instruments were also used: the Decision-Making Control Instrument (DMCI) and the Profile of Mood States (POMS). The factors that influenced decision-making were compared using Student's t test, and the scores of DMCI and POMS were compared using the Mann-Whitney test. RESULTS: Thirty-six parents and 16 patients who elected ovarian tissue cryopreservation (OTC) completed questionnaires. Five parents who declined OTC also completed questionnaires. Accepters thought OTC was a good idea and that, in the future, science would enable cryopreserved ovarian tissue to be used to restore fertility (100% parents, 93.8% patients). Among accepters, the desire for genetically related children and prevention of the stress of infertility drove parents' and patients' decisions (90.9 and 100%, respectively). The desire to prevent the stress of infertility was important to parents, but patients were less likely to report that a desire to prevent the stress of infertility factored into their decision making (66.7 vs. 50.0%; p < 0.001). All respondents felt in control of their decision and displayed low levels of mood disturbance. CONCLUSIONS: Though the decision to undergo experimental OTC is difficult and often urgent, this study suggests that families feel in control of their decision-making and report little emotional disturbance. PMID- 29392517 TI - Mental Health Diagnostic Frameworks, Imputed Causes of Mental Illness, and Alternative Treatments in Northern Tanzania: Exploring Mental Health Providers' Perspectives. AB - In Tanzania, a nation with a large mental health treatment gap, local stakeholders' perspectives are critical for informing effective treatment. The practice-based perspectives of mental health providers may be particularly instructive. Existing foundational literature on the professional population in this region is scarce. We conducted semi-structured interviews with 29 mental health providers in northern Tanzania. Interviews focused on three topics: use of international diagnostic frameworks for mental illness, beliefs about causes of mental health concerns, and alternative treatments sought by clients. Interview data were coded and analyzed using consensual qualitative research and the constant comparative method. Usage of diagnostic frameworks varied widely. Providers believed frameworks accurately described many patients but neglected somatic symptoms and contained diagnoses that they had never witnessed. Providers described supernatural and spiritual attributions of mental illness as substantially impacting treatment decisions. Other notable attributions included physical illness, drug/alcohol use, and heredity. Providers reported their clients routinely sought treatment from traditional and spiritual healers prior to seeking care in the formal health system. This study builds a foundation for the ongoing development of the mental health system in northern Tanzania. Findings also support exploration of integrative models of care and task-shifting to incorporate traditional and spiritual beliefs. PMID- 29392518 TI - PDGF Modulates Synaptic Excitability and Short-Latency Afferent Inhibition in Multiple Sclerosis. AB - Maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and PDGF plays a key role in this phenomenon. Indeed, higher cerebrospinal fluid PDGF concentration correlates with improved clinical recovery after a relapse, and the amplitude of LTP-like cortical plasticity in relapsing remitting MS patients. However, LTP-like cortical plasticity varies depending on the individual level of inhibitory cortical circuits. Aim of this study was to explore whether PDGF-CSF concentration correlates with inhibitory cortical circuits explored by means of transcranial magnetic stimulation in patients affected by relapsing-remitting MS. We further performed electrophysiological experiments evaluating GABAergic transmission in the experimental autoimmune encephalomyelitis (EAE) hippocampus. Our results reveal that increased CSF PDGF concentration correlates with decreased short afferent inhibition in the motor cortex in MS patients and decreased GABAergic activity in EAE. These findings show that PDGF affects GABAergic activity both in MS patients and in EAE hippocampus. PMID- 29392520 TI - Pre-participation screening of asymptomatic athletes : "Don't do stupid stuff". AB - Catastrophic events, be it traffic accidents, natural disasters or homicides, always lead to scrutiny. Could we have seen the event coming and could it have been prevented? In the case of a sudden cardiac arrest of a seemingly healthy athlete the public outcry is not any different. Despite an intrinsic appeal for screening to prevent similar events, there is no evidence that justifies routine cardiovascular pre-participation screening of athletes. On balance, cardiovascular screening in athletes will most likely do more harm than good. Fatal exercise-related cardiac arrests do not occur very often. The true diagnostic yield of the pre-participation evaluation is not known and once a cardiac condition has been identified, the most appropriate intervention is often unclear. It follows that pre-participation screening of large groups of athletes without known cardiac disease will inevitably result in many false positive findings, while at the same time providing a false sense of security to those screened negative. Except for compelling reasons (e. g. cascade screening, research settings, professional athletes), physicians should not engage in routine examination of asymptomatic athletes to prevent cardiac events. PMID- 29392519 TI - Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation. AB - Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-alpha and IL-1beta, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases. PMID- 29392521 TI - A new consensus document on electrocardiographic interpretation in athletes: does it help to prevent sudden cardiac death in athletes? AB - Sudden cardiac arrest or death (SCA/SCD) in athletes has a low event rate. Pre participation or eligibility screening is a widely accepted method of primary prevention of SCA/SCD in athletes. Most European countries and international sports governing bodies perform ECG-inclusive screening. However, implementation of a resting 12-lead ECG in pre-participation or eligibility cardiac screening is still a topic of debate. Recently, the 'International recommendations for electrocardiographic interpretation in athletes' was published in three leading international medical journals. These international ECG criteria are based on studies with detailed information on resting 12-lead ECG of Caucasian and Afro Caribbean athletes or on consensus in case evidence was lacking. Normal, borderline and abnormal ECG findings in young athletes (age 12-35 years) are clearly described and illustrated to assist the screening physician in interpreting ECGs of athletes correctly.In this 'point of view paper' we will discuss whether these new ECG criteria actually help prevent SCA/SCD in athletes. PMID- 29392522 TI - Virtual Reality as an Educational and Training Tool for Medicine. AB - Until very recently, we considered Virtual Reality as something that was very close, but it was still science fiction. However, today Virtual Reality is being integrated into many different areas of our lives, from videogames to different industrial use cases and, of course, it is starting to be used in medicine. There are two great general classifications for Virtual Reality. Firstly, we find a Virtual Reality in which we visualize a world completely created by computer, three-dimensional and where we can appreciate that the world we are visualizing is not real, at least for the moment as rendered images are improving very fast. Secondly, there is a Virtual Reality that basically consists of a reflection of our reality. This type of Virtual Reality is created using spherical or 360 images and videos, so we lose three-dimensional visualization capacity (until the 3D cameras are more developed), but on the other hand we gain in terms of realism in the images. We could also mention a third classification that merges the previous two, where virtual elements created by computer coexist with 360 images and videos. In this article we will show two systems that we have developed where each of them can be framed within one of the previous classifications, identifying the technologies used for their implementation as well as the advantages of each one. We will also analize how these systems can improve the current methodologies used for medical training. The implications of these developments as tools for teaching, learning and training are discussed. PMID- 29392525 TI - 2017 Everett Mendelsohn Prize. PMID- 29392524 TI - Is Mindful Parenting Associated with Adolescents' Well-being in Early and Middle/Late Adolescence? The Mediating Role of Adolescents' Attachment Representations, Self-Compassion and Mindfulness. AB - There is some evidence that mindful parenting, a parenting approach that involves the practice of bringing mindful awareness to the parent-child relationship, is associated with several positive psychosocial outcomes in adolescents. However, only a few studies have investigated the mechanisms that may underlie that association. This study explores whether the link between mindful parenting and adolescents' well-being is mediated by adolescents' attachment representations, self-compassion and mindfulness skills. The sample comprised 563 parent-child dyads (95.6% mothers). Adolescents (61.5% girls) had a mean age of 14.26 years (SD = 1.66, range = 12-20). Parents completed a measure of mindful parenting, and adolescents completed measures of attachment representations, self-compassion, mindfulness, and well-being. Mindful parenting was indirectly associated with adolescents' self-compassion and mindfulness through a more secure perception of the relationship with the parents, and was indirectly associated with adolescents' well-being through perceived attachment security, self-compassion and mindfulness. The path model was invariant across stages of adolescence but some relations in the model varied across gender. Self-compassion and mindfulness seem to develop within a parent-child relationship characterized by affection, self-regulation, and mindful awareness. These two resources, along with mindful parenting and positive representations of the parent-child relationship, are associated with adolescents' well-being. PMID- 29392526 TI - Ponticaulis profundi sp. nov. isolated from a deep-sea seamount. AB - A Gram-stain negative, rod-shaped, strictly aerobic, motile bacterial strain, designated YC239T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YC239T is related to the genus Ponticaulis and has high 16S rRNA gene sequence similarity with the type strain of Ponticaulis koreensis GSW 23T (97.9%). The predominant cellular fatty acids were C18:1omega7c, C16:0, C17:0 and C17:1omega6c. Strain YC239T had Q-10 as the predominant ubiquinone. The polar lipid profile contained phosphatidylglycerol, two unidentified aminolipids and six unidentified polar lipids. The genomic DNA G+C content of strain YC239T was 52.8 mol%. Strain YC239T shared DNA relatedness of 38% with Ponticaulis koreensis KCTC 22146T. On the basis of the evidence presented in this study, strain YC239T represents a novel species of the genus Ponticaulis, for which we propose the name Ponticaulis profundi sp. nov. (type strain YC239T = KACC 19027T = CGMCC 1.15741T). PMID- 29392527 TI - Lithobiontic life: "Atacama rocks are well and alive". AB - Our knowledge on the Microbiology of the Atacama Desert has increased steadily and substantially during the last two decades. This information now supports a paradigmatic change on the Atacama Desert from a sterile, uninhabitable territory to a hyperarid region colonized by a rich microbiota that includes extremophiles and extreme-tolerant microorganisms. Also, extensive reports are available on the prevalent physical and chemical environmental conditions, ecological niches and, the abundance, diversity and organization of the microbial life in the Atacama Desert. This territory is a highly desiccated environment due to the absence of regular rain events. Liquid water scarcity is the most serious environmental factor affecting the Atacama Desert microorganisms. The intense solar irradiation in this region contributes, in a synergistic fashion with desiccation, to limit the survival and growth of the microbial life. In order to overcome these two extreme conditions, successful microorganisms, organized as microbial consortia, take advantage of (a) the physical characteristics of lithic habitats, which provide sites for colonization on, within or below the rock substrate, the attenuation and filtration of the intense solar irradiation and, the collection of liquid water from incoming fog formations and by water vapour condensation and deliquescence on or within their surfaces, and (b) the biological adaptations of members of the microbial communities that allow them to synthesize hydrophilic macromolecules, antioxidants and UV-light absorbents. Lithic habitats have been considered specialized shelters where life forms can reach protection at environments subjected to extremes of desiccation and solar irradiation, here on Earth or elsewhere. This review is an overview of part of the scientific information collected on lithobionts from the Atacama Desert, their rock substrates and their strategies to cope with extremes of desiccation and intense photosynthetic active radiation and UV irradiations. PMID- 29392529 TI - Patient and Family Advisory Councils (PFACs): Identifying Challenges and Solutions to Support Engagement in Research. AB - OBJECTIVE: The aim was to describe barriers to patient and family advisory council (PFAC) member engagement in research and strategies to support engagement in this context. METHODS: We formed a study team comprising patient advisors, researchers, physicians, and nurses. We then undertook a qualitative study using focus groups and interviews. We invited PFAC members, PFAC leaders, hospital leaders, and researchers from nine academic medical centers that are part of a hospital medicine research network to participate. All participants were asked a standard set of questions exploring the study question. We used content analysis to analyze data. RESULTS: Eighty PFAC members and other stakeholders (45 patient/caregiver members of PFACs, 12 PFAC leaders, 12 hospital leaders, 11 researchers) participated in eight focus and 19 individual interviews. We identified ten barriers to PFAC member engagement in research. Codes were organized into three categories: (1) individual PFAC member reluctance; (2) lack of skills and training; and (3) problems connecting with the right person at the right time. We identified ten strategies to support engagement. These were organized into four categories: (1) creating an environment where the PFAC members are making a genuine and unique contribution; (2) building community between PFAC members and researchers; (3) best practice activities for researchers to facilitate engagement; and (4) tools and training. CONCLUSION: Barriers to engaging PFAC members in research include patients' negative perceptions of research and researchers' lack of training. Building community between PFAC members and researchers is a foundation for partnerships. There are shared training opportunities for PFAC members and researchers to build skills about research and research engagement. PMID- 29392530 TI - ENAP vs LANAP: assessment of revascularization using ultrasound Doppler flowmetry a split-mouth randomized controlled clinical trial. AB - Laser-assisted new attachment procedure (LANAP) is a new protocol that has been proposed for the treatment of periodontitis. However, there is little evidence regarding the rate of revascularization and the clinical efficacy of LANAP over conventional periodontal therapies. Hence, this study is done to evaluate and compare the clinical efficacy of LANAP vs Excisional new attachment procedure (ENAP) and also to assess the blood flow in both the techniques using ultrasound Doppler flowmetry. A split-mouth double-blinded controlled clinical trial was carried out in 15 subjects with chronic periodontitis. In every patient, 2 quadrants were treated with ENAP and the other 2 quadrants with LANAP. Clinical parameters like plaque index (PI), gingival index (GI), pocket depth (PD), clinical attachment level (CAL), and radiographic measurements (RBL) were recorded at baseline and 6, 9, and 12 months, postoperatively. Gingival blood flow assessment was done at baseline and on the ninth day postoperatively. Both the groups showed statistically significant reduction in all the clinical parameters when compared from baseline to subsequent follow-up visits. There was greater reduction in all the parameters in LANAP group than that of ENAP group. The rate of revascularization was higher in ENAP group than that of LANAP group when compared from baseline to the ninth day postoperatively. Although there is a delay in the rate of revascularization in the LANAP group, there was significant improvement in all the clinical and radiographic parameters than that of the ENAP group when compared from baseline to follow-up visits. PMID- 29392528 TI - Proteolytic cleavage of vascular adhesion protein-1 induced by vascular endothelial growth factor in retinal capillary endothelial cells. AB - PURPOSE: To investigate the mechanism of soluble vascular adhesion protein-1 (sVAP-1) accumulation induced by vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). STUDY DESIGN: Experimental. METHODS: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with proliferative diabetic retinopathy (PDR) with or without intravitreal bevacizumab (IVB) injection were determined by ELISA. The effect of VEGF on both mRNA expression of Vap-1 and secretion of sVAP-1 in rat retinal capillary endothelial cells (TR iBRB2) was analyzed by real-time PCR and western blotting, respectively. In addition, the impact of VEGF on production and activation ratios of matrix metalloproteinase (MMP)-2 and MMP-9 was examined by gelatin zymography. Hydrogen peroxide production and reactive oxygen species (ROS) levels were assessed in the supernatants of TR-iBRB2 cells treated with VEGF. RESULTS: IVB injection decreased vitreous levels of sVAP-1 and HEL in patients with PDR. VEGF stimulation released sVAP-1 protein from TR-iBRB2 cells as a consequence of membrane-anchored VAP-1 shedding by MMP-2 and MMP-9. In addition, VEGF increased hydrogen peroxide generation and ROS augmentation through spermine oxidation by sVAP-1 as semicarbazide-sensitive amine oxidase (SSAO) in the supernatant of cultured endothelial cells. CONCLUSIONS: The current data demonstrate that proangiogenic factor VEGF induces sVAP-1 release from retinal capillary endothelial cells and facilitates hydrogen peroxide generation via enzymatic property of sVAP-1, followed by the increase of oxidative stress, one of the crucial factors in the pathogenesis of DR. PMID- 29392531 TI - Salivary microbial profiles in 5-year old children with oral clefts: a comparative study. AB - AIM: To compare the salivary microbial profile in children with oral clefts to matched non-cleft controls in a cross-sectional study. METHODS: The cleft group consisted of 80 children aged 5 years and 144 age-matched non-cleft children were recruited as a control group. Stimulated whole saliva samples were collected and analysed with checkerboard DNA-DNA hybridisation using 12 pre-determined bacterial probes. Background data on caries, oral hygiene, dietary habits and fluoride exposure were collected from clinical examinations and questionnaires. RESULTS: Children in the cleft group had a significantly higher prevalence of dental caries but only minor differences in the salivary microbial profile were found. In general, the cleft-children displayed a lower prevalence of common commensal species (e.g. Streptococcus, Fusobacterium) when compared with the non cleft controls. The differences were statistically significant (p < 0.05) but the clinical significance was unclear. CONCLUSIONS: The profile of the salivary microflora in 5-year-old children with and without oral clefts was basically similar and displayed only marginal differences with respect to commensal bacteria. PMID- 29392532 TI - Arbuscular Mycorrhizal Fungi and Plant Chemical Defence: Effects of Colonisation on Aboveground and Belowground Metabolomes. AB - Arbuscular mycorrhizal fungal (AMF) colonisation of plant roots is one of the most ancient and widespread interactions in ecology, yet the systemic consequences for plant secondary chemistry remain unclear. We performed the first metabolomic investigation into the impact of AMF colonisation by Rhizophagus irregularis on the chemical defences, spanning above- and below-ground tissues, in its host-plant ragwort (Senecio jacobaea). We used a non-targeted metabolomics approach to profile, and where possible identify, compounds induced by AMF colonisation in both roots and shoots. Metabolomics analyses revealed that 33 compounds were significantly increased in the root tissue of AMF colonised plants, including seven blumenols, plant-derived compounds known to be associated with AMF colonisation. One of these was a novel structure conjugated with a malonyl-sugar and uronic acid moiety, hitherto an unreported combination. Such structural modifications of blumenols could be significant for their previously reported functional roles associated with the establishment and maintenance of AM colonisation. Pyrrolizidine alkaloids (PAs), key anti-herbivore defence compounds in ragwort, dominated the metabolomic profiles of root and shoot extracts. Analyses of the metabolomic profiles revealed an increase in four PAs in roots (but not shoots) of AMF colonised plants, with the potential to protect colonised plants from below-ground organisms. PMID- 29392533 TI - Time-dependent alterations in mRNA, protein and microRNA during in vitro adipogenesis. AB - Adipogenesis is a complex biological process involving synchronised interplay of different nuclear receptors. Aberration in the process leads to obesity and associated disorders. Addressing the complexity of molecular mechanisms, we worked on characterising the changes in NR1C3/PPARgamma-, NR1H3/LXRalpha- and NCoAs/SRCs-associated microRNA, genes and proteins during different time points of adipogenesis. Glucose uptake of differentiating cells was checked at selected time points with FACS. Observations on gene expression pattern pointed a correlation in adipogenic-related genes and increased expression of PPARgamma, but not LXRalpha. Western blot experiments also supported the gene expression pattern. MicroRNAs that vary during adipogenesis was selected using bioinformatics tools and database. Real-time PCR-based experiments showed a change in the expression of mmu-mir-23a-3p, 206-3p, 17-3p, 126a-3p and 1a-3p. Mmu mir-23a-3p showed a gradual decrease in expression corresponding to the progression of adipogenesis. MicroRNA 23a-3p and 1a-3p showed positive association to the mRNA levels of NCoA1 and 3. Overall, the study elaborates time dependent variations in nucleic acid and protein expression during adipogenesis in accordance to fatty acid and glucose metabolism. PMID- 29392535 TI - Innovative methods for biomarker discovery in the evaluation and development of cancer precision therapies. AB - The discovery of biomarkers able to detect cancer at an early stage, to evaluate its aggressiveness, and to predict the response to therapy remains a major challenge in clinical oncology and precision medicine. In this review, we summarize recent achievements in the discovery and development of cancer biomarkers. We also highlight emerging innovative methods in biomarker discovery and provide insights into the challenges faced in their evaluation and validation. PMID- 29392534 TI - Overexpression of WNK1 in POMC-expressing neurons reduces weigh gain via WNK4 mediated degradation of Kir6.2. AB - "With no lysine" (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20 weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice. Immunostaining of serial sections of the hypothalamus revealed that POMC-expressing neurons were smaller in WNK1 TG mice than in WT mice. In addition, expression of Kir6.2 was significantly reduced in WNK1 TG mice. Overexpression and knockdown of WNK4 demonstrated that WNK4 regulates protein expression of Kir6.2 via protein-protein interaction. Accordingly, reduced age-dependent weight gain of WNK1 TG mice seems to be related with the decreased Kir6.2 expression via WNK1- and WNK4-regulated protein stability of Kir6.2. PMID- 29392536 TI - Retrograde Coronary Venous Infusion as a Delivery Strategy in Regenerative Cardiac Therapy: an Overview of Preclinical and Clinical Data. AB - An important aspect of cell therapy in the field of cardiac disease is safe and effective delivery of cells. Commonly used delivery strategies such as intramyocardial injection and intracoronary infusion both present with advantages and disadvantages. Therefore, alternative delivery routes are explored, such as retrograde coronary venous infusion (RCVI). Our aim is to evaluate safety and efficiency of RCVI by providing a complete overview of preclinical and clinical studies applying RCVI in a broad range of disease types and experimental models. Available data on technical and safety aspects of RCVI are incomplete and insufficient. Improvement of cardiac function is seen after cell delivery via RCVI. However, cell retention in the heart after RCVI appears inferior compared to intracoronary infusion and intramyocardial injection. Adequately powered confirmatory studies on retention rates and safety are needed to proceed with RCVI in the future. PMID- 29392537 TI - Enhanced Cardiac S100A1 Expression Improves Recovery from Global Ischemia Reperfusion Injury. AB - Gene-targeted therapy with the inotropic Ca2 + -sensor protein S100A1 rescues contractile function in post-ischemic heart failure and is being developed towards clinical trials. Its proven beneficial effect on cardiac metabolism and mitochondrial function suggests a cardioprotective effect of S100A1 in myocardial ischemia-reperfusion injury (IRI). Fivefold cardiomyocyte-specific S100A1 overexpressing, isolated rat hearts perfused in working mode were subjected to 28 min ischemia (37 degrees C) followed by 60 min reperfusion. S100A1 overexpressing hearts showed superior hemodynamic recover: Left ventricular pressure recovered to 57 +/- 7.3% of baseline compared to 51 +/- 4.6% in control (p = 0.025), this effect mirrored in LV work and dP/dt(max). Troponin T and lactate dehydrogenase was decreased in the S100A1 group, as well as FoxO pro apoptotic transcription factor, indicating less tissue necrosis, whereas phosphocreatine content was higher after reperfusion. This is the first report of a cardioprotective effect of S100A1 overexpression in a global IRI model. PMID- 29392538 TI - Correction to: Nonlinear deformation of tractography in ultrasound-guided low grade gliomas resection. AB - The author would like to include grant number of NSERC Discovery grant in the acknowledgement section of the original article. PMID- 29392539 TI - Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes. AB - Background Breast cancer is highly prevalent among women worldwide. It is classified into three main subtypes: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative breast cancer (TNBC). This study has evaluated the effects of aspirin and metformin, isolated or in a combination, in breast cancer cells of the different subtypes. Methods The breast cancer cell lines MCF-7, MDA-MB-231, and SK-BR-3 were treated with aspirin and/or metformin (0.01 mM - 10 mM); functional in vitro assays were performed. The interactions with the estrogen receptors (ER) were evaluated in silico. Results Metformin (2.5, 5 and 10 mM) altered the morphology and reduced the viability and migration of the ER+ cell line MCF-7, whereas aspirin triggered this effect only at 10 mM. A synergistic effect for the combination of metformin and aspirin (2.5, 5 or 10 mM each) was observed in the TNBC cell subtype MDA-MB 231, according to the evaluation of its viability and colony formation. Partial inhibitory effects were observed for either of the drugs in the HER2+ cell subtype SK-BR-3. The effects of metformin and aspirin partly relied on cyclooxygenase-2 (COX-2) upregulation, without the production of lipoxins. In silico, metformin and aspirin bound to the ERalpha receptor with the same energy. Conclusion We have provided novel evidence on the mechanisms of action of aspirin and metformin in breast cancer cells, showing favorable outcomes for these drugs in the ER+ and TNBC subtypes. PMID- 29392540 TI - Association of urinary and plasma DNA in early breast cancer patients and its links to disease relapse. AB - PURPOSE: Identifying patients who are at risk of relapse is a key challenge of primary breast cancer. The current study investigates the utility of urinary DNA in breast cancer management and as a predictor of relapse. This work also compares the sensitivity of plasma DNA with urinary DNA. METHODS: Blood plasma and urine specimens were collected concurrently from 200 breast cancer patients receiving neoadjuvant chemotherapy. Comparison of both plasma and urinary DNA was performed at baseline to determine assay significance. Serial measurements of urinary DNA were conducted to gauge DNA variations after surgery. Correlations to disease relapse were performed to affirm the clinical utility of urinary DNA. RESULTS: Molecular analysis showed patients were successfully identified with mutant PIK3CA using urinary DNA. A strong correlation was affirmed from urinary and plasma DNA at baseline with the correlation coefficient r = 0.859. We analyzed post-surgery measurements of urinary DNA for disease-relapse predictions. In subsequent serial followup of urinary DNA samples, we confirmed increased sensitivity in predicting relapse of these patients. The hazard ratio determined at the 9-month was 1.51 that identified patients at greater risk of disease relapse. CONCLUSION: Urinary DNA offers a unique opportunity to glimpse upon dynamic changes in early breast cancer. Our results demonstrated good correlation to plasma DNA and post monitoring of cancer patients to identify individuals susceptible to a high risk of relapse. This potentially allows for early intervention such as adjuvant chemotherapy to be administered to better manage these patients. PMID- 29392541 TI - Dimensionality and R4P: A Health Equity Framework for Research Planning and Evaluation in African American Populations. AB - Introduction Existing health disparities frameworks do not adequately incorporate unique interacting contributing factors leading to health inequities among African Americans, resulting in public health stakeholders' inability to translate these frameworks into practice. Methods We developed dimensionality and R4P to integrate multiple theoretical perspectives into a framework of action to eliminate health inequities experienced by African Americans. Results The dimensional framework incorporates Critical Race Theory and intersectionality, and includes dimensions of time-past, present and future. Dimensionality captures the complex linear and non-linear array of influences that cause health inequities, but these pathways do not lend themselves to approaches to developing empirically derived programs, policies and interventions to promote health equity. R4P provides a framework for addressing the scope of actions needed. The five components of R4P are (1) Remove, (2) Repair, (3) Remediate, (4) Restructure and (5) Provide. Conclusion R4P is designed to translate complex causality into a public health equity planning, assessment, evaluation and research tool. PMID- 29392542 TI - Diffusion Profiling via a Histogram Approach Distinguishes Low-grade from High grade Meningiomas, Can Reflect the Respective Proliferative Potential and Progesterone Receptor Status. AB - PURPOSE: Presurgical grading, estimation of growth kinetics, and other prognostic factors are becoming increasingly important for selecting the best therapeutic approach for meningioma patients. Diffusion-weighted imaging (DWI) provides microstructural information and reflects tumor biology. A novel DWI approach, histogram profiling of apparent diffusion coefficient (ADC) volumes, provides more distinct information than conventional DWI. Therefore, our study investigated whether ADC histogram profiling distinguishes low-grade from high grade lesions and reflects Ki-67 expression and progesterone receptor status. PROCEDURES: Pretreatment ADC volumes of 37 meningioma patients (28 low-grade, 9 high-grade) were used for histogram profiling. WHO grade, Ki-67 expression, and progesterone receptor status were evaluated. Comparative and correlative statistics investigating the association between histogram profiling and neuropathology were performed. RESULTS: The entire ADC profile (p10, p25, p75, p90, mean, median) was significantly lower in high-grade versus low-grade meningiomas. The lower percentiles, mean, and modus showed significant correlations with Ki-67 expression. Skewness and entropy of the ADC volumes were significantly associated with progesterone receptor status and Ki-67 expression. ROC analysis revealed entropy to be the most accurate parameter distinguishing low-grade from high-grade meningiomas. CONCLUSIONS: ADC histogram profiling provides a distinct set of parameters, which help differentiate low-grade versus high-grade meningiomas. Also, histogram metrics correlate significantly with histological surrogates of the respective proliferative potential. More specifically, entropy revealed to be the most promising imaging biomarker for presurgical grading. Both, entropy and skewness were significantly associated with progesterone receptor status and Ki-67 expression and therefore should be investigated further as predictors for prognostically relevant tumor biological features. Since absolute ADC values vary between MRI scanners of different vendors and field strengths, their use is more limited in the presurgical setting. PMID- 29392543 TI - Salinity Effects on the Adsorption of Nucleic Acid Compounds on Na Montmorillonite: a Prebiotic Chemistry Experiment. AB - Any proposed model of Earth's primitive environments requires a combination of geochemical variables. Many experiments are prepared in aqueous solutions and in the presence of minerals. However, most sorption experiments are performed in distilled water, and just a few in seawater analogues, mostly inconsistent with a representative primitive ocean model. Therefore, it is necessary to perform experiments that consider the composition and concentration of dissolved salts in the early ocean to understand how these variables could have affected the absorption of organic molecules into minerals. In this work, the adsorption of adenine, adenosine, and 5'AMP onto Na+montmorillonite was studied using a primitive ocean analog (4.0 Ga) from experimental and computational approaches. The order of sorption of the molecules was: 5'AMP > adenine > adenosine. Infrared spectra showed that the interaction between these molecules and montmorillonite occurs through the NH2 group. In addition, electrostatic interaction between negatively charged montmorillonite and positively charge N1 of these molecules could occur. Results indicate that dissolved salts affect the sorption in all cases; the size and structure of each organic molecule influence the amount sorbed. Specifically, the X-ray diffraction patterns show that dissolved salts occupy the interlayer space in Na-montmorillonite and compete with organic molecules for available sites. The adsorption capacity is clearly affected by dissolved salts in thermodynamic terms as deduced by isotherm models. Indeed, molecular dynamic models suggest that salts are absorbed in the interlamellar space and can interact with oxygen atoms exposed in the edges of clay or in its surface, reducing the sorption of the organic molecules. This research shows that the sorption process could be affected by high concentration of salts, since ions and organic molecules may compete for available sites on inorganic surfaces. Salt concentration in primitive oceans may have strongly affected the sorption, and hence the concentration processes of organic molecules on minerals. PMID- 29392544 TI - The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). PMID- 29392545 TI - Using nanoparticles from water treatment residuals to reduce the mobility and phytoavailability of Cd and Pb in biosolid-amended soils. AB - Heavy metal pollution in soils amended with biosolids has been a serious problem worldwide for clean food production. Laboratory and greenhouse experiments were performed to assess the impact of water treatment residual nanoparticles (nWTRs), at different application rates (0.1, 0.2 and 0.3%), on immobilization and phytoavailability of Cd and Pb to canola (Brassica napus L.) plants in soils amended with biosolids spiked with three different rates of Cd or Pb. Application of nWTRs significantly increased the residual fractions of Cd and Pb in metal spiked biosolid-amended soil and thereby increased the immobilization of Cd and Pb in the amended soil. The greatest immobilization of Cd and Pb was exhibited at an application rate of 0.3% nWTRs. In addition, the application of nanoparticles to the biosolid-amended soil significantly increased canola grain yield and significantly decreased Cd and Pb phytoavailability due to immobilization of Cd and Pb in the contaminated soil. The results demonstrate, for the first time, the capability of nanoscale WTRs in stabilizing heavy metals in contaminated soils and restoring degraded agricultural land. PMID- 29392546 TI - Potential health risk assessment through ingestion and dermal contact arsenic contaminated groundwater in Jianghan Plain, China. AB - Groundwater contamination with high arsenic (As) levels has caused serious health problem in Jianghan Plain. This study presents a framework to evaluate the results and their probable influencing factors of non-carcinogenic risk and carcinogenic risk in Shahu Village. An appropriate health risk assessment for residents exposing to As through ingestion and dermal contact pathways is also discussed in the paper. Hazard quotient (HQ) and target cancer risk (TR) are adopted to compute the non-carcinogenic and carcinogenic effects for residents, respectively. Monte Carlo simulation technique is used to quantify the uncertainty of the risk assessment. The assessment results show that the HQs and TRs of 10-m-deep and 25-m-deep wells exhibit seasonal variations with higher values in rainy season and lower values in dry season. The HQ values exceeding 1 at the depths of 10 (from 0.09 to 23.21 m) and 25 m (from 0.29 to 130.55 m) account for 61 and 94%, respectively, which associate with the As contents distribution in the aquifer sediments. The estimated TR values at the depths of 10 (from 3.86E-05 to 1.04E-02) and 25 m (from 1.32E-04 to 5.87E-02) exceeding the highest acceptable standard (10-4) account for 95 and 100%, respectively. Comparison of the two exposure pathways, the ingestion exposure contributes much more than the dermal contact exposure for both non-carcinogenic risk and carcinogenic risk. The results of sensitivity analysis indicate that a more accurate measurement and better definition of probability distributions for As concentration in the groundwater can increase the accuracy of health risk assessment in Jianghan Plain. The findings demonstrate the importance of the drinking water safety, and the government should take measures to ensure the drinking water safety. PMID- 29392548 TI - Utilization of Waste Biomass (Kitchen Waste) Hydrolysis Residue as Adsorbent for Dye Removal: Kinetic, Equilibrium, and Thermodynamic Studies. AB - Kitchen waste hydrolysis residue (KWHR), which is produced in the bioproduction process from kitchen waste (KW), is usually wasted with potential threats to the environment. Herein, experiments were carried out to evaluate the potential of KWHR as adsorbent for dye (methylene blue, MB) removal from aqueous solution. The adsorbent was characterized using FT-IR and SEM. Adsorption results showed that the operating variables had great effects on the removal efficiency of MB. Kinetic study indicated pseudo-second-order model was suitable to describe the adsorption process. Afterwards, the equilibrium data were well fitted by using Langmuir isotherm model, suggesting a monolayer adsorption. The Langmuir monolayer adsorption capacity was calculated to be 110.13 mg/g, a level comparable to some other low-cost adsorbents. It was found that the adsorption process of MB onto KWHR was spontaneous and exothermic through the estimation of thermodynamic parameters. Thus, KWHR was of great potential to be an alternative adsorbent material to improve the utilization efficiency of bioresource (KW) and lower the cost of adsorbent for color treatment. PMID- 29392547 TI - Vibroarthrography for early detection of knee osteoarthritis using normalized frequency features. AB - Vibroarthrography is a radiation-free and inexpensive method of assessing the condition of knee cartilage damage during extension-flexion movements. Acoustic sensors were placed on the patella and medial tibial plateau (two accelerometers) as well as on the lateral tibial plateau (a piezoelectric disk) to measure the structure-borne noise in 59 asymptomatic knees and 40 knees with osteoarthritis. After semi-automatic segmentation of the acoustic signals, frequency features were generated for the extension as well as the flexion phase. We propose simple and robust features based on relative high-frequency components. The normalized nature of these frequency features makes them insusceptible to influences on the signal gain, such as attenuation by fat tissue and variance in acoustic coupling. We analyzed their ability to serve as classification features for detection of knee osteoarthritis, including the effect of normalization and the effect of combining frequency features of all three sensors. The features permitted a distinction between asymptomatic and non-healthy knees. Using machine learning with a linear support vector machine, a classification specificity of approximately 0.8 at a sensitivity of 0.75 could be achieved. This classification performance is comparable to existing diagnostic tests and hence qualifies vibroarthrography as an additional diagnostic tool. Graphical Abstract Acoustic frequency features were used to detect knee osteoarthritis at 80% specificity and 75% sensitivity. PMID- 29392549 TI - Acute fissuration of a giant splenic artery aneurysm detected by point-of-care ultrasound: case report. AB - BACKGROUND: Epigastric pain is frequent in Emergency Medicine and remains a challenging situation. Besides benign etiologies such as gastritis or uncomplicated cholelithiasis, it could reveal myocardial infarction or vascular disease. Point-of-care ultrasound (POCUS) could be performed in such situation. CASE PRESENTATION: A healthy 66-year-old man with no previous medical history was admitted to the Emergency Department for a rapid onset epigastric pain. He reported taking non-steroidal anti-inflammatories for 1 week prior to admission. His pain had rapidly subsided and the physical examination was inconclusive. ECG and blood samples were normal. POCUS revealed a vascular mass located between the spleen and the left kidney measuring 80 * 74 mm associated with small amounts of free peritoneal fluid. Computed tomography diagnosed a fissurated giant aneurysm of the splenic artery. The aneurysm was managed emergently by endovascular exclusion by selective splenic artery embolization. The post-intervention course was uneventful and the patient was discharged home 3 days later. The patient has remained free from any complications of the embolization 6 months after the procedure. CONCLUSION: Spontaneously regressive epigastric pain with a normal physical and biology/ECG should not necessarily reassure the physician, in particular if patients have cardiovascular risk factors. A POCUS should be considered for these patients. PMID- 29392550 TI - Knowledge, attitudes, and practices (KAP) related to brucellosis and factors affecting knowledge sharing on animal diseases: a cross-sectional survey in the dry zone of Sri Lanka. AB - Farmers' lack of knowledge is assumed to have affected the presence of brucellosis in Sri Lanka for decades. This study, carried out in the Ampara district in the dry zone of Sri Lanka, revealed that there is a significant knowledge gap for brucellosis compared to foot and mouth disease (FMD) (p < 0.001). Only 8.3% of farmers knew that brucellosis causes cattle abortions. Only 2.6% knew that it is zoonotic. The difference in knowledge of the symptoms and transmission of brucellosis and FMD was significant (p < 0.001). Farmers' attitudes and practices related to the spread of the disease were poor. Farmers' education and spoken language had a negative influence on knowledge. Young people and those with strong social relationships were efficient in knowledge sharing. It can be concluded that brucellosis knowledge, attitudes, and practices are poor; thus, there is a need for more attention in disease control policymaking. Backward farmer groups should be the focus in animal health extension programs. PMID- 29392552 TI - A Decision-Analytic Model to Assess the Cost-Effectiveness of Etelcalcetide vs. Cinacalcet. AB - INTRODUCTION: Etelcalcetide is a novel intravenous calcimimetic for the treatment of secondary hyperparathyroidism (SHPT) in haemodialysis patients. The clinical efficacy and safety of etelcalcetide (in addition to phosphate binders and vitamin D and/or analogues [PB/VD]) was evaluated in three phase III studies, including two placebo-controlled trials and a head-to-head study versus the oral calcimimetic cinacalcet. OBJECTIVE: The objective of this study was to develop a decision-analytic model for economic evaluation of etelcalcetide compared with cinacalcet. METHODS: We developed a life-time Markov model including potential treatment effects on mortality, cardiovascular events, fractures, and subjects' persistence. Long-term efficacy of etelcalcetide was extrapolated from the reduction in parathyroid hormone (PTH) in the phase III trials and the available data from the outcomes study in cinacalcet (EVOLVE trial). Etelcalcetide was compared with cinacalcet, both in addition to PB/VD. We applied unit costs averaged from five European countries and a range of potential etelcalcetide pricing options assuming parity price to weekly use of cinacalcet and varying it by a 15 or 30% increase. RESULTS: Compared with cinacalcet, the incremental cost effectiveness ratio of etelcalcetide was ?1,355 per QALY, ?24,521 per QALY, and ?47,687 per QALY for the three prices explored. The results were robust across the probabilistic and deterministic sensitivity analyses. CONCLUSIONS: Our modelling approach enabled cost-utility assessment of the novel therapy for SHPT based on the observed and extrapolated data. This model can be used for local adaptations in the context of reimbursement assessment. PMID- 29392551 TI - Evaluation of comparative advantages in the profitability and competitiveness of the small-scale dairy system of Tulancingo Valley, Mexico. AB - This article combines a Policy Analysis Matrix with a sensitivity and poverty line analysis with the objective of evaluating the economic contribution of comparative advantages to the private profitability and competitiveness of small scale dairy systems. For 1 year, socioeconomic data were collected from 82 farms selected from four strata via statistical sampling. Two scenarios were established to determine the quantitative contribution of comparative advantages: (1) a simulated scenario, which accounted for the cost of purchasing the total food and the opportunity cost of the family labour force (FLF), and (2) an actual production scenario, which accounted for the cost of producing food and eliminating the payment of the FLF and included other income. The E3 and E4 producers were the most profitable and competitive in the simulated scenario and actual production scenario. Of the four scales evaluated, the E2 and E1 producers were the most efficient in taking advantage of the economic contribution provided by the comparative advantages in their own production of food and employment of the FLF, in addition to accounting for other income, a condition that increased their profitability by 171 and 144% and competitiveness by 346 and 273%, respectively. The poverty results indicated that only E3 and E4 producers were non-vulnerable in the simulated scenario and actual production scenario. The purchase of food was the comparative advantage with the greatest sensitivity to cost increases in the two scenarios analysed, which exacerbated the effect on the E1 and E2 producers. PMID- 29392553 TI - CD27+TIM-1+ memory B cells promoted the development of Foxp3+ Tregs and were associated with better survival in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is a rapid onset life-threatening condition involving uncontrolled propagation of inflammatory responses. Here, we observed that ARDS patients that survived presented significantly higher frequencies of TIM-1+ B cells, especially the CD27+TIM-1+ B cells, than the ARDS patients who succumbed to the condition. We then found that using BCR/CD40 antigen-dependent stimulation or Staphylococcus aureus Cowan (SAC) antigen independent stimulation, TIM-1+ B cells presented significantly higher IL-10 secretion and/or TGF-beta1 secretion, with SAC stimulation being more effective. CD4+ T cells that incubated with TIM-1+ B cells presented significantly elevated IL-10 secretion, TGF-beta1 secretion, and Foxp3 expression, than CD4+ T cells that incubated with TIM-1- B cells, suggesting TIM-1+ B cells promoted the in vitro development of Foxp3+ Treg cells. Interestingly, this TIM-1+ B cell mediated promotion of Foxp3 expression was mostly dependent on TGF-beta1 but not IL-10, since neutralization of TGF-beta1, but not IL-10, resulted in the suppression of Foxp3 expression. We further showed that in TIM-1+ B cells, the CD27+ classical memory B cell subset demonstrated more regulatory potency than the CD27- subset. Together, our results suggested that the TIM-1+ B cells, especially those that expressed CD27, could promote Foxp3 expression. Their clinical efficacy in treating ARDS should be examined in in vivo experiments. PMID- 29392554 TI - Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis. AB - BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates. METHODS: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia. PMID- 29392555 TI - Isolation and characterization of Aspergillus flavus strains in China. AB - Important staple foods (peanuts, maize and rice) are susceptible to contamination by aflatoxin (AF)-producing fungi such as Aspergillus flavus. The objective of this study was to explore non-aflatoxin-producing (atoxigenic) A. flavus strains as biocontrol agents for the control of AFs. In the current study, a total of 724 A. flavus strains were isolated from different regions of China. Polyphasic approaches were utilized for species identification. Non-aflatoxin and non cyclopiazonic acid (CPA)-producing strains were further screened for aflatoxin B1 (AFB1) biosynthesis pathway gene clusters using a PCR assay. Strains lacking an amplicon for the regulatory gene aflR were then analyzed for the presence of the other 28 biosynthetic genes. Only 229 (32%) of the A. flavus strains were found to be atoxigenic. Smaller (S) sclerotial phenotypes were dominant (51%) compared to large (L, 34%) and non-sclerotial (NS, 15%) phenotypes. Among the atoxigenic strains, 24 strains were PCR-negative for the fas-1 and aflJ genes. Sixteen (67%) atoxigenic A. flavus strains were PCRnegative for 10 or more of the biosynthetic genes. Altogether, 18 new PCR product patterns were observed, indicating great diversity in the AFB1 biosynthesis pathway. The current study demonstrates that many atoxigenic A. flavus strains can be isolated from different regions of China. In the future laboratory as well as field based studies are recommended to test these atoxigenic strains as biocontrol agents for aflatoxin contamination. PMID- 29392556 TI - Contrasting patterns of the bacterial and archaeal communities in a high elevation river in northwestern China. AB - The patterns of macrobiota in lotic ecosystems have been extensively explored, however, the dynamics of microbiota remain poorly investigated, especially in the high-elevation region. To address this deficit, we collected eight samples to unveil the bacterial and archaeal community in the Kaidu river, located at the arid region of northwestern China (an average of 2,500 m a.s.l.). For the bacterial community, phylogenetically Betaproteobacteria prevailed, followed by Alphaproteobacteria and Actinobacteria; at the finer genus level, Limnohabitans and Variovorax were prominent. Along the river, the bacterial community showed a continuous succession. Specifically, their alpha- and beta-diversity gradually increased, suggesting a distance-decay pattern. Additionally, there was an ecological transition between the dominant and the rare sub-community along the river: the relative abundance of the dominant members gradually decreased as the rare members increased. We report that temperature and spatial distance were significantly related to the variation of bacterial community. Variance partitioning analysis showed that the environmental factors contributed more to the bacterial community than did the spatial distance. In the case of the archaeal community, the methanogenic groups, mainly Methanosaeta and Methanosarcina, were prominent within the Kaidu river. Unlike the continuous change in the patterns of the bacterial community, the archaeal community showed a constant pattern along the river. Our results showed that the archaeal community was independent of the environmental and spatial factors. We propose that the inoculation of soil-derived archaea is responsible for the archaeal community in the Kaidu river. Together, our study demonstrated that the bacterial community in the high-elevation Kaidu river is a continuum, whereas the archaeal community is not. PMID- 29392557 TI - The antimicrobial potential of a new derivative of cathelicidin from Bungarus fasciatus against methicillin-resistant Staphylococcus aureus. AB - Cathelicidins are a family of antimicrobial peptides which exhibit broad antimicrobial activities against antibiotic-resistant bacteria. Considering the progressive antibiotic resistance, cathelicidin is a candidate for use as an alternative approach to treat and overcome the challenge of antimicrobial resistance. Cathelicidin-BF (Cath-BF) is a short antimicrobial peptide, which was originally extracted from the venom of Bungarus fasciatus. Recent studies have reported that Cath-BF and some related derivatives exert strong antimicrobial and weak hemolytic properties. This study investigates the bactericidal and cytotoxic effects of Cath-BF and its analogs (Cath-A and Cath-B). Cath-A and Cath-B were designed to increase their net positive charge, to have more activity against methicillin resistant S. aureus (MRSA). The results of this study show that Cath A, with a +17-net charge, has the most noteworthy antimicrobial activity against MRSA strains, with minimum inhibitory concentration (MIC) ranging between 32-128 MUg/ml. The bacterial kinetic analysis by 1 * MIC concentration of each peptide shows that Cath-A neutralizes the clinical MRSA isolate for 60 min. The present data support the notion that increasing the positive net charge of antimicrobial peptides can increase their potential antimicrobial activity. Cath-A also displayed the weakest cytotoxicity effect against human umbilical vein endothelial and H9c2 rat cardiomyoblast cell lines. Analysis of the hemolytic activity reveals that all three peptides exhibit minor hemolytic activity against human erythrocytes at concentrations up to 250 MUg/ml. Altogether, these results suggest that Cath-A and Cath-B are competent candidates as novel antimicrobial compounds against MRSA and possibly other multidrug resistant bacteria. PMID- 29392558 TI - Spirosoma pomorum sp. nov., isolated from apple orchard soil. AB - A Gram-negative, motile, rod-shaped, aerobic bacterial strain, designated S7-2 11T, was isolated from apple orchard soil from Gyeongsangnam-do Province, Republic of Korea, and was characterized taxonomically using a polyphasic approach. 16S rRNA gene sequence analysis indicated that strain S7-2-11T belongs to the family Cytophagaceae in phylum Bacteroidetes, and is closely related to Spirosoma luteolum 16F6ET (94.2% identity), Spirosoma knui 15J8-12T (92.7%), and Spirosoma linguale DSM 74T (91.0%). The G + C content of the genomic DNA of strain S7-2-11T was 49.8 mol%. Strain S7-2-11T contained summed feature 3 (C16:1 omega7c/C16:1 omega6c; 35.1%), C16:1 omega5c (22.4%), C15:0 iso (13.9%), and C17:0 iso 3-OH (10.6%) as major cellular fatty acids, and MK-7 as the predominant respiratory quinone. The main polar lipids were phosphatidylethanolamine, an unidentified aminophospholipid, and two unidentified polar lipids. Phenotypic and chemotaxonomic data supported the affiliation of strain S7-2-11T with the genus Spirosoma. The results of physiological and biochemical tests showed the genotypic and phenotypic differentiation of the isolate from recognized Spirosoma species. On the basis of its phenotypic properties, genotypic distinctiveness, and chemotaxonomic features, strain S7-2-11T represents a novel species of the genus Spirosoma, for which the name Spirosoma pomorum sp. nov. is proposed. The type strain is S7-2-11T (= KCTC 52726T = JCM 32130T). PMID- 29392559 TI - Probiotic potential of novel Lactobacillus strains isolated from salted-fermented shrimp as antagonists for Vibrio parahaemolyticus. AB - Lactobacillus strains have been considered good candidates as biological control agents for prevention or treatment of plant and animal infections. One L. plantarum strain FB003 and three strains (FB011, FB081, and FB110) which closed to L. sakei were isolated from fermented and salted shrimp and their abilities in inhibiting growth of Vibrio parahaemolyticus were characterized. These strains were selected as potential probiotics based on their oro-gastro-intestinal resistance, gut colonization, adhesion to Caco-2 cells, antimicrobial activities, antibiotic resistance, and safety aspects. Results of this study revealed that these isolates possessed high aggregation activities against pathogens in host intestines. Strain FB011 strain showed higher coaggregation and immunomodulatory activity in the gastro-intestinal tract than L. plantarum. These difference effects of Lactobacillus strains provide valuable information about using them to prevent Vibrio infections in the aquaculture industry. PMID- 29392560 TI - A common evolutionary pathway for maintaining quorum sensing in Pseudomonas aeruginosa. AB - In the bacterium Pseudomonas aeruginosa, the synthesis and secretion of extracellular protease is a typical cooperative behavior regulated by quorum sensing. However, this type of cooperative behavior is easily exploited by other individuals who do not synthesize public goods, which is known as the "tragedy of the commons". Here P. aeruginosa was inoculated into casein media with different nitrogen salts added. In casein broth, protease (a type of public good) is necessary for bacterial growth. After 30 days of sequential transfer, some groups propagated stably and avoided "tragedy of the commons". The evolved cooperators who continued to synthesize protease were isolated from these stable groups. By comparing the characteristics of quorum sensing in these cooperators, an identical evolutionary pattern was found. A variety of cooperative behaviors regulated by quorum sensing, such as the synthesis and secretion of protease and signals, were significantly reduced during the process of evolution. Such reductions improved the efficiency of cooperation, helping to prevent cheating. In addition, the production of pyocyanin, which is regulated by the RhlIR system, increased during the process of evolution, possibly due to its role in stabilizing the cooperation. This study contributes towards our understanding of the evolution of quorum sensing of P. aeruginosa. PMID- 29392561 TI - Functional expression and enzymatic characterization of Lactobacillus plantarum cyclomaltodextrinase catalyzing novel acarbose hydrolysis. AB - Cyclomaltodextrinases (CDases) belong to Glycoside Hydrolases (GH) family 13, which show versatile hydrolyzing and/or transglycosylation activity against cyclodextrin (CD), starch, and pullulan. Especially, some CDases have been reported to hydrolyze acarbose, a potent alpha-glucosidase inhibitor, and transfer the resulting acarviosine-glucose to various acceptors. In this study, a novel CDase (LPCD) gene was cloned from Lactobacillus plantarum WCFS1, which encodes 574 amino acids (64.6 kDa) and shares less than 44% of identities with the known CDase-family enzymes. Recombinant LPCD with C-terminal six-histidines was produced and purified from Escherichia coli. It showed the highest activity on beta-CD at 45 degrees C and pH 5.0, respectively. Gel permeation chromatography analysis revealed that LPCD exists as a dodecameric form (~826 kDa). Its hydrolyzing activity on beta- CD is almost same as that on starch, whereas it can hardly attack pullulan. Most interestingly, LPCD catalyzed the unique modes of action in acarbose hydrolysis to produce maltose and acarviosine, as well as to glucose and acarviosineglucose. PMID- 29392562 TI - Effects of heat-killed Lactobacillus plantarum against influenza viruses in mice. AB - The potential use of dietary measures to treat influenza can be an important alternative for those who lack access to influenza vaccines or antiviral drugs. Lactobacillus plantarum (Lp) is one of many lactic acid bacteria that grow in 'kimchi', an essential part of Korean meal, and several strains of Lp reportedly show protective effects against influenza. Using heat-killed Lp (nF1) isolated from kimchi, which is known for its immunomodulatory effects, we investigated whether regular oral intake of nF1 could influence the outcome of influenza virus infection in a mouse model. In a lethal challenge with influenza A (H1N1 and H3N2 subtypes) and influenza B (Yamagata lineage) viruses, daily oral administration of nF1 delayed the mean number of days to death of the infected mice and resulted in increased survival rates compared with those of the non-treated mice. Consistent with these observations, nF1 treatment also significantly reduced viral replication in the lungs of the infected mice. Taken together, our results might suggest the remedial potential of heatkilled Lactobacillus probiotics against influenza. PMID- 29392563 TI - Lysobacter spongiae sp. nov., isolated from spongin. AB - A Gram-negative, motile, aerobic and rod-shaped bacterial strain designated 119BY6-57T was isolated from spongin. The taxonomic position of the novel isolate was confirmed using the polyphasic approach. Strain 119BY6-57T grew well at 25-30 degrees C on marine agar. On the basis of 16S rRNA gene sequence similarity, strain 119BY6-57T belongs to the family Xanthomonadaceae and is related to Lysobacter aestuarii S2-CT (99.8% sequence similarity), L. maris KMU-14T (97.5%), and L. daejeonensis GH1-9T (97.3%). Lower sequence similarities (97.0%) were found with all of the other recognized members of the genus Lysobacter. The G + C content of the genomic DNA was 69.9 mol%. The major respiratory quinone was Q-8 and the major fatty acids were C16:0 iso, C15:0 iso, summed feature 9 (comprising C17:1 iso omega9c and/or C16:0 10-methyl), summed feature 3 (comprising C16:1omega7c and/or C16:1omega6c), and C11:0 iso 3-OH. The polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, three unidentified phospholipids, and an unidentified polar lipid. DNADNA relatedness values between strain 119BY6-57T and its closest phylogenetically neighbors were below 48.0 +/- 2.1%. Based on genotypic and phenotypic characteristics, it is concluded that strain 119BY6-57T is a new member within the genus Lysobacter, for which the name Lysobacter spongiae sp. nov. is proposed. The type strain is 119BY6-57T (= KACC 19276T = LMG 30077T). PMID- 29392564 TI - Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling. AB - Craniosynostosis (occurrence: 1/2500 live births) is a result of premature fusion of cranial sutures, leading to alterations of the pattern of cranial growth, resulting in abnormal shape of the head and dysmorphic facial features. In approximately 85% of cases, the disease is isolated and nonsyndromic and mainly involves only one suture. Syndromic craniosynostoses such as Crouzon, Apert, Pfeiffer, Muenke, and Saethre-Chotzen syndromes not only affect multiple sutures, but are also associated with the presence of additional clinical symptoms, including hand and feet malformations, skeletal and cardiac defects, developmental delay, and others. The etiology of craniosynostoses may involve genetic (also somatic mosaicism and regulatory mutations) and epigenetic factors, as well as environmental factors. According to the published data, chromosomal aberrations, mostly submicroscopic ones, account for about 6.7-40% of cases of syndromic craniosynostoses presenting with premature fusion of metopic or sagittal sutures. The best characterized is the deletion or translocation of the 7p21 region containing the TWIST1 gene. The deletions of 9p22 or 11q23-qter (Jacobsen syndrome) are both associated with trigonocephaly. The genes related to the pathogenesis of the craniosynostoses itself are those encoding transcription factors, e.g., TWIST1, MSX2, EN1, and ZIC1, and proteins involved in osteogenic proliferation, differentiation, and homeostasis, such as FGFR1, FGFR2, RUNX2, POR, and many others. In this review, we present the clinical and molecular features of selected craniosynostosis syndromes, genotype-phenotype correlation, family genetic counseling, and propose the most appropriate diagnostic algorithm. PMID- 29392565 TI - Vwf K1362A resulted in failure of protein synthesis in mice. AB - Von Willebrand factor (VWF) is synthesized in megakaryocytes and endothelial cells (ECs) and has two main roles: to carry and protect coagulation factor VIII (FVIII) from degradation by forming VWF-FVIII complex; and to mediate platelet adhesion and aggregation at sites of vascular injury. Previous research using the HEK293 cell line revealed that the VWF K1362 mutation interacted directly with platelet glycoprotein Ib (GPIb). Vwf K1362A knock-in (KI) mice were therefore generated to verify the in vivo function of residue 1362 in binding to platelet GPIb. The Cre-loxP system was employed to introduce the Vwf K1362A mutation systemically in mice. In blood coagulation analysis, the VWF antigen (VWF:Ag) of Lys1362Ala KI homozygous (homo) mice was below the sensitivity of detection by enzyme-linked immunosorbent assay. FVIII activities (FVIII:C) were 47.9 +/- 0.3 and 3.3 +/- 0.3% (K1362A heterozygous (hetero) and K1362A KI homo mice, respectively) compared to wild-type mice. Immunohistochemical staining analysis revealed that VWF protein did not exist in ECs of K1362A KI homo mice. These results indicated that VWF protein synthesis of K1362A was impaired after transcription in mice. K1362 seems to represent a very important position not only for VWF function, but also for VWF synthesis in mice. PMID- 29392566 TI - Codon Optimization in the Production of Recombinant Biotherapeutics: Potential Risks and Considerations. AB - Biotherapeutics are increasingly becoming the mainstay in the treatment of a variety of human conditions, particularly in oncology and hematology. The production of therapeutic antibodies, cytokines, and fusion proteins have markedly accelerated these fields over the past decade and are probably the major contributor to improved patient outcomes. Today, most protein therapeutics are expressed as recombinant proteins in mammalian cell lines. An expression technology commonly used to increase protein levels involves codon optimization. This approach is possible because degeneracy of the genetic code enables most amino acids to be encoded by more than one synonymous codon and because codon usage can have a pronounced influence on levels of protein expression. Indeed, codon optimization has been reported to increase protein expression by > 1000 fold. The primary tactic of codon optimization is to increase the rate of translation elongation by overcoming limitations associated with species-specific differences in codon usage and transfer RNA (tRNA) abundance. However, in mammalian cells, assumptions underlying codon optimization appear to be poorly supported or unfounded. Moreover, because not all synonymous codon mutations are neutral, codon optimization can lead to alterations in protein conformation and function. This review discusses codon optimization for therapeutic protein production in mammalian cells. PMID- 29392567 TI - Response Mixture Modeling: Accounting for Heterogeneity in Item Characteristics across Response Times. AB - In item response theory modeling of responses and response times, it is commonly assumed that the item responses have the same characteristics across the response times. However, heterogeneity might arise in the data if subjects resort to different response processes when solving the test items. These differences may be within-subject effects, that is, a subject might use a certain process on some of the items and a different process with different item characteristics on the other items. If the probability of using one process over the other process depends on the subject's response time, within-subject heterogeneity of the item characteristics across the response times arises. In this paper, the method of response mixture modeling is presented to account for such heterogeneity. Contrary to traditional mixture modeling where the full response vectors are classified, response mixture modeling involves classification of the individual elements in the response vector. In a simulation study, the response mixture model is shown to be viable in terms of parameter recovery. In addition, the response mixture model is applied to a real dataset to illustrate its use in investigating within-subject heterogeneity in the item characteristics across response times. PMID- 29392568 TI - Effects of Human Sulfotransferase 2A1 Genetic Polymorphisms 3 on the Sulfation of Tibolone. AB - BACKGROUND AND OBJECTIVES: Previous studies have demonstrated the metabolism of tibolone through sulfation, with the cytosolic sulfotransferase (SULT) SULT2A1 as the major responsible enzyme. The current study aimed to investigate how SULT2A1 genetic polymorphisms may affect the dehydroepiandrosterone (DHEA)- and tibolone sulfating activity of SULT2A1. METHODS: Site-directed mutagenesis was employed to generate cDNAs encoding ten different SULT2A1 allozymes. Recombinant SULT2A1 allozymes were expressed in BL21 E. coli cells, and purified using glutathione sepharose affinity chromatography. An established sulfotransferase assay was used to analyze DHEA- and tibolone-sulfating activity of the purified SULT2A1 allozymes. RESULTS: The nine human SULT2A1 allozymes plus the wild-type SULT2A1 were found to display differential sulfating activity toward DHEA and tibolone. Kinetic analysis revealed that different SULT2A1 allozymes exhibited differential substrate affinity and catalytic efficiency toward the two substrates tested. CONCLUSION: The results obtained provided useful information concerning the differential metabolism of tibolone through sulfation in individuals with different SULT2A1 genotypes. PMID- 29392569 TI - Assessing Propylene Glycol Toxicity in Alcohol Withdrawal Patients Receiving Intravenous Benzodiazepines: A One-Compartment Pharmacokinetic Model. AB - BACKGROUND AND OBJECTIVES: While some case reports indicate that high doses of propylene glycol (PG) may result in metabolic acidosis, there has been no large scale study that evaluated the risk of metabolic acidosis in patients receiving PG-containing benzodiazepines for acute alcohol withdrawal. This study was undertaken to evaluate the potential toxicity of PG in patients with acute alcohol withdrawal treated with intermittent intravenous bolus doses of diazepam and/or lorazepam. METHODS: This is a retrospective case study using data collected from 18 randomly selected patients receiving one or both of these medications per a modified Clinical Institute Withdrawal Assessment for Alcohol (CIWA) Class 3 protocol. Plasma levels of PG were estimated using a one compartment pharmacokinetic model. RESULTS: Only two patients had an elevated anion gap compared to their baseline value with one also experiencing a significant increase in serum creatinine. No increases in serum osmolarity were noted. Analysis showed that the benzodiazepine dose received was a good predictor of the estimated PG concentration (r = 0.6), but was poorly correlated with the anion gap. No significant correlation was found with the creatinine clearance or serum creatinine. Patients receiving several daily doses were at higher risk of developing an anion gap (r = 0.33), but the estimated maximum PG concentration did not correlate with the anion gap or serum concentration. CONCLUSION: It does not appear that intermittent bolus administration of intravenous benzodiazepines for alcohol withdrawal influenced renal function or anion gap regardless of number of administered doses, amount of PG received, or the estimated PG concentration. PMID- 29392571 TI - Special Issue on the Life and Work of Donald Capps (1939-2015). PMID- 29392570 TI - Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab. AB - INTRODUCTION: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy in the treatment of moderate to severe plaque psoriasis (PsO) and psoriatic arthritis (PsA), demonstrating a rapid onset of action and sustained responses with a favorable safety profile. All biotherapeutics, including monoclonal antibodies (mAbs), can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in loss of response and adverse events such as hypersensitivity reactions. Thus, the immunogenicity potential of biotherapeutics is of particular interest for physicians. Of the 2842 patients receiving secukinumab across six phase 3 psoriasis clinical trials, only 0.4% developed treatment-emergent ADAs over 3 years of treatment. Direct comparison of clinical immunogenicity incidence rates is hampered by the nature of clinical immunogenicity assays, differences in study designs, patient populations, and treatment regimens. METHODS: We evaluated side by-side in the same healthy donors two recently approved IL-17A selective antibodies, secukinumab and ixekizumab, along with adalimumab and ustekinumab, for their capacity to induce anti-drug related T cell responses in vitro and estimated their potential for developing ADAs in patients. RESULTS: We found that healthy donors show both significantly less frequent T cell responses and lower numbers of pre-existing T cells to secukinumab than to ixekizumab and adalimumab. Although there was a tendency for a lower response to ustekinumab, this difference was not significant. CONCLUSION: In summary, this in vitro study confirms the significantly lower immunogenicity potential and provides an explanation for the lower clinical immunogenicity incidence found for secukinumab in comparison to other approved therapeutic antibodies used to treat plaque psoriasis. FUNDING: Novartis Pharmaceuticals AG. PMID- 29392572 TI - The influence of gender on symptoms associated with obstructive sleep apnea. AB - BACKGROUND: It has been reported that the clinical expression of obstructive sleep apnea (OSA) may differ in women and men. OBJECTIVE: The objective of this study was to evaluate the influence of gender on reported OSA-related symptoms in a large clinical population of patients. METHODS: The database from the sleep laboratory of a tertiary care center was examined. Adult patients who had undergone a diagnostic polysomnography and completed the Berlin questionnaire, a sleep questionnaire, and the Epworth sleepiness scale were selected. Multiple logistic regression analysis was performed to assess the relationship between OSA associated symptoms and different potential explanatory variables. RESULTS: The study sample included 1084 patients, median age was 53 years, 46.5% (504) were women, 72.7% (788) had OSA (apnea/hypopnea index >= 5), and 31.2% were obese. After adjusting for age, body mass index, and apnea/hypopnea index, men were more likely to report snoring (OR 4.06, p < 0.001), habitual or loud snoring (OR 2.34, p < 0.001; 2.14, p < 0.001, respectively) and apneas (OR 2.44, p < 0.001), than women. After controlling for multiple variables, female gender was an independent predictive factor for reported tiredness (OR 0.57, p 0.001), sleep onset insomnia (OR 0.59, p 0.0035), and morning headaches (OR 0.32, p < 0.001). Reports of excessive daytime sleepiness, nocturia, midnight insomnia, and subjective cognitive complaints were not significantly associated with gender. CONCLUSION: Women with OSA were more likely to report tiredness, initial insomnia, and morning headaches, and less likely to complain of typical OSA symptoms (snoring, apneas) than men. PMID- 29392573 TI - Predictors of heterogeneity in the first-line treatment of patients with advanced/metastatic gastric cancer in the U.S. AB - BACKGROUND: Patients with metastatic gastric cancer have a poor prognosis (5-year survival of less than 10%). This study was designed to describe the treatment patterns of patients with gastric cancer and to understand the factors associated with treatment choices to inform evidence-based care. METHODS: A retrospective observational study was conducted using two real-world databases to describe treatment trends and to quantify variability in treatment patterns of patients diagnosed with advanced/metastatic gastric cancer between 1/1/2007 and 9/30/2014 in the U.S. Heterogeneity was measured by the Herfindahl-Hirschman Index (HHI). Predictors (baseline clinical, treatment, and demographic variables) of treatment regimen choice were evaluated using logistic regression. RESULTS: A total of 5772 patients with advanced/metastatic gastric cancer were included in this study [5044 from claims data and 728 from electronic medical records (EMR)]. Of the 5044 from claims data, 2457 had evidence of metastatic disease at diagnosis. Only the fluorouracil + oxaliplatin regimen exceeded 10% utilization in the first-line setting [claims metastatic (12.1%), claims advanced (8.2%), and EMR metastatic (16.6%) cohorts]. The HHI demonstrated extreme heterogeneity (0.14 for first-line therapy and 0.13 for second-line therapy). Patient age and geographic region of residence were significantly associated with treatment choice across all three cohorts in the first-line setting (p < 0.05). CONCLUSION: Treatment of patients with gastric cancer was highly variable. Despite the availability of treatment guidelines, there is a lack of consistent treatment patterns. There is a need to improve evidence-based care for patients with gastric cancer. PMID- 29392574 TI - Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects. AB - BACKGROUND: Droxidopa is an oral prodrug of norepinephrine approved for the treatment of symptomatic neurogenic orthostatic hypotension. This two-part, randomized, crossover study evaluated the 24-h pharmacokinetic profile of droxidopa in 24 healthy elderly subjects. METHODS: Noncompartmental analysis was used to calculate the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time of Cmax (tmax), and elimination half life (t1/2e) of droxidopa and metabolites. Droxidopa was administered in the fed (high-fat/high-calorie meal) or fasted state either as a single 300-mg dose (three 100-mg capsules) or 3 times/day (TID) (three 100-mg capsules) at 4-h intervals. RESULTS: Administration of a single droxidopa dose in the fed versus fasted state decreased mean Cmax (2057 vs 3160 ng/mL) and mean AUC (10,927 vs 13,857 h * ng/mL) and increased median tmax twofold (4.00 vs 2.00 h). Differences between the fed and fasted state for mean t1/2e (2.58 vs 2.68 h) were not observed. Fed versus fasted geometric mean ratios for Cmax and AUC were 66% [90% confidence interval (CI) 60.7-71.7] and 80% (90% CI 72.6-88.1), respectively. With TID dosing, similar values for Cmax were observed after each dose (range 2789-3389 ng/mL) with no return to baseline between doses. Norepinephrine Cmax was 895 pg/mL following dose 1, with no further increases upon subsequent doses; norepinephrine levels remained above baseline for 12-16 h after dose 1. CONCLUSIONS: Absorption of a single dose of droxidopa is slowed after a high fat/high-calorie meal; for consistent effect, administer droxidopa in the same manner (with or without food). Pharmacokinetic parameters of droxidopa are similar after single and TID dosing. ClinicalTrials.gov Identifier: NCT01149629. PMID- 29392575 TI - Challenges in the diagnosis of sub-segmental pulmonary embolism in symptomatic patients: a case report. PMID- 29392576 TI - Effects of aging on temporal predictive mechanisms of speech and hand motor reaction time. AB - Evidence from previous studies has suggested that movement execution in younger adults is accelerated in response to temporally predictable vs. unpredictable sensory stimuli. This effect indicates that external temporal information can modulate motor behavior; however, how aging can influence temporal predictive mechanisms in motor system has yet to be understood. The objective of the present study was to investigate aging effects on the initiation and inhibition of speech and hand movement reaction times in response to temporally predictable and unpredictable sensory stimuli. Fifteen younger (mean age 22.6) and fifteen older (mean age 63.8) adults performed a randomized speech vowel vocalization or button press initiation and inhibition tasks in two counterbalanced blocks in response to temporally predictable and unpredictable visual cue stimuli. Results showed that motor reaction time was accelerated in both younger and older adults for predictable vs. unpredictable stimuli during initiation and inhibition of speech and hand movement. However, older adults were significantly slower than younger adults in motor execution of speech and hand movement when stimulus timing was unpredictable. Moreover, we found that overall, motor inhibition of speech and hand was executed faster than their initiation. Our findings suggest that older adults can compensate age-related decline in motor reaction times by incorporating external temporal information and execute faster movement in response to predictable stimuli, whereas unpredictable temporal information cannot counteract aging effects efficiently and lead to less accurate motor timing predictive codes for speech production and hand movement. PMID- 29392577 TI - Post-Obstructive Pneumonia in Patients with Cancer: A Review. AB - Published literature on post-obstructive pneumonia is difficult to find and consists mainly of case reports or small case series. This entity is encountered most often in patients with advanced lung malignancy but is also occasionally seen in patients with community-acquired pneumonia (CAP). There are substantial differences in the manifestations, treatment, and outcomes of post-obstructive pneumonia in these two settings. When obstruction is present in patients with CAP, it is almost always secondary to an underlying pulmonary malignancy. In fact, the observation of an obstructive component in patients with CAP leads to the detection of primary or metastatic lung cancer in more than 50% of such individuals. Post-obstructive pneumonia in patients with advanced lung malignancy is far more common (~ 50% of patients) and is associated with substantial morbidity and mortality. The management of these patients is very challenging and involves multiple disciplines including medical oncology, pulmonary medicine, infectious diseases, intervention radiology, surgery, and intensive care teams. The administration of broad-spectrum antibiotic regimens is generally required. Refractory or recurrent infections despite the administration of appropriate antimicrobial therapy are the norm. Frequent and prolonged antibiotic administration leads to the development of resistant microflora. Complications such as lung abscess, empyema, and local fistula formation develop often. Relief of obstruction generally produces only temporary symptomatic improvement. PMID- 29392578 TI - Circulating Biomarkers in Heart Failure. AB - Biological markers have served for diagnosis, risk stratification and guided therapy of heart failure (HF). Our knowledge regarding abilities of biomarkers to relate to several pathways of HF pathogenesis and reflect clinical worsening or improvement in the disease is steadily expanding. Although there are numerous clinical guidelines, which clearly diagnosis, prevention and evidence-based treatment of HF, a strategy regarding exclusion of HF, as well as risk stratification of HF, nature evolution of disease is not well established and requires more development. The aim of the chapter is to discuss a role of biomarker-based approaches for more accurate diagnosis, in-depth risk stratification and individual targeting in treatment of patients with HF. PMID- 29392579 TI - Tuberculosis of the Urogenital Tract in Adults in a Tertiary Referral Center. AB - The genitourinary system is the main location of extrapulmonary tuberculosis. In Poland, it occupies the third place after tuberculosis of the pleura and lymph nodes. The aim of this study was to evaluate the prevalence and characteristics of tuberculosis in the urogenital tract in adult patients in a tertiary referral center in the years 2007-2015. The retrospective study included 87 patients, 42 women and 45 men. The average age was 62 +/- 15 years. Changes in the urinary tract were diagnosed in 91% of women and 64% of men. Testicular tuberculosis was found in ten men, prostate tuberculosis in five, and in individual cases tuberculosis of the epididymis, scrotum, uterus, and the fallopian tube were found. The diagnosis was confirmed by bacteriological methods in 47% of patients, by histopathological in 41%, and by molecular methods in 23% of patients. In 84% of patients urological or gynecological interventions had to be applied. Patients were burdened with a number of urological diseases or diseases affecting other systems which hampered the diagnosis of tuberculosis. Antituberculosis treatment gave good results. Urogenital tuberculosis is a multivariate disease and a standard unified approach is impossible. PMID- 29392580 TI - Reproductive decision making: interviews with mothers of children with undiagnosed developmental delay. AB - Reproductive decision making is complex and personal. Having a child with undiagnosed developmental delay can further complicate these decisions, as recurrence risks are unknown. This qualitative study is an exploration of the experiences of parents who have a child with an undiagnosed developmental disorder, focusing on their reproductive decisions. The aims of the research were to explore the reproductive decision making process and examine the factors that influence these decisions. Data were collected from in-depth semi-structured interviews with five mothers of children without a diagnosis. Transcripts were analysed using an interpretative phenomenological analysis. Analysis identified five factors that were considered by participants when contemplating reproductive decisions: future uncertainty, perceptions of risk, the potential impact a child would have on their current children, expectations of a family and the desire for another child. Being aware of the factors that influence reproductive decisions for these mothers and being sensitive to them can enable genetic counsellors to carry out their role more effectively, as they are aware of the factors that need to be discussed and explored before a decision is made. PMID- 29392582 TI - Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience. AB - PURPOSE: Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. METHODS: A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. RESULTS: The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6 and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. CONCLUSIONS: IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients. PMID- 29392581 TI - A novel patient-derived xenograft model for claudin-low triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell line derived xenograft methods. METHODS: We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0. RESULTS: Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix. CONCLUSIONS: Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies. PMID- 29392583 TI - A comprehensive tool for measuring mammographic density changes over time. AB - BACKGROUND: Mammographic density is a marker of breast cancer risk and diagnostics accuracy. Density change over time is a strong proxy for response to endocrine treatment and potentially a stronger predictor of breast cancer incidence. We developed STRATUS to analyse digital and analogue images and enable automated measurements of density changes over time. METHOD: Raw and processed images from the same mammogram were randomly sampled from 41,353 healthy women. Measurements from raw images (using FDA approved software iCAD) were used as templates for STRATUS to measure density on processed images through machine learning. A similar two-step design was used to train density measures in analogue images. Relative risks of breast cancer were estimated in three unique datasets. An alignment protocol was developed using images from 11,409 women to reduce non-biological variability in density change. The protocol was evaluated in 55,073 women having two regular mammography screens. Differences and variances in densities were compared before and after image alignment. RESULTS: The average relative risk of breast cancer in the three datasets was 1.6 [95% confidence interval (CI) 1.3-1.8] per standard deviation of percent mammographic density. The discrimination was AUC 0.62 (CI 0.60-0.64). The type of image did not significantly influence the risk associations. Alignment decreased the non biological variability in density change and re-estimated the yearly overall percent density decrease from 1.5 to 0.9%, p < 0.001. CONCLUSIONS: The quality of STRATUS density measures was not influenced by mammogram type. The alignment protocol reduced the non-biological variability between images over time. STRATUS has the potential to become a useful tool for epidemiological studies and clinical follow-up. PMID- 29392584 TI - Keeping an eye on congenital disorders of O-glycosylation: a systematic literature review. AB - Congenital disorders of glycosylation (CDG) are a rapidly growing family comprising >100 genetic diseases. Some 25 CDG are pure O-glycosylation defects. Even among this CDG subgroup, phenotypic diversity is broad, ranging from mild to severe poly-organ/system dysfunction. Ophthalmic manifestations are present in 60% of these CDG. The ophthalmic manifestations in N-glycosylation-deficient patients have been described elsewhere. The present review documents the spectrum and incidence of eye disorders in patients with pure O-glycosylation defects with the aim of assisting diagnosis and management and promoting research. PMID- 29392585 TI - Timing of cognitive decline in CLN3 disease. AB - BACKGROUND: CLN3 disease is a major cause of childhood neurodegeneration. Onset of visual failure around 6 years of age is thought to precede cognitive deterioration by a few years, but casuistic reports question this paradigm. The aim of our study is to delineate timing of cognitive decline in CLN3 disease. METHODS: Early neurocognitive functioning in CLN3 disease was analyzed using age at onset of visual and cognitive decline and IQ scores from literature-derived patient descriptions, supplemented with IQ scores and school history from a retrospective referral center cohort. We analyzed protracted and classical CLN3 separately and added a control group of patients diagnosed with juvenile onset macular degeneration (early onset Stargardt disease) to control for possible effects of rapid vision loss on neurocognitive functioning. RESULTS: Onset of cognitive decline at a mean age of 6.8 years (range 2-13 years, n = 19) paralleled onset of visual deterioration at a mean age of 6.4 years (range 4-9 years, n = 81) as supported by an early decline in IQ scores in classical CLN3 disease. Onset and course of vision loss was similar in patients with protracted CLN3. The decreased IQ levels at diagnosis (mean 68.4, range 57-79, n = 9) in the referral cohort were consistently associated with an aberrant early school history contrasting normal school history and cognition in Stargardt disease patients. CONCLUSIONS: Cognitive dysfunction is universally present around diagnosis in classical CLN3 disease. PMID- 29392587 TI - On using multiple imputation for exploratory factor analysis of incomplete data. AB - A simple multiple imputation-based method is proposed to deal with missing data in exploratory factor analysis. Confidence intervals are obtained for the proportion of explained variance. Simulations and real data analysis are used to investigate and illustrate the use and performance of our proposal. PMID- 29392586 TI - Transplantation as disease modifying therapy in adults with inherited metabolic disorders. AB - Transplantation is an established disease modifying therapy in selected children with certain inherited metabolic diseases (IMDs). Transplantation of hematopoietic stem cells or solid organs can be used to partially correct the underlying metabolic defect, address life threatening disease manifestations (such as neutropenia) or correct organ failure caused by the disease process. Much less information is available on the use of transplantation in adults with IMDs. Transplantation is indicated for the same IMDs in adults as in children. Despite similar disease specific indications, the actual spectrum of diseases for which transplantation is used differs between these age groups and this is partly related to the natural history of disease. There are diseases (such as urea cycle defects and X-linked adrenoleukodystrophy) for which transplantation is recommended for selected symptomatic patients as a treatment strategy in both adults and children. In those diseases, the frequency with which transplantation is used in adults is lower than in children and this may be related in part to a reduced awareness of transplantation as a treatment strategy amongst adult clinicians as well as limited donor availability and allocation policies which may disadvantage adult patients with IMDs. Risks of transplantation and disease specific prognostic factors influencing outcomes also differ with age. We review the use of transplantation as a disease modifying strategy in adults focusing on how this differs from use in children to highlight areas for future research. PMID- 29392588 TI - Clinical applicability of and changes in perfusion MR imaging in brain metastases after stereotactic radiotherapy. AB - To assess the applicability of perfusion-weighted (PWI) magnetic resonance (MR) imaging in clinical practice, as well as to evaluate the changes in PWI in brain metastases before and after stereotactic radiotherapy (SRT), and to correlate these changes to tumor status on conventional MR imaging. Serial MR images at baseline and at least 3 and 6 months after SRT were retrospectively evaluated. Size of metastases and the relative cerebral blood volume (rCBV), assessed with subjective visual inspection in the contrast enhanced area, were evaluated at each time point. Tumor behavior of metastases was categorized into four groups based on predefined changes on MRI during follow-up, or on histologically confirmed diagnosis; progressive disease (PD), pseudoprogression (PsPD), non progressive disease (non-PD) and progression unspecified (PU). Twenty-six patients with 42 metastases were included. Fifteen percent (26/168) of all PW images could not be evaluated due to localization near large vessels or the scalp, presence of hemorrhage artefacts, and in 31% (52/168) due to unmeasurable residual metastases. The most common pattern (52%, 13/25 metastases) showed a high rCBV at baseline and low rCBV during follow-up, occurring in metastases with non-PD (23%, 3/13), PsPD (38%, 5/13) and PU (38%, 5/13). Including only metastases with a definite outcome generally showed low rCBV in PsPD or non-PD, and high rCBV in PD. Although non-PD and PsPD may be distinguished from PD after SRT using the PW images, the large proportion of images that could not be assessed due to artefacts and size severely hampers value of PWI in predicting tumor response after SRT. PMID- 29392590 TI - A time of transition in the Journal of Neuro-Oncology. PMID- 29392589 TI - Surgical treatment of glioblastoma in the elderly: the impact of complications. AB - The diagnosis of glioblastoma (GBM) often carries a dismal prognosis, with a median survival of 14.6 months. A particular challenge is the diagnosis of GBM in the elderly population (age > 75 years), who have significant comorbidities, present with worse functional status, and are at higher risk with surgical treatments. We sought to evaluate the impact of current GBM treatment, specifically in the elderly population. The authors undertook a retrospective review of all patients aged 75 or older who underwent treatment for GBM from 1997 to 2016. Patient outcomes were evaluated with regards to demographics, surgical variables, postoperative treatment, and complications. A total of 82 patients (mean age 80.5 +/- 3.8 years) were seen. Most patients presented with confusion (57.3%) and associated comorbidities, and prior anticoagulation use was common in this age group. Extent of resection (EOR) included no surgery (9.8%), biopsy (22.0%), subtotal resection (40.2%), and gross-total resection (23.2%). Postoperative adjuvant therapy included temozolomide (36.1%), radiation (52.5%), and bevacizumab (11.9%). A mean overall survival of 6.3 +/- 1.2 months was observed. There were 34 complications in 23 patients. Improved survival was seen with increased EOR only for patients without postoperative complications. A multivariate Cox proportional hazards model showed that complications (HR = 5.43, 95% CI 1.73, 17.04, p = 0.004) predicted poor outcome. Long-term survivors (> 12 months survival) and short-term survivors had similar median preoperative Karnofsky Performance Scale (KPS) score (80 vs. 80, p = 0.43), but long-term survivors had unchanged postoperative KPS (80 vs. 60, p = 0.02) and no complications (0/9 vs. 23/72, p = 0.04). The benefit of glioblastoma treatment in our series was limited by the postoperative complications and KPS. Presence of a complication served as an independent risk factor for worsened overall survival in this age group. It is likely that decreased patient function limits postoperative adjuvant therapy and predisposes to higher morbidity especially in this age group. PMID- 29392591 TI - A Systematic Review of the Benefits of Hiring People with Disabilities. AB - Purpose We reviewed literature on the benefits of hiring people with disabilities. Increasing attention is being paid to the role of people with disabilities in the workplace. Although most research focuses on employers' concerns, many companies are now beginning to share their successes. However, there is no synthesis of the peer-reviewed literature on the benefits of hiring people with disabilities. Methods Our team conducted a systematic review, completing comprehensive searches of seven databases from 1997 to May 2017. We selected articles for inclusion that were peer-reviewed publications, had a sample involving people with disabilities, conducted an empirical study with at least one outcome focusing on the benefits of hiring people with disabilities, and focused on competitive employment. Two reviewers independently applied the inclusion criteria, extracted the data, and rated the study quality. Results Of the 6176 studies identified in our search, 39 articles met our inclusion criteria. Findings show that benefits of hiring people with disabilities included improvements in profitability (e.g., profits and cost-effectiveness, turnover and retention, reliability and punctuality, employee loyalty, company image), competitive advantage (e.g., diverse customers, customer loyalty and satisfaction, innovation, productivity, work ethic, safety), inclusive work culture, and ability awareness. Secondary benefits for people with disabilities included improved quality of life and income, enhanced self-confidence, expanded social network, and a sense of community. Conclusions There are several benefits to hiring people with disabilities. Further research is needed to explore how benefits may vary by type of disability, industry, and job type. PMID- 29392592 TI - Myxobolus imparfinis n. sp. (Myxozoa: Myxosporea), a new gill parasite of Imparfinis mirini Haseman (Siluriformes: Heptapteridae) in Brazil. AB - A new species of myxozoan, Myxobolus imparfinis n. sp. is described based on material from the gills of Imparfinis mirini (Haseman) (Heptapteridae). Mature myxospores are round, measuring 7.1-8.4 (7.9 +/- 0.3) MUm in length, 4.5-6.2 (5.5 +/- 0.5) MUm in width and 3.1-4.2 (3.7 +/- 0.3) MUm in thickness. The polar capsules are of unequal size, the larger polar capsule measuring 3.4-4.5 (3.9 +/- 0.3) MUm in length and 1.4-2.0 (1.7 +/- 0.1) MUm in width and the smaller capsule measuring 3.1-3.8 (3.4 +/- 0.2) MUm in length and 1.2-1.8 (1.5 +/- 0.2) MUm in width. The polar filament presents 6-7 coils. Spores had a prevalence of infection of 75% (6/8). In histological analyses we detected the development site of spores in primary filaments, in afferent branchial artery, thus classifying the type of infection to the filamental type and vascular subtype. The phylogenetic analyses of a dataset including species Myxobolus Butschli, 1882 and Henneguya Thelohan, 1892 from South America recovered M. imparfinis n. sp. as a sister species of Myxobolus flavus Carriero, Adriano, Silva, Ceccarelli & Maia, 2013. To our knowledge, this is the first record of a myxozoan species parasitising I. mirini. PMID- 29392594 TI - Capsule Commentary on Sanz et al., A Composite of Functional Status and Pneumonia Severity Index Improves the Prediction of Pneumonia Mortality in Older Patients. PMID- 29392593 TI - Gastrointestinal Perforations with Biologics in Patients with Rheumatoid Arthritis: Implications for Clinicians. AB - Gastrointestinal (GI) perforations are rare events in rheumatoid arthritis (RA) patients, but cause significant morbidity and mortality. Several studies indicate that RA patients may be at higher risk of GI perforation. Traditional RA treatments such as glucocorticoids and non-steroidal anti-inflammatory drugs increase the risk of perforation. In the past two decades, a new class of therapeutic agents called biologics has been added to the RA treatment armamentarium. Biologics are effective in controlling disease activity and are generally well tolerated; however, reports of GI perforations in association with biologics have arisen. In particular, drugs that inhibit the interleukin (IL)-6 cytokine receptor have demonstrated a higher risk of perforation compared with other therapies. Recent reports also suggest that janus kinase inhibitors may increase the risk of perforation, perhaps via downstream effects on IL-6 signaling. In this review, we discuss current data on the risk of GI perforations among RA patients receiving targeted therapies and its clinical relevance. PMID- 29392595 TI - Enhancing Resident Well-being: Illuminating the Path Forward. PMID- 29392596 TI - Team-Based Health Information Exchange Use Increased Mammography Documentation and Referral in an Academic Primary Care Practice: An Interrupted Time Series. AB - BACKGROUND: Few studies have examined the impact of health information exchanges (HIE) on quality in ambulatory settings. METHODS: From September 29, 2014, to September 4, 2015, we conducted an interrupted time series analysis of query based use of the state HIE as part of team-based care to improve mammography screening in an academic primary care practice. Women aged 50-74 years with a practice visit and who were eligible for mammography were included. We conducted non-parametric data analysis using LOESS, followed by ARIMA analysis. RESULTS: During the study period, there were 2020 visits among 904 eligible patients, including 648 visits among 485 patients during 16 baseline weeks, and 1372 visits by 755 patients during 33 intervention weeks. During the intervention period, 16.0% of eligible women who were not up to date in our EHR had a mammogram in the HIE. Of eligible women, the proportion who had a documented up-to-date mammogram at the time of their visit increased by 11.3%, from 73.4% at baseline to 84.7% (p < 0.0001), the proportion who had mammography addressed at the time of their visit increased by 42.7%, from 32.7% at baseline to 75.4% (p < 0.0001), and the proportion who were up to date at 8 weeks post-visit increased by 11.7%, from 76.3% at baseline to 88.0% (p < 0.0001). DISCUSSION: Query-based use of the state HIE as part of team-based care improved documentation of mammography and led to an increase in the proportion of eligible women who received counseling on mammography screening in one primary care practice. These results suggest that HIE use in primary care could lead to improved delivery of other preventive services. PMID- 29392597 TI - Service and Education: The Association Between Workload, Patient Complexity, and Teaching on Internal Medicine Inpatient Services. AB - BACKGROUND: Attending rounds remain the primary venue for formal teaching and learning at academic medical centers. Little is known about the effect of increasing clinical demands on teaching during attending rounds. OBJECTIVE: To explore the relationships among teaching time, teaching topics, clinical workload, and patient complexity variables. DESIGN: Observational study of medicine teaching teams from September 2008 through August 2014. Teams at two large teaching hospitals associated with a single medical school were observed for periods of 2 to 4 weeks. PARTICIPANTS: Twelve medicine teaching teams consisting of one attending, one second- or third-year resident, two to three interns, and two to three medical students. MAIN MEASURES: The study examined relationships between patient complexity (comorbidities, complications) and clinical workload variables (census, turnover) with educational measures. Teams were clustered based on clinical workload and patient complexity. Educational measures of interest were time spent teaching and number of teaching topics. Data were analyzed both at the daily observation level and across a given patient's admission. KEY RESULTS: We observed 12 teams, 1994 discussions (approximately 373 h of rounds) of 563 patients over 244 observation days. Teams clustered into three groups: low patient complexity/high clinical workload, average patient complexity/low clinical workload, and high patient complexity/high clinical workload. Modest associations for team, patient complexity, and clinical workload variables were noted with total time spent teaching (9.1% of the variance in time spent teaching during a patient's admission; F[8,549] = 6.90, p < 0.001) and number of teaching topics (16% of the variance in the total number of teaching topics during a patient's admission; F[8,548] = 14.18, p < 0.001). CONCLUSIONS: Clinical workload and patient complexity characteristics among teams were only modestly associated with total teaching time and teaching topics. PMID- 29392598 TI - The impact of extended half-life versus conventional factor product on hemophilia caregiver burden. AB - INTRODUCTION: Extended half-life factor products have reduced annualized bleeding rates in hemophilia patients. The impact of extended half-life versus conventional factor products on hemophilia caregiver burden has not been investigated. This study aimed to evaluate caregiver burden in extended half-life versus conventional factor products for hemophilia A and B. METHODS: This cross sectional web-based study of caregivers of people with hemophilia A or B was recruited from a panel research company and by word of mouth. Participants completed the Hemophilia Caregiver Impact measure, the PedsQL Family Impact Module (PedsQL), and the Work Productivity and Activity Impairment Questionnaire (WPAI). We also collected demographic, insurance coverage, and medical information related to the hemophilia patient(s). Burden differences were assessed using linear regression and matched cohort analyses. RESULTS: The sample (n = 448) included 49 people who were caring for people on extended half-life factor products. Worse caregiver burden was associated with more infusions per week and more bleeds in the past 6 months. Regression analyses suggested that caring for someone who is on a extended half-life factor product is associated with lower emotional impact (beta = - 0.11, p < 0.05, Adjusted R2 = 0.06), and shows a trend association with lower practical impact (beta = - 0.09, p < 0.10, Adjusted R2 = 0.05). The matched cohort analysis also revealed that people on extended half-life factor product had lower Emotional Impact and Practical Impact scores (t = - 2.95 and - 2.94, respectively, p < 0.05 in both cases). No differences were detected on the PedsQL or the WPAI. CONCLUSION: The reduced required frequency of factor product infusions of extended half-life factor products appears to reduce the emotional distress and practical burden of caregiving. Future work should evaluate the longitudinal impact. PMID- 29392599 TI - Anxiety symptoms have a direct effect on oral health perception in young women. AB - PURPOSE: Assess the influence of anxiety symptoms on oral health related-quality of life in young women from a cohort study in Southern Brazil. METHODS: A sample of 535 young mothers were analyzed. Interviews and psychological evaluations were carried out by trained psychologists. The Brazilian version of the Corah's dental anxiety scale and the Beck anxiety inventory were used to evaluate dental anxiety and anxiety symptoms, respectively. The oral health-related quality of life (OHRQoL) was assessed by the Oral Impacts on Daily Performance instrument. Dental examinations were performed by trained dentists to assess oral health status (DMFT). The effect of anxiety symptoms on oral health-related quality of life was estimated using the parametric g-formula. RESULTS: The prevalence of negative impact on OHRQoL was of 46.3 and 28% of the women presented anxiety symptoms. Unadjusted analysis showed that women with anxiety symptoms had 2.5 higher impact on OHRQoL (OR 2.55; CI 95% 1.72-3.79). The parametric g-formula revealed that anxiety had a direct effect on oral health perception (OR 1.16; CI 95% 1.04 1.30), not mediated by dental anxiety. CONCLUSION: Oral health-related quality of life is influenced by anxiety symptoms, regardless of dental anxiety. PMID- 29392601 TI - School Refusal Behavior in Indian Children: Analysis of Clinical Profile, Psychopathology and Development of a Best-Fit Risk Assessment Model. AB - OBJECTIVES: School refusal is seen as an emergency in child psychiatry and various risk factors have been analyzed. Children who present with school refusal have been shown to have several associated psychiatric comorbidities. However, risk assessment of psychiatric comorbidities is lacking, particularly in the Indian context. The authors aimed to study the sociodemographic profile and associated psychopathology in children with school refusal. They compared the prevalence rates of psychiatric illnesses to that of the community. A best-fit model for risk assessment of psychopathology was formulated. METHODS: Past records of children aged 5-16 y, who presented with school refusal in the period from June 2013 through June 2015 to authors' Child Guidance Clinic were studied and their sociodemographic details, symptoms and diagnoses were obtained. Chi square test of proportion was used to compare the prevalence rates between the study population and community. Multinomial analysis was used to elucidate a best fit model of risk assessment. RESULTS: School refusal was seen in 3.6% of children. 77.8% of the children had a psychiatric diagnosis, most common being depression (26.7%), followed by anxiety (17.7%). Prevalence of psychiatric disorders was significantly higher in the study population than community (p < 0.05). A best-fit model of 4 factors: academic difficulties, adjustment problems at school, behavioral problems and parental conflicts is suggested (p < 0.05). CONCLUSIONS: School refusal is associated with significant psychopathology, most commonly depression, followed by anxiety. The best-fit model for risk assessment can predict the likelihood of psychopathology and help in early diagnosis. PMID- 29392600 TI - Poor medical care for people with migraine in Europe - evidence from the Eurolight study. AB - BACKGROUND: Migraine is prevalent everywhere, and disabling. It is also neglected: consequently, it is under-diagnosed and undertreated. We analysed data from the Eurolight study on consultations and utilization of migraine-specific medications as indicators of adequacy of medical care in Europe. METHODS: Eurolight was a cross-sectional questionnaire-based survey in 10 European countries. Sampling was population-based in six (Germany, Italy, Lithuania, Luxembourg, Netherlands, Spain) and from consecutive patients attending general practitioners (GPs) for any reason in three (Austria, France, UK). Additional samples in Netherlands and Spain, and the only sample from Ireland, were recruited by lay headache organisations. We recorded migraine prevalence and frequency, and utilization of medical services and medications (acute and preventative). RESULTS: Among 9247 participants (mean age 43.9 +/- 13.9 years, M/F ratio 1:1.4), 3466 (37.6%) were diagnosed with migraine (definite or probable). Of these, 1175 (33.8%) reported frequent migraine (> 5 days/month) and might clearly expect benefit from, and therefore had need of, preventative medication. In population-based samples, minorities of participants with migraine had seen a GP (9.5-18.0%) or specialist (3.1-15.0%), and smaller minorities received adequate treatment: triptans 3.4-11.0%, with Spain outlying at 22.4%; preventative medication (1.6-6.4% of those eligible, with Spain again outlying at 13.7%). Proportions were greater in GP-based samples (13.6-24.5% using triptans, 4.4-9.1% on preventative medication) and among those from lay organisations (46.2 68.2% and 16.0-41.7%). Participants with migraine who had consulted specialists (3.1-33.8%) were receiving the best care by these indicators; those treated by GPs (9.5-29.6%) fared less well, and those dependent on self-medication (48.0 84.2%) were, apparently, inadequately treated. CONCLUSION: In wealthy European countries, too few people with migraine consult physicians, with proportionately too many of these seeing specialists, and migraine-specific medications are used inadequately even among those who do. These findings represent yet another call for action in Europe to improve care for people with headache. Education of both health-care providers and the public should be central to this action. PMID- 29392602 TI - "Duodenal Adenocarcinoma Giving Rise to Rectal Metastasis" a Rare Disease with an Extremely Rare Metastatic Pattern. PMID- 29392603 TI - Lipid metabolism and benzo[a]pyrene degradation by Fusarium solani: an unexplored potential. AB - In a search for indigenous soil saprotrophic fungi for bioremediation purposes, Fusarium solani, a saprotrophic fungus belonging to the phylum Ascomycota, was isolated from a fossil carbon contaminated soil. The effect of the carbon source, glucose or olive oil, was investigated in vitro on the biomass produced by F. solani and on the degradation of benzo[a]pyrene (BaP) in mineral medium. After only 12 days of incubation, BaP degradation by F. solani was higher (37.4%) with olive oil used as the carbon source than the one obtained with glucose (4.2%). Catalase activity increased in the presence of olive oil (3.4 MUkat mg-1 protein) in comparison with glucose (2.1 MUkat mg-1 protein). When olive oil was used as the carbon source, BaP degradation increased up to 76.0% in the presence of a specific catalase inhibitor, 3-Amino-1,2,4-triazole (2 mM). This metabolic engineering strategy based both on the use of olive oil as carbon source (cultivation strategy) and on the blocking of the catalase activity could be an innovative and promising approach for fungal biodegradation of BaP and consequently for bioremediation of soil contaminated with polycyclic aromatic hydrocarbons. PMID- 29392604 TI - Influence of labile dissolved organic matter on nitrate reduction in a seepage face. AB - Seepage faces, the outer rim of subterranean estuaries, are an important reaction node for SGD-borne nitrate (NO3-) on a global scale. Labile dissolved organic matter (DOM) has been suggested to be a key factor constraining the NO3- removal rate in aquifer systems. To determine whether and to what extent the availability of labile DOM affects benthic NO3- reduction in seepage faces, a series of flow through reactor (FTR) experiments with sandy sediment collected from a seepage face was conducted under oxic conditions. Experimental results revealed that the addition of labile DOM (glucose) to porewater did not trigger a significant enhancement in NO3- reduction rate. In contrast, the aerobic respiration was boosted from ca. 50 to 90 MUmol dm-3 sediment h-1 by glucose amendments, accounting for approximately 70% consumption of the labile DOM pool. This rapid consumption may increase the NO3- reducing capability within the sediment, but only indirectly. Together with fluorescent DOM (FDOM) analyses, it can be inferred that NO3- reducers tend to choose sediment organic matter the prime electron donor under the experimental conditions. As a result, enrichment of DOM in seepage faces, depending on composition, might only stimulate aerobic respiration and nitrification, thus promoting the increase of ensuing NO3- fluxes to adjacent coastal waters. PMID- 29392605 TI - The impact of pesticides on the macroinvertebrate community in the water channels of the Rio Negro and Neuquen Valley, North Patagonia (Argentina). AB - Agriculture represents the second most important economic activity in the North Patagonian Region of Argentina and non-selective insecticides are still being used with significant implications to the quality of the environment. The range of concentrations (MUg/L) determined for azinphosmethyl, chlorpyrifos, and carbaryl in drainage channels were from non-detected to 1.02, 1.45, and 11.21, respectively. Macroinvertebrate abundance and taxon richness in drainage channels were significantly lower in November compared to the other sampling months (October, February). The decrease in taxon richness observed in November was associated with chlorpyrifos and azinphosmethyl peak concentrations. The most remarkable changes were the decrease in sensitive taxa such as Baetidae and the increase in some tolerant taxa such as Chironomidae and Gastropoda.For all three pesticides, the acute hazard quotient exceeded the risk criteria for invertebrates. The effects of the three pesticides on aquatic organisms, characterized by joint probability curves, showed that the LC50 of 10% of the species were exceeded five and three times by the concentrations of azinphosmethyl and chlorpyrifos during the study period, respectively. However, the correlation between the pesticide concentrations and both taxon richness and abundance of macroinvertebrates at each site (irrigation and drainage channels) was indicative that only chlorpyrifos was negatively correlated with both parameters (Spearman r2 - 0.61, p = 0.0051 and Spearman r2 - 0.59, p = 0.0068 for taxon richness and abundance correlation, respectively). We conclude that macroinvertebrate assemblages in drainage channels were highly affected by chlorpyrifos levels. PMID- 29392606 TI - Effects of cadmium on photosynthesis of Schima superba young plant detected by chlorophyll fluorescence. AB - Contamination by heavy metals has become a serious environmental pollution issue today due to its potential threat to plant, wildlife, and human health. Photosynthesis, a process in which light energy is used to produce sugar and other organic compounds, is sensitive to heavy metals. In the present study, the response of photosynthetic process and carbon assimilation of Schima superba was investigated under cadmium (Cd) stress. Three Cd concentrations (0, 300, and 600 mg kg-1) were used designated as control (CK), low Cd (L1), and high Cd treatment (L2) of plants. Results showed that photosystem II (PSII) acceptor and donor side electron transport were more easily blocked in treatment compared to control, and L2 have more significant changes than L1. A substantial decrease of 820 nm reflection curve absorption was observed both in L1 and L2 treatments. Special energy fluxes showed significant difference between the control group and the treated group, which indicated that low concentration Cd stress can cause decrease in quantum yield of PSII in plants studied. Non-stomatal factors resulted in a decrease in net photosynthetic rate and a decrease in photosystem activity. Our results suggested that Cd can damage structure and function of the photosynthesis of S. superba young plants. PMID- 29392607 TI - Analysis and utilization of temple waste flowers in Coimbatore District. AB - The present work deals with collection, handling, utilization, and management of the waste flowers that are coming out of the temples in Coimbatore District, Tamilnadu, India. An attempt has been made to provide a current situation and complete analysis of temple waste flowers (TWFs) with suggestions and recommendations. As a part of Clean India, Clean and Green Kovai (Green Coimbatore) mission, this paper gives an idea to reduce the volume of temple waste flowers by converting into activated carbon by direct pyrolysis process and chemical activation with sulfuric acid and phosphoric acid process, respectively. The products were analyzed and compared based on the results of physicochemical parameters including pH, conductivity, moisture content, ash content, volatile content, fixed carbon, bulk density, porosity, specific gravity, water soluble matter, acid soluble matter, iodine number, methylene blue number, yield, and Brunauer-Emmett-Teller (SBET) surface area. The structure, surface morphology, and chemical compositions of carbon were determined by field emission scanning electron microscopy (FeSEM), and energy-dispersive X-ray spectroscopy (EDS), respectively. From the comparison of results, the activated carbon produced from temple waste flowers by direct pyrolysis process is fairly better due to low moisture content, low ash content, better yield, and higher surface area. PMID- 29392608 TI - The environmental impact of informal and home productive arrangement in the jewelry and fashion jewelry chain on sanitary sewer system. AB - The outsourcing informal home practices adopted in jewelry and fashion jewelry chain can cause toxic substance elimination in the effluents and raise a concern for its environmental impact. This study evaluates if this informal work alters the concentration of potentially toxic elements (PTEs: As, Cd, Cr total and Cr VI, Cu, Hg, Ni, Pb, Sn, and Zn) in the sewage network. The sanitary sewage samples (n = 540) were collected in 15 manholes during two campaigns in three different areas of Limeira-SP, Brazil (industrial area, with informal work and without known industrial/informal activity). The sewage sludge (n = 12), raw (n = 12), and treated sewage (n = 12) were collected in two wastewater treatment plants (WWT: AS and TATU) operating with different treatment process. The PTE determination was performed by ICP-OES, direct mercury analysis, and UV-Vis spectroscopy. Cr-VI, Cu, Ni, and Zn were the only elements above the quantification limit. Four samples exceeded Cu or Zn values permitted to be discharged into sewage system; however, the concentration average was lower than that established by Brazilian legislation. A difference was found between values above and below the 75th percentile for campaign and total organic carbon values (p < 0.015). The AS-treated sewage presented low concentrations of Cu (p < 0.05), Zn (p = 0.02), and Ni (p = 0.01) compared to treated sewage from TATU. In the sludge samples, the Cu means exceeded the limits of the Brazilian legislation (1500 mg kg-1) and the Zn results were very close to the limits (2800 mg kg-1). The heterogeneity of the results can indicate the sporadic nature of the PTE's sanitary disposal. PTEs used in jewelry and fashion jewelry chain may precipitate on the sludge, where presented high concentrations of Cu and Zn which require controlled destination. PMID- 29392609 TI - Matrix effect in case of purification of oily waters by membrane separation combined with pre-ozonation. AB - In the present study, oil in water emulsions (coil = 100 ppm; doil droplets < 2 MUm) was purified with ozonation followed by microfiltration using polyethersulfone (PES) membrane (dpore = 0.2 MUm). The effects of pre-ozonation on membrane microfiltration were investigated in detail both in case of ultrapure and model groundwater matrices, applying different durations (0, 5, 10, and 20 min) of pre-ozonation. Simultaneously, the effects of added inorganic water components on the combined method were investigated. Size distribution of oil droplets, zeta potentials, fluxes, and purification efficiencies were measured and fouling mechanisms were described in all cases. It was found that the matrix significantly affected the size distribution and adherence ability of oil droplets onto the membrane surface, therefore fouling mechanisms also were strongly dependent on the matrix. In case of low salt concentration, the total resistance was caused mainly by reversible resistance, which could be significantly reduced (eliminated) by pre-ozonation. In case of model groundwater matrix, nearly twice higher total resistance was measured, and irreversible resistance was dominant, because of the higher adhesion ability of the oil droplets onto the membrane surface. In this case, pre-ozonation resulted in much lower irreversible, but higher reversible resistance. Increased duration of pre ozonation raised the total resistance and reduced the elimination efficiency (due to fragmented oil droplets and water soluble oxidation by-products) in both cases, therefore short pre-ozonation can be recommended both from economic and performance aspects. PMID- 29392610 TI - Sonocatalytic degradation of rhodamine B in presence of CdS. AB - A novel sonocatalyst CdS was prepared by a facile precipitation method, and characterized by X-ray powder diffraction, transmission electron microscopy, UV vis absorption spectroscopy, and photoluminescence spectroscopy. Comparative sonocatalytic degradation experiments were carried out in different conditions under ultrasonic irradiation and with rhodamine B (RhB) used as the model substrate. Results indicate that CdS is a highly active sonocatalyst. The efficiency of RhB sonodegradation in aqueous solutions within 4 h is up to 70% after the addition of CdS. Abundant *OH during the RhB sonodegradation was detected, which may be responsible for the high sonodegradation rate over CdS under ultrasonic radiation. PMID- 29392611 TI - Thermodynamic characterization of a non-commercial emulsifying agent for asphalt emulsion. AB - The objective of the present work was to characterize a non-commercial emulsifying agent: dodecylpyridinium thiocyanate (C12PCNS). This study was carried out by conductimetry technique in the temperature range 25-50 degrees C. Assuming the system conforms to the pseudo-phase separation model, change of standard Gibbs free energy, DeltaG m0, enthalpy, DeltaH m0, and entropy of micellization, DeltaS m0, were estimated. Values for critical micelle concentration (cmc) and the ionization degree, beta, were determined directly from the experimental data. The results show that the influence of the counter ion is very relevant, because the cmc for this compound is appreciably greater than the cmc of other pyridinium homologs of the same chain length. Finally, the compensation rule for this system has been found and the compensation temperature and the intercept DeltaH*-it is an indication of the stability of the micelle were estimated. PMID- 29392612 TI - Robotic-assisted renal transplantation with total extraperitonealization of the graft: experience of 34 cases. AB - The aim of the study is to elucidate the method of complete extraperitonealization of the graft while performing transperitoneal robotic renal transplant recipient operation. This is a retrospective study of 34 robotic assisted kidney transplant (RAKT) utilizing our technique from July 2015 to June 2017. The study is performed in a quaternary private hospital setting. The surgery was performed using our novel peritoneal flap technique allowing complete extraperitonealization of the kidney. Total of 34 patients underwent RAKT in our hospital. Mean age was 40.6 +/- 8.1 years, there were 25 males and 9 females. 30 had single vessel and four had double vessels. 27 patients received living donor graft while seven had deceased donor. The mean blood loss was 88 +/- 51 mL, mean anastomotic time was 32 +/- 3.3 min, mean total operative time was 145 +/- 15 min, mean hospital stay was 5.8 +/- 2.3 days, time to nadir creatinine was 4.3 +/ 1.9 days, median creatinine level at the end of 6 months was 1.3 mg/dL. There were three open conversions in our series, one of which had delayed graft function requiring hemodialytic support. Total extraperitonealization of the graft reproduces closely the technique of open kidney transplant with good graft function. This would be a step toward the ultimate goal of performing a complete extraperitoneal robotic transplant. Further refinements in robotic instruments would make this a reality in near future. PMID- 29392613 TI - Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: The aim of this study was to investigate the impact of decreased skeletal muscle (SM) volume on survival outcomes in patients undergoing surgical resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: Between March 2000 and February 2015, 323 patients who underwent upfront surgical resection for PDAC were identified from the Mayo Clinic SPORE in Pancreatic Cancer. Body composition data, including SM area, subcutaneous adipose tissue area, and visceral adipose tissue area were calculated using an abdominal computed tomography (CT) image at the third lumbar spinal level. The body composition data were normalized by patients' height (e.g., SM index, cm2/m2) and analyzed as continuous variables. Clinicopathological findings and body composition data at initial diagnosis were evaluated for association with overall survival and recurrence-free survival. RESULTS: Because the median SM index was significantly different between males vs. females (49.9 cm2/m2 [range, 32.0-70.3] vs. 39.4 cm2/m2 [range, 29.2-66.2], P < 0.001), it was standardized for each sex and used for further analyses. Parameters independently associated with a shorter overall survival were a larger tumor size (P = 0.007), a greater tumor extent (P = 0.037), a higher carbohydrate antigen 19-9 level (P < 0.001), and a smaller sex standardized SM index (P = 0.011). Parameters independently associated with a shorter recurrence-free survival were female sex (P = 0.029), a larger tumor size (P < 0.001), a higher carbohydrate antigen 19-9 level (P = 0.001), and a smaller sex-standardized SM index (P = 0.007). CONCLUSIONS: A smaller sex-standardized SM index is a predictive factor for shorter overall and recurrence-free survival in PDAC patients undergoing surgery. PMID- 29392614 TI - Treatment modalities and outcomes of pleomorphic hyalinizing angiectatic tumor: a systematic review of the literature. AB - A systematic review of the cases documented in the literature regarding Pleomorphic hyalinizing angiectatic tumor of soft parts (PHAT) was performed in order to identify (1) location on presentation (2) surgical treatment modality (3) recurrence rate (4) any associations between location, age, histology, surgery type on recurrence. A systematic review of medical literature listed on PubMed was conducted identifying any prior case report and/or case series of diagnosed PHAT, with no exclusion based on language or time. Twenty-nine articles were identified removing any articles with duplicated cases yielding a total of 93 cases. Cases were broken down by gender, presenting location (UE/LE/axial), surgery type [wide local resection, non-wide local, wide local with radiation therapy (RT), non-wide local with RT], recurrence, and time to recurrence. The mean age at presentation was 54.5 +/- 17.1 (range 10-89) with the 76% of cases appearing in the lower extremity (15% UE, 9% Axial). Of the 93 patients, 74 had a known surgical procedure, 31% WL, 40% NWL, 8% WL + RT, 1% NWL + RT. Of those treated surgically, 63 pts had documented follow-up and 18 (29%) had recurrence. A strong association was observed between surgery type and recurrence. Local recurrence was more common within the group undergoing NWLE in 52% (16/41) of cases (p = 0.002). Kaplan-Meier analysis showed an estimate mean time for recurrence of 43.87 months [95% confidence interval (CI) 24.52-63.22; and standard error (SE) 7.59] for the entire population. A trend was also seen toward males having a shorter disease-free survival than females (29.4 mos. vs. 69.5 mos.). No significant association seen between size, location, histology type and recurrence. PHAT has a characteristic presentation in the LE with a relatively high rate of local recurrence and slow-growing potential. Wide local excision appears to be superior in decreasing recurrence rates and a long-term follow-up period is needed. PMID- 29392615 TI - A comprehensive and narrative review of historical aspects and management of low grade hallux rigidus: conservative and surgical possibilities. AB - Hallux rigidus, Latin for Stiff Toe, is characterized by an osteoarthritic degeneration of the articular surfaces of the first metatarsophalangeal joint. The aim of this literature narrative overview is to summarize and expose the great amount of management concepts and information, including the well-codified operative procedures and the more up to date knowledge about non-operative and surgical treatment of hallux rigidus. This may provide current information for physicians, medschool attendants and researchers. A comprehensive literature search using PubMed database has been performed, up to April 1, 2017. Several different types of treatment are described in the literature for low-grade hallux rigidus. The management for hallux rigidus can involve a variety of therapeutic interventions, conservative or operative. Hallux rigidus is a complex disease characterized by several clinical and pathological findings, and to achieve optimal results, surgical treatment for low-grade forms should be chosen between several surgical techniques depending on the degree of arthritis and other different clinical conditions. PMID- 29392617 TI - Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin resistant mice by an indirect mechanism. AB - PURPOSE: Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. METHODS: Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 umol/kg) or PBS during 28 days. RESULTS: Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. CONCLUSIONS: Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes. PMID- 29392616 TI - Kaempferol attenuates hyperglycemia-induced cardiac injuries by inhibiting inflammatory responses and oxidative stress. AB - PURPOSE: Suppression of inflammation and oxidative stress is an attractive strategy to against diabetic cardiomyopathy (DCM). Kaempferol (KPF) exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of KPF on protecting myocardial injury in diabetes. The present study aimed to investigate the effect of KPF on DCM and underlying mechanism. METHODS: Anti-inflammation and anti-oxidative stress activities of KPF were evaluated in H9c2 cells or primary cardiomyocytes by real-time quantitate PCR, immunoblotting, immunofluorescence, ELISA, and FACS. Streptozotocin (STZ) induced type 1 diabetes mellitus mice were constructed. Corresponding to experiments in vitro, the therapeutic effect of KPF was also assessed using heart tissues from mice. RESULTS: KPF significantly inhibited high glocose (HG) induced expression of inflammatory cytokines and generation of ROS, leading to reduced fibrotic responses and cell apoptosis in vitro. KPF mediated DCM protective effects through inhibiting nuclear factor-kappaB (NF-kappaB) nucleus translocation and activating nuclear factor-erythroid 2 p45-related factor-2 (Nrf 2). In STZ-induced type 1 diabetic mouse model, KPF prevented diabetes-induced cardiac fibrosis and apoptosis. These changes were also accompanied by reducing inflammation and oxidative stress in diabetic mice hearts. CONCLUSION: KPF is a potential therapeutic agent for the treatment of DCM, mechanically linked to inhibition of NF-kappaB and Nrf-2 activation. PMID- 29392618 TI - Rapid recovery of hypogonadism in male patients with end stage renal disease after renal transplantation. AB - PURPOSE: End stage renal disease (ESRD) in male patients is associated with a high prevalence of hypogonadism. After renal transplantation (RTx) an improvement in gonadal function is often observed. However, the time course of changes in pituitary-gonadal axis after RTx and the influence of renal function, age and anthropometric parameters are not well characterized. We prospectively evaluated pituitary-gonadal axis in male patients with ESRD before and after RTx for up to 1 year. METHODS: Ninety-seven male patients with ESRD were consecutively investigated on day of surgery and 1, 3, 6, and 12 months after RTx. Time course of changes in sex hormones (total testosterone ((TT)), calculated free testosterone ((cfT)), estradiol (E2), LH, FSH and prolactin), and interdependence with renal function, age, anthropometric factors, cause of ERDS, time on dialysis, and transplant associated factors were analyzed. RESULTS: Hypogonadism (TT < 8 nmol/l) was present in 40% of pts prior to RTX and in only 18% at 1 year after RTX. Recovery from hypogonadism was significantly higher in pts < 50 years and occurred within 3 months. RTx resulted in a decrease in E2/T ratio starting at 1 month and suggesting a shift from estrogen to testosterone production. BMI and waist circumference had the similar impact on T levels after successful RTx compared to patients without renal disease. No specific impact on recovery of hypogonadism was found for time on dialysis prior to RTx and living or cadaver transplantation. CONCLUSIONS: Successful RTx is associated with a rapid recovery from hypogonadism within 3 months preceeded by improvement in renal function particularly in patients younger than 50 years. PMID- 29392619 TI - Hybrid techniques and patients' safety in implementing transoral sublingual thyroidectomy. AB - PURPOSE: Cosmetic advantages and minimally invasive aspects become more and more important for patients undergoing thyroidectomy. We report on our personal experience and conceptual design in dealing with approaches to the thyroid gland, which we were the first to describe. We report on ideas and experiences concerning its implementation. METHODS: Our own experiences and considerations in the process of finding an endoscopic minimally invasive access in thyroidectomy are compared in a systematic review with the available literature on minimally invasive or endoscopic thyroid surgery. We describe our failures and risk assessment. RESULTS: Our analysis of the literature on minimally invasive thyroidectomy and our own experiences lead us to the conclusion that using different hybrid technologies during the implementation of endoscopic procedures in thyroid surgery can be helpful and could improve patients' safety. A combination of transoral endoscopic and non-transoral techniques might be a useful safer, but more traumatizing alternative for implementation. Several studies show the feasibility of the transoral access in thyroid surgery. We believe that the implementation of these new procedures as routine surgery in specialized centers must be carefully considered and discussed. CONCLUSIONS: The transoral access seems to be less invasive than other extracollar endoscopic accesses in thyroid surgery. For a sublingual single-access routine surgery, better instruments are needed. The vestibular access is possible with standard instruments. Using hybrid technologies for implementation should not be considered as a failure. The transoral thyroidectomy can be a safe method in the hand of experienced surgeons. We expect this hybrid technique to play a major part in further spreading endoscopic transoral thyroid surgery. PMID- 29392621 TI - Spatial legend compatibility within versus between graphs in multiple graph comprehension. AB - Previous research has shown that spatial compatibility between the data region and the legend of a graph is beneficial for comprehension. However, in multiple graphs, data-legend compatibility can come at the cost of spatial between-graph legend incompatibility. Here we aimed at determining which type of compatibility is most important for performance: global (legend-legend) compatibility between graphs, or local (data-legend) compatibility within graphs. Additionally, a baseline condition (incompatible) was included. Participants chose one out of several line graphs from a multiple panel as the answer to a data-related question. Compatibility type and the number of graphs per panel were varied. Whereas Experiment 1 involved simple graphs with only two lines/legend entries within each graph, Experiment 2 explored more complex graphs. The results indicated that compatibility speeds up comprehension, at least when a certain threshold of graph complexity is exceeded. Furthermore, we found evidence for an advantage of local over global data-legend compatibility under specific conditions. Taken together, the results further support the idea that compatibility principles strongly determine the ease of integration processes in graph comprehension and should thus be considered in multiple-panel design. PMID- 29392620 TI - Treatment of Autoimmune Bullous Disorders in Pregnancy. AB - Autoimmune bullous diseases (AIBD), including pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid, and pemphigoid gestationis, pose significant therapeutic challenges, especially in pregnant and post-partum breastfeeding patients or those planning to conceive. Data on the safety and efficacy of therapeutic interventions during the perinatal period are lacking because randomized controlled trials are typically not performed in this setting. However, many of the treatments for AIBD are also used in other diseases, so data can be extrapolated from studies or case reports in these other patient populations. It appears that many of the treatments for AIBD can adversely affect the fetus or neonate, and alterations in immune status caused by pregnancy-associated hormonal changes can negatively impact disease control. This article summarizes and weighs the risks and benefits of the various agents used to treat AIBD during pregnancy. We also present the available information on lactation as well as effects on male fertility. PMID- 29392623 TI - Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis. AB - Elevated levels of pro-inflammatory markers are evident in patients with heart failure and are associated with disease severity and prognosis. Exercise training has been shown to reduce circulating levels of pro-inflammatory cytokines and other pro-inflammatory markers in healthy and clinical populations. The aim of the systematic review and meta-analysis was to investigate the effect of aerobic (AT) and resistance training (RT) interventions on circulating concentrations of inflammatory markers; tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL 6), C-reactive protein (CRP), fibrinogen, soluble intercellular adhesion molecule (sICAM) and soluble vascular adhesion molecule (sVCAM) in heart failure patients. We conducted database searches (PubMed, EMBASE and Cochrane Trials Register to 30 June 2017) for exercise-based trials in heart failure, using the following search terms: exercise training, inflammation, tumour necrosis factor-alpha, interleukin 6, C-reactive protein, fibrinogen, soluble intercellular adhesions molecule-1, soluble vascular adhesion molecule-1. Twenty studies, representing 18 independent trials, were included in the review. Pooled data of six studies indicated a minimally favourable effect of exercise training on circulating TNF-alpha [SMD 0.42 (95% CI 0.15, 0.68), p = 0.002)]. However, together the pooled and descriptive analyses failed to provide strong evidence for a reduction in other pro-inflammatory markers. However, given the complexity of heart failure and the pathways involved in the immune and inflammatory process, large prospective trials considering aetiology, comorbidities and local skeletal muscle inflammation are required to elucidate on the anti-inflammatory effect of exercise in this population. PMID- 29392622 TI - Clinical development of CDK4/6 inhibitor for breast cancer. AB - Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation. Currently positive data of several clinical trials using three CDK4/6 inhibitors (palbocilcib, ribociclib, abemaciclib) were published and primary endpoint were met in all phase III studies. Therefore, practice change of endocrine therapy has been achieved in ER positive MBC. This review will present clinical trial data, including both the efficacy and safety of CDK4/6 inhibitors for MBC, and describe the designs of the mainly ongoing clinical trials examining CDK4/6 inhibitors for the treatment of MBC and EBC. PMID- 29392624 TI - Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers. AB - BACKGROUND: Radiolabeled anti-myosin imaging is well-established for imaging doxorubicin-induced cardiotoxicity. However, to enable imaging of drug-induced cardiotoxicity in small experimental animals, pretargeting with bispecific anti myosin-anti-DTPA-Fab-Fab' and targeting with high-specific radioactivity Tc-99m DTPA-succinylated-polylysine (DSPL) was developed. METHODS: Mice were injected biweekly with 10 mg/kg Dox or its equivalent as D-Dox-PGA. Tc-99m-DSPL myocardial activity after pretargeting with bsAb-Fab-Fab' was determined after gamma imaging performed at day 7 for Dox-treated mice and day 39 for all others. RESULTS: Mice treated with 10 mg/kg Dox lost 10% total body weight in 1 week and 20% after a second dose. Pretargeted mice treated with 30 mg/kg cumulative D-Dox-PGA dose showed no loss of body weight for the duration of the study. Cardiotoxicity was confirmed by gamma imaging and scintillation counting (1.9 +/- 0.25 [mean% ID/g +/- SD]) after 1 dose of Dox. Mice injected with 3 * 10 mg/kg Dox equivalent as D Dox-PGA (0.4 +/- 0.04, P < .01) and untreated 2 control groups (0.20 +/- 0.05 and 0.19 +/- 0.04, P < .01) showed significantly lower myocardial anti-myosin radioactivity relative to the 10 mg/kg Dox group. CONCLUSION: Pretargeting with bsAb-Fab-Fab' and targeting with Tc-99m labeled high-specific activity polymers enabled early visualization of doxorubicin induce cardiotoxicity in mice. Tolerated dose of D-Dox-PGA was greater than to 30 mg/kg Dox-equivalent dose with minimal cardiotoxicity. PMID- 29392625 TI - Detection of chemotherapy-induced cardiotoxicity with antimyosin pretargeted imaging. PMID- 29392626 TI - FDG-PET for the detection of infection in left ventricle assist device: Is there light at the end of the tunnel? PMID- 29392627 TI - Left ventricular mechanical dyssynchrony assessment in long-standing type II diabetes mellitus patients with normal gated SPECT-MPI. AB - BACKGROUND: Assessment of left ventricular mechanical dyssynchrony (LVMD) using phase analysis of gated SPECT-MPI is well established. However, there is little information about the influence of diabetes mellitus on phase analysis. The present work was to evaluate the LVMD in longstanding type II diabetes mellitus (DM) patients with normal gated SPECT-MPI. METHODS: Retrospective analysis of 146 (86 type II diabetics for > 5 years' duration and 60 nondiabetics) consecutive patients with normal gated SPECT-MPI and adequate LVEF was done. Sixty age- and sex-matched nondiabetic served as control. LVMD was determined from the cutoff values (> mean + 2 SD) observed for phase standard deviation (PSD) and phase bandwidth (PBW) from the control subjects. Multivariate logistic regression analysis was applied to assess the correlation between various confounding factors. RESULTS: LVMD was detected in 24 (28%) diabetic patients with the pre defined cut-off values for PSD (> 10.8) and PBW (> 35.6) derived from the controls. Hyperlipidemia, overweight/obesity, duration of DM and its long-term complications were independently associated with LVMD, with long-term complications being the highest risk factor (OR 28.00; P < .001). CONCLUSION: The evolution time of the patients with type II diabetes mellitus affects the left ventricular mechanical synchrony. PMID- 29392628 TI - Prolonged dipyridamole administration reduces myocardial perfusion defects in experimental chronic Chagas cardiomyopathy. AB - BACKGROUND: Myocardial perfusion defects (MPD) due to coronary microvascular dysfunction is frequent in chronic Chagas cardiomyopathy (CCC) and may be involved with development of myocardial damage. We investigated whether MPD precedes left ventricular systolic dysfunction and tested the hypothesis that prolonged use of dipyridamole (DIPY) could reduce MPD in an experimental model of CCC in hamsters. METHODS AND RESULTS: We investigated female hamsters 6-months after T. cruzi infection (baseline condition) and control animals, divided into T. cruzi-infected animals treated with DIPY (CH + DIPY) or placebo (CH + PLB); and uninfected animals treated with DIPY (CO + DIPY) or placebo (CO + PLB). The animals were submitted to echocardiogram and rest SPECT-Sestamibi-Tc99m myocardial perfusion scintigraphy. Next, the animals were treated with DIPY (4 mg/kg bid, intraperitoneal) or saline for 30 days, and reevaluated with the same imaging methods. At baseline, the CH + PLB and CH + DIPY groups showed larger areas of perfusion defect (13.2 +/- 13.2% and 17.3 +/- 13.2%, respectively) compared with CO + PLB and CO + DIPY (3.8 +/- 2.2% e 3.5 +/- 2.7%, respectively), P < .05. After treatment, we observed: reduction of perfusion defects only in the CH + DIPY group (17.3 +/- 13.2% to 6.8 +/- 7.6%, P = .001) and reduction of LVEF in CH + DIPY and CH + PLB groups (from 65.3 +/- 9.0% to 53.6 +/- 6.9% and from 69.3 +/- 5.0% to 54.4 +/- 8.6%, respectively, P < .001). Quantitative histology revealed greater extents of inflammation and interstitial fibrosis in both Chagas groups, compared with control group (P < .001), but no difference between Chagas groups (P > .05). CONCLUSIONS: The prolonged use of DIPY in this experimental model of CCC has reduced the rest myocardial perfusion defects, supporting the notion that those areas correspond to viable hypoperfused myocardium. PMID- 29392629 TI - Need for Standardization of Perioperative Practices in MGB/OAGB. PMID- 29392630 TI - More on Patients Expectations and Success with Bariatric Surgery. PMID- 29392631 TI - Rapid Improvement in Diabetes After Simple Side-to-side Jejunoileal Bypass Surgery: Does It Need a Ligation or Not? AB - BACKGROUND: Dual-path side-to-side jejunoileal bypass (SSJIB) can markedly ameliorate diabetes and obesity. However, whether SSJIB requires the ligation of the bypassed loop (single-path) and what is the most appropriate length of the bypassed small bowel remain unknown. The aim of this study was to evaluate the role of ligation and the length of the bypassed small bowel in mediating changes in glucose homeostasis after SSJIB in streptozotocin (STZ)-induced diabetic rats. METHODS: Fourteen STZ-induced diabetic rats were randomized into two groups: one group was subjected to 50% SSJIB (SSJIB-50 group) and one group was subjected to sham surgery (sham group). Three weeks later, the SSJIB-50 group was re-operated, and the bypassed segment was ligated (SSJIBL-50 group). Three weeks later, the SSJIBL-50 group was operated again, and 60% of the length of the proximal small intestine was bypassed (SSJIBL-60 group). The measured primary outcomes were body weight, food intake, fasting blood glucose (FBG), and oral glucose tolerance test (OGTT). RESULTS: Body weight in the SSJIBL-60 group was lower than that in the sham group. Food intakes in the SSJIBL-50 and SSJIBL-60 groups were lower than that in the sham group. FBG and OGTT were not improved in the SSJIB-50 group compared with the sham group. However, FBG and OGTT were improved in the SSJIBL 50 group and were further improved in the SSJIBL-60 group. CONCLUSIONS: Ligation of the first portion of the bypassed loop is essential to SSJIB, and bypassing approximately 60% of the small intestine length may be appropriate in SSJIBL. PMID- 29392632 TI - Arabidopsis glutamate:glyoxylate aminotransferase 1 (Ler) mutants generated by CRISPR/Cas9 and their characteristics. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated 9 (CRISPR/Cas9) technology provides an efficient tool for editing the genomes of plants, animals and microorganisms. Glutamate:glyoxylate aminotransferase 1 (GGAT1) is a key enzyme in the photorespiration pathway; however, its regulation mechanism is largely unknown. Given that EMS-mutagenized ggat1 (Col-0 background) M2 pools have been generated, ggat1 (Ler background) should be very useful in the positional cloning of suppressor and/or enhancer genes of GGAT1. Unfortunately, such ggat1 (Ler) mutants are not currently available. In this study, CRISPR/Cas9 was used to generate ggat1 (Ler) mutants. Two GGAT1 target single-guide RNAs (sgRNAs) were constructed into pYLCRISPR/Cas9P35S-N, and flowering Arabidopsis (Ler) plants were transformed using an Agrobacterium tumefaciens-mediated floral dip protocol. Eleven chimeric and two heterozygous GGAT1-edited T1 lines of target 1 were separately screened from positive transgenic lines. Two ggat1 homozygous mutants, CTC-deletion and T deletion at target 1, were generated from T2 generations of the 13 T1 lines. The edited mutation sites were found to be stable through generations regardless of whether the T-DNA was present. In addition, the genetic segregation of the mutation sites obeyed the Mendelian single gene segregation rule, and no mutations were detected at the possible off-target site. Also, the two independent ggat1 mutants had similar photorespiration phenotypes and down regulated GGAT enzyme activity. Together, these results indicate that genetically stable ggat1 (Ler) mutants were generated by CRISPR/Cas9 genome editing, and these mutants will be used to promote the positional cloning of suppressor and/or enhancer genes of GGAT1 in our subsequent study. PMID- 29392633 TI - State anxiety and information processing: A 7.5% carbon dioxide challenge study. AB - We used the 7.5% carbon dioxide model of anxiety induction to investigate the effects of state anxiety on simple information processing. In both high- and low anxious states, participants (n = 36) completed an auditory-visual matching task and a visual binary categorization task. The stimuli were either degraded or clear, so as to investigate whether the effects of anxiety are greater when signal clarity is compromised. Accuracy in the matching task was lower during CO2 inhalation and for degraded stimuli. In the categorization task, response times and indecision (measured using mouse trajectories) were greater during CO2 inhalation and for degraded stimuli. For most measures, we found no evidence of Gas * Clarity interactions. These data indicate that state anxiety negatively impacts simple information processing and do not support claims that anxiety may benefit performance in low-cognitively-demanding tasks. These findings have important implications for understanding the impact of state anxiety in real world situations. PMID- 29392634 TI - Does letter rotation slow down orthographic processing in word recognition? AB - Leading neural models of visual word recognition assume that letter rotation slows down the conversion of the visual input to a stable orthographic representation (e.g., local detectors combination model; Dehaene, Cohen, Sigman, & Vinckier, 2005, Trends in Cognitive Sciences, 9, 335-341). If this premise is true, briefly presented rotated primes should be less effective at activating word representations than those primes with upright letters. To test this question, we conducted a masked priming lexical decision experiment with vertically presented words either rotated 90 degrees or in marquee format (i.e., vertically but with upright letters). We examined the impact of the format on both letter identity (masked identity priming: identity vs. unrelated) and letter position (masked transposed-letter priming: transposed-letter prime vs. replacement-letter prime). Results revealed sizeable masked identity and transposed-letter priming effects that were similar in magnitude for rotated and marquee words. Therefore, the reading cost from letter rotation does not arise in the initial access to orthographic/lexical representations. PMID- 29392636 TI - Dry eye and meibomian gland dysfunction in pseudophakic bullous keratopathy. AB - PURPOSE: To evaluate dry eye tests and meibography of patients with pseudophakic bullous keratopathy (PBK). MATERIALS AND METHODS: Thirty-seven patients with PBK were included. The eyes with PBK were compared with the normal pseudophakic fellow eyes. All patients had undergone a detailed ophthalmic examination including corneal and conjunctival fluorescein staining and Oxford scoring, tear film breakup time, Schirmer 1 test, Ocular Surface Disease Index (OSDI) score assessment, lid margin abnormalities, upper and lower eyelid Meibomian gland evaluation using infrared captures of a biomicroscope. Partial or complete loss of the Meibomian glands (Meibomian dropout) was scored for each eyelid from grade 0 (no loss) through grade 3 (lost area was > 2/3 of the total meibomian gland area). RESULTS: The mean age of the patients was 73.2 +/- 8.9 (range, 50-93). Mean tear film breakup time value was statistically lower in PBK eyes (P <= 0.001). OSDI, Oxford, lid margin abnormalities, inferior meibography, total meibography score were significantly higher in PBK eyes (P <= 0.001). The comparison of Schirmer 1 and superior meibography scores of the groups was insignificant (P = 0.143, P = 0.793, respectively). CONCLUSION: The Meibomian gland morphology of the PBK eyes demonstrates significant differences when compared with normal fellow eyes and might be related to evaporative dry eye. For this reason, patients with PBK should be monitored for Meibomian gland dysfunction and when needed start prompt treatment in order to prevent further disturbance of the ocular surface. PMID- 29392637 TI - Association of polymorphisms of complement factor I rs141853578 (G119R) with age related macular degeneration in Iranian population. AB - BACKGROUND: Age-related macular degeneration (AMD) is a complex disease, and recent studies have shown role of complement system genes in its development. Complement factor I regulates the complement pathways, and relationship between CFI polymorphisms and AMD is controversial. We evaluated the possible association of complement factor I rs141853578 (G119R) variation with advanced AMD in Iranian patients. MATERIALS AND METHODS: We included 371 case-control samples consisting of 220 advanced AMD patients and 151 genetically unrelated healthy controls. Extracted DNA samples amplified to obtain fragment including the polymorphic complement factor I rs141853578 (G119R) region. RESULTS: The distribution of the genotypes was significantly different in the AMD patients compared to that of controls (p = 0.035). The TT genotype frequencies for CFI were significantly higher in AMD group (7.7 vs. 2%, OR 4.67, CI 1.33-16.45, p = 0.016). This significant difference was maintained after adjustment for the effects of age and gender (OR 5.09, CI 1.42-18.20, p = 0.012). The minor allele frequency (T allele) was also significantly higher in AMD patients compared to that of controls (29.3 vs. 21.5% OR 1.51, CI 1.07-2.13, p = 0.018). CONCLUSION: Current study showed that CFI rs141853578 (G119R) is a risk factor for developing advanced type AMD. This study also suggests that the frequency of G119R polymorphism in our population is not as rare as reported from other populations. PMID- 29392638 TI - Long-term impact of dry eye symptoms on vision-related quality of life after phacoemulsification surgery. AB - PURPOSE: To observe the long-term changes in dry eye symptoms and vision-related quality of life in age-related cataract patients after phacoemulsification. METHODS: A total of 101 cataract patients after phacoemulsification combined with IOL implantation (Ph-IOL) in one eye were enrolled. Visual acuity, tear film breakup time (BUT), and Schirmer test 1 (ST1) were measured before and 1, 3, and 6 months after surgery. Ocular Surface Disease Index (OSDI) scores were used to evaluate the severity of dry eye symptoms. Utility values were assessed by the time trade-off (TTO), standard gamble for death (SGD), standard gamble for blindness (SGB) and rating scale (RS). RESULTS: The average LogMAR visual acuity in the operated eye was 1.35 +/- 0.50 and increased rapidly after Ph-IOL, approaching a peak at 3 months (0.26 +/- 0.15). The BUT and ST1 results decreased abruptly 1 month after surgery and gradually recovered until 6 months. OSDI scores increased significantly after surgery and gradually decreased until 6 months. Utility values evaluated by TTO, SGD, SGB and RS before surgery were 0.67 +/- 0.19, 0.75 +/- 0.15, 0.67 +/- 0.20 and 0.2 +/- 0.18, respectively, and increased to 0.91 +/- 0.06, 0.98 +/- 0.04, 0.92 +/- 0.52 and 0.91 +/- 0.06, 6 months after. Utility values measured with TTO, SGB or RS correlated significantly (P < 0.05) with visual acuity and OSDI scores pre- and postoperatively. CONCLUSIONS: Dry eye symptoms persist more than 3 months after Ph-IOL. Utility values were negatively influenced by dry eye symptoms. PMID- 29392639 TI - Modified technique of internal limiting membrane staining in idiopathic macular hole surgery. AB - PURPOSE: To describe a new method of ILM staining with TB under perfluorocarbon in cases of full thickness idiopathic macular hole using the inverted ILM flap technique. METHODS: This study was a prospective interventional case series that included 42 eyes of 42 patients who had full thickness idiopathic macular hole with a minimum diameter more than 400 um. Patients consecutively underwent vitrectomy with inverted ILM flap technique using the modified ILM staining method. RESULTS: Anatomic success was achieved in 40 patients (95.2%). The other two patients had flat-open macular holes with bare RPE (foveal defect of neurosensory retina). Among the 40 eyes with closed holes, 25 eyes were of the U type closure (normal foveal contour) and 15 eyes were of the V-type closure (steep foveal contour). These 40 eyes remained closed during the 6 months follow up period. CONCLUSION: The modified technique of ILM staining using TB under PFCL is safe and effective in cases of idiopathic macular hole combined with the inverted ILM flap technique. PMID- 29392640 TI - Corneal incision architecture after IOL implantation with three different injectors: an environmental scanning electron microscopy study. AB - PURPOSE: To evaluate by Environmental Scanning Electron Microscopy (ESEM) the corneal incision architecture after intraocular lens (IOL) implantation in pig eyes, using manual, automated injectors or preloaded delivery systems. METHODS: Twenty-four pig eyes underwent IOL implantation in the anterior chamber using three different injectors: manual (Monarch III) (n = 8), automated (AutoSert) (n = 8), or a preloaded system (UltraSert) (n = 8). Acrysof IQ IOLs, 21 Dioptres (D) (n = 12) and 27D (n = 12), were implanted through 2.2 mm clear corneal incisions. Incision width was measured using corneal calipers. The endothelial side of the incision was analyzed with ESEM. RESULTS: In each group, the final size of the corneal wound after IOL implantation, measured by calipers, was 2.3-2.4 mm. The incision architecture resulted more irregular in the Monarch group compared with the other injectors. In every group the 27D IOL-implanted specimens showed more alterations than in 21D IOL-implanted samples, and this was less evident in the UltraSert group. The Descemet tear length was higher in the Monarch group than AutoSert and UltraSert group. CONCLUSIONS: The automated and preloaded delivery systems provided a good corneal incision architecture; after high-power IOL implantation the incisions were more regular and less damaged with the preloaded system than with the other devices. PMID- 29392641 TI - Optical coherence tomography angiography findings of an optic disc melanocytoma in a glaucoma eye. AB - PURPOSE: To determine the optical coherence tomography angiography (OCTA) characteristics of a case of optic disc melanocytoma (ODM) associated with glaucomatous visual field and retinal nerve fiber layer (RNFL) defects in normal tension glaucoma. METHODS: The left eye of a 37-year-old female patient followed for a stable ODM for 10 years was investigated with OCT, OCTA, fluorescein (FA), and indocyanine green (ICGA) angiography. The ODM was unchanged, but a previously unknown inferotemporal neuroretinal rim loss and inferotemporal and superotemporal wedge shape glaucomatous RNFL thinning were seen with corresponding glaucomatous visual field defects. The intraocular pressure was 12 mmHg without treatment. RESULTS: In the area of the ODM, FA showed minimal vasculature, and week staining in the late phase, while ICGA showed no signal. In contrast, OCTA showed a dense vasculature in both the superficial and deep layers of the melanocytoma, which was clearly separated from the capillaries of the peripapillary retina. OCTA also showed reduced peripapillary perfusion in the areas of the glaucomatous RNFL bundle defects. CONCLUSIONS: In the presented case of a stable ODM and newly detected normal tension glaucoma, OCTA provided more information on perfusion than FA and ICGA which are limited by the heavy pigmentation of the ODM. OCTA also showed a similarly decreased capillary perfusion in both RNFL bundle defects suggesting that the structural damage was related to glaucoma and not compression by ODM. These results suggest that OCTA may be a method preferred over conventional angiography in ODM cases. PMID- 29392642 TI - Impairment of acquired color vision in multiple sclerosis: an early diagnostic sign linked to the greatness of disease. AB - OBJECTIVE: To assess the type and degree of both red-green and blue-yellow color vision deficiencies of Calabrian males affected by multiple sclerosis. MATERIAL: Eighty Calabrian male patients were enrolled (age range 18-70 years; mean age 40.6 +/- 12.4 years) showing a disease duration mean of 10.6 +/- 8.2 years (range = 0.5-46 years) coming from the Institute of Neurology, Magna Graecia University, Catanzaro. Optic neuritis present in the medical histories of the 21 patients does not influence color vision. Excluding seven colorblind subjects and one affected by a bilateral maculopathy, the analyzed sample group was 72. Seventy controls were matched for age and sex. METHOD: An ophthalmologist examined all patients and controls in order to rule out diabetic retinopathy, cataracts, senile maculopathy, or ocular fundus' anomalies. The Ishihara test identified the colorblind patients. The City University Test screened for people with abnormal color vision by grading the severity of color vision deficiency. The second part of the City University Test as well as the Farnsworth Test confirmed both the color vision deficiency type and degree. RESULTS: Fifty-one percentage (37/72) of the patients showing a color vision deficiency were subdivided into two subgroups: subgroup one showed red-green deficiency (57%, 21/37); subgroup two showed a coupled red-green and blue-yellow deficiency (43%, 16/37). Furthermore, we found two distinct curves showing a groove within the first 10 years of the disease. Both monocular and binocular analyses allowed us to identify the patients showing the monocular color vision deficiency, but they were well compensated by binocular vision. CONCLUSION: We think that the majority of the patients with the red-green deficiency will develop the coupled red-green and blue-yellow deficiency in the latter years of multiple sclerosis. PMID- 29392644 TI - Identifiability of Phylogenetic Parameters from k-mer Data Under the Coalescent. AB - Distances between sequences based on their k-mer frequency counts can be used to reconstruct phylogenies without first computing a sequence alignment. Past work has shown that effective use of k-mer methods depends on (1) model-based corrections to distances based on k-mers and (2) breaking long sequences into blocks to obtain repeated trials from the sequence-generating process. Good performance of such methods is based on having many high-quality blocks with many homologous sites, which can be problematic to guarantee a priori. Nature provides natural blocks of sequences into homologous regions-namely, the genes. However, directly using past work in this setting is problematic because of possible discordance between different gene trees and the underlying species tree. Using the multispecies coalescent model as a basis, we derive model-based moment formulas that involve the species divergence times and the coalescent parameters. From this setting, we prove identifiability results for the tree and branch length parameters under the Jukes-Cantor model of sequence mutations. PMID- 29392643 TI - A Review of Epidemiologic Studies on Greenness and Health: Updated Literature Through 2017. AB - PURPOSE OF REVIEW: Many studies suggest that exposure to natural vegetation, or greenness, may be beneficial for a variety of health outcomes. We summarize the recent research in this area. RECENT FINDINGS: We observed consistent and strong evidence of associations for higher greenness with improvements in birth weights and physical activity, as well as lower mortality rates. Recent studies also suggested that exposure to greenness may lower levels of depression and depressive symptoms. The evidence on greenness and cardiovascular health remains mixed. Findings are also inconsistent for greenness measures and asthma and allergies. Our knowledge of the impacts of greenness on a wide variety of health outcomes continues to evolve. Future research should incorporate information on specific species and some qualities of natural greenness that might drive health outcomes, integrate exposure assessments that incorporate personal mobility into analyses, and include prospective designs to add to the growing evidence that nature exposure positively affects health. PMID- 29392645 TI - Transient and sustained incentive effects on electrophysiological indices of cognitive control in younger and older adults. AB - Preparing for upcoming events, separating task-relevant from task-irrelevant information and efficiently responding to stimuli all require cognitive control. The adaptive recruitment of cognitive control depends on activity in the dopaminergic reward system as well as the frontoparietal control network. In healthy aging, dopaminergic neuromodulation is reduced, resulting in altered incentive-based recruitment of control mechanisms. In the present study, younger adults (18-28 years) and healthy older adults (66-89 years) completed an incentivized flanker task that included gain, loss, and neutral trials. Event related potentials (ERPs) were recorded at the time of incentive cue and target presentation. We examined the contingent negative variation (CNV), implicated in stimulus anticipation and response preparation, as well as the P3, which is involved in the evaluation of visual stimuli. Both younger and older adults showed transient incentive-based modulation of CNV. Critically, cue-locked and target-locked P3s were influenced by transient and sustained effects of incentives in younger adults, while such modulation was limited to a sustained effect of gain incentives on cue-P3 in older adults. Overall, these findings are in line with an age-related reduction in the flexible recruitment of preparatory and target-related cognitive control processes in the presence of motivational incentives. PMID- 29392646 TI - Postoperative recurrence from tract seeding after use of EUS-FNA for preoperative diagnosis of cancer in pancreatic tail. AB - A 50-year-old male underwent abdominal computed tomography at a city hospital in Japan, which revealed a tumor 38 mm in diameter in the tail of the pancreas. Based on findings from endoscopic ultrasonography-guided fine needle aspiration using a 22-gauge needle with a side hole, the tumor was diagnosed as an invasive ductal carcinoma. The patient was referred to our hospital and underwent a distal pancreatectomy. Esophagogastroduodenoscopy performed as part of a medical checkup at another hospital 2 years later revealed a 20-mm-sized submucosal tumor in the posterior wall of the upper body of the stomach. Examination of a biopsy specimen obtained from the top of the lesion revealed adenocarcinoma. Partial resection of the stomach was performed and pathological findings showed an adenocarcinoma in all layers of the stomach wall, consistent with recurrence derived from needle tract seeding of the previously excised cancerous tumor from the pancreatic tail. Additional experimentation performed for confirmation with an agar model showed that agar on the deep side leaked to the shallow side following puncture with a needle with a side hole used with a slow-pull technique. PMID- 29392647 TI - Evaluation of symmetrical increased echogenicity of bilateral caudothalamic grooves detected on cranial ultrasonography by comparing with susceptibility weighted imaging. AB - OBJECTIVE: To assess symmetrical increased echogenicity of bilateral caudothalamic grooves (SIEBCG) detected on newborn cranial ultrasonography (CUS) using magnetic resonance susceptibility-weighted imaging (SWI). MATERIALS AND METHODS: A total of 14 newborns (8 girls; 12 premature with mean gestational age of 30 weeks and 5 days, 2 mature) who were detected to have SIEBCG on routine serial CUS and underwent cranial magnetic resonance imaging (MRI) were recruited for the study. The cranial MRI examinations including SWI acquired on the same day of SIEBCG detection and serial CUS to assess the progress of SIEBCG lesions in the following 6 month period were retrospectively evaluated and compared for the presence of germinal matrix hemorrhage. RESULTS: On SWI, solely one patient (7, 1%) had signal alteration on caudothalamic groove compatible with grade 1 germinal matrix hemorrhage. Two patients (14, 2%) had parenchymal (on cerebellar and parietal white matter) millimetric hemorrhagic foci. Seven patients (50%) had signs of presumptive hypoxic insult including hyperintense dots on centrum semiovale and periventricular white matter in five, and increased signal intensity on the globus pallidi in two, on T1-weighted images. Four patients (28, 6%) had normal findings. Of these, 10 patients became normal on follow-up CUS at postterm-equivalent age, whereas four were missing. CONCLUSION: Symmetrical increased echogenicity of bilateral caudothalamic grooves seen on newborn CUS may be the indicator of other pathologies as ischemic insult or focal parenchymal hemorrhage. In the presence of SIEBCG, further examination with SWI should be performed. PMID- 29392648 TI - The first two confirmed sub-Saharan African families with germline TP53 mutations causing Li-Fraumeni syndrome. AB - Li-Fraumeni syndrome is a rare inherited cancer syndrome characterised by the early onset of specific cancers. Li-Fraumeni syndrome (LFS) is associated with germline mutations in the tumour suppressor gene, TP53. This study reports the first cases of molecularly confirmed LFS germline mutations in sub-Saharan Africa. Three black African patients, all with LFS-associated cancers, were seen through the Clinical and Counselling Section of the Division of Human Genetics at the National Health Laboratory Service and University of the Witwatersrand in Johannesburg, South Africa, during 2011-2012. All three patients (two were related) were recruited into this research study. Sequence analysis of the coding region of the TP53 gene identified a Class IV (likely pathogenic) variant, c.326T > C (p.Phe109Ser), in the two related patients, and a known pathogenic mutation, c.1010G > A (p.Arg337His), also referred to as the Brazilian founder mutation, in the other patient. A confirmed diagnosis in these patients will assist in tailored medical management (it is recommended that individuals carrying a germline TP53 mutation avoid radiotherapy as this might cause secondary radiotherapy-induced malignancies) and in addition, genetic testing of at-risk family members can be offered. Very little is known and documented on LFS in African individuals. Despite the small number of patients in this study, the results support the need for diagnostic genetic testing for LFS in South Africa. PMID- 29392649 TI - Investigating the cost implications of including all respiratory medicines in PCRS schemes. AB - AIM: This study estimates the additional cost to the State to pay for all respiratory medicines through the Primary Care Reimbursement Service (PCRS) schemes, reducing cost barriers to medication as a complement to existing chronic disease management programmes. Previous literature found higher medication adherence rates amongst medical card patients than those that had to pay or co pay themselves. METHOD: A review of medication expenditure on the PCRS schemes from 2005 to 2015. Data on medicines sold into and out of pharmacies was used to estimate the proportion to PCRS schemes or private. Scenario analyses were conducted to estimate what the cost to the State would be to provide funding for all respiratory medicines. RESULTS: Trend analysis findings showed that respiratory medicines have been less than 10% of total PCRS medicine expenditure for the years reviewed. The largest portion of the respiratory medicine expenditure is allocated to 'drugs for obstructive pulmonary disorder' (OPD), ranging from 90% in 2005 to 69% in 2015. Eighty-seven per cent of drugs to treat OPD are dispensed publicly and 13% privately. A scenario analysis estimated that the extra cost to the State to be ?20.2 m. CONCLUSIONS: Respiratory disease is included in the Irish Government's chronic disease management programme. This aims to deliver optimal care in the most appropriate setting so as to improve health outcomes and quality of life. Medication adherence is imperative to achieving these aims. Reducing cost barriers as a complement to other initiatives may improve medicine adherence thereby improving the effectiveness of disease management and patient outcomes. PMID- 29392650 TI - Cytomegalovirus infection and steroid-refractory inflammatory bowel disease: possible relationship from an updated meta-analysis. AB - AIMS: Many studies have suggested Cytomegalovirus infection might be implicated in steroid-refractory inflammatory bowel disease (IBD), in which situation management is extremely difficult. CMV infection being a potential cause of IBD have drawn great attention of clinicians, with insufficient evidence to reach conclusions. METHODS: We conduct this meta-analysis to explore the association of CMV infection and steroid-refractory IBD by collecting relevant articles. Literature collections were conducted by searching PubMed, EMBASE, and the cochrane library databases. Pooled risk ratios (RR) with corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the link between CMV infection and steroid resistance in IBD using Stata 12.0. RESULTS: Thirteen eligible studies with a total of 1119 patients conducted in eight countries were included. The steroid resistance rate in the CMV (+) groups was 62.8%, while that in the CMV (-) groups was 29.2%. The pooled RR of steroid resistance rate in CMV (+) groups compared to CMV (-) groups was 2.343 (95% CI 1.715-3.202, P = 0.0000). Due to marginal heterogeneity across studies (I2 = 77.6%), the random effects model was used. Subgroup analysis based on geographic differences did not alter the overall positive association between CMV infection and steroid resistance in IBD. There is no significant publication bias observed based on the funnel plot and Begg's test. CONCLUSIONS: This meta-analysis disclosed 2.34 fold increased risk of progressing into steroid-refractory IBD in CMV (+) group compared with the CMV (-) group, indicating that CMV infection might be a plausible cause of steroid-refractory IBD. PMID- 29392652 TI - Concepts and Types of Senescence in Plants. AB - Concepts, classification, and the relationship between different types of senescence are discussed in this chapter. Senescence-related terminology frequently used in yeast, animal, and plant systems and senescence processes at cellular, organ, and organismal levels are clarified. PMID- 29392651 TI - The role of liver resection in patients with metastatic breast cancer: a systematic review examining the survival impact. AB - INTRODUCTION: Approximately 10% of breast cancer patients will present with solid organ metastases, while up to 30% will develop metastatic disease during their treatment course. Liver metastases are usually treated with systemic chemotherapy. Although colorectal liver metastases are routinely resected, this is not yet the standard of care for breast cancer-related liver metastases. This review examines the evidence for resection of breast cancer-related liver metastases. METHODS: A systematic review identified 25 articles for inclusion, 12 papers concerning patients with isolated liver metastases, and 13 papers concerning patients with extrahepatic metastases. Data from 1080 patients were included. RESULTS: Two hundred eighty patients underwent hepatic resections for breast cancer-associated metastases with no extrahepatic metastases. Reported 5 year survival ranged from 24.6 to 78%. Median overall survival ranged from 29.5 to 116 months. For patients with oligometastatic disease undergoing resection, 5 year survival ranged from 21 to 57%, with median overall survival ranging from 32 to 58 months. Reported 30-day morbidity ranged from 14 to 42% for isolated and multiple metastases. CONCLUSION: Hepatic resection can be considered in the management of breast cancer patients with isolated liver metastases as well as those with oligometastatic disease. PMID- 29392653 TI - Initiation, Progression, and Genetic Manipulation of Leaf Senescence. AB - As a representative form of plant senescence, leaf senescence has received the most attention during the last two decades. In this chapter we summarize the initiation of leaf senescence by various internal and external signals, the progression of senescence including switches in gene expression, as well as changes at the biochemical and cellular levels during leaf senescence. Impacts of leaf senescence in agriculture and genetic approaches that have been used in manipulating leaf senescence of crop plants are discussed. PMID- 29392654 TI - Phenotypic Analysis and Molecular Markers of Leaf Senescence. AB - The process of leaf senescence consists of the final stage of leaf development. It has evolved as a mechanism to degrade macromolecules and micronutrients and remobilize them to other developing parts of the plant; hence it plays a central role for the survival of plants and crop production. During senescence, a range of physiological, morphological, cellular, and molecular events occur, which are generally referred to as the senescence syndrome that includes several hallmarks such as visible yellowing, loss of chlorophyll and water content, increase of ion leakage and cell death, deformation of chloroplast and cell structure, as well as the upregulation of thousands of so-called senescence-associated genes (SAGs) and downregulation of photosynthesis-associated genes (PAGs). This chapter is devoted to methods characterizing the onset and progression of leaf senescence at the morphological, physiological, cellular, and molecular levels. Leaf senescence normally progresses in an age-dependent manner but is also induced prematurely by a variety of environmental stresses in plants. Focused on the hallmarks of the senescence syndrome, a series of protocols is described to asses quantitatively the senescence process caused by developmental cues or environmental perturbations. We first briefly describe the senescence process, the events associated with the senescence syndrome, and the theories and methods to phenotype senescence. Detailed protocols for monitoring senescence in planta and in vitro, using the whole plant and the detached leaf, respectively, are presented. For convenience, most of the protocols use the model plant species Arabidopsis and rice, but they can be easily extended to other plants. PMID- 29392655 TI - Investigation of Petal Senescence by TRV-Mediated Virus-Induced Gene Silencing in Rose. AB - The classic reverse genetic screening, such as EMS-induced or T-DNA-mediated mutation, is a powerful tool to identify senescence-related genes in many model plants. For most non-model plants, however, this strategy is hard to achieve. Even for model plants, construction of a mutant library is usually labor and time consuming. Virus-induced gene silencing (VIGS) provides an alternative to characterize gene function in a wide spectrum of plants through transient gene expression. To date, more than a dozen of VIGS vector systems have been developed from different RNA and DNA viruses, while Tobacco rattle virus (TRV) system might be one of the most used due to its wide host range and ease of use. Here, we describe a modified TRV vector, TRV-GFP, in which a green fluorescent protein (GFP) is fused to 3'-end of the coat protein (CP) gene in the TRV2 vector. Since the GFP-tagged CP protein could be traced under UV light in planta, identification of TRV-GFP-infected plants is easy. Application of this system in identifying genes regulating petal senescence in rose is described. PMID- 29392656 TI - Phenotypic Analysis and Molecular Markers of Plant Nodule Senescence. AB - Leguminous crops can form nodules to fix atmospheric nitrogen (N2). Senescence of nodules is associated with a rapid decline in N fixation. During the process of nodule senescence, a number of visible or detectable changes on morphology, biochemistry, and physiology occur. Here we describe several methods for examining the senescing phenotypes of nodules, including rhizobium inoculation, nitrogenase activity determination with the acetylene reduction assay, leghemoglobin content determination, and apoptotic cell identification with TdT mediated dUTP-biotin nick end-labeling (TUNEL) staining. PMID- 29392657 TI - Quantitative Analysis of Floral Organ Abscission in Arabidopsis Via a Petal Breakstrength Assay. AB - Petal breakstrength (pBS) is a method to study floral organ abscission by quantitating the force required to pull a petal from the receptacle. However, it is only well established in some labs and used in a subset of abscission studies. Here, we describe the mechanism and operation of the pBS meter, as well as detailed measurement and further data analysis. We show that it is a powerful tool to detect early or delayed floral organ abscission in mutant or transgenic plants, which is not easily detected by phenotypic investigation. PMID- 29392658 TI - Characterization of Climacteric and Non-Climacteric Fruit Ripening. AB - Senescence is the terminal stage of plant development. It is a strategic and tactical response to seasonal and unpredictable stresses. As an important part of plant senescence, fruit ripening is normally viewed distinctly as climacteric or non-climacteric. In this chapter we describe protocols for the determination of a number of parameters that have been used in characterizing the ripening behavior of fruits. These include changes in respiratory rate, ethylene, flesh firmness, sugar, acidity, starch, pectin, enzymes, aroma volatiles, and expression of ripening-related genes during fruit ripening and senescence. PMID- 29392659 TI - Ethylene Treatment in Studying Leaf Senescence in Arabidopsis. AB - Plant leaf senescence is the final process of leaf development that involves the mobilization of nutrients from old leaves to newly growing tissues. Leaf senescence involves a coordinated action at the cellular and organism levels under the control of a highly regulated genetic program. However, leaf senescence is also influenced by multiple internal and environmental signals that are integrated into the age information. Among these internal factors, the simple gaseous phytohormone ethylene is well-known to be an important endogenous modulator of plant leaf senescence and fruit ripening. Ethylene and its biosynthetic precursor ACC (1-aminocyclopropane-l-carboxylic acid) as well as inhibitors of ethylene biosynthesis aminoethoxyvinylglycine (AVG) and action (AgNO3) or the inhibitor of ethylene perception 1-MCP (1-methylcyclopropene) have been widely used by the research community of plant leaf senescence. However, until now, no systemically experimental method about the usage of ethylene in studying the molecular mechanisms of leaf senescence in Arabidopsis is available. Here, we provide detailed methods for exogenous application of ethylene and its inhibitors in studying Arabidopsis leaf senescence, which has been successfully used in our laboratory. PMID- 29392660 TI - The Assay of Abscisic Acid-Induced Stomatal Movement in Leaf Senescence. AB - Abscisic acid (ABA) is a sesquiterpenoid (15-carbon) hormone that comprehensively regulates plant stress responses, development, and senescence. Stomata are epidermal pores on plant surface used for exchanging gases such as carbon dioxide, water vapor, and oxygen. One of the mechanisms that ABA regulates leaf senescence is to control stomatal movement and thus water loss during leaf senescence. Here we describe the procedure of measuring stomatal movement in response to ABA treatments, which will provide a useful protocol to investigate ABA signaling in leaf senescence. PMID- 29392661 TI - The EPR Method for Detecting Nitric Oxide in Plant Senescence. AB - Nitric oxide (NO) is gaining increasing attention as a central molecule with diverse signaling functions. It has been shown that NO acts as a negative regulator of leaf senescence. In this chapter, we describe a highly selective method, electron paramagnetic resonance ([EPR], also known as electron spin resonance [ESR]), for NO determination in leaf senescence. An iron complex of ferrous and mononitrosyl dithiocarbamate (Fe2+(DETC)2) is used as a chelating agent for NO. Using ethyl acetate as extracting solvent, the NOFe2+(DETC)2 complex is extracted and determined by EPR spectrometer. PMID- 29392662 TI - Hormone Treatments in Studying Leaf Senescence. AB - As the last stage of plant development, senescence can be regulated by a large number of signals such as aging, reproductive growth, nutrient availability, and stresses. Various plant hormones have been shown to be involved in regulating plant senescence. For example, ethylene, abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), and strigolactones (SLs) promote senescence, whereas cytokinins (CKs) inhibit senescence. Different hormones regulate senescence via distinct pathways, while cross talks between signaling pathways exist. In senescence-related studies, treating plants with various hormones to alter senescence is a common practice. In this chapter, we summarize experimental procedures of treating detached Arabidopsis leaves with a number of senescence regulating hormones including ABA, SLs, MeJA, SA peptide hormones. PMID- 29392663 TI - Methods to Study Darkness-Induced Leaf Senescence. AB - Leaf senescence is an intergral part of plant development, involving actively regulated molecular and biochemical processes, e.g. diverse transcriptome reprogramming, macromolecules degradation and nutrient remobilization. Natural and environment-induced leaf senescence directly affects crop yield and the shelf life of green vegetables. Darkness is considered as an inducer of leaf senescence and has been well used in laboratory setting. Here we described the setup of darkness-induced senescence in both detached and attached leaves and the methods to measure senescence-related parameters. PMID- 29392664 TI - Salt Treatments and Induction of Senescence. AB - High salinity, one of the most severe abiotic stresses encountered by land plants, often results from water deficit and also induces whole-plant senescence. Thus, salt treatment provides a useful technique for stress-mediated induction of senescence in plants. In this chapter, we describe the procedures to induce senescence in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), using NaCl or KCl. Furthermore, we present experimental approaches to measure salt stress-induced leaf senescence. PMID- 29392665 TI - Methods for Elucidation of Plant Senescence in Response to C/N-Nutrient Balance. AB - Carbon (C) and nitrogen (N) are essential elements for metabolism, and the ratio of C to N availability is called the C/N balance. C/N balance is very important for plant growth, but little is known about the detailed mechanisms of plant C/N responses. Previously a method of treating Arabidopsis plants with sugar supplemented medium for studying C/N responses at early post-germinative growth stages has been developed. This method, however, cannot be used to determine physiological C/N effects in plants of mature growth stages, including senescence. Here we present two methods of analyzing responses to C/N treatments in senescing plants: transient C/N treatment with liquid medium and long-term C/N treatment with elevated atmospheric CO2. PMID- 29392666 TI - Study of Cotton Leaf Senescence Induced by Alternaria alternata Infection. AB - Premature leaf senescence in cotton, which often happens during the mid to late growth period, has been occurring with an increasing frequency in many cotton growing areas and causing serious reduction in yield and quality. One of the key factors causing cotton leaf senescence is the infection of Alternaria leaf spot pathogens (Alternaria species), which often happens when cotton plants encounter adverse environmental conditions, such as chilling stress and physiological impairment. Stressed cotton leaves are apt to be infected by Alternaria leaf spot pathogens (Alternaria alternata) because of the reduction in disease resistance, leading to the initiation of leaf senescence. Here we describe the induction of cotton leaf senescence by Alternaria alternata infection, including the evaluation of the disease index and measure of physiological impairment associated with cotton leaf senescence and analysis of possible molecular mechanism using microarray. PMID- 29392667 TI - Study of Hydrogen Peroxide as a Senescence-Inducing Signal. AB - In many plant species, leaf senescence correlates with an increase in intracellular levels of reactive oxygen species (ROS) as well as differential regulation of anti-oxidative systems. Due to their reactive nature, reactive oxygen species (ROS) were considered to have only detrimental effects for long time. However, ROS turned out to be more than just toxic by-products of aerobic metabolism but rather major components in different signaling pathways. Considering its relatively long half-life, comparably low reactivity, and its ability to cross membranes, especially hydrogen peroxide, has gained attention as a signaling molecule. In this article, a set of tools to study hydrogen peroxide contents and the activity of its scavenging enzymes in correlation with leaf senescence parameters is presented. PMID- 29392668 TI - Identification of Postharvest Senescence Regulators Through Map-Based Cloning Using Detached Arabidopsis Inflorescences as a Model Tissue. AB - Postharvest deterioration of fruits and vegetables can be accelerated by biological, environmental, and physiological stresses. Fully understanding tissue response to harvest will provide new opportunities for limiting postharvest losses during handling and storage. The model plant Arabidopsis thaliana (Arabidopsis) has many attributes that make it excellent for studying the underlying control of postharvest responses. It is also one of the best resourced plants with numerous web-based bioinformatic programs and large numbers of mutant collections. Here we introduce a novel assay system called AIDA (the Arabidopsis Inflorescence Degreening Assay) that we developed for understanding postharvest response of immature tissues. We also demonstrate how the high-throughput screening capability of AIDA can be used with mapping technologies (high resolution melting [HRM] and needle in the k-stack [NIKS]) to identify regulators of postharvest senescence in ethyl methanesulfonate (EMS) mutagenized plant populations. Whether it is best to use HRM or NIKS or both technologies will depend on your laboratory facilities and computing capabilities. PMID- 29392669 TI - Chlorophyll and Chlorophyll Catabolite Analysis by HPLC. AB - The most obvious event of leaf senescence is the loss of chlorophyll. Chlorophyll degradation proceeds in a well-characterized pathway that, although being common to higher plants, yields a species-specific set of chlorophyll catabolites, termed phyllobilins. Analysis of chlorophyll degradation and phyllobilin accumulation by high-performance liquid chromatography (HPLC) is a valuable tool to investigate senescence processes in plants. In this chapter, methods for the extraction, separation, and quantification of chlorophyll and its degradation products are described. Because of their different physicochemical properties, chlorin-type pigments (chlorophylls and magnesium-free pheo-pigments) and phyllobilins (linear tetrapyrroles) are analyzed separately. Specific spectral properties and polarity differences allow the identification of the different classes of known chlorins and phyllobilins. The methods provided facilitate the analysis of chlorophyll degradation and the identification of chlorophyll catabolites in a wide range of plant species, in different tissues, and under a variety of physiological conditions that involve loss of chlorophyll. PMID- 29392670 TI - Identification and Functional Analysis of Senescence-Associated Genes in Wheat. AB - Senescence is the final stage of leaf development. During this process, different macromolecules undergo degradation, and the resulting components are transported to developing and storage tissues of the plant. Senescence-associated genes (SAGs) play important roles in this process. Identification and characterization of SAGs are the first steps to interpret the function of these genes and to elucidate the mechanisms of leaf senescence. One of the most effective ways to identify SAGs is to screen for candidate genes using massive genome-scale transcriptomic data such as microarray, RNA-seq, digital RNA expression level data, etc. The basic functional analysis of candidate genes is to observe the phenotypes of transgenic plants, in which the candidate SAGs are overexpressed, knocked down, or knocked out. In this chapter, we outline methods for identifying and characterizing SAGs by microarray analysis in wheat. Methods of gene functional analyses by screening transgenic plants are also described. The protocols described in this chapter could also be used in other plant species, especially for Poaceae plants. PMID- 29392671 TI - Isolation, Purification, and Detection of Micro RNAs in Plant Senescence. AB - Micro RNAs (miRNAs) are small noncoding RNA molecules that function in transcriptional level to regulate gene expression both in plants and animals. Increasing researches have shown that miRNAs are key regulators in plant development and stress responses, and emerging evidence indicates the potential role of miRNAs on plant senescence. In this chapter we summarize the daily methods used for identification and study of miRNAs in plants, including the isolation of total RNA, the purification of miRNAs, and the methods used to detect miRNAs in plants. The committed steps or modifications of these methods used in plant senescence research are noted. PMID- 29392672 TI - In Situ Detection of Programmed Cell Death in Senescing Nicotiana tabacum Leaves Using TUNEL Assay. AB - Leaf senescence constitutes a highly regulated final phase of leaf development, leading to cell death that is recognized as a type of programmed cell death (PCD). Degradation of nuclear DNA into oligonucleosomal fragments (DNA ladder) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay are methods commonly used to detect PCD-specific DNA cleavage. TUNEL reaction in situ labels free 3'-OH DNA strand breaks (nicks), thus allowing histological localization of nuclear DNA degradation during PCD. Here we describe in situ labeling of PCD-specific nuclear DNA fragmentation on conventional histological sections of senescing tobacco leaves. Incorporation of fluorescein labeled dUTPs is detected by fluorescence microscopy, which enables in situ visualization of PCD at the single-cell level in the leaf mesophyll tissues undergoing senescence. PMID- 29392673 TI - Activities of Vacuolar Cysteine Proteases in Plant Senescence. AB - Plant senescence is accompanied by a marked increase in proteolytic activities, and cysteine proteases (Cys-protease) represent the prevailing class among the responsible proteases. Cys-proteases predominantly locate to lytic compartments, i.e., to the central vacuole (CV) and to senescence-associated vacuoles (SAVs), the latter being specific to the photosynthetic cells of senescing leaves. Cellular fractionation of vacuolar compartments may facilitate Cys-proteases purification and their concentration for further analysis. Active Cys-proteases may be analyzed by different, albeit complementary approaches: (1) in vivo examination of proteolytic activity by fluorescence microscopy using specific substrates which become fluorescent upon cleavage by Cys-proteases, (2) protease labeling with specific probes that react irreversibly with the active enzymes, and (3) zymography, whereby protease activities are detected in polyacrylamide gels copolymerized with a substrate for proteases. Here we describe the three methods mentioned above for detection of active Cys-proteases and a cellular fractionation technique to isolate SAVs. PMID- 29392674 TI - Study of Autophagy in Plant Senescence. AB - As a major intracellular degradation pathway, autophagy contributes to nutrient recycling and is indispensable during plant senescence. Here we describe methods used for investigating the autophagic process during leaf senescence. These include transcript analysis of core machinery autophagy genes, immunoblotting of ATG8, and microscopic observation of autophagosome formation. PMID- 29392675 TI - Isolation of Chloroplasts for In Organelle Protein Degradation Assay. AB - A method for isolating intact chloroplasts from mature and senescent Arabidopsis thaliana leaves is described that utilizes two subsequent Percoll gradients. The isolated chloroplasts can be incubated in the dark to track in organelle protein degradation. To remove chloroplasts that lysed during the incubation period, a second Percoll gradient is performed prior to SDS-PAGE and immunoblot analysis. PMID- 29392676 TI - Plant Cell Walls: Isolation and Monosaccharide Composition Analysis. AB - Plant cell walls have important roles during all phases of plant growth and development. Polysaccharides are the major components of the primary walls surrounding growing plant cells, together with small amounts of protein and minerals. Secondary walls that are deposited when a cell has ceased to grow are also composed predominantly of polysaccharides, although lignin may account for up to 20% w/w of these walls. The types of polysaccharides and their structure and abundance often vary greatly in the cell walls of different plant species, different cell types, and different developmental stages. Significant changes in structure and composition of cell wall have been described in various types of plant senescence. Here we describe a general method for the isolation of cell wall polysaccharides as their alcohol-insoluble residues (AIR) and procedures for the determination of the neutral and acidic monosaccharides present in the wall. PMID- 29392677 TI - Visualizing Morphological Changes of Abscission Zone Cells in Arabidopsis by Scanning Electron Microscope. AB - Scanning electron microscope (SEM) is a type of electron microscope which produces detailed images of surface structures. It has been widely used in plants and animals to study cellular structures. Here, we describe a detailed protocol to prepare samples of floral abscission zones (AZs) for SEM, as well as further image analysis. We show that it is a powerful tool to detect morphologic changes at the cellular level during the course of abscission in wild-type plants and to establish the details of phenotypic alteration in abscission mutants. PMID- 29392678 TI - RNA-Seq Analysis of the Transcriptome of Leaf Senescence in Tobacco. AB - Leaf senescence is a complex developmental process which is under the control of a highly regulated genetic program and involves major changes in gene expression. During the past two decades, significant progress in molecular understanding of leaf senescence has been made through transcriptomic analysis, which, in comparison with traditional molecular biology, provides enormous amount of information on gene expression regulation at the whole genome level. In this chapter, we describe the protocol for RNA-seq, one of the most commonly used technologies in transcriptomic analysis, using tobacco leaf senescence as a model system. PMID- 29392679 TI - Comprehensive Metabolomics Studies of Plant Developmental Senescence. AB - Leaf senescence is an essential developmental process that involves diverse metabolic changes associated with degradation of macromolecules allowing nutrient recycling and remobilization. In contrast to the significant progress in transcriptomic analysis of leaf senescence, metabolomics analyses have been relatively limited. A broad overview of metabolic changes during leaf senescence including the interactions between various metabolic pathways is required to gain a better understanding of the leaf senescence allowing to link transcriptomics with metabolomics and physiology. In this chapter, we describe how to obtain comprehensive metabolite profiles and how to dissect metabolic shifts during leaf senescence in the model plant Arabidopsis thaliana. Unlike nucleic acid analysis for transcriptomics, a comprehensive metabolite profile can only be achieved by combining a suite of analytic tools. Here, information is provided for measurements of the contents of chlorophyll, soluble proteins, and starch by spectrophotometric methods, ions by ion chromatography, thiols and amino acids by HPLC, primary metabolites by GC/TOF-MS, and secondary metabolites and lipophilic metabolites by LC/ESI-MS. These metabolite profiles provide a rich catalogue of metabolic changes during leaf senescence, which is a helpful database and blueprint to be correlated to future studies such as transcriptome and proteome analyses, forward and reverse genetic studies, or stress-induced senescence studies. PMID- 29392680 TI - Power of Peer Support to Change Health Behavior to Reduce Risks for Heart Disease and Stroke for African American Men in a Faith-Based Community. AB - INTRODUCTION: Peer support has powerful potential to improve outcomes in a program of health behavior change; yet, how peer support is perceived by participants, its role, and how it contributes to intervention efficacy is not known, especially among African Americans. The purpose of this study was to identify the subjectively perceived experience and potential contributions of peer support to the outcomes of a peer group behavioral intervention designed to change health behavior to reduce risks for heart disease and stroke in African American men in a faith-based community. METHODS: A peer support group intervention was implemented to increase health knowledge and to improve health behaviors in line with the American Heart Association's Life Simple 7 domains (get active, control cholesterol, eat better, manage blood pressure, lose weight, reduce blood sugar, and stop smoking). Fourteen peer group sessions and eight follow-up interviews with program participants were recorded, transcribed, and analyzed. RESULTS: Seven key themes emerged, including (1) enhancing access to health behavior information and resources, (2) practicing and applying problem solving skills with group feedback and support, (3) discussing health behavior challenges and barriers, (4) sharing health behavior changes, (5) sharing perceived health outcome improvements and benefits, (6) feelings of belonging and being cared for, and (7) addressing health of family and community. CONCLUSION: Qualitative findings revealed a positive perception of peer support and greater understanding of potential reasons why it may be an effective strategy for African American men. PMID- 29392681 TI - Investigation on solution-to-gel characteristic of thermosensitive and mucoadhesive biopolymers for the development of moxifloxacin-loaded sustained release periodontal in situ gels. AB - The objectives of present research were to develop and characterize thermosensitive and mucoadhesive polymer-based sustained release moxifloxacin in situ gels for the treatment of periodontal diseases. Poloxamer- and chitosan based in situ gels are in liquid form at room temperature and transform into gel once administered into periodontal pocket due to raise in temperature to 37 degrees C. Besides solution-to-gel characteristic of polymers, their mucoadhesive nature aids the gel to adhere to mucosa in periodontal pocket for prolonged time and releases the drug in sustained manner. These formulations were prepared using cold method and evaluated for pH, solution-gel temperature, syringeability and viscosity. In vitro drug release studies were conducted using dialysis membrane at 37 degrees C and 50 rpm. Antimicrobial studies carried out against Aggregatibacter actinomycetemcomitans (A.A.) and Streptococcus mutans (S. Mutans) using agar cup-plate method. The prepared formulations were clear and pH was at 7.01-7.40. The viscosity of formulations was found to be satisfactory. Among the all, formulations comprising of 21% poloxamer 407 and 2% poloxamer 188 (P5) and in combination with 0.5% HPMC (P6) as well as 2% chitosan and 70% beta glycerophosphate (C6) demonstrated an ideal gelation temperature (33-37 degrees C) and sustained the drug release for 8 h. Formulations P6 and C6 showed promising antimicrobial efficacy with zone of inhibition of 27 mm for A.A. and 55 mm for S. Mutans. The developed sustained release in situ gel formulations could enhance patient's compliance by reducing the dosing frequency and also act as an alternative treatment to curb periodontitis. PMID- 29392682 TI - TRPC3 is required for the survival, pluripotency and neural differentiation of mouse embryonic stem cells (mESCs). AB - Transient receptor potential canonical subfamily member 3 (TRPC3) is known to be important for neural development and the formation of neuronal networks. Here, we investigated the role of TRPC3 in undifferentiated mouse embryonic stem cells (mESCs) and during the differentiation of mESCs into neurons. CRISPR/Cas9 mediated knockout (KO) of TRPC3 induced apoptosis and the disruption of mitochondrial membrane potential both in undifferentiated mESCs and in those undergoing neural differentiation. In addition, TRPC3 KO impaired the pluripotency of mESCs. TRPC3 KO also dramatically repressed the neural differentiation of mESCs by inhibiting the expression of markers for neural progenitors, neurons, astrocytes and oligodendrocytes. Taken together, our new data demonstrate an important function of TRPC3 with regards to the survival, pluripotency and neural differentiation of mESCs. PMID- 29392683 TI - Health Endowment at Birth and Variation in Intergenerational Economic Mobility: Evidence From U.S. County Birth Cohorts. AB - New estimates of intergenerational economic mobility reveal substantial variation in the spatial distribution of opportunity in the United States. Efforts to explain this variation in economic mobility have conspicuously omitted health despite it being a key pathway for the transmission of economic position across generations. We begin to fill this gap in the literature by examining the relationship between health endowment at birth and intergenerational economic mobility across county birth cohorts in the United States, drawing on estimates from two population-level data sets. Exploiting variation across counties and over time, we find a negative relationship between the incidence of low-weight births and the level of economic mobility as measured in adulthood for the county birth cohorts in our sample. Our results build on a large and growing literature detailing the role of early childhood health in the transmission of economic status across generations and suggest that the incidence of low-weight births is negatively associated with intergenerational economic mobility. PMID- 29392684 TI - Determining the Effect of Catechins on SOD1 Conformation and Aggregation by Ion Mobility Mass Spectrometry Combined with Optical Spectroscopy. AB - The aggregation of Cu,Zn-superoxide dismutase (SOD1) plays an important role in the etiology of amyotrophic lateral sclerosis (ALS). For the disruption of ALS progression, discovering new drugs or compounds that can prevent SOD1 aggregation is important. In this study, ESI-MS was used to investigate the interaction of catechins and SOD1. The noncovalent complex of catechins that interact with SOD1 was found and retained in the gas phase under native ESI-MS condition. The conformation changes of SOD1 after binding with catechins were also explored via traveling wave ion mobility (IM) spectrometry. Epigallocatechin gallate (EGCG) can stabilize SOD1 conformation against unfolding in three catechins. To further evaluate the efficacy of EGCG, we monitored the fluorescence changes of dimer E2,E2,-SOD1(apo-SOD1, E:empty) with and without ligands under denaturation conditions, and found that EGCG can inhibit apo-SOD1 aggregation. In addition, the circular dichroism spectra of the samples showed that EGCG can decrease the beta-sheet content of SOD1, which can produce aggregates. These results indicated that orthogonal separation dimension in the gas-phase IM coupled with ESI-MS (ESI IM-MS) can potentially provide insight into the interaction between SOD1 and small molecules. The advantage is that it dramatically decreases the analysis time. Meantime, optical spectroscopy techniques can be used to confirm ESI-IM-MS results. Graphical Abstract ?. PMID- 29392685 TI - A Simple Sonication Improves Protein Signal in Matrix-Assisted Laser Desorption Ionization Imaging. AB - Proper matrix application is crucial in obtaining high quality matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). Solvent-free sublimation was essentially introduced as an approach of homogeneous coating that gives small crystal size of the organic matrix. However, sublimation has lower extraction efficiency of analytes. Here, we present that a simple sonication step after the hydration in standard sublimation protocol significantly enhances the sensitivity of MALDI MSI. This modified procedure uses a common laboratory ultrasonicator to immobilize the analytes from tissue sections without noticeable delocalization. Improved imaging quality with additional peaks above 10 kDa in the spectra was thus obtained upon sonication treatment. Graphical Abstract ?. PMID- 29392686 TI - Ionization Mechanism of Positive-Ion Nitrogen Direct Analysis in Real Time. AB - Nitrogen can be an inexpensive alternative to helium used by direct analysis in real time (DART), especially in consideration of the looming helium shortage. Therefore, the ionization mechanism of positive-ion N2 DART has been systematically investigated. Our experiments suggest that a range of metastable nitrogen species with a variety of internal energies existed and all of them were less energetic than metastable helium atoms. However, compounds with ionization energies (IE) equal to or lower than 10.2 eV (all organic compounds except the extremely small ones) can be efficiently ionized. Because N2 DART was unable to efficiently ionize ambient moisture and common organic solvents such as methanol and acetonitrile, the most important ionization mechanism was direct Penning ionization followed by self-protonation of polar compounds generating [M+H]+ ions. On the other hand, N2 DART was able to efficiently ionize ammonia, which was beneficial in the ionization of hydrogen-bonding compounds with proton affinities (PA) weaker than ammonia generating [M+NH4]+ ions and large PAHs generating [M+H]+ ions through proton transfer. N2 DART was also able to efficiently ionize NO, which led to the ionization of nonpolar compounds such as alkanes and small aromatics generating [M-(2m+1)H]+ (m=0,1...) ions. Lastly, metastable nitrogen species was also able to produce oxygen atoms, which resulted in increased oxygen adducts as the polarity of organic compounds decreased. In comparison with He DART, N2 DART was approximately one order of magnitude less sensitive in generating [M+H]+ ions, but could be more sensitive in generating [M+NH4]+ ions. Graphical Abstract ?. PMID- 29392687 TI - Whole Genome Sequencing-Based Discovery of Structural Variants in Glioblastoma. AB - Next-generation DNA sequencing (NGS) technologies are currently being applied in both research and clinical settings for the understanding and management of disease. The goal is to use high-throughput sequencing to identify specific variants that drive tumorigenesis within each individual's tumor genomic profile. The significance of copy number and structural variants in glioblastoma makes it essential to broaden the search beyond oncogenic single nucleotide variants toward whole genome profiles of genetic aberrations that may contribute to disease progression. The heterogeneity of glioblastoma and its variability of cancer driver mutations necessitate a more robust examination of a patient's tumor genome. Here, we present patient whole genome sequencing (WGS) information to identify oncogenic structural variants that may contribute to glioblastoma pathogenesis. We provide WGS protocols and bioinformatics approaches to identify copy number and structural variations in 41 glioblastoma patient samples. We present how WGS can identify structural diversity within glioblastoma samples. We specifically show how to apply current bioinformatics tools to detect EGFR variants and other structural aberrations from DNA whole genome sequencing and how to validate those variants within the laboratory. These comprehensive WGS protocols can provide additional information directing more precise therapeutic options in the treatment of glioblastoma. PMID- 29392688 TI - Whole Genome DNA Methylation Analysis of Human Glioblastoma Using Illumina BeadArrays. AB - In this chapter, we describe the use of Illumina(r) Infinium(r) HD Assay in conjunction with Illumina's EPIC Methylation 8-sample array platform to obtain glioblastoma molecular profiles. The procedure spans four days, and can be performed by a single laboratory technician. Starting with as little as 250 ng of DNA input, this method allows the flexibility to begin with DNA derived from either formalin-fixed, paraffin-embedded (FFPE) or fresh tissue and is compatible with an Illumina iScan or HiScan system. PMID- 29392689 TI - Establishing Primary Human Glioblastoma Adherent Cultures from Operative Specimens. AB - This chapter describes a method for isolation, maintenance, and propagation of primary glioblastoma (GBM) cells in adherent monolayer cultures from patient tumor specimens. This method enables the establishment of GBM cultures with stem or progenitor-like cell characteristics, including self-renewal capacity, differentiation along restricted neural lineages, and tumor-initiating potential when orthotopically injected into immunocompromised mice. This experimentally tractable model system is therefore suitable for a wide variety of analyses in vitro as well as in vivo. Key examples of biological analyses that can be performed using these cells are also described. PMID- 29392690 TI - Establishing Primary Human Glioblastoma Tumorsphere Cultures from Operative Specimens. AB - In vitro propagation of patient-derived glioblastoma (GBM) cells can be achieved either by adherent monolayer culture, already described in Chapter 3 , or by tumorsphere culture in suspension. Here, we provide a detailed protocol for establishing patient-derived tumorsphere cultures. Such cultures are enriched for GBM stem cells (GSCs) and can be used to generate orthotopic tumor xenografts in the brain of immunocompromised mice. We also point out nuances in the protocol that can increase the yield of successful cultures from operative specimens. PMID- 29392691 TI - Isolation of Glioblastoma Stem Cells with Flow Cytometry. AB - This chapter describes a straightforward method for isolating glioblastoma stem cells (GSCs) from in vitro tissue cultures via fluorescence-activated cell sorting (FACS) using CD133 as a surface marker. The use of a directly conjugated antibody to an APC fluorophore against the CD133 molecule provides sufficient and clear detection of positive cells from the rest of the population. This strategy avoids an unnecessary secondary antibody incubation step thereby minimizing loss and increasing yield. The same protocol can be applied to other GSC surface markers. The described method allows for quick and efficient purification of GSCs, which can then be used in several downstream applications. PMID- 29392692 TI - Lentiviral Transduction of Primary Human Glioblastoma Cultures. AB - This chapter provides detailed step-by-step instructions for the production of lentiviral particles and the transduction of primary human glioblastoma cultures. Lentiviruses stably transduce both dividing and non-dividing cells, such as quiescent cancer stem cell populations. The viral envelope is pseudotyped with the vesicular stomatitis virus envelope glycoprotein G (VSV-G), which renders the lentiviral particles pantropic, so that they can infect theoretically all cell types. The third generation packaging system used in this protocol produces lentiviruses with important safety features, including replication incompetence and self-inactivation (SIN). The protocol we describe here leads to transduction of primary human glioblastoma cultures with efficiencies of up to 90%. PMID- 29392693 TI - Selective Targeting of CD133-Expressing Glioblastoma Stem Cells Using Lentiviral Vectors. AB - Several lines of evidence suggest a cellular hierarchy in glioblastoma (GBM). In this hierarchy, GBM stem-like cells (GSCs) play critical roles in tumor progression and recurrence, by virtue of their robust tumor-propagating potential and resistance to conventional chemoradiotherapy. Therefore, targeting GSCs holds significant therapeutic promise. Expression of CD133 (PROM1), a cell surface glycoprotein, has been associated with the GSC phenotype and used as a GSC marker. Here, we describe a protocol that allows the selective lentiviral transduction of CD133-expressing GBM cells. This selectivity is conferred by pseudotyping the lentiviral envelope with a single-chain antibody against an extracellular epitope on CD133. We previously demonstrated the efficacy and specificity of this lentiviral vector using patient-derived GBM cultures. This chapter outlines the preparation of the vector and the transduction of human GBM cells. PMID- 29392694 TI - Intracellular pH Measurements in Glioblastoma Cells Using the pH-Sensitive Dye BCECF. AB - The regulation of pH in glioblastoma (GBM) has received significant attention, because it has been linked to tumor metabolism and the stem cell phenotype. The variability in blood perfusion and oxygen tension within tumors suggests that ambient pH values fluctuate across different tumor territories. This chapter describes a detailed protocol for measuring intracellular pH in patient-derived GBM cells in vitro, using the fluorescent pH sensitive dye BCECF. PMID- 29392695 TI - Induction and Assessment of Hypoxia in Glioblastoma Cells In Vitro. AB - To simulate and study the hypoxic microenvironment associated with intracerebral glioma in vivo, simple and reproducible methods are described and discussed for inducing hypoxia or chemical pseudohypoxia in glioma cell cultures and assessing their effects on the expression and nuclear translocation of hypoxia-inducible factor (HIF)-1alpha, a key transcriptional factor of oxygen homeostasis, by Western blot analysis and immunocytochemistry. PMID- 29392696 TI - Metabolomic Analysis of Glioma Cells Using Nanoflow Liquid Chromatography-Tandem Mass Spectrometry. AB - Mass spectrometry (MS)-based techniques have been finding utility as sensitive, high throughput metabolite analysis tools for complex biological samples. We describe here a nanoflow liquid chromatography-tandem mass spectrometry (nano-LC MS/MS) system we developed and applied to metabolic profiling of human cells. Metabolites are extracted from cells using methanol, and filtered through a C18 StageTip to remove large particles. Metabolite samples are separated by HPLC at a flow rate of 400-500 nl/min, then analyzed in both positive and negative ion modes in an LTQ-Orbitrap MS. Metabolite identification and differential analysis are performed using commercial or open source software. Protocols outlined in this chapter describe how nano-LC-MS can be applied to investigate metabolic profiling with limited biomass amount. PMID- 29392697 TI - Sample Preparation for Relative Quantitation of Proteins Using Tandem Mass Tags (TMT) and Mass Spectrometry (MS). AB - Quantitative proteome analysis allows comparisons of protein or phosphoprotein levels across multiple cell types or conditions. A number of experimental approaches have been described toward quantitative proteomics. In this chapter, we focus on Tandem Mass Tag (TMT) isobaric labeling of peptides for global, relative quantitation of proteins and phosphopeptides. To date, there has been no published protocol describing chemical labeling of small amounts of peptides specifically extracted from small tumor samples, for which rigorous sample preparation is necessary to ensure reproducible TMT labeling. PMID- 29392698 TI - Single-Cell RNA Sequencing of Glioblastoma Cells. AB - Single-cell RNA sequencing (sc-RNASeq) is a recently developed technique used to evaluate the transcriptome of individual cells. As opposed to conventional RNASeq in which entire populations are sequenced in bulk, sc-RNASeq can be beneficial when trying to better understand gene expression patterns in markedly heterogeneous populations of cells or when trying to identify transcriptional signatures of rare cells that may be underrepresented when using conventional bulk RNASeq. In this method, we describe the generation and analysis of cDNA libraries from single patient-derived glioblastoma cells using the C1 Fluidigm system. The protocol details the use of the C1 integrated fluidics circuit (IFC) for capturing, imaging and lysing cells; performing reverse transcription; and generating cDNA libraries that are ready for sequencing and analysis. PMID- 29392699 TI - Evaluation of Radioresponse and Radiosensitizers in Glioblastoma Organotypic Cultures. AB - Glioblastoma (GBM), a deadly primary brain malignancy, manifests pronounced radioresistance. Identifying agents that improve the sensitivity of tumor tissue to radiotherapy is critical for improving patient outcomes. The response to ionizing radiation is regulated by both cell-intrinsic and -extrinsic mechanisms. In particular, the tumor microenvironment is known to promote radioresistance in GBM. Therefore, model systems used to test radiosensitizing agents need to take into account the tumor microenvironment. We recently showed that GBM explant cultures represent an adaptable ex vivo platform for rapid and personalized testing of radiosensitizers. These explants preserve the cellular composition and tissue architecture of parental patient tumors and therefore capture the microenvironmental context that critically determines the response to radiotherapy. This chapter focuses on the detailed protocol for testing candidate radiosensitizing agents in GBM explants. PMID- 29392700 TI - Orthotopic Patient-Derived Glioblastoma Xenografts in Mice. AB - Patient-derived xenografts (PDX) provide in vivo glioblastoma (GBM) models that recapitulate actual tumors. Orthotopic tumor xenografts within the mouse brain are obtained by injection of GBM stem-like cells derived from fresh surgical specimens. These xenografts reproduce GBM's histologic complexity and hallmark biological behaviors, such as brain invasion, angiogenesis, and resistance to therapy. This method has become essential for analyzing mechanisms of tumorigenesis and testing the therapeutic effect of candidate agents in the preclinical setting. Here, we describe a protocol for establishing orthotopic tumor xenografts in the mouse brain with human GBM cells. PMID- 29392701 TI - Bioluminescent In Vivo Imaging of Orthotopic Glioblastoma Xenografts in Mice. AB - Orthotopic rodent xenografts are an essential tool for studying glioblastoma in vivo. Xenograft growth as a function of time can only be monitored by noninvasive imaging. This chapter describes in detail how to assess xenograft size and growth using bioluminescent imaging with IVIS (in vivo imaging system). This form of imaging (a) can be performed without the help of a trained technician, (b) is a very quick procedure, allowing simultaneous imaging of up to five animals at a total experimental duration of 15 min, and (c) is cheaper than the alternatives (small animal MRI or CT). This technique relies on the stable expression of luciferase by the xenografted GBM cells. Luciferin, the substrate of luciferase, which is injected into host mice intraperitoneally, distributes throughout the mouse body and crosses the blood brain barrier. Luciferase expressed by the xenografted cells uses this substrate in a catalytic reaction, leading to the emission of visible light, which is detected by the CCD camera of the IVIS imaging system. The intensity of this emitted light correlates to the size of a given xenograft and allows comparisons of xenograft size across different animals, as well as within the same animal across different time points. PMID- 29392702 TI - Evaluation of Vascularity, Blood Perfusion, and Oxygen Tension in Tumor Xenografts with Fluorescent Microscopy. AB - Histologic heterogeneity in glioblastoma (GBM) is highlighted by regional variability in vascular density. Areas of vascular hyperplasia are interspersed with avascular territories, in which necrosis is surrounded by a zone of hypoxic tumor cells expressing stem cell markers, a phenomenon known as pseudopalisading necrosis. This vascular heterogeneity suggests intratumoral oxygen gradients, which regulate cellular and metabolic adaptations in tumor cells. Quantification of tumor vascularity, blood perfusion and oxygenation is therefore critical. In this chapter, we describe three different methods, all of which involve microscopy to analyze these parameters in tumor xenografts. We present detailed protocols for analysis of tumor endothelium using endothelial markers, blood perfusion by systemic infusion of Evans Blue and oxygen tension by pimonidazole injection, followed by immunostaining. PMID- 29392703 TI - Probing Glioblastoma Tissue Heterogeneity with Laser Capture Microdissection. AB - Among various methods now available to isolate distinct cell populations or even single cells for DNA/RNA and proteomic analysis, laser capture microdissection (LCM) offers a unique opportunity to study cells in their topological contexts. This chapter focuses on the preparation of LCM membrane slides, tissue staining and laser microdissection of cells of interest from frozen or formalin-fixed, paraffin-embedded glioblastoma tissue. PMID- 29392704 TI - Flow Cytometric Identification of Tumor-Infiltrating Lymphocytes from Glioblastoma. AB - We describe an isolation method of tumor-infiltrating lymphocytes (TILs) from glioblastoma tumors for the purpose of analysis by flow cytometry. This protocol is unique from many others in that the use of a selective lymphocyte isolation procedure, such as a Ficoll or Percoll gradient, is not used. We find that staining of TILs and analysis by flow cytometry is not affected by the presence of heterogeneous populations, while other selective isolation procedures can significantly decrease lymphocyte yield from already rare populations. PMID- 29392705 TI - Modeling Glioma with Human Embryonic Stem Cell-Derived Neural Lineages. AB - Gliomas are malignant primary tumors of the central nervous system. Their cell-of origin is thought to be a neural progenitor or stem cell that acquires mutations leading to oncogenic transformation. Thanks to advances in human stem cell biology, it has become possible to derive human cell types that represent putative cells-of-origin in vitro and model the gliomagenesis process by systematically introducing genetic alterations in these human cells. Here, we present methods to derive human neural stem cells (NSCs) from human embryonic stem cells (hESCs). Because these NSCs are genetically unmodified at baseline, they can be used as a cellular platform to study the effects of individual oncogenic hits in a well-controlled manner in the backdrop of a human genetic background. We also present some key applications of these NSCs, which include their transduction with lentiviral vectors, their neuroglial differentiation and xenografting methods into immunocompromised mice to assess in vivo behavior. PMID- 29392706 TI - Effect of olive oil phenolic compounds on osteoblast differentiation. AB - BACKGROUND: Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes individuals to an increased risk of fracture. Previous in vivo and in vitro studies have reported that phenolic compounds present in extra virgin olive oil have a beneficial effect on osteoblasts in terms of increase cell proliferation. The aim of this study was to determine whether phenolic compounds present in olive oil could modify the expression of cell differentiation markers on osteoblasts. STUDY DESIGN: An in vitro experimental design was performed using MG-63 osteoblasts cell line. METHODS: MG63 cells were exposed to different doses of luteolin, apigenin, or p-coumaric, caffeic or ferulic acid. Alkaline phosphatase (ALP) was evaluated by spectrophotometry and antigen expression (cluster of differentiation [CD] 54, CD80, CD86 and HLA-DR) by flow cytometry. RESULTS: At 24 hour, treated groups showed an increased ALP and modulated antigen profile, with respect to the nontreated group. CONCLUSION: These results demonstrate that the phenolic compounds studied induce cell maturation in vitro, increasing ALP synthesis and reducing the expression of antigens involved in immune functions of the osteoblast which would improve bone density. PMID- 29392707 TI - Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G-CSF in Breast Cancer Patients. AB - The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC AUEC. The models predicted that with 10 * 109 day/L of increase in ANC-AUEC, the mean DSN would decrease from 1.1 days to 0.93 day in Trial 1 and from 1.2 days to 1.0 day in Trial 2. The findings of the analysis provide useful information regarding the relationship between ANC and DSN that can be used for dose selection and optimization of clinical trial design for G-CSF. PMID- 29392708 TI - Annular erythema nodosum leprosum reaction in a young male: a rare presentation. PMID- 29392709 TI - Age-dependent variation in the terminal investment threshold in male crickets. AB - The terminal investment hypothesis proposes that decreased expectation of future reproduction (e.g., arising from a threat to survival) should precipitate increased investment in current reproduction. The level at which a cue of decreased survival is sufficient to trigger terminal investment (i.e., the terminal investment threshold) may vary according to other factors that influence expectation for future reproduction. We test whether the terminal investment threshold varies with age in male crickets, using heat-killed bacteria to simulate an immune-inducing infection. We measured calling effort (a behavior essential for mating) and hemolymph antimicrobial activity in young and old males across a gradient of increasing infection cue intensity. There was a significant interaction between the infection cue and age in their effect on calling effort, confirming the existence of a dynamic terminal investment threshold: young males reduced effort at all infection levels, whereas old males increased effort at the highest levels relative to naive individuals. A lack of a corresponding decrease in antibacterial activity suggests that altered reproductive effort is not traded against investment in this component of immunity. Collectively, these results support the existence of a dynamic terminal investment threshold, perhaps accounting for some of the conflicting evidence in support of terminal investment. PMID- 29392711 TI - The collective roots and rewards of upward educational mobility. AB - Drawing on in-depth interviews with descendants of North African working-class immigrants admitted to elite higher institutions in France, this paper investigates the under-researched role of family dynamics in facilitating upward educational mobility and informing the experience of social ascension. It shows that concrete mobility strategies, such as authoritative parenting and close mentorship from older siblings have been deployed to enable the respondents' educational attainment. Moreover, a set of moral resources transmitted through stories about family-rooted aspirations and stories about post-migration hardships and sacrifices have contributed to forging strong motivational dispositions that have facilitated school success among the respondents. These resources have further shaped the symbolic significance the interviewees associate with mobility. In contrast with the dominant individual-centred narrative of success, for second-generation North African immigrants, mobility represents a powerful way of 'giving back' to former-generation migrants whose mobility dreams often had to be relinquished. The respondents also position themselves as role-models for other youths of racially and socially disadvantaged backgrounds: their mobility pathways are described as vital for collective advancements particularly through the sense of minority empowerment these generate. PMID- 29392710 TI - Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. AB - The variant allele HLA-B*15:02 is strongly associated with greater risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine. The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes. PMID- 29392712 TI - Avian coronary endothelium is a mosaic of sinus venosus- and ventricle-derived endothelial cells in a region-specific manner. AB - The origin of coronary endothelial cells (ECs) has been investigated in avian species, and the results showed that the coronary ECs originate from the proepicardial organ (PEO) and developing epicardium. Genetic approaches in mouse models showed that the major source of coronary ECs is the sinus venosus endothelium or ventricular endocardium. To clarify and reconcile the differences between avian and mouse species, we examined the source of coronary ECs in avian embryonic hearts. Using an enhanced green fluorescent protein-Tol2 system and fluorescent dye labeling, four types of quail-chick chimeras were made and quail specific endothelial marker (QH1) immunohistochemistry was performed. The developing PEO consisted of at least two cellular populations in origin, one was sinus venosus endothelium-derived inner cells and the other was surface mesothelium-derived cells. The majority of ECs in the coronary stems, ventricular free wall, and dorsal ventricular septum originated from the sinus venosus endothelium. The ventricular endocardium contributed mainly to the septal artery and a few cells to the coronary stems. Surface mesothelial cells of the PEO differentiated mainly into a smooth muscle phenotype, but a few differentiated into ECs. In avian species, the coronary endothelium had a heterogeneous origin in a region-specific manner, and the sources of ECs were basically the same as those observed in mice. PMID- 29392713 TI - Insulo-opercular cortex generates oroalimentary automatisms in temporal seizures. AB - OBJECTIVE: Oroalimentary automatisms (OAAs) resembling normal alimentary behavior are stereotyped complex movements that may occur during epileptic seizures. They are considered common clinical signs in temporal lobe seizures, but their anatomofunctional mechanisms are not established. We took the opportunity of presurgical intracerebral recordings to study the relations between the occurrence of OAAs and temporal/spatial features of ictal activities. METHODS: We retrospectively reviewed patients with medically intractable medial temporal lobe epilepsy who underwent stereoelectroencephalography (SEEG) at Cleveland Clinic between 2009 and 2016. Patients presenting oroalimentary automatisms during seizures, with intracerebral electrodes spanning temporal and extratemporal areas, were selected. SEEG-clinical correlations with latency measurements were done. Coherence analyses were performed on regions of interest as defined by the areas involved at the onset of oroalimentary automatisms. RESULTS: Fifteen patients (115 seizures) were analyzed. Sixty-nine seizures exhibited overt oroalimentary automatisms. Only insulo-opercular cortex ictal involvement was consistently related to the occurrence of OAAs, with a linear correlation between OAA onset and ictal oscillatory activity onset in the insulo-opercular cortex. SEEG signal processing showed an increase in theta coherence preceding oroalimentary automatism onset between mediobasal-temporal structures and insulo opercular cortex, as well as between the 2 insulo-opercular regions. SIGNIFICANCE: The underlying mechanism for the production of oroalimentary automatisms in medial temporal seizures is based on temporal-insulo-opercular theta coherence leading to a synchronous state generating rhythmic patterned outputs from the cortical masticatory area. PMID- 29392714 TI - The evolution of floral sonication, a pollen foraging behavior used by bees (Anthophila). AB - Over 22,000 species of biotically pollinated flowering plants, including some major agricultural crops, depend primarily on bees capable of floral sonication for pollination services. The ability to sonicate ("buzz") flowers is widespread in bees but not ubiquitous. Despite the prevalence of this pollinator behavior and its importance to natural and agricultural systems, the evolutionary history of floral sonication in bees has not been previously studied. Here, we reconstruct the evolutionary history of floral sonication in bees by generating a time-calibrated phylogeny and reconstructing ancestral states for this pollen extraction behavior. We also test the hypothesis that the ability to sonicate flowers and thereby efficiently access pollen from a diverse assemblage of plant species, led to increased diversification among sonicating bee taxa. We find that floral sonication evolved on average 45 times within bees, possibly first during the Early Cretaceous (100-145 million years ago) in the common ancestor of bees. We find that sonicating lineages are significantly more species rich than nonsonicating sister lineages when comparing sister clades, but a probabilistic structured rate permutation on phylogenies approach failed to support the hypothesis that floral sonication is a key driver of bee diversification. This study provides the evolutionary framework needed to further study how floral sonication by bees may have facilitated the spread and common evolution of angiosperm species with poricidal floral morphology. PMID- 29392716 TI - N-acetyl-L-cysteine improves mesenchymal stem cell function in prolonged isolated thrombocytopenia post-allotransplant. AB - Prolonged isolated thrombocytopenia (PT) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Murine studies and in vitro experiments suggest that mesenchymal stem cells (MSCs) can, not only to support haematopoiesis, but also preferentially support megakaryocytopoiesis in bone marrow (BM). However, little is known about the quantity and function of BM MSCs in PT patients. In a case-control study, we found that BM MSCs from PT patients exhibited significantly reduced proliferative capacities, increased reactive oxygen species and senescence. Antioxidant (N-acetyl-L-cysteine, NAC) treatment in vitro not only quantitatively and functionally improved BM MSCs derived from PT patients through down-regulation of the p38 (also termed MAPK14) and p53 (also termed TP53) pathways but also partially rescued the impaired ability of BM MSCs to support megakaryocytopoiesis. Subsequently, a pilot study showed that the overall response of NAC treatment was obtained in 7 of the enrolled PT patients (N = 10) without significant side effects. Taken together, the results indicated that dysfunctional BM MSCs played a role in the pathogenesis of PT and the impaired BM MSCs could be improved by NAC in vitro. Although requiring further validation, our data indicate that NAC might be a potential therapeutic approach for PT patients after allo-HSCT. PMID- 29392715 TI - Laser ablation is effective for temporal lobe epilepsy with and without mesial temporal sclerosis if hippocampal seizure onsets are localized by stereoelectroencephalography. AB - OBJECTIVE: Selective laser amygdalohippocampotomy (SLAH) using magnetic resonance guided laser interstitial thermal therapy (MRgLITT) is emerging as a treatment option for drug-resistant mesial temporal lobe epilepsy (MTLE). SLAH is less invasive than open resection, but there are limited series reporting its safety and efficacy, particularly in patients without clear evidence of mesial temporal sclerosis (MTS). METHODS: We report seizure outcomes and complications in our first 30 patients who underwent SLAH for drug-resistant MTLE between January 2013 and December 2016. We compare patients who required stereoelectroencephalography (SEEG) to confirm mesial temporal onset with those treated based on imaging evidence of MTS. RESULTS: Twelve patients with SEEG-confirmed, non-MTS MTLE and 18 patients with MRI-confirmed MTS underwent SLAH. MTS patients were older (median age 50 vs 30 years) and had longer standing epilepsy (median 40.5 vs 5.5 years) than non-MTS patients. Engel class I seizure freedom was achieved in 7 of 12 non-MTS patients (58%, 95% confidence interval [CI] 30%-86%) and 10 of 18 MTS patients (56%, 95% CI 33%-79%), with no significant difference between groups (odds ratio [OR] 1.12, 95% CI 0.26-4.91, P = .88). Length of stay was 1 day for most patients (range 0-3 days). Procedural complications were rare and without long-term sequelae. SIGNIFICANCE: We report similar rates of seizure freedom following SLAH in patients with MTS and SEEG-confirmed, non-MTS MTLE. Consistent with early literature, these rates are slightly lower than typically observed with surgical resection (60%-80%). However, SLAH is less invasive than open surgery, with shorter hospital stays and recovery, and severe procedural complications are rare. SLAH may be a reasonable first-line surgical option for patients with both MTS and SEEG confirmed, non-MTS MTLE. PMID- 29392717 TI - Development of bimanual performance in young children with cerebral palsy. AB - AIM: To describe the development of bimanual performance among young children with unilateral or bilateral cerebral palsy (CP). METHOD: A population-based sample of 102 children (53 males, 49 females), median age 28.5 months (interquartile range [IQR] 16mo) at first assessment and 47 months (IQR 18mo) at last assessment, was assessed half-yearly with the Assisting Hand Assessment (AHA) or the Both Hands Assessment (BoHA) for a total of 329 assessments. Developmental limits and rates were estimated by nonlinear mixed-effects models. Developmental trajectories were compared between levels of manual ability (Mini Manual Ability Classification System [Mini-MACS] and MACS) and AHA or BoHA performance at 18 months of age (AHA-18/BoHA-18) for both CP subgroups, and additionally between children with bilateral CP with symmetric or asymmetric hand use. RESULTS: For both CP subgroups, children classified in Mini-MACS/MACS level I, and those with high AHA-18 or BoHA-18 reached the highest limits of performance. For children with bilateral CP the developmental change was small, and children with symmetric hand use reached the highest limits. INTERPRETATION: Mini-MACS/MACS levels and AHA-18 or BoHA-18 distinguished between various developmental trajectories both for children with unilateral and bilateral CP. Children with bilateral CP changed their performance to a smaller extent than children with unilateral CP. WHAT THIS PAPER ADDS: Manual Ability Classification System levels and Assisting Hand Assessment/Both Hands Assessment performance at 18 months are important predictors of hand use development in cerebral palsy (CP). Children with bilateral CP improved less than those with unilateral CP. Children with bilateral CP and symmetric hand use reached higher limits than those with asymmetry. PMID- 29392718 TI - Simulation-based point-of-care ultrasound training: a matter of competency rather than volume. AB - BACKGROUND: Point-of-care ultrasonography plays an increasingly important role in the initial resuscitation of critically ill patients but acquisition of the skill is associated with long learning curves. The skills required to perform ultrasound examinations can be practiced in a simulated setting before being performed on actual patients. The aim of this study was to investigate the learning curves for novices training the FAST protocol on a virtual-reality simulator. METHODS: Ultrasound novices (N = 25) were instructed to complete a FAST training program on a virtual-reality ultrasound simulator. Participants were instructed to continue training until they reached a previously established mastery learning level, which corresponds to the performance level of a group of ultrasound experts. Performance scores and time used during each FAST examination were used to determine participants' learning curves. RESULTS: The participants attained the mastery learning level within a median of three (range two to four) attempts corresponding to a median of 1 h 46 min (range 1 h 2 min to 3 h 37 min) of simulation training. The ultrasound novices' examination speed improved significantly with training, and continued to improve even after they attained the mastery learning level (P = 0.011). Twenty-three participants attained the mastery learning level. CONCLUSION: Novices can attain mastery learning levels using simulation-based ultrasound training with less than, on average, 2 h of practice. However, we found large variations in the amount of training needed, which raises questions about the adequacy of current volume-based models for determining ultrasound competency. PMID- 29392719 TI - Exposure to predators does not lead to the evolution of larger brains in experimental populations of threespine stickleback. AB - Natural selection is often invoked to explain differences in brain size among vertebrates. However, the particular agents of selection that shape brain size variation remain obscure. Recent studies suggest that predators may select for larger brains because increased cognitive and sensory abilities allow prey to better elude predators. Yet, there is little direct evidence that exposure to predators causes the evolution of larger brains in prey species. We experimentally tested this prediction by exposing families of 1000-2000 F2 hybrid benthic-limnetic threespine stickleback to predators under naturalistic conditions, along with matched controls. After two generations of selection, we found that fish from the predator addition treatment had significantly smaller brains (specifically smaller telencephalons and optic lobes) than fish from the control treatment. After an additional generation of selection, we reared experimental fish in a common environment and found that this difference in brain size was maintained in the offspring of fish from the predator addition treatment. Our results provide direct experimental evidence that (a) predators can indeed drive the evolution of brain size--but not in the fashion commonly expected and (b) that the tools of experimental evolution can be used to the study the evolution of the vertebrate brain. PMID- 29392720 TI - Preexisting cognitive impairment in intracerebral hemorrhage: Methodological issues. PMID- 29392721 TI - Response to the letter by Safiri et al. PMID- 29392722 TI - Diagnosis of small vestibular schwannomas using constructive interference steady state sequence. AB - OBJECTIVES/HYPOTHESIS: The objectives of this study were to evaluate the diagnostic accuracy of constructive interference steady state (CISS) sequencing compared to gadolinium-enhanced T1 (GdT1) magnetic resonance imaging (MRI) to screen for small vestibular schwannomas (VSs), and to assess the overall diagnostic confidence of neuroradiologists in their ability to accurately diagnose or rule out VSs using CISS imaging compared to a GdT1 MRI STUDY DESIGN: Retrospective chart review. METHODS: Chart review from 2011 to 2015 was performed for VS/benign cerebellopontine angle tumors. Two blinded, board-certified neuroradiologists each independently reviewed the axial CISS sequence and answered a set of questions that determined their confidence in diagnosis of VS. Next, each neuroradiologist independently reviewed the corresponding GdT1 MRI sequence and completed the same questionnaire. RESULTS: The majority of the lesions were in the lateral internal auditory canal, with eight intralabyrinthine tumors. The overall sensitivity of CISS for both readers was 93.5%. All tumor locations had high sensitivities except for the intralabyrinthine location (62.3%). Four of the eight total intralabyrinthine lesions were missed by at least one reader. Each reader was highly confident in diagnosing VSs with CISS, which approximated that of GdT1 MRI. CONCLUSIONS: This study's results showed that CISS examinations for screening of small VS approximated that of GdT1. Neuroradiologists had high sensitivity, perfect specificity, and felt confident in ruling out a VS on CISS sequence while feeling extremely confident in diagnosing one on CISS. Intralabyrinthine lesions and lesions <=3.0 mm are most at risk for not being detected on CISS examinations. LEVEL OF EVIDENCE: 4 Laryngoscope, 128:2128-2132, 2018. PMID- 29392723 TI - Role of narrow-band imaging in detection of head and neck unknown primary squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: There is no general consensus on what kind of examination to include in an optimal detection strategy for head and neck squamous cell carcinomas of unknown primary (SCCUPs). This study investigates the role of narrow-band imaging (NBI) in their identification. STUDY DESIGN: Case series. METHODS: Twenty-nine consecutive patients affected by SCCUPs were referred at two academic institutions. Selection criteria were: 1) lymph node cytology positive for squamous cell carcinoma (SCC); 2) no evidence of any primary at white light (WL); 3) negative contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging, and positron emission tomography-CT; and 4) no contraindication to general anesthesia. Each patient underwent office-based NBI panendoscopy. If a suspicious area was identified, a biopsy was performed for histological confirmation. When no suspicious area was detected in the office, patients underwent WL and NBI under general anesthesia. If this examination was still negative, bilateral tonsillectomy and base of the tongue (BOT) mucosectomy were performed. RESULTS: Office-based NBI identified 10 SCCs (34.5%), one in the nasopharynx, three in the tonsil, four in the BOT, and two in the supraglottis. In only one (3.5%) NBI-negative patient was a primary found in the BOT. In one (3.5%) we found an NBI suspicious area during panendoscopy under general anesthesia, but histology did not confirm this finding after BOT mucosectomy. Seventeen (58.6%) patients remained as having true SCCUPs. NBI sensitivity, specificity, positive, negative predictive values, and accuracy were 91%, 95%, 91%, 95%, and 90%, respectively. CONCLUSIONS: In the present study, office-based NBI increased the detection rate of head and neck SCCUPs by 34.5% and should be strongly recommended as an adjunctive tool in their diagnostic workup. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2060-2066, 2018. PMID- 29392724 TI - In reference to Evidence against the mucosal traction theory in cholesteatoma. PMID- 29392725 TI - Effects of UV Irradiation by Light Emitting Diodes on Heterotrophic Bacteria in Tap Water. AB - Ultraviolet light emitting diodes (UV-LEDs) are small mercury-free devices that can be installed at the point of use (POU) of water for disinfection. Considering that heterotrophic bacteria are of concern in drinking water systems, we applied a flow-through UV-LED apparatus to dechlorinated tap water, and determined the heterotrophic plate count (HPC) in samples after UV-LED exposure (UV+) compared to samples without UV-LED application (UV-). The UV+ and UV- samples were maintained at 20 degrees C to track HPC profiles during storage for 7 days. It was confirmed that UV+ samples showed negative HPC or lower HPC than UV- for 5 days of storage after the flow-through test. HPC bacteria formed colonies with different morphological characteristics, and yellow colonies were closest to Novosphingobium sp., with 99% identity, while white and pale pink colonies were closest to Methylobacterium sp., with 99-100% identity, based on 16S rRNA gene sequences. White colonies became dominant in UV+, indicating that UV-LED exposure can select UV-resistant species such as Methylobacterium. This study shows the effects of UV-LED application on HPC bacteria in tap water and implies that future research is required on the significance and impacts of microbial selection by UV-LED exposure. PMID- 29392726 TI - Univariate and Linear Composite Asymmetry Statistics for the "Pair-Matching" of Bone Antimeres. AB - This paper examines the distributional properties of univariate and linear composite measures of long bone asymmetry. The goal of this paper is to examine models that best fit the distribution of asymmetries with implications for the improvement of forensic pair-matching techniques. We use the software R to model reference data (N = 2343) and test data (N = 71) as normal distributions, an exponential power distribution, and a skew exponential power distribution-the latter two include the normal as a special case. Our results indicate that the data best fit the latter two distributions because the data are nonnormal. We also show how asymmetry statistics that use absolute values of side differences can be fit as folded distributions. This obviates the need for empirical distributions or for transformations that attempt to convert nonnormal distributions to normal distributions. The results of this study lay the framework for improving pair-matching methods that use comparative reference data. PMID- 29392727 TI - A prospective, randomized, placebo-controlled study of inferior turbinate surgery. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to compare radiofrequency ablation, diode laser, and microdebrider-assisted inferior turbinoplasty techniques in the treatment of chronic nasal obstruction caused by inferior turbinate enlargement, and to compare these techniques with a placebo procedure. STUDY DESIGN: Prospective, randomized, single-blinded, placebo-controlled study. METHODS: A total of 98 consecutive patients with enlarged inferior turbinates due to persistent year-round rhinitis were randomized into a placebo, radiofrequency ablation, diode laser, and microdebrider-assisted inferior turbinoplasty groups in a ratio of 1:2:2:2. All the procedures were carried out under local anesthesia with the patients' eyes covered. Assessments were conducted prior to surgery and 3 months subsequent to the surgery. RESULTS: The severity of nasal obstruction measured by visual analog scale score decreased statistically significantly in all the groups, including placebo. Radiofrequency ablation (P = .03), diode laser (P = .02), and microdebrider-assisted inferior turbinoplasty (P = .04) all decreased the symptom score of the severity of nasal obstruction statistically significantly more compared to the placebo procedure. CONCLUSIONS: The placebo effect had a large role in the overall improvement of the severity of nasal obstruction after the inferior turbinate surgery. However, all three techniques provided a statistically significant additional reduction of the severity of nasal obstruction compared to the placebo procedure. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:1997-2003, 2018. PMID- 29392728 TI - Soluble antigens in plasma allow mismatched transfusion without hemolysis. AB - BACKGROUND: Universal plasma is a scarce resource when a massive transfusion protocol has been initiated. Previous studies have reported success using group A plasma in place of the universal plasma, group AB. It is unclear why there are not more reports of hemolytic reactions occurring from this practice. One possible explanation is the presence of water-soluble antigens in the patient plasma that bind to, and neutralize, the soluble antibodies present in the transfused plasma. STUDY DESIGN AND METHODS: Expired units of plasma were used to make dilutions that consisted of mixtures of group A and B plasma and saline. Serial dilutions of these samples were performed starting from undiluted up to 1024. The dilutions were titrated using a group B red blood cell preparation. The titrations were read after incubation. RESULTS: The titers that resulted from the mixed plasma dilutions were significantly lower or showed no agglutination when compared to the group A-specific saline dilutions. The differences between the saline dilutions and mixed group dilutions were significant (p < 0.001). CONCLUSION: Our study shows that secretor status would provide protection from isoantibodies. The dissolved B antigens in the group B plasma absorb and/or bind to the group B isoantibodies in the group A plasma. This mechanism gives a protective effect against hemolytic reactions in massive transfusion situations in the trauma setting when group A plasma is used instead of group AB plasma. This protective effect is revealed with the paucity of intravascular hemolysis observed in these out-of-group massive transfusions. PMID- 29392730 TI - Three-dimensional mobility and muscle attachments in the pectoral limb of the Triassic cynodont Massetognathus pascuali (Romer, 1967). AB - The musculoskeletal configuration of the mammalian pectoral limb has been heralded as a key anatomical feature leading to the adaptive radiation of mammals, but limb function in the non-mammaliaform cynodont outgroup remains unresolved. Conflicting reconstructions of abducted and adducted posture are based on mutually incompatible interpretations of ambiguous osteology. We reconstruct the pectoral limb of the Triassic non-mammaliaform cynodont Massetognathus pascuali in three dimensions, by combining skeletal morphology from micro-computed tomography with muscle anatomy from an extended extant phylogenetic bracket. Conservative tests of maximum range of motion suggest a degree of girdle mobility, as well as substantial freedom at the shoulder and the elbow joints. The glenoid fossa supports a neutral pose in which the distal end of the humerus points 45 degrees posterolaterally from the body wall, intermediate between classically 'sprawling' and 'parasagittal' limb postures. Massetognathus pascuali is reconstructed as having a near-mammalian complement of shoulder muscles, including an incipient rotator cuff (m. subscapularis, m. infraspinatus, m. supraspinatus, and m. teres minor). Based on close inspection of the morphology of the glenoid fossa, we hypothesize a posture-driven scenario for the evolution of the therian ball-and-socket shoulder joint. The musculoskeletal reconstruction presented here provides the anatomical scaffolding for more detailed examination of locomotor evolution in the precursors to mammals. PMID- 29392729 TI - Umbilical cannulation optimizes circuit flows in premature lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND). AB - KEY POINTS: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel 'artificial womb' system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology. ABSTRACT: EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105-117 days (term 145-150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight-adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger-bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post-membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow. PMID- 29392732 TI - Effect of Cutting with an Abrasive Saw on Swarf Composition. AB - Crime scene investigators are often asked to examine swarf from break-in sites and compare it with swarf found on a suspect. Occasionally, elemental composition of swarf from these two sources does not match. It is generally assumed that cutting metal does not induce changes in chemical composition. However, this study shows that, if a matrix contains iron, chromium, and nickel, composition of swarf produced from cutting the matrix with an abrasive saw may indeed alter. In this study, we cut a stainless steel sheet using a standard cutoff saw. Swarf was sorted and chemically analyzed by EDS/SEM, and the following relationships between chip morphology and modified composition were discovered: elongated chips remained unchanged; changes in the irregular chips appeared to be random, possibly because they are formed in a number of different ways; composition of spherical chips changed with size. PMID- 29392731 TI - Immune modulatory effects of statins. AB - Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft-versus host disease still have major adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate-limiting enzyme of the l-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It was shown that blocking the l-mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, l-mevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases. PMID- 29392734 TI - Characteristics and Responses of Human Vocal Fold Cells in a Vibrational Culture Model. AB - OBJECTIVES/HYPOTHESIS: This study was conducted to provide a vibrational culture model to investigate the effects of mechanical environments on cellular functions, and elucidate physiological characteristics of two different types of cells in vocal folds under static and vibrational conditions. STUDY DESIGN: In vitro study of human vocal fold fibroblasts (hVFFs) and human macula flava stellate cells (hMF-SCs). METHODS: hVFFs and hMF-SCs were exposed to a 2-second on/2-second-off, 205 Hz vibration regime for 4 hours by using a vibrational culture model. We compared cell morphology, cell viability, and gene expression in extracellular matrix-related components, growth factors, and differentiation markers under static and vibratory conditions. RESULTS: hVFFs and hMF-SCs differed in their morphologies and gene expression levels under static condition. The applied vibration did not induce changes in morphology and viability of either cell type. However, gene expression levels changed in both cell types in response to vibration; in particular, hMF-SCs exhibited a more sensitive response to vibration than that shown by hVFFs. CONCLUSIONS: The vibrational culture model developed in this study enabled us to investigate the effects of the applied vibration on two types of vocal fold resident cells. As a result, we could demonstrate that hVFFs and hMF-SCs exhibited distinctively different characteristics under vibrational conditions. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E258-E264, 2018. PMID- 29392735 TI - Which Patients With Asymmetric Sensorineural Hearing Loss Should Undergo Imaging? PMID- 29392733 TI - The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. AB - The importance of the gut microbiome in the regulation of non-infectious diseases has earned unprecedented interest from biomedical researchers. Widespread use of next-generation sequencing techniques has prepared a foundation for further research by correlating the presence of specific bacterial species with the onset or severity of a disease state, heralding paradigm-shifting results. This review covers the mechanisms through which a dysbiotic gut microbiota contributes to the pathological symptoms in an autoimmune neurodegenerative disorder, multiple sclerosis (MS). Although the central nervous system (CNS) is protected by the blood-brain barrier (BBB), it is unclear how gut dysbiosis can trigger potential immunological changes in the CNS in the presence of the BBB. This review focuses on the immunoregulatory functionality of microbial metabolites, which can cross the BBB and mediate their effects directly on immune cells within the CNS and/or indirectly through modulating the response of peripheral T cells to stimulate or inhibit pro-inflammatory chemokines and cytokines, which in turn regulate the autoimmune response in the CNS. Although more research is clearly needed to directly link the changes in gut microbiome with neuroinflammation, focusing research on microbiota that produce beneficial metabolites with the ability to attenuate chronic inflammation systemically as well as in the CNS, can offer novel preventive and therapeutic modalities against a wide array of inflammatory and autoimmune diseases. PMID- 29392736 TI - Nutrition-Focused Quality Improvement Program Results in Significant Readmission and Length of Stay Reductions for Malnourished Surgical Patients. AB - BACKGROUND: Addressing nutrition needs of inpatients results in improved health outcomes. We conducted a post hoc analysis of previously published data. The aim of this analysis was to evaluate the clinical benefits of a nutrition quality improvement program (QIP) in surgical patients when compared with medical patients. METHODS: Data were collected from 1269 QIP patients and 1319 historical controls. These combined 2588 patients were categorized into surgical (390, 15%) and medical (2198, 85%) patient subgroups. RESULTS: Readmission rate relative risk reductions were significantly higher among surgical patients when compared with the medical patients (46.9% vs 20.6%, P < .001). Average length of stay decreased significantly for both groups (29.0% and 29.6%, P = .8). CONCLUSION: Malnourished hospitalized surgical and medical patients experienced improved readmission rates and length of stay. However, surgical patients saw a significantly greater reduction in the readmission rate when compared with the medical patients, thus highlighting the importance of nutrition on surgical outcomes. The ClinicalTrials.gov Identifier for this study is NCT02262429. PMID- 29392737 TI - Management of injured patients who were Jehovah's Witnesses, where blood transfusion may not be an option: a retrospective review. AB - INTRODUCTION: Management of major haemorrhage as a result of trauma is particularly challenging when blood is not an option (BNAO). Evidence on therapeutic strategies in this situation is limited. The aim of this study was to evaluate the management and outcomes of patients who identified themselves as Jehovah's Witnesses (who usually refuse blood products) with traumatic haemorrhage at an Australian major trauma centre. METHODS: A retrospective review of patients from The Alfred Trauma Registry was conducted, including patients who were Jehovah's Witnesses presenting between January 2010 and January 2017. We examined demographics, injury characteristics, clinical progress, therapeutic interventions and outcomes at hospital discharge. RESULTS: There were 34 patients meeting inclusion criteria, with 50% suffering major trauma. Anaemia was a clinical problem for 13 (38.2%) patients, with haemoglobin levels reaching a nadir of 69.7 g/l (95% CI: 56.7-82.7) on average 5.1 days (95% CI: 2.5-7.7) post admission. Various strategies were employed to reduce blood loss including six (46.2%) patients receiving tranexamic acid, nine (29.2%) patients receiving oral or intravenous iron and five (38.5%) receiving erythropoietin. Three patients received packed red cells, and two patients received synthetic haemoglobin-based oxygen carriers. CONCLUSIONS: Numerous therapeutic strategies were employed inconsistently in this unique population of patients. Augmenting circulatory volume with an oxygen carrier acceptable to JW patients presents a novel approach to be considered in adjunct to other strategies. An international resource centre would assist clinicians faced with anaemia and BNAO. PMID- 29392738 TI - Heart Transplantation in Patients Supported by ECMO: Is the APACHE IV Score a Predictor of Survival? AB - Bridge to heart transplantation (HTx) with ECMO is associated with poor outcome, but patient status, according to different levels of multiorgan compromise, is generally not considered. The aim of this study was to analyze the prognostic value of acute physiology, age, and chronic health evaluation IV (APACHE IV) score in this setting. Thirty-two patients underwent HTx bridged with ECMO at our institution between 2005 and 2017; they were divided into two groups, according to a cutoff value of APACHE IV score obtained by Receiver operating characteristic curve analysis for 30-day mortality. Kaplan-Meyer survival curves were plotted, and compared through the log-Rank test. Cox regression model was used to estimate which factors were associated with overall survival. The 30-day mortality prediction of the APACHE IV score showed an AUC of 0.98 [95% C.I. 0.84 0.99], with a cutoff value corresponding to a score value of 47 (specificity of 84.6% and sensitivity of 100%) in order to discriminate between a group with low probability (Group A, patients with an APACHE IV score <47), and a group with high probability (Group B, patients with an APACHE IV score >=47) of 30-day mortality. Median follow up was 26.9 months (range: 0.03-143.8). On overall, patients bridged with ECMO showed a high early mortality (18.7% <30 days, n = 6). All deaths occurred in Group B, where 30-day mortality was 60%. Survival probability among Group B patients was 26.6% at both 1 and 5 years. Conversely, in Group A no early mortality was reported, and the estimated survival was 89.7% at 1 year and 81.5% at 5 years, respectively. Mortality correlated at univariate analysis with recipient age, APACHE IV score and female sex, while the multivariate Cox regression analysis showed that only an APACHE IV score (HR 1.23 [1.08-1.39, 95% C.I.]) and female sex (HR 6.68 [1.42-31.43, 95% C.I.]) had an adverse impact on survival. This study shows that the APACHE IV score could be considered a powerful predictor of survival in patients bridged by ECMO to HTx, and can account for a better selection of patients on ECMO support at time of listing. PMID- 29392739 TI - Fish bone peptide promotes osteogenic differentiation of MC3T3-E1 pre-osteoblasts through upregulation of MAPKs and Smad pathways activated BMP-2 receptor. AB - Fish bone, a by-product of fishery processing, is composed of protein, calcium, and other minerals. The objective of this study was to investigate the effects of a bioactive peptide isolated from the bone of the marine fish, Johnius belengerii, on the osteoblastic differentiation of MC3T3-E1 pre-osteoblasts. Post consecutive purification by liquid chromatography, a potent osteogenic peptide, composed of 3 amino acids, Lys-Ser-Ala (KSA, MW: 304.17 Da), was identified. The purified peptide promoted cell proliferation, alkaline phosphatase activity, mineral deposition, and expression levels of phenotypic markers of osteoblastic differentiation in MC3T3-E1 pre-osteoblast. The purified peptide induced phosphorylation of mitogen-activated protein kinases, including p38 mitogen activated protein kinase, extracellular regulated kinase, and c-Jun N-terminal kinase as well as Smads. As attested by molecular modelling study, the purified peptide interacted with the core interface residues in bone morphogenetic protein receptors with high affinity. Thus, the purified peptide could serve as a potential pharmacological substance for controlling bone metabolism. PMID- 29392740 TI - How trust and emotions influence policy acceptance: The case of the Irish water charges. AB - The introduction of new policies can evoke strong emotional reactions by the public. Yet, social-psychological research has paid little attention to affective determinants of individual-level policy acceptance. Building on recent theoretical and empirical advances around emotions and decision-making, we evaluate how people's trust and integral emotions function as important antecedents of cognitive evaluations, and subsequent acceptance of policies. We test our hypotheses within a sample of Irish citizens (n = 505), who were subject to the introduction of water charges in 2015. In line with our hypotheses, results show that general trust in government shapes emotions regarding water charges, which in turn, directly and via expected costs and benefits, influence policy acceptance. Additionally, we find that negative emotions have a larger direct effect on policy acceptance than positive emotions. Specifically, 'anger' was the main negative emotion that influenced the acceptance of the water charge. We conclude by discussing directions for future research around emotions and policy acceptance. PMID- 29392741 TI - Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs. AB - To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5-1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25-0.5 mg/kg benazepril BID); D (0.25-0.5 mg/kg benazepril and 0.125-0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25-0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5-1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan. PMID- 29392742 TI - The Vitamin D3 analogue calcipotriol suppresses CpG-activated TLR9-MyD88 signalling in murine plasmacytoid dendritic cells. AB - BACKGROUND: Plasmacytoid dendritic cells (pDCs) are involved in the pathogenesis of psoriasis by secreting interferon-alpha. Vitamin D3 analogues are widely used to treat psoriasis, and the representative analogue calcipotriol (CAL) uniquely downregulates the cytokine production and chemotactic activity of pDCs. However, the molecular mechanism of action of CAL is not well understood. AIM: To investigate effects of CAL on the Toll-like receptor 9-myeloid differentiation primary response gene 88 (TLR9-MyD88) signalling pathway, which induces cytokine production, in murine pDCs. METHODS: pDCs were isolated from mouse spleen cells by negative selection or were generated from mouse bone-marrow cells, and were stimulated with CpG-oligodeoxynucleotide (ODN) with or without CAL for 24 h. mRNA expression of TLR9 and MyD88 was assessed by real-time PCR, and the amount of TLR9 was measured by western blotting. RESULTS: CAL suppressed the CpG-ODN induced increased expression of MyD88 and TLR9 in pDCs. CONCLUSIONS: CAL may downregulate pDCs by inhibiting TLR9-MyD88 signalling. PMID- 29392744 TI - International survey on high- and low-dose synacthen test and assessment of accuracy in preparing low-dose synacthen. AB - OBJECTIVE: The short synacthen test (SST) is widely used to assess patients for adrenal insufficiency, but the frequency and protocols used across different centres for the low-dose test (LDT) are unknown. This study aimed to survey centres and test the accuracy of ten different synacthen preparation strategies used for the LDT. METHODS: Members of 6 international endocrine societies were surveyed regarding diagnostic tests used for adrenal insufficiency, and in particular the SST. Synacthen was diluted for the LDT and concentrations measured using a synacthen ELISA. RESULTS: Survey responses were received from 766 individuals across 60 countries (52% adult, 45% paediatric endocrinologists). The SST is used by 98% of centres: 92% using high-dose (250 MUg), 43% low-dose and 37% both. Ten low-dose dilution methods were assessed and variation in synacthen concentration was demonstrated with intramethod coefficients of variation (CV) ranging from 2.1% to 109%. The method using 5% dextrose as a diluent was the least variable (CV of 2.1%). The variation in dilution methods means that the dose of synacthen administered in a LDT may vary between 0.16 and 0.81 MUg. CONCLUSIONS: The high-dose SST is the most popular diagnostic test of adrenal insufficiency, but up to 72% of paediatric endocrinologists use a LDT. There is considerable variation observed both within and between low-dose synacthen dilution methods creating considerable risk of inaccurate dosing and thereby invalid results. PMID- 29392745 TI - Latest advances in the extraction and determination of saffron apocarotenoids. AB - Saffron, the dried red stigmas of Crocus sativus L. plant, is the most expensive spice in the world. It is highly valued not only for the color and flavor that exerts to various foods and drinks but also for its functional properties. Various classes of apocarotenoids such as crocetin sugar esters, picrocrocin and safranal are responsible for these characteristics. In the present review, the evolution of the methods proposed by the ISO standard for extraction and determination of saffron apocarotenoids since 1980 is presented in parallel to other approaches proposed by various scientists to overcome limitations of the standard. Moreover, the latest advances regarding applications of novel extraction techniques and powerful analytical tools that require limited or no sample preparation are critically discussed. PMID- 29392743 TI - Different concentrations and volumes of p-phenylenediamine in pet. (equivalent doses) are associated with similar patch test outcomes: a pilot study. AB - BACKGROUND: Concern about causing active sensitization when patch testing is performed with p-phenylenediamine (PPD) 1% pet. has led to a recommendation to use PPD 0.3% pet. as a potentially safer preparation. However, the dose per area of allergen delivered, and hence the risk of active sensitization, depend on the amount dispensed into the patch test chamber, which can vary widely. OBJECTIVE: To evaluate whether patch testing with equivalent doses of different concentrations of PPD in pet. is associated with similar outcomes. METHODS: Seventeen known PPD-sensitive subjects were patch tested with different volumes and concentrations of PPD in pet. that deliver the same allergen dose per unit area (6 mg of PPD 1% pet. and 20 mg of PPD 0.3% pet. in Finn Chambers(r), both equivalent to ~ 0.09 mg/cm2 ). RESULTS: Eleven patients (65%) had positive reactions to both doses; 4 patients (24%) had negative results [percentage agreement of 88% (15/17)]. One patient each had a positive reaction to only one dose. CONCLUSIONS: The 88% concordance suggests that dose per unit area is more important in determining reactions to allergens than the excipient volume dispensed. Patch testing with a smaller volume of 1% PPD may be a reasonable alternative to testing with 20 mg of 0.3% PPD. PMID- 29392746 TI - Effect of sperm pooling with seminal plasma collected in breeding or nonbreeding season on Saanen goat sperm cryosurvival. AB - The aim of this study was to determine the effects of both the removal of seminal plasma (SP) and the pre-freezing addition of seminal plasma collected during the breeding or nonbreeding season on goat sperm survival after thawing. Semen samples were pooled. One aliquot of pooled semen was used as a control group. Four aliquots were then centrifuged, and the SP was removed in Group I, pipetted but not removed in Group II, removed and then pooled for animals collected in the breeding season in Group III and removed and pooled for animals collected in the nonbreeding season in Group IV. Group samples were frozen and then were assessed for rates of sperm motility, plasma membrane functional integrity hypo-osmotic swelling test (HOST), defective acrosomes (FITC-PSA), DNA fragmentation (TUNEL) and mitochondrial membrane damage (Rhodamine 123). The results showed that pre freezing addition of SP collected in breeding season maintained post-thaw sperm characteristics at 0 hr better than SP removal group, but removing seminal plasma showed positive effects on spermatozoa, as incubation time increased to 5 hr. In conclusion, the pre-freezing addition of seminal plasma did not maintain post thaw goat sperm characteristics as successfully as in the groups with seminal plasma removed after an incubation period. PMID- 29392747 TI - Validating semen processing for an intrauterine program should take into consideration the inputs, actions and the outputs of the process. AB - To validate semen preparation via density gradient centrifugation, we took into account the input via the semen sample, the action generated by technical and equipment characteristics and the output measured by the level of performance. Longer periods of abstinence reduced % yield, but increased viscosity and incomplete samples collected had no effect. Under controlled technical and equipment characteristics, precision and reproducibility were validated for density gradient. Additionally, as a good laboratory practice, internal and external quality control measures were implemented to guarantee the level of performance. Inseminating motile sperm count is an important predictive parameter for IUI success. In our group of patients, a yield of an absolute lower limit of 2 million motile spermatozoa was sufficient to contemplate IUI. Pregnancy rate of 13.8% where >2 million rapid progressive spermatozoa were inseminated was significantly higher than the pregnancies (4.4%) obtained with <2 million rapid progressive spermatozoa. This percentage was even higher than the national data registered for IUI (12.2%). To make IUI an attractive first-line treatment, standardization and proper validation of semen preparation procedure are mandatory. PMID- 29392748 TI - Preliminary validation of a self-efficacy scale for pediatric chronic illness. AB - BACKGROUND: Tracking self-efficacy may be useful for identifying children at risk for medical noncompliance. We created the Pediatric Rating of Chronic Illness Self-Efficacy (PRCISE) to measure self-efficacy in youth dealing with a chronic illness. METHOD: Data were collected from 217 families where one child aged 7-20 (Mage = 13.62, SDage = 2.92; 62.7% Latino, 58.1% female) had a chronic illness. Parent participants provided demographic information. Youth completed a depression measure, the Patient Health Questionnaire for Adolescents and the PRCISE. To determine the underlying latent structure of the scale, an exploratory factor analysis was conducted using parallel analysis. We also carried out two multiple linear regressions to explore the data and establish preliminary predictive validity. RESULTS: The measure was reduced to 15 items, demonstrating a one-factor solution with strong reliability. Predictors of lower self-efficacy included having parents who had not attended college, being African American, and having higher Patient Health Questionnaire for Adolescents scores, R2 = .23, F(11, 174) = 5.62, p < .001. Main effects were qualified by a two-way interaction, such that the decrease in PRCISE scores associated with depressive symptoms was attenuated in children with less educated parents. In terms of predictive validity, higher PRCISE scores unexpectedly predicted more number of emergency room visits, R2 = .12, F(9, 113) = 2.73, p < .01. CONCLUSIONS: The PRCISE appears to be a reliable measure of a single self-efficacy construct. Secondary analyses revealed important health disparities in pediatric chronic illness self-efficacy. Next steps may include validation of the PRCISE using confirmatory factor analysis. PMID- 29392749 TI - The impact of a mobile application-based treatment for urinary incontinence in adult women: Design of a mixed-methods randomized controlled trial in a primary care setting. AB - AIMS: We aim to assess whether a purpose-developed mobile application (app) is non-inferior regarding effectiveness and cost-effective when used to treat women with urinary incontinence (UI), as compared to care as usual in Dutch primary care. Additionally, we will explore the expectations and experiences of patients and care providers regarding app usage. METHODS: A mixed-methods study will be performed, combining a pragmatic, randomized-controlled, non-inferiority trial with an extensive process evaluation. Women aged >=18 years, suffering from UI >= 2 times per week and with access to a smartphone or tablet are eligible to participate. The primary outcome will be the change in UI symptom scores at 4 months after randomization, as assessed by the International Consultation on Incontinence Modular Questionnaire UI Short Form. Secondary outcomes will be the change in UI symptom scores at 12 months, as well as the patient-reported global impression of improvement, quality of life, change in sexual functioning, UI episodes per day, and costs at 4 and 12 months. In parallel, we will perform an extensive process evaluation to assess the expectations and experiences of patients and care providers regarding app usage, making use of interviews, focus group sessions, and log data analysis. CONCLUSION: This study will assess both the effectiveness and cost-effectiveness of app-based treatment for UI. The combination with the process evaluation, which will be performed in parallel, should also give valuable insights into the contextual factors that influence the effectiveness of such a treatment. PMID- 29392750 TI - Nasal obstruction during adolescence induces memory/learning impairments associated with BDNF/TrkB signaling pathway hypofunction and high corticosterone levels. AB - The hippocampus is an important brain region involved in memory and learning. Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), and phospho-p44/p42 mitogen-activated protein kinase (MAPK) are known to contribute to hippocampal memory/learning. The present study aimed to clarify the effects of nasal obstruction during the growth period on memory/learning in an animal model, using combined behavioral, biochemical, and histological approaches. Male BALB/C mice underwent unilateral nasal obstruction (UNO) by cauterization at 8 days of age and were subjected to Y-maze and passive avoidance tests at 15 weeks of age. The serum corticosterone levels were measured using an enzyme-linked immunosorbent assay, and brain tissues were subjected to hematoxylin-eosin staining and histological analysis or homogenization and Western blot analysis. Compared with control mice, UNO mice had lower blood oxygen saturation levels and exhibited apparent memory/learning impairments during behavioral testing. Additionally, the UNO group had higher hippocampal BDNF levels and serum corticosterone levels, lower hippocampal TrkB and phospho-p44/p42 MAPK levels, and reduced neuron numbers relative to controls. Our findings suggest that UNO during adolescence affects the hippocampus and causes memory/learning impairments. PMID- 29392751 TI - A systematic review of urinary bladder hypertrophy in experimental diabetes: Part I. Streptozotocin-induced rat models. AB - AIMS: To better understand the genesis and consequences of urinary bladder hypertrophy in animal models of diabetes. This part of a three-article series will analyze urinary bladder hypertrophy in the diabetes mellitus type 1 model of rats injected with streptozotocin (STZ). METHODS: A systematic search for the key word combination "diabetes," "bladder" and "hypertrophy" was performed in PubMed; additional references were identified from reference lists of those publications. All papers were systematically extracted for relevant information. RESULTS: A total of 39 studies were identified that quantitatively reported on bladder hypertrophy in rats upon injection of STZ; of which several reported on multiple time points yielding a total of 83 group comparisons. Bladder hypertrophy was found consistently, being fully developed as early as 1 week after STZ injection (bladder weight 188 +/- 59% of matched control). Hypertrophy was similar across sexes and STZ doses (35-40 vs 50-65 mg/kg) but appeared greater with Wistar rats than other rat strains. The extent of bladder hypertrophy was not correlated to blood glucose concentrations, but normalization of blood glucose concentration by insulin treatment starting early after STZ injection prevented hypertrophy; insulin treatment starting after hypertrophy had established largely reversed it. CONCLUSIONS: Bladder size approximately doubles after STZ injection in rats; the extent of hypertrophy is not linked to the severity of hyperglycemia but largely reversible by restoration of euglycemia. PMID- 29392752 TI - Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. AB - AIMS: Cellular senescence plays a role in tumour suppression and in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies. Less is known about the role of cellular senescence in cholangiopathies in children. With that in mind, we examined the expression of senescence-associated cell cycle regulators in biliary atresia, the most common form of paediatric obliterative cholangiopathy. METHODS AND RESULTS: The expression of senescence-associated cell cycle regulators (p16Ink4a and p21WAF1/Cip1 ) and a ductular reaction related marker (neural cell adhesion molecule: NCAM) was examined in bile ducts and bile ductules in liver samples taken from the patients with biliary atresia [n = 80; including 23 samples at the time of the Kasai procedure (KP) and 63 obtained from the explanted liver (LT) (six cases with samples at both surgical stages of disease)] and from appropriate controls (n = 17). The degree of ductular reaction and cholestasis was significantly more extensive in LT than KP (P < 0.01). The expression of p16INK4a and NCAM was significantly more extensive in bile ducts and bile ductules in ductular reaction in both KP and LT compared to controls and in LT compared to KP (P < 0.05). The expression of p21WAF1/Cip1 was significantly more extensive in bile ducts and bile ductules in KP compared to both LT and controls (P < 0.01). CONCLUSIONS: Cellular senescence may play a role in the progression of bile duct loss in biliary atresia in a manner similar to that of adult cholangiopathies. PMID- 29392753 TI - Value of urodynamic findings in predicting upper urinary tract damage in neuro urological patients: A systematic review. AB - AIM: The main goals of neurogenic lower urinary tract dysfunction (NLUTD) management are preventing upper urinary tract damage (UUTD), improving continence, and quality of life. Here, we aimed to systematically assess all available evidence on urodynamics predicting UUTD in patients with NLUTD. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed in March 2017. Only neuro-urological patients assessed by urodynamics were included. Any outcome of upper urinary tract function were evaluated. RESULTS: Forty-nine studies (1 randomized controlled trial, 9 prospective, and 39 retrospective case series) reported urodynamic data on 4930 neuro-urological patients. Of those, 2828 (98%) were spina bifida (SB) children. The total number of adults was 2044, mainly having spinal cord injury (SCI) (60%). A low bladder compliance was found in 568 (46.3%) and 341 (29.3%) of the paediatric and adult population, respectively. Hydronephrosis (HDN) was detected in 557 children (27.8%) in 19/28 studies and 178 adults (14.6%), mainly SCI, in 14/21 studies. Nine out of 30 multiple sclerosis (MS) patients affected by HDN (16.8%) showed low compliance in 4/14 studies. CONCLUSIONS: Patients with SB and SCI have a higher risk of developing UUTD (mainly reported as HDN) compared to those with MS. Reduced compliance and high DLPP were major risk factors for UUTD. Although our findings clarify the mandatory role of urodynamics in the management of NLUTD, standardization and better implementation of assessments in daily practice may further improve outcomes of neuro-urological patients based on objective measurements, that is, urodynamics. PMID- 29392754 TI - A New Kind of Nursing: Walking the labyrinth of Cook County Jail. AB - This paper examines the application of public health nursing education with an emphasis on the social determinants of health within a correctional facility. The innate tension between public health practice and the punitive nature of correctional confinement is discussed through the perspective of student involvement. Exemplars of unexpected contingencies endemic to this practice setting are provided as are insights gleaned from this pilot collaboration between a college of nursing and a county correctional system. PMID- 29392755 TI - Characteristics of Isolated Ventricular Septal Defects Less Likely to Close In Utero. AB - OBJECTIVES: To determine the characteristics of fetal ventricular septal defects (VSDs) that will be less likely to close prenatally. METHODS: In this 4-year retrospective cohort study, 148 fetuses had a diagnosis of a VSD during a comprehensive fetal anatomy survey. The VSD diagnosis was confirmed by color and pulsed wave Doppler studies. These fetuses were followed monthly until their birth. They had postnatal echocardiography performed within 1 month of age to assess the persistence of a VSD. Fisher exact, Wilcoxon rank sum, and log rank tests and bivariate and multivariate logistic regressions were used to examine the association of each individual variable with prenatal VSD closure. RESULTS: One hundred twenty-five of 148 fetuses (84%) had prenatal VSD closure at a mean gestational age +/- SD of 26.9 +/- 4.5 weeks. Fetuses with a persistent VSD more frequently had other cardiac defects than the closed VSD group (12 of 23 versus 5 of 125; P < .001). Fetuses having a persistent VSD more frequently had an abnormal karyotype (9 of 23 versus 5 of 125; P < .001). The persistent VSDs were larger in their initial size (5.9 +/- 8.4 mm versus 2.7 +/- 0.8 mm; P = .002) and in their maximal prenatal size (6.0 +/- 9.1 mm versus 2.9 +/- 0.9 mm; P < .001). The presence of associated cardiac defects (adjusted odds ratio = 0.071; P = .031) and an abnormal karyotype (adjusted odds ratio = 0.058; P = .021) were significantly associated with a lower likelihood of prenatal VSD closure. All VSDs with a maximal size of 2 mm or less closed prenatally. CONCLUSIONS: Fetuses with a complex cardiac defect or an abnormal karyotype were less likely to have prenatal VSD closure. PMID- 29392756 TI - Effect of in vitro vitamin E (alpha-tocopherol) supplementation in human spermatozoon submitted to oxidative stress. AB - The aim of this study was to evaluate the antioxidant effect of in vitro supplementation with vitamin E in human spermatozoon incubated with an oxidative stress inducer. In this study, semen samples from 30 patients were collected and with one aliquot we performed semen analysis according to WHO. The remaining volume was divided into four aliquots: group C: incubated with BWW medium; group I: incubated with 5 mmol 1-1 hydrogen peroxide; group A: incubated with 40 MUmol 1-1 vitamin E; and group AI: incubated with both them. After incubations, sperm functional analyses were performed and included: evaluation of oxidative stress, acrosome integrity, mitochondrial activity and DNA fragmentation. Groups were compared using a Friedman test with Bonferroni post hoc (alpha = 5%). In this study, we observed that in group I there was a decrease in acrosome integrity and mitochondrial activity, and an increase in DNA fragmentation, when compared to group C. Group AI showed an increase in acrosome integrity and mitochondrial activity when compared with group I. Based on our findings, we conclude that the vitamin E supplementation had a positive effect in protecting human spermatozoon from induced oxidative stress. PMID- 29392757 TI - Chronic spontaneous urticaria in children - a systematic review on interventions and comorbidities. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is not frequent in children. Management guidelines have been developed for adults and randomized controlled trials (RCTs) included teenagers aged 12-18, but data for children under age 12 are limited. We performed a systematic review to assess comorbidities in children <12 years old with CSU and the efficacy and safety of treatments. METHODS: We searched for original articles of epidemiologic and treatment data in children <12 years old with CSU that were published from 2005 to July 2016 in MEDLINE, EMBASE, CENTRAL, and LILACS. Article selection and data extraction were performed in duplicate. RESULTS: Our systematic review included 9 reports on epidemiologic data (633 children). Five comorbidities and laboratory anomalies associated with CSU found were atopy (28.1%), positive autologous serum skin test (36.8%), thyroid biologic anomalies (6.4%) and detectable antinuclear antigen (10.4%), seroprevalence for Helicobacter pylori (21.1%), low vitamin D level (69.1%), and psychiatric disorders (70.4%). Only one study allowed for comparison with a control group. Our review included 10 studies (322 children), describing 5 different drug families, mostly H1-antihistamines (n = 297). One randomized controlled study compared single-dose rupatadine with single-dose desloratadine and placebo. Cyclosporine was effective and had no adverse effects in 18 children. Omalizumab, montelukast, and cefuroxime were reported in very small series (5, 1, and 1 patients). CONCLUSIONS: H1-antihistamines are effective for CSU in children <12 years old, with reassuring safety data at licensed doses. Cyclosporine seems effective, but the level of evidence is low. PMID- 29392758 TI - Toward an Application Guide for Safety Integrity Level Allocation in Railway Systems. AB - The work in the article presents the development of an application guide based on feedback and comments stemming from various railway actors on their practices of SIL allocation to railway safety-related functions. The initial generic methodology for SIL allocation has been updated to be applied to railway rolling stock safety-related functions in order to solve the SIL concept application issues. Various actors dealing with railway SIL allocation problems are the intended target of the methodology; its principles will be summarized in this article with a focus on modifications and precisions made in order to establish a practical guide for railway safety authorities. The methodology is based on the flowchart formalism used in CSM (common safety method) European regulation. It starts with the use of quantitative safety requirements, particularly tolerable hazard rates (THR). THR apportioning rules are applied. On the one hand, the rules are related to classical logical combinations of safety-related functions preventing hazard occurrence. On the other hand, to take into account technical conditions (last safety weak link, functional dependencies, technological complexity, etc.), specific rules implicitly used in existing practices are defined for readjusting some THR values. SIL allocation process based on apportioned and validated THR values is finally illustrated through the example of "emergency brake" subsystems. Some specific SIL allocation rules are also defined and illustrated. PMID- 29392759 TI - Endothelial dysfunction marker YKL-40 is elevated in male patients with idiopathic infertility. AB - Metabolic syndrome represents a collection of cardiovascular risk factors, including overweight, hypertension, dyslipidemia and impaired glucose metabolism, with insulin resistance. In recent years, the potential relationship between metabolic syndrome and male factor infertility has been studied. As endothelial dysfunction is the hallmark of metabolic syndrome, the aim of this work was to assess serum levels of YKL-40 as a marker of endothelial dysfunction in male patients with idiopathic infertility. The study revealed that YKL-40 levels were elevated in patients than controls denoting that endothelial dysfunction might play a role in the pathogenesis of idiopathic infertility and that YKL-40 as a marker of endothelial dysfunction could be a useful marker of idiopathic infertility. PMID- 29392760 TI - Understanding Fear of Zika: Personal, Interpersonal, and Media Influences. AB - Fear of infectious disease often motivates people to protect themselves. But, it can also produce negative bio-social-psychological effects whose severity is on par with those of the disease. The WHO declaration of Zika as a world health crisis presented an opportunity to study factors that bring about fear. Beginning nine days after the WHO announcement, data were gathered from women aged 18-35 living in the southern United States (N = 719). Respondents reported experiencing fear of Zika at levels akin to those reported following other significant crises/disasters (e.g., the terrorist attacks of 9/11). Fear increased as a function of (1) personal, but not other-relevance, (2) frequency of media exposure, but not media content, and (3) frequency of interpersonal exposure and interpersonal content. It is argued that media and interpersonal message sources may be innately predisposed to amplify, rather than attenuate, risk. PMID- 29392761 TI - Clinical diagnosis of temporomandibular joint arthritis. AB - Evidence-based clinical diagnostic criteria for temporomandibular joint (TMJ) arthritis are not available. To establish (i) criteria for clinical diagnosis of TMJ arthritis and (ii) clinical variables useful to determine inflammatory activity in TMJ arthritis using synovial fluid levels of inflammatory mediators as the reference standard. A calibrated examiner assessed TMJ pain, function, noise and occlusal changes in 219 TMJs (141 patients, 15 healthy individuals). TMJ synovial fluid samples were obtained with a push-pull technique using the hydroxycobalamin method and analysed for TNF, TNFsRII, IL-1beta, IL-1ra, IL 1sRII, IL-6 and serotonin. If any inflammatory mediator concentration exceeded normal, the TMJ was considered as arthritic. In the patient group, 71% of the joints were arthritic. Of those, 93% were painful. About 66% of the non-arthritic TMJs were painful to some degree. Intensity of TMJ resting pain and TMJ maximum opening pain, number of jaw movements causing TMJ pain and laterotrusive movement to the contralateral side significantly explained presence of arthritis (AUC 0.72, P < .001). Based on these findings, criteria for possible, probable and definite TMJ arthritis were determined. Arthritic TMJs with high inflammatory activity showed higher pain intensity on maximum mouth opening (P < .001) and higher number of painful mandibular movements (P = .004) than TMJs with low inflammatory activity. The combination TMJ pain on maximum mouth opening and Contralateral laterotrusion <8 mm appears to have diagnostic value for TMJ arthritis. Among arthritic TMJs, higher TMJ pain intensity on maximum mouth opening and number of mandibular movements causing TMJ pain indicates higher inflammatory activity. PMID- 29392762 TI - Spanish population-study shows that healthy late preterm infants had worse outcomes one year after discharge than term-born infants. AB - AIM: This study assessed the risks associated with healthy late preterm infants and healthy term-born infants using national hospital discharge records. METHOD: We used the minimum basic data set of the Spanish hospital discharge records database for 2012-2013 to analyse the hospitalisation of newborn infants. The outcomes were in-hospital mortality and hospital re-admissions at 30 days and one year after their first discharge. RESULTS: Of the 95 011 newborn infants who were discharged, 2940 were healthy late preterm infants, born at 34 + 0-36 + 6 weeks, and 18 197 were healthy term-born infants. The mean and standard deviation (SD) length of hospital stay were 6.0 (4.5) days in late preterm infants versus 2.8 (1.3) days in term-born infants (p < 0.001). Re-admissions were also higher in the late preterm group at 30 days (9.0% versus 4.4%) and one year (22.0% versus 12.4) (p < 0.001). The relative risk for death at one year was 4.9 in the late preterm group, when compared to the term-born infants (p = 0.026). CONCLUSION: The hospital discharge codes for otherwise healthy newborn preterm infants were associated with significantly worse 30-day and one-year outcomes when their re admission and mortality rates were compared with healthy term-born newborn infants. PMID- 29392763 TI - A multilateral investigation of the effects of zinc level on pregnancy. AB - BACKROUND: The relationship between maternal zinc level and birth weight, birth week, delivery type, garvida, maternal age, etc., contribute to diagnosis and clinical follow-up. METHOD: Multivariate investigated for data of 275 patients were obtained during their pregnancy periods until birth. 3 cc blood samples were centrifuged for 15 minutes at 2500 g within a period of 30 minutes and were stored at -80 degrees C until the time of analysis. The zinc levels of the patients were found to be within the range of 49-129 MUg/dL. Patients were divided into 8 groups according to their zinc levels (49-59, 60-69, ..., 120-129) and the relationships of zinc level with the parameters related to the mode of delivery, week of delivery, birth weight, age, early membrane rupture, live stillbirth, and gravid were statistically analyzed to determine differences between the groups. RESULTS: There was a significant difference between the live births and stillbirths with a 95% confidence level regarding the zinc level. The zinc level affected the live-stillbirth status; patients with a zinc level of 49 59 MUg/dL had stillbirths, the live birth rate for 59-69 MUg/dL was approximately 50%, whereas it was approximately 88% for in the patients with a zinc level of 109-119 MUg/dL. All patients with a zinc level of 119 MUg/dL and above had live births. CONCLUSION: Based on the results of this study, it is suggested that zinc supplementation may be an appropriate treatment for the pregnant women with low zinc levels to provide the realization of live births. PMID- 29392764 TI - Genuine halitosis in patients with dental and laryngological etiologies of mouth odor: severity and role of oral hygiene behaviors. AB - The aims of the study were to determine the severity of halitosis and the association between oral hygiene practices and the severity of malodor in patients with dental and laryngological etiologies of genuine halitosis. Thirty five laryngological and 40 dental patients with halitosis completed a structured interview and underwent laryngological and dental examinations. Halitosis was assessed using organoleptic and halimeter tests. Greater halitosis severity in laryngological patients was associated with worse clinical status of the palatine tonsils, less frequent toothbrushing, less frequent use of tongue cleaners, fewer daily meals, and increased use of mouthrinses. Among dental patients, more severe halitosis was associated with worse clinical status of the periodontium, more tongue coating, less saliva secretion, and less frequent use of dental floss, interdental toothbrushes, and tongue cleaners. Oral hygiene was found to be a key moderator of the relationship between status of the periodontium or tonsils and severity of halitosis. The severity of halitosis in laryngological patients and dental patients is essentially similar; however, oral hygiene routines are associated with different effects in each group. Consequently, individual recommendations for patients with halitosis should be adjusted for the underlying disease and emphasize the role of effective specific hygiene behaviors. PMID- 29392765 TI - Epidemiology and prognostic indicators in laryngeal lymphoma: A population-based analysis. AB - OBJECTIVES/HYPOTHESIS: To characterize the epidemiology of primary laryngeal lymphoma and to determine the prognostic factors affecting survival in patients with this disease. STUDY DESIGN: A retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database, including cases from 1973 to 2014. METHODS: A population-based analysis was conducted with patients from more than 15 different geographic regions across the United States. Patients were chosen based on a diagnosis of lymphoma and a primary lymphoma site within the larynx. Two hundred cases were eligible based on the inclusion criteria, and characteristic as well as clinical variables were then extracted from the database and analyzed. Characteristic and clinical variables included age, race, sex, primary site of lymphoma involvement, general histology, specific histologic subtype, tumor grade, and Ann Arbor staging. Exposure variables that were analyzed included radiation therapy and chemotherapy. Overall survival (OS) and disease-specific survival (DSS) were the main outcomes calculated using multivariate analysis. RESULTS: A total of 200 cases of laryngeal lymphoma were identified. The mean age at diagnosis was 64.2 years. The cohort was composed of 53% males. B-cell non-Hodgkin's lymphoma (NHL) accounted for 74% of cases, whereas natural killer/T-cell NHL accounted for 10% of cases. A total of 53.1% of patients received radiation therapy, whereas 47.5% received chemotherapy. The median OS was 9.15 years and median DSS was 24.5 years. OS at 2, 5, and 10 years was 74%, 63%, and 44%, respectively. On multivariate analysis, older age, male sex, and advanced Ann Arbor staging were associated with worse OS, whereas only male sex and advanced Ann Arbor staging were associated with worse DSS (all P values < .05). Radiation and chemotherapy were not associated with improved survival. CONCLUSIONS: Female sex and lower Ann Arbor staging are independent positive prognostic indicators for survival, whereas other clinical variables such as grade and histology do not have an effect on survival. Radiation and chemotherapy do not appear to confer a mortality benefit in patients with primary laryngeal lymphoma, which may have implications on clinical decision making as well as patient education about disease prognosis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2044-2049, 2018. PMID- 29392766 TI - Duration of antibiotic treatment after endoscopic ultrasound-guided drainage of walled-off pancreatic necrosis not affecting outcomes. AB - BACKGROUND AND AIM: Although society guidelines recommend a short course of antibiotics after drainage of walled-off necrosis (WON), the exact duration is unclear. METHODS: This is a retrospective review of patients with no prior antibiotic exposure who underwent dual-modality drainage (DMD) for sterile WON from 2008 to 2017. Patients were grouped into short duration (SD, <=5 days) versus long duration (LD, >5 days). The main outcome was the frequency of recurrent infections. RESULTS: Sixty-one patients (25 in the SD group and 36 in the LD group) were included. Patients in the two groups had comparable age, comorbidities, and severity of disease (P = 0.89). Patients in the SD group were treated with antibiotics for a median of 3 days compared with 8.5 days in the LD group. There were no differences in recurrent febrile episodes within 30 days of procedure-44% of SD group versus 39% of LD (P = 0.69). There was also no difference in time to resolution of WON (64 days for both groups, P = 0.72) or duration of hospitalization post-DMD (SD 7.7 days versus LD 7.5 days, P = 0.42). Three cases of Clostridium difficile colitis were observed in the LD group. CONCLUSIONS: Longer course of antibiotics seems to have similar outcomes compared with shorter courses in patients with WON treated with DMD. Prolonged-course therapy may predispose to secondary infections like C. difficile colitis. A randomized controlled trial is needed to evaluate the role and duration of peri procedural antibiotics after drainage of sterile WON. PMID- 29392768 TI - Corrigendum. PMID- 29392767 TI - Does dietary fluid intake affect skin hydration in healthy humans? A systematic literature review. AB - BACKGROUND: Associations between daily amounts of drinking water and skin hydration and skin physiology receive increasingly attention in the daily life and in clinical practice. However, there is a lack of evidence of dermatological benefits from drinking increased amounts of water. MATERIALS AND METHODS: Pubmed and Web of Science were searched without any restrictions of publication dates. References of included papers and related reviews were checked. Eligibility criteria were primary intervention and observational studies investigating the effects of fluid intake on skin properties in English, German, Spanish or Portuguese language, including subjects being healthy and 18+ years. RESULTS: Searches resulted in 216 records, 23 articles were read in full text, and six were included. The mean age of the samples ranged from 24 to 56 years. Overall the evidence is weak in terms of quantity and methodological quality. Disregarding the methodological limitations a slight increase in stratum corneum and "deep" skin hydration was observed after additional water intake, particularly in individuals with lower prior water consumption. Reductions of clinical signs of dryness and roughness were observed. The extensibility and elasticity of the skin increased slightly. Unclear associations were shown between water intake and transepidermal water loss, sebum content, and skin surface pH. CONCLUSIONS: Additional dietary water intake may increase stratum corneum hydration. The underlying biological mechanism for this possible relationship is unknown. Whether this association also exists in aged subjects is unclear. Research is needed to answer the question whether increased fluid intake decreases signs of dry skin. PMID- 29392769 TI - Tolerability and palatability of donkey's milk in children with cow's milk allergy. PMID- 29392770 TI - The good, the (not so) bad and the ugly of immune homeostasis in melanoma. AB - Within the immune system multiple mechanisms balance the need for efficient pathogen recognition and destruction with the prevention of tissue damage by excessive, inappropriate or even self-targeting (auto)immune reactions. This immune homeostasis is a tightly regulated system which fails during tumor development, often due to the hijacking of its essential self-regulatory mechanisms by cancer cells. It is facilitated not only by tumor intrinsic properties, but also by the microbiome, host genetics and other factors. In certain ways many cancers can therefore be considered a rare failure of immune control rather than an uncommon or rare disease of the tissue of origin, as the acquisition of potentially oncogenic traits through mutation occurs constantly in most tissues during proliferation. Normally, aberrant cells are well-controlled by cell intrinsic (repair or apoptosis) and extrinsic (immune) mechanisms. However, occasionally oncogenic cells survive and escape control. Melanoma is one of the first cancer types where treatments aimed at restoring and enhancing an immune response to regain control over the tumor have been used with various success rates. With the advent of "modern" immunotherapeutics such as anti-CTLA-4 or anti-PD-1 antibodies that both target negative immune-regulatory pathways on immune cells resulting in durable responses in a proportion of patients, the importance of the interplay between the immune system and cancer has been established beyond doubt. PMID- 29392771 TI - The Redistribution of Reproductive Responsibility: On the Epigenetics of "Environment" in Prenatal Interventions. AB - The rapidly shifting field of epigenetics has expanded scientific understanding of how environmental conditions affect gene expression and development. This article focuses on two ongoing clinical trials-one in the United States and one in the United Kingdom-that have used epigenetics as the conceptual basis for testing the relationship between nutrition and obesity during pregnancy. Drawing on ethnographic research, I highlight the different ways that clinical scientists interpret epigenetics to target particular domains of the environment for prenatal intervention. Here I examine three environmental domains: the pregnant body, the home, and everyday experiences. In so doing, I show how different scientific approaches to epigenetics multiply concepts of "the environment," while also individualizing responsibility onto pregnant bodies. Ultimately, I argue that how the environment is conceptualized in epigenetics is both a scientific and a political project that opens up questions of reproductive responsibility. PMID- 29392772 TI - Eicosapentaenoic acid ethyl ester ameliorates atopic dermatitis-like symptoms in special diet-fed hairless mice, partly by restoring covalently bound ceramides in the stratum corneum. AB - Skin barrier dysfunction has a key role in the development of atopic dermatitis (AD). Covalently bound ceramides (Cer), which are essential lipids for permeability barrier homoeostasis, are reportedly decreased in the stratum corneum (SC) of AD patients. Hairless mice fed a special diet develop pruritic dermatitis resembling human AD. Our previous study found that oral administration of the n-3 polyunsaturated fatty acid alpha-linolenic acid ameliorated skin barrier dysfunction in AD mice with concomitant increase in serum eicosapentaenoic acid (EPA). In this study, we examined the effects of EPA ethyl ester (EPA-E) on diet-induced AD in hairless mice. Oral administration of EPA-E ameliorated skin barrier dysfunction and pruritus in AD mice. In the SC of AD mice, covalently bound Cer were markedly diminished. EPA-E administration restored the lack of bound Cer. Our findings imply the possible therapeutic clinical application of EPA-E in the treatment of human AD. PMID- 29392773 TI - The characteristics of small intestinal bacterial overgrowth in patients with gallstone diseases. AB - BACKGROUND AND AIM: Small intestinal bacterial overgrowth (SIBO) might be prevalent in gallstone disease, including cases involving cholecystectomy and gallstones. The study aimed to investigate the prevalence and characteristics of SIBO in patients with gallstone disease. METHODS: This prospective study evaluated 265 patients for gallstone disease (200, gallstones; 65, cholecystectomy) and 39 healthy controls. Laboratory data, abdominal ultrasonography, and glucose breath test (GBT) with bowel symptom questionnaire were performed. RESULTS: Glucose breath test positivity (+) in patients with gallstone disease (36.6%) was significantly higher than that in controls (20.5%). GBT+ in the gallstone group (40.5%) was significantly higher than that in the control or cholecystectomy group (24.6%). The number of patients with gallstone, tend to be higher in the GBT (H2 )+, (CH4 )+, and (mixed)+ groups (56 [28.0%], 11 [5.5%], and 14 [7.00%]), respectively. Gallbladder disease was independently associated with fatty liver, metabolic syndrome, and SIBO. Of 97 GBT+ patients, 70 (72.1%), 12 (12.4%), and 15 (15.5%) were in the GBT (H2 )+, (CH4 )+, and (mixed)+ groups, respectively. GBT (CH4 )+ or GBT (mixed)+ were significantly associated with the gallstone group compared with the cholecystectomy group. The GBT (mixed)+ group had higher total symptom scores than the GBT- group for hard stool and urgency tendency, or the GBT (H2 )+ group in hard stool and loose stool tendency. Gallstone was the only independent factor for SIBO in patients with gallstone diseases. CONCLUSIONS: Small intestinal bacterial overgrowth is common among patients with gallstone. Especially, CH4 or mixed-type SIBO seems to be prevalent and to worsen intestinal symptoms. PMID- 29392774 TI - Gait initiation is influenced by emotion processing in Parkinson's disease patients with freezing. AB - BACKGROUND: Freezing of gait is a symptom that affects more than 50% of Parkinson's disease (PD) patients and increasing evidence suggests that nonmotor systems (i.e., limbic system) are involved in its underlying mechanisms. OBJECTIVE: The objective of this study was to investigate whether gait initiation characteristics are influenced by emotional stimuli in patients with PD, with or without freezing of gait. METHODS: A total of 44 participants, divided into 3 groups (15 PD patients with and 15 PD patients without freezing of gait and 14 controls), stood on a sensorized mat and were asked to take a step forward in response to a pleasant image and a step backward in response to an unpleasant one (congruent task, low cognitive load) or to take a step backward in response to a pleasant image and a step forward in response to an unpleasant one (incongruent task, high cognitive load). Reaction time, step size, anticipatory postural adjustments, and sway path were measured. RESULTS: In PD with freezing of gait, the reaction time was longer and the step size was shorter than in the other groups when they took a step forward in response to an unpleasant image (incongruent task). Changes in reaction time performance in response to unpleasant images remained significant after having adjusted for executive dysfunction and positively correlated with the "frequency" of freezing episodes. CONCLUSIONS: This study demonstrates that gait initiation was influenced by the emotional valence of visual stimuli in addition to the cognitive load of the task suggesting that the limbic system may be involved in freezing of gait. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29392775 TI - Aggregation-Induced Emission (AIE) in Ag-Au Bimetallic Nanocluster. AB - Herein we report the synthesis and structure determination of a non-fluorescent Au4 Ag5 (dppm)2 (SAdm)6 (BPh4 ) (dppm=bis(diphenylphosphino)methane and HSAdm=1 adamantane mercaptan) nanocluster in methanol with extremely strong AIE when aggregating to the solid state (i.e., film or crystal). This phenomenon was rarely reported in structural determined noble metal nanoclusters. The extended X ray absorption fine structure (EXAFS) measurement ruled out the hypothesis that the luminescence originated from the structure change in different states. Besides, the crystal structure (determined by X-ray diffraction) revealed that the tightly combined left- and right-handed enantiomers induced the strong restriction of intramolecular motions (RIM), which may have an impact on aggregation-induced emission. PMID- 29392776 TI - A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. AB - BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29392778 TI - Erratum. PMID- 29392779 TI - Sociocultural Influences on the Association Between Negative Romantic Experiences and Psychological Maladjustment in Mexican Adolescents. AB - The goal of this study was to examine whether cultural values (familismo, female virginity) and gender moderated the associations between negative romantic experiences and psychological maladjustment (depressive, anxiety symptoms) in a sample of Mexican adolescents. Self-report survey data were collected from 973 adolescents (M = 15.14 years old; 56% girls) in Mexico. Findings revealed more depressive and anxiety symptoms among adolescents who reported more negative romantic experiences. These associations were stronger for female adolescents reporting greater beliefs of familismo and female virginity. Mental health practitioners may consider negative romantic experiences and cultural values when working with Mexican adolescents. PMID- 29392777 TI - p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression. AB - Malignant glioma is one of the deadliest types of cancer. Understanding how the cell of origin progressively evolves toward malignancy in greater detail could provide mechanistic insights and lead to novel concepts for tumor prevention and therapy. Previously we have identified oligodendrocyte precursor cell (OPC) as the cell of origin for glioma following the concurrent deletion of p53 and NF1 using a mouse genetic mosaic system that can reveal mutant cells prior to malignancy. In the current study, we set out to deconstruct the gliomagenic process in two aspects. First, we determined how the individual loss of p53 or NF1 contributes to aberrant behaviors of OPCs. Second, we determined how signaling aberrations in OPCs progressively change from pre-malignant to transformed stages. We found that while the deletion of NF1 leads to mutant OPC expansion through increased proliferation and decreased differentiation, the deletion of p53 impairs OPC senescence. Signaling analysis showed that, while PI3K and MEK pathways go through stepwise over-activation, mTOR signaling remains at the basal level in pre-transforming mutant OPCs but is abruptly up-regulated in tumor OPCs. Finally, inhibiting mTOR via pharmacological or genetic methods, led to a significant blockade of gliomagenesis but had little impact on pre transforming mutant OPCs, suggesting that mTOR is necessary for final transformation but not early progression. In summary, our findings show that deconstructing the tumorigenic process reveals specific aberrations caused by individual gene mutations and altered signaling events at precise timing during tumor progression, which may shed light on tumor-prevention strategies. PMID- 29392780 TI - Secondary causes of chylomicronemia: defining the underside of the iceberg. PMID- 29392781 TI - Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice. AB - Successful ovulation requires the actions of gonadotropins along with those mediated by growth factors binding to their receptor tyrosine kinases (RTKs). There are several growth factors such as epidermal growth factor family ligands and interleukins that play a role during ovulation initiated by the preovulatory surge of luteinizing hormone (LH). The aim of this project was to analyze growth factor signaling pathways induced by LH in mouse granulosa cells. Immature female mice were treated with equine chorionic gonadotropin (eCG) followed 48 hr later by human chorionic gonadotropin (hCG) to induce follicular growth and ovulation. We performed protein array analysis where we identified higher phosphorylation of insulin-like growth factor 1 receptor (IGF1R), the fibroblast growth factor receptor 2 (FGFR2) and ephrin receptor B1 (EPHB1) in granulosa cells at 4 hr post hCG compared to 0 hr hCG (p < 0.05). We report both a significant increase in transcript abundance (p < 0.05) and the phosphorylation level (p < 0.05) of the IGF1R in granulosa cells at hCG4h. The mRNA abundance of the Fgfr2 and Ephb1 receptors remained unaltered upon hCG treatment. Nonetheless, transcript abundance of the fibroblast growth factor 2 (Fgf2) ligand was elevated at hCG4h (p < 0.01). Based on these results we conclude that the preovulatory LH surge activates signaling pathways of IGF1R through increase in the expression of the Igf1r gene in granulosa cells of ovulating follicles in mice. The LH surge also appears to activate FGFR2 IIIc and EPHB1 signaling, although further investigation is required. PMID- 29392782 TI - Allergic contact dermatitis caused by triethylenetetramine: the glue is the clue. PMID- 29392783 TI - Hyperglycemia-induced mouse trophoblast spreading is mediated by reactive oxygen species. AB - During embryo implantation, the outer layer of the blastocyst interacts with the endometrium giving rise to the development of the trophoblast cell lineage. The cells in this lineage participate in the penetration of endometrium due to their motility and invasive properties. The mechanisms that regulate the differentiation and invasive ability of these cells are essential for the establishment and maintenance of an efficient exchange between maternal and fetal tissues during pregnancy. In this context, hyperglycemia can induce oxidative stress causing alterations in the placenta. This study evaluated the role of reactive oxygen species (ROS) in the actions of high glucose concentration (HG) on trophoblast spreading and the expression of extracellular proteases in cultured mouse conceptuses. Blastocysts from gestational day 4 (GD4) were cultured until GD7 in HAM-F10 medium and further treated for 48 hr with HG (25 mM glucose) from GD7 to GD9. This treatment induced larger trophoblast outgrowths and increased ROS concentration, which was associated with increased expression levels of urokinase-type plasminogen activator (PLAU), plasminogen activator inhibitor 1 (PAI-1), and matrix metalloproteinase 9 (MMP-9). These effects were prevented by treatment with the non-specific antioxidant N-acetylcysteine (NAC) or apocynin, an inhibitor of NADPH oxidase. Our data suggest that the HG-induced trophoblast spreading and the expression of PLAU, PAI-1, and MMP-9 were mediated by the production of ROS via NADPH oxidase activity. Our results shed light on placental alterations in gestational diabetes mellitus. PMID- 29392784 TI - Acupuncture for patients with chronic functional constipation: A randomized controlled trial. AB - BACKGROUND: Acupuncture is used to treat chronic functional constipation (CFC) in China, despite limited evidence. We aim to assess the effectiveness and safety of acupuncture in managing CFC. METHODS: A multicenter randomized controlled trial was performed involving 684 patients with CFC; the patients were randomly allocated to receive He acupuncture (n = 172), Shu-mu acupuncture (n = 171), He shu-mu acupuncture (n = 171), or oral administration of mosapride (n = 170). Sixteen sessions of acupuncture were given in the treatment duration of 4 weeks. The primary outcome was the change in spontaneous bowel movements (SBMs) at week 4 (at the end of treatment) compared to baseline. The secondary outcomes included stool consistency (Bristol scale), the degree of straining during defecation, and adverse events. KEY RESULTS: The SBMs increased in all the four groups at week 4, and the magnitude of increase was equivalent in the four groups (He acupuncture, 2.7 [95% CI, 2.3-3.1]; Shu-mu acupuncture, 2.7 [95% CI, 2.3-3.0]; He-shu-mu acupuncture, 2.2 [95% CI, 1.9-2.5]; and mosapride, 2.4 [95% CI, 2.0-2.9]; P = .226). However, the change in SBMs at week 8 was significantly smaller in mosapride group (1.4 [95% CI, 1.0-1.8]) than the three acupuncture groups (2.4 [95% CI, 2.1-2.7], 2.3 [95% CI, 1.9-2.7], 2.1 [95% CI, 1.7-2.5] in He, Shu-mu, and He-shu-mu group, respectively, P = .005). CONCLUSIONS & INTERFERENCES: The three acupuncture treatments were as effective as mosapride in improving stool frequency and stool consistency in CFC, but the magnitude of the treatment effect is unknown due to the lack of sham acupuncture control. PMID- 29392785 TI - Sperm DNA fragmentation in donors and normozoospermic patients attending for a first spermiogram: Static and dynamic assessment. AB - Static assessment of sperm DNA Fragmentation (SDF at the time of ejaculation or sperm thawing when cryopreserved) and the dynamic assessment of SDF (SDF assessed after T2 hr, T6 hr and T24 hr of sperm thawing) were used to establish cut-off values associated with sperm donors when compared with closely related normozoospermic patients. Cryopreserved samples from donors revealed SDF levels two times lower in comparison with the patients. Donor sperm DNA exhibited a 2.5 times higher longevity when compared with the patients. Static values of SDF after thawing of approximately 11% identify the donors with a 71% of sensitivity and 84% specificity. With respect to the dynamic assessment, SDF increases of 2.3 per hr during the first 2 hr of incubation identify the donors with 70% of sensitivity and 66% of specificity. Creating the Rate of Combined Damage (RCD) defined as the product of SDF-T0 by the increase in the damage registered during the first 2 hr of incubation (r-SDF-T0-2 ), an index of RCD = 22.2 units has an identification capacity of donors with a 78% sensitivity and 77% specificity. Such cut-off values could be used to characterise donors with high chromatin resistance to damage when meeting the above-established criteria. PMID- 29392787 TI - Efficacy and safety of sarolaner in the treatment of canine ear mite infestation caused by Otodectes cynotis: a non-inferiority study. AB - BACKGROUND: Various treatments are available for ear mite infestations in dogs. OBJECTIVE: The efficacy of sarolaner was evaluated against ear mite infestation caused by Otodectes cynotis in dogs and compared with topical moxidectin/imidacloprid in a single-masked, multi-centre field study. ANIMALS: Client-owned dogs with O. cynotis infestation were treated monthly with oral sarolaner (n = 163) or topical moxidectin/imidacloprid (n = 78). METHODS: The presence of mites in the ear canals and the clinical signs associated with otoacariasis (including head shaking, pruritus/ear scratching, trauma or alopecia of the pinnae, and erythema, ulceration and debris in the ear canals) was evaluated on days 0, 14 and 30, and, if applicable, on day 60. Dogs were considered cured of mite infestation following one (on day 0) or two (on days 0 and 30) monthly treatments, if no live mites were found in either ear. Non inferiority was evaluated at days 14 and 30. RESULTS: Parasitological cure was achieved in 76.4%, 90.5% and 93.3% of the sarolaner-treated and in 53.9%, 63.5% and 66.7% of the moxidectin/imidacloprid-treated dogs on days 14, 30 and 60, respectively. At study completion, on day 60 at the latest, parasitological cure was achieved overall in 99.4% of sarolaner-treated and 87.8% of moxidectin/imidacloprid-treated cases. The parasitological cure rate for sarolaner was non-inferior to moxidectin/imidacloprid at days 14 and 30. The clinical signs of otoacariasis improved throughout the study in both groups. There were no treatment-related adverse events. CONCLUSIONS: A single oral administration of sarolaner was safe and highly effective in the treatment of O. cynotis infestation in dogs. PMID- 29392788 TI - Fatal primary diffuse large B-cell lymphoma of the maxillary sinus initially treated as an infectious disease in an elderly patient: A clinicopathologic report. AB - OBJECTIVE: To report a case of primary diffuse large B-cell lymphoma (DLBCL) of the maxillary sinus in an 82-year-old Caucasian woman. BACKGROUND: Diffuse large B-cell lymphoma of the maxillary sinus has non-specific signs and symptoms that may be confused with benign inflammatory conditions and upper respiratory infections. METHODS: An incisional biopsy was performed. CD20+ /CD3- /Ki-67: 95% cells were observed. CONCLUSION: A good medical history, clinical and imaging evaluations and immunohistochemical reactions are crucial to establish a correct and early diagnosis of DLBCL. PMID- 29392790 TI - Contusion of the cervical spinal cord following dental treatment of a patient at risk to stroke: A case report. AB - OBJECTIVES: It is essential that especially elderly patients are correctly positioned in dental chairs, based on medical history and careful observation. METHOD: We report a case where reclination of the patient's head resulted in weakness of the limbs. RESULTS: Subsequent investigation determined traumatic contusion of the cervical spinal cord. CONCLUSIONS: This case highlights the need for accurate anamnesis, close observation and interdisciplinary communication to determine correct positioning. Exceptional circumstances necessitate speedy response to minimise adverse events in elderly patients. PMID- 29392786 TI - Day or overnight transfusion in critically ill patients: does it matter? AB - BACKGROUND AND OBJECTIVES: The timing of blood administration in critically ill patients is first driven by patients' needs. This study aimed to define the epidemiology and significance of overnight transfusion in critically ill patients. MATERIALS AND METHODS: This is a post hoc analysis of a prospective multicentre observational study including 874 critically ill patients receiving red blood cells, platelets, fresh frozen plasma (FFP) or cryoprecipitate. Characteristics of patients receiving blood only during the day (8 am up until 8 pm) were compared to those receiving blood only overnight (8 pm up until 8 am). Characteristics of transfusion were compared, and factors independently associated with major bleeding were analysed. RESULTS: The 287 patients transfused during the day only had similar severity and mortality to the 258 receiving blood products overnight only. Although bleeding-related admission diagnoses were similar, major bleeding was the indication for transfusion in 12% of patients transfused in daytime only versus 30% of patients transfused at night only (P < 0.001). Similar total amount of blood products were transfused at day and night (2856 versus 2927); however, patients were more likely to receive FFP and cryoprecipitate at night compared with daytime. Overnight transfusion was independently associated with increased odds of major bleeding (odds ratio, 3.16, 95% confidence interval, 2.00-5.01). CONCLUSION: Transfusion occurs evenly across day and night in ICU; nonetheless, there are differences in type of blood products administered that reflect differences in indication. Critically ill patients were more likely to receive blood for major bleeding at night irrespective of admission diagnosis. PMID- 29392791 TI - A transfusion prescription template and other human factor interventions to improve balanced transfusion delivery in major haemorrhage due to trauma. AB - OBJECTIVES: The aim of this study is to improve practice in the management of major haemorrhage, particularly in red cell to plasma transfusion ratios. BACKGROUND: A review of the management of major haemorrhage in trauma in Newcastle Hospitals Trust in 2012-2013 showed good mortality outcomes but found that red cell : plasma transfusion ratios could be improved. Human factors techniques transferable from industry and the military were identified, and a package of interventions was implemented, including an intensive multidisciplinary team training programme and a new major haemorrhage prescription template. METHODS/MATERIALS: We reviewed the management of all 243 adult trauma patients admitted with major haemorrhage to the Emergency Department in the Newcastle Hospitals Trust in the 4-year period from April 2012. We analysed clinical details, blood components transfused and patient outcomes and used Trauma Audit and Research Network data to correlate with injury severity and predicted survival. RESULTS: Mean transfusion ratios of red cells to plasma improved from 1.5 : 1 and 1.6 : 1 in the first 2 years to 1.1 : 1 in the 2 years following implementation of the new measures. There was a statistically significant improvement in the delivery of a balanced transfusion, defined as a red cell : plasma ratio of <1.3 : 1 following the changes. CONCLUSION: Simple changes to procedures, specifically implementation of a new major haemorrhage prescription template and multidisciplinary team training, have resulted in marked improvement in the ratio of red cells to plasma transfused to trauma patients with major haemorrhage or requiring emergency blood. The package of changes could be easily replicated in other health-care settings. PMID- 29392792 TI - Genetic diversity and population structure of Polish Arabian horses assessed through breeding and microsatellite data. AB - Polish Arabian horses are one of the most important populations of this breed in the world. Their post-war history can be divided into two periods, with the dominant role of state studs until 1989, and the increasing significance of private breeding in the next years. The goal of the study was to evaluate genetic diversity and structure of the population under a new breeding policy. The analyses of breeding and microsatellite data from 1996 to 2012 provide a coherent picture of the population with constant flow of horses only in one direction from state to private studs. An increase in the number of broodmares was observed, from 396 mares in 1996 to 1021 mares in 2012. The proportion of foreign sires used in Polish studs also increased, from 7.1% to 37.0%. An increasing number of alleles and progressive differentiation in mares were observed. STRUCTURE analysis indicated that the Polish horses were clearly separated from foreign horses used in Polish breeding, although only one of the 75 alleles found can be considered as typically Polish. The high heterozygosity is an important feature of the Polish population; however, the decrease of heterozygosity in state broodmares was noted. This issue needs to be studied further. PMID- 29392793 TI - Simultaneous separation and determination of praeruptorin A, B and C by micellar electrokinetic chromatography using sodium dodecyl sulphate and sodium cholate as mixed micelles. AB - INTRODUCTION: Praeruptorin A, B and C are major bioactive constituents in Peucedani Radix. They display anti-inflammatory effect, anti-hypertension effect, antiplatelet aggregation, potential anti-cancer activities and so on. They are worthy of investigation as potentially novel and versatile drugs. OBJECTIVE: To develop a method using micellar electrokinetic chromatography (MEKC) for the application in simultaneously separation and determination of praeruptorin A, B and C from Peucedani Radix and its medicinal preparations. METHODS: Method optimisation was carried out by investigating influences of significant factors on the separation. The method was subjected to validation. The determination of praeruptorin A, B and C in Peucedani Radix and its drug formulations was accomplished by the developed method. RESULTS: The optimal separation condition was 20 mM borate buffer containing 40 mM sodium cholate (SC), 22 mM sodium dodecyl sulphate (SDS) and 25% (v/v) acetonitrile (pH 10.00); 15 kV of voltage; 25 degrees C of temperature; detection at 224 nm. Under this condition, three analytes were baseline separated within 16 min. A good linearity was obtained with correlation coefficients from 0.9988 to 0.9995. The limits of detection (LODs) and limits of quantitation (LOQs) ranged from 0.50 to 0.80 MUg/mL and from 1.50 to 2.50 MUg/mL, respectively. The recoveries ranged between 95.3% and 103.4%. CONCLUSION: The proposed method has been successfully applied to the simultaneous determination of praeruptorin A, B and C in Peucedani Radix and its pharmaceutical preparations. Additionally, it could be a potential alternative to the quality control of Peucedani Radix. PMID- 29392794 TI - The Griffiths Development Scales-Chinese (GDS-C): A cross-cultural comparison of developmental trajectories between Chinese and British children. AB - BACKGROUND: The Griffiths Mental Development Scales (GMDS) are used in many countries to assess the development of children from birth to 8 years. There is a need for accurate and culturally appropriate developmental assessment tools for Chinese children. Here, we adapted the GMDS for use in Chinese children and compare the developmental trajectories between Chinese and British children. METHODS: Children with typical development were recruited from 7 urban cities in China between 2009 and 2013. The Griffiths Mental Development Scales-Chinese (GDS C) were adapted and used to assess the development of urban Chinese children. Developmental curves were computed for 6 subscales using learning management system methods and compare against the British curves from the Griffiths Mental Development Scales-Extended Revised (GMDS-ER). RESULTS: The GDS-C were used to assess the developmental status of 815 Chinese children. Plots of the 1st, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 99th percentiles, and full percentile tables were obtained, which showed similar trends to data from the British GMDS ER. CONCLUSIONS: The Chinese developmental curves obtained from the GDS-C showed similarities and differences to the developmental curves from the British GMDS ER. The development of urban Chinese children should be assessed with the culturally appropriate GDS-C. PMID- 29392795 TI - Hypolipidemic and anti-inflammatory effects of aorta and heart tissues of cattle and pigs in the atherosclerosis rat model. AB - The aim of this study was to investigate the effects of aorta and heart tissues obtained from cattle and pigs on atherosclerosis disorders. Atherosclerosis model rats were provided with the respective diets consisting of aorta and heart tissues. Administration of each tissue suppressed body weight gain as compared to that of the control. In particular, the aorta tissues of pigs and cattle demonstrated significant suppressions in body weight gain in the model rats. The aorta tissues of pigs and cattle showed a significant increase and decrease in the serum high-density lipoproteins and atherogenic index, respectively, which was correlated with the increase in apolipoprotein A1. Hematological analysis revealed that aorta tissues of pigs and cattle clearly reduced the ratio of granulocytes/lymphocytes in the atherosclerosis rats. Serum vascular cellular adhesion molecule-1 levels in the atherosclerosis rats, which were administered these aorta tissues, were also significantly reduced. Additionally, there was an increase in von Willebrand factor in the rat serum. Based on the results obtained, the aorta tissues of pigs and cattle, in particular, demonstrated positive effects in the atherosclerosis rats due to the alteration of lipid metabolism and reduction in inflammation related to atherosclerosis. PMID- 29392796 TI - Micro-inflammation in functional dyspepsia: A systematic review and meta analysis. AB - BACKGROUND AND PURPOSE: Functional dyspepsia (FD) is a gastrointestinal disorder of unknown etiology. Although micro-inflammation appears to be important in the pathogenesis, studies evaluating immune activation in FD have been inconsistent. A systematic review of literature and meta-analysis was performed to compare immunologic cell counts and cytokine levels in the mucosa and peripheral blood of individuals with FD and healthy controls. PubMed, Embase, and the Cochrane library were searched. Data on immunologic cell counts and cytokines levels among individuals with FD and control groups were extracted and compared by calculating standard mean differences (SMD). Thirty-seven studies met the inclusion criteria. Mast cell (SMD = 0.94, 95%CI 0.26-1.62, P = .007) and eosinophil counts (SMD = 0.36, 95%CI 0.06-0.68, P = .03) in the stomach were increased, among individuals with FD compared to controls. Similarly, mast cell (SMD = 0.66, 95%CI 0.20-1.13, P = 0.005) and eosinophil (SMD = 0.95, 95%CI 0.66-1.24; P < .001) counts in the duodenum were also increased in those with FD compared to controls. In a subgroup analysis, elevated eosinophil counts in the duodenum were observed in both post prandial distress syndrome (SMD = 0.97, 95%CI 0.46-1.47, P = .0002) and epigastric pain syndrome subtypes (SMD = 1.16, 95%CI 0.48-1.83, P = .0008). No differences in mucosal intraepithelial lymphocyte, enterochromaffin cell, and neutrophil counts, as well as, peripheral interlukin-6 (IL-6) and IL-10 levels were observed among individuals with FD and controls. Micro-inflammation in the form of local immune cell infiltration, particularly eosinophils and mast cells, characterizes the pathogenesis of FD. PMID- 29392797 TI - Biogastronomy: Factors that determine the biological response to meal ingestion. AB - BACKGROUND: The biological response to a meal includes physiological changes, primarily related to the digestive process, and a sensory experience, involving sensations related to the homeostatic control of food consumption, eg, satiety and fullness, with a hedonic dimension, ie associated with changes in digestive well-being and mood. The responses to a meal include a series of events before, during and after ingestion. While much attention has been paid to the events before and during ingestion, relatively little is known about the postprandial sensations, which are key to the gastronomical experience. PURPOSE: The aim of this narrative review is to provide a comprehensive overview and to define the framework to investigate the factors that determine the postprandial experience. Based on a series of proof-of-concept studies and related information, we propose that the biological responses to a meal depend on the characteristics of the meal, primarily its palatability and composition, and the responsiveness of the guest, which may be influenced by multiple previous and concurrent conditioning factors. This information provides the scientific backbone to the development of personalized gastronomy. PMID- 29392798 TI - Intraluminal pressure of uterine balloon tamponade in the management of severe post-partum hemorrhage. AB - AIM: Intrauterine balloon tamponade has been increasingly used for the management of post-partum hemorrhage (PPH) in recent years. However, data on the precise mechanisms and pressure required for the balloon tamponade are scanty in the literature. This study aims to review the intraluminal pressure (ILP) generated by the Bakri intrauterine balloon that is necessary to produce a 'positive tamponade test' during severe PPH. METHODS: This was a prospective cohort study. The ILP of the Bakri balloon was measured using a manometer after a positive tamponade test was clinically achieved during severe PPH (blood loss >1 L). The patient's blood pressure was recorded, and ultrasound scan was performed to verify the position of the balloon and the presence of forward flow in the uterine arteries. The main outcome measure is the ILP of the Bakri balloon required to achieve a positive tamponade test. RESULTS: Twenty patients were included for final analysis. The net ILP measured ranged from 67 to 92 mmHg, and this pressure was lower than the concurrent systolic pressure in all cases. Color Doppler confirmed positive forward flow in the uterine vessels in all cases. There were no differences in the pressure measured with the balloon position, and there was no relationship between the volumes of saline infused and the net pressure. CONCLUSION: A positive tamponade test in an intrauterine balloon is probably achieved by local compression pressure exerted on the vasculature of the placental bed rather than by generating an ILP exceeding systemic blood pressure or by occlusion of flow to the uterine arteries. PMID- 29392799 TI - Response to letter to the editor. PMID- 29392800 TI - Arbuscular mycorrhizal fungi spore propagation using single spore as starter inoculum and a plant host. AB - AIMS: The propagation of pure cultures of arbuscular mycorrhizal fungal (AMF) is an essential requirement for their large-scale agricultural application and commercialization as biofertilizers. The present study aimed to propagate AMF using the single-spore inoculation technique and compare their propagation ability with the known reference spores. METHODS AND RESULTS: Arbuscular mycorrhizal fungal spores were collected from salt-affected Saemangeum reclaimed soil in South Korea. The technique involved inoculation of sorghum-sudangrass (Sorghum bicolor L.) seedlings with single, healthy spores on filter paper followed by the transfer of successfully colonized seedlings to 1-kg capacity pots containing sterilized soil. After the first plant cycle, the contents were transferred to 2.5-kg capacity pots containing sterilized soil. Among the 150 inoculated seedlings, only 27 seedlings were colonized by AMF spores. After 240 days, among the 27 seedlings, five inoculants resulted in the production of over 500 spores. The 18S rDNA sequencing of spores revealed that the spores produced through single-spore inoculation method belonged to Gigaspora margarita, Claroideoglomus lamellosum and Funneliformis mosseae. Furthermore, indigenous spore F. mosseae M-1 reported a higher spore count than the reference spores. CONCLUSIONS: The AMF spores produced using the single-spore inoculation technique may serve as potential bio-inoculants with an advantage of being more readily adopted by farmers due to the lack of requirement of a skilled technique in spore propagation. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of the current study describe the feasible and cost-effective method to mass produce AMF spores for large-scale application. The AMF spores obtained from this method can effectively colonize plant roots and may be easily introduced to the new environment. PMID- 29392801 TI - KCa(H2 O)2 [FeIII (CN)6 ]?H2 O Nanoparticles as an Antimicrobial Agent against Staphylococcus aureus. AB - Biocompatible nanoparticles based on a calcium analogue of Prussian blue were designed and synthesized to take advantage of their ability to penetrate the cell membrane in Staphylococcus aureus and to undergo selective ion exchange with intracellular iron to disrupt iron metabolism in such pathogenic bacteria for antibacterial applications. KCa(H2 O)2 [FeIII (CN)6 ]?H2 O nanoparticles penetrate the bacterial cell membrane and sequester intracellular iron by ion exchange to form insoluble Prussian blue, thus inhibiting bacterial growth. PMID- 29392802 TI - Keiji Morokuma (1934-2017). AB - Keiji Morokuma, William Henry Emerson Professor Emeritus of Emory University and Research Leader at the Fukui Institute for Fundamental Chemistry, Kyoto University, passed away at the age of 83 on November 27, 2017. Morokuma made numerous contributions to theoretical methodologies for the determination of reaction mechanisms and the understanding of intermolecular interactions. PMID- 29392803 TI - Corrigendum. PMID- 29392804 TI - Antimicrobial resistance in companion animals. PMID- 29392805 TI - Strategic implementation of vaccines for control of equine influenza. PMID- 29392806 TI - PRGF in equine corneal cells: A standardised protocol is the key to achieve accurate results. PMID- 29392807 TI - A One-Step Route to CO2 -Based Block Copolymers by Simultaneous ROCOP of CO2 /Epoxides and RAFT Polymerization of Vinyl Monomers. AB - The one-step synthesis of well-defined CO2 -based diblock copolymers was achieved by simultaneous ring-opening copolymerization (ROCOP) of CO2 /epoxides and RAFT polymerization of vinyl monomers using a trithiocarbonate compound bearing a carboxylic group (TTC-COOH) as the bifunctional chain transfer agent (CTA). The double chain-transfer effect allows for independent and precise control over the molecular weight of the two blocks and ensures narrow polydispersities of the resultant block copolymers (1.09-1.14). Notably, an unusual axial group exchange reaction between the aluminum porphyrin catalyst and TTC-COOH impedes the formation of homopolycarbonates. By taking advantage of the RAFT technique, it is able to meet the stringent demand for functionality control to well expand the application scopes of CO2 -based polycarbonates. PMID- 29392810 TI - Multiple Pregnancies Following Assisted Conception: Scientific Impact Paper No. 22. PMID- 29392808 TI - Selected serum oxidative stress biomarkers in dogs with non-food-induced and food induced atopic dermatitis. AB - BACKGROUND: Oxidative stress (OS) has been shown to be involved in the pathogenesis of human and canine atopic dermatitis (AD) through several distinct mechanisms. Selected serum biomarkers of OS (sbOS) have been validated in normal dogs and studied in several canine diseases. To the best of the authors' knowledge, the sbOS evaluated in this study have not previously been described in canine AD. HYPOTHESIS/OBJECTIVES: The aims of the study were to evaluate a panel of sbOS in dogs with food-induced (FIAD) and non-food-induced (NFIAD) AD: cupric reducing antioxidant capacity (CUPRAC), ferrous oxidation-xylenol orange (FOX), ferric reducing ability of the plasma (FRAP), paraoxonase-1 (PON1), trolox equivalent antioxidant capacity (TEAC) and serum total thiol (THIOL). The aim was to compare these metabolites with those in healthy control dogs, and to correlate sbOS with validated pruritus and CADESI-04 severity scales in dogs with AD. ANIMALS: Forty six healthy, nine NFIAD and three FIAD client-owned dogs were included. METHODS: The study was designed as a cohort study. RESULTS: There were significant differences in atopic dogs when compared to healthy dogs for all of the sbOS analysed. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that OS could play a role in the pathogenesis of canine NFIAD and FIAD. In addition, the evaluation of sbOS could be useful for precision medicine to help to detect atopic dogs that might benefit from antioxidant-targeted therapies. PMID- 29392809 TI - Hierarchical Assembly of an Interlocked M8 L16 Container. AB - The self-assembly of eight PdII cations and sixteen phenanthrene-derived bridging ligands with 60 degrees bite angles yielded a novel M8 L16 metallosupramolecular architecture composed of two interlocked D4h -symmetric barrel-shaped containers. Mass spectrometry, NMR spectroscopy, and X-ray analysis revealed this self assembled structure to be a very large "Hopf link" catenane featuring channel like cavities, which are occupied by NO3- anions. The importance of the anions as catenation templates became imminent when we observed the nitrate-triggered structural rearrangement of a mixture of M3 L6 and M4 L8 assemblies formed in the presence of BF4- anions into the same interlocked molecule. Furthermore, the densely packed structure of the M8 L16 catenane was exploited in the preparation of a hexyloxy-functionalized analogue, which further self-assembled into vesicle like aggregates in a reversible manner. PMID- 29392811 TI - Optical treatment of amblyopia: a systematic review and meta-analysis. AB - BACKGROUND: Despite evidence that amblyopia can often be treated by optical treatment alone, many practitioners still do not use an optical-correction-only phase in amblyopia treatment and some investigators omit this important step in their research. This paper aims to systematically review the evidence for the optical treatment of strabismic, refractive and combined-mechanism amblyopia and to quantify the evidence via a meta-analysis. METHODS: A search of online databases MEDLINE, EMBASE, PsycInfo, the Cochrane Library, and bibliographies of review papers, along with subsequent personal communication, resulted in 29 papers that met our inclusion criteria, with 20 providing sufficient data for the calculation of effect sizes. A meta-analysis was performed to determine effect sizes and the heterogeneity thereof. Meta-regression was used to evaluate the contribution of the possible moderating factors of age, duration of optical correction, and initial visual acuity to the heterogeneity of the studies. In addition, effect sizes were analysed in subgroups based on amblyopia aetiology, that is refractive or strabismic or combined, and also in the fellow eyes. RESULTS: No evidence of publication bias in the included studies was found using a Galbraith plot. Optical treatment of amblyopia resulted in a large positive effect size of 1.07 (+/-0.49, 95 per cent confidence limits) on visual acuity, although the heterogeneity was significant (Q = 597.05, I2 = 96.65 per cent, p < 0.0001). Meta-regression indicated that effect sizes significantly decreased with age, increased with treatment duration, and that better initial acuity was associated with higher effect sizes. CONCLUSION: Effect sizes were always moderate to large, whether participants were younger or older children, or whether the aetiology was refractive or strabismic. Thus, optical treatment of amblyopia should be considered prior to other treatment in those with refractive error. Improved acuity before initiating other treatment would presumably make occlusion or penalisation less onerous and may improve compliance with further treatment. PMID- 29392812 TI - Mechanism-Based Inhibitor of DNA Cytosine-5 Methyltransferase by a SN Ar Reaction with an Oligodeoxyribonucleotide Containing a 2-Amino-4-Halopyridine-C Nucleoside. AB - In chromatin, 5-methylcytosine (mC), which represents the fifth nucleobase in genomic DNA, plays a role as an inducer of epigenetic changes. Tumor cells exhibit aberrant DNA methylation patterns, and inhibition of human DNA cytosine-5 methyltransferase (DNMT), which is responsible for generating mC in CpG sequences, is an effective strategy to treat various cancers. Here, we describe the design, synthesis, and evaluation of the properties of 2-amino-4-halopyridine C-nucleosides (dX P) and oligodeoxyribonucleotides (ODNs) containing dX P as a novel mechanism-based inhibitor of DNMTs. The designed ODN containing X PpG forms a complex with DNMTs by covalent bonding through a nucleophilic aromatic substitution (SN Ar) reaction, and its cell proliferation activity is investigated. This study suggests that dX P in a CpG sequence of DNA could serve as a potential nucleic acid drug lead in cancer chemotherapy and a useful chemical probe for studies of epigenetics. Our molecular design using a SN Ar reaction would be useful for DNMTs and other protein-DNA interactions. PMID- 29392813 TI - Dorsal thermal necrosis in dogs: a retrospective analysis of 16 cases in the southwestern USA (2009-2016). AB - BACKGROUND: Prolonged sun exposure in high ambient temperatures has been recognized as a cause of thermal burns on the dorsal skin of dogs, termed dorsal thermal necrosis (DTN). HYPOTHESES/OBJECTIVES: To characterize the clinical presentation, histopathology and outcomes of 16 dogs diagnosed with DTN and to identify associated risk factors. ANIMALS: Sixteen dogs diagnosed with DTN. METHODS: Medical records from 2009 to 2016 were reviewed retrospectively. Inclusion criteria included: (i) historical solar exposure; (ii) dorsal burn injuries and (iii) histopathological findings consistent with DTN. RESULTS: The majority of cases (15 of 16) occurred during warmer months (May-September) in the southwestern USA. Affected dogs had predominantly dark, short hair coats, whereas four of 16 dogs had lighter coat colours. Five dogs had naturally longer hair, but two hair coats had been recently clipped. Signs consistent with heat exhaustion or heatstroke were reported prior to the development of cutaneous lesions in four of 16 dogs. The most common skin lesions were alopecia, erythema, ulcerations, eschars/necrosis and crusts. Histological findings were consistent with other types of partial and full-thickness thermal burns, and included coagulation necrosis in the majority of cases. Most dogs were treated supportively with analgesics and antimicrobial therapies. The majority of DTN wounds healed via second intention, although surgery was performed on two dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Dorsal thermal necrosis should be considered as a differential diagnosis for dogs with dorsal cutaneous burns and a history of sun exposure in high external temperatures. Dogs with dark, short hair coats may be at an increased risk. PMID- 29392814 TI - The New York City Mental Health Needs Assessment Study (MHNAS): Objectives, design, and methods. AB - OBJECTIVES: This paper describes the objectives, design, and methods of the Mental Health Needs Assessment Study (MHNAS). The objective of the MHNAS was to assess the needs of individuals transitioning to the community following psychiatric hospitalization and again 3-5 months later to inform community service planning. Needs were defined broadly to include domains like housing, employment, treatment, and social support. METHODS: The MHNAS used a 2-stage clustered sampling approach where the primary sampling units were hospitals and secondary sampling units were patients. The study included an in-person patient interview, an assessment of need from a key hospital worker, and a follow-up telephone interview 3-5 months after discharge. RESULTS: One thousand one hundred twenty-nine patients from 8 randomly selected hospitals participated. The overall response rate was 54.3% with a cooperation rate of 71.8%. The sample was similar to the overall population of psychiatric patients with respect to several key demographics. CONCLUSION: The MHNAS demonstrates the feasibility of conducting a needs assessment with a random sample of psychiatric inpatients in a large urban setting. Results from this study may improve community service planning to better meet individuals' needs, with the ultimate goal of reducing rehospitalization and promoting recovery. PMID- 29392815 TI - A Carbon Electrode Functionalized by a Tricopper Cluster Complex: Overcoming Overpotential and Production of Hydrogen Peroxide in the Oxygen Reduction Reaction. AB - A study of the oxygen reduction reaction (ORR) on a screen printed carbon electrode surface mediated by the tricopper cluster complex Cu3 (7-N-Etppz(CH2 OH)) dispersed on electrochemically reduced carbon black, where 7-N-Etppz(CH2 OH) is the ligand 3,3'-(6-(hydroxymethyl)-1,4-diazepane-1,4-diyl)bis(1-(4-ethyl piperazin-1-yl)propan-2-ol), is described. Onset oxygen reduction potentials of about 0.92 V and about 0.77 V are observed at pH 13 and pH 7 vs. the reversible hydrogen electrode, which are comparable to the best values reported for any synthetic copper complex. Based on half-wave potentials (E1/2 ), the corresponding overpotentials are about 0.42 V and about 0.68 V, respectively. Kinetic studies indicate that the trinuclear copper catalyst can accomplish the 4 e- reduction of O2 efficiently and the ORR is accompanied by the production of only small amounts of H2 O2 . The involvement of the copper triad in the O2 activation process is also verified. PMID- 29392816 TI - Clinically relevant improvements achieved from a facilitated implementation of a gestational diabetes model of care. AB - AIM: Medical nutrition therapy is a cornerstone treatment in gestational diabetes; however, most Australian women diagnosed with gestational diabetes do not receive this. The project evaluated adaptation of a successful evidence-based gestational diabetes model of care implementation from a tertiary centre into regional sites with varied demographics, population size and service capacity. METHODS: The project used a hub (project team)-spoke (sites) model in Far North Queensland (Site 1) and regional South-East Queensland (Site 2). Sites selected demonstrated strong gestational diabetes team cohesiveness and project commitment. The project phases were consultation, baseline, transition and implementation. A best practice decision tree tool was provided to assess/manage barriers to the model of care and clinical outcomes captured through a project database. RESULTS: Role clarification of site members, management engagement, site visits, decision tree and database refinement were completed in the project's first phase. Unexpected organisational and team barriers prevented timeline implementation as planned. Sites negotiated relevant reallocation of resources to achieve project deliverables. The proportion of women seen according to best practice increased from 3.5 to 87.8% (P < 0.001) (Site 1) and nil to 4.8% (P = 0.09) (Site 2), and those on medication dropped by 3.4 (Site 1) and 9.1% (Site 2). CONCLUSIONS: This project demonstrates a successful implementation using a facilitated and rigorous approach. Support, engagement and tools at many levels were keys to success at both sites. The present study illustrates the opportunities and challenges of conducting implementation research within routine clinical care, particularly in resource-challenged sites. PMID- 29392817 TI - Dissecting the virulence-related functionality and cellular transcription mechanism of a conserved hypothetical protein in Xanthomonas oryzae pv. oryzae. AB - Hypothetical proteins without defined functions are largely distributed in all sequenced bacterial genomes. Understanding their potent functionalities is a basic demand for bacteriologists. Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight of rice, is one of the model systems for the study of molecular plant pathology. One-quarter of proteins in the genome of this bacterium are defined as hypothetical proteins, but their roles in Xoo pathogenicity are unknown. Here, we generated in-frame deletions for six hypothetical proteins selected from strain PXO99A and found that one of them (PXO_03177) is required for the full virulence of this strain. PXO_03177 is conserved in Xanthomonas, and is predicted to contain two domains relating to polysaccharide synthesis. However, we found that mutation of this gene did not affect the production or modification of extracellular polysaccharides (EPSs) and lipopolysaccharides (LPSs), two major polysaccharides produced by Xoo relating to its infection. Interestingly, we found that inactivation of PXO_03177 significantly impaired biofilm formation and tolerance to sodium dodecyl sulfate (SDS), both of which are considered to play key roles during Xoo infection in rice leaves. These findings thus enable us to define a function for PXO_03177 in the virulence of Xoo. Furthermore, we also found that the global regulator Clp controls the transcription of PXO_03177 by direct binding to its promoter region, presenting the first cellular regulatory pathway for the modulation of expression of this hypothetical protein gene. Our results provide reference information for PXO_03177 homologues in Xanthomonas. PMID- 29392818 TI - Hepatic angiomyolipoma presenting as an arterially enhancing liver lesion. PMID- 29392819 TI - A novel tubulin inhibitor STK899704 induces tumor regression in DMBA/TPA-induced skin carcinogenesis model. AB - Skin cancer is the most common type of cancer. The incidence rate of skin cancer has continuously increased over the past decades. In an effort to discover novel anticancer agents, we identified a novel tubulin inhibitor STK899704, which is structurally distinct from other microtubule-binding agents such as colchicine, vinca alkaloids and taxanes. STK899704 inhibited microtubule polymerization leading to mitotic arrest and suppressed the proliferation of various cancer cell lines as well as multidrug resistance cancer cell lines. In this study, our investigation is further extended into animal model to evaluate the effect of STK899704 on skin carcinogenesis in vivo. Surprisingly, almost 80% of the tumors treated with STK899704 were regressed with a one-fifth reduction in tumor volume. Furthermore, the efficacy of STK899704 was nearly 2 times higher than that of 5 fluorouracil, a widely used skin cancer therapeutic. Overall, our results suggest that STK899704 is a promising anticancer chemotherapeutic that may replace existing therapies, particularly for skin cancer. PMID- 29392821 TI - CHILD syndrome: A modified pathogenesis-targeted therapeutic approach. AB - Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment. PMID- 29392820 TI - Emerging roles of extracellular vesicles in cellular senescence and aging. AB - Cellular senescence is a cellular program that prevents the proliferation of cells at risk of neoplastic transformation. On the other hand, age-related accumulation of senescent cells promotes aging at least partially due to the senescence-associated secretory phenotype, whereby cells secrete high levels of inflammatory cytokines, chemokines, and matrix metalloproteinases. Emerging evidence, however, indicates that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Senescent cells secrete more EphA2 and DNA via EVs, which can promote cancer cell proliferation and inflammation, respectively. Extracellular vesicles secreted from DNA-damaged cells can also affect telomere regulation. Furthermore, it has now become clear that EVs actually play important roles in many aspects of aging. This review is intended to summarize these recent progresses, with emphasis on relationships between cellular senescence and EVs. PMID- 29392822 TI - High plasma adiponectin levels are associated with frailty in a general old-old population: The Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study. AB - AIM: The objective of the present study was to investigate the association between frailty and plasma adiponectin levels in a general population of Japanese older adults. METHODS: The volunteer older adults, aged approximately 83 years, were recruited randomly from a general population in the Japanese Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study. We used the modified Cardiovascular Health Study criteria to assess the frailty status of the study participants. The study participants were classified as non-frail, pre-frail and frail according to their physical activities. We compared plasma adiponectin levels among these three groups and applied a multivariate logistic regression analysis including plasma adiponectin levels to clarify the factors associated with frailty status in the cross-sectional design. RESULTS: The mean age of the participants was 83.1 +/- 0.9 years, and 51.8% were men. The frailty index was available to assess 353 participants, of whom 24.6% were classified as non-frail, 62.3% as prefrail and 13.0% as frail. The log transformed plasma adiponectin levels increased stepwise in the following order: non-frail, pre-frail and frail. A multivariate logistic regression analysis showed that higher plasma adiponectin levels, a higher estimated glomerular filtration rate and lower hemoglobin levels were independent determinants for pre frail/frail status compared with non-frail status. CONCLUSIONS: The present study showed that higher plasma adiponectin levels were associated with frailty status in older Japanese adults in the general population. Further longitudinal study is essential to clarify the role of plasma adiponectin in the progression of frailty. Geriatr Gerontol Int 2018; 18: 839-846. PMID- 29392823 TI - A Chiral Ligand Assembly That Confers One-Electron O2 Reduction Activity for a Cu2+ -Selective Metallohydrogel. AB - The design of functional metallohydrogels is attractive but challenging. A rational approach is introduced for designing functional metallohydrogels using chiral ligands, a phenylalanine derivative with a pyridyl group (l/d-PF). Intriguingly, the as-prepared metallohydrogel exhibits excellent O2 binding and activating properties. Insights into the O2 binding pathway reveals the presence of a novel [(l+d)-PF-Cu3+ -O2- ] species, which can efficiently reduce ferric cytochrome c with the reactive O2- by receiving an electron from reductant ascorbic acid. This study provides helpful instructions for developing new artificial systems with specific functions through the effective combination of chiral ligands with metal ions. PMID- 29392824 TI - Early childhood growth and cognitive outcomes: Findings from the MAL-ED study. AB - Although many studies around the world hope to measure or improve developmental progress in children to promote community flourishing and productivity, growth is sometimes used as a surrogate because cognitive skills are more difficult to measure. Our objective was to assess how childhood measures of anthropometry correlate with measures of child development in low-income settings with high prevalence of poor nutrition and enteric disease, to inform studies considering growth outcomes in the absence of direct child developmental skill assessment. Children from the MAL-ED study were followed from birth to 24 months of age in field sites in 8 low- and middle-income countries across 3 continents. Monthly weight, length, and head circumference measurements were performed. At 24 months, the Bayley Scales of Infant and Toddler Development was administered. We correlated cognitive measures at 24 months with anthropometric measurements from birth to 2 years comparing 3 constructs: absolute attained monthly measures, summative difference in measures from the mean growth curve, and rate of change in measures. Growth faltering at multiple time periods is related to Bayley cognitive outcomes at 24 months. Birthweight, overall growth by 18-24 months, and rate of growth in the 6- to 18-month period were most associated with 24-month developmental scores. In this study, head circumference measurements, compared with length, was more closely linked to cognitive scores at 24 months. Notably, all studies between growth and cognitive outcomes exhibited low r2 values (0.001 0.049). Anthropometric measures, particularly head circumference, were related to cognitive development, although explaining a low percent of variance. When feasible, direct measures of child development may be more useful. PMID- 29392825 TI - Physiological and pathological characterization of capsaicin-induced reversible nerve degeneration and hyperalgesia. AB - BACKGROUND: The study aimed to investigate the physiology, psychophysics, pathology and their relationship in reversible nociceptive nerve degeneration, and the physiology of acute hyperalgesia. METHODS: We enrolled 15 normal subjects to investigate intraepidermal nerve fibre (IENF) density, contact heat-evoked potential (CHEP) and thermal thresholds during the capsaicin-induced skin nerve degeneration-regeneration; and CHEP and thermal thresholds at capsaicin-induced acute hyperalgesia. RESULTS: After 2-week capsaicin treatment, IENF density of skin was markedly reduced with reduced amplitude and prolonged latency of CHEP, and increased warm and heat pain thresholds. The time courses of skin nerve regeneration and reversal of physiology and psychophysics were different: IENF density was still lower at 10 weeks after capsaicin treatment than that at baseline, whereas CHEP amplitude and warm threshold became normalized within 3 weeks after capsaicin treatment. Although CHEP amplitude and IENF density were best correlated in a multiple linear regression model, a one-phase exponential association model showed better fit than a simple linear one, that is in the regeneration phase, the slope of the regression line between CHEP amplitude and IENF density was steeper in the subgroup with lower IENF densities than in the one with higher IENF densities. During capsaicin-induced hyperalgesia, recordable rate of CHEP to 43 degrees C heat stimulation was higher with enhanced CHEP amplitude and pain perception compared to baseline. CONCLUSIONS: There were differential restoration of IENF density, CHEP and thermal thresholds, and changed CHEP-IENF relationships during skin reinnervation. CHEP can be a physiological signature of acute hyperalgesia. SIGNIFICANCE: These observations suggested the relationship between nociceptive nerve terminals and brain responses to thermal stimuli changed during different degree of skin denervation, and CHEP to low-intensity heat stimulus can reflect the physiology of hyperalgesia. PMID- 29392826 TI - Reduced angiogenic factor expression in intrauterine fetal growth restriction using semiquantitative immunohistochemistry and digital image analysis. AB - AIM: To localize, quantify and compare angiogenic factors, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), as well as their receptors fms-like tyrosine kinase receptor (Flt-1) and kinase insert domain receptor (KDR) in the placentas of normal pregnancy and complications of preeclampsia (PE), intrauterine fetal growth restriction (IUGR) and PE + IUGR. METHODS: In a prospective cross-sectional case-control study, 30 pregnant women between 24-40 weeks of gestation, were recruited into four clinical groups. Representative placental samples were stained for VEGF, PlGF, Flt-1 and KDR. Analysis was performed using semiquantitative methods and digital image analysis. RESULTS: The overall VEGF and Flt-1 were strongly expressed and did not show any conclusive difference in the expression between study groups. PlGF and KDR were significantly reduced in expression in the placentas from pregnancies complicated by IUGR compared with normal and preeclamptic pregnancies. CONCLUSION: The lack of PlGF and KDR may be a cause for the development of IUGR and may explain the loss of vasculature and villous architecture in IUGR. Automated digital image analysis software is a viable alternative method to the manual reading of placental immunohistochemical staining. PMID- 29392827 TI - Ten-year weight gain is associated with elevated fasting insulin levels and precedes glucose elevation. AB - BACKGROUND: Numerous studies have examined the relationship between endogenous insulin and weight change with mixed results. This study examined the relationship between fasting insulin levels, insulin resistance (IR), and 10-year weight change by glycaemic stage. METHODS: Using data from the US National Health and Nutrition Examination Survey 2011-2014, 3840 participants were divided into 6 groups based on fasting glucose and fasting insulin levels. Fasting insulin concentrations were dichotomized into <25th percentile (normal) and >=25th percentile (elevated). Ten-year weight change associated with fasting insulin was assessed by glycaemic stage. RESULTS: Average weight change over a 10-year period was higher in individuals with elevated insulin levels compared to the first quartile (1.40 lbs. vs 11.12 lbs, P < .0001). Across all groups, a 1 MUU increase in fasting insulin levels resulted in a 0.52-pound increase in weight (P < .0001). Similarly, an increase in HOMA-IR was associated with increase in weight (1.32 lbs per IR unit, P < .0001). Marginal increases in weight were most pronounced in the normal insulin groups compared to elevated insulin groups and diminished as glycaemic stage progressed. CONCLUSIONS: Elevated fasting insulin level was positively associated with weight gain. The impact of fasting insulin and IR on weight gain preceded hyperglycaemia and diminished as glycaemic stage progressed. PMID- 29392828 TI - Arm morbidity of axillary dissection with sentinel node biopsy versus delayed axillary dissection. AB - BACKGROUND: Staging of axillary lymph nodes in breast cancer is important for prognostication and planning of adjuvant therapy. The traditional practice of proceeding to axillary lymph node dissection (ALND) if sentinel lymph node biopsy (SLNB) is positive is being challenged and clinical trials are underway. For many centres, this will mean a move away from intra-operative SLNB assessment and utilization of a second procedure to perform ALND. It is sometimes perceived that a delayed ALND results in increased tissue damage and thus increased morbidity. We compared morbidity in those undergoing SLNB only, or ALND as a one- or two stage procedure. METHODS: A retrospective review of a prospectively collected institutional database was used to review rates of lymphoedema and shoulder function in women undergoing breast cancer surgery between 2008 and 2012. RESULTS: The overall lymphoedema rate in 745 patients was 8.2% at 12 months. There was no difference in lymphoedema rates between those undergoing immediate or delayed ALND (17.8 and 8.6%, respectively, P = 0.092). Post-operative shoulder elevation, odds ratio (OR) = 0.390, 95% confidence interval (CI) = (0.218, 0.698) and abduction, OR = 0.437 (95% CI = (0.271, 0.705)) were reduced if an ALND was performed although there was no difference between immediate or delayed. CONCLUSION: ALND remains a risk factor for post-operative morbidity. There is no increased risk of lymphoedema or shoulder function deficit with a positive SLNB and delayed ALND compared to immediate ALND. PMID- 29392830 TI - Depressive symptoms and all-cause mortality in Korean older adults: A 3-year population-based prospective study. AB - AIM: To examine the association between depressive symptoms and all-cause mortality in a population-based prospective study. METHODS: Data from the 2008 baseline and 2011 follow-up assessments of the Living Profiles of Older People Survey involving 14 976 Korean adults aged >=60 years (59% women) were used. Depressive symptoms were defined as a score of >=8 on the self-administered Korean version of the Geriatric Depression Scale. RESULTS: During the 3-year follow-up period, 873 deaths from all causes (372 women) occurred. The Cox proportional regression analyses showed that older men (hazard ratio 2.19, 95% confidence interval 1.83-2.62, P < 0.001) and women (hazard ratio 1.54, 95% confidence interval 1.25-1.89, P < 0.001) with baseline depressive symptoms were at significantly increased risk of all-cause mortality independent of age, as compared with older men (hazard ratio 1) and women (hazard ratio 1) without baseline depressive symptoms, respectively. When additionally controlled for body mass index, socioeconomic status, health behaviors and health conditions, however, the risk of baseline depressive symptoms for all-cause mortality still remained significant in men only (hazard ratio 1.40, 95% confidence interval 1.09 1.80, P = 0.008), but not in women only (hazard ratio 1.27, 95% confidence interval 0.98-1.66, P = 0.086). CONCLUSIONS: The current findings suggest that the prognostic importance of depressive symptoms for all-cause mortality might be sex-specific in Korean older adults. Geriatr Gerontol Int 2018; 18: 950-956. PMID- 29392829 TI - Fibromodulin reduces scar size and increases scar tensile strength in normal and excessive-mechanical-loading porcine cutaneous wounds. AB - Hypertrophic scarring is a major postoperative complication which leads to severe disfigurement and dysfunction in patients and usually requires multiple surgical revisions due to its high recurrence rates. Excessive-mechanical-loading across wounds is an important initiator of hypertrophic scarring formation. In this study, we demonstrate that intradermal administration of a single extracellular matrix (ECM) molecule-fibromodulin (FMOD) protein-can significantly reduce scar size, increase tensile strength, and improve dermal collagen architecture organization in the normal and even excessive-mechanical-loading red Duroc pig wound models. Since pig skin is recognized by the Food and Drug Administration as the closest animal equivalent to human skin, and because red Duroc pigs show scarring that closely resembles human proliferative scarring and hypertrophic scarring, FMOD-based technologies hold high translational potential and applicability to human patients suffering from scarring-especially hypertrophic scarring. PMID- 29392831 TI - Microgradient separation technique for purification and fractionation of permethylated N-glycans before mass spectrometric analyses. AB - Analysis of N-glycans released enzymatically from patients' sera or other clinical samples may provide diagnostically and prognostically important information on human disease. Permethylation of these biomolecules simultaneously increases their hydrophobicity and substantially improves their detection parameters in the following mass spectrometric analyses. The overall procedure, from the glycan cleavage to the final mass spectrometric determinations, includes several steps involving extraction, derivatization, and purification. During these steps, certain polymeric contaminants that may have been coincidentally introduced could hamper the final measurements. To understand and counter these interferences and further fractionate or preconcentrate these glycans, we introduce here an effective microgradient chromatographic technique that employs a small reversed-phase microcolumn connected to a gas-tight microsyringe delivering a mobile-phase gradient. After loading the glycan fraction onto the microcolumn, three elution steps are recommended: (1) remove polar contaminants; (2) recover permethylated glycans for either liquid chromatography with electrospray ionization mass spectrometry or matrix-assisted laser desorption/ionization mass spectrometry; and (3) remove larger polymeric contaminants and regenerate the precolumn. We further demonstrate that the trapped second fraction can be beneficially preconcentrated and further separated to achieve matrix-assisted laser desorption/ionization mass spectrometric detection of the derivatized N-glycans up to 6300 Da. The enhanced detection capabilities for tetra-antennary N-glycans are of increasing interest in disease biomarker discovery. PMID- 29392832 TI - Effects of C-Related Dangling Bonds and Functional Groups on the Fluorescent and Electrochemiluminescent Properties of Carbon-Based Dots. AB - Single-layer carbon-based dots (SCDs) were chosen as a model to investigate the effect of the C-related dangling bonds with spin S=1/2 and functional groups on the electrochemiluminescent (ECL) and fluorescent (FL) properties of CDs. The C related dangling bonds and functional groups of SCDs were tuned by chemical reduction with NaBH4 . There have several main findings via investigating the ECL and FL properties of SCDs before and after the chemical reduction. First, the FL and ECL of CDs are highly dependent on their concentration, and luminescent resonance energy transfer is observed in ECL studies when the concentration of CDs is high. Second, the ECL activity of CDs is greatly enhanced as the C-related dangling bonds increase, proving that the ECL of CDs originates from the C related dangling bonds. Third, the FL of CDs is the synthesis of the inner FL originated from the contained isolated sp2 units and the defect FL from the C related dangling bonds. The inner FL of CDs is enhanced greatly by removing the carboxyl groups, while the defect FL is increased slightly due to the increased C related dangling bonds. We believe this study would promote our understanding in the ECL and FL mechanisms of CDs, advancing the applications of CDs based on their ECL and FL properties. PMID- 29392833 TI - Brain aging: Evaluation of pH using phosphorus magnetic resonance spectroscopy. AB - AIM: Very important aspects of aging include age-related changes occurring in the brain. The aim of the present study was to identify the standard pH value in the entire brain volume using phosphorus magnetic resonance spectroscopy in healthy individuals of both sexes in different age groups, and then to determine whether there are differences in these values. METHODS: A total of 65 individuals aged 20 32 years (mean age 24.5 +/- 2.1 years, 31 women and 34 men) and 31 individuals aged 60-81 years (mean age 64.9 +/- 5.5 years, 17 women and 14 men) were studied. The phosphorus magnetic resonance spectroscopy examination was carried out using a 1.5-T magnetic resonance system. The signal was acquired from the volume of interest that covered the whole brain. RESULTS: A vast majority of the examined individuals had slightly alkaline brain pH regardless of age. In the >=20 years group, pH was 7.09 +/- 0.11, and in the >=60 years group, the average pH was 7.03 +/- 0.05. This comparison of the pH identified in all the tested individuals shows a negative correlation of pH with age. CONCLUSIONS: The present findings might provide a valuable basis for further research into "healthy aging" as well as pathology in older adults. Geriatr Gerontol Int 2018; 18: 881-885. PMID- 29392834 TI - Structural mechanisms for the S-nitrosylation-derived protection of mouse galectin-2 from oxidation-induced inactivation revealed by NMR. AB - : Galectin-2 (Gal-2) is a lectin thought to play protective roles in the gastrointestinal tract. Oxidation of mouse Gal-2 (mGal-2) by hydrogen peroxide (H2 O2 ) results in the loss of sugar-binding activity, whereas S-nitrosylation of mGal-2, which does not change its sugar-binding profile, has been shown to protect the protein from H2 O2 -induced inactivation. One of the two cysteine residues, C57, has been identified as being responsible for controlling H2 O2 induced inactivation; however, the underlying molecular mechanism has not been elucidated. We performed structural analyses of mGal-2 using nuclear magnetic resonance (NMR) and found that residues near C57 experienced significant chemical shift changes following S-nitrosylation, and that S-nitrosylation slowed the H2 O2 -induced aggregation of mGal-2. We also revealed that S-nitrosylation improves the thermal stability of mGal-2 and that the solvent accessibility and/or local dynamics of residues near C57 and the local dynamics of the core-forming residues in mGal-2 are reduced by S-nitrosylation. Structural models of Gal-2 indicated that C57 is located in a hydrophobic pocket that can be plugged by S nitrosylation, which was supported by the NMR experiments. Based on these results, we propose two structural mechanisms by which S-nitrosylation protects mGal-2 from H2 O2 -induced aggregation without changing its sugar-binding profile: (a) stabilization of the hydrophobic pocket around C57 that prevents oxidation-induced destabilization of the pocket, and (b) prevention of oxidation of C57 during the transiently unfolded state of the protein, in which the residue is exposed to H2 O2 . DATABASE: Nuclear magnetic resonance assignments for non-S nitrosylated mGal-2 and S-nitrosylated mGal-2 have been deposited in the BioMagResBank (http://www.bmrb.wisc.edu/) under ID code 27237 for non-S nitrosylated mGal-2 and ID code 27238 for S-nitrosylated mGal-2. PMID- 29392835 TI - Cortical oscillations and entrainment in speech processing during working memory load. AB - Neuronal oscillations are thought to play an important role in working memory (WM) and speech processing. Listening to speech in real-life situations is often cognitively demanding but it is unknown whether WM load influences how auditory cortical activity synchronizes to speech features. Here, we developed an auditory n-back paradigm to investigate cortical entrainment to speech envelope fluctuations under different degrees of WM load. We measured the electroencephalogram, pupil dilations and behavioural performance from 22 subjects listening to continuous speech with an embedded n-back task. The speech stimuli consisted of long spoken number sequences created to match natural speech in terms of sentence intonation, syllabic rate and phonetic content. To burden different WM functions during speech processing, listeners performed an n-back task on the speech sequences in different levels of background noise. Increasing WM load at higher n-back levels was associated with a decrease in posterior alpha power as well as increased pupil dilations. Frontal theta power increased at the start of the trial and increased additionally with higher n-back level. The observed alpha-theta power changes are consistent with visual n-back paradigms suggesting general oscillatory correlates of WM processing load. Speech entrainment was measured as a linear mapping between the envelope of the speech signal and low-frequency cortical activity (< 13 Hz). We found that increases in both types of WM load (background noise and n-back level) decreased cortical speech envelope entrainment. Although entrainment persisted under high load, our results suggest a top-down influence of WM processing on cortical speech entrainment. PMID- 29392836 TI - NOD1 is required for Helicobacter pylori induction of IL-33 responses in gastric epithelial cells. AB - Helicobacter pylori (H. pylori) causes chronic inflammation which is a key precursor to gastric carcinogenesis. It has been suggested that H. pylori may limit this immunopathology by inducing the production of interleukin 33 (IL-33) in gastric epithelial cells, thus promoting T helper 2 immune responses. The molecular mechanism underlying IL-33 production in response to H. pylori infection, however, remains unknown. In this study, we demonstrate that H. pylori activates signalling via the pathogen recognition molecule Nucleotide-Binding Oligomerisation Domain-Containing Protein 1 (NOD1) and its adaptor protein receptor-interacting serine-threonine Kinase 2, to promote production of both full-length and processed IL-33 in gastric epithelial cells. Furthermore, IL-33 responses were dependent on the actions of the H. pylori Type IV secretion system, required for activation of the NOD1 pathway, as well as on the Type IV secretion system effector protein, CagA. Importantly, Nod1+/+ mice with chronic H. pylori infection exhibited significantly increased gastric IL-33 and splenic IL-13 responses, but decreased IFN-gamma responses, when compared with Nod1-/- animals. Collectively, our data identify NOD1 as an important regulator of mucosal IL-33 responses in H. pylori infection. We suggest that NOD1 may play a role in protection against excessive inflammation. PMID- 29392837 TI - Highly Loaded Semipermeable Nanocapsules for Magnetic Resonance Imaging. AB - Magnetic resonance imaging has become an essential tool in medicine for the investigation of physiological processes. The key issues related to contrast agents, i.e., substances that are injected in the body for imaging, are the efficient enhancement of contrast, their low toxicity, and their defined biodistribution. Polyurea nanocapsules containing the gadolinium complex Gadobutrol as a contrast agent in high local concentration and high relaxivity up to 40 s-1 mmol-1 L are described. A high concentration of the contrast agent inside the nanocapsules can be ensured by increasing the crystallinity in the shell of the nanocapsules. Nanocapsules from aliphatic polyurea are found to display higher crystallinity and higher relaxivity at an initial Gadobutrol concentration of 0.1 m than aromatic polyurea nanocapsules. The nanocapsules and the contrast agent are clearly identified in cells. After injection, the nanocarriers containing the contrast agent are mostly found in the liver and in the spleen, which allow for a significant contrast enhancement in magnetic resonance imaging. PMID- 29392838 TI - Cortical differences in diverticular disease and correlation with symptom reports. AB - BACKGROUND: Recent studies have shown that the brain of patients with gastrointestinal disease differ both structurally and functionally from that of controls. Highly somatizing diverticular disease (HSDD) patients were also shown to differ from low somatizing (LSDD) patients functionally. This study aimed to investigate how they differed structurally. METHODS: Four diseases subgroups were studied in a cross-sectional design: 20 patients with asymptomatic diverticular disease (ADD), 18 LSDD, 16 HSDD, and 18 with irritable bowel syndrome. We divided DD patients into LSDD and HSDD using a cutoff of 6 on the Patient Health Questionnaire 12 Somatic Symptom (PHQ12-SS) scale. All patients underwent a 1-mm isotropic structural brain MRI scan and were assessed for somatization, hospital anxiety, depression, and pain catastrophizing. Whole brain volumetry, cortical thickness analysis and voxel-based morphometry were carried out using Freesurfer and SPM. KEY RESULTS: We observed decreases in gray matter density in the left and right dorsolateral prefrontal cortex (dlPFC), and in the mid-cingulate and motor cortex, and increases in the left (19, 20) and right (19, 38) Brodmann Areas. The average cortical thickness differed overall across groups (P = .002) and regionally: HSDD > ADD in the posterior cingulate cortex (P = .03), HSDD > LSDD in the dlPFC (P = .03) and in the ventrolateral PFC (P < .001). The thickness of the anterior cingulate cortex and of the mid-prefrontal cortex were also found to correlate with Pain Catastrophizing (Spearman's rho = 0.24, P = .043 uncorrected and Spearman's rho = 0.25, P = .03 uncorrected). CONCLUSION & INFERENCES: This is the first study of structural gray matter abnormalities in diverticular disease patients. The data show brain differences in the pain network. PMID- 29392840 TI - Relationship between hope and depression in college students: A cross-lagged regression analysis. AB - OBJECTIVE: This study aimed to examine the relationship between depression and two dimensions of hope (pathways thinking and agency thinking) in college students and explore the dynamics of the causal relationship between these variables. METHODS: A longitudinal study was conducted and included 381 college students. Hope and depression were measured using Snyder's State Hope Scale and the Center for Epidemiological Survey Depression Scale respectively, four times within a year (at 4-month intervals), and cross-lagged regression analysis was performed. RESULTS: The bidirectional paths between pathways thinking and depression were highly significant. The paths from agency thinking to depression were non-significant, but the paths from depression to agency thinking were significant. CONCLUSION: There was a significant bidirectional relationship between pathways thinking and depression. In addition, depression levels predicted levels of agency thinking, but levels of agency thinking did not predict depression levels. Therefore, interventions for depression should include strategies that assist individuals in the use of pathways thinking to establish specific routes via which to achieve their goals. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29392839 TI - Pharmacologic treatment of donor cells induced to have a Warburg effect-like metabolism does not alter embryonic development in vitro or survival during early gestation when used in somatic cell nuclear transfer in pigs. AB - Somatic cell nuclear transfer is a valuable technique for the generation of genetically engineered animals, however, the efficiency of cloning in mammalian species is low (1-3%). Differentiated somatic cells commonly used in nuclear transfer utilize the tricarboxylic acid cycle and cellular respiration for energy production. Comparatively the metabolism of somatic cells contrasts that of the cells within the early embryos which predominately use glycolysis. Early embryos (prior to implantation) are evidenced to exhibit characteristics of a Warburg Effect (WE)-like metabolism. We hypothesized that pharmacologically driven fibroblast cells can become more blastomere-like and result in improved in vitro embryonic development after SCNT. The goals were to determine if subsequent in vitro embryo development is impacted by (1) cloning pharmacologically treated donor cells pushed to have a WE-like metabolism or (2) culturing non-treated donor clones with pharmaceuticals used to push a WE-like metabolism. Additionally, we investigated early gestational survival of the donor-treated clone embryos. Here we demonstrate that in vitro development of clones is not hindered by pharmacologically treating either the donor cells or the embryos themselves with CPI, PS48, or the combination of these drugs. Furthermore, these experiments demonstrate that early embryos (or at least in vitro produced embryos) have a low proportion of mitochondria which have high membrane potential and treatment with these pharmaceuticals does not further alter the mitochondrial function in early embryos. Lastly, we show that survival in early gestation was not different between clones from pharmacologically induced WE-like donor cells and controls. PMID- 29392842 TI - Activation of 5-HT7 receptor by administration of its selective agonist, LP-211, modifies explorative-curiosity behavior in rats in two paradigms which differ in visuospatial parameters. AB - AIMS: The serotonin 7 receptor (5-HT7R) subtype, coded by Htr7 gene, is broadly expressed in the central nervous system (CNS) with clear involvement in behavioral functions such as learning/memory, regulation of mood, and circadian rhythms. In this study, we assessed effects of 5-HT7R stimulation by administration of its selective agonist, LP-211 (0.25 mg/kg i.p.), in adult Wistar-Han rats. METHODS: We used two different explorative-curiosity tests. Drug was administered either before one side-chamber familiarization (CF/V group) or immediately after it, to act on consolidation of familiarization (V/CF group). RESULTS: Exp. 1 for novelty seeking in black/white boxes (BWB), with door opening after 5 minutes in the familiar chamber, showed that (i) time spent in the novel environment (significantly higher than in familiar chamber for controls) is enhanced in V/CF group (potentiated recognition for a "visual" consolidation) and not different in CF/V group; (ii) activity and chamber transitions, made by CF/V rats, are significantly higher than for other groups (interference on recognition for a "spatial" acquisition). Exp. 2 for novelty preference in D- vs L-shaped chambers (D/L), with start from neutral center, gave different results: (i) time spent in the novel environment by CF/V group is significantly higher than other groups (potentiated "cognitive" acquisition); (ii) chamber transitions made by V/CF group are significantly higher than other groups (potentiated "emotional" consolidation). CONCLUSION: These apparently conflicting results may reflect LP 211 effects on visual vs spatial memory (D/L apparatus has more pronounced hippocampal components than BWB). However, further experiments are needed to analyze more in depth the mechanisms involved. PMID- 29392841 TI - Baicalein inhibits cell growth and increases cisplatin sensitivity of A549 and H460 cells via miR-424-3p and targeting PTEN/PI3K/Akt pathway. AB - Lung cancer is the leading cause of death in individuals with malignant disease. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, and chemotherapy drugs such as cisplatin are the most widely used treatment for this disease. Baicalein is a purified flavonoid compound that has been reported to inhibit cancer cell growth and metastasis and increase sensitization to chemotherapeutic drugs via different pathways. Therefore, we assessed the effects of baicalein on the proliferation, apoptosis and cisplatin sensitivity in the NSCLC A549 and H460 cell lines and determined the pathways through which baicalein exerts its effects. Baicalein was slightly toxic to normal human bronchial NHBE cells but inhibited growth, induced apoptosis and increased cisplatin sensitivity in A549 and H460 cells. Baicalein down-regulated miR-424 3p, up-regulated PTEN expression and down-regulated expression of PI3K and p-Akt in A549 and H460 cells. Dual-luciferase reporter assay demonstrated that PTEN is a target gene of miR-424-3p, and overexpression of miR-424-3p or silencing of PTEN partially attenuated the effects of baicalein on A549 and H460 cells. Taken together, we concluded that baicalein inhibits cell growth and increases cisplatin sensitivity to A549 and H460 cells via down-regulation of miR-424-3p and targeting the PTEN/PI3K/Akt pathway. PMID- 29392843 TI - Which One is Bulkier: The 3,5-Dimethylphenyl or the 2,6-Dimethylphenyl Group? Development of Size-Complementary Molecular and Macromolecular [2]Rotaxanes. AB - We developed novel size-complementary molecular and macromolecular rotaxanes using a 2,6-dimethylphenyl terminal group as the axle-end-cap group in dibenzo-24 crown-8-ether (DB24C8)-based rotaxanes, where the 2,6-dimethylphenyl group was found to be less bulky than the 3,5-dimethylphenyl group. A series of molecular and macromolecular [2]rotaxanes that bear a 2,6-dimethylphenyl group as the axle end-cap were synthesized using unsubstituted and fluorine-substituted DB24C8. Base-induced decomposition into their constituent components confirmed the occurrence of deslipping, which supports the size-complementarity of these rotaxanes. The deslipping rate was independent of the axle length but dependent on the DB24C8 substituents. A kinetic study indicated the rate-determining step was that in which the wheel is getting over the end-cap group, and deslipping proceeded via a hopping-over mechanism. Finally, the present deslipping behavior was applied to a stimulus-degradable polymer as an example for the versatile utility of this concept in the context of stimulus-responsive materials. PMID- 29392845 TI - Recurrence of eosinophilic granulomatosis with polyangitis after orthotopic heart transplant. AB - Eosinophilic granulomatosis with polyangitis (EGPA), previously referred to as Churg-Strauss syndrome, is a necrotizing small vessel vasculitis associated with eosinophilic infiltrates and extravascular granulomas. We report a case of a Caucasian woman successfully bridged to heart transplantation with a continuous flow left ventricular assist device (LVAD) who survived recurrence of EGPA in the allograft. PMID- 29392844 TI - Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. AB - Various diseases and toxic factors easily impair cellular and organic functions in mammals. Organ transplantation is used to rescue organ function, but is limited by scarce resources. Mesenchymal stem cell (MSC)-based therapy carries promising potential in regenerative medicine because of the self-renewal and multilineage potency of MSCs; however, MSCs may lose biological functions after isolation and cultivation for a long time in vitro. Moreover, after they are injected in vivo and migrate into the damaged tissues or organs, they encounter a harsh environment coupled with death signals due to the inadequate tensegrity structure between the cells and matrix. Preconditioning, genetic modification and optimization of MSC culture conditions are key strategies to improve MSC functions in vitro and in vivo, and all of these procedures will contribute to improving MSC transplantation efficacy in tissue engineering and regenerative medicine. Preconditioning with various physical, chemical and biological factors is possible to preserve the stemness of MSCs for further application in studies and clinical tests. In this review, we mainly focus on preconditioning and the corresponding mechanisms for improving MSC activities in vitro and in vivo; we provide a glimpse into the promotion of MSC-based cell therapy development for regenerative medicine. As a promising consequence, MSC transplantation can be applied for the treatment of some terminal diseases and can prolong the survival time of patients in the near future. PMID- 29392846 TI - High flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure. AB - INTRODUCTION: Severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a significant event that results in substantial mortality. OBJECTIVES: We evaluated the effectiveness of the high flow nasal cannulae (HFNC) therapy in severe AECOPD with moderate hypercapnic acute respiratory failure (ARF) compared to non-invasive ventilation (NIV). METHODS: The prospective observational trial was performed to compare the effectiveness between the HFNC and NIV in severe AECOPD with moderate hypercapnic ARF. The end point was the intubation rate and 30-day mortality. RESULTS: Ninety-two AECOPD patients enrolled during study periods. The median age was 73 (66.5-79) years, and 57 patients (64.8%) were male. Forty-four patients were assigned to HFNC, and 44 patients were assigned to NIV. The intubation rate at day 30 was 25.0% in the HFNC group and 27.3% in the NIV group (P = .857), and the 30-day mortality was 15.9% in the HFNC group and 18.2% in the NIV group (P = .845). The pH (7.38 +/- 0.59 vs 7.36 +/- 0.10, P = .295), PaO2 (82.2 +/- 24.9 vs 81.6 +/- 21.7 mm Hg, P = .899) and PaCO2 (46.8 +/- 15.2 vs 51.7 +/- 17.2 mm Hg, P = .160) after 6 hours and the pH (7.39 +/- 0.07 vs 7.39 +/- 0.08, P = .743), PaO2 (84.3 +/- 18.5 vs 84.7 +/- 23.2 mm Hg, P = .934) and PaCO2 (47.0 +/- 16.0 vs 49.6 +/- 13.7 mm Hg, P = .422) after 24 hours were not significantly different. CONCLUSION: There was no difference of the 30-day mortality and intubation rate between HFNC and NIV groups. PMID- 29392847 TI - Treatment of premenstrual syndrome: Appraising the effectiveness of cognitive behavioral therapy in addition to calcium supplement plus vitamin D. AB - Premenstrual syndrome (PMS) consists of repetitious physical and psychological symptoms. The symptoms occur during the luteal phase of the menstrual period and cease when the menstrual period starts. This study included pre-test and post test experiments between a control group and a test group. The statistical population involved 40 females, chosen based on multistage cluster sampling. The participants were then divided into four groups to undergo treatment with calcium supplement plus vitamin D together with cognitive behavioral therapy (CBT), and were screened with the Premenstrual Syndrome Screening Test (PSST). The pre-test and post-test scores in the PSST, the General Health Questionnaire (GHQ-28), and Bell's Adjustment Inventory (BAI) were used as assessment tools (p < .05). According to the parameters of PMS symptoms, when evaluating the pre-test and post-test scores, the overall score of each individual in the experimental group was improved and a significant effect for the combination of calcium supplement plus vitamin D together with CBT was observed in comparison to the post-test control group. A comparison of multivariate analysis of covariance (MANCOVA) results collected from the pre-test and post-test scores revealed that the method of treatment was beneficial for PMS, adjustment, and general health. PMID- 29392848 TI - Hydrophilic Oligo(lactic acid)s Captured by a Hydrophobic Polyaromatic Cavity in Water. AB - Biologically relevant hydrophilic molecules rarely interact with hydrophobic compounds and surfaces in water owing to effective hydration. Nevertheless, herein we report that the hydrophobic cavity of a polyaromatic capsule, formed through coordination-driven self-assembly, can encapsulate hydrophilic oligo(lactic acid)s in water with relatively high binding constants (up to Ka =3*105 m-1 ). X-ray crystallographic and ITC analyses revealed that the unusual host-guest behavior is caused by enthalpic stabilization through multiple CH-pi and hydrogen-bonding interactions. The polyaromatic cavity stabilizes hydrolyzable cyclic di(lactic acid) and captures tetra(lactic acid) preferentially from a mixture of oligo(lactic acid)s even in water. PMID- 29392849 TI - Risk of ESRD in prior living kidney donors. AB - We studied End-Stage Renal Disease (ESRD) in living kidney donors (LKDs) who donated in the United States between 1994 and 2016 (n = 123 526), using Organ Procurement and Transplantation Network and Centers for Medicare and Medicaid Services data. Two hundred eighteen LKDs developed ESRD, with a median of 11.1 years between donation and ESRD. Absolute 20-year risk was low but not uniform, with risk associated with race, age, and sex and increasing exponentially over time. LKDs had increased risk of ESRD if they were male (adjusted hazard ratio [aHR]: 1.75, 95% confidence interval [95%CI]: 1.33-2.31), had higher BMI (aHR: 1.34 per 5 kg/m2 , 95%CI: 1.10-1.64) or lower estimated GFR (aHR: 0.89 per 10 mL/min, 95% CI: 0.80-0.99), were first-degree relatives of the recipient (parent: [aHR: 2.01, 95% CI: 1.26-3.21]; full sibling [aHR: 1.87, 95%CI: 1.23-2.84]; identical twin [aHR: 19.79, 95%CI: 7.65-51.24]), or lived in lower socioeconomic status neighborhoods at donation (aHR: 0.87 per $10k increase; 95%CI: 0.77-0.99). We found a significant interaction between donation age and race, with higher risk at older ages for white LKDs (aHR: 1.26 per decade, 95%CI: 1.04-1.54), but higher risk at younger ages for black LKDs (aHR: 0.75 per decade, 95%CI: 0.57 0.99). These findings further inform risk assessment of potential LKDs. PMID- 29392850 TI - Construction of 3D Skeleton for Polymer Composites Achieving a High Thermal Conductivity. AB - Owing to the growing heat removal issue in modern electronic devices, electrically insulating polymer composites with high thermal conductivity have drawn much attention during the past decade. However, the conventional method to improve through-plane thermal conductivity of these polymer composites usually yields an undesired value (below 3.0 Wm-1 K-1 ). Here, construction of a 3D phonon skeleton is reported composed of stacked boron nitride (BN) platelets reinforced with reduced graphene oxide (rGO) for epoxy composites by the combination of ice-templated and infiltrating methods. At a low filler loading of 13.16 vol%, the resulting 3D BN-rGO/epoxy composites exhibit an ultrahigh through plane thermal conductivity of 5.05 Wm-1 K-1 as the best thermal-conduction performance reported so far for BN sheet-based composites. Theoretical models qualitatively demonstrate that this enhancement results from the formation of phonon-matching 3D BN-rGO networks, leading to high rates of phonon transport. The strong potential application for thermal management has been demonstrated by the surface temperature variations of the composites with time during heating and cooling. PMID- 29392851 TI - Do FDA label changes work? Assessment of the 2010 class label change for proton pump inhibitors using the Sentinel System's analytic tools. AB - PURPOSE: To pilot use of the US Food and Drug Administration's (FDA's) Sentinel System data and analytic tools by a non-FDA stakeholder through the Innovation in Medical Evidence Development and Surveillance system of the Reagan Udall Foundation. We evaluated the US FDA 2010 proton pump inhibitor (PPI) class label change that warned of increased risk of bone fracture, to use PPIs for the lowest dose and shortest duration, and to manage bone status for those at risk for osteoporosis. METHODS: The cohort consisted of adults aged 18 years or older prescribed PPIs without fracture risk factors. We evaluated incident and prevalent uses of the 8 PPIs noted in the label change. Outcomes evaluated before and after label change were PPI dispensing patterns, incident fractures, and osteoporosis screening or interventions. Consistent with FDA use of descriptive tools, we did not include direct comparisons or statistical testing. RESULTS: There were 1 488 869 and 2 224 420 incident PPI users in the before [PRE] and after [POST] periods, respectively. Users with 1 year or more of exposure decreased (8.4% vs 7.5%), as did mean days supplied/user (130.4 to 113.7 d among all users and 830.8 to 645.4 d among users with 1 y or more of exposure). Osteoporosis screening and interventions did not appear to increase, but the proportion of patients with fractures decreased (4.4% vs 3.1%). Prevalent user results were similar. CONCLUSIONS: This analysis demonstrated the ability to use Sentinel tools to assess the effectiveness of a label change and accompanying communication at the population level and suggests an influence on subsequent dispensing behavior. PMID- 29392852 TI - Ken Hashimoto, M.D., Ph.D. (1931-2017): A tribute. PMID- 29392853 TI - 2018-The year of (evidence-based) nurse workforce planning? PMID- 29392854 TI - Ghrelin secretion in humans - a role for the vagus nerve? AB - BACKGROUND: Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels. METHODS: We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. KEY RESULTS: We find that (i) ghrelin secretion is unchanged during indirect vagal stimulation as elicited by modified sham-feeding in vagotomized individuals and matched controls, (ii) ghrelin secretion is similarly suppressed after meal ingestion in vagotomized individuals and controls, and (iii) infusion of GLP-1 does not lower ghrelin levels. CONCLUSIONS & INFERENCES: We conclude that for postprandial suppression of circulating ghrelin levels, a circulating factor (but not GLP-1) or short (duodeno-gastric) reflexes seem to be implicated. PMID- 29392855 TI - Structure of DSM-5 and ICD-11 personality domains in Iranian community sample. AB - AIM: Personality disorders (PD) have been deemed the most problematic diagnostic grouping in terms of validity and utility, which particularly applies to non Western societies. The current study evaluated the structural validity of PD trait domains in the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM 5) Section III and the proposed International Classification of Diseases-11 (ICD 11) in the Iranian population. METHODS: Community-dwelling adults (n = 285; 66% women) were administered the Personality Inventory for DSM-5, whereas the proposed ICD-11 trait domains were delineated using an algorithm for Personality Inventory for DSM-5 trait facets. The five-factor organization and higher-order hierarchical structure of both models were examined using exploratory structural equation modelling analyses. RESULTS: The five-factor exploratory structural equation modelling loadings overall resembled international findings on DSM-5 Section III traits (including Psychoticism), whereas the ICD-11 five-factor structure aligned with the proposed ICD-11 domain features (including Anankastia). Additionally, we identified a hierarchical structure from one to five factors for both models that conceptually aligned with established models of personality and psychopathology. CONCLUSIONS: This study provided initial support for the structural validity of DSM-5 and ICD-11 PD trait models in Iranian culture. Future research warrants replication in larger samples and clinical populations. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29392856 TI - A Robust 3D Cage-like Ultramicroporous Network Structure with High Gas-Uptake Capacity. AB - A three-dimensional (3D) cage-like organic network (3D-CON) structure synthesized by the straightforward condensation of building blocks designed with gas adsorption properties is presented. The 3D-CON can be prepared using an easy but powerful route, which is essential for commercial scale-up. The resulting fused aromatic 3D-CON exhibited a high Brunauer-Emmett-Teller (BET) specific surface area of up to 2247 m2 g-1 . More importantly, the 3D-CON displayed outstanding low pressure hydrogen (H2 , 2.64 wt %, 1.0 bar and 77 K), methane (CH4 , 2.4 wt %, 1.0 bar and 273 K), and carbon dioxide (CO2 , 26.7 wt %, 1.0 bar and 273 K) uptake with a high isosteric heat of adsorption (H2 , 8.10 kJ mol-1 ; CH4 , 18.72 kJ mol-1 ; CO2 , 31.87 kJ mol-1 ). These values are among the best reported for organic networks with high thermal stability (ca. 600 degrees C). PMID- 29392857 TI - Competitive Affinity Release for Long-Term Delivery of Antibodies from Hydrogels. AB - With increased clinical use of antibodies, long-term delivery strategies are needed to decrease injection frequency and improve health outcomes. A three component drug-delivery system was developed for competitive affinity release of a streptavidin-antibody conjugate from agarose-desthiobiotin hydrogels via controlled dissolution of sparingly soluble biotin derivatives. The antibody conjugate was localized in the hydrogel through streptavidin-desthiobiotin complexation. Dissolution of sparingly soluble biotin derivatives disrupts streptavidin-desthiobiotin complexation for controlled release of the antibody conjugate. Release was tuned by altering the total biotin derivative concentration without further hydrogel or antibody modification. First-order tunable release of bioactive Avastin, a therapeutic anti-VEGF antibody, was demonstrated from a non-cytotoxic system for over 100 days. PMID- 29392859 TI - Hepatic angiomyolipoma detected using computed tomography. PMID- 29392858 TI - Diagnosis of a severe congenital anomaly: A qualitative analysis of parental decision making and the implications for healthcare encounters. AB - OBJECTIVE: To explore parental decision making following diagnosis of a severe congenital anomaly, and implications for healthcare encounters. DESIGN: Qualitative semi-structured interviews with 38 parents-to-be were collated and triangulated with data generated from consultation recordings. ANALYSIS: Data were analysed using a constant comparative-based approach. SETTING: Recruitment was undertaken across four fetal medicine sites in two tertiary referral trusts. PARTICIPANTS: Parents-to-be whose pregnancy was suspected or diagnosed as being affected by a severe congenital anomaly. This sample was purposive to include known factors affecting the decision to terminate or continue the affected pregnancy. FINDINGS: In trying to make a decision about how to proceed with their pregnancy, parents-to-be typically had to work hard to negotiate multiple uncertainties around the diagnosis and prognosis of the suspected anomaly. This was influenced by parents' capacity to cope with uncertainty and the way in which uncertainty was managed by the clinical team. This negotiation of uncertainty was enacted within a fluid, nonlinear three-phase process: "information seeking," reflecting the way parents-to-be face the uncertainty associated with a fetal diagnosis and associated prognosis; "implications," where consideration is given to future consequences of the decision; and "decision making," which reflects the way in which the decision is made (head- or heart-led). Spectrums of responses were apparent within each phase. CONCLUSIONS: This study provides important insights into how parents-to-be make decisions following diagnosis or suspicion of a severe congenital anomaly. The impact of these on healthcare encounters is discussed, alongside recommendations for clinical practice. PMID- 29392860 TI - CHIPMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators. AB - A common issue during drug design and development is the discovery of novel scaffolds for protein targets. On the one hand the chemical space of purchasable compounds is rather limited; on the other hand artificially generated molecules suffer from a grave lack of accessibility in practice. Therefore, we generated a novel virtual library of small molecules which are synthesizable from purchasable educts, called CHIPMUNK (CHemically feasible In silico Public Molecular UNiverse Knowledge base). Altogether, CHIPMUNK covers over 95 million compounds and encompasses regions of the chemical space that are not covered by existing databases. The coverage of CHIPMUNK exceeds the chemical space spanned by the Lipinski rule of five to foster the exploration of novel and difficult target classes. The analysis of the generated property space reveals that CHIPMUNK is well suited for the design of protein-protein interaction inhibitors (PPIIs). Furthermore, a recently developed structural clustering algorithm (StruClus) for big data was used to partition the sub-libraries into meaningful subsets and assist scientists to process the large amount of data. These clustered subsets also contain the target space based on ChEMBL data which was included during clustering. PMID- 29392861 TI - Living alone is associated with an increased risk of institutionalization in older men: A follow-up study in Hamanaka Town of Hokkaido, Japan. AB - AIM: In order to clarify the risks of institutionalization or mortality among older adults living alone compared with those not living alone, we carried out a prospective study on older adults in Hamanaka Town in the far eastern part of Hokkaido, Japan. METHODS: All 978 community-dwelling residents aged 70-85 years in the town were chosen as study candidates between February and May of 2014. Written informed consent was obtained from 562 residents (57.5%), and a self administered questionnaire, including a question about living arrangements, was mailed to them. They returned the completed questionnaire to us in 2014. A follow up survey was carried out with a questionnaire mailed to each participant about institutionalization and mortality, three times, in February of 2015 and 2016, and in April of 2017. Hazard ratios and 95% confidence intervals were calculated with the Cox proportional hazards model. RESULTS: Living alone was significantly associated with an increased risk of institutionalization in the male participants, after adjusting for age, sex and having daily support from family around a participant (hazard ratio 5.71, 95% confidence interval 1.17-27.83), although it was not significant in the total participants or the female participants. Additional adjustments for a history of having common diseases did not change the results meaningfully. Living alone was not associated with the risk of mortality in the total participants, the male participants or the female participants. CONCLUSIONS: Poor social support in social networks for older men living alone may be etiologically associated with increased risk of institutionalization in rural area. Further study with a larger sample size is necessary to confirm this finding. Geriatr Gerontol Int 2018; 18: 867-872. PMID- 29392862 TI - Synthesis of N-Doped Mesoporous Carbon Nanorods through Nano-Confined Reaction: High-Performance Catalyst Support for Hydrogenation of Phenol Derivatives. AB - Traditional hard-template methods for the preparation of mesoporous carbon structures have been well developed, but there are difficulties associated with complete filling of the organic precursors in ordered mesochannels and exact replication of the templates. Herein, mesoporous carbon nanorods (meso-CNRs) were synthesized through thermal condensation of furfuryl alcohol followed by the nano confined decomposition of polyfurfuryl alcohol in silica nanotubes (SiO2 NTs) with porous shells. Limited and slow release of gaseous water through the porous shells and finite polyfurfuryl precursor inside silica nanotubes are responsible for the formation of the mesoporous structures. Nitrogen can be doped into the meso-CNRs by adding guanidine hydrochloride to the precursors. The nitrogen dopant not only stabilizes the ultrasmall and active Pd nanocatalyst in the meso CNRs but also increases the electron density of Pd and accelerates the dissociation of H2 , both of which increase the catalytic activity of the Pd catalyst in hydrogenation reactions. PMID- 29392863 TI - Stem cell transplant in systemic sclerosis: An Indian experience. AB - AIM: To prospectively evaluate long term outcomes in a cohort of patients with Systemic sclerosis treated with Hematopoietic stem cell transplant (HSCT). METHOD: This is a prospective observational study of four SSc patients who underwent HSCT at a tertiary care center in India between 2008-2012. The selection criteria included young individuals with rapidly progressive disease and at least one major organ involvement. We used granulocyte colony-stimulating factor for peripheral blood stem cell mobilization, pre-transplant conditioning with fludarabine, cyclophosphamide and rabbit anti-thymocyte globulin followed by re-infusion of autologous stem cells as per standard institute protocol. RESULTS: A total of four patients (one male and three females) underwent autologous HSCT for SSc. Patients had heterogeneous disease manifestations including severe Raynaud's phenomenon with vasculopathic ulcers, gastrointestinal problems and mild interstitial lung disease (ILD). Patients were followed up for a mean duration of 7 years. There was significant sustained improvement in skin score, vasculopathy and gastrointestinal manifestations. Interstitial lung disease did not show any deterioration. The quality of life indices showed remarkable improvement in all subjects. No complications related to transplant were noted. CONCLUSION: In absence of an effective pharmacotherapy for SSc, autologous HSCT has a huge potential in management of cutaneous and internal organ manifestations. PMID- 29392864 TI - An efficient method for eccrine gland isolation from human scalp. AB - We describe a simple and efficient method to isolate eccrine sweat glands from the human scalp. This method is inspired by the hair graft harvesting method used in hair transplantation. Based on the recently described anatomical relationship between the scalp hair follicle and the eccrine gland, we have found that scalp follicular unit grafts are an excellent eccrine gland isolation source, especially for the coiled component. In order to make the gland visible for stereoscopic microdissection, the follicular units need to be previously stained with a vital dye like methylene blue or neutral red. The simplicity and efficiency of this isolation method should encourage further research into human eccrine sweat gland function which has always been hindered by the difficulty of gland isolation. PMID- 29392865 TI - Improving nutritional discharge planning and follow up in older medical inpatients: Hospital to Home Outreach for Malnourished Elders. AB - AIM: Nutritional decline during and after acute hospitalisation is common amongst older people. This quality improvement initiative aimed to introduce a dietitian led discharge planning and follow-up program (Hospital to Home Outreach for Malnourished Elders, HHOME) at two hospitals within usual resources to improve nutritional and functional recovery. METHODS: Prospective pre-post evaluation design was used. Medical patients aged 65+ years at-risk of malnutrition and discharged to independent living were eligible. Participants receiving nutrition discharge planning and dietetic telephone follow up for four weeks post-discharge ('HHOME') were compared to usual care ('pre-HHOME'). Nutritional (weight and mini nutritional assessment (MNA)), functional (gait speed, handgrip strength and modified Barthel index) and assessment of quality of life-6D (AQoL-6D) outcomes were measured on discharge and six weeks later. RESULTS: At six weeks, no significant difference in nutritional status was observed between pre-HHOME (n = 39) and HHOME cohorts, although the HHOME cohort on average maintained weight while pre-HHOME cohort lost weight (0.4 +/- 2.9 kg vs -1.0 +/- 3.7 kg, P = 0.060). Greater improvement in gait speed was seen in HHOME group (+0.24 +/- 0.27 vs +0.11 +/- 0.22, P = 0.046) with no other significant outcome improvements. Across both cohorts, half were readmitted to hospital and 10% died within 12 weeks post-discharge. CONCLUSIONS: The nutritional discharge planning and dietetic follow up provided to older community-living malnourished patients made a small impact on nutritional and functional parameters but clinical outcomes remained poor. PMID- 29392866 TI - Population-based study examining the utilization of preventive medicines by older people in the last year of life. AB - AIM: To examine the patterns of preventive medicines (PM) use in the last year of life of older adults. METHODS: This study cohort included individuals (n = 99 809) aged >=75 years who were in their last year of life. PM examined in this study included low-dose aspirin (<=325 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, statins and bisphosphonates. Logistic regression models examined the influence of age, sex, multimorbidity, socioeconomic status, and a diagnosis of cancer on the number and type of PM prescribed from 2007 to 2012. RESULTS: The number of PM prescribed was higher for men compared with women (OR 1.11, 95% CI 1.08-1.14). Increasing age did not have an effect on the number of PM prescribed. The use of clopidogrel increased almost threefold from 2007 to 2012 (OR 5.53, 95% CI 4.61-6.65). In contrast, bisphosphonates use decreased significantly during the same period (OR 0.35, 95% CI 0.32-0.39). Individuals with a diagnosis of cancer had increased odds of PM utilization for antiplatelets, aspirin monotherapy and statins, which had remarkably high odds (OR 4.11, 95% CI 3.88-4.34, P < 0.001). CONCLUSIONS: The present explorative study highlighted that some PM, such as statins, continue to be prescribed until death, particularly those that might have been beneficial earlier in life, but have an uncertain or unfavorable risk-benefit ratio towards the end-of-life. Geriatr Gerontol Int 2018; 18: 892-898. PMID- 29392867 TI - Impact of center volume and the adoption of laparoscopic donor nephrectomy on outcomes in pediatric kidney transplantation. AB - Reports for pediatric kidney transplant recipients suggested better outcomes for ODN compared to LDN. Contemporary outcomes stratified by donor type and center volume have not been evaluated in a national dataset. UNOS data (2000-2014) were analyzed for pediatric living donor kidney transplant recipients. The primary outcome was GF; secondary outcomes were DGF, rejection, and patient survival. Live donor nephrectomies for pediatric recipients decreased 30% and transitioned from ODN to LDN. GF rates did not differ for ODN vs LDN (P = .24). GF was lowest at high volume centers (P < .01). Donor operative approach did not contribute to GF. LDN was associated with less rejection than ODN (OR 0.66, CI 0.5-0.87, P < .01). Analysis of the 0- to 5-yr recipient group showed no effect of ODN vs LDN on GF or rejection. For the contemporary era, there was no association between DGF and LDN in the 0- to 5-yr group (OR 1.12, CI 0.67-1.89, P = .67). Outcomes of kidney transplants in pediatric recipients following LDN have improved since its introduction and LDN should be the approach for live donor nephrectomy regardless of recipient age. The association between case volume and improved outcomes highlights future challenges in organ transplantation. PMID- 29392868 TI - Editorial echoes. PMID- 29392869 TI - Comparison of the effectiveness of pulsed dye laser vs pulsed dye laser combined with ultrapulse fractional CO2 laser in the treatment of immature red hypertrophic scars. AB - INTRODUCTION: The objective was to investigate the clinical effect of an adjustable pulse width Pulsed Dye Laser (PDL) vs an adjustable pulse width PDL combined with fractional CO2 laser in treating immature red hypertrophic scars. METHODS: Fifty-six patients (56 sites)were randomly divided into a treatment group and control group. The control group was treated with the 595 nm PDL at a fluence of 7-15J/cm2 and pulse widths of 1.5-3 ms, 7 mm spot size. The treatment group was treated with a fractional CO2 laser (UltraPulse CO2 : Deep FX, Energy: 30~50 mJ, Frequency: 300 Hz, Density 5%, Scan Shape, and Spot Size were decided by shape and area of scar) after utilizing the 595 nm adjustable pulse width PDL (Fluence: 7-15J/cm2 , Pulse widths: 1.5-3 ms, Spot size: 7 mm). MEBT/MEBO, previously described as a post-treatment wound ointment, was used after laser treatment. The scars of the treatment group and the control group were evaluated for changes in pigment, height, vascularity, and pliability using the Vancouver Scar Scale (VSS) after two laser treatments. RESULTS: The total VSS score, as well as the score for melanin, height, vascularity, pliability in both groups, showed an obvious decrease following the treatments. There were statistically significant differences between before treatment and after treatment (P < .05); however, the total score of the VSS, and score of the melanin, height, vascularity, and pliability in the control group decreased more than that of treatment group, and there was a statistically significant difference (P < .05). CONCLUSIONS: The 595 nm adjustable pulse width PDL combined with the fractional CO2 fractional laser appears to have a beneficial clinical effect on fresh red hypertrophic scars, with no severe adverse reactions seen. PMID- 29392870 TI - Swine enteric coronavirus disease: A review of 4 years with porcine epidemic diarrhoea virus and porcine deltacoronavirus in the United States and Canada. AB - Swine enteric coronaviruses, including porcine epidemic diarrhoea virus (PEDV) and porcine deltacoronavirus (PDCoV), have emerged and spread throughout the North American swine industry over the last four years. These diseases cause significant losses within the pork industry and within the first year after PEDV introduction, approximately 10% of the US herd died due to the disease. Similar to other enteric coronaviruses, such as transmissible gastroenteritis virus (TGEV), these emerging swine enteric coronavirus diseases (SECD) are age dependent, with high morbidity and mortality in neonatal pigs. Since the introduction of SECD, research has focused on investigating viral pathogenesis through experimental inoculation, increasing maternal antibody for neonatal protection, understanding transmission risks through feed and transportation, and outlining the importance of biosecurity in preventing SECD introduction and spread. A survey of swine professionals conducted for this review revealed that the majority of respondents (75%) believe SECD can be eradicated and that most herds have been successful at long-term elimination of SECD after exposure (80%). However, unique properties of SECD, such as ineffective immunity through parenteral vaccination and a low oral infectious dose, play a major role in management of SECD. This review serves to describe the current knowledge of SECD and the characteristics of these viruses which provide both opportunities and challenges for long-term disease control and potential eradication from the US swine population. PMID- 29392871 TI - Challenges and Opportunities in Dose Finding in Oncology and Immuno-oncology. PMID- 29392872 TI - Transformative effects of Aboriginal health placements for medical, nursing, and allied health students: A systematic review. AB - The aim of the present systematic review was to investigate whether placements in Aboriginal health affect the self-perceived skill in working in Aboriginal health settings and career aspirations of health students, and in particular, aspects of the placement that had the greatest impact. The Embase, Cinahl, ProQuest, Scopus, Informit, Ovid MEDLINE, PsychINFO, and PubMed databases were searched in April/May 2016. Placements of at least 1 week duration in an Aboriginal health setting involving Australian students of medical, nursing, dentistry, or allied health disciplines, with outcomes relating to changes in students' knowledge, attitudes, and/or career aspirations, were included. The search retrieved 1351 papers. Fourteen studies were eligible for inclusion in this review. Narrative synthesis found that work placements in Aboriginal health increased understanding and awareness of Aboriginal culture, promoted deeper understanding of Aboriginal health determinant complexity, increased awareness of everyday racism toward Aboriginal Australians, and enhanced desire to work in Aboriginal health. There is a need for improved teaching and learning scholarship to understand whether placements improve students' skill working with Aboriginal people in health care or increase the likelihood of future employment in these settings. PMID- 29392873 TI - Gluten-free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring. AB - BACKGROUND: Gluten-free (GF) diet during pregnancy ameliorates autoimmune diabetes in nonobese diabetic (NOD) mouse offspring. Due to comorbidity of celiac disease in type 1 diabetes, we hypothesized that GF diet in utero alleviates the humoral and histopathological signs of celiac disease in NOD mice. We aimed to establish the mechanisms behind the diabetes-protective effect of GF diet in utero. METHODS: Breeding pairs of NOD mice were fed a GF or gluten-containing standard (STD) diet until parturition. The offspring were nursed by mothers on STD diet and continued on this diet until ages 4 and 13 weeks. Analyses of serum antitissue transglutaminase (anti-tTG) intestine and islet histology, islet transglutaminase (TG) activity, and cytokine expression in T cells from lymphoid organs were performed. RESULTS: GF versus STD diet in utero led to reduced serum anti-tTG titre and increased villus-to-crypt ratio at both ages. Insulitis along with systemic and local inflammation were decreased, but islet TG activity was unchanged in 13-week-old GF mice. These mice had unchanged beta-cell volumes, but increased islet numbers throughout the prediabetic period. CONCLUSIONS: Collectively, GF diet administered during pregnancy improves signs of celiac disease and autoimmune diabetes in the offspring. The diabetes-ameliorative effect of GF diet in utero is followed by dampening of inflammation, unchanged beta-cell volume, but increased islet numbers. PMID- 29392875 TI - Thermal Transport in Phosphorene. AB - Phosphorene, a novel elemental 2D semiconductor, possesses fascinating chemical and physical properties which are distinctively different from other 2D materials. The rapidly growing applications of phosphorene in nano/optoelectronics and thermoelectrics call for comprehensive studies of thermal transport properties. In this Review, based on the theoretical and experimental progresses, the thermal transport properties of single-layer phosphorene, multilayer phosphorene (nanofilms), and bulk black phosphorus are summarized to give a general view of the overall thermal conductivity trend from single-layer to bulk form. The mechanism underlying the discrepancy in the reported thermal conductivity of phosphorene is discussed by reviewing the effect of different functionals and cutoff distances on the thermal transport evaluations. This Review then provides fundamental insight into the thermal transport in phosphorene by reviewing the role of resonant bonding in driving giant phonon anharmonicity and long-range interactions. In addition, the extrinsic thermal conductivity of phosphorene is reviewed by discussing the effects of strain and substrate, together with phosphorene based heterostructures and nanoribbons. This Review summarizes the progress of thermal transport in phosphorene from both theoretical calculations and experimental measurements, which would be of significance to the design and development of efficient phosphorene based nanoelectronics. PMID- 29392874 TI - Graphene Scroll-Coated alpha-MnO2 Nanowires as High-Performance Cathode Materials for Aqueous Zn-Ion Battery. AB - The development of manganese dioxide as the cathode for aqueous Zn-ion battery (ZIB) is limited by the rapid capacity fading and material dissolution. Here, a highly reversible aqueous ZIB using graphene scroll-coated alpha-MnO2 as the cathode is proposed. The graphene scroll is uniformly coated on the MnO2 nanowire with an average width of 5 nm, which increases the electrical conductivity of the MnO2 nanowire and relieves the dissolution of the cathode material during cycling. An energy density of 406.6 Wh kg-1 (382.2 mA h g-1 ) at 0.3 A g-1 can be reached, which is the highest specific energy value among all the cathode materials for aqueous Zn-ion battery so far, and good long-term cycling stability with 94% capacity retention after 3000 cycles at 3 A g-1 are achieved. Meanwhile, a two-step intercalation mechanism that Zn ions first insert into the layers and then the tunnels of MnO2 framework is proved by in situ X-ray diffraction, galvanostatic intermittent titration technique, and X-ray photoelectron spectroscopy characterizations. The graphene scroll-coated metallic oxide strategy can also bring intensive interests for other energy storage systems. PMID- 29392876 TI - Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years. AB - This study assessed sperm quality declining on relation to paternal age and its impact on in vitro fertilization (IVF) outcomes in order to estimate the APA (Advanced Paternal Age) cutoff. For this, 83 couples undergoing IVF treatment for male factor infertility were enrolled. The women age was <=39 years, whereas the men were divided in two groups: APA (n = 41; age >= 40 years) and young (Y) (n = 42; age < 40 years). Conventional semen parameters (volume, concentration, motility, vitality, and morphology) were analyzed in the collected sperm samples. Furthermore, sperm genome decays (SGD) was assessed by TUNEL assay (DNA fragmentation), aniline blue staining (chromatin decondensation), and fluorescent in situ hybridization (aneuploidy). No significant difference was found concerning the conventional semen parameters between APA and Y groups. Conversely, SGD analysis showed increased DNA fragmentation; chromatin decondensation and sperm aneuploidy rates in the APA group (respectively, 41%, 43%, and 14% vs. 25%, 23%, and 4% in Y group). IVF outcomes also were affected by paternal age as indicated by the rates of cancelled embryo transfers, clinical pregnancy and miscarriage in the two groups APA and Y (29%, 17%, and 60% vs. 10%, 32%, and 42%). Finally, statistical analysis of the results suggests that the age of 40 should be considered as the APA cutoff during ART attempts. PMID- 29392877 TI - Japanese version of the Montreal Cognitive Assessment cut-off score to clarify improvement of mild cognitive impairment after exercise training in community dwelling older adults. AB - AIM: Physical exercise improves cognitive function in people with mild cognitive impairment (MCI). However, information about whether the degree of MCI before exercise training affects improvement in cognitive function is lacking. Therefore, we aimed to investigate the cut-off value in a MCI screening tool that predicts reversal to normal cognitive function after exercise training in older adults with MCI. METHODS: Participants included 112 Japanese community-dwelling older adult outpatients (37 men, 75 women; mean age 76.3 years). We administered the Japanese version of the Montreal Cognitive Assessment (MoCA-J) before and after exercise training. MCI was defined as a MoCA-J score <26. All participants underwent exercise training 2 days per week for 6 months, according to American Heart Association guidelines. RESULTS: The prevalence of MCI was 65.2%. After exercise training, 46.6% of participants with MCI reversed to normal cognitive function. The MoCA-J cut-off score to predict cognitive function potentially reversible to normal was 23, with receiver operating characteristic analysis showing an area under the curve of 0.80, sensitivity of 79.4% and specificity of 69.2%. Multiple logistic regression analysis to predict non-MCI after exercise training showed that MoCA-J score >=23 (OR 6.9, P < .001), female sex (OR 3.4, P = .04) and age (OR 0.9, P = .04) were independent determinants. CONCLUSIONS: The MoCA-J cut-off score of 23 might be useful to predict cognitive function that is potentially reversible to normal among community-dwelling Japanese older adults with MCI. Geriatr Gerontol Int 2018; 18: 833-838. PMID- 29392879 TI - One-year clinical outcomes and multislice computed tomography angiographic results following implantation of the NeoVas bioresorbable sirolimus-eluting scaffold in patients with single de novo coronary artery lesions. AB - BACKGROUND: Tremendous efforts have been made to establish the concept of vascular restoration therapy with a fully bioresorbable scaffold for coronary artery disease. With an improved scaffold design and technologies, the novel NeoVas scaffold has shown promising clinical performance at 6 months follow-up. OBJECTIVE: The aim of this study was to investigate the 1 year clinical outcomes and multislice computed tomography (MSCT) angiographic results after implantation of the NeoVas scaffold in patients with single de novo coronary artery lesions. METHODS: The NeoVas first-in-man study was a prospective, two-center, single-arm study enrolling 31 patients who were eligible for the treatment. The composite endpoint of target lesion failure (TLF)-defined as cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization (TLR)-was assessed. Of the 31 patients scheduled for 1 year clinical follow-up, 29 patients received MSCT examinations. RESULTS: At 1 year follow-up, there was only 1 (3.2%) TLF, attributed to 1 patient who suffered ischemia-driven TLR at 181 days postprocedure. No cardiac deaths or scaffold thrombosis were observed. MSCT analysis demonstrated excellent vessel patency, with a median in-scaffold lumen area of 10.6 mm2 (interquartile range [IQR]: 8.2-11.7 mm2 ) and a minimal lumen diameter of 2.7 mm (IQR: 2.4-3.0 mm). CONCLUSIONS: This study demonstrated the safety and efficacy of the NeoVas scaffold for patients with single de novo coronary artery lesions at 1 year of follow-up. Noninvasive MSCT data confirmed vessel patency and the maintenance of vessel dimensions following implantation of the NeoVas bioresorbable sirolimus-eluting scaffold. PMID- 29392878 TI - Presenilin PS1?E9 disrupts mobility of secretory organelles in rat astrocytes. AB - AIM: Alzheimer's disease (AD) is largely considered a neuron-derived insult, but also involves failure of astroglia. A recent study indicated that mutated presenilin 1 (PS1M146V), a putative endoplasmic reticulum (ER) Ca2+ channel with decreased Ca2+ conductance, impairs the traffic of astroglial peptidergic vesicles. Whether other pathogenically relevant PS1 mutants, such as PS1DeltaE9, which code for ER channel with putative increased Ca2+ conductance, similarly affect vesicle traffic, is unknown. METHODS: Here, we cotransfected rat astrocytes with plasmids encoding mutant PS1DeltaE9 and atrial natriuretic peptide or vesicular glutamate transporter 1 tagged with fluorescent proteins (pANP.emd or pVGLUT1-EGFP respectively), to microscopically examine whether alterations in vesicle mobility and Ca2+ -regulated release of gliosignalling molecules manifest as a general vesicle-based defect; control cells were transfected to co-express exogenous or native wild-type PS1 and pANP.emd or pVGLUT1-EGFP. The vesicle mobility was analysed at rest and after ATP stimulation that increased intracellular calcium activity. RESULTS: In PS1DeltaE9 astrocytes, spontaneous mobility of both vesicle types was reduced (P < .001) when compared to controls. Post-stimulatory recovery of fast vesicle mobility was hampered in PS1DeltaE9 astrocytes. The ATP-evoked peptide release was less efficient in PS1DeltaE9 astrocytes than in the controls (P < .05), as was the pre-stimulatory mobility of these vesicles. CONCLUSION: Although the PS1 mutants PS1M146V and PS1DeltaE9 differently affect ER Ca2+ conductance, our results revealed a common, vesicle-type indiscriminate trafficking defect in PS1DeltaE9 astrocytes, indicating that reduced secretory vesicle-based signalling is a general deficit in AD astrocytes. PMID- 29392880 TI - Poly(N-methylvinylamine)-Based Copolymers for Improved Gene Transfection. AB - Poly(N-methylvinylamines) with secondary amines can form complexes with plasmid DNA (pDNA) and provide transfection efficiency in HeLa cells in the same order as linear polyethyleneimine but with higher cell viability. Chemical modifications of poly(N-methylvinylamine) backbones are performed to further improve transfection efficiency while maintaining low degree of cytotoxicity. In a first type of polymer, primary amino groups are incorporated via a copolymerization strategy. In a second one, primary amino and imidazole groups are incorporated also via a copolymerization strategy. In a third one, secondary amino groups are substituted with methylguanidine functions through a postpolymerization reaction. Thus, novel polymers of various molecular masses are synthesized, characterized, and their interaction with pDNA studied. Then, their transfection efficiency and cytotoxicity are tested in HeLa cells. Two polymethylvinylamine-based copolymers, one containing 20% of imidazole moieties and another one composed of 12% of guanidinyl units allow remarkable transfection efficiency of HeLa, pulmonary (16HBE), skeletal muscle (C2C12), and dendritic (DC2.4) cells. Overall, this work thus identifies new promising DNA carriers and chemical modifications that improve the transfection efficiency while maintaining low degree of cytotoxicity. PMID- 29392881 TI - Acceptability and validity of a home exercise diary used in home-based pulmonary rehabilitation: A secondary analysis of a randomised controlled trial. AB - INTRODUCTION: Evaluating adherence to home-based pulmonary rehabilitation (PR) could be challenging due to lack of direct supervision and the complex nature of the rehabilitation model. To measure adherence to home-based PR in the HomeBase trial, participants were encouraged to work towards a goal of at least 30 min of whole-body exercise on most days of the week and report their participation using a home exercise diary. OBJECTIVE: This project aimed to evaluate the acceptability and validity of the home exercise diary. METHODS: Diary return and completion rates assessed acceptability of the home exercise diary. Home participants underwent physical activity (PA) monitoring using the Sensewear armband during the final week of an 8-week PR. The correlation between self documented and objective daily exercise minutes was calculated. Objective exercise minutes were defined as bouts of >=10 min spent in >= moderate PA. Differences in self-documented weekly exercise minutes between sufficiently active (>=7000 daily steps) and inactive participants were computed. RESULTS: Diaries were returned by 92% of programme completers. Of those who returned diaries, 72% have completed exercise documentation. Fifteen programme completers underwent PA monitoring [mean age 69 (9) (SD) years, FEV1 55 (19) %predicted]. A moderate correlation was observed between self-documented and objective mean daily exercise minutes (r = .59, P = .02). Active participants [n = 6, 10 253 (1521) daily steps] documented more exercise (111 min) during week eight compared with inactive participants [n = 9, 2705 (1772) daily steps, P = .002]. CONCLUSION: The self-documented home exercise diary is an acceptable and valid method to reflect exercise participation during home-based PR. PMID- 29392882 TI - One after the other: A novel Bluetongue virus strain related to Toggenburg virus detected in the Piedmont region (North-western Italy), extends the panel of novel atypical BTV strains. AB - In this rapid communication, a novel atypical bluetongue virus (BTV) strain detected in goats in the Piedmont region (north-western Italy) is described. This strain, BTV-Z ITA2017, is most related in Seg-2/VP-2 (83.8% nt/82.7% aa) to strain TOV of BTV-25. Reactive antisera of goats positive by cELISA for BTV antibodies failed to neutralize a chimeric virus expressing the outermost protein of TOV. Infected animals displayed low levels of RNAemia and absence of clinical signs consistent with bluetongue infection, a scenario described in animals infected with atypical BTV strains. PMID- 29392883 TI - In silico binding of 4,4'-bisphenols predicts in vitro estrogenic and antiandrogenic activity. AB - Bisphenols, anthropogenic pollutants, leach from consumer products and have potential to be ingested and are excreted in waste. The endocrine disrupting effects of highly manufactured bisphenols (BPA, BPS, and BPF) are known, however the activities of others are not. Here, the estrogenic and androgenic activities of a series of 4,4'-bisphenols that vary at the inter-connecting bisphenol bridge were determined (BPA, BPB, BPBP, BPC2, BPE, BPF, BPS, and BPZ) and compared to in silico binding to estrogen receptor-alpha and the androgen receptor. Bioassay results showed the order of estrogenicity (BPC2 (strongest) > BPBP > BPB > BPZ > BPE > BPF > BPA > BPS, r2 = 0.995) and anti-androgenicity (BPC2 (strongest) > BPE, BPB, BPA, BPF, and BPS, r2 = 0.996) correlated to nuclear receptor binding affinities. Like testosterone and the anti-androgen hydroxyflutamide, bisphenol fit in the ligand-binding domain through hydrogen-bonding at residues Thr877 and Asn705, but also interacted at either Cys784/Ser778 or Gln711 through the other phenol ring. This suggests the 4,4'-bisphenols, like hydroxyflutamide, are androgen receptor antagonists. Hydrogen-bond trends between ERalpha and the 4,4' bisphenols were limited to residue Glu353, which interacted with the -OH of one phenol and the -OH of the A ring of 17beta-estradiol; hydrogen-bonding varied at the -OH of ring D of 17beta-estradiol and the second phenol -OH group. While both estrogen and androgen bioassays correlated to in silico results, conservation of hydrogen-bonding residues in the androgen receptor provides a convincing picture of direct antagonist binding by 4,4'-bisphenols. PMID- 29392885 TI - Ex Vivo Expansion of CD34+ CD90+ CD49f+ Hematopoietic Stem and Progenitor Cells from Non-Enriched Umbilical Cord Blood with Azole Compounds. AB - Umbilical cord blood (UCB) transplants in adults have slower hematopoietic recovery compared to bone marrow (BM) or peripheral blood (PB) stem cells mainly due to low number of total nucleated cells and hematopoietic stem and progenitor cells (HSPC). As such in this study, we aimed to perform ex vivo expansion of UCB HSPC from non-enriched mononucleated cells (MNC) using novel azole-based small molecules. Freshly-thawed UCB-MNC were cultured in expansion medium supplemented with small molecules and basal cytokine cocktail. The effects of the expansion protocol were measured based on in vitro and in vivo assays. The proprietary library of >50 small molecules were developed using structure-activity relationship studies of SB203580, a known p38-MAPK inhibitor. A particular analog, C7, resulted in 1,554.1 +/- 27.8-fold increase of absolute viable CD45+ CD34+ CD38- CD45RA- progenitors which was at least 3.7-fold higher than control cultures (p < .001). In depth phenotypic analysis revealed >600-fold expansion of CD34+ /CD90+ /CD49f+ rare HSPCs coupled with significant (p < .01) increase of functional colonies from C7 treated cells. Transplantation of C7 expanded UCB grafts to immunodeficient mice resulted in significantly (p < .001) higher engraftment of human CD45+ and CD45+ CD34+ cells in the PB and BM by day 21 compared to non-expanded and cytokine expanded grafts. The C7 expanded grafts maintained long-term human multilineage chimerism in the BM of primary recipients with sustained human CD45 cell engraftment in secondary recipients. In conclusion, a small molecule, C7, could allow for clinical development of expanded UCB grafts without pre-culture stem cell enrichment that maintains in vitro and in vivo functionality. Stem Cells Translational Medicine 2018;7:376 393. PMID- 29392886 TI - Li7 Cd4.5 Ge4 Se16 and Li6.4 Cd4.8 Sn4 Se16 : Strong Nonlinear Optical Response in Quaternary Diamond-Like Selenide Networks. AB - Two new selenides with diamond-like structures, Li7 Cd4.5 Ge4 Se16 and Li6.4 Cd4.8 Sn4 Se16 , were synthesized by using a conventional high-temperature solid state reaction method. They crystallize in the space group Pna21 (no. 33) of the orthorhombic system. Their three-dimensional frameworks consist of corner-sharing LiSe4 , CdSe4 , and MSe4 (M=Ge, Sn) tetrahedra. These two compounds exhibit strong powder second-harmonic generation responses that are about 1.2 and 2.5 times that of the benchmark AgGaS2 at a laser wavelength of lambda=2.09 MUm, and also demonstrate type I phase-matchable behavior. The optical bandgaps were determined to be 2.18 and 1.95 eV for Li7 Cd4.5 Ge4 Se16 and Li6.4 Cd4.8 Sn4 Se16 , respectively. Furthermore, these two materials exhibit congruent melting behavior at rather low temperatures of 985 and 1060 K, respectively, which makes bulk single crystal growth by using the Bridgman-Stockbarger method possible. Our study indicates that these two materials show advantages over the traditional IR NLO material CdSe and are promising for practical applications. PMID- 29392887 TI - High-level expression of ARID1A predicts a favourable outcome in triple-negative breast cancer patients receiving paclitaxel-based chemotherapy. AB - Paclitaxel-based chemotherapy is a common strategy to treat patients with triple negative breast cancer (TNBC). As paclitaxel resistance is still a clinical issue in treating TNBCs, identifying molecular markers for predicting pathologic responses to paclitaxel treatment is thus urgently needed. Here, we report that an AT-rich interaction domain 1A (ARID1A) transcript is up-regulated in paclitaxel-sensitive TNBC cells but down-regulated in paclitaxel-resistant cells upon paclitaxel treatment. Moreover, ARID1A expression was negatively correlated with the IC50 concentration of paclitaxel in the tested TNBC cell lines. Kaplan Meier analyses revealed that ARID1A down-regulation was related to a poorer response to paclitaxel-based chemotherapy in patients with TNBCs as measured by the recurrence-free survival probability. The pharmaceutical inhibition with p38MAPK-specific inhibitor SCIO-469 revealed that p38MAPK-related signalling axis regulates ARID1A expression and thereby modulates paclitaxel sensitivity in TNBC cells. These findings suggest that ARID1A could be used as a prognostic factor to estimate the pathological complete response for TNBC patients who decide to receive paclitaxel-based chemotherapy. PMID- 29392884 TI - Crosstalk between long non-coding RNAs and Wnt/beta-catenin signalling in cancer. AB - Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the human genome which perform crucial functions in diverse biological processes. The abnormal expression of some lncRNAs has been found in tumorigenesis, development and therapy resistance of cancers. They may act as oncogenes or tumour suppressors and can be used as diagnostic or prognostic markers, prompting their therapeutic potentials in cancer treatments. Studies have indicated that many lncRNAs are involved in the regulation of several signal pathways, including Wnt/beta-catenin signalling pathway, which has been reported to play a significant role in regulating embryogenesis, cell proliferation and controlling tumour biology. Emerging evidences have suggested that lncRNAs can interact with several components of the Wnt/beta-catenin signalling pathway to regulate the expression of Wnt target genes in cancer. Moreover, the expression of lncRNAs can also be influenced by the pathway. Nevertheless, Wnt/beta-catenin signalling pathway-related lncRNAs and their interactions in cancer are not systematically analysed before. Considering these, this review emphasized the associations between lncRNAs and Wnt/beta-catenin signalling pathway in cancer initiation, progression and their therapeutic influence. We also provided an overview on characteristics of lncRNAs and Wnt/beta-catenin signalling pathway and discussed their functions in tumour biology. Finally, targeting lncRNAs or/and molecules associated with the Wnt/beta-catenin signalling pathway may be a feasible therapeutic method in the future. PMID- 29392888 TI - Organizing pneumonia related to electronic cigarette use: A case report and review of literature. AB - BACKGROUND AND OBJECTIVE: Electronic cigarettes (e cigarettes) are battery operated devices that produce aerosol by heating a solution typically made up of nicotine, propylene glycol, glycerin and flavouring agents. The use of e cigarettes has risen dramatically in recent years especially among adolescents and young adults. These devices have been marketed as safer alternatives to tobacco smoking by their manufactures despite lack of adequate safety data. METHODS: We present a case of 40-year-old female patient who developed significant pulmonary toxicity secondary to e cigarette use and searched existing literature relevant to the case. RESULTS: To our knowledge this is the second reported case of organizing pneumonia and tenth reported case of pulmonary toxicity related to e cigarette use. Our patient presented with symptoms of worsening dyspnoea and intermittent chest pain for past 1 month. She reported increased use of e cigarettes during this time period to help her quit smoking. Patient developed acute hypoxemic respiratory failure requiring intubation and mechanical ventilation. She was diagnosed with organizing pneumonia on open lung biopsy and was successfully treated with steroids along with abstinence from e cigarette use. CONCLUSIONS: As the current data on health effects of e cigarettes is limited, case reports can serve important piece of information in this regard. The use of e cigarettes has increased exponentially in recent years and continue to rise; therefore, physicians should be aware of adverse effects and toxicity related to its use. PMID- 29392889 TI - Regenerative Medicine Manufacturing. PMID- 29392891 TI - Acute Modulation of Mycobacterial Cell Envelope Biogenesis by Front-Line Tuberculosis Drugs. AB - Front-line tuberculosis (TB) drugs have been characterized extensively in vitro and in vivo with respect to gene expression and cell viability. However, little work has been devoted to understanding their effects on the physiology of the cell envelope, one of the main targets of this clinical regimen. Herein, we use metabolic labeling methods to visualize the effects of TB drugs on cell envelope dynamics in mycobacterial species. We developed a new fluorophore-trehalose conjugate to visualize trehalose monomycolates of the mycomembrane using super resolution microscopy. We also probed the relationship between mycomembrane and peptidoglycan dynamics using a dual metabolic labeling strategy. Finally, we found that metabolic labeling of both cell envelope structures reports on drug effects on cell physiology in two hours, far faster than a genetic sensor of cell envelope stress. Our work provides insight into acute drug effects on cell envelope biogenesis in live mycobacteria. PMID- 29392892 TI - The effectiveness of radiant catalytic ionization in inactivation of Listeria monocytogenes planktonic and biofilm cells from food and food contact surfaces as a method of food preservation. AB - AIMS: The aim of the study was to evaluate the microbicidal effectiveness of radiant catalytic ionization (RCI) against Listeria monocytogenes strains in the form of planktonic cells and biofilm on food products and food contact surfaces as a method of food preservation. METHODS AND RESULTS: The study material comprised six strains of L. monocytogenes, isolated from food. Samples of different types of food available by retail (raw carrot, frozen salmon filets, soft cheese) and the fragments of surfaces (stainless steel AISI 304, rubber, milled rock tiles, polypropylene) were used in the experiment. The obtained results showed the effectiveness of RCI in the inactivation of both forms of the tested L. monocytogenes strains on all the surfaces. The effectiveness of RCI for biofilm forms was lower as compared with planktonic forms. The PRR value ranged from 18.19 to 99.97% for planktonic form and from 3.92 to 70.10% for biofilm. CONCLUSIONS: The RCI phenomenon induces the inactivation of L. monocytogenes on surfaces of food and materials used in the processing industry to a varying degree, depending on the manner of surface contamination, the properties of the contaminated materials as well as on the origin of the strain and the properties of surrounding dispersive environment in which the micro-organisms were suspended. SIGNIFICANCE AND IMPACT OF THE STUDY: Searching of new actions aimed at the reduction of the microbial contamination of food and food contact surfaces are extremely important. RCI method has been already described as an effective technique of microbial and abiotic pollution removal from air. However, our studies provide new, additional data related to evaluation the RCI efficacy against microbes on different surfaces, both in planktonic and biofilm form. PMID- 29392893 TI - Case report: Calcium pyrophosphate dihydrate deposition of the temporomandibular joint diagnosed by fine-needle aspiration cytology. AB - Calcium pyrophosphate dihydrate deposition (CPDD) is the accepted name for a disease that mainly occurs in elderly patients. This disease affects many joints in particular the knee joint. CPDD is extremely rare in the temporomandibular joint (TMJ) with only few cases reported in the English literature. Herein, we present a case of an 89 years old woman with a radiological diagnosis of chondrosarcoma of TMJ. Fine-needle aspiration cytology however showed crystals, multinucleated giant cells and macrophages which allowed a correct diagnosis of CPDD. PMID- 29392890 TI - A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. AB - The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-beta (TGF-beta) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-beta signaling. More recently, TGF-beta ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-beta pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-beta signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database. PMID- 29392894 TI - Effect of pH on whitening efficacy of 35% hydrogen peroxide and enamel microhardness. AB - OBJECTIVE: This study aimed to evaluate the effect of 35% hydrogen peroxide at different pH values and the degree of tooth staining on whitening efficacy and enamel microhardness. MATERIALS AND METHODS: 90 enamel-dentin specimens were obtained from bovine incisors. They were randomly divided into 2 groups (n = 45), 1 group was immersed in a staining broth for 14 days, and another group was not stained and kept in distilled water at 37 degrees C. Twenty-four hours after the staining procedure, each group was distributed into 3 subgroups that were whitened by 35% hydrogen peroxide with different pH values (5, 7, and 8.4) for 30 minutes. The color was measured at baseline and 7 days after whitening. Microhardness was measured at baseline, immediate, 24 hours, and 1 month after the whitening procedure. Data were submitted to 2-way analysis of variance (ANOVA) and the Tukey test for multiple comparisons for color analysis. Repeated measures ANOVA and the Tukey test were used to analyze microhardness data. RESULTS: The color change of the stained groups (DeltaE00 = 4.6) was significantly higher than that of the nonstained groups (DeltaE00 = 3.7). Microhardness value decreased significantly immediately after whitening for all subgroups and did not return to initial values. For each measurement time, microhardness was not significantly different among subgroups with different pH values. CONCLUSIONS: Despite the effectiveness of 35% hydrogen peroxide, changes on gel pH did not affect the whitening efficacy, and the enamel was superficially demineralized, regardless of pH values. CLINICAL SIGNIFICANCE: Independently of the pH value of whitening gel, enamel undergoes superficial demineralization and with a reduction in superficial microhardness that does not return to the initial values. However, using hydrogen peroxide with different pH values does not alter the whitening effect. PMID- 29392895 TI - Identifying Different Halogen-/Hydrogen-Bonding Interaction Modes in Binary Systems that Contain an Acetate Ionic Liquid and Various Halobenzenes. AB - Elucidation of the nature of noncovalent interactions between ionic liquids (ILs) and halogenated molecules is of particular importance for both fundamental research and drug development. Herein, the noncovalent interactions between 1 butyl-3-methyl-imidazolium acetate and three halobenzenes C6 F5 X (X=I, Br, H) were investigated. The iodine derivative shows the strongest interaction with the IL, followed by C6 F5 Br and C6 F5 H. As indicated by the positive/negative peaks and "multi/two-state" phenomena in the excess IR spectra, combined with DFT calculations, various interaction modes were differentiated. Three complexes, namely anion-C6 F5 I, anion-2 C6 F5 I, and ion-pair-C6 F5 I in the IL-C6 F5 I system were identified, whereas only ion-pair-C6 F5 Br/C6 F5 H complexes, together with self-associates, were found in the other two systems. A possible reason for the behavior of the IL-C6 F5 I system could be that the iodine-based halogen-bonding interactions in the system are strong enough to break interactions between the IL cations and anions. This might make C6 F5 I a good co solvent to regulate the properties of acetate-based ILs. PMID- 29392896 TI - The emerging role of long non-coding RNA in spinal cord injury. AB - Spinal cord injury (SCI) is a significant health burden worldwide which causes permanent neurological deficits, and there are approximately 17,000 new cases each year. However, there are no effective and current treatments that lead to functional recovery because of the limited understanding of the pathogenic mechanism of SCI. In recent years, the biological roles of long non-coding RNAs (lncRNAs) in SCI have attracted great attention from the researchers all over the world, and an increasing number of studies have investigated the regulatory roles of lncRNAs in SCI. In this review, we summarized the biogenesis, classification and function of lncRNAs and focused on the investigations on the roles of lncRNAs involved in the pathogenic processes of SCI, including neuronal loss, astrocyte proliferation and activation, demyelination, microglia activation, inflammatory reaction and angiogenesis. This review will help understand the molecular mechanisms of SCI and facilitate the potential use of lncRNAs as diagnostic markers and therapeutic targets for SCI treatment. PMID- 29392898 TI - The role of ATP signalling in response to mechanical stimulation studied in T24 cells using new microphysiological tools. AB - The capacity to store urine and initiate voiding is a valued characteristic of the human urinary bladder. To maintain this feature, it is necessary that the bladder can sense when it is full and when it is time to void. The bladder has a specialized epithelium called urothelium that is believed to be important for its sensory function. It has been suggested that autocrine ATP signalling contributes to this sensory function of the urothelium. There is well-established evidence that ATP is released via vesicular exocytosis as well as by pannexin hemichannels upon mechanical stimulation. However, there are still many details that need elucidation and therefore there is a need for the development of new tools to further explore this fascinating field. In this work, we use new microphysiological systems to study mechanostimulation at a cellular level: a mechanostimulation microchip and a silicone-based cell stretcher. Using these tools, we show that ATP is released upon cell stretching and that extracellular ATP contributes to a major part of Ca2+ signalling induced by stretching in T24 cells. These results contribute to the increasing body of evidence for ATP signalling as an important component for the sensory function of urothelial cells. This encourages the development of drugs targeting P2 receptors to relieve suffering from overactive bladder disorder and incontinence. PMID- 29392899 TI - Challenges and recommendations for minimally resourced biobanks in tertiary Australian hospitals. PMID- 29392897 TI - Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. AB - Improvements in immunosuppression have modified short-term survival of deceased donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application. PMID- 29392900 TI - Re: Acute cholangitis: current concepts. PMID- 29392901 TI - Re: Cholangitis 3 years after laparoscopic cholecystectomy. PMID- 29392902 TI - Response to Re: Gastric lipoma: a rare cause of gastrointestinal bleeding. PMID- 29392903 TI - Surviving rejections, revisions and re-submissions. PMID- 29392904 TI - Massive rectal bleeding: empiric embolization of the superior rectal artery. PMID- 29392905 TI - Re: Gastric lipoma: a rare cause of gastrointestinal bleeding. PMID- 29392906 TI - Response to Re: How to do it: use of the Alexis wound protector as a laparostomy device. PMID- 29392907 TI - Ongoing evolution of preoperative chemoradiotherapy for rectal cancer. PMID- 29392909 TI - Medicine in small doses. PMID- 29392910 TI - Dissection should remain a key part of medical education. PMID- 29392911 TI - To drain or not to drain: Supreme Court has the answer. PMID- 29392913 TI - Corrigendum. PMID- 29392912 TI - Stem cell treatments within surgical specialities: what is the evidence? PMID- 29392914 TI - All 'complex' abdominal incisional hernia repairs using mesh must be drained: it's the law. PMID- 29392915 TI - Hazards of predatory publication. PMID- 29392917 TI - PROMS and LARS - will functional outcomes trump cancer survival?: Rectal cancer surgery has focussed on local recurrence and cancer survival. Will patient choice drive the options in the future? PMID- 29392921 TI - Effect of induction therapy on circulating T-helper 17 and T-regulatory cells in active proliferative lupus nephritis. AB - INTRODUCTION: T-helper 17 (Th17) cells and T-regulatory (Treg) cells have been suggested to play pathogenic roles in lupus nephritis. The in vivo effects of current therapies for lupus nephritis (LN) on these cells have not been adequately studied. METHODS: We conducted a prospective observational study among patients with active proliferative lupus nephritis (LN) who received Eurolupus induction therapy and assessed them as per the European League Against Rheumatism criteria for renal response. Peripheral circulatory Th17 and Treg cell numbers were enumerated at start of therapy, at 3 and 6 months follow-up periods using flow cytometry. Baseline values were compared with inactive lupus patients (iSLE) and healthy controls (HC). RESULTS: Thirty patients with LN, 20 iSLE and 22 HC were enrolled into the study. In LN, Th17 frequency was significantly higher compared to HC, and Treg frequency significantly lower compared to both iSLE and HC. Nineteen patients fulfilled criteria for response (partial or complete) at 6 months. Responder group showed a significant decline in Th17 frequency and an increasing trend in Treg frequency compared to baseline after 6 months of therapy. CONCLUSION: Circulating Th17 cells were significantly raised in patients with active proliferative LN and showed a significant reduction in responder patients following therapy. PMID- 29392923 TI - Self-Assembly of Achiral Shape Amphiphiles into Multi-Walled Nanotubes via Helicity-Selective Nucleation and Growth. AB - Soft nanotubes are normally constructed from chiral amphiphiles through helical self-assembly. Yet, how to self-assemble achiral molecules into nanotubes is still a challenge. Here, we report the nanotube construction with achiral shape amphiphiles through helical self-assembly and also unravel the formation mechanisms. The amphiphiles have a dumbbell shape and are composed by covalently linking three achiral moieties together: two unlike clusters and an organic tether. The difference in polarity between the unlike clusters drives the amphiphiles to self-assemble into single- and multi-walled nanotubes as well as intermediates. Analysis of the key intermediates unravels the self-assembly mechanism of helicity-selective nucleation and growth. Meanwhile, direct visualization of the individual clusters in the ribbons displays a two dimensional deformed hexagonal lattice. Thus, we speculate that it is the lattice deformation that creates anisotropic tension along different directions of the ribbon which further results in the formation of helical ribbons towards nanotubes by amphiphiles. PMID- 29392924 TI - RECORd1 project: what have we learned? PMID- 29392925 TI - Biological effect of neoadjuvant androgen-deprivation therapy assessed on specimens from radical prostatectomy: a systematic review. AB - INTRODUCTION: Androgen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of hormonal treatments in prostate cancer (PCa). This review summarizes the findings from published studies specifically focused on the biological effects of ADT assessed on specimens from RP. The aim is to provide a base of knowledge that might be used to design future studies on neoadjuvant therapy for PCa. EVIDENCE ACQUISITION: A systematic review of the literature was performed according to the PRISMA statements. Search protocol identified published studies including a detailed analysis on specimen from RP to assess the biological effects of neoadjuvant ADT. In November 2017, Medline, Embase, and Scopus databases were searched using the terms "neoadjuvant" AND ("hormone therapy" OR "androgen deprivation therapy") AND "prostate cancer" in the "Title/Abstract" fields. Effects of ADT were classified according to four pathways - suppression of cellular proliferation, induction of apoptosis, alteration of immune response and onset of hormonal refractoriness - and relative markers of response were identified. EVIDENCE SYNTHESIS: From 1856 papers initially retrieved, 19 studies were finally selected and included into the present review. ADT was constituted by luteinizing hormone-releasing hormone (LH RH) agonist alone in two, peripheral anti-androgen alone in one, both in 10, abiraterone acetate in one, unspecified in five. According to the above-mentioned four pathways, the following markers of response were identified: transcription of the oncogene TMPRSS2:ERG, translation of Aurora-A, coding of beta1C integrin gene, translation of Ki-67, expression of nerve growth factors TrkA and p75NGFR, anti-angiogenic activity and micro-vessel density were involved into suppression of proliferation; mRNA transcription of bcl-2, expression of cleaved caspase-3 and translation of insulin growth factor binding protein 3, into induction of apoptosis; expression of IL-7 gene, programmed death-ligand 1, and increase of intra-prostatic T-cell population were related to alteration of immune response; finally, expression of heat shock protein 27 and de-differentiation of PCa to neuroendocrine cells, influenced the onset of hormonal refractoriness. CONCLUSIONS: Despite a potential high interest, unexpectedly, only 19 heterogeneous studies investigated the effects of ADT through the analysis of specimens from RP. The present review summarizes the available evidences on this topic showing that ADT interferes on PCa at different levels that can be investigated by specific biological markers. PMID- 29392922 TI - Determinants of muscle preservation in individuals with cerebral palsy across the lifespan: a narrative review of the literature. AB - In individuals with cerebral palsy (CP), smaller muscle and atrophy are present at young age. Many people with CP also experience a decline in gross motor function as they age, which might be explained by the loss of muscle mass. The clinical observation of muscle wasting has prompted a comparison with sarcopenia in older adults, and the term accelerated musculoskeletal ageing is often used to describe the hallmark phenotype of CP through the lifespan. However, there has been very little research emphasis on the natural history of ageing with CP and even less with respect to the determinants or prevention of muscle loss with CP. Considering the burgeoning interest in the science of muscle preservation, this paper aims to (i) describe the characteristics of accelerated musculoskeletal ageing in people with CP, (ii) describe the pathophysiology of sarcopenia and parallels with CP, and (iii) discuss possible therapeutic approaches, based on established approaches for sarcopenia. PMID- 29392926 TI - Diagnosis and kidney-sparing treatments for upper tract urothelial carcinoma: state of the art. AB - INTRODUCTION: Conservative management of upper tract urothelial cancer (UTUC) is becoming increasingly popular: the key to success is correct selection of patients with low-risk UTUC based on size (<=2 cm), focality (single lesion), stage (< T2), and grade (low grade). Despite the recent growing interest in the conservative approach to UTUC, the diagnostic process is still a challenge, and kidney-sparing surgery (KSS) is traditionally reserved for patients with contraindications to radical nephroureterectomy. In order to explore the "state of the art" in the diagnosis and conservative treatment of UTUC, a systematic review of the literature was performed. EVIDENCE ACQUISITION: A PubMed, Scopus, and Cochrane search for peer-reviewed studies was performed using the keywords "upper tract urothelial carcinoma" OR "UTUC" OR "upper urinary tract" AND "biopsy" OR "diagnosis" OR "endomicroscopy" OR "imaging" AND "URS" OR "ureteroscopy" OR "kidney-sparing surgery" OR "laser ablation" OR "ureterectomy". We considered as relevant comparative prospective studies (randomized, quasi randomized, no randomized), retrospective studies, meta-analyses, systematic reviews, and case report series written in the English language. Letters to the editor and contributions written in languages other than English were not considered of value for this review. Eligible articles were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. EVIDENCE SYNTHESIS: Two hundred and sixty-three (263) records were identified using the above-mentioned keywords. Overall, 30 studies were considered relevant for the purpose of this systematic review and for the evidence evaluation process during qualitative synthesis. The outcomes evaluated in this review were the current diagnostic methods and the KSS approaches in UTUC. Furthermore, we included in the review the emerging technology for distinguishing between normal tissue, low-grade UTUC, and high-grade UTUC. CONCLUSIONS: Conclusive diagnosis is fundamental to the decision-making process in patients who could benefit from conservative treatment of UTUC. The most relevant diagnostic modalities are computed tomography urography, local urine cytology, and ureteroscopy with acquisition of an adequate biopsy sample for histology. KSS includes the endourological approach and segmental ureterectomy. Promising technology in the endourological management of UTUC helps in providing intraoperative information on UTUC grading and staging, with a high accuracy. Patients treated conservatively have to undergo stringent postoperative follow-up in order to detect and, if necessary, treat any recurrence promptly. Further larger and multicenter studies are needed to confirm these findings. PMID- 29392927 TI - Non-invasive method for assessing split renal function. PMID- 29392928 TI - Palladacycle Based Fluorescence Turn-On Probe for Sensitive Detection of Carbon Monoxide. AB - New selective and sensitive fluorescence probes have always been in great demand for carbon monoxide, an important gasotransmitter molecule, which is involved in critical physiological and pathophysiological processes in the mammalian cardiovascular system. In this work, we synthesized a new palladacycle compound as a fluorescence turn-on probe for selective and quantitative detection of carbon monoxide. The weakly fluorescent probe quickly and selectively reacts with carbon monoxide and releases a highly fluorescent benzimidazole moiety, due to protonolysis of the palladacycle, which greatly enhances the fluorescence intensity. The selective reaction was against interference from other possible coexisting reactive oxygen species, and achieved a detection limit of ~0.06 MUM. Furthermore, the fluorescence turn-on probe was demonstrated with a high cellular uptake rate and was successfully applied for cell imaging of carbon monoxide in living cells. PMID- 29392929 TI - Homologous Sodium Alginate/Chitosan-Based Scaffolds, but Contrasting Effect on Stem Cell Shape and Osteogenesis. AB - Stem cell shape appears to be involved in the regulation of osteogenesis, which has been confirmed in two-dimensional surfaces and three-dimensional hydrogels. The present study evaluated the effect of matrix-controlled cellular shape on osteogenesis in three-dimensional porous scaffolds based on sodium alginate (ALG) and chitosan (CS). Three ALG/CS scaffolds, especially including a stiff one, were fabricated from different precursor matrices. Soft scaffold A was fabricated from the ALG/CS polyelectrolyte and further cross-linked by Ca2+ and glutaraldehyde to achieve soft scaffold B with alternative hydrophilicity. Stiff scaffold C with "hard-to-deform" feature was fabricated from "ALG/CS preformed gel", which was an ALG gel network expanded by swelling force of the dissolving CS, and fixed using Ca2+ and glutaraldehyde. Scanning electron microscopy and F-actins staining showed rounded mesenchymal stem cells (MSCs) on the inner surfaces inside scaffold A with high swelling behavior, but spindlelike MSCs in scaffold B. Stiff scaffold C forced MSCs to adhere to polygonal shape. Fibronectin adsorption was found to be weakened in scaffold A. Integrin alpha5beta1 expression, as well as osteogenesis-related genes (ALP, OCN) expression, was detected to be higher in the stiff scaffold C. Thus, the present study illustrated that the stiff scaffold C responded to cells with hard-to-deform information, leading to the amplification of focal adhesions and induction of high tension of cells, consequently enhancement of osteogenesis. PMID- 29392930 TI - Labeling and Single-Particle-Tracking-Based Entry Mechanism Study of Vaccinia Virus from the Tiantan Strain. AB - Entry is the first and critical step of viral infection, while the entry mechanisms of many viruses are still unclear due to the lack of efficient technology. In this report, by taking advantage of the single-virion fluorescence tracking technique and simultaneous dual-labeling methods for viruses we developed, the entry pathway of vaccinia virus from tiantan strain (VACV-TT) was studied in real-time. By combining with the technologies of virology and cell biology, we found that VACV-TT moved toward the Vero cell body along the filopodia induced by the virions interaction, and then, they were internalized through macropinocytosis, which was an actin-, ATP-dependent but clathrin-, caveolin-independent endocytosis. These results are of significant importance for VACV-TT-based vaccine vectors and oncolytic virus study. PMID- 29392931 TI - Temperature-Responsive Anisotropic Slippery Surface for Smart Control of the Droplet Motion. AB - Development of stimulus-responsive anisotropic slippery surfaces is important because of the high demand for such materials in the field of liquid directional driven systems. However, current studies in the field of slippery surfaces are mainly conducted to prepare isotropic slippery surfaces. Although we have developed electric-responsive anisotropic slippery surfaces that enable smart control of the droplet motion, there remain challenges for designing temperature responsive anisotropic slippery surfaces to control the liquid droplet motion on the surface and in the tube. In this work, temperature-responsive anisotropic slippery surfaces have been prepared by using paraffin, a thermo-responsive phase transition material, as a lubricating fluid and directional porous polystyrene (PS) films as the substrate. The smart regulation of the droplet motion of several liquids on this surface was accomplished by tuning the substrate temperature. The uniqueness of this surface lies in the use of an anisotropic structure and temperature-responsive lubricating fluids to achieve temperature driven smart control of the anisotropic motion of the droplets. Furthermore, this surface was used to design temperature-driven anisotropic microreactors and to manipulate liquid transfer in tubes. This work advances the understanding of the principles underlying anisotropic slippery surfaces and provides a promising material for applications in the biochip and microreactor system. PMID- 29392932 TI - Function and Regulation of Phase-Separated Biological Condensates. AB - Achieving functional specificity while minimizing cost to fitness is a key constraint during evolution. Formation of biological condensates by liquid-liquid phase separation (LLPS) appears to serve as an important regulatory mechanism to generate moderate specificity in molecular recognition while maintaining a reasonable cost for fitness in terms of design complexity. Formation of biological condensates serves as a unique mechanism of molecular recognition achieving some level of specificity without a huge cost to fitness. Rapid formation of biological condensates in vivo induced by specific cellular or environmental triggers has been shown to be an important mechanism for increasing cellular fitness. Here we discuss the functions and regulation of biological condensates, especially those formed by LLPS, involving interactions between proteins and nucleic acids. These condensates are spatially isolated within the cytosol or nucleus and can facilitate specific biochemical functions under conditions such as stress. The misregulation of biological condensates resulting in nondynamic aggregates has been implicated in a number of diseases. Understanding the functional importance of biological condensates and their regulation opens doors for development of therapies targeting dysfunctional biological condensates, as well as spatiotemporal engineering of functions in cells. PMID- 29392933 TI - Fluorescence Immunoassay Based on the Phosphate-Triggered Fluorescence Turn-on Detection of Alkaline Phosphatase. AB - A simple and cost-effective fluorescence immunoassay for the sensitive quantitation of disease biomarker alpha-fetoprotein (AFP) has been developed based on the phosphate-triggered fluorescence turn-on detection of alkaline phosphatase (ALP), with the reversible binding between calcein and Ce3+ as a signaling element. In this immunoassay, fluorescent calcein is readily quenched by Ce3+ via a coordination process. The ALP-catalyzed hydrolysis of p-nitrophenyl phosphate leads to the formation of p-nitrophenol and inorganic orthophosphate, and the newly formed orthophosphate could potently combine with Ce3+ due to the higher affinity, thus, recovering the fluorescence of calcein. The corresponding fluorescence signal triggered by phosphate is related to ALP activities labeled on antibody, and thus could be applied to detect target antigen in an enzyme linked immunosorbent assay (ELISA) platform. The fluorescence intensity correlated well to the AFP concentration ranges of 0.2-1.0 and 1.0-4.0 ng/mL, with a detection limit of 0.041 ng/mL. The proposed fluorescence ELISA possesses convincing recognition mechanism and exhibits excellent assay performance in the evaluation of the AFP level in serologic test, which unambiguously reveals great application potential in the clinic diagnosis of disease biomarkers. PMID- 29392934 TI - ATP-Decorated Mesoporous Silica for Biomineralization of Calcium Carbonate and P2 Purinergic Receptor-Mediated Antitumor Activity against Aggressive Lymphoma. AB - Adenosine triphosphate (ATP) is an important transmitter that mediates various biological effects via purinergic receptors (P2 receptors) in cancer. We investigated the antitumor activity of ATP-decorated and doxorubicin (DOX)-loaded mesoporous silica with biomineralization of calcium carbonate against a highly aggressive and metastatic murine lymphoma called Dalton's lymphoma (DL). Our results suggest that this nanocomposite has unique effects with respect to the morphology and properties of calcium carbonate on the surface of the nanoparticle. DOX in the nanoparticles was prevented from quick release via the interactions of the phosphate group present on ATP and calcium carbonate. This construct is significantly tumoricidal against parental and DOX-resistant DL cells and is thus a promising candidate for applications in drug delivery. The composite nanomaterial has excellent biocompatibility with higher uptake and acts via the participation of the purinergic receptor P2X7. The nanocomposite induces significantly higher apoptosis in tumor cells compared with DOX alone. Treatment of DL-bearing mice with the construct significantly reduces tumor burden, in addition to augmenting the lifespan of tumor-bearing mice as demonstrated by a sustained healthy life of the animals and improved histopathological parameters. PMID- 29392935 TI - Validation and Verification of a Liquid Chromatography-Mass Spectrometry Method for the Determination of Total Docosahexaenoic Acid in Pig Serum. AB - The paper presents the validation and verification of an analytical method for the determination of total docosahexaenoic acid (DHA) in pig serum by liquid chromatography-electrospray ionization-tandem mass spectrometry. The characteristics studied during the validation included precision and accuracy, limit of quantitation (LOQ), selectivity, calibration range and linearity, parallelism, and stability. A separate verification study was also performed. The method was linear over the range. Precision and accuracy met acceptance criteria at all levels, and the LOQ was determined as 1 MUg/mL. Parallelism experiments were conducted to show that there was no bias introduced in using a surrogate matrix to quantify DHA. Recoveries of free DHA were obtained for quality control samples, and stability studies were conducted over 1, 7, 31, and 180 days. The results of the verification study were in line with the validation study, and in conclusion, the method was deemed fit for purpose for measuring total DHA in pig serum. PMID- 29392936 TI - Long-Lived Correlated Triplet Pairs in a pi-Stacked Crystalline Pentacene Derivative. AB - Singlet fission is the spin-conserving process by which a singlet exciton splits into two triplet excitons. Singlet fission occurs via a correlated triplet pair intermediate, but direct evidence of this state has been scant, and in films of TIPS-pentacene, a small molecule organic semiconductor, even the rate of fission has been unclear. We use polarization-resolved transient absorption microscopy on individual crystalline domains of TIPS-pentacene to establish the fission rate and demonstrate that the initially created triplets remain bound for a surprisingly long time, hundreds of picoseconds, before separating. Furthermore, using a broadband probe, we show that it is possible to determine absorbance spectra of individual excited species in a crystalline solid. We find that triplet interactions perturb the absorbance, and provide evidence that triplet interaction and binding could be caused by the pi-stacked geometry. Elucidating the relationship between the lattice structure and the electronic structure and dynamics has important implications for the creation of photovoltaic devices that aim to boost efficiency via singlet fission. PMID- 29392937 TI - Antifreeze Glycoproteins Bind Reversibly to Ice via Hydrophobic Groups. AB - Antifreeze molecules allow organisms to survive in subzero environments. Antifreeze glycoproteins (AFGPs), produced by polar fish, are the most potent inhibitors of ice recrystallization. To date, the molecular mechanism by which AFGPs bind to ice has not yet been elucidated. Mutation experiments cannot resolve whether the binding occurs through the peptide, the saccharides, or both. Here, we use molecular simulations to determine the mechanism and driving forces for binding of AFGP8 to ice, its selectivity for the primary prismatic plane, and the molecular origin of its exceptional ice recrystallization activity. Consistent with experiments, AFGP8 in simulations preferentially adopts the PPII helix secondary structure in solution. We show that the segregation of hydrophilic and hydrophobic groups in the PPII helix is vital for ice binding. Binding occurs through adsorption of methyl groups of the peptide and disaccharides to ice, driven by the entropy of dehydration of the hydrophobic groups as they nest in the cavities at the ice surface. The selectivity to the primary prismatic plane originates in the deeper cavities it has compared to the basal plane. We estimate the free energy of binding of AFGP8 and the longer AFGPs4-6, and find them to be consistent with the reversible binding demonstrated in experiments. The simulations reveal that AFGP8 binds to ice through a myriad of conformations that it uses to diffuse through the ice surface and find ice steps, to which it strongly adsorbs. We interpret that the existence of multiple, weak binding sites is the key for the exceptional ice recrystallization inhibition activity of AFGPs. PMID- 29392939 TI - Fabricating High-Performance T2-Weighted Contrast Agents via Adjusting Composition and Size of Nanomagnetic Iron Oxide. AB - Magnetic relaxation switch demonstrated that the aggregated nanomagnetic iron oxide (NMIO) nanocrystal possessed a lower T2 value and better relaxivity compared with monodispersed NMIO nanocrystal. However, we found that NMIO nanoclusters (NMIONCs) showed a different magnetic resonance (MR) imaging property in comparison with NMIO nanocrystals. Herein, three types of NMIONCs were used to explore the effects of size and compositions on the variations of magnetism and MR contrast ability. It was found that the transverse relaxation rate (r2) of NMIONCs depended on the contact area between particles and water molecules. The smaller size and higher solubility could carry out higher contact area between NMIONCs and water molecules. Therefore, the monodispersed NMIONC showed a better T2 contrast ability in comparison with the aggregated NMIONC. In addition, for NMIONCs with the same composition, the magnetism and contrast ability gradually increased with the particle size decreasing. In vivo, NMIONCs that possessed the best solubility and the smallest size showed the most effective MR contrast effect for the liver region of mice. As a result, the size and composition of NMIONCs played important roles for enhancing contrast behavior. This study provides a new idea to develop high-performance T2 contrast agents by modulating the size and composition of particles. PMID- 29392940 TI - In Situ Quantification of Surface Intermediates and Correlation to Discharge Products on Hematite Photoanodes Using a Combined Scanning Electrochemical Microscopy Approach. AB - Hematite is a promising photoanode for solar driven water splitting. Elucidating its surface chemical pathways is key to improving its performance. Here, we use redox titrations in the Surface Interrogation mode of Scanning Electrochemical Microscopy (SI-SECM) to quantitatively probe in situ the reactivity and time evolution of surface species formed on hematite during photo assisted water oxidation. Using SI-SECM, two distinct populations of oxidizing surface species were resolved with measured ksi of 316 m3/(mol.s) and 2 m3/(mol.s) for the more and less reactive species, respectively. While the surface coverage of both species was found to increase as a function of applied bias, the rate constants did not change appreciably, suggesting that the mechanism of water oxidation is independent of bias potential. In the absence of applied potential, both populations exhibit decay that is well described by second order kinetics, with kd values of 1.2 * 105 +/- 0.2 * 105 and 6.3 * 103 +/- 0.9 * 103 m2/(mol.s) for the fast and slow reacting adsorbates, respectively. Using transient substrate generation/tip collection mode, we detected the evolution of as much as 1.0 MUmol/m2 of H2O2 during this decay process, which correlates with the coverage observed by one of the titrated species. By deconvoluting the reactivity of multiple adsorbed reactants, these experiments demonstrate how SI-SECM enables direct observation of multiple adsorbates and reaction pathways on operating photoelectrodes. PMID- 29392938 TI - Fundamental Insights into Proton-Coupled Electron Transfer in Soybean Lipoxygenase from Quantum Mechanical/Molecular Mechanical Free Energy Simulations. AB - The proton-coupled electron transfer (PCET) reaction catalyzed by soybean lipoxygenase has served as a prototype for understanding hydrogen tunneling in enzymes. Herein this PCET reaction is studied with mixed quantum mechanical/molecular mechanical (QM/MM) free energy simulations. The free energy surfaces are computed as functions of the proton donor-acceptor (C-O) distance and the proton coordinate, and the potential of mean force is computed as a function of the C-O distance, inherently including anharmonicity. The simulation results are used to calculate the kinetic isotope effects for the wild-type enzyme (WT) and the L546A/L754A double mutant (DM), which have been measured experimentally to be ~80 and ~700, respectively. The PCET reaction is found to be exoergic for WT and slightly endoergic for the DM, and the equilibrium C-O distance for the reactant is found to be ~0.2 A greater for the DM than for WT. The larger equilibrium distance for the DM, which is due mainly to less optimal substrate binding in the expanded binding cavity, is primarily responsible for its higher kinetic isotope effect. The calculated potentials of mean force are anharmonic and relatively soft at shorter C-O distances, allowing efficient thermal sampling of the shorter distances required for effective hydrogen tunneling. The primarily local electrostatic field at the transferring hydrogen is ~100 MV/cm in the direction to facilitate proton transfer and increases dramatically as the C-O distance decreases. These simulations suggest that the overall protein environment is important for conformational sampling of active substrate configurations aligned for proton transfer, but the PCET reaction is influenced primarily by local electrostatic effects that facilitate conformational sampling of shorter proton donor-acceptor distances required for effective hydrogen tunneling. PMID- 29392941 TI - Investigation into the Selenization Mechanisms of Wurtzite CZTS Nanorods. AB - Here, we report the first detailed investigation into the selenization mechanism of thin films of wurtzite copper zinc tin sulfide (CZTS) nanorods (NRs), giving particular emphasis to the role of the long-chain organic ligands surrounding each NR. During selenization, the NRs undergo a selenium-mediated phase change from wurtzite to kesterite, concurrent with the replacement of sulfur with selenium in the lattice and in situ grain growth, along with the recrystallization of larger copper zinc tin selenide kesterite grains on top of the existing film. By utilizing a facile ligand removal technique, we demonstrate that the formation of a large-grain overlayer is achievable without the presence of ligands. In addition, we demonstrate an elegant ligand-exchange-based method for controlling the thickness of the fine-grain layer. This report emphasizes the key role played by ligands in determining the structural evolution of CZTS nanocrystal films during selenization, necessitating the identification of optimal ligand chemistries and processing conditions for desirable grain growth. PMID- 29392942 TI - Surface Interrogation Scanning Electrochemical Microscopy for a Photoelectrochemical Reaction: Water Oxidation on a Hematite Surface. AB - To understand the pathway of a photoelectrochemical (PEC) reaction, quantitative knowledge of reaction intermediates is important. We describe here surface interrogation scanning electrochemical microscopy for this purpose (PEC SI-SECM), where a light pulse to a photoactive semiconductor film at a given potential generates intermediates that are then analyzed by a tip generated titrant at known times after the light pulse. The improvements were demonstrated for photoelectrochemical water oxidation (oxygen evolution) reaction on a hematite surface. The density of photoactive sites, proposed to be Fe4+ species, on a hematite surface was successfully quantified, and the photoelectrochemical water oxidation reaction dynamics were elucidated by time-dependent redox titration experiments. The new configuration of PEC SI-SECM should find expanded usage to understand and investigate more complicated PEC reactions with other materials. PMID- 29392943 TI - Down-Conversion Nitride Materials for Solid State Lighting: Recent Advances and Perspectives. AB - Advances in solid state white lighting technologies witness the explosive development of phosphor materials (down-conversion luminescent materials). A large amount of evidence has demonstrated the revolutionary role of the emerging nitride phosphors in producing superior white light-emitting diodes for lighting and display applications. The structural and compositional versatility together with the unique local coordination environments enable nitride materials to have compelling luminescent properties such as abundant emission colors, controllable photoluminescence spectra, high conversion efficiency, and small thermal quenching/degradation. Here, we summarize the state-of-art progress on this novel family of luminescent materials and discuss the topics of materials discovery, crystal chemistry, structure-related luminescence, temperature-dependent luminescence, and spectral tailoring. We also overview different types of nitride phosphors and their applications in solid state lighting, including general illumination, backlighting, and laser-driven lighting. Finally, the challenges and outlooks in this type of promising down-conversion materials are highlighted. PMID- 29392944 TI - 2,5-Diaryltellurophenes: Effect of Electron-Donating and Electron-Withdrawing Groups on their Optoelectronic Properties. AB - The transformation of 1,2-bis(1-arylvinyl)ditellurides into 2,5 diaryltellurophenes by sequential ditelluride exchange and thermal intramolecular cyclization reactions is presented, and the optoelectronic properties of a series of 2,5-diaryltellurophenes with both electron-donating and electron-withdrawing aryl substituents are disclosed. Furthermore, the multicolored emissive tellurophenes in solution at room temperature have been demonstrated. PMID- 29392945 TI - TEMPO-Catalyzed Aerobic Oxidative Selenium Insertion Reaction: Synthesis of 3 Selenylindole Derivatives by Multicomponent Reaction of Isocyanides, Selenium Powder, Amines, and Indoles under Transition-Metal-Free Conditions. AB - A novel and efficient approach for the selenium functionalization of indoles was developed with selenium powder as the selenium source, catalyzed by 2,2,6,6 tetramethylpiperidinooxy (TEMPO) and employing O2 as the green oxidant. This protocol provides a practical route for the synthesis of 3-selenylindole derivatives and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates. Electron spin-resonance (ESR) studies reveal that the approach involves the formation of nitrogen centered radicals and selenium radicals via oxidation of in situ generated selenoates. PMID- 29392946 TI - Palladium/Norbornene-Catalyzed Ortho-Acylation and Ipso-Selenation via C(O)-Se Bond Cleavage: Synthesis of alpha-Carbonyl Selane. AB - A palladium/norbornene-catalyzed synthetic method that combines selective ortho C H bond activation with sequential reactions to form complex selenide compounds has been developed. The C(O)-Se bond in selenoates is successfully cleaved, and various kinds of alpha-carbonyl selanes were synthesized in decent to excellent yields. The reaction has good functional group tolerance and broad substrate scope. PMID- 29392947 TI - Cobalt(II)-Catalyzed Acyloxylation of C-H Bonds in Aromatic Amides with Carboxylic Acids. AB - The cobalt(II)-catalyzed acyloxylation of C-H bonds in aromatic amides containing an 8-aminoquinoline moiety as the directing group with carboxylic acids is reported. Various carboxylic acids including aromatic and aliphatic carboxylic acids are applicable to the reaction. The reaction displays a broad substrate scope and high functional group tolerance. The reaction is carried out under air. PMID- 29392948 TI - Enhanced Performance of Red Perovskite Light-Emitting Diodes through the Dimensional Tailoring of Perovskite Multiple Quantum Wells. AB - Halide perovskite multiple quantum wells (MQWs) have recently shown great potential in the field of light-emitting diodes. We report a facile solution based approach to fabricate dimensionality-tunable perovskite MQWs by introducing 1-naphthylmethylammonium (NMA) cations into CsPbI3 perovskites. Through the dimensional tailoring of (NMA)2Csn-1PbnI3n+1 perovskite MQWs, the crystallinity and photoluminescence quantum efficiencies (PLQEs) are significantly improved. We have obtained high-performance red perovskite light-emitting diodes (PeLEDs) with a luminance of 732 cd m-2 and a maximum external quantum efficiency of 7.3%, which are among the best-performing red PeLEDs. Significantly, the maximum luminance of our PeLEDs is obtained at a low applied voltage of 3.4 V, with a turn-on voltage close to the perovskite band gap (Vturn-on ~ 1.9 V). These outstanding performance characteristics demonstrate that dimensional tailoring of perovskite MQWs is a feasible and effective strategy to achieve high-performance PeLEDs, which is attractive for full-color display applications of perovskites. PMID- 29392949 TI - Investigating the Network Basis of Negative Genetic Interactions in Saccharomyces cerevisiae with Integrated Biological Networks and Triplet Motif Analysis. AB - Negative genetic interactions in Saccharomyces cerevisiae have been systematically screened to near-completeness, with >500 000 interactions identified. Nevertheless, the biological basis of these interactions remains poorly understood. To investigate this, we analyzed negative genetic interactions within an integrated biological network, being the union of protein-protein, kinase-substrate, and transcription factor-target gene interactions. Network triplets, containing two genes/proteins that show negative genetic interaction and a third protein from the network, were then analyzed. Strikingly, just six out of 15 possible triplet motif types were present, as compared to randomized networks. These were in three clear groups: protein-protein interactions, signaling, and regulatory triplets where the latter two showed no overlap. In the triplets, negative genetic interactions were associated with paralogs and ohnologs; however, these were very rare. Negative genetic interactions among the six triplet motifs did however show strong dosage constraints, with genes being significantly associated with toxicity on overexpression and periodicity in the cell cycle. Negative genetic interactions overlapped with other interaction types in 37% of cases; these were predominantly associated with protein complexes or signaling events. Finally, we highlight regions of "network vulnerability" containing multiple negative genetic interactions; these could be targeted in fungal species for the regulation of cell growth. PMID- 29392950 TI - Quantitation of Specific Barley, Rye, and Oat Marker Peptides by Targeted Liquid Chromatography-Mass Spectrometry To Determine Gluten Concentrations. AB - Celiac disease is triggered by the ingestion of gluten from wheat, barley, rye, and possibly oats. Gluten is quantitated by DNA-based methods or enzyme-linked immunosorbent assays (ELISAs). ELISAs mostly detect the prolamin fraction and potentially over- or underestimate gluten contents. Therefore, a new independent method is required to comprehensively detect gluten. A targeted liquid chromatography-tandem mass spectrometry method was developed to quantitate seven barley, seven rye, and three oat marker peptides derived from each gluten protein fraction (prolamin and glutelin) and type (barley, B-, C-, D-, and gamma hordeins; rye, gamma-75k-, gamma-40k-, omega-, and HMW-secalins). The quantitation of each marker peptide in the chymotryptic digest of a defined amount of the respective reference gluten protein type resulted in peptide specific yields, which enabled the conversion of peptide into protein concentrations. This method was applied to quantitate gluten in samples from the brewing process, in raw materials for sourdough fermentation, and in dried sourdoughs. PMID- 29392951 TI - Correction to Multiscale Reactive Molecular Dynamics for Absolute pKa Predictions and Amino Acid Deprotonation. PMID- 29392952 TI - Effect of Hydrogen Bonding and Partial Deprotonation on the Oxidation of Peptides. AB - In a recent computational study, we found that hydrogen bonding/partial deprotonation facilitates subsequent electron transfer from amides to HO*. We have now analyzed these and related reactions with a glycine derivative as a model peptide, investigating not only reaction energies but also barriers for the individual steps. We find that partial deprotonation not only assists subsequent electron transfer (a sequential proton-loss electron-transfer (SPLET)-type reaction pathway) but also promotes sequential hydrogen-atom transfer (HAT, in a sequential proton-loss hydrogen-atom-transfer (SPLHAT)-type process), both being potential alternatives to direct HAT as routes for peptide oxidation. Each of these alternative pathways is calculated to have energy requirements that make them accessible and competitive. These oxidative processes may produce alpha carbon-centered peptide radicals that, through deprotonation, are readily oxidized to the corresponding imines. We have also examined the possibility of competing reactions of amino acid side chains by comparing reactions of the glycine model with those of an analogous valine derivative. We find that, while the side chains of amino acids are more reactive toward direct HAT, a preceding partial deprotonation instead continues to favor the SPLET- and SPLHAT-type reactions, leading to the production of alpha-carbon-centered peptide radicals. Taken together, these processes have broad implications that impact many aspects of the science and utility of peptides. PMID- 29392953 TI - Successive Waste as Reagent: Two More Steps Forward in a Pinnick Oxidation. AB - The successful development of the classical Pinnick oxidation into a new and promising oxidative lactonization reaction is reported. Chiral 3 oxindolepropionic aldehydes, Michael adducts of 3-olefinic oxindoles with aliphatic aldehydes, are directly converted to spirocyclic oxindole-gamma lactones solely by sodium chlorite via a tandem Pinnick oxidation/chlorination/substitution sequence. This reaction uses waste ClO- generated in the initial Pinnick oxidation as an ecofriendly halogenating agent for the subsequent chlorination, and then it utilizes the byproduct OH- formed in the chlorination to facilitate the final internal substitution. PMID- 29392954 TI - Heparin and Heparan Sulfate Binding of the Antiparasitic Drug Imidocarb: Circular Dichroism Spectroscopy, Isothermal Titration Calorimetry, and Computational Studies. AB - This study is aimed to assess the binding interaction between the antiparasitic cationic drug imidocarb (IMD) and sulfated glycosaminoglycans (GAGs), the ubiquitious nonprotein macromolecules of living organisms. These complex, heterogeneous polyanions are the integral constituents of cell membranes and the extracellular matrix and display affinity toward basic compounds, the binding of which may affect their biological functions. Exciton-type circular dichroism (CD) spectroscopic features measured at low salt concentration verify the heparin and heparan sulfate binding of IMD, which occurs in a cooperative manner by association of several drug molecules to a disaccharide unit. Isothermal titration calorimetry (ITC) measurements reassured the heparin interaction, resulting in a Kd value in the low micromolar range. In contrast, when considering high molar excess of the heparin-binding sites, closer resembling in vivo conditions, an entirely different CD signature was induced, suggesting a shift from the oligo- to monomeric binding mode. This observation was also supported by ITC measurements using an identical sample setup. To better mimic in vivo conditions, several measurements were performed in physiological salt concentration ranges. On the basis of these, the inter- and intramolecular origin of CD activity observed under low- and high-salt conditions refer to electrostatically held oligomeric and intermolecular H-bonded monomeric drug-GAG adducts, respectively. To complement the experimental data, quantum chemical calculations were performed to assess the photophysical and conformational properties of IMD, indicating the existence of nonlinear, nonplanar interconverting conformer populations. Such a structural flexibility may be important in the multiple, cooperative binding of IMD to sterically adjacent GAG sites. PMID- 29392955 TI - Decarbonylative C-P Bond Formation Using Aromatic Esters and Organophosphorus Compounds. AB - Ni-catalyzed C-P bond formation was achieved using aromatic esters as unconventional aryl sources. The key to success was the use of a thiophene-based diphosphine ligand (dcypt). Several aromatic esters including heteroaromatics can be coupled with phosphine oxides and phosphates, providing aryl phosphorus compounds. The synthetic utility of the method was demonstrated by application of the present protocol to the sequential coupling reactions. PMID- 29392956 TI - Origins of Photodamage in Pheomelanin Constituents: Photochemistry of 4 Hydroxybenzothiazole. AB - 4-Hydroxybenzothiazole (4-HBT) is a molecular constituent of pheomelanin-a polymeric skin centered pigment which acts as a natural photoprotector against harmful solar-UV radiation. Its molecular structure is therefore required to sustain a degree of photostability upon electronic excitation with UV irradiation. Despite its function as a protector against UV, pheomelanin is known to be less photostable than that of its close derivative eumelanin-a dark skin centered pigment. The 4-HBT subunit has long being attributed as a key contributor to the lack of photostability of pheomelanin-a hypothesis which we aim to test in this paper. Using high-level multireference computational methods, coupled with on-the-fly surface-hopping molecular dynamics, we find excited state reaction paths that show potential detriment to 4-HBT, leading to phototoxic radicals and products that are distinct from the original ground state molecule. Such radicals and photoproducts include those formed by classic pisigma* photodissociations, intramolecular proton-transfer, and ring-opening reactions. Such reactions shed light on the types of molecular structure that show photodetrimental effects upon UV irradiation, allowing judicious predictions for synthetic analogues that may offer enhanced photoprotection in commercial sunscreens. PMID- 29392957 TI - Assessment of dose-dependent reproductive toxicity of diclofenac sodium in male rats. AB - Diclofenac sodium is widely used in the non-steroidal anti-inflammatory drug in the treatment of pain and inflammation. It is also particularly associated with its adverse effects on avian fauna and linked to environmental issues. The present study was aimed to assess the dose-dependent toxicity of diclofenac sodium on a male reproductive system of rats. Four groups of healthy adult fertile male rats were administered with saline (control) or 0.25 mg/kg, 0.50 mg/kg and 1.0 mg/kg of diclofenac sodium, respectively for 30 days. Alterations in body and organ weight, sperm and testicular cell population dynamics, serum biochemistry, histopathology, and hematology were investigated as per aimed objectives. Diclofenac sodium treatment significantly (p <= 0.001) reduced weights of testis, epididymis, ventral prostate and seminal vesicle. Sperm count, sperm density (in epididymis and testis), sperm motility and testicular cell population dynamics were lowered in a dose-dependent manner. Administration of diclofenac exhibited varying degrees of degeneration testis, abnormal histo architectures, and shrinkages in seminiferous tubules, particularly in higher doses. Diclofenac sodium treatments also altered hepatic and renal function parameters significantly. In conclusion, it may claim that diclofenac sodium treatment altered reproductive metabolic status, androgenic activities and histo architecture of the testis of male rats and induced hepatotoxicity and renal toxicity. PMID- 29392958 TI - Using Written Instructions to Improve the Quality of Emergency Department Discharge Communication: An Interdisciplinary, Patient-Centered Approach. PMID- 29392959 TI - Neural stem cell encapsulation and differentiation in strain promoted crosslinked polyethylene glycol-based hydrogels. AB - Encapsulated cell viability within crosslinked hydrogels is a critical factor to consider in regenerative medicine/cell delivery applications. Herein, a "click" hydrogel system is presented encompassing 4-dibenzocyclooctynol functionalized polyethylene glycol, a four arm polyethylene glycol tetraazide crosslinker, tethered native protein attachment ligands (laminin), and a tethered potent neurogenic differentiation factor (interferon-gamma). With this approach, hydrogel formation occurs via strain-promoted, metal-free, azide-alkyne cycloaddition in an aqueous buffer. This system demonstrated safe encapsulation of neural stem cells in biological conditions without chemical initiators/ultraviolet light, achieving high cell viability. Cell viability in click gels was nearly double that of ultraviolet exposed gels after 1 d as well as 14 d of subsequent culture; demonstrating the sensitivity of neural stem cells to ultraviolet light damage, as well as the need to develop safer encapsulation strategies. Finally, protein immobilized click hydrogel neural stem cell in vitro differentiation over 2 weeks demonstrated that the click gels specified primarily neurons without the need for additional protein differentiation factor media supplementation. PMID- 29392961 TI - Winston Churchill (1874-1965), Dr Robson Roose, MD Brux, FRCPE (1848-1905) and Dr Joseph Rutter, MD Lond, MRCP (1834-1913): Treatment for pneumonia in March 1886. AB - This paper will review Winston Churchill's severe respiratory illness in March 1886 when he developed pneumonia of the right lung as an 11-year-old boy. Winston was treated supportively with 'nourishment, stimulants [probably alcohol] and close watching' at his school by the 'celebrated' family physician, Dr Robson Roose, with the assistance of Dr Joseph Rutter. Roose was exemplary in his commitment to his young patient and assiduous in informing Lord Randolph Churchill of his son's clinical progress by letter. PMID- 29392960 TI - A randomized phase II trial of interleukin-2 and interferon-alpha plus bevacizumab versus interleukin-2 and interferon-alpha in metastatic renal-cell carcinoma (mRCC): results from the Danish Renal Cancer Group (DaRenCa) study-1. AB - BACKGROUND: Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression. PATIENT AND METHODS: We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (iv) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED). Primary end point was progression-free survival (PFS). RESULTS: Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2-11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1-11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively. CONCLUSIONS: The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.). PMID- 29392964 TI - Evaluation of Psychometric Properties and Factorial Structure of ADHD Module of K SADS-PL in Children From Rural Kenya. AB - OBJECTIVE: We determined the reliability of The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime (K-SADS PL) for screening and diagnosing ADHD in children. METHOD: K-SADS-PL was administered to 2,074 children in the community. Psychometric properties, factorial structure, and clinical validity of K-SADS-PL in screening or diagnosis of ADHD were examined. RESULTS: Internal consistency was excellent for items in the screening interview (Macdonald's Omega [omega] = 0.89; 95% confidence interval [CI] [0.87, 0.94]) and diagnostic supplement (omega = 0.95; 95% CI [0.92, 0.99]). The standardized coefficients for items in the screening interview were acceptable (0.59-0.85), while fit indices for single factorial structure reached acceptable levels. Screening items were associated with high sensitivity (97.8%; 95% CI [97.2, 98.5%]) and specificity (94.0%; 95% CI [93.0, 95.0%]) for diagnosis of ADHD in the supplement. The test-retest and interinformant reliability as measured by intraclass correlation coefficient was good for most of the items. CONCLUSION: This large study shows that K-SADS-PL can be reliably used to screen and diagnose ADHD in children in Kenya. PMID- 29392963 TI - Antioxidant activity and apoptotic induction as mechanisms of action of Withania somnifera (Ashwagandha) against a hepatocellular carcinoma cell line. AB - Objective To evaluate the antioxidant and apoptotic inductive effects of Withania somnifera (Ashwagandha) leaf extract against a hepatocellular carcinoma cell line. Methods After treating HepG2cells with Ashwagandha water extract (ASH-WX; 6.25 mg/ml-100 mg/ml), cell proliferation was assessed using a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activities (total antioxidant, glutathione S-transferase and glutathione reductase), Fas-ligand level, tumour necrosis factor-alpha (TNF-alpha) level and caspase-3, -8, and -9 activities were measured. Molecular modelling assessed the binding-free energies of Ashwagandha in the cyclin D1 receptor. Results The MTT assay demonstrated increased cytotoxicity following treatment of HepG2 cells with ASH-WX compared with control untreated cells and theIC50was 5% (approximately 5.0 mg/ml). Antioxidant activities, Fas-ligand levels and caspase-3, -8 and -9 activities significantly increased, while TNF-alpha level significantly decreased following ASH-WX treatment compared with control untreated cells. Molecular docking analysis revealed a good prediction of binding between cyclin D1 and Ashwagandha. There was significant accumulation of ASH-WX-treated HepG2cells in the G0/G1 and G2/M phases compared with the control untreated cells. Conclusion Ashwagandha could be a powerful antioxidant and a promising anticancer agent against HCC. PMID- 29392965 TI - Evaluation of quality of life in patients undergoing surgery for benign prostatic hyperplasia. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is one of the most common diseases in the world and also one of the most common causes of urinary complaints that occur with increasing age. Thus, BPH should be addressed with surgical procedures. To contribute to the relevant literature, the present study aims to investigate the effects of surgical therapies for BPH on the patients quality of life. MATERIALS AND METHODS: This study included 120 patients who underwent surgery for BPH at a Training and Research Hospital. The short-form health survey (SF-36) was administered to the patients before the surgery and at three months after the surgery. Eight parameters of the SF-36 and mental (MCS) and physical (PCS) component summary scores were calculated. The Student's t test, Wilcoxon, and chi-square test were used in the statistical analysis. RESULTS: When the eight parameters within the SF-36 health questionnaire were examined separately, the findings showed that patients quality of life increased significantly with respect to physical functioning, social functioning, and role limitations because of emotional problems , vitality, bodily pain, general health perceptions, and mental health domains three months after surgery (p < .001). The PCS and MCS significantly increased after surgery (p < .001). CONCLUSION: The SF 36 questionnaire results showed that a significant improvement in the patients quality of life was observed in patients who underwent surgery for BPH. Our findings suggest that SF-36 could be considered a reliable evaluation test to be used in the patients with BPH after surgery. PMID- 29392966 TI - The PLIANT trial gives trustworthy data. PMID- 29392967 TI - Sedation in the coronary intensive care unit: An adapted algorithm for critically ill cardiovascular patient. AB - In the current era, cardiovascular intensive care units care for more complex patients who are far sicker than historical post-myocardial infarction patients, and sedation has become a common intervention in these units. Current sedation best practices derive mainly from non-cardiac units which limits their generalization to the critically ill cardiac patient. Thus, a great variability in sedation protocols, especially the selection of sedative agents, is commonly seen in daily practice across cardiac units. We present an updated review on sedation in cardiovascular critical care medicine with emphasis on the hemodynamic impact. The goal of this review is to generate a general sedation algorithm specific for the cardiac patient. PMID- 29392969 TI - Metabolomics reveals the depletion of intracellular metabolites in HepG2 cells after treatment with gold nanoparticles. AB - Studies on the safety of gold nanoparticles (GNPs) are plentiful due to their successful application in drug delivery and treatment of diseases in trials. Cytotoxicity caused by GNPs has been studied on the physiological and biochemical level; yet, the effect of GNPs (particularly gold nano-spheres) on the metabolome of living organisms remains understudied. In this investigation, metabolomics was used to comprehensively study the metabolic alterations in HepG2 cells caused by GNPs; and to investigate the role of representative GNP coatings. GNPs were synthesized, coated and characterized before use on HepG2 cell cultures. Cells were treated for 3 h with citrate-, poly-(sodiumsterene sulfunate)-, and poly vinylpyrrolidone (PVP)-capped GNPs, respectively. The internalization of the different GNPs and their effect on mitochondrial respiration and the metabolome were studied. Results indicated that the PVP-capped GNPs internalized more and also caused a more observable effect on the metabolome. Conversely, it was the citrate- and poly-(sodiumsterene sulfunate) coated particles that influenced ATP production in addition to the metabolomic changes. A holistic depletion of intracellular metabolites was observed regardless of GNP coating, which hints to the binding of certain metabolites to the particles. PMID- 29392968 TI - Single institution validation of a modified graded prognostic assessment of patients with breast cancer brain metastases. AB - AIM: The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. PATIENTS & METHODS: We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan-Meier curves and Cox proportional hazards model. RESULTS & CONCLUSION: The Kaplan-Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome. PMID- 29392970 TI - New lower cutoff for serum high sensitive C-reactive protein in obese women indicates the risk of metabolic syndrome. AB - : Objective, materials and methods: The aim of this cross-sectional study with a consecutive enrolment was to analyse the role of high sensitive C-reactive protein (hs-CRP) measurement in similarly obese patients with and without the metabolic syndrome (MS). RESULTS: In total, 589 obese patients were screened, of whom 138 aged 50-75 years were enrolled. The others were rejected due to strict criteria of enrolment, so that the group was highly homogenous in numerous clinical aspects. The study group consisted of 96 patients (49 females and 47 males) with MS; 42 patients (20 females and 22 males) had isolated obesity without MS and served as a control group. hs-CRP levels were significantly higher in patients with MS (p = .0012). To find out the CRP cutoff between MS and non-MS obesity, we performed ROC curve analyses: hs-CRP lower than 1.96 mg/l was the best predictor of simple obesity without MS (sensitivity = 66.7%; specificity = 66.7%; AUC = 0.7; p = .0002). In a separate analysis, hs-CRP level lower than 1.96 mg/dl remained statistically significant as a predictor of isolated central obesity only for females. CONCLUSIONS: Already a relatively low level of hs-CRP around 2.0 mg/dl is observed in the MS, whereas patients with simple obesity without the accompanying features of MS would have hs-CRP lower than this value. PMID- 29392971 TI - The Dynamics of Intra-Family Relationships During Incarceration and the Implications for Children of Incarcerated Parents. AB - The current study examines effects of changes in intra-family relationships after parental incarceration on internalizing behaviors of the children of incarcerated parents. Using data from a sample of 249 incarcerated parents with minor children in South Korea, the present study found that perceived degradation of family relationships among inmate parents, their non-incarcerated spouses, and children was a significant risk factor of internalizing behaviors of children of incarcerated parents. The current study also found that inmate parents who had more frequent family contact were more likely to perceive improvements of all forms of intra-family relationships during incarceration. The implications of these findings are discussed. PMID- 29392972 TI - Working With Chinese Triad Youth Gangs: Correct Diagnosis and Strategic Intervention. AB - Across the world, youth workers have been active in helping vulnerable youth groups. In Hong Kong, government-funded youth services are conducted by professional social workers to help vulnerable youths. This article adopted a case study approach to investigate a youth group who committed a murder. Nine murderers and two social workers were interviewed. It aims to uncover the structure and activities of the group and analyse the gang intervention prior to the murder to find out what had gone wrong and identify the lessons that social workers can learn from the murder. Four misconceptions in gang intervention have been identified. First, because of the Triad (Chinese-organised crime) affiliation, this is not just a group of deviant youths but a youth gang. Second, because it is a gang, the social workers should not group them but should instead degroup them to avoid contamination. Third, diagnosis is different from labelling. With the right diagnosis, services can be tailor-made to delabel them. Fourth, when the youths are diagnosed as a gang, outreach work instead of centre work should be provided-social workers should reach out to the gangland to uncover the youths' gang participation and crime involvement. PMID- 29392973 TI - The Impact of Participation in Victim-Offender Mediation Sessions on Recidivism of Serious Offenders. AB - The federal correctional agency in Canada offers victim-offender mediation services to address serious crime. The current study used survival analysis to compare revocation rates of 122 offenders who participated in facilitated face-to face meetings to a matched sample of 122 of non-participants. Results indicated that there was no significant difference between revocation rates when offenders participated while incarcerated, although the trend was that participants did better. When the meetings were held in the community post-release, however, participants were significantly more likely to spend a longer period of time under supervision in the community without returning to custody and were less likely to be revoked than their matched counterparts. The findings support participation in restorative justice sessions while under community supervision for higher risk offenders with histories of serious and violent crimes. The authors discuss how factors not controlled in the matching procedure may have contributed to this effect. PMID- 29392974 TI - RF-energised intracoronary guidewire to enhance bipolar ablation of the interventricular septum: in-silico feasibility study. AB - PURPOSE: Although bipolar radiofrequency (RF) ablation (RFA) is broadly used to eliminate ventricular tachycardias in the interventricular septum wall, it can fail to create transmural lesions in thick ventricular walls. To solve this problem, we explored whether an RF-energised guidewire inserted into the ventricular wall would enhance bipolar RFA in the creation of transmural lesions through the ventricular wall. METHODS: We built three-dimensional computational models including two irrigated electrodes placed on opposing sides of the interventricular septum and a metal guidewire inserted into the septum. Computer simulations were conducted to compare the temperature distributions obtained with two ablation modes: bipolar mode (RF power delivered between both irrigated electrode) and time-division multiplexing (TDM) technique, which consists of activating the bipolar mode for 90% of the time and applying RF power between the guidewire and both irrigated electrodes during the remaining time. RESULTS: The TDM technique was the most suitable in terms of creating wider lesions through the entire ventricular wall, avoiding the hour-glass shape of thermal lesions associated with the bipolar mode. This was especially apparent in the case of thick walls (15 mm). Furthermore, the TDM technique was able to create transmural lesions even when the guidewire was displaced from the midplane of the wall. CONCLUSIONS: An RF-energised guidewire could enhance bipolar RFA by allowing transmural lesions to be made through thick ventricular walls. However, the safety of this new approach must be assessed in future pre-clinical studies, especially in terms of the risk of stenosis and its clinical impact. PMID- 29392975 TI - Respiratory-digestive tract fistula: two-center retrospective observational study. AB - Background Aerodigestive fistulae can be defined as abnormal communications between the gastrointestinal tract and the respiratory tract. Choking after meals, coughing, feeding difficulties, tachycardia, and persistent pneumonia are the main presentations. The aim of our study was to review our experience in the management of 27 cases of acquired aerodigestive fistulae of different types, levels, and management. Methods We conducted a retrospective observational study on 27 cases of fistulae between the respiratory and digestive tracts, which were managed in 2 hospitals in Saudi Arabia in the last 5 years. The patients comprised 16 females and 11 males, with a mean age of 29 years (range 17-67 years). Results The most common aerodigestive tract fistula was tracheoesophageal in 8 patients, followed by esophagobronchial in 6, and esophagopleural in 5. Four postendoscopic fistulae were included. The least common were gastropleural and esophagopulmonary fistulae. The most common etiologies were iatrogenic and esophageal cancer, and the least common was blunt chest trauma. The main presentations were fever, chocking after or during meals, and tachycardia. We used various modalities of treatment: conservative, cervical repair, thoracoabdominal repair, hybrid insertion of a T-tube, endoscopic esophageal stenting, and endoscopic clipping of the fistulous tract. During follow-up, 6 patients died due to advanced esophageal cancer in 5 and upper airway obstruction after iatrogenic tracheobronchial fistula in one. Conclusion Acquired aerodigestive fistula is a devastating condition that should be managed early and aggressively by a multidisciplinary team. PMID- 29392976 TI - Epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction. AB - Benign prostatic hyperplasia (BPH) is very common in aging men and causes lower urinary tract symptoms (LUTS), which decrease health-related quality of life. A number of evidence suggests that other than ageing, modifiable factors, such as increasing prostate volume, obesity, diet, dyslipidemia, hormonal imbalance, hypertension, metabolic syndrome, alcohol, and smoking, also contribute to the development of BPH and/or LUTS. More recently, erectile dysfunction (ED) has been linked to LUTS/BPH as a part of this syndrome, suggesting that patients with BPH or LUTS easily develop ED, and that LUTS/BPH symptoms often coexist with ED. This article focuses on the epidemiology and risk factors of the combined phenotype LUTS/BPH - ED. PMID- 29392978 TI - Safety margin after radiofrequency ablation of hepatocellular carcinoma: precise assessment with a three-dimensional reconstruction technique using CT imaging. AB - PURPOSE: To analyse the precise ablative margin (AM) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and the correlation between AM and local tumour progression (LTP) with a three-dimension (3D) reconstruction technique. METHODS: From March 2011 to May 2013, 134 patients who underwent RFA for 159 primary or recurrent HCCs within Milan criteria were enrolled. Contrast enhanced computed tomography (CECT) scans were performed 1 week before and 1 month after treatment. The AM was measured in various directions using a 3D reconstruction technique that shows the index tumour and ablated zone on the same image. The average of all obtained AMs (average AM) and the smallest AM (min-AM) were calculated. RESULTS: The min-AM after RFA ranged from 1 to 9.3 mm (median +/ standard deviation, 4.8 +/- 1.8 mm). LTP was observed in 19 tumours from 19 patients. The median min-AM was 3.1 +/- 1.6 mm for patients with LTP, while the median min-AM of patients without LTP was 5.1 +/- 1.8 mm (p = 0.023). After RFA, the 1-, 2- and 3-year LTP rates were 10.9, 25.9 and 35.1%, respectively, for patients with min-AM <5 mm, and 4.1, 4.1 and 4.1%, respectively, for patients with min-AM >=5 mm (p = 0.016). Multivariate analysis showed that only min-AM <5 mm was an independent risk factor for LTP after RFA (p = 0.044, hazard ratio =4.587, 95% confidence interval, 1.045-22.296). CONCLUSIONS: The 3D reconstruction technique is a precise method for evaluating the post-ablation margin. Patients with min-AM less than 5 mm had a higher probability of developing LTP. PMID- 29392977 TI - Assessment of association between lipoxygenase genes variants in elderly Greek population and type 2 diabetes mellitus. AB - BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of diabetes and its complications. Arachidonic acid lipoxygenases have been intensively studied in their role in inflammation in metabolic pathways. Thus, we aimed to explore variants of lipoxygenase genes (arachidonate lipoxygenase genes) in a diabetes adult population using a case-control study design. METHODS: Study population consisted of 1285 elderly participants, 716 of whom had type 2 diabetes mellitus. The control group consisted of non-diabetes individuals with no history of diabetes history and with a glycated haemoglobin <6.5% (<48 mmol/mol)] and fasting plasma glucose levels <126 mg/dL. Blood samples were genotyped on Illumina Infinium PsychArray. Variants of ALOX5, ALOX5AP, ALOX12, ALOX15 were selected. All statistical analyses were undertaken within PLINK and SPSS packages utilising permutation analysis tests. RESULTS: Our findings showed an association of rs9669952 (odds ratio = 0.738, p = 0.013) and rs1132340 (odds ratio = 0.652, p = 0.008) in ALOX5AP and rs11239524 in ALOX5 gene with disease (odds ratio = 0.808, p = 0.038). Rs9315029 which is located near arachidonate ALOX5AP also associated with type 2 diabetes mellitus ( p = 0.025). No variant of ALOX12 and ALOX15 genes associated with disease. CONCLUSION: These results indicate a potential protective role of ALOX5AP and 5-arachidonate lipoxygenase gene in diabetes pathogenesis, indicating further the importance of the relationship between diabetes and inflammation. Larger population studies are required to replicate our findings. PMID- 29392979 TI - Characterization of acetylated histidine b1-ion structure: A competition between oxazolone and side chain imidazole moiety. AB - The detection of post-translational modifications of proteins is an important comprehensive research area. Over the years, proteomic studies involving protein acetylation have attracted a great deal of attention. In the present study, we have focussed on the acetylation of histidine and the intrinsic stability of b1 ion of oxazolone ring and/or with side chain imidazole bicyclic product. The formation of oxazolone structure may occur when an amino moiety undergoes acetylation reaction and when it is present in the vicinity of the side chain imidazole moiety. Tryptic peptides generated from the proteins of Acenitobacter radioresistens MMC5-containing N-terminal histidine were explored in a standard proteomic workflow. Formation of [Formula: see text] ion with an oxazolone ring in these peptides has been supported by a tandem mass spectrometric study of a synthetic peptide and density functional theory calculations. The results obtained from this study have implications in understanding the fragmentation of the peptides generated in the proteomic workflows. PMID- 29392981 TI - The effects of energy concentration in roughage and allowance of concentrates on performance, health and energy efficiency of pluriparous dairy cows during early lactation. AB - The aim of this study was to investigate the effects of different energy supplies from roughage and concentrates on performance, health and energy efficiency during early lactation. For this purpose an experiment was conducted containing 64 pluriparous German Holstein cows from 3 weeks prepartum until 16 weeks postpartum. During dry period all cows received an equal dry cow ration. After calving, cows were assigned in a 2 * 2 factorial arrangement to one of four groups, receiving either a moderate (MR, 6.0 MJ NEL) or a high (HR, 6.4 MJ NEL) energy concentration in roughage and furthermore moderate (MC, 150 g/kg energy corrected milk (ECM)) or high amounts of concentrates (HC, 250 g/kg ECM) on dry matter (DM) basis, which were allocated from an automatic feeding system. Higher allocation of concentrates resulted in an increase of DM intake at expense of roughage intake. HC cows had a higher milk yield than MC cows, whereas ECM was higher in HR cows due to a decrease of milk fat yield in MR groups. Energy balance and body condition score were elevated in HC cows, but no differences occurred in development of subclinical ketosis. Furthermore, energy efficiency variables were lower in HC groups because the greater energy intake was not associated with a considerable elevation of milk yield. Consistency of faeces did not indicate digestive disorders in any of the treatment groups although the faecal manure score was significantly lower in HR groups. Our results underline the importance of a high energy uptake from roughage, which can contribute to an adequate performance and beneficial efficiency, especially at lower amounts of concentrates in ration. Feeding concentrates on an average amount of 9.4 kg/d compared to 6.4 kg/d on DM basis improved the energy balance in our trial, but without consequences for metabolic blood variables and general health of the cows. PMID- 29392983 TI - Efficiency of nitrogen and phosphorus compounds removal in hydroponic wastewater treatment plant. AB - Wastewater treatment with the use of plants is one of the most promising treatment technologies for municipal, domestic and industrial wastewater. The aim of this study was to evaluate the reduction of biogenic compounds concentrations in municipal wastewater treated with the use of hydroponic technology as a tertiary treatment. Research was conducted to assess the suitability of hydroponic lagoon use for municipal wastewater treatment. Samples of sewage for its quality tests were taken from a wastewater treatment plant (WWTP) located in the south-western part of Poland. Average efficiencies of nutrients removal were calculated. Analyses show that the effectiveness of purification is similar for systems with and without the use of the third stage of purification and reached around 82-83% for total nitrogen and 77-79% for ammonium nitrogen. N-NO2 and N NO3 removal efficiency was very low for both analysed systems where for total phosphorus and phosphates it oscillated around 83-84%. PMID- 29392982 TI - Left in limbo - Experiences and needs among postmenopausal women newly diagnosed with osteoporosis without preceding osteoporotic fractures: A qualitative study. AB - Introduction Despite the fact that the first osteoporotic fracture is preventable, osteoporosis is still a major health challenge. The disease is highly prevalent among postmenopausal women. However little is known about how to meet and support women, when they are diagnosed with osteoporosis without preceding fractures. Therefore this study aims at gaining a deeper understanding of how women experience being diagnosed. Furthermore to describe and identify their needs, which should be met in future healthcare services. Methods We conducted a phenomenological qualitative study. We included 17 women aged 52-65 and collected data through semi-structured interviews. We analysed data following Giorgi's methodology. Findings Needs among the women were classified into three main themes: (1) needs of targeted and tailored information about osteoporosis, (2) needs of being prepared for GP visit to participate in treatment decision making and (3) needs of being able to take care of bone health. Conclusion and implications In general the women experienced as been left 'in limbo', and they requested targeted and tailored information about osteoporosis. In particular, they want information about dual-energy X-ray absorptiometry (DXA) scan results and treatment options in advance of the GP visit. This will help them in being prepared and able to participate in treatment decisions. They ask for support in self-management of the disease with less focus on disease and risk of fracture. Instead, they demand more attention on the benefits of detecting early stage osteoporosis. The study highlights the call for new approaches to postmenopausal women newly diagnosed with osteoporosis without preceding fractures. PMID- 29392984 TI - ECAS score: a web-based risk model to predict moderate and severe extracranial carotid artery stenosis. AB - Background and purpose To develop and validate a risk model (Extracranial Carotid Artery Stenosis score, ECAS score) to predict moderate and severe ECAS. Furthermore, we compared discrimination of the ECAS score and three existing models with regard to both moderate and severe ECAS. Methods The ECAS score was developed based on the Renqiu Stroke Screening Study (RSSS), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. ECAS was diagnosed by carotid duplex ultrasound according to the published criteria. Independent predictors of moderate (>=50%) and severe (>=70%) ECAS were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow test were used to assess model discrimination and calibration. Results A total of 5010 participants were included and the mean age was 64.3. The proportion of ECAS of < 50%, 50-69%, 70-99% and occlusion was 4.4, 0.5, 0.4, and 0.4%, respectively. The ECAS score was developed from sets of predictors of moderate and severe ECAS. The ECAS score demonstrated good discrimination in the derivation and validation cohorts (AUROC range: 0.785-0.846). The Hosmer-Lemeshow tests of ECAS score for moderate and severe ECAS were not significant in the derivation and validation cohorts (all P > 0.05). When compared to the three existing models, the ECAS score showed significantly better discrimination for both moderate and severe ECAS (all P < 0.001). Conclusion The ECAS score is a valid model for predicting moderate and severe ECAS. Further validation of the ECAS score in different populations and larger samples is warranted. PMID- 29392985 TI - ? PMID- 29392987 TI - ? PMID- 29392986 TI - ? PMID- 29392988 TI - ? PMID- 29392990 TI - ? PMID- 29392991 TI - Can we look past people's race? The effect of combining race and a non-racial group affiliation on holistic processing. AB - Face memory is worse for races other than one's own, in part because other-race faces are less holistically processed. Both experiential factors and social factors have been suggested as reasons for this other-race effect. Direct measures of holistic processing for race and a non-racial category in faces have never been employed, making it difficult to establish how experience and group membership interact. This study is the first to directly explore holistic processing of own-race and other-race faces, also classed by a non-racial category (university affiliation). Using a crossover design, White undergraduates (in Australia) completed the part-whole task for White (American) and Black South African faces attributed to the University of Western Sydney (own) and University of Sydney (other). Black South African undergraduates completed the same task for White and Black South African faces attributed to the University of Cape Town (own) and Stellenbosch University (other). It was hypothesised that own-race faces would be processed more holistically than other-race faces and that own university faces would be processed more holistically than other-university faces. Results showed a significant effect of race for White participants (White faces were matched more accurately than Black faces), and wholes were matched more accurately than parts, suggesting holistic processing, but only for White faces. No effect of university was found. Black South African participants, who have more experience with other-race faces, processed wholes better than parts irrespective of race and university category. Overall, results suggest that experiential factors of race outweigh any effects of a non-racial shared group membership. The quality of experience for the named populations, stimuli presentation, and degree of individuation are discussed. PMID- 29392992 TI - Immunisation rates among children in Nuuk. AB - : The children immunisation programme in Greenland correlates to the one in Denmark with the addition of the Bacille Calmette-Guerin (BCG)-vaccine and the immunisation against Hepatitis B (HBV). The immunisation rate among children in Greenland has been and is currently unknown and this study aims to estimate the immunisation rates among children in Nuuk from 1 July 2015 until 30 June 2016. We did an observational cross-sectional study based on a statistical extraction identifying all children in Nuuk eligible for an immunization in the children immunisation programme from 1 July 2015 until 30 June 2016 and a review of their medical records. We found acceptable coverage rates among children younger than 12 months, but coverage rates lower than recommended by the World Health Organization (WHO) among older children. Among children between 15 months and 4 years the coverage dropped as low as 33.9 %. Increased awareness of child immunisation rates is suggested including continuously monitoring and adjusting of the organisation of the immunisation programme. ABBREVIATIONS: Bacille Calmette-Guerin immunisation (BCG); Chief Medical Officer (CMO); Diphtheria, Tetanus, Pertussis, Polio, Haemophilus influenza B, Pneumococcal (DTP); Electronic medical report (EMR); Hepatitis B (HBV); Human Papilloma Virus (HPV); Measles, Mumps, Rubella (MMR); World Health Organization (WHO). PMID- 29392993 TI - The Effects of Emotional Visual Context on the Encoding and Retrieval of Body Odor Information. AB - Conditions during information encoding and retrieval are known to influence the sensory material stored and its recapitulation. However, little is known about such processes in olfaction. Here, we capitalized on the uniqueness of body odors (BOs) which, similar to fingerprints, allow for the identification of a specific person, by associating their presentation to a negative or a neutral emotional context. One hundred twenty-five receivers (68 F) were exposed to a male BO while watching either criminal or neutral videos (encoding phase) and were subsequently asked to recognize the target BO within either a congruent or an incongruent visual context (retrieval phase). The results showed that criminal videos were rated as more vivid, unpleasant, and arousing than neutral videos both at encoding and retrieval. Moreover, in terms of BO ratings, we found that odor intensity and arousal allow to distinguish the target from the foils when congruent criminal information is presented at encoding and retrieval. Finally, the accuracy performance was not significantly different from chance level for either condition. These findings provide insights on how olfactory memories are processed in emotional situations. PMID- 29392994 TI - Understanding Health Behavior in Context. PMID- 29392995 TI - Leishmania major cutaneous leishmaniasis outbreak in the Jordanian side of the Northern Jordan Valley. AB - Cutaneous leishmaniasis (CL) is endemic in many foci of Jordan and the Jordanian Mid Jordan Valley (JMJV) is the most affected and the incidence is quite high. The situation in the northern part of the Jordanian side of the Jordan Valley (NJJV) was different; before 2008, CL has rarely been reported from this area. From April 2008 to May 2009, passive detection followed by active detection was used to trace cases of CL from the NJJV. DNA was extracted from seven clinical isolates of Leishmania promastigotes and lesion scrapings spotted on filter papers obtained from 51 suspected CL patients living in the NJJV. The identity of the causative species of CL in the NJJV was investigated using ITS1-PCR followed by RFLP. In 2008/2009, 183 cases were clinically diagnosed of having CL in the NJJV. The parasites in five of the isolates and in 48 PCR-positive scrapings were classified as Leishmania major. In two isolates and in one PCR-positive scraping Leishmania tropica was identified. Investigations on the origin of CL cases revealed that the L. tropica cases were residents of two towns outside the NJJV. Herein, we report the clinical features, parasitological diagnosis, etiology, and the geographical distribution of CL cases from NJJV with the aim of documenting, for the first time, an outbreak in this area. PMID- 29392996 TI - The influence of different curriculum designs on students' dropout rate: a case study. AB - The relationship between students' withdrawal and educational variables has generated a considerable number of publications. As the explosion of information in sciences and integration theories led to creating different curriculum designs, it has been assumed that differences among designs explain academic success and, therefore, students' retention. However, little attention has been given to examine explicitly how diverse designs influence dropout rates in practice, which questions if decisions to reform curricula are sufficiently informed. This article describes our curriculum reform, which exposes our former and current curriculum designs as having had dissimilar dropout percentages. Furthermore, we aimed to explore the influence of different curriculum designs on students' dropout rates. The conclusion is that dropout variations may be explained not only because of the curriculum design itself, but also because of the power relationship changes between teachers and students that brought out the design change. Consequently, more research is needed to fully understand the political implications of different curriculum designs and their influence on dropout rates. PMID- 29392997 TI - Relative age effects in Swiss talent development - a nationwide analysis of all sports. AB - Relative age effects (RAE) generate consistent participation inequalities and selection biases in sports. The study aimed to investigate RAE across all sports of the national Swiss talent development programme (STDP). In this study, 18 859 youth athletes (female N = 5353; mean age: 14.8 +/- 2.5 y and male N = 13 506; mean age: 14.4 +/- 2.4 y) in 70 sports who participated in the 2014 competitive season were evaluated. The sample was subdivided by sex and the national level selection (NLS, N = 2464). Odds ratios (ORs) of relative age quarters (Q1-Q4) and 95% confidence intervals (CI) were calculated. In STDP, small RAE were evident for females (OR 1.35 (95%-CI 1.24, 1.47)) and males (OR 1.84 (95%-CI 1.74, 1.95)). RAE were similar in female NLS athletes (OR 1.30 (95%-CI 1.08, 1.57)) and larger in male NLS athletes (OR 2.40 (95%-CI 1.42, 1.97)) compared to athletes in the lower selection level. In STDP, RAE are evident for both sexes in several sports with popular sports showing higher RAE. RAE were larger in males than females. A higher selection level showed higher RAE only for males. In Switzerland, talent identification and development should be considered as a long term process. PMID- 29392999 TI - Correlation of Palliative Performance Scale and Survival in Patients With Cancer Receiving Home-Based Palliative Care. AB - The main objective of this study was to examine whether and how the Palliative Performance Scale (PPS), a measure of a patient's function, was predictive of survival time for those in receipt of home-based palliative care. This was a prospective study, which included 194 cancer patients from November 17, 2013, to August 18, 2015. Data were collected from biweekly telephone interviews with caregivers. Kaplan-Meier survival curves were estimated to assess how survival time was correlated with initial PPS scores after admission to the home-based palliative care program. A multivariate extended Cox regression model was used to examine the association between PPS and survival. The results showed that patients with higher PPS scores, that is, better function, had a lower hazard ratio (0.977; 95% confidence interval: 0.965-0.989) and hence longer survival times. The PPS can be used in predicting survival time for home-based palliative care patients. PMID- 29393000 TI - Measuring diagnostic accuracy for biomarkers under tree-ordering. AB - In the field of diagnostic studies for tree or umbrella ordering, under which the marker measurement for one class is lower or higher than those for the rest unordered classes, there exist a few diagnostic measures such as the naive AUC ( NAUC), the umbrella volume ( UV), and the recently proposed TAUC, i.e. area under a ROC curve for tree or umbrella ordering (TROC). However, an important characteristic about tree or umbrella ordering has been neglected. This paper mainly focuses on promoting the use of the integrated false negative rate under tree ordering ( ITFNR) as an additional diagnostic measure besides TAUC, and proposing the idea of using ( TAUC, ITFNR) instead of TAUC to evaluate the diagnostic accuracy of a biomarker under tree or umbrella ordering. Parametric and non-parametric approaches for constructing joint confidence region of ( TAUC, ITFNR) are proposed. Simulation studies under a variety of settings are carried out to assess and compare the performance of these methods. In the end, a published microarray data set is analyzed. PMID- 29393001 TI - A combined computational/experimental study on HSA binding of two water-soluble Schiff base ligands derived from pyridine derivative and ethylendiamine. PMID- 29393002 TI - The effect of the diameter of cyclic peptide nanotube on its chirality discrimination. AB - In this work, the transport behaviors of the enantiomers of lactic acid (LA) in two cyclic peptide nanotubes (CPNTs) with different diameters were studied using steered molecular dynamic (SMD) simulation to investigate the effect of the diameter of CPNT on the discrimination of the enantiomers of LA. For this purpose, two cyclic peptides with two different sizes ([Ala-D-Ala-L]5 and [Ala-D Ala-L]4) were used for constructing two CPNTs so that each CPNT was composed of eight cyclic peptide units. The docking calculations were performed to obtain the appropriate position of each enantiomer at the lumen of each CPNT. The variation of the pulling force versus time, exerted on the enantiomers moving in the CPNTs was calculated using the SMD simulations with two different strategies (positional and directional).The obtained results showed that the diameter of CPNT has considerable effect on the discrimination of the LA enantiomers so that the increase of the diameter of CPNT, increased the velocity difference between two enantiomers and improved the performance of CPNT for the chirality discrimination. The SMD simulations indicated that the velocity of S-enantiomer became more than R-enantiomer and its motion became more comfortable than R enantiomer when the diameter of CNPT increased. The RDFs of the H and O atoms of the LA enantiomers relative to the O atoms of CPNT were calculated and it was found that the increase of the diameter of CPNT creates the significant changes in the RDFs of H1, H2 and H3 atoms of the enantiomers. PMID- 29393003 TI - The role of fresh frozen plasma in reducing the volume of anti-snake venom in snakebite envenomation. AB - Snakebite associated with a venom-induced consumption coagulopathy (VICC) is a major public health problem. Our study aims to evaluate if fresh frozen plasma (FFP), administered after anti-snake venom (ASV), restores coagulability rapidly. At admission, all snakebite victims with a whole blood clotting time (WBCT) >20 min received ten vials of ASV according to World Health Organization criteria. After 6 h, at the discretion of the physician, patients with WBCT >20 min were divided into two groups. The test group received both ASV and FFP and the control group received ASV only. The mean number of ASVs used in tests and controls were 17 and 31, respectively. The clotting time normalised at 24 h and 42 h in the test group and control group, respectively. FFP appears to aid restoration of clotting factors more rapidly and thus haemorrhage and the number of anti-snake venom vials used are both reduced. PMID- 29393004 TI - Impact of home remediation and household education on indoor air quality, respiratory visits and symptoms in Alaska Native children. AB - Alaska Native children experience high rates of lower respiratory tract infections (LRTIs) and lung conditions, which are associated with substandard indoor air quality (IAQ). We conducted an intervention of home remediation and education to assess the impact on IAQ, respiratory symptoms and LRTI visits. We enrolled households of children 1-12 years of age with lung conditions. Home remediation included improving ventilation and replacing leaky woodstoves. We provided education about IAQ and respiratory health. We monitored indoor airborne particles (PM2.5), CO2, relative humidity and volatile organic compounds (VOCs), and interviewed caregivers about children's symptoms before, and for 1 year after intervention. We evaluated the association between children's respiratory visits, symptoms and IAQ indicators using multiple logistic regression. A total of 60 of 63 homes completed the study. VOCs decreased (coefficient = -0.20; p < 0.001); however, PM2.5 (coeff. = -0.010; p = 0.89) did not decrease. Burning wood for heat, VOCs and PM2.5 were associated with respiratory symptoms. After remediation, parents reported decreases in runny nose, cough between colds, wet cough, wheezing with colds, wheezing between colds and school absences. Children had an age-adjusted decrease in LRTI visits (coefficient = -0.33; p = 0.028). Home remediation and education reduced respiratory symptoms, LRTI visits and school absenteeism in children with lung conditions. PMID- 29393005 TI - Movement and Motion of Soybean Cyst Nematode Heterodera glycines Populations and Individuals in Response to Abamectin. AB - Two new in vitro methods were developed to analyze plant-parasitic nematode behavior, at the population and the individual organism levels, through time lapse image analysis. The first method employed a high-resolution flatbed scanner to monitor the movement of a population of nematodes over a 24-h period at 25 degrees C. The second method tracked multiple motion parameters of individual nematodes on a microscopic scale, using a high-speed camera. Changes in movement and motion of second-stage juveniles (J2) of the soybean cyst nematode Heterodera glycines Ichinohe were measured after exposure to a serial dilution of abamectin (0.1 to 100 MUg/ml). Movement and motion of H. glycines were significantly reduced as the concentration of abamectin increased. The effective range of abamectin to inhibit movement and motion of H. glycines J2 was between 1.0 and 10 MUg/ml. Proof-of-concept experiments for both methods produced one of the first in vitro sensitivity studies of H. glycines to abamectin. The two methods developed allow for higher-throughput analysis of nematode movement and motion and provide objective and data-rich measurements that are difficult to achieve from conventional microscopic laboratory methods. PMID- 29393006 TI - Risk behaviors for sexually transmitted infections in noninjecting drug users: A cross-sectional study. AB - The objective of this study was to investigate risk behaviors for sexually transmitted infections (STIs) in noninjecting drug users (NIDUs), using STI diagnosis history as an indicator. A cross-sectional study was conducted in 323 NIDUs of two facilities for alcohol and/or drug dependence treatment in the Goias State, Central Brazil. All participants were interviewed about risk behaviors and STI history. Multivariable analysis was performed in order to identify predictors of STIs. Adjusted prevalence ratio (APR) with confidence intervals of 95% was obtained using a Poisson regression model. Prevalence of self-reported STIs in the previous 12 months was 25.4% (95% confidence interval [95% CI]: 21.0-30.4%). A multivariable model verified that age (APR: 1.01; 95% CI: 1.00-1.01), sexual contact with partners diagnosed with STIs (APR: 1.27; 95% CI: 1.12-1.45) and injecting drug users (IDUs) (APR: 1.14; 95% CI: 1.14; 95% CI: 1.01-1.31), exchange sex for money and/or drugs (APR: 1.12; 95% CI: 1.02-1.21), and a history of sexual violence (APR: 1.04; 95% CI: 1.04-1.32) were predictors of STIs. Elevated rates of STI history and risk behaviors were observed in NIDUs, supporting the vulnerability of this group for these infections. Public policies and health outreach should be intensified in this population, principally regular STI testing of individuals in treatment for drug dependence and their sexual partners. PMID- 29393007 TI - Systematic review of the prevalence of psychiatric illness and sleep disturbance as co-morbidities of HIV infection in the UK. AB - Psychiatric illness and sleeping disorders are important co-morbidities of human immunodeficiency virus (HIV) infection, which impact both the individual and antiretroviral therapy (ART) selection. This systematic review aimed to assess the prevalence of psychiatric illness and sleep disturbance in people living with HIV (PLHIV) in the UK. Systematic searches for publications reporting epidemiological data for psychiatric co-morbidities and sleep disturbance with HIV were conducted in Embase, MEDLINE, Cochrane Library, eight key conferences (2013-2015), and by hand-searching references of included publications. Data were extracted from publications (2000 onwards) reporting the UK prevalence of depression, anxiety, suicide ideation, or sleep disturbance as a co-morbidity of HIV infection. Comparative UK general population data were obtained from the 2007 Adult Psychiatric Morbidity in England household survey, the 2012 Health Survey for England, and 'PatientBase' (epidemiological database). Sixteen publications met the inclusion criteria. Amongst PLHIV in the UK, the prevalence of depression varied from 17-47%, compared with a reported 2-5% prevalence for the UK general population. A similar disparity was observed in the prevalence of anxiety (22-49% PLHIV versus 4-5% general population), depression or anxiety (50-58% PLHIV versus 27% general population), difficulty sleeping (61% PLHIV versus 10% population), and suicide ideation (31% PLHIV versus 1% general population). This systematic review of UK data demonstrates that rates of psychiatric illness and sleep disturbance are substantially higher amongst PLHIV than in the general population. These data underline the importance of fully considering sleep and psychiatric issues prior to selection and prescription of antiretroviral drugs, as well as the need for ongoing psychiatric and psychological support for PLHIV on ART. PMID- 29393008 TI - Intravenous metronidazole, liquid tinidazole, and intra-vaginal boric acid to cure trichomonas in a patient with gastric bypass surgery. AB - This study presents a case report of a female patient with symptomatic refractory Trichomonas vaginalis infection who was not able to clear her infection with high dose oral metronidazole, oral tinidazole, intra-vaginal zinc sulfate, intra vaginal metronidazole, intra-vaginal tinidazole, and intra-vaginal boric acid. She was unable to tolerate intra-vaginal paromomycin. A combination of intravenous metronidazole, oral tinidazole liquid suspension, and intra-vaginal boric acid for 14 days subsequently achieved a complete symptomatic and laboratory cure. PMID- 29393009 TI - Use of in vitro and haptic assessments in the characterisation of surface lubricity. AB - Lubricity is a key property of hydrophilic-coated urinary catheter surfaces. In vitro tests are commonly employed for evaluation of surface properties in the development of novel catheter coating technologies; however, their value in predicting the more subjective feeling of lubricity requires validation. We herein perform a range of in vitro assessments and human organoleptic studies to characterise surface properties of developmental hydrophilic coating formulations, including water wettability, coefficient of friction, dry-out kinetics and lubricity. Significant reductions of up to 40% in the contact angles and coefficient of friction values of the novel coating formulations in comparison with the control poly(vinylpyrrolidone)-coated surfaces were demonstrated during quantitative laboratory assessments. In contrast, no significant differences in the more subjective feeling of lubricity between the novel formulations and the control-coated surfaces were observed when formulations were haptically assessed by the techniques described herein. This study, importantly, highlights the need for optimisation of in vitro and human haptic assessments to more reliably predict patient preferences. PMID- 29393010 TI - Comparison of rigid and semi-rigid instrumentation under acute load on vertebrae treated with posterior lumbar interbody fusion/transforaminal lumbar interbody fusion procedures: An experimental study. AB - Rigid and semi-rigid fixations are investigated several times in order to compare their biomechanical stability. Interbody fusion techniques are also preferable for maintaining the sagittal balance by protecting the disk height. In this study, the biomechanical comparison of semi-rigid and rigid fixations with posterior lumbar interbody fusion or transforaminal lumbar interbody fusion procedures is conducted under trauma. There were four different test groups to analyze the effect of acute load on treated ovine vertebrae. First and second groups were fixed with polyetheretherketone rods and transforaminal lumbar interbody fusion and posterior lumbar interbody fusion cages, respectively. Third and fourth groups were fixed with titanium rods and posterior lumbar interbody fusion and transforaminal lumbar interbody fusion cages, respectively. The drop tests were conducted with 7 kg weight. There were six samples in each group so the drop test repeated 24 times in total. The test samples were photographed and X-rayed (laterally and anteroposteriorly) before and after drop test. Two fractures were observed on group 1. Conversely, there were no fractures observed for group 2. There were no anterior element fractures for both groups 1 and 2. However, one fracture seen on group 3 was anterior element fracture, whereas the other three were posterior element fractures. All three fractures were anterior element fractures for group 4. Treated vertebrae with polyetheretherketone rods and posterior lumbar interbody fusion cages showed the best durability to the drop tests among the groups. Semi-rigid fixation gave better results than rigid fixation according to failed segments. Posterior lumbar interbody fusion cages seem to be better option for semi-rigid fixation, however mentioned surgical disadvantages must be considered. PMID- 29393011 TI - Investigation of toggling effect on pullout performance of pedicle screws. AB - Objective of this study is to assess the pullout performance of various pedicle screws in different test materials after toggling tests comparatively. Solid core, cannulated (cemented), novel expandable and solid-core (cemented) pedicle screws were instrumented to the polyurethane foams (Grade 10 and Grade 40) produced in laboratory and bovine vertebra. ASTM F543 standard was used for preparation process of samples. Toggling tests were carried out. After toggling test procedures, pullout tests were performed. Load versus displacement graph was recorded, and the ultimate pullout force was defined as the maximum load (pullout strength) sustained before failure of screw. Anteriosuperior and oblique radiographs were taken from each sample after instrumentation in order to examine screw placement and cement distribution. The pullout strength of pedicle screws decreased after toggling tests with respect to the initial condition. While the cemented solid-core pedicle screws had the highest pullout strength in all test materials, they had the highest strength differences. The cemented solid-core pedicle screws had decrement rates of 27% and 16% in Grade 10 and Grade 40, respectively. There are almost same decrement rate (between 5.5% and 6.5%) for all types of pedicle screws instrumented to the samples of bovine vertebra. The pullout strengths of novel expandable pedicle screws in both of early period and after toggling conditions were almost similar, in other words, the decrement rates of it were lower than other types. According to the data collected from this study, polymethylmethacrylate augmentation significantly decreases pullout strength following the toggling loads. Higher brittleness of cured polymethylmethacrylate has adverse effect on the pullout strength. Although augmentation is an important process for enhancing pullout strength in early period, it has some disadvantages for preserving stabilization in a long time. Expandable pedicle screw with polyetheretherketone shell may be good alternative to polymethylmethacrylate augmentation on both primer stabilization and long-term loading application with toggling. PMID- 29393012 TI - Short stature is associated with the development of lower limb ischaemia during extracorporeal life support. AB - BACKGROUND: Percutaneous cannulation of femoral vessels has been widely used for the rapid deployment of extracorporeal life support (ECLS). Limb ischaemia is a devastating complication in patients receiving ECLS. Our aim was to evaluate the predictors of limb ischaemia during ECLS and to determine the role of preventative distal perfusion. METHODS: Two hundred and fifty-five consecutive patients who received veno-arterial ECLS due to cardiac and/or respiratory failure were enrolled from January 2009 to December 2015. All patients received ECLS for more than 6 hours and the data was reviewed retrospectively. Distal perfusion to minimise lower limb ischaemia was performed at the discretion of the physician. Predictors for lower limb ischaemia during ECLS were analysed using multivariate regression analysis. RESULTS: For the 255 patients, the mean age was 58 and 177 (69.4%) were male. Limb ischaemia developed in 24 patients (9.4%); 178 patients (69.8%) died within 30 days. Among the 24 patients, one patient (4.2%) developed limb ischaemia with preventative distal perfusion. Fourteen patients (58.3%) received therapeutic distal perfusion. After distal perfusion, two patients (8.3%) still required surgical intervention. Limb ischaemia was more frequent in female patients (54.2% in the ischaemia group versus 28.1% in the non ischaemia group, p=0.008) and shorter patients (162.0 +/- 9.5 cm in the ischaemia group versus 166.3 +/- 9.1 cm in the non-ischaemia group, p=0.027). Patients shorter than 165 cm were more commonly diagnosed with ischaemia compared to those who were taller than 165 cm (79.2% versus 40.7%, p<0.001). In a multivariate regression analysis, height under 165 cm was the only predictor for limb ischaemia (Odds ratio (OR) [95% confidence interval (CI)] = 12.645 [3.190 50.118]). CONCLUSION: Smaller female patients are more prone to developing limb ischaemia from femoral ECLS. Our findings might support preventative distal perfusion and more careful observation of these patients. PMID- 29393013 TI - [Can we not do without oxygen administration through a nasal cannula?] AB - Nasal cannulae for oxygen administration are applied abundantly in clinical medicine, even though their use may cause patient discomfort. Although nasal cannulae may be effective in increasing oxygen uptake to some degree, they are unlikely to prevent severe hypoxaemia. Furthermore, they are often used when arterial oxygen saturation is already >= 90%, in which case additional oxygenation is usually not required, nor does it relieve the sensation of dyspnoea. PMID- 29393014 TI - [Significance of p-values: misinterpreted and overrated]. AB - - An often provided interpretation of a significant p-value (p < 0.05) is that 'the probability the conclusion is incorrect, is only 5%'. This interpretation is incorrect.- It can be shown that for observational studies, in case of p < 0.05, the probability of a false positive signal is around 50%. This means that significant p-values give us much less certainty about the reliability of a conclusion than we like to believe.- Much would be gained already if the emphasis on p-values would be replaced by: (a) an estimation of the effect size in combination with the corresponding statistical uncertainty (represented by the confidence interval), (b) an assessment of the clinical relevance of that effect, and PMID- 29393015 TI - [Weak respiratory muscles as a first sign of ALS: symptoms may put the physician on the wrong track]. AB - BACKGROUND: Patients with decreased exercise tolerance and orthopnoea are often referred to an internist, a cardiologist or a pulmonologist. These symptoms can also be caused by weakness of the respiratory muscles, as an indication of a neuromuscular disease. If these symptoms are not recognized as such, this may result in a delay in timely diagnosis. CASE DESCRIPTION: An 82-year-old man had suffered from decreased exercise tolerance for 18 months. For the last months he had been sleeping upright and had lost 20 kg in weight. Analyses by the cardiologist and the internist had not led to a definitive diagnosis. He was finally brought to the emergency department with loss of consciousness and hypercapnic respiratory insufficiency. Neurological examination was suggestive of motor neuron disease such as progressive spinal muscular atrophy or amyotrophic lateral sclerosis. The patient died within 24 hours of admission. CONCLUSION: Patients with symptoms resulting from respiratory muscle weakness are commonly referred to non-neurological specialists, leading to a delay in diagnosis and treatment of an underlying neuromuscular disease. PMID- 29393016 TI - Analysis of the Mycoplasma bovis lactate dehydrogenase reveals typical enzymatic activity despite the presence of an atypical catalytic site motif. AB - The lactate dehydrogenase (LDH) of Mycoplasma genitalium has been predicted to also act as a malate dehydrogenase (MDH), but there has been no experimental validation of this hypothesized dual function for any mollicute. Our analysis of the metabolite profile of Mycoplasma bovis using gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) detected malate, suggesting that there may be MDH activity in M. bovis. To investigate whether the putative l-LDH enzyme of M. bovis has a dual function (MDH and LDH), we performed bioinformatic and functional biochemical analyses. Although the amino acid sequence and predicted structural analysis of M. bovisl-LDH revealed unusual residues within the catalytic site, suggesting that it may have the flexibility to possess a dual function, our biochemical studies using recombinant M. bovis -LDH did not detect any MDH activity. However, we did show that the enzyme has typical LDH activity that could be inhibited by both MDH substrates oxaloacetate (OAA) and malate, suggesting that these substrates may be able to bind to M. bovis LDH. Inhibition of the conversion of pyruvate to lactate by OAA may be one method the mycoplasma cell uses to reduce the potential for accumulation of intracellular lactate. PMID- 29393017 TI - A novel mechanism of fluconazole: fungicidal activity through dose-dependent apoptotic responses in Candida albicans. AB - Fluconazole (FLC) is a well-known fungistatic agent that inhibits ergosterol biosynthesis. We showed that FLC exhibits dose-dependent fungicidal activity, and investigated the fungicidal mechanism of FLC on Candida albicans. To confirm the relationship between fungicidal activity and the inhibition of ergosterol, we assessed membrane dysfunctions via propidium iodide influx and potassium leakage, as well as morphological change. Interestingly, while membrane disruption was not observed at all tested concentrations of FLC, potassium efflux and cell shrinkage were observed at high dosages of FLC (HDF). Low-dosage FLC (LDF) treatment did not induce significant changes. Next, we examined whether the fungicidal activity of FLC was associated with apoptosis in C. albicans. FLC caused dose-dependent apoptotic responses, including phosphatidylserine externalization and DNA fragmentation. It was also involved in glutathione depletion followed by oxidative damage. In particular, unlike LDF, HDF leads to the disruption of mitochondrial homeostasis, including mitochondrial membrane depolarization and accumulation of calcium and reactive oxygen species. HDF-induced mitochondrial dysfunction promoted the release of cytochrome c from mitochondria to the cytosol, and activated intracellular metacaspase. In conclusion, the dose dependent fungicidal activity of FLC was due to an apoptotic response in C. albicans. PMID- 29393018 TI - Glucose can be transported and utilized in Escherichia coli by an altered or overproduced N-acetylglucosamine phosphotransferase system (PTS). AB - Escherichia coli Deltaglk DeltamanZ DeltaptsG glucose- strains that lack the glucose phosphotransferase system (PTS) and the mannose PTS as well as glucokinase have been widely used by researchers studying the PTS. In this study we show that both fast- and slow-growing spontaneous glucose+ revertants can be readily obtained from Deltaglk DeltamanZ DeltaptsG glucose- strains. All of the fast-growing revertants either altered the N-acetylglucosamine PTS or caused its overproduction by inactivating the NagC repressor protein, which regulates the N acetylglucosamine PTS, and these revertants could utilize either glucose or N acetylglucosamine as a sole carbon source. When a DeltanagE deletion, which abolishes the N-acetylglucosamine PTS, was introduced into the Deltaglk DeltamanZ DeltaptsG glucose- strains, fast-growing revertants could no longer be isolated. Based on our results and other studies, it is clear that the N-acetylglucosamine PTS is the most easily adaptable PTS for transporting and phosphorylating glucose, other than the glucose PTS and mannose PTS, which are the primary glucose transport systems. While the slow-growing glucose+revertants were not characterized, they were likely mutations that other researchers have observed before and affect other PTSs or sugar kinases. PMID- 29393019 TI - Increased productivity in poultry birds by sub-lethal dose of antibiotics is arbitrated by selective enrichment of gut microbiota, particularly short-chain fatty acid producers. AB - Antibiotics are widely used at sub-lethal concentrations as a feed supplement to enhance poultry productivity. To understand antibiotic-induced temporal changes in the structure and function of gut microbiota of chicken, two flocks were maintained for six weeks on a carbohydrate- and protein-rich diet. The feed in the conventional diet (CD) group was supplemented with sub-lethal doses of chlorotetracycline, virginiamycin and amoxicillin, while the organic diet (OD) had no such addition. Antibiotic-fed birds were more productive, with a lower feed conversion ratio (FCR). Their faecal samples also had higher total heterotrophic bacterial load and antibiotic resistance capability. Deep sequencing of 16S rDNA V1-V2 amplicons revealed Firmicutes as the most dominant phylum at all time points, with the predominant presence of Lactobacillales members in the OD group. The productivity indicator, i.e. higher Firmicutes:Bacteroidetes ratio, particularly in the late growth phase, was more marked in CD amplicon sequences, which was supported by culture-based enumerations on selective media. CD datasets also showed the prevalence of known butyrate-producing genera such as Faecalibacterium, Ruminococcus, Blautia, Coprococcus and Bacteroides, which correlates closely with their higher PICRUSt based in silico predicted 'glycan biosynthesis and metabolism'-related Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues. Semi-quantitative end-point PCR targeting of the butyryl-CoA: acetate CoA-transferase gene also confirmed butyrate producers as being late colonizers, particularly in antibiotic-fed birds in both the CD flocks and commercial rearing farms. Thus, antibiotics preferentially enrich bacterial populations, particularly short-chain fatty acid producers that can efficiently metabolize hitherto undigestable feed material such as glycans, thereby increasing the energy budget of the host and its productivity. PMID- 29393021 TI - Evaluation of the population heterogeneity of TBEV laboratory variants using high throughput sequencing. AB - We studied minor variants within two tick-borne encephalitis virus (TBEV) populations with a common ancestor: the mouse brain-adapted variant EK-328c and the tick-adapted variant M. High-throughput sequencing with custom amplicons from RT-PCR viral RNA was performed on Illumina MiSeq 2*250 paired-end v2 chemistry. Using the LowFreq program (default settings) and Sanger-sequenced consensus as a reference, variants with an abundance of 1 % and above within the studied populations were identified. Using the obtained data in the context of our previous studies, we concluded that TBEV variants, which are different from the major population phenotype and can become a major part of the viral population under favourable environmental conditions, can exist at abundances of less than 1 % in the long-term. The comparison of our data with the literature allowed us to conclude that the laboratory variant EK-328c and variant M have similar SNV counts to TBEV variants from natural populations and some fast-evolving RNA viruses. PMID- 29393020 TI - Analysis of essential gene dynamics under antibiotic stress in Streptococcus sanguinis. AB - The paradoxical response of Streptococcus sanguinis to drugs prescribed for dental and clinical practices has complicated treatment guidelines and raised the need for further investigation. We conducted a high throughput study on concomitant transcriptome and proteome dynamics in a time course to assess S. sanguinis behaviour under a sub-inhibitory concentration of ampicillin. Temporal changes at the transcriptome and proteome level were monitored to cover essential genes and proteins over a physiological map of intricate pathways. Our findings revealed that translation was the functional category in S. sanguinis that was most enriched in essential proteins. Moreover, essential proteins in this category demonstrated the greatest conservation across 2774 bacterial proteomes, in comparison to other essential functional categories like cell wall biosynthesis and energy production. In comparison to non-essential proteins, essential proteins were less likely to contain 'degradation-prone' amino acids at their N-terminal position, suggesting a longer half-life. Despite the ampicillin induced stress, the transcriptional up-regulation of amino acid-tRNA synthetases and proteomic elevation of amino acid biosynthesis enzymes favoured the enriched components of essential proteins revealing 'proteomic signatures' that can be used to bridge the genotype-phenotype gap of S. sanguinis under ampicillin stress. Furthermore, we identified a significant correlation between the levels of mRNA and protein for essential genes and detected essential protein-enriched pathways differentially regulated through a persistent stress response pattern at late time points. We propose that the current findings will help characterize a bacterial model to study the dynamics of essential genes and proteins under clinically relevant stress conditions. PMID- 29393022 TI - The use of novel epitope-tagged arenaviruses reveals that Rab5c-positive endosomal membranes are targeted by the LCMV matrix protein. AB - We report the development of recombinant New World (Junin; JUNV) and Old World (lymphocytic choriomeningitis virus; LCMV) mammarenaviruses that encode an HA tagged matrix protein (Z). These viruses permit the robust affinity purification of Z from infected cells or virions, as well as the detection of Z by immunofluorescent microscopy. Importantly, the HA-tagged viruses grow with wild type kinetics in a multi-cycle growth assay. Using these viruses, we report a novel description of JUNV Z localization in infected cells, as well as the first description of colocalization between LCMV Z and the GTPase Rab5c. This latter result, when combined with our previous findings that LCMV genome and glycoprotein also colocalize with Rab5c, suggest that LCMV may target Rab5c positive membranes for preassembly of virus particles prior to budding. The recombinant viruses reported here will provide the field with new tools to better study Z protein functionality and identify key Z protein interactions with host machinery. PMID- 29393024 TI - Axitinib, cabozantinib, everolimus, nivolumab, sunitinib and best supportive care in previously treated renal cell carcinoma: a systematic review and economic evaluation. AB - BACKGROUND: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta(r), Pfizer Inc., NY, USA), cabozantinib (Cabometyx(r), Ipsen, Slough, UK), everolimus (Afinitor(r), Novartis, Basel, Switzerland), nivolumab (Opdivo(r), Bristol-Myers Squibb, NY, USA), sunitinib (Sutent(r), Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy. DATA SOURCES: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals. REVIEW METHODS: A fixed effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values. RESULTS: Four RCTs (n = 2618) and eight non-RCTs (n = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of L45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of L126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus. LIMITATIONS: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS. CONCLUSIONS: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042384. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29393023 TI - A comparison of the effect of molluscum contagiosum virus MC159 and MC160 proteins on vaccinia virus virulence in intranasal and intradermal infection routes. AB - Molluscum contagiosum virus (MCV) causes persistent, benign skin neoplasm in children and adults. MCV is refractive to growth in standard tissue culture and there is no relevant animal model of infection. Here we investigated whether another poxvirus (vaccinia virus; VACV) could be used to examine MCV immunoevasion protein properties in vivo. The MCV MC159L or MC160L genes, which encode NF-kappaB antagonists, were inserted into an attenuated VACV lacking an NF kappaB antagonist (vDeltaA49), creating vMC159 and vMC160. vMC160 slightly increased vDeltaA49 virulence in the intranasal and intradermal routes of inoculation. vMC159 infection was less virulent than vDeltaA49 in both inoculation routes. vMC159-infected ear pinnae did not form lesions, but virus replication still occurred. Thus, the lack of lesions was not due to abortive virus replication. This system provides a new approach to examine MCV immunoevasion proteins within the context of a complete and complex immune system. PMID- 29393025 TI - [Intrauterine necrotizing enterocolitis in premature newborns]. AB - Necrotizing enterocolitis (NEC) is a severe disorder associated with increased morbidity and mortality when found in premature infants. This report is about two cases of NEC initiated in utero but without a prior knowledge to neither parents nor health professionals. Both cases had similar courses postnatally, which included abdominal distension and nutritional problems. The surgical findings: case I was a classical NEC in 20-25 cm of distal ileum, and case II was a 1.5-cm necrosis with perforation in proximal ileum. The proposed aetiology was somehow dissimilar in the two cases, which led to the suggestion that the cases represented two various disease entities. PMID- 29393026 TI - [Advanced life support for cardiac arrest beyond the algorithm]. AB - In an advanced emergency medical service all parts of the advanced life support (ALS) algorithm can be provided. This evidence-based algorithm outlines resuscitative efforts for the first 10-15 minutes after cardiac arrest, whereafter the algorithm repeats itself. Restoration of spontaneous circulation fails in most cases, but in some circumstances the patient may benefit from additional interventional approaches, in which case transport to hospital with ongoing cardiopulmonary resuscitation is indicated. This paper has summarized treatments outside the ALS algorithm, which may be beneficial, but are not supported by firm scientific evidence. PMID- 29393027 TI - [Controlled attenuation parameter is a novel technique in screening for non alcoholic fatty liver disease]. AB - Non-alcoholic fatty liver disease afflicts 30% of the population and is tightly linked to the metabolic syndrome and development of cardiovascular disease and chronic liver disease. Regular ultrasound is currently used in liver steatosis diagnosing, but it is operator-dependent, fails to detect lower grades of steatosis, and is unable to graduate the degree of steatosis. Controlled attenuation parameter is a novel, ultrasound-based technique to accurately detect and grade steatosis. Further studies are needed to establish cut-offs, before it can be implemented in clinical practice. PMID- 29393028 TI - [Chronic pulmonary aspergillosis]. AB - Chronic pulmonary aspergillosis (CPA) is an overlooked disease category in which delay of diagnosis and treatment is associated with increased mortality. A prerequisite for prognostic optimization of CPA is an increased focus on predisposing factors and patients at risk. Diagnosis of CPA is challenging and requires a systematic approach to assessment and interpretation of findings, both of which are necessary for correct disease classification and selection of targeted antifungal treatment and duration. PMID- 29393029 TI - [Birt-Hogg-Dube syndrome is a rare but important cause of pneumothorax]. AB - Birt-Hogg-Dube syndrome (BHD) is an autosomal-dominant genodermatosis manifesting as a multisystemic disorder. The most common presentation of pulmonary involvement is spontaneous pneumothorax, and it has recently been estimated, that up to 5-10% of patients with primary spontaneous pneumothorax have underlying BHD. The purpose of this case report is to stress the paramount importance of a thorough family history in patients with spontaneous pneumothorax and to recommend, that patients with a spontaneous pneumothorax and a personal or family history of pneumothorax should be screened for BHD. PMID- 29393030 TI - [Cosmetic iris implantation can cause irreversible eye complications]. AB - Artificial iris implants were originally developed for therapeutic purposes but have recently been used for cosmetic alteration of the eye colour. A 21-year-old woman presented with bilateral eye redness, visual loss, raised intraocular pressure, corneal oedema and hyphaema following implantation of artificial irises in Tunisia. Combined medical and surgical management led to improvements, but reduced vision and photophobia persisted. Cosmetic iris implantation can lead to persistently sight-threatening eye complications, and we strongly advise against its use. PMID- 29393031 TI - [Heterotopic ossification in a midline incision]. AB - Heterotopic ossification (HO) is the formation of bone outside the skeletal system. It is a well-known complication in orthopaedic surgery but is infrequently reported in abdominal surgery. HO can be asymptomatic or cause chronic pain but can also cause complications during later surgery. In this case report we present a 54-year-old male with an HO in a midline incision following surgery 20 years earlier. PMID- 29393032 TI - [Treatment of primary and recurrent ovarian cancer]. AB - With 550 new cases/year ovarian cancer constitutes 3% of all cancers among women. The unspecific symptoms cause delayed diagnosis and hence poor survival rates. Screening initiatives have been disappointing. In order to accelerate diagnosis and correct surgical management, patients are referred to centralized, specialized units. The primary treatment comprises surgical total cytoreduction followed by platinum-based chemotherapy. Newer biological agents are added when randomized trials have shown a benefit. Recurrence is managed by chemotherapy alone or repeated radical surgery followed by chemotherapy. PMID- 29393033 TI - [Gynaecomastia]. AB - Gynaecomastia (GM) is a benign proliferation of the glandular tissue of the male breast and results from an imbalance between androgen and oestrogen. Pubertal GM is found in 50% and often resolves spontaneously without treatment. GM in adult men can be the first symptom of an underlying disease, and thorough investigation is recommended. Treatment of an underlying cause of GM is the first-line treatment. If GM persists, surgical excision with liposuction can provide excellent results and a low rate of complications. PMID- 29393034 TI - [Atopic dermatitis]. AB - Atopic dermatitis is a chronic and relapsing inflammatory skin disease. The clinical features vary among different age and ethnic groups, but pruritus is a hallmark. The treatment of atopic dermatitis includes skin barrier restoration with daily application of moisturizers. Topical corticosteroids and calcineurin inhibitors are first-line treatment for acute flares. In severe cases, immunosuppressive drugs are indicated. Targeted biological drugs are being tested in clinical trials. PMID- 29393035 TI - Long-term outcome after normal myocardial perfusion imaging in suspected ischaemic heart disease?. AB - INTRODUCTION: Ischaemic heart disease (IHD) is the leading cause of mortality in the Western world. Therefore, to focus on those at risk of having IHD while at the same time avoiding unnecessary patient concern, it is important to have diagnostic tools capable of refuting an IHD diagnosis. Within the past 30 years, myocardial perfusion imaging (MPI) has been used increasingly to detect myocardial perfusion defects. MPI is a safe and non-invasive method with a sensitivity and specificity of > 90%. The aim of this study was to evaluate the long-term prognostic outcome after a normal MPI. ?Methods: The study population comprised patients referred for MPI from one single department of cardiology with invasive facilities, from 2008 to 2009. The patients' demographics and the results of the MPIs were collected from their medical records. Only patients without known IHD and with a normal MPI were included. After a follow-up period of 7.8 years (range: 6.8-8.8 years), a retrospective database search was performed. The major outcomes were all-cause mortality, cardiac events defined as nonfatal myocardial infarct or coronary revascularisation by percutaneous coron ary intervention or coronary artery bypass grafting. ?Results: The risk of a cardiac event or death following a normal MPI was 9.6% during long-term follow up, with an estimated annual death rate of 1.4% per year (95% confidence interval: 0.8-2.5%). This was not different from the background population. ?Conclusion: A normal MPI predicts a favourable long-term prognostic outcome. ?Funding: none.? Trial registration: FSEID-00002257. PMID- 29393036 TI - Sleep apnoea in patients undergoing bariatric surgery?. AB - INTRODUCTION: The objective of this study was to investigate the presence of obstructive sleep apnoea (OSA) among patients awaiting bariatric surgery and to evaluate if a change in symptoms and clinical measurements of OSA was seen one year after bariatric surgery.? Methods: Patients awaiting bariatric surgery in the Region of Southern Denmark were invited to participate in an OSA examination during a 15-month period (2012-2013) using the Embletta device for cardiorespiratory monitoring before and one year after bariatric surgery. The Apnoea-Hypopnoea Index (AHI), weight, BMI and the Epworth Sleepiness Score (ESS) were measured prior to and one year after surgery. ?Results: A total of 56 patients were enrolled in the study, and 59% were found with OSA (AHI >= 5). Thirty-six patients were eligible for examination one year post-operatively. Twelve of these patients did not have OSA (AHI < 5) either at inclusion or at re examination. In the remaining 24 patients with OSA, the BMI dropped from 44.4 prior to surgery to 30.8 kg/m2 one year after surgery (p < 0.01). Mean AHI decreased from 12.8 prior to surgery to 3.7 one year after surgery (p < 0.01). There was no effect of weight reduction on the ESS.? Conclusions: A statistically significant reduction in AHI was seen in patients with OSA one year after surgery. ?No statistical differences were observed for ESS. ?Funding: This study was funded by "Fonden for Laege-videnskabelig Forskning m.v. ved sygehusene i Region Syd" and by "Edith og Vagn Hedegaard Jensen fond".?Trial registration: ClinGov (ID: S-20120004jln). PMID- 29393037 TI - Birth asphyxia in a Danish hospital uptake area was reduced after centralisation of deliveries?. AB - INTRODUCTION: Severe birth asphyxia is a major cause of neonatal morbidity and long-term disability and may be prevented. However, the consequences of organisational changes are rarely evaluated. ?Methods: A cohort study comparing morbidity and mortality for term-born infants born with severe birth asphyxia, defined as an Apgar score <= 5 at 5 min., before and after major changes in the organisation of births in a Danish district.? Results: The study included 77 infants born in 1997-2004 and 40 infants born in 2009-2013 who were admitted to a neonatal intensive care unit with an Apgar score <= 5 at 5 min. The rate of severe birth asphyxia was 1.9 per 1,000 births in the early years and 2.5 per 1,000 births for the 2009-2013 period (p = 0.16). Mortality in the first three years of life with severe birth asphyxia was 0.24 per 1,000 births in 1997-2004 (ten deaths) and 0.06 per 1,000 births in 2009-2013 (one death) (p = 0.20). We observed a highly significant difference between the two periods in the proportion of infants with neonatal seizures and age at discharge after birth. The outcome of death or cerebral palsy was present in 17/77 (22%) in the early period and 3/40 (7.5%) in the more recent period (p < 0.05).? Conclusions: Over a relative short time period, death and disability due to severe birth asphyxia at term decreased significantly. This improvement is most likely explained by changes in the organisation of births in the hospital uptake area. as well as in treatment ?Funding: none.?Trial registration: not relevant. PMID- 29393038 TI - A multifactorial approach to explaining the stagnation in national smoking rates?. AB - INTRODUCTION: The aim of this paper was to investigate if a multifactorial approach may be used to explain why national smoking rates have levelled off in Denmark after 60 years of decline. ?Methods: Seven hypothetical explanations for stagnation in smoking rate were explored. A period of five years with a declining smoking prevalence (2007-2011) was compared with four years of stalled smoking prevalence (2012-2015). We used individual and national level information sources, mostly cross-sectional data that were collected repeatedly, including large nationally representative surveys, sales stat-istics, nation-wide news and smoking cessation databases and legal information, among others. ?Results: Most theories were rejected, leaving some that might have contributed to the stagnation: substantially ?fewer smokers had tried to quit in the stagnation period. Furthermore, the price of tobacco had remained almost unchanged, tobacco control legislation and anti-smoking campaigns had not been very intensive, assistance to quit and the Health Authority's manpower allocated to tobacco control had decreased temporarily while the use of e-cigarettes had increased in the stagnation period.? Conclusions: Important components to focus on in future tobacco control in Denmark were identified. The study suggests that, in future, we need to focus on exploring why Danish smokers have an increasing wish to quit while fewer and fewer, nevertheless, actually attempt to quit. Neither the authors nor the Danish Health Authority were aware of this paradox. ?Funding: We would like to express our gratitude to the Danish Health Foundation for financial support. The researchers are independent of the founders.? Trial registration: not relevant. PMID- 29393039 TI - Glucagon treatment in type 1 diabetes -with focus on restoring plasma glucose during mild hypoglycemia?. AB - Type 1 diabetes is a chronic disease caused by an autoimmune destruction of the insulin-producing cells in the pancreas, leading to a condition with insulin deficiency and elevated blood glucose levels. Individuals with type 1 diabetes are therefore recommended to frequently inject insulin subcutaneously to keep near-normal blood glucose levels, preventing the progression and onset of diabetes-related complications, i.e. kidney failure, blindness, amputation, stroke and heart attack. Unfortunately, the intensified insulin therapy is associated with risk of hypoglycemia- impeding individuals from reaching recommended treatment goals. In this PhD thesis, we hypothesized that low-dose glucagon may complement existing insulin therapy in improving glucose control by treating and preventing mild hypoglycemia.? The aim was to determine whether low dose glucagon could treat insulin-induced mild hypoglycemia sufficiently, and to investigate conditions that might impair the efficacy of glucagon. We showed that the glucose response to low-dose glucagon was dose-dependent but was impaired during high blood levels of insulin, after one week of low carbohydrate diet and perhaps 8-9 hours after ethanol intake. These findings are clinically relevant when blood glucose levels are controlled through insulin and glucagon delivery. PMID- 29393040 TI - Perioperative treatment of patients undergoing acute high-risk abdominal surgery?. AB - Critically ill acute high-risk abdominal surgery patients represent a major challenge to health care providers, with the typical patient being elderly and frail, and with severe and multiple comorbidities. The mortality rate in this population is high, and the postoperative course is characterized by complications, prolonged hospitalisation and considerable risk of permanent disability. With an ageing population, the number of elderly patients, as well as challenges concerning treatment will arise, calling for a coordinated effort both nationally and internationally to enhance treatment in this vulnerable patient group. By the time of admission, the acute high-risk abdominal surgery patients are often physiologically deranged. The burden of multiple organ system dysfunction caused by an acute abdominal catastrophe, is associated with great risk. Timely stabilisation, diagnosis, pain management and surgical treatment are essential for a good out-come. Except from a few initiatives in subpopulations, there has, up until now, been an absence of organised multidisciplinary collaboration in approaching the critically ill emergency surgery patient. We have not been able, neither nationally or internationally, to introduce a standardised approach to the perioperative treatment based on the existing evidence. By analysing data from 4 hospitals in Denmark, we were able to illustrate a protracted critical period following acute high-risk abdominal surgery, where the frequency of postoperative complications is high, and associated with an increased risk of dying. The mortality in the cohort was 34% one year after surgery. A standardised, multimodal and multidisciplinary perioperative treatment protocol was implemented at Copenhagen University Hospital, Hvidovre. This resulted in a significant and persistent reduction in mortality during a follow-up period of 6 months. Despite the standardised course, we recognised the difficulty in mobilising patients during the first postoperative week due to fatigue and pain. Traditionally, the? success in treatment is measured by death- and complication rates, and length of hospital stay, but the literature is sparse when reporting patient outcome measures. We found a surprisingly good quality of life in a small group of elderly patients who had survived acute high risk abdominal surgery. In the future, it is essential to use patients' knowledge and experience to develop quality improvement initiatives in treatment, as well as to improve the dialogue between the patient, doctor, and closest relatives, helping them in forming realistic expectations of the postoperative outcomes. Unfortunately, as of now, we have no systematic collection of patient reported outcome measures in this critically ill and rather vulnerable population. This is a challenging group of patients with a need for extensive treatment, and specialized care, and rehabilitation. Future research should be conducted in dedicated specialized wards, where the staff is educated and motivated to see the complicated task through. The initiative from the research group behind this thesis should be considered as a clinically relevant, pragmatic introduction to a hopefully larger and necessary effort to improve the quality of care and the outcome following acute high-risk abdominal surgery. PMID- 29393041 TI - Surgical treatment for urinary incontinence in women - Danish nationwide cohort studies?. AB - This PhD thesis is based on three original articles. The studies were performed at the Department of Obstetrics and Gynaecology, Herlev University Hospital and at the Center for Clinical Epidemiology, Odense University Hospital. ?Urinary incontinence (UI) is a frequent disorder among women, which for the individual can have physical, psychological and social consequences. The current standard of surgical treatment is the synthetic midurethral sling (MUS), which is a minimal invasive procedure.?As the synthetic MUSs (TVT,TVT-O,TOT) were introduced in the late 1990s, there are only a few studies at the long-term follow-up based on nationwide populations; only a few have reported on the risk of reoperation and there is sparse evidence on which treatment should be used subsequently to failure of synthetic MUSs.?Several surgical specialties have documented that department volume, surgeon volume and patient-related factors influence the quality of care. There is little knowledge regarding this in the surgical treatment for UI.? The aims of the thesis were therefore:?1. To describe the five year incidence of reoperation after different surgical procedures for UI based on a nationwide population over a ten-year period (1998-2007) and to evaluate the influence of department volume (Study I).?2. To describe the choice of repeat surgery after failed synthetic MUSs and the departmental volume for the surgical treatment at reoperation over a ten-year period (1998-2007) based on a nationwide background population (Study II).?3. To evaluate efficacy of urethral injection therapy (UIT) based on patient reported outcome measures (PROMs) and hospital contacts within 30 days for women registered in the Danish Urogynaecological Database (DugaBase) over a five-year period (2007-2011) and the influence of department volume, surgeon volume and patient-related factors (Study III).? Study I: A total of 8671 women were recorded in the Danish National Patient Registry as having undergone surgical treatment for UI from 1998 through 2007.?The lowest rate of reoperation within five years was observed among women who had pubovaginal slings (6%), TVT (6%) and Burch colposuspension (6%) followed TOT (9%), and miscellaneous operations (12%), while the highest observed risk was for UIT (44%). After adjustment for patient's age, department volume and calendar effect TOT carried a 2-fold higher risk of reoperation (HR, 2.1; 95% CI, 1.5 2.9) compared with TVT.?? Study II: A total of 5820 women had synthetic MUSs at baseline from 1998 through 2007 and were registered in the Danish National Patient Registry and 354 (6%) of these women had a reoperation.?The first choice treatment for reoperation was a synthetic MUS and UIT was a frequent second choice. At reoperation, 289 (82%) of the women were treated at the department where they had undergone the primary synthetic MUS. Fewer treatment modalities were in usage and significantly more TOTs were implanted at low volume departments compared to high volume departments. ??Study III: A total of 731 women of age 18 or older with first time UITs were registered with first-time UIT in the DugaBase from 2007 through 2011. Logistic regression was used to predict the odds of success pertaining to department volume, surgeon volume and patient related factors on the Incontinence Questionnaire-Short Form (ICIQ-SF) (frequency of UI, amount of leakage and impact of UI on daily life) and the rate of 30-day hospital contacts. ??We applied the definition of "cure" as set out by the steering committee of the DugaBase where a satisfactory result is leakage once a week or less, often or never based on the frequency score and similarly "no leakage at all" based on the frequency score as answering never to leakage.??Among the 252 women who pre- and postoperatively had answered both questionnaires, 75 (29.8%) were cured and 23 (9.1%) achieved no leakage at all at three months follow-up. There was a statistically significant improvement on all three scores of the ICIQ-SF. The mean total ICIQ-SF score was 16.0 (SD 3.8) and after injection at three months follow-up 10.6 (SD 6.2) (p < 0.001).??UIT was performed at 16 departments, of which four high volume departments performed 547 of 814 UITs (67.2%). The risk of hospital contacts was lower for women treated at a high volume department (adjusted OR 0.27; 95% CI 0.09-0.76). Women treated by a high volume surgeon (> 75 UITs during the career as a surgeon) had a higher chance of cure on the frequency score than the low volume surgeon (<= 25 UITs) (adjusted OR 4.51; 95% CI, 1.21-16.82) and a lower risk of 30-day hospital contacts (adjusted OR 0.35; 95% CI, 0.16-0.79). Women with severe UI had less likelihood of cure in all ICIQ-SF scores. A preoperative use of antimuscarinic drugs lowered the chance of cure on the frequency (adjusted OR 0.14; 95%, CI 0.04 0.41) and the amount score (adjusted OR 0.33; 95%, CI 0.13-0.82). ??Conclusions:? Study I: The study provided physicians with a representative evaluation of the rate of reoperations after different surgical procedures for UI. The observation that TOT was associated with a significantly higher risk of reoperation than TVT is novel in the literature and has important implications for both surgeons and patients when they consider surgical options for UI. ??Study II: The majority of women had reoperation at the same department as the primary synthetic MUS. Fewer treatment modalities were in use at low volume departments compared with high volume departments. It seems appropriate in the absence of evidence for the best treatment after failed synthetic MUSs, that women are referred to highly specialized departments for diagnosing and treatment.?? Study III: This national population-based cohort study represented cure among women who had UIT in an everyday life setting. Results seemed to be in the lower end of the spectrum compared to the literature. A learning curve for UIT indicated that the treatment should be restricted to fewer hands to improve the surgical education and consequently be a success for women with UIT. The severity of UI was a strong predictor for a lower degree of cure. Similarly, the use of antimuscarinic drug preoperatively decreased the likelihood of cure indicating that women with severe MUI or UUI also have less chance of cure. PMID- 29393042 TI - Assessment and learning of ultrasound skills in Obstetrics & Gynecology?. AB - Ultrasound is a core skill in obstetrics-gynecology, but is highly operator dependent. The evidence supporting the use of different methods for assessment and training of ultrasound skills was examined from different perspectives through a series of explorative and experimental studies.?We found that ultrasound performance of trainees in obstetrics-gynecology depended on a combination of motor skills, visual skills, and cognitive skills. We then established international multispecialty consensus on an assessment instrument designed to evaluate ultrasound skills. The validity evidence of assessments made using this instrument was then examined using empirical data on the performances of obstetrician-gynecologists with different levels of clinical experience. There was evidence to suggest that technical aspects of trainee performance may need improvement, and that simulation-based ultrasound training may play a role by allowing trainees to achieve mastery levels prior to their clinical training. We found that the use of simulation-based ultrasound training led to immediate as well as sustained improvements in trainees' performances with patients. Moreover, simulation-based ultrasound training led to improvements in patient-reported discomfort, perceived safety, and confidence in the ultrasound operator. From an organizational perspective, we found evidence that providing initial simulation based ultrasound training combined with clinical training reduced the need for supervised practice and repeated patient examinations. This evidence supported the hypothesis that simulation-based medical education can act as preparation for future learning. Finally, by taking a health economics perspective, we examined how ultrasound training could be linked to monetary costs, and demonstrated how training efficiency could be doubled using collaborative learning without negative consequences. PMID- 29393043 TI - New determinants for gallstone disease??. AB - Gallstone disease is highly prevalent in Denmark and other countries of northern Europe, and cholecystectomy for the treatment of clinical gallstone disease is one the most frequently performed surgical procedures. Research efforts for the identification of mechanisms involved in gallstone formation have a long history and the most established include bile cholesterol saturation, gallbladder motor function, and the enterohepatic circulation of secondary bile salts produced by fecal microbiota. A small number of determinants that are believed to affect these mechanisms have been identified until now. However, much of this research on determinants for gallstone disease has been hampered by insufficient study designs and by insufficient assessment of gallstone disease by only assessing the selected minority of people with clinical gallstone disease. ?In a Danish general population cohort screened for gallstone disease with multiple ultrasound examinations, it was possible to both confirm previously identified determinants and to identify new determinants for gallstone disease. Temporal associations for incident gallstone disease and female sex, BMI, non-HDL cholesterol, and inverse associations for increasing alcohol consumption and cessation of hormone replacement therapy in females were confirmed. New determinants included testosterone and increase in SHBG in males which had directly and inverse associations with incident gallstone disease, respectively. All of the identified determinants for incident gallstone disease found in this thesis can be linked to the three biological mechanisms of gallstone formation.?Other modifiable factors such as tobacco smoking, coffee consumption, dietary habits, physical activity, and blood pressure were not identified as determinants of incident gallstone disease in this thesis. Previous findings from other studies may be hampered by study design without exploration of temporal associations or due to selective assessment of gallstone disease. A common information bias for all existing literature exploring lifestyle habits and gallstone disease is the self-reported exposures which may cause misclassification bias. If explored in future studies, assessment of lifestyle habits should include objective measures in order to contribute any further to existing evidence on determinants for gallstone disease.?Associations for biomarkers of insulin resistance and gallstone disease prevalence were found. Insulin resistance probably mediates the association between BMI and gallstone disease. Although only cross-sectional, the association for both BMI and insulin resistance with gallstone disease seems well established based on existing experimental and observational evidence.?New cross-sectional associations for gallstone disease prevalence were identified for biomarkers of systemic inflammation, genetic risk for obesity or diabetes type 2, and for biomarkers of renal function. Levels of vitamin D were not identified as the cause of the higher northern European gallstone disease prevalence, although birth during season of low sun and vitamin D exposure seemed associated. ?Future clinical or larger population-based interventional trials aiming at changing body weight, circulating levels of non-HDL cholesterol, or alcohol consumption are supported by the findings of this PhD thesis. Screening of gallstone disease through ultrasound examinations should be performed in future interventional trials aiming at preventing cardiovascular disease in order to monitor the effects of such interventions on gallstone formation and, further, to avoid the selection bias caused by just assessing clinical gallstone disease. Screening for gallstone disease on the population-level is not recommended due to an assumed increase in clinical gallstone disease without a survival advantage of treatment. Explorations of male reproductive hormones, biomarkers of systemic inflammation, circulating levels of vitamin D, and genetic risk alleles should be repeated in future cohort studies before these possible determinants may be subject for future strategies for prevention or treatment of gallstone disease. PMID- 29393044 TI - Early warning score challenges and opportunities in the care of deteriorating patients?. AB - Clinical deterioration of patients hospitalized on general wards is often preceded by worsening vital signs. If identified early and acted upon quickly, it is conjectured that further deterioration can be prevented. To this means the early warning score (EWS) was implemented in all hospitals in the Capital Region of Denmark in 2013. EWS consists of an aggregated weighted track-and-trigger system (TTS), to identify at-risk patients early, and a treatment protocol to escalate care appropriately and determine the level of competency of the provider. A similar system is endorsed by the Royal College of Physicians for use at hospitals in the UK. Despite wide dissemination of EWS and similar systems serious adverse events presaged by deteriorating vital signs continue to be a major source of morbidity. This is either due to inherent inadequacies of EWS, lack of adherence to the treatment protocol, or a combination of both.?All studies included in this thesis were conducted at Bispebjerg Hospital, an inner city Hospital in Copenhagen, Denmark with 500 beds and a catchment area of approximately 300,000. ?The aim of the thesis was to investigate the reasons for failure of the EWS by trying to answer the following research questions:?1. How often and why does the system fail??2. What are the barriers and facilitating factors related to the use of the EWS protocol??3. Is there a correlation between monitoring frequency and clinical deterioration?? To answer the first question an observational study was conducted, in which all unexpected deaths, cardiac arrests, and unintended ICU admission on general wards during a 6 months period were reviewed. A total of 144 events were recorded; in only 12 (8 %) of these the escalation protocol was adhered to strictly. Monitoring frequency was not adhered to in 81 % of cases; doctors were not notified about patients' condition in 42 % of cases, and the medical emergency team or senior doctors were not notified appropriately in 52 % of the cases. Leading to the conclusion that violations of the escalation protocol was common prior to serious adverse events on general wards.?To answer the second question semi-structured focus group interviews with nurses from the surgical and medical acute care wards were performed to investigate: 1) why monitoring frequencies are not adhered to, 2) why junior doctors are not notified about deteriorating patients, and 3) why review by the medical emergency team (MET) is often delayed or missed? The main findings from this study showed that time constraints and under staffing was mentioned as a main reason for non-adherence to monitoring frequencies. Confidence in their own abilities to take care of deteriorating patients, and the large number of patients with elevated EWS was mentioned as the main reason, for not notifying junior doctors. And fear of reprimands and lack of non-technical skills among members of the MET were mentioned among the main reasons for reluctance to call.?The third study investigated the role of monitoring frequency on clinical deterioration in a ward-level randomized study. It was hypothesized that 8 h monitoring intervals were superior to 12 h in preventing deterioration, defined as a rise in EWS to >= 2 after 24 h, among newly admitted patients with an initial EWS of 0 or 1. Of 3185 patients screened for eligibility, 1346 patients were included to the trial, and data from 544 patients were available for final analysis. Of these 49 % percent were allocated to the 8h group and 51% to the 12h group; of these, 23% and 20% had an elevated EWS>=2 at 24h, respectively (p=0.456), OR 1.17 (0.78-1.76). There were no significant differences in regard to the secondary outcomes: cardiac arrests, ICU admissions, review by MET, length of hospital stay, mortality, or elevated EWS at 48h. PMID- 29393046 TI - The Evolving Role of Nuclear Medicine and Molecular Imaging: Theranostics and Personalized Therapeutic Applications. PMID- 29393045 TI - Internal amino acid state modulates yeast taste neurons to support protein homeostasis in Drosophila. AB - To optimize fitness, animals must dynamically match food choices to their current needs. For drosophilids, yeast fulfills most dietary protein and micronutrient requirements. While several yeast metabolites activate known gustatory receptor neurons (GRNs) in Drosophila melanogaster, the chemosensory channels mediating yeast feeding remain unknown. Here we identify a class of proboscis GRNs required for yeast intake. Within this class, taste peg GRNs are specifically required to sustain yeast feeding. Sensillar GRNs, however, mediate feeding initiation. Furthermore, the response of yeast GRNs, but not sweet GRNs, is enhanced following deprivation from amino acids, providing a potential basis for protein specific appetite. Although nutritional and reproductive states synergistically increase yeast appetite, reproductive state acts independently of nutritional state, modulating processing downstream of GRNs. Together, these results suggest that different internal states act at distinct levels of a dedicated gustatory circuit to elicit nutrient-specific appetites towards a complex, ecologically relevant protein source. PMID- 29393047 TI - The Role of 18F-FDG PET/CT in Evaluating Elevated Levels of Tumor Markers in Breast Cancer. AB - OBJECTIVE: Our aim was to assess the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) in the follow-up of breast cancer patients, who underwent a PET/CT scan due to a suspicion of recurrence based on elevated levels of serum tumor markers. METHODS: Seventy seven consecutive patients were included in this study. PET/CT scan results were compared with the final diagnoses that were obtained from histopathological sampling or a minimum 6 months of radiological follow-up. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the diagnostic accuracy of PET/CT for detecting recurrence were calculated. RESULTS: All 77 patients had increased serum cancer antigen 15-3 levels while 37 had increased serum carcinoembryonic antigen levels. According to PET/CT scan results, 59 of 77 patients (PET/CT positive) had local recurrence and/or distant metastasis while there was no pathological finding in 18 patients (PET/CT negative). In a follow-up of minimum 6 months, tumor recurrence was confirmed in 58 of "PET/CT positive" patients while no tumor recurrence was detected in 16 of "PET/CT negative" patients. According to these results the sensitivity, specificity, PPV, NPV and the diagnostic accuracy of PET/CT for detecting recurrence on a per-person basis were calculated as 98%, 88%, 96%, 94% and 96%, respectively. CONCLUSION: In case of elevated levels of serum tumor markers, PET/CT has a high diagnostic accuracy in detecting tumor recurrence in patients with breast cancer, and it is an effective modality that can be used in addition to conventional imaging techniques. PMID- 29393048 TI - Evaluation of PET Scanner Performance in PET/MR and PET/CT Systems: NEMA Tests. AB - OBJECTIVE: The aim of the present study was to compare the performance of positron emission tomography (PET) component of PET/computed tomography (CT) with new emerging PET/magnetic resonance (MR) of the same vendor. METHODS: According to National Electrical Manufacturers Association NU2-07, five separate experimental tests were performed to evaluate the performance of PET scanner of General Electric GE company; SIGNATM model PET/MR and GE Discovery 710 model PET/CT. The main investigated aspects were spatial resolution, sensitivity, scatter fraction, count rate performance, image quality, count loss and random events correction accuracy. RESULTS: The findings of this study demonstrated superior sensitivity (~ 4 folds) of PET scanner in PET/MR compared to PET/CT system. Image quality test exhibited higher contrast in PET/MR (~ 9%) compared with PET/CT. The scatter fraction of PET/MR was 43.4% at noise equivalent count rate (NECR) peak of 218 kcps and the corresponding activity concentration was 17.7 kBq/cc. Whereas the scatter fraction of PET/CT was found as 39.2% at NECR peak of 72 kcps and activity concentration of 24.3 kBq/cc. The percentage error of the random event correction accuracy was 3.4% and 3.1% in PET/MR and PET/CT, respectively. CONCLUSION: It was concluded that PET/MR system is about 4 times more sensitive than PET/CT, and the contrast of hot lesions in PET/MR was ~ 9% higher than PET/CT. These outcomes also emphasize the possibility to achieve excellent clinical PET images with low administered dose and/or a short acquisition time in PET/MR. PMID- 29393049 TI - Contribution of 18F-FDG PET/CT to Staging of Head and Neck Malignancies. AB - OBJECTIVES: Accurate staging of head and neck cancer (HNC) plays an important role in patient management as well as protection of functional characteristics of the head and neck region. Our aim was to investigate the contribution of 2-[18F] fluoro-2-deoxy-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) as part of HNC staging to clinical evaluation and treatment planning. METHODS: Clinical records of 138 HNC cases who has undergone 18F-FDG PET/CT imaging were retrospectively reviewed. Sixty-five cases who had accessible clinical follow-up data were included in the study group, and their PET/CT and conventional imaging findings were evaluated. RESULTS: In the case group with a PET/CT and magnetic resonance imaging (MRI) for evaluation of primary lesion the sensitivity rates for PET/CT and MRI were calculated as 91.3% and 82.6%, the positive predictive values (PPV) as 91.3% and 82.6%, specificity as 71.4% and 42.8%, and the negative predictive value (NPV) as 71.4% and 42.8%, respectively. In terms of metastatic lymph node evaluation, the sensitivity was calculated as 100% and 88.8%, the NPV as 100% and 83.3%, respectively. The PPV and specificity was 100% for both modalities. In the case group with CT for primary lesion evaluation, the sensitivity and PPV were found as 95.2% and 100% for PET/CT, and as 85.7% and 94.7% for CT, respectively. in metastatic lymph node evaluation, the sensitivity was found as 100% for PET/CT and 50% for CT, and the PPV, specificity and NPV were determined as 100% for both methods. PET/CT findings resulted in a change in 'tumor, node, metastasis' staging in 5 cases. CONCLUSIONS: PET/CT in HNC contributes to staging, thus playing a role in treatment planning, especially in patients with locally advanced disease. PMID- 29393050 TI - Sphenoid Bone Fibrous Dysplasia Detected Incidentally on Bone Scintigraphy by the Contribution of SPECT/CT Hybrid Imaging. AB - Fibrous dysplasia (FD) is a benign fibroosseous bone disorder. It has poliostotic and monostotic patterns. Monostotic FD is frequently asymptomatic and is usually discovered incidentally by radiologic imaging performed for other reasons. Bone scintigraphy is valuable for identifying disease extent. Craniofacial FD (CFD) is a form of the disease where lesions are limited to contiguous bones of the craniofacial skeleton. We presented a case with monostotic CFD who was detected incidentally on bone scintigraphy single-photon emission computed tomography/computerized tomography while being investigated for inflammatory arthropaties. PMID- 29393051 TI - The Contribution of SPECT/CT in the Diagnosis of Stress Fracture of the Proximal Tibia. AB - Stress fractures are injuries most commonly seen in the lower limbs and are usually caused by repetitive stress. While the distal and middle third of the tibia is the most frequent site for stress fractures (almost 50%), stress fractures of the proximal tibia is relatively rare and could be confused with other types of tibial fractures, thus altering management plans for the clinician. Early diagnosis of stress fractures is also important to avoid complications. Imaging plays an important role in the diagnosis of stress fractures, especially bone scan. Combined with single-photon emission computed tomography/computed tomography (SPECT/CT) it is an important imaging technique for stress fractures in both upper and lower extremities, and is widely preferred over other imaging techniques. In this case, we present the case of a 39-year-old male patient diagnosed with stress fracture of the proximal tibia and demonstrate the contribution of CT scan fused with SPECT imaging in the early diagnosis of stress fracture prior to other imaging modalities. PMID- 29393052 TI - Unilateral Muscle Artifacts due to Non-compliance During Uptake Phase of 18F-FDG PET/CT in an Oncologic Patient. AB - A 49-year-old male patient with a prior history of poor compliance with medical appointments was referred for an 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for the staging of a rectal squamous cell carcinoma. The PET/CT showed unilateral diffuse skeletal muscle 18F FDG uptake as well as bilateral salivary gland uptake artifacts, suggestive of non-compliance with patient preparation instructions. The PET/CT nurse noted that during the 18F-FDG uptake phase, the patient appeared intoxicated, and she found two beer cans hidden in the waste disposal beside his chair just prior to imaging. The patient only admitted to eating a cookie approximately 30 minutes after the injection of 18F-FDG PET/CT and denied consuming alcohol during the uptake phase. We present the imaging findings of non-compliance with patient instructions during the uptake phase of 18F-FDG. PMID- 29393053 TI - Inflammatory and Ischemic Post Liver Transplant Complications Mimic Malignancy on 18F-FDG PET/CT. AB - A 65-year-old male patient with a one year history of liver transplantation was referred for an 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to rule out post transplant lymphoproliferative disease. Multiple foci of intense abnormal 18F-FDG uptake were seen in the transplanted liver which were concerning for malignancy. Explantation of the liver approximately 1 month following the PET/CT revealed multiple inflammatory and ischemic changes including large bile duct necrosis, acute cholangitis, bile duct obstruction changes and periportal fibrosis, with no evidence of malignancy. We present the 18F-FDG PET/CT image findings of this case. PMID- 29393054 TI - Primary Thyroid Lymphoma: External Beam Radiation Therapy Induced Thyroiditis Mimics Residual Disease on Serial 18F-FDG PET/CT Imaging. AB - A 67-year-old female patient with no prior history of benign thyroid disease was diagnosed with primary thyroid lymphoma and was staged with 18F-fluoro-2-deoxy-D glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). She was treated with chemotherapy and external beam radiation therapy, and a follow up PET/CT showed significant reduction in the size of the thyroid lymphoma with persistent intense 18F-FDG uptake, which was interpreted as partial response to therapy. However, two subsequent PET/CT studies showed no change in the persistent intense 18F-FDG uptake in the thyroid and a biopsy confirmed the presence of thyroiditis with no evidence of residual lymphoma. Follow-up PET/CTs performed over the subsequent three years showed stable intensely 18F-FDG avid thyroiditis with no evidence of lymphoma recurrence. We present the imaging characteristics of a long term radiation treatment induced thyroiditis mimicking 18F-FDG avid residual disease on PET/CT. PMID- 29393055 TI - Tc-99m MDP Bone SPECT/CT Findings of a Patient Detected with a New Mutation in LEMD3 Gene: A Case of Osteopoikilosis. AB - Osteopoikilosis is an inherited condition with autosomal dominant trait resulting in sclerotic foci throughout the skeleton. It has been suggested that loss-of function mutations of LEMD3 gene located on 12q14.3 result in osetopoikilosis. A bp heterozygote deletion was detected in our patient at the cytosine nucleotide at position 1105 with molecular genetic analysis. Although this mutation has not been previously described, it was considered to be the most likely cause of the disease in our patient due to frame shift and premature stop codon formation. As in our case, three phase bone scintigraphy and whole body imaging did not reflect the true extent of lesion sites and lesion activity. SPECT/CT images could reflect lesion location and activity more accurately, and could be a good alternative for differential diagnosis of unexplained bone pain and sclerotic lesions in one examination. PMID- 29393056 TI - Inguinal Endometriosis Visualized on I-131 Whole Body Scan. AB - We present a rare case with inguinal iodine-131 (I-131) uptake on whole body scan. The patient was suffering from a painful right inguinal mass during menstrual period, which was later sonographically and histopathologically confirmed to be an inguinal focus of endometriosis. Endometriosis is a previously reported site of radioiodine uptake and detection of radioiodine uptake in the inguinal region has also been described. Nevertheless, to the best of our knowledge, this is the first case report of I-131 uptake in an inguinal endometriosis focus. History and physical examination of the patient are both very important in identifying the etiology of the ectopic uptake sites on I-131 whole body scan, and inguinal endometriosis should be kept in mind while reporting inguinal radioiodine uptake on I-131 whole body scan. PMID- 29393057 TI - A generic EEG artifact removal algorithm based on the multi-channel Wiener filter. AB - OBJECTIVE: The electroencephalogram (EEG) is an essential neuro-monitoring tool for both clinical and research purposes, but is susceptible to a wide variety of undesired artifacts. Removal of these artifacts is often done using blind source separation techniques, relying on a purely data-driven transformation, which may sometimes fail to sufficiently isolate artifacts in only one or a few components. Furthermore, some algorithms perform well for specific artifacts, but not for others. In this paper, we aim to develop a generic EEG artifact removal algorithm, which allows the user to annotate a few artifact segments in the EEG recordings to inform the algorithm. APPROACH: We propose an algorithm based on the multi-channel Wiener filter (MWF), in which the artifact covariance matrix is replaced by a low-rank approximation based on the generalized eigenvalue decomposition. The algorithm is validated using both hybrid and real EEG data, and is compared to other algorithms frequently used for artifact removal. MAIN RESULTS: The MWF-based algorithm successfully removes a wide variety of artifacts with better performance than current state-of-the-art methods. SIGNIFICANCE: Current EEG artifact removal techniques often have limited applicability due to their specificity to one kind of artifact, their complexity, or simply because they are too 'blind'. This paper demonstrates a fast, robust and generic algorithm for removal of EEG artifacts of various types, i.e. those that were annotated as unwanted by the user. PMID- 29393058 TI - Emergence of a new valence-ordered structure and collapse of the magnetic order under high pressure in EuPtP. AB - The layered hexagonal EuPtP is a rare substance that exhibits two successive valence transitions occurring simultaneously with valence ordering transitions and an antiferromagnetic order. Anticipating that the application of pressure to this sample would induce a new valence-ordered structure and/or a new phenomenon associated with valence fluctuation, we examined the electrical resistivity rho, the Eu L3-edge x-ray absorption spectroscopy, and the powder x-ray diffraction under high pressure. We found a new valence transition at around P = 2.5 GPa. After the transition, a new valence-ordered structure is realized at the lowest temperature. The valence-ordered structure is inferred to be stacking of [Formula: see text] (2+: Eu2+ layer, 3+: Eu3+ layer) along the c-axis. Upon further increases in pressure, the valence-ordered structure is suppressed and another valance-ordered phase is realized up to P = 6 GPa. The antiferromagnetic order collapses in the pressure range between 6 GPa and 8 GPa. PMID- 29393059 TI - Origin of distorted 1T-phase ReS2: first-principles study. AB - Group-VIIB transition metal dichalcogenides (TMDCs) are known to be stabilized solely in a distorted 1T phase termed as 1T'' phase, which is compared to many stable or metastable phases in other TMDCs. Using first-principles calculations, we study the structural origin of 1T'' phase group-VIIB TMDCs. We find that quasi one-dimensional Peierls-like instability is responsible for the transition to the 1T'' phase ReS2 monolayer from the 1T' phase, another distorted 1T phase. Two half-filled bands in 1T'-ReS2 make sharp peaks in the Lindhard function that prompt the charge density wave (CDW) phase with large band gap opening. Our calculations show that overlapping of the two bands in a broad energy range leads to robust CDW phase or stable 1T'' phase in group-VIIB TMDCs against compositional variation, which is in stark contrast to typical Peierls instability driven by a single band. Calculated total energy curve near the critical point exhibits the feature of the first-order Landau transition due to local chemical bonding. The structural stability of the 1T'' phase in group-VIIB TMDCs is thus guaranteed by two half-filled bands and local chemical bonding. PMID- 29393060 TI - Magnetotransport study of topological superconductor Cu0.10Bi2Se3 single crystal. AB - We report a magnetotransport study of vortex-pinning in Cu0.10Bi2Se3 single crystal. The sample is demonstrated to be in clean limit and absent of Pauli spin-limiting effect. Interestingly, the resistivity versus magnetic field shows an anomalously pronounced increase when approaching the superconducting-normal state boundary for both B?ab and B?c configurations. We have investigated the flux-flowing behavior under various magnetic field and temperatures, enabling us to establish its anisotropic vortex phase diagram. Our results suggest the Cu0.10Bi2Se3 can be served as one unique material for exploring exotic surface vortex states in topological superconductors. PMID- 29393061 TI - Automated design evolution of stereochemically randomized protein foldamers. AB - Diversification of chain stereochemistry opens up the possibilities of an 'in principle' increase in the design space of proteins. This huge increase in the sequence and consequent structural variation is aimed at the generation of smart materials. To diversify protein structure stereochemically, we introduced L- and D-alpha-amino acids as the design alphabet. With a sequence design algorithm, we explored the usage of specific variables such as chirality and the sequence of this alphabet in independent steps. With molecular dynamics, we folded stereochemically diverse homopolypeptides and evaluated their 'fitness' for possible design as protein-like foldamers. We propose a fitness function to prune the most optimal fold among 1000 structures simulated with an automated repetitive simulated annealing molecular dynamics (AR-SAMD) approach. The highly scored poly-leucine fold with sequence lengths of 24 and 30 amino acids were later sequence-optimized using a Dead End Elimination cum Monte Carlo based optimization tool. This paper demonstrates a novel approach for the de novo design of protein-like foldamers. PMID- 29393062 TI - Subtractive fabrication of ferroelectric thin films with precisely controlled thickness. AB - The ability to control thin-film growth has led to advances in our understanding of fundamental physics as well as to the emergence of novel technologies. However, common thin-film growth techniques introduce a number of limitations related to the concentration of defects on film interfaces and surfaces that limit the scope of systems that can be produced and studied experimentally. Here, we developed an ion-beam based subtractive fabrication process that enables creation and modification of thin films with pre-defined thicknesses. To accomplish this we transformed a multimodal imaging platform that combines time of-flight secondary ion mass spectrometry with atomic force microscopy to a unique fabrication tool that allows for precise sputtering of the nanometer-thin layers of material. To demonstrate fabrication of thin-films with in situ feedback and control on film thickness and functionality we systematically studied thickness dependence of ferroelectric switching of lead-zirconate titanate, within a single epitaxial film. Our results demonstrate that through a subtractive film fabrication process we can control the piezoelectric response as a function of film thickness as well as improve on the overall piezoelectric response versus an untreated film. PMID- 29393063 TI - Development of real time abdominal compression force monitoring and visual biofeedback system. AB - In this study, we developed and evaluated a system that could monitor abdominal compression force (ACF) in real time and provide a surrogating signal, even under abdominal compression. The system could also provide visual-biofeedback (VBF). The real-time ACF monitoring system developed consists of an abdominal compression device, an ACF monitoring unit and a control system including an in house ACF management program. We anticipated that ACF variation information caused by respiratory abdominal motion could be used as a respiratory surrogate signal. Four volunteers participated in this test to obtain correlation coefficients between ACF variation and tidal volumes. A simulation study with another group of six volunteers was performed to evaluate the feasibility of the proposed system. In the simulation, we investigated the reproducibility of the compression setup and proposed a further enhanced shallow breathing (ESB) technique using VBF by intentionally reducing the amplitude of the breathing range under abdominal compression. The correlation coefficient between the ACF variation caused by the respiratory abdominal motion and the tidal volume signal for each volunteer was evaluated and R 2 values ranged from 0.79 to 0.84. The ACF variation was similar to a respiratory pattern and slight variations of ACF ranges were observed among sessions. About 73-77% average ACF control rate (i.e. compliance) over five trials was observed in all volunteer subjects except one (64%) when there was no VBF. The targeted ACF range was intentionally reduced to achieve ESB for VBF simulation. With VBF, in spite of the reduced target range, overall ACF control rate improved by about 20% in all volunteers except one (4%), demonstrating the effectiveness of VBF. The developed monitoring system could help reduce the inter-fraction ACF set up error and the intra fraction ACF variation. With the capability of providing a real time surrogating signal and VBF under compression, it could improve the quality of respiratory tumor motion management in abdominal compression radiation therapy. PMID- 29393064 TI - Topological insulation in a ladder model with particle-hole and reflection symmetries. AB - A two-legged ladder model, one dimensional, exhibiting the parity anomaly is constructed. The model belongs to the C and CI symmetry classes, depending on the parameters, but, due to reflection, it exhibits topological insulation. The model consists of two superimposed Creutz models with onsite potentials. The topological invariants of each Creutz model sum to give the mirror winding number, with winding numbers which are nonzero individually but equal and opposite in the topological phase, and both zero in the trivial phase. We demonstrate the presence of edge states and quantized Hall response in the topological region. Our model exhibits two distinct topological regions, distinguished by the different types of reflection symmetries. PMID- 29393065 TI - Modeling task-specific neuronal ensembles improves decoding of grasp. AB - OBJECTIVE: Dexterous movement involves the activation and coordination of networks of neuronal populations across multiple cortical regions. Attempts to model firing of individual neurons commonly treat the firing rate as directly modulating with motor behavior. However, motor behavior may additionally be associated with modulations in the activity and functional connectivity of neurons in a broader ensemble. Accounting for variations in neural ensemble connectivity may provide additional information about the behavior being performed. APPROACH: In this study, we examined neural ensemble activity in primary motor cortex (M1) and premotor cortex (PM) of two male rhesus monkeys during performance of a center-out reach, grasp and manipulate task. We constructed point process encoding models of neuronal firing that incorporated task-specific variations in the baseline firing rate as well as variations in functional connectivity with the neural ensemble. Models were evaluated both in terms of their encoding capabilities and their ability to properly classify the grasp being performed. MAIN RESULTS: Task-specific ensemble models correctly predicted the performed grasp with over 95% accuracy and were shown to outperform models of neuronal activity that assume only a variable baseline firing rate. Task-specific ensemble models exhibited superior decoding performance in 82% of units in both monkeys (p < 0.01). Inclusion of ensemble activity also broadly improved the ability of models to describe observed spiking. Encoding performance of task-specific ensemble models, measured by spike timing predictability, improved upon baseline models in 62% of units. SIGNIFICANCE: These results suggest that additional discriminative information about motor behavior found in the variations in functional connectivity of neuronal ensembles located in motor related cortical regions is relevant to decode complex tasks such as grasping objects, and may serve the basis for more reliable and accurate neural prosthesis. PMID- 29393067 TI - On dynamical properties of electrons in Anderson-Mott insulators. AB - Properties of electrons in non-crystalline (alias disordered) systems has been a very active research topic for over half a century, since Anderson's ground breaking paper on localization. In strongly disordered systems electrons become Anderson and Mott localized. Interactions become important because screening by localized electrons is ineffective. Dynamical theories for such systems have long been controversial. Nevertheless one theory came to prominence in the literature and is often invoked and/or used. It is shown here that that theory is unsatisfactory in several aspects. It is based on the one-particle density of states, which turns out to be irrelevant to the problem it addresses. Another shortcoming is an implicit conjecture that interacting electrons move independently of each other. The theory is also in questionable agreement with experiment. It is shown that two other theories are free of those problems. They are useful for different types of studies, are compatible with each other and in agreement with experiment. PMID- 29393066 TI - Investigating the effect of a magnetic field on dose distributions at phantom-air interfaces using PRESAGE(r) 3D dosimeter and Monte Carlo simulations. AB - Dosimetric quality assurance (QA) of the new Elekta Unity (MR-linac) will differ from the QA performed of a conventional linac due to the constant magnetic field, which creates an electron return effect (ERE). In this work we aim to validate PRESAGE(r) dosimetry in a transverse magnetic field, and assess its use to validate the research version of the Monaco TPS of the MR-linac. Cylindrical samples of PRESAGE(r) 3D dosimeter separated by an air gap were irradiated with a cobalt-60 unit, while placed between the poles of an electromagnet at 0.5 T and 1.5 T. This set-up was simulated in EGSnrc/Cavity Monte Carlo (MC) code and relative dose distributions were compared with measurements using 1D and 2D gamma criteria of 3% and 1.5 mm. The irradiation conditions were adapted for the MR linac and compared with Monaco TPS simulations. Measured and EGSnrc/Cavity simulated profiles showed good agreement with a gamma passing rate of 99.9% for 0.5 T and 99.8% for 1.5 T. Measurements on the MR-linac also compared well with Monaco TPS simulations, with a gamma passing rate of 98.4% at 1.5 T. Results demonstrated that PRESAGE(r) can accurately measure dose and detect the ERE, encouraging its use as a QA tool to validate the Monaco TPS of the MR-linac for clinically relevant dose distributions at tissue-air boundaries. PMID- 29393068 TI - A physico-genetic module for the polarisation of auxin efflux carriers PIN-FORMED (PIN). AB - Intracellular polarisation of auxin efflux carriers is crucial for understanding how auxin gradients form in plants. The polarisation dynamics of auxin efflux carriers PIN-FORMED (PIN) depends on both biomechanical forces as well as chemical, molecular and genetic factors. Biomechanical forces have shown to affect the localisation of PIN transporters to the plasma membrane. We propose a physico-genetic module of PIN polarisation that integrates biomechanical, molecular, and cellular processes as well as their non-linear interactions. The module was implemented as a discrete Boolean model and then approximated to a continuous dynamic system, in order to explore the relative contribution of the factors mediating PIN polarisation at the scale of single cell. Our models recovered qualitative behaviours that have been experimentally observed and enable us to predict that, in the context of PIN polarisation, the effects of the mechanical forces can predominate over the activity of molecular factors such as the GTPase ROP6 and the ROP-INTERACTIVE CRIB MOTIF-CONTAINING PROTEIN RIC1. PMID- 29393069 TI - Universal features underlying the magnetism in diluted magnetic semiconductors. AB - Investigation of a diverse variety of wide band gap semiconductors and metal oxides that exhibit magnetism on substitutional doping has revealed the existence of universal features that relate the magnetic moment of the dopant to a number of physical properties inherent to the dopants and the hosts. The investigated materials consist of ZnO, GaN, GaP, TiO2, SnO2, Sn3N4, MoS2, ZnS and CdS doped with 3d-transition metal atoms. The primary physical properties contributing to magnetism include the orbital hybridization and charge distribution, the d-band filling, d-band center, crystal field splitting, electron pairing energy and electronegativity. These features specify the strength of the spin-polarization induced by the dopants on their first nearest neighboring anions which in turn specify the long range magnetic coupling among the dopants through successively induced spin polarizations (SSP) on neighboring dopants. The proposed local SSP process for the establishment of the magnetic coupling among the TM-dopants appears as a competitor to other classical processes (superexchange, double exchange, etc). Furthermore, these properties can be used as a set of descriptors suitable for developing statistical predictive theories for a much larger class of magnetic materials. PMID- 29393070 TI - Spin filter effect of hBN/Co detector electrodes in a 3D topological insulator spin valve. AB - Topological insulators emerge as promising components of spintronic devices, in particular for applications where all-electrical spin control is essential. While the capability of these materials to generate spin-polarized currents is well established, only very little is known about the spin injection/extraction into/out of them. Here, we explore the switching behavior of lateral spin valves comprising the 3D topological insulator Bi2Te2Se as channel, which is separated from ferromagnetic Cobalt detector contacts by an ultrathin hexagonal boron nitride (hBN) tunnel barrier. The corresponding contact resistance displays a notable variation, which is correlated with a change of the switching characteristics of the spin valve. For contact resistances below ~5 kOmega, the hysteresis in the switching curve reverses upon reversing the applied current, as expected for spin-polarized currents carried by the helical surface states. By contrast, for higher contact resistances an opposite polarity of the hysteresis loop is observed, which is independent of the current direction, a behavior signifying negative spin detection efficiency of the multilayer hBN/Co contacts combined with bias-induced spin signal inversion. Our findings suggest the possibility to tune the spin exchange across the interface between a ferromagnetic metal and a topological insulator through the number of intervening hBN layers. PMID- 29393072 TI - The melting points of MgO up to 4 TPa predicted based on ab initio thermodynamic integration molecular dynamics. AB - The melting curve of MgO is extended up to 4 TPa, corresponding to the Jovian core pressure, based on the one-step thermodynamic integration method implemented on ab initio molecular dynamics. The calculated melting temperatures are 3100 and 16 000 K at 0 and 500 GPa, respectively, which are consistent with previous experimental results, and 20 600 K at 3900 GPa, which is inconsistent with a recent experimental extrapolation, which implies the molten Jovian core. A quite small Clapeyron slope ([Formula: see text]) of [Formula: see text] is found at 3900 GPa due to comparable densities of the liquid and B2 phases under extreme compression. The Mg-O coordination number in the liquid phase is saturated at around 7.5 above 1 TPa and remains smaller than that in the B2 phase (8) even at 4 TPa, suggesting no density crossover between liquid and crystal and thus no further denser crystalline phases. Dynamical properties (atomic diffusivity and viscosity) are also investigated along the melting curve to understand these behaviors in greater detail. PMID- 29393073 TI - A novel method to remove the background from x-ray diffraction signal. AB - The first step that is required to extract the correct information from a two dimensional (2D) diffraction signature is to remove the background accurately. However, direct background subtraction inevitably overcorrects the signal as it does not take into account the attenuation by the sample. Other traditional background removal methods, such as the rolling ball technique, can separate sharp diffraction peaks of crystalline materials from their background. These methods are unsuitable for biological tissue, which is amorphous and does not have sharp diffraction peaks. This technical note proposes a novel method that combines peak fitting and experimental results to estimate the background for 2D XRD signals. PMID- 29393074 TI - Laparoscopic appendectomy for the treatment of acute appendicitis: a single center experience. AB - AIM: The aim of our study is to compare the pre, intra- and post-operative variables of the two surgical techniques, to demonstrate if laparoscopic appendectomy can be considered safer and associated to better outcome. MATERIAL OF STUDY: A retrospective analysis of 175 patients has been carried out. Alvarado score, time of surgery, analgesic therapy and length of hospital stay calculated. Finally, postoperative complications were recorded. RESULTS: From January 2011 - April 2016 175 patients were enrolled: 128pts underwent laparoscopic technique and 47pts open technique. The average value of Alvarado score is lower in LA group than in OA group just as the average time of surgery and the use of post operative analgesic therapy. DISCUSSION: LA has become the surgical technique mostly performed for the treatment of simple and complicated acute appendicitis. Our study shows that LA pts are younger with a statistically significant difference CONCLUSIONS: Most of the emergency appendectomies were performed via laparoscopic technique, especially in young patients. Laparoscopy is safer and associated to better outcome. KEY WORDS: Alvarado Score, Laparoscopic appendectomy, Open appendectomy. PMID- 29393071 TI - MRI-only treatment planning: benefits and challenges. AB - Over the past decade, the application of magnetic resonance imaging (MRI) has increased, and there is growing evidence to suggest that improvements in the accuracy of target delineation in MRI-guided radiation therapy may improve clinical outcomes in a variety of cancer types. However, some considerations should be recognized including patient motion during image acquisition and geometric accuracy of images. Moreover, MR-compatible immobilization devices need to be used when acquiring images in the treatment position while minimizing patient motion during the scan time. Finally, synthetic CT images (i.e. electron density maps) and digitally reconstructed radiograph images should be generated from MRI images for dose calculation and image guidance prior to treatment. A short review of the concepts and techniques that have been developed for implementation of MRI-only workflows in radiation therapy is provided in this document. PMID- 29393075 TI - A rare case of multiple Becker's nevi without systemic involvement. PMID- 29393076 TI - Familial gigantic melanocytosis. PMID- 29393077 TI - Warty squamous cell carcinoma of glans penis. PMID- 29393078 TI - Eosinophilic fasciitis associated with Raynaud's phenomenon, esophageal dysmotility, positive antinuclear antibody and anti-neutrophil cytoplasmic antibody. PMID- 29393079 TI - Percutaneous ethanol injection as a promising and minimally invasive treatment for axillary osmidrosis: Double-blinded randomized controlled trial. AB - Background: Axillary osmidrosis is a common problem with a strong negative impact on the professional and social quality of life. Several options are available for its treatment. But there are no treatment guidelines. The objective of this study was to evaluate efficacy and safety of percutaneous ethanol injection for treatment of axillary osmidrosis. Methods: A randomized, double-blind, placebo controlled clinical trial to assess clinical efficacy and postoperative complications of percutaneous ethanol injection was performed among 60 patients (12-35 years of age) with axillary osmidrosis. The active agent used in the experimental group (n = 30) was sterile 90% ethanol and the placebo used in the control group (n = 30) was sterile normal saline administered in an identical syringe. The results of malodor elimination were graded by the patients as excellent, good, fair, and poor. All patients were followed-up for 10 months. Results: Malodor elimination was graded as good by 15 (50%) patients treated with percutaneous ethanol injection. A significant difference in the improvement of axillary osmidrosis was found between the experimental and control groups (P < 0.001). The most common post-procedure complication was transient subjective skin stiffness in the experimental group, which regressed spontaneously. There were no serious permanent side effects. Limitations: Relatively short duration of follow up; and lack of histopathological evidence of destruction of the apocrine glands after treatment in most patients. Conclusions: Percutaneous ethanol injection is an effective and safe treatment method for axillary osmidrosis and does not have permanent side effects. PMID- 29393080 TI - Wolf's isotopic nonresponse in healed herpes zoster in erythroderma. PMID- 29393081 TI - Kumkum-induced allergic contact dermatitis: Are we missing the actual culprit? AB - Background: Kumkum, made with turmeric and slaked lime along with colour enhancing dyes is known to cause allergic contact dermatitis. The possible contact allergens in kumkum include turmeric, Sudan-1, 4-aminoazobenzene, brilliant lake red R and cananga oil. We report patch test results among patients with suspected contact hypersensitivity to kumkum. Objective: To identify the allergen causing kumkum induced allergic contact dermatitis by patch testing and to advise patients about organic kumkum which doesnot contain colour enhancing dyes. Methods: Eighteen patients with suspected contact hypersensitivity to kumkum were patch tested with undiluted kumkum, undiluted turmeric, Sudan-1 (95%), 4-aminoazobenzene and allergens of the Indian Standard Series. Results: Of the 18 patients, 14 patients had patch test positivity to kumkum and 4 had a negative reaction to kumkum. Patch test with other suspected contact allergens showed positive reaction to turmeric in 4 patients, Sudan-1 in 3 patients and 4 aminoazobenzene in 2 patients. Among the allergens of the Indian Standard Series, positivity to nickel and fragrance mix was seen in 5 and 2 patients respectively. Positive reaction to PPD, chlorocresol and parthenium was seen in 1 patient each. Limitation: Small sample size. Conclusion: Allergic contact dermatitis to kumkum occurs both due to the dyes (added for enhancing the colour) and turmeric. All patients with suspected allergic contact dermatitis should be patch tested with kumkum, turmeric and dyes, based on which alternative non-allergic material could be advised. Kumkum dermatitis can also occur due to various other allergens, for which too patch testing should be done. PMID- 29393082 TI - Diffusion-Weighted and Perfusion-Weighted MRI to Evaluate Therapeutic Response in Lymphoma: A Comparison with FDG-PET/CT. PMID- 29393083 TI - Factors that Influence Sample Adequacy in Liquid-Based Cytology after Ultrasonography-Guided Fine-Needle Aspiration of Thyroid Nodules: A Single-Center Study. AB - OBJECTIVE: The factors that influence the acquisition of adequate samples during liquid-based cytology (LBC) remain unclear. This study aimed to identify factors that affect cytological adequacy in LBC after ultrasonography (US)-guided fine needle aspiration (US-FNA) of thyroid nodules. STUDY DESIGN: From January 2017 to May 2017, a single radiologist performed US-FNA to diagnose 112 thyroid nodules in 112 consecutive patients. Based on US findings after US-FNA, the size, location, position, composition, calcification, and vascularity of each nodule, as well as the US-based diagnosis, were investigated by the same radiologist. Blinded to US information, a single cytopathologist investigated cytological adequacy, cytological cellularity, and Bethesda category. RESULTS: Of the 112 thyroid nodules, cytological adequacy was achieved in 91.1% (102/112). Thyroid nodules with sizes >=20 mm or those that were predominantly cystic showed a higher rate of cytological inadequacy (p < 0.05). Thyroid nodule location, position, calcification status, and vascularity did not influence cytological adequacy, nor did US-based diagnosis (p > 0.05). Nodule composition or calcification significantly influenced cytological cellularity (p < 0.05), whereas nodule size, location, position, vascularity, and US-based diagnosis did not (p > 0.05). CONCLUSIONS: Most investigated factors did not influence cytological adequacy or cellularity. PMID- 29393084 TI - Clinical Course and Outcome of Childhood Acquired Platelet Dysfunction with Eosinophilia. AB - Acquired platelet dysfunction with eosinophilia (APDE) is a syndrome which manifests as a transient state of platelet dysfunction in the presence of eosinophilia. The aim of this work was to study the clinical course and outcomes of children diagnosed with APDE. The hospital records of children with APDE were retrospectively reviewed and a total of 69 children were included. The mean (standard deviation) age at diagnosis was 6.9 (3.1) years. All of the patients presented with ecchymoses on the extremities, body, and face. None had serious bleeding symptoms. Platelet counts were within the normal range but all of the patients had abnormal platelet morphology by light microscopy. Parasitic infestation was found in 38% and most (87%) were treated with antiparasitic drugs. The median time from the onset of symptoms to remission was 2.6 months (95% CI 1.8-3.1). The overall complete remission rates at 3, 6, and 12 months were 61, 90, and 94%, respectively, with a median follow-up time after remission of 14.0 months (interquartile range 6.0-30.8). Neither univariate nor multivariate analysis indicated any statistically significant determinants for remission time. In our study, APDE was transient with spontaneous remission, no serious bleeding manifestations, and had a benign clinical course. PMID- 29393085 TI - The Association between Serum Uric Acid and Renal Damage: The Takahata Study - New Insights. AB - BACKGROUND: Hyperuricemia is a risk factor for causing end-stage kidney disease and cardiovascular disease in the general population; however, several aspects, such as the site of kidney damaged by hyperuricemia and the threshold levels of serum uric acid for the development of renal damage, have not been fully clarified. SUMMARY: To examine these aspects, we analyzed data from the Takahata study, a community-based cohort study involving participants of an annual health check-up, and used urinary albumin creatinine ratio (UACR) and urinary beta2 microglobulin creatinine ratio (UBCR) in spot urine as indices of glomerular and tubular damage respectively. In cross-sectional analysis, increased serum uric acid levels were accompanied by higher UACR values and lower UBCR values. Multivariate analysis revealed that albuminuria (UACR >=30 mg/g), but not elevated UBCR, was independently associated with increased uric acid (>=7 mg/dL for males, >=6 mg/dL for females). In longitudinal analysis, uric acid at baseline was an independent factor for a 1-year increase in the UACR. Cox proportional hazard model analysis with adjustment for possible confounders including age, renal function, and comorbidities revealed that hyperuricemia was an independent risk factor for all-cause and cardiovascular mortality in females. Key Messages: Our results revealed that elevated uric acid is an independent risk factor for glomerular damage, but not tubular damage, and that the risk for renal damage and mortality might be increased at the high-normal range of uric acid in the community-based population. PMID- 29393086 TI - Uric Acid: The Unknown Uremic Toxin. AB - This review brings together concepts of uric acid metabolism affecting renal parenchyma and its function and the current therapies to reduce hyperuricemia (HyU) and avoid renal disease progression. High uric acid plays an important role in several chronic diseases including kidney diseases such as lithiasis, gout nephropathy, and preeclampsia. In the last 30 years, it has been shown that reducing HyU with low protein and low purine diets in addition to allopurinol creates physiopathological conditions that produce a slight increase in the glomerular filtration rate (GFR). In recent years, in a new era of research in clinical, genetics, pharmacological, and epidemiologic fields, they have been moving forward to support the idea that reduction in HyU could benefit the chronic renal failure (CRF) patients (stage III-IV), thereby avoiding the drop of GFR for undefined mechanisms. There are several clinical trials in progress that show the HyU reducing to very low values and an increased GFR. In a young population, when treating HyU there is a reduction in high blood pressure. There are some reports showing that HyU could play a role in the diabetic nephropathy. Therefore, there have been some speculations that HyU treatment could stop the progression of CRF modifying the natural history of the diseases. So there will be new clinical trials with old and new medication and metabolic procedure to maintain a very low blood levels in the unknown uremic toxin know as uric acid which seems to be the toxin to the damage kidney. PMID- 29393087 TI - Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy. AB - INTRODUCTION: Hepatitis C infection is highly prevalent worldwide and has a well known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear. CASE PRESENTATION: We present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response. One year after successful therapy, there was an unexplained decline of his liver function and atypical liver nodularity, which led to the diagnosis of a primary liver diffuse large B cell lymphoma. DISCUSSION: We review the evidence supporting possible mechanisms of lymphomagenesis after successful hepatitis C therapy, particularly involving late "second-hit" mutations after viral-induced DNA damage and antiviral therapy facilitating the emergence of latent malignant B-cell clones by decreasing local inflammation and immune surveillance. More reports may help elucidate any association between hepatitis C antiviral therapy and late lymphoid malignancies. PMID- 29393088 TI - The Pathophysiology of Uric Acid on Renal Diseases. AB - BACKGROUND: Asymptomatic hyperuricemia was regarded as a marker and considered secondary to some pathological conditions such as hypertension. During the last 16 years, a vast amount of experimental work has shown that uric acid can cause intracellular alterations that lead to cardiovascular, renal, and metabolic disease. Epidemiological and clinical studies support this notion in specific populations. However, the clinical studies done so far are of such a small number that it is difficult to reach a consensus in regard to the benefit of treating asymptomatic hyperuricemia. SUMMARY: Mild hyperuricemia in rodents induces hypertension associated to renal microvascular disease, tubulointerstitial inflammation, vasoconstriction, and glomerular hypertension. The cellular mechanisms that lead to those outcomes require an increase in intracellular concentrations of uric acid inducing oxidative stress that then activates the synthesis and secretion of proinflammatory factors and vasoconstrictive substances, and diminishes the bioavailability of nitric oxide produced by eNOS. Uric acid also induces proliferation, senescence, and fat accumulation or inhibits insulin secretion, depending on the cell type. Extracellular uric acid can act as an antioxidant; however, when it crystallizes it also induces the activation of prooxidant and proinflammatory pathways resulting in renal lesion. Key Messages: Experimental evidence shows that uric acid is a true mediator for cardiovascular, renal, and metabolic diseases. However, there is still need for greater and well-controlled intervention studies in humans to define whether treating asymptomatic hyperuricemia is worthwhile or not. PMID- 29393089 TI - Renal Effects of Hyperuricemia. AB - BACKGROUND: From a clinical point of view, uric acid has been dismissed as a cause of injury and renal progression, and the mechanisms by which uric acid directly causes renal injury have not been fully understood. Hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases. Although it remains controversial whether hyperuricemia is a causal factor for kidney disease, kidneys play a major role in the regulation of serum uric acid levels. SUMMARY: Similar to the management of other substances, renal uric acid management occurs mainly in the proximal tubule. The elevation of uric acid in blood is mainly due to an increase in its intake or a defect in its secretion. The mechanisms of renal damage go beyond the deposition of crystals at the tubular level; in this sense, renal damage also contributes to the production of chemotactic cytokines, cell proliferation, and inflammation, with the development of afferent arteriolopathy, glomerular hypertrophy and tubulointersticial fibrosis. Nevertheless, whether or not hyperuricemia plays a causal role or simply is a marker arising in the course of each related disorder remains unresolved. Although a strong relationship between hyperuricemia and metabolic syndrome has been established through animal and epidemiological studies, the potential pathophysiological mechanisms by which uric acid contributes to this disease state are just beginning to be explained and clarified. Key Messages: Experimental studies performed in animals have limitations due to the differences that exist between humans and other mammals in purine metabolism and in renal uric acid handling. Additional experimental studies aimed at evaluating the effects of lowering urate levels on the courses of these disorders are warranted in the future. PMID- 29393090 TI - Dietary Sodium/Potassium Intake Does Not Affect Cognitive Function or Brain Imaging Indices. AB - BACKGROUND: Dietary sodium may influence cognitive function through its effects on cerebrovascular function and cerebral blood flow. METHODS: The aim of this study was to evaluate the association of dietary sodium intake with cognitive decline in community-dwelling older adults. We also evaluated the associations of dietary potassium and sodium:potassium intake with cognitive decline, and associations of these nutrients with micro- and macro-structural brain magnetic resonance imaging (MRI) indices. In all, 1,194 participants in the Health Aging and Body Composition study with measurements of dietary sodium intake (food frequency questionnaire [FFQ]) and change in the modified Mini Mental State Exam (3MS) were included. RESULTS: The age of participants was 74 +/- 3 years with a mean dietary sodium intake of 2,677 +/- 1,060 mg/day. During follow-up (6.9 +/- 0.1 years), 340 (28%) had a clinically significant decline in 3MS score (>=1.5 SD of mean decline). After adjustment, dietary sodium intake was not associated with odds of cognitive decline (OR 0.96, 95% CI 0.50-1.84 per doubling of sodium). Similarly, potassium was not associated with cognitive decline; however, higher sodium:potassium intake was associated with increased odds of cognitive decline (OR 2.02 [95% CI 1.01-4.03] per unit increase). Neither sodium or potassium alone nor sodium:potassium were associated with micro- or macro-structural brain MRI indices. These results are limited by the use of FFQ. CONCLUSIONS: In community dwelling older adults, higher sodium:potassium, but not sodium or potassium intake alone, was associated with decline in cognitive function, with no associations observed with micro- and macro-structural brain MRI indices. These findings do not support reduction dietary sodium/increased potassium intake to prevent cognitive decline with aging. PMID- 29393091 TI - Increased Serum Leptin Levels in New-Onset, Untreated Female Patients with Coronary Artery Disease and Positively Associated with Inflammatory Markers. AB - BACKGROUND/AIMS: Previous studies have suggested that leptin was associated with atherosclerosis and involved in inflammation. Gender differences between leptin and inflammatory markers have been evaluated less in untreated patients with stable coronary artery disease (CAD). METHODS: In this study, a total of 394 consecutive Chinese patients who received coronary artery angiography were enrolled, including 243 patients with CAD and 151 non-CAD controls. The baseline clinical characteristics were collected and serum leptin levels were determined using ELISA. RESULTS: The relation of serum leptin levels to inflammatory markers was found only in female patients. Leptin and white blood cell count (WBCC) as well as its subsets were significantly higher in female patients than female controls. In female patients, leptin was positively associated with C-reactive protein (CRP; r = 0.28, p = 0.016), WBCC (r = 0.261, p = 0.02), neutrophil, r = 0.268, p = 0.018, and monocyte, r = 0.228, p = 0.044. Multivariable regression analysis revealed that leptin was significantly and independently associated with CRP (beta = 0.317, p = 0.004), WBCC (beta = 0.278, p = 0.020), neutrophil (beta = 0.262, p = 0.032), and monocyte (beta = 0.245, p = 0.032). CONCLUSIONS: The serum leptin levels were higher in female patients and independently associated with CRP, WBCC, and its subsets, suggesting a potential interaction between leptin and inflammation in female CAD patients. PMID- 29393092 TI - Predictors for Mortality after Mechanical Thrombectomy of Acute Basilar Artery Occlusion. AB - BACKGROUND: Modern endovascular thrombectomy (MET), using stent retrievers or large-bore distal aspiration catheters in stroke patients with acute basilar artery occlusion (BAO), is routinely performed to date. However, more than 35% of BAO patients treated with MET die within 90 days despite high recanalization rates. The purpose of this study is to investigate the parameters associated with 90-day mortality in patients with BAO after MET. METHODS: We analyzed 117 consecutive BAO patients included in the Endovascular Treatment in Ischemic Stroke prospective clinical registry of consecutive acute ischemic stroke patients treated with MET (60 patients [51.3%] treated with a stent retriever as first-line technique) between March 2010 and April 2017. Successful recanalization was defined as modified thrombolysis In cerebral infarction scores 2b-3 at the end of MET, and mortality was defined as modified Rankin Scale 6 at 90 days. Associations of baseline characteristics (patient and treatment characteristics) and intermediate outcomes (recanalization, complications) with 90-day mortality were investigated in univariate and multivariate analyses. RESULTS: Overall successful recanalization rate was 79.5, and 41.9% (95% CI 32.8 51.0%) of patients died within 90 days after MET. Patients with successful recanalization had a lower mortality rate (32.9 vs. 74.4%; p < 0.001). Failure of successful recanalization was an independent predictor of mortality (OR 5.1; 95% CI 1.34-19.33). In multivariate analysis, age >=60 years (OR 6.37; 95% CI 1.74 23.31), admission National Institute of Health Stroke Scale (NIHSS) >=13 (OR 4.62; 95% CI 1.42-15.03), lower posterior circulation-Alberta Stroke Program Early CT Score (pc-ASPECTS; OR 1.71; 95% CI 1.19-2.44), use of antithrombotic medication prior to stroke onset (OR 3.38; 95% CI 1.03-11.08), absence of intravenous thrombolysis (OR 3.36; 95% CI 1.12-10.03), and angioplasty/stenting of the basilar artery (OR 4.71; 95% CI 1.34-16.54) were independent predictors for mortality after MET. CONCLUSIONS: Failure of successful recanalization was a strong predictor for mortality. In the setting of recanalization, age, admission NIHSS, pc-ASPECTS, absence of intravenous thrombolysis, and angioplasty/stenting of the basilar artery were also independent predictors for mortality after MET of BAO patients. PMID- 29393093 TI - Routine Screening for KIT M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia. PMID- 29393094 TI - Body Mass Index Change and Hospitalization Risk in Elderly Hemodialysis Patients: Results from Japanese Dialysis Outcomes and Practice Patterns Study. AB - BACKGROUND: Short-term weight gains and losses are associated with a lower and higher mortality risk, respectively, in patients undergoing hemodialysis (HD). However, little is known about their association with the risk of subsequent hospitalization. METHODS: In a prospective cohort of 1,804 HD patients aged >=65 years enrolled in the Japanese Dialysis Outcomes and Practice Patterns Study phases 3 (2005-2008) and 4 (2009-2011), we examined the associations between changes in body mass index (BMI) over a 4-month baseline period (<-3%, -3 to < 1%, -1 to <1% [reference], 1 to <3%, and >=3%) and subsequent risk of all-cause, cardiovascular, and noncardiovascular hospitalization using Cox models with adjustment for potential confounders. RESULTS: During a median follow-up of 1.2 years, we noted 1,028 incident hospitalizations for any cause, including 275 and 753 hospitalizations for cardiovascular and noncardiovascular causes, respectively. An L-shaped association was observed between BMI change and all cause hospitalization. The multivariable-adjusted hazard ratios (HRs; 95% CI) of all-cause hospitalization associated with BMI changes of <-3%, -3 to <-1%, 1 to <3%, and >=3% (vs. -1 to <1%) were 1.29 (1.01-1.65), 1.22 (0.98-1.51), 1.04 (0.83 1.29), and 1.10 (0.83-1.45), respectively. Qualitatively similar associations were present for cardiovascular-related hospitalization (corresponding HRs [95% CI]: 1.58 [1.06-2.37], 1.09 [0.75-1.58], 0.99 [0.72-1.36], and 0.91 [0.51-1.64], respectively) but not for noncardiovascular-related hospitalization (corresponding HRs [95% CI]: 1.19 [0.90-1.57], 1.26 [0.99-1.59], 1.06 [0.84 1.35], and 1.18 [0.86-1.63], respectively). CONCLUSIONS: Decreases in BMI over a relatively short-term period were independently associated with higher risk of subsequent hospitalization, particularly cardiovascular-related hospitalization, among elderly HD patients. PMID- 29393095 TI - MYC Amplification in the Form of Ring Chromosomes 8 in Acute Myeloid Leukemia with t(11;16)(q13;p11.2). AB - Oncogene amplification is uncommon in acute myeloid leukemia (AML). Cytogenetically, it is primarily found as double minute chromosomes (dmin) or homogeneously staining regions (hsr). A 62-year-old woman was admitted to our hospital because of anemia and thrombocytopenia. Her bone marrow was hypercellular with 78.6% myeloperoxidase- positive blasts. Some had micronuclei. The patient was diagnosed with AML M2 and remains in complete remission (CR) after induction therapy. G-banding at diagnosis showed 51,XX,t(11;16)(q13;p11.2),+r1,+mar1*4. Spectral karyotyping confirmed t(11;16) and revealed that the ring and the marker chromosomes were derived from multiple copies of ring chromosome 8. Fluorescence in situ hybridization (FISH) with a MYC probe at 8q24 detected amplified MYC signals on 1 large and 4 small ring chromosomes 8. One MYC signal was deleted from one of the 2 chromosomes 8. FISH with a FUS probe at 16p11.2 showed monoallelic deletion of FUS. Immunohistochemistry demonstrated MYC protein overexpression at diagnosis and almost negative expression in CR. These results indicate that MYC amplification could occur in ring chromosomes without dmin. A cryptic MYC deletion suggests that an episome model could be applicable to MYC amplification in ring chromosomes as observed for dmin and hsr. Furthermore, considering 2 further reported cases, t(11;16)(q13;p11) may be a very rare but recurrent translocation in AML. PMID- 29393096 TI - Low Expression of FUS1 Is Negatively Correlated with miR-378 and May Predict Adverse Prognoses in Acute Myeloid Leukemia. AB - FUS1 is a tumor suppressor gene that has been found to be frequently lost in a variety of solid tumors. In this study, we aimed to investigate the expression status of the FUS1 gene in acute myeloid leukemia (AML), as well as its clinical significance. We further explored the correlation between the expression of FUS1 and miR-378 in AML. We detected expression of the FUS1 transcript in bone marrow mononuclear cells from 23 controls and 158 newly diagnosed AML patients by real time quantitative polymerase chain reaction. Downregulated FUS1 expression was found in 139 out of 158 (87.97%) AML cases; this rate was significantly lower than that in all 23 controls (p = 0.012). Receiver operating characteristic curve analysis revealed that the FUS1 transcript level could discriminate AML patients from controls effectively (area under the ROC curve = 0.663). Kaplan-Meier analysis demonstrated that non-M3-AML patients with a low FUS1 expression had a shorter overall survival (p = 0.049) and leukemia-free survival (p = 0.051) than those with a high FUS1 expression. Furthermore, we studied the correlation between the expression of FUS1 and miR-378 in 53 newly diagnosed AML patients. We found that the correlation coefficient was -0.346, which showed that FUS1 and miR 378 were negatively correlated in AML patients (p = 0.011). These results indicate that the low expression of FUS1 is a common molecular event in AML. PMID- 29393097 TI - Uric Acid: The Lower the Better? AB - BACKGROUND: Uric acid (UA) is still considered a risk factor, or even a causative agent, for chronic kidney disease (CKD); however, a few, important, clinical questions remain unanswered; in particular: when and whether urate-lowering therapy should be commenced in subjects with asymptomatic hyperuricemia and/or monosodium urate crystals deposition? What is the most appropriate UA target to be achieved and how long does it need to be maintained? How does treatment need be adjusted in patients with chronic kidney disease? SUMMARY: The observational and intervention studies available do not fully answer such questions, and a treatment to target trial is required. We provide here some preliminary opinion on how such a trial might be designed. A final unresolved issue relates to the possible (if any) dangers of overtreatment of hyperuricemia, leading to "hypouricemia," which may occur more frequently with newer, more potent, drugs. A U- or J-shaped association has been found between UA levels and mortality in epidemiologic studies; patients with congenital hypouricemia are more prone to exercise-induced renal failure; a theoretical concern, linked to more complete Xanthine Oxidase inhibition, may involve xanthine nephropathy, although up to now, it has been observed almost exclusively in patients with tumor lysis syndrome. Key Messages: Although there is no definite answer to the title question at the moment, available information tends to indicate a treatment target with serum UA levels between 5.0 and 6.0 mg/dL as reasonable. PMID- 29393098 TI - Marked Elevation of Serum Hyaluronic Acid in Patients Exhibiting Late-Phase Ascites after Allogeneic Hematopoietic Stem Cell Transplantation. PMID- 29393099 TI - Clinical Outcomes of Myocardial Bridging versus No Myocardial Bridging in Patients with Apical Hypertrophic Cardiomyopathy. AB - OBJECTIVE: To determine the prevalence and clinical effects of myocardial bridging (MB) in patients with apical hypertrophic cardiomyopathy (AHCM). METHODS: Angiograms from 212 AHCM patients were reviewed to identify MB. The patients were classified into 2 groups: AHCM with and AHCM without MB. We reviewed patient records on cardiovascular (CV) risk factors, symptoms, CV events, and CV mortality. RESULTS: In all, 60 patients with MB and 100 without MB were included. Rates of angina (61.7 vs. 40%; p = 0.008), mimicking non-ST segment elevation myocardial infarction (15 vs. 3%, p = 0.013), and Canadian Cardiovascular Society class III/IV angina (18.3 vs. 4%; p = 0.003) were higher in patients with MB than in those without. Mean follow-up periods (65.5 +/- 50.5 vs. 64.4 +/- 43.6 months, p = 0.378) and CV mortality (3.3 vs. 1%; p = 0.652) were similar in the 2 groups. Kaplan-Meier estimates demonstrated that CV event free survival rates were lower in patients with MB than in those without (71.7 vs. 88%; p = 0.022). MB, late gadolinium enhancement, and female sex were independent risk factors for CV events in a multivariate Cox regression analysis adjusted for other risk factors. CONCLUSION: More serious symptoms and a higher risk of CV events were observed in AHCM patients with MB than in those without MB. CV mortality was similar in these 2 groups. PMID- 29393100 TI - Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts. AB - BACKGROUND/AIM: A phase 3 trial of S-1, leucovorin (LV), and oxaliplatin for treating gastric cancer is now underway. However, the antitumor efficacy of the combination has not yet been examined in an in vivo preclinical study. This study examined the antitumor efficacy of combination therapy consisting of S-1, LV, and oxaliplatin against 4 human gastric cancer xenografts: NUGC-4, St-40, SC-2, and SC-4. METHODS: The antitumor efficacy was evaluated using human gastric cancer xenograft-bearing nude mice. S-1 and LV were administered orally once daily on days 1-7 at doses of 6.9 and 10 mg/kg, respectively. Oxaliplatin was administered intravenously at a dose of 8.3 mg/kg on day 1. The tumor volume was measured on day 15, and the relative tumor volume (RTV) was calculated. RESULTS: In all 4 xenograft models, S-1 alone and oxaliplatin alone, but not LV alone, had significant antitumor activities (p < 0.001). Combination therapy consisting of S 1 and LV resulted in a significantly smaller RTV than S-1 alone (p < 0.001). Combination therapy consisting of S-1 and oxaliplatin also resulted in a significantly smaller RTV than either S-1 alone (p < 0.001) or oxaliplatin alone (p < 0.001). Furthermore, combination therapy consisting of S-1, LV, and oxaliplatin resulted in the highest antitumor activity in these models (p < 0.001 vs. S-1 + LV; p < 0.001 or p = 0.003 vs. S-1 + oxaliplatin). CONCLUSION: Combination therapy consisting of S-1, LV, and oxaliplatin administered according to a 1-week-on/1-week-off schedule may be useful for the treatment of patients with gastric cancer. PMID- 29393101 TI - Resveratrol Promotes Recovery of Hearing following Intense Noise Exposure by Enhancing Cochlear SIRT1 Activity. AB - The sirtuin SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD) dependent protein deacetylase known to have protective effects against a wide range of neurological disorders. In the present study, we discovered that C57BL/6 mice fed a long-term diet supplemented with high-dose resveratrol exhibited increased cochlear SIRT1 activity and presented a better recovery of hearing and less loss of hair cells after intense noise exposure compared with those fed a standard chew. Moreover, resveratrol attenuated cochlear SIRT1 decrease and reduced oxidative stress in the cochlea after noise exposure. These results suggest a considerable therapeutic potential of resveratrol for the treatment of noise-induced hearing loss. PMID- 29393102 TI - Renal Handling of Uric Acid. AB - Hyperuricemia occurs in 21.4% of the adult population and is associated with several conditions that increase oxidative stress and contributes to the pathogenesis of inflammatory mechanisms for the development and progression of diseases. Serum blood or urine samples of uric acid levels were used to mainly identify clinical problems, depending on the uric acid pathway alterations, which include synthesis, reabsorption or its excretion. Several proteins that act particularly as transporters (URAT1, GLUT9, 1-NPT1, 1-NPT4, OAT4, 9-MCT9, hUAT1, etc.) have been identified in the recent past involving tubular transport and clearance leading to clinical benefits. Until now, the knowledge of uric acid homeostasis centers its primary investigation on understanding molecular and genetic mechanisms, including the genetic polymorphisms that induce genetic and acquire renal tubular disorder, which increases or diminishes urate excretion. PMID- 29393103 TI - The Relationship between the (In-)Stability of NORs and Their Chromosomal Location: The Example of Cercopithecidae and a Short Review of Other Primates. AB - Amongst Cercopithecidae, the species of the Cercopithecini tribe underwent a very active chromosome evolution, principally by fissions, which increased their chromosome number up to 72. In contrast, all the species of Papionini have fairly similar karyotypes with 42 chromosomes. In animals, nucleolus organizer regions (NORs) are generally considered as instable structures, which frequently vary in size, number, and location at both infra- and interspecific levels. Although in Cercopithecinae the NORs, involved in breaks, exchanges, and translocations, behave like fragile sites in somatic cells, their number and location appear to be very stable between species. Fluorescence in situ hybridization of a 28S rDNA probe on metaphase chromosomes displayed a unique interstitial location in either an acrocentric pair (in 12 species of Cercopithecini) or a metacentric pair (in 6 species of Papionini). A non-exhaustive survey of literature data on NOR location in other primates shows that numerical variations of the NORs principally depend on their location: most multiple NORs are in terminal positions, while almost all unique NORs are in interstitial positions. We propose that this correlation is the consequence of the selection against gametic imbalances involving the chromosomal material distal to the NORs, which is effective when they are interstitially, but not terminally, located. Thus, the consequences of the interstitial NOR instability for reproduction are essentially limited to their size variations, as observed in Cercopithecidae. PMID- 29393104 TI - Downregulated Expression of TRPV2 in Peripheral Blood Cells following Acute Myocardial Infarction Is Inversely Correlated with Serum Levels of CRP and Troponin I. AB - OBJECTIVES: We have recently shown that the transient receptor potential vanilloid 2 (TRPV2) channel is exclusively upregulated in rat/murine peri-infarct monocytes/macrophages following an acute myocardial infarction (AMI), and that this overexpression might be detrimental for cardiac recovery. We aimed to characterize the expression levels of TRPV2 in peripheral blood mononuclear cells (PBMCs) of AMI patients relative to individuals with normal coronaries, and to analyze potential associations with inflammatory and cardiac ischemic markers. METHODS: Patients who underwent coronary angiography due to AMI or chest pain were prospectively included. PBMCs were isolated from whole blood by Ficoll gradient centrifugation. TRPV2 expression was analyzed by real-time PCR. C reactive protein (CRP) and troponin I (TpI) levels were determined at the central chemistry laboratory; interleukin 6 and insulin-like growth factor (IGF)-1 levels were tested by ELISA. RESULTS: Following AMI, the number of TRPV2-expressing PBMCs was reduced when compared to in patients with normal coronaries. An inverse correlation was documented between the numbers of circulating macrophages and TRPV2 expression. Additionally, TRPV2 expression was inversely correlated with CRP and TpI and directly correlated with serum IGF-1. CONCLUSIONS: We assume that peripheral TRPV2 downregulation occurs concomitantly with the accumulation of TRPV2-white blood cells in the peri-infarct zone. TRPV2 may thus represent a novel target for treatment in the acute phase after MI. PMID- 29393105 TI - Regulation of Hypertension for Secondary Prevention of Stroke: The Possible 'Bridging Function' of Acupuncture. AB - Worldwide, stroke is the leading cause of mortality and disability, with hypertension being an independent risk factor for a secondary stroke. Acupuncture for the treatment of hypertension gains more attention in alternative and complementary medicine, but the results are inconsistent. Few studies regarding the secondary prevention of stroke by managing hypertension with acupuncture have been carried out as there are some problems regarding the antihypertensive drug status in the secondary prevention of stroke. Still, the potential of acupuncture in regulating the blood pressure for secondary stroke prevention deserves our focus. This review is based on papers recorded in the PubMed, Embase, and Web of Science databases, from their inception until March 28, 2017, and retrieved with the following search terms: hypertension and acupuncture, limited in spontaneously hypertensive rats (SHRs), stress-induced (or cold-induced) hypertensive or pre-hypertensive models. We find that, in these hypertensive animals, acupuncture could mainly influence factors related to the nervous system, oxidative stress, the endocrine system, cardiovascular function, and hemorheology, which are closely associated with the stroke outcome. This trend may give us a hint that acupuncture might well participate in the secondary prevention of stroke through these pathways when used in the management of hypertension. PMID- 29393106 TI - Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies. AB - AIMS: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). METHODS: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (ug/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. RESULTS: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA beta = 0.28, ALA beta = 0.13, EPA beta = 0.34, and DHA beta = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA beta = 0.19, ALA beta = 0.10, EPA beta = 0.31, and DHA beta = 0.41. CONCLUSIONS: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA. PMID- 29393108 TI - Gout: A Disease of Kings. AB - As a disease of kings, and the king of diseases, gout is one of the oldest joint diseases known to humans. First described as far back as 2640 B.C., gout is still the most common form of inflammatory arthritis haunting humans in the 21st century. The disease is caused by the chronic elevation of serum uric acid levels above the saturation point for monosodium urate crystal formation. Its incidence is progressively rising even today, but there are also regional and ethnic variations. Finally, the role of genetics is only beginning to be unraveled. PMID- 29393107 TI - Pazopanib-Induced Hepatotoxicity in an Experimental Rat Model. AB - Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity. PMID- 29393109 TI - Hyperuricemia and Progression of Chronic Kidney Disease: Role of Phenotype Transition of Renal Tubular and Endothelial Cells. AB - BACKGROUND: Although the clinical implication of hyperuricemia in chronic kidney disease has been an issue of active debate, recent data suggested a causative role of uric acid (UA) in the development of renal disease. Afferent arteriopathy, an induction of oxidative stress and an activation of local inflammation, have been regarded as the mechanisms of UA-induced renal disease, which contribute to glomerular hypertrophy and interstitial fibrosis via endothelial dysfunction. However, there have been rare studies on the direct effect of UA on phenotype transition of renal cells such as epithelial-to mesenchymal transition (EMT) or endothelial-to-mesenchymal transition (EndoMT). SUMMARY: We have reported that UA-induced EMT of cultured renal tubular cells, which was blocked by the organic anion transport inhibitor, probenecid. UA increased the expression of snail and slug, the transcriptional repressors of E cadherin, which resulted in a downregulation of E-cadherin production. UA also increased the degradation of E-cadherin via ubiquitination. UA also induced EndoMT with an increase in ROS generation and glycocalyx shedding of cultured vascular endothelial cells. Treatment with antioxidants ameliorated UA-induced EndoMT. In the kidney of hyperuricemic rats, there was an evidence of EMT before the development of significant tubulointerstitial fibrosis, as shown by decreased E-cadherin expression and an increased alpha-smooth muscle actin (alpha-SMA) in renal tubular cells. Allopurinol significantly inhibited UA-induced EMT with an amelioration of renal fibrosis. In addition, endothelial staining in peritubular capillaries (PTC) was substantially decreased with de-novo expression of alpha SMA in endothelial cells of PTC. Key Messages: UA per se induced a phenotypic transition of epithelial and endothelial cells via an induction of oxidative stress and glycocalyx shedding, which could be one of the mechanisms of UA induced kidney disease. PMID- 29393110 TI - Can We Avert an Acute Coronary Syndrome? Unmet Public and Professional Education/Information Needs. PMID- 29393111 TI - The Physiology and Mechanism of Growth. PMID- 29393112 TI - Obesity, Metabolic Syndrome and Nutrition. PMID- 29393113 TI - Term and Preterm Infants. PMID- 29393114 TI - Cognition. PMID- 29393115 TI - Nutrition and Growth in Chronic Disease. PMID- 29393116 TI - Early Nutrition and Its Effect on Growth, Body Composition and Later Obesity. PMID- 29393117 TI - Malnutrition and Catch-Up Growth during Childhood and Puberty. PMID- 29393118 TI - Pregnancy: Impact of Maternal Nutrition on Intrauterine Fetal Growth. PMID- 29393119 TI - Stunting in Developing Countries. PMID- 29393121 TI - Time to Target Uric Acid to Retard Chronic Kidney Disease Progression. AB - Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6.0 mg/dL to inhibit the progression towards end-stage renal disease. Underlying mechanisms whereby an increase in serum UA induces kidney injury have been elucidated in animal models. Hyperuricemic models can lead to systemic hypertension, arteriolosclerosis including afferent arteriolopathy as well as albuminuria probably due to the activation of oxidative stress. Discoveries of urate transporters have elucidated the novel mechanism of UA transport in the kidney and intestine. The intestinal ABCG2 may play a compensatory role in light of decreased renal clearance of UA in CKD model rats, the trigger of which is not a uremic toxin but serum UA itself. Insulin directly upregulates URAT1 and downregulates ABCG2 in the kidney tubules, suggesting a possible link between UA and metabolic syndrome. This review summarizes the recent knowledge on the causal effect of serum UA on the kidney injury. PMID- 29393120 TI - Prevalence of Chronic Kidney Disease, Thrombotic Cardiovascular Events, and Use of Oral P2Y12 Inhibitors among Veterans. AB - BACKGROUND: Contemporary prevalence of chronic kidney disease (CKD) and thrombotic cardiovascular (CV) events remains unclear in Veterans enrolled in the Veterans Affairs Health Care System (VA) care. Although oral P2Y12 inhibitors (P2Y12i) are increasingly being prescribed to this patient population, the overall prescription trend for P2Y12i remains unclear. METHODS: Using national VA corporate warehouse data, we used International Classification of Diseases-9 codes to identify Veterans with CKD, dialysis-dependent CKD, and CV events. VA pharmacy data were used to count P2Y12i prescriptions for the federal fiscal years (FY) 2011 through 2015. RESULTS: The period prevalence of Veterans with CKD was 378,233 (6.1%). The point prevalence of CKD increased by 49% from 132,979 (2.30%) in FY11 to 213,444 (3.42%) in FY15. The period prevalence of Veterans with dialysis-dependent CKD was 150,298 (2.4%). In all, 128,703 (56.7%) CV events occurred in Veterans with CKD. Veterans with CKD were given 50.1% of prescriptions for clopidogrel, 49.3% for prasugrel, and 60.4% for ticagrelor. In this patient population, year-to-year increases in P2Y12i prescriptions were observed with a dramatic increase in ticagrelor prescriptions. CONCLUSION: CKD is common among Veterans and its true prevalence is likely being underestimated. The prevalence of dialysis-dependent CKD is higher among Veterans than the non Veteran US population. CV events are widely co-prevalent and these patients are commonly prescribed P2Y12i. The recent increase in ticagrelor prescriptions in this patient population and large cost differences between the 3 P2Y12i underline the need for future studies to identify the preferred P2Y12i for these patients. PMID- 29393122 TI - Effect of the Valsalva Maneuver on the Second Heart Sound. AB - The Valsalva maneuver should be incorporated into the routine of auscultation even when a murmur is absent. Valsalva release affects the second heart sound. It is particularly helpful during detailed, non-perfunctory auscultation in patients with bundle branch block. PMID- 29393123 TI - The Secret Caverns of the Dragon's Brain: Current and Potential Contributions of Lizards to Evolutionary Neuroscience. PMID- 29393124 TI - Treatment of Hyperuricemia in Chronic Kidney Disease. AB - Hyperuricemia may be a major contributor to the development or progression of chronic kidney disease (CKD). Although there is no clear cutoff uric acid (UA) value associated to the risk for kidney damage, it appears to be an increased risk as UA rises. Lifestyle interventions such as exercise, weight reduction, low consumption of purine-rich meat, or avoiding high fructose intake are recommended for all hyperuricemic patients. Lowering urate drugs such as allopurinol or febuxostat may be an option as a renoprotective agent; yet, randomized clinical trials evaluating the safety and efficacy of these drugs are limited to a small number of single-center studies. Several ongoing clinical trials aim to evaluate the safety and efficacy of these drugs. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The purpose of this review is to summarize the evidence and future perspectives about the treatment of hyperuricemia in the prevention and progression of CKD. PMID- 29393125 TI - Validity of Predictive Equations for Resting Energy Expenditure in Greek Adults. AB - AIM: To examine the validity of published resting energy expenditure (REE) equations in Greek adults, and if indicated, develop new cohort-specific predictive REE equations. METHODS: Indirect calorimetry and anthropometric data were obtained from 226 adult volunteers of diverse age groups and body mass index ranges (18-60 years, 16.6-67.7 kg.m-2). Measured REE was compared to preexisting prediction equations via correlation, regression, and Bland-Altman analysis. Then, cohort-specific REE equations were developed using curve estimation and nonlinear regression. To reduce type I error, presently derived equations were validated by splitting the sample into a training and validation group. RESULTS: Preexisting equations over-predicted in-cohort REE. Equations by Livigston and Kohlstadt were most accurate at the individual level (63% accuracy), while formulas by Owen and collaborators elicited highest accuracy at the group level ( 1.8% bias). Bland-Altman analysis showed proportional bias for most equations. Currently developed equations showed highest overall accuracy with 70% at the individual and group level (1.0% bias), with small differences between measured and predicted REE values (mean, 95% CI 36 [-15 to 88] kcal.day-1). CONCLUSION: Data indicate currently developed equations to be the most accurate and valid for estimating REE in Greek adults. Further studies should examine the developed equations in an independent sample. PMID- 29393126 TI - Significance of Hyperuricemia among Community-Based Screening Participants. AB - BACKGROUND: Chronic kidney disease (CKD) is a risk factor of cardiovascular disease (CVD) and end-stage renal disease (ESRD). Early detection and management of risk factors of incidence and progression of CKD are necessary. We have been studying these risk factors among community-based screening participants in Okinawa, Japan. Okinawa was one of the longevity areas in the world; however, the incidence and prevalence of ESRD increased. In Japan, the incidence of ESRD is 2 times higher in men compared to that in women. Such gender difference in ESRD incidence may be explained by the difference in lifestyle-related factors such as obesity and metabolic syndrome. SUMMARY: We have shown the significance of hyperuricemia on the incidence of ESRD and progression of CKD. Hyperuricemia was associated with increased risk of developing ESRD, in particular women. Although the causal relationship between the levels of serum uric acid (SUA) and changes in estimated glomerular filtration rate (eGFR) was not clear, we observed that high SUA was associated with larger decrease in eGFR. People with hyperuricemia, >7.0 mg/dL, may have an unhealthy lifestyle. We observed to see if intensive care, involving regular monitoring of body mass index and lifestyle and intervention when appropriate by dietitians and general practitioners, led to improved renal outcomes among patients with stage 3 CKD, compared to standard care. The benefit was observed in patients with CKD stage 3b. Key Message: Hyperuricemia is closely associated with the incidence and progression of CKD. Lifestyle modification including hyperuricemia would be the basis of management of CKD patients. PMID- 29393127 TI - Uric Acid Renal Lithiasis: New Concepts. AB - BACKGROUND: Uric acid (UA) stones are responsible for 5-10% of the formation of all kidney stones. Recently, an association between UA stones and insulin resistance, diabetes mellitus, and obesity has been demonstrated and so the incidence has increased. The development of UA stones is dependent on several risk factors, including genetic predisposition, geographical location, dietary indiscretion, and various metabolic characteristics. SUMMARY: UA nephrolithiasis can arise from diverse etiologies, all with distinct underlying defects converging to one or more of 3 defects of hyperuricosuria, acidic urine pH, and low urinary volume. Low urinary pH is the commonest and by far the most important factor in UA nephrolithiasis, but the reason for this defect is unknown. Patients with UA nephrolithiasis have normal acid-base parameters assessed according to conventional clinical tests. Studies have revealed that there could be an insufficient production of urinary ammonium buffer. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Because low urine pH is the most important pathogenic factor of UA stone formation, urine alkalinization is an effective intervention to reduce UA crystallization and dissolve UA stones. Key Messages: Epidemiological and metabolic studies have indicated an association between UA nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule or due to substrate competition by free fatty acids. The identification of novel complementary DNA has provided an interesting insight into the renal handling of UA, including one genetic cause of renal UA wasting. PMID- 29393128 TI - Pediatric Acute Kidney Injury. AB - BACKGROUND: Acute kidney injury (AKI) in children is a serious condition with an important impact on morbidity and mortality. Onset can be insidious and it is frequently unrecognized in the early phase when the therapeutic opportunities are theoretically more effective. SUMMARY: The present review focuses on the most recent epidemiology studies and the progress in pediatric AKI (pAKI) research. Standardization of definition (presented in the Kidney Disease: Improving Global Outcomes) and novel biomarkers have been developed to help clinicians recognize kidney injury in a timely manner, both in adult and pediatric populations. Strengths and weaknesses of these diagnostic tools are discussed and the clinical scoring system (Renal Angina Index), which aims to provide a rational context for biomarker utilization, is also presented. Even if effective treatments are not currently available for established AKI, specific preventive approaches and some promising pharmacological treatments will be detailed. Renal replacement therapy is currently considered the most effective way to manage fluid balance when severe AKI occurs. Key Messages: Great efforts in pAKI research have today led to new strategies for early AKI detection and prevention strategies. Further studies have to be conducted in the next future in order to definitely improve the outcomes of pediatric patients experiencing this deadly syndrome. PMID- 29393129 TI - The Burden of Acute Kidney Injury and Related Financial Issues. AB - BACKGROUND: Acute kidney injury (AKI) is one of the most common complications in acutely ill patients. The epidemiology, clinical presentation, and outcome vary between patients and countries. SUMMARY: Patients with AKI often exhibit multiple organ dysfunction that is caused, in part, by marked cross-talk between the kidney and other organs and tissues. These deleterious interactions arise, at least in part, from systemic inflammatory changes, an increased cytokine load, increases in leukocyte trafficking and activation of neurohormonal processes. Typical short-term complications of AKI include acute lung injury, liver dysfunction, cardio-renal syndrome, brain dysfunction, systemic inflammation, and increased mortality. Survivors of AKI are at risk of chronic kidney disease, cardiovascular morbidity, strokes, infections, bone fractures and increased mortality. AKI is associated with high healthcare costs as a result of a longer stay in hospital, increased costs for investigations and interventions and the development of long-term complications including dialysis dependence, chronic comorbidities and re-hospitalisations. The outcomes and financial implications are worse in low-income countries compared to high-income countries. Key Message: AKI is common among hospitalised patients and associated with serious short- and long-term complications, increased mortality, and high health care costs. There are important differences in epidemiology and outcomes between low- and high income countries. PMID- 29393130 TI - Uric Acid in Pregnancy: New Concepts. AB - The relationship between hyperuricemia and hypertensive disorders is well established; however, until today, the role of uric acid in the clinical course of severe preeclampsia has not been elucidated. Some recent studies suggest that at the time of presentation, subjects with severe preeclampsia frequently have significantly elevated serum uric acid levels, and that the degree of elevation correlates with the severity of the maternal syndrome and fetal morbimortality. In this chapter, we present our workgroup experience. In 2016, we designed a prospective, cross-sectional comparative study. A sample of 200 patients - 100 with severe preeclampsia and 100 with normotensive pregnancy - was obtained. Plasmatic uric acid levels were recorded in units of mg/dL as clinical variables and as laboratory and fetal growth data. We considered uric acid equal to or more than 6.0 mg/dL as the elevated level. To relate the significance of elevated uric acid levels with variables, chi-square tests and Mann-Whitney U test were applied. Any p value equal or <0.05 was accepted as significant. We found significant difference (p = 0.05) between serum uric acid levels among both groups. In comparison with the healthy patients, patients with severe preeclampsia and uric acid greater than 6 mg/dl presented significant differences in relation to fetal complications and maternal laboratory and clinical variables. Our conclusion is that values equal to or greater than 6 mg/dL of serum uric acid in patients with severe preeclampsia may be a valuable biomarker for preeclampsia and an association with the presence of adverse fetal and maternal effects. PMID- 29393131 TI - Systemic Implications of Hyperuricemia. AB - Systemic implications of hyperuricemia need to be reconsidered in the context of the energy and protein wasting being an early indicator of organ deterioration in patients affected by the cardiometabolic syndrome and other frequent pathology states like pre-eclampsia, hyperparathyroidism, and chronic renal failure. This chapter points out physiological alterations that are to be made related to hyperuricemia, new diagnostic strategies, and early therapeutic interventions in the context of the old enemy: asymptomatic hyperuricemia. This chapter also concludes with a proposal to undertake research in this emerging, primary care, cost-efficient scenario. PMID- 29393132 TI - Emergent Start Peritoneal Dialysis for End-Stage Renal Disease: Outcomes and Advantages. AB - BACKGROUND/AIMS: Initiating renal replacement therapy in late referred patients with central venous catheter (CVC) hemodialysis (HD) causes serious complications. In urgent start peritoneal dialysis, initiating peritoneal dialysis (PD) within 14 days of catheter insertion still needs HD with CVC. We initiated Emergent start PD (ESPD) with Automated PD (APD) at our center within 48 h from the time of presentation. METHODS: A prospective, case-controlled, intention-to-treat study with 56 patients was conducted between March 2016 and August 2017. Group A (24 patients) underwent conventional PD 14 days after catheter insertion. Group B (32 patients), underwent ESPD with APD. Exit site leak (ESL), catheter blockage, and peritonitis at 90 days were primary outcomes. Technique survival was secondary outcome. RESULTS: Baseline characteristics were similar with 3 episodes of ESLs (9.4%) in the study group and none in the control group (p = 0.123). Catheter blockage (16.7%-Group A, 25%-Group B) and peritonitis (none vs. 9.4% in study group) were similar in terms of statistical details just as technique survival (95%-Group A, 88.2%-Group B at 90 days). CONCLUSION: ESPD with APD in the unplanned patient is an appropriate approach. PMID- 29393133 TI - Uric Acid as a Cause of the Metabolic Syndrome. AB - Hyperuricemia is common in subjects with obesity, metabolic syndrome, and type 2 diabetes. For many years, hyperuricemia was attributed to the effects of insulin resistance to reduce urinary excretion of uric acid, and it was believed that uric acid may not have any causal role in the metabolic syndrome. However, in recent years, hyperuricemia has been found to independently predict the development of diabetes. Experimental studies have also shown that hyperuricemia may mediate insulin resistance, fatty liver, and dyslipidemia in both fructose dependent and fructose-independent models of metabolic syndrome. The mechanism for uric acid-induced insulin resistance appears to be mediated by the development of mitochondrial oxidative stress and impairment of insulin-dependent stimulation of nitric oxide in endothelial cells. Pilot studies in humans have reported a potential benefit of lowering serum uric acid on insulin resistance. Large clinical trials are recommended. If uric acid is shown to be a mediator of incident type 2 diabetes in humans, then lowering serum uric acid would represent a simple and inexpensive way to help prevent the development of diabetes and to slow the epidemic. PMID- 29393135 TI - Acute Kidney Injury in the Geriatric Population. AB - The aging kidney is more susceptible to injury. Thus, it is not surprising that acute kidney injury (AKI) is a disorder with a relative high incidence in the elderly population, especially those with critical illness. Given the comorbid conditions common in the geriatric population as well as the increase in exposure to various nephrotoxic insults, it is likely that the incidence of AKI will grow in the coming decades. Thus, it is critical to gain an understanding of the cellular and molecular pathways operative in increasing the susceptibility to AKI with an aim to design therapies that will mitigate the risk of AKI. In the meanwhile, meticulous attention to preventative strategic is critical. When AKI does occur and renal replacement therapy is needed, individual decision making is required and should not be based on age alone. PMID- 29393134 TI - Safety of Cold Polypectomy for Colorectal Polyps in Patients on Antithrombotic Medication. AB - BACKGROUND: The cold polypectomy (CP) technique has been increasingly used in recent years. However, there have been few studies about post-polypectomy bleeding (PPB) in patients who underwent CP and who were on antithrombotic drugs. The objective of this study was to determine the safety of CP in patients on antithrombotic medication. METHODS: The subjects were patients who underwent CP in our hospital between April 2014 and March 2016. PPB rates were examined in relation to the use of antithrombotic medication. RESULTS: CP was performed to remove 2,466 polyps in 1,003 patients. There were 549 polyps (22.3%) in186 patients in the antithrombotic group and 1,917 polyps (77.7%) in 817 patients in the non-antithrombotic group. PPB occurred in 0.55% (3/549) of patients in the antithrombotic group and in 0.10% (2/1,917) of patients in the non-antithrombotic group, showing no significant difference (p = 0.07). Patients in the antithrombotic group in whom PPB occurred included 1 aspirin user with 1 polyp and 1 aspirin plus clopidogrel user with 2 polyps. No PPB occurred in patients on other antithrombotic agents or receiving heparin bridging. There was no significant difference between PPB rates in patients with small polyps (6-9 mm) in the antithrombotic and non-antithrombotic groups, but there was a significant difference between PPB rates in the 2 groups for patients with diminutive group (1-5 mm). CONCLUSION: CP is a safe procedure even in patients on antithrombotic medication. PMID- 29393136 TI - Acute Kidney Injury and Information Technology. AB - Acute kidney injury (AKI) is a common complication that occurs in critically ill patients and it is associated with a worse outcome. Since therapy options are limited, prevention and early detection are the essential cornerstones to improve patient outcomes. Therefore, using health information technology (HIT) to detect AKI early might be useful for clinicians. Patient data can be extracted real-time from electronic health records. Programmed electronic alert systems (e-alerts) can increase clinicians' awareness for AKI. Integrated into clinical decision support systems, implementation of HIT might improve clinical processes and patient outcomes. Several studies show the application of e-alerts in AKI detection and the implementation in processes of care. Monitoring nephrotoxic medication is one successful approach of implementing e-alerts in prevention of AKI. Information technology in AKI is in an early phase of development and further multicenter prospective studies are required to draw optimally on the maximum potential of this concept. PMID- 29393137 TI - Uric Acid and Diabetic Nephropathy Risk. AB - BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the western world. Current treatment methods, with better control of glycemia and blood pressure, including renin-angiotensin system blockade (RASB), appear to have slowed the DN progression rate but have not substantially decreased the annual incidence of new DN ESRD cases. Thus, new treatment targets are needed. SUMMARY: Higher levels of serum uric acid (UA) are associated with increased risk of the clinical manifestations of DN in persons with types 1 and 2 diabetes. Also, UA is a strong predictor of DN progression. Two small, short-term, proof-of-concept clinical trials in which a minority of the patients had diabetes suggested that reduction of UA with allopurinol could decrease the rate of glomerular filtration rate (GFR) loss in persons with chronic kidney disease (CKD). However, a definitive trial to check whether UA reduction can benefit DN progression has not been conducted as yet. Preventing Early Renal Loss in Diabetes (PERL) is an ongoing trial in persons with type 1 diabetes and early to moderate GFR reduction. This 3-year randomized placebo controlled trial in 530 subjects is to check whether UA reduction with allopurinol can slow the rate of GFR decline as determined by the plasma disappearance of iohexol. Key Message: If the results of the PERL trial are positive, initiation of UA reduction treatment while GFR is relatively well preserved could delay ESRD in DN by 8-10 years, that is, considerably longer than the period that has been demonstrated for RASB. This could have important implications for the treatment of DN in particular and of CKD in general. PMID- 29393138 TI - The Associations of School Oral Health-Related Environments with Oral Health Behaviours and Dental Caries in Children. AB - Creating supportive oral health-related environments in schools is an important strategy for promoting schoolchildren's oral health. This study determined the associations between school environments and children's oral behaviour and dental caries. The data on school oral health-related environments were obtained through observation and interviews. Oral behaviour and dental caries data were collected through interviews and oral examinations of 984 sixth grade children. chi2 and multiple logistic regression, adjusted for sociodemographic and economic status, other school environment variables, and oral behaviour were used. Providing fresh fruit with school meals was associated with low sweets consumption and low caries levels. Children's daily sweets consumption was positively associated with sweetened milk sales in schools. Selling sweetened beverages, including sweetened milk, sweetened drinks, and soft drinks, was associated with high caries levels, while selling meat and crispy packed snacks was associated with low caries levels. Children in schools with integrated oral health education were significantly more likely to brush their teeth twice a day and to brush after lunch. In conclusion, school oral health-related environments, especially available food choices, were associated with sweets consumption behaviour and caries levels. Children in schools with integrated oral health education had better brushing habits. PMID- 29393139 TI - Acute Kidney Injury Biomarkers: What Do They Tell Us? AB - The definition of acute kidney injury (AKI) is now well established and encompasses changes in both the urine output and the serum creatinine (SCr) over time. Many studies to date have concentrated solely on the SCr criteria, as this is relatively easy to monitor, given that accurate urine output is rarely measured outside critical care areas. However, many studies have emphasised the inadequacies of SCr in highlighting potential renal injury in a timely fashion. These limitations reflect not only acute changes in creatinine metabolism in the critically ill but also the kinetics of creatinine generation that may hinder early recognition of AKI. In turn, this may prevent judicious intervention promoting the misconception that little can be done for patients with this devastating condition except treating the consequences. Such observations have led to much research focused on identifying early indicators of AKI that may enable early treatment and hopefully lead to improved outcomes. This explains in part the reasoning behind the interest in biomarkers of AKI and which may see them develop a role as part of established clinical tool(s) in both the assessment of severity of AKI and the potential to assess recovery. However, much of the effort behind biomarker research has focused on the ability of such candidate molecules to predict AKI as defined by the imperfect gold standards used currently. It may be that the presence of renal biomarkers associated with renal stress or injury in isolation dictates poor outcomes and as such may provide diagnostic certainty in their own right. PMID- 29393140 TI - Acute Kidney Injury in Cardiac Surgery. AB - Patients who have undergone cardiac surgery are at high risk of acute kidney injury (AKI) and often associated with poor short- and long-term outcomes. It is considered that the burden of AKI can be reduced and the quality of care can be improved by raising the appropriate awareness and using the right tools for early prevention and better management, by (1) improving awareness by understanding the epidemiology and pathophysiology; (2) using tools for risk assessment for early prevention; (3) increasing the use of electronic screening for early diagnosis; and (4) developing right clinical strategies for better treatment. In this review, we will update some typical studies as well as some new concepts, which focus on the quality of care of CSA-AKI. PMID- 29393141 TI - LINC00037 Inhibits Proliferation of Renal Cell Carcinoma Cells in an Epidermal Growth Factor Receptor-Dependent Way. AB - BACKGROUND/AIMS: LINC00037 has previously been reported to be up-regulated in clear cell renal cell carcinoma (ccRCC), however, the underlying mechanism remained unknown. In this study, we designed to investigate the functional role of LINC00037 in ccRCC Methods: LINC00037 knockdown and re-expressing 786-O and A498 cells were established. CCK8 assay and EdU assay were performed to evaluate the proliferation rates of ccRCC cells. Flow cytometry assay was performed to detect the cell apoptosis and cell cycle. Subcutaneous injection xenotransplantation mouse model was used to observe the role of LINC00037 in tumor growth in vivo. Mass spectrometry (MS) was performed to find the interacting partner of LINC00037 and RNA immunoprecipitation (RIP) was carried out to validate their interaction. RESULTS: We found that knockdown of LINC00037 resulted in inhibited cell proliferation with activated apoptosis and cell cycle arrest in vitro. Over-expression of LINC00037 in LINC00037 knockdown cells restored and enhanced cell proliferation. In vivo mouse model indicated reduced tumor progression by LINC00037 depletion and promoted tumor progression by LINC00037 overexpression. LINC00037 could bind to epidermal growth factor receptor (EGFR) and increase the protein level of EGFR. CONCLUSION: LINC00037 could inhibit proliferation of ccRCC in an epidermal growth factor receptor dependent way. PMID- 29393142 TI - Optimized Management of Ulcerative Proctitis: When and How to Use Mesalazine Suppository. AB - BACKGROUND: Ulcerative proctitis, one of the disease types of ulcerative colitis, is considered one of the initial manifestations of ulcerative colitis. Prevention of aggravation of ulcerative proctitis is important for improving the prognosis of ulcerative colitis. Here we reviewed the epidemiology, diagnosis, and management of ulcerative proctitis. SUMMARY: The number of patients with ulcerative proctitis is increasing. Disease extension occurs in many patients with ulcerative proctitis. Differential diagnosis from other chronic proctitis is important and should be performed based on the clinical history and endoscopical and histological features. Mesalazine suppository has been the first-line therapy for patients with ulcerative proctitis because of its high effectiveness and safety. Topical treatment of ulcerative proctitis, particularly using mesalazine suppository has been underused in clinical practice. Key Messages: Mesalazine suppositories are more effective than dose intensification of oral mesalazine for relapsed patients with maintenance dose of oral mesalazine. However, low adherence to rectal mesalazine has hindered remission in patients with ulcerative proctitis. PMID- 29393143 TI - Mutans Streptococci and Dental Caries: A New Statistical Modeling Approach. AB - Survival analyses have been used to overcome some of the limitations encountered with other statistical analyses. Although extended Cox hazard modeling with time dependent variables has been utilized in several medical studies, it has never been utilized in assessing the complex relationship between mutans streptococci (MS) acquisition (time-dependent covariate) and time to having dental caries (outcome). This study involved secondary analyses of data from a prospective study conducted at the University of Alabama at Birmingham. Low socioeconomic status, African-American preschool children from Perry County, AL, USA (n = 95) had dental examinations at age 1 year and annually thereafter until age 6 years by three calibrated dentists. Salivary MS tests were done at ages 1, 1.5, 2, 2.5, 3, and 4 years. The patterns of and relationship between initial MS detection (time-dependent covariate) and dental caries experience occurrence were assessed, using extended Cox hazard modeling. The median time without MS acquisition (50% of the children not having positive MS test) was 2 years. Approximately 79% of the children had positive salivary MS tests by the age of 4 years. The median caries experience survival (50% of the children not having dental caries) was 4 years. During the follow-up period, 65 of the children (68.4%) had their initial primary caries experience. Results of the extended Cox hazard modeling showed a significant overall/global relationship between initial caries experience event at any given time during the follow-up period and having a positive salivary MS test at any time during the follow-up period (hazard ratio = 2.25, 95% CI 1.06 4.75). In conclusion, the extended Cox modeling was used for the first time and its results showed a significant global/overall relationship between MS acquisition and dental caries. Further research using causal mediation analysis with survival data is necessary, where the mediator "presence of MS" is treated as a time-dependent variable. PMID- 29393144 TI - Acute Kidney Injury in Cancer Patients. AB - BACKGROUND: Renal complications are a relevant clinical issue in patients with cancer; conversely, cancer in patients affected by kidney diseases is a growing problem mainly due to the aging of the general population. Onco-Nephrology is a novel subspecialty addressing these issues. SUMMARY: Acute kidney injury (AKI) is an important cause of morbidity and mortality in cancer patients, and recognizes a number of different causes, which can impact, directly and indirectly, on kidney function. Furthermore, the appearance of AKI may have a tremendously negative impact on oncological treatments, often denying cancer patients active and life-prolonging treatments. Overall, patients with cancer are at risk of AKI, which could be caused by antineoplastic treatments, sepsis, metabolic disturbances, hematopoietic stem cell transplantation, primary thrombotic micro angiopathies, and direct involvement of the kidney by hematological malignancies and also by solid cancer, in particular kidney and urothelial malignancies. Key Messages: (1) AKI is a frequent and increasing complication of cancer. (2) There is a bidirectional relationship between cancer and kidney disease, and in both cases, AKI is more likely to happen. (3) AKI in patients with cancer is associated with increased morbidity and mortality. (4) In cancer patients, a multidisciplinary approach and early intervention may reduce the incidence of AKI and its life-threatening consequences. (5) Onco-Nephrology is a growing area of nephrology that requires clinicians to have a better understanding of the renal complications of cancer including AKI. PMID- 29393145 TI - Osteocardiology: Defining the Go/No-Go Time Point for Therapy. AB - Recent epidemiological studies have revealed that the risk factors associated with coronary artery calcification (CAC), including male gender, smoking, hypertension, and elevated serum cholesterol, are similar to the risk factors associated with the development of calcific aortic valve disease (CAVD). The results of the experimental and clinical studies demonstrate that traditional risk factors initiate early atherosclerosis which over time differentiates to form bone in the heart causing clinical CAC and CAVD. Understanding the cellular mechanisms of cardiovascular calcification, the end-stage process of the atherosclerosis will help define the specific time point to modify this cellular process of bone formation in the heart termed osteocardiology. This time point between subclinical atherosclerosis and clinical calcification is the go/no-go time point, or the point of no return with severe clinical calcification in the heart. This review will summarize the development of bone formation in the heart termed osteocardiology, to define the go/no-go time point for therapy initiation to slow the progression of cardiovascular calcification. PMID- 29393146 TI - Correlation of Fecal Markers with Magnifying Endoscopic Stratification in Patients with Ulcerative Colitis Who Are in Clinical Remission. AB - BACKGROUND: Maintenance of mucosal healing is recommended during the treatment of ulcerative colitis (UC). However, symptoms of UC often do not reflect mucosal disease activity. Fecal markers such as calprotectin, lactoferrin, and hemoglobin have been reported to correlate well with the Mayo endoscopic subscore (MES) and are being considered alternative monitoring tools in endoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a new and more detailed endoscopic scoring system compared to MES. Furthermore, magnifying endoscopic stratification (ME) based on alterations in the mucosal surface pit patterns is noted in UC. However, the association between fecal markers and UCIES and magnifying endoscopy is relatively unexplored. SUMMARY: This study investigated the association between the aforementioned fecal markers and MES, UCEIS, and ME in patients with UC in clinical remission. This prospective study included 60 patients with UC in clinical remission who underwent colonoscopy at the Nagasaki University Hospital between June 2015 and November 2016. A significant correlation was observed between MES and all fecal markers. Notably, the fecal markers correlated well with UCEIS (calprotectin Spearman's correlation coefficient [r] = 0.54, p < 0.0001; lactoferrin r = 0.56, p < 0.0001; and hemoglobin r = 0.43, p < 0.001). Furthermore, ME findings correlated significantly with calprotectin (r = 0.50, p = 0.0002) and lactoferrin (r = 0.46, p = 0.0006) levels and slightly with hemoglobin (r = 0.28, p = 0.043) levels. Moreover, each cutoff level of fecal calprotectin, lactoferrin, or hemoglobin had a high sensitivity and specificity for the detection of MES = 0, UCEIS = 0, ME = A, for predicting mucosa healing. Key Messages: Fecal markers correlated not only with MES but also with UCEIS and ME and should be useful for monitoring patients with UC in clinical remission. PMID- 29393147 TI - Protein Profile of the Acquired Enamel Pellicle after Rinsing with Whole Milk, Fat-Free Milk, and Water: An in vivo Study. AB - This study detected changes in the protein profile of the acquired enamel pellicle (AEP) formed in vivo after rinsing with whole milk, fat-free milk, or water. Nine subjects in good oral condition took part in the study. The acquired pellicle was formed in the morning, for 120 min, after prophylaxis with pumice. Following this, the volunteers rinsed with 10 mL of whole milk, fat-free milk, or deionized water for 30 s, following a blinded crossover protocol. After 60 min, the pellicle was collected with filter paper soaked in 3% citric acid and processed for analysis by liquid chromatography-electrospray ionization tandem mass spectrometry. The obtained tandem mass spectrometry spectra were searched against a human protein database (Swiss-Prot). The proteomic data related to protein quantification were analysed using the PLGS software. A total of 260 proteins were successfully identified in the AEP samples collected from all groups. Forty-nine were common to all 3 groups, while 72, 62, and 49 were specific to the groups rinsing with whole milk, fat-free milk, and water, respectively. Some were typical components of the AEP, such as cystatin-B, cystatin-SN, isoforms of alpha-amylase, IgA and IgG, lysozyme C, protein S100 A78, histatin-1, proline-rich protein 27, statherin, and lactotransferrin. Other proteins are not commonly described as part of the AEP but could act in defence of the organism against pathogens. Distinct proteomic profiles were found in the AEP after rinsing with whole or fat-free milk, which could have an impact on bacterial adhesion and tooth dissolution. The use of fat-free milk could favourably modulate the adhesion of bacteria to the AEP as well as biofilm formation when compared with whole milk. PMID- 29393148 TI - Acute Kidney Injury: Diagnosis and Classification in Adults and Children. AB - BACKGROUND: The acute reduction of kidney function in critically and noncritically ill patients (regardless of their age) is one of the deadliest clinical conditions ever reported in modern medicine. Acute kidney injury (AKI) symptoms are sneaky and potentially difficult to be identified at the right time at the bedside. One of the greatest efforts of the recent history of critical care nephrology has been to find a common classification for AKI definition and staging with the purpose of allowing a timely diagnosis and push forward epidemiologic research. SUMMARY: AKI is currently defined by the Kidney Disease Improving Global Outcomes (KDIGO) consensus classification that applies conventional serum creatinine and urine output (UO) criteria. According to a recent large epidemiologic study, this classification led to the confirmation that AKI occurs in about half of adult critically ill patients admitted to the intensive care unit and that a stepwise increase in mortality is associated with the severity of AKI along KDIGO stages. Both serum creatinine and UO have inherent limitations in accurately diagnosing abrupt decreases of renal function, but their common and easy application in routine clinical practice is currently considered the standard of care for AKI diagnosis. Pediatric and neonatal AKI have recently been described and specific staging with KDIGO modification has been proposed. Key Messages: AKI is frequent in critically ill patients and significantly affects intensive outcomes independent of other clinical factors. AKI can be diagnosed and its severity accurately staged by the KDIGO classification and its modification for pediatric patients. Serum creatinine and UO criteria are applied in order to diagnose and stage AKI. Despite some significant limitations of these commonly applied biomarkers, their application has made it possible to clearly appraise the importance of accurate AKI identification in clinical practice in several studies for prognostic and therapeutic purposes. PMID- 29393150 TI - Contextual and Individual Determinants of Root Caries in Older People. AB - The aim of this study was to identify the association of the presence of root caries in older people with contextual and individual determinants using a multilevel model. Data from the National Survey of Oral Health collected in Brazil were used. A sample of older Brazilians (aged 65-74 years) was included and selected through multistage probability cluster sampling, using probability proportional to size. Contextual variables of municipalities and individual variables of older people were included. Descriptive, bivariate, and multilevel analyses were conducted. Of the 3,926 older people included in the study, 934 (21.8%) had at least 1 tooth with root caries. There seemed to be no pattern of involvement between the anterior and posterior teeth in the dental arches. Multilevel analysis showed a higher presence of root caries among older people resident in municipalities that were noncapital cities (OR = 1.50), who were over 70 years of age (odds ratio, OR = 1.22), had nonwhite skin color (OR 1.35), had coronal caries (OR = 5.58), were dissatisfied with their teeth and mouth (OR = 1.47), and had self-perceived dental treatment needs (OR = 1.33). Contextual and individual determinants were associated with the occurrence of root caries in older people. Lesion presence demonstrated a profile of social inequality. PMID- 29393149 TI - Redefining the Phenotype of Dental Caries. AB - Dental caries is a multifactorial infectious disease and a major public health problem estimated to affect 60-90% of school children as well as a vast number of adults. The aim of this work was to define patterns of progression of the disease based on longitudinal data in contrast to using a cross-sectional assessment. dmft/DMFT scores were collected at ages 5, 12, 14, 16, 17, and 18 from 876 individuals. We tested our newly defined phenotypes for association with genetic variants in genes shown to be associated with caries. We generated genotyping data using Taqman chemistry in markers of genes involved in processes such as enamel formation and salivary contributions. Kallikrein 4 (KLK4) was found to show a significant association with the created phenotypes (p = 0.0008 in a recessive model for low caries experience in the primary dentition vs. high caries experience in the primary dentition, and p = 0.0004 in a recessive model for caries free primary dentition vs. high caries experience in the primary dentition). PMID- 29393152 TI - Clinical Significance of Serum Uric Acid Levels in Mexican Young Adults. AB - BACKGROUND: High serum uric acid concentration (SUA >6 for women [W] or 7 mg/dL for men [M]) in adults is an independent risk factor for causing cardiovascular disease and chronic kidney disease (CKD); the risk of high SUA in young population is still being debated. SUMMARY: We conducted an epidemiological study to determine the association between SUA quartiles with cardiometabolic risk factors (CRF) and renal impairment in apparently healthy young adults. CRF (dyslipidemia, overweight [Ow], obesity [Ob], blood pressure [BP], hyperglycemia, insulin resistance [IR]) and renal impairment were defined as glomerular filtration rate (GFR) by CKD-Epidemiology Collaboration formula >130/120, <90 mL/min/1.73 m2, and proteinuria were measured in 18- to 25-year-old students (total n = 5,531). Adjusted ORs by sex were calculated using logistic regression. RESULTS: The mean SUA was 4.5 +/- 1.04 and 6.2 +/- 1.2 mg/dL in W and M respectively. High SUA was found in 13.9% (n = 767); prevalence of Ow/Ob 69% (528 of 767), high BP 9% (67), hyperglycemia 15% (112), IR 47% (214), hypertriglyceridemia 35% (269), high LDL-c 16% (120), low HDL-c 52% (399), and metabolic syndrome 33% (249). Prevalence of high GFR was 13% (103), low GFR 8% (62) and proteinuria 5% (37). All risk factors showed a positive relationship with the SUA quartiles with high LDL-c with lowest risk (OR 1.7) and Ow/Ob with highest risk (OR 4.1), independent of sex. Key Messages: High SUA concentrations (M >=6.2/W >=4.5 mg/dL) are associated with CRF and renal impairment in young adults. It is necessary to reevaluate the cutoff points for UA in young adults. PMID- 29393151 TI - Validation of the Cuban Version of Addenbrooke's Cognitive Examination-Revised for Screening Mild Cognitive Impairment. AB - BACKGROUND/AIMS: The diagnostic accuracy of the Cuban version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI) in comparison with the Mini-Mental State Examination (MMSE) was assessed. METHODS: The Cuban ACE-R was administered to a group of 129 elderly subjects (92 cognitively healthy and 37 subjects with MCI). The t tests for independent samples were used to compare scores of different psychometric scales between groups, and effect sizes (Cohen's d) were calculated. Cronbach's coefficient alpha was used to evaluate the reliability of psychometric scales. The validity of ACE-R to screen for MCI was assessed by receiver operating characteristic (ROC) curves. RESULTS: The Cuban ACE-R had reliable internal consistency (Cronbach's coefficient alpha = 0. 879). The optimal cut-off score for ACE-R for detecting MCI was 84/85. The sensitivity and specificity of ACE-R to screen for MCI was superior to those of MMSE. The area under the ROC curve of the Cuban ACE-R was much larger than that of MMSE (0.93 and 0.63) for detecting MCI. CONCLUSION: The Cuban ACE-R is a valid screening tool for detecting cognitive impairment. It is more sensitive and accurate in screening for MCI than MMSE. PMID- 29393153 TI - Acute Kidney Injury Recovery. AB - BACKGROUND: Acute kidney injury (AKI) is associated with both short- and long term clinical consequences including progression to chronic kidney disease. Recovery of renal function has gained importance, as interventions to prevent or treat AKI are limited. Basing recovery on a return of serum creatinine values excludes mounting evidence that AKI, even when reversible, is a very serious clinical event that will result in a significant number of both renal and extra renal complications such as late stage kidney disease, major cardiovascular events, and death. SUMMARY: Development of a definition for renal recovery is critical to organizing research in AKI treatment. Assessment of serum creatinine remains the primary measure of renal recovery despite known limitations. Patterns of renal recovery are highly associated with clinical outcomes including survival. Additional research in basic mechanisms of renal injury and repair is needed to help formulate a more comprehensive assessment of renal recovery. Novel biomarkers for assessment of AKI may also aid in the determination of renal recovery. Key Messages: (1) The concept of acute kidney disease (7-90 days post AKI) should direct clinicians as well as researchers to pay attention to a critical time period for renal recovery in which interventions may alter long term outcomes. (2) Recent studies have evaluated AKI recovery patterns, or trajectories, and is an important step towards defining long-term prognosis. (3) Serum creatinine alone is not a reliable marker of recovery after AKI and is associated with poor clinical outcomes despite a return to baseline levels. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel. PMID- 29393154 TI - Long Interspersed Element-1 Methylation Level as a Prognostic Biomarker in Gastrointestinal Cancers. AB - Epigenetic changes play a crucial role in human cancer development. DNA methylation is a central epigenetic process that regulates levels of gene expression. Changes in DNA methylation that occur in human tumors include global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Long interspersed element-1 (LINE-1) is a repetitive DNA retrotransposon that duplicates via a copy-and-paste genetic mechanism. As LINE-1 constitutes approximately 17% of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In a variety of gastrointestinal (GI) cancers, LINE-1 hypomethylation is strongly associated with a poor prognosis, supporting its potential role as a prognostic biomarker. In this article, we summarize current knowledge regarding LINE-1 methylation and its prognostic impact in GI cancers. PMID- 29393155 TI - Porous Chitosan/Nano-Hydroxyapatite Composite Scaffolds Incorporating Simvastatin Loaded PLGA Microspheres for Bone Repair. AB - The combination of bone tissue scaffolds with osteogenic induction factors is an effective strategy to facilitate bone healing processes. Here, chitosan (CS)/nano hydroxyapatite (HA) scaffolds containing simvastatin (SIM)-loaded PLGA microspheres were fabricated by combining a freeze-drying technique with a modified water-oil-water emulsion method. The CS/HA weight ratio of 1:2 was selected by analyzing the effect of HA content on the micro-architecture, mechanical strength, and biocompatibility of the scaffold. Drug release kinetics showed that the SIM encapsulated in the scaffold was released in a sustained manner for up to 30 days. In vitro bioactivity study in rat bone marrow-derived mesenchymal stem cells showed that the SIM-loaded scaffolds had a strong ability in accelerating cell proliferation and inducing osteogenic differentiation. Moreover, an in vivo experiment using a rat calvarial defect model also documented that the SIM-loaded scaffolds had a remarkable effect on bone promoting regeneration. The results of this study suggest that the SIM-loaded CS/HA scaffold is feasible and effective in bone repair and thus may provide a promising route for the treatment of critical-sized bone defects. PMID- 29393156 TI - Acute Kidney Injury Risk Assessment. AB - Acute kidney injury (AKI) is a common global health challenge, affecting patient morbidity adversely and resulting in an estimated 1.4 million deaths per year. Since the International Society of Nephrology proposed a goal of eliminating preventable deaths from AKI by 2025, implementation of this program remains far from optimistic not only because of the lack of resources but also because of the scarce data addressing the epidemiology and causes of AKI, especially in developing countries, the relative insufficient health care resources to diagnose and treat AKI, and the delayed awareness of the impact of AKI on patient outcomes. Therefore, quality measures of the AKI management are crucial to ensure a better outcome achieved with integrated resource. PMID- 29393158 TI - Acute Kidney Injury to Chronic Kidney Disease Transition. AB - BACKGROUND: Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end stage renal disease (ESRD). In the previous years, novel insights in the pathophysiology of CKD progression suggested a causal link between AKI and CKD due to a maladaptive repair after severe and repeated injury. SUMMARY: Several pathological mechanisms have been proposed to contribute to the progression of AKI and transition to CKD/ESRD including hypoxia and microvascular rarefaction, alterations of renal resident cell phenotypes and functions, cell cycle arrest in the G2/M phase, persistent chronic inflammation, and development of interstitial fibrosis, mitochondrial fragmentation, epigenetic changes, activation of renin angiotensin system (RAS), cell and tissue senescence. Furthermore, several clinical factors have been identified such as severity of AKI, age, and comorbidities. The identification of AKI-to-CKD biomarkers could improve the early identification of AKI patients with higher risk for CKD progression. However, although our understanding in the pathophysiology of AKI-to-CKD transition is significantly improved, no novel intervention has been validated. Potential therapeutic approaches to treat AKI and block the transition to CKD/ESRD have been recently reported, but they need further validations. Key Messages: Maladaptive repair after AKI is strongly associated to the development of CKD and long-term consequences. The prompt identification of patients at higher risk for late CKD progression and the development of new therapeutic interventions remain critical research goals. PMID- 29393157 TI - Tacrolimus Dose Optimization Strategy for Refractory Ulcerative Colitis Based on the Cytochrome P450 3A5 Polymorphism Prediction Using Trough Concentration after 24 Hours. AB - BACKGROUND: In the tacrolimus treatment for refractory ulcerative colitis (UC), dose adjustment is necessary because the required doses to keep appropriate drug concentrations are significantly different among individuals. Cytochrome P450 (CYP) 3A5 polymorphism affects tacrolimus blood concentrations. However, it is difficult to obtain genetic information in real clinical practice. In the present study, we investigated possible factors that may predict CYP3A5 polymorphism and proposed a dose optimization strategy based on the obtained predicting factors. SUMMARY: We retrospectively analyzed 41 patients who underwent remission induction therapy with tacrolimus for UC in our hospital. First, we performed a correlation analysis of CYP3A5 polymorphism and pharmacokinetics. In the CYP3A5 non-expressers, the dose of tacrolimus (mg/kg) was lower and dose-adjusted trough levels (ng/mL per mg/kg) were higher compared with those in expressers. Next, we investigated factors that could predict CYP3A5 polymorphism. Trough concentration 24 h following tacrolimus administration was extracted as a significant factor. When the trough cutoff value at 24 h was set to 2.6 ng/mL, sensitivity and specificity for estimation of CYP3A5 polymorphism were 63 and 96% respectively. Therefore, when the trough concentration 24 h after administration is <=2.6 ng/mL, the patient can be estimated as a CYP3A5 expresser and an increase in dose should be proposed. Key Message: The trough concentration 24 h after the first tacrolimus administration appears to be a useful predictor of -CYP3A5 polymorphism. Performing dose optimization strategy based on the prediction of CYP3A5 polymorphism can lead to earlier and safer remission induction. PMID- 29393159 TI - Current Status of Endoscopic Resection for Superficial Nonampullary Duodenal Epithelial Tumors. AB - BACKGROUND: Endoscopic resection (ER) is becoming the first choice of treatment for treating superficial nonampullary duodenal epithelial tumors (SNADETs), but ER procedures for SNADETs remain challenging because of the difficulty experienced in maneuvering the endoscope toward the thin duodenal wall, which results in a high rate of adverse events. Although several ER methods were used to overcome these technical difficulties and complications, ER methods for SNADETs are not standardized. A new technique, underwater endoscopic mucosal resection (UEMR), was developed recently in a western country, and its usefulness was reported. Beginning in 2014, we were the first to use UEMR for SNADETs in Japan. Thus, in our experience, we would propose an indication of the various ER methods for SNADETs according to the lesion size. SUMMARY: Endoscopic mucosal resection (EMR) and UEMR were effective and safe for small lesions (<=20 mm), but for large lesions (>20 mm), piecemeal removal of lesion by EMR and UEMR had high incidence of recurrence and adverse events. Especially, piecemeal EMR could cause delayed perforation. Cold snare polypectomy was useful for small lesions (<=10 mm), but further study of its recurrence is warranted. Endoscopic submucosal dissection (ESD) achieved a high complete resection rate regardless of the lesion size, but its rate of adverse events, including morbid complications, was high. Thus, after ESD for large lesions, secure prevention method for adverse events, such as closure of the wound by laparoscopic-endoscopic cooperative surgery, should be required. Key Messages: ER methods for treating SNADETs were proposed based on the lesion size. For large lesions, prophylactic methods for adverse events should be implemented. PMID- 29393160 TI - Diagnostic Accuracy of a Bioluminescence System for the Assessment of Caries Activity on Occlusal Surfaces. AB - OBJECTIVE: Assessment of caries lesion activity is usually performed using visual tactile criteria. A new approach is to use a system consisting of a photoprotein, which is specific for free calcium ions, along with an integrated camera that visualizes the elevated calcium ions on the lesion as a light signal (bioluminescence). This study aimed to evaluate the reproducibility and diagnostic accuracy of a newly developed bioluminescence system to assess caries lesion activity on occlusal surfaces in vitro. MATERIALS AND METHODS: Ninety-four extracted permanent teeth with sound surfaces and both active and inactive caries lesions were included. The extent and activity of the investigation sites were classified visually according to the International Caries Detection and Assessment System. Digital images of the teeth were produced by the bioluminescence system and the images were analyzed for the presence of caries activity (the bioluminescent areas at the investigation sites). The images were reanalyzed after 4 weeks. Teeth were hemisected and methyl red dye was applied on the sections to validate lesion activity histologically. RESULTS: Agreement between the bioluminescence readings was shown by kappa values of 0.802-0.917. A significant positive correlation (p < 0.001) was found across all methods (rs 0.618-0.811). Sensitivity and specificity for activity assessment using histology as the gold standard (cut-off: active/inactive) were, respectively, 83.6 and 85.0% for the visual assessment, and 92.5 and 90.0% for the bioluminescence method. Comparison of areas under the receiver-operating characteristic curves showed no significant difference between the visual and bioluminescence systems (p = 0.094). CONCLUSION: The bioluminescence system demonstrated high in vitro reproducibility and good diagnostic accuracy for activity assessment of caries lesions on occlusal surfaces which were not significantly different from the values obtained in the visual assessment. PMID- 29393161 TI - Human Embryonic Kidney 293 Cells: A Vehicle for Biopharmaceutical Manufacturing, Structural Biology, and Electrophysiology. AB - Mammalian cells, e.g., CHO, BHK, HEK293, HT-1080, and NS0 cells, represent important manufacturing platforms in bioengineering. They are widely used for the production of recombinant therapeutic proteins, vaccines, anticancer agents, and other clinically relevant drugs. HEK293 (human embryonic kidney 293) cells and their derived cell lines provide an attractive heterologous system for the development of recombinant proteins or adenovirus productions, not least due to their human-like posttranslational modification of protein molecules to provide the desired biological activity. Secondly, they also exhibit high transfection efficiency yielding high-quality recombinant proteins. They are easy to maintain and express with high fidelity membrane proteins, such as ion channels and transporters, and thus are attractive for structural biology and electrophysiology studies. In this article, we review the literature on HEK293 cells regarding their origins but also stress their advancements into the different cell lines engineered and discuss some significant aspects which make them versatile systems for biopharmaceutical manufacturing, drug screening, structural biology research, and electrophysiology applications. PMID- 29393162 TI - Microbiological Changes and Caries-Preventive Effect of an Innovative Varnish Containing Chlorhexidine in Orthodontic Patients. AB - : The aim of this study was to investigate the effects of Cervitec Plus(r) on the level of mutans streptococcus (SM) and lactobacillus (LB) colonies and the development of white spot lesions (WSLs) in patients with fixed orthodontic appliances. Informed consent was obtained from 32 volunteers (age 16.5 +/- 2.75 years). At baseline, levels of the bacterial colonies were determined in saliva and plaque using a chairside test (CRT Bacteria, Ivoclar-Vivadent, Schaan, Liechtenstein), and the number of WSLs was registered. After placing the fixed appliance, Cervitec Plus(r) or placebo varnishes (Ivoclar-Vivadent, Schaan, Liechtenstein) were applied monthly around the brackets and tubes, randomly in the right or left (test and placebo) quadrants of the same dental arch. SM and LB colonies in saliva and the SM colonies in plaque were determined on 11-21, 13-23, 15-25, and 16-26 teeth monthly over a 6-month period. At the sixth month, the number of new WSLs was determined. By the end of the study, compared with baseline, the ratio of saliva samples belonging to the low-risk category was significantly higher (p <= 0.01) from the 2nd month regarding the SM (76 vs. 52%) and LB (69 vs. 52%); reduction of SM in plaque was significantly greater on the test than placebo sides (6.69 +/- 1.71 and 4.45 +/- 1.60, respectively; p <= 0.01). The mean number of new WSLs was significantly lower in the test (0.06 +/- 1.60) than in the placebo quadrants (1.13 +/- 1.50, p <= 0.01). CONCLUSION: Monthly use of Cervitec Plus(r) could result in a significant improvement in oral health of orthodontic patients. PMID- 29393163 TI - Long-Term Imatinib Treatment for Patients with Unresectable or Recurrent Gastrointestinal Stromal Tumors. AB - BACKGROUND: Only limited data are available concerning the long-term outcomes of imatinib treatment among Japanese or Asian patients with advanced or recurrent gastrointestinal stromal tumors (GIST). Our multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent GIST. SUMMARY: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001 to 2011 were retrospectively reviewed (GREAT study). Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3, 74.9, and 53.8% respectively. In univariate and multivariate analyses, imatinib continuation with dose reduction and achieving a complete or partial response were found to be associated with increased OS. The results of 2 large-scale, long term trials demonstrate that the risk of tumor progression decreases with increased treatment duration. Furthermore, the interruption of imatinib treatment in responsive and controlled patients results in a high risk of disease progression. Key Messages: Long-term imatinib treatment is recommended for patients with nonprogressive disease. If patients experience significant toxicities, temporary dose reduction and treatment continuation might be useful. PMID- 29393164 TI - Interaction between Medical Treatment and Minimally Invasive Surgical Treatment for the Malignancies of the Digestive Tract. AB - Recently, endoscopic diagnosis and treatment methods for early cancer in the digestive tract have made rapid progress. As for surgery, laparoscopic and thoracoscopic techniques have achieved rapidly advancing development in the last 2 decades. Early detection of the malignant lesion and the evolution of endoscopic and surgical device enabled in performing the minimally invasive surgery. Collaboration of medical treatment and minimally invasive surgery for advanced cancer is ongoing in the case of some conditions and in a few institutes. In this review, the contents of the core symposia on "Interaction between medical treatment and minimally invasive surgical treatment for the malignancies of the digestive tract", held at the 11, 12 and 13th annual meeting of the Japanese Gastroenterological Association, are summarized. At each annual meeting, the core symposium focused primarily on gastric, colorectal, and esophageal cancer treatment. For gastric cancer, endoscopic resection and laparoscopic surgery were 2 important key words. For colorectal cancer, multidisciplinary therapy was a major key word. And for esophageal cancer, endoscopic resection, chemoradiotherapy, thoracoscopic surgery and salvage surgery were key words. Patients' survival and quality of life are expected to further advance as a result of the collaboration of such therapeutic modalities. PMID- 29393165 TI - Do Signs of Attention-Deficit/Hyperactivity Disorder Increase the Odds of Dental Caries? A Case-Control Study. AB - : Attention-deficit/hyperactivity disorder (ADHD) is a behavioural disorder that can affect one's performance in activities of daily living and can exert a negative impact on the oral health of children. OBJECTIVE: The aim of this work was to determine the association between ADHD (signs and executive functions) and dental caries in children aged 7-12 years. METHODS: A case-control study was conducted with 532 children in the city of Diamantina, Brazil. The case group was composed of children with caries and the control group was composed of children without caries. The children were submitted to a clinical oral examination for the determination of caries and neuropsychological evaluations of intellectual function and executive function. Other signs of attention deficit and hyperactivity were investigated using the Swanson, Nolan, and Pelham scale administered to parents/guardians and teachers. Socioeconomic and demographic characteristics were also evaluated. Statistical analysis involved the McNemar chi2 test and conditional logistic regression. RESULTS: The multivariate logistic regression model demonstrated that monthly household income and parental reports of signs of attention deficit were significantly associated with the occurrence of dental caries. CONCLUSION: Children considered by their parents/guardians to have attention deficit have a greater chance of exhibiting dental caries, independently of household income. PMID- 29393166 TI - A Methodological Perspective on the Longitudinal Cognitive Change after Stroke. AB - BACKGROUND/AIMS: Most studies of poststroke cognitive impairment (PSCI) have analyzed cognitive levels at specific time points rather than their changes over time. Furthermore, they seldom consider correlations between cognitive domains. We aimed to investigate the effects of these methodological considerations on determining significant PSCI predictors in a longitudinal stroke cohort. METHODS: In patients who underwent neuropsychological tests at least twice after stroke, we adopted a multilevel hierarchical mixed-effects model with domain-specific cognitive changes and a multivariate model for multiple outcomes to reflect their correlations. RESULTS: We enrolled 375 patients (median follow-up of 34.1 months). Known predictors of PSCI were generally associated with cognitive levels; however, most of the statistical significances disappeared when cognitive changes were set as outcomes, except age for memory, prior stroke and baseline cognition for executive/attention domain, and baseline cognition for visuospatial function. The multivariate analysis which considered multiple outcomes simultaneously further altered these associations. CONCLUSIONS: This study shows that defining outcomes as changes over time and reflecting correlations between outcomes may affect the identification of predictors of PSCI. PMID- 29393167 TI - Evaluation of Esophageal Mucosal Integrity in Patients with Gastroesophageal Reflux Disease. AB - BACKGROUND: Impaired esophageal mucosal integrity plays a role in causing symptoms of gastroesophageal reflux disease (GERD). Recently, the assessment of esophageal baseline impedance (BI) using the multichannel intraluminal impedance pH (MII-pH) test was suggested as a surrogate technique for the study of esophageal mucosal integrity and was reported to be useful in distinguishing GERD from non-GERD. However, measuring BI requires a 24-h testing period, is complicated, and causes considerable patient discomfort. SUMMARY: Recently, endoscopy-guided catheters that can measure mucosal impedance (MI) and mucosal admittance (MA), which is the inverse of impedance, were developed, and their usefulness in measuring MI and MA for the diagnosis of GERD has been reported. In these studies, esophageal MI values were significantly lower in patients with GERD than in those without GERD. In contrast, esophageal MA was significantly higher in patients with GERD than in those without. Furthermore, we reported that MA is inversely correlated with BI and correlated with acid exposure time. Key Messages: Endoscopy-guided real-time measurement of MI and MA may allow the estimation of mucosal integrity and may be a useful diagnostic tool for patients with GERD in a manner similar to 24-h MII-pH monitoring. PMID- 29393168 TI - Endoscopic Submucosal Dissection for Adenocarcinomas of the Esophagogastric Junction. AB - BACKGROUND: Adenocarcinoma of the esophagogastric junction (EGJ) is uncommon in Eastern countries, including Japan, but it is believed that the incidence of EGJ adenocarcinoma will increase in Asia in the future due to the decreasing incidence of Helicobacter pylori infection. Endoscopic submucosal dissection (ESD) is a minimally invasive and curative treatment that allows precise pathological assessment. SUMMARY: Magnifying endoscopy with narrow-band imaging may be useful for differential diagnoses and for delineating the cancer margin of EGJ adenocarcinoma, but subsquamous carcinoma extension, which is the invasion of EGJ adenocarcinoma beneath the normal esophageal squamous epithelium, makes it difficult to detect cancer margins of the oral side in ESD for EGJ adenocarcinoma. Since subsquamous carcinoma extension was reported to be less than 1 cm in most cases, the oral safety margin that is placed 1 cm from the squamocolumnar junction is useful for negative cancerous horizontal margin. A multicenter retrospective study of esophageal adenocarcinoma including EGJ adenocarcinoma showed that mucosal and submucosal cancer within 500 MUm from the muscularis mucosa without lymphovascular involvement, a poorly differentiated component, and lesion size over 3 cm were not associated with metastasis. Several retrospective studies about ESD for EGJ adenocarcinoma have suggested feasible short-term and long-term outcomes using curative criteria based on gastric cancer guidelines. Key Messages: ESD would be a good first-line treatment for superficial EGJ adenocarcinoma, including Barrett's adenocarcinoma. Additional information about the incidence of metastasis would help confirm the indication of ESD for EGJ adenocarcinoma. PMID- 29393169 TI - Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes. AB - Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients' quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease. PMID- 29393170 TI - Predictors of Persistent Milk Allergy in Children: A Retrospective Cohort Study. AB - BACKGROUND: Cow's milk (CM) allergy is the second most common food allergy developed during infancy in Japan. To identify predictors of persistent CM allergy, we investigated the tolerance acquisition rate based on an oral food challenge in children under 6 years of age, diagnosed with immediate-type CM allergy. METHODS: This retrospective cohort study included 131 children born in 2005 with a history of immediate allergic reaction to CM, of whom 39 were excluded because of ongoing oral immunotherapy (n = 18) or a lack of follow-up data (n = 21). The 92 remaining participants were followed for 6 years. Tolerance was defined as no adverse reaction to 200 mL of CM and regular intake of milk at home. Subjects were divided into 3 groups based on age at tolerance acquisition: group I (<3 years; n = 31), group II (3-6 years; n = 42), and group III (persistent allergic group; n = 19). RESULTS: Tolerance acquisition rates by 3, 5, and 6 years of age were 32.6% (30/92), 64.1% (59/92), and 84.8% (70/92), respectively. Age at first hospital visit was significantly higher in groups II and III than in group I (p < 0.001). The incidence of anaphylaxis to other foods was also higher in group III than in group I (p = 0.04), as was CM-induced anaphylaxis (p = 0.03). Furthermore, milk and casein-specific immunoglobulin E (IgE) levels were significantly higher in group III than in group II after birth and remained high thereafter (p < 0.05). CONCLUSIONS: The history of anaphylaxis and high milk-specific IgE levels were associated with persistent CM allergy. PMID- 29393171 TI - Ten-Year Survival after Liver Resection for Breast Metastases: A Single-Center Experience. AB - BACKGROUND: The role of liver resection for metastatic breast carcinoma is still debated. METHODS: Fifty-one resected patients were reviewed. All patients received adjuvant chemotherapy after resection of the primary tumor. Clinicopathological characteristics and immunohistochemistry expression of estrogen (ER), progesterone (PR), human epidermal growth factor (HER2), or Ki67 were evaluated. RESULTS: The median number of metastases was 2; single metastases were present in 24 (47%) patients. The median tumor diameter was 4 cm. Major hepatectomies were performed in 31 (61%) patients. Postoperative mortality was null. Postoperative morbidity was 13.7%. The 1-, 5-, and 10-year survival rates were 92, 36, and 16% respectively. Eleven (21.6%) patients survived longer than 5 years and 8.9% are alive without recurrence 10 years after surgery. At the univariate analysis, tumor diameter, lymph node status, PR receptor status, and triple positive receptors (ER+/PR+/Her2+) were significantly related to survival. At the multivariate analysis, tumor diameter, PR receptor, and triple negative status were significantly related to the long-term outcome. CONCLUSION: Liver resection seems to be a safe and effective treatment for metastases from breast cancer, and encouraging long-term survival can be obtained with acceptable risk in selected patients. Tumors less than 5 cm and positive hormone receptor status are the best prognostic factors. PMID- 29393173 TI - Comparison of Single-Incision Laparoscopic Cholecystectomy versus Needlescopic Cholecystectomy: A Single Institutional Randomized Clinical Trial. AB - BACKGROUND: Both single-incision laparoscopic cholecystectomy (SILC) and needlescopic cholecystectomy (NSC) are superior to conventional laparoscopic cholecystectomy in terms of cosmetic outcome and incisional pain. We conducted a prospective, randomized clinical trial to evaluate the surgical outcome, postoperative pain, and cosmetic outcome for SILC and NSC procedures. METHODS: In this trial, 105 patients were enrolled (52 in the SILC group; 53 in the NSC group). A visual analogue scale (VAS) was used to evaluate the cosmetic outcome and incisional pain for patients. Logistic regression analyses were used to evaluate the operative difficulty that was present for both procedures. RESULTS: There were no significant differences in patient characteristics or surgical outcomes, including operative time and blood loss. The mean VAS scores for cosmetic satisfaction were similar in both groups. There were significant differences in the mean VAS scores for incisional pain on postoperative day 1 (p = 0.009), and analgesics were required within 12 h of surgery (p = 0.007). Obesity (body mass index >=25 kg/m2) was the only significant influential factor for operating time over 100 min (p = 0.031). CONCLUSION: NSC is superior to SILC in terms of short-term incisional pain. Experienced laparoscopic surgeons can perform both SILC and NSC without an increase in operative time. PMID- 29393174 TI - Intellectual Functioning in In-Patients with Substance Use Disorders: Preliminary Results from a Clinical Mediation Study of Factors Contributing to IQ Variance. AB - AIMS: To investigate the direct effect of different childhood difficulties on adult intelligence coefficient (IQ) and their possible indirect effect through the mediating pathways of education and severity substance use. PARTICIPANTS: Ninety in-patients aged 19-64. The participants had abstained from substance use for at least 6 weeks and had different substance use profiles. MEASUREMENTS: Substance use disorder (SUD) and psychiatric illnesses were diagnosed according to the International Classification of Diseases 10th edition criteria. IQ was measured with the Wechsler Adult Intelligence Scale, 4th edition. Childhood difficulties, severity of substance use and level of education were assessed through a self-report questionnaire. FINDINGS: Mean full scale IQ for the studied population was 87.3. Learning and attention deficit/hyperactivity difficulties in childhood were directly related to adult IQ. Education had a mediating effect between childhood learning difficulties/conduct problems and the verbal comprehension index. There was no significant difference in IQ due to the specific substance used or severity of substance use. CONCLUSION: IQ variance in in-treatment individuals with SUD was related to childhood functioning alone or through the mediator of education. Substance-related factors did not contribute to IQ variance. The results fit a normal theory of IQ development with commonly known risk factors and no disturbing effect of substance use. PMID- 29393172 TI - Saccular Impairment in Alzheimer's Disease Is Associated with Driving Difficulty. AB - BACKGROUND/AIMS: Patients with Alzheimer's disease (AD) experience increased rates of vestibular loss. Recent studies suggest that saccular impairment in mild cognitive impairment (MCI) and AD patients is associated with impaired spatial cognitive function. However, the impact of saccular impairment on everyday behaviors that rely on spatial cognitive function is unknown. METHODS: We recruited 60 patients (21 MCI and 39 AD) from an interdisciplinary Memory Clinic. Saccular function was measured, and a visuospatial questionnaire was administered to assess whether participants experienced impairments in terms of driving difficulty, losing objects, falls, and fear of falling. RESULTS: In multiple logistic regression analyses, MCI and AD patients with bilateral saccular impairment had a significant, greater than 12-fold odds of driving difficulty (OR 12.1, 95% CI 1.2, 117.7) compared to MCI and AD patients with normal saccular function, and the association appears to be mediated by spatial cognition as measured by the Money Road Map Test. CONCLUSION: This study suggests a novel link between saccular impairment and driving difficulty in MCI and AD patients and demonstrates that driving difficulty may be a real-world manifestation of impaired spatial cognition associated with saccular impairment. PMID- 29393175 TI - Fractionated Radiotherapy of Intracranial Gliomas. AB - Fractionated radiotherapy (FRT) plays a critical role in the management of gliomas. For glioblastoma, the irradiation dose of 60 Gy in 30 fractions with concomitant and adjuvant temozolomide is currently considered as a standard of treatment, and further dose escalation has failed to be of benefit in clinical trials. Hypofractionated radiation schedules may be applied in elderly patients or those with poor performance status. For anaplastic gliomas, the high-risk region is typically irradiated to a total dose of approximately 60 Gy in 1.8-2 Gy per fraction. For patients with 1p/19q co-deleted WHO grade III tumors (i.e., anaplastic oligodendrogliomas), FRT alone is currently not considered as an acceptable therapeutic approach. The use of adjuvant irradiation for low-grade gliomas is controversial; in high-risk patients, treatment with a dose of 45-54 Gy in 1.8 Gy per fraction is usually used. Long-term risks of FRT include radiation necrosis, neurocognitive decline, and neuroendocrine dysfunction. Modern techniques, such as intensity-modulated radiation therapy (IMRT) and proton therapy allow for modifications in radiation dosing and delivery while improving conformality and limiting irradiation of normal tissue. PMID- 29393176 TI - Stereotactic Radiosurgery in the Multimodality Management of Residual or Recurrent Glioblastoma Multiforme. AB - Management options for residual or recurrent glioblastoma multiforme (GBM) are limited despite advances in surgical, chemotherapeutic, and radiotherapeutic techniques. Stereotactic radiosurgery (SRS) is often beneficial in such cases providing improved survival of patients, but still remains underutilized as part of the multimodality management of malignant gliomas. During the last 20 years, 297 patients with histologically proven residual or recurrent GBM underwent Gamma Knife surgery in the University of Pittsburgh. Retrospective analysis of outcomes revealed median survival after initial diagnosis of 18 months, and 1- and 2-year survival rates of 72.5 and 29.5%, respectively. Median survival from the time of SRS was 9 months. The use of modified RPA (recursive partitioning analysis) classification demonstrated superior survival in our series in comparison with historical data. Important prognostic variables include tumor volume <14 cm3, marginal radiation dose of >=15 Gy, and younger age of the patients (<60 years). Adverse radiation effects (ARE) were noted in 23% of cases and were mainly controlled with corticosteroids. Combining SRS with bevacizumab resulted in further improvement of the overall and progression-free survival and decreased incidence of ARE. Nevertheless, for future application of SRS in patients with GBM, evaluation of its efficacy in a well-designed prospective controlled clinical trials seems mandatory. PMID- 29393177 TI - Stereotactic Radiosurgery of Intracranial Low-Grade Gliomas. AB - Low-grade gliomas (LGG), corresponding to WHO grades I and II, are an uncommon and heterogeneous group of tumors, which include several distinct histopathological types and subtypes. Because of their rarity, acquiring adequate data on which to base therapeutic decisions in such cases is difficult. According to present knowledge, it is reasonable to consider radiosurgery (in particular, Gamma Knife surgery) as a therapeutic option for some LGG. Nevertheless, there is a clear need for multicenter cooperation in order to augment the currently scanty data. PMID- 29393178 TI - Brachytherapy of Intracranial Gliomas. AB - Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (<=10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of <=4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy. PMID- 29393179 TI - Irradiation of Intracranial Gliomas in Children. AB - Attainment of local control is a cornerstone in the management of brain tumors in children. Treatment of progressive low-grade and all high-grade gliomas traditionally includes resection followed by fractionated radiotherapy (FRT) or FRT alone in neoplasms not amenable to surgical removal. While in younger children chemotherapy is typically used as a first-line non-surgical management option, FRT in such patients remains the standard of salvage therapy. Recent improvements in techniques for radiation treatment planning and delivery allow conformal and selective coverage of the target volume with a prescribed dose, sparing adjacent normal tissues to assure maximal tumor control and minimal toxicity. Implementation of novel functional and metabolic neuroimaging allows better delineation of the lesion margins and organs at risk, which also reduces the incidence of adverse effects. Further improvements of outcome after radiation treatment of pediatric gliomas may be expected with wider application of intensity-modulated radiation therapy (IMRT), proton therapy, and stereotactic techniques, including brachytherapy. PMID- 29393180 TI - Role of Radiosensitizers in Radiation Treatment of Gliomas. AB - Malignant gliomas are the most common primary brain tumors and have devastatingly high mortality rates. Most recurrences are close to the surgical bed, despite adjuvant fractionated radiotherapy (FRT). Localized FRT to total dose of 60 Gy with concurrent and adjuvant temozolomide (TMZ) resulted in a statistically significant survival improvement of patients with newly diagnosed glioblastoma compared to those treated with FRT alone, and has emerged as the cornerstone of therapy. Despite this progress, long-term survival remains poor. Various signaling pathways have become the targets of different biological agents. Disruption of the vascular endothelial growth factor (VEGF) signaling is particularly attractive, but overall survival remained unchanged despite administration of bevacizumab. Cediranib and mammalian target of rapamycin (mTOR) inhibitors, which also alter VEGF signaling, are currently under investigation. Studies on epidermal growth factor receptor (EGFR) and integrin inhibitors (e.g., cilengitide) have had disappointing results. There is active investigation into other agents that will hopefully enhance the cytotoxic effects of FRT and TMZ. PMID- 29393181 TI - Chemotherapy of High-Grade Astrocytomas in Adults. AB - Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of the blood-brain barrier in preventing access of the cytotoxic agents to the tumor. However, recent studies have demonstrated the efficacy of specific drugs in subsets of patients with high-grade astrocytomas that has revived the enthusiasm for the role of systemic chemotherapy against these neoplasms. Temozolomide, a monofunctional alkylator, was the first chemotherapeutic agent to definitively improve survival in adults with newly diagnosed glioblastoma used in combination with radiation therapy with the most pronounced effect being in a subgroup of tumors with MGMT promoter methylation. Various other cytotoxic drugs and their combinations have been tested in this population with mostly anecdotal reports of benefit. Current efforts are directed towards identifying the subsets of patients most likely to benefit from chemotherapy and to determine the most effective treatment regimens likely to improve outcome. In addition, specific strategies in order to overcome resistance mechanisms to cytotoxic drugs and to disable cellular adaptive pathways are being explored to enhance cell kill and antitumor effects of chemotherapeutic agents. PMID- 29393182 TI - Chemotherapy of Diffuse Astrocytoma (WHO grade II) in Adults. AB - The effectiveness of chemotherapy or chemoradiotherapy for diffuse astrocytoma (DA) has been largely unknown until recently. However, a randomized controlled study (RTOG 9802) showed that adding of procarbazine, CCNU, and vincristine (PCV) chemotherapy to fractionated radiotherapy (FRT) in patients with "high-risk" WHO grade II gliomas, including DA, has significant positive impact on both progression-free survival and overall survival. Effectiveness of temozolomide (TMZ) in cases of low-grade gliomas was also reported, and a randomized phase III trial comparing FRT alone or in combination with TMZ in cases of unresectable DA (JCOG 1303) is currently ongoing. PMID- 29393183 TI - Chemotherapy of Oligodendrogliomas. AB - Oligodendrogliomas are therapy-responsive tumors, which have better prognosis compared to their astrocytic counterparts. The goal of treatment in such cases is not only prolongation of the patients' survival, but maintaining high neurologic functioning and quality of life. Traditionally, after maximal surgical resection fractionated radiation therapy was given. However, prospective randomized trials comparing irradiation alone and its combination with chemotherapy demonstrated strong impact of the latter on prolongation of overall survival in 1p/19q co deleted anaplastic and "high-risk" low-grade gliomas. In such cases the median survival of patients is well beyond a decade. The optimal chemotherapy regimen (PCV or temozolomide) remains an active clinical trial question, which may be resolved after completion of the ongoing phase III CODEL study (clinicaltrials.gov identifier NCT00887146). Additional investigations should also refine further the prognostic and predictive role of molecular markers in oligodendroglial tumors. PMID- 29393184 TI - Chemotherapy of Intracranial Gliomas in Children. AB - Under specific indications, chemotherapy may play an important role in the treatment of pediatric patients with intracranial gliomas. It can be effectively administered in inoperable low-grade tumors, particularly with the use of combination regimens based on carboplatin and vincristine. In very young children with high-grade gliomas (HGG), chemotherapy may result in control of tumor growth, which allows to postpone fractionated radiation therapy (FRT). At the same time, in difference with adults, there is no current evidence that addition of chemotherapy to aggressive surgical resection followed by FRT has any positive impact on survival of pediatric patients with non-pontine HGG. Similarly, chemotherapy is seemingly non-effective in the management of diffuse intrinsic pontine gliomas. Novel treatment strategies in such cases are desperately needed. PMID- 29393185 TI - Perspectives of Personalized Chemotherapy of Gliomas Based on Molecular Tumor Profiling. AB - Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations. These markers may have either a prognostic or a predictive value, differentiation of which is often difficult as both can coexist. At present, MGMT promoter methylation is considered as a predictive marker for response of glioblastoma to chemotherapy with temozolomide, particularly in elderly patients, 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and predictive marker for response of anaplastic gliomas to PCV chemotherapy, and IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades. PMID- 29393186 TI - Antiangiogenic Therapy of High-Grade Gliomas. AB - Angiogenesis plays a critical pathologic role in malignant gliomas. In the past few years, numerous studies using bevacizumab (BEV), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), have been conducted in patients with brain tumors. Current evidence suggests that such treatment produces favorable results in patients with recurrent glioblastoma multiforme (GBM), but is not associated with any benefits in newly diagnosed GBM and recurrent WHO grade III gliomas. Initial experience using BEV for management of central nervous system radiation necrosis demonstrated radiographic improvement in the majority of cases, but optimal dose and treatment duration in such cases still remain in question. The results of clinical trials on other antiangiogenic agents in patients with malignant gliomas were generally disappointing. Future therapeutic approaches should include strategies that targets different angiogenic pathways, block tumor invasiveness, and inhibit GBM stem cells. Evaluation of validated biomarkers and novel imaging parameters may eventually allow better selection of patients who will likely benefit from treatment with VEGF inhibitors. PMID- 29393187 TI - Search for More Effective Chemotherapeutic Regimens for Gliomas: Challenges and Hopes. AB - Are truly effective therapies for glioma finally within reach? An explosion of technologies and treatments in recent years brings with it the hope that the revolution is nigh, but decades of gains that can at best be considered incremental understandably temper optimism. Concepts such as "targeted therapy" and "personalized medicine" have grabbed the attention of the oncology community for over a decade; yet when applied to glioblastoma, our initial efforts have amounted to running into battle with limited armaments and an incomplete understanding of the enemy. Still, there is reason to believe that recent insights and advances have changed the equation, with real gains just over the horizon. PMID- 29393188 TI - Physical and Psychological Rehabilitation of Patients with Intracranial Glioma. AB - Patients with brain tumor frequently experience a combination of physical, cognitive, and communication deficits. These may cause severe psycho-emotional stress altering biological and mental conditions and complicating the course of the primary disease, and thus necessiate physical and psychological rehabilitation. While existing data on the effectiveness of such treatment in patients with intracranial glioma are limited and inconsistent, it is possible to suggest that systematic and multidisciplinary rehabilitation plays a very important therapeutic role and leads to improvements in functional independence, mental and emotional state, and quality of life. PMID- 29393189 TI - Palliative and Supportive Care of Patients with Intracranial Glioma. AB - Clinicians dealing with patients affected by malignant brain tumors are frequently involved in providing palliative and supportive care, particularly at the end of life. It requires a multidisciplinary approach by a well-trained specialized neuro-oncology team. Early initiation of palliative care integrated with standard anticancer therapy may be effective for symptom management and results in improvement of the quality of life. However, studies specifically addressing these issues are very limited, thus do not allow the creation of any reliable evidence-based guidelines. Therefore, there is a definite need for improvement in the quality of palliative and supportive care in neuro-oncology and for specific education for its providers. PMID- 29393190 TI - Pathology and Genetics of Gliomas. AB - Current World Health Organization (WHO) classification of the neuroepithelial tumors is cell lineage-oriented and based on a presumed developmental tree of the central nervous system (CNS). It defines three main groups of gliomas, namely astrocytomas, oligodendrogliomas, and ependymomas, and additionally presumes their 4-tiered histopathological grading (WHO grades I to IV). Nevertheless, the impact of tumor pathology on clinically related parameters may be frequently much better predicted by genetics, than by histological appearance of the lesion. Recent studies have revealed several major molecular alterations typical for different types of neoplasms, such as IDH1/IDH2 mutations in diffusely infiltrating gliomas, mutations of TP53 and ATRX in astrocytomas, 1p/19q co deletion in oligodendrogliomas, mutations of TERT promoter in oligodendrogliomas and IDH wild-type glioblastomas, and mutations or fusions of BRAF in circumscribed astrocytomas, particularly in children. Identification of those and several other genetic abnormalities in the tumor is clinically important and may help clinicians to determine proper treatment strategy and to predict prognosis. Therefore, the updated WHO classification of CNS tumors (2016) considers not only phenotype, but also some genetic characteristics of gliomas. PMID- 29393191 TI - Acute Kidney Injury and Big Data. AB - The recognition of a standardized, consensus definition for acute kidney injury (AKI) has been an important milestone in critical care nephrology, which has facilitated innovation in prevention, quality of care, and outcomes research among the growing population of hospitalized patients susceptible to AKI. Concomitantly, there have been substantial advances in "big data" technologies in medicine, including electronic health records (EHR), data registries and repositories, and data management and analytic methodologies. EHRs are increasingly being adopted, clinical informatics is constantly being refined, and the field of EHR-enabled care improvement and research has grown exponentially. While these fields have matured independently, integrating the two has the potential to redefine and integrate AKI-related care and research. AKI is an ideal condition to exploit big data health care innovation for several reasons: AKI is common, increasingly encountered in hospitalized settings, imposes meaningful risk for adverse events and poor outcomes, has incremental cost implications, and has been plagued by suboptimal quality of care. In this concise review, we discuss the potential applications of big data technologies, particularly modern EHR platforms and health data repositories, to transform our capacity for AKI prediction, detection, and care quality. PMID- 29393192 TI - Quality Measures in Acute Kidney Injury Management. AB - Acute kidney injury (AKI) is common in clinical practice and associated with increased risk for death and major morbidity. Although some meaningful clinical guidelines were published, the quality of AKI healthcare remains suboptimal. Some AKI quality improvement methods, such as guidelines-based training programs, the referral from nephrology, and electronic data system have been found to be potentially beneficial, but further validation is required. Quality measures (QMs) for structure, process, and outcome of AKI care need to be further developed, evaluated, and implemented to ensure utmost quality of AKI care. However, many unknowns remain in this field. Some commonly used QMs like mortality are still difficult to realize in AKI quality control because of the heterogeneity in AKI practice. More evidence is needed to improve the AKI quality control system. These are challenges that will need to be addressed in the future. PMID- 29393193 TI - Technology in Medicine: Moving Towards Precision Management of Acute Kidney Injury. AB - The integration of modern information communication technology and technologically advanced equipment to routine clinical practice are important technological stepping stones in the management of patients with acute kidney injury (AKI). These tools improve practice and patient outcomes by supporting and individualizing all phases of AKI management. This narrative review describes the most recent bedside technological advances in AKI diagnosis, renal replacement therapy education, prescription, monitoring, delivery, and measurement of outcomes with an emphasis on providing highly personalized patient care. PMID- 29393196 TI - Responsiveness of Infrapatellar Fat Pad Volume Change to Body Weight Loss or Gain: Data from the Osteoarthritis Initiative. AB - Obesity is a potent risk factor for knee osteoarthritis (OA) that is driven by mechanical and potentially endocrine mechanisms, and it affects women more frequently than men. The infrapatellar fat pat (IPFP) represents a potential link between obesity, intra-articular inflammation and structural pathology. Here we investigate whether the IPFP is responsive to body weight loss/gain in women and how its responsiveness to weight change compares to that of subcutaneous fat (SCF) of the thigh. All female participants of the Osteoarthritis Initiative (OAI) with >=10% weight loss/gain between baseline and a 2-year follow-up were included. Within-subject changes in IPFP volume and SCF cross-sectional areas (CSA) were determined from 3-T magnetic resonance imaging. Linear regression was used to assess the association between change in weight, IPFP volume, and SCF CSA. In the 38 participants with >=10% weight loss over 2 years (age 59.3 +/- 9.1 years, mean loss = 15.9%), there was a significant reduction in IPFP volume ( 2.2%, p = 0.02) as well as in SCF CSA (-22%, p < 0.001). In the 34 participants with >=10% gain (age 61.5 +/- 8.7 years, mean gain = 15.9%), there was a significant increase in SCF CSA (+26%, p < 0.001) but not in IPFP volume (0.2%, p = 0.87). Weight change was significantly associated with SCF CSA change (r = 0.76, p < 0.001) but not with IPFP volume change (r = 0.11, p = 0.37). In this first longitudinal, observational study investigating the responsiveness of IPFP and SCF to weight change, IPFP morphology was found responsive to weight loss but not to weight gain. Overall, the responsiveness of the IPFP was substantially less than that of the SCF. PMID- 29393194 TI - Vonoprazan, a Novel Potassium-Competitive Acid Blocker, Should Be Used for the Helicobacter pylori Eradication Therapy as First Choice: A Large Sample Study of Vonoprazan in Real World Compared with Our Randomized Control Trial Using Second Generation Proton Pump Inhibitors for Helicobacter pylori Eradication Therapy. AB - BACKGROUND/AIMS: Phase III study demonstrated that vonoprazan-based Helicobacter pylori eradication therapy achieved higher eradication rate compared with lansoprazole. However, there is no study that evaluated the efficacy of vonoprazan in a large sample in real world. We investigated the eradication rate and safety of vonoprazan-based eradication therapy compared with our randomized control trial using second-generation proton pump inhibitor (PPIs). METHODS: (First study) A total of 147 patients who have H. pylori infection were randomly assigned to receive either, esomeprazole (EPZ) group and rabeprazole (RPZ) group. (Second study) 1,688 patients who have H. pylori infection underwent primary eradication with triple therapy involving vonoprazan. In both studies, triple therapy with amoxicillin, clarithromycin, and PPI or vonoprazan was performed, and eradication effect was assessed by an urea breath test. RESULTS: (First study) Eradication rate was 77.5% in the EPZ group and 68.4% in the RPZ group; no significant difference was observed between the 2 groups. (Second study) The successful primary eradication rate was 90.8%. There was no severe adverse effect. CONCLUSIONS: The eradication rate of vonoprazan-based triple therapy was remarkably higher compared with second-generation PPIs-based triple therapy in real world. Vonoprazan is very likely to become the first option for future eradication therapy. PMID- 29393195 TI - Fecal Microbiome and Food Allergy in Pediatric Atopic Dermatitis: A Cross Sectional Pilot Study. AB - BACKGROUND: Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). METHODS: Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. RESULTS: Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). CONCLUSIONS: In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings. PMID- 29393197 TI - Comparative Study of Predictive Mortality Scores in Esophagectomy with Three Field Lymph Node Dissection in Patients with Esophageal Cancer. AB - BACKGROUND/AIM: Esophagectomy is still the best therapeutic option for curing resectable esophageal cancer (EC). Radical surgical resection with three-field lymphadenectomy (3FLD) is a potentially curative treatment option. We compared the predictive accuracy of 5 different scores in patients with EC who underwent 3FLD. METHODS: Five years' worth of medical records in a single institution were analyzed (January 2010 to January 2015) from 311 patients who underwent esophagectomy for EC. We selected 191 in whom 3FLD was performed. Mortality was calculated based on 5 predictive scores. Outcomes measures were intraoperative mortality, 30-day mortality, and 1- and 2-year mortality after surgery. RESULTS: Intraoperative mortality and 30-day mortality after surgery was 0%; 1 and 2-year mortality were 19.8 and 31.4%, respectively. The area under the curve showed poor discriminatory power for all 5 scores (<0.7). In one-way analysis of variance, for 1 year mortality, Portsmouth-Physiological and Operative Severity Score for mortality (P-Possum) was significant (p = 0.0424); in a multivariable analysis for 2-year mortality, P-Possum (p < 0.0001) remained significant. CONCLUSION: There is no accurate prognosis score for esophagectomy in patients who undergo high-risk procedures like 3FLD. New scores are needed to predict the mortality after 3FLD with good discriminatory power. Independent factors affect survival and may function as the baseline for obtaining a new accurate mortality score. PMID- 29393198 TI - Does the Novel Potassium-Competitive Acid Blocker Vonoprazan Cause More Hypergastrinemia than Conventional Proton Pump Inhibitors? A Multicenter Prospective Cross-Sectional Study. AB - BACKGROUND/AIM: The long-term administration of proton pump inhibitors (PPIs) is useful for preventing recurrent reflux esophagitis. On the other hand, several adverse reactions, such as an increase in the blood gastrin level, have been reported. The aim of the present study was to examine the increase in the blood gastrin level due to the long-term administration of conventional PPIs compared with vonoprazan. METHODS: A prospective cross-sectional study was conducted. We examined the blood gastrin levels of patients taking vonoprazan or conventional PPIs in whom the grade of atrophic gastritis had been endoscopically evaluated in the last year. RESULTS: The blood gastrin level was significantly higher in the vonoprazan group than that in the PPI group in patients with milder or no atrophic gastritis, irrespective of the administration periods. However, no significant difference was observed between the groups in patients with severe atrophic gastritis. CONCLUSION: Vonoprazan more markedly increased the blood gastrin level compared with conventional PPIs in patients with milder or no atrophic gastritis. This indicates that vonoprazan may have stronger acid suppressing effects in such patients than conventional PPIs. Key Message: We should be aware of the potential development of hypergastrinemia during the long term administration of vonoprazan, especially in patients with mild or no atrophic gastritis. PMID- 29393199 TI - New Frontiers in Gastroenterology: The 13th Annual Meeting of the Japanese Gastroenterological Association. PMID- 29393200 TI - Retraction Statement. PMID- 29393201 TI - Type-Specific Human Papillomavirus Prevalence in Iranian Women with Normal Cervical Cytology: The Impact of Current HPV Vaccines. AB - OBJECTIVE: Human papillomavirus (HPV) vaccination is currently not included in the national vaccination program in Iran. Regional data on the distribution of HPV types in women are important as they can predict the impact of currently available vaccines and help health policy makers to consider all the possibilities with regard to HPV vaccination. METHODS: A total of 1,218 Iranian women with normal cervical cytology were included in this study. The presence of the HPV genome was investigated in all specimens by PCR assay, and all HPV positive samples were genotyped. RESULTS: Totally, HPV was detected in 88 samples (7.2%). According to different geographical regions, the HPV prevalence varied: the highest HPV prevalence was observed in the North (11.7%) and the lowest in the Center (4.5%) of Iran, and this difference reached a statistically significant level (p < 0.05). In this study, the most frequent HPV types were HPV 16, 18, 66, and 11, representing 63.8% of all HPV infections. CONCLUSION: Based on this study, it is estimated that HPV vaccines could have a great impact on the prevention of cervical cancer in Iran. This study highlights the necessity of introducing educational programs in high schools, robust screening programs, and vaccination in Iran. PMID- 29393202 TI - Quantification of Adipose Tissue and Muscle Mass Based on Computed Tomography Scans: Comparison of Eight Planimetric and Diametric Techniques Including a Step By-Step Guide. AB - BACKGROUND: Recent scientific work proved that knowledge about body composition beyond the body mass index is essential. Both adipose tissue and muscular status are determining risk factors of morbidity and mortality. Analysis of single cross sectional computed tomography (CT) images, acquired during routine care only to prevent additional radiation exposure, provide a detailed insight into the body composition of chronically and critically ill patients. METHODS: This retrospective study included 490 trauma patients of whom a whole-body multiple detector CT scan was acquired at admission. From a single cross-sectional CT, we compared eight diametric and planimetric techniques for the assessment of core muscle mass as well as visceral and subcutaneous adipose tissue. Furthermore, we derived formulas for converting the measurement results of various techniques into each other. RESULTS: For intra- and interobserver reliability, we obtained intraclass correlation coefficients (ICCs) ranging from 0.947 to 0.997 (intraobserver reliability) and from 0.850 to 0.998 (interobserver reliability) for planimetric measurements. Diametric techniques conferred lower ICCs with 0.851-0.995 and 0.833-0.971, respectively. Overall, area-based measurements of abdominal adipose tissue yielded highly correlated results with diametric measures of obesity. For example, the Pearson correlation of visceral adipose tissue and sagittal abdominal diameter was 0.87 for male and 0.82 for female patients. Planimetric and diametric muscle measurements correlated best for lean psoas area and bilateral diametric measurement of the psoas with a Pearson correlation of 0.90 and 0.93 for male and female patients, respectively. CONCLUSION: Planimetric measurements should remain the gold standard to describe fat and muscle compartments. Diametric measurements could however serve as a surrogate if planimetric techniques are not readily available or feasible as for example in large registries. PMID- 29393203 TI - Importance of Proactive Treatment of Depression in Lewy Body Dementias: The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study. AB - OBJECTIVE: To examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). METHODS: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). RESULTS: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. CONCLUSION: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients. PMID- 29393204 TI - Distribution and Cellular Localization of KCC2 in the Ferret Neocortex. AB - KCC2 (a brain-specific potassium-chloride cotransporter) affects development of the cerebral cortex, including aspects of neuronal migration and cellular maturation and differentiation. KCC2 also modulates chloride homeostasis by influencing the switch of GABA from depolarizing in young neurons to hyperpolarizing in mature neurons. We describe the expression pattern, regional distribution, and cellular colocalization of KCC2 in the ferret cortex in normal kits and those treated with methylazoxymethanol acetate (MAM). We earlier developed a model of impaired cortical development by injecting MAM during mid cortical gestation, which briefly interferes with neuronal production and additionally results in increased levels of KCC2 at P0. Using immunohistochemistry, we show a shift in KCC2 expression during development, being high in the subplate at P0, repositioning into a subtle laminar pattern in the neocortex at P7-P14, and becoming homogeneous at P35. KCC2 colocalizes with neuronal markers in the developing and mature cerebral cortex of normal ferrets and those treated with MAM, but shows a differential pattern of expression at different ages and locates in distinct cellular compartments during development. Subcellular localization shows that KCC2 predominantly situates in the membrane fraction of neocortical samples. These findings reveal that KCC2 colocalizes differentially with neurons and its expression pattern alters during development. PMID- 29393206 TI - Erratum. PMID- 29393205 TI - Microglial Activation Induces Generation of Oligodendrocyte Progenitor Cells from the Subventricular Zone after Focal Demyelination in the Corpus Callosum. AB - Neuroblasts derived from neural stem cells (NSCs) in the subventricular zone (SVZ) migrate along the rostral migratory stream into the olfactory bulb to generate interneurons under normal physiological conditions. When demyelination occurs, NSCs or neural progenitor cells (NPCs) in the SVZ provide newly formed oligodendrocytes to demyelinated lesions. The plasticity of NSC/NPC lineages may tend to oligodendrogenesis under the influence of demyelinated lesions. The mechanisms, however, still remain unknown. This study revealed that focal demyelination in the corpus callosum caused activation of the microglia, not only at the site of demyelination but also in the SVZ, and dramatically increased the generation of oligodendrocyte progenitor cells (OPCs) in the SVZ. Furthermore, the inhibition of microglial activation by minocycline treatment decreased OPC generation in the SVZ, suggesting that microglial activation in the SVZ, induced by the focal demyelination in the corpus callosum, regulates NSC/NPC lineage plasticity in situ. In contrast to the findings regarding demyelination in the corpus callosum, inducing focal demyelination in the internal capsule did not induce either microglial activation or OPC generation in the SVZ. These results suggest that the mechanism of OPC generation in the SVZ after inducing demyelinating lesions could be different across the demyelinated regions. PMID- 29393207 TI - Psychometric Evaluation of the Electronic Pain Assessment Tool: An Innovative Instrument for Individuals with Moderate-to-Severe Dementia. AB - BACKGROUND/AIMS: Pain is common in aged care residents with dementia; yet it often goes undetected. A novel tool, the electronic Pain Assessment Tool (ePAT), was developed to address this challenging problem. We investigated the psychometric properties of the ePAT. METHODS: In a 10-week prospective observational study, the ePAT was evaluated by comparison against the Abbey Pain Scale (APS). Pain assessments were blindly co-performed by the ePAT rater against the nursing staff of two residential aged care facilities. The residents were assessed twice by each rater: at rest and following movement. RESULTS: The study involved 34 residents aged 85.5 +/- 6.3 years, predominantly with severe dementia (Psychogeriatric Assessment Scale - Cognitive Impairment score = 19.7 +/- 2.5). Four hundred paired assessments (n = 204 during rest; n = 196 following movement) were performed. Concurrent validity (r = 0.911) and all reliability measures (kappaw = 0.857; intraclass correlation coefficient = 0.904; alpha = 0.950) were excellent, while discriminant validity and predictive validity were good. CONCLUSION: The ePAT is a suitable tool for the assessment of pain in this vulnerable population. PMID- 29393208 TI - Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial. AB - AIMS: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL). METHODS: A multicenter randomized controlled trial was organized. RESULTS: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R methadone concentrations in the target range have a better therapeutic outcome than controls. PMID- 29393210 TI - Reply to the Letter to the Editor "Accurate Direct Measures Are Required to Validate Derived Measures". PMID- 29393209 TI - Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model. AB - BACKGROUND: Specific immunotherapy, including agonists for Toll-like receptor 2 (TLR2), have been shown to protect from allergies and to have a high immunomodulatory capacity. METHODS: A new antibody, TSP-2, reactive against an epitope of the extracellular domain of TLR2, was identified. The effect of the antibody on dendritic cells was assessed by immunohistochemistry, Western blot, and flow cytometric analysis. The effect of TSP-2 in a murine asthma model induced with ovalbumin (OVA) was assessed. The model is a form of airway hyperresponsiveness (AHR) and was analyzed by whole-body plethysmography, the measurement of Th1/Th2 cytokines in bronchial alveolar lavage fluid (BALF) and serum by ELISA, and the CCK-8 assay for lymphocyte proliferation. The effect of TSP-2 on the maturation of bone marrow-derived dendritic cells (BMDCs) was assessed by flow cytometric analysis. RESULTS: TSP-2 promoted the maturation of dendritic cells and the proliferation of lymphocyte in vitro and in vivo. The effect of TSP-2 on T helper 1 (Th1)/Th2 cytokine secretion was slightly more powerful than that of Pam3CSK4. TSP-2 antibody reduced AHR and OVA-specific IgE levels in allergic asthma. TSP-2 antibody also reduced lung inflammation and decreased leukocyte numbers in an OVA-sensitized and challenged asthma model. TSP 2 antibody increased OVA-stimulated I-A, CD80, CD86, and MHC-II levels on BMDCs. CONCLUSIONS: This study identifies a novel therapeutic strategy for AHR, which uses antibodies reactive against TLR2. It also provides theoretical evidence for the control of allergic asthma by targeting TLR2. PMID- 29393211 TI - The Radboud Dysarthria Assessment: Development and Clinimetric Evaluation. AB - OBJECTIVE: In the absence of an adequate dysarthria assessment in the Netherlands, we developed the Radboud Dysarthria Assessment (RDA). This article describes its development and clinimetric evaluation. PATIENTS AND METHODS: Forty three patients were assessed with the RDA. The recording forms were subjected to exploratory factor analysis and estimation of internal consistency. The self evaluation questionnaire was tested for internal consistency and the severity scale for intra- and inter-rater reliability. Construct validity of the severity scale and questionnaire was determined by relating them to the Speech Handicap Index (SHI), Dutch sentence intelligibility assessment (NSVO-Z), and category fluency task. RESULTS: Exploratory factor analysis extracted 4 factors (articulation, resonance, phonation, respiration/prosody) yielding an explained variance of 70.3%. Each factor showed good internal consistency (Cronbach's alpha: 0.89-0.91). The self-evaluation questionnaire showed excellent internal consistency (Cronbach's alpha: 0.90). Intra-class correlation coefficients of the severity scale (0.85-0.86) showed good reliability. The severity scores and self evaluation questionnaire correlated substantially to strongly with the SHI (rs = 0.40 and 0.80) and substantially with the NSVO-Z (rs = -0.65 and -0.52). CONCLUSIONS: The RDA is a valid and reliable tool, but further investigation is needed to demonstrate whether this instrument can successfully support speech language therapists in correctly diagnosing the type of dysarthria. PMID- 29393213 TI - Differential Neuroprotective Effects of Interleukin-1 Receptor Antagonist on Spinal Cord Neurons after Excitotoxic Injury. AB - Secondary damage following spinal cord injury (SCI) induces neuronal damage through inflammatory and excitotoxic pathways. We hypothesized that the interleukin-1 receptor antagonist (IL1RA) protects neuronal populations and suppresses apoptosis and gliosis after injury. Spinal cord slice cultures (SCSCs) were subjected to excitotoxic injury with N-methyl-D-aspartate (NMDA) and treated with IL1RA. Immunohistochemistry for neuronal nuclei (NeuN), MacII, glial fibrillary acidic protein, and TdT-mediated dUTP nick end labelling stains were used to evaluate neuronal survival, glial activation, and apoptosis. Treatment with IL1RA significantly reduced the number of apoptotic cells in both NMDA lesioned and unlesioned cultures. Experimental injury with NMDA reduced the number of NeuN-positive ventral horn neurons, and IL1RA treatment counteracted this loss 1 day after injury. However, IL1RA had no effect on the number of presumable Renshaw cells, identified by their selective expression of the cholinergic nicotinic alpha2-receptor subunit (Chrna2). Activated microglial cells were more numerous in NMDA-lesioned cultures 1 day after injury, and IL1RA significantly reduced their numbers. We conclude that IL1RA modulates neuronal apoptosis and microglial activation in excitotoxically injured SCSCs. Renshaw cells were more susceptible to excitotoxic injury than other neurons and were not rescued by IL1RA treatment. Modulation of IL-1-mediated pathways may thus be effective in reducing excitotoxically induced neuronal damage after SCI, however only in specific neuronal populations, such as ventral horn neurons. These findings motivate further investigations of the possibility to antagonize inflammatory pathways after SCI. PMID- 29393214 TI - Association of Circulating Levels of ADMA with Carotid Intima-Media Thickness in Patients with CKD: a Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: The incidence of cardiovascular disease in patients with chronic kidney disease (CKD) is significantly higher than that in the general population. Carotid intima-media thickness (CIMT) is considered to be an important predictor of atherosclerosis. Asymmetric dimethylarginine (ADMA) acted as an endogenous nitric oxide synthase inhibitor, which was elevated in patients with CKD, but whether plasma ADMA correlate with the CIMT in CKD patients is still not elucidated. METHODS: We searched the PubMed, Cochrane Library and Embase electronic database. A total of 334 related articles were retrieved, after screened by the inclusion and exclusion criterions, 6 articles were selected. RESULTS: After an overall pooled estimate of correlation coefficient (R) within the 6 articles, we found that levels of circulating ADMA were positively related to CIMT in the patients with CKD. Furthermore, the partial correlation coefficient (PR) was used to reduce the interference caused by the hybrid factors. After correction of other risk factors, it also turned out that levels of circulating ADMA were positively related to CIMT. CONCLUSION: Circulating levels of ADMA in CKD patients were positively related to CIMT, which could be a predictor of early-onset atherosclerosis and atherosclerotic disease in patients with CKD. PMID- 29393215 TI - Age Estimation with DNA: From Forensic DNA Fingerprinting to Forensic (Epi)Genomics: A Mini-Review. AB - Forensic genetics developed from protein-based techniques a quarter of a century ago and became famous as "DNA fingerprinting," this being based on restriction fragment length polymorphisms (RFLPs) of high-molecular-weight DNA. The amplification of much smaller short tandem repeat (STR) sequences using the polymerase chain reaction soon replaced RFLP analysis and advanced to become the gold standard in genetic identification. Meanwhile, STR multiplexes have been developed and made commercially available which simultaneously amplify up to 30 STR loci from as little as 15 cells or fewer. The enormous information content that comes with the large variety of observed STR genotypes allows for genetic individualisation (with the exception of identical twins). Carefully selected core STR loci form the basis of intelligence-led DNA databases that provide investigative leads by linking unsolved crime scenes and criminals through their matched STR profiles. Nevertheless, the success of modern DNA fingerprinting depends on the availability of reference material from suspects. In order to provide new investigative leads in cases where such reference samples are absent, forensic scientists started to explore the prediction of phenotypic traits from the DNA of the evidentiary sample. This paradigm change now uses DNA and epigenetic markers to forecast characteristics that are useful to triage further investigative work. So far, the best investigated externally visible characteristics are eye, hair and skin colour, as well as geographic ancestry and age. Information on the chronological age of a stain donor (or any sample donor) is elemental for forensic investigations in a number of aspects and has, therefore, been explored by researchers in some detail. Among different methodological approaches tested to date, the methylation-sensitive analysis of carefully selected DNA markers (CpG sites) has brought the most promising results by providing prediction accuracies of +/-3-4 years, which can be comparable to, or even surpass those from, eyewitness reports. This mini-review puts recent developments in age estimation via (epi)genetic methods in the context of the requirements and goals of forensic genetics and highlights paths to follow in the future of forensic genomics. PMID- 29393212 TI - Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice. AB - Toll-interacting protein (Tollip) is a key negative regulator of innate immunity by preventing excessive proinflammatory responses. Tollip genetic variation has been associated with airflow limitation in asthma subjects and Tollip expression. Whether Tollip regulates lung inflammation in a type 2 cytokine milieu (e.g., IL 13) is unclear. Our goal was to determine the in vivo role of Tollip in IL-13 mediated lung eosinophilic inflammation and the underlying mechanisms. Tollip knockout (KO) and wild-type (WT) mice were inoculated intranasally with recombinant mouse IL-13 protein to examine lung inflammation. To determine how Tollip regulates inflammation, alveolar macrophages and bone marrow-derived macrophages from Tollip KO and WT mice were cultured with or without IL-13 and/or IL-33. IL-13-treated Tollip KO mice significantly increased lung eosinophilic inflammation and eotaxin-2 (CCL24) levels compared with the WT mice. IL-13- treated Tollip KO (vs. WT) macrophages, in the absence and particularly in the presence of IL-33, increased expression of the IL-33 receptor ST2L and CCL24, which was in part dependent on enhanced activation of interleukin (IL)-1 receptor associated kinase 1 (IRAK1) and signal transducer and activator of transcription 6 (STAT6). Our results suggest that Tollip downregulates IL-13-mediated pulmonary eosinophilia in part through inhibiting the activity of the ST2L/IL-33/IRAK1 axis and STAT6. PMID- 29393216 TI - Establishing a Safe Administration of ASA in Cardiovascular Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity with Skin and/or Respiratory Involvement. AB - BACKGROUND: A history of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with cross-intolerance to several drugs is common in some patients with coronary artery disease. We present a series of patients with acute coronary syndrome undergoing ASA desensitization prior to a possible stent to evaluate the short- and long-term efficacy and safety. The aim was to evaluate the outcomes of an ASA desensitization protocol developed by our center based on the guidelines proposed by the EAACI drug allergy expert recommendations. METHODS: We developed a desensitization protocol that was based on both the patient characteristics and onset of reaction after NSAIDs, including premedication with a leukotriene antagonist and the H1-antagonist antihistamine. The clinical entities were NSAID-induced urticaria and/or angioedema in the absence of chronic spontaneous urticaria (NIUA) and NSAID-exacerbated respiratory disease (NERD). RESULTS: A total of 23 patients were challenged or desensitized with ASA: 19 NIUA and 4 NERD. All patients tolerated the protocol at the different times of 30, 45, 90, and 120 min. The dosages of oral ASA that were given included 10, 21, 41, 81, and 162 mg (cumulative dose 315 mg). One patient reacted during the procedure and 1 during follow-up. Symptoms were limited to the skin without manifestations in other organs. All patients tolerated the required dose of ASA within 30-120 min. Those requiring urgent catheterization were desensitized within 90 min. CONCLUSIONS: Our protocol addresses challenge or desensitization with the contribution of a specialist allergist. It provides an effective, dynamic, safe, and short administration of 81 mg or higher of ASA in patients with a history of NSAID hypersensitivity with skin involvement. PMID- 29393217 TI - Impact of Recurrent Acute Kidney Injury on Patient Outcomes. AB - BACKGROUND/AIMS: Recurrent acute kidney injury (AKI) is common among patients after a first hospitalized AKI. However, little is known about the prognosis of recurrent AKI episodes in chronic kidney disease (CKD) development, cardiovascular events and mortality. METHODS: A retrospective study included patients admitted to our Hospital from 2000 to 2010. AKI was defined according to the Acute Dialysis Quality Initiative criteria. In the follow-up period after the first AKI episode, clinical, laboratory data and the number of repeated AKI episodes, etiology and severity were recorded. RESULTS: Among the 359 AKI survivor patients included, 250 new AKI episodes were observed in 122 patients (34%). Variables independently associated to new episodes were: type 2 DM [OR 1.2, 95%CI 1.2-3.8, p=0.001], ischemic heart disease [OR 1.9; 95%CI 1.1-3.6, p=0.012], and SCr at the first AKI event>2,6 mg/dl [OR 1.2; 95%CI 1.03-1.42, p=0.02]. Development of CKD during four years follow-up was more frequent in patients with recurrent AKI, HR [2.2 (95% CI: 1.09-4.3, p=0.003)] and 44% of recurrent AKI patients who developed CKD occurred during the first 6 months after the initial event. Cardiovascular events were more frequent among patients with recurrent AKI patients than in those with one AKI episode (47.2% vs 24%, p=0.001). Mortality at 4 years was higher in the patient subgroup with several episodes of AKI as compared with those with a single episode [HR: 4.5 (95% CI 2.7 7.5) p<0.001]. CONCLUSION: Episodes of recurrent AKI have a high potential to be associated with relevant complications such as cardiovascular events, mortality and CKD development. PMID- 29393218 TI - Value of Placental Volume and Vascular Flow Indices as Predictors of Early and Late Preeclampsia at First Trimester. AB - INTRODUCTION: We evaluated the utility of placental volume and three-dimensional (3D) vascular flow indices to predict early and late preeclampsia. MATERIAL AND METHODS: In 1,004 pregnancies attending routine care, we recorded first-trimester screening program for aneuploidy (FTSA) parameter and measured uterine artery pulsatility index (uterine-a PI). Placental volume and vascular flow indices were obtained using 3D power Doppler and VOCAL techniques. RESULTS: Placental volume was lower and uterine-a PI was higher in both early and late preeclampsia groups versus nonaffected pregnancies. The prediction rate of placental volume in late preeclampsia was higher than that of uterine-a PI (AUROC 0.707 vs. 0.581, p < 0.011). The inclusion of placental volume improved significantly the prediction rate of total and late preeclampsia in the models constructed with maternal characteristics, FTSA, and uterine-a PI (AUROC 0.745 vs. 0.818, p < 0.004, and 0.740 vs. 0.812, p < 0.012, respectively). The inclusion of vascular indices did not improve the predictive value of these models. DISCUSSION: Placental volume was an independent predictor of total, early, and late preeclampsia and its inclusion in combined predictive models significantly improved prediction rates. Reduced placental volume observed at first trimester in women with early and late preeclampsia suggests that these entities are the clinical expression of a similar pathophysiological process. PMID- 29393219 TI - Ultra-Low Contrast Volume for Patients with Advanced Chronic Kidney Disease Undergoing Coronary Procedures. AB - BACKGROUND/AIMS: Contrast induced nephropathy (CIN) is associated with adverse clinical outcomes in patients undergoing coronary interventions, particularly in patients with advanced chronic kidney. The study was aimed to assess the real life feasibility and safety of ultra-low volume coronary procedures in patients with advanced chronic kidney disease. METHODS: A prospective study that included patients with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2) was conducted. Coronary procedures were performed using an ultra-low contrast volume technique. RESULTS: The 30 patients had a mean eGFR of 31.8(+/-8) mL/min/1.73 m2. Indications for coronary angiography were non-ST elevation myocardial infarction (63.3%), unstable (20%), and stable angina pectoris (16.7%). Median contrast volume for diagnostic coronary angiography was 13 mL (interquartile ranges [IQR] 12-14.9), and an additional 13 mL (IQR 8.8-14.3) for percutaneous coronary intervention (PCI). In 3 patients (10%), a >=25% increase was demonstrated in serum cystatin C levels 48 h following the procedure. None of the patients demonstrated a >=25% increase in serum creatinine levels at 48 h. Following 6 months, no patient required renal replacement therapy or unplanned coronary intervention. CONCLUSIONS: In patients with advanced chronic kidney disease, the ultra-low contrast technique is feasible and effective and can be used safely without a significant deterioration in renal function. This technique may increase the utilization of PCI in high-risk coronary patients with chronic kidney disease. PMID- 29393220 TI - Population-Based Cohort Study on Dementia Risk in Patients with Type 1 Diabetes Mellitus. AB - BACKGROUND: The risk of dementia increases by 15-28% in patients with type 2 diabetes mellitus (DM). However, studies on dementia risk in type 1 DM have been neither comprehensive nor conclusive. METHODS: We carried out a cohort study involving 1,077 patients registered to have type 1 DM from 1998 to 2009 and 32,310 matched non-DM controls who were selected from Taiwan National Health Insurance Claims. These participants were followed up from their first clinical appearance for type 1 DM treatment in 1998-2009 to the date of dementia diagnosis or the last day of 2011. The Cox proportional hazard model was employed to estimate the hazard ratio (HR) of dementia incidence. RESULTS: The incidence rates of dementia reached 42.8 and 13.1 per 104 person-years for the type 1 DM and control groups respectively. The adjusted HR of dementia in patients with type 1 DM was estimated at 3.01 (95% CI 2.18-4.14) after adjustment for demographics, comorbidity, urbanization, monthly income, and annual frequency of ambulatory care visits. No significant difference in sex-specific HR was observed. CONCLUSIONS: The relative risk of developing dementia (118-314%) in patients with type 1 DM was much higher than the -previously reported relative risk (15-28%) associated with type 2 DM. PMID- 29393221 TI - The Synergy of Endotoxin and (1->3)-beta-D-Glucan, from Gut Translocation, Worsens Sepsis Severity in a Lupus Model of Fc Gamma Receptor IIb-Deficient Mice. AB - We investigated the influence of spontaneous gut leakage upon polymicrobial sepsis in a lupus model with Fc gamma receptor IIb-deficient (FcGRIIb-/-) mice aged 8 and 40 weeks, as representing asymptomatic and symptomatic lupus, respectively. Spontaneous gut leakage, determined by (i) the presence of FITC dextran, (ii) elevated serum endotoxin, and (iii) elevated serum (1->3)-beta-D glucan (BG), was demonstrated in symptomatic lupus but not in the asymptomatic group. In parallel, spontaneous gut leakage, detected by elevated serum BG without fungal infection, was demonstrated in patients with active lupus nephritis. Gut leakage induced by dextran sulfate solution (DSS) or endotoxin administration together with BG or endotoxin alone, but not BG alone, enhanced the severity of cecal ligation and puncture (CLP) sepsis more prominently in 8 week-old FcGRIIb-/- mice. Additionally, the bone marrow-derived macrophages of FcGRIIb-/- mice produced higher cytokine levels when coexposed to endotoxin and BG, when compared to wild-type mice. In summary, spontaneous gut leakage was demonstrated in symptomatic FcGRIIb-/- mice and the induction of gut permeability worsened sepsis severity. Gut translocation of endotoxin and BG had a minor effect on wild-type mice, but the synergistic effect of BG and endotoxin was prominent in FcGRIIb-/- mice. The data suggest that therapeutic strategies addressing gut leakage may be of interest in sepsis conditions in patients with lupus. PMID- 29393222 TI - Functional Outcomes after Behavioral Treatment of Paradoxical Vocal Fold Motion in Adults. AB - OBJECTIVE: Paradoxical vocal fold motion (PVFM) is responsive to behavioral therapy, often resulting in a remission of symptoms, but little is known about whether treatment is beneficial with regard to PVFM-associated psychological symptoms or functional limitations. The goal of the study was to identify patient perceptions of the impact of treatment for PVFM and characteristics associated with treatment outcomes. METHODS: A survey was conducted of all adults who had received at least 1 session of treatment for PVFM in our outpatient clinic over a 2-year period. RESULTS: The 39 participants ranged in age from 18 to 82 and had received a median of 3 treatment sessions. At a median follow-up of 10 months following treatment, respondents reported improvements in a wide range of areas, including sports and leisure, daily activities, and social participation. The majority reported improvements in feelings of anxiety, helplessness, and control. Poorer outcomes were associated with more severe voice symptoms, fewer treatment sessions, and needing oral steroids for asthma control. CONCLUSION: There was a reduction in a wide range of activity limitations after treatment. Feelings of control were strongly associated with positive outcomes. The therapy appeared to be equally effective for adults with exercise-induced and environmental variants of PVFM. PMID- 29393224 TI - Vitamin D Intake in Preterm Infants: Too Little, Too Much, or Just the Right Amount? PMID- 29393223 TI - Mild Salt-Sensitive Hypertension in Genetically Determined Low Nephron Number is Associated with Chloride but Not Sodium Retention. AB - BACKGROUND/AIMS: One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number. METHODS: 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.03%, normal drinking water) or high salt (HSD, 4%, 0.9% drinking water) diet for 4 weeks. Blood pressure was continuously measured by telemetry in a subgroup. At the end of the experiment and after standardized ashing processes electrolyte- and water contents of the skin and the total body were determined. RESULTS: We found higher blood pressure in high salt treated GDNF+/-compared to wt mice. Of interest, we could not confirm an increase in total-body sodium as predicted by prevailing explanations, but found increased total body and skin chloride that interestingly correlated with relative kidney weight. CONCLUSION: We hereby firstly report significant total body and skin chloride retention in salt sensitive hypertension of GDNF+/-mice with genetically determined lower nephron number. Thus, in contrast to the prevailing opinion our data argue for the involvement of non-volume related mechanisms. PMID- 29393225 TI - Danhong Injection Protects Against Hypertension-Induced Renal Injury Via Down Regulation of Myoglobin Expression in Spontaneously Hypertensive Rats. AB - BACKGROUND/AIMS: High blood pressure is a major risk factor for chronic kidney disease. Currently, single-target anti-hypertensive drugs are not designed for high blood pressure-related organ damages. Danhong injection (DHI), made from the aqueous extracts of Radix Salviae miltiorrhizae and Flos Carthamus tinctorius, has various pharmacological effects, including BP lowering in SHR, mediated by the reduction of vascular remodeling and the up-regulation of Kallikrein-kinin system published recently by our team, yet if it renders renal protection remains unknown. The current study demonstrated a protective role of DHI in renal injury caused by hypertension and identified its molecular targets in the kidney of spontaneously hypertensive rats (SHR). METHODS: Adult SHR and age/gender-matched normotensive Wistar-Kyoto (WKY) rats were treated with DHI, Losartan, or saline for 4 weeks. Serum levels of Creatinine (CRE), Micro-albumin (mAlb), Beta2 microglobulin (beta2-MG), and Uric acid (UA) were detected using ELISA kits. Renal pathology was examined by hematoxylin and Eosin (H&E) stains. Microarray analysis was performed on kidney tissues, and gene expression changes were validated by quantitative reverse transcription polymerase chain reaction (qRT PCR) and Western blot analyses. RESULTS: Renal histopathological scores showed that SHR exhibited serious kidney injury compared to normotensive WKY rats. The intervention with DHI potently suppressed the renal injury biomarker (KIM-1) and kidney lesions compared to the untreated hypertensive subjects. Microarray analysis revealed that among the 124 genes that were differentially expressed by DHI treatment in SHR kidney, down-regulation of renal myoglobin (Mb) gene was the most prominent and was subsequently confirmed by qRT-PCR and Western blot analysis. CONCLUSION: Hypertension-induced renal injury in SHR may be alleviated by DHI in part by local suppression of Kidney injury molecule-1 and down regulation of Myoglobin. However, if this effect is independent of the known anti hypertensive action of DHI in blood vessel remains to be determined. PMID- 29393226 TI - 2018 Update on Intravitreal Injections: Euretina Expert Consensus Recommendations. AB - Intravitreal injections (IVI) have become the most common intraocular procedure worldwide with increasing numbers every year. The article presents the most up-to date review on IVI epidemiology and techniques. Unfortunately, important issues related to pre-, peri- and postinjection management lack randomized clinical trials for a final conclusion. Also, a great diversity of approaches exists worldwide. Therefore, expert consensus recommendations on IVI techniques are provided. PMID- 29393227 TI - Acute Menopausal Symptoms in Young Cancer Survivors Immediately following Chemotherapy. AB - PURPOSE: The aim of this study was to evaluate the prevalence of menopausal symptoms in young cancer survivors immediately following the completion of chemotherapy. METHODS: This prospective cohort study followed 124 young females with a new diagnosis of cancer requiring chemotherapy to assess symptoms of menopause before treatment and immediately following chemotherapy. Symptoms were compared before and after treatment using the McNemar test and between cancer patients and 133 similar-aged healthy controls using Pearson chi2 and Fisher's exact tests. RESULTS: Participants undergoing cancer therapy reported more menopausal symptoms compared to controls prior to the initiation of any treatment (hot flashes or night sweats 33 vs. 7%, p < 0.01, trouble sleeping 57 vs. 31%, p < 0.01, headaches 50 vs. 35%, p = 0.02, and decreased libido 36 vs. 16%, p < 0.01) and also reported a greater prevalence of symptoms immediately after cancer therapy compared to pretreatment prevalence (vasomotor symptoms, p < 0.01, vaginal dryness, p < 0.01, decreased concentration, p < 0.01, and body aches, p = 0.01). Cancer patients with lower anti-Mullerian hormone (AMH) levels after treatment (<0.10 ng/mL) had an increased risk of vasomotor symptoms (OR 2.2, p = 0.04), mood swings (OR 2.4, p = 0.03), feeling sad (OR 2.2, p = 0.04), trouble sleeping (OR 2.7, p = 0.02), and decreased libido (OR 3.0, p = 0.03) when controlled for age and cancer type, and the incidence of these symptoms was not affected by the use of systemic hormones or psychiatric medications. Treatment length, use of alkylating agents, pelvic radiation, and marital status were also not associated with the prevalence of menopausal symptoms. CONCLUSIONS: Premenopausal women with a new cancer diagnosis have more menopausal symptoms than females of similar age before and after cancer treatment, the effects of which are not mitigated by systemic hormone use. Decreased AMH levels were associated with an increased likelihood of reporting physiologic symptoms after therapy. IMPLICATIONS FOR CANCER SURVIVORS: This information is imperative for counseling; ultimately, improved symptom management during and after cancer therapies will improve quality of life in young cancer survivors. PMID- 29393229 TI - New Medical Approach to Functional Dyspepsia, from Core Symposium 3, Japan Gastroenterological Association 2015-2017. AB - In the annual meeting of the Japan Gastroenterological Association (JGA), the scientific organizing committee selected the serial topics for the core symposium. One of the core symposia held during 2015-2017 was entitled "New medical approach to functional dyspepsia (FD)." In 2015, the subtitle of this symposium was "Helicobacter pylori gastritis and FD." In 2016, the subtitle of this symposium was "overlap with other functional GI disorders." In 2017, the subtitle was "therapeutic approach to FD." During these 3 years, a total of 24 presentations were included in Core Symposium 3 and deep and intensive discussions were carried out. PMID- 29393228 TI - The Effect of a High-Fat Diet on the Development of Abdominal Aortic Aneurysm in a Vascular Hypoperfusion-Induced Animal Model. AB - Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Most cases of AAA remain asymptomatic until rupture, and the mortality rate of patients with AAA rupture is very high. Currently, the relation between dietary habits and AAA development remains unknown. In this study, we evaluated the effects of a high-fat diet on the development of AAA in a vascular hypoperfusion-induced animal model. The risk of AAA rupture and AAA diameter in the high-fat group significantly increased compared with those in the control group. The number and size of adipocytes in the vascular wall in the high-fat group significantly increased as compared with those in the control group. Additionally, the collagen-positive sections in the areas with adipocytes significantly decreased as compared with those without adipocytes. The protein levels of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12, and macrophage-positive areas in the parts with adipocytes also significantly increased as compared with those without adipocytes. These data suggested that AAA rupture risk increased through accelerating chronic inflammation due to the accumulation of adipocytes in the vascular wall in the high-fat group. PMID- 29393230 TI - Chronic Kidney Disease Elicits an Intestinal Inflammation Resulting in Intestinal Dysmotility Associated with the Activation of Inducible Nitric Oxide Synthesis in Rat. AB - This study was conducted to investigate whether chronic kidney disease (CKD) affects intestinal inflammation and intestinal motility and the underlying mechanisms. Rats were randomized into control group and uremic group. Uremia rats were induced by the 5/6 kidney resection, while the control went through the same procedures but without any kidney resection. Intestinal motility was assessed by charcoal transport assay; intestinal inflammation was assessed by analyses of levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 in the ileum tissue. The inducible nitric oxide synthesis (iNOS) activity was assessed in the ileum tissue. The results showed that the intestinal motility in uremic group was significantly decreased compared with that in the control group on postoperative weeks 8 and 10. Meanwhile, the uremic group presented significantly higher concentrations of TNF-alpha, IL-6, and IL-10 than control group on postoperative weeks 8 and/or 10, and higher gene expression on postoperative weeks 6, 8, and 10. Furthermore, the intestinal iNOS activity in the uremic group was significantly increased compared with that in control group on postoperative weeks 8 and 10. These results suggest that CKD could induce intestinal inflammation and lead to intestinal dysmotility, which may be associated with iNOS activation in the intestine. PMID- 29393231 TI - Increasing Burden of Stroke: The Dijon Stroke Registry (1987-2012). AB - BACKGROUND: We aimed to provide a representation of the global burden of stroke. METHODS: All cases of stroke were prospectively identified through the population based registry of Dijon, France (1987-2012). Attack rates and mortality rates (defined as stroke leading to death within 30 days) were standardized to the European standard. Sex differences and temporal trends were evaluated by calculating rate ratios (RRs). RESULTS: In all, 5,285 stroke cases (52.7% women) were recorded. The standardized attack rate was 98.2/100,000/year and the mortality rate was 12/100,000/year, and both were lower in women than in men (RR 0.67, p < 0.001, and RR 0.70, p < 0.001, respectively). Attack rates increased over time (RR 1.016; 95% CI 1.013-1.020) irrespective of the stroke subtype. In contrast, mortality rates declined (RR 0.985; 95% CI 0.976-0.995) with decreasing rates for ischemic stroke but no change for intracerebral hemorrhage and subarachnoid hemorrhage. The sex gap in both attack and mortality rates remained stable. Between the first (1987-1991) and the last (2007-2012) study periods, the annual number of stroke patients who survived beyond 30 days rose by 55%, Conclusions: Increasing attack rates and decreasing mortality have led to a rise in the number of stroke survivors in the population, thus indicating a growing need for the implementation of dedicated services. PMID- 29393232 TI - Minimally Invasive Salvage Operations for Esophageal Cancer after Definitive Chemoradiotherapy. AB - BACKGROUND/AIMS: Because salvage surgery after definitive chemoradiotherapy for esophageal cancer is associated with high postoperative mortality and morbidity, minimally invasive methods are desirable. We analyzed the validity of minimally invasive salvage operations (MISO). METHODS: Twenty-five patients underwent salvage operation between 2010 and 2016 in our institution, 10 having undergone right transthoracic salvage esophagectomy (TTSE group), 6 transhiatal salvage esophagectomy (THSE), 6 salvage lymphadenectomy (SLA), and 3 salvage endoscopic submucosal dissection (SESD). Patients who had undergone THSE, SLA, or SESD were categorized as the MISO group. Short- and long-term outcomes were assessed. RESULTS: The mean duration of surgery was significantly shorter in the SLA groups than in the TTSE group (p = 0.0248). Blood loss was significantly less in the SLA than the TTSE group (p = 0.0340). Intensive care unit stay was shorter in the THSE than the TTSE group (p = 0.0412). There was no significant difference in postoperative mortality between the MISO and THSE groups. Postoperative hospital stay was significantly shorter in the SLA than the TTSE group (p = 0.0061). Patients' survivals did not differ significantly between the MISO and TTSE groups (p = 0.752). Multivariate analysis revealed that residual disease (R0; HR 4.872, 95% CI 1.387-17.110, p = 0.013) was the only independent factor influencing overall survival. CONCLUSION: MISO is preferable because short-term outcomes are better and long-term outcomes do not differ from those of TTSE. PMID- 29393233 TI - Dose-Response Effects of Early Vitamin D Supplementation on Neurodevelopmental and Respiratory Outcomes of Extremely Preterm Infants at 2 Years of Age: A Randomized Trial. AB - BACKGROUND: Many extremely preterm infants have low vitamin D concentrations at birth, but early childhood outcomes after vitamin D supplementation have not been reported. OBJECTIVE: To determine a dose-response relationship between increasing doses of enteral vitamin D in the first 28 days after birth and cognitive scores at 2 years of age. METHODS: In this phase II double-blind dose-response randomized trial, infants with gestational ages between 23 and 27 weeks were randomly assigned to receive placebo or a vitamin D dose of 200 or 800 IU/day from day 1 of enteral feeding to postnatal day 28. The primary outcome of this follow-up study was Bayley III cognitive score at 22-26 months of age. RESULTS: Seventy of 80 survivors had a follow-up evaluation at 2 years of age (88%). There were no significant differences in cognitive scores between supplementation groups (p = 0.47). Cognitive scores did not differ between the higher vitamin D dose group and the placebo group (median difference favoring the 800 IU group: +5 points; 95% CI: -5 to 15; p = 0.23). The linear trend between increasing doses of vitamin D and reduction of neurodevelopmental impairment (placebo group: 54%; 200 IU group: 43%; 800 IU group: 30%; p = 0.08) or language impairment (placebo group: 64%; 200 IU group: 57%; 800 IU group: 45%; p = 0.15) was not statistically significant. Respiratory outcomes at 2 years of age (need for supplemental oxygen or asthma medications) did not differ between groups. CONCLUSION: In extremely preterm infants, early vitamin D supplementation did not significantly improve cognitive scores. Though underpowered for clinically meaningful differences in early childhood outcomes, this trial may help determine dosing for further investigation of vitamin D supplementation. PMID- 29393234 TI - Lipid Metabolism in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. AB - OBJECTIVE: Lipid metabolism has been implicated in autoimmune disorders, but its relationship with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unclear. This study examined the association of serum lipids with anti-NMDAR encephalitis. METHODS: Serum lipid profiles and C-reactive protein (CRP) were evaluated in 68 patients with anti-NMDAR encephalitis, and 68 age- and sex matched healthy controls (CTLs). Follow-up evaluations were conducted 3 months after admission in 32 of the 68 patients. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all patients. RESULTS: Compared with CTLs, patients with anti-NMDAR encephalitis had significantly lower serum high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels but significantly higher serum apoB levels and apoB/apoA-I ratios. Serum HDL and apoA-I were significantly and negatively associated with serum CRP levels, whereas serum aopB levels and apoB/apoA-I ratios were positively associated with age, CRP levels, and mRS scores. Follow-up evaluations revealed that serum total cholesterol, apoA-I, and HDL-C levels were significantly higher but mRS scores were significantly lower than those before treatment, and that the increased HDL-C levels were significantly and negatively correlated with decreased mRS scores. CONCLUSION: Serum HDL-C and apoA-I levels are reduced in the initial phase of anti-NMDAR encephalitis and recover after treatment. Further studies about the role of serum lipid in anti-NMDAR encephalitis are needed. PMID- 29393235 TI - Impact of Early Anatomical and Functional Responses to Bevacizumab in Macular Edema Secondary to Branch Retinal Vein Occlusion. AB - PURPOSE: To evaluate whether early anatomical and visual acuity (VA) responses to intravitreal bevacizumab (IVB) in macular edema secondary to branch retinal vein occlusion (BRVO) are associated with 1-year follow-up outcomes. METHODS: Ninety nine treatment-naive patients (99 eyes) with macular edema after BRVO treated with IVB were analyzed retrospectively. All patients received single injection and were followed up with pro re nata regimen for at least 12 months. The relationship between early (1 month) and late (12 months) anatomical (presence/absence of fluid) and functional response (an improvement of <1, 1 to <3, or >=3 logMAR lines from baseline in best corrected VA, BCVA) was explored. RESULTS: Fifty-eight eyes (58.6%) had absence of fluid at 1 month after the first injection, but 41 eyes (41.4%) did not. Those with absence of fluid at 1 month were more likely to be fluid-free at 12 months (p = 0.010). Thirty-seven (37.4%), 24 (24.2%), and 38 (38.4%) eyes showed an improvement of <1, 1 to <3, and >=3 lines, respectively, at 1 month after the first injection. Intercohort differences across three response categories in BCVA change from baseline were statistically significant throughout the follow-up. Each group maintained stable VA changes within 1 line during the follow-up after 1 month. CONCLUSION: The early anatomical and functional response was associated with anatomical and functional improvement at 12 months. PMID- 29393236 TI - An in vitro Experimental Insight into the Osteoblast Responses to Vitamin D3 and Its Metabolites. AB - BACKGROUND: 25-hydroxyvitamin D3 (25[OH]VD3) has recently been found to be an active hormone. Its biological actions are also demonstrated in various cell types. However, the precise influences of vitamin D3 (VD3) and its metabolites (25[OH]VD3, 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2VD3]) on the osteoblast differentiation remain largely unknown. In this work, we investigated the effects of VD3 and its metabolites in different concentrations on the early and later osteoblast differentiation and biomineralization. METHODS: We first used quantitative real-time polymerase chain reaction (RT-qPCR) to evaluate the responsiveness of osteoblasts to VD3, 25(OH)VD3 or 1alpha,25-(OH)2VD3. We also evaluated the proliferation, differentiation and biomineralization of osteoblast at different time points via cell counting kit-8 assay and the analysis of osteogenic markers. RESULTS: The experimental results confirmed that osteoblasts could be responsive to 25(OH)VD3 and 1alpha,25-(OH)2VD3 but could not directly metabolize VD3 and 25(OH)VD3. Only 200 nmol/L VD3 significantly promoted osteoblast proliferation, while 25(OH)VD3 and 1alpha,25-(OH)2VD3 did not show obvious actions. Moreover, the early osteogenic markers were increased by 25(OH)VD3 and 1alpha,25-(OH)2VD3 in a dose-dependent manner. More importantly, only 25(OH)VD3 had accelerated the gene and protein expressions of osteocalcin and the biomineralization level of osteoblasts. CONCLUSIONS: Our findings provide reliable evidence that 25(OH)VD3 at 100-200 nmol/L can induce the early and later osteoblast differentiation and biomineralization for clinical bone tissue engineering. PMID- 29393237 TI - High-Flow Nasal Cannula versus Nasal Continuous Positive Airway Pressure for Primary Respiratory Support in Preterm Infants with Respiratory Distress: A Randomized Controlled Trial. AB - BACKGROUND: Nasal continuous positive airway pressure (nCPAP) is the standard noninvasive respiratory support for newborns with respiratory distress. Evidence for high-flow nasal cannula (HFNC) as an alternative mode of respiratory support is inconclusive. OBJECTIVE: The aim of this work was to evaluate whether HFNC is not inferior to nCPAP in reducing the need for higher respiratory support in the first 72 h of life when applied as a noninvasive respiratory support mode for preterm neonates with respiratory distress. METHODS: Preterm infants (gestation >=28 weeks and birth weight >=1,000 g) with respiratory distress were randomized to either HFNC or nCPAP in a non-inferiority trial. Failure of the support mode in the first 72 h after birth was the primary outcome. Infants failing HFNC were rescued either with nCPAP or mechanical ventilation, and those failing nCPAP received mechanical ventilation. RESULTS: During the study period, 139 and 133 infants were randomized to the nCPAP and HFNC groups, respectively. The study was stopped after an interim analysis showed a significant difference (p < 0.001) in the primary outcome between the 2 groups. The treatment failure was significantly higher in the HFNC group (HFNC, n = 35, 26.3%, vs. CPAP, n = 11, 7.9%, risk difference 18.4 percentage points, 95% CI 9.7-27). Among the infants in the HFNC group who had treatment failure (n = 35), 32 were initially rescued with CPAP. The rate of mechanical ventilation in the first 3 and 7 days of life was similar between the 2 groups. Treatment failure was significantly higher in the HFNC group per protocol and also in the subgroups of infants with moderate (Silverman Anderson score, SAS <=5) or severe respiratory distress (SAS score >5). CONCLUSIONS: When comparing HFNC to nCPAP as a primary noninvasive respiratory support in preterm infants with respiratory distress, HFNC is inferior to nCPAP in avoiding the need for a higher mode of respiratory support in the first 72 h of life. PMID- 29393239 TI - Revived for Paradise: A History of Respite Sanctuaries. AB - Infant baptism originated when St. Augustine proclaimed the doctrine of original sin in 412 CE. Neonates stillborn or deceased before baptism were declared to go down to Hell and were buried outside of sacred ground. From the 15th century, parents carried these infants to "respite sanctuaries" in remote mountain chapels, where miraculous images were believed to revive the infant in order to allow baptism and a Christian burial. Monasteries made fortunes out of the parents' anguish. In 1528, the abuse of the Oberburen image ignited iconoclasm and heralded the beginning of the Reformation. From 1740, Pope Benedict XIV opposed the sanctuaries, especially Ursberg in Swabia, declaring as invalid any apparent signs of life, e.g., changes in skin color, a change from rigidity to flexibility, blood flowing from the nose, sweat on the skin, cessation of a cadaveric smell, and the movement of a feather held at the infant's mouth. Only crying and sounds of respiration remained valid signs of revivification. The debate ran for centuries, highlighting the difficulty of distinguishing a stillborn from a liveborn baby before the stethoscope became available. The existence of respite sanctuaries is an illustration of the failure of the doctrine of original sin, which was never accepted by the pious. PMID- 29393238 TI - Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer. AB - OBJECTIVE: A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. METHODS: Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. RESULTS: While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p < 0.036). Furthermore, a correlation was found between Del-1 expression and an aggressive histological grade, nuclear mitosis, and polymorphism, suggesting a possible role in tumor progression. In the survival analysis, a worse distant disease-free survival trend was noted for the group overexpressing Del-1. CONCLUSION: While all the investigated breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients. PMID- 29393241 TI - The Heterogeneity of Prostate Cancer: A Practical Approach. AB - Prostate cancer is a paradigm tumor model for heterogeneity in almost every sense. Its clinical, spatial, and morphological heterogeneity divided by the high level molecular genetic diversity outline the complexity of this disease in the clinical and research settings. In this review, we summarize the main aspects of prostate cancer heterogeneity at different levels, with special attention given to the spatial heterogeneity within the prostate, and to the standard morphological heterogeneity, with respect to tumor grading and modern classifications. We also cover the complex issue of molecular genetic heterogeneity, discussing it in the context of the current evidence of the genetic characterization of prostate carcinoma; the interpatient, intertumoral (multifocal disease), and intratumoral heterogeneity; tumor clonality; and metastatic disease. Clinical and research implications are summarized and serve to address the most pertinent problems stemming from the extreme heterogeneity of prostate cancer. PMID- 29393240 TI - Increased Small Intestinal Permeability during Severe Acute Exacerbations of COPD. AB - BACKGROUND: Disturbances of intestinal integrity, manifested by increased gastro intestinal (GI) permeability, have been found in chronic obstructive pulmonary disease (COPD) patients during physical activity, often associated with intermittent hypoxic periods. Evidence about extrapulmonary organ disturbances, especially of the GI tract, during hospitalised acute exacerbation of COPD (AE COPD) with hypoxaemic respiratory failure (RF) is lacking. OBJECTIVE: The aim was to assess changes in GI permeability in patients with AE-COPD and during recovery 4 weeks later. METHODS: All patients admitted to our hospital with AE-COPD accompanied by hypoxaemia at admission (PaO2 <8.7 kPa or O2 saturation <93%) were screened between October 2013 and February 2014. Patients with a history of GI or renal disease, chronic heart failure, or use of non-steroidal anti-inflammatory drugs in the 48 h before the test were excluded. GI permeability was assessed by evaluating urinary excretion ratios of the orally ingested sugars lactulose/L rhamnose (L/R ratio), sucrose/L-rhamnose (Su/R ratio) and sucralose/erythritol (S/E ratio). RESULTS: Seventeen patients with severe to very severe COPD completed the study. L/R ratio (*103) at admission of AE-COPD was significantly higher than in the recovery condition (40.9 [29.4-49.6] vs. 27.3 [19.5-47.7], p = 0.039), indicating increased small intestinal permeability. There were no significant differences in the individual sugar levels in urine nor in the 0- to 5-h urinary S/E and Su/R ratios between the 2 visits. CONCLUSION: This is the first study showing increased GI permeability during hospitalised AE-COPD accompanied by hypoxaemic RF. Therefore, GI integrity in COPD patients is an attractive target for future research and for the development of interventions to alleviate the consequences of AE-COPD. PMID- 29393242 TI - Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature. AB - BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients' quality of life (QoL) are still a matter of study. METHODS: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. RESULTS: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. CONCLUSIONS: Even when the rheumatological assessment scored EGPA "under control" according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients. PMID- 29393243 TI - Comparing a Right- Versus Left-Side Approach in Laparoscopy-Assisted D2 Radical Gastrectomies in Overweight Patients with Gastric Cancer: A Retrospective Case Controlled Study. AB - BACKGROUND: The safety and efficacy of the surgical path used in laparoscopy assisted radical gastrectomies (LARGs) is still unknown in obese patients. This study aimed to compare the value of a right-side (R-LARG) versus a left-side (L LARG) approach in LARGs in overweight patients (defined as a body mass index (BMI) >= 25 kg/m2). METHODS: 213 patients with gastric cancer were divided into 2 groups: an overweight group and a normal-weight group (BMI < 25 kg/m2). Clinical characteristics and perioperative outcomes were compared in the 2 groups. RESULTS: In the overweight group, patients who underwent R-LARG had a shorter operating time (204 +/- 15 vs. 248 +/- 21 min), less intraoperative blood loss (66 +/- 8 vs. 78 +/- 7 ml), less painkiller usage (2.0 +/- 0.2 vs. 2.5 +/- 0.3 days), shorter time to mobility (2.1 +/- 0.3 vs. 2.7 +/- 0.5 days), faster recovery of peristalsis (3.4 +/- 0.3 vs. 4.1 +/- 0.5 days) and more lymph node dissection per patient (37 +/- 4 vs. 31 +/- 2) compared with the patients who underwent L-LARG. No statistically significant differences in postoperative complications (11.9% vs. 10.8%), postoperative hospital stays or hospitalization expenses were found between the groups. In the normal-weight group, perioperative outcomes were similar between the R-LARG and L-LARG groups. CONCLUSION: R-LARG has obvious advantages in overweight patients with gastric cancer. PMID- 29393244 TI - Percutaneous Intraductal Radiofrequency Ablation for Malignant Biliary Obstruction Caused by Recurrence and Metastasis after Primary Tumor Resection. AB - BACKGROUND: To assess the feasibility and safety of percutaneous intraductal radiofrequency ablation (RFA) for malignant biliary obstruction caused by recurrence and metastasis after primary tumor resection. PATIENTS AND METHODS: Percutaneous intraductal biliary RFA and stent placement were performed in 19 consecutive patients with 24 RFA procedures. Procedure-related complications, stent patency, and survival after treatment were investigated. RESULTS: During 30 days after each RFA procedure there was no 30-day mortality, hemorrhage, bile duct perforation, or pancreatitis. Of the 19 patients, 2 are still alive and 17 are dead with a median survival time of 6.0 (range 1.2-16) months and a median stent patency of 3.2 (range 1.2-14) months. 10 patients had their stent patent at the time of last follow-up or death. 3 patients with stent blockage at 50, 182, and 200 days post procedure underwent repeat ablation. 1 patient with stent blockage underwent 2 repeat RFA procedures at 192 days after the first ablation and at 86 days after the repeat ablation. CONCLUSION: Percutaneous intraductal RFA is a technically safe and feasible therapeutic option for palliative treatment of these selected patients. PMID- 29393246 TI - Genetic Risk Factors Are Not Associated with Wet Age-Related Macular Degeneration Treatment Response to Ranibizumab. PMID- 29393245 TI - Serous Carcinoma of the Uterine Cervix, an Extremely Rare Aggressive Entity: A Literature Review. AB - BACKGROUND/AIMS: Serous carcinoma of the uterine cervix (USCC) is an extremely rare subtype. To establish the treatment strategy in patients with USCC is an important issue. METHODS: MEDLINE (PubMed) was searched for all articles published after the first publication by Lurie et al. [Eur J Obstet Gynecol Reprod Biol 1991; 40: 79-81], reporting woman diagnosed with USCC. Because of limited numbers of studies on the topic of the study, we could not keep a restriction of eliminating smaller sample sizes. RESULTS: A search of PubMed demonstrated that 113 cases of USCC have been reported in the literature since the first publication. The current treatment modality adopted for early cervical cancer is hysterectomy with bilateral iliac-obturator lymphadenectomy and postoperative radiotherapy (RT) or radiochemotherapy (RT-CT) if risk factors for cervical carcinoma appear. The treatment strategy for locally advanced USCC is preoperative RT-CT or chemotherapy (CHTH) with the intention to treat the patient surgically. The treatment option for disseminated disease is CHTH with paclitaxel and carboplatin. CONCLUSION: Risk factors and a more advanced clinical stage of USCC have an impact on poor outcomes despite the use of standard treatment methods, adapted for cervical cancer. The outside-pelvic failures tend to seek effective systemic treatment. PMID- 29393247 TI - Optical Coherence Tomography-Based Angiography in Retinal Artery Occlusion in Children. AB - PURPOSE: To evaluate the role of optical coherence tomography (OCT)-based angiography (OCTA) in the diagnosis and monitoring of pediatric patients with retinal artery occlusion (RAO). MATERIAL AND METHODS: This retrospective study was conducted at the Department of Ophthalmology, The Children's Memorial Health Institute, in Warsaw between March 2015 and May 2016. Every patient underwent a complete ophthalmological examination. The diagnosis of the disease was based on fundus examination and fluorescein angiography (FA). OCT and OCTA were performed at baseline and every follow-up visit. RESULTS: Four patients (4 eyes) (2 boys/2 girls, age 8-16 years) with RAO were enrolled in the study. In all cases, initial OCTA images revealed typical ischemic changes in superficial and deep retinal capillary plexuses. Follow-up OCTA revealed increasing areas of ischemia in the RAO region and persistent narrowing of the arteries. The loss of capillary network and the darker, smooth background due to ischemia were visible on OCTA images. CONCLUSIONS: OCTA enables clear visualization of progressive impairment of the retinal vascular perfusion in children with RAO and may be an alternative to the standard FA. Further studies are needed to confirm our results and establish the role of OCTA in pediatric patients. PMID- 29393248 TI - Meetings and Conferences. PMID- 29393249 TI - Upregulation of Vascular Endothelial Growth Factor in Amniotic Fluid Stem Cells Enhances Their Potential to Attenuate Lung Injury in a Preterm Rabbit Model of Bronchopulmonary Dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects extremely preterm infants and remains - despite improvements in neonatal intensive care - a major cause of neonatal mortality and morbidity. Cell therapeutic strategies employing mesenchymal stem cells (MSC) have been shown to modulate lung development in BPD models. OBJECTIVE: Herein, we evaluate the potential of human amniotic fluid (hAF)-SC and hAF-SC with upregulated expression of vascular endothelial growth factor (VEGF) as cell-therapeutic agents for BPD. METHODS: Preterm rabbit pups were raised in normoxia (21% O2) or hyperoxia (>=95% O2). Hyperoxia-exposed pups randomly received an intraperitoneal injection of fibroblasts, naive hAF-SC, or hAF-SC-VEGF on postnatal day (PN) 0. On PN7, surviving pups were tested for pulmonary (forced oscillation technique) and vascular (pulmonary artery Doppler ultrasound) function, and lungs were processed for morphometric measurements of parenchymal and vascular structure and inflammation. RESULTS: Intraperitoneal injection of cells resulted in homing to the lungs. The lungs of hyperoxia-exposed animals displayed parenchymal and vascular structural and functional damage reminiscent of BPD, which was significantly improved after treatment with hAF-SC-VEGF. Treating hyperoxia exposed animals with naive AF-SC attenuated only the lung inflammation and the vascular structural defect. Treatment with fibroblasts, which were used as a cellular control, did not lead to any improvements. CONCLUSION: hAF-SC with upregulated VEGF expression display enhanced potential to prevent/reverse lung injury in preterm rabbits, whereas naive hAF-SC only show a moderate therapeutic potential. These results point towards an added value of VEGF delivered by hAF-SC in the treatment of BPD. PMID- 29393250 TI - Risk Factors for Distant Metastasis in Patients with Oral Cavity Squamous Cell Carcinoma Undergoing Surgical Treatment. AB - OBJECTIVE: The aim of this study is to investigate the clinical and pathological factors related to distant metastasis in patients with oral cavity squamous cell carcinoma (OCSCC) undergoing surgery. STUDY DESIGN: A retrospective data review was conducted on patients who underwent primary surgery for OCSCC at the Instituto do Cancer do Estado de Sao Paulo (ICESP) between 2009 and 2015. Distant metastasis rates were calculated and predictive factors were determined by the Cox proportional-hazards model. RESULTS: There was a total of 274 patients, including 210 (76.6%) men and 64 (23.4%) women, with a mean age of 59.9 +/- 10.9 years. The incidence of distant metastasis was 9.6%, with the lung being the most common site. The mean time interval between surgical treatment and the diagnosis of distant metastasis was 12 months (range 2-40 months). In the multivariate analysis, angiolymphatic invasion (HR = 2,87; p = 0.023), contralateral cervical metastasis (HR = 3.3; p = 0,007), tumor thickness >25 mm (HR = 3.50; p = 0.009), and locoregional recurrence (HR = 6.59; p < 0.0001) were the only independent risk factors for distant metastasis. CONCLUSION: Patients with OCSCC who have contralateral lymph node metastasis, tumors with a thickness >25 mm, angiolymphatic invasion, or locoregional recurrence after surgical treatment have a greater risk of developing distant metastasis. PMID- 29393252 TI - Harvey A. Lincoff, MD, 1920-2017. PMID- 29393251 TI - The Impact of Skeletal Muscle Depletion on Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND: Skeletal muscle depletion and sarcopenia have been reported as poor prognostic factors for several types of cancer. The aim of this study was to investigate the prognostic impact of skeletal muscle depletion and sarcopenia on the outcomes in head and neck cancer patients. METHODS: Patients with head and neck squamous cell carcinoma (HNSCC) treated from January 2013 to June 2014 were included in this study. The pretreatment cross-sectional area of skeletal muscle at the third lumbar vertebra (L3) was measured by computed tomography image analysis using the ImageJ software. L3 skeletal muscle index (SMI) and fat-free mass (FFM) were calculated. RESULTS: Eighty-five patients with HNSCC were included. The cut-off value of sarcopenia was set at SMI <46.7 cm2/m2 (males) and 30.3 cm2/m2 (females). The cut-off value of FFM was set at 42.3 kg (males) and 30.6 kg (females). Patients with a low SMI (sarcopenia) and low FFM had a significantly poorer prognosis than others, especially those who received definitive radiotherapy. Sarcopenia and low FFM are independent factors for poor prognosis in patients with HNSCC. CONCLUSION: The skeletal muscle area at L3 should be calculated when considering treatment options for head and neck cancer. PMID- 29393253 TI - Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells. AB - BACKGROUND: Bombesin receptor subtype-3 (BRS-3) is a member of the bombesin-like peptide receptor family. Our previous studies demonstrated that activation of the human BRS-3 plays a protective role in oxidation-injured human bronchial epithelial cells (HBEC). The present study was designed to determine the role of BRS-3 activation in the antigen-presenting action of HBEC and the corresponding proliferation and differentiation of T cells. MATERIALS AND METHODS: In vivo, an asthma animal model was established and the expression and distribution of BRS-3 were analyzed by immunocytochemistry. In vitro, 2 kinds of B7 costimulatory molecules, i.e., B7H1 and B7DC, on HBEC were analyzed by flow cytometry. The antigen uptake by HBEC was examined by confocal microscopy and flow cytometry. The antigen-presenting-action-induced proliferation of T cells was determined by MTT assays. IFN-gamma and IL-4 levels were measured by ELISA. All studies were performed in the absence or presence of the synthetic peptide P3513. RESULTS: BRS 3 expression was induced in asthma animal models and mainly distributed in bronchial epithelial cells. HBEC express the costimulatory molecules B7H1 and B7DC. BRS-3 activation increased B7H1 expression but decreased B7DC expression on HBEC. BRS-3 activation also increased the antigen uptake by HBEC and the subsequent T cell proliferation. In addition, BRS-3 activation promoted the releases of IFN-gamma, but not IL-4, in the supernatant of cocultured HBEC and T cells. CONCLUSION: These data suggest that HBEC can present antigen to T cells and BRS-3 activation promotes the process of antigen presentation and subsequent T cell proliferation and Th1 differentiation. PMID- 29393255 TI - Erratum. PMID- 29393254 TI - Fungating Growth of Squamous Cell Carcinoma in Long-Standing Meningocele. AB - Squamous cell carcinoma is known to occur as a serious complication of chronic burns, scars, and ulcers, but very rarely has it been reported to occur in a long neglected meningocele. The authors wish to present the case of a 21-year-old man who presented to us when a previously asymptomatic meningocele developed a squamous cell carcinoma on the meningocele sac. The squamous cell carcinoma was excised in toto, followed by excision of the redundant meningocele sac. The neural placode was closed and dural closure done with an artificial dural patch. Reconstruction of the defect thus created was performed by a lumbar perforator based reverse latissimus dorsi myocutaneous flap. The patient did not develop any postoperative neurological deficits and made an uneventful recovery in the postoperative period. He received adjuvant radiation therapy and is doing well at 4 months' follow-up. PMID- 29393256 TI - Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis. AB - BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. OBJECTIVES: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. METHODS: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. RESULTS: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19 56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). CONCLUSIONS: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC. PMID- 29393257 TI - Clinical Utility of Capsule Endoscopy and Double-Balloon Enteroscopy in the Management of Obscure Gastrointestinal Bleeding. AB - BACKGROUND: Obscure gastrointestinal bleeding (OGIB) is a common but embarrassing problem for gastroenterologists. Most bleeding lesions associated with OGIB are present in the small intestine and sometimes cannot be identified due to the difficulty associated with physical accessibility. Capsule endoscopy (CE) and double-balloon enteroscopy (DBE) have enabled in the process of diagnosing and have evolved to become approaches to treating OGIB. SUMMARY: CE is a minimally invasive procedure and has a high diagnostic yield in patients with OGIB. DBE offers additional advantage of biopsy collection for pathological diagnosis and therapeutic intervention, but it should be noted that it sometimes causes severe adverse events such as acute pancreatitis, intestinal bleeding, and intestinal perforation. CE should be performed early in the workup course of OGIB. Positive CE findings enhance the diagnostic yield of subsequent DBE, and the effective therapeutic intervention improves the clinical outcomes of OGIB patients. On the contrary, there are no clear guidelines for further investigation of patients with negative CE findings at the present. Although patients in stable general condition may only require follow-up, repeated CE is useful to detect positive findings in patients with evidence of sustained bleeding and progressing anemia. We have revealed that repeated CE has higher positive finding rate than DBE in OGIB patients with negative CE findings in a preliminary study. Key Messages: CE and DBE have complementary roles in the management of OGIB, and the precise timing and proper sequence may be important for the approach to treating OGIB. PMID- 29393258 TI - Higher Serum Endocan Level Is Associated with Alzheimer Disease. AB - BACKGROUND: The novel molecule endocan, which is released by endothelium and is regulated by proangiogenic and proinflammatory cytokines, may have a role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to evaluate the relationship between serum endocan levels and AD. METHODS: A total of 134 patients (47 AD, 42 amnestic mild cognitive impairment [aMCI], and 45 control patients) 65 years of age and older were recruited in this study. Cognitive status of the patients was evaluated by performing the Montreal Cognitive Assessment (MOCA) and the Mini-Mental State Examination (MMSE). Serum endocan levels were measured with an enzyme-linked immunosorbent assay kit. RESULTS: Median serum endocan level was significantly higher in AD patients (380.1 ng/mL) than in both aMCI patients (247.7 ng/mL) and controls (277.6 ng/mL; p < 0.01). Serum endocan level had a weak but significant correlation with MMSE and MOCA scores (r = -0.219 and r = -0.232; p = 0.012 and p = 0.01, respectively). Serum endocan level was detected as a factor independently associated with AD. The cutoff serum level of endocan predicting AD was >288.94 ng/mL in receiver operating characteristic curve analysis (area under the curve 0.71, 95% CI 66.7 90.9, sensitivity 80.9%, specificity 59.8%; p < 0.01). CONCLUSION: Higher serum endocan levels may be associated with the pathogenesis of AD. PMID- 29393259 TI - Influence of Parathyroidectomy on Bone Metabolism and Bone Pain in Patients with Secondary Hyperparathyroidism. AB - BACKGROUND: After parathyroidectomy (PTX), hungry bone syndrome leads to hypocalcemia due to bone remineralization. The aim of this pilot study was to analyze changes in markers of bone metabolism in patients with secondary hyperparathyroidism (sHPT) after PTX and to correlate these markers with bone pain measured with a validated questionnaire. MATERIALS AND METHODS: All patients who underwent PTX for sHPT between March 2010 and February 2012 at out institution were included in this prospective observational pilot study. At the day before surgery and on the 3rd day thereafter, levels of parathyroid hormone (PTH), calcium, osteocalcin, alkaline phosphatase (AP), bone-specific AP (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), osteoprotegerin (OPG), sclerostin, fibroblast growth factor 23, and Klotho were measured. Additionally, all patients were requested to answer the Brief Pain Inventory preoperatively and on the 5th postoperative day. RESULTS: A total of 35 patients with a mean age of 49.8 years were analyzed. A significant difference between the pre- and postoperative values could be detected in PTH, calcium, BAP, TRAP5b, and sclerostin. The highest correlation of laboratory markers with bone pain was found for preoperative PTH (r = 0.3), postoperative OPG (r = 0.4), postoperative BAP (r = -0.4), and postoperative Klotho (r = -0.4). CONCLUSIONS: The present study revealed significant perioperative changes in PTH, BAP, sclerostin, and TRAP5b after PTX. These markers may serve as laboratory markers to monitor bone metabolism in patients with sHPT. PTH, OPG, and sclerostin were the parameters with the closest correlation to bone pain. However, larger prospective trials with a longer follow-up are required to confirm these results. PMID- 29393260 TI - Effects of Intravitreal Silicone Oil on Subfoveal Choroidal Thickness. AB - PURPOSE: To evaluate the effects of intravitreal silicone oil (SO) on subfoveal choroidal thickness (SFCT). METHODS: A total of 60 patients with unilateral pseudophakic macula-off rhegmatogenous retinal detachment were treated with a three-port pars plana vitrectomy and a 5,700-cSt SO endo-tamponade and subsequent SO removal. SFCT was measured before and 3 months after SO removal. The main outcome measure was the difference between the SFCT of operated eyes and the fellow eyes. RESULTS: Before SO removal, the mean SFCT differences in group 1 (3 6 months' duration of SO), group 2 (6-9 months' duration of SO), and group 3 (9 18 months' duration of SO) were -14.8, -25.5, and -62.1 um, respectively (p = 0.002, r = 0.398). Three months after SO removal, the mean SFCT differences in group 1, group 2, and group 3 were -13.4, -23.3, and -59.0 um, respectively (p = 0.002, r = 0.393). CONCLUSION: SFCT decreased significantly in eyes with long term (>=6 months) intravitreal SO tamponade. Choroidal thinning did not improve after SO removal. PMID- 29393261 TI - Body Composition following Necrotising Enterocolitis in Preterm Infants. AB - BACKGROUND: The optimal nutritional regimen for preterm infants, including those that develop necrotising enterocolitis (NEC), is unknown. OBJECTIVE: The objective here was to evaluate body composition at term in infants following NEC, in comparison with healthy infants. The primary outcome measure was non-adipose tissue mass (non-ATM). METHODS: We compared body composition assessed by magnetic resonance imaging at term in infants born <31 weeks of gestational age that participated in NEON, a trial comparing incremental versus immediate delivery of parenteral amino acids on non-ATM, and SMOF versus intralipid on intrahepatocellular lipid content. There were no differences in the primary outcomes. We compared infants that received surgery for NEC (NEC-surgical), infants with medically managed NEC (NEC-medical), and infants without NEC (reference). RESULTS: A total of 133 infants were included (8 NEC-surgical; 15 NEC-medical; 110 reference). In comparison with the reference group, infants in the NEC-surgical and NEC-medical groups were significantly lighter [adjusted mean difference (95% CI) NEC-surgical: -630 g (-1,010, -210), p = 0.003; NEC-medical: 440 g (-760, -110), p = 0.009] and the total adipose tissue volume (ATV) was significantly lower [NEC-surgical: -360 cm3 (-516, -204), p < 0.001; NEC-medical: -127 cm3 (-251, -4); p = 0.043]. There were no significant differences in non-ATM [adjusted mean difference (95% CI) NEC-surgical: -46 g (-281, 189), p = 0.70; NEC medical: -122 g (-308, 63), p = 0.20]. CONCLUSION: The lower weight at term in preterm infants following surgically and medically managed NEC, in comparison to preterm infants that did not develop the disease, was secondary to a reduction in ATV. This suggests that the nutritional regimen received was adequate to preserve non-ATM but not to support the normal third-trimester deposition of adipose tissue in preterm infants. PMID- 29393262 TI - Androgen Insensitivity Syndrome at Prepuberty: Marked Loss of Spermatogonial Cells at Early Childhood and Presence of Gonocytes up to Puberty. AB - Androgen insensitivity syndrome (AIS) is a hereditary condition in patients with a 46,XY karyotype in which loss-of-function mutations of the androgen receptor (AR) gene are responsible for defects in virilization. The aim of this study was to investigate the consequences of the lack of AR activity on germ cell survival and the degree of testicular development reached by these patients by analyzing gonadal tissue from patients with AIS prior to Sertoli cell maturation at puberty. Twenty-three gonads from 13 patients with AIS were assessed and compared to 18 testes from 17 subjects without endocrine disorders. The study of the gonadal structure using conventional microscopy and the ultrastructural characteristics of remnant germ cells using electron microscopy, combined with the immunohistochemical analysis of specific germ cell markers (MAGE-A4 for premeiotic germ cells and of OCT3/4 for gonocytes), enabled us to carry out a thorough investigation of germ cell life in an androgen-insensitive microenvironment throughout prepuberty until young adulthood. Here, we show that germ cell degeneration starts very early, with a marked decrease in number after only 2 years of life, and we demonstrate the permanence of gonocytes in AIS testis samples until puberty, describing 2 different populations. Additionally, our results provide further evidence for the importance of AR signaling in peritubular myoid cells during prepuberty to maintain Sertoli and spermatogonial cell health and survival. PMID- 29393263 TI - New Hydrogels Enriched with Antioxidants from Saffron Crocus Can Find Applications in Wound Treatment and/or Beautification. AB - Saffron extracts have a long history of application as skin protectant, possibly due to their ability to scavenge free radicals. In this work, the performance of a hydrogel enriched with antioxidant compounds isolated from saffron crocus (Crocus sativus L.) petals was tested. These hydrogels could be considered as new drug delivery system. Hydrogels are crosslinked polymer networks that absorb large quantities of water but retain the properties of a solid, thus making ideal dressings for sensitive skin. We tested antioxidant-enriched hydrogels on primary mouse fibroblasts. Hydrogels enriched with kaempferol and crocin extracted from saffron petals showed good biocompatibility with in vitro cultured fibroblasts. These new types of hydrogels may find applications in wound treatment and/or beautification. PMID- 29393265 TI - Accurate Direct Measures Are Required to Validate Derived Measures. PMID- 29393264 TI - Prevention of Doxorubicin-Induced Renal Toxicity by Theanine in Rats. AB - Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties. PMID- 29393266 TI - Modelling Population Viability of Three Independent Javan Gibbon (Hylobates moloch) Populations on Java, Indonesia. AB - Population viability analysis is a predictive procedure that uses a combination of different modelling approaches to estimate species vulnerability to extinction. Javan gibbons (Hylobates moloch) are vulnerable to local extinction primarily due to loss of habitat and hunting for the illegal pet trade. Using the modelling software VORTEX, we assessed the status of Javan gibbons in 3 areas (Ujung Kulon National Park, Halimun-Salak National Park, and Dieng Mountains) which hold over half of the remaining estimated number of gibbons on Java. Ujung Kulon and Halimun-Salak are long-time protected areas, whereas Dieng Mountains remain unprotected. For each area, we calculated the probability of extinction over a 100-year time period by testing different area-specific scenarios (e.g., hunting, deforestation, and increase in carrying capacity). Our modelling suggests each of the populations has a high chance of becoming extinct within the next 100 years if hunting and deforestation persist. If these threats are eliminated, the model shows each of the populations are large enough to persist in the long term whilst maintaining high levels of current genetic diversity. We conclude that specific actions should be implemented to develop more inclusive conservation management practices, especially improving awareness regarding the illegal wildlife trade and increased protection of wild populations and their habitats. PMID- 29393267 TI - Theoretical Effect of DBS on Axonal Fibers of Passage: Firing Rates, Entropy, and Information Content. AB - BACKGROUND: Deep brain stimulation (DBS) has effects on axons that originate and terminate outside the DBS target area. OBJECTIVE: We hypothesized that DBS generates action potentials (APs) in both directions in "axons of passage," altering their information content and that of all downstream cells and circuits, and sought to quantify the change in fiber information content. METHODS: We incorporated DBS parameters (fiber firing frequency and refractory time, and AP initiation location along the fiber and propagation velocity) in a filtering function determining the AP frequency reaching the postsynaptic cell. Using neural circuitry simulation software, we investigated the ability of the filtering function to predict the firing frequency of APs reaching neurons targeted by axons of passage. We calculated their entropy with and without DBS, and with the electrode applied at various distances from the cell body. RESULTS: The predictability of the filtering function exceeded 98%. Entropy calculations showed that the entropy ratio "without DBS" to "with DBS" was always >1.0, thus DBS reduces fiber entropy. CONCLUSIONS: (1) The results imply that DBS effects are due to entropy reduction within fibers, i.e., a reduction in their information. (2) Where fibers of passage do not terminate in target regions, DBS may have side effects on nontargeted circuitry. PMID- 29393268 TI - Integrated 68Gallium Labelled Prostate-Specific Membrane Antigen-11 Positron Emission Tomography/Magnetic Resonance Imaging Enhances Discriminatory Power of Multi-Parametric Prostate Magnetic Resonance Imaging. AB - PURPOSE: To evaluate diagnostic accuracy of integrated 68Gallium labelled prostate-specific membrane antigen (68Ga-PSMA)-11 positron emission tomography (PET)/MRI in patients with primary prostate cancer (PCa) as compared to multi parametric MRI. MATERIAL AND METHODS: A total of 22 patients with recently diagnosed primary PCa underwent clinically indicated 68Ga-PSMA-11 PET/CT for initial staging followed by integrated 68Ga-PSMA-11 PET/MRI. Images of multi parametric magnetic resonance imaging (mpMRI), PET and PET/MRI were evaluated separately by applying Prostate Imaging Reporting and Data System (PIRADSv2) for mpMRI and a 5-point Likert scale for PET and PET/MRI. Results were compared with pathology reports of biopsy or resection. Statistical analyses including receiver operating characteristics analysis were performed to compare the diagnostic performance of mpMRI, PET and PET/MRI. RESULTS: PET and integrated PET/MRI demonstrated a higher diagnostic accuracy than mpMRI (area under the curve: mpMRI: 0.679, PET and PET/MRI: 0.951). The proportion of equivocal results (PIRADS 3 and Likert 3) was considerably higher in mpMRI than in PET and PET/MRI. In a notable proportion of equivocal PIRADS results, PET led to a correct shift towards higher suspicion of malignancy and enabled correct lesion classification. CONCLUSION: Integrated 68Ga-PSMA-11 PET/MRI demonstrates higher diagnostic accuracy than mpMRI and is particularly valuable in tumours with equivocal results from PIRADS classification. PMID- 29393269 TI - Reply to the Commentary "Vitamin D Intake in Preterm Infants: Too Little, Too Much, or Just the Right Amount?" PMID- 29393270 TI - Vascular Endothelial Growth Factor-A165b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury. AB - BACKGROUND/AIMS: Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto protective effects of the splice isoform vascular endothelial growth factor (VEGF A165b). METHODS: The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. RESULTS: Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over expressed VEGF-A165b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A165b mice. CONCLUSION: Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease. PMID- 29393271 TI - Phenotypic Variation in 46,XX Disorders of Sex Development due to the NR5A1 p.R92W Variant: A Sibling Case Report and Literature Review. AB - Recently, a heterozygous missense mutation in NR5A1, p.R92W, was identified as a cause of 46,XX testicular/ovo-testicular disorders of sexual development (DSD). We report a sibling pair with 46,XX DSD due to an NR5A1 mutation with distinct phenotypes, including external and internal genitalia and gonads, for whom different rearing sexes were selected. Thus, the phenotypes of p.R92W vary, even within a family. The father of the patients showed oligozoospermia with the p.R92W mutation, suggesting that in 46,XY individuals, the mutation would cause various gonadal phenotypes. We review and discuss the general role of the R92W mutation in sexual development. PMID- 29393272 TI - The Combination of Trypan Blue and Brilliant Blue G-Assisted Vitrectomy for Macular Pucker: Histopathological Findings. AB - PURPOSE: To report on the combined use of trypan blue (TB) and brilliant blue G (BBG) for staining the epiretinal membrane (ERM) and internal limiting membrane (ILM) during vitrectomy and to describe the histopathological findings. METHODS: 10 surgical specimens were removed from 10 eyes with macular pucker during vitrectomy using a commercially available combination of TB and BBG for ERM and ILM staining and peeling. Specimens were evaluated using light and transmission electron microscopy. RESULTS: In all cases the combination of TB and BBG was useful for identifying and delineating ERM and ILM. No complications related to the use of the dye were observed during or after surgery. Glial cells were present in all specimens. Hyalocytes were observed in 6 cases and myofibroblasts in 3 of them. In 7 cases native vitreous collagen fibrils were found on the ILM, while in 5 specimens newly formed collagen was present. No clinical evidence of toxicity was observed during the 3-month follow-up. CONCLUSION: The combined use of TB and BBG appeared to be very useful intraoperatively to improve the visualization of ERM and ILM, thus facilitating their complete removal. Anatomical and histopathological findings demonstrated the safety and the efficacy of this vital dye. PMID- 29393273 TI - Pleural Dye Marking Using Radial Endobronchial Ultrasound and Virtual Bronchoscopy before Sublobar Pulmonary Resection for Small Peripheral Nodules. AB - BACKGROUND: Minimally invasive surgery of pulmonary nodules allows suboptimal palpation of the lung compared to open thoracotomy. OBJECTIVE: The objective of this study was to assess endoscopic pleural dye marking using radial endobronchial ultrasound (r-EBUS) and virtual bronchoscopy to localize small peripheral lung nodules immediately before minimally invasive resection. METHODS: The endoscopic procedure was performed without fluoroscopy, under general anesthesia in the operating room immediately before minimally invasive surgery. Then, 1 mL of methylene blue (0.5%) was instilled into the guide sheath, wedged in the subpleural space. Wedge resection or segmentectomy were guided by visualization of the dye on the pleural surface. Contribution of dye marking to the surgical procedure was rated by the surgeon. RESULTS: Twenty-five nodules, including 6 ground glass opacities, were resected in 22 patients by video assisted thoracoscopic wedge resection (n = 11) or robotic-assisted thoracoscopic surgery (10 segmentectomies and 1 wedge resection). The median greatest diameter of nodules was 8 mm. No conversion to open thoracotomy was needed. The endoscopic procedure added an average 10 min to surgical resection. The dye was visible on the pleural surface in 24 cases. Histological diagnosis and free margin resection were obtained in all cases. Median skin-to-skin operating time was 90 min for robotic segmentectomy and 40 min for video-assisted wedge resection. The same operative precision was considered impossible by the surgeon without dye marking in 21 cases. CONCLUSIONS: Dye marking using r-EBUS and virtual bronchoscopy can be easily and safely performed to localize small pulmonary nodules immediately before minimally invasive resection. PMID- 29393274 TI - Restless Legs Syndrome: An Unresolved Uremic Disorder after Renal Transplantation. AB - BACKGROUND: Restless legs syndrome (RLS) is a common complication of uremia that may improve after transplantation. Its frequency might not be as low as expected, as some uremic disturbances may continue even after a successful graft. Our aim was to investigate the prevalence and related conditions for RLS in renal transplant patients. METHODS: We carried out a cross-sectional, observational study. A self-administered questionnaire following the International Restless Legs Syndrome Study Group diagnostic criteria was administered to 129 patients (82 men and 47 women) aged 57 +/- 12.8 years followed up for at least 1 year, with stable renal function (Cr 1.5 +/- 0.54 mg/dL). Patients with probable RLS according to the screening questionnaire underwent comprehensive neurological examination to exclude RLS mimics. RESULTS: The frequency of RLS according to questionnaires was 29.5% (18 men/20 women). After neurological exam, RLS was confirmed in 19 patients providing an overall frequency of 14.8% (higher than the prevalence in the general population). A definitive diagnosis of RLS was established for 6 men (7.3%) and 13 women (27.7%), indicating a positive predictive value for the screening questionnaire of 65% for women and 33% for men. There were fewer patients under renin-angiotensin aldosterone system (RAAS) blocking treatment in the RLS group (21.1 vs. 47.3%). Women with RLS had poorer renal function (52 +/- 17.5 vs. 42 +/- 13.9 mL/min) and phosphate-reabsorption rate (75 +/- 10.5 vs. 65 +/- 9.2). There was no difference in age, comorbidities, anticalcineurin therapy, renal function, anemia and time since transplantation between transplant patients with and without RLS. CONCLUSION: The prevalence of RLS after transplantation remains high (14.8%). This condition is twice more prevalent for females. Contribution of RAAS, graft function and phosphate overload requires further investigation. PMID- 29393276 TI - Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation. AB - Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1beta into mature IL-1beta, which is critical for the development of non-steroidal anti inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1beta in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1beta in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1beta protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1beta. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1beta. NLRP3-/- and caspase-1-/- mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3-/- and caspase-1-/- mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation. PMID- 29393275 TI - Efficacy of Platinum-Based Chemotherapy for Relapsed Small-Cell Lung Cancer after Amrubicin Monotherapy in Elderly Patients and Patients with Poor Performance Status. AB - BACKGROUND: Previous studies have shown amrubicin to be an effective first- or second-line treatment option for small-cell lung cancer (SCLC). However, there have been few studies reporting the efficacy of platinum-based chemotherapy after amrubicin therapy. We aimed to evaluate the efficacy of platinum-based chemotherapy as second-line treatment for elderly patients and those with SCLC with poor performance status (PS) previously treated with amrubicin monotherapy. METHODS: The records of SCLC patients who received platinum-based chemotherapy as a second-line chemotherapy after first-line treatment with amrubicin monotherapy were retrospectively reviewed and the treatment outcomes were evaluated. RESULTS: A total of 48 patients were enrolled in this study. Forty-one patients (85%) received carboplatin plus etoposide. The overall response rate was 39.6%. The median progression-free survival and overall survival were 3.7 and 7.6 months, respectively. The efficacy of the platinum-based regimen did not differ with the type of relapse after amrubicin monotherapy. The most common adverse events were hematological toxicities, including grade 3 or 4 neutropenia (38%), leukopenia (33%), and thrombocytopenia (10%). CONCLUSIONS: Platinum-based chemotherapy is potentially a valid treatment option for elderly patients or those with extensive stage SCLC with poor PS as second-line chemotherapy, who progressed after first line treatment with amrubicin monotherapy. PMID- 29393277 TI - Variation in the Phototherapy Practices and Irradiance of Devices in a Major Metropolitan Area. AB - BACKGROUND: Phototherapy (PT) is widely used to prevent and treat severe hyperbilirubinemia and its associated risks for both acute and chronic bilirubin encephalopathy. Intensive PT, recommended for inpatient treatment of hyperbilirubinemia in term and near-term infants, is defined as having a spectral irradiance of >=30 MUW/cm2/nm. OBJECTIVES: We aimed to assess local PT practices by measuring the irradiance of PT devices in local neonatal intensive care units and newborn nurseries. METHODS: The irradiance footprint, including maximum irradiance at the center of the footprint, of 39 PT devices in 7 area hospitals was measured according to current practice in these facilities. RESULTS: The mean +/- SD (range) footprint irradiance was 20.7 +/- 5.8 (8.8-29.4) MUW/cm2/nm. The mean +/- SD maximum irradiance at the footprint center for all devices at a mean clinically used treatment distance of 33.1 +/- 9.3 (25.5-60.0) cm was 27.8 +/- 7.0 (14.7-42.0) MUW/cm2/nm. Sixty-two percent of the devices did not meet the minimum recommended spectral irradiance for intensive PT. For the sites without irradiance-based protocols, the maximum irradiance of the devices (n = 33) at the treatment distances was 25.8 +/- 6.1 MUW/cm2/nm. CONCLUSIONS: Despite established PT guidelines, local protocols and practices vary. Based on an assessment of 7 local hospitals, intensive PT was suboptimal for 62% of devices. Straightforward changes, such as decreasing the distance between an infant and the light source and establishing a consistent irradiance-based protocol, could substantially improve the quality of the intervention. PMID- 29393278 TI - Effect of Oridonin on Cytochrome P450 Expression and Activities in HepaRG Cell. AB - Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 MUmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS based metabolite assay. In general, ordonin has induced effects on the major member of CYP450s mRNA and protein expression, as well as on the enzyme activity in human HepaRG cells, especially on CYP3A4 and CYP2C9. To our knowledge, this is the first systematic research about the inductive effects of oridonin on the major member of CYP450s in human cell line. These results may provide at least partly of the basis for potential drug-drug interactions and oridonin should be used with caution to avoid potential risk. PMID- 29393279 TI - Clinical Components of Borderline Personality Disorder and Personality Functioning. AB - BACKGROUND: Impairment in personality functioning (PF) represents a salient criterion of the DSM-5 alternative diagnostic model for personality disorders (AMPD). The main goal of this study is to analyze the relationship of the borderline personality disorder (BPD) clinical components derived from the DSM-5 categorical diagnostic model (affective dysregulation, behavioral dysregulation, and disturbed relatedness) with personality organization (PO), i.e., PF, assessed by the Structured Interview of Personality Organization (STIPO). METHODS: STIPO and the Structured Clinical Interviews for DSM-IV (SCID-I and -II) were administered to 206 BPD patients. The relationship between PO and BPD components were studied using Spearman correlations and independent linear regression analyses. RESULTS: Significant positive correlations were observed between STIPO scores and several DSM-5 BPD criteria and comorbid psychiatric disorders. STIPO dimensions mainly correlated with disturbed relatedness and, to a lesser extent, affective dysregulation components. Each BPD clinical component was associated with specific STIPO dimensions. CONCLUSIONS: Both diagnostic models, DSM-5 BPD criteria and PO, are not only related but complementary concepts. The results of this study particularly recommend STIPO for the assessment of relational functioning, which is a major domain of the Personality Functioning Scale Levels of the DSM-5 AMPD. PMID- 29393280 TI - Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated. METHODS: We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms ("cetuximab" or "panitumumab") AND ("colorectal cancer" OR "colorectal carcinoma"). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A chi2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison. RESULTS: A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3-4 skin toxicities (OR = 0.62, 95% CI 0.53-0.62; p < 0.001), slightly more frequent G3-4 acne-like rash (OR = 1.24, 95% CI 1.04-1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1-1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44-0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35-0.58; p < 0.001) than PANI. CONCLUSIONS: In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events. PMID- 29393281 TI - [Carotid endarterectomy in patients with symptomatic occlusions of the contralateral internal carotid artery]. AB - The main aim of the study was to investigate the effect of carotid endarterectomy on the prognosis of chronic cerebral ischemia in patients with symptomatic occlusions of the contralateral internal carotid artery, assess risks of surgical complications, and substantiate the staged surgical approach for treatment of patients with this pathology. The article analyzes the experience in surgical treatment of 83 patients with symptomatic ICA occlusions who underwent surgery for contralateral carotid artery stenosis. In 40 patients, only carotid endarterectomy (CEA) was performed on the side of hemodynamically significant stenosis (group 1). In 43 (52%) cases, apart from CEA, extracranial-intracranial (EC-IC) bypass was performed at the second stage (23 cases, group 2) or the first stage (19 cases, group 3). A surgical treatment approach was chosen based on clinical symptoms, severity of contralateral carotid artery stenosis, and the magnitude of perfusion deficiency in the territory of carotid occlusion. The conducted analysis revealed that patients with symptomatic occlusions and contralateral carotid artery stenoses represented a heterogeneous group with a different efficacy of carotid endarterectomy and with risks of perioperative complications. As cerebrovascular insufficiency in the territory of carotid occlusion and a related neurological deficit worsen, the risks of complications of contralateral carotid endarterectomy increase, and its clinical efficacy decreases. In these cases, cerebral revascularization on the ICA occlusion side should be performed at the first stage. PMID- 29393282 TI - [Intracranial neurenteric cysts: experience of the Burdenko Neurosurgical Institute in the XXIth century]. AB - : We present a series of cases of a rare pathology, intracranial neuroenteric cysts, a review of the international literature, and the experience in treating this pathology. MATERIAL AND METHODS: Seven patients with intracranial neuroenteric cysts underwent surgery at the Neurosurgical Institute in the period between 2000 and 2015. CONCLUSION: The main and only technique for treatment of intracranial neurenteric cysts is their resection. PMID- 29393283 TI - [The spectrum of genetic alterations in anaplastic gliomas: and anaplastic oligodendrogliomas]. AB - The work explores the molecular genetic features of anaplastic astrocytomas and oligodendrogliomas in a series of 43 cases. The mutational status was studied using domestic chemicals and reagent kits. We revealed clear genetic differences between astrocytic and oligodendroglial tumors and proposed an algorithm to study diagnostic and prognostic markers. PMID- 29393284 TI - [Cerebrospinal fluid rhinorrhea in primary treatment of large and giant prolactinomas with dopamine agonists]. AB - : At present, pharmacological therapy of prolactinomas with dopamine agonists (DAs) is considered the treatment of choice. In most cases, giant prolactinomas respond to treatment with dopamine agonists and decrease in size during the first months of the treatment. One of the rare but dangerous complications of conservative treatment of prolactinomas with invasive growth is cerebrospinal fluid rhinorrhea. MATERIAL AND METHODS: We present a retrospective analysis of 15 patients with macropropactinomas who underwent surgery for cerebrospinal fluid rhinorrhea developed due to primary therapy with dopamine agonists at the Burdenko Neurosurgical Institute (BNI) in the period between 2005 and 2015. All patients had large and giant tumors (according to the classification adopted at the BNI). When cerebrospinal fluid rhinorrhea was detected, patients were hospitalized to the BNI for examination, detection of a CSF fistula, reconstruction of a defect, and resection (if possible) of the tumor. RESULTS: In the period between 2005 and 2015, 15 patients (8 males and 7 females) with prolactinomas of a large and giant size at the onset of conservative therapy underwent surgery for cerebrospinal fluid rhinorrhea at the BNI. All patients underwent transnasal reconstruction of a skull base defect, with 13 out of 15 patients undergoing simultaneous resection of the tumor. After tumor resection, reconstruction was performed using auto-fat, fascia, and glue (in 8 cases). In the remaining cases, apart from auto-fat, fascia, and glue, a mucoperiosteal flap and auto-bone were used. Fourteen patients were followe-up. In 13 cases, there was no relapse of cerebrospinal fluid rhinorrhea after skull base reconstruction. In 1 case, there was a relapse of cerebrospinal fluid rhinorrhea. CONCLUSION: Conservative treatment of patients with giant prolactinomas should be performed under regular control of ENT doctors and neurosurgeons for timely detection and surgical treatment of cerebrospinal fluid rhinorrhea. PMID- 29393285 TI - [Transient enlargement of craniopharyngioma cysts after stereotactic radiotherapy and radiosurgery]. AB - : Stereotactic radiotherapy/radiosurgery (RT/ES) is an effective technique for treating craniopharyngiomas (CPs). However, enlargement of the cystic part of the tumor occurs in some cases after irradiation. The enlargement may be transient and not require treatment or be a true relapse requiring treatment. MATERIAL AND METHODS: In this study, we performed a retrospective analysis of 79 pediatric patients who underwent stereotactic RT or RS after resection of craniopharyngioma. RESULTS: Five-year relapse-free survival after complex treatment of CP was 86%. In the early period after irradiation, 3.5 months (2.7 9.4) on average, enlargement of the cystic component of the tumor was detected in 10 (12.7%) patients; in 9 (11.4%) of them, the enlargement was transient and did not require treatment; in one case, the patient underwent surgery due to reduced visual acuity. In 8 (10.1%) patients, an increase in the residual tumor (a solid component of the tumor in 2 cases and a cystic component of the tumor in 6 cases) occurred in the long-term period after irradiation - after 26.3 months (16.6 48.9) and did not decrease during follow-up in none of the cases, i.e. continued growth of the tumor was diagnosed. A statistical analysis revealed that differences in the terms of transient enlargement and true continued growth were statistically significant (p<0.01). CONCLUSION: Enlargement of a craniopharyngioma cyst in the early period (up to 1 year) after RT/RS is usually transient and does not require surgical treatment (except cases where worsening of neurological symptoms occurs, or occlusive hydrocephalus develops). PMID- 29393286 TI - [Biodegradable fixation systems in pediatric craniofacial surgery: 10-year experience with 324 patients]. AB - INTRODUCTION: Over the past 15 years, resorbable materials have been successfully used for osteosynthesis, but their high cost prevents widespread application. However, the use of resorbable systems could be a method of choice, especially in treatment of children in the active growth period. Obviously, biodegradable materials not only are highly competitive with known metal constructs in terms of fixation rigidity, biocompatibility, and a low risk of infection but also have an undeniable advantage, such as gradual resorption allowing quick return of damaged bones to the physiological conditions of functioning. A special feature of bioresorbable systems is that they can be assembled using ultrasonic welding, which greatly facilitates the fixation process and also provides necessary rigidity, even in cases of joining very thin bones when reliable fixation with screws is impossible. MATERIAL AND METHODS: Over the past 10 years, we have used biodegradable systems in 324 patients. In 244 of them, we used traditional (plate/screw) systems; in 80 cases, an ultrasonic welding system was chosen for osteosynthesis. RESULTS: In the present work, we discuss, based on clinical evidence, the advantages and disadvantages of both fixation systems for reconstructive craniofacial surgery in children. PMID- 29393287 TI - [Drainage-associated meningitis in neurocritical care patients. The results of a five-year prospective study]. AB - AIM: to determine the incidence rate and risk factors for drainage-associated meningitis in neurocritical care patients. MATERIAL AND METHODS: The prospective study included 539 patients who spent more than 48 h at the Department of Neurocritical Care and underwent external ventricular drainage. The incidence rate and risk factors for drainage-associated meningitis were evaluated. RESULTS: Over a 5-year period, 2140 patients have been hospitalized to the Department of Critical and Intensive Care (DCIC) for more than 48 h; of these, 539 patients underwent external ventricular drainage (EVD). Drainage-associated meningitis developed in 99 patients, which amounted to 19.8 (CI 16.3-23.3) per 100 patients with drainage and 18.3 (CI 14.3-22.2) per 1000 days of drainage. The incidence rate of drainage-associated meningitis did not significantly correlate with different neurosurgical diseases, but there was a tendency for meningitis to predominate in EVD patients with vascular pathology of the central nervous system (CNS). The rate of artery catheterization for direct measurement of systemic BP and the use of vasopressor agents were significantly higher in the group of patients with drainage-associated meningitis (p<0.05). ALV was used in 98 (99%) of 99 patients with drainage-associated meningitis; respiratory support was used in 325 (80.8%) patients without meningitis (p<0.01). An analysis of the ventricular drainage duration revealed a significantly (p<0.05) larger number of days of using EVD in the group of patients with drainage-associated meningitis. In most critical care patients (57.6%), meningitis developed during the first week of drainage. Cerebrospinal fluid leakage occurred significantly more frequently in patients with drainage-associated meningitis than in patients with EVD and without meningitis (p<0.01). Based on a microbiological examination, the etiology of drainage-associated meningitis was established in 57.1% of cases. The leading pathogens were coagulase-negative staphylococci (48.3%) and Acinetobacter baumannii (18.3%). CONCLUSION: The incidence rate of drainage-associated meningitis was 19.8 per 100 patients and 18.3 per 1000 days of drainage. The risk factors significantly predominating in patients with drainage-associated meningitis include the duration of drainage, association with external CSF leakage, as well as factors associated with indicators of the overall severity of the condition. PMID- 29393288 TI - [Some features controlling the blood D-dimer level after resection of malignant brain glioma]. AB - : A high blood D-dimer level is often diagnosed in patients with malignant brain glioma (MBG), with 24% of these patients being detected with deep vein thrombosis of the leg and/or pulmonary embolism (PE). The cause of an elevated blood D-dimer level in most other cases remains unclear. The purpose of this study is to identify the features associated with an increased blood D-dimer level in patients after MBG resection, which may be used to improve the efficacy of adjuvant radiation therapy (ART). RESULTS: The study included 50 patients. Three to four weeks after resection of malignant brain glioma (MBG), the blood D-dimer level was determined in patients immediately before the onset of ART. An increase in the blood D-dimer level more than by 0.25 MUg/mL was detected in 78% of patients. More often, a high D-dimer level was detected in patients aged 60 years or more. In the same age group, an increase in the D-dimer level was significantly larger (p<0.05) than in younger patients (1.2 and 0.6 MUg/mL, respectively). The degree of brain tumor malignancy did not affect the rate and value of an increase in the blood D-dimer level. CONCLUSION: Our findings indicate that an increased blood D-dimer level in patients without symptoms of venous thrombosis after craniotomy for MBG is more pronounced in patients aged 60 years and over. The degree of glioma malignancy has no significant effect on this indicator. PMID- 29393289 TI - [Results of surgical treatment for lumbar spine segmental instability]. AB - AIM: To perform a comparative analysis of outcomes in patients with lumbar spine segmental instability who underwent surgical treatment using transforaminal lumbar interbody fusion (TLIF) and direct lateral interbody fusion (DLIF) techniques. MATERIAL AND METHODS: The multicenter study involved 209 patients who underwent surgery for lumbar spine segmental instability. Long-term outcomes (up to 2 years) were studied in 134 patients: patients of the first group (98 patients) underwent traditional transforaminal lumbar interbody fusion (TLIF) and transpedicular stabilization of vertebral segments; patients of the second group (36 patients) underwent direct lateral interbody fusion (DLIF) in combination with transpedicular stabilization of the lumbar vertebral segments. We used standard checkpoints for monitoring the patients' condition: before surgery, at discharge, at 3, 6 and, 9 months, and at 1 and 2 years after surgery. To follow up the patients, we used the Visual Analogue Scale, Oswestry Disability Index, and Goal Attainment Scaling. RESULTS: A comparative analysis of the two interbody fusion techniques was enabled by the developed Vertebrologic Registry profile (http://spineregistry.ru/Register_treatment.php) that was designed for entering data of Russian and foreign experts to analyze clinical characteristics, evaluate outcomes, and follow-up patients with degenerative lumbosacral spine diseases. In both groups of patients, a significant decrease in the pain intensity in the lumbar spine and lower extremities (VAS) occurred in the immediate postoperative period, which persisted in the long-term period. There were no differences in the disability level (Oswestry index) in both groups of patients (p<0.05). An analysis of treatment goal attainments one year after surgery revealed the best result in patients of the second group who underwent DLIF. CONCLUSIONS: 1. Indirect decompression using direct lateral interbody fusion (DLIF) minimizes the risks of intraoperative injury to the dura mater and neural structures. Kawabata class I outcomes (good) were achieved in 89% of patients who underwent direct lateral spinal fusion (DLIF) and in 81% of patients who underwent transforaminal interbody stabilization in combination with transpedicular fixation. PMID- 29393290 TI - [Correlation of intracranial pressure and diameter of the sheath of the optic nerve by computed tomography in severe traumatic brain injury]. AB - BACKGROUND: Noninvasive techniques to evaluate intracranial pressure (ICP) are important for everyday practice in intensive care and neurosurgery departments. CT data can be used to evaluate the optic nerve sheath diameter (ONSD) and, indirectly, the ICP value. The ONSD value is an additional criterion in deciding on invasive monitoring of ICP. AIM: To analyze a correlation between CT-based ONSD and the results of invasive measurements of ICP in patients with severe traumatic brain injury. MATERIAL AND METHODS: The study evaluated 41 patients with severe traumatic brain injury within the first 48 h after injury. Invasive monitoring of ICP (Codman & Shurtlett, MA, USA) was performed during 7+/-1.7 days. ONSD was measured using axial CT scans (CereTom, Neurologica Danvers, MA, USA) with a slice thickness of 2.5 mm. The ONSD value was measured at a distance of 3 mm from the posterior eyeball contour. The patients were allocated in a group with normal ICP (10 patients) and a group with high ICP (31 patients). ONSD served as an ICP classifier. The data were processed using ROC analysis. RESULTS: According to the CT data, the optimal threshold ONSD value was 6.35 mm in patients in the acute TBI period. The sensitivity was 0.93 (95% SI 0.84-1.00), the specificity was 0.80 (95% SI 0.50-1.00), and AUC was 0.87 (95% SI 0.69-1.00). CONCLUSION: We found a correlation between the CT-based ONSD and the median ICP (R=0.32, p<0.05). An ONSD value of 6.35 mm and more is one of the signs of previous or existing ICP. PMID- 29393291 TI - [The trans-eyebrow supraorbital approach for removal of anterior cranial fossa and suprasellar meningiomas]. AB - : Over the past two decades, improvements in surgical tools, navigation systems, and endoscopic techniques have resulted in the widespread use of keyhole surgery for a wide range of skull base tumors. Currently, the trans-eyebrow supraorbital approach is being increasingly used in surgery for anterior cranial fossa and parasellar tumors. MATERIAL AND METHODS: The study included 7 patients who underwent surgery for meningioma using the trans-eyebrow supraorbital approach at the Burdenko Neurosurgical Institute in the period between 2013 and 2017. The age of patients ranged from 51 to 75 years (median, 60 years); there were 5 females and 2 males. The maximum diameter of resected tumors ranged from 20 to 60 mm (median 40 mm). RESULTS: Total resection of the tumor was achieved in all 7 cases, which was confirmed by postoperative MRI control. All 7 patients had a good cosmetic result. In 1 case, there was postoperative cerebrospinal fluid rhinorrhea due to incomplete closure of the frontal sinus, which required the patient to be re-operated. None of 7 cases was associated with injury to the main vessels or cavernous sinus. CONCLUSION: Supraorbital trans-eyebrow craniotomy provides a minimally invasive approach for removing most anterior cranial fossa base and suprasellar tumors. The advantages of keyhole surgery, in comparison with traditional craniotomies, are minimal complications associated with the approach. PMID- 29393292 TI - [Surgery for intractable epilepsy in a patient with encephalocele of the temporal lobe: a case report]. AB - We describe a case of surgical treatment of intractable temporal epilepsy in a female patient with congenital middle cranial fossa encephalocele. We present clinical-anamnestic and neuroimaging data as well as the microscopic and macroscopic pictures of encephalocele. We analyze outcomes of surgery for this pathology, which have been reported in the literature. To date, there have been a few articles on this subject in the domestic literature. The development of neuroimaging techniques and a growing number of verified encephalocele cases promote the widespread use of surgery for treatment of intractable epilepsy. Congenital encephalocele should be considered in the differential diagnosis of intractable temporal epilepsy, and, if verified, surgical treatment is the method of choice in most cases. PMID- 29393293 TI - [Rupture of a giant aneurysm of the accessory middle cerebral artery: a case report and a literature review]. AB - The accessory middle cerebral artery is a rare congenital vascular abnormality. The international literature has reported cases of accessory MCA aneurysms. In this article, we describe a case of rupture of a giant partially thrombosed aneurysm of the accessory MCA. This case is of great interest due to rarity of the pathology and associated diagnostic errors. PMID- 29393294 TI - [A modern strategy of combined surgical and radiation treatment in patients with brain metastases]. AB - The treatment standards for patients with brain metastases have been developed for several decades. An important element in the evolution of approaches to the treatment of these patients is the development of microsurgery, stereotactic radiotherapy, and targeted therapy and introduction of these techniques into clinical practice. Surgery is an effective treatment option in patients having single brain metastases and/or occuring in life-threatening clinical situations. Irradiation of the whole brain after surgical treatment is a necessary step in achieving satisfactory local control of intracranial metastatic foci, but the development of neurocognitive disorders and deterioration of life quality after this irradiation necessitate the search for alternative radiotherapy techniques in this clinical situation. Currently, an alternative to postoperative irradiation of the whole brain is stereotactic radiotherapy, which is used before or after surgical treatment. Stereotactic radiotherapy improves local control of intracranial metastatic foci and reduces the risk of neurotoxicity. In this review, we analyze the literature data on outcomes of stereotactic irradiation as a component of combined treatment of patients with metastatic brain lesions. PMID- 29393295 TI - [Hypofractionated radiotherapy for glioblastoma: changing the radiation treatment paradigm]. AB - Hypofractionation has the dual advantage of increased cell death with a higher dose per fraction and a reduced effect of accelerated tumor cell repopulation due to a shorter overall treatment time. However, the potential advantage may be offset by increased toxicity in the late-responding neural tissues. Recently, investigators have attempted delivering radical doses of HFRT by escalating the dose in the immediate vicinity of the enhancing tumor and postoperative surgical cavity and reported reasonable outcomes with acceptable toxicity levels. Three different studies of high-dose HFRT have reported on the paradoxical phenomenon of improved survival in patients developing radiation necrosis at the primary tumor site. The toxicity criteria of RTOG and EORTC have defined clinically or radiographically suspected radionecrosis as Grade 4 toxicity. However, most patients diagnosed with radiation necrosis in the above studies remained asymptomatic. Furthermore, the probable association with improved survival would strongly argue against adopting a blind approach for classifying radiation necrosis as Grade 4 toxicity. The data emerging from the above studies is encouraging and strongly argues for further research. However, the majority of these studies are predominantly retrospective or relatively small single-arm prospective series that add little to the overall quality of evidence. Notwithstanding the above limitations, HFRT appears to be a safe and feasible strategy for glioblastoma patients. PMID- 29393297 TI - The histologic risk model is a useful and inexpensive tool to assess risk of recurrence and death in stage I or II squamous cell carcinoma of tongue and floor of mouth. AB - Surgery is the mainstay of treatment for low-stage (stage I/II, ie, T1N0/T2N0) squamous cell carcinoma of oral cavity. However, a significant percentage of low stage squamous cell carcinoma of oral cavity will develop local recurrence and disease-related mortality. In this study, we stratified 64 patients with low stage of oral tongue and floor of mouth patients into high-, intermediate- and low-risk categories based on existing histologic risk model. The classification of these risk categories was based on presence or absence of perineural invasion and evaluation of tumor-host junction for worst pattern of invasion and lymphocytic host response. We correlated risk category and other variables with recurrence and death. In a univariate model, high-risk category tumors had a significantly higher rate of recurrence and death due to recurrence compared with low/intermediate-risk categories (P=0.000 and P=0.047, respectively). Controlling for margin status and T-stage, high-risk category had a 12.4 odds ratio of later recurrence when compared with low/intermediate-risk categories, with a P-value of 0.001. In conclusion, we found low-stage oral cavity squamous cell carcinoma patients with high-risk category have a significantly higher risk for recurrence when compared with patients in the low- or intermediate-risk category, even when controlling for margin status and T-stage. These patients may be suitable candidates for adjuvant treatment to decrease morbidity and mortality associated with a recurrence. Our results indicate that the histologic risk model is a useful and simple tool to assess risk of recurrence in stage I or II squamous cell carcinoma of oral cavity. PMID- 29393296 TI - Tamoxifen enhances stemness and promotes metastasis of ERalpha36+ breast cancer by upregulating ALDH1A1 in cancer cells. AB - The 66 kDa estrogen receptor alpha (ERalpha66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERalpha36, a variant of ERalpha66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERalpha36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERalpha36 antibody. Thus, tamoxifen acts as an agonist on ERalpha36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERalpha36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID- 29393298 TI - Reproductive endocrinology: Hypoxia in endometrial repair. PMID- 29393300 TI - Adipose tissue: Bile acid-TGR5 axis promotes beiging. PMID- 29393301 TI - Reflections from the editor-in-chief on 20-year tenure. AB - [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393302 TI - When the competent patient refuses personal care. AB - [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393303 TI - Clinical Challenges in the Growing Medical Marijuana Field. AB - Unique clinical challenges arise with the growing number of patients who possess medical marijuana cards. Medical marijuana patients with mental disorders can have worsening symptoms with marijuana use. Often there is sparse continuity of care between the patient and the medical marijuana practitioner. Lack of communication between the patient's treating practitioners and the practitioner who has authorized the medical marijuana can be problematic. This article is a discussion of the new clinical challenges practitioners are likely to encounter with the growing number of medical marijuana patients. [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393304 TI - Challenges of delivering medical care in resource-poor countries; thoughts on personalized medicine in US. AB - [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393305 TI - Importance of screening for prevention, early detection of colorectal cancer. AB - [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393299 TI - Symptoms of menopause - global prevalence, physiology and implications. AB - The symptoms of menopause can be distressing, particularly as they occur at a time when women have important roles in society, within the family and at the workplace. Hormonal changes that begin during the menopausal transition affect many biological systems. Accordingly, the signs and symptoms of menopause include central nervous system-related disorders; metabolic, weight, cardiovascular and musculoskeletal changes; urogenital and skin atrophy; and sexual dysfunction. The physiological basis of these manifestations is emerging as complex and related, but not limited to, oestrogen deprivation. Findings generated mainly from longitudinal population studies have shown that ethnic, geographical and individual factors affect symptom prevalence and severity. Moreover, and of great importance to clinical practice, the latest research has highlighted how certain menopausal symptoms can be associated with the onset of other disorders and might therefore serve as predictors of future health risks in postmenopausal women. The goal of this Review is to describe in a timely manner new research findings on the global prevalence and physiology of menopausal symptoms and their impact on future health. PMID- 29393306 TI - Clinical and Translational Research in Rhode Island: Results of a Needs Assessment Survey. AB - The Advance-Clinical and Translational Research (CTR) program was established in Rhode Island in May of 2016 with an IDeA Program Infrastructure award to collaborating institutions: Brown University, the University of Rhode Island, with the Lifespan, Care New England and Providence VA Medical Center healthcare institutions and the Rhode Island Quality Institute. To support programmatic planning, the Tracking and Evaluation Key Component Activity (KCA) of Advance-CTR developed and implemented a needs assessment survey to identify the obstacles to clinical and translational research at the participating institutions. We describe the methods used and the responses, which identified needs for study design and data analysis support. Support for project development, pilot funding and grants administration showed significant variation, depending on the affiliation of the respondent. The results of the survey are discussed in the context of Rhode Island's significant opportunities to support and develop the capabilities of scientists who engage in translational research. [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393307 TI - Ghost Attack: The East Providence Carbon Monoxide Mass Casualty Incident. AB - A routine call for a common medical emergency was expeditiously identified by the responding emergency medical service as a multiple victim carbon monoxide exposure. The event circumstances, exemplary fire department emergency medical services response, and ensuing hos- pital emergency department response are described. [Full article available at http://rimed.org/rimedicaljournal-2018 02.asp]. PMID- 29393308 TI - Cocaine-Related Acute Spinal Cord Infarction. AB - We report a rare case of anterior spinal artery syndrome in the setting of acute cocaine use. A 31-year-old man presented to the hospital unarousable with leukocytosis and a positive toxicology screen for opioids, cocaine, benzodiazepines and cannabis. He was placed on intravenous naloxone. As the patient regained consciousness, he was found to have paraplegia, sensory loss below the level of T5, and urinary retention. MRI findings showed a signal intensity abnormality from the level of T1-4, highly suggestive of an acute ischemic spinal cord infarct. [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393309 TI - Transient Orbital Compartment Syndrome Caused by Spontaneous Lamina Papyracea Dehiscence. AB - Orbital compartment syndrome typically occurs due to trauma or burns. Here we discuss a case of spontaneous lamina papyracea dehiscence associated with transient orbital compartment syndrome. A previously healthy woman presented to the Emergency Department complaining of unilateral eye pain after nose blowing. The patient did not have any pupillary or extra-ocular movement abnormalities; however, she did have mildly decreased visual acuity in the affected eye. Intraocular pressure was found to be elevated and a subsequent CT scan showed orbital emphysema with spontaneous dehiscence of the lamina papyracea. The intraocular pressure decreased within hours, and ultimately, she required no intervention. [Full article available at http://rimed.org/rimedicaljournal-2018 02.asp]. PMID- 29393310 TI - Rhode Island Unintentional Drug Overdose Death Trends and Ranking - Office of the State Medical Examiners Database. AB - [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp]. PMID- 29393311 TI - A novel analytical approach for the determination of parathion methyl in water: quadrupole isotope dilution mass spectrometry-dispersive liquid-liquid microextraction using multivariate optimization. AB - Dispersive liquid-liquid microextraction was coupled with quadruple isotope dilution mass spectrometry for the sensitive and accurate determination of parathion methyl in water. The two methods were complementary to each other, with DLLME preconcentrating the analyte for trace determination, and ID4MS maintaining the integrity of the method's accuracy and precision. An experimental design was used to optimize the extraction process. The results from the design were evaluated with the analysis of variance to determine the statistical significance of the main factors of extraction and interaction effects of these factors. A three-point calibration blend and sample blend were prepared gravimetrically by spiking with isotopically labelled parathion methyl. All four blends were left to equilibrate for three hours, after which they were preconcentrated under the optimum extraction conditions. The percent recovery recorded by this method was 99.9%, and the percent relative standard deviation was 0.32%. These results validated the accuracy and precision of the combined method. PMID- 29393312 TI - Binding properties of mono- and dimeric pyridine dicarboxamide ligands to human telomeric higher-order G-quadruplex structures. AB - Here, we report on the in vitro binding properties of the known pyridine dicarboxamide G-quadruplex ligand 360A and a new dimeric analogue (360A)2A to human telomeric DNA higher-order G-quadruplex (G4) structures. This study points to original binding features never reported for G4 ligands, and reveals a greater efficiency for the dimeric ligand to displace RPA (a ssDNA binding protein involved in telomere replication) from telomeric DNA. PMID- 29393313 TI - Direct chemiluminescence detection of circulating microRNAs in serum samples using a single-strand specific nuclease-distinguishing nucleic acid hybrid system. AB - We developed a microplate-based enhanced chemiluminescence system for the direct detection of circulating miRNAs. The system exhibited a high target sensitivity and specificity, with a detection limit of 3.02 fM. PMID- 29393314 TI - Two halide-containing cesium manganese vanadates: synthesis, characterization, and magnetic properties. AB - Two new halide-containing cesium manganese vanadates have been synthesized by a high-temperature (580 degrees C) hydrothermal synthetic method from aqueous brine solutions. One compound, Cs3Mn(VO3)4Cl, (1) was prepared using a mixed cesium hydroxide/chloride mineralizer, and crystallizes in the polar noncentrosymmetric space group Cmm2, with a = 16.7820(8) A, b = 8.4765(4) A, c = 5.7867(3) A. This structure is built from sinusoidal zig-zag (VO3)n chains that run along the b-axis and are coordinated to Mn2+ containing (MnO4Cl) square pyramidal units that are linked together to form layers. The cesium cations reside between the layers, but also coordinate to the chloride ion, forming a cesium chloride chain that also propagates along the b-axis. The other compound, Cs2Mn(VO3)3F, (2) crystallizes in space group Pbca with a = 7.4286(2) A, b = 15.0175(5) A, c = 19.6957(7) A, and was prepared using a cesium fluoride mineralizer. The structure is comprised of corner sharing octahedral Mn2+ chains, with trans fluoride ligands acting as bridging units, whose ends are capped by (VO3)n vanadate chains to form slabs. The cesium atoms reside between the manganese vanadate layers, and also play an integral part in the structure, forming a cesium fluoride chain that runs along the b-axis. Both compounds were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and single-crystal Raman spectroscopy. Additionally, the magnetic properties of 2 were investigated. Above 50 K, it displays behavior typical of a low dimensional system with antiferromagnetic interactions, as to be expected for linear chains of manganese(ii) within the crystal structure. PMID- 29393315 TI - Molecular dynamics simulation of a nanofluidic energy absorption system: effects of the chiral vector of carbon nanotubes. AB - A Nanofluidic Energy Absorption System (NEAS) is a novel nanofluidic system with a small volume and weight. In this system, the input mechanical energy is converted to surface tension energy during liquid infiltration in the nanotube. The NEAS is made of a mixture of nanoporous material particles in a functional liquid. In this work, the effects of the chiral vector of a carbon nanotube (CNT) on the performance characteristics of the NEAS are investigated by using molecular dynamics simulation. For this purpose, six CNTs with different diameters for each type of armchair, zigzag and chiral, and several chiral CNTs with different chiral vectors (different values of indices (m,n)) are selected and studied. The results show that in the chiral CNTs, the contact angle shows the hydrophobicity of the CNT, and infiltration pressure is reduced by increasing the values of m and n (increasing the CNT diameter). Contact angle and infiltration pressure are decreased by almost 1.4% and 9% at all diameters, as the type of CNT is changed from chiral to zigzag and then to armchair. Absorbed energy density and efficiency are also decreased by increasing m and n and by changing the type of CNT from chiral to zigzag and then to armchair. PMID- 29393316 TI - Transamidation of N-acyl-glutarimides with amines. AB - The development of new transamidation reactions for the synthesis of amides is an important and active area of research due to the central role of amide linkage in various fields of chemistry. Herein, we report a new method for transamidation of N-acyl-glutarimides with amines under mild, metal-free conditions that relies on amide bond twist to weaken amidic resonance. A wide range of amines and functional groups, including electrophilic substituents that would be problematic in metal-catalyzed protocols, are tolerated under the reaction conditions. Mechanistic experiments implicate the amide bond twist, thermodynamic stability of the tetrahedral intermediate and leaving group ability of glutarimide as factors controlling the reactivity of this process. The method further establishes the synthetic utility of N-acyl-glutarimides as bench-stable, twist perpendicular, amide-based reagents in acyl-transfer reactions by a metal-free pathway. The origin of reactivity of N-acyl-glutarimides in metal-free and metal catalyzed processes is discussed and compared. PMID- 29393317 TI - Iodine-NH4OAc mediated regioselective synthesis of 2-aroyl-3-arylimidazo[1,2 a]pyridines from 1,3-diaryl-prop-2-en-1-ones. AB - The present protocol describes an efficient, metal-free regioselective synthesis of 2-aroyl-3-arylimidazo[1,2-a]pyridines from 1,3-diaryl-prop-2-en-1-ones and 2 aminopyridine. The iodine-NH4OAc promoted reaction offers a novel route in the synthesis of 2-aroyl-3-arylimidazo[1,2-a]pyridines. This protocol offers significant flexibility in accessing medicinally important 2-aroyl-3 arylimidazo[1,2-a]pyridines with various substitution patterns. PMID- 29393318 TI - Diels-Alder reactions between hexafluoro-2-butyne and bis-furyl dienes: kinetic versus thermodynamic control. AB - The tandem [4+2] cycloaddition between hexafluoro-2-butyne and bis-furyl dienes, like difurfuryl ester, at room temperature leads to the kinetically controlled "pincer"-adducts - annulated 4a,8a-bis(trifluoromethyl)hexahydro-1,4:5,8 diepoxynaphthalenes. On the other hand, if these reactions proceed at 140 degrees C, only the thermodynamically controlled "domino"-adducts - annulated 2,3 bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes - are formed. Therefore, a very rare and unexpected example of full kinetic and thermodynamic control in the Diels-Alder reaction is reported in this paper. PMID- 29393319 TI - Probiotic attributes and prevention of LPS-induced pro-inflammatory stress in RAW264.7 macrophages and human intestinal epithelial cell line (Caco-2) by newly isolated Weissella cibaria strains. AB - Probiotic lactic acid bacteria are known to modulate gut associated immune responses. Not many studies have reported on the role of Weissella species in preventing lipopolysaccharide (LPS) induced proinflammatory stress in murine macrophages as well as in human intestinal epithelial cells (Caco-2). Therefore, the present study was taken up to evaluate the probiotic attributes of four newly isolated Weissella strains (two each from fermented dosa batter and a human infant faecal sample); these attributes are cholesterol reduction, adhesion to Caco-2 cells and mucin and their ability to prevent LPS-induced nitric oxide and proinflammatory cytokine (IL-6, IL-1beta and TNFalpha) production by the murine macrophages and IL-8 production by the human epithelial cells. Reduction in LPS induced pro-inflammatory stress was compared with a well-studied probiotic bacterium Lactobacillus rhamnosus GG. The results suggested that the strains were tolerant to gastric conditions (pH 3.0) and bile salts. In addition, the strains exhibited moderate cell surface hydrophobicity, cholesterol reduction and adhesion to Caco-2 cells and gastric mucin. All the strains could prevent LPS induced nitric oxide and IL-6 production in murine macrophages, while strain 28 alone prevented IL-1beta production. All the strains could prevent IL-8 production by the human epithelial cells. The present study led to the first line selection of W. cibaria 28 as a putative strain for future studies as it showed adhesion to Caco-2 cells and gastric mucin and cholesterol reduction besides preventing LPS-induced pro-inflammatory stress in macrophages and in human colonic epithelial cells. PMID- 29393320 TI - The effect of connectivity on information in neural networks. AB - We present a mathematical model that quantifies the amount of information exchanged in bi-dimensional networks of nerve cells as a function of network connectivity Q. Upon varying Q over a significant range, we found that, from a certain cell density onwards, 90% of the maximal information transferred I(Q) in a random neuronal network is already reached with just 40% of the total possible connections Q among the cells. As a consequence, the system would not benefit from additional connections in terms of the amount of I(Q), in agreement with the tendency of brains to minimize Q because of its energetic costs. The model may reveal the circuits responsible for neurodegenerative disorders in that neurodegeneration can be regarded as a connective failure affecting information. PMID- 29393321 TI - Solar driven electrochromic photoelectrochemical fuel cells for simultaneous energy conversion, storage and self-powered sensing. AB - One solar-driven electrochromic photoelectrochemical fuel cell (PFC) with highly efficient energy conversion and storage is easily constructed to achieve quantitative self-powered sensing. Layered bismuth oxyiodide-zinc oxide nanorod arrays (ZnO@BiOI NRA) with a core/shell p-n heterostructure are fabricated as the photoanode with electrochromic Prussian blue (PB) as the cathode. The core/shell p-n heterostructure for the ZnO@BiOI photoanode can effectively boost the photoelectrochemical (PEC) performance through the improvement of photon absorption and charge carrier separation. The optimal assembled PFC yields an open-circuit voltage (VOC) of 0.48 V with the maximum power output density (Pmax) as high as 155 MUW cm-2 upon illumination. Benefitting from the interactive color changing behavior of PB, the cathode not only exhibits cathodic catalytic activity in the PFC but also serves as an electrochromic display for self-powered sensing. The as-constructed PFC possesses multiple readable signal output nanochannels through the maximum power output density (Pmax) of the PFC or the color change of PB. Meanwhile, the dual-signal-output makes the as-constructed self-powered sensor highly available in various operations demands with the enhanced reliability. With the advantages of high efficiency of PFCs, unique assay ability, and broad environmental suitability, the constructed self-powered platform shows broad application prospects as an integrated smart analytical device. PMID- 29393322 TI - Development of a novel scoring system for identifying emerging chemical risks in the food chain. AB - The European Food Safety Authority (EFSA) is responsible for risk assessment of all aspects of food safety, including the establishment of procedures aimed at the identification of emerging risks to food safety. Here, a scoring system was developed for identifying chemicals registered under the European REACH Regulation that could be of potential concern in the food chain using the following parameters: (i) environmental release based on maximum aggregated tonnages and environmental release categories; (ii) biodegradation in the environment; (iii) bioaccumulation and in vivo and in vitro toxicity. The screening approach was tested on 100 data-rich chemicals registered under the REACH Regulation at aggregated volumes of at least 1000 tonnes per annum. The results show that substance-specific data generated under the REACH Regulation can be used to identify potential emerging risks in the food chain. After application of the screening procedure, priority chemicals can be identified as potentially emerging risk chemicals through the integration of exposure, environmental fate and toxicity. The default approach is to generate a single total score for each substance using a predefined weighting scenario. However, it is also possible to use a pivot table approach to combine the individual scores in different ways that reflect user-defined priorities, which enables a very flexible, iterative definition of screening criteria. Possible applications of the approaches are discussed using illustrative examples. Either approach can then be followed by in-depth evaluation of priority substances to ensure the identification of substances that present a real emerging chemical risk in the food chain. PMID- 29393323 TI - Super-resolution imaging of lysosomes with a nitroso-caged rhodamine. AB - Caged-fluorophores are potentially suitable for photo-activated localization microscopy (PALM) for super-resolution imaging. N-Nitroso is a simple and robust photo-cage with biocompatible nitric oxide as the only byproduct upon photolysis. We herein reported a novel PALM probe (NOR535) for super-resolution imaging of lysosomes with high localization precision. PMID- 29393324 TI - Rb+ cations enable the change of luminescence properties in perovskite (RbxCs1 xPbBr3) quantum dots. AB - All-inorganic metal halide perovskites of the formulation ABX3 (where A is Cs+, B is commonly Pb2+, and X is a halide, X = Cl, Br, I) have been studied intensively for their unique properties. Most of the current studies focus on halogen exchange to modify the luminescence band gap. Herein we demonstrate a new avenue for changing the band gap of halide perovskites by designing mixed-monovalent cation perovskite-based colloidal quantum dot materials. We have synthesized monodisperse colloidal quantum dots of all-inorganic rubidium-cesium lead halide perovskites (APbBr3, A = mixed monovalent cation systems Rb/Cs) using inexpensive commercial precursors. Through the compositional modulation, the band gap and emission spectra are readily tunable over the visible spectral range of 474-532 nm. The photoluminescence (PL) of RbxCs1-xPbBr3 nanocrystals is characterized with excellent (NTCS color standard) wide color gamut coverage, which is similar to the cesium lead halide perovskites (CsPbX3, X = mixed halide systems Cl/Br), and narrow emission line-widths of 27-34 nm. Furthermore, simulated lattice models and band structures are used to explain the band gap variations. PMID- 29393325 TI - Fortification of dark chocolate with microencapsulated phytosterols: chemical and sensory evaluation. AB - Chocolate is one of the most consumed delicacies in the world. Nowadays high cocoa polyphenol-rich chocolates, probiotic chocolates, and prebiotic chocolates are getting more attention. In light of this, dark chocolate containing microencapsulated phytosterols (MPs) has been developed to reduce cholesterol in individuals. In particular, different dark chocolates containing 64, 72 and 85% of cocoa, fortified with 0, 5, 10 and 15% MP have been produced. The obtained chocolates were characterized by a particle size distribution lower than 30 MUm and were stable from a chemical point of view. Specifically, peroxide values were always lower than 2 meq O2 per kg of fat, also after three months of storage. The bioaccessibility of phytosterols was comparable with literature values and the antioxidant activity reached a value of 92 MUg trolox per g chocolate for samples obtained from 85% of cocoa. Moreover, sensory evaluation demonstrated a positive effect on the acceptability of the functional chocolate produced and a significant effect of the information on the final sample acceptability. PMID- 29393326 TI - "A bridge over troubled gaps": up-conversion driven photocatalysis for hydrogen generation and pollutant degradation by near-infrared excitation. AB - Spectral up-conversion (UC) has been attracting growing interest for the effective harvesting of the near-infrared (NIR) part of sunlight for photocatalytic hydrogen production and environmental purification. We present evidence of NIR-to-UV-VIS photon conversion for degradation of organic dyes and hydrogen and oxygen evolution via water-splitting by TiO2 and Rh-Cr oxide-loaded SrTiO3:Al photocatalysts, respectively. PMID- 29393327 TI - Aquatic photochemistry of sulfamethazine: multivariate effects of main water constituents and mechanisms. AB - The ubiquity of sulfonamides (SAs) in natural waters requires insight into their environmental fate for ecological risk assessment. Extensive studies focused on the effect of univariate water constituents on the photochemical fate of SAs, yet the multivariate effects of water constituents in environmentally relevant concentrations on SA photodegradation are poorly understood. Here, response surface methodology was employed to explore the integrative effects of main water constituents (dissolved organic matter (DOM), NO3-, HCO3-, Cu2+) on the photodegradation of a representative SA (sulfamethazine). Results showed that besides single factors, interaction of factors also significantly impacted the photodegradation. Radical scavenging experiments indicated that triplet-excited DOM (3DOM*) was responsible for the enhancing effect of DOM on the photodegradation. Additionally, DOM may also quench the 3DOM*-mediated oxidation intermediate of sulfamethazine causing the inhibiting effect of DOM-DOM interaction. We also found that HCO3- was oxidized by triplet-excited sulfamethazine producing CO3-, and the high reactivity of CO3- with sulfamethazine (second-order rate constant 2.2 * 108 M-1 s-1) determined by laser flash photolysis revealed the enhancing photodegradation mechanism of HCO3-. This study is among the first attempts to probe the photodegradation of SAs considering the integrative effects of water constituents, which is important in accurate ecological risk assessment of organic pollutants in the aquatic environment. PMID- 29393328 TI - Self-propulsion of catalytic nanomotors synthesised by seeded growth of asymmetric platinum-gold nanoparticles. AB - Asymmetric bimetallic nanomotors are synthesised by seeded growth in solution, providing a convenient and high-throughput alternative to the usual top-down lithographic fabrication of self-propelled catalytic nanoparticles. These synthetic nanomotors catalyse H2O2 decomposition and exhibit enhanced diffusion that depends on fuel concentration, consistent with their chemical propulsion. PMID- 29393329 TI - Panning for gold in mould: can we increase the odds for fungal genome mining? AB - Fungi are a rich source of bioactive small molecules. However, the large number of biosynthetic gene clusters (BGCs) encoding these molecules in their genomes suggests their biosynthetic potential is far greater than we previously appreciated. The mining of fungal genomes therefore holds great promise for the discovery of new chemical entities for pharmaceutical and agricultural applications. As more and more fungal genomes become available, the accompanying number of BGCs is quickly becoming unmanageable. Along with improving molecular genetic tools to accelerate the translation of BGCs to small molecules, we must devise strategies to prioritise BGCs most likely to encode the biosynthesis of novel small molecules and molecules with new or improved bioactivities or functions. In this perspective, we discuss existing and emerging strategies for prioritisation of BGCs to increase the odds of fruitful genome mining in fungi. PMID- 29393330 TI - Selectivity-switchable construction of benzo-fused polycyclic compounds through a gold-catalyzed reaction of enyne-lactone. AB - A gold-catalyzed selectivity-switchable reaction of enyne-lactone is reported. Different products, including naphthalenes and benzo-fused polycyclic compounds, can be selectively obtained from the same starting material. The choice of the gold complex is the key for the chemoselectivity of this system. PMID- 29393331 TI - Structure and dynamics of stereo-regular poly(methyl-methacrylate) melts through atomistic molecular dynamics simulations. AB - Poly(methyl-methacrylate), PMMA, is a disubstituted vinyl polymer whose properties depend significantly on its tacticity. Here we present a detailed study of the structure, conformation, and dynamics of syndiotactic, atactic, and isotactic PMMA melts at various temperatures (580, 550, 520, and 490 K) via all atom molecular dynamics simulations. The calculated volumetric properties are close to experimental data. The Tg and chain dimensions of PMMA model systems are found to depend strongly on tacticity in agreement with experimental findings. The backbone bonds in trans (t), diads in tt, and inter-diads in t|t torsional states are the most populated for all PMMA stereo-chemistries and their fractions increase with the number of syndiotactic sequences. Also, the effective torsional barrier heights for the backbone, ester side group, and alpha-methyl group are larger for syndiotactic PMMA compared to the isotactic one. The structure of the PMMA chains is studied by computing the intra- and inter-chain static structure factors, S(q), and the radial pair distribution functions. In the first peak of S(q), both intra- and inter-chain components contribute, whereas the second and third peaks mainly come from inter- and intra-chain parts, respectively. For all PMMA stereo-isomers a clear tendency of ester-methyl groups to aggregate is observed. The local dynamics are studied by analyzing torsional autocorrelation functions for various dihedral angles. A wide spectrum of correlation times and different activation energies are observed for the motions of different parts of PMMA chains. The stereo-chemistry affects the backbone, ester side group, and alpha-methyl motions, whereas the ester-methyl rotation remains unaffected. The dynamic heterogeneity of the PMMA chains is also studied in detail for the different stereo-chemistries via the temperature dependence of the stretching exponent. Furthermore, the reorientational dynamics at the chain level and translational dynamics for monomer and chain centers-of-mass are analyzed. PMID- 29393332 TI - Sulfonamides as new hydrogen atom transfer (HAT) catalysts for photoredox allylic and benzylic C-H arylations. AB - A catalytic amount of a sterically and electronically tuned diarylsulfonamide promoted allylic and benzylic C-H arylations in cooperation with a visible light photoredox catalyst. This is the first example of the catalytic use of a sulfonamidyl radical to promote the hydrogen atom transfer process. PMID- 29393333 TI - A 65-gene signature for prognostic prediction in colon adenocarcinoma. AB - The aim of the present study was to examine the molecular factors associated with the prognosis of colon cancer. Gene expression datasets were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases to screen differentially expressed genes (DEGs) between colon cancer samples and normal samples. Survival-related genes were selected from the DEGs using the Cox regression method. A co-expression network of survival-related genes was then constructed, and functional clusters were extracted from this network. The significantly enriched functions and pathways of the genes in the network were identified. Using Bayesian discriminant analysis, a prognostic prediction system was established to distinguish the positive from negative prognostic samples. The discrimination efficacy of the system was validated in the GSE17538 dataset using Kaplan-Meier survival analysis. A total of 636 and 1,892 DEGs between the colon cancer samples and normal samples were screened from the TCGA and GSE44861 dataset, respectively. There were 155 survival-related genes selected. The co expression network of survival-related genes included 138 genes, 534 lines (connections) and five functional clusters, including the signaling pathway, cellular response to cAMP, and immune system process functional clusters. The molecular function, cellular components and biological processes were the significantly enriched functions. The peroxisome proliferator-activated receptor signaling pathway, Wnt signaling pathway, B cell receptor signaling pathway, and cytokine-cytokine receptor interactions were the significant pathways. A prognostic prediction system based on a 65-gene signature was established using this co-expression network. Its discriminatory effect was validated in the TCGA dataset (P=3.56e-12) and the GSE17538 dataset (P=1.67e-6). The 65-gene signature included kallikrein-related peptidase 6 (KLK6), collagen type XI alpha1 (COL11A1), cartilage oligomeric matrix protein, wingless-type MMTV integration site family member 2 (WNT2) and keratin 6B. In conclusion, a 65-gene signature was screened in the present study, which showed a prognostic prediction effect in colon adenocarcinoma. KLK6, COL11A1, and WNT2 may be suitable prognostic predictors for colon adenocarcinoma. PMID- 29393334 TI - Two novel variants of the PHEX gene in patients with X-linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families. AB - X-linked hypophosphatemic rickets (XLHR; OMIM 307800) is an X-linked dominant disorder caused by mutations in the phosphate-regulating neutral endopeptidase homolog X-linked (PHEX) gene, which is located at Xp22.11. In the present study, two novel variants of the PHEX gene were identified in two unrelated families with XLHR by directly sequencing all 22 exon regions and intron/exon boundaries of the PHEX gene. One missense variant, NM_000444.5: c.1721T>A, was identified in exon 17 of the PHEX gene in Family 1, which led to an amino acid change in the p.Ile574Lys protein. The other splicing variant identified was NM_000444.5: c.591A>G, in exon 5 in Family 2, resulting in a deletion of 77 bp in the 3' site of exon 5 during splicing, which was verified by direct cDNA sequencing of the PHEX gene. According to the results of reverse transcription-quantitative polymerase chain reaction analysis, the affected male with the splicing variant c.591A>G showed normal gene expression of PHEX, whereas the affected female exhibited low gene expression, compared with normal females. Based on these findings, prenatal diagnoses were made for the fetuses with a family history of XLHR using the backup amniotic fluid samples. One fetus without the missense variant was confirmed to be a healthy girl in a follow-up visit 1 month following birth. PMID- 29393335 TI - Schizandrin B inhibits the cis-DDP-induced apoptosis of HK-2 cells by activating ERK/NF-kappaB signaling to regulate the expression of survivin. AB - The nephrotoxicity of cisplatin limits its clinical application. Schizandrin B (SchB) has been demonstrated to have a variety of potential cytoprotective activities. The present study explored the molecular mechanisms by which SchB inhibits the dichlorodiammine platinum (DDP)-induced apoptosis of HK-2 proximal tubule epithelial cells. In vitro assays demonstrated that SchB increased the viability of HK-2 cells, alleviated the cis-DDP-induced activation of caspase-3, reduced apoptosis and improved the nuclear morphology of HK-2 cells. Additionally, the mechanism underlying the cis-DDP-induced apoptosis was indicated to involve the activation of p53, c-Jun-N-terminal kinase (JNK) and p38 signaling. Furthermore, SchB was demonstrated to activate extracellular signal regulated kinase (ERK) and nuclear factor kappaB (NF-kappaB) signaling, and induce the expression of survivin. The inhibition of ERK and NF-kappaB signaling using U0126 and pyrollidine dithiocarbamate, respectively, inhibited the expression of survivin, whereas blocking the expression of survivin using small interfering RNA inhibited the alleviating effect of SchB on cis-DDP-induced apoptosis as indicated by a reduction in cleaved caspase-3 expression. In conclusion, SchB regulates ERK/NF-kappaB signaling to induce the expression of survivin, thereby alleviating cis-DDP-induced renal injury. PMID- 29393336 TI - Honokiol suppresses proliferation and induces apoptosis via regulation of the miR 21/PTEN/PI3K/AKT signaling pathway in human osteosarcoma cells. AB - Honokiol (HNK) is a small biphenolic compound, which exerts antineoplastic effects in various types of cancer. However, the mechanism underlying the antitumor effects of HNK in osteosarcoma (OS) cells is not yet fully understood. Emerging evidence has indicated that microRNAs (miRNAs/miRs) serve key roles in numerous pathological processes, including cancer. It has previously been reported that Chinese medicinal herbs harbor anticancer properties via modulating miRNA expression. Therefore, the present study aimed to determine whether HNK could suppress OS cell growth by regulating miRNA expression. The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis were used to evaluate the cell proliferation and apoptosis in human OS cells after treatment with HNK, respectively. The results demonstrated that HNK inhibits proliferation and induces apoptosis of human OS cells in a dose dependent manner. Furthermore, HNK-induced apoptosis was characterized by upregulation of proapoptotic proteins, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase and B-cell lymphoma 2 (Bcl-2)-associated X protein, and downregulation of the anti-apoptotic protein Bcl-2. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) verified that HNK was able to induce aberrant expression of miRNAs in human OS cells, and miR-21 was one of the miRNAs that was most significantly downregulated. To further investigate miR-21 function, the present study validated that HNK reduces miR-21 levels in a dose dependent manner. In addition, restoration of miR-21 expression abrogated the suppressive effects of HNK on OS cells. Luciferase assay and western blot analysis identified that miR-21 inhibits the expression of phosphatase and tensin homolog (PTEN) by directly targeting its 3'-UTR. Notably, HNK was able to suppress the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway; however, it was reactivated by miR-21 overexpression. Taken together, these data indicated that HNK may inhibit proliferation and induce apoptosis of human OS cells by modulating the miR-21/PTEN/PI3K/AKT signaling pathway. Therefore, miR-21 may be considered a potential therapeutic target for the treatment of osteosarcoma with HNK. PMID- 29393337 TI - Extracorporeal shock wave therapy with low-energy flux density inhibits hypertrophic scar formation in an animal model. AB - Hypertrophic scar is characterized by excessive deposits of collagen during skin wound healing, which could become a challenge to clinicians. This study assessed the effects of the extracorporeal shock wave therapy (ESWT) on hypertrophic scar formation and the underlying gene regu-lation. A rabbit ear hypertrophic scar model was generated and randomly divided into three groups: L-ESWT group to receive L-ESWT (energy flux density of 0.1 mJ/mm2), H-ESWT (energy flux density of 0.2 mJ/mm2) and sham ESWT group (S-ESWT). Hypertrophic scar tissues were then collected and stained with hematoxylin and eosin (H&E) and Masson's trichrome staining, respectively, to assess scar elevation index (SEI), fibroblast density and collagen fiber arrangement. Expression of cell proliferation marker proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (alpha SMA) were assessed using RT-PCR and immunohistochemistry in hypertrophic scar tissues. H&E staining sections showed significant reduction of SEI and fibroblast density in both ESWT treatment groups compared to S-ESWT, but there was no dramatic difference between L-ESWT and H-ESWT groups. Masson's trichrome staining showed that collagen fibers were more slender and broader and oriented in parallel to skin surface after administration of ESWT compared to control tissues. At the gene level, PCNA-positive fibroblasts and alpha-SMA-positive myofibroblasts were significantly decreased after L-ESWT or H-ESWT compared to the controls. Furthermore, there was no significant difference in expression of PCNA mRNA between L-ESWT or H-ESWT and S-ESWT, whereas expression of alpha-SMA mRNA significantly decreased in L-ESWT compared to that of H-ESWT and S-ESWT (P=0.002 and P=0.030, respectively). In conclusion, L-ESWT could be effective on suppression of hypertrophic scar formation by inhibition of scar elevation index and fibroblast density as well as alpha-SMA expression in hypertrophic scar tissues of the rabbit model. PMID- 29393338 TI - Redox induces diverse effects on recombinant human wild-type PrP and mutated PrP with inserted or deleted octarepeats. AB - Normal prion protein (PrP) contains two cysteines at amino acids 179 and 214, which may form intra- and interpeptide disulfide bonds. To determine the possible effects of this disulfide bridge on the biochemical features of PrP, prokaryotic recombinant human wild-type PrP (PG5), and mutated PrPs with seven extra octarepeats (PG12) or with all five octarepeats removed (PG0), were subjected to redox in vitro. Sedimentation assays revealed a large portion of aggregation in redox-treated PG5, but not in PG0 and PG12. Circular dichroism analysis detected increased beta-sheet and decreased alpha-helix in PG5 subjected to redox, increased random-coil and decreased beta-sheet in PG0, and increased random-coil, but limited changes to beta-sheet content, in PG12. Thioflavin T fluorescence tests indicated that fluorescent value was increased in PG5 subjected to redox. In addition, proteinase K (PK) digestions indicated that PK resistance was stronger in PG12 and PG0 compared with in PG5; redox enhanced the PK resistance of all three PrP constructs, particularly PG0 and PG12. These data indicated that formation of a disulfide bond induces marked alterations in the secondary structure and biochemical characteristics of PrP. In addition, the octarepeat region within the PrP peptide markedly influences the effects of redox on the biochemical phenotypes of PrP, thus highlighting the importance of the number of octarepeats in the biological functions of PrP. PMID- 29393339 TI - The NALP3 inflammasome is required for collagen synthesis via the NF-kappaB pathway. AB - The NALP3 inflammasome interacts with various immune and cell metabolic pathways and may participate in pulmonary fibrosis. However, little is known on its regulatory mechanism with respect to collagen synthesis. The objective of the present study was to investigate whether NALP3 inflammasome activation is involved in H2O2-mediated collagen synthesis, in addition to examining the possible cell signaling mechanisms underlying this effect. It was demonstrated that the NF-kappaB signaling pathway was activated under conditions of H2O2 mediated oxidative stress in NIH-3T3 mouse embryonic fibroblasts. H2O2-exposed fibroblasts exhibited activated NALP3 inflammasomes via increased NALP3, apoptosis-associated Speck-like protein and caspase-1 expression and the secretion of interleukin-1beta. H2O2 also elevated alpha-SMA and type I collagen expression. In vitro silencing of NALP3 attenuated the degradation of IkappaBalpha and decreased the synthesis of type I collagen. Furthermore, the NALP3 inflammasome was found to be activated in bleomycin-induced pulmonary fibrosis in mice, and this activation was relieved by a nuclear factor (NF) kappaB inhibitor. Taken together, these findings indicate that the NALP3 inflammasome is involved in H2O2-induced type I collagen synthesis, which is mediated by the NF-kappaB signaling pathway. Additionally, the NALP3 inflammasome contributes to the development of bleomycin-induced pulmonary fibrosis. PMID- 29393340 TI - Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours. AB - Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. In this study, the Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, western blot analysis and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) was determined using XTT proliferation assays. In total, 2/6 cell lines were Trp53 homozygous mutant (NHO2A and 844MYCN+/+) and 1/6 (282MYCN+/-) was Trp53 heterozygous mutant. For 1/6 cell lines (NHO2A), DNA from the corresponding primary tumour was found to be Trp53 wt. In all cases, the presence of a mutation was consistent with aberrant p53 signalling in response to Nutlin-3 and IR. In comparison to TP53 wt human neuroblastoma cells, Trp53 wt murine control and TH-MYCN cell lines were significantly less sensitive to growth inhibition mediated by MI-63 and RG7388. These murine Trp53 wt and mutant TH-MYCN cell lines are useful syngeneic, immunocompetent neuroblastoma models, the former to test p53-dependent therapies in combination with immunotherapies, such as anti-GD2, and the latter as models of chemoresistant relapsed neuroblastoma when aberrations in the p53 pathway are more common. The spontaneous development of Trp53 mutations in 3 cell lines from TH-MYCN mice may have arisen from MYCN oncogenic driven and/or ex vivo selection. The identified species-dependent selectivity of MI-63 and RG7388 should be considered when interpreting in vivo toxicity studies of MDM2 inhibitors. PMID- 29393341 TI - MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP-2 expression. AB - MicroRNAs (miRNAs or miRs) play important roles in carcinogenesis. The miRNA, miR 205-5p, has been reported to suppress the growth of various types of tumor; however, its functional contribution to oral squamous cell carcinoma (OSCC) is not yet clear. Thus, this study was conducted to determine the miRNA expression signatures in OSCC and to investigate the functional role of miR-205-5p in OSCC cells. We measured miR-205-5p expression by RT-qPCR, and examined the function of miR-205-5p by transfecting a miR-205-5p mimic or inhibitor into OSCC cells and measuring cell proliferation, migration and invasiveness. Genes targeted by miR 205-5p were identified using the TargetScan database and verified by western blot analysis, luciferase reporter assay and ELISA. We found that miR-205-5p was significantly downregulated in OSCC cell lines and tissue specimens. Following transfection of miR-205-5p mimic or inhibitor into the cancer cell lines, miR-205 5p overexpression significantly suppressed cancer cell migration and invasion. We further demonstrated that miR-205-5p directly targeted and regulated the tissue inhibitor of metalloproteinases-2 (TIMP-2) gene. The silencing of TIMP-2 suppressed cancer cell invasion and the activation of pro-matrix metalloproteinase-2 (pro-MMP-2). These results suggest that TIMP-2 promotes tumor progression, and that miR-205-5p directly regulates TIMP-2, thereby suppressing pro-MMP-2 activation and inhibiting OSCC cell invasiveness. Our data describing the pathways regulated by miR-205-5p provide new insight into the mechanisms responsible for OSCC development and metastasis. PMID- 29393342 TI - CTHRC1 mediates IL-1beta-induced apoptosis in chondrocytes via JNK1/2 signaling. AB - Osteoarthritis (OA), also known as degenerative joint disease or degenerative arthritis, is characterized by chondrocyte apoptosis. The aim of the present study was to investigate the effects of collagen triple helix repeat containing 1 (CTHRC1) and the c-Jun N-terminal kinase (JNK) 1/2 inhibitor SP600125 on rat chondrocytes cultured in vitro with interleukin (IL)-1beta. Chondrocytes were treated with different doses of IL-1beta and cell viability and CTHRC1 expression were assessed using Cell Counting Kit-8 and western blot assays, respectively. In separate experiments, chondrocytes were treated with CTHRC1-expressing constructs (pLVX-Puro-CTHRC1) and/or SP600125, or IL-1beta with either CTHRC1 short hairpin (sh)RNA constructs (shNRA-CTHRC1) or SP600125. The expression of CTHRC1, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), cleaved caspase-3, poly ADP ribose polymerase (PARP)-1 and matrix metalloproteinase (MMP)-13 was measured using reverse transcription-quantitative polymerase chain reaction and western blotting assays. A Cell Counting Kit-8 assay was performed to examine cell viability. Annexin V/propidium iodide staining and flow cytometry assays were used to detect chondrocyte apoptosis. The expression of JNK1/2 and phosphorylated JNK1/2 was measured using western blotting. CTHRC1 was highly expressed in patients with OA compared with normal controls. IL-1beta treatment (5, 10 and 20 ng/ml) increased the protein expression of CTHRC1 in a dose-dependent manner and decreased the viability of chondrocytes in a time-dependent manner. pLVX-Puro CTHRC1 mimics the effect of IL-1beta on chondrocyte apoptosis and JNK1/2 activity, and this is reversed by SP600125 treatment. However, transfection with shRNA-CTHRC1 or treatment with SP600125 inhibited IL-1beta-induced cell apoptosis and JNK1/2 activation. These results indicate that CTHRC1 downregulation may protect chondrocytes from IL-1beta-induced apoptosis by inactivating the JNK1/2 pathway. PMID- 29393343 TI - Preparation of liposome encapsulating angiotensin-I-converting enzyme inhibitory peptides from sunflower protein hydrolysates. AB - Liposomal angiotensin-I-converting enzyme inhibitory (ACEI) peptides were prepared from sunflower protein hydrolysates by the thin-film ultrasonic method. Response surface methodology (RSM), in combination with fractional factorial designs and central composite design methods were utilized to optimize entrapment efficiency and balance the drug release. We found that the ratio of phospholipids to cholesterol, ultrasound time and the ratio of phospholipids to ACEI peptides were significant factors affecting entrapment efficiency (P<0.001). Optimal preparation conditions of liposomal-ACEI peptides were the ratio of soybean phospholipids to cholesterol (w/w) of 4.1:1, PEG-2000 dosage (%) of 4, NaCl concentration in PBS (mM) of 50, hydration temperature of 45C, ultrasound time of 8.05 min and the ratio of soybean phospholipids to ACEI peptides of 15:1 (w/w). The experimental entrapment efficiency of liposomal-ACEI peptides was (91.25+/ 0.182%). Moreover, the balanced release rate of liposome encapsulated ACEI in phosphate buffer was 77.83% after 12 h. PMID- 29393344 TI - MicroRNA-32 silences WWP2 expression to maintain the pluripotency of human amniotic epithelial stem cells and beta islet-like cell differentiation. AB - Human amniotic epithelial stem cells (HuAECs) exhibit pluripotent characteristics, which are similar to those of embryonic stem cells, and can differentiate into various adult tissues and cells through directed induction. However, in culture, HuAECs tend to lose their pluripotency, and their directed differentiation capability declines with increasing passage number. The stem cell pluripotency factor octamer-binding protein 4 (Oct4) is an important transcription factor that promotes stem cell self-proliferation and maintains their pluripotency. Previous studies have demonstrated that WW domain containing E3 ubiquitin protein ligase 2 (WWP2) negatively regulates Oct4 expression and stem cell pluripotency. Therefore, the present study aimed to investigate the regulation of WWP2 by microRNAs (miRs), and to evaluate the expression of the downstream factor Oct4 and the maintenance of HuAEC pluripotency. Bioinformatics analysis identified a complementary binding site for miR-32 in the 3'untranslated region of the WWP2 gene, thus suggesting that it may be a target gene of miR-32. Post-infection of HuAECs with a vector overexpressing miR-32, the endogenous expression of WWP2 was significantly decreased, whereas Oct4 expression was significantly increased. Furthermore, miR-32-infected cells differentiated into beta islet-like cells by directed induction. The results indicated that after induction, HuAECs overexpressing miR-32 also overexpressed the biomarkers of beta islet-like cells. In addition, the ability to secrete insulin was markedly enhanced in response to glucose stimulation, in cells overexpressing miR-32. In conclusion, the present study suggested that miR-32 may effectively inhibit WWP2 expression in HuAECs and promote Oct4 overexpression to maintain their pluripotency. PMID- 29393345 TI - SLC35E3 identified as a target of novel-m1061-5p via microRNA profiling of patients with cardiovascular disease. AB - MicroRNAs (miRNA) are considered to be potential therapeutic targets for the treatment of various cardiovascular diseases (CVDs). To understand the underlying mechanism of miRNAs and target genes associated with CVD, deep sequencing of blood samples from three patients with CVD and three controls was performed using the Illumina HiSeq 2000 system. The results of the present study revealed that 65 abnormal hsa-miRNAs targeted 2,784 putative genes in patients with CVD; 59 upregulated miRNAs targeted 2,401 genes and six downregulated miRNAs targeted 383 genes. In addition, a total of 49 Gene Ontology (GO) biological processes and were enriched, and the target genes of downregulated miRNAs were enriched in 12 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Most of these pathways are responsible for lipid and glycan metabolism. In particular, three downregulated miRNAs, hsa-miR-1268b, hsa-miR-1273d, hsa-miR-3187-5p, were involved in a-linolenic acid metabolism. The target genes of upregulated miRNAs were enriched in 15 KEGG pathways, mainly in the 'neurodegenerative diseases and cancers' class. In the present study five novel upregulated miRNAs, including m0499-5p, m0970-5p, m1042-5p, m1061-5p and m1953-5p, and a downregulated miRNA, novel-m1627-5p, were identified in patients with CVD. Novel-m1627-5p was demonstrated to target 146 human genes. Additionally, Novel-m1061-5p targeted four genes, including fumarylacetoacetate hydrolase domain containing 2A, potassium voltage-gated channel, Shaw-related subfamily, member 4, coiled-coil domain containing 85C and solute carrier family 35 member E3 (SLC35E3). The GO term, 'carbohydrate derivative transport involving in biological process', was associated with SLC35E3. Novel-m1061-5p in patients with CVD may repress the expression levels of SLC35E3, a member of the nucleoside sugar transporter subfamily E, which is known to cause defective glycol-conjugation in the Golgi complex and/or the endoplasmic reticulum. Further investigation is required to understand the underlying mechanisms of the novel miRNAs. Novel-m1061-5p may serve as a marker for prognosis or a potential target for the treatment of CVD. PMID- 29393347 TI - Renal transplantation increases angiotensin II receptor-mediated vascular contractility associated with changes of epigenetic mechanisms. AB - Hypertension is one of the most common complications following renal transplantation, and it increases the risk of graft loss and other cardiovascular diseases. Previous studies have revealed that the use of angiotensin II (Ang II) blockers for preventing and treating hypertension is closely associated with higher survival following renal transplantation. However, the cellular and molecular mechanisms by which the vascular contractility of the recipient is altered in response to Ang II following renal transplantation have not been fully elucidated. In the present study, using the Fisher-Lewis rat kidney transplantation model, the blood pressure (BP) of the conscious transplant recipient was measured following the intravenous administration of Ang II. In addition, the mechanisms underlying the Ang II-mediated vascular contractility via the type 1 and type 2 Ang II receptors (AT1R and AT2R, respectively) in large and small-resistance blood vessels were determined in the recipient after renal transplantation. The results showed that renal transplantation significantly increased the Ang II-stimulated BP of the rats. Additionally, ex vivo contractility experiments using aorta and mesenteric arteries revealed that the contractions induced by Ang II were significantly strengthened in the recipient following renal transplantation, and were associated with an increased intracellular Ca2+ concentration. Losartan almost eradicated the Ang II-induced contractions whereas PD-123319 had no apparent effects on the Ang II-induced contractions in the aorta and mesenteric arteries of the recipient. Furthermore, the expression levels of AT1R but not AT2R were significantly increased in the vasculature of the recipient following renal transplantation, which exhibited a close association with selective DNA demethylation detected in the promoter region of the vascular AT1aR gene. These results indicate that changes of recipient vascular AT1R gene expression, occurring through a mechanism involving DNA methylation, increase the vascular contractility in response to Ang II. This may lead to the increased risk of hypertension following renal transplantation. PMID- 29393346 TI - Histone deacetylase-4 and histone deacetylase-8 regulate interleukin-1beta induced cartilage catabolic degradation through MAPK/JNK and ERK pathways. AB - Interleukin-1beta (IL-1beta)-induced inflammatory response is associated with osteoarthritis (OA) and its development. Histone deacetylase (HDAC) may be involved in regulating this pathogenesis, but the mechanism has yet to be elucidated. The aim of the present study was to investigate the mechanism underlying the regulation of IL-1beta-stimulated catabolic degradation of cartilage by HDAC. An in vitro model of OA was generated using rat articular chondrocytes (rACs) treated with IL-1beta. The role of HDAC in IL-1beta-induced gene expression was investigated using HDAC inhibitors and specific small interfering RNAs (siRNAs). The association of diverse mitogen-activated protein kinase (MAPK) pathways was examined. The IL-1beta-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5, and the production of collagen X and cyclooxygenase-2 in rACs was accompanied by the expression of HDAC4 and HDAC8, and were significantly downregulated by HDAC inhibitors and specific siRNAs. IL-1beta-induced activation of extracellular signal-regulated kinase was downregulated by the HDAC inhibitor Trichostatin A, but not significantly by PCI-34051. The activation of c-Jun N terminal kinase was observably downregulated by the latter, but only slightly by the former. These results suggest that HDAC4 and HDAC8 may serve as key upstream mediators of MAPK in regulating the IL-1beta-induced cartilage catabolic and degradation. Therefore, inhibiting HDAC4 or HDAC8 or both may be a promising therapeutic strategy in preventing and treating OA. PMID- 29393348 TI - Decreased ZONAB expression promotes excessive transdifferentiation of alveolar epithelial cells in hyperoxia-induced bronchopulmonary dysplasia. AB - Previous studies by our group have confirmed excessive transdifferentiation of alveolar epithelial cells (AECs) in a hyperoxia-induced bronchopulmonary dysplasia (BPD) model, but the underlying mechanism have remained elusive. The transcription factor zonula occludens 1-associated nucleic acid binding protein (ZONAB) has the biological functions of inhibition of epithelial cell differentiation and promotion of epithelial cell proliferation. The aim of the present study was to explore the regulatory effect of ZONAB on the transdifferentiation and proliferation of AECs in a model of hyperoxia-induced lung injury. Newborn Wistar rats were randomly allocated to a model group (inhalation of 85% O2) or a control group (inhalation of normal air), and ZONAB expression in lung tissues was detected at different time-points. Type II AECs (AEC II) isolated from normal newborn rats were primarily cultured under an atmosphere of 85 or 21% O2, and ZONAB expression in the cells was examined. The primary cells were further transfected with ZONAB plasmid or small interfering (si)RNA and then exposed to hyperoxia, and the indicators for transdifferentiation and proliferation were measured. The present study indicated that ZONAB expression in AEC II of the BPD rats was significantly decreased from 7 days of exposure to hyperoxia onwards. In the AEC II isolated from normal neonatal rats, ZONAB expression in the model group was also reduced compared with that in the control group. After transfection with the plasmid pCMV6-ZONAB, the expression of aquaporin 5 (type I alveolar epithelial cell marker) decreased and the expression of surfactant protein C (AEC II marker), proliferating-cell nuclear antigen and cyclin D1 increased, which was opposite to the effects of ZONAB siRNA. Transfection with pCMV6-ZONAB also alleviated excessive transdifferentiation and inhibited proliferation of AEC II induced by hyperoxia treatment. These results suggest that ZONAB expression in AEC II decreases under hyperoxia conditions, which promotes transdifferentiation and inhibits proliferation of AECs. This may, at least in part, be the underlying mechanism of lung epithelial injury in the hyperoxia-induced BPD model. PMID- 29393349 TI - Enhancement of tendon-bone healing following rotator cuff repair using hydroxyapatite with TGFbeta1. AB - The formation of fibrocartilage at the healing site following a rotator cuff tear repair is a major problem in the field of tendon-bone healing. The present study aimed to enhance the healing of the tendon-bone interface following rotator-cuff tear repair by the interposition of hydroxyapatite (HA) encapsulated with transforming growth factor beta1 (TGFbeta1). Using an acute rotator cuff repair model, rats were divided into three groups: i) Repair only (control); ii) HA group; and iii) HA-TGFbeta1 group. Animals were sacrificed at 2, 4 and 8 weeks following surgery. Micro-computed tomography (CT), histomorphometric analyses and biomechanical tests were used to evaluate the supraspinatus tendon-bone complex. The micro-CT images revealed notable novel bone formation in the groups treated with HA-TGFbeta1. The histomorphometric analyses demonstrated improved fibrocartilage formation and collagen organization at the tendon-bone interface. The HA-TGFbeta1 combination significantly improved the area of fibrocartilage, particularly at early time points (2 and 4 weeks). There was a significantly greater load-to-failure force achieved in the HA and HA-TGFbeta1 groups compared with the control group at 4 and 8 weeks. Augmentation of the ceramic powder with HA-TGFbeta1 at the tendon-bone interface was demonstrated to strengthen the healing entheses, increase bone and fibrocartilage formation and improve collagen organization compared with surgical repair alone. Local application of HA TGFbeta1 demonstrates potential in improving tendon-bone healing following rotator cuff repair. PMID- 29393352 TI - Effect of idebenone on bone marrow mesenchymal stem cells in vitro. AB - In recent years, stem cell research has continued to benefit from its crossover with chemistry, particularly the investigation of small molecular drugs modulating specific targets to regulate stem cell fate. Idebenone (IDB) is a yellow crystalline powder that is used in the treatment of chronic cerebrovascular diseases. The objective of the present study was to examine whether IDB had an influence on bone marrow-derived mesenchymal stem cells (BMSCs) extracted from the bone marrow of Sprague-Dawley rats. The effects of IDB on cell proliferation, cell cloning and migration were investigated. Cell cycle, apoptosis, DAPI nuclear staining and senescence-associated beta-galactosidase (SA beta-gal) staining were also examined. The results revealed that IDB at suitable concentrations enhanced cell cloning capacity, promoted the proliferation of BMSCs, delayed cellular senescence, and inhibited cell apoptosis and migration. Western blot analysis indicated that IDB increased the expression of B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription-3, Nanog, octamer-binding transcription factor 4, E-cadherin, proliferating cell nuclear antigen, cyclinD1 and cyclinD3, and decreased the expression of Bcl-2-associated X protein, cleaved caspase-3, N-cadherin, vimentin and alpha-smooth muscle actin. In conclusion, these experiments confirmed that IDB in low doses had no toxic effect and may exert protective effects on BMSCs. PMID- 29393351 TI - Preliminary study of microRNA-126 as a novel therapeutic target for primary hypertension. AB - The present study aimed to explore microRNA-126 (miR-126) as a novel therapeutic target for primary hypertension. The lentiviral vector containing human immunodeficiency virus 1 (HIV-1), the miR-126 gene knockdown viral vector (lenti miR-126-KD), and control lentiviral vector (lenti-scramble-miR) were constructed. Spontaneously hypertensive rats were randomly divided into 4 groups, which received a high dose of lenti-miR-126-KD (1x108, n=5), low dose of lenti-miR-126 KD (1x107, n=6), scramble-miR (5x107, n=6), and PBS (n=6). Lentiviral vectors were injected into the tail vein. Data on the systolic blood pressure, diastolic pressure, mean arterial pressure, and heart rate were collected weekly. After 8 weeks of virus administration, the distribution of lentiviral vectors in different tissues was observed by fluorescence microscopy. Picric acid Sirius red and H&E staining were used to observe the target organ damage, and the ELISA kit was used to determine the serum nitric oxide (NO) content. The lentiviral vector was found to be constructed successfully. Eight weeks after the lentiviral vector injection, green fluorescent protein was observed in different tissues in each group. The blood pressure and heart rate were not significantly altered after lentiviral vector injection (P>0.05). No significant differences in the heart-to body weight ratio among the four groups were observed (P=0.23). Picric acid Sirius red and H&E staining revealed that there was no significant difference in morphology among the four groups. No significant difference in the serum NO level among the four groups was noted (P=0.23). The miR-126 gene knockdown lentiviral vector was constructed successfully. No significant antihypertensive effect was observed by the knockdown of miR-126 for the treatment of primary hypertension. The target organs were not protected significantly after the treatment. The increased level of miR-126 expression in hypertensive patients may be due to a compensatory mechanism. PMID- 29393350 TI - beta-glucans and cholesterol (Review). AB - Hypercholesterolemia is one of primary risk factors of cardiovascular disease, together with metabolic syndrome, hypertension and diabetes. Although progress has been made, the search for novel methods of preventing and treating dyslipidemia is ongoing and current therapies for cardiovascular disease induce various side effects. beta-glucans are linear unbranched polysaccharides found in various natural sources, such as mushrooms. Due to their structure they are able to interact with innate immunity receptors, however they also act as dietary fibers in the digestive tract. As there are two forms of beta-glucans, insoluble and soluble forms, they are able to interact with lipids and biliary salts in the bowel and consequently reduce cholesterol levels. Therefore, they may be developed as a suitable therapeutic option to treat patients with dyslipidemia, as they are natural molecules that do not induce any significant side effects. The current review discusses the evidence supporting the effects of beta-glucans on cholesterol levels. PMID- 29393353 TI - Hydrogen sulfide attenuates myocardial fibrosis in diabetic rats through the JAK/STAT signaling pathway. AB - The aim of the present study was to determine the role of hydrogen sulfide (H2S) in improving myocardial fibrosis and its effects on oxidative stress, endoplasmic reticulum (ER) stress and cell apoptosis in diabetic rats, by regulating the Janus kinasesignal transducer and activator of transcription (JAKSTAT) signaling pathway. A total of 40 male Sprague-Dawley rats were randomly divided into four groups (n=10) as follows: normal (control group), diabetes mellitus [streptozotocin (STZ) group], diabetes mellitus treated with H2S (STZ + H2S group), and normal rats treated with H2S (H2S group). Diabetes in rats was induced by intraperitoneal (i.p.) injection of STZ at a dose of 40 mgkg. NaHS (100 umolkg, i.p.), which was used as an exogenous donor of H2S, was administered to rats in the STZ + H2S and H2S groups. After 8 weeks, the pathological morphological changes in myocardial fibers were observed following hematoxylin and eosin and Masson's trichrome staining. Apoptosis of myocardial tissue was analyzed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Oxidative stress was evaluated through detecting the content of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), glutathione (GSH) and superoxide dismutase (SOD) in the myocardial cells by ELISA. The expression of collagen III, matrix metalloproteinase (MMP)8, MMP14, tissue inhibitor of metalloproteinase (TIMP)2, transforming growth factor (TGF)-beta, cystathionine-gamma-lyase (CSE), eukaryotic initiation factor 2alpha (eIF2alpha), GRP94, Bcl-2, caspase-3, tumor necrosis factor (TNF)-alpha, nuclear factor-kappaB (NF-kappaB) and proteins related to the JAKSTAT pathway, was detected by western blot analysis. The results indicated that the array of myocardial cells was markedly disordered in STZ group rats; compared with the control group, both myocardial interstitial fibrosis and the deposition of collagen III were increased. Furthermore, the expression ratio of MMPsTIMPs was dysregulated, while the expression levels of TGF-beta, eIF2alpha, GRP94, caspase-3, TNF-alpha, NF-kappaB, MDA and 4-HNE were significantly increased. Furthermore, the expressions of JAK-12 and STAT1356 were also markedly upregulated, while those of CSE, SOD, GSH and Bcl-2 were downregulated. Compared with the STZ group, these changes were reversed in the STZ + H2S group. The results of the present study demonstrated that H2S can improve myocardial fibrosis in diabetic rats, and the underlying mechanism may be associated with the downregulation of the JAKSTAT signaling pathway, thereby suppressing oxidative stress and ER stress, inflammatory reaction and cell apoptosis. PMID- 29393354 TI - Effects of silencing the DUSP1 gene using lentiviral vector-mediated siRNA on the release of proinflammatory cytokines through regulation of the MAPK signaling pathway in mice with acute pancreatitis. AB - The present study investigated the effects of dual specificity phosphatase 1 (DUSP1) gene silencing using lentiviral vector-mediated small interfering (si)RNA on the release of proinflammatory cytokines through the regulation of the mitogen activated protein kinase (MAPK) signaling pathway in mice with acute pancreatitis (AP). Two siRNA-DUSP1 sequences and one scramble siRNA sequence were designed, and the expression of DUSP1 was detected using western blot analysis to screen for the one with a higher interference rate. An AP mouse model was established, and KM mice were assigned to either a control, siRNA, AP, AP+PD98059, AP+scramble, AP+siRNA or AP+PD98059+siRNA group. The expression of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, high mobility group box 1 (HMGB1), and S100A12 in serum samples were detected using an enzyme-linked immunosorbent assay at 12, 24 and 48 h post-modeling. The serum amylase levels were also detected. The expression levels of DUSP1, TNF-alpha, IL-1beta, IL-6, HMGB1, S100A12, phosphorylated (p-) extracellular signal-regulated kinase (ERK), p-c-Jun N terminal kinase (JNK), p-p38, ERK, JNK and p38 in pancreatic, liver, kidney and lung tissues were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Compared with the control group, the siRNA group demonstrated marginally upregulated serum amylase, lipase, urinary trypsinogen-2, and proinflammatory cytokines, HMGB1 and S100A12 in serum and tissues, with no statistically significant difference, elevated expression levels of p-ERK, p-JNK and p-p38, and decreased expression of DUSP1. The other five groups demonstrated increased expression levels of TNF-alpha, IL-1beta, IL-6, HMGB1, S100A12, amylase, lipase and urinary trypsinogen-2 in serum, and increased expression levels of DUSP1, TNF-alpha, IL-1beta, IL-6, HMGB1, S100A12, p-ERK, p JNK and p-p38 in tissues. Compared with the AP group, the AP+PD98059+siRNA group had decreased expression of DUSP1 in tissues, whereas the AP+PD98059 group had decreased serum expression levels of TNF-alpha, IL-1beta, IL-6, HMGB1, S100A12 and amylase, lipase and urinary trypsinogen-2. The expression levels of TNF alpha, IL-1beta, IL-6, HMGB1, S100A12, p-ERK, p-JNK, p-p38 in tissues, and edema of pancreatic tissue were alleviated, whereas the opposite results were observed in the AP+siRNA group with the decreased expression of DUSP1. The results suggested that DUSP1 gene silencing promoted the release of proinflammatory cytokines through activation of the MAPK signaling pathway in mice with AP. PMID- 29393355 TI - miR-21-5p confers doxorubicin resistance in gastric cancer cells by targeting PTEN and TIMP3. AB - Drug resistance and disease recurrence are major obstacles to the effective treatment of cancer, including gastric cancer (GC). However, the mechanisms of drug resistance remain to be fully elucidated. The present study investigated the roles of microRNA (miR)-21-5p in the doxorubicin (DOX) resistance of GC cells and the underlying mechanisms. miR-21-5p expression levels were identified to be inversely correlated with two well-known tumor suppressor genes, phosphatase and tensin homologue and tissue inhibitor of matrix metalloproteinases 3, and were upregulated in GC cell lines in proportion to their degree of resistance. Suppressing miR-21-5p expression partially sensitized SGC7901/DOX cells to DOX, suggesting that knockdown of miR-21-5p expression may be used as a therapeutic strategy to improve GC cell resistance. Importantly, increased miR-21-5p expression levels at diagnosis were correlated with clinicopathological characteristics including advanced stage and poor prognosis, further implying that a relapse of GC may be a consequence of miR-21-5p upregulation, thus providing evidence for the potential utility of miR-21-5p antagonism to sensitize GC cells to DOX chemotherapy. PMID- 29393356 TI - MicroRNA-327 regulates cardiac hypertrophy and fibrosis induced by pressure overload. AB - MicroRNA (miRNA/miR) dysregulation has been reported to be fundamental in the development and progression of cardiac hypertrophy and fibrosis. In the present study, miR-327 levels in fibroblasts were increased in response to cardiac hypertrophy induced by transverse aortic constriction with prominent cardiac fibrosis, particularly when compared with the levels in unstressed cardiomyocytes. In neonatal rat cardiac fibroblasts, induced expression of miR 327 upregulated fibrosis-associated gene expression and activated angiotensin II induced differentiation into myofibroblasts, as assessed via alpha-smooth muscle actin staining. By contrast, miR-327 knockdown mitigated angiotensin II-induced differentiation. Cardiac fibroblast proliferation was not affected under either condition. In a mouse model subjected to transverse aortic constriction, miR-327 knockdown through tail-vein injection reduced the development of cardiac fibrosis and ventricular dysfunction. miR-327 was demonstrated to target integrin beta3 and diminish the activation of cardiac fibroblasts. Thus, the present study supports the use of miR-327 as a therapeutic target in the reduction of cardiac fibrosis. PMID- 29393357 TI - Damage to dopaminergic neurons by oxidative stress in Parkinson's disease (Review). AB - Oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of Parkinson's disease (PD). Although reactive oxygen species (ROS) production is implicated as a causative factor in PD, the cellular and molecular mechanisms linking oxidative stress with dopaminergic neuron death are complex and not well characterized. The primary insults cause the greatest production of ROS, which contributes to oxidative damage by attacking all macromolecules, including lipids, proteins and nucleic acids, leading to defects in their physiological function. Consequently, the defects in these macromolecules result in mitochondrial dysfunction and neuroinflammation, which subsequently enhance the production of ROS and ultimately neuronal damage. The interaction between these various mechanisms forms a positive feedback loop that drives the progressive loss of dopaminergic neurons in PD, and oxidative stress-mediated neuron damage appears to serve a central role in the neurodegenerative process. Thus, understanding the cellular and molecular mechanisms by which oxidative stress contributes to the loss of dopaminergic neurons may provide a promising therapeutic approach in PD treatment. PMID- 29393358 TI - MicroRNA let-7g inhibits angiotensin II-induced endothelial senescence via the LOX-1-independent mechanism. AB - Endothelial senescence leads to cell dysfunction, which in turn eventually results in cardiovascular disease. Identifying factors that regulate endothelial senescence may provide insight into the pathogenesis of aging. Insulin-like growth factor (IGF) signaling has a significant role in the physiology of endothelial cells (ECs). Overactivation of IGF signaling has been implicated in promoting the aging process. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) is a scavenger receptor that mediates the internalization of oxLDL into cells. Previous studies by our group have indicated that microRNA let 7g exerts an anti-aging effect on ECs and also suppresses LOX-1 expression. Since LOX-1 also induces the aging process, the present study we explored whether let 7g still exerts an anti-aging effect on ECs when LOX-1 is suppressed. Angiotensin II (Ang II) was used to induce senescence in ECs. It was revealed that Ang II significantly increased the expression of aging markers, including beta galactosidase, LOX-1, IGF1 and its receptor IGF1R. On the contrary, Ang II decreased the expression of the anti-aging gene sirtuin 1 (SIRT1). When LOX-1 was knocked down by small interfering RNA, let-7g still dose-dependently decreased the expression of beta-galactosidase (beta-gal), LOX-1, IGF1 and IGF1R, and SIRT1 was still upregulated. Using senescence-associated beta-gal staining, it was confirmed that let-7g exerts a LOX-1-independent anti-aging effect on ECs. In conclusion, the present study demonstrated that let-7g has an anti-aging effect regardless of the presence or absence of LOX-1. PMID- 29393359 TI - Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV. AB - Connexin 43 (Cx43) can be modified and regulated by small ubiquitin-like modifier (SUMO)1; however, its role in liver cancer stem cells is poorly understood. In this study, we found a significant difference in the expression of Cx43 and SUMO1 between cancer stem cells and non-cancer stem cells in liver cancer. In liver cancer stem cells, Cx43 was almost absent, although the level of SUMO1 was significantly higher than that in non-cancer stem cells. Further experiments confirmed that the conjugated site of Cx43 by SUMO1 was located in Lys-144 and Lys-237, both of which are highly conserved among species. By the co-expression of Cx43 and SUMO1 in cancer stem cells, the gap junction intercellular communication (GJIC) of liver cancer stem cells was obviously improved. Using this feature, we verified whether it could effectively increase the sensitivity of cancer stem cells to the herpes simplex virus 1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV), a conventional chemotherapeutic drug, in vitro and in vivo. As expected, increasing the expression of Cx43 SUMOylation in liver cancer stem cells effectively enhanced their sensitivity to HSVtk/GCV. On the whole, this study revealed a novel method which may be used to effectively restore GJIC in cancer stem cells in liver cancer, which enhances their sensitivity to conventional chemotherapeutic drugs. PMID- 29393360 TI - EZH2-mediated suppression of lncRNA-LET promotes cell apoptosis and inhibits the proliferation of post-burn skin fibroblasts. AB - Although the upregulation of enhancer of zeste homolog 2 (EZH2) expression and downregulation of long non-coding RNA (lncRNA) LET expression are known to be associated with cell apoptosis and proliferation, little is known about the interaction of EZH2 with lncRNA LET. The present study aimed to investigate the interaction of EZH2 and lncRNA LET, and the mechanism of human dermal fibroblast (HDF) proliferation and apoptosis. Tissue samples from 33 burn patients with second- and third-degree burns and 8 controls were collected. mRNA was extracted from the burn tissues for analysis. Isolated primary HDFs were treated with heat or transfected with LET overexpression vectors, and the cell functions and associated proteins in the HDFs were analyzed. Decreased lncRNA LET expression was detected in burn tissues compared with normal skin. Heat-treated HDFs exhibited a reduction in lncRNA LET expression and increase in EZH2 expression. LET gain-of-function experiments in primary HDFs revealed increases in cell proliferation, the proportion of cells in the S stage, and cyclin D1 and cyclin dependent kinase 4 (CDK4) expression, and reductions in the percentage of apoptotic cells, the Bax/Bcl-2 ratio and caspase-3 expression. RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated the interaction of ZH2 with lncRNA LET, and of EZH2 with H3K27me3 in HDFs. Furthermore, a negative correlation between lncRNA LET and EZH2 expression was identified. It may be concluded that increased lncRNA-LET expression promoted cell proliferation and inhibited cell apoptosis via the cyclin D1-CDK4 and Bax/Bcl-2/caspase-3 signaling pathways, respectively. Furthermore, the inhibition of lncRNA LET may be regarded as an option for use in the healing of burns. PMID- 29393362 TI - Tanshinone IIA inhibits gastric carcinoma AGS cells by decreasing the protein expression of VEGFR and blocking Ras/Raf/MEK/ERK pathway. AB - The RAS/RAF/MEK/ERK pathway is one of the most frequently dysregulated kinase cascades in human cancer, that facilitate the proliferation and survival of cancers driven by growth factor receptors. Tanshinone IIA (Tan-IIA) was extracted from Danshen (Salviae Miltiorrhizae Radix). Tan-IIA inhibition of the proliferation of gastric cancer are well documented, but the molecular mechanisms of Tan-IIA inhibition of gastric cancer have not been well elucidated. We evaluated the protein expression of vascular epidermal growth factor receptor (VEGFR), human epidermal growth factor receptor 2 (HER2), Ras, Raf, MEK, ERK, PARP, caspase-3 and beta-actin in AGS cells by western blotting. The results showed that AGS cells treated with Tan-IIA upregulated the protein expression of PARP and caspase-3 but decreased VEGFR, HER2, Ras, Raf, MEK and ERK time- and dose-dependently. These findings demonstrated that Tan-IIA inhibited human gastric cancer AGS cells; one of the molecular mechanisms may be through decreasing the protein expression of VEGFR and HER2, then blocking the Ras/Raf/MEK/ERK pathway to induce the activation of PARP and caspase-3 to induce apoptosis. PMID- 29393361 TI - Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis. AB - Hepatic fibrosis is a physiological response to liver injury that includes a range of cell types. The pathogenesis of hepatic fibrosis currently focuses on hepatic stellate cell (HSC) activation into muscle fiber cells and fibroblasts. Baicalin is a flavone glycoside. It is the glucuronide of baicalein, which is extracted from the dried roots of Scutellaria baicalensis Georgi. Previous work focused on the anti-viral, -inflammatory and -tumor properties of baicalin. However, the potential anti-fibrotic effects and mechanisms of baicalin are not known. The present study demonstrated that baicalin influenced the activation, proliferation, apoptosis, invasion and migration of platelet-derived growth factor-BB-induced activated HSC-T6 cells in a dose-dependent manner. To investigate the anti-fibrotic effect of baicalin, a one-color micro (mi)RNA array and reverse transcription-quantitative polymerase chain reaction analyses were used. Results demonstrated that baicalin increased the expression of the miRNA, miR-3595. In addition, the inhibition of miR-3595 substantially reversed the anti fibrotic effect of baicalin. The present data also suggested that miR-3595 negatively regulates the long-chain-fatty-acid-CoA ligase 4 (ACSL4). Furthermore, ACSL4 acted in a baicalin-dependent manner to exhibit anti-fibrotic effects. Taken together, it was concluded that baicalin induces miR-3595 expression that modulates the expression levels of ACSL4. To the best of our knowledge, the present study is the first to demonstrate that baicalin induces overexpression of human miR-3595, and subsequently decreases the expression of ACSL4, resulting in an anti-fibrotic effect. PMID- 29393363 TI - Lentivirus-mediated overexpression of suppressor of cytokine signaling-3 reduces neutrophilic airway inflammation by suppressing T-helper 17 responses in mice with chronic Pseudomonas aeruginosa lung infections. AB - The aim of the present study was to explore the effect of overexpressed suppressor of cytokine signaling-3 (SOCS3) on T-helper (Th)17 cell responses and neutrophilic airway inflammation in mice with chronic Pseudomonas aeruginosa (PA) infections. SOCS3 expression was enhanced via the administration of tail vein injections of therapeutic lentivirus in mice with chronic PA lung infections. SOCS3 expression in the blood and lung tissue was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Total and differential cell numbers and myeloperoxidase levels in the bronchoalveolar lavage (BAL) fluid were assessed, as well as the number of bacterial colonies in the lungs. Histological analysis of lung tissue was performed using hematoxylin and eosin staining and phosphorylated-signal transducer and activator of transcription-3 (p-STAT3) expression was measured by western blot analysis and immunohistochemistry. The expression of STAT3 mRNA and retinoid-related orphan receptor (ROR)gammat were measured by RT-qPCR. The percentage of interleukin (IL)-17+ cells among cluster of differentiation (CD)4+ cells was calculated using flow cytometry and levels of IL-17A and IL-6 were assessed by ELISA. The expression of SOCS3 was significantly increased in CD4+ T cells following lentivirus injection and the inflammation of neutrophilic airways was notably ameliorated. Enhanced SOCS3 expression was associated with a significant decrease in the expression of p-STAT3 and RORgammat in CD4+ T cells. Additionally, the percentage of IL-17+ cells among CD4+ T cells and the IL-17 contents in the BAL fluid were significantly decreased. Lentivirus-mediated overexpression of SOCS3 was revealed to ameliorate neutrophilic airway inflammation by inhibiting pulmonary Th17 responses in mice with chronic PA lung infections. PMID- 29393364 TI - miR-195 suppresses abdominal aortic aneurysm through the TNF-alpha/NF-kappaB and VEGF/PI3K/Akt pathway. AB - In the present study, the function of microRNA (miR)-195 on abdominal aortic aneurysm (AAA) and its possible mechanism were investigated. Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the expression of miR-195 in patients with AAA. The expression levels of miR-195 in patients with AAA were effectively increased. The present study also used miR 195 mimics to increase the expression of miR-195, and ELISA kits and western blot analysis were used to analyze the levels of interleukin (IL)-1beta and IL-6, and the protein expression levels of matrix metalloproteinase (MMP)-2, MMP-9, tumor necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB, vascular endothelial growth factor (VEGF), phosphoinositide 3-kinase (PI3K) and phosphorylated (p )Akt. The overexpression of miR-195 promoted the levels of IL-1beta and IL-6, induced the protein expression of MMP-2 and MMP-9, upregulated the protein expression of TNF-alpha and NF-kappaB, and suppressed the protein expression levels of VEGF, PI3K and p-Akt in angiotensin II-vascular smooth muscle cells. In addition, TNF-alpha promoted the pre-inflammatory effect of miR-195 on the protein expression levels of TNF-alpha and NF-kappaB, levels of IL-1beta and IL 6, and protein expression levels of MMP-2 and MMP-9 in the angiotensin II vascular smooth muscle cells. Suppression of PI3K promoted the pre-inflammatory effect of miR-195 on the protein expression of PI3K, p-Akt and VEGF, the levels of IL-1beta and IL-6, and the protein expression of MMP-2 and MMP-9 in angiotensin II-vascular smooth muscle cells. Combined, these results suggested that miR-195 suppressed AAA inflammation through the TNF-alpha/NF-kappaB and VEGF/PI3K/Akt pathways. PMID- 29393365 TI - Gastrodin protects MC3T3-E1 osteoblasts from dexamethasone-induced cellular dysfunction and promotes bone formation via induction of the NRF2 signaling pathway. AB - Glucocorticoid (GC)-induced osteoporosis (GIO) is one of the most common secondary and iatrogenic forms of osteoporosis. GCs are widely used in clinical therapy and play a key role in the normal regulation of bone remodeling. However, the prolonged and high-dose administration of GCs results in the occurrence of osteoporosis, which is partially due to the dysfunction and apoptosis of osteoblasts and osteocytes. The aim of the present study was to investigate the effects of gastrodin, a natural bioactive compound isolated from the traditional Chinese herbal agent Gastrodia elata, on GC-treated MC3T3-E1 murine osteoblastic cells. MC3T3-E1 cells were exposed to dexamethasone (DEX), with or without gastrodin pretreatment, and cell viability was measured by the cell counting kit 8 (CCK-8) assay. Quantitative polymerase chain reaction analysis was performed to evaluate osteogenic gene expression, and cellular alkaline phosphatase (ALP) activity was measured as well. Alizarin Red staining of calcium deposits was found to reflect the degree of osteoblast maturity. Western blotting was performed to determine the expression of osteogenic and adipogenic differentiation key proteins, as well as nuclear factor-like 2 (NRF2) pathway related proteins. Annexin V-fluorescein isothiocyanatepropidium iodide flow cytometric analysis was performed to determine osteoblast apoptosis. JC-1 staining was used to detect the changes of the mitochondrial membrane potential in cells. The results revealed that gastrodin prevented the decrease in cell viability caused by DEX-induced MC3T3-E1 cell dysfunction, and that groups pretreated with gastrodin exhibited higher mRNA levels of osteogenic genes, such as Runx2, osterix, bone morphogenetic protein-2 and osteocalcin. Furthermore, treatment with both DEX and gastrodin was associated with increased ALP activity in MC3T3-E1 cells, as well as more calcium deposits, compared with cells treated with DEX alone. In addition, gastrodin increased osteogenic key marker protein Runx2 while activating NRF2 and downstream effector protein expression. Therefore, gastrodin may have the potential to reduce DEX-induced cell apoptosis and increase the mitochondrial membrane potential against DEX. These results demonstrated that gastrodin was able to prevent and/or delay DEX-induced osteoporosis by improving osteoblast function, and these protective effects were verified in an animal model. PMID- 29393366 TI - D-Pinitol alleviates cyclosporine A-induced renal tubulointerstitial fibrosis via activating Sirt1 and Nrf2 antioxidant pathways. AB - Although the mechanism of cyclosporine A (CsA)-induced renal injury remains to be fully elucidated, accumulating evidence suggests that oxidative stress is critical in producing CsA-induced structural and functional renal impairment. The present study investigated the effect of D-pinitol, a cyclitol present in soybean, on chronic CsA nephropathy. Male ICR mice were treated with vehicle, CsA (30 mg/kg/day), D-pinitol (50 mg/kg/day) or a combination of CsA and D-pinitol for 28 days. To assess which pathway responding to oxidative stress is augmented by D-pinitol, the expression levels of several antioxidant enzymes and their possible regulators were measured. Treatment with D-pinitol significantly suppressed the increase of serum creatinine and decrease of urine osmolality, compared with the CsA control group. Histological examination of Masson's trichrome- and alpha-smooth muscle actin-stained renal tissue demonstrated that the CsA-induced tubulointerstitial fibrosis and inflammation were attenuated by D pinitol. Following the administration of D-pinitol, there were increased expression levels of heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, superoxide dismutase 1 and catalase in CsA-treated kidneys. In addition, D pinitol increased the level of sirtuin 1 (Sirt1), and the total and nuclear expression levels of nuclear erythroid factor 2-related factor 2 (Nrf2), suggesting that activation of the Sirt1 and Nrf2 pathways may induce the cellular antioxidant system against CsA-induced nephropathy. Collectively, these data suggested that D-pinitol may protect the kidney from CsA-induced fibrosis, and that this renoprotective effect of D-pinitol was due to the inhibition of oxidative stress through the activation of Sirt1 and Nrf2, and the subsequent enhancement of antioxidant enzymes. PMID- 29393367 TI - Identification of tumor suppressive role of microRNA-132 and its target gene in tumorigenesis of prostate cancer. AB - Previous literature exists on the role of microRNA (miR)-132 in initiation and progression of various malignancies. In this study, we aimed at understanding the relationship of miR-132 of prostate tumorigenesis. We collected 32 prostate cancer tissues and adjacent non-cancerous controls, and detected the expression level of miR-132. Then the miRNA database was searched online and luciferase assay perform to understand the regulatory relationship between miR-132 and E2F5. Moreover, we also conducted real-time PCR and western blot analysis to study the mRNA and protein expression level of E2F5 among different groups (cancerous tissue, n=32; non-cancerous tissue, n=32) or cells treated with scramble control, miR-132 mimics, E2F5 siRNA and miR-132 inhibitors. miR-132 was upregulated in cancerous tissues of prostate cancer patients. E2F5 was the target of miR-132, and negative regulatory relationship between miR-132 and E2F5 was also confirmed by luciferase assay. The mRNA and protein expression level of E2F5 increased in cancerous tissue group. miR-132 decreased the expression of E2F5 in prostate cancer cells, and introduction of miR-132 reduced the viability and E2F5 and promoted the viability of prostate cancer cells. miR-132 inhibited apoptosis and E2F5 accelerated apoptosis. In conclusion, miR-132 was upregulated in cancerous tissue of prostate cancer. E2F5 was a direct target of miR-132, and downregulation of E2F5 caused by upregulation of miR-132 may contribute to the tumorigenesis of prostate cancer. PMID- 29393368 TI - Dexamethasone-induced production of reactive oxygen species promotes apoptosis via endoplasmic reticulum stress and autophagy in MC3T3-E1 cells. AB - Apoptosis of osteoblasts, triggered by prolonged or excessive use of glucocorticoids (GCs), has been identified as a dominant contributor to the development of osteoporosis and osteonecrosis. However, the molecular mechanisms underlying GC-induced apoptosis are multifaceted and remain to be fully elucidated. The present study aimed to explore the correlation between dexamethasone (DEX)-induced reactive oxygen species (ROS), autophagy and apoptosis in MC3T3-E1 osteoblast-like cells. Cell viability was assessed using a Cell Counting Kit-8 assay, and flow cytometry was performed to assess cellular apoptosis, cell cycle and ROS production. Immunofluorescence and western blot analysis were respectively used to detect autophagic vacuoles and the expression of proteins, including cyclin D kinase (CDK)2, poly[ADP ribose] polymerase, caspase-3, activating transcription factor (ATF)4, CCAAT/enhancer-binding protein homologous protein (CHOP), Beclin1, microtubule-associated proteins 1A/1B light chain (LC)3B and P62. It was revealed that DEX not only reduced cell viability, but also promoted apoptosis via the activation of endoplasmic reticulum (ER) stress. In addition, DEX induced cell cycle arrest at G0/G1 phase via inhibition of the expression of CDK2, and the production of ROS was activated. Of note, the DEX-mediated changes in viability and apoptosis were attenuated in MC3T3-E1 cells after treatment with 3-methyladenine, which is an autophagy inhibitor. Treatment with the antioxidant N-acetylcysteine abolished the effect of DEX on the proliferation, apoptosis, ER stress and autophagy of MC3T3-E1 cells. In conclusion, the present results indicated that DEX promoted the production of ROS, which enhanced apoptosis through activation of autophagy and ER stress in MC3T3-E1 cells. PMID- 29393369 TI - Aberrantly expressed long noncoding RNAs in hypertrophic scar fibroblasts in vitro: A microarray study. AB - A hypertrophic scar is the result of abnormal repair of the body after trauma. Histopathologically, it is mostly the result of the excessive proliferation of fibroblasts and the accumulation of extracellular matrix. Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) have a critical role in the regulation of gene expression and in the pathogenesis of diseases. However, the roles of lncRNAs in hypertrophic scars have remained elusive. The present study investigated the profiles of differentially expressed lncRNAs between fibroblasts derived from a hypertrophic scar and normal skin, and explored the possible mechanisms underlying the development of hypertrophic scars. Microarray data indicated that 6,104 lncRNAs and 2,952 mRNAs were differentially expressed. A set of differentially expressed transcripts as confirmed by reverse transcription quantitative polymerase chain reaction. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to determine the principal functions of the significantly deregulated genes. Furthermore, associated expression networks, including subgroup analysis, competing endogenous RNAs (ceRNAs) and coding-noncoding co-expression networks were constructed using bioinformatics methods. The homology between differentially expressed lncRNAs and mRNAs was assessed and two exon lncRNA were selected to explore their regulatory mechanisms. The ceRNA network inferred that NR_125715 acted as a competing endogenous RNA, bound to microRNA (miR)-141-3p, miR-200a-3p and miR-29 to regulate the expression of the miRs' targets, including transforming growth factor beta2 (TGFB2). Similarly, NR_046402 acted as a competing endogenous RNA, which bound to miR-133a-3p.1 and miR-4469 to then regulate the expression of the miRs' targets, including DNA polymerase delta1, catalytic subunit (POLD1). In addition, co-expression analysis indicated that the expression of lncRNAs NR_125715 and NR_046402 was correlated with that of TGFB2 and POLD1 mRNA. The identification of these differentially expressed lncRNAs in the hypertrophic scar derived fibroblasts in the present study, may provide novel insight into the functional interactions of lncRNA, miRNA and mRNA, and lead to novel theories for the pathogenesis and treatment of hypertrophic scars. PMID- 29393370 TI - A 63 signature genes prediction system is effective for glioblastoma prognosis. AB - The present study aimed to explore possible prognostic marker genes in glioblastoma (GBM). Differentially expressed genes (DEGs) were screened by comparing microarray data of tumor and normal tissue samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset GSE22866. Subsequently, the prognosis-associated DEGs were screened via Cox regression analysis, followed by construction of gene/protein/pathway interaction networks of these DEGs by calculating the correlation coefficient between the DEGs. Next, a prognostic prediction system was constructed using Bayes discriminant analysis, which was validated by the microarray data of samples from patients with good and bad prognosis from the TCGA and Chinese Glioma Genome Atlas (CGGA), as well as the GEO dataset. Finally, a co-expression network of the signature genes in the prediction system was constructed in combination with the significant pathways. A total of 288 overlapping DEGs (false discovery rate <0.5 and |log2 of fold change|>1) were screened, 123 of which were identified to be associated with the prognosis of GBM patients. The co-expression network of these prognosis associated DEGs included 1405 interactions and 112 DEGs, and 6 functional modules were identified in the network. The prognostic prediction system was comprised of 63 signature genes with a specificity value of 0.929 and a sensitivity value of 0.948. GBM samples with good and bad prognosis in the TCGA, CGGA and GEO datasets were distinguishable by these signature genes (P=1.33x10-6, 1.63x10-4 and 0.00534, respectively). The co-expression network of signature genes with significant pathways was comprised of 56 genes and 361 interactions. Protein kinase Cgamma (PRKCG), protein kinase Cbeta (PRKCB) and calcium/calmodulin dependent protein kinase IIalpha (CAMK2A) were important genes in the network, and based on the expression of these genes, it was possible to distinguish between samples with significantly different survival risks. In the present study, an effective prognostic prediction system for GBM patients was constructed and validated. PRKCG, PRKCB and CAMK2A may be potential prognostic factors for GBM. PMID- 29393371 TI - Resistant starch prevents tumorigenesis of dimethylhydrazine-induced colon tumors via regulation of an ER stress-mediated mitochondrial apoptosis pathway. AB - Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids, and may prevent tumorigenesis of gastrointestinal cancer. Epidemiology and other evidence have suggested that resistant starch may prevent colon cancer development. The aim of the current study was to explore the ameliorative effects and potential mechanisms of resistant starch in the tumorigenesis of colon tumors induced by dimethylhydrazine in C57BL/6 mice. Western blot analysis, ELISA, microscopy, immunofluorescence and immunohistochemistry were used to analyze the efficacy of resistant starch on the metabolic balance in the colon and tumorigenesis of colon tumors. The results demonstrated that a diet containing resistant starch decreased the animal body weight and reduced free ammonia, pH and short chain fatty acids in feces compared with mice that received a standard diet. Resistant starch reduced the incidence of colon tumors and suppressed the expression of carcinogenesis-associated proteins, including heat shock protein 25, protein kinase C-d and gastrointestinal glutathione peroxidase in colon epithelial cells compared with standard starch and control groups. Colon tumor cells proliferation and dedifferentiation were significantly decreased by a resistant starch diet. The results also demonstrated that resistant starch increased the apoptosis of colon tumor cells through regulation of apoptosis associated gene expression levels in colon tumor cells. Oxidative stress and endoplasmic reticulum stress were upregulated, and elevation eukaryotic translation initiation factor 2alpha (eIF2alpha), activating transcription factor 4 and secretase-beta expression levels were increased in the resistant starch diet group. Additionally, the activity of eIF2alpha and PERK were increased in colon tumor cells from mice that had received resistant starch. Increasing DNA damage-inducible transcript 3 protein (CHOP), binding immunoglobulin protein (BIP) and caspase-12 expression levels upregulated by resistant starch diet may contribute to the resistant starch-induced apoptosis of colon tumor cells induced by 1,2-dimethylhydrazine. In vitro assays demonstrated that knockdown of eIF2alpha inhibited apoptosis of colon tumor cells isolated from mice fed with resistant starch, which also downregulated CHOP, BIP and caspase-3 expression levels compared with controls. Furthermore, long-term survival of experimental mice was prolonged by the resistant starch diet compared with the standard diet group. In conclusion, the results indicate that resistant starch in the diet may prevent carcinogenesis of colon epithelial cells, mediated by enhancing apoptosis through an endoplasmic reticulum stress-mediated mitochondrial apoptosis pathway. PMID- 29393373 TI - miRNA-27a regulates arthritis via PPARgamma in vivo and in vitro. AB - The present study investigated the role of microRNA (miR)-27a in the development of arthritis and its mechanism of action. Initially, collagen was used to develop an in vivo rat model of arthritis. Changes in the miRs in the rats were analyzed. It was subsequently observed that miR-27a expression was reduced in patients with arthritis, compared with the control group. In the present study an in vitro miR 27a overexpression model of arthritis was established and it was observed that miR-27a increased the proliferation of osteoblast-like cells in vitro. miR-27a overexpression promoted osteogenic differentiation, increased alkaline phosphatase (ALP) and osteoporosis (OST) content, induced insulin-like growth factor binding protein-5 (IGFBP-5) protein expression, reduced inflammation and suppressed peroxisome proliferator-activated receptor gamma (PPARgamma) and matrix metalloproteinase-17 (MMP-17) protein expression in arthritis. However, miR-27a downregulation inhibited osteogenic differentiation, increased inflammation and PPARgamma and MMP-17 protein expression and suppressed ALP and OST content in an in vitro model of arthritis. The PPARgamma inhibitor reduced the function of miR-27a downregulation on arthritis. Therefore the results of the present study revealed that miR-27a regulates arthritis via PPARgamma. PMID- 29393372 TI - Effect of leukocyte inhibitory factor on neuron differentiation from human induced pluripotent stem cell-derived neural precursor cells. AB - Direct derivation of human induced pluripotent stem cells into neural precursor cells and differentiation of these into neurons holds great promise in the cell therapy of neurodegenerative diseases. However, the availability and survival rate of neurons requires improvement. In the present study, it was found that the addition of 5 ng/ml leukocyte inhibitory factor (LIF) during the process of differentiation significantly improved the expression of neuron-specific class III beta-tubulin (TUJ1) and microtubule-associated protein 2 (MAP2), as detected by immunofluorescence and western blotting. In addition, LIF improved the cell viability, increased the expression of phosphorylated-protein kinase B (AKT), downregulated the expression of proinflammatory cytokines, including interleukin 1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha), and upregulated the expression of anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). After adding the phosphatidylinositol 3-kinase (PI3K)/AKT signaling inhibitor LY294002 or wortmannin to the LIF differentiation group, LIF-induced changes in the protein expression of TUJ1 and MAP2 were reversed, but this effect could not be prevented by rapamycin, a mechanistic target of rapamycin signaling inhibitor. The expression of cytokines associated with inflammation and cell viability was reversed by LY294002 and wortmannin, but not by rapamycin. In conclusion, LIF could improve neuronal differentiation and survival through the activation of PI3K/AKT signaling and the anti-inflammatory effect. The anti-inflammatory effect may be mediated by the activation of PI3K/AKT. PMID- 29393374 TI - Low-dose cadmium activates the JNK signaling pathway in human renal podocytes. AB - Cadmium (Cd) is an environmental toxin. Our previous study demonstrated that low dose Cd damages the integrity of the glomerular filtration barrier (GFB); however, the underlying mechanisms are poorly understood. Podocytes are a major component of the GFB, which regulate the passage of proteins. The present study aimed to investigate the effects of low-dose Cd on human renal podocytes (HRPs). HRPs were treated with Cd and activation of the c-Jun N-terminal kinase (JNK) pathway was examined by western blot analysis. Proliferation, viability and apoptosis of HRPs were evaluated by MTT assay, trypan blue exclusion assay and flow cytometry, respectively. The properties of HRPs were validated by immunofluorescence staining and Phalloidin-labeling. The results indicated that 4 uM Cd may activate the JNK pathway, and increase the protein expression levels of c-Jun and c-Fos. However, proliferation, viability, apoptosis and alignment of the F-actin cytoskeleton in HRPs were not significantly affected by Cd treatment, with or without SP600125 pretreatment. In addition, the expression levels of CD2 associated protein and synaptopodin, which are differentiation markers of HRPs, remained unchanged following Cd treatment. These results indicated that low-dose Cd activates the JNK pathway but does not significantly affect HRP function. PMID- 29393375 TI - Expression level of 12-amino acid triggering receptor on myeloid cells-like transcript 1 derived peptide alleviates lipopolysaccharide-induced acute lung injury in mice. AB - Acute lung injury (ALI) is a critical illness with a high morbidity and mortality rate due to severe inflammation in the lungs. The effects and underlying mechanism of the triggering receptor expressed on myeloid cells-1 (TREM-1)-like transcript-1-derived peptide (LR12) on ALI remain unclear. The aim of the present study was to determine whether LR12 attenuates lipopolysaccharide (LPS)-induced ALI and elucidate the mechanism underlying it. Male C57BL/6 mice were randomly assigned to three groups as follows: Sham group, LPS + scramble group and LPS + LR12 group. Normal saline (NS) or LPS was administrated by intratracheal instillation, and NS, LR12 or LR12 scramble was administered intraperitoneally 30 min later. The treatment was repeated every 3 h three times. Mice were sacrificed 24 h later. Pulmonary pathological changes, the lung wet/dry weight ratio, the macrophage and neutrophil counts in bronchoalveolar lavage fluid and myeloperoxidase (MPO) activity in the lung tissues were observed. The inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay and lung neutrophil infiltration was detected by immunohistochemistry. Nuclear factor (NF)-kappaB p65 and TREM-1 were analyzed by western blotting, and the activation of NF-kappaB was detected by electrophoretic mobility shift assay. LPS-induced pathohistological injury, edema and neutrophil infiltration were significantly alleviated by TREM-1 inhibitor, LR12. The proinflammatory cytokines [interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha] and chemokines (keratinocyte chemokine and monocyte chemoattractant protein-1) were significantly reduced, whereas the anti-inflammatory cytokines, IL-10 were significantly increased by LR12. LR12 was identified to significantly decrease p65 expression levels in the nucleus and inhibit the activity of NF-kappaB. Furthermore, LR12 alleviated LPS induced ALI by reducing the expression of TREM-1, increasing the release of soluble TREM-1 and inhibiting activation of the NF-kappaB signaling pathway. PMID- 29393376 TI - MicroRNA expression profiling in placenta and maternal plasma in early pregnancy loss. AB - Early pregnancy loss (EPL), also termed early miscarriage, is determined as the unintentional expulsion of an embryo or fetus prior to the 12th week of gestation. EPL frequency is ~15% in pregnancies. Fetal development and growth is associate with placental function and vessel development; therefore, the placental genome would represent a useful miscarriage model for (epi)genetic and genomic studies. An important factor of placental development and function is epigenetic regulation of gene expression. microRNAs (miRNAs) are the primary epigenetic regulators which have an important role in placental development and function. In the present study, maternal plasma and villous tissue were collected from 16 EPL cases in 6th-8th gestational weeks (GWs) and 8 abortions (control group) in 6th-8th GWs. Detection of the differences in miRNA expression was performed using microarrays and dysregulated miRNAs were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miRNA microarray findings revealed that four miRNAs, including hsa-miRNA (miR)-125a-3p, hsa-miR 3663-3p, hsa-miR-423-5p and hsa-miR-575 were upregulated in tissue samples. In maternal plasma, two miRNAs (hsa-let-7c, hsa-miR-122) were upregulated and one miRNA (hsa-miR-135a) was downregulated. A total of 6 out of 7 dysregulated miRNAs were validated using RT-qPCR. The target genes of these dysregulated miRNAs were detected using the GeneSpring database. The aim of the present study was to detect dysregulated miRNAs in maternal plasma and villous cells and identify the target genes of dysregulated miRNAs and their associated pathways. The target gene analyses have revealed that the affected genes are primarily associated with cell migration, proliferation, implantation, adhesion, angiogenesis and differentiation and all are involved with EPL pathogenesis. Therefore, the present study may contribute to the understanding of the molecular mechanisms which lead to EPL. PMID- 29393377 TI - BCL6B suppresses proliferation and migration of colorectal carcinoma cells through inhibition of the PI3K/AKT signaling pathway. AB - B-cell CLL/lymphoma 6 member B (BCL6B), a BCL6-homologous gene, has been reported to be a tumor suppressor that is silenced in a variety of human cancers, including colorectal cancer (CRC). Although it was recently demonstrated that reduced expression of BCL6B is associated with tumor stage and lymph node metastasis in CRC, little is known on whether BCL6B contributes to CRC development, or the related underlying mechanism. The aim of the present study was to detect BCL6B expression in CRC cells, and determine the molecular mechanisms underlying the role of BCL6B in CRC development by investigating cell proliferation and migration in vitro. As a result, BCL6B expression was found to be notably repressed in CRC cells compared with normal intestinal epithelial cells by reverse transcription-polymerase chain reaction and western blot analysis. CRC cell proliferation was significantly inhibited by BCL6B upregulation, as indicated by MTT and colony-forming assays. Cell apoptosis was markedly induced, as indicated by flow cytometry, and BCL6B-transfected CRC cells exhibited decreased migration ability. Additionally, BCL6B overexpression diminished the phosphorylation level of AKT in CRC cells. These effects of BCL6B were empowered by treatment with the specific phosphoinositide 3 kinase (PI3K)/AKT inhibitor LY294002. Furthermore, overexpression of BCL6B resulted in upregulation of E-cadherin and downregulation of cyclin D1 and matrix metalloproteinase-9, which were strongly enhanced by LY294002. In conclusion, the findings of the present study demonstrated that BCL6B suppressed the proliferation and migration of CRC cells indirectly, via inhibition of PI3K. PMID- 29393379 TI - Role of microRNAs in progenitor cell commitment and osteogenic differentiation in health and disease (Review). AB - MicroRNAs (miRNAs) are considered 'micro- managers of gene expression' and awareness of their fundamental role in the control of biological functions is constantly increasing. Bone formation and homeostasis are complex processes involving the differentiation and interaction of various cell types. Several miRNAs have been shown to be involved in different pathways and stages in the regulation of normal and abnormal bone formation and turnover. This present review focuses on the involvement of miRNAs in terms of their effect on the commitment of bone marrow mesenchymal stem cells towards osteogenesis, adipogenesis and chondrogenesis, respectively. The miRNAs involved in regulating osteoblast, chondroblast and osteoclast activity, are also taken into consideration, as are their interactions. miRNA expression levels, which may differ significantly in healthy versus pathological conditions, can be readily monitored and represent useful biomarkers. Several studies have suggested that miRNAs offer potential as useful biomarkers of bone pathologies, including osteoporosis and osteosarcoma. The development of efficient methods of delivering miRNA mimics or miRNA inhibitors into specific cells remains a challenge for novel therapeutic applications in the field of personalized medicine. PMID- 29393380 TI - Annexin A9 promotes invasion and metastasis of colorectal cancer and predicts poor prognosis. AB - Annexin A9 (ANXA9), a member of annexin family, has been reported be associated with colorectal cancer (CRC) carcinogenesis. However, the clinical significance of ANXA9 in CRC, particularly its correlation to invasion and metastasis remains ambiguous. The aim of the present study was to investigate the significance of ANXA9 in CRC and understand the molecular mechanism of ANXA9 in CRC invasion and metastasis. Expression levels of the ANXA9 protein in CRC tissues were detected using immunohistochemistry (IHC), and the clinical and prognostic value of ANXA9 was investigated. ANXA9-siRNA was utilized to investigate the effect and molecular mechanism of ANXA9 in HCT116 cells. The IHC result demonstrated that the positivity rate of the ANXA9 protein in CRC tissue was significantly higher than that in adjacent mucosa (P<0.05), which was consistent with the western blot results. ANXA9 protein expression levels are associated with invasion depth and lymphatic metastasis. Furthermore, patients with ANXA9-positive expression demonstrated a poor prognosis and ANXA9 was an independent risk factor for survival (P<0.05). After inhibiting ANXA9 in HCT116 cells, the activity and metastatic and invasion capacity of cells decreased significantly, and expression levels of ADAM metallopeptidase domain 17 and matrix metallopeptidase 9 were significantly downregulated, while the expression levels of tissue inhibitors of metalloproteinases-1 and E-cadherin were upregulated (P<0.05). Thus, positive ANXA9 expression may present as a novel marker for predicting poor prognosis in CRC patients, and ANXA9 may promote the invasion and metastasis of CRC by regulating invasion and metastasis-associated genes. PMID- 29393381 TI - Feasibility analysis of treating severe intrauterine adhesions by transplanting menstrual blood-derived stem cells. AB - Intrauterine adhesions (IUA) are associated with the loss of stem cells in the endometrium. Menstrual blood-derived stem cells (MenSCs) can be isolated from the menstrual blood and differentiated into endometrial cells. To check the transplantation feasibility of MenSCs for the treatment of severe IUA, MenSCs were isolated from menstrual blood, cultured in Dulbecco's modified Eagle's medium (DMEM), identified by immunocytochemistry and flow cytometry, differentiated into endometrial cells in vitro, and finally transplanted into the axillary subcutaneous tissue of non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice to create endometrial tissue. Additionally, the cloning efficiency and POU domain class 5 transcription factor 1 (OCT-4) positivity of MenSCs from patients with severe IUA were compared with those from healthy women. Immunocytochemistry and flow cytometry results showed that 95.1+/ 0.8% cells were OCT-4-positive, 0.9+/-0.4% were cluster of differentiation (CD)45 positive, 1.8+/-0.9% were STRO-1-positive and 1.0+/-0.4% were human leukocyte antigen-antigen D related-positive. Following differentiation in vitro, the results of immunocytochemistry, reverse transcription-polymerase chain reaction and western blot analysis showed that the expression of cytokeratin (CK) and vimentin (VIM) was increased in MenSCs compared with that in control subjects. Subsequent to transplantation in mice administered with sequential 17beta estradiol and progesterone, CK, VIM, estrogen receptor and progesterone receptor were expressed in the transplantation regions, suggesting that MenSCs could differentiate into endometrial tissues in vivo. The cloning efficiency and OCT-4 positivity of MenSCs from patients with severe IUA was significantly decreased. In conclusion, to the best of our knowledge, this is the first study in which MenSCs could differentiate into endometrial cells in vitro and create endometrial tissue in NOD-SCID mice in vivo, with impaired cloning efficiency and OCT-4 expression of MenSCs from patients with IUA. This study will provide a theoretical basis for the treatment of IUA with MenSCs. PMID- 29393378 TI - Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review). AB - Human papilloma viruses (HPV) are a small group of non-enveloped viruses belonging to the Papillomaviridae family with strong similarities to polyoma viruses. The viral particles consist of a genome in the form of a circular double stranded DNA, encompassing eight open reading frames, as well as a non-enveloped icosahedral capsid. HPV infection is considered the most common sexually transmitted disease in both sexes and is strongly implicated in the pathogenesis of different types of cancer. 'High-risk' mucosal HPV types, predominantly types 16, 18, 31, 33 and 35, are associated with most cervical, penile, vulvar, vaginal, anal, oropharyngeal cancers and pre-cancers. Screening for HPV is necessary for the prognosis and for determining treatment strategies for cancer. Novel HPV markers, including proteomic and genomic markers, as well as anti papillomavirus vaccines are currently available. The aim of this comprehensive review was to thoroughly present the updated information on virus development, cancer occurrence, treatment and prevention strategies, in an attempt to shed further light into the field, including novel research avenues. PMID- 29393382 TI - Nano-hydroxyapatite/collagen film as a favorable substrate to maintain the phenotype and promote the growth of chondrocytes cultured in vitro. AB - Autologous chondrocyte implantation (ACI) has emerged as a novel approach to cartilage repair through the use of harvested chondrocytes. However, the expansion of the chondrocytes from the donor tissue in vitro is restricted by the limited cell numbers and the dedifferentiation of the chondrocytes. The present study investigated the effect of collagen-based films, including collagen, hydroxyapatite (HA)/collagen (HC) and in situ synthesis of nano-HC (nHC), on monolayer cultures of chondrocytes. As a substrate for the chondrocytes monolayer culture in vitro, nHC was able to restrain the dedifferentiation of chondrocytes and facilitate cell expansion, which was detected by methyl thiazolyl tetrazolium assay, scanning electron microscopy, calcein-acetoxymethyl/propidium iodide staining, hematoxylin and eosin staining, Safranin O staining, immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. Furthermore, the nHC films significantly facilitated cell growth and enhanced the expression of cartilage-specific extracellular matrix (ECM) components, including aggrecan and type II collagen. In addition, nHC films markedly downregulated the expression of collagen type I, an indicator of dedifferentiation. The results indicated that nHC, a collagen-based substrate optimized by nanoparticles, was able to better support cell growth and preserve cell phenotype compared with collagen alone or HC. The nHC film, which favors cell growth and prevents the dedifferentiation of chondrocytes, may therefore serve as a useful cartilage-like ECM for chondrocytes. In conclusion, nHC film is a promising substrate for the culture of chondrocytes in cell-based therapy. PMID- 29393383 TI - Functional role of miR-27b in the development of gastric cancer. AB - Previous studies have demonstrated that microRNAs (miRNAs/miRs) act as tumor suppressors or oncogenes during multiple processes in cancer. It has been observed that miR-27b may act as a tumor-suppressor and was significantly downregulated in a number of types of cancer. However, the functions of miR-27b in gastric cancer (GC) remain unclear. The present study aimed to investigate the functional role of miR-27b in the progression of GC. The downregulation of miR 27b in human GC plasma was confirmed using miRNA microarray and reverse transcription-quantitative polymerase chain reaction analyses. The association between circulating miR-27b expression and clinicopathological features of GC was analyzed and the results demonstrated that the level of circulating miR-27b was significantly correlated with GC differentiation. Receiver operating characteristic curve analysis identified that the plasma level of miR-27b may be a potential biomarker for differentiating patients with GC from healthy controls. In order to investigate the effect of miR-27b on GC cell behavior, miR-27b was overexpressed using miR-27b mimics, and it was observed that miR-27b was able to inhibit cell proliferation and induce apoptosis in SGC7901 cells. Previous studies have demonstrated that vascular endothelial growth factor C (VEGFC) is a target of miR-27b, and the results of the present study were consistent with these reports. Taken together, the results of the present study indicated that miR-27b may act as a potential biomarker for differentiating patients with GC from healthy controls, and serve as a tumor suppressor in GC by targeting VEGFC. PMID- 29393384 TI - Carbon monoxide releasing molecule-3 promotes the osteogenic differentiation of rat bone marrow mesenchymal stem cells by releasing carbon monoxide. AB - Stem cell-based therapies are promising strategies to stimulate bone regeneration. Carbon monoxide releasing molecule-3 (CORM-3) exhibits multiple regulatory effects in a number of cells by releasing carbon monoxide (CO). The present study aimed to investigate the influence of CORM-3 on the osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs). BMSCs were divided into five groups: A CORM-3-osteogenic group, in which cells were pretreated with CORM-3 and subjected to osteogenic differentiation induction using osteogenic medium; an osteogenic group, in which cells were cultured in osteogenic medium; a degassed CORM-3-osteogenic group, in which cells were pretreated with degassed CORM-3 and subjected to osteogenic differentiation induction; a CORM-3 group, in which cells were cultured in control medium containing CORM-3; and a control group, in which cells were cultured in control medium alone. The osteo-specific mRNA and protein expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN) and osteopontin (OPN) were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Alkaline phosphatase (ALP) activity was also examined and mineralization was detected using alizarin red staining. Levels of Runx2, OCN and OPN mRNA and protein in the CORM-3-osteogenic group were significantly increased compared with the osteogenic group (P<0.05), with the exception of OCN protein levels on day 3. The mRNA and protein expression of Runx2, OCN and OPN in the degassed CORM-3-osteogenic and osteogenic groups were similar. In addition, the mRNA and protein expression of Runx2, OCN and OPN in the CORM-3 and control group were similar. ALP activity in the CORM-3-osteogenic group was increased from day 3 and remained significantly higher compared with all other groups on days 3, 5 and 7 (P<0.05). Additionally, the results indicated that the optical density value of alizarin red staining in the CORM-3-osteogenic group was significantly increased compared with the other groups (P<0.05). Therefore, the present study demonstrated that CORM-3 may promote the osteogenic differentiation of BMSCs by releasing CO. PMID- 29393385 TI - BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells. AB - BI2536 is a highly selective and potent inhibitor of polo-like kinase 1 (PLK1). In this study, we aimed to determine whether BI2536 and cisplatin can synergistically inhibit the malignant behavior of gastric cancer cells. For this purpose, the expression of PLK1 in gastric cancer cells was determined. The effects of BI2536, cisplatin, and the combination of BI2536 and cisplatin on gastric cancer cell viability, invasion, cell cycle arrest and apoptosis were assessed. Furthermore, the expression of cell cycle-regulated proteins was examined. Moreover, the differentially expressed proteins between the SGC-7901 and SGC-7901/DDP (cisplatin-resistant) cells, and the enriched signaling pathways were analyzed by protein pathway array following treatment with BI2536 (IC50) for 48 h. Our results revealed that PLK1 was upregulated in the SGC-7901/DDP (cisplatin-resistant) gastric cancer cells compared with the SGC-7901 cells. BI2536 enhanced the inhibitory effect of cisplatin on SGC-7901 cell viability and invasion. BI2536 induced G2/M arrest in SGC-7901 and SGC-7901/DDP cells. BI2536 promoted cisplatin-induced gastric cancer SGC-7901/DDP cell apoptosis. It also induced the differential expression of 68 proteins between the SGC-7901 and SGC 7901/DDP cells, and these differentially expressed proteins were involved in a number of cellular functions and signaling pathways, such as cell death, cell development, tumorigenesis, the cell cycle, DNA duplication/recombination/repair, cellular movement, and the Wnt/beta-catenin and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)/ribosomal S6 kinase 1 (RSK1) signaling pathways. On the whole, our findings suggest that BI2536 and cisplatin synergistically inhibit the malignant behavior of SGC-7901/DDP (cisplatin resistant) gastric cancer cells. PMID- 29393386 TI - Adaptive unfolded protein response promotes cell survival in rifampicin-treated L02 cells. AB - An important concept in drug-induced liver injury (DILI) is adaptation, which means the injury reverses with the continuation of the drug. The mechanism of adaption of drugs remains enigmatic, adaptive unfolded protein response (UPR) is possibly involved. We once observed adaptation phenomenon of rifampicin (RFP) in animal models, in this study, we investigate the effects of RFP on adaptive UPR in L02 cells, and after inhibiting UPR by using 4-phenylbutyrate (4-PBA), the change of cell viability and cell apoptosis in RFP-treated cells. We found that with the concentration of RFP increased and the treatment time was prolonged, the glucose-regulated protein 78 (GRP78), a hallmark of the UPR, was upregulated, and was dose- and time-dependent. RFP also activates the p-eukaryotic initiation factor 2alpha (eIF2alpha) protein expression. 4-PBA decreased GRP78 and p eIF2alpha protein expression levels. Moreover, FCA showed that cell apoptosis rate obviously increased, and MTT assay showed that cell survival rate obviously decreased, this indicates that after inhibiting the UPR, the cell damage increased, which shows that the UPR is an adaptation mechanism to protect cells against injury induced by RFP. This also proves that when the degree of UPR induced by RFP is relatively mild, adaptive UPR is helpful for cell survival. PMID- 29393387 TI - Microenvironment-driven resistance to B-Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts. AB - The incidence of malignant melanoma is rapidly increasing and current medicine is offering only limited options for treatment of the advanced disease. For B-Raf mutated melanomas, treatment with mutation-specific drug inhibitors may be used. Unfortunately, tumors frequently acquire resistance to the treatment. Tumor microenvironment, namely cancer-associated fibroblasts, largely influence this acquired resistance. In the present study, fibroblasts were isolated from a patient suffering from acrolentiginous melanoma (Breslow, 4.0 mm; Clark, IV; B Raf V600E mutated). The present study focused on the expression of structural and functional markers of fibroblast activation in melanoma-associated fibroblasts (MAFs; isolated prior to therapy initiation) as well as in autologous control fibroblasts (ACFs) of the same patient isolated during B-Raf inhibitor therapy, yet before clinical progression of the disease. Analysis of gene transcription was also performed, as well as DNA methylation status analysis at the genomic scale of both isolates. MAFs were positive for smooth muscle actin (SMA), which is a marker of myofibroblasts and the hallmark of cancer stoma. Surprisingly, ACF isolated from the distant uninvolved skin of the same patient also exhibited strong SMA expression. A similar phenotype was also observed in control dermal fibroblasts (CDFs; from different donors) exclusively following stimulation by transforming growth factor (TGF)-beta1. Immunohistochemistry confirmed that melanoma cells potently produce TGF-beta1. Significant differences were also identified in gene transcription and in DNA methylation status at the genomic scale. Upregulation of SMA was observed in ACF cells at the protein and transcriptional levels. The present results support recent experimental findings that tumor microenvironment is driving resistance to B-Raf inhibition in patients with melanoma. Such an activated microenvironment may be viable for the growth of circulating melanoma cells. PMID- 29393389 TI - [Corrigendum] miRNA-1207-5p is associated with cancer progression by targeting stomatin-like protein 2 in esophageal carcinoma. AB - An interested reader drew to our attention that, in the above-mentioned article, there were two figures where identity in certain of the data was shared between panels within the same figure. First, in Fig. 3B, the data shown for the EC9706 cell line/negative control (NC) experiment were derived from the same original source as those for the EC-1/Blank control experiment. Secondly, in Fig. 6B the Bcl-2 bands for the two different cell lines, EC9706 and EC-1, were inadvertently duplicated (the data shown for the EC9706 cell line were correct). We have reviewed the original files and the individual figures for the submitted composite figures, and realize that the errors occurred when we produced the composite figures. The same images were accidentally inserted twice in Figs. 3 and 6 without us being fully aware of the error. We have identified all the original images, and the corrected versions of Figs. 3 and 6 are shown opposite. We regret that these errors went unnoticed prior to publication, and thank the Editor for affording us the opportunity to publish this Corrigendum. We also regret any inconvenience caused to the readership of the journal. [the original article was published in the International Journal of Oncology 46: 2163-2171, 2015; DOI: 10.3892/ijo.2015.2900]. PMID- 29393388 TI - Hypoxia-induced autophagy is inhibited by PADI4 knockdown, which promotes apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis. AB - Impaired apoptosis of rheumatoid arthritis (RA)-fibroblast-like synoviocytes (FLS) is pivotal in the process of RA. Peptidyl arginine deiminase type IV (PADI4) is associated with autoantibody regulation via histone citrullination in RA. The present study aimed to investigate the role of PADI4 in the apoptosis of RA-FLS. FLS were isolated from patients with RA and a rat model. The effects of PADI4 on RA-FLS were investigated in vitro and in vivo. Hypoxia-induced autophagy was induced by 1% O2 and was detected by immunohistochemical and immunofluorescence analysis; in addition, apoptosis was detected by flow cytometry. RA-FLS obtained from RA rat model exhibited significant proliferation under severe hypoxia conditions. Hypoxia also significantly induced autophagy and elevated the expression of PADI4. Subsequently, short hairpin RNA-mediated PADI4 knockdown was demonstrated to significantly inhibit hypoxia-induced autophagy and promote apoptosis in RA-FLS. The results of these in vitro and in vivo studies suggested that PADI4 may be closely associated with hypoxia-induced autophagy, and the inhibition of hypoxia-induced autophagy by PADI4 knockdown may contribute to an increase in the apoptosis of RA-FLS. PMID- 29393390 TI - miR-149-5p promotes chemotherapeutic resistance in ovarian cancer via the inactivation of the Hippo signaling pathway. AB - Chemotherapeutic resistance remains a critical clinical issue is responsible for treatment failure in patients with ovarian cancer. Evidence of the involvement of miRNAs in chemoresistance in ovarian cancer has been recently emerging. However, the underlying molecular links between chemoresistance and miRNAs remain largely unknown. In this study, we report that miR-149-5p expression is markedly elevated in chemoresistant ovarian cancer tissues compared with the chemosensitive ovarian cancer tissues. Furthermore, the silencing of miR-149-5p enhanced the chemosensitivity of ovarian cancer cells to cisplatin in vitro and in vivo. Conversely, the upregulation of miR-149-5p aggravated chemoresistance in ovarian cancer cells. Our results further revealed that miR-149-5p directly targeted the core kinase components of the Hippo signaling pathway, STE20-like kinase (MST)1 and protein salvador homolog 1 (SAV1), resulting in the inactivation of TEA domain (TEAD) transcription. On the whole, our findings reveal a novel mechanism of of action miR-149-5p in inducing chemotherapeutic resistance in ovarian cancer, indicating that miR-149-5p may serve as a chemotherapeutic response indicator and a potential therapeutic target in ovarian cancer. PMID- 29393391 TI - Stage-dependent changes of beta2-adrenergic receptor signaling in right ventricular remodeling in monocrotaline-induced pulmonary arterial hypertension. AB - Right ventricular (RV) remodeling coupled with extensive apoptosis in response to unrestrained biomechanical stress may lead to RV failure (RVF), which is the immediate cause of death in the majority of patients with pulmonary arterial hypertension (PAH). Overexpression of beta2-adrenergic receptor (beta2-AR) signaling has been reported to induce myocardiotoxicity in patients with left heart failure. However, the role of beta2-AR signaling in the pathophysiology of PAH development has remained elusive. To address this issue, the present study investigated the changes in cardiopulmonary function and structure, as well as the expression of regulators of fibrosis and apoptosis in RVF following monocrotaline (MCT; 60 mg/kg, i.p.)-induced PAH in rats. Cardiopulmonary function and structure, remodeling and apoptosis, as well as G protein-coupled receptor (GPCR) and beta2-AR signaling, were documented over a period of 6 weeks. In the early stages, elevated pulmonary arterial pressure, pulmonary lesions, RV hypertrophy, evidence of left ventricular (LV) hyperfunction and accelerated heart rate were observed in animals with MCT-induced PAH. The levels of angiotensin II receptor type 1b (Agtr1b), Agtr2 and Agt were markedly upregulated and the expression of beta2-AR phospho-Ser(355,356) steadily decreased in the right heart. As the disease progressed, LV dysfunction was observed, as evidenced by decreased LV systolic pressure and increased LV end-diastolic pressure, which was accompanied by a sustained increase in circulating brain natriuretic peptide levels. Of note, increased levels of cardiomyocyte apoptosis and concomitant RV remodeling, including hypertrophy, dilatation, inflammation and fibrosis, were observed, despite the enhanced RV contractility. Furthermore, alterations in GPCR signaling and activation in beta2-AR-Gs-protein kinase A/Ca2+/calmodulin dependent kinase II signaling were observed in the late stages of PAH. These results suggested that treatment with MCT results in adaptive and maladaptive RV remodeling and apoptosis during the progression of PAH, which is accompanied by distinct changes in the beta2-AR signaling. Therefore, these results enable researchers to better understand of pathophysiology of MCT-induced PAH, as well as to determine the effects of novel therapies. PMID- 29393392 TI - MicroRNA-139-5p/Flt1/Wnt/beta-catenin regulatory crosstalk modulates the progression of glioma. AB - Fms-related tyrosine kinase 1 (Flt1), the receptor of VEGF/PIGF, is associated with cancer angiogenesis and tumorigenesis. Although the high expression of Flt1 in glioma is identified, its regulatory mechanism remains unclear. In the present study, we demonstrate that miR-139-5p inhibits Flt1 expression mediated by binding its 3' untranslated region (3'UTR) to regulate the progression of human glioma. We found miR-139-5p was downregulated in glioma tissues compared with normal brain tissues whereas a converse expression level of Flt1 was observed. Additionally we proved that miR-139-5p directly integrated with the 3'UTR of Flt1 via luciferase activity assay and cells transfected with miR-139-5p characterized with a low expression of Flt1 in mRNA and protein levels. Furthermore, we validated that miR-139-5p enforced its biological modulation via targeting Flt1 through rescue experiments. miR-139-5p suppressed and Flt1 stimulated the malignant activities of glioma cells. We demonstrated that miR-139-5p inhibited the Flt1-mediated Wnt/beta-catenin signaling pathway in glioma cells. Conclusively, our study indicated that miR-139-5p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the Flt1-mediated Wnt/beta catenin signaling pathway. PMID- 29393393 TI - RNF113A promotes the proliferation, migration and invasion, and is associated with a poor prognosis of esophageal squamous cell carcinoma. AB - Ring finger protein 113A (RNF113A) possesses a C3HC4 zinc finger domain and this domain is found in E3 ubiquitin ligase and is involved in tumorigenesis. To date, and at least to the best of our knowledge, there are no studies available which have investigated RNF113A in cancer. Thus, this study aimed to explore the role of RNF113A in the development of esophageal squamous cell carcinoma (ESCC). For this purpose, paraffin-embedded samples from 117 patients with ESCC were selected, as well as 41 pairs of fresh-frozen ESCC and adjacent normal tissue samples. RNF113A expression was examined by immunohistochemistry and reverse transcription-quantitative PCR (RT-qPCR). RNF113A was overexpressed or silenced in the EC9706 and Eca109 cells. The cells were examined for cell cycle progression, apoptosis, invasiveness and migration. Xenograft tumors were also created in mice using the Eca109 cells. Tumor differentiation (P=0.008) and T classification (P<0.001) were found to be significantly associated with RNF113A expression. No statistically significant association was observed between RNF113A expression and sex, age, histological type, tumor location and lymph node metastasis (N classification). Kaplan-Meier analysis revealed that the patients with ESCC with ahigh expression of RNF113A had a lower survival rate than those with a low expression (P=0.002). Multivariate analysis revealed that RNF113A expression (HR=2.406; 95% CI, 1.301-4.449, P=0.005) was independently associated with overall survival in patients with ESCC. The overexpression of RNF113A promoted proliferation, migration, and invasiveness of ESCC cell lines in vitro, and RNF113A silencing reversed these malignant behaviors. RNF113A knockdown inhibited tumor growth in vivo. Thus, these results indicate that RNF113A promotes the proliferation, migration and invasiveness of ESCC cell lines. RNF113A expression in ESCC is this associated with a poor prognosis of affected patients. PMID- 29393394 TI - Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury. AB - Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-gamma, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-gamma may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain. PMID- 29393395 TI - Interleukin-1beta induces intercellular adhesion molecule-1 expression, thus enhancing the adhesion between mesenchymal stem cells and endothelial progenitor cells via the p38 MAPK signaling pathway. AB - Endothelial progenitor cells (EPCs) are an important component of stem-cell niches, which are able to promote the self-renewal and pluripotency of mesenchymal stem cells (MSCs). The biological functions of these two cell types is dependent on adhesion, and the adhesion between MSCs and EPCs is important due to their critical role in neovascularization and bone regeneration in tissue engineering. Intercellular adhesion molecule-1 (ICAM-1, also known as cluster of differentiation 54), is a member of the immunoglobulin supergene family, which functions in cell-cell and cell-matrix adhesive interactions. Compared with other adhesion molecules, ICAM-1 is expressed in hematopoietic and nonhematopoietic cells, and can mediate adhesive interactions. The present study aimed to investigate the importance of ICAM-1 in the adhesion of MSCs and EPCs, and demonstrated that adhesion between these cells could be regulated by interleukin (IL)-1beta via the p38 mitogen-activated protein kinase pathway. In addition, the results confirmed that ICAM-1 served a critical role in regulation of adhesion between MSCs and EPCs. ELISA, cell immunofluorescence, western blot analysis and adhesion assay were used to confirm our theory from phenomenon to essence. The present study provided evidence to support and explain the adhesion between MSCs and EPCs. Furthermore, the present findings provide a theoretical basis for further stem-cell niche transplantation to increase understanding of the function of MSCs and the crosstalk between MSCs and EPCs in the stem-cell niche. PMID- 29393396 TI - PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis. AB - 6-Phosphofructo 2-kinase/fructose 2, 6-bisphosphatase 3 (PFKFB3) has been reported to be overexpressed in human cancer tissues and to promote the proliferation and migration of cancer cells. However, the role of PFKFB3 in the progression and prognosis of breast cancer is not yet fully understood. In the present study, we investigated the specific role of PFKFB3 in breast cancer progression and its preliminary mechanisms of action. We first used an immunohistochemistry assay to determine that PFKFB3 was highly expressed in breast cancer tissues and that this high level of expression was involved in the poor overall survival of patients with breast cancer. In addition, the suppression of PFKFB3 by lentiviruses carrying shRNA against PFKFB3 (shPFKFB3) subsequently inhibited breast cancer cell (MDA-MB-231 and MDA-MB-468) proliferation, migration and invasion, and induced cell cycle G1 and S phase arrest in vitro. Moreover, PFKFB3 inhibition decreased p-AKT and increased p27 expression levels in breast cancer cells. Furthermore, PFKFB3 suppression inhibited breast cancer cell tumor xenograft growth in nude mice. We also found that PFKFB3 inhibition suppressed vascular endothelial growth factor alpha (VEGFalpha) protein expression and inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs). On the whole, our results indicate that PFKFB3 is involved in the proliferation, migration, invasion and angiogenesis of breast cancer. PMID- 29393397 TI - Development of single nanometer-sized ultrafine oxygen bubbles to overcome the hypoxia-induced resistance to radiation therapy via the suppression of hypoxia inducible factor-1alpha. AB - Radiation therapy can result in severe side-effects, including the development of radiation resistance. The aim of this study was to validate the use of oxygen nanobubble water to overcome resistance to radiation in cancer cell lines via the suppression of the hypoxia-inducible factor 1-alpha (HIF-1alpha) subunit. Oxygen nanobubble water was created using a newly developed method to produce nanobubbles in the single-nanometer range with the SigmaPM-5 device. The size and concentration of the oxygen nanobubbles in the water was examined using a cryo transmission electron microscope. The nanobubble size was ranged from 2 to 3 nm, and the concentration of the nanobubbles was calculated at 2x1018 particles/ml. Cell viability and HIF-1alpha levels were evaluated in EBC-1 lung cancer and MDA MB-231 breast cancer cells treated with or without the nanobubble water and radiation under normoxic and hypoxic conditions in vitro. The cancer cells grown in oxygen nanobubble-containing media exhibited a clear suppression of hypoxia induced HIF-1alpha expression compared to the cells grown in media made with distilled water. Under hypoxic conditions, the EBC-1 and MDA-MB231 cells displayed resistance to radiation compared to the cells cultured under normoxic cells. The use of oxygen nanobubble medium significantly suppressed the hypoxia induced resistance to radiation compared to the use of normal medium at 2, 6, 10 and 14 Gy doses. Importantly, the use of nanobubble media did not affect the viability and radiation sensitivity of the cancer cell lines, or the non cancerous cell line, BEAS-2B, under normoxic conditions. This newly created single-nanometer range oxygen nanobubble water, without any additives, may thus prove to be a promising agent which may be used to overcome the hypoxia-induced resistance of cancer cells to radiation via the suppression of HIF-1alpha. PMID- 29393398 TI - Structural characterization, immune regulation and antioxidant activity of a new heteropolysaccharide from Cantharellus cibarius Fr. AB - A new heteropolysaccharide was extracted and purified from the fruiting bodies of Cantharellus cibarius Fr. The Cantharellus cibarius Fr. polysaccharide (CC-1) had a molecular weight of 61,056 kDa and was mainly formed of the glucose and xylose at ratio of 5:1. Structure identification of CC-1 was analysed by a combined application of total hydrolysis, high performance liquid chromatography (HPLC), methylation analysis, gas chromatography-mass spectrometry (GC-MS), infrared (IR) spectra and nuclear magnetic resonance (NMR) spectroscopy. The experimental results showed that CC-1 had a backbone of 1,4-linked-beta-D-glucose which branched at O-6 and the branches were mainly composed of 6->1)-alpha-D xylopyranose residue. CC-1 exhibited significant in vitro antioxidant effect and proliferation effect of immune cells. The activity study showed CC-1 has ability to clear the ABTS+ free radical and DPPH- free radical in a certain range of concentration. The proliferation activity of the immune cells showed that the proliferation effect on B cells was very significant (P<0.001) in the concentration of 0.625-80 mg/ml; and the effect of T cell proliferation was also very significant (P<0.001) in the concentration of 5-20 mg/ml. The result of this study introduced Cantharellus cibarius Fr. as a possible valuable source in exhibiting unique immunoregulatory and antioxidant properties. PMID- 29393399 TI - Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells. AB - Reduced-gliotoxin is a small molecule derived from the secondary metabolites of marine fungi; compared to other gliotoxin analogues, it exhibits potent anticancer effects. However, the molecular basis of the death of colorectal cancer (CRC) cells induced by reduced-gliotoxin is unclear. Thus, the aim of this study was to investigate the potency of reduced-gliotoxin against CRC cells and to elucidate the underlying mechanisms. Cell morphology, flow cytometric analysis and western bolt analysis were performed to examine the functions and mechanisms of cell death induced by reduced-gliotoxin. Our findings demonstrated that reduced-gliotoxin triggered rapid cell detachment and induced anoikis in CRC cells. Mechanistically, our data indicated that the anoikis induced by reduced gliotoxin was associated with the disruption of integrin-associated cell detachment and multiple signaling pathways. Furthermore, reduced-gliotoxin induced the excessive production of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP), resulting in the activation of both endogenous and exogenous apoptotic pathways and eventually, in the apoptosis of CRC cells. The blockage of ROS generation with N-acetylcysteine (NAC) attenuated the anoikis induced by reduced-gliotoxin. Taken together, these results suggest that reduced-gliotoxin may prove to be a potential candidate in the treatment of CRC. PMID- 29393400 TI - beta-carotene reverses tobacco smoke-induced gastric EMT via Notch pathway in vivo. AB - Tobacco smoke is one of the serious risk factors of gastric cancer. Epithelial mesenchymal transition (EMT) has been shown to be associated with the initiation and carcinogenesis of gastric cancer. The role of Notch pathway in regulating tobacco smoke-induced EMT has not been investigated. beta-carotene, a carotenoid present in fruits, vegetables and rice, suppresses cancer progression. In this investigation, we evaluated the regulatory role of Notch pathway in tobacco smoke mediated gastric EMT and the preventive effect of beta-carotene using a BALB/c mouse smoking model. Exposure of mice to tobacco smoke reduced levels of epithelial markers, while the expression of mesenchymal markers were increased. We further found that Notch pathway modulated tobacco smoke-triggered EMT in the stomach of mice, as evidenced by these findings that tobacco smoke activated Notch activities, and tobacco smoke induced EMT was reversed by blocking Notch activities with FLI-06. Moreover, treatment of beta-carotene prevented tobacco smoke-mediated activation of Notch and EMT changes. Our data suggested that Notch regulate tobacco smoke induced gastric EMT and the protective effects of beta carotene in vivo. These findings may establish a new mechanism for tobacco smoke associated gastric tumorigenesis and its chemoprevention. PMID- 29393401 TI - Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species. AB - The majority of cancer cells maintain a high glycolytic activity and an increased lactate production, even in a well oxygenated environment. This phenomenon is known as the Warburg effect. Previous studies have revealed that various types of cancer selectively express the pyruvate kinase M2 isoform (PKM2), and that PKM2 plays a pivotal role in the Warburg effect. Although elevated PKM2 levels have been observed in pancreatic cancer and other types of cancer, little is known about the biological function of PKM2. In this study, in order to examine the expression and role of PKM2 in pancreatic ductal adenocarcinoma (PDAC), we knocked down PKM2 in PDAC cells by introducing small interfering and short hairpin RNAs, and examined the gene expression profiles in the cells by microarray analysis. We analyzed the energy-producing pathways in the cells by XFe Extracellular Flux Analyzers, and detected intracellular metabolites by capillary electrophoresis time-of-flight mass spectrometry. We found that the RNAi-mediated knockdown of PKM2 diminished the proliferative, migratory and tumorigenic ability of the PDAC cell-lines. PKM2 knockdown also resulted in lower glycolytic activities and decreased levels of some intracellular metabolites, such as pyruvate and polyamine; however, it led to elevated levels of reactive oxygen species. Microarray analysis revealed the functional association between PKM2 and the expression of genes that drive the cell cycle. On the whole, the findings of this study demonstrate that PKM2 plays an important role in metabolic activities, as well as in the malignancy of PDAC cells. PMID- 29393402 TI - Interplay between the NF-kappaB and hedgehog signaling pathways predicts prognosis in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy. AB - Tumor recurrence and metastasis in esophageal squamous cell carcinoma (ESCC) are primary causes of patient mortality. The nuclear factor (NF)-kappaB signaling pathway and hedgehog signaling pathway were previously reported to contribute to cell growth and metastasis in ESCC. The present study therefore investigated the roles of the NF-kappaB and hedgehog pathways in ESCC tumors following neoadjuvant chemoradiotherapy (NCRT). By immunohistochemistry staining, it was observed that NF-kappaB and glioma-associated oncogene homolog 1 (Gli1), key components of the NF-kappaB and hedgehog pathways, respectively, were decreased following NCRT, which was further confirmed by western blotting and reverse transcription quantitative polymerase chain reaction analysis. In addition, survival analysis suggested that high expression levels of either NF-kappaB or Gli1 were associated with poor overall survival (OS) of patients. In the esophageal cell line TE-8, NF kappaB and Gli1 formed a positive feedback loop, and inhibition of either NF kappaB or Gli1 may inhibit cell migration, invasion and proliferation. The results of the present study demonstrated that activation of the NF-kappaB and hedgehog signaling pathways limited the OS of patients with ESCC following NCRT, and may therefore be suitable targets for ESCC treatment. PMID- 29393403 TI - Reactive oxygen species mediated oxidative stress links diabetes and atrial fibrillation. AB - Diabetes is an independent risk factor for atrial fibrillation (AF); however, the underlying mechanism linking diabetes and AF remains to be clarified. The present study aimed to explore the molecular mechanism of increased reactive oxygen species (ROS) production in AF and the ROS-mediated downstream events in diabetes. Firstly, the atrial fibroblasts were isolated from the left atrium of rabbits using enzyme digestion and differential adhesion. Then, the isolated cells were identified by morphology analysis under a microscope, collagen distribution using Masson trichrome staining and vimentin by immunofluorescence. Following this, the collected atrial fibroblasts were randomly divided into 7 groups and administered with high glucose (25 mM glucose), H2O2 stimulation (100 nmol/l), glucose + apocynin (100 ug/ml), H2O2 + apocynin, glucose + H2O2, and a combination of glucose, apocynin and H2O2, as well as the negative control (NC). An MTS assay was performed to investigate cell proliferation following the different treatments, and western blotting was conducted to explore the expression of several proteins including NAD(P)H oxidative (NOX) subunits, key factors involved in mitogen-activated protein kinase (MAPK) signaling pathways and matrix metalloproteinases (MMPs). The atrial fibroblasts were spindle-shaped with one or more protuberances. Vimentin was positively expressed in collected cells under confocal laser scanning microscopy. This result indicated that the atrial fibroblasts were successfully prepared. High glucose and H2O2 stimulation significantly increased the proliferation of atrial fibroblasts and apocynin markedly attenuated the promoting effects on cell proliferation induced by high glucose and H2O2 treatment (P<0.05). Additionally, high glucose and H2O2 stimulation increased the expression of Rac1, phospho(p)-c-Jun N-terminal kinase 1, p38, p-p38 and MMP9, which was markedly decreased by the addition of apocynin (P<0.05). The mechanism associated with diabetes and AF may be attributed to oxidative stress (ROS production) derived from NOX activity, and then induced activation of the MAPK signaling pathways and MMP9 expression. PMID- 29393404 TI - Qiyusanlong decoction suppresses lung cancer in mice via Wnt/beta-catenin pathway. AB - Lung cancer is one of the most fatal cancers due to its high metastatic rate. Traditional Chinese medicine has been used in cancer patients for decades to improve quality of life and prolong survival time. The present study used a novel Qiyusanlong (QYSL) decoction composed of 10 kinds of Chinese medicine including astragalus membranaceus (Huangqi), polygonatumod oratum (yuzu), scolopendra (tianlong), pberetima (dilong), solanum nigrum (longkui), herbahedyotis (baihushecao), semen coicis (yiyiren), euphorbia helioscopia (zeqi), curcuma longa (eshu) and tendril-leaved fritillary bulb (chuanbei). The effects and function of the QYSL decoction remain to be elucidated. The present study established a mouse xenograft model using Lewis lung carcinoma cell injection and administered different doses of QYSL decoction to the mice. It was demonstrated that the chemotherapy drug Cisplatin (DDP) and QYSL decoction repressed lung tumor growth, and the inhibitory effect of DDP was more significant. Furthermore, QYSL decoction and DDP modulated the expression of regulatory proteins in the Wnt/beta-catenin pathway, including Wnt1, Wnt2, Wnt5a and glycogen synthase kinase 3beta, detected by western blotting, and affected the signals of cluster of differentiation 44 variation 6 and Survivin in tumor tissues, examined via immunohistochemistry. The combination of QYSL decoction and DDP enhanced the inhibitory effect. These data demonstrated that the QYSL decoction repressed lung tumor development via the Wnt/beta-catenin pathway. The therapeutic effect of QYSL decoction alone was milder compared with DDP, however the combination of QYSL decoction and chemotherapy exhibited an increased the rapeutic effect compared with the treatments administered alone. These findings revealed the function of QYSL decoction as a lung cancer treatment and provided insight for a novel lung cancer therapy. PMID- 29393405 TI - Aurora-A overexpression is linked to development of aggressive teratomas derived from human iPS cells. AB - The discovery of human induced pluripotent stem cells (hiPSCs) is a promising advancement in the field of regenerative and personalized medicine. Expression of SOX2, KLF4, OCT4 and MYC transcription factors induces the nuclear reprogramming of somatic cells into hiPSCs that share striking similarities with human embryonic stem cells (hESCs). However, several studies have demonstrated that hESCs and hiPSCs could lead to teratoma formation in vivo, thus limiting their current clinical applications. Aberrant cell cycle regulation of hESCs is linked to centrosome amplification, which may account, for their enhanced chromosomal instability (CIN), and thus increase their tumorigenicity. Significantly, the tumor suppressor p53 plays a key role as a 'guardian of reprogramming', safeguarding genomic integrity during hiPSC reprogramming. Nevertheless, the molecular mechanisms leading to development of CIN during reprogramming and increased tumorigenic potential of hiPSCs remains to be fully elucidated. In the present study, we analyzed CIN in hiPSCs derived from keratinocytes and established that chromosomal and mitotic aberrations were linked to centrosome amplification, Aurora-A overexpression, abrogation of p53-mediated G1/S cell cycle checkpoint and loss of Rb tumor-suppressor function. When hiPSCs were transplanted into the kidney capsules of immunocompromised mice, they developed high-grade teratomas characterized by the presence of cells that exhibited non uniform shapes and sizes, high nuclear pleomorphism and centrosome amplification. Significantly, ex vivo cells derived from teratomas exhibited high self-renewal capacity that was linked to Aurora-A kinase activity and gave rise to lung metastasis when injected into the tail vein of immunocompromised mice. Collectively, these findings demonstrated a high risk for malignancy of hiPSCs that exhibit Aurora-A overexpression, loss of Rb function, centrosome amplification and CIN. Based on these findings, we proposed that Aurora-A targeted therapy could represent a promising prophylactic therapeutic strategy to decrease the likelihood of CIN and development of aggressive teratomas derived from hiPSCs. PMID- 29393406 TI - Deoxycytidine kinase participates in the regulation of radiation-induced autophagy and apoptosis in breast cancer cells. AB - Deoxycytidine kinase (dCK) is a rate limiting enzyme critical for the phosphorylation of endogenous deoxynucleosides and for the anti-tumor activity of many nucleoside analogs. dCK is activated in response to ionizing radiation (IR) and it is required for the G2/M checkpoint induced by IR. However, whether dCK plays a role in radiation-induced autophagy and apoptosis is less clear. In this study, we reported that dCK decreased IR-induced total cell death and apoptosis, and increased IR-induced autophagy in SKBR3 and MDA-MB-231 breast cancer cell lines. A molecular switch exists between apoptosis and autophagy. We further demonstrated that serine 74 phosphorylation was required for the regulation of autophagy. In dCK wild-type (WT) or dCK S74E (mutant) MDA-MB-231 cell models, the expression levels of phospho-Akt, phospho-mammalian target of rapamycin (mTOR) and phospho-P70S6K significantly decreased following exposure to IR. Moreover, the ratio of Bcl-2/Beclin1 (BECN1) significantly decreased in the S74E mutant cells; however, no change was observed in the ratio of Bcl-2/BAX. Taken together, our findings indicate that phosphorylated and activated dCK inhibits IR-induced total cell death and apoptosis, and promotes IR-induced autophagy through the mTOR pathway and by inhibiting the binding of Bcl-2 protein to BECN1. PMID- 29393407 TI - PARP1-siRNA suppresses human prostate cancer cell growth and progression. AB - Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion. Additionally, PARP1-siRNA also inhibited the proliferation of PC3 and Du145 cells. After the induction of apoptosis by docetaxel, cleaved-caspase3 of DU145 and C4-2 cells increased significantly in the PARP1-siRNA group. In the xenograft nude mouse model, PARP1-siRNA could suppress xenograft tumor size of PC3 cells and produce a more regular morphology. In vitro and in vivo, PARP1 silencing significantly downregulated vimentin expression and upregulated E cadherin expression, both of which are epithelial-mesenchymal transition (EMT) markers. It has been revealed that PI3K inhibition could sensitize the effect of PARPi. Notably, PARP1-siRNA could suppress the expression of EGFR and p-GSK3beta (Ser9) in PCa cells, which was different from PARPi. Our results indicated that PARP1-siRNA can suppress the growth and invasion capacity of PCa cells, thereby suggesting that PARP1-siRNA, which is different from PARPi, may provide a potential treatment method for PCa. PMID- 29393408 TI - Anticancer activity of the supercritical extract of Brazilian green propolis and its active component, artepillin C: Bioinformatics and experimental analyses of its mechanisms of action. AB - Propolis, a resinous substance collected by honeybees by mixing their saliva with plant sources, including tree bark and leaves and then mixed with secreted beeswax, possesses a variety of bioactivities. Whereas caffeic acid phenethyl ester (CAPE) has been recognized as a major bioactive ingredient in New Zealand propolis, Brazilian green propolis, on the other hand, possesses artepillin C (ARC). In this study, we report that, similar to CAPE, ARC docks into and abrogates mortalin-p53 complexes, causing the activation of p53 and the growth arrest of cancer cells. Cell viability assays using ARC and green propolis supercritical extract (GPSE) revealed higher cytotoxicity in the latter, supported by nuclear translocation and the activation of p53. Furthermore, in vivo tumor suppression assays using nude mice, we found that GPSE and its conjugate with gamma cyclodextrin (gammaCD) possessed more potent anticancer activity than purified ARC. GPSE-gammaCD may thus be recommended as a natural, effective and economic anticancer amalgam. PMID- 29393409 TI - miR-24-p53 pathway evoked by oxidative stress promotes lens epithelial cell apoptosis in age-related cataracts. AB - MicroRNA-24 (miR-24) serves an important role in cell proliferation, migration and inflammation in various types of disease. In the present study, the biological function and molecular mechanism of miR-24 was investigated in association with the progression of age-associated cataracts. To the best of our knowledge the present study is the first to report that the expression of miR-24 was significantly increased in human anterior lens capsules affected by age associated cataracts as well as lens epithelial cells (LECs) exposed to oxidative stress. Overexpression of miR-24 induced p53 expression and p53 was verified as a direct target of miR-24. Overexpression of miR-24 enhanced LEC death by directly targeting p53. The present study revealed that oxidative stress induced the upregulation of miR-24 and enhanced LEC death by directly targeting p53. These results suggest that the miR-24-p53 signaling pathway is involved in a novel mechanism of age-associated cataractogenesis and miR-24 may be a useful therapeutic target for age-associated cataracts. PMID- 29393410 TI - Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells. AB - An increasing amount of evidence indicates that the inhibition of beta adrenergic signaling can result in the inhibition of tumor growth. However, the role of propranolol in liver cancer and the underlying mechanism remain to be elucidated. The present study aimed to investigate the role of propranolol in liver cancer cell lines and provide evidence for further clinical study. Propranolol was added at different concentrations to HepG2 and HepG2.2.15 liver cancer cells and HL 7702 normal human liver cells. The proliferation of the cell lines was monitored by live-cell imaging at a range of time intervals. Immunofluorescence using DAPI and Hoechst 33342/propidium iodide (PI) staining, Annexin V-FITC/PI double staining flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction were used to investigate the effect of propranolol on liver cancer cell apoptosis. The proliferation of HepG2 and HepG2.2.15 cells was inhibited by 40 and 80 umol/l propranolol. However, the proliferation of HL-7702 cells was not affected by <160 umol/l propranolol. Propranolol treatment decreased the expression of adrenergic receptor beta-2 to a greater extent than adrenergic receptor beta-1, and induced apoptosis in the liver cancer cells. The apoptotic rates of HepG2 and HepG2.2.15 cells increased following treatment with propranolol, while the apoptotic rate of HL-7702 cells was not affected. Propranolol promoted poly (ADP-ribose) polymerase cleavage and decreased the expression of full-length caspase-3 in liver cancer cell lines; it induced S phase arrest in HepG2 and HepG2.2.15 cell lines, while HL-7702 cells were arrested at the G0/G1 phase of the cell cycle. Thus, it was demonstrated that propranolol inhibited proliferation, promoted apoptosis and induced S-phase arrest in HepG2 and HepG2.2.15 cells. PMID- 29393411 TI - Bu-Fei decoction and modified Bu-Fei decoction inhibit the growth of non-small cell lung cancer, possibly via inhibition of apurinic/apyrimidinic endonuclease 1. AB - Human apurinic/apyrimidinic endonuclease 1 (APE1) is a ubiquitous multifunctional protein, which possesses DNA repair and redox activities. High levels of APE1 are associated with chemo- and radioresistance, and poor prognosis in various types of cancer, including non-small cell lung cancer (NSCLC). Bu-Fei decoction (BFD) is a traditional Chinese herbal formula, which is believed to supplement Qi, clear away heat and nourish the lungs. BFD and modified Bu-Fei decoction (MBFD) have been used in China to treat patients with lung cancer. The present study aimed to evaluate the potential antitumor effects of BFD and MBFD on NSCLC in vitro and in vivo. In addition, the possible contribution of APE1 was examined. MTT assay was used to investigated the anti-tumor activity of BFD and MBFD on H1975 and H292 NSCLC cell lines. The DNA damage of cells in the control and the experimental groups was detected using comet assay. The in vivo anti-tumor effects of BFD and MBFD were evaluated in a NSCLC tumor nude mouse xenograft model. Polymerase chain reaction (PCR), reverse transcription-quantitative PCR (RT-qPCR) analysis and western blot analysis were applied to analyze the mRNA and protein expression levels of APE1 in H1975 and H292 cells, so as to the xenograft tumor tissues. The concentration of APE1 in mice plasma was determined using enzyme linked immunosorbent assay (ELISA). In vitro, BFD and MBFD inhibited the growth of cultured H1975 and H292 NSCLC cells. The results of a comet assay revealed that BFD and MBFD increased DNA damage. Furthermore, the expression levels of APE1 were decreased in response to BFD and MBFD at the mRNA and protein levels. In mice carrying NSCLC xenografts, BFD and MBFD inhibited tumor growth and decreased APE1 expression. In addition, in normal human lung bronchial epithelial BEAS-2B cells, the half maximal inhibitory concentrations of BFD and MBFD were much higher compared with in NSCLC cells, and they had no effect on DNA damage. These results suggested that BFD and MBFD may inhibit the growth of NSCLC, possibly by inhibiting APE1 expression. PMID- 29393412 TI - WWC3 inhibits intimal proliferation following vascular injury via the Hippo signaling pathway. AB - The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet-derived growth factor BB (PDGF-BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post-injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs. The results demonstrated that following injury, WWC3 expression was suppressed in VSMCs and the rat carotid artery, and the activity of the Hippo signaling pathway was significantly downregulated. In addition, the expression of YY1-associated protein-1 (YAP) and a number of its downstream target genes, including connective tissue growth factor (CTGF), were enhanced, thus enhancing the proliferation and migration of VSMCs. Knockdown of WWC3 suppressed the levels of large tumor suppressor kinase 1 (LATS1) expression and YAP phosphorylation, and the expression of YAP, CTGF and cyclin E was subsequently enhanced, thus promoting cell proliferation and migration. Similar results were obtained following overexpression of WWC3. Treatment with PDGF-BB was revealed to suppress the proliferation and migration of VSMCs transfected with the WWC3 plasmid, compared with VSMCs transfected with an empty vector. The present study demonstrated that WWC3 may interact with LATS1 in order to upregulate the Hippo signaling pathway via co-immunoprecipitation and enhancement of the phosphorylation of LATS1, in addition to the corresponding suppression of the nuclear import of YAP. However, VSMCs transfected with WWC3 plasmid with a deletion of the WW domain fail to exhibit this effect. These results suggested that WWC3 expression is downregulated in VSMCs during neointimal hyperplasia following injury (PDGF-BB stimulation or balloon injury). WWC3 upregulates the activity of the Hippo signaling pathway, and weakens the proliferation and migration of VSMCs. Furthermore, the results of the present study suggested that WWC3 may interact with LATS1 to promote the phosphorylation of YAP and reduce its nuclear translocation, upregulate the activity of the Hippo pathway, and suppress the proliferation and migration of VSMCs following injury. PMID- 29393413 TI - Suppressive effects of berberine on atherosclerosis via downregulating visfatin expression and attenuating visfatin-induced endothelial dysfunction. AB - Berberine (BBR) possesses significant anti-atherosclerosis properties. Visfatin is one of the most promising biomarkers of incoming atherosclerosis. However, research on the effect of BBR on regulating visfatin expression in atherogenesis remains largely unknown. In this study, we investigated the effects of BBR on visfatin expression and atherogenesis in apolipoprotein E knockout (ApoE-/-) mice. The effect of BBR on attenuating visfatin-induced endothelial dysfunction was also evaluated in cultured human umbilical vein endothelial cells (HUVECs). In vivo experiments showed that BBR treatment (5 mg/kg/day) significantly reduced the serum levels of visfatin, lipid, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), the protein expression of visfatin, p-p38 MAPK and p-c Jun N-terminal kinase (JNK) in mice aorta and the distribution of visfatin in the atherosclerotic lesions in ApoE-/- mice fed with a Western diet. In addition, in vitro experiments indicated that visfatin (100 ug/l) significantly increased apoptosis, the contents of IL-6 and TNF-alpha, the protein levels of p-p38 MAPK, p-JNK and Bax in HUVECs, which were reversed by BBR administration (50 umol/l). Our findings suggest that BBR significantly ameliorates Western diet-induced atherosclerosis in ApoE-/- mice via downregulating visfatin expression, which is related to the inhibition of p38 MAPK and JNK signaling pathways and subsequent suppression of visfatin-induced endothelial dysfunction. PMID- 29393414 TI - Baicalein induces cervical cancer apoptosis through the NF-kappaB signaling pathway. AB - To investigate the mechanism of baicalein in inducing human cervical cancer cell line C33A apoptosis. Baicalein (200 uM) was used to treat C33A cells. Cell proliferation was tested by the MTT assay. Cell apoptosis was detected by the TUNEL assay and caspase-3 activity measurement. Cell cycle was determined by flow cytometry and associated gene expression at mRNA and protein levels. Nuclear factor (NF)-kappaB activity was assessed by luciferase assay and western blotting. Baicalein suppressed cervical cancer cell C33A proliferation and induced cell apoptosis by activating caspase-3 activity. Baicalein blocked cell cycle in G0/G1 phase through regulating the expression of associated genes. Baicalein inhibited NF-kappaB activity by repressing nuclear translocation. Baicalein suppressed C33A proliferation and promoted cellular apoptosis by inhibiting NF-kappaB signaling pathway. In conclusion, the results indicate that baicalein can inhibit cervical cancer cell proliferation and promote cell apoptosis by affecting NF-kappaB activity. PMID- 29393415 TI - Identification of risk factors for sepsis-associated mortality by gene expression profiling analysis. AB - Sepsis is a common cause of mortality due to systemic infection. Although numerous studies have investigated this life-threatening condition, there remains a lack of suitable markers to evaluate the severity of sepsis. The present study focused on the identification of risk factors for sepsis-associated mortality by genome-wide expression profiling. Initially, the GEO2R web tool was used to identify the differentially expressed genes (DEGs) between sepsis survivors and nonsurvivors. It was identified that the upregulated DEGs in the nonsurvivors compared with survivors were highly enriched in the type I interferon (IFN-I) signaling pathway. Furthermore, the associations of the upregulated genes were analyzed by STRING and the results demonstrated that a set of proteins in IFN-I signaling pathway closely interacted with each other. To further investigate whether the IFN-I signaling pathway is dysregulated in a subset of patients with a high risk of mortality due to sepsis, in this case neonates, the DEGs between the cord blood mononuclear cells of neonates and adult peripheral blood mononuclear cells were analyzed. It was identified that DEGs were not enriched in IFN-I signaling in the blood of untreated neonates and adults; however, IFN-I signaling was upregulated in the lipopolysaccharide (LPS)-treated cord blood mononuclear cells of healthy neonates compared with the LPS-treated peripheral blood mononuclear cells of adults. In addition, these data revealed that the proteins involved in the IFN-I signaling pathway possessed a higher number of interacting partners. These results indicated that upregulated IFN-I signaling may be a high-risk factor for mortality due to sepsis. PMID- 29393416 TI - Interaction of colon cancer cells with glycoconjugates triggers complex changes in gene expression, glucose transporters and cell invasion. AB - Glycan metabolism balance is critical for cell prosperity, and macromolecule glycosylation is essential for cell communication, signaling and survival. Thus, glycotherapy may be a potential cancer treatment. The aim of the present study was to determine whether combined synthetic glycoconjugates (GCs) induce changes in gene expression that alter the survival of colon cancer cells. The current study evaluated the effect of the GCs N-acetyl-D-glucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold on cancer cell proliferation, apoptosis, invasion and sensitivity to immune cell-mediated killing. Using reverse transcription-quantitative polymerase chain reaction, the expression of genes involved in the aforementioned processes was measured. It was determined that GCs reduce the expression of the glucosaminyltransferases Mgat3 and Mgat5 responsible for surface glycosylation and employed components of the Wnt signaling pathway Wnt2B and Wnt9B. In addition, the calix[4]arene-based GC reduced cell colony formation; this was accompanied by the downregulation of the metalloproteinase Mmp3. By contrast, the dendrimer-based GC affected the expression of the glucose transporter components Sglt1 and Egfr1. Therefore, to the best of our knowledge, the present study is the first to reveal that N-acetyl D-glucosamine-dendrimer/calix[4]arene GCs alter mRNA expression in a comprehensive way, resulting in the reduced malignant phenotype of the colon cancer cell line HT-29. PMID- 29393417 TI - Involvement of TRPV1 in the expression and release of calcitonin gene-related peptide induced by rutaecarpine. AB - The traditional Chinese herb Wu-Chu-Yu has been used to treat hypertension for hundreds of years. A previous study indicated that rutaecarpine was the effective component of Wu-Chu-Yu, which lowered blood pressure by elevating the expression level of calcitonin gene-related peptide (CGRP). The present study was performed to investigate the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) in CGRP expression and release induced by rutaecarpine. Dorsal root ganglia (DRG) obtained from Sprague-Dawley rats were cultured to analyze the mRNA expression and release of CGRP. Calcium influx, as an indicator of TRPV1 activation, was measured in 293 cells with stable overexpression of TRPV1. The results demonstrated that the amount of CGRP in the cell culture supernatant and the mRNA expression of CGRPalpha and CGRPbeta in DRG was upregulated by rutaecarpine in a concentration-dependent manner, and was inhibited by the TRPV1 receptor antagonist capsazepine. In addition, intracellular Ca2+ levels were increased by Rut in the aforementioned 293 cell line, indicating the activation of TRPV1 by Rut. Therefore, it was concluded that TRPV1 was involved in the expression and release of CGRP stimulated by rutaecarpine, which provided novel mechanistic understanding of the treatment of hypertension using the Chinese herb Wu-Chu-Yu. PMID- 29393418 TI - Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. AB - Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required. Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels. In the present study, we demonstrated that PL induced cancer cell death through, at least in part, the induction of ferroptosis, as the cancer cell-killing activity was inhibited by the antioxidant, N-acetylcysteine, ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) and the iron chelator, deferoxamine (DFO), but not by the apoptosis inhibitor, Z-VAD-FMK, or the necrosis inhibitor, necrostatin 1. Cotylenin A (CN-A; a plant growth regulator) exhibits potent antitumor activities in several cancer cell lines, including pancreatic cancer cell lines. We found that CN-A and PL synergistically induced the death of pancreatic cancer MIAPaCa-2 and PANC-1 cells for 16 h. CN-A enhanced the induction of ROS by PL for 4 h. The synergistic induction of cell death was also abrogated by the ferroptosis inhibitors and DFO. The present results revealed that clinically approved sulfasalazine (SSZ), a ferroptosis inducer, enhanced the death of pancreatic cancer cells induced by PL and the combined effects were abrogated by the ferroptosis inhibitors and DFO. SSZ further enhanced the cancer cell-killing activities induced by combined treatment with PL plus CN-A. On the other hand, the synergistic induction of cell death by PL and CN-A was not observed in mouse embryonic fibroblasts (MEFs), and SSZ did not enhance the death of MEFs induced by PL plus CN-A. These results suggest that the triple combined treatment with PL, CN-A and SSZ is highly effective against pancreatic cancer. PMID- 29393419 TI - HMGB1 mediates microglia activation via the TLR4/NF-kappaB pathway in coriaria lactone induced epilepsy. AB - Epilepsy is a chronic and recurrent disease of the central nervous system, with a complex pathology. Recent studies have demonstrated that the activation of glial cells serve an important role in the development of epilepsy. The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1) in mediating the activation of glial cells through the toll-like receptor 4 (TLR4)/nuclear factor (NF)-kappaB signaling pathway in seizure, and the underlying mechanism. The brain tissue of post-surgery patients with intractable epilepsy after resection and the normal control brain tissue of patients with craniocerebral trauma induced intracranial hypertension were collected. The expression level and distribution pattern of HMGB1, OX42 and NF-kappaB p65 were detected by immunohistochemistry. HMGB1, TLR4, receptor for advanced glycation end products (RAGE), NF-kappaB p65 and inducible nitric oxide synthase (iNOS) expression levels were detected by western blotting, and serum cytokine levels of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and IL-10 in patients with epilepsy and craniocerebral trauma were detected by ELISA. And cell model of epilepsy was established by coriaria lactone (CL)-stimulated HM cell, and the same factors were measured. The potential toxic effect of HMGB1 on HM cells was evaluated by MTT and 5-ethynyl-2 deoxyuridine assays. The results demonstrated that compared with the control group, levels of HMGB1, TLR4, RAGE, NF-kappaB p65 and iNOS in the brain of the epilepsy group were significantly increased, and increased cytokine levels of IL 1, IL-6, TNF-alpha, TGF-beta and IL-10 in patients with epilepsy were also observed. At the same time, the above results were also observed in HM cells stimulated with CL. Overexpression of HMGB1 enhanced the results, while HMGB1 small interfering RNA blocked the function of CL. There was no significant toxic effect of HMGB1 on HM cells. In conclusion, overexpression of HMGB1 potentially promoted epileptogenesis. CL-induced activation of glial cells may act via up regulation of HMGB1 and TLR4/RAGE receptors, and the downstream transcription factor NF-kappaB. PMID- 29393420 TI - Homocysteine-induced proliferation of vascular smooth muscle cells occurs via PTEN hypermethylation and is mitigated by Resveratrol. AB - Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in the development of atherosclerosis (AS), and the presence of homocysteine (Hcy) acts as an independent risk factor for AS. However, the underlying mechanisms remain to be elucidated. Phosphatase and tensin homologue on chromosome 10 (PTEN), is endogenously expressed in VSMCs and induces multiple signaling networks involved in cell proliferation, survival and inflammation, however, the specific role of PTEN is still unknown. The present study detected the proliferation ratio of VSMCs following treatment with Hcy and Resveratrol (RSV). In the 100 uM Hcy group, the proliferation ratio increased, and treatment with RSV decreased the proliferation ratio induced by Hcy. Reverse transcription quantitative polymerase chain reaction and western blotting were used to analyze PTEN expression, RSV treatment was associated with decreased PTEN expression levels in VSMCs. PTEN levels were decreased in Hcy treated cells, and the proliferation ratio of VSMCs were increased following treated with Hcy. To study the mechanism of regulation of PTEN by Hcy, the present study detected PTEN methylation levels in VSMCs, and PTEN DNA methylation levels were demonstrated to be increased in the 100 uM Hcy group, whereas treatment with RSV decreased the methylation status. DNA methyltransferase 1 is important role in the regulation of PTEN methylation. Overall, Hcy impacts the methylation status of PTEN, which is involved in cell proliferation, and induces the proliferation of VSMCs. This effect is alleviated by treatment with RSV, which exhibits an antagonistic mechanism against Hcy. PMID- 29393421 TI - Effects of nuclear factor-kappaB on the uptake of 131iodine and apoptosis of thyroid carcinoma cells. AB - Thyroid carcinoma is primarily treated by surgery combined with radioactive 131iodine (131I) treatment; however, certain patients exhibit resistance to 131I treatment. Previous research indicated that nuclear factor-kappaB (NF-kappaB) was associated with resistance to 131I in cancer cells. The present study aimed to investigate the effects of NF-kappaB on 131I uptake and apoptosis in thyroid carcinoma cells. TPC-1 and BCPAP cell lines were employed as research models in the present study, and the expression of NF-kappaB was inhibited by RNA interference (RNAi). The ability of TPC-1 and BCPAP cells to uptake 131I was measured and the cell viability was detected by an MTT assay. Finally, the expression of the apoptosis-associated proteins X-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and caspase-3 in TCP-1 and BCPAP cells was determined by western blotting. Western blotting results demonstrated that the expression levels of NF-kappaB in TPC-1 and BCPAP cells were successfully downregulated by RNAi (P<0.05), while analysis of 131I uptake revealed no significant alterations in the 131I uptake ability of cells following RNAi (P>0.05). MTT experiments demonstrated that the inhibition of NF-kappaB expression in combination with radiation (131I treatment) led to a marked reduction in cell viability (P<0.05). Furthermore, western blot analysis revealed that the inhibition of NF-kappaB expression downregulated the expression levels of XIAP and cIAP1 (P<0.05), while the expression levels of caspase-3 were upregulated, indicating that the observed reduction in cell viability following NF-kappaB inhibition may be due to an increased level of apoptosis. Although NF kappaB inhibition did not affect the 131I uptake of thyroid cancer cells, this inhibition may increase the apoptotic effects of radioactive 131I. PMID- 29393422 TI - KIF17 mediates the learning and memory impairment in offspring induced by maternal exposure to propofol during middle pregnancy. AB - Preclinical studies suggest that propofol may cause neuronal injury to the developing brain. A previous study demonstrated that, in a rat model, maternal exposure to propofol during early or late pregnancy caused learning and memory impairment in the offspring. However, whether propofol exposure during middle pregnancy can cause long-term behavioral deficits in the offspring remains to be elucidated. N-methyl-D-aspartate receptor 2B subunit (NR2B) serves a critical role in memory modulation. To exert its function, NR2B must be transported to the neuronal membrane by kinesin family member 17 (KIF17). The aim of the present study was to investigate the role of KIF17 in learning and memory impairment in rat offspring caused by propofol exposure during middle pregnancy. Pregnant rats were exposed to propofol on gestational day 14 (G14) for 4 and 8 h, with control pregnant rats receiving an equal volume of normal saline. The learning and memory of the offspring was assessed using Morris water maze tests from postnatal day 30 (P30) to P36. The levels of KIF17 protein, total NR2B (T-NR2B) and membrane NR2B (M-NR2B) in the hippocampus were detected using western blotting. The results demonstrated that propofol exposure caused learning and memory deficits and decreased KIF17 and M-NR2B protein levels in the hippocampus; however, no but changes in the expression of T-NR2B were observed. These results indicate that maternal propofol exposure during middle pregnancy impairs learning and memory in offspring rats by suppressing the expression of KIF17 and inhibiting the translocation of NR2B to the neuronal membrane. PMID- 29393423 TI - COL1A1 promotes metastasis in colorectal cancer by regulating the WNT/PCP pathway. AB - Colorectal cancer (CRC) is the third leading cause of cancer-associated mortality, and is a major health problem. Collagen type I alpha 1 (COL1A1) is a major component of collagen type I. Recently, it was reported to be overexpressed in a variety of tumor tissues and cells. However, the function of COL1A1 in CRC remains unclear. Herein, the present study demonstrated that COL1A1 was upregulated in CRC tissues and the paired lymph node tissues. Transwell assays showed that COL1A1 promoted CRC cell migration in vitro. Moreover, it was revealed that COL1A1 levels were correlated with those of WNT/planar cell polarity (PCP) signaling pathway genes; inhibition of COL1A1 decreased the expression levels of Ras-related C3 botulinum toxin substrate 1-GTP, phosphorylated-c-Jun N-terminal kinase, and RhoA-GTP, all of which are key genes in the WNT/PCP signaling pathway. These results may indicate the mechanisms underlying the oncogenic role of COL1A1 in CRC. In summary, the present data indicated that COL1A1 may serve as an oncoprotein, and that it may be used as a potential therapeutic target in CRC. PMID- 29393424 TI - Genetic correction of adipose tissue-derived mesenchymal stem cells mediated by TALEN targeting the GDF5 gene. AB - Stem cells and other associated cell types may be a potential alternative to treat various genetic disorders that currently do not benefit from traditional approaches. Functional recovery of cells could be induced via directional differentiation or genetic manipulation. In this study, mesenchymal stem cells (MSCs) were obtained from a patient with osteoarthritis (OA) carrying a functional single-nucleotide polymorphism (SNP rs143383, C/T transition) within the 5'-UTR of growth and differentiation factor 5 (GDF5) gene. The SNP causes GDF5 expression to be reduced and thus increases OA susceptibility. Aiming to correct the dysfunctional gene, a pair of transcription activator-like effector nucleases (TALENs) were designed to cleave the DNA around the mutated locus, coupled with a short single stranded DNA complementary to the cleavage site. Following in vitro cell colony formation and selection, two genetically corrected MSC colonies were identified out of a total of 142. These MSCs were induced and differentiated into chondrocytes. As a result, genetically corrected chondrocytes exhibited normal morphology and lower levels of apoptosis compared with cells carrying the SNP. In cultured cells, the secretion of matrix metalloproteinases was suppressed and TIMP metallopeptidase inhibitor 1 was increased by correction of the mutation. Furthermore, the expression of GDF5 target genes, cell vitality associated genes and extracellular matrix degrading genes were returned to normal levels in corrected cells compared with mutation-carrying cells, indicating the functional recovery of these corrected chondrocytes. The present study demonstrated that TALEN-mediated genetic correction can be used to edit genes in adipose-derived MSCs from patients with OA and may have clinical potential. PMID- 29393425 TI - AMPK/SIRT1/p38 MAPK signaling pathway regulates alcohol-induced neurodegeneration by resveratrol. AB - Resveratrol has also been approved for use in enhancing plant disease resistance and reducing pesticide use. A number of studies have shown that the disease resistance of crops treated with resveratrol is markedly improved. The aim of the present study was to examine the protective effect of resveratrol against alcohol induced neurodegeneration occurred and its association with AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/p38 in rats and humans. ELISA, caspase-3 activity and western blot analyses were employed in the present study. Sprague-Dawley rats and human neuroblastoma SH-SY5Y cells were treated with alcohol to establish the alcohol-induced model. Resveratrol protected against alcohol-induced neuron damage in the hippocampus of the rats. Treatment with resveratrol also inhibited the alcohol-induced inflammatory response, oxidative stress, caspase-3 activities and B-cell lymphoma (Bcl-2)-associated X protein/Bcl-2 in the alcohol-induced rat. Resveratrol also reduced the upregulated protein expression of AMPK and SIRT1, preventing the pro-apoptotic alcohol-induced protein expression of p38 in the rats exposed to alcohol. The downregulation of AMPK suppressed the expression of SIRT1 and activated the expression of p38 in the SH-SY5Y cell model. Taken together, the data obtained suggested that resveratrol protected against alcohol induced neurodegeneration via the AMPK/SIRT1/p38 pathway in rats and humans. PMID- 29393426 TI - Endoglin (CD105) and SMAD4 regulate spheroid formation and the suppression of the invasive ability of human pancreatic cancer cells. AB - In this study, we investigated the ability of pancreatic cancer cell lines to form spheroids with the aim of identifying factors involved in cell invasiveness, a property that leads to a poor prognosis in pancreatic cancer. For this purpose, 8 cell lines derived from human pancreatic cancer tissues were cultured in non adherent culture conditions to form spheroids, as well as normal monolayers. The morphology of the cells was observed and spheroid diameters measured. mRNA expression was compared between cells cultured under both culture conditions. The gene knockdown of endoglin (ENG) and SMAD4, components of the transforming growth factor-beta (TGF-beta) signaling system, using siRNAs was conducted in spheroids in order to identify affected protein signaling factors, determine the morphological changes occurring over time and to measure the invasive capacity of the cells constituting spheroids. The cell lines exhibited differences in their spheroid-forming abilities. The expression of SMAD4 and ENG concomitantly increased in the cells that formed spheroids. SMAD4 was transported into the nucleus when spheroids were formed. The expression of ENG was decreased in the cells in which SMAD4 was knocked down; by contrast, the expression of BMP and activin membrane-bound inhibitor (BAMBI) and noggin (NOG), further components of the TGF-beta signaling system, increased. In the cells in which ENG was knocked down, the decreased mRNA expression of TGF-beta receptor type 2 (TGFBR2) and SMAD9 was observed, as well as a change in the expression of pSMAD1/5/9, and a tendency of spheroids to decrease in size. Spheroids cultured on Matrigel exhibited a tendency towards a reduction in size over time, as well as a tendency to invade into the Matrigel. In particular, the cells in which ENG was knocked down exhibited spheroids which were reduced in size, and also exhibited an increase in invasiveness, and a decrease in adhesiveness. Thus, our data indicate that in pancreatic cancer cells, the expression of ENG may be controlled by a pathway mediated by SMAD4. In addition, ENG was found to be related to the spheroid-forming ability of cells and to be involved in the invasive capacity of pancreatic cancer cells. PMID- 29393427 TI - Plasma-stimulated medium kills TRAIL-resistant human malignant cells by promoting caspase-independent cell death via membrane potential and calcium dynamics modulation. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cold plasma stimulated medium (PSM) have been shown to exhibit tumor-selective cytotoxicity and have emerged as promising new tools for cancer treatment. However, to date, at least to the best of our knowledge, no data are available as to which substance is more potent in killing cancer cells. Thus, in this study, we systematically compared their abilities to kill human malignant cells from different origins. We found that PSM dose-dependently killed TRAIL-resistant melanoma, osteosarcoma and neuroblastoma cells. Moreover, PSM had little cytotoxicity toward osteoblasts. PSM was more potent than TRAIL in inducing caspase-3/7 activation, mitochondrial network aberration and caspase-independent cell death. We also found that PSM was more potent in inducing plasma membrane depolarization (PMD) and disrupting endoplasmic-mitochondrial Ca2+ homeostasis. Moreover, persistent PMD was caused by different membrane-depolarizing agents; the use of the anti-type II diabetes drug, glibenclamide, alone caused mitochondrial fragmentation and enhanced TRAIL-induced Ca2+ modulation, mitochondrial network abnormalities and caspase-independent cell killing. These results demonstrate that PSM has a therapeutic advantage over TRAIL owing to its greater capacity to evoke caspase-independent cell death via mitochondrial network aberration by disrupting membrane potential and Ca2+ homeostasis. These findings may provide a strong rationale for developing PSM as a novel approach for the treatment of TRAIL-resistant malignant cells. PMID- 29393428 TI - Integration of transcriptomics, proteomics, metabolomics and systems pharmacology data to reveal the therapeutic mechanism underlying Chinese herbal Bufei Yishen formula for the treatment of chronic obstructive pulmonary disease. AB - Bufei Yishen formula (BYF) is a traditional Chinese medicine formula, which has long been used as a therapeutic agent for the treatment of chronic obstructive pulmonary disease (COPD). Systems pharmacology has previously been used to identify the potential targets of BYF, and an experimental study has demonstrated that BYF is able to prevent COPD. In addition, the transcriptomic and metabolomic profiles of lung tissues from rats with COPD and BYF-treated rats have been characterized. The present study aimed to determine the therapeutic mechanisms underlying the effects of BYF on COPD treatment by integrating transcriptomics, proteomics and metabolomics, together with systems pharmacology datasets. Initially, the proteomic profiles of rats with COPD and BYF-treated rats were analyzed. Subsequently, pathway and network analyses were conducted to integrate three-omics data; the results demonstrated that the genes, proteins and metabolites were predominantly associated with oxidoreductase activity, antioxidant activity, focal adhesion and lipid metabolism. Finally, a comprehensive analysis of systems pharmacology, transcriptomic, proteomic and metabolomic datasets was performed, and numerous genes, proteins and metabolites were found to be regulated in BYF-treated rats; the potential target proteins of BYF were involved in lipid metabolism, inflammatory response, oxidative stress and focal adhesion. In conclusion, BYF exerted beneficial effects against COPD, potentially by modulating lipid metabolism, the inflammatory response, oxidative stress and cell junction pathways at the system level. PMID- 29393429 TI - Notch signaling molecule is involved in the invasion of MiaPaCa2 cells induced by CoCl2 via regulating epithelial-mesenchymal transition. AB - Pancreatic cancer exhibits a high mortality rate resulting from metastasis and there is currently no effective treatment strategy. Hypoxia serves an important role in cancer cells, where cellular metabolic rate is high. The underlying mechanisms that trigger hypoxia and the invasion of pancreatic cancer cells remain unknown. Investigation of the importance of hypoxia in the invasion of pancreatic cancer cells for potential, novel treatment strategies is of primary concern. Cell Counting Kit-8 assay, invasion assay, western blotting and reverse transcription-quantitative polymerase chain reaction were used to investigate invasion and epithelial mesenchymal transition (EMT) and the expression of Notch1 in MiaPaCa2 cells treated with cobalt II chloride (CoCl2). Hypoxia-inducible factor 1alpha (HIF-1alpha) small interfering (si)RNA and Notch1 inhibitor N-[N (3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) were also selected to investigate these mechanisms. Data indicated that CoCl2 increased the invasion ability and altered EMT in MiaPaCa2 cells. CoCl2 regulated the expression of HIF-1alpha and Notch1 in MiaPaCa2 cells. In addition, HIF-1alpha siRNA inhibited the effects of CoCl2 on the expression of Notch1 and decreased Snail, EMT and invasion in MiaPaCa2 cells. DAPT increased the expression of epithelial-cadherin and decreased the content of neural-cadherin, Snail and invasion in MiaPaCa2 cells in the presence or absence of CoCl2. CoCl2 promoted invasion by stimulating the expression of HIF-1alpha and regulating the expression of Notch1 and EMT in MiaPaCa2 cells. Targeting the Notch1 signaling molecule may be a novel treatment strategy for the prevention and treatment of pancreatic cancer. PMID- 29393430 TI - Silencing Lin28 promotes apoptosis in colorectal cancer cells by upregulating let 7c targeting of antiapoptotic BCL2L1. AB - Colorectal cancer (CRC) remains a primary contributor to cancer-associated mortality. The Lin28/let-7 axis has previously been verified to participate in numerous pathophysiological processes involved in CRC. However, the potential roles and underlying mechanisms of this axis in apoptosis during CRC remain to be fully elucidated. The present study aimed to evaluate the role and reveal the molecular mechanisms of the Lin28/let-7 axis in the apoptosis of CRC cells. An MTT assay was conducted to assess the cell viability of HCT116 and HT29 CRC cells, and caspase-3 activity was analyzed to measure the apoptosis of CRC cells. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to examine the expression of Lin28, B-cell lymphoma 2 (Bcl-2), Bcl 2-associated X protein, Bcl-2-like 1 (BCL2L1) and let-7c. The present study demonstrated that Lin28 was upregulated whereas let-7c was downregulated in CRC tissues and cell lines compared with normal tissues and NCM460 normal colon epithelial cells, respectively. Forced overexpression of let-7c promoted apoptosis in CRC cells, which was at least partially mediated via the targeting of BCL2L1. Furthermore, knockdown of Lin28 decreased viability and promoted apoptosis in CRC cells, whereas this effect was attenuated by let-7c inhibition. The findings of the present study suggest the involvement of the Lin28/let-7c axis in apoptosis during CRC, and indicate the potential role of this pathway as a novel therapeutic target in CRC. PMID- 29393431 TI - Knockout of Toll-like receptor 4 improves survival and cardiac function in a murine model of severe sepsis. AB - Toll-like receptor 4 (TLR4) is a transmembrane pattern-recognition receptor expressed in immune cells and the heart. Activation of TLR4 signaling during sepsis results in the release of cardiac depression mediators that may impair heart function. The present study aimed to determine whether TLR4 contributes to development of severe sepsis-induced myocardial dysfunction. A cecum ligation and puncture (CLP) procedure was employed to establish severe sepsis models. Wild type (WT) and TLR4 knock-out (TLR4-KO) mice were divided into four groups: WT sham, TLR4-KO-sham, WT-CLP, and TLR4-KO-CLP. Cardiac function of these animals was evaluated at various time points following the surgical procedure. The expression levels of proinflammatory cytokines in the heart tissues were detected by reverse transcription-semi quantitative polymerase chain reaction (RT-PCR). Myocardial neutrophil and macrophage infiltration were investigated by histopathological examination, as well as a myeloperoxidase activity assay in heart tissue by RT-PCR. Myocardium Fas cell surface death receptor/Fas ligand and caspase-3 were also analyzed by RT-PCR. Additionally, myeloid differentiation primary response 88 M, toll or interleukin-1 receptor-domain-containing adapter inducing interferon-beta and nuclear factor-kappaB expression levels were observed in the myocardium of all four groups. WT-CLP mice exhibited increased mortality rates, more severe cardiac dysfunction and had increased levels of interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha in heart tissues and increased neutrophil infiltration compared with TRL4-KO-CLP mice. The present study reported that TLR4 aggravates severe sepsis-induced cardiac impairment by promoting the release of proinflammatory cytokines and neutrophil infiltration in hearts. PMID- 29393432 TI - Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen-activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin. AB - Type 2 diabetic mellitus (T2DM), which is characterized by insulin resistance (IR), hyperglycemia and hyperlipidemia, is a comprehensive dysfunction of metabolism. The insulin receptor (INSR)/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is well acknowledged as a predominant pathway associated with glucose uptake; however, the effect of streptozotocin (STZ) plus a high fat and sugar diet (HFSD) on the proteins associated with this pathway requires further elucidation. In order to explore this effect, a T2DM rat model was constructed to investigate T2DM pathogenesis and potential therapeutic advantages. Rats were randomly divided into control and model groups, including normal diet (ND) and HFSD types. ND types were administered intraperitoneal (IP) injections of STZ (35 mg/kg) or a combination of STZ and alloxan monohydrate (AON) (40 mg/kg), whereas HFSD types were composed of HFSD pre-given, post-given and simul-given groups, and were modeled as follows: IP or intramuscular (IM) injection of STZ (35 mg/kg) or a combination of STZ and AON (40 mg/kg). Results indicated that, compared with controls, blood glucose, insulin, homeostatic model assessment-insulin resistance and total triglyceride were significantly elevated in groups with HFSD and modeling agents (P<0.05 or P<0.01), whereas total cholesterol and low-density lipoprotein levels were significantly elevated in groups simultaneously administered HFSD and modeling agents (P<0.05 or P<0.01), in addition to downregulation of the expression of insulin signaling pathway proteins in the liver, including INSR, PI3K, AKT1, phosphatidylinositol-5-phosphate 4-kinase type 2alpha (PIP5Kalpha) and glucose transporter (GLUT)2, and increased expression of inflammatory factors, including p38, tumor necrosis factor (TNF)alpha and interleukin (IL)6. Furthermore, compared with other two HFSD types including pre given and post-given group, the simul-given group that received IM injection with STZ exhibited decreased expression levels of major insulin signal pathway proteins INSR, PI3K, AKT1, PIP5Kalpha, GLUT2 or GLUT4 in the liver and pancreas (P<0.05 or P<0.01), whereas the opposite was observed in the skeletal muscle. In addition, the protein expression levels of phosphorylated-p38, p38, IL6 and TNFalpha in the simul-given group that received IM injection with STZ were increased (P<0.05 or P<0.01), and histopathology also indicated inflammation in pancreas and liver. The present findings suggest that a low dose of STZ may partially impair the beta cells of the pancreas, whereas long-term excess intake of HFSD may increase lipid metabolites, inhibit the insulin signaling pathway and activate the mitogen-activated protein kinase p38 signaling pathway. The combined action of STZ and AON may result in insulin resistance, which ultimately results in abnormalities in glucose and lipid metabolism. The present model, analogue to T2DM onset of humans, evaluated the medical effect on metabolic dysfunction and provides an insight into the underlining mechanism of IR. PMID- 29393434 TI - Novel TRERF1 mutations in Chinese patients with ovarian endometriosis. AB - Endometriosis is an estrogen-dependent precancerous lesion exhibiting frequently perturbed level of steroid hormones and transcriptional-regulating factor 1 (TRERF1) has a crucial role in the production of steroid hormones including estrogen. Endometriosis has previously been revealed to be a precancerous lesion that harbors somatic mutations in cancer-associated genes. Therefore, the authors of the present study hypothesize that TRERF1 aberrations may be involved in the development of endometriosis. In the present study, endometriotic lesions and paired blood samples from 92 individuals with ovarian endometriosis were analyzed for the potential presence of TRERF1 mutations by sequencing the entire coding region and the corresponding intron-exon boundaries of the TRERF1 gene. Two heterozygous missense somatic mutations [c.3166A>C (p.K1056Q) and c.3187 G>A (p.G1063R)] in the TRERF1 gene were identified in two out of 92 ectopic endometria (2.2%), to the best of our knowledge, these mutations have not been previously reported. From the two samples with TRERF1 mutations, one sample was from a 42-year-old patient also diagnosed with uterine leiomyoma and the other mutation was identified in a 36-year-old woman exhibiting no other apparent gynecological conditions. The evolutionary conservation analysis and in silico prediction of these TRERF1 mutations suggested that they may be pathogenic. To the best of our knowledge, the present study was the first to identify 2 novel, potentially 'disease-causing' TRERF1 somatic mutations in the endometriotic lesions in 2 out of 92 patients with ovarian endometriosis; therefore, TRERF1 mutations may be involved in the pathogenesis of ovarian endometriosis. PMID- 29393433 TI - Activin A inhibition attenuates sympathetic neural remodeling following myocardial infarction in rats. AB - Inflammation serves a critical role in driving sympathetic neural remodeling following myocardial infarction (MI), and activin A has been implicated as an important mediator of the inflammatory response post-MI. However, whether activin A impacts sympathetic neural remodeling post-MI remains unclear. In the present study, the authors assessed the effects of activin A on sympathetic neural remodeling in a rat model of MI. Rats were randomly divided into sham, MI, and MI + follistatin-300 (FS, activin A inhibitor) groups. Cardiac tissues from the peri infarct zone were assessed for expression of sympathetic neural remodeling and inflammatory factors in rats 4 weeks post-MI by western blotting and immunohistochemical methods. Heart function was assessed by echocardiography. It is demonstrated that FS administration significantly reduced post-MI upregulation of activin A, nerve growth factor protein lever, and the density of nerve fibers with positive and protein expression of sympathetic neural remodeling markers in nerve fibers, which included growth associated protein 43 and tyrosine hydroxylase. In addition, inhibition of activin A reduced cardiac inflammation post-MI based on the reduction of i) interleukin-1 and tumor necrosis factor alpha protein expression, ii) numbers and/or proportional area of infiltrating macrophages and myofibroblasts and iii) phosphorylated levels of p65 and IkappaBalpha. Furthermore, activin A inhibition lessened heart dysfunction post MI. These results suggested that activin A inhibition reduced sympathetic neural remodeling post-MI in part through inhibition of the inflammatory response. The current study implicates activin A as a potential therapeutic target to circumvent sympathetic neural remodeling post-MI. PMID- 29393435 TI - IL-22 inactivates hepatic stellate cells via downregulation of the TGF beta1/Notch signaling pathway. AB - Interleukin-22 (IL-22) inhibits liver fibrosis by inducing hepatic stellate cell (HSC) senescence, primarily through the activation of signal transducer and activator of transcription 3 signaling. However, whether other signaling pathways are involved remains unknown. The present study assessed the regulatory mechanism between IL-22 and the Notch signaling pathway in vitro. The results revealed that IL-22 had anti-proliferative effects on HSC-T6 cells, and cellular inactivation was reflected by simultaneous inhibition of alpha-smooth muscle actin, transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha and intercellular adhesion molecule 1. Treatment with TGF-beta1 resulted in significant Notch3 upregulation and activation of its downstream effectors Hes family basic helix-loop-helix (bHLH) transcription factor (Hes)-1, Hes-5 and Hes related family BHLH transcription factor with YRPW motif 1. Furthermore, this effect was markedly reversed by further treatment with IL-22, indicating there may be regulatory cascades of IL-22/TGF-beta1/Notch signaling in HSC-T6 cells. The results of the present study demonstrated an inhibitory function of IL-22 towards Notch signaling in hepatic cells, providing evidence that Notch may serve as a novel target for liver fibrosis. PMID- 29393436 TI - Identification of methylated genes and miRNA signatures in nasopharyngeal carcinoma by bioinformatics analysis. AB - Nasopharyngeal carcinoma (NPC) is prevalent in several regions, including. Southern China and Southeast Asia, with high mortality. The present study aimed to explore the epigenetic mechanisms of NPC and to provide novel biomarkers for prognosis. Two methylation data sets (GSE52068 and GSE62336) were downloaded from the Gene Expression Omnibus database. Following pretreatment of the raw data, differentially methylated regions (DMRs) and differentially methylated CpG islands (DMCs) were identified between the NPC samples and normal tissue controls using COHCAP software. The overlapped DMRs and DMCs in the two data sets were extracted and associated to relevant genes. Enrichment analysis and protein protein interaction (PPI) network analyses were performed on the identified genes using Database for Annotation, Visualization and Integration Discovery and Cytoscape, respectively. MicroRNAs (miRNAs) targeting the overlapped genes were identified based on the miRWalk database. NPC-related genes were analyzed with the Comparative Toxicogenomics Database. Multiple overlapping DMRs between the two data sets were identified and were associated with 1,854 hypermethylated and 18 hypomethylated genes, which were revealed to be enriched in certain pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Several nodes in the predicted PPI network were highlighted, including proto-oncogene tyrosine-protein kinase SRC, SMAD family member 3 (SMAD3), tyrosine 3-monooxygenase/tryptophan 5 monooxygenase activation protein zeta (YWHAZ) and Heat shock protein family A member 4 (HSPA4), all of which were hypomethylated. A total of 14 miRNAs were identified that correlated with the overlapped genes such as miRNA (miR)-148a-3p, which was predicted to target of HSPA4; and 17 genes were identified as related to NPC, including SMAD3 and SRC. miR129-2 was hypermethylated. Several novel methylated genes or miRNAs were suggested as biomarkers for NPC prognosis: Hypomethylation of SRC, SMAD3, YWHAZ and HSPA4, and hypermethylation of miR129-2 may be linked to poor prognosis of NPC. PMID- 29393437 TI - Polysaccharide from Fuzi protects against Ox-LDL-induced calcification of human vascular smooth muscle cells by increasing autophagic activity. AB - Polysaccharide from Fuzi (FPS) is a water-soluble polysaccharide isolated from the traditional Chinese herbal medicine Fuzi. It has been demonstrated to protect hepatocytes against ischemia-reperfusion injury through its potent antioxidant effects, and to attenuate starvation-induced cytotoxicity in H9c2 cells by increasing autophagic activity. In the present study, Alizarin Red S staining was used to detect mineral deposition and reverse transcription-quantitative polymerase chain reaction was used to detect the core binding factor alpha1 and smooth muscle 22alpha mRNA expression. To analyze autophagic activity, western blotting was used to detect microtubule-associated protein 1A/1B light chain 3 and nucleoporin P62 expression. In addition, green fluorescent protein-LC3 dots per-cell was observed by fluorescence microscopy. It was demonstrated that oxidized low-density lipoprotein (Ox-LDL) could increase the calcification of human vascular smooth muscle cells (VSMCs) in a concentration-dependent manner, and that FPS treatment had a significant protective effect against Ox-LDL-induced calcification of human VSMCs. Furthermore, FPS treatment alleviated the Ox-LDL induced downregulation of autophagic activity, and the protective effect of FPS on Ox-LDL-induced calcification was attenuated by the autophagy inhibitor 3 methyladenine. In conclusion, the present study demonstrated for the first time to the best of the authors' knowledge that FPS can protect against Ox-LDL-induced vascular calcification in human VSMCs, and that this likely occurs via the activation of autophagy. This supports the hypothesis that autophagy may be an endogenous protective mechanism counteracting vascular calcification, and that FPS may be used as a potential therapeutic for vascular calcification. PMID- 29393438 TI - MicroRNA-539 inhibits the proliferation and invasion of bladder cancer cells by regulating IGF-1R. AB - Bladder cancer is the most frequent malignancy of the urinary tract and the seventh most common cancer worldwide. The abnormal expression of microRNAs has been frequently observed in various types of human cancers, including bladder cancer. In addition, an increasing body of evidence has demonstrated that microRNAs are potential targets for cancer diagnosis, treatments and prognosis. The aim of the present study was to investigate the expression patterns and potential roles of microRNA-539 (miR-539) in bladder cancer and its underlying mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-539 expression in the bladder cancer tissues and cell lines. Following transfection, MTT and cell invasion assays were used to investigate the effects of miR-539 overexpression or IGF1R underexpression on bladder cancer cell proliferation and invasion. Bioinformatics analysis, a luciferase reporter assay, RT-qPCR and western blot analysis were utilized to determine the potential targets of miR-539 in bladder cancer. The results revealed that miR-539 levels were relatively decreased in bladder cancer tissues and cell lines when compared with those observed in the matched adjacent normal bladder tissues and normal bladder epithelial cell line. miR-539 expression was associated with the tumor stage and lymph node metastasis of patients with bladder cancer. In addition, the expression of miR-539 suppressed bladder cancer cell proliferation and invasion. Insulin like growth factor 1 receptor (IGF-1R) was identified as a direct target of miR-539, and miR-539 was also observed to regulate the protein kinase B and extracellular signal-regulated kinases signaling pathways. IGF-1R was markedly upregulated in bladder cancer tissues and negatively associated with miR-539 expression levels. Furthermore, IGF-1R knockdown in bladder cancer cells significantly inhibited cell proliferation and invasion. To the best of our knowledge, these results demonstrated for the first time that miR-539 may act as a tumor suppressor and serve important roles in tumorigenesis and progression of bladder cancer. Thus, miR-539/IGF-1R may be a potential therapeutic target for the treatment of bladder cancer. PMID- 29393439 TI - Role of IFT88 in icariin-regulated maintenance of the chondrocyte phenotype. AB - Maintenance of the chondrocyte phenotype is crucial for cartilage repair during tissue engineering. Intraflagellar transport protein 88 (IFT88) is an essential component of primary cilia, shuttling signals along the axoneme. The hypothesis of the present study was that IFT88 could exert an important role in icariin regulated maintenance of the chondrocyte phenotype. To this end, the effects of icariin on proliferation and differentiation of the chondrogenic cell line, ATDC5, were explored. Icariin-treated ATDC5 cells and primary chondrocytes expressed IFT88. Icariin has been demonstrated to aid in the maintenance of the articular cartilage phenotype in a rat model of post-traumatic osteoarthritis (PTOA). Icariin promoted chondrocyte proliferation and expression of the chondrogenesis marker genes, COL II and SOX9, increased ciliary assembly, and upregulated IFT88 expression in a concentration- and time-dependent manner. Icariin-treated PTOA rats secreted more cartilage matrix compared with the controls. Knockdown of IFT88 expression with siRNA reduced extracellular signal regulated kinase (ERK) phosphorylation, and icariin upregulated IFT88 expression by promoting ERK phosphorylation. Thus, IFT88 serves a major role in icariin mediated maintenance of the chondrocyte phenotype, promoting ciliogenesis and IFT88 expression by increasing ERK phosphorylation. Icariin may therefore be useful for maintenance of the cartilage phenotype during tissue engineering. PMID- 29393440 TI - Serum containing Gengnianchun formula suppresses amyloid beta-induced inflammatory cytokines in BV-2 microglial cells by inhibiting the NF-kappaB and JNK signaling pathways. AB - As the resident macrophages of the brain's innate immune system, microglial cells are key modulators in the neurodegenerative disease Alzheimer's disease (AD). In particular, the activation and accumulation of microglial cells around amyloid plaques is considered to result in chronic neuroinflammation. Although the pathologic mechanism remains to be fully elucidated, inflammation has been shown to be critical in the pathogenesis of AD. The Gengnianchun (GNC) formula has long been used to treat perimenopausal syndrome clinically, and is particularly effective in improving learning ability and memory. Our previous study demonstrated that GNC formula had an anti-inflammatory effect and offered neuroprotection in animal experiments. In the present study, the anti inflammatory properties of GNC and its underlying mechanism of action were examined in BV-2 microglial cells. Amyloid-beta peptide (Abeta)-stimulated microglial cells were examined for the production of proinflammatory cytokines and the underlying signaling pathways. Compared with the normal control group, the protein expression levels of IL-1beta and TNF-alpha were significantly increased following treatment with Abeta (P<0.01), but medicated rat serum containing GNC formula (MRS) could significantly attenuated the Abeta-induced secretion of these pro-inflammatory cytokines. It was identified by CCK-8 assay that the viability of the BV-2 cells was not reduced following treatment with various concentrations of MRS. The phosphorylation of factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) was markedly increased following treatment with Abeta, compared with the normal control group (P<0.01). However, treatment with MRS resulted in a significant reduction in the phosphorylation of NF-kappaB (P<0.05). These results suggested that MRS suppressed the Abeta-induced inflammatory response of microglial cells by inhibiting the NF-kappaB and JNK signaling pathways. These novel findings provide insights into the development of GNC formula as a therapeutic agent for the treatment of neurodegenerative disorders. PMID- 29393441 TI - Genetic variability in E5, E6, E7 and L1 genes of human papillomavirus type 31. AB - Human papillomavirus (HPV) type 31 is an important pathogenic subtype associated with cervical cancer. The aims of the present study were to analyze E5, E6, E7 and L1 gene mutations of HPV-31 among females, and to elucidate the evolutionary associations between them. In total, 87 positive samples were collected. The E5, E6, E7 and L1 genes were amplified by polymerase chain reaction and sequenced. Subsequently, two phylogenetic trees were constructed from the nucleotide sequences of the E5, E6 and E7 and the L1 variants of HPV-31. In total, 31 mutation sites of E5, E6 and E7 genes were identified, of which 16 were non synonymous. T4053A (F80I), C285T (H60Y), C520T (A138V) and A743G (K62E) were the most common non-synonymous mutations. A total of 30 mutation sites of L1 genes were identified, of which four were non-synonymous. The most common non synonymous mutations of L1 genes were A6350G (T29A) and C6372A (T36N). By phylogenetic analysis, A and C variants were most frequently detected, while B variants were less frequently detected in this population. The sequence variation data obtained in the present study provides a foundation for future research regarding HPV-induced oncogenesis, and may prove valuable for developing diagnostic probes and in the design of HPV vaccines for targeted populations. PMID- 29393442 TI - Serum starvation-induces down-regulation of Bcl-2/Bax confers apoptosis in tongue coating-related cells in vitro. AB - Tongue squamous epithelial cells are the main component of tongue coating, with proliferation, differentiation and apoptosis being the root cause of the formation and maintenance of tongue coating. The present study aimed to explore the molecular mechanism by which serum influences tongue coating, to enable a better understanding for future investigations. Tongue carcinoma squamous cells were exposed to serum-starvation in vitro. Cellular proliferation and apoptosis were observed by using 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, flow cytometry, Hoechst staining, scanning electron microscope (SEM), transmission electron microscope (TEM), and by measuring the expression ratio of B-cell lymphoma 2 apoptosis regulator (Bcl-2)/Bcl-2 associated protein X apoptosis regulator (Bax) mRNA and protein by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. MTT assays revealed that serum-starvation results in suppression of cellular proliferation, while flow cytometry data revealed that serum-starvation induces cell cycle arrest at G1 phase and increases apoptosis. In addition, chromatin condensation and membrane blebbing were observed through Hoechst staining, TEM and SEM. The Bcl-2/Bax ratio was found to be significantly decreased in cells that had undergone serum-starvation by both RT-qPCR and western blotting analysis, further indicating that serum-starvation induces apoptosis. Therefore, tongue carcinoma squamous cells in a serum-free medium can simulate apoptosis related to the formation of tongue coating, which may offer guidance for future investigations about other factors. PMID- 29393443 TI - NF-kappaB is a key modulator in the signaling pathway of Borrelia burgdorferi BmpA-induced inflammatory chemokines in murine microglia BV2 cells. AB - Lyme disease, caused by the bacterial spirochete Borrelia burgdorferi, is a tick borne zoonosis. Lyme neuroborreliosis is a principal manifestation of Lyme disease and its pathogenesis remains incompletely understood. Recent studies have demonstrated that Borrelia burgdorferi lipoproteins caused similar inflammatory effects as exhibited in Lyme neuroborreliosis. Basic membrane protein A (BmpA) is one of the dominant lipoproteins in the Borrelia burgdorferi membrane. In addition, nuclear factor kappa-B (NF-kappaB) modulates the regulation of gene transcription associated with immunity and inflammation; however, in unstimulated cells, NF-kappaB is combined with the inhibitor of NF-kappaB (IkappaB-beta). Therefore, it was hypothesized that NF-kappaB may be associated with BmpA-induced inflammation and the occurrence of Lyme neuroborreliosis. Therefore, the aim of the present study was to investigate the role that NF-kappaB serves in the signaling pathway of rBmpA-induced inflammatory chemokines. The present study measured the expression levels of NF-kappaB, IkappaB-beta and inflammatory chemokines following recombinant BmpA (rBmpA) stimulation of murine microglia BV2 cells. Following stimulation with rBmpA, concentrations of pro-inflammatory cytokines including C-X-C motif chemokine 2, C-C motif chemokine (CCL) 5 and CCL22 were determined by ELISA analysis. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression levels of NF-kappaB p65 and IkappaB-beta. The data demonstrated that concentrations of these chemokines in cell supernatants increased significantly following rBmpA stimulation. NF-kappaB was overexpressed, but IkappaB-beta expression was significantly decreased. In conclusion, these results suggested that NF-kappaB serves an important stimulatory role in the signaling pathway of rBmpA-induced inflammatory chemokines in BV2 cells. PMID- 29393444 TI - Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling. AB - Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug-resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)-induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA-resistant cells (PANC-1-TSA) had higher proliferative activity than non resistant cells (PANC-1). This over-proliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin-6 (IL-6), a STAT3-upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including c-Myc, c-Src, HIF 1alpha, and CCND1. In addition, increased expression of Bcl-2 mRNA and decreased expression of Bax mRNA in PANC-1-TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL-6/JAK2/STAT3 in a dose-dependent manner. As a result, tyrphostin B42 inhibited the over-proliferative activity of PANC-1-TSA cells, and downregulated the expression of IL-6/JAK2/STAT3-downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrial-related genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSA-mediated resistance in PCCs by antagonizing the IL-6/JAK2/STAT3 signaling. PMID- 29393445 TI - Study on the mechanism of JAK2/STAT3 signaling pathway-mediated inflammatory reaction after cerebral ischemia. AB - The present study aimed to investigate the mechanism by which the Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway mediates cerebral ischemia and the efficacy of pharmaceutical intervention. The rat model of middle cerebral artery occlusion (MCAO) was established and confirmed via assessment of changes in the expression of phosphorylated (p)-JAK2, p-STAT3, high-mobility group box 1 (HMGB1), and inflammatory factors using ELISA and western blot analysis. The effects of JAK2/STAT3 inhibitor and curcumin on the expression of p-JAK2, p-STAT3, HMGB1, and inflammatory factors after cerebral ischemia were observed with ELISA, western blotting and immunohistochemical staining. The concentrations of tumor necrosis factor (TNF)-alpha and HMGB1 in brain tissue homogenate of MCAO group were significantly higher than in the sham group (P<0.01). The concentration of p-JAK2/JAK2 and p-STAT3/STAT3 in the brain tissue homogenate of MCAO group was significantly higher than in the sham group (P<0.05). The concentrations of TNF-alpha, interleukin (IL)-1beta, IL-6, and HMGB1 in the group treated with STAT3 inhibitor (MCAO + rapamycin), JAK2 inhibitor (MCAO + AG490), and MCAO + curcumin were significantly lower than in the MCAO group (P<0.01), as well as the relative content of p-JAK2/JAK2 and p STAT3/STAT3 (P<0.05). Inhibition of the JAK2/STAT3 signaling pathway, such as curcumin can reduce the expression of HMGB1 in brain tissue after cerebral ischemia, which can significantly reduce the inflammatory response after cerebral ischemia. PMID- 29393446 TI - Angiotensin-(1-7) prevents lipopolysaccharide-induced hepatocellular inflammatory response by inhibiting the p38MAPK/AP-1 signaling pathway. AB - The pathological mechanism of lipopolysaccharide (LPS)-induced liver injury involves a number of inflammatory mediators and cytokines. Angiotensin (Ang)-(1 7), a ligand for the proto-oncogene Mas (Mas) receptor, antagonizes the actions of Ang II in the renin angiotensin system and exerts an anti-inflammatory effect on LPS-induced macrophages. The present study investigated the potential role of Ang-(1-7) in the regulation of inflammatory responses in LPS-induced hepatocytes using the rat liver BRL cell line. The results of the present study demonstrated that the inflammatory mediator, tumor necrosis factor (TNF)-alpha, its upstream transcriptional regulatory factor activator protein (AP)-1 and p38 mitogen activated protein kinase (MAPK) which were detected by reverse transcription quantitative polymerase chain reaction and western blotting were upregulated in LPS-induced hepatic cells in a time-dependent manner, peaking 12 h following LPS stimulation. By contrast, treatment with Ang-(1-7) significantly attenuated the expression of TNF-alpha, AP-1 and p38MAPK in a concentration-dependent manner. The anti-inflammatory effect of Ang-(1-7) was reversed by the Mas receptor selective antagonist, A779, in BRL cells. Furthermore, the p38MAPK inhibitor, SB 203580, abolished the protective effects of Ang-(1-7), suggesting the involvement of the p38MAPK pathway in the anti-inflammatory activity of Ang-(1-7). The results of the present study indicated that Ang-(1-7) may serve an anti inflammatory role in LPS-induced hepatocyte injury via the regulation of the p38MAPK/AP-1 signaling pathway. PMID- 29393447 TI - Simulated microgravity hampers Notch signaling in the fight against myocardial ischemia-reperfusion injury. AB - The gravitational field is an important determinant of cardiovascular function. Exposure to microgravity during spaceflight may lead to a series of maladaptive alterations in the cardiovascular system. The authors have previously demonstrated that microgravity can increase the susceptibility to myocardial ischemia-reperfusion (IR) injury under simulated microgravity. Although Notch1 signaling protects against myocardial IR injury, whether Notch1 protects against myocardial IR injury under simulated weightlessness remains unknown. The present study is designed to investigate the role of the Notch1 receptor in myocardial IR injury under simulated weightlessness. The differences in Notch signaling expression and myocardial infarct size following myocardial IR were compared between normal rats and tail-suspended rats that were kept in 30 head-down tilt and hindlimb unloading position. The data revealed low expression levels of Notch1 receptor and its endogenous ligand Jagged1 in normal adult rat hearts. However, significantly higher expression of Notch1 was observed in the border zone compared with the infarcted area and the remote zone following myocardial IR. Notch1 expression was notably reduced in the infarcted hearts of tail suspended rats compared with the control group. Conversely, the myocardial infarct size was significantly increased in tail-suspended rats compared with the control rats. In conclusion, these data suggested that the proper function of Notch signaling may be hampered under simulated microgravity. PMID- 29393448 TI - Potential roles of AMP-activated protein kinase in liver regeneration in mice with acute liver injury. AB - Liver regeneration post severe liver injury is crucial for the recovery of hepatic structure and function. The energy sensor AMP-activated protein kinase (AMPK) has a crucial role in the regulation of nutrition metabolism in addition to other energy-intensive physiological and pathophysiological processes. Cellular proliferation requires intensive energy and nutrition support, therefore the present study investigated whether AMPK is involved in liver regeneration post carbon tetrachloride (CCl4)-induced acute hepatic injury. The experimental data indicated that phosphorylation level of AMPK increased 48 h post-CCl4 exposure, which was accompanied with upregulation of proliferating cell nuclear antigen (PCNA) and recovery of alanine aminotransferase (ALT) level. Pretreatment with the AMPK inhibitor compound C had no obvious effects on ALT elevation in plasma and histological abnormalities in liver 24 h post CCl4 exposure. However, treatment with compound C 24 h post CCl4 exposure significantly suppressed CCl4 induced AMPK phosphorylation, PCNA expression and ALT recovery. These data suggest that endogenous AMPK was primarily activated at the regeneration stage in mice with CCl4-induced acute liver injury and may function as a positive regulator in liver regeneration. PMID- 29393449 TI - Effect of cyclooxygenase-2 inhibition on the development of post-traumatic stress disorder in rats. AB - Post-traumatic stress disorder (PTSD) is characterized by re-experiencing of a traumatic event, avoidance of trauma-associated stimulation, general changes in mood and cognition, and hyper arousal symptoms. Cyclooxygenase is involved in the production of prostaglandins and thromboxanes, and its inducible form cyclooxygenase-2(COX-2), an important mediator of cell injury in inflammation, is primarily expressed in leukocytes and brain cells. The present study investigated the expression of COX-2 in the hippocampi of rats with PTSD and evaluated the effect of COX-2 inhibition on PTSD. Adult male Wistar rats were randomly divided into three groups: Control (n=20), PTSD (n=20) and intervention group (PTSD+COX-2 inhibitor treatment, n=20). The expression of COX-2 was detected by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining was used to observe the apoptosis of rat hippocampal neurons. Tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and prostaglandin E2 (PGE2) levels were analyzed by ELISA. Nitric oxide (NO) was detected using the Griess test. The behavioral and cognitive function of rats in the PTSD group was significantly decreased compared with the control group, while the behavioral and cognitive function of rats in the intervention group were improved. The COX-2 mRNA and protein expression levels in hippocampi of rats in the PTSD group were higher than in the control and intervention group. The apoptosis of hippocampus in rats with PTSD was significantly increased compared with the control group and following treatment with COX-2 inhibitor, apoptosis was decreased. In addition, compared with the control group and intervention group, the levels of TNF-alpha, IL-6, PGE2 and NO in hippocampi of rats were increased in the PTSD group. The present study indicated that COX-2 may be involved in the pathogenesis of PTSD, and inhibition of its expression serves a neuroprotective role in hippocampi of PTSD rats. PMID- 29393450 TI - Cullin7 promotes epithelial-mesenchymal transition of esophageal carcinoma via the ERK-SNAI2 signaling pathway. AB - Cullin7 (CUL7) is a member of Cullin protein family and exhibits a tumor promoting role in several types of tumors, including breast, liver and ovarian. However, its roles in esophageal carcinoma (EC) have not yet been reported. In the present study, CUL7 expression in EC tissue was revealed to be significantly higher compared with nontumoral tissues, as detected by immunohistochemistry (IHC; P=0.000). chi2 analysis confirmed that CUL7 expression was positively associated with invasion depth (P=0.000), lymph node involvement (P=0.033) and advanced clinical stage (P=0.000). Survival analysis demonstrated that CUL7 was positively associated with poor overall survival (P=0.001) and poor disease-free survival (P=0.0019). An association of CUL7 with endothelial-mesenchymal transition (EMT) was examined, and IHC results indicated that high CUL7 expression was associated with increased zinc finger protein SNAI2 (SNAI2) expression (P=0.000) and decreased E-cadherin (P=0.000). Western blot analysis demonstrated that short hairpin RNA silencing CUL7 in EC1 cells increased epithelial (E)-cadherin protein expression level, and decreased expression of Vimentin and SNAI2; cell migration was also reduced. Western blot analysis demonstrated that over expression of CUL7 in EC9706 cells increased Vimentin and SNAI2 protein expression, but decreased E-cadherin expression, and the number of migratory cells. Investigation into the potential molecular mechanisms demonstrated that over expressing CUL7 in EC9706 cells stimulated the phosphorylation of ERK. Inhibiting ERK through treatment with U0126 significantly abrogated CUL7-induced alterations in Vimentin, SNAI2 and E-cadherin expression levels. Results from the present study demonstrated that CUL7 expression was associated with EC progression and poor prognosis. CUL7 may promote EMT via the ERK-SNAI2 pathway in EC. These data may improve our understanding of the role of CUL7 in tumors and provide supporting evidence for the development of novel therapeutic targets for EC. PMID- 29393451 TI - MicroRNA-195 is associated with regulating the pathophysiologic process of human laryngeal squamous cell carcinoma. AB - MicroRNAs (miRNAs) have been reported to be associated with the modulation of tumor development, including alterations associated with the development of human laryngeal squamous cell carcinoma (LSCC). The present study was designed to investigate whether miRNA-195 was associated with the pathophysiologic process of human LSCC and to identify its potential roles and underlying molecular mechanisms. To determine whether miRNA-195 serves a role in LSCC, reverse transcription-quantitative polymerase chain reaction was used to detect miRNA-195 expression in LSCC tissues. The tumor-suppressive effect of miRNA-195 was determined by in vitro assays. Gain-of-function studies using miRNA-195 mimics were performed to investigate cell viability, migration and invasion, and apoptosis in the AMC-HN-8 cell line. Western blotting was performed to reveal the molecular mechanisms of miRNA-195 and its downstream signaling pathways in the LSCC AMC-HN-8 cell line. The present study demonstrated that miRNA-195 is downregulated in primary LSCC tumors. Upregulating miRNA-195 in vitro suppressed cell viability, migration and invasion in AMC-HN-8 cells. Overexpression of miRNA 195 alone in AMC-HN-8 cells was sufficient to induce cell apoptosis, as identified by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Compared with the high expression of miRNA-195 in AMC-HN-8 cells, the expression levels of vascular endothelial growth factor receptor-II protein and downstream signaling pathway proteins, which were associated with cell viability, migration, invasion and apoptosis, were markedly decreased compared with control or miRNA 195 negative control treatment group. Together, these data suggest the therapeutic potential of miRNA-195 in modulating cell growth, migration and apoptosis during the pathophysiological progression of LSCC and that miRNA-195 may serve as a potential therapeutic target in human LSCC. PMID- 29393452 TI - Effect of T helper cell 1/T helper cell 2 balance and nuclear factor-kappaB on white matter injury in premature neonates. AB - Incidence of white matter injury (WMI), which is featured as softening of white matter tissues, has recently increased. Previous studies have demonstrated a close correlation between T helper cell 1 and T helper cell 2 (Th1/Th2) imbalance and nuclear factor-kappaB (NF-kappaB) with brain disease. Their role in premature WMI, however, remains to be illustrated. Serum samples were collected from 60 premature WMI neonates, plus another control group of 60 premature babies without WMI. Patients were further divided into mild, moderate and severe WMI groups. Reverse transcription quantitative polymerase chain reaction was used to test mRNA expression levels of Th1/Th2 cytokines, including interleukin 2 (IL)-2, tumor necrosis factor-alpha (TNF-alpha), IL-4, IL-10 and nuclear factor (NF) kappaB, whilst their serum levels were measured by ELISA. Their correlation with disease occurrence and progression were further analysed, to illustrate the effect of Th1/Th2 balance and NF-kappaB on pathology of premature WMI. Serum levels of IL-4 and IL-10 were significantly decreased in premature WMI babies, whilst IL-2, TNF-alpha and NF-kappaB were upregulated (P<0.05 vs. control group). With aggravated disease, IL-4 and IL-10 expression was further decreased while IL 2, TNF-alpha and NF-kappaB were increased (P<0.05 vs. mild WMI group). Th1 cytokines IL-2 and TNF-alpha and NF-kappaB were negatively correlated with Th2 cytokines IL-4 and IL-10. Disease severity was positively correlated with IL-2, TNF-alpha and NF-kappaB expression, and was negatively correlated with IL-4 and IL-10 (P<0.05). Th1/Th2 imbalance and NF-kappaB upregulation were observed in WMI pathogenesis, with elevated secretion of Th1 cytokines and decreased Th2 cytokines, suggesting that Th1/Th2 imbalance and NF-kappaB upregulation may be a potential indicator for the early diagnosis and treatment of WMI pathogenesis and progression. PMID- 29393453 TI - Synthetic E-selectin prevents postoperative vascular restenosis by inhibiting nuclear factor kappaB in rats. AB - During the development of postoperative vascular restenosis, the aberrant proliferation of vascular smooth muscle cells (VSMCs) is a critical event resulting in intimal hyperplasia. Inflammatory responses involving the activation of nuclear factor (NF)-kappaB are among the major molecular processes underlying restenosis. The present study aimed to investigate the roles of NF-kappaB in VSMC proliferation and restenosis following vascular anastomosis, as well as to evaluate the potential of synthetic E-selectin to downregulate NF-kappaB and thus inhibit vascular hyperplasia. A total of 72 adult male Sprague-Dawley rats were randomly assigned to three groups: Control, operation and treatment groups. Rats in the operation and treatment groups received longitudinal incisions in the right carotid arteries, which were closed using interrupted sutures. Following vascular anastomosis, synthetic E-selectin (10 mg/kg), or an equal volume of saline, was immediately injected into the right femoral vein of rats in the treatment and operation groups, respectively. Following surgery, the mRNA and protein expression levels of NF-kappaB at the site of anastomosis, the levels of tumor necrosis factor-alpha and interleukin-6 in the serum, NF-kappaB binding activity, and the presence of proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by western blotting, reverse transcription-quantitative polymerase chain reaction, ELISA, electrophoretic mobility shift assay and immunofluorescence staining. The present results demonstrated that following treatment with synthetic E-selectin, the levels of NF-kappaB and the inflammatory response, as well as the presence of PCNA-positive cells, were significantly reduced (P<0.01). In conclusion, the results of the present study suggested that synthetic E-selectin may exert anti-inflammatory and anti-restenotic effects following vascular anastomosis in vivo. PMID- 29393454 TI - Zoledronic acid sensitizes breast cancer cells to fulvestrant via ERK/HIF-1 pathway inhibition in vivo. AB - Previous studies have reported that hypoxia-inducible factor (HIF)-1alpha confers endocrine resistance and that zoledronic acid (ZOL) decreases HIF-1alpha expression in estrogen receptor-positive breast cancer. The present study investigated the effect of the combination treatment with ZOL and fulvestrant and its possible mechanism for HIF-1alpha inhibition in vitro and in vivo. First, cell proliferation, clonogenic ability and HIF-1alpha expression by western blotting were determined in MCF-7 breast cancer cells stably expressing HIF 1alpha in vitro. Next, a mouse xenograft model was established with the HIF 1alpha-overexpressing MCF-7 breast cancer cells, and treated with PBS, fulvestrant, ZOL or fulvestrant plus ZOL. Tumor volumes were compared and animal [18F]-fluoromisonidazole (FMISO) positron emission tomography-computer tomography (PET-CT) was used to detect the hypoxic status of the xenograft tumors. Protein expression levels of HIF-1alpha in the xenograft tumors were detected by immunohistochemistry and western blotting. The results demonstrated that the HIF 1alpha-overexpressing xenograft tumors grew faster and larger compared with control tumors. The animal [18F]-FMISO PET-CT also confirmed these results. [18F] FMISO uptake was significantly higher in HIF-1alpha-overexpressing xenograft tumors compared with control tumors. In addition, the combination treatment with ZOL and fulvestrant acted synergistically in the mouse xenograft model in vivo to significantly reduce tumor burden. Similarly, combination of ZOL and fulvestrant significantly reduced tumor cell growth in vitro. ZOL alone did not inhibit the tumor growth of MCF-7 cells stably expressing HIF-1alpha. Furthermore, ZOL significantly inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, while phosphoinositide 3-kinase/AKT signaling was not affected. In conclusion, the present study demonstrated that ZOL significantly increased the sensitivity of breast cancer cells to fulvestrant through inhibition of the ERK/HIF-1alpha pathway. PMID- 29393455 TI - Decreased Eph receptor-A1 expression is related to grade in ovarian serous carcinoma. AB - Eph receptor-A1 (EphA1) was the first member of the erythropoietin producing hepatocellular carcinoma (Eph) family of receptor tyrosine kinases. Although the roles of EphA1 in the tumorigenesis of various human cancers have been investigated, few studies have focused on ovarian carcinoma. The present study aimed to explore the profile of EphA1 expression in ovarian carcinomas, to analyzed the association between EphA1 expression and clinicopathologic parameters, and to investigate the roles of overexpressed EphA1 in ovarian cancer cells. EphA1 protein was detected in ovarian cancer cell lines and in a set of formalin-fixed tissues, including normal fallopian tube, ovarian benign serous cystadenoma, borderline serous tumors and serous carcinoma. Ovarian cancer cell lines HO8910 and A2780 were transiently transfected with EphA1-pCMV6-GFP plasmid, and the proliferation and apoptosis of cells were measured. The association between EphA1 expression and clinicopathological parameters was statistically analyzed. EphA1 expression was negative in HO8910 and weakly positive in A2780 cells. The proliferation rate was significantly reduced in ovarian cancer cells after transfection with EphA1 plasmid compared with cells transfected with mock plasmid or untreated cells, but no obvious alteration in apoptosis was detected among these groups. EphA1 expression was positively detected in all normal fallopian tubes (10/10, 100%) and ovarian benign serous cystadenomas (12/12, 100%) as well as in some borderline serous tumors (9/15, 60%) and ovarian serous carcinomas (33/76, 43.42%). EphA1 expression was associated with grade of ovarian serous carcinomas, with loss of EphA1 more often observed in high-grade tumors (P=0.016) and high Ki67 index tumors (P=0.007). These data suggest that EphA1 might be a useful marker for distinguishing low grade from high-grade ovarian serous carcinoma. PMID- 29393456 TI - Ethyl acetate extract from Inula helenium L. inhibits the proliferation of pancreatic cancer cells by regulating the STAT3/AKT pathway. AB - Sesquiterpene lactones are bioactive compounds that have been identified as responsible for the anticancer activity of the medicinal herb, Inula helenium L. (IHL). However, the mechanisms of action involved in the anti-pancreatic cancer activity of IHL have yet to be elucidated. The present study used an optimized extraction strategy to obtain sesquiterpene lactones from IHL (the resulting product termed ethyl acetate extract of IHL; EEIHL), and examined the potential mechanisms involved in the anti-pancreatic cancer activity of EEIHL. Ethanol and ethyl acetate were used to extract sesquiterpene lactones from IHL to give the final product EEIHL. Cell Counting Kit-8, colony formation and Annexin V/propidium iodide assays were used to detect the anti-proliferative activity of EEIHL. Cell migration was determined with a wound healing assay. mRNA and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. It was identified that low concentrations of EEIHL caused CFPAC-1 cell cycle arrest in the G0/G1 phase, whereas high concentrations of EEIHL induced mitochondria-dependent apoptosis. In addition, EEIHL could inhibit the phosphorylation of the signal transducer and activator of transcription (STAT)3/AKT pathway, potentially resulting in impeded cell mobility. In conclusion, EEIHL could activate mitochondrial-dependent apoptosis and inhibit cell migration through the STAT3/AKT pathway in CFPAC-1 cells. PMID- 29393458 TI - MicroRNA-126/stromal cell-derived factor 1/C-X-C chemokine receptor type 7 signaling pathway promotes post-stroke angiogenesis of endothelial progenitor cell transplantation. AB - Stroke is the most common cause of mortality worldwide. Post-stroke angiogenesis is of great significance to the treatment of strokes. The aim of the present study was to investigate the mechanism underlying the angiogenesis-promoting effect of microRNA-126 (miR-126)-associated signaling pathways using a stroke model in vivo and a cell migration model in vitro. Bone marrow-derived endothelial progenitor cells (EPCs) were extracted and identified using a density gradient method. Reverse transcription-quantitative polymerase chain reaction (RT qPCR) was performed to examine the expression levels of miR-126 and C-X-C chemokine receptor type 7 (CXCR7). Target genes of miR-126 were analyzed using TargetScan software version 7.1 (www.targetscan.org/). In addition, a reporter gene assay and RT-qPCR were performed to determine the target genes of miR-126. The effect of miR-126 on cell migration was examined using a cell migration model in vitro and a middle cerebral artery occlusion model of mice was established in vivo. The miR-126 antagomir-treated EPCs were infused into stroke mice. Microvessel density, nerve function score and infarction volume were assessed. Flow cytometric analysis indicated that cluster of differentiation (CD)34, CD133 and vascular endothelial growth factor receptor 2 were partly expressed on the cell surface of bone marrow-derived EPCs. In addition, the expression levels of Di-acetylated-low density lipoprotein and Ulex europaeus agglutinin 1 were positive. Stromal cell-derived factor 1 (SDF-1) was identified as a target gene of miR-126, which was confirmed by a reporter gene assay and RT-qPCR. Cell migration examination demonstrated that the neutralizing antibody of CXCR7 blocked miR-126 angomir-induced migration of EPCs. Microvessel density increased, while nerve function score and infarction volume decreased following infusion of miR-126 angomir-treated EPCs. Furthermore, miR-126 angomir improved the efficacy of EPC treatment. Thus, miR-126 improved the migration of EPCs via the miR 126/SDF-1/CXCR7 signaling pathway. PMID- 29393457 TI - Intermittent cyclic mechanical tension altered the microRNA expression profile of human cartilage endplate chondrocytes. AB - Previous studies have identified the association between cartilage endplate (CEP) degeneration and abnormal mechanical loading. Several studies have reported that intermittent cyclic mechanical tension (ICMT) regulates CEP degeneration via various biological processes and signaling pathways. However, the functions of microRNAs in regulating the cellular responses of CEP chondrocytes to ICMT remain to be elucidated. The current study determined the differentially expressed microRNAs in human CEP chondrocytes exposed to ICMT using microarray analysis. A total 21 significantly upregulated and 62 downregulated miRNAs were identified compared with the control. The findings were subsequently partially validated by reverse transcription-quantitative polymerase chain reaction. Potential target genes of the significantly differentially expressed miRNAs were predicted using bioinformatics analysis and were used for Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The present study revealed that the significantly differentially expressed microRNAs were involved in various signaling pathways and biological processes that are crucial to regulating the responses of CEP chondrocytes to ICMT. The current study provided a global view of microRNA expression in CEP chondrocytes under mechanical stimulation, suggesting that microRNAs are important for regulating the mechanical response of CEP chondrocytes. Additionally, it provided a novel insight into the association between mechanical stress and the establishment and progression of intervertebral disc degeneration. PMID- 29393459 TI - Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression. AB - The use of glucagon-like peptide-1 analogues, such as liraglutide, as hypoglycemic drugs has been widely employed in clinical practice. Liraglutide is reported to exert potential anti-breast cancer effects, however the specific mechanisms of this action remain unknown. In the present study, MCF-7 human breast cancer cells were cultured in vitro and treated with various concentrations of liraglutide. Cell Counting Kit-8, colony formation and flow cytometry assays were performed to determine the proliferation and apoptosis of cells following treatment. Furthermore, reverse transcription-quantitative polymerase chain reaction was employed to measure the expression level of microRNA (miRNA/miR)-27a. In addition, miR-27a mimics, inhibitors and negative controls were transfected into MCF-7 cells and the proliferation and apoptosis of cells following transfection was subsequently determined. Western blotting was performed to detect alterations in the protein expression of AMP-activated protein kinase catalytic subunit alpha2 (AMPKalpha2), proliferating cell nuclear antigen and cleaved-caspase-3 following treatments. The results demonstrated that, following treatment with liraglutide, the proliferation of MCF-7 cells was reduced and the apoptosis was increased, compared with the control group; this effect was increased with increasing concentrations of liraglutide. In addition, liraglutide treatment downregulated miR-27a expression in MCF-7 cells. While the overexpression of miR-27a promoted cell proliferation and inhibited apoptosis, knockdown of endogenous miR-27a inhibited cell proliferation and promoted apoptosis in MCF-7 cells. Furthermore, the expression of AMPKalpha2 protein in the group transfected with miR-27a mimics was decreased, while it was increased in MCF-7 cells transfected with miR-27a inhibitors. In conclusion, liraglutide may have a role in the inhibition of proliferation and promotion of apoptosis in MCF-7 cells. Concerning the mechanism of these effects, liraglutide may inhibit miR-27a expression, which subsequently increases the expression of AMPKalpha2 protein. The present study provides an experimental basis for the clinical treatment strategies of T2DM patients with breast cancer. PMID- 29393460 TI - LPS-induced proinflammatory cytokine expression in human airway epithelial cells and macrophages via NF-kappaB, STAT3 or AP-1 activation. AB - Lipopolysaccharide (LPS), the major outer surface membrane component of Gram negative bacteria, is one of the main etiological factors in the pathogenesis of several lung diseases, such as chronic obstructive pulmonary disease. The respiratory epithelium and the macrophages comprise the dynamic interface between the outside environment and the host response to bacterial infection via cytokine secretion. In the present study, the mechanisms of LPS induced-inflammatory response in human lung cells and macrophages were investigated. The effects of LPS exposure on cytokine production, inflammation-related transcription factors and intracellular signaling pathway activation were assessed in human lung mucoepidermoid carcinoma H292 cells and human macrophage THP-1 cells. The results demonstrated that LPS markedly increased the expression of interleukin (IL)-6, IL 8, tumor necrosis factor (TNF)-alpha, matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinases-1 in H292 cells, while it increased the production of IL-6, IL-8 and TNF-alpha in differentiated THP-1 cells. In addition, LPS exposure activated nuclear factor (NF)-kappaB and activator protein (AP)-1 signaling in H292 cells, while it activated NF-kappaB and signal transducer and activator of transcription (STAT) 3 signaling in THP-1 cells. Furthermore, treatment with NF-kappaB, AP-1 or STAT3 inhibitors significantly decreased the LPS-mediated expression of IL-8 and TNF-alpha in these cells, suggesting that these pathways might serve crucial roles in LPS-induced cytokine expression. In conclusion, LPS stimulation of H292 and THP-1 cells induced cytokine expression and NF-kappaB, mitogen-activated protein kinase and Janus kinase/STAT3 pathway activation with subsequent nuclear translocation of NF kappaB, AP-1 and STAT3, which demonstrated potential of the use of NF-kappaB, AP 1 and STAT3 in therapies for conditions and diseases associated with chronic inflammation. PMID- 29393461 TI - Lin28/microRNA-let-7a promotes metastasis under circumstances of hyperactive Wnt signaling in esophageal squamous cell carcinoma. AB - Dysregulation of micro (mi)RNA-let-7 has been associated with the development and prognosis of multiple cancer types. Lin28, a RNA-binding protein, plays a conserved role in regulating the maturation of let-7 family proteins. However, few studies have focused on the effects of Lin28/let-7 on Wnt-activated esophageal squamous cell carcinoma (ESCC). Analysis of the expression of let-7a, let-7b and let-7c in clinical tissues revealed that lower let-7a expression was correlated with higher tumor node metastasis staging and recurrence in patients with ESCC. Furthermore, it was demonstrated that let-7a was inversely correlated with the migration and invasion of ESCC cells. In addition, epithelial mesenchymal transition, and the expression of VEGF-C and MMP9 were effectively decreased by let-7a-mimic or siRNA-Lin28 pretreatment. Mechanistically, Lin28 functioned as the key factor in signal transduction, which regulated the expression of let-7a and the downstream genes along the Wnt signaling pathway. Taken together, these findings identified a biochemical and functional association between Lin28/let-7a, and the Wnt pathway in ESCC cells. PMID- 29393462 TI - Extracts from guava fruit protect renal tubular endothelial cells against acetaminophen-induced cytotoxicity. AB - Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide anti-inflammatory, anti-microbial, anti-oxidative and anti-diarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAP-induced renal cell damage. In the present study, extracts from guavas were obtained and added to APAP-treated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAP-induced cytotoxicity may be associated with inhibition of oxidative stress and caspase-3 activation. PMID- 29393463 TI - BMP4 knockdown of NCSCs leads to aganglionosis in the middle embryonic stage. AB - Transplacental bone morphogenetic protein (BMP)4 RNA interference (RNAi) is a technique used to knockdown genes in embryos. BMP4 are essential for the development of nervous system in the differentiation of neural crest stem cells (NCSCs). The failure of differentiation and migration of NCSCs may lead to aganglionosis. In the present study, pregnant mice were divided into three groups: Ringer's group, pSES group and RNAi-BMP4 group. In order to silence the BMP4 gene in the first generation (F1), 11.5 day pregnant mice were injected with the small interfering RNA BMP4 plasmid, pSES or Ringer's solution via the tail vein. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT PCR)and western blotting were employed to ensure the downregulation of BMP4. Finally, X-rays were performed following a barium enema. Aganglionosis was diagnosed by general anatomy and immunohistochemistry. Compared with the control group, transplacental RNAi was able to downregulate the BMP4-Smad4 of 11.5 day embryos, as determined by semi-quantitative RT-PCR and western blotting. The megacolons of the mice were demonstrated by X-ray and confirmed by general anatomy. Aganglionosis of colonic mucosa and submucosa were diagnosed by pathology, and immunohistochemistry. Knockdown of BMP4 in pregnant mice at the middle embryonic stage led to aganglionosis. It was therefore demonstrated that BMP-Smad was essential to the NCSCs of middle stage embryos. BMP-Smad served important roles in the generation of aganglionosis. This technique of knockdown BMP4 gene may be used to establish an aganglionosis mouse model. PMID- 29393464 TI - NLRP1 and NLRP3 inflammasomes mediate LPS/ATP-induced pyroptosis in knee osteoarthritis. AB - Pyroptosis is triggered by inflammasomes after its activation by various inflammatory stimulations, including lipopolysaccharide (LPS) and improper pH. This may result in programmed death of the affected cell. It is well known that NLRP1 and NLRP3 inflammasomes mediate the production of various cytokines in inflammatory disorders; however, it is still unknown whether NLRP1 and NLRP3 inflammasomes can influence the LPS-induced pyroptosis in the progression of knee osteoarthritis (KOA). In the present study, the correlation between the NLRP inflammasomes and fibroblast-like synoviocytes (FLSs) pyroptosis was investigated in vivo and in vitro. Human synovial samples were collected from KOA patients and the expression of NLRP1 and NLRP3 inflammasomes was analyzed. Human FLS were isolated in vitro and stimulated with LPS. To determine whether NLRP1 and NLRP3 inflammasomes are involved in FLS pyroptosis, NLRP1 and NLRP3 small interfering RNAs (siRNAs) were used. The results showed that the expression of NLRPs and inflammasome-related proteins were upregulated and FLS stimulated with LPS+ATP resulted in cell pyroptosis. However, LPS+ATP-induced pyroptosis was attenuated by NLRP1 and NLRP3 siRNAs. The results of the present study indicate that LPS induced FLS pyroptosis may be mediated by either NLRP1 or NLRP3 inflammsomes. Overall, based on the data obtained from patients and in vitro cells, the present finsings showed that NLRP1 and NLRP3 inflammasomes are highly involved in the FLS inflammation and pyroptosis. Furthermore, inhibition of NLRP1 and NLRP3 led to a remarkable reduction of pyroptosis-related cytokines. Thus, NLRP1 and NLRP3 inflammasomes may be important in the pathogenesis of OA and may represent a novel therapeutic target. PMID- 29393465 TI - Puerarin inhibits non-small cell lung cancer cell growth via the induction of apoptosis. AB - Puerarin, an isoflavone isolated from Kudzu roots, has been demonstrated to have beneficial effect on cardiovascular and cerebral vascular diseases. Recently research has revealed that puerarin exerts an anticancer role in many different types of cancer. The aim of the present study was to investigate the antitumor effects of puerarin on non-small cell lung cancer (NSCLC). Treatment of puerarin significantly inhibited the growth of NSCLC cell lines as determined by CCK-8 kit in vitro. Flow cytometry results indicated that puerarin treatments promoted NSCLC cell apoptosis. This result was further confirmed by western blot analysis of expression levels of proteins involved in the mitochondrial-mediated apoptosis pathway. Moreover, puerarin slightly induced cell autophagy through the PI3K/Akt and MAPK/Erk1/2 signaling pathways. In addition, a tumor xenograft model was established using nude mice, and the inhibitory effects on tumor growth by puerarin treatment were also detected. Taken together, these findings demonstrated that puerarin has anticancer activities and puerarin is a potential therapeutic agent for lung cancer. PMID- 29393466 TI - Upregulation of long non-coding RNA CCAT2 indicates a poor prognosis and promotes proliferation and metastasis in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (IHCC) is an aggressive cancer with a poor survival rate and is the second most common type of primary cancer of the hepatobiliary system. At present, the molecular mechanisms of IHCC initiation and progression remain unclear. Recent evidence has indicated that long non-coding RNAs (lncRNAs) serve a crucial role in cancer development; however, the functional role of lncRNAs in IHCC has not been investigated in detail. In the present study, a marked overexpression of lncRNA colon cancer-associated transcript 2 (CCAT2) was observed in IHCC cell lines and clinical specimens. Statistical analysis of IHCC clinicopathological characteristics and CCAT2 expression data revealed that high CCAT2 expression levels correlated with microvascular invasion, differentiation grade, tumor (T), lymph node (N), metastasis (M) and overall TNM stages of IHCC (P<0.05). Kaplan-Meier analysis demonstrated that CCAT2 upregulation was associated with poor overall survival and progression-free survival in IHCC. Furthermore, high CCAT2 expression was identified as an independent risk factor of IHCC poor prognosis in both univariate and multivariate Cox regression analyses. The role of CCAT2 in promoting IHCC cell proliferation, motility and invasion was further confirmed with in vitro assays. Therefore, CCAT2 may promote IHCC progression and metastasis, and may be a promising prognostic biomarker and therapeutic target in IHCC. PMID- 29393467 TI - Expression level and potential target pathways of miR-1-3p in colorectal carcinoma based on 645 cases from 9 microarray datasets. AB - For the purpose of demonstrating the clinical value and unraveling the molecular mechanisms of micro RNA (miR)-1-3p in colorectal carcinoma (CRC), the present study collected expression and diagnostic data from Gene Expression Omnibus (GEO), ArrayExpress and existing literature to conduct meta-analyses and diagnostic tests. Furthermore, the potential targets of miR-1-3p were attained from datasets that transfected miR-1-3p into CRC cells, online prediction databases and differentially expressed genes from The Cancer Genome Atlas and literature. Subsequently, bioinformatics analysis was conducted based on the aforementioned selected target genes. As a result, downregulation of miR-1-3p was observed. The combined standardized mean difference was -0.51 with 95% confidence interval (CI) of -0.68 to -0.33 using a fixed effect model, which demonstrated a significant downregulation of miR-1-3p in CRC. The combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio diagnostic score and odds ratio were 0.74 (95%CI: 0.48, 0.90), 0.75 (95%CI: 0.35, 0.94), 2.94 (95%CI: 1.01, 8.55), 0.34 (95%CI: 0.19, 0.60), 2.15 (95%CI: 1.06, 3.23) and 8.57 (95%CI: 2.89, 25.36). The summarized receiver operating characteristic curve demonstrated that the area under the curve was 0.81. In bioinformatics analyses based on 30 promising targets, the most enriched terms in Gene Ontology were positive regulation of transcription from RNA polymerase II promoter, extracellular region and transcription factor binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted the pathway termed cytokine cytokine receptor interaction. In protein-protein interaction analysis, platelet factor 4 was selected as the hub gene. To conclude, miR-1-3p is downregulated in CRC and likely suppresses CRC via multiple biological approaches, which indicates the diagnostic potential and tumor suppressive efficacy. PMID- 29393468 TI - Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells. AB - Signal transducer and activator of transcription 3 (STAT3) is involved in the survival, proliferation, angiogenesis, invasion and metastasis of tumor cells. In addition, interleukin-6 (IL-6) has been reported to be closely related to STAT3 activity. In the present study, we investigated whether crocin, a major glycosylated carotenoid derived from saffron, can modulate the IL-6/STAT3 pathway to induce growth inhibition and sensitivity to cancer cell apoptosis. We determined that crocin inhibited STAT3 activation induced by IL-6 in hepatocellular carcinoma Hep3B and HepG2 cells. STAT3 suppression was mediated through the inactivation of Janus kinase 1/2(JAK1, JAK2) and Src kinase in both liver cancer cell lines. Furthermore, crocin induced the expression of protein tyrosine phosphatase (PTP) SHP-1, which led to STAT3 dephosphorylation. Deletion of the SHP-1 gene by siRNA recovered the inhibitory effects of crocin, suggesting an important role for SHP-1. Moreover, crocin downregulated the expression of STAT3-regulated anti-apoptotic (Bcl-2, survivin), proliferative (cyclin D1), invasive (CXCR4) and angiogenic (VEGF) proteins. Conversely, crocin increased the pro-apoptotic (BAX) protein, which was correlated with the induction of apoptosis and inhibition of proliferation. Overall, these results provide evidence that crocin has the potential for anticancer activity through inhibition of the IL 6/STAT3 signaling pathway, especially in liver cancer. PMID- 29393469 TI - TRIM28 promotes cervical cancer growth through the mTOR signaling pathway. AB - Aberrant expression of tripartite motif-containing protein 28 (TRIM28) has been demonstrated in several human cancers; however, its biological function and related mechanism in cervical cancer remain unclear. In this study, we compared TRIM28 expression between cervical cancer and adjacent normal tissues, and detected significant elevation in TRIM28 expression levels in the cervical cancer tissues. Moreover, TRIM28 overexpression promoted the proliferation, colony formation, and cell cycle progression of cervical cancer cell lines, as well as the growth of xenograft tumors in nude mice, whereas knockdown of TRIM28 had the opposite effects. Evaluation of the potential mechanism demonstrated that TRIM28 promoted cervical cancer cell growth by activating the mammalian target of rapamycin (mTOR) signaling pathway. In support of this finding, TRIM28-induced cell proliferation was abolished by treatment with everolimus, a specific mTOR inhibitor. These results suggest that TRIM28 plays a pivotal role in cervical cancer cell proliferation and might serve as a potential therapeutic target. PMID- 29393470 TI - Effects of cullin 4B on the proliferation and invasion of human gastric cancer cells. AB - The major aim of the present study was to explore the effects of cullin 4B (CUL4B) on the proliferation and invasion of human gastric cancer cells. Gastric tumor tissues and paired adjacent non-tumor tissues were obtained from 21 gastric cancer patients, and gastric cancer cell lines (AGS, MGC-803, KATO-III, MKN-45, SGC-7901, BGC-823 and MKN-74) were cultured. BGC-823 cells were transfected with CUL4B small interfering (si)RNA or control siRNA. Reverse transcription quantitative polymerase chain reaction analysis was performed to detect the mRNA expression of CUL4B. Western blot analysis was performed to measure the protein levels of Wnt, beta-catenin, glutathione synthase kinase (GSK)-3beta, caspase-3 and cyclin E. MTT and Transwell assays were performed to examine cell proliferation and invasion following CUL4B knockdown. In addition, the effect of CUL4B knockdown on the cell cycle and apoptosis of BGC-823 cells was evaluated by flow cytometric analysis. The results indicated that compared with the adjacent non-tumor tissues and a normal gastric epithelial cell line, gastric cancer tissues and cell lines exhibited significantly higher expression of CUL4B. Knockdown of CUL4B in gastric cancer cells suppressed cell proliferation, caused G1 arrest and inhibited cell invasion. Silencing of CUL4B also resulted in decreased Wnt and beta-catenin expression, but increased expression of GSK-3beta, caspase-3 and cyclin E. These results indirectly demonstrate that CUL4B enhances the proliferation and invasion abilities of gastric cancer cells by upregulating the constituent factors Wnt and beta-catenin, as well as by negatively regulating the mRNA and protein expression of GSK-3beta, caspase-3 and cyclin E. The potential mechanism of CUL4B highlighted in the present study may be helpful for the treatment of patients with gastric cancer. PMID- 29393471 TI - Expression of immunoglobulin A in human mesangial cells and its effects on cell apoptosis and adhesion. AB - IgA nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. It has been considered that the deposited IgA is synthesized by B cells, although recent reports have suggested the implication of other cell types. Therefore, the present study investigated whether glomerular mesangial cells could produce IgA by themselves. Semi-quantitative reverse transcription-polymerase chain reaction, and immunostaining analysis revealed that the IgA protein and gene transcripts were expressed in primary human renal mesangial cells (HRMCs). Furthermore, the IgA heavy chain (alpha1 and alpha2) and the light chain (kappa and lambda) were localized in the cytoplasm or were located on the cell membranes of human mesangial cells (HMCs). Mass spectrometry results indicated that Ig alpha1 and Ig alpha2 were secreted in the culture media of HMCs. The transcripts of Ig alpha, Ig kappa and Ig lambda constant regions were detected. The predominant rearrangement pattern of the variable region of Ig kappa, was Vkappa3-20*01/Jkappa1*01 in HMCs and Vkappa1-12*01/Jkappa4*01 in HRMCs. In addition, knockdown of Ig alpha1 expression by small interfering RNA (siRNA) inhibited cell adhesion and promoted apoptosis. Our findings demonstrate that HMCs can express IgA, and that this expression is associated with cell functions, which may contribute to the deposition of IgA in patients with IgAN. PMID- 29393472 TI - Metastasis-associated protein 2 promotes the metastasis of non-small cell lung carcinoma by regulating the ERK/AKT and VEGF signaling pathways. AB - Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer associated mortality in the world and accounts for ~85% of human lung cancers. Metastasis-associated protein 2 (MTA2) is a component of the histone deacetylase complex and serves a role in tumor progression; however, the mechanism through which MTA2 is involved in the progression of NSCLC remains unclear. The aim of the present study was to investigate the expression and function of MTA2 and the MTA2-mediated signaling pathway in NSCLC cells. Expression of MTA2 and its target genes was analyzed in MTA2-overexpressing and anti-MTA2 antibody (AbMTA2)-treated NSCLC cells, as well as growth, migration, invasion and apoptotic-resistance. The inhibitory effects on tumor formation were analyzed using AbMTA2-treated NSCLC cells and in a mouse model. Histological assessment was conducted to analyze the expressions levels of extracellular signal-regulated kinase (ERK), RAC-alpha serine/threonine protein kinase (AKT) and vascular endothelial growth factor (VEGF) in experimental tumors. Results of the present study demonstrated that MTA2 was overexpressed in NSCLC cells. The growth, migration and invasion of NSCLC cells were markedly inhibited by AbMTA2. In addition, it was observed that the ERK/AKT and VEGF signaling pathways were both upregulated in MTA2 overexpressing NSCLC cells, and downregulated following silencing of MTA2 activation. ERK and AKT phosphorylation levels were downregulated in NSCLC cells and tumors following MTA2 silencing. The in vivo study demonstrated that tumor growth was markedly inhibited following siRNA-MTA2 treatment. In conclusion, the results of the present study suggested that MTA2 silencing may significantly inhibit the growth and aggressiveness of NSCLC cells. Results from the present study indicated that the mechanism underlying the MTA2-mediated invasive potential of NSCLC cells involved the ERK/AKT and VEGF signaling pathways, which may be a potential therapeutic target for the treatment of NSCLC. PMID- 29393473 TI - Protective effects of N(2)-L-alanyl-L-glutamine mediated by the JAK2/STAT3 signaling pathway on myocardial ischemia reperfusion. AB - To explore the protective effect of N(2)-L-alanyl-L-glutamine (NLAG) on myocardial ischemia-reperfusion injury (IRI), and observe the influence of NLAG on the Janus activated kinase signal transducer 2 and activator of transcription 3 (JAK2/STAT3) signaling pathway-associated molecules. Wistar rats were randomly divided into three groups: Sham, IRI and NLAG. In the IRI rat model, the cardiac hemodynamics, the maximum rate of left ventricular pressure (+dP/dtmax) and the left ventricular end-diastolic pressure (LVDP) were recorded. Hematoxylin-eosin and Masson staining were used to detect myocardial histological changes. The levels of plasma interleukin (IL)-1beta and -6, tumor necrosis factor (TNF) alpha, lactase dehydrogenase (LDH), troponin (cTn)I, creatine kinase (CK), heart type fatty acid binding protein (hFABP), malondialdehyde (MDA) and succinate dehydrogenase (SDH) were determined with ELISA. The protein expression levels of B-cell lymphoma (Bcl)-2, Bcl2-associated X protein (Bax), Caspase-3, JAK2, phosphorylated (p)-JAK2, STAT3 and p-STAT3 were detected by western blot analysis. The IRI model demonstrated notable myocardial injury; myocardial cells were arranged disorderly with some nuclei disappearing, and cardiac muscular fibers were degenerated. Following 60 min of reperfusion, LVDP, HR and +dP/dtmax were 31.3+/-4.53 mmHg, 239.17+/-8.45 beats/min and 615.17 mmHg/sec, respectively. Compared with the Sham group, the levels of LDH, cTnI, CK, hFABP release, inflammatory factors (IL-1beta, IL-6 and TNF-alpha) and oxygen free radical (MDA and SDH) levels were increased in the IRI group. In the NLAG group, myocardial injury was improved, the concentrations of LDH, cTnI, CK, hFABP, IL-1beta, IL-6, TNF-alpha, MDA were decreased, and SDH release was increased compared with the IRI group. In addition, NLAG significantly increased Bcl-2, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression, and decreased Bax protein expression compared with the IRI group. In conclusion, myocardial ischemia-reperfusion can lead to myocardial cell apoptosis and myocardial injury and NLAG attenuates the IRI induced mitochondrial oxidative stress injury and apoptosis by activating the JAK2/STAT3 signaling pathway, thus exerting protective effects against IRI. PMID- 29393474 TI - REC8 inhibits EMT by downregulating EGR1 in gastric cancer cells. AB - REC8 is a component of the meiotic cohesion complex that plays a critical role in chromosome dynamics during meiosis. However, the functional role of REC8 in gastric cancer has not been elucidated. In the present study, REC8 suppressed the growth and metastasis of gastric cancer cells in vitro. Whole Human Genome Oligo Microarray results revealed that a wide range of genes with broad function were targeted by REC8. Among them early growth response-1 (EGR1), a transcription factor and an epithelial-mesenchymal transition (EMT)-associated protein in the AGR-RAGE pathway was significantly downregulated when REC8 was overexpressed in gastric cancer cells. We hypothesized that REC8 inhibits EMT by downregulating EGR1 in gastric cancer cells. Consistent with our prediction, REC8 overexpression decreased EMT in gastric cancer cells, whereas the REC8 ablation reversed these effects. In addition, the phenotypes of EGR1 overexpressed cells were similar to the phenotypes of REC8 ablated cells. Furthermore, we determined that REC8 interacted with EGR1, and inhibited EMT in gastric cancer cells. We thus propose further studies of the pathways associated with REC8 and EGR1 to potentially find novel targets in the treatment for gastric cancer. PMID- 29393475 TI - FNDC3B promotes epithelial-mesenchymal transition in tongue squamous cell carcinoma cells in a hypoxic microenvironment. AB - The primary reasons for the treatment failure of patients with oral tongue squamous cell carcinoma (OTSCC) are metastasis and tumor recurrence. Identifying the exact mechanisms underlying metastasis is a key point in improving patient prognosis. It has been reported that a hypoxic microenvironment plays an important role during the metastasis of malignancies. We found that the expression of fibronectin type III domain containing 3B (FNDC3B) is positively correlated with lymph node metastasis and advanced cTNM stage of OTSCC by IHC assay and correlation analysis. Furthermore, we found that knockdown of FNDC3B could suppress the migratory and invasive abilities of OTSCC cells. In addition, treating OTSCC cells with CoCl2 (a hypoxia mimetic agent) upregulated the mRNA and protein expression of FNDC3B via HIF-1alpha. Moreover, the resultant increase in FNDC3B expression significantly induced epithelial-mesenchymal transition (EMT) in OTSCC cells. The present study elucidated the important role played by FNDC3B in OTSCC metastasis and indicates FNDC3B as a potential target for the treatment of OTSCC metastasis. However, many questions remain to be explored. PMID- 29393476 TI - Alterations in DNA methyltransferases and methyl-CpG binding domain proteins during cleft palate formation as induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. AB - Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cleft palate formation in mice. This TCDD treatment, which may be considered an environmental factor in cleft palate formation, is associated with alterations in DNA methylation. However, the underlying molecular mechanisms of DNA methylation produced by TCDD in mouse embryos are poorly understood. DNA methyltransferases (DNMTs) and methyl-CpG binding domain proteins (MBDs) are thought to be closely associated with the actions of DNA methylation. Therefore, the present study tested the hypothesis that this cleft palate inducing effect of TCDD will alter the expression levels of DNMTs and various MBDs in palate tissue of fetal mice. Pregnant C57BL/6J mice were treated with either TCDD (64 ug/kg) or corn oil (control) at embryonic day 10.5 (E10.5) and fetal palates were harvested for structural and molecular analyses at E13.5, E14.5, E15.5 and E17.5. Expression levels of DNMTs and MBDs were assayed using reverse transcription-quantitative polymerase chain reaction and western blotting. The incidence of cleft palates in the TCDD group was 98.24%, whereas no cases of cleft palate were observed in the control group. Expression levels of DNMTs and MBDs were significantly increased in the TCDD group compared with the control. The results demonstrate clear alterations in DNMTs and MBDs, as induced by TCDD, and suggest that such alterations are important in cleft palate formation in fetal mice. PMID- 29393477 TI - Long non-coding RNA regulates hair follicle stem cell proliferation and differentiation through PI3K/AKT signal pathway. AB - Long non-coding RNAs (lncRNAs) are defined as non-coding transcripts (>200 nucleotides) that serve important roles in the proliferation and differentiation of stem cells. Hair follicle stem cells (HFTs) have multidirectional differentiation potential and are able to differentiate into skin, hair follicles and sebaceous glands, serving a role in skin wound healing. The aim of the present study was to analyze the regulatory role of lncRNA AK015322 (IncRNA5322) in HFTs and the potential mechanism of IncRNA5322-mediated differentiation of HFTs. The results demonstrated that lncRNA5322 transfection promoted proliferation and differentiation in HFTs. It was identified that lncRNA5322 transfection upregulated the expression and phosphorylation of phosphoinositide 3 kinase (PI3K) and protein kinase B (AKT) in HFTs. It was also observed that lncRNA5322 transfection upregulated microRNA (miR)-21 and miR-21 agonist (agomir 21) eliminated lncRNA5322-induced expression and phosphorylation of PI3K and AKT. The present study also demonstrated that agomir-21 blocked IncRNA5322-induced expression and phosphorylation of PI3K and AKT in HFTs. The results indicated that agomir-21 transfection also suppressed the IncRNA5322-induced proliferation and differentiation of HFTs. In conclusion, the results of the present study suggest that lncRNA5322 is able to promote the proliferation and differentiation of HFTs by targeting the miR-21-mediated PI3K-AKT signaling pathway in HFTs. PMID- 29393478 TI - Co-treatment with gemcitabine and nab-paclitaxel exerts additive effects on pancreatic cancer cell death. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and current treatments exert small effects on life expectancy. The most common adjuvant treatment for PDAC is gemcitabine. However, relapse almost invariably occurs and most patients develop metastatic, incurable disease. The aim of the present study was to assess the activity of nanoparticle albumin-bound paclitaxel (nab paclitaxel) alone or in combination with gemcitabine in PDAC cell lines displaying different degrees of sensitivity to gemcitabine treatment. We evaluated the effects of gemcitabine and nab-paclitaxel and their combination on cell proliferation, death, apoptosis and cell cycle distribution in PDAC cell lines either sensitive to gemcitabine, or with primary or secondary resistance to gemcitabine. Our results indicated that the dose-response of PDAC cell lines to nab-paclitaxel was similar, regardless of their sensitivity to gemcitabine. In addition, nab-paclitaxel elicited similar cytotoxic effects on a PDAC cell line highly resistant to gemcitabine that was selected after prolonged exposure to the drug. Notably, we found that combined treatment with gemcitabine and nab paclitaxel exerted additive effects on cell death, even at lower doses of the drugs. The combined treatment caused an increase in cell death by apoptosis and in cell cycle blockage in S phase, as assessed by flow cytometry and western blot analysis of the PARP-1 cleavage. These results revealed that a combined treatment with nab-paclitaxel may overcome resistance to gemcitabine and may represent a valuable therapeutic approach for PDAC. PMID- 29393479 TI - Synergistic effect of metformin and medroxyprogesterone 17-acetate on the development of endometrial cancer. AB - Accumulating data indicate that insulin resistance and unopposed estrogen are important risk factors of endometrial cancer (EC). Medroxyprogesterone 17-acetate (MPA) has been used in the treatment of EC for many years. However, the therapeutic effect of this agent on EC has not been satisfactory. 36 arMetformin was recently reported to be a promising agent for the treatment of malignant diseases including EC. However, information on the synergistic effect of the two agents in EC is limited. With the aim to evaluate the synergistic effect of metformin and MPA, we conducted the present study in vitro and in vivo. We found that the combined application of metformin and MPA significantly inhibited the proliferation of the Ishikawa cells and arrested the cells in the G0/G1 phase. Furthermore, the apoptosis rate of the Ishikawa cells was significantly increased. In the animal study, the development of the xenograft tumors was significantly suppressed by the combined application of the two agents. Further investigation revealed that the synergistic inhibitory effect of the two agents on EC can be at least partly, explained by the decreased expression of cyclin D1 and cyclin E. The results of the current study provide novel insights into the treatment of EC. PMID- 29393480 TI - Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. AB - Chemotherapy is one of the methods to treat patients with non-small cell lung cancer (NSCLC) developing resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib. Previous studies revealed that the sensitivity to chemotherapy may depend on different cellular mechanisms of acquired EGFR-TKIs resistance. Thus, the present study aimed to investigate the sensitivity of distinct gefitinib-resistant NSCLC cell lines to chemotherapy in order to help select effective treatment regimens for patients with EGFR-TKI resistance. In the present study, we established two gefitinib-resistant cell lines (PC-9/ZD and PC-9/GR) with the human lung adenocarcinoma cell line PC-9 (carrying the delE746-A750 mutation in the EGFR gene). PC-9/ZD cell line expressed the T790M mutation, while PC-9/GR presented the phenotypes of epithelial to mesenchymal transition (EMT). PC-9/ZD cells were more sensitive to paclitaxel and docetaxel than PC-9 cells and knockdown of T790M decreased this sensitivity. In addition, PC-9/GR cells were less sensitive to chemotherapeutic drugs tested, including cisplatin, gemcitabine, pemetrexed, paclitaxel and docetaxel, compared to PC-9 and PC-9/ZD cells. CDH1 transfection reversed the EMT and restored the sensitivity to chemotherapy in PC-9/GR cells. Furthermore, PC-9 cells became resistant to chemotherapy after TGF-beta1-induced EMT. The EMT in NSCLC cells significantly increased cancer stem cell (CSC) properties and tumorgenicity. Collectively, the present study revealed that gefitinib-resistant NSCLC cells carrying the T790M mutation were sensitive to taxane chemotherapy, indicating that T790M is a useful biomarker for the selection of chemotherapy. EMT in NSCLC cells confers resistance to chemotherapy, which may be associated with enhanced CSC properties. PMID- 29393481 TI - Polygalacin D induces apoptosis and cell cycle arrest via the PI3K/Akt pathway in non-small cell lung cancer. AB - Polygalacin D (PGD) is a bioactive compound isolated from Platycodon grandiflorum (Jacq.) and it has a similar structure to platycodin D, which is a well known anticancer agent. In the present study, we investigated the anti-proliferative effects of PGD using NSCLC cell lines. We evaluated the effects of PGD on proliferation, apoptosis and cell cycle arrest in A549 and H460 cells. PGD significantly induced apoptosis and nuclear condensation in both cell lines. Furthermore, PGD upregulated the cleavage of apoptotic proteins such as caspase 3, -9 and PARP. Additionally, treatment with PGD suppressed the expression of the IAP family of proteins including survivin, cIAP-1 and cIAP-2. Furthermore, PGD induced G0/G1-phase arrest in both cell lines. After treatment with PGD, the expression of TIMP-1, CDK2, cyclin A and cyclin E was reduced at the protein level. In addition, PGD blocked the PI3K/Akt pathway by inhibiting the phosphorylation of GSK3beta, Akt and the expression of PI3K. Our results indicated that the anti-proliferative properties of PGD may result from the regulation of the PI3K/Akt pathway, which plays a critical role in cell survival and growth. PMID- 29393482 TI - Cooperation between ETS variant 2 and Jumonji domain-containing 2 histone demethylases. AB - The E26 transformation-specific (ETS) variant 2 (ETV2) protein, also designated as ETS-related 71, is a member of the ETS transcription factor family and is essential for blood and vascular development in the embryo. The role of ETV2 in cancer has not yet been investigated. In the present study, the expression of ETV2 mRNA was identified in a variety of tumor types, including prostate carcinoma. In addition, ETV2 gene amplification was identified in several types of cancer, suggesting that ETV2 plays an oncogenic role in tumorigenesis. It was demonstrated that ETV2 forms complexes with two histone demethylases: Jumonji domain-containing (JMJD)2A and JMJD2D; JMJD2A has been previously reported as a driver of prostate cancer development. In the present study, it was reported that ETV2 exhibited the potential to stimulate the promoters of matrix metalloproteinases (MMPs), including MMP1 and MMP7, within LNCaP prostate cancer cells. JMJD2A and JMJD2D could synergize with ETV2 to activate the MMP1 promoter, whereas only JMJD2A stimulated the MMP7 promoter in cooperation with ETV2. Furthermore, ETV2 expression was positively associated with JMJD2A and JMJD2D mRNA levels in neuroendocrine prostate tumors, in which an ETV2 gene amplification rate of 17.8% was identified. Collectively, the results of the present study indicated that ETV2, JMJD2A and JMJD2D may jointly promote tumorigenesis, particularly neuroendocrine prostate tumors. In addition, the interaction with the JMJD2A and JMJD2D epigenetic regulators may be important in the ability of ETV2 to reprogram cells, modulate normal and cancer stem cells, and affect spermatogenesis. PMID- 29393483 TI - Short hairpin RNA-mediated gene silencing of ADAM17 inhibits the growth of breast cancer MCF-7 cells in vitro and in vivo and its mechanism of action. AB - A disintegrin and metalloprotease 17 (ADAM17) is highly expressed in many malignant tumors and is closely related to their development. We showed in a previous study that silencing of ADAM17 by siRNA inhibited the growth of MCF-7 breast cancer cells in vitro and in vivo. In the present study, we investigated the effects of ADAM17-short hairpin RNA (ADAM17-shRNA) on MCF-7 breast cancer cells and explored the potential action pathway. In vitro, transfection of shRNAs was performed using a lentivirus, and the effects of ADAM17-shRNA on invasion, proliferation and cell cycle distribution of MCF-7 cells were assessed by Boyden chamber method, real-time cell analysis and flow cytometry, respectively. In vivo, MCF-7 cells with different administrations were transplanted subcutaneously into nude mice, and the effect of ADAM17-shRNA on the growth of transplanted tumors was assessed. In addition, the morphological structures were observed by H&E staining, and the expression of ADAM17 and Ki-67 was assessed by immunohistochemistry; expression of ADAM17, EGFR, p-EGFR, AKT, p-AKT, ERK and p ERK proteins was assessed by western blotting, respectively. Our data showed that ADAM17-shRNA successfully inhibited ADAM17 mRNA expression, invasion and proliferation of MCF-7 cells resulting in G0/G1 phase arrest, and significantly inhibited the growth of transplanted tumors with larger areas of necrosis, low expression of ADAM17 and Ki-67 and reduced protein expression of ADAM17, EGFR, p EGFR, AKT, p-AKT, ERK, and p-ERK in the tumor tissues. The present research suggests that ADAM17-shRNA can inhibit MCF-7 cell invasion and proliferation in vitro and inhibit MCF-7 xenograft growth in vivo through the EGFR/PI3K/AKT and EGFR/MEK/ERK signaling pathways. PMID- 29393484 TI - Effect of sinomenine hydrochloride on radiosensitivity of esophageal squamous cell carcinoma cells. AB - Radiation therapy is one of the most important treatments for unresectable and locally advanced esophageal squamous cell carcinoma (ESCC), however, the response to radiotherapy is sometimes limited by the development of radioresistance. Sinomenine hydrochloride (SH) has anticancer activity, but its effect on the radiosensitivity of ESCC is unclear. We determined the effect of SH on the radiosensitivity of ESCC cells and elucidated its potential radiosensitization mechanisms in vitro and in vivo. ESCC cells were subjected to SH and radiation, both separately and in combination. Untreated cells served as controls. The CCK-8 assay was used to evaluate cell proliferation, and the clonogenic assay to estimate radiosensitization. Flow cytometry was used to investigate cell cycle phases and cell apoptosis. Bcl-2, Bax, cyclin B1, CDK1, Ku86, Ku70, and Rad51 expression was evaluated using western blotting. In vivo, tumor xenografts were created using BALB/c nude mice. Tumor-growth inhibition was recorded, and Ki-67 and Bax expression in the tumor tissues was assessed using immunohistochemistry. SH inhibited ESCC cell growth and markedly increased their radiosensitivity by inducing G2/M phase arrest. SH combined with radiation therapy significantly increased ESCC cell apoptosis. The molecular mechanism by which SH enhanced radiosensitivity of ESCC cells was related to Bcl-2, cyclin B1, CDK1, Ku86, Ku70, and Rad51 downregulation and Bax protein expression upregulation. SH combined with radiation considerably delayed the growth of tumor xenografts in vivo. Immunohistochemical analysis showed that in the SH combined with radiation group, the expression of Bax was significantly higher while that of Ki-67 was lower than the expressions in the control groups. Taken together, our findings showed that SH could improve the sensitivity of radiation in ESCC cells by inducing G2/M phase arrest, promoting radiation-induced apoptosis and inhibiting DSB-repair pathways. SH appears to be a prospective radiosensitizer for improving the efficacy of radiotherapy for ESCC. PMID- 29393485 TI - Early changes in quasispecies variant after antiviral therapy for chronic hepatitis B. AB - Hepatitis B virus (HBV) polymerase gene is targeted by nucleos(t)ide analogues (NUC), but it is unclear how HBV quasispecies of whole genome changes during early period of NUC treatment. To understand the unknown region of drug sensitivity and treatment resistance, HBV quasispecies of whole genome during early period of NUC treatment was examined using ultra-deep sequencing. Eleven patients with chronic HBV infection who received NUC treatment were enrolled in the current study. Viral DNA was extracted from serum samples before and early period of NUC treatment. Polymerase chain reaction analysis was subsequently performed on the DNA products. The viral quasispecies of the entire genome was analyzed by ultra-deep sequencing. The regions and positions corresponding to the changes in the quasispecies were investigated before and early period of NUC treatment. The secondary structure changes were predicted by mutations/substitutions detected using Lasergene Protean v14.1 software. The frequency of quasispecies variants increased significantly in the polymerase domain from before to early period of NUC treatment (3.08+/-1.28 vs. 3.51+/ 1.47%, P<0.008), particularly the reverse transcription (RT) domain (3.76+/-1.25 vs. 4.52+/-1.37%, P<0.012). In addition, increased variation detected from HBsAg domain showed statistically significant during NUC treatment (6.81+/-3.26 vs. 7.81+/-3.26%, P<0.040). The amino acid (aa) mutations/substitutions were detected and compared from before to early period of treatment. Interestingly, most of them were located in the RT region (RT1 motif: aa21-aa51) and small S region in the early duration of NUC treatment. Furthermore, several mutation patterns, such as cI97L and cP130T showed alterations in the secondary structure and predicted antigenicity of HBV protein. Although the HBV whole genome can be affected by NUC treatment, RT 1 motif region and small S region are more sensitive to the early period of NUC treatment. This study suggested the initial changes of HBV quasispecies might affect the long-term drug sensitivity and resistance to NUC treatment. PMID- 29393486 TI - A 10-microRNA prognosis scoring system in esophageal squamous cell carcinoma constructed using bioinformatic methods. AB - MicroRNA (miR) signatures may aid the diagnosis and prediction of cancer; therefore, miRs associated with the prognosis of esophageal squamous cell carcinoma (ESCC) were screened. miR-sequencing (seq) and mRNA-seq data from early stage ESCC samples were downloaded from The Cancer Genome Atlas (TCGA) database, and samples from subjects with a >6-month survival time were assessed with Cox regression analysis for prognosis-associated miRs. A further two miR expression datasets of ESCC samples, GSE43732 and GSE13937, were downloaded from the Gene Expression Omnibus database. Common miRs between prognosis-associated miRs, and miRs in the GSE43732 and GSE13937, datasets were used for risk score calculations for each sample, and median risk scores were applied for the stratification of low- and high-risk samples. A prognostic scoring system of signature miRs was subsequently constructed and used for survival analysis for low- and high-risk samples. Differentially-expressed genes (DEGs) corresponding to all miRs were screened and functional annotation was performed. A total of 34 prognostic miRs were screened and a scoring system was created using 10 signature miRs (hsa-miR 140, -33b, -34b, -144, -486, -214, -129-2, -374a and -412). Using this system, low-risk samples were identified to be associated with longer survival compared with high-risk samples in the TCGA and GSE43732 datasets. Age, alcohol and tobacco use, and radiotherapy were prognostic factors for samples with different risk scores and the same clinical features. There were 168 DEGs, and the top 20 risk scores positively-correlated and the top 20 risk scores negatively correlated DEGs were significantly enriched for six and 10 functional terms, respectively. 'Tight junction' and 'melanogenesis' were two significantly enriched pathways of DEGs. miR-214, miR-129-2, miR-37a and miR-486 may predict ESCC patient survival, although further studies to validate this hypothesis are required. PMID- 29393487 TI - Effects of metformin on the expression of AMPK and STAT3 in the spinal dorsal horn of rats with neuropathic pain. AB - Neuropathic pain (NP) is a frustrating and burdensome problem. Current treatments for NP have unendurable side effects and/or questionable efficacy, and once these therapies are stopped, the symptoms often return. Thus, novel drugs are needed to enhance the effectiveness of treatments for NP. One novel target for pain treatments is adenosine monophosphate-activated protein kinase (AMPK), which regulates a variety of cellular processes, including protein translation, which is considered to be affected in NP. Metformin is a widely available drug that possesses the ability to activate AMPK. The signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in neuroinflammation. The present study investigated the analgesic effect of metformin on NP induced by chronic constriction injury (CCI), and the influence of metformin on the expression of AMPK and STAT3 in the spinal dorsal horn (SDH). In CCI rats, paw withdrawal latencies in response to thermal hyperalgesia were significantly shorter, while phosphorylated (p)-AMPK was expressed at lower levels and p-STAT3 was expressed at higher levels in the SDH. Administering intraperitoneal injections of metformin (200 mg/kg) for 6 successive days activated AMPK and suppressed the expression of p-STAT3, in addition to reversing hyperalgesia. Finally, metformin inhibited the activation of microglia and astrocytes in the SDH, which may explain how it alleviates NP. PMID- 29393488 TI - Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma. AB - Pterostilbene (Pter) is reported to exhibit an anticancer effect in hepatocellular carcinoma (HCC). In order to explore the anticancer mechanism in HCC cells, the present study aimed to investigate whether pterostilbene (Pter) may increase phosphatase and tensin homolog (PTEN) expression through targeted downregulation of microRNA (miRNA/miR)-19a in hepatocellular carcinoma (HCC). The proliferation, apoptosis and cell cycle was analyzed in the SMMC-7721 HCC cell line by MTT assays and flow cytometry methods. Cells were divided into five treatment groups: Pter treatment, miR-19a inhibitor transfection, Pter + miR-19a inhibitor, negative control transfection and blank control. The expression of miR 19a and PTEN was detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis following treatment. Furthermore, a luciferase reporter gene assay was performed to determine whether the PTEN gene was a direct target of miR-19a. The results demonstrated that Pter treatment or miR-19a inhibitor transfection downregulated miR-19a and induced PTEN/Akt pathway regulation, which led to proliferation inhibition, cell cycle arrest in the S phase, increased apoptosis and reduced cell invasion. These results indicated that Pter may increase PTEN expression through the direct downregulation of miR 19a in HCC. Therefore, miR-19a may have potential as a novel molecular marker for HCC and Pter may be a promising clinical target with the potential to be developed as a HCC therapy. PMID- 29393489 TI - Lysyl oxidase inhibition via beta-aminoproprionitrile hampers human umbilical vein endothelial cell angiogenesis and migration in vitro. AB - Lysyl oxidase (LOX) is an enzyme that oxidizes lysine residues in collagens and elastin. It stabilizes or remodels the extracellular matrix and basement membrane of blood vessels. Current oncology studies have revealed that LOX is upregulated in invasive cancer cells and bolstered cell movement, and LOX was observed to promote the angiogenesis and migration of endothelial cells. In the present study, angiogenesis and migration were examined in human umbilical vein endothelial cells (HUVECs). Following cell treatment with 0.1-0.4 mM beta aminoproprionitrile (BAPN), a specific inhibitor of LOX, angiogenesis was analyzed with a fibrin gel in vitro angiogenesis assay kit and migration was examined via a Boyden Chamber assay. Angiogenesis-associated gene expression was investigated with a microarray assay and confirmed with reverse transcription quantitative polymerase chain reaction (RT-qPCR). The results showed that HUVEC angiogenesis substantially increased in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and phorbol 12 myristate 13-acetate (PMA). In addition, LOX inhibition blocked the angiogenesis stimulated by VEGF bFGF and PMA, and the inhibition of LOX reduced the migration of HUVECs. Furthermore, the microarray and RT-qPCR revealed that BAPN downregulated myeloid progenitor inhibitory factor 1, and western blot analysis demonstrated that BAPN decreased the phosphorylation of MAPK and Akt, suggesting that the specific inhibitor of LOX, BAPN, may serve as an alternative strategy for preventing angiogenesis. PMID- 29393490 TI - Erythropoietin alleviates post-resuscitation myocardial dysfunction in rats potentially through increasing the expression of angiotensin II receptor type 2 in myocardial tissues. AB - Activation of renin-angiotensin system (RAS) is one of the pathological mechanisms associated with myocardial ischemia-reperfusion injury following resuscitation. The present study aimed to determine whether erythropoietin (EPO) improves post-resuscitation myocardial dysfunction and how it affects the renin angiotensin system. Sprague-Dawley rats were randomly divided into sham, vehicle, epinephrine (EP), EPO and EP + EPO groups. Excluding the sham group, all groups underwent cardiopulmonary resuscitation (CPR) 4 min after asphyxia-induced cardiac arrest (CA). EP and/or EPO was administrated by intravenous injection when CPR began. The results demonstrated that the vehicle group exhibited lower mean arterial pressure, left ventricular systolic pressure, maximal ascending rate of left ventricular pressure during left ventricular isovolumic contraction and maximal descending rate of left ventricular pressure during left ventricular isovolumic relaxation (+LVdP/dt max and -LVdP/dt max, respectively), and higher left ventricular end-diastolic pressure, compared with the sham group following return of spontaneous circulation (ROSC). Few significant differences were observed concerning the myocardial function between the vehicle and EP groups; however, compared with the vehicle group, EPO reversed myocardial function indices following ROSC, excluding-LVdP/dt max. Serum renin and angiotensin (Ang) II levels were measured by ELISA. The serum levels of renin and Ang II were significantly increased in the vehicle group compared with the sham group, which was also observed for the myocardial expression of renin and Ang II receptor type 1 (AT1R), as determined by reverse transcription-quantitative polymerase chain reaction and western blotting. EPO alone did not significantly reduce the high serum levels of renin and Ang II post-resuscitation, but changed the protein levels of renin and AT1R expression in myocardial tissues. However, EPO enhanced the myocardial expression of Ang II receptor type 2 (AT2R) following ROSC. In conclusion, the present study confirmed that CA resuscitation activated the renin Ang II-AT1R signaling pathway, which may contribute to myocardial dysfunction in rats. The present study confirmed that EPO treatment is beneficial for protecting cardiac function post-resuscitation, and the roles of EPO in alleviating post resuscitation myocardial dysfunction may potentially be associated with enhanced myocardial expression of AT2R. PMID- 29393491 TI - beta3GnT8 regulates oxaliplatin resistance by altering integrin beta1 glycosylation in colon cancer cells. AB - Correlations between drug resistance and glycosylation changes have been analyzed intensively in the field of tumor biology. The present study was aimed to investigate the glycan and glycogene alterations involved in oxaliplatin resistance in human colon cancer cells. Using the lectin microarray for glycan composition and FITC-lectin binding for glycan profiling, we found that polylactosamine-type N-glycans were significantly increased in oxaliplatin resistant SW620R cells. Using real-time PCR for quantification of glycogenes, we targeted beta-1,3-N-acetylglucosaminyltransferase 8 (beta3GnT8), which was overexpressed in SW620R cells. Using an RNA interference strategy, we revealed that the silencing of beta3GnT8 in SW620R cells resulted in increased chemosensitivity to oxaliplatin. Conversely, the engineered overexpression of beta3GnT8 in SW620 cells enhanced resistance to oxaliplatin. Further data revealed that manipulation of beta3GnT8 was able to modify polylactosamine chains on integrin beta1 and to regulate the integrin beta1 downstream signaling pathway. These results revealed that beta3GnT8 may play a key role in the development of oxaliplatin resistance in colon cancer cells possibly through the alteration of the glycosylation of integrin beta1. These findings may be valuable for overcoming drug resistance in colon cancer. PMID- 29393492 TI - Dexmedetomidine impairs P-glycoprotein-mediated efflux function in L02 cells via the adenosine 5'-monophosphate-activated protein kinase/nuclear factor-kappaB pathway. AB - Dexmedetomidine (DEX) a type of the anaesthetic that has been widely used in anaesthesia and intensive care. However, whether DEX affects the pharmacokinetics of drugs remains elusive. As hepatic P-glycoprotein (P-gp) serves a critical role in the disposition of drugs, the present study aimed to address whether P-gp function could be affected by DEX in vitro. In the present study, L02 cells (a normal human liver cell line) were exposed to DEX for 24 h and P-gp function was evaluated by the intracellular accumulation of Rhodamine 123. The results indicated that P-gp function was significantly impaired by DEX treatment and that the mRNA levels and protein levels of P-gp were downregulated in a dose- and time dependent manner. Importantly, DEX-induced downregulation of P-gp was associated with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation, as it was significantly attenuated by AMPK inhibition using dorsomorphin. Furthermore, the results revealed that changes in the subcellular localisation of nuclear factor (NF)-kappaB following AMPK activation were involved in the P-gp regulation in response to DEX treatment. Collectively, these results suggested that DEX impairs P-glycoprotein-mediated efflux function in L02 cells via the AMPK/NF kappaB pathway, which provided direct evidence that the hepatic disposition of drugs may be affected by DEX through the downregulation of P-gp. PMID- 29393493 TI - Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer. AB - Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81 (MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor; however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer (EOC) and have shown that its overexpression is associated with cisplatin sensitization. However, the exact functional role of MUS81 and its regulation in relation to chemotherapy sensitivity remains unknown. Our previous study using protein interaction chip revealed that minichromosome maintenance complex component 2 (MCM2) is closely correlated with MUS81. This study aimed to investigate the biological effects and mechanisms of MUS81 on cellular responses to chemotherapeutic drugs. To accomplish this, we downregulated MUS81 and MCM2 in A2780 and SKOV3 ovarian cancer cells using lentivirus-mediated RNAi. Using a qPCR-based HR assay kit to detect HR efficiency. The sensitivity of MUS81 to olaparib was investigated by cell proliferation, colony formation assays and flow cytometry. The results showed that MUS81 modulates MCM2 levels as well as homologous recombination (HR) activity. Moreover, downregulation of MUS81 increased the sensitivity of EOC cells to olaparib by inducing S phase arrest and promoting apoptosis through activation of MCM2. MUS81 may be a potential novel therapeutic target for EOC. PMID- 29393494 TI - Depletion of aquaporin 1 decreased ADAMTS-4 expression in human chondrocytes. AB - Inflammation serves an important role in the progression of osteoarthritis (OA), and IL-1beta may act as a catabolic factor on cartilage, reducing the synthesis of primary cartilage components type II collagen and aggrecan. Aquaporin 1 (AQP1) is a 28-kDa water channel formed of six transmembrane domains on the cell membrane. AQP1 is highly expressed in the anus, gallbladder and liver, and is moderately expressed in the hippocampus, ependymal cells of the central nervous system and articular cartilage. It was hypothesized that AQP1 may be highly expressed in OA cartilage and that it may increase the expression of catabolic factors during inflammatory OA progression. Therefore, the present study evaluated AQP1 functions in human OA articular chondrocytes. Primary chondrocytes were isolated from human hip and knee cartilage tissues, cultured and transfected with AQP1-specific small interfering RNA with or without subsequent IL-1beta treatment. In vitro explant culture from hip cartilages were also prepared. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to assess the expression of AQP genes in human articular cartilage, AQP1 immunohistochemistry of the cartilages and explant culture, as well as RT quantitative PCR, western blotting and immunocytochemistry/immunofluorescence of OA chondrocytes to evaluate the expression of AQP1, and catabolic and anabolic factors. RT-PCR results demonstrated that AQP0, 1, 3, 7, 9, and 11 were expressed in OA chondrocytes. Immunohistochemistry revealed that AQP1 was highly expressed in the superficial to middle zones of OA articular cartilages. Additionally, AQP1 mRNA was significantly higher in OA cartilage and IL-1beta treatment significantly increased AQP1 expression in hip explant cartilage. Furthermore, AQP1 downregulation decreased a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-4 expression in OA chondrocytes, though it did not affect other associated genes. Immunofluorescence showed that AQP1 and ADAMTS-4 were co-localized. These findings indicated that AQP1 depletion may decrease ADAMTS-4 expression in human OA chondrocytes. Therefore, regulating AQP1 expression may be a strategy to suppress catabolic factors during OA progression. PMID- 29393496 TI - Ultraviolet A radiation induces cortistatin overexpression and activation of somatostatin receptors in ARPE-19 cells. AB - Long-term exposure to ultraviolet (UV) radiation is associated with pathological alterations of the retinal pigment epithelium (RPE). It has been indicated that Cortistatin (CST) and somatostatin (SST) are able to inhibit the neurodegeneration of the RPE associated with diabetic retinopathy and retinal ischemia via activation of SST receptors (SSTRs). To the best of our knowledge, the present study indicated for the first time that treatment with UV-A (30 and 60 min) causes an increase of CST expression, rather than SST, which was linked with the upregulation of STTR3,4,5 subtype receptor gene expression levels. The study revealed that: i) SST and CST mRNA expression were both detected under basal conditions in a human retinal pigment epithelial cell line (Arpe-19); ii) SST expression remained constant from baseline to 1 h of UV-A treatment; iii) CST mRNA expression levels were 80 times increased compared with time 0 and after 30 min of exposition to ultraviolet irradiation; iv) SSTR1, SSTR2 mRNA and low levels of SSTR4 were expressed in basal conditions, whereas SSTR3 and SSTR5 mRNA were not detected under the same conditions; and v) only SSTR3, SSTR4 and SSTR5 were overexpressed after UV-A treatment, although in a different way. In conclusion, the findings provide reasonable evidence to support the pathophysiological role of the CST/SST/SSTRs system in the adaptive response of the RPE exposed to UV-A radiation. PMID- 29393495 TI - miR-195 inhibits cell proliferation and angiogenesis in human prostate cancer by downregulating PRR11 expression. AB - hsa-miR-195-5p (miR-195) has been proven to be a critical regulator in the progression of prostate cancer (PCa). To identify additional targets and molecular functions of miR-195, we overexpressed miR-195 by transient oligonucleotide transfection in DU145 and LNCaP cells and examined the effects. RNA-based microarray and dual-luciferase assays were carried out to identify novel targets of miR-195, while in vitro functional assays, a subcutaneous xenograft model, tissue microarray (TMA) analysis and a cohort of publicly available data (Taylor cohort) were used to investigate the biological function and clinical value of miR-195 targeting. The results shown that miR-195 overexpression could markedly suppress cellular proliferation and tube formation compared with miR-negative control. The RNA-based microarray identified a total of 153 differentially regulated genes with fold changes of <=|1.5|, including 138 (90.2%) downregulated and 15 (9.8%) upregulated genes. Among the downregulated genes, we found that proline-rich protein 11 (PRR11) combined with miR-195 expression (miR-195/PRR11) could be used as an independent predictor of the risk of biochemical recurrence in the Taylor cohort. Additionally, the dual-luciferase assay identified PRR11 as a novel target of miR-195, and the in vitro assays indicated that PRR11 abrogated the suppressive effects of miR-195 on cell proliferation, tube formation and cell cycling. Furthermore, the subcutaneous tumor xenograft model indicated that knockdown of PRR11 inhibited xenograft growth and angiogenesis, while the results of the TMA and Taylor cohort analyses collectively demonstrated that PRR11 expression was upregulated in aggressive tumors and is associated with poor clinical outcome. Taken together, these findings further illustrate the suppressive role of miR-195 in PCa, and indicate a novel role of PRR11 in PCa. Importantly, the newly identified miR-195/PRR11 axis may aid with identifying potential therapeutic targets in PCa. PMID- 29393497 TI - Leptin, leptin receptors and hypoxia-induced factor-1alpha expression in the placental bed of patients with and without preeclampsia during pregnancy. AB - The mechanism underlying the pathogenesis of preeclampsia (PE) has been previously investigated but remains to be elucidated. Among numerous biomarkers that are associated with the pathogenesis of PE, leptin is most frequently investigated. Although studies concerning the association between PE and the expression of leptin in the serum and placenta have been conducted, the results are conflicting and inconsistent. Furthermore, the expression of leptin and its receptors in the placental bed and their association with PE, to the best of our knowledge, has not been previously reported. Therefore, to determine the association between the expression of leptin and its receptor, and pathogenesis and onset period of PE, placental bed tissues were obtained from cesarean section deliveries. The mRNA and protein expression levels of leptin and its receptor were investigated in normal pregnancies (n=18), pregnancies complicated with early-onset PE (n=9) and late-onset PE (n=9) by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that the mRNA and protein expression of leptin in the placental bed was significantly increased in the PE groups compared with normal controls and was associated with the onset period of PE. Furthermore, as evidenced by immunostaining, leptin was upregulated in endothelial cells of the placental bed in the PE groups, with a particularly strong upregulation in activated endothelial cells from patients with early-onset PE. The results of the present study indicate that altered expression of leptin in the placental bed may contribute to the pathogenesis of PE. PMID- 29393498 TI - Induction of apoptosis in nasal polyp-derived fibroblasts by bleomycin A5 in vitro. AB - The present study aimed to evaluate the pro-apoptotic effects of bleomycin A5 on nasal polyp-derived fibroblasts (NPDFs) and the underlying molecular mechanisms. Nasal polyp tissue was acquired from 10 patients during surgery and NPDFs were isolated from surgical tissues. Fibroblasts were identified using immunohistochemistry. Bleomycin A5 was used to treat NPDFs along a concentration gradient. Cell viability was evaluated using a Cell Counting Kit-8 assay. A flow cytometric Annexin V-fluorescein isothiocyanate/propidium iodide assay was used to determine the percentage of apoptotic NPDFs. The mRNA expression levels of apoptotic genes were determined by reverse transcription-quantitative polymerase chain reaction and levels of proteins associated with apoptosis were determined by western blotting. The results indicated that bleomycin A5 was able to induce apoptosis in NPDFs in a dose-dependent manner. NPDFs treated with bleomycin A5 were identified to contain significantly high amounts of the active forms of caspase-3 and showed considerable cleavage of poly(ADP-ribose) polymerase. The mRNA and protein expression levels of the pro-apoptotic molecule Bcl-2-associated X protein were significantly higher in treated NPDFs than in untreated NPDFs. In contrast, the mRNA and protein expression of the anti-apoptotic molecule B-cell lymphoma 2 (Bcl-2) was significantly lower in treated NPDFs. These results indicated that bleomycin A5 could induce apoptosis in primary NPDFs through activation of the Bcl-2 family and caspase cascades in a time-, and concentration dependent manner. PMID- 29393500 TI - Indoleamine 2, 3-dioxygenase regulation of immune response (Review). AB - Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO-mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation. The present review evaluates the recent progress in elucidating how catabolism of tryptophan regulated by IDO modulates the immune response to inflammatory and immunological signals. Blocking this pathway may be a novel adjuvant therapeutic strategy for clinical application in immunotherapy. PMID- 29393499 TI - Small heterodimer partner deficiency exacerbates binge drinking-induced liver injury via modulation of natural killer T cell and neutrophil infiltration. AB - Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor small heterodimer partner (SHP), which is encoded by the NR0B2 gene, in acute binge drinking-induced liver injury was investigated. SHP-knockout (KO) and wild-type (WT) control mice were intragastrically administered single doses of alcohol. The plasma concentrations of alanine aminotransferase and aspartate aminotransferase in SHP-KO mice following alcohol treatment were significantly increased compared with WT mice. However, results of oil red O staining and 2',7'-dichlorodihydrofluorescein diacetate staining indicated that levels of acute binge drinking-associated hepatic lipid accumulation and oxidative stress were not significantly different between WT and SHP-KO alcohol-treated mice. Notably, tumor necrosis factor-alpha mRNA expression in the liver of SHP-KO mice was significantly increased following alcohol administration, compared with WT mice. Furthermore, the mRNA expression levels of C-C motif chemokine ligand 2, C-X-C motif chemokine ligand 2 and interleukin-4, which are all potent chemoattractants of NKT cells, as well as neutrophil expression levels, were significantly increased in the livers of SHP KO mice compared with WT mice following alcohol administration, as determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry. Enhanced infiltration of NKT cells, determined by flow cytometry, was also demonstrated in the livers of SHP-KO mice following alcohol administration, compared with WT mice. The results of the present study indicate that SHP may be involved in liver-associated protective mechanisms, with regards to the attenuation of damage caused by acute binge drinking, via regulation of NKT cell and neutrophil migration to the liver. The modulation of SHP may be a novel therapeutic strategy for the treatment of acute binge drinking-induced liver injury. PMID- 29393501 TI - Long non-coding RNA XIST exerts oncogenic functions in pancreatic cancer via miR 34a-5p. AB - Long non-coding RNAs (lncRNAs) have been implicated in the occurrence and progression of multiple cancers. In the present study, we investigated the role of lncRNA X inactive-specific transcript (XIST) in the development and progression of pancreatic cancer (PC). Firstly, we found that lncRNA XIST was markedly upregulated in PC tissues and PC cell lines, respectively. Overexpression of XIST significantly promoted the proliferation, migration and invasion, and suppressed cell apoptosis of BxPC-3 cells; knockdown of XIST significantly inhibited the proliferation, migration and invasion, and accelerated cell apoptosis of PANC-1 cells. Furthermore, BxPC-3 and PANC-1 cells transfected with different vectors were injected subcutaneously into nude mice to explore tumor formation. We found that XIST promoted tumor formation in vivo. Subsequently, we found that microRNA-34a-5p (miR-34a-5p) was downregulated in PC tissues, and predicted a poor prognosis in PC patients. In addition, the results indicated that miR-34a-5p is a target gene of XIST and was significantly negatively correlated with XIST. More importantly, we found that miR-34a-5p rescued the facilitation of malignant behavior mediated by XIST. These results indicated that XIST and miR-34a-5p may be potential effective therapeutic targets for PC. PMID- 29393502 TI - Using drugs to target necroptosis: dual roles in disease therapy. AB - Necroptosis is programmed necrosis, a process which has been studied for over a decade. The most common accepted mechanism is through the RIP1-RIP3-MLKL axis to regulate necroptotic cell death. As a result of previous studies on necroptosis, positive regulation for promoting necroptosis such as HSP90 stabilization and hyperactivation of TAK1 on RIP1 is clear. Similarly, the negative regulation of necroptosis, such as through caspase 8, c-FLIP, CHIP, MK2, PELI1, ABIN-1, is also clear. Therefore, the promise of corresponding applications in treating diseases becomes hopeful. Studies have shown that necroptosis is involved in the development of many diseases, such as ischemic injury diseases in various organs, neurodegenerative diseases, infectious diseases, and cancer. Given these results, drugs that inhibit or trigger necroptosis can be discovered to treat diseases. In this review, we briefly introduce up to date concepts concerning the mechanism of necroptosis, the diseases that involve necroptosis, and the drugs that can be applied to treat such diseases. PMID- 29393503 TI - Circular RNAs: Characteristics, function, and role in human cancer. AB - Circular RNAs (circRNAs) are universal and diverse endogenous noncoding RNAs (ncRNAs) that are widely found in eukaryotic cells. They form a covalently closed, continuous stable loop structure without 3' or 5' tails, which are different from linear RNAs. As new members of the ncRNAs, circRNAs' formation, function, and mechanism are attracting increased research attention. CircRNAs play important roles in all kinds of cancer and may be potential novel biomarkers and therapeutic targets for cancer treatment through their function as microRNA (miRNA) molecular "sponges", RNA-binding protein (RBP) sponges, protein translators, and gene transcription regulators. In this review, we introduce the formation and function of circRNAs, and summarize the biological effects of circRNA in tumorigenesis and progression, providing evidence for the potential use of circRNAs in the diagnosis and clinical treatment of cancer. PMID- 29393504 TI - Taxonomy characterization and plumbum bioremediation of novel fungi. AB - The objective of this study was to investigate the screening, taxonomy characterization, Pb biosorption, and application of the high Pb-resistant fungus F1 separated from the heavy metal contaminated soil. Fungus F1 was screened through metal concentration gradient ranging from 25 to 4000 mg L-1 . The internal transcribed spacers (ITS) of the strain was analyzed by molecular biotechnology. The adsorption conditions were also evaluated. The precipitation of fungus F1 was analyzed by Scanning Electron Microscopy (SEM), Fourier transformer infrared spectroscopy (FTIR) and energy dispersive X-ray (EDX) techniques. The Pb speciation was determined by BCR three-step sequential extraction. The highest concentration of fungus F1 resistance to Pb2+ was 3500 mg L-1 . The fungus was identified as Trichoderma asperellum. The optimum condition for the Pb2+ removal rate was discovered as follows: MTL: 3500 mg L-1 ; pH: 7; Pb2+ concentration: 800 mg L-1 ; temperature was 30 degrees C; initial biosorbent dosage: 6% (v/v). The surface chemical functional groups of fungus F1 were amino, hydroxyl, and carbonyl groups, which may be involved in the biosorption of Pb. Application test showed that the exchangeable, acid-and water soluble Pb were reduced, and the sulfide, organic combination state, and residual Pb were increased. With the preferable absorption capacity, fungus F1 was considered to have good prospects of bioremediation. PMID- 29393505 TI - Can pelvic floor trauma be predicted antenatally? AB - INTRODUCTION: Levator trauma is a risk factor for the development of pelvic organ prolapse. We aimed to identify antenatal predictors for significant damage to the levator ani muscle during a first vaginal delivery. MATERIAL AND METHODS: A retrospective observational study utilizing data from two studies with identical inclusion criteria and assessment protocols between 2005 and 2014. A total of 1148 primiparae with an uncomplicated singleton pregnancy were recruited and assessed with translabial ultrasound at 36 weeks antepartum and 871 (76%) returned for reassessment 3-6 months postpartum. The ultrasound data of vaginally parous women were analyzed for levator avulsion and microtrauma. The former was diagnosed if the muscle insertion at the inferior pubic ramus in the plane of minimal hiatal dimensions and within 5 mm above were abnormal on tomographic ultrasound imaging. Microtrauma was diagnosed in women with an intact levator and if there was a postpartum increase in hiatal area on Valsalva by >20% with the resultant area >=25 cm2 . RESULTS: The complete datasets of 844 women were analyzed. Among them, 609 delivered vaginally: by normal vaginal delivery in 452 (54%), a vacuum birth in 102 (12%) and a forceps delivery in 55 (6%). Levator avulsion was diagnosed in 98 and microtrauma in 97. On multivariate analysis, increasing maternal age, lower body mass index and lower bladder neck descent were associated with avulsion. Increased bladder neck descent and a family history of cesarean section (CS) were associcated with microtrauma. CONCLUSIONS: Maternal age, body mass index, bladder neck descent and family history of CS are antenatal predictors for levator trauma. PMID- 29393506 TI - Analytical incorporation of fractionation effects in probabilistic treatment planning for intensity-modulated proton therapy. AB - PURPOSE: We show that it is possible to explicitly incorporate fractionation effects into closed-form probabilistic treatment plan analysis and optimization for intensity-modulated proton therapy with analytical probabilistic modeling (APM). We study the impact of different fractionation schemes on the dosimetric uncertainty induced by random and systematic sources of range and setup uncertainty for treatment plans that were optimized with and without consideration of the number of treatment fractions. METHODS: The APM framework is capable of handling arbitrarily correlated uncertainty models including systematic and random errors in the context of fractionation. On this basis, we construct an analytical dose variance computation pipeline that explicitly considers the number of treatment fractions for uncertainty quantitation and minimization during treatment planning. We evaluate the variance computation model in comparison to random sampling of 100 treatments for conventional and probabilistic treatment plans under different fractionation schemes (1, 5, 30 fractions) for an intracranial, a paraspinal and a prostate case. The impact of neglecting the fractionation scheme during treatment planning is investigated by applying treatment plans that were generated with probabilistic optimization for 1 fraction in a higher number of fractions and comparing them to the probabilistic plans optimized under explicit consideration of the number of fractions. RESULTS: APM enables the construction of an analytical variance computation model for dose uncertainty considering fractionation at negligible computational overhead. It is computationally feasible (a) to simultaneously perform a robustness analysis for all possible fraction numbers and (b) to perform a probabilistic treatment plan optimization for a specific fraction number. The incorporation of fractionation assumptions for robustness analysis exposes a dose to uncertainty trade-off, i.e., the dose in the organs at risk is increased for a reduced fraction number and/or for more robust treatment plans. By explicit consideration of fractionation effects during planning, we demonstrate that it is possible to exploit this trade-off during optimization. APM optimization considering the fraction number reduced the dose in organs at risk compared to conventional probabilistic optimization neglecting the fraction number. CONCLUSION: APM enables computationally efficient incorporation of fractionation effects in probabilistic uncertainty analysis and probabilistic treatment plan optimization. The consideration of the fractionation scheme in probabilistic treatment planning reveals the trade-off between number of fractions, nominal dose, and treatment plan robustness. PMID- 29393507 TI - The induced RNA-binding protein, HuR, targets 3'-UTR region of IL-6 mRNA and enhances its stabilization in periodontitis. AB - RNA-binding proteins (RBPs) regulate mRNA stability by binding to the 3' untranslated region (UTR) region of mRNA. Human antigen-R (HuR), one of the RBPs, is involved in the progression of diseases, such as rheumatoid arthritis, diabetes mellitus and some inflammatory diseases. Interleukin (IL)-6 is a major inflammatory cytokine regulated by HuR binding to mRNA. Periodontal disease (PD) is also an inflammatory disease caused by elevations in IL-6 following an infection by periodontopathogenic bacteria. The involvement of HuR in the progression of PD was assessed using in-vitro and in-vivo experiments. Immunohistochemistry of inflamed periodontal tissue showed strong staining of HuR in the epithelium and connective tissue. HuR mRNA and protein level was increased following stimulation with Porphyromonas gingivalis (Pg), one of the periodontopathogenic bacteria, lipopolysacchride (LPS)-derived from Pg (PgLPS) and tumour necrosis factor (TNF)-alpha in OBA-9, an immortalized human gingival epithelial cell. The luciferase activity of 3'-UTR of IL-6 mRNA was increased by TNF-alpha, Pg and PgLPS in OBA-9. Luciferase activity was also increased in HuR over-expressing OBA-9 following a bacterial stimulation. Down-regulation of HuR by siRNA resulted in a decrease in mRNA expression and production of IL-6. In contrast, the over-expression of HuR increased IL-6 mRNA expression and production in OBA-9. The HuR inhibitor, quercetin, suppressed Pg-induced HuR mRNA expression and IL-6 production in OBA-9. An oral inoculation with quercetin also inhibited bone resorption in ligature-induced periodontitis model mice as a result of down-regulation of IL-6. These results show that HuR modulates inflammatory responses by regulating IL-6. PMID- 29393508 TI - Comments on "Clinical characteristics of chronic lymphocytic leukemia occurring in Chornobyl cleanup workers" by S.C. Finch, I. Dyagil et al., Vol. 35 (2), 2017, p. 215-224. PMID- 29393509 TI - Human lactoferrin attenuates the proinflammatory response of neonatal monocyte derived macrophages. AB - Bioactive components of human milk, such as human lactoferrin (hLF), play an essential role in gut microbiome homeostasis and protection against neonatal inflammatory diseases. Neonatal intestinal macrophages display a proinflammatory profile that might contribute to inflammatory mucosal injury. Therefore, the aim of the study was to investigate the immunomodulatory effects of hLF on differentiation and activation of monocyte-derived macrophages (moMphi). Monocytes isolated from umbilical cord blood of term neonates and peripheral blood of healthy adults were differentiated in the absence or presence of hLF, and differentiation, apoptosis and phagocytosis were evaluated. Cytokine production, Toll-like receptor (TLR) signalling and activation marker expression were investigated upon activation with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) challenge. We demonstrate that hLF-differentiated moMphi exhibit decreased TLR-4 expression, TLR signalling, proinflammatory cytokine secretion and intracellular tumour necrosis factor (TNF)-alpha production. Investigation of differentiation markers, morphology and induction of apoptosis showed no alteration in lactoferrin-differentiated moMphi. Taken together, hLF promote anergic/anti-inflammatory effects by TLR expression and pathway interference, resulting in a diminished proinflammatory moMphi phenotype. The anergic/anti inflammatory properties of hLF might contribute to the prevention of harmful TLR mediated inflammatory disorders in the developing gut of premature infants. PMID- 29393510 TI - SWEET11 and 15 as key players in seed filling in rice. AB - Despite the relevance of seed-filling mechanisms for crop yield, we still have only a rudimentary understanding of the transport processes that supply the caryopsis with sugars. We hypothesized that SWEET sucrose transporters may play important roles in nutrient import pathways in the rice caryopsis. We used a combination of mRNA quantification, histochemical analyses, translational promoter-reporter fusions and analysis of knockout mutants created by genomic editing to evaluate the contribution of SWEET transporters to seed filling. In rice caryopses, SWEET11 and 15 had the highest mRNA levels and proteins localized to four key sites: all regions of the nucellus at early stages; the nucellar projection close to the dorsal vein; the nucellar epidermis that surrounds the endosperm; and the aleurone. ossweet11;15 double knockout lines accumulated starch in the pericarp, whereas caryopses did not contain a functional endosperm. Jointly, SWEET11 and 15 show all the hallmarks of being necessary for seed filling with sucrose efflux functions at the nucellar projection and a role in transfer across the nucellar epidermis/aleurone interface, delineating two major steps for apoplasmic seed filling, observations that are discussed in relation to observations made in rice and barley regarding the relative prevalence of these two potential import routes. PMID- 29393512 TI - FTIR spectroscopy for prediction of quality parameters and antimicrobial activity of commercial vinegars with chemometrics. AB - BACKGROUND: The aim of this study was to discriminate between commercial apple, rice, balsamic, red-wine, rose, white-wine, grape, and pomegranate vinegars according to their antimicrobial activities, total phenolic contents (TPC), antioxidant activities, and color parameters, and to predict the quality characteristics of vinegars using Fourier transform infrared (FTIR) spectroscopy. RESULTS: Results showed that the highest TPC (3971.43 +/- 25.00) was found in balsamic vinegar whereas the lowest TPC was observed in rice vinegar (14.36 +/- 0.16). Antioxidant activities of vinegars were correlated with TPC. Grape-based vinegars exhibited higher antimicrobial activity against Staphylococcus aureus (S. aureus), Escherichia coli (E.coli) and Pseudomonas aeruginosa (P.aeruginosa). However, there were no statistically significant differences among vinegars in terms of antimicrobial activities. According to principal component analysis (PCA) and hierarchical cluster analysis (HCA), vinegars were classified into three groups and each group consisted of vinegars from different raw materials. Prediction models were constructed successfully using partial least squares (PLS) considering whole FTIR spectral data. CONCLUSION: The results indicated that FTIR could be used as a rapid method to estimate the antimicrobial activities, TPC, color and antioxidant activities of vinegars. (c) 2018 Society of Chemical Industry. PMID- 29393513 TI - Do Women Find the Progesterone Vaginal Ring Acceptable? Findings from Kenya, Nigeria, and Senegal. AB - The progesterone vaginal ring (PVR) is a contraceptive designed for use by breastfeeding women in the first year postpartum. This Report presents results of an acceptability study of the PVR in Kenya, Nigeria, and Senegal. Women seeking postpartum family planning services were offered various contraceptive options including the PVR. Of the 174 participating women, 110 (63 percent) used one ring and 94 (54 percent) completed the study by using two rings over a six-month period. Women were interviewed up to three times: at the time they entered the study, at 3 months (the end of the first ring cycle), and at 6 months (the end of the second ring cycle or when they exited if they had discontinued earlier). Many participants found the ring to be acceptable, with over three-quarters reporting that it was easy to insert, remove, and reinsert. While a small proportion of women experienced ring expulsion, the majority did not. These findings suggest that even in countries with little or no use of vaginal health products, contraceptive vaginal rings offer women a new option that they are able and willing to use. PMID- 29393511 TI - Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission. AB - BACKGROUND: The 8-aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6 phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. OBJECTIVES: To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using 'malaria*', 'falciparum', 'primaquine', '8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria. DATA COLLECTION AND ANALYSIS: Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. MAIN RESULTS: We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing.No cluster trials evaluating community effects on malaria transmission met the inclusion criteria.With artemisinin treatmentLow dose PQInfectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence).Moderate dose PQInfectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups.High dose PQInfectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis.With non-artemisinin treatmentTrials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis.Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). AUTHORS' CONCLUSIONS: A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce malaria transmission at community level. PMID- 29393515 TI - CLE peptide tri-arabinosylation and peptide domain sequence composition are essential for SUNN-dependent autoregulation of nodulation in Medicago truncatula. AB - MtCLE12 and MtCLE13 encode CLAVATA3/EMBRYO-SURROUNDING REGION RELATED (CLE) peptides which regulate autoregulation of nodulation (AON) in Medicago through the shoot receptor, SUNN (SUPER NUMERIC NODULES). Genetics suggests RDN1 (ROOT DETERMINED NODULATION 1) arabinosylates MtCLE12 to enable SUNN perception. The functional structures of MtCLE12 and MtCLE13 peptides, however, remain elusive. We combined genetic and chemical synthesis approaches to determine if glyco modifications of three nodule-expressed CLE peptides are essential for AON. We also examined how root and shoot applied AON-CLEs inhibit nodulation. MtCLE12, MtCLE13 and MtCLE42 peptides were synthesized with hydroxylation, mono arabinosylation or tri-arabinosylation (TaP) at proline 7. Only MtCLE12-TaP and MtCLE13-TaP peptides induced AON in wild-type (WT) and rdn1-1, but not in sunn-4. The application of MtCLE13-TaP to cotyledons 1 d before rhizobial inoculation completely inhibited both rhizobial infection and nodulation. By contrast, MtCLE12-TaP induced significant AON without abolishing rhizobial infection. The results indicate that key CLE domain amino acids and TaP modifications to MtCLE12 and MtCLE13 are essential for SUNN-dependent AON. We also show evidence that RDN1 does not tri-arabinosylate MtCLE13. Finally, MtCLE13-TaP can induce a strong AON response in shoots that inhibits the entire symbiotic processes in roots. We present a new model for AON in Medicago. PMID- 29393514 TI - Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage. AB - OBJECTIVE: We assessed the influence of age on warfarin dose, percentage time in target range (PTTR), and risk of major hemorrhage. DESIGN: Warfarin users recruited into a large prospective inception cohort study were categorized into three age groups: young (younger than 50 yrs), middle aged (50-70 yrs), and elderly (older than 70 yrs). The influence of age on warfarin dose and PTTR was assessed using regression analysis; risk of major hemorrhage was assessed using proportional hazards analysis. Models were adjusted for demographic, clinical, and genetic factors. SETTING: Two outpatient anticoagulation clinics. PARTICIPANTS: A total of 1498 anticoagulated patients. OUTCOMES: Warfarin dose (mg/day), PTTR, major hemorrhage. RESULTS: Of the 1498 patients, 22.8% were young, 44.1% were middle aged, and 33.1% were elderly. After accounting for clinical and genetic factors, compared with young warfarin users, warfarin dose requirements were 10.6% lower among the middle aged and an additional 10.6% lower for the elderly. Compared with young patients, middle-aged and elderly patients spent more time in target international normalized ratio (INR) range (p<0.0001), despite having fewer INR assessments (p<0.0001). Compared with young warfarin users, absolute risk of hemorrhage was marginally higher among the middle aged (p=0.08) and significantly higher among the elderly (p=0.016). Compared with young warfarin users, after adjustment, the relative risk of hemorrhage increased by 31% for each age category (p=0.026). CONCLUSIONS: In a real-world setting, despite achieving better anticoagulation control, elderly patients had a higher risk of major hemorrhagic events. As the population ages and the candidacy for oral anticoagulation increases, strategies that mitigate the elevated risk of hemorrhage need to be identified. PMID- 29393517 TI - Does genotypic and species diversity of mycorrhizal plants and fungi affect ecosystem function? AB - Contents Summary 1122 I. Introduction 1122 II. Are there consistent patterns in diversity of mycorrhizal fungal genotypes and species across space? 1125 III. What is the variation in functional traits and genes of mycorrhizal fungi at different taxonomic scales? 1125 IV. How will environmental change impact the relationships between genotypic and species diversity of mycorrhizal fungi and ecosystem function? 1126 V. Conclusions: considerations for future MEF research 1127 Acknowledgements 1127 References 1127 SUMMARY: Both genotypes and species of mycorrhizal fungi exhibit considerable variation in traits, and this variation can result in their diversity regulating ecosystem function. Yet, the nature of mycorrhizal fungal diversity-ecosystem function (MEF) relationships for both genotypes and species is currently poorly defined. New experiments should reflect the richness of genotypes and species in nature, but we still lack information about the extent to which fungal populations in particular are structured. Sampling designs should quantify the diversity of mycorrhizal fungal genotypes and species at three key broad spatial scales (root fragment, root system and interacting root systems) in order to inform manipulation experiments and to test how mycorrhizal fungal diversity both responds, and confers resilience to, environmental drivers. PMID- 29393516 TI - The application of pomelo peel as a carrier for adsorption of epigallocatechin-3 gallate. AB - BACKGROUND: Pomelo (Citrus grandis) is the largest citrus fruit, the peel of which is a well-known agricultural wastes. Disposal of pomelo peel after consumption is a serious environment problem. As a natural, versatile bio absorbent, pomelo peel has shown excellent adsorption capacity for several pollutants, attributed to its micro-pores; however, there is no relevant report on its adsorption capacity for natural products or food ingredients. The ability of pomelo peel to adsorb epigallocatechin-3-gallate (EGCG) was examined in this study. The physicochemical characterizations of pomelo peel were determined by Fourier transform infrared spectroscopy, scanning electron microscopy and high performance liquid chromatography. The adsorption process of EGCG onto pomelo peel from aqueous solution was carried out at a range of concentrations (50-800 mg L-1 ) and temperatures (25, 40 and 55 degrees C). RESULTS: The main components of pomelo peel are composed of dietary fiber, which provide sufficient adsorption sites during the adsorption process. The adsorption of EGCG onto pomelo peel showed excellent fitness with a pseudo-second-order model. Both Langmuir and Freundlich models were able to describe the isothermal adsorption of EGCG onto pomelo peel. The results of thermodynamic analysis suggested that adsorption is spontaneous and endothermic in nature, and that the process is likely to be dominated by a physisorption mechanism. CONCLUSION: The results of this study indicate that pomelo peel has potential adsorption capacity for EGCG, which can be used as an effective, low-cost carrier for delivery of natural products in functional food and dietary supplement applications. (c) 2018 Society of Chemical Industry. PMID- 29393518 TI - A brief peer gatekeeper suicide prevention training: Results of an open pilot trial. AB - OBJECTIVE: The purpose of the present study was to test a 1-hour peer suicide gatekeeper training for students from the broad college community in the context of an open pilot trial. METHOD: Two-hundred and thirty-one college students were recruited university-wide, Mage = 20.7, 65.4% female, and completed a peer suicide prevention gatekeeping training program. Assessments were completed at pre-training and post-training as well as 3-month follow-up. RESULTS: This brief peer suicide gatekeeper training program was associated with increases in suicide prevention knowledge. It was also associated with an increase in the number of students who identified suicidal youth and made mental health referrals, as well as total number of referrals made, over the course of three months. Females reported greater improvement in suicide prevention skills and knowledge post training than males. CONCLUSIONS: Offering peer suicide gatekeeper training to students from the general college population may hold promise in suicide prevention efforts. PMID- 29393519 TI - Investigating the relationship between two home numeracy measures: A questionnaire and observations during Lego building and book reading. AB - Home numeracy has been defined as the parent-child interactions that include experiences with numerical content in daily-life settings. Previous studies have commonly operationalized home numeracy either via questionnaires or via observational methods. These studies have shown that both types of measures are positively related to variability in children's mathematical skills. This study investigated whether these distinctive data collection methods index the same aspect of home numeracy. The frequencies of home numeracy activities and parents' opinions about their children's mathematics education were assessed via a questionnaire. The amount of home numeracy talk was observed via two semi structured videotaped parent-child activity sessions (Lego building and book reading). Children's mathematical skills were examined with two calculation subtests. We observed that parents' reports and number of observed numeracy interactions were not related to each other. Interestingly, parents' reports of numeracy activities were positively related to children's calculation abilities, whereas the observed home numeracy talk was negatively related to children's calculation abilities. These results indicate that these two methods tap on different aspects of home numeracy. Statement of contribution What is already known on this subject? Home numeracy, that is, parent-child interactions that include experiences with numerical content, is supposed to have a positive impact on calculation or mathematical ability in general. Despite many positive results, some studies have failed to find such an association. Home numeracy has been assessed with questionnaires on the frequency of numerical experiences and observations of parent-child interactions; however, those two measures of home numeracy have never been compared directly. What does this study add? This study assessed home numeracy through questionnaires and observations in the 44 parent child dyads and showed that home numeracy measures derived from questionnaires and observations are not related. Moreover, the relation between the reported frequency of home numeracy activities and calculation on the one hand, and parent child number talk (derived from observations) and calculation on the other hand is in opposite directions; the frequency of activities is positively related to calculation performance; and the amount of number talk is negatively related to calculation. This study shows that both measures tap into different aspects of home numeracy and can be an important factor explaining inconsistencies in literature. PMID- 29393520 TI - Magnetic field pattern synthesis and its application in targeted drug delivery: Design and implementation. AB - In cancer therapy, magnetic drug targeting is considered as an effective treatment to reduce chemotherapy's side effects. The accurate design and shaping of magnetic fields are crucial for healthy cells to be immune from chemotherapeutics. In this paper, arbitrary 2-dimensional spatial patterns of magnetic fields from DC to megahertz are represented in terms of spatial Fourier spectra with sinusoidal eigenfunctions. Realization of each spatial frequency was investigated by a set of elliptical coils. Therefore, it is shown that the desired pattern was synthesized by simultaneous use of coil sets. Currents running on each set were obtained via fast and straightforward analytical Fourier series calculation. Experimentally scanned sample patterns were in close agreement with full wave analysis. Discussions include the evaluation of the Fourier series approximation error and cross-polarization of produced magnetic fields. It was observed that by employing the controlled magnetic field produced by the proposed setup, we were able to steer therapeutic particles toward the right or left half-spheres of the breast, with an efficiency of 90%. Such a pattern synthesizer may be employed in numerous human arteries as well as other bioelectromagnetic patterning applications, e.g., wireless power transfer, magnetic innervation, and tomography. Bioelectromagnetics. 39:325-338, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29393521 TI - Alpha particle spectroscopy using FNTD and SIM super-resolution microscopy. AB - Structured illumination microscopy (SIM) for the imaging of alpha particle tracks in fluorescent nuclear track detectors (FNTD) was evaluated and compared to confocal laser scanning microscopy (CLSM). FNTDs were irradiated with an external alpha source and imaged using both methodologies. SIM imaging resulted in improved resolution, without increase in scan time. Alpha particle energy estimation based on the track length, direction and intensity produced results in good agreement with the expected alpha particle energy distribution. A pronounced difference was seen in the spatial scattering of alpha particles in the detectors, where SIM showed an almost 50% reduction compared to CLSM. The improved resolution of SIM allows for more detailed studies of the tracks induced by ionising particles. The combination of SIM and FNTDs for alpha radiation paves the way for affordable and fast alpha spectroscopy and dosimetry. PMID- 29393522 TI - Derivation and Validation of a Clostridium difficile Infection Recurrence Prediction Rule in a National Cohort of Veterans. AB - STUDY OBJECTIVE: Prior studies have identified risk factors for recurrent Clostridium difficile infection (CDI), but few studies have integrated these factors into a clinical prediction rule that can aid clinical decision-making. The objectives of this study were to derive and validate a CDI recurrence prediction rule to identify patients at risk for first recurrence in a national cohort of veterans. DESIGN: Retrospective cohort study. DATA SOURCE: Veterans Affairs Informatics and Computing Infrastructure. PATIENTS: A total of 22,615 adult Veterans Health Administration beneficiaries with first-episode CDI between October 1, 2002, and September 30, 2014; of these patients, 7538 were assigned to the derivation cohort and 15,077 to the validation cohort. MEASUREMENTS AND MAIN RESULTS: A 60-day CDI recurrence prediction rule was created in a derivation cohort using backward logistic regression. Those variables significant at p<0.01 were assigned an integer score proportional to the regression coefficient. The model was then validated in the derivation cohort and a separate validation cohort. Patients were then split into three risk categories, and rates of recurrence were described for each category. The CDI recurrence prediction rule included the following predictor variables with their respective point values: prior third- and fourth-generation cephalosporins (1 point), prior proton pump inhibitors (1 point), prior antidiarrheals (1 point), nonsevere CDI (2 points), and community-onset CDI (3 points). In the derivation cohort, the 60-day CDI recurrence risk for each score ranged from 7.5% (0 points) to 57.9% (8 points). The risk score was strongly correlated with recurrence (R2 = 0.94). Patients were split into low-risk (0-2 points), medium-risk (3-5 points), and high-risk (6 8 points) classes and had the following recurrence rates: 8.9%, 20.2%, and 35.0%, respectively. Findings were similar in the validation cohort. CONCLUSION: Several CDI and patient-specific factors were independently associated with 60-day CDI recurrence risk. When integrated into a clinical prediction rule, higher risk scores and risk classes were strongly correlated with CDI recurrence. This clinical prediction rule can be used by providers to identify patients at high risk for CDI recurrence and help guide preventive strategy decisions, while accounting for clinical judgment. PMID- 29393524 TI - Corrigendum. PMID- 29393523 TI - Measurement of kinaesthetic properties of in-brine table olives by microstructure of fracture surface, sensory evaluation and texture profile analysis (TPA). AB - BACKGROUND: A series of transformations occur in olive fruit both during ripening and processing. In particular, significant changes in the microstructural composition affect the flavour, texture, nutrients and overall quality of the end product. Texture is one of the sensory quality attributes of greatest importance to consumer acceptance. In the present work, kinaesthetic properties of in-brine table olives of three cultivars of Olea europaea L. (Bella di Cerignola, Peranzana and Taggiasca cvs) were provided by several measurements of olive tissue texture by sensory, rheological and microstructural approaches. RESULTS: Olives at the same stage of ripening and processed with the same technology, but belonging to different cultivars, showed significant differences at microstructural, sensorial and rheological levels. To describe the relationship between the three variables, multiple regression analysis and principal component analysis were chosen. CONCLUSION: Differences in microstructure were closely related both in terms of hardness measured by texture profile analysis and hardness measured by sensory analysis. The information provided could be an aid for screening and training of a sensory panel. (c) 2018 Society of Chemical Industry. PMID- 29393526 TI - Microfluidics and Miniaturization 2018. PMID- 29393528 TI - Some diffuse large B cell lymphomas (DLBCLs) present with clone-dependent TTF-1 positivity. PMID- 29393529 TI - Surreptitious apple cider vinegar treatment of a melanocytic nevus: Newly described histologic features. PMID- 29393530 TI - Synthesis and Applications of Stenhouse Salts and Derivatives. AB - In recent years, Stenhouse salts have attracted much attention as intermediates for the synthesis of cyclopenten-2-enones. This Minireview aims to present an overview of the methods for preparation, further transformation and applications of Stenhouse and Stenhouse-like salts. In this context, the Piancatelli rearrangement and its variants, and the recently reported donor-acceptor Stenhouse salts (DASA) will be addressed. The photophysical properties of DASA and its applications in colorimetric detection of amines, functionalization of polymers for detection of heat and nerve agents, photolithography and orthogonal photoswitching systems are discussed. PMID- 29393531 TI - Diffusion kurtosis imaging with free water elimination: A bayesian estimation approach. AB - PURPOSE: Diffusion kurtosis imaging (DKI) is an advanced magnetic resonance imaging modality that is known to be sensitive to changes in the underlying microstructure of the brain. Image voxels in diffusion weighted images, however, are typically relatively large making them susceptible to partial volume effects, especially when part of the voxel contains cerebrospinal fluid. In this work, we introduce the "Diffusion Kurtosis Imaging with Free Water Elimination" (DKI-FWE) model that separates the signal contributions of free water and tissue, where the latter is modeled using DKI. THEORY AND METHODS: A theoretical study of the DKI FWE model, including an optimal experiment design and an evaluation of the relative goodness of fit, is carried out. To stabilize the ill-conditioned estimation process, a Bayesian approach with a shrinkage prior (BSP) is proposed. In subsequent steps, the DKI-FWE model and the BSP estimation approach are evaluated in terms of estimation error, both in simulation and real data experiments. RESULTS: Although it is shown that the DKI-FWE model parameter estimation problem is ill-conditioned, DKI-FWE was found to describe the data significantly better compared to the standard DKI model for a large range of free water fractions. The acquisition protocol was optimized in terms of the maximally attainable precision of the DKI-FWE model parameters. The BSP estimator is shown to provide reliable DKI-FWE model parameter estimates. CONCLUSION: The combination of the DKI-FWE model with BSP is shown to be a feasible approach to estimate DKI parameters, while simultaneously eliminating free water partial volume effects. Magn Reson Med 80:802-813, 2018. (c) 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29393532 TI - Effects of low phosphorus supply on the availability of calcium and phosphorus, and musculoskeletal development of growing dogs of two different breeds. AB - To investigate the impact of a selective reduction in dietary phosphorus (P) supply on healthy growing dogs, a total of 23 Beagles and 30 Foxhound crossbreds (FBI) were used in a feeding trial between 6 and 24 weeks of age. Sixteen Beagles and 19 FBI were fed with selectively reduced P concentrations (low phosphorus, LP). The remaining puppies received a completely balanced control diet (CON). With these diets, the P supply in the Beagles at the age of 12 weeks added up to 2.5 +/- 0.6 (LP) and 9.8 +/- 1.4 g P/kg DM (CON), and in the FBI 4.3 +/- 0.9 (LP) and 13.0 +/- 1.6 g P/kg DM (CON). Therefore, the LP Beagles received an average of 33 +/- 11% of the recommended daily allowances (RDA) of P, the LP FBI 41 +/- 11%. The calcium (Ca) concentration stayed unaltered and led to a Ca/P ratio above the recommended range of 1.3/1 to 2/1. The apparent digestibility (aD) of phosphorus was reduced in the LP Beagle; otherwise, the aD of both minerals was not affected by the P concentration of the diet. The renal excretion of P was reduced to zero in both LP groups while the renal calcium excretion increased significantly. Several of the puppies from both breeds showed impaired appetite, growth, skin and fur quality, and a few also clinically showed relevant signs of a disturbed musculoskeletal system after the LP feeding. A rapid loss of muscle strength and posture within hours led to severe deviation of the limb axis with hyperflexion of the joints but no radiological aberrations or signs of pain. Immediate transition of affected puppies to a balanced diet with sufficient phosphorus resulted in a complete recovery of the puppies in less than one month. The results demonstrate the importance of an adequate P supply on the healthy development of growing dogs. PMID- 29393533 TI - Efficacy, safety, and cost of pomalidomide in relapsed and refractory multiple myeloma. AB - OBJECTIVES: To investigate the efficacy, safety, and cost of a pomalidomide dexamethasone regimen in patients with relapsed and refractory multiple myeloma (RRMM). METHODS: All patients (n = 63) treated with pomalidomide-dexamethasone for RRMM in our university hospital between August 2013 and October 2015 were included. RESULTS: Pomalidomide was discontinued early due to progression (before the 4th cycle) in 17 (27%) patients. No case was discontinued for intolerance. The only independent factor that predicted early pomalidomide discontinuation was time from diagnosis to pomalidomide initiation <3 years. Overall response rate was 51% including complete response in 8%, very good partial response in 25%, and partial response in 19% patients. Thirteen (33%) patients showed stable disease. Median overall survival was 6.4 months in the 17 patients who discontinued pomalidomide early vs 26.8 months in the 14 patients with stable disease vs not achieved in the 32 responders (log-rank; P < 10-3 ). The most common grade >=3 adverse events were neutropenia (14%) and infections (25%). The incremental cost effectiveness ratio of pomalidomide-dexamethasone compared with dexamethasone alone was estimated at ?39 911 per life-year gained. CONCLUSIONS: The study demonstrated that pomalidomide-dexamethasone regimen has a long-term favorable safety-efficacy profile in RRMM patients. The survival benefit is substantial even in patients with stable disease. PMID- 29393534 TI - Regionally distinct patterns of STAT3 phosphorylation in the seminiferous epithelia of mouse testes. AB - In mouse testes, Sertoli cells support the continuous process of spermatogenesis, which is dependent on seminiferous epithelial cycles along the longitudinal axis of the seminiferous tubule. Sertoli cell function is modulated partly by local cytokines and/or growth factors derived from adjacent tissues such as blood vessels, macrophages, rete testis, etc. However, the spatial activation patterns by local signals in vivo remain unclear. In this study, we focused on Signal Transducers and Activators of Transcription (STAT) signaling in Sertoli cells, because STAT is a major crucial cytokine transducer for somatic cyst cell regulation in Drosophila testis niches. In mouse testes, STAT3 was ubiquitously expressed in Sertoli cells throughout the seminiferous tubules. Phosphorylated STAT3 (p-STAT3) was predominantly observed in the Sertoli cells within the valve like structure adjacent to the rete testis (i.e., the Sertoli valve [SV]) in the terminal segment of the proximal seminiferous tubules. In the distal seminiferous tubules with active spermatogenesis, most Sertoli cells were negative for anti-p STAT3 staining. Albeit rarely, a small patch of several p-STAT3-positive Sertoli cells was detected frequently in seminiferous epithelial cycle stages I-VI. Such p-STAT3-positive ratios in the convoluted seminiferous epithelia were significantly increased in germ cell-less testes than in the wild-type testes, but with considerably lower ratios than in the SV region. These findings imply that regionally distinct patterns of STAT3 phosphorylation in the Sertoli cells depend on either location or spermatogenic activity in normal healthy testes in vivo, highlighting a novel entry point to understanding STAT signaling in mammalian spermatogenesis. PMID- 29393535 TI - Clinical effect of corticosteroids in asthma-affected horses: A quantitative synthesis. AB - BACKGROUND: There are limited findings from low-powered studies based on few number of subjects with equine asthma. Furthermore, no studies have been performed to assess a meaningful clinically detectable impact of corticosteroids in equine asthma. OBJECTIVES: To assess and compare the clinical effect of inhaled and systemic corticosteroids in equine asthma and identify a quantitative clinical score suitable to assess the Minimal Important Difference (MID), expressed as the Minimally Clinically Detectable Difference (MCDD). STUDY DESIGN: Pair-wise and network meta-analysis. METHODS: Literature searches for studies on corticosteroid therapy in equine asthma were performed. The risk of publication bias was assessed by Funnel plots and Egger's test. The effect on changes in clinical scores vs. control was analysed via random-effects models and Bayesian networks. RESULTS: Corticosteroids significantly improved the clinical condition (Standardised Mean Difference: -1.52, 95% CrI -2.07 to -0.98; P<0.001 vs. control). No difference was detected between inhaled and systemic corticosteroids with regard to the changes in clinical scores (Relative Effect: 0.08, 95% CrI 1.45 to 1.32; P = 0.8). An Improved clinically Detectable Equine Asthma Scoring System (IDEASS) indicated that corticosteroids improved the clinical condition of asthmatic horses by 30% compared with controls (IDEASS value: -2.36, 95% CI -3.39 to -1.33; P<0.001). A one-point change in IDEASS represented the MCDD in equine asthma. MAIN LIMITATIONS: Moderate quality of evidence for systemic corticosteroids. CONCLUSIONS: Inhaled corticosteroids are effective in improving the clinical condition of horses with equine asthma and prevent exacerbations. Systemic corticosteroids should be used only in selected cases with symptomatic airway hyperresponsiveness during exacerbation. IDEASS requires further validation but may represent a suitable approach to rank the level of asthma severity and assess the clinical effect of pharmacotherapy in horses with equine asthma. PMID- 29393536 TI - Hierarchical Nanostructures of Metal-Organic Frameworks Applied in Gas Separating ZIF-8-on-ZIF-67 Membranes. AB - Membranes from metal-organic frameworks (MOFs) are highly interesting for industrial gas separation applications. Strongly improved performances for carbon capture and H2 purification tasks in MOF membranes are obtained by using highly reproducable and very accuratly, hierarchically grown ZIF-8-on-ZIF-67 (ZIF-8@ZIF 67) nanostructures. To forgo hardly controllable solvothermal synthesis, particles and layers are prepared by self-assembling methods. It was possible for the first time to confirm ZIF-8-on-ZIF-67 membrane growth on rough and porous ceramic supports using the layer-by-layer deposition. Additionally, hierarchical particles are made in a fast RT synthesis with high monodispersity. Characterization of the hierarchical and epitaxial grown layers and particles is performed by SEM, TEM, EDXM and gas permeation. The system ZIF-8@ZIF-67 shows a nearly doubled H2 /CO2 separation factor, regardless of whether neat membrane or mixed-matrix-membrane in comparison to other MOF materials. PMID- 29393537 TI - Mouse meiosis expressed gene 1 is not phosphorylated in vivo. PMID- 29393538 TI - Process optimization of the extraction condition of beta-amylase from brewer's malt and its application in the maltose syrup production. AB - beta-Amylase is of important biotechnological aid in maltose syrup production. In this study, the extraction condition of beta-amylase from brewer's malt and the optimal dosage of beta-amylase in maltose syrup production were optimized using response surface methodology and uniform design method. The optimal extraction condition of beta-amylase from brewer's malt was composed of 1:17 (g/v) material/liquid ratio, 44 degrees C extraction temperature, pH 6.4 buffer pH, 2.3 H extraction time, and 1.64 g L-1 NaSO3 dosage with a predicted beta-amylase activity of 1,290.99 U g-1 , which was close to the experimental beta-amylase activity of 1,230.22 U g-1 . The optimal dosages of beta-amylase used in maltose syrup production were 455.67 U g-1 starch and its application in maltose syrup production led to a 68.37% maltose content in maltose syrup, which was 11.2% and 28.9% higher than those using beta-amylases from soybean and microbe (P < 0.01). Thus, beta-amylase from brewer's malt was beneficial for production of high maltose syrup. PMID- 29393539 TI - Pulsed gradient stimulated echo (PGStE) NMR shows spatial dependence of fluid diffusion in human stage IV osteoarthritic cartilage. AB - PURPOSE: Human osteoarthritic (OA) articular cartilage was investigated with spatially resolved pulsed gradient stimulated echo (PGStE) NMR using strong gradients. In this study, the diffusivity of fluid and biopolymer was characterized as a function of depth within human OA cartilage cores. METHODS: One dimensional (1D) spatially resolved diffusion profiles were measured for human OA cartilage using a standard pulsed gradient stimulated echo (PGStE) sequence with the addition of a read imaging gradient. Low gradient values (0.05 to 1.5 Tm-1 ) were used to measure fluid motion and high gradients (2.50 to 17.81 Tm-1 ) enabled analysis of biopolymer motion. Structural damage to cartilage was simulated using either salt or collagenase. RESULTS: These data demonstrate that fluid diffusion is sensitive to salt treatment and collagenase digestion, while biopolymer diffusion is sensitive only to collagenase digestion. Biopolymer and fluid diffusion are donor specific for human OA cartilage samples. CONCLUSION: These data support that fluid diffusion is sensitive to the structure of cartilage while biopolymer diffusion is sensitive to the molecular weight of the biopolymers. The results show that diffusion of fluid and biopolymers in articular cartilage are sensitive to OA and provide complimentary information. Magn Reson Med 80:1170-1177, 2018. (c) 2018 International Society for Magnetic Resonance in Medicine. PMID- 29393540 TI - Serogroup Y primary meningococcal arthritis in a child. PMID- 29393541 TI - The association of discharge decisions after deceased donor kidney transplantation with the risk of early readmission: Results from the deceased donor study. AB - BACKGROUND: Kidney transplant (KT) recipients experience high rates of early (<=30 days) hospital readmission (EHR) after KT, and existing studies provide limited data on modifiable discharge factors that may mitigate EHR risk. METHODS: We performed a retrospective cohort study of 468 adult deceased donor KT recipients transplanted between 4/2010 and 11/2013 at 5 United States transplant centers. We fit multivariable mixed effects models to assess the association of two potentially modifiable discharge factors with the probability of EHR after KT: (i) weekend discharge and (ii) days to first scheduled follow-up. RESULTS: Among 468 KT recipients, 38% (n = 178) experienced EHR after KT. In fully adjusted analyses, compared to weekday discharges, KT recipients discharged on the weekend had a 29% lower risk of EHR (adjusted odds ratio [aOR] 0.71, 95% confidence interval [CI] 0.41-0.94). Compared to follow-up within 2 days of discharge, KT recipients with follow-up within 3 to 6 days had a 28% higher probability of EHR (aOR 1.28, 95% CI 1.13-1.45). CONCLUSIONS: These findings suggest that clinical decisions related to the timing of discharge and follow-up modify EHR risk after KT, independent of traditional risk factors. PMID- 29393542 TI - Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors. PMID- 29393543 TI - Mucosal-associated invariant T cell receptor recognition of small molecules presented by MR1. AB - The major histocompatibility complex (MHC) class-I related molecule MR1 is a monomorphic and evolutionary conserved antigen (Ag)-presenting molecule that shares the overall architecture of MHC-I and CD1 proteins. However, in contrast to MHC-I and the CD1 family that present peptides and lipids, respectively, MR1 specifically presents small organic molecules. During microbial infection of mammalian cells, MR1 captures and presents vitamin B precursors, derived from the microbial biosynthesis of riboflavin, on the surface of antigen-presenting cells. These MR1-Ag complexes are recognized by the mucosal-associated invariant T cell receptor (MAIT TCR), which subsequently leads to MAIT cell activation. Recently, MR1 was shown to trap chemical scaffolds including drug and drug-like molecules. Here, we review this metabolite Ag-presenting molecule and further define the key molecular interactions underlying the recognition and reactivity of MAIT TCRs to MR1 in an Ag-dependent manner. PMID- 29393544 TI - A single-cell analysis reveals multiple roles of oligodendroglial lineage cells during post-ischemic regeneration. AB - NG2 cells represent precursors of oligodendrocytes under physiological conditions; however, following cerebral ischemia they play an important role in glial scar formation. Here, we compared the expression profiles of oligodendroglial lineage cells, after focal cerebral ischemia (FCI) and in Alzheimer's-like pathology using transgenic mice, which enables genetic fate mapping of Cspg4-positive NG2 cells and their progeny, based on the expression of red fluorescent protein tdTomato. tdTomato-positive cells possessed the expression profile of NG2 cells and oligodendrocytes; however, based on the expression of cell type-specific genes, we were able to distinguish between them. To shed light on the changes in the expression patterns caused by FCI, we employed self-organizing Kohonen maps, enabling the division of NG2 cells and oligodendrocytes into subpopulations based on similarities in the expression profiles of individual cells. We identified three subpopulations of NG2 cells emerging after FCI: proliferative; astrocyte-like and oligodendrocyte-like NG2 cells; such phenotypes were further confirmed by immunohistochemistry. Oligodendrocytes themselves formed four subpopulations, which reflected the process of oligodendrocytes maturation. Finally, we used 5-ethynyl-2' deoxyuridine (EdU) labeling to reveal that NG2 cells can differentiate directly into reactive astrocytes without preceding proliferation. In contrast, in Alzheimer's-like pathology we failed to identify these subpopulations. Collectively, here we identified several yet unknown differences between the expression profiles of NG2 cells and oligodendrocytes, and characterized specific genes contributing to oligodendrocyte maturation and phenotypical changes of NG2 cells after FCI. Moreover, our results suggest that, unlike in Alzheimer's-like pathology, NG2 cells acquire a multipotent phenotype following FCI. PMID- 29393545 TI - Bu-Shen-Huo-Xue-Fang (BSHXF) modulates nucleus pulposus cell proliferation and extracellular matrix (ECM) remodeling in intervertebral disc degeneration through miR-483 regulation of Wnt pathway. AB - Intervertebral disc degeneration (IDD) has been widely considered as one of the main causes for low back pain (LBP) which can cause severe impact to human health and huge economic burden to worldwide society. IDD pathogenesis can be affected by extensive degradation of extracellular matrix (ECM) and the hyperproliferation of nucleus pulposus (NP) cell. During IDD process, ECM degradation enzymes MMP and ADAMTS expression increases, while ECM synthesis-related Aggrecan and COL2A1 expression decreases. In addition, Wnt signaling pathway is reportedly involved in the process of IDD. Bu-Shen-Huo-Xue-Fang (BSHXF), a Chinese traditional medicine formula which contains six Chinese traditional medicine herbs, is widely used to treat IDD. Herein, we obtained the serum containing BSHXF by using BSHXF fed rat, and demonstrated that BSHXF promoted NP cell proliferation and ECM synthesis through Wnt signaling pathway. By using DIANA online tools and luciferase reporter gene assays, we confirmed that miR-483-3p and miR-23c regulated CTNNB1 and GSK3B, respectively, through direct targeting; thereby affecting the effect of BSHXF on NP cell proliferation and ECM synthesis through Wnt signaling pathway. Taken together, we demonstrated the function and mechanism of BSHXF in regulating NP cell proliferation and ECM remodeling through Wnt signaling pathway during IDD. This article is protected by copyright. All rights reserved. PMID- 29393546 TI - Comparison of metabolic adaptations between endurance- and sprint-trained athletes after an exhaustive exercise in two different calf muscles using a multi slice 31 P-MR spectroscopic sequence. AB - Measurements of exercise-induced metabolic changes, such as oxygen consumption, carbon dioxide exhalation or lactate concentration, are important indicators for assessing the current performance level of athletes in training science. With exercise-limiting metabolic processes occurring in loaded muscles, 31 P-MRS represents a particularly powerful modality to identify and analyze corresponding training-induced alterations. Against this background, the current study aimed to analyze metabolic adaptations after an exhaustive exercise in two calf muscles (m. soleus - SOL - and m. gastrocnemius medialis - GM) of sprinters and endurance athletes by using localized dynamic 31 P-MRS. In addition, the respiratory parameters VO2 and VCO2 , as well as blood lactate concentrations, were monitored simultaneously to assess the effects of local metabolic adjustments in the loaded muscles on global physiological parameters. Besides noting obvious differences between the SOL and the GM muscles, we were also able to identify distinct physiological strategies in dealing with the exhaustive exercise by recruiting two athlete groups with opposing metabolic profiles. Endurance athletes tended to use the aerobic pathway in the metabolism of glucose, whereas sprinters produced a significantly higher peak concentration of lactate. These global findings go along with locally measured differences, especially in the main performer GM, with sprinters revealing a higher degree of acidification at the end of exercise (pH 6.29 +/- 0.20 vs. 6.57 +/- 0.21). Endurance athletes were able to partially recover their PCr stores during the exhaustive exercise and seemed to distribute their metabolic activity more consistently over both investigated muscles. In contrast, sprinters mainly stressed Type II muscle fibers, which corresponds more to their training orientation preferring the glycolytic energy supply pathway. In conclusion, we were able to analyze the relation between specific local metabolic processes in loaded muscles and typical global adaptation parameters, conventionally used to monitor the training status of athletes, in two cohorts with different sports orientations. PMID- 29393547 TI - Computational evaluation of TKR stability using feedback-controlled compressive loading. AB - Pre-clinical assessment of stability in total knee replacement is crucial for developing preferred implant performance. Current total knee replacement patients often experience joint instability that the human body addresses with compensatory strategies. Specifically, an increased quadriceps-hamstrings co contraction serves to increase joint stability through an increased compressive force across the tibiofemoral joint. The aim of this study is to introduce a novel method to evaluate total knee replacement by determining the compressive loading required to achieve natural knee stability. Four current total knee replacement geometries in both their cruciate-retaining and posterior-stabilized forms are modeled in a finite-element framework. The finite-element model is initially validated experimentally using traditional knee laxity testing with a constant compressive load and anterior-posterior displacement or internal external rotation. Model predictions of constraint are in reasonable agreement with experimental results (average root mean square errors: 0.46 Nm, 62.5 N). The finite-element model is subsequently interfaced with a feedback controller to vary the compressive force that the implant requires in order to match experimental natural knee internal-external and anterior-posterior stability at different flexion angles. Results show that the lower constraint total knee replacement designs require on average 66.7% more compressive load than the higher constraint designs to achieve natural knee constraint. As expected, total knee replacement stability and compressive load requirements to replicate natural kinematics vary with inclusion of tibiofemoral ligaments. The current study represents a novel approach to evaluate stability in existing total knee replacement geometries and to design implants that better restore natural knee mechanics. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1901-1909, 2018. PMID- 29393549 TI - Effects of various culture conditions on pluripotent stem cell derivation from chick embryos. AB - Pluripotent stem cell (PSC) lines derived from embryonated avian eggs are a convenient platform for production of various recombinant proteins and vaccines. In chicks, both embryonic stem cells (ESC) and embryonic germ cells (EGC) are considered to be pluripotent cells obtained from early blastodermal cells (stage X) and gonadal tissues (stage HH28), respectively. However, the establishment and long-term maintenance of avian PSC lines faces several challenges and differs in efficiency between chick strains. This study aims to determine the effects of PSC culture media, including serum-based and serum-free media as well as various feeder layers, growth factors, and small molecules on derivation and maintenance of avian embryonic derived-PSCs. Our results have shown that among the different culture conditions, N2B27 serum-free medium supplemented with PD0325901 and SB431542, MEK and TGFbeta chemical inhibitors, named as R2i and cytokine leukemia inhibitory factor (LIF) improved PSC derivation from stages X- and HH28 embryos. The application of N2B27/R2i + LIF medium validates the effect of defined pluripotency supporting medium on efficient derivation of chick PSCs and facilitates the use of these cells in biotechnology and biobanking of valuable species. PMID- 29393548 TI - Synthesis of a Novel Type of 2,3'-BIMs via Platinum-Catalysed Reaction of Indolylallenes with Indoles. AB - Optimisation, scope and mechanism of the platinum-catalysed addition of indoles to indolylallenes is reported here to give 2,3'-BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3'-BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt-catalysed 6-endo-trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl-platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs. PMID- 29393550 TI - Analysis of the number of enlarged pores according to site, age, and sex. AB - BACKGROUND: Increasing the number of enlarged pores causes cosmetic problems. The difference in the number of enlarged pores according to facial site, age, and sex is unclear. OBJECTIVE: To analyze the distribution of the number of enlarged pores according to facial site, age, and sex. METHODS AND MATERIALS: We analyzed the number of the enlarged pores and the percentage of wrinkles in the nose, forehead, and cheek from 434 polarized images. The measurement results were analyzed according to site, age, and sex. Relationship between enlarged pore counts and wrinkle severity was also analyzed. The study was conducted by using DermaVision,TM which can take cross-polarization, parallel polarization, and ultraviolet light images. RESULTS: The enlarged pores of the nose and forehead were more prominent than in the cheeks. Pore counts were increased with age, and the increment was significant between the 30's and 40's. There was no significant difference by gender. Enlarged pore counts were related to wrinkle severity. CONCLUSIONS: The number of enlarged pores differs depending on body site and increased with age. The enlarged pore counts correlate with wrinkle severity and the correlation varies depending on the body site. PMID- 29393551 TI - Comparison of Resting Energy Expenditure Assessment in Pediatric Oncology Patients. AB - BACKGROUND: Evaluation of energy requirements is an important part of the nutrition assessment of pediatric oncology patients. Adequate provision of energy in this population is of extreme importance because of the prevalence of malnutrition and its effect on growth, development, quality of life, morbidity, and mortality. Numerous methods are used in clinical practice for estimating the resting energy expenditures (REE), specifically indirect calorimetry and predictive equations. A relatively new instrument used to assess REE is the hand held indirect calorimeter. The purpose of this quality improvement project was to compare the accuracy of REE measurements taken by a hand-held indirect calorimeter and predictive equations to that of a standard indirect calorimeter metabolic cart. METHODS: Patients receiving therapy for pediatric cancer, aged 7 18 years, and having a weight >=15 kg and scheduled for a REE nutrition assessment were eligible. Sequentially, the patient's REE was assessed with the cart and the hand-held indirect calorimeter along with the predictive equation calculation. RESULTS: Post hoc pairwise comparisons revealed that all 3 methods were significantly different from one another (P < .0001). When compared with the cart, the portable hand-held calorimeter was found to underestimate REE by 11.9%, whereas predictive equations overestimated REE by 12.4%. CONCLUSION: Our quality improvement project suggests that the hand-held indirect calorimeter underestimated REE, and predictive equations overestimated REE in pediatric oncology nutrition assessment. Therefore, we recommend that these limitations in assessment be considered when assessing REE using a hand-held indirect calorimeter or predictive equations. PMID- 29393552 TI - Simultaneous recording of pulsed-wave Doppler signals in innominate vein and transverse aortic arch: new technique to evaluate atrioventricular conduction and fetal heart rhythm. PMID- 29393553 TI - Distribution of thermophilic endospores in a temperate estuary indicate that dispersal history structures sediment microbial communities. AB - Endospores of thermophilic bacteria are found in cold and temperate sediments where they persist in a dormant state. As inactive endospores that cannot grow at the low ambient temperatures, they are akin to tracer particles in cold sediments, unaffected by factors normally governing microbial biogeography (e.g., selection, drift, mutation). This makes thermophilic endospores ideal model organisms for studying microbial biogeography since their spatial distribution can be directly related to their dispersal history. To assess dispersal histories of estuarine bacteria, thermophilic endospores were enriched from sediments along a freshwater-to-marine transect of the River Tyne in high temperature incubations (50 degrees C). Dispersal histories for 75 different taxa indicated that the majority of estuarine endospores were of terrestrial origin; most closely related to bacteria from warm habitats associated with industrial activity. A subset of the taxa detected were marine derived, with close relatives from hot deep marine biosphere habitats. These patterns are consistent with the sources of sediment in the River Tyne being predominantly terrestrial in origin. The results point to microbial communities in estuarine and marine sediments being structured by bi directional currents, terrestrial run-off and industrial effluent as vectors of passive dispersal and immigration. PMID- 29393555 TI - Single-Molecule Kinetics of an Enzyme in the Presence of Multiple Substrates. AB - Herein, the catalytic activity of a single enzyme in the presence of multiple substrates is studied. Three different mechanisms of bisubstrate binding, namely, ordered sequential, random sequential and ping-pong nonsequential pathway, are broadly discussed. By means of the chemical master equation approach, exact expressions for the waiting-time distributions, the mean turnover time and the randomness parameter as a function of the substrate concentration, such that both concentrations are fixed, but one of them is changed quasi-statically are obtained. The randomness parameter is not equal to unity at intermediate to high substrate concentrations, which indicates the presence of multiple rate-limiting steps in the reaction pathway in all three modes of bisubstrate binding. This arises due to transitions between the free enzyme and the enzyme-substrate complexes that occur on comparable timescales. Such turnover statistics of the single enzyme can also distinguish between the different types of bisubstrate binding mechanisms. PMID- 29393554 TI - Genome-wide and expression-profiling analyses suggest the main cytochrome P450 genes related to pyrethroid resistance in the malaria vector, Anopheles sinensis (Diptera Culicidae). AB - BACKGROUND: Anopheles sinensis is one of the major malaria vectors. However, pyrethroid resistance in An. sinensis is threatening malaria control. Cytochrome P450-mediated detoxification is an important pyrethroid resistance mechanism that has been unexplored in An. sinensis. In this study, we performed a comprehensive analysis of the An. sinensis P450 gene superfamily with special attention to their role in pyrethroid resistance using bioinformatics and molecular approaches. RESULTS: Our data revealed the presence of 112 individual P450 genes in An. sinensis, which were classified into four major clans (mitochondrial, CYP2, CYP3 and CYP4), 18 families and 50 subfamilies. Sixty-seven genes formed nine gene clusters, and genes within the same cluster and the same gene family had a similar gene structure. Phylogenetic analysis showed that most of An. sinensis P450s (82/112) had very close 1: 1 orthology with Anopheles gambiae P450s. Five genes (AsCYP6Z2, AsCYP6P3v1, AsCYP6P3v2, AsCYP9J5 and AsCYP306A1) were significantly upregulated in three pyrethroid-resistant populations in both RNA-seq and RT-qPCR analyses, suggesting that they could be the most important P450 genes involved in pyrethroid resistance in An. sinensis. CONCLUSION: Our study provides insight on the diversity of An. sinensis P450 superfamily and basis for further elucidating pyrethroid resistance mechanism in this mosquito species. (c) 2018 Society of Chemical Industry. PMID- 29393556 TI - Contrast-enhanced ultrasound complements two-dimensional ultrasonography in diagnosing gallbladder diseases in dogs. AB - Gall-bladder diseases are common in dogs and two-dimensional ultrasonography is a current standard method for diagnosis and treatment planning. However, findings from this modality can be nonspecific. The aim of this retrospective, case series study was to describe conventional and contrast-enhanced ultrasound (using SonoVue(r) ) findings in a group of dogs with histologically confirmed gall bladder disease. A total of 65 dogs were included. Branchlike, heterogeneous, and homogeneous contrast enhancement of echogenic intraluminal mass-forming lesions was a contrast-enhanced ultrasound characteristic of polypoid lesions due to cystic mucosal hyperplasia of the gallbladder and/or tumor, which had different wash-in and washout characteristics. In dogs with mobile or immobile biliary sludge or mucocele, the echogenic intraluminal masses remained unenhanced. A double rim mark or enhancement defect in the gallbladder wall was a characteristic of edema or necrosis/rupture of the wall, respectively. Conventional ultrasonography correctly identified biliary sludge or mucocele in 36/37 dogs, cholecystitis/edema in 44/47 dogs, necrosis/rupture in 19/25 dogs, and gallbladder neoplasia in three of three dogs with these pathologies. It falsely identified biliary sludge or mucocele in eight of 28 dogs, cholecystitis/edema in three of 15 dogs, necrosis/rupture in 13/37 dogs, and gall bladder neoplasia in 20/59 dogs that did not have these pathologies. Contrast enhanced ultrasound correctly identified cholecystitis/edema in 42/47 dogs, but falsely identified cholecystitis/edema in three of 18 dogs. It correctly identified necrosis/rupture, benign polypoid lesions, and gallbladder neoplasia in all dogs with no false-positive results. Findings supported contrast-enhanced ultrasound as a complement to conventional ultrasonography for dogs with suspected gallbladder pathologies such as edema, necrosis, and rupture. PMID- 29393557 TI - TALEN-mediated gene targeting in porcine spermatogonia. AB - Spermatogonia represent a diploid germ cell population that includes spermatogonial stem cells. In this report, we describe new methods for isolation of highly enriched porcine spermatogonia based on light scatter properties, and for targeted mutagenesis in porcine spermatogonia using nucleofection and TALENs. We optimized a nucleofection protocol to deliver TALENs specifically targeting the DMD locus in porcine spermatogonia. We also validated specific sorting of porcine spermatogonia based on light scatter properties. We were able to obtain a highly enriched germ cell population with over 90% of cells being UCH-L1 positive undifferentiated spermatogonia. After gene targeting in porcine spermatogonia, indel (insertion or deletion) mutations as a result of non-homologous end joining (NHEJ) were detected in up to 18% of transfected cells. Our report demonstrates for the first time an approach to obtain a live cell population highly enriched in undifferentiated spermatogonia from immature porcine testes, and that gene targeting can be achieved in porcine spermatogonia which will enable germ line modification. PMID- 29393558 TI - The virome of the arbuscular mycorrhizal fungus Gigaspora margarita reveals the first report of DNA fragments corresponding to replicating non-retroviral RNA viruses in fungi. AB - Arbuscular Mycorrhizal Fungi (AMF) are key components of the plant microbiota. AMF genetic complexity is increased by the presence of endobacteria, which live inside many species. A further component of such complexity is the virome associated to AMF, whose knowledge is still very limited. Here, by exploiting transcriptomic data we describe the virome of Gigaspora margarita. A BLAST search for viral RNA-dependent RNA polymerases sequences allowed the identification of four mitoviruses, one Ourmia-like narnavirus, one Giardia-like virus, and two sequences related to Fusarium graminearum mycoviruses. Northern blot and RT-PCR confirmed the authenticity of all the sequences with the exception of the F. graminearum-related ones. All the mitoviruses are replicative and functional since both positive strand and negative strand RNA are present. The abundance of the viral RNA molecules is not regulated by the presence or absence of Candidatus Glomeribacter gigasporarum, the endobacterium hosted by G. margarita, with the exception of the Ourmia-like sequence which is absent in bacteria-cured spores. In addition, we report, for the first time, DNA fragments corresponding to mitovirus sequences associated to the presence of viral RNA. These sequences are not integrated in the mitochondrial DNA and preliminary evidence seems to exclude integration in the nuclear genome. PMID- 29393559 TI - Coexistence of novel gammaproteobacterial and Arsenophonus symbionts in the scale insect Greenisca brachypodii (Hemiptera, Coccomorpha: Eriococcidae). AB - Scale insects are commonly associated with obligate, intracellular microorganisms which play important roles in complementing their hosts with essential nutrients. Here we characterized the symbiotic system of Greenisca brachypodii, a member of the family Eriococcidae. Histological and ultrastructural analyses have indicated that G. brachypodii is stably associated with coccoid and rod-shaped bacteria. Phylogenetic analyses have revealed that the coccoid bacteria represent a sister group to the secondary symbiont of the mealybug Melanococcus albizziae, whereas the rod-shaped symbionts are close relatives of Arsenophonus symbionts in insects - to our knowledge, this is the first report of the presence of Arsenophonus bacterium in scale insects. As a comparison of 16S and 23S rRNA genes sequences of the G. brachypodii coccoid symbiont with other gammaprotebacterial sequences showed only low similarity (~90%), we propose the name 'Candidatus Kotejella greeniscae' for its tentative classification. Both symbionts are transovarially transmitted from one generation to the next. The infection takes place in the neck region of the ovariole. The bacteria migrate between follicular cells, as well as through the cytoplasm of those cells to the perivitelline space, where they form a characteristic 'symbiont ball'. Our findings provide evidence for a polyphyletic origin of symbionts of Eriococcidae. PMID- 29393560 TI - Histopathology of immature (ongoing) squamous metaplasia of the stomach. PMID- 29393561 TI - Ultrasound and computed tomography of sacculitis and appendicitis in a rabbit. AB - A 9-month-old neutered male rabbit was referred for lethargy, anorexia, and gastrointestinal stasis. Routine hematology, serum biochemistry, and diagnostic imaging were performed. Computed tomography revealed a wall thickening of the sacculus rotundus and appendix, which was further confirmed on abdominal ultrasound. Full thickness biopsies were collected with histopathology diagnosing a chronic multifocal heterophilic granulomatous sacculitis and appendicitis. The patient was treated medically and at 6 weeks follow-up, clinical signs and intestinal changes had completely regressed. Inflammation of the sacculus rotundus and appendix should be considered as a cause of gastrointestinal stasis in rabbits. PMID- 29393562 TI - A novel MADS-box transcription factor PstMCM1-1 is responsible for full virulence of Puccinia striiformis f. sp. tritici. AB - In many eukaryotes, transcription factor MCM1 gene plays crucial roles in regulating mating processes and pathogenesis by interacting with other co factors. However, little is known about the role of MCM1 in rust fungi. Here, we identified two MCM1 orthologs, PstMCM1-1 and PstMCM1-2, in the stripe rust pathogen Puccinia striiformis f. sp. tritici (Pst). Sequence analysis indicated that both PstMCM1-1 and PstMCM1-2 contain conserved MADS domains and that PstMCM1 1 belongs to a group of SRF-like proteins that are evolutionarily specific to rust fungi. Yeast two-hybrid assays indicated that PstMCM1-1 interacts with transcription factors PstSTE12 and PstbE1. PstMCM1-1 was found to be highly induced during early infection stages in wheat and during pycniospore formation on the alternate host barberry (Berberis shensiana). PstMCM1-1 could complement the lethal phenotype and mating defects in a mcm1 mutant of Saccharomyces cerevisiae. In addition, it partially complemented the defects in appressorium formation and plant infection in a Magnaporthe oryzae Momcm1 mutant. Knock down of PstMCM1-1 resulted in a significant reduction of hyphal extension and haustorium formation and the virulence of Pst on wheat. Our results suggest that PstMCM1-1 plays important roles in the regulation of mating and pathogenesis of Pst most likely by interacting with co-factors. PMID- 29393563 TI - Iron-Catalyzed Reductive Ethylation of Imines with Ethanol. AB - The borrowing hydrogen strategy has been applied to the ethylation of imines with an air-stable iron complex as precatalyst. This approach opens new perspectives in this area as it enables the synthesis of unsymmetric tertiary amines from readily available substrates and ethanol as a C2 building block. A variety of imines bearing electron-rich aryl or alkyl groups at the nitrogen atom could be efficiently reductively alkylated without the need for molecular hydrogen. The mechanism of this reaction, which shows complete selectivity for ethanol over other alcohols, has been studied experimentally and by means of DFT computations. PMID- 29393565 TI - Emergence of azole resistant Aspergillus fumigatus and One Health: time to implement environmental stewardship. PMID- 29393564 TI - Larvicidal efficacy of Adiantobischrysene from Adiantum latifolium against Oryctes rhinoceros through disrupting metamorphosis and impeding microbial mediated digestion. AB - BACKGROUND: Oryctes rhinoceros Linn. (Coleoptera: Scarabaeidae) is a serious pest of coconuts and other palms. Symbiotic gut bacteria play significant roles in the digestion of cellulosic materials as well as in some other physiological processes essential for the existence of O. rhinoceros larvae. The study was undertaken to isolate a compound with antibacterial and larvicidal activities from the leaves of Adiantum latifolium Lam. following a bioassay-guided method. RESULTS: Methanol extract (ME) of dry leaf powder of A. latifolium showed larvicidal activity against third-instar O. rhinoceros (LD50 , 5018 mg/kg) with antibacterial activity on its gut microbiota. An in vitro study showed the bacteria Bacillus cereus, Micrococcus lylae, Stenotrophomonas maltophilia, Kocuria rosea, Burkholderia mallei, Staphylococcus epidermidis, S. arlettae and Corynebacterium afermentans identified from the larval gut were sensitive to ME. Bioactivity-guided isolation of the compound by liquid-liquid extraction and column chromatography resulted in Adiantobischrysene which showed antibacterial and larvicidal activity (LD50 , 8.4 mg/kg) and led to weight loss and precocious metamorphosis in larvae. An enzyme immunoassay showed a large peak in 20 hydroxyecdysone that commits larvae to precocious metamorphosis. CONCLUSION: This study demonstrated that the antibacterial and metamorphosis disrupting activity of Adiantobischrysene make it a natural pesticidal compound against O. rhinoceros. (c) 2018 Society of Chemical Industry. PMID- 29393566 TI - Imaging of Colorectal Cancers Using Activatable Nanoprobes with Second Near Infrared Window Emission. AB - Fluorescent probes in the second near-infrared window (NIR-II) allow high resolution bioimaging with deep-tissue penetration. However, existing NIR-II materials often have poor signal-to-background ratios because of the lack of target specificity. Herein, an activatable NIR-II nanoprobe for visualizing colorectal cancers was devised. This designed probe displays H2 S-activated ratiometric fluorescence and light-up NIR-II emission at 900-1300 nm. By using this activatable and target specific probe for deep-tissue imaging of H2 S-rich colon cancer cells, accurate identification of colorectal tumors in animal models were performed. It is anticipated that the development of activatable NIR-II probes will find widespread applications in biological and clinical systems. PMID- 29393567 TI - Acute kidney injury, but not sepsis, is associated with higher procedure-related bleeding in patients with decompensated cirrhosis. AB - BACKGROUND: Bleeding after low-risk invasive procedures can be life-threatening or can lead to further complications in decompensated cirrhosis patients. In unstratified cohorts of hospitalized patients with cirrhosis, the rate of procedure-related bleeding is low despite abnormal coagulation parameters. Our objective was to identify patients with decompensated cirrhosis at a high risk of developing procedure-related bleeding in whom the value of pre-procedure transfusions could be assessed. METHODS: Hospitalized patients with cirrhosis who developed post-paracentesis hemoperitoneum confirmed by CT scan, from the period of January 2012 to August 2016, constituted the study group. They were compared to patients hospitalized in the same period in whom post-paracentesis hemoperitoneum was suspected but ruled out by CT scan. A retrospective chart review was conducted to determine specifics of the adverse event, patient characteristics and risk factors for bleeding. RESULTS: On multivariate analysis, acute kidney injury prior to paracentesis was the only independent predictor of post-paracentesis hemoperitoneum (OR 4.3, 95% CI 1.3-13.5, P = .01), independent of MELD score, large volume paracentesis, sepsis, platelets, INR and haemoglobin levels. CONCLUSIONS: Infection/sepsis is generally considered predictive of bleeding in cirrhosis. Our study suggests that acute kidney injury, and not sepsis, is the most important predictor of post-procedure bleeding in patients with decompensated cirrhosis. Although end-stage renal disease is a known cause of bleeding in non-cirrhotic patients, there are no studies establishing acute kidney injury as a risk factor for post-procedure bleeding in cirrhosis. Future studies investigating blood product transfusion needs in cirrhosis prior to procedures should carefully look at patients with acute kidney injury. PMID- 29393568 TI - Experimental insights into the importance of ecologically dissimilar bacteria to community assembly along a salinity gradient. AB - The response of local communities to marine-freshwater transitions and the processes that underlie community assembly are unclear, particularly with respect to bacteria that differ in their life strategies. Here, we implemented a transplant experiment where bacterioplankton from three regions of the Baltic Sea with differing salinities (~3, 7 and 28 psu) were exposed to each other's environmental conditions. We found that habitat specialists were more abundant than generalists after exposure to salinity changes, irrespective of their origins. Most specialists that were selected following a salinity change were rare in the starting communities. Selection for generalists, however, was not specifically driven by the recruitment of either rare or abundant members, suggesting that taxon's initial abundance is minor relevant to the growth of generalists. Patterns in phylogenetic relatedness indicated that environmental filtering was the most influential assembly mechanism for specialists, whereas competitive interaction was more important for the assembly of generalists. Altogether, this study shows that large salinity changes promote the establishment of habitat specialists and that deterministic processes vary during community assembly for ecologically dissimilar taxa. We, therefore, propose that distinguishing assembly mechanisms of different community members helps understand and predict community dynamics in response to environmental change. PMID- 29393569 TI - Contra-Thermodynamic, Photocatalytic E->Z Isomerization of Styrenyl Boron Species: Vectors to Facilitate Exploration of Two-Dimensional Chemical Space. AB - Designing strategies to access stereodefined olefinic organoboron species is an important synthetic challenge. Despite significant advances, there is a striking paucity of routes to Z-alpha-substituted styrenyl organoborons. Herein, this strategic imbalance is redressed by exploiting the polarity of the C(sp2 )-B bond to activate the neighboring pi system, thus enabling a mild, traceless photocatalytic isomerization of readily accessible E-alpha-substituted styrenyl BPins to generate the corresponding Z-isomers with high fidelity. Preliminary validation of this contra-thermodynamic E->Z isomerization is demonstrated in a series of stereoretentive transformations to generate Z-configured trisubstituted alkenes, as well as in a concise synthesis of the anti-tumor agent Combretastatin A4. PMID- 29393570 TI - Lose it or keep it: (how bivalves can provide) insights into mitochondrial inheritance mechanisms. AB - The strictly maternal inheritance (SMI) is a pattern of mitochondrial inheritance observed across the whole animal kingdom. However, some interesting exceptions are known for the class Bivalvia, in which several species show an unusual pattern called doubly uniparental inheritance (DUI) whose outcome is a heteroplasmic pool of mtDNA in males. Even if DUI has been studied for long, its molecular basis has not been established yet. The aim of this work is to select classes of proteins known to be involved in the maintenance of SMI and to compare their features in two clam species differing for their mitochondrial inheritance mechanism, that is, the SMI species Ruditapes decussatus and the DUI species Ruditapes philippinarum. Data have been obtained from the transcriptomes of male and female ripe gonads of both species. Our analysis focused on nucleases and polymerases, ubiquitination and ubiquitin-like modifier pathways, and proteins involved in autophagy and mitophagy. For each protein group of interest, transcription bias (male or female), annotation, and mitochondrial targeting (when appropriate) were assessed. We did not find evidence supporting a role of nucleases/polymerases or autophagic machinery in the enforcement of SMI in R. decussatus. On the other hand, ubiquitinating enzymes with the expected features have been retrieved, providing us with two alternative testable models for mitochondrial inheritance mechanisms at the molecular level. PMID- 29393571 TI - RNase reverses segment sequence in the anterior of a beetle egg (Callosobruchus maculatus, Coleoptera). AB - The genetic regulation of anterior-posterior segment pattern development has been elucidated in detail for Drosophila, but it is not canonical for insects. A surprising diversity of regulatory mechanisms is being uncovered not only between insect orders, but also within the order of the Diptera. The question is whether the same diversity of regulatory mechanisms exists within other insect orders. I show that anterior puncture of the egg of the pea beetle Callosobruchus maculatus submerged in RNase can induce double abdomen development suggesting a role for maternal mRNA. In a double abdomen, anterior segments are replaced by posterior segments oriented in mirror image symmetry to the original posterior segments. This effect is specific for RNase activity, for treatment of the anterior egg pole and for cytoplasmic RNA. Yield depends on developmental stage, enzyme concentration, and temperature. A maximum of 30% of treated eggs reversed segment sequence after submersion and puncture in 10 MUg/mL RNase S reconstituted from S protein and S-peptide at 30 degrees C. This result sets the stage for an analysis of the genetic regulation of segment pattern formation in the long germ embryo of the coleopteran Callosobruchus and for comparison with the short germ embryo of the coleopteran Tribolium. PMID- 29393572 TI - Tetracycline alters gene expression in Salmonella strains that harbor the Tn10 transposon. AB - In this report, we show that bacterial plasmids that harbor the Tn10 transposon (i.e., the IncHI1 plasmid R27) modify expression of different Salmonella regulons responding to the presence of tetracycline (Tc) in the medium. By using as a model the Tc-dependent upregulation of the ibpAB operon (which belongs to the heat shock regulon), we have identified Tn10-tetA (coding for a Tc efflux pump) and adjacent tetC sequences as required for ibpAB upregulation. Characterization of transcripts in the tetAC region showed that tetA transcription can continue into tetC sequences, generating a long 3'UTR sequence, which can protect transcripts from RNA processing, thus increasing the expression of TetA protein. In the presence of Tc, the DnaK and IbpA chaperones are overexpressed and translocated to the periplasm and to the membrane fraction respectively. DnaK targeting unfolded proteins is known to induce heat shock by avoiding RpoH proteolysis. We correlate expression levels of Tn10-encoded TetA protein with heat shock induction in Salmonella, likely because TetA activity compromises protein secretion. PMID- 29393573 TI - Regulation of sigma factors by conserved partner switches controlled by divergent signalling systems. AB - Partner-Switching Systems (PSS) are widespread regulatory systems, each comprising a kinase-anti-sigma, a phosphorylatable anti-sigma antagonist and a phosphatase module. The anti-sigma domain quickly sequesters or delivers the target sigma factor according to the phosphorylation state of the anti-sigma antagonist induced by environmental signals. The PSS components are proteins alone or merged to other domains probably to adapt to the input signals. PSS are involved in major cellular processes including stress response, sporulation, biofilm formation and pathogenesis. Surprisingly, the target sigma factors are often unknown and the sensing modules acting upstream from the PSS diverge according to the bacterial species. Indeed, they belong to either two-component systems or complex pathways as the stressosome or Chemosensory Systems (CS). Based on a phylogenetic analysis, we propose that the sensing module in Gram negative bacteria is often a CS. PMID- 29393574 TI - Rare BCR-ABL1 transcript in a RUNX1-RUNX1T1-positive de novo acute myeloid leukemia: The chicken and egg tale. PMID- 29393575 TI - Where is, in 2017, the evo in evo-devo (evolutionary developmental biology)? AB - After the inaugural Pan-American-Evo-Devo meeting (2015, Berkeley), I showed how major concerns about evo-devo (Evolutionary Developmental Biology) research were demonstrated by a simple, non-biased quantitative analysis of the titles/abstracts of that meeting's talks. Here, I apply the same methodology to the titles/abstracts of the recent Pan-American-Evo-Devo meeting (2017, Calgary). The aim is to evaluate if the concerns raised by me in that paper and by other authors have been addressed and/or if there are other types of differences between the two meetings that may reflect trends within the field of evo-devo. This analysis shows that the proportion of presentations referring to "morphology", "organism", "selection", "adaptive", "phylogeny", and their derivatives was higher in the 2017 meeting, which therefore had a more "organismal" feel. However, there was a decrease in the use of "evolution"/its derivatives and of macroevolutionary terms related to the tempo and mode of evolution in the 2017 meeting. Moreover, the disproportionately high use of genetic/genomic terms clearly shows that evo-devo continues to be mainly focused on devo, and particularly on "Geno", that is, on molecular/genetic studies. Furthermore, the vast majority of animal evo-devo studies are focused only on hard tissues, which are just a small fraction of the whole organism-for example, only 15% of the tissue mass of the human body. The lack of an integrative approach is also evidenced by the lack of studies addressing conceptual/long standing broader questions, including the links between ecology and particularly behavior and developmental/evolutionary variability and between evo-devo and evolutionary medicine. PMID- 29393576 TI - Phot2-regulated relocation of NPH3 mediates phototropic response to high intensity blue light in Arabidopsis thaliana. AB - Two redundant blue-light receptors, known as phototropins (phot1 and phot2), influence a variety of physiological responses, including phototropism, chloroplast positioning, and stomatal opening in Arabidopsis thaliana. Whereas phot1 functions in both low- and high-intensity blue light (HBL), phot2 functions primarily in HBL. Here, we aimed to elucidate phot2-specific functions by screening for HBL-insensitive mutants among mutagenized Arabidopsis phot1 mutants. One of the resulting phot2 signaling associated (p2sa) double mutants, phot1 p2sa2, exhibited phototropic defects that could be restored by constitutively expressing NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3), indicating that P2SA2 was allelic to NPH3. It was observed that NPH3-GFP signal mainly localized to and clustered on the plasma membrane in darkness. This NPH3 clustering on the plasma membrane was not affected by mutations in genes encoding proteins that interact with NPH3, including PHOT1, PHOT2 and ROOT PHOTOTROPISM 2 (RPT2). However, the HBL irradiation-mediated release of NPH3 proteins into the cytoplasm was inhibited in phot1 mutants and enhanced in phot2 and rpt2-2 mutants. Furthermore, HBL-induced hypocotyl phototropism was enhanced in phot1 mutants and inhibited in the phot2 and rpt2-2 mutants. Our findings indicate that phot1 regulates the dissociation of NPH3 from the plasma membrane, whereas phot2 mediates the stabilization and relocation of NPH3 to the plasma membrane to acclimate to HBL. PMID- 29393577 TI - Adhesion and invasion attributes of Burkholderia pseudomallei are dependent on airway surface liquid and glucose concentrations in lung epithelial cells. AB - Physiological constituents in airway surface liquids (ASL) appear to impact the adherence and invasion potentials of Burkholderia pseudomallei contributing to recrudescent melioidosis. Here, we investigated the factors present in ASL that is likely to influence bacterial adhesion and invasion leading to improved understanding of bacterial pathogenesis. Six B. pseudomallei clinical isolates from different origins were used to investigate the ability of the bacteria to adhere and invade A549 human lung epithelial cells using a system that mimics the physiological ASL with different pH, NaCl, KCl, CaCl2 and glucose concentrations. These parameters resulted in markedly differential adherence and invasion abilities of B. pseudomallei to the lung epithelial cells. The concentration of 20 mM glucose dramatically increased adherence and invasion by increasing the rate of pili formation in depiliated bacteria. Glucose significantly increased adherence and invasion of B. pseudomallei to A549 cells, and presence of NaCl, KCl and CaCl2 markedly ablated the effect despite the presence of glucose. Our data established a link between glucose, enhanced adhesion and invasion potentials of B. pseudomallei, hinting increased susceptibility of individuals with diabetes mellitus to clinical melioidosis. PMID- 29393578 TI - A KLF1 gene mutation causes beta-thalassemia minor in a Chinese family. PMID- 29393579 TI - KNAT7 positively regulates xylan biosynthesis by directly activating IRX9 expression in Arabidopsis. AB - Xylan is the major plant hemicellulosic polysaccharide in the secondary cell wall. The transcription factor KNOTTED-LIKE HOMEOBOX OF ARABIDOPSIS THALIANA 7 (KNAT7) regulates secondary cell wall biosynthesis, but its exact role in regulating xylan biosynthesis remains unclear. Using transactivation analyses, we demonstrate that KNAT7 activates the promoters of the xylan biosynthetic genes, IRREGULAR XYLEM 9 (IRX9), IRX10, IRREGULAR XYLEM 14-LIKE (IRX14L), and FRAGILE FIBER 8 (FRA8). The knat7 T-DNA insertion mutants have thinner vessel element walls and xylary fibers, and thicker interfascicular fiber walls in inflorescence stems, relative to wild-type (WT). KNAT7 overexpression plants exhibited opposite effects. Glycosyl linkage and sugar composition analyses revealed lower xylan levels in knat7 inflorescence stems, relative to WT; a finding supported by labeling of inflorescence walls with xylan-specific antibodies. The knat7 loss-of function mutants had lower transcript levels of the xylan biosynthetic genes IRX9, IRX10, and FRA8, whereas KNAT7 overexpression plants had higher mRNA levels for IRX9, IRX10, IRX14L, and FRA8. Electrophoretic mobility shift assays indicated that KNAT7 binds to the IRX9 promoter. These results support the hypothesis that KNAT7 positively regulates xylan biosynthesis. PMID- 29393580 TI - Bosentan therapy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: A systemic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Bosentan therapy has been recommended for pulmonary arterial hypertension (PAH) and might be beneficial for chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to evaluate the specific effects of bosentan for PAH and CTEPH. MATERIALS AND METHODS: We performed a systemic review and meta-analysis of randomized controlled trials (RCTs), comparing efficacy and safety of bosentan treatment for PAH and CTEPH through major biomedical database. RESULTS: A total of 10 RCTs including 1185 patients were enrolled. For PAH patients, bosentan prolonged 6-minute walk distance with a weighted mean difference of 35.7 m, reduced mean pulmonary arterial pressure by 5.7 mm Hg, increased cardiac index by 0.4 L/min/m2 , reduced pulmonary vascular resistance by 305.1 dyn.s/cm5 , prevented functional class from deterioration and reduced clinical worsening as compared with placebo. For CTEPH patients, bosentan improved cardiac index by 0.3 L/min/m2 and reduced pulmonary vascular resistance by 176.0 dyn.s/cm5 . Other efficacy outcomes regarding CTEPH did not attain statistical difference. For both PAH and CTEPH, there was no significant difference in mortality or adverse event between bosentan and placebo group. However, bosentan raised the risk of abnormal liver function in both PAH and CTEPH patients. CONCLUSIONS: Bosentan is effective in treating PAH, whereas it improves only certain hemodynamic parameters of CTEPH. Incidence of liver function abnormality is higher in bosentan treatment. PMID- 29393581 TI - Response of Biomass Development, Essential Oil, and Composition of Plectranthus amboinicus (Lour.) Spreng. to Irrigation Frequency and Harvest Time. AB - A greenhouse experiment was conducted to study the effects of four irrigation intervals (4, 8, 12, and 16 days) and six harvests (2, 4, 6, 8, 10, and 12 months after transplanting) on biomass, essential oil content, and composition of Plectranthus amboinicus (Lour.) Spreng. Fresh weight and essential oil yield decreased with increasing irrigation interval; whereas, essential oil content was stimulated by water stress and increased as the irrigation interval increased. Fresh weight of Plectranthus amboinicus irrigated every 4 days peaked when harvested at 6 months, but essential oil content peaked when irrigated every 16 days and harvested at 2 months after transplantation. On the other hand, essential oil yield peaked when irrigated every 8 days and harvested at 6 months. Thymol, p-cymene, gamma-terpinene, and beta-caryophyllene were the major compounds, and they peaked at different irrigation intervals and harvest times. This study showed biomass, essential oil content, and yield as well as the major and minor constituents of Plectranthus amboinicus are influenced by irrigation interval and the timing of harvest. PMID- 29393582 TI - Substrate and electron donor limitation induce phenotypic heterogeneity in different metabolic activities in a green sulphur bacterium. AB - Populations of genetically identical cells can display marked variation in phenotypic traits; such variation is termed phenotypic heterogeneity. Here, we investigate the effect of substrate and electron donor limitation on phenotypic heterogeneity in N2 and CO2 fixation in the green sulphur bacterium Chlorobium phaeobacteroides. We grew populations in chemostats and batch cultures and used stable isotope labelling combined with nanometer-scale secondary ion mass spectrometry (NanoSIMS) to quantify phenotypic heterogeneity. Experiments in H2 S (i.e. electron donor) limited chemostats show that varying levels of NH4+ limitation induce heterogeneity in N2 fixation. Comparison of phenotypic heterogeneity between chemostats and batch (unlimited for H2 S) populations indicates that electron donor limitation drives heterogeneity in N2 and CO2 fixation. Our results demonstrate that phenotypic heterogeneity in a certain metabolic activity can be driven by different modes of limitation and that heterogeneity can emerge in different metabolic processes upon the same mode of limitation. In conclusion, our data suggest that limitation is a general driver of phenotypic heterogeneity in microbial populations. PMID- 29393583 TI - Mitosis count and number of cancer cells in cases of primary pulmonary adenocarcinoma: Correlations among phosphorylated histone 3, number of cancer cells, nuclear grade, pathologic features and prognosis. AB - Immunohistochemistry findings for the phosphorylated form of histone 3 (pHH3) have been shown to be a reliable mitosis-specific marker. We evaluated the correlation between pHH3-stained mitotic figures (PHMFs) and clinical outcome, and compared the results with findings for numbers of PHMFs and cancer cells. The primary tumor was obtained from 113 patients with pulmonary adenocarcinomas (<=2 cm maximum dimension). All specimens were stained with pHH3, then the number of cancer cells in each was determined. Cases with a cancer-cell index >=1000 showed worse recurrence-free survival as compared to those with a value <1000 (P < 0.001). Also, cases with a pHH3 index >=0.27 showed worse recurrence-free survival as compared to <0.27 (P = 0.001) and cases with a pHH3/cancer-cell index >=0.001 showed worse recurrence-free survival as compared to <0.001 (P = 0.002). Multivariate analysis demonstrated that pHH3/cancer-cell index was significantly correlated with prognosis, but not Ki-67 index. The number of cancer cells was also strongly correlated with progression of Noguchi's classification and WHO pathologic type. pHH3/cancer-cell index was correlated with prognosis, and those were useful for prognostic evaluation of pulmonary adenocarcinoma patients. Furthermore, cancer cell number was correlated with Noguchi's classification and WHO pathologic type. PMID- 29393584 TI - Complications and risk factors in pediatric bronchoscopy in a tertiary pediatric respiratory center. AB - : Bronchoscopy is an established procedure routinely used by pediatric pulmonologists. Despite its frequent application, data on complications and specific risk factors are scarce and sometimes conflicting. AIM: The aim of this study was to evaluate frequency and severity of clearly defined complications of bronchoscopy in children that occur both during and after the procedure, and to identify potential risk factors. METHOD: A retrospective single-center analysis of 670 elective bronchoscopies in 522 children aged 0-17 years during the time period of 2008-2012 was performed. Procedures in intensive care unit patients and children after lung transplantation were excluded. RESULTS: Mean patient age was 5.58 years, 61.5% had underlying chronic diseases. Intraprocedural complications occurred in 7.2% of all procedures; of these, hypoxemia was the most common, occuring in 4.8% of cases. Postprocedural adverse events were documented in 25.8%, the most frequent of which were fever in 14.2% and transient oxygen dependency in 13.4% of cases. No bronchoscopy related deaths occurred. Multivariate logistic regression was used to identify risk factors for (1) any complication, or (2) severe complications. Age below two years (OR 1.837 [1.224 2.757], P = 0.003) and primary ciliary dyskinesia (OR 4.821 [2.018-11.552], P < 0.001) significantly contributed to risk of any complication. Age below 2 years (OR 2.478 [1.072-5.728], P = 0.034) and underlying cardiovascular disease (OR 2.678 [1.013-7.077], P = 0.047) were independent risk factors for severe complications. CONCLUSION: Bronchoscopy in children is relatively safe. Nevertheless, adverse events can occur and knowledge of risk factors may help prevent complications. PMID- 29393585 TI - Metabolic Engineering of Lactobacillus plantarum for Direct l-Lactic Acid Production From Raw Corn Starch. AB - Fermentative production of optically pure lactic acid (LA) has attracted great interest because of the increased demand for plant-based plastics. For cost effective LA production, an engineered Lactobacillus plantarum NCIMB 8826 strain, which enables the production of optically pure l-LA from raw starch, is constructed. The wild-type strain produces a racemic mixture of d- and l-LA from pyruvate by the action of the respective lactate dehydrogenases (LDHs). Therefore, the gene encoding D-LDH (ldhD) is deleted. Although no decrease in d LA formation is observed in the DeltaldhD mutant, additional disruption of the operon encoding lactate racemase (larA-E), which catalyzes the interconversion between d- and l-LA, completely abolished d-LA production. From 100 g L-1 glucose, the DeltaldhD DeltalarA-E mutant produces 87.0 g L-1 of l-LA with an optical purity of 99.4%. Subsequently, a plasmid is introduced into the DeltaldhD DeltalarA-E mutant for the secretion of alpha-amylase from Streptococcus bovis 148. The resulting strain could produce 50.3 g L-1 of l-LA from raw corn starch with a yield of 0.91 (g per g of consumed sugar) and an optical purity of 98.6%. The engineered L. plantarum strain would be useful in the production of l-LA from starchy materials. PMID- 29393586 TI - Population structure and antimicrobial susceptibility of Paenibacillus larvae isolates from American foulbrood cases in Apis mellifera in Japan. AB - Paenibacillus larvae is the causative agent of American foulbrood (AFB), the most destructive disease of the honey bee brood. In this study, we investigated the population structure and antimicrobial susceptibility of Japanese P. larvae using 100 isolates isolated between 1993 and 2017 in 17 prefectures. Using repetitive element PCR and multilocus sequence typing, isolates from diverse origins were classified into six genotypes, including the novel genotype ERIC II-ST24. Among these genotypes, ERIC I-ST15 is the most common in Japan, while ERIC II-ST10 isolates were found to be increasing during the 2010s. Regardless of genotype or origin, all isolates were susceptible to the major antimicrobials used in the control of AFB, including mirosamicin and tylosin, which were approved for the prevention of AFB in Japan in 1999 and 2017 respectively. Despite nearly 20 years of use, mirosamicin is still effective against Japanese P. larvae in vitro; however, the development of AFB in honey bee colonies may not always be suppressed by this drug. The case information collected in this study provides insight into the conditions under which prophylactic medicine may not exert sufficient preventive effects in vivo. PMID- 29393587 TI - Impact of CHO Metabolism on Cell Growth and Protein Production: An Overview of Toxic and Inhibiting Metabolites and Nutrients. AB - For over three decades, Chinese hamster ovary (CHO) cells have been the chosen expression platform for the production of therapeutic proteins with complex post translational modifications. However, the metabolism of these cells is far from perfect and optimized, and requires substantial know how and process optimization and monitoring to perform efficiently. One of the main reasons for this is the production and accumulation of toxic and growth-inhibiting metabolites during culture. Lactate and ammonium are the most known, but many more have been identified. In this review, an overview of metabolites that deplete and accumulate throughout the course of cultivations with toxic and growth inhibitory effects to the cells is presented. Further, an overview of the CHO metabolism with emphasis to metabolic pathways of amino acids, glutathione (GSH), and related compounds which have growth-inhibiting and/or toxic effect on the cells is provided. Additionally, relevant publications which describe the applications of metabolomics as a powerful tool for revealing which reactions occur in the cell under certain conditions are surveyed and growth-inhibiting and toxic metabolites are identified. Also, a number of resources that describe the cellular mechanisms of CHO and are available on-line are presented. Finally, the application of this knowledge for bioprocess and medium development and cell line engineering is discussed. PMID- 29393588 TI - Growth trajectories and oxygen use in neuroendocrine cell hyperplasia of infancy. AB - RATIONALE: Neuroendocrine cell hyperplasia of infancy (NEHI) typically presents in infancy with tachypnea, retractions, and hypoxemia. Some infants have failure to thrive, yet the frequency of this and other non-respiratory phenotypic features have not been delineated. While gradual improvement occurs, the clinical course is variable and the duration of supplemental oxygen requirement has not been defined. OBJECTIVES: Our objective was to identify factors in NEHI that may drive differences in clinical course. We hypothesized that failure to thrive would be associated with greater duration of supplemental oxygen use. METHODS: Children with NEHI were identified as a nested retrospective cohort within an ongoing observational prospective study. An electronic questionnaire evaluating health status was distributed to the parents/guardians. Clinical data were obtained via chart review and parent interview. RESULTS: Of 42 children, 74% had a diagnosis of failure to thrive during their clinical course. Time to event analysis demonstrated that 50% discontinued daytime and nighttime oxygen at 32 and 87.5 months after initiation, respectively. Diagnosis of failure to thrive was associated with longer continuous oxygen supplementation, P = 0.03. Additional parental concerns identified through the electronic questionnaire included developmental delays, multiple hospitalizations, and delays in diagnosis. CONCLUSIONS: NEHI is associated with substantial respiratory and extra pulmonary morbidity. Failure to thrive may be associated with greater respiratory morbidity, though further studies are required to define this interaction. Determining the association of these comorbidities and respiratory course in NEHI may enable development of strategies to improve these modifiable factors and potentially pulmonary outcomes. PMID- 29393589 TI - Reaction-Mediated Desorption of Macromolecules: Novel Phenomenon Enabling Simultaneous Reaction and Separation. AB - Combining chemical reaction with separation offers several advantages. In this work possibility to induce spontaneous desorption of adsorbed macromolecules, once being PEGylated, through adjustment of the reagent composition is investigated. Bovine serum albumin (BSA) and activated oligonucleotide, 9T, are used as the test molecules and 20 kDa linear activated PEG is used for their PEGylation. BSA solid-phase PEGylation is performed on Q Sepharose HP. Distribution coefficient of BSA and PEG-BSA as a function of NaCl is determined using linear gradient elution (LGE) experiments and Yamamoto model. According to the distribution coefficient the selectivity between BSA and PEG - BSA of around 15 is adjusted by using NaCl. Spontaneous desorption of PEG - BSA is detected with no presence of BSA. However, due to a rather low selectivity, also desorption of BSA occurred at high elution volume. A similar procedure is applied for activated 9T oligonucleotide, this time using monolithic CIM QA disk monolithic column for adsorption. Selectivity of over 2000 is obtained by proper adjustment of PEG reagent composition. High selectivity enables spontaneous desorption of PEG-9T without any desorption of activated 9T. Both experiments demonstrates that reaction-mediated desorption of macromolecules is possible when the reaction conditions are properly tuned. PMID- 29393590 TI - Silk nanofibril self-assembly versus electrospinning. AB - Natural silk fibers represent one of the most advanced blueprints for (bio)polymer scientists, displaying highly optimized mechanical properties due to their hierarchical structures. Biotechnological production of silk proteins and implementation of advanced processing methods enabled harnessing the potential of these biopolymer not just based on the mechanical properties. In addition to fibers, diverse morphologies can be produced, such as nonwoven meshes, films, hydrogels, foams, capsules and particles. Among them, nanoscale fibrils and fibers are particularly interesting concerning medical and technical applications due to their biocompatibility, environmental and mechanical robustness as well as high surface-to-volume ratio. Therefore, we introduce here self-assembly of silk proteins into hierarchically organized structures such as supramolecular nanofibrils and fabricated materials based thereon. As an alternative to self assembly, we also present electrospinning a technique to produce nanofibers and nanofibrous mats. Accordingly, we introduce a broad range of silk-based dopes, used in self-assembly and electrospinning: natural silk proteins originating from natural spinning glands, natural silk protein solutions reconstituted from fibers, engineered recombinant silk proteins designed from natural blueprints, genetic fusions of recombinant silk proteins with other structural or functional peptides and moieties, as well as hybrids of recombinant silk proteins chemically conjugated with nonproteinaceous biotic or abiotic molecules. We highlight the advantages but also point out drawbacks of each particular production route. The scope includes studies of the natural self-assembly mechanism during natural silk spinning, production of silk fibrils as new nanostructured non-native scaffolds allowing dynamic morphological switches, as well as studying potential applications. This article is categorized under: Biology-Inspired Nanomaterials > Peptide-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Protein and Virus-Based Structures. PMID- 29393591 TI - Treatment outcome for locally advanced non-small-cell lung cancer using TomoDirect plan and its characteristics compared to the TomoHelical plan. AB - INTRODUCTION: TomoDirect (TD) is an intensity-modulated radiotherapy system that uses a fixed gantry angle instead of the rotational beam delivery used in the TomoHelical (TH) system. This study was performed (1) to evaluate the treatment outcome of the TD plan for locally advanced non-small-cell lung cancer (NSCLC) and (2) to compare the characteristics of TD plans with those of TH plans. METHODS: Twenty-one patients with NSCLC were treated using the TD system. The prescribed dose was 40 Gy/20 Fx for the initial planning target volume (PTV), which included the gross tumour volume (GTV) and lymph node regions. A boost plan of 20 Gy/10 Fx was then applied, focusing on the GTV. For the planning study, matched TH plans of 40 Gy for the initial PTV were created for each patient, to meet the same dosimetric constraints specified in the TD plans. RESULTS: The 2 year overall survival, progression-free survival and local control rates were 47%, 45% and 74% respectively. Grade 2 treatment-related pneumonitis occurred in three (14%) patients. The planning study comparing TD and TH showed that dose distribution to GTV and PTV were not significantly different. The lung V5 Gy was lower in the TD plans than TH plans (46.4 +/- 5.4 vs. 52.3 +/- 8.5), while the V20 Gy was higher (26.2 +/- 4 vs. 24 +/- 4.3). The TD plans had a significantly shorter treatment time than TH plans (4.5 +/- 1.3 min vs. 9.8 +/- 1.5 min). CONCLUSIONS: TD is a clinically acceptable treatment option for NSCSL. The quality of the TD and TH plans are comparable. PMID- 29393592 TI - Detection of atypical porcine pestivirus in Brazil in the central nervous system of suckling piglets with congenital tremor. AB - Atypical porcine pestivirus (APPV) has been detected in piglets with congenital tremor (CT) from three different continents including North America, Europe and Asia. Thirteen piglets from four farms in two different states in Brazil with CT were sampled. Viral RNA was detected by quantitative real-time PCR in the cerebellum or cerebellum and spinal cord in the 100% of the piglets with CT, and APPV was not detected in any tissue sample from clinically non-affected piglets with the exception of the cerebellum of one piglet from Farm A. Piglets with CT had an odds ratio of 99.0 (95% CI 3.4, 2823.8; p = .0072) compared to piglets without CT to test positive for APPV by qRT-PCR. A subset of positive samples was selected for sequencing of the NS3 gene. Phylogenetic analysis revealed that Brazilian sequences of the NS3 formed an independent cluster and had the highest sequence identity with a sequence from the United States. This is the first identification of APPV infection in piglets with CT in South America. PMID- 29393593 TI - Don't know responses to cognitive and affective risk perception measures: Exploring prevalence and socio-demographic moderators. AB - OBJECTIVES: Many people report uncertainty when appraising their risk of cancer and other diseases, but prior research about the topic has focused solely on cognitive risk perceptions. We investigated uncertainty related to cognitive and affective risk questions. We also explored whether any differences in uncertainty between cognitive and affective questions varied in magnitude by item-specific or socio-demographic characteristics. DESIGN: Secondary analysis of data collected for a 2 * 2 * 3 full-factorial risk communication experiment (N = 835) that was embedded within an online survey. METHODS: We investigated the frequency of 'don't know' responses (DKR) to eight perceived risk items that varied according to whether they assessed (1) cognitive versus affective perceived risk, (2) absolute versus comparative risk, and (3) colon cancer versus 'any exercise related diseases'. Socio-demographics were as follows: sex, age, education, family history, and numeracy. We analysed the data using multilevel logistic regression. RESULTS: The odds of DKR were lower for affective than cognitive perceived risk (OR = 0.64, p < .001). This difference occurred for absolute but not comparative risk perceptions (interaction effect, p = .004), but no interactions for disease type or demographic characteristics were found (ps > .05). CONCLUSIONS: Lower uncertainty for affective (vs. cognitive) absolute perceived risk items is consistent with research stating: (1) Risk perceptions are grounded in people's feelings about a hazard, and (2) feelings are easier for people to access than facts. Including affective perceived risk items in health behaviour surveys may reduce missing data and improve data quality. Statement of contribution What is already known on this subject? Many people report that they don't know their risk (i.e., risk uncertainty). Evidence is growing for the importance of feelings of risk in explaining health behaviour. Feelings are easier for people to access than facts. What does this study add? Don't know responding is higher for absolute cognitive than absolute affective risk questions. This difference does not vary in magnitude by demographic characteristics. Affective perceived risk questions in surveys may reduce missing data and improve data quality. PMID- 29393594 TI - The Peptide Repertoire of HLA-B27 may include Ligands with Lysine at P2 Anchor Position. AB - The HLA-B*27 peptidome has drawn significant attention due to the genetic association between some of the HLA-B*27 alleles and the inflammatory rheumatic disease ankylosing spondylitis (AS), for which a comprehensive biological explanation is still lacking. This study aims to expand the known limits of the HLA-B*27 peptidome to facilitate selection and testing of new peptides, possibly involved in the disease. The HLA peptidomes of HeLa and C1R cell lines stably transfected with the AS-associated HLA-B*27:05 allele, the nonassociated HLA B*27:09 allele, or their cysteine 67 to serine mutants (C67S), are analyzed on a very large scale. In addition, the peptidomes of HLA-B*27:05 and HLA-B*27:05-C67S are analyzed from the spleens of rats transgenic for these alleles. The results indicate that C67S mutation increases the percentage of peptides with glutamine or lysine at their P2 position (P2-Lys), in both HLA-B*27:05 and HLA-B*27:09. Furthermore, a small fraction of HLA-B*27 peptides contains lysine at their second position (P2), in addition to the more commonly found peptides with arginine (P2-Arg) or the less common glutamine (P2-Gln) located at this anchor position. Overall these data indicate that peptides with P2-Lys should be considered as real ligands of HLA-B*27 molecules and taken into account while looking for putative peptides implicated in the AS. PMID- 29393595 TI - Multicomponent Synthesis of Isoindolinone Frameworks via RhIII -Catalysed in situ Directing Group-Assisted Tandem Oxidative Olefination/Michael Addition. AB - A RhIII -catalysed three-component synthesis of isoindolinone frameworks via direct assembly of benzoyl chlorides, o-aminophenols and activated alkenes has been developed. The process involves in situ generation of o-aminophenol (OAP) based bidentate directing group (DG), RhIII -catalysed tandem ortho C-H olefination and subsequent cyclization via aza-Michael addition. This protocol exhibits good chemoselectivity and functional group tolerance. Computational studies showed that the presence of hydroxyl group on the N-aryl ring could enhance the chemoselectivity of the reaction. PMID- 29393596 TI - Initial neurogenesis in Drosophila. PMID- 29393597 TI - Editorial 2018. PMID- 29393598 TI - Integrative conservation genetics: Prioritizing populations using climate predictions, adaptive potential and habitat connectivity. AB - Conservation decisions often involve allocation of scarce resources among many areas of need. Various approaches exist to help prioritize species and populations for conservation. Past efforts have often used relatively narrow, one dimensional criteria, such as genetic resource value or exposure to threats. What is lacking is a refined, comprehensive prioritization approach including ecological and evolutionary aspects, informed by rich and reliable data. In this issue of Molecular Ecology Resources, Razgour et al. () present a new prioritization framework that coherently integrates three dimensions of population vulnerability: exposure to change, sensitivity to change and range shift potential. They measure these dimensions for 10 populations of a European bat using a suite of advanced analysis methods that leverage genomic, environmental and occurrence data. Explicitly recognizing and quantifying the multidimensional nature of conservation priorities is a key advance because it enables a nuanced assessment of each population and identification of populations of high concern along all three dimensions. With some caveats and modifications, this framework could be a major step for conservation prioritization and intervention that is proactive and informed by evolutionary principles. PMID- 29393599 TI - Dysphagia and associated clinical markers in neurologically intact children with respiratory disease. AB - OBJECTIVE: The identification of oropharyngeal aspiration is paramount since it can have negative consequences on a compromised respiratory status. Our hypothesis was that dysphagia in neurologically intact children with respiratory disease is associated to specific clinical markers. STUDY DESIGN: Using the medical files we conducted a retrospective, observational cohort study on children admitted to the pediatric hospital unit due to respiratory disease. We collected data on specific parameters of a clinical swallowing assessment and dysphagia was classified according to the Dysphagia Management Staging Scale. We also included the following clinical markers: age, days of hospitalization, need for orotracheal intubation (OTI), duration of orotracheal intubation (in hours), number of previous hospital admissions due to respiratory disease, number of previous hospital admissions due to other causes, and previous orotracheal intubations. RESULTS: The final study sample consisted of 102 patients (mean age of 5.88 months). For the purposes of statistical analysis, the patients were grouped according to the classification of dysphagia (ie, no dysphagia, mild dysphagia, and moderate-severe dysphagia). Data analysis indicated that the clinical markers of orotracheal intubation (P = 0.042), duration of orotracheal intubation (P = 0.025), and days of hospitalization (P = 0.037) were significant in children with moderate-severe dysphagia. CONCLUSIONS: Our data indicate that neurologically intact children with respiratory disease who were submitted to prolonged OTI (ie, over 48 h) should be prioritized for receiving a detailed swallowing assessment. PMID- 29393600 TI - Temporal trends in frequency, management and outcomes of coronary perforations. AB - BACKGROUND: Coronary perforations (CP) have been described as a rare but potentially fatal complication in percutaneous coronary interventions (PCI). Our aim is to compare temporal trends in frequency, management and outcomes of coronary perforations (CP). METHODS: All cases of CP recorded in our prospective institutional percutaneous coronary intervention (PCI) registry from 2003 to 2015 were included. Patients were divided in 2 groups according to the time frame in which the CP occurred: the early period (before 2009, when the chronic total occlusions and primary PCI programs started) and the current period. The primary endpoint was the composite of in-hospital serious adverse events, including final TIMI flow 0-1, cardiac tamponade, emergent cardiac surgery or death. RESULTS: Overall, 88 CP occurred in 17,566 procedures (0.50%). Of these, 17 (0.26%) occurred during the early period and 71 (0.64%) during the current period (P<0.001). CP management differed between groups, with less CP sealed by intracoronary devices in the early period than in the current one (23.5% vs. 47.9%, P=0.068). Moreover, patients with CP during the early period experienced more in-hospital serious adverse events (69% vs. 31% respectively, OR 3.18, 95% CI: 1.07-9.45, P=0.037). CONCLUSIONS: Expansion of indications and complexity of PCI in the current era may be associated with an increased frequency of CP. However, progress in technical and device management of CP have led to an improvement in the prognosis of this feared complication. PMID- 29393602 TI - Association between left ventricular ejection fraction and renal impairment in patients with cardio-renal syndrome type 2. PMID- 29393601 TI - Comprehensive non-invasive cardiac and autonomic assessment in acute ischemic stroke patients: a pilot study. AB - BACKGROUND: The aim of this study was to comprehensively determine hemodynamic and autonomic responses during-head up tilt test (HUT) in the acute and recovery phase of ischemic stroke. METHODS: Cardiovascular parameters, baroreflex sensitivity (BRS), spectral-indices of heart rate (HRV), systolic (sBPV) and diastolic blood pressure variability (dBPV) were measured at rest in ischemic stroke patients (N.=17) and control group (N.=34). Dynamic cardiac autonomic function was assessed using HUT (Delta [rest-tilt]. Controls were examined once whereas stroke group at two timepoints: on admission and in day 10 (recovery period). RESULTS: After a recovery period the stroke group showed significantly higher resting values of systolic blood pressure (sBP, P=0.028), systolic time ratio (STR, P=0.023), high frequency sBPV (HF-sBP, P=0.027), high frequency R-R interval (HF-RRI, P=0.048), power spectral density of sBPV (PSD-sBP, P=0.004) and lower sympathovagal ratio (LF/HF, P=0.005), low frequency R-R interval (LF-RRI, P=0.045), BRS and significantly lower increase in post tilt changes in systolic blood pressure (Delta sBP), total peripheral resistance (Delta TPR) compared to controls. No significant differences were observed for post-tilt in all hemodynamic changes compared to admission. After the recovery period the patient group showed an improved blood pressure profile, left ventricular work index, systolic time ratio and BRS compared to admission. CONCLUSIONS: Patients with acute ischemic stroke after a recovery period presented autonomic imbalance and impaired cardiac sympathetic modulation at rest and in response to orthostatic challenge compared to a control group. Furthermore, there was a statistically significant decrease in baroreflex sensitivity, suggesting parasympathetic deficiency. PMID- 29393603 TI - Evolution of STEMI network in Italy. AB - Italy has been one of the first countries in Europe to perform primary percutaneous coronary intervention (p-PCI) and some regions are still a model for the ST-elevation myocardial infarction (STEMI) network organization. However, in Italy, as in other European countries, some regional disparities emerge that are related to geographical, economic, organizing, and structural issues. Although some regions have excellent STEMI networks, others still have to optimize their models allowing to each STEMI patient to receive the best reperfusion treatment. The RETE IMA Web surveys documented that extraordinary advances have been made in the recent past in Italy in development of STEMI networks, in part thanks to the activity of the Stent for Life project. Indeed, the current annual rate of p PCI/million inhabitants in 2016 is quite compliant with the standards recommended from the European Society of Cardiology. PMID- 29393604 TI - How the functional assessment of culprit and non-culprit lesions may improve stratification and treatment of STEMI patients. AB - Reperfusion therapy of the infarct-related artery (IRA) with primary percutaneous coronary intervention is the cornerstone for the treatment of patients with ST elevation myocardial infarction (STEMI). However, up to 30% of STEMI patients present a multi-vessel coronary artery disease. Several methods are now available for the assessment of functional severity of a coronary stenosis both for IRA and non-culprit coronary lesions. The functional assessment of the IRA has mainly a prognostic implication in terms of major adverse cardiovascular events, recovery of left ventricular function and evaluation myocardial viability. Conversely, the functional assessment of the non-culprit coronary lesions has a fundamental role to guide staged revascularization. The aim of this review is to revise the most validated methods to perform the functional assessment of both culprit and non culprit lesion in ST-elevation myocardial infarction. PMID- 29393605 TI - Parenteral antithrombotic therapy during primary percutaneous coronary intervention. AB - Acute myocardial infarction (AMI) is a major cause of morbidity, mortality and disability worldwide. ST-segment elevation myocardial infarction (STEMI) accounts for 25-40% of AMI presentations. Arterial thrombosis due to atherosclerotic plaque rupture with formation of an occlusive thrombus is the main cause of STEMI. Platelets and coagulation factors are the two principal elements involved in this process. The main goal of STEMI treatment is the early reperfusion. Prompt primary percutaneous coronary intervention (pPCI) together with an appropriate antithrombotic therapy are the treatment of choice in this setting. In this chapter, we provide an overview of currently available parenteral antithrombotic therapies used in patients with STEMI undergoing pPCI. PMID- 29393606 TI - Choice of vascular access in primary PCI. AB - Primary angioplasty (PPCI), introduced in the early '90s, has now become the preferred reperfusion strategy in ST-segment elevation myocardial infarction (STEMI). PPCI has traditionally been performed through transfemoral artery access (TFA) for about two decades. Such an access, however, has been associated to a not negligible rate of vascular complications and bleedings that, in turn, may significantly affect the overall prognosis. For this reason, transradial artery access (TRA), introduced by Campeau et al. in 1989 for diagnostic and by Kiemeneij et al. in 1993 for interventional procedures, and associated with significant reduction of vascular complications and bleedings in observational studies and registries, has been validated as alternative vascular access for PPCI procedures as well. However, because of its steep learning curve and for the smaller size of the radial artery compared with the femoral, concerns have been raised about its feasibility in urgent settings and in very complex cases. Despite these limitations, the advantages of TRA PPCI procedures have been confirmed by large nationwide registries and randomized trials, whose RIVAL, RIFLE-STEACS, STEMI RADIAL and MATRIX are the largest. All these studies showed that not only the vascular complications and bleedings, but the mortality and overall NACE (major cardiovascular events or major bleedings) were reduced as well. As a result, the TRA is now considered the "gold standard" access in the PPCI setting and has been endorsed by the european guidelines as the default access (class I, level of evidence A). PMID- 29393607 TI - Blood flow changes in pelvic vessels associated with the application of an abdominal compression belt in healthy postpartum women AB - Introduction: Postpartum haemorrhage (PPH) accounts for a high proportion of maternal mortality and morbidity throughout the world. A uterine compression belt which has been developed recently represents a very low tech, low cost solution in managing postpartum haemorrhage. Objectives: To evaluate the blood flow changes in pelvic vessels following application of the postpartum haemorrhage compression belt (Laerdal Global Health, Stavanger, Norway). Methods: The sample included healthy postpartum women within 6 hours of vaginal delivery. The study was performed at Teaching Hospital, Ragama, Sri Lanka. PPH compression belt was applied on the lower abdomen in a supine position with a slight lateral tilt. Patient's pulse, blood pressure and Doppler indices (RI, PI and PFV) of the uterine, internal iliac and femoral arteries were measured using transabdominal Doppler ultrasonography. Lower limb oxygen saturation was also measured. Measurements were obtained by connecting the subjects to a multimonitor throughout the study period of 20 minutes. Median RI, PI and PFV was calculated and comparisons were made between the baseline and after belt application at 10 and 20 minutes. Results: A total of 20 healthy women were included and the mean time from delivery to study inclusion was 2.5 (range 0.5-5.0) hours. There were no adverse outcomes or altered vital signs noted among participants. Overall there were no significant changes in the internal iliac, uterine and femoral artery blood flow after application of the compression belt. Conclusions: There were no significant changes in the internal iliac, uterine and femoral artery blood flow after application of the compression belt. This preliminary study only shows that the application of the PPH compression belt has no apparent adverse changes in the iliac, uterine and femoral artery blood flow in postpartum mothers. PMID- 29393608 TI - How many doctors should we train for Sri Lanka? System dynamics modelling for training needs AB - Introduction: Over the years, Sri Lanka has achieved remarkable health gains for the money spent on health. Currently about 1450 doctors enter the health system annually. While some advocate opening up of new medical schools to address an apparent shortage of doctors in the country, others argue against it. Objective: To identify the number of doctors Sri Lanka need. Methodology: System dynamics, an analytical modelling approach and a methodology for studying complex feedback systems was used. Two sub models of "need" and "supply" were developed and simulated for a period of 15 years from 2017 to 2032 Results: At present the doctor to population ratio is 1:671 and 91% of the need has been met. This study shows that currently there is a shortage of doctors in the country. However, the supply will match the need by 2025/26. Increasing the number of doctors, will result in oversupply of doctors towards the latter part of the next decade. Conclusions: There is no acute necessity to open up new Medical Schools. However comprehensive health workforce analysis needs to be done once in 5 years and the number of doctors to be trained, decided accordingly. PMID- 29393610 TI - Developing Healthy Communities: Civic Health Symposium. PMID- 29393609 TI - Nutcracker syndrome in pregnancy: a worrying presentation of a benign condition PMID- 29393611 TI - The Institutional Contribution of Community Based NonProfit Organizations to Civic Health. PMID- 29393612 TI - Salmonellosis beyond the gastrointestinal tract: a case series PMID- 29393613 TI - Questioning Stakeholder Legitimacy: A Philanthropic Accountability Model. AB - Philanthropic organizations contribute to important work that solves complex problems to strengthen communities. Many of these organizations are moving toward engaging in public policy work, in addition to funding programs. This paper raises questions of legitimacy for foundations, as well as issues of transparency and accountability in a pluralistic democracy. Measures of civic health also inform how philanthropic organizations can be accountable to stakeholders. We propose a holistic model for philanthropic accountability that combines elements of transparency and performance accountability, as well as practices associated with the American pluralistic model for democratic accountability. We argue that philanthropic institutions should seek stakeholder and public input when shaping any public policy agenda. This paper suggests a new paradigm, called philanthropic accountability that can be used for legitimacy and democratic governance of private foundations engaged in policy work. The Philanthropic Accountability Model can be empirically tested and used as a governance tool. PMID- 29393614 TI - Hypocalcaemia leading to supra ventricular tachycardia in a three-month old Sri Lankan infant with vitamin D deficient rickets: a case report PMID- 29393615 TI - Global Perspectives on Civic Health: Applying Lessons from Post-Communist Societies to Enable Greater Civic Outcomes in the United States. AB - Civic engagement and volunteerism in post-communist societies is poor; there are limited traditions of civic activity, and those traditions that have existed have meanings associated with a historical period when free engagement was risky and volunteerism was coerced. Today, in nations like Lithuania, there are efforts underway to reclaim the labels "volunteerism" and "participation" and to craft more civically healthy communities. This paper will address two questions: (1) How has Lithuania's civic health evolved since independence from the Soviet Union? (2) What lessons are in the emergence of a civic and volunteer culture provide for scholars, government and nonprofit officials, and civic leaders interested in moving communities within the United States out of their civic ruts? Underlying the second question is an assumption, which will be argued within the paper, that officials in the United States have more to learn from emergent civic cultures than those emergent cultures do from us, though there are certainly lessons from the United States that may be applicable. PMID- 29393617 TI - The Civic Health Generated by Neighborhood Associations in Seoul, South Korea: A Consideration of Internal and External Advocacy Roles. PMID- 29393616 TI - Transanal total mesorectal excision (TaTME) of a low rectal cancer using transanal minimally invasive surgery PMID- 29393618 TI - An unusual cause of panhypopituitarism PMID- 29393619 TI - Acute Neurotoxicity Models of Prion Disease. AB - Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrPC) into disease-associated conformers (PrPSc) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrPSc species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease patho-biology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time-consuming, and it can be problematic to clearly discern evidence of direct PrPSc neurotoxicity in the overall context of pathogenesis. In vitro models, in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic, and overall there remains a relative paucity of validated, biologically relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we provide an overview of the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies. PMID- 29393620 TI - Halloysite Nanotube-Modified Plasmonic Interface for Highly Sensitive Refractive Index Sensing. AB - We propose and demonstrate a novel strategy to modify the plasmonic interface by using a thin layer of halloysite nanotubes (HNTs). The modified surface plasmon resonance (SPR) sensor achieves a greatly improved sensitivity because the large surface area and high refractive index of the HNTs layer significantly increase the probing electric field intensity and hence the measurement sensitivity. More significantly, the thickness of the HNTs layer can be tailored by spraying different concentrations of HNTs ethanol suspension. The proposed sensors show significant superiority in terms of the highest sensitivity (10431 nm/RIU) and the enhancement fold (5.6-folds) over those reported previously. Additionally, the proposed approach is a chemical-free and environment-friendly modification method for the sensor interface, without additional chemical or biological amplification steps (no toxic solvents are used). These unique features make the proposed HNTs-SPR biosensor a simple, biocompatible, and low-cost platform for the trace-level detection of biochemical species in a rapid, sensitive, and nondestructive manner. PMID- 29393621 TI - Gelled Graphene Oxide-Ionic Liquid Composite Membranes with Enriched Ionic Liquid Surfaces for Improved CO2 Separation. AB - Blends containing ionic liquid (IL) 1-ethyl-3-methyimidazolium tetrafluoroborate [emim][BF4] gelled with Pebax 1657 block copolymers were modified by adding graphene oxide (GO) and fabricated in the form of thin film composite hollow fiber membranes. Their carbon dioxide (CO2) separation performance was evaluated using CO2 and N2 gas permeation and low-pressure adsorption measurements, and the morphology of films was characterized using scanning electron microscopy, atomic force microscopy, and transmission electron microscopy. Upon small addition of GO into the IL-dominated environment, the interaction between IL and GO facilitated the migration of IL to the surface while suppressing the interaction between IL and Pebax, which was confirmed using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Amplified migration of IL to the surface and better dispersion of GO stacks were further achieved under alkaline conditions. With the enriched IL on the surface, the gas permeation through the films at 0.5 wt % GO and approximately 80 wt % IL loading reached 1000 GPU for CO2 with their CO2/N2 selectivity (up to 44) approaching that of pure IL. PMID- 29393622 TI - Novel Balanced Charged Alginate/PEI Polyelectrolyte Hydrogel that Resists Foreign Body Reaction. AB - Foreign-body reaction (FBR) has been a long-term obstacle for implantable biomedical devices and materials, especially to those that require mass/signal transport between the implants and the body. However, currently, very limited biomaterials can mitigate FBR. In this work, we develop a balanced charged polyelectrolyte hydrogel that can efficiently resist FBR and collagenous capsule formation in a mouse model. Using this new strategy, we can easily tune the antifouling properties of the polyelectrolyte hydrogels by changing the ratio of negatively charged alginate and positively charged poly(ethylene imine). We find that at the optimum ratio where the net charge of hydrogel is neutral, the adhesion of proteins, cells, bacteria, and fresh blood on its surface can be significantly inhibited, indicating its excellent antifouling properties. In vivo studies show that after being implanted subcutaneously, this balanced charged hydrogel can prevent the capsule formation for at least 3 months. Furthermore, immunofluorescent staining results indicate that this balanced charged hydrogel elicits negligible inflammation, significantly reducing macrophage migration to the tissue-implant interface. This flexible and versatile approach holds a great promise for designing a wide spread of new antifouling hydrogels and using as immunoisolation materials for biomedical applications. PMID- 29393623 TI - Correction to Accuracy and Mechanistic Details of Optical Printing of Single Au and Ag Nanoparticles. PMID- 29393624 TI - Atmospherically Relevant Radicals Derived from the Oxidation of Dimethyl Sulfide. AB - The large number and amounts of volatile organosulfur compounds emitted to the atmosphere and the enormous variety of their reactions in various oxidation states make experimental measurements of even a small fraction of them a daunting task. Dimethyl sulfide (DMS) is a product of biological processes involving marine phytoplankton, and it is estimated to account for approximately 60% of the total natural sulfur gases released to the atmosphere. Ocean-emitted DMS has been suggested to play a role in atmospheric aerosol formation and thereby cloud formation. The reaction of .OH with DMS is known to proceed by two independent channels: abstraction and addition. The oxidation of DMS is believed to be initiated by the reaction with .OH and NO3. radicals, which eventually leads to the formation of sulfuric acid (H2SO4) and methanesulfonic acid (CH3SO3H). The reaction of DMS with NO3. appears to proceed exclusively by hydrogen abstraction. The oxidation of DMS consists of a complex sequence of reactions. Depending on the time of the day or altitude, it may take a variety of pathways. In general, however, the oxidation proceeds via chains of radical reactions. Dimethyl sulfoxide (DMSO) has been reported to be a major product of the addition channel. Dimethyl sulfone (DMSO2), SO2, CH3SO3H, and methanesulfinic acid (CH3S(O)OH) have been observed as products of further oxidation of DMSO. Understanding the details of DMS oxidation requires in-depth knowledge of the elementary steps of this seemingly simple transformation, which in turn requires a combination of experimental and theoretical methods. The methylthiyl (CH3S.), methylsulfinyl (CH3SO.), methylsulfonyl (CH3SO2.), and methylsulfonyloxyl (CH3SO3.) radicals have been postulated as intermediates in the oxidation of DMS. Therefore, studying the chemistry of sulfur-containing free radicals in the laboratory also is the basis for understanding the mechanism of DMS oxidation in the atmosphere. The application of matrix-isolation techniques in combination with quantum mechanical calculations on the generation and structural elucidation of CH3SOx (x = 0-3) radicals is reviewed in the present Account. Experimental matrix IR and UV/vis data for all known species of this substance class are summarized together with data obtained using other spectroscopic techniques, including time-resolved spectroscopy, electron paramagnetic resonance spectroscopy, and others. We also discuss the reactivity and experimental characterization of these species to illustrate their practical relevance and highlight spectroscopic techniques available for the elucidation of their geometric and electronic structures. The present Account summarizes recent results regarding the preparation, characterization, and reactivity of various radical species with the formula CH3SOx (x = 0-3). PMID- 29393625 TI - High-Nuclearity Lanthanide-Containing Clusters as Potential Molecular Magnetic Coolers. AB - High-nuclearity cluster-type metal complexes are a unique class of compounds, many of which have aesthetically pleasing molecular structures. Their interesting physical and chemical properties arise primarily from the electronic and/or magnetic interplay between the component metal ions. Among the extensive studies in the past two decades, those on lanthanide-containing clusters, lanthanide exclusive or heterometallic with transition metal elements, are most notable. The research was driven by both the synthetic challenges for these generally elusive species and their intriguing magnetic properties, which are useful for the development of energy-efficient and environmentally friendly magnetic cooling technologies. Our efforts in this vein have been concentrated on developing rational synthetic methods for high-nuclearity lanthanide-containing clusters. By means of the now widely adopted approach of "ligand-controlled hydrolysis" of lanthanide ions, a great variety of cluster-type lanthanide hydroxide complexes had been prepared in the first half of this developing period (1999-2006). In this Account, our efforts since 2007 are summarized. These include (1) further development of synthetic strategies in order to expand the ligand scope and/or to increase the nuclearity (>25) of the cluster species and (2) magnetic studies pertinent to the pursuit of materials with a large magnetocaloric effect (MCE). Specifically, with the hope of expanding the family of ligands and producing clusters of previously unknown structures, we tested under hydrothermal or solvothermal conditions the use of readily available yet not commonly used ligands for controlling lanthanide hydrolysis; such ligands, carboxylates as mundane examples, tend to form insoluble complexes prior to any possible hydrolysis. We have also validated the use of preformed transition metal complexes as metalloligands for subsequent control of lanthanide hydrolysis toward heterometallic 3d-4f clusters. Furthermore, we demonstrated using ample examples that the presence of small anions as templates is essential to the assembly of high-nuclearity lanthanide-containing clusters and that maintaining a low concentration of the anion template(s) is a key to such success. It has been found that slow production/release of such anion templates by in situ ligand decomposition or absorption of atmospheric CO2 is effective in preventing precipitation of their lanthanide salts, allowing not only controllable lanthanide hydrolysis but also gradual and modular assembly of the giant cluster species. Magnetic studies targeting potential applications of such clusters as molecular magnetic coolers have also been conducted. The results are summarized in the second portion of this Account in an effort to establish a certain magneto structure relationship. Of particular relevance is the possible correlation between MCE (evaluated using the isothermal magnetic entropy change, -DeltaSM) and magnetic density, and the intracluster antiferromagnetic exchange coupling. We have also made some preliminary attempts at preparing processable and practically useful materials in the form of a monodisperse core-shell nanostructure. We succeeded in encapsulating a single nanosized heterometallic molecular cluster in a nanoshell of silica. It was found that such passivation not only helped stabilize the cluster but also reduced the magnetic interactions between individual clusters. These effects are reflected in the slightly enhanced value of -DeltaSM for the core-shell composite over the parent unprotected cluster. PMID- 29393626 TI - Synthesis and Crystal Structure of the Layered Lanthanide Oxychlorides Ba3Ln2O5Cl2. AB - Single crystals of a new family of layered lanthanide oxychlorides, Ba3Ln2O5Cl2 (Ln = Gd-Lu), have been synthesized from a molten barium flux. This family crystallizes in the space group I4/mmm (No. 139; Z = 2) with lattice parameters a = 4.3384(1)-4.4541(1) A and c = 24.5108(7)-24.8448(9) A. Ba3Ln2O5Cl2 phases are built up of two different blocks: a perovskite double layer of stoichiometry Ba2Ln2O5 formed by corner-connected LnO5 tetragonal bipyramids and a puckered rock-salt-like interlayer of composition BaCl2. A complete structural study along with bond-valence-sum calculations shows that, for lanthanides larger than gadolinium, the structure becomes unstable. Density functional theory calculations show that the valence-band edge is dominated by oxygen orbitals, whereas the conduction band forms from Ba 5d orbitals. The synthesis of this family suggests a route to other potential multianion phases. PMID- 29393627 TI - Unifying Concepts Linking Dissolved Organic Matter Composition to Persistence in Aquatic Ecosystems. AB - The link between composition and reactivity of dissolved organic matter (DOM) is central to understanding the role aquatic systems play in the global carbon cycle; yet, unifying concepts driving molecular composition have yet to be established. We characterized 37 DOM isolates from diverse aquatic ecosystems, including their stable and radiocarbon isotopes (delta13C-dissolved organic carbon (DOC) and Delta14C-DOC), optical properties (absorbance and fluorescence), and molecular composition (ultrahigh resolution mass spectrometry). Isolates encompassed end-members of allochthonous and autochthonous DOM from sites across the United States, the Pacific Ocean, and Antarctic lakes. Modern Delta14C-DOC and optical properties reflecting increased aromaticity, such as carbon specific UV absorbance at 254 nm (SUVA254), were directly related to polyphenolic and polycyclic aromatic compounds, whereas enriched delta13C-DOC and optical properties reflecting autochthonous end-members were positively correlated to more aliphatic compounds. Furthermore, the two sets of autochthonous end-members (Pacific Ocean and Antarctic lakes) exhibited distinct molecular composition due to differences in extent of degradation. Across all sites and end-members studied, we find a consistent shift in composition with aging, highlighting the persistence of certain biomolecules concurrent with degradation time. PMID- 29393628 TI - Acid-Base Control of Valency within Carboranedithiol Self-Assembled Monolayers: Molecules Do the Can-Can. AB - We use simple acid-base chemistry to control the valency in self-assembled monolayers of two different carboranedithiol isomers on Au{111}. Monolayer formation proceeds via Au-S bonding, where manipulation of pH prior to or during deposition enables the assembly of dithiolate species, monothiol/monothiolate species, or combination. Scanning tunneling microscopy (STM) images identify two distinct binding modes in each unmodified monolayer, where simultaneous spectroscopic imaging confirms different dipole offsets for each binding mode. Density functional theory calculations and STM image simulations yield detailed understanding of molecular chemisorption modes and their relation with the STM images, including inverted contrast with respect to the geometric differences found for one isomer. Deposition conditions are modified with controlled equivalents of either acid or base, where the coordination of the molecules in the monolayers is controlled by protonating or deprotonating the second thiol/thiolate on each molecule. This control can be exercised during deposition to change the valency of the molecules in the monolayers, a process that we affectionately refer to as the "can-can." This control enables us to vary the density of molecule-substrate bonds by a factor of 2 without changing the molecular density of the monolayer. PMID- 29393629 TI - Synergistic Bacterial Stress Results from Exposure to Nano-Ag and Nano-TiO2 Mixtures under Light in Environmental Media. AB - Due to their widespread use and subsequent release, engineered nanomaterials (ENMs) will create complex mixtures and emergent systems in the natural environment where their chemical interactions may cause toxic stress to microorganisms. We previously showed that under dark conditions n-TiO2 attenuated bacterial stress caused by low concentrations of n-Ag (<20 MUg L-1) due to Ag+ adsorption, yet, since both n-Ag and n-TiO2 are photoactive, their photochemistries may play a key role in their interactions. In this work, we study the chemical interactions of n-Ag and n-TiO2 mixtures in a natural aqueous medium under simulated solar irradiation to investigate photoinduced stress. Using ATP levels and cell membrane integrity as probes, we observe that n-Ag and n-TiO2 together exert synergistic toxic stress in Escherichia coli. We find increased production of hydrogen peroxide by the n-Ag/n-TiO2 mixture, revealing that the enhanced photocatalytic activity and production of ROS likely contribute to the stress response observed. Based on STEM-EDS evidence, we propose that a new composite Ag/TiO2 nanomaterial forms under these conditions and explains the synergistic effects of the ENM mixture. Overall, this work reveals that environmental transformations of ENM mixtures under irradiation can enhance biological stress beyond that of individual components. PMID- 29393630 TI - Visible Light-Induced Hydrogelation of an Alginate Derivative and Application to Stereolithographic Bioprinting Using a Visible Light Projector and Acid Red. AB - Visible light-induced hydrogelation is attractive for various biomedical applications. In this study, hydrogels of alginate with phenolic hydroxyl groups (Alg-Ph) were obtained by irradiating a solution containing the polymer, ruthenium II trisbipyridyl chloride ([Ru(bpy)3]2+) and sodium persulfate (SPS), with visible light. The hydrogelation kinetics and the mechanical properties of the resultant hydrogels were tunable by controlling the intensity of the light and the concentrations of [Ru(bpy)3]2+ and SPS. With appropriate concentrations of [Ru(bpy)3]2+ and SPS, the hydrogel could be obtained following approximately 10 s of irradiation using a normal desktop lamp. The hydrogelation process and the resultant hydrogel were cytocompatible; mouse fibroblast cells enclosed in the Alg-Ph hydrogel maintained more than 90% viability for 1 week. The solution containing Alg-Ph, [Ru(bpy)3]2+ and SPS was useful as a bioink for stereolithographic bioprinting. Cell-laden hydrogel constructs could be printed using the bioprinting system equipped with a visible light projector without a significant decrease in cell viability in the presence of photoabsorbent Acid Red 18. The hydrogel construct including a perfusable helical lumen of 1 mm in diameter could be fabricated using the printing system. These results demonstrate the significant potential of this visible light-induced hydrogelation system and the stereolithographic bioprinting using the hydrogelation system for tissue engineering and regenerative medicine. PMID- 29393631 TI - Engineering Bifunctional Enzymes Capable of Adenylating and Selectively Methylating the Side Chain or Core of Amino Acids. AB - Nonribosomal peptides (NRPs) are known sources of therapeutics. Some nonribosomal peptide synthetase assembly lines contain unique functional interrupted adenylation (A) domains, where nature has combined two different functional domains into one bifunctional enzyme. Most often these interrupted A domains contain a part of a methylation (M) domain embedded in their sequence. Herein, we aimed to emulate nature and create fully functional interrupted A domains by inserting two different noncognate M domains, KtzH(MH) and TioS(M3S), into a naturally occurring uninterrupted A domain, Ecm6(A1T1). We evaluated the engineered enzymes, Ecm6(A1aMHA1bT1) and Ecm6(A1aM3SA1bT1), by a series of radiometric assays and found that not only do they maintain A domain activity, but also they gain the site-specific methylation patterns observed in the parent M domain donors. These findings provide an exciting proof-of-concept for generating interrupted A domains as future tools to modify NRPs and increase the diversity and activity of potential therapeutics. PMID- 29393632 TI - Long-Lived Emissive Probes for Time-Resolved Photoluminescence Bioimaging and Biosensing. AB - In this Review article, we systematically summarize the design and applications of various kinds of long-lived emissive probes for bioimaging and biosensing via time-resolved photoluminescence techniques. The probes reviewed, including lanthanides, transition-metal complexes, organic dyes, carbon and silicon nanoparticles, metal clusters, and persistent phosphores, exhibit longer luminescence lifetimes than that of autofluorescence from biological tissue and organs. When these probes are internalized into living cells or animals, time gated photoluminescence imaging selectively collects long-lived signals for intensity analysis, while photoluminescence lifetime imaging reports the decay details of each pixel. Since the long-lived signals are differentiated from autofluorescence in the time domain, the imaging contrast and sensing sensitivity are remarkably improved. The future prospects and challenges in this rapidly growing field are addressed. PMID- 29393633 TI - Enhancing the Visible-Light Absorption and Excited-State Properties of Cu(I) MLCT Excited States. AB - A computationally inspired Cu(I) metal-to-ligand charge transfer (MLCT) chromophore, [Cu(sbmpep)2]+ (sbmpep = 2,9-di(sec-butyl)-3,8-dimethyl-4,7 di(phenylethynyl)-1,10-phenanthroline), was synthesized in seven total steps, prepared from either dichloro- or dibromophenanthroline precursors. Complete synthesis, structural characterization, and electrochemistry, in addition to static and dynamic photophysical properties of [Cu(sbmpep)2]+, are reported on all relevant time scales. UV-Vis absorption spectroscopy revealed significant increases in oscillator strength along with a concomitant bathochromic shift in the MLCT absorption bands with respect to structurally related model complexes (epsilon = 16 500 M-1 cm-1 at 491 nm). Strong red photoluminescence (Phi = 2.7%, lambdamax = 687 nm) was observed from [Cu(sbmpep)2]+, which featured an average excited-state lifetime of 1.4 MUs in deaerated dichloromethane. Cyclic and differential pulse voltammetry revealed ~300 mV positive shifts in the measured one-electron reversible reduction and oxidation waves in relation to a Cu(I) model complex possessing identical structural elements without the pi-conjugated 4,7-substituents. The excited-state redox potential of [Cu(sbmpep)2]+ was estimated to be -1.36 V, a notably powerful reductant for driving photoredox chemistry. The combination of conventional and ultrafast transient absorption and luminescence spectroscopy successfully map the excited-state dynamics of [Cu(sbmpep)2]+ from initial photoexcitation to the formation of the lowest-energy MLCT excited state and ultimately its relaxation to the ground state. This newly conceived molecule appears poised for photosensitization reactions involving energy and electron-transfer processes relevant to photochemical upconversion, photoredox catalysis, and solar fuels photochemistry. PMID- 29393634 TI - Molecular Interactions between a Fluoride Ion Channel and Synthetic Protein Blockers. AB - Fluoride ion channels of the Fluc family selectively export F- ions to rescue unicellular organisms from acute F- toxicity. Crystal structures of bacterial Fluc channels in complex with synthetic monobodies, fibronectin-derived soluble beta-sandwich fold proteins, show 2-fold symmetric homodimers with an antiparallel transmembrane topology. Monobodies also block Fluc F- current via a pore blocking mechanism. However, little is known about the energetic contributions of individual monobody residues to the affinity of the monobody channel complex or whether the structural paratope corresponds to functional reality. This study seeks to structurally identify and compare residues interacting with Fluc between two highly similar monobodies and subjects them to mutagenesis and functional measurements of equilibrium affinities via a fluorescence anisotropy binding assay to determine their energetic contributions. The results indicate that the functional and structural paratopes strongly agree and that many Tyr residues at the interface, while playing a key role in affinity, can be substituted with Phe and Trp without large disruptions. PMID- 29393635 TI - Pip-HoGu: An Artificial Assembly with Cooperative DNA Recognition Capable of Mimicking Transcription Factor Pairs. AB - Cooperation between pairs of transcription factors (TFs) has been widely demonstrated to play a pivotal role in the spatiotemporal regulation of gene expression, but blocking cooperative TF pair-DNA interactions synergistically has been challenging. To achieve this, we designed programmable DNA binder pyrrole imidazole polyamides conjugated to host-guest assemblies (Pip-HoGu) to mimic the cooperation between natural TF pairs. By incorporating cyclodextrin (Cyd) adamantane (Ada), we synthesized Ada1 (PIP1-Ada) and Cyd1 (PIP2-Cyd), which were evaluated using Tm, EMSA, competitive, and SPR assays and molecular dynamics studies. The results consistently demonstrated that Pip-HoGu system formed stable noncovalent cooperative complexes, thereby meeting key criteria for mimicking a TF pair. The system also had a longer recognition sequence (two-PIP binding length plus gap distance), favorable sequence selectivity, higher binding affinity, and in particular, a flexible gap distance (0-5 bp). For example, Ada1 Cyd1 showed thermal stability of 7.2 degrees C and a minimum free energy of interaction of -2.32 kcal.mol-1 with a targeting length of 14 bp. Furthermore, cell-based evaluation validated the capability of Pip-HoGu to exhibit potent cooperative inhibitory effects on gene expression under physiological conditions by disrupting TF pair-DNA function. In conclusion, the modular design of Pip-HoGu defines a general framework for mimicking naturally occurring cooperative TF pair DNA interactions that offers a promising strategy for applications in the precise manipulation of cell fate. PMID- 29393636 TI - Pseudohalogen-Based 2D Perovskite: A More Complex Thermal Degradation Mechanism Than 3D Perovskite. AB - (MA)2Pb(SCN)2I2, a new pseudohalogen-based 2D perovskite material, was reported as a very stable and promising photo-absorber in PSCs previously. However, the later researchers found that MA2Pb(SCN)2I2 was not as stable as claimed. Thus, it is very critical to clarify the controversy and reveal the degradation mechanism of MA2Pb(SCN)2I2. On the other hand, a large number of studies have indicated that adding a small amount of SCN- improves surface topography and crystallinity. However, whether SCN- ions can be incorporated into a 3D perovskite film remains debatable. In this work, the thermal degradation pathway of (MA)2Pb(SCN)2I2 is revealed by thermal gravimetric and differential thermal analysis coupled with quadrupole mass spectrometry and density functional theory calculations. The decomposition of (MA)2Pb(SCN)2I2 has been proved experimentally to be more complex than that of MAPbI3, involving four stages and multi-reactions from room temperature to above 500 degrees C. By combining the experimental results and theoretical calculations, it is found that 2D (MA)2Pb(SCN)2I2 actually is unstable when serving as photo-absorber in PSCs. Moreover, the role of SCN- in improving the crystallinity of 3D perovskite has also been discussed in detail. PMID- 29393637 TI - Size-Selective Detection of Picric Acid by Fluorescent Palladium Macrocycles. AB - This work presents the synthesis and characterization of two palladium-based fluorescent macrocycles offering hydrogen-bonding cavities of contrasting dimensions. Both palladium macrocycles function as chemosensors for the detection of nitroaromatics, whereas the larger macrocycle not only illustrates nanomolar detection of picric acid but also transports its significant amount from an aqueous to an organic phase. PMID- 29393638 TI - o-Carborane, Ferrocene, and Phthalocyanine Triad for High-Mobility Organic Field Effect Transistors. AB - An unsymmetrical zinc phthalocyanine with ferrocenylcarborane linked to the phthalocyanine ring through a phenylethynyl spacer was designed for organic field effect transistor (OFET). The unsymmetrical phthalocyanine derivatives were characterized using a wide range of spectroscopic and electrochemical methods. In particular, the ferrocenylcarborane structure was unambiguously revealed based on the single-crystal X-ray diffraction analysis. In-depth investigations of the electrochemical properties demonstrated that the ferrocenylcarborane insertion extended the electrochemical character of ferrocenylcarborane-substituted phthalocyanine (7). Moreover, in the anodic potential scans, the oxidative electropolymerization of etynylphthalocyanine (6) and 7 was recorded. To clarify the effect of the insertion of ferrocenylcarborane (2) on the field-effect mobility, solution-processed films of 2, 6, and 7 were used as an active layer to fabricate the bottom-gate top-contact OFET devices. An analysis of the output and transfer characteristics of the fabricated devices indicated that the phthalocyanine derivative functionalized with ferrocenylcarborane moiety has great potential in the production of high-mobility OFET. PMID- 29393639 TI - A Fully Noble Metal-Free Photosystem Based on Cobalt-Polyoxometalates Immobilized in a Porphyrinic Metal-Organic Framework for Water Oxidation. AB - The sandwich-type polyoxometalate (POM) [(PW9O34)2Co4(H2O)2]10- was immobilized in the hexagonal channels of the Zr(IV) porphyrinic MOF-545 hybrid framework. The resulting composite was fully characterized by a panel of physicochemical techniques. Calculations allowed identifying the localization of the POM in the vicinity of the Zr6 clusters and porphyrin linkers constituting the MOF. The material exhibits a high photocatalytic activity and good stability for visible light-driven water oxidation. It thus represents a rare example of an all-in-one fully noble metal-free supramolecular heterogeneous photocatalytic system, with the catalyst and the photosensitizer within the same porous solid material. PMID- 29393640 TI - A 3D Calcium Spirobifluorene Metal-Organic Framework: Single-Crystal-to-Single Crystal Transformation and Toluene Detection by a Quartz Crystal Microbalance Sensor. AB - A new 3D metal-organic framework Ca-SBF based on a zigzag-shaped tetranuclear calcium oxocluster and 9,9'-spirobi[9H-fluorene]-2,2',7,7'-tetracarboxylic acid was obtained and exhibited flu topology. Ca-SBF underwent a single-crystal-to single-crystal transformation to form Ca-SBF-1 with a slight structure shrinkage. Activated Ca-SBF showed permanent porosity and CO2 adsorption properties. A Ca SBF-modified quartz crystal microbalance sensor demonstrated selective response to toluene vapor. PMID- 29393641 TI - A Luminescent Manganese PhotoCORM for CO Delivery to Cellular Targets under the Control of Visible Light. AB - A photoactive manganese carbonyl complex derived from dansylimidazole (Imdansyl), namely, [Mn(Imdansyl)(CO)3(phen)](CF3SO3) (1), has been synthesized and structurally characterized. This is the first luminescent manganese carbonyl based photoCORM reported in the literature. This complex exhibits CO release under the exclusive control of low-power broadband visible light. The corresponding rhenium carbonyl complex, namely, [Re(Imdansyl)(CO)3(phen)](CF3SO3) (2), has also been reported, which is luminescent but sensitive only to UV-B (lambda<315 nm) light. The entry of the manganese photoCORM into the human colorectal adenocarcinoma cells (HT-29) has been demonstrated with the aid of fluorescence microscopy. Irradiation of the photoCORM-loaded cancer cells to visible light leads to a dose-dependent apoptotic cell death. PMID- 29393643 TI - Use of Caenorhabditis elegans To Study the Potential Bioactivity of Natural Compounds. AB - There is growing need and interest in finding specific compounds in natural products that have health benefits. Despite ongoing efforts to discover such compounds, the scientific evidence lags behind the vision, and it is important to find an effective paradigm for discovering such compounds. The model organism Caenorhabditis elegans offers a promising solution for studying the potential bioactivity and molecular mechanisms of natural compounds in vivo. This perspective discusses its use to study potential human health benefits, with focus on antioxidative, anti-aging, antimetabolic disorders (diabetes and obesity), and antineurodegenerative activities (Alzheimer's disease and Parkinson's disease), with practical examples. Finally, future directions in using a C. elegans-based model for discovering bioactive compounds for health promotion are discussed. PMID- 29393642 TI - Protective Effects of Blueberry Anthocyanins against H2O2-Induced Oxidative Injuries in Human Retinal Pigment Epithelial Cells. AB - Blueberry anthocyanins are considered protective of eye health because of their recognized antioxidant properties. In this study, blueberry anthocyanin extract (BAE), malvidin (Mv), malvidin-3-glucoside (Mv-3-glc), and malvidin-3-galactoside (Mv-3-gal) all reduced H2O2-induced oxidative stress by decreasing the levels of reactive oxygen species and malondialdehyde and increasing the levels of superoxide dismutase, catalase, and glutathione peroxidase in human retinal pigment epithelial cells. BAE and the anthocyanin standards enhanced cell viability from 63.69 +/- 3.36 to 86.57 +/- 6.92% (BAE), 115.72 +/- 23.41% (Mv), 98.15 +/- 9.39% (Mv-3-glc), and 127.97 +/- 20.09% (Mv-3-gal) and significantly inhibited cell apoptosis (P < 0.01 for all). Mitogen-activated-protein-kinase pathways, including ERK1/2 and p38, were involved in the bioactivities. In addition, the anthocyanins decreased vascular-endothelial-cell-growth-factor levels and activated Akt-signal pathways. These combined results supported the hypothesis that blueberry anthocyanins could inhibit the induction and progression of age-related macular degeneration (AMD) through antioxidant mechanisms. PMID- 29393644 TI - Magnetic Structure, Single-Crystal to Single-Crystal Transition, and Thermal Expansion Study of the (Edimim)[FeCl4] Halometalate Compound. AB - This contribution addresses standing questions about the nature and consequences of the ion self-assembly and magnetic structures, as well as the molecular motion of the crystalline structure as a function of the temperature, in halometalate materials based on imidazolium cation. We present the magnetic structure and magnetostructural correlations of 1-ethyl-2,3-dimethylimidazolium tetrachloridoferrate, (Edimim)[FeCl4], resolved by neutron diffraction studies. Single-crystal, synchrotron powder X-ray diffraction and powder neutron diffraction techniques have been combined to follow the temperature evolution on its crystallographic structure from 2 K close to its melting point (340 K). In this sense, slightly above room temperature (307 K) (Edimim)[FeCl4] presents a single-crystal to single-crystal transition (SCSC), from phase I (space group P21/n) to phase II (P21/m), accompanied by a notable increase in the disorder of the imidazolium cation, as well as in the metal complex anion. The temperature evolution and solid-phase transitions of the presented compound were followed in detail by synchrotron X-ray powder diffraction (SXPD), which confirms the occurrence of another phase transition at 330 K, phase III (P21/m), the crystal structure of which was elucidated from the SXPD pattern. Moreover, this material presents an anisotropic thermal expansion with a switch from axial positive to negative thermal expansion coefficients as the temperature is raised above the first phase transition, which has been correlated with the molecular motion of the imidazolium-based molecules, producing not only a shortening of the counterion...counterion distances but also the occurrence of different quasi isoenergetic crystal structures as a function of the temperature. PMID- 29393645 TI - Utility of Lithium in Rare-Earth Metal Reduction Reactions to Form Nontraditional Ln2+ Complexes and Unusual [Li(2.2.2-cryptand)]1+ Cations. AB - The utility of lithium compared to other alkali metals in generating Ln2+ rare earth metal complexes via reduction of Ln3+ precursors in reactions abbreviated as LnA3/M (Ln = rare-earth metal; A = anionic ligand; M = alkali metal) is described. Lithium reduction of Cp'3Ln (Cp' = C5H4SiMe3; Ln = Y, Tb, Dy, Ho) under Ar in the presence of 2.2.2-cryptand (crypt) forms new examples of crystallographically characterizable Ln2+ complexes of these metals, [Li(crypt)][Cp'3Ln]. In each complex, lithium is found in an N2O4 donor atom coordination geometry that is unusual for the cryptand ligand. Magnetic susceptibility data on these new examples of nontraditional divalent lanthanide complexes are consistent with 4fn5d1 electronic configurations. The Dy and Ho complexes have exceptionally high single-ion magnetic moments, 11.35 and 11.67 MUB, respectively. Lithium reduction of Cp'3Y under N2 at -35 degrees C forms the Y2+ complex (Cp'3Y)1-, which reduces dinitrogen upon warming to room temperature to generate the (N2)2- complex [Cp'2Y(THF)]2(MU-eta2:eta2-N2). These results provide insight on the factors that lead to reduced dinitrogen complexes and/or stable divalent lanthanide complexes as a function of the specific reducing agent and conditions. PMID- 29393646 TI - Can Stereoclusters Separated by Two Methylene Groups Be Related by DFT Studies? The Case of the Cytotoxic Meroditerpenes Halioxepines. AB - QM/NMR-DFT (quantum mechanics combined with nuclear magnetic resonance parameters calculated by density functional theory approximations) studies allowed us to link two stereoclusters separated by two methylene groups present in the new meroditerpenes halioxepine B (2) and halioxepine C (3) and the known halioxepine (1), isolated from two Indonesian sponges of the genus Haliclona (Reniera). DP4 and DP4+ probabilities were used to discriminate the two diastereotopic arrangements of the two stereoclusters, whose unconnected relative configurations were determined by ROESY and J-based configurational analysis. To confirm the DFT studies, the full relative configuration of 1 was deduced using a mixture of benzene-d6 and pyridine-d5 as the NMR solvent. ROESY measurements connected the two stereoclusters and demonstrated that DFT calculations accurately predict the configuration when two methylenes separate the two stereoclusters. The different arrangements of the distant stereoclusters C-1/C-2/C-7 and C-10/C-15 for compounds 2 and 3 were deduced by DFT calculations and explained the opposite optical rotations observed for the two compounds. Halioxepines B (2) and C (3) display moderate cytotoxicity against different human cancer cell lines. PMID- 29393647 TI - Cu(OAc)2 Mediated Synthesis of 3-Sulfonyl Chromen-4-ones. AB - Copper acetate mediated (4 + 2) annulation of sulfonylacetylenes with salicylic acids provides sulfonyl chromen-4-ones in the presence of benzotriazol-1-yloxy tri(dimethylamino)phosphonium hexafluorophosphate (BOP, Castro's reagent) and 4 dimethylaminopyridine (DMAP) in MeNO2 at reflux for 3 h. The uses of various metal complexes and activating reagents are investigated for facile and efficient transformation. A plausible mechanism is proposed. PMID- 29393648 TI - Copper(II)-Catalyzed Reactions of alpha-Keto Thioesters with Azides via C-C and C S Bond Cleavages: Synthesis of N-Acylureas and Amides. AB - Cu(II)-catalyzed reaction of alpha-keto thioesters with trimethylsilyl azide (TMSN3) proceeds with the transformation of the thioester group into urea through C-C and C-S bond cleavages, constituting a practical and straightforward synthesis of N-acylureas. When diphenyl phosphoryl azide (DPPA) is used instead as the azide source in an aqueous environment, primary amides are formed via substitution of the thioester group. The reactions are proposed to proceed through Curtius rearrangement of the initially formed alpha-keto acyl azide to generate an acyl isocyanate intermediate, which reacts further with an additional amount of azide or water and rearranges to afford the corresponding products. To demonstrate the potentiality of the method, one-step syntheses of pivaloylurea and isovaleroylurea, displaying anticonvulsant activities, have been carried out. PMID- 29393649 TI - Synthesis of 5-(Trifluoromethyl)pyrazolines by Formal [4 + 1]-Annulation of Fluorinated Sulfur Ylides and Azoalkenes. AB - In situ formed 1,2-diaza-1,3-dienes were used in formal [4 + 1]-annulation reactions with fluorinated sulfur ylides. This protocol provides a novel and efficient method for the synthesis of 5-(trifluoromethyl)pyrazolines in moderate to excellent yields. PMID- 29393650 TI - Design of Magnetically Labeled Cells (Mag-Cells) for in Vivo Control of Stem Cell Migration and Differentiation. AB - Cell-based therapies are attractive for treating various degenerative disorders and cancer but delivering functional cells to the region of interest in vivo remains difficult. The problem is exacerbated in dense biological matrices such as solid tissues because these environments impose significant steric hindrances for cell movement. Here, we show that neural stem cells transfected with zinc doped ferrite magnetic nanoparticles (ZnMNPs) can be pulled by an external magnet to migrate to the desired location in the brain. These magnetically labeled cells (Mag-Cells) can migrate because ZnMNPs generate sufficiently strong mechanical forces to overcome steric hindrances in the brain tissues. Once at the site of lesion, Mag-Cells show enhanced neuronal differentiation and greater secretion of neurotrophic factors than unlabeled control stem cells. Our study shows that ZnMNPs activate zinc-mediated Wnt signaling to facilitate neuronal differentiation. When implemented in a rodent brain stroke model, Mag-Cells led to significant recovery of locomotor performance in the impaired limbs of the animals. Our findings provide a simple magnetic method for controlling migration of stem cells with high therapeutic functions, offering a valuable tool for other cell-based therapies. PMID- 29393651 TI - Imaging of Optically Active Defects with Nanometer Resolution. AB - Point defects significantly influence the optical and electrical properties of solid-state materials due to their interactions with charge carriers, which reduce the band-to-band optical transition energy. There has been a demand for developing direct optical imaging methods that would allow in situ characterization of individual defects with nanometer resolution. Here, we demonstrate the localization and quantitative counting of individual optically active defects in monolayer hexagonal boron nitride using single molecule localization microscopy. By exploiting the blinking behavior of defect emitters to temporally isolate multiple emitters within one diffraction limited region, we could resolve two defect emitters with a point-to-point distance down to ten nanometers. The results and conclusion presented in this work add unprecedented dimensions toward future applications of defects in quantum information processing and biological imaging. PMID- 29393652 TI - Palladium-Catalyzed Amination of Aryl Sulfoxides. AB - Amination of diaryl sulfoxides with anilines and alkylamines has been accomplished under palladium/N-heterocyclic carbene (NHC) catalysis. Owing to its electron deficiency, the leaving arenesulfenate anion would be smoothly released from the palladium center to result in uneventful catalyst turnover under milder reaction conditions in comparison with previous C-S bond amination reactions. This amination accommodated a wider range of functional groups such as silyl, boryl, methylsulfanyl, and halogen moieties. Regioselective amination of unsymmetrical diaryl sulfoxides was also executed by means of steric bias. PMID- 29393653 TI - Delocalized Impurity Phonon Induced Electron-Hole Recombination in Doped Semiconductors. AB - Semiconductor doping is often proposed as an effective route to improving the solar energy conversion efficiency by engineering the band gap; however, it may also introduce electron-hole (e-h) recombination centers, where the determining element for e-h recombination is still unclear. Taking doped TiO2 as a prototype system and by using time domain ab initio nonadiabatic molecular dynamics, we find that the localization of impurity-phonon modes (IPMs) is the key parameter to determine the e-h recombination time scale. Noncompensated charge doping introduces delocalized impurity-phonon modes that induce ultrafast e-h recombination within several picoseconds. However, the recombination can be largely suppressed using charge-compensated light-mass dopants due to the localization of their IPMs. For different doping systems, the e-h recombination time is shown to depend exponentially on the IPM localization. We propose that the observation that delocalized IPMs can induce fast e-h recombination is broadly applicable and can be used in the design and synthesis of functional semiconductors with optimal dopant control. PMID- 29393654 TI - TRPV4 Stimulation Releases ATP via Pannexin Channels in Human Pulmonary Fibroblasts. AB - We previously described several ionic conductances in human pulmonary fibroblasts, including one activated by two structurally distinct TRPV4 (transient receptor potential, vanilloid-type, subtype 4)-channel agonists: 4alphaPDD (4alpha-phorbol-12,13-didecanoate) and GSK1016790A. However, the TRPV4 activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 and HC-067047). In this study, we characterized that conductance more carefully. We found that 4alphaPDD stimulated a delayed release of ATP into the extracellular space, which was reduced by genetic silencing of pannexin expression, and that the 4alphaPDD-evoked current could be blocked by apyrase (which rapidly degrades ATP) or by the P2Y purinergic receptor/channel blocker pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), and could be mimicked by exogenous addition of ATP. In addition, we found that the 4alphaPDD-evoked current was blocked by pretreatment with RN-1734 or HC-067047, by Gd3+ or La3+, or by two distinct blockers of pannexin channels (carbenoxolone and probenecid), but not by a blocker of connexin hemichannels (flufenamic acid). We also found expression of TRPV4- and pannexin-channel proteins. 4alphaPDD markedly increased calcium flashing in our cells. The latter was abrogated by the P2Y channel blocker PPADS, and the 4alphaPDD-evoked current was eliminated by loading the cytosol with 1,2-bis(o-aminophenoxy)ethane N,N,N',N'-tetraacetic acid or by inhibiting Ca2+/calmodulin-sensitive kinase II using KN93. Altogether, we interpret these findings as suggesting that 4alphaPDD triggers the release of ATP via pannexin channels, which in turn acts in an autocrine and/or paracrine fashion to stimulate PPADS-sensitive purinergic receptors on human pulmonary fibroblasts. PMID- 29393655 TI - Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials. AB - RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = 17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33). PMID- 29393656 TI - Healthcare Reform: An Update. PMID- 29393659 TI - Influence of food structure on dairy protein, lipid and calcium bioavailability: A narrative review of evidence. AB - Beyond nutrient composition matrix plays an important role on food health potential, notably acting on the kinetics of nutrient release, and finally on their bioavailability. This is particularly true for dairy products that present both solid (cheeses), semi-solid (yogurts) and liquid (milks) matrices. The main objective of this narrative review has been to synthesize available data in relation with the impact of physical structure of main dairy matrices on nutrient bio-accessibility, bioavailability and metabolic effects, in vitro, in animals and in humans. Focus has been made on dairy nutrients the most studied, i.e., proteins, lipids and calcium. Data collected show different kinetics of bioavailability of amino acids, fatty acids and calcium according to the physicochemical parameters of these matrices, including compactness, hardness, elasticity, protein/lipid ratio, P/Ca ratio, effect of ferments, size of fat globules, and possibly other qualitative parameters yet to be discovered. This could be of great interest for the development of innovative dairy products for older populations, sometimes in protein denutrition or with poor dentition, involving the development of dairy matrices with optimized metabolic effects by playing on gastric retention time and thus on the kinetics of release of the amino acids within bloodstream. PMID- 29393658 TI - Water transport and homeostasis as a major function of erythrocytes. AB - Erythrocytes have long been known to change volumes and shapes in response to different salt concentrations. Aquaporin-1 (AQP1) was discovered in their membranes more than 20 yr ago. The physiological roles of volume changes and AQP1 expression, however, have remained unclear. We propose that rapid water exchange through AQP1 coupled with large capacity for volume change may allow erythrocytes to play an important role in water regulation. In this study, we showed that erythrocytes in situ gradually reduced their volumes by 39% in response to the hyperosmotic corticomedullary gradient within mouse kidneys. AQP1 knockout (KO) erythrocytes, however, displayed only minimal reduction. Constructing a microfluidic device resembling capillary flow with an extracellular fluorescent reporter demonstrated that water exchanges between erythrocytes and their hypotonic or hypertonic surroundings in vitro reached steady state in ~60 ms. AQP1 KO erythrocytes, however, did not show significant change. To simulate the water transport in circulation, we built basic units consisting of three compartments (i.e., erythrocyte, plasma, and interstitial fluid) using Kedem Katchalsky equations for membrane transport, and connected multiple units to account for the blood flow. These simulations agreed with experimental results. Importantly, volume-changing erythrocytes in capillaries always "increase" the osmotic gradient between plasma and interstitial fluid, making them function as "micropumps" to speed up the regulation of local osmolarity. Trillions of these micropumps, mobile throughout the body, may further contribute to water homeostasis. These insights suggest that the enhanced exchange of water, in addition to O2 and CO2, may well be the third major function of erythrocytes. NEW & NOTEWORTHY Physiological roles of erythrocyte volume change and aquaporin-1 were proposed and investigated here. We conclude that fast water transport by aquaporin-1 coupled with large volume-change capacity allows erythrocytes to enhance water exchange with local tissues. Furthermore, their huge number and mobility allow them to contribute to body water homeostasis. PMID- 29393660 TI - Effect of two different commercially available white light LED fixtures on broiler hatchability and chick quality. AB - 1. The objective of this study was to evaluate the effect of two different spectra of white light on hatchability and chick quality of broiler chickens. 2. A total of 8424 Ross 708 broiler eggs were divided over three light exposure treatments during incubation: No light (DARK), a light emitting diode (LED) light with high levels of blue light (BLUE), or a LED light with high levels of red light (RED). Hatchability, embryo mortality and chick quality were assessed at hatch. 3. DARK had a higher percentage of chicks with unhealed navels (21.1 +/- 1.3%) and fewer overall chicks with no defects (77.0 +/- 1.2%) compared to both the BLUE (9.9 +/- 0.9% and 88.4 +/- 1.1%) and RED treatments (7.7 +/- 0.8% and 90.2 +/- 1.0%). 4. Both the BLUE (80.9 +/- 1.0%) and RED treatments (82.9 +/- 1.4%) had higher hatchability of fertile eggs than the DARK treatment (76.0 +/- 2.2%). 5. These results indicate that either of these LED fixtures could be used to improve hatchability and chick quality in broiler chickens. Utilising these types of lightings in commercial hatcheries will improve the efficiency via increased hatchability and quality of the chicks hatched. PMID- 29393657 TI - A population neuroscience approach to the study of cerebral small vessel disease in midlife and late life: an invited review. AB - Aging in later life engenders numerous changes to the cerebral microvasculature. Such changes can remain clinically silent but are associated with greater risk for negative health outcomes over time. Knowledge is limited about the pathogenesis, prevention, and treatment of potentially detrimental changes in the cerebral microvasculature that occur with advancing age. In this review, we summarize literature on aging of the cerebral microvasculature, and we propose a conceptual framework to fill existing research gaps and advance future work on this heterogeneous phenomenon. We propose that the major gaps in this area are attributable to an incomplete characterization of cerebrovascular pathology, the populations being studied, and the temporality of exposure to risk factors. Specifically, currently available measures of age-related cerebral microvasculature changes are indirect, primarily related to parenchymal damage rather than direct quantification of small vessel damage, limiting the understanding of cerebral small vessel disease (cSVD) itself. Moreover, studies seldom account for variability in the health-related conditions or interactions with risk factors, which are likely determinants of cSVD pathogenesis. Finally, study designs are predominantly cross-sectional and/or have relied on single time point measures, leaving no clear evidence of time trajectories of risk factors or of change in cerebral microvasculature. We argue that more resources should be invested in 1) developing methodological approaches and basic science models to better understand the pathogenic and etiological nature of age-related brain microvascular diseases and 2) implementing state-of-the-science population study designs that account for the temporal evolution of cerebral microvascular changes in diverse populations across the lifespan. PMID- 29393661 TI - The Use of Anecdotal Information in a Hypothetical Lung Cancer Treatment Decision. AB - This mixed-methods study examined variables associated with use of experience based (i.e., anecdotal) decisional strategies among 85 undergraduate students presented with 2 hypothetical lung cancer scenarios. Participants were asked to think aloud while they made their treatment choice. Eleven decisional strategies were identified and grouped into either data or experience-based strategies. Approximately, 25% of participants used experience-based strategies. Use of experience-based strategies was more likely if the participant reported involvement in the life of someone going through cancer treatment, and if they rated print-based media sources as less important. Use of experience-based strategies was associated with choosing surgery instead of radiation for lung cancer treatment. PMID- 29393662 TI - Postpartum depression and vitamin D: A systematic review. AB - Postpartum depression (PPD) is a prevalent mood disorder estimated to affect 20% 40% of women worldwide after childbirth. In recent studies, the effect of vitamin D on prevention of mood disorders and depression has been investigated, but it is still unclear how vitamin D may affect PPD. The evidence on the relevance between vitamin D deficiency and PPD is inconsistent, and assessment of the recent literature has not previously been carried out. Moreover, there are few clinical studies on PPD and vitamin D supplementation. Five studies have so far assessed the relationship between the levels of vitamin D and PPD. Findings from cohort studies suggest that vitamin-D deficiency is related to the incidence of PPD and vitamin D may play a significant role in the recovery of women with PPD, but it is uncertain whether these actions are the effect of vitamin D on the function of hypothalamic-pituitary-adrenal (HPA) axis, the levels of estradiol, serotonin, pro-inflammatory cytokines, and/or of other mechanisms involved in PPD. PMID- 29393663 TI - Sense-making, Socialization, and Stigma: Exploring Narratives Told in Families About Mental Illness. AB - Guided by Communicated Narrative Sense-making Theory (CNSM), the current study investigated mental illness (MI) narratives told within families and the lessons younger members learned from these stories. Individual, semi-structured interviews with young adults (N = 24) revealed that family members, mainly parents, share stories about the MIs of individual family members and narratives reflected themes of struggle and caution. Participants reported learning important lessons from these MI narratives (i.e., MI awareness, importance of understanding MI). Findings illuminate the ways family narratives about MI teach younger members lessons and expectations for managing MI despite sometimes reinforcing MI stigma. Limitations, future directions, and implications for narrative interventions are also discussed. PMID- 29393664 TI - The 2018 Revision of the ISBER Best Practices: Summary of Changes and the Editorial Team's Development Process. AB - An increased need for specimens of reliable and consistent quality for research purposes requires the development of standardized policies and practices for the collection, handling, storage, retrieval, and distribution of specimens and specimen-related data. Providers of specimen resources should strive to incorporate new technologies and state-of-the-science approaches and thus ensure the availability of fit-for-purpose research specimens. Strategies to achieve quality outcomes and performance improvements often include adherence to established standards and implementation of best practices. Although standards represent a rigid set of guidelines that define exactly how a task should be completed, best practices are recommended actions and principles that demonstrate an awareness of standards, solve problems, can be replicated, and work in a given context. Adoption of best practice elements will vary based on the goals and circumstances of a given initiative, and in some instances, may not be possible to implement or may represent an aspirational achievement. In an effort to harmonize the scientific, technical, legal, and ethical issues relevant to repositories of biological and environmental specimens, the International Society for Biological and Environmental Repositories (ISBER) has released the updated ISBER Best Practices: Recommendations for Repositories (ISBER Best Practices). The document provides a comprehensive tool to guide repository professionals in both managerial and technical aspects such as practical details on repository governance, development, and operation; regulatory compliance; and ethical, legal, and social issues relevant to repositories. This summary describes the process for revising the document and summarizes the new topics, updates, and areas of expansion included in the fourth edition of ISBER Best Practices. PMID- 29393665 TI - The effects of ginger intake on weight loss and metabolic profiles among overweight and obese subjects: A systematic review and meta-analysis of randomized controlled trials. AB - This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effect of ginger intake on weight loss, glycemic control and lipid profiles among overweight and obese subjects. We searched the following databases through November 2017: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. The relevant data were extracted and assessed for quality of the studies according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as Standardized Mean Difference (SMD) with 95% Confidence Intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I squared tests (I2). Overall, 14 studies were included in the meta-analyses. Fourteen RCTs with 473 subjects were included in our meta-analysis. The results indicated that the supplementation with ginger significantly decreased body weight (BW) (SMD -0.66; 95% CI, -1.31, -0.01; P = 0.04), waist-to-hip ratio (WHR) (SMD -0.49; 95% CI, -0.82, -0.17; P = 0.003), hip ratio (HR) (SMD -0.42; 95% CI, 0.77, -0.08; P = 0.01), fasting glucose (SMD -0.68; 95% CI, -1.23, -0.05; P = 0.03) and insulin resistance index (HOMA-IR) (SMD -1.67; 95% CI, -2.86, -0.48; P = 0.006), and significantly increased HDL-cholesterol levels (SMD 0.40; 95% CI, 0.10, 0.70; P = 0.009). We found no detrimental effect of ginger on body mass index (BMI) (SMD -0.65; 95% CI, -1.36, 0.06; P = 0.074), insulin (SMD -0.54; 95% CI, -1.43, 0.35; P = 0.23), triglycerides (SMD -0.27; 95% CI, -0.71, 0.18; P = 0.24), total- (SMD -0.20; 95% CI, -0.58, 0.18; P = 0.30) and LDL-cholesterol (SMD -0.13; 95% CI, -0.51, 0.24; P = 0.48). Overall, the current meta-analysis demonstrated that ginger intake reduced BW, WHR, HR, fasting glucose and HOMA-IR, and increased HDL-cholesterol, but did not affect insulin, BMI, triglycerides, total- and LDL-cholesterol levels. PMID- 29393666 TI - Current and future prospects for the use of pulsed electric field in the meat industry. AB - Pulsed electric field (PEF) is a novel non-thermal technology that has recently attracted the attention of meat scientists and technologists due to its ability to modify membrane structure and enhance mass transfer. Several studies have confirmed the potential of pulsed electric field for improving meat tenderness in both pre-rigor and post-rigor muscles during aging. However, there is a high degree of variability between studies and the underlying mechanisms are not clearly understood. While some studies have suggested physical disruption as the main cause of PEF induced tenderness, enzymatic nature of the tenderization seems to be the most plausible mechanism. Several studies have suggested the potential of PEF to mediate the tenderization process due to its membrane altering properties causing early release of calcium ions and early activation of the calpain proteases. However, experimental research is yet to confirm this postulation. Recent studies have also reported increased post-mortem proteolysis in PEF treated muscles during aging. PEF has also been reported to accelerate curing, enhance drying and reduce the numbers of both pathogens and spoilage organisms in meat, although that demands intense processing conditions. While tenderization, meat safety and accelerated curing appears to be the areas where PEF could provide attractive options in meat processing, further research is required before the application of PEF becomes a commercial reality in the meat industry. It needs to deal with carcasses which vary biochemically and in composition (muscle, fat, and bones). This review critically evaluates the published reports on the topic with the aim of reaching a clear understanding of the possible applications of PEF in the meat sector in addition to providing some insight on critical issues that need to be addressed for the technology to be a practical option for the meat industry. PMID- 29393667 TI - Enhancing Food Processing by Pulsed and High Voltage Electric Fields: Principles and Applications. AB - Improvements in living standards result in a growing demand for food with high quality attributes including freshness, nutrition and safety. However, current industrial processing methods rely on traditional thermal and chemical methods, such as sterilization and solvent extraction, which could induce negative effects on food quality and safety. The electric fields (EFs) involving pulsed electric fields (PEFs) and high voltage electric fields (HVEFs) have been studied and developed for assisting and enhancing various food processes. In this review, the principles and applications of pulsed and high voltage electric fields are described in details for a range of food processes, including microbial inactivation, component extraction, and winemaking, thawing and drying, freezing and enzymatic inactivation. Moreover, the advantages and limitations of electric field related technologies are discussed to foresee future developments in the food industry. This review demonstrates that electric field technology has a great potential to enhance food processing by supplementing or replacing the conventional methods employed in different food manufacturing processes. Successful industrial applications of electric field treatments have been achieved in some areas such as microbial inactivation and extraction. However, investigations of HVEFs are still in an early stage and translating the technology into industrial applications need further research efforts. PMID- 29393670 TI - FABP4 as a biomarker for knee osteoarthritis. AB - AIM: To explore the role of an adipokine-termed fatty acid-binding protein 4 (FABP4) in osteoarthritis (OA). METHODS: Patients with primary knee OA and non-OA controls were included. Paired tissues including plasma, synovial fluid (SF), subcutaneous fat and infrapatellar fat pad (IPFP) were harvested during surgery. FABP4 concentration was determined by ELISA. RESULTS: Plasma FABP4 increased significantly with OA stage (n = 263). OA patients (n = 38) had significantly higher plasma and SF FABP4 than non-OA patients (n = 29). FABP4 level of IPFP was positively correlated with SF FABP4. CONCLUSION: OA patients had significantly high systemic and local FABP4, and IPFP may be the main source of FABP4 in synovial cavity. FABP4 may be a promising biomarker for OA. PMID- 29393668 TI - Detection of vertebral metastases: a comparison between the modified Dixon turbo spin echo T2 weighted MRI and conventional T1 weighted MRI: a preliminary study in a tertiary centre. AB - OBJECTIVE: To compare the diagnostic performance of modified Dixon (mDixon) turbo spin echo (TSE) T2 weighted MRI and conventional T1 weighted MRI in vertebral metastasis detection. METHODS: Between September 2014 and October 2016, 33 patients with 68 metastases who had undergone whole-spine MRI were enrolled. The following sagittal image sets were evaluated: T1WI, and mDixon TSE T2 weighted water and fat images. Two radiologists independently evaluated each image-set for metastasis. The MR findings were compared with positron emission tomography-CT (PET-CT) scans. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each sequence. The diagnostic performance of each sequence was evaluated using receiver operating characteristic (ROC) curves. RESULTS: Sensitivity, specificity, PPV and NPV for reviewer 1 were 83.8, 99.1, 89.1 and 98.6%, respectively, with T1WI; 79.4, 98.8, 85.7 and 98.2%, respectively, with mDixon TSE T2 weighted water imaging; and 86.8, 99.1, 89.4 and 98.8%, respectively, with mDixon TSE T2 weighted fat imaging. For reviewer 2, the respective scores were 91.2, 99.2, 91.2 and 99.2%; 85.3, 99.5, 93.4 and 98.7%; and 89.7, 99.3, 92.4 and 99.1%. With PET-CT as the gold standard, the ROC curves of the three sequences showed no significant difference (all p > 0.05). CONCLUSION: The diagnostic performance of mDixon TSE T2 weighted water and fat imaging was comparable to that of conventional T1WI in the detection of vertebral metastases. Advances in knowledge: mDixon TSE T2WI can be a good alternative to conventional T1WI for detecting vertebral metastases. PMID- 29393671 TI - Importance of maternal diet in the training of the infant's immune system during gestation and lactation. AB - Latest forecasts predict that half of the European population will be allergic within the coming 15 years, with food allergies contributing substantially to the total burden; preventive measures are urgently needed. Unfortunately, all attempted alimentary strategies for primary prevention of allergic diseases through allergen avoidance so far have failed. This also holds true for the prevention of food allergies in breastfed infants by the common practice of excluding certain foods with allergenic potential from the maternal diet. As a preventive measure, therefore, exclusion diets should be discouraged. They can exhaust nursing mothers and negatively impact both their nutritional status as well as their motivation to breastfeed. A prolonged exclusion diet may be indicated solely in cases of doctor-diagnosed food allergy following rigid medical tests (e.g. double-blind placebo-controlled food challenges). Indicated cases usually involve exclusion of only a few food items. Continued breastfeeding is generally important for many aspects of the infant's health, including the training of the infant's immune responses to foreign compounds and avoidance of overshooting inflammatory responses. Recent studies suggest that the presence of maternal dietary proteins in amniotic fluid, cord blood, and human milk might support the induction of tolerance towards solid foods in infants. These are exactly the same species of proteins or remnants thereof that, in comparatively few cases, trigger allergic responses. However, the insight that the proteins of maternal dietary origin in human milk are more likely to be cure (or, more precise, directing prevention) than curse has still largely evaded the attention of health care professionals consulted by worried breastfeeding mothers. In this paper, we summarize recent literature on the importance of exposure to dietary proteins in the establishment of immunological tolerance and hence prevention of allergic disease. Multiple organizations have used the scientific knowledge to build (local) guidelines (e.g. AAAAI, EAACI, BSACI) that can support health care professionals to provide the best strategy to prevent the onset of allergic diseases. We thus hope to clarify existing confusion about the allergenic propensities of dietary proteins during early life, which has contributed to exaggerated fears around the diet of pregnant and breastfeeding mothers. PMID- 29393673 TI - New pyranosyl cembranoid diterpenes from Sarcophyton trocheliophorum. AB - During our continual searching programme for novel bioactive metabolites from Sarcophyton trocheliophorum, collected from Red Sea, we describe herein the isolation and structural elucidation of further two new pyrane-based cembranoid diterpenes: 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and 8,9-expoy sarcotrocheliol acetate (2), along with the well-known sarcotrocheliol acetate (3), (+)-sarcophine (4), (+)-sarcophytoxide (5) and (-)-sarcophytoxide (6). The chemical structures of compounds 1 and 2 were determined on the basis of 1D and 2D NMR (1H, 13C, 1H-1H COSY, HMQC, HMBC and NOE), mass spectra (ESI and HR-ESIMS) and by comparison with related structures. The antimicrobial activities of the reported compounds 1-6 were investigated. According to the molecular docking study of compounds 1-6 using 3D structure of alpha,beta tubulin in complex with taxol (PDB code 1JFF) and epothilone A (PDB code 1TVK), sarcophine (4) displayed the highest affinity towards both crystal structures, followed by 5 and 6, meanwhile pyrane-based cembranoid diterpenes (1-3) showed less affinity. PMID- 29393672 TI - Functional and molecular MRI of the bone marrow in multiple myeloma. AB - MRI plays an important role in the management of patients with plasma cell neoplasms and has been recognized as a biomarker of malignancy in the novel criteria for the diagnosis of multiple myeloma. Functional and molecular MRI techniques such as diffusion-weighted imaging (spinal or whole body), intravoxel incoherent motion, and dynamic contrast enhanced MRI, provide additional information related to tumor cellularity and angiogenesis, which may have prognostic implications for patients with smoldering and symptomatic myeloma. These non-invasive functional techniques are also being evaluated as imaging biomarkers for response assessment in myeloma patients. The purpose of this article is to provide a comprehensive critical review on the current use and potential future applications of these advanced MRI techniques in multiple myeloma. In addition, we will address the technologies involved and describe the qualitative and quantitative characteristics of normal bone marrow with these techniques. PMID- 29393674 TI - Target volume motion during anal cancer image guided radiotherapy using cone-beam computed tomography. AB - OBJECTIVE: Literature regarding image-guidance and interfractional motion of the anal canal (AC) during anal cancer radiotherapy is sparse. This study investigates interfractional AC motion during anal cancer radiotherapy. METHODS: Bone matched cone beam CT (CBCT) images were acquired for 20 patients receiving anal cancer radiotherapy allowing population systematic and random error calculations. 12 were selected to investigate interfractional AC motion. Primary anal gross tumour volume and clinical target volume (CTVa) were contoured on each CBCT. CBCT CTVa volumes were compared to planning CTVa. CBCT CTVa volumes were combined into a CBCT-CTVa envelope for each patient. Maximum distortion between each orthogonal border of the planning CTVa and CBCT-CTVa envelope was measured. Frequency, volume and location of CBCT-CTVa envelope beyond the planning target volume (PTVa) was analysed. RESULTS: Population systematic and random errors were 1 and 3 mm respectively. 112 CBCTs were analysed in the interfractional motion study. CTVa varied between each imaging session particularly T location patients of anorectal origin. CTVa border expansions >= 1 cm were seen inferiorly, anteriorly, posteriorly and left direction. The CBCT-CTVa envelope fell beyond the PTVa >= 50% imaging sessions (n = 5). Of these CBCT CTVa distortions beyond PTVa, 44% and 32% were in the upper and lower thirds of PTVa respectively. CONCLUSION: The AC is susceptible to volume changes and shape deformations. Care must be taken when calculating or considering reducing the PTV margin to the anus. Advances in knowledge: Within a limited field of research, this study provides further knowledge of how the AC deforms during anal cancer radiotherapy. PMID- 29393675 TI - Overnight Glucose Control with Dual- and Single-Hormone Artificial Pancreas in Type 1 Diabetes with Hypoglycemia Unawareness: A Randomized Controlled Trial. AB - BACKGROUND: The dual-hormone (insulin and glucagon) artificial pancreas may be justifiable in some, but not all, patients. We sought to compare dual- and single hormone artificial pancreas systems in patients with hypoglycemia unawareness and documented nocturnal hypoglycemia. METHODS: We conducted a randomized crossover trial comparing the efficacy of dual- and single-hormone artificial pancreas systems in controlling plasma glucose levels over the course of one night's sleep. We recruited 18 adult participants with hypoglycemia unawareness and 17 participants with hypoglycemia awareness, all of whom had documented nocturnal hypoglycemia during 2 weeks of screening. Outcomes were calculated using plasma glucose. RESULTS: In participants with hypoglycemia unawareness, the median (interquartile range [IQR]) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on dual-hormone artificial pancreas nights and 0% (0-10) on single-hormone artificial pancreas nights (P = 0.20). Additionally, participants with hypoglycemia unawareness experienced two hypoglycemic events (<3.0 mmol/L) on dual-hormone artificial pancreas nights and three hypoglycemic events on single-hormone artificial pancreas nights. In participants with hypoglycemia awareness, the median (IQR) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on both dual- and single-hormone artificial pancreas nights. Hypoglycemia awareness participants experienced zero hypoglycemic events on dual hormone artificial pancreas nights and one event on single-hormone artificial pancreas nights. DISCUSSION: In this study, dual-hormone and single-hormone systems performed equally well in preventing nocturnal hypoglycemia in participants with hypoglycemia unawareness. Longer studies over the course of multiple days and nights may be needed to explore possible specific benefits in this population. ClinicalTrials.gov No. NCT02282254. PMID- 29393676 TI - Male-to-female aggression in cage-housed common pheasants (Phasianus colchicus) during the breeding season was not related to male plasma testosterone level. AB - 1. The aim of this study was to investigate if male-to-female aggression of common pheasants in the course of the breeding season was related to the concentration of plasma testosterone and/or other biochemical plasma indicators in male pheasants housed in breeding cages. The influence of season on the concentration of testosterone and biochemical indicators was also investigated. 2. Males were divided into non-aggressive and aggressive groups during the breeding season based on ethological evaluation. At the beginning, in the middle and at the end of the breeding season, a blood sample was taken from all males on the same day and the concentration of selected biochemical indicators and the total circulating testosterone in the plasma were determined. 3. Male-to-female aggression during the breeding season of pheasants was not influenced by the total plasma testosterone of males. 4. The concentration of total plasma testosterone in males decreased gradually during the breeding season. 5. Male-to female aggression of pheasants did not have a significant effect on any of the assessed biochemical indicators. 6. The influence of the breeding season affected the activities of alanine aminotransferase and aspartate aminotransferase as well as the concentrations of glucose, magnesium, potassium and chloride in the blood plasma of cage-housed male pheasants. PMID- 29393677 TI - Effects of repetitive subconcussive head trauma on the neuropsychological test performance of high school athletes: A comparison of high, moderate, and low contact sports. AB - The aim of this study was to examine the neuropsychological test results of non concussed high school athletes playing at three different levels of contact sports. Based on the concussion risk data of 12 different sports, a High Contact group (n=2819; wrestling/martial arts, cheerleading, track and field, football), a Moderate Contact group (n=2323; softball, basketball, soccer), and a Low Contact group (n=1580; baseball, volleyball, water polo, tennis, cross-country) were formed and compared in terms of their scores on the Immediate Post Concussion Assessment and Cognitive Testing (ImPACT). The results revealed that the High Contact group obtained small but statistically poorer performances in ImPACT Visual Memory, Visual Motor Speed, Impulse Control, and Total Symptom scores compared to the Moderate and Low Contact groups. The High Contact group also had poorer Reaction Time scores compared to the Low Contact group. No differences between the Moderate and Low Contact groups were noted. The findings, along with prior similar results, tentatively raise concerns that participant in high contact sports, exposed to repetitive subconcussive head trauma, may be at greater risk for lowered neuropsychological functioning and increased symptoms, compared to other high school athletes. In view of the preliminary nature of this investigation, more research into the effects of frequent head impacts in high school sports is strongly recommended. PMID- 29393678 TI - On the virtues of automated quantitative structure-activity relationship: the new kid on the block. AB - Quantitative structure-activity relationship (QSAR) has proved to be an invaluable tool in medicinal chemistry. Data availability at unprecedented levels through various databases have collaborated to a resurgence in the interest for QSAR. In this context, rapid generation of quality predictive models is highly desirable for hit identification and lead optimization. We showcase the application of an automated QSAR approach, which randomly selects multiple training/test sets and utilizes machine-learning algorithms to generate predictive models. Results demonstrate that AutoQSAR produces models of improved or similar quality to those generated by practitioners in the field but in just a fraction of the time. Despite the potential of the concept to the benefit of the community, the AutoQSAR opportunity has been largely undervalued. PMID- 29393679 TI - Lessons Learned Through the Implementation of an eHealth Physical Activity Gaming Intervention with High School Youth. AB - OBJECTIVE: To encourage high school students to meet physical activity goals using a newly developed game, and to document the feasibility, benefits, and challenges of using an electronic gaming application to promote physical activity in high school students. MATERIALS AND METHODS: Working with youth and game designers an electronic game, Camp Conquer, was developed to motivate high school students to meet physical activity goals. One-hundred-five high school students were recruited to participate in a 12-week pilot test of the game and randomly assigned to a Game Condition or Control Condition. Students in both conditions received a FitBit to track their activity, and participants in the Game Condition received access to Camp Conquer. Number of steps and active minutes each day were tracked for all participants. FitBit use, game logins, and qualitative feedback from researchers, school personnel, and participants were used to determine intervention engagement. RESULTS: The majority of study participants did not consistently wear their FitBit or engage with the gaming intervention. Numerous design challenges and barriers to successful implementation such as the randomized design, absence of a true school-based champion, ease of use, and game glitches were identified. CONCLUSION: Developing games is an exciting technique for motivating the completion of a variety of health behaviors. Although the present intervention was not successful in increasing physical activity in high school students, important lessons were learned regarding how to best structure a gaming intervention for the high school population. PMID- 29393680 TI - Comprehensive metabolite profiling in distinct chemotypes of Commiphora wightii. AB - Commiphora wightii (Arn.) Bhandari, known as guggul, produces a medicinally important gum resin which is used extensively by Ayurvedic physicians to treat various ailments. However, most of the studies on C. wightii have been limited to its gum resin. Comprehensive metabolic profiling of leaves, stem and gum resin samples was undertaken to analyse aqueous and non-aqueous metabolites from three distinct chemotypes (NBRI-101, NBRI-102 and NBRI-103) shortlisted from different agro-climatic zones. GC-MS, HPLC and NMR spectroscopy were used for comprehensive metabolomics. Multivariate analysis showed characteristic variation in quinic and citric acids, myo-inositol and glycine (aqueous metabolites) and 2,6-di-tert butyl-phenol, trans-farnesol and guggulsterones (non-aqueous metabolites) amongst the three chemotypes. Quinic acid, citric acid and myo-ionositol were detected in substantial quantities from leaves and stem samples which provide opportunities for novel nutraceutical and pharmaceutical formulations. Quinic acid, from the leaves, was identified as a marker metabolite for early selection of high guggulsterones-yielding cultivars. PMID- 29393681 TI - Adjusting Processing Parameters in an Entry-Level Commercial Dehydrator To Achieve a 5-Log Reduction of Salmonella during the Cooking Step. AB - The U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) guidance encourages jerky processors to use a single lethality step that will achieve a 5-log reduction of Salmonella. Many processors rely on internal temperature-time combinations recommended in this guidance. However, the efficacy of convective heating is highly dependent on relative humidity (RH). RH recommendations are vague because of variability in processing conditions and limited available data. This study was conducted to establish processing conditions for an entry-level commercial dehydrator (Harvest Saver R5A) to achieve a 5-log reduction of Salmonella. Unseasoned, unmarinated top round beef strips (65 mm thick) were inoculated with Salmonella (>7 log CFU/g) and processed with the chamber temperature set to 82.2 degrees C for a total cook time of 60 min with the intake closed (closed oven). Modifications (product load and fan speed) were made in subsequent trials to improve lethality. After incubation at 37 degrees C for 24 to 48 h, surviving Salmonella populations were enumerated on tryptic soy agar. In trial A, the maximum fan speed (2.5 m/s) with 30 kg of product resulted in 45 to 48.5% RH at 60 min, and a 5-log reduction of Salmonella was achieved in only 35.5% of the meat samples (54 of 152 samples). Increasing the product load by 40% (42 kg; trial B) increased RH in the chamber (57 to 85%) and resulted in improved lethality; a 5-log reduction was achieved in 95.0% of samples (131 of 138 samples). Because samples with reduced lethality were located on the windward side of the chamber, the fan speed was reduced (0.9 m/s; trial C1) to increase the RH, resulting in a 5-log reduction in 100% of the samples (138 of 138 samples). A replicate trial (trial C2) was conducted, and a 5-log reduction again was achieved in 100% of the samples. All trials exceeded recommendations by the FSIS; however, adequate Salmonella reduction was achieved only when the RH was >65% throughout. Product load and fan speed are practical parameters for processors to manipulate to increase the RH in closed systems and thus improve Salmonella lethality. PMID- 29393682 TI - Inactivation of Listeria monocytogenes on and within Apples Destined for Caramel Apple Production by Using Sequential Forced Air Ozone Gas Followed by a Continuous Advanced Oxidative Process Treatment. AB - This study evaluated the efficacy of using sequential forced air ozone followed by an advanced oxidative process (AOP) treatment to inactivate Listeria monocytogenes on and within Empire apples. The forced air ozone treatment consisted of a reactor that introduced ozone (6 g/h) into an airstream that flowed through an apple bed (ca. 30 cm in depth). Before treatment, the apples were conditioned at 4 degrees C to ensure that condensate had formed before the apples were transferred to the reactor. The condensate ensured sufficient relative humidity to enhance the antimicrobial action of ozone. Air was passed through the apple bed at 9.3 m/s, and the ozone was introduced after 10 min. The ozone concentration measured after exiting the apple bed reached a steady state of 23 ppm. A 20-min ozone treatment supported a 2.12- to 3.07-log CFU reduction of L. monocytogenes, with no significant effect of apple position within the bed. The AOP-based method was a continuous process whereby hydrogen peroxide was introduced as a vapor into a reactor illuminated by UV-C and ozone-emitting lamps that collectively generated hydroxyl radicals. Operating the AOP reactor with UV C light (54-mJ cm2 dose), 6% (v/v) hydrogen peroxide, 2 g/h ozone, and a chamber temperature of 48 degrees C resulted in a 3-log CFU reduction of L. monocytogenes on the surface of the apples and internally within the scar tissue. Applying a caramel coating, from a molten solution (at 80 degrees C), resulted in a 0.5-log CFU reduction of L. monocytogenes on the apple surface. In apples treated with the sequential process, L. monocytogenes could only be recovered sporadically by enrichment and did not undergo outgrowth when the caramel apples were stored at 22 degrees C for 19 days. However, growth of L. monocytogenes within the core, but not the surface, was observed from caramel apples prepared from nontreated control fruit. PMID- 29393683 TI - A Cardiology Exhibit at a Science Museum, Viewed as Speech Acts in Sequence. AB - An exhibit about cardiology at a science museum is an elaborate form of health communication, with messaging happening across text, pictures, models, and videos. This qualitative case study uses concepts of speech act sequencing and interpellation to explain a series of multimodal exhibits about cardiovascular health. Health exhibits are described as verbal and audiovisual arguments combining assertions of information; directives to change behavior, and designations of risk candidacy-or sequences of assertive, directive, and declarative speech acts. Visitors are targeted as heart disease candidates according to their risk factors, such as hypertension, overweight, and inactivity. Communication research focused on health exhibits is rare, and this article presents a new way of looking at them that contributes to the current discussions about controlling language. Implications for health communication scholars and multimedia message designers are explored. PMID- 29393684 TI - Memorable Messages from Family Members About Mental Health: Young Adult Perceptions of Relational Closeness, Message Satisfaction, and Clinical Help Seeking Attitudes. AB - This study investigates memorable messages about mental health that young adults (YAs) recall receiving from family members. A memorable messages conceptual framework is adopted to explore message types and their associations with relevant individual and relational outcomes. Findings from a study of 193 memorable messages about mental health revealed three types of messages about mental health transmitted by family members: strategizing, normalizing, and minimizing messages. Statistical analyses indicated that memorable message types were significantly related to YA satisfaction with the message, perceptions of relational closeness between the message source and the YA message recipient, and YA attitudes about mental-health help seeking. Overall, participants who reported minimizing messages about mental health also reported the least favorable outcomes on the set of dependent variables. Implications of these findings and future directions for research are discussed. PMID- 29393685 TI - Shared Decision Making for Psychiatric Rehabilitation Services Before Discharge from Psychiatric Hospitals. AB - Shared decision making (SDM) is an effective health communication model designed to facilitate patient engagement in treatment decision making. In mental health, SDM has been applied and evaluated for medications decision making but less for its contribution to personal recovery and rehabilitation in psychiatric settings. The purpose of this pilot study was to assess the effect of SDM in choosing community psychiatric rehabilitation services before discharge from psychiatric hospitalization. A pre-post non-randomized design with two consecutive inpatient cohorts, SDM intervention (N = 51) and standard care (N = 50), was applied in two psychiatric hospitals in Israel. Participants in the intervention cohort reported greater engagement and knowledge after choosing rehabilitation services and greater services use at 6-to-12-month follow-up than those receiving standard care. No difference was found for rehospitalization rate. Two significant interaction effects indicated greater improvement in personal recovery over time for the SDM cohort. SDM can be applied to psychiatric rehabilitation decision making and can help promote personal recovery as part of the discharge process. PMID- 29393686 TI - Reliability of the balance error scoring system in a population with protracted recovery from mild traumatic brain injury. AB - OBJECTIVE: This study aimed to identify the Balance Error Scoring System's (BESS) intraclass reliability in a cohort of patients with prolonged symptoms using variance component analysis and intraclass correlation coefficient (ICC). SETTING: Outpatient sports medicine/concussion clinic. PARTICIPANTS: A total of 241 paediatric and 102 adult patients with symptoms lasting longer than 10 days. INTERVENTIONS: BESS testing. DESIGN: Retrospective review. MAIN OUTCOME MEASURES: Percent variance for each BESS component and intraclass reliability. A five component model (including all components except for firm double-leg) and a four- component model (including all components except for firm and foam doubleleg) were also performed to compare ICC values. RESULTS: The largest source of variance came from stance (41.1%). The BESS components firm single (25.5%) and foam tandem (27.5%) stances accounted for the largest percentages of variance, while firm double (1.1%) and foam double (6.9%) accounted for the smallest percentages. The ICC for all patients was 0.800, and increased both if the firm double stance was excluded, or if both double-leg stances were excluded. CONCLUSION: BESS reliability appears to be high in a concussed cohort, regardless of age. Removing the two double-leg stance portions increases the ICC of the test without failing to identify balance deficits. PMID- 29393687 TI - Correction to: Rosetta et al., Ovulatory status and menstrual cycle duration assessed by self-collection of urine on pH strips in a population-based sample of French women not using hormonal contraception. PMID- 29393688 TI - Systematic review of high-level mobility training in people with a neurological impairment. AB - AIM: The objective of this paper was to systematically review the efficacy of interventions targeting high-level mobility skills in people with a neurological impairment. METHODS: A comprehensive electronic database search was conducted. Study designs were graded using the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) system and methodological quality was described using the Physiotherapy Evidence Database (PEDro) scale. RESULTS: Twelve exploratory studies (AACPDM levels IV/V), of limited methodological quality (PEDro scores of 2-3 out of 10), were included. Interventions included treadmill training, a three-phase programme, a high-level mobility group, plyometric training, running technique coaching and walk training with blood flow restriction. Diagnoses included acquired brain injury, cerebral palsy, incomplete spinal cord injury and neurofibromatosis type 1. There were difficulties generalizing results from exploratory designs with a broad range of participants, interventions and outcome measures. However, it seems that people with a neurological impairment have the capacity to improve high-level mobility skills, running speed and distance with intervention. There were no adverse events that limited participation. CONCLUSION: There is preliminary evidence to support the efficacy of interventions to improve high-level mobility skills in people with neurological impairments. Well-controlled research with a larger sample is required to provide sufficient evidence to change clinical practice. PMID- 29393689 TI - Zolpidem efficacy and safety in disorders of consciousness. AB - Sutton and Clauss presented a detailed review about the effectiveness of zolpidem, discussing recoveries from brain damage due to strokes, trauma and hypoxia. A significant finding has been the unexpected and paradoxical increment of brain activity in vegetative state/unresponsive wakefulness syndrome (VS/UWS). On the contrary, zolpidem is considered one of the best sleep inducers in normal subjects. We have studied series of VS/UWS cases after zolpidem intake. We have demonstrated EEG activation, increment of BOLD signal in different brain regions, and an autonomic influence, mainly characterized by a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. As this autonomic imbalance might induce cardio- circulatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that the paradoxical arousing zolpidem effect might be certainly related to brain function improvement, we agree with Sutton and Clauss that future multicentre and multinational clinical trials should be developed, but under control of physiological indices. PMID- 29393690 TI - Benefits of vaginal misoprostol prior to IUD insertion in women with previous caesarean delivery: a randomised controlled trial. AB - OBJECTIVE: The aim of the study was to evaluate the value of vaginal misoprostol 6 h prior to intrauterine device (IUD) insertion in women with previous Caesarean delivery. METHODS: A double-blind randomised controlled trial was conducted in 120 women who were eligible for IUD insertion. Participants were randomly divided to receive either 600 MUg vaginal misoprostol or placebo 6 h before IUD insertion. The primary outcome measure was the pain score during the procedure. Secondary outcome measures were failure of insertion, insertion difficulty score, complications of IUD insertion and side effects related to misoprostol. RESULTS: Pain and insertion difficulty scores were significantly lower in the misoprostol group compared with the placebo group (5.7 +/- 1.4 vs. 6.5 +/- 0.9 and 4.1 +/- 1.1 vs. 5.4 +/- 2.2, respectively; p < .001). More women experienced nausea, vomiting (5 vs. 0; p = .06) and cramps (10 vs. 0; p < .001) in the misoprostol group than in the placebo group, respectively. CONCLUSIONS: The use of misoprostol before IUD insertion is associated with less painful and easier placement. PMID- 29393691 TI - A historical review of the evolution of the Tardieu Scale. AB - There are many clinical assessment tools that can be used to quantify spasticity, one feature of the Upper Motor Neurone (UMN) syndrome. The focus of this short paper is on three; the Tardieu Scale, the Modified Tardieu Scale and the Australian Spasticity Assessment Scale, because a fundamental concept of these tests is their velocity dependent nature. Other bedside assessments such as the Modified Ashworth Scale examine hypertonicity, another feature of the UMN syndrome, but in this instance, the stretching movement is not velocity dependent. The Tardieu Scale, while not officially named until 1997, was conceived in the 1950s and since that time it has been revised by multiple authors and it is these additions that will be discussed in this article. The advantages and disadvantages of these assessment tools will be discussed with the ultimate aim of identifying one that has greater clinical utility. PMID- 29393692 TI - Beyond anger: emotion regulation and social connectedness in veterans with traumatic brain injury. AB - PRIMARY OBJECTIVE: Patients with traumatic brain injury (TBI) often present with emotion dysregulation. Most TBI rehabilitation has addressed this impairment primarily in relation to anger, irritability and aggressiveness. Yet, emotion regulation (ER) may have broader ramifications for psychological well-being. The present study examined ER's association to several aspects of social connectedness. RESEARCH DESIGN: Cross-sectional study Methods and procedures: 83 veterans with TBI who were outpatients at a VA medical rehabilitation service were interviewed in their homes. A 5-item ER subscale, drawn from the Patient Competency Rating Scale, was subjected to psychometric analysis and examined as a predictor of five social connectedness measures: community reintegration (CR), interpersonal functioning, quality of relationship with key family members and social role limitations due to physical problems and due to emotional problems. Sociodemographic, military and medical information was also collected. MAIN OUTCOMES AND RESULTS: The ER subscale showed good psychometric properties. ER contributed significantly to CR, interpersonal functioning and limitations in social roles. This underscores ER's role in social connectedness among veterans with TBI. CONCLUSIONS: Impairments in ER should be regarded as a risk factor for poor interpersonal outcomes, a target for mental health treatment and a focus for interventions aimed at improving psychological well-being in TBI. PMID- 29393693 TI - Combined use of adipose derived stem cells and TGF-beta3 microspheres promotes articular cartilage regeneration in vivo. AB - We investigated enhancement of articular cartilage regeneration using a combination of human adipose derived stem cells (hADSCs) and TGF-beta3 microspheres (MS) in vivo. Poly-lactic-co-glycolic acid (PLGA)MS were prepared using a solid/oil/water emulsion solvent evaporation-extraction method. The morphology of the MS was evaluated by scanning electron microscopy (SEM). The release characteristic of the TGF-beta3 MS was evaluated. A New Zealand rabbit model for experimental osteoarthritis (OA) was established using the anterior medial meniscus excision method. Thirty OA rabbits were divided randomly into three groups according to different treatments of the right knee joints on day 7 after surgery: hADSCs/MS group received injection of both hADSCs and TGF-beta3 MS; hADSCs group was injected with hADSCs; control group was injected with normal saline. Gross observation, histological staining and RT-PCR for collagen II and aggrecan) were used to assess the severity of OA and for evaluating the effect of combined use of hADSCs and TGF-beta3 MS on articular cartilage regeneration in vivo. The MS were spherical with a smooth surface and the average diameter was 28 +/- 2.3 um. The encapsulation efficiency test showed that 73.8 +/- 2.9% of TGF beta3 were encapsulated in the MS. The release of TGF- beta3 lasted for at least 30 days. At both 6 and 12 weeks after injection, three groups exhibited different degrees of OA. Histological analysis showed that the hADSCs/MS group exhibited less OA than the hADSCs group, and the control group exhibited the most severe OA. Real-time RT-PCR showed that the gene expression of both collagen II and aggrecan were significantly up-regulated in the hADSCs/MS group. At 12 weeks after injection, the hADSCs/MS group also exhibited less OA than the other two groups. Combined use of hADSCs and TGF-beta3 MS promoted articular cartilage regeneration in rabbit OA models. PMID- 29393694 TI - Rights language and disorders of consciousness: a call for advocacy. AB - Drawing upon sources in neuroethics, civil rights, and disability rights law, we argue for the reintegration of people with severe brain injury back into the nexus of their families and communities consistent with the Americans with Disabilities Act (ADA) and the UN Convention on the Rights of Persons with Disabilities, both of which call for the maximal integration of people with disability into society. To this end, we offer a rights-based argument to address the care of people with severe brain injury. Instead of viewing the provision of rehabilitation as a reimbursement issue, which it surely is, we argue that it can be productively understood as a question of civil rights for a population generally segregated from the medical mainstream and from society itself. Their segregation in the chronic care sector constitutes disrespect for persons, made all the more consequential because recent advances in brain injury rehabilitation make reintegration into civil society an aspirational, if not achievable goal. PMID- 29393695 TI - Prevalence of hypertension in argentinean indigenous children living at high altitudes versus US children. AB - BACKGROUND: Exposure to hypoxia at high altitude is increasingly being recognized as a risk factor for hypertension. OBJECTIVE: To compare the prevalence of hypertension in Indigenous Argentinean children living at high altitude with that reported in the 2011-2012 National Health and Nutrition Examination Survey (NHANES) of US children. METHODS: A cross-sectional study of 811 (400 females) Argentinean Indigenous school children (8-14 years) from San Antonio de los Cobres (SAC) was performed between 2011-2014. SAC is located in the Andean foothills 3,750 m above sea level. 98% of its population is Indigenous. Anthropometric, BP, and biochemical data were obtained from SAC and compared with those of 1279 (625 females) US children. Pre-hypertension and hypertension were defined by BP>=90th to <95th percentile or >=95th percentile, respectively. RESULTS: The prevalence of obesity was significantly lower in SAC (22; 2.7%) than in the US (310; 24.3%). However, the prevalence of hypertension was significantly higher in SAC (129; 15.9%) than in US children (35; 2.9%). Multiple logistic regression analyses showed that SAC children had four times the odds of having pre-hypertension compared with US children (OR 4.47; 95% CI 3.29-6.08), and eight times the odds of presenting hypertension (OR 8.36; 95% CI 5.36-13.05), adjusted for age, gender, and BMI. CONCLUSIONS: This study shows a higher prevalence of hypertension in Indigenous Argentinean children living at high altitude compared with US children. Various factors such as high hemoglobin levels, lifestyle behavior, and genetics may have an influence on BP in high altitude Indigenous SAC children. ABBREVIATIONS: BP: Blood pressure; SAC: San Antonio de los Cobres; CDC: Centers for Disease Control and Prevention; NHANES: National Health and Nutrition Examination Survey. PMID- 29393696 TI - Non-Orthogonal Corneal Astigmatism among Normal and Keratoconic Brazilian and Chinese populations. AB - PURPOSE: To investigate the prevalence of non-orthogonal astigmatism among normal and keratoconic Brazilian and Chinese populations. METHODS: Topography data were obtained using the Pentacam High Resolution (HR) system (r) from 458 Brazilian (aged 35.6 +/- 15.8 years) and 505 Chinese (aged 31.6 +/- 10.8 years) eyes with no history of keratoconus or refractive surgery, and 314 Brazilian (aged 24.2 +/- 5.7 years) and 74 Chinese (aged 22.0 +/- 5.5 years) keratoconic eyes. Orthogonal values of optical flat and steep powers were determined by finding the angular positions of two perpendicular meridians that gave the maximum difference in power. Additionally, the angular positions of the meridians with the minimum and maximum optical powers were located while being unrestricted by the usual orthogonality assumption. Eyes were determined to have non-orthogonal astigmatism if the angle between the two meridians with maximum and minimum optical power deviated by more than 5 degrees from 90 degrees . RESULTS: Evidence of non orthogonal astigmatism was found in 39% of the Brazilian keratoconic eyes, 26% of the Chinese keratoconic eyes, 29% of the Brazilian normal eyes and 20% of the Chinese normal eyes. CONCLUSIONS: The large percentage of participants with non orthogonal astigmatism in both normal and keratoconic eyes illustrates the need for the common orthogonality assumption to be reviewed when correcting for astigmatism. The prevalence of non-orthogonality should be considered by expanding the prescription system to consider the two power meridians and their independent positions. PMID- 29393697 TI - Context processing during irony comprehension in right-frontal brain-damaged individuals. AB - The aim of the present study was to investigate whether the degree of incongruity between contextual information and a target sentence influences the extent to which irony is understood in individuals with right-frontal-hemisphere damage (RHD). A psycholinguistic paradigm was used, allowing us to assess whether impairment in irony understanding is likely to be due to insensitivity (i.e. difficulty in capturing or detecting relevant contextual information) to relevant contextual information or to difficulties in integrating contextual information. Twenty individuals with RHD and 20 healthy control (HC) participants were tested on their understanding of a speaker's ironic intent and their executive functions. The main results revealed that individuals with RHD exhibit different patterns of performance, some of them being able to understand irony while in others this ability was impaired. The present study gives support to the hypothesis that difficulties in adequately using contextual information may account for pragmatic impairment of individuals with RHD. More importantly, the results suggested that these difficulties are related to a lack of sensitivity to contextual information instead of difficulty integrating it along with the ironic utterance. A subgroup of individuals with RHD processed the speaker's utterance without any reference to contextual information, which led them to a literal interpretation of the utterance. PMID- 29393698 TI - Assessment of olfactory function after traumatic brain injury: comparison of single odour tool with detailed assessment tool. AB - OBJECTIVES: Olfactory disturbance (OD) is common after traumatic brain injury (TBI). Screening for OD can be performed by several different methods. While odour identification tools are considered more accurate, they are time consuming. The predominant method in clinical practice remains the use of a single odour. This study aimed to compare a brief single-odour identification tool (BSOIT) with a more detailed 12-odour assessment tool. MATERIALS/METHODS: One hundred seventy consecutive patients with TBI had their olfaction assessed using BSOIT and a 12 item tool at a single time point. The sensitivity and specificity of the BSOIT were calculated. RESULTS: The sensitivity and specificity of the BSOIT as compared to the Burghart tool were 57.5% and 100%, respectively, for all ODs (anosmia and hyposmia). The sensitivity and specificity for anosmia only were 93.5% and 96.7%, respectively. For the two tools, the Cohen's kappa coefficient showed moderate agreement when both anosmia and hyposmia were considered (k = 0.619, p < 0.001) but a very strong agreement when only anosmia was considered (k = 0.844, p < 0.001). For both the tools, anosmia had a significant association with TBI severity (p < 0.001). However, hyposmia showed no such association. CONCLUSIONS: The BSOIT is very effective at identifying anosmia but not hyposmia, producing comparable results to a more detailed test. It can be effective in clinical practice and takes considerably less time. PMID- 29393699 TI - Clinical implications of combined glucose intolerance in treatment-naive hypertensive patients. AB - BACKGROUND: This study is the first study to evaluate clinical significance of combined glucose intolerance (CGI) in treatment-naive hypertensive patients. METHODS: We compared the results of demographic, anthropometric, clinical, laboratory examinations, echocardiography, arterial stiffness, central blood pressure (BP) and ambulatory BP monitoring (ABPM) between the groups according to fasting blood sugar (FBS), postprandial 2 hour blood glucose (PP2) and gender in treatment-naive hypertensive patients. A total of 376 concecutively-eligible patients were categorized as follows: (1) normal glucose tolerance (NGT); FBS<100 mg/dL and PP2 < 140 (2) isolated glucose intolerance (IGI); 100<=FBS<126 or 140<=PP2 < 200, but not both 100<=FBS<126 and 140<=PP2 < 200 (3) CGI; both 100<=FBS<126 and 140<=PP2 < 200. RESULTS: Males were divided into NGT (n = 58, 33.1%), IGI (n = 88, 50.3%), CGI (n = 29, 16.6%) and females were divided into NGT (n = 59, 43.1%), IGI (n = 48, 35%), CGI (n = 30, 21.9%). In males multivariate analyses revealed that mitral average E/Ea (IGI vs CGI, p = 0.022), brachial-ankle pulse wave velocity baPWV(Rt.) (IGI vs CGI, p = 0.026), baPWV(Lt.) (IGI vs CGI, p = 0.018), office systolic BP (SBP) (NGT vs. CGI, p = 0.005; IGI vs. CGI, p = 0.001), office diastolic BP (DBP) (NGT vs. CGI, p = 0.034; IGI vs. CGI, p = 0.019), night-time SBP (NGT vs. CGI, p = 0.049; IGI vs. CGI, p = 0.018) were significantly higher in the CGI group than in the NGT or IGI group. However, there were no significant differences between the female groups. CONCLUSIONS: Treatment-naive hypertensive males with CGI revealed subclinical diastolic dysfunction, arterial stiffness, and BPs. PMID- 29393700 TI - Adsorption of ethylenediaminetetraacetic dianhydride modified oxalate decarboxylase on calcium oxalate. AB - We used ethylenediaminetetraacetic acid dianhydride (EDTAD) to modify oxalate decarboxylase (OXDC) to improve its adsorption on calcium oxalate stones. The modified sites were identified by Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) and the adsorption mechanism of the EDTAD-modified OXDC on calcium oxalate (CaOx) was investigated. We investigated adsorption time, initial enzyme concentration, temperature and solution pH on the adsorption process. Data were analyzed using kinetics, thermodynamics and isotherm adsorption models. UPLC MS showed that EDTAD was attached to OXDC covalently and suggested that the chemical modification occurred at both the free amino of the side chain and the alpha-NH2 of the peptide. The adsorption capacity of the EDTAD-OXDC on calcium oxalate was 53.37% greater than that of OXDC at the initial enzyme concentration of 5 mg/ml, pH = 7.0, at 37 degrees C. The modified enzyme (EDTAD-OXDC) demonstrated improved oxalate degradation activity at pH 4.5-6.0. Kinetic data fitting analysis suggested a pseudo second order kinetic model. Estimates of the thermodynamic parameters including DeltaG0, DeltaH0 and DeltaS0 of the adsorption process showed it to be feasible, spontaneous and endothermic. Isotherm data fitting analysis indicated that the adsorption process is reduced to monolayer adsorption at a low enzyme concentration and to multilayer adsorption at a high enzyme concentration. It may be possible to apply OXDC to degradation of calcium oxalate stones. PMID- 29393701 TI - Efficacy and Tolerability of Bacillus Calmette-Guerin Therapy as the First-Line Therapy for Upper Urinary Tract Carcinoma In Situ. AB - There are few data on Bacillus Calmette-Guerin (BCG) therapy for upper urinary tract carcinoma in situ (UUT CIS). We retrospectively evaluated the efficacy and tolerability of BCG therapy for 41 patients [52 renal units(RUs)] with UUT CIS. Of 52 RUs, complete response was achieved in 47 (90%). The 5-year recurrence-, progression-free survival rates were 60.2% and 74.2%, respectively. Adverse events were observed in 31 (76%) patients, but most of them were mild. The scheduled instillations were completed in 31 (74%) of 42 patients. Our results demonstrated that BCG therapy for UUT CIS was satisfactory with high efficacy and tolerability. PMID- 29393702 TI - Radiolabeled mAbs as Molecular Imaging and/or Therapy Agents Targeting PSMA. AB - Molecular imaging and therapy is a rapidly evolving field in research and clinical medicine. The use of the exciting and attractive properties of radioisotopes for imaging and therapy has made Nuclear Medicine very significant when it comes to molecular imaging/therapy. Monoclonal Antibodies (mAbs) on the other hand are very important targeting biomolecules with high affinity that can "carry" the radioisotope of choice. Herein we make a brief overview of the radiolabeled mAbs that target prostate specific membrane antigen (PSMA) and their use in the management of patients with prostate cancer (PCa). PMID- 29393703 TI - Dichotic listening and sentence repetition performance in children with reading difficulties. AB - Numerous investigations have identified weaknesses in speech processing and language skills in children with dyslexia; however, little is known about these abilities in children with reading difficulties (RD). The primary objective of this investigation was to determine the utility of auditory speech processing tasks in differentiating children with RD from those with typical reading skills. It was hypothesized that children, who perform below grade level in reading, would also show poorer performance on both dichotic listening and sentence repetition tasks because of the reciprocal influences of deficient auditory speech processing and language abilities. A total of 180 Hungarian-speaking, monolingual 8-, 9- and 10-year-old children, with and without RD, participated in dichotic listening and sentence repetition (modified by noise and morphosyntactic complexity) tasks. Performances were compared across ability groups, age and gender. Children with RD evidenced significantly poorer performance than controls on both tasks. Effects for age and gender were more noticeable in students with RD. Our findings support the notion that reading deficiencies are also associated with poor auditory speech processing and language abilities in cases where dyslexia is not diagnosed. We suggest that these tasks may be used as easy and fast screening tests in the identification of RD. PMID- 29393704 TI - Fertility awareness-based mobile application. PMID- 29393705 TI - Alpha-1 Antitrypsin Deficiency Detection in a Portuguese Population. AB - Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease characterised by low serum levels of this molecule. Its epidemiology remains unknown in many countries, mainly due to its underdiagnosed state and lack of patients' registries. We aim to evaluate and characterise a sample of Portuguese individuals tested for AATD, between 2006 and 2015, based on a retrospective analysis from the database of a laboratory offering AATD genetic diagnosis service. 1684 individuals were considered, covering almost every region in Portugal. Genetic diagnosis resulted from requests of clinicians from different areas of expertise, mainly pulmonology (35.5%). Most subjects could be distributed into more common genotypes: MZ (25.4%, n = 427), MS (15.5%, n = 261), SZ (11.2%, n = 188), ZZ (9.4%, n = 158) and SS (5.6%, n = 95). 9.5% of the subjects were found to carry at least one rare deleterious allele, including the recently described PGaia, Q0Oliveira do Douro, Q0Vila Real and a novel SGaia variant. This study comprises 417 subjects (24.7%) with severe to very severe AATD and 761 carriers (45.2%), 22.7% of those identified by familial screening. The present study represents the most complete survey of AATD in Portugal so far and discloses a high rate of severe and very severe deficiency cases, attributed not only to ZZ and SZ genotypes but also to a large number of rare combinations with other null and deficiency alleles. It also uncovers a low awareness to AATD among the medical community, highlighting the need to create a Portuguese national registry and AATD guidelines and increase the awareness about this condition. PMID- 29393706 TI - Biomarkers in Recurrent Grade III Glioma Patients Treated with Bevacizumab and Irinotecan. AB - Predictive biomarkers and prognostic models are required to identify recurrent grade III glioma patients who benefit from existing treatment. In this study of 62 recurrent grade III glioma patients, a range of clinical and paraclinical factors are tested for association with progression-free survival, overall survival, and response to bevacizumab and irinotecan therapy. Significant factors from univariate screening are included in multivariate analysis. Biomarkers previously advanced as predictive or prognostic in the first-line setting did not affect outcome in this patient cohort. Based on the optimized model for overall survival, comprising performance status and p53 expression, a prognostic index is established. PMID- 29393707 TI - Kaempferol attenuates acute lung injury in caecal ligation and puncture model of sepsis in mice. AB - AIM OF THE STUDY: Kaempferol is a flavonoid and important part of the diet. Kaempferol has shown antioxidant, antiinflammatory and antidiabetic activities in various studies. However, protective potential of kaempferol in acute lung injury induced by sepsis and its mechanism remains unclear. The present study was undertaken to evaluate the effect of kaempferol in sepsis-induced acute lung injury in mice and its possible mechanism of action. MATERIALS AND METHODS: Acute lung injury was induced by CLP surgery in mice. Kaempferol (100 mg/kg bw) was administered orally one hour before caecal ligation and puncture surgery in mice. Mice were divided into four groups sham, KEM+sham, sepsis (CLP), and KEM+sepsis. Assessment of lung injury was done by estimation of protein content in lung tissue, lung edema, proinflammatory cytokines in plasma and lung tissue, oxidative stress, antioxidant enzymes, nitrite production, and histopathology. RESULTS: Kaempferol pretreated mice showed significant (P < 0.001) decrease in water content in lungs. Kaempferol pretreatment showed reduction in cytokines IL 6, IL-1beta, and TNF-alpha in plasma as well as in lung tissue in comparison with septic mice without pretreatment. Pretreatment with kaempferol did not show any reduction in MDA level in comparison with septic mice. Antioxidant enzymes SOD and catalase and nonenzymatic antioxidant GSH activities were also increased with kaempferol pretreatment in septic mice. Further, kaempferol pretreatment reduced the lung tissue nitrite level (P < 0.01) and iNOS (P < 0.05) level in septic mice. A significant (P < 0.01) downregulation of mRNA expression of ICAM-1 and iNOS was observed with this pretreatment. Kaempferol pretreatment did not decrease bacterial load in septic mice. Mice pretreated with kaempferol followed by sepsis showed lesser infiltration of cells and more arranged alveolar structure in histopathological analysis. CONCLUSIONS: The study suggests that kaempferol showed attenuation in sepsis-induced acute lung injury in mice through suppression of oxidative stress, iNOS, and ICAM-1 pathways. PMID- 29393708 TI - Choice of contraception at 6-8 weeks postpartum in south-eastern Hungary. AB - OBJECTIVES: The aims of the study were to describe the sociodemographic determinants, breastfeeding- and sexual life-related predictive factors of contraceptive use at 6-8 weeks postpartum. METHODS: A prospective, web-based questionnaire survey was carried out by distributing an access code to women immediately after delivery at the Department of Obstetrics and Gynaecology, the University of Szeged, Szeged, Hungary, between 1 September 2013 and 1 May 2015. RESULTS: In total, 1875 women were invited to participate in the study, 632 of whom refused or were excluded and 644 were not sexually active. The remaining sexually active women (n = 599) completed the questionnaire. At 6-8 weeks postpartum, 22.5% were using an effective contraceptive method and 40.2% were relying on lactational amenorrhoea (LAM). We found a significant direct association between the educational level of a woman's partner and her use of an effective contraceptive method (p < .001) (adjusted odds ratio [AOR]: 1.9) or LAM (AOR: 1.49). Use of an effective contraceptive method before pregnancy increased the likelihood of using the same method after delivery (AOR: 3.16) and decreased the likelihood of LAM use at weeks 6-8 (AOR: 0.31). The AOR for effective contraceptive use was 2.23 times higher in women who had sexual intercourse once or more a week compared with those who had sexual intercourse less frequently. CONCLUSIONS: Concerted efforts to promote the use of long-acting reversible contraception (LARC) are required, particularly among women who would like future childbearing. Further research is needed on the factors contributing to the low uptake of LARC in this population. PMID- 29393709 TI - Challenges for clinical practice and research in family medicine in reducing the risk of chronic diseases. Notes on the EGPRN Spring Conference 2017 in Riga. AB - Chronic diseases in most cases belong to the category of non-communicable diseases (NCDs), which are the main cause of mortality globally. Cardiovascular diseases, diabetes, chronic obstructive pulmonary disease and cancer are the four NCDs responsible for 82% of NCD deaths. Prevention of NCDs implies health promotion activities that encourage healthy lifestyle and limit the initial onset of chronic diseases. Prevention also includes early detection activities, such as screening at-risk populations, as well as strategies for appropriate management of existing diseases and related complications. Early intervention, reducing morbidity and mortality rates could be an appealing idea for patients, physicians and governmental institutions but could also cause harm. Healthcare is undergoing profound changes, and the role of technology in diagnostics and management of chronic diseases in primary healthcare (PHC) is increasing remarkably. However, studies show that the standards of care for chronic diseases and preventive care are met by less than 50%. We still lack clear standards for patients with multiple chronic diseases. The applicability of a single evidence-based guideline to multimorbid patients is limited and can be problematic. Well-designed PHC studies focusing on the impact of medical interventions on morbidity, mortality and quality of life in the fields of early diagnosis, early treatment and multimorbidity are still needed. PMID- 29393710 TI - The global fight to develop antipoverty vaccines in the anti-vaccine era. AB - Antipoverty vaccines are the vaccines targeting a group of approximately 20 neglected tropical diseases (NTDs), as currently defined by the World Health Organization (WHO). The "antipoverty" moniker refers to the fact that NTDs trap populations in poverty due to their chronic and deleterious effects on child intellect and worker productivity. Therefore, NTD vaccines can be expected to promote both global health and economic advancement. Unfortunately, antipoverty vaccine development has lagged behind vaccines for major childhood infections and pandemic threats, despite evidence for their cost-effectiveness and cost-savings. Currently, the only licensed vaccines for NTDs include those for yellow fever, dengue, and rabies, although several other NTD vaccines for hookworm disease, schistosomiasis, leishmaniasis, and Zika and Ebola virus infections are in different stages of clinical development, while others are at the preclinical development stage. With the exception of the viral NTD vaccines there so far has been minimal industry interest in the antipoverty vaccines, leaving their development to a handful of non-profit product development partnerships. The major scientific and geopolitical hurdles to antipoverty vaccine development are discussed, including a rising antivaccine ("antivax") movement now entering highly populated low- and middle-income countries. PMID- 29393711 TI - Role of ethanolic extract of Morus alba leaves on some biochemical and hematological alterations in irradiated male rats. AB - PURPOSE: The present study aimed to evaluate the protective role of "Morus alba Linn (Family: Moraceae) commonly known as mulberry" leaves extract against hazardous effects of gamma rays in male rats. MATERIALS AND METHODS: Thirty six male albino rats were divided into six groups (six rats/group); (1) control group received 1 ml distilled water, (2) low dose of extract (100 mg/kg) group treated daily with low oral dose of ethanolic extract of mulberry leaves (100 mg/kg body weight (b.wt.)) for 21 consecutive days, (3) high dose of extract (200 mg/kg) group treated daily with high oral dose of ethanolic extract of mulberry leaves (200 mg/kg b.wt.) for the same period, (4) irradiated group rats were subjected to whole body gamma irradiation at a shot dose of 7 Gy, (5) low dose of extract + irradiated group treated daily with low oral dose of ethanolic extract of mulberry leaves (100 mg/kg b.wt.) for 21 consecutive days then rats were exposed to gamma irradiation at a single dose of 7 Gy, (6) high dose of extract + irradiation group treated daily with high oral dose of ethanolic extract of mulberry leaves (200 mg/kg b.wt.) for 21 consecutive days then rats were exposed to gamma irradiation at a single dose of 7 Gy. Rats were sacrificed 1, 7, 15 days post gamma irradiation in all groups. Blood samples were taken at three intervals time in the six groups. RESULTS: The results showed that whole body irradiation of rats induced significant decrease (p < 0.05) in red blood cells (RBCs), hemoglobin (Hb), hematocrit percentage (HCT%), platelet, white blood cells (WBCs), lymphocytes, neutrophils, serum glucose-6-phosphate dehydrogenase (G-6 PD) and insulin. The data also showed significant increase (p < 0.05) in serum total lipids, phospholipids, cholesterol, triglycerides, lactate dehydrogenase (LDH), creatine kinase (CK), and plasma glucose. Administration of mulberry leaves extract, either low or high concentrations to rats prior to irradiation caused significant improvement in the studied parameters. CONCLUSIONS: Mulberry leaves extract prior to exposure to gamma irradiation has radio protector against hazardous effect of irradiation in male rats. PMID- 29393712 TI - Role of a Standardized Prism Under Cover Test in the Assessment of Dissociated Vertical Deviation. AB - BACKGROUND: Dissociated vertical deviation (DVD) is commonly measured using a prism and alternate cover test (PACT), but some providers use a prism under cover test (PUCT). The aim of this study was to compare a standardized PUCT measurement with a PACT measurement, for assessing the magnitude of DVD. METHODS: Thirty-six patients with a clinical diagnosis of DVD underwent measurement of the angle of deviation with the PACT, fixing with the habitually fixing eye, and with PUCT, fixing both right and left eyes. The PUCT was standardized, using a 10-second cover for each prism magnitude, until the deviation was neutralized. The magnitude of hyperdeviation by PACT and PUCT was compared for the non-fixing eye, using paired non-parametric tests. The frequency of discrepancies more than 4 prism diopters (PD) between PACT and PUCT was calculated. RESULTS: The magnitude of hyperdeviation was greater when measured with PUCT (range 8PD hypodeviation to 20PD hyperdeviation) vs. PACT (18PD hypodeviation to 25PD hyperdeviation) with a median difference of 4.5PD (range -5PD to 21PD); P < 0.0001. Eighteen (50%) of 36 measurements elicited >4PD hyperdeviation (or >4PD less hypodeviation) by PUCT than by PACT. CONCLUSIONS: A standardized 10-second PUCT yields greater values than a prism and alternate cover test in the majority of patients with DVD, providing better quantification of the severity of DVD, which may be important for management decisions. PMID- 29393713 TI - Modeling excess zeroes in an integrated analysis of vaccine safety. AB - In prophylactic vaccine studies in healthy populations, many subjects do not experience a single adverse event (AE). Thus, the number of AEs observed in such clinical trials may be difficult to model because of an excess of zeroes relative to the parametric distributions assumed. To determine which type of modeling provides a better fit for observed AE data, a variety of models were applied to data from an integrated safety database from clinical trials of the meningococcal vaccine MenB-FHbp (Trumenba(r), bivalent rLP2086; Pfizer Inc, Philadelphia, PA). MenB-FHbp was the first vaccine approved in the United States to prevent meningococcal serogroup B disease in individuals aged 10 to 25 years. Specifically, this report presents an integrated analysis of AEs from 8 randomized controlled trials that compared MenB-FHbp to placebo or active controls. The number of AEs occurring from dose one to 30 days after the last dose was analyzed. Six models were compared: standard Poisson and negative binomial models and their corresponding zero-inflation and hurdle models. Models were evaluated for their ability to predict the number of AEs and by goodness-of fit statistics. Models based on the Poisson distribution were a poor fit. The zero-inflated negative binomial model and negative binomial hurdle model provided the closest fit. These results suggest that zero-inflated or hurdle models may provide a better fit to AE data from healthy populations compared with conventional parametric models. PMID- 29393714 TI - Learning and knowing bodies: Norwegian psychomotor physiotherapists' reflections on embodied knowledge. AB - BACKGROUND: The lived experience is irreducible, and can give access to pre reflective and implicit, embodied knowledge. There is a lack of research concerning how specialists in Norwegian Psychomotor physiotherapy (NPMP) utilize their patients' embodied knowledge. AIM: The aim of this study was to explore if the NPMP therapists experience the phenomenon "listening to the body" as a useful source of personal knowledge and motivation in the patient's process of' recovery, and if there could be too much "listening to the body"? DESIGN AND METHODS: A qualitative study based on empirical data from the interviews with 12 specialists in NPMP. The research data were analyzed using systematic text condensation as analyzing method. RESULTS: Four themes emerged: (1) "The negative imperative of the body"; (2) "The embodied traumatic experiences"; (3) "The process of creating meaning"; and (4) "The embodied person emerges-who am I and what choice do I have?" The results revealed the importance of becoming aware of embodied experiences, which might represent different aspects of the patients' lives. CONCLUSION: Embodied knowledge can support the physiotherapists in their clinical practice. The learning and knowing body represents resources of empowerment for the patients. PMID- 29393715 TI - Inter-rater and intra-rater reliability of a clinical protocol for measuring turnout in collegiate dancers. AB - Reliable methods of measuring turnout in dancers and comparing active turnout (used in class) with functional (uncompensated) turnout are needed. Authors have suggested measurement techniques but there is no clinically useful, easily reproducible technique with established inter-rater and intra-rater reliability. We adapted a technique based on previous research, which is easily reproducible. We hypothesized excellent inter-rater and intra-rater reliability between experienced physical therapists (PTs) and a briefly trained faculty member from a university's department of dance. Thirty-two participants were recruited from the same dance department. Dancers' active and functional turnout was measured by each rater. We found that our technique for measuring active and functional turnout has excellent inter-rater and intra-rater reliability when performed by two experienced PTs and by one briefly trained university-level dance faculty member. For active turnout, inter-rater reliability was 0.78 among all raters and 0.82 among only the PT raters; intra-rater reliability was 0.82 among all raters and 0.85 among only the PT raters. For functional turnout, inter-rater reliability was 0.86 among all raters and 0.88 among only the PT raters; intra rater reliability was 0.87 among all raters and 0.88 among only the PT raters. The measurement technique described provides a standardized protocol with excellent inter-rater and intra-rater reliability when performed by experienced PTs or by a briefly trained university-level dance faculty member. PMID- 29393716 TI - Theta-band Oscillations in the Middle Temporal Gyrus Reflect Novel Word Consolidation. AB - Like many other types of memory formation, novel word learning benefits from an offline consolidation period after the initial encoding phase. A previous EEG study has shown that retrieval of novel words elicited more word-like-induced electrophysiological brain activity in the theta band after consolidation [Bakker, I., Takashima, A., van Hell, J. G., Janzen, G., & McQueen, J. M. Changes in theta and beta oscillations as signatures of novel word consolidation. Journal of Cognitive Neuroscience, 27, 1286-1297, 2015]. This suggests that theta-band oscillations play a role in lexicalization, but it has not been demonstrated that this effect is directly caused by the formation of lexical representations. This study used magnetoencephalography to localize the theta consolidation effect to the left posterior middle temporal gyrus (pMTG), a region known to be involved in lexical storage. Both untrained novel words and words learned immediately before test elicited lower theta power during retrieval than existing words in this region. After a 24-hr consolidation period, the difference between novel and existing words decreased significantly, most strongly in the left pMTG. The magnitude of the decrease after consolidation correlated with an increase in behavioral competition effects between novel words and existing words with similar spelling, reflecting functional integration into the mental lexicon. These results thus provide new evidence that consolidation aids the development of lexical representations mediated by the left pMTG. Theta synchronization may enable lexical access by facilitating the simultaneous activation of distributed semantic, phonological, and orthographic representations that are bound together in the pMTG. PMID- 29393717 TI - Stress Elevates Frontal Midline Theta in Feedback-based Category Learning of Exceptions. AB - Adapting behavior based on category knowledge is a fundamental cognitive function, which can be achieved via different learning strategies relying on different systems in the brain. Whereas the learning of typical category members has been linked to implicit, prototype abstraction learning, which relies predominantly on prefrontal areas, the learning of exceptions is associated with explicit, exemplar-based learning, which has been linked to the hippocampus. Stress is known to foster implicit learning strategies at the expense of explicit learning. Procedural, prefrontal learning and cognitive control processes are reflected in frontal midline theta (4-8 Hz) oscillations during feedback processing. In the current study, we examined the effect of acute stress on feedback-based category learning of typical category members and exceptions and the oscillatory correlates of feedback processing in the EEG. A computational modeling procedure was applied to estimate the use of abstraction and exemplar strategies during category learning. We tested healthy, male participants who underwent either the socially evaluated cold pressor test or a nonstressful control procedure before they learned to categorize typical members and exceptions based on feedback. The groups did not differ significantly in their categorization accuracy or use of categorization strategies. In the EEG, however, stressed participants revealed elevated theta power specifically during the learning of exceptions, whereas the theta power during the learning of typical members did not differ between the groups. Elevated frontal theta power may reflect an increased involvement of medial prefrontal areas in the learning of exceptions under stress. PMID- 29393718 TI - Polarity-dependent Effects of Biparietal Transcranial Direct Current Stimulation on the Interplay between Target Location and Distractor Saliency in Visual Attention. AB - Visual attention allows the allocation of limited neural processing resources to stimuli based on their behavioral priorities. The selection of task-relevant visual targets entails the processing of multiple competing stimuli and the suppression of distractors that may be either perceptually salient or perceptually similar to targets. The posterior parietal cortex controls the interaction between top-down (task-driven) and bottom-up (stimulus-driven) processes competing for attentional selection, as well as spatial distribution of attention. Here, we examined whether biparietal transcranial direct current stimulation (tDCS) would modulate the interaction between top-down and bottom-up processes in visual attention. Visual attention function was assessed with a visual discrimination task, in which a lateralized target was presented alone or together with a contralateral, similar or salient, distractor. The accuracy and RTs were measured before and during three stimulation sessions (sham, right anodal/left cathodal, left anodal/right cathodal). The analyses demonstrated (i) polarity-dependent effects of tDCS on the accuracy of target discrimination, but only when the target was presented with a similar distractor; (ii) the tDCS triggered effects on the accuracy of discriminating targets, accompanied by a similar distractor, varied according to the target location; and (iii) overall detrimental effects of tDCS on RTs were observed, regardless of target location, distractor type, and polarity of the stimulation. We conclude that the observed polarity, distractor type, and target location-dependent effects of biparietal tDCS on the accuracy of target detection resulted from both a modulation of the interaction between top-down and bottom-up attentional processes and the interhemispheric competition mechanisms guiding attentional selection and spatial deployment of attention. PMID- 29393719 TI - Behavioral and Neural Adaptation in Approach Behavior. AB - People often make approachability decisions based on perceived facial trustworthiness. However, it remains unclear how people learn trustworthiness from a population of faces and whether this learning influences their approachability decisions. Here we investigated the neural underpinning of approach behavior and tested two important hypotheses: whether the amygdala adapts to different trustworthiness ranges and whether the amygdala is modulated by task instructions and evaluative goals. We showed that participants adapted to the stimulus range of perceived trustworthiness when making approach decisions and that these decisions were further modulated by the social context. The right amygdala showed both linear response and quadratic response to trustworthiness level, as observed in prior studies. Notably, the amygdala's response to trustworthiness was not modulated by stimulus range or social context, a possible neural dynamic adaptation. Together, our data have revealed a robust behavioral adaptation to different trustworthiness ranges as well as a neural substrate underlying approach behavior based on perceived facial trustworthiness. PMID- 29393720 TI - Evaluation of clinically and physiologically atypical asthma: If it doesn't wheeze it may still be asthma. AB - OBJECTIVE: Children with asthma-like symptoms may not clinically wheeze. The objectives of this study were to evaluate if children, without physician documented wheeze, wheeze during bronchial-challenge-testing (BCT), and if measurements of O2Sat and respiratory rate during BCT improve the BCT sensitivity? METHODS: Seven hundred and twenty-four children, who were referred for suspicion of asthma, performed a BCT. Positive BCT was determined by the provocation concentration (PC) which resulted in a 20% decrease in FEV1 (PC20), (in those who were able to perform spirometry, group B), or (in those unable to perform spirometry, group A) a 50% increase in respiratory rate (PCRR), or a 5% decrease in oxygen-saturation (PCO2-Sat) or appearance of wheezing (PCwheeze). RESULTS: Five hundred and seven BCTs were positive: group A n = 89 age, median (IQR), 3 (2.5-3.7) years (17.6%), were unable to perform spirometry, and group B n = 418 age 10.7 (6.8-15.6) years (82.4%), were able to perform spirometry. Children, without physician-documented wheeze in the total population (groups A plus B), were more likely (65.5%) to have a positive BCT without wheeze compared with those with physician-documented wheeze (41.0%, P < 0.001). In group A, adding PCRR and PCO2-Sat increased BCT sensitivity by 23.6%. CONCLUSIONS: Many children in both groups did not wheeze despite reaching BCT endpoints. Children without physician-documented wheeze tended not to wheeze at BCT. This may result in clinical under-diagnosis of asthma if depending on the presence of wheeze. In young children, adding PCRR and PCO2-Sat substantially increases BCT sensitivity and may improve asthma diagnosis. PMID- 29393721 TI - Rockwood Type III Acromioclavicular Joint Dislocation; Are We Still Fighting? PMID- 29393722 TI - Neurotic Personality Traits and Risk for Adverse Alcohol Outcomes: Chained Mediation through Emotional Disorder Symptoms and Drinking to Cope. AB - BACKGROUND: Rates of alcohol abuse are high on Canadian postsecondary campuses. Individual trait differences have been linked to indices of alcohol use/misuse, including neurotic traits like anxiety sensitivity (AS) and hopelessness (HOP). We know little, though, about how these traits confer vulnerability. AS and HOP are related to anxiety and depression, respectively, and to drinking to cope with symptoms of those disorders. Neurotic personality may therefore increase risk of alcohol use/abuse via (1) emotional disorder symptoms and/or (2) coping drinking motives. OBJECTIVES: Allan and colleagues (2014) found chained mediation through AS-generalized anxiety-coping motives-alcohol problems and AS-depression-coping motives-alcohol problems. We sought to expand their research by investigating how emotional disorder symptoms (anxiety, depression) and specific coping motives (drinking to cope with anxiety, depression) may sequentially mediate the AS/HOP to-hazardous alcohol use/drinking harms relationships among university students. METHODS: This study used cross-sectional data collected in Fall 2014 as part of the Movember-funded Caring Campus Project (N = 1,883). The survey included the SURPS, adapted DMQ-R SF, and AUDIT-3. RESULTS: AS and HOP were both related to hazardous alcohol and drinking harms via emotional disorder symptoms and, in turn, coping drinking motives. All indirect pathways incorporating both mediators were statistically significant, and additional evidence of partial specificity was found. Conclusions/Importance: The study's results have important implications for personality-matched interventions for addictive disorders. PMID- 29393723 TI - Strong associations of nine-point body condition scoring with survival and lifespan in cats. AB - OBJECTIVES: The objective of the study was to investigate the associations of a nine-point body condition score (BCS) with survival time and lifespan in cats. METHODS: Electronic patient records from a cat-dominant primary practice in metropolitan Sydney, Australia, where the body condition of cats was regularly recorded using a nine-point BCS scale were obtained. The maximum BCS of each cat during the visits was used as the primary exposure variable. Two survival analyses were conducted to evaluate the associations of BCS with cats' survival and lifespan. RESULTS: In total, 2609 cats met the selection criteria from 4020 cats screened. The median of the maximum BCS was 6 (interquartile range [IQR] 5 7). Compared with cats with a maximum BCS of 6, increased hazards of death were observed in cats with a maximum BCS of 3 (hazard ratio [HR] 4.67, 95% confidence interval [CI] 3.00-7.27), 4 (HR 2.61, 95% CI 1.95-3.49), 5 (HR 1.43, 95% CI 11.5 1.76) and 9 (HR 1.80, 95% CI 1.11-2.93). Median lifespan was 15.8 (IQR 13.5-17.6) years. Compared with cats reaching a maximum BCS of 6 in the same age group, cats reaching a maximum BCS of 4 (HR 4.15, 95% CI 1.26-13.67) or 5 (HR 1.75, 95% CI 1.07-2.85) between age 1 and 3 years, and a maximum BCS of 3 (HR 6.09, 95% CI 1.47-25.25) and 9 (HR 2.27, 95% CI 1.27-4.04) between the age of 3 and 11 years had shorter lifespans. CONCLUSIONS AND RELEVANCE: There are significant associations of nine-point body condition scoring with survival and lifespan, and BCSs <5 and of 9 were found to be negatively associated with both. The study yielded information regarding a desirable BCS for cat longevity that veterinarians could consult with. PMID- 29393724 TI - A Historical Report on Preparing Sustained Release Dosage Forms for Addicts in Medieval Persia, 16th Century AD. AB - For several centuries, opium addiction has been a social problem all over the world. It has been prevalent in Iran from the Safavid era (1501-1736 A.D). During this period, Hakim Imad al-Din Mahmud ibn-Mas'ud Shirazi (1515-1592 A.D), also known as Imad was one of the Persian physicians who wrote one of the earliest books in the field of opium and addiction (called Afiounieh) in history. In this book, he introduced two sustained release rectal (suppository) and oral (pill) dosage forms for Muslim addicts who fast in the month of Ramadan. He aimed to formulate them for these people so that they could keep fasting by using the slow release drugs. In these formulations, his innovation has important impacts in the history of both addiction and pharmaceutical sciences. PMID- 29393725 TI - Effects of Laparascopic Hernia Repair by PIRS (Percutan Internal Ring Suturing) Technique on Testicular Artery Blood Supply. AB - PURPOSE: Percutaneous internal ring suturing technique (PIRS) is a minimally invasive technique in pediatric inguinal hernia repair. In the present study, a negative effect on testicular blood flow using PIRS technique has been investigated. METHODS: Forty male patients were included in the study prospectively. Two groups were formed as conventional open surgery (Group I) and PIRS technique (Group II). The resistive index (RI) value of the testicular artery was measured prospectively by using SMI (superb micro-vascular imaging) software with the color doppler ultrasound technique preoperatively and postoperatively at the first month. RESULTS: Inguinal hernia was present on the left in 35% (n = 14) of the patients and on the right in 65% (n = 26) of the patients. There was no statistically significant difference (p = 0.727) between Group I and II with regard to preoperative RI value (0.66 +/- 0.07 vs. 0.66 +/- 0.45, respectively). Similarly, there was no statistically significant difference (p = 0.220) between Group I and II with regard to the RI values measured at the postoperative first month (0.58 +/- 0.04 vs. 0.60 +/- 0.04, respectively). Although the postoperative RI values decreased compared to the preoperative values in both groups, this difference was not statistically significant. (p = 0.447 in Group I, and p = 0.175 in Group II for intragroup comparison). CONCLUSIONS: Besides PIRS technique has the advantages provided by all other laparoscopic techniques defined for inguinal hernia repair, there is no significant difference between this technique and conventional open surgery with regard to testicular blood flow. It is an innovative candidate technique instead of the open surgery method besides its additional advantages. PMID- 29393727 TI - Correction to: The Effect of Posture on Intraocular Pressure and Systemic Hemodynamic Parameters in Treated and Untreated Patients with Primary Open-Angle Glaucoma, by Katsanos, A., Dastiridou, A.I., Quaranta, L., Rulli, E., Riva, I., Dimasi, V., Tsironi, E.E., and Weinreb, R.N. J Ocul Pharmacol Ther 2017;33(8):598 603. DOI: 10.1089/jop.2017.0030. PMID- 29393726 TI - OTU5 tunes environmental responses by sustaining chromatin structure. AB - Phenotypic plasticity is dependent on the correct interpretation of environmental cues. We recently showed that the deubiquitinase OTU5 is required for orchestrating internal and external signals, tuning the morphogenesis of epidermal cells to the prevailing conditions. Homozygous otu5 mutants developed long and dense root hairs, resembling phosphate-deficient plants. The phenotype of otu5 plants was similar to that of arp6 plants, which carries a mutation that compromises the deposition of H2A.Z. Homozygous otu5 arp6 double mutants exhibited a synergistic phenotype, suggesting that the two mutations are functionally related. In a multi-omics approach comprising genome-wide DNA methylation, detection of various post-translational histone modifications as well as transcriptomic and proteomic surveys, we found that OTU5 is critical for maintaining the abundance of stimulus-responsive proteins, probably by modulating chromatin structure. It is concluded that changes in protein abundance and phenotypic readout in response to environmental signals are regulated by a complex interplay between various levels of gene expression. PMID- 29393728 TI - All Things Death and Dying: Health Professional Students Participating in the Death Cafe Model. AB - Death and dying remains a taboo topic in many social settings, and is underrepresented in health profession training. This report describes the use of the Death Cafe model as a forum for engaging students in discussion of death and dying with their peers and other health professionals. A Death Cafe is an opportunity for individuals to gather in an informal environment to exchange thoughts about issues associated with death, dying, loss, and illness. This report outlines the preparation, implementation, and evaluation of a Death Cafe event hosted at a nursing school as part of an academic health center. Twenty four participants from five disciplines participated in discussions, reported positive experiences, and desired to learn more about issues surrounding death and dying. Findings from this event suggest that this approach may be useful for institutions seeking to provide additional learning opportunities for students and/or healthcare professionals on palliative and end-of-life care in a supportive and enabling context. PMID- 29393730 TI - In this issue: Role of specific and non-specific immunity in disease. PMID- 29393729 TI - Challenges and opportunities for meningococcal vaccination in the developing world. AB - Meningococcal disease continues to be a life threatening infection with high morbidity and mortality even in appropriately treated patients. Meningococcal vaccination plays a major role in the control of the disease; however, implementing vaccination remains problematic in the developing world. The objective of this review is to identify the challenges facing the use of meningococcal vaccines in the developing world in order to discuss the opportunities and available solutions to improve immunization in these countries. Inadequate epidemiologic information necessary to implement vaccination and financial challenges predominate. Multiple measures are needed to achieve the successful implementation of meningococcal conjugate vaccination programs that protect against circulating serogroups in developing countries including enhanced surveillance systems, financial support and aid through grants, product development partnerships that are the end result of effective collaboration and communication between different interdependent stakeholders to develop affordable vaccines, and demonstration of the cost-effectiveness of new meningococcal vaccines. PMID- 29393732 TI - Outcome of limb fracture repair in rabbits: 139 cases (2007-2015). AB - OBJECTIVE To evaluate outcome of limb fracture repair in rabbits. DESIGN Retrospective case series. ANIMALS 139 client-owned rabbits with limb fractures treated between 2007 and 2015. PROCEDURES Medical records were reviewed for information on fracture location, fracture treatment, and time to fracture healing. RESULTS 25 rabbits had fractures involving the distal aspects of the limbs (ie, metacarpal or metatarsal bones, phalanges, and calcaneus or talus). Fractures were treated in 23 of these 25 rabbits (external coaptation, n = 17; external skeletal fixation, 4; and intramedullary pinning, 2) and healed in all 23, with a median healing time of 28 days (range, 20 to 45 days). One hundred ten rabbits had long bone fractures, and fractures were treated in 100 of the 110 (external skeletal fixation, n = 89; bone plating, 1; intramedullary pinning, 3; and external coaptation, 7). The percentage of fractures that healed was significantly lower for open (14/18) than for closed (26/26) tibial fractures and was significantly lower for femoral (19/26) and treated humeral (4/6) fractures than for radial (23/24) or closed tibial (26/26) fractures. Micro-CT was used to assess fracture realignment during external skeletal fixator application and to evaluate fracture healing. CONCLUSIONS AND CLINICAL RELEVANCE The prognosis for rabbits with limb fractures was good, with fractures healing in most rabbits following fracture repair (109/123). Micro-CT was useful in assessing fracture realignment and evaluating fracture healing. PMID- 29393731 TI - Double duty: ZMYND8 in the DNA damage response and cancer. AB - Our genetic information is organized into chromatin, which consists of histones and proteins involved in regulating DNA compaction, accessibility and function. Chromatin is decorated by histone modifications, which provide signals that coordinate DNA-based processes including transcription and DNA damage response (DDR) pathways. A major signal involved in these processes is acetylation, which when attached to lysines within proteins, including histones, can be recognized and read by bromodomain-containing proteins. We recently identified the bromodomain protein ZMYND8 (also known as RACK7 and PRKCBP1) as a critical DNA damage response factor involved in regulating transcriptional responses and DNA repair activities at DNA double-strand breaks. Other studies have further defined the molecular details for how ZMYND8 interacts with chromatin and other chromatin modifying proteins to exert its DNA damage response functions. ZMYND8 also plays essential roles in regulating transcription during normal cellular growth, perturbation of which promotes cellular processes involved in cancer initiation and progression. In addition to acetylation, histone methylation and demethylase enzymes have emerged as important regulators of ZMYND8. Here we discuss our current understanding of the molecular mechanisms that govern ZMYND8 function within chromatin, highlighting the importance of this protein for genome maintenance both during the DDR and in cancer. PMID- 29393733 TI - Pathology in Practice. PMID- 29393734 TI - Retrospective analysis of necropsy reports suggestive of abuse in dogs and cats. AB - OBJECTIVE To identify historical and necropsy findings suggestive of neglect or abuse of dogs and cats by retrospective analysis of necropsy reports from a veterinary diagnostic laboratory. DESIGN Retrospective cohort study. SAMPLE 119 necropsy reports of dogs and cats. PROCEDURES Necropsy reports from February 2001 to May 2012 were electronically searched to identify potential animal abuse or neglect cases. Cases were selected and categorized according to a previously proposed method for classification of animal abuse. Inclusion criteria included signs of neglect, nonaccidental injury (NAI; blunt-force or sharp-force trauma, gunshot, burns, drowning, asphyxiation, and suspicious intoxications), and sexual abuse. Poor preservation of cadavers, age < 6 weeks, and signs of chronic illness (eg, cachexia) or injuries consistent with history indicating natural or accidental causes resulted in exclusion. Variables of interest were compared between identified cases and a reference population. RESULTS Prevalence of potential abuse cases, determined on the basis of all necropsies performed in the study period, was 73 of 8,417 (0.87%) in dogs and 46 of 4,905 (0.94%) in cats. Neglect and NAI were commonly identified in cats; NAI was most commonly found in dogs. Gunshot and blunt-force trauma were the most common NAIs in dogs and cats, respectively. Pit bull-type dogs (29/73 [40%]) were overrepresented in several abuse categories. Most cats (29/46 [63%]) were domestic shorthair, but no breed association was found. Most (41/71 [58%]) affected animals with age data available were <= 2 years old. CONCLUSIONS AND CLINICAL RELEVANCE Approximately 1% of dogs and cats necropsied in the study period had signs suggestive of abuse. Medical findings alone are not necessarily indicative of abuse, but some findings can increase the index of suspicion. PMID- 29393735 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 29393736 TI - What Is Your Diagnosis? PMID- 29393739 TI - Letters to the Editor. PMID- 29393738 TI - Lumbar hemilaminectomy for treatment of diskospondylitis in an aardvark (Orycteropus afer). AB - CASE DESCRIPTION A 17-year-old sexually intact male aardvark (Orycteropus afer) was evaluated because of hind limb proprioception deficits and ataxia. CLINICAL FINDINGS Results of examination and CT suggested a diagnosis of intervertebral disk disease and diskospondylitis at the L2-3 intervertebral space. Magnetic resonance imaging of the vertebral column also indicated intervertebral disk rupture with spinal cord compression and inflammation of the adjacent epaxial musculature TREATMENT AND OUTCOME Hemilaminectomy was performed according to the technique described for dogs. Anatomic variations encountered intraoperatively limited the ability to completely remove the affected disk material; however, adequate decompression of the spinal cord was achieved. Microbial culture and susceptibility testing of surgical biopsy specimens yielded a multidrug-resistant Enterococcus faecalis that was treated with a 10-week course of linezolid. Intensive postoperative care required constant rate infusions for adequate sedation, analgesia, and antimicrobial treatment. Dehiscence of the surgical site occurred 3 weeks after surgery and was treated with negative pressure wound therapy. Physical rehabilitation initiated 5 days after surgery progressed from passive range of motion to the use of an underwater treadmill. Despite initial improvement, acute deterioration occurred 5.5 months after surgery. Repeated CT revealed progression of diskospondylitis, which prompted euthanasia. CLINICAL RELEVANCE Postoperative hind limb paresis and paralysis in this species presented considerable challenges for care and rehabilitation. Patient demeanor, size, and anatomy required development of custom mechanical devices. Despite the inability to eliminate the multidrug-resistant bacterial osteomyelitis that resulted in the death of this aardvark, information gained may benefit treatment of subsequent patients. PMID- 29393740 TI - In This Issue * February 15, 2018. PMID- 29393741 TI - Intestinal lymphoma in dogs: 84 cases (1997-2012). AB - OBJECTIVE To describe signalment, clinicopathologic features, and outcomes of dogs with confirmed primary intestinal lymphoma and assess factors associated with survival times in these patients. DESIGN Retrospective case series. ANIMALS 84 client-owned dogs. PROCEDURES Medical records from 7 veterinary institutions were retrospectively reviewed to identify dogs with primary intestinal lymphoma. Data collected included signalment, clinical signs, anatomic location of tumors, diagnostic procedures, treatment, outcome, and dates of diagnosis and death. RESULTS Overall median survival time (MST) was 62 days (range, 1 to 537 days). Factors associated with shorter survival time on univariate analysis included anorexia or septic peritonitis at the time of diagnosis and tumor location (intestinal tract only, intestinal tract and abdominal lymph nodes, or intestinal tract and extraintestinal organs). The most commonly noted changes in the intestinal tract were altered wall thickening with loss of layering (41 dogs) and presence of >= 1 discrete mass (24 dogs). Protocols based on cyclophosphamide, doxorubicin, vincristine, and prednisone with or without l-asparaginase (48 dogs) or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (14 dogs) were most commonly used as first-line treatment; the MSTs of dogs receiving these treatments (60 and 144 days, respectively) did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE The MST of dogs with primary intestinal lymphoma was poor, regardless of first-line treatment used. Anorexia and septic peritonitis were associated with poor prognosis. PMID- 29393742 TI - Pathology in Practice. PMID- 29393743 TI - What Is Your Neurologic Diagnosis? PMID- 29393744 TI - Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. AB - OBJECTIVE To investigate the effectiveness of tramadol for treatment of osteoarthritis in dogs. DESIGN Randomized, blinded, placebo-controlled crossover study. ANIMALS 40 dogs with clinical osteoarthritis of the elbow or stifle joint. PROCEDURES Dogs orally received 3 times/d (morning, midday, and night) for a 10 day period each of 3 identically appearing treatments (placebo; carprofen at 2.2 mg/kg [1 mg/lb], q 12 h [morning and night], with placebo at midday; or tramadol hydrochloride at 5 mg/kg [2.3 mg/lb], q 8 h) in random order, with treatment sessions separated by a minimum 7-day washout period. Vertical ground reaction forces (vertical impulse [VI] and peak vertical force [PVF]) were measured and Canine Brief Pain Inventory (CBPI) scores assigned prior to (baseline) and at the end of each treatment period. Repeated-measures ANOVA was performed to compare VI and PVF data among and within treatments, and the chi2 test was used to compare proportions of dogs with a CBPI-defined positive response to treatment. RESULTS 35 dogs completed the study. No significant changes from baseline in VI and PVF were identified for placebo and tramadol treatments; however, these values increased significantly with carprofen treatment. Changes from baseline in VI and PVF values were significantly greater with carprofen versus placebo or tramadol treatment. A significant improvement from baseline in CBPI scores was identified with carprofen treatment but not placebo or tramadol treatment. CONCLUSIONS AND CLINICAL RELEVANCE 10 days of treatment with tramadol as administered (5 mg/kg, PO, q 8 h) provided no clinical benefit for dogs with osteoarthritis of the elbow or stifle joint. PMID- 29393746 TI - ECG of the Month. PMID- 29393745 TI - Analysis of platinum content in biodegradable carboplatin-impregnated beads and retrospective assessment of tolerability for intralesional use of the beads in dogs following excision of subcutaneous sarcomas: 29 cases (2011-2014). AB - OBJECTIVE To evaluate platinum content in biodegradable carboplatin-impregnated beads and retrospectively assess tolerability and outcome data for dogs treated by intralesional placement of such beads following surgical excision of subcutaneous sarcomas. DESIGN Evaluation study and retrospective case series. SAMPLE 9 carboplatin-impregnated beads and 29 client-owned dogs. PROCEDURES Platinum content in 9 carboplatin-impregnated beads from 3 lots was measured by spectrophotometry, and calculated carboplatin content was compared with the labeled content. Medical records were searched to identify dogs with subcutaneous sarcomas for which treatment included placement of carboplatin-impregnated beads between 2011 and 2014. Signalment, tumor characteristics, surgical and histologic data, adverse events, and local recurrences were recorded. Associations between variables of interest and adverse events or local disease-free interval were analyzed. RESULTS In vitro analysis identified a mean +/- SD platinum content of 5.38 +/- 0.97 mg/bead. Calculated carboplatin content (10.24 +/- 1.84 mg/bead) was significantly greater than the labeled amount (4.6 mg/bead). Bead weight and total platinum content differed significantly among lots, but platinum content per bead weight did not. Mild-to-moderate local adverse events were reported for 11 of 29 tumors; all resolved without additional surgery. No dogs had signs of systemic toxicosis. Overall local disease-free rates 1, 2, and 3 years after surgery were 70%, 70%, and 58%, respectively, as determined by Kaplan-Meier analysis. CONCLUSIONS AND CLINICAL RELEVANCE Carboplatin-impregnated beads were well tolerated; however, results of in vitro tests indicated that caution is needed because of manufacturing inconsistencies. PMID- 29393747 TI - Practical approaches for overcoming challenges in heightened characterization of antibody-drug conjugates with new methodologies and ultrahigh-resolution mass spectrometry. AB - Antibody-drug conjugation strategies are continuously evolving as researchers work to improve the safety and efficacy of the molecules. However, as a part of process and product development, confirmation of the resulting innovative structures requires new, specialized mass spectrometry (MS) approaches and methods, as compared to those already established for antibody-drug conjugates (ADCs) and the heightened characterization practices used for monoclonal antibodies (mAbs), in order to accurately elucidate the resulting conjugate forms, which can sometimes have labile chemical bonds and more extreme chemical properties like hydrophobic patches. Here, we discuss practical approaches for characterization of ADCs using new methodologies and ultrahigh-resolution MS, and provide specific examples of these approaches. Denaturing conditions of typical liquid chromatography (LC)/MS analyses impede the successful detection of intact, 4-chain ADCs generated via cysteine site-directed chemistry approaches where hinge region disulfide bonds are partially reduced. However, this class of ADCs is detected intact reliably under non-denaturing size-exclusion chromatography/MS conditions, also referred to as native MS. For ADCs with acid labile linkers such as one used for conjugation of calicheamicin, careful selection of mobile phase composition is critical to the retention of intact linker-payload during LC/MS analysis. Increasing the pH of the mobile phase prevented cleavage of a labile bond in the linker moiety, and resulted in retention of the intact linker payload. In-source fragmentation also was observed with typical electrospray ionization (ESI) source parameters during intact ADC mass analysis for a particular surface-accessible linker-payload moiety conjugated to the heavy chain C-terminal tag, LLQGA (via transglutaminase chemistry). Optimization of additional ESI source parameters such as cone voltages, gas pressures and ion transfer parameters led to minimal fragmentation and optimal sensitivity. Ultrahigh-resolution (UHR) MS, combined with reversed phase-ultrahigh performance (RP-UHP)LC and use of the FabRICATOR(r) enzyme, provides a highly resolving, antibody subunit-domain mapping method that allows rapid confirmation of integrity and the extent of conjugation. For some ADCs, the hydrophobic nature of the linker-payload hinders chromatographic separation of the modified subunit/domains or causes very late elution/poor recovery. As an alternative to the traditionally used C4 UHPLC column chemistry, a diphenyl column resulted in the complete recovery of modified subunit/domains. For ADCs based on maleimide chemistry, control of pH during proteolytic digestion is critical to minimize ring-opening. The optimum pH to balance digestion efficiency and one that does not cause ring opening needed to be established for successful peptide mapping. PMID- 29393748 TI - Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5 years old in Spain. AB - INTRODUCTION: Up to date the impact of rotavirus (RV) vaccines on seizures has been poorly evaluated, with some studies but not all, showing different degrees of protection. OBJECTIVES: To assess the impact of RV vaccines on convulsions related hospitalizations among children under 5 years of age residing in the Region of Valencia, Spain. METHODS: A population-based, ecological study using the hospital discharge record (MBDS), the population-based administrative database (SIP) and the vaccine register (SIV), among Valencia Region's children <5 years old, during 2003 - 2015. Impact of vaccination on seizures-related hospitalization rates (780.3* ICD-9-MC code) was estimated by a multivariate Bayesian mixed Poisson regression model. RESULTS: Since RV vaccines licensure in 2007, its coverage rate increased up to around 42%. When the impact of vaccination against seizures was controlled for potential confounders in the multivariate analysis, there was a non-statistically significant protective effect. CONCLUSIONS: We could not find any impact of RV vaccine coverage on seizure-related hospitalizations in children <5 years. PMID- 29393749 TI - Increase in callosal angle and decrease in ventricular volume after shunt surgery in patients with idiopathic normal pressure hydrocephalus. AB - OBJECTIVE Postoperative decrease in ventricle size is usually not detectable either by visual assessment or by measuring the Evans index in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of the present study was to investigate whether the angle between the lateral ventricles (the callosal angle [CA]) increases and ventricular volume decreases after shunt surgery in patients with iNPH. METHODS Magnetic resonance imaging of the brain was performed before and 3 months after shunt surgery in 18 patients with iNPH. The CA and Evans index were measured on T1-weighted 3D MR images, and ventricular volume contralateral to the shunt valve was measured with quantitative MRI. RESULTS The CA was larger postoperatively (mean 78 degrees , 95% CI 69 degrees -87 degrees ) than preoperatively (mean 67 degrees , 95% CI 60 degrees -73 degrees ; p < 0.001). The volume of the lateral ventricle contralateral to the shunt valve decreased from 73 ml (95% CI 66-80 ml) preoperatively to 63 ml (95% CI 54-72 ml) postoperatively (p < 0.001). The Evans index was 0.365 (95% CI 0.35-0.38) preoperatively and 0.358 (95% CI 0.34-0.38) postoperatively (p < 0.05). Postoperative change of CA showed a negative correlation with change of ventricular volume (r = -0.76, p < 0.01). CONCLUSIONS In this sample of patients with iNPH, the CA increased and ventricular volume decreased after shunt surgery. The relative difference was most pronounced for the CA, indicating that this accessible, noninvasive radiological marker should be evaluated further as an indirect method to determine shunt function in patients with iNPH. PMID- 29393750 TI - Desmopressin administration and rebleeding in subarachnoid hemorrhage: analysis of an observational prospective database. AB - OBJECTIVE Rebleeding remains a frequent and catastrophic event leading to poor outcome after subarachnoid hemorrhage (SAH). Reduced platelet function after the initial bleed is associated with higher risk of early rebleeding. Desmopressin (DDAVP) is a well-known hemostatic agent, and recent guidelines already suggest its use in individuals exposed to antiplatelet drugs. The authors hypothesized that DDAVP administration in patients with SAH at admission would be associated with lower risks of rebleeding. METHODS The authors performed an observational cohort study of patients enrolled in the Columbia University SAH Outcome Project between August 1996 and July 2015. The authors compared the rate of rebleeding between patients who were and those who were not treated with DDAVP. After adjustment for known predictors, logistic regression was used to measure the association between treatment with DDAVP and risks of rebleeding. RESULTS Among 1639 patients with SAH, 12% were treated with DDAVP. The main indication for treatment was suspected exposure to an antiplatelet agent. The overall incidence of rebleeding was 9% (1% among patients treated with DDAVP compared with 8% among those not treated). After adjustment for antiplatelet use and known predictors, treatment with DDAVP was associated with a 45% reduction in the risks of rebleeding (adjusted OR 0.55, 95% CI 0.27-0.97). DDAVP was associated with a higher incidence of hyponatremia but not with thrombotic events or delayed cerebral ischemia. CONCLUSIONS Treatment with DDAVP was associated with a lower risk of rebleeding among patients with SAH. These findings support further study of DDAVP as first-line therapy for medical hemostasis in patients with SAH. PMID- 29393751 TI - Endoscopic anterior transmaxillary "transalisphenoid" approach to Meckel's cave and the middle cranial fossa: an anatomical study and clinical application. AB - OBJECTIVE Multiple approaches have been designed to reach the medial middle fossa (for lesions in Meckel's cave, in particular), but an anterior approach through the greater wing of the sphenoid (transalisphenoid) has not been explored. In this study, the authors sought to assess the feasibility of and define the anatomical landmarks for an endoscopic anterior transmaxillary transalisphenoid (EATT) approach to Meckel's cave and the middle cranial fossa. METHODS Endoscopic dissection was performed on 5 cadaver heads injected intravascularly with colored silicone bilaterally to develop the approach and define surgical landmarks. The authors then used this approach in 2 patients with tumors that involved Meckel's cave and provide their illustrative clinical case reports. RESULTS The EATT approach is divided into the following 4 stages: 1) entry into the maxillary sinus, 2) exposure of the greater wing of the sphenoid, 3) exposure of the medial middle fossa, and 4) exposure of Meckel's cave and lateral wall of the cavernous sinus. The approach provided excellent surgical access to the anterior and lateral portions of Meckel's cave and offered the possibility of expanding into the infratemporal fossa and lateral middle fossa and, in combination with an endonasal transpterygoid approach, accessing the anteromedial aspect of Meckel's cave. CONCLUSIONS The EATT approach to Meckel's cave and the middle cranial fossa is technically feasible and confers certain advantages in specific clinical situations. The approach might complement current surgical approaches for lesions of Meckel's cave and could be ideal for lesions that are lateral to the trigeminal ganglion in Meckel's cave or extend from the maxillary sinus, infratemporal fossa, or pterygopalatine fossa into the middle cranial fossa, Meckel's cave, and cavernous sinus, such as schwannomas, meningiomas, and sinonasal tumors and perineural spread of cutaneous malignancy. PMID- 29393752 TI - Treatment of idiopathic intracranial hypertension via stereotactic placement of biventriculoperitoneal shunts. AB - OBJECTIVE Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a complex and difficult-to-manage condition that can lead to permanent vision loss and refractory headaches if untreated. Traditional treatment options, such as unilateral ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt placement, have high complication and failure rates and often require multiple revisions. The use of bilateral proximal catheters has been hypothesized as a method to improve shunt survival. The use of stereotactic technology has improved the accuracy of catheter placement and may improve treatment of IIH, with fewer complications and greater shunt patency time. METHODS The authors performed a retrospective chart review for all patients with IIH who underwent stereotactic placement of biventriculoperitoneal (BVP) shunt catheters from 2008 to 2016 at their institution. Bilateral proximal catheters were Y-connected to a Strata valve with a single distal catheter. We evaluated clinical, surgical, and ophthalmological variables and outcomes. RESULTS Most patients in this series of 34 patients (mean age 34.4 +/- 8.2 years, mean body mass index 38.7 +/- 8.3 kg/m2; 91.2% were women) undergoing 41 shunt procedures presented with headache (94.1%) and visual deficits (85.3%). The mean opening pressure was 39.6 +/- 9.0 cm H2O. In addition, 50.0% had undergone previous unilateral shunt placement, and 20.6% had undergone prior optic nerve sheath fenestration. After BVP shunt placement, there were no cases of proximal catheter obstruction and only a single case of valve obstruction at 41.9 months, with a mean follow-up of 24.8 +/- 20.0 months. Most patients showed improvement in their headache (82.4%), subjective vision (70.6%), and papilledema (61.5% preoperatively vs 20.0% postoperatively, p = 0.02) at follow-up. Additional primary complications included 4 patients with migration of their distal catheters out of the peritoneum (twice in 1 patient), and an infection of the distal catheter after catheter dislodgment. The proximal obstructive shunt complication rate in this series (2.9%) was lower than that with LP (53.5%) or unilateral VP (37.8%) shunts seen in the literature. CONCLUSIONS This small series suggests that stereotactic placement of BVP shunt catheters appears to improve shunt survival rates and presenting symptoms in patients with IIH. Compared with unilateral VP or LP shunts, the use of BVP shunts may be a more effective and more functionally sustained method for the treatment of IIH. PMID- 29393753 TI - Bedside optical coherence tomography for Terson's syndrome screening in acute subarachnoid hemorrhage: a pilot study. AB - OBJECTIVE Approximately 10% of patients with subarachnoid hemorrhage (SAH) become permanently, legally blind. The average cost of lifetime support and unpaid taxes for each blind person amounts to approximately $900,000. This study evaluates the feasibility and potential role of bedside optical coherence tomography (OCT) in Terson's syndrome (TS) in patients with acute SAH (aSAH) and its potential role in blindness prevention. METHODS The authors conducted an open-label pilot study, in which 31 patients with an angiographic diagnosis of aSAH were first screened for TS with dilated funduscopy and then with OCT in the acute phase and at 6-week follow-up visits. Outpatient mood assessments (Patient Health Questionnaire depression module, Hamilton Depression Scale), and quality of life general (NIH Patient-Reported Outcomes Measurement Information System) and visual scales (25 item National Eye Institute Visual Functioning Questionnaire) were measured at 1 and 6 weeks after discharge. Exclusion criteria included current or previous history of severe cataracts, severe diabetic retinopathy, severe macular degeneration, or glaucoma. RESULTS OCT identified 7 patients with TS, i.e., a 22.6% incidence in our aSAH sample: 7 in the acute phase, including a large retinal detachment that was initially missed by funduscopy and diagnosed by OCT in follow-up clinic. Dilated retinal funduscopy significantly failed to detect TS in 4 (57.1%) of these 7 cases. Intraventricular hemorrhage was significantly more common in TS cases (85.7% vs 25%). None of the participants experienced any complications from OCT examinations. Neither decreased quality of life visual scale scores nor a depressed mood correlated with objective OCT pathological findings at the 6-week follow-up after discharge. There were no significant mood differences between TS cases and controls. CONCLUSIONS OCT is the gold standard in retinal disease diagnosis. This pilot study shows that bedside OCT examination is feasible in aSAH. In this series, OCT was a safe procedure that enhanced TS detection by decreasing false-negative/inconclusive funduscopic examinations. It allows early diagnosis of macular holes and severe retinal detachments, which require acute surgical therapy to prevent legal blindness. In addition, OCT aids in ruling out potential false-positive visual deficits in individuals with a depressed mood at follow-up. PMID- 29393754 TI - Letter to the Editor. Development of periventricular lucency with low CSF pressure. PMID- 29393755 TI - Effect of treatment period on outcomes after stereotactic radiosurgery for brain arteriovenous malformations: an international multicenter study. AB - OBJECTIVE The role of and technique for stereotactic radiosurgery (SRS) in the management of arteriovenous malformations (AVMs) have evolved over the past four decades. The aim of this multicenter, retrospective cohort study was to compare the SRS outcomes of AVMs treated during different time periods. METHODS The authors selected patients with AVMs who underwent single-session SRS at 8 different centers from 1988 to 2014 with follow-up >= 6 months. The SRS eras were categorized as early (1988-2000) or modern (2001-2014). Statistical analyses were performed to compare the baseline characteristics and outcomes of the early versus modern SRS eras. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs). RESULTS The study cohort comprised 2248 patients with AVMs, including 1584 in the early and 664 in the modern SRS eras. AVMs in the early SRS era were significantly smaller (p < 0.001 for maximum diameter and volume), and they were treated with a significantly higher radiosurgical margin dose (p < 0.001). The obliteration rate was significantly higher in the early SRS era (65% vs 51%, p < 0.001), and earlier SRS treatment period was an independent predictor of obliteration in the multivariate analysis (p < 0.001). The rates of post-SRS hemorrhage and radiological, symptomatic, and permanent RICs were not significantly different between the two groups. Favorable outcome was achieved in a significantly higher proportion of patients in the early SRS era (61% vs 45%, p < 0.001), but the earlier SRS era was not statistically significant in the multivariate analysis (p = 0.470) with favorable outcome. CONCLUSIONS Despite considerable advances in SRS technology, refinement of AVM selection, and contemporary multimodality AVM treatment, the study failed to observe substantial improvements in SRS favorable outcomes or obliteration for patients with AVMs over time. Differences in baseline AVM characteristics and SRS treatment parameters may partially account for the significantly lower obliteration rates in the modern SRS era. However, improvements in patient selection and dose planning are necessary to optimize the utility of SRS in the contemporary management of AVMs. PMID- 29393756 TI - The microneurosurgical anatomy legacy of Albert L. Rhoton Jr., MD: an analysis of transition and evolution over 50 years. AB - Dr. Albert L. Rhoton Jr. was a pioneer of the study of microneurosurgical anatomy. Championing this field over the past half century, he produced more than 500 publications. In this paper, the authors review his body of work, focusing on approximately 160 original articles authored by Rhoton and his microneuroanatomy fellows. The articles are categorized chronologically into 5 stages: 1) dawn of microneurosurgical anatomy, 2) study of basic anatomy for general neurosurgery, 3) study for skull base surgery, 4) study of the internal structures of the brain by fiber dissection, and 5) surgical anatomy dealing with new advanced surgical approaches. Rhoton introduced many new research ideas and surgical techniques and approaches, along with better microsurgery instruments, through studying and teaching microsurgical anatomy, especially during the first stage. The characteristic features of each stage are explained and the transition phases of his projects are reviewed. PMID- 29393757 TI - Outcomes of chronic subdural hematoma in patients with liver cirrhosis. AB - OBJECTIVE Burr hole craniostomy is an effective and simple procedure for treating chronic subdural hematoma (CSDH). However, the surgical outcomes and recurrence of CSDH in patients with liver cirrhosis (LC) remain unknown. METHODS A nationwide population-based cohort study was retrospectively conducted using data from the Taiwan National Health Insurance Research Database. The study included 29,163 patients who underwent first-time craniostomy for CSDH removal between January 1, 2001, and December 31, 2013. In total, 1223 patients with LC and 2446 matched non-LC control patients were eligible for analysis. All-cause mortality, surgical complications, repeat craniostomy, extended craniotomy, and long-term medical costs were analyzed. RESULTS The in-hospital mortality rate (8.7% vs 3.1% for patients with LC and non-LC patients, respectively), frequency of hospital admission, length of ICU stay, number of blood transfusions, and medical expenditures of patients with LC who underwent craniostomy for CSDH were considerably higher than those of non-LC control patients. Patients with LC tended to require an extended craniotomy to remove subdural hematomas in the hospital or during long-term follow-up. The surgical outcome worsened with an increase in the severity of LC. CONCLUSIONS Even for simple procedures following minor head trauma, LC remains a serious comorbidity with a poor prognosis. PMID- 29393759 TI - Letter to the Editor. The intraoperative use of mannitol. PMID- 29393758 TI - Risk of intracranial hemorrhage after carotid artery stenting versus endarterectomy: a population-based study. AB - OBJECTIVE Intracranial hemorrhage (ICH) associated with cerebral hyperperfusion syndrome is a rare but major complication of carotid artery revascularization. The objective of this study was to compare the rate of ICH after carotid artery stenting (CAS) with that after endarterectomy (CEA). METHODS The authors performed a retrospective population-based cohort study of patients who underwent carotid artery revascularization in the province of Ontario, Canada, between 2002 and 2015. The primary outcome was the rate of ICH that occurred within 90 days after carotid artery intervention among patients who underwent CAS versus that of those who underwent CEA. The authors used inverse probability of treatment weighting and propensity scores to account for selection bias. In sensitivity analyses, patients who had postprocedure ischemic stroke were excluded, and the following subgroups were examined: patients with symptomatic and asymptomatic carotid artery stenosis, patients treated between 2010 and 2015, and patients aged >= 66 years (to account for antiplatelet and anticoagulant use). RESULTS A total of 16,688 patients underwent carotid artery revascularization (14% CAS, 86% CEA). Patients with more comorbid illnesses, symptomatic carotid artery stenosis, or cardiac disease and those who were taking antiplatelet agents or warfarin before surgery were more likely to undergo CAS. Among the overall cohort, 80 (0.48%) patients developed ICH within 90 days (0.85% after CAS, 0.42% after CEA). The 180-day mortality rate after ICH in the overall cohort was 2.7%, whereas the 180-day mortality rate among patients who suffered ICH was 42.5% (40% for CAS treated patients, 43.3% for CEA-treated patients). In the adjusted analysis, patients who underwent CAS were significantly more likely to have ICH than those who underwent CEA (adjusted OR 1.77; 95% CI 1.32-2.36; p < 0.001). These results were consistent after excluding patients who developed postprocedure ischemic stroke (adjusted OR 1.90; 95% CI 1.41-2.56) and consistent among symptomatic (adjusted OR 1.74; 95% CI 1.16-2.63) and asymptomatic (adjusted OR 1.75; 95% CI 1.16-2.63) patients with carotid artery stenosis, among patients treated between 2010 and 2015 (adjusted OR 2.21; 95% CI 1.45-3.38), and among the subgroup of patients aged >= 66 years (adjusted OR 1.53; 95% CI 1.05-2.24) after adjusting for medication use. CONCLUSIONS CAS is associated with a rare but higher risk of ICH relative to CEA. Future research is needed to devise strategies that minimize the risk of this serious complication after carotid artery revascularization. PMID- 29393760 TI - Letter to the Editor. Is it time to evaluate multiple familial cavernous malformations with ultra-high resolution flat-detector CT angiography? PMID- 29393761 TI - Distal peroneal nerve decompression after sciatic nerve injury secondary to total hip arthroplasty. AB - OBJECTIVE The sciatic nerve, particularly its peroneal division, is at risk for injury during total hip arthroplasty (THA), especially when a posterior approach is used. The majority of the morbidity results from the loss of peroneal nerve innervated muscle function. Approximately one-third of patients recover spontaneously. The objectives of this study were to report the outcomes of distal decompression of the peroneal nerve at the fibular tunnel following sciatic nerve injury secondary to THA and to attempt to identify predictors of a positive surgical outcome. METHODS A retrospective study of all patients who underwent peroneal decompression for the indication of sciatic nerve injury following THA at the Mayo Clinic or Washington University School of Medicine in St. Louis was performed. Patients with less than 6 months of postoperative follow-up were excluded. The primary outcome was dorsiflexion strength at latest follow-up. Univariate and multivariate logistic regression analyses were performed to assess the ability of the independent variables to predict a good surgical outcome. RESULTS The total included cohort consisted of 37 patients. The median preoperative dorsiflexion grade at the time of peroneal decompression was 0. Dorsiflexion at latest follow-up was Medical Research Council (MRC) >= 3 for 24 (65%) patients. Dorsiflexion recovered to MRC >= 4- for 15 (41%) patients. In multivariate logistic regression analysis, motor unit potentials in the tibialis anterior (OR 19.84, 95% CI 2.44-364.05; p = 0.004) and in the peroneus longus (OR 8.68, 95% CI 1.05-135.53; p = 0.04) on preoperative electromyography were significant predictors of a good surgical outcome. CONCLUSIONS After performing peroneal nerve decompression at the fibular tunnel, 65% of the patients in this study recovered dorsiflexion strength of MRC >= 3 at latest follow-up, potentially representing a significant improvement over the natural history. PMID- 29393762 TI - Effective Use of Nonablative Fractional Laser on Multiple Whip Scars. AB - BACKGROUND: Laser technology provides different solutions for scar treatment from the traditional ablative lasers to the more recent fractional devices. PATIENTS AND METHODS: We present the case of a young woman treated for scars induced by severe whipping since the age of 10. She received four monthly nonablative fractional 1550 nm erbium glass laser treatments. Fluence used was 20 mJ/cm2 with 1500 microthermal zones/cm2. RESULTS: Significant improvement was documented in the color and texture of the lesion at the end of treatment and at follow-up. Treatment had no major side effects and was well tolerated. CONCLUSIONS: We believe that nonablative fractional lasers, used mainly for cosmetic purposes, may be useful in managing post-traumatic scars as well. PMID- 29393763 TI - Conversation Analysis of Veterinarians' Proposals for Long-Term Dietary Change in Companion Animal Practice in Ontario, Canada. AB - Nutritional changes recommended by veterinarians to clients can have a major role in animal-patient health. Although there is literature on best practices that can inform veterinary communication training, little is known specifically about how veterinarians communicate their recommendations to clients in real-life interactions. This study used the qualitative research method of conversation analysis to investigate the form and content of veterinarian-initiated proposals for long-term dietary change in canine and feline patients to further inform veterinary communication training. We analyzed the characteristics and design of veterinarian-initiated proposals for long-term nutritional modification as well as the appointment phases during which they occurred, in a subsample of 42 videotaped segments drawn from 35 companion animal appointments in eastern Ontario, Canada. Analyses indicated that veterinarians initiated proposals at various points during the consultations rather than as a predictable part of treatment planning at the end. While some proposals were worded strongly (e.g., "She should be on..."), most proposals avoided the presumption that dietary change would inevitably occur. Such proposals described dietary items as options (e.g., "There are also special diets...") or used mitigating language (e.g., "you may want to try..."). These findings seem to reflect delicate veterinarian-client dynamics associated with dietary advice-giving in veterinary medicine that can impact adherence and limit shared decision-making. Our analyses offer guidance for communication training in veterinary education related to dietary treatment decision-making. PMID- 29393764 TI - Assessment of Depression and Health-Related Quality of Life in Veterinary Medical Students: Use of the 2-Item Primary Care Evaluation of Mental Disorders Questionnaire (PRIME-MD PHQ) and the 8-Item Short Form-8 Survey (SF-8). AB - Depression and health-related quality of life (HRQOL) are major concerns affecting veterinary students' well-being. Shorter versions of instruments to assess depression and HRQOL are timesaving and preferable. To the authors' knowledge there are no studies available that assess HRQOL in veterinary students. The objectives of this study were to screen veterinary students for depression during two semesters using a 2-item Primary Care Evaluation of Mental Disorders Procedure Health Questionnaire (PRIME-MD PHQ), and to assess HRQOL over two semesters using the Optum Short Form-8 (SF-8) Health Survey. A cohort of 273 students from two classes were invited to complete the PRIME-MD PHQ and the SF-8 survey during the fall semester of their first year, and again in the spring semester of the second year. Descriptive statistics, factor analysis, multiple regression, and logistic regression were used to perform data analysis. The proportion of students with symptoms of depression was high, ranging from 37.4% to 56.8% between the two classes. The SF-8 survey indicated a mental component summary (MCS) score of <50, indicating poor mental health for both classes, whereas the physical component summary (PCS) was >50, suggesting good physical health. Female students (p =.043) had low MCS scores compared to males. Students from both classes had lower MCS scores in spring compared to fall (p =.019). The PRIME-MD PHQ and the SF-8 were acceptable instruments for assessing depression and HRQOL in veterinary students, respectively. PMID- 29393765 TI - Implementing the Flipped Classroom in a Veterinary Pre-clinical Science Course: Student Engagement, Performance, and Satisfaction. AB - There has been a recent move toward active learning pedagogies in veterinary education, with increasing use of a blended approach that incorporates both online resources and live classroom sessions. In this study, an established veterinary pre-clinical course in introductory animal health was transitioned from a traditional didactic lecture delivery mode to a flipped classroom approach with core content delivered online. This study compared the experiences of two cohorts of students who studied the same course in the different formats in consecutive years. Online learning resources included short video segments and a variety of short problems and activities. Online materials were complemented with weekly small-group case-based learning classes facilitated by academic staff. A mixed methods evaluation strategy was applied using student grades, surveys, and focus groups to compare student academic performance, satisfaction, and engagement between the two cohorts. The flipped classroom cohort achieved significantly higher grades in the written answer section of the final examination. Student satisfaction with learning resources was also higher in this cohort. However, satisfaction with other aspects of the course was largely the same for both cohorts. This study revealed some of the challenges associated with achieving adequate student preparation for class using online resources. The outcomes of this study have implications for veterinary educators considering the design and development of new online learning resources. PMID- 29393766 TI - Recruiting Research Higher Degree Students into Veterinary Science. AB - Research at veterinary schools is usually driven by post-graduate students, yet there has been little or no study of how these students are selected. We undertook a review of the challenges faced in enlisting research higher degree (RHD) students at a long-established veterinary school, the School of Veterinary Science at the University of Queensland. Our aim was to identify the best methods of developing a strategic recruitment program that would enhance veterinary research in the school. A total of 21 academic research supervisors completed a quantitative survey assessing the associated importance placed on a variety of selection criteria and the level of potential challenges presented in recruiting suitable RHD students. Thirteen of these respondents completed a semi-structured qualitative interview to obtain further information. Respondents rated the motivation levels of potential students as the most important area of concern with regard to the assessment of student suitability, followed by their academic strength and English competency levels. The biggest challenge reported was that of obtaining sufficient funding for research projects and matching that funding to suitable students, followed by the geographical and student culture challenges of a rural campus. During the interviews, interviewees drew attention to the importance of developing a strong research culture in veterinary schools, and there was some concern centered on taking students with diverse cultural backgrounds. These constraints are discussed in light of the development of a broad-ranging strategy for developing an active and effective RHD program within veterinary schools. PMID- 29393767 TI - Examining the Validity of the North American Veterinary Licensing Examination (NAVLE) Time Constraints. AB - Individuals who want to become licensed veterinarians in North America must complete several qualifying steps including obtaining a passing score on the North American Veterinary Licensing Examination (NAVLE). Given the high-stakes nature of the NAVLE, it is essential to provide evidence supporting the validity of the reported test scores. One important way to assess validity is to evaluate the degree to which scores are impacted by the allotted testing time which, if inadequate, can hinder examinees from demonstrating their true level of proficiency. We used item response data from the November-December 2014 and April 2015 NAVLE administrations (n =5,292), to conduct timing analyses comparing performance across several examinee subgroups. Our results provide evidence that conditions were sufficient for most examinees, thereby supporting the current time limits. For the relatively few examinees who may have been impacted, results suggest the cause is not a bias with the test but rather the effect of poor pacing behavior combined with knowledge deficits. PMID- 29393768 TI - The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. AB - BACKGROUND: Pediatric acquired demyelinating syndromes (ADSs) are monophasic (mono-ADS) in 70% of cases and represent the first attack of multiple sclerosis (MS) in 30%. Secondhand tobacco smoke (SHS) exposure has been implicated as a risk factor for adult-onset MS. Little is known about whether SHS presents an additive risk beyond genetic factors and other environmental exposures associated with pediatric MS. METHODS: This study examined SHS exposure in 216 children with mono-ADS and 81 children with MS. Interactions between SHS, HLA-DRB1*15 alleles, serum 25-hydroxyvitamin D concentrations, and serological evidence of remote Epstein-Barr virus (EBV) exposure were evaluated. RESULTS: SHS exposure was more common in children with MS (37% exposed) compared to mono-ADS (29.5% exposed). Compared to mono-ADS, SHS exposure was not an independent risk factor for MS. When both SHS exposure and HLA-DRB1*15 were present, the odds for MS increased (odds ratio (OR) = 3.7; 95% confidence interval (CI): 1.17-11.9) compared to mono ADS. Interactions between SHS and vitamin D or EBV did not associate with MS. CONCLUSION: Exposure to SHS is a risk factor for central nervous system (CNS) demyelination. Results suggest that SHS exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with mono-ADS. PMID- 29393769 TI - Patterns and Correlates of Internet Use, Cell Phone Use, and Attitudes Toward Patient Portals Among a Predominantly Mexican-American Clinic Population. AB - OBJECTIVES: The purpose of this study was to describe access and health-related use of the Internet and cell phones, and attitudes toward patient portals among a predominantly Hispanic patient population residing along the U.S.-Mexico border. METHODS: A bilingual cross-sectional survey was conducted in two clinics to describe use and attitudes toward use of Web 2.0 technology for health-related activities. Univariate and multivariable analyses were conducted to identify factors associated with past Web 2.0 use and willingness to use these technologies in the future. RESULTS: Two hundred and one participants were recruited (response rate: 53.3%). Respondents had an average age of 61.5 years, were predominantly female (63.2%), Hispanic (71.6%), of low income (93.0% <$25,000), and low educational attainment (49.8% 0.05). Postoperatively, the ventricle size FOHR decreased significantly more following VPS surgery (-0.15) than following ETV/CPC (-0.02) (p < 0.001), yielding a lower postoperative FOHR in the VPS arm (0.42 vs 0.51; p = 0.01). The HC percentile was greater in the ETV/CPC cohort than in the VPS treated patients (76th vs 54th percentile; p = 0.046). A significant difference in the postoperative z-score was not observed. With both treatment modalities, a bulging fontanelle reliably normalized at last follow-up. CONCLUSIONS Clinical and radiographic parameters following successful treatment of hydrocephalus in infants differed between ETV/CPC and VPS treatment. At 6 months post-ETV/CPC, ventricle size remained unchanged, whereas VPS-treated ventricles decreased to a near-normal FOHR. The HC growth control between the procedures was similar, although the final HC percentile may be lower after VPS. The fontanelle remained a reliable indicator of success for both treatments. This study establishes expected cranial and ventricular parameters following ETV/CPC, which may be used to guide preoperative counseling and postoperative decision making. PMID- 29393810 TI - Effect of concussion history on symptom burden and recovery following pediatric sports-related concussion. AB - OBJECTIVE The aim of this study was to examine differences in symptom burden and duration until physician-documented clinical recovery among pediatric patients with sports-related concussion (SRC) with and without a history of concussion. METHODS A retrospective chart review was performed for all pediatric patients (7 19 years old) referred to the Pan Am Concussion Program in Winnipeg, Canada, with an SRC and evaluated < 30 days postinjury between September 1, 2013, and August 1, 2015. RESULTS A total of 322 patients with SRC (64.91% male, mean age 13.96 years) who were evaluated a median of 7 days (interquartile range [IQR] 5-11 days) postinjury were included. Patients without a history of concussion endorsed significantly fewer concussion symptoms at initial assessment (median 5.5 symptoms, IQR 1-10 symptoms) than those with a previous concussion (median 7 symptoms, IQR 2-13.25 symptoms; p = 0.036). The median Post-Concussion Symptom Scale scores were 9 (IQR 1-23) for patients with no concussion history and 13 (IQR 3-33) for those with a history of concussion (p = 0.032). For patients with no previous concussion, the median number of days until physician-documented clinical recovery was 23 (IQR 15-44 days) compared with 25 days (IQR 18-43 days) for those with a history of concussion (p = 0.281). There was no significant difference in the proportion of patients who experienced delayed time until physician-documented clinical recovery (> 1 month postinjury) between the groups (p = 0.584). CONCLUSIONS Although a history of concussion may be associated with increased symptom burden following pediatric SRC, there was no difference in the time until physician-documented clinical recovery. Pediatric patients with SRC who have a history of concussion should be managed on an individualized basis. Future work is needed to examine the short- and long-term effects of multiple concussions in children and adolescents. PMID- 29393812 TI - Letter to the Editor. Steroid administration in Cognard type V dural arteriovenous fistula. PMID- 29393811 TI - Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases. AB - The responsive neurostimulation (RNS) system, an adjunctive treatment for pharmacoresistant partial-onset seizures with 1 or 2 foci, has been available to patients aged 18 years or older since the device's FDA approval in 2013. Herein, the authors describe their off-label application of this technology in 2 pediatric patients and the consequent therapeutic benefit without surgical complications or treatment side effects. A 14-year-old nonambulatory, nonverbal male with severe developmental delay was considered for RNS therapy for medically and surgically refractory epilepsy with bilateral seizure onsets in the setting of a normal radiological examination and a known neuropathological diagnosis of type I cortical dysplasia. The RNS system was implanted with strip electrodes placed on the left lateral frontal and right lateral temporal neocortex. At 19 months' follow-up, cortical stimulation resulted in sustained reduction in both seizure frequency-3 seizures per day down from 15 to 30 per day-and seizure severity. The patient subsequently underwent a trial of corticothalamic stimulation with a right temporal cortical strip and a left thalamic depth electrode, which resulted in a further 50% reduction in seizure frequency. In a second case, a 9-year-old right-handed female with radiological evidence of a small watershed infarct on the left and medically refractory seizures was referred for presurgical evaluation. Invasive monitoring revealed an unresectable seizure focus in the eloquent cortex of the left posterior frontal and parietal lobes. The RNS device was implanted with cortical leads placed at the putative seizure focus. At 21 months after surgery, the patient had been seizure free for 4 months, following a 17-month period in which the seizure frequency had decreased from 12 per month to 2 per month, with associated functional and behavioral improvement. The authors' results suggest that RNS may be a palliative option for children with intractable seizures whose condition warrants off-label use of the surgical device. The improved therapeutic effect noted with time and sustained RNS treatment points to a possible neuromodulatory effect. PMID- 29393814 TI - Extended middle fossa approach to lateralized pontine cavernomas in children. AB - OBJECTIVE Treatment of hemorrhagic cavernous malformations within the lateral pontine region demands meticulous surgical planning and execution to maximize resection while minimizing morbidity. The authors report a single institution's experience using the extended middle fossa rhomboid approach for the safe resection of hemorrhagic cavernomas involving the lateral pons. METHODS A retrospective chart review was performed to identify and review the surgical outcomes of patients who underwent an extended middle fossa rhomboid approach for the resection of hemorrhagic cavernomas involving the lateral pons during a 10 year period at Rady Children's Hospital of San Diego. Surgical landmarks for this extradural approach were based on the Fukushima dual-fan model, which defines the rhomboid based on the following anatomical structures: 1) the junction of the greater superficial petrosal nerve (GSPN) and mandibular branch of the trigeminal nerve; 2) the lateral edge of the porus trigeminus; 3) the intersection of the petrous ridge and arcuate eminence; and 4) the intersection of the GSPN, geniculate ganglion, and arcuate eminence. The boundaries of maximal bony removal for this approach are the clivus inferiorly below the inferior petrosal sinus; unroofing of the internal auditory canal posteriorly; skeletonizing the geniculate ganglion, GSPN, and internal carotid artery laterally; and drilling under the Gasserian ganglion anteriorly. This extradural petrosectomy allowed for an approach to all lesions from an area posterolateral to the basilar artery near its junction with cranial nerve (CN) VI, superior to the anterior inferior cerebellar artery and lateral to the origin of CN V. Retraction of the mandibular branch of the trigeminal nerve during this approach allowed avoidance of the region involving CN IV and the superior cerebellar artery. RESULTS Eight pediatric patients (4 girls and 4 boys, mean age of 13.2 +/- 4.6 years) with hemorrhagic cavernomas involving the lateral pons and extension to the pial surface were treated using the surgical approach described above. Seven cavernomas were completely resected. In the eighth patient, a second peripheral lesion was not resected with the primary lesion. One patient had a transient CN VI palsy, and 2 patients had transient trigeminal hypesthesia/dysesthesia. One patient experienced a CSF leak that was successfully treated by oversewing the wound. CONCLUSIONS The extended middle fossa approach can be used for resection of lateral pontine hemorrhagic cavernomas with minimal morbidity in the pediatric population. PMID- 29393815 TI - Choroid plexus adenoma in a child: expanding the clinical and pathological spectrum. AB - Primary choroid plexus tumors encompass a variety of tumors, with choroid plexus papilloma and carcinoma being the most common. Also in the differential diagnosis is the rare benign choroid plexus adenoma. As these tumors are infrequently described, the histological profile continues to evolve. The authors present a case with unusual characteristics that will broaden the pathological spectrum for choroid plexus adenomas. PMID- 29393813 TI - Reinfection after treatment of first cerebrospinal fluid shunt infection: a prospective observational cohort study. AB - OBJECTIVE CSF shunt infection requires both surgical and antibiotic treatment. Surgical treatment includes either total shunt removal with external ventricular drain (EVD) placement followed by new shunt insertion, or distal shunt externalization followed by new shunt insertion once the CSF is sterile. Antibiotic treatment includes the administration of intravenous antibiotics. The Hydrocephalus Clinical Research Network (HCRN) registry provides a unique opportunity to understand reinfection following treatment for CSF shunt infection. This study examines the association of surgical and antibiotic decisions in the treatment of first CSF shunt infection with reinfection. METHODS A prospective cohort study of children undergoing treatment for first CSF infection at 7 HCRN hospitals from April 2008 to December 2012 was performed. The HCRN consensus definition was used to define CSF shunt infection and reinfection. The key surgical predictor variable was surgical approach to treatment for CSF shunt infection, and the key antibiotic treatment predictor variable was intravenous antibiotic selection and duration. Cox proportional hazards models were constructed to address the time-varying nature of the characteristics associated with shunt surgeries. RESULTS Of 233 children in the HCRN registry with an initial CSF shunt infection during the study period, 38 patients (16%) developed reinfection over a median time of 44 days (interquartile range [IQR] 19 437). The majority of initial CSF shunt infections were treated with total shunt removal and EVD placement (175 patients; 75%). The median time between infection surgeries was 15 days (IQR 10-22). For the subset of 172 infections diagnosed by CSF culture, the mean +/- SD duration of antibiotic treatment was 18.7 +/- 12.8 days. In all Cox proportional hazards models, neither surgical approach to infection treatment nor overall intravenous antibiotic duration was independently associated with reinfection. The only treatment decision independently associated with decreased infection risk was the use of rifampin. While this finding did not achieve statistical significance, in all 5 Cox proportional hazards models both surgical approach (other than total shunt removal at initial CSF shunt infection) and nonventriculoperitoneal shunt location were consistently associated with a higher hazard of reinfection, while the use of ultrasound was consistently associated with a lower hazard of reinfection. CONCLUSIONS Neither surgical approach to treatment nor antibiotic duration was associated with reinfection risk. While these findings did not achieve statistical significance, surgical approach other than total removal at initial CSF shunt infection was consistently associated with a higher hazard of reinfection in this study and suggests the feasibility of controlling and standardizing the surgical approach (shunt removal with EVD placement). Considerably more variation and equipoise exists in the duration and selection of intravenous antibiotic treatment. Further consideration should be given to the use of rifampin in the treatment of CSF shunt infection. High-quality studies of the optimal duration of antibiotic treatment are critical to the creation of evidence-based guidelines for CSF shunt infection treatment. PMID- 29393816 TI - Referral patterns and patient characteristics at the first visit to a scoliosis center: a 2-year experience in South Korea without a school scoliosis-screening program. AB - OBJECTIVE The need for scoliosis screening remains controversial. Nationwide school screening for scoliosis has not been performed in South Korea, and there are few studies on the referral patterns of patients suspected of having scoliosis. This study aimed to examine the referral patterns to the largest scoliosis center in South Korea in the absence of a school screening program and to analyze the factors that influence the appropriateness of referral. METHODS The medical records of patients who visited a single scoliosis center for a spinal deformity evaluation were reviewed. Among 1895 new patients who visited this scoliosis center between April 2014 and March 2016, 1211 with presumed adolescent idiopathic scoliosis were included in the study. Patients were classified into 4 groups according to the referral method: non-health care provider, primary physician, hospital specialist, or school screening program. The appropriateness of referral was labeled as inappropriate, late, or appropriate. In total, 213 of 1211 patients were excluded because they had received treatment at another medical facility; 998 patients were evaluated to determine the appropriateness of referral. RESULTS Of the 998 referrals of new patients with presumed adolescent idiopathic scoliosis, 162 (16.2%) were classified as an inappropriate referral, 272 (27.3%) were classified as a late referral, and 564 (56.5%) were classified as an appropriate referral. Age, sex, Cobb angle of the major curve, and skeletal maturity were identified as statistically significant factors that correlated with the appropriateness of referral. The referral method did not correlate with the appropriateness of referral. CONCLUSIONS Under the current health care system in South Korea, a substantial number of patients with presumed adolescent idiopathic scoliosis are referred either late or inappropriately to a tertiary medical center. Although patients referred by school screening programs had a significantly lower late referral rate and higher appropriate referral rate than the other 3 groups, the referral method was not a significant factor in terms of the appropriateness of referral. PMID- 29393817 TI - Relationship Between Paraoxonase-1 and Butyrylcholinesterase Activities and Nutritional Status in Mexican Children. AB - BACKGROUND: The enzymes butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) are the primary bioscavenging enzymes in serum and exhibit antioxidant and anti inflammatory activities. PON1 has been associated with diseases caused by high oxidative stress, whereas BuChE appears to be involved in the pathophysiology of the metabolic syndrome and related disorders. It has been suggested that children from rural communities in Mexico may have a predisposition to develop obesity or type 2 diabetes during adolescence or adulthood. The objective of this study was to determine whether associations exist between the paraoxonase (PONase)/arylesterase (AREase) activity of PON1, its PON1-Q192R and PON1-L55M polymorphisms, and BuChE activity with the nutritional status and lipid profiles in a group of children from rural communities in Mexico. METHODS: A group of 97 boys and girls from a rural community in Mexico were assessed for body mass index, the enzymatic activities of BuChE, PONase, and AREase were measured in serum, and their lipid profiles were determined. Genetic polymorphisms of PON1 L55M and PON1-Q192R were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The children were classified into four groups: thinness, normal weight, overweight, and obese. Of the children studied, 34.4% were overweight and obese. The mean age of the participants was 9.5 years (standard deviation = 1.8). The L allele of the PON1-L55M genotype was the most frequent (83.3%), and the R allele of the PON1-Q192R genotype was the most frequent (61.8%). Overweight and obese children had higher values of BuChE, total cholesterol, triglycerides (TG), and lower high-density lipoprotein (HDL-C) values than children with thinness or normal weight (P = 0.028, P = 0.019, P = 0.004, P = 0.069 and P = 0.021, respectively). The levels of AREase and PONase and the prevalence of PON1-L55M and PON1-Q192R genotypes were similar between groups (P = 0.484 and P = 0.380, respectively). CONCLUSIONS: This study establishes a positive association of BuChE activity with nutritional status and serum TG. PMID- 29393818 TI - Comparison of Intraperitoneal Nebulization of Ropivacaine with Ropivacaine Fentanyl Combination for Pain Control Following Laparoscopic Cholecystectomy: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - PURPOSE: Intraperitoneal local anesthetic nebulization is a new and novel technique for providing pain relief following laparoscopic cholecystectomy. We compared the analgesic efficacy of intraperitoneal ropivacaine-fentanyl nebulization with ropivacaine nebulization alone for providing pain relief following laparoscopic cholecystectomy Materials and Methods: This prospective, randomized, double-blind, placebo-controlled trial included 75 American Society of Anesthesiologists I/II patients, 18-60 years old, scheduled to undergo laparoscopic cholecystectomy under general anesthesia. Patients were randomly allocated to one of the three groups of 25 patients each to receive intraperitoneal nebulization using normal saline (group I), 30 mg of 0.75% ropivacaine (group II), or 30 mg of 0.75% ropivacaine with 100 MUg fentanyl (group III). Visual analogue scale (VAS) scores for pain during rest and movement, shoulder pain, nausea or vomiting, and sedation were recorded for 48 hours postoperatively. Time to providing first rescue analgesia and 48-hour tramadol consumption were also noted. RESULTS: Significantly greater number of patients in the placebo group had overall VAS >30 both at rest and during movement. Greater number of these patients also complained of postoperative shoulder pain and had significantly more tramadol consumption in the postoperative period. Furthermore, patients in the ropivacaine-fentanyl group demanded first dose of rescue analgesic significantly later than the other two groups. CONCLUSIONS: Nebulization results in better and uniform dispersion of analgesic drug intraperitoneally. Following laparoscopic cholecystectomy surgeries, ropivacaine nebulization of intraperitoneal cavity, with or without fentanyl, provides highly effective postoperative analgesia, with decreased incidence of shoulder pain. Furthermore, addition of fentanyl to ropivacaine prolongs the duration of analgesia. PMID- 29393819 TI - The role of value in the attentional boost effect. AB - Focusing attention on one item typically interferes with the ability to process other information. Yet, target detection can both facilitate memory for items paired with the target (the attentional boost effect) and increase the perceived value of those items (cued approach). Because long-term memory is better for valuable items than for neutral items, we asked whether the attentional boost effect is due to changes in the perceived value of items that are paired with targets. In three experiments, participants memorised a series of briefly presented images that depicted valuable (e.g., food) or neutral (e.g., children's toys) items. Whenever an item appeared, a square flashed in its centre. Participants pressed a button if the square was a target colour but not if it was a distractor colour. Consistent with previous research, target-paired items were remembered better than distractor-paired items and were rated as more valuable. Importantly, if memory for target-paired items is enhanced because they increased in perceived value, then valuable items should have been better remembered than neutral items. However, we found no evidence that value enhanced memory for the items in this task. Thus, it is unlikely that the attentional boost effect is due to changes in perceived value. PMID- 29393820 TI - How intensive care nurses perceive good death. AB - This study was to determine the attitude of nurses regarding the concept of a good death and terminal phase was conducted to determine the effect on patient care. This is a descriptive and analytical study. The study was conducted with 102 nurses who worked at an intensive care unit and were willing to participate to the study. The mean Good Death Scale total score was 56.75 +/- 8.90 and the Frommelt Scale score was 95.10 +/- 8.53. In conclusion, our study results suggest that the attitudes of the nurses during care to moribund patients are moderate and, when appropriate care is given, they perceive the death as a positive experience. PMID- 29393821 TI - Diagnosis of Prostate Cancer with Noninvasive Estimation of Prostate Tissue Composition by Using Hybrid Multidimensional MR Imaging: A Feasibility Study. AB - Purpose To evaluate whether compartmental analysis by using hybrid multidimensional magnetic resonance (MR) imaging can be used to diagnose prostate cancer and determine its aggressiveness. Materials and Methods Twenty-two patients with prostate cancer underwent preoperative 3.0-T MR imaging. Axial images were obtained with hybrid multidimensional MR imaging by using all combinations of echo times (47, 75, 100 msec) and b values of 0, 750, 1500 sec/mm2, resulting in a 3 * 3 array of data associated with each voxel. Volumes of the tissue components stroma, epithelium, and lumen were calculated by fitting the hybrid data to a three-compartment signal model, with distinct, paired apparent diffusion coefficient (ADC) and T2 values associated with each compartment. Volume fractions and conventional ADC and T2 were measured for regions of interest in sites of prostatectomy-verified malignancy (n = 28) and normal tissue (n = 71). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of various parameters in differentiating prostate cancer from benign tissue. Results Compared with normal tissue, prostate cancer showed significantly increased fractional volumes of epithelium (23.2% +/- 7.1 vs 48.8% +/- 9.2, respectively) and reduced fractional volumes of lumen (26.4% +/- 14.1 vs 14.0% +/- 5.2) and stroma (50.5% +/- 15.7 vs 37.2% +/- 9.1) by using hybrid multidimensional MR imaging. The fractional volumes of tissue components show a significantly higher Spearman correlation coefficient with Gleason score (epithelium: rho = 0.652, P = .0001; stroma: rho = -0.439, P = .020; lumen: rho = -0.390, P = .040) compared with traditional T2 values (rho = -0.292, P = .132) and ADCs (rho = -0.315, P = .102). The area under the ROC curve for differentiation of cancer from normal prostate was highest for fractional volume of epithelium (0.991), followed by fractional volumes of lumen (0.800) and stroma (0.789). Conclusion Fractional volumes of prostatic lumen, stroma, and epithelium change significantly when cancer is present. These parameters can be measured noninvasively by using hybrid multidimensional MR imaging and have the potential to improve the diagnosis of prostate cancer and determine its aggressiveness. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29393822 TI - Development and validation of LC-MS/MS method for the determination of Ochratoxin A and its metabolite Ochratoxin alpha in poultry tissues and eggs. AB - The objective of this study was to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of Ochratoxin A (OTA) and Ochratoxin alpha (OTalpha) in poultry tissues and eggs. The two toxins were extracted by a mixture of acetonitrile/water, purified with a reversed phase C18 solid phase extraction column (SPE) and determined by LC-MS/MS. The LC-MS/MS method performances were evaluated in terms of linearity in solvent and in matrix (ranged from 0.5 to 15.10 ug L-1 for OTA and from 0.60 to 17.85 ug L-1 for OTalpha), limit of detection (LOD), limit of quantitation (LOQ), specificity, accuracy and precision in repeatability conditions. Recovery experiments were performed by spiking poultry liver, kidney, muscle and eggs around 1 ug kg-1 and 10 ug kg-1. LODs were 0.27 and 0.26 ug kg-1 while LOQs were fixed at 1.0 and 1.2 ug kg-1 for OTA and OTalpha, respectively. Main recoveries for OTA ranged from 82 to 109% and for OTalpha ranged from 55 to 89%. The values of within-laboratory relative standard deviation (RSDr) were equal to or below 20%. Considering the results obtained and that all analytical performance criteria were fulfilled, the new extraction and purification method developed for OTA and OTalpha determination in animal tissues and eggs was found appropriate for control laboratories and research activities designed to ensure food safety. PMID- 29393823 TI - Evidence that thiol-based redox state is critical for xylem vessel cell differentiation. AB - Nitric oxide (NO), which plays essential roles in a variety of cell signaling processes, is the precursor of a family of NO-derived molecules, including toxic reactive nitrogen species. The NO-based regulation of cellular activity is mediated by the reversible modification of cysteine thiol groups in redox sensitive proteins. One such modification is protein S-nitrosylation, i.e., the addition of an NO moiety to a cysteine thiol, and this S-nitrosylation is regulated by enzymes such as S-nitrosoglutathione reductase (GSNOR). Recently, we reported a novel loss-of-function allele of gsnor1, named suppressor of ectopic vessel cell differentiation induced by VND7-1 (seiv1), based on the VND7 inducible system, in which almost all cell types are transdifferentiated into xylem vessel cells upon activation of the NAC transcription factor VND7. We also found that VND7 can be S-nitrosylated and that the target cysteine residues for S nitrosylation are critical for VND7 transactivation activity. Here, we further discuss roles for GSNOR1 in xylem vessel cell differentiation, and provide additional data on the effects of cellular NO level on VND7 activity. PMID- 29393824 TI - Strategic Review Process for an Accountable Care Organization and Emerging Accountable Care Best Practices. AB - Accountable Care Organizations (ACOs), like other care entities, must be strategic about which initiatives they support in the quest for higher value. This article reviews the current strategic planning process for the Johns Hopkins Medicine Alliance for Patients (JMAP), a Medicare Shared Savings Program Track 1 ACO. It reviews the 3 focus areas for the 2017 strategic review process - (1) optimizing care coordination for complex, at-risk patients, (2) post-acute care, and (3) specialty care integration - reviewing cost savings and quality improvement opportunities, associated best practices from the literature, and opportunities to leverage and advance existing ACO and health system efforts in each area. It then reviews the ultimate selection of priorities for the coming year and early thoughts on implementation. After the robust review process, key stakeholders voted to select interventions targeted at care coordination, post acute care, and specialty integration including Part B drug and imaging costs. The interventions selected incorporate a mixture of enhancing current ACO initiatives, working collaboratively and synergistically on other health system initiatives, and taking on new projects deemed targeted, cost-effective, and manageable in scope. The annual strategic review has been an essential and iterative process based on performance data and informed by the collective experience of other organizations. The process allows for an evidence-based strategic plan for the ACO in pursuit of the best care for patients. PMID- 29393825 TI - Association of sense of coherence and supernatural beliefs with death anxiety and death depression among Romanian cancer patients. AB - The aim of this cross-sectional study was to examine the association of supernatural beliefs and sense of coherence with death anxiety and death depression in a Romanian sample of cancer patients. We found support for the terror management theory worldview defence hypothesis postulating the presence of a curvilinear relation between death anxiety and supernatural beliefs among cancer patients. Results conformed to an inverted U-shape quadratic regression, indicating that cancer patients who scored moderately on supernatural beliefs were afraid of death the most, while death anxiety was lowest for the extreme atheists and extreme believers in supernatural entities. PMID- 29393826 TI - Help-seeking experiences of bereaved adolescents: A qualitative study. AB - Despite the potentially devastating effects of a death on the lives of adolescents, little is known about their help-seeking experiences. We interviewed by telephone 39 bereaved adolescents on their help-seeking experiences. Thematic analysis resulted in three themes: Formal support, Informal support and School related support. Participants provided a critical appraisal of positive and negative experiences, and noted barriers and facilitators for help-seeking. As adolescents bereaved through suicide may receive less social support, professional help is a much-needed auxiliary. Parental encouragement is important in accessing adequate professional help. PMID- 29393827 TI - Change in death metaphors among university students in Hong Kong from 2004 to 2016. AB - Death metaphors are a meaningful way to understand personal perceptions of death, an important construct affecting how people live. This study collected death metaphor data among 100 university students in Hong Kong in 2016 and compared the findings with another study reported in 2004. Interpersonally oriented death metaphors were still popular among students a decade later. There was a general decrease in positive perception of death and an increase in negative perception of death from 2004 to 2016. Death metaphors are useful tools in death education programs, especially in cultures where death is a taboo topic. PMID- 29393828 TI - Differentiating Suicide Attempters from Suicide Ideators: The Role of Capability for Suicide. AB - This study examined whether different components of capability for suicide (i.e., fearlessness about death, pain tolerance, pain insensitivity, preparation for suicide, suicide plan, and courage), as well as painful and provocative events, nonsuicidal self-injury, depressive symptoms, and hopelessness, could distinguish between suicide attempters, suicide ideators, and non-suicidal controls. A total of 930 Chinese adolescents completed questionnaires, and a multinomial logistic regression was conducted to identify factors that could distinguish among the 3 groups. We found that higher levels of pain tolerance, more detailed suicide plans, more positive attitudes towards suicide, as well as more painful and provocative experiences and more severe depressive symptoms were positively associated with increased likelihood of the engagement in both suicide ideation and suicide attempts. Only nonsuicidal self-injury increased the likelihood of falling in the suicide attempt group as compared to the suicide ideation group. Findings of this study emphasize the role of nonsuicidal self-injury in intervening suicidality. PMID- 29393829 TI - Low-Wage Workers and Health Benefits Use: Are We Missing an Opportunity? PMID- 29393830 TI - S-1 alar/iliac screw technique for spinopelvic fixation. AB - Spinopelvic fixation provides an important anchor for long fusions in spinal deformity surgery, and it is also used in the treatment of other spine pathologies. Iliac screws are known to sometimes require reoperation due to pain resulting from hardware prominence and skin injury. S-2 alar/iliac (S2AI) screws do not often require removal, but they may provide inadequate fixation in select cases. In this paper the authors describe a technique for S-1 alar/iliac screws that may be used independently or as a supplement to S2AI screws. A preliminary biomechanical analysis and 2 clinical case examples are also provided. PMID- 29393831 TI - A historical recount of chordoma. AB - Chordoma, a rare bone tumor that occurs along the spine, has led scientists on a fascinating journey of discoveries. In this historical vignette, the authors track these discoveries in diagnosis and treatment, noting events and clinicians that played pivotal roles in our current understanding of chordoma. The study of chordoma begins in 1846 when Rudolf Virchow first observed its occurrence on a dorsum sellae; he coined the term "chordomata" 11 years later. The chordoma's origin was greatly disputed by members of the scientific community. Eventually, Muller's notochord hypothesis was accepted 36 years after its proposal. Chordomas were considered benign and slow growing until the early 1900s, when reported autopsy cases drew attention to their possible malignant nature. Between 1864 and 1919, the first-ever symptomatic descriptions of various forms of chordoma were reported, with the subsequent characterization of chordoma histology and the establishment of classification criteria shortly thereafter. The authors discuss the critical historical steps in diagnosis and treatment, as well as pioneering operations and treatment modalities, noting the physicians and cases responsible for advancing our understanding of chordoma. PMID- 29393832 TI - Letter to the Editor. Hybrid cervical disc arthroplasty for cervical myelopathy associated with congenital cervical stenosis. PMID- 29393833 TI - Myelopathy after cervical disc arthroplasty due to progression of spondylosis at the index level: case report. AB - Cervical disc arthroplasty (CDA) has emerged as a popular alternative to anterior cervical discectomy and fusion (ACDF) for the surgical treatment of cervical degenerative disc disease. CDA has been well studied, with efficacy reported to be equivalent to or better than that seen with ACDF, and it is associated with a consistently low incidence of adverse events. The development or progression of myelopathy after CDA is a particularly rare occurrence. In this report, the authors describe the first known case of recurrence of myelopathy at the index level of surgery after CDA implantation due the continuation of the spondylitic process after placement of the artificial disc. PMID- 29393834 TI - Suicide Postvention for the United States Military: Literature Review, Conceptual Model, and Recommendations. AB - Suicide continues to be a significant public health problem in the United States and the Department of Defense (DoD). Timely and systematic postvention efforts can play an instrumental role in helping family members, peers, and military command to best manage the aftermath of a suicide. To date, several postvention efforts have been implemented in the military. However, there continues to be an overall lack of understanding of the specific short- and long-term effects of exposure to military suicide. In addition, more emphasis needs to be placed on empirically driven approaches to postvention and program evaluation. The purpose of this article is threefold: (1) to provide a summary of the postvention literature with special emphasis placed on the military organization; (2) to propose a conceptual model as a framework for understanding Military-Unit Suicide Survivorship; and (3) to briefly highlight postvention strategies within the DoD in the context of a number of research, clinical, and policy recommendations. PMID- 29393835 TI - The anti-human trafficking collaboration model and serving victims: Providers' perspectives on the impact and experience. AB - PURPOSE: A coalition model is often used to serve victims of human trafficking but little is known about whether the model is adequately meeting the needs of the victims. The purpose of this study was to examine anti-human trafficking collaboration model in terms of its impact and the collaborative experience, including challenges and lessons learned from the service providers' perspective. METHOD: Mixed methods study was conducted to evaluate the impact of a citywide anti-trafficking coalition model from the providers' perspectives. Web-based survey was administered with service providers (n = 32) and focus groups were conducted with Core Group members (n = 10). RESULTS: Providers reported the coalition model has made important impacts in the community by increasing coordination among the key agencies, law enforcement, and service providers and improving quality of service provision. Providers identified the improved and expanded partnerships among coalition members as the key contributing factor to the success of the coalition model. DISCUSSION: Several key strategies were suggested to improve the coalition model: improved referral tracking, key partner and protocol development, and information sharing. PMID- 29393836 TI - Extracurricular Activities are Associated with Lower Suicidality through Decreased Thwarted Belongingness in Young Adults. AB - Research has shown a negative association between extracurricular activities (ECAs) and suicidality. This study builds upon past research by using the interpersonal psychological theory of suicide to better understand the mechanisms involved in the relationship between ECAs and suicide risk. A total of 121 community and online-recruited adults ages 18 to 24-years-old participated. Self report measures of suicidality, thwarted belongingness, and perceived burdensomeness were collected. Duration and breadth of participation in ECAs were assessed. ECA involvement was negatively associated with thwarted belongingness and perceived burdensomeness. An indirect effect of ECAs on suicidality through thwarted belongingness was statistically significant, but not for perceived burdensomeness. ECA involvement was associated with decreased suicidality through lower levels of thwarted belongingness. Interventions utilizing ECAs may be a low cost, high-access option for decreasing suicide risk. PMID- 29393837 TI - Depressive Symptoms and Perceived Burdensomeness Mediate the Association between Anxiety and Suicidal Ideation in Adolescents. AB - A relationship between anxiety disorders and suicide-related behaviors has been demonstrated in adolescents, with a paucity of research examining mediators of this association. The present study hypothesized that anxiety would be associated with suicidal ideation via a serial mediation pathway through depressive symptoms and perceived burdensomeness and/or thwarted belongingness. A sample of 80 adolescents (68.8% female, 65.8% Hispanic), 13-19 years of age (mean = 16.93, SD = 1.66), completed 3 interviews as part of a randomized controlled trial. Results indicated a significant serial mediation from anxiety to suicidal ideation via depressive symptoms and perceived burdensomeness, but not thwarted belongingness. Clinicians and mental health service providers working with adolescents experiencing elevated anxiety should regularly assess for perceived burdensomeness and suicidal ideation. PMID- 29393838 TI - Psychometrics of the PTSD and Depression Screener for Bereaved Youth. AB - Interventions for bereaved children and families range from supportive counseling, designed to promote social connectedness and expression of feelings and thoughts about the deceased, to intensive trauma/grief-specific therapy, designed to ameliorate symptoms of posttraumatic stress disorder (PTSD) and depression. That said, professionals have few brief assessment instruments to match response and functioning to appropriate interventions. To expedite the screening and referral process for bereaved families, Brown, Goodman, and Swiecicki ( 2008 ) developed the PTSD and Depression Screener for Bereaved Youth, a 19-item measure of bereavement-related history and symptoms of PTSD and depression. The current study is a psychometric evaluation of the Screener for Bereaved Youth. Data were collected from 284 bereaved children, 6-17 years of age (M = 12.4; SD = 2.9). A factor analysis revealed distinct subscales for PTSD (eight items) and depression (four items). The PTSD and depression subscales showed both concurrent and discriminant validity. Endorsement of four items on either subscale was associated with meeting full criteria on more extensive measures of PTSD and depression. These findings are discussed with specific consideration to the multiple systems in which the measure could be used and applications to clinical services. PMID- 29393839 TI - Effect of time since loss on grief, resilience, and depression among bereaved emerging adults. AB - Grief research has typically centered on one time point, without considering the impact of multiple losses over time. In this study, 546 bereaved emerging adults were divided into three groups: those who experienced a recent loss (0-2 years ago), a past loss (>2 years ago), or a combination of both recent and past losses. Differences between the groups on resilience, depression, and grief symptomatology were examined. Those who had experienced both losses (recent and past) and recent losses endorsed significantly more grief symptoms than those in the past loss group. Findings highlight how multiple losses impact grief. PMID- 29393840 TI - Palliative care professional's perceptions of barriers and challenges to accessing children's hospice and palliative care services in South East London: A preliminary study. AB - OBJECTIVES: Several barriers have been identified as preventing or delaying access to children's palliative care services. The aim of this study is to further explore such barriers from palliative care professionals' perspective from two London boroughs. METHODS: Qualitative-five children's palliative care professionals' perceptions were obtained from semi-structured interviews. RESULTS: Three themes emerged: availability and adequacy of child palliative care (e.g., unreliability of services), obstacles to accessing palliative care (e.g., logistical challenges), and cultural values and family priorities. CONCLUSION: These findings contribute to the equal opportunities dialogue in this sector and the need for future research to address the challenges identified. PMID- 29393841 TI - The Infectious Disease Network (IDN): Development and Use for Evaluation of Potential Ebola Cases in Georgia. AB - In response to the 2014 Ebola virus disease (EVD) outbreak in West Africa, the Georgia Department of Public Health developed the Infectious Disease Network (IDN) based on an EVD preparedness needs assessment of hospitals and Emergency Medical Services (EMS) providers. The network consists of 12 hospitals and 16 EMS providers with staff specially trained to provide a coordinated response and utilize appropriate personal protective equipment (PPE) for the transport or treatment of a suspected or confirmed serious communicable disease patient. To become a part of the network, each hospital and EMS provider had to demonstrate EVD capabilities in areas such as infection control, PPE, waste management, staffing and ongoing training, and patient transport and placement. To establish the network, the Georgia Department of Public Health provided training and equipment for EMS personnel, evaluated hospitals for EVD capabilities, structured communication flow, and defined responsibilities among partners. Since March 2015, the IDN has been used to transport, treat, and/or evaluate suspected or confirmed serious communicable disease cases while ensuring health care worker safety. Integrated infectious disease response systems among hospitals and EMS providers are critical to ensuring health care worker safety, and preventing or mitigating a serious communicable disease outbreak. (Disaster Med Public Health Preparedness. 2018; page 1 of 7). PMID- 29393842 TI - A study of urinary Tamm-Horsfall protein excretion in adult type 2 diabetes mellitus?. AB - AIM: To study the excretion of urinary Tamm-Horsfall protein (THP) with a wide range of urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in a population with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A retrospective investigation was performed in 3,599 adult inpatients with T2DM in Anhui Provincial Hospital of China. Demographic information, urinary THP data, and other lab reports were obtained from the Electronic Patient Record (EPR). RESULTS: (1) In T2DM, average HbA1c was 8.6%, and 55.2% of the patients had an HbA1c > 9%. The percentages with normal excretion, decreased excretion, and increased excretion of urinary THP were 49.8%, 41.7%, and 8.5%, respectively. Serum creatinine (Scr), blood urea nitrogen (BUN), and UACR levels were highest, and eGFR was lowest, in the decreased urinary THP group. (2) The proportion of decreased urinary THP excretion rose, and the level of urinary THP declined when UACR increased or eGFR decreased. (3) Urinary THP showed a negative correlation to Scr, BUN, triglyceride (TG), and UACR (rs = -0.173, -0.228, -0.060 and -0.237, respectively), but a positive correlation with eGFR and high-density lipoprotein cholesterol (HDL-C) (rs =0.128 and 0.040, respectively). (4) Logistical regression analysis showed that Scr, BUN, TG, UACR, and eGFR were independent risk factors for decreased urinary THP (OR = 3.477, 1.461, 1.160, 2.124, and 2.087, respectively). CONCLUSION: Increased albuminuria and decreased GFR are predictors of decreased urinary THP excretion. Distal convoluted tubule lesion may precede glomerular damage in a portion of T2DM patients.?. PMID- 29393843 TI - Successful treatment of nephrotic syndrome induced by lambda light chain deposition disease using lenalidomide: A case report and review of the literature?. AB - BACKGROUND: Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the kappa form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment. CASE PRESENTATION: An 80-year-old woman was referred to our department with severe nephrotic syndrome (13.6 g/gCr) and anemia. A renal biopsy showed mesangial proliferation and mesangial matrix expansion, and immunohistochemistry showed positive staining for lambda chains along the glomerular basement membrane, but was negative for kappa chains or amyloid deposition. A bone marrow biopsy revealed 64% plasma cells. Immunoglobulin G (IgG)-lambda type M protein was detected, and the levels of free lambda chain was significantly increased. We concluded that her nephrotic syndrome was caused by LCDD, which resulted from IgG-lambda MM. The induction of a BCD (bortezomib, cyclophosphamide, and dexamethasone) treatment regimen did not lead to a hematological response or decrease in proteinuria. The administration of combination therapy of lenalidomide and prednisolone led to the successful reduction of proteinuria and hematuria. CONCLUSIONS: We presented a very rare case report describing the successful treatment of LCDD (lambda chain) induced nephrotic syndrome with lenalidomide.?. PMID- 29393844 TI - What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Women's Day?. AB - Chronic kidney disease affects ~ 10% of the world's adult population: It is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health, and specifically their kidney health, on the community and the next generations as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those insights more broadly. Girls and women, who make up ~ 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in terms of access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women, with profound consequences for child bearing and on the fetus. Women have different complications on dialysis than men and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide.?. PMID- 29393845 TI - H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis. AB - BACKGROUND: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors with other morphologies, including gangliogliomas (GGs), anaplastic GGs, pilocytic astrocytomas (PAs), and posterior fossa ependymomas. In a few patients with H3 K27M;mutant tumors with these alternate morphologies, longer survival has been reported, making grading difficult for the neuropathologist. Few series compare tumors in adult vs. pediatric cohorts; we report our 4-year experience. MATERIALS AND METHODS: Text Word database searches using H3 K27M in reports generated between January 2013 and November 10, 2017 were used to identify patients. Clinical and histological features as well as survival were evaluated for each case. RESULTS: 28 H3 K27M-mutant tumors were identified, with equal numbers of adults (13) vs. children (15). For adults, mean and median age was 52 years (range = 27 - 81 years), 2 decades older than a recently-published adult series. Tumors involved thalamic (adult = 7; pediatric = 7), spinal cord (adult = 4; pediatric = 2), pons (adult = 1; pediatric = 6), and hypothalamic (n = 1) sites. Other morphologies at presentation included pure GG (n = 3, pediatric) and PA (n = 1, adult). One adult and 1 pediatric patient each presented with leptomeningeal dissemination or developed leptomeningeal dissemination within 1 year after diagnosis, with transformation from PA or GG histology to glioblastoma. Mean survival was 9.3 (adults) vs. 8.9 (pediatric) months. Patients with tumors of other morphologies (GG, PA) did not enjoy extended survival. CONCLUSION: H3 K27M mutant tumors can affect patients at advanced ages, may show leptomeningeal dissemination at time of presentation, and "pure" GG or PA morphology is not rare. Regardless of patient age or tumor morphology, patients fare equally poorly.?. PMID- 29393846 TI - Population pharmacokinetic model of levetiracetam in Korean neonates with seizures?. AB - OBJECTIVE: This study was conducted to develop a population pharmacokinetic (PK) model of levetiracetam in Korean neonates with seizures. MATERIALS AND METHODS: Data were obtained from a retrospective study of 18 neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of Severance Children's Hospital for the period of from 2013 to 2015. Sampling and dosing times were recorded by clinical research coordinators on case report forms. Demographic factors and laboratory results were tested as potential covariates for PK parameters. Model development was performed within a mixed-effect modeling framework using NONMEM. RESULTS: With a one-compartment model with first-order elimination chosen as a basic PK model based on theory-based allometric relationships, postmenstrual age and serum creatinine were found to have significant influences on clearance (CL). Typical parameter estimates of the final PK model obtained, evaluated at covariate medians, were 1.08 L/kg for volume of distribution (V) and 0.073 L/h/kg (= 1.23 mL/min/kg) for CL, illustrating that V in Korean neonates is a little larger than in Western population while CL is similar. CONCLUSION: A population PK model of levetiracetam for Korean neonates with seizures was developed in this study. The result of this study can be used as a basis to develop an optimal dosage regimen in Korean neonates with seizures.?. PMID- 29393847 TI - Persistence with antihypertensive drugs in patients with depression in Germany. AB - AIM: The goal of the present retrospective work was to study the impact of depression on persistence with antihypertensive drugs in general practices in Germany. MATERIALS AND METHODS: This study included adults with hypertension and depression who initially received antihypertensive drugs from physicians in 1,262 general practices in Germany between January 2013 and December 2015. Hypertension controls without depression were matched (1:1) to the hypertension cases with depression based on age, gender, physician, and initial antihypertensive therapy, using a propensity score method. The main outcome of the study was the rate of persistence with antihypertensive drugs in individuals with hypertension with and without depression in the 12 months following the index date. Persistence was estimated as therapy duration without treatment disruption, which was defined as at least 3 months without oral antihypertensive drugs. The effect of depression on persistence with antihypertensive treatment was analyzed in the entire population and in various subgroups using Cox regression models. RESULTS: The study included 24,627 hypertension patients with depression and 24,627 hypertension patients without depression. The mean age was 59.7 years (SD = 12.1 years), and 37.3% were men. After 12 months of follow-up, the rate of persistence with antihypertensive therapy was 64.5% in individuals with depression and 66.9% in individuals without depression (p-value = 0.232). Depression was found to have no significant impact on discontinuation in the overall population (HR = 1.01, 95% CI: 0.99 - 1.03) or in the different subgroups (HRs ranging from 0.93 to 1.03). CONCLUSION: Depression was not significantly associated with persistence with antihypertensive drugs in Germany.?. PMID- 29393848 TI - Population pharmacokinetics of 25-hydroxy vitamin D in children with asthma?. AB - OBJECTIVES: Asthma and vitamin D deficiency are widespread in the pediatric and adolescent population. The aim of this study was to develop a population pharmacokinetic (PPK) model and to evaluate the most important factors that can significantly affect clearance of 25-hydroxy vitamin D in asthmatic children using PPK analysis. MATERIALS AND METHODS: The study population included school children and adolescents from 7 to 18 years of age of both sexes. PPK analysis was performed by non-linear mixed-effects modeling (NONMEM), and 19 covariates were assessed. Goodness-of-fit plots, validation set and bootstrap analysis were conducted to confirm predictive performance of the final model. RESULTS: A total of 60 patients were included in the basic NONMEM data set for PPK modeling with a mean age of 10.2 years and body weight of 41.3 kg. The final pharmacokinetic model for the clearance of 25-hydroxy vitamin D included as covariates intake of vitamin D from foods (DD), hereditary predisposition to asthma (HPA) and the ratio of forced expiratory volume in first second and forced vital capacity (FEV1/FVC ratio). A validation set consisted of 14 separate patients with similar characteristics to the basic data set. The final model was confirmed by internal and external validation and also through goodness-of-fit plots. CONCLUSION: These results could be of help for individualization of vitamin D supplementation doses in this vulnerable population.?. PMID- 29393849 TI - Prevalence and treatment of sexually transmitted diseases in gynecological practices in Germany: A retrospective study with more than 1,000,000 patients?. AB - BACKGROUND: The aim of this study was to analyze the prevalence and treatment of sexually transmitted diseases (STDs) in gynecological practices in Germany. MATERIALS AND METHODS: This study included women who were followed in gynecological practices in Germany between 2013 and 2015. The first outcome was the prevalence of women diagnosed with STDs during this time period. Eight different types of STD infections were included in the analysis: chlamydial infection, gonococcal infection, anogenital warts, anogenital herpes infection, trichomoniasis, ulcus molle, phthiriasis, and syphilis. The second outcome was the prevalence of women with STDs who received appropriate medication within 90 days of STD diagnosis. RESULTS: There were 1,030,968 patients available for analysis. The most frequent infection was chlamydia (0.59%), and the least frequent one was syphilis (0.01%). The prevalence of STDs was found to be the highest in women aged 21 - 25 years (3.42%). Mean age at diagnosis ranged from 27.3 years (chlamydia infection) to 40.6 years (syphilis). Finally, the share of women receiving medication therapy was the highest for syphilis (83.3%) and the lowest for anogenital warts (52.7%). CONCLUSIONS: The prevalence of STDs ranged from 0.01 to 0.59% in women followed in gynecological practices in Germany between 2013 and 2015.?. PMID- 29393850 TI - Voriconazole therapeutic drug monitoring: Factors associated with supratherapeutic and subtherapeutic voriconazole concentrations. AB - OBJECTIVE: The voriconazole trough concentration (Cmin) varies widely, and Cmin outside the therapeutic range (COTR) is associated with response failure and toxicity. The objective of this study was to identify potential factors associated with COTR in patients, and specifically the population at a high risk of COTR. MATERIALS AND METHODS: We performed a retrospective study of patients who received voriconazole from 2009 to 2016. Voriconazole Cmin values were analyzed with high-performance liquid chromatography, and values of < 1 mg/L and > 4 mg/L were defined as COTR. Logistic regression and the classification and regression tree (CART) were used to explore the potential factors associated with COTR. RESULTS: In total, 134 voriconazole Cmin values were measured in 64 patients who met the eligibility criteria: 55 (41.0%) were subtherapeutic, and 79 (59.0%) were supertherapeutic. Logistic regression revealed that voriconazole COTR was significantly associated with age, CYP2C19 genetic status, and liver function after voriconazole treatment. CART identified the high-risk population of COTR: (1) patients' age < 47 years and with underlying liver disease, (2) patients' age > 47 years and with acute liver dysfunction after voriconazole treatment, (3) non poor metabolizers, aged from 46 to 65 years and with normal liver function after voriconazole treatment, and (4) old (age > 65 years) patients with normal liver function and body weight < 66 kg. CONCLUSION: Our findings suggest that age, CYP2C19 genetic status, and liver function status are strongest predictors of voriconazole COTR. Clinically, these results can be used to estimate the probability of voriconazole COTR in individual patients.?. PMID- 29393851 TI - Gq activity- and beta-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. AB - Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and beta-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or beta-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that beta-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2 Gq/beta-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility. PMID- 29393852 TI - Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response. AB - Models for regulation of the eukaryotic heat shock response typically invoke a negative feedback loop consisting of the transcriptional activator Hsf1 and a molecular chaperone. Previously we identified Hsp70 as the chaperone responsible for Hsf1 repression and constructed a mathematical model that recapitulated the yeast heat shock response (Zheng et al., 2016). The model was based on two assumptions: dissociation of Hsp70 activates Hsf1, and transcriptional induction of Hsp70 deactivates Hsf1. Here we validate these assumptions. First, we severed the feedback loop by uncoupling Hsp70 expression from Hsf1 regulation. As predicted by the model, Hsf1 was unable to efficiently deactivate in the absence of Hsp70 transcriptional induction. Next, we mapped a discrete Hsp70 binding site on Hsf1 to a C-terminal segment known as conserved element 2 (CE2). In vitro, CE2 binds to Hsp70 with low affinity (9 uM), in agreement with model requirements. In cells, removal of CE2 resulted in increased basal Hsf1 activity and delayed deactivation during heat shock, while tandem repeats of CE2 sped up Hsf1 deactivation. Finally, we uncovered a role for the N-terminal domain of Hsf1 in negatively regulating DNA binding. These results reveal the quantitative control mechanisms underlying the heat shock response. PMID- 29393854 TI - A Rare Cause of Paraplegia: Myeloid Sarcoma PMID- 29393855 TI - Electronic structure of stoichiometric and oxygen-deficient ferroelectric Hf0.5Zr0.5O2. AB - The electronic structure of oxygen-deficient Hf0.5Zr0.5O2 in the non centrosymmetric orthorhombic (ferroelectric) phase was investigated by means of x ray photoelectron spectroscopy and first-principle density functional theory calculations. It was established that a peak in the photoelectron spectra observed at an energy above the valence band top of ferroelectric Hf0.5Zr0.5O2 in ion-etched samples was due to oxygen vacancies. A method for evaluating the oxygen vacancies concentration in the material from the comparison of experimental and theoretical photoelectron spectra of the valence band is proposed. It is found that oxygen polyvacancies are not formed in ferroelectric Hf0.5Zr0.5O2: an energy-favorable spatial arrangement of several oxygen vacancies in the crystal corresponds to the configuration formed by noninteracting vacancies distant from each other. The oxygen vacancies in five charged states were simulated. The electron levels in the bandgap caused by charged oxygen vacancies indicate that any type of oxygen vacancies in ferroelectric Hf0.5Zr0.5O2 can capture both electrons and holes, i.e. can act as an amphoteric localization center for charge carriers. PMID- 29393853 TI - Integrative and distinctive coding of visual and conceptual object features in the ventral visual stream. AB - A significant body of research in cognitive neuroscience is aimed at understanding how object concepts are represented in the human brain. However, it remains unknown whether and where the visual and abstract conceptual features that define an object concept are integrated. We addressed this issue by comparing the neural pattern similarities among object-evoked fMRI responses with behavior-based models that independently captured the visual and conceptual similarities among these stimuli. Our results revealed evidence for distinctive coding of visual features in lateral occipital cortex, and conceptual features in the temporal pole and parahippocampal cortex. By contrast, we found evidence for integrative coding of visual and conceptual object features in perirhinal cortex. The neuroanatomical specificity of this effect was highlighted by results from a searchlight analysis. Taken together, our findings suggest that perirhinal cortex uniquely supports the representation of fully specified object concepts through the integration of their visual and conceptual features. PMID- 29393856 TI - Aerobic method for the synthesis of nearly size-monodisperse bismuth nanoparticles from a redox non-innocent precursor. AB - Herein, we report an aerobic synthesis method to produce bismuth nanoparticles (Bi NPs) with average diameters in the range 40-80 nm using commercially available bismuth triiodide (BiI3) as the starting material; the method uses only readily available chemicals and conventional laboratory equipment. Furthermore, size data from replicates of the synthesis under standard reaction conditions indicate that this method is highly reproducible in achieving Bi NP populations with low standard deviations in the mean diameters. We also investigated the mechanism of the reaction, which we determined results from the reduction of a soluble alkylammonium iodobismuthate precursor species formed in situ. Under appropriate concentration conditions of iodobismuthate anion, we demonstrate that burst nucleation of Bi NPs results from reduction of Bi3+ by the coordinated, redox non-innocent iodide ligands when a threshold temperature is exceeded. Finally, we demonstrate phase transfer and silica coating of the Bi NPs, which results in stable aqueous colloids with retention of size, morphology, and colloidal stability. The resultant, high atomic number, hydrophilic Bi NPs prepared using this synthesis method have potential for application in emerging x ray contrast and x-ray therapeutic applications. PMID- 29393857 TI - Oscillatory behavior of P wave duration and PR interval in experimental congestive heart failure: a preliminary study. AB - OBJECTIVE: The relationship between the autonomic nervous system (ANS) modulation of the sinus node and heart rate variability has been extensively investigated. The current study sought to evaluate, in an animal experimental model of pacing induced tachycardia congestive heart failure (CHF), a possible ANS influence on the P wave duration and PR interval oscillations. APPROACH: Short-term (5 min) time and frequency domain analysis has been obtained in six dogs for the following electrocardiographic intervals: P wave duration (P), from the onset to peak of P wave (P p), from the onset of P wave to the q onset (PR) and from the end of P wave to the onset of q wave (P e R). Direct vagal nerve activity (VNA), stellate ganglion nerve activity (SGNA) and electrocardiogram (ECG) intervals have been evaluated contextually by implantation of three bipolar recording leads. MAIN RESULTS: At the baseline, multiple regression analysis pointed out that VNA was strongly positively associated with the standard deviation of PP and P e R intervals (r 2:0.997, p < 0.05). The same variable was also positively associated with high-frequency (HF) of P expressed in normalized units, of P p, and of P e R (b: 0.001) (r 2: 0.993; p < 0.05). During CHF, most of the time and frequency domain variability significantly decreased from 20% to 50% in comparison to the baseline values (p < 0.05) and SGNA correlated inversely with the low frequency (LF) obtained from P e R (p < 0.05) and PR (p < 0.05) (r 2:0.899, p < 0.05). LF components, expressed in absolute and normalized power, obtained from all studied intervals, were reduced significantly during CHF. Any difference between the RR and PP spectral components was observed. SIGNIFICANCE: The data showed a significant relationship between ANS and atrial ECG variables, independent of the cycle duration. In particular, the oscillations were vagal mediated at the baseline, while sympathetic mediated during CHF. Whereas P wave variability might have a clinical utility in CHF management, it needs to be addressed in specific studies. PMID- 29393858 TI - Enhanced sensitivity in non-enzymatic glucose detection by improved growth kinetics of Ni-based nanostructures. AB - Ni-based nanostructures are attractive catalytic materials for many electrochemical applications, among which are non-enzymatic sensing, charge storage, and water splitting. In this work, we clarify the synthesis kinetics of Ni(OH)2/NiOOH nanowalls grown by chemical bath deposition at room temperature and at 50 degrees C. We applied the results to non-enzymatic glucose sensing, reaching a highest sensitivity of 31 mA cm-2mM-1. Using scanning electron microscopy, x-ray diffraction analysis and Rutherford backscattering spectrometry we found that the growth occurs through two regimes: first, a quick random growth leading to disordered sheets of Ni oxy-hydroxide, followed by a slower growth of well-aligned sheets of Ni hydroxide. A high growth temperature (50 degrees C), leading mainly to well-aligned sheets, offers superior electrochemical properties in terms of charge storage, charge carrier transport and catalytic action, as confirmed by cyclic voltammetry and electrochemical impedance spectroscopy analyses. The reported results on the optimization and application of low-cost synthesis of these Ni-based nanostructures have a large potential for application in catalysis, (bio)sensing, and supercapacitors areas. PMID- 29393859 TI - Introducing correlations into carrier transport simulations of disordered materials through seeded nucleation: impact on density of states, carrier mobility, and carrier statistics. AB - Disorder in organic semiconductors has made it challenging to achieve performance gains; this is a result of the many competing and often nuanced mechanisms effecting charge transport. In this article, we attempt to illuminate one of these mechanisms in the hopes of aiding experimentalists in exceeding current performance thresholds. Using a heuristic exponential function, energetic correlation has been added to the Gaussian disorder model (GDM). The new model is grounded in the concept that energetic correlations can arise in materials without strong dipoles or dopants, but may be a result of an incomplete crystal formation process. The proposed correlation has been used to explain the exponential tail states often observed in these materials; it is also better able to capture the carrier mobility field dependence, commonly known as the Poole Frenkel dependence, when compared to the GDM. Investigation of simulated current transients shows that the exponential tail states do not necessitate Montroll and Scher fits. Montroll and Scher fits occur in the form of two distinct power law curves that share a common constant in their exponent; they are clearly observed as linear lines when the current transient is plotted using a log-log scale. Typically, these fits have been found appropriate for describing amorphous silicon and other disordered materials which display exponential tail states. Furthermore, we observe the proposed correlation function leads to domains of energetically similar sites separated by boundaries where the site energies exhibit stochastic deviation. These boundary sites are found to be the source of the extended exponential tail states, and are responsible for high charge visitation frequency, which may be associated with the molecular turnover number and ultimately the material stability. PMID- 29393860 TI - Water at surfaces with tunable surface chemistries. AB - Aqueous interfaces are ubiquitous in natural environments, spanning atmospheric, geological, oceanographic, and biological systems, as well as in technical applications, such as fuel cells and membrane filtration. Where liquid water terminates at a surface, an interfacial region is formed, which exhibits distinct properties from the bulk aqueous phase. The unique properties of water are governed by the hydrogen-bonded network. The chemical and physical properties of the surface dictate the boundary conditions of the bulk hydrogen-bonded network and thus the interfacial properties of the water and any molecules in that region. Understanding the properties of interfacial water requires systematically characterizing the structure and dynamics of interfacial water as a function of the surface chemistry. In this review, we focus on the use of experimental surface-specific spectroscopic methods to understand the properties of interfacial water as a function of surface chemistry. Investigations of the air water interface, as well as efforts in tuning the properties of the air-water interface by adding solutes or surfactants, are briefly discussed. Buried aqueous interfaces can be accessed with careful selection of spectroscopic technique and sample configuration, further expanding the range of chemical environments that can be probed, including solid inorganic materials, polymers, and water immiscible liquids. Solid substrates can be finely tuned by functionalization with self-assembled monolayers, polymers, or biomolecules. These variables provide a platform for systematically tuning the chemical nature of the interface and examining the resulting water structure. Finally, time-resolved methods to probe the dynamics of interfacial water are briefly summarized before discussing the current status and future directions in studying the structure and dynamics of interfacial water. PMID- 29393861 TI - Immunotherapy: A New Strategy for the Treatment of Cervical Cancer. Interview with Dr. Christian Marth and Dr. Sharad Ghamande. AB - At the European Gynecological Oncology Congress (ESGO) 2017, held in Vienna, a symposium on immunotherapy took place: A New Strategy for the Treatment of Cervical Cancer, sponsored by Advaxis, Inc. PMID- 29393862 TI - On-Line Temperature Estimation for Noisy Thermal Sensors Using a Smoothing Filter Based Kalman Predictor. AB - Dynamic thermal management (DTM) mechanisms utilize embedded thermal sensors to collect fine-grained temperature information for monitoring the real-time thermal behavior of multi-core processors. However, embedded thermal sensors are very susceptible to a variety of sources of noise, including environmental uncertainty and process variation. This causes the discrepancies between actual temperatures and those observed by on-chip thermal sensors, which seriously affect the efficiency of DTM. In this paper, a smoothing filter-based Kalman prediction technique is proposed to accurately estimate the temperatures from noisy sensor readings. For the multi-sensor estimation scenario, the spatial correlations among different sensor locations are exploited. On this basis, a multi-sensor synergistic calibration algorithm (known as MSSCA) is proposed to improve the simultaneous prediction accuracy of multiple sensors. Moreover, an infrared imaging-based temperature measurement technique is also proposed to capture the thermal traces of an advanced micro devices (AMD) quad-core processor in real time. The acquired real temperature data are used to evaluate our prediction performance. Simulation shows that the proposed synergistic calibration scheme can reduce the root-mean-square error (RMSE) by 1.2 ? C and increase the signal to-noise ratio (SNR) by 15.8 dB (with a very small average runtime overhead) compared with assuming the thermal sensor readings to be ideal. Additionally, the average false alarm rate (FAR) of the corrected sensor temperature readings can be reduced by 28.6%. These results clearly demonstrate that if our approach is used to perform temperature estimation, the response mechanisms of DTM can be triggered to adjust the voltages, frequencies, and cooling fan speeds at more appropriate times. PMID- 29393863 TI - Risk Factors for Obesity and Overfat among Primary School Children in Mashonaland West Province, Zimbabwe. AB - Associated childhood obesity risk factors are not well established in developing countries such as Zimbabwe and this information is essential for tailored intervention development. This study aimed to identify prominent risk factors for overweight/obese and overfat/obese among primary school children of Mashonaland West Province in Zimbabwe. A school-based cross-sectional study was conducted using multi-stage random cluster sampling approach (30 * 30). Bivariate and multivariable logistic regression was employed and identified the risk factors for overweight/obese and overfat/obese. A total of 974 participants were enrolled in the study. Prominent significant risk factors of overweight/obese after multivariable adjustment were higher socio-economic households; parental diabetes status; and living in Makonde, Zvimba, Sanyati or Mhondoro-Ngezi district as opposed to Hurungwe district. Risk factors for overfat/obese that remained statically significant were children in urban areas (aOR = 3.19, 95% CI: 2.18 4.66, p = 0.000), being one child in a household, and parents who have diabetes mellitus. Living in Makonde, Sanyati, and Zvimba district remained associated with overfat/obese compared to Hurungwe district. This study has identified prominent proximal determinants of overweight/obese and overfat/obese among primary school children in Zimbabwe, to better assist policy guidance. Aggressive education on good nutrition activities should be tailored and targeted to most affected urban areas within high-risk districts. PMID- 29393864 TI - Sex Steroid-Mediated Control of Oviductal Function in Cattle. AB - In cattle, the oviduct is a tubular organ that connects the ovary and the uterus. The oviduct lumen stages a dynamic set of cellular and molecular interactions to fulfill the noble role of generating a new individual. Specific anatomical niches along the oviduct lumen provide the appropriate microenvironment for final sperm capacitation, oocyte capture and fertilization, and early embryo development and transport. To accomplish such complex tasks, the oviduct undergoes spatially and temporally-regulated morphological, biochemical, and physiological changes that are associated with endocrine events of the estrous cycle. Specifically, elevated periovulatory concentrations of estradiol (E2) and progesterone (P4) influence gene expression and morphological changes that have been associated positively to fertility in beef cattle. In this review, we explore how E2 and P4 influence oviductal function in the beginning of the estrous cycle, and prepare the oviductal lumen for interactions with gametes and embryos. PMID- 29393865 TI - Antioxidant Activity of Zein Hydrolysates from Zea Species and Their Cytotoxic Effects in a Hepatic Cell Culture. AB - In recent years, food proteins with bioactivity have been studied for cancer treatment. Zein peptides have shown an important set of bioactivities. This work compares the cytotoxic activity of zein hydrolyzed, extracted from four Zea species: teosinte, native, hybrid, and transgenic (Teo, Nat, Hyb, and HT) in a hepatic cell culture. Zein fraction was extracted, quantified, and hydrolyzed. Antioxidant capacity and cytotoxicity assays were performed on HepG2 cells. The levels of expression of caspase 3, 8, and 9 were evaluated in zein-treated cell cultures. Zea parviglumis showed the highest zein content (46.0 mg/g) and antioxidant activity (673.40 TE/g) out of all native zeins. Peptides from Hyb and HT showed high antioxidant activity compared to their native counterparts (1055.45 and 724.32 TE/g, respectively). Cytotoxic activity was observed in the cell culture using peptides of the four Zea species; Teo and Nat (IC50: 1781.63 and 1546.23 ng/mL) had no significant difference between them but showed more cytotoxic activity than Hyb and HT (IC50: 1252.25 and 1155.56 ng/mL). Increased expression of caspase 3 was observed in the peptide-treated HepG2 cells (at least two-fold more with respect to the control sample). These data indicate the potential for zein peptides to prevent or treat cancer, possibly by apoptosis induction. PMID- 29393866 TI - Similarities and Differences between Silver Ions and Silver in Nanoforms as Antibacterial Agents. AB - Silver is considered as antibacterial agent with well-known mode of action and bacterial resistance against it is well described. The development of nanotechnology provided different methods for the modification of the chemical and physical structure of silver, which may increase its antibacterial potential. The physico-chemical properties of silver nanoparticles and their interaction with living cells differs substantially from those of silver ions. Moreover, the variety of the forms and characteristics of various silver nanoparticles are also responsible for differences in their antibacterial mode of action and probably bacterial mechanism of resistance. The paper discusses in details the aforementioned aspects of silver activity. PMID- 29393867 TI - Tulbaghia violacea and Allium ursinum Extracts Exhibit Anti-Parasitic and Antimicrobial Activities. AB - Garlic has played an important role in culinary arts and remedies in the traditional medicine throughout human history. Parasitic infections represent a burden in the society of especially poor countries, causing more than 1 billion infections every year and leading to around one million deaths. In this study, we investigated the mode of anti-parasitic activity of "wild garlics" Tulbaghia violacea and Allium ursinum dichloromethane extracts against parasites Trypanosoma brucei brucei and Leishmania tarentolae with regard to their already known antimicrobial activity. We also evaluated their cytotoxic potential against human cells. Both extracts showed a relevant trypanocidal and leishmanicidal activity, although L. tarentolae was less sensitive. We determined that the probable mode of action of both extracts is the irreversible inhibition of the activity of Trypanosoma brucei trypanothione reductase enzyme. The extracts showed a mild cytotoxic activity against human keratinocytes. They also exhibited weak-in most cases comparable-antibacterial and antifungal activity. HPLC-MS/MS analysis showed that both extracts are abundant in sulfur compounds. Thus, for the first time, the ability of Allium ursinum and Tulbaghia violacea to kill Trypanosoma sp. and Leishmania sp. parasites, probably by binding to and inactivating sulfur-containing compounds essential for the survival of the parasite, is shown. PMID- 29393869 TI - Using Twitter to Better Understand the Spatiotemporal Patterns of Public Sentiment: A Case Study in Massachusetts, USA. AB - Twitter provides a rich database of spatiotemporal information about users who broadcast their real-time opinions, sentiment, and activities. In this paper, we sought to investigate the holistic influence of land use and time period on public sentiment. A total of 880,937 tweets posted by 26,060 active users were collected across Massachusetts (MA), USA, through 31 November 2012 to 3 June 2013. The IBM Watson Alchemy API (application program interface) was employed to quantify the sentiment scores conveyed by tweets on a large scale. Then we statistically analyzed the sentiment scores across different spaces and times. A multivariate linear mixed-effects model was used to quantify the fixed effects of land use and the time period on the variations in sentiment scores, considering the clustering effect of users. The results exposed clear spatiotemporal patterns of users' sentiment. Higher sentiment scores were mainly observed in the commercial and public areas, during the noon/evening and on weekends. Our findings suggest that social media outputs can be used to better understand the spatial and temporal patterns of public happiness and well-being in cities and regions. PMID- 29393868 TI - Galectin-3: The Impact on the Clinical Management of Patients with Thyroid Nodules and Future Perspectives. AB - Galectins (S-type lectins) are an evolutionarily-conserved family of lectin molecules, which can be expressed intracellularly and in the extracellular matrix, as well. Galectins bind beta-galactose-containing glycoconjugates and are functionally active in converting glycan-related information into cell biological programs. Altered glycosylation notably occurring in cancer cells and expression of specific galectins provide, indeed, a fashionable mechanism of molecular interactions able to regulate several tumor relevant functions, among which are cell adhesion and migration, cell differentiation, gene transcription and RNA splicing, cell cycle and apoptosis. Furthermore, several galectin molecules also play a role in regulating the immune response. These functions are strongly dependent on the cell context, in which specific galectins and related glyco ligands are expressed. Thyroid cancer likely represents the paradigmatic tumor model in which experimental studies on galectins' glycobiology, in particular on galectin-3 expression and function, contributed greatly to the improvement of cancer diagnosis. The discovery of a restricted expression of galectin-3 in well differentiated thyroid carcinomas (WDTC), compared to normal and benign thyroid conditions, contributed also to promoting preclinical studies aimed at exploring new strategies for imaging thyroid cancer in vivo based on galectin-3 immuno targeting. Results derived from these recent experimental studies promise a further improvement of both thyroid cancer diagnosis and therapy in the near future. In this review, the biological role of galectin-3 expression in thyroid cancer, the validation and translation to a clinical setting of a galectin-3 test method for the preoperative characterization of thyroid nodules and a galectin-3 based immuno-positron emission tomography (immuno-PET) imaging of thyroid cancer in vivo are presented and discussed. PMID- 29393870 TI - Radiation Resistance of the U(Al, Si)3 Alloy: Ion-Induced Disordering. AB - During the exploitation of nuclear reactors, various U-Al based ternary intermetallides are formed in the fuel-cladding interaction layer. Structure and physical properties of these intermetallides determine the radiation resistance of cladding and, ultimately, the reliability and lifetime of the nuclear reactor. In current research, U(Al, Si)3 composition was studied as a potential constituent of an interaction layer. Phase content of the alloy of an interest was ordered U(Al, Si)3, structure of which was reported earlier, and pure Al (constituting less than 20 vol % of the alloy). This alloy was investigated prior and after the irradiation performed by Ar ions at 30 keV. The irradiation was performed on the transmission electron microscopy (TEM, JEOL, Japan) samples, characterized before and after the irradiation process. Irradiation induced disorder accompanied by stress relief. Furthermore, it was found that there is a dose threshold for disordering of the crystalline matter in the irradiated region. Irradiation at doses equal or higher than this threshold resulted in almost solely disordered phase. Using the program "Stopping and Range of Ions in Matter" (SRIM), the parameters of penetration of Ar ions into the irradiated samples were estimated. Based on these estimations, the dose threshold for ion induced disordering of the studied material was assessed. PMID- 29393871 TI - Combination Treatment of Deep Sea Water and Fucoidan Attenuates High Glucose Induced Insulin-Resistance in HepG2 Hepatocytes. AB - Insulin resistance (IR) plays a central role in the development of several metabolic diseases, which leads to increased morbidity and mortality rates, in addition to soaring health-care costs. Deep sea water (DSW) and fucoidans (FPS) have drawn much attention in recent years because of their potential medical and pharmaceutical applications. This study investigated the effects and mechanisms of combination treatment of DSW and FPS in improving IR in HepG2 hepatocytes induced by a high glucose concentration. The results elucidated that co-treatment with DSW and FPS could synergistically repress hepatic glucose production and increase the glycogen level in IR-HepG2 cells. In addition, they stimulated the phosphorylation levels of the components of the insulin signaling pathway, including tyrosine phosphorylation of IRS-1, and serine phosphorylation of Akt and GSK-3beta. Furthermore, they increased the phosphorylation of AMPK and ACC, which in turn decreased the intracellular triglyceride level. Taken together, these results suggested that co-treatment with DSW and FPS had a greater improving effect than DSW or FPS alone on IR. They might attenuate IR by targeting Akt/GSK-3beta and AMPK pathways. These results may have some implications in the treatment of metabolic diseases. PMID- 29393872 TI - Lipase-Catalyzed Acidolysis of Egg-Yolk Phosphatidylcholine with Citronellic Acid. New Insight into Synthesis of Isoprenoid-Phospholipids. AB - The development of a biotechnological method for the production of new biologically active phosphatidylcholine containing monoterpene citronellic acid (CA) was the aim of this work. Incorporation of citronellic acid (CA) into egg yolk phosphatidylcholine (PC) in the lipase-catalyzed acidolysis process was studied. Isoprenoid acid CA was used as an acyl donor and five commercially available immobilized lipases were examined as biocatalysts. The effects of organic solvent, enzyme load, reaction time and molar ratio of substrates on the incorporation of citronellic acid (CA) into the phospholipids were evaluated. Modified phospholipid fraction enriched with CA in the sn-1 position (39% of incorporation) was obtained in high 33% yield using Novozym 435 as biocatalyst. In this study a biotechnological method for production of new phospholipid biopreparation enriched with citronellic acid, which can play an important role as a nutraceutical, was applied. PMID- 29393873 TI - Nine New Gingerols from the Rhizoma of Zingiber officinale and Their Cytotoxic Activities. AB - Nine new gingerols, including three 6-oxo-shogaol derivatives [(Z)-6-oxo-[6] shogaol (1), (Z)-6-oxo-[8]-shogaol (2), (Z)-6-oxo-[10]-shogaol (3)], one 6 oxoparadol derivative [6-oxo-[6]-paradol (4)], one isoshogaol derivative [(E)-[4] isoshogaol (5)], and four paradoldiene derivatives [(4E,6Z)-[4]-paradoldiene (8), (4E,6E)-[6]-paradoldiene (9), (4E,6E)-[8]-paradoldiene (10), (4E,6Z)-[8] paradoldiene (11)], together with eight known analogues, were isolated from the rhizoma of Zingiber officinale. Their structures were elucidated on the basis of spectroscopic data. It was noted that the isolation of 6-oxo-shogaol derivatives represents the first report of gingerols containing one 1,4-enedione motif. Their structures were elucidated on the basis of spectroscopic and HRESIMS data. All the new compounds were evaluated for their cytotoxic activities against human cancer cells (MCF-7, HepG-2, KYSE-150). PMID- 29393874 TI - Efficacy of Octacalcium Phosphate Collagen Composite for Titanium Dental Implants in Dogs. AB - BACKGROUND: Previous studies showed that octacalcium (OCP) collagen composite (OCP/Col) can be used to repair human jaw bone defects without any associated abnormalities. The present study investigated whether OCP/Col could be applied to dental implant treatment using a dog tooth extraction socket model. METHODS: The premolars of dogs were extracted; each extraction socket was extended, and titanium dental implants were placed in each socket. OCP/Col was inserted in the space around a titanium dental implant. Autologous bone was used to fill the other sockets, while the untreated socket (i.e., no bone substitute material) served as a control. Three months after the operation, these specimens were analyzed for the osseointegration of each bone substitute material with the surface of the titanium dental implant. RESULTS: In histomorphometric analyses, the peri-implant bone areas (BA%) and bone-implant contact (BIC%) were measured. There was no difference in BA% or BIC% between OCP/Col and autologous bone. CONCLUSION: These results suggested that OCP/Col could be used for implant treatment as a bone substitute. PMID- 29393875 TI - Professional Well-Being of Practicing Physicians: The Roles of Autonomy, Competence, and Relatedness. AB - This study investigated the roles of basic psychological needs-autonomy, competence, and relatedness-in physicians' professional well-being, specifically satisfaction with professional life, work-related engagement, and exhaustion. Using an online survey, quantitative data were collected from 57 practicing physicians. Overall, 65% of the participants were female; 49% were family medicine (FM) physicians, with the rest of the participants practicing in various non-FM specialties (e.g., internal medicine, pediatrics, surgery); and 47% were in the early-career stage (<=10 years in practice). Multivariate regression analyses indicated that of the three psychological needs, the need for relatedness had the largest unique contributions to physicians' satisfaction with professional life, work-related engagement, and exhaustion, respectively. The unique contributions of the needs for autonomy and competence were relatively small. These findings extend basic psychological needs theory to the work domain of practicing physicians in an attempt to examine underpinnings of physicians' professional well-being, a critical component of quality patient care. PMID- 29393876 TI - La-CTP: Loop-Aware Routing for Energy-Harvesting Wireless Sensor Networks. AB - In emerging energy-harvesting wireless sensor networks (EH-WSN), the sensor nodes can harvest environmental energy to drive their operation, releasing the user's burden in terms of frequent battery replacement, and even enabling perpetual sensing systems. In EH-WSN applications, usually, the node in energy-harvesting or recharging state has to stop working until it completes the energy replenishment. However, such temporary departures of recharging nodes severely impact the packet routing, and one immediate result is the routing loop problem. Controlling loops in connectivity-intermittent EH-WSN in an efficient way is a big challenge in practice, and so far, users still lack of effective and practicable routing protocols with loop handling. Based on the Collection Tree Protocol (CTP) widely used in traditional wireless sensor networks, this paper proposes a loop-aware routing protocol for real-world EH-WSNs, called La-CTP, which involves a new parent updating metric and a proactive, adaptive beaconing scheme to effectively suppress the occurrence of loops and unlock unavoidable loops, respectively. We constructed a 100-node testbed to evaluate La-CTP, and the experimental results showed its efficacy and efficiency. PMID- 29393877 TI - Molecularly Imprinted Polymers as Extracting Media for the Chromatographic Determination of Antibiotics in Milk. AB - Milk-producing animals are typically kept stationary in overcrowded large-scale farms and in most cases under unsanitary conditions, which promotes the development of infections. In order to maintain sufficient health status among the herd or promote growth and increase production, farmers administer preventative antibiotic doses to the animals through their feed. However, many antibiotics used in cattle farms are intended for the treatment of bacterial infections in humans. This results in the development of antibiotic-resistant bacteria which pose a great risk for public health. Additionally, antibiotic residues are found in milk and dairy products, with potential toxic effects for the consumers. Hence the need of antibiotic residues monitoring in milk arises. Analytical methods were developed for the determination of antibiotics in milk, with key priority given to the analyte extraction and preconcentration step. Extraction can benefit from the production of molecularly imprinted polymers (MIPs) that can be applied as sorbents for the extraction of specific antibiotics. This review focuses on the principals of molecular imprinting technology and synthesis methods of MIPs, as well as the application of MIPs and MIPs composites for the chromatographic determination of various antibiotic categories in milk found in the recent literature. PMID- 29393878 TI - MicroRNA-125a-5p Mediates 3T3-L1 Preadipocyte Proliferation and Differentiation. AB - Excessive accumulation of adipose tissue is a main cause of obesity or overweight, which is significantly involved in increasing the risk of diseases. Recently, numerous studies have proved that microRNAs (miRNAs) play important roles in adipogenesis by negatively regulating gene expression at posttranscriptional levels. In this study, we showed that miR-125a-5p was expressed at lower levels in the adipose tissues of high-fat diet (HFD)-fed mice than the normal chow (NCW)-fed mice. MiR-125a-5p expression were strongly up regulated by nearly five-fold, when 3T3-L1 preadipocyte were induced and differentiated into mature adipocytes. Functional analysis indicated that overexpression of miR-125a-5p promoted 3T3-L1 preadipocyte proliferation and inhibited its differentiation. By contrast, inhibition of miR-125a-5p repressed 3T3-L1 preadipocyte proliferation and accelerated its differentiation. Furthermore, a dual-luciferase reporter assay demonstrated that signal transducer and activator of transcription 3 (STAT3) is a direct target gene of miR-125a-5p during 3T3-L1 preadipocyte differentiation. Further analysis confirmed that the process of miR-125a-5p inhibiting 3T3-L1 preadipocyte differentiation might be associated with the regulation of fatty acid metabolism related genes. Taken together, our results indicated that miR-125a-5p might promote 3T3-L1 preadipocyte proliferation, whereas inhibiting 3T3-L1 preadipocyte differentiation by negatively regulating STAT3. PMID- 29393879 TI - Graphene-Derivatized Silica Composite as Solid-Phase Extraction Sorbent Combined with GC-MS/MS for the Determination of Polycyclic Musks in Aqueous Samples. AB - Polycyclic musks (PCMs) have recently received growing attention as emerging contaminants because of their bioaccumulation and potential ecotoxicological effects. Herein, an effective method for the determination of five PCMs in aqueous samples is presented. Reduced graphene oxide-derivatized silica (rGO@silica) particles were prepared from graphene oxide and aminosilica microparticles and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. PCMs were preconcentrated using rGO@silica as the solid-phase extraction sorbent and quantified by gas chromatography-tandem mass spectrometry. Several experimental parameters, such as eluent, elution volume, sorbent amount, pH, and sample volume were optimized. The correlation coefficient (R) ranged from 0.9958 to 0.9992, while the limits of detection and quantitation for the five PCMs were 0.3-0.8 ng/L and 1.1-2.1 ng/L, respectively. Satisfactory recoveries were obtained for tap water (86.6-105.9%) and river water samples (82.9-107.1%), with relative standard deviations <10% under optimal conditions. The developed method was applied to analyze PCMs in tap and river water samples from Beijing, China. Galaxolide (HHCB) and tonalide (AHTN) were the main PCM components detected in one river water sample at concentrations of 18.7 for HHCB, and 11.7 ng/L for AHTN. PMID- 29393881 TI - The Role of Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia. AB - BACKGROUND: vulvar intraepithelial neoplasia is a non-invasive precursor lesion found in 50-70% of patients affected by vulvar squamous cell carcinoma. In the past, radical surgery was the standard treatment for vulvar intraepithelial neoplasia, however, considering the psychological and physical morbidities related to extensive surgery, several less aggressive treatment modalities have been proposed since the late 1970s. Photodynamic therapy is an effective and safe treatment for cutaneous non-melanoma skin cancer, with favorable cosmetic outcomes. METHODS: in the present paper, the results of selected studies on photodynamic therapy in the treatment of vulvar intraepithelial neoplasia are reported and discussed. RESULTS: Overall, complete histological response rates ranged between 20% and 67% and symptom response rates ranged between 52% and 89% according to different studies and case series. CONCLUSIONS: the real benefit of photodynamic therapy in the setting of vulvar intraepithelial neoplasia lies in its ability to treat multi-focal disease with minimal tissue destruction, preservation of vulvar anatomy and excellent cosmetic outcomes. These properties explain why photodynamic therapy is an attractive option for vulvar intraepithelial neoplasia treatment. PMID- 29393882 TI - Nutritional Value, Chemical Characterization and Bulb Morphology of Greek Garlic Landraces. AB - Garlic (Allium sativum L.) is an important vegetable crop throughout the world. In Greece there are many areas which have specialized in garlic cultivation through the last decades, considered the main production areas. However, despite the significance of garlic as a food product and the high annual income of this crop, there is a decreasing trend in total cultivated area in Greece, and the local landraces are gradually neglected in favor of new imported genotypes. In the present study, garlic genotypes (local landraces/varieties, imported genotypes, commercial cultivars) from the main production regions of Greece were assessed for their chemical composition and quality (total soluble solids, dry matter content, nutritional value, mineral composition, organic acids, fatty acids content and free sugars content), and bulb morphology. The results of the present study showed significant diversity in quality features and bulb morphology, not only between the genotypes from different growing regions, but also between those of the same region. This result is interesting since it could be implemented for further improvement and valorization of this important vegetable crop through extensive breeding programs within the framework of sustainability and genetic, material conservation. PMID- 29393883 TI - Relationship between the Polymeric Ionization Degree and Powder and Surface Properties in Materials Derived from Poly(maleic anhydride-alt-octadecene). AB - Polymeric materials derived from poly(maleic anhydride-alt-octadecene)-here referred as PAM-18-have shown interesting properties that make them potential pharmaceutical excipients. In this work, eight polymers derived from PAM-18 were obtained using NaOH and KOH at 1:1; 1:0.75, 1:0.5, and 1:0.25 molar ratios. The resulting products were labeled as PAM-18Na and PAM-18K, respectively. Each polymer was purified by ultrafiltration/lyophilization, and the ionization degree was determined by potentiometric studies, which was related to the zeta potential. The structural characterization was performed using the Fourier transform infrared (FT-IR) espectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD) techniques. The physical characterization was carried out by SEM, particle analysis, and humidity loss and gain studies; the surface studies were performed by the sessile drop method. PAM-18Na had ionization degrees of 95%, 63%, 39% and 22%, whereas those for PAM-18K were 99%, 52%, 35% and 20%, respectively. The results also showed that for higher inorganic base amounts used, the polymeric materials obtained possess high ionization degrees, which could form polymeric solutions or hetero-dispersed systems. Likewise, it was observed that for higher proportions of carboxylate groups in the polymeric structure, the capability to retain water is increased and, only can be eliminated by drying at temperatures greater than 160 degrees C. On the other hand, the modification of PAM-18 to its ionized forms led to the formation of powder materials with low flowability and surfaces that ranged from very hydrophobic to slightly wettable. PMID- 29393884 TI - Optimized Sensor Network and Multi-Agent Decision Support for Smart Traffic Light Management. AB - One of the biggest challenges in modern societies is to solve vehicular traffic problems. Sensor networks in traffic environments have contributed to improving the decision-making process of Intelligent Transportation Systems. However, one of the limiting factors for the effectiveness of these systems is in the deployment of sensors to provide accurate information about the traffic. Our proposal is using the centrality measurement of a graph as a base to locate the best locations for sensor installation in a traffic network. After integrating these sensors in a simulation scenario, we define a Multi-Agent Systems composed of three types of agents: traffic light management agents, traffic jam detection agents, and agents that control the traffic lights at an intersection. The ultimate goal of these Multi-Agent Systems is to improve the trip duration for vehicles in the network. To validate our solution, we have developed the needed elements for modelling the sensors and agents in the simulation environment. We have carried out experiments using the Simulation of Urban MObility (SUMO) traffic simulator and the Travel and Activity PAtterns Simulation (TAPAS) Cologne traffic scenario. The obtained results show that our proposal allows to reduce the sensor network while still obtaining relevant information to have a global view of the environment. Finally, regarding the Multi-Agent Systems, we have carried out experiments that show that our proposal is able to improve other existing solutions such as conventional traffic light management systems (static or dynamic) in terms of reduction of vehicle trip duration and reduction of the message exchange overhead in the sensor network. PMID- 29393880 TI - Temporomandibular Joint Regenerative Medicine. AB - The temporomandibular joint (TMJ) is an articulation formed between the temporal bone and the mandibular condyle which is commonly affected. These affections are often so painful during fundamental oral activities that patients have lower quality of life. Limitations of therapeutics for severe TMJ diseases have led to increased interest in regenerative strategies combining stem cells, implantable scaffolds and well-targeting bioactive molecules. To succeed in functional and structural regeneration of TMJ is very challenging. Innovative strategies and biomaterials are absolutely crucial because TMJ can be considered as one of the most difficult tissues to regenerate due to its limited healing capacity, its unique histological and structural properties and the necessity for long-term prevention of its ossified or fibrous adhesions. The ideal approach for TMJ regeneration is a unique scaffold functionalized with an osteochondral molecular gradient containing a single stem cell population able to undergo osteogenic and chondrogenic differentiation such as BMSCs, ADSCs or DPSCs. The key for this complex regeneration is the functionalization with active molecules such as IGF 1, TGF-beta1 or bFGF. This regeneration can be optimized by nano/micro-assisted functionalization and by spatiotemporal drug delivery systems orchestrating the 3D formation of TMJ tissues. PMID- 29393885 TI - Virus-Bacteria Interactions: Implications and Potential for the Applied and Agricultural Sciences. AB - Eukaryotic virus-bacteria interactions have recently become an emerging topic of study due to multiple significant examples related to human pathogens of clinical interest. However, such omnipresent and likely important interactions for viruses and bacteria relevant to the applied and agricultural sciences have not been reviewed or compiled. The fundamental basis of this review is that these interactions have importance and deserve more investigation, as numerous potential consequences and applications arising from their discovery are relevant to the applied sciences. The purpose of this review is to highlight and summarize eukaryotic virus-bacteria findings in the food/water, horticultural, and animal sciences. In many cases in the agricultural sciences, mechanistic understandings of the effects of virus-bacteria interactions remain unstudied, and many studies solely focus on co-infections of bacterial and viral pathogens. Given recent findings relative to human viral pathogens, further research related to virus bacteria interactions would likely result in numerous discoveries and beneficial applications. PMID- 29393887 TI - A Real-Time Construction Safety Monitoring System for Hazardous Gas Integrating Wireless Sensor Network and Building Information Modeling Technologies. AB - In recent years, many studies have focused on the application of advanced technology as a way to improve management of construction safety management. A Wireless Sensor Network (WSN), one of the key technologies in Internet of Things (IoT) development, enables objects and devices to sense and communicate environmental conditions; Building Information Modeling (BIM), a revolutionary technology in construction, integrates database and geometry into a digital model which provides a visualized way in all construction lifecycle management. This paper integrates BIM and WSN into a unique system which enables the construction site to visually monitor the safety status via a spatial, colored interface and remove any hazardous gas automatically. Many wireless sensor nodes were placed on an underground construction site and to collect hazardous gas level and environmental condition (temperature and humidity) data, and in any region where an abnormal status is detected, the BIM model will alert the region and an alarm and ventilator on site will start automatically for warning and removing the hazard. The proposed system can greatly enhance the efficiency in construction safety management and provide an important reference information in rescue tasks. Finally, a case study demonstrates the applicability of the proposed system and the practical benefits, limitations, conclusions, and suggestions are summarized for further applications. PMID- 29393886 TI - Apoptosis: A Target for Anticancer Therapy. AB - Apoptosis, the cell's natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression of antiapoptotic proteins and under-expression of proapoptotic proteins. Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway. PMID- 29393888 TI - Bringing the next Generation of Immuno-Oncology Biomarkers to the Clinic. AB - The recent successes in the use of immunotherapy to treat cancer have led to a multiplicity of new compounds in development. Novel clinical-grade biomarkers are needed to guide the choice of these agents to obtain the maximal likelihood of patient benefit. Predictive biomarkers for immunotherapy differ from the traditional biomarkers used for targeted therapies: the complexity of the immune response and tumour biology requires a more holistic approach than the use of a single analyte biomarker. This paper reviews novel biomarker approaches for the effective development of immune-oncology therapies, highlighting the promise of the advances in next-generation gene expression profiling that allow biologic information to be efficiently organized and interpreted for a maximum predictive value at the individual patient level. PMID- 29393889 TI - Black Border Increases Stomoxys calcitrans Catch on White Sticky Traps. AB - Stable fly, Stomoxys calcitrans, is a biting fly that can cause severe irritation to livestock resulting in reduced productivity. The most common method of monitoring S. calcitrans is through the use of sticky traps and many designs have been developed using different colours and materials such as alsynite fibreglass and polypropylene sheeting. Laboratory experiments and some field experimentation have demonstrated that colour contrast can attract S. calcitrans. However, this response has not been fully utilised in trap design. To test that simple colour contrast could increase trap efficacy, white sticky traps were mounted on three differently coloured backgrounds (white, yellow, and black) and positioned at five sites on a mixed livestock farm. White sticky traps on a black background caught significantly more S. calcitrans than the yellow or white backgrounds. An incidental result was that Pollenia sp. were caught in greater numbers on the yellow framed traps. The reasons for S. calcitrans attraction to black-white contrast are most likely due to conspicuousness in the environment although the extent to which flies are using this feature as a host-location cue or a perching site are unknown. PMID- 29393891 TI - Luteolin Inhibits Tumorigenesis and Induces Apoptosis of Non-Small Cell Lung Cancer Cells via Regulation of MicroRNA-34a-5p. AB - Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated the anti tumor effects of LTL on NSCLC in vitro and in vivo. The results revealed that LTL could inhibit cell proliferation and induce apoptosis in both A549 and H460 cells. In a H460 xenograft tumor model of nude mice, LTL significantly suppressed tumor growth, inhibited cell proliferation, and induced apoptosis. miRNA microarray and quantitative PCR (qPCR) analysis indicated that miR-34a-5p was dramatically upregulated upon LTL treatment in tumor tissues. Furthermore, MDM4 was proved to be a direct target of miR-34a-5p by luciferase reporter gene assay. LTL treatment was associated with increased p53 and p21 protein expressions and decreased MDM4 protein expression in both NSCLC cells and tumor tissues. When miR 34a-5p was inhibited in vitro, the protein expressions of Bcl-2 and MDM4 were recovered, while that of p53, p21, and Bax were attenuated. Moreover, caspase-3 and caspase-9 activation induced by LHL treatment in vitro were also suppressed by miR-34a-5p inhibition. Overall, LTL could inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p via targeting MDM4. These findings provide novel insight into the molecular functions of LTL that suggest its potential as a therapeutic agent for human NSCLC. PMID- 29393892 TI - Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain. AB - Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 uM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold. The reverse mutant R800D at the corresponding position in Nav1.5 greatly increased its binding affinity to JZTX 34. This implies that JZTX-34 binds to DIIS3-S4 linker of Nav1.7 and the critical residue of Nav1.7 is D816. Unlike beta-scorpion toxin trapping sodium channel in an open state, activity of JZTX-34 requires the sodium channel to be in a resting state. JZTX-34 exhibits an obvious analgesic effect in a rodent pain model. Especially, it shows a longer duration and is more effective than morphine in hot pain models. In a formalin-induced pain model, JZTX-34 at dose of 2 mg/kg is equipotent with morphine (5 mg/kg) in the first phase and several-fold more effective than morphine in second phase. Taken together, our data indicate that JZTX-34 releases pain by selectively binding to the domain II voltage sensor of Nav1.7 in a closed configuration. PMID- 29393890 TI - Alternative Erythropoietin Receptors in the Nervous System. AB - In addition to its regulatory function in the formation of red blood cells (erythropoiesis) in vertebrates, Erythropoietin (Epo) contributes to beneficial functions in a variety of non-hematopoietic tissues including the nervous system. Epo protects cells from apoptosis, reduces inflammatory responses and supports re establishment of compromised functions by stimulating proliferation, migration and differentiation to compensate for lost or injured cells. Similar neuroprotective and regenerative functions of Epo have been described in the nervous systems of both vertebrates and invertebrates, indicating that tissue protective Epo-like signaling has evolved prior to its erythropoietic function in the vertebrate lineage. Epo mediates its erythropoietic function through a homodimeric Epo receptor (EpoR) that is also widely expressed in the nervous system. However, identification of neuroprotective but non-erythropoietic Epo splice variants and Epo derivatives indicated the existence of other types of Epo receptors. In this review, we summarize evidence for potential Epo receptors that might mediate Epo's tissue-protective function in non-hematopoietic tissue, with focus on the nervous system. In particular, besides EpoR, we discuss three other potential neuroprotective Epo receptors: (1) a heteroreceptor consisting of EpoR and common beta receptor (betacR), (2) the Ephrin (Eph) B4 receptor and (3) the human orphan cytokine receptor-like factor 3 (CRLF3). PMID- 29393893 TI - Characterization of Essential Oils Obtained from Abruzzo Autochthonous Plants: Antioxidant and Antimicrobial Activities Assessment for Food Application. AB - In the present study, the essential oils (EOs) of some officinal plants from Abruzzo territory (Italy) were evaluated for their antimicrobial and antioxidant activities and their volatile fraction chemical characterization. The EOs were extracted from Rosmarinus officinalis, Origanum vulgare, Salvia officinalis, Mentha piperita, Allium sativum, Foeniculum vulgare, Satureja montana, Thymus vulgaris and Coriandrum sativum seeds. The antimicrobial activity was screened against thirteen Gram-positive and Gram-negative strains to determine the Minimal Inhibitory Concentration (MIC). The total phenolic content (TPC) and the antioxidant capacity (AOC) were assessed by means of Folin-Ciocalteu method, and Trolox Equivalent Antioxidant Capacity with 2,2'-azinobis-(3-ethylbenzothiazoline 6-sulfonic acid (TEAC/ABTS), Ferric Reducing Antioxidant Power (FRAP) and 2,2 diphenyl-1-picrylhydrazyl (DPPH) assays respectively. Among the nine EOs tested, T. vulgaris, S. montana, O. vulgare and C. sativum EOs showed MIC values ranging from 0.625 to 5 MUL/mL. The AOC and TPC results for these species were also interesting. The major components for these EOs were thymol for T. vulgaris (44%) and O. vulgare (40%), linalool (77%) for C. sativum, and carvacrol for S. montana (54%). The results allowed the study to establish that these EOs are good candidates for potential application as biopreservatives in foods and/or food manufacture environments. PMID- 29393894 TI - Comparison of a New Multiplex Immunoassay for Measurement of Ferritin, Soluble Transferrin Receptor, Retinol-Binding Protein, C-Reactive Protein and alpha1-Acid glycoprotein Concentrations against a Widely-Used s-ELISA Method. AB - Recently, a multiplex ELISA (Quansys Biosciences) was developed that measures ferritin, soluble transferrin receptor (sTfR), retinol-binding protein (RBP), C reactive protein (CRP), alpha1-acid glycoprotein (AGP), thyroglobulin, and histidine-rich protein 2. Our primary aim was to conduct a method-comparison study to compare five biomarkers (ferritin, sTfR, RBP, CRP, and AGP) measured with the Quansys assay and a widely-used s-ELISA (VitMin Lab, Willstaett, Germany) with use of serum samples from 180 women and children from Burkina Faso, Cambodia, and Malaysia. Bias and concordance were used to describe the agreement in values measured by the two methods. We observed poor overall agreement between the methods, both with regard to biomarker concentrations and deficiency prevalence estimates. Several measurements were outside of the limit of detection with use of the Quansys ELISA (total n = 42 for ferritin, n = 2 for sTfR, n = 0 for AGP, n = 5 for CRP, n = 22 for RBP), limiting our ability to interpret assay findings. Although the Quansys ELISA has great potential to simplify laboratory analysis of key nutritional and inflammation biomarkers, there are some weaknesses in the procedures. Overall, we found poor comparability of results between methods. Besides addressing procedural issues, additional validation of the Quansys against a gold standard method is warranted for future research. PMID- 29393895 TI - Glycosylphosphatidylinositol Anchors from Galactomannan and GPI-Anchored Protein Are Synthesized by Distinct Pathways in Aspergillus fumigatus. AB - Glycosylphosphatidylinositols (GPIs) are lipid anchors allowing the exposure of proteins at the outer layer of the plasma membrane. In fungi, a number of GPI anchored proteins (GPI-APs) are involved in the remodeling of the cell wall polymers. GPIs follow a specific biosynthetic pathway in the endoplasmic reticulum. After the transfer of the protein onto the GPI-anchor, a lipid remodeling occurs to substitute the diacylglycerol moiety by a ceramide. In addition to GPI-APs, A. fumigatus produces a GPI-anchored polysaccharide, the galactomannan (GM), that remains unique in the fungal kingdom. To investigate the role of the GPI pathway in the biosynthesis of the GM and cell wall organization, the deletion of PER1-coding for a phospholipase required for the first step of the GPI lipid remodeling-was undertaken. Biochemical characterization of the GPI anchor isolated from GPI-APs showed that the PER1 deficient mutant produced a lipid anchor with a diacylglycerol. The absence of a ceramide on GPI-anchors in the Deltaper1 mutant led to a mislocation of GPI-APs and to an alteration of the composition of the cell wall alkali-insoluble fraction. On the other hand, the GM isolated from the Deltaper1 mutant membranes possesses a ceramide moiety as the parental strain, showing that GPI anchor of the GM follow a distinct unknown biosynthetic pathway. PMID- 29393897 TI - Modal Parameters Evaluation in a Full-Scale Aircraft Demonstrator under Different Environmental Conditions Using HS 3D-DIC. AB - In real aircraft structures the comfort and the occupational performance of crewmembers and passengers are affected by the presence of noise. In this sense, special attention is focused on mechanical and material design for isolation and vibration control. Experimental characterization and, in particular, experimental modal analysis, provides information for adequate cabin noise control. Traditional sensors employed in the aircraft industry for this purpose are invasive and provide a low spatial resolution. This paper presents a methodology for experimental modal characterization of a front fuselage full-scale demonstrator using high-speed 3D digital image correlation, which is non invasive, ensuring that the structural response is unperturbed by the instrumentation mass. Specifically, full-field measurements on the passenger window area were conducted when the structure was excited using an electrodynamic shaker. The spectral analysis of the measured time-domain displacements made it possible to identify natural frequencies and full-field operational deflection shapes. Changes in the modal parameters due to cabin pressurization and the behavior of different local structural modifications were assessed using this methodology. The proposed full-field methodology allowed the characterization of relevant dynamic response patterns, complementing the capabilities provided by accelerometers. PMID- 29393896 TI - Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition. AB - We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6 selective inhibitor bufexamac. PMID- 29393898 TI - Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo. AB - Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM) producing cells in the injured liver and the key mediators of liver fibrosis; they also promote the progression of hepatocellular carcinoma (HCC). In the acidic extracellular microenvironment of HCC, HSCs are activated to promote the migration of HCC cells. It is worth attempting to alter the weak acidic microenvironment to promote activated HSC apoptosis to treat liver fibrosis and liver cancer. In the present study, a series of novel OA-amino acids analogues were designed and synthesized to introduce different amino acids in the 3 hydroxyl of OA using the ester condensation reaction to enhance hydrophilicity, alkalinity, and biological activity. We found that OA-lysine derivative (3g) could improve the hydrophilic of OA and induce HSCs apoptosis via inducing MMP depolarization and increasing intracellular Ca2+ levels. Additionally, 3g displayed a better hepatoprotective effect than OA (20 mg/kg, intragastric administration) against the acute liver injury induced by carbon tetrachloride (CCl4) in mice. The results suggested that basic amino acids (lysine) could effectively enhance OA's hydrophilicity, alkalinity, and hepatoprotective activity in vitro and in vivo, which might be likely associated with increasing bioavailability and altering an extracellular weak acidic microenvironment with further verification. Therefore, the OA-lysine derivative (3g) has the potential to be developed as an agent with hepatoprotective activity. PMID- 29393899 TI - Towards Additive Manufacture of Functional, Spline-Based Morphometric Models of Healthy and Diseased Coronary Arteries: In Vitro Proof-of-Concept Using a Porcine Template. AB - The aim of this study is to assess the additive manufacture of morphometric models of healthy and diseased coronary arteries. Using a dissected porcine coronary artery, a model was developed with the use of computer aided engineering, with splines used to design arteries in health and disease. The model was altered to demonstrate four cases of stenosis displaying varying severity, based on published morphometric data available. Both an Objet Eden 250 printer and a Solidscape 3Z Pro printer were used in this analysis. A wax printed model was set into a flexible thermoplastic and was valuable for experimental testing with helical flow patterns observed in healthy models, dominating the distal LAD (left anterior descending) and left circumflex arteries. Recirculation zones were detected in all models, but were visibly larger in the stenosed cases. Resin models provide useful analytical tools for understanding the spatial relationships of blood vessels, and could be applied to preoperative planning techniques, but were not suitable for physical testing. In conclusion, it is feasible to develop blood vessel models enabling experimental work; further, through additive manufacture of bio-compatible materials, there is the possibility of manufacturing customized replacement arteries. PMID- 29393900 TI - Accurate Energy Consumption Modeling of IEEE 802.15.4e TSCH Using Dual BandOpenMote Hardware. AB - The Time-Slotted Channel Hopping (TSCH) mode of the IEEE 802.15.4e amendment aims to improve reliability and energy efficiency in industrial and other challenging Internet-of-Things (IoT) environments. This paper presents an accurate and up-to date energy consumption model for devices using this IEEE 802.15.4e TSCH mode. The model identifies all network-related CPU and radio state changes, thus providing a precise representation of the device behavior and an accurate prediction of its energy consumption. Moreover, energy measurements were performed with a dual-band OpenMote device, running the OpenWSN firmware. This allows the model to be used for devices using 2.4 GHz, as well as 868 MHz. Using these measurements, several network simulations were conducted to observe the TSCH energy consumption effects in end-to-end communication for both frequency bands. Experimental verification of the model shows that it accurately models the consumption for all possible packet sizes and that the calculated consumption on average differs less than 3% from the measured consumption. This deviation includes measurement inaccuracies and the variations of the guard time. As such, the proposed model is very suitable for accurate energy consumption modeling of TSCH networks. PMID- 29393901 TI - Effects of Heterologous tRNA Modifications on the Production of Proteins Containing Noncanonical Amino Acids. AB - Synthesis of proteins with noncanonical amino acids (ncAAs) enables the creation of protein-based biomaterials with diverse new chemical properties that may be attractive for material science. Current methods for large-scale production of ncAA-containing proteins, frequently carried out in Escherichia coli, involve the use of orthogonal aminoacyl-tRNA synthetases (o-aaRSs) and tRNAs (o-tRNAs). Although o-tRNAs are designed to be orthogonal to endogenous aaRSs, their orthogonality to the components of the E. coli metabolism remains largely unexplored. We systematically investigated how the E. coli tRNA modification machinery affects the efficiency and orthogonality of o-tRNASep used for production of proteins with the ncAA O-phosphoserine (Sep). The incorporation of Sep into a green fluorescent protein (GFP) in 42 E. coli strains carrying deletions of single tRNA modification genes identified several genes that affect the o-tRNA activity. Deletion of cysteine desulfurase (iscS) increased the yield of Sep-containing GFP more than eightfold, while overexpression of dimethylallyltransferase MiaA and pseudouridine synthase TruB improved the specificity of Sep incorporation. These results highlight the importance of tRNA modifications for the biosynthesis of proteins containing ncAAs, and provide a novel framework for optimization of o-tRNAs. PMID- 29393902 TI - Improved Anticancer Effect of Magnetite Nanocomposite Formulation of GALLIC Acid (Fe3O4-PEG-GA) Against Lung, Breast and Colon Cancer Cells. AB - Lung cancer, breast cancer and colorectal cancer are the most prevalent fatal types of cancers globally. Gallic acid (3,4,5-trihydroxybenzoic acid) is a bioactive compound found in plants and foods, such as white tea, witch hazel and it has been reported to possess anticancer, antioxidant and anti-inflammatory properties. In this study we have redesigned our previously reported anticancer nanocomposite formulation with improved drug loading based on iron oxide magnetite nanoparticles coated with polyethylene glycol and loaded with anticancer drug gallic acid (Fe3O4-PEG-GA). The in vitro release profile and percentage drug loading were found to be better than our previously reported formulation. The anticancer activity of pure gallic acid (GA), empty carrier (Fe3O4-PEG) nanocarrier and of anticancer nanocomposite (Fe3O4-PEG-GA) were screened against human lung cancer cells (A549), human breast cancer cells (MCF 7), human colon cancer cells (HT-29) and normal fibroblast cells (3T3) after incubation of 24, 48 and 72 h using (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) MTT assay. The designed formulation (Fe3O4-PEG-GA) showed better anticancer activity than free gallic acid (GA). The results of the in vitro studies are highly encouraging to conduct the in vivo studies. PMID- 29393903 TI - Standardized Parenteral Nutrition for the Transition Phase in Preterm Infants: A Bag That Fits. AB - The optimal composition of standardized parenteral nutrition (SPN) is not yet known, contributing to nutrient deficit accrual and growth failure, with the period of parenteral nutrition weaning, i.e., transition (TN) phase, being identified as particularly vulnerable. We created a comprehensive nutrition database, representative of the nutritional course of a diverse range of preterm infants (n = 59, birth weight <= 1500 g, gestation < 34 weeks) by collecting hourly macronutrient intake data as part of a prospective, observational study over 19 months. Using a nutrient modeling technique for the TN phase, various amino acid (AA) concentrations of SPN were tested within the database, whilst acknowledging the nutritional contribution from enteral feeds until target AA intakes were consistently achieved. From the modeling, the AA composition of SPN was determined at 3.5 g/100 mL, which was the maximum to avoid exceeding target intakes at any point in the TN phase. However, in order to consistently achieve target AA intakes, additional nutritional strategies were required, which included increasing the exclusion of enteral feeds in fluid and nutrient calculations from <20 mL/kg/day to <40 mL/kg/day, and earlier fortification of breastmilk at 80 mL/kg/day. This data-driven nutrient modeling process supported the development of an improved SPN regimen for our preterm population in the TN phase. PMID- 29393904 TI - Degradation of Organophosphorus and Pyrethroid Insecticides in Beverages: Implications for Risk Assessment. AB - Since urinary insecticide metabolites are commonly used as biomarkers of exposure, it is important that we quantify whether insecticides degrade in food and beverages in order to better perform risk assessment. This study was designed to quantify degradation of organophosphorus and pyrethroid insecticides in beverages. Purified water, white grape juice, orange juice, and red wine were fortified with 500 ng/mL diazinon, malathion, chlorpyrifos, permethrin, cyfluthrin, cypermethrin, and deltamethrin, and aliquots were extracted several times over a 15-day storage period at 2.5 degrees C. Overall, statistically significant loss of at least one insecticide was observed in each matrix, and at least five out of seven insecticides demonstrated a statistically significant loss in all matrices except orange juice. An investigation of an alternative mechanism of insecticide loss-adsorption onto the glass surface of the storage jars-was carried out, which indicated that this mechanism of loss is insignificant. Results of this work suggest that insecticides degrade in these beverages, and this degradation may lead to pre-existing insecticide degradates in the beverages, suggesting that caution should be exercised when using urinary insecticide metabolites to assess exposure and risk. PMID- 29393906 TI - The Effect of Botulinum Neurotoxin Serotype a Heavy Chain on the Growth Related Proteins and Neurite Outgrowth after Spinal Cord Injury in Rats. AB - (1) Background: The botulinum toxin A (BoNT-A) heavy chain (HC) can stimulate the growth of primary motor neurites. (2) Methods: A recombinant BoNT/A HC was injected locally plus interval intrathecal catheter of BoNT/A HC to rats with ipsilateral semi-dissociated lumbar spinal cord injuries (SCIs). First, 2D gel with a silver nitrate stain was applied to detect the general pattern of protein expression. Growth associated protein 43 (GAP-43) and superior cervical ganglion 10 (SCG10) were chosen to represent the altered proteins, based on their molecular weight and pI, and were used to further detect their expression. Meanwhile, the neuronal processes were measured. The measurements of thermal hyperalgesia and grasp power at the ipsilateral hindlimb were used to evaluate spinal sensory and motor function, respectively. (3) Results: The local injection of BoNT/A HC followed by its intrathecal catheter intervally altered the spinal protein expression pattern after an SCI; protein expression was similar to normal levels or displayed a remarkable increase. The changes in the expression and distribution of phosphorylated growth associated protein 43(p-GAP 43) and superior cervical ganglion 10 (SCG 10) indicated that the administration of BoNT/A HC to the SCI significantly amplified the expression of p-GAP43 and SCG10 (p < 0.05). Meanwhile, the positive immunofluorescent staining for both p-GAP43 and SCG10 was mainly present near the rostral aspect of the injury, both in the cytoplasm and the neuronal processes. Moreover, the outgrowth of neurites was stimulated by the BoNT/A HC treatment; this was evident from the increase in neurite length, number of branches and the percentage of cells with neuronal processes. The results from the spinal function tests suggested that the BoNT/A HC did not affect sensation, but had a large role in improving the ipsilateral hindlimb grasp power (p < 0.05). (4) Conclusions: The local injection with the intermittent intrathecal administration of BoNT/A heavy chain to rats with SCI increased the local expression of GAP-43 and SCG 10, which might be affiliated with the regeneration of neuronal processes surrounding the injury, and might also be favorable to the relief of spinal motor dysfunction. PMID- 29393905 TI - A Review of Current Methods for Analysis of Mycotoxins in Herbal Medicines. AB - The presence of mycotoxins in herbal medicines is an established problem throughout the entire world. The sensitive and accurate analysis of mycotoxin in complicated matrices (e.g., herbs) typically involves challenging sample pretreatment procedures and an efficient detection instrument. However, although numerous reviews have been published regarding the occurrence of mycotoxins in herbal medicines, few of them provided a detailed summary of related analytical methods for mycotoxin determination. This review focuses on analytical techniques including sampling, extraction, cleanup, and detection for mycotoxin determination in herbal medicines established within the past ten years. Dedicated sections of this article address the significant developments in sample preparation, and highlight the importance of this procedure in the analytical technology. This review also summarizes conventional chromatographic techniques for mycotoxin qualification or quantitation, as well as recent studies regarding the development and application of screening assays such as enzyme-linked immunosorbent assays, lateral flow immunoassays, aptamer-based lateral flow assays, and cytometric bead arrays. The present work provides a good insight regarding the advanced research that has been done and closes with an indication of future demand for the emerging technologies. PMID- 29393907 TI - Chloro-Furanocembranolides from Leptogorgia sp. Improve Pancreatic Beta-Cell Proliferation. AB - Two new chloro-furanocembranolides (1, 2) and two new 1,4-diketo cembranolides (3, 4) were isolated from the crude extract of Leptogorgia sp. together with a new seco-furanocembranolide (5) and the known Z-deoxypukalide (6), rubifolide (7), scabrolide D (8) and epoxylophodione (9). Their structures were determined based on spectroscopic evidence. Four compounds: 1, 2, 7 and 8 were found to activate the proliferation of pancreatic insulin-producing (beta) cells. PMID- 29393908 TI - From Fibrils to Toughness: Multi-Scale Mechanics of Fibrillating Interfaces in Stretchable Electronics. AB - Metal-elastomer interfacial systems, often encountered in stretchable electronics, demonstrate remarkably high interface fracture toughness values. Evidently, a large gap exists between the rather small adhesion energy levels at the microscopic scale ('intrinsic adhesion') and the large measured macroscopic work-of-separation. This energy gap is closed here by unravelling the underlying dissipative mechanisms through a systematic numerical/experimental multi-scale approach. This self-containing contribution collects and reviews previously published results and addresses the remaining open questions by providing new and independent results obtained from an alternative experimental set-up. In particular, the experimental studies on Cu-PDMS (Poly(dimethylsiloxane)) samples conclusively reveal the essential role of fibrillation mechanisms at the micro meter scale during the metal-elastomer delamination process. The micro-scale numerical analyses on single and multiple fibrils show that the dynamic release of the stored elastic energy by multiple fibril fracture, including the interaction with the adjacent deforming bulk PDMS and its highly nonlinear behaviour, provide a mechanistic understanding of the high work-of-separation. An experimentally validated quantitative relation between the macroscopic work-of separation and peel front height is established from the simulation results. Finally, it is shown that a micro-mechanically motivated shape of the traction separation law in cohesive zone models is essential to describe the delamination process in fibrillating metal-elastomer systems in a physically meaningful way. PMID- 29393910 TI - Scale-Up of the Electrodeposition of ZnO/Eosin Y Hybrid Thin Films for the Fabrication of Flexible Dye-Sensitized Solar Cell Modules. AB - The low-temperature fabrication of flexible ZnO photo-anodes for dye-sensitized solar cells (DSSCs) by templated electrochemical deposition of films was performed in an enlarged and technical simplified deposition setup to demonstrate the feasibility of the scale-up of the deposition process. After extraction of eosin Y (EY) from the initially deposited ZnO/EY hybrid films, mesoporous ZnO films with an area of about 40 cm2 were reproducibly obtained on fluorine doped tin oxide (FTO)-glass as well as flexible indium tin oxide (ITO) polyethylenterephthalate (PET) substrates. With a film thickness of up to 9 um and a high specific surface area of up to about 77 m2.cm-3 the ZnO films on the flexible substrates show suitable properties for DSSCs. Operative flexible DSSC modules proved the suitability of the ZnO films for use as DSSC photo-anodes. Under a low light intensity of about 0.007 sun these modules achieved decent performance parameters with conversion efficiencies of up to 2.58%. With rising light intensity the performance parameters deteriorated, leading to conversion efficiencies below 1% at light intensities above 0.5 sun. The poor performance of the modules under high light intensities can be attributed to their high series resistances. PMID- 29393909 TI - Beyond the Matrix: The Many Non-ECM Ligands for Integrins. AB - The traditional view of integrins portrays these highly conserved cell surface receptors as mediators of cellular attachment to the extracellular matrix (ECM), and to a lesser degree, as coordinators of leukocyte adhesion to the endothelium. These canonical activities are indispensable; however, there is also a wide variety of integrin functions mediated by non-ECM ligands that transcend the traditional roles of integrins. Some of these unorthodox roles involve cell-cell interactions and are engaged to support immune functions such as leukocyte transmigration, recognition of opsonization factors, and stimulation of neutrophil extracellular traps. Other cell-cell interactions mediated by integrins include hematopoietic stem cell and tumor cell homing to target tissues. Integrins also serve as cell-surface receptors for various growth factors, hormones, and small molecules. Interestingly, integrins have also been exploited by a wide variety of organisms including viruses and bacteria to support infectious activities such as cellular adhesion and/or cellular internalization. Additionally, the disruption of integrin function through the use of soluble integrin ligands is a common strategy adopted by several parasites in order to inhibit blood clotting during hematophagy, or by venomous snakes to kill prey. In this review, we strive to go beyond the matrix and summarize non ECM ligands that interact with integrins in order to highlight these non traditional functions of integrins. PMID- 29393913 TI - Control of Fusarium verticillioides (Sacc.) Nirenberg and Fumonisins by Using a Combination of Crop Protection Products and Fertilization. AB - Fusarium verticillioides is the most common fungal pathogen associated with maize ear rot in Tanzania. In a two-year trial, we investigated the efficacy of crop protection (insecticide and/or fungicide) and fertilizer (nitrogen and/or phosphorus) treatments in reducing the occurrence of F. verticillioides and its mycotoxins in maize grown in Tanzania. Seasonal differences were seen to have a substantial influence on the incidence and severity of insect infestation, Fusarium ear and kernel rot, biomass of F. verticillioides and contamination with fumonisins. With regard to the application of fertilizers, it was concluded that the impact on maize stalk borer injury, Fusarium symptoms and fumonisin levels was not significant, whereas crop protection significantly reduced maize damage. The application of an insecticide was most effective in reducing insect injury and as a result of the reduced insect injury the insecticide treatment also resulted in a significant decrease in Fusarium symptoms. In 2014, fumonisin levels were also significantly lower in maize treated with an insecticide. Additionally, significant positive correlations between insect damage and Fusarium symptoms were observed. In conclusion, this study clearly shows that application of an insecticide alone or in combination with a fungicide at anthesis significantly reduces insect damage and consequently reduces F. verticillioides infection and associated fumonisin contamination. PMID- 29393912 TI - Common Variable Immunodeficiency and Gastric Malignancies. AB - Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal manifestations and an increased risk of gastric carcinoma and lymphoma. This review discusses the latest advancements into the immunological, clinical and diagnostic aspects of gastric malignancies in patients with CVID. The exact molecular pathways underlying the relationships between CVID and gastric malignancies remain poorly understood. These include genetics, immune dysregulation and chronic infections by Helicobacter pylori. Further studies are needed to better stratify the risk for cancer in these patients, to elaborate surveillance programs aimed at preventing these complications, and to develop new and more effective therapeutic approaches. PMID- 29393915 TI - A Real-Time Reaction Obstacle Avoidance Algorithm for Autonomous Underwater Vehicles in Unknown Environments. AB - A novel real-time reaction obstacle avoidance algorithm (RRA) is proposed for autonomous underwater vehicles (AUVs) that must adapt to unknown complex terrains, based on forward looking sonar (FLS). To accomplish this algorithm, obstacle avoidance rules are planned, and the RRA processes are split into five steps Introduction only lists 4 so AUVs can rapidly respond to various environment obstacles. The largest polar angle algorithm (LPAA) is designed to change detected obstacle's irregular outline into a convex polygon, which simplifies the obstacle avoidance process. A solution is designed to solve the trapping problem existing in U-shape obstacle avoidance by an outline memory algorithm. Finally, simulations in three unknown obstacle scenes are carried out to demonstrate the performance of this algorithm, where the obtained obstacle avoidance trajectories are safety, smooth and near-optimal. PMID- 29393914 TI - The Application of Non-Invasive Apoptosis Detection Sensor (NIADS) on Histone Deacetylation Inhibitor (HDACi)-Induced Breast Cancer Cell Death. AB - Breast cancer is the most common malignancy in women and the second leading cause of cancer death in women. Triple negative breast cancer (TNBC) subtype is a breast cancer subset without ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2) expression, limiting treatment options and presenting a poorer survival rate. Thus, we investigated whether histone deacetylation inhibitor (HDACi) could be used as potential anti cancer therapy on breast cancer cells. In this study, we found TNBC and HER2 enriched breast cancers are extremely sensitive to Panobinostat, Belinostat of HDACi via experiments of cell viability assay, apoptotic marker identification and flow cytometry measurement. On the other hand, we developed a bioluminescence based live cell non-invasive apoptosis detection sensor (NIADS) detection system to evaluate the quantitative and kinetic analyses of apoptotic cell death by HDAC treatment on breast cancer cells. In addition, the use of HDACi may also contribute a synergic anti-cancer effect with co-treatment of chemotherapeutic agent such as doxorubicin on TNBC cells (MDA-MB-231), but not in breast normal epithelia cells (MCF-10A), providing therapeutic benefits against breast tumor in the clinic. PMID- 29393916 TI - Design Optimization and Fabrication of a Novel Structural SOI Piezoresistive Pressure Sensor with High Accuracy. AB - This paper presents a novel structural piezoresistive pressure sensor with four grooved membrane combined with rood beam to measure low pressure. In this investigation, the design, optimization, fabrication, and measurements of the sensor are involved. By analyzing the stress distribution and deflection of sensitive elements using finite element method, a novel structure featuring high concentrated stress profile (HCSP) and locally stiffened membrane (LSM) is built. Curve fittings of the mechanical stress and deflection based on FEM simulation results are performed to establish the relationship between mechanical performance and structure dimension. A combination of FEM and curve fitting method is carried out to determine the structural dimensions. The optimized sensor chip is fabricated on a SOI wafer by traditional MEMS bulk-micromachining and anodic bonding technology. When the applied pressure is 1 psi, the sensor achieves a sensitivity of 30.9 mV/V/psi, a pressure nonlinearity of 0.21% FSS and an accuracy of 0.30%, and thereby the contradiction between sensitivity and linearity is alleviated. In terms of size, accuracy and high temperature characteristic, the proposed sensor is a proper choice for measuring pressure of less than 1 psi. PMID- 29393911 TI - The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression. AB - Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients. PMID- 29393917 TI - Improvement in Limit of Detection of Enzymatic Biogas Sensor Utilizing Chromatography Paper for Breath Analysis. AB - Breath analysis is considered to be an effective method for point-of-care diagnosis due to its noninvasiveness, quickness and simplicity. Gas sensors for breath analysis require detection of low-concentration substances. In this paper, we propose that reduction of the background current improves the limit of detection of enzymatic biogas sensors utilizing chromatography paper. After clarifying the cause of the background current, we reduced the background current by improving the fabrication process of the sensors utilizing paper. Finally, we evaluated the limit of detection of the sensor with the sample vapor of ethanol gas. The experiment showed about a 50% reduction of the limit of detection compared to previously-reported sensor. This result presents the possibility of the sensor being applied in diagnosis, such as for diabetes, by further lowering the limit of detection. PMID- 29393918 TI - Nanotherapeutics Containing Lithocholic Acid-Based Amphiphilic Scorpion-Like Macromolecules Reduce In Vitro Inflammation in Macrophages: Implications for Atherosclerosis. AB - Previously-designed amphiphilic scorpion-like macromolecule (AScM) nanoparticles (NPs) showed elevated potency to counteract oxidized low-density lipoprotein (oxLDL) uptake in atherosclerotic macrophages, but failed to ameliorate oxLDL induced inflammation. We designed a new class of composite AScMs incorporating lithocholic acid (LCA), a natural agonist for the TGR5 receptor that is known to counteract atherosclerotic inflammation, with two complementary goals: to simultaneously decrease lipid uptake and inhibit pro-inflammatory cytokine secretion by macrophages. LCA was conjugated to AScMs for favorable interaction with TGR5 and was also hydrophobically modified to enable encapsulation in the core of AScM-based NPs. Conjugates were formulated into negatively charged NPs with different core/shell combinations, inspired by the negative charge on oxLDL to enable competitive interaction with scavenger receptors (SRs). NPs with LCA containing shells exhibited reduced sizes, and all NPs lowered oxLDL uptake to <30% of untreated, human derived macrophages in vitro, while slightly downregulating SR expression. Pro-inflammatory cytokine expression, including IL 1beta, IL-8, and IL-10, is known to be modulated by TGR5, and was dependent on NP composition, with LCA-modified cores downregulating inflammation. Our studies indicate that LCA-conjugated AScM NPs offer a unique approach to minimize atherogenesis and counteract inflammation. PMID- 29393919 TI - A Community-Based Study to Estimate the Seroprevalence of Trichinellosis and Echinococcosis in the Roma and Non-Roma Population of Slovakia. AB - Trichinellosis and cystic and alveolar echinococcosis are serious parasitic diseases transmissible between animals and humans. Moreover, alveolar echinococcosis is considered one of the most dangerous of human helminthoses. Roma communities are particularly numerous in Central and Eastern Europe. They are often concentrated in economically undeveloped regions and live in segregated localities with unsatisfactory housing and sanitary conditions. The study aimed to find out the seroprevalence of Trichinella and Echinococcus infections in the Roma population of segregated settlements and to compare it with the seropositivity of the non-Roma population of eastern Slovakia. Out of 823 samples, three sera showed seropositivity to Trichinella in the ELISA (Enzyme linked immunosorbent assay) test. Subsequent Western blot reaction (WB) confirmed seropositivity in two Roma women. ELISA seropositivity to E. multilocularis was recorded in six persons (0.73%), and five (0.61%) respondents were seropositive to E. granulosus, but WB confirmed the presence of antibodies to Echinococcus spp. in one Roma participant. Positive persons suffered from unspecific clinical symptoms; Trichinella-positive persons reported headache, cough, fatigue, and muscle pain. The Echinococcus-positive participant suffered from headache and back pain. The study showed that the worse living conditions of the Roma community did not significantly influence the occurrence of Trichinella and Echinococcus infections in this minority. PMID- 29393920 TI - Residents' Self-Reported Health Effects and Annoyance in Relation to Air Pollution Exposure in an Industrial Area in Eastern-Estonia. AB - Eastern Estonia has large oil shale mines and industrial facilities mainly focused on electricity generation from oil shale and shale oil extraction, which produce high air pollution emissions. The "Study of the health impact of the oil shale sector-SOHOS" was aimed at identifying the impacts on residents' health and annoyance due to the industrial processing. First, a population-wide survey about health effects and annoyance was carried out. Second, the total and oil shale sectors' emitted concentrations of benzene, phenol, and PM2.5 were modelled. Third, the differences between groups were tested and relationships between health effects and environmental pollution studied using multiple regression analysis. Compared to the control groups from non-industrial areas in Tartu or Laane-Viru, residents of Ida-Viru more frequently (p < 0.05) reported wheezing, chest tightness, shortness of breath, asthma attacks, a long-term cough, hypertension, heart diseases, myocardial infarction, stroke, and diabetes. All health effects except asthma were reported more frequently among non-Estonians. People living in regions with higher levels of PM2.5, had significantly higher odds (p < 0.05) of experiencing chest tightness (OR = 1.13, 95% CI 1.02-1.26), shortness of breath (1.16, 1.03-1.31) or an asthma attack (1.22, 1.04-1.42) during the previous year. People living in regions with higher levels of benzene had higher odds of experiencing myocardial infarction (1.98, 1.11-3.53) and with higher levels of phenol chest tightness (1.44, 1.03-2.00), long-term cough (1.48, 1.06-2.07) and myocardial infarction (2.17, 1.23-3.83). The prevalence of adverse health effects was also higher among those who had been working in the oil shale sector. Next to direct health effects, up to a quarter of the residents of Ida Viru County were highly annoyed about air pollution. Perceived health risk from air pollution increased the odds of being annoyed. Annoyed people in Ida-Viru had significantly higher odds of experiencing respiratory symptoms during the last 12 months, e.g., wheezing (2.30, 1.31-4.04), chest tightness (2.88, 1.91-4.33 or attack of coughing (1.99, 1.34-2.95). PMID- 29393921 TI - Specim IQ: Evaluation of a New, Miniaturized Handheld Hyperspectral Camera and Its Application for Plant Phenotyping and Disease Detection. AB - Hyperspectral imaging sensors are promising tools for monitoring crop plants or vegetation in different environments. Information on physiology, architecture or biochemistry of plants can be assessed non-invasively and on different scales. For instance, hyperspectral sensors are implemented for stress detection in plant phenotyping processes or in precision agriculture. Up to date, a variety of non imaging and imaging hyperspectral sensors is available. The measuring process and the handling of most of these sensors is rather complex. Thus, during the last years the demand for sensors with easy user operability arose. The present study introduces the novel hyperspectral camera Specim IQ from Specim (Oulu, Finland). The Specim IQ is a handheld push broom system with integrated operating system and controls. Basic data handling and data analysis processes, such as pre processing and classification routines are implemented within the camera software. This study provides an introduction into the measurement pipeline of the Specim IQ as well as a radiometric performance comparison with a well established hyperspectral imager. Case studies for the detection of powdery mildew on barley at the canopy scale and the spectral characterization of Arabidopsis thaliana mutants grown under stressed and non-stressed conditions are presented. PMID- 29393922 TI - Imaging and Spectroscopy of Natural Fluorophores in Pine Needles. AB - Many plant tissues fluoresce due to the natural fluorophores present in cell walls or within the cell protoplast or lumen. While lignin and chlorophyll are well-known fluorophores, other components are less well characterized. Confocal fluorescence microscopy of fresh or fixed vibratome-cut sections of radiata pine needles revealed the presence of suberin, lignin, ferulate, and flavonoids associated with cell walls as well as several different extractive components and chlorophyll within tissues. Comparison of needles in different physiological states demonstrated the loss of chlorophyll in both chlorotic and necrotic needles. Necrotic needles showed a dramatic change in the fluorescence of extractives within mesophyll cells from ultraviolet (UV) excited weak blue fluorescence to blue excited strong green fluorescence associated with tissue browning. Comparisons were made among fluorophores in terms of optimal excitation, relative brightness compared to lignin, and the effect of pH of mounting medium. Fluorophores in cell walls and extractives in lumens were associated with blue or green emission, compared to the red emission of chlorophyll. Autofluorescence is, therefore, a useful method for comparing the histology of healthy and diseased needles without the need for multiple staining techniques, potentially aiding visual screening of host resistance and disease progression in needle tissue. PMID- 29393923 TI - Habitual Intakes, Food Sources and Excretions of Phosphorus and Calcium in Three German Study Collectives. AB - Phosphorus intake in Europe is far above recommendations. We present baseline data from three human intervention studies between 2006 and 2014 regarding intake and excretion of phosphorus and calcium. All subjects documented their nutritional habits in weighed dietary records. Fasting blood samples were drawn, and feces and urine were quantitatively collected. Dietary phosphorus intake was estimated based on weighed dietary records and urine phosphorus excretions. Food sources were identified by allocation to defined food product groups. Average phosphorus consumption was 1338 mg/day and did not change from 2006 to 2014, while calcium intake decreased during this period (1150 to 895 mg/day). The main sources for phosphorus intake were bread/cereal products, milk/milk products and meat/meat products/sausage products and the main sources of calcium intake included milk/milk products/cheese, bread/cereal products and beverages. There was no difference between estimated phosphorus intake from the weighed dietary records and urine phosphorus excretion. In conclusion, we demonstrated constant phosphorus intakes far above the recommendations and decreasing calcium intakes below the recommendations in three German collectives from 2006 to 2014. Furthermore, we could show in case of usual intakes that an estimated phosphorus intake from urine phosphorus excretion is similar to the calculated intake from weighed dietary records. PMID- 29393925 TI - Corrigendum: Experimental Certification of Random Numbers via Quantum Contextuality. AB - This corrects the article DOI: 10.1038/srep01627. PMID- 29393926 TI - Suture lateralisation plus arytenoid cartilage release for treating bilateral vocal fold immobility with mechanical fixation. AB - A suture lateralisation (SL) instead of an endolaryngeal tissue ablation procedure under endoscopy has been utilised to treat bilateral vocal fold immobility (BVFI) since 1980. However, mechanical fixation (MF) of the cricoarytenoid joint (CAJ) has continually challenged the effectiveness of glottic dilatation both in the SL procedure and the tissue ablation procedure. From 2007 to 2015, a total of 38 patients with BVFI underwent 40 exo endolaryngeal suture lateralisation (exoeSL) procedures and three were diagnosed with MF in our hospital. For these MF, we introduced an external approach method to release the CAJ followed by a similar exoeSL procedure. The CAJ release procedure enabled the preservation of the endolaryngeal mucous membrane (ELM) and consequently spared the use of laser surgery. All three CAJ release procedures led to decannulations (one patient) or improvement of dyspnoea (two patients). The difference between the exoeSL and the endo-exolaryngeal suture lateralisation (endoeSL) procedure is discussed based on their effectiveness in MF management. PMID- 29393927 TI - Unravelling the risk factors that underlie oral and oropharyngeal surgery in elderly. AB - Oral squamous cell carcinoma (OSCC) diagnoses in elderly patients are expected to double in the next 20 years. Current guidelines suggest surgery as a preferred approach, but elderly patients are hardly considered suitable to challenging surgical treatments. Using a multi-centric retrospective analysis, we evaluated the outcomes of 99 patients affected by OSCC and aged at least 70, who underwent to either transoral procedures (TP), open neck resection without (OR) or with reconstruction (ORR). In our cohort, overall survival was significantly hampered by concomitant diseases and postsurgical complications, whose development is driven by the former. Thus, our findings support the growing acceptance that chronological age alone should not be a sufficient contraindication for aggressive surgery in the treatment of OSCC. However, elderly patients affected by OSCC are undoubtedly delicate surgical candidates and accurate selection prior to surgery with curative intent is mandatory. PMID- 29393928 TI - Erratum: Preclinical evaluation of the effect of the combined use of the Ethicon Securestrap(r) Open Absorbable Strap Fixation Device and Ethicon PhysiomeshTM Open Flexible Composite Mesh Device on surgeon stress during ventral hernia repair [Corrigendum]. AB - [This corrects the article on p. 1 in vol. 11, PMID: 29296101.]. PMID- 29393929 TI - Illustrating phallic worship: uses of material objects and the production of sexual knowledge in eighteenth-century antiquarianism and early twentieth-century sexual science. AB - This article reveals previously overlooked connections between eighteenth-century antiquarianism and early twentieth-century sexual science by presenting a comparative reading of two illustrated books: An Account of the Remains of the Worship of Priapus, by British antiquarian scholar Richard Payne Knight (1750 1824), and Die Weltreise eines Sexualforschers (The World Journey of a Sexologist), by German sexual scientist Magnus Hirschfeld (1868-1935). A close analysis of these publications demonstrates the special status of material artefacts and the strategic engagement with visual evidence in antiquarian and scientific writings about sex. Through its exploration of the similarities between antiquarian and sexual scientific thought, the article demonstrates the centrality of material culture to the production of sexual knowledge in the Western world. It also opens up new perspectives on Western intellectual history and on the intellectual origins of sexual science. While previous scholarship has traced the beginnings of sexual science back to nineteenth-century medical disciplines, this article shows that sexual scientists drew upon different forms of evidence and varied methodologies to produce sexual knowledge and secure scientific authority. As such, sexual science needs to be understood as a field with diverse intellectual roots that can be traced back (at least) to the eighteenth century. PMID- 29393924 TI - Outbreak of Seoul Virus Among Rats and Rat Owners - United States and Canada, 2017. AB - In December 2016, the Wisconsin Department of Health Services (WDHS) notified CDC of a patient hospitalized with fever, leukopenia, elevated transaminases, and proteinuria. The patient owned and operated an in-home rattery, or rat-breeding facility, with approximately 100 Norway rats, primarily bred as pets. A family member developed similar symptoms 4 weeks later, but was not hospitalized. Because both patients were known to have rodent contact, they were tested for hantavirus infections. In January 2017, CDC confirmed recent, acute Seoul virus infection in both patients. An investigation was conducted to identify additional human and rat infections and prevent further transmission. Ultimately, the investigation identified 31 facilities in 11 states with human and/or rat Seoul virus infections; six facilities also reported exchanging rats with Canadian ratteries. Testing of serum samples from 183 persons in the United States and Canada identified 24 (13.1%) with Seoul virus antibodies; three (12.5%) were hospitalized and no deaths occurred. This investigation, including cases described in a previously published report from Tennessee (1), identified the first known transmission of Seoul virus from pet rats to humans in the United States and Canada. Pet rat owners should practice safe rodent handling to prevent Seoul virus infection (2). PMID- 29393930 TI - Erratum to: Dual Pathologies of Parathyroid Adenoma and Papillary Thyroid Cancer on Fluorocholine and Fluorodeoxyglucose PET/CT. AB - [This corrects the article DOI: 10.1007/s13139-017-0488-3.]. PMID- 29393931 TI - Corrigendum: Longitudinal "Real-World" Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece. AB - [This corrects the article on p. 213 in vol. 4, PMID: 29238708.]. PMID- 29393932 TI - Corrigenda: Polyphyly of the traditional family Flabellinidae affects a major group of Nudibranchia: aeolidacean taxonomic reassessment with descriptions of several new families, genera, and species (Mollusca, Gastropoda). https://doi.org/10.3897/zookeys.717.21885. AB - [This corrects the article DOI: 10.3897/zookeys.717.21885.]. PMID- 29393933 TI - Corrigendum: Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key? AB - [This corrects the article on p. 72 in vol. 4, PMID: 29181379.]. PMID- 29393934 TI - The interfacial electrostatic potential modulates the insertion of cell penetrating peptides into lipid bilayers. AB - Cell-penetrating peptides (CPP) are short sequences of cationic amino-acids that show a surprising ability to traverse lipid bilayers. CPP are considered to be some of the most effective vectors to introduce membrane-impermeable cargos into cells, but the molecular basis of the membrane translocation mechanisms and its dependence on relevant membrane physicochemical properties have yet to be fully determined. In this paper we resort to Molecular Dynamics simulations and experiments to investigate how the electrostatic potential across the lipid/water interface affects the insertion of hydrophilic and amphipathic CPP into two dimensional lipid structures. Simulations are used to quantify the effect of the transmembrane potential on the free-energy profile associated with the transfer of the CPP across a neutral lipid bilayer. It is found that the electrostatic bias has a relatively small effect on the binding of the peptides to the membrane surface, but that it significantly lowers the permeation barrier. A charge compensation mechanism, arising from the segregation of counter-ions while the peptide traverses the membrane, determines the shape and symmetry of the free energy curves and underlines relevant mechanistic considerations. Langmuir monolayer experiments performed with a variety of amphiphiles model the incorporation of the CPP into the external membrane leaflet. It is shown that the dipole potential of the monolayer controls the extent of penetration of the CPP into the lipid aggregate, to a greater degree than its surface charge. PMID- 29393935 TI - Impact of screw and edge dislocations on the thermal conductivity of individual nanowires and bulk GaN: a molecular dynamics study. AB - We report the thermal transport properties of wurtzite GaN in the presence of dislocations using molecular dynamics simulations. A variety of isolated dislocations in a nanowire configuration are analyzed and found to considerably reduce the thermal conductivity while impacting its temperature dependence in a different manner. Isolated screw dislocations reduce the thermal conductivity by a factor of two, while the influence of edge dislocations is less pronounced. The relative reduction of thermal conductivity is correlated with the strain energy of each of the five studied types of dislocations and the nature of the bonds around the dislocation core. The temperature dependence of the thermal conductivity follows a physical law described by a T-1 variation in combination with an exponent factor that depends on the material's nature, type and the structural characteristics of the dislocation core. Furthermore, the impact of the dislocation density on the thermal conductivity of bulk GaN is examined. The variation and absolute values of the total thermal conductivity as a function of the dislocation density are similar for defected systems with both screw and edge dislocations. Nevertheless, we reveal that the thermal conductivity tensors along the parallel and perpendicular directions to the dislocation lines are different. The discrepancy of the anisotropy of the thermal conductivity grows with increasing density of dislocations and it is more pronounced for the systems with edge dislocations. Besides the fundamental insights of the presented results, these could also be used for the identification of the type of dislocations when one experimentally obtains the evolution of thermal conductivity with temperature since each type of dislocation has a different signature, or one could extract the density of dislocations with a simple measurement of thermal anisotropy. PMID- 29393936 TI - Amorphous TiO2@NH2-MIL-125(Ti) homologous MOF-encapsulated heterostructures with enhanced photocatalytic activity. AB - We have provided the first case of successfully synthesising amorphous TiO2@NH2 MIL-125(Ti) MOF-encapsulated heterostructures by a facile process. The homologous heterostructures exhibited higher photocatalytic activity via efficient transfer of photoinduced carriers as well as preservation of trivalent titanium ions. PMID- 29393937 TI - Oxalic/malonic acids as carbon building blocks for benzazole, quinazoline and quinazolinone synthesis. AB - An oxidant, base and metal free methodology has been developed for the synthesis of various 2-substituted and non-substituted benzazoles, quinazolines and quinazolinones using oxalic/malonic acids as an in situ carbon source. This methodology is applicable for a wide range of substituted o-phenylenediamine, o aminothiophenol, o-aminophenol and o-aminobenzamide containing various functional groups and provides good to excellent yields of the corresponding product. Furthermore an easy workup procedure, high yield and easy isolation of products are key features of this methodology. The developed protocol is also applicable for the gram scale synthesis of benzimidazoles. PMID- 29393938 TI - Enzymatically cleavable traceless biotin tags for protein PEGylation and purification. AB - Here we report an example of a protein-PEG conjugate with a biotin tag cleavable by lipase-catalyzed hydrolysis. Very mild cleavage conditions, heterogeneous, easily separable catalysts, and traceless design make this method attractive for the preparation and purification of PEGylated proteins. PMID- 29393939 TI - Toward aplyronine payloads for antibody-drug conjugates: total synthesis of aplyronines A and D. AB - The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame. PMID- 29393940 TI - A QM/MM study of the initial excited state dynamics of green-absorbing proteorhodopsin. AB - The primary photochemical reaction of the green-absorbing proteorhodopsin is studied by means of a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. The simulations are based on a homology model derived from the blue absorbing proteorhodopsin crystal structure. The geometry of retinal and the surrounding sidechains in the protein binding pocket were optimized using the QM/MM method. Starting from this geometry the isomerization was studied with a relaxed scan along the C13[double bond, length as m-dash]C14 dihedral. It revealed an "aborted bicycle pedal" mechanism of isomerization that was originally proposed by Warshel for bovine rhodopsin and bacteriorhodopsin. However, the isomerization involved the concerted rotation about C13[double bond, length as m-dash]C14 and C15[double bond, length as m-dash]N, with the latter being highly twisted but not isomerized. Further, the simulation showed an increased steric interaction between the hydrogen at the C14 of the isomerizing bond and the hydroxyl group at the neighbouring tyrosine 200. In addition, we have simulated a nonadiabatic trajectory which showed the timing of the isomerization. In the first 20 fs upon excitation the order of the conjugated double and single bonds is inverted, consecutively the C13[double bond, length as m-dash]C14 rotation is activated for 200 fs until the S1-S0 transition is detected. However, the isomerization is reverted due to the specific interaction with the tyrosine as observed along the relaxed scan calculation. Our simulations indicate that the retinal - tyrosine 200 interaction plays an important role in the outcome of the photoisomerization. PMID- 29393941 TI - A photoelectron spectroscopy and quantum chemical study on ternary Al-B-O clusters: AlnBO2- and AlnBO2 (n = 2, 3). AB - Both B and Al have high oxygen affinity and their oxidation processes are highly exothermic, hinting at intriguing physical chemistry in ternary Al-B-O clusters. We report a combined photoelectron spectroscopy and density-functional study on the structural, electronic, and bonding properties of AlnBO2- and AlnBO2 (n = 2, 3) clusters. Ground-state vertical detachment energies (VDEs) are measured to be 2.83 and 2.24 eV for Al2BO2- and Al3BO2-, respectively. A weak isomer is also observed for Al3BO2- with a VDE of 1.31 eV. Coalescence-kick global searches allow the identification of candidate structures, confirmed via comparisons with experiment. The Al2BO2- anion is V-shaped in geometry, Cs (1A'), with an Al center connecting to OB and OAl terminals. It can be viewed alternatively as the fusion of BOAl and AlOAl by sharing an Al atom. Al3BO2- has a Cs (2A'') global minimum in which an Al2 dimer interacts with bridging boronyl (BO) and an OAl unit, as well as a low-lying C2v (2B2) isomer consisting of boronyl and OAl that are doubly bridged by two Al atoms. The BO2 block (linear O[double bond, length as m-dash]B[double bond, length as m-dash]O chain) is nonexistent in any of the anion and neutral species. Chemical bonding in these Al-B-O clusters is elucidated via canonical molecular orbitals and adaptive natural density partitioning. The cluster structures are also rationalized using the concept of sequential and competitive oxidation of B versus Al centers in AlnB. The first O atom prefers to oxidize B and form BO, whereas the second O atom has options to interact with a fresh Al/Aln/AlnB unit or a BO group. The former route wins thermodynamically, leading to the observed geometries. PMID- 29393942 TI - Ionic liquids and derived materials for lithium and sodium batteries. AB - The ever-growing demand for advanced energy storage devices in portable electronics, electric vehicles and large scale power grids has triggered intensive research efforts over the past decade on lithium and sodium batteries. The key to improve their electrochemical performance and enhance the service safety lies in the development of advanced electrode, electrolyte, and auxiliary materials. Ionic liquids (ILs) are liquids consisting entirely of ions near room temperature, and are characterized by many unique properties such as ultralow volatility, high ionic conductivity, good thermal stability, low flammability, a wide electrochemical window, and tunable polarity and basicity/acidity. These properties create the possibilities of designing batteries with excellent safety, high energy/power density and long-term stability, and also provide better ways to synthesize known materials. IL-derived materials, such as poly(ionic liquids), ionogels and IL-tethered nanoparticles, retain most of the characteristics of ILs while being endowed with other favourable features, and thus they have received a great deal of attention as well. This review provides a comprehensive review of the various applications of ILs and derived materials in lithium and sodium batteries including Li/Na-ion, dual-ion, Li/Na-S and Li/Na-air (O2) batteries, with a particular emphasis on recent advances in the literature. Their unique characteristics enable them to serve as advanced resources, medium, or ingredient for almost all the components of batteries, including electrodes, liquid electrolytes, solid electrolytes, artificial solid-electrolyte interphases, and current collectors. Some thoughts on the emerging challenges and opportunities are also presented in this review for further development. PMID- 29393943 TI - The influence of interactions between isotopoloques on coherent, ultrafast vibrational dynamics of liquid C2Cl4. AB - The dynamics of intramolecular and intermolecular vibrations in liquid tetrachloroethylene are studied for the first time by use of femtosecond time resolved techniques, such as transient transmission spectroscopy and optical Kerr effect spectroscopy. Fourier transforms of time signals are compared with spontaneous Raman spectra for both isotropic and anisotropic components. The isotopic effect resulting from natural abundance of chlorine isotopes manifests itself as splitting of the isotropic spectra of intramolecular symmetric vibrations. Application of windowed Fourier transform enables us to study the dynamics of both spectral responses in real time and to analyze the role of intermolecular interactions on the coherence in the system. In order to describe the dynamics of molecules in a liquid and to explain the experimental results, we use a simple theoretical model taking into account intermolecular interactions, which allowed us to find vibrational and rotational life times. PMID- 29393944 TI - Role of antimicrobial peptides in controlling symbiotic bacterial populations. AB - Covering: up to 2018 Antimicrobial peptides (AMPs) have been known for well over three decades as crucial mediators of the innate immune response in animals and plants, where they are involved in the killing of infecting microbes. However, AMPs have now also been found to be produced by eukaryotic hosts during symbiotic interactions with bacteria. These symbiotic AMPs target the symbionts and therefore have a more subtle biological role: not eliminating the microbial symbiont population but rather keeping it in check. The arsenal of AMPs and the symbionts' adaptations to resist them are in a careful balance, which contributes to the establishment of the host-microbe homeostasis. Although in many cases the biological roles of symbiotic AMPs remain elusive, for a number of symbiotic interactions, precise functions have been assigned or proposed to the AMPs, which are discussed here. The microbiota living on epithelia in animals, from the most primitive ones to the mammals, are challenged by a cocktail of AMPs that determine the specific composition of the bacterial community as well as its spatial organization. In the symbiosis of legume plants with nitrogen-fixing rhizobium bacteria, the host deploys an extremely large panel of AMPs - called nodule-specific cysteine-rich (NCR) peptides - that drive the bacteria into a terminally differentiated state and manipulate the symbiont physiology to maximize the benefit for the host. The NCR peptides are used as tools to enslave the bacterial symbionts, limiting their reproduction but keeping them metabolically active for nitrogen fixation. In the nutritional symbiotic interactions of insects and protists that have vertically transmitted bacterial symbionts with reduced genomes, symbiotic AMPs could facilitate the integration of the endosymbiont and host metabolism by favouring the flow of metabolites across the symbiont membrane through membrane permeabilization. PMID- 29393945 TI - Structural definition of the BIL and DL: a new universal methodology to rationalize non-linear chi(2)(omega) SFG signals at charged interfaces, including chi(3)(omega) contributions. AB - This work provides unambiguous definitions from theoretical simulations of the two interfacial regions named the BIL (binding interfacial layer) and DL (diffuse layer) at charged solid/water and air/water interfaces. The BIL and DL nomenclature follows the pioneering work of Wen et al. [Phys. Rev. Lett. 2016, 116, 016101]. Our definitions are based on the intrinsic structural properties of water only. Knowing the BIL and DL interfacial regions, one is then able to deconvolve the chi(2)(omega) non-linear SFG (sum frequency generation) response into chi(omega) and chi(omega) contributions, thus providing a detailed molecular interpretation of these signals and of the measured total SFG. We furthermore show that the chi(omega) spectrum arises from the chi(3)(omega) non-linear third order contribution of bulk liquid water, here calculated for several charged interfaces and shown to be universal. The chi(omega) contribution therefore has the same origin in terms of molecular normal modes at any charged interface. The molecular interpretation of chi(omega) is hence at the heart of the unambiguous molecular comprehension and interpretation of the measured total SFG signal at any charged interface. PMID- 29393946 TI - Combinatorial selection of a two-dimensional 3d-TM-tetracyanoquinodimethane (TM TCNQ) monolayer as a high-activity nanocatalyst for CO oxidation. AB - The CO oxidation reaction on single 3d-transition metal catalytic sites in experimentally realized tetracyanoquinodimethane (TM-TCNQ) monolayers (TM = Sc Zn) is systematically investigated by means of first-principles calculations. Considering the stabilities, adsorption characteristics and thermodynamics of all the ten candidates (Sc-Zn), Sc-TCNQ is found to display the lowest activation energies and yield the highest catalytic activity for room temperature CO oxidation. Exploring the Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms, we find that the rate-limiting step of CO oxidation catalyzed by Sc TCNQ (CO + O2* -> OOCO*) can follow the LH mechanism with free energy barriers as low as 0.73 eV at 300 K. The second step of CO + O* -> CO2 can occur with rather small energy barriers via either LH or ER mechanisms. The high activity of Sc TCNQ can be attributed to its unique structural and electronic features by possessing high stability, optimum adsorption energies with adsorbates, and fast reaction kinetics. These results have significant implications for the synthesis of two-dimensional single atom catalysis for CO oxidation with low-cost and high activity at low temperature. PMID- 29393947 TI - Potential- and concentration-dependent self-assembly structures at solid/liquid interfaces. AB - We report the potential and concentration controlled assembly of an alkyl substituted benzo[1,2-b:4,5-b']dithiophene (DDBDT) on an Au(111) electrode by in situ electrochemical scanning tunneling microscopy (ECSTM). It is found that a lamellar structure is formed at low concentrations, while herringbone-like and rhombus structures are obtained at high concentrations. In situ STM results reveal that herringbone-like and rhombus structures could transform into lamellar structures when the electrode potential is tuned negatively. A phase diagram is obtained to illustrate the relationship and effects of concentration and substrate potential on the interfacial structures of DDBDT. Both the substrate potential and the solute concentration can modulate the self-assembly structure through changing the molecular surface density. The results provide important insights into the understanding and precise control of molecular self-assembly on solid surfaces through a combination of different approaches. PMID- 29393948 TI - Ultrafast intersystem crossing for nitrophenols: ab initio nonadiabatic molecular dynamics simulation. AB - Ultrafast intersystem crossing mechanisms for two p- and m-nitrophenol groups (PNP and MNP) have been investigated using ab initio nonadiabatic molecular dynamics simulations at the 6SA-CASSCF level of theory. Trajectory surface hopping simulation has been performed within an intersystem crossing network constructed from two low-lying singlets (S0 and S1) and two low-lying triplets (T1 and T2). It is found that the dominant relaxation S1 -> T2 pathway accounts for 65.4% (85.0%) of the quantum yield with a time constant of 13.4 fs (22 fs) and the S1 -> T2 -> S0 pathway accounts for 33.1% (13.5%) with a time constant of 275 fs (375 fs) for PNP (MNP). In comparison with the previously studied excited state proton transfer process for ONP, the dominant relaxation S1 -> T2 -> T1 pathway accounts for 49.3% with a time constant of 40 fs and the S1 -> T2 -> T1 > S0 pathway accounts for 47.5% with a time constant of 300 fs. The relaxation mechanisms and electronic structures of the intersystem crossings are in close relation with the relative motion between the torsion motions of the nitro-group and the hydroxyl group. The present simulation provides new physical insight for understanding ultrafast photochemical intersystem crossing dynamics. PMID- 29393949 TI - MoSx-coated NbS2 nanoflakes grown on glass carbon: an advanced electrocatalyst for the hydrogen evolution reaction. AB - Recent experimental and theoretical studies have demonstrated that two dimensional (2D) transition metal dichalcogenide (TMDC) nanoflakes are one of the most promising candidates for non-noblemetal electrocatalysts for hydrogen evolution reaction (HER). However, it is still challenging to optimize their conductivity and enrich active sites for highly efficient electrochemical performance. Herein, we report a chemical vapor deposition (CVD) and thermal annealing two-step strategy to controllably synthesize hybrid electrocatalysts consisting of metallic NbS2 nanoflake backbones and a highly catalytic active MoSx nanocrystalline shell on polished commercial glass carbon (GC). In addition, the amount of MoSx in the hybrids can be easily adjusted. We first demonstrate that a small amount of MoSx significantly promotes the HER activity of 2D NbS2 nanoflakes, which is in good agreement with the density functional theory (DFT) calculation results. Moreover, the optimized MoSx@NbS2/GC electrocatalyst displays superior HER activity with overpotential of -164 mV at -10 mA cm-2, a small Tafel slope of 43.2 mV dec-1, and prominent electrochemical stability. This study provides a new path for enhancing the HER performance of 2D TMDC nanoflakes. PMID- 29393950 TI - Extracting shape from curvature evolution in moving surfaces. AB - Shape is a crucial geometric property of surfaces, interfaces, and membranes in biology, colloidal and interface science, and many areas of physics. This paper presents theory, simulation and scaling of local shape and curvedness changes in moving surfaces and interfaces, under uniform normal motion, as in phase ordering transitions in liquid crystals. Previously presented measures of shape and curvedness are introduced in quantities and equations used in colloidal science and interfacial transport phenomena to separate shape effects from those of curvedness. Considering in parallel the new shape formalism with the classical curvature formalism, this paper sheds new light on what effects originate only from shape. The new shape evolution equations are solved under uniform normal surface flow. It is found that the solutions obey the so-called "astigmatism equation" fixing the linear relation between the radii of curvature. Astigmatic trajectories in the shape-curvedness phase plane, can be clearly classified into two modes: (i) constant shape evolution, and (ii) variable shape-variable curvedness. Shapes between spheres and cylinders follow the former mode for large curvedness and transition at smaller curvedness into the latter. Shapes' transitions between cylinder and saddles only follow the second mode. Under geometry-driven stagnation (i.e. zero normal velocity) shapes can be frozen. Evolving spheres and cylinders freeze into the same original shape, but perturbed cylinders can freeze into a variety of shapes including saddles. The results provide a useful complementary view on how to describe and control shape evolution in surfaces and interfaces, of wide interest in soft matter materials. PMID- 29393951 TI - Doping controlled pyro-phototronic effect in self-powered zinc oxide photodetector for enhancement of photoresponse. AB - The pyro-phototronic effect can be used in pyroelectric semiconductor materials to significantly contribute in enhancing the self-powered photoresponse of photodetectors (PDs) via modulation of the photogenerated charge density. The pyro-phototronic effect in zinc oxide (ZnO) nanorods (NRs) was exploited thoroughly by doping with halogen elements, such as fluorine, chlorine (Cl), bromine and iodine. Cl-doped ZnO NRs (Cl : ZnO NRs) induces a large number of free charge carriers to enhance the self-powered photoresponse behavior (nearly 333% enhancement in response current) due to the pyro-phototronic effect as compared to pristine ZnO NRs. Moreover, 405% enhancement in pyrocurrent was measured for the Cl : ZnO NRs PD under a ultraviolet illumination intensity of 3 mW cm-2, as compared to 0.3 mW cm-2, in the absence of external bias voltage. Furthermore, other photoresponse parameters such as responsivity, external quantum efficiency and specific detectivity are measured to be higher due to the pyro-phototronic effect. Therefore, this study reveals the direct use of the pyro phototronic effect to enhance the self-powered photoresponse. PMID- 29393952 TI - Single cells in nanoshells for the functionalization of living cells. AB - Inspired by the characteristics of cells in live organisms, new types of hybrids have been designed comprising live cells and abiotic materials having a variety of structures and functionalities. The major goal of these studies is to uncover hybridization approaches that promote cell stabilization and enable the introduction of new functions into living cells. Single-cells in nanoshells have great potential in a large number of applications including bioelectronics, cell protection, cell therapy, and biocatalysis. In this review, we discuss the results of investigations that have focused on the synthesis, structuration, functionalization, and applications of these single-cells in nanoshells. We describe synthesis methods to control the structural and functional features of single-cells in nanoshells, and further develop their applications in sustainable energy, environmental remediation, green biocatalysis, and smart cell therapy. Perceived limitations of single-cells in nanoshells have been also identified. PMID- 29393953 TI - Tin(iv) chalcogenoether complexes as single source precursors for the chemical vapour deposition of SnE2 and SnE (E = S, Se) thin films. AB - The molecular Sn(iv) complexes, [SnCl4{nBuS(CH2)3SnBu}] (2), [SnCl4(nBu2S)2] (3) and [SnCl4(nBu2Se)2] (4) have been prepared in good yield from reaction of SnCl4 with the appropriate chalcogenoether ligand in anhydrous hexane and, together with the known [SnCl4{nBuSe(CH2)3SenBu}] (1), employed as single source precursors for the low pressure chemical vapour deposition of the corresponding tin dichalcogenide thin films. At elevated temperatures the bidentate ligand precursors, (1) and (2), also form the tin monochalcogenides, SnSe and SnS, respectively. In contrast, (3) gave a mixture of phases, SnS2, Sn2S3 and SnS and (4) gave SnSe2 only. The morphologies, elemental compositions and crystal structures of the resulting films have been determined by scanning electron microscopy, energy dispersive X-ray spectroscopy, grazing incidence X-ray diffraction and Raman spectroscopy. Van der Pauw measurements on the SnS2, SnS and SnSe2 films confirm their resistivities to be 2.9(9), 266(3) and 4.4(3) Omega cm, respectively. PMID- 29393959 TI - Three-dimensional GaN dodecagonal ring structures for highly efficient phosphor free warm white light-emitting diodes. AB - Warm and natural white light (i.e., with a correlated colour temperature <5000 K) with good colour rendition (i.e., a colour rendering index >75) is in demand as an indoor lighting source of comfortable interior lighting and mood lighting. However, for warm white light, phosphor-converted white light-emitting diodes (WLEDs) require a red phosphor instead of a commercial yellow phosphor (YAG:Ce3+), and suffer from limitations such as unavoidable energy conversion losses, degraded phosphors and high manufacturing costs. Phosphor-free WLEDs based on three-dimensional (3D) indium gallium nitride (InGaN)/gallium nitride (GaN) structures are promising alternatives. Here, we propose a new concept for highly efficient phosphor-free warm WLEDs using 3D core-shell InGaN/GaN dodecagonal ring structures, fabricated by selective area growth and the KOH wet etching method. Electrically driven, phosphor-free warm WLEDs were successfully demonstrated with a low correlated colour temperature (4500 K) and high colour rendering index (Ra = 81). From our findings, we believe that WLEDs based on dodecagonal ring structures become a platform enabling a high-efficiency warm white light-emitting source without the use of phosphors. PMID- 29393960 TI - MD Anderson's Population Health Approaches to Cancer Prevention. AB - Texas's size and unique population demographics present challenges to addressing the state's cancer burden. The University of Texas MD Anderson Cancer Center is one of 69 National Cancer Institute-designated cancer centers across the United States. While these centers traditionally have focused on research, education and training, and providing research-driven patient care, they are in a unique position to collaboratively advance population health through cancer control. Unlike the traditional academic model of a three-legged stool representing research, education, and patient care, MD Anderson's mission includes a fourth leg that incorporates population health approaches. MD Anderson has leveraged state- and national-level data and freely available resources to develop population-health priorities and a set of evidence-based actions across policy, public and professional education, and community-based clinical service domains to address these priorities. Population health approaches complement dissemination and implementation research and treatment, and will be increasingly needed to address the growing cancer burden in Texas and the nation. PMID- 29393961 TI - Measuring and Managing Population Health. AB - Health care delivery and health promotion require timely, accurate, and useful information. Nowhere are useful data more needed than population health management. Although mountains of health-related data exist, useful information is often diffuse, poorly organized, and often inaccurate and incomplete, and doesn't serve those providing health care to individual patients, managing care for groups of patients, or promoting health for communities. Information and communication technologies are rapidly evolving to enhance population health management. These tools include electronic health records, health information exchanges, patient portals and personal health records, telemedicine and virtual health tools, the internet and social media, mobile devices, and wearable sensors. We describe each of these emerging health technologies and their future opportunities for enhancing population health. PMID- 29393962 TI - The State of Health in Texas. AB - At the beginning of the 20th century, the major health threats to individual and community health in the United States were infectious diseases, injuries due to unsafe workplaces, diseases due to poor nutrition, and poor maternal and infant health. During the next 100-plus years, tremendous advances were made in longevity and health status. As the impact of certain historically significant diseases decreased, however, the pattern of public/population disease burden became dominated by chronic diseases such as cardiovascular disease, diabetes, asthma, and cancer. In Texas in 2015, chronic diseases made up the top four causes of death. Public health professionals are largely focused on identifying the risk factors for these chronic diseases via enhanced morbidity and mortality surveillance. In addition to health care providers and the health care sector, a cross-section of other stakeholders, including businesses, communities, and social services, must work collaboratively, creatively, and effectively to reduce the chronic disease burden. PMID- 29393963 TI - Improving Health in Hard-to-Reach Communities. AB - The health impact pyramid offers a framework for considering the relative significance of socioeconomic determinants of health and for prioritizing interventions that may be effective in improving health outcomes in hard-to-reach and rural populations. Barriers to health care delivery in rural settings are outlined with examples provided. Demonstration projects in East and West Texas are reviewed. Those programs reach unique populations such as agricultural and migrant workers and those with mental illness by using innovative approaches, such as the use of specially trained community health workers and telehealth and telemedicine. Having a health impact on hard-to-reach groups and rural populations is largely a function of overcoming numerous barriers. Adopting a population health approach that engages the community in overcoming those barriers is likely to be more effective in producing improved health outcomes. PMID- 29393964 TI - Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014. AB - BACKGROUND: No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed. METHODS: Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use. RESULTS: This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival. CONCLUSIONS: Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. (c) 2018 American Cancer Society. PMID- 29393966 TI - Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: A systematic review. AB - Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated; however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyze the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF. PMID- 29393965 TI - De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review. AB - De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an a vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome. PMID- 29393968 TI - Battle in stem cell niches: Canonical versus noncanonical Wnt signaling. PMID- 29393967 TI - Inpatient utilization and disparities: The last year of life of adolescent and young adult oncology patients in California. AB - BACKGROUND: Studies of adolescent and young adult (AYA) oncology end-of-life care utilization are critical because cancer is the leading cause of nonaccidental AYA death and end-of-life care contributes significantly to health care expenditures. This study was designed to determine the quantity of and disparities in inpatient utilization in the last year of life of AYAs with cancer. METHODS: The California Office of Statewide Health Planning and Development administrative discharge database, linked to death certificates, was used to perform a population-based analysis of cancer patients aged 15 to 39 years who died in 2000-2011. The number of hospital days and the inpatient costs were determined for each patient in the last year of his or her life, as were clinical and sociodemographic factors associated with high inpatient utilization. Admission patterns as death approached were also evaluated. RESULTS: The 12,883 patients were admitted for 40 days on average in the last year of life, and this cost $151,072 per patient in inpatient costs. As death approached, the admission rates and the percentage of all admissions occurring at nonspecialty centers increased. Five percent of patients used 20% of bed days in the last year (high utilizers). Factors associated with high utilization included younger age (15-30 years), Hispanic ethnicity, non-health maintenance organization insurance, and hematologic malignancies. CONCLUSIONS: AYA oncology decedents were admitted for 40 days in their last year of life. Subgroups with high utilization had distinct sociodemographic and clinical characteristics, and nonspecialty center admissions increased as death approached. This demonstrates the need for palliative care at nonspecialty centers. Future studies need to determine whether these patterns are goal-concurrent, include high utilizers, and monitor the effects of health care reform. Cancer 2018;124:1819-27. (c) 2018 American Cancer Society. PMID- 29393969 TI - Worldwide distribution of common IDUA pathogenic variants. AB - Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the alpha-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analyzed on a worldwide scale. To address this, we analyzed the genotypes of MPS I patients from 35 published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in Northern and Eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management. PMID- 29393970 TI - Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation. AB - The brief lifespan of the polymorphonuclear neutrophil (PMN) is regulated through its capacity to undergo apoptosis, a constitutive process that is actively inhibited during sepsis. We sought to define the cellular mechanisms through which Heat Shock Protein 90 (Hsp90) prolongs the survival of inflammatory PMN. We evaluated Hsp90 expression and interaction with client proteins in PMNs from patients with sepsis and in healthy control PMNs treated with LPS (1 MUg/mL). Hsp90 activity was inhibited pharmacologically using radicicol (Rad; 1 MUM), and Hsp90 transcription was silenced in septic PMN using siRNA. PMN apoptosis was evaluated by flow cytometry and expression of cleaved caspase-8 and -3. Septic PMNs showed reduced rates of apoptosis compared with control PMNs 21 h after isolation, and Hsp90-alpha mRNA was significantly more abundant in septic PMN. Caspase-8 coimmunoprecipitated with Hsp90, c-Src, and the p85 inhibitory subunit of PI3K in both septic and LPS-treated PMN. Inhibition of Hsp90 activity with Rad or its translation using siRNA restored basal rates of apoptosis in both septic and LPS-treated PMN. Radicicol further reduced c-Src protein abundance, increased the ubiquitination of caspase-8 and c-Src, and enhanced the cleavage of caspase-8 and -3. We conclude that Hsp90 prolongs the survival of activated neutrophils by stabilizing a molecular complex of c-Src kinase and caspase-8, preventing their ubiquitination, and resulting in inhibition of the catalytic activity of caspase 8 and -3. PMID- 29393971 TI - Oliceridine, a Novel G Protein-Biased Ligand at the MU-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model. AB - Oliceridine is a novel G protein-biased ligand at the MU-opioid receptor that differentially activates G protein coupling while mitigating beta-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (>=4 on a 0-10 scale). In addition, regimens in which oliceridine was self administered via a patient-controlled analgesia device were also simulated. The simulated population included 10% CYP2D6 poor metabolizers (PM). The simulation results suggest that oliceridine doses of 1-3 mg prn should be effective in reducing NPRS scores relative to placebo. The simulations also revealed that a 1 mg "supplemental dose" given 0.25 hour after the loading dose would decrease NPRS scores further in almost one-third of patients. In addition, if oliceridine is administered prn, a longer interval between doses is observed in simulated PM patients, consistent with their reduced oliceridine clearance. Because this longer average dosing interval is predicted to decrease oliceridine exposure in PM patients, the need to know the patient's CYP2D6 genotype for dosing is effectively obviated. PMID- 29393972 TI - Evaluation of microRNA stability in feces from healthy dogs. AB - BACKGROUND: Gastrointestinal cancer accounts for approximately 8% of all canine malignancies. Early detection of cancer may have a tremendous impact on both treatment options and prognosis. MicroRNAs (miRNAs), a class of noncoding RNAs that can be found stably expressed in body fluids and feces, have been suggested as valuable human cancer biomarkers. OBJECTIVES: The purpose of the study was to investigate the feasibility of detecting miRNAs in canine feces and to determine the miRNA stability in fecal samples stored at different temperatures for different duration. METHODS: The levels of 4 Canine familiaris (cfa) miRNAs (cfa miR-16, cfa-miR-20a, cfa-miR-21, and cfa-miR-92a) were investigated by quantitative real-time PCR(qPCR) in fecal samples from 10 healthy dogs. Fecal samples were collected at 3 different time points and samples from the first time point were stored at different temperatures and for a different duration. RESULTS: A statistically significant difference was found in miRNA levels from samples stored at room temperature compared with samples stored at -20 degrees C for cfa-miR-16 and cfa-miR-21. No significant difference was found in the level of the investigated miRNAs over time. CONCLUSIONS: Overall, miRNAs are present in dog feces at measurable levels. Some miRNAs seem to be subject to a higher degree of degradation in samples stored at room temperature for 24 hours compared with samples frozen after collection at -20 degrees C. The investigated miRNAs were stably expressed over time. This study provides the basis for further research on miRNA expression profiles as biomarkers for gastrointestinal cancer in dogs. PMID- 29393973 TI - Application of tendon plating to manage failed calcaneal tendon repairs in a dog. AB - OBJECTIVE: To report the application of a plate to treat a complicated calcaneal tendon rupture and the resulting outcome. STUDY DESIGN: Clinical case report. ANIMALS: A 3-year-old Labrador retriever. METHODS: A 3-year-old Labrador retriever was treated for a partially ruptured calcaneal tendon. Two primary tendon repairs with sutures and external fixation had failed. A veterinary cuttable plate was placed to internally span the tendon over the primary repair. The external fixation that had been previously placed was maintained, and the dog was placed in a non-weight-bearing sling for 3 weeks after surgery. Adjunct therapy included an injection of platelet-rich plasma in the tendon and laser therapy. The external fixator was removed 4 weeks postoperatively, and the plate was removed 8 weeks postoperatively. RESULTS: A mature fibrous union bridged the site of anastomosis 8 weeks after surgery. The owners reported normal activity 6 months after surgery and symmetric hock angles and musculature 2 years after surgery. CONCLUSION: Adjunct plating of previously failed calcaneal tendon repairs in a dog resulted in an excellent long-term outcome. CLINICAL SIGNIFICANCE: Plating tendons can be considered as an additional method that may improve tendon apposition and decrease gap formation. PMID- 29393974 TI - Contrasting metabolic profiles of tasty Andean varieties of tomato fruit in comparison with commercial ones. AB - BACKGROUND: The fruits of most commercial tomato cultivars (Solanum lycopersicum L.) are deficient in flavour. In contrast, traditional 'criollo' tomato varieties are appreciated for fruit of excellent organoleptic quality. Small farmers from the Andean valleys in Argentina have maintained their own tomato varieties, which were selected mainly for flavour. This work aims to correlate the chemical composition of the fruit with the sensory attributes of eight heirloom tomato varieties. The long-term goal is to identify potential candidate genes capable of altering the chemicals involved in flavour. RESULTS: A sensory analysis was conducted and the metabolomics of fruit were determined. The data revealed that defined tomato aroma and sourness correlated with citrate and several volatile organic compounds (VOC), such as alpha-terpineol, p-menth-1-en-9-al, linalool and 3,6-dimethyl-2,3,3a,4,5,7a-hexahydrobenzofuran (DMHEX), a novel volatile recently identified in tomato. Two sensory attributes - sweetness and a not-acidic taste - correlated with the characteristic tomato taste, and also with fructose, glucose, and two VOCs, benzaldehyde, and 2-methyl-2-octen-4-one. CONCLUSIONS: These data provide new evidence of the complex chemical combination that induced the flavour and aroma of the good-tasting 'criollo' tomato fruit. That is, the compounds that correlated with defined tomato aroma and acidic taste did not correlate with sweetness, or with characteristic tomato taste. (c) 2018 Society of Chemical Industry. PMID- 29393975 TI - The pharmacodynamic and clinical trial evidence for statin dose. AB - Statin doses around estimated effective dose 50 (ED50) can reduce myocardial infarction by over 25% and mortality by around 10%. Being a competitive enzyme inhibitor, statin efficacy plateaus at doses that are multiples above the ED50, whilst on- and off-target adverse events increase in number and severity with increasing dose. For example, myopathy has been shown to increase by up to 29 fold and liver dysfunction by up to nine-fold as statin dose is increased. Doses of up to 40-fold ED50 have been promoted, but above five-fold ED50, for example 10 mg of atorvastatin, there is no randomized controlled clinical trial evidence that coronary mortality is lowered, or that survival is increased. PMID- 29393977 TI - ITGB4 is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness. AB - Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to increase asthma susceptibility and exacerbate asthma severity, the mechanism and implication of these defects remain uncertain. Integrin beta4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. In this study, we demonstrated that ITGB4 deficiency leads to severe allergy-induced airway inflammation and airway hyper responsiveness (AHR) in mice. After house dust mite (HDM) challenge, epithelial cell-specific ITGB4-deleted mice showed increased lymphocyte, eosinophil, and neutrophil infiltration into lung compared with that of the wild-type mice. ITGB4 deficiency also resulted in increased expression of the Th2 cytokine IL-4, IL-13, and the Th17 cytokine IL-17A in the lung tissue and in the T cells after HDM challenge. The aggravated inflammation in ITGB4 defect mice was partly caused by enhanced disrupted epithelial barrier integrity after HDM stress, which induced the increased thymic stromal lymphopoietin secretion from airway epithelial cells. This study therefore demonstrates that ITGB4 plays a pivotal role in containing allergen-mediated lung inflammation and airway hyper-responsiveness in allergic asthma. PMID- 29393976 TI - Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury. AB - Bacterial pneumonia is a leading cause of death late after burn injury due to the severe immune dysfunction that follows this traumatic injury. The Mechanistic/Mammalian Target of Rapamycin (mTOR) pathway drives many effector functions of innate immune cells required for bacterial clearance. Studies have demonstrated alterations in multiple cellular processes in patients and animal models following burn injury in which mTOR is a central component. Goals of this study were to (1) investigate the importance of mTOR signaling in antimicrobial activity by neutrophils and (2) therapeutically target mTOR to promote normalization of the immune response. We utilized a murine model of 20% total body surface area burn and the mTOR-specific inhibitor rapamycin. Burn injury led to innate immune hyperresponsiveness in the lung including recruitment of neutrophils with greater ex vivo oxidative activity compared with neutrophils from sham-injured mice. Elevated oxidative function correlated with improved clearance of Pseudomonas aeruginosa, despite down-regulated expression of the bacterial-sensing TLR molecules. Rapamycin administration reversed the burn injury-induced lung innate immune hyperresponsiveness and inhibited enhanced bacterial clearance in burn mice compared with untreated burn mice, resulting in significantly higher mortality. Neutrophil ex vivo oxidative burst was decreased by rapamycin treatment. These data indicate that (1) neutrophil function within the lung is more important than recruitment for bacterial clearance following burn injury and (2) mTOR inhibition significantly impacts innate immune hyperresponsiveness, including neutrophil effector function, allowing normalization of the immune response late after burn injury. PMID- 29393978 TI - Hu antigen R (HuR) heterogeneous expression quantification as a prognostic marker of melanoma. AB - BACKGROUND: Prognostic markers for melanoma, particularly for stage II disease, are needed for the risk-benefit evaluation of future adjuvant therapies. The mainly nuclear RNA-binding protein human antigen R (HuR) regulates the protein expression of thousands of mRNAs, its own heterogeneous expression could therefore reflect tumor heterogeneity and plasticity. Here, we evaluate its quantification in primary melanoma as a marker of metastatic outcome. METHODS: We conducted an immunohistochemistry-based automated quantification of HuR nuclear expression heterogeneity in primary melanomas, most with Breslow thickness >= 1 mm and calculated the dimensionless fourth moment, that is, the kurtosis of HuR (HuR K) expression distribution. Twelve tumors from patients with no metastatic disease were compared to a similar number of tumors from patients who had metastatic disease at 2 years follow up. RESULTS: HuR K value appeared significantly higher in the non-metastatic group comparatively to the metastatic group (P = 2.84 * 10-3 , 1-tailed Wilcoxon rank-sum test). Moreover, compared to the Breslow thickness, HuR K value appeared as a more robust marker of metastatic outcome (respective areas under receiver operating characteristic curves 0.84 and 0.87). CONCLUSION: Our data need confirmation on a large cohort, however strongly suggest that HuR expression heterogeneity quantification using kurtosis, could be used as a prognostic marker in melanoma. PMID- 29393979 TI - Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation. AB - The generation and regulation of innate immune signals are key determinants of autoimmune pathogenesis. Emerging evidence suggests that parallel processes operating in the setting of solid tumors can similarly determine the balance between tolerance and immunity and ultimately the effectiveness of the antitumor immune response. In both contexts, self-specific responses start with innate immune cell activation that leads to the initial break in self-tolerance, which can be followed by immune response amplification and maturation through innate adaptive crosstalk, and finally immune-mediated tissue/tumor destruction that can further potentiate inflammation. Of particular importance for these processes is type I IFN, which is induced in response to endogenous ligands, such as self nucleic acids, and acts on myeloid cells to promote the expansion of autoreactive or tumor-specific T cells and their influx into the target tissue. Evidence from the study of human disease pathophysiology and genetics and mouse models of disease has revealed an extensive and complex network of negative regulatory pathways that has evolved to restrain type I IFN production and activity. Here, we review the overlapping features of self- and tumor-specific immune responses, including the central role that regulators of the type I IFN response and innate immune cell activation play in maintaining tolerance, and discuss how a better understanding of the pathophysiology of autoimmunity can help to identify new approaches to promote immune-mediated tumor destruction. PMID- 29393980 TI - Bartonella henselae infection in a dog with recalcitrant ineffective erythropoiesis. AB - Ineffective erythropoiesis was diagnosed in an 8-year-old male castrated Labrador Retriever. Despite treatment with immunosuppressive therapy for suspected immune mediated erythrocyte maturation arrest, resolution of the nonregenerative anemia was not achieved. Following documentation of Bartonella henselae bacteremia by Bartonella alpha proteobacteria growth medium (BAPGM) enrichment blood culture, immunosuppressive therapy was discontinued, and the anemia resolved following prolonged antibiotic therapy. Bartonella immunofluorescent antibody testing was negative, whereas B henselae western blot was consistently positive. The contribution of B henselae bacteremia to ineffective erythropoiesis remains unknown; however, the potential role of B henselae in the pathophysiology of bone marrow dyscrasias warrants additional investigation. PMID- 29393981 TI - MADA: Malagasy Animal trait Data Archive. AB - Species are characterized by their behavioral, physiological, and ecological attributes, which determine their role in ecosystems. In turn, ecosystems and their functions are defined by the species that inhabit them. Thus, evaluating the functional diversity and distributions of species is of utmost importance to studies of biogeography, community ecology, macroevolution, and conservation. The functional diversity of species are determined by traits such as diet, foraging strata, trophic level, activity cycle, litter size, generation length, habitat breadth, and body mass. While there has been a recent growth of information regarding the vertebrate taxa of Madagascar, this information is not always easy to access (non-digitized), and is often fragmented by taxon, location, trait, or combinations thereof. Here, we present the Malagasy Animal trait Data Archive (MADA), a compilation of these and other functional traits, representing the ecological and geographical diversity of all 214 extant mammal and 242 bird species of Madagascar. Data were collected from extensive literature reviews. This Archive is currently limited by select cases of missing data, errors, and uncertainty in the literature; however, it represents the most comprehensive collection of functional trait data of Malagasy mammals and birds to date. The structure of the database allows for different levels of information (and specificity) in each entry and organization by taxon, range, bioclimate, and trait. MADA will be continuously updated as new data become available. Potential uses of MADA include ecological research on the trait or trophic structure of communities, inquiries regarding the mechanisms of community assembly, comparative studies of functionally (dis)similar species, and conservation efforts concerned with the loss of ecosystem function. Madagascar is simultaneously home to one of the most exclusive, diverse, and endangered faunas of the world, making MADA a uniquely valuable resource for biodiversity science and conservation. No copyright restrictions are associated with this dataset. We would appreciate that researchers cite this paper if using all or part of the datasets. PMID- 29393982 TI - Propagules are not all equal: traits of vegetative fragments and disturbance regulate invasion success. AB - Invasion success is regulated by multiple factors. While the roles of disturbance and propagule pressure in regulating the establishment of non-native species are widely acknowledged, that of propagule morphology (a proxy for quality) is poorly known. By means of a multi-factorial field experiment, we tested how the number (5 vs. 10) and quality (intact, without fronds or without rhizoids) of fragments of the clonal invasive seaweed, Caulerpa cylindracea, influenced its ability to establish in patches of the native seagrass, Posidonia oceanica, exposed to different intensities of disturbance (0, 50, or 100% reduction in canopy cover). We hypothesized that the ability of fragments to establish would be greater for intact fragments (high quality) and reduced more by frond removal (low quality) than rhizoid removal (intermediate quality). At low propagule pressure or quality, fragment establishment was predicted to increase with increasing disturbance, whereas, at high propagule pressure or quality, it was predicted to be high regardless of disturbance intensity. Disturbance intensity, fragment number and quality had independent effects on C. cylindracea establishment success. Disturbance always facilitated fragment establishment. However, fragments retaining fronds, either intact or deprived of rhizoids, had higher establishment success than fragments deprived of fronds. Increasing propagule number had weak effects on the cover of C. cylindracea. Our results demonstrate that propagule traits enabling the acquisition of resources made available by disturbance can be more important than propagule number in determining the establishment and spread of clonal non-native plants. More generally, our study suggests that propagule quality is a key, yet underexplored, determinant of invasion success. PMID- 29393983 TI - A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis. AB - Coinhibitory molecules, such as PD-1, CTLA-4, 2B4, and BTLA, are an important new family of mediators in the pathophysiology of severe bacterial and/or fungal infection, as well as the combined insults of shock and sepsis. Further, the expression of these molecules may serve as indicators of the immune status of the septic individual. Using PD-1:PD-L as an example, we discuss in this review how such checkpoint molecules may affect the host response to infection by mediating the balance between effective immune defense and immune-mediated tissue injury. Additionally, we explore how the up-regulation of PD-1 and/or PD-L1 expression on not only adaptive immune cells (e.g., T cells), but also on innate immune cells (e.g., macrophages, monocytes, and neutrophils), as well as nonimmune cells during sepsis and/or shock contributes to functional alterations often with detrimental sequelae. PMID- 29393984 TI - Underestimation of Vertebral Fractures After Denosumab Discontinuation. PMID- 29393985 TI - Validation of molecular force field parameters for peptides including isomerized amino acids. AB - Recently, stereoinversions and isomerizations of amino acid residues in the proteins of living beings have been observed. Because isomerized amino acids cause structural changes and denaturation of proteins, isomerizations of amino acid residues are suspected to cause age-related diseases. In this study, AMBER molecular force field parameters were tested by using computationally generated nonapeptides and tripeptides including stereoinverted and/or isomerized amino acid residues. Energy calculations by using density functional theory were also performed for comparison. Although the force field parameters were developed by parameter fitting for l-alpha-amino acids, the accuracy of the computational results for d-amino acids and beta-amino acids was comparable to those for l alpha-amino acids. The conformational energies for tripeptides calculated by using density functional theory were reproduced more accurately than those for nonapeptides calculated by using the molecular mechanical force field. The evaluations were performed for the ff99SB, ff03, ff12SB, and the latest ff14SB force field parameters. PMID- 29393986 TI - Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice. AB - OBJECTIVES: This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. METHODS: Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. RESULTS: Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70 years and cohort 2: 75 years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. CONCLUSION: Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086). PMID- 29393987 TI - Method for retrospective estimation of natural head movement during structural MRI. AB - BACKGROUND: Head motion during brain structural MRI scans biases brain morphometry measurements but quantitative retrospective methods estimating head motion from structural MRI have not been evaluated. PURPOSE: To verify the hypothesis that two metrics retrospectively computed from MR images: 1) average edge strength (AES, reduced with image blurring) and 2) entropy (ENT, increased with blurring and ringing artifacts) could be sensitive to in-scanner head motion during acquisition of T1 -weighted MR images. STUDY TYPE: Retrospective. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: In all, 83 healthy control (HC) and 120 Parkinson's disease (PD) patients. FIELD STRENGTH/SEQUENCE: 3D magnetization-prepared rapid gradient-echo (MPRAGE) images at 3T. ASSESSMENT: We 1) compared AES and ENT distribution between HC and PD; 2) evaluated the correlation between tremor score (TS) and AES (or ENT) in PD; and 3) investigated cortical regions showing an association between AES (or ENT) and local and network-level covariance measures of cortical thickness (CT), gray to white matter contrast (GWC) and gray matter density maps (GMx). STATISTICAL TESTS: 1) Student's t-test. 2) Spearman's rank correlation. 3) General linear model and partial least square analysis. RESULTS: AES, but not ENT, differentiated HC and PD (P = 0.02, HC median AES = 39.8, interquartile range = 9.8, PD median AES = 37.6, interquartile range = 8.1). In PD, AES correlated negatively with TS (rho = -0.21, P = 0.02) and showed a significant relationship (|Z| >3, P < 0.001) with structural covariance of CT and GWC in 54 out of 68 cortical regions. DATA CONCLUSION: In clinical populations prone to head motion, AES can provide a reliable retrospective index of motion during structural scans, identifying brain areas whose morphometric measures covary with motion. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:927-937. PMID- 29393988 TI - Biocatalytic Conversion of Cyclic Ketones Bearing alpha-Quaternary Stereocenters into Lactones in an Enantioselective Radical Approach to Medium-Sized Carbocycles. AB - Cyclic ketones bearing alpha-quaternary stereocenters underwent efficient kinetic resolution using cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus. Lactones possessing tetrasubstituted stereocenters were obtained with high enantioselectivity (up to >99 % ee) and complete chemoselectivity. Preparative-scale biotransformations were exploited in conjunction with a SmI2 mediated cyclization process to access complex, enantiomerically enriched cycloheptan- and cycloctan-1,4-diols. In a parallel approach to structurally distinct products, enantiomerically enriched ketones from the resolution with an alpha-quaternary stereocenter were used in a SmI2 -mediated cyclization process to give cyclobutanol products (up to >99 % ee). PMID- 29393990 TI - Simulating the human body's microclimate using automatic coupling of CFD and an advanced thermoregulation model. AB - This study aims to develop an approach to couple a computational fluid dynamics (CFD) solver to the University of California, Berkeley (UCB) thermal comfort model to accurately evaluate thermal comfort. The coupling was made using an iterative JavaScript to automatically transfer data for each individual segment of the human body back and forth between the CFD solver and the UCB model until reaching convergence defined by a stopping criterion. The location from which data are transferred to the UCB model was determined using a new approach based on the temperature difference between subsequent points on the temperature profile curve in the vicinity of the body surface. This approach was used because the microclimate surrounding the human body differs in thickness depending on the body segment and the surrounding environment. To accurately simulate the thermal environment, the numerical model was validated beforehand using experimental data collected in a climate chamber equipped with a thermal manikin. Furthermore, an example of the practical implementations of this coupling is reported in this paper through radiant floor cooling simulation cases, in which overall and local thermal sensation and comfort were investigated using the coupled UCB model. PMID- 29393989 TI - Selective Anion Extraction and Recovery Using a FeII4 L4 Cage. AB - Selective anion extraction is useful for the recovery and purification of valuable chemicals, and in the removal of pollutants from the environment. Here we report that FeII4 L4 cage 1 is able to extract an equimolar amount of ReO4- , a high-value anion and a nonradioactive surrogate of TcO4- , from water into nitromethane. Importantly, the extraction was efficiently performed even in the presence of 10 other common anions in water, highlighting the high selectivity of 1 for ReO4- . The extracted guest could be released into water as the cage disassembled in ethyl acetate, and then 1 could be recycled by switching the solvent to acetonitrile. The versatile solubility of the cage also enabled complete extraction of ReO4- (as the tetrabutylammonium salt) from an organic phase into water by using the sulfate salt of 1 as the extractant. PMID- 29393991 TI - Comparison of crop yield sensitivity to ozone between open-top chamber and free air experiments. AB - Assessments of the impacts of ozone (O3 ) on regional and global food production are currently based on results from experiments using open-top chambers (OTCs). However, there are concerns that these impact estimates might be biased due to the environmental artifacts imposed by this enclosure system. In this study, we collated O3 exposure and yield data for three major crop species-wheat, rice, and soybean-for which O3 experiments have been conducted with OTCs as well as the ecologically more realistic free-air O3 elevation (O3 -FACE) exposure system; both within the same cultivation region and country. For all three crops, we found that the sensitivity of crop yield to the O3 metric AOT40 (accumulated hourly O3 exposure above a cut-off threshold concentration of 40 ppb) significantly differed between OTC and O3 -FACE experiments. In wheat and rice, O3 sensitivity was higher in O3 -FACE than OTC experiments, while the opposite was the case for soybean. In all three crops, these differences could be linked to factors influencing stomatal conductance (manipulation of water inputs, passive chamber warming, and cultivar differences in gas exchange). Our study thus highlights the importance of accounting for factors that control stomatal O3 flux when applying experimental data to assess O3 impacts on crops at large spatial scales. PMID- 29393992 TI - Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder resulting in vascular dysplasia and formation of arteriovenous malformations. Recurrent epistaxis is a hallmark of the disease. An array of medical therapies are used in this patient population, but robust evidence-based recommendations regarding the medical treatment of epistaxis are lacking. This systematic review was performed to look at the current literature and make meaningful evidence-based recommendations. METHODS: A search of the Ovid MEDLINE, Embase, and Cochrane databases was conducted by a research librarian. Abstracts in the English language and published in a peer-review journal were reviewed for relevance and inclusion. PRISMA guidelines were followed. RESULTS: Eighteen studies met the inclusion criteria. In a few small studies, thalidomide was shown to consistently improve severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion. Tranexamic acid appeared to only impact the epistaxis severity score and not other clinical outcomes. Selective estrogen modulators (SERMs), propranolol, rose geranium oil, and N-acetylcysteine, have demonstrated promising efficacy in small trials. CONCLUSION: Appropriate medical therapies for epistaxis outcomes in HHT remain undefined, and there is no "gold standard." Many of the studies are small and the data reported are heterogeneous, and therefore the ability to make strong evidence-based recommendations is limited. However, many different medications appear to be promising options. PMID- 29393994 TI - Characterization of the novel HLA-A*24:391 allele by sequencing-based typing. AB - HLA-A*24:391 differs from HLA-A*24:02:01:01 by one nucleotide substitution at position 33. PMID- 29393993 TI - A Fluorescent Ditopic Rotaxane Ion-Pair Host. AB - We report a rotaxane based on a simple urea motif that binds Cl- selectively as a separated ion pair with H+ and reports the anion binding event through a fluorescence switch-on response. The host selectively binds Cl- over more basic anions, which deprotonate the framework, and less basic anions, which bind more weakly. The mechanical bond also imparts size selectivity to the ditopic host. PMID- 29393995 TI - Aqueous-Phase Synthesis of Mesoporous Zr-Based MOFs Templated by Amphoteric Surfactants. AB - Zr-based mesoporous metal-organic frameworks (mesoMOFs) with uniform mesochannels and crystallized microporous framework were constructed in a water-based system using amphoteric surfactants as templates. Aqueous-phase synthesis guaranteed the formation of rod-shaped surfactant micelles. Meanwhile, the carboxylate groups of amphoteric surfactants provided the anchoring to bridge Zr-oxo clusters and surfactant assemblies. As a result, the directed crystallization of MOFs proceeded around cylindrical micelles and the hierarchical micro- and mesostructure was produced. The dimensions of mesopores were easily tailored by changing the alkyl chain length of the applied surfactants. The included surfactant was effectively extracted thanks to the exceptional stability of the obtained Zr-based mesoMOFs. The almost complete occupation of the mesopore by cytochrome c exemplifies the accessibility of the mesochannels, suggesting the potential applications of the obtained mesoMOFs with bulky molecules. PMID- 29393996 TI - Surfboard-related intraorbital foreign bodies: a case series and radiological considerations. PMID- 29393997 TI - A multicentre integration of a computer-led follow-up of prostate cancer is valid and safe. AB - OBJECTIVE: To test a computer-led follow-up service for prostate cancer in two UK hospitals; the testing aimed to validate the computer expert system in making clinical decisions according to the individual patient's clinical need with a valid model accurately identify patients with disease recurrence or treatment failure based on their blood test and clinical picture. PATIENTS AND METHODS: A clinical-decision support system (CDSS) was developed from European (European Association of Urology) and national (National Institute for Health and Care Excellence) guidelines along with knowledge acquired from Urologists. This model was then applied in two UK hospitals to review patients after prostate cancer treatment. These patients' data (n = 200) were then reviewed by two independent urology consultants (blinded from the CDSS and the other consultant's rating) and the agreement was calculated by kappa statistics for validation. The second endpoint was to verify the system by estimating the system reliability. RESULTS: The two individual urology consultants identified 12% and 15% of the patients to have potential disease progression and recommended their referral to urology care. The kappa coefficient for the agreement between the CDSS and the two consultants was 0.81 (P < 0.001) and 0.84 (P < 0.001). The agreement amongst both specialist was also high with k = 0.83 (P < 0.001). The system reliability was estimated on all cases and this demonstrated 100% repeatability of the decisions. CONCLUSION: A CDSS follow-up is a valid model for providing safe follow-up for prostate cancer. PMID- 29393998 TI - Prevention and Treatment of Postoperative Pain after Lumbar Spine Procedures: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: In the past 2 decades, in developed countries, spine procedures (surgical and percutaneous) had the highest absolute increase in case volume trend. The optimal approach to prevent and treat postoperative pain is continuously evolving. This systematic literature review presents evidence on safety and efficacy of pharmacological and nonpharmacological therapies to prevent and treat postoperative pain after lumbar spine procedures. DATABASES AND DATA TREATMENT: Publications listed in PUBMED and EMBASE were considered to identify randomized clinical trials suitable for inclusion in this systematic review. Key words for literature search were selected, with authors' agreement, using the PICOS approach (participants, interventions, comparisons, outcomes, and study design). RESULTS: Fifty-nine randomized clinical trials (involving a total of 4,238 patients, with ages ranging from 18 to 86 years) published between January 2012 and September 2017 were retrieved. Data are presented according to the timing of therapy administration. CONCLUSION AND RECOMMENDATIONS: Clinical evidence on perioperative pain management in patients undergoing spine procedures have significantly evolved after the review published in 2012. The aim of this systematic review was to report the latest evidence published. These include the preoperative use of dexamethasone, which was shown to be able to reduce pain at mobilization but not to reduce pain at rest or total morphine consumption; the use of gabapentinoids as part of a multimodal analgesic approach; and the safety and effectiveness of the intraoperative use of ketamine, dexketoprofen, and tramadol. Finally, electrical nerve stimulation is gaining interest and is potentially suitable for clinical needs. PMID- 29393999 TI - Quantitative Monitoring and Visualization of Hydrogen Sulfide In Vivo Using a Luminescent Probe Based on a Ruthenium(II) Complex. AB - Development of novel bioanalytical methods for monitoring of H2 S is key toward understanding the physiological and pathological functions of this gasotransmitter in live organisms. A ruthenium(II)-complex-based luminescence probe, Ru-MDB (MDB: 4'-methyl-[2,2'-bipyridine]-4-yl)methyl 2-((2,4 dinitrophenyl)thio)benzoate), was developed by introducing a new H2 S responsive masking moiety to a red-emitting RuII luminophore. Cleavage of this masking group by a H2 S-triggered reaction leads to a luminescence "off-on" response. The long lived emissions of Ru-MDB and its reaction product with H2 S allowed quantitative detection of H2 S in autofluorescence-rich human sera and adult zebrafish organs using the time-gated luminescence mode. Ru-MDB exhibits red emission, a large Stokes shift, high specificity and sensitivity for H2 S detection, and low cytotoxicity, which enables imaging and flow cytometry analysis of lysosomal H2 S generation in live inflamed cells under drug stimulation. Monitoring of H2 S in live Daphnia magna, zebrafish embryos, adult zebrafish, and mice, was conducted by in vivo imaging using Ru-MDB as a probe. PMID- 29394000 TI - Influence of the location of nasal polyps on olfactory airflow and olfaction. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) often results in decreased olfaction. In this study, we examined the relationship between nasal polyp location and olfactory airflow and odorant transport changes using virtual nasal polyp models at different locations and computational fluid dynamics (CFD) analysis. We also compared olfactory airflow and olfaction between patients with nasal polyps at different locations using CFD analysis and an olfactory test. METHODS: Nasal computed tomography images were used to generate a normal model and 4 virtual nasal polyp models based on polyp locations, including the olfactory region (all-olfactory model), the region anterior to the olfactory region (preolfactory model), the middle meatus (middle-meatus model), and the superior meatus (superior-meatus model). Various airflow parameters were compared between these models and a normal model without polyps. We then performed a similar comparison between the 3-dimensional (3D) reconstruction models of patients with nasal polyps, and retrospectively investigated the correlation between olfaction and nasal polyp location in those patients. RESULTS: Virtual nasal polyp analysis revealed dispersion of olfactory airflow in the all olfactory model. Olfactory airflow and odorant transport showed maximum decrease in the preolfactory model and a slight decrease in the superior-meatus model. Olfactory airflow by polyps was further decreased by blockade of the olfactory airflow inlet than of the outlet. The findings obtained by patients corresponded well to those of the virtual polyp analysis. CONCLUSION: Olfactory airflow and olfaction are differentially affected by nasal polyp location. This finding is important for planning polyp-removal surgeries from the perspective of improving patient olfaction. PMID- 29394001 TI - Potassium-Zincate-Catalyzed Benzylic C-H Bond Addition of Diarylmethanes to Styrenes. AB - Direct functionalization of the benzylic C-H bond of diarylmethanes is an important strategy for the synthesis of diarylmethine-containing compounds. However, the methods developed to date for this purpose require a stoichiometric amount (usually more) of either a strong base or an oxidant. Reported here is the first catalytic benzylic C-H bond addition of diarylmethanes to styrenes and conjugated dienes. A potassium zincate complex, generated from potassium benzyl and zinc amide, acts as a catalyst and displays good activity and chemoselectivity. Considering the atom economy of the reaction and the ready availability of the catalyst, this reaction constitutes a practical, efficient method for diarylalkane synthesis. PMID- 29394002 TI - Site-Specific Labelling of Native Mammalian Proteins for Single-Molecule FRET Measurements. AB - Human cells are complex entities in which molecular recognition and selection are critical for cellular processes often driven by structural changes and dynamic interactions. Biomolecules appear in different chemical states, and modifications, such as phosphorylation, affect their function. Hence, using proteins in their chemically native state in biochemical and biophysical assays is essential. Single-molecule FRET measurements allow exploration of the structure, function and dynamics of biomolecules but cannot be fully exploited for the human proteome, as a method for the site-specific coupling of organic dyes into native, non-recombinant mammalian proteins is lacking. We address this issue showing the site-specific engineering of fluorescent dyes into human proteins on the basis of bioorthogonal reactions. We show the applicability of the method to study functional and post-translationally modified proteins on the single-molecule level, among them the hitherto inaccessible human Argonaute 2. PMID- 29394003 TI - Pharmacokinetic Evaluation of Two Nicotine Patches in Smokers. AB - Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference). The test and reference patches were bioequivalent, as determined by the PK parameters of Cmax and AUC0-t . In addition, the parameters Tmax and t1/2 did not significantly differ between the 2 patches, supporting the bioequivalence finding from the primary analysis. The tolerability profiles of the patches containing the replacement and previously used PIB adhesives were similar; application-site adverse events did not significantly differ between test and reference patches. Overall, these data establish the bioequivalence of the nicotine patch with the replacement PIB adhesive formulation and the previously utilized PIB adhesive formulation. PMID- 29394004 TI - Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. AB - BACKGROUND: Persistent mucosal inflammation in patients with chronic rhinosinusitis (CRS) often results in ongoing symptoms, recurrence of polypoid mucosa, infective exacerbations, and further systemic medication despite surgical intervention. Debate exists as to the most effective topical therapy in CRS. METHODS: The objective was to determine if corticosteroid delivered via a nasal irrigation or via a simple nasal spray would be more effective in controlling the symptoms and signs of CRS. A double-blind placebo-controlled randomized trial over 12 months was performed between 3 tertiary rhinologic clinics. After sinus surgery, all patients performed a nasal irrigation followed by a nasal spray once a day for 12 months. Groups were defined by corticosteroid (2 mg mometasone) delivered by either spray or irrigation. The primary outcomes were patient reported symptoms: visual analogue score (VAS) and 22-item Sino-Nasal Outcome Test (SNOT-22), a global rating of sinonasal function. Secondary outcomes were also recorded from radiology (Lund-Mackay score [LMS]) and endoscopic (Modified Lund-Kennedy score [mLKS]) assessments. RESULTS: A total of 44 patients were randomized (age 50.3 +/- 13.0 years; 40.9% female). Overall, patients improved significantly from either intervention. However, the corticosteroid nasal irrigation group had greater improvement in nasal blockage (-69.91 +/- 29.37 vs 36.12 +/- 42.94; p = 0.029), a greater improvement on LMS (-12.07 +/- 4.43 vs 7.39 +/- 6.94; p = 0.031) and less inflammation on mLKS at 12 months (7.33 +/- 11.55 vs 21.78 +/- 23.37; p = 0.018). One-year posttreatment blockage, drainage, fever, and total VAS scores were all lower in the corticosteroid irrigation group. CONCLUSION: In the setting of diffuse or patchy CRS disease, the use of corticosteroid delivered by nasal irrigation is superior to simple nasal spray in postsurgical patients. PMID- 29394005 TI - Radiomics Strategy for Molecular Subtype Stratification of Lower-Grade Glioma: Detecting IDH and TP53 Mutations Based on Multimodal MRI. AB - BACKGROUND: Noninvasive detection of isocitrate dehydrogenase (IDH) and TP53 mutations are meaningful for molecular stratification of lower-grade gliomas (LrGG). PURPOSE: To explore potential MRI features reflecting IDH and TP53 mutations of LrGG, and propose a radiomics strategy for detecting them. STUDY TYPE: Retrospective, radiomics. POPULATION/SUBJECTS: A total of 103 LrGG patients were separated into development (n = 73) and validation (n = 30) cohorts. FIELD STRENGTH/SEQUENCE: T1 -weighted (before and after contrast-enhanced), T2 weighted, and fluid-attenuation inversion recovery images from 1.5T (n = 37) or 3T (n = 66) scanners. ASSESSMENT: After data preprocessing, high-throughput features were derived from patients' volumes of interests of different sequences. The support vector machine-based recursive feature elimination (SVM-RFE) was adopted to find the optimal features for IDH and TP53 mutation detection. SVM models were trained and tested on development and validation cohort. The commonly used metric was used for assessing the efficiency. STATISTICAL TESTS: One-way analysis of variance (ANOVA), chi-square, or Fisher's exact test were applied on clinical characteristics to confirm whether significant differences exist between three molecular subtypes decided by IDH and TP53 status. Intraclass correlation coefficients were calculated to assess the robustness of the radiomics features. RESULTS: The constituent ratio of histopathologic subtypes was significantly different among three molecular subtypes (P = 0.017). SVM models for detecting IDH and TP53 mutation were established using 12 and 22 optimal features selected by SVM-RFE. The accuracies and area under the curves for IDH and TP53 mutations on the development cohort were 84.9%, 0.830, and 92.0%, 0.949, while on the validation cohort were 80.0%, 0.792, and 85.0%, 0.869, respectively. Furthermore, the stratified accuracies of three subtypes were 72.8%, 71.9%, and 70%, respectively. DATA CONCLUSION: Using a radiomics approach integrating SVM model and multimodal MRI features, molecular subtype stratification of LGG patients was implemented through detecting IDH and TP53 mutations. The results suggested that the proposed approach has promising detecting efficiency and T2 -weighted image features are more important than features from other images. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:916-926. PMID- 29394006 TI - Metastasis to the extraocular muscles: a case report, literature review and pooled data analysis. AB - Metastasis to the extraocular muscles (EOM) is rare. The existing literature comprises only of isolated case reports therefore a summative description of these lesions is lacking. This study presents a case of bilateral rectus muscle metastasis from malignant melanoma. Furthermore a literature review and pooled data analysis is undertaken with 43 articles encompassing 77 patients and 101 eyes. Mean age was 53 years, 54% were male, 66% had unilateral involvement and 34% had bilateral involvement. The primary malignancies were melanoma (n = 17, 22%), breast (n = 15, 15%) and carcinoid (n = 11, 14%). A single muscle was involved in 56 eyes (67%) and multiple muscles in 27 eyes (33%). Lateral rectus was most commonly affected (n = 44, 53%). Presenting symptoms included restricted eye movements (n = 48, 62%), proptosis (n = 45, 58%), diplopia (n = 27, 35%) and pain (n = 18, 23%). Scattered case reports have previously made it difficult to characterise this phenomenon thus a pooled data analysis is presented. PMID- 29394007 TI - Increased intrusion of warming Atlantic water leads to rapid expansion of temperate phytoplankton in the Arctic. AB - The Arctic Ocean and its surrounding shelf seas are warming much faster than the global average, which potentially opens up new distribution areas for temperate origin marine phytoplankton. Using over three decades of continuous satellite observations, we show that increased inflow and temperature of Atlantic waters in the Barents Sea resulted in a striking poleward shift in the distribution of blooms of Emiliania huxleyi, a marine calcifying phytoplankton species. This species' blooms are typically associated with temperate waters and have expanded north to 76 degrees N, five degrees further north of its first bloom occurrence in 1989. E. huxleyi's blooms keep pace with the changing climate of the Barents Sea, namely ocean warming and shifts in the position of the Polar Front, resulting in an exceptionally rapid range shift compared to what is generally detected in the marine realm. We propose that as the Eurasian Basin of the Arctic Ocean further atlantifies and ocean temperatures continue to rise, E. huxleyi and other temperate-origin phytoplankton could well become resident bloom formers in the Arctic Ocean. PMID- 29394008 TI - Identification of the novel HLA-C*03 allele, HLA-C*03:03:35. AB - The new allele HLA-C*03:03:35 showed one nucleotide difference with C*03:03:01:01 at position 408 (G>T). PMID- 29394009 TI - Validity of Lateral Flow Immunochromatographic-Assays (LFIA) in diagnosis of leptospirosis PMID- 29394010 TI - Streaming potential measurements to understand the rheological properties of surfactant formulations containing anionic and zwitterionic surfactant. AB - Surfactant formulations are often based on an anionic primary surfactant combined with an amphoteric secondary surfactant. One popular option is the combination of lauryl ether sulfate and cocamidopropyl betaine, because such formulations are not only mild but also easy to thicken. Changes in the molecular structure of the betaine in terms of alkyl chain length distribution and headgroup structure do have dramatic effects on the viscosity of these formulations, as can be explained in terms of properties of rod-like micelles and exchange kinetics by oscillatory rheological measurements. The root cause of the effect of the different betaine derivatives on the micellar structure, however, remains unclear when considering rheology only. Although the streaming potential of colloidal objects is typically determined to forecast the stability of dispersions, we have used the streaming potential to characterize micellar solutions of different betaine surfactant structures. It could be shown that (a) the hydrophilicity of the surfactants can be nicely probed by this method and (b) there is a good correlation of these values with the rheological properties of binary mixtures of the betaines with anionic surfactant. Also, the chemical structure of the headgroups has a significant influence on both the isoelectric point and the magnitude of the streaming potential of the zwitterionic surfactants. These effects have again a dramatic influence on the interaction with anionic surfactants, as becomes obvious when looking at the rheology of such mixtures. Therefore, the findings obtained can be utilized to better understand and design surfactant formulations of a desired viscosity profile. PMID- 29394011 TI - Free radical scavenging capacity and protective effect of natural substances in peloids from the thermal spring pool Bagnaccio (Viterbo, Italy). AB - Natural peloids from sulfurous thermal springs are largely used in cosmetic and pelotherapy for the treatment of different dermatological conditions, including skin aging, dermatitis, and other eczemas. The beneficial effects are correlated to mineralogical and other thermal properties, as well as to the presence of natural substances with specific antioxidant activity. Few data are available for the comparison between natural peloids and synthetic (i.e., artificially maturated) muds. In this context, the natural substances and antioxidant activity of natural white mud (WM) and dark mud (DM) peloids from the sulfurous thermal spring pool Bagnaccio (Viterbo, Italy) have been studied in detail to evaluate possible relationships between physicochemical properties and therapeutic effect. A large panel of natural substances in WM and DM were characterized for the first time by 31P-nuclear magnetic resonance and gas chromatography associated to mass spectrometry analysis. Polar fractions of WM and DM peloids were characterized by the presence of several bioactive natural compounds, showing high antioxidant activity and DNA protective effect, as evaluated by 2,2-diphenyl-1-picrylhydrazyl assay, and hydrogen peroxide-induced DNA breakage in the alkaline comet assay. The antioxidant activity and DNA protective effect could be attributed to radical scavenging rather than a modulatory effect on the induced DNA repair, and are of order of intensity higher than that reported for synthetic muds. PMID- 29394012 TI - Use of optical profilometry and visual grading for measurement of longitudinal striations of the nail. AB - Consumer perception of longitudinal striations of the nail is one of the drivers of nail cosmetic purchase and use. The following work investigates the use of objective instrumental methods for the characterization of longitudinal striations. Striations are quantified by Ra (the average maximum height of the profile), Rq (the root mean square average of the roughness profile), and Rz (the mean roughness depth), industrial roughness parameters, which are calculated using optical profilometry of the three-dimensional surface structure of the nail. A visual assessment is conducted by cosmetologists in vivo and on images captured in several lighting conditions. With this evaluation, the cosmetologists provide ratings of surface ridges on a 0-5 scale to complement and validate the instrumental method. Both the optical profilometry and the cosmetologist-graded methods are used to evaluate 33 nails of visually-varying levels of ridges from female volunteers. The evaluations from these methods yield well-correlated and repeatable results, and these preliminary findings suggest that this new instrumental method can be used to objectively measure longitudinal striations of the nail. PMID- 29394014 TI - Letter to the Editor: The Entrance Echo corresponds to Epidermis on High Frequency Skin Ultrasound. PMID- 29394013 TI - A new in vitro method to determine sun protection factor. AB - A new in vitro sun protection factor (SPF) test method to determine the efficacy of sun care products is proposed and evaluated. Based on ultraviolet (UV) dose cumulate response protocols, the new method employs Gafchromic EBT3 film, a self-developing dosimetry film originally created for applications in radiotherapy. Unlike the current standardized method, a UV spectrophotometer is not required. In vitro SPF values of 15 commercial products were measured with EBT3 film and compared with labeled in vivo SPF values. It is apparent that the new method is accurate, cost-effective, and reproducible. These results can be seen across sun care product lines, including sunscreen lotions, blemish balm (BB) creams, foundations, and sprays with organic and?/or inorganic UV filters. PMID- 29394015 TI - Probing the textures of composite skin care formulations using large amplitude oscillatory shear. AB - Identifying meaningful and measurable rheological parameters that shadow the dynamic shear stresses sustained in the initial application and subsequent spreading of structured cosmetic formulations onto the skin is quite challenging. When applied to non-Newtonian soft solids, traditional oscillatory rheological testing tends to best correlate with the "at-rest" state, or, more fundamentally, with the initial and thermodynamically reversible perturbations in the physiochemical networking that binds components of the amalgamated microstructure. In addition, after yielding, as an applied film is further thinned while spreading on the skin surface, shear rates during flow processes may rapidly and dynamically increase to 104 s-1 , which is a magnitude that is not practically simulated with a standard rotational rheometer. Realistically speaking, it is rare that a single rheological measurement or resultant parameter predicts the sensorial appeal of a complex fluid during the entire scope of a spreading process. Large amplitude oscillatory shear (LAOS) methodology is an augmentation of standard oscillatory rheology, or small amplitude oscillatory shear (SAOS), and delivers a means to dynamically probe the deforming microstructure of a soft solid as it rheologically transitioned from a viscoplastic material to a structured fluid. LAOS rheology was performed on four different prototypes having different skincare textures to produce Bowditch Lissajous plots (henceforth truncated to Lissajous in the remainder of the document) for subsequent association with previously measured sensorial properties. Insights into the shapes of the curves and their relation to paralleled sensorial analyses are primarily based on the performance of the composite prototypes rather than speculating on the individual contribution of each constituent to the dynamics of the adapting microstructure. Therefore, transitions in the Lissajous trajectories may be used to visually describe changes in the bulk rheology as the physical components of the local viscoelastic environment are controllably sheared. In this work, Lissajous profiles are amassed with smooth and rough surfaces data utilizing standard rheological techniques, including oscillatory SAOS, stress ramps, Brookfield viscometry, and the manifestation of interfacial or complex flow properties, such as wall-slip and shear-banding phenomena. Practical influences on the human stratum corneum, including thermal softening and electrostatic shielding, are also considered. Additionally, outcomes from texture profile analysis are reported and contrasted with the accompanying results. Ultimately, the objective is to make meaningful connections between trends in Lissajous trajectories and paralleled sensorial analyses conducted by a trained expert panel. For the reader, a basic level of rheological knowledge is assumed. PMID- 29394016 TI - Development and clinical evaluation of green tea hair tonic for greasy scalp treatment. AB - Green tea has cosmetic benefits that include activities against androgen disorders. A hair tonic containing green tea for reduction of scalp sebum was developed and clinically evaluated. Stable green tea hair tonics were closed patch tested and clinically evaluated in 20 volunteers for 28 days by using a Sebumeter (r) . Hair tonic base with glycerin and butylene glycol (total 4%) gained the highest consumers' preference was incorporated with green tea extract. All of the products were stable and none caused skin irritation. Green tea hair tonic (2%) significantly (p <= 0.024) lowered scalp sebum for 21 and 28 days following the application, suggesting that this topical therapy of scalp greasiness is safe and efficient. PMID- 29394017 TI - Analysis of octyl methoxycinnamate in sunscreen products by a validated UV spectrophotometric method. AB - An inexpensive, rapid method for the determination of octyl methoxycinnamate (OMC) in sunscreen products using ultraviolet-spectrophotometry has been developed and validated according to International Council for Harmonisation and Association of Official Analytical Chemists guidelines. Methanol was the optimal solvent used with a linearity range of 4-12 ug?/ml (r = 0.999) being obtainable. The accuracy of the method is highlighted by the % recovery (98.23-98.50) and relative standard deviation (%RSD, 0.12), and it is widely applicable to prototype products composed of oil in water, and water in oil emulsions. Mineral oils containing low, intermediate, and high OMC levels (1%, 4%, and 7.5%) gave recovery percentages of 99.76-100.76 with %RSD of 0.02-0.28. In addition, this method is repeatable and affords a high degree of precision (%RSD = 0.12 and 0) with 96.08-99.27% recovery. The method is suitable for quality assurance of suncare product formulations, and could be applicable to product development and validation. PMID- 29394018 TI - Comparison of skin hydration in combination and single use of common moisturizers (cream, toner, and spray water). AB - This study aims to assess the moisturization in combination or single use (including seven general applications) of three common moisturizers: cream, toner, and spray water. Groups were set as C: cream only; T: toner only; C+T, T+C: cream or toner applied successively within a few minutes; C-T, C-S: cream applied with repeated toner or spray water every 2 h; T-T: toner applied with repeated toner every 2 h; and N: untreated group. Outcomes were the change in skin hydration from baseline at 2, 4, 6, and 8 h after applications. All treated zones displayed a significantly higher degree of hydration compared with the untreated zone ( p < 0.05). For normal skin (hydration value at baseline >35 a.u.), C-T led to greatest hydration change rate compared with others, followed by C+T, T+C, and C. Those three applications exhibited analogous hydration at each test point ( p > 0.05). The hydration rate of C-S differed slightly from T T, followed by those four mentioned above, with T being the last. For dry skin (hydration value at baseline <35 a.u.), no statistical significance could be detected between C-T zone and C+T, T+C, and C zones ( p > 0.05), the other results were identical. When cream and toner were applied successively, the application order has little effect on skin hydration. The application of cream only was an effective and brief way to achieve favorable moisturization especially for dry skin. As a complement, repeated application of toner rather than spray water is efficacious for skin hydration. PMID- 29394019 TI - Effects of season stratum corneum barrier function and skin biomarkers. AB - The skin on the lower legs of 25 female subjects was evaluated first in the winter, and then again in the summer of the same subjects. Barrier function was determined by measuring transepidermal water loss (TEWL), and skin hydration and dryness were evaluated by electrical measurements (Corneometer (r) CM825) and visual grading. Stratum corneum (SC) was sampled using 10 sequential D-Squame sampling discs and analyzed for 2-pyrrolidone-5-carboxylic acid (PCA), keratin 1,10,11, interleukin 1alpha (IL-1alpha), interleukin 1 receptor antagonist (IL 1ra), selected ceramides, cholesterol, cholesterol sulfate, and selected free fatty acids. TEWL as well as the visual dryness grades were significantly lower in the summer while hydration was higher. PCA was significantly higher in the summer as were the keratins. The ratio IL-1ra:IL-1alpha, an indicator of skin inflammation, was significantly lower in the summer. The amount of protein removed by the tape strips was also significantly lower in summer indicating better SC cohesion. Among the SC lipids measured, total ceramides, individual ceramides, total fatty acids, and cholesterol were higher in summer compared to winter. Stearic acid and cholesterol sulfate were not significantly different between winter and summer. PMID- 29394020 TI - Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions. AB - Following the serendipitous discovery of the anticancer activity of cisplatin over 50 years ago, a deep understanding of the chemical and biochemical transformations giving rise to its medicinal properties has developed allowing for improved treatment regimens and rational design of second and third generation drugs. This chapter begins with a brief historical review detailing initial results that led to the worldwide clinical approval of cisplatin and development of the field of metal anticancer agents. Later sections summarize our understanding of key mechanistic features including drug uptake, formation of covalent adducts with DNA, recognition and repair of Pt-DNA adducts, and the DNA damage response, with respect to cisplatin and oxaliplatin. The final section highlights known shortcomings of classical platinum anticancer agents, including problems with toxicity and mutagenicity, and the development of resistance and enrichment of cancer stem cells brought about through treatment. Instances where specific differences in the response or mechanism of action of cisplatin versus oxaliplatin have been demonstrated are discussed in the text. In this manner the chapter provides a broad overview of our current understanding of the mechanism of action of platinum anticancer agents, providing a framework for improving the rational design of better Pt-based anticancer agents. PMID- 29394021 TI - Polynuclear Platinum Complexes. Structural Diversity and DNA Binding. AB - Polynuclear platinum complexes (PPCs) represent a discrete structural class of DNA-binding agents with excellent antitumor properties. The use of at least two platinum coordinating units automatically means that multifunctional DNA binding modes are possible. The structural variability inherent in a polynuclear platinum structure can be harnessed to produce discrete modes of DNA binding, with conformational changes distinct from and indeed inaccessible to, the mononuclear agents such as cisplatin. Since our original contributions in this field a wide variety of dinuclear complexes especially have been prepared, their DNA binding studied, and potential relevance to cytotoxicity examined. This chapter focuses on how DNA structure and reactivity is modulated through interactions with PPCs with emphasis on novel aspects of such structure and reactivity. How these major changes are further reflected in damaged DNA-protein binding and cellular effects are reviewed. We further review, for the first time, the great structural diversity achieved in PPC complex design and summarize their major DNA binding effects. PMID- 29394022 TI - Platinum(IV) Prodrugs. AB - This chapter is an overview of recent progress in the design of Pt(IV) prodrugs. These kinetically-inert octahedral prodrugs can be reduced in cancer cells to active squareplanar Pt(II) complexes, for example by intracellular reducing agents such as glutathione or by photoexcitation. The additional axial ligands in Pt(IV) complexes which are released on reduction, allow bioactive molecules to be delivered which can act synergistically with Pt(II) in killing cancer cells, or act as targeting vectors, allow attachment to polymer and nanoparticle delivery systems, or labelling with fluorescent probes. Pt(IV) prodrugs have yet to be approved for clinical use, although some offer the promise of increased efficacy and reduced side effects. PMID- 29394023 TI - Metalloglycomics. AB - Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are explained in detail. Sulfate cluster anchoring shields the sulfates from recognition by charged protein residues preventing the exercise of the HS-enzyme/protein function, such as growth factor recognition and the activity of heparanase on HS. The cellular consequences are inhibition of invasion and angiogenesis. Metalloglycomics is a potentially rich new area of endeavor for bioinorganic chemists to study the relevance of intrinsic metal ions in heparin/ HS-protein interactions and for development of new compounds for therapeutic, analytical, and imaging applications. PMID- 29394024 TI - The Deceptively Similar Ruthenium(III) Drug Candidates KP1019 and NAMI-A Have Different Actions. What Did We Learn in the Past 30 Years? AB - The general interest in anticancer metal-based drugs and some encouraging pharmacological results obtained at the beginning of the investigations on innovative Ru-based drugs triggered a lot of attention on NAMI-A and KP1019, the two Ru(III) coordination compounds that are the subject of this review. This great attention led to a considerable amount of scientific results and, more importantly, to their eventual admission into clinical trials. Both complexes share a relatively low systemic toxicity that allows reaching rather high dosages, comparable to those of carboplatin. Soon it became evident that NAMI-A and KP1019, in spite of their structural similarity, manifest very distinct chemical and biological properties. The pharmacological performances qualified KP1019 mainly as a cytotoxic drug for the treatment of platinum-resistant colorectal cancers, whereas NAMI-A gained the reputation of a potential anticancer drug with negligible effects on the primary tumor but a pronounced ability to affect metastases. We believe that a strictly comparative exam of NAMI A and KP1019, based on the substantial body of studies accomplished since their discovery almost 30 years ago, might be an useful exercise, both for assessing the state of the art in terms of biological and clinical profiles, and of the inherent mechanisms, and for envisaging possible future developments in the light of past achievements. PMID- 29394025 TI - Multinuclear Organometallic Ruthenium-Arene Complexes for Cancer Therapy. AB - There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes. PMID- 29394026 TI - Medicinal Chemistry of Gold Anticancer Metallodrugs. AB - Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action. PMID- 29394027 TI - Coordination Complexes of Titanium(IV) for Anticancer Therapy. AB - Titanium(IV) coordination complexes represent attractive alternatives to platinumbased anticancer drugs. The advantage of the titanium metal lies in its low toxicity, and the hydrolysis of titanium(IV) coordination complexes in biological water-based environment to the safe and inert titanium dioxide is an enormous benefit. On the other hand, the rapid hydrolysis of titanium(IV) complexes in biological environment and their rich aquatic chemistry hampered the exploration and the development of effective compounds. Titanium(IV) complexes were the first to enter clinical trials for cancer treatment following the success of platinum-based chemotherapy, with the pioneering compounds titanocene dichloride and budotitane. Despite the high efficacy and low toxicity observed in vivo, the compounds failed the trials due to insufficient efficacy to toxicity ratio and formulation complications. The rapid hydrolysis of the complexes led to formation of multiple undefined aggregates and difficulties in isolating and identifying the particular active species and its precise cellular target. Numerous derivatives with different labile ligands or substitutions on the inert ones contributed to improve the complex anticancer features, and the best ones were comparable with, and occasionally better than cisplatin. Hydrolytic stability was improved in some cases but remained challenging. The following generation of phenolato-based complexes that came three decades later exhibited high activity and markedly improved stability, where no dissociation was observed for weeks in biological solutions. Complexes of no labile ligands whatsoever that remain intact in solution demonstrated in vitro and in vivo efficacy, with no signs of toxicity to the treated animals. Mechanistic insights gained for the different complexes analyzed include, among others, possible interaction with DNA and induction of apoptosis. Such complexes are highly promising for future exploration and clinical development. PMID- 29394028 TI - Health Benefits of Vanadium and Its Potential as an Anticancer Agent. AB - Vanadium compounds have been known to have beneficial therapeutic properties since the turn of the century, but it was not until 1965 when it was discovered that those effects could be extended to treating cancer. Some vanadium compounds can combat common markers of cancer, which include metabolic processes that are important to initiating and developing the phenotypes of cancer. It is appropriate to consider vanadium as a treatment option due to the similarities in some of the metabolic pathways utilized by both diabetes and cancer and therefore is among the few drugs that are effective against more than one disease. The development of vanadium compounds as protein phosphatase inhibitors for the treatment of diabetes may be useful for potential applications as an anticancer agent. Furthermore, the ability of vanadium to redox cycle is also important for biological properties and is involved in the pathways of reactive oxygen species. Early agents including vanadocene and peroxovanadium compounds have been investigated in detail, and the results can be used to gain a better understanding of how some vanadium compounds are modifying the metabolic pathways potentially developing cancer. Considering the importance of coordination chemistry to biological responses, it is likely that proper consideration of compound formulation will improve the efficacy of the drug. Future development of vanadium-based drugs should include consideration of drug formulation at earlier stages of drug development. PMID- 29394029 TI - Gallium Complexes as Anticancer Drugs. AB - Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron binding proteins and disrupt iron-dependent tumor cell growth. Gallium's mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds. PMID- 29394030 TI - Non-covalent Metallo-Drugs: Using Shape to Target DNA and RNA Junctions and Other Nucleic Acid Structures. AB - The most effective class of anticancer drugs in clinical use are the platins which act by binding to duplex B-DNA. Yet duplex DNA is not DNA in its active form, and many other structures are formed in cells; for example, Y-shaped fork structures are involved in DNA replication and transcription and 4-way junctions with DNA repair. In this chapter we explore how large, cationic metallo supramolecular structures can be used to bind to these less common, yet active, nucleic acid structures. PMID- 29394031 TI - Nucleic Acid Quadruplexes and Metallo-Drugs. AB - Guanine-rich sequences of DNA can readily fold into tetra-stranded helical assemblies known as G-quadruplexes (G4s). It has been proposed that these structures play important biological roles in transcription, translation, replication, and telomere maintenance. Therefore, over the past 20 years they have been investigated as potential drug targets for small molecules including metal complexes. This chapter provides an overview of the different classes of metal complexes as G4-binders and discusses the application of these species as optical probes for G-quadruplexes as well as metallo-drugs. PMID- 29394032 TI - Antitumor Metallodrugs that Target Proteins. AB - Anticancer platinum-based drugs are widely used in the treatment of a variety of tumorigenic diseases. They have been identified to target DNA and thereby induce apoptosis in cancer cells. Their reactivity to biomolecules other than DNA has often been associated with side effects that many cancer patients experience during chemotherapy. The development of metal compounds that target proteins rather than DNA has the potential to overcome or at least reduce the disadvantages of commonly used chemotherapeutics. Many exciting new metal complexes with novel modes of action have been reported and their anticancer activity was linked to selective protein interaction that may lead to improved accumulation in the tumor, higher selectivity and/or enhanced antiproliferative efficacy. The development of new lead structures requires bioanalytical methods to confirm the hypothesized modes of action or identify new, previously unexplored biological targets and pathways. We have selected original developments for review in this chapter and highlighted compounds on track toward clinical application. PMID- 29394033 TI - Metallointercalators and Metalloinsertors: Structural Requirements for DNA Recognition and Anticancer Activity. AB - As the carrier of the inheritable information in cells, DNA has been the target of metal complexes for over 40 years. In this chapter, the focus will be on non covalent recognition of the highly structured DNA surface by substitutionally inert metal complexes capable of either sliding in between the normal base pairs as metallointercalators or flipping out thermodynamically destabilized mispaired nucleobases as metalloinsertors. While most of the compounds discussed are based on ruthenium(II) and rhodium(III) due to their stable octahedral coordination environment and low-spin 4d6 electronic configuration, most recent developments of alternative metal complexes, based on both transition metals and main group elements, will also be highlighted. A particular focus of the coverage is on structural data from X-ray structure analysis, which now provides details of the interaction at unprecedented details and will enable development of novel DNA binding probes for fundamental studies as well as new anticancer drug candidates. PMID- 29394034 TI - Iron and Its Role in Cancer Defense: A Double-Edged Sword. AB - Iron (Fe) is an essential metal, vital for biological functions, including electron transport, DNA synthesis, detoxification, and erythropoiesis that all contribute to metabolism, cell growth, and proliferation. Interactions between Fe and O2 can result in the generation of reactive oxygen species (ROS), which is based on the ability of Fe to redox cycle. Excess Fe may cause oxidative damage with ensuing cell death, but DNA damage may also lead to permanent mutations. Hence Fe is carcinogenic and may initiate tumor formation and growth, and also nurture the tumor microenvironment and metastasis. However, Fe can also contribute to cancer defense. Fe may induce toxic ROS and/or initiate specific forms of cell death, including ferroptosis that will benefit cancer treatment. Furthermore, Fe-binding and Fe-regulatory proteins, such as hepcidin, lipocalin 2/NGAL, heme oxygenase-1, ferritin, and iron-sulfur clusters can display antitumor properties under specific conditions and in particular cancer types. In addition, the milk protein lactoferrin may synergize with other established anticancer agents in the prevention and therapy of cancer. Consequently, drugs that target Fe metabolism in tumors are promising candidates for the prevention and therapy of cancer, but consideration of context specificity (e.g., tumor type; systemic versus tumor microenvironment Fe homeostasis) is mandatory. PMID- 29394035 TI - Copper Complexes in Cancer Therapy. AB - Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials. PMID- 29394036 TI - Targeting Zinc(II) Signalling to Prevent Cancer. AB - Zinc is an important element that is gaining momentum as a potential target for cancer therapy. In recent years zinc has been accepted as a second messenger that is now recognized to be able to activate many signalling pathways within a few minutes of an extracellular stimulus by release of zinc(II) from intracellular stores. One of the major effects of this store release of zinc is to inhibit a multitude of tyrosine phosphatases which will prevent the inactivation of tyrosine kinases and hence, encourage further activation of tyrosine kinasedependent signalling pathways. Most of these signalling pathways are not only known to be involved in driving aberrant cancer growth, they are usually the main driving force. All this data together now positions zinc and zinc signalling as potentially important new targets to prevent aggressive cancer growth. PMID- 29394037 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. PMID- 29394038 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. PMID- 29394039 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. PMID- 29394040 TI - The Inductive Effect in Nitridosilicates and Oxysilicates and Its Effects on 5d Energy Levels of Ce3. AB - The inductive effect exists widely in inorganic compounds and accounts well for many physicochemical properties. However, until now this effect has not been characterized quantitatively. In this work, we collected and analyzed the structural data of more than 100 nitridosilicates and oxysilicates, whose structures typically consist of [SiN4] or [SiO4] tetrahedra. We introduce a new parameter, the inductive effect factor MUDeltachi, related to the difference of electronegativity between constituent metal elements and silicon. Then, a linear relationship is established between average length of Si-N/Si-O bonds and the inductive factor with the help of statistical method, that is, l = 1.7313 + 0.0166 MUDeltachi (A) with adjusted (adj) R2 = 0.800 for Si-N and l = 1.6221 + 0.0035 MUDeltachi(A) with adj R2 = 0.240 for Si-O. Furthermore, our research shows that the distinct positive correlation does exist between the inductive factor and the centroid shift of 5d levels of Ce3+. This work will help us understanding the inductive effect deeply and quantitatively. PMID- 29394042 TI - Dynamic Tracking of Highly Toxic Intermediates in Photocatalytic Degradation of Pentachlorophenol by Continuous Flow Chemiluminescence. AB - Photocatalytic degradation is a powerful technique for the decomposition of pollutants. However, toxic intermediates might be generated which have become a great concern recently. In the present work, a continuous flow chemiluminescence (CFCL) method was developed for dynamic monitoring of toxic intermediates generated in the photocatalytic degradation of pentachlorophenol (PCP). Among the main intermediates, tetrachloro-1,4-benzoquinone (TCBQ) and trichlorohydroxy-1,4 benzoquinone (OH-TrCBQ) showed higher or similar toxicity to PCP. As both TCBQ and OH-TrCBQ can produce chemiluminescence (CL) in the presence of H2O2, a CFCL system was established for the dynamic tracking of the two toxic intermediates. A PCP/TiO2 suspension was irradiated in a photoreactor, pumped continuously into a detection cell, and mixed with H2O2 to produce CL. The time-dependent CL response displayed two distinctive peaks at pH 7, which were attributed to the generation of OH-TrCBQ and TCBQ, respectively, by comparing with their changes measured by high-performance liquid chromatography (HPLC). Furthermore, the CL response curve of PCP/TiO2 suspension showed a pattern very similar to their bacteria inhibition. Therefore, the CFCL could be used as a simple and low-cost method for online monitoring of TCBQ and OH-TrCBQ to ensure complete removal of not only PCP but also highly toxic degradation intermediates. PMID- 29394041 TI - Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Abeta-Fibrinogen Interaction and Abeta-Induced Contact System Activation. AB - Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and beta-amyloid (Abeta), a hallmark pathological protein in AD, induces plasmin resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Abeta oligomers have a much stronger affinity for fibrinogen than Abeta monomers, we tested whether amyloid aggregation inhibitors could block the Abeta-fibrinogen interaction and found that some Abeta aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the Abeta-fibrinogen interaction but also retained its potency toward the Abeta42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated Abeta42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the Abeta-fibrinogen interaction and Abeta aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as Abeta aggregation-driven pathology in AD. PMID- 29394043 TI - Ligand Binding Pathways and Conformational Transitions of the HIV Protease. AB - It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein-drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500-2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 A during 2.5 MUs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ~5.73 A during an earlier 14 MUs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug-receptor interactions for the HIV protease and by extension many other target proteins. PMID- 29394044 TI - Thermal Stabilization of Biologics with Photoresponsive Hydrogels. AB - Modern medicine, biological research, and clinical diagnostics depend on the reliable supply and storage of complex biomolecules. However, biomolecules are inherently susceptible to thermal stress and the global distribution of value added biologics, including vaccines, biotherapeutics, and Research Use Only (RUO) proteins, requires an integrated cold chain from point of manufacture to point of use. To mitigate reliance on the cold chain, formulations have been engineered to protect biologics from thermal stress, including materials-based strategies that impart thermal stability via direct encapsulation of the molecule. While direct encapsulation has demonstrated pronounced stabilization of proteins and complex biological fluids, no solution offers thermal stability while enabling facile and on-demand release from the encapsulating material, a critical feature for broad use. Here we show that direct encapsulation within synthetic, photoresponsive hydrogels protected biologics from thermal stress and afforded user-defined release at the point of use. The poly(ethylene glycol) (PEG)-based hydrogel was formed via a bioorthogonal, click reaction in the presence of biologics without impact on biologic activity. Cleavage of the installed photolabile moiety enabled subsequent dissolution of the network with light and release of the encapsulated biologic. Hydrogel encapsulation improved stability for encapsulated enzymes commonly used in molecular biology (beta-galactosidase, alkaline phosphatase, and T4 DNA ligase) following thermal stress. beta-galactosidase and alkaline phosphatase were stabilized for 4 weeks at temperatures up to 60 degrees C, and for 60 min at 85 degrees C for alkaline phosphatase. T4 DNA ligase, which loses activity rapidly at moderately elevated temperatures, was protected during thermal stress of 40 degrees C for 24 h and 60 degrees C for 30 min. These data demonstrate a general method to employ reversible polymer networks as robust excipients for thermal stability of complex biologics during storage and shipment that additionally enable on-demand release of active molecules at the point of use. PMID- 29394045 TI - Self-Powered Electrostatic Adsorption Face Mask Based on a Triboelectric Nanogenerator. AB - The physical filtration mechanism of a traditional face mask has a low removal efficiency of ultrafine particulates in the size range of 10-1000 nm, which are badly harmful to human health. Herein, a novel self-powered electrostatic adsorption face mask (SEA-FM) based on the poly(vinylidene fluoride) electrospun nanofiber film (PVDF-ESNF) and a triboelectric nanogenerator (TENG) driven by respiration (R-TENG) is developed. The ultrafine particulates are electrostatically adsorbed by the PVDF-ESNF, and the R-TENG can continually provide electrostatic charges in this adsorption process by respiration. On the basis of the R-TENG, the SEA-FM shows that the removal efficiency of coarse and fine particulates is higher than 99.2 wt % and the removal efficiency of ultrafine particulates is still as high as 86.9 wt % after continually wearing for 240 min and a 30-day interval. This work has proposed as a new method of wearable air filtration and may have great prospects in human health, self powered electronics, and wearable devices. PMID- 29394046 TI - Dissolution of Cellulosic Fibers: Impact of Crystallinity and Fiber Diameter. AB - With the aim of informing the selection of biomass pretreatment options and to assist in interpreting experimental results from different biomass/solvent combinations, this study addresses the impact of crystallinity and size on the kinetics of semicrystalline cellulose fiber swelling and dissolution. To this end, a newly developed phenomenological model is utilized that accounts for the role of decrystallization and disentanglement as two rate-determinant steps in the cellulose dissolution process. Although fibers with lower crystallinity swell more and faster, the degree of crystallinity does not affect the dissolution rate. Fibers of smaller diameter swell more and become amorphous faster. When decrystallization is important, the solubility of thinner fibers increases more with a reduction in the crystallinity compared to the diameter. However, when the dissolution is controlled by chain disentanglement, or in the case of dissolution of fibers having larger diameters, milling the fibers to reduce the particle size could increase the solubility. PMID- 29394047 TI - Understanding the Molecular Mechanisms of the CRISPR Toolbox Using Single Molecule Approaches. AB - Adaptive immunity against foreign genetic elements conferred by the CRISPR systems in microbial species has been repurposed as a revolutionary technology for wide-ranging biological applications-chiefly genome engineering. Biochemical, structural, genetic, and genomics studies have revealed important insights into their function and mechanisms, but most ensemble studies cannot observe structural changes of these molecules during their function and are often blind to key reaction intermediates. Here, we review the use of single molecule approaches such as fluorescent particle tracking, FRET, magnetic tweezers, and atomic force microscopy imaging in improving our understanding of the CRISPR toolbox. PMID- 29394049 TI - Unusual and Tunable Negative Linear Compressibility in the Metal-Organic Framework MFM-133(M) (M = Zr, Hf). AB - High-pressure single-crystal X-ray structural analyses of isostructural MFM 133(M) (M = Zr, Hf) of flu topology and incorporating the tetracarboxylate ligand TCHB4- [H4TCHB = 3,3',5,5'-tetrakis(4-carboxyphenyl)-2,2',4,4',6,6'-hexamethyl 1,1'-biphenyl] and {M6(MU3-OH)8(OH)8(COO)8} clusters confirm negative linear compressibility (NLC) behavior along the c axis. This occurs via a three dimensional wine-rack NLC mechanism leading to distortion of the octahedral cage toward a more elongated polyhedron under static compression. Despite the isomorphous nature of these two structures, MFM-133(Hf) shows a higher degree of NLC than the Zr(IV) analogue. Thus, for the first time, we demonstrate here that the NLC property can be effectively tuned in a framework material by simply varying the inorganic component of the frameworks without changing the network topology and structure. PMID- 29394048 TI - Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of alpha Synuclein. AB - 3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic and reactive product of dopamine catabolism. In the catecholaldehyde hypothesis for Parkinson's disease, it is a critical driver of the selective loss of dopaminergic neurons that characterizes the disease. DOPAL also cross-links alpha-synuclein, the main component of Lewy bodies, which are a pathological hallmark of the disease. We previously described the initial adduct formed in reactions between DOPAL and alpha-synuclein, a dicatechol pyrrole lysine (DCPL). Here, we examine the chemical basis for DOPAL-based cross-linking. We find that autoxidation of DCPL's catechol rings spurs its decomposition, yielding an intermediate dicatechol isoindole lysine (DCIL) product formed by an intramolecular reaction of the two catechol rings to give an unstable tetracyclic structure. DCIL then reacts with a second DCIL to give a dimeric, di-DCIL. This product is formed by an intermolecular carbon-carbon bond between the isoindole rings of the two DCILs that generates two structurally nonequivalent and separable atropisomers. Using alpha-synuclein, we demonstrate that the DOPAL-catalyzed formation of oligomers can be separated into two steps. The initial adduct formation occurs robustly within an hour, with DCPL as the main product, and the second step cross-links alpha-synuclein molecules. Exploiting this two-stage reaction, we use an isotopic labeling approach to show the predominant cross-linking mechanism is an interadduct reaction. Finally, we confirm that a mass consistent with a di-DCIL linkage can be observed in dimeric alpha-synuclein by mass spectrometry. Our work elucidates previously unknown pathways of catechol-based oxidative protein damage and will facilitate efforts to detect DOPAL-based cross-links in disease-state neurons. PMID- 29394050 TI - ent-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells. AB - Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by clonal proliferation of myeloid blasts. Despite the progress that has been made in the treatment of various malignant hematopoietic diseases, the effective treatment of AML remains very challenging. Differentiation therapy has emerged as a promising approach for leukemia treatment, and new and effective chemical agents to trigger the differentiation of AML cells, especially drug-resistant cells, are urgently required. Herein, the natural product jungermannenone C, a tetracyclic diterpenoid isolated from liverworts, is reported to induce cell differentiation in AML cells. Interestingly, the unnatural enantiomer of jungermannenone C (1) was found to be more potent than jungermannenone C in inducing cell differentiation. Furthermore, compound 1 targets peroxiredoxins I and II by selectively binding to the conserved cysteine residues and leads to cellular reactive oxygen species accumulation. Accordingly, ent-jungermannenone C (1) shows potential for further investigation as an effective differentiation therapy against AML. PMID- 29394051 TI - Structural Elucidation and Bioinspired Total Syntheses of Ascorbylated Diterpenoid Hongkonoids A-D. AB - Hongkonoids A-D (1-4), the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused tricyclic spiroketal butyrolactone moiety and diterpenoid derived long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of spectroscopic data, chemical degradation, X-ray crystallography, CD analysis, and total synthesis. The total syntheses of compounds 1-4 were effectively accomplished by a convergent strategy with the longest linear sequences of 12-14 steps and overall yields of 5.4-9.6%. Notably, we exploited a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving the cascade reactions of an elaborate Claisen rearrangement, deprotections, and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework of 1-4. Some of the hongkonoids and/or synthetic analogs showed significant to moderate inhibitory activities against NF-kappaB, 11beta-HSD1, and sterol synthesis. The most active NF-kappaB inhibitor 34 exhibited distinct inhibition on the LPS-induced inflammatory responses in RAW 246.7 and primary BMDM cells. PMID- 29394052 TI - Efficient Solution of the Electronic Eigenvalue Problem Using Wavepacket Propagation. AB - We report how imaginary time wavepacket propagation may be used to efficiently calculate the lowest-lying eigenstates of the electronic Hamiltonian. This approach, known as the relaxation method in the quantum dynamics community, represents a fundamentally different approach to the solution of the electronic eigenvalue problem in comparison to traditional iterative subspace diagonalization schemes such as the Davidson and Lanczos methods. In order to render the relaxation method computationally competitive with existing iterative subspace methods, an extended short iterative Lanczos wavepacket propagation scheme is proposed and implemented. In the examples presented here, we show that by using an efficient wavepacket propagation algorithm the relaxation method is, at worst, as computationally expensive as the commonly used block Davidson-Liu algorithm, and in certain cases, significantly less so. PMID- 29394053 TI - Selective Vapor Pressure Dependent Proton Transport in a Metal-Organic Framework with Two Distinct Hydrophilic Pores. AB - The mechanism of proton conductivity in porous solids (i.e., Grotthuss or vehicular) is related to the structure and chemical environment of the pores. Direct observation of structure-function relationships is difficult because state of-the-art solid proton conductors are often amorphous. Here, we present a systematic elucidation of two distinct proton transport pathways within MIT-25, a mesoporous metal-organic framework that exhibits parallel channels of ~27 A and ~4.5 A width. We characterize transport through these pores using temperature- and humidity-dependent proton conductivity measurements and density functional theory. Through control of vapor pressure we are able to sequentially fill the small and large pores, promoting proton conductivity with distinct activation energies at low and high relative humidity, respectively. PMID- 29394054 TI - Genetic Engineering of Maize (Zea mays L.) with Improved Grain Nutrients. AB - Cell-wall invertase plays important roles in the grain filling of crop plants. However, its functions in the improvement of grain nutrients have not been investigated. In this work, the stable expression of cell-wall-invertase-encoding genes from different plant species and the contents of total starch, protein, amino acid, nitrogen, lipid, and phosphorus were examined in transgenic maize plants. High expressions of the cell-wall-invertase gene conferred enhanced invertase activity and sugar content in transgenic plants, leading to increased grain yield and improved grain nutrients. Transgenic plants with high expressions of the transgene produced more total starch, protein, nitrogen, and essential amino acids in the seeds. Overall, the results indicate that the cell-wall invertase gene can be used as a potential candidate for the genetic breeding of grain crops with both improved grain yield and quality. PMID- 29394055 TI - A Long-Lived Triplet State Is the Entrance Gateway to Oxidative Photochemistry in Green Fluorescent Proteins. AB - Though ubiquitously used as selective fluorescence markers in cellular biology, fluorescent proteins (FPs) still have not disclosed all of their surprising properties. One important issue, notably for single-molecule applications, is the nature of the triplet state, suggested to be the starting point for many possible photochemical reactions leading to phenomena such as blinking or bleaching. Here, we applied transient absorption spectroscopy to characterize dark states in the prototypical enhanced green fluorescent protein (EGFP) of hydrozoan origin and, for comparison, in IrisFP, a representative phototransformable FP of anthozoan origin. We identified a long-lived (approximately 5 ms) dark state that is formed with a quantum yield of approximately 1% and has pronounced absorption throughout the visible-NIR range (peak at around 900 nm). Detection of phosphorescence emission with identical kinetics and excitation spectrum allowed unambiguous identification of this state as the first excited triplet state of the deprotonated chromophore. This triplet state was further characterized by determining its phosphorescence emission spectrum, the temperature dependence of its decay kinetics and its reactivity toward oxygen and electron acceptors and donors. It is suggested that it is this triplet state that lies at the origin of oxidative photochemistry in green FPs, leading to phenomena such as so-called "oxidative redding", "primed photoconversion", or, in a manner similar to that previously observed for organic dyes, redox induced blinking control with the reducing and oxidizing system ("ROXS"). PMID- 29394056 TI - Metal Complexes as Self-Indicating Titrants for Acid-Base Reactions in Chloroform. AB - The paper reports an unprecedented spectrophotometric determination of amines in chloroform, in which amines are not transformed into colored derivatives. This result has been achieved by exploiting the acid-base properties of the tight-ion paired metal complexes [(HR2DTO)Pt(H2R2DTO)][Cl], which are able to donate a HCl molecule to an amine, giving rise to an ammonium salt and to the neutral complexes [(HR2DTO)2Pt]. The circumstance that [(HR2DTO)Pt(H2R2DTO)][Cl] and [(HR2DTO)2Pt] species show different absorptions in the visible region of the electromagnetic spectrum enables the aforementioned platinum complexes to behave as self-indicating titrants in the spectrophotometric determination of aliphatic amines, which are known to be UV-vis transparent. The new method has been tested by determining a series of fatty amines in the bulk and gave excellent results. The limits of applicability of this method (pKa > 4) were found by testing a series of benzodiazepines. PMID- 29394057 TI - Thermodynamic, Structural, and Computational Investigation on the Complexation between UO22+ and Amine-Functionalized Diacetamide Ligands in Aqueous Solution. AB - The stability constants (log beta), enthalpies of complexation (DeltaH), and entropies of complexation (DeltaS) for the complexes of uranium(VI) with a series of amine-functionalized diaetamide ligands, 2,2'-benzylazanediylbis(N,N' dimethylacetamide) (BnABDMA), 2,2'-azanediylbis(N,N'-dimethylacetamide) (ABDMA), and 2,2'-methylazanediylbis(N,N'-dimethylacetamide) (MABDMA), in aqueous solution were determined by potentiometry and calorimetry. Electronspray ionization mass spectrometry was used to verify the presence of uranium(VI) complexes in solution. The thermodynamic data indicate that the binding strengths of the three ligands with UO22+ follow the order BnABDMA < ABDMA < MABDMA, parallel to the order of the protonation constants as well as the order of the stability of the Nd3+ complexes, suggesting that the complexation of UO22+ with the ligands consist predominantly of electrostatic interactions. Denisty functional theory calculations were conducted to reveal the structures, electronic charge distribution, and energetics of the uranium(VI) complexes, providing insight into the thermodynamic trends of the complexation. Extended X-ray absorption fine structure spectroscopy was used to identify the structures of the uranium(VI) complexes in aqueous solution. PMID- 29394058 TI - Microscopic Origins of Poor Crystallinity in the Synthesis of Covalent Organic Framework COF-5. AB - Covalent organic frameworks (COFs) are porous crystalline materials that are entirely composed of organic building blocks and can be assembled straightforwardly from solution. The main synthetic challenge associated with COFs, compared to other porous materials such as zeolites or metal-organic frameworks, is their poor long-range order; typical sizes of crystal domains do not exceed a few tens of nanometers. Here, we develop a model of the molecular constituents of COF-5 and follow the early stages of its assembly dynamics from dilute solution. Our simulations indicate that under typical experimental conditions COF-5 formation happens not through nucleation but far from equilibrium through spinodal decomposition. This rapid assembly mode leads to a plethora of defects that are difficult to anneal and that are likely responsible for the limited crystallinity observed in the synthesis of many COFs. We analyze the driving forces for COF-5 formation and find that stacking interactions between aromatic molecular constituents are too strong. When these interactions are weakened, assembly proceeds through single nucleation events followed by slow growth. The COF-5 crystallites obtained in this way are essentially defect-free. These results suggest experimental strategies for growing COFs with enhanced crystalline quality. PMID- 29394059 TI - Probing the Most Stable Isomer of Zirconium Bis(phenoxy-imine) Cation: A Computational Investigation. AB - The possibility of coexistence of multiple isomers for zirconium bis(phenoxy imine) catalyst has been systematically studied by computational approaches. The energetics among the five different isomers of neutral Zr-catalyst have been assessed quantum mechanically. The results suggest that isomer cis-N/trans-O/cis Me is the most stable among the five isomers in accordance with the general observations of these kinds of phenoxy-imine catalyst. However, for the polymerization reaction, the active species is known to be the cationic form of the Zr-catalyst. The Zr-cation can exist in three different isomers, viz., cis N/trans-O (A), cis-N/cis-O (B), and trans-N/cis-O (C), and the presence of flexible ligands makes the modeling considerably challenging to determine the most preferable isomers. For the efficient modeling, altogether 80 different structures for each of the three cationic isomers have been generated by using molecular dynamics simulations, and subsequently, the quantum mechanical optimization of these structures has been performed to obtain the most preferable conformation for each isomer. The existing probability derived from the obtained free energy values suggests that isomer C is comparable with isomer A. Even more, isomer A of the cation can be present in two different conformations, where the orientation of side groups is altered at the imine nitrogen atoms. The transition state calculations also confirm that the Zr-cation can exist as a mixture of three structures, "up-down" and "down-down" orientations of the isomers A along with isomer C's "up-up" orientation. However, by varying the substituents at imine nitrogen atoms, one could modulate multimodal to unimodal polymerization behavior of the Zr-catalysts. We believe that this study should provide a starting point for theoretically exploring the mechanistic pathway of the complicated polymerization reactions. PMID- 29394060 TI - Characterization of Interactions between Curcumin and Different Types of Lipid Bilayers by Molecular Dynamics Simulation. AB - Curcumin (CUR) is a natural food ingredient with known ability to target microbial cell membrane. In this study, the interactions of CUR with different types of model lipid bilayers (POPE, POPG, POPC, DOPC, and DPPE), mixtures of model lipid bilayers (POPE/POPG), and biological membrane mimics (Escherichia coli and yeast) were investigated by all-atom explicit solvent molecular dynamics (MD) simulation. CUR readily inserts into different types of model lipid bilayer systems in the liquid crystalline state, staying in the lipid tails region near the interface of lipid head and lipid tail. Parallel orientation to the membrane surface is found to be more probable than perpendicular for CUR, as indicated by the tilt angle distribution. This orientation preference is less significant as the fraction of POPE is increased in the system, likely due to the better water solvation of perpendicular orientation in the POPE bilayer. In E. coli and yeast bilayers, tilt angle distributions were similar to that for POPE/POPG mixed bilayer, with water hydration number around CUR for the former being higher. Insertion of CUR resulted in membrane thinning. The results from these simulations provide insights into the possible differences in membrane disrupting activity of CUR against different types of microorganisms. PMID- 29394061 TI - Infrared Dynamics of Iron Carbonyl Diene Complexes. AB - The temperature dependence of the low-frequency C-O bands in the IR spectrum of [(eta4-norbornadiene)Fe(CO)3], reminiscent of signal coalescence in dynamic NMR, was interpreted by Grevels (in 1987) as chemical exchange due to very fast rotation of the diene group. Since then, there has been both support and objection to this interpretation. We discuss these various claims involving both one- and two-dimensional IR and, largely on the basis of new density functional theory calculations, furnish support for Grevels' original interpretation. PMID- 29394062 TI - Protein Hydration Thermodynamics: The Influence of Flexibility and Salt on Hydrophobin II Hydration. AB - The solubility of proteins and other macromolecular solutes plays an important role in numerous biological, chemical, and medicinal processes. An important determinant of protein solubility is the solvation free energy of the protein, which quantifies the overall strength of the interactions between the protein and the aqueous solution that surrounds it. Here we present an all-atom explicit solvent computational framework for the rapid estimation of protein solvation free energies. Using this framework, we estimate the hydration free energy of hydrophobin II, an amphiphilic fungal protein, in a computationally efficient manner. We further explore how the protein hydration free energy is influenced by enhancing flexibility and by the addition of sodium chloride, and find that it increases in both cases, making protein hydration less favorable. PMID- 29394063 TI - Anti-Influenza Triterpene Saponins from the Bark of Burkea africana. AB - In an in vitro cytopathic effect inhibition assay with the H3N2 influenza virus A/Hong Kong/68 (HK/68), the bark extract of Burkea africana was found to be a promising antiviral lead with an IC50 value of 5.5 MUg/mL without noteworthy cytotoxicity in Madin Darby canine kidney cells. After several chromatographic steps, triterpene saponins of the lupane and oleanane types were identified as the bioactive principles. In total, eight new triterpene saponins (1-8) with four so far undescribed aglycone structures were isolated and characterized via HRESIMS, GC-MS, and 1D and 2D NMR spectroscopy. Their anti-influenza virus activity on HK/68 and the 2009 pandemic H1N1 strain A/Jena/8178/09 revealed the most potent effects by compounds 7 and 8, with IC50 values between 0.05 and 0.27 MUM. This is the first time triterpene saponins have been reported as constituents of the investigated plant material. PMID- 29394064 TI - Facile and Efficient Decontamination of Thorium from Rare Earths Based on Selective Selenite Crystallization. AB - The coexistence of radioactive contaminants (e.g., thorium, uranium, and their daughters) in rare earth minerals introduces significant environmental, economic, and technological hurdles in modern rare earth production. Efficient, low cost, and green decontamination strategies are therefore desired to ameliorate this problem. We report here a single-step and quantitative decontamination strategy of thorium from rare earths based on a unique periodic trend in the formation of crystalline selenite compounds across the lanthanide series, where Ce(III) is fully oxidized in situ to Ce(IV). This gives rise to a crystallization system that is highly selective to trap tetravalent f-blocks while all other trivalent lanthanides completely remain in solution when coexist. These results are bolstered by first-principles calculations of lattice energies and an examination of bonding in these compounds. This system is contrasted with typical natural and synthetic systems, where trivalent and tetravalent f-block elements often cocrystallize. The separation factors after one round of crystallization were determined from binary systems of Th(IV)/La(III), Th(IV)/Eu(III), and Th(IV)/Yb(III) to reach 2.1 * 105, 1.2 * 105, and 9 * 104, respectively. Selective crystallization of thorium from a simulated monazite composite yields a separation factor of 1.9 * 103 with nearly quantitative removal of thorium. PMID- 29394065 TI - Total Synthesis of the Flavonoid Natural Product Houttuynoid A. AB - The first total synthesis of the antiviral flavonoid houttuynoid A (1) has been achieved from aryl ketone 6 and benzofuran aldehyde 5 in nine linear steps. The C6-C3-C6 structure of the flavonoid was synthesized by an I2-catalyzed oxa Michael addition of a chalcone intermediate, generated by the Claisen-Schmidt condensation of 5 and 6. This work provides a method for the synthesis of houttuynoids and provides a reference for the synthesis of the remaining members of the houttuynoid family. PMID- 29394066 TI - Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles To Prepare Rutaecarpine Derivatives. AB - An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride. PMID- 29394067 TI - Integrating Multiple Accelerated Molecular Dynamics To Improve Accuracy of Free Energy Calculations. AB - Accelerated Molecular Dynamics (aMD) is a promising enhanced sampling method to explore the conformational space of biomolecules. However, the large statistical noise in reweighting limits its accuracy to recover the original free energy profile. In this work, we propose an Integrated accelerated Molecule Dynamics (IaMD) method by integrating a series of aMD subterms with different acceleration parameters to improve the sampling efficiency and maintain the reweighting accuracy simultaneously. We use Alanine Dipeptide and three fast-folded proteins (Chignolin, Trp-cage, and Villin Headpiece) as the test objects to compare our IaMD method with aMD systematically. These case studies indicate that the statistical noise of IaMD in reweighting for free energy profiles is much smaller than that of aMD at the same level of acceleration and simulation time. To achieve the same accuracy as IaMD, aMD requires 1-3 orders of magnitude longer simulation time, depending on the complexity of the simulated system and the level of acceleration. Our method also outperforms aMD in controlling systematic error caused by the disappearance of the low-energy conformations when high acceleration parameters are used in aMD simulations for fast-folded proteins. Furthermore, the performance comparison between IaMD and the Integrated Tempering Sampling (ITS) in the case of Alanine Dipeptide demonstrates that IaMD possesses a better ability to control the potential energy region of sampling. PMID- 29394068 TI - Cation-Size-Dependent Conformational Locking of Glutamic Acid by Alkali Ions: Infrared Photodissociation Spectroscopy of Cryogenic Ions. AB - Consolidated knowledge of conformation and stability of amino acids and their clusters is required to understand their biochemical recognition. Often, alkali ions interact with amino acids and proteins. Herein, infrared photodissociation (IRPD) spectra of cryogenic metalated glutamic acid ions (GluM+, M = Li-Cs) are systematically analyzed in the isomer-specific fingerprint and XH stretch ranges (1100-1900, 2600-3600 cm-1) to provide a direct measure for cation-size-dependent conformational locking. GluM+ ions are generated by electrospray ionization and cooled down to 15 K in a cryogenic quadrupole ion trap. The assignment of the IRPD spectra is supported by density functional theory calculations at the dispersion-corrected B3LYP-D3/aug-cc-pVTZ level. In the global minimum of GluM+, the flexibility of Glu is strongly reduced by the formation of rigid ionic CO...M+...OC metal bridges, corresponding to charge solvation. The M+ binding energy decreases monotonically with increasing cation size from D0 = 314 to 119 kJ/mol for Li-Cs. Whereas for Li and Na only the global minimum of GluM+ is observed, for K-Cs at least three isomers exist at cryogenic temperature. The IRPD spectra of cold GluM+ ions are compared to IR multiple-photon dissociation spectra measured at room temperature. Furthermore, we elucidate the differences of the impact of protonation and metalation on the structure and conformational locking of Glu. PMID- 29394069 TI - The Interplay of Structure and Dynamics in the Raman Spectrum of Liquid Water over the Full Frequency and Temperature Range. AB - While many vibrational Raman spectroscopy studies of liquid water have investigated the temperature dependence of the high-frequency O-H stretching region, few have analyzed the changes in the Raman spectrum as a function of temperature over the entire spectral range. Here, we obtain the Raman spectra of water from its melting to boiling point, both experimentally and from simulations using an ab initio-trained machine learning potential. We use these to assign the Raman bands and show that the entire spectrum can be well described as a combination of two temperature-independent spectra. We then assess which spectral regions exhibit strong dependence on the local tetrahedral order in the liquid. Further, this work demonstrates that changes in this structural parameter can be used to elucidate the temperature dependence of the Raman spectrum of liquid water and provides a guide to the Raman features that signal water ordering in more complex aqueous systems. PMID- 29394070 TI - Coupling of Elementary Electronic Excitations: Drawing Parallels Between Excitons and Plasmons. AB - Recent advances in understanding the theoretical and experimental properties of excitons and plasmons have led to several technological breakthroughs. Though emerging from different schools of research, the parallels they possess both in their isolated and assembled forms are indeed interesting. Employing the larger framework of the dipolar coupling model, these aspects are discussed based on the excitonic transitions in chromophores and plasmonic resonances in noble metal nanostructures. The emergence of novel optical properties in linear, parallel, and helical assemblies of chromophores and nanostructures with varying separation distances, orientations, and interaction strengths of interacting dipolar components is discussed. The very high dipolar strengths of plasmonic transitions compared to the excitonic transitions, arising due to the collective nature of the electronic excitations in nanostructures, leads to the emergence of hot spots in plasmonically coupled assemblies. Correlations on the distance dependence of electric field with Raman signal enhancements have paved the way to the development of capillary tube-based plasmonic platforms for the detection of analytes. PMID- 29394071 TI - Tetramethyl Orthosilicate (TMOS) as a Reagent for Direct Amidation of Carboxylic Acids. AB - Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity. PMID- 29394073 TI - Negative Dipole Potentials and Carboxylic Polar Head Groups Foster the Insertion of Cell-Penetrating Peptides into Lipid Monolayers. AB - Cell-penetrating peptides (CPPs) are polycationic sequences of amino acids recognized as some of the most effective vehicles for delivering membrane impermeable cargos into cells. CPPs can traverse cell membranes by direct translocation, and assessing the role of lipids on the membrane permeation process is important to convene a complete model of the CPP translocation. In this work, we focus on the biophysical basis of peptide-fatty acid interactions, analyzing how the acid-base and electrostatic properties of the lipids determine the CPP adsorption and incorporation into a Langmuir monolayer, focusing thus on the first two stages of the direct translocation mechanism. We sense the binding and insertion of the peptide into the lipid structure by measuring the changes in the surface pressure, the surface potential, and the reflectivity of the interface. We show that, beyond the presence of anionic moieties, negative dipole potentials and carboxylic polar head groups significantly promote the insertion of the peptide into the monolayer. On the basis of our results, we propose the appearance of stable CPP-lipid complexes whose kinetics of formation depends on the length of the lipids' hydrocarbon chains. PMID- 29394072 TI - Molecular Profile of Priapism Associated with Low Nitric Oxide Bioavailability. AB - Priapism is a disorder in which prolonged penile erection persists uncontrollably, potentially leading to tissue damage. Priapism commonly afflicts patient populations with severely low nitric oxide (NO) bioavailability. Because NO is a primary mediator of erection, the molecular mechanisms involved in priapism pathophysiology associated with low NO bioavailability are not well understood. The objective of this study was to identify dysregulated molecular targets and signaling pathways in penile tissue of a mouse model of low NO bioavailability that have potential relevance to priapism. Neuronal plus endothelial NO synthase double knockout mice (NOS1/3-/-) were used as a model of low NO bioavailability. Priapic-like activity was demonstrated in the NOS1/3-/- mice relative to wild-type (WT) mice by the measurement of prolonged erections following cessation of electrical stimulation of the cavernous nerve. Penile tissue was processed and analyzed by reverse-phase liquid chromatography tandem mass spectrometry. As a result, 1279 total proteins were identified and quantified by spectral counting, 46 of which were down-regulated and 110 of which were up-regulated in NOS1/3-/- versus WT (P < 0.05). Ingenuity Pathway Analysis of differentially expressed proteins revealed increased protein kinase A and G protein coupled receptor signaling in NOS1/3-/- penises, which represent potential mechanisms contributing to priapism for secondary to low NO bioavailability. PMID- 29394074 TI - Incidence of cataract following implantation of a posterior-chamber phakic lens ICL (Implantable Collamer Lens) - long-term results. AB - AIM: To evaluate late postoperative complications, especially cataract occurrence, its morphological type and factors affecting its development in patients implanted with ICL (Implantable Collamer Lens). METHODS: We analysed the results of ICL implantation in 34 patients (type ICM V4 for myopia, ICH V3 for hyperopia, TICM V4 for astigmatism) in our department between 1998 and 2013. The cohort comprised 62 eyes (40 myopic and 22 hyperopic). Seven eyes with a toric ICL implanted were included in these groups according to spherical equivalent (SE). The average follow-up period was 10.5 +/- 3.5 years. We examined uncorrected and best-corrected visual acuity (UCVA and BCVA), SE, ICL vaulting (using anterior segment OCT) and occurrence of late postoperative complications, especially cataract formation in 2 groups of patients - myopes and hyperopes. RESULTS: Among the most common late postoperative complications were pigment dispersion syndrome in 27 eyes, 43.5% (12 myopic eyes and 15 hyperopic eyes) and cataract formation. Lens opacities, including opacities without loss of BCVA, were observed in 18 eyes (29%). Opacities affecting visual acuity were observed in 10 eyes (16.1%). Cataract significantly affecting visual acuity occurred in 7 eyes, i.e. 11.3% (5 myopic eyes and 2 hyperopic eyes). In these eyes, ICL removal and cataract surgery with implantation of posterior chamber intraocular lens (PC IOL) was performed. The most common morphological type of cataract were anterior subcapsular opacities (83.3%), the average time of onset was 3.4 +/- 1.9 years after ICL implantation. We did not prove a statistically significant association either between cataract occurrence and age at the time of surgery, or between cataract occurrence and higher preoperative spherical equivalent. We did not prove a significant association between cataract occurrence and low vault, however in 7 eyes after cataract surgery and ICL removal we do not know the vault values. In one eye uveitis with cystoid macular oedema was observed, in two highly myopic eyes repeated ICL dislocation and cataract occurred. In both of these cases the ICL was removed. CONCLUSIONS: According to our experience, implantation of ICL in moderate and high ametropia was relatively safe upon assessing the long-term outcomes. Among the most common complications were pigment dispersion syndrome and anterior subcapsular cataract formation. Cataract can be managed effectively surgically with good refractive outcomes without loss of BCVA. However, loss of accommodation after cataract surgery and risk of vitreoretinal complications must be considered.Key words: ICL (Implantable Collamer Lens), posterior chamber phakic intraocular lens, refractive surgery, cataract occurrence. PMID- 29394075 TI - Intraoperative Optical Coherence Tomography in Vitreoretinal Surgery. AB - INTRODUCTION: The objective of this article is to provide an overview of the current situation with the use of intraoperative optical coherence tomography (iOCT), and to present our own experience with this technology. METHODOLOGY: retrospective evaluation of case reports of typical pathologies of the retina which were resolved by means of standard pars plana vitrectomy (PPV) with the use of intraoperative optical coherence tomography (iOCT) integrated into the surgical microscope OPMI Lumera 700 / Rescan 700 (Zeiss). Auxiliary techniques: best corrected visual acuity (BCVA) was tested on ETDRS tables, biomicroscopy was performed with a 78D lens and optical coherence tomography (OCT) with a Zeiss Cirrus instrument. The operations were performed in retrobulbar anaesthesia, three-port 23G PPV and with the aid of the surgical unit Constellation (ALCON). RESULTS: we present three case reports of 2 women (pathology of type of disorder of the vitreoretinal interface) and 1 man (proliferative diabetic retinopathy), with an average age of 63 years. In the first 2 cases the observation period was 3 months, while the man with diabetic retinopathy was observed for 15 months. All surgical procedures with the use of iOCT were conducted without perioperative or postoperative complications. In all cases full anatomical success was achieved. In the first two cases BCVA improved substantially, and in the last case very good initial BCVA was stabilised over the long term. CONCLUSION: The use of iOCT provides the surgeon with simultaneous control both in surgical manipulations in close proximity to the retina and also in detailed virtualisation of the finding on the ocular fundus. The result is an excellent perioperative overview, up-to date information for the surgeon, higher precision of the procedure and thus also improved postoperative results.Key words: intraoperative optical coherence tomography, vitreoretinal surgery. PMID- 29394076 TI - Diagnostic potential of tears in ophthalmology. AB - In research circles, there is an increasing need to seek and identify new methods in the diagnosis of pathologies, monitoring the progression of the disease and response to treatment. The sensitivity of detection technologies has improved markedly, and enables the quantification of analyses in very small quantities. Tears represent a biological material with ever increasingly developing possibilities in the diagnosis of various pathologies. Our objective was to compile a basic overview of the diagnostic potential of tears via a summary of the potential lachrymal biomarkers of various pathologies. The article contains descriptions of protein biomarkers studied particularly in recent years, which correlate with a certain ocular pathology (dry eye, allergy, glaucoma etc.). It also summarises the results published to date in the field of systemic pathologies in patients with scleroderma, cystic fibrosis, diabetes mellitus, multiple sclerosis, cancers and Parkinson's disease. It concentrates on proteomic analyses, with the aim of improving the effectiveness of markers which could be used in future also in the timely diagnosis of ocular pathologies in clinical practice.Key words: Tears, proteins, biomarker, ocular pathologies, systemic pathologies. PMID- 29394077 TI - IgG-4 related disease in ophthalmology. AB - IgG-4 related disease (IgG4-RD) is a recently discovered systemic fibro inflammatory disease which affects the ocular system. This pathology is not limited only to the orbit, but may also frequently affect the anatomical structures of the eye, as well as other organs. Suspicion of IgG4-RD is based on careful clinical, radiological and immuno-histological examination with a finding of characteristic histopathological changes. Increased values of serum IgG4 need not necessarily be an unequivocal diagnostic criterion for the diagnosis of IgG4 RD. Only a careful histological and immunophenotyping examination together with a clinical finding provide a basis for distinguishing IgG4-RD from other inflammatory pathologies. Corticoids are applied in the treatment of this disease, but they do not exclude the possibility of relapses of clinical manifestations. Second choice pharmaceuticals are azathioprine, mycophenolate mofetil, and the effect of treating relapse of the disease with rituximab is significant.Key words: IgG4 related disease, eye, diagnosis, treatment. PMID- 29394079 TI - Colour vision in group of subjects with and without chromagen filter. AB - Our aim in this study was to prove influence of chromagen filter on color vision quality. Further we wanted to compare quality of color vision in groups of young healthy persons with persons with maculopathy. In our study we had in total 39 subjects. First group contained 13 subjects with average age 23 years without important eye pathology. In the second group we had 13 patients (average age 68 years) with maculopathy. Third group contained subjects with average age 64 years without important eye pathology. While examination we used sorting tests for color vision: Farnsworth-Munsell test and Lanthony test. Results were evaluated according the Vingryse and King-Smith technique. We found that average total error score (TES) in young healthy subjects with color chromagen filter doesnt differ from TES value gained from patients with disease of macula (p = 0.86). Further we found that chromagen filter changes color vision in group of young subjects on statistical significant level (p = 0.01). But in clinical view this is not important color vision defect (TES = 107.46 and CI = 1.42). Next study result showed statistically not important difference between the color vision in young healthy patient (average age 23 years) and older healthy patients with average age 64 years (p = 0.58). Finally we can conclude that green color chromagen filter doesnt have negative influence for dyslectic patients who will use this filter all day. Further we proved that color vision deterioration of patients with macular disease is not important for practical distinguishing of colors but is important clinically for diagnostic purposes. Last but not least we brought result which shows not important difference between young healthy subjects and older subjects (23 versus 64 years).Key words: Color vision, chromagen lens, total error score, maculopathy. PMID- 29394078 TI - Prevalence of refractive errors in the Slovak population calculated using the Gullstrand schematic eye model. AB - PURPOSE: A substantial part of the population suffers from some kind of refractive errors. It is envisaged that their prevalence may change with the development of society. The aim of this study is to determine the prevalence of refractive errors using calculations based on the Gullstrand schematic eye model. METHODS: We used the Gullstrand schematic eye model to calculate refraction retrospectively. Refraction was presented as the need for glasses correction at a vertex distance of 12 mm. The necessary data was obtained using the optical biometer Lenstar LS900. Data which could not be obtained due to the limitations of the device was substituted by theoretical data from the Gullstrand schematic eye model. Only analyses from the right eyes were presented. The data was interpreted using descriptive statistics, Pearson correlation and t-test. The statistical tests were conducted at a level of significance of 5%. RESULTS: Our sample included 1663 patients (665 male, 998 female) within the age range of 19 to 96 years. Average age was 70.8 +/- 9.53 years. Average refraction of the eye was 2.73 +/- 2.13D (males 2.49 +/- 2.34, females 2.90 +/- 2.76). The mean absolute error from emmetropia was 3.01 +/- 1.58 (males 2.83 +/- 2.95, females 3.25 +/- 3.35). 89.06% of the sample was hyperopic, 6.61% was myopic and 4.33% emmetropic. We did not find any correlation between refraction and age. CONCLUSION: Females were more hyperopic than males. We did not find any statistically significant hypermetopic shift of refraction with age. According to our estimation, the calculations of refractive errors using the Gullstrand schematic eye model showed a significant hypermetropic shift of more than +2D. Our results could be used in future for comparing the prevalence of refractive errors using same methods we used.Key words: refractive errors, refraction, Gullstrand schematic eye model, population, emmetropia. PMID- 29394080 TI - Activated Leukocyte Cell Adhesion Molecule Stimulates the T-Cell Response in Allergic Asthma. AB - RATIONALE: The activated leukocyte cell adhesion molecule (ALCAM) is a cluster of differentiation 6 ligand that is important for stabilizing the immunological synapse and inducing T-cell activation and proliferation. OBJECTIVES: In this study, we investigated the role of ALCAM in the development of inflammation in allergic asthma. METHODS: An ovalbumin (OVA)-induced allergic asthma model was established in wild-type (WT) and ALCAM-deficient (ALCAM-/-) mice. T-cell proliferation was evaluated in cocultures with dendritic cells (DCs). Bone marrow derived dendritic cells (BMDCs) from WT and ALCAM-/- mice were cultured and adoptively transferred to OT-II mice for either OVA sensitization or challenge. An anti-ALCAM antibody was administered to assess its therapeutic potential. ALCAM concentrations in the sputum and serum of children with asthma were quantified by ELISA. MEASUREMENTS AND MAIN RESULTS: Inflammatory responses were lower in ALCAM-/- mice than in WT mice, and T cells cocultured with DCs from ALCAM-/- mice showed reduced proliferation relative to those cocultured with DCs from WT mice. A decreased inflammatory response was observed upon adoptive transfer of BMDCs from ALCAM-/- mice as compared with that observed after transfer of BMDCs from WT mice. In addition, anti-ALCAM antibody-treated mice showed a reduced inflammatory response, and sputum and serum ALCAM concentrations were higher in children with asthma than in control subjects. CONCLUSIONS: ALCAM contributes to OVA-induced allergic asthma by stimulating T-cell activation and proliferation, suggesting it as a potential therapeutic target for allergic asthma. PMID- 29394081 TI - Taking Another View on Lung Fibrosis. PMID- 29394083 TI - Exclusive Breastfeeding and Complementary Feedings Are Not Mutually Exclusive. PMID- 29394084 TI - Standardization and Innovation in Paving a Path to a Better Future: An Update of Activities in ISO/TC276/WG2 Biobanks and Bioresources. AB - Recent advances in biotechnology are making it possible to advance science and improve healthcare with increasing speed and precision. Biobanking, as a foundation of the biotechnology infrastructure, is critical to the assurance of quality for many of the key components for these advancing technologies in both the human and nonhuman domains. Biobanking must advance to support the increased complexity and required precision needs of biological resources. Standards development can provide an important link for the research and development community by providing tools to ensure quality, fitness-for-purpose, and reproducibility in biobanking. ISBER has been developing the ISBER Best Practices revision. At the same time, ISO/TC276/ WG2 has been developing an International Standard (IS) ISO/DIS 20387 General requirements for biobanking standard. It is important that ISBER and ISO/TC276/WG2 harmonize and/or align their products to enable members of the diverse biobanking community to tailor their own suite of tools to support their specific needs. The availability of both standards and best practices that are complementary will maximize available support for all biobanks. The increased availability of complementary standards, tools, and best practices will facilitate the path to new biotechnology advances and a better future. PMID- 29394086 TI - Exploration of collagen recovered from animal by-products as a precursor of bioactive peptides: Successes and challenges. AB - A large amount of food-grade animal by-products is annually produced during industrial processing and they are normally utilized as animal feed or other low value purposes. These by-products are good sources of valuable proteins, including collagen or gelatin. The revalorization of collagen may lead to development of a high benefit-to-cost ratio. In this review, the major approaches for generation of collagen peptides with a wide variety of bioactivities were summarized, including antihypertensive, antioxidant and antidiabetic activities, and beneficial effects on bone, joint and skin health. The biological potentials of collagen peptides and their bioavailability were reviewed. Moreover, the unique advantages of collagen peptides over other therapeutic peptides were highlighted. In addition, the current challenges for development of collagen peptides as functional food ingredients were also discussed. This article discusses the opportunity to utilize collagen peptides as high value-added bio functional ingredients in the food industry. PMID- 29394082 TI - A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos. AB - RATIONALE: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. OBJECTIVES: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. METHODS: GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies. MEASUREMENTS AND MAIN RESULTS: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV1 in ZSWIM7 (rs4791658; P = 4.99 * 10-9) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV1/FVC (P = 9.59 * 10-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; P = 1.92 * 10-8) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 * 10-8) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level. CONCLUSIONS: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD. PMID- 29394088 TI - Control of Breathing in Preterm Infants. Neonatal ICU and Beyond. PMID- 29394087 TI - The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years. AB - The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents. PMID- 29394089 TI - Timing of Dialysis in Sepsis and Acute Respiratory Distress Syndrome. PMID- 29394090 TI - Failure patterns of different bracket systems and their influence on treatment duration: A retrospective cohort study. AB - OBJECTIVES: To compare the failure pattern of four different bracket types and to assess its effect on treatment duration. MATERIALS AND METHODS: A total of 78 white patients (28 male, 50 female) with a mean age of 12.6 years were included in this retrospective cohort study and treated for a mean period of 30.6 months. The patients were treated in a private practice with stainless steel conventionally ligated brackets, ceramic conventionally ligated brackets, stainless steel self-ligating brackets, or nickel-free self-ligating brackets. The loss of at least one bracket during the course of treatment was analyzed with Cox proportional hazards survival analyses and generalized linear regression. RESULTS: The overall bracket failure rate at the tooth level was 14.1% (217 brackets), with significant differences according to tooth type (between 8.0% 23.4%) and bracket type (between 11.2%-20.0%). After taking confounders into account, patients treated with ceramic brackets lost more brackets (hazard ratio = 1.62; 95% confidence interval = 1.14-2.29; P = .007) than patients with stainless steel brackets. On average, treatment time increased by 0.6 months (95% confidence interval = 0.21-1.05; P = .004) for each additional failed bracket. CONCLUSIONS: Bracket failure was more often observed with ceramic brackets and was associated with increased treatment duration. PMID- 29394091 TI - Hypoxia Upregulates Estrogen Receptor beta in Pulmonary Artery Endothelial Cells in a HIF-1alpha-Dependent Manner. AB - 17beta-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent increases in ERbeta expression. Sprague-Dawley rats and ERalpha or ERbeta knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs). Hypoxia increased expression of ERbeta, but not ERalpha, in lungs from HPH rats as well as in rat and human PAECs. ERbeta mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1alpha/HIF-2alpha stabilization increased PAEC ERbeta, whereas HIF-1alpha knockdown decreased ERbeta abundance in hypoxic PAECs. In turn, ERbeta knockdown in hypoxic PAECs increased HIF-2alpha expression, suggesting a hypoxia-sensitive feedback mechanism. ERbeta knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERbeta activation increased PHD2 and decreased both HIF-1alpha and HIF-2alpha, suggesting that ERbeta regulates the PHD2/HIF 1alpha/HIF-2alpha axis during hypoxia. Whereas hypoxic wild-type or ERalpha knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1alpha after hypoxia compared with untreated hypoxic mice, ERbeta knockout mice exhibited increased HIF-2alpha and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1alpha, increases ERbeta expression and the E2-ERbeta axis targets PHD2, HIF-1alpha, and HIF-2alpha to attenuate HPH development. PMID- 29394093 TI - Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and limited therapeutic options. Although the mechanisms contributing to vascular remodeling in PAH are still unclear, several features, including hyperproliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs), have led to the emergence of the cancer-like concept. The molecular chaperone HSP90 (heat shock protein 90) is directly associated with malignant growth and proliferation under stress conditions. In addition to being highly expressed in the cytosol, HSP90 exists in a subcellular pool compartmentalized in the mitochondria (mtHSP90) of tumor cells, but not in normal cells, where it promotes cell survival. OBJECTIVES: We hypothesized that mtHSP90 in PAH-PASMCs represents a protective mechanism against stress, promoting their proliferation and resistance to apoptosis. METHODS: Expression and localization of HSP90 were analyzed by Western blot, immunofluorescence, and immunogold electron microscopy. In vitro, effects of mtHSP90 inhibition on mitochondrial DNA integrity, bioenergetics, cell proliferation and resistance to apoptosis were assessed. In vivo, the therapeutic potential of Gamitrinib, a mitochondria-targeted HSP90 inhibitor, was tested in fawn-hooded and monocrotaline rats. MEASUREMENTS AND MAIN RESULTS: We demonstrated that, in response to stress, HSP90 preferentially accumulates in PAH-PASMC mitochondria (dual immunostaining, immunoblot, and immunogold electron microscopy) to ensure cell survival by preserving mitochondrial DNA integrity and bioenergetic functions. Whereas cytosolic HSP90 inhibition displays a lack of absolute specificity for PAH-PASMCs, Gamitrinib decreased mitochondrial DNA content and repair capacity and bioenergetic functions, thus repressing PAH-PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In vivo, Gamitrinib improves PAH in two experimental rat models (monocrotaline and fawn-hooded rat). CONCLUSIONS: Our data show for the first time that accumulation of mtHSP90 is a feature of PAH PASMCs and a key regulator of mitochondrial homeostasis contributing to vascular remodeling in PAH. PMID- 29394092 TI - Deficient Follistatin-like 3 Secretion by Asthmatic Airway Epithelium Impairs Fibroblast Regulation and Fibroblast-to-Myofibroblast Transition. AB - Bronchial epithelial cells (BECs) from healthy children inhibit human lung fibroblast (HLF) expression of collagen and fibroblast-to-myofibroblast transition (FMT), whereas asthmatic BECs do so less effectively, suggesting that diminished epithelial-derived regulatory factors contribute to airway remodeling. Preliminary data demonstrated that secretion of the activin A inhibitor follistatin-like 3 (FSTL3) by healthy BECs was greater than that by asthmatic BECs. We sought to determine the relative secretion of FSTL3 and activin A by asthmatic and healthy BECs, and whether FSTL3 inhibits FMT. To quantify the abundance of the total proteome FSTL3 and activin A in supernatants of differentiated BEC cultures from healthy children and children with asthma, we performed mass spectrometry and ELISA. HLFs were cocultured with primary BECs and then HLF expression of collagen I and alpha-smooth muscle actin (alpha-SMA) was quantified by qPCR, and FMT was quantified by flow cytometry. Loss-of-function studies were conducted using lentivirus-delivered shRNA. Using mass spectrometry and ELISA results from larger cohorts, we found that FSTL3 concentrations were greater in media conditioned by healthy BECs compared with asthmatic BECs (4,012 vs. 2,553 pg/ml; P = 0.002), and in media conditioned by asthmatic BECs from children with normal lung function relative to those with airflow obstruction (FEV1/FVC ratio < 0.8; n = 9; 3,026 vs. 1,922 pg/ml; P = 0.04). shRNA depletion of FSTL3 in BECs (n = 8) increased HLF collagen I expression by 92% (P = 0.001) and alpha-SMA expression by 88% (P = 0.02), and increased FMT by flow cytometry in cocultured HLFs, whereas shRNA depletion of activin A (n = 6) resulted in decreased alpha-SMA (22%; P = 0.01) expression and decreased FMT. Together, these results indicate that deficient FSTL3 expression by asthmatic BECs impairs epithelial regulation of HLFs and FMT. PMID- 29394094 TI - Integration of Antibody Array Technology into Drug Discovery and Development. AB - Antibody arrays represent a high-throughput technique that enables the parallel detection of multiple proteins with minimal sample volume requirements. In recent years, antibody arrays have been widely used to identify new biomarkers for disease diagnosis or prognosis. Moreover, many academic research laboratories and commercial biotechnology companies are starting to apply antibody arrays in the field of drug discovery. In this review, some technical aspects of antibody array development and the various platforms currently available will be addressed; however, the main focus will be on the discussion of antibody array technologies and their applications in drug discovery. Aspects of the drug discovery process, including target identification, mechanisms of drug resistance, molecular mechanisms of drug action, drug side effects, and the application in clinical trials and in managing patient care, which have been investigated using antibody arrays in recent literature will be examined and the relevance of this technology in progressing this process will be discussed. Protein profiling with antibody array technology, in addition to other applications, has emerged as a successful, novel approach for drug discovery because of the well-known importance of proteins in cell events and disease development. PMID- 29394095 TI - New Standards and Updated Best Practices Will Give Modern Biobanking a Boost in Professionalism. PMID- 29394096 TI - Protein Quality Control of the Endoplasmic Reticulum and Ubiquitin-Proteasome Triggered Degradation of Aberrant Proteins: Yeast Pioneers the Path. AB - Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin-proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol. PMID- 29394097 TI - CRISPR Typing and Antibiotic Resistance Correlates with Polyphyletic Distribution in Human Isolates of Salmonella Kentucky. AB - Although infrequently associated with reported salmonellosis in humans, Salmonella enterica, subsp. enterica serovar Kentucky (ser. Kentucky) is the most common nonclinical, nonhuman serovar reported in the United States. The goal of this study was to use Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-multi-virulence-locus sequence typing (MVLST) to subtype a collection of human clinical isolates of ser. Kentucky submitted to the Pennsylvania Department of Health and to determine the extent of antibiotic resistance in these strains. This analysis highlighted the polyphyletic nature of ser. Kentucky, and separated our isolates into two groups, Group I and Group II, which were equally represented in our collection. Furthermore, antimicrobial susceptibility testing on all isolates using a National Antimicrobial Resistance Monitoring System (NARMS) panel of antibiotics demonstrated that resistance profiles could be divided into two groups. Group I isolates were resistant to cephems and penicillins, whereas Group II isolates were resistant to quinolones, gentamicin, and sulfisoxazole. Collectively, 50% of isolates were resistant to three or more classes of antibiotics and 30% were resistant to five or more classes. The correlation of antibiotic resistance with the two different lineages may reflect adaptation within two distinct reservoirs of ser. Kentucky, with differential exposure to antimicrobials. PMID- 29394098 TI - miR-522 Modulated the Expression of Proinflammatory Cytokines and Matrix Metalloproteinases Partly via Targeting Suppressor of Cytokine Signaling 3 in Rheumatoid Arthritis Synovial Fibroblasts. AB - microRNAs have been reported to play important roles in the pathogenesis of rheumatoid arthritis (RA). This study examined the effects of miR-522 on the biological behaviors of RA synovial fibroblasts. The expression levels of miR-522 and relevant genes were measured by quantitative real-time PCR. The protein levels of cytokines were determined by ELISA assay. The protein levels of matrix metalloproteinases (MMPs) and suppressor of cytokine signaling 3 (SOCS3) were determined by western blot assay. Luciferase reporter assay was used to confirm the potential target of miR-522. Our results showed that miR-522 was upregulated in synovial fibroblasts from RA patients, and miR-522 expression level was significantly associated with the RA-associated clinical parameters. miR-522 overexpression increased the mRNA and protein expression levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and MMPs (MMP-1, MMP-3, and MMP-13) in RA synovial fibroblasts. Lipopolysaccharide induced the upregulation of TNF-alpha, IL-1beta, and MMPs in RA synovial fibroblasts, which was reversed by miR-522 knockdown. Bioinformatics analysis identified SOCS3 as a potential target of miR-522, and this target of miR-522 was confirmed by luciferase reporter assay, and miR-522 overexpression suppressed the mRNA and protein expression levels of SOCS3. The enforced expression of SOCS3 attenuated the enhanced effects of miR-522 on mRNA expression levels of TNF-alpha, IL-1beta, and MMPs. Collectively, our results suggested that miR-522 regulated the expression of proinflammatory cytokines and MMPs partly via targeting SOCS3 in RA synovial fibroblasts, which may contribute to pathogenesis of RA. PMID- 29394099 TI - Antimicrobial Resistance of Staphylococcus aureus Isolates from Dairy Cows and Genetic Diversity of Resistant Isolates. AB - Staphylococcus aureus is a frequent and major contagious mastitis bacterial pathogen. The antibiotic treatment cure rates vary considerably from 4% to 92%. Staphylococcus aureus readily becomes resistant to antibiotics, resulting in persistent noncurable intramammary infection that usually results in culling of infected animals. Because of its notorious ability to acquire resistance to the commonly used as well as last resort antimicrobials such as methicillin and vancomycin and the development of multidrug-resistant strains, antimicrobial resistance (AMR) in S. aureus is of paramount importance in human medicine. The objective of this study was to evaluate the prevalence of AMR and genetic diversity of S. aureus isolates from milk of dairy cattle. Staphylococcus aureus isolates (n = 239) from 33 dairy farms in Tennessee were tested against 10 antimicrobials by broth microdilution method using the Sensititer system. Genetic diversity of resistant isolates was evaluated by pulsed-field gel electrophoresis (PFGE). Overall, AMR of the S. aureus isolates varied from as low as 1.3% for ceftiofur to as high as 25% for sulfadimethoxine. Out of 239 S. aureus isolates, 82 (34.3%) of them were resistant to at least 1 of the 10 antimicrobials. The AMR isolates belonged to two major PFGE types, indicating the presence of dominant clonal patterns among the resistant isolates. In general, there was a variation of prevalence of AMR within and among farms over time, with an increasing trend in tetracycline resistance. Judicious use of antimicrobials in dairy cattle farms can reduce the development of antimicrobial-resistant S. aureus. PMID- 29394100 TI - Sleep Health and Psychopathology Mediate Executive Deficits in Pediatric Obesity. AB - OBJECTIVE: Executive and motivational dysfunction have been associated with pediatric obesity. Poor sleep quality and psychopathology, often comorbid with obesity, are also associated with executive and motivational dysfunction. We examined the contribution of these comorbid factors to the association between obesity and executive function and reward-related decision-making. METHODS: Seven to 18-year-old children with and without obesity performed a working memory task with low and high loads, a response inhibition task, and a probabilistic reward related decision-making task. Parents filled out standardized measures of executive function in everyday behavior, sleep health, and psychiatric symptoms. Analyses controlled for age, gender, IQ, and parental education. RESULTS: Children with obesity showed worse working memory performance under higher load (p = 0.007), and worse parent-reported behavioral regulation (p = 0.05) and metacognition (p = 0.04) in everyday behavior and their reward-related decision making was less consistent with learned probabilistic conditions (p = 0.04). Response inhibition did not differ between groups. Children with obesity had worse parent-reported sleep health (p < 0.01) and 4.27 greater odds of clinically relevant internalizing symptomology (p = 0.03), both of which mediated the effect of obesity on behavioral regulation (p's < 0.01) and metacognition (p's < 0.01). Performance-based assessments were not associated with sleep health or psychopathology. CONCLUSIONS: Sleep quality and internalizing psychopathology were worse in children with obesity and contributed to parent-reported executive dysfunction in their everyday behavior. Performance-based measures of working memory and decision-making were not associated with those comorbidities of obesity. PMID- 29394101 TI - Risperidone Treatment for Irritability in Fragile X Syndrome. AB - OBJECTIVE: The goal of this study was to assess the effectiveness of risperidone monoantipsychotic therapy targeting irritability in patients with Fragile X syndrome (FXS) in a naturalistic outpatient clinical setting. METHODS: We examined the use of risperidone, predominantly in combination with other nonantipsychotic psychotropic agents, targeting irritability in 21 male patients with FXS with a retrospective analysis of a prospectively collected large developmental disabilities-specific treatment database. Mean age at start of treatment, treatment duration, final dose, body mass index (BMI), and Clinical Global Impressions-Improvement (CGI-I) Scale score at final visit were determined, and changes with treatment were analyzed using paired t-tests. RESULTS: Mean age at start of treatment was 14.0 years. The final mean dose of risperidone was 2.5 mg/day. The mean duration of treatment was 22 months. Seven (33.33%) participants were considered treatment responders based on the CGI-I. Change in BMI between initiation and cessation of treatment episode was not significant, however, these data were only available for a subset (n = 11) of patients. CONCLUSIONS: Risperidone may be effective in the treatment of irritability in males with FXS. The overall effectiveness of monoantipsychotic treatment with risperidone was limited in this study compared with previous published reports; however, this may be the result of differences in outcome measures as well as a reflection of the level of functioning and severity of irritability in this sample. PMID- 29394103 TI - Researchers experience of misconduct in research in Malaysian higher education institutions. AB - This article offers a qualitative analysis of research misconduct witnessed by researchers during their careers, either by research students or fellow researchers, when conducting or supervising research in their respective departments. Interviews were conducted with 21 participants from various research backgrounds and with a range of research experience, from selected universities in Malaysia. Our study found that misbehavior such as manipulating research data, misrepresentation of research outcomes, plagiarism, authorship disputes, breaching of research protocols, and unethical research management was witnessed by participants among junior and senior researchers, albeit for different reasons. This indicates that despite the steps taken by the institutions to monitor research misconduct, it still occurs in the research community in Malaysian institution of higher education. Therefore, it is important to admit that misconduct still occurs and to create awareness and knowledge of it, particularly among the younger generation of researchers. The study concludes that it is better for researchers to be aware of the behaviors that are considered misconduct as well as the factors that contribute to misconduct to solve this problem. PMID- 29394102 TI - Virtual Sprouts: A Virtual Gardening Pilot Intervention Increases Self-Efficacy to Cook and Eat Fruits and Vegetables in Minority Youth. AB - OBJECTIVE: To examine the effect of the Virtual Sprouts intervention, an interactive multiplatform mobile gardening game, on dietary intake and psychosocial determinants of dietary behavior in minority youth. MATERIALS AND METHODS: In this quasi-experimental pilot intervention, 180 third-, fourth-, and fifth-grade students in Los Angeles Unified School District participated in a 3 week program that included three Virtual Sprouts gaming sessions, three in-school lessons, and three in-home activities, using a nutrition- and gardening-focused curriculum. Pre- and postintervention questionnaires were used to assess psychosocial determinants of dietary behavior, including knowledge about and self efficacy to eat fruits and vegetables (FV). Data were collected on FV, whole grains, fiber, total sugar, added sugar, and energy from sugary beverages through the Block Kids Food Screener ("last week" version) for Ages 2-17. Repeated measures analysis of covariance models was used for continuous outcomes, controlling for age, sex, ethnicity, school, and free school lunch. RESULTS: After the intervention, the intervention group (n = 116) compared with the control group (n = 64) had a significantly improved self-efficacy to eat FV score (+1.6% vs. -10.3%, P = 0.01), and an improved self-efficacy to cook FV score (+2.9% vs. -5.0%, P = 0.05). There were no significant differences in dietary intake or self-efficacy to garden scores between intervention and control groups. CONCLUSION: The results from this 3-week pilot study suggest that an interactive mobile game with a nutrition- and gardening-focused curriculum can improve psychosocial determinants of dietary behavior in minority youth. PMID- 29394104 TI - Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes. AB - Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20- to 60-fold) between white and black populations are largely attributable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color-based differences in KC incidence. Along with melanin quantity, solar simulated radiation-induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0-fold in the overall epidermis and by 59.0-, 16.5-, and 5.0-fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer of black skin. These results may explain, at least in part, the considerable skin color differences in KC incidence. These data suggest that a DNA protection factor of at least 60 is necessary in sunscreens to reduce white skin KC incidence to a level that is comparable with that of black skin.-Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., Young, A. R. Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes. PMID- 29394105 TI - Down-regulation of transcription factor OVOL2 contributes to epithelial mesenchymal transition in a noninvasive type of trophoblast implantation to the maternal endometrium. AB - Embryo implantation into the uterine endometrium is required for pregnancy establishment in most mammals. By using global expression analysis, we investigated the molecules that are related to epithelial-mesenchymal transition (EMT) in noninvasive bovine trophoblasts and found that the transcription factor, ovo-like zinc finger 2 ( OVOL2), which is essential for mesenchymal-epithelial transition in various cancers, was down-regulated after trophoblast attachment to the endometrial epithelium in utero. In cultured bovine trophoblast cells, OVOL2 down-regulation occurred only when cells were allowed to attach to bovine endometrial epithelial cells via the TEAD3/YAP signaling pathway. This resulted in the up-regulation of the EMT-associated transcription factors, ZEB1 and SNAI2, and the mesenchymal cell markers, N-cadherin ( CDH2) and vimentin ( VIM), whereas epithelial cell marker, E-cadherin ( CDH1), was down-regulated. In contrast, OVOL2 overexpression in bovine trophoblast cells exhibited a decrease in ZEB1 transcripts and an increase in E-cadherin. These observations revealed that ovo like protein (OVOL)2 down-regulation occurred concurrently with conceptus implantation into the uterine endometrium via the YAP/TEAD3 signaling pathway, and suggest that the down-regulation of OVOL2 expression contributes to the up regulation of EMT-related transcription factor expression, which enables EMT progression in the noninvasive bovine trophectoderm postimplantation.-Bai, R., Kusama, K., Nakamura, K., Sakurai, T., Kimura, K., Ideta, A., Aoyagi, Y., Imakawa, K. Down-regulation of transcription factor OVOL2 contributes to epithelial-mesenchymal transition in a noninvasive type of trophoblast implantation to the maternal endometrium. PMID- 29394107 TI - Acknowledgment of Reviewers: 2017. PMID- 29394106 TI - Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. AB - The axonal guidance proteins semaphorin (Sema)4D and Sema3A play important roles in communication between osteoclasts and osteoblasts. As stimulation of adenosine A2A receptors (A2AR) regulates both osteoclast and osteoblast function, we asked whether A2AR regulates both osteoclast and osteoblast expression of Semas. In vivo bone formation and Sema3A/PlexinA1/Neuropilin-1, Sema4D/PlexinB1 protein expression were studied in a murine model of wear particle-induced osteolysis. Osteoclast/osteoblast differentiation were studied in vitro as the number of tartrate-resistant acid phosphatase+/Alizarin Red+ cells after challenge with CGS21680 (A2AR agonist, 1 uM) or ZM241385 (A2AR antagonist, 1 uM), with or without Sema4D or Sema3A (10 ng/ml). Sema3A/PlexinA1/Neuropilin-1, Sema4D/PlexinB1, and receptor activator of NF-kappaB ligand/osteoprotegerin (RANKL/OPG) expression was studied by RT-PCR and Western blot. beta-Catenin activation and cytoskeleton changes were studied by fluorescence microscopy and Western blot. In mice with wear particles implanted over the calvaria, CGS21680 treatment increased bone formation in vivo, reduced Sema4D, and increased Sema3A expression compared with mice with wear particle-induced osteolysis treated with vehicle alone. During osteoclast differentiation, CGS21680 abrogated RANKL induced Sema4D mRNA expression (1.3 +/- 0.3- vs. 2.5 +/- 0.1-fold change, P < 0.001, n = 4). PlexinA1, but not Neuropilin-1, mRNA was enhanced by CGS21680 treatment. CGS21680 enhanced Sema3A mRNA expression during osteoblast differentiation (8.7 +/- 0.2-fold increase, P < 0.001, n = 4); PlexinB1 mRNA was increased 2-fold during osteoblast differentiation and was not altered by CGS21680. Similar changes were observed at the protein level. CGS21680 decreased RANKL, increased OPG, and increased total/nuclear beta-catenin expression in osteoblasts. Sema4D increased Ras homolog gene family, member A phosphorylation and focal adhesion kinase activation in osteoclast precursors, and CGS21680 abrogated these effects. In summary, A2AR activation diminishes secretion of Sema4D by osteoclasts, inhibits Sema4D-mediated osteoclast activation, and enhances secretion of Sema3A by osteoblasts, increasing osteoblast differentiation and diminishing inflammatory osteolysis.-Mediero, A., Wilder, T., Shah, L., Cronstein, B. N. Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. PMID- 29394108 TI - Participant Outcomes from Methods of Recruitment for Videogame Research. AB - OBJECTIVE: The most productive methods of recruitment for a videogame for health (G4H) trial are not known. Success or failure of recruitment methods has been reported for a variety of clinical trials, but few specifically for G4H trials. This study's goal was to recruit 444 overweight or obese (body mass index percentile between the 84.5th-99.4th percentiles) children between the ages of 10 12 years. The article reports the results of different methods of participant recruitment. MATERIALS AND METHODS: Participants had to agree to three fasting blood samples (baseline, immediately after, and 2 months later); be willing to wear an accelerometer for 7 days at each assessment; read and speak English fluently (because the games were in English); have no history of any condition that would affect what he/she could eat or how much physical activity he/she could get; and have an eligible home computer purchased in the last 5 years with high-speed internet. Hardware criteria reflected the types of computers upon which Diab-Nano could be effectively played. Recruitment was conducted over a 35 month period and included electronic media, print advertising, community recruitment, and an internal volunteer list. Respondents were guided to a web based screening questionnaire that asked for source of hearing about the study. RESULTS: Although diverse recruitment methods were used, slow recruitment resulted in obtaining only 45% of the recruitment goal (n = 199). Electronic media (e.g., radio, television, and internet), which reached millions of targeted parents, resulted in only 76 respondents, of whom 13 became participants; print media (e.g., magazine, newsletter/newspaper, and mail), which also reached large numbers of parents, resulted in 192 respondents, of whom 19 became participants; community recruitment (e.g., school, friend or family, doctors office, flyer, work, community program) resulted in 162 respondents, of whom 38 became participants; and the internal volunteer list resulted in 413 respondents, of whom 128 became participants. CONCLUSION: Inclusionary and exclusionary criteria and restricted access by gatekeepers could be deterrents to successful recruitment. The documented payoff of alternative comprehensive methods of recruitment should benefit other investigations in optimally allocating their recruitment resources. PMID- 29394109 TI - A Multi-Week Assessment of a Mobile Exergame Intervention in an Elementary School. AB - BACKGROUND: Exergaming is potentially useful to promote physical activity in children; however, long-term effectiveness is unclear. MobileKids Monster Manor (MKMM) is a mobile exergame developed with the help of young advisors. The game wirelessly transmits physical activity data from an accelerometer to a mobile device. Players' steps are redeemed for in-game rewards, for example, new characters. OBJECTIVE: First, to evaluate whether increased physical activity previously observed in a 1-week intervention is sustained over a 2-week intervention and 1-week follow-up, and second, to compare impact in schools within different socioeconomic environments. METHODS: Thirty-seven elementary school students participated in a 4-week randomized controlled study (1-week baseline; 2-week intervention [with only the Game group receiving MKMM]; and 1 week follow-up). All participants wore a Tractivity(r) accelerometer throughout. Linear mixed models were applied to assess sustainability; a second 42-children based dataset and age-/sex-adjusted linear regression models were used to compare effect across socioeconomic environments. RESULTS: In the first week of intervention, the Game group compared to the Control group showed a greater increase in physical activity (of 1,758 steps/day [95% confidence interval, CI = 133-3,385] and 31 active minutes/day [95% CI = 4-59]), relative to baseline (13,986 steps/day; 231 active minutes/day). However, this was not sustained in the second intervention week or follow-up. The school within a lower socioeconomic status environment showed lower baseline activity and the 1-week intervention resulted in a greater increase relative to baseline (3,633 steps/day more [95% CI = 1,281-5,985]). CONCLUSION: MKMM could be a useful short-term physical activity promotion tool; however, effectiveness may decrease as novelty diminishes. PMID- 29394110 TI - Stem cell and skin rejuvenation. AB - Stem cell-based therapies have been widely used for their abilities to repair and regenerate different types of tissues and organs in cosmetic and plastic surgeries. It involves the clinical application of different types of stem cells. Different stem cells have been reported to be applicable in different areas of cosmetic surgeries like face lipoatrophy, skin rejuvenation, breast enhancement, and body contouring. However, adipose-derived stem cells remain the most widely used by cosmetic surgeons as they have the potential and capability to differentiate into mesenchymal, ectodermal, and endodermal lineages and are easily accessible to harvest. The purpose of this review is to summarize available applications of stem in cosmetic and plastic surgeries. PMID- 29394111 TI - Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro. AB - 1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro. 2. Wild type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10-500 MUM substrate for 40 min at 37 degrees C and terminated at -80 degrees C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone. 3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (Vmax/Km) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20~435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity. 4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles. PMID- 29394112 TI - Medications for addiction treatment (MAT). PMID- 29394113 TI - TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis. AB - In the atherosclerotic plaque, macrophages are the key catabolic workhorse responsible for clearing lipid and dead cell debris. To survive the highly proinflammatory and lipotoxic plaque environment, macrophages must adopt strategies for maintaining tight homeostasis and self-renewal. Macroautophagy/autophagy is a pro-survival cellular pathway wherein damaged or excess cellular cargoes are encapsulated by a double-membrane compartment and delivered to the lysosome for hydrolysis. Previously, macrophage-specific autophagy deficiency has been shown to be atherogenic through several complementary mechanisms including hyperactivation of the inflammasome, defective efferocytosis, accumulation of cytotoxic protein aggregates, and impaired lipid degradation. Conversely, in a recent study we hypothesized that enhancing the macrophage autophagy-lysosomal system through genetic or pharmacological means could protect against atherosclerosis. We demonstrated that TFEB, a transcription factor master regulator of autophagy and lysosome biogenesis, coordinately enhances the function of this system to reduce atherosclerotic plaque burden. Further, we characterized the disaccharide trehalose as a novel inducer of TFEB with similar atheroprotective effects. Overall, these findings mechanistically interrogate the importance and therapeutic promise of a functional autophagy lysosome degradation system in plaque macrophage biology. PMID- 29394114 TI - Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review. AB - We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms. PMID- 29394115 TI - Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation. AB - OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin. In addition, our results provide new mechanistic insights into how phosphorylation of UBAN would regulate the ubiquitin-binding ability of OPTN and how disease-associated mutations in the OPTN UBAN domain disrupt its interaction with ubiquitin. Finally, we show that defects in ubiquitin-binding may affect the recruitment of OPTN to linear ubiquitin-decorated mutant Huntington protein aggregates. Taken together, our findings clarify the interaction mode between UBAN and linear ubiquitin chain in general, and expand our knowledge of the molecular mechanism of ubiquitin decorated substrates recognition by OPTN as well as the pathogenesis of neurodegenerative diseases caused by OPTN mutations. PMID- 29394116 TI - Normal scores of deep breathing tests: beware of dysrhythmia in transthyretin amyloidosis. AB - BACKGROUND: The heart rate (HR) response to paced deep breathing (DB) is a common test of cardiac autonomic function, where high heart rate variability (HRV) is considered to reflect normal autonomic function. We evaluated the DB test in patients with hereditary transthyretin amyloid (ATTRm) amyloidosis, where autonomic dysregulation and atrial arrhythmias are common. METHODS: Paced DB was performed during one minute (six breaths/min) in 165 recordings in adult ATTRm amyloidosis patients with the TTR Val30Met mutation, 42 hypertrophic cardiomyopathy (HCM) patients and 211 healthy subjects. HRV was scored by traditional DB indices and by a novel regularity index, estimating the fraction of the HRV that was coherent with the breathing pattern. RESULTS: Twenty per cent of ATTRm amyloidosis patients presented with age-adjusted HRV scores within normal limits but poor regularity due to subtle atrial arrhythmias and cardiac conduction disturbances. Forty-seven per cent of ATTRm amyloidosis patients presented with HRV scores below normal limits, whereas HCM patients presented with higher HRV than ATTRm amyloidosis patients. CONCLUSIONS: Reduced HRV is common in ATTRm amyloidosis patients during DB, however, autonomic function cannot be evaluated in patients presenting with the combination of "normal" scores and low regularity, since their HR responses often reflects dysrhythmias. PMID- 29394117 TI - Design and fabrication of a magnetically actuated non-invasive reusable drug delivery device. AB - We present a novel approach of designing and fabricating a noninvasive drug delivery device which is capable of delivering the drug to the target site in a controlled manner. The device utilizes a reservoir which can be reused once the drug has completely diffused from it. This micro-reservoir based fabricated device has been successfully tested using niosomes of insulin drug filled in, which was then sealed with a magnetic membrane of 20 um thick and was actuated by applying magnetic field. The deflection of the membrane on application of magnetic field results in the drug release from the reservoir. The discharge of the drug solution and the release rates was controlled by external magnetic field. The simulation of the membrane deflection using COMSOL software was carried out to optimize the concentration of the ferrous nanopowder in PDMS matrix. The characterization of the devices was implemented in-vitro on water and in-vivo on Wistar rats. It was also validated using high-performance liquid chromatography (HPLC) by observing characteristic peak of insulin. The blood samples showed the retention time of 2.79 min at lambdamax of 280 nm which further authenticated the effectiveness of the proposed work. This noninvasive fabricated device provides reusability, precise control and can enable the patient or a physician to actively administrate the drug when required. PMID- 29394118 TI - Clinical Features and Treatment Outcomes of Vitreoretinal Lymphoma according to Its Association with CNS Lymphoma. AB - PURPOSE: To compare the clinical features and treatment outcomes of different types of vitreoretinal lymphoma (VRL) that presents primarily, secondarily, or concurrently in association with CNS lymphoma. METHODS: We retrospectively reviewed the medical records of 53 patients with VRL pathologically confirmed between 2000 and 2014 in two of the largest tertiary hospitals in Korea. RESULTS: The proportions of primary, secondary, and concurrent VRL were 26%, 34%, and 40%, respectively. The primary VRL group had retinal infiltration most frequently (68%) among all groups and presented with the worst visual acuity at diagnosis (P = 0.035). The diagnostic delay was significantly shorter in patients with secondary VRL (1.4 months; P < 0.001). Median overall survival was 31 months in the entire cohort, and it was shortest in the concurrent VRL/CNS lymphoma group (18 months; P = 0.007). CONCLUSIONS: Ocular presentation and survival times may be different in VRL patients according to the association with CNS involvement. PMID- 29394119 TI - Safety and Efficacy of Intravitreal Dexamethasone Implant for Refractory Uveitic Macular Edema in Adults and Children. AB - PURPOSE: To assess safety and efficacy of intravitreal dexamethasone (DEX) implant in refractory uveitic macular edema (ME). METHODS: We retrospectively analyzed medical records of patients with nonresponsive ME secondary to chronic, noninfectious intermediate or posterior uveitis, treated with intravitreal DEX implants. RESULTS: A total of 42 eyes of 34 patients (aged 6-67 years) received 56 implants. Mean follow-up was 19.2 +/- 2.2 months after DEX implant. The mean visual acuity (0.48 +/- 0.06 logMAR to 0.34 +/- 0.1 logMAR) and mean central retinal thickness (472.2 +/- 35 to 274.7 +/- 60.6 um) improved considerably before and after DEX implant. A total of 11 eyes needed repeat implants after a prolonged time to recurrence (12.6-20.9 months). A total of 10 eyes needed no additional treatment. Oral steroids could be stopped in 40% patients. Intraocular pressure increased in seven and cataract progressed in six eyes. CONCLUSION: Intravitreal DEX implant is safe and effective adjunct therapy. It reduces dependence on systemic steroids, immunosuppressives and provides long-term effects. PMID- 29394120 TI - Glaucoma Secondary to Uveitis in Children in a Tertiary Care Referral Center. AB - PURPOSE: To study outcome of secondary glaucoma in pediatric uveitis patients. METHODS: Retrospective analysis of records of uveitis patients <=16 years. RESULTS: Of 182 pediatric uveitis patients, secondary glaucoma was seen in 48 patients (75 eyes, 26.23%) with female preponderance (F:M-29:19) . JIA was the most common etiology (35.71%). BCVA of >=20/40 was seen in 22 eyes at presentation and in 38 eyes at final follow up (p<0.001). Twenty eight children (66.67%) received systemic antiglaucoma therapy while 17 children (21 eyes) required surgery (60.71%). Logistic regression showed pseudophakia could predict the higher use of oral antiglaucoma medication (p=0.03) while anatomical site of involvement was predictive of higher chances of surgery (p=0.003). Overall success was seen in 82.10% and 71.64% using IOP limit of 21 and 18 mmHg respectively at mean follow-up of 3.9 years. CONCLUSION: Pediatric uveitic glaucoma though require multitude of therapies, can be managed effectively with appropriate therapy. PMID- 29394121 TI - Genetics of Natural Killer Cells in Human Health, Disease, and Survival. AB - Natural killer (NK) cells have vital functions in human immunity and reproduction. In the innate and adaptive immune responses to infection, particularly by viruses, NK cells respond by secreting inflammatory cytokines and killing infected cells. In reproduction, NK cells are critical for genesis of the placenta, the organ that controls the supply of oxygen and nutrients to the growing fetus. Controlling NK cell functions are interactions of HLA class I with inhibitory NK cell receptors. First evolved was the conserved interaction of HLA E with CD94:NKG2A; later established were diverse interactions of HLA-A, -B, and C with killer cell immunoglobulin-like receptors. Characterizing the latter interactions is rapid evolution, which distinguishes human populations and all species of higher primate. Driving this evolution are the different and competing selections imposed by pathogens on NK cell-mediated immunity and by the constraints of human reproduction on NK cell-mediated placentation. Promoting rapid evolution is independent segregation of polymorphic receptors and ligands throughout human populations. PMID- 29394123 TI - High-Dose Cisplatin for Head and Neck Cancer Lives On. PMID- 29394122 TI - Attitudes toward text recycling in academic writing across disciplines. AB - Text recycling, the reuse of material from one's own previously published writing in a new text without attribution, is a common academic writing practice that is not yet well understood. While some studies of text recycling in academic writing have been published, no previous study has focused on scholars' attitudes toward text recycling. This article presents results from a survey of over 300 journal editors and editorial board members from 86 top English-language journals in 16 different academic fields regarding text recycling in scholarly articles. Responses indicate that a large majority of academic gatekeepers believe text recycling is allowable in some circumstances; however, there is a lack of clear consensus about when text recycling is or is not appropriate. Opinions varied according to the source of the recycled material, its structural location and rhetorical purpose, and conditions of authorship conditions-as well as by the level of experience as a journal editor. Our study suggests the need for further research on text recycling utilizing focus groups and interviews. PMID- 29394124 TI - Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial. AB - Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed. PMID- 29394126 TI - Biopsychosocial Distress in Young Adult Oncology Patients: Examining Sex Differences in Sources of High Distress and Requests for Assistance. AB - PURPOSE: This study examines biopsychosocial problem-related distress and requests for assistance with male and female young adult patients by applying a large-scale analysis among individuals diagnosed with a variety of cancers. METHODS: A retrospective study was conducted involving 630 patients of ages 18-39 treated for cancer at City of Hope between 2009 and 2014. Patients were asked to complete a biopsychosocial problem-related distress touch-screen instrument before treatment as part of their routine clinical care. RESULTS: Overall, male patients rated more biopsychosocial problems as highly distressing than female patients. Some problems were consistently endorsed as highly distressing to both male and female patients. In fact, six of the top seven highly distressing problems for each sex were similar: finances, fatigue, sleeping, side effects of treatment, pain, and feeling anxious or fearful. There were differences in the ways male and female patients preferred to ask for assistance from the medical team, as males more often preferred to speak with someone, whereas females more often preferred to receive written information. CONCLUSION: Results indicate that sex may have a significant relationship with biopsychosocial topics of distress, likelihood of reporting distress, and preferred methods of receiving assistance. Tailoring information and resources to specific areas of distress may reduce high distress with common problems (such as finances, treatment side effects, and infertility.). PMID- 29394125 TI - Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. AB - Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-beta2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of beta2 microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I. PMID- 29394127 TI - Urinary Urgency in Working Women: What Factors Are Associated with Urinary Urgency Progression? AB - BACKGROUND: Urinary urgency is the primary symptom of overactive bladder (OAB). This study aimed to identify targets for effective intervention to delay progression of urinary urgency. MATERIAL AND METHODS: Secondary analyses of data from a study conducted with female employees of a large academic medical center were conducted. Women were >=18 years and nonpregnant at the time of the survey. An online questionnaire obtained demographic information, presence of lower urinary tract symptoms, and toileting behaviors. Bivariate analyses and multivariate logistic regression were applied to explore factors related to different stages of urinary urgency. RESULTS: Four stages of urinary urgency were constructed: (1) Stage 1: no urinary symptoms (n = 20), (2) Stage 2: continent but urinary urgency reported (n = 19), (3) Stage 3: nonsevere urgency urinary incontinence (UUI) (incontinent but leakage <=1/day, n = 74); and (4) Stage 4: severe UUI (leakage >=1/day, n = 26). In multivariate analyses, older women were more likely to be in Stage 3 than in Stage 2 (aOR 1.053, 95% CI 1.012-1.096). Women who lost urine with defecation were more likely to be in Stage 4 than Stage 3 (aOR 3.828, 95% CI 1.921-7.629). Women who habitually strained to empty the bladder faster were more likely to be in Stage 4 than in Stage 3 (aOR 6.588, 95% CI 1.317-32.971). CONCLUSIONS: Losing urine with defecation and making the bladder empty faster by pushing down should be explored as intervention targets to prevent women from progressing from Stage 3 to Stage 4. PMID- 29394128 TI - Impact of Hyaluronic Acid-Containing Artificial Tear Products on Reepithelialization in an In Vivo Corneal Wound Model. AB - PURPOSE: To evaluate the effect of 6 commercially available hyaluronic acid (HA) containing topical artificial tear products on corneal reepithelialization following injury, in an in vivo mouse model. METHODS: Ninety-six C57Bl/6 mice (16 per treatment group; male to female ratio, 1:1 per group) were anesthetized. Epithelial debridement was performed on 1 cornea per animal, and the debrided eye was imaged. A 30 MUL masked test solution containing 1 of 6 artificial tear products was instilled, immediately on debridement, and subsequently, every 2 h, for a total of 4 administrations. At 24 h post debridement, corneas were stained with fluorescein and imaged to calculate corneal healing rate (number of fluorescein-negative corneas). RESULTS: All 6 artificial tear products used in this study permitted the initial process of corneal wound healing. However, the corneal reepithelialization rate after 24 h was higher with Hydroxypropyl guar (HPG)/HA (53.33%) compared with other HA-containing artificial tear products [HA1 (12.5%), HA2 (26.67%), HA3 (31.25%), HA4 (6.25%), and HA5 (43.75%)]. The average area and percentage area of reepithelialization after 24 h were also higher with HPG/HA compared with other treatment groups. CONCLUSIONS: Percentage of eyes with complete corneal reepithelialization 24 h post debridement was highest with HPG/HA compared with other HA-containing artificial tear products tested. The results of this study provide additional evidence on the potential benefits of HPG/HA in the management of dry eye and its role in the rapid restoration of a healthy ocular epithelium. However, further studies are required to confirm the effects on human corneal wounds. PMID- 29394129 TI - Development of multiple-unit pellet system tablets by employing the SeDeM expert diagram system II: pellets containing different active pharmaceutical ingredients. AB - The SeDeM Expert Diagram System (SeDeM EDS) was originally developed to provide information about the suitability of powders to produce direct compressible tablets. Multiple-unit pellet systems (MUPS) are dosage forms consisting of pellets compressed into tablets or loaded into hard gelatin capsules. The aim of this study was to apply the SeDeM EDS to different size pellets (i.e. 0.5, 1.0, 1.5, 2.0, and 2.5 mm) containing different APIs (i.e. doxylamine, ibuprofen or paracetamol) to determine which properties should be corrected to yield MUPS tablet formulations. The SeDeM parameter tests were conducted on the pellets, selected excipients, intermediate blends, and final blends. The study showed that the properties of the pellets depended on the active ingredient and pellet size. The SeDeM compressibility indices indicated that the final pellet blends should be suitable for compression into MUPS tablets. MUPS tablets were prepared from the final blends and evaluated in terms of physico-chemical properties and dissolution profiles. Only three of the MUPS tablet formulations containing ibuprofen and one MUPS tablet formulation containing paracetamol failed content uniformity. The water solubility of the APIs as well as the pellet size (surface area exposed to the dissolution medium) attributed to the difference in drug dissolution rate. PMID- 29394130 TI - DZNep represses Bcl-2 expression and modulates apoptosis sensitivity in response to Nutlin-3a. AB - MDM2 antagonists stabilize and activate wild-type p53, and histone methyltransferase (HMT) inhibitors reduce methylation on histone lysines and arginines. Both MDM2 antagonists and HMT inhibitors are being developed as cancer therapeutics. Wild-type p53 expressing HCT116 colon cancer cells were resistant to apoptosis in response to the MDM2 antagonist Nutlin-3a. However, co-treatment with the HMT inhibitor DZNep sensitized the cells to Nutlin-3a-induced apoptosis. This sensitization resulted from reduced activity of the Bcl-2 gene promoter and a reduction in Bcl-2 mRNA and protein. Surprisingly, DZNep reduced Bcl-2 expression in other colon cancer cell lines (RKO, SW48, and LoVo) but failed to sensitize them to Nutlin-3a. We found these cell lines express elevated levels of Bcl-2 or other Bcl-2-family proteins, including Bcl-xL, Mcl-1, and Bcl-w. Knockdown of Mcl-1 and/or treatment with specific or pan Bcl-2-family inhibitors (BH3 mimetics) sensitized RKO, SW48, and LoVo cells to apoptosis by Nutlin-3a. The results demonstrate 1) DZNep represses the Bcl-2 gene promoter and affects apoptosis sensitivity by reducing Bcl-2 protein expression, and 2) elevated expression of pro-survival Bcl-2 family members protects colon cancer cells from Nutlin-3a-induced apoptosis. Targeting Bcl-2 proteins via DZNep or BH3 mimetics could increase the therapeutic potential of MDM2-antagonists like Nutlin-3a in colon cancer. PMID- 29394131 TI - Epitope Mapping of Monoclonal Antibody PMab-52 Against Cat Podoplanin. AB - The mucin-type membrane glycoprotein podoplanin (PDPN) is frequently overexpressed in numerous malignant cancers, including squamous cell carcinoma, germinal neoplasia, mesothelioma, lung cancer, oral cancer, and brain tumor. PDPN expression is strongly associated with cancer progression and poor prognosis. Furthermore, PDPN binds to C-type lectin-like receptor 2 (CLEC-2) on platelets, followed by PDPN-mediated platelet aggregation to facilitate tumor metastasis. We have previously reported a novel anti-cat PDPN (cPDPN) monoclonal antibody (mAb), PMab-52, which specifically detects cPDPN using flow cytometry analysis and successfully identifies cPDPN in feline squamous cell carcinomas. However, the specific binding epitope of cPDPN for PMab-52 remains unelucidated. In this study, a series of deletion or point mutants of cPDPN were utilized for investigating the binding epitopes of PMab-52 using flow cytometry and Western blotting. The findings of this study revealed that the critical epitopes of platelet aggregation-stimulating domain 4 (PLAG4) of cPDPN are responsible for the binding of PMab-52 to cPDPN. PMID- 29394132 TI - Decrease in invasion of HTR-8/SVneo trophoblastic cells by interferon gamma involves cross-communication of STAT1 and BATF2 that regulates the expression of JUN. AB - Trophoblast invasion is one of the critical steps during embryo implantation. IFNG secreted during pregnancy by uterine NK cells acts as a negative regulator of invasion. IFNG in a dose dependent fashion inhibits invasion of HTR-8/SVneo trophoblastic cells. It phosphorylates STAT1 both at tyr 701 and ser 727 residues. Silencing of STAT1 significantly increases invasion (~59%) of the cells. Based on NGS data, out of 207 genes, BATF2 expression was significantly increased after IFNG treatment. Silencing of BATF2 significantly increases the invasion of cells with (~53%) or without (~44%) treatment with IFNG. Expression of BATF2 and STAT1 is dependent on each other, silencing of one significantly inhibit the expression of other. Interestingly, phosphorylated JUN is also regulated by BATF2 and STAT1. Collectively, these findings showed that decrease in the invasion of HTR-8/SVneo cells after IFNG treatment is controlled by STAT1 and BATF2, which further regulates the expression of JUN. PMID- 29394133 TI - MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1. AB - In this study, we investigated the mechanism of miR-200c-3p and SLC6A1 in regulating cell activity of clear cell renal cell carcinoma (CCRCC). The mRNA and miRNA expressions of tissue specimens were analyzed by CapitalBio Corporation (Beijing, China). The expression of SLC6A1 in CCRCC cells was examined through qRT-PCR and western blot. The migration and invasion ability of 786-O cells was testified by transwell assay after transfected. 786-O cell proliferation ability was detected by MTT assay. Dual luciferase reporter assay verified the association between SLC6A1 and miR-200c-3p. SLC6A1 was high expressed and miR 200c-3p was low expressed in CCRCC tissues and cells. Besides, lower SLC6A1 expression indicated longer survival time and higher survival rate. MiR-200c-3p could directly target at SLC6A1 and reduce its expression. MiR-200c-3p inhibited the proliferation, migration and invasion in 786-O cells by down-regulating SLC6A1 expression. The results suggested that the miR-200c-3p served as a suppressor for CCRCC via down-regulating SLC6A1. PMID- 29394134 TI - Chronic Cystitis Associated with Plesiochorus cymbiformis ( Rudolphi, 1819 ) Looss, 1901 (Digenea: Gorgoderidae) in a Loggerhead Turtle Caretta caretta (Linnaeus 1758) (Testudines, Cheloniidae) from Brazil: A Case Report. AB - This paper reports the first occurrence of Plesiochorus cymbiformis (Digenea: Gorgoderidae) in a loggerhead turtle ( Caretta caretta [Testudines, Cheloniidae]) in Brazil and describes the histological findings of related injuries to the urinary bladder. PMID- 29394135 TI - Comparison of Different Energy Levels of Er:YAG Laser Regarding Intrapulpal Temperature Change During Safe Ceramic Bracket Removal. AB - OBJECTIVE: This study was done to compare the intrapulpal temperature change generated by different energy levels of Er:YAG laser used during debonding of ceramic brackets and find the most suitable level for clinical use. MATERIAL AND METHODS: Eighty polycrystalline alumina brackets were bonded on bovine incisor teeth, which were randomly divided into 4 groups of 20. One group was assigned as control. In the study groups, after laser exposure with 2, 4, or 6 Watt energy levels, brackets were debonded using an Instron Universal Testing machine. Adhesive remnant index (ARI) scores were recorded to evaluate the site of debonding. To assess intrapulpal thermal increase, 60 human premolar teeth that were prepared in the same way, at the same energy levels, by a thermocouple were used. RESULTS: When the debonding forces, intrapulpal temperature increases, and ARI of the groups were examined, statistically significant difference was observed between the groups. Mean temperature increases of 0.67 degrees C +/- 0.12 degrees C, 1.25 degrees C +/- 0.16 degrees C, and 2.36 degrees C +/- 0.23 degrees C were recorded for the 2, 4, and 6 Watt laser groups. The mean shear bond strength was 21.35 +/- 3.43 megapascals (MPa) for the control group, whereas they were 8.79 +/- 2.47, 3.28 +/- 0.73, and 2.46 +/- 0.54 MPa for the 2, 4, and 6 Watt laser groups, respectively. CONCLUSIONS: Four watts is the most efficient and safe energy level to be used, utilizing Er:YAG laser with water cooling spray for 6 sec by scanning method during debonding of polycrystalline alumina brackets without any carbonization effects and detrimental temperature changes at debond sites. PMID- 29394136 TI - EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas. AB - INTRODUCTION: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process. OBJECTIVES: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS. MATERIALS AND METHODS: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs. RESULTS: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness. CONCLUSIONS: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas. PMID- 29394137 TI - Genetic effects of PRNP gene insertion/deletion (indel) on phenotypic traits in sheep. AB - Prion protein (PRNP) gene is well known for affecting mammal transmissible spongiform encephalopathies (TSE), and is also reported to regulate phenotypic traits (e.g. growth traits) in healthy ruminants. To identify the insertion/deletion (indel) variations of the PRNP gene and evaluate their effects on growth traits, 768 healthy individuals from five sheep breeds located in China and Mongolia were identified and analyzed. Herein, four novel indel polymorphisms, namely, Intron-1-insertion-7bp (I1-7bp), Intron-2-insertion-15bp (I2-15bp), Intron-2-insertion-19bp (I2-19bp), and 3' UTR-insertion-7bp (3' UTR 7bp), were found in the sheep PRNP gene. In five analyzed breeds, the minor allelic frequencies (MAF) of the above indels were in the range of 0.008 to 0.986 (I1-7bp), 0.113 to 0.336 (I2-15bp), 0.281 to 0.510 (I2-19bp), and 0.040 to 0.238 (3' UTR-7bp). Additionally, there were 15 haplotypes and the haplotype 'II2-15bp D3'UTR-7bp-DI2-19bp-DI1-7bp' had the highest frequency, which varied from 0.464 to 0.629 in five breeds. Moreover, association analysis revealed that all novel indel polymorphisms were significantly associated with 13 different growth traits (P < 0.05). Particularly, the influences of I2-15bp on chest width (P = 0.001) in Small Tail Han sheep (ewe), 3' UTR-7bp on chest circumference (P = 0.003) in Hu sheep, and I2-19bp on tail length (P = 0.001) in Tong sheep, were highly significant (P < 0.01). These findings may be a further step toward the detection of indel-based typing within and across sheep breeds, and of promising target loci for accelerating the progress of marker-assisted selection in sheep breeding. PMID- 29394138 TI - In Vitro Influence of Low-Power Diode Laser Irradiation Time on Human Red Blood Cells. AB - OBJECTIVE: The present study investigates whether the exposure to low-power diode laser induces denaturation in red blood cell (RBC) membrane protein composition, and determines the irradiation time for when denaturation of membrane protein process begins. BACKGROUND: A low-energy laser has been used extensively in medical applications. Several studies indicated significant positive effects of laser therapy on biological systems. In contrast, other studies reported that laser induced unwanted changes in cell structure and biological systems. The present work studied the effect of irradiation time of low-power diode laser on the structure of membrane proteins of human RBCs. MATERIALS AND METHODS: The RBC suspension was divided into five equal aliquots. One aliquot served as control. The remaining four aliquots were exposed to low-power diode laser (wave length = 650 nm, power = 50 mW) for 10, 20, 30, and 40 min, respectively. After each given time, the percentage of denatured RBCs was calculated in each sample as described later. RESULTS: Irradiation of RBCs by this laser for 20 min did not cause any change in membrane protein composition. While increasing the irradiation time to 30 min caused denaturation of membrane proteins, resulting in the formation of cross-bonding in a considerable number of RBCs, and the percentage of denatured cells increased in a dose-dependent manner to the irradiation. CONCLUSIONS: It can be concluded that the effect of low-power diode laser on RBC membrane protein structure depends on irradiation time. PMID- 29394139 TI - Longitudinal Evaluation of Radiopacity of Resin Composites: Influence of Photoactivation and Accelerated Photoaging. AB - This study aimed to assess longitudinally the radiopacity of resin composites under the influence of photoactivation and photoaging processes. Ten specimens (1 mm thick and 4 mm in diameter) of three different microhybrid resin composites, Filtek Z250 XT (R1), TPH 3 Spectrum (R2), and Opallis (R3), were prepared for this study. For longitudinal assessment of radiopacity, radiographic images were obtained five times. The first time (T1), the specimens were not photoactivated; the second time (T2), the specimens were photoactivated; and the next three times, photoaging was carried out, with images obtained at 24 hours (T3), 48 hours (T4), and 72 hours (T5) after this process. The photoaging was conducted using LED light (700 lumens, 9 W, 6400 k) under controlled environmental conditions at 37 degrees C (+/-1 degrees C) and 65% (+/-5%) relative humidity. The digital system DIGORA Optime was used. The digital images were measured using the histogram function, and then the pixel intensity values were converted into mmAl (the standard unit of radiopacity) using a linear regression function, with minimal adjustment of R2 >= 0.9. Data in mmAl were statistically analyzed using an analysis of variance (alpha=0.05). R2 resin composite showed higher values of radiopacity, R1 resin composite showed intermediate values, and R3 resin composite showed lower values. Only at T1 did the higher radiopacity of R2 composite differ significantly from other groups ( p = 0.0000). After application of treatments (photoactivation and photoaging), all radiopacity values were similar ( p-values to T2=0.0507, T3=0.0536, T4=0.0502, T5=0.0501) due to consecutive increase of radiopacity of R1 and R3 composites from T2. Photoactivation and photoaging processes influenced the radiopacity, but changes occurring in the degree of radiopacity were dependent on the composition and chemical characteristics of each composite used. PMID- 29394140 TI - Effect of Sonic Resin Composite Delivery on Void Formation Assessed by Micro computed Tomography. AB - OBJECTIVES: The aim of this study was to quantify the internal void volume formation in commercially available, resin composites inserted using conventional or sonic insertion methods, and analyzed using three-dimensional (3D) micro computed tomography (MUCT). METHODS AND MATERIALS: Four resin composites were evaluated: one conventional (Herculite, Ultra, Kerr Corporation, Orange, CA, USA), one flowable bulk fill (SureFil SDR Flow, Dentsply International, York, PA, USA), and two packable bulk fill (SonicFill, Kerr Corporation, and Tetric EvoCeram Bulk Fill, Ivoclar Vivadent Inc, Schaan, Liechtenstein). Eight groups were evaluated according to each resin composite type and insertion method (conventional or sonic; n=5). Forty ABS 3D-printed cylindrical molds, 5.0 mm in diameter and 4.0 mm in depth, were fabricated. For the conventional resin composite, the mold was filled incrementally (two layers), while for bulk-fill resin composites, insertion was performed in a single increment. The sonic insertion method was performed using a specific handpiece (SonicFill Handpiece, Kerr Corporation). Resin composites were light cured using a multipeak light emitting diode light-curing unit (VALO, Ultradent Products Inc, South Jordan, UT, USA) in its regular mode. Samples were evaluated by MUCT, and data were imported into software (Amira, version 5.5.2, VSG, Burlington, MA, USA) for 3D reconstruction, from which the percentage of void volume was calculated. Data were analyzed using two-way analysis of variance and Tukey post hoc test at a preset alpha of 0.05. RESULTS: The conventional insertion method resulted in reduced porosity, compared with sonic insertion, for SureFil SDR Flow and Tetric EvoCeram bulk fill. The sonic insertion method did not demonstrate any influence on void formation for Herculite Ultra or SonicFill. CONCLUSION: Results suggest that the sonic insertion method might increase void formation during resin composite delivery, depending on restorative material brand. PMID- 29394141 TI - Marginal Fit and Retention Strength of Zirconia Crowns Cemented by Self-adhesive Resin Cements. AB - The absolute marginal gap (AMG) precementation and postcementation and the retention of zirconia crowns cemented to standardized molar preparations (4*10) by self-adhesive resin cements (SARCs) were evaluated. The following SARCs were used: RelyX U-200 (RXU200; 3M ESPE, Seefeld, Germany), SmartCem 2 (SC2; Dentsply, Milford, DE, USA), and G-Cem Automix (GCA; GC, Alsip, IL, USA). The control adhesive resin cement was Panavia 21 (PAN; Kuraray Dental Co Ltd, Osaka, Japan). Twenty measuring locations at a constant interval along the margins were marked, and the AMG was measured by an image analysis system connected to a stereomicroscope (20*). The cemented copings were aged 270 days at 100% humidity and 37 degrees C and then underwent 10,000 thermal cycles, 5 degrees C-55 degrees C. After aging, the crowns were tested for retention, and the debonded surfaces were examined at 3* magnification. The mean marginal gaps precementation and postcementation were 34.8 +/- 17.4 MUm and 72.1 +/- 31 MUm, respectively, with no statistically significant differences between the cements. A significant difference ( p<=0.001) in retention between the cements was found. The highest values were obtained for SC2 and GCA (1385 Pa and 1229 Pa, respectively), but these presented no statistically significant differences. The lowest values were found for PAN and RXU200 (738 Pa and 489 Pa, respectively), but these showed no statistically significant differences. The predominant mode of failure in all of the groups was mixed, and no correlations were found between marginal gap and retention. PMID- 29394142 TI - Hypermetabolism and Nutritional Support in Sepsis. AB - BACKGROUND: Surgical metabolism has been a founding field of investigation in surgery without which the boundaries of critical care, trauma, and surgical oncology could not have advanced. Traditionally, understanding the shifts in electrolytes, carbohydrates, fats, and amino acids that could explain the rapidly evolving proteolysis after catabolic stress and tumor growth has been a major focus of research that led to our current approach to maintaining homeostasis over the course of major surgical intervention and injury. METHOD: Review of the English-language literature. RESULTS: With the emerging field of inflammation and the discovery of cytokines and chemokines, surgical metabolism has taken a second seat in the surgical research arena. Yet central to all patient management after injury is an understanding of how catabolic stress erodes vital organ function and how current approaches can support metabolism through the most physiologically stressful perturbations known to man, for which there is no evolutionary precedent. Although it is well accepted that unabated proteolysis is not a sustainable physiologic state, in the era of modern medicine, precisely how to manipulate the body nutritionally to drive a recovery-directed immune response remains highly debated. This review incorporates multiple lines of inquiry in surgical metabolism, with a particular focus on sepsis. CONCLUSION: The changing landscape of previous paradigms in the field is discussed. Finally, how next generation technology might spark renewed interest in this field among surgical investigators is considered. PMID- 29394143 TI - Left Ventricle Function During Therapeutic Hypothermia with Beta1-Adrenergic Receptor Blockade. AB - Therapeutic hypothermia is an established treatment in patients resuscitated from cardiac arrest. It is usually well-tolerated circulatory, but hypothermia negatively effects myocardial contraction and relaxation velocities and increases diastolic filling restrictions. A significant proportion of resuscitated patients are treated with long-acting beta-receptor blocking agents' prearrest, but the combined effects of hypothermia and beta-blockade on left ventricle (LV) function are not previously investigated. We hypothesized that beta1-adrenergic receptor blockade (esmolol infusion) exacerbates the negative effects of hypothermia on active myocardial motions, affecting both systolic and diastolic LV function. A pig (n = 10) study was performed to evaluate the myocardial effects of esmolol during hypothermia (33 degrees C) and during normothermia, at spontaneous and pacing-increased heart rates (HRs). LV function was assessed by a LV pressure transducer, an epicardial ultrasonic transducer (wall thickness, wall thickening/thinning velocity) and an aortic ultrasonic flow-probe (stroke volume, cardiac output). The data were compared using a paired two-tailed Students t test, and also analyzed using a linear mixed model to handle dependencies introduced by repeated measurements within each subject. The significance level was p <= 0.05. The effects of hypothermia and beta blockade were distinct and additive. Hypothermia reduced myocardial motion velocities and increased diastolic filling restrictions, but end-systolic wall thickness increased, and stroke volume and dP/dtmax (pumping function) were maintained. In contrast, esmolol predominantly affected systolic pumping function, by a negative inotropic effect. In combination, hypothermia and esmolol reduced myocardial velocities in systole and diastole by ~40%, compared with normothermia without esmolol, inducing in combination both systolic and diastolic LV function impairment. The cardiac dysfunction deteriorated at increased HRs during hypothermia. Beta1 adrenergic receptor blockade (esmolol) exacerbates the negative effects of hypothermia on active myocardial contraction and relaxation. The combination of hypothermia with beta-blockade induces both systolic and diastolic LV function impairment. PMID- 29394144 TI - High-Intensity Focused Ultrasound for Pain Management in Patients with Cancer. AB - Cancer-related pain affects up to 80% of patients with malignancies. Pain is an important distressing symptom that diminishes the quality of life and negatively affects the survival of patients. Opioid analgesics are generally the primary therapy for cancer-related pain, with surgery, radiation therapy, chemotherapy, and other interventions used in cases of treatment-resistant pain. These treatments, which can be associated with substantial side effects and systemic toxicity, may not be effective. High-intensity focused ultrasound is an entirely noninvasive technique that is approved for treatment of uterine fibroids, bone metastases, and essential tremors. With magnetic resonance imaging or ultrasonographic guidance, high-intensity ultrasound waves are focused on a small well-demarcated region to result in precise localized ablation. This treatment may represent a multimodality approach to treating patients with malignant diseases-facilitating pain palliation, enhanced local drug delivery and radiation therapy effects, and stimulation of anticancer specific immune responses, and potentially facilitating local tumor control. Focused ultrasound can be used to achieve pain palliation by producing several effects, including tissue denervation, tumor mass reduction, and neuromodulation, that can influence different pathways at the origin of the pain. This technology has several key advantages compared with other analgesic therapies: It is completely noninvasive, might be used to achieve rapid pain control, can be safely repeated, and can be used in combination with chemotherapy and radiation therapy to enhance their effects. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29394147 TI - Immunological Effect of aGV Rabies Vaccine Administered Using the Essen and Zagreb Regimens: A Double-Blind, Randomized Clinical Trial. AB - This study evaluated the immunological effect of an aGV rabies virus strain using the Essen and Zagreb immunization programs. A total of 1,944 subjects were enrolled and divided into three groups: the Essen test group, Essen control group, and Zagreb test group. Neutralizing antibody levels and antibody seroconversion rates were determined at 7 and 14 days after the initial inoculations and then 14 days after the final inoculation in all of the subjects. The seroconversion rates for the Essen test group, Essen control group, and Zagreb test group, which were assessed 7 days after the first dosing in a susceptible population, were 35.74%, 26.92%, and 45.49%, respectively, and at 14 days, the seroconversion rates in this population were 100%, 100%, and 99.63%, respectively. At 14 days after the final dosing, the seroconversion rates were 100% in all three of the groups. The neutralizing serum antibody levels of the Essen test group, Essen control group, and Zagreb test group at 7 days after the first dosing in the susceptible population were 0.37, 0.26, and 0.56 IU/mL, respectively, and at 14 days after the initial dosing, these levels were 16.71, 13.85, and 16.80 IU/mL. At 14 days after the final dosing, the neutralizing antibody levels were 22.9, 16.3, and 18.62 IU/mL, respectively. The results of this study suggested that the aGV rabies vaccine using the Essen program resulted in a good serum immune response, and the seroconversion rates and the neutralizing antibody levels generated with the Zagreb regimen were higher than those with the Essen regimen when measured 7 days after the first dose. PMID- 29394148 TI - Effects of intermittent hypoxic training performed at high hypoxia level on exercise performance in highly trained runners. AB - This study exanimated the effects of intermittent hypoxic training (IHT) conducted at a high level of hypoxia with recovery at ambient air on aerobic/anaerobic capacities at sea level and hematological variations. According to a double-blind randomized design, fifteen highly endurance-trained runners completed a 6-weeks regimented training with 3 sessions per week consisting of intermittent runs (6x work-rest ratio of 5':5') on a treadmill at 80-85% of maximal aerobic speed ([Formula: see text]). Nine athletes (hypoxic group, HG) performed the exercise bouts at FI02 = 10.6-11.4% while six athletes (normoxic group, NG) exercised at ambient air. Running time to exhaustion at a velocity corresponding to 95% [Formula: see text] significantly increased for HG while no effect was found for NG. Regarding [Formula: see text], no significant effects were found in either training group. In addition, the decline of jumping performances over a 45s-continuous maximal vertical jump test (i.e. anaerobic capacity index) tended to be lower in HG compared to NG. The levels of the studied hematological variables, including erythropoietin and hematocrit, did not significantly change for either HG or NG. These results highlight that our IHT protocol may induce additional effects on aerobic performance without compromising the anaerobic capacity index in highly-trained athletes. PMID- 29394149 TI - Outcomes of Surgical Sepsis. AB - BACKGROUND: Discussion of outcomes of surgical sepsis is no longer straightforward. Definitions of sepsis have changed recently and updated data are scant. Surgical patient populations are often heterogeneous; the patient population being considered must be described with precision. Traditional 30-d operative mortality may not be the most relevant outcome to consider. What should change or be the emphasis going forward? METHODS: Review and synthesis of pertinent English-language literature. RESULTS: Epidemiologic data are abundant for short-term outcomes of sepsis in general, but despite the fact that approximately 30% of patients with sepsis are surgical patients, sepsis outcome data for surgical patients are scant, especially for durations longer than 30 d, and essentially non-existent for patients defined under the new Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria. Interpretability of extant data is hampered by non-standard and changing definitions. CONCLUSIONS: Sepsis and organ dysfunction may be decreasing in prevalence and magnitude among surgical patients, but terminology must be standardized to enhance the interpretability of data generated in the future. It behooves journal editors, reviewers, and authors to insist upon standardized definitions and rigorous study design and data interpretation. Longer term data (e.g., 90-d mortality as opposed to in-hospital or traditional 30-d mortality) will be needed to justify to payers the complex, expensive care that these patients require. There is an urgent need to redefine the research agenda for surgical infections. PMID- 29394145 TI - The journey of islet cell transplantation and future development. AB - Intraportal islet transplantation has proven to be efficacious in preventing severe hypoglycemia and restoring insulin independence in selected patients with type 1 diabetes. Multiple islet infusions are often required to achieve and maintain insulin independence. Many challenges remain in clinical islet transplantation, including substantial islet cell loss early and late after islet infusion. Contributions to graft loss include the instant blood-mediated inflammatory reaction, potent host auto- and alloimmune responses, and beta cell toxicity from immunosuppressive agents. Protective strategies are being tested to circumvent several of these events including exploration of alternative transplantation sites, stem cell-derived insulin producing cell therapies, co transplantation with mesenchymal stem cells or exploration of novel immune protective agents. Herein, we provide a brief introduction and history of islet cell transplantation, limitations associated with this procedure and methods to alleviate islet cell loss as a means to improve engraftment outcomes. PMID- 29394150 TI - Pediatric Sepsis Update: How Are Children Different? AB - BACKGROUND: Although there are some commonalities between pediatric and adult sepsis, there are important differences in pathophysiology, clinical presentation, and therapeutic approaches. The recognition and diagnosis of sepsis is a significant challenge in pediatric patients as vital sign aberrations and examination findings are often subtle as compared to those observed in adults. Gaps in knowledge that have been studied in depth in adult sepsis are still being investigated in pediatric patients such as best practices in ventilation, invasive monitoring, and resuscitation. DISCUSSION: In this review, we address key differences in the etiology, presentation, resuscitation, and outcomes of sepsis in children compared with adults. PMID- 29394151 TI - Straightening the Hierarchical Staircase for Basis Set Extrapolations: A Low-Cost Approach to High-Accuracy Computational Chemistry. AB - Because the one-electron basis set limit is difficult to reach in correlated post Hartree-Fock ab initio calculations, the low-cost route of using methods that extrapolate to the estimated basis set limit attracts immediate interest. The situation is somewhat more satisfactory at the Hartree-Fock level because numerical calculation of the energy is often affordable at nearly converged basis set levels. Still, extrapolation schemes for the Hartree-Fock energy are addressed here, although the focus is on the more slowly convergent and computationally demanding correlation energy. Because they are frequently based on the gold-standard coupled-cluster theory with single, double, and perturbative triple excitations [CCSD(T)], correlated calculations are often affordable only with the smallest basis sets, and hence single-level extrapolations from one raw energy could attain maximum usefulness. This possibility is examined. Whenever possible, this review uses raw data from second-order Moller-Plesset perturbation theory, as well as CCSD, CCSD(T), and multireference configuration interaction methods. Inescapably, the emphasis is on work done by the author's research group. Certain issues in need of further research or review are pinpointed. PMID- 29394152 TI - Validation of the positive health behaviours scale: a nationwide survey of nurses in Poland. AB - PURPOSE: The aim was to adjust the positive health behaviours scale (PHBS) to make it suitable for use by nurses, and to validate the new version of the tool. METHODS: A previously formulated PHBS was modified. The scale comprises 29 statements describing certain positive health behaviours in four subscales: nutrition, physical activity, relaxation and behaviours related to mental health, and preventive behaviours. The scale was enriched with items on avoiding risky behaviours and a question regarding respondents' own assessment of their care for health. Analyses were conducted of reliability, construct validity, criterion validity and dimensionality of subscales. The questionnaire was completed by 1017 nurses. RESULTS: Cronbach's alpha reached 0.844 for the entire scale and 0.623 0.761 for specific subscales. Empirical data did not confirm theoretical assumptions regarding the existence of a four-element structure of the PHBS. The scale's diagnostic criteria were validated on the basis of positive results of correlation and trend analysis. Only one of the subscales proved homogeneous and could be considered unidimensional. CONCLUSIONS: The results confirmed the high internal consistency of the scale and its subscales. The factor structure of the PHBS was equivocal. The PHBS could be used in workplace-based health promotion programmes designed for nurses. PMID- 29394154 TI - Correction to: Increased Paracrine Immunomodulatory Potential of Mesenchymal Stromal Cells in Three-Dimensional Culture, by Follin B, Juhl M, Cohen S, Pedersen AE, Kastrup J, and Ekblond A. Tissue Eng Part B Reviews 2016;22(4):322 329. DOI: 10.1089/ten.teb.2015.0532. PMID- 29394155 TI - Remote Presence Robotic Technology Reduces Need for Pediatric Interfacility Transportation from an Isolated Northern Community. AB - BACKGROUND: Providing acutely ill children in isolated communities access to specialized care is challenging. This study aimed to evaluate remote presence robotic technology (RPRT) for enhancing pediatric remote assessments, expediting initiation of treatment, refining triaging, and reducing the need for transport. METHODS: We conducted a pilot prospective observational study at a primary/urgent care clinic in an isolated northern community. Participants (n = 38) were acutely ill children <17 years presenting to the clinic, whom local healthcare professionals had considered for interfacility transportation (IFT). Participants were assessed and managed by a tertiary center pediatric intensivist through a remote presence robot. The intensivist triaged participants to either remain at the clinic or be transported to regional/tertiary care. Controls from a pre existing local transport database were matched using propensity scoring. The primary outcome was the number of IFTs among participants versus controls. RESULTS: Fourteen of 38 (37%) participants required transport, whereas all controls were transported (p < 0.0001). Six of 14 (43%) transported participants were triaged to a nearby regional hospital, while no controls were regionalized (p = 0.0001). All participants who remained at the clinic stayed <24 h, and were matched to controls who stayed 4.9 days in tertiary care (p < 0.001). There was no statistically significant difference in hospital length of stay between transported participants and controls (6.0 vs. 5.7 days). CONCLUSIONS: RPRT reduced the need for specialized pediatric IFT, while enabling regionalization when appropriate. This study may have implications for the broader implementation of RPRT, while reducing costs to the healthcare system. PMID- 29394153 TI - Bench-to-Bedside: A Translational Perspective on Murine Models of Sepsis. AB - BACKGROUND: Considerable research effort has focused on the development of novel therapies for the treatment of sepsis, yet after decades of clinical trials, few significant advances have been achieved. This limitation persists despite a wealth of data yielded by basic science that has expanded our knowledge of the biology of this disease exponentially. METHOD: Review of the English-language literature. RESULTS: Translational researchers may address the resultant gap between the basic science laboratory and clinical research worlds. Herein, we review potential causes for the challenges of translating basic laboratory discovery into clinical benefit. CONCLUSION: We propose conceptual platforms to further the development of translational sepsis research efforts. PMID- 29394156 TI - Cultural versus classic risk and protective factors for suicide. AB - The current study examined the predictive value of cultural versus classic risk and protective factors for suicide in a community sample of 322 ethnic, sexual, and gender minority adults. Cultural factors played a significant and substantial role in predicting suicide attempts (explained 8% of variance in attempts and correctly classified 8.5% of attempters) over and above the classic factors of hopelessness, depression, and reason for living (which explained 17% of variance in attempts and correctly classified 14.1% of attempters). Findings suggest that cultural factors are important to include in standard suicide practice. PMID- 29394157 TI - Age of pubertal events among school girls in Lagos, Nigeria. AB - BACKGROUND: Globally, there is a secular trend towards the reduced age for sexual maturity and menarche. This study aimed to determine the current age and factors associated with attainment of various stages of puberty in Nigerian girls. METHODS: This study was a cross-sectional study involving 800 girls aged 6-15 years. The subjects were selected by stratified random sampling method from schools in Oshodi Local Government Area, Lagos State. They were interviewed and a physical examination was carried out to classify them into the various Tanner stages of breast and pubic hair maturational stages. RESULTS: The median age of girls at first stage of breast maturation (B2), first stage of pubic hair development (PH2) and at menarche were 9.0, 9.0 and 12.0 years, respectively. Breast development was significantly related to normal nutritional status (adjusted odds ratio [AOR] 4.5, p<0.001), overweight (AOR 40.2, p<0.001), obesity (AOR 154.2, p<0.001) and upper social class (AOR 15.7, p<0.031). Pubic hair development was significantly related only to overweight (AOR 4.7, p<0.007) and obesity (AOR 15.7, p<0.001) while achievement of menarche was significantly related to overweight (AOR 0.1, p=0.005), obesity (AOR 0.1, p=0.0009), high social class (AOR 4.7, p<0.001) and being a member of the Hausa tribe (AOR 35.8, p<0.029). CONCLUSIONS: There is decline in age of pubertal maturation of girls in Nigeria and the major contributory factors appear to be overweight and obesity. These findings are consistent with the pattern in developed countries. PMID- 29394158 TI - Microspheres containing decellularized cartilage induce chondrogenesis in vitro and remain functional after incorporation within a poly(caprolactone) filament useful for fabricating a 3D scaffold. AB - In this study, articular cartilage was decellularized preserving a majority of the inherent proteins, cytokines, growth factors and sGAGs. The decellularized cartilage matrix (dCM) was then encapsulated in poly(lactic acid) microspheres (MS + dCM) via double emulsion. Blank microspheres without dCM, MS(-), were also produced. The microspheres were spherical in shape and protein encapsulation efficiency within MS + dCM was 63.4%. The sustained release of proteins from MS + dCM was observed over 4 weeks in vitro. Both MS + dCM and MS(-) were cytocompatible. The sustained delivery of retained growth factors and cytokines from MS + dCM promoted cell migration in contrast to MS(-). Subsequently, chondrogenesis of human mesenchymal stem cells was upregulated in presence of MS + dCM as evidenced from immunohistochemistry, biochemical quantification and qPCR studies. Specifically, collagen II, aggrecan and SOX 9 gene expression were increased in the presence of MS + dCM by an order or more in magnitude compared to MS(-) with concomitant downregulation of hypertrophic genes (COL X) despite being cultured in the absence of chondrogenic media, (p < 0.05). Lastly, microspheres containing alkaline phosphatase (MS + ALP), a surrogate to assess the thermal stability of dCM proteins, incorporated within poly(caprolactone) filaments showed that the enzyme remained functional after filament production by melt extrusion. The establishment of a novel, thermally stable process for producing filaments containing chondroinductive microspheres provides evidence supporting subsequent development of a clinically-relevant, 3D scaffold fabricated from them for osteochondral regeneration and repair. PMID- 29394159 TI - Body-terrain interaction affects large bump traversal of insects and legged robots. AB - Small animals and robots must often rapidly traverse large bump-like obstacles when moving through complex 3D terrains, during which, in addition to leg-ground contact, their body inevitably comes into physical contact with the obstacles. However, we know little about the performance limits of large bump traversal and how body-terrain interaction affects traversal. To address these, we challenged the discoid cockroach and an open-loop six-legged robot to dynamically run into a large bump of varying height to discover the maximal traversal performance, and studied how locomotor modes and traversal performance are affected by body terrain interaction. Remarkably, during rapid running, both the animal and the robot were capable of dynamically traversing a bump much higher than its hip height (up to 4 times the hip height for the animal and 3 times for the robot, respectively) at traversal speeds typical of running, with decreasing traversal probability with increasing bump height. A stability analysis using a novel locomotion energy landscape model explained why traversal was more likely when the animal or robot approached the bump with a low initial body yaw and a high initial body pitch, and why deflection was more likely otherwise. Inspired by these principles, we demonstrated a novel control strategy of active body pitching that increased the robot's maximal traversable bump height by 75%. Our study is a major step in establishing the framework of locomotion energy landscapes to understand locomotion in complex 3D terrains. PMID- 29394160 TI - Dynamic traversal of large gaps by insects and legged robots reveals a template. AB - It is well known that animals can use neural and sensory feedback via vision, tactile sensing, and echolocation to negotiate obstacles. Similarly, most robots use deliberate or reactive planning to avoid obstacles, which relies on prior knowledge or high-fidelity sensing of the environment. However, during dynamic locomotion in complex, novel, 3D terrains, such as a forest floor and building rubble, sensing and planning suffer bandwidth limitation and large noise and are sometimes even impossible. Here, we study rapid locomotion over a large gap-a simple, ubiquitous obstacle-to begin to discover the general principles of the dynamic traversal of large 3D obstacles. We challenged the discoid cockroach and an open-loop six-legged robot to traverse a large gap of varying length. Both the animal and the robot could dynamically traverse a gap as large as one body length by bridging the gap with its head, but traversal probability decreased with gap length. Based on these observations, we developed a template that accurately captured body dynamics and quantitatively predicted traversal performance. Our template revealed that a high approach speed, initial body pitch, and initial body pitch angular velocity facilitated dynamic traversal, and successfully predicted a new strategy for using body pitch control that increased the robot's maximal traversal gap length by 50%. Our study established the first template of dynamic locomotion beyond planar surfaces, and is an important step in expanding terradynamics into complex 3D terrains. PMID- 29394161 TI - Electro-architected porous platinum on metallic multijunction nanolayers to optimize their optical properties for infrared sensor application. AB - Tailoring the physicochemical properties of the metallic multijunction nanolayers is a prerequisite for the development of microelectronics. From this perspective, a desired lower reflectance of infrared radiation was achieved by an electrochemical deposition of porous platinum in nonaqueous media on silver mirror supported nickel-chrome and nickel-titanium metallic films with incremental decreasing thicknesses from 80-10 nm. The electro-assembled architectures were examined by means of scanning electron microscopy and Fourier transform infrared spectroscopy and it was observed that the layer and sublayer thicknesses and resistivities have a substantial effect upon the porous platinum morphology and its optical properties. It is here reported that the augmentation of the metallic layer electrical conductivity determines the electroformation of more compact platinum nanolayers. Moreover, the platinum black coating of metallic nanolayers causes a considerable decrease of the reflectance in the region from 1000-8000 cm-1. PMID- 29394162 TI - Tracheal A-frame Deformity: A Challenging Variant of Tracheal Stenosis. PMID- 29394164 TI - Obstructing Respiratory Papillomatosis. PMID- 29394163 TI - Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling. AB - BACKGROUND: Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing. METHODS: Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincare analyses. RESULTS: Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincare analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation. CONCLUSIONS: The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincare plots illustrate that the buprenorphine induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress. PMID- 29394165 TI - Alcohol, liver disease, and transplantation: shifting attitudes and new understanding leads to changes in practice. AB - PURPOSE OF REVIEW: Review the current status of liver transplantation for patients with alcohol use disorder (AUD). RECENT FINDINGS: Alcohol-related liver disease (ALD) will increase as a source of patients requiring liver transplantation. Attitudes to use of liver transplantation as rescue therapy for patients with severe alcohol-related hepatitis are changing. The long-term health of ALD liver transplantation recipients requires continued assistance to patients with AUD. SUMMARY: Liver transplantation of patients with ALD increased during the last decade and we predict that this trend will continue because of the decline in the number of hepatitis C virus-infected candidates. Concomitantly, a shift in the selection for liver transplantation has occurred of patients with severe alcohol-related hepatitis not responding to medical therapy. Although rescue liver transplantation is a valuable option for patients with severe alcohol-related hepatitis, worldwide practice regarding rescue liver transplantation remains very heterogeneous. There is increasing recognition that excessive consumption of alcohol after liver transplantation is harmful to graft function and patient survival. Factors associated with relapse are younger age at liver transplantation and shorter duration of sobriety prior to liver transplantation. The long-term health of the ALD liver transplant recipient requires continued assistance regarding AUD, a lifelong disorder of craving, relapse, and remission. However, there have been very few studies evaluating best practices for long-term addiction care in transplant recipients. After liver transplantation, the prevalence of cardiovascular disease, infections, and cancer increases over time. Addiction to tobacco constitutes an important issue that must be considered as tobacco cessation may decrease the incidence of tobacco related cardiovascular and lung disease and aerodigestive cancers. PMID- 29394166 TI - Migraine Surgery: An All or Nothing Phenomenon? Prospective Evaluation of Surgical Outcomes. AB - OBJECTIVE: A detailed analysis of outcomes after migraine surgery suggests an anatomic etiology of pain, such as peripheral nerve compression, in select patients. BACKGROUND: Historically, surgeons have not played a role in the treatment of migraine. However, a subgroup of patients with extracranial anatomic triggers appear to benefit from surgical intervention. Traditionally, the determination of success or failure of migraine surgery is based on whether there is greater or less than 50% improvement of the migraine headache index (MHI) after surgery. However, in this study, patients either did not respond to treatment (<=5%) or improved completely (>=80%). Detailed analysis is provided of this surprising finding. METHODS: Subjects completed a prospective migraine questionnaire preoperatively as well as at 3 and 12 months postoperatively. RESULTS: All variables improved significantly from baseline. Interestingly, in 83% of patients, the MHI improved either >=80% or <=5%, suggesting a more binary distribution. Only 17% of indices fell in the intermediate (5% to 80%) range. Moreover, 69% of patients had >=80% improvement resulting in a mean improvement of 96% in this group. The remaining 14% had <=5% improvement, with an average improvement of 0%. CONCLUSION: Migraine surgery remains controversial. Traditional conservative therapy targets the central theory of migraine propagation. This study again prospectively demonstrates the efficacy of surgical trigger site deactivation in migraine patients. Patients either failed to improve or improved after surgery, with few intermediate outcomes. The binary distribution of data lends further support to an anatomic etiology of pain, that is, peripheral nerve compression, in select patients. PMID- 29394167 TI - Outcomes With Overlapping Surgery at a Large Academic Medical Center. AB - OBJECTIVE: The aim of the study was to evaluate the efficiency and safety of overlapping surgery (OS) at a training institution by comparing it with nonoverlapping surgery (NO) with respect to operative time, mortality, readmissions, and complications. BACKGROUND: OS is the practice of an attending physician providing supervision to 2 surgeries that are scheduled at overlapping times. Recent media and government attention have raised concerns about this practice and the need for informed patient consent. METHODS: A population-based, retrospective, cohort study was conducted using data on operative procedures from January 1, 2014 to December 31, 2015 at a large tertiary academic center. Patients who had undergone surgery by attending surgeons who performed >=10% of their cases overlapping were selected. Thirty-day mortality, readmission within 30 days, and 7 patient safety indicators (PSIs) were recorded. RESULTS: A total of 26,260 cases met our criteria for analysis for surgical time and 15,106 cases for outcomes. OS patients had an average case length of 2.18 hours compared with 1.64 hours among NO patients (P < 0.0001), a decreased risk of mortality [relative risk (RR) 0.42, 95% confidence interval (CI), 0.34-0.52, P < 0.0001), a decreased risk of readmission (RR 0.92, 95% CI, 0.86-0.98, P = 0.0148), and a decreased risk of experiencing any PSI (RR 0.67, 95% CI, 0.55-0.83, P = 0.0002). CONCLUSIONS: The present study confirms prior reports and addresses gaps in the literature regarding OS, such as the effect of resident involvement and the individual effect of OS in 13 different surgical specialties. The findings highlight the need for additional investigation and suggest that the practice of OS does not expose patients to increased risk of negative outcomes. PMID- 29394168 TI - Low-grade Endometrioid Stromal Sarcoma of the Paratestis: A Novel Report With Molecular Confirmation of JAZF1/SUZ12 Translocation. AB - Tumors with Mullerian-like serous or mucinous phenotypes originating in the testis and its adnexa are rare neoplasms that have been increasingly recognized in recent years. Cystadenomas with or without ovarian-type stroma, borderline tumors, and adenocarcinomas are the main documented types. Although a handful cases of putative endometrioid adenocarcinomas have been reported, to our knowledge no case of endometrial stromal-type neoplasm has ever been reported in the literature. A 59-year-old man presented with a 2 cm left intrascrotal mass that was found on sonographic examination to arise from the epididymal tail with prominent vascularization. He was otherwise healthy without significant clinical history, endocrinopathy, or external hormone therapy. His testicular tumor markers (beta-HCG, AFP) were normal. Histologic examination of the resection showed a multinodular tumor closely associated with the epididymis and composed of monotonous rounded to ovoid cells with scanty cytoplasm and prominent spiral like arterioles and capillaries. Mitotic activity was high. No other tumor component was seen. Immunohistochemistry revealed strong and diffuse expression of vimentin, CD10, estrogen receptor, and progesterone receptor. Molecular examination (performed on paraffin-embedded tumor tissue using a 517 gene fusion next-generation sequencing assay) showed a JAZF1/SUZ12 translocation, which was then confirmed by fluorescence in situ hybridization (FISH). These findings are consistent with a low-grade endometrioid stromal sarcoma originating in the paratestis. This report represents a novel addition to the growing spectrum of Mullerian-analog testicular adnexal neoplasms. PMID- 29394169 TI - Pure Intralymphatic Invasion in the Absence of Stromal Invasion After Neoadjuvant Therapy: A Rare Pattern of Residual Breast Carcinoma. AB - Rarely is intralymphatic/lymph-vascular invasion (LVI) the only residual disease in the breast after neoadjuvant chemotherapy. Only 12 patients have been reported in 2 prior studies. Prognosis was poor, with only 2 patients remaining alive and disease-free. The purpose of this study was to gather more data on this pattern of residual disease. Cases in which LVI was the only residual disease in the breast were retrospectively identified. Eighteen cases were identified including 10 of 669 (1.5%) consecutive surgical cases between 2003 and 2015. The mean tumor size was 3.4 cm. Seven cancers were negative for estrogen receptor and HER2, 8 were HER2 positive, and 3 were estrogen receptor positive and HER2 negative. In 15 cases, lymph nodes were either suspicious by imaging or proven positive by biopsy. After neoadjuvant chemotherapy, 9 patients were node negative, 7 were node positive, and 2 had isolated tumor cells. Mean follow-up was 63.8 months (7 to 138 mo). Two deaths occurred in patients with positive nodes. One death occurred and 2 patients are alive with metastatic disease in the node-negative group. The remaining 13 patients are alive without disease. The outcome associated with residual LVI might not be as dismal as previously reported. Although the better outcome may be due to stage at presentation or the type of chemotherapy, it is difficult to compare the cohorts of the 3 studies. However, the death of 3 of 13 node-negative patients over the 3 studies supports not classifying residual LVI as a pathologic complete response. PMID- 29394170 TI - Harnessing the PD-1 Pathway in Myelodysplastic Syndrome. PMID- 29394171 TI - HPV-related Oropharyngeal Carcinoma: A Review of Clinical and Pathologic Features With Emphasis on Updates in Clinical and Pathologic Staging. AB - There has been a sharp increase in the incidence of the human papilloma virus related oropharyngeal squamous cell carcinoma, partly due to the increasingly widespread awareness and recognition of this entity. This review assimilates the recent histopathologic classifications, staging systems, rapidly expanding research base and developments in management of human papilloma virus-related oropharyngeal squamous cell carcinoma and summarizes their implications for routine diagnostic practice. Differential diagnoses and their cytologic appearances are detailed and the utility of p16 staining and other immunohistochemistry testing is discussed. PMID- 29394172 TI - The emerging spectrum of exposure-related bronchiolitis. AB - PURPOSE OF REVIEW: Exposure-related bronchiolitis is increasingly recognized as an important but challenging clinical diagnosis. Acute and chronic inhalational exposures are associated with variable clinical presentations and a spectrum of histopathologic abnormalities affecting the small airways. This review provides an overview of the histologic patterns and occupational settings for exposure related bronchiolitis, along with recent advances in disease diagnosis and management. RECENT FINDINGS: The entire histopathologic spectrum of bronchiolitis (constrictive, obliterative, proliferative, lymphocytic, respiratory) has been reported in exposure-related bronchiolitis. Recent studies have shown that lung clearance index testing and impulse oscillometry are more sensitive than spirometry in detecting small airways abnormalities and may augment the diagnosis of occupational bronchiolitis. Prognosis in indolent occupational bronchiolitis appears more favorable than some other types of bronchiolitis but is variable depending on the extent of bronchiolar inflammation and the stage of disease at which exposure removal occurs. SUMMARY: No specific histopathologic pattern of bronchiolitis is pathognomonic for occupational bronchiolitis as one or more histologic patterns may be present. A high index of suspicion is needed for exposure and disease recognition. Recent advances that may aid in diagnosis include transbronchial cryobiopsy, lung clearance index testing, and impulse oscillometry, although further research is needed. PMID- 29394173 TI - "Meniscus Sign" to Identify the Lenticule Edge in Small-Incision Lenticule Extraction. AB - PURPOSE: To describe our technique of lenticule edge identification in small incision lenticule extraction using the "meniscus sign" to prevent lenticule misdissection. METHODS: Femtosecond laser application for small-incision lenticule extraction was performed. A "double ring" was visible, signifying the edge of the cap cut (outer ring) and lenticule cut (inner ring). The anterior and posterior lamellar planes were delineated in 2 different directions. During creation of the posterior lamellar channel, the lenticule edge was slightly pushed away from the surgeon to create a gap between the inner ring (diameter of the lenticule cut) and the lenticule edge. The lenticule edge assumed a frilled wavy appearance, and the meniscus sign was observed as a gap between the lenticule edge and the inner ring. The meniscus-shaped gap served as a landmark to identify the lenticule edge, and the relationship between the frilled lenticule edge and surgical instruments further acted as a guide to identify the correct plane of dissection. RESULTS: This technique was successfully undertaken in 50 eyes of 25 patients. The meniscus sign was observed in all cases, and no case had cap lenticular adhesions. CONCLUSIONS: The meniscus sign helps to identify the lenticule edge and correct dissection planes and provides a visual landmark during the entire surgical procedure. PMID- 29394174 TI - A Fourth Wave of Psychotherapies: Moving Beyond Recovery Toward Well-Being. PMID- 29394175 TI - Effects of Navigated Repetitive Transcranial Magnetic Stimulation After Stroke. AB - PURPOSE: The purpose of this study was to test the effects of navigated repetitive transcranial magnetic stimulation, delivered in different modes, on motor impairments and functional limitations after stroke. METHODS: The study sample included 42 patients (58.5 +/- 10.7 years; 26 males) who experienced a single unilateral stroke (1-12 months previously) in the area of the middle cerebral artery. Patients completed a course of conventional rehabilitation, together with 10 sessions of navigated repetitive transcranial magnetic stimulation or sham stimulation. Stimulation was scheduled five times a week over two consecutive weeks in an inpatient clinical setting. Patients were randomly assigned to one of four groups and received sham stimulation (n = 10), low frequency (1-Hz) stimulation of the nonaffected hemisphere (n = 11), high frequency (10-Hz) stimulation of the affected hemisphere (n = 13), or sequential combination of low- and high-frequency stimulations (n = 8). Participants were evaluated before and after stimulation with clinical tests, including the arm and hand section of the Fugl-Meyer Assessment Scale, modified Ashworth Scale of Muscle Spasticity, and Barthel Index of Activities of Daily Living. RESULTS: Participants in the three groups receiving navigated repetitive transcranial magnetic stimulation showed improvements in arm and hand functions on the Fugl Meyer Stroke Assessment Scale. Ashworth Scale of Muscle Spasticity and Barthel Index scores were significantly reduced in groups receiving low- or high frequency stimulation alone. CONCLUSIONS: Including navigated repetitive transcranial magnetic stimulation in a conventional rehabilitation program positively influenced motor and functional recovery in study participants, demonstrating the clinical potential of the method. The results of this study will be used for designing a large-scale clinical trial. PMID- 29394176 TI - Virtual Chromoendoscopy With FICE for the Classification of Polypoid and Nonpolypoid Raised Lesions in Ulcerative Colitis. AB - GOALS: The aim of this study was to analyze the performance of Fuji Intelligent Color Enhancement (FICE) using the classification of Kudo in the differentiation of neoplastic and non-neoplastic raised lesions in ulcerative colitis (UC). BACKGROUND: The Kudo classification of mucosal pit patterns is an aid for the differential diagnosis of colorectal polyps in the general population, but no systematic studies are available for all forms of raised lesions in UC. STUDY: All raised, polypoid and nonpolypoid, lesions found during consecutive surveillance colonoscopies with FICE for long-standing UC were included. In the primary prospective analysis, the Kudo classification was used to predict the histology by FICE. In a post hoc analysis, further endoscopic markers were also explored. RESULTS: Two hundred and five lesions (mean size, 8 mm; range, 2 to 30 mm) from 59 patients (mean age, 56 y; range, 21 to 79 y) were analyzed. Twenty three neoplastic (11%), 18 hyperplastic (9%), and 164 inflammatory (80%) lesions were found. Thirty-one lesions (15%), none of which were neoplastic, were unclassifiable according to Kudo. After logistic regression, a strong negative association resulted between endoscopic activity and neoplasia, whereas the presence of a fibrin cap was significantly associated with endoscopic activity. Using FICE, the sensitivity, specificity, and positive and negative likelihood ratios of the Kudo classification were 91%, 76%, 3.8, and 0.12, respectively. The corresponding values by adding the fibrin cap as a marker of inflammation were 91%, 93%, 13, and 0.10, respectively. CONCLUSIONS: FICE can help to predict the histology of raised lesions in UC. A new classification of pit patterns, based on inflammatory markers, should be developed in the setting of UC to improve the diagnostic performance. PMID- 29394177 TI - Outcomes of Alveolar Ridge Preservation With Recombinant Human Bone Morphogenetic Protein-2: A Systematic Review. AB - PURPOSE: The main focused question of this systematic review was as follows: Does the application of recombinant human bone morphogenetic protein-2 (rhBMP-2) placed in extraction sockets reduce the alveolar ridge changes? METHODS: A systematic literature search was performed up to February 2017. Clinical studies published in English were included. Outcome variables of interest were as follows: changes in alveolar ridge width and height, the quality of new bone, patient's safety, adverse events, and postoperative complications. RESULTS: Seven articles were included. Because of the vast heterogeneity and high risk of bias among the studies, performing a meta-analysis deemed not feasible. Application of rhBMP-2 in the extraction socket was more effective in the reduction of ridge width compared with that of ridge height. The superiority of 1.5 mg/mL rhBMP 2/absorbable collagen sponge over the carrier alone on alveolar ridge width/height remodeling was more significant when it was applied in the sockets with >=50% buccal bone dehiscence. The limited available data showed that rhBMP-2 did not improve the quality of new bone. Antibodies against rhBMP-2 were detected in the serum in 1 trial. CONCLUSIONS: Within the limits of this review, 1.5 mg/mL rhBMP-2 might be beneficial for preserving the alveolar ridge width within extraction sockets given as to whether the cost-effectiveness is justifiable. Studies with lower risk of bias should be performed to confirm the above findings. PMID- 29394178 TI - Coating of Sandblasted and Acid-Etched Dental Implants With Tantalum Using Vacuum Plasma Spraying. AB - PURPOSE: The objective was to prepare tantalum (Ta)-coated sandblasted and acid etched (SLA) dental implants using vacuum plasma spraying (VPS) and to analyze their morphologies. MATERIALS AND METHODS: Twelve SLA implants were coated with Ta using VPS. The topographies of the coatings and Ta/SLA surface interfaces were examined using scanning electron microscopy. The thickness at 4 locations for 6 Ta-coated and 6 uncoated SLA implants and pore sizes of the neck, central, and root areas of Ta-coated implants were measured. SPSS v20.0 was used for statistical analysis. RESULTS: The Ta coatings were rough and consisted of pitted structures with various pore sizes; no cracks were observed. The Ta/SLA surface interface was tightly bonded. The 95% confidence interval of the Ta coating thickness was (114.0759, 129.3574). The maximal pore diameter was concentrated at 200 to 400 nm. CONCLUSION: SLA dental implants were successfully coated with Ta using VPS. The nanoporous structure of these implants may facilitate osseointegration compared with uncoated SLA implants. PMID- 29394179 TI - Zygoma Quad Compared With 2 Zygomatic Implants: A Systematic Review and Meta analysis. AB - PURPOSE: The aim of this study was to systematically review and compare the survival rates (SRs) of oral rehabilitations performed with 2 zygomatic implants (ZIs) combined with regular implants (RIs) versus 4 ZI. MATERIAL AND METHODS: An electronic search was performed in several databases for articles published in English between 2007 and 2015. Articles reporting human studies were included in this systematic review. RESULTS: The search yielded to a total of 417 studies, of which 6 were included in this study. ZIs SR weighted mean was 98.0% with a 95% confidence interval (CI) of 96.7% to 99.8%. For the control group (2 ZIs + 2 RIs) and the test group (4 ZIs), the implant SR was 98.6% and 97.4%, respectively, with a 95% CI. No statistically significant differences in terms of SRs were obtained between both groups P = 0.286. CONCLUSIONS: The data analysis showed favorable results for treatment with 4 ZIs. The results showed no statistical differences in using 1 or another treatment, in terms of survival and failure rates. The reduction on treatment time and morbidity related to regenerative approaches may be its main advantage. In conclusion, the zygoma quad seems to be the treatment of choice for the rehabilitation of the severely atrophic maxilla. PMID- 29394180 TI - A Case Study of Clozapine and Cognition: Friend or Foe? PMID- 29394182 TI - The Utility of ICU Readmission as a Quality Indicator and the Effect of Selection. AB - OBJECTIVES: Intensive care readmission rates are used to signal quality, yet it is unclear whether they represent poor quality in the transition of care from the ICU to the ward, patient factors, or differences in survival of the initial admission. This study aims to measure the selection effect of surviving the initial ICU admission on readmission rates. DESIGN: Retrospective cohort study of adult patients admitted to ICUs participating in the Case Mix Program database from the Intensive Care National Audit Research Centre. SETTINGS: The study includes 262 ICUs in the United Kingdom. PATIENTS: The study includes 682,975 patients admitted to ICUs between 2010 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study includes 682,975 patients admitted to ICUs in the United Kingdom. There were 591,710 patients discharged alive, of which 9,093 (1.53%) were readmitted within the first 2 days of ICU discharge. Post-ICU admission hospital mortality and ICU readmission were poorly correlated (r = 0.130). The addition of a selection model resulted in a weaker correlation (r = 0.082). CONCLUSIONS: ICU readmission performed poorly as a performance metric. The selection process by which only patients who survive their index admission are eligible for readmission has a significant effect on ICU readmission rankings, particularly the higher ranked ICUs. Failure to consider this selection bias gives misleading signals about ICU performance and leads to faulty design of incentive schemes. PMID- 29394181 TI - The Association Between Acute Respiratory Distress Syndrome Hospital Case Volume and Mortality in a U.S. Cohort, 2002-2011. AB - OBJECTIVES: This study examines the relationships between hospitals' annual acute respiratory distress syndrome case volume with hospitals' acute respiratory distress syndrome case fatality rates and individuals' odds of acute respiratory distress syndrome hospital mortality. DESIGN: Retrospective cohort study. SETTING: The U.S. Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, 2002-2011. PATIENTS: Acute respiratory distress syndrome discharges defined by the presence of an acute respiratory distress syndrome International Classification of Diseases, 9th revision, Clinical Modification diagnosis code (518.82 or 518.5) and a mechanical ventilation procedure code (96.70, 96.71 or 96.72) on the discharge diagnosis and procedure lists. If the procedure code 96.71 was on the discharge record (mechanical ventilation < 96 hr duration), the patient also needed to be classified as deceased. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 2,686 hospitals and 117,204 cases of acute respiratory distress syndrome. Average annual hospital acute respiratory distress syndrome in-hospital mortality was 47%. Acute respiratory distress syndrome case volume was categorized as low (1-9), medium (10-49), and high (50 423 cases per year). In a hospital-level Poisson regression adjusting for hospital characteristics, when compared with low-volume acute respiratory distress syndrome hospitals, high- and medium-volume acute respiratory distress syndrome hospitals had lower annual acute respiratory distress syndrome case fatality (rate ratio, 0.75; 99% CI, 0.71-0.79 and rate ratio, 0.86; 99% CI, 0.82 0.90, respectively; p <= 0.001 for both). In an individual-level, multivariable model adjusting for hospital and individual characteristics, high and medium acute respiratory distress syndrome volume hospitals were associated with lower odds of acute respiratory distress syndrome mortality compared with low-volume hospitals (odds ratio, 0.85 [99% CI, 0.74-0.99]; p = 0.006 and odds ratio, 0.89 [99% CI 0.79-1.00]; p = 0.01, respectively). CONCLUSIONS: In this cohort, at both an individual- and hospital-level, higher acute respiratory distress syndrome hospital case volume is associated with lower acute respiratory distress syndrome hospital mortality. PMID- 29394183 TI - Outcomes of Ethics Consultations in Adult ICUs: A Systematic Review and Meta Analysis. AB - OBJECTIVES: Clinical ethics consultation as a mechanism for supporting patients, family, and staff during ethically challenging situations has become standard of care. Despite this, there is a lack of consensus about the effectiveness of clinical ethics consultation consultation in the ICU. We performed a systematic review of outcomes associated with clinical ethics consultation within adult ICUs. DATA SOURCES: We searched MEDLINE, PubMed, Cochrane CENTRAL, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature from 1984 to May 2017. STUDY SELECTION: Two reviewers independently screened articles, assessed eligibility, extracted data, and assessed risk of bias using the Cochrane Collaboration Risk of Bias tool and the Newcastle-Ottawa Scale. Pooled estimates of effect were calculated where possible. We screened 3,970 abstracts and reviewed 325 full-text articles of which 16 met all eligibility criteria. DATA EXTRACTION: We examined changes in processes and outcomes as a result of clinical ethics consultation in the ICU. Categories of outcomes included user perception, clinical decision, or conflict resolution and resource utilization. DATA SYNTHESIS: The use of clinical ethics consultation in the ICU was associated with positive user experience (383/435 found clinical ethics consultation helpful), although stress and disagreement with clinical ethics consultation recommendations was greater in a subset (113/431 surrogates and providers). Consensus for a clinical decision was more frequently achieved with clinical ethics consultation (odds ratio, 4.09; 95% CI, 1.01-16.55; p = 0.05). Clinical ethics consultation was associated with lower resource utilization including significantly decreased ICU length of stay (mean difference, -4.65 d; 95% CI, 8.86 to -0.44; p = 0.03). CONCLUSIONS: Our review identified outcome-based assessment as the predominant measure used to report effectiveness of clinical ethics consultation consultations. In particular, clinical ethics consultation decreased ICU length of stay and increased family and healthcare provider satisfaction. However, using outcome measures as the primary endpoint may not reflect the original intent of the clinical ethics consultation service. Based on our review, we propose a list of process measures that may better capture the key domains of a quality clinical ethics consultation. PMID- 29394184 TI - Cerebral Autoregulation in the Prediction of Delayed Cerebral Ischemia and Clinical Outcome in Poor-Grade Aneurysmal Subarachnoid Hemorrhage Patients. AB - OBJECTIVES: Pressure reactivity index and oxygen reactivity index are used to assess cerebral autoregulation after acute brain injury. The value of autoregulation indices in the prediction of delayed cerebral ischemia and outcome in patients with subarachnoid hemorrhage is still inconclusive. In this study, we aimed to focus on the predictive value of the first 72 hours commonly referred to as "early brain injury" in comparison to the overall monitoring period. DESIGN: Retrospective observational cohort study. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Forty-three consecutive poor-grade patients with nontraumatic subarachnoid hemorrhage admitted between 2012 and 2016 undergoing continuous high-frequency monitoring. INTERVENTIONS: High-frequency monitoring includes arterial blood pressure, intracranial pressure, and brain tissue oxygen tension. Pressure reactivity index and oxygen reactivity index were evaluated as moving correlation coefficient between mean arterial pressure/intracranial pressure and cerebral perfusion pressure/brain tissue oxygen tension, respectively. MEASUREMENTS AND MAIN RESULTS: Median autoregulation monitoring time was 188 +/- 91 hours per patient. Initial pressure reactivity index was 0.31 +/- 0.02 and decreased significantly to 0.01 +/- 0.01 (p < 0.001) 3 days after admission with a second peak 10 days after admission (0.18 +/- 0.14; p = 0.001). Admission oxygen reactivity index was high, 0.25 +/- 0.03, and decreased to a minimum of 0.11 +/- 0.02 eight days after admission (p = 0.008). Patients with delayed cerebral ischemia had significantly higher overall mean pressure reactivity index values (p < 0.04), which were more pronounced during the first 72 hours, reflecting early brain injury (p < 0.02). High pressure reactivity index during the first 72 hours was associated with poor functional outcome (p < 0.001). No association between oxygen reactivity index and delayed cerebral ischemia or clinical outcome was observed (p = 0.8/0.78). CONCLUSIONS: High initial pressure reactivity index, presumably reflecting early brain injury, but not oxygen reactivity index, was associated with delayed cerebral ischemia and worse clinical outcome in poor-grade subarachnoid hemorrhage patients. Our data indicate that autoregulation indices should be interpreted cautiously when used in these patients and that timing is crucial when autoregulation indices are evaluated as predictor for delayed cerebral ischemia and outcome. PMID- 29394185 TI - Recognizing excellence in coronary artery disease: the Sobel Distinguished Scholarship Award. PMID- 29394186 TI - Cardiac rupture during acute myocardial infarction diagnosed clinically. PMID- 29394187 TI - Functional Stroke Mimics: Incidence and Characteristics at a Primary Stroke Center in the Middle East. AB - OBJECTIVE: Approximately 30% of individuals who initially present with stroke are found to be stroke mimics (SM), with functional/psychological SM (FSM) accounting for up to 6.4% of all stroke presentations. Middle Eastern countries may have higher rates of somatization of emotional distress. The aim of this study was to evaluate the incidence and characteristics of FSM at a large general hospital in the Middle East. METHODS: All patients presenting with an initial diagnosis of stroke from June 2015 to September 2016 were eligible for this study. Clinical and sociodemographic data were obtained from the hospital's stroke database. All SM and strokes were diagnosed by Joint Commission International-certified stroke program neurologists. SM was defined as any discharge diagnosis (other than acute stroke) for symptoms that prompted initial admission for suspected stroke. FSM were compared with medical stroke mimics (MSM) and strokes (ischemic, hemorrhagic, and transient ischemic attacks). RESULTS: A total of 1961 patients were identified; 161 FSM (8.2%), 390 MSM (19.9%), and 1410 strokes (71.9%) (985 ischemic strokes, 196 transient ischemic attacks, 229 intracerebral hemorrhages). Admission with FSM was related to patients' nationality, with the highest frequency in Arabic (15.6%) and African (16.8%) patients. FSM patients were younger, more often female, and had fewer cardiovascular risk factors except for smoking compared with the strokes. FSM patients presented with more left-sided weakness and had more magnetic resonance imagings than the stroke and MSM groups. A total of 9.9% of FSM patients received thrombolysis versus only 0.5% of the MSM and 16.4% of ischemic strokes. CONCLUSIONS: FSM frequencies varied by nationality, with Arab and African nationals being twice as prevalent. Stress, vulnerable status as expats, sociopolitical instability, and exposure to trauma are proposed as potential factors contributing to FSM. PMID- 29394188 TI - Effects of Resistance Training on Fatigue-Related Domains of Quality of Life and Mood During Pregnancy: A Randomized Trial in Pregnant Women With Increased Risk of Back Pain. AB - OBJECTIVE: The aim of the study was to test whether the adoption of twice weekly, low-to-moderate intensity resistance training during weeks 22 to 34 of pregnancy can improve quality of life and mood. METHODS: A parallel-group trial was conducted. Women in their second trimester (N = 134) were randomly assigned to 12 weeks of wait list, bimonthly pregnancy education classes, or twice weekly low-to moderate intensity resistance training. Resistance training involved one abdominal exercise with no external load and five exercises (leg extension, leg press, arm lat pull, leg curl, and lumbar extension) with an external load that gradually progressed, and the total active exercise time during each exercise session was approximately 17 minutes. Quality of life and mood were measured before and after the interventions using the 36-item Short Form Health Survey and Profile of Mood States. Intent-to-treat mixed-model analyses of variance (3 groups by 2 times, pre- and postintervention) tested the hypothesis that outcomes would worsen for the controls and not change or improve for the resistance training group. RESULTS: The group by time interaction (F(2,131) = 3.144, eta = .046, p = .046) for 36-item Short Form Health Survey vitality and subsequent simple main effects showed that scores were unchanged across time after resistance training (-1.8 (14.8)) but significantly decreased for the education ( 6.44 (12.69), t = 3.408, df = 44, p = .001) and wait list (-9.11 (14.78), t = 4.135, df = 44, p < .001) groups, whereas posttest vitality scores for the pregnancy group (45.9 (16.9)) were significantly higher than the wait list (40.1 (16.3), t = 1.989, df = 87, p = .05) but not the education group (42.1 (15.4), p = .27). Profile of mood states fatigue scores showed a similar pattern. CONCLUSIONS: Adverse changes in symptoms of energy and fatigue during pregnancy are attenuated by adopting low-to-moderate intensity resistance training. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT02557893. PMID- 29394189 TI - Incidence and Risk Factors for Prediabetes and Diabetes Mellitus Among HIV infected Adults on Antiretroviral Therapy: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To summarize evidence on the rates and drivers of progression from normoglycemia to prediabetes and/or diabetes mellitus (hereafter "diabetes") in antiretroviral treatment (ART)-exposed HIV-infected people. METHODS: We searched EMBASE, PubMed, Web of Science, and Global Index Medicus to identify articles published from 1 January 2000 to 30 April 2017. A random-effects model produced a summary estimate of the incidence across studies and heterogeneity was assessed using Cochrane's Q statistic. RESULTS: We included 44 studies, whose methodologic quality was high with only 10 (30%) medium-quality studies and none of low quality. There was substantial heterogeneity between studies in estimates of the incidence of diabetes and prediabetes. The pooled incidence rate of overt diabetes and prediabetes were 13.7 per 1,000 person-years of follow-up (95% CI = 13, 20; I = 98.1%) among 396,496 person-years and 125 per 1,000 person-years (95% CI = 0, 123; I = 99.4) among 1,532 person-years, respectively. The major risk factors for diabetes and prediabetes were aging, family history of diabetes, Black or Hispanic origin, overweight/obesity, central obesity, lipodystrophy/lipoatrophy, dyslipidemia, metabolic syndrome, increased baseline fasting glycemia, and certain ART regimens. CONCLUSIONS: These data highlight the important and fast-increasing burden of diabetes and prediabetes among the ART exposed HIV-infected population. More research is needed to better capture the interplay between prediabetes/diabetes and ART in HIV-infected patients, considering the increasing number of ART-exposed patients subsequent to the World Health Organization's recommendation of initiating ART at HIV infection diagnosis regardless of CD4 count and age. PMID- 29394190 TI - Post-diagnostic calcium channel blocker use and breast cancer mortality: a population-based cohort study. AB - BACKGROUND: There have long been concerns that calcium channel blockers (CCBs), widely used to treat hypertension, may contribute to malignant growth through the evasion of apoptosis and proliferation of cancer cells. Worryingly, a recent cohort study found breast cancer patients who used CCBs had higher death rates, but interpreting these results was difficult as they were based on all-cause mortality and medication use before cancer diagnosis. We used UK population-based data to more robustly investigate the association between CCB use and cancer specific mortality. PATIENTS AND METHODS: We selected a cohort of patients with breast cancer newly diagnosed between 1998 and 2012 from English cancer registries. We linked to prescription and clinical records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used adjusted, time-dependent Cox-regression models to calculate hazard ratios (HRs) comparing breast cancer-specific and all-cause mortality between post-diagnostic CCB users and non-users. RESULTS: Our cohort included 23,669 breast cancer patients, of whom 5,141 used CCBs and 3,053 died due to their breast cancer during follow-up. After adjustment, CCB users had similar breast cancer-specific mortality to non-users (HR=0.98, 95% CI: 0.88, 1.08). There was no evidence of a dose-response relationship. We found similar associations for specific CCBs, and for all-cause mortality. CONCLUSIONS: In this large population-based breast cancer cohort, we did not find any evidence that CCB use is associated with increased mortality. PMID- 29394191 TI - Implementation of Instrumental Variable Bounds for Data Missing Not at Random. AB - Instrumental variables are routinely used to recover a consistent estimator of an exposure causal effect in the presence of unmeasured confounding. Instrumental variable approaches to account for nonignorable missing data also exist but are less familiar to epidemiologists. Like instrumental variables for exposure causal effects, instrumental variables for missing data rely on exclusion restriction and instrumental variable relevance assumptions. Yet these two conditions alone are insufficient for point identification. For estimation, researchers have invoked a third assumption, typically involving fairly restrictive parametric constraints. Inferences can be sensitive to these parametric assumptions, which are typically not empirically testable. The purpose of our article is to discuss another approach for leveraging a valid instrumental variable. Although the approach is insufficient for nonparametric identification, it can nonetheless provide informative inferences about the presence, direction, and magnitude of selection bias, without invoking a third untestable parametric assumption. An important contribution of this article is an Excel spreadsheet tool that can be used to obtain empirical evidence of selection bias and calculate bounds and corresponding Bayesian 95% credible intervals for a nonidentifiable population proportion. For illustrative purposes, we used the spreadsheet tool to analyze HIV prevalence data collected by the 2007 Zambia Demographic and Health Survey (DHS). PMID- 29394192 TI - The Relationship Between Difficulties in Daily Living and Suicidal Ideation Among Older Adults: Results From a Population-Based Survey in Shandong. AB - To date, few studies have examined the association between difficulties in activities of daily living (ADL) and suicidal ideation (SI) among the seniors in China. This study aims to explore this association among older adults in China. A total of 3313 older people (60+) were included in this study, and questionnaires were administered by face-to-face interview. In total, 4.2% of the participants reported SI. The mean score of ADL among older adults with SI (21.06 +/- 10.92) was much higher than that in those without SI (16.13 +/- 5.60). Multivariate analyses showed that some specific domains of ADL including using transport, medical care, and household activities were associated with SI even after we controlled the psychological conditions. An association was observed between difficulties in daily living and SI among older adults in China. Psychological interventions should be taken to prevent potential risk of suicide targeting the seniors with certain disabilities. PMID- 29394193 TI - Suicide Behavior and Chronic Pain: An Exploration of Pain-Related Catastrophic Thinking, Disability, and Descriptions of the Pain Experience. AB - This study examined differences in suicidal ideation (SI) and suicide attempts (SAs) among veterans with chronic pain. Pain-specific variables, including catastrophic thinking, disability, and sensory, affective, and evaluative pain descriptors, were a focus. Structured diagnostic and clinical interviews were conducted to examine SI/SA and mental health. Veterans completed the Structured Clinical Interview for DSM-IV and the Columbia-Suicide Severity Rating Scale to assess Axis I symptoms and suicidal behavior(s). Self-report questionnaires were used to evaluate the participants' subjective experience of chronic pain, which included the McGill Pain Questionnaire, Pain Catastrophizing Scale, and Pain Disability Index. The findings add to previous literature by suggesting pain related catastrophic thinking specifically is related to elevated risk for SA, whereas affective and sensory pain are associated with SI. The study results support the need to assess pain from a multifaceted perspective and to examine the different experiences of pain, such as sensory and affective constructs, when discussing suicide risk in veterans. PMID- 29394194 TI - The Longitudinal Effect of Vertigo and Dizziness Symptoms on Psychological Distress: Symptom-Related Fears and Beliefs as Mediators. AB - Despite the frequent observation that vertigo and dizziness (VD) disorders may trigger or exacerbate secondary psychiatric comorbidities, there is limited understanding of the mechanisms underlying this development. To address this gap, we investigated whether symptom-related fears and cognitions as indicated by questionnaire-based measures are mediators of the longitudinal effect of VD symptoms on anxiety and depression after 1 year. We analyzed data from a large study with patients of a treatment center specialized in vertigo (N = 210). Simple and multiple parallel mediation models strengthened our hypothesis that fear of bodily sensations and cognitions about these symptoms play a mediating role in the relationship between VD symptoms and psychopathology at follow-up after baseline scores of the outcome were controlled for. Results are discussed within a cognitive theory framework and point to the potential benefits of interventions that modify symptom-related beliefs and fears via cognitive psychotherapy in this therapeutically underserved population. PMID- 29394195 TI - Exploring and Evaluating Patient Safety Culture in a Community-Based Primary Care Setting. AB - OBJECTIVES: The primary aim was to measure patient safety culture in two home care services in Belgium (Flanders). In addition, variability based on respondents' profession was examined. METHODS: A cross-sectional study was conducted by administering the SCOPE-Primary Care questionnaire in two home care service organizations. RESULTS: In total, 1875 valid questionnaires were returned from 2930 employees, representing a response rate of 64%. The highest mean patient safety culture score was found for "organizational learning" (mean [SD] = 3.81 [0.53]), followed by "support and fellowship" (mean [SD] = 3.76 [0.61]), "open communication and learning from error" (mean [SD] = 3.73 [0.64]), and "patient safety management" (mean [SD] = 3.71 [0.60]). The lowest mean scores were found for "handover and teamwork" (mean [SD] = 3.28 [0.58]) and "adequate procedures and working conditions" (mean [SD] = 3.30 [0.56]). Moreover, managers/supervisors scored significantly higher on the dimensions "open communication and learning from error," "adequate procedures and working conditions," "patient safety management," "support and fellowship," and "organizational learning" than clinical and nonclinical staff. CONCLUSIONS: In conclusion, organizational learning is perceived as most positive. However, large gaps remain in the continuity of care as "handover and teamwork" is perceived as the most negative safety culture dimension. With knowledge of the current patient safety culture, organizations can redesign processes or implement improvement strategies to avoid patient safety incidents and patient harm in the future. PMID- 29394196 TI - Total Health-Related Costs Due to Absenteeism, Presenteeism, and Medical and Pharmaceutical Expenses in Japanese Employers. AB - OBJECTIVE: This study aimed to examine a detailed breakdown of costs (absenteeism, presenteeism, and medical/pharmaceutical expenses), of the employees in four pharmaceutical companies in Japan. METHODS: This is a cross sectional study. Absenteeism and presenteeism were measured by a self administered questionnaire for workers, and their costs were estimated using the human capital approach. Presenteeism was evaluated by the degree affected quality and quantity of work. Medical and pharmaceutical expenses were obtained by insurance claims. RESULTS: The monetary value due to absenteeism was $520 per person per year (11%), that of presenteeism was $3055 (64%), and medical/pharmaceutical expenses were $1165 (25%). Two of the highest total cost burdens from chronic illness were related to mental (behavioral) health conditions and musculoskeletal disorders. CONCLUSION: A total cost approach can help employers set priorities for occupational health, safety, and population health management initiatives. PMID- 29394197 TI - Microcatheter-assisted Trabeculotomy Versus 2-site Trabeculotomy With the Rigid Probe Trabeculotome in Primary Congenital Glaucoma. AB - PURPOSE: The purpose of this study was to compare the outcomes of microcatheter assisted trabeculotomy to circumferential trabeculotomy using the rigid probe trabeculotome in primary congenital glaucoma. METHODS: This retrospective study was performed in an institutional setting. The medical records of primary congenital glaucoma patients who underwent circumferential trabeculotomy (>=270 degrees incised) using Glaucolight-illuminated microcatheter or a rigid probe trabeculotome were reviewed. The primary outcomes were the percent reduction of intraocular pressure (IOP) and success rates. Complete success was defined as achieving an IOP<18 mm Hg without medications. Secondary outcomes were the postoperative IOP and glaucoma medications. RESULTS: The study included 92 eyes of 92 patients. Of these, 33 eyes of 33 patients aged 6.4+/-8.7 months underwent microcatheter-assisted trabeculotomy creating a 336+/-34-degree incision, with 19 eyes (58%) having a complete 360-degree incision. The other 59 eyes of 59 patients aged 8.2+/-13.1 months underwent 2-site trabeculotomy, using a rigid probe trabeculotome through a combined superonasal and inferotemporal approach, creating a 338+/-29-degree incision, with 33 eyes (56%) having a complete incision. After a follow-up of 21.2+/-8.9 months, there was a 42%+/-25% IOP reduction and a 73% rate of complete success in the microcatheter group, compared with 40%+/-22% IOP reduction and an 80% success rate in the rigid probe group (P=0.7 and 0.3, respectively). There was no significant difference in survival time in both groups (P=0.6). CONCLUSION: Circumferential trabeculotomy using either the illuminated microcatheter or rigid probe trabeculotome yielded comparable results; however, the added cost of the microcatheter should be considered. PMID- 29394198 TI - Distribution of Anterior Chamber Parameters in Normal Chinese Children and the Associated Factors. AB - PURPOSE: To describe the distribution of anterior chamber depth (ACD), anterior chamber volume (ACV), and anterior chamber angle (ACA) and establish the associated factors in the pediatric population in Shanghai, China. MATERIALS AND METHODS: In this cross-sectional study, children aged 6 to 18 years from 9 primary and middle schools in Shanghai were enrolled. The Pentacam Scheimpflug camera was used to measure anterior eye chamber parameters. The distribution of ACD, ACV, ACA, and their associations with age, sex, body mass index, cycloplegic refractive error, axial length, intraocular pressure, and other parameters were analyzed. RESULTS: A total of 1321 children were included, with a mean age of 9.65+/-2.95 years. The mean ACA, ACD, and ACV values were 37.95+/-7.96 degrees, 3.22+/-0.23 mm and 194.89+/-28.95 mm, respectively, and were higher in boys than in girls. ACV and ACD had similar growth trend curves with age, whereas ACA was stable. Overall, 5% of the tested children had ACA values <=24.91 degrees. Greater ACV, deeper ACD, shorter pupil diameter, shorter axial length, and thinner apex corneal thickness were the independent factors associated with wider ACA (R=13.0%, P<0.001). CONCLUSIONS: As one of diagnostic indicators of angle closure, ACA was stable with age. The results of this study should improve the current understanding of the distribution of anterior chamber parameters and the main factors affecting their variation. PMID- 29394199 TI - Baerveldt Attached to XEN: A New Technique to Manage Failed XEN Glaucoma Surgery. AB - PURPOSE: To describe a new surgical technique for refractory glaucoma with failed XEN gel stent surgery with insertion of the Baerveldt implant. SURGICAL TECHNIQUE: In a patient with a failed XEN gel stent, a gentle conjunctival dissection was performed to expose the XEN and remove subconjunctival obstruction thus restoring patency and flow. A Baerveldt 250 implant was inserted in the superonasal quadrant above the extraocular muscles and sutured to the sclera. The Baerveldt tube was correctly positioned to accept insertion of the present XEN gel stent. The double lumen was sutured to secure the position. Two corneal patches were sutured over the tube to prevent exposure. The usual conjunctival suturing closure was performed. CONCLUSION: This technique is simple and restores lowering of intraocular pressure in patient with failed XEN and potentially increases the safety of refractory glaucoma surgeries in these patients. PMID- 29394200 TI - Effect of a Short-term Cycle Ergometer Sprint Training Against Heavy and Light Resistances on Intraocular Pressure Responses. AB - PURPOSE: The purpose of this study is to determinate the long-term effect of a cycle ergometer sprint training program against heavy and light resistances on baseline intraocular pressure (IOP), and on the acute IOP response to cycling sprints. METHODS: A total 27 physically active males were randomly assigned to a heavy loads group (HLG, n=9), low loads group (LLG, n=9), and control group (CG, n=9). Participants performed 12 training sessions during 6 weeks (2 sessions per week), and each training session consisted in performing 8 cycling sprints against either heavy (HLG) or light (LLG) resistances. Before and after intervention, they performed an identical protocol, which consisted in performing maximal cycling sprints against 5 different resistances in random order. In these protocols, IOP was measured before and after each sprint by rebound tonometry. RESULTS: A Bayesian analysis revealed that baseline IOP was reduced in the LLG after the intervention [Bayes factor (BF01)=0.043 and effect size (ES)=1.255; pretest=15.22+/-0.94 mm Hg and posttest=15.39+/-1.02 mm Hg], whereas the HLG did not manifest any baseline IOP change (BF01=2.363 and ES=-0.205; pretest=15.28+/ 1.44 mm Hg and posttest=14.17+/-1.77 mm Hg). The acute IOP response to maximal sprints was modified for the HLG, showing a more stable IOP response with heavier loads (resistance, 4 and 5) after the intervention (BF01<0.01 in both cases, and ESs=1.847 and 1.920, respectively). CONCLUSIONS: A short-term cycle ergometer sprint training impacts long-term IOP depending on the level of resistance imposed, showing that training with low loads permits to reduce baseline IOP, whereas training with heavy loads attenuates the acute IOP changes after sprinting against heavy loads. PMID- 29394202 TI - Urrets-Zavalia Syndrome After Combined Trabeculotomy-Trabeculectomy Surgery. AB - We report a case of a rare complication after trabeculotomy combined with a small trabeculectomy with mitomycin C in a young patient with juvenile glaucoma. The patient underwent uneventful surgery. However, postoperatively, he experienced a long-lasting hypotony with the need of 2 revision surgeries and 2 short episodes of high-intraocular pressure. He developed a fixed dilated pupil over time. PMID- 29394201 TI - Structural and Functional Associations of Macular Microcirculation in the Ganglion Cell-Inner Plexiform Layer in Glaucoma Using Optical Coherence Tomography Angiography. AB - PURPOSE: To quantify retinal microvasculature within the macular ganglion cell inner plexiform layer (GCIPL) in primary open-angle glaucoma (POAG) and normal eyes, determine association of vessel parameters with structural and functional measures, and report diagnostic accuracy of vessel parameters. METHODS: POAG and normal patients underwent 6*6 mm macula scans [Angioplex optical coherence tomography angiography (OCTA); Cirrus HD-OCT 5000]; and Humphrey Field Analyzer II-i 24-2 visual field (VF). Prototype software performed semiautomatic segmentation to create GCIPL en face images, and quantified vessel area density (VAD), vessel skeleton density (VSD), and vessel complexity index (VCI) for the macula (globally, hemifields, and 6 focal sectors). Linear regression assessed association of OCTA parameters with VF mean deviation (MD) and GCIPL thickness globally and focally. RESULTS: A total of 34 POAG and 21 normal eyes were studied. VAD, VSD, and VCI were reduced in POAG versus normal (0.463 vs. 0.486, P=0.00029; 0.230 vs. 0.219, P=0.0014; 1.15 vs. 1.09, P=0.0044, respectively), with a trend of worsening with increased POAG severity. Reduced global VF MD was associated with reduced VAD and VCI, controlling for age and intereye correlation (P=0.0060, 0.0080; R=0.205, 0.211). Both superior and inferior hemifield MD were associated with corresponding VAD, VSD, and VCI (all P<0.007; R ranged from 0.12 to 0.29). Global GCIPL thickness was not associated with global OCTA parameters, and only inferior sector GCIPL thickness was associated with corresponding VAD, VSD, and VCI (P<0.05; R ranged from 0.15 to 0.16). Area under curves for VAD, VSD, and VCI were fair to good (0.83, 0.79, 0.82; respectively; P<0.0001). CONCLUSIONS: Glaucomatous eyes had reduced GCIPL microcirculation. OCTA parameters had stronger associations with functional rather than structural measures of glaucoma. This observation deserves further study. PMID- 29394203 TI - Results of an Adaptive Surgical Approach for Managing Late Onset Hypotony After Trabeculectomy With Mitomycin C. AB - OBJECTIVES: The objective of this study is to investigate the results of an adaptive approach of bleb revision surgery for late onset hypotony after trabeculectomy with mitomycin C because of bleb leakage and/or scleral melting. METHODS: A total of 29 eyes of 27 patients, aged 63.8+/-11.7 years with hypotony maculopathy [intraocular pressure (IOP), <=6 mm Hg] because of late onset bleb leakage and/or scleral melting after trabeculectomy with mitomycin C in which minimally invasive transconjunctival suturing of the scleral flap was impossible were enrolled in this retrospective interventional case series. External bleb leakage was seen in 16 eyes, 11 eyes suffered from scleral melting. Because of the intraoperative findings regarding appearance of conjunctiva and sclera 4 different surgical approaches were used: (1) bleb excision (in case of external leakage) and conjunctival reapproximation, (2) bleb excision and free conjunctival autografting, (3) human donor scleral patch grafting (in case of scleral flap defect) with conjunctiva reapproximation and (4) combined conjunctival and scleral patch grafting. Outcome measures were IOP and visual acuity (VA) development over time. Data analysis comparing changes in the parameters (IOP and VA) before and after bleb revision surgery was carried out using the paired t test. RESULTS: Changes in IOP and VA were analyzed over 9.3+/ 8.3 months (range, 1.1 to 36.5 mo). IOP increased from 4.0+/-1.8 mm Hg, (P<0.001) before revision surgery to 13.1+/-4.1 mm Hg at 3 months after revision and 12.6+/ 3.8 mm Hg at last follow-up visit, showing no significant difference in IOP between 3 months post revision and at the last documented patients' follow-up visit (P=0.28). The VA before revision surgery (0.42+/-0.28 logMAR) significantly increased (P=0.05) 3 months after revision (0.32+/-0.23 logMAR) and remained stable (P=0.65) until the last follow-up visit (9.3+/-8.3 mo; range, 1.1 to 36.5) (0.35+/-0.32 logMAR). CONCLUSIONS: In patients with hypotony an adaptive approach of bleb management shows good results both in terms of IOP control and improvement in VA. PMID- 29394204 TI - Visual Disability Among Juvenile Open-angle Glaucoma Patients. AB - AIM: Juvenile onset primary open-angle glaucoma (JOAG) unlike adult onset primary open-angle glaucoma presents with high intraocular pressure and diffuse visual field loss, which if left untreated leads to severe visual disability. The study aimed to evaluate the extent of visual disability among JOAG patients presenting to a tertiary eye care facility. METHODS: Visual acuity and perimetry records of unrelated JOAG patients presenting to our Glaucoma facility were analyzed. Low vision and blindness was categorized by the WHO criteria and percentage impairment was calculated as per the guidelines provided by the American Medical Association (AMA). RESULTS: Fifty-two (15%) of the 348 JOAG patients were bilaterally blind at presentation and 32 (9%) had low vision according to WHO criteria. Ninety JOAG patients (26%) had a visual impairment of 75% or more. CONCLUSIONS: Visual disability at presentation among JOAG patients is high. This entails a huge economic burden, given their young age and associated social responsibilities. PMID- 29394205 TI - Differences in Optic Nerve Head, Retinal Nerve Fiber Layer, and Ganglion Cell Complex Parameters Between Caucasian and Chinese Subjects. AB - PURPOSE: To compare optic nerve head, peripapillary retinal nerve fiber layer (pRNFL), and ganglion cell complex (GCC) parameters between Caucasian and ethnic Chinese. MATERIALS AND METHODS: Normal subjects above 40 years old and self identified as being Caucasian and Chinese were recruited. They were evaluated with spectral-domain optical coherence tomography (RTVue-100). Parameters related to the optic nerve head, pRNFL, and GCC analysis protocols were acquired. Multivariable linear regression was performed adjusting for potential confounders. RESULTS: Data from 116 Caucasian and 130 Chinese subjects were available for analysis. Mean age of all participants was 66.72 (SD 10.82) years. There were statistically significant differences for disc area (DA), area cup-to disc, vertical cup-to-disc, and cup volume (P=0.02, 0.004, 0.02, and 0.03, respectively), greater in Chinese. After adjusting for age, sex, axial length (AL), intraocular pressure (IOP), DA, and GCC thickness, Chinese subjects had significantly greater thickness in all pRNFL parameters (mean differences ranged between 4.29 and 9.93 MUm; all P<0.001) except the nasal quadrant. GCC outcomes were also adjusted for DA and pRNFL; Caucasians had significantly higher average GCC and inferior GCC (mean difference 2.97 and 3.45 MUm, respectively; P<0.01), whereas the Chinese group had significantly higher ganglion cell global loss volume (mean difference 2.47 %, P<0.001). CONCLUSIONS: This study suggests there is significantly greater pRNFL thickness in Chinese, which were independent of age, AL, IOP, and DA, and possibly greater GCC in Caucasians after adjustment for age, AL, IOP, DA, and pRNFL thickness. PMID- 29394206 TI - Secondary Glaucoma due to Iridescent Crystalline Particles Masquerading as Refractory Hypertensive Uveitis in an Eye With Irradiated Iris Melanoma. AB - PURPOSE: We report a previously unrecognized mechanism of secondary glaucoma due to iridescent crystalline particles released from an irradiated iris melanoma. It masqueraded as refractory hypertensive uveitis following uncomplicated phacoemulsification. MATERIALS AND METHODS: A 58-year-old gentleman had an iris melanoma that underwent successful regression following irradiation with proton beam radiotherapy. Three years later an uncomplicated phacoemulsification with intraocular lens implant was performed and subsequently the patient presented with apparently "refractory hypertensive uveitis." Closer examination identified unique iridescent crystalline particles originating from a disintegrating tumor and dispersing within the anterior chamber and drainage angle. The patient developed a unilateral secondary open-angle glaucoma attributable to these particles. Ultrasound biomicroscopy of the anterior segment confirmed absence of tumor recurrence or intrascleral spread and systemic investigations ruled out distant metastases. RESULTS: The intraocular pressure was refractory to maximal medical treatment, but was eventually controlled with trans-scleral diode laser cyclo-photocoagulation. CONCLUSIONS: This is the first report of a secondary glaucoma attributable to trabecular blockage with iridescent crystalline particulate material released from a disintegrating, previously irradiated, iris melanoma. Proton beam radiotherapy and possibly phacoemulsification may have played a role in triggering the release of these previously undescribed particles from the atrophied tumor surface. This unique mechanism of secondary glaucoma needs to be kept in mind in such rare cases. Trans-scleral cyclodiode laser may be used as a good initial option in such cases to minimize potential risk of tumor seeding with incisional glaucoma surgery. PMID- 29394207 TI - Systemic effects of epidural steroid injections for spinal stenosis. AB - This analysis of the lumbar epidural steroid injections for spinal stenosis multicenter randomized controlled trial data identifies the degree of and risk factors for cortisol suppression after epidural steroid injections in older adults with spinal stenosis. Four hundred patients aged 50 years and older with back or leg pain and central lumbar spinal stenosis completed baseline demographic and psychosocial measures. Morning serum cortisol levels were measured at baseline and 3 weeks after initial injection. Patients were randomized to receive epidural injections of either local anesthetic with corticosteroid (n = 200) or local anesthetic only (n = 200). The specific corticosteroid was chosen at the treating physician's discretion (methylprednisolone, betamethasone, triamcinolone, or dexamethasone). Thirty-two patients (20.3%) treated with corticosteroid experienced cortisol reduction at 3 weeks of >50% compared with 10 patients (6.7%) treated with lidocaine only (adjusted treatment effect = 3.5, 95% confidence interval: 1.6-7.9, P = 0.002). The effect on 3-week cortisol changes did not differ by demographic or patient level characteristics. Those treated with methylprednisolone or triamcinolone had an average 3-week cortisol reduction of 41.0% (P = 0.005) and 41.6% (P < 0.001) from baseline, respectively, whereas patients treated with betamethasone or dexamethasone were not significantly different than comparable patients in the lidocaine arm. The higher rates of cortisol suppression at 3 weeks in those receiving epidural corticosteroid injections, particularly with longer-acting insoluble corticosteroid formulations, are consistent with sustained systemic absorption of corticosteroid. PMID- 29394208 TI - Caring Interactions in Secondary Prevention Programs: A Qualitative Inquiry of Individuals With Parkinson's Disease. AB - BACKGROUND AND PURPOSE: With Parkinson's disease (PD) prevalence rates steadily increasing and long-term adherence to regular physical activity and exercise often difficult to achieve, it is imperative to investigate factors promoting adherence to secondary prevention programs (SPP) that help limit the progression of motor and nonmotor signs and symptoms of the disease. Caring interactions between patients and their rehabilitation team may be particularly germane to individuals with PD, given the physical and psychosocial issues that often accompany this disease (eg, loss of physical function, depression, apathy, and cognitive impairments). Considering this reasoning, the purpose of the present study was twofold: (1) to gain a better understanding of the nature of caring in an SPP setting from a patient perspective and (2) to discover what implications, if any, caring has on relevant patient-centered behaviors such as effort and adherence to SPPs. METHOD: Ten individuals with PD were recruited. In-depth, qualitative interviews were performed using a semistructured interview guide. Inductive content analysis was used to identify themes representing participants' experiences of caring in the SPP setting. RESULTS AND DISCUSSION: Six themes emerged from the data analysis. The first 4 themes described how rehabilitation providers fostered caring in the SPP setting: showing interest, creating a supportive atmosphere, benevolence, and paying attention. Participants described instances when rehabilitation providers (physical therapy assistants, physical therapy students, and exercise specialists) showed interest by asking personal questions and remembering personal information. A supportive environment was facilitated by making participants feel supported, welcomed, and valued. Benevolence was apparent when rehabilitation providers demonstrated kindness and approached their work as "more than just a job." Finally, the importance of feeling that rehabilitation providers "paid attention" to patients by giving them undivided consideration and by aiding with exercises was emphasized. This latter finding is akin to Nodding's concept of "engrossment," a key component of caring, which may be an important issue in the face of increasing use of technological devices (eg, laptop computers and i-pads) that may unintentionally direct rehabilitation providers' attention away from their patients. The final 2 themes rehabilitation attendance and rehabilitation effort-pertaining to aim 2 of the study, are novel in underscoring the importance of caring with respect to patient behaviors. CONCLUSIONS: Several practical implications can be gleaned from the current study including (but not limited to) remembering personal information about the patient, providing patients with undivided attention, providing support for patients, and making patients feel welcome. These findings underscore the importance of addressing affective skills in training future rehabilitation practitioners. Findings also reveal salient implications associated with caring, namely enhanced rehabilitation attendance and effort. Finally, results highlight the need to examine the generalizability of caring elements identified in the current study and to quantitatively assess caring antecedents and outcomes in SPP settings. PMID- 29394209 TI - Dynamic Handgrip Strength Endurance: A Reliable Measurement in Older Women. AB - BACKGROUND AND PURPOSE: Dynamic handgrip strength endurance is essential for daily activities that require repetitive gripping movements for a sustained period. At this time, there is no information about the reliability of measurement of dynamic handgrip strength endurance in older individuals. Thus, the purpose of this study was to investigate the test-retest reliability of dynamic handgrip strength endurance in older women. METHODS: A cross-sectional study was performed. Thirty older women aged 70.5 (3.6) years performed 2 assessment sessions (test and retest), separated by 3 days. During these sessions, the dynamic handgrip strength endurance was evaluated using a testing protocol consisted of 12 repeated maximal isometric contractions for 3 seconds, with a 5-second rest between contractions (repetitions). The maximal handgrip strength at each repetition (repeated maximal repetitions) was evaluated in both hands (preferred and nonpreferred hand) using an hydraulic dynamometer Jamar; while the percentage change (using the mean of the first and the last 3 repetitions as well as the mean of the first and the last 6 repetitions) and the fatigue index were calculated. RESULTS: The test-retest reliability for the assessment of repeated maximal repetitions (intraclass correlation coefficient [ICC] = 0.82-0.95, standard error of measurement [SEM] = 0.76-1.22 kg, SEM 95% confidence interval [CI] = 0.53-1.69 kg, SEM% = 3.6-8.6) and of percentage change (ICC = 0.81-0.87, SEM = 3.26%-4.40%, SEM 95% CI = 2.23-6.33%, SEM% = 3.4-4.7) was found to be high, whereas fatigue index exhibited lower reliability (ICC = 0.69 0.84, SEM% = 10.9-11.8). CONCLUSION: A dynamic protocol of 12 repeated maximal repetitions may be used for the evaluation of dynamic handgrip strength endurance, using the repeated maximal repetitions and the percentage change as the most reliable indicators for the determination of muscle endurance. The assessment, however, of fatigue index should be interpreted with more caution. PMID- 29394210 TI - Achievement of Therapeutic Vancomycin Exposure With Continuous Infusion in Critically Ill Children. AB - OBJECTIVE: Describe and assess a continuous infusion dosing scheme of vancomycin therapy in critically ill children. DESIGN: Retrospective single-center study, January to June 2015. SETTING: PICU located within a French tertiary academic pediatric hospital. PATIENTS: All children admitted in the PICU from January 2015 to June 2015, receiving continuous infusion of vancomycin therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and biological data, vancomycin dosing information, and plasma concentrations were recorded. Using a previously published population pharmacokinetics model, pharmacokinetic parameters were derived for each patient and vancomycin concentrations described after the loading dose. Areas under the curve were estimated for each patient, and an initial covariate-adjusted dose was calculated for every patient. A total of 87 vancomycin concentrations were analyzed from 28 patients between 1 month and 17 years old. The median (range) loading dose was 14.8 (12-16) mg/kg followed by a continuous infusion of vancomycin of 44 (35-61) mg/kg/d. On their first sample, 12 patients (43%) had a concentration between 15 and 30 mg/L. On day 1, the median (range) estimated area under the curve was 349 (201-1,001) mg/L * hr, and seven patients (25%) had an area under the curve greater than 400 mg/L * hr. Using the pharmacokinetics model, the median (range) calculated initial daily dose, taking into account age, bodyweight, and serum creatinine concentration, was 53 (36-69) mg/kg/d resulting in a simulated day 1 area under the curve of 409 (341-593) mg/L * h with a theoretical pharmacokinetic target attainment of 57%. CONCLUSIONS: The current continuous infusion of vancomycin dosing scheme used in our population was inappropriate and led to underexposure. Using pharmacokinetic approaches such as covariate-adjusted initial dosing and Bayesian estimation of exposure should prove useful for achieving the pharmacokinetic target. PMID- 29394212 TI - Survey on the Adherence to the 2009 NASPGHAN-ESPGHAN Gastroesophageal Reflux Guidelines by Brazilian Paediatricians. AB - OBJECTIVE: The aim of the study was to evaluate the management of gastroesophageal reflux in children among Brazilian pediatricians and adherence to the 2009 North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN), and European Society of Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Guideline in Brazil. METHODS: An observational cross sectional study was conducted, applying a standard questionnaire with 12 questions about gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD) management in infants, children, and adolescents to the pediatricians during the 37th Brazilian Pediatrics Congress in October, 2015. Adherence to the 2009 NASPGHAN-ESPGHAN Guideline was verified through analyses of interviewees' answers. Pediatricians' demographic and professional characteristics were screened. RESULTS: A total of 390 Brazilian pediatricians answered the questionnaire. None showed complete adherence to Guideline recommendations. GERD diagnosis by history alone was reported by 67%, irrespective of the child's age. The mean score for diagnostic adherence to the guidelines was 0.94 +/- 0.86 (range 0-4). Working in public health services (P = 0.026) was the only variable retained as a significant predictor of poor adherence for GER/GERD diagnosis after multivariate logistic regression analysis. No significant statistical differences were found between Brazilian regions on total score (P = 0.774). Proton pump inhibitors were prescribed by 28.4% of the pediatricians independent of child's age, and 59% use proton pump inhibitors to treat babies with unexplained crying and/or distressed behavior. CONCLUSIONS: 2009 NASPGHAN-ESPGHAN Guideline recommendations had poor adherence by Brazilian pediatricians. Studies evaluating the reasons for the poor adherence to NASPGHAN/ESPGHAN guidelines are urgently needed. PMID- 29394211 TI - Literature Review and Meta-Analysis of Transcutaneous Electrical Nerve Stimulation in Treating Chronic Back Pain. AB - BACKGROUND AND OBJECTIVES: This study is a meta-analysis of randomized controlled trials comparing the efficacy of transcutaneous electrical nerve stimulation (TENS) to a control and to other nerve stimulation therapies (NSTs) for the treatment of chronic back pain. METHODS: Citations were identified in MEDLINE, the Cochrane Library, Google Scholar, and ClinicalTrials.gov through June 2014 using the following keywords: nerve stimulation therapy, transcutaneous electrical nerve stimulation, back pain, chronic pain. Control treatments included sham, placebo, or medication only. Other NSTs included electroacupuncture, percutaneous electrical nerve stimulation, and percutaneous neuromodulation therapy. RESULTS: Twelve randomized controlled trials including 700 patients were included in the analysis. The efficacy of TENS was similar to that of control treatment for providing pain relief (standardized difference in means [SDM] = -0.20; 95% confidence interval [CI], -0.58 to 0.18; P = 0.293). Other types of NSTs were more effective than TENS in providing pain relief (SDM = 0.86; 95% CI, 0.15-1.57; P = 0.017). Transcutaneous electrical nerve stimulation was more effective than control treatment in improving functional disability only in patients with follow-up of less than 6 weeks (SDM = -1.24; 95% CI, -1.83 to 0.65; P < 0.001). There was no difference in functional disability outcomes between TENS and other NSTs. CONCLUSIONS: These results suggest that TENS does not improve symptoms of lower back pain, but may offer short-term improvement of functional disability. PMID- 29394213 TI - Eosinophil Counts in the Small Intestine and Colon of Children Without Apparent Gastrointestinal Disease: A Meta-analysis. AB - The aim of the current study was to review the available data regarding eosinophil density in healthy tissue specimen originating from lower gastrointestinal segments to support suggested diagnostic cutoffs widely used in clinical practice. A systematic search was performed in 3 different databases. Calculations were made with Comprehensive MetaAnalysis software using random effects model. Cell number measurements were pooled using the random-effects model and displayed on forest plots. Summary point estimations, 95% confidence intervals (CIs), and 95% prediction intervals (PIs) were calculated. The cumulative mean cell numbers were 8.26 (95% CI 4.71-11.80) with PI of 0-25.32 for the duodenum, 11.52 (95% CI 7.21-15.83) with PI 0-60.64 for the terminal ileum, and 11.10/ high-power field (HPF) (95% CI 9.11-13.09) with PI of 0.96 to 21.23 in the large intestine and the rectum (HPF area = 0.2 mm). Previous studies included control patients with irritable bowel syndrome and functional gastrointestinal disorders. As mucosal eosinophils have a role in their pathomechanism, those patients should have been excluded. A critical point of interpreting reported data is that HPF is relative to the technical parameters of the microscopes; therefore, it is important to report findings in cell/mm. The present meta analysis does not support the higher (>20) or lower (<10) cutoff values for healthy tissue eosinophil number. In contrast to the esophagus, there is no normal cutoff eosinophil density in the small intestine and the colon. A prospective, multicenter study to establish normal mucosal eosinophil density is clearly needed. PMID- 29394214 TI - NMDA-receptor Antagonism in Pediatric Pancreatitis: Use of Ketamine and Methadone in a Teenager With Refractory Pain. PMID- 29394215 TI - Practice Differences in the Diagnosis and Management of Eosinophilic Esophagitis Among Adult and Pediatric Gastroenterologists in Israel. AB - OBJECTIVES: Eosinophilic esophagitis (EoE) guidelines call for similar practices in adults and children with EoE. We compared the diagnostic and management practices of gastroenterologists treating adult and pediatric patients suspected of having, or diagnosed with, EoE. METHODS: A 19-question multiple-choice questionnaire was given to gastroenterologists treating either adults or children. Questions explored 4 areas of interest: physician demographics, diagnosis and tissue sampling practices, management, and the need for societal publications on EoE. RESULTS: Completed questionnaires were returned by 85/180 adult and 30/40 pediatric gastroenterologists (PGs). Compared to PGs, adult gastroenterologists (AGs) took esophageal biopsies significantly less frequently in the following scenarios: endoscopy without esophageal symptoms or macroscopic endoscopic findings (10% vs 57%; P < 0.001), dysphagia without macroscopic findings (83% vs 100%; P = 0.019), and gastroesophageal reflux symptoms with distal esophageal erythema (44% vs 100%; P < 0.001). Significantly fewer AGs reported taking gastric and duodenal biopsies when EoE was suspected (29% vs 90%; P < 0.001). AGs more often followed patients clinically (30% vs 0%; P < 0.001) rather than endoscopically, and were far less inclined to implement elimination diets compared to PGs (23% vs 68%; P < 0.001). CONCLUSIONS: Significant disparities exist between gastroenterologists treating adult and pediatric patients with EoE. These findings may impact rates of diagnosis, appropriate treatment, monitoring, long-term outcomes, and may affect negatively transition from pediatric to adult care. PMID- 29394217 TI - Should Giant Cell Hepatitis With Autoimmune Hemolythic Anemia Be Considered A Pediatric Autoimmune Liver Disease? PMID- 29394216 TI - Should Giant Cell Hepatitis With Autoimmune Hemolytic Anemia Be Considered a Pediatric Autoimmune Liver Disease? PMID- 29394218 TI - Urinary Management With an External Female Collection Device. AB - BACKGROUND: Strategies to decrease use of female indwelling urinary catheters and catheter-associated urinary tract infections are challenging due to the limited availability of proper fitting external collection devices. Female urinary incontinence predisposes the skin to potential pain, itching, burning, infection, or pressure injuries. CASE STUDIES: This article discusses 3 patients' trajectory of care with use of an external female urinary collection device. All of these females were incontinent of urine after the indwelling urinary catheter was removed and managed with an external female urinary collection device. CONCLUSIONS: The use of an external female urinary collection device is a feasible alternative to an indwelling urinary catheter as well as managing urinary incontinence. PMID- 29394219 TI - Multimodality Imaging Findings of Metaplastic Breast Carcinomas: A Report of Five Cases. AB - Metaplastic carcinoma is a rare subtype of breast cancer that comprises histologically diverse malignancies. Metaplastic carcinoma tends to have an aggressive clinical presentation, high metastatic potential, and more chances of local recurrence, as compared with intraductal carcinoma. Although many clinical and pathologic finding have been reported, to our knowledge, there are few reports of imaging findings for this type of tumor.In this study, we reviewed data of 5 patients with histopathologically proven metaplastic breast carcinoma. Multimodality imaging findings including those from mammography, ultrasonography, magnetic resonance imaging, and positron emission tomography-computed tomography were recorded.The results indicated that metaplastic carcinomas tend to show more benign imaging features such as round or oval shape with circumscribed margins and less axillary lymph node metastasis compared with invasive ductal carcinoma. High signal intensity on T2-weighted magnetic resonance imaging due to its cystic or necrotic component may be useful for diagnosis of metaplastic carcinoma. PMID- 29394220 TI - Beneficial effect of atorvastatin-modified dendritic cells pulsed with myelin oligodendrocyte glycoprotein autoantigen on experimental autoimmune encephalomyelitis. AB - It is well known that dendritic cells play a key role in producing antigen specific responses. Inversely, tolerogenic dendritic cells (TolDCs), a specialized subset, induce immune tolerance and negatively regulate autoimmune responses. Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the mevalonate pathway for cholesterol biosynthesis, might be a promising inductive agent for inducing TolDCs. This study aimed to investigate the effectiveness of TolDCs induced by atorvastatin pulsed with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) in experimental autoimmune encephalomyelitis mice established by MOG35-55 immunization and to investigate the potential effects on Th17/Treg balance in the murine model of multiple sclerosis. Our results showed that atorvastatin-treated dendritic cells maintained a steady semimature phenotype with a low level of costimulatory molecules and proinflammatory cytokines. Upon an intraperitoneal injection into experimental autoimmune encephalomyelitis mice, TolDCs pulsed with MOG (TolDCs MOG) significantly alleviated disease activity and regulated Th17/Treg balance with a marked decrease in Th17 cells and an obvious increase in regulatory T cells. Taken together, TolDCs-MOG modified by atorvastatin showed a characteristic tolerogenic phenotype and the antigen-specific TolDCs might represent a new promising strategy for the future treatments for multiple sclerosis. PMID- 29394221 TI - Functional Recovery in Critically Ill Children, the "WeeCover" Multicenter Study. AB - OBJECTIVES: To evaluate functional outcomes and evaluate predictors of an unfavorable functional outcome in children following a critical illness. DESIGN: Prospective observational longitudinal cohort study. SETTING: Two tertiary care, Canadian PICUs: McMaster Children's Hospital and London Health Sciences. PATIENTS: Children 12 months to 17 years old, admitted to PICU for at least 48 hours with one or more organ dysfunction, were eligible. Patients not expected to survive, direct transfers from neonatal ICU and patients in whom long-term follow up would not be able to be conducted, were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was functional outcome up to 6 months post PICU discharge, measured using the Pediatric Evaluation of Disabilities Inventory Computer Adaptive Test. Secondary outcomes included predictors of unfavorable functional outcome, caregiver stress, health-related quality-of-life, and clinical outcomes such as mortality, length of stay, and PICU-acquired complications. One hundred eighty-two patients were enrolled; 78 children (43.6%) had functional limitations at baseline and 143 (81.5%) experienced functional deterioration following critical illness. Ninety-two (67.1%) demonstrated some functional recovery by 6 months. Higher baseline function and a neurologic insult at PICU admission were the most significant predictors of functional deterioration. Higher baseline function and increasing age were associated with slower functional recovery. Different factors affect the domains of functioning differently. Preexisting comorbidities and iatrogenic PICU acquired morbidities were associated with persistent requirement for caregiver support (responsibility function) at 6 months. The degree of functional deterioration after critical illness was a significant predictor of increased hospital length of stay. CONCLUSIONS: This study provides new information regarding functional outcomes and the factors that influence meaningful aspects of functioning in critically ill children. Identifying patients at greatest risk and modifiable targets for improvement in PICU care guides us in developing strategies to improve functional outcomes and tailor to the rehabilitation needs of these patients and their families. PMID- 29394223 TI - Cognitive Development One Year After Infantile Critical Pertussis. PMID- 29394222 TI - Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock. AB - OBJECTIVE: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock. DESIGN: Retrospective analysis of a pediatric septic shock database. SETTING: Twenty-nine PICUs in the United States. PATIENTS: Eight hundred ninety children 10 years and younger with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1-3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0-6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3-3.5; p = 0.002). The secondary analysis yielded similar results. CONCLUSION: Hyperchloremia is independently associated with poor outcomes among children with septic shock. PMID- 29394224 TI - When Is it Best to "BURP"? PMID- 29394225 TI - If You Give a Mouse a Cookie, There Will Be Requests for More and More.... PMID- 29394226 TI - Extracorporeal Cardiopulmonary Resuscitation in Pediatric Cardiac Arrest: Same Principles, Different Practices. PMID- 29394228 TI - Enteral Feeding of Infants Undergoing Congenital Heart Surgery: Consensus Needed! PMID- 29394227 TI - Feast and Famine: Nutrition and Fluid Restriction After Infant Cardiac Surgery. PMID- 29394229 TI - Hyperchloremic IV Solutions: Have We Seen Enough?...or "Still Good Medicine?" PMID- 29394230 TI - Transporting Critically Ill Children-Are We All on the Same Page? PMID- 29394231 TI - Red Cell Transfusion and Prolonged Mechanical Ventilation-The Perpetrator Finally Identified or Guilt by Association Again? PMID- 29394233 TI - Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death-Summary Report: Erratum. PMID- 29394232 TI - Aligning Interests in Critical Care Trial Design. PMID- 29394234 TI - Beyond Survival: Pediatric Critical Care Interventional Trial Outcome Measure Preferences of Families and Healthcare Professionals. AB - OBJECTIVES: To identify, in addition to survival, preferred outcome measures of PICU family care providers and PICU healthcare professionals for interventional trials enrolling critically ill children, and to describe general attitudes of family care providers and healthcare professionals regarding research in the PICU. DESIGN: Cross-sectional survey examining subject experience with clinical research and personal preferences for outcome measures for a hypothetical interventional clinical trial. SETTING: PICUs within four academic children's hospitals in the United States and Canada. SUBJECTS: Two cohorts including family members of critically ill children in PICUs (family care providers) and multidisciplinary staff working in the PICUs (healthcare professionals). INTERVENTIONS: Administration of a short, deidentified survey. MEASUREMENTS: Demographic data were collated for the two subject groups. Participants were queried regarding their attitudes related to research conducted in the PICU. In addition to survival, each group was asked to identify their three most important outcomes for an investigation examining whether or not an intervention helps seriously ill children recover. MAIN RESULTS: Demographics for family care providers (n = 40) and healthcare professionals (n = 53) were similarly distributed. Female respondents (79.8%) predominated. Participants (98.9%) ascertained the importance of conducting research in the PICU, but significant challenges associated with this goal in the high stress PICU environment. Both quality of life and functioning after leaving the hospital were chosen as the most preferred outcome measure, with 77.5% of family care providers and 84.9% of healthcare professionals indicating this choice. Duration of organ dysfunction was identified by 70.0% of family care providers and 40.7% of healthcare professionals as the second most preferred outcome measure. CONCLUSIONS: In addition to survival, long-term quality of life/functional status and duration of organ dysfunction represent important interventional trial outcome measures for both families of critically ill children, as well as the multidisciplinary team who provides critical care. PMID- 29394235 TI - IMPACT OF INNER LIMITING MEMBRANE PEELING ON VISUAL RECOVERY AFTER VITRECTOMY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT INVOLVING THE FOVEA. AB - PURPOSE: To assess the impact of inner limiting membrane peeling during vitrectomy for macula-involving retinal detachment on best-corrected visual acuity (VA). METHODS: Retrospective analysis of 89 eyes with primary macula involving retinal detachment, which was undergoing vitrectomy, endolaser, retinotomy, endodrainage, and SF6 tamponade. Membrane-blue-assisted membrane peeling had been performed in 61 of the eyes (Group 1) but not in the other 28 (Group 2), which served as controls. RESULTS: Age, lens status, and incidence of proliferative vitreoretinopathy 26.2% versus 39.3%; P = 0.23 in the 2 groups were comparable. The preoperative visual acuity (Early Treatment Diabetic Retinopathy Study letters) was 25.7 +/- 27.9 in Group 1 and 28.8 +/- 29.9 in Group 2 (P = 0.47). After surgery, these rose from 62.3 +/- 30.5 (Group 1) and 34.2 +/- 35.8 (Group 2) after 1 week (P = 0.090), through 83.1 +/- 8.0 and 57.2 +/- 32.4 at 1 month (P = 0.0005), to 92.1 +/- 4.5 and 74.4 +/- 23.1 Early Treatment Diabetic Retinopathy Study letters after 6 months (P = 0.0005). More than 6-month incidences of proliferative vitreoretinopathy (13.1% vs. 28.6%; P = 0.13) were similar, whereas the redetachment rate (9.8% vs. 32.1%; P = 0.014), the incidence of secondary epiretinal membranes (1.6% vs. 35.7%; P = 0.0005), and the revitrectomy rate were lower in group 1 (9.8% vs. 53.6%; P = 0.0005). CONCLUSION: Inner limiting membrane peeling during vitrectomy for macula-involving retinal detachment may substantially contribute to the visual recovery, reducing the incidence of secondary epiretinal membrane formation. PMID- 29394236 TI - IDENTIFICATION OF FACTORS RELATED TO SUBFOVEAL DETACHMENT SECONDARY TO EPIRETINAL MEMBRANE. AB - PURPOSE: To demonstrate factors related to the presence of subfoveal detachment (SD) secondary to epiretinal membrane (ERM) and to characterize the predictors for the resolution of SD after membrane peeling. METHODS: A retrospective chart review was conducted for the patients who underwent pars plana vitrectomy for the idiopathic ERM peeling. Preoperative spectral domain optical coherence tomography characteristics of the eyes including central foveal thickness, foveal center point thickness, presence of intraretinal cyst, continuity of the membrane, area of the membrane within fovea (1 mm), and entire macula (6 mm) were evaluated to find the best predictors for the presence of SD. These predictors as well as perioperative parameters including use of internal tamponade and volume of SD were considered for time of resolution of SD. RESULTS: Of 158 included eyes, 20.2% eyes (32 eyes) had SD, and the presence of SD was significantly related to involvement of the membrane within the macula. After surgery, SD completely resolved in 90.6% of eyes (29 eyes) at a median of 2.97 months (range: 0.03-12.0 months). The area of the membrane within fovea was the only significant predictor for time to resolution of SD (hazard ratio = 1.20, 95% confidence interval = 1.100-1.324, P = 0.021). A small percent of eyes showed some further changes including fluctuation (6.2%) or persistence (3.1%) of fluid. CONCLUSION: A larger extension of ERM over the macula is related to higher likelihood of the presence of SD. Time for resolution of subfoveal detachment does not seem to be affected by the preoperative and perioperative factors except the extent of membrane within 1,000 MUm of the fovea. PMID- 29394237 TI - SYSTEMIC BETA-BLOCKERS AND RISK OF PROGRESSION TO NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To determine whether oral beta-blockers (BBs) are associated with the development of neovascular age-related macular degeneration (nAMD). METHODS: Retrospective cohort study of patients from 2000 to 2014 using data from a large national U.S. insurer's administrative medical claims database. Patients with nonexudative AMD who initiated (index date) BB, a calcium channel blocker (CCB), an angiotensin-converting enzyme/angiotensin receptor blocker, or a diuretic. Patients were excluded for <2 years in the plan before the index date, any history of nAMD or diagnosis, or treatment for an ocular disease that could be confused with nAMD. Hazard of developing of nAMD was the main outcome measure. Primary analysis compared BB with CCB patients with BB versus the other classes as secondary analyses. In addition, a sensitivity analysis was performed between BB and CCB cohorts using 1:1 propensity score matching. Cox proportional hazard regression was performed to estimate the hazard ratio (HR) of developing nAMD at 90, 180, and 365 days for BB. Covariates of interest included demographic information, year of index date, number of antihypertensive medications, and other comorbid systemic conditions. RESULTS: Eighteen thousand seven hundred and fifty-four BB patients and 12,784 CCB patients met criteria for inclusion. After controlling for covariates, patients on BB had a lower hazard for nAMD at both 90 and 180 days than patients on CCB (HRs: 0.67-0.71; P < 0.01 for both) and diuretics (HRs: 0.55-0.62; P < 0.01). Patients on BB versus angiotensin converting enzyme/angiotensin receptor blocker at all time points and BB versus CCB and diuretics at 365 days did not have a significantly lower association with nAMD (HR: 0.73-0.85; P > 0.06 for all comparisons). A sensitivity analysis using propensity score matching yielded similar results with patients on BB significantly less likely to develop nAMD at 90 and 180 days (HR: 0.70-0.76; P < 0.049 for both) but not at 365 days (HR: 0.88; P = 0.30) compared with patients on CCB. CONCLUSION: No evidence was found that BB usage increased the hazard for nAMD relative to other antihypertensive medications. PMID- 29394238 TI - Plasmodium-Salmonella Coinfection Induces Intense Inflammatory Response, Oxidative Stress, and Liver Damage: A Mice Model Study for Therapeutic Strategy. AB - Impairment of host immune response in malaria favors bacteremia caused by typhoidal or nontyphoidal serovars of Salmonella enterica. Ofloxacin and Artesunate are the drugs that are clinically proven for treating typhoid and malaria, respectively. The study evaluates the host responses upon treatment with antibiotic (Ofloxacin) and antimalarial (Artesunate) in a standardized mice model harboring coinfection. BALB/c mice (18-22 g) were simultaneously coinfected with Plasmodium yoelii nigeriensis (Pyn) and S. enterica serovar Typhimurium (STm) and then treated with Ofloxacin or/and Artesunate from day 4 to day 7. The bacterial burden, liver function enzymes, oxidative stress, m-RNA expression of Toll-like receptors (TLR-2 and TLR-4), Th1/Th2 cytokines, hemeoxygenase-1, and NFkB were assessed. Ofloxacin treatment failed to counter the bacterial proliferation in Pyn-STm coinfected mice. However, upon controlling parasitemia with antimalarial, the efficacy of Ofloxacin could be regained. Elevated bacterial burden with malaria induces the expression of TLR-2 and TLR-4 triggering intense inflammatory response (NFkappaB, Th1/Th2 cytokines) in coinfected mice. This results in critical liver damage (ALT, AST, and ALP), oxidative stress (lipid peroxidation, total GSH, catalase, and super oxide dismutase), and hemeoxygenase-1 (HO-1). The study concludes that malaria infection aggravates the secondary infection of Salmonella serovars and the control of septicemia is critical in recovery of the coinfected subject. PMID- 29394239 TI - Matrine Protects Cardiomyocytes From Ischemia/Reperfusion Injury by Regulating HSP70 Expression Via Activation of the JAK2/STAT3 Pathway. AB - Studies have shown that matrine showed cardiovascular protective effects; however, its role and mechanism in myocardial ischemia/reperfusion (I/R) injury remain unknown. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway activation and elevated heat shock protein (HSP) 70 are closely related to the prevention of myocardial I/R injury. The cardioprotective effects of matrine were determined in hypoxia/reoxygenation (H/R)-treated primary rat cardiomyocytes and left anterior descending coronary artery ligation and reperfusion animal models. The molecular mechanisms of matrine in myocardial I/R injury were focused on JAK2/STAT3 pathway activation and HSP70 expression. We found that matrine significantly increased H/R-induced the suppression of cell viability, decreased lactate dehydrogenase release, creatine kinase activity, and cardiomyocytes apoptosis in vitro. Moreover, matrine notably reduced the serum levels of creatine kinase-myocardial band (CK MB) and cardiac troponin I, lessened the infarcted area of the heart, and decreased the apoptotic index of cardiomyocytes induced by I/R in vivo. Matrine activated the JAK2/STAT3 signaling, upregulated HSP70 expression both in vitro and in vivo. The cardioprotective effects of matrine were abrogated by AG490, a JAK2 inhibitor, and HSP70 siRNA. In addition, AG490 reduced HSP70 expression increased by matrine. In conclusion, matrine attenuates myocardial I/R injury by upregulating HSP70 expression via the activation of the JAK2/STAT3 pathway. PMID- 29394240 TI - Beneficial Effects of Adrenal Androgen Supplement in Bleeding Cirrhotic Rats. AB - Critical illness is accompanied by hypothalamic-pituitary-adrenal axis activation, but adrenal insufficiency characterized by inadequate glucocorticoid synthesis is common in critically ill cirrhotic patients, the "hepato-adrenal syndrome." Adrenal cortex also synthesizes androgen (dehydroepiandrosterone, DHEA). DHEA maintains microcirculation by enhancing vascular endothelial nitric oxide synthase (eNOS) activity. In critical patients of other disease entities, a shift of adrenal steroidogenesis away from androgens toward glucocorticoid has been noted, arousing interests in androgen replacement in critical settings. Nevertheless, this has not been surveyed in cirrhosis with hemorrhage. In this study, liver cirrhosis was induced with common bile duct ligation (BDL) in Spraque-Dawley rats. Sham rats were controls. DHEA or vehicle was injected at the beginning of hemorrhage-transfused procedure, followed by terlipressin injection. Hemodynamic parameters were measured. Then abdominal aorta, superior mesenteric arteries (SMA) and splenorenal shunt (prominent portosystemic collateral vessel in rodents) eNOS and inducible NOS protein expressions were evaluated. In bleeding BDL groups without terlipressin injection, adrenocorticotropic hormone (ACTH) stimulation test was performed to evaluate the DHEA response. The results showed that DHEA significantly elevated mean arterial pressure, cardiac output, and stroke volume of bleeding cirrhotic rats treated with terlipressin and reduced systemic vascular resistance without affecting SMA flow, resistance, and portal pressure. DHEA upregulated abdominal aorta and SMA eNOS expressions. ACTH did not stimulate DHEA synthesis in bleeding BDL rats. In conclusion, androgen deficiency exists in bleeding cirrhotic rats. DHEA augments terlipressin-induced amelioration of shock without influencing splanchnic hemodynamics, possibly rendering it a feasible adjunct to vasoconstrictors in variceal hemorrhage. PMID- 29394241 TI - Chlorinated Lipids Elicit Inflammatory Responses In Vitro and In Vivo. AB - Increased endothelial cell adhesion molecule (ECAM) expression, leukocyte endothelial cell adhesive interactions (LECA), platelet-endothelial cell adhesion (PECA), mast cell activation, production of reactive oxygen species (ROS), and microvascular permeability are hallmarks of the inflammatory response. The infiltration of inflammatory phagocytes is associated with myeloperoxidase (MPO) dependent production of hypochlorous acid (HOCl), a reactive chlorinating species (RCS) that targets membrane lipids to produce halogenated lipids such as 2 chlorohexadecanal (2-ClHDA) and 2-chloropalmitic acid (2-ClPA). Whether these chlorinated lipids contribute to microcirculatory dysfunction is largely unknown. Thus, the objectives of this study were to determine if chlorinated lipids exposure induces such inflammatory responses in an in vitro model employing cultured human intestinal mesenteric vascular endothelial cells (HIMVEC), and in an in vivo model examining responses in small intestinal and mesenteric postcapillary venules of naive rats. Following the addition of either 2-ClPA or 2 ClHDA to the culture medium, HIMVEC displayed increased platelet and neutrophil adherence that was associated with elevated expression of ECAMs and increased permeability. In vivo, chlorinated lipid exposure significantly increased LECA, PECA, ROS production, and albumin leakage, inflammatory events that were associated with mast cell activation and increased tissue MPO activity and expression. Our data provide proof-of-principle that 2-ClPA and 2-ClHDA induce powerful proinflammatory responses both in vitro and in vivo, suggesting the possibility that these chlorinated lipid products of the MPO/H2O2/chloride system may contribute to inflammation noted in neutrophil-dependent, myeloperoxidase mediated pathologic states such as ischemia/reperfusion, hemorrhagic shock, and sepsis. PMID- 29394242 TI - Pulmonary Arterial Thrombosis in a Murine Model of Blunt Thoracic Trauma. AB - Pulmonary thromboembolic events cause significant morbidity and mortality after severe trauma. Clinically, these lesions are believed to be emboli arising secondary to deep venous thrombosis (DVT) in the lower extremities. Recently, this notion has been challenged by clinical studies, showing that pulmonary clots arise after trauma in the absence of DVT. This suggests that pulmonary blood clots arise in situ via de novo thrombosis. In the present study, we characterize a murine weight-drop model of lateral blunt thoracic trauma. Our model demonstrates severe unilateral lung contusion injury with low (10%) mortality in the absence of extrapulmonary injury, after impact with a 50-g weight dropped from 45 cm height (657 J/m). At 24 h after injury, immunofluorescence and histological evidence revealed early pulmonary arterial thrombosis in the form of eccentric accumulation of fibrin and CD41 positive eosinophilic proteinaceous material, on both coup and contrecoup lung lobes of injured mice, indicating early thrombotic events both within and outside of the area of primary lung injury. Our model is ideal in that lateral impact enables greater impact energy to be applied to achieve significant lung contusion without significant mortality or extrapulmonary injury, and the model has additional translational value in creating thrombosis analogous to pulmonary embolism observed clinically after blunt thoracic trauma. To our knowledge, this is the first demonstration of de novo pulmonary thrombosis in a clinically translational model of blunt thoracic trauma, and supports challenges to current assumptions about the origin of pulmonary blood clots in the wake of severe traumatic injury. PMID- 29394243 TI - Effects of Ovariectomy in an hSOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS). AB - BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive muscular dystrophy and paralysis; most ALS patients die from respiratory failure within 3 to 5 years, and there is currently no effective treatment. Some studies have indicated sex differences in the incidence of ALS, and evidence suggests a neuroprotective role for estrogen. MATERIAL AND METHODS We used human Cu/Zn superoxide dismutase (hSOD1-G93A) transgenic mice to determine the effects of ovariotomy on the onset of disease and behavior; we also used Western blotting to measure the expression of aromatase and estrogen receptors, as well as the inflammatory cytokines and apoptosis markers, in the lumbar spinal cord to determine the mechanism of estrogen-mediated neuroprotection. RESULTS Ovariectomy advanced the onset of disease, down-regulated aromatase and estrogen receptor alpha (ER-a) expression, and inhibited expression of the anti-inflammatory factors arginase-1 and the anti apoptotic factor B-cell lymphoma-2 (Bcl-2) in the lumbar spinal cord of hSOD1 G93A transgenic mice. CONCLUSIONS Ovariectomy resulted in earlier disease onset and attenuated the anti-inflammatory and anti-apoptotic actions of estrogen in hSOD1-G93A transgenic mice. Therefore, estrogen may play an important role in protecting spinal cord motor neurons. PMID- 29394244 TI - With a pinch of extra salt-Did predatory protists steal genes from their food? AB - The cellular adjustment of Bacteria and Archaea to high-salinity habitats is well studied and has generally been classified into one of two strategies. These are to accumulate high levels either of ions (the "salt-in" strategy) or of physiologically compliant organic osmolytes, the compatible solutes (the "salt out" strategy). Halophilic protists are ecophysiological important inhabitants of salt-stressed ecosystems because they are not only very abundant but also represent the majority of eukaryotic lineages in nature. However, their cellular osmostress responses have been largely neglected. Recent reports have now shed new light on this issue using the geographically widely distributed halophilic heterotrophic protists Halocafeteria seosinensis, Pharyngomonas kirbyi, and Schmidingerothrix salinarum as model systems. Different approaches led to the joint conclusion that these unicellular Eukarya use the salt-out strategy to cope successfully with the persistent high salinity in their habitat. They accumulate various compatible solutes, e.g., glycine betaine, myo-inositol, and ectoines. The finding of intron-containing biosynthetic genes for ectoine and hydroxyectoine, their salt stress-responsive transcription in H. seosinensis, and the production of ectoine and its import by S. salinarum come as a considerable surprise because ectoines have thus far been considered exclusive prokaryotic compatible solutes. Phylogenetic considerations of the ectoine/hydroxyectoine biosynthetic genes of H. seosinensis suggest that they have been acquired via lateral gene transfer by these bacterivorous Eukarya from ectoine/hydroxyectoine producing food bacteria that populate the same habitat. PMID- 29394245 TI - Simulation enabled search for explanatory mechanisms of the fracture healing process. AB - A significant portion of bone fractures fail to heal properly, increasing healthcare costs. Advances in fracture management have slowed because translation barriers have limited generation of mechanism-based explanations for the healing process. When uncertainties are numerous, analogical modeling can be an effective strategy for developing plausible explanations of complex phenomena. We demonstrate the feasibility of engineering analogical models in software to facilitate discovery of biomimetic explanations for how fracture healing may progress. Concrete analogical models-Callus Analogs-were created using the MASON simulation toolkit. We designated a Target Region initial state within a characteristic tissue section of mouse tibia fracture at day-7 and posited a corresponding day-10 Target Region final state. The goal was to discover a coarse grain analog mechanism that would enable the discretized initial state to transform itself into the corresponding Target Region final state, thereby providing an alternative way to study the healing process. One of nine quasi autonomous Tissue Unit types is assigned to each grid space, which maps to an 80*80 MUm region of the tissue section. All Tissue Units have an opportunity each time step to act based on individualized logic, probabilities, and information about adjacent neighbors. Action causes transition from one Tissue Unit type to another, and simulation through several thousand time steps generates a coarse grain analog-a theory-of the healing process. We prespecified a minimum measure of success: simulated and actual Target Region states achieve >= 70% Similarity. We used an iterative refinement protocol to explore many combinations of Tissue Unit logic and action constraints. Workflows progressed through four stages of analog mechanisms. Similarities of 73-90% were achieved for Mechanisms 2-4. The range of Upper-Level similarities increased to 83-94% when we allowed for uncertainty about two Tissue Unit designations. We have demonstrated how Callus Analog experiments provide domain experts with a fresh medium and tools for thinking about and understanding the fracture healing process. PMID- 29394246 TI - Nuclear re-localization of Dicer in primary mouse embryonic fibroblast nuclei following DNA damage. AB - Dicer is a key component of RNA interference (RNAi) and well-known for its role in biogenesis of micro (mi)RNA in the cytoplasm. Increasing evidence suggests that mammalian Dicer is also present and active in the nucleus. We have previously shown that phosphorylated human Dicer associates with chromatin in response to DNA damage and processes double-stranded (ds)RNA in the nucleus. However, a recent study by Much et al. investigated endogenously tagged HA-Dicer both in primary mouse embryonic fibroblasts (PMEFs) as well as adult homozygous viable and fertile HA-Dicer mice under physiological conditions and concluded that murine Dicer is exclusively cytoplasmic. The authors challenged several findings, reporting functions of Dicer in mammalian nuclei. We have re investigated this issue by applying subcellular fractionation, super-resolution microscopy followed by 3D reconstitution, and phospho-Dicer-specific antibodies using the same HA-Dicer PMEF cell line. Our data show that a small fraction of the murine HA-Dicer pool, approximately 5%, localises in the nucleus and is phosphorylated upon DNA damage. We propose that Dicer localisation is dynamic and not exclusively cytoplasmic, particularly in cells exposed to DNA damage. PMID- 29394247 TI - Health and socio-demographic profile of women of reproductive age in rural communities of southern Mozambique. AB - Reliable statistics on maternal morbidity and mortality are scarce in low and middle-income countries, especially in rural areas. This is the case in Mozambique where many births happen at home. Furthermore, a sizeable number of facility births have inadequate registration. Such information is crucial for developing effective national and global health policies for maternal and child health. The aim of this study was to generate reliable baseline socio-demographic information on women of reproductive age as well as to establish a demographic surveillance platform to support the planning and implementation of the Community Level Intervention for Pre-eclampsia (CLIP) study, a cluster randomized controlled trial. This study represents a census of all women of reproductive age (12-49 years) in twelve rural communities in Maputo and Gaza provinces of Mozambique. The data were collected through electronic forms implemented in Open Data Kit (ODK) (an app for android based tablets) and household and individual characteristics. Verbal autopsies were conducted on all reported maternal deaths to determine the underlying cause of death. Between March and October 2014, 50,493 households and 80,483 women of reproductive age (mean age 26.9 years) were surveyed. A total of 14,617 pregnancies were reported in the twelve months prior to the census, resulting in 9,029 completed pregnancies. Of completed pregnancies, 8,796 resulted in live births, 466 resulted in stillbirths and 288 resulted in miscarriages. The remaining pregnancies had not yet been completed during the time of the survey (5,588 pregnancies). The age specific fertility indicates that highest rate (188 live births per 1,000 women) occurs in the age 20-24 years old. The estimated stillbirth rate was 50.3/1,000 live and stillbirths; neonatal mortality rate was 13.3/1,000 live births and maternal mortality ratio was 204.6/100,000 live births. The most common direct cause of maternal death was eclampsia and tuberculosis was the most common indirect cause of death. This study found that fertility rate is high at age 20-24 years old. Pregnancy in the advanced age (>35 years of age) in this study was associated with higher poor outcomes such as miscarriage and stillbirth. The study also found high stillbirth rate indicating a need for increased attention to maternal health in southern Mozambique. Tuberculosis and HIV/AIDS are prominent indirect causes of maternal death, while eclampsia represents the number one direct obstetric cause of maternal deaths in these communities. Additional efforts to promote safe motherhood and improve child survival are crucial in these communities. PMID- 29394248 TI - Elevations of novel cytokines in bacterial meningitis in infants. AB - BACKGROUND: Bacterial meningitis is challenging to diagnose in infants, especially in the common setting of antibiotic pre-treatment, which diminishes yield of cerebrospinal fluid (CSF) cultures. Prior studies of diagnostic markers have not demonstrated sufficient accuracy. Interleukin-23 (IL-23), interleukin-18 (IL-18) and soluble receptor for advanced glycation end products (sRAGE) possess biologic plausibility, and may be useful as diagnostic markers in bacterial meningitis. METHODS: In a prospective cohort study, we measured IL-23, IL-18 and sRAGE levels in CSF. We compared differences between infected and non-infected infants, and conducted receiver operating characteristic (ROC) analyses to identify individual markers and combinations of markers with the best diagnostic accuracy. RESULTS: 189 infants <6 months, including 8 with bacterial meningitis, 30 without meningitis, and 151 with indeterminate diagnosis (due to antibiotic pretreatment) were included. CSF IL-23, IL-18 and sRAGE levels were significantly elevated in infants with culture proven meningitis. Among individual markers, IL 23 possessed the greatest accuracy for diagnosis of bacterial meningitis (area under the curve (AUC) 0.9698). The combination of all three markers had an AUC of 1. CONCLUSIONS: IL-23, alone and in combination with IL-18 and sRAGE, identified bacterial meningitis with excellent accuracy. Following validation, these markers could aid clinicians in diagnosis of bacterial meningitis and decision-making regarding prolongation of antibiotic therapy. PMID- 29394249 TI - Functional analysis of the C. elegans cyld-1 gene reveals extensive similarity with its human homolog. AB - The human cylindromatosis tumor suppressor (HsCyld) has attracted extensive attention due to its association with the development of multiple types of cancer. HsCyld encodes a deubiquitinating enzyme (HsCYLD) with a broad range of functions that include the regulation of several cell growth, differentiation and death pathways. HsCyld is an evolutionarily conserved gene. Homologs of HsCyld have been identified in simple model organisms such as Drosophila melanogaster and Caenorhabditis elegans (C. elegans) which offer extensive possibilities for functional analyses. In the present report we have investigated and compared the functional properties of HsCYLD and its C. elegans homolog (CeCYLD). As expected from the mammalian CYLD expression pattern, the CeCyld promoter is active in multiple tissues with certain gastrointestinal epithelia and neuronal cells showing the most prominent activity. CeCYLD is a functional deubiquitinating enzyme with similar specificity to HsCYLD towards K63- and M1-linked polyubiquiting chains. CeCYLD was capable of suppressing the TRAF2-mediated activation of NF-kappaB and AP1 similarly to HsCYLD. Finally, CeCYLD could suppress the induction of TNF-dependent gene expression in mammalian cells similarly to HsCYLD. Our results demonstrate extensively overlapping functions between the HsCYLD and CeCYLD, which establish the C. elegans protein as a valuable model for the elucidation of the complex activity of the human tumor suppressor protein. PMID- 29394250 TI - A computational framework for cortical microtubule dynamics in realistically shaped plant cells. AB - Plant morphogenesis is strongly dependent on the directional growth and the subsequent oriented division of individual cells. It has been shown that the plant cortical microtubule array plays a key role in controlling both these processes. This ordered structure emerges as the collective result of stochastic interactions between large numbers of dynamic microtubules. To elucidate this complex self-organization process a number of analytical and computational approaches to study the dynamics of cortical microtubules have been proposed. To date, however, these models have been restricted to two dimensional planes or geometrically simple surfaces in three dimensions, which strongly limits their applicability as plant cells display a wide variety of shapes. This limitation is even more acute, as both local as well as global geometrical features of cells are expected to influence the overall organization of the array. Here we describe a framework for efficiently simulating microtubule dynamics on triangulated approximations of arbitrary three dimensional surfaces. This allows the study of microtubule array organization on realistic cell surfaces obtained by segmentation of microscopic images. We validate the framework against expected or known results for the spherical and cubical geometry. We then use it to systematically study the individual contributions of global geometry, cell-edge induced catastrophes and cell-face induced stability to array organization in a cuboidal geometry. Finally, we apply our framework to analyze the highly non trivial geometry of leaf pavement cells of Arabidopsis thaliana, Nicotiana benthamiana and Hedera helix. We show that our simulations can predict multiple features of the microtubule array structure in these cells, revealing, among others, strong constraints on the orientation of division planes. PMID- 29394252 TI - Tau accumulations in the brains of woodpeckers. AB - Woodpeckers experience forces up to 1200-1400 g while pecking. It is assumed due to evolutionary adaptations, the woodpecker is immune to brain injury. This assumption has led to the use of the woodpecker as a model in the development of sports safety equipment such as football helmets. However, it is unknown at this time if the woodpecker brain develops neuro-trauma in relation to the high g forces experienced during pecking. The brains of 10 ethanol preserved woodpeckers and 5 ethanol preserved red-winged black bird experimental controls were examined using Gallyas silver stain and anti-phospho-tau. The results demonstrated perivascular and white matter tract silver-positive deposits in eight out of the 10 woodpecker brains. The tau positive accumulations were seen in white matter tracts in 2 of the 3 woodpeckers examined. No staining was identified in control birds. The negative staining of controls birds contrasted with the diffuse positive staining woodpecker sections suggest the possibility that pecking may induce the accumulation of tau in the woodpecker brain. Further research is needed to better understand the relationship. PMID- 29394251 TI - Examining the short-term anxiolytic and antidepressant effect of Floatation-REST. AB - : Floatation-REST (Reduced Environmental Stimulation Therapy) reduces sensory input to the nervous system through the act of floating supine in a pool of water saturated with Epsom salt. The float experience is calibrated so that sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational and proprioceptive channels are minimized, as is most movement and speech. This open-label study aimed to examine whether Floatation REST would attenuate symptoms of anxiety, stress, and depression in a clinical sample. Fifty participants were recruited across a spectrum of anxiety and stress related disorders (posttraumatic stress, generalized anxiety, panic, agoraphobia, and social anxiety), most (n = 46) with comorbid unipolar depression. Measures of self-reported affect were collected immediately before and after a 1-hour float session, with the primary outcome measure being the pre- to post-float change score on the Spielberger State Anxiety Inventory. Irrespective of diagnosis, Floatation-REST substantially reduced state anxiety (estimated Cohen's d > 2). Moreover, participants reported significant reductions in stress, muscle tension, pain, depression and negative affect, accompanied by a significant improvement in mood characterized by increases in serenity, relaxation, happiness and overall well-being (p < .0001 for all variables). In reference to a group of 30 non anxious participants, the effects were found to be more robust in the anxious sample and approaching non-anxious levels during the post-float period. Further analysis revealed that the most severely anxious participants reported the largest effects. Overall, the procedure was well-tolerated, with no major safety concerns stemming from this single session. The findings from this initial study need to be replicated in larger controlled trials, but suggest that Floatation REST may be a promising technique for transiently reducing the suffering in those with anxiety and depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT03051074. PMID- 29394253 TI - Risk factors for heart failure hospitalizations among patients with atrial fibrillation. AB - BACKGROUND: Patients with atrial fibrillation (AF) have an increased risk for the development of heart failure (HF). In this study, we aimed to detect predictors of HF hospitalizations in an unselected AF population. METHODS: The Basel Atrial Fibrillation Cohort Study is an ongoing observational multicenter cohort study in Switzerland. For this analysis, 1193 patients with documented AF underwent clinical examination, venous blood sampling and resting 12-lead ECG at baseline. Questionnaires about lifestyle and medical history were obtained in person at baseline and during yearly follow-up phone calls. HF hospitalizations were validated by two independent physicians. Cox regression analyses were performed using a forward selection strategy. RESULTS: Overall, 29.8% of all patients were female and mean age was 69 +/-12 years. Mean follow-up time was 3.7 +/-1.5 years. Hospitalization for HF occurred in 110 patients, corresponding to an incidence of 2.5 events per 100 person years of follow-up. Independent predictors for HF were body mass index (HR 1.40 [95%CI 1.17; 1.66], p = 0.0002), chronic kidney disease (2.27 [1.49; 3.45], p = 0.0001), diabetes mellitus (2.13 [1.41; 3.24], p = 0.0004), QTc interval (1.25 [1.04; 1.49], p = 0.02), brain natriuretic peptide (2.19 [1.73; 2.77], p<0.0001), diastolic blood pressure (0.79 [0.65; 0.96], p = 0.02), history of pulmonary vein isolation or electrical cardioversion (0.54 [0.36; 0.80], p = 0.003) and serum chloride (0.82 [0.70; 0.96], p = 0.02). CONCLUSIONS: In this unselected AF population, several traditional cardiovascular risk factors and arrhythmia interventions predicted HF hospitalizations, providing potential opportunities for the implementation of strategies to reduce HF among AF patients. PMID- 29394254 TI - Differential expression of genes identified by suppression subtractive hybridization in liver and adipose tissue of gerbils with diabetes. AB - OBJECTIVES: We aimed at identifying genes related to hereditary type 2 diabetes expressed in the liver and the adipose tissue of spontaneous diabetic gerbils using suppression subtractive hybridization (SSH) screening. METHODS: Two gerbil littermates, one with high and the other with normal blood glucose level, from our previously bred spontaneous diabetic gerbil strain were used in this study. To identify differentially expressed genes in the liver and the adipose tissue, mRNA from these tissues was extracted and SSH libraries were constructed for screening. After sequencing and BLAST analyzing, up or down-regulated genes possibly involved in metabolism and diabetes were selected, and their expression levels in diabetic gerbils and normal controls were analyzed using quantitative RT-PCR and Western blotting. RESULTS: A total of 4 SSH libraries were prepared from the liver and the adipose tissue of gerbils. There are 95 up or down regulated genes were identified to be involved in metabolism, oxidoreduction, RNA binding, cell proliferation, and differentiation or other function. Expression of 17 genes most possibly associated with diabetes was analyzed and seven genes (Sardh, Slc39a7, Pfn1, Arg1, Cth, Sod1 and P4hb) in the liver and one gene (Fabp4) in the adipose tissue were identified that were significantly differentially expressed between diabetic gerbils and control animals. CONCLUSIONS: We identified eight genes associated with type 2 diabetes from the liver and the adipose tissue of gerbils via SSH screening. These findings provide further insights into the molecular mechanisms of diabetes and imply the value of our spontaneous diabetic gerbil strain as a diabetes model. PMID- 29394255 TI - Albuminuria and neck circumference are determinate factors of successful accurate estimation of glomerular filtration rate in high cardiovascular risk patients. AB - BACKGROUND: Estimated glomerular filtration rate (eGFR) is used for diagnosis of chronic kidney disease (CKD). The eGFR models based on serum creatinine or cystatin C are used more in clinical practice. Albuminuria and neck circumference are associated with CKD and may have correlations with eGFR. AIM: We explored the correlations and modelling formulates among various indicators such as serum creatinine, cystatin C, albuminuria, and neck circumference for eGFR. DESIGN: Cross-sectional study. METHODS: We reviewed the records of patients with high cardiovascular risk from 2010 to 2011 in Taiwan. 24-hour urine creatinine clearance was used as the standard. We utilized a decision tree to select for variables and adopted a stepwise regression method to generate five models. Model 1 was based on only serum creatinine and was adjusted for age and gender. Model 2 added serum cystatin C, models 3 and 4 added albuminuria and neck circumference, respectively. Model 5 simultaneously added both albuminuria and neck circumference. RESULTS: Total 177 patients were recruited in this study. In model 1, the bias was 2.01 and its precision was 14.04. In model 2, the bias was reduced to 1.86 with a precision of 13.48. The bias of model 3 was 1.49 with a precision of 12.89, and the bias for model 4 was 1.74 with a precision of 12.97. In model 5, the bias could be lower to 1.40 with a precision of 12.53. CONCLUSIONS: In this study, the predicting ability of eGFR was improved after the addition of serum cystatin C compared to serum creatinine alone. The bias was more significantly reduced by the calculation of albuminuria. Furthermore, the model generated by combined albuminuria and neck circumference could provide the best eGFR predictions among these five eGFR models. Neck circumference can be investigated potentially in the further studies. PMID- 29394257 TI - Comparison among cognitive diagnostic models for the TIMSS 2007 fourth grade mathematics assessment. AB - A variety of cognitive diagnostic models (CDMs) have been developed in recent years to help with the diagnostic assessment and evaluation of students. Each model makes different assumptions about the relationship between students' achievement and skills, which makes it important to empirically investigate which CDMs better fit the actual data. In this study, we examined this question by comparatively fitting representative CDMs to the Trends in International Mathematics and Science Study (TIMSS) 2007 assessment data across seven countries. The following two major findings emerged. First, in accordance with former studies, CDMs had a better fit than did the item response theory models. Second, main effects models generally had a better fit than other parsimonious or the saturated models. Related to the second finding, the fit of the traditional parsimonious models such as the DINA and DINO models were not optimal. The empirical educational implications of these findings are discussed. PMID- 29394256 TI - The natural anti-tumor compound Celastrol targets a Myb-C/EBPbeta-p300 transcriptional module implicated in myeloid gene expression. AB - Myb is a key regulator of hematopoietic progenitor cell proliferation and differentiation and has emerged as a potential target for the treatment of acute leukemia. Using a myeloid cell line with a stably integrated Myb-inducible reporter gene as a screening tool we have previously identified Celastrol, a natural compound with anti-tumor activity, as a potent Myb inhibitor that disrupts the interaction of Myb with the co-activator p300. We showed that Celastrol inhibits the proliferation of acute myeloid leukemia (AML) cells and prolongs the survival of mice in an in vivo model of AML, demonstrating that targeting Myb with a small-molecule inhibitor is feasible and might have potential as a therapeutic approach against AML. Recently we became aware that the reporter system used for Myb inhibitor screening also responds to inhibition of C/EBPbeta, a transcription factor known to cooperate with Myb in myeloid cells. By re-investigating the inhibitory potential of Celastrol we have found that Celastrol also strongly inhibits the activity of C/EBPbeta by disrupting its interaction with the Taz2 domain of p300. Together with previous studies our work reveals that Celastrol independently targets Myb and C/EBPbeta by disrupting the interaction of both transcription factors with p300. Myb, C/EBPbeta and p300 cooperate in myeloid-specific gene expression and, as shown recently, are associated with so-called super-enhancers in AML cells that have been implicated in the maintenance of the leukemia. We hypothesize that the ability of Celastrol to disrupt the activity of a transcriptional Myb-C/EBPbeta-p300 module might explain its promising anti-leukemic activity. PMID- 29394258 TI - Microblog sentiment analysis using social and topic context. AB - Analyzing massive user-generated microblogs is very crucial in many fields, attracting many researchers to study. However, it is very challenging to process such noisy and short microblogs. Most prior works only use texts to identify sentiment polarity and assume that microblogs are independent and identically distributed, which ignore microblogs are networked data. Therefore, their performance is not usually satisfactory. Inspired by two sociological theories (sentimental consistency and emotional contagion), in this paper, we propose a new method combining social context and topic context to analyze microblog sentiment. In particular, different from previous work using direct user relations, we introduce structure similarity context into social contexts and propose a method to measure structure similarity. In addition, we also introduce topic context to model the semantic relations between microblogs. Social context and topic context are combined by the Laplacian matrix of the graph built by these contexts and Laplacian regularization are added into the microblog sentiment analysis model. Experimental results on two real Twitter datasets demonstrate that our proposed model can outperform baseline methods consistently and significantly. PMID- 29394259 TI - It's all in the timing: Acceptability of a financial incentive intervention for linkage to HIV care in the HPTN 065 (TLC-Plus) study. AB - The HPTN 065 (TLC-Plus) study tested the feasibility and effectiveness of using financial incentives (FIs) to increase linkage to care (L2C) among individuals with newly diagnosed HIV and those out of care in the Bronx, NY and Washington, DC. Qualitative data collection with a subset of participating patients and staff focused on experiences with and attitudes about the FI intervention. Semi structured interviews were conducted with 15 patients and 14 site investigators. Four focus group discussions were conducted with a total of 15 staff members. The use of FIs for L2C was generally viewed favorably. Patients were grateful and benefited financially, but sites had some challenges implementing the program. Challenges included the timing and sensitive introduction of the intervention immediately after an HIV diagnosis, negative attitudes towards paying people for health behaviors, and the existence and strength of existing linkage programs. Future programs should consider optimal timing and presentation of FIs. PMID- 29394260 TI - Healthcare resource use and costs of managing children and adults with lysosomal acid lipase deficiency at a tertiary referral centre in the United Kingdom. AB - OBJECTIVE: To estimate clinical progression and resource utilisation together with the associated costs of managing children and adults with LAL Deficiency, at a tertiary referral centre in the UK. METHODS: A retrospective chart review was undertaken of patients in the UK with a confirmed diagnosis of LAL Deficiency who were managed at a LAL Deficiency tertiary referral treatment centre. Patients' pathways, treatment patterns, health outcomes and resource use were quantified over differing lengths of time for each patient enabling the NHS cost of patient management in tertiary care to be estimated. RESULTS: The study population comprised 19 patients of whom 58% were male. Mean age at the time of initial presentation was 15.5 years and the mean age at diagnosis was 18.0 years. 63%, 53% and 42% of patients had hepatomegaly, abnormal lipid storage and splenomegaly at a mean age of presentation of 17.8, 17.1 and 20.9 years, respectively. Over a period of 50 years there were a mean of 48.5 clinician visits and 3.4 hospital admissions per patient. The mean NHS cost of patient management at a LAL Deficiency tertiary referral treatment centre, spanning a period of over 50 years was L61,454 per patient. CONCLUSION: This study provides important insights into a number of aspects of the disease that are difficult to ascertain from published case reports. Additionally, it provides the best estimate available of NHS resource use and costs with which to inform policy and budgetary decisions pertaining to managing this ultra-orphan disease. PMID- 29394261 TI - Regulating BMI1 expression via miRNAs promote Mesenchymal to Epithelial Transition (MET) and sensitizes breast cancer cell to chemotherapeutic drug. AB - Polycomb group (PcG) proteinB lymphoma Mo-MLV insertion region 1 homolog (BMI1) is a transcriptional repressor that plays an important role in human carcinogenesis. MicroRNAs (miRNAs) are endogenous small non-coding RNAsthat implicate a negative regulation on gene expression. Deregulation of the expression of miRNAs has been implicated in tumorigenesis. Here, we have shown that knock-down ofBMI1increases theexpression of tumor-suppressivemiRNAs. Elevated levels of expression of miR-200a, miR-200b, miR-15a, miR-429, miR 203were observed upon knock-down of BMI1. Up-regulation of these miRNAsleads to down-regulation ofPRC1 group of proteins i.e. BMI1, RING1A, RING1B and Ub-H2A. Interestingly, overexpression of miR-200a, miR-200b and miR-15aalso produced decreased BMI1 and Ub-H2A protein expression in the CD44+ Cancer Stem Cellpopulation of MDAMB-231cells. Also,elevating the levels of BMI1 regulated miRNAspromoted Mesenchymal to Epithelial transition by regulating the expression of N-Cadherin, Vimentin, beta-Catenin, Zeb, Snail thereby resulting in decreased invasion, migration and proliferation. Here, we also report that miR-200a, miR 200b, miR-203 accretes the sensitivity of MDAMB-231 cells to the histone deacetylase inhibitor (HDACi) SAHA and miR-15a sensitized breast cancer cells to the chemotherapeutic drug cisplatin leading to apoptosis. These findings suggest that modulatingspecific miRNAs may serve as a therapeutic approach for the treatment of breast cancer. PMID- 29394262 TI - Synthesis and characterization of a magnetic adsorbent from negatively-valued iron mud for methylene blue adsorption. AB - With increasing awareness of reduction of energy and CO2 footprint, more waste is considered recyclable for generating value-added products. Here we reported the negatively-valued iron mud, a waste from groundwater treatment plant, was successfully converted into magnetic adsorbent. Comparing with the conventional calcination method under the high temperature and pressure, the synthesis of the magnetic particles (MPs) by Fe2+/Fe3+ coprecipitation was conducted at environment-friendly condition using ascorbic acid (H2A) as reduction reagent and nitric acid (or acid wastewater) as leaching solution. The MPs with major component of Fe3O4 were synthesized at the molar ratio (called ratio subsequently) of H2A to Fe3+ of iron mud >= 0.1; while amorphous ferrihydrite phase was formed at the ratio <= 0.05, which were confirmed by vibrating sample magnetometer (VSM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). With the ratio increased, the crystalline size and the crystallization degree of MPs increased, and thus the Brunauer-Emmett-Teller (BET) surface and the cation-exchange capacity (CEC) decreased. MPs-3 prepared with H2A to Fe3+ ratio of 0.1 demonstrated the highest methylene blue (MB) adsorption of 87.3 mg/g and good magnetic response. The adsorption of MB onto MPs agreed well with the non-linear Langmuir isotherm model and the pseudo-second-order model. Pilot-scale experiment showed that 99% of MB was removed by adding 10 g/L of MPs-3. After five adsorption-desorption cycles, MPs-3 still showed 62% removal efficiency for MB adsorption. When nitric acid was replaced by acid wastewater from a propylene plant, the synthesized MPs-3w showed 3.7 emu/g of saturation magnetization (Ms) and 56.7 mg/g of MB adsorption capacity, 2.8 times of the widely used commercial adsorbent of granular active carbon (GAC). The major mechanism of MPs adsorption for MB was electrostatic attraction and cation exchange. This study synthesized a magnetic adsorbent from the negatively-valued iron mud waste by using an environment-friendly coprecipitation method, which had a potential for treatment of dye wastewater. PMID- 29394263 TI - Impaired retinal microcirculation in patients with Alzheimer's disease. AB - The goal of this study was to determine the retinal blood flow rate (BFR) and blood flow velocity (BFV) of pre-capillary arterioles and post-capillary venules in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Forty patients (20 AD and 20 MCI) and 21 cognitively normal (CN) controls with a similar age range (+/- 5 yrs) were recruited. A retinal function imager (RFI) was used to measure BFRs and BFVs of arterioles and venules in the macular region. The thickness of the ganglion cell-inner plexiform layer (GCIPL) was measured using Zeiss Cirrus optical coherence tomography. Macular BFRs in AD group were 2.64 +/- 0.20 nl/s (mean +/- standard deviation) in arterioles and 2.23 +/- 0.19 nl/s in venules, which were significantly lower than in MCI and CN groups (P < 0.05). In addition, BFRs in MCI were lower than in CN in both arterioles and venules (P < 0.05). The BFV of the arterioles was 3.20 +/- 1.07 mm/s in AD patients, which was significantly lower than in CN controls (3.91 +/- 0.77 mm/s, P = 0.01). The thicknesses of GCIPL in patients with AD and MCI were significantly lower than in CN controls (P < 0.05). Neither BFV nor BFR in arterioles and venules was related to age, GCIPL thickness, mini mental state examination (MMSE) score and disease duration in patients with AD and MCI (P > 0.05). The lower BFR in both arterioles and venules in AD and MCI patients together with the loss of GCIPL were evident, indicating the impairment of the two components in the neurovascular-hemodynamic system, which may play a role in disease progression. PMID- 29394264 TI - Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. AB - Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology. PMID- 29394265 TI - Impact of 2015 earthquakes on a local hospital in Nepal: A prospective hospital based study. AB - INTRODUCTION: Natural disasters pose a great challenge to the health systems and individual health facilities. In low-resource settings, disaster preparedness systems are often limited and not been well described. Two devastating earthquakes hit Nepal within a 17-days period in 2015. This study aims to describe the burden and distribution of emergency cases to a local hospital. METHODS: This is a prospective observational study of patients presenting to a local hospital for a period of 21 days following the earthquake on April 25, 2015. Demographic and clinical information was prospectively registered for all patients in the systematic emergency registry. Systematic telephone interviews were conducted in a random sample of the patients 90 days after admission to the hospital. RESULTS: A total of 2,003 emergency patients were registered during the period. The average daily number of emergency patients during the first five days was almost five times higher (n = 150) than the pre-incident daily average (n = 35). The majority of injuries were fractures (58%), 348 (56%) in the lower extremities. A total of 345 surgical procedures were performed and the hospital treated 111 patients with severe injuries related to the earthquake (compartment syndrome, crush injury, and internal injury). Among those with follow-up interviews, over 90% reported that they had been severely affected by the earthquakes; complete house damage, living in temporary shelter, or loss of close family member. CONCLUSION: The hospital experienced a very high caseload during the first days, and the majority of patients needed orthopaedic services. The proportion of severely injured and in-hospital deaths were relatively low, probably indicating that the most severely injured did not reach the hospital in time. The experiences underline the need for robust and easily available local health services that can respond to disasters. PMID- 29394266 TI - Impact of transgenic soybean expressing Cry1Ac and Cry1F proteins on the non target arthropod community associated with soybean in Brazil. AB - Field-scale studies that examine the potential for adverse effects of Bt crop technology on non-target arthropods may supplement data from laboratory studies to support an environmental risk assessment. A three year field study was conducted in Brazil to evaluate potential for adverse effects of cultivating soybean event DAS-81419-2 that produces the Cry1Ac and Cry1F proteins. To do so, we examined the diversity and abundance of non-target arthropods (NTAs) in Bt soybean in comparison with its non-Bt near isoline, with and without conventional insecticide applications, in three Brazilian soybean producing regions. Non target arthropod abundance was surveyed using Moericke traps (yellow pan) and pitfall trapping. Total abundance (N), richness (S), Shannon-Wiener (H'), Simpson's (D) and Pielou's evenness (J) values for arthropod samples were calculated for each treatment and sampling period (soybean growth stages). A faunistic analysis was used to select the most representative NTAs which were used to describe the NTA community structure associated with soybean, and to test for effects due to the treatments effects via application of the Principal Response Curve (PRC) method. Across all years and sites, a total of 254,054 individuals from 190 taxa were collected by Moericke traps, while 29,813 individuals from 100 taxa were collected using pitfall traps. Across sites and sampling dates, the abundance and diversity measurements of representative NTAs were not significantly affected by Bt soybean as compared with non-sprayed non-Bt soybean. Similarly, community analyses and repeated measures ANOVA, when applicable, indicated that neither Bt soybean nor insecticide sprays altered the structure of the NTA communities under study. These results support the conclusion that transgenic soybean event DAS-81419-2 producing Cry1Ac and Cry1F toxins does not adversely affect the NTA community associated with soybean. PMID- 29394268 TI - Governator vs. Hunter and Aggregator: A simulation of party competition with vote seeking and office-seeking rules. AB - The policy positions parties choose are central to both attracting voters and forming coalition governments. How then should parties choose positions to best represent voters? Laver and Sergenti show that in an agent-based model with boundedly rational actors a decision rule (Aggregator) that takes the mean policy position of its supporters is the best rule to achieve high congruence between voter preferences and party positions. But this result only pertains to representation by the legislature, not representation by the government. To evaluate this we add a coalition formation procedure with boundedly rational parties to the Laver and Sergenti model of party competition. We also add two new decision rules that are sensitive to government formation outcomes rather than voter positions. We develop two simulations: a single-rule one in which parties with the same rule compete and an evolutionary simulation in which parties with different rules compete. In these simulations we analyze party behavior under a large number of different parameters that describe real-world variance in political parties' motives and party system characteristics. Our most important conclusion is that Aggregators also produce the best match between government policy and voter preferences. Moreover, even though citizens often frown upon politicians' interest in the prestige and rents that come with winning political office (office pay-offs), we find that citizens actually receive better representation by the government if politicians are motivated by these office pay offs in contrast to politicians with ideological motivations (policy pay-offs). Finally, we show that while more parties are linked to better political representation, how parties choose policy positions affects political representation as well. Overall, we conclude that to understand variation in the quality of political representation scholars should look beyond electoral systems and take into account variation in party behavior as well. PMID- 29394267 TI - Environmental enrichment normalizes hippocampal timing coding in a malformed hippocampus. AB - Neurodevelopmental insults leading to malformations of cortical development (MCD) are a common cause of psychiatric disorders, learning impairments and epilepsy. In the methylazoxymethanol (MAM) model of MCDs, animals have impairments in spatial cognition that, remarkably, are improved by post-weaning environmental enrichment (EE). To establish how EE impacts network-level mechanisms of spatial cognition, hippocampal in vivo single unit recordings were performed in freely moving animals in an open arena. We took a generalized linear modeling approach to extract fine spike timing (FST) characteristics and related these to place cell fidelity used as a surrogate of spatial cognition. We find that MAM disrupts FST and place-modulated rate coding in hippocampal CA1 and that EE improves many FST parameters towards normal. Moreover, FST parameters predict spatial coherence of neurons, suggesting that mechanisms determining altered FST are responsible for impaired cognition in MCDs. This suggests that FST parameters could represent a therapeutic target to improve cognition even in the context of a brain that develops with a structural abnormality. PMID- 29394269 TI - Tuberculous meningitis is associated with higher cerebrospinal HIV-1 viral loads compared to other HIV-1-associated meningitides. AB - To gain a better understanding of the immunopathogenesis of tuberculous meningitis (TBM) and identify potential diagnostic biomarkers that may discriminate TBM from other HIV-1-associated meningitides, we assessed HIV-1 viral load levels, drug resistance patterns in antiretroviral therapy (ART) experienced patients with persistent viremia and soluble immunological analytes in peripheral blood and cerebrospinal fluid (CSF) of HIV-1 infected patients with TBM versus other meningitides. One hundred and three matched blood and CSF samples collected from HIV-1 infected patients with TBM or other meningitides presenting at a hospital in Durban, South Africa, from January 2009 to December 2011 were studied. HIV-1 RNA and 28 soluble immunological potential biomarkers were quantified in blood plasma and CSF. Viremic samples were assessed for HIV-1 drug resistance mutations. There were 16 TBM, 46 probable TBM, 35 non-TBM patients, and six unclassifiable patients. TBM and non-TBM patients did not differ in median plasma viral load but TBM patients had significantly higher median CSF viral load than non-TBM participants (p = 0.0005). No major drug resistance mutations were detected in viremic samples. Interleukin (IL)-1beta, IL 17, platelet derived growth factor (PDGF)-BB, granulocyte colony stimulating factor (G-CSF) and cathelicidin were significantly elevated in the CNS of TBM participants compared to other patients although these associations were lost after correction for false discovery. Our data suggest that TB co-infection of the CNS is associated with enhanced localized HIV-1 viral replication but none of the evaluated soluble immunological potential biomarkers could reliably distinguish TBM from other HIV-associated meningitides. PMID- 29394270 TI - Establishment of an Arabidopsis callus system to study the interrelations of biosynthesis, degradation and accumulation of carotenoids. AB - The net amounts of carotenoids accumulating in plant tissues are determined by the rates of biosynthesis and degradation. While biosynthesis is rate-limited by the activity of PHYTOENE SYNTHASE (PSY), carotenoid losses are caused by catabolic enzymatic and non-enzymatic degradation. We established a system based on non-green Arabidopsis callus which allowed investigating major determinants for high steady-state levels of beta-carotene. Wild-type callus development was characterized by strong carotenoid degradation which was only marginally caused by the activity of carotenoid cleavage oxygenases. In contrast, carotenoid degradation occurred mostly non-enzymatically and selectively affected carotenoids in a molecule-dependent manner. Using carotenogenic pathway mutants, we found that linear carotenes such as phytoene, phytofluene and pro-lycopene resisted degradation and accumulated while beta-carotene was highly susceptible towards degradation. Moderately increased pathway activity through PSY overexpression was compensated by degradation revealing no net increase in beta carotene. However, higher pathway activities outcompeted carotenoid degradation and efficiently increased steady-state beta-carotene amounts to up to 500 MUg g-1 dry mass. Furthermore, we identified oxidative beta-carotene degradation products which correlated with pathway activities, yielding beta-apocarotenals of different chain length and various apocarotene-dialdehydes. The latter included methylglyoxal and glyoxal as putative oxidative end products suggesting a potential recovery of carotenoid-derived carbon for primary metabolic pathways. Moreover, we investigated the site of beta-carotene sequestration by co localization experiments which revealed that beta-carotene accumulated as intra plastid crystals which was confirmed by electron microscopy with carotenoid accumulating roots. The results are discussed in the context of using the non green calli carotenoid assay system for approaches targeting high steady-state beta-carotene levels prior to their application in crops. PMID- 29394271 TI - Barriers to early presentation of breast cancer among women in Soweto, South Africa. AB - PURPOSE: Reported breast cancer incidence is rising in South Africa, where some women are diagnosed late and have poor outcomes. We studied patient and provider factors associated with clinical stage at diagnosis among women diagnosed at the Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg in 2015-2016. METHODS: From face-to-face interviewer-administered questionnaires we compared self-reported socioeconomics, demographics, comorbidities, risk factors, personal and health system barriers, and from patient clinical records, clinical staging, receptor subtype, and tumor grade among 499 consecutive women newly diagnosed with advanced stage (III/IV) breast cancer versus those diagnosed early (stage 0/I/II). Logistic regression models were used to identify factors associated with advanced stage at diagnosis. RESULTS: Among the women, 243 (49%) were diagnosed at early and 256 (51%) at advanced stages. In the multiple logistic regression adjusted model, completion of high school or beyond (odds ratio (OR) 0.59, and greater breast cancer knowledge and awareness (OR 0.86) were associated with lower stage of breast cancer at presentation. Advanced stage was associated with Luminal B (OR 2.25) and triple-negative subtypes (OR 3.17) compared to luminal A, with delays >3 months from first breast symptoms to accessing the health system (OR 2.79) and with having more than 1 visit within the referral health system (OR 3.19) for 2 visits; OR 2.73 for >=3 visits). CONCLUSIONS: Limited patient education, breast cancer knowledge and awareness, and health system inefficiencies were associated with advanced stage at diagnosis. Sustained community and healthcare worker education may down-stage disease and improve cancer outcomes. PMID- 29394272 TI - Effect of dolomite and biochar addition on N2O and CO2 emissions from acidic tea field soil. AB - A laboratory study was conducted to study the effects of liming and different biochar amendments on N2O and CO2 emissions from acidic tea field soil. The first experiment was done with three different rates of N treatment; N 300 (300 kg N ha 1), N 600 (600 kg N ha-1) and N 900 (900 kg N ha-1) and four different rates of bamboo biochar amendment; 0%, 0.5%, 1% and 2% biochar. The second experiment was done with three different biochars at a rate of 2% (rice husk, sawdust, and bamboo) and a control and lime treatment (dolomite) and control at two moisture levels (50% and 90% water filled pore space (WFPS)). The results showed that dolomite and biochar amendment significantly increased soil pH. However, only biochar amendment showed a significant increase in total carbon (C), C/N (the ratio of total carbon and total nitrogen), and C/IN ratio (the ratio of total carbon and inorganic nitrogen) at the end of incubation. Reduction in soil NO3--N concentration was observed under different biochar amendments. Bamboo biochar with the rates of 0.5, 1 and 2% reduced cumulative N2O emission by 38%, 48% and 61%, respectively, compare to the control soil in experiment 1. Dolomite and biochar, either alone or combined significantly reduced cumulative N2O emission by 4.6% to 32.7% in experiment 2. Reduction in N2O production under biochar amendment was due to increases in soil pH and decreases in the magnitude of mineral-N in soil. Although, both dolomite and biochar increased cumulative CO2 emission, only biochar amendment had a significant effect. The present study suggests that application of dolomite and biochar to acidic tea field soil can mitigate N2O emissions. PMID- 29394273 TI - In vitro and in vivo antioxidant activities of inulin. AB - This study was designed to investigate the in vitro and in vivo antioxidant activities of inulin. The in vitro assays demonstrated that the antioxidant activities of inulin, including the DPPH radical scavenging activity, ABTS scavenging activity and ferric reducing power, were weak and significantly lower than those of Vitamin C (P < 0.05). The influence of dietary supplementation with inulin on the antioxidant status of laying hens was evaluated with in vivo antioxidant assays. The results indicated that inulin supplementation quadratically improved the egg production rate of the laying hens (P < 0.01). The antioxidant enzyme activities in the serum, including SOD, CAT, and GSH-Px, and the total antioxidant capacity increased quadratically as inulin levels increased (P < 0.001). The levels of MDA in the serum decreased quadratically as inulin levels increased (P < 0.001). These findings suggest that inulin has the potential to improve the antioxidant status of laying hens. PMID- 29394274 TI - XRCC3 Thr241Met and TYMS variable number tandem repeat polymorphisms are associated with time-to-metastasis in colorectal cancer. AB - BACKGROUND: Metastasis is a major cause of mortality in cancer. Identifying prognostic factors that distinguish patients who will experience metastasis in the short-term and those that will be free of metastasis in the long-term is of particular interest in current medical research. The objective of this study was to examine if select genetic polymorphisms can differentiate colorectal cancer patients based on timing and long-term risk of metastasis. METHODS: The patient cohort consisted of 402 stage I-III colorectal cancer patients with microsatellite instability (MSI)-low (MSI-L) or microsatellite stable (MSS) tumors. We applied multivariable mixture cure model, which is the proper model when there is a substantial group of patients who remain free of metastasis in the long-term, to 26 polymorphisms. Time-dependent receiver operator characteristic (ROC) curve analysis was performed to determine the change in discriminatory accuracy of the models when the significant SNPs were included. RESULTS: After adjusting for significant baseline characteristics, two polymorphisms were significantly associated with time-to-metastasis: TT and TC genotypes of the XRCC3 Thr241Met (p = 0.042) and the 3R/3R genotype of TYMS 5' UTR variable number tandem repeat (VNTR) (p = 0.009) were associated with decreased time-to-metastasis. ROC curves showed that the discriminatory accuracy of the model is increased slightly when these polymorphisms were added to the significant baseline characteristics. CONCLUSIONS: Our results indicate XRCC3 Thr241Met and TYMS 5'-UTR VNTR polymorphisms are associated with time-to metastasis, and may have potential biological roles in expediting the metastatic process. Once replicated, these associations could contribute to the development of precision medicine for colorectal cancer patients. PMID- 29394275 TI - Rapid identification of mycobacteria from positive MGIT broths of primary cultures by MALDI-TOF mass spectrometry. AB - BACKGROUND: Rapid identification of mycobacteria is important for timely treatment and the implementation of public health measures. The MGIT system ensures rapid detection of mycobacteria, but identification is usually delayed by days to weeks due to further subculture on solid medium. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS) was demonstrated to effectively identify mycobacteria isolates subcultured from solid or liquid media. Reports of identification directly from MGIT broths of both sterile and non-sterile clinical specimens, omitting the subculture step, were limited and not satisfactory before. Our identification method dramatically shortened delay from detection to identification of mycobacteria. METHODOLOGY: We assessed the performance of the Vitek MS IVD version 3.0 for direct identification of NTM and M.tuberculosis from primary MGIT cultures, and assessed two sample preparation methods. RESULTS: Direct identification of NTM from positive MGIT broths, using MALDI-TOF VITEK MS with IVD v.3.0, generated high rates of acceptable results reaching 96.4% (80/83), and up to 100% (83/83) for sample preparations including a 0.1% SDS washing step. The sensitivity of VITEK MS to identify M.tuberculosis from MGIT tubes was 58/72 (80.6%), when using immunochromatography (ICA) test as gold standard. A characteristic colony clumping, wool-like appearance was observed in 48, and all 58 (100%) were correctly identified as M.tuberculosis using MALDI-TOF. The detection rate of M.tuberculosis complex was low (10/24, 41.6%) in the 24 MGIT tubes that was polymicrobial. Our method significantly reduced both the reagent cost and turnaround time. CONCLUSIONS: Based on a simplified protocol, we showed that MALDI-TOF MS can be used for rapid identification of NTM directly from primary MGIT cultures within the routine clinical laboratory workflow. However, we recommend an initial ICA test to screen for M.tuberculosis complex, due to a low identification rate of M. tuberculosis in the presence of polymicrobial cultures using MALDI-TOF. PMID- 29394276 TI - Lactobacillus gasseri CRISPR-Cas9 characterization In Vitro reveals a flexible mode of protospacer-adjacent motif recognition. AB - While the CRISPR-Cas9 system from S. pyogenes is a powerful genome engineering tool, additional programmed nucleases would enable added flexibility in targeting space and multiplexing. Here, we characterized a CRISPR-Cas9 system from L. gasseri and found that it has modest activity in a cell-free lysate assay but no activity in mammalian cells even when altering promoter, position of tag sequences and NLS, and length of crRNA:tracrRNA. In the lysate assay we tested over 400 sequential crRNA target sequences and found that the Lga Cas9 PAM is NNGA/NDRA, different than NTAA predicted from the native bacterial host. In addition, we found multiple instances of consecutive crRNA target sites, indicating flexibility in either PAM sequence or distance from the crRNA target site. This work highlights the need for characterization of new CRISPR systems and highlights the non-triviality of porting them into eukaryotes as gene editing tools. PMID- 29394278 TI - Resolution of ranking hierarchies in directed networks. AB - Identifying hierarchies and rankings of nodes in directed graphs is fundamental in many applications such as social network analysis, biology, economics, and finance. A recently proposed method identifies the hierarchy by finding the ordered partition of nodes which minimises a score function, termed agony. This function penalises the links violating the hierarchy in a way depending on the strength of the violation. To investigate the resolution of ranking hierarchies we introduce an ensemble of random graphs, the Ranked Stochastic Block Model. We find that agony may fail to identify hierarchies when the structure is not strong enough and the size of the classes is small with respect to the whole network. We analytically characterise the resolution threshold and we show that an iterated version of agony can partly overcome this resolution limit. PMID- 29394277 TI - Transporter genes identified in landraces associated with high zinc in polished rice through panicle transcriptome for biofortification. AB - Polished rice is poor source of micronutrients, however wide genotypic variability exists for zinc uptake and remobilization and zinc content in brown and polished grains in rice. Two landraces (Chittimutyalu and Kala Jeera Joha) and one popular improved variety (BPT 5204) were grown under zinc sufficient soil and their analyses showed high zinc in straw of improved variety, but high zinc in polished rice in landraces suggesting better translocation ability of zinc into the grain in landraces. Transcriptome analyses of the panicle tissue showed 41182 novel transcripts across three samples. Out of 1011 differentially expressed exclusive transcripts by two landraces, 311 were up regulated and 534 were down regulated. Phosphate transporter-exporter (PHO), proton-coupled peptide transporters (POT) and vacuolar iron transporter (VIT) showed enhanced and significant differential expression in landraces. Out of 24 genes subjected to quantitative real time analyses for confirmation, eight genes showed significant differential expression in landraces. Through mapping, six rice microsatellite markers spanning the genomic regions of six differentially expressed genes were validated for their association with zinc in brown and polished rice using recombinant inbred lines (RIL) of BPT 5204/Chittimutyalu. Thus, this study reports repertoire of genes associated with high zinc in polished rice and a proof concept for deployment of transcriptome information for validation in mapping population and its use in marker assisted selection for biofortification of rice with zinc. PMID- 29394279 TI - Characterisation of the vasodilation effects of DHA and EPA, n-3 PUFAs (fish oils), in rat aorta and mesenteric resistance arteries. AB - BACKGROUND AND PURPOSE: Increasing evidence suggests that the omega-3 polyunsaturated acids (n-3 PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are beneficial to cardiovascular health, promoting relaxation of vascular smooth muscle cells and vasodilation. Numerous studies have attempted to study these responses, but to date there has not been a systematic characterisation of both DHA and EPA mediated vasodilation in conduit and resistance arteries. Therefore, we aimed to fully characterise the n-3 PUFA induced vasodilation pathways in rat aorta and mesenteric artery. METHODS: Wire myography was used to measure the vasomotor responses of freshly dissected rat mesenteric artery and aorta. Arteries were pre-constricted with U46619 and cumulative concentrations of either DHA or EPA (10 nM-30 MUM) were added. The mechanisms by which n-3 PUFA relaxed arteries were investigated using inhibitors of vasodilator pathways, which include: nitric oxide synthase (NOS; L-NAME), cycloxygenase (COX; indomethacin), cytochrome P450 epoxygenase (CYP450; clotrimazole); and calcium-activated potassium channels (KCa), SKCa (apamin), IKCa (TRAM-34) and BKCa (paxilline). RESULTS: Both DHA- and EPA-induced relaxations were partially inhibited following endothelium removal in rat mesenteric arteries. Similarly, in aorta EPA-induced relaxation was partially suppressed due to endothelium removal. CYP450 also contributed to EPA-induced relaxation in mesenteric artery. Inhibition of IKCa partially attenuated DHA induced relaxation in aorta and mesenteric artery along with EPA-induced relaxation in mesenteric artery. Furthermore, this inhibition of DHA- and EPA induced relaxation was increased following the additional blockade of BKCa in these arteries. CONCLUSIONS: This study provides evidence of heterogeneity in the vasodilation mechanisms of DHA and EPA in different vascular beds. Our data also demonstrates that endothelium removal has little effect on relaxations produced by either PUFA. We demonstrate IKCa and BKCa are involved in DHA-induced relaxation in rat aorta and mesenteric artery; and EPA-induced relaxation in rat mesenteric artery only. CYP450 derived metabolites of EPA may also be involved in BKCa dependent relaxation. To our knowledge this is the first study indicating the involvement of IKCa in n-3 PUFA mediated relaxation. PMID- 29394280 TI - Impact of childhood wheezing on lung function in adulthood: A meta-analysis. AB - BACKGROUND: A growing body of evidence shows that childhood wheezing may lead to recurrent or persistent symptoms in adulthood, such that persistent wheezing associated with lung function deficits often have their roots in the first few years of life. OBJECTIVES: We summarized information from several prospective cohort studies following children with or without wheezing into adulthood, to estimate the effect of childhood wheezing on adulthood lung function. METHODS: Medical literatures were searched in the Medline, PubMed, ScienceDirect, Web of Science and Embase databases up to October 31, 2016. The adulthood lung function was selected as primary outcome, and chronic obstructive pulmonary disease (COPD) prevalence was selected as secondary outcome. The meta-analysis was performed with the Stata Version 14.0. A random-effects model was applied to estimate standardized mean difference (SMD) of lung function, and relative risk (RR) of COPD. RESULTS: Six articles enrolling 1141 and 1005 children with and without wheezing, respectively. Meta-analysis showed that childhood wheezing decreased adulthood lung function as compared with no-wheezing subjects (SMD = -0.365, 95% confidence interval (CI): -0.569~-0.161, P = 0.000). Subgroup analyses indicated that childhood atopic wheezing reduced adulthood FEV1/FVC and FEV1%pred when compared with no-wheezing subjects. In addition, childhood atopic wheezing was significantly associated with COPD prevalence (RR = 5.307, 95% CI:1.033~27.271, P = 0.046). CONCLUSIONS: Our meta-analysis suggests that childhood wheezing may induce ongoing declined lung function that extends into adult life, as well as an increased risk of COPD prevalence when accompanied with atopy. PMID- 29394281 TI - Comparative transcriptomics reveals CrebA as a novel regulator of infection tolerance in D. melanogaster. AB - Host responses to infection encompass many processes in addition to activation of the immune system, including metabolic adaptations, stress responses, tissue repair, and other reactions. The response to bacterial infection in Drosophila melanogaster has been classically described in studies that focused on the immune response elicited by a small set of largely avirulent microbes. Thus, we have surprisingly limited knowledge of responses to infection that are outside the canonical immune response, of how the response to pathogenic infection differs from that to avirulent bacteria, or even of how generic the response to various microbes is and what regulates that core response. In this study, we addressed these questions by profiling the D. melanogaster transcriptomic response to 10 bacteria that span the spectrum of virulence. We found that each bacterium triggers a unique transcriptional response, with distinct genes making up to one third of the response elicited by highly virulent bacteria. We also identified a core set of 252 genes that are differentially expressed in response to the majority of bacteria tested. Among these, we determined that the transcription factor CrebA is a novel regulator of infection tolerance. Knock-down of CrebA significantly increased mortality from microbial infection without any concomitant change in bacterial number. Upon infection, CrebA is upregulated by both the Toll and Imd pathways in the fat body, where it is required to induce the expression of secretory pathway genes. Loss of CrebA during infection triggered endoplasmic reticulum (ER) stress and activated the unfolded protein response (UPR), which contributed to infection-induced mortality. Altogether, our study reveals essential features of the response to bacterial infection and elucidates the function of a novel regulator of infection tolerance. PMID- 29394282 TI - Metabolomic profiling for the identification of potential biomarkers involved in a laboratory azole resistance in Candida albicans. AB - Candida albicans, one of the most common fungal pathogens, is responsible for several yeast infections in human hosts, being resistant to classically used antifungal drugs, such as azole drugs. Multifactorial and multistep alterations are involved in the azole resistance in Candida albicans. In this study, a FCZ resistant C. albicans strain was obtained by serial cultures of a FCZ-susceptible C. albicans strain in incrementally increasing concentrations of FCZ. We performed an integrated profile of different classes of molecules related to azole resistance in C. albicans by combining several mass-spectrometry based methodologies. The comparative metabolomic study was performed with the sensitive and resistant strains of C.albicans to identify metabolites altered during the development of resistance to fluconazole, while the intervention strains and non intervention strains of C.albicans to identify metabolites altered involved in cross-resistant to azole drugs. Our analysis of the different metabolites identified molecules mainly involved in metabolic processes such as amino acid metabolism, tricarboxylic acid cycle and phospholipid metabolism. We also compared the phospholipid composition of each group, revealing that the relative content of phospholipids significantly changed during the development of resistance to azole drugs. According with these results, we hypothesized that the metabolism shift might contribute to azole drugs resistance in C.albicans from multifactorial alterations. Our result paves the way to understand processes underlying the resistance to azole drugs in C. albicans, providing the basis for developing new antifungal drugs. PMID- 29394283 TI - Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock. AB - In severe trauma and hemorrhage the early and empiric use of fresh frozen plasma (FFP) is associated with decreased morbidity and mortality. However, utilization of FFP comes with the significant burden of shipping and storage of frozen blood products. Dried or lyophilized plasma (LP) can be stored at room temperature, transported easily, reconstituted rapidly with ready availability in remote and austere environments. We have previously demonstrated that FFP mitigates the endothelial injury that ensues after hemorrhagic shock (HS). In the current study, we sought to determine whether LP has similar properties to FFP in its ability to modulate endothelial dysfunction in vitro and in vivo. Single donor LP was compared to single donor FFP using the following measures of endothelial cell (EC) function in vitro: permeability and transendothelial monolayer resistance; adherens junction preservation; and leukocyte-EC adhesion. In vivo, using a model of murine HS, LP and FFP were compared in measures of HS- induced pulmonary vascular inflammation and edema. Both in vitro and in vivo in all measures of EC function, LP demonstrated similar effects to FFP. Both FFP and LP similarly reduced EC permeability, increased transendothelial resistance, decreased leukocyte-EC binding and persevered adherens junctions. In vivo, LP and FFP both comparably reduced pulmonary injury, inflammation and vascular leak. Both FFP and LP have similar potent protective effects on the vascular endothelium in vitro and in lung function in vivo following hemorrhagic shock. These data support the further development of LP as an effective plasma product for human use after trauma and hemorrhagic shock. PMID- 29394284 TI - The role of the type VI secretion system vgrG gene in the virulence and antimicrobial resistance of Acinetobacter baumannii ATCC 19606. AB - The Type VI Secretion System (T6SS) is an important virulence system that exists in many bacterial pathogens, and has emerged as a potent mediator of pathogenicity in Acinetobacter baumannii. In this study, we inactivated one of the T6SS components vgrG (valine-glycine repeat G) gene in A. baumannii ATCC 19606 and constructed a complementation strain. BEAS-2b human alveolar epithelial cells was adopted to assess bacterial adhesion, and wild female BALB/c mice were used for in vivo experiments to assess the bacterial killing ability to host. Upon deletion of the vgrG gene, increased antimicrobial resistance to ampicillin/sulbactam, but reduced resistance to chloramphenicol were observed. The vgrG mutant strain showed lower growth rate, reduced eukaryotic cell adherence and impaired lethality in mice. However, the vgrG mutant strain is not implicated in biofilm formation. Our study suggests that the Type VI Secretion System core component VgrG contributes to both virulence and antimicrobial resistance in A. baumannii ATCC 19606. PMID- 29394285 TI - Fatty acid-binding protein 4 predicts gestational hypertension and preeclampsia in women with gestational diabetes mellitus. AB - OBJECTIVE: Fatty acid-binding protein 4 (FABP4) has been proposed to be a potential predictive factor of gestational hypertension or preeclampsia (GH/PE) because of its integrating metabolic and inflammatory responses. Women with gestational diabetes mellitus (GDM) are more likely to develop both GH/PE, than the normal population. The aim of our study was to examine the relationship between plasma FABP4 in the second trimester of pregnancy and the risk of GH/PE in women with GDM. METHODS: This was a nested case-control study conducted within a large on-going prospective cohort study conducted at Peking University First Hospital. A total of 1344 women, who were diagnosed with GDM, according to a 75 g oral glucose tolerance test, participated in the GDM One-Day Clinic at Peking University First Hospital from February 24, 2016 to February 9, 2017. Of the 748 GDM women who agreed to the blood sample collection, 637 were followed until their delivery. The cases included GDM patients who developed gestational hypertension or preeclampsia (GDM-GH/PE group, n = 41). Another 41 matched GDM women without major complications were selected as the control group (GDM group). RESULTS: The incidence of GH/PE was 6.44% and 3.30% for preeclampsia. The level of the second trimester plasma FABP4 in the GDM-GH/PE group was significantly higher than the GDM group (17.53+/-11.35 vs. 12.79+/-6.04 ng/ml, P = 0.020). The AUC ROC for the second trimester plasma FABP4 predicted GH/PE in the GDM patients alone was 0.647 (95%CI 0.529-0.766). Multivariate analysis showed that the elevated second trimester FABP4 level was independently associated with GH/PE in the GDM patients (OR 1.136 [95% CI 1.003-1.286], P = 0.045). CONCLUSIONS: Increased second trimester plasma FABP4 independently predicted GH/PE in GDM patients. PMID- 29394287 TI - Correction: Rural Household Preferences for Active Participation in "Payment for Ecosystem Service" Programs: A Case in the Miyun Reservoir Catchment, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0169483.]. PMID- 29394286 TI - Circulating levels of carbamylated protein and neutrophil extracellular traps are associated with periodontitis severity in patients with rheumatoid arthritis: A pilot case-control study. AB - OBJECTIVES: An interrelationship between rheumatoid arthritis (RA) and periodontitis has been suggested due to their common pathogenic mechanisms. Protein carbamylation and neutrophil extracellular traps (NETs) formation have been shown to be related to autoimmune conditions, including RA, but their association with periodontitis has not been elucidated. Therefore, we assessed whether or not circulating levels of carbamylated protein (CarP) and NETs are associated with periodontitis severity and influenced by periodontal treatment. METHODS: We conducted a retrospective case-control study that included 40 patients with RA and periodontitis, 30 patients with periodontitis, and 43 systemically and periodontally healthy controls to assess the circulating levels of CarP and NETs and rheumatologic and periodontal conditions. The same assessments were also performed in 22 patients with RA and periodontitis after 2 months of periodontal treatment, including oral hygiene instruction and full mouth supragingival scaling. RESULTS: Patients with RA and periodontitis showed significantly higher serum levels of CarP and NETs than the control group (P = 0.04 and P < 0.001, respectively). The serum levels of CarP and NETs were significantly correlated positively with the mean values of probing depth (P = 0.01 and P = 0.007, respectively) and clinical attachment level (P = 0.007 and P = 0.001, respectively) in the 40 patients with RA and periodontitis. Multiple logistic regression analyses also revealed significantly positive associations between the serum levels of CarP and NETs and moderate to severe periodontitis (P = 0.03 and P = 0.001, respectively). Furthermore, periodontal treatment significantly decreased the serum levels of CarP and NETs in patients with RA and periodontitis (P = 0.03 and P = 0.02). CONCLUSION: The circulating levels of CarP and NETs are associated with periodontitis severity and influenced by periodontal treatment in patients with RA. PMID- 29394288 TI - High risk exposure to HIV among sexually active individuals who tested negative on rapid HIV Tests in the Tshwane District of South Africa-The importance of behavioural prevention measures. AB - OBJECTIVE: To assess the prevalence of HIV risk behaviour among sexually active HIV sero-negative individuals in the Tshwane district of South Africa (SA). METHODS: Demographic and HIV risk behaviour data were collected on a questionnaire from participants of a cross-sectional study that screened for early HIV infection using pooled nucleic acid amplification testing (NAAT). The study enrolled individuals who tested negative on rapid HIV tests performed at five HIV counseling and testing (HCT) clinics, which included four antenatal clinics and one general HCT clinic. RESULTS: The study enrolled 9547 predominantly black participants (96.6%) with a median age of 27 years (interquartile range [IQR]: 23-31). There were 1661 non-pregnant and 7886 pregnant participants largely enrolled from the general and antenatal HCT clinics, respectively. NAAT detected HIV infection in 61 participants (0.6%; 95% confidence interval [CI]: 0.4-0.8) in the whole study. A high proportion of study participants, 62.8% and 63.0%, were unaware of their partner's HIV status; and also had high prevalence, 88.5% and 99.5%, of recent unprotected sex in the general and pregnant population, respectively. Consistent use of condoms was associated with protection against HIV infection in the general population. Trends of higher odds for HIV infection were observed with most demographic and HIV risk factors at univariate analysis, however, multivariate analysis did not show statistical significance for almost all these factors. A significantly lower risk of HIV infection was observed in circumcised men (p <0.001). CONCLUSIONS: These data show that a large segment of sexually active people in the Tshwane district of SA have high risk exposure to HIV. The detection of newly diagnosed HIV infections in all study clinics reflects a wide distribution of individuals who are capable of sustaining HIV transmission in the setting where HIV risk behaviour is highly prevalent. A questionnaire that captures HIV risk behaviour would be useful during HIV counselling and testing to ensure that there is a systematic way of identifying HIV risk factors and that counselling is optimised for each individual. HIV risk behaviour surveillance could be used to inform relevant HIV prevention interventions that could be implemented at a community or population level. PMID- 29394289 TI - Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2. AB - Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells. PMID- 29394290 TI - Impact of the 24-h ultramarathon race on homocysteine, oxidized low-density lipoprotein, and paraoxonase 1 levels in professional runners. AB - The impact of the 24-h ultramarathon race on homocysteine (Hcy) and oxidized low density lipoprotein (oxLDL) levels, two well-recognized cardiovascular risk factors, has not been deeply investigated. Similarly, no information exists on paraoxonase 1 (PON1), an antioxidant enzyme associated with high-density lipoproteins, which may detoxify oxLDL and Hcy-thiolactone, hence preventing their proatherogenic action. Taking this into account, a competitive 24-h ultramarathon race was organized in Reggio-Emilia (Italy) recruiting professional runners (n = 14) from the Italian Ultramarathon and Trail Association. Blood samples were collected from each participant before, during (14 h), and immediately after (24 h) the competition, thus to monitor the serum changes in Hcy, oxLDL, and PON1 levels, as well as other oxidative stress-related parameters, namely reactive oxygen metabolites (ROM) and total antioxidant capacity (PAT). As a result, a significant PON1 increase was recorded after 14 h of racing that persisted until the end of the performance. The same trend was observed for PAT values, which positively correlated to PON1 levels (R = 0.643, P<0.001). Hcy, oxLDL, and ROM remained almost unchanged throughout the competition. In conclusion, the present study suggested a protective role of PON1 in sustaining the antioxidant defense system and contrasting lipoprotein oxidative modifications over the 24-h race, and did not specifically evidence either Hcy or oxLDL accumulation in such challenging sporting events. PMID- 29394291 TI - Choroidal thickness measured using swept-source optical coherence tomography is reduced in patients with type 2 diabetes. AB - OBJECTIVE: To compare choroidal thickness between patients with type 2 diabetes (T2D) and healthy controls measured using swept-source optical coherence tomography (SS-OCT). METHODS: The sample comprised 157 eyes of 94 T2D patients, 48 eyes of which had diabetic macular edema (DME), and 71 normal eyes of 38 healthy patients. Subfoveal (SF) choroidal thickness, and choroidal thickness at 500-MUm intervals up to 2500 MUm nasal and temporal from the fovea were measured using the SS-OCT. Choroidal thicknesses were compared between groups using Student's t-test. Additionally, Pearson correlations were calculated between diabetes duration, glycosylated hemoglobin (HbA1c) levels, and choroidal thickness. RESULTS: Mean diabetes duration was 16.6+/-9.5 years, while mean glycosylated hemoglobin was 7.7+/-1.3%. Overall, the choroid was significantly thinner in T2D patients. Individuals with DME had reduced choroidal thickness in all measurements, except at 2000 and 2500-MUm nasal positions, compared to healthy controls. There was a moderate correlation between choroidal thickness and HbA1c levels in DME patients (SF: r = 0.342; p = 0.017). Diabetes duration did not correlate significantly with choroidal thickness. CONCLUSION: SS-OCT measurements revealed that the choroid was significantly thinner in T2D patients, moderate non-proliferative diabetic retinopathy patients, and DME patients than in healthy individuals. Further studies are needed to clarify the effect of diabetes on this layer and the relationship between choroidal thickness and DME. PMID- 29394292 TI - Correction: Gbm.auto: A software tool to simplify spatial modelling and Marine Protected Area planning. AB - [This corrects the article DOI: 10.1371/journal.pone.0188955.]. PMID- 29394293 TI - Crystal structure and enzymatic properties of chalcone isomerase from the Antarctic vascular plant Deschampsia antarctica Desv. AB - Chalcone isomerase (CHI) is an important enzyme for flavonoid biosynthesis that catalyzes the intramolecular cyclization of chalcones into (S)-flavanones. CHIs have been classified into two types based on their substrate specificity. Type I CHIs use naringenin chalcone as a substrate and are found in most of plants besides legumes, whereas type II CHIs in leguminous plants can also utilize isoliquiritigenin. In this study, we found that the CHI from the Antarctic plant Deschampsia antarctica (DaCHI1) is of type I based on sequence homology but can use type II CHI substrates. To clarify the enzymatic mechanism of DaCHI1 at the molecular level, the crystal structures of unliganded DaCHI1 and isoliquiritigenin-bound DaCHI1 were determined at 2.7 and 2.1 A resolutions, respectively. The structures revealed that isoliquiritigenin binds to the active site of DaCHI1 and induces conformational changes. Additionally, the activity assay showed that while DaCHI1 exhibits substrate preference for naringenin chalcone, it can also utilize isoliquiritigenin although the catalytic activity was relatively low. Based on these results, we propose that DaCHI1 uses various substrates to produce antioxidant flavonoids as an adaptation to oxidative stresses associated with harsh environmental conditions. PMID- 29394294 TI - A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway. AB - Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and gamma-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC 7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs. PMID- 29394296 TI - Correction: Real-time computed tomography fluoroscopy-guided solitary lung tumor model in a rabbit. AB - [This corrects the article DOI: 10.1371/journal.pone.0179220.]. PMID- 29394297 TI - A novel selection method of seismic attributes based on gray relational degree and support vector machine. AB - The selection of seismic attributes is a key process in reservoir prediction because the prediction accuracy relies on the reliability and credibility of the seismic attributes. However, effective selection method for useful seismic attributes is still a challenge. This paper presents a novel selection method of seismic attributes for reservoir prediction based on the gray relational degree (GRD) and support vector machine (SVM). The proposed method has a two hierarchical structure. In the first hierarchy, the primary selection of seismic attributes is achieved by calculating the GRD between seismic attributes and reservoir parameters, and the GRD between the seismic attributes. The principle of the primary selection is that these seismic attributes with higher GRD to the reservoir parameters will have smaller GRD between themselves as compared to those with lower GRD to the reservoir parameters. Then the SVM is employed in the second hierarchy to perform an interactive error verification using training samples for the purpose of determining the final seismic attributes. A real-world case study was conducted to evaluate the proposed GRD-SVM method. Reliable seismic attributes were selected to predict the coalbed methane (CBM) content in southern Qinshui basin, China. In the analysis, the instantaneous amplitude, instantaneous bandwidth, instantaneous frequency, and minimum negative curvature were selected, and the predicted CBM content was fundamentally consistent with the measured CBM content. This real-world case study demonstrates that the proposed method is able to effectively select seismic attributes, and improve the prediction accuracy. Thus, the proposed GRD-SVM method can be used for the selection of seismic attributes in practice. PMID- 29394298 TI - Preparing from the Outside Looking In for Safely Transitioning Pediatric Inpatients to Home. PMID- 29394295 TI - Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments. AB - Pseudomonas aeruginosa causes devastating infections in immunocompromised individuals. Once established, P. aeruginosa infections become incredibly difficult to treat due to the development of antibiotic tolerant, aggregated communities known as biofilms. A hyper-biofilm forming clinical variant of P. aeruginosa, known as a rugose small-colony variant (RSCV), is frequently isolated from chronic infections and is correlated with poor clinical outcome. The development of these mutants during infection suggests a selective advantage for this phenotype, but it remains unclear how this phenotype promotes persistence. While prior studies suggest RSCVs could survive by evading the host immune response, our study reveals infection with the RSCV, PAO1DeltawspF, stimulated an extensive inflammatory response that caused significant damage to the surrounding host tissue. In both a chronic wound model and acute pulmonary model of infection, we observed increased bacterial burden, host tissue damage, and a robust neutrophil response during RSCV infection. Given the essential role of neutrophils in P. aeruginosa-mediated disease, we investigated the impact of the RSCV phenotype on neutrophil function. The RSCV phenotype promoted phagocytic evasion and stimulated neutrophil reactive oxygen species (ROS) production. We also demonstrate that bacterial aggregation and TLR-mediated pro-inflammatory cytokine production contribute to the immune response to RSCVs. Additionally, RSCVs exhibited enhanced tolerance to neutrophil-produced antimicrobials including H2O2 and the antimicrobial peptide LL-37. Collectively, these data indicate RSCVs elicit a robust but ineffective neutrophil response that causes significant host tissue damage. This study provides new insight on RSCV persistence, and indicates this variant may have a critical role in the recurring tissue damage often associated with chronic infections. PMID- 29394299 TI - Accuracy Comparisons between Manual and Automated Respiratory Rate for Detecting Clinical Deterioration in Ward Patients. PMID- 29394300 TI - Lean-Based Redesign of Multidisciplinary Rounds on General Medicine Service. AB - BACKGROUND: Multidisciplinary rounds (MDR) facilitate timely communication amongst the care team and with patients. We used Lean techniques to redesign MDR on the teaching general medicine service. OBJECTIVE: To examine if our Lean-based new model of MDR was associated with change in the primary outcome of length of stay (LOS) and secondary outcomes of discharges before noon, documentation of estimated discharge date (EDD), and patient satisfaction. DESIGN, SETTING, PATIENTS: This is a pre-post study. The preperiod (in which the old model of MDR was followed) comprised 4000 patients discharged between September 1, 2013, and October 22, 2014. The postperiod (in which the new model of MDR was followed) comprised 2085 patients between October 23, 2014, and April 30, 2015. INTERVENTION: Lean-based redesign of MDR. MEASUREMENTS: LOS, discharges before noon, EDD, and patient satisfaction. RESULTS: There was no change in the mean LOS. Discharges before noon increased from 6.9% to 10.7% (P < .001). Recording of EDD increased from 31.4% to 41.3% (P < .001). There was no change in patient satisfaction. CONCLUSIONS: Lean-based redesign of MDR was associated with an increase in discharges before noon and in recording of EDD. PMID- 29394301 TI - Issues Identified by Postdischarge Contact after Pediatric Hospitalization: A Multisite Study. AB - BACKGROUND: Many hospitals are considering contacting hospitalized patients soon after discharge to help with issues that arise. OBJECTIVE: To (1) describe the prevalence of contactidentified postdischarge issues (PDI) and (2) assess characteristics of children with the highest likelihood of having a PDI. DESIGN, SETTING, PATIENTS: A retrospective analysis of hospital-initiated follow-up contact for 12,986 children discharged from January 2012 to July 2015 from 4 US children's hospitals. Contact was made within 14 days of discharge by hospital staff via telephone call, text message, or e-mail. Standardized questions were asked about issues with medications, appointments, and other PDIs. For each hospital, patient characteristics were compared with the likelihood of PDI by using logistic regression. RESULTS: Median (interquartile range) age of children at admission was 4.0 years (0-11); 59.9% were nonHispanic white, and 51.0% used Medicaid. The most common reasons for admission were bronchiolitis (6.3%), pneumonia (6.2%), asthma (5.1%), and seizure (4.9%). Twenty-five percent of hospitalized children (n=3263) reported a PDI at contact (hospital range: 16.0% 62.8%). Most (76.3%) PDIs were related to follow-up appointments (eg, difficulty getting one); 20.8% of PDIs were related to medications (eg, problems filling a prescription). Patient characteristics associated with the likelihood of PDI varied across hospitals. Older age (age 10-18 years vs <1 year) was significantly (P<.001) associated with an increased likelihood of PDI in 3 of 4 hospitals. CONCLUSIONS: PDIs were identified often through hospital-initiated follow-up contact. Most PDIs were related to appointments. Hospitals caring for children may find this information useful as they strive to optimize their processes for follow-up contact after discharge. PMID- 29394302 TI - Hydrogen detachment driven by a repulsive 1pisigma* state - an electron localization function study of 3-amino-1,2,4-triazole. AB - Electron localization function analysis reveals the details of a charge induced hydrogen detachment mechanism of 3-amino-1,2,4-triazole, identified recently to be responsible for phototautomerization of the molecule. In this process vertical excitation to the 1pisigma* state is followed by the barrier-less migration of a H atom along the N-H bond toward the conical intersection with the S0 ground state. The most striking feature revealed for the 1pisigma* state is partial ejection of sigma* electrons outside the molecule, even beyond the NH group, at the Franck-Condon point. Further gradual spatial localization of the electron around the proton moving along the N-H stretching coordinate gives a plausible explanation for the repulsive character of the 1pisigma* potential energy surface with the proton wading through the region of space where some negative charge is accumulated ('a virtual acceptor'), dragging some electron density. This mechanism resembles the one postulated for the hydrogen transfer from a donor molecule (D-H) to an acceptor one (A) in a class of vertically excited molecules with a preexisting inter- or intramolecular D-HA motif, even though the acceptor molecule is absent. The present analysis demonstrates also that the bond evolution and changes in the electron density along the excited state reaction path can be effectively studied with the use of an electron localization function. PMID- 29394303 TI - Increasing stomatal conductance in response to rising atmospheric CO2. AB - Background and Aims: Studies have indicated that plant stomatal conductance (gs) decreases in response to elevated atmospheric CO2, a phenomenon of significance for the global hydrological cycle. However, gs increases across certain CO2 ranges have been predicted by optimization models. The aim of this work was to demonstrate that under certain environmental conditions, gs can increase in response to elevated CO2. Methods: Using (1) an extensive, up-to-date synthesis of gs responses in free air CO2 enrichment (FACE)experiments, (2) in situ measurements across four biomes showing dynamic gs responses to a CO2 rise of ~50 ppm (characterizing the change in this greenhouse gas over the past three decades) and (3) a photosynthesis-stomatal conductance model, it is demonstrated that gs can in some cases increase in response to increasing atmospheric CO2. Key Results: Field observations are corroborated by an extensive synthesis of gs responses in FACE experiments showing that 11.8 % of gs responses under experimentally elevated CO2 are positive. They are further supported by a strong data-model fit (r2 = 0.607) using a stomatal optimization model applied to the field gs dataset. A parameter space identified in the Farquhar-Ball-Berry photosynthesis-stomatal conductance model confirms field observations of increasing gs under elevated CO2 in hot dry conditions. Contrary to the general assumption, positive gs responses to elevated CO2, although relatively rare, are a feature of woody taxa adapted to warm, low-humidity conditions, and this response is also demonstrated in global simulations using the Community Land Model (CLM4). Conclusions: The results contradict the over-simplistic notion that global vegetation always responds with decreasing gs to elevated CO2, a finding that has important implications for predicting future vegetation feedbacks on the hydrological cycle at the regional level. PMID- 29394304 TI - The Brazilian Longitudinal Study of Aging (ELSI-Brazil): Objectives and Design. AB - Brazil is experiencing among the world's fastest demographic aging worldwide. This demographic transition is occurring in a context of few resources and great social inequalities. The Brazilian Longitudinal Study of Aging (ELSI-Brazil) is a nationally representative study of 9,412 people aged 50 years or older, residing in 70 municipalities across the 5 Brazilian regions. ELSI-Brazil allows investigations of the aging process, its health, psychosocial and economic determinants, and societal consequences. The baseline examination (2015-2016) included detailed household and individual interviews and physical measurements (blood pressure, anthropometry, grip strength, and timed walk and balance tests). Blood tests and sample storage were performed in a subsample of study participants. Subsequent waves are planned for every 3 years. The study adopts a conceptual framework common to other large-scale longitudinal studies of aging in the world, such as the Health and Retirement Study, allowing cross-national comparisons. The goal of ELSI-Brazil is not only to build an understanding of aging in a large, Western, middle-income country in a rapid demographic transition but also to provide scientific data to support and study policy changes that may affect older adults. We describe the methodology of the study and some descriptive results of the baseline survey. PMID- 29394305 TI - Hemoglobin A1c Level and Cardiovascular Disease Incidence in Persons With Type 1 Diabetes: An Application of Joint Modeling of Longitudinal and Time-to-Event Data in the Pittsburgh Epidemiology of Diabetes Complications Study. AB - Type 1 diabetes (T1D) is associated with increased risk of cardiovascular disease (CVD), but hyperglycemia (measured by hemoglobin A1c (HbA1c) level), which characterizes T1D, has itself been an inconsistent predictor of CVD incidence. However, only baseline HbA1c or a summary measure (e.g., mean level over follow up) is usually analyzed. Joint models allow simultaneous modeling of repeatedly measured longitudinal covariates, using random effects, and time-to-event data. We evaluated data from the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing prospective cohort study of childhood-onset T1D that has followed participants since 1986-1988 and has repeatedly found little association between baseline HbA1c or mean follow-up HbA1c and coronary artery disease incidence. Of 561 participants without CVD at baseline, 263 (46.9%) developed CVD over a period of 25 years (1986-2014). In joint models, each 1% unit increase in HbA1c trajectory was associated with a 1.26-fold increased risk of CVD (95% confidence interval: 1.07, 1.45), after adjustment for baseline levels of other CVD risk factors, and a 1.13-fold increased risk (95% confidence interval: 0.99, 1.32) after adjustment for updated mean levels of other CVD risk factors. These findings, which support the need for good glycemic control to prevent CVD in persons with T1D, underscore the importance of utilizing methods incorporating within-subject variation over time when analyzing and interpreting longitudinal cohort study data. PMID- 29394306 TI - Therapy for Spinal Muscular Atrophy. PMID- 29394307 TI - Variation of Caregiver Health and Mortality Risks by Age: A Census-Based Record Linkage Study. AB - Due to the focus of studies about caregiving responsibilities on older caregivers, there has been a deficit of research on young caregivers. We aimed to investigate the association between caregiving and health/mortality risk in young caregivers when compared with their noncaregiving peers and older caregivers. A census-based record linkage was implemented, linking all residents enumerated in the 2011 Northern Ireland Census with subsequently registered deaths data, until the end of 2015. Among those aged 5-24 years at the 2011 Census, approximately 4.5% (19,621) of the cohort reported that they were caregivers. The presence of a chronic physical condition (such as mobility difficulties) and/or mental health condition was measured through the Census; all-cause mortality was assessed by official mortality records. Young caregivers were less likely than their noncaregiving peers to report chronic mobility problems (adjusted odds ratio (OR) = 0.84, 95% confidence interval (CI): 0.73, 0.96) but more likely to report chronic poor mental health (adjusted OR = 1.44, 95% CI: 1.31, 1.58). They also differed from older caregivers (P < 0.001) and were at significantly higher mortality risk than their peers (adjusted hazard ratio = 1.54, 95% CI: 1.10, 2.14). A dose-response relationship between hours devoted to caregiving duties and mortality risk was evident. We found that young caregivers were at significantly increased risk of poor health outcomes. PMID- 29394309 TI - Oral Contraceptive Use and Risks of Cancer in the NIH-AARP Diet and Health Study. AB - Although use of oral contraceptives (OC) is common, their influence on carcinogenesis is not fully understood. We used Cox proportional hazards models to examine OC use (never/<1 year (reference), 1-4, 5-9, 10+ years) and development of incident cancers across body sites within the same base population: women in the prospective NIH-AARP Diet and Health Study (enrolled 1995-1996, followed until 2011). Adjustment for confounding varied by outcome; all models accounted for age, race, body mass index, and smoking status and included >=100,000 women. Any OC use conferred a 3% reduction in the risk for any cancer (hazard ratio = 0.97, 95% confidence interval: 0.95, 0.99). Expected risk reductions that strengthened with duration of use were identified for ovarian and endometrial cancers and were suggested for kidney cancer (P-trends < 0.05). We noted reduced risk for non-Hodgkin lymphoma (hazard ratio = 0.79, confidence interval: 0.64, 0.97) with 10+ years of use. We observed a 37% reduced risk for bladder cancer and 46% increased risk for pancreatic cancer among long-term users who were <=60 at baseline. OC use did not influence risks for most other cancers evaluated. Given the high prevalence of use and changing formulations, future studies are warranted to fully understand the chemopreventive effects of these medications. PMID- 29394308 TI - Root hair abundance impacts cadmium accumulation in Arabidopsis thaliana shoots. AB - Background and Aims: Root hairs increase the contact area of roots with soil and thereby enhance the capacity for solute uptake. The strict hair/non-hair pattern of Arabidopsis thaliana can change with nutrient deficiency or exposure to toxic elements, which modify root hair density. The effects of root hair density on cadmium (Cd) accumulation in shoots of arabidopsis genotypes with altered root hair development and patterning were studied. Methods: Arabidopsis mutants that are unable to develop root hairs (rhd6-1 and cpc/try) or produce hairy roots (wer/myb23) were compared with the ecotype Columbia (Col-0). Plants were cultivated on nutrient agar for 2 weeks with or without Cd. Cadmium was applied as Cd(NO3)2 at two concentrations, 10 and 100 um. Shoot biomass, root characteristics (primary root length, lateral root number, lateral root length and root hair density) and Cd concentrations in shoots were assessed. Anatomical features (suberization of the endodermis and development of the xylem) that might influence Cd uptake and translocation were also examined. Key Results: Cadmium inhibited plant growth and reduced root length and the number of lateral roots and root hairs per plant. Suberin lamellae in the root endodermis and xylem differentiation developed closer to the root apex in plants exposed to 100 um Cd. The latter effect was genotype dependent. Shoot Cd accumulation was correlated with root hair abundance when plants were grown in the presence of 10 um Cd, but not when grown in the presence of 100 um Cd, in which treatment the development of suberin lamellae closer to the root tip appeared to restrict Cd accumulation in shoots. Conclusions: Root hair density can have a large effect on Cd accumulation in shoots, suggesting that the symplasmic pathway might play a significant role in the uptake and accumulation of this toxic element. PMID- 29394310 TI - The Objective Eye: An Oxymoron? PMID- 29394311 TI - Scroll Reconstruction: Fine Tuning of the Interface Between Middle and Lower Thirds in Rhinoplasty. AB - Background: The junction between upper and lower lateral cartilages, known as "the scroll area," is an important determinant of the spatial relationship between the middle and lower nasal thirds. Objectives: We offer a graduated and reproducible surgical technique of scroll area management that takes into consideration anatomic, functional, and aesthetic relationships. Methods: This study was a retrospective review of the recorded intraoperative information to investigate the frequency of the use of scroll reconstruction techniques and perioperative parameters that relate to unintended component alterations in the scroll area. A total of 364 consecutive primary open approach rhinoplasty cases performed by the first author (O.B.) between July 2011 and September 2015 were included in the study. Results: Of the 364 cases who underwent primary open approach rhinoplasty, 329 received some form of scroll reconstruction. Scroll reconstruction was performed in all deviated cases, and 88% of straight noses. The most common technique for scroll reconstruction was overlapping repair (88.3%). As expected, both alar rim and alar crease asymmetries were very frequent in the deviated nose group, 89.4% and 75% respectively. Alar rim and alar crease asymmetries were frequent enough in the straight nose group to deserve special attention, 14.2% and 10.4% respectively. Conclusions: With careful attention to anatomic details of the scroll area, nasal tip refinements can be performed with predictable safety and accuracy. Our approach is a graduated, reproducible, and individualized way of scroll area management that aims to create the ideal cartilage configuration while preventing unintended component alterations. Level of Evidence 4: PMID- 29394312 TI - Added Healthcare Charges Conferred by Smoking in Outpatient Plastic Surgery. AB - Background: A history of smoking confers additional risk of complications following plastic surgical procedures, which may require hospital-based care to address. Objectives: To determine if patients with a smoking history experience higher rates of complications leading to higher hospital-based care utilization, and therefore greater healthcare charges, after common outpatient plastic surgeries. Methods: Using ambulatory surgery data from California, Florida, Nebraska, and New York, we identified adult patients who underwent common facial, breast, or abdominal contouring procedures from January 2009 to November 2013. Our primary outcomes were hospital-based, acute care (hospital admissions and emergency department visits), serious adverse events, and cumulative healthcare charges within 30 days of discharge. Multivariable regression models were used to compare outcomes between patients with and without a smoking history. Results: The final sample included 214,761 patients, of which 10,426 (4.9%) had a smoking history. Compared to patients without, those with a smoking history were more likely to have a hospital-based, acute care encounter (3.4% vs 7.1%; AOR = 1.36 [1.25-1.48]) or serious adverse event (0.9% vs 2.2%; AOR = 1.38 [1.18-1.60]) within 30 days. On average, these events added $1826 per patient with a smoking history. These findings were consistent when stratified by specific procedure and controlled for patient factors. Conclusions: Patients undergoing common outpatient plastic surgery procedures who have a history of smoking are at risk for more frequent complications, and incur higher healthcare charges than patients who are nonsmokers. Level of Evidence 2: PMID- 29394313 TI - The Stress Factor of Social Media. PMID- 29394315 TI - How to design a single-cell RNA-sequencing experiment: pitfalls, challenges and perspectives. AB - The sequencing of the transcriptome of single cells, or single-cell RNA sequencing, has now become the dominant technology for the identification of novel cell types in heterogeneous cell populations or for the study of stochastic gene expression. In recent years, various experimental methods and computational tools for analysing single-cell RNA-sequencing data have been proposed. However, most of them are tailored to different experimental designs or biological questions, and in many cases, their performance has not been benchmarked yet, thus increasing the difficulty for a researcher to choose the optimal single-cell transcriptome sequencing (scRNA-seq) experiment and analysis workflow. In this review, we aim to provide an overview of the current available experimental and computational methods developed to handle single-cell RNA-sequencing data and, based on their peculiarities, we suggest possible analysis frameworks depending on specific experimental designs. Together, we propose an evaluation of challenges and open questions and future perspectives in the field. In particular, we go through the different steps of scRNA-seq experimental protocols such as cell isolation, messenger RNA capture, reverse transcription, amplification and use of quantitative standards such as spike-ins and Unique Molecular Identifiers (UMIs). We then analyse the current methodological challenges related to preprocessing, alignment, quantification, normalization, batch effect correction and methods to control for confounding effects. PMID- 29394314 TI - Regulatory networks controlling the development of the root system and the formation of lateral roots: a comparative analysis of the roles of pericycle and vascular cambium. AB - Background: The production of a new lateral root from parental root primary tissues has been investigated extensively, and the most important regulatory mechanisms are now well known. A first regulatory mechanism is based on the synthesis of small peptides which interact ectopically with membrane receptors to elicit a modulation of transcription factor target genes. A second mechanism involves a complex cross-talk between plant hormones. It is known that lateral roots are formed even in parental root portions characterized by the presence of secondary tissues, but there is not yet agreement about the putative tissue source providing the cells competent to become founder cells of a new root primordium. Scope: We suggest models of possible regulatory mechanisms for inducing specific root vascular cambium (VC) stem cells to abandon their activity in the production of xylem and phloem elements and to start instead the construction of a new lateral root primordium. Considering the ontogenic nature of the VC, the models which we suggest are the result of a comparative review of mechanisms known to control the activity of stem cells in the root apical meristem, procambium and VC. Stem cells in the root meristems can inherit various competences to play different roles, and their fate could be decided in response to cross-talk between endogenous and exogenous signals. Conclusions: We have found a high degree of relatedness among the regulatory mechanisms controlling the various root meristems. This fact suggests that competence to form new lateral roots can be inherited by some stem cells of the VC lineage. This kind of competence could be represented by a sensitivity of specific stem cells to factors such as those presented in our models. PMID- 29394316 TI - Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. AB - Many studies support the pro-nociceptive role of brain-derived neurotrophin factor (BDNF) in pain processes in the peripheral and central nervous system. We have previously shown that nociceptor-derived BDNF is involved in inflammatory pain. Microglial-derived BDNF has also been shown to be involved in neuropathic pain. However, the distinct contribution of primary afferent-derived BNDF to chronic pain processing remains undetermined. In this study, we used Avil-CreERT2 mice to delete Bdnf from all adult peripheral sensory neurons. Conditional BDNF knockouts were healthy with no sensory neuron loss. Behavioural assays and in vivo electrophysiology indicated that spinal excitability was normal. Following formalin inflammation or neuropathy with a modified Chung model, we observed normal development of acute pain behaviour, but a deficit in second phase formalin-induced nocifensive responses and a reversal of neuropathy-induced mechanical hypersensitivity during the later chronic pain phase in conditional BDNF knockout mice. In contrast, we observed normal development of acute and chronic neuropathic pain in the Seltzer model, indicating differences in the contribution of BDNF to distinct models of neuropathy. We further used a model of hyperalgesic priming to examine the contribution of primary afferent-derived BDNF in the transition from acute to chronic pain, and found that primed BDNF knockout mice do not develop prolonged mechanical hypersensitivity to an inflammatory insult. Our data suggest that BDNF derived from sensory neurons plays a critical role in mediating the transition from acute to chronic pain. PMID- 29394317 TI - Everyday Stepping Quantity and Quality Among Older Adult Fallers With and Without Mild Cognitive Impairment: Initial Evidence for New Motor Markers of Cognitive Deficits? AB - Background: Recent work demonstrated that the gait of people with mild cognitive impairment (MCI) differs from that of age-matched controls and, in general, that walking ability, as measured in the clinic, does not necessarily reflect actual, daily performance. We evaluated if the quantity and quality of everyday walking (ie, community ambulation) differs in older adults with MCI, compared to age matched controls. Methods: Inclusion criteria included: age 65-90 years, able to walk at least 5 minutes unassisted, and >=2 falls in the past 6 months. Subjects with MCI were included if they scored 0.5 on the Clinical Dementia Rating Scale. To assess stepping quantity and quality, subjects wore a tri-axial accelerometer on the lower-back for 7 days. Results: Age and gender were similar (p > .10) in MCI (n = 36, 77.8 +/- 6.4 years; 27.8% men) and controls (n = 100, 76.0 +/- 6.2 years; 22.0% men). As expected, Montreal Cognitive Assessment scores were lower (p < .001) in MCI (21.31 +/- 4.05), compared to controls (25.81 +/- 2.64). Walking time was lower (p = .016) in MCI (0.74 +/- 0.48 hours/d), compared to controls (1.05 +/- 0.66 hours/d). Within-bout walking (eg, stride regularity) was less consistent (p = .024) in MCI (0.51 +/- 0.14), compared to controls (0.58 +/- 0.14). Changes in stride regularity across bouts were lower (p < .001) in MCI (0.13 +/- 0.04), compared to controls (0.17 +/- 0.01). Conclusions: Older adults with MCI walk less and with a more variable within-bout and less variable across bout walking pattern, as compared to cognitively-intact subjects matched with respect to age and gender. These findings extend previous clinical work and suggest that MCI affects both the quantity and quality of community ambulation. PMID- 29394318 TI - Phylogenetic profiling, an untapped resource for the prediction of secreted proteins and its complementation with sequence-based classifiers in bacterial type III, IV and VI secretion systems. AB - In the establishment and maintenance of the interaction between pathogenic or symbiotic bacteria with a eukaryotic organism, protein substrates of specialized bacterial secretion systems called effectors play a critical role once translocated into the host cell. Proteins are also secreted to the extracellular medium by free-living bacteria or directly injected into other competing organisms to hinder or kill. In this work, we explore an approach based on the evolutionary dependence that most of the effectors maintain with their specific secretion system that analyzes the co-occurrence of any orthologous protein group and their corresponding secretion system across multiple genomes. We compared and complemented our methodology with sequence-based machine learning prediction tools for the type III, IV and VI secretion systems. Finally, we provide the predictive results for the three secretion systems in 1606 complete genomes at http://www.iib.unsam.edu.ar/orgsissec/. PMID- 29394320 TI - Commentary on: The Nasal Ligaments and Tip Support in Rhinoplasty: An Anatomical Study. PMID- 29394319 TI - The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epigenetic regulation of gene expression may allow tumoral cells to acquire new functions in order to escape from the primary tumor. The aim of this study was to investigate the expression and function of proteins of the Polycomb family of epigenetic regulators in the metastatic process of cSCC. A higher expression of RING1B and EZH2 was detected by immunohistochemistry in a series of primary cSCC tumors that metastasized (MSCCs) when compared with non-metastasizing cSCCs (non MSCCs). Stable downregulation of RING1B and EZH2 in cSCC cells results in enhanced expression of inflammatory cytokines and activation of the NF-kappaB signaling pathway. Accordingly, non-MSCCs display higher levels of membranous pS176-inhibitor of NF-kB kinase, and their stroma is enriched in neutrophils and eosinophils when compared with MSCCs. In vitro, hematopoietic cells exhibit a substantial migratory response to supernatants from Polycomb-depleted cSCC cells. Altogether, these data indicate that RING1B and EZH2 repress the innate inflammatory cSCC function and impair tumor immunosurveillance and suggest that patients with high-risk cSCCs could benefit from clinical therapies addressed to harness the immune response. PMID- 29394321 TI - Treatment of Nasal Deviation With Underlying Bony Asymmetry Secondary to Augmentation Rhinoplasty in Asian Patients. AB - Background: In Asian patients, nasal deviation secondary to augmentation rhinoplasty may result from underlying bony asymmetry that was not corrected intraoperatively. Diagnosis and treatment of this condition are complicated by the masking effect of dorsal implants. Objectives: The authors applied computed tomography (CT) to examine the causes of nasal deviation after augmentation rhinoplasty. CT results were utilized in preoperative planning for revisional surgery. Methods: Fifteen women with nasal deviation after augmentation rhinoplasty and CT-confirmed bony asymmetry were included in a retrospective study. To correct nasal deviation, the authors performed revisional rhinoplasty with paramedian osteotomy and unilateral placement of extended spreader grafts at the concave side of the keystone region. For patients with concomitant glabella radix deviation, implants comprising expanded polytetrafluoroethylene or autologous fascia were placed. Results: Of the 15 patients with nasal bony asymmetry, 14 had developmental keystone asymmetry, and 1 had osteotomy-induced keystone deviation. Six patients had developmental glabella asymmetry. Patients received follow-up for an average of 11.2 months (range, 6-24 months). Revisional procedures were considered successful in 13 patients; 2 patients required additional surgery to address residual nasal deviation. Conclusions: CT is valuable for the diagnosis of postaugmentation nasal deviation owing to underlying bony asymmetry. Paramedian osteotomy with extended spreader grafting at the concave side of the keystone area and correction of the glabella-radix deviation are effective procedures to reposition the nasal axis along the midline of the face. Level of Evidence 4: PMID- 29394322 TI - Commentary on: Enhanced Recovery After Surgery: The Plastic Surgery Paradigm Shift. PMID- 29394323 TI - pymzML v2.0: introducing a highly compressed and seekable gzip format. AB - Motivation: In the new release of pymzML (v2.0), we have optimized the speed of this established tool for mass spectrometry data analysis to adapt to increasing amounts of data in mass spectrometry. Thus, we integrated faster libraries for numerical calculations, improved data retrieving algorithms and have optimized the source code. Importantly, to adapt to rapidly growing file sizes, we developed a generalizable compression scheme for very fast random access and applied this concept to mzML files to retrieve spectral data. Results: pymzML performs at par with established C programs when it comes to processing times. However, it offers the versatility of a scripting language, while adding unprecedented fast random access to compressed files. Additionally, we designed our compression scheme in such a general way that it can be applied to any field where fast random access to large data blocks in compressed files is desired. Availability and implementation: pymzML is freely available on https://github.com/pymzML/pymzML under GPL license. pymzML requires Python3.4+ and optionally numpy. Documentation available on http://pymzml.readthedocs.io. PMID- 29394324 TI - Modeling biological problems in computer science: a case study in genome assembly. AB - As computer scientists working in bioinformatics/computational biology, we often face the challenge of coming up with an algorithm to answer a biological question. This occurs in many areas, such as variant calling, alignment and assembly. In this tutorial, we use the example of the genome assembly problem to demonstrate how to go from a question in the biological realm to a solution in the computer science realm. We show the modeling process step-by-step, including all the intermediate failed attempts. Please note this is not an introduction to how genome assembly algorithms work and, if treated as such, would be incomplete and unnecessarily long-winded. PMID- 29394325 TI - Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who stutter. AB - See Crinion (doi:10.1093/brain/awy075) for a scientific commentary on this article.Stuttering is a neurodevelopmental condition affecting 5% of children, and persisting in 1% of adults. Promoting lasting fluency improvement in adults who stutter is a particular challenge. Novel interventions to improve outcomes are of value, therefore. Previous work in patients with acquired motor and language disorders reported enhanced benefits of behavioural therapies when paired with transcranial direct current stimulation. Here, we report the results of the first trial investigating whether transcranial direct current stimulation can improve speech fluency in adults who stutter. We predicted that applying anodal stimulation to the left inferior frontal cortex during speech production with temporary fluency inducers would result in longer-lasting fluency improvements. Thirty male adults who stutter completed a randomized, double blind, controlled trial of anodal transcranial direct current stimulation over left inferior frontal cortex. Fifteen participants received 20 min of 1-mA stimulation on five consecutive days while speech fluency was temporarily induced using choral and metronome-timed speech. The other 15 participants received the same speech fluency intervention with sham stimulation. Speech fluency during reading and conversation was assessed at baseline, before and after the stimulation on each day of the 5-day intervention, and at 1 and 6 weeks after the end of the intervention. Anodal stimulation combined with speech fluency training significantly reduced the percentage of disfluent speech measured 1 week after the intervention compared with fluency intervention alone. At 6 weeks after the intervention, this improvement was maintained during reading but not during conversation. Outcome scores at both post-intervention time points on a clinical assessment tool (the Stuttering Severity Instrument, version 4) also showed significant improvement in the group receiving transcranial direct current stimulation compared with the sham group, in whom fluency was unchanged from baseline. We conclude that transcranial direct current stimulation combined with behavioural fluency intervention can improve fluency in adults who stutter. Transcranial direct current stimulation thereby offers a potentially useful adjunct to future speech therapy interventions for this population, for whom fluency therapy outcomes are currently limited. PMID- 29394327 TI - Estimation of clinical trial success rates and related parameters. AB - Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential selection biases. Using a sample of 406 038 entries of clinical trial data for over 21 143 compounds from January 1, 2000 to October 31, 2015, we estimate aggregate clinical trial success rates and durations. We also compute disaggregated estimates across several trial features including disease type, clinical phase, industry or academic sponsor, biomarker presence, lead indication status, and time. In several cases, our results differ significantly in detail from widely cited statistics. For example, oncology has a 3.4% success rate in our sample vs. 5.1% in prior studies. However, after declining to 1.7% in 2012, this rate has improved to 2.5% and 8.3% in 2014 and 2015, respectively. In addition, trials that use biomarkers in patient-selection have higher overall success probabilities than trials without biomarkers. PMID- 29394326 TI - Evidence for a subcortical origin of mirror movements after stroke: a longitudinal study. AB - Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system. PMID- 29394329 TI - Corrigendum. PMID- 29394328 TI - Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy. AB - High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001. PMID- 29394330 TI - RESOLVING AN APPARENT PARADOX IN DOUBLY ROBUST ESTIMATORS. PMID- 29394332 TI - Beyond the face: how context modulates emotion processing in frontotemporal dementia subtypes. AB - The importance of assessing social cognition to characterize dementia syndromes is increasingly recognized, with lower social cognition capacity associated with reduced functional independence and greater carer burden. Emotion recognition is impaired in both behavioural-variant frontotemporal dementia and semantic dementia, yet the social and behavioural changes observed in these syndromes in everyday situations varies. To date, most studies have investigated isolated, context-free stimuli indexing recognition of facial emotions only. Here, we aimed to investigate how contextual information (i.e. emotional body language) influences emotion recognition, within the framework of the Social Context Network Model. Thirty-one patients with frontotemporal dementia (19 behavioural variant frontotemporal dementia; 12 semantic dementia) and 20 healthy age- and education-matched controls were assessed on three tasks which varied contextual cues: (i) face alone; (ii) context alone; and (iii) face embedded in context. Voxel-based morphometry was used to identify neural correlates of task performance. Our results demonstrated that both behavioural-variant frontotemporal dementia and semantic dementia patients performed worse than controls in recognizing emotions from face alone and context alone. Importantly, performance differed when faces were presented in context. While both behavioural variant frontotemporal dementia and semantic dementia patients performed similarly to controls on congruent items (i.e. face emotion and body emotion are the same) (P-values > 0.05), patients with behavioural-variant frontotemporal dementia performed worse than both controls (P < 0.001) and patients with semantic dementia (P = 0.044) for incongruent items (i.e. face emotion and body emotion are different). Neuroimaging analyses revealed that abnormal contextual influence was associated with lower integrity of the right parahippocampal gyrus/amygdala and left precentral gyrus. Together, these results indicate that patients with behavioural-variant frontotemporal dementia are over-reliant on external contextual information. Conversely, in semantic dementia and controls, contextual influence varies, with the degree of contextual influence appearing to be mediated, at least in part, by the facial expression depicted. The profile in behavioural-variant frontotemporal dementia is reminiscent of the 'environmental dependency syndrome' described in frontal lesion patients. It also converges with recent evidence of abnormal face perception in this group. From a theoretical perspective, our findings demonstrate that the capacity to incorporate contextual body language is dependent on the integrity of both contextual association brain regions (i.e. parahippocampal gyrus), as well as regions necessary for processing dynamic body movements. Clinically, these results open new avenues for rehabilitation of social impairments in dementia. PMID- 29394333 TI - The Fogarty International Center at 50: Accomplishments and Priorities for the Next 50 Years. PMID- 29394334 TI - Reply to Troppy et al. PMID- 29394331 TI - Vascular smooth muscle contraction in hypertension. AB - Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin-myosin cross bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase, protein Kinase C and mitogen-activated protein kinase signalling, reactive oxygen species, and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and non-coding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signalling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here, we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension. PMID- 29394335 TI - Geographic Disparities in Access to Syringe Services Programs Among Young Persons With Hepatitis C Virus Infection in Massachusetts. PMID- 29394336 TI - Prospective Trials Are Required to Alter Practice for Follow-up Blood Cultures for Gram-Negative Bacilli Bacteremia. PMID- 29394337 TI - Raising the Stakes: Loss of Efflux Pump Regulation Decreases Meropenem Susceptibility in Burkholderia pseudomallei. AB - Background: Burkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug meropenem is the current gold standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance toward meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure. Methods: We examined our 30-year clinical collection of melioidosis cases to identify B. pseudomallei isolates with reduced meropenem susceptibility. Isolates were subjected to minimum inhibitory concentration (MIC) testing toward meropenem. Paired isolates from patients who had evolved decreased susceptibility were subjected to whole-genome sequencing. Select agent-compliant genetic manipulation was carried out to confirm the molecular mechanisms conferring resistance. Results: We identified 11 melioidosis cases where B. pseudomallei isolates developed decreased susceptibility toward meropenem during treatment, including 2 cases not treated with this antibiotic. Meropenem MICs increased from 0.5-0.75 ug/mL to 3-8 ug/mL. Comparative genomics identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, with concomitant overexpression of their corresponding pumps. All cases were refractory to treatment despite aggressive, targeted therapy, and 2 were associated with a fatal outcome. Conclusions: This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. These findings have important ramifications for the diagnosis, treatment, and management of life-threatening melioidosis cases. PMID- 29394338 TI - Reply to Jones et al. PMID- 29394340 TI - Trends in optimal medical therapy prescription and mortality after admission for acute coronary syndrome: a 9-year experience in a real-world setting. AB - Aims: Optimal medical therapy (OMT) is recommended in acute coronary syndrome (ACS) patients. Few studies present temporal trends of OMT prescription and its impact on outcomes in a real-world setting. We aimed to evaluate OMT prescription in a real-world ACS population and its relation to mortality during almost a decade. Methods and results: Consecutive ST-elevation myocardial infarction and non-ST-elevation myocardial infarction (NSTEMI) patients (n = 9202) admitted to a single Dutch tertiary hospital between 2006 and 2014 were included and followed for drug prescription and mortality up to 1 year. Optimal medical therapy was defined as prescription of aspirin, P2Y12inhibitors, statin, beta-blockers, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB). Optimal medical therapy prescription was 43.7% at discharge, 46.6% at 30-days, and 25.5% at 1-year. Optimal medical therapy prescription at discharge was lower among NSTEMI patients (34.5% vs. 49.2%, P < 0.001). Optimal medical therapy prescription at discharge, 30-days and 1-year and mortality outcomes did not change during the study period. After adjustment for baseline and admission characteristics, OMT at discharge was associated with a reduction in mortality in patients who survived hospitalization for the index event [adjusted hazard ratio: 0.66, 95% confidence interval (0.46-0.93)]. Conclusions: In this single-centre observational registry with >9000 patients reflecting almost a decade of ACS care, <50% of patients were on OMT at discharge. Prescription of OMT and mortality outcomes remained stable during the study period. After adjustment, OMT prescription at discharge was associated with reduced mortality in ACS survivors. Further contemporary randomized studies are warranted to determine the role of beta-blockers and ACEi/ARBs in ACS patients with preserved left ventricular ejection fraction. PMID- 29394339 TI - The genomes of two Eutrema species provide insight into plant adaptation to high altitudes. AB - Eutrema is a genus in the Brassicaceae, which includes species of scientific and economic importance. Many Eutrema species are montane and/or alpine species that arose very recently, making them ideal candidates for comparative studies to understand both ecological speciation and high-altitude adaptation in plants. Here we provide de novo whole-genome assemblies for a pair of recently diverged perennials with contrasting altitude preferences, the high-altitude E. heterophyllum from the eastern Qinghai-Tibet Plateau and its lowland congener E. yunnanense. The two assembled genomes are 350 Mb and 412 Mb, respectively, with 29,606 and 28,881 predicted genes. Comparative analysis of the two species revealed contrasting demographic trajectories and evolution of gene families. Gene family expansions shared between E. heterophyllum and other alpine species were identified, including the disease resistance R genes (NBS-LRRs or NLRs). Genes that are duplicated specifically in the high-altitude E. heterophyllum are involved mainly in reproduction, DNA damage repair and cold tolerance. The two Eutrema genomes reported here constitute important genetic resources for diverse studies, including the evolution of the genus Eutrema, of the Brassicaceae as a whole and of alpine plants across the world. PMID- 29394341 TI - Healthcare-Associated Measles After a Nationwide Outbreak in Mongolia. AB - Measles virus is highly infectious and can spread rapidly where vaccine coverage is low and isolation precautions suboptimal. We describe healthcare-associated measles transmission during the 2015-2016 measles outbreak in Mongolia, describe infection prevention gaps, and outline preventive strategies. PMID- 29394342 TI - PTH1R signalling regulates the mechanotransduction process of cementoblasts under cyclic tensile stress. AB - Objective: To investigate the regulatory role of type I parathyroid hormone receptor (PTH1R) signalling in the mechanotransduction process of cementoblasts under cyclic tensile stress (CTS). Materials and methods: Immortalized cementoblast cell line OCCM-30 were employed and subjected to cyclic tensile strain applied by a four-point bending system. The expression of PTHrP and PTH1R, as well as cementoblastic transcription factor Runx-2, Osterix, and extracellular matrix protein COL-1 and OPN were assessed by quantitative real-time polymerase chain reaction and western blot analysis. PTH1R expression was knocked down by siPTH1R transfection, and the alteration of cementoblastic biomarkers expression was examined to evaluate the function of PTH1R. Furthermore, to investigate possible downstream molecules, expression of signal molecule ERK1/2 with or without siPTH1R transfection, and the effect of ERK inhibitor PD98059 on the expression of cementoblastic biomarkers was also examined. Results: Cyclic tensile strain elevated the expression of PTHrP and PTH1R, as well as cementoblastic biomarkers Runx-2, Osterix, COL-1, and OPN in a time-dependent manner, which was inhibited by siPTH1R transfection. The expression of phosphorylated ERK1/2 was upregulated time-dependently under cyclic stretch, which was also inhibited by siPTH1R transfection, and pretreatment of p-ERK1/2 inhibitor PD98059 undermined the increase of Runx-2, Osterix, COL-1, and OPN prominently. Conclusion: The findings of the present study indicate that PTH1R signalling plays a regulatory role in the CTS induced cementoblastic differentiation in mature cementoblasts, and ERK1/2 is essentially involved as a downstream intracellular signal molecule in this mechanotransduction process. PMID- 29394343 TI - Looking behind the bars: emerging health issues for people in prison. AB - Introduction: There are more than 10 million people imprisoned worldwide. These individuals experience a higher burden of communicable and non-communicable disease, mental health and substance misuse problems than the general population and often come from marginalized and underserved groups in the community. Prisons offer an important opportunity for tackling health problems in a way that can deliver benefits to the individual and to the community. This paper focuses specifically on emerging health issues for prisons across the world. Sources of data: This paper uses sources of international data from published systematic reviews and research studies, the Ministry of Justice for England and Wales, the Prisons and Probations Ombudsmen Review and other United Kingdom government briefing papers. Areas of agreement: Deaths in custody are a key concern for the justice system as well as the health system. Areas of controversy: Suicide is the leading cause of mortality in prisons worldwide but non-communicable diseases, such as cardiovascular disease, are increasing in importance in high-income countries and are now the leading cause of mortality in prisons in England and Wales. Growing points: The prison population is ageing in most high-income countries. Older people in prison typically have multiple and complex medical and social care needs including reduced mobility and personal care needs as well as poor health. Areas timely for developing research: Further research is needed to understand the complex relationship between sentencing patterns, the ageing prison population and deaths in custody; to model its impact on prisons and healthcare provision in the future and to determine effective and cost-effective models of care. Research into the health of prisoners is important in improving the health of prisoners but there is considerable variation in quantity and quality between countries. Recent innovations seek to address this disparity and facilitate the sharing of good practice. PMID- 29394344 TI - Evaluation of the ability of commercial wine yeasts to form biofilms (mats) and adhere to plastic: implications for the microbiota of the winery environment. AB - Commercially available active dried wine yeasts are regularly used by winemakers worldwide to achieve reliable fermentations and obtain quality wine. This practice has led to increased evidence of traces of commercial wine yeast in the vineyard, winery and uninoculated musts. The mechanism(s) that enables commercial wine yeast to persist in the winery environment and the influence to native microbial communities on this persistence is poorly understood. This study has investigated the ability of commercial wine yeasts to form biofilms and adhere to plastic. The results indicate that the biofilms formed by commercial yeasts consist of cells with a combination of different lifestyles (replicative and non replicative) and growth modes including invasive growth, bud elongation, sporulation and a mat sectoring-like phenotype. Invasive growth was greatly enhanced on grape pulp regardless of strain, while adhesion on plastic varied between strains. The findings suggest a possible mechanism that allows commercial yeast to colonise and survive in the winery environment, which may have implications for the indigenous microbiota profile as well as the population profile in uninoculated fermentations if their dissemination is not controlled. PMID- 29394345 TI - Roles of IL-22 in allergic airway inflammation in mice and humans. AB - Asthma is a chronic inflammatory disease of the airways that is characterized by eosinophilic inflammation, mucus hypersecretion and airway remodeling that leads to airway obstruction. Although these pathognomonic features of asthma are primarily mediated by allergen-specific T helper type 2 cells (Th2 cells) and their cytokines, recent studies have revealed critical roles of lung epithelial cells in the pathogenesis of asthma. Lung epithelial cells not only form physical barriers by covering the surfaces of the airways but also sense inhaled allergens and initiate communication between the environment and the immune system. The causative involvement of lung epithelium in the pathogenesis of asthma suggests that some molecules that modulate epithelial function have a regulatory role in asthma. IL-22, an IL-10-family cytokine produced by IL-17A-producing T helper cells (Th17 cells), gammadelta T cells and group 3 innate lymphoid cells (ILC3s), primarily targets epithelial cells and promotes their proliferation. In addition, IL-22 has been shown to induce epithelial production of various molecules that regulate local immune responses. These findings indicate that IL-22 plays crucial roles in the pathogenesis of asthma by regulating epithelial function. Here, we review the current understanding of the molecular and cellular mechanisms underlying IL-22-mediated regulation of airway inflammation in asthma. PMID- 29394346 TI - QTc in the elderly. PMID- 29394347 TI - Prognostic value of 3-dimensional echocardiographical heart volume assessment in patients scheduled for left ventricular assist device implantation. AB - OBJECTIVES: Left ventricular assist device (LVAD) support is an increasingly important and successful therapeutic option for patients with end-stage heart failure. As chronic heart failure progresses, the left and right ventricles adapt by enlarging its volume and patients present for LVAD implantation with varying degrees of dilatation. By quantitatively assessing right ventricular (RV) and left ventricular (LV) volumes using 3D transoesophageal echocardiography and correlating the findings with clinical outcomes, we aim to investigate the prognostic value of LV and RV volumes for early survival after LVAD implantation. METHODS: This is a single-centre, non-randomized diagnostic cohort study using prospectively collected clinical and 3D echocardiographic data from 65 patients scheduled for LVAD implantation, using centrifugal pumps for long-term support (HeartWare and HeartMate 3). The primary end-point for this study is 60-day mortality, with longer term survival as a secondary end-point. RESULTS: We divided our cohort group into survivors and non-survivors at 60 days [49 patients (75%) and 16 patients (25%), respectively]. Right to left end-diastolic ratio assessed by 2D echocardiography was significantly higher in the 60-day non survivors group (0.70 +/- 0.09 vs 0.62 +/- 0.11; P = 0.01). Indexed end-diastolic volume parameters (LV, RV and overall heart) showed significant differences among the groups and were higher in the 60-day survivors group (LV volume 154 +/- 51 ml/m2 vs 110 +/- 40 ml/m2, P = 0.004; RV volume 96 +/- 27 ml/m2 vs 80 +/- 23 ml/m2, P = 0.05; heart 250 +/- 64 ml/m2 vs 190 +/- 57 ml/m2, P= 0.003). To investigate haemodynamic and echocardiographic parameters, the right to left end diastolic ratio and indexed RV end-diastolic volume were associated with 60-day mortality in the logistic regression analysis. The Kaplan-Meier survival curves for patients with indexed RV end-diastolic volume >82 ml/m2 vs indexed RV end diastolic volume <=82 ml/m2 showed better 1-year survival (P = 0.005) for the group with more RV dilatation. CONCLUSIONS: Patients with moderately increased end-diastolic RV volume index carry a higher postoperative risk, while severe RV dilatation seems to be protective. In future, postoperative management of patients with moderately dilated RVs should be focussed on adjusting individually appropriate LVAD flows and providing frequent follow-up. PMID- 29394348 TI - Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. AB - Aims: Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. Methods and results: Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIII:C. In total, five coagulation factors were measured: FVIII:C, von Willebrand factor:Ag, FVII:C, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIII:C where mean FVIII:C levels were 7.2 IU/dL [95% CI (confidence interval) 2.9-11.5] lower in rosuvastatin users, while among non-users, no change in FVIII:C was observed (mean difference -0.1; 95% CI -3.0 to 2.9). The mean age and sex adjusted difference in FVIII:C change was -6.7 IU/dL (95% CI -12.0 to -1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. Conclusion: Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT. PMID- 29394349 TI - The impact of coexisting lung diseases on outcomes in patients with pathological Stage I non-small-cell lung cancer. AB - OBJECTIVES: Cigarette smoking is a well-known cause of interstitial lung disease (ILD), pulmonary emphysema and lung cancer. Coexisting pulmonary disease can affect prognosis in patients with lung cancer. The aim of this study was to determine the influence of pulmonary disease on outcomes in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. METHODS: Medical records of 257 patients with a smoking history who underwent surgery for pathological Stage I non-small-cell lung cancer between June 2009 and December 2014 were reviewed. Coexisting ILDs were evaluated using high-resolution computed tomography. The degree of pulmonary emphysema was determined using image analysis software according to the Goddard classification. The impact of clinicopathological factors on outcome was evaluated. RESULTS: Among the 257 patients, ILDs were detected via high-resolution computed tomography in 60 (23.3%) patients; of these, usual interstitial pneumonia (UIP) patterns and non-UIP patterns were seen in 25 (9.7%) and 35 (13.6%) patients, respectively. The degree of pulmonary emphysema was classified as none, mild and moderate and included 50 (19.5%), 162 (63.0%) and 45 (17.5%) patients, respectively. The 5-year overall survival, cancer-specific survival and relapse free survival were 80.7%, 88.0% and 74.9%, respectively, during a median follow up period of 50.5 months. In multivariate analysis, the presence of a UIP pattern was shown to be an independent risk factor for poor outcome. CONCLUSIONS: The presence of a UIP-pattern ILD on high-resolution computed tomography images was shown to be a risk factor for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. PMID- 29394350 TI - Blood pressure and cardiovascular outcomes in patients with diabetes and high cardiovascular risk. AB - Aims: Optimal blood pressure for prevention of cardiovascular (CV) events in patients with Type 2 diabetes mellitus (T2DM) remains uncertain and there is concern for increased risk with low diastolic blood pressure (DBP). This study analysed the association between blood pressure and CV outcomes in high-risk patients with T2DM. Methods and results: Patients with T2DM and elevated CV risk were enrolled in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-Thrombolysis in Myocardial Infarction 53 trial. Cardiovascular outcomes were compared in the biomarker subgroup (n = 12 175) after stratification by baseline systolic blood pressure (SBP) and DBP. Adjusted risk was calculated by blood pressure stratum using clinical covariates plus N terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). Trends were tested using linear and quadratic models. Adjusted risk of the composite endpoint of CV death, myocardial infarction (MI), or ischaemic stroke showed U-shaped relationships with baseline SBP and DBP (Pquadratic <= 0.01) with nadirs at SBP 130-140 or DBP 80-90 mmHg. Diastolic blood pressure <60 mmHg was associated with increased risk of MI (adjusted hazard ratio 2.30; 95% confidence interval 1.50-3.53) relative to DBP 80-90 mmHg. Adjusted odds of hsTnT concentration >=14 ng/L showed U-shaped relationships with SBP and DBP (Pquadratic <= 0.01). The relationships between low DBP, elevated hsTnT, and increased MI remained after exclusion of patients with prior heart failure or NT proBNP >median, suggesting that the relationship was not due to confounding from diagnosed or undiagnosed heart failure. Conclusions: In patients with diabetes and elevated CV risk, even after extensive adjustment for underlying disease burden, there was a persistent association for low DBP with subclinical myocardial injury and risk of MI. PMID- 29394351 TI - Validation of a Modified Life-Space Assessment in Multimorbid Older Persons With Cognitive Impairment. AB - Background and Objectives: To investigate the validity, reliability, sensitivity to change, and feasibility of a modified University of Alabama at Birmingham Study of Aging Life-Space Assessment (UAB-LSA) in older persons with cognitive impairment (CI). Research Design and Methods: The UAB-LSA was modified for use in persons with CI Life-Space Assessment for Persons with Cognitive Impairment (LSA CI). Measurement properties of the LSA-CI were investigated using data of 118 multimorbid older participants with CI [mean age (SD): 82.3 (6.0) years, mean Mini-Mental State Examination score: 23.3 (2.4) points] from a randomized controlled trial (RCT) to improve motor performance and physical activity. Construct validity was asessed by Spearman's rank (rs) and point-biseral correlations (rpb) with age, gender, motor, and cognitive status, psychosocial factors, and sensor-derived (outdoor) physical activity variables. Test-retest reliability was analyzed using intra-class correlation coefficients (ICCs). Sensitivity to change was determined by standardized response means (SRMs) calculated for the RCT intervention group. Results: The LSA-CI demonstrated moderate to high construct validity, with significant correlations of the LSA-CI scores with (outdoor) physical activity (rs = .23-.63), motor status (rs = .27 .56), fear of falling-related psychosocial variables (rs = |.24-.44|), and demographic characteristics (rpb = |.27-.32|). Test-retest reliability was good to excellent (ICC = .65-.91). Sensitivity to change was excellent for the LSA-CI composite score (SRM = .80) and small to moderate for the LSA-CI subscores (SRM = .35-.60). A completion rate of 100% and a mean completion time of 4.1 min) documented good feasibility. Discussion and Implications: The LSA-CI represents a valid, reliable, sensitive, and feasible interview-based life-space assessment tool in multimorbid older persons with CI. PMID- 29394352 TI - Cyclic di-AMP-mediated interaction between Mycobacterium tuberculosis DeltacnpB and macrophages implicates a novel strategy for improving BCG vaccination. AB - Cyclic di-AMP (c-di-AMP) has been shown to play an important role in bacterial physiology and pathogen-host interactions. We previously reported that deletion of the sole c-di-AMP phosphodiesterase-encoding gene (cnpB) in Mycobacterium tuberculosis (Mtb) led to significant virulence attenuation. In this study, we found that DeltacnpB of M. bovisbacillus Calmette-Guerin (BCG) was unable to secrete c-di-AMP, which differs from Mtb DeltacnpB. We infected bone marrow derived macrophages (BMDMs) with c-di-AMP-associated mutants generated from both Mtb and BCG. Our results showed that upon infection with Mtb DeltacnpB, BMDMs of wildtype mice secreted a large amount of interferon-beta (IFN-beta) post infection similarly as we reported previously. In contrast, the response was less pronounced with BMDMs isolated from cGAS-/- mice and was nearly abolished with BMDMs prepared from STING-/- mice. Deletion of the region of difference 1 (RD1) locus in Mtb DeltacnpB did not alter the c-di-AMP secretion of DeltacnpB but eliminated the IFN-beta production in the infected cells. In contrast, neither BCG DeltacnpB nor a recombinant BCG DeltacnpB with a pRD1 cosmid induced a type I interferon response. Interestingly, multiple studies have demonstrated that type I IFN enhances BCG's immunity. Thus, amending BCG based on our findings might improve BCG vaccination. PMID- 29394353 TI - Burden of hypertension in The Gambia: evidence from a national World Health Organization (WHO) STEP survey. AB - Background: Non-communicable diseases are increasing in sub-Saharan Africa and are estimated to account for 32% of adult deaths in The Gambia. Worldwide, prevalence of hypertension is highest in the African region (46%) and a very high proportion is undiagnosed. This study examined diagnosed and undiagnosed hypertension in The Gambian adult population. Methods: Data were collected in 2010 from a nationally representative random sample of 4111 adults aged 25-64 years, using the World Health Organization STEPwise cross-sectional survey methods. Analyses were restricted to non-pregnant participants with three valid blood pressure measurements (n = 3573). We conducted gender-stratified univariate and multivariate regression analyses to identify the strongest sociodemographic, behavioural and biological risk factors associated with hypertension. Results: Almost one-third of adults were hypertensive; a high proportion were undiagnosed, particularly among men (86% of men vs 71% of women with hypertension, P < 0.001). Rural and semi-urban residents and overweight/obese persons had increased odds of hypertension. Compared with urban residents, participants from one of the most rural regions had higher odds of hypertension among both men [adjusted odds ratio (AOR) 3.2; 95% CI: 1.6-6.4] and women (AOR 2.5; 95% CI: 1.3-4.6). Other factors strongly associated with hypertension in multivariate analyses were age, smoking, physical inactivity and ethnicity. Conclusions: Rural and semi-urban residence were strongly associated with hypertension, contrary to what has been found in similar studies in sub-Saharan Africa. Intervention to reduce the burden of hypertension in The Gambia could be further targeted towards rural areas. PMID- 29394354 TI - The spectrum of ethical issues in a Learning Health Care System: a systematic qualitative review. AB - Purpose: To determine systematically the spectrum of ethical issues that is raised for stakeholders in a 'Learning Health Care System' (LHCS). Data sources: The systematic review was conducted in PubMed and Google Books between the years 2007 and 2015. Study selection: The literature search retrieved 1258 publications. Each publication was independently screened by two reviewers for eligibility for inclusion. Ethical issues were defined as arising when a relevant normative principle is not adequately considered or two principles come into conflict. Data extraction: A total of 65 publications were included in the final analysis and were analysed using an adapted version of qualitative content analysis. A coding frame was developed inductively from the data, only the highest-level categories were generated deductively for a life-cycle perspective. Results of data synthesis: A total of 67 distinct ethical issues could be categorized under different phases of the LHCS life-cycle. An overarching theme that was repeatedly raised was the conflict between the current regulatory system and learning health care. Conclusion: The implementation of a LHCS can help realize the ethical imperative to continuously improve the quality of health care. However, the implementation of a LHCS can also raise a number of important ethical issues itself. This review highlights the importance for health care leaders and policy makers to balance the need to protect and respect individual participants involved in learning health care activities with the social value of improving health care. PMID- 29394355 TI - Rotavirus-Specific Immunoglobulin A Responses Are Impaired and Serve as a Suboptimal Correlate of Protection Among Infants in Bangladesh. AB - Background: Rotavirus (RV)-specific immunoglobulin A (IgA) responses following oral RV vaccination are impaired in low-income countries, where the utility of RV IgA as a correlate of protection (CoP) remains unclear. In a monovalent oral RV vaccine (Rotarix) efficacy trial among infants in Dhaka, Bangladesh, we identified factors associated with poor RV-IgA responses and explored the utility of RV-IgA as a CoP. Methods: Infants were randomized to receive Rotarix or no Rotarix at 10 and 17 weeks of life and followed with active diarrheal surveillance. RV-IgA concentration, seroconversion, and seropositivity were determined at 18 weeks of life and analyzed for correlation(s) with rotavirus diarrhea (RVD) and for contribution to Rotarix vaccine effect. Results: Among vaccinated infants, overall RV-IgA geometric mean concentration was 21 U/mL; only 27% seroconverted and 32% were seropositive after vaccination. Increased RV specific maternal antibodies significantly impaired immunogenicity. Seroconversion was associated with reduced risk of RVD through 1 year of life, but RV-IgA seropositivity only explained 7.8% of the vaccine effect demonstrated by the clinical endpoint (RVD). Conclusions: RV-IgA responses were low among infants in Bangladesh and were significantly impaired by maternal antibodies. RV IgA is a suboptimal CoP in this setting; an improved CoP for RV in low-income countries is needed. Clinical Trials Registration: NCT01375647. PMID- 29394356 TI - Carriage of Cronobacter sakazakii in the Very Preterm Infant Gut. AB - Background: Cronobacter sakazakii causes severe neonatal infections, but we know little about gut carriage of this pathogen in very low birthweight infants. Methods: We sequenced 16S ribosomal RNA (rRNA) genes from 2304 stools from 121 children at St Louis Children's Hospital whose birthweight was <=1500 g, attempted to isolate C. sakazakii from 157 of these stools, genome-sequenced the recovered isolates, and sought correlations between indices of Cronobacter excretion, host characteristics, and unit formula use. Results: Of these 2304 stools, 1271 (55.2%) contained Cronobacter rRNA gene sequences. The median (interquartile range) per-subject percentage of specimens with at least 1 Cronobacter sequence and the median per-subject read density were 57.1 (25.5 87.3) and 0.07 (0.01-0.67), respectively. There was no variation according to commercially prepared liquid vs powdered formula use in the neonatal intensive care unit, or the day of life that specimens were produced. However, the proportion of specimens containing >4.0% of reads mapping to Cronobacter fell from 4.3% to 0.9% after powdered infant formula was discontinued (P < .0001). We isolated sequence type 4 (ST4) C. sakazakii from multiple specimens from 2 subjects; 1 also harbored sequence type 233. The sequenced ST4 isolates from the 2 subjects had >99.9% sequence identity in the approximately 93% of best-match reference genome that they contained, and shared multiple virulence loci. Conclusions: Very low birthweight infants excrete putatively pathogenic Cronobacter. High-density Cronobacter sequence samples were more common during the use of powdered infant formula. Better understanding of the ecology of Cronobacter in infant guts will inform future prevention and control strategies. PMID- 29394357 TI - Increased Virulence of an Encapsulated Streptococcus pneumoniae Upon Expression of Pneumococcal Surface Protein K. AB - Background: Current Streptococcus pneumoniae vaccines selectively target capsular polysaccharide of specific serotypes, leading to an increase in nonencapsulated S. pneumoniae (NESp). Cocolonization by encapsulated pneumococci and NESp increases the opportunity for intraspecies genetic exchange. Acquisition of NESp genes by encapsulated pneumococci could alter virulence and help vaccine-targeted serotypes persist in the host. Methods: Adhesion and invasion assays were performed using immortalized human pharyngeal or lung epithelial cells. In vivo models assessing murine nasopharyngeal colonization and pneumonia, as well as chinchilla otitis media (OM), were also used. Results: Pneumococcal surface protein K (PspK) expression increased encapsulated pneumococcal adhesion and invasion of lung cells and enhanced virulence during pneumonia and OM. Additionally, PspK increased nasopharyngeal colonization, persistence in the lungs, and persistence in the middle ear when expressed in a capsule deletion mutant. Competition experiments demonstrated encapsulated pneumococci expressing PspK also had a selective advantage in both the lungs and nasopharynx. Conclusions: PspK increases pneumococcal virulence during pneumonia and OM. PspK also partially compensates for loss of virulence in the absence of capsule. Additionally, PspK provides a selective advantage in a competitive environment. Therefore, acquisition of PspK increases encapsulated virulence in a condition dependent manner. Together, these studies demonstrate risks associated with pneumococcal intraspecies genetic exchange. PMID- 29394358 TI - Treatment Outcomes of Multidrug-Resistant Tuberculosis in Taiwan: Tackling Loss to Follow-up. AB - Background: The proportion of treatment success among patients with multidrug resistant tuberculosis (MDR-TB) enrolled between 1992 and 1996 was 51.2%, and that among patients enrolled between 2000 and April 2007 was 61%. To address the challenge of MDR-TB, the Taiwan MDR-TB Consortium (TMTC) was established in May 2007. To assess the performance of the TMTC, we analyzed the data of patients enrolled in its first 5 years. Methods: Comprehensive care was provided at no cost to patients, who were usually hospitalized for 1 month initially. Treatment regimens consisted of 4-5 drugs and the duration of treatment was 18-24 months. A case manager and a directly observed therapy provider were assigned to each patient. Psychosocial support was provided to address emotional stress and stigma. Financial support was offered to avoid the financial hardship faced by patients and their families. We assessed treatment outcomes at 30 months using internationally recommended outcome definitions. Results: Of the 692 MDR-TB patients, 570 (82.4%) were successfully treated, 84 (12.1%) died, 18 (2.6%) had treatment failure, and 20 (2.9%) were lost to follow-up. Age >=65 years (adjusted odds ratio [aOR], 6.78 [95% confidence interval {CI}, 3.14-14.63]), cancer (aOR, 11.82 [95% CI, 5.55-25.18]), and chronic kidney disease (aOR, 3.62 [95% CI, 1.70 7.71]) were significantly associated with death. Resistance to fluoroquinolone (aOR, 10.89 [95% CI, 3.97-29.88]) was significantly associated with treatment failure. Conclusions: The TMTC, which operates under a strong collaboration between the public health authority and clinical teams, has been a highly effective model of care in the management of MDR-TB. PMID- 29394359 TI - Ribitol-phosphate-a newly identified posttranslational glycosylation unit in mammals: structure, modification enzymes and relationship to human diseases. AB - Glycosylation is a crucial posttranslational modification that is involved in numerous biological events. Therefore, abnormal glycosylation can impair the functions of glycoproteins or glycolipids and is occasionally associated with cell dysfunction and human diseases. For example, aberrant glycosylation of dystroglycan (DG), a cellular receptor for matrix and synaptic proteins, is associated with muscular dystrophy and lissencephaly. DG sugar chains are required for high-affinity binding to ligand proteins, and thus disruption of DG ligand linkages underlies disease conditions. Although their biological significance is well recognized, the sugar-chain structure of DG and its modification enzymes have long remained incompletely elucidated. However, recent seminal studies have finally revealed a highly regulated mechanism for DG glycosylation and have discovered a posttranslational unit, ribitol-phosphate, that was not previously known to be used in mammals. This review article introduces the structure, modification enzymes and functions of the sugar chains of DG, and then discusses their relationship to human diseases and therapeutic strategies: . PMID- 29394360 TI - The roles of muscle stem cells in muscle injury, atrophy and hypertrophy. AB - Skeletal muscle is composed of multinuclear cells called myofibers. Muscular dystrophy (a genetic muscle disorder) induces instability in the cell membrane of myofibers and eventually causes myofibre damage. Non-genetic muscle disorders, including sarcopenia, diabetes, bedridden immobility and cancer cachexia, lead to atrophy of myofibres. In contrast, resistance training induces myofibre hypertrophy. Thus, myofibres exhibit a plasticity that is strongly affected by both intrinsic and extrinsic factors. There is no doubt that muscle stem cells (MuSCs, also known as muscle satellite cells) are indispensable for muscle repair/regeneration, but their contributions to atrophy and hypertrophy are still controversial. The present review focuses on the relevance of MuSCs to (i) muscle diseases and (ii) hypertrophy. Further, this review addresses fundamental questions about MuSCs to clarify the onset or progression of these diseases and which might lead to development of a MuSC-based therapy. PMID- 29394361 TI - Serological response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin. AB - Background: Some syphilitic patients remain in a serologically positive state after the recommended therapy. Although we often retreat patients in clinical practice, the optimal treatment protocol remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. Methods: We examined rapid plasma reagin serological test results of 70 serofast early syphilis cases who were retreated with 2.4 million units of benzathine penicillin weekly for 3 weeks. Serological retreatment success was defined as a minimum 4-fold decrease in baseline rapid plasma reagin test antibody titre within 6 months. Results: Thirty-four (48.6%) of the patients who failed to achieve serological cure at 6 months after initial therapy achieved serological cure at 12 months. Patients who had higher non-treponemal titres at baseline and at 6 months were more likely to exhibit serological cure after retreatment than those with lower titres. Conclusions: Our results suggest that the incremental benefit of retreating serofast patients with early syphilis is moderate, considering the almost 1:1 ratio of serological response to serofast state at follow-up. PMID- 29394363 TI - Association between use of different antibiotics and trimethoprim resistance: going beyond the obvious crude association. AB - Objectives: To evaluate the association between use of different antibiotics and trimethoprim resistance at the population level. Methods: Monthly primary care prescribing data were obtained from NHS Digital. Positive Enterobacteriaceae records from urine samples from patients between April 2014 and January 2016 in England were extracted from PHE's Second Generation Surveillance System (SGSS). Elastic net regularization and generalized boosted regression models were used to evaluate associations between antibiotic prescribing and trimethoprim resistance, both measured at Clinical Commission Group level. Results: In total, 2 487 635 (99%) of 2 513 285 urine Enterobacteriaceae samples from 1 667 839 patients were tested for trimethoprim resistance. Using both elastic net regularization and generalized boosted regression models, geographical variation in trimethoprim resistance among Enterobacteriaceae urinary samples could be partly explained by geographical variation in use of trimethoprim (relative risk = 1.14, 95% CI = 1.02-1.75; relative influence = 4.1) and penicillins with extended spectrum (mainly amoxicillin/ampicillin in England) (relative risk = 1.19, 95% CI = 1.11 1.30; relative influence = 7.4). Nitrofurantoin use was associated with lower trimethoprim resistance levels (relative risk = 0.83, 95% CI = 0.57-0.96; relative influence = 9.2). Conclusions: Use of amoxicillin/ampicillin explained more of the variance in trimethoprim resistance than trimethoprim use, suggesting that co-selection by these antibiotics is an important driver of trimethoprim resistance levels at the population level. Nitrofurantoin use was consistently associated with lower trimethoprim resistance levels, indicating that trimethoprim resistance levels could be lowered if trimethoprim use is replaced by nitrofurantoin. PMID- 29394362 TI - Prevalence and Risk Factors for Anal Human Papillomavirus Infection in Human Immunodeficiency Virus-Positive Men Who Have Sex with Men. AB - Background: We assessed prevalence and risk factors for anal human papillomavirus (HPV) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), who are at high-risk of HPV-related anal cancer. Methods: APACHES is a multicentric, prospective study of anal HPV infection and lesions in HIV-positive MSM aged >=35 years. At baseline, participants underwent anal swabs for HPV and cytology, plus high-resolution anoscopy. High-risk HPV (HR-HPV) was tested by Cobas4800, with genotyping of HR-HPV positives by PapilloCheck. Results: Among 490 participants, prevalence of HPV16 and HR-HPV was 29% and 70%, respectively, and did not differ significantly by age, sexual behavior, or markers of HIV or immune deficiency. Smoking was the only, albeit weak (odds ratio, 1.8; 95% confidence interval, 1.2-2.7), predictor of HR-HPV. High-risk HPV and HPV16 prevalence increased strongly with anal diagnosis severity, both by worse cytological/histological (composite) diagnosis at APACHES baseline and worse historical diagnosis. HPV16 rose from 19% among participants who were negative for lesions to 63% among participants with high-grade lesions. In contrast, non HPV16 HR-HPVs were less prevalent in high-grade (37%) than negative (64%) composite diagnosis, and their causal attribution was further challenged by multiple HPV infections. Conclusions: Human papillomavirus 16 is ubiquitously frequent among human immunodeficiency virus -positive men having sex with men, and more strongly associated with high-grade anal lesions than other high-risk types, confirming it as a target for anal cancer prevention. PMID- 29394364 TI - Waxing Understanding of Waning Immunity. PMID- 29394365 TI - Live birth rate following frozen-thawed blastocyst transfer is higher with blastocysts expanded on Day 5 than on Day 6. AB - STUDY QUESTION: The aim of this study was to evaluate the live birth rate (LBR) after frozen-thawed Day 5 (D5) and Day 6 (D6) blastocyst transfers. SUMMARY ANSWER: LBR following frozen-thawed blastocyst transfer is significantly lower with D6 than with D5 blastocyst regardless of embryo quality. WHAT IS KNOWN ALREADY: During fresh embryo transfer cycles, pregnancy rates (PR) are significantly higher when transferring blastocysts expanded on D5 compared with slow developing blastocysts (D6). In programmed thawed blastocyst transfer (TBT) cycles, the same clinical outcomes should be expected when transferring D5 or D6 blastocysts because of endometrial/embryonic synchronization due to hormonal priming of endometrial receptivity. However, the impact of delayed blastocyst expansion at D6 on clinical outcomes remains unclear. Some reports have shown higher PRs after D5 TBT compared with those of D6, while others have shown equivalent TBT outcomes after D5 and D6 cryopreserved blastocysts transfers. STUDY, DESIGN, SIZE, DURATION: This retrospective cohort follow-up study included 1347 single autologous frozen-thawed blastocyst transfers performed between January 2012 and December 2015 at a tertiary care university hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: All of the patients scheduled for TBT were allocated to two groups according to the day of blastocyst expansion: on D5 (n = 994) or on D6 (n = 353). The primary outcome was LBR per embryo transfer in the first blastocyst thawing cycle. Secondary outcomes were clinical pregnancy rate (cPR), early miscarriage rate and neonatal outcomes following TBT for the two groups. Statistical analyses were conducted using univariate and multivariate logistic regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The LBR was significantly increased in the D5 group compared to the D6 group [294/994 (29.6%) versus 60/353 (17.0%); P < 0.001]. The cPR was also higher when blastocysts were vitrified on D5 compared with those vitrified on D6 [429/994 (43.2%) versus 95/353 (26.9%); P < 0.001]. No significant differences were found between groups in terms of early miscarriage rate (P = 0.862). More good-quality embryos (defined as an B3-B4 or B5 embryo >=BB according to the grading scale proposed by Gardner) were transferred in the D5 group than in the D6 group [807 (81.2%) versus 214 (60.6%); P < 0.001]. However, a comparison of TBT cycles with equal embryo quality (good versus low) also supported the superiority of D5 blastocysts. Concerning neonatal outcomes, the D5 group infants had a lower mean birth weight compared to those of the D6 group (P = 0.001). In addition, a significantly shorter gestational age at birth is reported in the D5 blastocyst group as compared to the D6 group (P = 0.004). After multivariate logistic regression taking into account potential confounders such as the women's age, number of previous IVF/ICSI procedures, the day of the blastocyst vitrification (D5 or D6) and embryo quality, blastocyst expansion at D6 was independently associated with a significant decrease in LBR compared to D5 expanded-blastocysts (OR 0.52; 95% CI 0.38-0.72; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The poor predictive value of the morphological approach in embryo selection could constitute a limitation in this study. However, blastocyst quality was evaluated similarly in both groups. WIDER IMPLICATIONS OF THE FINDINGS: The LBR following frozen-thawed blastocyst transfer was significantly lower with D6 than with D5 blastocysts, regardless of their quality. These results could affect cryopreservation procedures as they suggest that the use of D5-expanded blastocysts for TBT may be preferred in order to shorten the time of conceiving. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 29394366 TI - Amblyomma americanum (Acari: Ixodidae) Ticks Are Not Vectors of the Lyme Disease Agent, Borrelia burgdorferi (Spirocheatales: Spirochaetaceae): A Review of the Evidence. AB - In the early 1980s, Ixodes spp. ticks were implicated as the key North American vectors of Borrelia burgdorferi (Johnson, Schmid, Hyde, Steigerwalt and Brenner) (Spirocheatales: Spirochaetaceae), the etiological agent of Lyme disease. Concurrently, other human-biting tick species were investigated as potential B. burgdorferi vectors. Rashes thought to be erythema migrans were observed in patients bitten by Amblyomma americanum (L.) (Acari: Ixodidae) ticks, and spirochetes were visualized in a small percentage of A. americanum using fluorescent antibody staining methods, sparking interest in this species as a candidate vector of B. burgdorferi. Using molecular methods, the spirochetes were subsequently described as Borrelia lonestari sp. nov. (Spirocheatales: Spirochaetaceae), a transovarially transmitted relapsing fever Borrelia of uncertain clinical significance. In total, 54 surveys from more than 35 research groups, involving more than 52,000 ticks, have revealed a low prevalence of B. lonestari, and scarce B. burgdorferi, in A. americanum. In Lyme disease-endemic areas, A. americanum commonly feeds on B. burgdorferi-infected hosts; the extremely low prevalence of B. burgdorferi in this tick results from a saliva barrier to acquiring infection from infected hosts. At least nine transmission experiments involving B. burgdorferi in A. americanum have failed to demonstrate vector competency. Advancements in molecular analysis strongly suggest that initial reports of B. burgdorferi in A. americanum across many states were misidentified B. lonestari, or DNA contamination, yet the early reports continue to be cited without regard to the later clarifying studies. In this article, the surveillance and vector competency studies of B. burgdorferi in A. americanum are reviewed, and we conclude that A. americanum is not a vector of B. burgdorferi. PMID- 29394367 TI - Contribution to Malaria Transmission of Symptomatic and Asymptomatic Parasite Carriers in Cambodia. AB - Background: Eliminating falciparum malaria in Cambodia is a top priority, requiring the implementation of novel tools and strategies to interrupt its transmission. To date, few data are available regarding the contributions to malaria transmission of symptomatic and asymptomatic carriers. Methods: Direct membrane and skin feeding assays (DMFAs, SFAs) were performed, using Anopheles minimus and Anopheles dirus, to determine infectivity of symptomatic falciparum infected patients and malaria asymptomatic carriers; a subset of the latter were followed up for 2 months to assess their transmission potential. Results: By microscopy and real-time polymerase chain reaction, Plasmodium falciparum gametocyte prevalence rates were, respectively, 19.3% (n = 21/109) and 44% (n = 47/109) on day (D) 0 and 17.9% (n = 5/28) and 89.3% (n = 25/28) in recrudescent patients (Drec) (RT-PCR Drec vs D0 P = .002). Falciparum malaria patient infectivity was low on D0 (6.2%; n = 3/48) and in Drec (8.3%; n = 1/12). Direct membrane feeding assays and SFAs gave similar results. None of the falciparum (n = 0/19) and 3 of 28 Plasmodium vivax asymptomatic carriers were infectious to mosquitoes, including those that were followed up for 2 months. Overall, P. falciparum gametocytemias were low except in a few symptomatic carriers. Conclusions: Only symptomatic falciparum malaria patients were infectious to mosquito vectors at baseline and recrudescence, highlighting the need to detect promptly and treat effectively P. falciparum patients. PMID- 29394368 TI - Maternal anaemia and folate intake in early pregnancy. AB - Background: The World Health Organization recommends that women take 400 ug of folate supplementation daily throughout pregnancy. We examined the relationship between total folate intake from the diet and supplements at the first prenatal visit and haematological indices at this visit and subsequently. Methods: Women were recruited at their convenience and in addition to clinical and sociodemographic details, detailed questionnaires on dietary intakes and supplementation consumption were completed under supervision. A full blood count and serum and red blood cell (RBC) folate levels were taken. Results: Of the 502 women studied, 97.5% had inadequate total dietary folate intake at the first visit, but, 98.2% were taking folic acid (FA) supplementation. Only 1.8% (n = 9) had anaemia at their first visit (with no case of macrocytosis). Subsequently, 212 women had a further Hb sample in the third trimester and 8.5% (n = 18) were anaemic and 43.4% (89/205) were anaemic postnatally. There was a relationship between the development of anaemia postnatally and lower RBC folate levels at the first visit (P = 0.02). Conclusions: In a country where FA food fortification remains voluntary, these findings support the recommendation that women should start FA supplementation before pregnancy and continue FA after the first trimester. PMID- 29394369 TI - The elusive ligand complexes of the DWARF14 strigolactone receptor. AB - Strigolactones, a group of terpenoid lactones, control many aspects of plant growth and development, but the active forms of these plant hormones and their mode of action at the molecular level are still unknown. The strigolactone protein receptor is unusual because it has been shown to cleave the hormone and supposedly forms a covalent bond with the cleaved hormone fragment. This interaction is suggested to induce a conformational change in the receptor that primes it for subsequent interaction with partners in the signalling pathway. Substantial efforts have been invested into describing the interaction of synthetic strigolactone analogues with the receptor, resulting in a number of crystal structures. This investigation combines a re-evaluation of models in the Protein Data Bank with a search for new conditions that may permit the capture of a receptor-ligand complex. While weak difference density is frequently observed in the binding cavity, possibly due to a low-occupancy compound, the models often contain features not supported by the X-ray data. Thus, at this stage, we do not believe that any detailed deductions about the nature, conformation, or binding mode of the ligand can be made with any confidence. PMID- 29394370 TI - Gene duplication and dosage effects during the early emergence of C4 photosynthesis in the grass genus Alloteropsis. AB - The importance of gene duplication for evolutionary diversification has been mainly discussed in terms of genetic redundancy allowing neofunctionalization. In the case of C4 photosynthesis, which evolved via the co-option of multiple enzymes to boost carbon fixation in tropical conditions, the importance of genetic redundancy has not been consistently supported by genomic studies. Here, we test for a different role for gene duplication in the early evolution of C4 photosynthesis, via dosage effects creating rapid step changes in expression levels. Using genome-wide data for accessions of the grass genus Alloteropsis that recently diversified into different photosynthetic types, we estimate gene copy numbers and demonstrate that recurrent duplications in two important families of C4 genes coincided with increases in transcript abundance along the phylogeny, in some cases via a pure dosage effect. While increased gene copy number during the initial emergence of C4 photosynthesis probably offered a rapid route to enhanced expression, we also find losses of duplicates following the acquisition of genes encoding better-suited isoforms. The dosage effect of gene duplication might therefore act as a transient process during the evolution of a C4 biochemistry, rendered obsolete by the fixation of regulatory mutations increasing expression levels. PMID- 29394371 TI - OneD: increasing reproducibility of Hi-C samples with abnormal karyotypes. AB - The three-dimensional conformation of genomes is an essential component of their biological activity. The advent of the Hi-C technology enabled an unprecedented progress in our understanding of genome structures. However, Hi-C is subject to systematic biases that can compromise downstream analyses. Several strategies have been proposed to remove those biases, but the issue of abnormal karyotypes received little attention. Many experiments are performed in cancer cell lines, which typically harbor large-scale copy number variations that create visible defects on the raw Hi-C maps. The consequences of these widespread artifacts on the normalized maps are mostly unexplored. We observed that current normalization methods are not robust to the presence of large-scale copy number variations, potentially obscuring biological differences and enhancing batch effects. To address this issue, we developed an alternative approach designed to take into account chromosomal abnormalities. The method, called OneD, increases reproducibility among replicates of Hi-C samples with abnormal karyotype, outperforming previous methods significantly. On normal karyotypes, OneD fared equally well as state-of-the-art methods, making it a safe choice for Hi-C normalization. OneD is fast and scales well in terms of computing resources for resolutions up to 5 kb. PMID- 29394372 TI - Jasmonate-responsive MYB factors spatially repress rutin biosynthesis in Fagopyrum tataricum. AB - Jasmonates are plant hormones that induce the accumulation of many secondary metabolites, such as rutin in buckwheat, via regulation of jasmonate-responsive transcription factors. Here, we report on the identification of a clade of jasmonate-responsive subgroup 4 MYB transcription factors, FtMYB13, FtMYB14, FtMYB15, and FtMYB16, which directly repress rutin biosynthesis in Fagopyrum tataricum. Immunoblot analysis showed that FtMYB13, FtMYB14, and FtMYB15 could be degraded via the 26S proteasome in the COI1-dependent jasmonate signaling pathway, and that this degradation is due to the SID motif in their C-terminus. Yeast two-hybrid and bimolecular fluorescence complementation assays revealed that FtMYB13, FtMYB14, and FtMYB15 interact with the importin protein Sensitive to ABA and Drought 2 (FtSAD2) in stem and inflorescence. Furthermore, the key repressor of jasmonate signaling FtJAZ1 specifically interacts with FtMYB13. Point mutation analysis showed that the conserved Asp residue of the SID domain contributes to mediating protein-protein interaction. Protoplast transient activation assays demonstrated that FtMYB13, FtMYB14, and FtMYB15 directly repress phenylalanine ammonia lyase (FtPAL) gene expression, and FtSAD2 and FtJAZ1 significantly promote the repressing activity of FtMYBs. These findings may ultimately be promising for further engineering of plant secondary metabolism. PMID- 29394374 TI - Down-regulation of respiration in pear fruit depends on temperature. AB - The respiration rate of plant tissues decreases when the amount of available O2 is reduced. There is, however, a debate on whether the respiration rate is controlled either by diffusion limitation of oxygen or through regulatory processes at the level of the transcriptome. We used experimental and modelling approaches to demonstrate that both diffusion limitation and metabolic regulation affect the response of respiration of bulky plant organs such as fruit to reduced O2 levels in the surrounding atmosphere. Diffusion limitation greatly affects fruit respiration at high temperature, but at low temperature respiration is reduced through a regulatory process, presumably a response to a signal generated by a plant oxygen sensor. The response of respiration to O2 is time dependent and is highly sensitive, particularly at low O2 levels in the surrounding atmosphere. Down-regulation of the respiration at low temperatures may save internal O2 and relieve hypoxic conditions in the fruit. PMID- 29394375 TI - Replication stress induces accumulation of FANCD2 at central region of large fragile genes. AB - During mild replication stress provoked by low dose aphidicolin (APH) treatment, the key Fanconi anemia protein FANCD2 accumulates on common fragile sites, observed as sister foci, and protects genome stability. To gain further insights into FANCD2 function and its regulatory mechanisms, we examined the genome-wide chromatin localization of FANCD2 in this setting by ChIP-seq analysis. We found that FANCD2 mostly accumulates in the central regions of a set of large transcribed genes that were extensively overlapped with known CFS. Consistent with previous studies, we found that this FANCD2 retention is R-loop-dependent. However, FANCD2 monoubiquitination and RPA foci formation were still induced in cells depleted of R-loops. Interestingly, we detected increased Proximal Ligation Assay dots between FANCD2 and R-loops following APH treatment, which was suppressed by transcriptional inhibition. Collectively, our data suggested that R loops are required to retain FANCD2 in chromatin at the middle intronic region of large genes, while the replication stress-induced upstream events leading to the FA pathway activation are not triggered by R-loops. PMID- 29394376 TI - Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens. AB - Organoid cultures in 3D matrices are relevant models to mimic the complex in vivo environment that supports cell physiological and pathological behaviors. For instance, 3D epithelial organoids recapitulate numerous features of glandular tissues including the development of fully differentiated acini that maintain apico-basal polarity with hollow lumen. Effective genetic engineering in organoids would bring new insights in organogenesis and carcinogenesis. However, direct 3D transfection on already formed organoids remains challenging. One limitation is that organoids are embedded in extracellular matrix and grow into compact structures that hinder transfection using traditional techniques. To address this issue, we developed an innovative approach for transgene expression in 3D organoids by combining single-cell encapsulation in Matrigel microbeads using a microfluidic device and electroporation. We demonstrate that direct electroporation of encapsulated organoids reaches up to 80% of transfection efficiency. Using this technique and a morphological read-out that recapitulate the different stages of tumor development, we further validate the role of p63 and PTEN as key genes in acinar development in breast and prostate tissues. We believe that the combination of controlled organoid generation and efficient 3D transfection developed here opens new perspectives for flow-based high-throughput genetic screening and functional genomic applications. PMID- 29394377 TI - Overexpression of lily HsfA3s in Arabidopsis confers increased thermotolerance and salt sensitivity via alterations in proline catabolism. AB - Although HsfA3 (heat-stress transcription factor A3) is well characterized in heat stress, its roles in other abiotic stresses are less clear. In this study, we isolated two homologous HsfA3 genes, LlHsfA3A and LlHsfA3B, from lily (Lilium longiflorum). Both genes were induced by heat stress, but not by salt stress. Overexpressing LlHsfA3A in Arabidopsis enhanced its basal and acquired thermotolerance, while overexpressing LlHsfA3B just enhanced its acquired thermotolerance. In both cases, overexpressing plants showed hypersensitivity to salt stress, and a lack of sucrose exacerbated this salt sensitivity. Using a transient assay, the opposite effects were observed in lily. Further analysis revealed that either LlHsfA3A or LlHsfA3B overexpression altered normal proline accumulation. During heat treatments, proline increased in wild-type Arabidopsis plants, but no such increase was detected in transgenic plants that showed better basal or acquired thermotolerance. Under salt stress, proline accumulation was decreased in Arabidopsis and lily with the overexpression of LlHsfA3A or LlHsfA3B. Proline catabolism was activated by overexpression, and both LlHsfA3A and LlHsfA3B affected proline oxidation via regulation of AtbZIP11, AtbZIP44, and AtbZIP53 to activate AtproDH1 and AtproDH2 in transgenic Arabidopsis. Taken together, our results suggested that overexpression of LlHsfA3A or LlHsfA3B caused opposite effects on heat and salt tolerance, which may implicate proline catabolism. PMID- 29394378 TI - Structural analyses of NEAT1 lncRNAs suggest long-range RNA interactions that may contribute to paraspeckle architecture. AB - Paraspeckles are nuclear bodies that regulate multiple aspects of gene expression. The long non-coding RNA (lncRNA) NEAT1 is essential for paraspeckle formation. NEAT1 has a highly ordered spatial organization within the paraspeckle, such that its 5' and 3' ends localize on the periphery of paraspeckle, while central sequences of NEAT1 are found within the paraspeckle core. As such, the structure of NEAT1 RNA may be important as a scaffold for the paraspeckle. In this study, we used SHAPE probing and computational analyses to investigate the secondary structure of human and mouse NEAT1. We propose a secondary structural model of the shorter (3,735 nt) isoform hNEAT1_S, in which the RNA folds into four separate domains. The secondary structures of mouse and human NEAT1 are largely different, with the exception of several short regions that have high structural similarity. Long-range base-pairing interactions between the 5' and 3' ends of the long isoform NEAT1 (NEAT1_L) were predicted computationally and verified using an in vitro RNA-RNA interaction assay. These results suggest that the conserved role of NEAT1 as a paraspeckle scaffold does not require extensively conserved RNA secondary structure and that long-range interactions among NEAT1 transcripts may have an important architectural function in paraspeckle formation. PMID- 29394379 TI - The evolutionary origins of cell type diversification and the role of intrinsically disordered proteins. AB - The evolution of complex multicellular life forms occurred multiple times and was attended by cell type specialization. We review seven lines of evidence indicating that intrinsically disordered/ductile proteins (IDPs) played a significant role in the evolution of multicellularity and cell type specification: (i) most eukaryotic transcription factors (TFs) and multifunctional enzymes contain disproportionately long IDP sequences (>=30 residues in length), whereas highly conserved enzymes are normally IDP region poor; (ii) ~80% of the proteome involved in development are IDPs; (iii) the majority of proteins undergoing alternative splicing (AS) of pre-mRNA contain significant IDP regions; (iv) proteins encoded by DNA regions flanking crossing over 'hot spots' are significantly enriched in IDP regions; (v) IDP regions are disproportionately subject to combinatorial post-translational modifications (PTMs) as well as AS; (vi) proteins involved in transcription and RNA processing are enriched in IDP regions; and (vii) a strong positive correlation exists between the number of different cell types and the IDP proteome fraction across a broad spectrum of uni- and multicellular algae, plants, and animals. We argue that the multifunctionalities conferred by IDPs and the disproportionate involvement of IDPs with AS and PTMs provided a IDP-AS-PTM 'motif' that significantly contributed to the evolution of multicellularity in all major eukaryotic lineages. PMID- 29394381 TI - Case report of the patient source of the Babesia microti R1 reference strain and implications for travelers. AB - Background: In 2002, a previously healthy 69-year-old man travelled to France from the United States and presented to our hospital with a febrile illness that subsequently was determined to be babesiosis. The blood isolated from this patient served as a source for propagation of the Babesia microti R1 strain with subsequent sequencing and annotation of the parasite genome. Methods: Upon admission, we obtained a medical history, performed a physical examination, and examined his blood for the presence of a blood borne pathogen by microscopy, PCR and indirect immunofluorescence antibody testing. Once the diagnosis of babesiosis was made, we reviewed the literature to assess the distribution of B. microti-associated babesiosis cases in immunocompetent patients from outside the USA. Results: The patient recalled a tick bite during the previous month on Cape Cod, Massachusetts. The diagnosis was confirmed by identification of Babesia infected red blood cells on blood smears, amplification of B. microti DNA in blood by PCR and the presence of B. microti antibody in the serum. This strain was the first isolate of B. microti to be fully sequenced and its annotated genome serves as a reference for molecular and cell biology studies aimed at understanding B. microti pathophysiology and developing diagnostic tests and therapies. A review of babesiosis cases demonstrates a worldwide distribution of B. microti and identifies potential emerging endemic areas where travelers may be at risk of contracting B. microti infection. Conclusion: This case provides clinical information about the patient infected with the R1 isolate and a review of travel risk, diagnosis and treatment of babesiosis in endemic and non-endemic areas. PMID- 29394380 TI - The mechanisms of a mammalian splicing enhancer. AB - Exonic splicing enhancer (ESE) sequences are bound by serine & arginine-rich (SR) proteins, which in turn enhance the recruitment of splicing factors. It was inferred from measurements of splicing around twenty years ago that Drosophila doublesex ESEs are bound stably by SR proteins, and that the bound proteins interact directly but with low probability with their targets. However, it has not been possible with conventional methods to demonstrate whether mammalian ESEs behave likewise. Using single molecule multi-colour colocalization methods to study SRSF1-dependent ESEs, we have found that that the proportion of RNA molecules bound by SRSF1 increases with the number of ESE repeats, but only a single molecule of SRSF1 is bound. We conclude that initial interactions between SRSF1 and an ESE are weak and transient, and that these limit the activity of a mammalian ESE. We tested whether the activation step involves the propagation of proteins along the RNA or direct interactions with 3' splice site components by inserting hexaethylene glycol or abasic RNA between the ESE and the target 3' splice site. These insertions did not block activation, and we conclude that the activation step involves direct interactions. These results support a model in which regulatory proteins bind transiently and in dynamic competition, with the result that each ESE in an exon contributes independently to the probability that an activator protein is bound and in close proximity to a splice site. PMID- 29394382 TI - A summary of the imported cases of Chikungunya fever in Japan from 2006 to June 2016. AB - Background: Due to the huge 2-way human traffic between Japan and Chikungunya (CHIK) fever-endemic regions, 89 imported cases of CHIK fever were confirmed in Japan from January 2006 to June 2016. Fifty-four of 89 cases were confirmed virologically and serologically at the National Institute of Infectious Diseases, Japan and we present the demographic profiles of the patients and the phylogenetic features of 14 CHIK virus (CHIKV) isolates. Methods: Patients were diagnosed with CHIK fever by a combination of virus isolation, viral RNA amplification, IgM antibody-, IgG antibody-, and/or neutralizing antibody detection. The whole-genome sequences of the CHIKV isolates were determined by next-generation sequencing. Results: Prior to 2014, the source countries of the imported CHIK fever cases were limited to South and Southeast Asian countries. After 2014, when outbreaks occurred in the Pacific and Caribbean Islands and Latin American countries, there was an increase in the number of imported cases from these regions. A phylogenetic analysis of 14 isolates revealed that four isolates recovered from three patients who returned from Sri Lanka, Malaysia and Angola, belonged to the East/Central/South African genotype, while 10 isolates from 10 patients who returned from Indonesia, the Philippines, Tonga, the Commonwealth of Dominica, Colombia and Cuba, belonged to the Asian genotype. Conclusion: Through the phylogenetic analysis of the isolates, we could predict the situations of the CHIK fever epidemics in Indonesia, Angola and Cuba. Although Japan has not yet experienced an autochthonous outbreak of CHIK fever, the possibility of the future introduction of CHIKV through an imported case and subsequent local transmission should be considered, especially during the mosquito-active season. The monitoring and reporting of imported cases will be useful to understand the situation of the global epidemic, to increase awareness of and facilitate the diagnosis of CHIK fever, and to identify a future CHIK fever outbreak in Japan. PMID- 29394383 TI - Safety of live vaccines on immunosuppressive or immunomodulatory therapy-a retrospective study in three Swiss Travel Clinics. AB - Background: Patients increasingly benefit from immunosuppressive/immunomodulatory medications for a range of conditions allowing them a lifestyle similar to healthy individuals, including travel. However, the administration of live vaccines to immunodeficient patients bears the risk of replication of the attenuated vaccine microorganism. Therefore, live vaccines are generally contraindicated on immunosuppression. Data on live vaccinations on immunosuppressive/immunomodulatory medication are scarce. We identified all travellers seeking pre-travel advice in three Swiss travel clinics with a live vaccine during immunosuppressive/immunomodulatory therapy to ascertain experienced side effects. A retrospective and multi-centre study design was chosen to increase the sample size. Methods: This study was conducted in the travel clinics of the University of Zurich; the Swiss TPH, Basel; and Geneva University Hospitals. Travellers on immunosuppressive/immunomodulatory therapy who received live vaccines [yellow fever vaccination (YFV), measles/mumps/rubella (MMR), varicella and/ or oral typhoid vaccination (OTV)] between 2008 and 2015 were identified and interviewed. A total of 60 age- and sex-matched controls (matched to Basel/Zurich travel clinics travellers) were included. Results: Overall, 197 patients were identified. And 116 patients (59%) and 60 controls were interviewed. YFV was administered 92 times, MMR 21 times, varicella 4 times and OTV 6 times to patients on immunosuppressive/immunomodulatory therapy. Most common medications were corticosteroids (n = 45), mesalazine (n = 28) and methotrexate (n = 19). Live vaccines were also administered on biological treatment, e.g. TNF-alpha inhibitors (n = 8). Systemic reactions were observed in 12.2% of the immunosuppressed vs 13.3% of controls; local reactions in 7.8% of the immunosuppressed vs 11.7% of controls. In controls, all reactions were mild/moderate. In the immunosuppressed, 2/21 severe reactions occurred: severe local pain on interferon-beta and severe muscle/joint pain on sulfasalazine. Conclusion: Safety of live vaccines given to immunosuppressed patients cannot be concluded. However, it is re-assuring that in the examined patient groups no serious side effects or infections by the attenuated vaccine strain occurred. PMID- 29394384 TI - Rickettsia sibirica mongolitimonae infection in a woman travelling from Cameroon: a case report and review of the literature. AB - Rickettsia sibirica mongolitimonae is now a well-known cause of human rickettsial infection, with 52 reported cases, including 47 in southern Europe and one in South Africa. We report the first case of R. sibirica mongolitimonae in Central Africa, likely a sentinel case for a more common disease than originally suspected. PMID- 29394385 TI - Use of a multiplex DNA extraction PCR in the identification of pathogens in travelers' diarrhea. AB - Background: Diarrhea is one of the most common ailments afflicting travelers with attack rates of 30-40% for medium to high-risk destinations. As travelers' diarrhea (TD) is syndromic and caused by a wide range of pathogens, including bacteria, parasites and viruses, multiplex deoxyribonucleic acid (DNA) extraction polymerase chain reaction (PCR) technology can be useful for determining the etiology of TD pathogens. Objective: The goal of this retrospective study was to produce clinically relevant and useful data on gastrointestinal illness related to travel identified by culture-independent methods of diagnosis-use of the multiplex DNA extraction PCR platform (BioFire FilmArray GI Panel) and to describe the use of this technology in detection of enteric pathogens. Method: We reviewed our data in returned travelers from May 2014 to March 2017, looking at demographics, country of travel, number of pathogens found and pathogens by specific region. Results: Stool analysis by DNA extraction PCR was obtained in 388 post-travel patients. Three hundred and twenty-seven of these had diarrhea or other enteric symptoms. Sixty-one travelers presented with enteric symptoms and were diagnosed with post infectious irritable bowel syndrome (PI-IBS) after stool analyses were negative. Of those with diarrhea or gastrointestinal (GI) symptoms and excluding those diagnosed with PI-IBS, 207 patients tested positive for at least 1 enteric pathogen (63.4%). Eighty of those patients were found to have multiple pathogens. Viral pathogens were identified in 38 patients, 18% of the total number of cases. Conclusion: The BioFire FilmArray GI Panel was associated with better detection of pathogens than historical controls while also allowing prompt and accurate diagnosis and potential treatment. A higher proportion of viral pathogens compared with historical assumptions was identified as well as mixed infections with multiple pathogens, a phenomenon largely unknown to clinicians before this technology became available. PMID- 29394386 TI - Multiplex PCR for determining aetiology of travellers' diarrhoea: too much information or too little? PMID- 29394387 TI - Severe post-artesunate delayed onset anaemia responding to corticotherapy: a case report. AB - Delayed onset haemolysis occurring post-artesunate and post-artemisinin combination therapy is secondary to delayed clearance of infected erythrocytes spared by pitting during treatment. We report a case of severe post-treatment delayed haemolytic anaemia with a positive direct antiglobulin test and a positive response to corticosteroid therapy, suggesting an associated immune mechanism. PMID- 29394388 TI - Protecting the health of medical students on international electives in low resource settings. AB - Background: Increasingly, medical students from developed countries are undertaking international medical electives in developing countries. Medical students understand the many benefits of these electives, such as the opportunity to develop clinical skills, to gain insight into global health issues and to travel to interesting regions of the world. However, they may be much less aware of the risk to their health and wellbeing while abroad. Compounding this problem, medical students may not seek advice from travel medicine practitioners and often receive inadequate or no information from their medical school prior to departure. Methods: The PubMed database was searched for relevant literature relating to the health of medical elective students. Combinations of the following key words were used as search terms: 'international health elective', 'medical student' and 'health risks'. Articles were restricted to those published in English from 1997 through June 2017. A secondary review of the reference lists of these articles was performed. The grey literature was also searched for relevant material. Results: This narrative literature review outlines the risks of clinical electives in resource-poor settings which include exposure to infectious illness, trauma, sexual health problems, excessive sun exposure, mental health issues and crime. Medical students may mitigate these health risks by being informed and well prepared for high-risk situations. The authors provide evidence-based travel advice which aims to improve pre-travel preparation and maximize student traveller safety. A safer and more enjoyable elective may be achieved if students follow road safety advice, take personal safety measures, demonstrate cultural awareness, attend to their psychological wellbeing and avoid risk-taking behaviours. Conclusion: This article may benefit global health educators, international elective coordinators and travel medicine practitioners. For students, a comprehensive elective checklist, an inventory of health kit items and useful web-based educational resources are provided to help prepare for electives abroad. PMID- 29394389 TI - Blackwater fever in a non-immune patient with Plasmodium falciparum malaria after intravenous artesunate. AB - Blackwater fever was typically reported after quinine administration, although it is poor recognized in patients receiving artesunate. This case describes a blackwater fever in a non-immune patient after artesunate for severe malaria. It highlights the importance of monitoring haemolytic parameters in severe malaria to avoid renal impairment or severe anaemia. PMID- 29394390 TI - Reply to Comment 'Nocturnal decrease of arterial oxygen content-hidden stimulus for erythropoietin secretion at altitude by Boning et al. on Oxygen saturation increases over the course of the night in mountaineers at high altitude (3050m 6354 m) by Tannheimer et al.' PMID- 29394391 TI - Travelers' diarrhea in children: a blind spot in the expert panel guidelines on prevention and treatment. PMID- 29394392 TI - Female genital mutilation: an evaluation of the knowledge of French general and specialized travel medicine practitioners. AB - We investigated the knowledge of female genital mutilation (FGM) among 60 general and 52 specialized travel medicine practitioners. Less than 50% of these practitioners had adequate knowledge of FGM. Only 42.9% declared having encountered FGM. FGM is likely underestimated in health facilities. Medical education and supporting information should be developed to better address and prevent FGM. PMID- 29394394 TI - Phosphatidylinositol 3-kinase function at very early symbiont perception: a local nodulation control under stress conditions? AB - Root hair curling is an early and essential morphological change required for the success of the symbiotic interaction between legumes and rhizobia. At this stage rhizobia grow as an infection thread within root hairs and are internalized into the plant cells by endocytosis, where the PI3K enzyme plays important roles. Previous observations show that stress conditions affect early stages of the symbiotic interaction, from 2 to 30 min post-inoculation, which we term as very early host responses, and affect symbiosis establishment. Herein, we demonstrated the relevance of the very early host responses for the symbiotic interaction. PI3K and the NADPH oxidase complex are found to have key roles in the microsymbiont recognition response, modulating the apoplastic and intracellular/endosomal ROS induction in root hairs. Interestingly, compared with soybean mutant plants that do not perceive the symbiont, we demonstrated that the very early symbiont perception under sublethal saline stress conditions induced root hair death. Together, these results highlight not only the importance of the very early host-responses on later stages of the symbiont interaction, but also suggest that they act as a mechanism for local control of nodulation capacity, prior to the abortion of the infection thread, preventing the allocation of resources/energy for nodule formation under unfavorable environmental conditions. PMID- 29394393 TI - Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC. AB - Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5 hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineage-specific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmC-rim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC. PMID- 29394396 TI - Prevalence of and factors associated with MDR Neisseria gonorrhoeae in England and Wales between 2004 and 2015: analysis of annual cross-sectional surveillance surveys. AB - Objectives: To describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales. Methods: Isolates from 16 242 gonorrhoea episodes at sexual health clinics within the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) underwent antimicrobial susceptibility testing. MDR-NG was defined as resistance to ceftriaxone, cefixime or azithromycin, plus at least two of penicillin, ciprofloxacin and spectinomycin. Trends in resistance are presented for 2004-15; prevalence and logistic regression analyses for MDR-NG cover the period of the most recent treatment guideline (ceftriaxone plus azithromycin), 2011-15. Results: Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all antimicrobial classes fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5%. In 2011-15, 3.5% of isolates were MDR-NG, most of which were resistant to cefixime (100% in 2011, decreasing to 36.9% in 2015) and/or azithromycin (4.2% in 2011, increasing to 84.3% in 2015). After excluding azithromycin-resistant isolates, modal azithromycin MICs were higher in MDR versus non-MDR isolates (0.5 versus 0.125 mg/L), with similar results for ceftriaxone (modal MICs 0.03 versus <=0.002 mg/L). After adjustment for confounders, MDR-NG was more common among isolates from heterosexual men, although absolute differences in prevalence were small [4.6% versus 3.3% (MSM) and 2.5% (women)]. Conclusions: N. gonorrhoeae is becoming less susceptible to available antimicrobials. Since 2011, a minority of isolates were MDR-NG; however, MICs of azithromycin or ceftriaxone (first-line therapies) for many of these were elevated. These findings highlight the importance of continued antimicrobial stewardship for gonorrhoea. PMID- 29394395 TI - Systems assessment of transcriptional regulation on central carbon metabolism by Cra and CRP. AB - Two major transcriptional regulators of carbon metabolism in bacteria are Cra and CRP. CRP is considered to be the main mediator of catabolite repression. Unlike for CRP, in vivo DNA binding information of Cra is scarce. Here we generate and integrate ChIP-exo and RNA-seq data to identify 39 binding sites for Cra and 97 regulon genes that are regulated by Cra in Escherichia coli. An integrated metabolic-regulatory network was formed by including experimentally-derived regulatory information and a genome-scale metabolic network reconstruction. Applying analysis methods of systems biology to this integrated network showed that Cra enables optimal bacterial growth on poor carbon sources by redirecting and repressing glycolysis flux, by activating the glyoxylate shunt pathway, and by activating the respiratory pathway. In these regulatory mechanisms, the overriding regulatory activity of Cra over CRP is fundamental. Thus, elucidation of interacting transcriptional regulation of core carbon metabolism in bacteria by two key transcription factors was possible by combining genome-wide experimental measurement and simulation with a genome-scale metabolic model. PMID- 29394397 TI - Identification of novel variants of the colistin resistance gene mcr-3 in Aeromonas spp. from the national resistance monitoring programme GERM-Vet and from diagnostic submissions. AB - Objectives: To investigate Aeromonas spp. isolates for the presence of the novel resistance gene mcr-3 or variants thereof and to characterize the positive isolates by whole genome sequence analysis. Methods: A total of 479 unrelated Aeromonas isolates were investigated by PCR for the genes mcr-1, mcr-2 and mcr-3. Positive isolates were investigated for their colistin MICs. Species assignment was based on sequence analysis of 16s rRNA and gyrB and rpoB genes. The mcr carrying contigs obtained by WGS were analysed for the genetic environments of the mcr genes. Results: Four (0.84%) Aeromonas isolates were positive in the mcr 3-specific PCR assay, whereas none of the isolates harboured mcr-1 or mcr-2. Each of the four mcr-3 genes encoded a novel variant, which showed amino acid identities of 95.0%-98.0% to the original Mcr-3 protein. These variants were designated Mcr-3.6 [Aeromonas allosaccharophila from golden orfe (Leuciscus idus)], Mcr-3.7 [Aeromonas media from turkey (Meleagris gallopavo)], Mcr-3.8 [Aeromonas jandaei from koi carp (Cyprinus carpio)] and Mcr-3.9 [Aeromonas hydrophila from koi carp]. The isolate harbouring the mcr-3.9 gene carried an additional mcr-3.8 gene and showed a distinctly higher colistin MIC of >=128 mg/L than all other isolates. The genetic environments of the mcr-3 variant genes in all four isolates differed, but in part resembled the flanking regions of mcr-3.3 from Aeromonas veronii of chicken meat. Conclusions: This study identified four novel Mcr-3 variants. The isolates carrying the respective genes dated back to 2005 suggesting that this gene has existed for more than 12 years. PMID- 29394398 TI - Response to letter to the editor. PMID- 29394399 TI - Epidemiology of invasive aspergillosis and triazole-resistant Aspergillus fumigatus in patients with haematological malignancies: a single-centre retrospective cohort study. AB - Objectives: To investigate the epidemiology and clinical relevance of triazole resistance among patients undergoing treatment for haematological malignancies who are at risk of invasive aspergillosis (IA). Methods: This was a retrospective cohort study for which the records of consecutive patients given chemotherapy for AML or myelodysplastic syndrome (MDS) or who had received an allogeneic HSCT from 2006 to 2012 were reviewed for IA. Triazole resistance was detected by the VIPcheckTM screening method and confirmed by determining the MIC by EUCAST methodology. Results: A total of 432 patients were included, comprising 182 (42.1%) patients who had undergone chemotherapy for AML or MDS, and 250 (57.9%) patients who had undergone an allogeneic HSCT. Probable or proven IA was diagnosed in 36 cases (8.3%, 95% CI 6.0%-11.4%). Of these, 12 (33.3%) were based on recovery of Aspergillus fumigatus from sputum, bronchoalveolar lavage or biopsy, and triazole resistance was found in 2 instances. A. fumigatus was also recovered from one or more specimens from 13 patients without probable or proven IA. Triazole resistance was documented for three patients. The survival rate of patients with IA caused by voriconazole-resistant isolates could not be assessed. Conclusions: The overall frequency of voriconazole-resistant IA among patients at high risk was low. However, the rate of triazole resistance may have been underestimated by the low detection rate based on recovery of A. fumigatus. Alternative diagnostic tests, such as PCR-based assays, may prove better at detecting IA due to triazole-resistant A. fumigatus. PMID- 29394400 TI - Bouveret syndrome. PMID- 29394401 TI - Using Pain Medication Intensity to Stratify Back Pain Among Older Adults. AB - Objective: To examine the prevalence of musculoskeletal back pain among older adults stratified by pain medication intensity to 1) review treatment patterns and 2) consider targeted back pain prevention interventions. Methods: A random sample of older adults age 64 years and older was utilized to identify new and recurring back pain. Prescription pain medications from drug claims were used to stratify to five unique intensity levels. The characteristics of each level were determined using regression models. Results: About 10% had musculoskeletal back pain. Of these, 54% (N = 20,645) had new back pain and 46% (N = 17,252) had recurring back pain. Overall, about 35% received physical therapy. Pain medication intensity levels included no prescription pain medications, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, low-dose opioids, and high-dose opioids (new back pain: 39%, 10%, 6%, 23%, and 23%, respectively; recurring back pain 32%, 9%, 4%, 17%, and 38%, respectively). NSAID and muscle relaxant users were younger, healthier, and received physical therapy. Opioid users were younger, in poorer health, used sleep medications, received physical therapy, and had more falls and higher health care utilization and expenditures. Conclusions: New and recurring back pain patients can be stratified by pain medication intensity to review treatment patterns and target back pain prevention programs. Those with back pain but taking no prescription pain medications may benefit from back pain prevention programs. More research on guidelines for treatment options for those on high levels of pain medications is warranted. PMID- 29394402 TI - Perceived interrelations of pain and cigarette smoking in a sample of adult smokers living with HIV/AIDS. AB - Introduction: Persons living with HIV/AIDS (PLWH) have very high prevalences of both cigarette smoking and pain yet little is known about the relationship between smoking and pain for PLWH. The current study examined the factor structure, reliability, and validity of a measure of perceived interrelations of pain and smoking in a sample of PLWH. Methods: Participants in this study were 108 current cigarette smoking PLWH (64.8% reporting current pain) in the Bronx, New York. Participants completed assessments of demographics, smoking behaviors, and pain. Interrelations of pain and smoking were measured using the 9-item Pain and Smoking Inventory (PSI). The dimensionality of the PSI was evaluated using Horn's Parallel Analysis and exploratory factor analysis. Internal consistency was evaluated using Cronbach's alpha and validity analyses evaluated the relationship between the PSI and demographics, HIV clinical characteristics, smoking, and pain in the total sample. Results: A single factor structure was the best fit for the PSI. The internal consistency of the PSI total score was excellent in the total sample (alpha=0.94) and among participants with pain (alpha=0.93). The PSI total score was significantly higher for PLWH who smoke and had current pain versus no current pain. Among smokers with HIV and pain, higher PSI scores were associated with higher pain interference, pain severity, and certain neuropathic pain symptoms (i.e., numbness, pain to touch). Conclusions: Among a sample of PLWH, the PSI appeared to be a reliable and valid instrument as a one-factor measure to assess perceived interrelations among pain and cigarette smoking. Implications: Even though persons living with HIV (PLWH) have very high prevalences of both pain and cigarette smoking, little is known about the relationship of pain and smoking for PLWH. This study is the first to examine a measure of the perceived interrelations of pain and smoking in a sample of PLWH. The measure was reliable and valid, and higher scores, reflecting that higher perceived interrelations of pain and smoking, were associated with more intense pain and pain interference. Learning more about pain and smoking among PLWH will help to better target smoking interventions to this key subgroup of smokers. PMID- 29394403 TI - Arabidopsis plants exposed to dioxin result in a WRINKLED seed phenotype due to 20S proteasomal degradation of WRI1. AB - Dioxins are highly toxic persistent organic pollutants bioaccumulated by both plants and animals that cause severe developmental abnormalities in humans. We investigated the effects of dioxins on seed development in Arabidopsis. Plants were exposed to various concentrations of the most toxic congener of dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the effects on seed development were analysed in-depth at transcriptome, proteome and metabolome levels. Exposure to dioxin led to generalized effects on vegetative tissues plus a specific set of perturbations to seed development. Mature seeds from TCDD-treated plants had a characteristic 'wrinkled' phenotype, due to a two-thirds reduction in storage oil content. Transcriptional analysis of a panel of genes related to lipid and carbohydrate metabolism was consistent with the observed biochemical phenotypes. There were increases in WRI1 and LEC1 expression but decreases in ABI3 and FUS3 expression, which is puzzling in view of the low seed oil phenotype. This anomaly was explained by increased expression of 20S proteasome components that resulted in a substantial degradation of WRI1 protein, despite the up-regulation of the WRI1 gene. Our findings reveal novel effects of dioxins that lead to altered gene regulation patterns that profoundly affect seed development in Arabidopsis. PMID- 29394404 TI - Scleroderma-like renal crisis in a patient with anti-threonyl-tRNA synthetase associated antisynthetase syndrome. PMID- 29394405 TI - Stillbirth among women prescribed nicotine replacement therapy in pregnancy: Analysis of a large UK pregnancy cohort. AB - Objective: To compare risk of stillbirth between maternal smokers and those prescribed NRT during pregnancy. Design: Cross-sectional analysis nested in a pregnancy cohort with longitudinal routinely-recorded medical data. Setting: United Kingdom primary care; The Health Improvement Network (THIN) general practice database. Population: 220,630 singleton pregnancies ending in live or stillbirth, 2001-2012. Methods: Women were categorised into three groups: NRT (prescribed during pregnancy or one month before conception); smokers; controls (non-smokers without a pregnancy NRT prescription). Main Outcome Measure: odds ratios (OR) adjusted to maternal characteristics and 95% confidence intervals (CIs) for stillbirth. Results: A total of 805 pregnancies ended in stillbirth (3.6/1,000 births). Absolute risks of stillbirth in NRT and smoker groups were both 5/1,000 births compared with 3.5/1,000 births in the control group. Compared with the control group, the adjusted odds of stillbirth in the NRT group was not statistically significant (OR=1.35, 95% CI 0.91-2.00), although it was similar in magnitude to that in the smokers group (OR=1.41, 95% CI 1.13-1.77). Conclusions: We found no evidence of a statistically significant association between being prescribed NRT during pregnancy and odds of stillbirth compared with non-smoking women. Although our study had much larger numbers than any previously, an even larger study with biochemically-validated smoking outcome data and close monitoring of NRT use throughout pregnancy is required to exclude effects on findings of potential exposure misclassification. PMID- 29394406 TI - Well-trained sonographers are worth their weight in gold: ultrasound in systemic sclerosis. PMID- 29394408 TI - Secukinumab for the maintenance of glucocorticoid-free remission in a patient with giant cell arteritis and psoriatic arthritis. PMID- 29394407 TI - A context-specific cardiac beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart. AB - Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675 beta-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-beta catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of beta-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2-5 and GATA4 in stabilized-beta catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/beta-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing beta-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/beta-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway. PMID- 29394409 TI - Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction. AB - Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex (PFC) is a hallmark of schizophrenia pathophysiology. Although N-methyl-D-aspartate receptor (NMDAR) hypofunction is also implicated in schizophrenia, it remains unclear whether NMDAR hypofunction leads to dopamine release abnormalities. We previously demonstrated schizophrenia-like phenotypes in GABAergic neuron-specific NMDAR hypofunctional mutant mice, in which Ppp1r2 Cre dependent deletion of indispensable NMDAR channel subunit Grin1 is induced in corticolimbic GABAergic neurons including parvalbumin (PV)-positive neurons, in postnatal development, but not in adulthood. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: nucleus accumbens (NAc) dopamine release was enhanced by amphetamine in postnatal Ppp1r2-Cre/Grin1 knockout (KO) mice, whereas dopamine release was dramatically reduced in the medial PFC (mPFC) compared to controls. Basal tissue dopamine levels in both the NAc and mPFC were unaffected. Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area (VTA). These effects appear to be both developmentally and cell-type specifically modulated, since PV-specific Grin1 KO mice could induce the same effects as seen in postnatal-onset Ppp1r2-Cre/Grin1 KO mice, but no such abnormalities were observed in somatostatin-Cre/Grin1 KO mice or adult onset Ppp1r2-Cre/Grin1 KO mice. These results suggest that PV GABAergic neuron NMDAR hypofunction in postnatal development confers bidirectional NAc hyper- and mPFC hypo-sensitivity to amphetamine-induced dopamine release, similar to that classically observed in schizophrenia pathophysiology. PMID- 29394410 TI - Sleep lengthening in late adulthood signals increased risk of mortality. AB - Study Objectives: Epidemiological evidence indicates that both short and long sleep at midlife increase mortality risk, but few studies have examined how change in sleep duration between midlife and later life affects this risk. We examined the association between change in sleep duration and mortality risk. Methods: The Singapore Chinese Health Study is a prospective cohort of 63257 Chinese in Singapore aged 45-74 years at recruitment (1993-1998). Self-reported sleep duration was collected from 39523 participants who completed both baseline (mean age 54.8 years) and follow-up II (mean age 67.9 years; 2006-2010) interviews, which were on average 12.7 years apart. Mortality data were obtained via linkage with national death registry up to December 31, 2015. Results: Compared with participants who reported sleeping the recommended duration (7 hr) at both interviews, those with persistently short sleep (<=5 hr) had increased risk of all-cause mortality (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.06-1.53). Similarly, those with persistently long sleep (>=9 hr) had increased risk of all-cause (HR 1.47, 95% CI 1.24-1.73) and cardiovascular (HR 1.40, 95% CI 1.04-1.89) mortality. The proportion of long-sleepers increased with aging (6% 23.7%). Progression to long sleep from short (HR 1.50, 95% CI 1.24-1.81) or recommended (HR 1.43, 95% CI 1.25-1.64) duration was associated with increased all-cause mortality, especially for cardiovascular mortality. Change in sleep duration was not linked to cancer mortality. Conclusions: Persistent short or long sleep or increasing sleep duration in late adulthood was associated with increased risk of all-cause mortality, especially from cardiovascular causes. PMID- 29394411 TI - Changing epidemiology of visceral leishmaniasis in northeastern Brazil: a 25-year follow-up of an urban outbreak. AB - Background: Visceral leishmaniasis (VL) continues to be a deadly parasitic disease in Brazil but the epidemiology has changed. The objective of this study was to assess the evolution of urban VL in the city of Natal, Brazil, over the past 25 y. Methods: A retrospective study of human VL was performed, considering reported cases over the past 25 y in Natal. Analyses considered the spatial distribution of VL cases, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) co-infection, Leishmania infantum infection in dogs, density of the insect vector (Lutzomyia longipalpis) and socio-economic factors. Results: Paralleling migration of the population, VL cases changed from mostly rural to predominantly urban regions. The incidence of human VL was highest during the initial years (1990-1994) of our study. Human VL was positively associated with a high density of L. longipalpis, a high prevalence of canine L. infantum infection and HIV/AIDS co-infection. The average age at diagnosis increased over prior years and males were more frequently affected. The overall fatality rate was 6%. Socio-economic variables indicative of poverty were associated with a greater incidence of VL and clusters of VL. Conclusion: VL has become endemic in Natal. The disease is associated with poverty and male gender. Surprisingly, there has been an increase in the age at diagnosis. PMID- 29394412 TI - Footprints of divergent evolution in two Na+/H+ type antiporter gene families (NHX and SOS1) in the genus Populus. AB - Populus, a deciduous tree species of major economic and ecological value, grows across the range in which trees are distributed in the Northern Hemisphere. Patterns of DNA variation are often used to identify the evolutionary forces shaping the genotypes of distinctive species lineages. Sodium/hydrogen (Na+/H+) antiporter genes have been shown to play a central role in plant salt tolerance. Here, we analyzed DNA nucleotide polymorphisms in the Na+/H+ antiporter (NHX and SOS1) gene families across 30 different Populus species using several methods of phylogenetic analysis and functional verification. NHX and SOS1 gene families in the genus Populus have expanded from the state in their common ancestors by duplication events, and their distinct lineages have been retained. Signals of positive selection at certain amino acid sites in different members of the Na/H antiporter gene families show that the dynamics that drive the evolution of each gene vary. SOS1 has undergone duplication in Populus euphratica and been subjected to adaptive evolution in section Turanga; the paralog of PeSOS1 (PeSOS1.2) can complement the Escherichia coli mutant EP432; and the expression pattern of PeSOS1.2 is different from that of PeSOS1, a fact which may have been beneficial for P. euphratica, conferring a fitness advantage in saline habitats. The divergent evolution of the individual members of the NHX and SOS1 gene families is likely to have been influenced by the varied ecological and environmental niches occupied by the different poplar species, giving rise to evolutionary footprints that reflect the specific functions and subcellular localizations of the proteins encoded by these genes. PMID- 29394413 TI - Sleep-disordered breathing in epilepsy: epidemiology, mechanisms, and treatment. AB - Epilepsy is a group of neurological conditions in which there is a pathological and enduring predisposition to generate recurrent seizures. Evidence over the last few decades suggests that epilepsy may be associated with increased sleep disordered breathing, which may contribute towards sleep fragmentation, daytime somnolence, reduced seizure control, and cardiovascular-related morbidity and mortality. Chronic sleep-disordered breathing can result in loss of gray matter and cause deficits to memory and global cognitive function. Sleep-disordered breathing is a novel and independent predictor of sudden cardiac death and, as such, may be involved in the mechanisms leading to sudden unexpected death in epilepsy. Despite this, the long-term consequences of sleep-disordered breathing in epilepsy remain unknown, and there are no guidelines for screening or treating this population. There is currently insufficient evidence to indicate continuous positive airway pressure (CPAP) for the primary or secondary prevention of cardiovascular disease, and recent evidence has failed to show any reduction of fatal or nonfatal cardiovascular endpoints. Treatment of sleep-disordered breathing may potentially improve seizure control, daytime somnolence, and neurocognitive outcomes, but few studies have examined this relationship. In this review, we examine sleep-disordered breathing in epilepsy, and discuss the potential effect of epilepsy treatments. We consider the role of CPAP and other interventions for sleep-disordered breathing and discuss their implications for epilepsy management. PMID- 29394414 TI - Ultrafine Particulate Matter Combined With Ozone Exacerbates Lung Injury in Mature Adult Rats With Cardiovascular Disease. AB - Particulate matter (PM) and ozone (O3) are dominant air pollutants that contribute to development and exacerbation of multiple cardiopulmonary diseases. Mature adults with cardiovascular disease (CVD) are particularly susceptible to air pollution-related cardiopulmonary morbidities and mortalities. The aim was to investigate the biologic potency of ultrafine particulate matter (UFPM) combined with O3 in the lungs of mature adult normotensive and spontaneously hypertensive (SH) Wistar-Kyoto rats. Conscious, mature adult male normal Wistar-Kyoto (NW) and SH rats were exposed to one of the following atmospheres: filtered air (FA); UFPM (~ 250 MUg/m3); O3 (1.0 ppm); or UFPM + O3 (~ 250 MUg/m3 + 1.0 ppm) combined for 6 h, followed by an 8 h FA recovery period. Lung sections were evaluated for lesions in the large airways, terminal bronchiolar/alveolar duct regions, alveolar parenchyma, and vasculature. NW and SH rats were similarly affected by the combined-pollutant exposure, displaying severe injury in both large and small airways. SH rats were particularly susceptible to O3 exposure, exhibiting increased injury scores in terminal bronchioles and epithelial degeneration in large airways. UFPM-exposure groups had minimal histologic changes. The chemical composition of UFPM was altered by the addition of O3, indicating that ozonolysis promoted compound degradation. O3 increased the biologic potency of UFPM, resulting in greater lung injury following exposure. Pathologic manifestations of CVD may confer susceptibility to air pollution by impairing normal lung defenses and responses to exposure. PMID- 29394415 TI - Zika virus transmission in Angola and the potential for further spread to other African settings. AB - Background: Cases of Zika virus were recently detected in Luanda, Angola, a major travel hub in Africa. The risk of Zika virus transmission throughout the continent from Angola is evaluated. Methods: Travel volumes were assessed using monthly passenger-level flight data from Luanda to all locations throughout Africa. Travel data was superimposed onto seasonal environmental suitability maps that predict the potential for subsequent Zika virus transmission. Results and Conclusions: Windhoek, Maputo, Durban and Kinshasa have the greatest potential for Zika virus introduction and transmission during the southern hemisphere summer months, and Nairobi during the northern hemisphere summer months. PMID- 29394416 TI - Sex-Chromosome Recombination in Common Frogs Brings Water to the Fountain-of Youth. AB - According to the canonical model of sex-chromosome evolution, the degeneration of Y or W chromosomes (as observed in mammals and birds, respectively) results from an arrest of recombination in the heterogametic sex, driven by the fixation of sexually antagonistic mutations. However, sex chromosomes have remained homomorphic in many lineages of fishes, amphibians, and nonavian reptiles. According to the "fountain-of-youth" model, this homomorphy results from occasional events of sex reversal. If recombination arrest in males is controlled by maleness per se (and not by genotype), then Y chromosomes are expected to recombine in XY females, preventing their long-term degeneration. Here, we provide field support for the fountain-of-youth, by showing that sex-chromosome recombination in Rana temporaria only depends on phenotypic sex: naturally occurring XX males show the same restriction of recombination as XY males (average map length ~2 cM), while XY females recombine as much as XX females (average map length ~150 cM). Our results challenge several common assumptions regarding the evolution of sex chromosomes, including the role of sexually antagonistic genes as drivers of recombination arrest, and that of chromosomal inversions as underlying mechanisms. PMID- 29394417 TI - Association Analysis Identifies New Risk Loci for Coal Workers' Pneumoconiosis in Han Chinese Men. AB - Coal worker's pneumoconiosis (CWP) is a debilitating and progressive occupational lung disease resulted from long-term inhalation of airborne silica-containing coal mine dust. Both environmental factors and genetic variations contribute to CWP. Our previous genome-wide association study (GWAS) revealed a tiny fraction of variants with the top associations in Chinese Han population. To identify novel susceptibility loci of CWP, functional variants with suboptimal associations in the GWAS scan were further studied here. Imputation was firstly performed to access the associations between ungenotyped variants and CWP risk, and suboptimal associations with p < 1.0 * 10-3 were annotated with genotype tissue expression (GTEx) and dbNSFP. Further, expression quantitative trait loci (eQTL) and nonsynonymous variants were validated within an independent cohort with 703 CWP cases and 705 exposed controls. Comprehensively functional annotations were performed for identified single nucleotide polymorphism (SNPs) based on multiple bioinformatics databases and websites. We found 4 CWP risk associated eQTL SNPs, including rs10797062 at 1q23.2 (p = 6.91 * 10-4, OR = 1.28), rs1667614 at 2q13.1 (p = 1.48 * 10-4, OR = 0.53), rs2540438 at 2q33.1 (p = 2.13 * 10-3, OR = 1.33), and rs2274554 at 13q31.1 (p = 9.01 * 10-5, OR = 1.35). Based on the results from GTEx, the identified variants were significantly associated with host genes in lung tissues: rs10797062-ATP1A4 (p = 8.60 * 10-11), rs1667614-FNBP1P1 (p = 1.00 * 10-20), rs2540438-ALS2CR12 (p = 1.90 * 10-7), and rs2274554-RBM26 (p = 5.00 * 10-6). Joint effect analysis showed the risk of CWP was significantly increased with the number of risk variant alleles in an allele dosage manner (ptrend = 2.20 * 10-12). Enrichment pathway analysis suggested coexpressed genes of ATP1A4, FNBP1P1, and RBM26 were enriched in Ubiquitin mediated proteolysis pathway simultaneously. These results may provide a deeper understanding of the genetic predisposition of CWP. PMID- 29394418 TI - The Registrar. PMID- 29394419 TI - Tobacco price increases and population interest in smoking cessation in Japan between 2004 and 2016: a Google Trends analysis. AB - Introduction: Tobacco price increases can generate increased public interest in smoking cessation, but it is not clear how long this interest lasts. Our objective was to evaluate the duration of the impact of cigarette price increase in Japan using Google search data. Methods: Monthly or daily aggregated Google search volume for smoking cessation in Japan from 2004 to 2016 was collected in terms of relative search volume (RSV) ranging from 0-100. Using monthly RSV data, we evaluated possible relationships between the RSVs and tobacco control measures in Japan. Time periods within which the impact of search volume significantly increased were identified by cluster detection test, using daily RSV data. A spike in RSV preceding the enforcement of a cigarette price increase revealed an anticipation effect. Results: Between 2004 and 2016 the three highest monthly RSV spikes were observed in July 2006 (RSV=66), when cigarette prices increased by 11%, and in September (RSV=90) and October 2010 (RSV=100), when cigarette prices increased by 37%. Regarding daily RSV, the detected cluster size around the price increase in 2010 (52 days) was longer than that in 2006 (17 days). In 2010, a cluster period of 25 days before the date of the price increase was observed, suggesting an anticipation effect. After the onset of the price increase, a cluster of 27 days was detected. When the cigarette price increased due to consumption tax in April 2014, almost no anticipation effect was observed. Conclusions: The population impact of tobacco price increases on smoking cessation may be assessed using Google Trends data. The cluster indicates that a higher cigarette price increase had a higher and longer-lasting effect on population interest in cessation, but the impact may continue for a relatively short time. Implications: To examine the duration of the impact of cigarette price increases on population interest in smoking cessation in Japan, Google search data for smoking cessation was analyzed. Between 2004 and 2016 the three highest spikes of monthly relative search volume (RSV) were observed in October 2010, when cigarette prices increased by 37%. Analyzing daily RSV data, the detected cluster size around the price increase in 2010 was 52 days and a cluster period of 25 days before the date of the price increase was observed, suggesting an anticipation effect. The cluster indicates that a higher cigarette price increase had a higher and longer-lasting effect, but the population impact continues for a relatively short time. Further increases in the price of cigarettes are necessary. PMID- 29394420 TI - Cognitive Behavioral Therapy in the Treatment of Insomnia. AB - Insomnia disorder is present in as much as 30% of the general adult population. Given the significant adverse effects of pharmacotherapy, cognitive behavioral therapy (CBT) has been found to be an effective alternative in individuals with insomnia. CBT for insomnia (CBTi) encompasses sleep hygiene, stimulus control, sleep restriction, cognitive therapy, and relaxation training. In this article we review evidence that establishes CBTi as a useful treatment affecting remission, sleep onset latency, wakefulness after sleep, sleep efficiency, and sleep quality in adults with insomnia to include older adults and adolescents. In addition, we briefly highlight various CBTi delivery methods as well as barriers to accessing this safe and effective therapy. PMID- 29394421 TI - On "Improving Mental Health Services Through Physician Assistants: Legislation in Several Southern States". PMID- 29394422 TI - Authors' Response. PMID- 29394423 TI - Assessing Correlation of Residency Applicants' Interview Dates With Likelihood of Matching. AB - OBJECTIVES: This study aimed to determine whether the timing of an interview relative to the recruitment season was associated with being ranked or matched at an academic medical center. METHODS: Eleven specialties (anesthesiology, diagnostic radiology, emergency medicine, family medicine, general surgery, internal medicine, neurology, neurosurgery, obstetrics-gynecology, orthopedic surgery, and psychiatry) that participated in the National Resident Matching Program were included in the study. Each program's total number of interview days during the October 2014-January 2015 interview season were divided equally into three interview time periods. The Cochran-Armitage trend test was used to evaluate associations among the three interview time periods (early, middle, and late) and interviewee outcomes (ranked or matched at our institution) for all subjects combined for each of the 11 programs and for specialty groups (medical, surgical, and hospital). RESULTS: Of 1034 applicants included in the analyses, 60% were men. Most were graduated from US medical schools (59.8%; a total of 103 applicants obtained first-year training positions through the Match [95.4% combined fill rate]). Twenty-nine interviewed early, 38 in the middle, and 36 in the late period (P = 0.3877). A total of 864 applicants were ranked by 1 of the 11 residency programs at the study site: 267 in the early period, 319 in the middle, and 278 in the late period (P = 0.4184). Being ranked in association with specialty classification also showed no significant differences. CONCLUSIONS: Interview timing had no relation to the likelihood of a match or being ranked by 1 of the 11 programs studied at our institution. These findings help dispel misconceptions about the importance of the interview date for a successful match. PMID- 29394424 TI - Implementation of a New Guideline and Educational Sessions to Reduce Low-Value Continuous Pulse Oximetry Among Hospitalized Patients. AB - OBJECTIVES: The use of continuous pulse oximetry (CPOX) is ubiquitous among hospitalized patients, despite limited evidence that it improves clinical outcomes. The objective of this study was to reduce the use of CPOX among hospitalized patients in the nonintensive care unit and nonprogressive care unit settings. METHODS: This interventional trial included the creation a new local guideline for CPOX use and subsequent staff education. CPOX use, patient acuity, hospital length of stay, and code blue events were measured before and after the intervention. RESULTS: Postintervention there was a clinically significant and sustained decrease in CPOX use of 18% over 1 year. There were no significant changes postintervention in hospital length of stay or number of code blue events. CONCLUSIONS: Development of a guideline for CPOX use and staff education successfully led to a decrease in CPOX use, without an increase in hospital length of stay or code blue events. PMID- 29394425 TI - Hospital Readmission Rates Following AMI: Potential Interventions to Improve Efficiency. AB - OBJECTIVES: Quality of care utilization measures for patients admitted to the hospital with an acute myocardial infarction (AMI) include length of stay (LOS) and 30-day readmission rates. Our aim was to test whether efforts resulting in reduced LOS in patients diagnosed as having AMI would result in a higher risk of readmission within 30 days of hospital discharge and whether specific interventions could be targeted to reduce readmissions. METHODS: Using data supplied by the Veterans Affairs Inpatient Evaluation Center, we analyzed both the readmissions within 30 days of an AMI and LOS and determined the timing of readmissions and associated diagnoses. RESULTS: During 2013-2015, 35 (13.3%) of 263 patients with AMI were readmitted within 30 days of discharge compared with 19 (13.4%) of 142 patients during 2016 (not significant). During the same time, LOS was <3 days in most patients. From 2013 to 2015, the initial hospital time was 6 +/- 6 days, whereas time out of the hospital before readmission was 11 +/- 8 days; these times did not differ from 2016. Initial therapeutic decisions were based on coronary anatomy in >90% of patients with a decision to proceed with revascularization in most patients. Diagnoses during readmission to the hospital were also similar during early and later time periods and most frequently were a result of either coronary artery bypass grafting-related complications from the initial hospitalization or elective coronary artery bypass grafting. Acute coronary syndrome-related diagnoses and recurrent noncardiac causes of chest pain also were common diagnoses during both time periods and did not involve extensive workup during the readmission. CONCLUSIONS: Readmissions for patients with AMI were stable during a 4-year period, at a time that efforts to reduce LOS were emphasized. Because a significant proportion of readmissions involved noncardiac sources of chest pain, improved communication between the emergency department and in-patient cardiology services at the time of triage may be a feasible way to improve efficiency of utilization. PMID- 29394426 TI - History of Music Therapy and Its Contemporary Applications in Cardiovascular Diseases. AB - Contrary to what is commonly believed, music therapy is an old cure, the use of which is lost in the mists of time. Music always has been perceived to have particular healing powers, and the entire history of civilization contains aspects that link music to physical and mental healing. It seems that the adoption of music for therapeutic purposes harks back to a distant past, probably since the Paleolithic period: it was believed that listening to music could affect the behavior of human beings. In later centuries, the concept of "musical organ-tropism" was born and developed, because according to the type of music, one may affect the cardiovascular, respiratory, and neuroendocrine systems. Studies have shown that music can powerfully evoke and modulate emotions and moods, along with changes in heart activity, blood pressure, and breathing. Indeed, the following findings arise from the literature: heart and respiratory rates are higher in response to exciting music than in the case of tranquilizing music. In addition, music produces activity changes in brain structures (amygdala, hypothalamus, insular and orbitofrontal cortex) known to modulate heart function. This article provides a careful overview of music therapy history from prehistory to the present and a review of the latest applications of music therapy in cardiovascular diseases. PMID- 29394427 TI - Association of Anemia with Outcomes of Acute Heart Failure. AB - OBJECTIVES: Anemia is common in patients presenting with acute congestive heart failure (CHF); when hemoglobin (HGB) declines to low levels, it can result in worse outcomes. The aim of this study was to determine a level of HGB on admission or discharge that affects outcomes in patients with CHF and then to evaluate the effect of the low HGB levels on these outcomes. METHODS: We conducted a retrospective cohort study of 756 patients admitted with acute CHF during the period January 1, 2011-December 31, 2014. We used multivariable regression analysis to evaluate the relation among HGB levels and three major outcomes: 3-year mortality, 30-day readmission rate, and length of stay (LOS). RESULTS: Compared with patients with HGB >=10 g/dL, patients with HGB <10 g/dL on discharge from the hospital had higher mortality (3-year survival 46% vs 33%, P = 0.023) and 30-day readmission rates (23% vs 14%; P = 0.008) and increased LOS (4.8 vs 3.2 days, P < 0.001). Patients with admission HGB <10 g/dL had higher mortality rates (3-year survival 45% vs 32%, P = 0.019) and increased LOS (4.5 vs 3.4 days, P = 0.014). A lower admission HGB value was associated with higher 30 day readmission rates, but it was not statistically significant (P = 0.06). CONCLUSIONS: An HGB level <10 g/dL on admission or discharge in patients hospitalized with acute CHF is associated with a significantly worse outcome. PMID- 29394428 TI - Vision Screening in Adults Across the Life Span. AB - OBJECTIVES: The goal of this study was to determine whether adults across the life span differ in responses to quick vision screening and how those responses relate to adults' use of specialized eye care. METHODS: Subjects were 363 community-dwelling ambulatory adults, 21 to 95 years old, who were tested while they wore their corrective lenses during routine visits to a tertiary care facility. No subjects had known neurological impairments, age-related macular degeneration, or other significant eye disease. A wall-mounted Early Treatment in Diabetic Retinopathy Study chart was used. RESULTS: Older adults 58 years old or older had significantly worse scores than younger adults. Scores did not differ between subjects who had been tested within or prior to the last 10 months. Older subjects had their vision tested significantly more recently than younger subjects. CONCLUSIONS: Vision screening is quick, inexpensive, and easily performed by ancillary staff, and it may provide the physician with useful additional information for treatment planning. PMID- 29394429 TI - Differences Between Snakebites with Concomitant Use of Alcohol or Drugs and Single Snakebites. AB - OBJECTIVES: Published reports have suggested that the concurrent use of alcohol or drugs occurs among some snakebite victims, but no national assessment of such data exists. METHODS: We used data from US poison control centers collected during telephone calls in calendar years 2000-2013 to compare snake envenomations with concomitant use of drugs, alcohol, or both to snakebites lacking such use. RESULTS: A total of 608 snakebites with 659 instances of concomitant alcohol/drug use were reported, which represent approximately 1% of 92,751 snakebites reported to US poison control centers. An annual mean of 48 snakebites with concomitant use of alcohol/drugs was reported, compared with a mean of 6625 snakebites per year with no concomitant use of alcohol/drugs. Most cases involved men, peaked during the summer months, and involved copperheads or rattlesnakes, which mirrored overall trends. Snakebite victims who also used alcohol/drugs were more likely than victims with only a snakebite reported to be bitten by rattlesnakes, to be admitted to the hospital, and die. Alcohol was the most common reported concomitant substance, but other substances were reported. CONCLUSIONS: Snakebites with concomitant use of alcohol/drugs are uncommon, accounting for approximately 1% of the snakebite envenomations reported annually to US poison control centers; however, snakebite victims also reporting alcohol/drug use are more likely to be bitten by rattlesnakes, be admitted to a healthcare facility, and die. PMID- 29394430 TI - Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center. AB - OBJECTIVES: To design and implement a formal otolaryngology inpatient consultation service that improves satisfaction of consulting services, increases educational opportunities, improves the quality of patient care, and ensures sustainability after implementation. METHODS: This was a retrospective cohort study in a large academic medical center encompassing all inpatient otolaryngology service consultations from July 2005 to June 2014. Staged interventions included adding fellow coverage (July 2007 onward), intermittent hospitalist coverage (July 2010 onward), and a physician assistant (October 2011 onward). Billing data were collected for incidences of new patient and subsequent consultation charges. The 2-year preimplementation period (July 2005-June 2007) was compared with the postimplementation periods, divided into 2-year blocks (July 2007-June 2013). Outcome measures of patient encounters and work relative value units were compared between pre- and postimplementation blocks. RESULTS: Total encounters increased from 321 preimplementation to 1211, 1347, and 1073 in postimplementation groups (P < 0.001). Total work relative value units increased from 515 preimplementation to 2090, 1934, and 1273 in postimplementation groups (P < 0.001). CONCLUSIONS: A formal inpatient consultation service was designed with supervisory oversight by non-Accreditation Council for Graduate Medical Education fellows and then expanded to include intermittent hospitalist management, followed by the addition of a dedicated physician assistant. These additions have led to the formation of a sustainable consultation service that supports the mission of high-quality care and service to consulting teams. PMID- 29394431 TI - Commentary on "Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center". PMID- 29394432 TI - Risk Factors for Failure in Complicated Intraabdominal Infections. AB - OBJECTIVES: Approximately 20% of patients with complicated intraabdominal infections (cIAIs) fail therapy. The purpose of this study was to identify risk factors for clinical failure in patients with cIAIs. METHODS: International Classification of Diseases, Ninth Revision codes for cIAIs were obtained to identify patients. Adult patients who received at least 48 hours of intravenous antibiotics were included. Patients were chronologically matched for age, sex, and comorbidities. The primary outcome was clinical failure. Statistical analysis included bivariate tests and multivariable logistic regression. RESULTS: A total of 1405 patients were screened; 139 patients were included. The median (interquartile range) age and Charlson Comorbidity Index were 54 (37-62) years and 0 (0-1), respectively. Clinical failure was observed in 47 patients (34%), with 5 deaths (3.6%). Multivariate analysis of the unmatched population showed older age was protective (odds ratio [OR] 0.967, 95% confidence interval [CI] 0.944-0.991). In the matched population elevated serum creatinine (OR 2.2168, 95% CI 1.091-4.308) and increased time to source control (OR 1.015, 95% CI 1.000 1.030) were predictive of clinical failure. CONCLUSIONS: In a low comorbid cIAI population with and without surgical intervention, serum creatinine was an independent risk factor for clinical failure. In the matched case-control of patients, time to source-control procedure was an independent predictor of clinical failure. PMID- 29394433 TI - Biomechanics of Lumbar Motion-Segments in Dynamic Compression. AB - Recent epidemiology studies have reported increase in lumbar spine injuries in frontal crashes. Whole human body finite element models (FEHBM) are frequently used to delineate mechanisms of such injuries. However, the accuracy of these models in mimicking the response of human spine relies on the characterization data of the spine model. The current study set out to generate characterization data that can be input to FEHBM lumbar spine, to obtain biofidelic responses from the models. Twenty-five lumbar functional spinal units were tested under compressive loading. A hydraulic testing machine was used to load the superior ends of the specimens. A 75N load was placed on the superior PMMA to remove the laxity in the joint and mimic the physiological load. There were three loading sequences, namely, preconditioning, 0.5 m/s (non-injurious) and 1.0 m/s (failure). Forces and displacements were collected using six-axis load cell and VICON targets. In addition, acoustic signals were collected to identify the times of failures. Finally, response corridors were generated for the two speeds. To demonstrate the corridors, GHBMC FE model was simulated in frontal impact condition with the default and updated lumbar stiffness. Bi-linear trend was observed in the force versus displacement plots. In the 0.5 m/s tests, mean toe- and linear-region stiffnesses were 0.96+/-0.37 and 2.44+/-0.92 kN/mm. In 1.0 m/s tests, the toe and linear-region stiffnesses were 1.13+/-0.56 and 4.6+/-2.5 kN/mm. Lumbar joints demonstrated 2.5 times higher stiffness in the linear-region when the loading rate was increased by 0.5 m/s. PMID- 29394434 TI - Human Shoulder Response to High Velocity Lateral Impact. AB - The armies of the North Atlantic Treaty Organization need a shoulder injury criterion for the EuroSID-2re dummy that must be reliable over a large range of loading conditions, from high velocity, short duration impacts (28 m/s - 3 ms) to low velocity long, duration impacts (4 m/s - 50 ms). In the literature, the human shoulder response to lateral impact was investigated at bounds of the loading condition spectrum as previously mentioned. For the low velocities, the injuries were mainly clavicle fractures and the maximum compression between the acromion and the sternum (Cmax) was proposed as an injury criterion. For the high velocities, the typical injury was humerus fractures, including a crushed humeral head. The present study investigates the human shoulder response at an intermediate loading condition (14 m/s - 9 ms). Six lateral shoulder impact tests have been performed with three Post Mortem Human Subjects using a rigid impactor. The duration of the impact was controlled by means of an aluminum honeycomb that decelerated the impactor during the impact. The shoulder external deflection (impactor-to-sternum) ranged between 40 to 64 mm and the applied forces ranged from 4.3 kN to 8 kN. Four shoulders out of six sustained AIS2 injuries. Two acromio-clavicular joint dislocations, one clavicle fracture, and one scapula fracture were observed. Though the shoulder force responses were closer to those induced by the high velocity, short duration impacts, the injury patterns resembled those observed for low velocity, long duration loading conditions. Furthermore, the estimated acromion-to-sternum deflection values were not inconsistent with the prediction of the shoulder injury risk curve of the literature. Despite the relatively high-velocity impact (14.3 m/s), the shoulder injury mechanism appeared to be similar to those observed in the automotive field. PMID- 29394435 TI - Strain-Rate Dependency of Axonal Tolerance for Uniaxial Stretching. AB - This study aims to clarify the relation between axonal deformation and the onset of axonal injury. Firstly, to examine the influence of strain rate on the threshold for axonal injury, cultured neurons were subjected to 12 types of stretching (strains were 0.10, 0.15, and 0.20 and strain rates were 10, 30, 50, and 70 s-1). The formation of axonal swellings and bulbs increased significantly at strain rates of 50 and 30 s-1 with strains of 0.15 and 0.20, respectively, even though those formations did not depend on strain rates in cultures exposed to a strain of 0.10. Then, to examine the influence of the strain along an axon on axonal injury, swellings were measured at every axonal angle in the stretching direction. The axons that were parallel to stretching direction were injured the most. Finally, we proposed an experimental model that subjected an axon to more accurate strain. This model observed the process of axonal injury formation by detecting the same neuron before and after stretching. These results suggest that the strain-rate dependency of axonal tolerance is induced by a higher magnitude of loading strain and an experiment focusing on axonal strain is required for obtaining more detailed injury criteria for an axon. PMID- 29394436 TI - Optimizing Seat Belt and Airbag Designs for Rear Seat Occupant Protection in Frontal Crashes. AB - Recent field data have shown that the occupant protection in vehicle rear seats failed to keep pace with advances in the front seats likely due to the lack of advanced safety technologies. The objective of this study was to optimize advanced restraint systems for protecting rear seat occupants with a range of body sizes under different frontal crash pulses. Three series of sled tests (baseline tests, advanced restraint trial tests, and final tests), MADYMO model validations against a subset of the sled tests, and design optimizations using the validated models were conducted to investigate rear seat occupant protection with 4 Anthropomorphic Test Devices (ATDs) and 2 crash pulses. The sled tests and computer simulations were conducted with a variety of restraint systems including the baseline rear-seat 3-point belt, 3-point belts with a pre-tensioner, load limiter, dynamic locking tongue, 4-point belts, inflatable belts, Bag in Roof (BiR) concept, and Self Conforming Rear seat Air Bag (SCaRAB) concept. The results of the first two sled series demonstrated that the baseline 3-point belt system are associated with many injury measures exceeding injury assessment reference values (IARVs); showed the significance of crash pulse and occupant size in predicting injury risks; and verified the potential need of advanced restraint features for better protecting the rear-seat occupants. Good correlations between the tests and simulations were achieved through a combination of optimization and manual fine-tuning, as determined by a correlation method. Parametric simulations showed that optimized belt-only designs (3-point belt with pre-tensioner and load limiter) met all of the IARVs under the soft crash pulse but not the severe crash pulse, while the optimized belt and SCaRAB design met all the IARVs under both the soft and severe crash pulses. Two physical prototype restraint systems, namely an "advanced-belt only" design and an "advanced-belt and SCaRAB" design, were then tested in the final sled series. With the soft crash pulse, both advanced restraint systems were able to reduce all the injury measures below the IARVs for all four ATDs. Both advanced restraint systems also effectively reduced almost all the injury measures for all ATDs under the severe crash pulse, except for the THOR. The design with the advanced-belt and SCaRAB generally provided lower injury measures than those using the advanced belt-only design. This study highlighted the potential benefit of using advanced seatbelt and airbag systems for rear-seat occupant protection in frontal crashes. PMID- 29394437 TI - Occupant Kinematics in Simulated Autonomous Driving Vehicle Collisions: Influence of Seating Position, Direction and Angle. AB - This two-part study analyzed occupant kinematics in simulated collisions of future automated driving vehicles in terms of seating configuration. In part one, a frontal collision was simulated with four occupants with the front seats reversed. The left front seat occupant was unbelted while the others were belted. In part two of the study, occupant restraint was examined in various seating configurations using a single seat model with a three-point seatbelt. The seat direction with respect to impact was considered as forward, rearward, and lateral facing in 45 degree increments. The effect of seat recline was also studied in the forward-facing and rear-facing cases by assuming three positions: driving position, resting position and relaxed position. Occupants were represented by human body finite element models. The results of part one showed that the front seat (rear-facing) occupants were restrained by the seatback, resulting in T1 forward displacement less than 100 mm; the rear seat occupants were restrained by the seatbelt resulting larger T1 forward displacement more than 500 mm. The results of the part two showed the directional dependence of occupant restraint. Greater T1 displacements were observed when the occupant faced lateral or front oblique. However, the seatbelt provided some restraint in all directions considered. The seatback generated contact force to the occupant when it was in the impact direction, including the lateral directions. The relaxed position allowed increased excursion compared to the driving position when the occupant faced rearward, but the magnitude of this increase was lower with lower impact speed. PMID- 29394438 TI - Human Foot-Ankle Injuries and Associated Risk Curves from Under Body Blast Loading Conditions. AB - Under body blast (UBB) loading to military transport vehicles is known to cause foot-ankle fractures to occupants due to energy transfer from the vehicle floor to the feet of the soldier. The soldier posture, the proximity of the event with respect to the soldier, the personal protective equipment (PPE) and age/sex of the soldier are some variables that can influence injury severity and injury patterns. Recently conducted experiments to simulate the loading environment to the human foot/ankle in UBB events (~5ms rise time) with variables such as posture, age and PPE were used for the current study. The objective of this study was to determine statistically if these variables affected the primary injury predictors, and develop injury risk curves. Fifty belowknee post mortem human surrogate (PMHS) legs were used for statistical analysis. Injuries to specimens involved isolated and multiple fractures of varying severity. The Sanders classification was used to grade calcaneus severity and the AO/OTA classification for distal tibia fracture. Injury risk curves were developed using survival regression analysis and covariates were included whenever statistically significant (p<0.05). With peak force as the injury predictor and age and boot as covariates, the model was statistically significant. However, boot use changed the pattern of injury from predominately calcaneus to predominantly tibia. Also, a severity based risk curve showed tolerance differences between calcaneus (minor/major) and tibia (severity-I/ severity- II) injuries. The tibia demonstrated higher tolerance as compared to either minor or major calcaneus injury. These findings can play a vital role in development of safety systems to mitigate injuries to the occupant. PMID- 29394439 TI - Development of the CAVEMAN Human Body Model: Validation of Lower Extremity Sub Injurious Response to Vertical Accelerative Loading. AB - Improving injury prediction accuracy and fidelity for mounted Warfighters has become an area of focus for the U.S. military in response to improvised explosive device (IED) use in both Iraq and Afghanistan. Although the Hybrid III anthropomorphic test device (ATD) has historically been used for crew injury analysis, it is only capable of predicting a few select skeletal injuries. The Computational Anthropomorphic Virtual Experiment Man (CAVEMAN) human body model is being developed to expand the injury analysis capability to both skeletal and soft tissues. The CAVEMAN model is built upon the Zygote 50th percentile male human CAD model and uses a finite element modeling approach developed for high performance computing (HPC). The lower extremity subset of the CAVEMAN human body model presented herein includes: 28 bones, 26 muscles, 40 ligaments, fascia, cartilage and skin. Sensitivity studies have been conducted with the CAVEMAN lower extremity model to determine the structures critical for load transmission through the leg in the underbody blast (UBB) environment. An evaluation of the CAVEMAN lower extremity biofidelity was also carried out using 14 unique data sets derived by the Warrior Injury Assessment Manikin (WIAMan) program cadaveric lower leg testing. Extension of the CAVEMAN lower extremity model into anatomical tissue failure will provide additional injury prediction capabilities, beyond what is currently achievable using ATDs, to improve occupant survivability analyses within military vehicles. PMID- 29394440 TI - Neck Injury Response in High Vertical Accelerations and its Algorithmical Formalization to Mitigate Neck Injuries. AB - Tank Automotive Research, Development and Engineering Center (TARDEC) conducted a comprehensive analysis of data collected during the evaluation of head and neck impact during injurious and non-injurious loading. This evaluation included impact velocity, helmet to roof clearance, and neck angle using a fully instrumented Hybrid III head and neck assembly. The results of this effort were compared against post mortem human subject (PMHS) data from similar testing conducted in conjunction with the Warrior Injury Assessment Manikin (WIAMan) program. The results identified the most severe helmet to roof clearance and neck angles. TARDEC used this knowledge as the foundation for continued research into head and neck impact injury mitigation through the use of passive technology and interior vehicle design. PMID- 29394441 TI - Biofidelity Evaluation of the THOR and Hybrid III 50th Percentile Male Frontal Impact Anthropomorphic Test Devices. AB - The objective of this study is to present a quantitative comparison of the biofidelity of the THOR and Hybrid III 50th percentile male ATDs. Quantitative biofidelity was assessed using NHTSA's Biofidelity Ranking System in a total of 21 test conditions, including impacts to the head, face, neck, upper thorax, lower oblique thorax, upper abdomen, lower abdomen, femur, knee, lower leg, and whole-body sled tests to evaluate upper body kinematics and thoracic response under frontal and frontal oblique restraint loading. Biofidelity Ranking System scores for THOR were better (lower) than Hybrid III in 5 of 7 body regions for internal biofidelity and 6 of 7 body regions for external biofidelity. Nomenclature is presented to categorize the quantitative results, which show overall good internal and external biofidelity of the THOR compared to the good (internal) and marginal (external) biofidelity of the Hybrid III. The results highlight the excellent internal and external biofidelity of the THOR thorax. PMID- 29394442 TI - Analysis of Repeatability and Reproducibility Standards of ATD Response for the Correlation Method. AB - Statistical methods, using the entire time-history, can be used to assess the impact response of an ATD (Anthropomorphic Test Device) in terms of its repeatability and reproducibility. In general, the methods generate a correlation relationship described as shape, magnitude and phase-difference between two time histories' in a given set of similar tests: for repeatability the relationship it is for the same ATD, for reproducibility it is for different ATDs of the same design and for biofidelity it is a relationship between ATDs and biomechanical response data from a series of human surrogate impact tests. The method uses the phase relationship to minimize the difference between any two time-histories through an alignment procedure and the magnitude and shape correlations are used to generate a parametric evaluation of the differences between any two time histories, or set of time-histories. This paper introduces a variance analysis using the entire time history to build additional foundation to the parametric evaluations using the magnitude and shape correlations and how they can be used to define repeatability and reproducibility ratings/criterion. The proposed methodology has been evaluated using two data sets based on HIII 50th dummy's chest acceleration time histories observed in USNCAP tests. The first set consists of five tests from a single Lab. The second set consists of seven tests from labs different from the first set. A time-history parameter, V, (the normalized summation of squared point to point difference between a pair of signals) was introduced and used to perform statistical analysis of Variance (ANOVA) of the reproducibility of the time histories under investigation. In particular, the V-parameter has been analyzed using both ANOVA and T-test approaches. The relationship between the parameter V and the parameters shape correlation and magnitude correlation is derived analytically. Using this relationship, criterions have been defined for reproducibility and/or repeatability with respect to the shape and magnitude correlations metrics. The criterions have been developed using a limited data set and may change as more data becomes available and is analyzed. PMID- 29394443 TI - Application of Extreme Value Theory to Crash Data Analysis. AB - A parametric model obtained by fitting a set of data to a function generally uses a procedure such as maximum likelihood or least squares. In general this will generate the best estimate for the distribution of the data overall but will not necessarily generate a reasonable estimation for the tail of the distribution unless the function fitted resembles the underlying distribution function. A distribution function can represent an estimate that is significantly different from the actual tail data, while the bulk of the data is reasonably represented by the central part of the fitted distribution. Extreme value theory can be used to improve the predictive capabilities of the fitted function in the tail region. In this study the peak-over-threshold approach from the extreme value theory was utilized to show that it is possible to obtain a better fit of the tail of a distribution than the procedures that use the entire distribution only. Additional constraints, on the current use of the extreme value approach with respect to the selection of the threshold (an estimate of the beginning of the tail region) that minimize the sensitivity to individual data samples associated with the tail section as well as contamination from the central distribution are used. Once the threshold is determined, the maximum likelihood method was used to fit the exceedances with the Generalized Pareto Distribution to obtain the tail distribution. The approach was then used in the analysis of airbag inflator pressure data from tank tests, crash velocity distribution and mass distribution from the field crash data (NASS). From the examples, the extreme (tail) distributions were better estimated with the Generalized Pareto Distribution, than a single overall distribution, along with the probability of the occurrence for a given extreme value, or a rare observation such as a high speed crash. It was concluded that the peak-over-threshold approach from extreme value theory can be a useful tool in the vehicle crash, biomechanics and injury tolerance data analysis and in estimation of the occurrence probability of an extreme phenomenon given a set of accurate observations. PMID- 29394444 TI - New Reference PMHS Tests to Assess Whole-Body Pedestrian Impact Using a Simplified Generic Vehicle Front-End. AB - This study aims to provide a set of reference post-mortem human subject tests which can be used, with easily reproducible test conditions, for developing and/or validating pedestrian dummies and computational human body models against a road vehicle. An adjustable generic buck was first developed to represent vehicle front-ends. It was composed of four components: two steel cylindrical tubes screwed on rigid supports in V-form represent the bumper and spoiler respectively, a quarter of a steel cylindrical tube represents the bonnet leading edge, and a steel plate represents the bonnet. These components were positioned differently to represent three types of vehicle profile: a sedan, a SUV and a van. Eleven post-mortem human subjects were then impacted laterally in a mid-gait stance by the bucks at 40 km/h: three tests with the sedan, five with the SUV, and three with the van. Kinematics of the subjects were recorded via high speed videos, impact forces between the subjects and the bucks were measured via load cells behind each tube, femur and tibia deformation and fractures were monitored via gauges on these bones. Based on these tests, biofidelity corridors were established in terms of: 1) displacement time history and trajectory of the head, shoulder, T1, T4, T12, sacrum, knee and ankle, 2) impact forces between the subjects and the buck. Injury outcome was established for each PMHS via autopsy. Simplicity of its geometry and use of standard steel tubes and plates for the buck will make it easy to perform future, new post-mortem human subject tests in the same conditions, or to assess dummies or computational human body models using these reference tests. PMID- 29394445 TI - Association of Impact Velocity with Serious-injury and Fatality Risks to Cyclists in Commercial Truck-Cyclist Accidents. AB - This study aimed to clarify the relationship between truck-cyclist collision impact velocity and the serious-injury and fatality risks to cyclists, and to investigate the effects of road type and driving scenario on the frequency of cyclist fatalities due to collisions with vehicles. We used micro and macro truck cyclist collision data from the Japanese Institute for Traffic Accident Research and Data Analysis (ITARDA) database. We classified vehicle type into five categories: heavy-duty trucks (gross vehicle weight [GVW] >=11 * 103 kg [11 tons (t)], medium-duty trucks (5 * 103 kg [5 t] <= GVW < 11 * 103 kg [11 t]), light duty trucks (GVW <5 * 103 kg [5 t]), box vans, and sedans. The fatality risk was <=5% for light-duty trucks, box vans, and sedans at impact velocities <=40 km/h and for medium-duty trucks at impact velocities <=30 km/h. The fatality risk was 6% for heavy-duty trucks at impact velocities <=10 km/h. Thus, the fatality risk appears strongly associated with vehicle class and impact velocity. The results revealed that a 10 km/h reduction in impact velocities could mitigate the severity of cyclist injuries at impact velocities >=30 km/h for all five vehicle types. The frequency of cyclist fatalities at intersections with traffic signals involving heavy-duty trucks was significantly higher during daytime than that at nighttime. Fatalities involving vehicles making a left turn generally increased with vehicle weight. The frequency of cyclist fatalities involving vehicles making a left turn was the largest for heavy-duty trucks both during daytime (67.6%) and at nighttime (52.3%). PMID- 29394446 TI - Optimal Specifications for the Advanced Pedestrian Legform Impactor. AB - This study addresses the virtual optimization of the technical specifications for a recently developed Advanced Pedestrian Legform Impactor (aPLI). The aPLI incorporates a number of enhancements for improved lower limb injury predictability with respect to its predecessor, the FlexPLI. It also incorporates an attached Simplified Upper Body Part (SUBP) that enables the impactor's applicability to evaluate pedestrian's lower limb injury risk also with high bumper cars. The response surface methodology was applied to optimize both the aPLI's lower limb and SUBP specifications, while imposing a total mass upper limit of 25 kg that complies with international standards for maximum weight lifting allowed for a single operator in the laboratory setting. All parameters were virtually optimized considering variable interaction, which proved critical to avoid misleading specifications. The results from this study can be used to construct physical aPLIs that are expected to be used in future car-to-pedestrian crash safety testing programs worldwide. PMID- 29394447 TI - Technical Note: An efficient daily QA procedure for proton pencil beam scanning. AB - PURPOSE: The aim of this work was to develop an efficient daily quality assurance (QA) program with strict tolerance levels for pencil beam scanning (PBS) proton radiotherapy featuring simultaneous dosimetric testing on a single, nonuniform field. METHODS: A nonuniform field measuring beam output, proton range, and spot position was designed for delivery onto a Sun Nuclear Daily-QA 3 device. A custom acrylic block permitted simultaneous measurement of low- and high-energy proton ranges in addition to beam output. Sensitivities to output, range, and spot position were evaluated to quantitate the device's response. Reproducibility tests were used to identify and control sources of measurement error as well as to assess the QA procedure's robustness. This procedure was implemented in each of our four treatment rooms independently; 4-6 months of daily QA measurements were collected. RESULTS: The 1% output, 0.5 mm range, and 1.5 mm spot position tolerances derived from preliminary tests were tighter overall than tolerances found in the literature and equivalent to the limits used for proton system commissioning. The simplicity and automation of the procedure reduced the time required for daily QA to 10 min per treatment room, and competition for beam between multiple treatment rooms was minimized. CONCLUSIONS: An efficient daily PBS QA procedure can be performed using a single, nonuniform field on a nondedicated QA device. A thorough quantitation of the device's response and careful control of measurement uncertainties allowed daily tolerances to match commissioning standards. PMID- 29394448 TI - Technical Note: On the size of susceptibility-induced MR image distortions in prostate and cervix in the context of MR-guided radiation therapy. AB - PURPOSE: To investigate the extent of MR image distortions in the pelvis caused by susceptibility-induced field inhomogeneities in MR images in the context of a study on MR-guided radiotherapy. METHODS: Using a high-bandwidth double-echo gradient echo sequence, field maps and distortion maps of the pelvis were calculated and evaluated for 219 exams (92 of female and 127 of male patients) to investigate patient-related image distortions caused by susceptibility differences in an ongoing study on MR-guided radiotherapy. The evaluation of distortions in the regions "rectum", "prostate", "cervix", and in a reference region in the gluteus maximus was based on masks drawn by two readers. RESULTS: Distortions in the prostate and cervix were smaller than 0.03 px (0.1 mm) for 99% of voxels, and reached a maximum value of 0.09 px (0.3 mm). In the reference region, maximum distortions were smaller than in the prostate and cervix. CONCLUSIONS: Using a geometric uncertainty of 0.2 px (0.6 mm) in margin definition for organs that are close to the rectum like the prostate and the cervix would be a cautious choice to account for susceptibility-induced distortions that can arise during MR-based treatment guidance for the imaging setting used in this study. Since distortions are inversely proportional to the readout bandwidth of the sequence, safety margins need to be adapted adequately. Additional sources of image distortions like gradient nonlinearities are not included in our margin recommendations and should be considered separately. PMID- 29394449 TI - Hospital Diet Enriched With Rapeseed or Sunflower Oils Is Associated With a Decrease in Plasma 16:1n-7 and Some Metabolic Disorders in the Elderly. AB - We recently demonstrated that the prevalence of dysglycemia was high among hospitalized elderly people who were fed a low fat diet (27.7% of energy) and was positively associated with plasma 16:1n-7, an indicator of de novo lipogenesis (DNL). Fatty acids in the DNL pathway have been shown to be associated with a higher risk of metabolic syndrome (MetS). The purpose of this study was to investigate the potential beneficial effects of fat enrichment (up to 34.1%en) of the hospital diet in 111 patients (30 men and 81 women, 84 +/- 7 years) during 6 weeks. Based on gender, they were randomly given a diet supplemented either with rapeseed oil (RO) or with sunflower oil (SO). Fatty acids of cholesteryl esters and erythrocyte phospholipids and markers of metabolic disorders were evaluated before and after dietary intervention. Both enriched diets significantly, and to a similar extent, decreased (1) the overall prevalence of dysglycemia (by 25-33%) and MetS (by 31-43%) and (2) plasma 16:1n-7 mol% in men and women. Dysglycemia prevalence adjusted by the diets was reduced in men versus baseline; no change was found in women. Enrichment of the diet with RO or SO resulted in a difference in fatty acid compositions, that is, EPA (mol%) and the omega-3 index increased with RO, while proportions of 18:1n-7, 18:1n-9, and EPA decreased with SO. These findings highlight the need for adequate fat intake in the elderly. For supplementation of the hospital diet, RO, which led to a higher proportion of circulating n-3 polyunsaturated fatty acids (PUFA) and is known to be beneficial, may be preferred to SO. PMID- 29394450 TI - The Expression of Lipoprotein Receptors Is Increased in the Infarcted Area After Myocardial Infarction Induced in Rats With Cardiac Dysfunction. AB - Left ventricular (LV) remodeling after myocardial infarction constitutes the structural basis for ventricular dysfunction and heart failure. The characterization underlying the expression of lipoprotein receptors in cardiac dysfunction is scarcely explored. The aim of this study was to analyze the status of lipoprotein receptors on the infarcted and noninfarcted areas of LV and to verify whether nanoparticles that mimic the lipid structure of low-density lipoprotein (LDL) and have the ability to bind to LDL receptors (LDE) are taken up more avidly by the noninfarcted LV. 13 male Wistar rats with left coronary artery ligation (myocardial infarction [MI]) and 12 animals with SHAM operation (SHAM) were used in this study. 6 weeks after the procedure, the quantification of low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), scavenger receptor-class B type I (SR-BI) lipoprotein receptors, and PCNA proliferation marker, and tissue uptake of radioactively labeled LDE were performed. Immunohistochemistry and Western blot analysis showed that LDLR, LRP1, SR-BI, and PCNA, expression in infarcted area of MI was remarkably higher than SHAM and noninfarcted subendocardial (SEN) and interstitial (INT) areas. In addition, in SEN noninfarcted area of MI, the presence of LDLR was about threefold higher than in SHAM SEN and INT noninfarcted areas. The LDE uptake of noninfarcted LV of MI group was about 30% greater than that of SHAM group. In conclusion, these findings regarding the status of lipoprotein receptors after MI induction could help to establish mechanisms on myocardial repairing. In conclusion, infarcted rats with LV dysfunction showed increased expression of lipoprotein receptors mainly in the infarcted area. PMID- 29394451 TI - PTH, vitamin D, and the FGF-23-klotho axis and heart: Going beyond the confines of nephrology. AB - BACKGROUND: Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart. AIM: The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting. RESULTS: Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF-23-klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF-23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation. CONCLUSIONS: Among all mineral components, an increase in systemic FGF-23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF-23, especially those related to cardiomyocyte function, remain to be discovered. PMID- 29394452 TI - Development of a portable quality control application using a tablet-type electronic device. AB - PURPOSE: Our aim was to develop a portable quality control (QC) application using a thermometer, a barometer, an angle gauge, and a range finder implemented in a tablet-type consumer electronic device (CED) and to assess the accuracies of the measurements made. METHODS: The QC application was programmed using Java and OpenCV libraries. First, temperature and atmospheric pressure were measured over 30 days using the temperature and pressure sensors of the CED and compared with those measured by a double-tube thermometer and a digital barometer. Second, the angle gauge was developed using the accelerometer of the CED. The roll and pitch angles of the CED were measured from 0 to 90 degrees at intervals of 10 degrees in the clockwise (CW) and counterclockwise (CCW) directions. The values were compared with those measured by a digital angle gauge. Third, a range finder was developed using the tablet's built-in camera and image-processing capacities. Surrogate markers were detected by the camera and their positions converted to actual positions using a homographic transformation method. Fiducial markers were placed on a treatment couch and moved 100 mm in 10-mm steps in both the lateral and longitudinal directions. The values were compared with those measured by the digital output of the treatment couch. The differences between CED values and those of other devices were compared by calculating means +/- standard deviations (SDs). RESULTS: The means +/- SDs of differences in temperature and atmospheric pressure were -0.07 +/- 0.25 degrees C and 0.05 +/- 0.10 hPa, respectively. The means +/- SDs of the difference in angle was -0.17 +/- 0.87 degrees (0.15 +/- 0.23 degrees degrees excluding the 90 degrees angle). The means +/- SDs of distances were 0.01 +/- 0.07 mm in both the lateral and longitudinal directions. CONCLUSIONS: Our portable QC application was accurate and may be used instead of standard measuring devices. Our portable CED is efficient and simple when used in the field of medical physics. PMID- 29394453 TI - Exercise-based cardiac rehabilitation for adults with stable angina. AB - BACKGROUND: A previous Cochrane review has shown that exercise-based cardiac rehabilitation (CR) can benefit myocardial infarction and post-revascularisation patients. However, the impact on stable angina remains unclear and guidance is inconsistent. Whilst recommended in the guidelines of American College of Cardiology/American Heart Association and the European Society of Cardiology, in the UK the National Institute for Health and Care Excellence (NICE) states that there is "no evidence to suggest that CR is clinically or cost-effective for managing stable angina". OBJECTIVES: To assess the effects of exercise-based CR compared to usual care for adults with stable angina. SEARCH METHODS: We updated searches from the previous Cochrane review 'Exercise-based cardiac rehabilitation for patients with coronary heart disease' by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, DARE, CINAHL and Web of Science on 2 October 2017. We searched two trials registers, and performed reference checking and forward-citation searching of all primary studies and review articles, to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a follow-up period of at least six months, which compared structured exercise-based CR with usual care for people with stable angina. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data according to the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors also independently assessed the quality of the evidence using GRADE principles and we presented this information in a 'Summary of findings' table. MAIN RESULTS: Seven studies (581 participants) met our inclusion criteria. Trials had an intervention length of 6 weeks to 12 months and follow-up length of 6 to 12 months. The comparison group in all trials was usual care (without any form of structured exercise training or advice) or a no-exercise comparator. The mean age of participants within the trials ranged from 50 to 66 years, the majority of participants being male (range: 74% to 100%). In terms of risk of bias, the majority of studies were unclear about their generation of the randomisation sequence and concealment processes. One study was at high risk of detection bias as it did not blind its participants or outcome assessors, and two studies had a high risk of attrition bias due to the numbers of participants lost to follow-up. Two trials were at high risk of outcome reporting bias. Given the high risk of bias, small number of trials and participants, and concerns about applicability, we downgraded our assessments of the quality of the evidence using the GRADE tool.Due to the very low-quality of the evidence base, we are uncertain about the effect of exercise-based CR on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.18 to 5.67; 195 participants; 3 studies; very low quality evidence), acute myocardial infarction (RR 0.33, 95% CI 0.07 to 1.63; 254 participants; 3 studies; very low-quality evidence) and cardiovascular-related hospital admissions (RR 0.14, 95% CI 0.02 to 1.1; 101 participants; 1 study; very low-quality evidence). We found low-quality evidence that exercise-based CR may result in a small improvement in exercise capacity compared to control (standardised mean difference (SMD) 0.45, 95% CI 0.20 to 0.70; 267 participants; 5 studies, low-quality evidence). We were unable to draw conclusions about the impact of exercise-based CR on quality of life (angina frequency and emotional health-related quality-of-life score) and CR-related adverse events (e.g. skeletomuscular injury, cardiac arrhythmia), due to the very low quality of evidence. No data were reported on return to work. AUTHORS' CONCLUSIONS: Due to the small number of trials and their small size, potential risk of bias and concerns about imprecision and lack of applicability, we are uncertain of the effects of exercise-based CR compared to control on mortality, morbidity, cardiovascular hospital admissions, adverse events, return to work and health related quality of life in people with stable angina. Low-quality evidence indicates that exercise-based CR may result in a small increase in exercise capacity compared to usual care. High-quality, well-reported randomised trials are needed to assess the benefits and harms of exercise-based CR for adults with stable angina. Such trials need to collect patient-relevant outcomes, including clinical events and health-related quality of life. They should also assess cost effectiveness, and recruit participants that are reflective of the real-world population of people with angina. PMID- 29394455 TI - Retinol-binding protein 4 is positively associated with bone mineral density in patients with type 2 diabetes and osteopenia or osteoporosis. AB - OBJECTIVE: This study intends to study the association between serum retinol binding protein 4 (RBP4), bone mineral density (BMD) and other bone metabolic related parameters in type 2 diabetic patients older than 50 years, with or without osteopenia or osteoporosis. METHODS: Patients (n = 274 cases) with type 2 diabetes, hospitalized in the Endocrinology Department of Yantai Yuhuangding Hospital from December 2015 to March 2017, were enrolled in the study. The bone mineral density (BMD) was recorded by the dual-energy X-ray absorptiometer, and patients were divided into normal bone mineral density (148 cases), osteopenia (93 cases) and osteoporosis (33 cases) groups. The serum adipokine RBP4 and other biomarkers were determined accordingly. RESULTS: Serum RBP4, body weight, calcium and body mass index (BMI) demonstrated a positive correlation with BMD at all tested body sites in osteopenia and osteoporosis groups compared with normal bone mineral density group. In contrast, age, duration of diabetes and alkaline phosphatase (ALP) were inversely correlated with BMD at all tested body sites. In nonadjusted analyses, age, gender, duration of diabetes and ALP were inversely associated with BMD at the femoral neck, total hip and lumbar spine, while body weight, BMI and RBP4 were positively associated with BMD at all sites. In multiple regression analyses, adjusted for age, weight, BMI and other bone related factors, a graded stepwise positive association between serum RBP4 and BMD was shown, at all sites. CONCLUSION: Serum RBP4 was positively associated with BMD at all sites after adjustments for other factors in osteopenia and osteoporosis groups compared with normal bone mineral density group of type 2 diabetic patients. PMID- 29394454 TI - Integrated beam orientation and scanning-spot optimization in intensity-modulated proton therapy for brain and unilateral head and neck tumors. AB - PURPOSE: Intensity-Modulated Proton Therapy (IMPT) is the state-of-the-art method of delivering proton radiotherapy. Previous research has been mainly focused on optimization of scanning spots with manually selected beam angles. Due to the computational complexity, the potential benefit of simultaneously optimizing beam orientations and spot pattern could not be realized. In this study, we developed a novel integrated beam orientation optimization (BOO) and scanning-spot optimization algorithm for intensity-modulated proton therapy (IMPT). METHODS: A brain chordoma and three unilateral head-and-neck patients with a maximal target size of 112.49 cm3 were included in this study. A total number of 1162 noncoplanar candidate beams evenly distributed across 4pi steradians were included in the optimization. For each candidate beam, the pencil-beam doses of all scanning spots covering the PTV and a margin were calculated. The beam angle selection and spot intensity optimization problem was formulated to include three terms: a dose fidelity term to penalize the deviation of PTV and OAR doses from ideal dose distribution; an L1-norm sparsity term to reduce the number of active spots and improve delivery efficiency; a group sparsity term to control the number of active beams between 2 and 4. For the group sparsity term, convex L2,1 norm and nonconvex L2,1/2-norm were tested. For the dose fidelity term, both quadratic function and linearized equivalent uniform dose (LEUD) cost function were implemented. The optimization problem was solved using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA). The IMPT BOO method was tested on three head-and-neck patients and one skull base chordoma patient. The results were compared with IMPT plans created using column generation selected beams or manually selected beams. RESULTS: The L2,1-norm plan selected spatially aggregated beams, indicating potential degeneracy using this norm. L2,1/2-norm was able to select spatially separated beams and achieve smaller deviation from the ideal dose. In the L2,1/2-norm plans, the [mean dose, maximum dose] of OAR were reduced by an average of [2.38%, 4.24%] and[2.32%, 3.76%] of the prescription dose for the quadratic and LEUD cost function, respectively, compared with the IMPT plan using manual beam selection while maintaining the same PTV coverage. The L2,1/2 group sparsity plans were dosimetrically superior to the column generation plans as well. Besides beam orientation selection, spot sparsification was observed. Generally, with the quadratic cost function, 30%~60% spots in the selected beams remained active. With the LEUD cost function, the percentages of active spots were in the range of 35%~85%.The BOO-IMPT run time was approximately 20 min. CONCLUSION: This work shows the first IMPT approach integrating noncoplanar BOO and scanning-spot optimization in a single mathematical framework. This method is computationally efficient, dosimetrically superior and produces delivery-friendly IMPT plans. PMID- 29394456 TI - The impact of negative childbirth experience on future reproductive decisions: A quantitative systematic review. AB - AIM: The aim of this study was to systematically retrieve, critique and synthesize available evidence regarding the association between negative childbirth experiences and future reproductive decisions. BACKGROUND: A child's birth is often a joyous event; however, there is a proportion of women who undergo negative childbirth experiences that have long-term implications on their reproductive decisions. DESIGN: A systematic review of quantitative studies was undertaken using Joanna Briggs Institute's methods. REVIEW METHODS: A search was carried out in CINAHL Plus with Full Text, Embase, PsycINFO, PubMed, Scopus and Web of Science from January 1996 - July 2016. Studies that fulfilled the inclusion criteria were assessed by two independent reviewers using the Joanna Briggs Institute's Critical Appraisal Tools. Data were extracted under subheadings adapted from the institute's data extraction forms. RESULTS: Twelve studies, which examined either one or more influences of negative childbirth experiences, were identified. The included studies were either cohort or cross sectional designs. Five studies observed positive associations between prior negative childbirth experiences and decisions to not have another child, three studies found positive associations between negative childbirth experiences and decisions to delay a subsequent birth and six studies concluded positive associations between negative childbirth experiences and maternal requests for caesarean section in subsequent pregnancies. CONCLUSION: To receive a holistic understanding on negative childbirth experiences, a suitable definition and validated measuring tools should be used to understand this phenomenon. Future studies or reviews should include a qualitative component and/or the exploration of specific factors such as cultural and regional differences that influence childbirth experiences. PMID- 29394457 TI - Risk and resiliency factors related to body dissatisfaction and disordered eating: The identity disruption model. AB - OBJECTIVE: The current study examined a theoretical model (the identity disruption model) linking negative early life experiences to body dissatisfaction and disordered eating via self-concept clarity and sociocultural factors (internalization of beauty ideals and appearance comparison tendencies). METHOD: 1,023 participants (52% women) completed a series of questionnaires online, including measures of negative early life experiences and childhood abuse, self concept clarity, internalization of beauty ideals, appearance comparison tendencies, sociocultural pressure to improve one's appearance, body dissatisfaction, and disordered eating. RESULTS: Structural equation modeling indicated that self-reported early adversity was associated with lower self concept clarity, which in turn was associated with greater internalization of beauty ideals and more frequent appearance comparisons. Internalization and appearance comparisons were associated with body image concerns, which in turn were associated with disordered eating and exercise behaviors. There were few sex differences in these paths. DISCUSSION: These findings provide initial conceptual support for the identity disruption model and extend previous models of body dissatisfaction and disordered eating to include processes that occur earlier in life. This model opens up the possibility for new interventions that are targeted toward those who are most vulnerable to developing body dissatisfaction and disordered eating. PMID- 29394458 TI - People who survive an episode of severe alcoholic hepatitis should be advised to maintain total abstinence from alcohol. PMID- 29394459 TI - Treatment of co-occurring food avoidance and alcohol use disorder in an adult: Possible avoidant restrictive food intake disorder? AB - OBJECTIVE: This case report details the presentation and treatment of a 42-year old male self-presenting for treatment who reported having been a restrictive eater since childhood; since adolescence he had failed to meet appropriate nutritional intake with one meal at night followed by around 10-20 standard alcoholic drinks. METHOD: Ten sessions of cognitive behavioral therapy were offered emphasizing the need to adhere to regular eating patterns in conjunction with significant reduction of binge drinking. RESULTS: At the end of treatment, and 1-month follow-up, improvements in nutritional intake and alcohol intake were observed, accompanied by improvements in depression, anxiety, and stress. DISCUSSION: However, excessive alcohol intake had reoccurred at 3-month follow up, accompanied by increases in negative affect and impairment due to eating, indicating that longer-term therapy may be required for this group of people. PMID- 29394460 TI - A fast 4D IMRT/VMAT planning method based on segment aperture morphing. AB - PURPOSE: Four-dimensional volumetric modulated arc therapy (4D VMAT) and four dimensional intensity-modulated radiotherapy (4D IMRT) are developing radiation therapy treatment strategies designed to maximize dose conformality, minimize normal tissue dose, and deliver the treatment as efficiently as possible. The patient's entire breathing cycle is captured through 4D imaging modalities and then separated into individual breathing phases for planning purposes. Optimizing multiphase VMAT and IMRT plans is computationally demanding and currently impractical for clinical application. The purpose of this study is to assess a new planning process decreasing the upfront computational time required to optimize multiphased treatment plans while maintaining good plan quality. METHODS: Optimized VMAT and IMRT plans were created on the end-of-exhale (EOE) breathing phase of 10-phase 4D CT scans with planning tumor volume (PTV)-based targets. These single-phase optimized plans are analogous to single-phase gated treatment plans. The simulated tracked plans were created by deformably registering EOE contours to the remaining breathing phases, recalculating the optimized EOE plan onto the other individual phases and realigning the MLC's relative positions to the PTV border in each of the individual breathing phases using a segment aperture morphing (SAM) algorithm. Doses for each of the 10 phases were calculated with the treatment planning system and deformably transferred back onto the EOE phase and averaged with equal weighting simulating the actual delivered dose a patient would potentially receive in a tracked treatment plan. RESULTS: Plan DVH quality for the 10-phase 4D SAM plans were comparable with the individual EOE optimized treatment plans for the PTV structures as well as the organ at risk structures. SAM-based algorithms out performed simpler isocenter-shifted only approaches. SAM-based 4D planning greatly reduced plan computation time vs individually optimizing all 10 phases. In addition, since this technique allows irradiation during all 10 breathing phases it will also decrease the treatment times required to treat each fraction in comparison to the gated treatment planning approach. CONCLUSIONS: Segment aperture morphing (SAM) can successfully be used to transfer radiation therapy plans originally planned on a single breathing phase image set to other patient breathing phase image sets. SAM is a useful tool for the fast creation of 4D, multibreathing phase radiation therapy treatment plans. PMID- 29394461 TI - Prognostic value of lymph node ratio in head and neck squamous cell carcinoma. AB - BACKGROUND: Lymph node ratio (LNR) is increasingly reported as a potential prognostic tool. The purpose of this review was to analyze the available literature on the prognostic significance of LNR in head and neck squamous cell carcinoma (HNSCC). METHODS: A PubMed internet search was performed and articles meeting selection criteria were reviewed. RESULTS: Twenty-eight studies were identified in the literature dealing with the prognostic value of LNR. The published results are variable with a range of cutoff values of LNR associated with prognosis (overall survival [OS] and/or disease-specific survival [DSS]) between 0.02 and 0.20, with an average of 0.09. CONCLUSION: The LNR is reported to be of value in assessing prognosis in the patients with HNSCC. Although it is easy to calculate and could be considered in the staging of these patients, the currently available evidence in the literature does not yet provide a solid base for implementation. PMID- 29394462 TI - Sex-, Ethnic-, and Age-Specific Centile Curves for pQCT- and HR-pQCT-Derived Measures of Bone Structure and Strength in Adolescents and Young Adults. AB - There are presently no adolescent centile curves for bone parameters at the tibial midshaft using peripheral quantitative computed tomography (pQCT) or at the distal radius and tibia using high-resolution pQCT (HR-pQCT). Thus, we aimed to develop sex-, ethnic-, site-, and age-specific centile curves for pQCT and HR pQCT-derived bone outcomes for youth and young adults aged 10 to 21 years. We acquired pQCT scans (XCT3000 or XCT2000) at the tibial midshaft (50% site) and HR pQCT scans (XtremeCT) at the distal radius (7% site) and tibia (8% site) in a convenience sample of participants in the mixed-longitudinal University of British Columbia Healthy Bones III Study. We scanned 778 10- to 21-year-olds annually for a maximum of 11 years using pQCT (413 girls, 56% Asian; 365 boys, 54% Asian; n = 3160 observations) and 349 10- to 21-year-olds annually for a maximum of 4 years using HR-pQCT (189 girls, 51% Asian; 165 boys, 50% Asian; n = 1090 observations). For pQCT, we report cortical bone mineral density (BMD), total bone cross-sectional area, and polar strength-strain index. For HR-pQCT, we report standard measures (total BMD, trabecular number, thickness, and bone volume fraction) and automated segmentation measures (total bone cross-sectional area, cortical BMD, porosity, and thickness). We applied finite element analysis to estimate failure load. We applied the lamda, mu, sigma (LMS) method using LMS ChartMaker Light (version 2.5, The Institute of Child Health, London, UK) to construct LMS tables and centile plots. We report sex- and age-specific centiles (3rd, 10th, 25th, 50th, 75th, and 97th) for whites and Asians for pQCT bone parameters at the tibial midshaft and HR-pQCT bone parameters at the distal radius and tibia. These centile curves might be used by clinicians and scientists to interpret values or better understand trajectories of bone parameters in clinical populations, those from different geographic regions or of different ethnic origins. (c) 2018 American Society for Bone and Mineral Research. PMID- 29394463 TI - Primary orbital melanoma treated with orbital exenteration and postoperative radiotherapy: A case report and review of the literature. AB - BACKGROUND: We report on a patient with human immunodeficiency virus (HIV) positive disease with a primary orbital melanoma treated with surgery and adjuvant radiation. METHODS: A 53-year-old woman with HIV-positive disease presented with left-sided progressive ipsilateral vision loss and proptosis. An MRI scan revealed a mass-enhancing lesion measuring 2.1 * 2.6 * 2.5 cm abutting the optic nerve. The patient underwent left orbital exenteration with temporalis flap reconstruction, pathology revealing malignant melanoma, stage T1N0M0. Posterior margins were positive and lymphovascular invasion was present; therefore, the patient received adjuvant radiation to a total dose of 70 Gy in 35 fractions. RESULTS: The patient remains with no evidence of disease (NED) at a follow-up time of 3.5 years. CONCLUSION: Surgery remains the mainstay of treatment in patients with primary orbital melanomas, and adjuvant radiotherapy should be considered for those with positive margins or other risk factors for recurrence. We present a patient with significant risk factors with NED at 3.5 year follow-up. PMID- 29394464 TI - Knockout of ULK1/2 protects against acetaminophen-induced acute liver injury independent of autophagy? PMID- 29394465 TI - National disparities in treatment package time for resected locally advanced head and neck cancer and impact on overall survival. AB - BACKGROUND: The purpose of this study was to determine national disparities in head and neck cancer treatment package time (the time interval from surgery through the completion of radiation) and the associated impact on survival. METHODS: We conducted an observational cohort study using the National Cancer Database of 15 234 patients with resected head and neck cancer who underwent adjuvant radiotherapy from 2004-2012. Predictors of prolonged package time were identified by multivariable linear regression. Survival outcomes were assessed using a multivariable Cox model. RESULTS: Mean package time was 100 days (SD 23). Package time was 7.52 days (95% confidence interval [CI] 6.23-8.81; P < .001) longer with Medicaid versus commercial insurance. Low income and African American race also predicted for longer package times. All-cause mortality increased an average of 4% with each 1 week increase in treatment package time (hazard ratio [HR] 1.04; 95% CI 1.03-1.05; P < .001). CONCLUSION: Significant national socioeconomic disparities exist in treatment package time. Treatment delays in this setting may contribute to worse survival outcomes. PMID- 29394466 TI - Hemostatic Ability of Chitosan-Phosphate Inspired by Coagulation Mechanisms of Platelet Polyphosphates. AB - Hemostatic materials have been studied to minimize bleeding time. Recently, polyphosphate (polyP) have received attention as potential hemostatic compounds, which are released from activated platelets. Long polyP chains are essential to form thick fibrin clots. Herein, chitosan is functionalized by covalently tethering phosphate groups to mimic polyP. It is hypothesized that utilizing a known hemostatic polysaccharide, chitosan, and tethering phosphate groups to mimic polyP's functionality show synergistic effect in hemostasis. Five different phosphorylated chitosan conjugates (Chi-Ps), s-Chi-7P, s-Chi-28P, s-Chi-74P, is Chi-29P, and is-Chi-56P are prepared, where "s" indicates water soluble Chi-Ps and "is" represents water insoluble Chi-Ps. Unexpectedly, an important carbon in D-glucosamine is found, which determines chitosan solubility. Phosphate groups conjugated to C6 carbon resulted in water soluble Chi-P, but conjugation to C3 group exhibited water insoluble behavior. Hemostasis capability showed a positive correlation with the degree of phosphate conjugations regardless of water solubility of Chi-P. PMID- 29394468 TI - Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy. AB - Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression. We also discuss the possible mechanisms of platinum drug resistance mediated by ATP7A/7B and provide novel strategies for overcoming resistance. This review may be helpful for understanding the roles of ATP7A and ATP7B in platinum drug resistance. (c) 2018 IUBMB Life, 70(3):183-191, 2018. PMID- 29394467 TI - Super-Absorbent Polymer Valves and Colorimetric Chemistries for Time-Sequenced Discrete Sampling and Chloride Analysis of Sweat via Skin-Mounted Soft Microfluidics. AB - This paper introduces super absorbent polymer valves and colorimetric sensing reagents as enabling components of soft, skin-mounted microfluidic devices designed to capture, store, and chemically analyze sweat released from eccrine glands. The valving technology enables robust means for guiding the flow of sweat from an inlet location into a collection of isolated reservoirs, in a well defined sequence. Analysis in these reservoirs involves a color responsive indicator of chloride concentration with a formulation tailored to offer stable operation with sensitivity optimized for the relevant physiological range. Evaluations on human subjects with comparisons against ex situ analysis illustrate the practical utility of these advances. PMID- 29394469 TI - Glutathione Mediated Size-Tunable UCNPs-Pt(IV)-ZnFe2 O4 Nanocomposite for Multiple Bioimaging Guided Synergetic Therapy. AB - Here a multifunctional nanoplatform (upconversion nanoparticles (UCNPs) platinum(IV) (Pt(IV))-ZnFe2 O4 , denoted as UCPZ) is designed for collaborative cancer treatment, including photodynamic therapy (PDT), chemotherapy, and Fenton reaction. In the system, the UCNPs triggered by near-infrared light can convert low energy photons to high energy ones, which act as the UV-vis source to simultaneously mediate the PDT effect and Fenton's reaction of ZnFe2 O4 nanoparticles. Meanwhile, the Pt(IV) prodrugs can be reduced to high virulent Pt(II) by glutathione in the cancer cells, which can bond to DNA and inhibit the copy of DNA. The synergistic therapeutic effect is verified in vitro and in vivo results. The cleavage of Pt(IV) from UCNPs during the reduction process can shift the larger UCPZ nanoparticles (NPs) to the smaller ones, which promotes the enhanced permeability and retention (EPR) and deep tumor penetration. In addition, due to the inherent upconversion luminescence (UCL) and the doped Yb3+ and Fe3+ in UCPZ, this system can serve as a multimodality bioimaging contrast agent, covering UCL, X-ray computed tomography, magnetic resonance imaging, and photoacoustic. A smart all-in-one imaging-guided diagnosis and treatment system is realized, which should have a potential value in the treatment of tumor. PMID- 29394470 TI - Serum neurofilament light as diagnostic biomarker for acute cerebral ischemia: a promising tool. PMID- 29394471 TI - Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. AB - : Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRalpha) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018, 11: 707-712. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors. PMID- 29394472 TI - Template Synthesis of Three-Dimensional Hexakisimidazolium Cages. AB - A procedure for the synthesis of three-dimensional hexakisimidazolium cage compounds has been developed. The reaction of the trigonal trisimidazolium salts H3 L(PF6 )3 , decorated with three N-olefinic pendants, and silver oxide yielded trinuclear trisilver(I) hexacarbene molecular cylinders of the type [Ag3 L2 ]3+ with the olefinic pendants from the two different tricarbene ligands arranged in three pairs. Subsequent UV irradiation gave three cyclobutane links between the two tris-NHC ligands in three [2+2] cycloaddition reactions, thereby generating a three-dimensional hexakis-NHC ligand. Removal of the metal ions resulted in the formation of three-dimensional hexakisimidazolium cages with a large internal cavity. PMID- 29394473 TI - Therapy for Spinal Muscular Atrophy. PMID- 29394474 TI - Tolvaptan in Later-Stage Polycystic Kidney Disease. PMID- 29394475 TI - Tolvaptan in Later-Stage Polycystic Kidney Disease. PMID- 29394476 TI - Gene Therapy for Cerebral Adrenoleukodystrophy. PMID- 29394477 TI - Monogenic Diseases of DNA Repair. PMID- 29394478 TI - Deformational Plagiocephaly: A Review. AB - Deformational plagiocephaly (DP) is a common condition and the leading cause of head shape abnormalities in infants. It is characterized by asymmetrical distortion of the skull resulting from external forces on the back of the head. DP has become more prevalent in infants and has increased dramatically since the introduction in 1994 of the "Back to Sleep" campaign. Management of this condition is not often covered by insurance, and can be costly and lengthy; However, DP can be prevented. Early recognition and management can make a significant difference in patients' outcomes and reduce the cost of treatment. Nurses play a key role in recognition and prevention, are instrumental in educating parents and caregivers, and have a significant impact on preventing and reducing the risk of DP. Current systematic approaches to clinical assessment, diagnosis, and management strategies of DP can help nurses who care for infants and their families understand DP and take the necessary steps to prevent it. PMID- 29394479 TI - Quality Improvement Initiative on Pain Knowledge, Assessment, and Documentation Skills of Pediatric Nurses. AB - Pain treatment begins with a nurse's assessment, which relies on effective assessment skills. Hospital settings have implemented pain assessment education, but there is limited evidence in pediatric transitional care settings. The purpose of this quality improvement (QI) initiative was to develop, implement, and evaluate an evidence-based pain education session with 20 nurses in a pediatric specialty hospital that provides transitional care. Specific aims were to assess nurses' knowledge and attitudes of pain, and evaluate assessment skills based on nurses' documentation. A prospective pre-post design with three assessments (baseline, post-intervention, and one-month follow-up) was used. The Shriner's Pediatric Nurses' Knowledge and Attitudes Regarding Pain questionnaire and an electronic health record review were completed at each assessment. There was significant improvement in nurses' knowledge and attitudes of pain after the education session (F[2,6] = 50.281, p < 0.0001) from baseline to post intervention (p < 0.0001), which was maintained at follow-up (p = 0.009). Pain assessment frequency by nurses significantly increased from 43.1% at baseline to 64.8% at post-intervention, and 67.7% at follow-up (chi2[2] = 20.55, p < 0.0001). Developmentally appropriate pain scale usage increased significantly, from 13.1% at baseline to 77.4% at post-intervention, and 81.8% at follow-up (chi2[2] = 169.19, p < 0.0001). Nursing interventions for pain increased significantly, from 33.3% at baseline to 84.0% at post-intervention, and stabilized at 80.0% at follow-up (chi2[2] = 8.91, p = 0.012). Frequency of pain reassessments did not show a statistically significant change, decreasing from 77.8% at baseline to 44.0% at post-intervention and 40.0% at follow-up (chi2[2]= 3.538, p = 0.171). Nurses' pain knowledge and documentation of assessment skills were improved in this QI initiative. PMID- 29394480 TI - Interprofessional Huddle: One Children's Hospital's Approach to Improving Patient Flow. AB - Admitting pediatric patients promptly to the appropriate unit where they can receive specialty care is of critical importance to safe, quality care. A daily morning huddle was implemented at one children's hospital as a quality improvement project. The aim of this project was to improve patient flow throughout the children's hospital by improving interprofessional and interdepartmental communication and collaboration. This article reports on changes in patient flow before and after implementation of the daily huddle, as measured by pediatric emergency department (ED) boarding times. This retrospective, descriptive study was conducted at a regional children's hospital within an academic hospital. Data were collected from the electronic medical record over two separate time periods coinciding with pre/post-huddle implementation. Non-random, purposive sampling was used, resulting in a prehuddle sample (n = 450) and post-huddle sample (n = 329). Times were significantly shorter after huddle implementation compared to pre-huddle (p < 0.001) from admission orders in the ED to transfer to the PICU or pediatric ward. The median time decreased from 3.0 to 2.6 hours post-huddle implementation. These findings suggest huddles as one potential factor in the formula to improve patient flow from the ED by enhancing interprofessional and interdepartmental collaboration and communication. Findings from this study are of vital importance to pediatric patients, nurses, and physicians. Promptly admitting patients from the ED to the appropriate unit where they can receive needed specialty care that potentially improves the quality and safety of patient care is paramount. Further research is needed to determine what format and contexts the huddle can be utilized to facilitate efficient patient flow and improve patient outcomes. PMID- 29394481 TI - Transitioning Patients from the Intensive Care Unit to the General Pediatric Unit: A Piece of the Puzzle in Family-Centered Care. AB - Transitioning patients from one unit to another is a nursing function that occurs daily. When done effectively, it streamlines continuity of care, decreases anxiety, ensures patients and families maintain confidence in care providers, and avoids readmissions to the intensive care unit (ICU). This article describes a transition plan for transferring patients from the ICU to the general pediatric unit developed by an inpatient, non-critical care cardiology/neuro logical unit to facilitate a smooth and informational transition from the ICU to the non critical unit. Subse quently, this program incorporated the development of educational materials and a program that provides patients and families with clear information on what to expect, the differences between the two units, and the services available by their healthcare team on the unit to which they are transferred. By establishing a process and a liaison to guide and educate patients and families on what to expect during transition, fears and anxieties are decreased or eliminated, while the promotion of healing and successful outcomes for discharge home becomes the focus. PMID- 29394482 TI - Factors Associated with Parental Compliance with Supine Infant Sleep: An Integrative Review. AB - Despite educational programs, sudden infant death syndrome (SIDS) rates remain unacceptably high, especially among low-income and African-American populations. The purpose of this review is to examine reasons for parental noncompliance with supine sleep recommendations. A database search in Cochrane Database of Systematic Reviews, PubMed, EBSCOhost, and CINAHL was conducted using keywords SIDS, prevention and control, parental compliance, nursing, supine position, Back to Sleep campaign, and Safe to Sleep campaign. Literature was included from 2002 to 2014. Types of studies included randomized control trials, literature reviews, and descriptive studies. Literature from academic journals was also included. Included literature discussed parental knowledge, the Back to Sleep and the Safe to Sleep campaigns, compliance with recommendations from the American Academy of Pediatrics (AAP), and interventions and education. Seventeen studies were included that used data collection methods, including surveys, focus groups, face to-face interviews, and questionnaires. Major trends identified as being associated with noncompliance included parent knowledge, sources of advice, infant comfort and quality of infant sleep, safety concerns (i.e., choking), race/ethnicity, education level, and income. Noncompliance was highest among single, less-educated, low-income, or African-American parents. PMID- 29394483 TI - Nurse Perceptions of Pain in Pediatric Traumatic Brain Injury: A Pilot Study. AB - Pain assessment in the pediatric population is challenging because of age, developmental stage, and patient cooperation. Cognitive impairment, impaired communication, and physical disability that may accompany traumatic brain injury (TBI) further complicate pain assessments. A pilot descriptive qualitative research study was conducted to investigate nurse perceptions of pain in pediatric patients diagnosed with TBI. Specifically, this study sought to answer the following questions: a) Is pain accurately assessed in this population? b) Is pain adequately treated in this population? and c) What obstacles exist, if any, to the assessment and treatment of pain? A convenience sample of three registered nurses employed in a pediatric neurosurgery setting participated in this study. Each nurse participated in one individual, semi-structured, face-to-face interview lasting approximately 30 minutes. Interviews were transcribed verbatim and analyzed for common themes. Common themes identified across all interviews were a) challenging assessments; b) limited, although effective, treatments; and c) communication as an area of opportunity for improvement. Implications for practice and policy include a need for more sensitive pain assessment tools to improve the objectivity and accuracy of pain assessment, clarification of care priorities and organization of care from clinical and management perspectives, and additional research in alternative pain treatments for this population. Findings from this study will guide the development of a larger, more comprehensive study, with the aim of improving practice and policy in pain management for this population. PMID- 29394484 TI - Non-Traumatic Limp and Fever in a School-Age Child. PMID- 29394485 TI - Non-Pharmacological Strategies for Addressing Infant Pain. PMID- 29394486 TI - Healthcare: It's 'So Complicated'. PMID- 29394487 TI - Lipid and carotenoid synthesis by Rhodosporidium diobovatum, grown on glucose versus glycerol, and its biodiesel properties. AB - Relationships between lipid and carotenoid synthesis by Rhodosporidium diobovatum were investigated for cell cultures in nitrogen-limited medium (GMY) containing equimolar amounts of carbon of glucose or glycerol. The cultures were also supplemented with additional substrate at 120 h postinoculation (pi) and during a fed-batch experiment. Growth of R. diobovatum on glucose resulted in higher yields of triacyglycerides (TAGs) and carotenoid than when grown on glycerol, even though the cultures contained equimolar amounts of carbon. After the addition of fresh substrate at 120 h pi, total carotenoid concentrations were significantly different from the concentrations measured at 120 h pi in both glucose and glycerol cultures, with no concomitant increase in lipid concentrations, suggesting that carotenoid synthesis is linked to exponential phase growth, while lipid synthesis is linked to stationary phase. We also compared the calculated properties of biodiesel that could be made with TAGs derived from R. diobovatum with properties of biodiesel made from TAGs of other oleaginous yeasts, microalgae, vegetable oils, and animal fats. This study shows that R. diobovatum can be an effective strain for production of neutral lipids containing high percentages of oleic acid, palmitic acid, and linoleic acid, as well as carotenoids. PMID- 29394488 TI - Effect of 7 days of exercise on exogenous carbohydrate oxidation and insulin resistance in children with obesity. AB - The capacity to match carbohydrate (CHO) oxidation with CHO availability (deemed metabolic flexibility (MetFlex)) may be important for type 2 diabetes prevention. In adults, impaired MetFlex is associated with insulin resistance (IR), which can be improved with as little as 7 days of exercise. Whether this occurs similarly in children is unknown. We hypothesized that 7 consecutive days of exercise would improve MetFlex and IR in children with obesity. Twelve children (8 boys, 4 girls) completed 2 study visits before (PRE) and 2 study visits after (POST) exercise training. At visit 1, fasting blood was collected, and anthropometry and maximal oxygen uptake were assessed. At visit 2, a 13C-enriched CHO drink was ingested before exercise (3 * 20 min) at ~59% maximal oxygen uptake. Exogenous CHO oxidative efficiency, used as a surrogate measurement of MetFlex, was calculated from breath samples. During training, participants alternated between continuous and high-intensity interval cycling sessions at home under supervision. In spite of good training adherence, there was no improvement in MetFlex (PRE: 20.7% +/- 1.8%, POST: 18.9% +/- 4.9%, p = 0.22) or homeostasis model assessment of insulin resistance (PRE: 8.7 +/- 4.6, POST: 8.1 +/- 6.0, p = 0.51). Future research should investigate exercise volume, sex, and pubertal effects on the early responsiveness of MetFlex to exercise therapy. PMID- 29394489 TI - Sodium pump alpha-2 subunit (ATP1A2) alleviates cardiomyocyte anoxia reoxygenation injury via inhibition of endoplasmic reticulum stress-related apoptosis. AB - Previous studies have found decreased functional capacity of the sodium pump (Na+ K+-ATPase) alpha and beta subunits and recovery of Na+-K+-ATPase activity significantly decreased myocyte apoptosis in myocardial ischemia-reperfusion (I/R) injury. However, the potential role of the Na+-K+-ATPase alpha-2 subunit (ATP1A2) in cardiomyocyte anoxia-reoxygenation (A/R) injury has not been elucidated. Rat myocardial cells were subjected to siRNA transfection followed by A/R injury. Apoptosis and expression of endoplasmic reticulum (ER) stress proteins CHOP, GRP78, and caspase-12 were detected in 4 groups of cells: ATP1A2 siRNA + A/R, control siRNA + A/R, control, and A/R injury model. We found that apoptosis was significantly elevated in the ATP1A2 siRNA + A/R group as compared with control siRNA + A/R, control, and A/R injury model groups (p < 0.05, p < 0.01, and p < 0.05). Furthermore, expression of CHOP, GRP78, and caspase-12 were significantly elevated in the ATP1A2 siRNA + A/R group as compared with control siRNA + A/R, control, and A/R injury model groups (p < 0.05, p < 0.01, and p < 0.05). Our findings suggest that cardiomyocyte ATP1A2 is a target of A/R injury, and its cardioprotective function may be mediated via inhibiting the ER-stress related apoptosis. PMID- 29394490 TI - Enzymatic and bactericidal activity of myeloperoxidase in conditions of halogenative stress. AB - Myeloperoxidase (MPO), found mainly in neutrophils, is released in inflammation. MPO produces reactive halogen species (RHS), which are bactericidal agents. However, RHS overproduction, i.e., halogenative stress, can also damage host biomolecules, and MPO itself may be targeted by RHS. Therefore, we examined the susceptibility of MPO to inactivation by its primary products (HOCl, HOBr, HOSCN) and secondary products such as taurine monochloramine (TauCl) and taurine monobromamine (TauBr). MPO was dose-dependently inhibited up to complete inactivity by treatment with HOCl or HOBr. TauBr diminished the activity but did not eliminate it. TauCl had no effect. MPO became inactivated when producing HOCl or HOBr but not HOSCN. Taurine protected MPO against inactivation when MPO was catalyzing oxidation of Cl- to HOCl, whereas taurine failed to prevent inactivation when MPO was working with Br-, either alone or in combination with Cl-. SCN- interfered with HOCl-mediated MPO inhibition. UV-vis spectra showed that heme degradation is involved in HOCl- and HOBr-mediated MPO inactivation. A negative linear correlation between the remaining chlorinating activity of HOCl- or HOBr-modified MPO and Escherichia coli survival upon incubation with MPO/H2O2/Cl- was found. This study elucidated the possibility of MPO downregulation by MPO-derived RHS, which could counteract halogenative stress. PMID- 29394491 TI - Impact of l-citrulline supplementation on oxygen uptake kinetics during walking. AB - Supplementation with l-citrulline (Cit) has been shown to improve muscle oxygenation and oxygen uptake kinetics during moderate- to high-intensity cycling in young men. The aim of this study was to test the hypothesis that Cit would improve oxygen uptake kinetics during walking in older and young adults. In a randomized, double-blind study, 26 (15 women, 11 men) adults between the ages of 20-35 years (n = 15) and 64-86 years (n = 11) completed 7-day periods of taking placebo and Cit (6 g/day) in a crossover manner. Participants walked on a treadmill at 40% heart rate reserve while pulmonary oxygen uptake was measured using indirect calorimetry. Net oxygen cost, mean response time (MRT), and the oxygen deficit were calculated before and after each supplement period. There was no significant change (P > 0.05) in net oxygen cost, MRT, or the oxygen deficit after Cit in older adults, while young adults showed a decrease (P = 0.05) in the oxygen deficit after Cit that tended (P = 0.053) to be different than the change after placebo. Sex-stratified analysis revealed that Cit decreased MRT (P = 0.04, Cohen's d = 0.41) and the oxygen deficit (P < 0.01, Cohen's d = 0.56) in men with the change after Cit being greater than the change after placebo (MRT: -4.5 +/- 2.1 vs. 3.4 +/- 2.1 s, P = 0.01; deficit: -0.15 +/- 0.05 vs. 0.01 +/- 0.05 L, P = 0.02). All oxygen uptake parameters were unchanged (P > 0.05) following Cit and placebo in women. Cit does not alter the oxygen cost of moderate-intensity walking in young or older adults, but Cit improved the rate of rise in oxygen uptake at exercise onset in men. PMID- 29394492 TI - Influence of 5'-flanking sequence on 4.5SI RNA gene transcription by RNA polymerase III. AB - Short nuclear 4.5SI RNA can be found in three related rodent families. Its function remains unknown. The genes of 4.5SI RNA contain an internal promoter of RNA polymerase III composed of the boxes A and B. Here, the effect of the sequence immediately upstream of the mouse 4.5SI RNA gene on its transcription was studied. The gene with deletions and substitutions in the 5'-flanking sequence was used to transfect HeLa cells and its transcriptional activity was evaluated from the cellular level of 4.5SI RNA. Single-nucleotide substitutions in the region adjacent to the transcription start site (positions -2 to -8) decreased the expression activity of the gene down to 40%-60% of the control. The substitution of the conserved pentanucleotide AGAAT (positions -14 to -18) could either decrease (43%-56%) or increase (134%) the gene expression. A TATA-like box (TACATGA) was found at positions -24 to -30 of the 4.5SI RNA gene. Its replacement with a polylinker fragment of the vector did not decrease the transcription level, while its replacement with a GC-rich sequence almost completely (down to 2%-5%) suppressed the transcription of the 4.5SI RNA gene. The effect of plasmid sequences bordering the gene on its transcription by RNA polymerase III is discussed. PMID- 29394493 TI - Mouse models in squamous cell lung cancer: impact for drug discovery. AB - INTRODUCTION: Squamous cell lung cancer (SQCLC) is the second most common subtype of non-small cell lung cancer (NSCLC) and has limited therapeutic options. Its development is likely a result of a multistep process in response to chronic tobacco exposure, involving sequential metaplasia, dysplasia and invasive carcinoma. Its complex genomic landscape has recently been revealed but no driver mutations have been validated that could lead to molecularly targeted therapy as have emerged in lung adenocarcinoma. Few preclinical murine models exist for testing and developing novel therapeutics in SQCLC. Areas covered: This review discusses the pathophysiology and molecular underpinnings of SQCLC that have limited the development of animal models. It then explores the advantages and limitations of a variety of existing mouse models and illustrates their potential application in drug discovery and chemoprevention. Expert opinion: There are several challenges in the development of mouse models for SQCLC, such as lack of validated driver genetic alterations, unclear cell of origin, and difficulty in reproducing the sophisticated tumor microenvironment of human disease. Nevertheless, several successful SQCLC murine models have emerged, especially Patient Derived Xenografts (PDXs) and Genetically Engineered Mouse Models (GEMMs). Continued efforts are needed to generate more SQCLC animal models to better understand its carcinogenesis and metastasis and to further test novel therapeutic strategies. PMID- 29394494 TI - Quercetin suppresses the chymotrypsin-like activity of proteasome via inhibition of MEK1/ERK1/2 signaling pathway in hepatocellular carcinoma HepG2 cells. AB - The proteasomal system is a promising target for cancer treatment. Quercetin (Que), a flavonoid compound with antitumor ability, displays the inhibitory effect on proteasome activity. However, the underlying molecular mechanisms are ill defined. The present study found that Que treatment significantly reduced the chymotrypsin-like protease activity of proteasome whereas the trypsin- and caspase-like protease activities remained unchanged in HepG2 cancer cells, along with activation of p38 MAPK and JNK and reduction of ERK1/2 phosphorylation. Que reduced proteasome activity could not be reverted by inhibition of p38 MAPK and JNK signaling pathway. In addition, MEK1 overexpression or knockdown upregulated or downregulated the chymotrypsin-like protease activity of proteasome, respectively. Both Que and MEK1/ERK1/2 inhibitor attenuated the expression levels of proteasome beta subunits. These results indicate that Que-induced suppression of MEK1/ERK1/2 signaling and subsequent reduction of proteasome beta subunits is responsible for its inhibitory impacts on proteasome activity. PMID- 29394495 TI - Biological age of transplanted livers. PMID- 29394496 TI - Glioblastoma in older adults. PMID- 29394497 TI - The current state of GPCR-based drug discovery to treat metabolic disease. AB - : One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. PMID- 29394498 TI - Cortical perception. PMID- 29394500 TI - Mutations in MICAL-1cause autosomal-dominant lateral temporal epilepsy. AB - OBJECTIVE: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. METHODS: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. RESULTS: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. INTERPRETATION: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483-493. PMID- 29394502 TI - Toward personalized medicine for intrahepatic cholangiocarcinoma: Pharmacogenomic stratification of patients. PMID- 29394501 TI - Functional interplay between liver X receptor and AMP-activated protein kinase alpha inhibits atherosclerosis in apolipoprotein E-deficient mice - a new anti atherogenic strategy. AB - BACKGROUND AND PURPOSE: The liver X receptor (LXR) agonist T317 reduces atherosclerosis but induces fatty liver. Metformin activates energy metabolism by activating AMPKalpha. In this study, we determined if interactions between metformin and T317 could inhibit atherosclerosis without activation of hepatic lipogenesis. EXPERIMENTAL APPROACH: Apolipoprotein E-deficient mice were treated with T317, metformin or both agents, in a high-fat diet for 16 weeks. Then, samples of aorta, liver, macrophage and serum were collected to determine atherosclerotic lesions, fatty liver, lipid profiles and expression of related proteins. Techniques used included immunohistochemistry, histology, qRT-PCR and Western blot. KEY RESULTS: T317 inhibited en face and aortic root sinus lesions, and the inhibition was further enhanced by addition of metformin. Co-treatment with metformin and T317 increased lesion stability, by increasing collagen content, and reducing necrotic cores and calcification. Formation of macrophages/foam cells and their accumulation in arterial wall were inhibited by the co-treatment, which was accompanied by increased ABCA1/ABCG1 expression, reduced monocyte adhesion and apparent local proliferation of macrophages. Metformin blocked T317-induced fatty liver by inhibiting T317-induced hepatic LXRalpha nuclear translocation and expression of lipogenic genes and by activating AMPKalpha. Moreover, co-treatment with T317 and metformin improved triglyceride metabolism by inducing expression of adipose triglyceride lipase, hormone-sensitive lipase, PPARalpha and carnitine acetyltransferase and by inhibiting acyl-CoA:diacylglycerol acyltransferase 1 expression. CONCLUSIONS AND IMPLICATIONS: Co-treatment with T317 and metformin inhibited the development of atherosclerosis without activation of lipogenesis, suggesting that combined treatment with T317 and metformin may be a novel approach to inhibition of atherosclerosis. PMID- 29394503 TI - The Wnt/beta-catenin pathway determines the predisposition and efficiency of liver-to-pancreas reprogramming. AB - : Transdifferentiation (TD) is the direct reprogramming of adult cells into cells of alternate fate and function. We have previously shown that liver cells can be transdifferentiated into beta-like, insulin-producing cells through ectopic expression of pancreatic transcription factors (pTFs). However, the efficiency of the process was consistently limited to <15% of the human liver cells treated in culture. The data in the current study suggest that liver-to-pancreas TD is restricted to a specific population of liver cells that is predisposed to undergo reprogramming. We isolated TD-predisposed subpopulation of liver cells from >15 human donors using a lineage tracing system based on the Wnt response element, part of the pericentral-specific promoter of glutamine synthetase. The cells, that were propagated separately, consistently exhibited efficient fate switch and insulin production and secretion in >60% of the cells upon pTF expression. The rest of the cells, which originated from 85% of the culture, resisted TD. Both populations expressed the ectopic pTFs with similar efficiencies, followed by similar repression of hepatic genes. Our data suggest that the TD-predisposed cells originate from a distinct population of liver cells that are enriched for Wnt signaling, which is obligatory for efficient TD. In TD-resistant populations, Wnt induction is insufficient to induce TD. An additional step of chromatin opening enables TD of these cells. CONCLUSION: Liver-to-pancreas TD occurs in defined predisposed cells. These cells' predisposition is maintained by Wnt signaling that endows the cells with the plasticity needed to alter their transcriptional program and developmental fate when triggered by ectopic pTFs. These results may have clinical implications by drastically increasing the efficacy of TD in future clinical uses. (Hepatology 2018). PMID- 29394499 TI - Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. AB - In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design. PMID- 29394504 TI - Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage. AB - OBJECTIVE: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. METHODS: In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev <= 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev >= 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves. RESULTS: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev(<=137ng/ml) occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev <= 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev >= 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR <= 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev <= 100ng/ml. INR >= 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev >= 75ng/ml. INTERPRETATION: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459. PMID- 29394505 TI - Sleep and cognitive decline: A prospective nondemented elderly cohort study. AB - OBJECTIVE: To investigate sleep disturbances that induce cognitive changes over 4 years in nondemented elderlies. METHODS: Data were acquired from a nationwide, population-based, prospective cohort of Korean elderlies (2,238 normal cognition [NC] and 655 mild cognitive impairment [MCI]). At baseline and 4-year follow-up assessments, sleep-related parameters (midsleep time, sleep duration, sleep latency, subjective sleep quality, sleep efficiency, and daytime dysfunction) and cognitive status were measured using the Pittsburgh Sleep Quality Index and Consortium to Establish a Registry for Alzheimer's Disease Assessment, respectively. We used logistic regression models adjusted for covariates including age, sex, education, apolipoprotein E genotype, Geriatric Depression Scale, Cumulative Illness Rating Scale, and physical activity. RESULTS: In participants with NC, long sleep latency (>30 minutes), long sleep duration (>=7.95 hours), and late midsleep time (after 3:00 am) at baseline were related to the risk of cognitive decline at 4-year follow-up assessment; odds ratio (OR) was 1.40 for long sleep latency, 1.67 for long sleep duration, and 0.61 for late midsleep time. These relationships remained significant when these variables maintained their status throughout the follow-up period. Newly developed long sleep latency also doubled the risk of cognitive decline. In those with MCI, however, only long sleep latency reduced the chance of reversion to NC (OR = 0.69). INTERPRETATION: As early markers of cognitive decline, long sleep latency can be used for elderlies with NC or MCI, whereas long sleep duration and relatively early sleep time might be used for cognitively normal elderlies only. Ann Neurol 2018;83:472-482. PMID- 29394506 TI - When less is more (brain)-comment on "Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage". PMID- 29394507 TI - Interpreting Alzheimer disease polygenic scores. PMID- 29394509 TI - Increase of hyperpolarization-activated cyclic nucleotide-gated current in the aberrant excitability of spinal muscular atrophy. AB - OBJECTIVE: The pathophysiology of spinal muscular atrophy (SMA) is still unclear. METHODS: The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, western blotting, and whole-cell patch-clamp recording were used for the identified hypothesis. RESULTS: The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold relationship was reproducible in a mouse model of mild SMA, and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in SMA mice, and voltage-clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA. INTERPRETATION: This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN target for SMA therapy. Ann Neurol 2018;83:494-507. PMID- 29394508 TI - Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. AB - OBJECTIVE: Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood-brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when. METHODS: Investigating cellular events in the meninges shortly after CSD, we used in vivo two-photon imaging to identify changes in macrophages and dendritic cells (DCs) that reside in the pia, arachnoid, and dura and their anatomical relationship to TRPV1 axons. RESULTS: We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DCs stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid, and dural DCs 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DCs can appear in close proximity to TRPV1-positive axons. INTERPRETATION: The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20 to 30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DCs in the subarachnoid space and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and DCs supports a role for these immune cells in the modulation of head pain. Ann Neurol 2018;83:508-521. PMID- 29394510 TI - A longitudinal study of women's depression symptom profiles during and after the postpartum phase. AB - BACKGROUND: An issue of critical importance for psychiatry and women's health is whether postpartum depression (PPD) represents a unique condition. The Diagnostic and Statistical Manual of Mental Disorders asserts that major depressive disorder (MDD) may present with peripartum onset, without suggesting any other differences between MDD and PPD. The absence of any distinct features calls into question the nosologic validity of PPD as a diagnostic category. The present study investigates whether symptom profiles differ between PPD and depression occurring outside the postpartum phase. METHODS: In a prospective, longitudinal study of parturient women (N = 239), we examine the manifestation of depression symptoms. We assess factor structure of symptom profiles, and whether factors are differentially pronounced during and after the postpartum period. RESULTS: Factors were revealed representing: Worry, Emotional/Circadian/Energetic Dysregulation, Somatic/Cognitive, Appetite, Distress Display, and Anger symptoms. The factor structure was validated at postpartum and after-postpartum timepoints. Interestingly, the Worry factor, comprising anxiety and guilt, was significantly more pronounced during the postpartum timepoint, and the Emotional/Circadian/Energetic Dysregulation factor, which contained sadness and anhedonia, was significantly less pronounced during the postpartum period. CONCLUSIONS: These results suggest that PPD may be a unique syndrome, necessitating research, diagnosis, and treatment strategies distinct from those for MDD. Results indicate the possibility that Worry is an enhanced feature of PPD compared to depression outside the postpartum period, and the crucial role of sadness/anhedonia in MDD diagnosis may be less applicable to PPD diagnosis. PMID- 29394511 TI - Behavioral avoidance predicts treatment outcome with exposure and response prevention for obsessive-compulsive disorder. AB - BACKGROUND: Many individuals with obsessive-compulsive disorder (OCD) display behavioral avoidance related to their obsessional thoughts and compulsive behaviors. However, how these avoidance behaviors impact treatment outcomes with exposure and response prevention (EX/RP) remains unclear. We examined pretreatment avoidance behaviors as predictors of EX/RP outcomes. METHODS: Data came from a randomized controlled trial of augmentation strategies for inadequate response to serotonin reuptake inhibitors comparing EX/RP (N = 40), risperidone (N = 40), and placebo (N = 20). Baseline avoidance was rated with the avoidance item from the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Primary analyses examined avoidance behaviors as predictors of EX/RP outcomes. To test specificity, we explored whether avoidance also related to outcomes among patients receiving risperidone and placebo. RESULTS: More than half (69%) of the full sample had moderate or severe avoidance behaviors at baseline. In EX/RP, controlling for baseline severity, pretreatment avoidance predicted posttreatment YBOCS symptoms (beta = 0.45, P < .01). Avoidant individuals were less likely to achieve remission with EX/RP (odds ratio = 0.04, 95% confidence interval [CI] range 0.01-0.28, P = .001). Baseline avoidance was also associated with degree of patient adherence to between-session EX/RP assignments, which mediated the relationship between baseline avoidance and EX/RP outcomes (P < .05). Baseline avoidance did not predict outcomes or wellness among patients receiving risperidone or placebo. CONCLUSIONS: These results suggest that avoidance behaviors are an important clinical factor in EX/RP outcomes and indicate that assessing avoidance may provide an efficient method for predicting EX/RP outcomes. Avoidance may be particularly relevant in EX/RP as compared to medication treatment, though future replication of these initial results is required. PMID- 29394512 TI - The end game: Mortality outcomes in North American professional athletes. AB - Comprehensive investigations into the mortality outcomes of elite athletes can assist in decoding risk factors for premature mortality and provide avenues for exploring human health through engagement in sport. As such, the purpose of this study was to comprehensively examine lifespan trends of athletes from the 4 major sports in North America: Major League Baseball (MLB), National Basketball Association (NBA), National Football League (NFL), and National Hockey League (NHL). We hypothesized that proportional death rates would be similar across the 4 sports, when standardizing the data by debut years. Overall, 17 523 of 50 515 (34.7%) athletes were deceased as of the respective data collection cutoff date for their sport, with MLB players having the highest risk of imminent mortality. Professional basketball players generally had the highest relative proportion of death when standardizing data by debut year, although NHL and NFL players who debuted after 2005 had the highest proportion of death. In addition, a 1-year increase in career length significantly decreased the risk of death (HR: 0.982, 95% CI: 0.978-0.985), even after adjusting for sport type (HR: 0.977, 95% CI: 0.974-0.980). Meaningful significance should be considered given the historical and unique nature of the sample. Nevertheless, investigating risk of death differences through different occupational and biological variables can help highlight aversive trends to lifespan that permeate throughout high-performance athlete populations. PMID- 29394513 TI - Aortic bypass surgery for asymptomatic patients awaiting a kidney transplant: A word of caution. AB - INTRODUCTION: In the presence of severe aorto-iliac calcification, aortic bypass surgery can be mandatory to allow kidney transplantation. The aim of our study was to evaluate the safety and outcomes of this strategy among asymptomatic patients. MATERIALS AND METHODS: We retrospectively reviewed the files of all patients that had undergone vascular bypass surgery prior to kidney transplantation between November 2004 and March 2016. All patients undergoing aortic bypass surgery prior to kidney transplantation without any vascular related symptoms were included. RESULTS: Twenty-one asymptomatic patients were included. Ten patients (48%) have not received a kidney transplant. Four patients died before kidney transplantation, including 2 deaths related to the bypass surgery (9.5%). Early post-operative morbidity involved 11 cases. Eleven patients (52%) were transplanted. Transplanted patients were significantly younger (median age 60 [56-61] vs 67 [60-72] years, P = .04) at the time of bypass and were less frequently treated for coronary heart disease (9% vs 50%, P = .06). CONCLUSION: Aortic bypass surgery performed prior to kidney transplantation among asymptomatic patients has significant mortality and morbidity rates. When transplantation is possible, the results are satisfying. Larger studies are required to define the selection criteria, such as age and coronary heart disease. PMID- 29394514 TI - Angioplasty vs stent in the treatment of transplant renal artery stenosis. AB - OBJECTIVE: To compare outcomes between percutaneous transluminal angioplasty and stent placement in the treatment of transplant renal artery stenosis (TRAS). METHODS: We retrospectively studied patients who underwent angiography for TRAS between 1/1/2008 and 9/20/2016 at 1 center. We compared the rates of restenosis in patients who were treated with angioplasty alone vs those who were treated with stenting. Secondary outcomes included serum creatinine and blood pressure after intervention and graft and patient survival. RESULTS: A total of 82 patients were identified as having TRAS after angiography. Restenosis occurred in 28% (16 of 58) of the angioplasty patients compared with 8% (2 of 24) of the stented patients (P = .04). Repeat angiography occurred in 14% (8 of 58) of angioplasty patients vs 13% (3 of 24) of stented patients (P = .9). The stented group had significantly higher pre-intervention stenosis (71% vs 64%, P = .01) and lower postintervention stenosis (4% vs 30%, P < .001). Serum creatinine and blood pressures were not significantly different between the 2 groups at 30, 90, or 360 days postintervention. There was no statistically significant difference in graft or patient survival between groups (P = .37). CONCLUSIONS: Stent placement resulted in fewer cases of restenosis compared with angioplasty alone, although no benefit in terms of serum creatinine, blood pressure, or patient and graft survival was shown. PMID- 29394515 TI - Which is more nephrotoxic for kidney transplants: BK nephropathy or rejection? AB - Little data exist comparing outcomes following BK nephropathy (BKN) vs acute rejection. We reviewed outcomes among recipients who had a primary diagnosis of biopsy-proven BKN or rejection between 1 and 18 months post-transplant. There were 96 cases of BKN and 256 cases of rejections. We compared outcomes of BKN with all rejection combined and also with cellular rejection. Seven of 256 (2.7%) patients developed BKN after treatment of rejection. Conversely, 8 of 96 (8.3%) developed rejection after BKN. The eGFR at time of diagnosis in the BKN group (33.7 +/- 12.6) was lower than the rejection group (44.8 +/- 23.3, P < .001). The eGFR at 6 months after diagnosis of BKN was 32.7 +/- 14.9 and for rejection was 48.8 +/- 20.7 (P <= .001). The mean eGFR at 3 years postdiagnosis was 41.6 +/- 18.5 in BKN and 53 +/- 21.3 for rejection (P = .001). The graft failure incidence rates were similar between 2 groups. A similar pattern was observed comparing BKN with cellular rejection. While the difference in rate of graft loss between BKN and rejection did not reach statistical significance, kidney function up to 3 years after diagnosis was worse for BKN than for rejection, suggesting that BKN is at least as damaging to kidneys as rejection. PMID- 29394517 TI - A population genetics analysis in clinical isolates of Sporothrix schenckii based on calmodulin and calcium/calmodulin-dependent kinase partial gene sequences. AB - Sporotrichosis is a subcutaneous mycosis that is caused by diverse species of Sporothrix. High levels of genetic diversity in Sporothrix isolates have been reported, but few population genetics analyses have been documented. To analyse the genetic variability and population genetics relations of Sporothrix schenckii Mexican clinical isolates and to compare them with other reported isolates. We studied the partial sequences of calmodulin and calcium/calmodulin-dependent kinase genes in 24 isolates; 22 from Mexico, one from Colombia, and one ATCC(r) 6331TM; the latter was used as a positive control. In total, 24 isolates were analysed. Phylogenetic, haplotype and population genetic analyses were performed with 24 sequences obtained by us and 345 sequences obtained from GenBank. The frequency of S. schenckii sensu stricto was 81% in the 22 Mexican isolates, while the remaining 19% were Sporothrix globosa. Mexican S. schenckii sensu stricto had high genetic diversity and was related to isolates from South America. In contrast, S. globosa showed one haplotype related to isolates from Asia, Brazil, Spain and the USA. In S. schenckii sensu stricto, S. brasiliensis and S. globosa, haplotype polymorphism (theta) values were higher than the nucleotide diversity data (pi). In addition, Tajima's D plus Fu and Li's tests analyses displayed negative values, suggesting directional selection and arguing against the model of neutral evolution in these populations. In addition, analyses showed that calcium/calmodulin-dependent kinase was a suitable genetic marker to discriminate between common Sporothrix species. PMID- 29394518 TI - Novel encoding and updating of positional, or directional, spatial cues are processed by distinct hippocampal subfields: Evidence for parallel information processing and the "what" stream. AB - The specific roles of hippocampal subfields in spatial information processing and encoding are, as yet, unclear. The parallel map theory postulates that whereas the CA1 processes discrete environmental features (positional cues used to generate a "sketch map"), the dentate gyrus (DG) processes large navigation relevant landmarks (directional cues used to generate a "bearing map"). Additionally, the two-streams hypothesis suggests that hippocampal subfields engage in differentiated processing of information from the "where" and the "what" streams. We investigated these hypotheses by analyzing the effect of exploration of discrete "positional" features and large "directional" spatial landmarks on hippocampal neuronal activity in rats. As an indicator of neuronal activity we measured the mRNA induction of the immediate early genes (IEGs), Arc and Homer1a. We observed an increase of this IEG mRNA in CA1 neurons of the distal neuronal compartment and in proximal CA3, after novel spatial exploration of discrete positional cues, whereas novel exploration of directional cues led to increases in IEG mRNA in the lower blade of the DG and in proximal CA3. Strikingly, the CA1 did not respond to directional cues and the DG did not respond to positional cues. Our data provide evidence for both the parallel map theory and the two-streams hypothesis and suggest a precise compartmentalization of the encoding and processing of "what" and "where" information occurs within the hippocampal subfields. PMID- 29394516 TI - CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation. AB - Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (~6 months of age and ~11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD associated neurodegeneration related to amyloid-beta peptide (Abeta) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD. PMID- 29394519 TI - Eccentric exercise induces spatial changes in the mechanomyographic activity of the upper trapezius muscle. AB - In this study, we hypothesized that the recordings of multichannel mechanomyography (MMG) of the upper trapezius muscle would reveal spatially dependent manifestations in the presence of delayed onset muscle soreness occurring 24 hours after eccentric exercise (ECC). Sixteen participants performed high-intensity eccentric exercises (5 sets of 10 eccentric contractions at 100% of max elevation force) targeting the upper trapezius on their dominant side. Twelve accelerometers were attached to record MMG activity during submaximal exercise consisting of static and dynamic arm flexion and abduction. Measurements were taken before and 24 hours after ECC. Average rectified value (ARV), percentage of determinism (% DET), and recurrence (% REC) of the MMG signals were computed to estimate the level of muscular activity and the magnitude of regularity of the MMG. The ARV, % REC, and % DET maps revealed heterogeneous MMG activity of the upper trapezius 24 hours after ECC when compared with before. Increased ARV, % REC, and % DET were found 24 hours after ECC when compared with before. The study provides new key information on how a single muscle responds to ECC. Our findings suggest that multichannel MMG and nonlinear analyses may detect muscular and musculo-tendinous alterations due to ECC. PMID- 29394520 TI - Prenatal exposure to maternal and paternal depressive symptoms and white matter microstructure in children. AB - BACKGROUND: Prenatal maternal depression has been associated with multiple problems in offspring involving affect, cognition, and neuroendocrine functioning. This suggests that prenatal depression influences neurodevelopment. However, the underlying neurodevelopmental mechanism remains unclear. We prospectively assessed whether maternal depressive symptoms during pregnancy and at the child's age 3 years are related to white matter microstructure in 690 children. The association of paternal depressive symptoms with childhood white matter microstructure was assessed to evaluate genetic or familial confounding. METHODS: Parental depressive symptoms were measured using the Brief Symptom Inventory. In children aged 6-9 years, we used diffusion tensor imaging to assess white matter microstructure characteristics including fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Exposure to maternal depressive symptoms during pregnancy was associated with higher MD in the uncinate fasciculus and to lower FA and higher MD in the cingulum bundle. No associations of maternal depressive symptoms at the child's age of 3 years with white matter characteristics were observed. Paternal depressive symptoms also showed a trend toward significance for a lower FA in the cingulum bundle. CONCLUSIONS: Prenatal maternal depressive symptoms were associated with higher MD in the uncinate fasciculus and the cingulum bundle. These structures are part of the limbic system, which is involved in motivation, emotion, learning, and memory. As paternal depressive symptoms were also related to lower FA in the cingulum, the observed effect may partly reflect a genetic predisposition and shared environmental family factors and to a lesser extent a specific intrauterine effect. PMID- 29394521 TI - Resolving allele dosage in duplicated loci using genotyping-by-sequencing data: A path forward for population genetic analysis. AB - Whole-genome duplications have occurred in the recent ancestors of many plants, fish and amphibians. Signals of these whole-genome duplications still exist in the form of paralogous loci. Recent advances have allowed reliable identification of paralogs in genotyping-by-sequencing (GBS) data such as that generated from restriction-site-associated DNA sequencing (RADSeq); however, excluding paralogs from analyses is still routine due to difficulties in genotyping. This exclusion of paralogs may filter a large fraction of loci, including loci that may be adaptively important or informative for population genetic analyses. We present a maximum-likelihood method for inferring allele dosage in paralogs and assess its accuracy using simulated GBS, empirical RADSeq and amplicon sequencing data from Chinook salmon. We accurately infer allele dosage for some paralogs from a RADSeq data set and show how accuracy is dependent upon both read depth and allele frequency. The amplicon sequencing data set, using RADSeq-derived markers, achieved sufficient depth to infer allele dosage for all paralogs. This study demonstrates that RADSeq locus discovery combined with amplicon sequencing of targeted loci is an effective method for incorporating paralogs into population genetic analyses. PMID- 29394522 TI - Etiology and antimicrobial resistance patterns in pediatric urinary tract infection. AB - BACKGROUND: Urinary tract infection (UTI) is one of most common pediatric infections. The aim of this study was to investigate the etiology and antimicrobial resistance patterns in children hospitalized at Children's Hospital of Nanjing Medical University. METHODS: We conducted a retrospective, descriptive study of all UTI from 1 January 2013 to 30 November 2016 in children discharged from Nanjing Children's Hospital. The isolated pathogens and their resistance patterns were examined using midstream urine culture. RESULTS: A total of 2,316 children with UTI were included in the study. The occurrence rates of isolated pathogens were as follows: Enterococcus spp., 35.15%; Escherichia coli, 22.32%; Staphylococcus aureus spp., 7.73%; Streptococcus spp., 7.51%; and Klebsiella spp., 6.95%. Uropathogens had a low susceptibility to linezolid (3.47%), vancomycin (0.92%), imipenem (5.74%), and amikacin (3.17%), but they had a high susceptibility to erythromycin (90.52%), penicillin G (74.01%), cefotaxime (71.41%), cefazolin (73.41%), cefuroxime (72.52%), and aztreonam (70.11%). CONCLUSIONS: There is high antibiotic resistance in hospitalized children with UTI. Susceptibility testing should be carried out on all clinical isolates, and the empirical antibiotic treatment should be altered accordingly. PMID- 29394523 TI - Leaf blade structure of Verbesina macrophylla (Cass.) F. S. Blake (Asteraceae): ontogeny, duct secretion mechanism and essential oil composition. AB - Secretory structures are common in Asteraceae, where they exhibit a high degree of morphological diversity. The species Verbesina macrophylla, popularly known as assa-peixe, is native to Brazil where it is widely used for medicinal purposes. Despite its potential medical importance, there have been no studies of the anatomy of this species, especially its secretory structures and secreted compounds. This study examined leaves of V. macrophylla with emphasis on secretory structures and secreted secondary metabolites. Development of secretory ducts and the mechanism of secretion production are described for V. macrophylla using ultrastructure, yield and chemical composition of its essential oils. Verbesina macrophylla has a hypostomatic leaf blade with dorsiventral mesophyll and secretory ducts associated with vascular bundles of schizogenous origin. Histochemistry identified the presence of lipids, terpenes, alkaloids and mucopolysaccharides. Ultrastructure suggests that the secretion released into the duct lumen is produced in plastids of transfer cells, parenchymal sheath cells and stored in vacuoles in these cells and duct epithelial cells. The essential oil content was 0.8%, and its major components were germacrene D, germacrene D-4 ol, beta-caryophyllene, bicyclogermacrene and alpha-cadinol. Secretory ducts of V. macrophylla are squizogenous. Substances identified in tissues suggest that both secretions stored in the ducts and in adjacent parenchyma cells are involved in chemical defence. The essential oil is rich in sesquiterpenes, with germacrene D and its derivatives being notable components. PMID- 29394524 TI - Epidemiology, treatment, disposition and outcome of patients with acute exacerbation of COPD presenting to emergency departments in Australia and South East Asia: An AANZDEM study. AB - BACKGROUND AND OBJECTIVE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common presentation to emergency departments (ED) but data regarding its epidemiology and outcomes are scarce. We describe the epidemiology, clinical features, treatment and outcome of patients treated for AECOPD in ED. METHODS: This was a planned sub-study of patients with an ED diagnosis of AECOPD identified in the Asia, Australia and New Zealand Dyspnoea in Emergency Departments (AANZDEM) study. The AANZDEM was a prospective, interrupted time series cohort study conducted in 46 ED in Australia, New Zealand, Singapore, Hong Kong and Malaysia over three 72-h periods in May, August and October 2014. Primary outcomes were patient epidemiology, clinical features, treatment and outcomes (hospital length of stay (LOS) and mortality). RESULTS: Forty-six ED participated. There were 415 patients with an ED primary diagnosis of AECOPD (13.6% of the overall cohort; 95% CI: 12.5-14.9%). Median age was 73 years, 60% males and 65% arrived by ambulance. Ninety-one percent had an existing COPD diagnosis. Eighty percent of patients received inhaled bronchodilators, 66% received systemic corticosteroids and 57% of those with pH < 7.30 were treated with non-invasive ventilation (NIV). Seventy-eight percent of patients were admitted to hospital, 7% to an intensive care unit. In-hospital mortality was 4% and median LOS was 4 days (95% CI: 2-7). CONCLUSION: Patients treated in ED for AECOPD commonly arrive by ambulance, have a high admission rate and significant in-hospital mortality. Compliance with evidence-based treatments in ED is suboptimal affording an opportunity to improve care and potentially outcomes. PMID- 29394525 TI - Optimal extraction methods for the simultaneous analysis of DNA from diverse organisms and sample types. AB - Using environmental DNA (eDNA) to assess the distribution of micro- and macroorganisms is becoming increasingly popular. However, the comparability and reliability of these studies is not well understood as we lack evidence on how different DNA extraction methods affect the detection of different organisms, and how this varies among sample types. Our aim was to quantify biases associated with six DNA extraction methods and identify one which is optimal for eDNA research targeting multiple organisms and sample types. We assessed each methods' ability to simultaneously extract bacterial, fungal, plant, animal and fish DNA from soil, leaf litter, stream water, stream sediment, stream biofilm and kick net samples, as well as from mock communities. Method choice affected alpha diversity for several combinations of taxon and sample type, with the majority of the differences occurring in the bacterial communities. While a single method performed optimally for the extraction of DNA from bacterial, fungal and plant mock communities, different methods performed best for invertebrate and fish mock communities. The consistency of methods, as measured by the similarity of community compositions resulting from replicate extractions, varied and was lowest for the animal communities. Collectively, these data provide the first comprehensive assessment of the biases associated with DNA extraction for both different sample types and taxa types, allowing us to identify DNeasy PowerSoil as a universal DNA extraction method. The adoption of standardized approaches for eDNA extraction will ensure that results can be more reliably compared, and biases quantified, thereby advancing eDNA as an ecological research tool. PMID- 29394526 TI - A 5' AMP-Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma. AB - 5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment. Compound 59 induced apoptosis as indicated by caspase activation and PARP cleavage. In addition, it inhibited JAK/STAT3 signalling, arrested cells in the G1 phase, increased reactive oxygen species (ROS) generation and promoted autophagy. Interestingly, pre-treatment with a protein tyrosine phosphatase (PP2A) inhibitor, cantharidin, partially reversed compound 59-induced down-regulation of p-JAK2 and p-STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. Together, these findings substantiate the potential of compound 59 for the treatment of OSCC patients. PMID- 29394527 TI - Insights into intraspecific wood density variation and its relationship to growth, height and elevation in a treeline species. AB - The wood economics spectrum provides a general framework for interspecific trait trait coordination across wide environmental gradients. Whether global patterns are mirrored within species constitutes a poorly explored subject. In this study, I first determined whether wood density co-varies together with elevation, tree growth and height at the within-species level. Second, I determined the variation of wood density in different stem parts (trunk, branch and twigs). In situ trunk sapwood, trunk heartwood, branch and twig densities, in addition to stem growth rates and tree height were determined in adult trees of Nothofagus pumilio at four elevations in five locations spanning 18 degrees of latitude. Mixed effects models were fitted to test relationships among variables. The variation in wood density reported in this study was narrow (ca. 0.4-0.6 g cm-3 ) relative to global density variation (ca. 0.3-1.0 g cm-3 ). There was no significant relationship between stem growth rates and wood density. Furthermore, the elevation gradient did not alter the wood density of any stem part. Trunk sapwood density was negatively related to tree height. Twig density was higher than branch and trunk densities. Trunk heartwood density was always significantly higher than sapwood density. Negative across-species trends found in the growth wood density relationship may not emerge as the aggregate of parallel intraspecific patterns. Actually, trees with contrasting growth rates show similar wood density values. Tree height, which is tightly related to elevation, showed a negative relationship with sapwood density. PMID- 29394528 TI - Understanding biological and ecological factors affecting seed germination of the multipurpose tree Anogeissus leiocarpa. AB - Anogeissus leiocarpa (DC.) Guill. & Perr. (Combretaceae) has important economic and cultural value in West Africa as source of wood, dye and medicine. Although this tree is in high demand by local communities, its planting remains limited due to its very low propagation via seed. In this study, X-rays were used to select filled fruits in order to characterise their morphology and seed germination responses to treatment with sulphuric acid and different incubation temperatures. Morphological observations highlighted a straight orthotropous seed structure. The increase in mass detected for both intact and scarified fruits through imbibition tests, as well as morphological observations of fruits soaked in methylene blue solution, confirmed that they are water-permeable, although acid-scarified fruits reached significantly higher mass increment values than intact ones. Acid scarification (10 min soaking in 98% H2 SO4 ) positively affected seed germination rate but not final germination proportions. When intact fruits where incubated at a range of temperatures, no seeds germinated at 10 degrees C, while maximum seed germination (ca. 80%) was reached at 20 degrees C. T50 values ranged from a minimum of ca. 12 days at 25 degrees C to a maximum of ca. 34 days at 15 and 35 degrees C. A theoretical base temperature for germination (Tb ) of ca. 10 degrees C and a thermal requirement for 50% germination (S) of ca. 195 degrees Cd were also identified for intact fruits. The results of this study revealed the seed germination characteristics driven by fruit and seed morphology of this species, which will help in its wider propagation in plantations. PMID- 29394529 TI - Regulation of Transforming Growth Factor-beta/Smad-mediated Epithelial Mesenchymal Transition by Celastrol Provides Protection against Bleomycin-induced Pulmonary Fibrosis. AB - The respiratory disease pulmonary fibrosis (PF), which is characterized by scar formation throughout the lung, imposes a serious health burden. No effective drug without side effects has been proven to prevent this fatal lung disease. In this context, this study was undertaken to elucidate the protective effect of celastrol, a quinine methide pentacyclic triterpenoid from a Chinese medicinal plant 'thunder god vine' against bleomycin (BLM)-induced PF. We also attempted to study how the cytokine transforming growth factor-beta (TGF-beta) stimulates fibrosis through the induction of epithelial-mesenchymal transition (EMT) and the role of celastrol in regulating EMT. TGF-beta (5 ng/ml) was administered to human alveolar epithelial adenocarcinoma A549 cells to induce fibrotic response in cells. Induction of EMT was analysed in cells through morphological analysis and expression of epithelial and mesenchymal markers by Western blotting. Bleomycin at a concentration of 3 U/Kg b.w was used to induce fibrosis in adult male rat lungs. Celastrol (5 mg/kg b.w) was given to rats twice a week after BLM administration for a period of 28 days. Western blot and immunofluorescence analyses were performed with lung tissue sample to find out the potential of celastrol in regulating EMT during the progression of fibrosis. TGF-beta induces EMT in A549 cells as demonstrated by changes in epithelial cell morphology and expression of epithelial and mesenchymal marker proteins. The expressions of epithelial marker proteins E-cadherin and claudin were found to be reduced in the BLM-induced group of rats. Expression of mesenchymal markers, such as N-cadherin, snail, slug, vimentin and beta-catenin, was enhanced in BLM-induced rat lungs. Celastrol reverts these cellular changes in rat lungs, and it was found that celastrol regulates EMT through the inhibition of heat shock protein 90 (HSP 90). Together, the results indicate that EMT is a crucial phenomenon for the progression of fibrosis, and celastrol provides protection against PF through the regulation of EMT. PMID- 29394530 TI - Breeding system and bumblebee drone pollination of an explosively pollen releasing plant, Meliosma tenuis (Sabiaceae). AB - Explosive pollen release is a mechanism used by some angiosperms that serves to attach pollen to a pollinator's body. It is usually adopted by species with zygomorphic tubular flowers and pollinated by birds and bees. The tree genus Meliosma (Sabiaceae, Proteales) has unique disc-like flowers that are externally actinomorphic, but internally zygomorphic, and release pollen explosively. To elucidate the adaptive significance of explosive pollen release, we observed flowering behaviour, the breeding system and pollinator visits to flowers of the Japanese species Meliosma tenuis in a temperate forest. Flowers bloomed in June and were nectariferous and protandrous. Explosive pollen release was triggered by slight tactile stimuli to anther filaments or staminodes in male-stage flowers. Because pollen cannot come into contact with the pistils enclosed by staminodes, M. tenuis is functionally protandrous. Artificial pollination treatments revealed that M. tenuis is allogamous. The dominant flower visitors were nectar-seeking drones of the bumblebee species Bombus ardens (Apidae). The drones' behaviour, pollen attachment on their bodies and fruit set of visit-restricted flowers suggest that they are the only agent triggering the explosive pollen release mechanism, and are the main pollinator of M. tenuis. The finding that bumblebee workers rarely visit these flowers suggests that the explosive pollen release has another function, namely to discourage pollen-harvesting bumblebee workers. PMID- 29394531 TI - [Successful Multimodality Treatment Including Three-Stage Operation for Esophageal Cancer with Esophagorespiratory Fistula - A Case Report]. AB - The esophagorespiratory fistula(ERF)is a fatal complication ofesophageal cancer, because ofadvanced oncological status and poor conditions due to pneumonia and/or malnutrition.We report here a case of patient who was successfully treated for esophageal cancer with ERF with multimodality therapy including three-stage operation. A 65-year-old woman ofesophageal cancer received preoperative chemotherapy, and developed EFR before operation. Prolonged conservative therapies for ERF let her general condition get worse. Therefore, the patient underwent esophagostomy and gastrostomy to recover her condition. She received chemo-radiotherapy followed by esophagectomy. And she was performed the reconstruction next month. She is still alive without recurrence at 20 months after resection. In previous reports, a total of 6 cases have been performed esophagectomy for esophageal cancer with ERF in Japan. Only one case was reported that had survived longer than 12 months. This multimodality therapy can be one ofthe best strategies for the patients ofesophageal cancer with ERF, even ifthey have poor condition. PMID- 29394532 TI - [A Case of Breast Cancer with Local Recurrence in the Reconstructed Breast Tissue]. AB - The rate of local recurrence after mastectomy is reportedly similar to that of one-stage reconstruction. Most recurrences are in the skin or chest wall, while recurrence in the reconstructed breast is rare and the causes are uncertain. We report a case of a 42-year-old female who underwent partial mastectomy for left breast cancer with cT4aN0M1(PUL), cStage IV after endocrine therapy 3 years ago. Histopathological diagnosis was solid-tubular carcinoma. She had been treated with only endocrine therapy but diagnosed with local recurrence in the left breast. She underwent total mastectomy and rectus abdominis musculocutaneous flap reconstruction. Partial flap necrosis occurred following conservative therapy. She was accordingly treated with anastrozole and GnRH agonist. A mass approximately 1.5 cm in size was palpated inside of the reconstructed breast. As such, she was diagnosed with recurrence in the reconstructed breast through ultrasound biopsy. She underwent partial resection of the left precordial tumor, and histopathological examination revealed scirrhous cancer. She is currently well without any recurrence. PMID- 29394533 TI - [A Case of T1a Breast Cancer with Axillary Lymph Node Metastasis]. AB - A breast cancer with tumors smaller than or equal to 5mm in diameter is treated as a microscopic lesion and axially lymph node metastasis is considered to be rare. A 52-year-old female was found to have an abnormal shadow on mammography. An ultrasonography revealed a poorly defined and irregular shaped mass with calcification, 4mm in diameter, in the AC area of her left breast. We performed vacuum-assisted biopsy and diagnosed with invasive ductal carcinoma. Under a preoperative diagnosis of left breast cancer with cT1aN0M0, stage I , Luminal A like, we underwent partial mastectomy with sentinel lymph node biopsy. The intraoperative consultation suggested sentinel lymph node metastasis and we therefore performed level II axillary lymph node dissection. The size of the tumor was 4mm and diagnosed with pT1a breast cancer. Histopathological diagnosis was papillotubular carcinoma. Radiotherapy was performed(total: 50 Gy)followed by endocrine therapy (tamoxifen). She is alive without recurrence and metastasis 5 years after surgery. PMID- 29394534 TI - [Local Control of Advanced Breast Cancer with Giant Ulcer]. AB - This study reports the treatment and local control of advanced breast cancer with a giant ulcer. A 53-year-old woman presented with a large left breast tumor and an associated giant ulcer, with massive exudates, bleeding, and an offensive odor. Histopathological examination revealed an invasive ductal carcinoma(Luminal B type). Computed tomography(CT) showed multiple metastases to the lymph nodes, lungs, liver and bones. The patient received chemotherapy with a combina- tion of paclitaxel(PTX 90mg/m / 2)and bevacizumab(BEV 10 mg/kg). After 4 courses of chemotherapy, there was a significant reduction in the tumor size, the discharge of exudates and bleeding as well as lumbago and femoral pain. High CEA and CA15-3 levels had been normalized and CT showed a remarkable decrease in metastases. Compared to the tumor itself, the ulcer associated with it had shown a smaller decrease in size, and there was the possibility of perforation in the thin chest wall. Suspecting these outcomes to the adverse events of BEV, its use was discontinued, and starting with course 5 of chemothera- py, we administrated only PTX(90mg/m2). Subsequently, the ulcer showed obvious granulation and was infected. CT of the chest prior to the second course of PTX revealed pleurisy, pneumonia and atelectasis. Following the administration of antibiotics, while infection in the ulcer had subsided, pleurisy and pneumonia continued, with increased right pleural effusion, which finally required drainage. We had to discontinue the administration of PTX. BEV, although effective as first-line therapy, has the adverse effect of slowing wound healing. Therefore, even though the combination therapy of BEV and PTX is markedly effective for systemic therapy, it should be altered for local wound healing as in this case. PMID- 29394535 TI - [Long-Term Survival in a Patient with Combined Hepatocellular-Cholangiocarcinoma Treated with Multidisciplinary Therapy - A Case Report]. AB - The patient was a woman in her 50's. She went to the hospitalfor epigastric discomfort. Numerous hypovascular tumors spreading almost to the entire liver were detected via abdominal CT. We diagnosed the tumors as unresectable intrahepatic cholangiocarcinoma(ICC). Chemotherapy with gemcitabine(GEM)and S-1 was given. The tumors shrunk markedly, and stable disease status was maintained for 2 years and 4 months. Thereafter, the regimen was changed to GEM plus cisplatin (CDDP)because of progressive disease, which was then uncontrolled. Although proton beam therapy and radiofrequency ablation were subsequently performed, multiple lesions appeared in the liver, and metastasis was also observed shortly in the left lung. Right hepatic trisegmentectomy and thoracoscopic left lung partial resection were performed in 2 stages. Histopathological findings showed morphological hepatocellular carcinoma(HCC)as well as positive immunostaining with CEA, CK7, and CK19. The final diagnosis was combined hepatocellular-cholangiocarcinoma. The patient is without recurrence for 9 months following operation, and long-term survivalfor 4 years and 6 months has been obtained. PMID- 29394536 TI - [A Case of Leiomyosarcoma of the Small Intestine with Intestinal Hemorrhage Due to Intraluminal Penetration]. AB - A 40-year-old man was referred to our hospital because of severe anemia and small intestinal tumor revealed by computed tomography. The enteroscopy exam showed the intraluminal penetration of the tumor, which was considered as a cause of anemia. Although emergency operation was performed laparoscopically, intraoperative findings indicated tumor invasion into peritoneum, and we converted from laparoscopic surgery to open surgery that included concomitant peritoneum resection. Histopathological findings showed spindle-shaped tumor cells with severe atypia. Immunohistochemical study showed tumor cells to be positive for aSMA, but negative for c-kit and CD34, then we diagnosed the tumor as leiomyosarcoma of the ileum. Since leiomyosarcoma of the small intestine is a rare entity, we have reported with literature consideration. PMID- 29394537 TI - [A Case of Adenoma of the Nipple Suspected of Breast Cancer]. AB - Adenoma of the nipple is a rare benign tumor, and it is important to distinguish from Paget's disease or breast cancer. A 45- year-old woman had found induration under the right areola before 2 months and visited our hospital. Ultrasonography showed a 2.4 cm solid tumor in a cystic lesion, which had high blood flow in E area of the right mammary gland. The tumor suspected as duct papillomatosis by core needle biopsy. No metastasis lesion was found by computed tomography and bone scintigraphy. But magnetic resonance imaging showed as a marginally clear tumor with contrast enhanced findings that were relatively early reinforced and prolonged. Because there was a possibility of malignancy based on these findings, tumorectomy was done with patient consent. Histological examination revealed usual ductal hyperplasia(duct papillomatosis)and no malignancy. No recurrence was seen for a year after operation. When diagnosing a tumor under areola, be careful not to misdiagnose malignancy. PMID- 29394538 TI - [A Case of Synchronous Triple Cancer of the Breast, Duodenal and Lung]. AB - A 71-year-old woman visited her nearby hospital because jaundice and right hypochondralgia. She was diagnosed as obstructive jaundice due to duodenal papillary carcinoma and was introduced to our hospital. Chest computed tomography showed some tumors in both lung and left breast, then the breast tumor was diagnosed as primary breast cancer by needle biopsy. Since it was difficult to distinguish whether multiple tumor of lung was primary lung cancer or metastasis, right pulmonary partial resection using a thoracoscope was performed. In histopathological examination, it was diagnosed as adenocarcinoma of the pulmonary primary. Multiple bone metastases were also showed by bone scintigraphy. Therefore, the diagnosis was advanced progressive synchronous triple cancer with bone metastasis. She did not hope for aggressive treatment, it has now reached observation of no treatment. In recent years, due to advances in diagnostic technology reports of duplicated cancer cases are increasing, but I have experienced a case of extremely rare triple cancer of the breast, duodenal and lung. PMID- 29394539 TI - [A Patient with Scirrhous Gastric Cancer Diagnosed and Resected Subsequently by Laparotomy Examination Due to Difficulty to Take Cancer Specimen by Endoscopic Biopsy]. AB - Some of scirrhous gastric cancer are difficult to diagnose on the surface view or to take correct biopsy specimen.A 85-yearold man with dysphagia was diagnosed scirrhous gastric cancer endoscopically, but could not be taken a biopsy specimen showing cancer.We informed cases of scirrhous gastric cancer difficult to take correct biopsy specimen and recommended surgical operation to take correct specimen and to start a treatment.Patient underwent total gastrectomy after cancer diagnosis( P0CY0cT4aN0).He can eat more food and survive longer than 1 year without any chemotherapies.Scirrhous gastric cancer needs early diagnosis and treatment to improve patient prognosis. PMID- 29394540 TI - [A Case of Recurrent Gastric Cancer with Grade 3 Proteinuria Caused by Ramucirumab plus Paclitaxel Therapy]. AB - Proteinuria is one of the characteristic adverse events by ramucirumab(RAM)plus paclitaxel(PTX)combination therapy for advanced gastric cancer. We reported a case of recurrent gastric cancer with grade(gr)3 proteinuria caused by RAM plus PTX therapy. 77-year-old woman was underwent distal gastrectomy in 76 years old for gastric cancer that was diagnosed mucinous adenocarcinoma, fStage III C(T4aN3H0P0CY0M0)and received adjuvant chemotherapy of S-1 for 1 year. She suffered from peritoneal recurrence with ascites after 1 year and 4 months of the operation and RAM(8mg/kg; day 1 and 15)plus PTX(80mg/m2; day 1, 8 and 15)therapy was administrated as second-line chemotherapy. After 1 course, weekly PTX has been continued for gr 3 proteinuria and the ascites disappeared after 4 courses. This successful case might indicate that it was important for patients with gr 3 proteinuria as adverse event to consider discontinuance of RAM and continuation of PTX according to the proper usage guide of RAM. PMID- 29394541 TI - [Quality of Life of Patients after Colorectal Cancer Surgery as Assessed Using EQ 5D-5L Scores]. AB - This study aimed to evaluate the health-related quality of life(QOL)using EQ-5D 5L scores for patients who underwent surgery for colorectal cancer. A total of 30 consecutive patients(14 men and 16 women; median age: 67.5 years)from the outpatient clinic of our institute in January 2017 were eligible for this study. The primary tumor was located in the colon(n= 18)or rectum/anu(s n=12). Twelve patient(s 40.0%)had cancer recurrence, and 3 patient(s 10.0%)had a stoma. In addition, 11 patients(36.7%)underwent chemotherapy. The median EQ-5D-5L score for all the patients was 0.867(range, 0.324- 1.000). The EQ-5D-5L score of patients with recurrence was significantly lower(0.820)than that of patients without recurrence( 0.948)(p=0.002). Furthermore, the EQ-5D-5L score of women(0.834)was significantly lower than that of men (0.942)(p=0.015). No significant difference was noted between the EQ-5D-5L score and other factors, such as age, cancer stage, location of primary tumor, absence/presence of chemotherapy, and absence/presence of stoma. In conclusion, using EQ-5D-5L scores, female gender and cancer recurrence were found to be associated with low QOL of patients after surgery for colorectal cancer. PMID- 29394542 TI - [Three Cases of Remnant Pancreatic Cancer after Surgery for Invasive Ductal Carcinoma of Pancreas]. AB - We report here 3 cases of remnant pancreatic cancer after surgery for invasive ductal carcinoma. Case 1 was a 73-year-old male who underwent distal pancreatectomy(pap, pT3, pN0, M0): fStage II A(JPS 7th). He developed a remnant pancreatic cancer 39 months later, and total remnant pancreatectomy was performed. He died from sepsis 9 months after surgery. Case 2 was a 72-year-old female who underwent subtotal stomach-preserving pancreatoduodenectomy(SSPPD)(tub2, pT1c, pN1a, M0): fStage II B. She developed a remnant pancreatic cancer 82 months later. This lesion seemed to be resectable. But she hoped to take a best supportive care, and died 13 months after diagnosis. Case 3 was a 68-year-old female who underwent SSPPD(tub1, pT3, pN1a, M0): fStage II B. She developed a remnant pancreatic cancer 20 months later and was successfully treated by chemotherapy and carbon-ion radiotherapy. PMID- 29394543 TI - [A Case of Ductal Carcinoma In Situ in Sclerosing Adenosis]. AB - A 67-year-old female was referred to our hospital because she was pointed out mass in her right breast by her previous doctor. Core needle biopsy examination was performed at that time which revealed invasive ductal carcinoma. There'reno palpable masses in her breast or any superficial lymph nodes on her visiting our hospital. Breast ultrasonography images showed multiple nodules in C area of right breast. Breast enhanced MRI image revealed multiple enhanced nodules which showed rapid arising and plateau or slowly decreasing pattern in time intensity curve. CT scan and bone scintigraphy revealed no distant metastasis. Based on these findings, the case was diagnosed as right breast cancer, cT1N0M0, Stage I . For this case, we performed right mastectomy and sentinel lymph node biopsy. The pathological findings was ductal carcinoma in situ (DCIS)accompanied by sclerosing adenosis. Though we didn't perform adjuvant chemotherapy, she has been alive without recurrence for 6 years. Because it's difficult to make correct diagnosis with small specimen collected by core needle biopsy, we should take DCIS in sclerosing adenosis into consideration to prevent overdiagnosis. PMID- 29394544 TI - [Prognostic Analysis of Breast Cancer Patients Who Underwent Neoadjuvant Chemotherapy Using QOL-ACD]. AB - We investigated into association of quality of life(QOL)and prognosis of breast cancer patients who underwent neoadjuvant chemotherapy(NAC). We retrospectively studied 228 patients with breast cancer who were performed NAC during a period between 2007 and 2015. TheQ OL score was measured with"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs(QOL-ACD)". We evaluate association between QOL score with antitumor effect and prognosis. Changes in the QOL score between before and after NAC were compared as well. We divided 2 groups by QOL ACD scoreinto high and low groups. Therapeautic effect of NAC on 75 patients were pathological complete response(pCR). QOL-ACD score was not significantly associated with pCR rate in both high and low groups(p=0.199). High group was significantly associated with higher survival rate in both of disease free survival(p=0.009, logrank)and overall survival(p=0.040, logrank). QOLACD score decreased after NAC in both of pCR and non-pCR patients. In conclusion, QOL evaluation using QOL-ACD could be an indicator of breast cancer patients' prognosis who underwent NAC. PMID- 29394545 TI - [A Case of Occult Breast Cancer]. AB - We report a case of occult breast cancer. A 61-years-old woman underwent tumorectomy of right axillary mass. Pathological diagnosis was adenocarcinoma. Two years after, right axillary mass was discovered again. Wide local excision, axillary lymph node dissection and radiation therapy of the breast was performed. Pathological findings showed lymph node metastasis of breast cancer, or primary cancer of the axially tail of the breast. Ten months after second operation, she presented an axillary mass again. She underwent resection of the axillary tumor. The pathological findings showed lymph node metastasis of breast cancer. There was no evidence of primary tumor of the breast during the period. We suspected lymph node metastasis of occult breast cancer. Irradiation was administered to the right axilla, and she is receiving endocrine therapy. PMID- 29394546 TI - [Cystic Duct Cancer with Postoperative Liver Metastasis That Achieved Complete Response after Gemcitabine Treatment - A Case Report]. AB - A 72-year-old woman was diagnosed with gallbladder cancer and underwent extended cholecystectomy and extrahepatic bile duct resection. The pathological findings were CGnBdGb, circ, nodular infiltrating type, 20*10 mm, tub2, pT3b, int, INF c, ly1, v1, ne3, pN0, pDM0, pHM0, pEM0, pPV0, pA0, R0, Stage III A. Because the main localization was in the cystic duct, we diagnosed this as cystic duct cancer. Seven months after surgery, follow-up computed tomography scan revealed a metastatic region in segment 7 of the liver. She underwent chemotherapy with gemcitabine(GEM). After 3 courses of GEM, the metastatic lesion became obscure. After 8 courses, the metastatic lesion disappeared, and the patient showed complete response. We discontinued chemotherapy after 21courses of GEM, and the patient is alive with no signs of recurrence 4 years and 4 months after surgery. PMID- 29394547 TI - [A Case of Inflammatory Breast Cancer with Very Severe Obesity]. AB - A 39-year-old woman with very sever obesity was admitted to our hospital for a right breast redness and hardness. Her height, weight and BMI were 166 cm, 145 kg and 52.6 kg/m2. Her breast had peau d'orange. CT scan showed swelling of whole right breast and Level I , II lymph node. We performed core needle biopsy and diagnosed as the inflammatory breast cancer with ER and HER2 positive. We introduced chemotherapy(pertuzumab, trastuzumab and paclitaxel)and nutrition counseling in order to reduce her body weight. After 4 courses of chemotherapy, the clinical complete response was obtained and her body weight decreased to 125 kg. We performed mastectomy and axillary node resection and confirmed pathological complete response. Adjuvant chemotherapy(5-FU, epirubicin and cyclophosphamide), adjuvant trastuzumab therapy, postmastectomy radiation therapy and adjuvant hormonal therapy were administered. There have been no signs of recurrence as of 2 years after the operation. PMID- 29394548 TI - [Clinical Experience of a Primary Accessory Breast Cancer Patient]. AB - A 59-year-old woman attended a previous hospital complaining of a nodule of the right axilla. Although ultrasonography had shown no evidenceof malignancy, a growth of thenodulewas found on follow-up. Excisional biopsy revealed a primary accessory breast cancer. Because the resected margins were involved, she was referred to our hospital for additional treatment. Based on imaging, both bilateral mammary glands and axillary lymph nodes were reported normal, and distant metastasis was not observed. We performed additional resection of the right axillary tissue around the biopsy site and the right axillary lymph nodedisse ction. Histo-pathological examination revealed the residual invasive ductal carcinoma in the resected specimen. Both the new surgical margins and the lymph nodes were free of disease. Accessory breast cancer is relatively rare, with the incidence being less than 1% of all breast cancers. It is most frequent in the axillary region. Local extensive resection with sufficient surgical margin and axillary lymph node dissection are generally required. This case report presents our clinical experience of accessory breast cancer with some discussion of the literature. PMID- 29394549 TI - [A Long-Surviving Case of HER2-Positive Breast Cancer with Brain Metastasis Treated through Multidisciplinary Therapy]. AB - We present a case of a 48-year-old woman who visited our hospital due to a lump in her left breast. She was diagnosed with HER2-positive, hormone-positive stage III A breast cancer. The patient underwent trastuzumab-based neoadjuvant chemotherapy and surgery(Bt+Ax). The pathological effect of neoadjuvant chemotherapy was Grade 1b. The patient underwent radiotherapy and was administered hormone therapy and adjuvant trastuzumab. Seven months postsurgery, the patient was taken to the hospital for loss of consciousness. Single brain metastasis with a diameter of 3 cm was found in the right frontal lobe with edema. She underwent surgery and was administered chemotherapy with lapatinib and capecitabine. Because of relapse of brain metastasis, she underwent 4 surgeries and 5 sessions of gamma-knife radiosurgery. She died 7 years after the detection of brain metastasis. The prolonged survival of this breast cancer patient with brain metastasis seems to be a result of multidisciplinary therapy, local therapy(surgery and radiation), and systemic therapy(chemotherapy). Cooperation between the radiation therapy department and the neurosurgery department was thought to be important for the treatment of the metastatic brain tumor. PMID- 29394550 TI - [A Patient with Basaloid Carcinoma of the Esophagus Removed Surgically after Pre Operative Chemotherapy Who Developed TTP during Post-Operative Chemotherapy]. AB - A 63-year-old man presented with the chief complaint of an unpleasant feeling in the chest after a meal.Esophagogastroduodenoscopy revealed interminglement of ulcer infiltration type lesions and protruding lesions in the lower esophagus.A large type 1 protruding lesion was located mainly in the esophagogastric junction(EGJ)and it progressed towards the stomach.A hypertrophic and protruding lesion on the lower esophageal wall and a 6 cm tumor in the major axis of the fornix were observed on thoracic and abdominal CT, and an endocrine cell carcinoma or basaloid carcinoma were suggested after biopsy.Finally, we diagnosed a basaloid carcinoma after immunohistochemistry analysis.We administered 4 courses of TS-1 plus CDDP as pre-operative chemotherapy.Because of a significant reduction in tumor size, approximately 5 months after first presentation, we performed esophageal resection by right thoracotomy and laparotomy, and reconstructive surgery for the thoracic gastric duct.The pathological diagnosis was basaloid carcinoma with multiple foci of squamous cell carcinoma.After surgery, we continued chemotherapy with TS-1 plus CDDP, which was previously effective, but a liver metastasis appeared 8 months later.We discontinued chemotherapy because of a prominent decline in platelets.Because of the clinical symptoms, we diagnosed secondary thrombotic thrombocytopenic purpura accompanied by a malignant tumor.We implemented plasma exchange and steroid pulse therapy, but this patient experienced no therapeutic effect and died. PMID- 29394551 TI - [Laparoscopic Total Gastrectomy(LTG)in Patient with Multiple Gastric Neuroendocrine Tumor Related to Multiple Endocrine Neoplasia Type 1 - Two Case Reports]. AB - We herein report 2 cases of laparoscopic total gastrectomy(LTG)in patient with multiple gastric neuroendocrine tumor (NET)related to multiple endocrine neoplasia type 1(MEN1). Case 1: A 66-year-old female was diagnosed with multiple gastric NET. There was no finding of any other tumor, and parathyroid function was normal. She underwent LTG. Case 2: A 58-year-old female was diagnosed with multiple gastric NET. The patient had a previous history of surgery for pituitary gland tumor. There was no finding of any other tumor, and parathyroid function was normal. She underwent LTG. In our cases, we could perform complete resection of gastric NET by laparoscopic surgery. Multiple gastric NET is a good indication of laparoscopic gastrectomy. PMID- 29394552 TI - [Assessment of Short-Term Outcomes of Laparoscopic-Assisted Distal Gastrectomy in Elderly Patients Using Comorbidities as Predictive Factors]. AB - Laparoscopic-assisted distal gastrectomy(LADG)is a recently developed minimally invasive surgery for management of early gastric cancer. We describe short-term results obtained from a retrospective study of LADG, performed in elderly patients, using comorbidities as predictive factors. We studied 160 patients diagnosed with gastric cancer who underwent LADG between January 2005 and October 2016. We compared 48 patients, aged>=75 years(elder group), with 112 patients, aged <75 years(non-elder group), who underwent LADG. Preoperative physical status was assessed using the American Society of Anesthesiologists physical status(ASA PS)score, Charlson comorbidity index(CCI), and the prognostic nutritional index (PNI). Demographics of patients, primarily, sex, tumor lesion, and histology did not significantly differ between the groups. However, the mean ASA-PS score and CCI were significantly higher, and the PNI was significantly lower in the elder group. Surgical duration, volume of blood loss, lymph node clearance, and length of postoperative hospital stay did not significantly differ between the groups. Cardiorespiratory and surgical complications developed in 2(4.2%)and 3(2.7%), and in 5(10%) and 12(11%)patients in the elder and non-elder groups, respectively. However, the rates of intra and postoperative complications were not significantly different between them. LADG can be considered a safe and effective minimally invasive surgical procedure for management of early gastric cancer in elderly patients. PMID- 29394553 TI - [A Case of Primary Neuroendocrine Carcinoma of the Duodenal Bulb]. AB - A 82-year-old man with anemia underwent upper endoscopy, and a hemorrhagic type 1 tumor was detected on the posterior wall of the duodenal bulb. This patient was diagnosed with neuroendocrine carcinoma(NEC)using biopsy. Distant metastasis was not found on imaging. He was referred to our department for the purpose of surgical therapy and underwent pancreaticoduodenectomy. Based on pathological findings, we diagnosed this patient as having NEC. No postoperative adjuvant chemotherapy was administered, but outpatient clinical follow-up was performed. The patient achieved 16 relapse-free months after surgery. Among the cases of NEC with a primary tumor arising from the digestive tract, cases of NEC of the duodenum that are not papillary carcinoma are rare. We report this case in along with a literature review. PMID- 29394554 TI - [Laparoscopic Surgery for an Intussusception Caused by Rectosigmoid Colon Cancer after Pre-Operative Reduction by Transanal Insertion of a Circular Sizer - A Case Report]. AB - An octogenarian man complaining of bloody stool was referred to our hospital. A digital examination, abdominal enhanced CT and endoscopy led to a diagnosis of intussusception due to rectosigmoid colon cancer, but he was not suffering from bowel obstruction. An elective laparoscopic Hartmann's operation was performed after reduction by transanal insertion of a circular sizer. It may be difficult to reduce an intussusception induced by rectal cancer. We report this case with a review of the relevant literature. PMID- 29394555 TI - [A Case of Ascending Colon Cancer with Synchronous Liver Metastases and Peritoneal Dissemination]. AB - The patient was a 73-year-old man with ascending colon cancer and synchronous liver metastases. A right hemicolectomy with a lymph node dissection was performed for the primary lesion. The resected specimen revealed a KRAS codon 12 mutation. After 6 courses of chemotherapy with capecitabine, oxaliplatin, and bevacizumab(Bv), we performed a partial hepatectomy and resection of the peritoneal dissemination. A computed tomography(CT)scan 5 months later revealed the recurrence of the liver metastases. After 8 courses of chemotherapy with 5 fluorouracil, Leucovorin, irinotecan, and Bv, we performed a partial hepatectomy. CT scan after 13 months revealed a recurrence in the peritoneal dissemination in the Douglas pouch and the right subphrenic space; therefore, we performed a low anterior resection and resection of the peritoneal dissemination with curative intent. CT scan after 19 months revealed a recurrence in the right subphrenic dissemination, a lung metastasis, and pleural dissemination. Chemotherapy with 5 fluorouracil, Leucovorin, and Bv was administered for 2 years and 5 months. After 5 years and 9 months of the primary operation, the patient is alive. Recently, we have focused on the mechanism of multidrug resistance through NAD(P)H: quinone oxidoreductase-1(NQO1)overexpression, which can be used to determine the role of an enzyme in sensitivity to toxicity and carcinogenesis. In this case, the pathological examination of the resected specimen revealed NQO1 negative expression. In conclusion, NQO1 may play a significant role in chemotherapy resistance in colorectal cancer patients. PMID- 29394556 TI - [A Case of Huge Colon Cancer Accompanied with Severe Hypoproteinemia]. AB - We report a case of huge colon cancer accompanied with severe hypoproteinemia. A7 4-year-old woman was referred to our hospital because of abdominal fullness. Blood examinations revealed anemia(hemoglobin 8.8 g/dL)and sever hypopro- teinemia(total protein 4.5 g/dL, albumin 1.1 g/dL). Computed tomography examination of abdomen revealed ascites and large tumor(12.5*10.5 cm)at the right side colon. By further examinations ascending colon cancer without distant metastasis was diagnosed, then we performed right hemicolectomy and primary intestinal anastomosis by open surgery. Ahuge type 1 tumor(18*12 cm)was observed in the excised specimen, which invaded to terminal ileum directly. The tumor was diagnosed moderately differentiated adenocarcinoma without lymph node metastasis(pT3N0M0, fStage II ). Postoperative course was uneventful and serum protein concentration recovered gradually to normal range. Protein leakage from the tumor cannot be proved by this case, so we can't diagnose as protein-losing enteropathy, but we strongly doubt this etiology from postoperative course in this case. PMID- 29394557 TI - [Two Resected Cases of Non-Isolated Splenic Metastasis of Colon Cancer]. AB - We report 2 resected cases of patients with non-isolated splenic metastasis of colon cancer. Case 1: A 67-year-old man who underwent partial transverse colectomy and partial hepatectomy for transverse colon cancer and liver metastasis. Approximately 18 months after the operation, splenectomy and partial hepatectomy were performed for metastasis to the spleen and liver. After partial hepatectomy for another recurrence, no signs of new recurrence have been observed for 42 months after splenectomy. Case 2: A 53-year-old woman who presented with bloating. CT and MRI scans revealed masses of the ileocecum, both ovaries, and spleen. We performed right hemicolectomy, total hysterectomy, bilateral salpingo oophorectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy, omentectomy, and splenectomy. Histological findings showed cecal cancer metastasizing to the bilateral ovaries and spleen. Metastatic splenic tumor is relatively rare(0.3 7.3%). Splenectomy was reported to be an effective treatment modality for isolated splenic metastasis, while that for non-isolated metastasis is uncertain. Surgical resection should be considered even in non-isolated splenic metastasis cases because of the evidence of long-term survival in case 1. PMID- 29394558 TI - [Hepatic Lateral Segmentectomy for Management of Liver and Adrenal Abscess Following a Laparoscopy-Assisted Left Hemicolectomy - A Case Report]. AB - A 67-year-old woman underwent laparoscopy-assisted left hemicolectomy for early descending colon cancer(pTis, pN0, cH0, cM0, Stage 0).Her postoperative course was uneventful, without fever and/or tenderness at the anastomotic site.A month following discharge from the hospital, enhanced computed tomography revealed a liver abscess measuring 80mm in diameter at the lateral segment and a left adrenal abscess measuring 30mm in diameter.Although some free air and fluid collection was noted near the anastomotic site, there was no tenderness, and a gastrografin enema did not reveal leakage and/or pooling of the contrast agent near the anastomotic site.We administered antibiotics and performed percutaneous transhepatic abscess drainage following which imaging revealed shrinkage of her liver and adrenal abscesses and lowering of fever.However, enhanced computed tomography, performed a month later, revealed recurrence of the liver abscess, for which we performed a hepatic lateral segmentectomy.After undergoing the hepatectomy, she has shown no recurrence of the liver and adrenal abscesses.Several cases of liver abscess have been reported in association with colorectal cancer; however, an adrenal abscess occurring in association with colorectal cancer has not yet been reported.This case reveals that a minor leak could be associated with a liver and adrenal abscess. PMID- 29394559 TI - [Two Cases of Laparoscopic Resection of Colon Cancer Manifested by Liver Abscess]. AB - We report 2 cases of laparoscopic surgery for patients who had liver abscess as the initial manifestation of underlying colon cancer. The first case was in an 80 year-old woman who presented to our hospital with a diagnosis ofliver abscess. Percutaneous transhepatic abscess drainage(PTAD)was performed as initial treatment. Subsequent colonoscopy revealed a type 1 tumor in the cecum, and biopsy results ofthe mass indicated adenocarcinoma. The patient underwent laparoscopic right hemicolectomy as curative treatment. The pathological findings were as follows: tub1, T2, N0, M0 and Stage I . Two years later, she remains disease free. The second case was in a 59-year-old man with liver abscess. Colonoscopy also revealed a type 2 tumor in the sigmoid colon. After treatment of the liver abscess with PTAD, laparoscopic sigmoidectomy was performed with a preoperative diagnosis of sigmoid colon cancer. The pathological findings were as follows: tub2, T3, N0, M0 and Stage II . Lung metastases appeared 10 months after surgery, and systemic chemotherapy was administered. In conclusion, liver abscess is occasionally caused by malignancy, and complete gastrointestinal evaluation should be conducted. Laparoscopic radical surgery can be safely performed in cases in which the liver abscesses are controlled. PMID- 29394560 TI - [A Case of Infectious Pseudoaneurysm That Developed after Surgery for Local Recurrence of Rectal Cancer]. AB - In February 2011, a male patient in his 60's underwent a low anterior resection and lateral lymph node dissection for lower rectal cancer. Due to large intestinal obstruction from local recurrence, an abdominoperineal resection was performed 5 years 8 months after his first surgery. Inflammation of the pelvic dead space persisted, requiring drainage after the surgery. Although bloody discharge was observed on the 12th and 30th postoperative day, the source of bleeding was not identified on contrast-enhanced CT. On the 35th postoperative day, the patient suddenly lost 700 mL of blood via the abdominal drain and perineal wound. Urgent angiography revealed an aneurysm on the branch of the left iliac artery. Therefore, transcatheter arterial embolization was performed for hemostasis. Infectious complications associated with surgery for locally recurrent rectal cancer frequently occur due to impaired tissue blood flow. This case highlights the importance of paying close attention to the possibility of infectious pseudoaneurysm. PMID- 29394561 TI - [A Case of Surgical Resection of a Combined Hepatocellular and Cholangiocarcinoma with Hemobilia from Intraductal Tumor Thrombus]. AB - We report a case of combined hepatocellular and cholangiocarcinoma with hemobilia. A 65-year-old man was admitted to our hospital because of pain in the right hypochondralrigion. Abdominal ultrasonography revealed bile duct dilatation in the lateral segment of liver and blood test findings showed elevation of the hepatobiliary enzyme, so ERC was performed and hemorrhage from the duodenal papilla was observed. In cholangiography, dilation of the left hepatic bile duct and filling defect were observed, and in the peroral cholangioscopy, a hemorrhagic papillary elevated lesion was identified in the left hepatic bile duct and diagnosed as adenocarcinoma as a result of biopsy. Left hepatectomy with caudate lobe, extrahepatic bile duct resection, lymph node dissection was performed by diagnosis of intrahepatic cholangiocarcinoma. In the resected specimen, tumor size was 16 mm, which was found in the left hepatic duct and invasived into the liver parenchyma. Histopathological examination revealed a combined hepatocellular and cholangiocarcinoma. Gemcitabin was administered as adjuvant chemotherapy for 8 months, but 1 year and 8 months after the operation, it recurred in the liver. Gemcitabin was administered, but it became PD, now it has changed to S-1 and it is SD for 2 years. PMID- 29394562 TI - [A Case of Giant Malignant Phyllodes Tumor Associated with Severe Anemia]. AB - A 72-year-old woman noted a mass in the left breast about 5 years ago, but she did not consult a medical institution. She was taken in the ambulance and hospitalized to our department due to severe anemia and malnutrition. A computed tomography( CT)scan indicated an 18*12 cm tumor in her left breast. A fiborsarcoma protuberance was suspected based on needle core biopsy results. Simple mastectomy was performed to control hemorrhage and infection. The resected tumor weighed 2.6 kg. The pathological diagnosis was a malignant phyllodes tumor. We report a patient with giant malignant phyllodes tumor associated with severe anemia. PMID- 29394563 TI - [Four Cases of Occult Breast Cancer Treated with Breast Conserving Therapy after Neoadjuvant Chemotherapy]. AB - We report 4 patients with occult breast cancer(OBC)who underwent breast conserving therapy(BCT)after neoadjuvant chemotherapy(NAC). All patients complained of axillary tumor and were diagnosed by core needle biopsy. Pathological examination of the axillary lymph nodes proved that 3 cases were adenocarcinomas and 1 case was squamous cell carcinoma, but imaging studies could not depict any primary lesions in the breast and other organs. Since distant metastasis was not observed, BCT with axillary lymph node dissection(ALND)was performed after NAC. All patients were undergoing whole breast irradiation. There were no residual cancer cells in the axillary lymph nodes in case 1 due to the treatment effect of NAC, but lymph node metastasis remained in other 3 cases. In the second case, she followed a rapid outcome, and pulmonary metastasis appeared in 7 months after surgery and died in 10 months. In the other 3 cases, there has not been found local and distant recurrence. Although OBC requires appropriate systemic treatment, present observation indicated that ALND with breast irradiation after NAC could be a useful option. PMID- 29394564 TI - [Papillary Carcinoma Arising in Thyroglossal Duct Cyst in the Right Lateral Neck]. AB - A 47-year-old woman was admitted to our institution with the chief complaint of a right cervical mass. Imaging examination findings showed a cystic mass of 25mm with a nodular lesion in the right cervical region. Therefore, we performed extirpation of the right cervical cystic mass to allow diagnosis of the lesion. The histopathological findings showed a partial thyroid tissue on the cyst wall covered with glandular epithelium or metaplastic squamous epithelium, and tumor cells proliferating in the papillary form. Considering the histopathological evidence of the characteristic epithelium of the thyroglossal duct cyst, the potential carcinogenesis from the remnant thyroid tissues, and the absence of primary tumor in the thyroid gland, the patient was diagnosed with thyroid papillary carcinoma arising from the thyroglossal duct cyst in the right lateral cervical region. We found recurrence of the right cervical lymph node at 1 year and 5 months after the initial operation. Thus, we performed dissection of the right cervical lymph nodes. Two years and 10 months after the operation, neither recurrence nor metastasis have been observed. It was suggested that, thyroid papillary carcinoma arising from the thyroglossal duct cyst should be taken into consideration when a lateral cervical mass lesion is found. PMID- 29394565 TI - [Mixed Type Liposarcoma with Intra-Abdominal Bleeding - Report of a Case]. AB - A 71-year-old man presented with sudden abdominal pain. He had past history of atrial fibrillation, cerebral infarction and heart-valve replacement and received anticoagulant therapy with warfarin. Computed tomography of the abdomen revealed bloody ascites and a huge mass in contact with the third portion of the duodenum. The mass was encapsulated and consisted of a solid component with calcification and hematoma. Under the preoperative diagnosis of gastrointestinal stromal tumor with intra-abdominal bleeding, laparotomy was performed. Intraoperative findings revealed the tumor arising from the right mesocolon and excision of the tumor with right hemicolectomy was performed. Histologic examination confirmed a diagnosis of mixed type liposarcoma. No postoperative complication was observed and he was discharged home on the 8th postoperative day. He remains alive and well with no evidence of disease 52 months after resection. PMID- 29394566 TI - [A Case of Retroperitoneal Liposarcoma That Required Three Times Surgical Resections during Four Years]. AB - The patient was a 64-year-old man, who had undergone surgical resection for a right retroperitoneal giant tumor. The histopathological diagnosis was a well differentiated liposarcoma. Two years and 4 months after the initial surgery, 3 recurrent lesions were found on the dorsal side of the colon hepatic flexure, and resection was performed. One year and 1 month after the secondary surgery, the tumor recurred again, and invaded the right abdominal wall and right transverse colon. Tumor was completely resected macroscopically. All resected tumors were well-differentiated liposarcoma. There have not been any signs of recurrence until 1 year and 6 months after the last operation. For retroperitoneal liposarcoma, complete surgical resection is the only established treatment, but the tumor often recurs. Aggressive resection against recurrent cases is known to contribute to life prognosis, but there is a possibility of the degeneration to a highly malignant dedifferentiated tumor while recurrence is repeated. Therefore, sufficient follow-up observation is needed. PMID- 29394567 TI - [Eight Cases of Esophagus and Tracheobronchial Stenting for Advanced Esophageal Cancer]. AB - Malignant stricture and fistula of the esophagus and tracheobronchus adversely affect the quality of life(QOL)in patients with advanced esophageal cancer. Stenting is one ofthe therapies available for these patients. We investigated the outcomes ofesophagus and tracheobronchial stenting in our institution. Eight patients with advanced esophageal cancer underwent double stenting from 2010 to 2016. Among them, 4 patients underwent double stenting as planned. One patient underwent an emergency tracheal stenting because ofstenosis ofthe trachea caused by esophageal stenting. Three patients underwent tracheobronchial stenting later on because ofan increase in the tumor size after esophageal stenting. Dysphagia score was improved in 5(67.5%)out ofthe 8 patients. Respiratory symptoms were improved in all patients, and 4 patients(50.0%) were discharged. The median survival time after esophageal stenting was 70.5 days. Esophagus and tracheobronchial stenting for advanced esophageal cancer was useful for the improvement of the QOL. PMID- 29394568 TI - [Which Should be Treated First - Breast Cancer or Uterine Myoma?] AB - The patient was a 51-year-old woman with a mass in the left breast.At the first presentation, she had abdominal distension and liver dysfunction.Mammography showed a category 5 mass in the left breast and a category 4, unstructured region in the right breast.Pathological examination revealed bilateral, invasive ductal carcinomas.Stage II B disease(clinical T2N1M0)was diagnosed in the left breast, and Stage I disease(clinical T1N0M0)was diagnosed in the right breast.Computed tomography revealed a massive uterine myoma compressing the inferior vena cava.Liver dysfunction was suspected to be caused by these factors.Preoperative chemotherapy was scheduled to treat breast cancer.A gynecologist stated that "uterine myoma is unlikely to cause liver dysfunction" and refused to perform a hysterectomy.However, we diligently negotiated with him to avoid chemotherapy induced venous thrombosis and pulmonary infarction; eventually, a hysterectomy(3.6 kg)was performed. After surgery, liver function was normal.Subsequently, breast cancer could be safely and adequately treated.In patients who have benign disease, as well as malignant tumors, treatment of the malignant tumors is generally given the highest priority.However, there are cases when the treatment of benign disease has priority over the treatment of malignant tumors.It is therefore important to intensively discuss such cases with physicians from other departments. PMID- 29394569 TI - [A Case of Sigmoid Colon Cancer with Distant Metastasis Successfully Treated with First-Line Cetuximab Monotherapy]. AB - The patient was a 59-year-old woman with progressive sigmoid colon cancer with multiple metastasis(T3N2M1b[P2, H3, PUL2]Stage IV ). As the RAS gene in the patient was wild-type, we administered cetuximab monotherapy every week. One month after chemotherapy initiation, the tumor marker levels declined and the tumor size reduced. Patient's general condition was improved and mFOLFOX6 therapy was then continued in addition to cetuximab. As a side effect, acne-like rash is only grade 1 to 2, and there are no other serious side effects. Cetuximab monotherapy may contribute to the treatment of poor PS patients. PMID- 29394570 TI - [A Case of Duodenum Dissemination after Surgery for Transverse Colon Carcinoma Which Was Unresponsive to Chemotherapy, but Immunotherapy Was Significantly Effective]. AB - The patient was a 73-year-old woman who received surgery for transverse colon cancer(laparoscopic right hemicolectomy) in December 2014. Histopathologic examination findings were tub2, pT4b, pN1, sH0, sM0, ly2, v0, Stage III a. XELOX 2 courses->FOLFIRI plus panitumumab(Pmab)12 courses was performed after surgery. Stenosis due to duodenum dissemination was observed in the follow-up period(December 2015), and a laparoscopic gastrojejunostomy was performed. Later, the patient's tumor marker value significantly increased, and enlargement of duodenum dissemination was observed by abdominalCT. From April 2016, treatment was switched to mFOLFOX6 plus Pmab and 5 courses were subsequently performed. Still, metastasis to the abdominal wall was observed. According to results of the microsatellite instability test of MSIH, the patient was registered into a clinicaltrialfor pembrolizumab, which is anti-PD-1, and administration began from June. The tumor marker value significantly decreased, and a reduction in the size of the duodenum dissemination over time could also be observed by abdominal CT. Significant tumor reduction was observed, indicating that immune therapy may be significantly effective in some cases. PMID- 29394571 TI - [Long-Term Complete Response of Peritoneal Recurrence from Advanced Gastric Cancer Using CapeOx Therapy Following Radical Gastrectomy]. AB - Since the national insurance to use oxaliplatin(L-OHP)for gastric cancer was approved in Japan, patients with advanced or recurrent gastric cancer have been treated by CapeOX therapy as one of the standard regimens. Here, we report a case of long-term complete response of peritoneal recurrence from advanced gastric cancer using CapeOx therapy following radical gastrectomy. The patient underwent total gastrectomy with curative intent for advanced gastric cancer with cytology positive, and received S-1 based adjuvant chemotherapy for 13 months. However, tumor marker elevation and peritoneal recurrence were detected by following examinations. The patient received capecitabine, which is a 5-FU prodrug, plus L OHP therapy. Complete disappearance of peritoneal recurrence was confirmed under laparotomy after the 8th course. L-OHP-induced upregulationof thymidine phosphorylase(TP)was reported to enhance the effectiveness of capecitabine in vivo. CapeOX therapy was also an effective treatment strategy for recurrence following S-1 based chemotherapy. PMID- 29394572 TI - [A Case of Perforative Peritonitis Due to Intestinal Metastasis from Lung Cancer]. AB - We here describe a case of an acute peritonitis due to perforation of a small intestine tumor metastasized from a lung cancer. A 66-year-old man who had undergone a bladder cancer procedure 2 years ago and was hospitalized for the second operation, complained sudden abdominal pain. An enhanced abdominal CTrevealed a small amount of free gas and ascites in the abdominal cavity. On the same day, emergency exploratory surgery was performed with the diagnosis of perforative peritonitis. A laparotomy revealed a jejunal tumor with perforation 40 cm distal from the Treitz ligament. After surgery, the patient confessed that he had got a notice of the recurrence of lung cancer which had been treated 9 years ago. The pathological result indicated the lesion was metastasis from lung cancer. Although small intestinal metastatic tumor from lung cancer is rare, it should be considered when acute abdomen is observed. PMID- 29394573 TI - [Long-Term Survival of a Case with Brain and Lung Metastases from Resected Rectal Cancer by Gamma Knife Radiosurgery]. AB - A 69-year-oldfemale hadund ergone low anterior resection for rectal cancer(Rb). Histological examination showedwell differentiated adenocarcinoma with lymph node metastasis. Adjuvant chemotherapy with UFT was performed postoperatively. Nineteen months later, abdominoperineal resection was performedfor anastomotic recurrence andS -1 chemotherapy was made. As 2 left lung metastases appearedat the 44 months after first surgery, capecitabine was performedfor 4 years. At the 101 months after first surgery, sensory difficulty of right lower limb appearedandMRI revealedbrain tumor(single, 18mm) in the left parietal lobe. We performedgamma knife radiosurgery for the brain metastasis andmultiagent chemotherapy for lung metastases. Although the brain metastases have relapsedtwice, gamma knife providedgoodlocal control. She is surviving without symptom of brain metastases 37 months after the detection. PMID- 29394574 TI - [A Case of Gallbladder Carcinoma Producing Alpha-Fetoprotein(AFP)with Metastatic Liver Tumor]. AB - Gallbladder carcinoma producing alpha-fetoprotein(AFP)is rare.We report a case of AFP producing carcinoma of the gallbladder with huge metastatic hepatic tumor.A 81-year-old female with a hepatitis B virus(HBV)had a fever and right hypochondralgia.Abdominal CT showed an enlarged gallbladder with gallbladder stones, a huge tumor in the right lobe of liver, and swelling paraaortic lymph nodes.Acute cholecystitis was treated by percutaneous transhepatic gallbladder drainage (PTGBD).The hepatic tumor was diagnosed as hepatocellular carcinoma for HBV carrier and the high level of AFP and PIVKA- II .We performed right lobectomy, cholecystectomy and the resection of paraaortic lymph nodes.In the resected gallbladder, the papillary tumor was detected.Histopathological diagnosis was moderately to poorly differentiated adenocarcinoma of the gallbladder.The liver tumor and paraaortic lymph nodes were metastases of the gallbladder carcinoma.The both of gallbladder and liver tumor immunohistochemically stained positive to AFP.It was difficult to diagnose the hepatic tumor because of HBV carrier, the high level of AFP and the unnoticed gallbladder tumor.Gallbladder carcinoma with the high level of AFP might have relation to liver metastases. PMID- 29394575 TI - [A Case of Breast Carcinoma Associated with Osteoclast-Like Giant Cells]. AB - Mammary carcinoma with osteoclast-like giant cells is uncommon, and its onset mechanism and malignancy are unknown. We report a case of mammary carcinoma with osteoclast-like giant cells. A 41-year-old woman noticed a lump in her left breast. Ultrasound sonography findings suggested breast cancer. A core needle biopsy revealed invasive ductal carcinoma of the breast. Modified radicalmastectomy and sentinell ymph node biopsy were performed. Histopathologicalexamination revealed papillotubular carcinoma with osteoclast like giant cells. Cells were positive for estrogen receptor and progesterone, and negative for HER2. MIB-1 index was under 5%. The giant cells were generally associated with an inflammatory, fibroblastic, hyper-vascular stroma. The carcinomatous part of the lesion was most frequently a well-to moderately differentiated invasive ductalcarcinoma. Immunohistochemicaland ultrastructuralstudies suggested that the osteoclast-like giant cells were of stromalhistiocytic origin. To understand biochemicalfindings of this carcinoma, more case studies are required to be reported. PMID- 29394576 TI - [Clinical Evaluation of Perforated Gastric Cancer Cases]. AB - Perforated gastric cancer is relatively rare disease. Between 2006 and 2016, we treated 8 cases with perforative gastric cancer. These cases accounted for 15%of the 53 cases with the upper gastrointestinal tract perforated cases. The median age of perforated gastric cancer case was 66(37-80)years, which was significantly higher than that of perforated benign upper gastrointestinal ulcer(55, 12-97 years)(p=0.033). These patients were divided into 2 groups; 3 cases who died up to 3 months as poor prognosis group and 5 cases who survived more than 4 months as good prognosis group. Poor prognosis group tended to be higher Glasgow prognostic score(GPS)(p=0.05)and lower serum albumin level(p=0.05)than good prognosis group. GPS and serum albumin level may predict the prognosis of perforated gastric cancer patients. PMID- 29394577 TI - [A Case of Conversion Surgery for a Patient with Initially Unresectable Pancreatic Cancer with a Pathological Complete Response to S-1 Chemotherapy]. AB - We present a case ofa 67-year-old woman with Stage IV pancreatic head cancer with invasion to the superior mesenteric vein and artery, and distant lymph node metastases. The patient received S-1 mono-chemotherapy. After 2 courses of chemotherapy, the tumor marker was decreased to the normal levels, and the tumor size was dramatically reduced with undetectable lymph node metastases on CT. As the disease status was maintained following chemotherapy, the patient underwent subtotal stomach preserving pancreaticoduodenectomy, 8 months after initiation of the chemotherapy. Histopathologically, no cancer cells were found in the main tumor and dissected lymph nodes. Final diagnosis was made with pathological complete response. The patient was alive without recurrence for 10 months after surgery. PMID- 29394578 TI - [Investigation of Cases with Curative Resection for Recurrent Colorectal Cancer]. AB - The aim of this study was to clarify the prognosis of cases with recurrent colorectal cancer that underwent curative resection in order to determine index for recurrent colorectal cancer treatment. Of the cases that exhibited recurrence after undergoing curative resection for primary colorectal cancer at our hospital between 1993 and 2013, this study targeted the 109 cases for which curative resection was possible. The sites of recurrence were the liver(58 cases), the lungs(27 cases), the peritoneum (11 cases), local sites(9 cases), lymph nodes(8 cases), and the anastomotic sites(6 cases). Of these, 10 cases exhibited metastasis to 2 organs. The median survival time after metastasectomy was 75.3 months, and the 5-year survival rate was 53.8%. The primary lesion histological type being a poorly differentiated adenocarcinoma/mucinous carcinoma, degree of progression upon initial onset being Stage III b or greater, and disease-free interval being less than 2 years were associated with poorpr ognosis. Specifically, histological type and disease-free interval were found to be independent factors that correlated with prognosis. Meanwhile, no differences were observed for prognosis related to the number of recurrent organs, the number of recurrent nodules, or the number of times curative resection was performed after recurrence. While the histological type and disease-free interval determine prognosis in cases with recurrent colorectal cancer performed curative resection, it appears that if curative resection is possible, aggressive resection should be pursued even for cases of multiple or repeated recurrence. PMID- 29394579 TI - [A Case of Recurrence in the Posterior Wall of the Virginal after Radical Resection for Rectal Cancer Well Responded in a Long Period by Chemo Radiotherapy]. AB - We report a case of an advanced rectal cancer recurrence that responded completely to chemo-radiotherapy. The patient was an 80-year-old woman. Low anterior resection with D2(prxD3)lymph node dissection was performed. Sixteen months after operation, CEA level elevated but no recurrence foci were found in any image tests. Administration of TS-1 was initiated since recurrence was highly suspected. Twenty seven months after operation, PET-CT detected local recurrence in the posterior wall of the vagina. After construction colostomy, chemo radiotherapy(60 Gy+oral UFT)was performed and CEA level dropped promptly to the normal value. No relapse was pointed out in CT scans or MRI tests. There were not any signs of recurrence through 112 months after chemo-radiotherapy. PMID- 29394580 TI - [Treatment Out Come of Eribulin in Patients with Advanced or Metastatic Breast Cancer Who Resistant to Anthracycline and Taxane]. AB - PATIENTS AND METHODS: This retrospective observational study contains advanced or metastatic breast cancer female patients who pretreated with anthracycline and/or taxane received eribulin(ERI)mesylate. The primary endpoint was the progressionfree survival(PFS)and secondary endopoints were objective response rate(ORR), clinical benefit rate(CBR), overall survival (OS), and post progression survival(PPS). RESULTS: A total of 32 patients underwent chemotherapy cycles(median 3; range 1-9 cycles). The ORR was 15.6% and the CBR was 31.3%. The median PFS, OS and PPS were 2.9 months, 8.5 months, 5.6 months respectively. The OS, PPS for relative dose intensity(RDI)<85% and RDI>=85% were 7.2 months, 3.4 months and 14.5 months, 11.4 months, respectively(p=0.005, 0.004). In multivariate analysis for OS and PPS, the visceral disease, total dose of ERI and RDI correlated with OS and PPS. The most frequent treatment-related Grade 3/4 adverse events was neutropenia( 56%). No Grade 3 and 4 peripheral sensory neuropathy was occurred. CONCLUSIONS: ERI exhibited efficacy and tolera- bility in patients with heavily pretreated A/MBC. The total dose and RDI of ERI would induce favorable effect for prognosis. PMID- 29394581 TI - [A Comparison of the Treatment Methods for Obstructive Colorectal Cancer]. AB - PURPOSE: Emergency surgery for obstructive colorectal cancer is considered to be associated with a high degree of risk, and surgery may after decompression is considered to be safer. In cases of obstructive colorectal cancer, decompression can be achieved with surgery, an ileus tube, or a stent, depending on the disease condition. We herein compare the treatment methods for obstructive colorectal cancer. METHODS: Forty-two patients with obstructive colorectal cancer underwent emergency treatment between January 2012 and December 2016. RESULTS: Among the patients with obstructive colorectal cancer, 18 receiveda stent, 10 receiveda nasal ileus tube, 6 receiveda transanal ileus tube, 5 underwent stoma construction, and 3 underwent emergency surgery without decompression. The stent group showed the highest laparoscopic operation rate. There was no significant difference in the overall survival of the treatment groups. One patient in the stent group developed duplicated cancer. CONCLUSION: Stent placement can be considered to be a viable option in the emergency treatment for obstructive colorectal cancer because laparoscopic surgery anda preoperative examination can be performed. PMID- 29394582 TI - [A Case Report of Maintaining Continuous Ambulatory Peritoneal Dialysis after Total Gastrectomy for Perforated Gastric Cancer with ESD]. AB - A 73-year-old man, receiving maintenance continuous ambulatory peritoneal dialysis(CAPD)was admitted to our hospital for chief complaining of heartburn. Gastrointestinal endoscopy disclosed 0- II a on the greater curvature of the upper gastric body. On further examination, the clinical diagnosis was defined as gastric cancer and c-stage I A(cT1aN0M0). The patient was recovered with conservative treatment from the perforated peritonitis after undergoing endoscopic submucosal dissection(ESD). Pathology revealed pT1b, INF b, UL(-), ly2, v0, pHM0, pVM0, for which he underwent total gastrectomy after changed to temporary hemodialysis(HD). On the 3rd postoperative day, blood examination showed WBC and CRP value of 16,100/mL and 20.282mg/dL, respectively. On the 6th postoperative day, nasal endoscopy revealed no anastomotic leakage and started oral take. The patient was discharged on the 20th postoperative day with changed to CAPD from the 7th postoperative day. PMID- 29394583 TI - [Conversion Surgery for Stage IV Gastric Cancer]. AB - This study aimed to examine the clinicopathological factors and prognoses of 5 patients with Stage IV gastric cancer(GC) who underwent chemotherapy followed by R0 resection at our institute from 2004 to 2013. Two patients had non-regional lymph node metastases, another 2 patients had peritoneal disseminations, and 1 patient had peritoneal dissemination and non-regional lymph node and left adrenal metastases. All patients underwent R0 resections following 2-6 courses of chemotherapy using multiple anticancer drugs. The disappearance of GC cells in non-regional lymph nodes and peritoneal nodules was confirmed. Clavien-Dindo II or less postoperative complications were found in 3 patients, but no perioperative mortality was observed. The histological response of the primary tumor to preoperative chemotherapy was determined as grade 1b or higher in every case. Although GC recurrence was found in 3 patients, 2 patients are alive without any recurrence. The median survival time of 5 patients was 28(range: 14 61)months. Some patients with Stage IV GC could achieve long-term survival due to chemotherapy followed by R0 resection. PMID- 29394584 TI - [Appropriate Range of Lymph Node Dissection in Elderly Patients with Colorectal Cancer]. AB - In elderly patients, surgical procesure is decided considering the general condition and surgical invasion. The aim of this study was to clarify the appropriate rage of lymph node dissection for elderly colorectal cancer patients. One hundred forty one colorectal cancer patients aged 75 years or more, who underwent R0 colorectal resection with D2 or D3 lymph node dissection in clinical T3/T4 or clinical N+, were enrolled in this study. The patients whose tumor located in the rectum below the peritoneal reflection(Rb)were excluded. Five-year overall survival(OS)rate and disease specific survival(DSS)rate were 79.1% and 89.4%, respectively. More than 2 preoperative co-morbidities and macroscopic type 3-5 were independent prognostic factors in OS, whereas the rage of lymph node dissection was not risk factor. When comparing the outcomes of D2 and D3 dissections by age, D3 dissection was better tendency in DSS in patients aged under 80, however, D2 dissection was better tendency in patients aged 80 or more. In elderly colorectal cancer patients, there was no difference in prognosis between D2 and D3 dissection, and especially in patients aged 80 years or more, D2 might be sufficient if R0 resection was possible. PMID- 29394585 TI - [A Case of HER2-Positive Breast Cancer with Newly Diagnosed Stage IV That Responded to First-Line Pertuzumab and Trastuzumab-Based Therapy]. AB - A 48-year-old woman who observed swelling and erosion in her left breast was diagnosed with locally advanced, ERnegative, HER2-positive breast cancer with de novo liver metastasis, T4cN1M1, Stage IV . She underwent primary systemic therapy with weekly paclitaxel, and pertuzumab and trastuzumab every 3 weeks. The tumor responded remarkably with 57.0% reduction in 5 weeks of treatment. Because of an anaphylactic shock to paclitaxel in day 8, exchanging to eribulin was considered less toxic than taxane, and was continued for 8 cycles until local relapse. The liver metastasis showed 75.4% reduction. The patient received bilateral mastectomy, which resulted in histological response Grade 1b of the left breast and the right breast of DCIS. After the left thoracic radiation, marginal liver metastasis was observed in the S4 segment on PET-CT. Treatment consisted of docetaxel and dual HER2 blockade therapy in 6 more cycles. As a result, complete remission was achieved. PMID- 29394586 TI - [A Case of Solitary Lymph Node Recurrence Accompanied by Metachronous Multiple Lesion after Definitive Chemoradiotherapy for Esophageal Cancer]. AB - A 53-year-old man was diagnosed with squamous cell carcinoma of the upper thoracic esophagus in cT3N1M0, cStage III (UICC 6th edition). The patient underwent definitive chemoradiotherapy(dCRT)and achieved a complete response in May 2008. Five and a half years after dCRT, swelling of the cardiac lymph node was detected on CT. Frequent check-up was performed in the subsequent 1 year and 10 months, during which the recurrent lesion was revealed as solitarybyPET -CT. No signs of recurrence were detected at the site of the primarylesion byendoscopic examination; however, another superficial cancer was found at a different site. Endoscopic submucosal dissection was performed for the esophageal lesion, and laparoscopic lymphadenectomy was applied to the cardiac lymph node. We herein report a case of a male patient who underwent minimal invasive locoregional treatments for both metachronous multiple lesions and solitaryly mph node recurrence after dCRT. PMID- 29394587 TI - [A Case of Remnant Gastric Cancer That Completely Responded to Neoadjuvant S-1 and Cisplatin Therapy]. AB - A 69-year-old man, who had undergone distal gastrectomy for duodenal ulcer, was diagnosed with remnant gastric cancer and jejunal mesenteric lymph node metastasis. To improve curability, we planned 2 courses of S-1 and cisplatin therapy. After chemotherapy, primary lesion and lymph node metastases reduced in size drastically. Completion gastrectomy and lymph node dissection were performed with curative intent. The tumor was found to have a pathological complete response(pCR) to chemotherapy on histological examination. PMID- 29394588 TI - [Laparoscopic Lymphadenectomy without Gastrectomy for Lymph Nodes Recurrence after Endoscopic Submucosal Dissection (ESD)]. AB - A case oflaparoscopic lymphadenectomy in a patient with lymph node recurrence after endoscopic submucosal dissection (ESD)is presented. A 77-year-old man underwent ESD for gastric cancer. After 2 years, the patient was referred to our hospital with the diagnosis of lymph node recurrence. We offered radical surgery, including gastrectomy and lymphadenectomy; however, this suggestion was denied by the patient because ofstrong anxiety for gastrectomy. As an alternative therapy, laparoscopic lymphadenectomy for the limited area of high recurrence, without gastrectomy, was performed. Postoperative course was uneventful. The patient was discharged on the 10th postoperative day and remains cancer-free over 2 years after the operation. Laparoscopic lymphadenectomy for high risk area of recurrence may be considered in frail elderly patients to avoid the high burden ofgastrectomy. PMID- 29394589 TI - [A Case of Esophagogastric Junction Adenocarcinoma with Neuroendocrine Differentiation]. AB - Gastric cancer rarely contains neuroendocrine component. This mixed tumor is defined as neuroendocrine carcinoma (NEC), mixed adenoneuroendocrine carcinoma(MANEC)and so on according to the WHO classification. We report a patient with esophagogastric junction cancer with neuroendocrine differentiation(NED). The patient was 54-year-old man who diagnosed of esophagogastric junction cancer at the medical examination. Upper gastrointestinal endoscopy revealed a type 3 tumor at esophagogastric junction, and the pathological findings were poorly differentiated adenocarcinoma with focal positivity of chromogranin A. CT and FDG/PET revealed a metastatic regional lymph node. He had undergone proximal gastrectomy and lower esophagectomy, with dissection of D1+and double-tract reconstruction. Pathological findings revealed moderate to poorly differentiated adenocarcinoma containing chromogranin A positive tumor cells. Neuroendocrine components were lower than 30%, and we diagnosed adenocarcinoma with NED. Standard treatment for gastric cancer with NED has not been established and more reports and reviews are required. PMID- 29394590 TI - [Results of Preoperative Colon Stent Placement for Obstructive Colorectal Cancer]. AB - We examined short-term outcomes in 34 patients who had stenting as a bridge to surgery(BTS)for obstructive colorectal cancer during the 5-year period between April 2012 and March 2017.T he patients were 22 men and 12 women with a mean age of 72.6 years. Stenting and decompression were successful in all patients, and the mean time to oral intake after stenting was 2.5 days.No serious complications related to stenting occurred.Elective surgery could be performed in all patients after stenting.The mean number of days to surgery was 24.7 days.Laparoscopic surgery was performed in 14 patients.Postoperative complications included minor leakage in 1 patient, an abdominal wall abscess due to tumor invasion of the abdominal wall in 1 patient, and heart failure and pneumonia, as serious complications, in 1 patient each.Colorectal stenting in patients with obstructive colorectal cancer is a safe and relatively simple procedure.This is an effective treatment strategy in which preoperative colorectal decompression enables a one stage resection. PMID- 29394591 TI - [A Case of Successful Collective Treatment of Colon Cancer with Multiple Metachronous Pulmonary Metastases]. AB - A case is a 46-year-old woman visited us with a chief complaint of bloody stools. A diagnosis of rectal cancer(Rs)was made, and laparoscopic resectomy plus D3 was performed. After progressing to pT4a(SE)N2, M0, pStage III b, postoperative adjuvant chemotherapy(6 courses of XELOX)was administered. Two months after initiating chemotherapy, since the CEA value increased, chest abdominal CT was performed. Five nodules were found in the bilateral lungs and diagnosed as lung metastases(PUL2). Systemic chemotherapy(IRIS plus BV)is administered to PUL2(Grade C)of rectal cancer metachronous metastases. After 3 courses, the effect judgment was SD. Based on the recurrence period from postoperative adjuvant chemotherapy and the findings during this time, it was judged that weight loss surgery was appropriate for the rectal cancer lung metastatic lesions in which chemotherapy was ineffective, and partial resection of both lungs under thoracoscopic assistance was performed. Systemic chemotherapy(TAS-102 plus BV)was initiated to prevent postoperative recurrence. The patient is currently alive without relapse after 12 months. We reported a case of metachronous metastasis of colon cancer in which multidisciplinary treatment was successful. PMID- 29394592 TI - [A Difficult Diagnostic Case of Pancreatic Acinar Cell Carcinoma]. AB - The patient was a 46-year-old woman with left lower abdominal pain.Abdominal dynamic CT revealed a 40 mm, gradually- enhanced pancreatic head mass.The interior of the tumor was heterogeneous and partly low in density.Endoscopic ultrasonography showed a well-defined and heterogeneous tumor with an echoic area in the pancreatic head.Therefore, the cystic lesion with solid components was suspected to be a solid pseudopapillary neoplasm(SPN), considering the age of the patient.Subtotal stomach-preserving pancreaticoduodenectomy was performed.The postoperative course was uneventful, and she was discharged on the 13th day after surgery.Postoperative pathology confirmed a diagnosis of pancreatic acinar cell carcinoma.SPNs often show an image very similar to pancreatic acinar cell carcinoma and it is difficult to distinguish between the two only by imaging findings.Due to the divergence between clinical findings such as age and image findings, it was difficult to confirm a diagnosis of pancreatic acinar cell carcinoma in this case. PMID- 29394593 TI - [Findings from Total Colonoscopy in Obstructive Colorectal Cancer Patients Who Underwent Stent Placement as a Bridge to Surgery(BTS)]. AB - We clinically investigated 34 patients with obstructive colorectal cancer who underwent placement of a colonic stent as a bridge to surgery(BTS), focusing on endoscopic findings after stent placement.Twenty -nine patients(85.3%)underwent colonoscopy after stent placement, and the entire large intestine could be observed in 28(96.6%).Coexisting lesions were observed in 22(78.6%)of these 28 patients.The lesions comprised adenomatous polyps in 17 patients(60.7%), synchronous colon cancers in 5 patients(17.9%), and obstructive colitis in 3 patients(10.7%), with some overlapping cases.All patients with multiple cancers underwent one-stage surgery, and all lesions were excised at the same time.Colonoscopy after colonic stent placement is important for preoperative diagnosis of coexisting lesions and planning the extent of resection. These considerations support the utility of colonic stenting for BTS. PMID- 29394594 TI - [Multidisciplinary Therapy with Gemcitabine and Nab-Paclitaxel for Unresectable Pancreatic Cancer]. AB - Gemcitabine with nab-paclitaxel(GN)shows promisinganti -tumor effect and has been established standard regimen for metastatic pancreatic cancer(PC). Conversion surgery(CS), recently reported about initially unresectable PC with favorable response to non-surgical treatment, might provide long-term survival. The aim of this study is to evaluate the efficacy of multi-modal treatment includingCS after GN therapy for initially unresectable PC. From 2015 to 2016, 29 initially unresectable PC treated with chemotherapy includingGN were eligible for the retrospective analysis. Unresectability was defined over 180- degree abutment to major arteries(UR-LA)or suspicious small metastases(UR-M). CS was planed after clinical favorable response over 6 months of treatment duration. Median age of the patients was 62.5 years old, including 18 males and 11 females. Tumor in the pancreas head(n=20)was dominant. Eighteen patients were UR-LA and remaining1 1 were UR-M. CS was performed in 9 cases(31%)with no significant difference between UR-LA and UR-M. CS showed significant better survival with 67%of 2-year survival rate, compared to without CS(p=0.039). GN regimen effectively induced CS for initially unresectable PC. Multidisciplinary therapy includinginduction GN and CS might have survival impact on unresectable PC. PMID- 29394595 TI - [Two Cases of Colon Cancer with Severe Liver Dysfunction Due to Multiple Liver Metastases Effectively Treated with Hepatic Arterial Infusion Chemotherapy plus CetuximabFollowed by Systemic Chemotherapy]. AB - Case 1: An 80-year-old man was diagnosed with cecal cancer plus multiple liver metastases and peritoneal disseminations. He underwent surgical resection of the primary tumor to prevent bowel obstruction. Initially, hepatic arterial infusion(HAI) plus cetuximab(Cmab)was administered to reduce the size of the metastatic tumors and prevent liver failure. A partial response(PR)was observed in the liver metastases after 12 courses of treatment and S-1 plus oxaliplatin(SOX)plus bevacizumab was started. Case 2: A 44-year-old man was diagnosed with sigmoid colon cancer with multiple liver, lung and bone metastases, and with obstructive jaundice and cholangitis due to severe liver hilum lymph node metastases. His performance status(PS)score was 3 because of severe liver damage. Initially, he underwent endoscopic nasobiliary drainage for obstructive jaundice, and HAI plus Cmab was started to prevent liver dysfunction and to control all metastases. A PR in the metastatic liver tumors was observed after 18 courses. His PS increased to 1 and he was treated with mFOLFOX6 plus Cmab. HAI plus Cmab might be a treatment option for patients who have RAS-wild type tumors with severe liver dysfunction due to multiple liver metastases; HAI is intended to have few side effects and has a high local control rate. PMID- 29394596 TI - [A Case of Intussusception Caused by Colon Cancer in A 25-Year-Old Woman]. AB - A 25-year-old woman presented to our hospital with left flank pain and diarrhea. Contrast-enhanced abdominal computed tomography(CT)showed a target sign in the descending colon. She was diagnosed with intussusception of the colon. Colonoscopy revealed a tumor at the splenic flexure. We performed surgery and found an invaginated transverse colon at the splenic flexure. Reduction was unsuccessful with Hutchinson's maneuver, and we performed partial resection of the invaginated colon. Histopathological diagnosis was adenocarcinoma, tub1, SM2. Adult intussusception is uncommon, especially in young adults. It is usually caused by a polyp or tumor. We report a case of intussusception caused by colon cancer in a young female patient, and review the literature. PMID- 29394598 TI - [A Case of Rectal Metastasis from Breast Cancer Diagnosed Two Years after Surgery]. AB - We report a case of rectal metastasis from breast cancer.Colorectal metastasis from breast cancer is sometimes difficult to diagnose before surgery.A transanal needle biopsy was thought to be useful for a diagnosis and selection of treatment method. PMID- 29394597 TI - [A Case of Long-Term Survival with Multidisciplinary Therapy for a Patient with Multiple Metastases from Rectal Cancer]. AB - Combined modality therapy is sufficient to treat advanced rectal cancer with multiple metastases. Her, we report a case of long-term survival in a patient with multiple metastases from rectal cancer. A5 8-year-old man had previously undergone low anterior resection for advanced rectal cancer. Multiple liver and lung metastases were identified prior to operation; therefore, we initiated chemotherapy(FOLFOX). Partial resection of metastatic lesions and radiofrequency ablation(RFA)were also administered, but newly developed liver, lung, and adrenal gland metastases were identified. We changed the chemotherapy regimen and administered topical therapies(partial resection, RFA, hepatic arterial infusion chemotherapy, radiotherapy)for each chemotherapy-refractory metastatic lesion. Although the patient is in a tumor-bearing state, he is still alive 10 years after his first operation. This combined modality therapy is an option for patients with chemotherapy-refractory metastases from rectal cancer. PMID- 29394599 TI - [A Case of Granulocyte-Colony Stimulating Factor Producing Breast Cancer That Caused Rapid Progression]. AB - We report a case of granulocyte-colony stimulating factor(G-CSF)producing breast cancer in a 54-year-old woman. Eight months after surgery, multiple liver and pulmonary metastases appeared. They progressed rapidly in 2 weeks and she had a high fever of 38 degrees. Serum G-CSF was high, and positive cells were found by immunostaining of the primary tumor. Chemotherapy was initially successful but she died 4 months after relapse. PMID- 29394600 TI - [Efficacy and Safety of Everolimus plus Exemetane in Postmenopausal Endocrine Responsive Metastatic Breast Cancer Patients]. AB - Everolimus and exemestane combination therapy represents a treatment option for estrogen receptor(ER)-positive metastatic breast cancer. We evaluated the efficacy and safety of everolimus and exemestane therapy, retrospectively. After a median follow-up of 10.5 months, the median progression-free survivalin patients was 4.7 months. The clinicalbenefit rate was 27%and the disease controlrate was 64%. The most common all-grade adverse events(AEs)were stomatitis(82%) and non-infectious lung disease(27%). The most commonB3 grade AEs were cellulitis(18%)and hyperglycemia(18%). The AEs reported were mostly grade 1 and 2, and manageable with appropriate intervention. Combination therapy with everolimus and exemestane appears to be a useful addition for ER-positive metastatic breast cancer, with carefulmanage- ment of specific AEs. PMID- 29394601 TI - [A Case of Advanced Gastric Cancer with Synchronous Liver Metastases Responding to Preoperative Combination Chemotherapy with S-1 plus Oxaliplatin(SOX)]. AB - A 67-year-old man was admitted to our hospital because of anemia and weight loss, and diagnosed with a type 3 tumor in the upper gastric body. Pathological examination suggested moderately differentiated adenocarcinoma with immunohistochemically negative staining for HER2. Abdominal CT revealed thickening of the gastric wall and multiple liver metastases. The clinical findings suggested Stage IV disease(T4aN0M1). Chemotherapy was administered with a combination of S-1 plus CDDP(SP). However, the level of CEA(ng/mL)increased from 49.2 to 634.6, and the treatment schedule was changed to a combination of S 1 plus oxaliplatin(SOX). After 3 courses of the SOX regimen, abdominal CT showed a reduction of liver metastases and the level of CEA decreased to 8.4 ng/mL. We performed total gastrectomy with D1 lymph node dissection in September 2016. Post operative pathological findings were ypStage IV (T3N0M1)and chemotherapeutic effect was grade 2. CT scan revealed regrowth of the tumor in S2 3 months after the operation. The patient underwent transcatheter arterial chemoembolization(TACE)followed by a regimen of paclitaxel plus ramucirumab(PTX/RAM). At present, he is being treated with the PTX/RAM regimen in the outpatient department with no signs of tumor growth. Although the prognosis of gastric cancer with synchronous liver metastases is very poor, it is possible for survival to be prolonged with multimodality therapy. PMID- 29394602 TI - [A Case of HER2-Positive Unresectable Gastric Cancer with Multiple Lymph Node and Liver Metastases Controlled Effectively by Combination Chemotherapy with Capecitabine, Oxaliplatin, and Trastuzumab]. AB - A 77-year-old woman was diagnosed with HER2-positive unresectable gastric cancer with multiple lymph node and liver metastases(cT3-4, cN3, cM1[HEP, LYM], cStage IV ). Four courses of combination chemotherapy with capecitabine, oxaliplatin, and trastuzumab(XELOX plus Tras)were administered. Though all lesions showed a complete or partial response, anorexia and body weight loss appeared because of the stenosis in the primary gastric lesion. After another course, these symptoms became worse and she underwent laparoscopic gastrojejunostomy. She progressed favorably after the surgery, her anorexia improved and her weight increased. Thirty-four days after the surgery, the same chemotherapy was continued. At present, the metastases are well controlled 12months after the initial treatment. It is suggested that XELOX plus Tras is an effective chemotherapy regimen for HER2-positive unresectable gastric cancer. PMID- 29394603 TI - [A Case of Intestinal Obstruction Caused by a Bezoar after Pylous-Preserving Gastrectomy]. AB - A 65-year-old woman with a history of pylorus-preserving gastrectomy(PPG)for early gastric cancer visited our hospital because of vomiting. Gastrointestinal endoscopy revealed a large bezoar in the anastomotic site of the stomach. Because the bezoar was too large to be collected orally, the dissolution therapy with taking Coca-Cola(r)was continued. On the 3rd day after hospitalization, she felt acute abdominal pain with vomiting. Computed tomography revealed intestinal obstruction by a mass with air bubbles inside in the ileum. Emergency operation was performed under a diagnosis of intestinal obstruction due to the bezoar. The black brown bezoar sized 80*35*30mm was extracted through an ileotomy. The delayed gastric empty is considered to involve in the bezoar formation. Therefore, the appropriate education of diet and periodic endoscopic screening are necessary for patients with large amounts of gastric residues especially after PPG. In the dissolution therapy, physicians need to be careful of intestinal obstruction by a bezoar. PMID- 29394604 TI - [A Case of Conversion Surgery for Unresectable Colorectal Liver Metastases, Following Effective Combined Chemotherapy with Molecular Targeting Agents]. AB - A 50-year-old man with complaints of epigastralgia, pyrexia, and malaise was diagnosed with sigmoid colon cancer, descending colon cancer, and unresectable colorectal liver metastases. Because the prognosticator was liver metastases, he went through chemotherapy(biweekly CapeOX plus cetuximab)as soon as possible. After 6 courses of this regimen, multiple liver metastases were markedly reduced in size(partial response[PR]), resulting in conversion therapy with complete resection. Recently, some reports showed that patients who had R0 resection after conversion chemotherapy could expect favorable long-term prognosis. It is important to select the appropriate first-line chemotherapy and the timing of the conversion resection. PMID- 29394605 TI - [A Long-Term Disease-Free Survival Case of Synchronous Pulmonary and Liver Metastasis of Rectal Cancer with Systemic Chemotherapy and Radiofrequency Ablation Therapy for Liver Metastasis]. AB - A 55-year-old woman underwent laparoscopic anterior resection and D2 lymph node dissection for recto-sigmoid colon cancer in November 2014, which was diagnosed as T3N1M1(H3, PUL2), stage IV , for the purpose of preserving the ileus. FOLFOX therapy with panitumumab(Pmab)was started in January 2015.A t the end of 11 courses, pulmonary metastasis changed to CR, and liver metastasis was down-graded to H2 on the CT.Because of the risk of hepatic dysfunction with advanced fatty liver due to chemotherapy and extrahepatic lesions, we chose radiofrequency ablation(RFA)therapy for liver metastasis.Pmab combined FOLFIRI therapy was administered, and maintenance therapy was initiated.This patient is alive 2 years and 7 months after surgery and 10 months after RFA without relapse.It is suggested that RFA therapy for liver metastasis of colon cancer with pulmonary metastasis combined with chemotherapy could be an effective treatment strategy. PMID- 29394607 TI - [A Case of Goblet Cell Carcinoid of the Appendix Treated by Laparoscopic Ileocecal Resection after Diagnosis by Colonoscopic Examination for Positive Occult Blood]. AB - A79 -year-old woman underwent colonoscopic examination for positive occult blood. Aneoplastic lesion was seen in the orifice of the vermiform appendix. She was referred to our hospital and underwent colonoscopic examination again. The biopsy revealed poorly differentiated adenocarcinoma or mixed adenoneuroendocrine carcinoma(MANEC), and she was diagnosed with carcinoma of the appendix. She was treated by laparoscopic ileocecal resection with lymph node dissection (D3). Histopathological examination revealed goblet cell carcinoid(GCC)of the appendix with serosal invasion. No metastasis was detected in the dissected lymph nodes. This patient has been followed-up for 6 months after surgery and no recurrences have been detected. PMID- 29394606 TI - [Two Cases of Laparoscopic Simultaneous Resection for Synchronous Liver Metastasis of Colon Cancer]. AB - We report 2 cases of laparoscopic simultaneous resection for synchronous liver metastasis of colon cancer. Case 1: A 76- year-old woman was diagnosed with advanced cecum cancer(type 3)with synchronous liver metastasis(segment 5: 23mm), Laparoscopic ileocecal resection and partial liver resection were performed for 414 minutes, with 20 mL of blood loss. The patient was discharged 11 days after the operation. Case 2: A 78-year-old woman was diagnosed with advanced sigmoid colon cancer(type 2)with synchronous liver metastasis(segment 2: 70mm). Laparoscopic sigmoidectomy and extrahepatic resection were performed for 382 minutes, with 10 mL of blood loss. Portal vein thrombus(umbilicus)was recognized but relieved with warfarin. The patient was discharged 15 days after the operation. Simultaneous laparoscopic colon and hepatectomy for synchronous liver metastasis of colorectal cancer can be safely performed for selected indications. PMID- 29394608 TI - [Pancreaticoduodenectomy in a Patient with Severe Hyperbilirubinemia - A Case Report]. AB - Although the safety of pancreaticoduodenectomy(PD)with hyperbilirubinemia has been reported, the permissible value of preoperative serum bilirubin is unknown. A 58-year-old man developed obstructive jaundice due to duodenal adenocarcino- ma. The initial serum bilirubin value was 26.8mg/dL, and preoperative biliary drainage was performed. However, the serum bilirubin value only decreased to 17.7mg/dL. The other liver function tests were normal. Therefore, we decided to perform PD despite persistent severe hyperbilirubinemia. The postoperative course was uneventful and the bilirubin value improved. He was discharged 17 days after the operation. In the present case, we safely performed PD despite severe jaundice after adequate preoperative liver function evaluation. The attempt to reduce the bilirubin value before surgery did not appear to affect the postoperative course. PMID- 29394609 TI - [A Contrivance for Closure and Dressing of Orocutaneous Fistula Developed in Advanced Oral Cancer]. AB - Orocutaneous fistula sometimes occurs in locallyadvanced unresectable or recurrent oral squamous cell carcinoma. The developed orocutaneous fistula results in constant leakage of saliva, ingested foods and liquids and decline in patients' quality of life(QOL). A 47-year-old Japanese man had received treatment for tongue carcinoma. At the routine follow-up, a cystic lesion in the right submandibular region was detected. Biopsyof the specimen of the cystic lesion revealed squamous cell carcinoma. After chemotherapy, an orocutaneous fistula between the right oropharyngeal and the right submandibular region developed and graduallyincreased. Although closure and dressing of the orocutaneous fistula with various materials was attempted, it was ultimatelyunsuccessful. Finally, application of a rubber film and silicone adhesive agent to the skin was successful for closure and dressing of the fistula. Orocutaneous fistula is one of major contributors to decline in patients' QOL. The sharing of information regarding effective methods or materials for closure and dressing of orocutaneous fistula is necessaryto maintain patients' QOL. PMID- 29394610 TI - [A Case of Transverse Colon Cancer Metastasized to the Spermatic Cord after Resection of Peritoneal Dissemination]. AB - We report a rare case of spermatic cord metastasis from colon cancer. A man in his 50s underwent extended right hemicolectomy for transverse colon cancer followed by resection of a peritoneal recurrence. After receiving adjuvant chemotherapy for 6 months, he became aware of a right inguinal mass. A spermatic cord tumor was noted on computed tomography(CT) and FDG/PET-CT. He underwent radical orchiectomy. The resected tumor was histologically compatible with the colon cancer. Although he received additional chemotherapy, right inguinal recurrence was resected 6 months after orchiectomy. Colon cancer is the second most common origin, after gastric cancer, of metastatic spermatic tumor. As several metastatic routes have been reported, peritoneal seeding is mostly suspected in this case. PMID- 29394611 TI - [A Case of Cecal Cancer with Para-Aortic Lymph Node Metastasis and Peritoneum Dissemination Treated with Curative Resection after mFOLFOX6 plus Panitumumab Chemotherapy]. AB - A 67-year-old woman was diagnosed with cecal cancer, para-aortic lymph node metastasis, peritoneum dissemination, and left breast cancer. We administered mFOLFOX6 plus panitumumab for cecal cancer and an aromatase inhibitor for her breast cancer. She received 7 courses of systemic chemotherapy and showed a partial response. She additionally received 5 courses of mFOLFOX6 plus panitumumab. We performed ileocecal resection, sigmoidectomy, right oophorectomy, dissection of the para-aortic lymph nodes, and peritoneal dissemination. The histopathological findings revealed adenocarcinoma, ypT3, ypN0, ycM0, ypStage II (therapeutic effect Grade 2). One month later, she underwent an enforced left breast segmental resection and sentinel lymph node biopsy(0/2). The results of the pathological examination indicated no residual cancers (therapeutic effect Grade 3). The patient is now in good health and was administered S-1 as an outpatient. PMID- 29394612 TI - [Utility of Preoperative Chemotherapy for Locally Advanced Colorectal Cancer]. AB - Preoperative chemotherapy has been performed for locally advanced colorectal cancer, to achieve cytoreduction, local control, and prevention of distant metastasis. The regimens of mFOLFOX6/XELOX plus bevacizumab for 3 months have been adopted to succeed curative resection for borderline resectable colorectal cancer. We examined treatment results for locally advanced colorectal cancer without distant metastasis. Thirty-four patients were examined and the mean age was 62.7 years old. The cohort comprised of 23 cases of rectal cancer and 11 of sigmoid colon cancer. Thirty cases were diagnosed as cT4b and 25 cases were as cN+before chemotherapy. Stoma creations were performed in 26 patients before preoperative chemotherapy. Reduction ratio of the tumor diameter was 33.6+/ 28.2%. The reduction in CEA was 38.5+/-39.4%, and the reduction in CA19-9 was 62.8+/-42.3%. There were 23 extended resections combined with involved organs including 8 total pelvic exenterations. Chemotherapeutic effect was diagnosed as Grade 1a or less, 20 cases; Grade 1b, 6 cases; Grade 2, 5 cases; Grade 3, 3 cases. Recurrence was found in 9 cases and 8 of them were Grade 1a or less. Overall 5-year survival rate was 74.6%. The utility of preoperative chemotherapy for locally advanced rectal cancer is suggested not only for local treatment but also systemic therapy, especially in chemotherapeutic effective cases. PMID- 29394613 TI - [A Case Report of Gastric Carcinoma with Lymphoid Stroma Differentially Diagnosed from Malignant Lymphoma]. AB - A 49-year-old man was referred to our hospital for close examination of a submucosal tumor with ulceration located in the upper gastric body. PET-CT showed FDG uptake both in the gastric tumor and an enlarged lymph node. Although routine biopsies and EUS-FNA of this tumor did not demonstrate any malignant findings, he underwent excisional biopsy of the enlarged lymph nodes to rule out malignant lymphoma. Histopathological examination revealed that the excised specimens were metastatic nodes of poorly differentiated carcinoma probably from the known gastric tumor. Subsequently, he underwent total gastrectomy with D2, and histopathological findings confirmed the final diagnosis of gastric carcinoma with lymphoid stroma(GCLS). We report a case of GCLS that was difficult to diagnose. PMID- 29394615 TI - [A Case of Gastric Cancer with Peritoneal Dissemination Effectively Treated with Ramucirumab and Paclitaxel]. AB - A 66-year-old man was diagnosed with unresectable distal gastric cancer due to a locally advanced tumor and peritoneal dissemination. After gastrojejunostomy, he underwent S-1 plus cisplatin combination chemotherapy. After 2 courses of chemotherapy, weekly paclitaxel(PTX)was administered as second-line chemotherapy owing to tumor growth(PD). Although 4 courses of chemotherapy had been administered, he developed carcinomatous peritonitis and was hospitalized urgently. Despite diuretic therapy and drainage, the malignant ascites was not adequately controlled. However, he started ramucirumab (RAM)plus PTX chemotherapy as third-line therapy and ascites subsequently reduced, he regained oral intake and was discharged from hospital. PMID- 29394614 TI - [A Case of Advanced Gastric Cancer Responding Effectively to Neoadjuvant Chemotherapy]. AB - A 78-year-old man underwent an upper gastrointestinal endoscopy for evaluation of epigastralgia. Endoscopy revealed a bulky type 3 tumor in the lesser curvature of the upper body. A biopsy showed a poorly differentiated adenocarcinoma with signet ring cell carcinoma. Additionally, abdominal computed tomography(CT)showed bulky lymph node metastases leading to a diagnosis of cT3N2M0, Stage III A carcinoma. Following administration of 2 courses of neoadjuvant chemotherapy (NAC)using S-1/cisplatin(CDDP), CT revealed significant regression of the primary lesion and lymph nodes. Eventually, laparoscopic total gastrectomy was performed. Histopathologically, almost all viable cancer cells had been cleared from the primary lesion, and no cancer cells were found in the lymph nodes, which indicated a pathological partial response(Grade 2). NAC could be a valid option for the treatment of advanced gastric cancer. PMID- 29394617 TI - [Outcomes of Elderly Patients with Perforated Colorectal Cancer]. AB - We retrospectively investigatedoutcomes in surgically treatedeld erly patients with perforatedcolorectal cancer. The clinicopathological andsurvival data on 54 perforatedcolorectal cancer patients treatedwith surgery were analyzed. They included 12 patients>=75 years old(elderly group)and4 2 patients<75 years old(non elderly group). There were no significant differences in terms of clinicopathological features, the severity of peritonitis and classification of sepsis, the development of disseminatedintravascular coagulopathy, andmortality within 30days between the 2 groups. The frequency of using chemo- therapy for Stage IV disease did not differ significantly in the 2 groups. The use of adjuvant chemotherapy for Stage II / III disease was significantly less frequent in elderly group than in non-elderly group(p=0.01). The progression-free and overall survival time for Stage II / III diseases did not significantly differ between the 2 groups. In conclusion, the prognosis of elderly patients with perforated colorectal cancer seems to be equivalent to that of the non-elderly patients. The indication of (adjuvant)chemotherapy may be controversial in such elderly patients. PMID- 29394616 TI - [Laparoscopic Local Resection for a Gastric GIST with Ulcer Locating Near to the Esophagogastric Junction - A Case Report]. AB - A 39-year-old woman visited our hospital because of epigastric pain. Gastrointestinal endoscopy revealed a gastric submucosal tumor, 30mm in size, with ulcer locating near to the esophagogastric junction, and it was diagnosed with GIST by the endoscopic ultrasonography-guided fine needle aspiration. Then, she underwent laparoscopic surgery for the removal of gastric GIST. After peeling around the upper stomach, the local resection of the stomach was performed with linear staplers in the minor axis direction under the vision of the endoscope and laparoscope. Histopathological examinations confirmed that the tumor was GIST with an intermediate risk, and all surgical margins were free of GIST cells. Local resection with the laparoscopy endoscopy cooperative surgery(LECS)technique is a very useful way of the removal of gastric GISTs locating near to the esophagogastric junction in terms of the remnant gastric functions. Meanwhile, because the standard LECS requires the opening of the gastric lumen, there remains concerns about the intraperitoneal tumor dissemination for the gastric GIST with ulcer. We herein reported a case of laparoscopic local resection for a gastric GIST with ulcer locating near to the esophagogastric junction without gastric opening. PMID- 29394618 TI - [A Case of Resected Metachronous Cholangiocarcinoma after Pancreaticoduodenectomy]. AB - The patient was a 79-year-old woman, who had undergone pancreaticoduodenectomy(PD)for lower bile duct carcinoma in our hospital(pT3N0H0P0M0, fStage III ). Four years 6 months after the initial operation, abdominal CT revealed left bile duct expansion and hilar bile duct thickening. Therefore, based on the diagnosis of perihilar cholangiocarcinoma originating from the left hilar duct, we performed left lobectomy with caudate lobectomy and biliary tract reconstruction. The surgical specimen showed a tumor in the left hilar bile duct. Histopathological diagnosis of the tumor was a moderately differentiated adenocarcinoma(pT2aN0H0P0M0, fStage II ). Surgical margins were histologically negative. Since the tumor was located away from the anastomosed site of the cholangiojejunostomy, we determined that the tumor was not a recurrence but a metachronous cholangiocarcinoma. The postoperative course was uneventful. The patient survived without recurrence 2 years after the second operation. The possibility of heterochronic biliary carcinomas should be considered during follow-up evaluation. We report this case of metachronous cholangiocarcinoma that occurred 4 years 6 months after PD, with a review of the literature. PMID- 29394619 TI - [Long-Term Survival after Resection for Repeated Abdominal Wall Recurrence of Gallbladder Cancer]. AB - We report the case of a 79-year-old woman with repeated abdominal wall recurrence of gallbladder cancer. The original diagnosis was gallbladder carcinoma. She underwent open liver bed dissection and lymph node dissection. Postoperative pathological examination indicated T2N1M0, Stage III disease. She received 6 courses of postoperative chemotherapy with gemcitabine. Two years and 2 months after the surgery, we detected a 13 mm mass under the abdominal wall scar on CT, and we resected this tumor. Pathological findings indicated adenocarcinoma, which was found to be metastasis of the gallbladder cancer. She was treated with S-1 for 8 courses postoperatively. However, 3 years 4 months after the first surgery, a tumor of 22mm was detected in the abdominal wall on the caudal side away from the previous tumor excision site. We resected the abdominal wall including the tumor. The pathological examination revealed adenocarcinoma, which was again metastasis from gallbladder cancer. The increase of CA19-9 was confirmed around 4 years and 7months after the first operation. An abdominal wall tumor of 45mm was detected in contact with the iliac bone near the last excision site and it proved to be a recurrence of gallbladder carcinoma. We performed abdominal wall tumor resection, again identifying adenocarcinoma, which was the third recurrence of gallbladder cancer. Despite continued abdominal wall recurrence, she is alive and well without metastasis for more than 5 years. PMID- 29394620 TI - [A Case of a Retroperitoneal Liposarcoma with Long-Term Survival after Four Surgical Resections]. AB - Retroperitoneal liposarcoma is a relatively rare tumor. The only established therapy is surgical resection and the tumor often recurs. This paper deals with a case of a retroperitoneal liposarcoma in which frequent surgical resections for recurrent tumors have provided relatively long-term survival for the patient. The patient was a 70-year-old woman who had undergone surgical resection for a right retroperitoneal tumor. The pathological diagnosis was dedifferentiated liposarcoma. Thereafter she experienced frequent recurrences which required 3 surgical resections. By means of positive margin for the last surgery, chemotherapy with eribulin was administered. There has been no recurrence 13 months after the last surgery. PMID- 29394621 TI - [A Case Report of Laparoscopy Assisted Distal Gastrectomy for Gastric Cancer with an Adachi Type VI Anomaly (Group 27)Institution]. AB - We report the case of a 79-year-old man, with gastric cancer detected on upper gastrointestinal endoscopic examination performed by a nearby medical clinic, and referred to our hospital, in April 201X. He was diagnosed with gastric cancer(ML, less, 0- II a+ II c, tub 1-2, cT1bN0M0, cStage I A). We performed laparoscopy assisted distal gastrectomy, D1+lymph node dissection, and Billroth I (B- I )reconstruction. Abdominal CT scan before surgery confirmed vascular anomaly of the celiac artery. We diagnosed Adachi type VI, preserved hepato-gastric artery trunk, and performed D1 plus dissection plus B- I reconstruction with small incision in the epigastrium. The operation time was 244 minutes and the blood loss was 5 mL. There were no postoperative complications, and the patient was discharged from hospital 7 days after the surgery. Pathological findings revealed pT4aN0M0, pStage II B, and the patient has been treated with TS-1(r)postoperative adjuvant chemotherapy. At present, there is no recurrence. As vascular anomalies of the celiac artery branch exhibit various forms, occasional blood vessel preventing surgery is required. Examining blood vessels through CT scan before the surgery made it possible to perform Laparoscopic gastrectomy safely. PMID- 29394622 TI - [A Case of Pneumocystis Pneumonia Developed during Chemotherapy for Sigmoid Colon Cancer]. AB - A 69-year-old man with multiple liver metastases from sigmoid colon cancer received mFOLFOX6 plus cetuximab(Cmab) chemotherapy. A partial response was observed; hence, we performed an extended left hepatectomy, 3 partial liver resections, and a sigmoidectomy. After 4 courses of CapeOX, a recurrent lesion occurred between S8 and S7 of the liver, and we changed the regimen to FOLFIRI plus bevacizumab(BV). Three months later, he had Grade 3 febrile neutropenia and CT scan findings showed ground glass opacity in the superior lobes of both lungs. We diagnosed pneumocystis pneumonia(PCP)and administered steroids and trimethoprim/sulfamethoxazole. The signs of PCP thus improved. PCP during chemotherapy for gastrointestinal cancer is rarely reported, but recently it has increased. PMID- 29394623 TI - [Two Cases of Achieving a Pathological Complete Response via Hepatic Arterial Infusion Chemotherapy for Liver-Limited and Unresectable Liver Metastases from Colorectal Cancer with RAS Mutations]. AB - We had 2 cases of liver-limited and unresectable liver metastases from colorectal cancer with RAS mutations. These patients received hepatic arterial infusion chemotherapy(HAI), finally achieving pCR. Case 1 was a 76-year-old female with rectosigmoid cancer and multiple liver metastases. We underwent anterior resection for primary lesion. After surgery, the patient had received first-line and second-line systemic chemotherapy for the multiple liver metastases. The patient achieved SD and had Grade 3 neutropenia. We then performed HAI as third line chemotherapy and we therefore underwent hepatectomy. The results of the pathological examination after hepatectomy pCR and is currently alive without cancer recurrence for 61 months. Case 2 was a 53-year-old male with sigmoid colon cancer and multiple liver metastases. We underwent sigmoidectomy with laparoscopic assistance. Three months after surgery, we underwent resection of the lateral segment of the liver under laparoscopy. This patient had cancer recurrence in the remnant liver at 6 months after surgery and had received first line systemic chemotherapy. The patient had Grade 3 neutropenia after 1 course of chemotherapy and showed no improvement. We then performed HAI as second-line chemotherapy, and we therefore underwent hepatectomy. The results of the pathological examination after hepatectomy were pCR and he is currently alive without cancer recurrence for 30 months. PMID- 29394624 TI - [A Case Report of Adenocarcinoma with Pagetoid Growth(Secondary Paget's Disease)of the Anal Canal]. AB - : Differentiating primary Paget's disease from secondary Paget's disease, which is also known as Pagetoid growth of other cancers, in the perianal region is difficult. Given that the treatment strategies of both disease are significantly different, diagnosis of such conditions should be performed with caution. We report a case of secondary Paget's disease. A 76-year-old man previously visited a hospital because of erythematous plaque around the anus. It was diagnosed as extramammary Paget's disease based on skin biopsy results; consequently, perianal skin resection was performed. Pathological examination of the resected specimen indicated Pagetoid growth of mucinous carcinoma, and it was positive for stump. Consequently, laparoscopic abdominoperineal resection was performed. Finally, the plaque was diagnosed as anal canal adenocarcinoma with Pagetoid growth, and all the previous results were deemed as initial diagnosis. CONCLUSION: Discriminating between primary and secondary Paget's disease, even with immunohistological techniques, is difficult. Novel methodology that might facilitatemoreaccuratediagnosis preoperatively for erythematous plaquearound theanus and morecurativethe rapeutic strategy are needed. PMID- 29394625 TI - [A Case of Metastasis to the Base of the Skull after Rectal Cancer Operation with Symptom Management via Radiotherapy]. AB - In 2009, A 67-year-old woman underwent high anterior resection for rectal cancer(RS, type 2, pT3, pN1, cM0, pStage III a). U FT/LV was administered for 6 months as adjuvant chemotherapy after the operation. Because peritoneum dissemination and pelvic lymph node metastasis developed 9 months after the operation, CapeOX plus Bmab therapy was started, and we monitored the cancer partial response for the next 6 years. Six years and 9 months after the operation, we detected metastasis to the sacrum; thus, radiotherapy was started. Seven years after the first operation, we detected pulmonary, liver, distant lymph node, and subcutaneous metastasis. Additionally, in the next month, she complained of double vision and dysarthria, and metastasis to the base of the skull was diagnosed via head MRI scanning. We started radiotherapy, and the symptoms gradually improved. Although we started IRIS plus Bmab therapy for pulmonary, liver, distant lymph node, and subcutaneous metastasis, it became a progressive disease(PD). She passed away 7 years and 6 months after the first operation. In this case, radiotherapy was useful for symptom management of metastasis to the base of the skull after surgery for rectal cancer, which is an extremely rare occurrence. PMID- 29394626 TI - [A Case of Retroperitoneal Liposarcoma That Invaded and Filled the Jejunal Lumen]. AB - A jejunal tumor was found with computed tomography in a 79-year-old man with a history of gastrectomy reconstructed with Billroth II method for gastric ulcers. The tumor with contrast effect extended into the afferent loop and invaded the retroperitoneum in the dorsal side. The tumor occupied the jejunal lumen in endoscopic examination. Malignant spindle cells were found in the biopsy specimen. An increase of MDM2 and CDK4 signals were observed in fluorescence in situ hybridization( FISH). Given the preoperative diagnosis of jejunal liposarcoma, we performed a resection of the tumor with partial jejunectomy and partial gastrectomy. In the pathological examination of the surgical specimen, the majority of the tumor was dedifferentiated sarcoma; relatively highly differentiated sarcoma cells were observed in the retroperitoneal lesion. Therefore, it was suspected that the retroperitoneal-derived liposarcoma had invaded the jejunal lumen. PMID- 29394627 TI - [A Case of Rectal Cancer Presenting with Schistosomiasis Japonica Eggs]. AB - A 87-year-old man had used to live in Shizuoka Prefecture. He got colonoscopy due to melena, and a type 1 tumor about 3 cm was detected in the rectum. He was diagnosed with rectal cancer. We performed a laparoscopic low anterior resection with lymphadenectomy. Histopathological findings shows tub1, pSM(7mm), med, INF a, ly1, v0, pPM0, pDM0, pN0(0/7), T1bN0M0, Stage I . Schistosoma japonica eggs were seen in submucosal of the rectum not around the tumor but also normal tissue. The eggs embolized microvessels. It has been 5 year since the operation, the patient has survived without recurrence. PMID- 29394628 TI - [A Case of Skull Base Metastasis of Breast Cancer with Dysphasia, Odynophagia and Dysarthria]. AB - While skull base metastases from breast cancer are not uncommon, there are relatively few reported cases in the literature. We report a case of skull base metastasis of breast cancer that resulted in dysphasia, odynophagia, and dysarthria. The case involved a woman in her 50 s who was diagnosed with cancer of the right breast(cT4N1M0, cStage III B)at another medical institution 9 years previously and who underwent a partial mastectomy and an axillary lymph node dissection following neoadjuvant chemotherapy. She began experiencing neck pain 6 months previously, followed by dysphasia, odynophagia, and dysarthria 1 month previously. The patient was referred to our hospital for detailed examination and treatment. PET-CT and cranial MRI was conducted and detected metastatic lesion from the skull base to the upper cervical vertebrae. An orthopedic surgeon performed a posterior decompression and fusion surgery on the occipital bone, cervical vertebra, and thoracic vertebra. A histological examination of bone tissue extracted during surgery revealed that the breast cancer had metastasized. We then performed irradiation of the cervical vertebra from the cranial base and initiated treatment with zoledronic acid and anastrozole. Symptoms such as dysphasia, odynophagia and dysarthria lessened, and the patient is currently being followedupas an outpatient. PMID- 29394629 TI - [A Case of Extrarenal Retroperitoneal Angiomyolipoma]. AB - We report a rare case of a extrarenal retroperitoneal angiomyolipoma. A 64-year old female visited our hospital because of an abdominal mass in her lower right abdomen. Enhanced CT scan revealed a 67*52mm tumor in lower right retroperitoneal space. MRI revealed adipose component in the tumor on T1 weighted images and T2 weighted images. Our preoperative diagnosis was retroperitoneal liposarcoma, and we performed retroperitoneal tumor resection. At operation the tumor was on the fossa iliaca, which was covered with capsule. It did not invade surrounding tissues. The resected tumor measured 90* 60*45 mm, and tiny hemorrhage was seen in the tumor. Histopathological findings showed that the tumor was composed of a mixture of adipose tissue, vessels, and smooth muscle. Immunohistochemistry demonstrated the tumor was stained with asmooth muscle actin(aSMA). We diagnosed the tumor as extrarenal retroperitoneal angiomyolipoma. PMID- 29394630 TI - [Neoadjuvant FOLFIRINOX for Unresectable Adenocarcinoma of the Pancreas - A Case Report]. AB - A 38-year-old male presented to our hospital with complaint of vomiting. A CT demonstrated a mass sized 42mm in the pancreatic head invading to the duodenum and a liver mass sized 15mm in the medial segment. Biopsy revealed adenocarcinoma. Due to liver metastasis, he was deemed surgically unresectable. He was started on FOLFIRINOX therapy after gastrojejunum bypass operation. After 15 courses of the therapy, restaging showed a decrease in pancreatic tumor size and a disappearance of a liver mass along with PET-CT revealing no FDG-avid uptake. A serum value of DUPAN-2 was also normalized. He was offered resection as a potentially curative treatment. He underwent curative pancreaticoduodenectomy(PD), which was difficult to perform because of adhesion and hard fibrous tissues. Operating time and blood loss were 600 minutes and 1,933 mL, respectively. Histologic examination revealed Grade 1a histological chemotherapy effect. His cancer recurred 11 months after PD. He received nab paclitaxel and gemcitabine regimen at out-patients clinic. PMID- 29394631 TI - [Treatment Outcomes and Prognosis of Patients with Recurrent Diseases after Esophagectomy for Esophageal Cancer]. AB - We retrospectively analyzed the treatment outcomes of 52 patients with recurrent diseases after radical esophagectomy for esophagealcancer. Median time of diagnosis of recurrent diseases was 180 days after surgery, and 90.4%of allpatients were diagnosed with recurrent diseases within 2 years. Twenty-seven patients were diagnosed with single area recurrence, and the remaining 25 were diagnosed with complex recurrence. Among patients with single area recurrence, surgical intervention was indicated in 9, and chemoradiotherapy(CRT)was indicated in 14. Meanwhile, among patients with complex recurrence, surgicaltreatment was indicated in only 2 patients. Median survivaltime was 293 days in allpatients, 611 days in single area recurrence, and 148 days in complex recurrence. Among patients with single area recurrence, those treated with surgical intervention or CRT had significantly better survival than those who underwent other treatment modalities. Although the prognosis of the patients with recurrent diseases after esophagectomy was poor, the patients with single area recurrence or treated with local therapy were expected to survive longer than patients with complex recurrence or those treated with other modalities. PMID- 29394633 TI - [A Case of Shock Due to nabPTX Administration Successfully Treated with Cytokine Adsorption Therapy]. AB - The patient was a 71-year-old woman with ER(+), PgR(-), HER2(3+), and Ki-674 2% breast cancer. After surgery for left breast cancer(Bt+Ax), epirubicin, cyclophosphamide therapy was administered as postoperative adjuvant chemotherapy, and nabPTX plus trastuzumab therapy was started sequentially. The patient was hospitalized due to severe neutrope- nia(neutrophils 0/mm3)from nabPTX, but her condition stabilized after admission. However, the patient suddenly went into shock after 3 days and was thus transferred to the ICU. Her general condition was rapidly improved through cytokine adsorption therapy in the ICU. After 5 days, she was extubated and wheeled back to a general ward. She was discharged without problems in the succeeding months. In this case, FN or cardiovascular diseases was ruled out, and engraftment syndrome was considered given that cytokine adsorption therapy significantly improved the patient's condition. Considering the risk for severe neutropenia in nabPTX administration, clinicians should exercise caution when administering the drug. PMID- 29394632 TI - [Combination Chemotherapy Including Intraperitoneal(IP)Administration of Paclitaxel(PTX)followed by PTX, CDDP and S-1Triplet Chemotherapy for CY1P0 Gastric Cancer]. AB - BACKGROUND AND OBJECTIVES: We evaluate the feasibility and efficacy of combination chemotherapy including single intraperitoneal( IP)administration of paclitaxel(PTX), followed by triplet chemotherapy(PTX, cisplatin[CDDP]and S-1: PCS)for CY1P0 gastric cancer. METHODS: First of all, we performed staging laparoscopy and confirmed CY1P0, and secondary, administrated PTX intraperitoneally. Thirdly, patients received PCS chemotherapy for 2 courses. After antitumor effect had been confirmed, we performed second look laparoscopy. In the case of CY0P0, we performed gastrectomy with D2 lymph nodes dissection. RESULTS: Total 4 patients were enrolled. Grade 3 leukopenia and neutropenia were observed in one patient while intraperitoneal and systemic-chemotherapy. One patients showed PR and 3 patients showed SD. All patients underwent second look laparoscopy. CY0P0 was observed in all patients and gastrectomy with D2 dissection was performed for all patients. Postoperative complications were observed in 2 patients. Two patients were still alive without recurrence, while the remaining 2 had died of liver metastasis and #16 LN metastasis. CONCLUSIONS: Combination chemotherapy including single IP PTX followed by PCS systemic chemotherapy for CY1P0 gastric cancer is feasible and efficient. PMID- 29394634 TI - [A Case of Solitary Metastatic Diaphragmatic Tumor from Resected Rectal Cancer]. AB - A 54-year-old woman underwent high anterior resection with D3 lymphadenectomy for rectal cancer at another hospital. She was diagnosed with well-differentiated adenocarcinoma of rectal cancer, pT3, N1, H0, P0, M0, fStage III a. She did not receive adjuvant chemotherapy. Eighteen months after surgery, abdominal CT at our hospital showed a 19mm-sized mass in S7 of the liver. EOB-MRI also showed a mass in the same location. The mass was a ring contrast-enhanced lesion on dynamic phase, had a low signal pattern on liver cell phase, and had high signal pattern on diffusion-weighted imaging. As such, it was diagnosed as liver metastasis of rectal cancer, and surgery was performed. During surgery, the tumor was found to be located between the liver and diaphragm. Thus, we performed partial resection of the liver diaphragm. Histopathologically, the tumor was the same well differentiated adenocarcinoma as the primary tumor. In addition, the tumor existed only in the diaphragm and was pumping out the liver. Therefore, we diagnosed the tumor as a diaphragm metastasis of rectal cancer. On literature review, only 8 reports of colorectal metastatic tumors involving the diaphragm were found. PMID- 29394635 TI - [Abdominoperineal Resection for Anal Metastasis of Rectal Cancer]. AB - Anal metastasis of colorectal cancer is rare, and no standardized effective therapeutic strategy exists. We report a case of abdominoperineal resection for anal metastasis of rectal cancer. A 65-year-old man underwent laparoscopic low anterior resection for rectal cancer in August 2013. Histopathological examination revealed a moderately differentiated adenocarcinoma( tub2, pSS, ly3, v2, pN1, H0, P0, M0, Stage III a, Cur A). In February 2015, he complained of anal discomfort, and tumor markers were elevated. Enhanced CT revealed a 15-mm high density solid tumor in the anal canal. The results of needle biopsy indicated a moderately differentiated adenocarcinoma. This tumor was suspected to be metastasis from rectal cancer, and we performed abdominoperineal resection. Histopathological examination revealed a moderately differentiated adenocarcinoma, which was the same histological type as the primary rectal cancer and was covered with normal anal epithelium. Collectively, the findings indicated anal metastasis from rectal cancer. The patient is alive without recurrence for 18 months after resection. Anal metastasis should be considered as a differential diagnosis in patients with anal discomfort who have a history of colon/rectal cancer. Abdominoperineal resection may be an effective treatment modality for this condition. PMID- 29394636 TI - [An Enhanced Multimodality Treatment Strategy in Pancreatic Ductal Carcinoma Requiring Heminephrectomy for Radical Resection - A Case Report]. AB - A 76-year-old male visited a clinic and the images incidentally revealed a tumor in the tail of pancreas. Pancreatic ductal adenocarcinoma was diagnosed by the following examination, indicating that the tumor invasion to spleen, left adrenal gland and left kidney(cT3N0M0, cStage II A), requiring heminephrectomy for radical resection. Enhanced preoperative treatments were performed while taking into account a possibility of any restrictions for the age and the standard adjuvant chemotherapies after heminephrectomy. Although the direct tumor invasion to other organs still remained, we found the significant reductions of tumor size and FDG uptake level with the decrease of serum tumor marker levels without an appearance of distant metastasis and another disease, so a radical surgery was performed. We performed distal pancreatectomy with left heminephrectomy and left adrenalectomy. The histopathological findings showed pathological stage was ypT3N1aM0, fStage II B with the direct invasion to the spleen and left adrenal gland with the effect of preoperative therapy as Grade II b in Evans classification. He has survived so far without recurrence for 11 months after surgery without operative complications. PMID- 29394637 TI - [A Case of Recurrent Rectal Cancer with Adrenal and Lung Metastasis with More than Ten-Year Survival after Surgery]. AB - A 60-year-old man underwent low anterior resection for rectal cancer. Histological findings indicated well-differentiated adenocarcinoma(T3[SS]N1M0, ly3, v2, Stage III a). Two years and 1 month later, right adrenalectomy was performed for solitary adrenal metastasis. Three months thereafter, left partial pulmonary resection was performed for a metastatic lung tumor. All resected specimens showed metastatic adenocarcinoma derived from the rectal cancer. The patient is alive and well without recurrence for more than 10years after lung resection. Given that adrenal metastasis is usually found as widespread metastasis, aggressive resection of well-controlled metastatic lesions including those in the adrenal glands is recommended. PMID- 29394638 TI - [Long-Term Survival Due to Combination Therapy in a Patient with Locally Advanced Body-Tail Pancreatic Cancer]. AB - A 49-year-old man was referred to a neighboring hospital with a chief complaint of abdominal pain.He was diagnosed with locally advanced body-tail pancreatic cancer that had invaded the celiac artery and SMA.He came to our department after undergoing radiotherapy, 2.5 Gy*22 Fr, and chemotherapy with gemcitabine(GEM)and S-1.The same chemotherapy was continued for 15 months until DIC occurred.He was subsequently treated with GEM only and then S-1 only in sequence for 6 years.We decided to stop the chemotherapy because the original lesion had been stable for a long time.After 1 month, a hard nodule appeared in the subcutaneous layer of the navel.Although resection was performed and he received chemotherapy, he died after surviving a total of 7 years and 10 months.This case is important when considering whether to discontinue chemotherapy with a stable long-term pancreatic cancer patient. PMID- 29394639 TI - [A Case of Advanced Rectal Cancer with Synchronous Pulmonary Metastasis Undergoing Laparoscopic Curative Resection after Chemotherapy]. AB - The patient was a 50-year-old man who complained of bloody stool and proctal discomfort. After hospitalization, he was diagnosed bearing advanced lower rectal cancer with lateral lymph nodes and bilateral pulmonary metastases(cT3N3M1a, Stage IV ). He was treated with irinotecan, Leucovorin and 5 fluorouracil(FOLFIRI)plus cetuximab because of RAS wild type. After 11 courses of the chemotherapy, all pulmonary metastases were disappeared(CR). Six months after the initialtreatment, laparoscopic abdominoperineal resection with lateral lymph node resection was performed with curative intent. After the operation, additional1 2 courses of the same chemotherapy were carried out. One year after operation, there is no sign of recurrence. Though used to be considered non curative, advanced rectal cancer with distant metastases could be potentially cured by multidisciplinary treatments. PMID- 29394640 TI - [A Two-Stage Right Hemicolectomy Case in Which the First Surgery Was Laparoscopic Ileocecal Resection Based on Preoperative Diagnosis of Acute Appendicitis]. AB - We report a case oftwo -stage right hemicolectomy in which the first surgery performed was laparoscopic ileocecal resection based on the preoperative diagnosis ofacute appendicitis. The second surgery was performed based on pathological diagnosis ofadvanced cecal cancer accompanied by appendicitis. A 49 year-old woman came to our hospital with a chief complaint of abdominal pain in the lower quadrant for 1 week. Blood test results indicated an inflammatory response, with white blood cells at 10,000/mL and C-reactive protein of1 7.5mg/dL. Abdominal computed tomography showed a swollen appendix and increased uptake in adipose tissue around the appendix. The patient was diagnosed with acute appendicitis, and emergency laparoscopic surgery was performed. Because the cecum wall was thickened and formed an inflammatory mass, ileocecal resection was performed. The pathological diagnosis was advanced cecal cancer accompanied by appendicitis, with metastasis to lymph node No. 201; thus, right hemicolectomy and D3 dissection were performed 14 days after the first surgery. No tumor was found in additional resected tissues. The final diagnosis was cecal cancer: adenocarcinoma tub1, SE, N1, M0, Stage III a. The patient received adjuvant chemotherapy with XELOX and remains relapse free. Acute appendicitis is induced by certain mechanisms that cause appendiceal obstruction. Unlike young patients, middle-aged and elderly patients rarely develop acute appendicitis because ofa tumor causing appendiceal obstruction, which often makes preoperative or perioperative diagnosis difficult. The presence of cancer, such as cecal cancer, should be considered when appendicitis is accompanied by severe inflammation in elderly patients. PMID- 29394641 TI - [A Case of Advanced Transverse Colon Cancer with Relapse behind the Rectum after Laparoscopic-Assisted Resection]. AB - A 60's male patient underwent laparoscopic left hemicolectomy with D3 lymph node dissection for transverse colon cancer. Adjuvant chemotherapy with tegafur-uracil and leucovorin was administered.Thirty -four months later, MRI scan revealed a mass with sacrum invasion.Radiation therapy(39 Gy/13 Fr)was performed followed by chemotherapy(modified oxaliplatin, leucovorin, and 5-fluorouracil plus bevacizumab).Two weeks after the completion of radiation therapy, staging laparoscopy and tissue biopsy was performed in the hard tumor, which was located at the caudal end of the incisional scar of the retroperitoneum, in front of the sacrum.The pathological diagnosis revealed metastasis from transverse colon cancer.Radiographic examination showed partial response to radiochemotherapy, and buttock pain decreased.CT review before pain developed showed a small tumor located mainly in the mesorectum slightly adjacent to the sacrum, suggesting the implantation of cancer cells to the stripped plane behind the mesorectum during the surgery. PMID- 29394642 TI - [A Case of Advanced Sigmoid Colon Cancer Successfully Resected via Laparoscopic Surgery after Preoperative Chemotherapy]. AB - We report a case of advanced sigmoid colon cancer resected via laparoscopic surgery after preoperative chemotherapy. A- 55-year-old man visited our hospital with diarrhea. CTrevealed a giant tumor in the sigmoid colon, and surrounding lymph node enlargement was also noted. The tumor appeared to be locally advanced; thus, preoperative chemotherapy was started. Due to the possibility of obstruction, we constructed an ileostomy laparoscopically. The tumor was found to be RAS wild, and 4 courses of mFOLFOX6 plus panitumumab were given. Follow-up CTshowed remarkable tumor reduction allowing laparoscopic resection; as such, laparoscopic sigmoidectomy was performed successfully. Chemotherapy with molecular-targeted drugs is a promising method to make laparoscopic surgery possible for advanced colorectal cancer. PMID- 29394643 TI - [A Case with Solitary Brain Metastatic Tumor from Colon Cancer]. AB - We report a rare long-surviving case of solitary brain metastasis from colon cancer. The patient was a 64-year-old female. She had undergone laparoscopic right hemicolectomy for ascending colon cancer in October 2012(pStage III b). She was discharged from the hospitalin a satisfactory state, but 26 days after the operation, she was transported to the emergency department for systemic tonic clonic convulsions. Magnetic resonance imaging revealed solitary metastatic tumor in the brain, but there were no metastatic lesions in other organs. Metastatic lesion was small and complete removal was considered to be difficult. Thus, we planned stereotactic radiosurgery for the metastases, and then regimen of mFOLFOX6 plus Bmab, tegafur-uracil plus Leucovorin were administered. As a means of evaluating recurrence of brain metastasis, methionine positron emission tomography(methionine PET)was also performed, and the patient has survived for 54 months since the surgery, to date, without recurrence. Cases with brain metastasis of colorectal cancer often have metastases involving other organs and are considered to have a poor prognosis. For solitary brain metastasis, long-term survival can be obtained with multidisciplinary treatments, and methionine PET is considered to be usefulfor recurrence evaluation after radiation treatment. PMID- 29394644 TI - [Clinical Efficacy of Paclitaxel plus Bevacizumab Combination Therapy for Bone Marrow Carcinomatosis Arising from Breast Cancer - A Case Report]. AB - We report a case of a 42-year-old woman with bone marrow carcinomatosis in the course of metastatic breast cancer who responded well to paclitaxel plus bevacizumab(PTX plus Bev)combination therapy. Four years after initial breast conserving surgery, she was admitted to our hospital with back pain and general malaise and was diagnosed as multiple bone metastases with bone marrow carcinomatosis originating from previous breast cancer(ER+/HER2-). While administering denosumab, we initiated systemic chemotherapy with PTX plus Bev. There has been no sign of progression at 1 year after beginning the treatment. Therefore, we conclude that PTX plus Bev combination therapy could be effective and sustainable treatment for bone marrow carcinomatosis arising from metastatic breast cancer. PMID- 29394645 TI - [A Case of Long-Term Survival of Cutaneous Metastasis from Primary Gastric Cancer]. AB - A 65-year-old female received distal gastrectomy for gastric cancer.The pathological diagnosis was well differentiated adenocarcinoma(tub1), type 2, pT3, ly: 1, v: 1, N0, H0, P0, M0, CY0, pStage II A.She had been observed without adjuvant chemotherapy.Five years after the resection, umbilical tumor and intraperitoneal nodules were detected by computed tomography. Needle biopsy cytology of umbilical tumor revealed metastasis from gastric cancer.Based on the diagnosis of umbilical metastasis and peritoneal dissemination, S-1(80mg/m / 2, day 1-21)and CDDP(60mg/m2, day 8)were administered for 7 courses.Because of diarrhea(Grade 3), chemotherapy was changed to paclitaxel(80mg/m2, day 1, 8, 15).To date, the patient has undergone 33 courses of paclitaxel.The response evaluation is complete response and no other metastases are detected.She has survived more than 3 years from recurrence of gastric cancer.We report a long surviving case of umbilical metastasis from post operative gastric cancer with chemotherapy. PMID- 29394646 TI - [Two Cases of Non-Occlusive Mesenteric Ischemia That Developed after Chemotherapy]. AB - Non-occlusive mesenteric ischemia(NOMI)causes intestinal necrosis due to irreversible ischemia of the intestinal tract despite the absence of organic obstruction in the mesenteric blood vessels. The disease has extremely poor prognosis. We encountered 2 cases of NOMI hypothesized to have developed after chemotherapy; thus, we report these cases considering the available literature. Case 1: A7 9-year-old man. The patient complained of abdominal pain during the first week after introducing docetaxel for local recurrence of prostate cancer. Abdominal computed tomography(CT)revealed mesenteric ischemia and intestinal emphysema. The patient was diagnosed with NOMI, and an emergency operation was performed. Upon laparotomy, the small intestine; ascending, transverse, and descending colon; recto sigmoid; and gall bladder appeared mottled necrotic. As such, all these were excised. He was admitted back to the hospital 3 weeks after surgery due to pneumonia. Case 2: A7 4-year-old man. Combination chemotherapy of docetaxel, cisplatin, and 5-FU was given for oropharyngeal cancer. After 1 week, fever and abdominal pain were noted. Abdominal contrast CT examination was performed, and mesenteric ischemia was confirmed as NOMI. Emergency surgery was performed on the same day. The entire ileum was discolored with mottling, and it was determined to be necrotic. Thus, it was excised. Postoperative course is good, and the patient was followed up after discharge from the hospital. Before NOMI onset in both cases, docetaxel was used to treat myelosuppression. Considering the patient conditions, the association between NOMI onset and docetaxel was suspected. In general, mesenteric ischemia after administration of anticancer drugs is rare, and only a few cases have been reported. PMID- 29394647 TI - [Severe Therapy-Related Pancytopenia Caused by UFT and LV in a Patient with Ascending Colon Cancer]. AB - We report a case of a 79-year-old man who developed severe therapy-related pancytopenia from tegafur uracil(UFT)and Leucovorin(LV)as adjuvant chemotherapy for ascending colon cancer. Laparoscopic right hemicolectomy resection was performed for the ascending colon cancer. Pathohistological analysis revealed that the ascending colon tumor was moderately differentiated tubular adenocarcinoma(T3, N1, M0, and Stage III a). Postoperative adjuvant chemotherapy with UFT and LV was administered. After 2 courses of chemotherapies, severe thrombocytopenia(Grade 4)and neutropenia(Grade 4)were noted. Platelet and granulocyte-colony stimulating factor(G-CSF)were transfused. Furthermore, red blood cell transfusions were given for anemia(Grade 3). Dihydropyrimidine dehydrogenase(DPD)deficiency was suspected as the cause of the pancytopenia, and the ratio of dihydrouracil(DHU)and uracil(URA)was measured. However, the result was negative for DPD deficiency. Bone marrowaspiration revealed that therapy related leukemia(TRL)and therapy-related myelodysplastic syndrome(T-MDS)were not the causes of the pancytopenia either. A total of 230 units of platelet transfusions and 20 units of red blood cell transfusions have been given for 32 weeks, and the patient currently requires routine blood transfusions. Fortunately, infection and bleeding never occurred. Subsequently, the patient should be monitored carefully. PMID- 29394648 TI - [Pneumatosis Cystoides Intestinalis after Hematopoietic Stem Cell Transplantation for Malignant Lymphoma - A Case Report]. AB - A 47-year-old man underwent hematopoietic stem cell transplantation for malignant lymphoma. He developed acute skin graft versus host disease(GVHD)and pneumomycosis which were treated with steroids. One hundred and fifteen days later, the patient had a diagnosis of free gas images in the abdominal cavity and streakly air collections in the bowel wall from the ascending colon to the sigmoid colon in the CT scan. He was asymptomatic and his physical examination was unrevealing. We diagnosed his condition as pneumatosis cystoides intestinalis(PCI). He was managed conservatively with the high concentration oxygen administration. The CT scan performed 3 days later revealed the marked improvement of intramural gas and disappearance of free gas. We considered image in the abdominal cavity that the occurrence of PCI was related to the damage of the bowel mucosa due to long term corticosteroid administration. In patients demonstrating PCI with free air in the abdominal cavity, it is important to evaluate not only the diagnostic date based on the physical, laboratory, and imaging findings, but also their medical history. Furthermore, it is important to make a correct diagnosis to avoid unnecessary surgery. PMID- 29394649 TI - [A Curatively Resected Case of Lateral Lymph Node Metastasis Five-Years after Initial Surgery for Rectal Cancer]. AB - A 74-year-old male had undergone laparoscopic abdominoperineal resection for lower rectal cancer in July 2009. The pathological diagnosis was T2, N0, M0, pStage I (TNM 7th). Because of pathological venous invasion, adjuvant chemotherapy with Tegafur-uracil(UFT)plus Leucovorin for a year was performed. A CT examination revealed slowly growing peripheral right internal iliaclymph node. PET-CT demonstrated a 20mm right lateral lymph node(LLN)metastasis without other distant metastases. On diagnosis of solitary LLN metastasis of rectal cancer, the patient underwent surgical lymph node resection in September 2014. The pathological diagnosis was lymph node metastasis from rectal cancer. Subsequently, the patient received mFOLFOX6 adjuvant chemotherapy for 6 months. The patient remains alive without any recurrence 31 months after the second surgical treatment. lt is important to consider that LLN metastasis of Stage I rectal cancer might still occur a long time after the curative operation. PMID- 29394650 TI - [A Case of Diaphragmatic Metastasis from Adenocarcinoma of the Rectum Treated via Surgical Resection]. AB - A 67-year-oldman underwent lower anterior resection for rectal cancer andresection of liver metastatic tumor 5 years later. Seven years and 2 months after the initial surgery, a soft tissue mass was detected in the left diaphragm. Further retrospective review of CT scan images showedthat the diaphragmatic tumor was present just before the hepatectomy. Partial resection of the left diaphragm was performed, and no relapse has occurred since then for 2 years. Most cases of diaphragmatic metastasis are considered to arise from dissemination, but we considered this case as more likely to be hematogenous. When surgery is chosen to treat metastatic tumors of colorectal cancer, checking for other metastasis via preoperative imaging andperforming curative resection is important. PMID- 29394651 TI - [Solitary Splenic Hilar Nodes Metastasis from Ovarian Cancer Managed by Splenectomy with Pancreas Tail]. AB - Solitary splenic metastasis from cancer is known as a rare disorder in cancer patients. In the present study, we report our experience regarding pathophysiology and treatment tactics of the splenic metastasis caused by ovarian cancer after perioperative chemotherapy. A 50s female presented to our clinic complaining of growing solitary splenic hilar node in CT. Hysterectomy, bilateral oophorectomy, omentectomy and adjuvant therapy was performed after neoadjuvant therapy with TC regimen. Five years and 3 months after surgery, she presented growing solitary splenic hilar nodule in CT. After staging laparoscopy, this lesion is judged to be able to be resected absolutely. Splenectomy and pancreas tail resection was performed. She has survived 39 months after 2nd surgery without recurrence. She recieved a diagnosis of solitary splenic metastasis from past ovarian cancer with whitch pattern of immunostaining was accord closely. Therapeutic tactics for solitary splenic metastasis is splenectomy because of the prognosis after complete resection is thought to be well. PMID- 29394652 TI - [Four Cases of Locally Advanced Colorectal Cancer Resected after Neoadjuvant Chemotherapy with mFOLFOX6 plus Bevacizumab]. AB - We describe 4 cases of locally advanced colorectal cancer resected successfully after neoadjuvant chemotherapy(NAC) conducted between April 2015 and August 2016. The NAC with mFOLFOX6 plus bevacizumab was performed after ileostomy for prevention of obstruction, because of tumor invasion into other organs. After chemotherapy, we could perform resection and avoid invasive surgery in either cases. PMID- 29394653 TI - [A Case of Bladder Metastasis Occurring after Rectosigmoid Cancer Operation]. AB - A 55-year-old man was admitted to our hospital for rectosigmoid(RS)cancer. We performed high anterior resection in the patient. Pathological findings showed mucinous adenocarcinoma, pT3(SS), pN1, sM0, sP0, pCy0, fStage III a. Two years and 3 months after the first operation, the patient visited our hospital due to lumbago, and we conducted a detailed abdominal examination. CT images showed the bladder tumor expanding into the vesical trigon and invading the prostate and mesorectum. Cystoscopy revealed the tumor, and tumor biopsy indicated poorly differentiated adenocarcinoma. These findings were consistent with metastasis of RS cancer; therefore, we performed total cystectomy, prostatectomy, and partial resection of the rectum. We performed a change of the ileum conduit to the urinary tract. Pathological findings showed many poorly differentiated adenocarcinomas in the lymph ducts ofthe bladder and prostate. Therefore, we diagnosed the condition as bladder cancer lymphogenous metastasis. The patient continues to do well without signs ofrecurrence 6 months later. PMID- 29394654 TI - [Case Report of Long-Term Survival for Stage IV Advanced Sigmoid Colon Cancer with Para-Aortic Nodes by R0 Resection and Chemotherapy]. AB - The patient was a man in his early 30s. He underwent sigmoidectomy with D3+ #216 for advanced sigmoid colon cancer with metastatic para-aortic lymph nodes. The pathological diagnosis was colon cancer(S), type 2, moderately differentiated, pT4a(SE), pN3(19/33), pM1a(LYM), pStage IV , KRAS wild-type, EGFR(+). He received FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively, he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab, SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then administered. The patient has survived for 4 years and 11 months from operation. PMID- 29394655 TI - [A Difficult Case of Invagination of the Protruding Colon Cancer]. AB - A 88-year-old female suffered of ileus due to advanced transverse colon cancer. Pneumonia was observed and nutrient condition was bad. Operation was found to be difficult because of the bad condition with complication on this present time. Self-expandable metallic stent(SEMS)was inserted to extend obstruction. But SEMS dropped out next day and SEMS, thicker than previous one, was reinserted. Main tumor was huge protruding tumor and the reason of ileus was invagination of the cancer. The fixation of SEMS was not so good, but the generalcondition was improved while a week after reinsertion of SEMS. Laparoscopic colon partial resection was performed safely. Bridge to surgery with SEMS for the case of invagination of protruding colon cancer was thought to be useful. PMID- 29394656 TI - [A Case of Appendiceal Mucinous Adenocarcinoma Detected with a Bladder Tumor]. AB - A 74-year-oldwoman hadconsultedthe department of urology in our hospital because of microscopic hematuria. Cystoscopy revealeda urinary bladder tumor, suspectedas an adenocarcinoma basedon biopsy. MRI showeda cystic tumor of the appendix with vesical fistula; therefore, she underwent an operation with a diagnosis of appendiceal cancer invading the urinary bladder. During the operation, we found that the appendix sunk into the urinary bladder with right adnexa. Therefore, we performed ileocecal resection, partial resection of the urinary bladder, and right adnexectomy. Macroscopically, the bladder was filled with a large number of mucus lumps. A papillary tumor, 4 cm in size, growing in the lumen of the bladder was detectedat the invasion site. Microscopically, proliferating carcinoma cells in a papillary form were observedin the lumen of the appendix with mucus production, invading the wall of the urinary bladder at the fundus of the appendix. Thus, the patient was diagnosed with mucinous adenocarcinoma of the appendix(V, type 1, 45*30 mm, muc, pT4b[SI, urinary bladder], int, INF c, ly0, v0, pN0, cM0, pStage II ). Primary appendiceal cancer invading the urinary bladder is very rare; herein, we report a rare case of appendiceal mucinous adenocarcinoma detected with a bladder tumor and present a literature review. PMID- 29394657 TI - [A Case of Angiosarcoma of the Breast Following Breast-Conserving Surgery with Radiotherapy for Breast Cancer]. AB - We report a case of angiosarcoma of the breast following breast-conserving surgerywith radiotherapyfor breast cancer. The patient was 82-year-old woman, developed induration and eruption in the bilateral breast more than 8 years after the initial operation for breast cancer. The induration was diagnosed as angiosarcoma based on skin-biopsyand vacuum-assisted biopsy. The patient received simple mastectomy, and has been become recurrent condition about one month after simple mastectomy. We operated partial excision for recurrence tumor. She is still alive after rearly 1 year of past operation. There are no established therapies for angiosarcoma of the breast following breast-conserving surgerywith radiotherapyfor breast cancer. Although radiotherapy-induced sarcoma is rare, earlydetection of the tumor in the irradiation area is important, as radiotherapyis often performed for the breast cancer patients. This interesting case of angiosarcoma of the breast after breast-conserving surgeryfor breast cancer is reported. PMID- 29394658 TI - [Surgical Dissection for an Abdominal Para-Aortic Lymph Node Recurrence after Curative Resection for Early Gastric Cancer - Report of a Case]. AB - A 72-year-old man underwent endoscopic submucosal dissection for early gastric cancer at antrum in July 2015. The histopathological examination revealed an adenocarcinoma invading the deep submucosal layer(SM2)with lymphatic invasion, consistent with the diagnosis of non-curative resection. Additional surgery was recommended, and he underwent laparoscopic distal gastrectomy in August 2015. The histopathological examination of resected specimen revealed there were no lymph node metastases, and postoperative diagnosis was Stage I A. However, 8 months after the surgery, abdominal enhanced computed tomography(CT)revealed an enlargement of para-aortic lymph node. Positron emission tomography-CT showed high accumulation at the enlarged lymph node. A para-aortic lymph node metastasis was suspected, and laparoscopic lymph node dissection was performed in July 2016. The histopathological examination revealed lymph node metastasis of gastric cancer. He was given systematic chemotherapy using S-1 plus cisplatin after the surgery, and has been followed-up without recurrences for 21 months after the first operation. Although recurrence of the para-aortic lymph nodes was assumed as part of a systemic metastasis, some population certainly benefit from multidisciplinary treatment including surgical approach. PMID- 29394659 TI - [A Resected Case of the Vaginal Metastasis from Rectal Cancer]. AB - The vaginal metastasis from colorectal cancer has rarely been reported. Here, we report a resected case of the vaginal metastasis from rectal cancer. A 51-year old woman underwent radical hysterectomy and bilateral oophorectomy for uterus cancer. Five years after the operation, vaginal tumor was observed during an internal examination. Biopsy was positive for adenocarcinoma. Enhanced computed tomography demonstrated the wall thickening of the lower rectum and the mass of 20 mm at the inferior lobe of the left lung. Colonoscopy revealed the wall thickening of the lower rectum, and biopsy indicated a diagnosis of rectal cancer. We performed abdominoperineal resection and partial resection of the vagina. Pathological examination confirmed the vaginal metastasis from the rectal cancer. PMID- 29394660 TI - [Neoadjuvant Chemoradiotherapy for Locally Advanced Carcinoma Associated with Anal Fistula]. AB - The patient was a 59-year-old man. He was admitted to our hospital because of increasing anal pain with induration of the perianal region. There were large secondary orifices with mucous discharge on the left side of the perineal resion and buttock. We diagnosed adenocarcinoma on analysis of a biopsy specimen from induration of the perianal region. Pelvic CT and MRI showed that the tumor spreaded within the pelvis, with invasion of the prostate and sacrum. We performed neoadjuvant chemoradiotherapy preoperatively. After chemoradiotherapy, the tumor reduced in size greatly. We performed abdominoperineal resection and massive resection of skin of the perianal region. The defect of the pelvic floor and perianal skin was repaired using skin flap. The surgical margin was tumor free. Neoadjuvant chemoradiotherapy was considered effective for locally advanced carcinoma associated with anal fistula. PMID- 29394661 TI - [Two Cases of Single-Incision Laparoscopic Ileocecal Resection for Patients over 90 with Colon Cancer]. AB - Single-incision laparoscopic surgery(SILS)is superior to multiport laparoscopic surgery in terms ofcosmetics, but in other terms it is still disputable and needs further investigation. The treatment of SILS for colon cancer has increased, however, the feasibility of single-incision laparoscopic colectomy(SILC)for patients over 90 with colon cancer has not been well examined. We report 2 cases ofsingle -incision laparoscopic ileocecal resection without complications. Case 1: A 104-year-old woman who had been diagnosed with pStage III a obstructive ascending colon cancer. There were no perioperative complications. She was discharged 15 days after the operation. During the 26 months of follow-up, there was no evidence oflocal recurrence or distant metastasis. Case 2: A 90-year-old woman who had been diagnosed with pStage I cecal cancer. There were no perioperative complications. She was discharged 10 days after the operation. Single-incision laparoscopic ileocecal resection for the aged patients is feasible when performed on patients selected by surgeons with extensive SILC experience. PMID- 29394662 TI - [Esophagogastric Junction Cancer Resection with Bilateral Adrenal Metastasis - A Case Report]. AB - The patient was a 64-year-old man with esophagogastric junction cancer. We performed right thoracotomy-laparotomy for lower esophageal and cardiac gastric resection, D2 lymphadenectomy, and reconstruction of a gastric tube in October 2011. Histopathology confirmed T4aN1M1(LYM), Stage IV cancer(Japanese Classification of Gastric Carcinoma, 14th edition) with R0 resection. Because of preexisting alcoholic cirrhosis, postoperative chemotherapy was not an option. In March 2014, we performed left adrenalectomy for left adrenal metastasis, and in December 2014, we performed right adrenalectomy for metastasis to the right adrenal gland. The patient was prescribed 20mg/day of hydrocortisone postoperatively. Survival from the right adrenalectomy was 2 years and 2 months, and survival from the first operation was 5 years and 4 months, without recurrence. This case of esophagogastric junction cancer resection with bilateral adrenal metastasis is rare, with only one previously reported case in Japan. PMID- 29394663 TI - [A Case of Advanced Gastric Cancer with Liver Metastasis Treated by Curative Surgery after Chemotherapy Using S-1 plus Oxaliplatin]. AB - A 76-year-old man was referred to our hospital with gastric cancer.Esophagogastroduodenoscopy (EGD)revealed an irregular, nodulated lesion with ulcers in the lower part of the stomach, for which biopsy specimens indicated poorly differentiated adenocarcinoma.Abdominal computed tomography(CT)showed a well-defined mass lesion measuring 5.3 cm in the posterior segment of the liver.Under the clinical diagnosis of advanced gastric cancer with liver metastasis, the patient received chemotherapy using S-1 and oxaliplatin.After 8 courses of chemotherapy, abdominal CT and EGD revealed that the size of liver metastasis was reduced to 2.3 cm. He underwent distal gastrectomy with D2 lymphadenectomy and resection of the liver metastases because there was no evidence of further metastatic lesions in any other organs after 10 courses of chemotherapy.The gross appearance of the surgically resected specimen showed a shrunk gastric tumor measuring 3.5*3.0 cm and a well-circumscribed, solid liver mass.Pathological examination confirmed the diagnosis of solid-type, poorly differentiated adenocarcinoma in the stomach that had invaded the submucosal layer with no lymph node metastasis, and necrotic change of the liver mass.The postoperative course was uneventful, and the patient has been well, receiving maintenance chemotherapy using S-1, without evidence of recurrence for 9 months following the operation.Conversion surgery following chemotherapy might be a proposed treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to establish this treatment strategy. PMID- 29394664 TI - [The Characteristics and Treatment Outcomes for Desmoid Tumors Associated with Familial Adenomatous Polyposis]. AB - INTRODUCTION: The characteristics of desmoid tumors(DTs)associated with familial adenomatous polyposis(FAP)and relationships between the development of DTs and the sites of APC germline mutation have not closely been examined Japan. PATIENTS AND METHODS: This retrospective study was performed to address these issues by examining patients with FAP who underwent proctocolectomy between 1981 and 2015. RESULTS: The cumulative 2-year incidence of DT development was 50%. The DTs developed in the abdominal wall only in 2, in the abdominal wall plus intra abdominally in 4, and intra-abdominally in 2. Clinical stages according to the Church's classification included Stage I in 3, Stage II in 2, Stage III in 1, and Stage IV in 2. Among 31 patients with a confirmed pathogenic germline APC mutation, patients with mutation in 3' site of codon 1400 (n=7)tended to develop DTs more frequently than those with mutation in 5' site of codon 1400(n=24)(p=0.08). The cumulative 5-year survival rate in patients with DT development was 73.3%. Including 2 patients undergoing initial colectomy at other institutions, the therapeutic efficacy in 4 patients with severe intraabdominal DTs(Stage III /Stage IV )who were given chemotherapy comprising doxorubicin plus dacarbazine(DOX plus DTIC)revealed partial response in 3 and complete response in 1. Febrile neutropenia was recorded in 2 of these patients. CONCLUSION: The frequency of DTs development and genotype-phenotype relationship of FAP patients seems to concur with those reported from Western countries. Since the DOX plus DTIC therapy for severe DTs is valid but toxicity is high, the development of less toxic regimens are warranted. PMID- 29394665 TI - [Subtotal Esophagectomy for Mediastinal Lymph Node Oligo-Recurrence of ALK Positive Lung Adenocarcinoma - A Case Report]. AB - The patient was a 54-year-old woman with anaplastic lymphoma kinase-positive stage III B lung cancer. She received 4 courses of carboplatin(CBDCA)plus paclitaxel(PTX)plus bevacizumab(Bev)chemotherapy and crizotinib. Chemotherapy reduced the size of the primary site and mediastinal lymphadenopathy; however, the right supraclavicular and subcarinal lymph nodes were enlarged again during crizotinib treatment. Because it was an oligo-recurrence, we performed radiotherapy for these lymph nodes and changed systemic chemotherapy to alectinib. After 16 months, the patient exhibited esophageal stenosis due to subcarinal lymphadenopathy. We performed a subtotal esophagectomy, which improved the quality of life, and she was continued on an oral treatment of alectinib. Therefore, we suggest that an invasive surgical treatment is useful for oligo recurrence cases. PMID- 29394666 TI - [The Case of HER2 Positive Advanced Gastric Cancer with Para-Aorta Lymph Node Recurrence Responding to Capecitabine plus CDDP plus Trastuzumab Chemotherapy]. AB - We report the case of a 69-year-old man diagnosed with gastric cancer.The patient underwent distal gastrectomy(D2) and Billroth I reconstruction in March, 2010. Postoperative histopathological examination indicated M, Ant, Type 5, 100*50 mm, pap>por2>sig, T4aN3M0, pStage III C.We performed S-1 therapy as adjuvant chemotherapy.Abdominal CT showed para-aortic lymph node recurrence in February, 2015. Since HER2 protein was overexpressed in primary tumor immunostaining, he was treated with capecitabine plus CDDP plus trastuzumab therapy.After the chemotherapy, CEA levels decreased to the normal range and the enlarged lymph node was remarkably decreased in size in May, 2015.T he patient is alive 24 months after the chemotherapy with no evidence of recurrence. PMID- 29394667 TI - [The Clinical Outcome of Conversion Surgery for Unresectable Gastric Cancers in Our Institution]. AB - BACKGROUND: In recent years, the development of chemotherapy has been remarkable. Some cases of conversion surgery for unresectable gastric cancer have been reported. METHODS: The clinical outcome of 11 patients with far advanced gastric cancer who underwent conversion surgery in our hospital from January 2013 to May 2017 were analyzed retrospectively. RESULTS: The median survival time was 592 days(355-1,460). Four patients died of recurrent gastric cancer. Patients with undifferentiated carcinoma dominant had significantly poor survival rather than with differentiated carcinoma dominant(p= 0.039). Meanwhile, the pathological responders for chemotherapy did not have significantly better survival rather than nonresponders. CONCLUSIONS: Although the short term outcome of conversion surgery was acceptable, recurrent rate was still high. To improve the prognosis, clarifying the optimal timing of operation and more effective adjuvant chemotherapy are mandatory. PMID- 29394668 TI - [Prognostic Impact of Tumor Location of Colorectal Cancer in Patients with Resected Liver Metastasis]. AB - Recently, metastatic colorectal cancer(CRC)patients with a left-side primary tumor have been reported to have a significantly longer survival period than those with a right-side primary tumor. However, the impact of the location of the primary lesion on the survival outcomes of patients with resectable liver metastases of CRC has not yet been fully investigated. The subjects of this retrospective study were 113 consecutive patients who underwent a hepatic metastatectomy for CRC between 2001 and 2016 at our institution. The background data and survival times were compared between 32 patients whose primary lesions were located in the cecum or the ascending colon(right-side group)and 81 patients whose primary lesions were located in the descending colon, sigmoid colon, or rectum(left-side group). No significant differences in various clinicopathological variables were observed between the 2 groups. The 5-year overall and relapse-free survival rates after hepatectomy were 62.1% for the right-side group vs 49.2% for the left-side group(p=0.55)and 37.1% for the right side group vs 33.4%for the left-sided group(p=0.76), respectively. In conclusion, colorectal liver metastasis should be resected regardless of the primary tumor location. PMID- 29394669 TI - [A Case of Local Recurrence with Negative FDG/PET Findings after a Total Proctocolectomy for Ulcerative Colitis Associated with Colon Cancer with Retroperitoneal Penetration]. AB - We report the case of a 55-year-old man who successfully underwent resection of a recurrence of ulcerative colitis(UC)- associated colon cancer located in the pancreatic body and left kidney. The patient had undergone an emergency laparotomy (total proctocolectomy with stapled ileal-pouch anal anastomosis)for the treatment of a descending colon cancer with retroperitoneal penetration associated with UC at the age of 50 years. At that time, histological examinations revealed a mucinous carcinoma that was classified as Stage II colon cancer. Three years after the patient's initial operation, a CT scan revealed a small mass located between the pancreatic tail and the left kidney. However, the accumulation of FDG was not observed during a positron emission tomography(PET)examination, resulting in close observation. As the size of the tumor and the levels of serum carcinoembryonic antigen and carbohydrate antigen 19-9 gradually increased, recurrence was highly suspected. A distal pancreatectomy and left nephrectomy were performed. Pathological examination showed findings concurrent with a local recurrence of colon cancer. Special histological types, such as mucinous carcinoma, often occur in some colitic cancers. For the postoperative surveillance of patients with colitic cancer, it should be noted that the sensitivity of FDG/PET is lower for mucinous carcinoma of the colon than it is for more common colon cancers. PMID- 29394670 TI - [Fluorescence-Imaging of Nerves - A Novel Trial of Intraoperative Nerve Preservation]. AB - Nerve-preservation technique during surgery is important. Intraoperative nerve injury often causes permanent palsy or numbness and/or neurogenic functional disorders. To evade such intraoperative nerve injuries, we proposed a novel manner to specifically visualize peripheral nerve fibers. Low-toxic agents clinically available, amphotericin B(AmB)or fluorescein isothiocyanate(FITC)were used as neuro-indicators. In in vitro, we used Schwann cells as nerve models to basically confirm these agents effectively functioned as neural markers. In in vivo, we examined whether this novel method was clinically applicable. The Schwann cells reacted with AmB or FITC emitted blue or yellow-green fluorescence in a dark environment. The rat nerve models also fluorescently glimmered in blue tone when each agent was given. These data suggested that we could clinically discriminate nerve fibers from the surrounding tissues. Our fluorescent-imaging methods warrant further studies for clinical applications. PMID- 29394671 TI - [A Case of Duodenal Invasive Advanced Gastric Cancer in Which the Primary Tumor Achieved pCR, but Viable Cancer Cells Remained in Lymph Node No.13 after Neoadjuvant Chemotherapy]. AB - A woman approximately 70-years-old with duodenal invasive advanced gastric cancer was referred to our hospital. Meta- stasis to lymph node(LN)No.13 was suspected based on FDG/PET-CT. For better curability, we selected neoadjuvant chemotherapy( NAC)with S-1 plus oxaliplatin(SOX therapy). After 3 courses of SOX, distal gastrectomy with D2(+No.13) lymphadenectomy was performed. Upon pathological evaluation, no viable cancer cells were found in the primary tumor, but viable cancer cells were identified in LN No.6 and 13. LN No.13 was defined as M1 according to the current Japanese classification of gastric carcinoma. On the other hand, the 2014 Japanese gastric cancer treatment guidelines(ver. 4)mentioned that D2(+No.13)lymphadenectomy may be an option in potentially curative gastrectomy for tumors invading the duodenum. This case suggests that No.13 lymphadenectomy is necessary as a curative operation for duodenal invasive advanced gastric cancer, even if the primary tumor has achieved pCR after NAC. PMID- 29394672 TI - [Can Lateral Pelvic Node Dissection Omitted in Rectal Cancer with Suspected Lateral Node Metastasis after Chemoradiotherapy ?] AB - To elucidate ideal strategy of treatment for advanced lower rectal cancer, we investigated 11 patients with clinically suspected lateral pelvic node(LPN)metastasis among 36 patients who received neoadjuvant chemoradiation therapy(NCRT). Nodal metastasis was diagnosed as positive when the major axis of a lymph node was over 7mm in computed tomography(CT). Both tumor and nodal downstaging were observed in CT after NCRT; pathological complete response and ypN0 was obtained in 2(18.2%)and 6(54.5%)cases, respectively, and positive LPN was observed only in 2 cases. All of 4 cases who were diagnosed as ycN0 in CT after chemoradiation were confirmed as ypN0. Extended examination with 36 patients who underwent NCRT showed that 85% of 21 ycN0-cases were confirmed to be ypN0. As a conclusion, NCRT for lower rectal cancer with suspected LPN metastasis was highly effective, and omitting lateral node dissection when all nodes turned to be less than 7mm on CT, can be a hopeful option. PMID- 29394673 TI - [Case Report of an Acute Focal Bacterial Nephritis Associated with Adjuvant Chemotherapy in Esophageal Cancer Patient]. AB - We report a case of acute focal bacterial nephritis(AFBN)as a complication of chemotherapy in esophageal cancer patient. A 54-year-old woman underwent thoracoscopic esophagectomy for thoracic esophageal cancer. The final pathological diagnosis was a squamous cell carcinoma, pT1b, N2(No. 110), M0, pStage II . She received adjuvant chemotherapy with docetaxel, CDDP and 5 FU(mDCF)in our hospital from February, 2016. There was no complication in first course. She visited our hospital with complaints of a fever and right flank pain on the 22 nd day after second course of chemotherapy. There was a severe inflammation reaction in the laboratory test. An enhanced CT revealed swelling and partial low density area in the right kidney. Therefore, we diagnosed AFBN, and administrated antibiotic levofloxacin for 16 days. Her symptom improved immediately, and renal function was normal when followed up 10 months later. PMID- 29394674 TI - [A Case of Stage IV Breast Cancer with Extensive Metastasis Successfully Treated with S-1 plus Anastrozole Therapy]. AB - We report the case of a patient in which S-1 plus anastrozole was administered as first-line chemotherapy for Stage IV breast cancer with skin invasion, multiple lymph node metastasis, and lymphangitis carcinomatosis. A 77-year-old woman had a mass destroyed immediately outside the axilla with dry coughs. An 11mm unpalpable mass in the right breast and an axillary mass were confirmed to be scirrhous carcinoma(Luminal type B), respectively, by core needle biopsy. In one course, S- 1(100mg/day)therapy involves taking 2 courses of 14 days of administration and 7 days off the drug. Anastrozole(1mg/ day)was administered daily. After completion of one course, marked shrinkage of the axillary tumor and supraclavicular lymph node, and lightness of coughing was observed. The metastatic lymph nodes and pulmonary metastatic lesions reduced in size by over 30%, as revealed using CT. The adverse event was only grade 1 pigmentation and lacrimation. Ten months later, the self-destructed skin was completely scarred, and metastatic lesions had maintained their reduction in size. According to the results of the SELECT BC study, S-1 as primary chemotherapy for breast cancer is an evidence-based drug that can reduce the decrease in QOL, such as hair loss, and it can be positively selected. PMID- 29394675 TI - [A Case of Locally Advanced Rectal Cancer with Abscess and Rectovesical Fistula Curatively Resected Following Preoperative Chemotherapy]. AB - A 63-year-old man with bloody stools, anal incompetence, and feeling of fatigue was diagnosed as having a RAS mutanttype rectal cancer with abscess and rectovesical fistula. Computed tomography revealed that the tumor had invaded the seminal vesicle, prostate, and bladder and formed an abscess. In addition, his general condition was poor. Thus, we evaluated the lesion as unresectable. His nutritional status improved, and the infection was controlled after colostomy. Then, we performed chemotherapy with 5-fluorouracil, Leucovorin, and oxaliplatin(FOLFOX)plus bevacizumab. However, after a single course of chemotherapy, the systemic inflammatory reaction was prolonged. Despite treatment of the infection with antibiotics, it was not fully controlled, making it difficult to continue chemotherapy. A new lesion did not appear, but the primary tumor increased in size. Thus, we performed pelvic exenteration. Pathological examination revealed that the tumor was a well-differentiated adenocarcinoma invading the sigmoid colon and bladder. We resected it curatively and administered adjuvant chemotherapy postoperatively. No recurrence was observed during 10 months' follow-up. PMID- 29394676 TI - [Two Cases of Hepatocellular Carcinoma Skin Metastasis]. AB - Case 1: A7 2-year-old man, during diabetes medical treatment, was introduced at our hospital for liver cancer treatment. He had a subcutaneous mass 4 cm in size in the right precordial region, and subsequently underwent an operation. Histopathological findings indicated subcutaneous metastasis of hepatocellular carcinoma. Case 2: A6 0-year-old man presented with a subcutaneous mass noted in the right shoulder during hepatocellular carcinoma treatment. It was diagnosed as metastasis of the hepatocellular carcinoma to the dermis. Metastasis to the skin of internal organ-related tumors is relatively rare and is reported with approximately a 1.4-6.7%frequency of all dissection cases. Hepatocellular carcinoma is infrequent and it is reported that hypodermal and skin metastasis is 0.3-0.7% in autopsy cases. In addition, metastasis of hepatocellular carcinoma to the skin is a relatively terminal symptom. PMID- 29394677 TI - [Conversion Therapy Using Etoposide and Cisplatin Chemotherapy for Liver Metastases from Advanced Gastric Mixed Adenoneuroendocrine Carcinoma - A Case Report]. AB - Gastric mixed adenoneuroendocrine carcinoma(MANEC)with multiple liver metastases is a rare condition with most data being derived from case reports. We present a case with liver metastases from gastric MANEC that respond remarkably to chemotherapy. Sixty-one-year-old male with severe anemia referred to surgical consultation due to advanced gastric cancer with multiple liver metastases. To relieve uncontrollable tumor bleeding, simple distal gastrectomy for symptom palliation was performed. Based on the tentative diagnosis with gastric poorly differentiated adenocarcinoma, a course of TS-1 and oxaliplatin therapy was administrated. Thereafter final diagnosis with neuroendocrine carcinoma with tubular adenocarcinoma was made, and the chemotherapy was switched to etoposide and cisplatin. Follow up abdominal CT scan after the third course of the therapy showed remarkable tumor shrinkages(PR). In anticipation of the chemotherapy effects in the adjuvant setting, we performed liver metastasectomy for curative intent. Two of 6 resected liver specimens showed no viable cancer cells at all (pCR). However, immediately after the surgery, multiple liver metastases developed, and the recurrent masses had kept growing up rapidly. The third line carboplatin and etoposide chemotherapy was given once but was withdrawn because of bone marrow suppression. At the present, the patient is alive with recurrent diseases for 18 months after initial diagnosis. PMID- 29394678 TI - [Early Enteral Nutrition for Gastric Cancer Patients with Extended Surgery]. AB - The effectiveness of multi-modal therapy for advanced gastric cancer were reported recently.These therapies are highly invasive, therefore the peri operative management for regulation of general condition is important.We introduced early enteral nutrition for these cases aiming for improvement of post operative course.We examined 18 cases with early enteral nutrition in 76 gastrectomised patient after pre-operative chemotherapy.In 15 of 18 patients, maximum dose of enteral nutrition was 960 kcal/day or more.Side effects of enteral nutrition, such as diarrhea or vomiting, abdominal pain, were observed in 11 cases.These symptoms ware controllable except 1 case with severe diarrhea.The weight loss during hospitalization was suppressed with early enteral nutrition.Early enteral nutrition was safe and essential peri-operative management for advanced gastric cancer patients received highly invasive multi modal therapy. PMID- 29394679 TI - [Bowel Perforation in a Patient with Adult T-Cell Leukemia/Lymphoma]. AB - Adult T-cell leukemia/lymphoma(ATLL)can infiltrate throughout various organs and frequently involves the gastrointestinal tract. However, bowel perforation in ATLL patients is rare. Herein, we present a case of ATLL with bowel perforation. A 75-year-old man presented with bowel distension. Computed tomography showed a large mass of the cecum. Edema and stenosis of the ascending colon was seen on colonoscopy, and tumor on the anal side of the stenosis was also found. After admission, the patient complained of abdominal pain with a peritoneal irritation sign. Free air was seen around a large mass of the cecum on computed tomography and an emergency operation was performed under the diagnosis of bowel perforation. Microscopic examination revealed bowel infiltration of ATLL. Gastrointestinal perforation can be caused by ATLL itself and is associated with a poor prognosis. The standard treatment for ATLL is chemotherapy but emergency surgery is necessary in case of perforation. It is important to observe the patient with ATLL carefully. PMID- 29394680 TI - [A Case of Gastric Cancer with Splenic Artery Aneurysm, Intraoperative ICG Fluorography Is Useful in Evaluating the Blood Flow of Stomach and Spleen]. AB - An 81-year-oldwoman with advancedgastric cancer was referredto our hospital. Preoperative contrast-enhancedCT revealeda roundcalcification of the splenic hilum with 15mm in diameter as a splenic artery aneurysm. She underwent transcatheter arterial embolization(TAE)for the splenic artery aneurysm. Celiac artery angiography showedcollateral arterial network of the spleen from left gastric artery. Surgery for the gastric cancer was performed1 4 days after TAE. We cut the right gastric andbilateral epigastric arteries. After the left gastric artery clamping, we performedintraoperative indocyanine green(ICG)fluorography. ICG fluorography confirmedthat the bloodflow of the upper thirdof the stomach andspleen were maintained. We safely performed distal gastrectomy, and the postoperative course was uneventful. PMID- 29394681 TI - [Assessment of Long-Term Sexual Function after Radical Resection for Lower Rectal Cancer]. AB - : The aim of this study was to evaluate the long-term sexual function and risk factors of dysfunction after the autonomic nerve preserving operation for lower rectal cancer. METHODS: We evaluated postoperative sexual function assessed by IIEF5 in 91 patients who responded to the questionnaire by mail. RESULTS: After a median follow-up of 5.5 years, univariate analysis identified 4 risk factors associated with poor sexual function: the elder, over 3 years after surgery, pathological stage III , and lateral lymph node dissection(both side). Poor sexual function assessed by multivariate analysis was significantly associated with the elder(over 60 years). CONCLUSION: From the viewpoint of sexual dysfunction, the autonomic nerve preserving operation( AN4)should be considered for elderly people. PMID- 29394682 TI - [Strut Adjusted Volume Implant(SAVI) - An Interim Report of Patient Satisfaction and Outcomes]. AB - BACKGROUND: Strut adjusted volume implant(SAVI)was approved by the Food and Drug Administration(FDA)for the treatment of breast cancer in 2006. MATERIAL AND METHODS: The phase II study was conducted to investigate the activity and safety of SAVI in breast cancer patients. Criteria for SAVI treatments were N0, T<2 cm, and age>=40. After patients underwent breast-conserving surgery, they received SAVI twice a day*5 days(34 Gy). The primary endpoint are feasibility and safety. Second endpoint are local recurrence rate and cosmesis. RESULTS: Three patients were enrolled and the median duration of administration is 18.7 days(17-20). Further, the most common treatment-related adverse events were thickening and redness of skin(grade 1/2), while there was no deformity of breast in each case. CONCLUSION: The current study demonstrated that SAVI is well tolerated treatment in breast cancer patients and may be convenient for use in patient treatment. PMID- 29394683 TI - [Safety of Laparoscopic Surgery after Preoperative Short Course Radiotherapy for Lower Rectal Cancer]. AB - BACKGROUNDS: In the setting of routine use of preoperative chemoradiotherapy(CRT)for cStage II / III rectal cancer, shortcourse radiotherapy(short-RT)is selectively used for reducing local recurrence.The purpose of this study is to clarify the safety of laparoscopic surgery after preoperative short-RT for lower rectal cancer. METHODS: Twenty-eight patients who un- derwent short-RT followed by laparoscopic total mesorectal excision for cStage II / III lower rectal cancer were retrospectively analyzed. RESULTS: The reasons for selecting short-RT included comorbidity(n=10), refusal of CRT(n=8), multiple cancers (n=6)and others(n=4).All patients completed planned dose of radiation without severe acute toxicity.Median interval from completion of short RT to surgery was 17 days(range 7-58).All patients underwent laparoscopic surgery without conversion to open surgery.Median operation time, blood loss and the number of dissected lymph nodes were 379 minutes (range 175-890), 90mL(range 0 1,185)and 27(range 12-71), respectively.Grade 3-4 complications occurred in 3 cases (10.7%).There were 2 cases with pathological complete response. CONCLUSIONS: Laparoscopic surgery for lower rectal cancer after short-RT is safe and feasible. PMID- 29394684 TI - [Laparoscopic Pancreatectomy for Pancreatic Neuroendocrine Tumor - A Single Institution Experience]. AB - BACKGROUND: Pancreatic neuroendocrine tumor(P-NET)is relatively rare and often has less aggressive biological behavior. P-NET was re-designated by the WHO in 2010 and 2017. Laparoscopic surgery is minimally invasive but has technical difficulties such as limitation of movement and laparoscopic view. The purpose of this study is to evaluate the efficacy of laparoscopic pancreatectomy(LPT)for P NET. METHODS: Between January 2012 and June 2017, 6 patients underwent LPT for P NET at Kansai Rosai Hospital. Five patients who received open pancreatectomy(OPT)for P-NET and 41 patients who received laparoscopic distal pancreatectomy(LDP)for cystic tumor(CyT)or invasive ductal carcinoma(IDC)were included for comparison. RESULTS: All patients who underwent LPT for P-NET were NET G1 in WHO Classification 2017 and Stage I in UICC TNM 2016. No significant differences were noted between LPT and OPT groups with respect to patient age or gender. Operation time was 421.5 versus 423.5 minutes(ns), blood loss was 121.7 versus 1,918.3mL(ns), hospital stay was 20.5 versus 58.0 days(ns)for LPT and OPT respectively. In LDP, there were no significant differences between PNEN, CyT, and IDC groups with respect to patient age, gender, operation time, blood loss and hospital stay. All patients who underwent LPT for P-NET alive without recurrence. The average observation period was 58.4 months. CONCLUSIONS: Laparoscopic pancreatectomy is safe and effective approach to the management of pancreatic neuroendocrine neoplasm. PMID- 29394685 TI - [A Case of Successful Repeated Metastectomy for Peritoneal Recurrence of over 90 Years Old Colon Cancer Patient]. AB - Treatment for cancer recurrence in elderly people over 90 years old is usually less advantageous in chemotherapy, and surgical resection is considered rather invasive if cure can be expected. We experienced a case of colon cancer in which recurrence of peritoneal dissemination was discovered and resected at the age of 90 years and at 92 years twice. Laparoscopic surgery for colon cancer at the age of 89 years was performed. At 13 months after primary surgery, CT revealed a nodule of 10mm in diameter in the abdominal cavity, and it was also positive in PET-CT. Because there was no other recurrent foci, radical resection was performed. After 14 months(2 years and 4 months after primary surgery), a 17mm large nodule was pointed out and radical resection was done again. Three years later(5 years and 6 months from primary surgery)have passed, she survives without recurrence at 95-years-old and 4 months without any decline in QOL. When recurrence of peritoneal dissemination can obtain radicality in resection, even for elderly persons, surgery should be considered if invasion is minor. PMID- 29394686 TI - [A Case of Liver Metastasis from Esophageal Cancer Successfully Treated by Surgical Resection after Chemotherapy with Weekly-Paclitaxel]. AB - A 58-year-old man complaining of dysphagia was admitted to our hospital and diagnosed with esophageal cancer.He underwent thoracoscopic subtotal esophagectomy with 3-field lymph node dissection and reconstruction with a gastric tube created by hand-assisted laparoscopy.The pathological diagnosis was classified as AeLtG, pT3N2M0, pStage III .He was subsequently treated with systemic chemotherapy with 5-fluorouracil and cisplatin.After 2 courses, a single liver metastatic tumor appeared at segment 5.As chemotherapy against the recurrence, weekly-paclitaxel was administered.After 2 courses, the metastatic liver tumor reduced in size.Subsequently, laparoscopic partial liver resection was performed 11 months after first surgery.The pathological finding was negative for malignancy(pathological complete response). PMID- 29394687 TI - [Continued Chemotherapy for Advanced Gastric Cancer and Seven Year Survival after Operation]. AB - The patient was a 66-year-old man. Total abdominal gastrectomy and D2 dissection were performed for gastric cancer (cT3N0M0P0CYXH0, cStage II A). Pathological examination confirmed a diagnosis of Stage III C mucinous adenocarcinoma (pT4pN3pM0, pStage III C). He underwent adjuvant chemotherapy with TS 1(120mg/body). One year after adjuvant chemotherapy, anastomotic stricture was caused. Although it was not possible to point out recurrent lesions on the CT image, we strongly suspected that extrinsic compression around the anastomotic portion was due to peritoneal dissemination recurrence because of symptoms and marked tumor elevation. Therefore, TS-1(120mg/body)plus cisplatin(CDDP 60mg/m2)were administered as first-line therapy for advanced gastric cancer. TS-1 plus CDDP(SP)chemotherapy resulted in marked tumor reduction and improved symptoms. However, after 33 courses of SP chemotherapy, renal function was worse due to cisplatin; thus, docetaxel(DTX 70mg/m2)was administered as second line therapy. After 8 courses of DTX, peritoneal dissemination recurrence was diagnosed, and the patient was treated with irinotecan(CPT-11 150mg/m / 2), ramucirumab(RAM 8 mg/kg) plus paclitaxel(PTX 80mg/m2 day 1, 8, 15). However, the disease worsened. The side effect of SP therapy was renal dysfunction. Nonetheless, we experienced that long-term disease control could be achieved by administering chemotherapy under strict follow-up. PMID- 29394688 TI - [A Case of Small Intestinal GIST with Long-Term Survival after Tumor Resection for Repeated Peritoneal Recurrence]. AB - A 70-year-old woman presenting with abdominal pain was admitted to our hospital. Abdominal contrast CT revealed a small intestine tumor of 10 cm with active bleeding and performed partial resection of the small intestine including tumor. Pathological findings were high risk GIST of the small intestine because of spindle cells and c-kit positive. Imatinib 400mg/day as adjuvant chemotherapy was administered. However administration was stopped for 15 days because of the Grade 4 erythema multiforme. Recurrence of peritoneal dissemination was observed in 2 years after surgery and tumor resection was performed, but complete resection was difficult. Within 5 years after surgery, tumor resection was performed on a total of 5 times peritoneal disseminative recurrences, and it was possible to avoid the appearance of symptoms due to tumor augmentation. PMID- 29394689 TI - [A Case of Laparoscopic Surgery Performed for Locally Advanced Rectal Cancer Suspected of Invasion to Prostate]. AB - A-58-year-old man was admitted to other hospital with complaints of anal pain and bloody stools, diagnosed as rectal cancer with invasion to prostate, and performed sigmoid colostomy. After taking 6 courses of mFOLFOX6 as preoperative chemotherapy, he introduced our hospital for the purpose of operation. Preoperative evaluation of chemotherapy was PR, but infiltration of the prostate remained. Therefore, laparoscopic abdomino-perineal resection of rectum, prostatectomy and urethral reconstruction by urethral-bladder anastomosis were performed. Postoperative course was good and he was discharged on 10 days after surgery. Currently 2 years after surgery, he has no dysurea and relapse free survival. This procedure was considered to be a very useful technique in that a good operative field and reliable resection can be obtained. PMID- 29394690 TI - [A Case with Metastatic Huge Ovarian Tumor from Transverse Colon Cancer, Who Underwent Systemic Chemotherapy after Bilateral Oophorectomy and Right Hemi Colectomy]. AB - Metastatic ovarian tumors from colon cancer would be resistant to chemotherapy, and compromising quality of life(QOL) of these patients was caused by acute enlargement of the tumors. A 37-year-old woman with abdominal distension was diagnosed with transverse colon cancer, bilateral ovarian metastases, liver metastases, and peritoneal dissemination at prior hospital. Two courses of chemotherapy(FOLFOX)were administered, but metastaticovarian tumors enlarged. Chemotherapy was discontinued and she was referred to our institution. To achieve symptom relief, improving QOL, and to resume chemotherapy, we planned bilateral oophorectomy and primary tumor resection if other stenotic lesion was not present. As a result, we safely performed open bilateral oophorectomy and right hemi colectomy, and the patient discharged on postoperative day 11 without complications. Chemotherapy was resumed and continued for 7 months up to this time. Even though, curative resection could not be achieved, oophorectomy should be performed in patients with enlarged metastatic ovarian tumor from colon cancer, in spite of administration of chemotherapy. PMID- 29394691 TI - [A Case of Locally Advanced Gastric Cancer - R0 Resection Was Performed by Pancreaticoduodenectomy with Portal Vein Resection Following Neoadjuvant Therapy]. AB - A 76-year-old woman, complained of weight loss, was admitted in our hospital. After investigation, she was diagnosed with clinical Stage III B gastric cancer with invasion into the pancreas and transverse colon. After performing the staging laparoscopy and gastrojejunostomy for pyloric stenosis, she was treated with 2 courses of SOX therapy as neoadjuvant therapy, and subsequently underwent pancreaticoduodenectomy and right hemicolectomy combined with portal vein resection due to severe adhesion by the tumor. The pathological diagnosis was pT4b(colon), pN0(0/22), pM0, pStage III B. There were no findings of tumor invasion into the pancreas or the portal vein. She was discharged without any complications. She did not receive the adjuvant chemotherapy, and died of other illness at 10 months after surgery. For the locally advanced gastric cancer such as invasion to the pancreas, the extended resection as an R0 resection could be achieved more safely, by evaluating accurately the incurable factors and planning an effective strategy according to the patient's condition. PMID- 29394692 TI - [A Case of Locally Advanced Neuroendocrine Carcinoma of the Stomach Could be Curably Resected after Chemotherapy with CPT-11/CDDP]. AB - A 64-year-old man was admitted to our hospital because of epigastralgia. Gastrointestinal endoscopyrevealed a submucosal tumor with ulceration in the upper bodyof the stomach. The tumor was histologicallydiagnosed as a neuroendocrine carcinoma. CT showed that the tumor had directlyinfiltrated the pancreas and splenic vessels. The patient underwent onlyan exploratorylaparotomybecause the tumor seemed to involve the celiac artery. Chemotherapywas conducted using CPT-11/ CDDP. After 15 courses of chemotherapy, a significant tumor reduction was obtained. We performed total gastrectomy with D2 lymphadenectomy, distal pancreatectomy and splenectomy. Histopathological examination of surgical specimens showed that onlyfew carcinoma cells remained in the stomach and pancreas. Neoadjuvant chemotherapycan be a useful treatment for unresectable locallyadvanced neuroendocrine carcinoma of the stomach. PMID- 29394693 TI - [Combination Treatments to the Huge Ovarian Cancer with Liver Metastases]. AB - We report a CR case of huge ovarian cancer with peritoneal and liver metastases who was operated bilateral ovaries, uterus and peritoneal metastases at first, followed by systemic chemotherapy and performed 4 times of radiofrequency ablation (RFA)and 2 times of liver resection(LR). The case was a 50-year-old woman. She suffered with bowel enlargement from over 1 year ago. Preoperative MRI finding was huge ovarian serous cyst with partial solid tumor inside. The major axis was about 30 cm. CA125 and CA19-9 levels were elevated. Tumor reduction surgery was performed with bilateral salpingooophorectomy and hysterectomy with resecting peritoneal metastatic lesions. Postoperative systemic chemotherapy(carbo- platin 550mg/day 1 plus paclitaxel 130mg/day 1, 8, 15)(CBDCA plus PTX)were performed amount 6 courses. Unfortu- nately liver metastases at S3, S4, S6, S7 and S8/5 appeared about 7months after operation.We restarted the CBDCA plus PTX therapy from 15 months after operation when the tumor maker elevated. After 18 courses of CBDCA plus PTX therapy liver metastases remained only at S3. But gradually tumors grew up and size of tumors increased in spite of 3 more courses of CBDCA plus PTX therapy. So we challenged 2 times of RFA at S8/5 metastases that grew most rapidly and the values of increasing tumor makers stopped elevating. Then we performed LR at S3 and S4 metastases and the values of tumor makers returned to the normal level. But next S6 and S7 metastases appeared, we chose the RFA at first. At last recurrence of S7 was resected and all of liver metastases were treated. We checked no peritoneal metastases twice at the time of operation. The values of tumor makers became the normal level. Now she is alive well without metastases over 6 years after first operation. RFA and LR were effective at liver metastases from ovarian cancer that became resistant to systemic chemotherapy. PMID- 29394694 TI - [Jejunal Interposition after Totally Laparoscopic Proximal Gastrectomy Using Overlap Method]. AB - : There are several reconstruction methods in laparoscopic proximal gastrectomy(LPG)for earlygastric cancer at the upper part of the stomach. To prevent the esophageal reflux after gastrectomy, we chose jejunal interposition(JI)via the retrocolic route for LPG. We performed totallyLPG with JI using overlap method. METHODS: Five ports were placed. After the lymph nodes dissection bythe standard procedure, the esophagus and the proximal side of the stomach were transected byliner staplers. The jejunum was moved to the upper abdomen through the small hole of the mesocolon. The interposing jejunum was made, and the esophagojejunostomyand jejunogastrostomywere done byusing overlap method. At the end, the jujunum was pulled under the mosocolon escluding the interposing jejunum. The JI reconstruction via a retrocolic route after LPG was completed. DISCUSSION: Following LPG, the JI reconstruction is not so popular because the surgical procedure is complicated. In our technique, the JI reconstruction accomplished easier byoverlap method. CONCLUSION: Our procedure is a considerable operation of reconstruction following LPG. PMID- 29394695 TI - [A Patient Who Underwent Resection of Liver Metastases after Receiving Systemic Chemotherapy for Advanced Rectal Cancer and Multiple Liver Metastases]. AB - The patient was a 52-year-old man who had a positive fecal occult-blood test on a medical check-upi n April 2015 and was referred to our hospital in June. Detailed preoperative examinations resulted in a diagnosis of cancer of the lower rectum, multiple liver metastases, and clinical Stage IV . A biopsy showed moderately differentiated tubular adenocarcinoma. All-RAS was wild type, and the patient was asymptomatic. Unresectable advanced rectal cancer was diagnosed, and the patient was scheduled to receive systemic chemotherapy. The patient received a total of 16 courses of combination chemotherapy with 5- fluorouracil, Leucovorin, and oxaliplatin(FOLFOX)plus panitumumab, starting in October 2015. In July 2016, Colonoscopy showed scar findings at the site of the primary rectal cancer lesion. A biopsy revealed no cancer cells. It was difficult to identify the primary lesion on computed tomography, and there was no evidence of clinically significant lymphadenopathy. Positronemission tomography and computed tomography showed shrinkage of the liver metastases, with no accumulation of tracer in the primary lesion or lymph nodes. The primary lesion had a clinical complete response(CR), and the metastatic lesions had a clinical partial response(PR). In October 2016, laparoscopic partial hepatectomy was performed to treat the liver metastases. Histologic examination showed that the liver metastases were from rectal cancer. It is currently under observation. PMID- 29394696 TI - [A Case of Extragastric-Developing Gastric Cancer with Hepatic and Pancreatic Invasion Suggesting Squamous Differentiation]. AB - A 69-year-old man presented with left upper abdominal pain and weight loss. Contrast-enhanced CT showed a 9 cmsized extragastric tumor located between the left lateral liver section and the gastric lesser curvature. Gastroendoscopy showed a type 3 tumor located at the lesser curvature of the antrum. Biopsy confirmed that the tumor was an adenocarcinoma. With a diagnosis of extragastric developing gastric cancer with hepatic and pancreatic invasion, the patient underwent a totalgastrectomy, D2 lymph node dissection, partiall iver resection, and pancreatic body tailexcision. The pathologicaldiagnosis was poorly differentiated adenocarcinoma suggesting squamous differentiation. Despite receiving postoperative adjuvant chemotherapy, the patient died of recurrence 7 months later. PMID- 29394697 TI - [A Case of T4 Esophageal Cancer with Refractory Chylothorax Developed Postoperatively]. AB - A 65-year-old man was diagnosed as having middle thoracic esophageal cancer(c T3N2M0, stage III ), and neoadjuvant chemoradiotherapy was performed.We performed surgical therapy.However, tumor and #113 lymph node invasion into the aortic arch was observed; therefore, it was judged that curative resection was difficult, and R2 surgery was performed instead. Postoperative diagnosis was Mt, CRT-type 5b, s T4(aortic arch)N4(#113)M0, stage IV a.After surgery, pleural effusion was abundant and was diagnosed as chylothorax.Even though intestinal rest and octreotide administration were performed as a conservative treatment, chylothorax was not improved.Therefore, thoracoscopic thoracic duct ligation was performed on 8POD.After that, pleural effusion was still sustained, and pleural adhesions were performed.However, it did not prove to be effective.Furthermore, when Lipiodol lymphangiography was performed to identify the leakage site, the leakage of contrast medium was observed from the remaining lymph node.After lymphangiography twice(in total), pleural effusion disappeared, and the patient was discharged on the 75POD.In this case, we report an example in which lymph leakage disappeared due to lymphangiography for diagnostic purpose, while no improvement was observed in the lymphatic leakage from the remaining metastatic lymph node in T4 esophageal cancer with R2 surgery, nor with some treatments for chylothorax, including thoracic duct ligation. PMID- 29394698 TI - [A Case of Breast Apocrine Carcinoma in Which Eribulin Was Effective]. AB - A 79-year-old woman presented with a chief complaint of a palpated tumor on her right axilla. The right breast tumor size was 18mm and the axillary lymph node size was 30 mm, as detected with ultrasonography. Pathological findings indicated the presence of an ER(-), Pg R(-), HER2-negative apocrine carcinoma. The presence of axillary lymph node metastasis was diagnosed from the apocrine carcinoma. Eribulin(1.5mg)was administered 3 times before surgery. Tumors were significantly reduced. The Bt+Ax(Patey procedure)dissection was performed until Level 2. The pathological findings of the tumor revealed coagulation, necrosis, and the remaininglimited cancer lesions in the periphery zone. No remainingcancer cells were detected in the lymph nodes. The breast apocrine carcinoma was determined as a special type of invasive cancer. Although the prognosis is positive, the current case was considered highly malignant with a 50% positive Ki-67 rating. Although eribulin was effective, it seems that this case requires strict follow up observations. PMID- 29394699 TI - [Laparoscopic and Endoscopic Cooporative Surgery(LECS)for Superficial Non Ampullary Duodenal Tumor - A Case Report]. AB - INTRODUCTION: We report a case ofsuperf icial non-ampullary duodenal tumor(SNADT)resected by laparoscopic and endoscopic cooperative surgery(LECS)technique. CASE PRESENTATION: A 55-year-old man underwent screening esophagogastroduodenoscopy. Endoscopy revealed 0- II a+ II c mucosal lesion measuring 15mm in size located the portion ofduodenum contralateral to the ampulla ofVater. During observation, irregularity in depressed mucosa was observed and malignant alteration was suspected. So, we performed local resection with LECS as diagnostic therapy. During operation, endoscopic mucosal resection(ESD)was performed first. Next, duodenum was mobilized laparoscopically and the floor of the ulcer was closed with endoscopy guided laparoscopic suturing technique. Histopathology revealed tubular adenoma and the resection margin was negative. DISCUSSION: SNADT is rare condition and therapeutic strategy for SNADT has not established. Further study are needed. PMID- 29394700 TI - [Cell-Free and Concentrated Ascites Reinfusion Therapy for Malignant Intractable Ascites from Colorectal Cancer]. AB - Malignant intractable ascites worsens not only patient symptoms but also their daily activities. It often leads to a patient discontinuing or postponing chemotherapy. In the present study, we introduced cell-free and concentrated ascites reinfusion therapy(CART)for malignant intractable ascites from colorectal cancer. Six patients underwent 12 CART treatments using AHF-WMO as the ascites filterand AHF-UP as the concentrator(Asahi Kasei Medical Co., Ltd.)from January 2014 to January 2017. The patients included 2 men and 4 women aged 67-89 years. Primary locations were 3 rectums, 1 transverse colon, 1 descending colon, and 1 cecum. Five patients had peritoneal dissemination, and 1 patient had liver metastasis. All the patients were administrated diuretics, but they were all refractory to the treatment. The median punctured ascites volume was 3,850 mL, and the ascites reinfusion after CART was 485 mL, the median concentration was 7.5. Only one patient had a fever. Performance status(PS)improved significantly after the treatment, and appetite score also improved. One patient was fit to undergo chemotherapy after the treatment. In summary, we found that CART is a safe and acceptable procedure for malignant intractable ascites in colorectal cancer patients. PMID- 29394701 TI - [Experience of Ramucirumab plus FOLFIRI as Second-Line Treatment for Metastatic Colorectal Cancer in Our Hospital]. AB - We experienced 2 cases in which ramucirumab plus FOLFIRI as second-line treatment was beneficial. Case 1 was a 67-yearold man, underwent panitumumab plus mFOLFOX6 as first-line treatment for unresectable rectal cancer with ureteral invasion and multiple liver metastases, but the disease became worse at 9.3 months. We changed to ramucirumab plus FOLFIRI as second-line treatment. After 2 courses, a grade 3 febrile neutropenia was observed, but treatment was beneficial and continued administration for 9 months or more. Case 2 was a 73-year-old man who underwent panitumumab plus mFOLFOX6 as first-line treatment after cytoreductive surgery of the primary lesion for sigmoid colon cancer with intestinal obstruction and liver metastasis, but the disease became worse at 4.7 months. Upon entering ramucirumab plus FOLFIRI therapy, the metastatic lesions shrinked remarkably. Adverse events of grade 3 or higher were not observed and finally continued administration for 7.9 months. It was suggested that ramucirumab plus FOLFIRI combination therapy for metastatic colorectal cancer could be an effective as second-line treatment. PMID- 29394702 TI - [A Case of Lymph Node Metastasis of Rectal Laterally Spreading Tumor with Mucosal Cancer after Endoscopic Submucosal Dissection]. AB - A screening fecal occult blood test was positive in a 76-year-old female. Colonoscopy showed laterally spreading tumor (LST)over 15 cm at lower rectum. endoscopic submucosal dissection(ESD)was performed. Pathological findings showed LST-G, 150*100 mm, adenocarcinoma(tub1-tub2), tubular adenoma, moderate-severe atypia, Tis(M), ly(-), v(-), HMX, VMX. Two years later CT detected one swollen lymph node at mesorectum and PET-CT showed FDG up take at the lymph node. We diagnosed lymph node metastasis, performed laparoscopic very low anterior resection. Pathological findings showed one lymph node metastasis, but there were no residual cancer at rectum. We cut the surgical specimen at 5mm intervals because of it's big size. It might be impossible with this procedure to detect SM invasion at this specimen. PMID- 29394703 TI - [A Case of Hepatocellular Carcinoma with Lymph Node Metastasis Successfully Treated by Multidisciplinary Treatment]. AB - Lymph node metastasis has a poor prognosis in patients with hepatocellular carcinoma(HCC). We report a case of HCC with lymph node metastasis successfully treated by multidisciplinary treatment. An 81-year-old woman who was followed up for liver cirrhosis received a diagnosis of HCC, which was detected by CT as a solitary tumor 20mm in diameter in the couinaud segment 7 of the liver. She underwent transcatheter arterial chemoembolization(TACE)twice for HCC because of her advanced age and no intention to undergo hepatectomy. Some 12 months later, local recurrence was managed by repeat TACE and paraaortic lymph node metastasis by surgical resection. The patient received radiotherapy for mediastinal nodal disease 6 months after the resection. She remains alive and well without no evidence of disease 84 months after the initial treatment. This case and a review of the literature suggest that multidisciplinary treatment with TACE, surgical resection and radiotherapy may provide a survival benefit for selected patients with HCC with isolated lymph node metastasis. PMID- 29394704 TI - [A Case Report of Acinar Cell Carcinoma of Pancreas with Extensive Intraductal Growth to the Branch - Main Pancreatic Duct]. AB - Since acinar cell carcinoma(ACC)of pancreas is rare, we sometimes meet a case hard to make diagnosis before surgery. We here reported a case of ACC of pancreas with extensive intraductal growth to the main pancreatic duct and the branch of the pancreatic duct. A 43-year-old man visit a clinic with a concern of uncomfortable feeling on left side abdomen. CT/MRI examination showed a ischemic tumor, 38*25 mm, in the body-tail of the pancreas, and the tumor infiltrated to left renal capsule. ERCP showed the interruption and stenosis of the pancreatic duct at the point adjacent to tumor. Cytological diagnosis of the pancreatic juice was performed, but malignant cells were not detected(Class III ). The tumor abnormally accumulated FDGin PET-CT examination(SUVmax 3.3). We diagnosed the tumor PDAC with infiltrating to the left renal capsule, and the distal pancreatectomy was performed. The pathological examination of the resected specimen showed that the tumor progressed into main pancreatic duct and the branch of the pancreatic duct accompanying with fibrosis around pancreatic duct. The tumor was diagnosed ACC with immunohistochemistry; positive to ACC phenotype(a1-antitrypsin, a1-antichymotrypsin, BCL10). The patient is alive without any recurrence findings 3 years 2 months after surgery. PMID- 29394705 TI - [A Case of Metastases to the Bone, Skin, and Ovary from Gastric Cancer Occurring More Than Eight Years after Distal Gastrectomy]. AB - We report a 72-year-old woman with rare metastases of gastric cancer to the bone, skin, and ovary occurring more than 8 years after distal gastrectomy, which were subsequently effectively controlled. Histopathological diagnosis revealed signetring cell carcinoma, and the comprehensive findings were pT4a, pN3, ly2, v0, and Stage III c. The adjuvant chemotherapy of S- 1 plus cisplatin(CDDP)was switched to S-1monotherapy for 4 years and then to tegafur/uracil(UFT)for an additional year. Eight years after the operation, I-CTP and alkaline phosphatase(ALP)levels were elevated, and bone scintigraphy revealed bone metastasis. The patient's ALP levels, which had increased to 6,617 U/L, remarkably decreased to 359 U/L 17 months after treatment with zoledronic acid. About 9 years after the operation, a 2cm subcutaneous node was seen on the patient's scalp, and a biopsy was performed. Histologically, the node was confirmed as a signet-ring cell carcinoma. S-1 therapy was initiated, and the node disappeared within 8 months. About 10 years after the gastrectomy, abdominal computed tomography( CT)scans indicated a tumor sized 11*10 cm in the pelvis, and a biopsy was performed. Histologically, the tumor was a signet-ring cell carcinoma appearing as an ovarian metastasis of gastric cancer. Ovariectomy was performed. Peritoneal dissemination was not detected. The patient was treated with S-1 plus oxaliplatin and zoledronic acid, and continues to remain in good condition 9 months after the ovariectomy. PMID- 29394706 TI - [A Case of Surgical Treatment of Pulmonary Metastasis from Gastric Cancer]. AB - An 87-year-old woman was diagnosed with advanced gastric cancer and primary lung cancer in November 2012. She underwent distal gastrectomy for the gastric cancer in December 2012, and right upper wedge resection for the primary lung cancer in February 2013. After surgery, the patient received S-1 chemotherapy. However, she subsequently experienced adverse effects, and so S-1 chemotherapy was stopped. In February 2016, a computed tomographic scan of the chest showed a nodular shadow at S8 in the left lung. Because the nodular shadow gradually increased in size, we suspected that the diagnosis would be either primary lung cancer or metastatic lung cancer arising from gastric cancer. In July 2016, we performed left lower wedge resection. Histopathological examination of the resected specimen resulted in a diagnosis of metastatic lung cancer arising from gastric cancer. After pulmonary resection, the patient had no recurrent tumor. It is thought that surgery is an effective treatment for solitary pulmonary metastasis arising from gastric cancer. PMID- 29394707 TI - [Resection of the Distal Part of the Gastric Tube for the Gastric Tube Cancer after Esophagectomy - A Case Report]. AB - A 76-year-old man was admitted to our hospital for treatment of gastric tube cancer(cT2N0M0, cStage II A)detected by a screening upper gastrointestinal endoscopy. Seven years previously, he had undergone subtotal esophagectomy for esophageal cancer with gastric pull-up via the retrosternal route. At that time, he experienced cardiopulmonary arrest due to ventric- ular tachycardia. He was in a state of poor nutrition(BMI 15 kg/m2). Therefore, reducing operative stress as much as possible, minimizing complications after surgery, and aiming for a satisfactory postoperative course are all important goals. Based on his past history, we performed distal gastrectomy(resection of the distal part of the gastric tube)without excision of the right gastroepiploic artery. The postoperative course was uneventful. He was discharged 40 days after surgery. By considering the risks of surgery due to cardiac dysfunction and malnutrition, we were able to provide effective and safe therapy for the patient. PMID- 29394708 TI - [Strangulation Ileus Caused by Incarcerated Esophageal Hiatal Hernia after Laparoscopic Total Gastrectomy - A Case Report]. AB - Laparoscopic total gastrectomy(LTG)is one of the most increasing surgeries among gastric cancer surgery. Although LTG has many advantages on the patient, we should be more careful of its specific complications. Here we report a case of 72 year-old man with the complaint of severe acute upper abdominal pain due to strangulation ileus caused by incarcerated esophageal hiatal hernia(EHH)after LTG. Emergent operation has performed on the patient and total 180 cm length of necrotic small intestine was resected. EHH after gastrectomy was thought to be rare complication. However, some literature reported that EHH after gastrectomy, especially after LTG has more possibility than it has ever thought to be. Laparoscopic surgery has more advantages than open surgery in terms of less invasiveness, rapid postoperative recovery, and less intraabdominal adhesion. One of the causes for EHH after LTG is ironically thought to be its less intraabdominal adhesion. We concluded that crus repair is one of the effective methods for the prevention of EHH after LTG through experiencing this case. PMID- 29394709 TI - [The Experience of the Intensity Modulated Radiation Therapy for Abdominal Lymph Node Metastases from Gastric Cancer]. AB - The recurrence ofgastric cancer has a poor prognosis in spite ofsystemic chemotherapy. We report three cases oflocal control ofdisease after the recurrence owing to intensity modulated radiation therapy(IMRT). The first case was a 66-yearsold man. He was received distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer. Abdominal lymph node metastases appeared 1 year and 7 months after the surgery. IMRT was performed and he keeps CR for 1 year and 8 months. The second case was a 72-years-old man. He received proximal gastrectomy for early gastric cancer. Abdominal lymph node metastasis appeared 1 year and 9 months after the surgery. IMRT was performed and he keeps CR for 1 year. The third case was a 71-years-old woman. She received distal gastrectomy for advanced gastric cancer. Abdominal lymph node metastasis appeared 2 years after the surgery. IMRT was performed and she keeps CR for 10 months. We experienced longtime CR after IMRT against abdominal lymph node metastasis. IMRT could be one ofthe strategies ofthe comprehensive treatment for the recurrence of gastric cancer. PMID- 29394710 TI - [A Case of Huge Advanced Neuroendocrine Carcinoma of the Transverse Colon Resected Successfully]. AB - The patient, 49-year-old woman, who was referred to our hospital in August 2016 because of left abdominal pain. The abdominal CT scan showed a large tumor, over 10 cm dimeter at splenic flexure of the transverse colon, and colonoscopy detected transvers colon cancer(por, cT4b, cN1, M0, cStage III A). There was no distant metastasis, although invasion to the retroperitoneum and the abdominal wall. Left hemicolectomy was successfully performed with D3 lymph node dissection. Pathological diagnosis was endocrine cell carcinoma, pT4a(SE), pN0, M0, pStage II . The Surgical margin was completely free of carcinoma(R0). The postoperative course was uneventful, and she has been in good health with no recurrence for 8 months after surgery. Neuroendocrine cell carcinoma is recommended for adjuvant treatment based on small cell lung cancer, but there are not effective clinical trials nor established treatment methods because it is rare disease. PMID- 29394711 TI - [A Case Report of Long-Term Survival after Excision for Needle Tract Implantation of Biopsy and Hepatectomy for Cholangiocarcinoma with Gall Bladder Hemorrhage]. AB - A 77-year-old men with abdominal pain suffered from gall bladder hemorrhage and liver abcess was admitted for intensive care of severe acute cholangitis. He had hemobilia which was treated by the endoscopic retrograde bile duct drainage. After 2 months treatment with rest for purulent myelitis, he had neoplastic change of liver abcess diagnosed as intrahepatic bile duct cancer by percutaneous core needle biopsy. He underwent surgery as central bisegmentectomy and left the hospital at home 3 months later after rehabilitation for surgical site infection. He noticed growing mass on right chest 6 months later after hepatectomy and was diagnosed as needle tract implantation in chest wall by CT examination. Pathological exam revealed cholangiocarcinoma by radical excision. He have disease free for 5 years after second operation. Although percutaneous biopsy for hepatic tumor increases risks of needle tract implantation and dissemination, there is an advantage of radical resection for tract implantaion. PMID- 29394712 TI - [A Case of Neuroendocrine Ductal Carcinoma In Situ of the Breast Detected as an Intra-Cystic Tumor Using Ultrasonography]. AB - We report a case of neuroendocrine ductal carcinoma in situ of the breast. The tumor was shown to be an intra-cystic tumor on performing ultrasonography. The patient was a 40-year-old woman. Amorphous calcifications were detected on her right breast on performing mammography during breast cancer screening. Ultrasonography indicated that the tumor was 9mm in diameter, and displayed features of an intra-cystic tumor. A vacuum-assisted core needle biopsy for breast tumor led to a diagnosis. The pathological diagnosis was mastopathy. We could not rule out malignancy of the tumor. Subsequently, we performed surgical resection with 5mm margins. The pathological diagnosis was intra-cystic neuroendocrine carcinoma in situ, positive for estrogen receptor and progesterone receptor, and negative for HER2/neu. The Ki-67 positive cell index was 5%. The surgical margin was negative. We performed a whole-body checkup, and confirmed a diagnosis of TisN0M0, Stage 0. She was initiated endocrine therapy with tamoxifen(20mg/day). Four years after surgery, she was well without metastases. PMID- 29394713 TI - [A Case Report of Ipsilateral Nipple Skin Recurrence]. AB - We report our experience with a patient with breast cancer who showed recurrence in the nipple skin 5 years and 10 months after a breast-preserving surgery. The patient was a woman, and was 65-years old at the time of initial surgery. Breast preserving surgery and axillary lymph-node dissection were performed for left breast cancer. Invasive ductal carcinoma of the breast(pT3N0M0)was triple negative, and the patient postoperatively received adjuvant chemotherapy. Left breast pain developed 5 years and 6 months after surgery. Computed tomography showed no evidence of recurrence, and the symptoms resolved after treatment with non-steroidal anti-inflammatory drugs(NSAIDs). After 3 months, however, the left nipple had enlarged to about 1.5 cm, and the surrounding skin was red and painful. Treatment with NSAIDs was thus resumed. After 1 week, redness of the nipple skin and pain were improved. However, the nipple had enlarged to twice its normal size. Nipple skin biopsy was subsequently performed, and revealed adenocarcinoma invading the skin. Left axillary lymph-node metastasis was suspected, but there was no evidence of metastasis to other sites or recurrence. Conservative total mastectomy with axillary lymph-node dissection was thus performed. The histopathological diagnosis was the recurrence of invasive ductal carcinoma, arising mainly in the reticular layer of the dermis. Chemotherapy was administered postoperatively. There has been no evidence of recurrence as of 1 year after surgery. PMID- 29394714 TI - [A Case of Paget-Type Recurrence 20 Years after Breast Conserving Surgery for Invasive Ductal Carcinoma]. AB - We report an 85-year-old female suffered Paget-type recurrence at right remnant breast. The patient had undergone breast conserving surgery(BCS)20 years ago in another hospital for invasive ductal carcinoma of the right breast(pT1N0M0, Stage I ). Her chief complain was a skin ulcer of the right nipple. The pathological diagnosis for biopsy specimen from the areola was Paget's disease. She underwent total mastectomy. Paget cells were detected pathologically in the epidermis of the nipple and nearby mammary duct connected with fibrous tissue after BCS, suggesting Paget-type recurrence of invasive breast carcinoma. PMID- 29394715 TI - [Results of Neoadjuvant Chemoradiotherapy for Rectal Cancer with Invasion to the Adjacent Organs]. AB - We reviewed the clinical records of 14 cases who received neoadjuvant chemoradiotherapy(CRT)to evaluate the clinical effectiveness of the CRT for T4b rectal cancer. The preoperative radiotherapy consisted of 40-50 Gy delivered in fractions of 1.8-2.0 Gy per day, 5 days per week. A treatment with intravenous 5 fluorouracil, or oral tegafur-uracil(UFT)with l-leucovorin, or oral S-1, or capecitabine or intravenous irinotecan with oral S-1, was administered during radiotherapy. One patient died due to pelvic abscess at 69 days after CRT. Complete response(CR)or partial response(PR)was observed in 8 cases, 1 month after CRT. Curative surgery was performed in 10 patients. Among 10 patients who underwent curative surgery, both urinary and anal function were preserved in 5 patients. Although no lymph node metastasis was found in 9 patients of 10 patients who underwent curative surgery, recurrence was found in 5 patients, and local recurrence was found in 4 of these patients. Recurrence occurred in all patients who had recurrence within 1 year. Preoperative CRT was expected to be an effective treatment to improve the resection rate and prognosis for T4b rectal cancer. However, it was thought that it was necessary to be careful about local recurrence, especially within 1 year after surgery. PMID- 29394716 TI - [Four Cases of Gastrointestinal Perforation Associated with Bevacizumab]. AB - Four cases of gastrointestinal perforation associated with bevacizumab(BEV)were examined. Case 1: A 82-year-old male received FOLFIRI plus BEV for recurrent liver metastasis after rectal cancer resection. A lower esophageal perforation occurred 22 days after BEV administration and drainage was performed. Case 2: A 69-year-old female received FOLFOX4 plus BEV for unresectable rectal cancer and liver and lung metastasis. A rectal perforation occurred 6 days after BEV administration and suturing closure of the hole and colostomy was performed. Case 3: A 69-year-old female, received carboplatin(CBDCA) plus pemetrexed(PEM)plus BEV for unresectable left lung cancer and adrenal gland and lymph node metastasis. A small intestinal perforation occurred 15 days after BEV administration and ileocecal resection and primary anastomosis was performed. Case 4: A 73-year-old female received CBDCA plus PEM plus BEV for unresectable left lung carcinoma and pleural metastasis. A diverticulum of sigmoid colon perforation occurred 30 days after BEV administration and suturing closure of the hole and colostomy was performed. When we observe fever, abdominal pain, elevation of the inflammatory reaction after BEV administration, we should immediately examine gastrointestinal perforation. PMID- 29394717 TI - [Experiences of Colonic Stents in Patients with Colonic Stenosis Due to Peritoneal Dissemination of Gastric Cancer]. AB - Stoma is a treatment option often adopted for large bowel obstruction accompanying peritoneal dissemination of gastric cancer, but the invasiveness of this intervention can be an issue for patients with limited prognosis and reduced quality of life. In our hospital, colonic stenting for bowel obstruction due to peritoneal dissemination from gastric cancer was performed for 7 consecutive patients. Oral ingestion became possible in 5 cases, and colonic stent was considered a useful treatment choice for appropriate cases. PMID- 29394718 TI - [A Case of a Rupture of the Carotid Artery Caused by the Lenvatinib Medication]. AB - We report a case of a rupture of the common carotid artery caused by the medication of lenvatinib. The patient, 70-yearold female, was referred to our hospital by unresectable papillary thyroid cancer infiltrated the left common carotid artery. Externalbeam radiotherapy and radioiodine therapy were undergone after totalthyroidectomy. After 1 year 7 months from operation, she admitted our hospital due to left shoulder pain and dysphagia caused by the growing left cervical tumor. The medication of lenvatinib was decided after the careful informed consent. Computed tomography on the eighth day of lenvatinib medication showed the existence of air infiltration into the tumor surrounded left common carotid artery. So, a discontinuance of lenvatinib medication was decided immediately. But, on the ninth day, a rupture of the left common carotid artery occurred and on the tenth day, she died. Lenvatinib medication for the patient with the tumor surrounded artery should be decided carefully. PMID- 29394719 TI - [A Case of Para-Aortic Lymph Node Metastasis of Rectal Cancer Successfully Treated Using Multidisciplinary Therapy]. AB - A 66-year-old man diagnosed with rectal cancer underwent high anterior resection and received adjuvant chemotherapy (UFT plus UZEL). One year after the surgery, lung and para-aortic lymph node(PLN)metastases were identified. We chose mFOLFOX6 for first-line chemotherapy. After 7 courses, we changed the regimen to sLV5FU2 because of Grade 3 neuropathy. After 5 courses, to treat progressive disease(PD), we changed the regimen to FOLFIRI. Then, the patient had stable disease (SD), and surgical excision was performed for both lung and lymph node recurrence without adjuvant chemotherapy. Six years after the excision, a CT scan revealed PLNagain. We chose FOLFIRI plus cetuximab. After 9 courses, the lymph nodes decreased in size and there was no other recurrence; thus we performed resection. However, a third PLNrecurrence was identified 20 months after the resection. Chemotherapy has continued for 47 courses, and he has maintained SD for more than 2 years. PMID- 29394720 TI - [A Case Where Function Preservation Was Possible for Quadruple Cancer Metastasis]. AB - The patient was a 69-year-old man visited our hospital because of fecal occlt blood test at medical checkup and diagnosed with rectal cancer and gastric cancer. The patient underwent super low anterior resection for rectal cancer cStage III b and underwent endoscopic submucosal dissection(ESD)for early gastric cancer. In 1 year after surgery the patient had recurrence of gastric cancer after ESD and recurrent gastric cancer was additionally resected. In 1 year and 4 months after surgery pulmonary metastasis was recognized and the patient underwent pulmonary segmentectomy. In 5 years after surgery renal cell carcinoma was recognized and the patient underwent partical renal excision. In 8 years after surgery esophagus cancer was recognized and the patient underwent radical chemoradiationtherapy and completed local complete remission. Current the patient is alive without relapse. We report a case where function preservation was possible for quadruple cancer by appropriate preoperative and postoperative examination and appropriate treatment. PMID- 29394721 TI - [A Case of Long-Term Survival of Recurrent Bile Duct Cancer with Peritoneal Metastasis Successfully Treated with Surgical Resection]. AB - We report a case of peritoneal metastasis of bile duct cancer that was successfully treated by surgical resection. A 70s man underwent pancreatoduodenectomy(PD)for bile duct cancer, and abdominal CT revealed a tumor in the peritoneum along the right kidney at 55 months after PD. As FDG uptake was seen at the lesion on PET-CT, he was diagnosed as recurrence of bile duct cancer or primary malignant tumor in the retroperitoneum. Because the tumor was solitary on CT and PET-CT, we conducted surgical resection of the tumor. Pathological diagnosis was well differentiated adenocarcinoma that was similar to the primary lesion, and the tumor was confirmed as recurrence of bile duct cancer. He remains alive without 2nd recurrence for 60 months since tumor resection(117 months since PD). PMID- 29394722 TI - [A Case of Advanced Esophageal Cancer Successfully Treated with DCF Chemotherapy Followed by Conversion Surgery]. AB - A 66-year-old man was admitted to our hospital complaining of dysphagia. Endoscopic examination showed type 1 tumor in the middle intrathoracic esophagus. The biopsy specimen showed moderately differentiated squamous cell carcinoma. Abdominal CT scan revealed the swelling of lymph nodes along the celiac artery. We diagnosed unresectable advanced esophageal cancer(cT3N4M0, cStage IV a). Systemic chemotherapy was initiated using a regimen of docetaxel, CDDP, and 5- FU(DCF). Abdominal CT scan indicated regression of the swelling lymph nodes after 3 courses. Subtotal esophagectomy with 3 field lymph nodes dissection was performed, because the bulky lymph node could not be resected. Histological effect of chemotherapy diagnosed from resected specimen was Grade 2. In summary, we experienced a case of esophageal cancer successfully treated with DCF chemotherapy followed by conversion surgery. PMID- 29394723 TI - [A Case Report of Gastric Cancer with Positive Peritoneal Lavage Cytology and Metachronous Schnitzler's Metastasis Treated with Multimodality Therapy]. AB - A69 -year-old male patient with type 3 gastric cancer in pyloric antrum underwent distal gastrectomy with regional lymphadenectomy. Serosal infiltration of cancer tissue was found in the anterior wall of antrum, and the evaluation of peritoneal lavage cytology were positive. Pathological analysis showed the tumor was mainly consist of moderately tubular adenocarcinoma and strongly positive for HER2 stain. Postoperatively, combined therapy of capecitabine and trastuzumab was carried out, but cisplatin was excluded because of the patient's rejection. However, nine months after drug withdrawal, singular tumor located at left anterior side of rectum was detected by abdominal CT scan. Colonoscopy revealed its mucosal invasion and the result of biopsy was metastasis of gastric cancer, also known as Schnitzler's metastasis. Local radiation therapy aimed at the tumor was performed, followed by capecitabine and oxaliplatin therapy for 18 months. After the therapy, Schnitzler's metastatic lesion was disappeared and biopsy from colonic mucosa revealed there was no tumor tissue left. The patient has been in good health 5 years after surgery. This case suggests that multimodality therapy including radiation and chemotherapy might improve survival of gastric cancer patient with positive peritoneal lavage cytology and metachronous metastasis. PMID- 29394724 TI - [A Case Report of Anal Canal Squamous Cell Carcinoma with Poor Prognosis That Occurred Nine Years after Subtotal Colectomy for Ulcerative Colitis]. AB - Ulcerative colitis(UC)is a chronic inflammatorydisease. Since it is known to be a risk factor for colorectal cancer, severe cases, refractorycases, or cases with cancer are often treated with surgery. We report a case of anal canal squamous cell carcinoma(SCC)found 9 years after subtotal colectomy for UC. A 32-year-old man underwent subtotal colectomyand ileorectum anastomosis 9 years ago for fulminant UC. Anemia was detected during treatment with infliximab, which was initiated 2 years ago. Endoscopic findings revealed a type 3 tumor at the anal canal in the anastomotic region, and he presented to our department. Further examination confirmed the diagnosis of anal SCC. Multimodalitytherapywas performed; however, the patient died 9 months after the first presentation to our hospital. UC has a high incidence of juvenile onset and is associated with increased risk for developing cancer; therefore, considering this case, we want to emphasize on the importance of long- term surveillance. PMID- 29394725 TI - [A Case of Non-Functioning Pancreatic Neuroendocrine Tumor Accompanied by Stenosis of the Main Pancreatic Duct]. AB - We experienced a rare case of pancreatic neuroendocrine tumor(pNET)in which stenosis of the main pancreatic duct occurred despite the tumor diameter being less than 1 cm; therefore, here, we report this case with some literature review.A 41-year-old woman showed dilation of the main pancreatic duct on an abdominal ultrasound as part of a health examination, and she visited our department for a more detailed examination.Enhanced CT scan showed a 7mm subtle enhancing mass in the head of the pancreas and the upstream main pancreatic duct was dilated up to 7 mm.ERCP and MRCP images also showed a dilated main pancreas duct.We suspected that her tumor was a pNET.We decided not to perform surgery immediately. After 6 months of follow-up, the tumor size increased to 10 mm; therefore, we performed subtotal stomach-preserving pancreaticoduodenectomy considering the possibility of pancreatic cancer.Histopathological findings showed that the pancreatic tumor had the property of a neuroendocrine tumor and the proliferated fibrous stroma around it caused the pancreas duct stenosis. PMID- 29394726 TI - [Breast Cancer Occurring in the Axillary Area - A Case Report]. AB - A 50-year-old woman aware a lump in the right axillary area 5 years ago.She noticed that the lump gradually became bigger, accompanied by redness and gathering of the skin; therefore, she consulted a dermatologist.On receiving the result of skin biopsy, she was referred for a suspected metastatic lesion from breast cancer.The mass was 20mm in diameter, was palpable in the right axillary area, and accompanied by redness of the skin.Ultrasonography revealed 2 irregular shaped masses in the right axillary area.An FDG/PET study showed some abnormal uptake in the right axillary area, but there were no other primary lesions in any other organs.We performed tumorectomy, and the axillary tumors was histopathologically diagnosed as invasive ductal carcinoma.This case was comprehensively presumed to be accessory breast cancer.In the case of malignant tumor in the axillary area, differential diagnoses are axillary lymph node metastasis of latent breast cancer, ectopic breast cancer, accessory breast cancer, and malignant tumors of skin and its appendages.We presented here a case of carcinoma that was estimated as accessory breast cancer considering clinical, radiological and pathological findings in an integrating manner. PMID- 29394727 TI - [A Case Report of Inguinal Malignant Lymphoma after Surgery for Hepatocellular Carcinoma]. AB - An 81-year-old woman was followed up for hepatitis C from 1994. Sheh ad a previous history of hypertension and appendicitis. In October 2014, the patient underwent subsegmentectomy(S8)and cholecystectomy for hepatocellular carcinoma (HCC)(T2N0M0, Stage II ). From December 2015, the patient had taken ledipasvir sofosbuvir orally for hepatitis C virus (HCV). In January 2016, we confirmed HCV RNA shade transformation. In September 2016, enhanced CT showed a mass in theright lower quadrant of her abdomen. Shehad a hard 3 cm mass in thesameplaceon physical exam. PET-CT showed no significant abnormality except for the mass in the right lower quadrant of her abdomen. Therefore, we identified the differential diagnosis as a lymph node metastasis of HCC, an abdominal wall primary tumor, or a malignant lymphoma. We resected theinguinal malignant lymphoma to confirm thediagnosis. Examination of tissuefrom theinguinal malignant lymphoma indicated diffuselargeB -cell lymphoma. We report an interesting case of an inguinal malignant lymphoma in a patient with chronic HCV who had experienced hepatectomy. PMID- 29394728 TI - [Long-Term Survivor of a Barrett's Esophageal Adenocarcinoma, Who Underwent Three Times Surgical Resection and MultidisciplinaryTherapyfor Lymph Node Recurrences - Report of a Case]. AB - We report a case of a 42-year-old man who underwent 3 times surgical resection for lymph nodes recurrence and multidisciplinary therapy for Stage IV b Barrett's esophageal adenocarcinoma, and was well 6 years and 3 months after the first resection. The prognosis of the recurrence cases after radical recection of the esophageal cancer is extremely poor. Long-term prognosis may be obtained in few patients, but the cases are squamous cell carcinoma in most of the reported cases. The number of Barrett's esophageal adenocarcinoma patients is increasing, but it is not many. There is little reports, and there is no fixed treatment policy. PMID- 29394729 TI - [A Case of Recurrent Jejunal Stenosis after Total Gastrectomy Treated with Self Expandable Metallic Stent]. AB - Case is a 66-year-old male. He was inserted covered self expandable metallic stent(SEMS)for jejunal stenosis due to gastric cancer recurrence. Migration was occurred after 4 days from stent replacement. We had removed SEMS by endoscopy, and re-inserted non-covered SEMS. Two months later, stent stenosis was occurred by tumor ingrowth. We tried to insert another stent in the stenotic stent. The patient was able to maintain oral intake without complication for 3 months. SEMS placement would improve a quality of life for selected patients with recurrent jejunal stenosis. PMID- 29394730 TI - [Clinical Outcome of the Patients with Anal Squamous Cell Carcinoma]. AB - We studied 14 patients with anal squamous cell carcinoma(ASCC)who were treated in our hospital between 1994 and 2016. As initial therapies, surgeries were performed in 5 patients. Of these, disease recurrence appeared in 4 patients, and 3 patients died within 1 year after operation. Other 9 patients were treated with chemoradiotherapy. As a result, 9 of 6 patients were considered as complete response(CR), and 4 patients are still alive without recurrence. Although other 2 patients were recurred, recurrent lesions were removed and then, they are still alive. Of 3 patients who were considered as partial response (PR), 1 patient who was treated with local excision is still alive without recurrence, however, 2 patients were died for distant metastases. Chemoradiotherapy is considered to be effective and expected to cure without surgery, however, a careful surveillance should be needed for distant metastases. PMID- 29394731 TI - [A Case of Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis Treated Successfully with Multidisciplinary Therapy Including Preoperative Stereotactic Body Radiotherapy(SBRT)]. AB - A 61-year-old man untreated with hepatitis C virus presented to our hospital.He was diagnosed advanced hepatocellular carcinoma(HCC)with portal vein tumor thrombosis(PVTT).The hazy tumor was located in the left lobe, and the tumor thrombus extended into the left portal vein.The patient received stereotactic body radiotherapy(SBRT, 48 Gy/4 Fr)for PVTT. The extended left lobectomy with thrombectomy was performed 12 days after SBRT.Resected specimen was diagnosed histopathologically as a poorly differentiated HCC, vp1, and no viable tumor cells in the tumor thrombosis.The patient's postoperative course was uneventful, and hepatic arterial infusion chemotherapy was started 1 month after the operation.He remains free of recurrence 5 years after the hepatectomy.Multidisciplinary therapy including preoperative SBRT was feasible and might be a treatment option for HCC with PVTT. PMID- 29394732 TI - [A Case of Unresectable Advanced Gastric Cancer Treated with Palliative Radiation Therapy for Massive Bleeding]. AB - The patient was a 77-year-old man. He was diagnosed with Stage IV gastric cancer with pancreatic invasion and pyloric stenosis. After gastrojejunostomy, S-1 monotherapy was started. Melena and fatigue appeared 2 months after chemotherapy, and Grade 3 anemia was confirmed. Palliative radiotherapy of 30 Gy in 10 Fr was administered to control bleeding from the lesion. The progression of anemia stopped and outpatient chemotherapy became possible. Palliative radiotherapy for persistent bleeding from unresectable advanced gastric cancer is considered an effective treatment option to control bleeding. PMID- 29394733 TI - [Surgical Treatment for Extremely Elderly Patients over 90 Years of Age with Stage IV Colorectal Cancer - A Report of Four Cases]. AB - We report 4 cases ofStage IV colorectal cancer patients over 90 years ofage who received surgical treatment. All of 4 cases were right-sided advanced colon cancer(1 case had also recto-sigmoid advanced cancer)and were received emergency operation. Two cases received resection ofprimary tumors and anastomosis, the other 2 cases received only ileostomy or colostomy. Three cases were able to be discharged from hospital successfully, but unfortunately, we lost one case because of cerebrovascular complication after surgery. We could provide palliative care facilities or home care services for survived three cases after spending certain time with their families peacefully. We treated them successfully with a collaborative medical team including experienced staffs for oral care, skin care, rehabilitation, mental care and social workers and others. Regarding to surgical treatment ofStage IV colorectal cancer patient, especially for extremely elderly patients over 90 years of age, we should consider not only perioperative treatment but also post- discharge comprehensive and palliative care. PMID- 29394734 TI - [A Case Report of Neuroendocrine Carcinoma of the Esophagus Treated with Multidisciplinary Therapy]. AB - A 72-year-old man was referred to our department because of esophageal tumor. Immunohistochemical findings were CD56-positive, synaptophysin-positive, chromogranin A-positive, Ki-67(labeling index)>=90%. The diagnosis was esophageal neuroendocrine carcinoma, categorized as cT4b(106recR-main bronchus), cN1(106recR), cM0, cStage III C. We had initiated irinotecan plus cisplatin(IP)as neoadjuvant chemotherapy(NAC). Biopsy specimens of primary lesion after 1 course chemotherapy showed a change to squamous cell carcinoma(SCC). The target lesion exhibited partial response(PR)after 2 courses of chemotherapy, and the primary lesion was reduced, but was still present. We performed subtotal esophagectomy and subtotal stomach reconstruction with lymphadenectomy(R0, Cur A). The histopathological findings showed the primary lesion was SCC, metastatic lymph nodes(106recR)was NEC. The final diagnosis was SCC plus NEC, categorized as CT pT1a (MM), pN1(106recR), M0, fStage II B. After that, we selected treatment regimen considering tissue type, and performed surgery and chemotherapy for 2 times of recurrences. At a follow-up examination 1 year and 2 months after the start of first chemotherapy, the patient is alive without recurrence. Esophageal neuroendocrine carcinoma is relatively rare and the prognosis is poor, but there is as yet no standard therapy. We experienced a case of neuroendocrine carcinoma of the esophagus treated with multidisciplinary therapy. PMID- 29394735 TI - [Two Cases of HER2-Positive Gastric Cancer with Multiple Liver Metastases Leading to Conversion Therapy with Chemotherapy]. AB - Case 1: A 69-year-old man underwent chemotherapy with capecitabine plus cisplatin plus trastuzumab to treat advanced gastric cancer that was diagnosed as cStage IV adenocarcinoma(T3N2M1[P0, CYX, H1]). After 12 courses, liver metastases were absent on computed tomography images. The patient underwent total gastrectomy with D2 lymphadenectomy. It has been 22 months since the patient had gastrectomy without recurrence of the cancer. Case 2: A 70-year-old man underwent chemotherapy with capecitabine plus cisplatin plus trastuzumab for treatment of advanced gastric cancer that was diagnosed as cStage IV adenocarcinoma(T4aN1M1[P0, CY0, H1]). After 12 courses, regrowth of multiple liver metastases led to a treatment with weekly paclitaxel plus trastuzumab as a second-line chemotherapy. After 9 courses of second-line chemotherapy, multiple liver metastases were absent in computed tomography images. The patient underwent total gastrectomy with D2 lymphadenectomy. A small white nodule on the surface of S2 and S3 of the liver led to the patient receiving a partial liver resection. The pathological finding of the resected liver specimen was a metastasis of an adenocarcinoma. During continuous chemotherapy with weekly paclitaxel plus trastuzumab after gastrectomy, multiple liver metastases were revealed. The patient died 19 months after gastrectomy. PMID- 29394736 TI - [Surgical Resection of Peritoneal Recurrence of Hepatocellular Carcinoma with Endoscopic Fluorescence Imaging System]. AB - A 66-year-old man presented with recurrences in the peritoneum 3 years after heavy particle beam therapy with hepatocellular carcinoma(HCC)and underwent laparoscopic surgery.Five months after surgery, a new peritoneal dissemination found in the vicinity of the colon hepatic flexure area by CT examination, and laparoscopic resection was planned again.Indocyanine green(ICG)0.5 mg/kg was administered on the day before surgery.ICG imaging by the PINPOINT(r)system revealed 2 small ICG accumulation sites in the diaphragm, as well as the main lesion, and each lesion was excised laparoscopically.All lesions were diagnosed as peritoneal dissemination of HCC, and the postoperative course was uneventful.Although new dissemination nodules were appeared 6 months after surgery, he underwent laparoscopic surgery again and survives.In PINPOINT fluorescence mode, high-definition white-light image and fluorescence image was combined, and it was easy to determine the cut line but also to visualize the small lesion difficult to identify in the visible light mode.It was suggested that the PINPOINT(r)system might be useful in cases of HCC peritoneal dissemination. PMID- 29394737 TI - [Evaluation of the Occurrence of Surgical Site Infection(SSI)after Hepatectomy in Elderly Patients with Hepatocellular Carcinoma(HCC)]. AB - The aim of this study was to evaluate the rate of surgical site infection(SSI)after hepatectomy in elderly patients with hepatocellular carcinoma(HCC). From June 2010 through December 2016, 276 cases of hepatectomy for HCC were performed in our hospital, and 39 cases included patients aged>80 years. The rate of SSI in the elderly group compared to the non-elderly group was 15.38%(6/39 cases)vs 7.73%(p=0.0855). The Child-Pugh classification(A/B/C)in the SSI group (n=6)vs in the non-SSI group(n=33)was 6/0/0 vs 32/1/0(p=0.5605), the liver damage classification(A/B/C)was 4/ 2/0 vs 25/8/0(p=0.6467), BMI was 23.3 kg/m / 2 vs 22.8 kg/m2(p=0.6544), PNI was 43.1 vs 46.2(p=0.3804), the operation time was 348.5 minutes vs 315.1 minutes(p=0.4478), blood loss was a small amount vs 401.5mL(p=0.0143), and the hospital stay after the operation was 27.5 days vs 10.0 days(p=0.0401), respectively. Hepatectomy for elderly patients was safe and feasible, and the only significant risk factor for SSI in elderly HCC patients was intraoperative blood loss. PMID- 29394738 TI - [Long-Term Survivors after Resection for Primary Pancreatic Carcinoma Stage IV]. AB - We discuss the prognosis of cases of Stage IV pancreatic carcinoma with distant metastases(7th Edition of General Rules for the Study of Pancreatic Cancer, Japan Pancreas Society)for which any treatment was performed at our hospital. Fiftythree patients were radiographically or pathologically diagnosed as having Stage IV pancreatic carcinoma with definite prognosis, and received treatments, includingsurg ery or chemotherapy, at our department. Twenty-two cases showed more metastases, and celiac artery or superior mesenteric artery invasion was suspected in 28 cases. The 5-year survival rate of all 53 cases was 3.8%, and the median survival time(MST)was 6.2 months. The MST in the palliative surgery cases was 6.7 months, and that in the cases given best supportive care(BSC)was only 1.9 months. There were no 2-year survivors in the group given chemotherapy without any other treatments and in the group given BSC alone, while the longest survival time and MST were 66.9 and 31.3 months(p<0.001), respectively, in the 10 patients treated by primary tumor resection. There was only 1 patient who showed relapse free survival. Primary site resection and chemotherapy over 4 cycles was revealed as an independent prognostic factor by multivariable analysis. Patients with Stage IV pancreatic carcinoma have a poor prognosis. However, the possibility of achievingimproved prognosis was noted with combined-modality therapy, including aggressive resection in limited cases showinga good response to chemotherapy or cases in whom preoperative metastasis assessment was difficult. PMID- 29394739 TI - [Tumor Displacement Resulting from Core Needle Biopsy of Breast Cancer - A Case Report]. AB - Tumor cell displacement is occasionally observed in surgical specimens after core needle biopsy. We report a case involving a 58-year-old woman in whom a microlobulated mass was detected on mammography, after which she underwent an ultrasonography- guided core needle biopsy. Thirty-six days later, a new low echoic lesion was detected on ultrasonography, located from the original mass to the subcutaneous insertion site of the needle biopsy. Fifty days after the biopsy, breast-conserving surgery was performed. Histopathology showed a main tumor containing 2 components, namely invasive carcinoma of no special type, which showed tubule and gland formation, and invasive papillary carcinoma(WHO Classification). The invasive carcinoma with tubule formation was also observed in the adjacent collagen fibers, suggesting tumor displacement in the needle tracks. It has been suggested that malignant cells displaced by core needle biopsy do not survive. However, based on the present case, we recommend ascertaining the absence of extensive tumor displacement using ultrasonography unless all needle tracks are included in the planned resection area. PMID- 29394740 TI - [A Case of Esophago-Gastric Junctional Carcinoma with Intramural Invasion and Cervical Lymph Node Metastasis]. AB - The patient was a 66-year-old man who was diagnosed with a type 3 lesion in the esophago-gastric junction and a type 1 lesion in the upper esophagus. Both the lesions were diagnosed as adenocarcinoma. Chest and abdominal computed tomography examinations pointed out No. 106recL lymph node metastasis. He was diagnosed with Stage III esophago-gastric cancer( T2N3M0)and treated by a laparoscopic subtotal esophagectomy with 2-field lymph node dissection. The histological diagnosis was type 3 adenocarcinoma in the esophago-gastric junction with intramural metastasis and massive lymph node metastasis(No. 1, No. 2, No. 101L, No. 106recL). A vertical connection of venous invasion in the submucosal layer was also observed from the primary lesion to the cervical esophagus via intramural invasion. Treatment based on esophageal cancer is necessary in advanced esophago-gastric cancers with intramural metastasis or massive venous invasion. PMID- 29394741 TI - [A Case of Gastric Remnant Cancer after Proximal Gastrectomy with Jejunum Pouch Interposing Reconstruction]. AB - A 83-year-old man was diagnosed an earlygastric remnant cancer on the site of jejuno-gastrostomyafter proximal gastrectomywith jejunum interposing reconstruction 23 years ago. A total gastrectomywas performed due to the difficultyof endoscopic submucosal resection. The surgical operation took 200 minutes and the blood loss was 180 mL. Histologically, tumor size was 28*22mm invading to submucosal layer with a lymph node metastasis. To reduce the risk of surgical operation for gastric remnant cancer of aged patients, a simple reconstruction method is important for proximal gastrectomy, like a esophagogastrostomyplacing a gastric tube in the mediastinum. PMID- 29394742 TI - [A Case of Duodenal Cancer with Familial Adenomatous Polyposis]. AB - A 34-year-old man was diagnosed with familial adenomatous polyposis(FAP)in September 2011, and he underwent endoscopic mucosal resection(EMR)due to multiple polyps in the duodenum and small intestine. Three months later, duodenal cancer was found, and he underwent a subsequent EMR. The pathological findings showed residual cancer cells in the lateral margin; therefore, EMR was performed again. Total colectomy and partial resection of the small intestine was performed in December 2012. Esophagogastroduodenoscopy(EGD)was then performed every 3-6 months, and EMR was performed 4 times. We followed up the patient annually, starting 2014. In January 2016, recurrence of the duodenal cancer was found; therefore, he underwent a pancreatoduodenectomy. The pathological diagnosis was adenocarcinoma, tub2> tub1, pT1a, N0, M0, fStage I A. There were many adenomas ranging from low-grade to high-grade in the duodenal mucosa. The patient remains well without any evidence of cancer recurrence more than 18 months after the last operation. When treating patients with duodenal adenoma complicated by FAP, regardless of age, strict follow-up is important. PMID- 29394743 TI - [A Case of Duodenum Neuroendocrine Tumor with Multiple Liver Metastasis Treated with Multimodal Therapy]. AB - The patient is a 65-year-old woman with anemia. The multiple liver tumors detected by ultrasonography, it was diagnosed as neuroendocrine tumor(NET), G2 by biopsy. There was an ulcer at the bulb of the duodenum, so we diagnosed liver metastasis of duodenum NET. Because the liver tumors spreaded to both right and left lobes, we carrying out a transcatheter arterial embolization(TAE)twice to liver metastasis, and chemotherapy by octreotide was performed. 20 months after the beginning of treatment, a 4 cm tumor was remained in the left lobe but others were not detected by computed tomography, so we performed cytoreductive surgery. Duodenum bulb resection and left hepatectomy was performed and the specimens were NET, G2 in the pathological findings. We detected a lot of tumors less than 1 cm in the right lobe during the operation, so TAE was carried out for the right lobe after surgery. The disease showed no progression for 28 months after the first admission(post operation5 months). PMID- 29394744 TI - [Single Incision Laparoscopic Ileocecal Resection for Small Intestinal Malignant Lymphoma - A Case Report]. AB - A 76-year-old man with the chiefcomplaint ofmelena visited our hospital. A mass was palpable in the right lower abdomen. We diagnosed the illness as small intestinal malignant lymphoma in the terminal ileum and performed a single incision laparoscopic ileocecal resection "TANKO-ICR" with D3 lymph node dissection with the idea ofobtaining a wide visualization and surgical field. The Aesculap(r)internal organ retractor(B BRAUN)is very useful in such cases. We grasped the pedicle of the ileocecal artery using the retractor and pulled out the nylon line connected to the retractor by using ENDO CLOSETM (COVIDIEN)to extraabdomen for drawing the pedicle. Single incision laparoscopic surgery can be performed with only an umbilical wound; therefore, it is minimally invasive and has a superior aesthetic outcome. Small intestinal malignant lymphoma is a relatively rare malignant tumor ofthe digestive organs. We report this case demonstrating that single incision laparoscopic surgery was possible and provide a review ofthe relevant literature. PMID- 29394745 TI - [A Case of Effective Neoadjuvant Chemotherapy for Transverse Colon Cancer with Extensive Abdominal Wall Invasion]. AB - A 68-year-old man with abdominal mass and anorexia was diagnosed with transvers colon cancer invading the abdominal wall. Considering the difficulty of curative resection, we first performed ileostomy. After surgery, the patient received mFOL FOX6 with bevacizumab as neoadjuvant chemotherapy. After 10 course of the regimen, computed tomography revealed shrinkage of the lesion, with the efficacy evaluated as a partial response. The patient underwent right hemicolectomy and partial resection of the abdominal wall. The pathological findings was ypT3(SS), ypN3, ly0, v1, ypPM0, ypDM0, ypRM0, ypStage III b. On histopathological examination, the efficacy of the chemotherapy was evaluated as Grade 1b. The patient received adjuvant chemotherapy with mFOLFOX6 and remains well without any evidence of recurrence more than 7 months after surgery. PMID- 29394746 TI - [Complete Response Achieved with Oral Anticancer Monotherapy for Unresectable Lymph Node Metastasis after Cecal Cancer Surgery - A Case Report]. AB - We herein report an interesting case in which a complete response was achieved with oral anticancer monotherapy for unresectable lymph node metastasis after surgery for cecal cancer. A 78-year-old woman was referred to our hospital to undergo a detailed examination for anemia. The examination led to a diagnosis of cecal cancer. She underwent open right hemicolectomy combined with adjacent abdominal wall resection and reconstruction of abdominal wall defects the next month. During follow-up without adjuvant therapy at her request, right iliac lymph node metastasis was detected 5 months later. A lymphadenectomy by laparotomy was attempted 6 months later but ended as only an exploratory laparotomy because the metastatic lymph node was difficult to detach from the vascular wall. Starting the next month, oral anticancer monothera- py(TS-1, 80mg/day for 2weeks followed by 1week of rest)was started at the patient's request. Abdominal ultrasonography performed in March 2011 revealed no evidence of lymphadenopathy, and subsequent imaging tests also confirmed the absence of lymphadenopathy. The anticancer monotherapy was discontinued after 4 years of medication. The patient remains alive, after 3 years and 5 months of medication to date, without recurrence. PMID- 29394747 TI - [Long-Term Survival of a Patient with Mediastinal Lymph Node Metastasis Treated with Chemo-Radiotherapy after Surgery for Cecal Cancer]. AB - In June 1997, the patient underwent an operation for cecal colon cancer pStage II .I n May 1999, a liver metastasis at S6 was detected and the patient received a partial liver resection.In April 2004, a liver metastasis in S4 was detected and another partial liver resection was performed.In November 2008, he complained of hemoptysis and cough.The chest CT examination showed lymph node metastases in the mediastinum that invaded the left main bronchus.We performed chemo-radiotherapy for local control from January 2009. Because the lymph nodes were reduced remarkably and clinical complaints disappeared, we administrated a mFOLFOX6 regimen from June.We recognized the effect of treatment to be a complete response.In February 2014, we detected a lymph nodes recurrence around a right pulmonary artery.We performed chemo-radiotherapy again because the patient declined surgery.However, lymph node metastases did not completely respond.We then performed chemotherapy 30 times using a FOLFIRI plus panitumumab regimen.On PET-CT, the recurrent lesion did not show a hot spot.We experienced a case that responded to chemo-radiotherapy for long-term control of lymph node recurrence. PMID- 29394748 TI - [A Case of Laparoscopic Low Anterior Dissection for Rectal Carcinoma with Left Sided Inferior Vena Cava]. AB - A 43-year old-male was admitted to the hospital for the treatment of rectal carcinoma. Preoperative abdominal computed tomography(CT)revealed a left inferior vena cava. There is no report of the patient with left inferior vena cava which focused on an anatomical feature of autonomic nerves. We report a case of rectal cancer patient with left inferior vena cava who underwent autonomic nerve-sparing laparoscopic low anterior resection, and review the relevant literature here. PMID- 29394749 TI - [A Case of Colorectal Cancer with Peritoneal Dissemination and Liver Metastasis That Responded to Comprehensive Treatment by Chemotherapy and CRS plus HIPEC]. AB - We report a case of colorectal cancer with peritoneal dissemination and liver metastasis that achieved R0 resection by preoperative chemotherapy and CRS plus HIPEC. A 33-year-old man presented with a complaint of abdominal bloating. After further examination, he was diagnosed with transverse colon cancer with peritoneal dissemination and liver metastasis. After 9 courses of preoperative XELOX plus cetuximab and 4 courses of preoperative XELIRI plus bevacizumab, he underwent transverse colon resection, peritoneal resection, and HIPEC(MMC 20mg/4,000mL physiological saline, 40mins). There was little histological evidence of peritoneal dissemination around the region of the primary tumor. Moreover, no tumor cells were found in other peritoneal disseminations or in the liver metastasis. As a result, he was able to undergo curative resection. Colorectal cancer with peritoneal dissemination still has a poor prognosis, but combination therapy with chemotherapy and CRS plus HIPEC is expected to improve prognosis. PMID- 29394750 TI - [Examination of Cases of Hepatectomy for Metastatic Colorectal Cancer]. AB - OBJECTIVES: Resection of liver metastasis from colorectal cancer is known to improve prognosis; therefore, surgical treatment is recommended for resectable metastases in the Japanese Society for Cancer of the Colon and Rectum Guidelines for the Treatment of Colorectal Cancer. In this study, we investigated factors that affect the prognosis of resection of such metastatic liver tumors. RESULTS: Thirty-three cases of liver resection performed during the period from 1998 to 2017 were investigated. The 5-year overall survival rate after liver resection was 47.3%, and the 5-year recurrence-free survival rate after liver resection was 29.9%. Univariate analysis identified CA19-9(p=0.02)and operative procedure(p=0.0046)as prognostic factors, while multivariate analysis revealed operative procedure(p=0.03)to be a prognostic factor. When prognosis was examined in terms of operative procedure(ie, lobectomy, segmental resection, or partial resection), the prognosis of patients undergoing lobectomy was significantly poorer compared to those undergoing segmental resection(p=0.0092, RR=28.94)and partial resection(p=0.0092, RR=25.37). CONCLUSION: In this study, operative procedure was identified as a poor prognostic factor. The prognosis of liver metastasis requiring lobectomy is considered to be poor. Further accumulation of cases is needed to investigate the effects of other factors in the choice of operative procedure. PMID- 29394751 TI - [A Case of Curatively Resected Ascending Colon Cancer with Ovarian Metastasis and Peritoneal Dissemination after Chemotherapy]. AB - A52 -year-old woman was diagnosed with ascending colon cancer with ovarian metastasis and peritoneal dissemination. Since the patient did not have symptoms with intestinal obstruction, mFOLFOX6 plus bevacizumab(Bmab)was performed for 12 cycles. After chemotherapy, the tumors of ascending colon and ovary were significantly shrunken and novel distant metastasis was not observed by CT scans. Therefore, the tumors were considered to be resectable and curative resection was performed. In the surgical findings, the peritoneal disseminations were localized, and right colectomy, bilateral oophorectomy and extirpation of the peritoneal disseminations were performed. R0 resection was pathologically achieved and adjuvant chemotherapy with UFT/UZEL was administrated for 6 months. The patient is alive without recurrence for 1 year. Since right sided colon cancer is less likely to have obstruction, upfront chemotherapy can be a strategy for locally advanced right sided colon cancer with distant metastasis. PMID- 29394752 TI - [Curative Resection for Metastatic Lower Rectal Tumor from Ovarian Cancer - Report of a Case]. AB - We here report the case of a 56-year-old female patient who underwent curative resection for right ovarian cancer with intraperitoneal dissemination and liver metastases. She received following adjuvant chemotherapy, and had been visited hospital for regular follow-up since then. One and half a year after surgery, blood examination showed increasing value of CA125. Contrast-enhanced CT scan revealed a tumor whose long diameter was 5 cm at front side of lower rectum. Following MRI and PET-CT examinations indicated the pelvic tumor as recurrence of ovarian cancer, so that laparotomy was carried out. As the tumor was palped through Douglas cavum, we performed low-anterior rectal resection for en bloc tumor extirpation. Tumor cells mainly developed at peri-rectal wall and proper muscle by HE staining of pathological findings, and ER(positive), vimentin(positive), CD56(positive), synaptophysin(negative)and chromogranin A(negative)by immunostaining indicated the tumor as metastasis of ovarian cancer. Though rectal metastasis from ovarian cancer is basically rare, it might be necessary to rule out possibility of metastatic colon tumor from ovarian cancer when treating patient with rectal tumor who had underwent surgery for ovarian cancer before. PMID- 29394753 TI - [Multidisciplinary Therapy for Hepatocellular Carcinoma with Peritoneal Dissemination]. AB - We report a case of bilobar multiple hepatocellular carcinoma(HCC)with peritoneal dissemination successfullytreated by dual treatment with reductive surgeryplus percutaneous isolated hepatic perfusion(PIHP). A 73-year-old man had sudden abdominal pain and was diagnosed bilobar multiple HCC through some examinations. The abdominal CT scan demonstrated onlya peritoneal dissemination under the liver. We performed partial hepatectomyof the lateral segment and the Spiegel lobe, and resected a peritoneal dissemination. Subsequently, we underwent PIHP twice. The tumor marker was normalized, and CT images demonstrated complete response according to the RECIST. Dual treatment is considered to be a unique therapeutic modalityfor severe advanced HCC. PMID- 29394754 TI - [A Case of Locally Advanced Thoracic Esophageal Cancer with Larynx Preservation and Curative Resection via Combined Modality Therapy]. AB - Prognosis of locally advanced esophageal cancer is poor. The greatest prognostic factor of locally advanced esophageal cancer is a local control. We experienced a case of T4 locally advanced thoracic esophageal cancer who was successfully resected without any combined resection after multimodality therapy. A male in 75 year-old. was diagnosed with type 3 locally advanced upper thoracic esophageal cancer whose metastatic right recurrent laryngeal lymph node invaded into the trachea. Definitive chemoradiation therapy(CRT)was performed, leading to a significant shrinkage of the main tumor, but T4 lesion remained. Next, adding DCF therapy(docetaxel, CDDP and 5-FU), a relief of T4 was finally obtained. Then, salvage surgery with subtotalesophagectomy and retrosternalesophagealreconstruction with gastric tube was performed, resulting in R0 resection without any combined resection. The postoperative course was uneventful, and the patient has been alive without recurrence for 1 year after surgery. In locally advanced cancer, focusing on T4 downstaging, it is significantly important in terms of safety, curativity and organ preservation to perform surgery after a sure sign of T4 relief by multimodality therapy. PMID- 29394755 TI - [Radical Resection of Huge Gastrointestinal Stromal Tumor of the Stomach Following Neoadjuvant Chemotherapy with lmatinib - ACase Report]. AB - The usefulness and safety of imatinibfor neoadjuvant chemotherapy for resectable gastrointestinal stromal tumor(GIST) has not been established. We reported a case of a huge GIST of the stomach that was safely resected following preoperative imatinibtherapy. A 69-year-old man was hospitalized with abdominal fullness which increased rapidly from a month ago. A CT scan showed a huge tumor containing solid and cystic component which was accompanied by an extra-wall nodule. The tumor was strongly suspected to be originated from the stomach and EUS-FNA revealed GIST. We diagnosed GIST of the stomach and initiated preoperative adjuvant chemotherapy with imatinib because there was a risk for the break of tumor capsule and composite resection of the other organs without prior chemotherapy. After the administration of imatinib4 00 mg/day for 6months, the solid component was decreased in size and its' activity by PET-CT had declined, but the size of the cystic component was not changed and the patient's complaint of fullness was not reduced. Then, after a week cessation of imatinib, we performed surgical removal of the tumor with partial gastrectomy without surgical complication during and after the operation. Imatinibwas resumed 2 weeks later postoperatively and 1 year and 8 months has passed since the operation without recurrence. Neoadjuvant chemotherapy with imatinibhas the potential to become an important therapeutic option for the treatment of huge GISTs. PMID- 29394756 TI - [A Case of Gastrointestinal Stromal Tumor of the Small Intestine Complicated by Hemorrhagic Shock Due to Gastrointestinal and Intraperitoneal Bleedings]. AB - A 44-years-old man presented to our hospital with bloody stool. CT of the abdomen revealed a 90mm mass adjacent to small intestine and high density ascites in lower abdomen. On the day of the admission, he lapsed into hemorrhagic shock caused by gastrointestinal bleedings. So emergency operation was performed. Operative findings showed a solid tumor of small intestine that were 95mm in diameter and a small amount of bloody ascites(100mL). Another tumor was also found in analis small intestine from primary lesion. Small bowel resections were performed for each lesion. Resected specimen showed the solid tumor, 95*70*50mm in size, in the small intestine. Histopathological findings showed outgrowth of spindle cells from the proper muscular layer to the subserosal layer. Immunohistochemical findings revealed positive staining for c-kit and CD34. c-kit positive GIST was thus diagnosed. Chemotherapy with imatinib was administered after surgery and the patient has been free from recurrent disease for 6 months after surgery. PMID- 29394757 TI - [Analysis of the Relationship between the Change of Drain Amylase Value and Postoperative Pancreatic Fistula after Pancreaticoduodenectomy]. AB - To diagnose postoperative pancreatic fistula(POPF)after pancreaticoduodenectomy(PD)during early post operative days, we evaluatedwhether a change in drain amylase value(DAV), WBC value, or CRP value predicted clinically significant POPF. One hundred thirty patients underwent substomach preserving PD(SSPPD)from 2005 to 2016 in our institution andwe examinedDAV, WBC, andCRP values at POD 1, 3, and 5. Seventy-five patients(57.7%)were equivalent to ISGPF grade A at POD 3.We analyzedthese 75 cases by following 5 factors(DAV at POD 3>1,500 U/L, DAV at POD 5>1,000 U/L,WBC value at POD 5<=9,000/mL, DAV of POD 5 decreased to 1/3 from DAV of POD 3, CRP value not improved>=50%from POD 3 to 5) andwere concernedwith the crisis of the grade B/C POPF at final diagnosis after POD 5. In conclusion, DAV of POD 5 decreased to 1/3 from DAV of POD 3, andthe CRP value having not improved(>=50%from POD 3 to 5)were significant risk factors for POPF grade B andC by Cox proportional hazard models. PMID- 29394758 TI - [Long-Term Survival of a Patient with Metastatic Liver and Para-Aortic Lymph Node Cancer from Colon Cancer Treated with Regorafenib]. AB - A 54-year-old man was presented at our hospital with weight loss.He diagnosed with colorectal cancer, multiple liver metastases and para-aortic lymph node metastasis.After undergoing colostomy, he was treated sequentially with mFOLFOX6 plus bevacizumab(Bmab), FOLFIRI plus Bmab or Pmab, according to the guideline.Since these chemotherapy resulted in progressive disease, regorafenib was administered as a salvage-line treatment.PET -CT showed only para-aortic lymph node swelling with high FDG uptake.Severe adverse effects were developed shortly after regorafenib treatment so he requireda reduction in dose.Three years after treatment with regorafenib, the response of the target lesion was stable disease according to the RECIST criteria.Tumor growth had been controlled for a long time. PMID- 29394759 TI - [A Case of Pathological Complete Response Following Neoadjuvant Chemotherapy with Gemcitabine plus Nab-Paclitaxel in Borderline Resectable Pancreatic Cancer]. AB - We report a resected case with a pathological complete response(pCR)after neoadjuvant chemotherapy for borderline resectable pancreatic cancer(BRPC). A 67 year-old woman who had been treated for type 2 diabetes mellitus in our hospital presented with an exacerbation of diabetes. An abdominal CT scan confirmed a hypovascular mass in the pancreas body consistent with BRPC. After 3 courses of chemotherapy with gemcitabine plus nab-paclitaxel(GnP), her elevated DUPAN-2 level normalized. A follow up CT scan revealed that the tumor had decreased in size, and no distant metastasis was detected. Distal pancreatectomy with en-bloc celiac axis resection was performed. Histopathological examination of the resected specimens showed no evidence of residual cancer cells(pCR). The patient remains disease-free 8 months after surgery. Neoadjuvant GnP chemotherapy may be useful for BRPC. PMID- 29394760 TI - [Recurrence of a Giant Retroperitoneal Leiomyosarcoma Six Years after the Initial Surgery]. AB - A 51-year-old man came to our department because of a large abdominal mass. CT, MRI, and sonography revealed a large tumor adjacent to the retroperitoneal area. A resection was performed, and histologically we confirmed the diagnosis as a leiomyosarcoma originating from the retroperitoneum. Six years after the initial surgery, the patient came to our outpatient department with a complaint of nausea. A relatively large tumor was seen on a CT scan that was causing obstruction of the duodenum. Another surgery was performed with the final diagnosis as a recurrence of the leiomyosarcoma. After 3 courses of adjuvant chemotherapy with eribulin, the patient presented with abdominal distension. CT revealed a very large tumor with massive invasion to the ileum and colon. This time, we considered the tumor unresectable, and administered chemotherapy with a combination of doxorubicin and ifosfamide. However, after 1 course, the patient's condition worsened and he died of the disease 3 months after the chemotherapy. PMID- 29394761 TI - [Clinical Outcome of Hepatectomy of Liver Metastasis of Duodenal Ampullary Cancer]. AB - We evaluated the clinical outcome and assessed the indication of hepatectomy for liver metastasis of duodenal ampullary cancer. We analyzed 42 cases of duodenal ampullary cancer and 4 patients who underwent hepatectomy for liver metastasis. Eleven(50%)of 22 cases with recurrence of duodenal ampullary cancer had liver metastasis. Four cases were solitary and 7 cases were multiple. Four patients underwent hepatectomy didn't had other organ metastasis. Three of 4 cases with solitary liver metastases and one of 7 cases with multiple metastasis underwent hepatectomy. One of 3 cases of solitary liver metastasis died of lung and bone metastases without liver recurrence 2 years and 8 months after hepatectomy. Other 2 cases are long surviving without recurrence 8 years and 8 months and 4 years and 9 months after hepatectomy respectively. One case of multiple liver metastases died of early liver recurrence 10 months after hepatectomy. The indication of hepatectomy for liver metastasis was restrictive. However the prognosis of patients with solitary liver metastasis was relatively favorable. Therefore hepatectomy could be indicated for solitary liver metastasis of duodenal ampullary cancer. PMID- 29394762 TI - [A Case of Anaplastic Carcinoma Spindle Cell Type of the Pancreas]. AB - Anaplastic carcinoma spindle cell type is an extremely rare disease and its prognosis is very poor. We herein report a case of anaplastic carcinoma spindle cell type of the pancreas. A 50-year-old man complaining of epigastralgia was found to have a pancreatic body-tail tumor by abdominal US and CT studies. Abdominal CT showed an irregular poorly-enhanced 33mm tumor containing a cystic component. ERCP revealed the main pancreatic duct was cut off at the tumor. Cytology of the pancreatic fluids did not indicate malignancy. A pancreatic tumor with a cystic component similar to pancreatic neoplasms containing cystic degeneration or a mass-forming pancreatitis concomitant with pancreatic pseudocyst was suspected. Therefore, we performed distal pancreatectomy. Histological findings showed the center of the tumor was severely necrotized and oval or spindle dysplastic cells proliferated around the peripheral area. According to the immunohistological staining pattern, the patient was diagnosed as having anaplastic carcinoma spindle cell type. He was administered oral S-1 for 6 months and is now recurrence-free, surviving for 15 months after pancreatectomy. Reports of long-term survival cases that also demonstrated R0 resection should be indicated in the treatment of anaplastic carcinoma spindle cell type despite the poor prognosis. PMID- 29394763 TI - [A Case of Mixed Hepatocellular and Primary Hepatic Neuroendocrine Carcinomas with Remnant Liver Recurrence and Rapid Exacerbation]. AB - The patient was a 77-year-old man with a 4.0 cm hepatictumor in hepaticsegment 4. Plain computed tomography(CT) showed the tumor with low density. On dynamicexamination, the tumor showed heterogeneous enhancement during the arterial phase. Magneticresonanc e imaging showed the tumor as a low intensity area in the hepatobiliary phase in hepatic segments 4, 6, and 8. A month later, CT showed an enlarged tumor in segment 4 measuring 7.0 cm. We diagnosed the tumor as primary liver cancer and suspected it to be hepatocellular carcinoma(HCC)preoperatively. We performed extended medial segmentectomy and partial hepatectomy of segment 6. The histopathological diagnosis was mixed HCC and primary hepatic neuroendocrine carcinoma(PHNEC). Three months after hepatectomy, the patient died of multiple intrahepatic recurrences. In most of the reported cases of mixed HCC and PHNEC, only the PHNEC component has been detected in the biopsy of the metastatic lesions. This fact might suggest that PHNEC has a higher proliferative activity and malignant potential than HCC. Standard treatment for mixed HCC and PHNEC is unclear; therefore, development of multidisciplinary treatment strategies combining surgical treatment and systemic chemotherapy is required. PMID- 29394764 TI - [The Treatment Outcomes of FOLFIRINOX for Unresectable and Recurrent Pancreatic Cancer]. AB - FOLFIRINOX is now considered to be a highly effective regimen for patients with metastatic pancreatic cancer. We administered FOLFIRINOX therapy in 18 patients between October 2014 and April 2017 as follows: 2-hour infusion of L-OHP at a dose of 85mg/m2, 2-hour infusion of LV at a dose of 200 mg/m2, infusion of CPT-11 for over 90 minutes at a dose of 150 mg/m2, followed by continuous infusion of 5 FU over 46 hours at a dose of 2,400mg/m2. The median age of the patients was 66.5 years. There were 15 patients with performance status(PS)0, and 3 with PS 1. Two patients were Stage III and 16 patients were Stage IV . More than half of the patients had over Grade 3 hematological or non-hematological toxicities. The most common adverse event was neutropenia. Two patients had Grade 5 adverse events: severe cholangitis occurred in the patient with a biliary stent and overwhelmingpost -splenectomy infection occurred in the patient who underwent distal pancreatectomy. The response rate was 11.1%, and the disease control rate was 77.8%. FOLFIRINOX was effective in the patients with unresectable and recurrent pancreatic cancer. However, it is necessary to examine the eligibility of the patients. PMID- 29394765 TI - [A Case of More Than Five-Year Survival of Carcinoma Associated with Anal Fistula Effectively Treated by Combined Modality Therapy]. AB - The patient was a 56-year-old man who presented with perianal pain and a perianal abscess. After admission, he underwent debridement and colostomy due to poor control of the perianal abscess. Following a biopsy of the resected specimens, he was diagnosed with adenocarcinoma in the anorectal fistula. CT and MRI revealed that the tumor had invaded into the internal obturator muscle. Therefore, preoperative chemoradiotherapy and chemotherapy were given for locally advanced cancer. Subsequent to tumor shrinkage, we performed an abdominoperineal resection. Histopathologically, no cancer cells were detected on the surgical margin, and the effect of the preoperative therapy was judged to be Grade 1b. There has been no indication of recurrence of cancer after 5 years. PMID- 29394766 TI - [Two Cases of Colorectal Cancer with SRC Amplification]. AB - Carcinoma with elevated SRC expression is associated with distant metastasis and drug resistance. We report 2 cases of SRC amplification observed after retrospective comprehensive genomic sequencing. Case 1 was a 62-year-old man who had RAS wild-type stage IV carcinoma of the sigmoid colon with multiple liver metastases in both lobes. He underwent low anterior resection and systemic chemotherapy was initiated to treat the unresectable multiple liver metastases. Case 2 was a 73-yearold man who had RAS wild-type stage IV carcinoma of the descending colon with metastasis in the lateral segment of the liver. He underwent left hemicolectomy and lateral segmentectomy. He subsequently underwent open radiofrequency ablation and systemic chemotherapy to treat a hepatic recurrence. Several previous studies have found that molecular targeted therapy with tyrosine kinase inhibitors is effective against colorectal cancer with elevated SRC expression. This suggests that the results of comprehensive genomic sequencing may support the implementation of new treatments. PMID- 29394767 TI - [A Case of Rapidly Advancing G-CSF Producing Pleomorphic Carcinoma of the Breast Appearing as an Inflammatory Breast Cancer]. AB - We report a rare case of pleomorphic carcinoma of the breast, suspected of being a granulocyte-colony stimulating factor (G-CSF)producing tumor, in a 75-year-old woman. She presented with a red and swollen breast, 3 weeks after undergoing core needle biopsy(CNB). Her leukocyte counts and C-reactive protein(CRP)levels were markedly high. At first, she was suspected to have an abscess and was initiated on a course of antibiotics. However, her condition rapidly deteriorated; therefore, she underwent an emergency mastectomy. Despite undergoing postoperative radiation therapy, 2 months after the operation, multiple metastatic foci were found in the lungs and liver, and she died of the disease 3 months after her first visit. After the operation, her leukocyte count had quickly returned to normal, but it increased as the disease progressed. These findings support the conclusion that this carcinoma was producing G-CSF. The final pathological diagnosis was G-CSF producing pleomorphic carcinoma of the breast. PMID- 29394768 TI - [A Case Report of Post-Radiochemotherapy Perineum Abscess Concurrent with Recurrence of Vaginal Cancer for Which Total Pelvic Exenteration Was Performed]. AB - We report a case of a woman who was suffering from post-radiochemotherapy perineum abscess concurrent with the recurrence of vaginal cancer for which total pelvic exenteration was performed. A 66-year-oldwoman presentedat our hospital with irregular genital bleeding in November 2014. A series of examinations showedthat she was suffering from vaginal cancer(cT2N0M0, cStage II ). A radiochemotherapy regimen(external irradiation 45 Gy/25 Fr, CDDP 40mg/m2, 5 course)was commencedin January 2015. In the meantime, MRI revealedsome therapeutic effect, but in October 2015, MRI indicated the enlargement of the primary tumor(PD). The chemotherapy regimen was alteredanda regimen of paclitaxel plus nedaplatin was commenced in November 2015 andw as continueduntil April 2016. MRI was performedin March 2016 to distinguish the therapeutic response between PR and CR. In May 2016, the patient complainedof an increasedfrequency of melena. Colonoscopy was performedto reveal Grade 3 radiation enteritis, andargon plasma coagulation was requiredto stop bleeding. In June 2016, MRI was performedandrevealedCR. In July 2016, however, the radiation enteritis led to rectovaginal fistula, for which we performed transverse colostomy. Thereafter, the necrotic tissue gradually expanded into the perineum area to involve the urethra. Recurrence of the cancer was suspected; therefore, we decided to perform total pelvic exenteration in December 2016. Pathological examination of the surgical specimen indicated the recurrence of the vaginal cancer. We report this rare case andd iscuss the usefulness of total pelvic exenteration for the recurrence of vaginal cancer. PMID- 29394769 TI - [A Case of Curatively Resected Ascending Colon Cancer after Long-Term Chemotherapy Found in Abdominal Trauma]. AB - A 46-year old man presented with lower right quadrant abdominal pain caused by abdominal trauma. Abscess drainage was performed after the diagnosis of retroperitoneal abscess in the ileocecal portion of the colon. Type 2 advanced cancer was found in the cecum and ascending colon. Surgery was performed after improvement of inflammation. Considering the difficulty of curative resection for retroperitoneal invasion, we first performed ileo-transverse colon anastomosis. After surgery, the patient received FOLFOX with panitumumab(Pmab)as neoadjuvant chemotherapy. After 6 courses of this regimen, contrast enhanced computed tomography revealed shrinkage of the tumor. We performed a second surgery but the tumor was unresectable because of retroperitoneal invasion. After 47 courses of chemotherapy(5-FU plus LV with Pmab), the tumor was stable and we observed no distant metastasis. A third surgery was performed, and we were able to perform ileocecal resection including the retroperitoneum. The pathological diagnosis was pT4b(SI), pN1, ly2, V2, pPM0, pDM0, R0, pStage III a. On histological examination, the efficacy of chemotherapy was evaluated as Grade 1a. The patient received adjuvant chemotherapy with capecitabine and remains healthy without any evidence of recurrence more than 10 months after surgery. PMID- 29394770 TI - [Surgical Therapy for Locally Recurrent Rectal Cancer]. AB - We examined 40 cases of locally recurrent rectal cancer surgically treated at our hospital. The sites of recurrence were the anastomosis site(16 cases), pelvic lymph nodes(10 cases), pelvis(10 cases), and perineum(5 cases). Intraoperative complications were confirmed in 5% and postoperative complications in 45% of cases. The R0 resection rate was 60.0%, and positive radial margins were confirmed in 35.0% of cases. Second recurrences were confirmed in 60.0% of cases. The 3-year overall survival rate was 68.7%, and the 3-year relapse-free survival rate was 20.3%. Surgery for locally recurrent rectal cancer was performed relatively safely; however, the R1 resection rate and recurrence rate after surgery were high. R0 resection significantly improved the overall survival rate, and it seems that a treatment strategy to raise R0 resection rate is necessary. PMID- 29394771 TI - [Twenty-Five Cases of Locally Advanced Rectal Cancer That Underwent Laparoscopic Surgery after Preoperative Chemotherapy]. AB - Several recent reports have described the administration of preoperative chemotherapy for locally advanced rectal cancer. In our hospital, preoperative chemotherapy based on oxaliplatin was administered for locally advanced rectal cancer with a tumor diameter of 5 cm or more and half semicircularity or more, and curative resection with laparoscopic surgery was performed after tumor shrinkage. We have experienced 25 cases that underwent preoperative chemotherapy for local advanced rectal cancer in our hospital from May 2012 to April 2016. No tumor increased in size during preoperative chemotherapy and there were no cases where R0 resection was impossible. In addition, no distant metastasis during chemotherapy was observed. Postoperative complications were observed in 3 cases(12%), and anastomotic leakage was observed in 1 case (4%), but conservative treatment was possible. Multidisciplinary treatment of preoperative chemotherapy and surgery should be considered as a therapeutic strategy for locally advanced rectal cancer, mainly in medical institutions without radiation treatment facilities. PMID- 29394772 TI - [A Case of Alpha-Fetoprotein-Producing Gastric Cancer with Synchronous Liver Metastasis Achieving Recurrence-Free Survival for Five Years by Gastrectomy, Hepatectomy, and Adjuvant Chemotherapy]. AB - a-fetoprotein(AFP)-producing gastric cancer is relatively rare and tends to show a poor prognosis because of hepatic and lymph node metastasis. We experienced a case of AFP-producing gastric cancer with synchronous liver metastasis wherein the patient survived for 5 years without recurrence after undergoing surgery and adjuvant chemotherapy. A 39-year-old woman was admitted to our hospital complaining of tarry stool. Upper gastrointestinal endoscopy revealed a 40mm type 2 tumor in the greater curvature of the lower gastric body, and abdominal CT indicated a 50mm liver metastasis at the S2 segment. The AFP serum level had risen to 71,000 ng/mL. We performed distal gastrectomy and hepatic left lateral segmentectomy. The primary gastric tumor and the hepatic metastasis were both positive for AFP by immunohistochemistry. After conducting 3 courses of S 1/CDDP(SP)therapy as adjuvant chemotherapy, the serum level of AFP had decreased to normal levels. Be- cause the level had risen to 116 ng/mL after a change to S 1 oral administration alone, we decided to re-start SP therapy and carried out 16 courses through the third postoperative year. The patient is still alive without recurrence 5 years after surgery. PMID- 29394773 TI - [Two Cases of Stage IV Pancreatic Cancer Has Gained Relatively Long Free Survival in Multimodality Therapy]. AB - We experienced 2 cases in which Stage IV pancreatic cancer(General rules for the study of pancreatic cancer, The 6th edition, Japanese Pancreas Society)underwent chemotherapy and radiotherapy after surgical operation and had relatively long term relapse-free survival. Local control by adding radiation therapy to surgical resection and suppressing the distant metastases in adjuvant chemotherapy may improve the prognosis. PMID- 29394774 TI - [A Case of Unresectable Gastric Cancer with Multiple Metastases Responding to Chemotherapy]. AB - A 73-year-old man presented to a clinic complaining of upper abdominal pain with nausea and diarrhea. The patient was subsequently diagnosed with progressive gastric cancer: cT4a(SE), N3M1(H1P1), Stage IV . For first-line therapy, SP: S 1(120 mg, 3 weeks)and CDDP(90 mg, 8 days iv) were selected. Though the patient had Grade 3 thrombocytopenia and renal dysfunction, 13 courses were performed over 1 year 6 months. The primary lesion in the stomach showed complete response, while the metastatic foci in the liver reduced in size. Because of renal dysfunction and thrombocytopenia, 19 courses of SOX: S-1(80 mg, 2 weeks)and oxaliplatin(100 mg, 3 weeks)were administered for 1 year. Thereafter, S-1(80 mg, 4 weeks) was continued for 6 months. Appropriate administration of chemotherapy led to complete radiographic resolution of the gastric tumor, with survival currently approaching 3 years 6 months. PMID- 29394775 TI - [Radical Thoracoscopic Esophagectomy for Elderly Patients with Advanced Esophageal Cancer]. AB - We report a case of an elderly patient with advanced esophageal cancer who underwent multidisciplinary treatment. An 86-year-old male consulted our hospital with complaints of pharynx discomfort and difficulty in swallowing. He was preoperatively diagnosed with esophageal cancer, T3N2M0, Stage III . We performed 2 courses of cisplatin plus 5-FU therapy as neoadjuvant chemotherapy. The primary tumor and metastatic lymph nodes reduced in size, and thoracoscopic esophagectomy in the prone position was performed. Pathological findings were esophageal cancer, pT3-Ad, INF b, ly2, v1, IM0, pPM0, pDM0, pRM1, pN3, pStage III . As the radical margin was positive, chemoradiotherapy was performed. We continued postoperative chemotherapy for approximately 1 year, and the patient has survived without relapse for 4 years from esophagectomy. Even in patients over 80 years old, long-term prognosis can be expected by performing radical surgery and chemoradiotherapy. PMID- 29394776 TI - [A Rare Case of Abdominal Malignant Triton Tumor]. AB - A 60-year-old woman presented at our hospital with abdominal pain and vomiting.Three abdominal tumors were detected, and she was referred to our department for surgery.She underwent an enterectomy including 2 of the tumors.The third tumor could not be resected because it had invaded the superior mesenteric artery(SMA)and superior mesenteric vein(SMV). Based on positive immunohistochemistry results for S-100 protein and desmin, nerve sheath differentiation with rhabdomyoblastic differentiation was confirmed, and she was diagnosed with a malignant triton tumor(MTT).She received postoperative chemotherapy with adriamycin and dacarbazine.However, she died 7 months after surgery, with multiple peritoneal metastases.MTT is a subtype of malignant peripheral nerve sheath tumor and is very rare.MTT has a poor prognosis with a high tendency of local recurrence and early metastasis.The most common treatment strategy is radical resection followed by postoperative chemoradiotherapy.When preoperative diagnosis is possible, radical resection with clear margins should be performed. PMID- 29394777 TI - [Postoperative Bile Leakage Following Liver Resection Due to Stenosis of a Choledochojejunostomy Anastomosis after Pancreaticoduodenectomy - A Case Report]. AB - We report a rare case of intractable bile leakage after liver resection due to stenosis of the anastomosis of a choledochojejunostomy after pancreaticoduodenectomy. A 65-year-old woman was diagnosed with pancreatic and right breast cancer, and underwent pancreaticoduodenectomy and right mastectomy with simultaneous axillary lymph node dissection. Adjuvant chemotherapy and follow-up were performed in our department. After 18 months, computed tomography revealed a liver metastasis of 2.5 cm in segment 8. Because the primary nest of liver metastasis was unknown and performing a biopsy was difficult due to the location, partial resection of the liver was performed. Pathological examination confirmed liver metastasis from the breast cancer. She was rehospitalized due to a right subdiaphragmatic abscess 33 days post-surgery. Abscess drainage revealed bile leakage, and the cause was believed to be stenosis of the anastomosis created by the choledochojejunostomy. Percutaneous transhepatic cholangiographic drainage was performed, and the bile leakage disappeared immediately. However, it was difficult to release the anastomotic stenosis by choledochoscopy; therefore, a retrograde drainage tube was placed in the hepatic duct using enteroscopy, and it formed an internal fistula. The patient has continued to undergo chemotherapy for recurrence in the remnant liver that was observed 16 months after the hepatectomy. In conclusion, when hepatic resection is performed after pancreaticoduodenectomy, attention should be paid to the possible occurrence of bile leakage. PMID- 29394778 TI - [A Case of Metachronous Resection for Advanced Esophageal Cancer with Pheochromocytoma]. AB - A 66-year-old man reporting chest stenosis was examined. Upper gastrointestinal endoscopy showed type 2 esophageal cancer. An enhanced CT scan showed several swollen lymph nodes in the lesser curvature of the esophagus. We diagnosed the patient as having advanced esophageal cancer with multiple lymph node metastases(cT3N2M0, Stage III ). After 2 courses of chemotherapy(DCF), a significant reduction was observed in the esophageal tumor; however, the tumor at the lesser curvature was almost unchanged. MIBG scintigraphy showed high uptake in the left adrenal gland. In addition, urinary adrenaline was elevated. Therefore, we diagnosed the patient with pheochromocytoma. Metachronous surgery was performed. First, left adrenalectomy was performed. After we confirmed stability of blood pressure, esophagectomy was performed. The patient is alive without recurrence for 7 months after these operations. PMID- 29394779 TI - [Outcome of Patients with Pathological Complete Response after Neoadjuvant Chemotherapy in Advanced Esophageal Cancer]. AB - Neoadjuvant chemotherapy(NAC)has been proven to have survival benefit for patients with resectable advanced esophageal squamous cell carcinoma(ESCC). Among a total of 208 patients with ESCC who underwent radical surgery following NAC between March 2000 and January 2017, 6 patients achieved histologically complete response. Before NAC, the average major axis length of the tumor was 57 mm, and the clinical stages were Stage II (2 patients)and Stage III (4 patients). FP therapy(cisplatin and 5-fluorouracil)was administered to 4 patients, and DCF therapy(docetaxel, cisplatin, and 5-fluorouracil) to 2 patients. Five patients showed partial response(PR)and 1 showed stable disease(SD). The average number of days between NAC and surgery was 26.2(16-44). Postoperative complications were observed in 2 patients(anastomotic leakage and recurrent nerve paralysis). There was no treatment-related mortality. All patients are surviving without relapse. The present study indicated that DCF therapy for patients with resectable advanced ESCC prior to surgery could further improve prognosis. PMID- 29394780 TI - [Prognosis of Conversion Gastrectomy Cases for Stage IV Gastric Cancer]. AB - BACKGROUND: We evaluated the efficacy of surgical resection following response to primary chemotherapy for prospective registered Stage IV gastric cancer patients. PATIENTS AND METHODS: We analyzed the details and prognosis of 6 patients having advanced gastric cancer clinically diagnosed as resectable following primary chemotherapy between 2011 and 2015. RESULTS: The reason for being diagnosed as unresectable before chemotherapy was metastasis to distant sites, including paraaortic lymph node metastasis in 3 cases, peritoneal metastasis in 2 cases, and liver metastasis in 1 case.Two patients were able to undergo R0 resection, and the remaining 4 patients were unable to undergo complete resection.The median survival time (MST)of the patients who underwent R0 resection was 567.5 days, and the MST of the patients who could not undergo R0 resection was 474 days. CONCLUSION: Careful consideration of conversion gastrectomy may be important in inducing longterm survival in clinical Stage IV gastric cancer patients. PMID- 29394781 TI - [A Case of Early Colon Cancer Discovered by Granulomatous Inflammation of the Ileum Caused by Fish Bone]. AB - A 63-year-old man presented with abdominal pain in the lower right quadrant and high fever. An abdominal CT scan on admission revealed ileocecal wall thickening and inflammation of the terminal ileum. No foreign body was observed on CT scan. He received antibiotic therapy, but no improvement was noticed. Colonoscopy showed a sporadic type 0- I s+ II c lesion in the sigmoid colon. Histological examination showed well differentiated adenocarcinoma. We diagnosed the patient as having inflammation of the terminal ileum and sigmoid colon cancer. Laparoscopic surgery was performed. Inflammation was present in the terminal ileum, and local resection and sigmoidectomy were performed. A foreign body that appeared to be a fish bone was present in the resected specimen, and this led to the diagnosis of granulomatous inflammation of the ileum caused by fish bone. In the sigmoid colon, the pathological diagnosis was pT1b(sm), pN0, ly1, v1, pDM0, pPM0, R0, pStage I . He was discharged without any complication and has not shown any evidence of recurrence more than 1 year after surgery. PMID- 29394782 TI - [Laparoscopic Total Gastrectomy with Pancreatosplenectomy after Neoadjuvant Chemotherapy for Advanced Gastric Cancer with Adjacent Organs Invasion]. AB - A 71-year-old man was diagnosed with locally advanced gastric cancer(cT4b[Panc], N2, M0, cStage III C). He was treated with a triplet neoadjuvant chemotherapy regimen including docetaxel, oxaliplatin and S-1, followed by laparoscopic total gastrectomy with pancreatosplenectomy which achieved R0 resection. He had no pancreatic fistula, leakage and abscess and was transferred to other hospital on POD18 for rehabilitation. Adjuvant chemotherapy wish S-1was started on 7 weeks after surgery. Although multidisciplinary treatment such as perioperative chemotherapy and radical surgery is necessary, careful and precise interpretation of diagnostic image is mandatory for undergoing curative surgery with composite resection laparoscopically. In this report, we demonstrated that totally laparoscopic radical surgery safely and allowed the patient to initiate adjuvant chemotherapy in the early postoperative period. PMID- 29394783 TI - [A Case of Obstructive Jaundice Caused by Recurrent Gastric Cancer Previously Treated with Distal Gastrectomy and Roux-en-Y Reconstruction Whose Obstruction Was Relieved by ERCP for Altered Gastrointestinal Anatomy Using Conventional Endoscopes]. AB - There have been many reports on ERCP for patients with alteredgastrointestinal anatomy(AGA), using balloon-assisted enteroscopy(BAE); however, BAE is not commonly usedin practice because it requires special endoscopic systems and accessories, which are time-consuming to operate. For this reason, patients with AGA who suffer from obstructive jaundice (OJ)might receive PTBD in general practice during emergency situations. We report a case of OJ, caused by recurrent gastric cancer andpreviously treatedwith distal gastrectomy andRoux -en-Y reconstruction(DGRY). The obstruction was relieved by ERCP for AGA, using conventional endoscopes. A 74-year-oldwoman, who hadpreviously undergone DGRY for advanced gastric cancer(AGC)andhadbeen receiving first-line chemotherapy for AGC recurrence, was admitted to our hospital for treatment of OJ, causedby progression of recurrent AGC, in July 2016. ERCP for AGA was performedusing conventional endoscopes, andOJ was successfully relievedby the insertion of a self-expandable metallic stent. Subsequently, second-line chemotherapy was administeredandthe patient enteredPR after 2 courses of chemotherapy. PMID- 29394784 TI - [A Case of Recurrent Colon Cancer Successfully Treated with Capecitabine plus Bevacizumab]. AB - A 76-year-old woman had undergone a laparoscopic low anterior resection for rectal cancer. After 12 months, CT showed 2 tumors measuring 25mm in diameter in the pelvis and hydronephrosis. The patient was treated with CapeOX plus bevacizumab( Bmab). After 3 courses of chemotherapy, the size of the tumors was remarkably reduced. After 6 courses, the chemotherapy was withdrawn because of cystitis. Anaphylactic shock occurred after the 7th course after resumption of treatment. After 42 days, the chemotherapy(Cape plus Bmab)was resumed. The patient is recurrence free 13 months after achieving a complete response(CR). PMID- 29394785 TI - [A Colorectal Cancer with Invasive Micropapillary Carcinoma]. AB - A 76-year-old woman with bloody stool visited a nearby hospital. Colonoscopy showed a type 1 tumor in the rectum, and the biopsy indicated moderately differentiated adenocarcinoma. She was referred to our hospital. Abdominal contrast-enhanced CT did not show swollen lymph nodes in the regional nodes or distant metastases. Laparoscopic lower anterior resection was performed. Histopathological examination indicated pT1b, pN3, ly3, and v1, fStage III b, which had a partial invasive micropapillary carcinoma(IMPC)component of papillary adenocarcinoma. Although she received postoperative adjuvant chemotherapy, she died of a thromboembolism with paraneoplastic syndrome 20 months after the operation. IMPC has a high incidence of lymphatic invasion and lymph node metastases. IMPC is rare in cases of colorectal cancer and it is important to accumulate and investigate colorectal cancer patients with IMPC. PMID- 29394786 TI - [Anorectal Malignant Melanoma Is a Very Rare Disease and Has a Poor Prognosis]. AB - We performed abdomino-perineal-resection(APR)on 2 cases of anorectal malignant melanoma. The first case was a 70- year-old woman suffering from bloody stool. Colonoscopy showed a black tumor in the rectum. Biopsy revealed a malignant melanoma. A CT scan showed multiple lung metastases and liver metastasis. She underwent surgery for the purpose of bleeding control, but died shortly thereafter because her liver and lung metastases had worsened. The second case was a 43- years-old man suffering from bloody stool. He had a black type 3 tumor in the rectum. A biopsy revealed malignant melanoma. A CT scan showed lateral lymph node swelling. He underwent APR with right side-lateral dissection. An established treatment for anorectal malignant melanoma has not been agreed upon and it is controversial. We experienced 2 cases that underwent surgery and we report them along with relevant information from the literature. PMID- 29394787 TI - [A Successful Curative Resection Case of Metastatic Hepatocellular Carcinoma to the Kidney Which Extended into the Renal Vein]. AB - A 78-year-old woman underwent partial hepatectomy for the treatment of hepatocellular carcinoma(HCC).After surgery, she was further treated with radiofrequency ablation(RFA)and transcatheter arterial embolization(TAE)for the intrahepatic reccurence of HCC.Thirty months after surgery, her tumor marker levels increased and computed tomography (CT)revealed an intrahepatic mass and right renal tumor which extended into the renal vein.We therefore suspected a reccurence of HCC and right renal cell carcinoma which extended into the renal vein, and thus performed right nephrectomy before again performing TAE to treat the reccurence of HCC.The pathological findings showed HCC metastasis in the kidney. Nephrectomy should be performed as soon as possible in patients with a renal vein tumor thrombus in order to prevent the occurrence of a pulmonary embolism.We herein describe a very rare oncologic emergency case and review the relevant literature. PMID- 29394788 TI - [A Case Report of an Elderly Patient's Intrahepatic Cholangiocellular Carcinoma with Cholangitis]. AB - We report a case of an elderly patient diagnosed with intrahepatic cholangiocellular carcinoma with cholangitis.An 88- year-old woman presented with fever.Computed tomography examination showed a hepatic tumor and dilation of the peripheral bile duct.Cholangiocarcinoma was diagnosed.Biliary tract drainage and palliative care were suggested because of her age.However, her family asked for a second opinion about operative management and consulted our hospital.Radical operations for intrahepatic cholangiocellular carcinoma that has spread to the left lobe are usually accompanied by widespread lymph node dissection and extensive hepatectomy with biliary tract reconstruction.However, in this case, the patient was very elderly and was able to safely undergo an operation by reduction of the excision range and by omitting lymph node dissection.We conclude that appropriate surgery and postoperative care to prevent complications are necessary when performing very invasive surgery in elderly patients. PMID- 29394789 TI - [A Case of Gemcitabine and Nab-Paclitaxel Therapy for Multiple Metastatic Pancreatic Cancer]. AB - Pancreatic cancer is one of the leading causes of cancer-related death in Japan. Nab-paclitaxel(nab-PTX)and gemcitabine( GEM)combination chemotherapysignificantlyimproved overall survival in a phase III trial(MPACT). This combination chemotherapyhas become one of the first-line treatments for patients with metastatic pancreatic cancer since December 2014. We report a case of a patient who underwent this chemotherapyfor recurrence of pancreatic head cancer. A 64-yearold man, who underwent curative resection of pancreatic cancer 2 years ago, relapsed with multiple lung metastases and a para-aortic nodal metastasis. The patient was treated with combination chemotherapyof nab-PTX 125mg/m2 plus GEM 1,000mg/m2. He died from carcinomatous pleurisy1 9 months after starting the chemotherapy. The patient skipped scheduled chemotherapyonly3 times due to Grade 3 neutropenia during his clinical course over 19 months. The combination regimen of nab-paclitaxel and gemcitabine is thought to be a well tolerated and standard treatment for metastatic pancreatic cancer. PMID- 29394790 TI - [A Case of Jejunal Ectopic Pancreatic Cancer with Small Bowel Obstruction]. AB - Were port a caseof an 82-year-old man who presented with vomiting. Computed tomography(CT)revealed a jejunum tumor and small bowel obstruction. Enteroscopy revealed a protruded lesion and biopsy indicated adenocarcinoma. PET-CT revealed nothing without jejunal tumor. Therefore, with a preoperative diagnosis of primary small bowel cancer, we performed operation. Surgery indicated peritoneal disseminations and a jejunal tumor 40 cm distal from the ligament of Treitz, and we performed small bowel partial resection. Pathological examination revealed adenocarcinoma originating from a Heinrich type I ectopic pancreas in the jejunum. Ectopic pancreatic cancer in the jejunum is rare, and we review case reports in the literature. PMID- 29394791 TI - [Experience with Using the EnCor ENSPIRE(r)System in Mammary Tissue Biopsy]. AB - We investigated the usefulness of vacuum-assisted biopsy(VAB)using the EnCor ENSPIRE(r)system for initial biopsy of breast tumors. We analyzed 24 cases of VAB using the EnCor ENSPIRE(r)system performed for breast tumors. Of 24 mammary lesions, 12 cases(50.0%)were diagnosed as malignant. Among them, 7 cases(29.2%)were invasive ductal carcinoma(IDC) and 5 cases(20.8%)were ductal carcinoma in situ(DCIS). Six cases required tumor resection for definitive diagnosis; 1 case was diagnosed with IDC, 2 cases with DCIS, 2 cases with intraductal papilloma(IDP), and 1 case with atypical ductal hyperplasia( ADH). Moreover, EnCor ENSPIRE(r)system biopsy was performed in 15 cases because malignancy could not be diagnosed using core needle biopsy. There were 4 cases of IDC, 4 cases of DCIS, 2 cases of IDP, 2 cases of usual ductal hyperplasia, and 2 cases of ADH. There were no complications due to a series of procedures. We believe that the EnCor ENSPIRE(r)system is an effective technique having both convenience and great diagnostic accuracy. PMID- 29394792 TI - [A Case of Noninvasive Ductal Carcinoma of the Breast in a Male]. AB - Breast cancer in male is rare, accounting for 1%of all breast cancers.Among male breast cancers, noninvasive carcinoma is extremely rare.We experienced a case of noninvasive carcinoma of the breast in a male.A 72-year-old male was referred to our hospital with a chief complaint of the tumor and blood secretion from the left nipple.Mammography revealed a highdensity mass.Ultrasound examination revealed low echoic mass at the E area, and it measured 1.5 cm.Core needle biopsy failed to provide a definitive diagnosis, and we performed an excisional biopsy of the tumor.The pathological diagnosis was noninvasive ductal carcinoma.He underwent a mastectomy without sentinel lymph node biopsy because the resection margin was positive.The patient received no adjuvant therapy and the patient's postoperative course was uneventful for 1 year.As there have been few reports on male noninvasive ductal carcinoma, we do not have evidence for indication of the sentinel lymph nodes and postoperative adjuvant therapy such as tamoxifen.We may confuse the treatment policy. PMID- 29394793 TI - [A Case of Long-Term Survival of Breast Cancer with Lymph Node and Liver Metastases Treated with Sequential Anti-HER2 Drugs, Chemotherapy, and Endocrine Therapy]. AB - A 50s-year-old woman underwent left partial mastectomy with axillary lymphadenectomy for breast cancer. Histological examination indicated invasive ductal carcinoma, pT1c, pN0, Stage I , ly(+), ER(+), PgR(+). She received adjuvant therapy with tamoxifen and 50 Gy of irradiation to the residual breast. Four years after mastectomy, she was found to have left Rotter lymph node metastasis; then, anastrozole was administered instead of tamoxifen. Nine months later, she was found to have liver metastasis. Immunohistostaining revealed that the breast cancer was HER2-positive; she received AC followed by paclitaxel(PTX)with trastuzumab(T), and achieved complete response(CR). Subsequently, abdominal, cervical lymph node, and liver metastases appeared. Letrozole followed by lapatinib with capecitabine, FEC100, PTX with T, eribulin, S-1, docetaxel with pertuzumab and T, everolimus with exemestane, bevacizumab, and PTX were then administered, resulting in long-term disease control. Sixteen years after mastectomy, she receives outpatient chemotherapy in performance status 1 state. PMID- 29394794 TI - [A Resected Case of Castleman's Disease That Was Difficult to Diagnose Preoperatively]. AB - A 70-year-old man was referred to our hospital and admitted after abdominal computed tomography(CT)examination revealed a tumor in the retroperitoneum. The specific blood test findings were poor, and surveillance CT demonstrated a wellcircumscribed, enhanced mass measuring 40mm with calcification behind the horizontal portion of the duodenum. The tumor presented with a slightly high signal in low signal, T2 in T1, and it showed a diffusion decrease in DWI; the simple abdominal MRIrevealed heterogeneous accumulation of SUVmax 3.0 only for the lesion in FDG/PET-CT. Specific findings did not lead to a diagnosis, although EUS-FNA lower aspiration biopsy cytology was performed. Laparoscopic tumorectomy was performed to help determine the treatment strategy. Histopathological examination indicated that the tumor was composed of multiple lymph follicles with concentric layers of mantle zone cells, showing an onion skin-like lesion and atrophic germinal centers. The germinal centers had penetrating arterioles with hyalinized vessel walls, and Castleman's disease(hyaline vascular type)was therefore diagnosed. In this case, it was difficult to diagnose Castleman's disease before surgery. Surgical excision is a diagnostic as well as a curative method for management of this disease. PMID- 29394795 TI - [A Case Report on Successful Larynx-Preserving Surgery for a Cervical Esophageal Cancer That Invaded the Hypopharynx]. AB - The patient was a 58-year-old man suffering from dysphagia. He was diagnosed with T3 cervicalesophagealcancer that invaded the posterior hypopharyngealwal lwith lymph node metastasis. The patient received neoadjuvant chemoradiotherapy (30 Gy with CDDP/5-FU), followed by larynx-preserving surgery(LPS)for cervicalesophagealcancer. Two techniques for successfulLPS consist of the dissections of cricopharyngealmuscl e and the inferior pharyngealsphincter, and the complete division of the bilateral infrahyoid muscles attached to the sternum(CDBIMS). The former technique of releasing the esophagus from the trachea at the cricoid cartilage level results in the extension of the oral surgical margin. The latter technique is expected to prevent postoperative aspiration pneumonia, as the lack of flexibility of scarred infrahyoid muscles is regarded as one of the major causes of dysfunction in swallowing. Free jejunum was transferred for cervical reconstruction. Pathological examination indicated degenerated squamous cell carcinoma(ypT2, INF b, ly0, v0, PM0, ypN0, ypStage II A). Although the patient had recurrent nerve palsy, he could eat meals without aspiration. He returned to normal life after discharge from the hospital. Five years after surgery, no recurrence had been observed. PMID- 29394796 TI - [Optimal Dissection of the Intestinal Tract and Preservation of Vascular Supply in Left Hemicolectomy Using Simulation Computed Tomography Colonography]. AB - Left hemicolectomy is a standard surgical method for cancer of the descending colon. Resection involves the region from the left side of the transverse colon to the sigmoid colon. Although laparoscopic hemicolectomy is widely used, it is difficult to determine an appropriate resection range during surgery because of the limited visual field. Simulation computed tomography colonography(S-CTC), which combines CTC and 3-dimensional vascular imaging, enables the surgeon to clearly identify the position of the primary lesion and dominant vessel. We present 3 cases of cancer of the descending colon with different affected sites and lesion grades, in which appropriate dissection of the large intestine and treatment of the vessels was simulated by S-CTC, enabling laparoscopic surgery in accordance with the simulation. Case 1: Splenic flexure, cT1bN0M0, Stage I . The dominant vessels were identified by S-CTC as accompanying vessels branching from the accessary middle colic artery(A-MCA)and inferior mesenteric vein(IMV). The left branch of the MCA and the left colic artery(LCA)were 10 cm or more apart. A D2-type dissection was performed, and simulation was conducted for dissection of the branching root of the vein and the same level of the A-MCA. Case 2: Mid descending colon, cT3N0M0, Stage II . The dominant A-MCA and LCA were identified with S-CTC. The intestinal tract was dissected to 5 cm from the dominant artery, and D3-type dissection was simulated with a retained inferior mesenteric artery(IMA)for preservation of the sigmoid colon. Case 3: Site adjacent to the sigmoid colon, cT3N0M0, Stage II . S-CTC identified the first sigmoid artery(S1)as the dominant artery, and revealed that the LCA and IMV were defective and that the A-MCA was 10 cm or more apart. Simulation of S1 selective resection was conducted such that D3-type dissection was performed, with a retained IMA for preservation of the sigmoid colon. In all 3 cases, laparoscopic surgeries were performed in accordance with the simulation. S-CTC was useful for optimal preservation of the intestinal tract and vascular supply in laparoscopic surgery for descending colon cancer. PMID- 29394797 TI - [A Case of Ipsilateral Breast Tumor Recurrence with Breast Ulcer]. AB - The patient was a 61-year-old woman with a history of treatment for breast cancer. She had undergone left breast-conserving surgery and axillary lymph node dissection followed by radiation therapy for left breast cancer when she was 43 years old and later presented to our hospital with a chief complaint of a left breast ulcer with a messy exudate. Core needle biopsy (CNB)from the ulcer showed no malignancy. PET-CT showed low FDG uptake at the left breast and high FDG uptake at a contralateral axillary lymph node. CNB of a contralateral axillary lymph node showed metastasis of breast cancer. She underwent left mastectomy and right axillary lymph node dissection for local control. Ipsilateral breast tumor recurrence in the left breast and contralateral axillary metastases were identified in the final pathological findings. The patient was treated with FEC 100 and tri-weekly docetaxel and has been recurrence-free for 2 years after surgery. PMID- 29394798 TI - [A Case of Uterine Body Metastasis from Sigmoid Colon Adenocarcinoma]. AB - We report a case of metastatic carcinoma to the uterine body from a colorectal adenocarcinoma. A 73-year-old woman underwent laparoscopic sigmoidectomy for sigmoid colon carcinoma 2 years before. In the following study, her serum carcinoembryonic antigen level was elevated, and a uterine body tumor invading the rectal wall was detected via enhanced computed tomography. Colonoscopic examination revealed an elevated lesion at the rectum, which was diagnosed as an adenocarcinoma. Based on these results, we diagnosed the uterine tumor as metastatic tumor from the colon carcinoma. Immunostaining was negative for CK7, but positive for CK20. Thus, we confirmed metastasis of the sigmoid colon cancer to the uterus. Metastasis to the female genital tract from extragenital malignancies are rare, and the prognosis is extremely poor. However, some patients attain long-term survival by surgical intervention even in such cases. PMID- 29394799 TI - [Radiofrequency Ablation Pulmonary Metastasis of Colorectal Cancer - Two Cases of Report]. AB - Case 1: 63-year-old woman received abdominoperineal resection with lateral lymph node dissection for rectal cancer in 2008. After adjuvant chemotherapy, she suffered from lung metastasis and received partial pneumonectomy in 2012. However, chemotherapy was performed again for lung metastasis and mediastinal lymph nodes in 2013. Radiofrequency ablation (RFA)was performed to lung metastasis in 2016 due to ineffectiveness of chemotherapy. Case 2: 81-year-old man received Hartmann's procedure for rectal cancer with lung and liver metastasis in 2012. After 6 months of chemotherapy, liver partial resection and pulmonary partial resection were performed. In spite of additional chemotherapy, He received partial pneumonectomy in 2013. In 2014, he restart chemotherapy due to lung metastasis. In 2016, he received RFA for lung metastasis because of ineffectiveness of chemotherapy. After that, he received g-knife for brain metastasis. He is going to receive RFA for another lung metastasis. PMID- 29394800 TI - [A Case of Unresectable Locally Advanced Pancreatic Cancer Resulted in R0 Surgery after Chemotherapy]. AB - A 67-year-old man visited our hospital for jaundice. Abdominal dynamic CT showed the hypovascular tumor at the head of the pancreas that surrounded superior mesenteric artery(SMA)at an angle of 220 degree. No metastasis in lymph nodes and other organs was observed. We diagnosed the tumor unresectable locally advanced(UR-LA)pancreatic cancer. Chemotherapy was administered with gemcitabine and nab-paclitaxel(GEM+nab-PTX)and achieved partial response. Regression in size and in range around SMA to an angle of 150 was observed. We assessed it possible to resect the tumor curatively, and performed subtotal stomach preserving pancreaticoduodenectomy and dissection of the plexus around the SMA, resulted in R0 surgery. Adjuvant chemotherapy was administered, and no recurrence was observed up to present, more than a year. It is suggested that GEM+nab-PTX can be effective as the primary therapy against UR-LA pancreatic cancer. PMID- 29394801 TI - [A Case of Locally Advanced Rectal Cancer Invading Posteriorly Adjacent to Sacrum Resected by Laparoscopic Low Anterior Resection]. AB - We report a case of locally advanced rectal cancer invading toward sacrum treated by laparoscopic low anterior resection. A man in his 60's was diagnosed with rectal cancer expanding near to sacrum. The circumferential resection margin was assessed to be scarce. After preoperative chemotherapy, we performed laparoscopic low anterior resection. In order to obtain surgical margin, we had to cut into presacral venous plexus. With prepared sufficient devices, hemostasis was safely acquired. Pathological findings revealed clear surgical margin. It is important to prepare appropriate hemostasis devices in managing cases with high risks of intraoperative hemorrhage. Laparoscopic approach may contribute to these cases, making hemostasis easier than laparotomy with the magnified view, pneumoperitoneum and Trendelenburg position. PMID- 29394802 TI - [A Case of Laparoscopic-Endoscopic Cooperative Surgery for Duodenal Neuroendocrine Tumor(NET G1)]. AB - We report a case of duodenal neuroendocrine tumor(NET)G1 resected by laparoscopic endoscopic cooperative surgery (LECS). A 78-year-old woman underwent upper gastrointestinal endoscopy, revealing an 8 mm, rising tumor on the anterior wall of the duodenal bulb. The tumor was pathologically diagnosed as a G1 duodenal NET, by biopsy. Endoscopic ultrasonography showed the tumor might invade the submucosal layer. We performed LECS. The endoscopist marked the dissection line around the tumor and penetrated the duodenal wall. The duodenal wall in the excision area around the tumor was dissected using ultrasonically activated scalpel by the laparoscopist. The closure of the defect in the duodenal wall was performed by the laparoscopic hand-suturing technique. The patient was discharged with no complication on postoperative day 8. The horizontal and vertical margins were free of tumor cells. We demonstrated that LECS for NET of the duodenal bulb anterior wall was useful and safe method to enable appropriate surgical margin and minimum intestinal resection. PMID- 29394803 TI - [Obstructive Colon Cancer with Triple-Vessel Coronary Artery Disease - A Case Report]. AB - The patient was a 70-year-old woman who was diagnosed with obstructive transverse colon cancer suspected of invading the abdominal wall by abdominal CT imaging. Since the preoperative electrocardiogram showed an ischemic change, echocardiography and coronary angiography were performed. We diagnosed chronic heart failure and angina pectoris because echocardiography showed low cardiac function(left ventricular ejection fraction; LVEF 37%)and coronary angiography indicated triple-vessel disease. We firstly performed coronary artery bypass graft surgery following self-expanding metallic stent placement as a bridge to surgery(BTS), because we judged this patient as a perioperative high-risk case. After improvement of cardiac function(LVEF 49%), expanded right hemicolectomy with partial resection of abdominal wall could be performed without perioperative complications. Colonic stenting as a BTS allowed us to treat comorbidities properly, and perform a radical surgery safely for such a high-risk patient. PMID- 29394804 TI - [A Case of Synchronous Quadruple Cancers Treated with Neoadjuvant Chemotherapy Followed by Surgery]. AB - The patient is male in his 60's. He underwent endoscopic examination for anemia, which was found during screening of high PSA value. Endoscopic examination revealed a gastric cancer and 3 colorectal cancers. Histological results from biopsy was HER2 positive poorly differentiated adenocarcinoma in gastric tumor and moderately differentiated adenocarcinoma in colorectal tumor. Chest CT showed a pulmonary nodule in the middle right lung. Histological diagnosis was TTF-1 positive adenocarcinoma, meaning primary lung cancer. Histological examination of prostate biopsy also showed adenocarcinoma. Clinical stages were Stage III B of gastric cancer, Stage III a of colorectal cancer, Stage I A of lung cancer and Stage I of prostate cancer. Neoadjuvant chemotherapy for gastric cancer was performed because gastric cancer with advanced clinical stage was regard as a prognostic factor. Neoadjuvant chemotherapy shrinked gastric and colorectal cancers, so we performed distal gastrectomy for gastric cancer and super low anterior resection for colorectal cancer. Patient was discharged 22 days after operation without any serious adverse events. Hormonal treatment for prostate cancer and radiation therapy for lung cancer were performed. Now this patient is alive without any recurrence. PMID- 29394805 TI - [A Case of Resection for Metastatic Osseous Tumor from Rectal Cancer]. AB - A 67-year-old male was referred to our hospital for further investigation of fecal occult blood. We diagnosed him with rectal cancer with osseous metastasis. Chemo-and radiation therapy were administered following resection of the rectal cancer. There were no other lesions except for the osseous metastasis remaining after these interventions. The osseous lesion was then resected. There have no signs of recurrence for 1 year and 9 months since the last operation. We report a case of successful resection of osseous metastasis from rectal cancer. PMID- 29394806 TI - [A Case of Intrahepatic Cholangiocarcinoma with Ductal Plate Malformation Pattern]. AB - A 56-year-old man with HCV infection was referred to our hospital for further evaluation and treatment of hepatic tumor. Abdominal enhanced computed tomography demonstrated an S8 hepatic tumor, about 15mm in maximal diameter. The tumor showed enhancement on the arterial phase and washout on equilibrium phase. EOB MRI scan also showed the hepatic tumor with enhancement in the early phase and washout in the delayed phase. Liver function was normal. Serum AFP and PIVKA- II were normal and CEA and CA19-9 were elevated. However, no other tumor was detected by the colonoscopy, esophagogastroduodenoscopy and PET-CT. Under the diagnosis of HCC, partial hepatectomy was performed. Histologically, the tumor was composed of neoplastic glands with irregularly dilated lumen of adenocarcinoma, resembling ductal plate malformation(DPM). And Von Meyenburg complexes and foci of ordinary intrahepatic cholangiocarcinoma(ICC)were also found. ICC with this histologic features reported as a new subtype of ICCs. PMID- 29394807 TI - [A Case of Successful Adjuvant Surgery for the Pancreas Head Cancer with Peritoneal Metastasis]. AB - We report a case of the pancreas head cancer with peritoneal metastasis, which was resected curatively after chemotherapy. A6 6-year-old male was referred to our hospital for the treatment of biliary stenosis. The serum CA19-9 level was elevated and abdominal CT scan showed stenosis of distal bile duct. By laparotomy, we noticed mass in the head of the pancreas with 8mm of the seeding nodule in a diameter at jejunal mesentery which was diagnosed as adenocarcinoma by intraoperative frozen sections. Therefore, the patient was diagnosed as pancreas head cancer with peritoneal metastasis. After hepaticojejunostomy, we started chemotherapy planning adjuvant surgery if the clinical response was observed. Systemic chemotherapy with gemcitabine and nab-paclitaxel was administrated on days 1, 8 and 15 every 4 weeks. After 5 courses, therapeutic effect was stable disease(SD)in response evaluation criteria in solid tumor(RECIST). All of tumor markers were normalized. Subtotal stomach-preserving pancreatoduodenectomy(SSPPD)was performed 6 months after the initial surgery. Histopathologically, most cancer cells showed degeneration and eliminated in the head of the pancreas. R0 resection was achieved with diagnosis of ypT3, ypN1, pM1(PER), Stage IV . Histological therapeutic effect was Grade III according to the Evans classification. The patient is alive, with no sign of recurrence 8 months after surgery. Adjuvant surgery was suggested to be one of the therapeutic options for pancreatic cancer with peritoneal metastasis. PMID- 29394808 TI - [Long-Term Survival after Multidisciplinary Treatment for Resected Pancreatic Adenocarcinoma with Recurrence of Pulmonary Metastases - A Case Report]. AB - Recent studies indicated that isolated pulmonary metastases could define a favorable subgroup in metastatic pancreatic cancer. We report a case of isolated pulmonary metastases after curative resection of pancreas head cancer treated with chemotherapy and pulmonary metastasectomy survived for 79 months after recurrence. A 72-year-old male underwent pancreatoduodenectomy for pancreas head cancer. Adjuvant chemotherapy was done with gemcitabine hydrochloride (GEM)for 6 months and then S-1 for 2 months. Twenty-seven months after surgery, 2 small metastatic nodules in the left lung was detected. Chemotherapy with GEM was performed but the lesions grew larger very slowly. A new metastatic nodule was detected in the right lung 40 months after surgery and pleural effusion was detected 52 months after surgery. Then combination chemotherapy with GEM and S-1 was performed for 3 months followed chemotherapy with S-1 alone. Seventytwo months after surgery, chemotherapy with GEM was performed again because of patient's intolerance to S-1. Ninety months after initial surgery, pulmonary metastasectomy of the right lung was performed because of its resistance to chemotherapy. Chemotherapy with GEM was started again 4 months after pulmonary metastasectomy but serum levels of tumor markers remained increase. Combination chemotherapy with GEM and nab-paclitaxel was started 8 months after pulmonary metastasectomy but the patient died 16 months after pulmonary metastasectomy. PMID- 29394809 TI - [A Case of Pancreatic Cancer with Multiple Lymph Node Swelling Caused by Sarcoidosis]. AB - A 69-year-old woman who was identified the tumor of the pancreas tail by CT scan for postoperative inspection of breast cancer. Pancreas tail cancer with para aortic lymph node metastases was diagnosed by close inspection. She consulted a different hospital to receive their second opinion. She was diagnosed of sarcoidosis from points with lymphadenopathy in hilar region and para-aorta for 3 years and uveitis. The patient was referred to our institution for treatment. We performed distal pancreatectomy in March, 2014. No.16 lymph nodes were cancer negative, but lymph nodes around the pancreas were cancer positive. Abdominal CT, 9 months after surgery, showed lymph node swelling. We recommended a definitive diagnosis by EUS-FNA, but she refused the inspection. She was checked by CT scan regularly afterwards and is alive without recurrence 39 months after the operation. Diagnosis for lymph node metastases is difficult for a malignant tumor when the sarcoidosis coexisted. PMID- 29394810 TI - [A Case of Neuroendocrine Carcinoma with Liver Metastasis Treated with Multimodality Therapy and Leading to Complete Response]. AB - A 79-year-old man with cStage II A(T2N1H0P0CYXM0)advanced gastric cancer in angle. Distal gastrectomy was performed and liver metastasis was recognized during the operation. The pathological diagnosis was shown as neuroendocrine carcinoma(NEC). Chemotherapy(S-1/cisplatin[CDDP]: 1 course, etoposide/CDDP: 5 courses)was administered. After chemotherapy, liver metastasis disappeared for 9months. PMID- 29394811 TI - [A Successful Treatment for Stage III c Gastric Cancer with Low Cardiac Function Using S-1 plus Oxaliplatin(SOX)as a Neoadjuvant Chemotherapy]. AB - A 83-year-old female, with oppression in her chest, was subjected to type 2 advanced gasteric cancer in esophagogastric junction. Examinations revealed Stage III c of cT4, cN2, cM0. For adopting neoadjuvant chemotherapy, S-1 plus CDDP was not on the list, but S-1 plus oxaliplatin (SOX) was, because massive load of infusion along with the chemotherapy was not appropriate for the patient with low cardiac function. After 2 courses of SOX, the primary tumor as well as metastatic lymph nodes were shown with marked reduction in size by CT scan, which enabled total gastrectomy with D2 lymphadenectomy to be performed as a curative resection, leading to patient living with no recurrence more than 3 years. SOX was considered as one of safe neoadjuvant agent for gastric cancer combined with low cardiac function. PMID- 29394812 TI - [A Case of Successful CDDP plus CPT-11 Therapy for Recurrent Carcinomatous Lymphangiosis Occurring during Postoperative Adjuvant Therapy for Gastric Cancer]. AB - The case involved a 67-year-old man. Type 2 gastric cancer in the body of stomach was discovered, and the patient was referred to this department, where distal gastrectomy with Roux-en-Y reconstruction was carried out. The pathological classification was pT2N2H0P0CY0M0, pStage II B, and S-1 administration was started as postoperative adjuvant therapy. After 10 months of administration, a chest computed tomography(CT)scan revealed fine nodular shadows and irregular thickening of the alveolar septa in both lungs, a finding that was judged to be carcinomatous lymphangiosis. CDDP plus CPT- 11 therapy was subsequently started. Chest CT scan after 2 courses of administration showed the disappearance of the carcinomatous lymphangiosis. However, peritoneal metastasis was noted immediately below the abdominal wall. After completing 6courses of administration, the recurrence of peritoneal metastasis disappeared, and the administration of chemotherapy was terminated. There was no subsequent recurrence, and the patient remains alive today, 6years after the surgery. In the present case, the CT scan did not show clear mediastinal or hilar lymph node enlargement, but nodular shadows were noted at the periphery of the lung field, which were thought to be carcinomatous lymphangiosis as a result of haematogenous or anterograde metastasis into the lungs. PMID- 29394813 TI - [A Long-Term Survivor Who Are Responding to Sunitinib Treatment for Recurrent Imatinib-Resistant Gastrointestinal Stromal Tumor(GIST)of the Stomach]. AB - A 63-year-old man underwent a laparoscopic partial gastrectomy for GIST on September, 2001. Three years and 2 months after the gastrectomy, an abdominal CT showed multiple recurrences in S5 and S6 in the liver and peritoneum. After 4 months from the start of imatinib treatment(400mg/day), peritoneal tumors disappeared and the patient maintained stable disease by imatinib treatment for 8 years. However, on December, 2012, an abdominal CT scan revealed the regrowth of the tumor in S6 in the liver, and PET-CT showed focal progression of only the S6 lesion. Although the lesion was resectable, the patient did not request surgical intervention. So, we initiated sunitinib treatment(50mg/day), and the residual liver metastasis has been well controlled with favorable response of sunitinib for 4 years without severe side effects. PMID- 29394814 TI - [A Case of Laparoscopic Total Gastrectomy for Gastric Cancer with Diffuse Cystic Malformation]. AB - A 75-years-old man was diagnosed with a cystic submucosal tumor of the middle body of the stomach and diffuse cystic malformation. Laparoscopic total gastrectomy was performed since a type II c gastric cancer was found at the lower body of the stomach after 1-year follow-up. Histopathological examination revealed mucosal adenocarcinoma with diffuse cystic malformation. Strict observation and appropriate treatment are needed for diffuse cystic malformation because of its significant carcinogenic rate. PMID- 29394815 TI - [A Case of Laparoscopic Remnant Gastrojejunal Bypass Surgery for Postoperative Peritoneal Recurrence of Gastric Cancer]. AB - A 77-year-old female case who underwent laparoscopic distal gastrectomy with D2 dissection, Billroth I reconstruction for gastric cancer. Since the stage was III A, she received an adjuvant chemotherapy with S-1 after surgery. However, about 2 years after surgery, she was referred to our hospital for anorexia and vomiting. As a result of the examination, we diagnosed stenosis due to peritoneal recurrence near the anastomotic site. We performed laparoscopic remnant gastrojejunal bypass (Billroth II method, with Braun anastomosis). A camera port was inserted into a median umbilical incision. Following this, 4 additional ports(1 ports of 12mm in diameter and 3 ports of 5mm in diameter)were inserted under laparoscopic imaging into the right lower, right upper, left upper, and left lower quadrants. We first detached the adhesion considered as the influence of the previous surgery, and the anastomosis of remnant stomach and jejunum and the Braun anastomosis were performed by the linear stapler. The postoperative course was good. She started oral intake from the day after surgery, was discharged on the 6 days after operation, and received chemotherapy promptly. This procedure was effective for recurrent gastric cancer with stenosis which is difficult to resect and it was considered to be a minimally invasive method with a view to initiating chemotherapy early after operation. PMID- 29394816 TI - [A Case of Recurrent Stenosis after Metallic Stenting for Esophagogastric Junction Adenocarcinoma with Peritoneal Metastases]. AB - A 65-year-old man presented with severe strictures from the esophagogastric junction to the body of the stomach and was histopathologically diagnosed with adenocarcinoma. Computed tomography showed multiple peritoneal metastases. A long, covered metallic stent was placed, and chemotherapy was started. Subsequent granulation from the oral side of the stent caused stricture formation, and a covered stent was also placed. After 8 months, granulation from the oral side of the stent caused recurrent stricture formation. We again placed a metallic stent. Successful chemotherapy for stomach cancer with long-term benefit is possible with new molecularly targeted drugs. Stenting may cause adverse events such as stenosis, but can enable oral intake and is minimally invasive. This report describes a case that required multiple stent placement and reviews the relevant literature. PMID- 29394817 TI - [A Case of Orange-Induced Small Bowel Diverticular Obstruction Treated with Laparoscopically-Assisted Surgery]. AB - We report a case of orange-induced small bowel diverticular obstruction treated with laparoscopically-assisted surgery. A 64-year-old man was seen at the hospitalbecause of abdominalpain and vomiting after dinner. Abdominalcomputed tomography( CT)showed a small intestinal ileus. We performed laparoscopically assisted surgery on the same day for definitive diagnosis and treatment. The postoperative course was uneventful. The pathological diagnosis was orange induced small boweldiverticul ar obstruction. Food-induced smallbowelobstruction is rare disease, but often requires surgery. Laparoscopic surgery is an effective option for surgery of food-induced smallbowel obstruction. PMID- 29394818 TI - [A Case of Synchronous Multiple Liver Metastases from Ascending Colon Cancer Showing Pathological Complete Response to CapeOX Treatment]. AB - The patient was a 30-year-old man who underwent a medical examination for shortness of breath.An abdominal computed tomography(CT)scan revealed advanced ascending colon cancer with multiple metastases to the liver.We performed a laparoscopic right hemicolectomy first, due to the obstruction.Postoperatively, the patient received capecitabine plus oxaliplatin( CapeOX)chemotherapy.After 10 courses of CapeOX, the multiple liver metastases had reduced remarkably in size. Colectomy of the anastomosis and partial hepatectomy were then performed.Histological examination of the resected tissue revealed no residual cancer cells, suggestive of a pathological complete response. PMID- 29394819 TI - [A Case of Phrenic Nerve Paralysis During Adjuvant Chemotherapy for Rectal Cancer]. AB - A man aged 66 years presented with pneumaturia as a major complaint. Cancer of the sigmoid colon with infiltration to the urinary bladder was diagnosed and the patient underwent colectomy of the sigmoid colon and partial cystectomy of the bladder in May 2015. Histopathologic examinations revealed pT4b, Si(bladder), pN( ), cM0, fStage II . Because intestinal sub-obstruction and lymphatic invasion were present, CapeOX was administered as an adjunctive chemotherapy for the high risk Stage II cancer. Because Grade 2 peripheral neuropathy appeared as a side effect, the dose was decreased to 80% from the 3 cycle. After the 7 cycle, cough and disturbed breathing appeared. The chest CT scans did not reveal drug-induced interstitial pneumonia, but indicated an elevated right diaphragm and zosteroid changes in the medial lobe of the right lung due to discoid atelectatic condition. The Grade 1 respiratory symptoms were mild, and the lung field was considered to exhibit no problems. Thus, the 8 cycle was administered. The symptoms disappeared after about 2 weeks following completion of oral administration of capecitabine. The diaphragm also recovered to its original height. In the attached document, the frequency is unknown and "dyspnea" is written for L-OHP and capecitabine, respectively. It is unknown whether phrenic nerve paralysis occurs. However, because other organic lesions were absent and the symptoms appeared during chemotherapy, the possibility is not deniable. At present, 2 years postoperatively, recurrent lesions in the mediastinum and recurrent respiratory difficulties are absent. Generally, although phrenic nerve paralysis is not considered to be a specific side effect, it was considered that for respiratory difficulties, CT reveals not only the affected condition in the lung fields, but is also useful for detection. PMID- 29394820 TI - [A Case Involving the Re-Application of TAE for the Rupture of Recurrent Dissemination Lesion after Initial TAE and Hepatectomy Was Performed for A Previous Rupture of HCC]. AB - The patient was a 65-year-old man who had been previously diagnosed with chronic hepatitis B, but the patient had discontinued treatment while in his thirties. The patient was admitted to the emergency department after losing consciousness due to abdominal pain. Emergency contrast CT was performed in the shock state, and the diagnosis was hemorrhagic shock due to rupture of hepatocellular carcinoma(HCC). Emergency TAE was performed, and hemostasis was successful due to left hepatic arterial embolism. The tumor was confined to the liver lateral area and it was judged to be resectable curatively, upon state restoration. Ten days after TAE, lateral segmentectomy of the liver was performed. Pathological findings indicated moderately differentiated HCC, mostly necrotic and partially viable. He was discharged on 11POD. On 69POD, the patient reexperienced sudden abdominal pain after lunch. The abdominal pain continued while emergency contrast CT was performed at the time of visit in the shock state. Recurrence of multiple dissemination via high-absorption ascites was found around the largest tumor nest with lower left diaphragm diameter of 15cm, and it was judged that the HCC disseminated recurrence had ruptured. Emergency TAE was performed again, and hemostasis was successful by embolization of the left gastric artery and lower left diaphragm artery. Subsequently, tumor growth slowed after initiating oral administration of sorafenib, and the patient is alive 8 months after re-TAE. PMID- 29394821 TI - [A Case of an IgG4-Related Inflammatory Pseudotumor of the Liver Showing Enlargement That Was Difficult to Differentiate from Hepatic Cancer]. AB - A 60-year-old man was admitted for a liver mass(S3), which rapidly increased in size during intraductal papillary mucinous neoplasm(IPMN)follow-up. Although EOB MRIwas performed, the mass could not be accurately diagnosed as hepatic cancer. Thus, we performed a lateral segmentectomy. In the resected specimen, a solid tumor mass was clearly bound in segment 3 of the liver. Since histopathology revealed no malignant cells and many IgG4-positive cells, we confirmed the diagnosis as IgG4-related inflammatory pseudotumor of the liver. IgG4-related diseases occur in various organs in the body, and they are known to associate with autoimmune pancreatitis and sclerosing cholangitis, but an IgG4-related inflammatory pseudotumor of the liver is a rare disease. It is often difficult to distinguish from hepatic cancer and surgical resection is performed. PMID- 29394822 TI - [A Case of Xanthogranulomatous Cholecystitis That Changed Over Time and Was Difficult to Distinguish from Advanced Gallbladder Cancer]. AB - A 70-year-old man was referred because of suspected gallbladder cancer and gallstones. Contrast-enhanced CT, EOB-MRI and PET-CT could not completely rule out gallbladder cancer. The patient preferred follow-up without surgery. At 4 months after initial examination, the gallbladder wall thickening showed improvement, but appeared worse at 9 months after initial examination. Therefore, we decided to perform surgery. Since malignant findings were not observed on rapid intraoperative pathology, we performed a cholecystectomy and right hemicolectomy because of inflammation in the transverse colon. Pathological examination diagnosed xanthogranulomatous cholecystitis. The imaging appearance of xanthogranulomatous cholecystitis varies, and also changes over time, making it difficult to distinguish from advanced gallbladder cancer. We experienced a case of xanthogranulomatous cholecystitis that changed over time, and report this case with a review of the literature. PMID- 29394823 TI - [Metastatic Pancreatic Carcinoma from Renal Cell Carcinoma Indistinguishable from Primary Pancreatic Endocrine Tumor - A Case Report]. AB - A hypervascularized tumor was detected in a 65-year-old man who had underwent a nephrectomy for a right renal cell carcinoma at the age of 55 years. We diagnosed the tumor as a non-functioning pancreatic neuroendocrine tumor or a metastatic tumor from the renal cell carcinoma. We performed distal pancreatectomy with splenectomy and lymph node dissection. The tumor was histopathologically diagnosed as metastatic renal cell carcinoma. PMID- 29394824 TI - [A Case of Breast Cancer Associated with Dermatitis That Was Difficult to Differentiate from Dermatomyositis]. AB - A 46-year-old woman visited our hospital with a chief complaint of a mass in the right breast. Breast ultrasonography revealed a hypoechoic area with an indistinct border on the right breast, and right axillary lymph node swelling. A core needle biopsy revealed invasive ductal carcinoma, and the diagnosis was right breast cancer, cT2N2M0, Stage III A, HER2-enriched type. We administered 4 courses of FEC followed by weekly paclitaxel plus trastuzumab. After the treatment, she had eruption and erythema on the face, precordium and forearm. Though dermatomyositis associated cancer was suspected, a definite diagnosis was not made. However, skin symptoms were improved significantly after mastectomy, suggesting that she had dermatomyositis. For the skin symptom during breast cancer treatment, the examination should be made with the possibility of the adverse effect of chemotherapy and dermatomyositis associated cancer. PMID- 29394825 TI - [A Case of Bladder Metastasis from Breast Cancer]. AB - A 64-year-old woman visited hospital with a chief complaint of a nodule at the left neck skin. Skin biopsy revealed adenocarcinoma, and the diagnosis was skin metastasis of unknown primary origin. Positron emission tomography and computed tomography showed multiple bone and lymph node metastasis, left breast tumor, bladder tumor, and hydronephrosis. A needle biopsy of breast revealed invasive ductal carcinoma, and transurethral biopsy of bladder revealed adenocarcinoma. The findings were similar to those for the breast and the expression pattern of estrogen-receptor was the same. We diagnosed her with breast cancer and bladder metastasis. We administered systemic chemotherapy, however she died 10 days later. Bladder metastasis of breast cancer is rarely encountered in clinical practice and is often accompanied by life threatening symptoms. Careful histopathological examinations and rapid systemic chemotherapy are significant. PMID- 29394826 TI - [A Patient with Lower Lip Verrucous Carcinoma Treated with a Tongue Flap for Functional and Esthetic Reconstruction]. AB - Surgery is generally indicated for the treatment of lower lip carcinoma. However, surgery can lead to esthetic as well as functional issues, with disturbances in eating and articulation. If the defect involves less than one-third of the width of the lower lip, primary closure is possible. If the defect is wider, reconstructive local flaps may be necessary for both esthetic and functional recovery. This report describes a case of lower lip verrucous carcinoma in which a tongue flap was used to treat a defect involving more than half the width of the lower lip following resection. The patient was a 91-year-old woman who complained of lower lip discomfort. A biopsy revealed verrucous carcinoma, and we performed resection. After a 3-week waiting period, we performed secondary tongue flap reconstruction. Satisfactory function and cosmetic results were achieved. PMID- 29394827 TI - Comprehensive Treatment Using Cytoreductive Surgery Combined with Perioperative Chemotherapy Improved Outcome of Colorectal Cancer Patients with Metachronous Peritoneal Metastasis. AB - To analyze the role of cytoreductive surgery(CRS)plus perioperative chemotherapy on the survival of colorectal cancer(CRC)patients with metachronous peritoneal metastasis(PM). A comprehensive treatment consisting of neoadjuvant chemotherapy plus CRS was performed in 291 CRC patients. Among the 291, 142 and 149 patients had synchronous and metachronous PM, respectively. The results showed no survival difference between the 2 groups. Median survival time(MST)of patients with metachronous PM with complete cytoreduction(CCR-0), small bowel(SB)-PCIC2, PCIC14 and differentiated histologic type ranged from 3.1 to 4.1 years. Five-year survival rates of metachronous group of the CCR-0, SB-PCIC2, PCI C14 and differentiated histologic type ranged from 25.8 to 38.9%. However, the 5-year survival rates of the incomplete cytoreduction(CCR-1), SB-PCIB3, PCIB15 and poorly differentiated type were significantly lower than those of the CCR-0, SB PCIC2, PCIC14 and differentiated histologic type. Postoperative Grade 3, and Grade 4 morbidity were experienced in 11(5.8%)and 16(10.7%)in metachronous group. Mortalities of metachronous group were 1.3%(2/149). The comprehensive treatment can be performed safely and improves the survival of CRC patients with metachronous PM. After NAC, patients with SB-PCIC2, PCIC14 and differentiated type of histology are candidates for CRS, and CCR-0 resection combined with HIPEC is recommended. PMID- 29394828 TI - [A Case of Emergency Resection of Esophageal Cancer Which is on the Brink of Perforation after Neoadjuvant Chemotherapy]. AB - According to the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus in Japan, the standard treatment of esophageal cancer with cStage II / III is preoperative chemotherapy and radical resection. But when the tumor has deep ulcer, the perforation of it is sometimes occurred due of the anti-tumor effect and we are forced to change the standard treatment. In this time, we report a case of emergency resection of esophageal cancer which is on the brink of perforation after neoadjuvant chemotherapy. A 62-year-old woman had locally advanced esophageal cancer(cT4N2M0)and performed neoadjuvant chemotherapy(NAC). After 2 courses of NAC, the patient got into critical condition that the esophageal cancer was on the brink of perforation, thus we immediately performed emergency resection of the tumor. Unfortunately, the tumor was not completely resected because of invasion to the Botallo ligament, but we were able to avoid a critical state such as mediastinitis or penetration to the aorta. In multimodality therapy for locally advanced tumor, immediate response to oncologic emergency is significantly required, impacting on the prognosis and quality of life. PMID- 29394829 TI - [Sixteen Cases of Colon Stenting as a Bridge to Surgery(BTS)for Obstructive Colorectal Cancer]. AB - INTRODUCTION: Colonic stent insertion is widely used as a bridge to surgery(BTS)for obstructive colorectal cancer. Stenting can shorten hospitalization and decrease complication and colostomy rates in comparison with emergency surgery. We investigated patients who underwent colonic stent insertion for BTS in our hospital. PATIENTS: Sixteen patients(8 men, 8 women) with a colorectal obstruction score of 0 or 1 who underwent colonic stent insertion as a BTS between April 2015 and April 2017 period were investigated. RESULTS: Mean patient age was 68.2(45-94)years. Technical success was obtained in all patients, and clinical success in 14(87%). Total colonoscopy was possible via stent in 10 patients. Nine patients were temporarily discharged from the hospital, and median time to operation was 18(2-43)days. Laparoscopic resection was performed in 14 patients, and anastomotic leakage was a postoperative complication in 1 patient. Colostomy was performed in only 1 patient with anastomotic leakage. CONCLUSION: Good results were obtained with careful patient selection and safe colonic stent insertion. PMID- 29394830 TI - [Prolonged Survival Following Chemotherapy in Bone Marrow Carcinomatosis Due to Esophagogastric Junctional Carcinoma - A Case Report]. AB - A 60s-year-old Japanese male underwent curative resection for an advanced adenocarcinoma of the esophagogastric junction(Stage III C), followed by adjuvant chemotherapy.Twenty -one months later, he was admitted to our hospital with a complaint of marked decline in activities of daily living(ADL).The patient was diagnosed with pancytopenia, disseminated intravascular coagulation(DIC), multiple lymph node and bone metastases, and bone marrow carcinomatosis.After completing a sufficient informed consent process, he received chemotherapy along with blood transfusion, and then DIC, pancytopenia, and ADL of the patient improved.However, the lack of response of pancytopenia and DIC to transfusion relapsed and his ADL worsened after the second course of chemotherapy.It was difficult to administer additional chemotherapy in the patient and he died 24 months after surgery.There is no established treatment for disseminated carcinomatosis of the bone marrow, and the prognosis of these patients without treatment is reported to be only one month.Our case with prolonged survival following chemotherapy and blood transfusion may support the clinical usefulness of chemotherapy for bone marrow carcinomatosis from esophagogastric junctional carcinoma. PMID- 29394831 TI - [A Case of a Two-Stage Hepatectomy for Irresectable Colorectal Cancer Liver Metastases]. AB - A 60-year-oldman was diagnosedwith ascending colon cancer with multiple bilobar metastases. He then received7 courses of tegafur-gimeracil-oteracil andoxaliplatin (SOX)plus panitumumab as downstaging chemotherapy. This treatment significantly reducedthe size of the metastatic tumor, andwe subsequently triedto perform a curative resection. A twostage hepatectomy was plannedto avoidthe risk of hepatic failure from small future liver remnant. First, the anterior segmentectomy andthe left portal vein ligation were performed. Then, a curative resection consisting of a left lobectomy andextend - edright hemicolectomy were performed2 0 days after the first surgery. No recurrence was observed1 5 months after the operation. Two-stage hepatectomy as well as a combination of induction chemotherapy and portal vein ligation may have contributedto the improvedprognosis of the initially unresectable multiple bilobar liver metastases. PMID- 29394832 TI - [A Case of Pararectal Epidermoid Cyst Removed by Sacral Approach]. AB - A 30-year-old woman was admittedto the hospital because of fecal occult bloodpositivity . Endoscopic colonoscopy indicated pressure on the right side of the rectum from the wall. Abdominal contrast CT and pelvic MRI revealed a cystic lesion with a maximum diameter of 5 cm on the pre-coccyx andthe right side of rectum. There was no continuity between the tumor andthe uterus/ovary. We diagnoseda pararectal tumor andremovedit via a sacral approach. The cyst was diagnosed as an epidermoid cyst. She was discharged on the 5th postoperative day. We could resect the tumor completely, because we chose an appropriate approach, considering the position, developmental direction, and size of the tumor. PMID- 29394833 TI - [Adjuvant Chemotherapy for Hemophilia B - A Case Report]. AB - A 80s-year-old man with hemophilia B underwent operation for rectal cancer.Metastasis of the lymph nodes was revealed, so he was treated with adjuvant chemotherapy involving capecitabine and oxaliplatin(CapeOX).For safety, we measured tissue factor IX before every course of chemotherapy, and he completed 8 courses safely. PMID- 29394834 TI - [Splenic Artery Left Common Iliac Artery Bypass for Hepatocellular Carcinoma with Celiac Artery Compression Syndrome - A Case Report]. AB - Celiac artery compression syndrome(CACS)is a rare disorder characterized by postprandial intestinal angina caused by insufficient blood supply to the gastrointestinal organs. In this syndrome, the root of the celiac artery is compressed and narrowed by the median arcuate ligament of the diaphragm during expiration, sometimes causing difficulties in trans-arterial intervention. We report here a case that trans-hepatic arterial intervention was able to performed by splenic bypass. A 74- year-old man with multiple hepatocellular carcinoma(HCC)was performed the angiography, and diagnosed as CACS due to celiac artery root obstruction. The median arcuate ligament was incised in order to introduce trans-arterial intervention, but sufficient resumption of blood flow in the root of celiac artery could not be obtained, so bypass surgery was added from left common iliac artery to splenic artery with grafted right saphenous vein. One month later, trans hepatic arterial intervention is performed via graft, and treatment of HCC is ongoing. Splenic artery left common iliac artery bypass surgery was also considered to be an option for cases in which the resurgence of the blood flow in the root of the celiac artery was not obtained even in the median arcuate ligament dissection for CACS. PMID- 29394835 TI - [A Case of Small-Sized Acinar Cell Carcinoma of the Pancreas Resected by Laparoscopic Distal Pancreatectomy]. AB - A 81-year-old woman was referred to our hospital for a stomach pain. Abdominal enhanced CT scan showed a pancreatic hypovascular tumor 10mm in size. Abnormal FDG uptake was found on the tumor at FDG/PET-CT examination. The tumor was identified also at endoscopic ultrasonography, and the endoscopic ultrasound guided fine needle aspiration biopsy of this tumor gave the diagnosis of pancreatic adenocarcinoma. Under the preoperative diagnosis, laparoscopic distal pancreatectomy was performed. There were no postoperative complications. Histopathological examination of the resected tumor revealed acinar cell carcinoma of the pancreas, not pancreatic adenocarcinoma. The patient is alive without any postoperative recurrences 1 year after the pancreatectomy. PMID- 29394836 TI - [Long-Term Disease-Free Survival by Curative Resection in a Case of Remnant Gastric Cancer with Peritoneal Recurrence]. AB - The patient was 69-year-old man. For the remnant gastric cancer, partial resection of the remnant stomach with combined resection of mesentery of transverse colon was performed. Pathological diagnosis was adenocarcinoma(tub2>tub1), M, B- 50-AJ, type 3, pT4b(mesentery of transverse colon), pN0, CY0. A CT scan of 6 months after the surgery showed a tumor on the left side abdomen and diagnosed as peritoneal recurrence. Chemotherapy consisted of 1 course of TS-1(100mg/body) plus cisplatin(70mg/body), 4 courses(2 weeks administration and 1 week break)of TS-1(100mg/body), 8 courses of docetaxel(80mg/body). Tumor shrinkage and internal necrosis were observed. Peritoneal tumor was resected 19 months after the first surgery, and partial resection of the invaded transverse colon and jejunum was performed. Pathological diagnosis was metastasis of remnant gastric cancer. After that, it is 61 months since the first surgery and 42 months from the recurrence surgery without relapse. PMID- 29394837 TI - [A Case of Resection of Obstructive Colon Cancer Associated with Aspiration Pneumonia, Under Combined Epidural-Spinal Anesthesia]. AB - An 89-year-old woman was admitted to our hospital with vomiting, abdominal distension, and anorexia.A CT scan revealed an enhanced thickening lesion on the wall of the ascending colon, and intestinal expansion from the small intestine to the caecum.On colon fibroscopy, a round tumor was observed adjacent to the oral side of the hepatic flexure even though the end of the microscope could not progress toward the deeper regions.As the obstructive colon cancer was complicated by the presence of aspiration pneumonia, surgery could not be performed under general anesthesia.We initiated curative therapy for aspiration pneumonia right at the onset.Subsequently, due to lack of improvement in the patient's general condition, we conducted a right hemicolectomy under combined epidural-spinal anesthesia. PMID- 29394838 TI - [A Case of Small Intestinal Metastasis with Intussusception Due to Barium]. AB - A 48-year-old man noticed nausea and took health examination. After chest X-ray and gastrointestinal barium study was underwent, he was referred to our hospital because of abnormal shadow in the chest X-ray. CT scan revealed about 4 cm tumor in the hilum of left lung and target sign in the small intestine. He was diagnosed with intussusception and emergency operation was performed. During the laparotomy, we found 2 intussusceptions in the small intestine and we performed manual reduction using Hutchinson's maneuver. We confirmed the mass in oral side of the intussusception site but we did not confirmed any tumor in anal of the intussusception. This suggests the intussusception was caused by barium. Finally 3 small intestine tumor was observed and we resected and reconstructed each of the tumor. Histopathological examination showed small intestinal metastasis from pleomorphic carcinoma of the lung. PMID- 29394839 TI - [A Surgical Resected Case of VIPoma with Para-Aortic Lymph Node Involvement]. AB - A 72-year-old woman had severe watery diarrhea and weight loss. Computed tomography demonstrated a 55mm tumor in pancreatic tail with enlargement of para aortic lymph nodes. There was no apparent liver metastasis. Endoscopic ultrasound demonstrated a well-circumscribed heterogenous tumor, which was diagnosed neuroendocrine tumor by endoscopic ultrasound-guided fine needle aspiration biopsy. For suspected VIPoma with para-aortic lymph node involvement, distal pancreatectomy and para-aortic lymphadenectomy was performed. The tumor was diagnosed as VIPoma by immunohistochemistry. The diarrhea improved after surgery. No evidence of recurrence was detected after a follow-up of 11 months. PMID- 29394840 TI - [Examination of Stereotactic Mammotome Biopsy for Microcalcification in Our Hospital]. AB - We introduced stereotactic mammotome biopsy(ST-MMT)for the purpose of screening and other institutions. There are many benign cases to be diagnosed by pathological findings, so it is thought to be necessary to examine the adaptation of STMMT again. We examined the performance of ST-MMT in a case of a non palpating calcification lesion. Between August 2013 and December 2016, ST-MMT biopsies were performed for 247 microcalcified lesions revealed by mammography(in both breasts in 9 patients; twice in the ipsilateral breast in 2 patients). The mean age of all patients was 46 years(range, 24- 89 years). We found 39 cases(15.8%)of breast cancer. A final diagnosis of breast cancer was made in 39 patients, who comprised 0% of those with Category 2, 53.8% of those with Category 3, 35.9% of those with Category 4, and 10.3% of those with Category 5. Regarding the morphology and distribution of microcalcifications, breast cancer accounted for 46.2%, 5.1%, 2.6%, 35.9%, 7.7%, and 2.6% of the cases with small round/clustered, amorphous/clustered, pleomorphic/clus- tered, pleomorphic/linear segmental, and fine linear/clustered patterns, respectively. Also, we examined each of the patients, (1) who underwent mammography for medical examinations, (2) who underwent mammography performed at other institutions, (3) who underwent follow-up for microcalcifications and postoperative follow-up mammography. The proportions of breast cancer diagnoses were (1) 11.4%, (2) 20.6%, and (3) 7.1%. Proportions of Category 3 breast cancer were (1) 10.3%, (2) 38.5%, and (3) 5.1%. Among the cases in which ST-MMT was performed in this study, Category 3 accounted for more than half. However, 10.9%(21/192 lesions)were diagnosed as malignant in Category 3. The diagnosis of breast cancer in pa- tients who underwent mammography performed at other institutions was not observed in 79.4%(104/131 lesions), and among the 104 lesions, as a result of reassessment of calcification in our hospital, Category 2 was also included. Calcification in Category 2 lesions was benign in all cases. It was suggested that the indication for ST-MMT biopsy could be further narrowed down by being careful not to over-diagnose. PMID- 29394841 TI - [Two Successful Cases of Surgical Treatment of Reconstructed Gastric Tube Bronchial Fistula after Esophagectomy for Esophageal Cancer by Pedunculated Latissimus Dorsi Flap]. AB - We herein report 2 cases of successful surgical treatment of reconstructed gastric tube-bronchial fistulas caused by leakage after esophagectomy for esophageal cancer. One patient was a 56-year-old man who developed a reconstructed gastric tube-bronchial fistula, and the fistula was closed by conservative treatment. However, he developed pneumonia on postoperative day 117, and the reconstructed gastric tube-bronchial fistula was found to have recurred. Fibrin glue was endoscopically injected into the fistula, but this treatment was unsuccessful. The other patient was a 60-year-old man who developed a reconstructed gastric tube-bronchial fistula and severe pneumonia, and his condition did not improve by conservative treatment. We performed a reoperation for both patients using a pedunculated latissimus dorsi flap, and both patients recovered well. PMID- 29394842 TI - [Stereotactic Body Radiotherapy for Liver Metastasis of Gastric Cancer]. AB - Case 1: A 69-year-old man underwent distal gastrectomy in September 2007 for type 2 gastric cancer with liver metastasis (S5). After the operation, we administered chemotherapy. After that, we performed partial hepatectomy in July 2008. After hepatectomy, liver metastases appeared as 2 lesions in February 2009. Thus, we administered another type of chemotherapy. The effect of the chemotherapy was not favorable. Therefore, SBRT was performed for the liver metastases in December. After SBRT, he did not present with any recurrent tumors. Case 2: A 67-year-old woman underwent distal gastrectomy in March 2015. In August 2015, hepatic metastasis(S5 single shoot)was confirmed. Although chemotherapy was administered and SD was continued, it was ceased due to the patient's request. Thus, SBRT was performed in July 2016. However, from October 2016, multiple liver metastases developed and she died in January 2017. PMID- 29394843 TI - [A Case of Anal Canal Cancer with Skin Invasion to Which Abdominoperineal Resection and Perineum Reconstruction Were Performed after Neoadjuvant Chemoradiotherapy]. AB - A 74-year-old man visited our hospital with an awareness of anal mass and bleeding. He was diagnosed as adenocarcino- ma of anal canal with wide spreading skin invasion. After neoadjuvant chemoradiotherapy(radiationtotal 45 Gy/25 Fr; cape- citabine 825mg/m2)was performed to reduce the mass volume, laparoscopic abdominoperineal resection with large perineum skin resection and lateral lymph node dissection was carried out. The perineal defect was repaired with a rectus abdominis musculocutaneous flap. Six days after surgery, the rectus abdominis musculocutaneous flap necrotized, and second perineum reconstruction by the bilateral gracilis musculocutaneous flaps was performed after debridement of necrotic tissue. We reported a case of radical resection of local advanced anal canal cancer with skin invasion by performing combined modality therapy and perineum reconstruction. PMID- 29394844 TI - [A Case of QOL Improvement after Intestinal Stenosis Due to Peritoneal Dissemination of Gastric Cancer in Elderly Patients]. AB - Nearly 70% of gastric cancer recurrences occur as peritoneal dissemination. Most of the treatment for recurrence of gastric cancer dissemination is chemotherapy; depending on the symptoms and the site of recurrence, palliative bypass surgery may be performed. Intensive treatment is often difficult for elderly patients over 85-years-old. This case was a 91-year-old female who underwent total gastrectomy for gastric cancer(signet-ring cell carcinoma)7years prior. Two years ago, a stenosis due to recurrence was revealed in the small intestine and bypass surgery was performed. At that time, she was 89-years-old, and chemotherapy was continued for 1 year. Six months ago, recurrence was revealed in the esophago jejuno anastomosis. Since the stenosis was severe, it was possible to resume oral reconstitution by inserting a metallic stent. Chemotherapy(S-1)is currently ongoing. There are few reports of long-term treatment for recurrence of gastric cancer peritoneal dissemination in elderly people over 80 years of age. This report is a case of long-term survival involving multidisciplinary treatments, which improved the quality of life(QOL)over the age of 90 years. PMID- 29394845 TI - [Treatment Outcome of Intersphincteric Resection in Tokyo Medical University Hospital]. AB - PURPOSE: This study aimed to consider the oncological validity of intersphincteric resection(hereinafter referred to as ISR) performed at Tokyo Medical University Hospital, as well as associated dysfunction. SUBJECTS: Subjects included 73 cases in which ISR was performed at Tokyo Medical University Hospital between November 2004 and January 2016. RESULTS: The 5- year overall and relapse-free survival rates for cases with Stage 0 to III were 90.4% and 77.3%, respectively. Two cases with recurrence among cases with Stage I were both of local recurrence.The Wexner score of the cases 12 months after closure of ileostomy was 4.2+/-2.5 points, while it had not been performed for the other 10 cases. DISCUSSION: In consideration of the relatively preferable local control observed with ISRs that had been performed at our hospital, defecation disorder was considered to be within an allowance.However, there remained a problem that closure of ileostomy could not be performed for 10% of the cases. CONCLUSION: ISR was believed to be valid as a sphincter-preserving procedure in consideration of the function and curability. PMID- 29394846 TI - [A Case of Local Resection for Rectal GIST Following Neoadjuvant Imatinib Mesylate Treatment]. AB - A 67-year-old woman presented with bloody stools and constipation. A rectal digital examination revealed a smooth and elastic hard tumor in the posterior wall of the rectum. We diagnosed the tumor as rectal GIST measuring 5 cm in diameter. Because the patient desired anal preservation, neoadjuvant imatinib mesylate(IM)(400mg/day)treatment was administered. Although the diameter of the tumor reduced to 2 cm in the third week of administration, the patient experienced erythema-type drug eruption(Grade 3). We discontinued the IM treatment and initiated steroid therapy. After the eruption had disappeared, IM treatment was resumed, initially with half doses. Local transanal resection was performed 36days after the neoadjuvant IM treatment. Currently, the indication and the administration period of IM for preoperative treatment is not clear. It may be necessary to accumulate cases to evaluate neoadjuvant IM therapy. PMID- 29394847 TI - [A Case in Which S-1/Oxaliplatin(SOX)/Trastuzumab Therapy Was Effective for Unresectable HER2 Positive Advanced Gastric Cancer and Radical Resection Could Be Performed]. AB - The case was a 70s-year-old man. In July 2016, he was admitted to our hospital with a complaint of epigastralgia. Upper gastrointestinal endoscopy revealed type 3 advanced gastric cancer in the vestibule, directly infiltrating the pancreas and the left lobe of the liver to form an abscess, and swelling of the aortic lymph node and multiple liver metastases were observed. The cancer was diagnosed as cT4b(liver/pancreas), N2M1(H1P0CYX), cStage IV and diagnosed it as a chemotherapy policy. We initiated SOX plus trastuzumab therapy from August 2016. After 4 courses, the primary tumor shrunk significantly and invasion to the pancreas/liver had disappeared. Furthermore, the periarterial lymph node and multiple liver metastases were obscured(chemotherapy effect judgment: PR). With a diagnosis of ycT4aN1MX(HXP0CYX), in December 2016, we performed a pyloric side gastrectomy D2(+No.16)dissection and partial resection of the liver(S3, S4, S6), liver RFA(S4, S6, S7). Due to recent progress in chemotherapy and multidisciplinary therapy, there is a possibility that radical resection may be carried out for advanced gastric cancer, which was previously unresectable, by performing a treatment with surgery in mind. PMID- 29394848 TI - [A Case of Urothelial Carcinoma Who Underwent Pancreaticoduodenectomy and Was Diagnosed with Groove Pancreatitis and Preoperatively Suffered from Duodenal Stenosis]. AB - We report a case of a highly advanced urothelial carcinoma accompanied by duodenal stenosis with pancreaticoduodenectomy. A6 6-year-old man presented with upper abdominal pain and vomiting. Acute pancreatitis and hydronephrosis were diagnosed with urgent hospitalization, but jaundice appeared, and stenosis of the duodenum was also found. Thus, we suspected groove pancreatitis or pancreatic cancer, and performed pancreaticoduodenectomy. However, poorly differentiated adenocarcinoma was observed in the retroperitoneal dissection surface in the intraoperative rapid tissue and right hemicolectomy, right nephrectomy, and right ureteral resection were added to the diagnosis. The final diagnosis was urothelial carcinoma. GEM plus CBDCAtherapy was administered as adjuvant chemotherapy. However, obstructive jaundice, acute cholangitis, and acute pancreatitis developed due to occlusion of the intestine due to local recurrence 4 months after surgery. We attempted to reduce yellowing by PTCD; perforation of the small intestine also occurred and a drainage tube was placed in the abdominal cavity. Although a lull condition was obtained, intestinal obstruction due to cancer peritonitis worsened and the patient died 8 months after the operation. In this case, there was no hematuria before surgery and cytology results of urine were negative, so a diagnosis of urinary tract cancer was difficult. There was no report of duodenal stenosis due to urothelial carcinoma. PMID- 29394849 TI - [Three-Year Survival after Lymphadenectomy for Residual Lymph Node Metastasis of Esophageal Cancer with Invasion into the Trachea and Carotid Artery after Chemoradiotherapy - A Case Report]. AB - INTRODUCTION: Chemoradiotherapy(CRT)is an effective treatment method for esophageal cancer. In early stages, it is a standard therapy combined with surgery. However, CRT achieves definitive complete response(CR)in only about 20% of advanced cancer with invasion into adjacent organs. Then, surgery is the only treatment for curative therapy. We report a case of a patient with 3-year survival who underwent lymphadenectomy for residual cancer after CRT for advanced esophageal cancer with invasion into the trachea and right cervical artery. CASE DESCRIPTION: The patient was a 71-year-old woman. Various examinations revealed a cervical esophageal cancer, which had a right cervical lymph node metastasis with invasion into the trachea and right common cervical artery(cT4b[LYM-Tr, RCCA], N1, M0, cStage III C(UICC TNM classification). Induction chemotherapy(DCF; docetaxel[DTX]plus cisplatin[CDDP]plus 5-fluorouracil[5-FU])was initiated, but neither the cancer primary site nor the lymph node metastasis decreased. Then, she received chemoradiotherapy(5-FU plus CDDP and 40.8 Gy). After that, endoscopic and pathological examination showed CR of the primary site, but CT still indicated the presence of a residual lesion in the lymph node. As we diagnosed the residual tumor as being close to the trachea and RCCA, but not infiltrating them, lymphadenectomy was performed, which was possible to preserve the trachea and RCCA. The postoperative histopathological report indicated lymph node metastasis in the right cervical lymph node with a negative radial margin. It has now been about 3 years since her operation, and she is alive and disease free. PMID- 29394850 TI - [Multidisciplinary Treatment for Squamous Cell Carcinoma of the Anal Canal]. AB - Chemoradiotherapy(CRT)has been recognized as a standard treatment for locoregional squamous cell carcinoma of the anal canal in Western countries. However, surgery had historically been considered as a standard treatment and there are only a few reports on CRT for anal canal cancer in Japan. In this study, we analyzed medical records of 5 anal canal cancer patients treated with CRT in our hospital between 2005 and 2015. Patients' characteristics were as follows: median age, 70 years (range 42-80 years); male/female, 1/4; and clinical Stage I / III a/ III b, 3/1/1. The regimens of chemotherapy were MMC plus 5-FU in 4 patients and CDDP in 1 patient. The median follow-up period was 30 months(range, 6 to 100 months). After CRT, 4 patients achieved complete response. The other patient with partial response underwent salvage surgery. All patients were alive without recurrence. In conclusion, our retrospective study showed that CRT is considered to be a standard treat- ment for anal canal cancer. PMID- 29394851 TI - [Multimodality Therapy for Cecal Cancer with Peritoneal Dissemination]. AB - We report a case of cecal cancer with peritoneal dissemination. A 72-year-old man with cecal cancer(pT4N2M0H0P3, pStage IV )underwent ileocecal resection in 2010. The patient received 106 courses of chemotherapy(FOLFIRI plus Cmab) for peritoneal dissemination after surgery. However, follow-up CT performed 50 months after primary resection detected liver metastasis, which was resected in 2015. The patient received 19 courses of chemotherapy(FOLFIRI plus Cmab)after hepatectomy. The peritoneal dissemination with the diaphragm, retroperitoneal and right inguinal region, were growing 20 months after the 2nd operation. Surgical resection of the peritoneal dissemination was performed in 2016. The patient is alive 81 months after the 1st operation. PMID- 29394852 TI - [A Case Report of Curative Surgery for Pancreatic Ductal Adenocarcinoma with Peritoneal Dissemination after Gemcitabine Chemotherapy]. AB - A 70-year-old man was diagnosed with pancreatic ductal adenocarcinoma(PDAC)with peritoneal dissemination and received systemic chemotherapy of gemcitabine(GEM)plus nab-paclitaxel. Since the patient could not continue the regimen due to an adverse event of liver dysfunction, he was administered GEM alone except for the first administration. GEM monotherapy resulted in remarkable anti-tumor effects with a distinct decrease of both tumor markers and size. Peritoneal metastases were not detected in images after 12 courses of the GEM regimen, and the vanished tumor metastasis in images was maintained until 16 courses were administered. After the laparoscopic examination proved no peritoneal metastasis, we performed curative surgery. The presence of peritoneal metastasis of PDAC indicated that it was at a lethal stage; however, a few cases were reported as receiving curative surgery after chemotherapy with modest long term survival. We herein report a rare case of curative surgery following chemotherapy with GEM alone for unresectable PDAC accompanied with peritoneal dissemination. PMID- 29394853 TI - [Gastrectomy with Intra-Aortic Balloon Pumping Support for a Hemorrhagic Advanced Gastric Cancer Patient with Severe Coronary Stenosis]. AB - Here we report a case of a hemorrhagic gastric cancer patient with severe coronary artery disease, in whom the cancer was successfully resected with the support of intra-aortic balloon pumping(IABP). An 80-year-old man was referred to our hospital for further examination of his anemia and tumor around the pancreatic head. He was diagnosed with type 3 gastric cancer with multiple bulky lymph node metastases invadingto the pancreas(cT4b[LN-Panc], N3a, M1[LYM No.16a2int], cStage IV ). Tarry stools continued and blood transfusion was repeatedly required. To control tumor bleeding, we considered that gastrectomy should be performed prior to chemotherapy. Since he had a history of acute myocardial infarction, coronary angiography was performed, which showed severe coronary stenosis in 3 vessels. Preoperative percutaneous coronary intervention or coronary artery bypass grafting were inappropriate because of tumor bleeding. We performed palliative distal gastrectomy under the support of IABP. The postoperative course was uneventful and he could initiate subsequent chemotherapy smoothly. IABP may be a useful option for hemorrhagic gastric cancer patients with severe coronary stenosis. PMID- 29394854 TI - [Early Gastric Cancer with Many Enlarged Lymph Nodes as Sarcoid Reaction - A Case Report]. AB - The patient was a 57-year-old man. Upper gastrointestinal endoscopy revealed a 0- II c lesion at the anterior wall of the greater curvature in the lower third of the stomach, and the biopsy of this tumor gave the diagnosis of tubular adenocarcinoma. Abdominal contrast-enhanced computed tomography revealed many enlarged regional and non-regional lymph nodes. Because there was no definite evidence of lymph node metastasis, distal gastrectomy with D2 was performed. Histopathological examinations found the sarcoid reaction(SR)in lymph nodes, but could not demonstrate any cancer cells. SR is the epithelioid cell granuloma in lymph nodes found in patients without systemic sarcoidosis but with cancer. Early gastric cancer with SR is rare, with only 22 reported cases in Japan. SR is considered as one of the differential diagnoses when we find many enlarged lymph nodes in patients with early gastric cancer. PMID- 29394855 TI - [A Case of Perforation Peritonitis with Multiple Duodenal and Intestinal Malignant Lymphomas]. AB - Malignant lymphomas of the duodenum and small intestine are relatively rare, but are clinically important, as they may result in perforation peritonitis. Here, we report a case of perforation peritonitis caused by multiple duodenal and small intestinal malignant lymphomas. An 84-year-old man was diagnosed with malignant lymphoma of the duodenum. Although chemotherapy was planned, emergency surgery was performed to treat perforation peritonitis. Laparoscopic observation revealed that the perforation was not in the duodenum, but in the ileum. In addition, numerous lymphoma lesions were revealed throughout the small intestine. Partial resection of the small intestine including the perforation was performed. Primary gastrointestinal malignant lymphoma may exist over multiple digestive tracts and it is necessary to carefully diagnose and treat, even in emergency surgery. PMID- 29394856 TI - [A Case of Malignant Transformation of Intraductal Papillary Mucinous Neoplasm of the Pancreas Accompanied by Metachronous Triple Primary Cancer]. AB - A 70's woman with a history of abdominal surgery for gastric cancer visited our hospital for the evaluation of bleeding during defecation.We diagnosed her with advanced rectal cancer and performed laparoscopic low anterior resection.As postoperative pathological staging was pT3N2M0, pStage III b, we included CapeOx therapy as adjuvant chemotherapy.One year and 4 months after the surgery, lung and liver metastases were revealed by CT and PET-CT scans.At the same time, dilatation of the main pancreatic duct(intraductal papillary mucinous neoplasm: IPMN)was detected.Thus, we first performed liver resection and then lung resection.After the surgery, new lung nodules and a mass lesion with IPMN with superior mesenteric venous invasion was found on CT scans.We then administered chemo-radiation therapy(CRT).After CRT, the lung and pancreatic lesions seemed to decrease slightly.Accidentally, a nodule on the cystic bladder was found, resected by transurethral resection of the bladder tumor(TUR-Bt), and diagnosed as a bladder cancer.Thirty months after the rectal surgery, she is continuing the S-1 chemotherapy with stable disease. PMID- 29394857 TI - [A Case of a Hepatic Inflammatory Pseudotumor Difficult to Distinguish from Metastatic Liver Cancer and Potentially Caused by Colon Diverticula]. AB - This report describes the case of an 85-year-old man who underwent left hemicolectomy for descending colon cancer and hepatic segmentectomy for metastatic liver cancer. Seven years after the liver surgery, an abdominal CT scan revealed a tumor in the remnant liver. He also presented with colon diverticula in the ascending colon, which was located close to the liver tumor. With a preoperative diagnosis of metastatic liver cancer, the tumor was resected with S8 segmentectomy. Histopathological examination of the resected tumor revealed a hepatic inflammatory pseudotumor, not metastatic liver cancer. The present case showed the difficulty of preoperatively diagnosing inflammatory pseudotumors. Furthermore, it is noted in the case that since the liver tumor was located close to the colon diverticula in the ascending colon, the diverticula was potentially associated with the formation of hepatic inflammatory pseudotumor. PMID- 29394858 TI - [Case of Adenocarcinoma with Neuroendocrine Carcinoma Component in the Gallbladder]. AB - A 73-year-old man visited our hospital complaining of abdominal pain. An abdominal CT scan revealed diffuse wall thickening of the gallbladder with a gallstone. Urgent laparoscopic cholecystectomy was performed with the diagnosis of acute cholecystitis. Histopathological examination indicated adenocarcinoma with a small neuroendocrine carcinoma component invading the subserous layer. Additional gallbladder bed resection and lymphadenectomy were performed. The final pathological diagnosis was adenocarcinoma with NEC, pT2N0M0, pStage II . The patient is alive without any recurrence 7 months after the last surgery. PMID- 29394859 TI - [Applicability of Pedicled Coronoid Process and Temporal Muscle(Fascial)Combined(PCPTM)Flap for Reconstruction of Orbital Floor Defect Following Hemi-Maxillectomy for Advanced Maxillary Cancer - A Report of Two Cases]. AB - We usually perform surgery for resectable oral and maxillofacial carcinomas. Following complete cancer resection, reconstruction of soft and hard tissues using various types of local flaps and/or vascularized free flaps is usually performed. The maxilla is composed of various anatomical structures. In particular, reconstruction of the orbit is one of the most important and challenging procedures for prevention of functional and esthetic complications. Here we report 2 cases of orbital floor defect reconstruction following advanced maxillary cancer resection using a pedicled coronoid process and temporal muscle (fascial)combined(PCPTM)flap. Case 1: A 69-year-old Japanese man with squamous cell carcinoma of the left maxilla (cT4aN2bM0, Stage IV A). Case 2: An 86-year old Japanese woman with recurrence of myoepithelial carcinoma of the left maxilla. In both cases, the orbital floor defect was reconstructed following hemi maxillectomy using a PCPTM flap. Minor infection and/or partial necrosis were observed postoperatively, and a maxillofacial prosthesis was used in one case. A PCPTM flap was feasible for reconstruction of surgical defects of the orbital floor following maxillectomy for cancer. PMID- 29394865 TI - The role of flexible sigmoidoscopy in the evaluation of isolated rectal bleeding PMID- 29394866 TI - Exercise caution in prescribing medications for lower urinary tract symptoms in the elderly PMID- 29394867 TI - Re: Anaemia and iron deficiency in pregnant women attending an antenatal clinic in a Teaching Hospital in Southern Sri Lanka PMID- 29394868 TI - Authors response: Anaemia and iron deficiency in pregnant women attending an antenatal clinic in a Teaching Hospital in Southern Sri Lanka PMID- 29394869 TI - Analgesic efficacy and safety of non-prescription doses of naproxen sodium in the management of moderate osteoarthritis of the knee or hip. AB - OBJECTIVES: Current osteoarthritis therapies aim to alleviate pain and maintain joint function. Non-prescription oral non-steroidal anti-inflammatory drugs are frequently used alone for pain relief in osteoarthritis. This post-hoc pooled analysis evaluated the analgesic efficacy and safety of two non-prescription doses of naproxen sodium for short-term use in patients with osteoarthritis of the knee or hip. A separate sub-group analysis of older patients who were administered a lower dose of naproxen sodium was performed. METHODS: In four multi-center, multi-dose, randomized, parallel, double-blind, placebo-controlled studies, oral naproxen sodium (age-based dosing regimen: <65 years, 660 mg/day; >=65 years, 440 mg/day) or placebo was administered over 7 days. Data at baseline and after 7 days in 818 patients who received naproxen sodium or placebo (n = 409 in each group) was pooled and analyzed. Five-point rating scales were used to assess knee or hip joint pain, stiffness after rest, day and night pain, and patient and investigator assessment of treatment, while function was evaluated using a timed 50-foot walk test. RESULTS: Compared with placebo, there were significant improvements in pain and physical function with naproxen sodium (p < .05), and treatment was rated "good" to "excellent" significantly more often (p < .001) by investigators and patients. Efficacy results were similar among younger and older patients. There were no significant differences in adverse events between groups, regardless of age. CONCLUSIONS: For the acute management of underlying pain in patients with moderate osteoarthritis of the hip or knee, non prescription naproxen sodium is effective and well tolerated in patients of all ages. PMID- 29394870 TI - A 3-year study of patients with tinnitus and jaw muscle tenderness. AB - OBJECTIVE: This study evaluated three-year results of treatment with an interocclusal appliance in 89 tinnitus patients with jaw muscle tenderness. METHODS: Subjective tinnitus severity was recorded using a visual analog scale (VAS). The number of tender muscles was registered. The patients were followed annually. After three years, 64 patients were examined (72%). RESULTS: Tinnitus severity at baseline was high (mean VAS value 68.3). After one year, the VAS values were substantially lower (mean 37.4; p < 0.001). During the following two years, there were no significant changes in VAS values. The mean number of tender muscles decreased from seven to two after one year and remained at this number for up to three years. CONCLUSION: In many tinnitus patients with signs of temporomandibular disorders (TMDs), intraoral splint therapy reduced tinnitus severity and jaw muscle symptoms. The favorable results after one year remained for up to three years without significant changes. PMID- 29394871 TI - Structural characterisation and ACE-inhibitory activities of polysaccharide from Gastrodia elata Blume. AB - The structural properties and Angiotensin-I converting enzyme (ACE) inhibition activities of a polysaccharide (PGE) extracted from Gastrodia elata Blume were investigated. PGE was extracted using hot water and purified by Sephadex G-200 followed by ultra-filtration. The structural characterisation of PGE was analysed by FT-IR, NMR spectroscopy, specific rotation determination, periodate oxidation smith degradation, methylation analysis, GC-MS and Congo red test. The results revealed that PGE was composed by glucose, with an average molecular weight of 1.54 * 103 kDa. The structure of PGE was 1->3 and 1->4,6-branched-glucopyranose that had a linear backbone of (1 -> 4)-linked-d-glucopyranose (Glcp). ACE inhibitory activity results showed that PGE was efficient to inhibit ACE and the IC50 value was 0.66 mg/mL. PMID- 29394873 TI - Composition of essential oil of lemon thyme (Thymus * citriodorus) at different hydrodistillation times. AB - Distillation time can both to optimise the production and to engineer the composition of essential oil in essential oil bearing plants. Purpose of this study was to evaluate the effect of duration of hydrodistillation on composition of essential oil of Thymus * citriodorus, the natural source of commercially important geraniol and citral, a component with valuable biological properties. Essential oils were isolated by hydrodistillation at different distillation times and analysed by GC/MS analytical methods. Increase in percentage of essential oil during all hydrodistillation time gradient was uneven. Elongation of hydrodistillation time decreased percentages of monoterpenes but increased percentages of sesquiterpenes in essential oil. Results showed that the hydrodistillation of essential oil from lemon thyme longer than 60 min is useless. PMID- 29394872 TI - Design for patient safety: a systems-based risk identification framework. AB - Current risk identification practices applied to patient safety in healthcare are insufficient. The situation can be improved, however, by studying systems approaches broadly and successfully utilised in other safety-critical industries, such as aviation and chemical industries. To illustrate this, this paper first investigates current risk identification practices in the healthcare field, and then examines the potential of systems approaches. A systems-based approach, called the Risk Identification Framework (RID Framework), is then developed to enhance improvement in risk identification. Demonstrating the strengths of using multiple inputs and methods, the RID Framework helps to facilitate the proactive identification of new risks. In this study, the potential value of the RID Framework is discussed by examining its application and evaluation, as conducted in a real-world healthcare setting. Both the application and evaluation of the RID Framework indicate positive results, as well as the need for further research. Practitioner Summary: The findings in this study provide insights into how to make a better amalgamation of risk identification inputs to the safer design and more proactive risk management of healthcare delivery systems, which have been an increasing research interest amongst human factor professionals and ergonomists. PMID- 29394874 TI - Alcoholic monoterpenes found in essential oil of aromatic spices reduce allergic inflammation by the modulation of inflammatory cytokines. AB - Allergic inflammation is a response of the body against pathogens by cytokine release and leucocyte recruitment. Recently, there was an increase in morbimortality associated with allergic inflammation, especially asthma. The treatment has many adverse effects, requiring the search for new therapies. Monoterpenes are natural products with anti-inflammatory activity demonstrated in several studies and can be an option to inflammation management. Thus, we investigated the effects of citronellol, alpha-terpineol and carvacrol on allergic inflammation. The model of asthma was established by OVA induction in male Swiss mice. The monoterpenes were administered (25, 50 or 100 mg/kg, i.p.) 1 h before induction. After 24hs, the animals were sacrificed to leucocytes and TNF alpha quantification. Monoterpenes significantly decrease leucocyte migration and TNF-alpha levels, possibly by modulation of COX, PGE2 and H1 receptor, as demonstrated by molecular docking. These findings indicate that alcoholic monoterpenes can be an alternative for treatment of allergic inflammation and asthma. PMID- 29394875 TI - Enzymatic inhibitory activity of Ficus deltoidea leaf extract on matrix metalloproteinase-2, 8 and 9. AB - Dysregulation of matrix metalloproteinases (MMPs) activity is known in many pathological conditions with which most of the conditions are related to elevate MMPs activities. Ficus deltoidea (FD) is a plant known for its therapeutic properties. In order to evaluate the therapeutic potential of FD leaf extract, we study the enzymatic inhibition properties of FD leaf extract and its major bioactive compounds (vitexin and isovitexin) on a panel of MMPs (MMP-2, MMP-8 and MMP-9) using experimental and computational approaches. FD leaf extract and its major bioactive compounds showed pronounced inhibition activity towards the MMPs tested. Computational docking analysis revealed that vitexin and isovitexin bind to the active site of the three tested MMPs. We also evaluated the cytotoxicity and cell migration inhibition activity of FD leaf extract in the endothelial EA.hy 926 cell line. Conclusively, this study provided additional information on the potential of FD leaf extract for therapeutical application. PMID- 29394876 TI - The development of biological therapies for neurological diseases: moving on from previous failures. AB - INTRODUCTION: Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases. Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed. Moreover, the authors describe the key challenges in the development of therapeutically safe and effective biologics for the treatment of neurological diseases. Expert opinion: Several biologics have shown promise in the treatment of neurological diseases. However, the complexity of the CNS, as well as a limited understanding of disease progression, and restricted access of biologics to the CNS has limited successful development. Therefore, more research needs to be conducted to overcome these hurdles before developing effective and safe biologics for neurological diseases. The emergence of new technologies for the design, production and delivery of biologics will accelerate translating biologics to the clinic. PMID- 29394878 TI - Real-world clinical responses in patients with type 2 diabetes mellitus adding exenatide BID (EBID) or mealtime insulin to basal insulin: a retrospective study using electronic medical record data. AB - AIM: Exenatide twice daily (EBID) and mealtime insulin are effective add-on therapies to basal insulin for type 2 diabetes patients in clinical trials. This study used electronic medical record (EMR) data to evaluate analogous real-world clinical responses. MATERIALS AND METHODS: Adult patients initiating EBID or mealtime insulin as add-on to basal insulin during January 2008-March 2013 were identified in a US EMR database. EBID patients were propensity score matched 1:1 to mealtime insulin patients. Cohorts were followed for 12 months before (baseline) and 6 months after the index. A1C, hypoglycemic events, change in weight, and other clinical measures were evaluated by A1C attainment level (<6.5, < 7, < 7.5, <8, <9%) and baseline A1C. RESULTS: In total, 1249 EBID patients were matched to 1249 mealtime insulin patients. During follow-up, the percentage reaching A1C levels was similar for EBID vs mealtime insulin cohorts for all attainment levels (<7%: 27.8% vs 24.2%; < 9%: 79.7% vs 79.2%; p = NS). The percentage reaching A1C < 7% was similar for both cohorts with different baseline A1C. EBID patients had less hypoglycemia at all attainment levels (3.1% vs 11.1% [<6.5%]; 2.5% vs 4.7% [<9%]; all p < .03) and more weight loss (-9.0 vs -3.2 lb [<6.5%]; -3.4 vs +0.8 lb [<9%]; all p < .01). CONCLUSIONS: EBID added to basal insulin was as effective in a real-world setting as mealtime insulin added to basal insulin in reducing A1C, with less weight gain and less hypoglycemia for a wide range of A1C attainment levels and baseline values. PMID- 29394877 TI - Differences in the Lateral Compartment Joint Space Width After Anterior Cruciate Ligament Reconstruction: Data From the MOON Onsite Cohort. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. PURPOSE: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged <=33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. RESULTS: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL reconstructed knee included lateral meniscectomy ( P < .001) and a Marx activity score less than 16 points ( P < .001). CONCLUSION: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury. PMID- 29394879 TI - Dysbiotic Biofilms Deregulate the Periodontal Inflammatory Response. AB - Periodontal diseases originate from a dysbiosis within the oral microbiota, which is associated with a deregulation of the host immune response. Although little is known about the initiation of dysbiosis, it has been shown that H2O2 production is one of the main mechanisms by which some commensal bacteria suppress the outgrowth of pathobionts. Current models emphasize the critical nature of complex microbial biofilms that form unique microbial ecologies and of their change during transition from health (homeostatic) to disease (dysbiotic). However, very little is known on how this alters their virulence and host responses. The objective of this study was to determine differences in virulence gene expression by pathobionts and the inflammatory host response in homeostatic and dysbiotic biofilms originating from the same ecology. Quantitative polymerase chain reaction was performed to quantify the pathobiont outgrowth. Expression analysis of bacterial virulence and cellular inflammatory genes together with cytokine enzyme-linked immunosorbent assays were used to detect differences in bacterial virulence and to analyze potential differences in inflammatory response. An increase in pathobionts in induced dysbiotic biofilms was observed compared to homeostatic biofilms. The main virulence genes of all pathobionts were upregulated in dysbiotic biofilms. Exposure of these dysbiotic biofilms to epithelial and fibroblast cultures increased the expression of interleukin (IL) 6, IL-1beta, tumor necrosis factor-alpha, and matrix metalloprotease 8, but especially the chemokine CXCL8 (IL-8). Conversely, homeostatic and beneficial biofilms had a minor immune response at the messenger RNA and protein level. Overall, induced dysbiotic biofilms enriched in pathobionts and virulence factors significantly increased the inflammatory response compared to homeostatic and commensal biofilms. PMID- 29394880 TI - Patients' experiences of living with medically unexplained symptoms (MUS): a qualitative study. AB - BACKGROUND: Patients with medically unexplained symptoms (MUS) are common in primary care, and pose a communicative and therapeutic challenge to GPs. Although much has been written about GPs' frustration and difficulties while dealing with these patients, research presenting the patients' perspectives on MUS still seems to be scarce. Existing studies have demonstrated the patients' desire to make sense of symptoms, addressed the necessity for appropriate and acceptable explanation of MUS, and revealed stigmatization of patients with symptoms of mental origin. Treatment in primary care should focus on the patient's most essential needs and concerns. The objective of this paper is to explore Polish patients' perspectives on living with MUS. METHODS: A qualitative content analysis of 20 filmed, semi-structured interviews with patients presenting MUS (8 men and 12 women, aged 18 to 57) was conducted. All patients were diagnosed with distinctive somatoform disorders (F45), and presented the symptoms for at least 2 years. The interviews were transcribed verbatim and analysed independently by two researchers. RESULTS: Four major themes emerged: (1) experiences of symptoms; (2) explanations for symptoms; (3) coping; (4) expectations about healthcare. Within the first theme, the patients identified the following sub-themes: persistence of symptoms or variability, and negative emotions. Patients who observed that their symptoms had changed over time were better disposed to accept the existence of a relationship between the symptoms and the mind. The second theme embraced the following sub-themes: (1) personal explanations; (2) social explanations; (3) somatic explanations. The most effective coping strategies the patients mentioned included: the rationalization of the symptoms, self-development and ignoring the symptoms. The majority of our respondents had no expectations from the healthcare system, and stated they did not use medical services; instead, they admitted to visiting psychologists or psychiatrists privately. CONCLUSION: Patients with MUS have their own experiences of illness. They undertake attempts to interpret their symptoms and learn to live with them. The role of the GP in this process is significant, especially when access to psychological help is restricted. Management of patients with MUS in the Polish healthcare system can be improved, if access to psychologists and psychotherapists is facilitated and increased financial resources are allocated for primary care. Patients with MUS can benefit from a video/filmed consultation with a follow-up analysis with their GP. PMID- 29394881 TI - Wnt signaling and polarity in freshwater sponges. AB - BACKGROUND: The Wnt signaling pathway is uniquely metazoan and used in many processes during development, including the formation of polarity and body axes. In sponges, one of the earliest diverging animal groups, Wnt pathway genes have diverse expression patterns in different groups including along the anterior posterior axis of two sponge larvae, and in the osculum and ostia of others. We studied the function of Wnt signaling and body polarity formation through expression, knockdown, and larval manipulation in several freshwater sponge species. RESULTS: Sponge Wnts fall into sponge-specific and sponge-class specific subfamilies of Wnt proteins. Notably Wnt genes were not found in transcriptomes of the glass sponge Aphrocallistes vastus. Wnt and its signaling genes were expressed in archaeocytes of the mesohyl throughout developing freshwater sponges. Osculum formation was enhanced by GSK3 knockdown, and Wnt antagonists inhibited both osculum development and regeneration. Using dye tracking we found that the posterior poles of freshwater sponge larvae give rise to tissue that will form the osculum following metamorphosis. CONCLUSIONS: Together the data indicate that while components of canonical Wnt signaling may be used in development and maintenance of osculum tissue, it is likely that Wnt signaling itself occurs between individual cells rather than whole tissues or structures in freshwater sponges. PMID- 29394882 TI - Genome analysis of Mycoplasma synoviae strain MS-H, the most common M. synoviae strain with a worldwide distribution. AB - BACKGROUND: The bacterial pathogen Mycoplasma synoviae can cause subclinical respiratory disease, synovitis, airsacculitis and reproductive tract disease in poultry and is a major cause of economic loss worldwide. The M. synoviae strain MS-H was developed by chemical mutagenesis of an Australian isolate and has been used as a live attenuated vaccine in many countries over the past two decades. As a result it may now be the most prevalent strain of M. synoviae globally. Differentiation of the MS-H vaccine from local field strains is important for epidemiological investigations and is often required for registration of the vaccine. RESULTS: The complete genomic sequence of the MS-H strain was determined using a combination of Illumina and Nanopore methods and compared to WVU-1853, the M. synoviae type strain isolated in the USA 30 years before the parent strain of MS-H, and MS53, a more recent isolate from Brazil. The vaccine strain genome had a slightly larger number of pseudogenes than the two other strains and contained a unique 55 kb chromosomal inversion partially affecting a putative genomic island. Variations in gene content were also noted, including a deoxyribose-phosphate aldolase (deoC) fragment and an ATP-dependent DNA helicase gene found only in MS-H. Some of these sequences may have been acquired horizontally from other avian mycoplasma species. CONCLUSIONS: MS-H was somewhat more similar to WVU-1853 than to MS53. The genome sequence of MS-H will enable identification of vaccine-specific genetic markers for use as diagnostic and epidemiological tools to better control M. synoviae. PMID- 29394883 TI - Contiguous 22.1-kb deletion embracing AVPR2 and ARHGAP4 genes at novel breakpoints leads to nephrogenic diabetes insipidus in a Chinese pedigree. AB - BACKGROUND: It has been reported that mutations in arginine vasopressin type 2 receptor (AVPR2) cause congenital X-linked nephrogenic diabetes insipidus (NDI). However, only a few cases of AVPR2 deletion have been documented in China. METHODS: An NDI pedigree was included in this study, including the proband and his mother. All NDI patients had polyuria, polydipsia, and growth retardation. PCR mapping, long range PCR and sanger sequencing were used to identify genetic causes of NDI. RESULTS: A novel 22,110 bp deletion comprising AVPR2 and ARH4GAP4 genes was identified by PCR mapping, long range PCR and sanger sequencing. The deletion happened perhaps due to the 4-bp homologous sequence (TTTT) at the junctions of both 5' and 3' breakpoints. The gross deletion co-segregates with NDI. After analyzing available data of putative clinical signs of AVPR2 and ARH4GAP4 deletion, we reconsider the potential role of AVPR2 deletion in short stature. CONCLUSIONS: We identified a novel 22.1-kb deletion leading to X-linked NDI in a Chinese pedigree, which would increase the current knowledge in AVPR2 mutation. PMID- 29394884 TI - Effects of tai chi on cognition and instrumental activities of daily living in community dwelling older people with mild cognitive impairment. AB - BACKGROUND: Cognitive impairment places older adults at high risk of functional disability in their daily-life activities, and thus affecting their quality of life. This study aimed to examine the effects of Tai Chi on general cognitive functions and instrumental activities of daily living (IADL) in community dwelling older people with mild cognitive impairment (MCI) in Hong Kong. METHODS: The study adopted a multi-site nonequivalent control-group pretest-posttest design. 160 community-dwelling older people, aged >=60, with MCI, from four community elderly centers participated in the study. The intervention group (IG, n = 80) received training in the Yang-style simple form of Tai Chi, at a frequency of two lessons per week for 16 weeks. Each lesson lasted for one hour. The control group (CG, n = 80) had no treatment regime and joined different recreational activity groups in community centers as usual within the study period. Outcome measures included measures of global cognitive status and IADL. The Chinese version of the Mini-Mental State Examination (CMMSE) was used for global cognitive assessment. The Hong Kong Chinese version of Lawton's Instrumental Activities of Daily Living (IADL-CV) was used to assess the participants' IADL levels. General Estimating Equations (GEE) was used to examine each of the outcome variables for the two groups at the two study time points (the baseline and at the end of the study). Meanwhile, minimum detectable change (MDC) was calculated to estimate the magnitude of changes required to eradicate the possibility of measurement error of outcome measures. RESULTS: Seventy four participants in the IG and 71 participants in the CG completed the study. With adjustments for differences in age, education, marital status and living conditions, the findings revealed that the participants in the IG scored significantly better on the CMMSE test (P = 0.001), and the instrumental ADL questionnaire (P = 0.004). However, those scores changes did not exceed the limits of the respective MDCs in the study, the possibility of measurement variation due to error could not be excluded. CONCLUSION: Tai Chi may be an effective strategy to enhance cognitive health and maintain functional abilities in instrumental ADL in older people with MCI. TRIAL REGISTRATION: NCT03404765 (Retrospectively registered January 19, 2018). PMID- 29394885 TI - Cortical and trabecular bone are equally affected in rats with renal failure and secondary hyperparathyroidism. AB - BACKGROUND: Changes in mineral metabolism and bone structure develop early in the course of chronic kidney disease and at end-stage are associated with increased risk of fragility fractures. The disruption of phosphorus homeostasis leads to secondary hyperparathyroidism, a common complication of chronic kidney disease. However, the molecular pathways by which high phosphorus influences bone metabolism in the early stages of the disease are not completely understood. We investigated the effects of a high phosphorus diet on bone and mineral metabolism using a 5/6 nephrectomy model of chronic kidney disease. METHODS: Four-week old rats were randomly assigned into groups: 1) Control with standard diet, 2) Nephrectomy with standard rodent diet, and 3) Nephrectomy with high phosphorus diet. Rats underwent in vivo imaging at baseline, day 14, and day 28, followed by ex vivo imaging. RESULTS: Cortical bone density at the femoral mid-diaphysis was reduced in nephrectomy-control and nephrectomy-high phosphorus compared to control rats. In contrast, trabecular bone mass was reduced at both the lumbar vertebrae and the femoral secondary spongiosa in nephrectomy-high phosphorus but not in nephrectomy-control. Reduced trabecular bone volume adjusted for tissue volume was caused by changes in trabecular number and separation at day 35. Histomorphometry revealed increased bone resorption in tibial secondary spongiosa in nephrectomy-control. High phosphorus diet-induced changes in bone microstructure were accompanied by increased serum parathyroid hormone and fibroblast growth factor 23 levels. CONCLUSION: Our study demonstrates that changes in mineral metabolism and hormonal dysfunction contribute to trabecular and cortical bone changes in this model of early chronic kidney disease. PMID- 29394886 TI - Clinical characteristics associated with the onset of delirium among long-term nursing home residents. AB - BACKGROUND: Nursing home residents are frail, have multiple medical comorbidities, and are at high risk for delirium. Most of the existing evidence base on delirium is derived from studies in the acute in-patient population. We examine the association between clinical characteristics and medication use with the incidence of delirium during the nursing home stay. METHODS: This is a retrospective cohort study of 1571 residents from 12 nursing homes operated by a single care provider in Ontario, Canada. Residents were over the age of 55 and admitted between February 2010 and December 2015 with no baseline delirium and a minimum stay of 180 days. Residents with moderate or worse cognitive impairment at baseline were excluded. The baseline and follow-up characteristics of residents were collected from the Resident Assessment Instrument-Minimal Data Set 2.0 completed at admission and repeated quarterly until death or discharge. Multivariate logistic regression was used to identify characteristics and medication use associated with the onset of delirium. RESULTS: The incidence of delirium was 40.4% over the nursing home stay (mean LOS: 32 months). A diagnosis of dementia (OR: 2.54, p < .001), the presence of pain (OR: 1.64, p < .001), and the use of antipsychotics (OR: 1.87, p < .001) were significantly associated with the onset of delirium. Compared to residents who did not develop delirium, residents who developed a delirium had a greater increase in the use of antipsychotics and antidepressants over the nursing home stay. CONCLUSIONS: Dementia, the presence of pain, and the use of antipsychotics were associated with the onset of delirium. Pain monitoring and treatment may be important to decrease delirium in nursing homes. Future studies are necessary to examine the prescribing patterns in nursing homes and their association with delirium. PMID- 29394887 TI - Standard set of health outcome measures for older persons. AB - BACKGROUND: The International Consortium for Health Outcomes Measurement (ICHOM) was founded in 2012 to propose consensus-based measurement tools and documentation for different conditions and populations.This article describes how the ICHOM Older Person Working Group followed a consensus-driven modified Delphi technique to develop multiple global outcome measures in older persons. The standard set of outcome measures developed by this group will support the ability of healthcare systems to improve their care pathways and quality of care. An additional benefit will be the opportunity to compare variations in outcomes which encourages and supports learning between different health care systems that drives quality improvement. These outcome measures were not developed for use in research. They are aimed at non researchers in healthcare provision and those who pay for these services. METHODS: A modified Delphi technique utilising a value based healthcare framework was applied by an international panel to arrive at consensus decisions.To inform the panel meetings, information was sought from literature reviews, longitudinal ageing surveys and a focus group. RESULTS: The outcome measures developed and recommended were participation in decision making, autonomy and control, mood and emotional health, loneliness and isolation, pain, activities of daily living, frailty, time spent in hospital, overall survival, carer burden, polypharmacy, falls and place of death mapped to a three tier value based healthcare framework. CONCLUSIONS: The first global health standard set of outcome measures in older persons has been developed to enable health care systems improve the quality of care provided to older persons. PMID- 29394888 TI - Diabetic kidney disease in the elderly: prevalence and clinical correlates. AB - BACKGROUND: Diabetic kidney disease (DKD) is a major burden in elderly patients with type 2 diabetes (T2DM). Low estimated glomerular filtration rate (eGFR+, < 60 mL/min/1.73 m2) and albuminuria (Alb+) are essential for the diagnosis of DKD, but their association with clinical variables and quality of care may be influenced by ageing. METHODS: Here we investigated the association of clinical variables and quality of care measures with eGFR+ and Alb+ in 157,595 T2DM individuals participating to the Italian Association of Clinical Diabetologists (AMD) Annals Initiative, stratified by age. RESULTS: The prevalence of eGFR+ and Alb+ increased with ageing, although this increment was more pronounced for low eGFR. Irrespective of age, both the eGFR+ and Alb + groups had the worst risk factors profile when compared to subjects without renal disease, showing a higher prevalence of out-of target values of HbA1c, BMI, triglycerides, HDL-C, blood pressure and more complex cardiovascular (CVD) and anti-diabetic therapies, including a larger use of insulin In all age groups, these associations differed according to the specific renal outcome examined: male sex and smoking were positively associated with Alb+ and negatively with eGFR+; age and anti hypertensive therapies were more strongly associated with eGFR+, glucose control with Alb+, whereas BMI, and lipid-related variables with both abnormalities. All these associations were attenuated in the older (> 75 years) as compared to the younger groups (< 65 years; 65-75 years), and they were confirmed by multivariate analysis. Notably, Q-score values < 15, indicating a low quality of care, were strongly associated with Alb+ (OR 8.54; P < 0.001), but not with eGFR+. CONCLUSIONS: In T2DM patients, the prevalence of both eGFR and Albuminuria increase with age. DKD is associated with poor cardiovascular risk profile and a lower quality of care, although these associations are influenced by the type of renal abnormality and by ageing. These data indicate that clinical surveillance of DKD should not be unerestimated in old T2DM patients. PMID- 29394889 TI - Comparative transcriptomic analysis of resistant and susceptible alfalfa cultivars (Medicago sativa L.) after thrips infestation. AB - BACKGROUND: Plant breeding for resistance to agricultural pests is an essential element in the development of integrated crop management systems; however, the molecular and genetic mechanisms underlying resistance are poorly understood. In this pilot study, a transcriptomic analysis of a resistant (R) vs. a susceptible (S) variety of alfalfa, with (+T) or without (-T) thrips (= 4 treatments) was conducted, 'GN-1' (China) was defined as the resistant cultivar, and 'WL323' (America) was defined as the susceptible cultivar. RESULTS: A total of 970 mRNAs were differentially expressed, of which 129 up- and 191 down-regulated genes were identified in the R + T/R-T plants, while 413 up- and 237 down-regulated genes were identified in the S + T/S-T plants. KEGG analysis mapped 33 and 80 differentially expressed genes to 11 and 14 substantially enriched pathways for GN-1 and WL323, respectively. Five shared pathways were linked to plant resistance traits, including beta-Alanine metabolism, fatty acid degradation, chloroalkane and chloroalkene degradation, flavonoid biosynthesis, and phenylalanine metabolism. CONCLUSIONS: Results indicated both thrips resistant and susceptible alfalfa cultivars can regulate gene expression in the salicylic acid (SA) and flavonoid biosynthesis pathways to induce defensive genes and protein expression (e.g. polyphenol oxidase, protease inhibitor), which enhances plant defence capacity. PMID- 29394890 TI - Incidence, aetiology and outcomes of obstetric-related acute kidney injury in Malawi: a prospective observational study. AB - BACKGROUND: Obstetric-related acute kidney injury (AKI) is thought to be a key contributor to the overall burden of AKI in low resource settings, causing significant and preventable morbidity and mortality. However, epidemiological data to corroborate these hypotheses is sparse. This prospective observational study aims to determine the incidence, aetiology and maternal-fetal outcomes of obstetric-related AKI in Malawi. METHODS: Women greater than 20 weeks gestation or less than 6 weeks postpartum admitted to obstetric wards at a tertiary hospital in Blantyre, Malawi, and at high-risk of AKI were recruited between 21st September and 11th December 2015. All participants had serum creatinine tested at enrolment; those with creatinine above normal range (> 82 MUmol/L) underwent serial measurement, investigations to determine cause of kidney injury, and were managed by obstetric and nephrology teams. AKI was diagnosed and staged by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Primary outcomes were the incidence proportion and aetiology of AKI. Secondary outcomes were in-hospital maternal mortality, need for dialysis, renal recovery and length of stay; in hospital perinatal mortality, gestational age at delivery, birthweight and Apgar score. RESULTS: 354 patients were identified at risk of AKI from the approximate 2300 deliveries that occurred during the study period. Three hundred twenty-two were enrolled and 26 (8.1%) had AKI (median age 27 years; HIV 3.9%). The most common primary causes of AKI were preeclampsia/eclampsia (n = 19, 73.1%), antepartum haemorrhage (n = 3, 11.5%), and sepsis (n = 3, 11.5%). There was an association between preeclampsia spectrum and AKI (12.2% AKI incidence in preeclampsia spectrum vs. 4.3% in other patients, p = 0.015). No women with AKI died or required dialysis and complete renal recovery occurred in 22 (84.6%) cases. The perinatal mortality rate across all high-risk admissions was 13.8%. AKI did not impact on maternal or fetal outcomes. CONCLUSIONS: The incidence of AKI in high-risk obstetric admissions in Malawi is 8.1% and preeclampsia was the commonest cause. With tertiary nephrology and obstetric care the majority of AKI resolved with no effect on maternal-fetal outcomes. Maternal-fetal outcomes in Sub-Saharan Africa may be improved with earlier detection of hypertensive disease in pregnancy. PMID- 29394891 TI - A set of microsatellite markers to differentiate Plasmodium falciparum progeny of four genetic crosses. AB - BACKGROUND: Four Plasmodium falciparum genetic crosses (HB3*3D7, HB3*Dd2, 7G8*GB4, and 803*GB4) have produced sets of recombinant progeny that are widely used for malaria research, including investigations of anti-malarial drug resistance. It is critical to maintain the progeny free from cross-contamination. Microsatellite polymorphisms can be used to validate parasite identity. RESULTS: A set of 12 markers was developed that differentiates the parents of the four P. falciparum crosses. This typing set identified distinguishing patterns of inheritance (fingerprints) in segregant collections of 15 progeny clones from HB3*3D7, 32 from HB3*Dd2, 33 from 7G8*GB4, and 81 from 803*GB4. Stronger amplification was observed with shorter relative to longer alleles of individual microsatellites. In experiments with mixed parental DNAs, electropherograms showed that signals of cross-contamination can be missed when minor peaks less than 1/4 or 1/3 the height of the major peak are disregarded by threshold settings commonly used for population studies. CONCLUSIONS: Microsatellite typing is an effective method to check the identity of P. falciparum lines and detect parasite cross-contamination in cultures; however, care must be taken not to ignore minor peaks that can be overlooked. The 12 microsatellite markers presented here provide a rapid and efficient means to distinguish the segregants of laboratory crosses. Fingerprint patterns from these markers are useful to maintain the integrity of diverse parasite lines in and between research laboratories. PMID- 29394892 TI - Acacia hydaspica R. Parker ameliorates cisplatin induced oxidative stress, DNA damage and morphological alterations in rat pulmonary tissue. AB - BACKGROUND: Cisplatin (CP) drug is platinum compounds used for the treatment of various human malignancies. However, adverse outcomes related to CP restrict its usage. Acacia hydaspica is a natural shrub with various pharmacological properties. The current investigation aimed to assess the protective potential of A. hydaspica polyphenol rich ethyl acetate extract (AHE) against cisplatin (CP) induced pulmonary toxicity. METHODS: Rats were divided into six groups. Group 1 served as control (saline); Group 2 (drug control) recieved single dose of CP (7.5 mg/kg i.p.) on 1st day; Group 3 (extract control) (400 mg/kg bw, p.o.) received AHE for one week; Group 4 (Post-treated) and Group 5 (pretreated) received AHE (400 mg/kg bw/day, p.o) for 7 days after and before CP (7.5 mg/kg b.w., i.p.) respectively; Group 6 (Standard control) received silymarin (100 mg/kg b.w/7 days) before CP. At the end of dosing rats were sacrificed and pulmonary tissue samples were processed for the evaluation of antioxidant enzymes, oxidative stress markers, genotoxicity and histopathological alterations. RESULTS: CP caused body weights loss and increase pulmonary tissue weight. The CP significantly increases oxidative stress markers and decreases tissue antioxidant enzyme levels. Furthermore, CP induced deleterious changes in the microanatomy of pulmonary tissue by rupturing the alveolar septa, thickening of alveolar walls, and injuring the cells with subsequent collapse of blood vessels. AHE pretreatment returned MDA, NO, H2O2 production and improved tissue antioxidant enzyme levels to near normalcy. The histological observations evidenced that AHE effectively rescues the lungs from CP-mediated oxidative damage. CP induction in rats also caused DNA fragmentation which was restored by AHE treatment. Our results suggest that pretreatment more significantly improve CP induced deleterious effects compared with post treatment indicating protective effect. Potency of AHE pretreatment is similar to silymarin. CONCLUSION: These findings demonstrated that A. hydaspica AHE extract might serve as potential adjuvant that prevents CP persuaded pulmonary toxicity due to its intrinsic antioxidant potential and polyphenolic constituents. PMID- 29394893 TI - Influence of indoor work environments on health, safety, and human rights among migrant sex workers at the Guatemala-Mexico Border: a call for occupational health and safety interventions. AB - BACKGROUND: Migrant women are over-represented in the sex industry, and migrant sex workers experience disproportionate health inequities, including those related to health access, HIV and sexually transmitted infections (STIs), and violence. Despite calls for occupational sex work interventions situated in labour rights frameworks, there remains a paucity of evidence pertaining to migrant sex workers' needs and realities, particularly within Mexico and Central America. This study investigated migrant sex workers' narratives regarding the ways in which structural features of work environments shape vulnerability and agency related to HIV/STI prevention and violence at the Guatemala-Mexico border. METHODS: Drawing on theoretical perspectives on risk environments and structural determinants of HIV in sex work, we analyzed in-depth interviews, focus groups, and ethnographic fieldwork conducted with 39 migrant sex workers in indoor work environments between 2012 and 2015 in Tecun Uman, Guatemala. RESULTS: Participant narratives revealed the following intersecting themes to be most closely linked to safety and agency to engage in HIV/STI prevention: physical features of indoor work environments (e.g., physical layout of venue, proximity to peers and third parties); social norms and practices for alcohol use within the workplace; the existence and nature of management practices and policies on health and safety practices; and economic influences relating to control over earnings and clients. Across work environments, health and safety were greatly shaped by human rights concerns stemming from workplace interactions with police, immigration authorities, and health authorities. CONCLUSIONS: Physical isolation, establishment norms promoting alcohol use, restricted economic agency, and human rights violations related to sex work policies and immigration enforcement were found to exacerbate risks. However, some establishment policies and practices promoted 'enabling environments' for health and safety, supporting HIV/STI prevention, economic agency, and protection from violence and exploitation; these practices and policies were especially crucial for recent migrants. Policy reforms and structural workplace interventions tailored to migrant sex workers' needs are recommended to promote improved working conditions and migrant sex workers' health, safety, and human rights. PMID- 29394894 TI - Differential effects of innate immune variants of surfactant protein-A1 (SFTPA1) and SP-A2 (SFTPA2) in airway function after Klebsiella pneumoniae infection and sex differences. AB - BACKGROUND: Surfactant Protein-A (SP-A) is a major protein component of surfactant and plays a role in surfactant-related functions and innate immunity. Human SP-A consists of two functional genes, SFTPA1 and SFTPA2, encoding SP-A1 and SP-A2 proteins, respectively and each is identified with numerous genetic variants. These differentially enhance bacterial phagocytosis, with SP-A2 variants being more effective than SP-A1. METHODS: Lung functions of humanized transgenic (hTG) mice that carry different SP-A1 and SP-A2 variants or both variants SP-A1/SP-A2 (6A2/1A0, co-ex), as well as SP-A knockout (KO), were studied. The animals were connected to a flexiVent system to obtain forced oscillation technique (FOT) measurements and the data were analyzed using various models. Lung function was assessed after infection (baseline) and following inhaled methacholine concentrations (0-50 mg/mL). RESULTS: Here, we investigated the role of SP-A variants on airway function after Klebsiella pneumoniae (Kp) infection (baseline) and following inhaled methacholine. We found that: 1) in the absence of methacholine no significant differences were observed between SP-A1 and SP-A2 variants and/or SP-A knockout (KO) except for sex differences in most of the parameters studied. 2) In response to methacholine, i) sex differences were observed that were reverse of those observed in the absence of methacholine; ii) SP-A2 (1A3) gene variant in males exhibited increased total and central airway resistance (Rrs and Rn) versus all other variants; iii) In females, SP-A2 (1A3) and SP-A1 (6A2) variants had similar increases in total and central airway resistance (Rrs and Rn) versus all other variants; iv) Allele-specific differences were observed, a) with SP-A2 (1A3) exhibiting significantly higher lung functions versus SP-A2 (1A0) in both sexes, except for Crs, and b) SP-A1 (6A2, 6A4) had more diverse changes in lung function in both sexes. CONCLUSION: We conclude that, in response to infection and methacholine, SP-A variants differentially affect lung function and exhibit sex-specific differences consistent with previously reported findings of functional differences of SP-A variants. Thus, the observed changes in respiratory function mechanics provide insight into the role and importance of genetic variation of innate immune molecules, such as SP-A, on mechanical consequences of lung function after infection and inhaled substances. PMID- 29394895 TI - The serostatus of Brucella spp., Chlamydia abortus, Coxiella burnetii and Neospora caninum in cattle in three cantons in Bosnia and Herzegovina. AB - BACKGROUND: Dairy production in Bosnia and Herzegovina exhibits limited productivity, which may partly, be explained by extensive reproductive problems of non-infectious and infectious origin. Brucella spp., Chlamydia abortus, Coxiella burnetii and Neospora caninum are common infectious causes of decreased reproductive outcomes in cattle worldwide. Little is, however, known about the disease status of herds with reduced reproductive performances. A cross-sectional study was designed to document the status of these pathogens in dairy cattle in Bosnia and Herzegovina. A total of 1970 serum samples were collected from cattle in farms located in three cantons (regions). Enzyme linked immunosorbent assays were used to screen for seropositivity against four selected pathogens. RESULTS: The overall seroprevalence was estimated at both the herd level and at individual level for each pathogen. At the individual animal level, the prevalence for C. abortus, C. burnetii, N. caninum and Brucella spp. was 52.1% (95% CI: 41.2-62.7), 8.8% (95% CI: 5.3-14.2), 9.2% (95% CI: 6.0-12.3 and 0.2% (95% CI: 0.1-0.5), respectively. The corresponding estimates for herd level were 87.9% (95% CI: 82.6 91.8), 19.6% (95% CI: 14.6-25.8), 35.2% (95% CI: 28.8-42.1), and 1.5% (95% CI: 0.5-4.6). A substantial overlap was observed in the presence of N. caninum, C. abortus and C. burnetii at individual and herd level. CONCLUSION: Our study demonstrated a high level of antibodies to Chlamydia abortus. Considering the association of this agent with reproductive disorders in cattle, future studies should be directed to the epidemiological traits of this infection. Additionally, the relatively high levels of exposure to C. burnetii and N. caninum found in this study highlights the need for targeted control of infectious causes of reproductive disorders in dairy cattle of the studied areas. Given the low seroprevalence, Brucella spp. does not seem to represent a problem in the reproductive health of cattle in the studied areas. PMID- 29394896 TI - Long-term preservation of planar cell polarity in reversed tracheal epithelium. AB - BACKGROUND: Planar cell polarity (PCP) coordinates the patterning and orientation of cells and their structures along tissue planes, and although its acquisition during the formation of airway epithelium has been described, the mechanisms for its maintenance and reconstruction are poorly understood. We aimed to clarify whether ambient environment change by orthotropic autologous transplantation affected PCP at the cellular level. METHODS: We performed orthotropic autologous transplantation by inverting tracheal segments in rats, and then performed morphological evaluation by microscopy. The PCP of the tracheal epithelium was assessed over time by analyzing the directions of mucociliary transport and ciliary beat, the positional relationship between the basal body and basal foot, and the bias of Vang-like protein 1 (Vangl1) at 2, 4, and 6 months postoperatively. RESULTS: After 2 months, the directions of mucociliary transport and ciliary beat were preserved toward the lung in the inverted tracheal segments. The positional relationship between the basal body and the basal foot, and the bias of Vangl1, also indicated preservation of PCP in the inverted tracheal segments. Similar results were obtained at 6 months. CONCLUSION: The PCP of ciliated epithelium was preserved in reversed trachea, even after long-term observation. PMID- 29394897 TI - A dose-escalation ex vivo study on the effects of intracameral benzalkonium chloride in rabbits. AB - BACKGROUND: Rabbits are currently not a good model for studying diseases of the corneal endothelium because their corneal endothelial cells (CECs) maintain a high proliferative capacity throughout almost all their life. Addressing this particular feature might allow the use of this species for such a purpose. The aim of this study was to evaluate the corneal endothelial injury after intracameral benzalkonium chloride (BAC) injection into rabbit eyes ex vivo, and to establish the most suitable starting dose for an in vivo study aimed at developing an animal model of corneal endothelial disease. RESULTS: Forty rabbit eyes obtained postmortem by transconjunctival enucleation were divided into 8 groups according to the injected compound: Control (no injection), BSS, and increasing BAC concentrations (0.005%, 0.01%, 0.025%, 0.05%, 0.1% and 0.2%). At 0, 6, 24 and 48 h, ophthalmologic examination of the anterior segment, pachymetry and specular microscopy were performed, and corneas were finally vital-stained and observed under the light microscope to assess the CECs morphology and mortality rate. When compared to BSS, CECs density started to decrease significantly at 0.025% BAC concentration, while mean cell area, corneal edema and corneal thickness began to increase significantly at 0.05%, 0.005% and 0.1% BAC concentrations, respectively. Concentrations of 0.05% BAC and above caused significant increases in CECs pleomorphism (decreased hexagonality) and mortality, compared to control and BSS. CONCLUSIONS: Ex vivo intracameral BAC injection induces corneal endothelial toxicity in rabbits. However, confirmatory in vivo studies are required to develop the desired model, with 0.05% BAC being a suggested starting point. PMID- 29394898 TI - Methylation of the genes ROD1, NLRC5, and HKR1 is associated with aging in Hainan centenarians. AB - BACKGROUND: Human aging is a hot topic in biology, and it has been associated with DNA methylation changes at specific genomic sites. We aimed to study the changes of DNA methylation at a single-CpG-site resolution using peripheral blood samples from centenarians. METHODS: Using Illumina 450 K Methylation BeadChip microarray assays, we carried out a pool-based, epigenome-wide investigation of DNA methylation of blood samples from 12 centenarians and 12 healthy controls. Differentially methylated cytosine-phosphate-guanosine (CpG) sites were selected for further pyrosequencing analysis of blood samples from 30 centenarians and 30 healthy controls. RESULT: We identified a total of 31 high-confidence CpG sites with differential methylation profiles between the groups: 9 (29%) were hypermethylated and 22 (71%) were hypomethylated in centenarians. It was also found that hypermethylation of HKR1 and hypomethylation of ROD1 and NLRC5 genes strongly correlated with age in centenarians. CONCLUSION: Our results indicate that the methylation profile combination of HKR1, ROD1, and NLRC5 could be a promising biomarker for aging in Hainan centenarians. PMID- 29394899 TI - Menstrual hygiene management among women and adolescent girls in the aftermath of the earthquake in Nepal. AB - BACKGROUND: Menstrual hygiene management (MHM) is an essential aspect of hygiene for women and adolescent girls between menarche and menopause. Despite being an important issue concerning women and girls in the menstruating age group MHM is often overlooked in post-disaster responses. Further, there is limited evidence of menstrual hygiene management in humanitarian settings. This study aims to describe the experiences and perceptions of women and adolescent girls on menstrual hygiene management in post-earthquake Nepal. METHODS: A mixed methods study was carried out among the earthquake affected women and adolescent girls in three villages of Sindhupalchowk district of Nepal. Data was collected using a semi-structured questionnaire that captured experiences and perceptions of respondents on menstrual hygiene management in the aftermath of the Nepal earthquake. Quantitative data were triangulated with in-depth interview regarding respondent's personal experiences of menstrual hygiene management. RESULTS: Menstrual hygiene was rated as the sixth highest overall need and perceived as an immediate need by 18.8% of the respondents. There were 42.8% women & girls who menstruated within first week of the earthquake. Reusable sanitary cloth were used by about 66.7% of the respondents before the earthquake and remained a popular method (76.1%) post-earthquake. None of the respondents reported receiving menstrual adsorbents as relief materials in the first month following the earthquake. Disposable pads (77.8%) were preferred by respondents as they were perceived to be clean and convenient to use. Most respondents (73.5%) felt that reusable sanitary pads were a sustainable choice. Women who were in the age group of 15-34 years (OR = 3.14; CI = (1.07-9.20), did not go to school (OR = 9.68; CI = 2.16-43.33), married (OR = 2.99; CI = 1.22-7.31) and previously used reusable sanitary cloth (OR = 5.82; CI = 2.33-14.55) were more likely to use the reusable sanitary cloth. CONCLUSIONS: In the immediate aftermath of the earthquake, women and girls completely depended on the use of locally available resources as adsorbents during menstruation. Immediate relief activities by humanitarian agencies, lacked MHM activities. Understanding the previous practice and using local resources, the reusable sanitary cloth is a way to address the menstrual hygiene needs in the post-disaster situations in Nepal. PMID- 29394900 TI - How to interpret the role of SDF-1alpha on diabetic complications during therapy with DPP-4 inhibitors. PMID- 29394901 TI - Foxg1 deletion impairs the development of the epithalamus. AB - The epithalamus, which is dorsal to the thalamus, consists of the habenula, pineal gland and third ventricle choroid plexus and plays important roles in the stress response and sleep-wake cycle in vertebrates. During development, the epithalamus arises from the most dorsal part of prosomere 2. However, the mechanism underlying epithalamic development remains largely unknown. Foxg1 is critical for the development of the telencephalon, but its role in diencephalic development has been under-investigated. Patients suffering from FOXG1-related disorders exhibit severe anxiety, sleep disturbance and choroid plexus cysts, indicating that Foxg1 likely plays a role in epithalamic development. In this study, we identified the specific expression of Foxg1 in the developing epithalamus. Using a "self-deletion" approach, we found that the habenula significantly expanded and included an increased number of habenular subtype neurons. The innervations, particularly the habenular commissure, were severely impaired. Meanwhile, the Foxg1 mutants exhibited a reduced pineal gland and more branched choroid plexus. After ablation of Foxg1 no obvious changes in Shh and Fgf signalling were observed, suggesting that Foxg1 regulates the development of the epithalamus without the involvement of Shh and Fgfs. Our findings provide new insights into the regulation of the development of the epithalamus. PMID- 29394902 TI - Factors influencing postoperative length of stay in an enhanced recovery after surgery program for primary total knee arthroplasty. AB - BACKGROUND: Hospital length of stay (LOS) after primary total knee arthroplasty (TKA) has decreased obviously following the implementation of enhanced recovery after surgery (ERAS) program in the last few years. However, there are still some patients that cannot be discharged at early time for a variety of reasons, and it is necessary to explore factors leading to prolonged LOS. Therefore, the purpose of this study was to identify the complete preoperative, perioperative, and postoperative factors associated with prolonged postoperative LOS (PLOS) after primary TKA in a detailed ERAS program. METHODS: In a consecutive series from July 2015 to March 2017, all patients who underwent unilateral elective primary TKA were included in the retrospective study. A PLOS greater than 3 days was considered a prolonged PLOS. Multivariable logistic regression analysis was performed to identify patient characteristics and relevant preoperative, perioperative, and postoperative variables that were associated with prolonged PLOS and postoperative complications. RESULTS: A total of 241 patients were included with a mean PLOS of 3.8 days. Prolonged PLOS was significantly associated with preoperative valgus deformity of the knee (OR 4.95, 95%CI 1.56 15.77, P = 0.007), increased serum level of interleukin-6 on postoperative day 1 (OR 1.01, 95%CI 1.00-1.03, P = 0.039), increased visual analogue scale pain score and serum level of C-reactive protein on postoperative day 3 (OR 2.56, 95%CI 1.28 5.13, P = 0.008; OR 1.01, 95%CI 1.00-1.03, P = 0.019), increased day to achieve 90 degrees active knee flexion after surgery (OR 2.19, 95%CI 1.27-3.79, P = 0.005), and postoperative wound complications (OR 8.58, 95%CI 2.10-35.03, P = 0.003) and other minor complications (OR 6.04, 95%CI 2.40-15.19, P < 0.001). Preoperative pulmonary infection (OR 2.75, 95%CI 1.20-6.28, P = 0.016), American Society of Anesthesiologists score 3/4 (OR 2.14, 95%CI 1.01-4.52, P = 0.046), and utilization of catheter after surgery (OR 2.53, 95%CI 1.23-5.19, P = 0.012) were significantly associated with postoperative complications. CONCLUSIONS: Multiple factors were associated with prolonged PLOS and postoperative complications after TKA in the ERAS program. It is important to recognize all the factors to try to maximize the use of medical resources and ultimately optimize the care of our patients. PMID- 29394903 TI - Impact of amyloid-beta changes on cognitive outcomes in Alzheimer's disease: analysis of clinical trials using a quantitative systems pharmacology model. AB - BACKGROUND: Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. METHODS: We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Abeta40 and Abeta42) oligomers on glutamate and nicotinic neurotransmission. RESULTS: Preclinical data suggest a beneficial effect of shorter Abeta forms within a limited dose range. Such a beneficial effect of Abeta40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Abeta in MCI subjects. We further derive a relationship between units of Abeta load in our model and the standard uptake value ratio from amyloid imaging. When introducing the documented clinical pharmacodynamic effects on Abeta levels for various amyloid-related clinical interventions in patients with low Abeta baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Abeta levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid interventions in transgene animals with an artificial high level of Abeta, but not in AD patients with a large variability of amyloid loads. CONCLUSIONS: If these predictions are confirmed in post-hoc analyses of failed clinical amyloid-modulating trials, one should question the rationale behind testing these interventions in early and prodromal subjects with low or zero amyloid load. PMID- 29394904 TI - Operative Treatment of Intra-Articular Distal Radius Fractures With versus Without Arthroscopy: study protocol for a randomised controlled trial. AB - BACKGROUND: In the past several years, an increase in open reduction and internal fixation (ORIF) for intra-articular distal radius fractures has been observed. This technique leads to a quicker recovery of function compared to non-operative treatment. However, some patients continue to have a painful and stiff wrist postoperatively. Arthroscopically assisted removal of intra-articular fracture haematoma and debris may improve the functional outcomes following operative treatment of intra-articular distal radius fractures. The purpose of this randomised controlled trial is to determine the difference in functional outcome, assessed with the Patient-Rated Wrist Evaluation (PRWE) score, after ORIF with and without an additional wrist arthroscopy in adult patients with displaced complete articular distal radius fractures. METHODS: In this multicentre trial, adult patients with a displaced complete articular distal radius fracture are randomised between ORIF with an additional wrist arthroscopy to remove fracture haematoma and debris (intervention group) and conventional fluoroscopic-assisted ORIF (control group). The primary outcome is functional outcome assessed with the PRWE score after three months. Secondary outcomes are wrist function assessed with the Disability of the Arm, Shoulder and Hand (DASH) score, postoperative pain, range of motion, grip strength, complications and cost-effectiveness. Additionally, in the intervention group, the quality of reduction, associated ligamentous injuries and cartilage damage will be assessed. A total of 50 patients will be included in this study. DISCUSSION: Although ORIF of intra articular distal radius fractures leads to a quicker resume of function compared to non-operative treatment, some patients continue to have a painful and stiff wrist postoperatively. We hypothesise that, due to the removal of fracture haematoma and debris by an additional arthroscopy, functional outcomes will be better compared to the non-arthroscopically treated group. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660515 . Registered on 13 January 2016. PMID- 29394905 TI - National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme research funding and UK burden of disease. AB - BACKGROUND: HTA Programme funding is governed by the need for evidence and scientific quality, reflecting funding of the National Institute for Health Research (NIHR) by the NHS. The need criterion incorporates covering the spectrum of diseases, but also taking account of research supported by other funders. This study compared the NIHR HTA Programme portfolio of research with the UK burden of disease as measured by Disability-adjusted Life Years (DALYs). METHODS: A retrospective cross-sectional study using a cohort of all funded primary research and evidence syntheses projects received by the HTA Programme from April 2011 to March 2016 (n = 363); to determine the proportion of spend by disease compared with burden of disease in the UK calculated using 2015 UK DALY data. RESULTS: The programme costing just under L44 million broadly reflected UK DALY burden by disease. Spend was lower than disease burden for cancer, cardiovascular and musculoskeletal diseases, which may reflect the importance of other funders, notably medical charities, which concentrate on these diseases. CONCLUSION: The HTA Programme spend, adjusted for other relevant funders, broadly matches disease burden in the UK; no diseases are being neglected. PMID- 29394907 TI - The effect of an intraoperative, lung-protective ventilation strategy in neurosurgical patients undergoing craniotomy: study protocol for a randomized controlled trial. AB - BACKGROUND: Ventilator-induced lung injury is a major cause of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgery after general anesthesia. However, there is no study on the effect of a lung-protective ventilation strategy in patients undergoing neurosurgery. METHODS: This is a single-center, randomized, parallel-group controlled trial which will be carried out at Beijing Tiantan Hospital, Capital Medical University. Three hundred and thirty-four patients undergoing intracranial tumor surgery will be randomly allocated to the control group and the protective-ventilation strategy group. In the control group, tidal volume (VT) will be set at 10-12 ml/kg of predicted body weight but PEEP and recruitment maneuvers will not be used. In the protective group, VT will be set at 6-8 ml/kg of predicted body weight, PEEP at 6-8 cmH2O, and a recruitment maneuver will be used intermittently. The primary outcome is pulmonary complications within 7 days postoperatively. Secondary outcomes include intraoperative brain relaxation, the postoperative complications within 30 days and the cost analysis. DISCUSSION: This study aims to determine if the protective, pulmonary-ventilation strategy decreases the incidence of PPCs in patients undergoing neurosurgical anesthesia. If our results are positive, the study will indicate whether the protective, pulmonary-ventilation strategy is efficiently and safely used in neurosurgical patients undergoing the craniotomy. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02386683 . Registered on 18 October 2014. PMID- 29394906 TI - The spatial and temporal scales of local dengue virus transmission in natural settings: a retrospective analysis. AB - BACKGROUND: Dengue is a vector-borne disease caused by the dengue virus (DENV). Despite the crucial role of Aedes mosquitoes in DENV transmission, pure vector indices poorly correlate with human infections. Therefore there is great need for a better understanding of the spatial and temporal scales of DENV transmission between mosquitoes and humans. Here, we have systematically monitored the circulation of DENV in individual Aedes spp. mosquitoes and human patients from Caratinga, a dengue endemic city in the state of Minas Gerais, in Southeast Brazil. From these data, we have developed a novel stochastic point process pattern algorithm to identify the spatial and temporal association between DENV infected mosquitoes and human patients. METHODS: The algorithm comprises of: (i) parameterization of the variogram for the incidence of each DENV serotype in mosquitoes; (ii) identification of the spatial and temporal ranges and variances of DENV incidence in mosquitoes in the proximity of humans infected with dengue; and (iii) analysis of the association between a set of environmental variables and DENV incidence in mosquitoes in the proximity of humans infected with dengue using a spatio-temporal additive, geostatistical linear model. RESULTS: DENV serotypes 1 and 3 were the most common virus serotypes detected in both mosquitoes and humans. Using the data on each virus serotype separately, our spatio-temporal analyses indicated that infected humans were located in areas with the highest DENV incidence in mosquitoes, when incidence is calculated within 2.5-3 km and 50 days (credible interval 30-70 days) before onset of symptoms in humans. These measurements are in agreement with expected distances covered by mosquitoes and humans and the time for virus incubation. Finally, DENV incidence in mosquitoes found in the vicinity of infected humans correlated well with the low wind speed, higher air temperature and northerly winds that were more likely to favor vector survival and dispersal in Caratinga. CONCLUSIONS: We have proposed a new way of modeling bivariate point pattern on the transmission of arthropod-borne pathogens between vector and host when the location of infection in the latter is known. This strategy avoids some of the strong and unrealistic assumptions made by other point-process models. Regarding virus transmission in Caratinga, our model showed a strong and significant association between high DENV incidence in mosquitoes and the onset of symptoms in humans at specific spatial and temporal windows. Together, our results indicate that vector surveillance must be a priority for dengue control. Nevertheless, localized vector control at distances lower than 2.5 km around premises with infected vectors in densely populated areas are not likely to be effective. PMID- 29394908 TI - Intermittent fasting, energy balance and associated health outcomes in adults: study protocol for a randomised controlled trial. AB - BACKGROUND: Prior studies have shown that intermittent fasting is capable of producing improvements in body weight and fasted health markers. However, the extent to which intermittent fasting incurs compensatory changes in the components of energy balance and its impact on postprandial metabolism are yet to be ascertained. METHODS: A total of 30-36 lean participants and 30-36 overweight/obese participants will be recruited to provide two separate study groups who will undergo the same protocol. Following an initial assessment of basic anthropometry and key health markers, measurements of habitual energy intake (weighed food and fluid intake) and physical activity energy expenditure (combined heart rate and accelerometry) will be obtained over 4 weeks under conditions of energy balance. Participants will then be randomly allocated to one of three experimental conditions for 20 days, namely (1) daily calorie restriction (reduce habitual daily energy intake by 25%), (2) intermittent fasting with calorie restriction (alternate between 24-hour periods of fasting and feeding to 150% of habitual daily energy intake), (3) intermittent fasting without calorie restriction (alternate between 24-hour periods of fasting and feeding to 200% of habitual daily energy intake). In addition to continued monitoring of energy intake and physical activity during the intervention, participants will report for laboratory-based assessments of various metabolic parameters both before and after the intervention. Specifically, fasting and postprandial measurements of resting metabolic rate, substrate oxidation, appetite, food preference, and plasma concentrations of key metabolites and hormones will be made, in addition to subcutaneous abdominal adipose tissue biopsies in the fasted state and an assessment of body composition via dual energy x-ray absorptiometry. DISCUSSION: Comparing observed changes in these measures across the three intervention arms in each group will establish the impact of intermittent fasting on postprandial metabolism and the components of energy balance in both lean and overweight/obese populations. Furthermore, this will be benchmarked against current nutritional interventions for weight management and the relative contributions of negative energy balance and fasting dependent mechanisms in inducing any observed effects will be elucidated. TRIAL REGISTRATION: Trial retrospectively registered at clinicaltrials.gov under reference number NCT02498002 (version: IMF-02, date: July 6, 2015). PMID- 29394909 TI - Long-term results after non-operative and operative treatment of radial neck fractures in adults. AB - BACKGROUND: The aim of this study is to determine the functional long-term outcome after non-operative and operative treatment of radial neck fractures in adults. METHODS: Thirty-four consecutive patients with a mean age of 46.4 (18.0 to 63.0) years with a fracture of the radial neck who were treated between 2000 and 2014 were examined regarding the clinical and radiological outcome. Twenty patients were treated non-operatively, and 14 patients underwent surgery. RESULTS: After a mean follow-up of 5.7 (2.0 to 15.7) years, the clinical scores showed good results in both groups. The Disabilities of Arm, Shoulder and Hand score was 16.1 (0 to 71.6) in the non-operative group and 8.8 (0 to 50.8) in the operative group, respectively. The Mayo Elbow Performance Score was 80.0 (30 to 95) in the non-operative group and 82.5 (35 to 95) in the non-operative group, respectively. The initial angle of the radial head towards the shaft (RHSA) was significantly higher in the operative group in the anterior-posterior plane (12.8 degrees [2 to 23] vs. 26.3 degrees [1 to 90], p = 0.015). In the follow-up radiographs, the RHSA was significantly lower in the operative group (15.1 degrees [3 to 30] vs. 10.9 degrees [3 to 18], p = 0.043). Five patients developed 7 complications in the non-operative group, and 7 patients developed 12 complications in the operative group. Revision rates were higher in the operative groups as 1 patient received radial head resection in the non-operative (5%) group while 7 patients in the operative group (50%) needed revision surgery. CONCLUSION: A good functional long-term outcome can be expected after operative and non-operative treatment of radial neck fractures in adults. If needed due to major displacement, open reduction is associated with a higher risk of complications and the need for revision surgery but can achieve similar clinical results. TRIAL REGISTRATION: DRKS DRKS00012836 (retrospectively registered). PMID- 29394910 TI - Larval superiority of Culex pipiens to Aedes albopictus in a replacement series experiment: prospects for coexistence in Germany. AB - BACKGROUND: The Asian tiger mosquito Aedes albopictus is an extremely invasive, globally distributed and medically important vector of various human and veterinary pathogens. In Germany, where this species was recently introduced, its establishment may become modulated by interspecific competition from autochthonous mosquito species, especially Culex pipiens (s.l.). While competitive superiority of Ae. albopictus to Cx. pipiens (s.l.) has been described elsewhere, it has not been assessed in the epidemiological conditions of Germany. The present study aimed to determine if such superiority exists under the physicochemical and microclimatic conditions typical for container habitats in Germany. METHODS: In a replacement series experiment, the larval and pupal responses of Ae. albopictus and Cx. pipiens (s.l.) (mortality, development time, growth) to interspecific interaction (five larval ratios) at (sub-)optimal temperatures (15, 20 and 25 degrees C) and differing food supply (3 and 6 mg animal-based food larva-1) were investigated using a randomized split-plot design. In addition to physicochemical measurements of the test media, natural physicochemical conditions were determined for comparative analyses in mosquito breeding sites across the Rhine-Main metropolitan region of Germany. RESULTS: Under the physicochemical and microclimatic conditions similar to the breeding sites of the Rhine-Main region, competitive superiority of Cx. pipiens (s.l.) to Ae. albopictus in terms of larval survival was more frequently observed than balanced coexistence. Food regime and multifactorial interactions, but not temperature alone, were controlling factors for interspecific competition. Larval food regime and the larval ratio of Ae. albopictus influenced the physicochemistry and algal growth at 15 degrees C, with increased Ae. albopictus mortality linked to a decreasing number of Scenedesmus, Oocystis and Anabaena algae. CONCLUSIONS: Under the present environmental conditions, the spread of Ae. albopictus from isolated foci in Germany may generally be slowed by biotic interactions with the ubiquitous Cx. pipiens (s.l.) (and potentially other container-breeding mosquito species) and by limnic microalgae in microhabitats with high resource levels. Detailed knowledge of the context dependency in temperate mosquito ecology, and interrelations of physicochemistry and phycology may help to achieve a better understanding of the upcoming Ae. albopictus colonization processes in central and northern Europe. PMID- 29394911 TI - How does the sagittal spinal balance of the scoliotic population deviate from the asymptomatic population? AB - BACKGROUND: Previously, the sagittal spinal balance in both asymptomatic and scoliotic Caucasian people has been characterized and compared. Very recently, the sagittal spino-pelvic parameters among asymptomatic Chinese adults have been studied, and the results were compared with Caucasian adults, indicating that a difference did exist. Unfortunately, the distribution of sagittal standing posture patterns among the Chinese population has not been characterized in either asymptomatic or scoliotic groups. METHODS: We conducted a radiographic comparison study to define the deviation of sagittal balance in scoliotic patients from that of an asymptomatic population. A total of 126 asymptomatic and 117 idiopathic scoliotic (IS) young adults were recruited. Radiographic data from each subject were reviewed, and sagittal spinopelvic parameters were measured. The Roussouly type was then determined, as well as the relative position of the C7 plumbline with respect to the sacrum and hip axis. Comparison analyses were undertaken between the two different groups. RESULTS: The IS group had a larger pelvic incidence, pelvic tilt and sacral slope, but a smaller spinal tilt than the asymptomatic group (P < 0.05), while other sagittal parameters were similar. The distribution of Roussouly types was similar between the asymptomatic and IS groups, of which 49.2% and 45.3% belonged to Roussouly Type 3, respectively. Asymptomatic males and females had a similar distribution, which was different between the two genders in the IS group (P < 0.05), with more females possessing a neutral sagittal standing posture. In addition, more IS subjects had forward displacement of the C7 plumbline than asymptomatic ones (P < 0.05), while there was no difference between the two genders in either group. CONCLUSIONS: Although sagittal pelvic parameters were greater in the IS population, their sagittal spinal balance was maintained and there was no sagittal standing posture pattern correlated with IS. The occurrence of anterior displacement of the C7 plumbline was more common in IS patients than asymptomatic adults, but did not appear to be correlated with gender in both populations. PMID- 29394912 TI - Education and indoor smoking among parents who smoke: the mediating role of perceived social norms of smoking. AB - BACKGROUND: Parents with less formal education are more likely to smoke indoors, causing socioeconomic disparity in children's exposure to second-hand smoke. However, little is known about the roles of social factors in the socioeconomic gradients of indoor smoking. We tested the potential mediating role of perceived smoking norms on the associations between education and indoor smoking among parents who smoke. METHODS: In this cross-sectional study, 822 smoking fathers and 823 smoking mothers, who lived with young children and were members of a Japanese online survey panel, participated. Structural equation modelling tested the mediating effects of perceived descriptive and subjective norms on the association between education and indoor smoking. RESULTS: Perceived pro-smoking norms, which were more prevalent among less-educated parents, mediated the association between education and indoor smoking. Household smoking status and worksite smoking ban also mediated this association via perceived norms, but only for fathers. Perceived descriptive norms explained 28.5% of the association for fathers and 37.6% for mothers; the corresponding percentages for perceived subjective norms were 9.8% and 26.6%, respectively. CONCLUSIONS: Perceived smoking norms, household smoking status, and a worksite smoking ban could be vital targets of a strategy aimed at reducing the socioeconomic disparity in parental home smoking behaviours. PMID- 29394913 TI - Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer. AB - BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice. PMID- 29394914 TI - Associations between social capital and maternal depression: results from a follow-up study in China. AB - BACKGROUND: This study aims to investigate the association between social capital (SC) and depressive symptoms among Chinese primiparas at different time-points from their late pregnancy to postpartum. METHODS: A total of 450 primiparas were recruited for the current study. The assessments were conducted at three different time-points: T1 - while the participants were recruited at their 30-36 weeks of pregnancy in the antenatal clinic in the maternity hospital in Zhejiang, China; T2 - at their 2nd or 3rd days in the wards after delivery; T3 - at week 6 to 8 after the delivery in the postpartum examination clinic. SC was measured by the 29-item SC scale; while depressive symptoms were measured by the Edinburgh Postnatal Depression Scale. The relationships between SC and depressive symptoms were explored separately at each of the three time-points. RESULTS: The prevalence of depression among the primiparas was 25% at T1, 13.5% at T2 and 20.8% at T3, respectively. However, the score of SC and its components at three time-points followed an opposite 'V' direction, with the highest score at T2, following by T3 and T1. At T1, the analysis suggested that depressive symptoms among the primiparas were negatively correlated with their social trust and social network levels. At T2, only social trust was negatively associated with depression. While at T3, it is social trust and social participations that were significantly negatively associated with depression. CONCLUSIONS: SC was associated with depression at all three time-points during and after pregnancy. More attention should be given to SC in the maternal health promotion programs of community pregnancy health care management. PMID- 29394915 TI - Trend analysis of the quality indicators for the Brazilian cervical cancer screening programme by region and state from 2006 to 2013. AB - BACKGROUND: Quality indicators for the Brazilian cervical cancer screening programme can provide a perspective on its effectiveness in Brazilian macro regions and states. The aim of this study was to perform a trend analysis of the cervical cancer screening program's quality indicators, according to Brazilian regions and states, from 2006 to 2013. METHODS: Using information from approximately 62,000,000 exams obtained from the Information System of Cervical Cancer Screening (SISCOLO), joinpoint analysis was used to calculate the Annual Percentage Change (APC). RESULTS: The estimated number of women in the target age group (25-64 years) who underwent Pap testing over a three-year interval was lower than that recommended by international guidelines in the North, Northeast and Midwest regions, and the trends for this indicator remained stationary over the years in all regions of Brazil. Overall, the index of positivity in Brazilian regions and states is below that preconized by the Brazilian National Cancer Institute (INCA). Additionally, the frequencies of unsatisfactory cases are in line with international guidelines but above those preconized by INCA guidelines. All positive cytological diagnoses were lower than those preconized by INCA. CONCLUSIONS: The results show that the cervical cancer screening programme is still far from efficient because most of the quality indicators in Brazilian regions and states are outside of the parameters preconized by national and international organizations. PMID- 29394916 TI - Multi-modality imaging findings of huge intrachoroidal cavitation and myopic peripapillary sinkhole. AB - BACKGROUND: Peripapillary intrachoroidal cavitation was described as the presence of an asymptomatic, well-circumscribed, yellow-orange, peripapillary lesion at the inferior border of the myopic conus in eyes with high myopia. CASE PRESENTATION: A 66-year-old myopic Chinese man was enrolled and his multi-color imaging examination showed a well-circumscribed, caesious, peripapillary lesion coalesced with the optic nerve head vertically rotated and obliquely tilted, together with an inferotemporal sinkhole in the myopic conus. The optical coherence tomography images showed an intrachoroidal hyporeflective space, schisis, an intracavitary septum located below the retinal pigment epithelium and inserted beneath the optic nerve head, as well as a sinkhole between the peripapillary intrachoroidal cavitation and the vitreous space. CONCLUSIONS: Both myopic colobomas and sinkhole in myopic conus may contribute the coalescence of intrachoroidal cavitation with optic nerve head. These qualitative and quantitative new findings will be beneficial for understanding its pathomorphological mechanism, and the impact on optic nerve tissue of myopic patients. PMID- 29394917 TI - Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ. AB - BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been demonstrated to significantly influence prognosis and response to therapy of invasive breast cancer (IBC). Thus, it has been suggested that TIL density or/and immunophenotype could serve as biomarkers for selection of IBC patients for immunotherapy. However, much less is known about significance of TILs in breast ductal carcinoma in situ (DCIS). METHODS: We retrospectively investigated TIL density and immunophenotype in 96 pure DCIS and 35 microinvasive carcinomas (miCa). TIL density was assessed on H&E-stained breast biopsy sections as the percentage of tumour stromal area occupied by TILs, and classified into 4 grades: 0 (0%-9%), 1 (10-29%), 2 (30-49%) and 3 (50%-100%). TIL immunophenotype was assessed by immunohistochemistry for CD8, CD4, FoxP3, CD38 or CD20. RESULTS: Compared to pure DCIS, miCa contained significantly more cases with TIL density grade 3 (p = 0.028). Concordantly, CD8+, CD4+ and CD38+ cells were more numerous in miCa than in pure DCIS. In the pure DCIS subgroup with TIL density grades 2 and 3, all TIL subpopulations were more numerous than in the pure DCIS with TIL density grades 0 and 1, however the ratio between T-lymphocytes (CD8+ and CD4+) and B-lymphocytes (CD20+) was significantly lower (p = 0.029). On the other side, this ratio was significantly higher in miCa, in comparison with pure DCIS having TIL density grades 2 and 3 (p = 0.017). By cluster analysis of tumour cell pathobiological features we demonstrated similarity between miCa and the pure DCIS with TIL density grades 2 and 3. The only significant difference between those two categories was in the ratio of T- to B-TILs, higher in miCa. CONCLUSION: Results indicate that TIL density level can distinguish 2 biologically different DCIS subgroups, one of which (DCIS with >=30% TILs, the TIL-rich DCIS) is like miCa. Similarity of TIL-rich pure DCIS and miCa as well as the role of B-lymphocytes in DCIS invasiveness are worth further investigating with regards to the potential development of immunotherapy-based prevention of DCIS progression. PMID- 29394920 TI - Occipital lobe infarction: a rare presentation of bilateral giant cavernous carotid aneurysms: a case report. AB - BACKGROUND: Cavernous carotid aneurysm (CCA) represents 2-9% of all intracranial aneurysms and 15% of internal carotid artery (ICA) aneurysms; additionally, giant aneurysms are those aneurysms that are > 25 mm in size. Bilateral CCAs account for 11-29% of patients and are commonly associated with structural weaknesses in the ICA wall, secondary to systemic hypertension. CCAs are considered benign lesions, given the low risk for developing major neurologic morbidities (i.e., subarachnoid hemorrhage, cerebral infarction, or carotid cavernous fistula). Moreover, concurrent presentation with posterior circulation cerebral infarction is even rarer, given different circulation territory from CCA. Here, we report on a patient with bilateral giant CCAs who presented with both typical and atypical symptoms. CASE PRESENTATION: An 88-year-old hypertensive woman presented with acute vertical oblique binocular diplopia, followed by complete ptosis of the right eye. Ophthalmic examination showed dysfunction of the right third, fourth, and sixth cranial nerves. Further examination revealed hypesthesia of the areas supplied by the ophthalmic (V1) and maxillary (V2) branches of the right trigeminal nerve. Bilateral giant cavernous carotid aneurysms, with a concurrent subacute right occipital lobe infarction, were discovered on brain imaging and angiogram. Additionally, a prominent right posterior communicating artery (PCOM) was revealed. Seven months later, clinical improvement with stable radiographic findings was documented without any intervention. CONCLUSIONS: Dysfunction of the third, fourth, and sixth cranial nerves, and the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerves, should necessitate brain imaging, with special attention given to the cavernous sinus. Despite unilateral symptomatic presentation, bilateral lesions cannot be excluded solely on the basis of clinical findings. CCA should be included in the differential diagnosis of cavernous sinus lesions. Although rare, ipsilateral posterior circulation cerebral infarction (i.e., occipital lobe infarction) can occur in CCA patients, presumably as a result of distal embolization through an ipsilateral, prominent PCOM. Spontaneous clinical improvement with stable radiographic support may occur. PMID- 29394918 TI - Expanded HIV pre-exposure prophylaxis (PrEP) implementation in communities in New South Wales, Australia (EPIC-NSW): design of an open label, single arm implementation trial. AB - BACKGROUND: The New South Wales (NSW) HIV Strategy 2016-2020 aims for the virtual elimination of HIV transmission in NSW, Australia, by 2020. Despite high and increasing levels of HIV testing and treatment since 2012, the annual number of HIV diagnoses in NSW has remained generally unchanged. Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV infection among gay and bisexual men (GBM) when taken appropriately. However, there have been no population-level studies that evaluate the impact of rapid PrEP scale-up in high-risk GBM. Expanded PrEP Implementation in Communities in NSW (EPIC-NSW) is a population level evaluation of the rapid, targeted roll-out of PrEP to high-risk individuals. METHODS: EPIC-NSW, is an open-label, single-arm, multi-centre prospective observational study of PrEP implementation and impact. Over 20 public and private clinics across urban and regional areas in NSW have participated in the rapid roll-out of PrEP, supported by strong community mobilization and PrEP promotion. The study began on 1 March 2016, aiming to enroll at least 3700 HIV negative people at high risk of HIV. This estimate took into consideration criteria for PrEP prescription in people at high risk for acquiring HIV as defined in the NSW PrEP guidelines. Study participants receive once daily co formulated tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and are followed for up to 24 months. Follow-up includes: testing for HIV at 1 month, HIV and other sexually transmissible infections three-monthly, HCV annually and monitoring of renal function six-monthly. Optional online behavioural surveys are conducted quarterly. The co-primary endpoints are (i) HIV diagnoses and incidence in the cohort and (ii) HIV diagnoses in NSW. DISCUSSION: EPIC-NSW is a population based PrEP implementation trial which targets the entire estimated population of GBM at high risk for HIV infection in NSW. It will provide a unique opportunity to evaluate the population impact of PrEP on a concentrated HIV epidemic. TRIAL REGISTRATION: https://clinicaltrials.gov/ (identifying number NCT02870790 ; registration date 14 August 2016), pre-results stage. PMID- 29394919 TI - Prevention of violent revictimization in depressed patients with an add-on internet-based emotion regulation training (iERT): study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Psychiatric patients are at high risk of becoming victim of a violent crime compared to the general population. Although most research has focused on patients with severe mental illness, depressed patients have been demonstrated to be prone to victimization as well. Victimization is associated with more severe symptomatology, decreased quality of life, and high risk of revictimization. Hence, there is a strong need for interventions that focus on preventing violent revictimization. Since emotion dysregulation is associated with both victimization and depression, we developed an internet-based Emotion Regulation Training (iERT) to reduce revictimization in depressed patients. This study aims to evaluate the clinical and cost-effectiveness of iERT added to Treatment As Usual (TAU) in reducing incidents of violent revictimization among depressed patients with a recent history of victimization. Furthermore, this study aims to examine secondary clinical outcomes, and moderators and mediators that may be associated with treatment outcomes. METHODS: In a multicenter randomized controlled trial with parallel group design, patients with a major depressive disorder and a history of violent victimization over the past three years (N = 200) will be allocated to either TAU + iERT (N = 100) or TAU only (N = 100), based on computer-generated stratified block randomization. Assessments will take place at baseline, 8 weeks, 14 weeks, and 6 months after start of treatment, and 12, 24, and 36 months after baseline. The primary outcome measure is the total number of violent victimization incidents at 12 months after baseline, measured with the Safety Monitor: an adequate self-report questionnaire that assesses victimization over the preceding 12 months. Secondary outcome measures and mediators include emotion dysregulation and depressive symptomatology. An economic evaluation with the societal perspective will be performed alongside the trial. DISCUSSION: This study is the first to examine the effectiveness of an intervention aimed at reducing violent revictimization in depressed patients. If effective, iERT can be implemented in mental health care, and contribute to the well-being of depressed patients. Furthermore, the results will provide insight into underlying mechanisms of revictimization. TRIAL REGISTRATION: The study is registered at the Netherlands Trial Register ( NTR5822 ). Date of registration: 4 April 2016. PMID- 29394921 TI - Barriers to sealant guideline implementation within a multi-site managed care dental practice. AB - BACKGROUND: The purpose of this study was to identify barriers frequently endorsed by dentists in a large, multi-site dental practice to implementing the American Dental Association's recommendation for sealing noncavitated occlusal carious lesions as established in their 2016 pit-and-fissure sealant clinical practice guideline. Although previous research has identified barriers to using sealants perceived by dentists in private practice, barriers frequently endorsed by dentists in large, multi-site dental practices have yet to be identified. Identifying barriers for these dentists is important, because it is expected that in the future, the multi-site group practice configuration will comprise more dental practices. METHODS: We anonymously surveyed the 110 general and pediatric dentists at a multi-site dental practice in the U.S. The survey assessed potential barriers in three domains: practice environment, prevailing opinion, and knowledge and attitudes. Results were summarized using descriptive statistics. RESULTS: The response rate to the survey was 62%. The principal barrier characterizing the practice environment was concern regarding liability; endorsed by 33% of the dentists. Many barriers of prevailing opinion were frequently endorsed. These included misunderstanding the standard of practice (59%), being unaware of the expectations of opinion leaders (56%) including being unaware of the guideline itself (67%), and being unaware of what is currently being taught in dental schools (58%). Finally, barriers of knowledge and attitudes were frequently endorsed. These included having suboptimal skill in applying sealants (23% - 47%) and lacking knowledge regarding the relative efficacy of the different ways to manage noncavitated occlusal carious lesions (50%). CONCLUSIONS: We identified barriers frequently endorsed by dentists in a large, multi-site dental practice relating to the practice environment, prevailing opinion, and knowledge and attitudes. All the barriers we identified have the potential to be addressed by implementation strategies. Future studies should devise and test implementation strategies to target these barriers. PMID- 29394922 TI - Relationship between muscle strength and dyslipidemia, serum 25(OH)D, and weight status among diverse schoolchildren: a cross-sectional analysis. AB - BACKGROUND: The relationship between muscle strength and cardiometabolic risk factors in youth, and the potential influence of vitamin D status on this relationship, is not well understood. This study examined associations between muscle strength and dyslipidemia, serum 25-hydroxyvitamin D [25(OH)D], and weight status in diverse schoolchildren. METHODS: Measures of hand-grip strength (standardized for sex and body weight), anthropometrics (height and weight converted to BMI z-score [BMIz]), sociodemographics, and fasting blood concentrations of plasma HDL-C and triglycerides and serum 25(OH)D were collected from 350 4th-8th grade schoolchildren (11.2 +/- 1.3 y, 49.4% female, 56.3% non white/Caucasian). Logistic regression was used to measure associations between standardized tertiles of grip strength and blood lipids, 25(OH)D, and weight status along with associations between 25(OH)D and dyslipidemia and weight status. RESULTS: Children with higher grip strength had lower odds of overweight/obesity (OR: 0.03, 95% CI: 0.01-0.06, in the highest tertile of grip strength vs. lowest, p for trend< 0.0001), borderline/low HDL-C (OR: 0.28, 95% CI: 0.16-0.50, p for trend< 0.0001), and borderline/high triglycerides (OR: 0.48, 95% CI: 0.25-0.92, p for trend< 0.05), adjusting for covariates. Associations between blood lipids and grip strength became non-significant after further adjustment for BMIz. No association was observed between grip strength and 25(OH)D, nor between 25(OH)D and borderline/low HDL-C or weight status; however, vitamin D sufficiency was associated with lower odds of borderline/high triglycerides compared with vitamin D deficiency (OR: 0.26, 95% CI: 0.09-0.74, p for trend< 0.05) before BMIz adjustment. CONCLUSION: Among racially/ethnically diverse children, muscle strength was associated with lower dyslipidemia. Longitudinal studies are needed to explore whether changes in muscle strength impact this relationship in children, independent of weight status. TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov (No. NCT01537809 ) on February 17, 2012. PMID- 29394924 TI - Spousal age difference and associated predictors of intimate partner violence in Nigeria. AB - BACKGROUND: The growth in Intimate Partner Violence (IPV) cases among couples in Nigeria has been significant in recent years. Victims, which are often females, face numerous health challenges, including early death. I examined the linkages between spousal age differences and IPV in Nigeria. METHOD: The couples recode data section of the 2013 Nigeria Demographic Health and Survey was used (n = 6765). Intimate partner violence was measured using 13-item questions. Data were analyzed using the logistic regression model (alpha = .05). RESULTS: The mean spousal age difference was 8.20 +/- 5.0 years. About 23.5, 18.0, 13.5 and 4.7% of couples surveyed had experienced some form of IPV, emotional, physical and sexual violence respectively. Also, IPV prevalence was 27.0, 23.7, 22.0 and 18.7% among couples with age differences of 0-4, 5-9, 10-14 and >=15 years respectively; this pattern was exhibited across all domains of IPV. Among women who experienced physical violence, 20.5% had only bruises, 8.0% had at least one case of eye injuries, sprains and/or dislocations, and 3.7% had either one or more cases of wounds, broken bones or broken teeth. The identified predictors of IPV were: family size, ethnicity, household wealth, education, number of marital unions and husband drinks alcohol. The unadjusted likelihood of IPV was 1.60 (C.I = 1.30 1.98, p < 0.001) and 1.35 (C.I = 1.10-1.64, p < 0.01) higher in households where the spousal age difference was 0-4 and 5-9 years respectively, than the likelihoods among those with a spousal age difference >= 15 years, but the strength of the association weakens when other variables were included in the model. CONCLUSION: The level of IPV was generally high in Nigeria, but it reduced with increasing spousal age difference. This study underscores the need for men to reach a certain level of maturity before marriage, as this is likely to reduce the level of IPV in Nigeria. PMID- 29394923 TI - Screening for distress in patients with primary brain tumor using distress thermometer: a systematic review and meta-analysis. AB - BACKGROUND: Patients with primary brain tumors are reported to have an elevated level of distress prevalence, due to the functional sequelae and the unfavorable prognosis, but the estimated prevalence of this disorder varies among studies. The Distress Thermometer (DT) is widely used distress screening tools to identify patients suffering from elevated psychosocial distress. The objective of this meta-analysis is to get a summarized estimate of distress prevalence in adult primary brain tumor patients screened by the DT instrument to identify distress in brain tumor patients. METHOD: We searched studies published in PubMed, PsycINFO, and Cochrane library through August 2017 and checked related reviews and meta-analyses for eligible studies. Studies were eligible if they were published in the peer-reviewed literature and evaluated distress level by Distress Thermometer. The prevalence of distress symptoms in patients with the intracranial tumor was estimated by study-level characteristics using stratified meta-analysis. The prevalence of distress level or symptoms during the follow-up examination at different time points was detected by secondary analysis of the longitudinal studies included. RESULTS: Twelve studies including a total of 2145 brain tumor patients were included in this analysis. Eight used a cross-sectional design and four were longitudinal. The pooled prevalence of distress was 38.2% (95% confidence interval (CI) 28.7%-47.7%) for the overall sample. The pooled prevalence of distress DT >=4 was 41.1% (642/1686, 95% CI 28.6%-53.5%) and the pooled prevalence of distress by DT >=6 was 29.7% (137/459, 95% CI 19.5%-39.9%). The distress symptom did not decrease in follow-up studies (Relative Increase Ratio:1.02, 95% CI, (0.78, 1.35)). A huge heterogeneity in different studies was detected, and different screening scales were not compared. CONCLUSION: The high prevalence of distress becomes an enormous challenge for primary brain tumor patients. Routine screening and evaluation of distress in brain tumor patients may assist medical workers to develop proper interventions, which may lead to better quality of life and oncology management. PMID- 29394925 TI - Nc886 is epigenetically repressed in prostate cancer and acts as a tumor suppressor through the inhibition of cell growth. AB - BACKGROUND: Nc886 is a 102 bp non-coding RNA transcript initially classified as a microRNA precursor (Pre-miR-886), later as a divergent homologue of the vault RNAs (vtRNA 2-1) and more recently as a novel type of RNA (nc886). Although nc886/vtRNA2-1/Pre-miR-886 identity is still controversial, it was shown to be epigenetically controlled, presenting both tumor suppressor and oncogenic function in different cancers. Here, we study for the first time the role of nc886 in prostate cancer. METHODS: Nc886 promoter methylation status and its correlation with patient clinical parameters or DNMTs levels were evaluated in TCGA and specific GEO prostate tissue datasets. Nc886 level was measured by RT qPCR to compare normal/neoplastic prostate cells from radical prostatectomies and cell lines, and to assess nc886 response to demethylating agents. The effect of nc886 recovery in cell proliferation (in vitro and in vivo) and invasion (in vitro) was evaluated using lentiviral transduced DU145 and LNCaP cell lines. The association between the expression of nc886 and selected genes was analyzed in the TCGA-PRAD cohort. RESULTS: Nc886 promoter methylation increases in tumor vs. normal prostate tissue, as well as in metastatic vs. normal prostate tissue. Additionally, nc886 promoter methylation correlates with prostate cancer clinical staging, including biochemical recurrence, Clinical T-value and Gleason score. Nc886 transcript is downregulated in tumor vs. normal tissue -in agreement with its promoter methylation status- and increases upon demethylating treatment. In functional studies, the overexpression of nc886 in the LNCaP and DU145 cell line leads to a decreased in vitro cell proliferation and invasion, as well as a reduced in vivo cell growth in NUDE-mice tumor xenografts. Finally, nc886 expression associates with the prostate cancer cell cycle progression gene signature in TCGA-PRAD. CONCLUSIONS: Our data suggest a tumor suppressor role for nc886 in the prostate, whose expression is epigenetically silenced in cancer leading to an increase in cell proliferation and invasion. Nc886 might hold clinical value in prostate cancer due to its association with clinical parameters and with a clinically validated gene signature. PMID- 29394926 TI - Intravescical prostatic protrusion is a predictor of alpha blockers response: results from an observational study. AB - BACKGROUND: To investigate the efficacy of tamsulosin in patients with lower urinary tract symptoms (LUTS) and benign prostatic enlargement (BPE) with intravesical prostatic protrusion (IPP). Ultrasound measurement of the IPP has been previously described as an effective instrument for the evaluation of benign prostatic obstruction (BPO) and could help in clarifying the role of alpha blockers in patients with (BPE). METHODS: Patients with BPE and LUTS were enrolled in this observational study. Intravesical prostatic protrusion was graded as grade 1 (< 5 ml), 2 (5 < IPP < 10 ml) and 3 (> 10 ml). Patients were treated with tamsulosin for twelve weeks. Evaluation was performed before and at the end of treatment by means of International Prostate Symptom Score (IPSS) and uroflowmetry. Patients were considered responders if a reduction of IPSS > 3 points was reported. RESULTS: One hundred forty-two patients were enrolled. Twelve patients were excluded because of incomplete data. Fifty patients showed an IPP grade 1 (group A), 52 a grade 2 (group B) and 28 a grade 3 (group C). Treatment success was obtained in 82%, 38,5% and 7,1% of patients respectively; these differences (group A vs B-C and group B vs C) were highly significant. The odd ratio to obtain a treatment success was of 59 and 8.1 in group A and group B respectively, in comparison to group C. After a multivariate regression, the relationship between IPP grade and treatment success remained significant. Improvement of uroflowmetry parameters has been reported in all the groups especially in patients with a low grade IPP (p value = 0,016 group A vs group B; p value = 0,005 group A vs group C). Prostate volume seems not to influence this relationship. CONCLUSIONS: Intravesical prostatic protrusion has found to be significantly and inversely correlated with treatment success in patients with LUTS and BPE under alpha-blockers therapy. Alpha blockers odd ratio of success is 59 times higher in patients with a low grade IPP in comparison to patients with a high grade. PMID- 29394927 TI - Quantification of cancer risk in glomerulonephritis. AB - BACKGROUND: The association of increased cancer risk with glomerulonephritis (GN) is well known, but controversy exists concerning which types of GN are involved, and the size of the association. A national registry survey was performed to assess the size of this association, and the temporal relationship of cancer diagnosis to GN diagnosis. METHODS: All patients with biopsy-proven GN between 1985 and 2015 in Denmark were extracted from The Danish Renal Biopsy Registry and the National Pathology Data Bank. Incident cancer diagnoses between 10 years previous and 10 years subsequent to the GN diagnosis were extracted from the Danish Cancer Registry. Residence, birth and death data were obtained from the National Patient Register. Expected cancer incidence, classified according to cohort, age and sex were extracted from the Nordcan database. RESULTS: Nine hundred eleven cancers were diagnosed in 5594 patients. Thirty five percent were prevalent at renal biopsy. Prevalence at biopsy was 5.5% (expected 3.1%), but incidence was not increased < 1 year before biopsy. Increased cancer rates were seen for GN forms: minimal change, endocapillary, focal segmental glomerulosclerosis, mesangioproliferative, membranous, focal segmental, membranoproliferative, proliferative, ANCA-associated vasculitis, lupus nephritis and unclassified. Increased cancer rates were seen for lung, prostate, renal, non Hodgkin lymphoma, myeloma, leukaemia and skin. The increased incidence was mainly limited to - 1 to 1 year after biopsy, but skin cancer showed an increased risk over time. Some diagnoses showed an increase 5-10 years after biopsy. Incidence was raised for patients with uraemia and nephrosis, but less for proteinuria or haematuria. Cancers in patients < 45 years were rare. The risk of developing cancer 0-3 years after biopsy for patients 45-64 years varied from 7.3% (minimal change) to 15.8% (unclassified GN); > 64 years from 11.8 (endocapillary GN) to 20.3% (unclassified). The diagnosis with the highest risk was membranoproliferative GN (8.6 & 19.6%). CONCLUSIONS: Cancer rates are increased for many cancer and most GN diagnoses. Cancer screening for patients < 45 years and for patients without nephrosis or uraemia may not be necessary. The findings suggest that screening programs for specific GN diagnoses can be extended to other GN forms. PMID- 29394928 TI - Level of invasion into fibromuscular band is an independent factor for positive surgical margin and biochemical recurrence in men with organ confined prostate cancer. AB - BACKGROUND: This study aimed investigate the effect of the level of invasion into fibromuscular band (FMB) of prostate on the positive surgical margin (PSM) and biochemical recurrence (BCR) after radical prostatectomy (RP) in patients with organ-confined (pT2) prostate cancer. METHODS: The clinical and pathological data of 461 consecutive patients with pT2 prostate cancer were evaluated regarding the level of invasion into FMB. The relationship between levels of invasion into FMB and PSM / BCR was assessed. RESULTS: The rate of PSM at an FMB level of at 2 was 18.8%, which was significantly greater than the rates at levels 0 (5.4%) and 1 (7.8%). The level of FMB (p = 0.007) and percentage of tumor volume (p = 0.012) were identified as independent factors predictive of a positive surgical margin in a multivariate analysis. The 5-year BCR-free survival rates for a level 0-1 FMB with negative surgical margin, level 0-1 FMB with positive surgical margin, level 2 FMB with negative surgical margin, and level 2 FMB with positive surgical margin were 96.6%, 86.4%, 85.6%, and 72.9%, respectively (p < 0.001). A level 2 FMB (p = 0.050), positive surgical margin (p = 0.001), and surgical Gleason score (p = 0.001) were identified as independent predictors of a BCR of pT2 prostate cancer. CONCLUSIONS: Among patients with negative surgical margins, the surgical Gleason score and level of FMB independently affected the incidence of a BCR of pT2 prostate cancer. The level of FMB was an independent predictor of both a positive surgical margin and a BCR of pT2 disease. Accordingly, the level of FMB might help to further stratify the prognosis of patients with pT2 disease. PMID- 29394929 TI - Femtosecond laser-assisted cataract surgery in a public teaching hospital setting. AB - BACKGROUND: To evaluate the efficiency and practicality of femtosecond laser assisted cataract surgery (FLACS) in a public teaching hospital setting using a mobile FLACS system compared to conventional phacoemulsification cataract surgery (CPCS). METHODS: Ninety eyes from 90 patients underwent either FLACS or CPCS (45 in each group). Cataracts were graded using the Lens Opacities Classification System III system. Outcome measures included total surgery duration, femtosecond laser treatment time, vacuum time (VT), total phacoemulsification time (TPT) and total phacoemulsification power (TPP). RESULTS: No differences were observed in the preoperative mean cataract grades and co-morbidities. FLACS took longer than CPCS with a mean difference of 5.2 +/- 4.5 min (range: 0-18.8 min). The average femtosecond laser treatment time was 4.3 +/- 3.4 min (range: 1-15.5 min). The VT was 2.51 +/- 0.45 min (range: 1.59-4.10 min). Although not significant, TPT in FLACS showed a trend towards improvement (mean 1.0 +/- 0.6 s; range: 0.1-2.4 s) compared to CPCS (mean 1.2 +/- 0.6 min; range: 0.5-2.5 min). Whereas, TPP was significantly less in FLACS (mean 17.9 +/- 5.0%; range: 5-27%) compared to CPCS (mean 20.3 +/- 4.1%; range: 12.0-28.7%)(p = 0.031). CONCLUSIONS: The mobile FLACS system housed in the same operating room increased the surgical duration by 5.2 min. The average VT was 2.51 min, which was lower in comparison to published experience using non-mobile FLACS systems. PMID- 29394930 TI - Evaluating the prevalence and opportunity for technology use in chronic kidney disease patients: a cross-sectional study. AB - BACKGROUND: Chronic kidney disease (CKD) is increasing worldwide and early education to improve adherence to self-management is a key strategy to slow CKD progression. The use of the internet and mobile phone technologies (mHealth) to support patients is considered an effective tool in many other chronic disease populations. While a number of mHealth platforms for CKD exist, few studies have investigated if and how this population use technology to engage in self management. METHODS: Using a cross-sectional design across five health districts in Queensland (Australia), a 38-item self-report survey was distributed to adults with CKD attending outpatient clinics or dialysis units to measure current use and type of engagement with mHealth, perceived barriers to use, and opportunities to support CKD self-management. Odds ratio (OR) were calculated to identify associations between demographic characteristic and mHealth use. RESULTS: Of the 708 participants surveyed, the majority had computer access (89.2%) and owned a mobile phone (83.5%). The most likely users of the internet were those aged <= 60 years (OR: 7.35, 95% confidence interval [CI]: 4.25-12.75, p < 0.001), employed (OR: 7.67, 95% CI: 2.58-22.78, p < 0.001), from non-indigenous background (OR: 6.98, 95% CI: 3.50-13.93, p < 0.001), or having completed higher levels of education (OR: 3.69, CI: 2.38-5.73, p < 0.001). Those using a mobile phone for complex communication were also younger (OR: 6.01, 95% CI: 3.55-10.19, p < 0.001), more educated (OR: 1.99, 95% CI: 1.29-3.18, p < 0.01), or from non indigenous background (OR: 3.22, 95% CI: 1.58-6.55, p < 0.001). Overall, less than 25% were aware of websites to obtain information about renal healthcare. The mHealth technologies most preferred for communication with their renal healthcare teams were by telephone (56.5%), internet (50%), email (48.3%) and text messages (46%). CONCLUSION: In the CKD cohort, younger patients are more likely than older patients to use mHealth intensively and interactively although all patients' technology literacy ought to be thoroughly assessed by renal teams before implementing in practice. Further research testing mHealth interventions to improve self-management in a range of patient cohorts is warranted. PMID- 29394931 TI - Fitting NTCP models to bladder doses and acute urinary symptoms during post prostatectomy radiotherapy. AB - BACKGROUND: To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms. METHODS: Ninety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by >=2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods. RESULTS: For the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D50 = 64.2Gy, m = 0.50, n = 1.0; 2) D50 = 95.0Gy, m = 0.45, n = 0.50; 3) D50 = 83.1Gy, m = 0.56, n = 1.00; and 4) D50 = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3. CONCLUSIONS: Different dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes. PMID- 29394932 TI - Moving knowledge into action for more effective practice, programmes and policy: protocol for a research programme on integrated knowledge translation. AB - BACKGROUND: Health research is conducted with the expectation that it advances knowledge and eventually translates into improved health systems and population health. However, research findings are often caught in the know-do gap: they are not acted upon in a timely way or not applied at all. Integrated knowledge translation (IKT) is advanced as a way to increase the relevance, applicability and impact of research. With IKT, knowledge users work with researchers throughout the research process, starting with identification of the research question. Knowledge users represent those who would be able to use research results to inform their decisions (e.g. clinicians, managers, policy makers, patients/families and others). Stakeholders are increasingly interested in the idea that IKT generates greater and faster societal impact. Stakeholders are all those who are interested in the use of research results but may not necessarily use them for their own decision-making (e.g. governments, funders, researchers, health system managers and policy makers, patients and clinicians). Although IKT is broadly accepted, the actual research supporting it is limited and there is uncertainty about how best to conduct and support IKT. This paper presents a protocol for a programme of research testing the assumption that engaging the users of research in phases of its production leads to (a) greater appreciation of and capacity to use research; (b) the production of more relevant, useful and applicable research that results in greater impact; and (c) conditions under which it is more likely that research results will influence policy, managerial and clinical decision-making. METHODS: The research programme will adopt an interdisciplinary, international, cross-sector approach, using multiple and mixed methods to reflect the complex and social nature of research partnerships. We will use ongoing and future natural IKT experiments as multiple cases to study IKT in depth, and we will take advantage of the team's existing relationships with provincial, national and international organizations. Case studies will be retrospective and prospective, and the 7-year grant period will enable longitudinal studies. The initiation of partnerships, funding processes, the research lifecycle and then outcomes/impacts post project will be studied in real time. These living laboratories will also allow testing of strategies to improve the efficiency and effectiveness of the IKT approach. DISCUSSION: This is the first interdisciplinary, systematic and programmatic research study on IKT. The research will provide scientific evidence on how to reliably and validly measure collaborative research partnerships and their impacts. The proposed research will build the science base for IKT, assess its relationship with research use and identify best practices and appropriate conditions for conducting IKT to achieve the greatest impact. It will also train and mentor the next generation of IKT researchers. PMID- 29394933 TI - Social health insurance, healthcare utilization, and costs in middle-aged and elderly community-dwelling adults in China. AB - BACKGROUND: Although many studies have analyzed health insurance worldwide, most focus on whole populations rather than specific vulnerable groups. There is a lack of studies that compare different schemes. This paper evaluates the impact of different types of social health insurance and other associated factors on healthcare utilization and costs among middle-aged and elderly Chinese adults. METHODS: Data were obtained from a nationally representative middle-aged and elderly household survey, the China Health and Retirement Longitudinal Study, which was conducted in 2015. Middle-aged and elderly are defined as people who are >=45 years. Descriptive statistics were used to show the prevalence of each variable. Both logistic and multiple linear regression models were used to evaluate the association between healthcare utilization/healthcare costs and health insurance in addition to other related factors. RESULTS: Although the rapid expansion of social health insurance coverage has significantly improved the healthcare utilization among middle-aged and elderly adults, the difference between three schemes is large. Urban Employee Medical Insurance (UEMI) has had a greater effect in improving healthcare utilization than New Cooperative Medical Insurance (NCMI) or Urban Resident Medical Insurance (URMI). Unification of health insurance programs and optimization of health resource allocations should be a practical way to alleviate healthcare utilization inequality across schemes. People having social health insurance spend more on total and out-of-pocket (OOP) healthcare costs than people not covered by social health insurance, suggesting that enrollment in social health insurance induces significant increases in both total and OOP healthcare expenses. UEMI for the urban employed has relatively higher funding criteria and reimbursement rate, which makes the greatest extent to induce increase in healthcare costs. Some demographic or socioeconomic factors significantly affect healthcare utilization and costs among middle-aged and elderly adults. CONCLUSION: Our study demonstrates the differences in healthcare utilization and costs between those with and without social health insurance and between those with different health insurance schemes. Policy efforts should further focus on adjusting social health insurance and optimizing healthcare resource allocation in order to enhance effective utilization of healthcare services and control cost increases among middle-aged and elderly adults. PMID- 29394934 TI - IRE1alpha inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17 5p after neonatal hypoxic-ischemic brain injury in rats. AB - BACKGROUND: The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia-ischemia (HI), there is an accumulation of unfolded proteins thereby triggering the unfolded protein response (UPR) and causing ER stress which is associated with activation of several stress sensor signaling pathways, one of them being the inositol requiring enzyme-1 alpha (IRE1alpha) signaling pathway. The UPR is regarded as a potential contributor to neuronal cell death and inflammation after HI. In the present study, we sought to investigate whether microRNA-17 (miR-17), a potential IRE1alpha ribonuclease (RNase) substrate, arbitrates downregulation of thioredoxin-interacting protein (TXNIP) and consequent NLRP3 inflammasome activation in the immature brain after HI injury and whether inhibition of IRE1alpha may attenuate inflammation via miR-17/TXNIP regulation. METHODS: Postnatal day 10 rat pups (n = 287) were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2). STF-083010, an IRE1alpha RNase inhibitor, was intranasally delivered at 1 h post-HI or followed by an additional one administration per day for 2 days. MiR-17-5p mimic or anti-miR-17-5p inhibitor was injected intracerebroventricularly at 48 h before HI. Infarct volume and body weight were used to evaluate the short-term effects while brain weight, gross and microscopic brain tissue morphologies, and neurobehavioral tests were conducted for the long-term evaluation. Western blots, immunofluorescence staining, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (Co-IP) were used for mechanism studies. RESULTS: Endogenous phosphorylated IRE1alpha expression was significantly increased after HI. Intranasal administration of STF-083010 alleviated brain injury and improved neurological behavior. MiR-17-5p expression was reduced after HI, and this decrease was attenuated by STF-083010 treatment. MiR-17-5p mimic administration ameliorated TXNIP expression, NLRP3 inflammasome activation, caspase-1 cleavage, and IL-1beta production, as well as brain infarct volume. Conversely, anti-miR-17-5p inhibitor reversed IRE1alpha inhibition induced decrease in TXNIP expression and inflammasome activation, as well as exacerbated brain injury after HI. CONCLUSIONS: IRE1a-induced UPR pathway may contribute to inflammatory activation and brain injury following neonatal HI. IRE1a activation, through decay of miR-17-5p, elevated TXNIP expression to activate NLRP3 inflammasome and aggravated brain damage. PMID- 29394936 TI - Risk factors for non-fusion segment disease after anterior cervical spondylosis surgery: a retrospective study with long-term follow-up of 171 patients. AB - BACKGROUND: The purpose of this study was to investigate the incidence and causes of non-fusion segment disease (NFSD), both adjacent and non-adjacent to a fused segment, after anterior cervical arthrodesis. METHODS: This is a single-center study. Between January 1998 and January 2011, two surgeons' 171 patients who had an anterior cervical decompression and fusion were followed clinically for more than 5 years. The correlation between the incidence of symptomatic non-fusion segment disease and the following clinical parameters (age at operation, fusion levels,) and radiological parameters (number of patients who had a plate, anterior cervical decompression and fusion (ACDF) or corpectomies, preoperative and postoperative cervical spine alignment, Pavlov's ratio at the C5 level, and preoperative existence of a non-fusion segment degeneration on magnetic resonance imaging) was evaluated. RESULTS: Of the 171 patients reviewed, 16 patients had non-fusion segment disease (9.36%), of which 12 had adjacent segment disease and 4 had non-adjacent segment disease. Postoperative cervical lordosis in the non fusion segment disease group was significantly smaller than that of the disease free group (P < 0.001). Fusion levels in the NFSD group were 1.69 whereas 2.26 in disease-free group (P = 0.005). The incidences of disc degeneration in unfused segments was more severe in the NFSD group than in the disease-free group (P = 0.004). The results of binary logistic regression showed that the major factor affecting NFSD is postoperative cervical lordosis (P = 0.000) followed by disc degeneration (P = 0.024). The other parameters did not show a statistically significant difference. CONCLUSIONS: The incidence of symptomatic non-fusion segment disease after anterior cervical arthrodesis has multifactorial causes. Postoperative cervical lordosis and disc degeneration in non-fusion segments were major factors in the incidence of NFSD. PMID- 29394935 TI - Beyond the replication-competent HIV reservoir: transcription and translation competent reservoirs. AB - Recent years have seen a substantial increase in the number of tools available to monitor and study HIV reservoirs. Here, we discuss recent technological advances that enable an understanding of reservoir dynamics beyond classical assays to measure the frequency of cells containing provirus able to propagate a spreading infection (replication-competent reservoir). Specifically, we focus on the characterization of cellular reservoirs containing proviruses able to transcribe viral mRNAs (so called transcription-competent) and translate viral proteins (translation-competent). We suggest that the study of these alternative reservoirs provides complementary information to classical approaches, crucially at a single-cell level. This enables an in-depth characterization of the cellular reservoir, both following reactivation from latency and, importantly, directly ex vivo at baseline. Furthermore, we propose that the study of cellular reservoirs that may not contain fully replication-competent virus, but are able to produce HIV mRNAs and proteins, is of biological importance. Lastly, we detail some of the key contributions that the study of these transcription and translation competent reservoirs has made thus far to investigations into HIV persistence, and outline where these approaches may take the field next. PMID- 29394937 TI - Side effects of CT-guided implantation of 125I seeds for recurrent malignant tumors of the head and neck assisted by 3D printing non co-planar template. AB - BACKGROUND: For the recurrence of head and neck cancer after operation and radiotherapy, the local control of radioactive seed implantation is good, and it has a certain palliative effect. This study aims to investigate the acute and late side effects of a three-dimentional printing non co-planar template (3D PNCT) for computed tomography (CT)-guided radioactive 125I seed (RIS) implantation in recurrent cancer of the head and neck. METHODS: Between January 2016 and December 2016, forty-two patients with local recurrent malignant tumors of the head and neck received 3D-PNCT-assisted RIS implantation. The prescribed dose was 110-160 Gy. Preoperative planning design, production of individual guide plates, RIS implantation, postoperative dose evaluation, and follow-up were completed for all patients. Side effects in the skin, mucous membranes, blood and spinal cord were evaluated. RESULTS: All patients underwent surgery successfully. Duration of follow-up was 4-14 (median, of 8.5) months. The activity of a single RIS was 0.34-0.7 (median, 0.6) mCi. The number of RIS was 10-126 (median, 34). The number of implantation needles was 4-31 (median, 11). The mean D2cc (dose to the most exposed 2-cc volume) and D0.1cc (dose to the most exposed 0.1-cc volume) of the skin were 24.9 (7.1-85.5) and 47.5 (9.4-167.2), respectively, whereas those of the spinal cord were 8.4 (4.5-33.3) and 14.2 (13.6-63.0), mucosa were 35.1 (4.2-82.8) and 87.0 (6.6-214.1), parotid glands were 16.2 (12.8-19.7) and 29.8 (26.1-33.4) and those of the trachea were 17.9 (2.5-45.9) and 32.7 (3.9 83.9), respectively. No case had an acute reaction of grade >= 3. Three cases had a grade-1 skin reaction. Blood toxicity did not occur, nor spinal-cord injury. Xerostomia was not aggravated than that of before brachytherapy. One case had a grade-3 nerve response. CONCLUSIONS: 3D-PNCT-assisted RIS implantation can provide good accuracy for positioning. For local recurrent malignant tumor of head and neck, there were no obvious adverse reactions. PMID- 29394938 TI - Expertise in evidence-based medicine: a tale of three models. AB - BACKGROUND: Expertise has been a contentious concept in Evidence-Based Medicine (EBM). Especially in the early days of the movement, expertise was taken to be exactly what EBM was rebelling against-the authoritarian pronouncements about "best" interventions dutifully learned in medical schools, sometimes with dire consequences. Since then, some proponents of EBM have tried various ways of reincorporating the idea of expertise into EBM, with mixed results. However, questions remain. Is expertise evidence? If not, what is it good for, if anything? METHODS: In this article, I describe and analyze the three historical models of expertise integration in EBM and discuss the difficulties in putting each into practice. I also examine accounts of expertise from disciplines outside of medicine, including philosophy, sociology, psychology, and science and technology studies to see if these accounts can strengthen and clarify what EBM has to say about expertise. RESULTS: Of the accounts of expertise discussed here, the Collins and Evans account can do most to clarify the concept of expertise in EBM. CONCLUSIONS: With some additional clarification from EBM proper, theoretical resources from other disciplines might augment the current EBM account of expertise. PMID- 29394939 TI - Lipidomic analysis of serum samples from migraine patients. AB - BACKGROUND: Migraine is a prevalent, disabling type of primary headache disorder associated with a high socioeconomic burden. The clinical management of migraine is challenging. This study was to identify potential serum lipidomic biomarkers of migraine. METHODS: The serum lipidomic profile of migraine sufferers was compared with healthy individuals using Liquid Chromatography coupled to Mass Spectrometry (LC-MS). Volcano plot analysis by Student's t-test was performed to identify the differential metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under ROC curves (AUC) was calculated to evaluate whether the metabolites could be efficiently exploited for constructing a sensitive biomarker of migraine. RESULTS: A total of 29 serum metabolites from 4 classes of lipids including acylcarnitines, non-alpha-hydroxy-sphingosine ceramides (Cer_NSs), lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs) were significantly different in migraine patients and controls. Of note, Cer_NSs were significantly elevated and lysoPEs were significantly decreased in migraine patients. LysoPE 18:1, lysoPE 18:2 and lysoPE 22:5 were found to be decreased in both positive and negative ion mode. Moreover, except for lysoPC 20:0, other lysoPCs were decreased in migraine patients. ROC curve analysis indicated that lysoPC 16:0 and lysoPC 20:0 are potential sensitive and specific biomarkers for migraine. CONCLUSION: LysoPC 16:0 and lysoPC 20:0 may be potential biomarkers for migraine. We suggest therapeutic management of these metabolites may be helpful in the prevention and treatment of migraine. PMID- 29394940 TI - From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience. AB - BACKGROUND: Despite screening campaigns, cervical cancers remain among the most prevalent malignancies and carry significant mortality, especially in developing countries. Most studies report outcomes of patients receiving the usual standard of care. It is possible that these selected patients may not correctly represent patients in a real-world setting, which may be a limitation in interpreting outcomes. This study was undertaken to identify prognostic factors, management strategies and outcomes of locally advanced cervical cancers (LACC) treated in daily clinical practice. METHODS: Medical files of all consecutive patients treated with curative intent for LACC in a French Cancer Care Center between 2004 and 2014 were reviewed retrospectively. RESULTS: Ninety-four patients were identified. Performance status was >= 2 in 10.6%. Median age at diagnosis was 63.0. Based on the International Federation of Gynecology and Obstetrics classification, tumours were classified as follows: 10.6% IB2, 22.3% IIA, 51.0% IIB, 4.3% IIIA and 11.7% IIIB. Pelvic lymph nodes were involved in 34.0% of cases. Radiotherapy was delivered for all patients. Radiotherapy technique was intensity modulated radiation therapy or volumetric modulated arc therapy in 39.4% of cases. A concurrent cisplatin chemotherapy was delivered in 68.1% of patients. Brachytherapy was performed in 77.7% of cases. The recommended standard care (concurrent chemoradiotherapy with at least five chemotherapy cycles during radiotherapy, followed by brachytherapy) was delivered in 43.6%. The median overall treatment time was 56 days. Complete tumour sterilisation was achieved in 55.2% of cases. Mean follow-up was 54.3 months. Local recurrence rate was 18.1%. Five-year overall survival was 61.9% (95% Confident Interval (CI) = 52.3-73.2) and five-year disease-specific survival was 68.5% (95% CI = 59.2-79.2). Poor performance status, lymph nodes metastasis and absence of concurrent chemotherapy were identified as poor prognostic factors in multivariate analysis. CONCLUSIONS: Less than 50% of patients received the standard care. Because LACC patients and disease are heterogeneous, treatment tailoring appears to be common in current clinical practice. However, guidelines for tailoring management are not currently available. More data about real-world settings are required in order to to optimise clinical trials' aims and designs, and make them translatable in daily clinical practice. TRIAL REGISTRATION: retrospectively registered. PMID- 29394941 TI - Health related quality of life in patients with community-acquired pneumococcal pneumonia in France. AB - BACKGROUND: Community Acquired Pneumococcal Pneumonia is a lung infection that causes serious health problems and can lead to complications and death. The aim of this study was to observe and analyze health related quality of life after a hospital episode for patients with community acquired pneumococcal pneumonia in France. METHODS: A total of 524 individuals were enrolled prospectively in the study and were followed for 12 months after hospital discharge. Presence of streptococcus pneumoniae was confirmed by microbiological sampling. Quality of life was reported at four different points of time with the EQ-5D-3 L health states using the French reference tariff. Complete data on all four periods was available for 269 patients. We used descriptive and econometric analysis to assess quality of life over time during follow-up, and to identify factors that impact the utility indexes and their evolution through time. We used Tobit panel data estimators to deal with the bounded nature of utility values. RESULTS: Average age of patients was 63 and 55% of patients were men. Negative predictors of quality of life were the severity of the initial event, history of pneumonia, smokers, age and being male. On average, quality of life improved in the first 6 months after discharge and stabilized beyond. At month 1, mean utility index was 0.53 (SD: 0.34) for men and 0.45 (SD: 0.34) for women, versus mean of 0.69 (SD: 0.33) and 0.70 (SD: 0.35) at Month 12. "Usual activities" was the dimension the most impacted by the disease episode. Utilities for men were significantly higher than for women, although male patients were more severe. Individuals over 85 years old did not improve quality of life during follow-up, and quality of life did not improve or deteriorated for 34% of patients. We found that length of hospital stay was negatively correlated with quality of life immediately after discharge. CONCLUSION: This study provides with evidence that quality of life after an episode of community acquired pneumococcal pneumonia improves overall until the sixth month after hospital discharge, but older patients with previous history of pneumonia may not experience health gains after the initial episode. PMID- 29394942 TI - Factors influencing health-related quality of life in patients with Type 1 diabetes. AB - AIMS: Generic, preference-based measures of health-related quality of life (HRQoL) are a common input to the economic evaluation of new health technologies. As such, it is important to explore what characteristics of patients with Type 1 diabetes might impact scores on such measures. METHODS: This study utilizes baseline data from a cluster-randomized trial that recruited patients with Type 1 diabetes at six centers across Ireland. Health-related quality of life was assessed using the three-level EuroQol EQ-5D (EQ-5D) measure. Patients' responses to individual dimensions of the EQ-5D were explored. To see which patient factors influenced EQ-5D scores, multivariate regression analysis was conducted with EQ 5D scores as the outcome variable. RESULTS: Data was available for 437 Type 1 diabetes patients. The median age of these patients was 40 (IQR: 31-49) years and 53.8% were female. Overall, patients reported a high HRQoL based on EQ-5D scores (0.87 (SD: 0.19). Fifty-four percent of patients reported a perfect HRQoL. For those that reported problems, the most common dimension was the anxiety/depression dimension of the EQ-5D (29.6%). In the multivariate regression analysis, self-reported mental illness (- 0.22 (95% CI: -0.34, - 0.10)) and being unemployed (- 0.07 (95% CI: -0.13, - 0.02)) were negatively associated with EQ-5D scores (p < 0.05). The influence of self-reported mental illness was persistent in sensitivity analyses. CONCLUSIONS: The study results indicate that patients with Type 1 diabetes report a high HRQoL based on responses to the EQ-5D. However, there are a substantial number of Type 1 diabetes patients that report problems in the anxiety/depression dimension, which may provide avenues to improve patients' HRQoL. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79759174 . PMID- 29394943 TI - Efficacy of genogroup 1 based porcine epidemic diarrhea live vaccine against genogroup 2 field strain in Japan. AB - BACKGROUND: Porcine epidemic diarrhea (PED) is a lethal infectious disease in suckling piglets with symptoms including watery diarrhea caused by PED virus (PEDV). Since the late 1990's, live vaccines based on genogroup 1 virus have been used in Japan, and a significant amount of the vaccine has been used even after new genogroups invaded in 2013. In this study, we evaluated the effect of a conventional PED live vaccine on a newly prevalent genogroup 2 field strain in experimental and field situations. METHODS: Two pregnant sows were administered twice the live vaccine before farrowing. A pregnant sow was served as a negative control. All newborn piglets were challenged with the genogroup 2 virus, and clinical signs were monitored for 7 days post challenge. PEDV-specific immune responses in serum and milk of the sows were assayed by virus neutralization assay. The efficacy of PED live vaccine in vaccinated or non-vaccinated farms was evaluated by comparing the mortality rate of suckling piglets after the onset of PED. RESULTS: The challenged piglets exhibited watery diarrhea with or without vaccination. However, the clinical score of piglets born from vaccinated sows significantly improved after the 4th day of the challenge. The survival rate of piglets in the vaccinated group at the end of the experimental period was 80%, whereas in the control group was 0%. Neutralizing antibody titers in serum and milk of control sow was negative throughout the experimental period, whereas high titers were observed in the vaccinated sows. The vaccinated farms significantly reduced the mortality rate of suckling piglets after the onset of PED, compared to farms not vaccinated. CONCLUSIONS: The conventional PED live vaccine induced the lactogenic immunity to vaccinated sows and showed partial protection against the genogroup 2 virus both under the experimental and field conditions. PMID- 29394944 TI - Windkessel model of hemodynamic state supported by a pulsatile ventricular assist device in premature ventricle contraction. AB - BACKGROUND: Counter-pulsation control (CPC) by ventricular assist devices (VADs) is believed to reduce cardiac load and increase coronary perfusion. However, patients with VADs have a higher risk of arrhythmia, which may cause the CPC to fail. Consequently, CPC has not been applied by VADs in clinical practice. The phase-locked loop (PLL) algorithm for CPC is readily implemented in VADs; however, it requires a normal, consistent heartbeat for adequate performance. When an arrhythmia occurs, the algorithm maintains a constant pumping rate despite the unstable heartbeat. Therefore, to apply the PLL algorithm to CPC, the hemodynamic effects of abnormal heartbeats must be analyzed. OBJECTIVES: This study sought to predict the hemodynamic effects in patients undergoing CPC using VADs, based on electrocardiogram (ECG) data, including a wide range of heart rate (HR) changes caused by premature ventricular contraction (PVC) or other reasons. METHODS: A four-element Windkessel hemodynamic model was used to reproduce the patient's aortic blood pressure in this study. ECG data from 15 patients with severe congestive heart failure were used to assess the effect of the CPC on the patients' hemodynamic state. The input and output flow characteristics of the pulsatile VAD (LibraHeart I, Cervika, Korea) were measured using an ultrasound blood flow meter (TS410, Transonic, USA), with the aortic pressure maintained at 80-120 mmHg. All other patient conditions were also reproduced. RESULTS: In patients with PVCs or normal heartbeats, CPC controlled by a VAD reduced the cardiac load by 20 and 40%, respectively. When the HR was greater for other reasons, such as sinus tachycardia, simultaneous ejection from the heart and VAD was observed; however, the cardiac load was not increased by rapid cardiac contractions resulting from decreased left ventricle volume. These data suggest that the PLL algorithm reduces the cardiac load and maintains consistent hemodynamic changes. PMID- 29394945 TI - Computer aided sentiment analysis of anorexia nervosa patients' vocabulary. AB - BACKGROUND: Diagnosing and treating anorexia nervosa is an important challenge for modern psychiatry. Taking into account a connection between the mental state of a person and the characteristics of their language, this paper presents developed and tested method for analyzing the written statements of patients with anorexia nervosa and healthy individuals, including the identification of keywords. METHODS: Due to the short nature of the texts, which is related to the difficulty of expressing oneself about one's body when suffering from anorexia, the bag of words approach was used for documents' information representation. The document is represented as a vector, where its various elements indicate the number of individual words. Then, a rule-based model was created, where as a collection of rules, dictionary files were used corresponding to three groups of positive, negative and neutral sounds for each subcategory. Next in the analyzed texts were searched and counted keywords. Based on the keywords found, each of the documents was categorized into one of the groups in every subcategory. RESULTS: It is possible to indicate a set of characteristics sentiment for every person. Additionally, the results of specific patient could be analyzed in six specific subcategories: self-esteem, acceptance of the assessment of the environment, emotions, autoimmune, functioning of the body and body image. CONCLUSIONS: The described analysis indicates the existence of a relationship between the mental state of the author's textual health and the vocabulary he or she uses. It is possible to indicate a set of characteristic sentiment terms specific to a given group of people. Their presence is related to the author's mental state and their body image. It could help focus on specific topics during therapy. PMID- 29394947 TI - 'What gets measured gets managed': revisiting the indicators for maternal and newborn health programmes. AB - BACKGROUND: The health of women and children are critical for global development. The Sustainable Development Goals (SDG) agenda and the Global Strategy for Women's, Children's, and Adolescent's Health 2016-2030 aim to reduce maternal and newborn deaths, disability, and enhancement of well-being. However, information and data on measuring countries' progress are limited given the variety of methodological challenges of measuring care around the time of birth, when most maternal and neonatal deaths and morbidities occur. MAIN BODY: In 2015, the World Health Organization launched Mother and Newborn Information for Tracking Outcomes and Results (MoNITOR), a technical advisory group to WHO. MoNITOR comprises 14 independent global experts from a variety of disciplines selected in a competitive process for their technical expertise and regional representation. MoNITOR will provide technical guidance to WHO to ensure harmonized guidance, messages, and tools so that countries can collect useful data to track progress toward achieving the Sustainable Development Goals. SHORT CONCLUSION: Ultimately, MoNITOR will provide technical guidance to WHO to ensure harmonized guidance, messages, and tools so that countries can collect useful data to track progress toward achieving the Sustainable Development Goals. PMID- 29394946 TI - Clinical value of miR-198-5p in lung squamous cell carcinoma assessed using microarray and RT-qPCR. AB - BACKGROUND: To examine the clinical value of miR-198-5p in lung squamous cell carcinoma (LUSC). METHODS: Gene Expression Omnibus (GEO) microarray datasets were used to explore the miR-198-5p expression and its diagnostic value in LUSC. Real time reverse transcription quantitative polymerase chain reaction was used to evaluate the expression of miR-198-5p in 23 formalin-fixed, paraffin-embedded (FFPE) LUSC tissues and corresponding non-cancerous tissues. The correlation between miR-198-5p expression and clinic pathological features was assessed. Meanwhile, putative target messenger RNAs of miR-198-5p were identified based on the analysis of differentially expressed genes in the Cancer Genome Atlas (TCGA) and 12 miRNA prediction tools. Subsequently, the putative target genes were sent to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. RESULTS: MiR-198-5p was low expressed in LUSC tissues. The combined standard mean difference (SMD) values of miR-198-5p expression based on GEO datasets were - 0.30 (95% confidence interval (CI) - 0.54, - 0.06) and - 0.39 (95% CI - 0.83, 0.05) using fixed effect model and random effect model, respectively. The sensitivity and specificity were not sufficiently high, as the area under the curve (AUC) was 0.7749 (Q* = 0.7143) based on summarized receiver operating characteristic (SROC) curves constructed using GEO datasets. Based on the in house RT-qPCR, miR-198-5p expression was 4.3826 +/- 1.7660 in LUSC tissues and 4.4522 +/- 1.8263 in adjacent normal tissues (P = 0.885). The expression of miR 198-5p was significantly higher in patients with early TNM stages (I-II) than that in cases with advanced TNM stages (III-IV) (5.4400 +/- 1.5277 vs 3.5690 +/- 1.5228, P = 0.008). Continuous variable-based meta-analysis of GEO and PCR data displayed the SMD values of - 0.26 (95% CI - 0.48, - 0.04) and - 0.34 (95% CI - 0.71, 0.04) based on fixed and random effect models, respectively. As for the diagnostic value of miR-198-5p, the AUC based on the SROC curve using GEO and PCR data was 0.7351 (Q* = 0.6812). In total, 542 genes were identified as the targets of miR-198-5p. The most enriched Gene Ontology terms were epidermis development among biological processes, cell junction among cellular components, and protein dimerization activity among molecule functions. The pathway of non-small cell lung cancer was the most significant pathway identified using Kyoto Encyclopedia of Genes and Genomes analysis. CONCLUSION: The expression of miR-198-5p is related to the TNM stage. Thus, miR-198-5p might play an important role via its target genes in LUSC. PMID- 29394948 TI - High-energy extracorporeal shock wave therapy for nontraumatic osteonecrosis of the femoral head. AB - BACKGROUND: Nontraumatic osteonecrosis of the femoral head (ONFH) is treated with a series of methods. High-energy extracorporeal shock wave therapy (ESWT) is an option with promising mid-term outcomes. The objective of this study was to determine the long-term outcomes of ESWT for ONFH. METHODS: Fifty-three hips in 39 consecutive patients were treated with ESWT in our hospital between January 2005 and July 2006. Forty-four hips in 31 patients with stage I-III nontraumatic ONFH, according to the Association Research Circulation Osseous (ARCO) system, were reviewed in the current retrospective study. The visual analog pain scale (VAS), Harris hip score, radiography, and magnetic resonance imaging were used to estimate treatment results. The progression of ONFH was evaluated by imaging examination and clinical outcomes. The results were classified as clinical success (no progression of hip symptoms) and imaging success (no progression of stage or substage on radiography and MRI). RESULTS: The mean follow-up duration was 130.6 months (range, 121 to 138 months). The mean VAS decreased from 3.8 before ESWT to 2.2 points at the 10-year follow-up (p < 0.001). The mean Harris hip score improved from 77.4 before ESWT to 86.9 points at the 10-year follow-up. The clinical success rates were 87.5% in ARCO stage I patients, 71.4% in ARCO stage II patients, and 75.0% in ARCO stage III patients. Imaging success was observed in all stage I hips, 64.3% of stage II hips, and 12.5% of stage III hips. Seventeen hips showed progression of the ARCO stage/substage on imaging examination. Eight hips showed femoral head collapse at the 10-year follow-up. Four hips in ARCO stage III and one hip in ARCO stage II were treated with total hip arthroplasty during the follow-up. Three were performed 1 year after ESWT, one at 2 years, and one at 5 years. CONCLUSIONS: The results of the current study indicated that ESWT is an effective treatment method for nontraumatic ONFH, resulting in pain relief and function restoration, especially for patients with ARCO stage I-II ONFH. PMID- 29394949 TI - Warning about drinking during pregnancy: lessons from the French experience. AB - BACKGROUND: In France, since 2007, there is a compulsory warning recommending abstinence during pregnancy on every container of alcohol. Awareness of this warning, which consists of a small pictogram, is unknown. The aim of this study was to assess awareness of the warning and risk perceptions about prenatal drinking in pregnant and postpartum women. METHODS: A cross-sectional survey was carried out by telephone five years after the introduction of the warning label. A total of 3603 pregnant or postpartum French women participated. A quota sampling method was used to ensure the sample reflected the population. Multivariate analyses examined the characteristics associated with knowledge of risks and with awareness of the warning label. RESULTS: The warning label had been noticed by 66.1% of women and 77.3% of drinkers. Of those who had noticed the warning, 98.6% thought that it suggested abstinence. Overall, 40.8% of the women thought that spirits were more harmful than wine or beer, and 8.9% thought that drinking beer was recommended for lactation. CONCLUSION: Awareness of the warning is high but knowledge about the risks associated with wine and beer is poor. PRACTICE IMPLICATIONS: Future information campaigns should educate women about standard drinks and their pure alcohol equivalent. They should emphasize the risks associated with drinking during breastfeeding. PMID- 29394950 TI - Evaluation of the psychometric properties of self-reported measures of alcohol consumption: a COSMIN systematic review. AB - PURPOSE: To review studies about the reliability and validity of self-reported alcohol consumption measures among adults, an area which needs updating to reflect current research. METHODS: Databases (PUBMED (1966-present), MEDLINE (1946-present), EMBASE (1947-present), Cumulative Index of Nursing and Allied Health Literature (CINAHL) (1937-present), PsycINFO (1887-present) and Social Science Citation Index (1976-present)) were searched systematically for studies from inception to 11th August 2017. Pairs of independent reviewers screened study titles, abstracts and full texts with high agreement and a third author resolved disagreements. A comprehensive quality assessment was conducted of the reported psychometric properties of measures of alcohol consumption using the COnsensus based Standards for the selection of health Measurement Instruments (COSMIN) to derive ratings of poor, fair, good or excellent for each checklist item relating to each psychometric property. RESULTS: Twenty-eight studies met inclusion criteria and, collectively, they investigated twenty-one short-term recall measures, fourteen quantity-frequency measures and eleven graduated-frequency measures. All measures demonstrated adequate/good test-retest reliability and convergent validity. Quantity-frequency measures demonstrated adequate/good criterion validity; graduated-frequency and short-term recall measures demonstrated adequate/good divergent validity. Quantity-frequency measures and short-term recall measures demonstrated adequate/good hypothesis validity; short term recall measures demonstrated adequate construct validity. Methodological quality varied within and between studies. CONCLUSIONS: It was difficult to discern conclusively which measure was the most reliable and valid given that no study assessed all psychometric properties and the included studies varied in the psychometric properties that they selected to assess. However, when the results from the range of studies were considered and summed, they tended to indicate that the quantity-frequency measure compared to the other two measures performed best in psychometric terms and, therefore, it is likely to produce the most reliable and valid assessment of alcohol consumption in population surveys. PMID- 29394951 TI - Analysis of C5 palsy in cervical myelopathy with massive anterior compression following laminoplasty. AB - BACKGROUND: Little data is available about comparison of the incidence and clinical characteristics of the C5 palsy between patients of cervical myelopathy with occupying ratio greater than 50% and those with occupying ratio less than 50% following laminoplasty. METHODS: One-hundred eighteen patients with cervical myelopathy who underwent open door laminoplasty were reviewed in this study. The patients were divided into two groups: group A comprising 55 patients with an anterior occupying ratio greater than 50% and group B comprising 63 patients with an anterior occupying less than 50%. Clinical and radiological outcomes were assessed between two groups. RESULTS: No statistically difference was found in preoperative Japanese Orthopedic Association (JOA) score of both groups (10.7 +/- 1.7 in group A vs 10.9 +/- 1.1 in group B, P > 0.05). Improvements in postoperative JOA score were achieved, and there was a statistical difference (14.0 +/- 1.4 in group A vs 14.8 +/- 0.9 in group B, P < 0.05). Group A had a lower rate of recovery than group B (P < 0.05). Totally, 12 of 118 (10.2%) patients developed the C5 palsy postoperatively. C5 palsy occurred in 3 of 63 patients in the group B compared with 9 of 55 in the group A. Statistically significant difference was found in the incidence of C5 palsy between the two groups (P < 0.05). Furthermore, patients in group A required significantly longer recovery periods than group B. Both preoperative and postoperative MRI presented more levels of T2 high-signal lesion in group A than group B. The degree of posterior shift of the cord after posterior decompression in group A was less than group B (P < 0.05). CONCLUSIONS: Patients with a high degree of anterior compression have higher risk of C5 palsy than those with a relative low degree of anterior compression. PMID- 29394952 TI - Renal protective effect of a hydration supplemented with magnesium in patients receiving cisplatin for head and neck cancer. AB - BACKGROUND: Our study analyzes the effect of magnesium supplementation on nephrotoxicity in patients receiving cisplatin for head and neck cancer. METHODS: We retrospectively reviewed the medical records of patients with head and neck cancer who received two doses of cisplatin (80 mg/m2) and 5-fluorouracil (800 mg/m2) 3 weeks apart from August 2008 to October 2012. The regimen prior to 2011 (crystalloid-only) involved the administration of 1000 mL of lactated Ringer's solution on the day prior to cisplatin infusion and 2000 mL of continuous infusion of saline on the day of cisplatin infusion. The regimen after 2011 (magnesium-supplemented) did not involve hydration on the day before cisplatin administration but used 1000 mL of 0.9% saline with magnesium sulfate (20 mEq) administered for 3 hours before cisplatin infusion. RESULTS: Sixty-five patients were treated with the crystalloid-only regimen and 56 patients with the magnesium supplemented regimen. The mean creatinine clearance in the magnesium-supplemented group decreased by 4.9 mL/kg/min, whereas that in the crystalloid-only group decreased by 15.0 mL/kg/min after two courses. In multivariate analysis, only magnesium-supplemented hydration was an independent predictive factor for preventing cisplatin-induced nephrotoxicity (odds ratio = 0.157, 95% confidence interval 0.030-0.670, P = 0.0124). CONCLUSION: We demonstrated that an intravenous hydration regimen supplemented with magnesium prevented cisplatin induced nephrotoxicity in patients with head and neck cancer. PMID- 29394953 TI - BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury. AB - BACKGROUND: Radiation-induced gastrointestinal syndrome (RIGS) results from the acute loss of intestinal stem cells (ISC), impaired epithelial regeneration, and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, sepsis, and mortality. The high radiosensitivity of the intestinal epithelium limits effective radiotherapy against abdominal malignancies and limits the survival of victims of nuclear accidents or terrorism. Currently, there is no approved therapy to mitigate radiation toxicity in the intestine. Here we demonstrate that BCN057, an anti-neoplastic small molecular agent, induces ISC proliferation and promotes intestinal epithelial repair against radiation injury. METHODS: BCN057 (90 mg/kg body weight, subcutaneously) was injected into C57Bl6 male mice (JAX) at 24 h following abdominal irradiation (AIR) and was continued for 8 days post-irradiation. BCN057 mediated rescue of Lgr5-positive ISC was validated in Lgr5-EGFP-Cre-ERT2 mice exposed to AIR. The regenerative response of Lgr5-positive ISC was examined by lineage tracing assay using Lgr5-EGFP-ires-CreERT2-TdT mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from surgical specimens of human colon or from mice jejunum and were used to examine the radio-mitigating role of BCN057 on ISC ex vivo. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test. RESULTS: Treatment with BCN057 24 h after a lethal dose of AIR rescues ISC, promotes regeneration of the intestinal epithelium, and thereby mitigates RIGS. Irradiated mice without BCN057 treatment suffered from RIGS, resulting in 100% mortality within 15 days post-radiation. Intestinal organoids developed from mice jejunum or human colon demonstrated a regenerative response with BCN057 treatment and mitigated radiation toxicity. However, BCN057 did not deliver radio protection to mouse or human colon tumor tissue. CONCLUSION: BCN057 is a potential mitigator against RIGS and may be useful for improving the therapeutic ratio of abdominal radiotherapy. This is the first report demonstrating that a small molecular agent mitigates radiation-induced intestinal injury by inducing ISC self-renewal and proliferation. PMID- 29394954 TI - Crawling-induced floor dust resuspension affects the microbiota of the infant breathing zone. AB - BACKGROUND: Floor dust is commonly used for microbial determinations in epidemiological studies to estimate early-life indoor microbial exposures. Resuspension of floor dust and its impact on infant microbial exposure is, however, little explored. The aim of our study was to investigate how floor dust resuspension induced by an infant's crawling motion and an adult walking affects infant inhalation exposure to microbes. RESULTS: We conducted controlled chamber experiments with a simplified mechanical crawling infant robot and an adult volunteer walking over carpeted flooring. We applied bacterial 16S rRNA gene sequencing and quantitative PCR to monitor the infant breathing zone microbial content and compared that to the adult breathing zone and the carpet dust as the source. During crawling, fungal and bacterial levels were, on average, 8- to 21 fold higher in the infant breathing zone compared to measurements from the adult breathing zone. During walking experiments, the increase in microbial levels in the infant breathing zone was far less pronounced. The correlation in rank orders of microbial levels in the carpet dust and the corresponding infant breathing zone sample varied between different microbial groups but was mostly moderate. The relative abundance of bacterial taxa was characteristically distinct in carpet dust and infant and adult breathing zones during the infant crawling experiments. Bacterial diversity in carpet dust and the infant breathing zone did not correlate significantly. CONCLUSIONS: The microbiota in the infant breathing zone differ in absolute quantitative and compositional terms from that of the adult breathing zone and of floor dust. Crawling induces resuspension of floor dust from carpeted flooring, creating a concentrated and localized cloud of microbial content around the infant. Thus, the microbial exposure of infants following dust resuspension is difficult to predict based on common house dust or bulk air measurements. Improved approaches for the assessment of infant microbial exposure, such as sampling at the infant breathing zone level, are needed. PMID- 29394955 TI - The genetic structure of the Belgian population. AB - BACKGROUND: National and international efforts like the 1000 Genomes Project are leading to increasing insights in the genetic structure of populations worldwide. Variation between different populations necessitates access to population-based genetic reference datasets. These data, which are important not only in clinical settings but also to potentiate future transitions towards a more personalized public health approach, are currently not available for the Belgian population. RESULTS: To obtain a representative genetic dataset of the Belgian population, participants in the 2013 National Health Interview Survey (NHIS) were invited to donate saliva samples for DNA analysis. DNA was isolated and single nucleotide polymorphisms (SNPs) were determined using a genome-wide SNP array of around 300,000 sites, resulting in a high-quality dataset of 189 samples that was used for further analysis. A principal component analysis demonstrated the typical European genetic constitution of the Belgian population, as compared to other continents. Within Europe, the Belgian population could be clearly distinguished from other European populations. Furthermore, obvious signs from recent migration were found, mainly from Southern Europe and Africa, corresponding with migration trends from the past decades. Within Belgium, a small north-west to south-east gradient in genetic variability was noted, with differences between Flanders and Wallonia. CONCLUSIONS: This is the first study on the genetic structure of the Belgian population and its regional variation. The Belgian genetic structure mirrors its geographic location in Europe with regional differences and clear signs of recent migration. PMID- 29394956 TI - Establishment of xenogeneic serum-free culture methods for handling human dental pulp stem cells using clinically oriented in-vitro and in-vivo conditions. AB - BACKGROUND: Currently, ex-vivo handling of stem cells, including transport after harvest and therapeutic preparation, is generally done in culture media containing fetal bovine serum (FBS), which promotes cell attachment, proliferation, and differentiation. However, because of safety concerns associated with the use of FBS, including potential transmission of zoonotic agents and transplant rejection because of the incorporation of foreign proteins into the stem cells, there is a need for xenogeneic serum-free culture media for clinical handling of stem cells. METHODS: Dental pulp stem cells were derived from wisdom teeth donated by eight healthy volunteers and cultured in xenogeneic serum-free culture medium (XFM) or xenogeneic serum-containing culture medium (SCM). Cells were subjected to morphological, proliferation, karyotype, differentiation, marker expression, cryopreservation, and cytotoxic susceptibility analyses in vitro, as well as transplantation in vivo. RESULTS: In primary culture, XFM cells showed lower adhesion and slightly different morphology, although the single-cell size was similar to that of SCM cells. XFM cells exhibited typical mesenchymal stem cell (MSC) characteristics in vitro and in vivo, including marker gene/protein expression, trilineage differentiation potential, and hard, osteo-dentin tissue formation. Additionally, XFM cells maintained a normal karyotype in vitro and nontumorigenic potential in vivo; however, XFM cells were more susceptible to H2O2 and ultraviolet cytotoxic stimuli. XFM cells formed a multilayered structure showing excessive cell death/division in contrast to the monolayered structure of SCM cells when reaching overconfluence. Proliferation was disrupted in overconfluent XFM cells, and these cells could not be subcultured. Dimethyl sulfoxide-free cryopreserved XFM cells yielded similar results in all of the experiments. CONCLUSIONS: This study is the first reporting successful isolation and expansion of an MSC population from donor-derived tissue (dental pulp) under xenogeneic serum-free culture conditions, as well as the application of cryopreservation, using a research strategy based on clinically oriented in-vitro and in-vivo experiments. PMID- 29394957 TI - Individual and household attributes influence the dynamics of the personal skin microbiota and its association network. AB - BACKGROUND: Numerous studies have thus far characterized the temporal dynamics of the skin microbiota of healthy individuals. However, there is no information regarding the dynamics of different microbial association network properties. Also, there is little understanding of how living conditions, specifically cohabitation and household occupancy, may be associated with the nature and extent (or degree) of cutaneous microbiota change within individuals over time. In this study, the dynamics of the skin microbiota, and its association networks, on the skin of urban residents over four seasons were characterized. RESULTS: Similar to western cohorts, the individuals of this cohort show different extents of variations in relative abundance of common skin colonizers, concomitant with individual- and household-associated changes in differential abundances of bacterial taxa. Interestingly, the individualized nature of the skin microbiota extends to various aspects of microbial association networks, including co occurring and excluding taxa, as well as overall network structural properties. Household occupancy is correlated with the extent of variations in relative abundance of Propionibacterium, Acinetobacter, and Bacillus over multiple skin sites. In addition, household occupancy is also associated with the extent of temporal changes in microbial diversity and composition within a resident's skin. CONCLUSIONS: This is the first study investigating the potential roles household occupancy has on the extent of change in one's cutaneous microbiota and its association network structures. In particular, we show that relationships between the skin microbiota of a resident, his/her cohabitants, and those of non cohabitants over time are highly personal and are possibly governed by living conditions and nature of interactions between cohabitants within households over 1 year. This study calls for increased awareness to personal and lifestyle factors that may govern relationships between the skin microbiota of one individual and those of cohabitants, and changes in the microbial association network structures within a person over time. The current study will act as a baseline for future assessments in comparing against temporal dynamics of microbiota from individuals with different skin conditions and for identifying residential factors that are beneficial in promoting the dynamics of the skin microbiota associated with health. PMID- 29394959 TI - Validation of the NoSAS Score for the Screening of Sleep-Disordered Breathing: A Hospital-Based Retrospective Study in China. AB - STUDY OBJECTIVES: This study was conducted to validate the NoSAS score in clinical populations and to compare it with the Berlin, STOP, and STOP-Bang questionnaires, as well as the Epworth Sleepiness Scale (ESS), in screening for sleep-disordered breathing (SDB). METHODS: A retrospective analysis was conducted of all patients aged 18 to 80 years who had completed a full-night polysomnography (PSG) at the sleep center of the First Affiliated Hospital of Guangzhou Medical University from October 2012 to November 2016. Patients who had incomplete or unanswered questionnaires were excluded. The data for the NoSAS score, ESS, STOP, STOP-Bang, and Berlin questionnaires were collected, after which the NoSAS score was compared against the other questionnaires for SDB screening. RESULTS: A total of 2,208 participants were enrolled in this study. The NoSAS scores, which ranged from 0 to 17 and allocated a threshold of 8 points, identified individuals at risk of clinically significant SDB (defined as an apnea-hypopnea index [AHI] cutoff of >= 20 events/h), with an area under the curve (AUC) of 0.707. The NoSAS score performed significantly better than the STOP (AUC 0.655) and STOP-Bang (AUC 0.704) questionnaires and the ESS (AUC 0.642), and it was at par with the Berlin (AUC 0.697) scores for SDB screening. A significant correlation was found between the AHI and NoSAS score (r = .386, P < .001). CONCLUSIONS: The NoSAS score is a simple, efficient, and easy method for screening SDB in the clinical setting, especially in moderate to severe SDB. It demonstrates a moderately high level of sensitivity for SDB. PMID- 29394958 TI - Real-time PCR diagnosis of Schistosoma japonicum in low transmission areas of China. AB - BACKGROUND: Schistosomiasis in the People's Republic of China (PRC) can be traced back to antiquity. In the past 60 years, the Chinese government has made great efforts to control this persistent disease with elimination slated by 2020 through the implementation of a comprehensive control strategy. This strategy aims to reduce the role of bovines and humans as sources of infection as a pre requisite for elimination through transmission interruption. The goal of elimination will be achievable only by the implementation of a sustainable surveillance and control system, with sensitive diagnosis a key feature so that the true disease burden is not underestimated. Currently used diagnostics lack the necessary sensitivity to accurately determine the prevalence of Schistosoma japonicum infection in areas with low infection intensities. It is of critical importance to find and treat people and to identify animals with low-level infections if the National Control Programme for China is to achieve schistosomiasis elimination. METHODS: We evaluated a real-time polymerase chain reaction (qPCR) assay using 633 human stool samples collected from five villages in Hunan, Anhui, Hubei, and Jiangxi provinces, and 182 bovine (70 cattle and 112 buffalo) stool samples obtained from four villages in Hunan, Anhui, and Jiangxi provinces in the PRC. All stool samples were subjected to the miracidium hatching test (MHT, a diagnostic procedure used in the National Schistosomiasis Control Programme) and the qPCR assay. Samples positive by MHT were subjected to either the Kato-Katz technique for humans, or the formalin-ethyl acetate sedimentation digestion (FEA-SD) procedure for bovines, to determine infection intensities. RESULTS: The qPCR assay exhibited a high level of sensitivity in the detection of S. japonicum infections. With both the human and bovine samples, a significantly higher prevalence was determined using the qPCR assay (11.06% humans, 24.73% bovines) than with the MHT (0.93% humans, 7.69% bovines). The animal contamination index (calculated using data obtained with the qPCR technique) for all positive bovines was 27 618 000 eggs per day, indicating a considerable amount of environmental egg contamination that would be underestimated using less sensitive diagnostic procedures. CONCLUSIONS: The qPCR assay we have evaluated will be applicable as a future field diagnostic and surveillance tool in low transmission zones where schistosomiasis elimination is targeted and for monitoring post-intervention areas to verify that elimination has been maintained. PMID- 29394960 TI - Increased EEG Theta Spectral Power in Sleep in Myotonic Dystrophy Type 1. AB - STUDY OBJECTIVES: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that involves the central nervous system (CNS). Individuals with DM1 commonly present with sleep dysregulation, including excessive daytime sleepiness and sleep-disordered breathing. We aim to characterize electroencephalogram (EEG) power spectra from nocturnal polysomnography (PSG) in patients with DM1 compared to matched controls to better understand the potential CNS sleep dysfunction in DM1. METHODS: A retrospective, case-control (1:2) chart review of patients with DM1 (n = 18) and matched controls (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, sex, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics for the two groups were compared. Power spectral analysis of the EEG C3-M2 signal was performed using the fast Fourier transformation. RESULTS: Patients with DM1 had significantly increased theta percent power in stage N2 sleep compared to matched controls. Theta/beta and theta/alpha percent power spectral ratios were found to be significantly increased in stage N2, N3, all sleep stages combined, and all wake periods combined in patients with DM1 compared to controls. A significantly lower nadir O2 saturation was also found in patients with DM1 versus controls. CONCLUSIONS: Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal PSG may reflect DM1 pathology in the CNS. PMID- 29394961 TI - Effects of Coexisting Asthma and Obstructive Sleep Apnea on Sleep Architecture, Oxygen Saturation, and Systemic Inflammation in Women. AB - STUDY OBJECTIVES: Both asthma and obstructive sleep apnea (OSA) are strongly associated with poor sleep. Asthma and OSA also have several features in common, including airway obstruction, systemic inflammation, and an association with obesity. The aim was to analyze the effect of asthma, OSA, and the combination of asthma and OSA on objectively measured sleep quality and systemic inflammation. METHODS: Sleep and health in women is an ongoing community-based study in Uppsala, Sweden. Three hundred eighty-four women ages 20 to 70 years underwent overnight polysomnography and completed questionnaires on airway diseases and sleep complaints. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha were analyzed. RESULTS: The group with both asthma and OSA had higher CRP, higher IL-6, a longer sleeping time in stage N1 sleep and stage N2 sleep, and less time in stage R sleep than the control group with no asthma or OSA. The group with both asthma and OSA had lower mean oxygen saturation (93.4% versus 94.7%, P = .04) than the group with OSA alone. The results were consistent after adjusting for age, body mass index, and smoking status. Asthma was independently associated with lower oxygen saturation, whereas OSA was not. CONCLUSIONS: Our data indicate that coexisting asthma and OSA are associated with poorer sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The results are similar to earlier findings related to OSA and chronic obstructive pulmonary disease, but they have not previously been described for asthma. PMID- 29394962 TI - Evaluating DSM-5 Insomnia Disorder and the Treatment of Sleep Problems in a Psychiatric Population. AB - STUDY OBJECTIVES: With the introduction of insomnia disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), greater emphasis has been placed on the diagnosis and treatment of sleep disorder even in the presence of a coexisting mental disorder. The current study seeks to explore the clinical picture of insomnia in the context of psychiatric disorders commonly associated with sleep complaints by assessing the prevalence and correlates of DSM-5 insomnia disorder, and examining the extent to which insomnia symptoms have been addressed in this population. METHODS: Four hundred treatment-seeking outpatients suffering from depressive, bipolar affective, anxiety, and schizophrenia spectrum disorders were recruited. DSM-5 insomnia was established using the modified Brief Insomnia Questionnaire. Differences in sociodemographic factors, clinical status, impairment outcomes, and mental health services utilization were compared. Information on patients' help-seeking experiences for insomnia-related symptoms was collected to determine the treatment received and treatment effectiveness. RESULTS: Almost one-third of our sample (31.8%) had DSM 5 insomnia disorder. Those with insomnia disorder had significantly higher impairment outcomes than their counterparts but no group difference was observed for mental health services utilization. Findings based on past treatment contact for sleep problems suggest that diagnosis and treatment of insomnia is lacking in this population. CONCLUSIONS: With the new calling from DSM-5, clinicians treating psychiatric patients should view insomnia less as a symptom of their mental illnesses and treat clinical insomnia as a primary disorder. Patients should also be educated on the importance of reporting and treating their sleep complaints. Nonmedical (cognitive and behavioral) interventions for insomnia need to be further explored given their proven clinical effectiveness. PMID- 29394963 TI - Breast Cancer in Pakistan: A Looming Epidemic. PMID- 29394964 TI - Correlation between Serum Amyloid A-Low Density Lipoprotein and Genotoxicity in Smokers. AB - OBJECTIVE: To investigate the relation between serum amyloid A-low density lipoprotein (SAA-LDL) and genotoxicity in smokers. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Army Medical College, Rawalpindi and National Institute of Health (NIH), Islamabad, from June 2014 to February 2015. METHODOLOGY: Seventy healthy Sprague Dawley rats were purchased from NIH and exposed to cigarette smoke in smoke chamber for three months. Blood samples were drawn from each rat at the end of the study period. SAA-LDL was determined by enzyme-linked immunosorbent assay (ELISA). Genotoxicity was assessed by cytokinesis block micronucleus (CBMN) assay. Pearson correlation was used to find correlation between SAA-LDL and genotoxicity. RESULTS: Strong positive correlation was found between SAA-LDL and micronuclei frequency in smoke-exposed rats (r=0.799, N=70, p <0.01). CONCLUSION: Statistically significant strong positive correlation between SAA-LDL and genotoxicity in smoke-exposed rats shows that changes in one is associated with changes in other and vice versa. PMID- 29394965 TI - Frequency of Macroprolactin in Hyperprolactinemia. AB - OBJECTIVE: To determine the frequency of Macroprolactin (MaPRL) in patients with increased total prolactin and its clinical and financial impact. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from March to May 2015. METHODOLOGY: Patients with high total prolactin were screened by polyethylene glycol (PEG) precipitation for determination of MaPRL. Clinical history, imaging work-ups, and cost incurred in further investigations were collected by telephonic interview after verbal consent. Patients were stratified into true hyperprolactinemia and macroprolactinemia after PEG treatment, based on monomeric prolactin levels. Medical records of cases registered with AKUH were reviewed to confirm the diagnosis. RESULTS: Two hundred and thirty-nine patients were identified with high prolactin levels. Macroprolactinemia was identified in 145 (60.7%) and true hyperprolactinemia in 94 (39.3%) patients. Galactorrhea was significantly more in true hyperprolactinemic females (p=0.022), followed by visual disturbances (p=0.01) and headache (p=0.006). Moreover, as majority of population were females, the clinical features in the macroprolactinemia group as compared to true hyperprolactinemic group were mostly related to non-pituitary causes like drug intake [42.5% (54) vs. 37% (30)], heat intolerance due to thyroidal illness [41.7% (53) vs. 38.3% (31)] and surgery [26.8% (34) vs 22.2% (18)] in females. Further radiological workup (MRI, CT) were conducted in 35 (37.2%) patients with true hyperprolactinemia. Twenty-one (60%) of the patients were confirmed to have pituitary adenomas. In eight (5.5%) patients with MaPRL, only one had pituitary microadenoma on radiological workup. Total cost impact on the basis of investigations, was significantly higher in the group undergone imaging, despite 7 out of 8 individuals found to have normal imaging results. The median total cost in true hyperprolactinemic group undergone imaging was Rs. 4370 (IQR=2412.5, 22850) as compared to macroprolactinemic groups; Rs. 3,250 (IQR=2150, 4278). There was significant difference in the cost burden of both the groups (p <0.001). CONCLUSION: High frequency of MaPRL was identified in patients with hyperprolactinemia. Screening with PEG precipitation in hyperprolactinemic sera is simple and cost-effective. PMID- 29394966 TI - Factors Affecting Dermatological Manifestations in Patients with End Stage Renal Disease. AB - OBJECTIVE: To determine skin changes in patients of End Stage Renal Disease (ESRD) on maintenance hemodialysis (MHD) and factors affecting these changes. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Nephrology Department, Mayo Hospital, Lahore in collaboration with Dermatology Department, King Edward Medical University, Lahore, from October 2015 to January 2016. METHODOLOGY: Two hundred patients who were undergoing MHD for more than three months were included in the study. Patients' demographic data, laboratory reports and dialysis records were noted in a predesigned questionnaire. Skin examination was carried out by consultant dermatologist after patient's permission. RESULTS: Among 200 patients included in study, 105 were malesand rest of them were females. Major causes of ESRD were Diabetes Mellitus (n=83, 41.5%, followed by Hypertension (n=80, 40%), Nephrolithiasis (n=15, 7.5%) and Chronic glomerulonephritis (n=5, 2.5%). At least one cutaneous finding was present in every patient. Common skin findings observed were pigmentation (86%), xerosis (83%), pallor (79%), pruritus (69%), acquired ichthyosis (50.5%), and bacterial skin infections (18.5%). Among them, nail manifestations were half-and-half nails (52%), onychomycosis (30.5%), onycholysis (20.5%), subungual hyperkeratosis (23.5%), and Mee's lines (7.5). Among hair changes were sparse scalp hair (38.5%), brittle and lustreless hair (28%). The factors contributing to skin changes were patient's age, cause of ESRD, anti HCV positivity, high urea and creatinine levels, duration and frequency of hemodialysis, hemoglobin levels, calcium phosphate product and socioeconomic status. Some skin manifestations were interrelated with each other like xerosis with pruritus (p<0.001), pruritus with bacterial infection (p<0.022), acquired Ichthyosis (p=0.008) and hair changes (p=0.035). CONCLUSION: ESRD patients on hemodialysis develop various skin changes during the course of disease process, which contribute to increased morbidity. Different factors affecting skin changes were the cause of ESRD, adequacy and duration of dialysis, employment, financial status, anti HCV positivity, and metabolic factors. PMID- 29394967 TI - Utility of Diffusion Weighted Magnetic Resonance Imaging with Multiple B Values in Evaluation of Pancreatic Malignant and Benign Lesions and Pancreatitis. AB - OBJECTIVE: To determine the feasibility of diffusion-weighted imaging in evaluation of pancreatic lesions and in differentiation of benign from malignant lesions. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Baskent University Adana Teaching and Research Center, Adana, Turkey, between September 2013 and May 2015. METHODOLOGY: Forty-three lesions [pancreas adenocarcinoma (n=25)], pancreatitis (n=10), benign lesion (n=8)] were utilized with diffusion weighted magnetic resonance imaging with multiple b-values. Different ADC maps of diffusion weighted images by using b-values were acquired. RESULTS: The median ADC at all b values for malignant lesions was significantly different from that for benign lesions (p<0.001). When ADCs at all b values were compared between benign lesions/normal parenchyma and malignant lesions/normal parenchyma, there was a significant statistical difference in all b values between benign and malignant lesions except at b 50 and b 200 (p<0.05). The lesion/normal parenchyma ADC ratio for b 600 value (AUC=0.804) was more effective than the lesion ADC for b 600 value (AUC=0.766) in differentiation of benign and malignant lesions. The specificity and sensitivity of the lesion/normal parenchyma ADC ratio were higher than those of ADC values of lesions. When the ADC was compared between benign lesions and pancreatitis, a significant difference was found at all b values (p<0.001). There was not a statistically significant difference between the ADC for pancreatitis and that for malignant lesions at any b value combinations (p>0.05). CONCLUSION: Diffusion-weighted magnetic resonance images can be helpful in differentiation of pancreatic carcinoma and benign lesions. Lesion ADC / normal parenchyma ADC ratios are more important than lesion ADC values in assessment of pancreatic lesions. PMID- 29394968 TI - Evaluation of Diagnostic Scores for Acute Appendicitis. AB - OBJECTIVE: To assess the sensitivity of the Alvarado score (AS), modified Alvarado score (MAS), Fenyo-Lindberg score (FS), Lintula score (LS), Eskelinen score (ES), Teicher score (TS), and Christian score (CS) [seven scorings] in patients with acute appendicitis (AA). STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: The First Affiliated Hospital of Chongqing Medical University, China, from January 2012 to June 2015. METHODOLOGY: Patients with diagnosis of AA were evaluated retrospectively to compare the scoring systems. The diagnostic sensitivity (the correct number of diagnoses divided by the total number) was compared. Data were analyzed using SPSS software. RESULTS: One hundred and seventy-nine patients were studied. The sensitivity of AS was 92.7%; It outperformed each of the other scores. The sensitivity of FS, LS, and TS in women was lower than that in men (p=0.016, p<0.001, and p<0.001, respectively). The sensitivity of the FS, ES, TS, and CS in patients with a duration of illness greater than 48 hours was lower than that in patients with a duration of illness less than 48 hours (p<0.001 for all). CONCLUSION: AS is the most useful and sensitive diagnostic tool for AA. FS, LS, and TS had a lower diagnostic sensitivity in women; and FS, ES, TS, and CS had a low sensitivity in patients with a duration of illness greater than 48 hours. PMID- 29394969 TI - Is Lactulose Plus Rifaximin Better than Lactulose Alone in the Management of Hepatic Encephalopathy? AB - OBJECTIVE: To compare the efficacy of lactulose plus rifaximin with efficacy of lactulose alone in the treatment of hepatic encephalopathy. STUDY DESIGN: A randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Medicine, Jinnah Hospital, Lahore, from December 2014 to June 2015. METHODOLOGY: All patients who presented with hepatic encephalopathy due to decompensated chronic liver disease were randomly divided into two groups of 65 patients each. One group was given 30 ml thrice daily lactulose alone and the other lactulose plus rifaximin 550 mg twice daily for 10 days. Informed consents were taken from the participants' attendants. Grades II-IV hepatic encephalopathy was noted according to West-Haven Classification. All subjects were followed until 10 days after admission. RESULTS: The mean age of patients was 56.06 +11.2 years, among which 46.9% were females and 53.1% were males. After ten days of follow-up, reversal was seen in 58.46% in lactulose alone group and 67.69% in lactulose plus rifaximin group (Chi-square p=0.276). CONCLUSION: There was no difference in effectiveness of lactulose plus rifaximin and lactulose alone in treatment of hepatic encephalopathy. PMID- 29394970 TI - Remission Rate of Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA). AB - OBJECTIVE: To determine the remission rate in adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL). STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Oncology, Jinnah Postgraduate Medical Centre (JPMC), Karachi from January, 2016 to March, 2017. METHODOLOGY: Adolescent and young adult (AYA) patients aged 15-39 years, newly diagnosed with acute lymphoblastic leukemia from January, 2016 to March, 2017. Diagnosis was confirmed by bone marrow trephine biopsy and immunophenotyping. All the patients were treated with daunorubicin, vincristine, prednisone, and L-asparaginase in the induction phase. The response evaluation was done on day 35 of the induction phase and the remission rate was assessed by the bone marrow examination. RESULTS: Of the total 50 AYA patients diagnosed with ALL, 41 patients could complete induction phase and 9 patients died during the first week of induction, therefore excluded from the study. Forty (97.8%) patients were <35years of age, 28 (68.3%) were male, of female 10 (24.4%) were housewives, 33 (80.5%) patients belonged to Sindh, 28 (68.3%) presented with fever and body ache, 17 (41.5%) patients had precursor B cell type ALL, with 7 (17.1%) patients had hemoglobin of <7 g/dL,11 (26.8%) patients had white cell count of >30x109/L, platelet count of <20x103/uL in 6 (14.6%) patients and complete morphological remission was reported in 29 (70.7%) patients. CONCLUSION: The remission induction rate was 70.7% in the adolescents and young adults with acute lymphoblastic leukemia at the study centre. PMID- 29394971 TI - Role of Weight-Bearing Exercises in the Treatment of Post-Menopausal Osteoporosis. AB - OBJECTIVE: To determine the change in T-score of post-menopausal osteoporosis patients with weight-bearing exercises. STUDY DESIGN: A quasi-experimental study. PLACE AND DURATION OF STUDY: Physiotherapy Department and Orthopedic Unit I, Mayo Hospital, Lahore, from May to October 2014. METHODOLOGY: Two hundred and seventy four patients were randomly divided into two groups according to inclusion and exclusion criteria using non-probability purposive sampling technique. The group 1 was treated by medication and weightbearing exercises and group 2 was given medication alone. The dual energy X-ray absorptiometry (DEXA)scan was used tofind the T-score before and after treatment and improvement was compared. A p-value less than 0.05 was taken as significant. RESULTS: The results showed that improvement was occurred in both groups after treatment. The DEXAscan median values after treatment were changed to 3.00 (0) for group 1 (exercises and medication) and 2.00 (1) for group 2 (medication). CONCLUSION: The physical activity along with medication play vital role in the treatment of post menopausal osteoporosis than medication alone. PMID- 29394972 TI - Extended Islanded Reverse Sural Artery flap for Staged Reconstruction of Foot Defects Proximal to Toes. AB - : Obective:To assess the outcome of extended delayed reverse sural artery flap for reconstruction of foot defects proximal to toes in terms of flap survival, complication and extended area. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Jinnah Burn and Reconstructive Surgery Centre, Lahore, from February 2015 to April 2017. METHODOLOGY: Cases who underwent delayed sural artery flap were inducted. Preoperative hand-held doppler was done to confirm the location of perforator. Two suitable perforators were chosen to raise the extended flap by crossing the proximal limit in all cases. The pedicle was kept minimum 3 cm wide and perfusion was assessed. Flap was delayed for one week and vaccum-assisted closure (VAC) dressing was applied over wound. The second surgery was performed after one week. Proximal perforator was clamped and ligated after checking adequate perfusion of flap. Flap was insetted into defect. RESULTS: Thirty-two patients were reconstructed with delayed reverse sural artery flap. The mean age of the patients was 26.5 12.2 years. Twenty-four (75%) patients were males and 8 (25%) were females. Twenty-two (68.7%) cases were degloving wounds after road traffic accidents (RTA), 6 (18.7%) were diabetic foot wounds, 4 (12.5%) sustained injury after falling from height and 7 (21.8%) patients had fracture of metatarsals. Twenty-eight flaps were transferred after one week delay, and only in 4 cases, flap were transferred after two weeks. All flaps survived completely. Complications of infection noted in 3 (9.3%) flaps, 3 (9.3%) flaps showed tip necrosis, 2 (6.2%) flaps undergone epidermolysis and only 2 (6.2%) showed venous congestion. CONCLUSION: Delayed islanded reverse sural artery perforator flap is a reliable and versatile option for resurfacing soft tissue defects of lower limb proximal to the toes with lesser complications and extended coverage area. PMID- 29394973 TI - Distally Based Medial Hemisoleus Flap: Reliable Option for Distal Tibial Wounds. AB - OBJECTIVE: To determine the success (flap survival as a whole without necrosis or dehiscence up to two months as judged clinically) of distally based medial hemisoleus muscle flap for the coverage of distal tibial defects. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Jinnah Burn and Reconstructive Surgery Centre, AIMC, Lahore, from July 2014 to July 2017. METHODOLOGY: Patients with middle and distal third tibial defects were enrolled and stratified according to the site of the wound in middle or distal third of tibia. Soft tissue coverage was provided with distally based medial hemisoleus muscle flap on which split thickness skin graft was applied. Postoperatively, patients were followed-up after one week of discharge and then fortnightly for at least 2 months. Outcome variable was taken as flap success. RESULTS: Out of 37 cases, flap was successful in 33 patients as complete flap survived with primary wound healing. Partial flap necrosis without dehiscence was seen in 3 cases and partial necrosis of flap with dehiscence in only one case that required another surgery for the defect. Complete flap loss was not seen in any case. CONCLUSION: Distally based medial hemisoleus muscle flap is reliable coverage option for middle and distal third of tibial defects. PMID- 29394974 TI - Proteomic Profile of Lymphoid Leukemia. AB - Lymphoid (or lymphocytic/lymphoblastic) leukemia, one of two major types of leukemias (lymphoid and myeloid), is divided into two subtypes, acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), depending on the maturation stage and speed of multiplication of the bone marrow lymphocytes. Early diagnosis and treatment can make the difference between life and death. Advancements in the field of proteomics may allow the development of early biomarkers and more effective agents to combat both these types of cancer, and to better understand the underlying mechanisms of the disease. The aim of this review was to elucidate the pathophysiology of lymphocytic leukemia using cancer proteomics techniques from 2007 until 2017. Only relevant original research articles archived in the Science Direct, PubMed and/or the Google Scholar databases within this period were included, which were a total of 30 studies. The role of proteomes in the detection, diagnosis and treatment of ALL and CLL was examined separately. Overall, the findings of this study confirm the viability of proteome analysis in profiling lymphocytic leukemia; and highlight novel leukemia biomarkers and potential therapeutic targets. PMID- 29394975 TI - Sofosbuvir Adverse Events Profile in a Subset of Pakistani Population. AB - OBJECTIVE: To determine frequency and pattern of adverse events reporting in a subset of Pakistani population being treated for chronic hepatitis C with sofosbuvir combination therapy. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Medicine, Gastroenterology Division, Shalamar Hospital, Lahore, from September 2015 to May 2016. METHODOLOGY: Patients who were offered sofosbuvir therapy for treatment of chronic hepatitis C were randomly enrolled. The study subset included both treatment nave as well as retreatment groups. Patients were screened for subjective as well as objective evidence of adverse events at regular intervals. Frequency was determined. RESULTS: Among 196 patients with chronic hepatitis C, 192 patients received dual therapy consisting of ribavirin and sofosbuvir. The most frequent complaints in these subjects were fatigue, fever, myalgias and nausea accounting for 55%, 42%, 44.2% and 50%, respectively. Twenty-seven percent of patients reported with drop in hemoglobin of >2g/dl, while absolute neutropenia and moderate to severe thrombocytopenia was observed in 3% and 5% of patients, respectively. One patient died as a result of severe pancytopenia. Later derangements were all observed in patients with decompensated disease. CONCLUSION: Sofosbuvir showed less severe adverse effects in terms of symptomatology and less frequent neutropenia and thrombocytopenia as compared to previous regimens. Careful monitoring is required, especially in those with decompensated liver disease. PMID- 29394976 TI - Improving Outcomes of Emergency Bowel Surgery Using NELA Model. AB - OBJECTIVE: To find outcomes of emergency bowel surgery and review the processes involved in the care of these patients on the same template used in National Emergency Laparotomy Audit (NELA). STUDY DESIGN: An audit. PLACE AND DURATION OF STUDY: Surgery Department, The Aga Khan University Hospital, Karachi, from December 2013 to November 2014. METHODOLOGY: Patients undergone emergency bowel surgery during the review period were included. Demographic data, type of admission, ASA grade, urgency of surgery, P-POSSUM score, indication of surgery, length of stay and outcome was recorded. Data was then compared with the data published by NELA team in their first report. P-value for categorical variables was calculated using Chi-square tests. RESULTS: Although the patients were younger with nearly same spectrum of disease, the mortality rate was significantly more than reported in NELA (24% versus 11%, p=0.004). Comparison showed that care at AKUH was significantly lacking in terms of proper preoperative risk assessment and documentation, case booking to operating room timing, intraoperative goal directed fluid therapy using cardiac output monitoring, postoperative intensive care for highest risk patients and review of elderly patients by MCOP specialist. CONCLUSION: This study helped in understanding the deficiencies in the care of patients undergoing emergency bowel surgery and alarmingly poor outcomes in a very systematic manner. In view of results of this study, it is planned to do interventions in the deficient areas to improve care given to these patients and their outcomes with the limited resources of a developing country. PMID- 29394978 TI - Congenital Synechia and Syngnathia: Two Case Reports. AB - This case report presents two cases of rare congenital malformation, i.e syngnathia. First case is of 2-day infant with bilateral fusion of maxilla and mandible, leaving a small anterior portion. After consultation with other concerned specialties, early intervention was planned and fusion was released to facilitate feeding. The infant suffered from frequent respiratory tract infections and subsequently died at the age of ten months. The second case is of 8-month baby girl with unilateral congenital maxillomandibular bony fusion without any other anomaly. She underwent general anesthesia for thorough examination and release of soft tissue union. Second surgery was performed after few months for removal of bony fusion. Good mouth opening was seen on 1 month follow-up. PMID- 29394977 TI - Bladder Distension as a Cause of Abdominal Compartment Syndrome. AB - Abdominal compartment syndrome (ACS) is increasingly identified in critically ill patient and its harmful effects are well documented. The disparity among the pressure, volume in abdominal cavity and its contents, results in ACS. The actual incidence of ACS is not known. However, it has been observed predominantly in patients with severe blunt and penetrating abdominal trauma, ruptured abdominal aortic aneurysms, retro- and intra-peritoneal hemorrhage, pneumoperitoneum, neoplasm, pancreatitis, ascites and multiple bone fracture. We present a case of 40-year female who underwent emergency cesarean section and developed abdominal compartment syndrome due to urinary bladder distension secondary to blockade of urinary catheter with blood clots. This is a very unusual cause of ACS. PMID- 29394979 TI - Lupus Enteritis: An Atypical Initial Presentation of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus may rarely present initially with gastroenteric features labelled as lupus enteritis, that may lead to serious complications, if it remains undiagnosed for a long period of time. It is difficult to diagnose because the clinical picture of lupus enteritis mimics gastroenteritis. The diagnosis is made on radiological findings, rather than histopathology, and supported by autoimmune profile. Here is a case of a 40-year lady who presented with diarrhea and vomiting that was unresponsive to treatment with intravenous antibiotics. The diagnosis of lupus enteritis was made on the basis of CT scan abdomen, that showed classic target sign due to bowel edema. There was non specific inflammation found in the biopsy specimen taken on colonoscopy and her autoimmune workup showed ANA and anti-ds-DNA positive. She was treated with high dose of intravenous steroids and recovered. PMID- 29394980 TI - Endobronchial Mucosal Neuroma with Sarcoidosis. AB - A first case of endobronchial mucosal neuroma with sarcoidosis is hereby reported. A 67-year female patient, who was diagnosed as sarcoidosis previously, was admitted to our hospital with symptoms of dyspnea, chest pain and fatigue. Middle lobe atelectasis and endobronchial lesion were observed in thorax computed tomography (CT). Fiberoptic bronchoscopy revealed polypoid lesions and histopathological examination of biopsy material showed clustered nerve bundles consistent with mucosal neuroma and non-necrotising granulomas consistent with sarcoidosis. Mucosal neuromas are pathognomonic features of multiple endocrine neoplasia (MEN) type 2B. But other components of MEN type 2B such as medullary tyroid carcinoma or pheochromocytoma were not detected in our patient. Hence, a diagnosis of solitary mucosal neuroma and sarcoidosis in the bronchi was made. PMID- 29394981 TI - Isolated Involvement of Penis in Fournier's Gangrene: A Rare Possibility. AB - skin and subcutaneous tissue. Penis may be secondarily affected in some cases; however, primary isolated involvement of penis is rare. A 48-year male smoker presented with pain and blackish discoloration of the distal part of penis for the last 4 days which developed following rupture of a papulo-vesicular lesion over the prepuce of penis. It rapidly progressed to involve half of the skin of the penis. The patient was hospitalized and broad spectrum antibiotics were administered parenterally. Emergency wound debridement and urinary diversion by suprapubic cystostomy was done. After repeated wound debridement and dressings, the wound healed. Our case was unusual as the penis was the sole site of affection, which is very unusual and only few such cases are reported in the literature. PMID- 29394982 TI - Descriptive Epidemiology of Congenital Clubfoot Deformity in Sri Lanka. AB - A retrospective descriptive study was conducted, based on database of Sri Lanka Clubfoot Program, under theInternational Clubfoot Registry. Patients with Clubfoot deformity treated at Orthopaedic unit of Lady Ridgeway Children's Hospital (LRCH), Sri Lanka were evaluated from June 2012 to March 2015. There were a total of 354 patients with male: female ratio of 2.7:1. Bilateral deformity was detected in 48% (171) with positive family history in 14% (49). Majority was hospital births (95%) and 14% were preterm deliveries-pregnancy, and birth-related complications were found in 28.5% (101) and 11% (39), respectively. Cause of clubfoot was idiopathic in 87% (309) and syndromic in 13%. None of the mothers were smoker; three mothers have consumed alcohol during pregnancy. No significant associations among sex of the patient, laterality of clubfoot and the cause of the clubfoot, and there was no seasonal variation among births of clubfoot patients. PMID- 29394983 TI - Important Decision for an Oral Physician to Make in High-Risk Chronic Kidney Disease Patients: It is Not Only to Recordthe Associated Resistant Hypertension, but Whether to Use Manual Sphygmomanometer or Automated Blood Pressure Device? PMID- 29394984 TI - Letter to the Editor Regarding the Manuscript Titled 'Surgical Outcome of Pancreaticoduodenectomy in Pancreatic and Periampullary Neoplasms'. PMID- 29394985 TI - Utilization of Unconventional Methodologies for Teaching Anatomy in Medical Colleges: Challenging Fixed Mindsets. PMID- 29394986 TI - Anti-NMDA Receptor Encephalitis: A Masquerade Ball of Neuropsychiatric Symptoms. PMID- 29394987 TI - Aneurysmal Bone Cyst of Mandible with Classical Histopathological Presentation. PMID- 29394988 TI - Benign Migratory Glossitis. PMID- 29394989 TI - Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. AB - Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ?99% probability of pathogenicity, and 73 had ?95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly (p < 0.05) over-predicted pathogenic variants. We subsequently combined functional and Align GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the overall probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, we used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay. Together, the results show that systematic functional assays in combination with in silico predictors of pathogenicity provide robust tools for clinical annotation of BRCA2 VUS. PMID- 29394992 TI - Trends in Aortic Valve Replacement Procedures Between 2009 and 2015: Has Transcatheter Aortic Valve Replacement Made a Difference? AB - BACKGROUND: This study reports trends in volume and adverse events associated with isolated aortic valve procedures performed in Medicare beneficiaries between 2009 and 2015. METHODS: This retrospective study used the annual fiscal year Medicare Provider Analysis and Review file to identify all Medicare beneficiaries undergoing an isolated aortic valve procedure. Outcome measures included three mortality rates and nine in-hospital adverse events. The final study population consisted of 233,660 hospitalizations. RESULTS: During the study period, Medicare beneficiaries undergoing an aortic valve procedure increased from 22,076 to 49,362, for an average annual growth rate of 14.45%. Transcatheter aortic valve replacement (TAVR) procedures per 100,000 Medicare beneficiaries grew from 10.7 in 2012 to 41.1 in 2015. Overall, in-hospital mortality rates, cumulative 30-day mortality rates, and 90-day postdischarge mortality rates declined annually during the study period. However, the 90-day mortality rate for TAVR was nearly double the rate for the tissue surgical aortic valve replacement group. Nearly 68% of Medicare beneficiaries experienced at least one in-hospital adverse event during their index hospitalization. Medicare beneficiaries undergoing TAVR had the lowest observed adverse events rates among the aortic valve procedures in 2015. CONCLUSIONS: The total number of Medicare beneficiaries undergoing isolated aortic valve procedures increased from 47.5 to 88.9 per 100,000 Medicare beneficiaries during the study period. Aortic valve procedures increased significantly during this study period primarily due to the increase in TAVR, with clinical outcomes improving as well. Although long-term outcomes of TAVR are still under investigation, these results are promising. PMID- 29394991 TI - Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy. AB - Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses. PMID- 29394993 TI - The Value of Prognostic Factors for Survival in Synchronous Multifocal Lung Cancer: A Retrospective Analysis of 164 Patients. AB - BACKGROUND: We reviewed patients treated for synchronous multifocal lung cancers (SMLCs) to analyze outcomes and evaluate valuable prognostic factors. METHODS: From January 2010 to June 2016, 3,031 patients underwent lung cancer resection at Jinling Hospital and Suzhou Hospital affiliated to Nanjing Medical University, and 164 (5.4%) had SMLC. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used for identification of independent survival predictors. RESULTS: The overall survival and progression-free survival rates with SMLC were 72.6% and 61.0%, respectively. A statistically significant difference existed for overall survival and progression-free survival between synchronous multiple primary lung cancer and intrapulmonary metastases according to Martini criteria. There was no statistical difference among the subgroups categorized by the TNM classification. Furthermore, small tumor size showed a benefit for overall survival and progression-free survival. Patients whose tumors were 0.8 cm or smaller had a 5 year survival rate of 100%. Tumor size, lymphatic metastases, and histologic differentiation were identified by univariate and multivariate regression analysis as independent survival predictors. CONCLUSIONS: Survival of patients with SMLC is strongly correlated with the tumor size, differentiation, and lymphatic metastases but not with clinical TNM stage. The Martini criteria based on histologic subtyping has certain predictive value to survival. In comparison, tumor size is of greater value for prognosis. Both of the criteria above are much better than the TNM classification. The 5-year survival rate of 100% in patients with tumors sized 0.8 cm or smaller is extremely valuable for predicting survival after surgical resection. PMID- 29394994 TI - Long-Term Survival in Bilateral Lung Transplantation for Scleroderma-Related Lung Disease. AB - BACKGROUND: Lung disease is the leading cause of morbidity and death in scleroderma patients, but scleroderma is often considered a contraindication to lung transplantation because of concerns for worse outcomes. We evaluated whether 5-year survival in scleroderma patients after lung transplantation differed from other patients with restrictive lung disease. METHODS: This was a single-center, retrospective cohort study of all patients undergoing bilateral lung transplantation for scleroderma-related pulmonary disease between January 2006 and December 2014. This cohort was compared with patients undergoing bilateral lung transplantation for nonscleroderma group D restrictive disease. Primary outcomes reported were 1-year and 5-year survival. Diagnoses were identified by United Network of Organ Sharing listing and were confirmed by clinical examination and prelisting workup. RESULTS: We compared 26 patients who underwent BLT for scleroderma and 155 patients who underwent BLT for group D restrictive disease. Overall, the nonscleroderma cohort was younger, with lower lung allocation score but no difference in functional status. Donor characteristics were not different between the cohorts. Survival at 1 year was not different (73.1% vs 80.0%, p = 0.323). Long-term survival at 5 years was also not significantly different (65.4% vs 66.5%, p = 0.608). Multivariate Cox proportional hazards analysis found no differences in survival between scleroderma and nonscleroderma group D restrictive disease (hazard ratio, 2.19; p = 0.122). CONCLUSIONS: Despite being at high risk for extrapulmonary complications, patients undergoing bilateral lung transplantation for scleroderma have similar 1-year and 5-year survival as those with restrictive lung disease. Transplantation is a reasonable treatment option for a carefully selected population of candidates. PMID- 29394990 TI - Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes. AB - Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation. PMID- 29394995 TI - Venous Thromboembolism in Patients Hospitalized for Lung Transplantation. AB - BACKGROUND: Venous thromboembolism (VTE) is an important complication after solid organ transplantation. We sought to evaluate any association between VTE and in hospital death, length of hospitalization, and total hospital charges for patients hospitalized for lung transplantation (LT). METHODS: We retrospectively reviewed the Nationwide Inpatient Sample to identify patients hospitalized for LT from 2000 to 2011. We evaluated the incidence of VTE during hospitalization for LT, risk factors for VTE, and the association between VTE and in-hospital death, length of hospitalization, and total hospital charges. RESULTS: Of the 16,318 adults hospitalized for LT during the study period, VTE developed in 1,029 (6.3%), including 854 (5.4%) with deep vein thrombosis alone and 175 (1.1%) with pulmonary embolism. The factors associated with VTE included age older than 60 years (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.03 to 1.94), female sex (OR, 0.61; 95% CI, 0.44 to 0.86), and receiving mechanical ventilation support for 96 hours or more (OR, 3.38; 95% CI, 2.49 to 4.58). The adjusted odds of in-hospital death in patients with pulmonary embolism was thrice as high as those without any VTE (OR, 3.40; 95% CI, 1.29 to 8.99). Among LT patients with VTE, the average length of hospitalization was 38% (95% CI, 27% to 48%) longer, and the total cost of hospitalization was 23% (95% CI, 16% to 30%) higher compared with LT patients without VTE. CONCLUSIONS: VTE is a relatively frequent complication among LT recipients and is associated with increased death, total hospital length of stay, and hospital charges. These data indicate that prophylaxis practices should be reexamined to reduce this preventable complication. PMID- 29394996 TI - Long-Term Prognostic Significance of Plasma B-Type Natriuretic Peptide Level in Patients With Acute Heart Failure With Reduced, Mid-Range, and Preserved Ejection Fractions. AB - Plasma B-type natriuretic peptide (BNP) is an important prognostic marker in patients with acute heart failure (AHF). However, it is unclear which BNP parameter, on admission, at discharge, or change during hospitalization, has the highest predictive performance for long-term adverse outcomes, and whether its prognostic impact differs according to the new European heart failure (HF) phenotype classification by left ventricular ejection fraction: heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). We examined 1,792 patients with AHF consisting of 860 (48%) HFrEFs, 318 (18%) HFmrEFs, and 614 (34%) HFpEFs. Prognostic performance of each BNP parameter was assessed by the Harrell c-index. During a median follow-up of 664 days, 344 (19%) patients died. Discharge BNP had the highest c-index (0.69) for mortality among all BNP parameters (p <0.001). In multivariate Cox proportional hazard modeling, discharge BNP was associated with mortality in HFrEF, HFmrEF, and HFpEF patients with significant interaction (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.57 to 2.41; HR 1.76, 95% CI 1.10 to 2.82; HR 1.46, 95% CI 1.12 to 1.91, respectively; p = 0.011 for interaction). Moreover, the c-index of discharge BNP for mortality in HFrEF patients (0.72) was higher than that in HFmrEF patients (0.68) and HFpEF patients (0.65). Similar results were obtained for mortality or HF rehospitalization as alternative outcomes, except there was no statistically significant interaction among HF phenotypes. In conclusion, discharge BNP is a more reliable marker than other BNP parameters on long-term outcome prediction in patients with AHF, but its prognostic impact may be weakened in HFmrEF and HFpEF compared with HFrEF. PMID- 29394997 TI - Influence of Atrial Fibrillation on Outcomes in Patients Who Underwent Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. AB - Atrial fibrillation (AF) is a common co-morbidity among patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Previously, small studies have reported an association between AF and poorer outcomes among patients with STEMI. We performed this study to investigate the impact of AF on in-hospital outcomes in patients with STEMI treated with primary percutaneous coronary intervention (PPCI) using a large national database. The study population constituted of patients 18 years and older with a primary discharge diagnosis of STEMI and who underwent PPCI. Using a 2:1 matching protocol, matched groups of patients with AF (N = 24,680) and without (N = 49,198) were developed. Among 1,493,859 patients with STEMI who underwent PPCI, 129,354 patients (8.7%) had AF. In the propensity-matched cohort, adjusted in-hospital mortality was significantly higher for patients with AF compared with patients with no AF (10.3% vs 9.4%) (adjusted odds ratio [OR] 1.10; confidence interval [CI] 1.06 to 1.16; p <0.0001). Patients with AF were also at higher risk of heart failure, cardiogenic shock, acute stroke, acute kidney injury, vascular complications, need for blood transfusion, and a composite outcome of gastrointestinal and retroperitoneal bleeding. Patients with AF were less likely to be treated with drug-eluting stent compared with patients without AF (51.4% vs 56.6%) (adjusted OR 0.81; CI 0.79 to 0.84; p <0.001). Among patients presenting with STEMI and who underwent PPCI, AF is present in about 8% of patients. In a propensity-matched analysis using a large national database, AF was found to be independently associated with a higher risk of in-hospital mortality and of other complications in these patients. PMID- 29394998 TI - Predictors of Left Ventricular Ejection Fraction Improvement After Primary Stenting in ST-Segment Elevation Myocardial Infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial). AB - The predictors of improvement in left ventricular ejection fraction (LVEF) after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) are poorly understood. We sought to determine the prevalence and clinical and angiographic predictors of LVEF improvement after primary PCI in STEMI. In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction trial, 3,602 patients presenting with STEMI were randomized to heparin + a glycoprotein IIb/IIIa inhibitor versus bivalirudin. Routine 13-month angiographic follow-up was performed in a prespecified substudy of 656 stented patients. The median [25%, 75%] change in LVEF from baseline to 13 months was +2.4% [-5.9%, 11.8%]; LVEF increased or remained unchanged in 379 patients (57.8%; median Delta +9.8% [4.3%, 16.4%]) and fell in 277 patients (42.2%; median Delta -7.0% [-11.8%, -3.6%]). Independent predictors of LVEF improvement were female gender (p = 0.002), lower baseline LVEF (p <0.0001), Thrombolysis in Myocardial Infarction 3 flow after PCI (p = 0.03), shorter lesion length (p = 0.04), and lower post-PCI peak MB isoenzyme of creatine kinase (p <0.0001). In conclusion, in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction trial, although LVEF improved during follow-up after primary PCI in more than half of patients, left ventricular function worsened over time in a substantial proportion, the occurrence of which may be predicted by clinical, angiographic, and laboratory variables. PMID- 29394999 TI - Pharmacologic Treatment of Patients With Myocardial Ischemia With No Obstructive Coronary Artery Disease. AB - Half of women and 1/3 of men with angina and ischemia on stress testing have ischemia with no obstructive coronary artery disease (INOCA). These patients have quality of life (QoL) impairment comparable with patients with obstructive coronary artery disease. Clinicians generally treat INOCA with traditional antianginal agents despite previous studies demonstrating variable response to these medications. We performed a systematic review to evaluate the efficacy and safety of available pharmacologic therapies for INOCA. We systematically searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform in July 2017 for randomized controlled trials (RCTs) evaluating pharmacologic agents for INOCA. The primary outcome of interest was QoL. Secondary outcomes included subjective and objective efficacy measures and safety outcomes. We included 35 RCTs from 333 identified studies. Interventions that improved QoL with moderate quality evidence included angiotensin-converting enzyme (ACE) inhibitor (+/ statin) and ranolazine. Low-to-very-low-quality evidence also suggests that ACE inhibitors, beta blockers, calcium-channel blockers, nicorandil, ranolazine, and statins may decrease angina frequency and delay ischemia on stress testing. Other interventions, most notably nitrates, did not significantly improve any outcome. In conclusion, evidence for pharmacologic treatment of INOCA is generally poor, and higher-quality RCTs using a standardized definition of INOCA are needed. Moderate-quality evidence suggests that ACE inhibitors and ranolazine improve QoL. Other interventions had low-quality evidence or no evidence of efficacy. PMID- 29395000 TI - Syncope, Junctional Premature Complexes, and Pseudo-Type II Atrioventricular Block. AB - In a woman with syncope, junctional premature complexes and what appeared to be intermittent atrioventricular block suggested concealed conduction of His bundle extrasystoles. PMID- 29395001 TI - Effect of Antiplatelet Therapy on Cardiac Outcomes in Patients With Acute Coronary Syndrome. PMID- 29395003 TI - Implant site preparation performed with piezoelectric drills does not have different outcomes than those performed with conventional drills. PMID- 29395002 TI - Resolving Apparent Inconsistencies Between Area, Flow, and Gradient Measurements in Patients With Aortic Valve Stenosis and Preserved Left Ventricular Ejection Fraction. AB - Inconsistencies between area (aortic valve area [AVA])-flow-gradient are common during the echocardiographic assessment of aortic stenosis (AS). This study was conducted to investigate the importance of these inconsistencies and the impact of 3 methods to resolve these inconsistencies. The study population consisted of 327 patients (age: 76.3 +/- 8.6 years, 49.5% males) with severe AS (SAS) (AVA <= 1 cm2) and preserved left ventricular ejection fraction (>=50%). Inconsistent findings between AVA, flow, and mean gradient (MG) were observed in 78 (23.9%) patients with low flow and a high MG, 52 (15.9%) patients with normal flow and a low MG, and 37 (11.3%) patients with a low flow and a low MG. Using stroke volume index by catheterization for AVA recalculation showed the greatest effect to resolve inconsistencies in the low flow and a high MG group (85%). Decreasing the AVA cut-off values for SAS to <=0.8 cm2 resulted in a shift from SAS to moderate AS in 36 patients (69%) in the normal flow and a low MG. Indexing AVA to body surface area had only a minor impact on reclassification. In conclusion, in patients with SAS and preserved left ventricular ejection fraction, the majority of area-flow-gradient inconsistencies at echocardiography can be resolved by correcting errors in stroke volume index measurements by alternative techniques and by redefining the cut-off value for SAS to <=0.8 cm2. PMID- 29395004 TI - Silver diamine fluoride is probably more effective than atraumatic restorative treatment, fluoride varnish, or no treatment for controlling caries progression in children. PMID- 29395005 TI - Orthodontic treatment with fixed appliances may result in small clinical attachment level loss. PMID- 29395006 TI - No evidence of differences important to patients between bonded and vacuum-formed retainers after 1 year of use. PMID- 29395007 TI - Expandable short dental implants seem to have an acceptable rate of success after 3 years. PMID- 29395008 TI - Guided tooth preparation for a pediatric zirconia crown. AB - BACKGROUND AND OVERVIEW: Unesthetic primary incisors can produce negative self perceptions in preschool-aged children. In recent years, because of increased esthetic demands, prefabricated zirconia crowns have become increasingly popular. However, zirconia crowns cannot be crimped, and the clinician must prepare the teeth to fit the zirconia crowns. Therefore, extended preparation and fitting times are necessary, especially for inexperienced practitioners. A 1- to 2 millimeter subgingival feather margin also is required. Gingival hemorrhage after subgingival preparation compromises the retention of zirconia crowns. CASE DESCRIPTION: In this clinical report, the author presents a step-by-step description of the clinical and laboratory procedures for restoring a discolored traumatized incisor with a zirconia crown. The author used a polyvinyl siloxane occlusal registration material as an impression material and made 2 identical casts. The author fabricated 3 reduction guides after prospective tooth preparation on the casts. The author rapidly prepared the discolored incisor with the reduction guides and ultrasonic burs. A zirconia crown provided an optimal esthetic result and gingival health. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Because the reduction guides provided a visibility intraorally, fast tooth reduction, less trial placement, and passive adaptation of the crown were successful. Because the ultrasonic burs prevented gingival injuries, hemorrhage control was not necessary. The presented technique reduced the patient's discomfort and total chair time. Therefore, this alternative technique is helpful for inexperienced practitioners. PMID- 29395009 TI - Feeling welcomed, time spent on appointment, and receiving information were associated with patient satisfaction in highly satisfied patients from a primary care setting. PMID- 29395010 TI - Pulsed electromagnetic field seems to decrease pain levels in females from 24 through 72 hours after initial archwire placement. PMID- 29395011 TI - Probiotics seem to decrease organoleptic scores in patients with halitosis, but there is uncertainty about their effect on volatile sulfur compounds. PMID- 29395012 TI - Understanding patients' oral health information needs: Findings of a survey on use of patient portals in dentistry. AB - BACKGROUND: Patient engagement through web-based patient health portals (PHP) can offer important benefits to patients and provider organizations by improving both quality and access to care. The authors studied the most relevant, patient identified, oral health information available in the PHP to inform their assessment of patient-centered care. METHODS: The authors distributed a 17 question, paper-based survey to patients aged 18 through 80 years in the waiting rooms of 8 dental centers in Wisconsin. Descriptive statistics, along with differences in percentages by sex, age group, and metropolitan status were reported using the chi2 and Wilcoxon rank sum test. RESULTS: A 75% (813 of 1,090) response rate was achieved. More than one-third of patients selected access to previous dental procedures, dental history, routine dental appointment reminders, date of last dental visit, tooth chart, date of last full-mouth radiograph, and dental problem list via the PHP. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Patients identified and recommended incorporation of different types of oral health data for access via the PHP as vital to strengthening the communication between patients and dental professionals. Incorporating patient-identified oral health information in the PHP will inform strategies for improving patient engagement, strengthen patient-provider communication, and offer a venue for increasing oral health literacy and awareness. PMID- 29395013 TI - [Outcomes after a 2-year pharmaceutical care program for patients taking vitamin K antagonist therapy? Community pharmacist's perception]. AB - OBJECTIVES: Since 2013 French community pharmacist are involved in pharmaceutical care program (PCP) for patients treated with vitamin K antagonist (VKA). While PCPs are now extending to other patient populations, we aimed to evaluate pharmacists' perception after 2-years implementation and leading of PCP. METHODS: A prospective investigational survey from 1st August to 31st December, 2015 from 400 community pharmacies in Champagne-Ardenne Region. Survey focuses on 3 points: first about implementation and leading of PCP; secondly about patient's population description; finally on the global perception by CP about new tasks. RESULTS: Among n=47, 72% of pharmacists performed VKA PCP. Almost all received appropriate training (96%). Remuneration appears to be insufficient given the time spent for 73%. Ninety-five percent met patient's refusal mainly because of interest lacking or time lacking (54% and 22%, respectively). Pharmacists reported 3 main lacks of knowledges of patients: drugs, which increase drug-drug interaction risk (28%), VKA overdose effects (27%) and VKA-food interactions (23%). Overall view of pharmacist for PCP appears to be positive (81%) in part because of improvement of pharmacist-patient relationship perception for 66%. CONCLUSIONS: Community pharmacists' perception for PCP for patients treated by VKA is broadly positive. However, organizational or economic constraints can lead to a decreasing adherence by pharmacists to PCPs. A global issue about amount of compensation and communications campaigns to patients and others health professionals will be useful in order to reinforced PCP implementation and leading taxonomy. PMID- 29395014 TI - [HEV and transfusion-recipient risk]. AB - HEV infections are mainly food- and water-borne but transfusion-transmission has occurred in both developing and developed countries. The infection is usually asymptomatic but it can lead to fulminant hepatitis in patients with underlying liver disease and pregnant women living in developing countries. It also causes chronic hepatitis E, with progressive fibrosis and cirrhosis, in approximately 60 % of immunocompromised patients infected with HEV genotype 3. Extra-hepatic manifestations such as neurological and renal manifestations have been reported. The risk of a transfusion-transmitted HEV infection is linked to the frequency of viremia in blood donors, the donor virus load and the volume of plasma in the final transfused blood component. Several developed countries have adopted measures to improve blood safety based on the epidemiology of HEV. PMID- 29395015 TI - [Physicochemical stability of individualized parenteral nutrition in neonatal period]. AB - Individualized parenteral nutrition is frequently used in neonatal period because of specific nutritional needs of preterm neonates which are not always covered by industrially produced parenteral nutrition. This review summarizes the risks of physicochemical instability associated with parenteral nutrition preparation in order to make recommendations to secure this mode of preparation. PMID- 29395016 TI - [Economic impact of centralization of chemotherapy preparation: Experience of the National institute of oncology of Rabat]. AB - INTRODUCTION: Centralized preparation of anticancer drugs meets quality and safety objectives. Its economic interest has been the subject of several studies, with very heterogeneous methodological approaches. OBJECTIVE: This study evaluates the economic impact of the centralization of the preparation of chemotherapy in the national institute of oncology of Rabat, the referral institute in the management of cancer in Morocco. MATERIALS AND METHODS: The analysis included 3000 preparations. It compared the costs of anticancer drugs in a centralized unit at theoretical costs in the healthcare units, modelled according to two approaches. RESULT: With a conservative approach, the impact of centralization was estimated at 80%. The centralized system made it possible to materialize 80% of the potential gain. The remaining 20% is considered a loss. It was very much related to the preparation of the expensive molecules (90%). CONCLUSION: Centralization thus allows a better distribution of roles within the hospital and provides a source of self-financing for quality improvement. PMID- 29395017 TI - Neural monitoring represent central safety asset for new technologies in thyroid surgery in translational protocols. AB - Commentary on the published paper by Chavez KV, Barajas EM, Soroa F, Gamboa Dominguez A, Ordonez S, Pantoja JP, Sierra M, Velazquez-Fernandez D, Herrera MF. Safety assessment of the use of ultrasonic energy in the proximity of the recurrent laryngeal nerve in a porcine model. Am J Surg. 2018 Jan;215(1):186-190. doi: 10.1016/j.amjsurg.2017.04.013. Epub 2017 Jun 7. PubMed PMID: 28622836. PMID- 29395018 TI - Instant replay: Evaluation of instant video feedback in surgical novices for a laparoscopic gallbladder dissection. AB - BACKGROUND: Athletes often use video to improve their technique. We hypothesized that surgical novices given feedback using video-replay would outperform surgical novices given verbal feedback in the performance of a laparoscopic task. METHODS: Our study used a prospective, randomized control design. The surgical task involved the laparoscopic dissection of a pig gallbladder. Our participants performed a dissection, pre- and post-traditional or video feedback. Each recording was independently scored by two staff surgeons using the previously validated rating tools. RESULTS: There was no significant difference between video feedback or traditional feedback groups in their mean overall or task specific scores. Both traditional and video-feedback groups had a trend towards improved performance post-feedback. CONCLUSIONS: No significant difference in performance by both our global assessment metrics or task-specific metrics was observed. Video feedback requires further study to investigate its impact on surgical training. PMID- 29395019 TI - TLR3 expression status predicts prognosis in patients with advanced thoracic esophageal squamous cell carcinoma after esophagectomy. AB - BACKGROUND: The relationship between Toll-like receptors (TLRs) and esophageal squamous cell carcinoma (ESCC) is not completely understood. METHODS: RT-qPCR was used to evaluate the mRNA expression of TLR1-10 in 13 ESCC lines. We then used ESCC tissue microarray (TMA) to confirm expression of TLR3 protein in patients with ESCC. RESULTS: All ESCC lines showed 10-60 times higher TLR3 mRNA expression than PBLs. High expression of TLR3 correlated with favorable 5-year overall survival (OS) and disease specific survival (DSS) among patients with ESCC after esophagectomy (p < 0.01). Additionally, In the adjuvant chemotherapy group, TLR3 high patients had significantly better 5-year OS compared to TLR3 low patients (60.2%, 34.4%, respectively) but not in the surgery alone group. CONCLUSION: High TLR3 expression is an independent prognostic factor and has the potential to serve as a clinically useful marker of the need for adjuvant chemotherapy after esophagectomy in patients with advanced thoracic ESCC. PMID- 29395020 TI - Facility disparities in reporting comorbidities to the National Trauma Data Bank. AB - BACKGROUND: The National Trauma Data Bank (NTDB) includes patient comorbidities. This study evaluates factors of trauma centers associated with higher rates of missing comorbidity data. METHODS: Proportions of missing comorbidity data from facilities in the NTDB from 2011 to 2014 were evaluated for associations with facility characteristics. Proportional impact analysis was performed to identify potential policy targets. RESULTS: Of 919 included facilities, 85% reported comorbidity data in 95% or more cases; only 31.3% were missing no data. Missing rates were significantly different based on most facility categories, but independently associated only with hospital size, region, and trauma center level. Only 15% of centers were responsible for over 80% of cases missing data. CONCLUSIONS: There is significant nonrandom variation in reporting trauma patient comorbidities to the NTDB. Missing data needs to be recognized and considered in studies of trauma comorbidities. Targeted intervention may improve data quality. PMID- 29395021 TI - North Pacific Surgical Association Presidential Address 2017- From Cayman to Vancouver: One surgeon's journey. AB - This is the Presidential Address at the 104th Annual Meeting of the North Pacific Surgical Association held in Vancouver, BC, Canada, November 10-11, 2017. PMID- 29395022 TI - Indocyanine green and fluorescence lymphangiography for sentinel node identification in patients with melanoma. AB - BACKGROUND: Infrared fluorescence imaging with indocyanine green (ICG) is a novel method for sentinel node localization. Our objective was to assess ICG and fluorescence imaging for preoperative and intraoperative utility. METHODS: 87 eligible patients participated in this prospective study. All patients received injection of ICG dye in addition to both methylene blue and 99mTc. Each sentinel node was assessed for the presence of each dye. RESULTS: ICG was visible prior to incision in 44% of subjects. 99mTc identified a mean of 1.89 SLN per patient. ICG identified a mean of 1.87 SLN while methylene blue (MB) dye identified a mean of 0.71 SLN. 99mTc and ICG identified the same number of sentinel nodes per patient (P = .73) while methylene blue was inferior in its ability to localize sentinel nodes (P < .001). CONCLUSION: Our findings indicate that ICG/fluorescence imaging has limited ability to identify the nodal basin preoperatively, but is equivalent to 99mTc for intraoperative identification of sentinel nodes and superior to MB. PMID- 29395024 TI - Discussion of "The presence of papillary features in thyroid nodules diagnosed as atypia of undetermined significance or follicular lesion of undetermined significance increases cancer risk and should influence treatment". PMID- 29395023 TI - Is there a role for Ytrrium-90 in the treatment of unresectable and metastatic intrahepatic cholangiocarcinoma? AB - BACKGROUND: Selective internal radiation therapy (SIRT) with Ytrrium-90 (Y-90) has been used to treat hepatic malignancies with success. This study focuses on the efficacy and safety of Y-90 in the treatment of unresectable and metastatic intrahepatic cholangiocarcinoma (ICC). METHODS: A single-institution retrospective case review was performed for patients with unresectable and metastatic ICC treated with Y-90 between 2006 and 2016. RESULTS: Seventeen patients with ICC underwent 21 Y-90 treatments. Four patients had undergone prior liver resection, and six patients had extrahepatic disease at the time of treatment. Five year overall survival was 26.8%, with a median survival of 33.6 months. One patient underwent margin negative liver resection after a single treatment. Complications were appreciated in two cases. Ninety-day mortality was 0%. CONCLUSION: Treatment of ICC using Y-90 is a safe and promising procedure. Further research is needed to clarify its role in the treatment of unresectable and metastatic ICC. PMID- 29395025 TI - Discussion of "Traumatic thoracic rib cage hernias: Operative management and proposal for a new anatomic-based grading system". PMID- 29395026 TI - Association of shared decision-making on patient-reported health outcomes and healthcare utilization. AB - BACKGROUND: Shared decision-making (SDM) is a process that respects the rights of patients to be fully involved in decisions about their care. By evaluating all available healthcare options and weighing patients' personal values and preferences against available unbiased evidence, patients and healthcare professionals can make health-related decisions together, as partners. We sought to evaluate the impact of perceived SDM on patient-reported outcomes, healthcare quality, and healthcare utilization. METHODS: Patients were identified from the 2010-2014 Medical Expenditure Panel Survey (MEPS) cohort. The Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey was levied to create a weighted composite score of satisfaction with SDM on a 12-point scale, and then categorized as optimal, average or poor SDM based on weighted scores. Weighting and variance techniques were applied to assure results were representative of the U.S. civilian population. Chi-square analysis was used to estimate differences across SDM groupings and multivariate logistic regression was performed to generate odds ratios (OR) and confidence intervals (CI). RESULTS: The study cohort included 63,931 responses to the survey tool. Results of SDM satisfaction across the three categories were skewed, with 46.6% (n = 29,807) of the respondents reporting optimal SDM, 42.1% (n = 26,887) reporting average scores and only 11.3% (n = 7237) reporting poor perceived SDM. Non-white race, lower educational level, low socioeconomic status, non-married status, and uninsured or underinsured status were all associated with higher incidence of poor perceived SDM (p < .05). Poor SDM was associated with increased odds of poor physical health scores (OR: 1.17; 95% CI 1.01-1.36) and poor mental health scores (OR: 1.53; 95% CI 1.25-1.86). Poor SDM was associated with lower use of statins (OR: 0.77; 95% CI 0.68-0.87) and aspirin (OR: 0.86; 95% CI 0.77-0.95), both of which are established quality of care metrics. Poor SDM was also associated with increased emergency department (ED) utilization, with an increased likelihood of 2 or more ED visits associated with poor SDM (OR: 1.25; 95% CI 1.06-1.49). CONCLUSIONS: Poor SDM was associated with worse patient-reported health outcomes, worse established quality indicators, and higher healthcare utilization. While increasing physician education may help optimize SDM, differences in patient perceived SDM were also strongly driven by inherent patient characteristics. PMID- 29395027 TI - Urinary retention in early urinary catheter removal after colorectal surgery. AB - BACKGROUND: High urinary infection (UTI) rate (12%) for our rectal surgery prompted practice change to early catheter removal (postoperative day 2) and prophylactic tamsulosin. Here we report urinary retention (UR) and UTI after this change. METHODS: Retrospective cohort study in male patients 50+ years undergoing elective colorectal surgery from July 2015 to July 2017. Multivariate regression was used to determine risk factors for urinary retention. RESULTS: 157 patients, 57 without and 100 with tamsulosin had UR 11.46% and UTI 5.13%. Of all potential risk factors, ileus (OR 5.50, 95% CI: 1.86-16.24) was an independent risk factor for urinary retention. CONCLUSIONS: Urinary retention of 11% after colorectal resection is within literature range and associated with post-operative ileus. Tamsulosin did not affect UR in our small study sample. Early catheter removal was associated with decreased UTI rate. PMID- 29395028 TI - The effect of hospital familiarity with complex procedures on overall healthcare burden. AB - BACKGROUND: This study aimed to evaluate variations in prolonged outcome after proctectomy based on hospital volume. STUDY DESIGN: From the Premier Perspective database (2012-2014), hospital volumes for proctectomy of benign and malignant conditions were classified as low, intermediate and high. Hospitals were grouped into tertiles. Impact of procedure volume on in-hospital as well as 90-day post discharge complications, length of stay, discharge destination and costs was evaluated. RESULTS: Of 9306 proctectomy procedures, 6960 occurred at high, 1695 at intermediate and 651 at low volume hospitals. After adjustment, high volume institutions were associated with lower in-hospital surgical complications while low volume centers had higher ninety-day post-discharge medical and surgical complications (p < .05 for all). High volume centers had a shorter hospital stay while the need for extended care facility was higher in low volume centers (p < .05 for all). Healthcare costs were higher for low volume hospitals. CONCLUSION: These data suggest that variations in outcomes and costs after complex procedures such as proctectomy exist and are related to institutional familiarity with a procedure. PMID- 29395029 TI - Changing practices: The addition of a novel surgical approach to gynecomastia. AB - INTRODUCTION: Gynecomastia can be a significant impediment to quality of life for men who suffer from this affliction. Numerous surgical techniques have been described in the literature ranging from minimally invasive options such as liposuction to incision based reductions. The standard for the general surgeons at our institution has been subcutaneous mastectomy through a circumareolar incision, which often proved inadequate for patients with grade II or III gynecomastia. In November 2013 we adopted a new technique, the "double donut", that offers the post-operative appearance of a limited incision, with the additional benefits of mastopexy, skin reduction, and mastectomy through an enlarged incision which is not superficially evident at the completion of the procedure. METHODS: We reviewed our surgical database for all cases performed for gynecomastia in the period from May 2005 to August 2016. Basic demographic information, diagnostic modality, symptoms, indication for procedure, operation performed, and final pathology were collected and analyzed. RESULTS: There were 70 mastectomies performed on 52 subjects. All subjects were male; 14 were African American and 38 were Caucasian. The average age was 47 (23-73) years old. The majority of the patients were evaluated with mammogram and/or ultrasound. All but one patient presented with pain as the chief complaint. There were 41 mastectomies done prior to initiation of this technique and 29 were performed after. The average total volume of breast tissue excised via the previous technique was 97.4 cm3, this increased to 186.5 cm3 with the new technique. No necrosis of the NAC was seen and no wound infections resulted in complication. Cosmetic satisfaction was seen in 98% of patients. CONCLUSION: The "double donut" technique is particularly useful for males with grades II or III gynecomastia. It provides good wound results, with acceptable patient satisfaction and cosmetic outcomes. Although initially developed for patients with higher grade gynecomastia, the improved visibility and increased patient satisfaction allowed this to become the preferred technique at our institution. PMID- 29395030 TI - Medical student perceptions of a mistreatment program during the surgery clerkship. AB - BACKGROUND: Medical student mistreatment remains a concern, particularly in the surgery clerkship. This is a single academic institution's report of medical student perceptions of a mistreatment program embedded in the surgery clerkship. METHODS: Students who completed the surgery clerkship and the mistreatment program volunteered to be interviewed individually or in focus groups. The interviews were transcribed and qualitatively analyzed. RESULTS: Twenty-four medical students were interviewed and nine transcripts were obtained. Codes were identified independently then nested into four codes: Student Growth, Faculty Champion and Team, Student Perspectives on Surgical Culture, and Program Methods. Rank orders were then calculated for each major code. CONCLUSION: Our mistreatment program has shown that providing students with an opportunity to define mistreatment, a safe environment for them to debrief, and staff to support and advocate for them empowers them with the knowledge and skillset to confront what is too often considered part of the hidden curriculum. PMID- 29395031 TI - Facial Papules in Frontal Fibrosing Alopecia: Good Response to Isotretinoin. PMID- 29395032 TI - Rapidly Growing Lesion on the Chest. PMID- 29395033 TI - Assessment of countermeasure effectiveness and informativeness in mitigating wrong-way entries onto limited-access facilities. AB - Wrong-way crashes are a major cause for safety concerns along freeways and limited-access facilities. Although wrong-way crashes account for a relatively small portion of total crashes, the impact between two cars crashing into each other at high speeds in opposite directions often results in severe injuries or fatalities compared to any other type of crash. To seek solutions for mitigating wrong-way driving (WWD), multiple field tests involving a number of countermeasures using Intelligent Transportation Systems (ITS) technologies have been conducted in Florida. This study was aimed to evaluate these WWD countermeasures in Florida and develop recommendations regarding the most effective and informing WWD countermeasures through (1) analysis of existing data and studies, (2) field WWD testing using focus groups, (3) a public opinion survey, and (4) capturing human factors elements using simulation via a driving simulator. The results proved that red Rectangular Rapid Flashing Beacons (RRFBs) are the top countermeasure for mitigating WWD at freeway off-ramps, with wigwag flashing beacons as the second best, and detection-triggered blank-out signs and detection-triggered LED lights around "WRONG WAY" signs (tie) as third best. Red flush-mount Internally Illuminated Raised Pavement Markers (IIRPMs) were found to be statistically significantly effective for possible consideration as a supplemental countermeasure for mitigating WWD at freeway off-ramps. The countermeasure of delineators along off-ramps was found to be the least effective and was not considered for recommendation for deterring WWD at freeway off-ramps. This study further confirms that the newly-developed signing and pavement marking standards in Florida are a positive countermeasure on arterials to mitigate wrong way entries onto freeway off-ramps. PMID- 29395034 TI - Methods for the detection of Cryptosporidium and Giardia: From microscopy to nucleic acid based tools in clinical and environmental regimes. AB - The detection and characterization of genotypes and sub genotypes of Cryptosporidium and Giardia is essential for their enumeration, surveillance, prevention, and control. Different diagnostic methods are available for the analysis of Cryptosporidium and Giardia including conventional phenotypic tools that face major limitations in the specific diagnosis of these protozoan parasites. The substantial advancement in the development of genetic signature based molecular tools for the quantification, diagnosis and genetic variation analysis has increased the understanding of the epidemiology and preventive measures of related infections. The conventional methods such as microscopy, antibody and enzyme based approaches, offer better detection results when combined with advanced molecular methods. Gene based approaches increase the precision of identification, for example, many signatures detected in environmental matrices represent species/genotype that are not infectious to humans. This review summarizes the available methods and the advantages and limitations of advance detection techniques like nucleic acid-based approaches for the detection of viable oocysts and cysts of Cryptosporidium and Giardia along with the conventional and widely accepted detection techniques like microscopy, antibody and enzyme based ones. This technical article also encourages the wide application of molecular methods in genetic characterization of distinct species of Cryptosporidium and Giardia, to adopt necessary preventive measures with reliable identification and mapping the source of contamination. PMID- 29395035 TI - Recent developments in dopamine-based materials for cancer diagnosis and therapy. AB - Dopamine-based materials are emerging as novel biomaterials and have attracted considerable interests in the fields of biosensing, bioimaging and cancer therapy due to their unique physicochemical properties, such as versatile adhesion property, high chemical reactivity, excellent biocompatibility and biodegradability, strong photothermal conversion capacity, etc. In this review, we present an overview of recent research progress on dopamine-based materials for diagnosis and therapy of cancer. The review starts with a summary of the physicochemical properties of dopamine-based materials in general. Then detailed description is followed on their applications in the fields of diagnosis and treatment of cancers. The review concludes with an outline of some remaining challenges for dopamine-based materials to be used for clinical applications. PMID- 29395036 TI - Oxidation of factor VIII increases its immunogenicity in mice with severe hemophilia A. AB - The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the presence of active bleeding or hemarthrosis has been evoked. Endothelium damage is typically associated with the release of oxidative compounds. Here, we addressed whether oxidation contributes to FVIII immunogenicity. The control with N-acetyl cysteine of the oxidative status in FVIII-deficient mice, a model of severe hemophilia A, reduced the immune response to exogenous FVIII. Ex vivo exposure of therapeutic FVIII to HOCl induced a mild oxidation of the molecule as evidenced by the loss of free amines and resulted in increased FVIII immunogenicity in vivo when compared to native FVIII. The increased immunogenicity of oxidized FVIII was not reverted by treatment of mice with N-acetyl cysteine, and did not implicate an increased maturation of professional antigen-presenting cells. Our data document that oxidation influences the immunogenicity of therapeutic FVIII. PMID- 29395037 TI - Metabolic regulation of macrophages in tissues. AB - Macrophages are innate immune cells that provide host defense and have tissue specific roles in the maintenance of organ homeostasis and integrity. In most cases macrophages keep us healthy but when their balanced response to damage or homeostatic signals is perturbed, they can drive chronic inflammatory responses and pathology. To fulfil their broad range of functions, macrophages adopt a plethora of activation states. Understanding their regulation and phenotypic heterogeneity is crucial because macrophages are critical in many diseases. Consequently, macrophages have emerged as attractive targets for therapy of diseases in which they determine disease outcome, such as cardiovascular disease, cancer and other Western killer diseases. Recent advances in the flourishing field of immunometabolism highlight that the metabolic profile of macrophages directly regulates their activation status and associated functions. In this short review, we summarize how recent research on the metabolic regulation of macrophages has vividly improved our understanding of macrophage activation. Most of our existing knowledge results from in vitro studies with murine bone marrow derived macrophages which can't fully grasp the complexity of (micro)environmental control of macrophages in tissues. We therefore highlight current weaknesses and missing links in macrophage immunometabolism research and provide future directions to make the step from the well-controlled plastic in vitro cell culture systems to the complex in vivo tissue environment. PMID- 29395038 TI - Letter to the Editor: Metacognitive training and metacognitive therapy. A reply to Lora Capobianco and Adrian Wells. PMID- 29395039 TI - [Funding of anticancer drugs in France]. AB - This short review presents the modalities of funding of anticancer agents administrated in hospitals in France. PMID- 29395040 TI - [Erratum to: "Histological and molecular classification of endometrial carcinoma and therapeutical implications" [Bull. Cancer 104 (2017) 1001-1012]]. PMID- 29395041 TI - [Intravenous chemotherapy at home: A pediatric monocentric experience]. AB - INTRODUCTION: Our home care unit (HCU) developed the administration of IV chemotherapy at home for some pediatric oncologic patients. METHODS: We conducted a retrospective monocentric analysis, leading to identify patients with at least one sequence of chemotherapy at home in 2015. RESULTS: Two hundred and forty four sequences of home chemotherapy have been administered in 2015. We identified two situations for home IV chemotherapy. Pediatric oncologist of day hospital prescribes the sequence. The chemotherapy is delivered at hospital for the first day. HCU takes over for the next days at home. For a sequence replacing a conventional hospitalization, the attending physician examines the patient, and confirm the clinical validation. The pediatric oncologist of HCU checks lab exams, and prescribes the chemotherapy. For both situations, IV chemotherapy is prepared by our hospital pharmacy, delivers at home or at day hospital, and HCU team manages home material and organizes hospitalization. CONCLUSIONS: This kind of organization allows setting up home IV CT for more and more patients. It allows to limit daily hospitalization for some patients living far from the hospital, and whose therapies lead to several hospitalizations. PMID- 29395042 TI - Metabolic and Cardiovascular Complications in Obsessive-Compulsive Disorder: A Total Population, Sibling Comparison Study With Long-Term Follow-up. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with increased mortality, but the causes of this increase are poorly understood. This study examined whether OCD is associated with an increased risk of metabolic and cardiovascular complications. METHODS: Individuals diagnosed with OCD (n = 25,415) were identified from a cohort of 12,497,002 individuals living in Sweden between 1973 and 2013. Cox proportional hazard regression analyses were used to investigate the risk of metabolic and cardiovascular complications in OCD patients compared with the general population and unaffected full siblings of OCD individuals. Exploratory analyses were used to examine the effect of treatment with serotonin reuptake inhibitors, with or without antipsychotics, on the outcomes of interest. RESULTS: Individuals with OCD had a higher risk of any metabolic or cardiovascular complications compared with the general population (adjusted hazard ratio = 1.45; 95% confidence interval = 1.42-1.49) and their unaffected full siblings (adjusted hazard ratio = 1.47; 95% confidence interval = 1.40-1.54). In the fully adjusted sibling comparison models, patients had higher risks of obesity, type 2 diabetes mellitus, and circulatory system diseases. The risks were already evident from the beginning of the follow-up period and remained largely unchanged when excluding different groups of psychiatric comorbidities. Compared with patients who were not taking serotonin reuptake inhibitors, patients taking higher doses of serotonin reuptake inhibitors and who had a longer duration of treatment had significantly lower risks of metabolic and cardiovascular complications, regardless of whether they were also taking antipsychotics. CONCLUSIONS: OCD is associated with an increased risk of metabolic and cardiovascular complications. Our results underscore the importance of carefully monitoring metabolic and cardiovascular health in patients with OCD early in the course of the disorder. PMID- 29395043 TI - Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine. AB - BACKGROUND: Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. METHODS: To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice. We analyzed the effects biochemically and behaviorally, using the forced swim, tail suspension, and novelty suppressed feeding tests. RESULTS: Consistent with the literature, one of the major pathways mediating the antidepressant action of ketamine was reduction of phosphorylation of eEF2 via eEF2K. Specifically, knocking out eEF2K in mice eliminated phosphorylation of eEF2 at threonine at position 56, resulting in increased protein synthesis, and made mice resistant both biochemically and behaviorally to the antidepressant effects of ketamine. In addition, administration of ketamine led to differential regulation of CaMKII function, manifested as autoinhibition (pT305 phosphorylation) followed by autoactivation (pT286) of CaMKIIalpha in the hippocampus and cortex. The inhibition phase of CaMKII, which lasted 10 to 20 minutes after administration of ketamine, occurred concurrently with eEF2K-dependent increased protein synthesis. Moreover, ketamine administration-dependent delayed induction of GluA1 (24 hours) was regulated by the activation of CaMKII. Importantly, systemic administration of the CaMKII inhibitor tatCN21 increased global protein synthesis and induced behavioral resistance to ketamine. CONCLUSIONS: Our data suggest that drugs that selectively target CaMKs and regulate protein synthesis offer novel strategies for treatment of major depressive disorder. PMID- 29395045 TI - Effect of Grafting on Aggregation of Intrinsically Disordered Proteins. AB - A significant part of the proteome is composed of intrinsically disordered proteins (IDPs). These proteins do not fold into a well-defined structure and behave like ordinary polymers. In this work, we consider IDPs that have the tendency to aggregate, model them as heteropolymers that contain a small number of associating monomers, and use computer simulations to compare the aggregation of such IDPs that are grafted to a surface or free in solution. We then discuss how such grafting may affect the analysis of in vitro experiments and could also be used to suppress harmful aggregation. PMID- 29395046 TI - Chromatin Configuration Affects the Dynamics and Distribution of a Transiently Interacting Protein. PMID- 29395044 TI - TDP43 and RNA instability in amyotrophic lateral sclerosis. AB - The nuclear RNA-binding protein TDP43 is integrally involved in RNA processing. In accord with this central function, TDP43 levels are tightly regulated through a negative feedback loop, in which TDP43 recognizes its own RNA transcript, destabilizes it, and reduces new TDP43 protein production. In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), cytoplasmic mislocalization and accumulation of TDP43 disrupt autoregulation; conversely, inefficient TDP43 autoregulation can lead to cytoplasmic TDP43 deposition and subsequent neurodegeneration. Because TDP43 plays a multifaceted role in maintaining RNA metabolism, its mislocalization and accumulation interrupt several RNA processing pathways that in turn affect RNA stability and gene expression. TDP43-mediated disruption of these pathways-including alternative mRNA splicing, non-coding RNA processing, and RNA granule dynamics-may directly or indirectly contribute to ALS pathogenesis. Therefore, strategies that restore effective TDP43 autoregulation may ultimately prevent neurodegeneration in ALS and related disorders. PMID- 29395047 TI - Structural Conservation and Effects of Alterations in T Cell Receptor Transmembrane Interfaces. AB - T cell receptors (TCRs) are octameric assemblies of type-I membrane proteins in which a receptor heterodimer (alphabeta, deltagamma, or pre-Talphabeta) is associated with three dimeric signaling modules (CD3deltaepsilon, CD3gammaepsilon, and zetazeta) at the T cell or pre-T cell surface. In the human alphabetaTCR, the alpha and beta transmembrane (TM) domains form a specific structure that acts as a hub for assembly with the signaling modules inside the lipid bilayer. Conservation of key polar contacts across the C-terminal half of this TM interface suggests that the structure is a common feature of all TCR types. In this study, using molecular dynamics simulations in explicit lipid bilayers, we show that human deltagamma and pre-Talphabeta TM domains also adopt stable alphabeta-like interfaces, yet each displays unique features that modulate the stability of the interaction and are related to sequences that are conserved within TCR types, but are distinct from the alphabeta sequences. We also performed simulations probing effects of previously reported mutations in the human alphabeta TM interface, and observed that the most disruptive mutations caused substantial departures from the wild-type TM structure and increased dynamics. These simulations show a strong correlation between structural instability, increased conformational variation, and the severity of structural defects in whole-TCR complexes measured in our previous biochemical assays. These results thus support the view that the stability of the core TM structure is a key determinant of TCR structural integrity and suggest that the interface has been evolutionarily optimized for different forms of TCRs. PMID- 29395048 TI - Meddling with METTLs in Normal and Leukemia Stem Cells. AB - Three recent studies independently identified the m6A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer. PMID- 29395049 TI - FAOund the Link: Phospholipid Remodeling and Intestinal Stem Cell Growth and Tumorigenesis. AB - In this issue of Cell Stem Cell, Wang et al. (2018) identify a novel link between Lpcat3-mediated phospholipid remodeling (the Lands cycle) and cholesterol biosynthesis that modulates intestinal stem cell proliferation and tumorigenesis. Notably, inhibition of cholesterol biosynthesis dampens many of the Lpcat3 deficiency-mediated effects in the intestine. PMID- 29395050 TI - Slow Your Roll: Inhibiting SETD7 Activity Permits Ex Vivo Expansion of Muscle Stem Cells. AB - Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell, Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program. PMID- 29395051 TI - Shaping the Pluripotent Genome: Switches, Borders, and Loops. AB - Three-dimensional genome organization is largely cell type specific and requires reorganization during cell fate transitions. A recent study in Nature Genetics (Stadhouders et al., 2018) offers important insights into the principles and drivers of such reorganization during reprogramming of somatic cells into pluripotent stem cells. PMID- 29395052 TI - Japan Strengthens Regenerative Medicine Oversight. AB - The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy. PMID- 29395053 TI - Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. AB - Clonal hematopoiesis (CH) broadly describes the expansion of a clonal population of blood cells with one or more somatic mutations. Individuals with CH are at greater risk for hematological malignancies, cardiovascular disease, and increased mortality from non-hematological cancers. Understanding the causes of CH and how these mutant cells interact with cells of other tissues will provide critical insights into preleukemic development, stem cell biology, host-immune interactions, and cancer evolution. Here we discuss the clinical manifestations of CH, mechanisms contributing to its development, the role of CH in clonal evolution toward leukemia, and the contribution of CH to non-hematological disease states. PMID- 29395054 TI - Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential. AB - The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of beta catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease. PMID- 29395055 TI - Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis. AB - Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo. Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apcmin mice. These findings identify a critical dietary responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis. PMID- 29395057 TI - Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. PMID- 29395058 TI - Guilty by Association: Mapping Out the Molecular Sociology of Droplet Compartments. AB - The molecular interactions driving the formation of stress-inducible granules have largely remained unknown. In two recent papers, Youn et al. (2018) and Markmiller et al. (2018) use proximity labeling proteomics to map out the protein interactome of stress-inducible ribonucleoprotein granules. PMID- 29395059 TI - Protein S-Nitrosylation: Enzymatically Controlled, but Intrinsically Unstable, Post-translational Modification. AB - Reports by Seth et al. (2018) and Wolhuter et al. (2018) in this issue of Molecular Cell highlight the enzymatic synthesis, functionality, and propagation of S-nitrosylation-based signaling and address its low stability due to the elevated reactivity toward other cellular thiols. PMID- 29395056 TI - Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation. AB - Somatic stem cells have been identified in multiple adult tissues. Whether self renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthood for lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vast majority of B1 cells divide symmetrically. Whereas 20%-30% symmetrically self renew and can remain in the niche for several months before generating neurons, 70%-80% undergo consuming divisions generating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouples self-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consuming symmetric differentiation divisions can explain the levels of neurogenesis observed throughout life. PMID- 29395060 TI - Advances in CLIP Technologies for Studies of Protein-RNA Interactions. AB - RNA binding proteins (RBPs) regulate all aspects in the life cycle of RNA molecules. To elucidate the elements that guide RNA specificity, regulatory mechanisms, and functions of RBPs, methods that identify direct endogenous protein-RNA interactions are particularly valuable. UV crosslinking and immunoprecipitation (CLIP) purifies short RNA fragments that crosslink to a specific protein and then identifies these fragments by sequencing. When combined with high-throughput sequencing, CLIP can produce transcriptome-wide maps of RNA crosslink sites. The protocol is comprised of several dozen biochemical steps, and improvements made over the last 15 years have increased its resolution, sensitivity, and convenience. Adaptations of CLIP are also emerging in the epitranscriptomic field to map the positions of RNA modifications accurately. Here, we describe the rationale for each step in the protocol and discuss the impact of variations to help users determine the most suitable option. PMID- 29395061 TI - SLFN11 Blocks Stressed Replication Forks Independently of ATR. AB - SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites. PMID- 29395062 TI - PKCalpha-LSD1-NF-kappaB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response. AB - The inflammatory response mediated by nuclear factor kappaB (NF-kappaB) signaling is essential for host defense against pathogens. Although the regulatory mechanism of NF-kappaB signaling has been well studied, the molecular basis for epigenetic regulation of the inflammatory response is poorly understood. Here we identify a new signaling axis of PKCalpha-LSD1-NF-kappaB, which is critical for activation and amplification of the inflammatory response. In response to excessive inflammatory stimuli, PKCalpha translocates to the nucleus and phosphorylates LSD1. LSD1 phosphorylation is required for p65 binding and facilitates p65 demethylation, leading to enhanced stability. In vivo genetic analysis using Lsd1SA/SA mice with ablation of LSD1 phosphorylation and chemical approaches in wild-type mice with inhibition of PKCalpha or LSD1 activity show attenuated sepsis-induced inflammatory lung injury and mortality. Together, we demonstrate that the PKCalpha-LSD1-NF-kappaB signaling cascade is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be a powerful therapeutic strategy for systemic inflammatory diseases, including sepsis. PMID- 29395063 TI - The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations. AB - Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway. We further demonstrate that enhanced R-loops, opposite to the expectation from gained RNA binding with mutant SRSF2, result from impaired transcription pause release because the mutant protein loses its ability to extract the RNA polymerase II (Pol II) C-terminal domain (CTD) kinase-the positive transcription elongation factor complex (P-TEFb)-from the 7SK complex. Enhanced R-loops are linked to compromised proliferation of bone-marrow-derived blood progenitors, which can be partially rescued by RNase H overexpression, suggesting a direct contribution of augmented R-loops to the MDS phenotype. PMID- 29395065 TI - Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation. AB - Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPbeta, a rate-limiting enzyme in FAO. Although TPbeta activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPbeta association results in Nur77 self-sacrifice to protect TPbeta from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPbeta interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma. PMID- 29395064 TI - Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters. AB - R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor beta (TGF-beta), is reduced; that then leads to the activation of the TGF-beta pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins. PMID- 29395066 TI - OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling. AB - Ubiquitination is a major mechanism that regulates numerous cellular processes, including autophagy, DNA damage signaling, and inflammation. While hundreds of ubiquitin ligases exist to conjugate ubiquitin onto substrates, approximately 100 deubiquitinases are encoded by the human genome. Thus, deubiquitinases are likely regulated by unidentified mechanisms to target distinct substrates and cellular functions. Here, we demonstrate that the deubiquitinase OTUD4, which nominally encodes a K48-specific deubiquitinase, is phosphorylated near its catalytic domain, activating a latent K63-specific deubiquitinase. Besides phosphorylation, this latter activity requires an adjacent ubiquitin-interacting motif, which increases the affinity of OTUD4 for K63-linked chains. We reveal the Toll-like receptor (TLR)-associated factor MyD88 as a target of this K63 deubiquitinase activity. Consequently, TLR-mediated activation of NF-kappaB is negatively regulated by OTUD4, and macrophages from Otud4-/- mice exhibit increased inflammatory signaling upon TLR stimulation. Our results reveal insights into how a deubiquitinase may modulate diverse processes through post-translational modification. PMID- 29395067 TI - High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA Associated Granules and Bodies. AB - mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules (SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs. PMID- 29395068 TI - Intracellular Crotonyl-CoA Stimulates Transcription through p300-Catalyzed Histone Crotonylation. PMID- 29395069 TI - Greater Than the Sum of Parts: Complexity of the Dynamic Epigenome. PMID- 29395070 TI - Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs. PMID- 29395071 TI - Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis. PMID- 29395072 TI - Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome. AB - Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS. PMID- 29395073 TI - Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA. PMID- 29395074 TI - OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome. AB - Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development. PMID- 29395076 TI - Bible Says Israelites Didn't Exterminate Sidonians. PMID- 29395075 TI - Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome. AB - 15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity. PMID- 29395077 TI - Response to Giem. PMID- 29395078 TI - Implantation of a Matrigel-loaded agarose scaffold promotes functional regeneration of axons after spinal cord injury in rat. AB - An agarose scaffold can be useful for supporting and guiding injured axons after spinal cord injury (SCI), but the electrophysiological signal of regenerated axon in scaffolds has not yet been determined. The current study investigated whether a Matrigel-loaded agarose scaffold would enhance the regeneration of axons after SCI. Moreover, the functional connectivity of regenerated axons within the channels of the scaffold was evaluated by directly recording motor evoked potentials. Our data showed that the agarose scaffold containing Matrigel can support and enhance linearly organized axon regeneration after SCI. Additionally, motor evoked potentials were successfully recorded from regenerated axons. These results demonstrate that an agarose scaffold loaded with Matrigel could promote the regeneration of axons and guide the reconnection of functional axons after SCI. PMID- 29395079 TI - Ceramidase critically affects GPVI-dependent platelet activation and thrombus formation. AB - Platelet aggregation, dense granule secretion and thrombus formation are dependent on sphingolipids like ceramide and sphingosine as well as sphingosine-1 phosphate. Sphingosine/ceramide metabolism involves ceramide synthases and ceramidases. However, the role of ceramide synthase and ceramidase in the regulation of platelet function remained ill-defined. The present study determined transmission light aggregometry, employed luciferase based ATP release measurements and studied in vitro thrombus formation under high arterial shear rates in order to define the impact of pharmacological inhibition of serine palmitoyltransferase, ceramide synthase and ceramidase on platelet function. As a result, inhibition of ceramidase significantly blunted collagen related peptide (CRP) induced glyocoprotein VI (GPVI)-dependent platelet aggregation, ATP release and thrombus formation on a collagen-coated surface under shear rates of 1700 sec. Defective platelet aggregation after ceramidase inhibition could partially be overcome by exogenous sphingosine treatment reflecting a pivotal role of ceramidase-derived sphingosine in platelet function. Inhibition of serine palmitoyltransferase and ceramide synthase did not significantly modify GPVI dependent platelet activation. In conclusion, the present study unraveled ceramidase as a crucial player in sphingosine-induced platelet activation following GPVI-dependent signaling. PMID- 29395080 TI - Biophysical and biochemical characterization of Rv3405c, a tetracycline repressor protein from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis disease, is one among the deadliest pathogens in the world. Due to long treatment regimen, HIV co infection, persistence of bacilli in latent form and development of XDR and TDR strains of Mtb, tuberculosis has posed serious concerns for managing the disease, and calls for discovery of new drugs and drug targets. Using a computational pipeline involving analysis of the structural models of the Mtb proteome and an analysis of the ATPome, followed by a series of filters to identify druggable proteins, solubility and length of the protein, several candidate proteins were shortlisted. From this, Rv3405c, a tetR family of DNA binding protein involved in antibiotic resistance, was identified as one of the good drug targets. Rv3405c binds to the upstream non-coding region of Rv3406 and causes repression of Rv3406 activity there by affecting the downstream processes involved in antibiotic resistance was further characterized. The Rv3405c gene was cloned; the gene product was over-expressed in E. coli and purified by Ni NTA chromatography. DNA binding studies by EMSA showed that the recombinant Rv3405c protein binds to the DNA sequence corresponding to the promoter region of Rv3406 and upon addition of tetracycline, the DNA binding activity was lost. beta-galactosidase reporter assay in E. coli using both wild type and a DNA binding defective mutant protein indeed proved that Rv3405c acts as a repressor. PMID- 29395081 TI - Methionine sulfoxide reductase B1 regulates proliferation and invasion by affecting mitogen-activated protein kinase pathway and epithelial-mesenchymal transition in u2os cells. AB - Methionine sulfoxide reductase B1 (MsrB1), a member of the selenoprotein family and contributes significantly to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS). However, few studies have examined the role of MsrB1 in tumors. Here We tested the proliferation and invasion in MsrB1 knockdown u2os cells under H2O2/thioredoxin. As shown in our result, knockdown of MsrB1 inhibited the proliferation of u2os cells and regulates mitogen-activated protein kinase (MAPK) pathway by down-regulation of Erk, MeK phosphorylation and p53 expression in u2os cells. In a xenograft tumorigenicity mice, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown resulted in migration and invasion reducement of u2os cells. MsrB1 regulates epithelial mesenchymal transition (EMT) via affecting cytoskeleton by increasing E-cadherin expression and decreasing N-cadherin, TGF-beta1, slug, fibronectin, vimentin, c myc, snail and beta-catenin expressions. In vivo, MsrB1 shRNAi can inhibit lung metastasis in metastasis model. In conclusion, MsrB1 regulates proliferation and invasion of u2os cells by affecting MAPK pathway and EMT, and MsrB1 gene may be a novel therapeutic target against tumors. PMID- 29395082 TI - Kinetic profiles of photocurrents in cells expressing two types of channelrhodopsin genes. AB - Channelrhodopsin-2 (ChR2), a light-activated cation-selective ion channel, has been widely used as a tool in optogenetic research. ChR2 is specifically sensitive to wavelengths less than 550 nm. One of the methods to expand the sensitivity of a channelrhodopsin to a wider range of wavelengths is to express another channelrhodopsin in the cells by the transduction of an additional gene. Here, we report the characteristic features of cells expressing two types of channelrhodopsins, each having different wavelength sensitivities. In HEK293 cells stably expressing ChR2, photocurrents were elicited at stimuli of 400-550 nm, and the wavelength sensitivity range was expanded by the additional transduction of the modified Volvox channelrhodopsin-1 (mVChR1) gene, which has broad wavelength sensitivities, ranging from 400 to 600 nm. However, the photocurrent at 550 nm was lower than that of the mVChR1-expressing cell; moreover, the turning-on and turning-off constants were delayed, and the deactivation rates were decreased. Meanwhile, the response to lower light intensity was improved by the additional gene. Thus, the transduction of an additional gene is a useful method to improve the light and wavelength sensitivities, as well as photocurrent kinetic profiles, of channelrhodopsins. PMID- 29395083 TI - Use of CK-548 and CK-869 as Arp2/3 complex inhibitors directly suppresses microtubule assembly both in vitro and in vivo. AB - Two types of Arp2/3 complex inhibitors, CK-666/636 and CK-548/869, are commonly used to study Arp2/3 complex-dependent actin assembly both in vitro and in vivo. However, we found that CK-548 and CK-869 directly suppress microtubule (MT) assembly independent of the actin cytoskeleton. Treatment of cultured mammalian cells with 50 MUM CK-869 dramatically decreased MT networks and, instead, accumulated tubulin at the cell periphery, as did nocodazole that inhibits MT assembly. An in vitro MT-sedimentation assay revealed that CK-548 and CK-869 significantly suppressed MT polymerization. In budding yeast, although CK-548 and CK-869 are reported to lack binding abilities in the yeast Arp3, CK-548 treatment decreased cytoplasmic MT at several tens of micromolar concentrations. In addition, we found that the effects of CK-548 and CK-869 on MT assembly varied according to species. We propose that CK-548 and CK-869 are not suitable for studying the cytoskeleton in living cells. PMID- 29395084 TI - Perturbations in carotenoid and porphyrin status result in differential photooxidative stress signaling and antioxidant responses. AB - We examined differential photooxidative stress signaling and antioxidant responses in rice plants treated with norflurazon (NF) and oxyfluorfen (OF), which are inhibitors of carotenoid and porphyrin biosynthesis, respectively. Plants treated with OF markedly increased levels of cellular leakage and malondialdehyde, compared with NF-treated plants, showing that OF plants suffered greater oxidative damage with respect to membrane integrity. The enhanced production of H2O2 in response to OF, but not NF, indicates the important role of H2O2 in activation of photooxidative stress signaling in OF plants. In response to NF and OF, the increased levels of free salicylic acid as well as maintenance of the redox ratio of ascorbate and glutathione pools to a certain level are considered to be crucial factors in the protection against photooxidation. Plants treated with OF greatly up-regulated catalase (CAT) activity and Cat transcript levels, compared with NF-treated plants. Interestingly, NF plants showed no noticeable increase in oxidative metabolism, although they did show considerable increases in ascorbate peroxidase (APX) and peroxidase activities and transcript levels of APX, as in OF plants. Our results suggest that perturbations in carotenoid and porphyrin status by NF and OF can be sensed by differential photooxidative stress signaling, such as that involving H2O2, redox state of ascorbate and glutathione, and salicylic acid, which may be responsible for at least part of the induction of ROS-scavenging enzymes. PMID- 29395085 TI - Preservation of rat hearts in subfreezing temperature isochoric conditions to - 8 degrees C and 78 MPa. AB - Isochoric (constant volume) preservation at subfreezing temperatures is being investigated as a novel method for preserving cells and organs. This study is a first initial effort to evaluate the efficacy of this method for heart preservation, and to provide a preliminary outline of appropriate preservation parameters. To establish a baseline for further studies, rat hearts were preserved in a University of Wisconsin (UW) intracellular solution for one hour under isochoric conditions at: 0 degrees C (atmospheric pressure - 0.1 MPa), - 4 degrees C (41 MPa), - 6 degrees C (60 MPa) and - 8 degrees C (78 MPa). The viability of the heart was evaluated using Langendorff perfusion and histological examination. The physiological performance of hearts preserved at - 4 degrees C (41 MPa) was comparable to that of a heart preserved on ice at atmospheric pressure, with no statistically significant difference in histological injury score. However, hearts preserved at -4 degrees C displayed substantially reduced interstitial edema compared to hearts preserved by conventional hypothermic preservation in UW on ice at atmospheric pressure, suggesting significant protection from increased vascular permeability following preservation. Hearts preserved at - 6 degrees C (60 MPa) suffered injury from cellular swelling and extensive edema, and at - 8 degrees C (78 MPa) hearts experienced significant morphological disruption. To the best of our knowledge, this is the first publication showing that a mammalian organ can survive low subfreezing temperatures without the use of a cryoprotective additive. Lowering the preservation temperature reduces metabolism and improves preservation quality, and these results suggest that improvements in preservation are possible at subzero temperatures with low to moderate pressures observed at -4 degrees C. Notably, tissue damage was observed at lower temperatures (-6 degrees C or below) accompanying further elevation of pressure associated with isochoric preservation that may prove detrimental. Therefore, subfreezing temperature isochoric preservation protocols should optimize, a combination of temperature and pressure that will minimize the negative effects of elevated pressure while retaining the beneficial effect of lower temperatures and reduced metabolism. PMID- 29395086 TI - Mitochondrial dynamics and protective effects of a mitochondrial division inhibitor, Mdivi-1, in lipopolysaccharide-induced brain damage. AB - Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE. PMID- 29395087 TI - A dual-ligand-modulable fluorescent protein based on UnaG and calmodulin. AB - UnaG is a green-emitting fluorescent protein that utilizes unconjugated bilirubin (BR) as its fluorophore. While BR has captured the attention of physiologists as an important antioxidant that scavenges reactive oxygen species in biological membranes, its excessive accumulation causes several clinical symptoms. Although the optimal regulation of BR concentration would result in clinical therapies for aging as well as reduce risks of clinical symptoms, UnaG hardly releases BR owing to its extremely high affinity for BR (Kd = 98 pM). Herein, we engineered the BR binding and fluorescence of UnaG to be Ca2+-sensitive via a genetic insertion of calmodulin (CaM). The resultant UnaG/CaM hybrid protein is a dual-ligand modulable fluorescent protein; binding of the fluorogenic ligand BR is negatively regulated by the other ligand, Ca2+ ion. The affinity for BR differed by three orders of magnitude between the Ca2+-free state (Kd = 9.70 nM) and Ca2+-saturated state (Kd = 9.65 MUM). The chimeric protein can release nano- to micro-molar levels of BR with Ca2+ control, and is thus named BReleaCa (BR + releaser + Ca2+). Such a protein hybridization technique will be generally applicable to change the ligand binding properties of a variety of ligand-inducible functional proteins. PMID- 29395088 TI - Trek2a regulates gnrh3 expression under control of melatonin receptor Mt1 and alpha2-adrenoceptor. AB - Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K+) channel-related K+ (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and alpha2-adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and alpha2-adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and alpha2-adrenoceptor. PMID- 29395089 TI - Rapid identification of cyclopropyl fentanyl/crotonyl fentanyl in clinical urine specimens: A case study of clinical laboratory collaboration in Canada. PMID- 29395090 TI - Point-of-care testing: A position statement from the Canadian Society of Clinical Chemists. PMID- 29395091 TI - Assessment of biotin interference with qualitative point-of-care hCG test devices. AB - Biotin is commonly used as a dietary supplement for the claimed benefits of promoting healthy hair and nail growth and is available without a prescription at doses up to 10mg/capsule. Biotin-mediated interference in immunoassay testing is an emerging issue for clinical laboratories and previous studies have indicated that biotin at regularly encountered doses may interfere with these assays. In this study, we evaluated the effect of supplemental biotin on seven POC urine hCG test devices using purified biotin and urine collected from four volunteers consuming 10mg biotin/day. Six of the seven devices showed no evidence of biotin interference as each device's control line remained clearly detectable at all biotin concentrations tested. However, the QuickVue device control line demonstrated a marked decrease in intensity when used to test solutions containing >5MUg/mL biotin. The absence of a control line during patient testing has the potential to delay care due to the generation of an invalid test result and lead to additional unnecessary testing. It is not realistic to measure urinary biotin concentrations in every patient undergoing qualitative urine hCG testing but biotin supplementation should be considered if repeat testing on a patient sample generates an invalid test result. PMID- 29395092 TI - Foreword. PMID- 29395093 TI - Post-stroke depression: Risk assessment. PMID- 29395094 TI - Robotic-assisted surgery in live-donor uterus transplantation. PMID- 29395095 TI - Nature versus science, transferring embryos or blame. PMID- 29395097 TI - Total cholesterol and the risk of stroke: A double-edged sword or a blunt knife? PMID- 29395096 TI - Exome and genome sequencing in reproductive medicine. AB - The advent of next-generation sequencing has enabled clinicians to assess many genes simultaneously and at high resolution. This is advantageous for diagnosing patients in whom a genetic disorder is suspected but who have a nonspecific or atypical phenotype or when the disorder has significant genetic heterogeneity. Herein, we describe common clinical applications of next-generation sequencing technology, as well as their respective benefits and limitations. We then discuss key considerations of variant interpretation and reporting, clinical utility, pre and posttest genetic counseling, and ethical challenges. We will present these topics with an emphasis on their applicability to the reproductive medicine setting. PMID- 29395098 TI - Distinctive molecular signature and activated signaling pathways in aortic smooth muscle cells of patients with myocardial infarction. AB - BACKGROUND AND AIMS: We aim to identify significant transcriptome alterations of vascular smooth muscle cells (VSMCs) in the aortic wall of myocardial infarction (MI) patients. Providing a robust transcriptomic signature, we aim to highlight the most likely aberrant pathway(s) in MI VSMCs. METHODS AND RESULTS: Laser captured microdissection (LCM) was used to obtain VSMCs from aortic wall tissues harvested during coronary artery bypass surgery. Microarray gene analysis was applied to analyse VSMCs from 17 MI and 19 non-MI patients. Prediction Analysis of Microarray (PAM) identified 370 genes that significantly discriminated MI and non-MI samples and were enriched in genes responsible for muscle development, differentiation and phenotype regulation. Incorporation of gene ontology (GO) led to the identification of a 21-gene VSMCs-associated classifier that discriminated between MI and non-MI patients with 92% accuracy. The mass spectrometry-based iTRAQ analysis of the MI and non-MI samples revealed 94 proteins significantly differentiating these tissues. Ingenuity Pathway Analysis (IPA) of 370 genes revealed top pathways associated with hypoxia signaling in the cardiovascular system. Enrichment analysis of these proteins suggested an activation of the superoxide radical degradation pathway. An integrated transcriptome-proteome pathway analysis revealed that superoxide radical degradation pathway remained the most implicated pathway. The intersection of the top candidate molecules from the transcriptome and proteome highlighted superoxide dismutase (SOD1) overexpression. CONCLUSIONS: We provided a novel 21-gene VSMCs-associated MI classifier in reference to significant VSMCs transcriptome alterations that, in combination with proteomics data, suggests the activation of superoxide radical degradation pathway in VSMCs of MI patients. PMID- 29395099 TI - The multifaceted role of macrophages in cardiovascular calcification. PMID- 29395100 TI - The challenge of peripheral arterial disease: How do we improve outcome? PMID- 29395101 TI - From individual heterogeneity to population-level overdispersion: quantifying the relative roles of host exposure and parasite establishment in driving aggregated helminth distributions. AB - In most host-parasite systems, variation in parasite burden among hosts drives transmission dynamics. Heavily infected individuals introduce disproportionate numbers of infective stages into host populations or surrounding environments, causing sharp increases in frequency of infection. Parasite aggregation within host populations may result from variation among hosts in exposure to infective propagules and probability of subsequent establishment of parasites in the host. This is because individual host heterogeneities contribute to a pattern of parasite overdispersion that emerges at the population level. We quantified relative roles of host exposure and parasite establishment in producing variation in parasite burdens, to predict which hosts are more likely to bear heavy burdens, using big brown bats (Eptesicus fuscus) and their helminths as a model system. We captured bats from seven colonies in Michigan and Indiana, USA, assessed their helminth burdens, and collected data on intrinsic and extrinsic variables related to exposure, establishment, or both. Digenetic trematodes had the highest prevalence and mean abundance while cestodes and nematodes had much lower prevalence and mean abundance. Structural equation modeling revealed that best-fitting models to explain variations in parasite burden included genetic heterozygosity and immunocompetence as well as distance to the nearest water source and the year of host capture. Thus, both differential host exposure and differential parasite establishment significantly influence heterogeneous helminth burdens, thus driving population-level patterns of parasite aggregation. PMID- 29395102 TI - The invasion risk of species associated with Japanese Tsunami Marine Debris in Pacific North America and Hawaii. AB - Marine debris from the Great Tsunami of 2011 represents a unique transport vector for Japanese species to reach Pacific North America and Hawaii. Here we characterize the invasion risk of invertebrate species associated with tsunami debris using a screening-level risk assessment tool - the Canadian Marine Invasive Screening Tool (CMIST). Higher-risk invertebrate invaders were identified for each of five different ecoregions. Some of these are well-known global invaders, such as the mussel Mytilus galloprovincialis and the ascidian Didemnum vexillum which already have invasion histories in some of the assessed ecoregions, while others like the sea star Asterias amurensis and the shore crab Hemigrapsus sanguineus have yet to invade large portions of the assessed ecoregions but also are recognized global invaders. In general, the probability of invasion was lower for the Gulf of Alaska and Hawaii, in part due to lower climate matches and the availability of other invasion vectors. PMID- 29395104 TI - Renal denervation as a second-line option in a patient with electrical storm resistant to medical treatment and conventional radiofrequency catheter ablation. AB - Electrical storm (ES) represents a critical state of electrical instability. We describe a patient with coronary artery disease, mechanical aortic valve replacement, and reduced left ventricular function with recurrent ICD shocks. Despite medical treatment with beta-blocker and amiodarone, and after successful ablation of different VT morphologies in combination with substrate modification, ES could not be controlled. We performed renal denervation (RDN) to reduce arrhythmic burden. Thereafter, patient remained free from sustained and non sustained VTs at 6-month follow-up. RDN is an effective second-line treatment option in patients in whom conventional catheter ablation and medical treatment failed to control the VTs. PMID- 29395103 TI - Performance variability on perceptual discrimination tasks in profoundly deaf adults with cochlear implants. AB - OBJECTIVES: The purpose of this study was to evaluate performance on two challenging listening tasks, talker and regional accent discrimination, and to assess variables that could have affected the outcomes. STUDY DESIGN: A prospective study using 35 adults with one cochlear implant (CI) or a CI and a contralateral hearing aid (bimodal hearing) was conducted. Adults completed talker and regional accent discrimination tasks. METHODS: Two-alternative forced choice tasks were used to assess talker and accent discrimination in a group of adults who ranged in age from 30 years old to 81 years old. RESULTS: A large amount of performance variability was observed across listeners for both discrimination tasks. Three listeners successfully discriminated between talkers for both listening tasks, 14 participants successfully completed one discrimination task and 18 participants were not able to discriminate between talkers for either listening task. Some adults who used bimodal hearing benefitted from the addition of acoustic cues provided through a HA but for others the HA did not help with discrimination abilities. Acoustic speech feature analysis of the test signals indicated that both the talker speaking rate and the fundamental frequency (F0) helped with talker discrimination. For accent discrimination, findings suggested that access to more salient spectral cues was important for better discrimination performance. CONCLUSIONS: The ability to perform challenging discrimination tasks successfully likely involves a number of complex interactions between auditory and non-auditory pre- and post-implant factors. To understand why some adults with CIs perform similarly to adults with normal hearing and others experience difficulty discriminating between talkers, further research will be required with larger populations of adults who use unilateral CIs, bilateral CIs and bimodal hearing. PMID- 29395105 TI - New formula for defining "normal" and "prolonged" QT in patients with bundle branch block. AB - OBJECTIVES: To predict the QT interval in the presence of normal QRS for patients with left bundle branch block (LBBB). BACKGROUND: There is no acceptable method for simple and reliable QT correction for patients with bundle branch block (BBB). METHODS: We measured the QT interval in patients with new onset LBBB who had a recent electrocardiogram with narrow QRS for comparison. 48 patients who developed in-hospital LBBB were studied. Patients who had similar heart rate before and after LBBB were included. We used linear regression, the Bogossian method, and our new fixed QRS replacement method to evaluate the most reliable correction method. RESULTS: JTc (QTc-QRS) interval was preserved before and after LBBB (328.9 +/- 25.4 ms before LBBB vs. 327.3 ms post LBBB (p = 0.550). Mean predicted preLBBB QTc difference was 1.3 ms, -21.3 ms and 1.6 ms for the three methods respectively (p < 0.001 for Bogossian comparison with the other methods). Coefficients of correlation (R) between actual preLBBB QTc with predicted preLBBB QTc were 0.707, 0.683 and 0.665 respectively (p > 0.3 for R comparisons between all methods). The average absolute difference in preLBBB QTc was 15.5 ms and 16.7 ms for the regression and fixed-gender methods (p value between the two = 0.321) and 25.5 ms for the Bogossian method, which was found to be significantly underperforming. CONCLUSIONS: In patients with LBBB, replacing of the QRS duration after deriving the QTc interval with a fixed value of 88 ms for female and 95 ms for male provides a simple and reliable method for predicting the QTc before the development of LBBB. PMID- 29395106 TI - Sickle cell disease; An overview of the disease and its systemic effects. PMID- 29395107 TI - Painter and scribe: From model of mind to cognitive strategy. AB - Since antiquity the mind has been conceived to operate via images and words. Pre scientific thinkers (and some scientific) who presented the mind as operating in such a way tended to i) bias one representational mode over the other, and ii) claim the dominance of the mode to be the case universally. The rise of empirical psychological science in the late 19th-century rehearses the word/image division of thought but makes universal statements - e.g., that recollection is a verbal process for everyone - untenable. Since then, the investigation of individual differences and case studies of imagery loss have shown rather that words and images present alternative cognitive "strategies" that individuals will be predisposed to employing - but which, should the necessity arise, can be relearned using the other representational mode. The following sketches out this historical shift in understanding, and concludes by inviting consideration of the wider context in which discussion of the relationships between 'images' and 'words' (as both internal and external forms of representation) must take place. PMID- 29395108 TI - Studying the complications of bariatric surgery with intravenous contrast enhanced multidetector computed tomography. AB - OBJECTIVE: To review the complications of bariatric surgery and their diagnosis with intravenous contrast-enhanced multidetector computed tomography (MDCT). MATERIAL AND METHODS: We retrospectively studied all patients who underwent gastric bypass or sleeve gastrectomy at our center during 2013 or 2014. We classified complications into early complications (appearing within 30 days of the intervention) and late complications. RESULTS: We reviewed 155 cases and found 24 complications in 22 patients: 16 early complications (7 intraperitoneal hematomas, 5 anastomotic dehiscences, 2 intestinal obstructions, and 2 external hernias) and 8 late complications (3 internal hernias, 3 intestinal perforations, and 2 marginal ulcers). Two patients died. All of these complications were diagnosed with intravenous contrast-enhanced MDCT, except one, which required a barium transit study. CONCLUSION: The rate of complications in bariatric surgery is high and the associated mortality is not negligible. Radiologists need to know the normal findings in these patients so they can quickly identify possible complications, most of which can be diagnosed with intravenous contrast-enhanced MDCT. PMID- 29395109 TI - Diagnostic performance of imaging-guided core needle biopsy of the mesentery and peritoneum. AB - OBJECTIVE: To evaluate the diagnostic performance of imaging-guided core needle biopsy of nodules and diffuse infiltration of the omentum or of the peritoneum. MATERIAL AND METHODS: We retrospectively evaluated 57 patients who underwent core needle biopsy of the peritoneum or of the omentum between March 2014 and January 2017. We used computed tomography (CT) to plan the biopsy. Biopsies were guided by CT or ultrasonography (US). We classified the results as diagnostic (benign / malignant) or inconclusive (inadequate sample). We calculated the sensitivity, specificity, positive-predictive value, and negative predictive value. We analyzed whether the specimen was diagnostic depending on the imaging technique used (CT or US) and on the type of omental or peritoneal involvement from which the specimen was obtained (mass, nodule, or diffuse involvement). RESULTS: All (100%) the percutaneous biopsies were diagnostic. The sensitivity of the technique was 98.18% and the specificity was 100%. The positive predictive value was 100% and the negative predictive value was 50%. Both the specimens obtained under CT guidance (n=10) and those obtained under US guidance (n=47) were diagnostic. Likewise, biopsies of masses (n=24), of nodules (n=17), and even of diffuse infiltration (n=16) of the peritoneum or omentum enabled the histologic diagnosis. The rate of complications was 1.75% (one death). CONCLUSION: Percutaneous core needle biopsy has high sensitivity regardless of the imaging technique used to guide the technique (CT or US) and of the type of lesion biopsied (mass, nodule, diffuse infiltration). It is a useful technique with a very low rate of complications, although severe complications can occur. PMID- 29395110 TI - Recruitment manoeuvres in anaesthesia: How many more excuses are there not to use them? AB - Pulmonary recruitment manoeuvres (RM) are intended to reopen collapsed lung areas. RMs are present in nature as a physiological mechanism to get a newborn to open their lungs for the first time at birth, and we also use them, in our usual anaesthesiological clinical practice, after induction or during general anaesthesia when a patient is desaturated. However, there is much confusion in clinical practice regarding their safety, the best way to perform them, when to do them, in which patients they are indicated, and in those where they are totally contraindicated. There are important differences between RM in the patient with adult respiratory distress syndrome, and in a healthy patient during general anaesthesia. Our intention is to review, from a clinical and practical point of view, the use of RM, specifically in anaesthesia. PMID- 29395111 TI - The structural proteins of epidemic and historical strains of Zika virus differ in their ability to initiate viral infection in human host cells. AB - Mosquito-borne Zika virus (ZIKV) recently emerged in South Pacific islands and Americas where large epidemics were documented. In the present study, we investigated the contribution of the structural proteins C, prM and E in the permissiveness of human host cells to epidemic strains of ZIKV. To this end, we evaluated the capacity of the epidemic strain BeH819015 to infect epithelial A549 and neuronal SH-SY5Y cells in comparison to the African historical MR766 strain. For that purpose, we generated a molecular clone of BeH819015 and a chimeric clone of MR766 which contains the BeH819015 structural protein region. We showed that ZIKV containing BeH819015 structural proteins was much less efficient in cell-attachment leading to a reduced susceptibility of A549 and SH-SY5Y cells to viral infection. Our data illustrate a previously underrated role for C, prM, and E in ZIKV epidemic strain ability to initiate viral infection in human host cells. PMID- 29395112 TI - Endoscopic Stapes Surgery. AB - The management of stapes fixation using transcanal endoscopic ear surgery is a viable alternative approach. The advantages of transcanal endoscopic ear surgery are improved visualization and illumination of the stapes and oval window regardless of the size and geometry of the external auditory canal. Footplate work and prosthesis placement pose significant but surmountable challenges using transcanal endoscopic ear surgery secondary to the lack of depth perception. Several recent studies demonstrate the efficacy and safety of transcanal endoscopic ear surgery. PMID- 29395113 TI - Clinical Evaluation of the Patient with Otosclerosis. AB - Otosclerosis is a disorder presenting most commonly with unilateral conductive hearing loss. It can present as a mixed hearing loss also. Evaluation for otosclerosis relies on a specific history and physical examination, including tuning fork assessment and audiometric testing. Otosclerosis differs from other etiologies in that symptoms of imbalance are rare, and the ear most commonly appears normal on otoscopy. PMID- 29395114 TI - Evaluation of Quality and Preparation Time of Retrograde Cavities in Root Canals Filled with GuttaCore and Cold Lateral Condensation Technique. AB - INTRODUCTION: The aim of this study was to measure the time consumed preparing retrograde cavities in root canals of maxillary molars filled using the GuttaCore (Dentsply Tulsa Dental Specialties, Tulsa, OK) technique and the cold lateral condensation technique (CLC) and to examine the quality of the root-end cavity preparation by ultrasonic tips using micro-computed tomographic (micro-CT) scanning. METHODS: A total of 24 maxillary molars were included; distobuccal and palatal canals were instrumented to size #40 and size #50, respectively. Teeth were randomly distributed into 2 experimental groups; half of the samples were filled with CLC, and half were filled with the GuttaCore technique. After 2 months, the apical 3 mm of each root apex was resected. A retrograde cavity was then prepared 3 mm deep into the root-end-filled canals using ultrasonic tips. The quality of the preparation was first confirmed by a surgical stereomicroscope, and the time required for the root-end preparation was recorded. After root-end cavity preparation, all samples were scanned by micro-CT scanning. RESULTS: There was no significant difference between the palatal and distobuccal canals in the time required to prepare a retrograde cavity. Less time was required in the GuttaCore group to remove all root filling material and finish the cavity preparation than in the CLC group (P < .05), especially in the palatal canals. Micro-CT results confirmed that all material was removed from the root-end cavities and the absence of microcracks. CONCLUSIONS: GuttaCore was removed in less time from root-end cavities than root filling performed with the CLC technique. No damage to the surrounding dentin was detected by micro-CT scanning in the 2 groups. PMID- 29395115 TI - Prevalence and Size of Periapical Radiolucencies Using Cone-beam Computed Tomography in Teeth without Apparent Intraoral Radiographic Lesions: A New Periapical Index with a Clinical Recommendation. AB - INTRODUCTION: The purpose of this study was to determine the prevalence and size of periapical radiolucencies using cone-beam computed tomographic (CBCT) imaging in teeth without apparent signs of intraoral radiographic lesions. METHODS: One hundred twenty roots from 53 patients who had been determined to have no signs of intraoral radiographic lesions were included in this study. Limited-volume CBCT scans were taken at 0.125-mm3 voxel size. The widest area of apical radiolucency of each root canal-treated tooth was measured and assigned a numeric score based on the CBCT-Endodontic Radiolucency Index (ERI). CBCT data were evaluated by 2 radiologists with an interclass correlation coefficient of 0.96. RESULTS: The majority of roots (53.3%) had periodontal ligament widths <=0.5 mm; 26.7% had radiolucency widths of 0.5 < x <= 1 mm, 15.0% had radiolucency widths of 1.0 < x <= 1.5 mm, 0.8% had radiolucency widths of 1.5 < x <= 2.0 mm, 1.7% had radiolucency widths of 2.0 < x <= 2.5 mm, and 2.5% had radiolucency widths of >2.5 mm. Patient age, recall interval, tooth type, and arch type had no statistically significant effect on the ERI distribution. CONCLUSIONS: Twenty percent of teeth with successful root canal treatment based on conventional periapical imaging had CBCT radiolucencies measuring greater than 1 mm. Because these radiolucencies may not be pathological changes, clinicians are cautioned against overtreatment of them before determining the true nature of these findings. Clinical studies with long follow-up times are needed to determine the proper course of actions for these cases. PMID- 29395116 TI - Optical coherence tomography in diagnosis and monitoring multiple sclerosis. AB - This paper presents application of optical coherence tomography (OCT) for diagnosis and monitoring of multiple sclerosis (MS). The peripapillary retinal nerve fibre layer thinning and the reduced total macular volume analysis are shown. With the course of the MS, the severity of these abnormalities increases which reflects the progressive degeneration of retinal ganglion cells and nerve fibres. The OCT parameters are sensitive, non-invasive indicators useful in assessing the progression of inflammation and neurodegeneration in MS. PMID- 29395117 TI - Letter to the Readership of the Polish Journal of Neurology and Neurosurgery. PMID- 29395118 TI - New Insights into Modes of GPCR Activation. AB - In classical G-protein-coupled receptor (GPCR) activation, GPCRs couple to a variety of heterotrimeric G proteins on the membrane and then activate downstream signaling pathways. More recently, GPCRs have been found to couple to different effector proteins, including different G protein subtypes and regulatory proteins, such as arrestins. Some novel modes of GPCR activation have been proposed to explain their complex behaviors. In this review, we summarize the main novel modes of GPCR activation, including biased activation, intracellular activation, dimerization activation, transactivation, and biphasic activation. In addition, we also discuss the relationship among the five modes to show the complex picture of GPCR activation. The complex activation modes regulate precisely GPCR downstream signaling, including physiological and pathological signaling. Thus, there is the potential to develop GPCR precision drugs that target precise GPCR activation modes to accurately strengthen their beneficial functions and block specific pathological processes. PMID- 29395119 TI - Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study). AB - PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged >=18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5+/-1.3, whereas in the PRP monotherapy group, it was 4.6+/-1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months. PMID- 29395120 TI - Blockage of spinal endothelin A receptors attenuates bone cancer pain via regulation of the Akt/ERK signaling pathway in mice. AB - Bone cancer pain (BCP) is a common source of pain in patients with advanced stage and metastatic cancer; however, existing treatment for this kind of pain remains deficient. Being closely related to sensory change and inflammatory pain in both the central and peripheral nervous systems, endothelin A receptor (ETAR) plays an essential role in pain processing. As a result, ETAR antagonist has been reported to alleviate both neuropathic and inflammatory pain. Thus far, the role of ETAR in the process of BCP is still ambiguous. In this study, by using a BCP mouse model, the analgesic effect and molecular mechanism of the ETAR antagonist BQ-123 was investigated. Pain sensation in the BCP mouse model was investigated by the number of spontaneous flinches (NSF) and pain withdrawal threshold (PWT), and the mechanism of BCP was assessed by measuring p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p ERK-1/2/t-ERK-1/2 levels in L4-6 segments of the spinal cord. Our results demonstrated that BCP mice showed a higher NSF and a lower PWT score than Sham mice. In addition to the development of nociceptive sensitization, p-Akt, p-Akt/t Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 were up-regulated correspondingly in L4-6 segments of the spinal cord in BCP mice. BQ-123 treatment showed a promising analgesic effect, and the effect was correlated to the down-regulation of p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 in spinal cord cells. The results suggested that intrathecal administration of BQ-123 was able to relieve BCP in mice as a consequence of suppressing the Akt and ERK signalling pathways. PMID- 29395121 TI - Prognostic role of the VeriStrat test in first line patients with non-small cell lung cancer treated with platinum-based chemotherapy. AB - OBJECTIVES: VeriStrat(r) is a blood-based test that utilizes matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry to assign a binary classification of VeriStrat Good or VeriStrat Poor that is associated with treatment outcomes in cancer patients. A number of other studies have shown an association between VeriStrat status and clinical outcomes in second and subsequent lines of therapy. The prognostic properties of VeriStrat were demonstrated in the placebo arms of two randomized studies in non-small cell lung cancer (NSCLC): TOPICAL and BR.21; the predictive properties of the test were shown in a prospective randomized phase III study PROSE in the second line treatment of NSCLC with erlotinib versus chemotherapy. Motivated by these observations, we sought to extend the clinical utility of VeriStrat to standard first line chemotherapy and evaluated the performance of the test in a number of clinical studies of patients treated with platinum-based regimens. MATERIALS AND METHODS: We examine the performance of VeriStrat in three independent clinical trials where the test classification was acquired for prospectively collected baseline samples from 481 patients treated with platinum-based chemotherapy in first line. RESULTS: Across these trials, 66-70% of patients were classified as VeriStrat Good; patients classified as VeriStrat Good had significantly longer progression-free survival and overall survival than VeriStrat Poor patients, with hazard ratios ranging from 0.36 to 0.72 and 0.26 to 0.51, respectively. These results demonstrated that VeriStrat is a strong prognostic test in NSCLC patients treated with platinum-based regimens in the first line. CONCLUSION: VeriStrat provides valuable clinical information that may be used to support patient physician conversations regarding prognosis and treatment options, and to identify a subset of patients who might benefit from other treatment strategies, possibly in the framework of clinical trials. PMID- 29395122 TI - Methodology and preliminary results of a systematic literature review of ante mortem and post-mortem diagnostic tests for bovine tuberculosis. AB - A systematic review was conducted to identify studies with data for statistical meta-analyses of sensitivity (Se) and specificity (Sp) of ante-mortem and post mortem diagnostic tests for bovine tuberculosis (bTB) in cattle. Members of a working group (WG) developed and tested search criteria and developed a standardised two-stage review process, to identify primary studies with numerator and denominator data for test performance and an agreed range of covariate data. No limits were applied to year, language, region or type of test in initial searches of electronic databases. In stage 1, titles and available abstracts were reviewed. References that complied with stage 1 selection criteria were reviewed in entirety and agreed data were extracted from references that complied with stage 2 selection criteria. At stage 1, 9782 references were reviewed and 261 (2.6%) passed through to stage 2 where 215 English language references were each randomly allocated to two of 18 WG reviewers and 46 references in other languages were allocated to native speakers. Agreement regarding eligibility between reviewers of the same reference at stage 2 was moderate (Kappa statistic = 0.51) and a resolution procedure was conducted. Only 119 references (published 1934 2009) were identified with eligible performance estimates for one or more of 14 different diagnostic test types; despite a comprehensive search strategy and the global impact of bTB. Searches of electronic databases for diagnostic test performance data were found to be nonspecific with regard to identifying references with diagnostic test Se or Sp data. Guidelines for the content of abstracts to research papers reporting diagnostic test performance are presented. The results of meta-analyses of the sensitivity and specificity of the tests, and of an evaluation of the methodological quality of the source references, are presented in accompanying papers (Nunez-Garcia et al., 2017; Downs et al., 2017). PMID- 29395123 TI - [Clinical-demographic factors associated with fear-avoidance in subjects with non specific chronic low back pain in Primary Care: secondary analysis of intervention study]. AB - OBJECTIVE: To describe some sociodemographics and clinical characteristics of subjects with Non-specific Chronic Low Back Pain (NCLBP) in Primary Care, as well as to investigate their association with Fear-Avoidance (FA). DESIGN: Cross sectional. Secondary analysis of an intervention study. LOCATION: Basic Health Areas in Costa del Sol Health District (Malaga, Spain). PARTICIPANTS: An analysis was performed on 147 subjects with NCLBP from a previous intervention study database in Primary Care Physiotherapy (PCP). Characteristics: age 18-65; understanding of the Spanish language; absence of cognitive disorders, fibromyalgia or dorsolumbar surgery, and to be able to perform physical exercise. MAIN MEASUREMENTS: The main variable was FA level (FABQ and the FABQ-PA and FABQ W) sub-scales. Clinical variables included: pain (NRPS-11), disability (RMQ), evolution, previous treatments and diagnostic imaging. The sociodemographic variables included: gender, age, educational level, and employment status. RESULTS: Just over half (51.7%) of the subjects had high FA on the FABQ-PA sub scale. Sick leave (SL) [beta=24.45 (P=.009*); beta=13.03 (P=.016*); beta=14.04 (P=.011*) for FABQ, FABQ-PA and FABQ-W, respectively]; primary studies level [beta=15.09 (P=.01*); beta=9.73 (P=.01*) for FABQ and FABQ-PA], and disability [beta=1.45 (P<.001); beta=0.61 (P<.001); beta=0.68 (P<.001) for FABQ, FABQ-PA and FABQ-W, respectively] were associated with FA when they were modeled by multivariate regression. CONCLUSIONS: Some sociodemographic and clinical features of the NCLBP population are presented. Imaging tests (81.63%) and previous passive treatments (55.78%) could reflect problems of adherence to recommendations of CPGs. Sick leave, primary studies level, and disability were associated with FA. The findings should be interpreted in the light of possible limitations. Some suggestions for clinical practice are provided. PMID- 29395124 TI - Hydraulic conductivity of soil-grown lupine and maize unbranched roots and maize root-shoot junctions. AB - Improving or maintaining crop productivity under conditions of long term change of soil water availability and atmosphere demand for water is one the big challenges of this century. It requires a deep understanding of crop water acquisition properties, i.e. root system architecture and root hydraulic properties among other characteristics of the soil-plant-atmosphere continuum. A root pressure probe technique was used to measure the root hydraulic conductances of seven-week old maize and lupine plants grown in sandy soil. Unbranched root segments were excised in lateral, seminal, crown and brace roots of maize, and in lateral roots of lupine. Their total hydraulic conductance was quantified under steady-state hydrostatic gradient for progressively shorter segments. Furthermore, the axial conductance of proximal root regions removed at each step of root shortening was measured as well. Analytical solutions of the water flow equations in unbranched roots developed recently and relating root total conductance profiles to axial and radial conductivities were used to retrieve the root radial hydraulic conductivity profile along each root type, and quantify its uncertainty. Interestingly, the optimized root radial conductivities and measured axial conductances displayed significant differences across root types and species. However, the measured root total conductances did not differ significantly. As compared to measurements reported in the literature, our axial and radial conductivities concentrate in the lower range of herbaceous species hydraulic properties. In a final experiment, the hydraulic conductances of root junctions to maize stem were observed to highly depend on root type. Surprisingly maize brace root junctions were an order of magnitude more conductive than the other crown and seminal roots, suggesting potential regulation mechanism for root water uptake location and a potential role of the maize brace roots for water uptake more important than reported in the literature. PMID- 29395125 TI - [The road to patient safety: facts and desire]. AB - OBJECTIVE: To evaluate differences between the need and degree of implementation of safe practices recommended for patient safety and to check the usefulness of traffic sign iconicity to promote their implementation. METHOD: The study was developed in two stages: 1) review of safe practices recommended by different organizations and 2) a survey to assess the perceptions for the need and implementation of them and the usefulness of signs to improve their implementation. The sample consisted of professionals from Spain and Latin America working in healthcare settings and in the academic field related to patient safety. RESULTS: 365 questionnaires were collected. All safe practices included were considered necessary (mean and lower limit of confidence interval over 3 out of 5 points). However, in six of the patient safety practices evaluated the implementation was considered insufficient: illegible handwriting, medication reconciliation, standardization of communication systems, early warning systems, procedures performed or equipment used only by trained people, and compliance with patient preferences at the end of life. Improve compliance of with hand hygiene and barrier precautions to prevent infections, ensure the correct identification of patients and the use of checklists are the four practices in which more than 75% of respondents found a high degree of consensus on the usefulness of traffic sings to broaden their use. CONCLUSION: The differences between perceived need and actual implementation in some safe practices indicate areas for improvement in patient safety. With this aim, the common language and the iconicity of traffic signs could constitute a simple instrument to improve compliance with safe practices for patient safety. PMID- 29395126 TI - [Research on faith-based interventions and faith-placed health interventions: current situation and perspectives in Latin America]. PMID- 29395127 TI - Robust sensorless vector control of an induction machine using Multiobjective Adaptive Fuzzy Luenberger Observer. AB - This paper presents an inherent speed estimation scheme associated to the Indirect Field Oriented Control in case of Induction motor sensorless control. Indeed, through the design of a Multiobjective Adaptive Fuzzy Luenberger Observer, the speed sensorless control issue even at low speed, the observer poles' assignment issues and the speed estimation's sensitivity to rotor resistance uncertainties issue are treated concurrently. First of all, the structure of the proposed Takagi-Sugeno adaptive observer is described. Secondly, based on Lyapunov theory, observer gains are designed and a fuzzy speed estimation scheme is provided. The design's objectives consist of minimizing the sensitivity of the proposed observer to rotor resistance uncertainties (using the L2 techniques) and to guarantee a specified observer dynamic performances through a D-stability analysis. The design conditions are formulated into Linear Matrix Inequalities terms. Finally, experiments are conducted to demonstrate the effectiveness of the proposed results regardless of uncertainties in the rotor resistance. PMID- 29395128 TI - Trajectory tracking for two-degree of freedom helicopter system using a controller-disturbance observer integrated design. AB - Trajectory tracking control for helicopters, which are widely used in severe situations such as military and rescue missions, is a challenging field of research. In helicopter system, the stability problem and predefined trajectories tracking are main challenges, especially in the presence of external disturbances and dynamic model uncertainties. Hence, a robust control design is needed for tracking the desired references. There has been a lot of motivation for solving these problems with simpler methods and also reducing the couplings in the helicopter system to achieve better performance, as the presented paper attempts to fill these gaps. This paper focuses on designing control laws for two-degree of freedom helicopter system while assuring the closed-loop stability. A nonlinear disturbance observer-based control (NDOBC) is designed for attenuating the effects of exogenous disturbances. Trajectory tracking controller and nonlinear disturbance observer are formulated in the form of two linear matrix inequality (LMI) problems. The closed-loop system stability, including controller and observer, is investigated by Lyapunov theorem. The effectiveness of the proposed design for tracking the trajectories (vertical flight and pitch angle rotor blade) and disturbance estimation is verified by simulation results. PMID- 29395129 TI - An efficient algorithm for low-order direct discrete-time implementation of fractional order transfer functions. AB - Fractional order systems become increasingly popular due to their versatility in modelling and control applications across various disciplines. However, the bottleneck in deploying these tools in practice is related to their implementation on real-life systems. Numerical approximations are employed but their complexity no longer match the attractive simplicity of the original fractional order systems. This paper proposes a low-order, computationally stable and efficient method for direct approximation of general order (fractional order) systems in the form of discrete-time rational transfer functions, e.g. processes, controllers. A fair comparison to other direct discretization methods is presented, demonstrating its added value with respect to the state of art. PMID- 29395130 TI - A simple tuning method of fractional order PIlambda-PDMU controllers for time delay systems. AB - In this paper, a practical tuning technique is presented to obtain all stabilizing fractional order PIlambda-PDMU controller parameters ensuring stability for processes with time delay using the stability boundary locus and the weighted geometrical center (WGC) methods. The method is based on obtaining of stability regions plotted by using the stability boundary locus in the (kd,kf) plane and (kp,ki)-plane, and then computing the weighted geometrical centers of these regions. After obtaining PDMU controller parameters using the WGC method from the stability region, desired PIlambda controller parameters are computed by the same procedure. This paper provides a simple and efficient tuning method to obtain stabilizing parameters of PIlambda-PDMU controller for time delay systems. The important advantages of the method are both calculating of controller parameters without using any complex solution methods and ensuring the stability of closed loop system. Illustrative examples are given to demonstrate the benefits and the simplicity of the proposed method. PMID- 29395131 TI - A new continuous sliding mode control approach with actuator saturation for control of 2-DOF helicopter system. AB - The 2-degree of freedom (DOF) helicopter system is a typical higher-order, multi variable, nonlinear and strong coupled control system. The helicopter dynamics also includes parametric uncertainties and is subject to unknown external disturbances. Such complicated system requires designing a sophisticated control algorithm that can handle these difficulties. This paper presents a new robust control algorithm which is a combination of two continuous control techniques, composite nonlinear feedback (CNF) and super-twisting control (STC) methods. In the existing integral sliding mode (ISM) based CNF control law, the discontinuous term exhibits chattering which is not desirable for many practical applications. As the continuity of well known STC reduces chattering in the system, the proposed strategy is beneficial over the current ISM based CNF control law which has a discontinuous term. Two controllers with integral sliding surface are designed to control the position of the pitch and the yaw angles of the 2- DOF helicopter. The adequacy of this specific combination has been exhibited through general analysis, simulation and experimental results of 2-DOF helicopter setup. The acquired results demonstrate the good execution of the proposed controller regarding stabilization, following reference input without overshoot against actuator saturation and robustness concerning to the limited matched disturbances. PMID- 29395132 TI - Distributed ESO based cooperative tracking control for high-order nonlinear multiagent systems with lumped disturbance and application in multi flight simulators systems. AB - Based on extended state observer, a novel and practical design method is developed to solve the distributed cooperative tracking problem of higher-order nonlinear multiagent systems with lumped disturbance in a fixed communication topology directed graph. The proposed method is designed to guarantee all the follower nodes ultimately and uniformly converge to the leader node with bounded residual errors. The leader node, modeled as a higher-order non-autonomous nonlinear system, acts as a command generator giving commands only to a small portion of the networked follower nodes. Extended state observer is used to estimate the local states and lumped disturbance of each follower node. Moreover, each distributed controller can work independently only requiring the relative states and/or the estimated relative states information between itself and its neighbors. Finally an engineering application of multi flight simulators systems is demonstrated to test and verify the effectiveness of the proposed algorithm. PMID- 29395133 TI - The Growth arrest specific 1 (Gas1) gene is transcriptionally regulated by NeuroD1 via two distal E-boxes. AB - Growth arrest specific 1 (GAS1) is a signaling mediator for the development of the central nervous system that works as a co-receptor for sonic hedgehog (SHH) to induce the amplification of neural progenitors during the patterning of the mammalian neural tube and establishing granular cells in the cerebellum. Recently, we confirmed that Gas1 is also expressed by neural progenitors of the developing cortex and the dentate gyrus of the hippocampus. The presence of GAS1 in progenitor stages indicates that one of its principal roles is the maintenance of these cells during neurogenic events. However, the signals responsible for the expression of Gas1 in progenitor cells are unknown, an aspect that is relevant to understand its functions during neurogenesis. Here, we focused on elucidating the mechanisms of the transcriptional regulation of Gas1 and using comparative genomics methods found two highly conserved E-boxes in the Gas1 promoter which mediate its up-regulation by NeuroD1. Additionally, we found that GAS1 and NeuroD1 co-localize in the neocortex, the dentate gyrus of the hippocampus and the external granular layer of the cerebellum, suggesting a previously unsuspected regulatory relationship. Our data indicate that Gas1 is a direct target of NeuroD1 during the induction of the neurogenic program. PMID- 29395134 TI - Mutation in KCNE1 associated to early repolarization syndrome by modulation of slowly activating delayed rectifier K+ current. AB - BACKGROUND: Recent studies have revealed that mutation in KCNE1, beta-subunits of cardiac potassium channel, involved in ventricular fibrillation. Whereas its role in early repolarization syndrome (ERS) is less well understood. OBJECTIVE: To study whether mutant in KCNE1 is associated with ERS and explore the possible underlying molecular mechanisms. METHODS: Whole genome from four unrelated families with ERS was amplified and sequenced. Wild-type (WT) KCNE1 and/or KCNE1 S38G (S38G) were expressed in HEK293 cells with KCNQ1. Functional studies included whole-cell patch-clamp, western blot and immunofluorescence were performed to reveal the possible underlying mechanisms. RESULTS: The co expression of KCNE1-S38G and KCNQ1 decreased tail current density of IKs but had little effect in modulation channel kinetics of IKs. Compared with KCNE1-WT, the expression and membrane location of KCNE1-S38G decreased. Co-expression of KCNE1 WT and KCNE1-S38G partially rescued the function of IKs channel. CONCLUSIONS: The S38G mutation induced a loss-of-function of IKs due to decreasing of KCNE1 protein expression and defecting in KCNE1 protein membrane trafficking. Our findings suggested that KCNE1 may be one of the possible modulatory genes associated to ERS. PMID- 29395135 TI - Genome-wide association analyses based on a multiple-trait approach for modeling feed efficiency. AB - Genome-wide association (GWA) of feed efficiency (FE) could help target important genomic regions influencing FE. Data provided by an international dairy FE research consortium consisted of phenotypic records on dry matter intakes (DMI), milk energy (MILKE), and metabolic body weight (MBW) on 6,937 cows from 16 stations in 4 counties. Of these cows, 4,916 had genotypes on 57,347 single nucleotide polymorphism (SNP) markers. We compared a GWA analysis based on the more classical residual feed intake (RFI) model with one based on a previously proposed multiple trait (MT) approach for modeling FE using an alternative measure (DMI|MILKE,MBW). Both models were based on a single-step genomic BLUP procedure that allowed the use of phenotypes from both genotyped and nongenotyped cows. Estimated effects for single SNP markers were small and not statistically important but virtually identical for either FE measure (RFI vs. DMI|MILKE,MBW). However, upon further refining this analysis to develop joint tests within nonoverlapping 1-Mb windows, significant associations were detected between either measure of FE with a window on each of Bos taurus autosomes BTA12 and BTA26. There was, as expected, no overlap between detected genomic regions for DMI|MILKE,MBW and genomic regions influencing the energy sink traits (i.e., MILKE and MBW) because of orthogonal relationships clearly defined between the various traits. Conversely, GWA inferences on DMI can be demonstrated to be partly driven by genetic associations between DMI with these same energy sink traits, thereby having clear implications when comparing GWA studies on DMI to GWA studies on FE like measures such as RFI. PMID- 29395136 TI - Combining genetic and physiological data to identify predictors of lifetime reproductive success and the effect of selection on these predictors on underlying fertility traits. AB - Fertility of the dairy cow relies on complex interactions between genetics, physiology, and management. Mathematical modeling can combine a range of information sources to facilitate informed predictions of cow fertility in scenarios that are difficult to evaluate empirically. We have developed a stochastic model that incorporates genetic and physiological data from more than 70 published reports on a wide range of fertility-related traits in dairy cattle. The model simulates pedigree, random mating, genetically correlated traits (in the form of breeding values for traits such as hours in estrus, estrous cycle length, age at puberty, milk yield, and so on), and interacting environmental variables. This model was used to generate a large simulated data set (200,000 cows replicated 100 times) of herd records within a seasonal dairy production system (based on an average New Zealand system). Using these simulated data, we investigated the genetic component of lifetime reproductive success (LRS), which, in reality, would be impractical to assess empirically. We defined LRS as the total number of times, during her lifetime, a cow calved within the first 42 d of the calving season. Sire estimated breeding values for LRS and other traits were calculated using simulated daughter records. Daughter pregnancy rate in the first lactation (PD_1) was the strongest single predictor of a sire's genetic merit for LRS (R2 = 0.81). A simple predictive model containing PD_1, calving date for the second season and calving rate in the first season provided a good estimate of sire LRS (R2 = 0.97). Daughters from sires with extremely high (n = 99,995 daughters, sire LRS = +0.70) or low (n = 99,635 daughters, sire LRS = -0.73) LRS estimated breeding values were compared over a single generation. Of the 14 underlying component traits of fertility, 12 were divergent between the 2 lines. This suggests that genetic variation in female fertility has a complex and multifactorial genetic basis. When simulated phenotypes were compared, daughters of the high LRS sires (HiFERT) reached puberty 44.5 d younger and calved ~14 d younger at each parity than daughters from low LRS sires (LoFERT). Despite having a much lower genetic potential for milk production (-400 L/lactation) than LoFERT cows, HiFERT cows produced 33% more milk over their lifetime due to additional lactations before culling. In summary, this simulation model suggests that LRS contributes substantially to cow productivity, and novel selection criteria would facilitate a more accurate prediction at a younger age. PMID- 29395137 TI - Tolerance to bovine clinical mastitis: Total, direct, and indirect milk losses. AB - The objectives of this paper were to estimate direct and indirect milk losses associated with mastitis. Indirect losses, linked to indirect tolerance, are mediated by the increase in milk somatic cell count (SCC) in response to bacterial infection. Direct losses, linked to weak direct tolerance, are not mediated by the increase in SCC. So far, studies have evaluated milk loss associated with clinical mastitis without considering both components, which may lead to biased estimates of their sum; that is, the total loss in milk. A total of 43,903 test-day records on milk and SCC from 3,716 cows and 5,858 lactations were analyzed with mediation mixed models and health trajectories to estimate the amount of direct, indirect, and total milk losses after adjustment for known and potentially unmeasured (sensitivity analyses) confounding factors. Estimates were formalized under the counterfactual causal theory of causation. In this study, milk losses were mostly mediated by an increase in SCC. They were highest in the first month of lactation, when SCC were highest. Milk losses were estimated at 0.5, 0.8, and 1.1 kg/d in first, second, and third and greater parity, respectively. Two phases described how changes in milk were associated with changes in SCC: on average, one occurred before and one after the day preceding the clinical diagnosis. In both phases, changes in milk were estimated at 1 mg/d per 103 cells/mL. After adjusting for known confounders, cow effect accounted for 20.7 and 64.2% of the variation in milk in the first and second phases, respectively. This suggests that deviations from the resilient path were highest during the second phase of inflammation and that selection for cows more tolerant to mastitis is feasible. As discussed herein, epigenetic regulation of macrophage polarization may contribute to the variation in milk observed in the second phase. PMID- 29395138 TI - Effect of pH on dissociation of casein micelles in yak skim milk. AB - The dissociation of yak casein (CN) micelles was evaluated by scanning electron microscopy, particle size, fluorescence properties, and soluble mineral and CN molecule content at pH 4.6 to 8.2. The results showed that the size of CN micelles remained constant with decreasing pH from 8.2 to 5.8 but sharply increased at pH <=5.4. Casein micelles began to aggregate at pH 5.4, and the serum magnesium, potassium, iron, zinc, copper, and manganese levels had their minimum values at this pH level. During acidification, colloidal calcium phosphate dramatically disassociated from yak CN micelles, but the soluble CN monomer content decreased slightly. During alkalization, the soluble calcium and phosphorus content decreased below pH 6.8 but increased with pH increases from 6.8 to 8.2. However, the soluble CN content increased markedly during alkalization. The emission wavelength of 8-anilino-1-naphthalenesulfonic acid sodium salt fluorescence decreased during both acidification and alkalization from pH 6.6, whereas the opposite was found for intrinsic fluorescence. PMID- 29395139 TI - Effects of feeding hulled and hull-less barley with low- and high-forage diets on lactation performance, nutrient digestibility, and milk fatty acid composition of lactating dairy cows. AB - The objective of this study was to evaluate lactation performance, nutrient digestibility, and milk fatty acid composition of high-producing dairy cows consuming diets containing hulled or hull-less barley as the grain source when feeding low-forage (LF) or high-forage (HF) diets. Eight primiparous (610 +/- 40 kg of body weight and 72 +/- 14 d in milk) and 16 multiparous (650 +/- 58 kg of body weight and 58 +/- 16 d in milk) Holstein cows were randomly assigned to 1 of 4 diets in a replicated 4 * 4 Latin square design with a 2 * 2 factorial arrangement of treatments and 21-d periods. Cows were assigned to squares based on parity (1, 2, and >=3) and days in milk. Diets were formulated to contain on a dry matter basis (1) 45% forage and hulled barley as the sole grain source, (2) 65% forage and hulled barley as the sole grain source, (3) 45% forage and hull less barley as the sole grain source, and (4) 65% forage and hull-less barley as the sole grain source. Dry matter intake tended to be lower for the diet with 65% forage and hulled barley than for the rest of the diets (24.4 vs. 26.6 kg/d). Neither the type of barley nor the forage-to-concentrate ratio affected milk yield (41.7 kg/d). Barley type did not affect milk fat or protein concentrations. Feeding LF diets decreased milk fat concentration from 3.91% to 3.50%. This decrease was less than anticipated and resulted in a 7% decrease in milk fat yield relative to cows consuming HF diets (1.60 and 1.49 kg/d for HF and LF diets, respectively). Feeding LF diets increased the concentration of C18:1 trans 10 in milk fat, suggesting that feeding LF diets may have marginally altered rumen function. In conclusion, LF diets containing barley grains can marginally decrease milk fat concentration. Overall, and based on the conditions of this study, there is limited evidence to anticipate a dramatic or acute milk fat depression when feeding hull-less barley as the grain source in diets for high producing dairy cows. PMID- 29395140 TI - Early-life events associated with first-lactation performance in pasture-based dairy herds. AB - This was a prospective cohort study to determine how events from birth until first calving affect performance during the first lactation in pasture-based dairy herds in Victoria, Australia. Events during the preweaning (0-84 d), prepubertal (85-473 d), and postpubertal (474-804 d) periods were recorded in 6 herds, and their association with first-lactation 100-d and 250-d total milk, fat, and protein yields was quantified. Predictors of first-lactation performance included passive transfer status as a calf; season of birth; age of dam; the presence or absence of dystocia at the time of the heifer's birth; the presence or absence of preweaning diarrhea; preweaning, prepubertal, and postpubertal average daily weight gain; age at first calving; the presence or absence of periparturient disease at first calving; sex of the first-born calf; the presence or absence of a stillborn calf at the first calving; and requirement of assistance at the first calving. Lactation performance was quantified using cumulative 100-d and 250-d milk, fat, and protein yields estimated from herd recording. A multivariable linear regression model was developed for each outcome: cumulative 100-d milk, fat, and protein yield and cumulative 250-d milk, fat, and protein yield. Heifers that experienced dystocia at the time of their birth produced 7.6 kg [95% confidence interval (CI): 1.8-13.3] less fat and 4.8 kg (95% CI: 0.6-8.9) less protein at 100 d in milk in the first lactation compared with heifers that were delivered without dystocia. Heifers born in the summer and autumn produced 20 L (95% CI: 0.8-40) more milk and 20 kg (95% CI: 5.9 33) more protein at 250 d in milk in the first lactation compared with heifers born in the spring. For 100 g/d increases in prepubertal average daily gain, heifers produced an additional 182 L (95% CI: 149-216) of milk, 4.1 kg (95% CI: 2.8-5.5) of fat, and 4.0 kg (95% CI 3.1-5.0) of protein at 100 d in milk and an additional 345 L (95% CI 264-425) of milk, 6.1 kg (95% CI 3.2-9.0) of fat, and 7.5 kg (95% CI 5.3-9.7) of protein at 250 d in milk. Postpubertal average daily gain was positively associated with 100-d milk yield and 250-d milk yield and protein production. We conclude that of all the growth periods assessed in this study, events that occurred during the prepubertal period (85-473 d of age) had the greatest effect on first-lactation performance. PMID- 29395141 TI - Evaluation of an ear-tag-based accelerometer for monitoring rumination in dairy cows. AB - The objective of this study was to evaluate the ear-tag-based accelerometer system Smartbow (Smartbow GmbH, Weibern, Austria) for detecting rumination time, chewing cycles, and rumination bouts in indoor-housed dairy cows. For this, the parameters were determined by analyses of video recordings as reference and compared with the results of the accelerometer system. Additionally, we tested the intra- and inter-observer reliability as well as the agreement of direct cow observations and video recordings. Ten Simmental dairy cows in early lactation were equipped with 10-Hz accelerometer ear tags and kept in a pen separated from herd mates. A total mixed ration was fed twice a day via a roughage intake control system. During the study, cows' rumination and other activities were directly observed for 20 h by 2 trained observers. Additionally, cows were video recorded for 19 d, 24 h a day. After exclusion of unsuitable videos, 2,490 h of cow individual 1-h video sequences were eligible for further analyses. Out of this, one hundred 1-h video sequences were randomly selected and visually and manually classified by a trained observer using professional video analyses software. Based on these analyses, half of the data was used for development (based on data of 50-h video analyses) and testing (based on data of additional 50-h video analyses) of the Smartbow algorithms, respectively. Inter- and intra observer reliability as well as the comparison of direct against video observations revealed in high agreements for rumination time and chewing cycles with Pearson correlation coefficients >0.99. The rumination time, chewing cycles, as well as rumination bouts detected by Smartbow were highly associated (r > 0.99) with the analyses of video recordings. Algorithm testing revealed in an underestimation of the average +/- standard deviation rumination time per 1-h period by the Smartbow system of 17.0 +/- 35.3 s (i.e., -1.2%), compared with visual observations. The average number +/- standard deviation of chewing cycles and rumination bouts was overestimated by Smartbow by 59.8 +/- 79.6 (i.e., 3.7%) and by 0.5 +/- 0.9 (i.e., 1.6%), respectively, compared with the video analyses. In summary, the agreement between the Smartbow system with video analyses was excellent. From a practical and clinical point of view, the detected differences were negligible. However, further research is necessary to test the system under various field conditions and to evaluate the benefit of incorporating rumination data into herd management decisions. PMID- 29395142 TI - Effects of reduced intramammary antimicrobial use during the dry period on udder health in Dutch dairy herds. AB - Dry cow therapy (DCT) in the Netherlands changed from mainly blanket to selective antimicrobial DCT. This transition was supported by a national guideline, with the individual somatic cell count (SCC) at the last milk recording before dry-off as the main selection criterion for antimicrobial DCT. The aim of this retrospective observational study is to evaluate the SCC dynamics during the dry period at the herd and individual dry period level following the national transition from mainly blanket to selective antimicrobial DCT. At the herd level, we used 2 data sets to evaluate the SCC dynamics during the dry period: (1) a national data set containing 3,493 herds with data available from 2011 through 2015 and (2) a veterinary practice data set containing 280 herds with data available from 2013 through 2015. The herd level analysis was carried out using key performance indicators provided via milk recording (CRV, Arnhem, the Netherlands): the percentage of cows that developed a new intramammary infection (IMI) during the dry period and the percentage of cows cured of an IMI during the dry period. The effect of DCT at individual dry period level was analyzed with a mixed-effects logistic regression model based on 4,404 dry periods from 2,638 cows in 20 herds within the veterinary practice data set. For these 20 herds, individual SCC data from milk recordings and individual cow DCT were available from 2013 through 2015. No significant changes were observed to the SCC dynamics during the dry period at the herd level. The percentage of cows that developed a new IMI during the dry period ranged between 16 and 18%, and the percentage of cows cured from an IMI during the dry period ranged between 74 and 76%. At the individual dry period level, a low SCC at the first milk recording following a dry period was associated with the use of intramammary antimicrobial DCT with or without the concurrent use of an intramammary teat sealer [odds ratio (OR) = 2.16 and OR = 2.07, respectively], the use of DCT with an intramammary teat sealer only (OR = 1.35), and a low SCC at the last milk recording before dry-off (OR = 1.78). This study demonstrates that the selection of cows for DCT without antimicrobials based on SCC thresholds at the last milk recording is possible without significant changes to udder health and reduced the use of antimicrobials. PMID- 29395143 TI - Long-term palmitic acid supplementation interacts with parity in lactating dairy cows: Production responses, nutrient digestibility, and energy partitioning. AB - The objective of our study was to evaluate the effects of long-term palmitic acid (C16:0) supplementation and parity on production, nutrient digestibility, and energy partitioning of mid-lactation dairy cows. Forty mid-lactation Holstein cows (18 primiparous and 22 multiparous) were used in a block design. Cows were assigned to receive either a control diet containing no supplemental fat (CON) or a C16:0-enriched supplemented diet (PA; 1.5% diet dry matter) fed for 10 wk. Compared with CON, PA increased dry matter intake, milk yield, cumulative milk yield, milk fat content, milk fat yield, 16-carbon milk fatty acid (FA) yield, 3.5% fat-corrected milk yield, and energy-corrected milk yield. Additionally, PA increased body weight change, but did not affect body condition score change compared with CON. A tendency for a treatment by parity interaction was observed for milk yield due to PA increasing milk yield in multiparous but not in primiparous cows. In addition, we observed interactions between treatment and parity for fat-corrected milk, energy-corrected milk, and milk fat yield due to PA increasing these variables to a greater extent in multiparous compared with primiparous cows. Interestingly, we observed an interaction between treatment and parity for body weight change, due to PA increasing body weight change in primiparous but not in multiparous cows. The PA treatment increased dry matter and neutral detergent fiber digestibilities compared with CON. Although PA did not affect 18-carbon FA digestibility, compared with CON, PA decreased 16-carbon and total FA digestibilities and increased total FA intake by 470 g/d and absorbed total FA by 316 g/d. We also observed an interaction between treatment and parity for total absorbed FA due to PA increasing it to a greater extent in multiparous than in primiparous cows. Compared with CON, PA increased apparent energy intake and milk energy output. We observed an interaction between treatment and parity for milk energy output due to PA increasing milk energy output to a greater extent in multiparous than primiparous cows. Additionally, an interaction between treatment and parity was observed for energy output in body reserves due to PA increasing energy output in body reserves in primiparous but not in multiparous cows. In conclusion, production responses of dairy cows to PA were consistent throughout the 10-wk treatment period. In addition, PA supplementation interacted with parity, with production responses increased to a greater extent in multiparous than primiparous cows and energy partitioned to body reserves only increased in primiparous cows. PMID- 29395144 TI - Hot topic: Ceramide inhibits insulin sensitivity in primary bovine adipocytes. AB - In nonruminants, the sphingolipid ceramide inhibits insulin sensitivity by inactivating protein kinase B (AKT) within the insulin-signaling pathway. We have established that ceramide accrual develops with impaired systemic insulin action in ruminants during the transition from gestation to lactation, dietary palmitic acid supplementation, or controlled nutrient restriction. We hypothesized that ceramide promotes AKT inactivation and antagonizes insulin sensitivity in primary bovine adipocytes. Stromal-vascular cells were grown from bovine adipose tissue explants and cultured in differentiation media. To modify ceramide supply, we treated differentiated adipocytes with (1) myriocin, an inhibitor of de novo ceramide synthesis, or (2) cell-permeable C2:0-ceramide. Insulin-stimulated AKT activation (i.e., phosphorylation) and 2-deoxy-D-[3H]-glucose (2DOG) uptake were measured. Treatment of adipocytes with myriocin consistently decreased concentrations of ceramide, monohexosylceramide, and lactosylceramide. The insulin-stimulated ratio of phosphorylated AKT to total AKT was increased with myriocin but decreased with C2:0-ceramide. Moreover, adipocyte insulin-stimulated 2DOG uptake was decreased with C2:0-ceramide and increased with myriocin. We conclude that ceramide inhibits insulin-stimulated glucose uptake by downregulating AKT activation in primary bovine adipocytes. PMID- 29395145 TI - Symposium review: Reduction in oocyte developmental competence by stress is associated with alterations in mitochondrial function. AB - Stress can affect reproductive performance of lactating cows by targeting the ovarian pool of follicles and their enclosed oocytes. Among the documented stressors are heat stress (i.e., high temperature-humidity index) as well as environmental and food toxins. Oocytes collected during the hot season are of lower quality than those collected in the winter, expressed by reduced oocyte maturation and developmental competence. A similar pattern has been reported for oocytes exposed to endocrine-disrupting chemicals. Whereas the underlying mechanism might differ among stressors, accumulating evidence suggests that stress-induced impairment of oocyte developmental competence involves alterations in mitochondrial functioning. Within the oocyte, mitochondria are involved in ATP generation, calcium homeostasis, regulation of cytoplasmic reduction-oxidation, signal transduction, and apoptosis. Summer heat stress is strongly associated with alterations in mitochondrial distribution and alterations in mitochondria membrane potential. Heat stress impairs the expression of mitochondrion associated genes, in particular those related to mitochondrial DNA transcription and replication and encoding oxidative phosphorylation complexes for ATP production. Reduction of ATP levels below the required threshold is suggested to compromise the progression of oocyte maturation and, subsequently, embryonic development. Another mechanism associated with mitochondrial function is the increase in reactive oxygen species (ROS), which has been documented in oocytes exposed to heat stress or environmental toxicants. Oxidative phosphorylation in mitochondria is the major source of ROS. Under physiological conditions, ROS are essential for nuclear maturation; however, disequilibrium between ROS production and antioxidative capacity might lead to DNA damage and apoptosis. The current review provides new insights into the oocyte's cellular and molecular responses to stress with an emphasis on the mitochondria. It discusses some strategies to mitigate the effects of stress on the mitochondria, such as incorporation of coenzyme Q10-a key component of the mitochondrial respiratory chain administration of antioxidants, and injection of healthy mitochondria. Exploring the oocyte's cellular and molecular responses, in particular that of the mitochondria, might lead to the development of new strategies to mitigate the effects of various stressors on fertility. PMID- 29395146 TI - Short communication: Methicillin-resistant Staphylococcus aureus in conventional and organic dairy herds in Germany. AB - Methicillin-resistant Staphylococcus aureus (MRSA) have been described repeatedly in dairy herds. In this study, we compared the prevalence and antimicrobial resistance of MRSA in bulk tank milk from conventional and organic dairy herds in Germany. Samples were collected from 372 conventional and 303 organic dairy herds throughout Germany. Bulk tank milk (25 mL) was tested for MRSA using an established double selective enrichment method. The MRSA isolates were typed using spa typing and tested for resistance to 19 antimicrobials using the broth microdilution method. Methicillin-resistant Staph. aureus was detected more frequently in bulk tank milk from conventional (9.7%) than from organic (1.7%) dairy herds. Herd size and region were associated with differences in prevalence. Most isolates (38/41) were from spa types associated with the livestock associated clonal complex CC398. Isolates from conventional herds tended to be more resistant to antimicrobials; however, because of the limited number of isolates from organic herds, no statistical tests were performed. In conclusion, prevalence of MRSA in dairy herds in Germany seems to be increasing and is more prevalent in regions with high livestock density. Organic herds are also affected although at a lower level. Therefore, MRSA should be specifically included in biosecurity protocols for dairy herds, and effective control measures need to be investigated. PMID- 29395147 TI - Bacterial and fungal communities, fermentation, and aerobic stability of conventional hybrids and brown midrib hybrids ensiled at low moisture with or without a homo- and heterofermentative inoculant. AB - We evaluated the effects of adding a combination inoculant to 4 corn (Zea mays L.) hybrids harvested at low moisture on the nutritive value, fermentation profile, aerobic stability, bacterial and fungal populations, and community structure. The treatment design was the factorial combination of 4 corn hybrids ensiled with (INO) and without (CON) inoculant. The hybrids were TMF2R737 (MCN), F2F817 (MBR), P2089YHR (PCN), and PI144XR (PBR), ensiled at 44.0, 38.1, 42.0, and 41.3% of dry matter, respectively; MBR and PBR were brown midrib mutants. The inoculant contained Lactobacillus buchneri and Pediococcus pentosaceus (4 * 105 and 1 * 105 cfu/g of fresh corn). The experimental design was a complete randomized design with treatments replicated 6 times. Corn was chopped, treated or not with inoculant, packed into 7.6-L bucket silos, and stored for 100 d. At d 0, we found higher bacterial observed operational taxonomic units in the brown midrib mutants (MBR and PBR) relative to MCN and PCN (654 and 534 vs. 434 and 444 +/- 15.5, respectively). The bacterial and fungal families with the highest relative abundance (RA) were Enterobacteriaceae (61.4%) and incertae sedis Tremellales (12.5%). At silo opening, we observed no effects of INO treatment on dry matter recovery (~94.3 +/- 1.07%), but aerobic stability was extended for all INO-treated hybrids (~217 vs. ~34.7 h), except for MBR (~49 +/- 38 h), due to a decreased yeast population (3.78 vs. 5.13 +/- 0.440 log cfu/g of fresh corn) and increased acetic acid concentration (1.69 vs. 0.51 +/- 0.132%) compared with the control. Furthermore, INO treatment reduced bacterial (61.2 vs. 276 +/- 8.70) and increased fungal (59.8 vs. 43.6 +/- 2.95) observed operational taxonomic units compared with CON. We observed that INO treatment increased the RA of Lactobacillaceae across all hybrids (~99.1 vs. ~58.9), and to larger extent MBR (98.3 vs. 34.3 +/- 5.29), and decreased Enterobacteriaceae (0.614 vs. 23.5 +/- 2.825%) among 4 other bacterial families relative to CON. For fungi, INO treatment increased the RA of Debaryomycetaceae (63.1 vs. 17.3 +/- 8.55) and 5 other fungal families and decreased the RA of Pichiaceae (6.47 vs. 47.3 +/- 10.95) and incertae sedis Saccharomycetales (8.47 vs. 25.9 +/- 5.748) compared with CON. The bacterial and fungal community structures changed, due to ensiling, to a distinct and more stable community dominated by Lactobacillaceae and Debaryomycetaceae, respectively, when INO treatment was applied relative to CON. In conclusion, the INO treatment used in this study improved low-moisture whole crop corn silage quality because of a shift in the bacterial and fungal community composition during ensiling. PMID- 29395148 TI - Symposium review: Lactococcus lactis from nondairy sources: Their genetic and metabolic diversity and potential applications in cheese. AB - The widespread dissemination of species of the lactic acid bacteria (LAB) group in different environments testifies to their extraordinary niche adaptability. Members of the LAB are present on grass and other plant material, in dairy products, on human skin, and in the gastrointestinal and reproductive tracts. The selective pressure imparted by these specific environments is a key driver in the genomic diversity observed between strains of the same species deriving from distinct habitats. Strains that are exploited in the dairy industry for the production of fermented dairy products are often referred to as "domesticated" strains. These strains, which initially may have occupied a nondairy niche, have become specialized for growth in the milk environment. In fact, comparative genome analysis of multiple LAB species and strains has revealed a central trend in LAB evolution: the loss of ancestral genes and metabolic simplification toward adaptation to nutritionally rich environments. In contrast, "environmental" strains, or those from raw milk, plants, and animals, exhibit diverse metabolic capabilities and lifestyle characteristics compared with their domesticated counterparts. Because of the limited number of established dairy strains used in fermented food production today, demand is increasing for novel strains, with concerted efforts to mine the microbiota of natural environments for strains of technological interest. Many studies have concentrated on uncovering the genomic and metabolic potential of these organisms, facilitating comparative genome analysis of strains from diverse environments and providing insight into the natural diversity of the LAB, a group of organisms that is at the core of the dairy industry. The natural biodiversity that exists in these environments may be exploited in dairy fermentations to expand flavor profiles, to produce natural "clean label" ingredients, or to develop safer products. PMID- 29395149 TI - An immunohistochemical analysis of the effects of androgen receptor knock out on gubernacular differentiation in the mouse. AB - AIM: Cryptorchidism affects 2%-4% of newborn boys and causes infertility and cancer. While normal androgen function is required for successful inguinoscrotal descent, its exact role on gubernacular morphology remains unidentified. We aimed to decipher the effect of androgen blockade on the gubernaculum and surrounding structures. METHODS: Genetically modified mice with androgen receptor knock out (ARKO) were sectioned at ages E17, D0, and D2 for immunohistochemical analysis and D4 for morphological analysis (with ethical approval; A644). Mutants and control littermates were labeled with Ki67, Desmin, and Pax7 to identify the degree of gubernaculuar eversion and the composition of the growth center in the gubernaculum, using light or confocal microscopy. RESULTS: Androgen blockade prevented gubernacular eversion in all animals aged between E17 and D2 when compared to wild types. Furthermore, a growth center was visible, as indicated by a 'swirl' of immature fibroblasts, in D2 animals but was absent in ARKO mice. Moreover, the gubernacular cord was seen to increase in ARKO mice when compared to wild types and increased in size with age. There were no labeling differences in the antibodies tested for gubernacular differentiation. CONCLUSION: Gubernacular eversion in rodents prior to inguinoscrotal migration was androgen dependent, as well as maintenance of gubernacular cord length. This study shows that androgen blockade causes cryptorchidism in mice by preventing gubernacular eversion and possibly by preventing shortening of the gubernacular cord. Altering the morphology of the gubernaculum in response to androgen clearly contributes to the clinical problem of cryptorchidism. PMID- 29395150 TI - Does application of topical steroids for lichen sclerosus (balanitis xerotica obliterans) affect the rate of circumcision? A systematic review. AB - PURPOSE: To determine whether treatment of lichen sclerosus et atrophicus (LS), with topical steroids reduces the rate of circumcision. METHODS: Two independent reviewers performed a literature search of studies reporting treatment of LS with topical steroids using EMBASE and MEDLINE database(s). INCLUSION CRITERIA: boys aged 0-18 years, clinical diagnosis of LS, treatment with topical steroids. Literature reviews, studies of phimosis without LS and adult patients were excluded. Data analysed for each paper included age, duration of treatment, length of follow up and outcome, notably circumcision or no surgery. RESULTS: The original search identified 26 titles. Application of exclusion criteria left 6 articles for inclusion in the study. Eighty nine patients with LS were treated with topical corticosteroids. Circumcision was avoided in 31/89 (35%; range 0 100%). Median patient age was 6.5 years (1 month-15 years). Median duration of treatment was 2 months (1-23 months); median follow-up 4 months (6 weeks-5 years). CONCLUSIONS: Treatment of LS with topical steroids reportedly avoided circumcision in 35% of boys. Duration of medical therapy and patient follow up in analysed studies were, however, short. A prospective randomised trial would provide a definitive answer. TYPE OF STUDY: Systematic review. LEVEL OF EVIDENCE: III. PMID- 29395151 TI - Outcome of initially nonoperative treatment for acute simple appendicitis in children. AB - PURPOSE: To compare the outcome of initially nonoperative treatment with immediate appendectomy for simple appendicitis in children. METHODS: Between September 2012 and June 2014 children aged 7-17 years with a radiologically confirmed simple appendicitis were invited to participate in a multicentre prospective cohort study in which they were treated with an initially nonoperative treatment strategy; nonparticipants underwent immediate appendectomy. In October 2015, their rates of complications and subsequent appendectomies, and health-related quality of life (HRQOL) were assessed. RESULTS: In this period, 25 children were treated with an initially nonoperative treatment strategy and 19 with immediate appendectomy; median (range) follow-up was 25 (16-36) and 26 (17-34) months, respectively. The percentage [95%CI] of patients experiencing complications in the initially nonoperative group and the immediate appendectomy group was 12 [4-30]% and 11 [3-31]%, respectively. In total 6/25 children (24%) underwent an appendectomy; none of the 6 patients operated subsequently experienced any postappendectomy complications. Overall, HRQOL in the nonoperative treatment group was similar to that of healthy peers. CONCLUSIONS: Outcome of initially nonoperative treatment for acute simple appendicitis in children is similar to the outcome in those who undergo immediate appendectomy. Initially nonoperative management seems to be able to avoid appendectomy in 3 out of 4 children. LEVEL OF EVIDENCE: 2 (prospective comparative study). This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. PMID- 29395152 TI - Controversies in the management of ovarian tumours in prepubertal children - A BAPS and UK CCLG Surgeons Cancer Group National Survey. AB - BACKGROUND: No clear treatment and follow-up protocols have been established for prepubertal patients with ovarian tumours. The lack of adequate prospective data in the literature includes all aspects of their management. A significant number of children with ovarian masses present out of hours as a surgical emergency and are initially managed by paediatric surgeons without special interest in surgical oncology. Clear guidance on the management of such tumours is therefore fundamental. We hypothesised that - owing to the lack of clear guidelines - the current approach to prepubertal ovarian tumours amongst paediatric surgeons is highly heterogenous. METHODS: An eleven-item multiple choice questionnaire was distributed amongst all BAPS consultant paediatric surgeons in the UK and simultaneously to all paediatric surgical oncology members of the UK Children's Cancer and Leukaemia Group in order to survey the management of ovarian masses in children. We aimed to compare the management approaches in both groups. RESULTS: 63 consultants participated in the survey; 49% with a special interest in surgical oncology, 48% with different subspecialty interests. The majority of participants (56%) performed 1-5 operations on ovarian tumours per year. Preoperative imaging of choice for the oncology surgeons was US and MRI (77.3%) versus 41.4% in the group of surgeons with different special interests. Surgeons with different special interests were more likely to request Ca125 as a preoperative tumour marker (62.1% vs 32.3%). 19.3% of oncology surgeons, and 27.6% of surgeons with other special interest stated they would never remove an ovarian tumour via the laparoscopic approach. Follow-up practise was highly variable amongst survey participants in both surgeon groups regarding frequency, duration and further investigations during follow-up. Almost 50% of participants follow their patients up according to personal practice protocols. CONCLUSION: This first national survey on the management of prepubertal ovarian tumours demonstrates great heterogeneity in the current approach amongst UK paediatric surgeons. Better evidence is needed to formulate clear guidance for the management of such tumours. We propose instigation of a multicentre registry for ovarian tumours to generate prospective data and clarify guidance for the future. LEVEL OF EVIDENCE STATEMENT: This is a level II evidence study. In itself it is a retrospective study, with the literature review including one large, high-quality prospective cohort study, and further prospective cohort studies of ordinary quality. PMID- 29395153 TI - Elongation of esophageal segments by bougienage stretching technique for long gap esophageal atresia to achieve delayed primary anastomosis by thoracotomy or thoracoscopic repair: A first experience from China. AB - OBJECTIVES: The treatment of long gap esophageal atresia (LGEA) is one of the most challenging congenital malformations in neonatal surgery. A preoperative bougienage stretching technique for elongation of the two segments of esophagus is applied to achieve utilizing the native esophagus to establish esophageal continuity by open or thoracoscopic approach. METHODS: From January 2015 to May 2017, 12 neonates who suffered from LGEA were admitted to our department. They were divided into 2 groups (A and B) according to their admission time. They all accepted bougienage stretching technique before esophageal anastomosis. RESULTS: Initially the lengths of esophageal gap in 12 infants ranged from 4 to 7.5 vertebral bodies (M=5.8+/-1.1). The gap lengths became -1 to 2.5 vertebral bodies after bougienage stretching technique and tension-free anastomosis were performed successfully for all 12 cases: Group A (n=5) by thoracotomy and group B (n=7) by thoracoscopic approach. 12 cases have been followed up for 1-25 months (M=12.4+/ 8.5) after definitive surgery. CONCLUSIONS: Bougienage stretching technique for LGEA is feasible with satisfactory clinical results. Thoracoscopic approach is a good choice for primary anastomosis in LGEA. LEVELS OF EVIDENCE: Treatment Study Level IV. PMID- 29395154 TI - Botulinum toxin injection for childhood constipation is safe and can be effective regardless of anal sphincter dynamics. AB - BACKGROUND: Childhood constipation is common. Previously, internal anal sphincterotomy has been used for hypertensive/non-relaxing sphincters; however, recent benefit has been shown with Botulinum Toxin (BT) injections. The aim is to investigate BT, including response duration, symptom association and effectiveness in relation to sphincter dynamics. METHODS: Retrospective study of 164 children receiving sphincter BT for severe constipation unresponsive to medication management. Charts reviewed for symptoms, anorectal manometry (ARM) findings and response defined by decreased pain or increased defecation. Patients were grouped: normal sphincter pressure (<=50 mmHg), elevated (>50 mmHg), normal and abnormal rectoanal inhibitory reflex (RAIR). RESULTS: There were 142 analyzed and 124 completed ARMs; 98 (70%) had positive response with 57% lasting greater than 6 months. 36 had normal sphincter pressure with 24 (69%) responding. 88 had elevated pressure with 60 (68%) responding (p=0.87). 90 normal RAIRs with 64 (71%) responding. 34 abnormal RAIRs with 22 (64%) responding (p=0.41). With logistic regression, fecal incontinence prior to BT was a predictor of poor response (p= 0.02). The most common side effect was fecal incontinence typically resolving within week with equal frequency regardless of sphincter dynamics. CONCLUSIONS: BT is effective for children with chronic constipation. Patients with fecal incontinence are less likely to respond. More than half had prolonged beneficial response. Those with normal and abnormal sphincter dynamics had similar responses and without differences in side effects. Therefore, injection may be considered in patients with intractable constipation unresponsive to medication, regardless of anal sphincter dynamics. LEVEL OF EVIDENCE: Level III (Treatment Study: Retrospective comparative study). PMID- 29395155 TI - Expanding the use of polymeric ionic liquids in headspace solid-phase microextraction: Determination of ultraviolet filters in water samples. AB - Three crosslinked polymeric ionic liquid (PIL) sorbent coatings were used in headspace solid-phase microextraction for the determination of a group of ultraviolet filters. The developed crosslinked PIL-based materials include two polycations and a double confined PIL. The method, in combination with gas chromatography-mass spectrometry, is simple, solvent free, and does not require of any derivatization step. After proper optimization of the methodologies with each developed fiber, the analytical performance was compared with a commercial polyacrylate fiber. A study of the normalized calibration slopes, obtained by dividing the calibration slope of each analyte by the coating volume, revealed that the crosslinked fibers can be used as alternatives to commercial fibers for the determination of the selected group of compounds. In particular, the coating nature of the PIL containing the 1-vinylbenzyl-3-hexadecylimidazolium bis[(trifluoromethyl)sulfonyl]imide IL as monomer and the 1,12-di(3 vinylbenzylimidazolium)dodecane bis[(trifluoromethyl)sulfonyl]imide IL as crosslinker is the most suitable for the extraction of the selected compounds despite their coating volume, being 3.6 times lower than the commercial polyacrylate fiber. For this fiber, wide linear ranges, correlation coefficients higher than 0.990, limits of detection ranging from 2.8 ng L-1 to 26 ng L-1 and relative standard deviations ranging from 2.5 to 15% were achieved. Finally, all proposed PIL-based fibers were applied towards the analysis of tap water, pool water and lake water, with the majority of the ultraviolet filters being detected and quantified in the last two types of samples. PMID- 29395156 TI - Determination of adsorbable organic halogens in surface water samples by combustion-microcoulometry versus combustion-ion chromatography titration. AB - Adsorbable Organic Halogen (AOX) is an analytical parameter of considerable interest since it allows to evaluate the amount of organohalogen disinfection by products (OXBPs) present in a water sample. Halogen speciation of AOX into adsorbable organic chlorine, bromine and iodine, respectively AOCl, AOBr and AOI, is extremely important since it has been shown that iodinated and brominated organic by-products tend to be more toxic than their chlorinated analogues. Chemical speciation of AOX can be performed by combustion-ion chromatography (C IC). In the present work, the effectiveness of the nitrate wash according to ISO 9562 standard method protocol to eliminate halide ions interferences was firstly examined. False positive AOX values were observed when chloride concentration exceeded 100 ppm. The improvements made to the washing protocol have eliminated chloride interference for concentrations up to 1000 ppm. A C-IC method for chemical speciation of AOX into AOCl, AOBr, and AOI has been developed and validated. The most important analytical parameters were investigated. The following optimal conditions were established: an aqueous solution containing 2.4 mM sodium bicarbonate/2.0 mM sodium carbonate, and 2% acetone (v/v) as mobile phase, 2 mL of aqueous sodium thiosulfate (500 ppm) as absorption solution, 0.2 mL min-1 as water inlet flow rate for hydropyrolysis, and 10 min as post combustion time. The method was validated according to NF T90-210 standard method. Calibration curves fitted through a quadratic equation show coefficients of determination (r2) greater than 0.9998, and RSD less than 5%. The LOQs were 0.9, 4.3, and 5.7 MUg L-1 Cl for AOCl, AOBr, and AOI, respectively. The accuracy, in terms of relative error, was within a +/- 10% interval. The applicability of the validated method was demonstrated by the analysis of twenty four water samples from three rivers in France. The measurements reveals AOX amounts above 10 MUg L-1 Cl in all untreated samples, suggesting the presence of organohalogen compounds in the sampled rivers. On weight concentration basis, AOCl accounted for 77-100% of AOX in the treated water samples. A good agreement between the conventional AOX method and the developed C-IC method was found. PMID- 29395157 TI - Global profiling combined with predicted metabolites screening for discovery of natural compounds: Characterization of ginsenosides in the leaves of Panax notoginseng as a case study. AB - Liquid chromatography-mass spectrometry (LC-MS) guided isolation is a favored strategy to quickly and efficiently explore the chemical diversity of herbal medicines. In this study, two methods were adopted to improve the performance of the strategy, including offline two-dimensional (2D) LC to extend the peak capacities and predicted metabolites screening (PMS) to automatically screen the targets with expanded databases. Ginsenosides in the leaves of Panax notoginseng (PNL) were taken as a case. An offline 2D LC system was constructed with an orthogonality of 0.69 and peak capacity of 8925. Quadrupole time-of-flight mass spectrometry-fast data directed analysis (QTOF-Fast DDA) was employed for detection of the ginsenosides in the fractioned samples. Four modified groups, including glucose, xylose, rhamnose and malonyl, were adopted and markedly extended the screening coverage. The combined strategy showed about 7.5 times improvement in the screening capability. PMS is conveniently and automatically implemented in UNIFI. Using this strategy, 945 ginsenosides were discovered from PNL, including 662 potentially novel ginsenosides. Furthermore, two new ginsenosides were purified, and unambiguously identified by NMR analysis, partially demonstrating the LC-MS guided isolation. The combined strategy can also be applied in characterizing and discovering new bioactive constituents from other herbal medicines. PMID- 29395158 TI - Determination of free thyroid hormones in animal serum/plasma using ultrafiltration in combination with ultra-fast liquid chromatography-tandem mass spectrometry. AB - Thyroid hormones (THs), which mainly consist of 3, 3', 5-triiodo-l-thyronine (T3) and L-thyroxine (T4), play a critical role in regulating biological processes such as growth and metabolism in various animal species. Thus, accurate measurement of T3 and T4, especially physiologically active free (protein unbound) forms, in serum/plasma is needed for the evaluation of TH homeostasis. However, such high-precision determination of free THs is lacking for non-human species. The present study aimed to develop a highly sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of six free THs in serum/plasma, which is applicable to not only humans but also non-human species. Two different physical separation steps, ultrafiltration (UF) and equilibrium dialysis (ED), were examined to obtain the free TH fraction. Several experimental conditions were carefully optimized and validated for UF or ED using the commercially available bovine serum. As a result, UF at 1100 * g and 37 degrees C for 30 min with a 30 kDa ultrafiltration device (Centrifree YM-30, Millipore) yielded excellent precision (CV: <10%). The optimized ED step also yielded high precision (CV: <10%) and the measurement values were approximately equal to those of UF, but at least 16 h were required to reach equilibrium. Thus, UF combined with LC-MS/MS was finally chosen, in terms of the time needed for the measurement. Acceptable accuracy (recovery: 70% 110%) and intra- and inter-day precision (CV: <10% and <12%, respectively) were obtained, when triplicate analyses in three different days were conducted using the bovine serum. The developed analytical method was successfully applied to the determination of free THs in serum/plasma samples of humans, cats, and dogs. Furthermore, comparison with free T4 concentrations measured by a common immunoassay method evidently indicated that the ultrafiltration-LC-MS/MS method developed in this study can increase the specificity and accuracy of TH measurement. PMID- 29395159 TI - Assessment study of ion-exchange chromatography combined with solution X-ray scattering measurement for protein characterization. AB - The performance of ion-exchange chromatography combined with small-angle X-ray scattering measurement was evaluated by characterization of the hen egg white lysozyme as a model protein. The X-ray transmittance was estimated using a micro ionization chamber equipped with a sample cell holder for the real-time monitoring of the X-ray beam strength through the salt gradient elution. The radius of gyration of the eluted protein was estimated to be 1.50 +/- 0.06 (n = 3) nm and 1.4 +/- 0.1 nm as the value at the zero protein concentration. By using the X-ray transmittance values for the scattering intensity correction, the molecular weight of the eluted protein was estimated to be 15,200 +/- 500 (n = 3) and 14,400 +/- 200 as the value at the zero protein concentration. These values are close to those of the monomer of this protein. The ion-exchange chromatography combined with the small-angle X-ray scattering measurement system equipped with the X-ray transmittance monitor is a reliable method for protein characterization in solution. PMID- 29395160 TI - Effect of salts on retention in hydrophilic interaction chromatography. AB - There is a widespread belief that salts promote retention of solutes in hydrophilic interaction chromatography (HILIC) by expanding the volume of the immobilized layer of water on the surface of the stationary phase. To date, all studies of this premise have had flaws or limitations that left the question open. This study explored the effects of salt type and concentration. The effect of the anion was studied with four triethylammonium salts, ranging from the kosmotropic sulfate to the chaotropic perchlorate, at pH values of both 3 and 6. Concentrations ranged from 5-120 mM. All analytes were neutral except for cytosine and cytidine, which had (+) charge at pH 3. Sulfate markedly promoted retention of cytosine, cytidine and phloroglucinol. At high sulfate levels retention of cytosine and cytidine decreased again, presumably due to a "salting out" effect. With perchlorate anion, retention of cytosine decreased steadily as salt concentration increased, while retention of other standards increased or was unchanged. The effect of the cation was examined by comparing the retention of a tryptic peptide containing either phosphoserine or aspartic acid at the same position. Salts of methylphosphonic acid were used at pH 2.5. The higher the hydration number of the cation, the better the selectivity between the two peptides. The best separation was obtained with the magnesium salt and the worst with the tetramethylammonium salt. The retention contributed by a highly hydrated cation exceeded retention due to electrostatic attraction. These results demonstrate that counterions that are well hydrated serve to promote partitioning of charged solutes into the immobilized aqueous layer in HILIC, while poorly hydrated counterions have the opposite effect. Effects on neutral solutes were more modest; retention times remained unchanged or increased modestly with an increase in concentration of any salt. PMID- 29395161 TI - Surface fitting for calculating the second dimension retention index in comprehensive two-dimensional gas chromatography mass spectrometry. AB - Comprehensive two-dimensional gas chromatography mass spectrometry (GC * GC-MS) has been widely used for analysis of volatile compounds. However, the second dimension retention index (I) of each compound is not widely used to aid compound identification owing to the limited accuracy of I calculation. We report a surface fitting approach to the calculation of I using n-alkanes (C7-C30) as references, where the second dimension retention time (2tR) and the second dimension column temperature (2Te) formed the X-Y plane and the I was the Z-axis to form the I surface. Compared to the conventional approach for calculating I using isovolatility curves, the surface fitting approach eliminated the construction of isovolatility curves for the reference compounds and gives better reproducibility. The goodness of the proposed surface fitting achieved R2 = 0.9999 and RMSE = 6.1 retention index units (iu). Ten-fold cross validation demonstrated the surface fitting approach had a good predictability with average R2 = 0.9999 and RMSE = 6.6 iu. The developed method was also applied to calculate the second dimension retention indices of compound standards in two commercial mixtures MegaMix A and MegaMix B. The mean standard deviation of the calculated I was only 1.6 iu for compounds in MegaMix A and 3.4 iu for compounds in MegaMix B. Compared with the literature results, the small value of standard deviation in the calculated retention index using surface fitting method shows that the surface fitting method has less measurement variability than the conventional isovolatility curve approach. PMID- 29395162 TI - Fast preparation of hybrid monolithic columns via photo-initiated thiol-yne polymerization for capillary liquid chromatography. AB - Although several approaches have been developed to fabricate hybrid monoliths, it would still take a few hours to finish the formation of monoliths. Herein, photo initiated thiol-yne polymerization was first adopted to in situ fabricate hybrid monoliths within the confines of UV-transparent fused-silica capillary. A silicon containing diyne (1,3-diethynyltetramethyl-disiloxane, DYDS) was copolymerized with three multithiols, 1,6-hexanedithiol, trimethylolpropane tris(3 mercaptopropionate) and pentaerythriol tetrakis(3-mercaptopropionate), by using a binary porogenic system of diethylene glycol diethyl ether (DEGDE)/poly(ethylene glycol) (PEG200) within 10 min. Several characterizations of three hybrid monoliths (assigned as I, II and III, respectively) were performed. The results showed that these hybrid monoliths possessed bicontinuous porous structure, which was remarkably different from that via typical free-radical polymerization. The highest column efficiency of 76,000 plates per meter for butylbenzene was obtained on the column I in reversed-phase liquid chromatography (RPLC). It was observed that the efficiencies for strong-retained butylbenzene were almost close to those of weak-retained benzene, indicating a retention-independent efficient performance of small molecules on hybrid column I. The surface area of this hybrid monolith was very small in the dry state (less than 10.0 m2/g), and the chromatographic behavior of hybrid monolithic columns would be possibly explained by radical-mediated step-growth process of thiol-yne polymerization. Finally, the column I was applied for separation of BSA tryptic digest by cLC-MS/MS, indicating satisfactory separation ability for complicated samples. PMID- 29395163 TI - Determination of dicoumarol in Melilotus officinalis L. by using molecularly imprinted polymer solid-phase extraction coupled with high performance liquid chromatography. AB - In this work, a method for the extraction of dicoumarol from plant sample utilizing selective adsorbent based on molecularly imprinted polymer was developed. Molecularly imprinted polymer (MIP) was synthesized by bulk polymerization, and on the surface of magnetic particles using dicoumarol as a template, methacrylic acid as functional monomer, chloroform as a porogen, and ethyleneglycol dimethacrylate as a cross-linker. Prepared polymeric materials were evaluated on the base of capacity, selectivity, and morphology. The maximal specific adsoption capacities of the sorbents were 45 MUg (for bulk MIP) and 36 MUg (for MIP on the magnetic particles) of dicoumarol per 1 g of polymer. An efficiencies of sorption processes of dicoumarol on prepared sorbents were evaluated under various conditions (type of sample solvent, pH, types of washing and elution solvents). The MIP based sorbents were used for solid phase extraction of dicoumarol. Applicability of MIP-SPE coupled to HPLC-DAD was tested for the selective extraction of dicoumarol from sample of sweet clover. The method was linear over concentration range from 1 to 100 MUg mL-1 (the correlation coefficient 0.9984) with limit of detection 0.2 MUg mL-1. Accuracy of the method was assessed for spiked sample at three concentration levels and recovery values were higher than 84% with relative standard deviation lower than 3.2%. PMID- 29395164 TI - Common murine immunoglobulin detection reagents have diminished reactivity with IgG3 - A vulnerability to misinterpretation. AB - Methods designed to monitor humoral immune responses, in a variety of settings, typically use a broadly reactive detection reagent (e.g. polyclonal anti-Ig (immunoglobulin)) in order to characterize antibody responses. In the context of murine models of immunity, which are widely used, this would typically be antisera to mouse Ig or mouse IgG. However, there are 4 different subtypes of mouse IgG; thus, the validity of the above approach, as a general screen for humoral immune responses, depends upon the assumption that the antisera recognize all IgG subtypes. This seems like a reasonable assumption, since polyclonal antisera recognize multiple epitopes; however, herein we report that two commercial sources of goat anti-mouse Ig are hyporeactive with IgG3. Given that relative IgG3 levels are different in distinct types of immune response, these findings demonstrate a potential for misinterpretation, and suggest a need to modify immunological methods in this context. PMID- 29395165 TI - Anti-neutrophil cytoplasm antibodies (ANCA): Recent methodological advances-Lead to new consensus recommendations for ANCA detection. AB - The current practice for detection of anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) has been screening by indirect immunofluorescence (IIF) followed by an antigen specific tests for PR3- and MPO-ANCA. However, ANCA diagnostics have undergone many technical developments that have affected the 1999 international consensus recommendations, and lead to a revision of the existing ANCA detection strategy. Recent European multicentre studies have compared the diagnostic performance of various ANCA detection methods and demonstrated that PR3- and MPO-ANCA immunoassays yielded the highest diagnostic accuracy. New guidelines for ANCA testing have been developed based on these data. According to the revised 2017 international consensus recommendations, testing for ANCA in small vessel vasculitis can be done by PR3- and MPO-ANCA immunoassays, without the categorical need for IIF. Thus, IIF can be discarded completely, or can be used as confirmation assays instead a screening test. Clearly, though, the new testing strategy for ANCA in vasculitis must identify the ANCA target antigen, as PR3- and MPO-ANCA serotype correlate well with disease expression. Furthermore, recent studies have shown that AAV can be classified based on ANCA serotype, since PR3- and MPO-ANCA- diseases are strongly associated with distinguishable genetic alleles, different clinical and histological features. ANCA presence and the antigen specificity also may have important value as a prognostic factor and may serve as a guide for immunosuppressive therapy. In the current review, we summarize the novelties in ANCA testing, present the 2017 revised international consensus on ANCA testing in vasculitis, evaluate the diagnostic significance of ANCA, and discuss the role of ANCA serotypes in the diagnostic work-up of patients with AAV. PMID- 29395166 TI - Usefulness of FC-TRIPLEX Chagas/Leish IgG1 as confirmatory assay for non-negative results in blood bank screening of Chagas disease. AB - A relevant issue in Chagas disease serological diagnosis regards the requirement of using several confirmatory methods to elucidate the status of non-negative results from blood bank screening. The development of a single reliable method may potentially contribute to distinguish true and false positive results. Our aim was to evaluate the performance of the multiplexed flow-cytometry anti-T. cruzi/Leishmania IgG1 serology/(FC-TRIPLEX Chagas/Leish IgG1) with three conventional confirmatory criteria (ELISA-EIA, Immunofluorescence assay-IIF and EIA/IIF consensus criterion) to define the final status of samples with actual/previous non-negative results during anti-T. cruzi ELISA-screening in blood banks. Apart from inconclusive results, the FC-TRIPLEX presented a weak agreement index with EIA, while a strong agreement was observed when either IIF or EIA/IIF consensus criteria were applied. Discriminant analysis and Spearman's correlation further corroborates the agreement scores. ROC curve analysis showed that FC-TRIPLEX performance indexes were higher when IIF and EIA/IIF consensus were used as a confirmatory criterion. Logistic regression analysis further demonstrated that the probability of FC-TRIPLEX to yield positive results was higher for inconclusive results from IIF and EIA/IIF consensus. Machine learning tools illustrated the high level of categorical agreement between FC-TRIPLEX versus IIF or EIA/IIF consensus. Together, these findings demonstrated the usefulness of FC-TRIPLEX as a tool to elucidate the status of non-negative results in blood bank screening of Chagas disease. PMID- 29395168 TI - Comparing Topical Treatments for Basal Cell Carcinoma. AB - Superficial basal cell carcinoma is a type of keratinocyte carcinoma that has increasing incidence and substantial morbidity. Jansen et al. report on a randomized trial with 5 years of follow-up that found imiquimod to be more effective than 5-fluorouracil or methyl aminolevulinate photodynamic therapy in preventing superficial basal cell carcinoma recurrence. However, the toxicity and cost of topical treatments, as well as patient preferences, need to be evaluated when making treatment decisions in clinical practice. PMID- 29395167 TI - Optimization and qualification of an Fc Array assay for assessments of antibodies against HIV-1/SIV. AB - The Fc Array is a multiplexed assay that assesses the Fc domain characteristics of antigen-specific antibodies with the potential to evaluate up to 500 antigen specificities simultaneously. Antigen-specific antibodies are captured on antigen conjugated beads and their functional capacity is probed via an array of Fc binding proteins including antibody subclassing reagents, Fcgamma receptors, complement proteins, and lectins. Here we present the results of the optimization and formal qualification of the Fc Array, performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines. Assay conditions were optimized for performance and reproducibility, and the final version of the assay was then evaluated for specificity, accuracy, precision, limits of detection and quantitation, linearity, range and robustness. PMID- 29395169 TI - Torticollis in Infants with a History of Neonatal Abstinence Syndrome. AB - In this retrospective cohort study, we assessed the incidence of torticollis in infants with a history of neonatal abstinence syndrome. Understanding the elevated risk of torticollis in this population is important for early identification and treatment. PMID- 29395170 TI - Impact of Discharge Components on Readmission Rates for Children Hospitalized with Asthma. AB - OBJECTIVES: To describe hospital-based asthma-specific discharge components at children's hospitals and determine the association of these discharge components with pediatric asthma readmission rates. STUDY DESIGN: This is a multicenter retrospective cohort study of pediatric asthma hospitalizations in 2015 at children's hospitals participating in the Pediatric Health Information System. Children ages 5 to 17 years were included. An electronic survey assessing 13 asthma-specific discharge components was sent to quality leaders at all 49 hospitals. Correlations of combinations of asthma-specific discharge components and adjusted readmission rates were calculated. RESULTS: The survey response rate was 92% (45 of 49 hospitals). Thirty-day and 3-month adjusted readmission rates varied across hospitals, ranging from 1.9% to 3.9% for 30-day readmissions and 5.7% to 9.1% for 3-month readmissions. No individual or combination discharge components were associated with lower 30-day adjusted readmission rates. The only single-component significantly associated with a lower rate of readmission at 3 months was having comprehensive content of education (P < .029). Increasing intensity of discharge components in bundles was associated with reduced adjusted 3-month readmission rates, but this did not reach statistical significance. This was seen in a 2-discharge component bundle including content of education and communication with the primary medical doctor, as well as a 3-discharge component bundle, which included content of education, medications in-hand, and home-based environmental mitigation. CONCLUSIONS: Children's hospitals demonstrate a range of asthma-specific discharge components. Although we found no significant associations for specific hospital-level discharge components and asthma readmission rates at 30 days, certain combinations of discharge components may support hospitals to reduce healthcare utilization at 3 months. PMID- 29395171 TI - De Novo Allergy and Immune-Mediated Disorders Following Solid-Organ Transplantation-Prevalence, Natural History, and Risk Factors. AB - OBJECTIVES: To describe the prevalence, natural course, outcome, and risk factors of post-transplant de novo allergy and autoimmunity. STUDY DESIGN: A cross sectional, cohort study of all children (<18 years) who underwent a solid-organ transplantation, between 2000 and 2012, in a single transplant center, with a follow-up period of 6 months or more post-transplant and without history of allergy or immune-mediated disorder pretransplant. RESULTS: A total of 626 eligible patients were screened, and 273 patients (160 males; 59%) met the inclusion criteria; this included 111 liver, 103 heart, 52 kidney, and 7 multivisceral recipients. Patients were followed for a median period of 3.6 years. A total of 92 (34%) patients (42 males, 46%) developed allergy or autoimmune disease after transplantation, with a high prevalence among liver (41%), heart (40%), and multivisceral (57%) transplant recipients compared with kidney recipients (4%; P < .001). Post-transplant allergies included eczema (n = 44), food allergy (22), eosinophilic gastrointestinal disease (11), and asthma (28). Autoimmunity occurred in 18 (6.6%) patients, presenting mainly as autoimmune cytopenia (n = 10). In a multivariate analysis, female sex, young age at transplantation, family history of allergy, Epstein-Barr virus infection, and elevated eosinophil count >6 months post-transplantation were associated with an increased risk for allergy or autoimmunity. Two patients (0.7%) died from autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis, and 52 episodes of post-transplant allergy, autoimmunity, and immune-mediated disorders (37%) did not improve over time. CONCLUSIONS: Allergy and autoimmunity are common in pediatric liver, heart, and multivisceral transplant recipients and pose a significant health burden. Further studies are required to clarify the mechanisms behind this post-transplant immune dysregulation. PMID- 29395172 TI - Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas. AB - OBJECTIVES: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. STUDY DESIGN: We retrospectively reviewed 160 patients <=18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). RESULTS: Mean age was 12.9 +/- 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets. CONCLUSIONS: Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00001595 and NCT00060541. PMID- 29395173 TI - The Sensitivity of Clinician Diagnosis of Sepsis in Tertiary and Community-Based Emergency Settings. AB - OBJECTIVES: To assess whether the risk of missed clinician diagnosis of pediatric sepsis requiring care in the intensive care unit (ICU) was greater in community vs tertiary pediatric emergency care settings with sepsis pathways. STUDY DESIGN: An observational cohort study in a tertiary pediatric emergency department (ED) staffed by pediatric emergency physicians and 4 affiliated community pediatric ED/urgent care sites staffed by general pediatricians. Use of an institutional sepsis order set or pathway was considered clinician diagnosis of sepsis. Risk of missed diagnosis was compared for 2 outcomes: suspected infection plus ICU admission (sepsis-ICU) and suspected infection plus vasoactive agent/positive pressure ventilation (sepsis-VV). RESULTS: From January 1, 2014 to December 31, 2015, there were 141 552 tertiary and 139 332 community emergency visits. Clinicians diagnosed sepsis in 1136 visits; median age was 5.7 (2.4, 12.0) years. In the tertiary ED, there were 306 sepsis-ICU visits (0.2%) and 112 sepsis-VV visits (0.08%). In community sites, there were 46 sepsis-ICU visits (0.03%) and 20 sepsis-VV visits (0.01%). The risk of missed diagnosis in community vs tertiary sites was significantly greater for sepsis-ICU (relative risk 4.30, CI 2.15-8.60) and sepsis-VV (relative risk 14.0, CI 2.91-67.24). Sensitivity for sepsis-ICU was 94.4% (91.3%-96.5%) at the tertiary site and 76.1% (62.1%-86.1%) at community sites. CONCLUSIONS: The risk of missed diagnosis of sepsis-ICU was greater in community vs tertiary emergency care settings despite shared pathways and education, but with differences in resources, providers, and sepsis incidence. More research is needed to optimize diagnostic approaches in all settings. PMID- 29395174 TI - Efficacy of a Novel Palivizumab Prophylaxis Protocol for Respiratory Syncytial Virus Infection in Congenital Heart Disease: A Multicenter Study. AB - OBJECTIVE: To analyze the efficacy of a novel palivizumab protocol for hemodynamically significant congenital heart disease (hsCHD) in subtropical areas without clear respiratory syncytial virus seasonality. STUDY DESIGN: Since July 2013, the National Health Insurance program has provided reimbursement for palivizumab prophylaxis with a novel monthly protocol in selected patients with hsCHD under 1 year of age. We performed a multicenter study to assess the trend of respiratory syncytial virus hospitalizations in patients with hsCHD from 2010 to 2016 during the prepalivizumab, transition, and postpalivizumab periods, and compared treatment and propensity-matched control groups. RESULTS: A total of 747 patients were enrolled in the study group and 809 in the control group. The male:female was 836:720. Cyanotic CHD was observed in 42.9% of patients. The mean age at diagnosis of CHD was 32.9 days. After 516 685 patient-days of follow-up and a mean of 3.9 doses of palivizumab in the treatment group, respiratory syncytial virus hospitalization rates decreased by 53% and 49% before and after match compared with the control group (P = .009 and .029, respectively). Hospitalization days and intensive care unit admission rate also decreased similarly in the treatment group. The efficacy of this protocol was more prominent in patients with cyanotic hsCHD. The annual respiratory syncytial virus associated hospitalization rates also decreased significantly from the prepalivizumab to the palivizumab period (from 4.8% to 2.0%; P = .038). CONCLUSION: Palivizumab prophylaxis through the novel monthly protocol for patients with hsCHD is effective in reducing respiratory syncytial virus-related hospitalizations. PMID- 29395175 TI - Too Hot to Handle? When Vaporizers Explode. PMID- 29395176 TI - Putting Out the Fire in Acute Kawasaki Disease. PMID- 29395177 TI - Delirium is a Common and Early Finding in Patients in the Pediatric Cardiac Intensive Care Unit. AB - OBJECTIVE: To determine incidence, associated risk factors, and characteristics of delirium in a pediatric cardiac intensive care unit (CICU). Delirium is a frequent and serious complication in adults after cardiac surgery, but there is limited understanding of its impact in children with critical cardiac disease. STUDY DESIGN: Single-center prospective observational study of CICU patients <=21 years old. All were screened for delirium using the Cornell Assessment for Pediatric Delirium each 12-hour shift. RESULTS: Ninety-nine patients were included. Incidence of delirium was 57%. Median time to development of delirium was 1 day (95% CI 0, 1 days). Children with delirium were younger (geometric mean age 4 vs 46 months; P < .001), had longer periods of mechanical ventilation (mean 35.9 vs 8.8 hours; P = .002) and had longer cardiopulmonary bypass times (geometric mean 126 vs 81 minutes; P = .001). Delirious patients had longer length of CICU stay than those without delirium (median 3 (IQR 2, 12.5) vs 1 (IQR1, 2) days; P < .0001). A multivariable generalized linear mixed model showed a significant association between delirium and younger age (OR 0.35 for each additional month, 95% CI 0.19, 0.64), need for mechanical ventilation (OR 4.1, 95% CI 1.7, 9.89), and receipt of benzodiazepines (OR 3.78, 95% CI 1.46, 9.79). CONCLUSIONS: Delirium is common in patients in the pediatric CICU and is associated with longer length of stay. There may be opportunities for prevention of delirium by targeting modifiable risk factors, such as use of benzodiazepines. PMID- 29395179 TI - A Heterozygous NDUFV1 Variant Aggravates Mitochondrial Complex I Deficiency in a Family with a Homoplasmic ND1 Variant. AB - We demonstrate that a heterozygous nuclear variant in the gene encoding mitochondrial complex I subunit NDUFV1 aggravates the cellular phenotype in the presence of a mitochondrial DNA variant in complex I subunit ND1. Our findings suggest that heterozygous variants could be more significant in inherited mitochondrial diseases than hitherto assumed. PMID- 29395178 TI - Early Post-Therapy Prescription Drug Usage among Childhood and Adolescent Cancer Survivors. AB - OBJECTIVE: To describe the patterns of prescription drug use among child and adolescent survivors of cancer in the early post-therapy period compared with matched peers without a cancer history. STUDY DESIGN: Using the MarketScan commercial insurance claims database, we performed a retrospective cohort study identifying survivors of pediatric (0-21 years of age at diagnosis) leukemia, lymphoma, central nervous system, bone, or gonadal cancers who completed therapy from 2000 to 2011 and remained insured for 3 years post-therapy. Prescription fills during the first 3 years post-therapy were examined, categorized by drug class, and compared with age-, sex-, and region-matched individuals without cancer. RESULTS: We identified 1414 survivors and 14 007 comparators. Compared with those without cancer, survivors had 1.5-4.5 times greater risk for filling opioids. Survivors of leukemia, lymphoma, central nervous system, and bone cancers had 2-5 times the risk for antidepressant and 3-7 times the risk for anxiolytic use. Survivors of leukemia, lymphoma, and bone tumors had 3-13 times the risk for angiotensin-converting enzyme inhibitors by the third year post therapy. CONCLUSION: Compared with peers without cancer, survivors of childhood cancer have greater rates of prescription use across many drug classes, suggesting greater medical morbidity. Survivors were more likely to use opioid, psychoactive, hormone, and cardiovascular medications. All general pediatricians and subspecialists should be aware of potentially emerging morbidities during the early post-therapy period to guide risk-based surveillance and survivorship care. PMID- 29395180 TI - Mercury Poisoning in a Toddler from Home Contamination due to Skin-Lightening Cream. AB - A 17-month-old child presented with hypertension, fussiness, constipation, and arthralgia due to mercury toxicity from a skin-lightening cosmetic used by her mother and grandmother. Blood mercury level was 26 mcg/L and urine level was 243 mcg/g creatinine. She was chelated with succimer. The home was contaminated and needed remediation. PMID- 29395181 TI - PEG 3350 Administration Is Not Associated with Sustained Elevation of Glycol Levels. AB - OBJECTIVE: To determine whether trace amounts of ethylene glycol (EG), diethylene glycol (DEG), or triethylene glycol (TEG) in PEG 3350 are associated with increased blood levels of EG, DEG, or TEG in children receiving daily PEG 3350 therapy. STUDY DESIGN: Blood samples were drawn from 9 children who were being treated for constipation with PEG 3350 (6-12 years old) before and every 30 minutes for 3 hours after receiving 17 g of PEG 3350. PEG 3350, tap water, and blood samples from 18 age- and sex-matched controls also were analyzed. RESULTS: Baseline blood levels of EG and TEG did not differ between control and treated groups. DEG levels (median [IQR]) were lower in the PEG 3350 group (40.13 ng/mL [36.69, 63.94] vs 92.83 ng/mL [51.06, 128.93], P = .008). After PEG 3350 dose, levels of EG (390.51 ng/mL [326.06, 624.55]) and TEG (2.21 ng/mL [0, 4.5]) peaked at 90 minutes at 1032.81 ng/mL (826.84, 1486.13) (P = .009) and 35.17 ng/mL (15.81, 45.13) (P = .0005), respectively. DEG levels did not significantly change. Standard 17-g doses of PEG 3350 in 8 oz (237 mL) of water resulted in concentrations (mean +/- SD) of EG, DEG, and TEG of 1.32 +/- 0.23 ug/mL, 0.18 +/- 0.03 ug/mL, and 0.12 +/- 0.01 ug/mL, respectively. EG, DEG, and TEG levels in public water supply were 0.07 ug/mL, 0.21 ug/mL, and 0.02 ug/mL, respectively. CONCLUSIONS: Daily PEG 3350 therapy in children was not associated with sustained elevation of EG, DEG, or TEG blood levels over levels in matched controls. Although EG and TEG levels increased after a standard dose of PEG 3350, their peak values remained well below toxic levels. PMID- 29395182 TI - Infant Iron Deficiency and Iron Supplementation Predict Adolescent Internalizing, Externalizing, and Social Problems. AB - OBJECTIVE: To evaluate associations between iron supplementation and iron deficiency in infancy and internalizing, externalizing, and social problems in adolescence. STUDY DESIGN: The study is a follow-up of infants as adolescents from working-class communities around Santiago, Chile who participated in a preventive trial of iron supplementation at 6 months of age. Inclusionary criteria included birth weight >=3.0 kg, healthy singleton term birth, vaginal delivery, and a stable caregiver. Iron status was assessed at 12 and 18 months of age. At 11-17 years of age, internalizing, externalizing, and social problems were reported by 1018 adolescents with the Youth Self Report and by parents with the Child Behavior Checklist. RESULTS: Adolescents who received iron supplementation in infancy had greater self-reported attention deficit/hyperactivity disorder but lower parent-reported conduct disorder symptoms than those who did not (Ps < .05). Iron deficiency with or without anemia at 12 or 18 months of age predicted greater adolescent behavior problems compared with iron sufficiency: more adolescent-reported anxiety and social problems, and parent-reported social, post-traumatic stress disorder, attention deficit/hyperactivity disorder, oppositional defiant, conduct, aggression, and rule breaking problems (Ps < .05). The threshold was iron deficiency with or without anemia for each of these outcomes. CONCLUSIONS: Iron deficiency with or without anemia in infancy was associated with increased internalizing, externalizing, and social problems in adolescence. PMID- 29395183 TI - To Split or Not to Split? That is No Longer the Question. PMID- 29395184 TI - Management of Hypertension and High Low-Density Lipoprotein in Pediatric Type 1 Diabetes. AB - OBJECTIVE: To evaluate hypertension and hyperlipidemia management patterns in youth with type 1 diabetes and to assess perceived effectiveness of management strategies and barriers to management. STUDY DESIGN: An electronic survey, including clinical scenarios, fielded to pediatric providers (members of the American Diabetes Association Diabetes in Youth Interest Group, Pediatric Endocrine Society, or T1D Exchange). RESULTS: Respondents (N = 207, 86% MDs, 68% female) were practicing clinicians for youth with type 1 diabetes. As an initial recommendation, the overwhelming majority of respondents (83%-99%) endorsed lifestyle and nonmedical recommendations (eg, improve glycemic control) for hypertension and hyperlipidemia. Yet, few (6%-17%) reported these recommendations as effective. Many respondents (57%) reported referring to another specialist for hypertension, whereas few (8%) reported referring to another specialist for hyperlipidemia management. Approximately one-fifth (21%) of respondents never initiate antihypertensive medications, whereas only 8% never initiate lipid lowering medication. Among prescribers, the majority of respondents only started antihypertensive or lipid-lowering medications after persistent elevations and in the setting of either ineffective lifestyle or nonmedical interventions or additional cardiovascular risk factors. More than two-thirds of respondents endorsed medications as often effective for hypertension and hyperlipidemia (68% and 69%, respectively). CONCLUSIONS: Pediatric diabetes providers commonly defer prescribing antihypertensive and lipid-lowering medications until nonmedication interventions have been ineffective. Most providers describe medications, but not lifestyle interventions, as often effective. Efforts to align clinical practice with clinical guidelines are needed. PMID- 29395185 TI - Variation in Part-Time Work among Pediatric Subspecialties. AB - OBJECTIVE: To assess the part-time workforce and average hours worked per week among pediatric subspecialists in the 15 medical subspecialties certified by the American Board of Pediatrics. STUDY DESIGN: We examined data from pediatric subspecialists who enrolled in Maintenance of Certification with the American Board of Pediatrics from 2009 to 2015. Data were collected via an online survey. Providers indicated whether they worked full time or part time and estimated the average number of hours worked per week in clinical, research, education, and administrative tasks, excluding time on call. We calculated and compared the range of hours worked by those in full- and part-time positions overall, by demographic characteristics, and by subspecialty. RESULTS: Overall, 9.6% of subspecialists worked part time. There was significant variation in part-time employment rates between subspecialties, ranging from 3.8% among critical care pediatricians to 22.9% among developmental-behavioral pediatricians. Women, American medical graduates, and physicians older than 70 years of age reported higher rates of part-time employment than men, international medical graduates, and younger physicians. There was marked variation in the number of hours worked across subspecialties. Most, but not all, full-time subspecialists reported working at least 40 hours per week. More than one-half of physicians working part time in hematology and oncology, pulmonology, and transplant hepatology reported working at least 40 hours per week. CONCLUSIONS: There are unique patterns of part-time employment and hours worked per week among pediatric medical subspecialists that make simple head counts inadequate to determine the effective workforce. Our findings are limited to the 15 American Board of Pediatrics certified medical subspecialties. PMID- 29395187 TI - Effects of participation in and connectedness to the LGBT community on substance use involvement of sexual minority young people. AB - INTRODUCTION: Research shows disproportionate levels of substance use among sexual minority young people. A range of reasons for these disparities have been suggested, including connectedness to and participation in the LGBT community. Little is known about how these constructs are related to substance use involvement in sexual minority (sub)groups or how these relationships are affected by other factors. METHODS: 1266 young sexual minority Australians completed a cross-sectional online survey. Multiple regressions were conducted to assess associations between connectedness to and participation in the LGBT community on substance use involvement, before and after controlling for other factors such as substance use motives, psychological distress, wellbeing, resilience, minority stress, and age. RESULTS/CONCLUSION: Most participants identified as homosexual (57%, n=726) and male (54%, n=683). In the overall sample, participation in and connectedness the LGBT community were significantly associated with increased substance use involvement before (F(2,1263)=35.930, p<=0.001, R2=0.052) and after controlling for other variables (F(8,1095)=33.538, p<=0.001, R2=0.191), with meaningfully higher effect sizes for participation than for connectedness. After controlling for other variables, connectedness only remained significant for homosexuals. Effect sizes for participation were higher for females than males, and bisexuals than homosexuals. However, participation in the LGBT Community was not associated with substance use in participants identifying with a non-binary gender identity. In conclusion, substance use involvement was associated with participation in the LGBT community, but connectedness to the LGBT community only had a weak association with substance use involvement in the homosexual subgroup. PMID- 29395189 TI - Small needles for big surgery? PMID- 29395190 TI - Discussion. PMID- 29395188 TI - Real-time assessment of alcohol craving and naltrexone treatment responsiveness in a randomized clinical trial. AB - INTRODUCTION: This secondary data analysis examined whether and how the dopamine receptor D4 gene (DRD4) influenced naltrexone treatment responsiveness in a randomized clinical trial. We leveraged intensive experience sampling methods to test the hypothesis that craving recorded at drinking and non-drinking moments would mediate naltrexone effects on the likelihood of heavy drinking, but only among carriers of the DRD4 long (DRD4-L) allele. METHODS: Participants (Mage=29.8years, SD=12.1) were non-treatment seeking heavy drinkers (n=104, 54.8% female, 61.5% alcohol dependent) randomized to 3weeks of daily naltrexone (50mg) or placebo. During these 3weeks, participants used handheld electronic devices to complete real-time reports of alcohol use and craving multiple times per day in their natural environments. This approach afforded intensive repeated assessment of focal variables and provided in-the-moment data to test whether craving when not drinking or early in drinking episodes explained naltrexone effects on drinking. RESULTS: Moderated-mediation multilevel structural equation models showed that craving during non-drinking moments mediated the treatment effect of naltrexone on heavy drinking but only among carriers of the DRD4-L allele. The same pattern of associations was not shown when evaluating craving while participants were consuming alcoholic beverages. CONCLUSIONS: Findings provide the first in vivo evidence that, among carriers of the DRD4-L allele, naltrexone blunts craving in real-world settings, and this effect in turn reduces the likelihood of heavy drinking. This work highlights the utility of EMA methods for elucidating how treatments work and further demonstrates the importance of genetic factors for understanding individual differences in pharmacotherapy responsiveness. PMID- 29395192 TI - Should urinary biomarkers be a standard component of evaluation after cardiac surgery? PMID- 29395191 TI - Beneficial effects of restrictive annuloplasty on subvalvular geometry in patients with functional mitral regurgitation and advanced cardiomyopathy. AB - OBJECTIVES: The effects of restrictive mitral annuloplasty (RMA) on subvalvular geometry remains unknown. We evaluated changes in left ventricular (LV) function, severity of mitral regurgitation (MR), and leaflet tethering parameters after RMA and clarified their associations. METHODS: In 44 patients with clinically relevant functional MR who underwent RMA, distances between papillary muscle (PM) tips and anterior mitral annulus (PM tethering distance), leaflet angles relative to lines connecting annuli, and interpapillary muscle distance (IPMD) were serially quantified. RESULTS: One month after surgery, LV function and MR severity improved with decreased anterior (34 +/- 5 to 30 +/- 4 mm) and posterior PM tethering distance (37 +/- 4 to 32 +/- 4 mm), anterior leaflet angle (32 +/- 8 degrees to 22 +/- 7 degrees ), and IPMD (31 +/- 6 to 25 +/- 5 mm), whereas these variables remained abnormal and posterior leaflet angle increased (34 +/- 8 degrees to 48 +/- 14 degrees ; P < .01 for all). During follow-up (66 +/- 37 months), these effects were maintained in 33 patients without MR recurrence, whereas 11 with it showed worsened tethering with less LV function recovery. Multiple linear regression analyses identified that change in MR severity from baseline to 12-month examination independently associated with corresponding change in IPMD (parameter estimate of 0.100 with standard error of 0.039; P = .019) and that in posterior PM tethering distance (parameter estimate of -0.104 with standard error of 0.045; P = .035), whereas not with change in posterior leaflet angle. The IPMD change was independently associated with change in LV end systolic dimension (parameter estimate of 0.299 with standard error of 0.110; P = .013). CONCLUSIONS: The RMA procedure partially relieved leaflet tethering, evidenced by decreased tethering distances and IPMD; the latter was the main determinant of MR. These beneficial effects might be mainly attributed to post RMA reverse LV remodeling, potentially offsetting the negative effect of augmented posterior leaflet angle in selected patients. PMID- 29395193 TI - Severe tricuspid or mitral regurgitation in inoperable patients with aortic stenosis. Can we leave them alone? PMID- 29395195 TI - Frank(ly), Star(t)ling: A structural protein contributes to changes in left ventricular performance with cardiomyopathies? PMID- 29395194 TI - Resolving the Fontan paradox: Addressing socioeconomic and racial disparities in patients with a single ventricle. PMID- 29395196 TI - Pulmonary valve replacement: A new paradigm. PMID- 29395197 TI - Zone zero thoracic endovascular aortic repair: A proposed modification to the classification of landing zones. AB - OBJECTIVE: Endovascular stent-grafting provides an alternative treatment option for high-risk patients with ascending aortic disease. The feasibility of this approach has been demonstrated before. We assess the updated experience with ascending thoracic endovascular aortic repair and propose a modification of the landing zone classification based on the outcomes. METHODS: From 2006 to 2016, 39 patients deemed very high risk for open replacement underwent endovascular repair of ascending aorta for acute type A dissection (12, 31%), intramural hematoma (2, 5%), pseudoaneurysm (22, 56%), and chronic dissection suture line entry tear (3, 8%). Ascending thoracic endovascular aortic repair was performed in 36 patients. In 3 patients with pseudoaneurysm, occluder devices were used. Computed tomography imaging analysis was performed, and the extent of aortic pathology was designated by segmental proximity to the left ventricle. Segmental anatomy of the proximal aorta was designed as zone 0A from the annulus to the distal margin of highest coronary, 0B extends from above the coronary to the distal margin of right pulmonary artery, and 0C extends from the right pulmonary artery border to the innominate artery. Multivariable time to event Cox regression analysis was performed to predict mortality, and long-term survival was estimated using the Kaplan-Meier method. RESULTS: Operative mortality was 13%; all 5 deaths occurred after emergency ascending thoracic endovascular aortic repair for type A dissection. Other complications included stroke in 4 patients (10%), myocardial infarction in 2 patients (5%), tracheostomy in 2 patients (5%), and dialysis in 2 patients (5%). In patients with acute type A dissection, the ascending pathology extended into zone 0A in 10 (71%) and 0B in 4 (29%). Among those with pseudoaneurysm, the location of the defect was in 0B in 11 (50%), 0C in 10 (45%), and 0A in 1. Among the patients with chronic dissection, the defect was located in 0C in all 3 (100%). After multivariable adjustment, Cox regression predicted significantly higher hazard of mortality with disease involving zone 0A versus 0C (P = .020) and older age (P = .026). Kaplan-Meier estimate of survival was also significantly worse in patients with disease extension into 0A versus 0C (P = .0018). At 30 days, 1 year, and 5 years, the overall survival was 81%, 74%, and 64% and freedom from reintervention was 85%, 77%, and 68%, respectively. CONCLUSIONS: The modified zone zero classification is useful for characterizing extent of ascending aortic pathology and assessing prognosis. Location of the defect varies by pathology, and the presence of 0A disease predicts worse outcomes. Design of endovascular devices should be tailored to the aortic pathology and zone characteristics. PMID- 29395198 TI - Pediatric mechanical circulatory support: A new era of "using the right tools, for the right job, at the right time". PMID- 29395199 TI - What's happening next. PMID- 29395200 TI - Discussion. PMID- 29395186 TI - Antecedents and Outcomes of Abnormal Cranial Imaging in Moderately Preterm Infants. AB - OBJECTIVES: To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics. STUDY DESIGN: We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (<=28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center. RESULTS: Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3-4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%), and ventriculomegaly (6.6%). Histologic chorioamnionitis (OR, 1.47; 95% CI, 1.19-1.83), gestational age (0.95; 95% CI, 0.94-0.97), antenatal steroids (OR, 0.55; 95% CI, 0.41-0.74), and cesarean delivery (OR, 0.66; 95% CI, 0.53-0.81) were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging (OR, 2.08; 95% CI, 1.10-3.92). On the classification and regression-tree model, cesarean delivery, center, antenatal steroids, and chorioamnionitis, in that order, predicted abnormal imaging. CONCLUSION: Among the 60% of moderately preterm infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in moderately preterm infants is needed. PMID- 29395202 TI - Go with the flow, but do not get mixed up. PMID- 29395201 TI - Duration of extracorporeal membrane oxygenation support and survival in cardiovascular surgery patients. AB - OBJECTIVE: The overall therapeutic goal of venoarterial extracorporeal membrane oxygenation (ECMO) in patients with postcardiotomy shock is bridging to myocardial recovery. However, in patients with irreversible myocardial damage prolonged ECMO treatment would cause a delay or even withholding of further permanent potentially life-saving therapeutic options. We therefore assessed the prognostic effect of duration of ECMO support on survival in adult patients after cardiovascular surgery. METHODS: We enrolled into our single-center registry a total of 354 patients who underwent venoarterial ECMO support after cardiovascular surgery at a university-affiliated tertiary care center. RESULTS: Through a median follow-up period of 45 months (interquartile range, 20-81 months), 245 patients (69%) died. We observed an increase in mortality with increasing duration of ECMO support. The association between increased duration of ECMO support and mortality persisted in patients who survived ECMO support with a crude hazard ratio of 1.96 (95% confidence interval, 1.40-2.74; P < .001) for 2-year mortality compared with the third tertile and the second tertile of ECMO duration. This effect was even more pronounced after multivariate adjustment using a bootstrap-selected confounder model with an adjusted hazard ratio of 2.30 (95% confidence interval, 1.52-3.48; P < .001) for 2-year long-term mortality. CONCLUSIONS: Prolonged venoarterial ECMO support is associated with poor outcome in adult patients after cardiovascular surgery. Our data suggest reevaluation of therapeutic strategies after 7 days of ECMO support because mortality disproportionally increases afterward. PMID- 29395203 TI - Dissolution is not the solution. PMID- 29395204 TI - Intercostal artery management in thoracoabdominal aortic surgery: To reattach or not to reattach? AB - BACKGROUND: The need for intercostal artery (ICA) reattachment in surgery for descending thoracic aortic aneurysm (DTAA) or thoracoabdominal aortic aneurysm (TAAA) remains controversial. We reviewed our experience over a 14-year period to assess the effects of ICA management on neurologic outcome after DTAA/TAAA repair. METHODS: Intraoperative data were reviewed to ascertain the status of T3 12 ICAs and L1-4 ICAs. Arteries were classified as reattached, ligated, occluded, or not exposed. Temporality of reattachment or ligation in response to an intraoperative ischemic event (ie, loss of motor evoked potentials [MEPs]) was noted. Adjustment for other predictors of immediate or delayed paraplegia (DP) was performed by multiple logistic regression. The effects of specific artery level and type of reattachment technique were assessed using stratified contingency tables. RESULTS: A total of 1096 DTAA/TAAAs were performed between 2001 and 2014. The mean patient age was 64 +/- 15 years, and 37% were female. Spinal cord ischemia was identified in 10% of patients, including 35 (3%) immediate cases and 77 (7%) DP cases. Overall DP resolution was 47% at discharge. ICA ligation and intraoperative MEP changes were strong predictors of postoperative paraplegia. Multivariable analysis demonstrated that T8-12 ICA ligation significantly increased the risk for paraplegia (odds ratio, 1.3/artery; P < .041) even after adjustment for age >65 years, glomerular filtration rate, extent of II/III aneurysm, increased operative time, and intraoperative MEP loss. CONCLUSIONS: Loss of intraoperative MEPs is serious, and increases the risk of paraplegia in any ICA management strategy. Even with intact MEP, ligation of T8 12 ICAs is associated with increased risk. These findings support reattachment of T8-12 ICAs whenever feasible. PMID- 29395205 TI - Cardiac (valve) surgery in the elderly-who decides you are too old? PMID- 29395206 TI - Esophagectomy versus endoscopic resection for patients with early-stage adenocarcinoma: Mercedes versus Tesla. PMID- 29395207 TI - Direct repair of the aortic root and arch in acute type A dissection: Is outcome related to technique, patient selection, or experience? PMID- 29395208 TI - Impact of induction chemoradiotherapy on pulmonary function after lobectomy for lung cancer. AB - OBJECTIVE: Our study aim was to determine whether there are differential changes in whole-lung and regional lung functions after lobectomy for lung cancer between propensity score-matched patients treated with and without induction chemoradiotherapy, by using single-photon emission computed tomography lung perfusion. METHODS: This study was a retrospective matched cohort study of consecutively acquired data. Pulmonary function test and perfusion scintigraphy were conducted before lobectomy and 6 months after lobectomy in patients treated with induction therapy (n = 72) and in those not treated (n = 170), for measuring functional changes of whole lung, contralateral lung, and lobes. After exact matching on resected lobe site, propensity scores for age, smoking status, preoperative pulmonary functions, and predicted postoperative pulmonary function were used to match the groups. RESULTS: After the matching, 46 patients were selected from the groups. Standardized mean differences of the 5 matched variables were <0.1. Whole lung function significantly decreased after lobectomy in the induction therapy group than in the noninduction therapy group (P < .001). Although ipsilateral preserved lobe function before surgery was not different between the groups (P = .33), postoperative value was significantly lower in the induction therapy group than in the noninduction therapy group (P < .001). Although both groups showed a significant increase of contralateral lung function after lobectomy (P < .01), the increases were not significantly different between the groups (P = .81). CONCLUSIONS: Induction chemoradiotherapy was associated with reduced pulmonary function after lobectomy because of a decrease in ipsilateral preserved lobe function, which could be caused by the chronic effects of the induction chemoradiotherapy. PMID- 29395209 TI - Endoscopic mucosal resection: The new gold standard or the "Bitcoin" of the present. PMID- 29395210 TI - The value and generalizability of cost-effectiveness research. PMID- 29395211 TI - Height alone, rather than body surface area, suffices for risk estimation in ascending aortic aneurysm. AB - BACKGROUND: In international guidelines, risk estimation for thoracic ascending aortic aneurysm (TAAA) is based on aortic diameter. We previously introduced the aortic size index (ASI), defined as aortic size/body surface area (BSA), as a predictor of aortic dissection, rupture, and death. However, weight might not contribute substantially to aortic size and growth. We seek to evaluate the height-based aortic height index (AHI) versus ASI for risk estimation and revisit our natural history calculations. METHODS: Aortic diameters and long-term complications of 780 patients with TAAA were analyzed. Growth rate estimates, yearly complication rates, and survival were assessed. Risk stratification was performed using regression models. The predictive value of AHI and ASI was compared. RESULTS: Patients were stratified into 4 categories of yearly risk of complications based on their ASI and AHI. ASIs (cm/m2) of <=2.05, 2.08 to 2.95, 3.00 to 3.95 and >=4, and AHIs (cm/m) of <=2.43, 2.44 to 3.17, 3.21 to 4.06, and >=4.1 were associated with a 4%, 7%, 12%, and 18% average yearly risk of complications, respectively. Five-year complication-free survival was progressively worse with increasing ASI and AHI. Both ASI and AHI were shown to be significant predictors of complications (P < .05). AHI categories 3.05 to 3.69, 3.70 to 4.34, and >=4.35 cm/m were associated with a significantly increased risk of complications (P < .05). The overall fit of the model using AHI was modestly superior according to the concordance statistic. CONCLUSIONS: Compared with indices including weight, the simpler height-based ratio (excluding weight and BSA calculations) yields satisfactory results for evaluating the risk of natural complications in patients with TAAA. PMID- 29395212 TI - Transcatheter versus surgical valve replacement for a failed pulmonary homograft in the Ross population. AB - BACKGROUND: Patients who undergo the Ross procedure are at increased risk of pulmonary valve (PV) homograft dysfunction. For those who require reintervention on the homograft, transcatheter PV replacement (tPVR) provides a less invasive therapeutic option than surgical PVR (sPVR). We examined the outcomes following tPVR versus sPVR in a cohort of patients who underwent the Ross procedure. METHODS: We performed a retrospective analysis of Ross patients age >=14 years who underwent tPVR (n = 47) or sPVR (n = 41) at our institution. The patients' clinical and echocardiographic data were reviewed. RESULTS: Baseline parameters, including demographic data and left ventricular and right ventricular (RV) systolic function, were similar in the 2 groups. The mean follow-up was 56 +/- 24 months for the tPVR group and 89 +/- 46 months for the sPVR group (P < .001). No procedure-related mortality was noted in either group. At 6-year follow-up, there was no significant between-group difference in event-free survival (tPVR, 79% +/- 7% vs sPVR, 91% +/- 4%; P = .15) or PV reintervention (tPVR, 26% +/- 9% vs sPVR, 8% +/- 5%; P = .31). PV-associated infective endocarditis (IE) was significantly more common with tPVR (tPVR, 13% vs sPVR, 0%; P = .04), with an annualized rate of 2.98% per patient-year. In addition, there was a trend toward more valve dysfunction following sPVR (sPVR, 67% +/- 8% vs tPVR, 35% +/- 8%; P = .08). CONCLUSIONS: In Ross patients who require reintervention on the PV homograft, both tPVR and sPVR provide low procedural mortality and comparable midterm outcome with no significant difference in mortality or PV reintervention. However, IE is more common following tPVR. A larger randomized study is needed to determine the role of each procedure in patient management. PMID- 29395213 TI - Discussion. PMID- 29395214 TI - Transcatheter pulmonary valve replacement using the melody valve for treatment of dysfunctional surgical bioprostheses: A multicenter study. AB - BACKGROUND: Stented bioprosthetic valves (BPVs) are commonly used for surgical pulmonary valve (PV) replacement in postoperative congenital heart disease, but develop structural failure in a time-related fashion. The Melody transcatheter PV (TPV) (Medtronic, Minneapolis, Minn) has been used to treat BPV dysfunction, but there have been few studies in this population. METHODS: We performed a retrospective, multicenter study to evaluate Melody valve function in patients who underwent TPV replacement (TPVR) into a dysfunctional pulmonary BPV. RESULTS: One hundred patients who underwent TPVR at 10 centers between January 2010 and June 2015 were enrolled. The median patient age was 22 years (range, 5-79 years), and 32 patients were age <18 years. The underlying diagnosis was tetralogy of Fallot in 80 patients, and moderate or severe pulmonary regurgitation (PR) was present in 84%. The TPV was implanted into various types of BPVs, with a median size of 23 mm (range, 19-33 mm). At hospital discharge, PR was mild or less in all but 1 patient, and the mean Doppler right ventricular outflow tract (RVOT) gradient was reduced from a mean of 29.3 +/- 12.0 mm Hg to 16.2 +/- 6.9 mm Hg (median, 29 mm Hg to 16 mm Hg; P < .001). During follow-up (median, 12.4 months), no patients underwent reintervention on the TPV. Endocarditis was diagnosed in 1 patient who was managed medically without intervention. The mean RVOT gradient at the most recent follow-up was <=35 mm Hg in all patients, and was similar to that at early postimplantation. PR was more than mild in only 1 patient. Hemodynamic outcomes did not differ between patients with small BPVs (<=23 mm) and those with large BPVs (>=25 mm). CONCLUSIONS: TPVR restores competence and relieves the obstruction of dysfunctional surgical BPVs, with excellent early results in both small and large BPVs, highlighting the potential for TPVR to extend the life of existing BPVs in adults and children. Collaboration between surgeons and cardiologists is important to determine the optimal lifetime management, combining surgical PV replacement and TPVR in this population. PMID- 29395215 TI - KEYNOTE-024: Unlocking a pathway to lung cancer cure? PMID- 29395216 TI - Early macular toxicity following 2 months of hydroxychloroquine therapy. PMID- 29395217 TI - A double-plating approach to distal femur fracture: A clinical study; how apt is the technique? How strong is the evidence? PMID- 29395218 TI - Angiogenic approaches to meniscal healing. AB - Meniscal injuries commonly result in osteoarthritis causing long term morbidity, lifelong treatment, joint replacement and significant financial burden to the Canadian healthcare system. Injuries to the outer third of the meniscus often heal well due to adequate blood supply. Healing of injuries in the inner two thirds of the meniscus are often critically retarded due to a lack of blood flow necessitating partial meniscectomy in many instances. Localized angiogenesis in the inner meniscus has yet to be achieved despite a belief that vascularization of these lesions corresponds with meniscal healing. This review briefly summarizes the growth factors that have been assessed for a role in meniscal healing and points to a significant knowledge gap in our understanding of meniscal healing. PMID- 29395219 TI - A systematic literature review of tibial plateau fractures: What classifications are used and how reliable and useful are they? AB - INTRODUCTION: Classification systems such as the Schatzker and AO/OTA have been proposed for standardised assessment of tibial plateau fractures and to guide clinical decision making. However, there has been no comprehensive literature review of all classification systems for tibial plateau fractures, including assessment of their reliability. The aim of this systematic review was to identify and appraise previously established classification systems for tibial plateau fractures and determine their reliability for fracture classification. METHODS: Six databases were searched from inception until October 2016. Classification systems for tibial plateau fractures were identified. No restriction was placed on imaging modality (plain film X-ray, CT, MRI). Data synthesis was performed to identify common features of the systems, their prevalence within the literature and studies of intra and inter-rater reliability of fracture classification using Kappa coefficient (kappa). RESULTS: Thirty-eight classification systems were identified, five of which were a sub-classification of a single fracture type from a previous tool. The Schatzker and AO/OTA classification systems were the most commonly reported. Of the tools identified only five have been tested for inter and intra-observer reliability (Schatzker, AO/OTA, Duparc, Hohl and Luo). Reliability of more simplistic classification systems, such as that by Luo et al. (three-column) was typically high (intra kappa = 0.67-0.81, inter-kappa = 0.71-0.87), but with the disadvantage of providing less information on fracture patterns and morphology. Intra and inter observer reliability using plain film X-ray was frequently moderate (kappa = 0.40 0.60), with 2D and 3D CT typically improving reliability of classification. Only 11 of the 32 complete classification systems identified association of fracture classification with clinical outcome. DISCUSSION: Frequently used systems for classification of tibial plateau fractures display moderate intra and inter observer reliability. More sophisticated imaging modalities such as 2D and 3D CT typically improve reliability estimates. Using fracture classification based on imaging findings to predict clinical outcome was not a commonly reported goal of newly developed systems. More detailed assessment of fracture patterns and morphology, in conjunction with information on surgical fixation, may be desirable for predicting outcomes and to guide clinical decision making. PMID- 29395220 TI - Comparison of two closed surgical techniques at isolated pediatric radial neck fractures. AB - INTRODUCTION: This paper aims to compare the clinical and radiological results of children operated using elastic stable intramedullary nailing as described by Metaizeau to those with the closed reduction and percutaneous pinning (CRPP). METHODS: Results of 21 pediatric patients with radial neck fracture who were treated by two pediatric surgeons between January 2011 and December 2013 were reviewed retrospectively. 10 were treated with the Metaizeau method versus 11 with the CRPP. Operation time, fluoroscopic exposure time, Mayo elbow performance score (MEPS) and radiological assessment at final follow-up 1 year or greater and complications were main outcome measures. RESULTS: The MEPS were excellent in all the patients of both groups. Reduction quality was excellent in 8 patients and good in 2 of the Metaizeau, and excellent in 9 and good in 2 of the CRPP. The fluoroscopy and operating times were statistically significantly greater, 3-fold and 2-fold respectively, in the Metaizeau method compared to the CRPP with comparable functional and radiological results. CONCLUSION: Surgeon should adhere to a closed surgical method of his/her experience for excellent result. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 29395221 TI - [Letter to the Editor in response to "Evaluation of the efficacy of lidocaine and magnesium sulphate in reducing the hemodynamic effects caused after intubation/laryngoscopy"]. PMID- 29395222 TI - Contrast-enhanced CT findings of intravenous leiomyomatosis. AB - AIM: To characterise the contrast-enhanced computed tomography (CT) imaging findings of nine patients with intravenous leiomyomatosis (IVL). MATERIALS AND METHODS: The contrast-enhanced CT imaging findings of nine patients with histopathologically proven IVL were examined. The location, morphology, extension pathway, adhesion, and degree and pattern of enhancement of the tumour were assessed. RESULTS: Four patients had tumours located within the inferior vena cava, and five had tumours that involved the right heart. Seven patients with residual uterus myoma showed enhanced heterogeneous contrast of the uterus. Eight tumours extended into the inferior vena cava through the iliac veins and one through the bilateral iliac veins. All the IVLs demonstrated heterogeneous enhancement on contrast-enhanced CT and appeared to have lower density than the contrast-enhanced venous blood. On the coronal and sagittal images, tumours were continuous and, when the right heart was involved, the lesions displayed a characteristic "walking stick head" or "snake head" appearance. The lesion looked similar to a "sieve" on axial contrast-enhanced CT images, and a "luffa sponge" on post-processing coronal or sagittal images. CONCLUSION: Contrast-enhanced CT imaging has unique advantages in the diagnosis of IVL, namely, luffa sponge and sieve appearance, which can be helpful for differential diagnosis. Contrast enhanced CT can demonstrate tumour location and full-scale extension pathway, which are important for diagnosis, surgical planning, and follow-up of the tumour. PMID- 29395223 TI - Role of performance metrics in breast screening imaging - where are we and where should we be? AB - The NHS Breast Screening Programme (NHSBSP) was started in 1988 and is a large, organised cancer screening programme. It is delivered by 80 services across England and screens over 2 million women each year. As a screening programme, it must balance the detection of cancers against possible harm to women who do not have cancer. The NHSBSP was therefore designed with detailed information gathering and performance metrics right from the start. In this review paper, we examine how performance metrics in screening mammography have improved the national screening programme and the further developments and challenges that are expected in the years to come. PMID- 29395224 TI - Bomb blast imaging: bringing order to chaos. AB - Blast injuries are complex, severe, and outside of our everyday clinical practice, but every radiologist needs to understand them. By their nature, bomb blasts are unpredictable and affect multiple victims, yet require an immediate, coordinated, and whole-hearted response from all members of the clinical team, including all radiology staff. This article will help you gain the requisite expertise in blast imaging including recognising primary, secondary, and tertiary blast injuries. It will also help you understand the fundamental role that imaging plays during mass casualty attacks and how to avoid radiology becoming a bottleneck to the forward flow of severely injured patients as they are triaged and treated. PMID- 29395226 TI - Three-dimensional primary and coupled range of motions and movement coordination of the pelvis, lumbar and thoracic spine in standing posture using inertial tracking device. AB - Evaluation of spinal range of motions (RoMs) and movement coordination between its segments (thorax, lumbar, and pelvis) has clinical and biomechanical implications. Previous studies have not recorded three-dimensional primary/coupled motions of all spinal segments simultaneously. Moreover, magnitude/direction of the coupled motions of the thorax/pelvis in standing posture and lumbopelvic rhythms in the frontal/transverse planes have not been investigated. This study, hence, used an inertial tracking device to measure T1, T5, T12, total (T1-T12) thoracic, lower (T5-T12) and upper (T1-T5) thoracic, lumbar (T12-S1), and pelvis primary and coupled RoMs as well as their movement coordination in all anatomical planes/directions in twenty-two healthy individuals. RoMs were statistically compared between the anatomical planes and spinal segments as well as with available data in the literature. The spine had different primary RoMs in different planes/directions (flexion: lumbar: 55.4 +/- 12.4 degrees , pelvis: 42.8 +/- 21.6 degrees , and T1-T12 thoracic: 19.9 +/- 6.4 degrees , extension: lumbar: 23.4 +/- 10.1 degrees , thoracic: 11.7 +/- 3.4 degrees , and pelvis: 10.2 +/- 6.4 degrees , left/right lateral bending: thoracic: 24.5 +/- 7.4 degrees /26.5 +/- 6.1 degrees , lumbar: 16.4 +/- 7.2 degrees /18.3 +/- 5.7 degrees , and pelvis: 11.0 +/- 4.4 degrees /9.3 +/- 6.2 degrees , and left/right axial rotation: thoracic: 33.5 +/- 10.0 degrees /37.1 +/ 11.7 degrees , pelvis: 31.6 +/- 12.5 degrees /27.2 +/- 12.0 degrees and lumbar: 7.5 +/- 4.5 degrees /9.2 +/- 7.3 degrees ). Pelvis, lumbar and thoracic spine had different/varying contributions/rhythms to generate total trunk (T1) movement, both within and between planes. Pattern of the coupled motions was inconsistent between subjects but side bending was generally associated with twisting to the same side at the thoracic spine and to the opposite side at the lumbar spine. PMID- 29395225 TI - Mechanical properties of porcine brain tissue in vivo and ex vivo estimated by MR elastography. AB - The mechanical properties of brain tissue in vivo determine the response of the brain to rapid skull acceleration. These properties are thus of great interest to the developers of mathematical models of traumatic brain injury (TBI) or neurosurgical simulations. Animal models provide valuable insight that can improve TBI modeling. In this study we compare estimates of mechanical properties of the Yucatan mini-pig brain in vivo and ex vivo using magnetic resonance elastography (MRE) at multiple frequencies. MRE allows estimations of properties in soft tissue, either in vivo or ex vivo, by imaging harmonic shear wave propagation. Most direct measurements of brain mechanical properties have been performed using samples of brain tissue ex vivo. It has been observed that direct estimates of brain mechanical properties depend on the frequency and amplitude of loading, as well as the time post-mortem and condition of the sample. Using MRE in the same animals at overlapping frequencies, we observe that porcine brain tissue in vivo appears stiffer than porcine brain tissue samples ex vivo at frequencies of 100 Hz and 125 Hz, but measurements show closer agreement at lower frequencies. PMID- 29395227 TI - The relationships between physical capacity and biomechanical plasticity in old adults during level and incline walking. AB - Old compared to young adults exhibit increased hip and decreased ankle mechanical output during walking - a phenomenon known as biomechanical plasticity. Previous comparison studies suggest that low compared to high capacity old adults exhibit larger magnitudes of this plasticity, however the precise relationship between capacity and plasticity magnitude remains unclear. The purpose of this study was to quantify the relationships between physical capacity and biomechanical plasticity magnitude during level and incline walking. Data were collected for 32 old adults walking over level and inclined (+10 degrees ) surfaces at self selected, comfortable speeds. Physical capacity was measured using the Short-Form Health Survey Physical Component (SF-36 PC) and biomechanical plasticity was quantified by ratios of hip extensor to ankle plantarfexor peak torques, angular impulses, peak positive powers, and positive work (larger ratios indicate larger magnitudes of plasticity). SF-36 PC scores correlated positively with all four biomechanical plasticity ratios during level walking and three of the four ratios during incline walking. Some of the biomechanical plasticity ratios correlated positively with comfortable walking speeds and stride frequencies, indicating better walking performance with larger magnitudes of plasticity. Additionally, all four biomechanical plasticity ratios were larger during incline compared to level walking, suggesting the need for larger magnitudes of plasticity during the more difficult task. These results indicate that larger magnitudes of biomechanical plasticity afford functional benefits such as increased level and incline walking performance for old adults. Increased walking performance has the potential to increase quality of life in the growing population of old adults. PMID- 29395228 TI - Defining the medial-lateral axis of the femur: Medical imaging, conventional and functional calibration methods lead to differences in hip rotation kinematics for children with torsional deformities. AB - Hip rotation during gait is a major indicator for femoral derotation osteotomy. However, repeatability of hip rotation is poor because of discrepancies in determining the medial-lateral axis of the femur. Combining 3D gait analysis with medical imaging allows in vivo evaluation of current clinical methods. We used the condylar axis, identified from low dose biplanar radiographs (EOS imaging Inc), as our reference to evaluate conventional, functional calibration and freehand 3D ultrasound methods to define the medial-lateral axis in children with lower-limb torsional deformities. Twenty participants underwent 3D gait analysis accompanied by freehand 3D ultrasound and biplanar radiographs. The condylar axis identified from biplanar radiographs provided the reference method used to construct the femoral coordinate system. This was used to evaluate a conventional, two functional calibration methods (axis transformation technique and 2DoFKnee) and freehand 3D ultrasound. We measured reliability of 3D localisation of skin markers and anatomical landmarks from the biplanar radiographs. Localisation of skin markers (SD 0.4 mm) and anatomical landmarks (SD 1.3 mm) from the biplanar radiographs were reliable, leading to a precision of 1 degrees for the condylar axis after registration in the motion capture system. The freehand 3D ultrasound produced similar results to the biplanar radiographs reference, with internal hip rotation during gait of 18 degrees and 19 degrees respectively. The conventional and functional calibration methods were predominantly external compared to the reference, with average hip rotation of 4-6 degrees internal. Freehand 3D ultrasound and biplanar radiographs provide reliable means to define the medial-lateral axis of femur for gait analysis, and aid clinical interpretation in children with torsional deformities. PMID- 29395229 TI - Getting in shape: Reconstructing three-dimensional long-track speed skating kinematics by comparing several body pose reconstruction techniques. AB - In gait studies body pose reconstruction (BPR) techniques have been widely explored, but no previous protocols have been developed for speed skating, while the peculiarities of the skating posture and technique do not automatically allow for the transfer of the results of those explorations to kinematic skating data. The aim of this paper is to determine the best procedure for body pose reconstruction and inverse dynamics of speed skating, and to what extend this choice influences the estimation of joint power. The results show that an eight body segment model together with a global optimization method with revolute joint in the knee and in the lumbosacral joint, while keeping the other joints spherical, would be the most realistic model to use for the inverse kinematics in speed skating. To determine joint power, this method should be combined with a least-square error method for the inverse dynamics. Reporting on the BPR technique and the inverse dynamic method is crucial to enable comparison between studies. Our data showed an underestimation of up to 74% in mean joint power when no optimization procedure was applied for BPR and an underestimation of up to 31% in mean joint power when a bottom-up inverse dynamics method was chosen instead of a least square error approach. Although these results are aimed at speed skating, reporting on the BPR procedure and the inverse dynamics method, together with setting a golden standard should be common practice in all human movement research to allow comparison between studies. PMID- 29395230 TI - Effects of intervertebral disc lesion and multifidus muscle resection on the structure of the lumbar intervertebral discs and paraspinal musculature of the rat. AB - The aim of this study was to investigate whether elimination of multifidus muscle in rats causes intervertebral disc (IVD) degeneration similar to that found after IVD lesion. Data were obtained from 36 male Wistar rats randomly assigned to one of three groups: (i) IVD lesion, in which the L4/L5 IVD was stabbed; (ii) multifidus muscle resection, in which all multifidus tissue between L3 and L6 was excised bilaterally; (iii) control, in which no intervention was applied. At 7, 14, and 28 days post-intervention, L4/L5 IVDs were harvested for histological analysis; left and right multifidus fascicles between L3 and S1 (from control and IVD lesion animals) and medial longissimus between L1 and S3 (from all animals) were dissected and weighed. ANOVA indicated significant group differences and a significant interaction between group and days for relative nucleus pulposus area and for multifidus mass normalized to body mass. No significant effects were observed for whole IVD area. At 14 days post-op, the IVD lesion group had a significantly smaller relative nucleus pulposus area than control and multifidus resection groups. Nucleus pulposus size did not differ from control at 7 and 28 days. At 7 days post-intervention, normalized multifidus mass was significantly lower (20%) in the IVD lesion group. For longissimus mass, no between-group differences were found. These results indicate that, in rats, IVD recovers quickly after lumbar IVD lesion and multifidus disruption does not cause IVD degeneration within the time studied. PMID- 29395231 TI - Original article submission: Platelet stress accumulation analysis to predict thrombogenicity of an artificial kidney. AB - An implantable artificial kidney using a hemofilter constructed from an array of silicon membranes to provide ultrafiltration requires a suitable blood flow path to ensure stable operation in vivo. Two types of flow paths distributing blood to the array of membranes were evaluated: parallel and serpentine. Computational fluid dynamics (CFD) simulations were used to guide the development of the blood flow paths. Pressure data from animal tests were used to obtain pulsatile flow conditions imposed in the transient simulations. A key consideration for stable operation in vivo is limiting platelet stress accumulation to avoid platelet activation and thrombus formation. Platelet stress exposure was evaluated by CFD particle tracking methods through the devices to provide distributions of platelet stress accumulation. The distributions of stress accumulation over the duration of a platelet lifetime for each device revealed that stress accumulation for the serpentine flow path exceeded levels expected to cause platelet activation while the accumulated stress for the parallel flow path was below expected activation levels. PMID- 29395232 TI - A flow-chart for developing water quality criteria from two field-based methods. AB - Field-based methods increase relevance and realism when setting water quality criteria. They also pose challenges. To enable a consistent process, a flow chart was developed for choosing between two field-based methods and then selecting among candidate results. The two field-based methods estimated specific conductivity (SC) levels likely to extirpate 5% of benthic invertebrate genera: an extirpation concentration distribution (XCD) method and a background-to criterion (B-C) model developed by the U.S. Environmental Protection Agency. The B-C model is a least squares regression of the 5th centile of XCD (XCD05) values against estimates of background SC. Selection of an XCD05 from the flowchart is determined by characteristics of the paired chemical and biological data sets and method for estimating the XCD05 values. Confidence in these example SC XCD05 values is based on the size of the data sets and ecoregional SC disturbance. The level of ecoregional SC disturbance was judged by comparing the background SC (the 25th centile of the data set used to calculate a XCD05) and an estimate of natural base-flow SC modeled from geophysical attributes in the region. The B-C approach appears to be a viable option for estimating a SC benchmark with inexpensive estimates of SC background while the XCD method is used when the data are abundant. To illustrate the use of the flow chart, example SC XCD05 values were calculated for 63 of 86 Level III ecoregions in the conterminous United States of America. PMID- 29395233 TI - Predictors of cardiogenic shock in cardiac surgery patients receiving intra aortic balloon pumps. AB - BACKGROUND: Cardiogenic shock after cardiac surgery leads to severely increased mortality. Intra-aortic balloon pumps may be used during the preoperative period to increase coronary perfusion. The purpose of this study was to characterize predictors of postoperative cardiogenic shock in cardiac surgery patients with and without intra-aortic balloon pumps support. METHODS: We performed a retrospective analysis of our institutional database of the Society of Thoracic Surgeons for patients operated between January 2008 to July 2015. Multivariable logistic regression was used to model postoperative cardiogenic shock in both the intra-aortic balloon pumps and matched control cohorts. RESULTS: Overall, 4,741 cardiac surgery patients were identified during the study period, of whom 192 (4%) received a preoperative intra-aortic balloon pump. Intra-aortic balloon pumps patients had a greater prevalence of diabetes, previous cardiac surgery, congestive heart failure, and an urgent/emergent status (P < .001). Intra-aortic balloon pumps patients also had greater 30-day mortality and more postoperative cardiogenic shock (9% vs 3%, P < .001). On multivariable analysis of the matched control cohort, postoperative cardiogenic shock remained multifactorial. Among the intra-aortic balloon pumps cohort, only sex, previous percutaneous coronary intervention and preoperative arrhythmia remained significant on multivariable analysis (all P < .05). CONCLUSION: Factors associated with cardiogenic shock among postcardiac surgery patients differ between those patients receiving intra aortic balloon pumps and those who do not. Further analysis of the effects of prophylactic intra-aortic balloon pumps support is warranted. (Surgery 2017;160:XXX-XXX.). PMID- 29395235 TI - Human diabetic mesenchymal stem cells from peripheral arterial disease patients promote angiogenesis through unique secretome signatures. AB - BACKGROUND: Diabetic patients are at increased risk of complications from severe peripheral arterial disease. Mesenchymal stem cells (MSC) may be useful in limiting these complications. Our objective is to test the angiogenic potential of diabetic versus healthy MSCs. METHODS: MSCs' angiogenic potential was tested by endothelial cell (EC) proliferation, migration, and 3-dimensional sprouting. Diabetic conditions were simulated with 5.5, 20, or 40 mM glucose. MSC secretome was quantified by enzyme-linked immunosorbent assay. RESULTS: Human aortic ECs were most sensitive to glucose conditions and were used for all MSC experiments. Diabetic MSCs had greater 3-dimensional invasion than healthy MSCs (P<.05), but EC sprouting was decreased in high glucose conditions in both diabetic and healthy MSCs. Secretome analysis demonstrated that 20mM glucose stimulated epidermal growth factor (EGF) expression in diabetic and healthy MSCs, but that diabetic MSCs had a unique secretome with increased levels of chemokine (C-X-C motif) ligand 1 (CXCL-1), interleukin six (IL-6), and monocyte chemoattractant protein 1 (MCP-1) (P<.05). CONCLUSION: Despite having similar in vitro angiogenic activity, diabetic MSCs secrete a unique and inflammatory angiogenic signature that may influence MSC survival and function after transplantation in cell therapy applications. Strategies that normalize secretome in diabetic patients may improve the utility of autologous MSCs in this population of patients. PMID- 29395234 TI - Postoperative complications after resection of borderline resectable and locally advanced pancreatic cancer: The impact of neoadjuvant chemotherapy with conventional radiation or stereotactic body radiation therapy. AB - BACKGROUND: The impact of neoadjuvant stereotactic body radiation therapy on postoperative complications for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma remains unclear. Limited studies have compared neoadjuvant stereotactic body radiation therapy versus conventional chemoradiation therapy. A retrospective study was performed to determine if perioperative complications were different among patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant stereotactic body radiation therapy or chemoradiation therapy. METHODS: Patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma who underwent neoadjuvant chemotherapy with stereotactic body radiation therapy or chemoradiation therapy followed by pancreatectomy at the Johns Hopkins Hospital between 2008 and 2015 were included. Predictive factors for severe complications (Clavien grade >= III) were assessed by univariate and multivariate analyses. RESULTS: A total of 168 patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma underwent neoadjuvant chemotherapy and RT followed by pancreatectomy. Sixty-one (36%) patients underwent stereotactic body radiation therapy and 107 (64%) patients received chemoradiation therapy. Compared with the chemoradiation therapy cohort, the neoadjuvant stereotactic body radiation therapy cohort was more likely to have locally advanced pancreatic ductal adenocarcinoma (62% vs 43% P = .017) and a require vascular resection (54% vs 37%, P = .027). Multiagent chemotherapy was used more commonly in the stereotactic body radiation therapy cohort (97% vs 75%, P < .001). Postoperative complications (Clavien grade >= III 23% vs 28%, P = .471) were similar between stereotactic body radiation therapy and chemoradiation therapy cohort. No significant difference in postoperative bleeding or infection was noted in either group. CONCLUSION: Compared with chemoradiation therapy, neoadjuvant stereotactic body radiation therapy appears to offer equivalent rates of perioperative complications in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma despite a greater percentage of locally advanced disease and more complex operative treatment. PMID- 29395236 TI - Randomized trial of low versus high carbon dioxide insufflation pressures in posterior retroperitoneoscopic adrenalectomy. AB - BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has gained widespread acceptance for the removal of benign adrenal tumors. Higher insufflation pressures using carbon dioxide (CO2) are required, although the ideal starting pressure is unclear. This prospective, randomized, single-blinded, study aims to compare physiologic differences with 2 different CO2 insufflation pressures during posterior retroperitoneoscopic adrenalectomy. METHODS: Participants were randomly assigned to a starting insufflation pressure of 20 mm Hg (low pressure) or 25 mm Hg (high pressure). The primary outcome measure was partial pressure of arterial CO2 at 60 minutes. Secondary outcomes included end-tidal CO2, arterial pH, blood pressure, and peak airway pressure. Breaches of protocol to change insufflation pressure were permitted if required and were recorded. RESULTS: A prospective randomized trial including 31 patients (low pressure: n = 16; high pressure: n = 15) was undertaken. At 60 minutes, the high pressure group had greater mean partial pressure of arterial CO2 (64 vs 50 mm Hg, P = .003) and end tidal CO2 (54 vs 45 mm Hg, P = .008) and a lesser pH (7.21 vs 7.29, P = .0005). There were no significant differences in base excess, peak airway pressure, operative time, or duration of hospital stay. Clinically indicated protocol breaches were more common in the low pressure than the high pressure group (8 vs 3, P = .03). CONCLUSION: In posterior retroperitoneoscopic adrenalectomy, greater insufflation pressures are associated with greater partial pressure of arterial CO2 and end-tidal CO2 and lesser pH at 60 minutes, be significant. Commencing with lesser CO2 insufflation pressures decreases intraoperative acidosis. PMID- 29395237 TI - Learning preferences of surgery residents: a multi-institutional study. AB - BACKGROUND: The VARK model categorizes learners by preferences for 4 modalities: visual, aural, read/write, and kinesthetic. Previous single-institution studies found that VARK preferences are associated with academic performance. This multi institutional study was conducted to test the hypothesis that the VARK learning preferences of residents differ from the general population and that they are associated with performance on the American Board of Surgery In-Training Examination (ABSITE). METHODS: The VARK inventory was administered to residents at 5 general surgery programs. The distribution of the VARK preferences of residents was compared with the general population. ABSITE results were analyzed for associations with VARK preferences. chi2, Analysis of variance, and multiple linear regression were used for statistical analysis. RESULTS: A total of 132 residents completed the VARK inventory. The distribution of the VARK preferences of residents was different than the general population (P < .001). The number of aural responses on the VARK inventory was an independent predictor of ABSITE percentile rank (P = .03), percent of questions correct (P = .01), and standard score (P = .01). CONCLUSION: This study represents the first multi-institutional study to examine VARK preferences among surgery residents. The distribution of preferences among residents was different than that of the general population. Residents with a greater number of aural responses on VARK had greater ABSITE scores. The VARK model may have potential to improve learning efficiency among residents. PMID- 29395238 TI - Identification of risk factors for 30-day postoperative complications in patients undergoing primary ventral hernia repair: a prospective cohort study of 2,374 patients. AB - BACKGROUND: Primary ventral hernia is a common condition. Surgical repair is associated with complications, but no clear predictive risk factors have been identified. The European Hernia Society classification offers a structured framework to describe hernias and to analyze postoperative complications. Given this structured nature, the European Hernia Society classification might prove useful for preoperative patient or treatment classification. The objective of this study was to investigate the European Hernia Society classification as a predictor for complications within 30 days after primary ventral hernia surgery. METHODS: A registry-based, prospective cohort study was performed, including all patients undergoing primary ventral hernia surgery between September 1, 2011 and February 29, 2016. Univariate analyses and multivariable logistic regression analysis were performed to identify risk factors for postoperative complications. RESULTS: A total of 2,374 patients were included, of whom 105 (4.4%) patients had >=1 complications, either a wound, surgical, or medical complication. Factors associated with complications in univariate analyses (P<.10) and clinically relevant factors were included into the multivariable analyses. In the multivariable analyses, age, body mass index, and the duration of the operation were independent risk factors. The diameter of the hernia was not an independent risk factor. CONCLUSION: Primary ventral hernia repair is associated with a 4.4% rate of complications. No correlation was found between the European Hernia Society classification and postoperative complications. Age, body mass index, and duration of the operation were correlated with postoperative complications. Therefore, age and body mass index should be used in the preoperative risk assessment. PMID- 29395239 TI - Re: Each procedure matters: threshold for surgeon volume to minimize complications and decrease cost associated with adrenalectomy. PMID- 29395240 TI - Using epistemic network analysis to identify targets for educational interventions in trauma team communication. AB - BACKGROUND: Epistemic Network Analysis (ENA) is a technique for modeling and comparing the structure of connections between elements in coded data. We hypothesized that connections among team discourse elements as modeled by ENA would predict the quality of team performance in trauma simulation. METHODS: The Modified Non-technical Skills Scale for Trauma (T-NOTECHS) was used to score a simulation-based trauma team resuscitation. Sixteen teams of 5 trainees participated. Dialogue was coded using Verbal Response Modes (VRM), a speech classification system. ENA was used to model the connections between VRM codes. ENA models of teams with lesser T-NOTECHS scores (n = 9, mean = 16.98, standard deviation [SD] = 1.45) were compared with models of teams with greater T-NOTECHS scores (n = 7, mean = 21.02, SD = 1.09). RESULTS: Teams had different patterns of connections among VRM speech form codes with regard to connections among questions and edifications (meanHIGH = 0.115, meanLOW = -0.089; t = 2.21; P = .046, Cohen d = 1.021). Greater-scoring groups had stronger connections between stating information and providing acknowledgments, confirmation, or advising. Lesser-scoring groups had a stronger connection between asking questions and stating information. Discourse data suggest that this pattern reflected increased uncertainty. Lesser-scoring groups also had stronger connections from edifications to disclosures (revealing thoughts, feelings, and intentions) and interpretations (explaining, judging, and evaluating the behavior of others). CONCLUSION: ENA is a novel and valid method to assess communication among trauma teams. Differences in communication among higher- and lower-performing teams appear to result from the ways teams use questions. ENA allowed us to identify targets for improvement related to the use of questions and stating information by team members. PMID- 29395241 TI - Anticoagulant drug choice in patients who have had bariatric surgery - Presently, DOACs are not the preferred choice. PMID- 29395242 TI - Suitability for catheter-directed thrombolysis in patients with acute lower extremity deep vein thrombosis according to various international consensus guidelines. PMID- 29395243 TI - Risk prediction of cancer-associated thrombosis: Appraising the first decade and developing the future. AB - Cancer-associated venous thromboembolism (VTE) has major consequences for patients, including morbidity and risk of mortality. However, there is substantial variation in risk depending on a multitude of clinical risk factors and many cancer patients are at low risk for VTE. This critical concept of risk variation has led to efforts to identify patients at high or low risk for developing VTE. Our research group and others have focused on understanding and predicting risk of cancer-associated VTE. This narrative review describe research efforts conducted over the past decade, beginning with the 2008 publication of the first validated risk assessment tool in this setting. We describe current applications of the "Khorana score" including identification of high- and low risk patients, selecting and excluding patients for thromboprophylaxis and screening high-risk patients for early detection of VTE. New approaches to risk prediction including precision medicine and next-generation sequencing are discussed. Finally, we offer suggestions on improving the field of risk prediction in this setting in the near future. PMID- 29395244 TI - The effects of ghrelin on sleep, appetite, and memory, and its possible role in depression: A review of the literature. AB - OBJECTIVES: Ghrelin is an orexigenic digestive hormone that plays a role in sleep and memory. Our work aims is to synthesize the effects of ghrelin on appetite, sleep and memory, and also to evidence its role in depressive disorders. METHODS: A systematic search was carried out on PubMed with no time boundaries. The following MeSH terms were used: ghrelin AND (appetite regulation OR obesity), (sleep wake disorders OR sleep) (memory OR cognition disorders) (depression OR depressive disorder OR mood disorder). RESULTS: Ghrelin triggers appetite and alters meal patterns by making them longer and richer. This can lead to pathologies, obesity and insulin-resistance. Ghrelin seems to have a favourable effect on sleep in human beings. It tends to make sleep more efficacious and better quality. Finally, it seems to have an effect on synaptic plasticity in the zones involved in memory and it has been shown to improve memory capacity in rodents. Regarding depression, the administration of ghrelin leads to an anti depressive effect in animals and in humans. Conversely, post anti-depressant ghrelin titrations have generally shown a decrease in ghrelin levels. Resistant patients seem to retain high levels. Finally, the seriousness of depression could be related to ghrelin levels. CONCLUSION: Ghrelin plays a probable part in depression, especially for particular endophenotypes. A better understanding of ghrelin in depression could potentially help to optimize future therapeutic treatments. PMID- 29395245 TI - Exploration of mental health of health students: Dental and medical formations promote anhedonia. AB - OBJECTIVES: Health students usually report to experience stress during their formation. This is due to their exposure to patient's disease or death, to their learning of interpersonal relationships, and to the discovery of health practitioner's responsibility. Anhedonia represents a deficit in experiencing pleasure that is promoted by stressful living conditions. We hypothesized that health formations promote anhedonia. Our objectives have consisted in measuring anhedonia and analyzing its variation and heterogeneity among health students. METHODS: The Temporal Experience of Pleasure Scale (TEPS) was used to assess anhedonia and its anticipatory and consummatory dimensions. TEPS corresponds to an 18-item questionnaire, the score of which is based on a 6-point Likert scale. Low score indicates a high anhedonia propensity. Score differences were analyzed by considering gender, curriculum and formation as independent variables. A cluster analysis was used to explore anhedonia heterogeneity among our sample. RESULTS: We collected 1231 responses. Our data confirm French TEPS as a reliable tool for anhedonia evaluation in dental and medical students. Statistical analyses reveal a significant effect of gender (male>female), curriculum (clinical>preclinical) and formation (dental>medical) on anhedonia propensity. Cluster analysis highlights four sub-groups of students characterized by increasing anhedonia traits and by different gender, formation and curriculum proportions. CONCLUSION: This work describes the first analysis of anhedonia manifestation during dental and medical studies in France. The consequences of our findings for the comprehension of dental and medical students' mental health during their formation are discussed. PMID- 29395246 TI - How to stay in touch with adolescents and young adults after a suicide attempt? Implementation of a 4-phones-calls procedure over 1 year after discharge from hospital, in a Parisian suburb. AB - OBJECTIVES: Post-discharge treatment is a major part of youth suicide prevention. However, many adolescents and young adults suicidal patients released from emergency department (ED) fail to follow through with subsequent outpatient psychiatric appointments. The aims were to (1) implement a one-year follow-up phone-call program for adolescent and young adults suicide attempters admitted at the ED (2) assess its feasibility (3) describe outcomes measures (repeated suicide attempt and observance of outpatient care) and (4) access risk factors to be out of sight at one year follow up and (5) elicit subjective feedback after one year, using narrative data. METHOD: A cohort of adolescents and young adults aged 15-21 years admitted to Avicenne University Hospital ED for suicide attempt (SA) was created and re-contacted using phone calls at one week, one month, six months and twelve months after discharge. Sociodemographic information was collected at baseline. At one year, qualitative data was collected from patients or their parents. RESULTS: One hundred and seventy-three adolescents and young adults were included. At 1 year, 93 young patients had been successfully contacted, among whom 23 had reattempted suicide, at least once. Adolescents and young adults that were unreachable at one year showed a higher rate of school dropout and had more migration history at baseline. Feedback showed that the intervention was experienced as supportive. CONCLUSION: Phone-calls after discharge from hospital might help enhance compliance to aftercare treatment, and were well-accepted by both adolescents and parents. Nevertheless, half of our sample was lost of sight at one year. Further studies are needed to find the most effective prevention strategy with young suicide attempters, especially for migrants and school droppers. PMID- 29395247 TI - [Dicosemiopsy, a lexicon app of video-illustrated psychiatric semiology]. PMID- 29395248 TI - Corrigendum to "Attractive names sustain increased vegetable intake in schools" [Prev. Med. 55 (4) (2012) 330-332]. PMID- 29395249 TI - New data on intimate partner violence and intimate relationships: Implications for gun laws and federal data collection. AB - Age at first marriage has risen substantially and birth rates are at a record low; people are spending more time in relationships that, by comparison, have fewer emotional, financial, and legal commitments. Little research has examined intimate partner violence (IPV) prevalence in current and former adult (vs. adolescent) dating relationships. Such information is relevant to federal firearms policies that are based on the nature of an intimate relationship. We examined assaultive behaviors by the type and status of the relationship - current spouse, former spouse, current boyfriend or girlfriend, and former boyfriend or girlfriend - in 31,206 IPV incidents responded to by Philadelphia police in 2013. Over 80% of the IPV incidents involved individuals in non-marital relationships. Incidents involving current boyfriends or girlfriends had the highest percentage of violent behaviors (e.g., punch, strangle). They also were more likely than current spouses to use bodily weapons (hands, fists, or feet) or non-gun weapons (knives, bats, etc.) (AOR = 1.19 and 1.43, respectively), to injure their victims (AOR = 1.37), and to be arrested (AOR = 1.46). Former unmarried partners had the highest odds of stalking their intimate (AOR = 3.37) and violating a restraining order (AOR = 2.61). Gun use was similar across relationship type. A growing portion of the population is not protected by federal policies designed to keep guns out of the hands of abusers. Current boyfriends and girlfriends are a risk to their intimates. Federal data collection practices and firearm policies merit updating to more fully take into account dating, same-sex marriage, and other partnerships. PMID- 29395250 TI - A common genetic variant in CACNA1C predicts heart rate in patients with bipolar disorder. PMID- 29395251 TI - The potential of nanoparticle vaccines as a treatment for cancer. AB - A complex and multifaceted relationship exists between cancer and the immune system. Advances in our understanding of this relationship have resulted in significant clinical attention in the possibilities of cancer immunotherapy. Harnessing the immune system's potent and selective destructive capability is a major focus of attempts to treat cancer. Despite significant progress in the field, cancer therapy still remains significantly deficient, with cancer being one of the largest contributors to morbidity and mortality in the developed world. It is evident that the design of new treatment regimes is required to exploit cancer immunotherapy. Herein we review the potential for nanotechnology to overcome the challenges that have limited the more widespread implementation of immunotherapy to cancer treatment. PMID- 29395252 TI - Laparoscopic Sleeve Gastrectomy: A Radiological Guide to Common Postsurgical Failure. AB - Laparoscopic sleeve gastrectomy is one of the most common bariatric procedures worldwide. It has recently gained in popularity because of a low complication rate, satisfactory resolution of comorbidities, and excellent weight loss outcome. This article reviews the surgical technique, expected postsurgical imaging appearance, and imaging findings of common complications after laparoscopic sleeve gastrectomy. Understanding of the surgical technique of laparoscopic sleeve gastrectomy and of the normal postsurgical anatomy allows accurate interpretation of imaging findings in cases of insufficient weight loss, weight regain, and postsurgical complications. PMID- 29395253 TI - Financial Impact of PEVAR Compared With Standard Endovascular Repair in Canadian Hospitals. AB - OBJECTIVES: The percutaneous endovascular abdominal aortic repair (PEVAR) approach is a minimally invasive technique that has demonstrated clinical benefit over traditional surgical cut down associated with standard endovascular abdominal aortic aneurysm (AAA) repair (EVAR). The objective of our study was to evaluate the budget impact to a Canadian hospital of changing the technique for AAA repair from the EVAR approach to the PEVAR approach. METHODS: We examined the budget impact of replacing the EVAR approach with the PEVAR approach in a Canadian hospital that performs 100 endovascular AAA repairs annually. The model incorporates the costs associated with surgery, length of stay, and postoperative complications occurring within 30 days. RESULTS: The use of PEVAR in AAA repair is associated with increased access device costs when compared with the EVAR approach (CAD$1000 vs CAD$400). However, AAA repair completed with the PEVAR approach demonstrates reduced operating time (101 minutes vs 133 minutes), length of stay (2.2 days vs 3.5 days), time in the recovery room (174 minutes vs 193 minutes), and postoperative complications (6% vs 30%), which offset the increased device costs. The model establishes that switching to the PEVAR approach in a Canadian hospital performing 100 AAA repairs annually would result in a potential cost avoidance of CAD$245,120. CONCLUSIONS: A change in AAA repair technique from EVAR to PEVAR can be a cost-effective solution for Canadian hospitals. PMID- 29395254 TI - Urinary tract infection after acute stroke: Impact of indwelling urinary catheterization and assessment of catheter-use practices in French stroke centers. AB - INTRODUCTION: Urinary catheterization and acute urinary retention increase the risk of urinary tract infection (UTI). Our study aimed to investigate the incidence of UTI following acute stroke at our stroke center (SC) and to assess urinary catheter-care practices among French SCs. METHODS: Stroke patients hospitalized within 24h of stroke onset were prospectively enrolled between May and September 2013. Neurological deficit level was assessed on admission using the US National Institutes of Health Stroke Scale (NIHSS). Patients were followed up until discharge. Indwelling urinary catheterization (IUC) was the only technique authorized during the study. An electronic survey was also conducted among French SCs to assess their practices regarding urinary catheterization in acute stroke patients. RESULTS: A total of 212 patients were included, with 45 (21.2%) receiving indwelling urinary catheters. The overall estimated incidence of UTI was 14.2%, and 18% among patients receiving IUC. On univariate analysis, IUC was significantly associated with older age, longer hospital stays and higher NIHSS scores. Of the 30 SCs that responded to our survey, 19 (63.3%) declared using IUC when urinary catheterization was needed. The main argument given to justify its use was that it was departmental policy to adopt this technique. Also, 27 participants (90%) stated that conducting a study to assess the impact of urinary catheterization techniques on UTI rates in acute stroke patients would be relevant. DISCUSSION: Our results are in accord with previously reported data and confirm the high burden of UTI among acute stroke subjects. However, no association was found between IUC and UTI on univariate analysis due to a lack of statistical power. Also, our survey showed high heterogeneity in catheter-use practices among French SCs, but offered no data to help determine the best urinary catheterization technique. CONCLUSION: Urinary catheterization is common after acute stroke and a well-known risk factor of UTI. However, as high heterogeneity in catheter-use practices is found among French SCs, randomized studies comparing the efficacy of urinary catheterization techniques in terms of UTI prevention in acute stroke patients are now warranted. PMID- 29395256 TI - Membrane attack complex (mac) deposition in lupus nephritis is associated with hypertension and poor clinical response to treatment. AB - OBJECTIVE: To study membrane attack complex in lupus nephritis as a potential biomarker for disease intensity and prognostic indicator for response to treatment. METHODS: Immunohistochemistry was performed using unconjugated, murine anti-human complement C9 on kidney biopsies from 30 SLE patients who fulfilled 4 ACR or SLICC criteria. Clinical parameters were assessed at time of biopsy, 6 and 12 months. RESULTS: 30 renal biopsies were obtained from patients with Class II (2), III (5), IV (8), V (5), III+V (8) and IV+V (2). 13/30 (43.3%) biopsies stained positive for glomerular C9. Patients with positive C9 had significantly higher blood pressure, trend towards lower C3, and male gender. There was no significant difference for ISN/RPN class, activity or chronicity indices between C9 positive and negative groups. 5/11 (45.5%) patients positive for C9 did not respond to therapy at 6 months compared with 2/15 (13.3%) patients negative for C9. C9 positive patients were more likely to be a non-responder at 6 months (OR = 5.4, 95% CI: 0.8, 36.4) compared to C9 negative patients. After adjusting for systolic blood pressure, compliance to treatment and proteinuria in a multivariate logistic model, C9 positive patients remained more likely to be non responders (OR = 4.6, 95% CI: 0.3, 70.9). CONCLUSION: This study suggests that MAC deposition measured as C9 staining may be a biomarker for more intense disease and poor response to treatment in lupus nephritis. MAC staining may be useful in routine studies of lupus biopsies and identify patients at risk for aggressive disease who may be candidates for novel therapies targeting terminal complement pathway. PMID- 29395255 TI - Lessons learned from bone marrow failure in systemic lupus erythematosus: Case reports and review of the literature. AB - OBJECTIVE: In the present review, four new cases of bone marrow failure are presented and the potential contribution of systemic lupus erythematosus (SLE) is discussed. Furthermore, a comprehensive literature review of cases of autoimmune myelofibrosis (AIMF), aplastic anemia (AA), and paroxysmal nocturnal hemoglobinuria (PNH) with concurrent SLE aims to allow their direct comparison. Based on a clearer characterization of reported cases and our own experience, diagnostic and therapeutic strategies of these disorders in SLE are proposed based on lessons learned from the present and previous cases. METHODS: A literature search was done in PubMed, accessed via the National Library of Medicine PubMed interface (http://www.ncbi.nlm.nih.gov/pubmed). Using PubMed, a Boolean search of the literature was performed by crossing the keywords "systemic lupus erythematosus," AND ["bone marrow fibrosis" or "bone marrow failure" or "myelofibrosis" or "aplastic anemia" or "paroxysmal nocturnal hemoglobinuria"]. RESULTS: After a stringent selection of previous cases with a clear diagnosis of SLE, we summarized in the present review 31 cases of AIMF, 26 cases of AA, and 3 cases of PNH. In addition, four new cases illustrate the problem of attribution of bone marrow failure to SLE. CONCLUSIONS: The attribution of SLE to bone marrow failure is challenging due to a lack of biomarkers, which complicates treatment decisions. Autoimmune myelofibrosis is likely underreported, but corticosteroids and intravenous immunoglobulin appear to be effective immediate therapies. In AA attributable to SLE, a serum inhibitor of bone marrow precursors should be tested, since plasma exchange has been universally successful in these cases, and a PNH clone should be tested for in the setting of ongoing hemolysis, as complement inhibition may be effective. Further research is warranted to elucidate pathophysiological mechanisms of bone marrow failure in SLE. PMID- 29395257 TI - Assessing health-related quality of life in primary Sjogren's syndrome-The PSS QoL. AB - OBJECTIVES: To develop a questionnaire for the assessment of health-related quality of life (HRQL) in primary Sjogren's syndrome (PSS), and to test its psychometric properties. METHODS: Based on the concepts of a previous qualitative study, a questionnaire for the assessment of HRQL in PSS (PSS-QoL) was developed. Psychometric testing of PSS-QoL was performed after revising the first draft with feedback of patients (n = 6) and clinicians (n = 4). Convergent construct validity was assessed by correlating the score with the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) and Euro-QoL 5D (EQ-5D). Reliability was examined by asking patients to complete the questionnaire twice 1-2 weeks apart. An English Version of the PSS QoL was developed by using standard methodology with forward and back translation. RESULTS: Out of the 75 PSS patients, 91% were female, mean (+/-SD) age was 58.5 +/- 12.5 years. PSS-QoL consists of 25 questions and can be divided into two main categories: physical (discomfort and dryness) and psychosocial. The internal consistency of the PSS-QoL revealed a Crohnbach's alpha of 0.892. Strong and moderate correlations were found between the PSS-QoL and ESSPRI (corrcoeff = 0.755) and EQ. 5D-pain/discomfort (corrcoeff = 0.531). Reproducibility of the PSS QoL was high, yielding an ICC of 0.958 (95% CI: 0.926-0.981). CONCLUSIONS: The PSS-QoL is the first specific tool for the assessment of patients' HRQL in PSS and showed good psychometric properties. It may serve as a novel patient-reported outcome measure in future clinical studies. PMID- 29395259 TI - Biomarkers in mood disorders: Are we there yet? PMID- 29395258 TI - Extra-criteria manifestations of antiphospholipid syndrome: Risk assessment and management. AB - OBJECTIVES: Extra-criteria manifestations of antiphospholipid syndrome (APS) might impact on prognosis and morbidity of the disease. In this study, we aimed to evaluate a population of patients with primary APS (PAPS) whether the extra criteria manifestations were more frequently found in subjects with higher adjusted Global APS Score (aGAPSS) values when compared to patients with thrombotic and/or obstetric APS ("criteria" manifestations) only. METHODS: Clinical records were analyzed to retrieve extra-criteria manifestation of APS, cardiovascular risk factors and antiphospholipid antibodies profile. The aGAPSS was calculated by adding the points, as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for anticardiolipin antibodies IgG/IgM, 4 for anti-beta2 glycoprotein I IgG/IgM, and 4 for lupus anticoagulant. RESULTS: This retrospective multicenter study included 89 consecutive PAPS [mean age 43.1 (S.D. +/- 12.9), female 67%, 52% arterial and 65% venous]. Twenty-seven patients (30.3%) had a history of livedo, 19 (21.3%) had a history of confirmed thrombocytopenia, 3 (3.4%) had biopsy-proven antiphospholipid antibodies (aPL) related nephropathy and 3 (3.4%) had a history of valvulopathy. Patients with extra-criteria manifestations presented a mean aGAPSS significantly higher [mean 10.30 (S.D. +/- 3.57, range: 4-17) vs mean 8.16 (S.D. +/- 3.52;range: 4-16, p = 0.005). When comparing patients with and without extra-criteria manifestations, the first group had significantly higher incidence of anti-beta2GPI antibodies positivity (59% and 33%, respectively, p = 0.015), double aPL positivities (53% and 31%, respectively, p = 0.034), cerebrovascular events history (52% and 24%, respectively, p = 0.007) and arterial hypertension (52% and 24%, respectively, p = 0.007). CONCLUSIONS: Our results suggest that patients with higher aGAPSS, might be at higher risk for developing extra-criteria manifestations of APS and should therefore undergo a thorough laboratory and instrumental evaluation. PMID- 29395260 TI - Drivers of shell growth of the bivalve, Callista chione (L. 1758) - Combined environmental and biological factors. AB - Seasonal shell growth patterns were analyzed using the stable oxygen and carbon isotope values of live-collected specimens of the bivalve Callista chione from two sites in the Adriatic Sea (Pag and Cetina, Croatia). Micromilling was performed on the shell surface of three shells per site and shell oxygen isotopes of the powder samples were measured. The timing and rate of seasonal shell growth was determined by aligning the delta18Oshell-derived temperatures so that the best fit was achieved with the instrumental temperature curve. According to the data, shells grew only at very low rates or not at all during the winter months, i.e., between January and March. Shell growth slowdown/shutdown temperatures varied among sites, i.e., 13.6 degrees C at Pag and 16.6 degrees C at Cetina, indicating that temperature was not the only driver of shell growth. Likely, seasonal differences in seawater temperature and food supply were the major component explaining contrasting growth rates of C. chione at two study sites. Decreasing shell growth rates were also associated with the onset of gametogenesis suggesting a major energy reallocation toward reproduction rather than growth. These results highlight the need to combine sclerochronological analyses with ecological studies to understand life history traits of bivalves as archives of environmental variables. PMID- 29395261 TI - The mechanisms of filter feeding on oil droplets: Theoretical considerations. AB - Filter feeding animals capture food particles and oil droplets from the fluid environment using cilia or appendages composed of arrays of fibers. Here we review the theoretical models that have provided a foundation for observations on the efficiency of particle capture. We then provide the mathematical theoretical framework to characterize the efficient filtration of oil droplets. In the aquatic and marine environments oil droplets are released from the decay of organisms or as hydrocarbons. Droplet size and flow velocity, oil-to-water viscosity ratio, oil-water interfacial tension, oil and water density difference, and the surface wettability, or surface texture, of the filter fiber are the key parameters for oil droplet capture. Following capture, capillary force maintains the droplet at its location due to the oil-water interfacial tension. If the oil coated fiber is subject to any external force such as viscous or gravitational forces, it may deform and separate from the fiber and re-enter the fluid stream. We show oil droplet capture in Daphnia and the barnacle Balanus glandula, and outline some of the ecological unknowns regarding oil capture in the oceans. Awareness of these mechanisms and their interrelationships will provide a foundation for investigations into the efficiency of various modes of filter feeding on oil droplets. PMID- 29395262 TI - Profiles of environmental contaminants in hawksbill turtle egg yolks reflect local to distant pollution sources among nesting beaches in the Yucatan Peninsula, Mexico. AB - Knowledge of spatial variation in pollutant profiles among sea turtle nesting locations is limited. This poses challenges in identifying processes shaping this variability and sets constraints to the conservation management of sea turtles and their use as biomonitoring tools for environmental pollutants. We aimed to increase understanding of the spatial variation in polycyclic aromatic hydrocarbon (PAH), organochlorine pesticide (OCP) and polychlorinated biphenyl (PCB) compounds among nesting beaches. We link the spatial variation to turtle migration patterns and the persistence of these pollutants. Specifically, using gas chromatography, we confirmed maternal transfer of a large number of compounds (n = 68 out of 69) among 104 eggs collected from 21 nests across three nesting beaches within the Yucatan Peninsula, one of the world's most important rookeries for hawksbill turtles (Eretmochelys imbricata). High variation in PAH profiles was observed among beaches, using multivariate correspondence analysis and univariate Peto-Prentice tests, reflecting local acquisition during recent migration movements. Diagnostic PAH ratios reflected petrogenic origins in Celestun, the beach closest to petroleum industries in the Gulf of Mexico. By contrast, pollution profiles of OCPs and PCBs showed high similarity among beaches, reflecting the long-term accumulation of these pollutants at regional scales. Therefore, spatial planning of protected areas and the use of turtle eggs in biomonitoring needs to account for the spatial variation in pollution profiles among nesting beaches. PMID- 29395263 TI - Thermal resistances and acclimation potential during coral larval ontogeny in Acropora pulchra. AB - Rising temperature can adversely affect specific functions of corals. Coral gametes and planulae of Acropora pulchra were evaluated to determine their temperature resistances, and the potential of developmental thermal acclimation was examined on gametes. Results highlight that fertilization success displays a relatively high thermal resistance at ET50 (median effective temperature) 31.5 +/ 0.5 degrees C after 4 h and 30 min. Additionally, probability of larval survival is halved at LT50 (median lethal temperature) 28.4 +/- 0.42 degrees C after 14 days. The pre-exposure of oocytes to 30 degrees C and 32 degrees C for 1 h increases the cell development pace during fertilization at ambient temperature. Pre-exposure of gametes, separately at 32 degrees C for 1 h, increases fertilization success rate by 63% at 32 degrees C, conversely, pre exposure to 30 degrees C induces more variable results. These results evidenced the occurrence of developmental thermal acclimation as a result of thermal pre exposure of oocytes. PMID- 29395264 TI - Effect of symptoms on physical performance in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients experience multiple symptoms including dyspnea, anxiety, depression, and fatigue, which are highly correlated with each other. Together, those symptoms may contribute to impaired physical performance. OBJECTIVES: The purpose of this study was to examine interrelationships among dyspnea, anxiety, depressive symptoms, and fatigue as contributing factors to physical performance in COPD. METHODS: This study used baseline data of 282 COPD patients from a longitudinal observational study to explore the relationship between depression, inflammation, and functional status. Data analyses included confirmatory factor analyses and structural equation modeling. RESULTS: Dyspnea, anxiety and depression had direct effects on fatigue, and both dyspnea and anxiety had direct effects on physical performance. Higher levels of dyspnea were significantly associated with impaired physical performance whereas higher levels of anxiety were significantly associated with enhanced physical performance. CONCLUSION: Dyspnea was the strongest predictor of impaired physical performance in patients with COPD. PMID- 29395265 TI - An investigation of factors influencing self-care behaviors in young and middle aged adults with hypertension based on a health belief model. AB - OBJECTIVES: To explore whether five variables of the health belief model were factors influencing self-care behaviors in young and middle-aged adults with hypertension. BACKGROUND: The self-care behaviors of young and middle-aged adults with hypertension are suboptimal in China, and the factors associated with self care behaviors have rarely been studied in the population. METHODS: A questionnaire survey was adopted in the study. 382 eligible participants were recruited from two tertiary teaching hospitals using the convenience sampling. RESULTS: The predictors of self-care behaviors in young and middle-aged adults with hypertension included age, complications related to hypertension, perceived susceptibility, severity, benefits, barriers and self-efficacy. Five aspects of health beliefs model accounted for 47.0% of total variance. CONCLUSIONS: The perceived susceptibility, severity, benefits, barriers, and self-efficacy were key factors affecting self-care behaviors in young and middle-aged adults with hypertension. A health education program targeting improving health beliefs for the population should be developed. PMID- 29395266 TI - The reliability and validity of the L-test in people with Parkinson's disease. AB - OBJECTIVE: To evaluate the test-retest and concurrent validity of the L-test in a group of participants with mild to moderate Parkinson's disease. The L-test is an extended version of the Timed up and Go test, incorporating a longer walking distance and turns in two directions. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: 16 participants (13 male), mean age 75 (SD 6.7) mean duration since diagnosis 7.1 years (+/-2.8). Disease severity was mild to moderate on the Hoehn and Yahr scale (mean 2.1; mode 2; range 1-3). 14 participants (12 male) completed the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A Bland and Altman plot examined the agreement between first and second testing occasion of the L-test. Intra-class correlation coefficients (ICC) assessed the test-retest reliability. Concurrent validity was established by correlating the L-test with the Timed up and Go test (TUG). The Minimal Detectable Change with 95% confidence interval (MDC95) was calculated to determine the true change not due to chance. RESULTS: The L-test showed excellent test-retest reliability on the Bland & Altman plot and the ICC. There was a high degree of agreement between measurements taken on days 1 and 2. The L-test correlated strongly with the Timed up and Go test on both measurement days with r=0.97 (p<0.001) and r=0.96 (p<0.001). The MDC95 was 5.31seconds. CONCLUSIONS: The L-test is a reliable and valid outcome measurement for the assessment of walking ability in participants with mild to moderate Parkinson's disease. PMID- 29395267 TI - Amid US funding cuts, UNRWA appeals for health and dignity of Palestinian refugees. PMID- 29395268 TI - Countdown to 2030: tracking progress towards universal coverage for reproductive, maternal, newborn, and child health. AB - Building upon the successes of Countdown to 2015, Countdown to 2030 aims to support the monitoring and measurement of women's, children's, and adolescents' health in the 81 countries that account for 95% of maternal and 90% of all child deaths worldwide. To achieve the Sustainable Development Goals by 2030, the rate of decline in prevalence of maternal and child mortality, stillbirths, and stunting among children younger than 5 years of age needs to accelerate considerably compared with progress since 2000. Such accelerations are only possible with a rapid scale-up of effective interventions to all population groups within countries (particularly in countries with the highest mortality and in those affected by conflict), supported by improvements in underlying socioeconomic conditions, including women's empowerment. Three main conclusions emerge from our analysis of intervention coverage, equity, and drivers of reproductive, maternal, newborn, and child health (RMNCH) in the 81 Countdown countries. First, even though strong progress was made in the coverage of many essential RMNCH interventions during the past decade, many countries are still a long way from universal coverage for most essential interventions. Furthermore, a growing body of evidence suggests that available services in many countries are of poor quality, limiting the potential effect on RMNCH outcomes. Second, within country inequalities in intervention coverage are reducing in most countries (and are now almost non-existent in a few countries), but the pace is too slow. Third, health-sector (eg, weak country health systems) and non-health-sector drivers (eg, conflict settings) are major impediments to delivering high-quality services to all populations. Although more data for RMNCH interventions are available now, major data gaps still preclude the use of evidence to drive decision making and accountability. Countdown to 2030 is investing in improvements in measurement in several areas, such as quality of care and effective coverage, nutrition programmes, adolescent health, early childhood development, and evidence for conflict settings, and is prioritising its regional networks to enhance local analytic capacity and evidence for RMNCH. PMID- 29395270 TI - A call to action: improving women's, children's, and adolescents' health in the Muslim world. PMID- 29395271 TI - Achieving better cancer intelligence for global cancer control. PMID- 29395272 TI - Status and drivers of maternal, newborn, child and adolescent health in the Islamic world: a comparative analysis. AB - BACKGROUND: The Millennium Development Goal (MDG) period saw dramatic gains in health goals MDG 4 and MDG 5 for improving child and maternal health. However, many Muslim countries in the south Asian, Middle Eastern, and African regions lagged behind. In this study, we aimed to evaluate the status of, progress in, and key determinants of reproductive, maternal, newborn, child, and adolescent health in Muslim majority countries (MMCs). The specific objectives were to understand the current status and progress in reproductive, maternal, newborn, child, and adolescent health in MMCs, and the determinants of child survival among the least developed countries among the MMCs; to explore differences in outcomes and the key contextual determinants of health between MMCs and non-MMCs; and to understand the health service coverage and contextual determinants that differ between best and poor or moderate performing MMCs. METHODS: In this country-level ecological study, we examined data from between 1990 and 2015 from multiple publicly available data repositories. We examined 47 MMCs, of which 26 were among the 75 high-burden Countdown to 2015 countries. These 26 MMCs were compared with 48 non-Muslim Countdown countries. We also examined characteristics of the eight best performing MMCs that had accelerated improvement in child survival (ie, that reached their MDG 4 targets). We estimated adolescent, maternal, under-5, and newborn mortality, and stillbirths, and the causes of death, essential interventions coverage, and contextual determinants for all MMCs and comparative groups using standardised methods. We also did a hierarchical multivariable analysis of determinants of under-5 mortality and newborn mortality in low-income and middle-income MMCs. FINDINGS: Despite notable reductions between 1990 and 2015, MMCs compared with a global esimate of all countries including MMCs had higher mortality rates, and MMCs relative to non-MMCs within Countdown countries also performed worse. Coverage of essential interventions across the continuum of care was on average lower among MMCs, especially for indicators of reproductive health, prenatal care, delivery, and labour, and childhood vaccines. Outcomes within MMCs for mortality and many reproductive, maternal, newborn, child, and adolescent health indicators varied considerably. Structural and contextual factors, especially state governance, conflict, and women and girl's empowerment indicators, were significantly worse in MMCs compared with non-MMCs within the high-burden Countdown countries, and were shown to be strongly associated with child and newborn mortality within low-income and middle-income MMCs. In adjusted hierarchical models, among other factors, under-5 mortality in MMCs increased with more refugees originating from a country (beta=23.67, p=0.0116), and decreased with better political stability or absence of terrorism (beta=-0.99, p=0.0285), greater political rights or government effectiveness (beta=-1.17, p<0.0001), improvements in log gross national income per capita (beta=-4.44, p<0.0001), higher total adult literacy (beta=-1.69, p<0.0001), higher female adult literacy (beta=-0.97, p<0.0001), and greater female to male enrolment in secondary school (beta=-16.1, p<0.0001). The best performing MMCs were Azerbaijan, Bangladesh, Egypt, Indonesia, Kyrgyzstan, Morocco, Niger, and Senegal, which had higher coverage of family planning interventions and newborn or child vaccinations, and excelled in many of the above contextual determinants when compared with moderate or poorly performing MMCs. INTERPRETATION: The status and progress in reproductive, maternal, newborn, child, and adolescent health is heterogeneous among MMCs, with little indication that religion and its practice affects outcomes systemically. Some Islamic countries such as Niger and Bangladesh have made great progress, despite poverty. Key findings from this study have policy and programmatic implications that could be prioritised by national heads of state and policy makers, development partners, funders, and the Organization of the Islamic Cooperation to scale up and improve these health outcomes in Muslim countries in the post-2015 era. FUNDING: US Fund for UNICEF under the Countdown to 2015 for Maternal, Newborn, and Child Survival, the Centre for Global Child Health, Hospital for Sick Children, and the Aga Khan University. PMID- 29395274 TI - Cannabidiol for drop seizures in Lennox-Gastaut syndrome. PMID- 29395273 TI - Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. AB - BACKGROUND: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS: In this randomised, double blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR -69.6 to -1.9) in the cannibidiol group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was 17.21 (95% CI -30.32 to -4.09; p=0.0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING: GW Pharmaceuticals. PMID- 29395275 TI - Influences on Polish migrants' breast screening uptake in Lothian, Scotland. AB - OBJECTIVES: Ethnic minorities are known to have low uptake of cancer screening programmes and Polish populations to have low breast screening uptake. Breast screening uptake by women in Poland and Polish migrants to Scotland is low. We interviewed Polish women living in Lothian, Scotland, about their attitudes to breast screening. STUDY DESIGN AND METHOD: Telephone interviews were held with a sample of 11 Polish women registered with Lothian general practices and invited for breast screening in 2013 or 2014. Interviews were between November 2014 and February 2015 and were held in Polish then translated, transcribed and analysed thematically. RESULTS: Women interviewed (mean age 58 years) had lived in Scotland for an average of 7.5 years. Seven had undergone breast screening in both Poland and Scotland, three in only Scotland and one in Poland alone. Respondents usually used Scottish and Polish health systems and screening programmes in parallel. Convenience and familiarity shaped screening choices with written information neither accessed nor answering key questions e.g. about coordination between programmes. CONCLUSION: Polish women living in Scotland have difficulties in accessing screening there and often use both Polish and Scottish system. Language issues, misunderstandings about screening and different health cultures are key barriers. Combined information in Polish about all cancer screening programmes could help address low uptake. PMID- 29395276 TI - HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus. AB - Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR = 3.36; 95% CI = 1.46-7.74; p = .005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR = 6.47, 95% CI = 2.58-16.26; p < .0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR = 7.06, 95% CI = 0.07-2.19; p = .002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38 +/- 28.49 MUmol/L) compared to SLE patients HLA-C1 negative (108.37 +/- 86.09 MUmol/L) (p = .03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients. PMID- 29395277 TI - Shorter telomere length in cord blood associated with prenatal air pollution exposure: Benefits of intervention. AB - BACKGROUND: To examine the molecular benefits of the government action to close the local coal burning power plant in Tongliang County, Chongqing Municipality, we compared biologic markers and health outcomes in two successive birth cohorts enrolled before and after the plant was shut down. In this city, polycyclic aromatic hydrocarbons (PAH) were primarily emitted by the coal burning facility. We previously reported that cord blood levels of PAH-DNA adducts (a biomarker of exposure) and various adverse health outcomes were reduced in the second cohort, whereas levels of brain-derived neurotrophic factor/BDNF (a protein involved in neuronal growth) were increased. Here we assessed telomere length (TL), which has been associated with risk of certain chronic diseases, early mortality, aging and cognitive decline in adults. OBJECTIVES: The goals of the present study were to determine whether TL differed between the two cohorts and whether prenatal PAH exposure, estimated by PAH-DNA adducts in cord white blood cells of newborns in China, were predictive of shorter TL in cord blood, suggesting the potential accrual of risk of certain chronic diseases during the prenatal period. We explored relationships of TL with BDNF and neurodevelopmental outcomes, each previously associated with PAH-DNA adducts in these cohorts, as well as the potential mediating role of TL in the associations between adducts and neurodevelopmental outcomes. METHODS: We analyzed TL in cord blood of 255 newborns who also had data on PAH-DNA adducts, BDNF, and relevant covariates. Multiple regression analysis was carried out to test associations between adducts and TL and between TL and BDNF, adjusting for relevant covariates. In the subset with developmental quotient (DQ) scores from Gesell testing at age 2 (N = 210), we explored whether TL was a mediator of the relationship between PAH-DNA adducts and DQ scores by first examining the associations between cord adducts and DQ, cord adducts and TL, and TL and DQ, adjusting for the same covariates. RESULTS: As hypothesized, the mean TL was significantly higher in the second cohort compared to the first cohort. Overall, PAH-DNA cord adducts were significantly and inversely correlated with TL. Multiple regression analysis showed a significant association between adducts and TL, after adjusting for key covariates: beta (effect size per standard deviation adducts) = -0.019, p = .003. The regression coefficient of TL on (Ln) BDNF was also significant (beta = 0.167, p < .001). Exploratory analysis, regressing TL on Gesell developmental scores, showed generally inverse, but not significant associations. TL was not, therefore, deemed to be a potential mediator of the association between adducts and developmental scores at age two. CONCLUSION: This study provides the first evidence that prenatal PAH exposure from coal burning may adversely affect TL, with potential implications for future risk of chronic diseases including cardiovascular disease. The improvement in TL in the second cohort and the observed correlation between increased TL and higher levels of BDNF indicate direct benefits to the health and development of children resulting from the government's closure of the power plant. PMID- 29395278 TI - Tonsillectomy sparing transoral robot assisted styloidectomy. AB - Eagle Syndrome can present with a variety of symptoms and be caused by an elongated styloid process or calcified stylohyoid ligament. Patients failing medical management of this disorder may be treated with surgical excision of the styloid process. In the literature, transoral and transcervical approach have both been described. Although transoral approaches typically begin with a tonsillectomy, tonsil-sparing approaches have also been utilized. With the advent of robotic surgery, the potential for a tonsillectomy sparing approach has become a feasible alternative, preventing the pain and morbidity associated with adult tonsillectomy while continuing to provide superior exposure and instrumentation. We report three successful cases of patients treated with tonsillectomy sparing transoral robot assisted styloidectomy. This represents the first application of this technique in the literature and suggests the potential for a paradigm shift in the surgical management of this disease. PMID- 29395279 TI - Safety and efficacy of intratympanic ciprofloxacin otic suspension post-tubes in a real-world pediatric population. AB - PURPOSE: Otorrhea frequently follows tympanostomy tube (TT) placement. We evaluated otorrhea following single 6mg OTO-201 (OTIPRIO(r), ciprofloxacin otic suspension 6%) intraoperative injection into each middle ear in a variety of effusion types and concurrent procedures in children undergoing TT placement. SECONDARY OBJECTIVE: Efficacy based on Medicaid status and safety. BASIC PROCEDURES: In this prospective, 8-week, multicenter, open-label study, 501 patients were enrolled: mean age 2.9years, male (56.9%), wet/wet ears (66.9%), wet/dry (16.8%), dry/dry (16.3%), and Medicaid-insured (32.9%). MAIN FINDINGS: In per-protocol population (n=410), otorrhea rate through Day 15 were 8.8% (CI:5.7% 12.8%), 6.6% (CI:2.2%-14.7%), 3.3% (CI:0.4%-11.3%) in wet/wet, wet/dry, and dry/dry ears, respectively. For Medicaid patients through Day 15, Week 4 and Week 8, otorrhea rates were 8.1% (CI:4.1%-14.1%), 17.0% (CI:11.1%-24.5%), and 17.8% (CI:11.7%-25.3%) compared with those non-Medicaid insured: 7.3% (CI:4.5%-11.0%), 14.5% (CI:10.6%-19.3%), and 21.8% (CI:17.1%-27.2%), respectively. Safety was similar to previous Phase 3 trials. PRINCIPAL CONCLUSIONS: OTO-201 demonstrated otorrhea rates consistent with Phase 3 trials in a broader, real-world, ENT practice-based pediatric population. Outcomes were similar in Medicaid- and non Medicaid insured patients. OTO-201 was well-tolerated. PMID- 29395280 TI - Pediatric Cochlear implant soft failure. AB - PURPOSE: Hard cochlear implant failures are diagnosed by objective tests whereas soft failures are suspected on the basis of clinical signs and symptoms. This study reviews our experience with children in tertiary pediatric medical center who underwent revision cochlear implantation, with emphasis on soft failures. MATERIALS AND METHODS: Children (age<18years) who underwent revision cochlear implantation from 2000 to 2012 were identified by database search. Pre- and post explantation data were collected. RESULTS: Twenty-six revision surgeries were performed, accounting for 7.4% of all cochlear implant surgeries at our center during the study period. The pre-explantation diagnosis was hard failure in 7 cases (27%), soft failure in 12 (46%), and medical failure in 7 (27%). On post explantation analysis, 7/12 devices from the soft-failure group with a normal integrity test had abnormal findings, yielding a 63% false-negative rate (12/19) for the integrity test. All children regained their initial performance. Compared to hard failures, soft failures were associated with a shorter median time from first implantation to symptom onset (8 vs 25months) but a significantly longer time from symptom onset to revision surgery (17.5 vs 3months; P=0.004). CONCLUSIONS: Soft cochlear implant failure in young patients poses a diagnostic challenge. A high index of suspicion is important because a delayed diagnosis may have severe consequences for language development. A normal integrity test does not unequivocally exclude device failure and is unrelated to functional outcome after revision surgery. Better education of parents and rehabilitation teams is needed in addition to more accurate diagnostic tests. PMID- 29395281 TI - Simple laryngeal suspension procedure by suturing the digastric muscle to the periosteum of the mandible in neck dissection for tongue cancer. AB - PURPOSE: In this article, a simple, new laryngeal suspension procedure is described. The effect of hyoid bone suspension by suturing the digastric muscle to the periosteum of the mandible is analyzed. MATERIALS AND METHODS: To elucidate the effect of hyoid bone suspension, CT scans of 26 patients who underwent ipsilateral neck dissection with primary resection of tongue cancer were retrospectively reviewed, and the distance between the hyoid bone and the mandible was measured on the operated and unoperated sides of the neck. A total of 14 patients who underwent suturing of the digastric muscle to the mandible (digastric muscle-sutured group) and the 12 patients who did not (control group) were compared. RESULTS: In the digastric muscle-sutured group, the average distance between the hyoid bone and the mandible was significantly smaller on the operated side (17.8 +/- 0.57 mm) than on the unoperated side (19.8 +/- 0.93 mm; p < 0.05). In the control group, there was no significant difference between the operated side (21.0 +/- 1.42 mm) and the unoperated side (19.7 +/- 1.39 mm). The difference in the distance between the operated and unoperated sides was significantly larger in the digastric muscle-sutured group (1.97 +/- 0.79 mm) than in the control group (-1.32 +/- 0.61; p < 0.05). CONCLUSIONS: It was shown for the first time that suturing of the digastric muscle to the periosteum of the mandible in neck dissection with primary resection of tongue cancer resulted in hyoid bone suspension. This simple procedure can be useful for laryngeal suspension. PMID- 29395282 TI - Anatomical anomalies of the Eustachian tube and chronic otitis media. PMID- 29395283 TI - A rare primary leiomyosarcoma of the parotid gland: A case report and literature review. AB - BACKGROUND: Leiomyosarcoma of the head and neck region is very rare. Primary parotid leiomyosarcoma has only been reported nine times in the medical literature. METHODS: A 68-year-old female presented with a left facial mass. Physical examination revealed a firm immobile mass at the level of the left parotid tail. No facial nerve dysfunction or palpable adenopathy was noted at the time of presentation. This patient underwent a superficial parotidectomy with a facial nerve dissection and left selective neck dissection. RESULTS: Pathologic findings revealed a sarcoma of intermediate to high-grade, composed of spindle cells with herringbone pattern, eosinophilic fibrillary cytoplasm, and focal granularity. Immunohistochemistry was positive for vimentin and smooth muscle actin and negative for desmin, S100 and CD34. The findings are consistent with a leiomyosarcoma. Following complete surgical resection, adjuvant radiation therapy was administered. CONCLUSION: Primary sarcomas of the parotid gland, specifically parotid leiomyosarcomas, are extremely rare. Based on this patient's tumor size, grade and resectability, this case met the criteria for a primary leiomyosarcoma. We present only the tenth case of a primary parotid leiomyosarcoma to be reported in the English literature. PMID- 29395284 TI - Safety and Efficacy of Intravenous Lidocaine for Pain Management in the Emergency Department: A Systematic Review. AB - STUDY OBJECTIVE: We evaluate the safety and efficacy of intravenous lidocaine in adult patients with acute and chronic pain who are undergoing pain management in the emergency department (ED). METHODS: We searched Ovid CENTRAL, Ovid EMBASE, and Ovid MEDLINE databases for randomized controlled trials and observational studies from inception to January 2017. Efficacy outcomes included reduction in pain scores from baseline to postintervention and need for rescue analgesia. Safety outcomes included incidence of serious (eg, cardiac arrest) and nonserious (eg, dizziness) adverse events. We used the Cochrane Collaboration tool and a modified Newcastle-Ottawa Scale to evaluate the risk of bias across studies. The Grading of Recommendations Assessment, Development and Evaluation approach was used to evaluate the confidence in the evidence available. RESULTS: From a total of 1,947 titles screened, 61 articles were selected for full-text review. Eight studies met the inclusion criteria and underwent qualitative analysis, including 536 patients. The significant clinical heterogeneity and low quality of studies precluded a meta-analysis. Among the 6 randomized controlled trials included, intravenous lidocaine had efficacy equivalent to that of active controls in 2 studies, and was better than active controls in 2 other studies. In particular, intravenous lidocaine had pain score reduction comparable to or higher than that of intravenous morphine for pain associated with renal colic and critical limb ischemia. Lidocaine did not appear to be effective for migraine headache in 2 studies. There were 20 adverse events reported by 6 studies among 225 patients who received intravenous lidocaine in the ED, 19 nonserious and 1 serious (rate 8.9%, 95% confidence interval 5.5% to 13.4% for any adverse event; and 0.4%, 95% confidence interval 0% to 2.5% for serious adverse events). The confidence in the evidence available for the outcomes evaluated was deemed to be very low because of methodological limitations, including risk of bias, inconsistency, and imprecision. CONCLUSION: There is limited current evidence to define the role of intravenous lidocaine as an analgesic for patients with acute renal colic and critical limb ischemia pain in the ED. Its efficacy for other indications has not been adequately tested. The safety of lidocaine for ED pain management has not been adequately examined. PMID- 29395269 TI - Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. AB - BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15 year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5 year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation. PMID- 29395285 TI - The effect of rare variants in TREM2 and PLD3 on longitudinal cognitive function in the Wisconsin Registry for Alzheimer's Prevention. AB - Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36-73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (~N [0, 1]); the mean of these z scores was also calculated. In linear mixed models adjusted for age, gender, practice effects, and self-reported race/ethnicity, PLD3 V232M carriers had significantly lower mean z scores (p = 0.02) and lower z scores for story recall (p = 0.04), visual learning and memory (p = 0.049), and speed and flexibility (p = 0.02) than noncarriers. TREM2 R47H carriers had marginally lower z scores for speed and flexibility (p = 0.06). In conclusion, a functional variant in PLD3 was associated with significantly lower cognitive function in individuals carrying the variant than in noncarriers. PMID- 29395286 TI - An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk. AB - Although multiple susceptibility loci for late-onset Alzheimer's disease (LOAD) have been identified, a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single-nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method). We identified a cis-regulatory eSNP (rs2927438) located on chromosome 19q13.32, for which subsequent analyses confirmed the association with both LOAD risk and the expression level of several nearby genes. Importantly, rs2927438 may represent an APOE-independent LOAD eSNP according to the weak linkage disequilibrium of rs2927438 with the 2 polymorphisms (rs7412 and rs429358) defining the APOE-epsilon2, -epsilon3, and -epsilon4 alleles. Furthermore, rs2927438 does not influence chromatin interaction events at the APOE locus or cis-regulation of APOE expression. Further exploratory analysis revealed that rs2927438 is significantly associated with tau levels in the cerebrospinal fluid. Our findings suggest that rs2927438 may confer APOE independent risk for LOAD. PMID- 29395287 TI - Development and validation of an MRI-based model to predict response to chemoradiotherapy for rectal cancer. AB - BACKGROUND AND PURPOSE: To safely implement organ preserving treatment strategies for patients with rectal cancer, well-considered selection of patients with favourable response is needed. In this study, we develop and validate an MRI based response predicting model. METHODS: A multivariate model using T2 volumetric and DWI parameters before and 6 weeks after chemoradiation (CRT) was developed using a cohort of 85 rectal cancer patients and validated in an external cohort of 55 patients that underwent preoperative CRT. RESULTS: Twenty two patients (26%) achieved ypT0-1N0 response in the development cohort versus 13 patients (24%) in the validation cohort. Two T2-volumetric parameters (DeltaVolume% and Sphere_post) and two DWI parameters (ADC_avg_post and ADCratio_avg) were retained in a model predicting (near-)complete response (ypT0 1N0). In the development cohort, this model had a good predictive performance (AUC = 0.89; 95% CI 0.80-0.98). Validation of the model in an external cohort resulted in a similar performance (AUC = 0.88 95% CI 0.79-0.98). CONCLUSION: An MRI-based prediction model of (near-)complete pathological response following CRT in rectal cancer patients, shows a high predictive performance in an external validation cohort. The clinically relevant features in the model make it an interesting tool for implementation of organ-preserving strategies in rectal cancer. PMID- 29395288 TI - Review of the patient positioning reproducibility in head-and-neck radiotherapy using Statistical Process Control. AB - BACKGROUND AND PURPOSE: A remarkable improvement in patient positioning was observed after the implementation of various process changes aiming to increase the consistency of patient positioning throughout the radiotherapy treatment chain. However, no tool was available to describe these changes over time in a standardised way. This study reports on the feasibility of Statistical Process Control (SPC) to highlight changes in patient positioning accuracy and facilitate correlation of these changes with the underlying process changes. MATERIALS AND METHODS: Metrics were designed to quantify the systematic and random patient deformation as input for the SPC charts. These metrics were based on data obtained from multiple local ROI matches for 191 patients who were treated for head-and-neck cancer during the period 2011-2016. RESULTS: SPC highlighted a significant improvement in patient positioning that coincided with multiple intentional process changes. The observed improvements could be described as a combination of a reduction in outliers and a systematic improvement in the patient positioning accuracy of all patients. CONCLUSION: SPC is able to track changes in the reproducibility of patient positioning in head-and-neck radiation oncology, and distinguish between systematic and random process changes. Identification of process changes underlying these trends requires additional statistical analysis and seems only possible when the changes do not overlap in time. PMID- 29395289 TI - Role of different receptors and actin filaments on Salmonella Typhimurium invasion in chicken macrophages. AB - Bacterial attachment to host cell is the first event for pathogen entry. The attachment is mediated through membrane expressed adhesins present on the organism and receptors on the cell surface of host. The objective of this study was to investigate the significance of Fc receptors (FcRs), actin filament polymerization, mannose receptors (MRs), carbohydrate moieties like N-linked glycans and sialic acid on chicken macrophages for invasion of S. Typhimurium. Opsonisation of S. Typhimurium resulted in three folds more invasion in chicken monocyte derived macrophages. Cytochalasin D, an inhibitor of actin filament polymerization prevented uptake of S. Typhimurium. Pre-incubation of macrophages with cytochalasin D, showed severe decrease (28 folds) in S. Typhimurium invasion. Next we attempted to analyse the role of carbohydrate receptors of macrophages in S. Typhimurium invasion. Treatment of macrophages with methyl alpha-d-mannopyranoside, PNGase F and neuraminidase, showed 2.5, 5 and 2.5 folds decrease in invasion respectively. Our data suggest that deglycosylation of N linked glycans including sialic acid by PNGase F is more effective in inhibition of S. Typhimurium invasion than neuraminidase which removes only sialic acid. These findings suggested FcRs, actin filament polymerization, MRs, N-linked glycans and sialic acid may act as gateway for entry of S. Typhimurium. PMID- 29395290 TI - An Observational Study of Concomitant Use of Emerging Therapies and Denosumab or Zoledronic Acid in Prostate Cancer. AB - PURPOSE: This observational study of oncologic clinical practices was designed to describe real-world patterns of use of emerging therapies (abiraterone acetate, cabazitaxel, enzalutamide, radium-223, sipuleucel-T) in patients with castration resistant prostate cancer and to characterize their concomitant use with denosumab or zoledronic acid. METHODS: A retrospective cohort study was conducted using a database of electronic health records from oncology practices across the United States. Eligible patients had a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision [ICD-9] code 185/International Classification of Diseases, Tenth Revision [ICD-10] code C61) before or concurrent with a visit between January 1, 2013, and December 31, 2015; follow-up was performed through June 30, 2016. From this population, we identified those who received an emerging therapy and a subset who also received denosumab or zoledronic acid. FINDINGS: A total of 71,606 men met the eligibility criteria, and 5131 (7%) received emerging therapy. In the emerging therapy cohort (at the time of the first use), median age was 75 years, median prostate-specific antigen value was 22.7 ng/mL, 56% had bone metastases, and 80% were docetaxel naive. Abiraterone and enzalutamide were the most commonly used first emerging therapies (52% and 31%, respectively), followed by sipuleucel-T (9%), cabazitaxel (5%), and radium-223 (1.5%). Of the emerging therapy cohort, 3121 patients (61%) received concomitant denosumab (70%) or zoledronic acid (35%); 5% received both. IMPLICATIONS: Among patients with prostate cancer treated in the United States, most of those treated with an emerging therapy between 2013 and 2015 also received denosumab or zoledronic acid, suggesting that the concomitant use of these therapy types is currently a common practice. Use of denosumab or zoledronic acid was higher in patients with verified bone metastases. PMID- 29395291 TI - The Opioid Epidemic: Overcoming Challenges by Using a Sex and Gender Lens. PMID- 29395292 TI - A Tribute to Gertrude Belle Elion on the 100th Anniversary of her Birth. PMID- 29395293 TI - Atypical xanthogranulomatous inflammation of the female genital tract. PMID- 29395294 TI - Extensive uterine arteriovenous malformation with hemodynamic instability: Embolization for whole myometrium affection. AB - Uterine arteriovenous malformation is abnormal and nonfunctional connections between the uterine arteries and veins. Patients typically present with vaginal bleeding which may be life-threatening. Treatment depends on the symptoms, age, desire for future fertility, localization and size of the lesion. Embolization of the uterine artery is the first choice in symptomatic AVM in patients in the reproductive age. We report a case of acquired AVM with an extensive lesion on ultrasound and MRI, which was successfully treated with uterine artery embolization for severe bleeding (UAE). PMID- 29395295 TI - [Emphysematous cystitis: Report of one case]. AB - INTRODUCTION: Emphysematous cystitis is a rare urinary tract infection characterized by gas in the bladder wall and lumen. CASE REPORT: We report a 92 year-old women admitted with confusion and abdominal pain without fever. Her past medical history included diabetes, urinary incontinence, high blood pressure and mild cognitive impairment. A computed tomography scan (CT scan) revealed emphysematous cystitis. The patient completely recovered within ten days. The main characteristics and the treatment of this uncommon disorder are presented. CONCLUSION: Clinicians should be aware of this diagnosis: early management is essential to reduce morbidity and mortality. PMID- 29395296 TI - [Usefulness of eosinopenia for the diagnosis of sepsis in emergency department: Still debated]. PMID- 29395297 TI - Reply. PMID- 29395298 TI - Editorial Comment. PMID- 29395299 TI - Desensitization and Counterconditioning: When and How? AB - Desensitization and counterconditioning are behavioral techniques widely used in veterinary behavioral medicine to treat anxieties, fears, and phobias. With desensitization, the patient is taught to relax as it is exposed to anxiety provoked stimuli in a gradual fashion. The controlled exposures start with the patient relaxing in the presence of a muted stimulus (ie, a stimulus that does not trigger a fearful response). Over time, the patient will be introduced gradually to a more intense stimulus with the hope that eventually it will remain relaxed at all levels of exposure. PMID- 29395301 TI - Intravenous amiodarone-induced acute liver failure in cardiac surgery intensive care unit. PMID- 29395300 TI - Effect of body weight and composition on efavirenz, atazanavir or darunavir concentration. AB - BACKGROUND: To compare the steady state plasma concentrations (Css) of three antiretroviral drugs in both normal and overweight patients, and to determine the relationship between Css and fat mass (FM) or lean body mass. METHODS: Patients treated for more than 6 months once daily with one of the antiretroviral drugs: efavirenz (EFV) 600mg, atazanavir boosted with ritonavir (ATV-r) 300mg/100mg, or darunavir boosted with ritonavir (DRV-r) 800mg/100mg, combined with two nucleoside analogues, were enrolled prospectively. One at steady state, plasma samples for the assessment of drug concentration were taken and body composition was assessed by bioelectrical impedance. RESULTS: One hundred and thirty-nine patients were enrolled (46, 45 and 48 in the groups EFV, ATV-r and DRV-r respectively). Their mean age was 46.2+/-10.4 years, 58% were male, 55.4% were from Sub Sahara African (SSA); body mass index (BMI) was 25.4+/-4.4kg/m2. Mean drug plasma Css of the three drugs did not differ according to BMI group. DRV-r Css tended to be higher in patients with BMI>=25kg/m2 (2896.7+/-1689 versus 2091.9+/-1038, P=0.09) and was significantly correlated with FM (r=0.3, P=0.02). In subgroup analysis, the effect of FM on DRV-r Css was significant in patients from SSA (r=0.4, P=0.04). CONCLUSIONS: Css result from many factors and body composition has been shown to only weakly influence interindividual variability but should be investigated in morbidly obese patients treated with DRV-r. PMID- 29395302 TI - ? PMID- 29395303 TI - Care pathway, towards the establishment of tailored funding: Reasons and criteria for success. AB - Care pathways are often at the forefront of political thinking about health care practices in France without ever finding a durable means for their extension. Closely linked to funding of healthcare system, they have, once again, been the object of so many economical discussions in 2017, as part of a more optimistic climate of governance which is therefore more open to change. Our changing system, the development and increasingly chronic nature of diseases, the scale of technological breakthroughs, these are all factors driving this topic forward. The object of this work, after a necessary study of the semantics of the term "pathway" and even "funding", was to identify all prerequisites and good practices for the stakeholders to develop a pilot pathway and then its relevant implementation in France. To do so, the members of the Round Table have relied on the presentation of examples of care pathways in order to identify triggers to a progressive, adapted extension to the whole territory. The group has identified key elements and priorities for the establishment of public funding beyond existing funding to incentive team work, particularly in the case of treatment rupture points and/or when they have diverging interests. Finally, creating a climate of confidence among patients, professionals, hospitals, the ARS, payers and manufacturers in handling change management will become the key challenges of the implementation of future pathways. PMID- 29395304 TI - Management of the toxicities of common targeted therapeutics for gynecologic cancers. AB - As precision medicine has become a focus in oncology in recent years, many targeted and biologic agents are being used along with or in place of traditional cytotoxic chemotherapy. As these drugs have been developed and some have received FDA approval, we have gained substantial data about the adverse event profiles. However, the management and approach to the toxicities incurred and subsequent complications are often not well understood, especially for physicians who have a varied clinical practice. The purpose of this review is to provide an overview of the frequency and types of adverse events and appropriate management steps when prescribing modern targeted therapies for gynecologic cancers in the classes of anti-angiogenic agents, poly-ADP-ribose polymerase (PARP) inhibitors, and immunotherapy drugs. PMID- 29395305 TI - Secondary debulking surgery for para-aortic nodal recurrence in endometrial cancer requiring circumferential resection of the inferior vena cava. PMID- 29395306 TI - The role of physical activity in breast and gynecologic cancer survivorship. AB - Physical activity improves physical functioning, cancer-related symptoms, and quality of life in cancer survivors, and is beneficial across all phases of survivorship. Observational studies suggest that high levels of physical activity may also improve cancer outcomes such as survival, but randomized controlled trials of exercise interventions in oncology patients with survival outcomes as a primary endpoint are needed and ongoing. This review focuses on the role of physical activity in breast and gynecologic cancer survivorship, based on the available evidence. It discusses specific guidelines for exercise prescription, highlights the role of the clinician in promoting physical activity, and provides useful resources for cancer survivors. PMID- 29395307 TI - Tumor associated macrophages in gynecologic cancers. AB - The complex tumor microenvironment in gynecologic cancers plays a major role in modulating anti-tumor immune responses. The interaction of cancer cells with the diverse spectrum of immune effector cells has an important impact on the efficacy of standard chemotherapy and novel immunotherapy approaches. In this review, we specifically focus on the role of macrophages in ovarian, endometrial and cervical cancers. We discuss the origins of macrophages and their polarization state dictated by the microenvironment's cues. Within the tumor niche, tumor associated macrophages (TAMs) promote tumor growth and mediate immune-suppression thereby effecting treatment responses. We outline clinical strategies that directly target TAMs, including inhibition of macrophage differentiation, prevention of the recruitment of monocytes to the tumor, enhancement of phagocytosis and immune checkpoint blockade. PMID- 29395308 TI - A collagen-fibrin patch for the prevention of symptomatic lymphoceles after pelvic lymphadenectomy in women with gynecologic malignancies: A randomized clinical trial. AB - OBJECTIVE: To evaluate the efficacy of a collagen-fibrin patch for the prevention of symptomatic lymphoceles after pelvic lymphadenectomy in women with gynecologic malignancies. METHODS: In a multicenter, randomized, clinical trial, 164 women with pelvic lymphadenectomy were allocated either to bilateral pelvic application of two collagen-fibrin patches or no intervention. Main outcome was efficacy, defined as reduction of symptomatic lymphocele rate diagnosed within four weeks after surgery. Secondary outcomes were asymptomatic lymphoceles and subsequent interventions. Sample size was based on the assumption that application of a collagen-fibrin patch reduces the prevalence of symptomatic lymphoceles by at least 66%. The study was single-blinded, i.e., patients and primary outcome assessors, but not surgeons, were blinded to the treatment allocation. RESULTS: A total of 75 women were randomized to the intervention and 89 to the control group. All women received the allocated intervention. In total, 42 (27.4%) lymphoceles and 8 (5.2%) symptomatic lymphoceles were observed. Symptomatic lymphoceles were observed in 5/68 (7.4%) women in the intervention group and 3/85 (3.5%) women in the control group (p = 0.47). Asymptomatic lymphoceles were observed in 16 (23.5%) women in the intervention group compared to 18 (21.2%) in the control group (p = 0.85). In a multivariate logistic regression model, no independent risk factor for the development of a symptomatic lymphocele was ascertained. DISCUSSION: Intraoperative application of collagen-fibrin patches to the pelvic side walls does not reduce the incidence of symptomatic lymphoceles in women with gynecologic malignancies undergoing pelvic lymphadenectomy. PMID- 29395309 TI - ROR1 and ROR2 play distinct and opposing roles in endometrial cancer. AB - OBJECTIVE: In recent years, the Wnt signalling pathway and the ROR1 and ROR2 receptors have been implicated in a range of gynecological cancers. These receptors have been described as prospective therapeutic targets, and this study investigated such potential in an endometrial cancer context. METHOD: Immunohistochemistry for ROR1 and ROR2 was performed in a patient cohort, and expression was correlated with clinicopathological parameters including type, stage, grade, myometrial invasion, lymphovascular involvement, patient age and survival. The functional role of these receptors in endometrial cancer was investigated via siRNA knockdown of ROR1 and ROR2 in three cell line models (KLE, RL95-2 and MFE-319). Effects on proliferation, adhesion, migration and invasion were measured. RESULTS: High ROR1 expression in patient samples correlated with worse overall survival (p = 0.0169) while high ROR2 expression correlated with better overall survival (p = 0.06). ROR1 knockdown in KLE cells significantly decreased proliferation (p = 0.047) and reduced migration and invasion. ROR2 knockdown in RL95-2 cells increased cell migration and invasion (p = 0.011). Double ROR1 and ROR2 knockdown in MFE-319 cells decreased adhesion and significantly increased cell migration (P = 0.008) and invasion (p < 0.001). CONCLUSION: ROR1 and ROR2 play distinct roles in endometrial cancer. ROR1 may promote tumor progression, similar to its role in ovarian cancer, while ROR2 may act as a tumor suppressor in endometrioid endometrial cancer, similar to its role in colorectal cancer. With several ROR-targeting therapies currently in development and phase I clinical trials for other tumor types, this study supports the potential of these receptors as therapeutic targets for women with endometrial cancer. PMID- 29395310 TI - Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer. AB - OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naive patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival. RESULTS: In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively. CONCLUSION: Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naive patients. PMID- 29395311 TI - Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices. AB - OBJECTIVE: Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. METHODS: We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (chi2) tests for categorical variables. Free text comments were qualitatively reviewed. RESULTS: Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae. CONCLUSIONS: Changes in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors. PMID- 29395312 TI - Society of Gynecologic Oncology Clinical Outcomes Registry: From small beginnings come great things. AB - OBJECTIVE: Clinical registries within medical societies have demonstrated the capacity to promote quality improvement. Opportunities for well-designed data repositories could yield reliable national standards for informing reimbursement, determining adherence to care guidelines, maintaining board certification, and developing bundled payment models. Looking to the future, we set out to develop a gynecologic cancer registry serving the members of the Society of Gynecologic Oncology (SGO). METHODS: The SGO Clinical Outcomes Registry (COR) initiated a web based data entry platform as a foray into developing a functional registry, compiling data elements specific to gynecologic oncology. Endometrial and ovarian cancer patients began enrollment in early 2014. Within one year, 19 sites were participating with the addition of cervical cancer patients in January 2015. RESULTS: To date, >6500 patients are currently entered from 29 sites, and the COR is being queried to address topics of quality improvement, disparities, and cancer outcomes. CONCLUSIONS: The SGO COR has proven the feasibility of developing a functional gynecologic cancer registry, with high uptake, rapid accrual, and ability to investigate topics of quality and outcome using the COR. PMID- 29395313 TI - Myosin 1b promotes cell proliferation, migration, and invasion in cervical cancer. AB - OBJECTIVE: Recent evidence suggests an important role of Myosin 1b (Myo1b) in the progression of several cancers, including prostate cancer and head and neck squamous cell carcinoma (HNSCC). However, the contribution of Myo1b to cervical cancer (CC) remains elusive. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry and western blotting assays were used to confirm the expression of Myo1b in CC tissues compared with matched non-tumor tissues and CC cells, and analyze its clinical significance. In vitro, RNA interference (siRNA or shRNA) was used to investigate the biological function and underlying mechanism of Myo1b in cervical carcinogenesis. Furthermore, tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. RESULTS: Here, for the first time we reported that Myo1b expression was significantly increased in human CC, compared to cervical intraepithelial neoplasia (CIN) and normal cervical tissues and that the upregulation of Myo1b was significantly correlated with FIGO Stage, HPV infection, lymph node metastasis and pathological grade. In vitro, knockdown of Myo1b significantly suppressed proliferation, migration, and invasion of CaSki and SiHa cells, and markedly decreased the MMP1/MMP9 activities. Also, silencing the expression of Myo1b dramatically repressed tumor growth in a mouse xenograft model. Further investigations showed that HPV16 E6 or E7 could enhance the expression of Myo1b via upregulating c-MYC. CONCLUSION: Taken together, our data suggested a potential role of Myo1b in cervical carcinogenesis and tumor progression and provided novel insights into the mechanism of how this factor promotes cell proliferation, migration, and invasion in CC cells. PMID- 29395314 TI - Endometrial cancer survivors' sleep patterns before and after a physical activity intervention: A retrospective cohort analysis. AB - OBJECTIVE: To identify the baseline sleep patterns of endometrial cancer survivors and examine the impact of a physical activity intervention on their sleep quality via retrospective secondary analysis. METHODS: Early-stage endometrial cancer survivors participated in a 6-month single-arm exercise intervention using printed materials, telephone-based counseling, and pedometers to encourage adherence to exercise guidelines. Participants completed questionnaires evaluating their sleep (PSQI), physical activity (CHAMPS), quality of life (SF-36), and stress (PSS) at baseline and study completion. RESULTS: Ninety-five survivors had PSQI data at both time points. Mean age was 57.1 years (range, 25-76). Mean body mass index was 34.3 kg/m2. The majority were non Hispanic white (75%) and had stage I disease (80%). At baseline, most survivors (61%) had poor sleep quality (PSQI > 5), with 24% reporting fairly or very bad sleep. The majority (63%) slept <7 h/night. At least once during the preceding month, 83% had an episode of daytime dysfunction. A pairwise comparison showed that obese survivors had more sleep disturbances than normal weight survivors (p = 0.029). No other clinicodemographic factors were associated with sleep. In unadjusted analyses, sleep quality significantly improved in women who increased weekly total or moderate/vigorous physical activity (p = 0.004 and p < 0.050, respectively). This association persisted after adjusting for the potential covariates of age, time since diagnosis, obesity status, disease stage, and treatment (p = 0.026). CONCLUSIONS: Our data demonstrated that poor sleep is common and detrimental to endometrial cancer survivors. Increasing exercise may improve this dysfunction and should be investigated as part of a prospective study. PMID- 29395315 TI - Patterns of palliative care referral in ovarian cancer: A single institution 5 year retrospective analysis. AB - BACKGROUND: The American Society of Clinical Oncology recommends that patients with advanced cancer receive dedicated palliative care services early in their disease course. This investigation serves to understand how palliative care services are utilized for ovarian cancer patients in a tertiary referral center. METHODS: We conducted a retrospective review of women treated for ovarian cancer at our institution from 2010 through 2015. Clinical variables included presence and timing of palliative care referral. Data were correlated utilizing univariable and multivariable parametric and non-parametric testing, and survivals were analyzed using the Kaplan-Meier method and cox-proportional hazard models. RESULTS: We identified 391 women treated for ovarian cancer, of whom 68% were diagnosed with stage III or IV disease. Palliative care referral was utilized in 28% in the outpatient (42%) and inpatient (58%) settings. Earlier use of referral was observed in those who never underwent surgical cytoreduction or had interval cytoreductive surgery (p < 0.001). Palliative care referral was independently associated with advanced stage (OR 1.7, p = 0.02), recurrence (OR 2.0, p = 0.002) and hospice referral (OR 6.0, p < 0.001). In 38% of women referral occurred within 30 days of death, and 17% within one week of death. Outpatient initial consultation was associated with an unadjusted 1 year overall survival benefit (p < 0.01) compared to inpatient consultation. CONCLUSIONS: The outcomes in this study suggest a late use of palliative care that is reactionary to patient needs and not a routine component of ovarian cancer care as national guidelines recommend. PMID- 29395316 TI - Apelin/APJ expression in the heart and kidneys of hypertensive rats. AB - Hypertension is an important health problem that is manifested by systemic arterial blood pressure being permanently elevated and leading to serious complications. Hypertension is the basis for coronary heart diseases, heart failure, kidney damage, cerebrovascular diseases. Due to ethical concerns, there is no detailed study of the mechanism, side effects and treatment of hypertension in humans. For this reason, specific studies related to the organ of hypertension are performed in experimental animals. The heart and kidney tissue, which are the most important organs that hypertension has damaged, have formed specific organs of our work. In our experimental study, a total of 35 (hypertensive group: 20, control group: 15) Rattus Norvegicus Wistar albino rats were used. In order to obtain our hypertension model, our experimental animals were given L-NAME together with drinking water for six weeks. After six weeks, the experimental procedures were terminated. Heart and kidney tissues of the hypertensive and control group were obtained. Expression of apelin and apelin receptor (APJ) was demonstrated by immunohistochemical and Western Blot protocols. Hypertrophic cardiac atrium of the hearts of the large cavities, interventricular septum and myocardium to the disintegration, as well as an increase in the diameter of the coronary artery has been observed. In general, kidney tissues of the hypertensive group showed narrowing in cortical renal structures and enlargement in structures in the renal medulla. As a result, in hypertensive cases, there was an increase in expression of Apelin and APJ receptor in heart tissue, and a decrease in expression of Apelin and APJ receptor in kidney tissue. We think that our findings may contribute to experimental or clinical studies related to hypertension and apelin. PMID- 29395317 TI - Dystrophin 71 and alpha1syntrophin in morpho-functional plasticity of rat supraoptic nuclei: Effect of saline surcharge and reversibly normal hydration. AB - Dystrophin (Dp) is a multidomain protein that links the actin cytoskeleton to the extracellular matrix through the dystrophin associated proteins complex (DAPC). Dp of 71 kDa (Dp71), corresponding to the COOH-terminal domain of dystrophin, and alpha1-syntrophin (alpha1Syn) as the principal component of the DAPC, are strongly expressed in the brain. To clarify their involvement in the central control of osmotic homeostasis, we investigated the effect of 14 days of salt loading (with drinking water containing 2% NaCl) and then reversibly to 30 days of normal hydration (with drinking water without salt), first on the expression by western-blotting and the distribution by immunochemistry of Dp71 and alpha1Syn in the SON of the rat and, second, on the level of some physiological parameters, as the plasma osmolality, natremia and hematocrit. Dp71 is the most abundant form of dystrophin revealed in the supraoptic nucleu (SON) of control rat. Dp71 was localized in magnocellular neurons (MCNs) and astrocytes, when alpha1Syn was observed essentially in astrocytes end feet. After 14 days of salt-loading, Dp71 and alpha1Syn signals decreased and a dual signal for these two proteins was revealed in the astrocytes processes SON surrounding blood capillaries. In addition, salt loading leads to an increase in plasma osmolality, natremia and hematocrit. Reversibly, after 30 days of normal hydration, the intensity of the signal for the two proteins, Dp71 and alpha1Syn, increased and approached that of control. Furtheremore, the levels of the physiological parameters decreased and approximated those of control. This suggests that Dp71 and alpha1Syn may be involved in the functional activity of the SON. Their localization in astrocyte end feet emphasizes their importance in neuronal-vascular-astrocyte interactions for the central detection of osmolality. In the SON, Dp71 and alpha1Syn may be involved in osmosensitivity. PMID- 29395318 TI - The MTT-formazan assay: Complementary technical approaches and in vivo validation in Drosophila larvae. AB - The MTT assay was the first widely accepted method to assess cytotoxicity and cell viability. However, there is controversy on whether this indicator is a useful tool. In this work we intend to expand the interpretability of the MTT study by its combination with widely used cellular biology techniques. We propose complementary approaches to the colorimetric assay, based on the use of measurements in three different settings: confocal microscopy, multi-well plate assay and flow cytometry. Using confocal microscopy, we confirmed that MTT uptake and reduction by cells is a time-dependent process, and that formazan accumulates in round-shaped organelles. Quantitative measurements with a multi-well fluorimeter combined with nuclear staining result in a useful method, yielding a ratio between formazan production and cell number that informs about the average cell metabolic state. We also found that flow cytometry is a suitable technique to measure MTT reduction in large cell populations. When assaying the effect of an oxidizing agent such as paraquat (PQ), this approach allows for the distinction of subpopulations of cells with different reducing power. Finally, we prove that it is feasible to monitor MTT reduction in an in vivo model, the Drosophila larvae, without affecting its survival rate. Formazan accumulates exclusively in the larval fat body, confirming its lipid solubility. The methods explored in this work expand the MTT potential as a useful tool to provide information of the physiological state of cells and organisms. PMID- 29395319 TI - Minocycline decreases CD36 and increases CD44 in LPS-induced microglia. AB - Microglia are the resident macrophages patrolling the central nervous system (CNS) to find dangerous signals and infectious agents mediating catastrophic cascades resulting in neuronal degeneration. Their morphological and biochemical properties made them enable to swift activation in response to neural insults and site-directed phagocytosis. Beside of beneficial roles in homeostasis of the brain and spinal cord, microglia can be participating in neuronal destruction and propagation of inflammation when they are unregulated or hyper-activated. A large body of research indicates that various cluster of differentiations (CDs) contribute to flame/quench the inflammatory processes occurred in immune system. In this study, we investigated the expression of CD36 and CD44 in LPS-activated primary rat microglia in response to treatment of minocycline at the levels of protein and gene using flow cytometry and real-time PCR, respectively. The results showed that minocycline decreased the expression of CD36 in cells treated with minocycline with respect to cells treated with LPS. Inversely, the expression of CD44 was increased in cells treated with minocycline in comparison to LPS-induced microglia. It seems that minocycline can modulate the expression of CDs involved in inflammatory reactions and enrich the armamentarium of therapeutic agents used for the treatment of neuroinflammatory and neurodegenerative disorders. PMID- 29395320 TI - Pattern recognition receptor mRNA expression and cytokine and granzyme levels in HIV infected individuals with neurotuberculosis. AB - Neurotuberculosis is one of the commonest HIV-associated opportunistic infections (OI) of the CNS. Cross-talk between HIV, Mycobacterium tuberculosis and host immune responses may alter expression of pattern recognition receptors (PRRs), thereby affecting cytokine profiles and functional responses. We examined PRR mRNA expression and cytokine and granzyme levels in HIV infected individuals with neurotuberculosis and found significant downregulation of TLR9 and increased MDA5 expression compared to healthy subjects. Significantly higher Granzyme A and IFN gamma levels were also observed in the CSF of this group compared to CSF from non infectious controls. These alterations may lead to inappropriate recruitment of immune cells to the CNS, leading to disease severity. PMID- 29395321 TI - Expressions of chemokines and their receptors in the brain after heat stroke induced cortical damage. AB - Despite growing evidence that cytokines and chemokines are expressed in humans and rats after heat stress, the cellular mechanisms underlying the effects on the brain after heatstroke (HS) are not fully understood. In this study, we observed time course changes of chemokines in rat brain tissues and elucidated what kinds of cortical cells were affected after HS. Male SD rats were anesthetized and randomly separated into two groups as follows: (a) normothermic sham and (b) HS rats. Rats were sacrificed at different time points (0, 1, 3, 6, and 12h after heat exposure, n=5 in each group) to the end of the experiment in order to extract the mRNA/proteins of cortical tissues. Cerebrospinal fluid (CSF) of sham and HS rats was also collected before sacrifice. In the HS group, an elevated body temperature (Tco>40 degrees C) and abnormality of cortical cells (e.g., pyknotic nuclei) were observed. When compared to the sham group, expression levels of either mRNAs or proteins of chemokines and their receptors (including CXCL1, MIP2, MCP1, CXCR1, CXCR2, and CCR2) peaked at different time points after heat exposure. We also found that CXCR2 was expressed in the cortex of rat brain and was colocalized with neurons and microglia after HS. Hence, MCP1, MIP2, and CXCR2 might play important roles in the brain after HS, possibly indicating a new direction for treating HS. PMID- 29395322 TI - Thymoma-associated myasthenia gravis and LGI1-encephalitis, with nephrotic syndrome post-thymectomy. AB - Thymoma is associated with a wide spectrum of autoimmune paraneoplastic syndromes, though it is uncommon for multiple paraneoplastic syndromes to be present in a single individual. We report a rare case of an elderly gentleman who was found to have thymoma-associated myasthenia gravis and LGI1-encephalitis with myokymia, who presented with nephrotic syndrome (minimal change glomerulopathy) after thymectomy. The latter two paraneoplastic syndromes had manifested when prednisolone was tapered down to low dose. This case serves to remind neurologists that apart from paraneoplastic neurological manifestations, thymoma may also be associated with renal disease. Nephropathy in myasthenia patients with thymoma should be properly evaluated, as it is treatable with immunotherapy, and it may even occur post-thymectomy. PMID- 29395323 TI - alpha7 nicotinic acetylcholine receptors are involved in suppression of the antibody immune response. AB - This study demonstrates that alpha7 nicotinic acetylcholine receptors (nAChRs) regulate mouse B lymphocyte proliferation and IgM production in ion-independent manner. The high alpha7 nAChR levels were found in CD5+ and Foxp3+ B cells; induction of Foxp3+ cells in vitro was attenuated in the absence or upon inhibition of alpha7 nAChRs. The adoptively transferred B lymphocytes, stimulated in presence of methyllicaconitine, decreased the IgM response and abolished the IgG response in the host. The data obtained demonstrate the importance of cholinergic regulation for the antibody immune response and immunosuppression. PMID- 29395324 TI - FasL incapacitation alleviates CD4+ T cells-induced brain injury through remodeling of microglia polarization in mouse ischemic stroke. AB - Inflammation responses involving the crosstalk between infiltrated T cells and microglia play crucial roles in ischemia stroke. Recent studies showed that Fas ligand (FasL) mutation could reduce post-stroke T cell invasion and microglia activation. In this study, we demonstrated that CD4+ T cells could induce M1 microglia polarization through NF-kappaB signaling pathway, whereas FasL mutant CD4+ T cells significantly reversed this effect. Besides, Th17/Treg cells balance was skewed into Treg cells after FasL mutation. In addition, conditioned medium from co-culture of FasL mutant CD4+ T cells and microglia could alleviate neuronal injury. Collectively, FasL incapacitation could alleviate CD4+ T cells induced inflammation through remodeling microglia polarization, suggesting a therapeutic potential for control of inflammation responses after ischemic stroke. PMID- 29395325 TI - Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown. AB - Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutieres syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation. PMID- 29395326 TI - Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation. AB - Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutieres syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system. PMID- 29395327 TI - Cloning of Macaque Monkeys by Somatic Cell Nuclear Transfer. AB - Generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. In this study, we have successfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nuclear transfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at one-cell stage following SCNT greatly improved blastocyst development and pregnancy rate of transplanted SCNT embryos in surrogate monkeys. For SCNT using fetal monkey fibroblasts, 6 pregnancies were confirmed in 21 surrogates and yielded 2 healthy babies. For SCNT using adult monkey cumulus cells, 22 pregnancies were confirmed in 42 surrogates and yielded 2 babies that were short-lived. In both cases, genetic analyses confirmed that the nuclear DNA and mitochondria DNA of the monkey offspring originated from the nucleus donor cell and the oocyte donor monkey, respectively. Thus, cloning macaque monkeys by SCNT is feasible using fetal fibroblasts. PMID- 29395328 TI - CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. AB - Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-kappaB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors. PMID- 29395329 TI - Do Standard Instrumental Acoustic, Perceptual, and Subjective Voice Outcomes Indicate Therapy Success in Patients With Functional Dysphonia? AB - OBJECTIVES: The validity and sensitivity to change of instrumental acoustic measurements in patients with functional dysphonia have been controversially discussed. This work examines combined voice therapy effects on standard acoustic measurements, and if these agree with perceptual and subjective voice outcomes. STUDY DESIGN: Retrospective study. METHODS: Thirty-nine patients (26 women, 13 men) aged 20-70 years (mean: 46.3, standard deviation 12.8) with functional dysphonia were investigated before and after combined voice therapy. Instrumental parameters included mean and range of speaking fundamental frequency (fo) and intensity (SPL (dBA)); maximum SPL and mean fo of calling voice; minimum, maximum, range of singing voice fo and SPL, jitter (%), and the Dysphonia Severity Index. Voice Handicap Index-9 international was used for subjective and Grading-Roughness-Breathiness-Asthenia-Strain scale for perceptual assessment. Differences were investigated by Wilcoxon signed ranks test and coherences by Spearman rank correlation coefficient. RESULTS: After treatment, the speaking voice fo range (7-8.13 semitones) and SPL range (12.9-14.85 dB(A)) were significantly larger (P < 0.05). Both parameters were highly correlated (P < 0.001). Subjective symptoms were significantly reduced from a mean Voice Handicap Index-9 international of 15.6-8.6, and all perceptual Grading-Roughness Breathiness-Asthenia-Strain scale parameters were significantly improved (G: 1.05 0.51) after therapy (P < 0.05). These findings were not associated with any acoustic parameter (P > 0.05). CONCLUSIONS: Significantly improved subjective and perceptual findings verify positive combined voice therapy effects in patients with functional dysphonia. The larger fo and SPL speaking voice range after treatment indicate an altered voice technique. These instrumental measures may be clinical indicators of therapy success and transfer effects. PMID- 29395330 TI - Efficacy of Two-dimensional Scanning Digital Kymography in Evaluation of Atrophic Vocal Folds. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical feasibility and diagnostic accuracy of two-dimensional scanning digital kymography (2D DKG) in patients with vocal cord atrophy before and after treatment. MATERIALS AND METHODS: We analyzed the characteristics of vocal fold vibration in five patients with unilateral vocal fold paralysis and five patients with presbyphonia. In patients with vocal cord paralysis, the status before and after intracordal injection was compared. Furthermore, in patients with presbyphonia, we compared the status before and after voice therapy (Seong-Tae Kim's laryngeal calibration technique). Quantitative parameters such as amplitude and phase symmetry indices, jitter, shimmer, noise-to-harmonic ratio, and maximum phonation time and qualitative parameters such as Voice Handicap Index, glottal gap, amplitude, and phase difference were used to evaluate the pre- and post-treatment status. RESULTS: In cases of vocal cord paralysis, vibratory changes of the vocal folds before and after intracordal injection could be identified immediately using 2D DKG. In overcorrection cases, all of the measured parameters were poor except for improvement of the glottal gap. In addition, 2D DKG showed appropriately the changes in vocal cord vibration before and after voice therapy in patients with presbyphonia. CONCLUSION: Two-dimensional DKG may be a useful diagnostic tool in evaluation of the vibratory characteristics of entire vocal cords. In addition, it may also play a role in providing a decision for treatment modalities. PMID- 29395331 TI - Detection of Arytenoid Dislocation Using Pixel-valued Cuneiform Movement. AB - OBJECTIVES: This study aims to assess utility of pixel-valued movement software in detecting arytenoid dislocation preoperatively. STUDY DESIGN: This is a retrospective analysis. METHODS: Twenty-seven patients diagnosed with unilateral arytenoid dislocation were included. Diagnosis of arytenoid dislocation was confirmed by lack of vocal fold paralysis on preoperative laryngeal electromyography and by intraoperative findings of cricoarytenoid dislocation. A region-tracking software algorithm developed by Zhuang et al was used to analyze 27 preoperative endoscopic videos of patients diagnosed with arytenoid dislocation. Vector analysis measuring cuneiform movement during inspiration was used as an indirect measure of arytenoid movement. Values were normalized using vocal fold length. Two raters blinded to diagnosis of arytenoid dislocation measured vocal fold length and cuneiform movement on both the dislocated and the nondislocated sides. RESULTS: A Wilcoxon signed-rank test indicated that the mean pixel-valued cuneiform movement and standard deviation (SD) were greater for nondislocated (159.24, SD = 73.35) than for dislocated (92.49, SD = 72.11) arytenoids (Z = 3.29, P = 0.001). The interrater correlation coefficient was 0.87 for the dislocated side and 0.75 for the nondislocated side. The intrarater correlation coefficient was 0.87 for the dislocated side and 0.91 for the nondislocated side. The receiver operating characteristic curve revealed an area under the curve between 0.76 and 0.83 (95% confidence interval 0.63-0.90). Analysis by the first and second raters revealed misdiagnosis of laterality of arytenoid dislocation in four and six patients, respectively. CONCLUSIONS: The software program developed by Zhuang et al provides a high-degree of precision, with good interrater and intrarater correlation coefficients. However, high rates of misdiagnosis of arytenoid dislocation and the laborious analysis process using this software program make it of limited utility as a clinical diagnostic tool in its present state. PMID- 29395332 TI - Voice Tremor in Parkinson's Disease: An Acoustic Study. AB - BACKGROUND: Voice tremor associated with Parkinson disease (PD) has not been characterized. Its relationship with voice disability and disease variables is unknown. OBJECTIVES: This study aimed to evaluate voice tremor in people with PD (pwPD) and a matched control group using acoustic analysis, and to examine correlations with voice disability and disease variables. METHODS: Acoustic voice tremor analysis was completed on 30 pwPD and 28 age-gender matched controls. Voice disability (Voice Handicap Index), and disease variables of disease duration, Activities of Daily Living (Unified Parkinson's Disease Rating Scale [UPDRS II]), and motor symptoms related to PD (UPDRS III) were examined for relationship with voice tremor measures. RESULTS: Voice tremor was detected acoustically in pwPD and controls with similar frequency. PwPD had a statistically significantly higher rate of amplitude tremor (Hz) than controls (P = 0.001). Rate of amplitude tremor was negatively and significantly correlated with UPDRS III total score (rho -0.509). For pwPD, the magnitude and periodicity of acoustic tremor was higher than for controls without statistical significance. The magnitude of frequency tremor (Mftr%) was positively and significantly correlated with disease duration (rho 0.463). PwPD had higher Voice Handicap Index total, functional, emotional, and physical subscale scores than matched controls (P < 0.001). Voice disability did not correlate significantly with acoustic voice tremor measures. CONCLUSION: Acoustic analysis enhances understanding of PD voice tremor characteristics, its pathophysiology, and its relationship with voice disability and disease symptomatology. PMID- 29395333 TI - Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. AB - It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI. PMID- 29395334 TI - Metabolic syndrome but not obesity measures are risk factors for accelerated age related glomerular filtration rate decline in the general population. AB - Rapid age-related glomerular filtration rate (GFR) decline increases the risk of end-stage renal disease, and a low GFR increases the risk of mortality and cardiovascular disease. High body mass index and the metabolic syndrome are well known risk factors for patients with advanced chronic kidney disease, but their role in accelerating age-related GFR decline independent of cardiovascular disease, hypertension and diabetes is not adequately understood. We studied body mass index, waist circumference, waist-hip ratio and metabolic syndrome as risk factors for accelerated GFR decline in 1261 middle-aged people representative of the general population without diabetes, cardiovascular disease or kidney disease. GFR was measured as iohexol clearance at baseline and repeated after a median of 5.6 years. Metabolic syndrome was defined as fulfilling three out of five criteria, based on waist circumference, blood pressure, glucose, high density lipoprotein cholesterol and triglycerides. The mean GFR decline rate was 0.95 ml/min/year. Neither the body mass index, waist circumference nor waist-hip ratio predicted statistically significant changes in age-related GFR decline, but individuals with baseline metabolic syndrome had a significant mean of 0.30 ml/min/year faster decline than individuals without metabolic syndrome in a multivariable adjusted linear regression model. This association was mainly driven by the triglyceride criterion of metabolic syndrome, which was associated with a significant 0.36 ml/min/year faster decline when analyzed separately. Results differed significantly when GFR was estimated using creatinine and/or cystatin C. Thus, metabolic syndrome, but not the body mass index, waist circumference or waist-hip ratio, is an independent risk factor for accelerated age-related GFR decline in the general population. PMID- 29395335 TI - The atypical chemokine receptor 2 limits renal inflammation and fibrosis in murine progressive immune complex glomerulonephritis. AB - The atypical chemokine receptor 2 (ACKR2), also named D6, regulates local levels of inflammatory chemokines by internalization and degradation. To explore potential anti-inflammatory functions of ACKR2 in glomerulonephritis, we induced autologous nephrotoxic nephritis in C57/BL6 wild-type and Ackr2-deficient mice. Renal ACKR2 expression increased and localized to interstitial lymphatic endothelium during nephritis. At two weeks Ackr2-/-mice developed increased albuminuria and urea levels compared to wild-type mice. Histological analysis revealed increased structural damage in the glomerular and tubulointerstitial compartments within Ackr2-/- kidneys. This correlated with excessive renal leukocyte infiltration of CD4+ T cells and mononuclear phagocytes with increased numbers in the tubulointerstitium but not glomeruli in knockout mice. Expression of inflammatory mediators and especially markers of fibrotic tissue remodeling were increased along with higher levels of ACKR2 inflammatory chemokine ligands like CCL2 in nephritic Ackr2-/- kidneys. In vitro, Ackr2 deficiency in TNF stimulated tubulointerstitial tissue but not glomeruli increased chemokine levels. These results are in line with ACKR2 expression in interstitial lymphatic endothelial cells, which also assures efflux of activated leukocytes into regional lymph nodes. Consistently, nephritic Ackr2-/- mice showed reduced adaptive cellular immune responses indicated by decreased regional T-cell activation. However, this did not prevent aggravated injury in the kidneys of Ackr2-/- mice with nephrotoxic nephritis due to simultaneously increased tubulointerstitial chemokine levels, leukocyte infiltration and fibrosis. Thus, ACKR2 is important in limiting renal inflammation and fibrotic remodeling in progressive nephrotoxic nephritis. Hence, ACKR2 may be a potential target for therapeutic interventions in immune complex glomerulonephritis. PMID- 29395336 TI - Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria. AB - Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets. PMID- 29395337 TI - Declining comorbidity-adjusted mortality rates in English patients receiving maintenance renal replacement therapy. AB - We aimed to compare long-term mortality trends in end-stage renal disease versus general population controls after accounting for differences in age, sex and comorbidity. Cohorts of 45,000 patients starting maintenance renal replacement therapy (RRT) and 5.3 million hospital controls were identified from two large electronic hospital inpatient data sets: the Oxford Record Linkage Study (1965 1999) and all-England Hospital Episode Statistics (2000-2011). All-cause and cause-specific three-year mortality rates for both populations were calculated using Poisson regression and standardized to the age, sex, and comorbidity structure of an average 1970-2008 RRT population. The median age at initiation of RRT in 1970-1990 was 49 years, increasing to 61 years by 2006-2008. Over that period, there were increases in the prevalence of vascular disease (from 10.0 to 25.2%) and diabetes (from 6.7 to 33.9%). After accounting for age, sex and comorbidity differences, standardized three-year all-cause mortality rates in treated patients with end-stage renal disease between 1970 and 2011 fell by about one-half (relative decline 51%, 95% confidence interval 41-60%) steeper than the one-third decline (34%, 31-36%) observed in the general population. Declines in three-year mortality rates were evident among those who received a kidney transplant and those who remained on dialysis, and among those with and without diabetes. These data suggest that the full extent of mortality rate declines among RRT patients since 1970 is only apparent when changes in comorbidity over time are taken into account, and that mortality rates in RRT patients appear to have declined faster than in the general population. PMID- 29395338 TI - Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) are exposed to uremic toxins and have an increased risk of cardiovascular disease. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AHR). These toxins induce a vascular procoagulant phenotype. Here we investigated AHR activation in patients with CKD and in a murine model of CKD. We performed a prospective study in 116 patients with CKD stage 3 to 5D and measured the AHR-Activating Potential of serum by bioassay. Compared to sera from healthy controls, sera from CKD patients displayed a strong AHR-Activating Potential; strongly correlated with eGFR and with the indoxyl sulfate concentration. The expression of the AHR target genes Cyp1A1 and AHRR was up-regulated in whole blood from patients with CKD. Survival analyses revealed that cardiovascular events were more frequent in CKD patients with an AHR-Activating Potential above the median. In mice with 5/6 nephrectomy, there was an increased serum AHR Activating Potential, and an induction of Cyp1a1 mRNA in the aorta and heart, absent in AhR-/- CKD mice. After serial indoxyl sulfate injections, we observed an increase in serum AHR-AP and in expression of Cyp1a1 mRNA in aorta and heart in WT mice, but not in AhR-/- mice. Thus, the AHR pathway is activated both in patients and mice with CKD. Hence, AHR activation could be a key mechanism involved in the deleterious cardiovascular effects observed in CKD. PMID- 29395339 TI - The Inv compartment of renal cilia is an intraciliary signal-activating center to phosphorylate ANKS6. AB - Connections between cilia and renal cystic diseases are well known, yet molecular mechanisms remain undefined. Cysto-proteins localized in the Inv compartment of cilia (INV, NPHP3, NEK8, and ANKS6) constitute a distinct group. Here we created and analyzed mutant mice (G2A mice) with a defective cilia localization signal in the Nphp3 gene. Mutant NPHP3 was absent the binding capacity of UNC119, a carrier protein responsible for the delivery of myristoylated cargo to the cilium, so ciliary localization was reduced or lost in the kidney but not in the embryonic node. Mutant mice developed renal cysts but not situs abnormalities. Although ciliary localization of INV, NEK8, and ANKS6 did not change in the kidneys of Nphp3 mutant mice, ANKS6 phosphorylation was impaired. In general, ANKS6 levels decrease with age in the kidneys of wild-type mice. However, cystic kidneys in G2A and Inv mice maintained high levels of a non-phosphorylated form of ANKS6. We found INV and NPHP3 cooperate and promote ANKS6 phosphorylation by NEK8 in renal cilia. Thus, there is a novel signaling path from cilia in which ANKS6 functions as a signal mediator and link between cilia and the cytoplasm to regulate kidney morphogenesis. PMID- 29395341 TI - Vancomycin incorporated chitosan/gelatin coatings coupled with TiO2-SrHAP surface modified cp-titanium for osteomyelitis treatment. AB - Commercially pure Titanium (Cp-Ti) was electrophoretically modified using double layer coatings consisting of TiO2-SrHAP as the first layer (TH) followed by vancomycin incorporated Chitosan/Gelatin as the second layer (THV). The nano crystalline phase of coated Strontium incorporated hydroxyapatite (Sr-HAP) confirmed through X-ray diffraction studies (XRD). The polyelectrolyte complex formation between chitosan and gelatin, the stability of the drug, the bonding between chitosan and Sr-HAP were confirmed through infra-red spectroscopic studies (IR). The average roughness (Ra) value calculated from atomic force microscopy (AFM) corroborates with the water contact angle data, which clearly confirms the tuning property of the surface in relation to the surface energy and roughness of the coated samples. The total amount of vancomycin encapsulated was calculated to be 11.5 MUg. Antibacterial activity was found against both Staphylococcus aureus strains methicillin resistant Staphylococcus aureus (MRSA) and methicillin sensitive Staphylococcus aureus (MRSA) for a drug concentration of 2.74 MUg released after 12 h of immersion. The in-vitro cell culture studies showed enhanced cellular activity for THV samples. Thus, THV samples have a dual action at the surface, by resisting the bacterial adhesion and enhancing cellular interaction at the bio-interface, making it a promising candidate to treat osteomyelitis infection. PMID- 29395340 TI - Primary outcomes of the Monitoring in Dialysis Study indicate that clinically significant arrhythmias are common in hemodialysis patients and related to dialytic cycle. AB - Sudden death is one of the more frequent causes of death for hemodialysis patients, but the underlying mechanisms, contribution of arrhythmia, and associations with serum chemistries or the dialysis procedure are incompletely understood. To study this, implantable loop recorders were utilized for continuous cardiac rhythm monitoring to detect clinically significant arrhythmias including sustained ventricular tachycardia, bradycardia, asystole, or symptomatic arrhythmias in hemodialysis patients over six months. Serum chemistries were tested pre- and post-dialysis at least weekly. Dialysis procedure data were collected at every session. Associations with clinically significant arrhythmias were assessed using negative binomial regression modeling. Sixty-six patients were implanted and 1678 events were recorded in 44 patients. The majority were bradycardias (1461), with 14 episodes of asystole and only one of sustained ventricular tachycardia. Atrial fibrillation, although not defined as clinically significant arrhythmias, was detected in 41% of patients. With thrice-weekly dialysis, the rate was highest during the first dialysis session of the week and was increased during the last 12 hours of each inter dialytic interval, particularly the long interval. Among serum and dialytic parameters, only higher pre-dialysis serum sodium and dialysate calcium over 2.5 mEq/L were independently associated with clinically significant arrhythmias. Thus, clinically significant arrhythmias are common in hemodialysis patients, and bradycardia and asystole rather than ventricular tachycardia may be key causes of sudden death in hemodialysis patients. Associations with the temporal pattern of dialysis suggest that modification of current dialysis practices could reduce the incidence of sudden death. PMID- 29395343 TI - Designing Reactor Microbiomes for Chemical Production from Organic Waste. AB - Microorganisms are responsible for biochemical cycles and therefore play essential roles in the environment. By using omics approaches and network analysis to understand the interaction and cooperation within mixed microbial communities, it would be possible to engineer microbiomes in fermentation and digestion reactors to convert organic waste into valuable products. PMID- 29395342 TI - Purification, characterization and immunomodulatory activity of a novel polysaccharide from Grifola frondosa. AB - A novel bioactive polysaccharide, GFP-22, was isolated from the fruit bodies of Grifola frondosa by anion-exchange and gel filtration chromatography. Structure of GFP-22 was investigated using gas chromatography-mass spectrometry (GC-MS), methylation, nuclear magnetic resonance (NMR), high-performance size exclusion chromatography-multi-angle laser light scattering-refractive index detector (HPSEC-MALLS-RI) and atomic force microscopy (AFM) analysis. The backbone of GFP 22 is composed of 1,4-beta-d-Glcp, 1,3-beta-d-Glcp, 1,6-alpha-d-Glcp, 1,6-alpha-d Galp, 1,4,6-alpha-d-Manp and 1,3,6-alpha-d-Manp units. Molecular weight of GFP-22 is 2.72 * 104 Da. GFP-22 has a linear filamentous structure. The administration of GFP-22 could improve or reverse the CTX-induced immunosuppression, significantly enhance the spleen and thymus indices, spleen lymphocyte proliferation and cytokines production in splenocytes. These findings suggest that GFP-22 could be explored as a natural and potential immunomodulatory agent and as an alternative means of lessening chemotherapy-induced immunosuppression. PMID- 29395344 TI - Therapeutic Opportunities in Intestinal Microbiota-Virus Interactions. AB - The host microbiota has emerged a third player in interactions between hosts and viral pathogens. This opens new possibilities to use different tools to modulate the intestinal microbial composition, aimed at reducing the risk of or treating viral enteric infections. PMID- 29395345 TI - Diagnostic Potential of Imaging Flow Cytometry. AB - Imaging flow cytometry (IFC) captures multichannel images of hundreds of thousands of single cells within minutes. IFC is seeing a paradigm shift from low to high-information-content analysis, driven partly by deep learning algorithms. We predict a wealth of applications with potential translation into clinical practice. PMID- 29395346 TI - Applied Hologenomics: Feasibility and Potential in Aquaculture. AB - Aquaculture will play an essential role in feeding a growing human population, but several biological challenges impede sustainable growth of production. Emerging evidence across all areas of life has revealed the importance of the intimate biological interactions between animals and their associated gut microbiota. Based on challenges in aquaculture, we leverage current knowledge in molecular biology and host microbiota interactions to propose an applied holo omic framework that integrates molecular data including genomes, transcriptomes, epigenomes, proteomes, and metabolomes for analyzing fish and their gut microbiota as interconnected and coregulated systems. With an eye towards aquaculture, we discuss the feasibility and potential of our holo-omic framework to improve growth, health, and sustainability in any area of food production, including livestock and agriculture. PMID- 29395347 TI - Can We Approach Theoretical Lipid Yields in Microalgae? AB - Can we approach theoretical lipid yields in microalgae? Yes: we can substantially reduce the gap between current and theoretical maximum yield. A realistic maximum is approximately 0.5g triacylglycerol (TAG) per mol photons, about five times higher than what is currently achieved in outdoor cultivation. Achieving this realistic maximum will require several breakthroughs. First, outdoor operation typically has low yields, mainly caused by fluctuating insolation. Future adaptive control models will help increase these yields. Additionally, the lipid production capacity of currently used strains needs to increase. Powerful strain specific molecular toolboxes are being developed, shifting the bottleneck towards understanding metabolism and identifying target genes. Finally, strains and processes should be improved concurrently to fully exploit the potential lipid production from microalgae. PMID- 29395348 TI - The Current Role of Bevacizumab in the Treatment of Hereditary Hemorrhagic Telangiectasia-Related Bleeding. PMID- 29395349 TI - Disease Progression and End-Stage Renal Disease in Diverse Glomerulopathies. PMID- 29395350 TI - Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Gastrointestinal Bleeding. AB - OBJECTIVE: To present a multiyear clinical experience with intravenous bevacizumab for the management of severe gastrointestinal bleeding and/or epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). PATIENTS AND METHODS: All patients treated with intravenous bevacizumab for severe hereditary hemorrhagic telangiectasia-related bleeding from June 1, 2013, through January 31, 2017, were included in this report. Severity of epistaxis (determined using the Epistaxis Severity Score questionnaire); hemoglobin, iron, and ferritin levels; and quality of life data were collected serially in all patients. RESULTS: Intravenous bevacizumab was administered to 34 patients using a standardized treatment protocol. Anemia was primarily related to severe epistaxis (n=15, 44%), severe gastrointestinal bleeding (n=4, 12%), or both (n=15, 44%), with a median baseline hemoglobin level of 9.1 g/dL (range, 8.3-10.5 gm/dL; to convert to mmol/L, multiply by 0.62). Red blood cell (RBC) transfusions had been administered to 28 patients (82%). Of these, 16 patients (47%) were RBC transfusion dependent and had received a median of 75 RBC transfusions (range, 4 >500 RBC units) before bevacizumab initiation. The median length of follow-up was 17.6 months from the beginning of bevacizumab treatment (range, 3-42.5 months). There was a significant reduction in epistaxis severity scores (P<.001) and RBC transfusion requirements (P=.007) after completion of the initial bevacizumab treatment cycle. New-onset or worsened hypertension was noted in 4 patients, with 1 patient experiencing hypertensive urgency with a temporary decline in renal function. CONCLUSION: Intravenous bevacizumab is an effective treatment option for patients with severe anemia related to epistaxis and/or gastrointestinal bleeding. Further studies are needed to establish a dose-response relationship as well as clinical, genetic, and biomarker predictors of response. PMID- 29395351 TI - End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population. AB - OBJECTIVE: To compare renal function decline, incident end-stage renal disease (ESRD), and mortality among patients with 5 common glomerular diseases in a large diverse population. PATIENTS AND METHODS: A retrospective cohort study (between January 1, 2000, and December 31, 2011) of patients with glomerulonephropathy using the electronic health record of an integrated health system was performed. Estimated glomerular filtration rate (eGFR) change, incident ESRD, and mortality were compared among patients with biopsy-proven focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MN), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), and lupus nephritis (LN). Competing risk models were used to estimate hazard ratios for different glomerulonephropathies for incident ESRD, with mortality as a competing outcome after adjusting for potential confounders. RESULTS: Of the 2350 patients with glomerulonephropathy (208 patients [9%] younger than 18 years) with a mean follow up of 4.5+/-3.6 years, 497 (21%) progressed to ESRD and 195 (8%) died before ESRD. The median eGFR decline was 1.0 mL/min per 1.73 m2 per year but varied across different glomerulonephropathies (P<.001). The highest ESRD incidence (per 100 person-years) was observed in FSGS 8.72 (95% CI, 3.93-16.72) followed by IgAN (4.54; 95% CI, 1.37-11.02), LN (2.38; 95% CI, 0.37-7.82), MN (2.15; 95% CI, 0.29 7.46), and MCD (1.67; 95% CI, 0.15-6.69). Compared with MCD, hazard ratios (95% CIs) for incident ESRD were 3.43 (2.32-5.08) and 2.35 (1.46-3.81), 1.28 (0.79 2.07), and 1.02 (0.62-1.68) for FSGS, IgAN, LN, and MN, respectively. No significant association between glomerulonephropathy types and mortality was detected (P=.24). CONCLUSION: Our findings from a real-world clinical environment revealed significant differences in eGFR decline and ESRD risk among patients with 5 glomerulonephropathies. These variations in presentation and outcomes warrant different management strategies and expectations. PMID- 29395352 TI - In Reply-Cardiac Compromise in Zika Virus Infection. PMID- 29395353 TI - 65-Year-Old Woman With Chronic Eosinophilia. PMID- 29395354 TI - 28-Year-Old Man With Fever, Malaise, and Diarrhea. PMID- 29395355 TI - 70-Year-Old Woman With Sudden Onset of Chest Pain and Diaphoresis. PMID- 29395356 TI - 42-Year-Old Woman With Bilateral Arm Tightness. PMID- 29395357 TI - 52-Year-Old Man With Hyposmia, Rhinorrhea, and Wheezing. PMID- 29395358 TI - Stimulation-induced changes in diffusion and structure of calmodulin and calmodulin-dependent protein kinase II proteins in neurons. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) and calmodulin (CaM) play essential roles in synaptic plasticity, which is an elementary process of learning and memory. In this study, fluorescence correlation spectroscopy (FCS) revealed diffusion properties of CaM, CaMKIIalpha and CaMKIIbeta proteins in human embryonic kidney 293 (HEK293) cells and hippocampal neurons. A simultaneous multiple-point FCS recording system was developed on a random-access two-photon microscope, which facilitated efficient analysis of molecular dynamics in neuronal compartments. The diffusion of CaM in neurons was slower than that in HEK293 cells at rest, while the diffusion in stimulated neurons was accelerated and indistinguishable from that in HEK293 cells. This implied that activity dependent binding partners of CaM exist in neurons, which slow down the diffusion at rest. Diffusion properties of CaMKIIalpha and beta proteins implied that major populations of these proteins exist as holoenzymatic forms. Upon stimulation of neurons, the diffusion of CaMKIIalpha and beta proteins became faster with reduced particle brightness, indicating drastic structural changes of the proteins such as dismissal from holoenzyme structure and further fragmentation. PMID- 29395359 TI - U1 small nuclear RNA overexpression implicates autophagic-lysosomal system associated with AD. AB - Recently, we reported that presenilin 1 considerably increased the expression level of U1 small nuclear RNA (snRNA) accompanied with the adverse change of amyloid precursor protein (APP) expression, beta-amyloid (Abeta) production and cell apoptosis. In the present study, it was found that U1 snRNA overexpression significantly elevated the expression level of autophagy. Moreover, rapamycin further enhanced the Abeta production and cell apoptosis, whereas these processes were effectively inhibited by 3-MA. Acridine orange staining images showed that U1 snRNA overexpression not only activated autophagy pathway, but also led to the autophagic-lysosomal system dysfunction in cells. Immunofluorescence assay showed autophagic vacuoles localization with APP, which was the precursor protein of main component of toxic protein in AD. Meanwhile, the superoxide dismutase activity was remarkably decreased and MDA level was significantly increased by U1 snRNA overexpression in cells, suggesting that there was a possible pathway to elucidate how the U1 snRNA overexpression induced cell damage. We further found that U1 snRNA overexpression altered lysosomal biogenesis and autophagic lysosomal fusion. In combination with our previous results, it suggests that the malfunction of autophagy pathway provides important insight into molecular mechanisms of augment the aggregation of Abeta and induction of cell apoptosis contributed to AD. PMID- 29395360 TI - Triple functioning renal allograft after repeated liver-kidney transplantation due to liver failure. PMID- 29395361 TI - Clinical events after interruption of anticoagulation in patients with atrial fibrillation: An analysis from the ENGAGE AF-TIMI 48 trial. AB - BACKGROUND: Patients with atrial fibrillation (AF) who interrupt anticoagulation are at high risk of thromboembolism and death. METHODS AND RESULTS: Patients enrolled in the ENGAGE AF-TIMI 48 trial (randomized comparison of edoxaban vs. warfarin) who interrupted study anticoagulant for >3 days were identified. Clinical events (ischemic stroke/systemic embolism, major cardiac and cerebrovascular events [MACCE]) were analyzed from day 4 after interruption until day 34 or study drug resumption. During 2.8 years median follow-up, 13,311 (63%) patients interrupted study drug for >3 days. After excluding those who received open-label anticoagulation during the at-risk window, the population for analysis included 9148 patients. The rates of ischemic stroke/systemic embolism and MACCE post interruption were substantially greater than in patients who never interrupted (15.42 vs. 0.26 and 60.82 vs. 0.36 per 100 patient-years, respectively, padj < .001). Patients who interrupted study drug for an adverse event (44.1% of the cohort), compared to those who interrupted for other reasons, had an increased risk of MACCE (HRadj 2.75; 95% CI 2.02-3.74, p < .0001), but similar rates of ischemic stroke/systemic embolism. Rates of clinical events after interruption of warfarin and edoxaban were similar. CONCLUSION: Interruption of study drug was frequent in patients with AF and was associated with a substantial risk of major cardiac and cerebrovascular events over the ensuing 30 days. This risk was particularly high in patients who interrupted as a result of an adverse event; these patients deserve close monitoring and resumption of anticoagulation as soon as it is safe to do so. PMID- 29395362 TI - Methods to identify heart failure patients in general practice and their impact on patient characteristics: A systematic review. AB - BACKGROUND: Identifying patients with heart failure (HF) in general practice is challenging. Our aim was to provide an overview of methods used to identify patients with HF in general practice and to assess their impact on patient characteristics. METHODS AND RESULTS: A systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Taken together, 105 studies on HF in general practice were included, totalling 196,105 patients. Five main identification methods for HF were distinguished, including 1) echocardiographic assessments, 2) results of echocardiography in general practitioner (GP) charts, 3) GP judgment after chart review, 4) GP judgment of consecutive patients and 5) only chart review. Only 30% of studies used the results of echocardiography. Despite a large heterogeneity between studies the pooled data revealed a predominant phenotype of older women with hypertension rather than ischaemic heart disease. Linear regression analysis showed that the impact of the identification method on patient characteristics was limited. However, study design had a greater impact, with randomized-controlled trials (RCTs) including younger, male patients with ischaemic heart disease and higher HF drug prescription rates at baseline. CONCLUSION: Pooled data of 196,105 patients with HF confirmed a phenotype of older women with hypertension rather than ischaemic heart disease as the predominant HF population in general practice. The lack of a gold standard definition of HF introduced a large heterogeneity in identification methods with remarkably limited impact on patient characteristics. However, RCTs did include patients with a different phenotype, emphasizing the need to promote inclusion of real-world HF patients. PMID- 29395363 TI - Letter regarding Morsbach et al. "Quantitative comparison of 2D and 3D late gadolinium enhancement MR imaging in patients with Fabry disease and hypertrophic cardiomyopathy". PMID- 29395364 TI - Proposed rationale for anticoagulants in nonvalvular atrial fibrillation with zero CHA2DS2-Vasc score. PMID- 29395365 TI - Prognostic impact of Interleukin-1 receptor antagonist in patients with documented coronary artery disease. AB - BACKGROUND: IL-1beta-mediated inflammation contributes to development and progression of coronary artery disease (CAD). We aimed to assess the prognostic impact of the inflammatory marker Interleukin-1 receptor antagonist (IL1-Ra), reflecting high IL-1beta activity, in patients with documented CAD. METHODS: IL 1Ra levels were determined in 1337 subjects of the AtheroGene study, a prospective cardiovascular registry comprising patients with CAD as detected by coronary angiography presenting with acute coronary syndrome (ACS) or stable angina. Median follow-up was 6.4 years. RESULTS: Patients with IL1-Ra levels in the highest tertile presented more often with ACS (55% vs. 40% vs. 34%, p < 0.001), were more commonly treated with PCI (47% vs. 39% vs. 34%, p < 0.001), had lower left ventricular ejection fraction (LVEF) (61 +/- 15% vs. 62 +/- 15% vs. 65 +/- 14%, p = 0.001) and higher hs-CRP levels (10.0 vs. 4.2 vs. 2.5 mg/L, p < 0.001). IL1-Ra levels at baseline were predictive for all-cause mortality in the total study cohort after adjustment for conventional cardiovascular risk factors, LVEF, hs-CRP and Troponin T (adjusted HR 1.45 (95% CI 1.16-1.82), p < 0.001). In a subgroup of patients with ACS, but not in those with stable angina, IL1-Ra was an independent predictor for cardiovascular mortality (ACS: adjusted HR 1.93 (95% CI 1.33-2.80), p < 0.001; stable angina: adjusted HR: 1.26 (95% CI 0.92-1.73), p = 0.16). CONCLUSION: IL1-Ra is an independent predictor for adverse outcome in patients with documented CAD, beyond the prognostic value of hs-CRP and Troponin T in particular in the setting of ACS. For CAD patients our finding might improve both, risk assessment in secondary prevention and patient selection for anti inflammatory treatment. PMID- 29395366 TI - Acute intraoperative echocardiographic changes after transapical off-pump mitral valve repair with NeoChord implantation. AB - OBJECTIVES: Our aim is to investigate the acute intraoperative effects of the NeoChord repair procedure on mitral valve (MV) annular geometry and LV function and the impact of these changes on MR at 1-year follow-up. BACKGROUND: Recently transapical off-pump mitral valve repair with NeoChord implantation has been demonstrated to be safe and effective in patients with degenerative mitral regurgitation (DMR). METHODS: We retrospectively analyzed baseline and early postoperative 3-dimensional transesophageal echocardiography of 66 patients who underwent NeoChord repair for isolated posterior leaflet MV disease using semiautomatic off-line analysis software. RESULTS: We observed a significant acute reduction of indexed LV end diastolic volume (Delta% = 14, p < .001), LV ejection fraction (Delta = 5.7%, p = .002), indexed left atrial volume (Delta = 14.7%, p = .045), and pulmonary artery pressure (Delta = 2.1%, p = .026). Among MV geometric parameters, we observed a significant reduction of MV antero posterior diameter (Delta = 7%, p < .001), sphericity index (Delta = 8%, p < .001), annulus circumference (Delta = 0.9%, p = .021), and annulus area (Delta = 2.7%, p = .018). At 1-year, 53 patients (85.5%) presented MR <= mild, while 9 patients (14.5%) had MR >= moderate. Reduction of AP diameter (OR = 0.14, CI 3.83; 0.08, p < .001), annulus circumference (OR = 0.27, CI -2.98; 0.37, p = .005), MV area (OR = 0.39, CI -2.46; 0.61, p = .04), aorto-mitral angle (OR = 0.38, CI -2.49; 0.54, p = .002) and iEDV (OR = 0.44, CI -2.44; 0.81, p = .001) were independent protective factors against recurrence of MR greater than mild at 1-year follow-up. CONCLUSIONS: Transapical NeoChord repair produces important acute intraoperative changes in MV anatomy in DMR patients. The acute changes observed were associated with procedure durability at 1-year FU. PMID- 29395367 TI - Reply. PMID- 29395368 TI - Timely focus on breast-feeding in the peanut allergy debate. PMID- 29395369 TI - Analysis of postoperative and hematogenous prosthetic joint-infection microbiological patterns in a large cohort. AB - OBJECTIVES: This study was undertaken to analyze prosthetic joint infection (PJI) causing microorganisms and compare their distribution patterns according to PJI classification. METHODS: Cohort study from a single referral center for bone-and joint infections from January 2004 to December 2015. RESULTS: Nine hundred and twenty-six patients, who developed 997 PJIs, involving the hip (62%), knee (35%) and/or shoulder (1%), were included. PJIs were classified as early postoperative (19%), late chronic (30%), hematogenous (35%) and undetermined (16%). Pathogens most frequently isolated from early-postoperative PJIs were staphylococci (57%), with 25% each Staphylococcus aureus or Staphylococcus epidermidis; 21% were polymicrobial and 10% Gram-negative rods. For late-chronic PJIs, the most frequent microbes were staphylococci (61%), predominantly S. epidermidis (35%); anaerobic bacteria were isolated from 15%; 11% were polymicrobial. Hematogenous PJIs were 99% monomicrobial. Although S. aureus was the most frequently isolated species (28%), streptococci were isolated slightly more often than staphylococci (39% vs. 36%). Among streptococci, group B streptococci were the most frequent (15%). The portal of entry was identified for 52% of hematogenous PJIs: 15% cutaneous, 11% dental, 9% gastrointestinal, 6% urinary, and 11% miscellaneous. CONCLUSION: Although a wide variety of microorganisms was isolated from PJIs, specific microbiological patterns were observed according to infection classification. PMID- 29395370 TI - Adequacy of nutrition support during extracorporeal membrane oxygenation. AB - BACKGROUND: The use of veno-venous extracorporeal membrane oxygenation (vv-ECMO) is increasing in adults with severe respiratory failure. Observational data suggest that there are significant challenges to providing adequate nutrition support for patients on vv-ECMO. We aimed to describe firstly the nutrition support practices in a large single-centre providing vv-ECMO to adults and secondly any association with clinical outcome. METHODS: We conducted a retrospective review of patients receiving vv-ECMO on the Intensive Care Unit (ICU) of a large London teaching hospital. Adult patients admitted to the ICU with severe respiratory failure between December 2010 and December 2015 were included. Daily energy and protein delivery were compared with estimated targets and reasons for feeding interruptions were collected from electronic medical records. Adequate feeding was defined as 80-110% of estimated targets. RESULTS: We analysed 203 eligible patients. Median duration of ICU stay was 21.0 (IQR, 15.0-33.0) days and vv-ECMO 10.0 (IQR, 7.0-16.0) days. Although median energy (89.8% (IQR, 80.5-96.0%)) and protein (84.7% (IQR, 74.0-96.7%)) delivery was adequate, underfeeding of either energy or protein occurred on nearly one third (28.3%) of nutrition support days. A higher admission severity of illness score was associated with inadequate protein delivery (p = 0.040). Patients with more severe organ dysfunction on the first day of vv-ECMO received inadequate energy (p = 0.026). The most common reasons for interrupted feeding were medical procedures (39.1%) followed by poor gastric motility (22.8%). CONCLUSION: Adequate energy and protein delivery during vv-ECMO is possible but underfeeding is still common, especially in those who are more severely ill or who have more severe organ dysfunction. Patients with inadequate energy or protein delivery did not differ in ICU and 6-month survival. Prospective studies investigating optimal feeding in this patient cohort are required. PMID- 29395371 TI - ASPEN-AND-ESPEN: A postacute-care comparison of the basic definition of malnutrition from the American Society of Parenteral and Enteral Nutrition and Academy of Nutrition and Dietetics with the European Society for Clinical Nutrition and Metabolism definition. AB - BACKGROUND: The aim of this study was to assess the prevalence of malnutrition by applying the ASPEN/AND definition and the ESPEN consensus definition in a postacute-care population, and secondly, to determine the metrological properties of the set of six clinical characteristics that constitute the ASPEN/AND basic diagnosis, compared to the ESPEN consensus, based mostly on objective anthropometric measurements. METHODS: Prospective study of 84 consecutive deconditioned older inpatients (85.4 +/- 6.2; 59.5% women) admitted for rehabilitation in postacute care. ASPEN/AND diagnosis of malnutrition was considered in presence of at least two of the following: low energy intake, fluid accumulation, diminished handgrip strength, and loss of weight, muscle mass, or subcutaneous fat. Sensitivity, specificity, positive and negative predictive values, accuracy, likelihood ratios, and kappa statistics were calculated for ASPEN/AND criteria and compared with ESPEN consensus. RESULTS: The prevalence of malnutrition by ASPEN/AND criteria was 63.1% and by ESPEN consensus, 20.2%; both diagnoses were associated with significantly longer length of stay, but the ESPEN definition was significantly associated with poorer functional outcomes after the rehabilitation program. Compared to ESPEN consensus, ASPEN/AND diagnosis showed fair validity (sensitivity = 94.1%; specificity = 44.8%); kappa statistic was 2.217. CONCLUSIONS: Applying the ASPEN/AND definition obtained a higher prevalence of malnutrition in a postacute-care population than was identified by the ESPEN definition. ASPEN/AND criteria had fair validity and agreement compared with the ESPEN definition. A simple, evidence-based, unified malnutrition definition might improve geriatric care. PMID- 29395372 TI - A high whey protein, vitamin D and E supplement preserves muscle mass, strength, and quality of life in sarcopenic older adults: A double-blind randomized controlled trial. AB - OBJECTIVE: Sarcopenia, an age-related decline of muscle mass, strength, and physical function, was associated with falls, frailty, and poor quality of life. The aim of the current study is to examine the effect of nutritional supplement containing whey protein, vitamin D and E on measures of sarcopenia. METHODS: A total of 60 sarcopenic older adult subjects participated in the current randomized, double-blind, placebo-controlled (iso-caloric control product) trial for 6 months. Muscle mass [Relative skeletal mass index (RSMI) measured by bioimpedance analysis (BIA)], muscle strength (handgrip strength), physical function (6-m gait speed, chair stand test, and timed-up-and-go test, TUG), quality of life (measured by Short-Form 36-Item Health Survey, SF-36), and blood biochemical indexes were measured before and after the 6-month intervention. RESULTS: Compared to placebo group, nutritional supplementation improves RSMI (mean difference: 0.18 kg/m2, 95%CI: 0.01-0.35, P = 0.040), handgrip strength (mean difference: 2.68 kg, 95%CI: 0.71-4.65, P = 0.009), SF-36 mental component summary (SF-36 MCS) (mean difference: 11.26, 95%CI: 3.86-18.65, P = 0.004), SF-36 physical component summary (SF-36 PCS) (mean difference: 20.21, 95%CI: 11.30 29.12, P < 0.001), serum IGF-1 (mean difference: 14.34 ng/mL, 95%CI: 2.06-26.73), IL-2 (mean difference: -575.32 pg/mL, 95%CI: -1116.94 ~ -33.70, P = 0.038), serum vitamin D3 (mean difference: 11.01 ng/mL, 95%CI: 6.44-15,58, P < 0.001), and serum vitamin E (mean difference: 4.17 ng/L, 95%CI: 1.89-6.45, P = 0.001). CONCLUSION: The current study demonstrated that the combined supplementation of whey protein, vitamin D and E can significantly improve RSMI, muscle strength, and anabolic markers such as IGF-I and IL-2 in older adults with sarcopenia. Further larger well-designed studies are warranted to evaluate whether long-term whey protein supplementation can blunt the declines of muscle function and mass in older adults with sarcopenia. PMID- 29395373 TI - Cross-sectional associations of dietary and circulating magnesium with skeletal muscle mass in the EPIC-Norfolk cohort. AB - BACKGROUND: Maintenance of skeletal muscle in older age is critical to reducing frailty and the risk of falls and fractures. Nutrition has established importance for muscle health in general, but less research has looked at associations of dietary intake of specific micronutrients on skeletal muscle mass in older adults. AIMS: This study aimed to investigate the influence of dietary and circulating magnesium on skeletal muscle mass in a UK population of 14,340 middle to older-aged men and women participating in the EPIC-Norfolk cohort study. METHODS: Dietary nutrient intakes were estimated from 7-day food diaries and fat free mass (FFM) by bioelectrical impedance analysis. Multivariable regression was used to investigate associations of FFM-based indices of muscle mass with quintiles of dietary magnesium intake or serum magnesium concentration groups. All analyses were stratified by sex, and regression models were adjusted for relevant covariates. RESULTS: Significant positive trends in FFM measures were evident across magnesium dietary intake quintiles for both sexes (all p < 0.001; n = 6350 men; n = 7990 women) and both <60 and >= 60 year olds, with all-age quintile 5 versus quintile 1 maximal differences of 4.6% in men and 6.3% in women; highly relevant compared to the estimated 1% decline per year after 40 years of age. These observations were not reflected in serum magnesium analyses, where no consistent trends were found across the skeletal muscle mass indices tested. CONCLUSION: Further investigation will be required to improve our understanding of the relationship between serum magnesium concentration and skeletal muscle mass. However, this study has demonstrated strong associations between dietary magnesium intake and indices of skeletal muscle mass in a UK population of middle to older-aged adults, highlighting the likely importance of dietary magnesium for optimal muscle health in this population. PMID- 29395374 TI - Effects of weight changes in the autonomic nervous system: A systematic review and meta-analysis. AB - BACKGROUND: Obesity has been linked to autonomic dysfunction, which is thought to be one of the main contributors for hypertension, cardiac remodelling and death. Exercise and diet-based weight loss are the mainstay therapy for obesity, but there is a paucity of data regarding the effect of weight changes in autonomic nervous system (ANS) activity. OBJECTIVE: To describe the impact of weight changes in autonomic nervous system. METHODS: A systematic literature search of four biomedical databases was performed evaluating effects of weight changes, thorough diet and/or exercise-based interventions, in the following ANS outcomes: heart rate variability, namely low frequency (LF)/high frequency (HF) ratio (LF/HF ratio), normalized units of LF (LFnu) and HF (HFnu), muscle sympathetic nerve activity (MSNA), noradrenaline spillover rate (NA-SR), standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), baroreflex sensitivity and pupillometry. Quality appraisal was performed using the GRADE methodology and, where fitting, studies with comparable outcomes were pooled for meta-analysis. RESULTS: Twenty-seven studies - 7 controlled clinical trials and 20 observational studies - were included. Weight gain was reported in 4 studies and weight loss in all the other studies. Interventions inducing weight changes included: hypocaloric or hypercaloric diets, exercise (strength, endurance or aerobic training) and hypocaloric diet coupled with exercise programs. Most studies which resulted in weight loss reported decreases in LF/HF ratio, LFnu, MSNA burst frequency and incidence, NA-SR, and an increase of baroreflex sensitivity, HF, HFnu and RMSSD, pointing to a parasympathetic nervous system activation. Meta-analysis regarding weight loss interventions showed a significant pooled effect size (95% CI) with a decreased of MSNA burst frequency -5.09 (-8.42, -1.75), MSNA incidence -6.66 (-12.40, -0.62), however this was not significant for SDNN 14.32 (-4.31, 32.96). Weight gain was associated with an increase in LF/HF, LFnu, MSNA burst frequency and incidence. The weight loss effects were potentiated by the association of hypocaloric diet with exercise. Nevertheless, weight changes effects in these outcomes were based in low or very low quality of evidence. CONCLUSIONS: Diet and exercise based weight loss appears to increase parasympathetic and decrease sympathetic activity, the opposing effects being observed with weight gain. These findings are not uniformly reported in the literature, possibly due to differences in study design, methodology, characteristics of the participants and techniques used to estimate autonomic nervous activity. PMID- 29395375 TI - Evidence of rock matrix back-diffusion and abiotic dechlorination using a field testing approach. AB - An in situ field demonstration was performed in fractured rock impacted with trichloroethene (TCE) and cis-1,2-dichloroethene (DCE) to assess the impacts of contaminant rebound after removing dissolved contaminants within hydraulically conductive fractures. Using a bedrock well pair spaced 2.4m apart, TCE and DCE were first flushed with water to create a decrease in dissolved contaminant concentrations. While hydraulically isolating the well pair from upgradient contaminant impacts, contaminant rebound then was observed between the well pair over 151days. The magnitude, but not trend, of TCE rebound was reasonably described by a matrix back-diffusion screening model that employed an effective diffusion coefficient and first-order abiotic TCE dechlorination rate constant that was based on bench-scale testing. Furthermore, a shift in the TCE:DCE ratio and carbon isotopic enrichment was observed during the rebound, suggesting that both biotic and abiotic dechlorination were occurring within the rock matrix. The isotopic data and back-diffusion model together served as a convincing argument that matrix back-diffusion was the mechanism responsible for the observed contaminant rebound. Results of this field demonstration highlight the importance and applicability of rock matrix parameters determined at the bench-scale, and suggest that carbon isotopic enrichment can be used as a line of evidence for abiotic dechlorination within rock matrices. PMID- 29395376 TI - Effect of wettability on two-phase quasi-static displacement: Validation of two pore scale modeling approaches. AB - Understanding of pore-scale physics for multiphase flow in porous media is essential for accurate description of various flow phenomena. In particular, capillarity and wettability strongly influence capillary pressure-saturation and relative permeability relationships. Wettability is quantified by the contact angle of the fluid-fluid interface at the pore walls. In this work we focus on the non-trivial interface equilibria in presence of non-neutral wetting and complex geometries. We quantify the accuracy of a volume-of-fluid (VOF) formulation, implemented in a popular open-source computational fluid dynamics code, compared with a new formulation of a level set (LS) method, specifically developed for quasi-static capillarity-dominated displacement. The methods are tested in rhomboidal packings of spheres for a range of contact angles and for different rhomboidal configurations and the accuracy is evaluated against the semi-analytical solutions obtained by Mason and Morrow (1994). While the VOF method is implemented in a general purpose code that solves the full Navier Stokes (NS) dynamics in a finite volume formulation, with additional terms to model surface tension, the LS method is optimized for the quasi-static case and, therefore, less computationally expensive. To overcome the shortcomings of the finite volume NS-VOF system for low capillary number flows, and its computational cost, we introduce an overdamped dynamics and a local time stepping to speed up the convergence to the steady state, for every given imposed pressure gradient (and therefore saturation condition). Despite these modifications, the methods fundamentally differ in the way they capture the interface, as well as in the number of equations solved and in the way the mean curvature (or equivalently capillary pressure) is computed. This study is intended to provide a rigorous validation study and gives important indications on the errors committed by these methods in solving more complex geometry and dynamics, where usually many sources of errors are interplaying. PMID- 29395377 TI - Groundwater nitrate remediation using plant-chip bioreactors under phosphorus limited environment. AB - Groundwater denitrification bioreactors under limited phosphorus conditions were studied in column experiments using four types of plant-chips. When the phosphate P concentration in the influent increased from 0.04mg/L to 0.4mg/L, the nitrate removal ratio increased from 61.6% to 86.1% in reed, from 7.2% to 12.6% in Japanese cedar, from 37.0% to 73.6% in Moso bamboo, and from 19.2% to 50.5% in Lithocarpus edulis. The carbon source of the denitrifiers' growth was indicated by the content of acid detergent soluble organic matter in the chips. Furthermore, according to the modified Michaelis-Menten-type equation proposed in the study, the denitrification rate was largely limited by the phosphate-P concentration in reed and L. eduilis, and by the dissolved organic carbon (DOC) in Japanese cedar. Denitrification in Moso bamboo was affected by both phosphate P and DOC. Besides the DOC, phosphorus emerged as an important limiting element of denitrification in some bioreactor plant-chips. PMID- 29395378 TI - Insights into Modern Human Prehistory Using Ancient Genomes. AB - The genetic relationship of past modern humans to today's populations and each other was largely unknown until recently, when advances in ancient DNA sequencing allowed for unprecedented analysis of the genomes of these early people. These ancient genomes reveal new insights into human prehistory not always observed studying present-day populations, including greater details on the genetic diversity, population structure, and gene flow that characterized past human populations, particularly in early Eurasia, as well as increased insight on the relationship between archaic and modern humans. Here, we review genetic studies on ~45000- to 7500-year-old individuals associated with mainly preagricultural cultures found in Eurasia, the Americas, and Africa. PMID- 29395380 TI - A Toolkit of Engineered Recombinational Balancers in C. elegans. AB - Dejima and colleagues report using CRISPR/Cas9 to generate a new collection of greatly improved balancer chromosomes in the standard laboratory nematode Caenorhabditis elegans, using methods previously reported by the same laboratory, expanding the set of C. elegans balancers to cover nearly 90% of coding genes. PMID- 29395379 TI - RNA Biology in Retinal Development and Disease. AB - For decades, RNA has served in a supporting role between the genetic carrier (DNA) and the functional molecules (proteins). It is finally time for RNA to take center stage in all aspects of biology. The retina provides a unique opportunity to dissect the molecular underpinnings of neuronal diversity and disease. Transcriptome profiles of the retina and its resident cell types have unraveled unique features of the RNA landscape. The discovery of distinct RNA molecules and the recognition that RNA processing is a major cause of retinal neurodegeneration have prompted the design of biomarkers and novel therapeutic paradigms. We review here RNA biology as it pertains to the retina, emphasizing new avenues for investigations in development and disease. PMID- 29395382 TI - Optimizing insulin delivery for patients with diabetes. AB - Management of diabetes for residents in long-term care settings is particularly challenging, due to the wide range of physical and mental limitations that bear on efficacy of their medications, as well as practical issues associated with the optimal administration of these medications. Foremost among the practical issues for residents requiring insulin injections, is the need to ensure that it is consistently delivered to the circulation at the target rate and dosage, thereby avoiding life-threatening episodes of hypoglycemia. Recent evidence from a multinational survey has elucidated principles of insulin injection technique, including optimal needle length and site rotation that can greatly improve consistency in delivering insulin to the subcutaneous compartment, while reducing pain, improving patient compliance, and limiting the total daily dosage. The present review consolidates these findings and highlights the most critical take home messages for healthcare professionals working in this area. PMID- 29395381 TI - Time for Bed: Genetic Mechanisms Mediating the Circadian Regulation of Sleep. AB - Sleep is an evolutionarily conserved behavior that is increasingly recognized as important for human health. While its precise function remains controversial, sleep has been suggested to play a key role in a variety of biological phenomena ranging from synaptic plasticity to metabolic clearance. Although it is clear that sleep is regulated by the circadian clock, how this occurs remains enigmatic. Here we examine the genetic mechanisms by which the circadian clock regulates sleep, drawing on recent work in fruit flies, zebrafish, mice, and humans. These studies reveal that central and local clocks utilize diverse mechanisms to regulate different aspects of sleep, and a better understanding of this multilayered regulation may lead to a better understanding of the functions of sleep. PMID- 29395383 TI - Surface-driven first-step events of nanoscale self-assembly for molecular peptide fibers: An experimental and theoretical study. AB - New experimental results are reported on the self-assembling behavior of EAK16 II, the first discovered ionic self-complementary peptide, incubated at ultralow concentration (10-6 M) at neutral pH onto differently charged surfaces. It is found that strongly negatively charged surfaces promote the self-assembly of flat, micrometer-long mono-molecular fibers of side-on assembled sequences, lying onto a continuous monolayer of flat-on EAK16-II molecules. These results suggest that the monomolecular EAK16-II self-assembly is driven by the peculiar matching condition between peptide and surface electrostatic properties. Molecular Mechanics simulations of the basic bimolecular interactions confirmed the experimental inferences, showing that the flat-on state is the most stable arrangement for two interacting EAK16-II sequences onto strongly negatively charged surfaces, where indeed EAK16-II beta-sheet conformation is stabilized, while the weak electrostatic interactions with mildly charged substrates promote an "entangled" EAK16-II geometry. Molecular Dynamics simulations further showed that the mobility and diffusional freedom of the peptides from the surfaces are ruled by the relative strength of peptide-surface electrostatic interactions, so that desorption probability for the peptide sequences is negligible from strongly charged surfaces and high from mildly-charged surfaces. Furthermore, it has been found that an oligopeptide sequence lying onto two flat-on EAK16-II molecules, gains a remarkable lateral mobility, while remaining weakly bound to the surface, thus allowing the further molecular self-alignment responsible for the micrometer long fiber formation. The reported results pave the way to the understanding and control of the subtle peptide-surface structural motifs matching enabling the formation of micrometer-long, but nanometer-wide monomolecular fibers. PMID- 29395384 TI - The polyplex, protein corona, cell interplay: Tips and drawbacks. AB - Polyplexes (PX) are soft materials, obtained by blending polycations and nucleic acids, designed for gene delivery applications. While much is known about the transfection properties of PX, their protein corona, the biomolecules interacting with colloids once in a biological environment, represents an underlooked parameter in gene transfection. In this study, linear and branched polyethylenimines (lPEI and bPEI), the golden standard among non-viral vectors, were selected and used throughout the work: their physicochemical properties and protein corona when complexed to DNA were studied and linked to the toxicity and transfection efficiency arisen upon their delivery to cells. Interestingly, lPEIDNA and bPEIDNA complexes were characterized by similar physicochemical features, but different biological behavior. In fact, the biological milieu where cells and PX interact greatly influences their size, stability and transfection abilities. Using PX as a soft material model system, we spotlighted structure activity relationships and methodologies that can help interpret their biological behavior and guide future studies in the field. PMID- 29395385 TI - Hybrid vesicles from lipids and block copolymers: Phase behavior from the micro- to the nano-scale. AB - In recent years, there has been a growing interest in the formation of copolymers lipids hybrid self-assemblies, which allow combining and improving the main features of pure lipids-based and copolymer-based systems known for their potential applications in the biomedical field. In this contribution we investigate the self-assembly behavior of dipalmitoylphosphatidylcholine (DPPC) mixed with poly(butadiene-b-ethyleneoxide) (PBD-PEO), both at the micro- and at the nano-length scale. Epifluorescence microscopy and Laser Scanning Confocal microscopy are employed to characterize the morphology of micron-sized hybrid vesicles. The presence of fluid-like inhomogeneities in their membrane has been evidenced in all the investigated range of compositions. Furthermore, a microfluidic set-up characterizes the mechanical properties of the prepared assemblies by measuring their deformation upon flow: hybrids with low lipid content behave like pure polymer vesicles, whereas objects mainly composed of lipids show more variability from one vesicle to the other. Finally, the structure of the nanosized assemblies is characterized through a combination of Dynamic Light Scattering, Small Angle Neutron Scattering and Transmission Electron Microscopy. A vesicles-to-wormlike transition has been evidenced due to the intimate mixing of DPPC and PBD-PEO at the nanoscale. Combining experimental results at the micron and at the nanoscale improves the fundamental understanding on the phase behavior of copolymer-lipid hybrid assemblies, which is a necessary prerequisite to tailor efficient copolymer-lipid hybrid devices. PMID- 29395386 TI - Our experience in the management of prostate cancer in renal transplant recipients. AB - INTRODUCTION AND OBJECTIVES: The management of Prostate cancer (PCa) in renal transplant recipients (RTR) is challenging and remain controversial. Currently there is no consensus about this condition. The aim of the study was to analyse our experience in the diagnosis and management of PCa in RTR. METHOD: Retrospective monocentric study of a prospective and consecutive database from 2003-2017. Inclusion of RTR diagnosed of PCa. Staging and treatment in agreement with the contemporary guidelines. The main outcome measures included clinical staging, type of treatment, oncological outcomes and follow-up. RESULTS: 1,330 renal transplants were performed (787 males), diagnosed of PCa in 33 RTR (4.2%), mean age 66years+/-6.3 (51-78). Median PSA was 8.8ng/ml and PSA ratio 0.19. Mean time between renal transplantation and PCa diagnosis 130months+/-90 (2-236). TREATMENTS: Radical prostatectomy (RP) (n=22; 66.7%), Radiation therapy (RT) with Androgen deprivation therapy (ADT) (n=7; 21.2%), Active surveillance (n=3; 9.1%), ADT (n=1; 3%). No graft loss neither impaired renal function due to PCa treatment was reported. After RP two patients (9.1%) presented biochemical recurrence treated with RT. Remission of the 100%. Mean follow-up was 61months+/-37 (6-132). CONCLUSIONS: PCa in renal transplant patients can be managed with the same therapeutic options as in the general population. Active surveillance should also be provided in RTR despite being under immunosuppressive therapy. PMID- 29395387 TI - Validation of EN ISO method 10273 - Detection of pathogenic Yersinia enterocolitica in foods. AB - EN ISO 10273 method for the detection of pathogenic Yersinia enterocolitica in foods was validated in the project Mandate M/381 funded by European Commission. A total of 14 laboratories from five European countries participated in the interlaboratory study (ILS) organized during 2013 and 2014. Before the ILS, the method was revised by an international group of experts and the performance of the revised method was assessed in an ILS study. The results are published as a part of the standard EN ISO 10273 revision. The study included three rounds with different sample types; raw milk, iceberg lettuce and minced meat, inoculated with a low and high level of pathogenic Y. enterocolitica strains representing major pathogenic bioserotypes 4/O:3 and 2/O:9. The homogeneity and stability of the samples were verified before dispatching them to the laboratories. The results demonstrated the method sensitivity of 96% in raw milk, 97% in minced meat, and 98% in lettuce at high inoculation level of pathogenic Y. enterocolitica. The specificity was 100% in raw milk, 96% in minced meat, and 98% in lettuce. The level of detection, LOD50, varied between study rounds, being 9.4 CFU/25 ml in raw milk, 9.9 CFU/25 g in minced meat and 63 CFU/25 g in lettuce samples. During the study, confirmation by using real-time PCR method ISO/TS 18867 together with pyrazinamidase testing was also validated, as alternative to conventional biochemical confirmation. When comparing different isolation steps used in the revised method during the study rounds, PSB enrichment and plating on CIN after alkaline (KOH) treatment showed the highest sensitivity (52-92%) in raw milk and minced meat samples. In lettuce samples, however, ITC with KOH treatment before plating on CIN showed higher sensitivity (64% at low level; 82% at high level) than plating on CIN from PSB with KOH treatment (44% at low level; 74% at high level). Statistical analysis of different isolation steps supported the use of two enrichment media, PSB and ITC, in the revised method. Recovery of pathogenic Y. enterocolitica on CIN was most efficient after KOH treatment and, based on the analysis, plating on CIN agar without KOH treatment could be left as optional procedure in the method. PMID- 29395388 TI - Segment-specific prevalence of carotid artery plaque and stenosis in middle-aged adults and elders in Taiwan: A community-based study. AB - BACKGROUND: Plaque in carotid arteries (CAs) is a major factor of systemic atherosclerosis and cardiovascular disease (CVD). The left and right CAs have different anatomic and geometric features and may influence the predictability of CVD. However, the site- and segment-specific prevalence of carotid plaques (CP) and study on severity of carotid atherosclerosis with CVD risks was very limited. METHODS: We enrolled 1539 healthy residents aged 40-to-74 years from two northern districts in Taiwan. All volunteers received high resolution B-mode carotid ultrasound scans and CVD risk factors evaluations. RESULTS: The prevalence rate of extracranial CP was 21.9% in females and 33.8% in males. Carotid bifurcation is the most affected segment. As compared with the right CAs, the age-sex adjusted matched odds ratio of having plaques in the left CAs was 1.32 (95% confidence interval = 1.02-1.73). The proportions of subjects had a total plaque number>=2, maximum stenosis>=30%, and plaque score>=3 were 8.9, 10.3, and 7.2%, respectively, in females and were 17.7, 17.2, and 15.1%, respectively, in males. Among subjects with moderate and severe carotid atherosclerosis, the mean +/- SD of estimated 10-year CVD risk was 19.1 +/- 14.6% and more than 65% of them need intensive blood pressure, lipids, or sugar controls. CONCLUSION: We found that bifurcation was the most prevalent segment, and left CAs was more likely to form plaque than right CAs. The major CVD risk factors were highly prevalent and the estimated CVD risks were high in subjects with more advanced carotid atherosclerosis. The study provides further direction for CVD prevention and treatment. PMID- 29395389 TI - Increased cancer incidence of Changhua residents living in Taisi Village north to the No. 6 Naphtha Cracking Complex. AB - BACKGROUND/PURPOSE: Cancer risks of residents living north to the No. 6 Naphtha Cracking Complex has not been studied before. METHODS: Our study subjects were recruited in 2014-16 from three zones north to the No. 6 Naphtha Cracking Complex, which included 229 participants from the Taisi Village (average 5.5 km from the complex), 1333 participants from the other 14 villages in Dacheng Township (9.2 km), and 372 participants from the Zhutang Township (19.9 km). Their occurrence of cancer in years-post-complex-operation (YPO) was defined by having a new cancer recorded (ICD-9: 140-208) in National Health Insurance Research Database since 1999. Poisson regression was conducted to compare incidence rate ratio among three zones in 10-16 YPO. RESULTS: We found that all cause cancer incidence of 10-16 YPO (per 1,000 person-years) in Taisi Village (8.44) was higher than that in Dacheng (3.42) and Zhutang (2.72). Taisi residents had significantly higher concentrations of V, Cr, Mn, Ni, Cu, As, Cd, and Tl than Dacheng and Zhutang residents. The all-cause cancer incidence rate ratio between 10-16 and 0-9 YPO was 8.44 for Taisi residents. All-cause cancer incidence rate of Taisi residents was 2.55 times higher than Dacheng residents (95% CI: 1.89 3.45) and 2.43 times higher than Zhutang residents (95% CI: 1.54-3.84) in 10-16 YPO. CONCLUSION: We conclude that all-cause cancer risk was significantly increased for Taisi residents living near the No. 6 Naphtha Cracking Complex for 10-16 years after the complex began operating. PMID- 29395390 TI - Strontium ion can significantly decrease enamel demineralization and prevent the enamel surface hardness loss in acidic environment. AB - BACKGROUND/PURPOSE: Strontium ion may play a role similar to calcium ion in enamel remineralization. The aim of this study was to investigate the effect of strontium ion concentration gradient on the demineralization of enamel. METHODS: Citric acid and sodium citrate were used to prepare 16 different experimental acidic solutions with four different pH values (2.5, 3.5, 4.5, and 5.5) and four different strontium ion concentrations (0 M, 10-4 M, 10-3 M, and 10-2 M). Forty eight human enamel samples were divided into 16 groups (n = 3) and immersed into the 16 different acidic solutions for 3 min. The phosphorus ion concentrations in 16 different acidic solutions were measured and compared. The enamel surface hardness was measured with a Vickers hardness tester. The energy dispersive spectrometer was used to detect the strontium ion content in the enamel surface. RESULTS: Addition the strontium ions to the acidic solution could reduce the dissolution of the enamel. At pH 3.5 and pH 5.5, significantly lower phosphorus ion concentrations were detected in the acidic solutions with the addition of 10 2 M strontium ions. There was a less reduction of enamel surface hardness, while the strontium ion concentration increased in the acidic solution. At pH 2.5, the addition of 10-4 M, 10-3 M, or 10-2 M strontium ions to the acidic solution resulted in a significant increase in the strontium ion content in the enamel surface. CONCLUSION: Strontium ion can decrease the dissolution of the enamel and prevent the enamel surface hardness loss in acidic environment. PMID- 29395391 TI - A CRYBB2 mutation in a Taiwanese family with autosomal dominant cataract. AB - BACKGROUND/PURPOSE: To identify the underlying genetic cause of a Taiwanese family with autosomal dominant cerulean cataract. METHODS: A three-generation cerulean cataract family with 13 affected and 13 normal was identified. Whole exome sequencing, whole genome single nucleotide polymorphism genotyping and haplotype analysis, and fine mapping using polymorphic short tandem repeat markers were used to identify the causative gene mutation. RESULTS: Whole genome single nucleotide polymorphism genotyping and haplotype analysis mapped the candidate disease loci to chromosome 18 and chromosome 22. Polymorphic short tandem repeat markers further narrowed down the disease interval to chromosome 22 between markers D22S1174 and D22S1163. Whole exome sequencing was performed on selected individuals. Polymorphisms detected were filtered based on their genomic positions, allele frequency (<1%), and segregation within the pedigree. Affected individuals were found to be heterozygous carrying a C to T mutation on exon 6 of the CRYBB2 gene (with SNP ID: rs74315489). The mutation was predicted to produce a premature stop mutation Q155X. The mutation is co-segregation across the pedigree and the disease "T" allele was not detected in healthy members of the family and in additional 50 normal controls (100 chromosomes). Phylogenic protein alignment was also performed for the CRYBB2 gene across 68 species ranging from fishes, Sauropsida, Placentalia, carnivores, rodents, and primates with total 56 orthologous genes. The Q155 residue is 100% conserved across the evolutionary tree, indicating its crucial function. CONCLUSION: Here we identify the first Taiwanese cerulean cataract family carrying a CRYBB2_Q155X mutation. PMID- 29395392 TI - Response to Letter to the Editor. PMID- 29395393 TI - Three-dimensional imaging is a novel and reliable technique to measure total body surface area. AB - OBJECTIVE: The aim of this study was to explore the diverse clinimetric aspects of three-dimensional imaging measurements of TBSA in clinical practice compared with the methods currently used in clinical practice (i.e., the rule of nines and palm method) to measure TBSA in clinical practice. METHOD: To assess reliability, two independent researchers measured the TBSAs of 48 burn patients using Artec MHTTM Scanner and software. Subsequently, a resident and burn specialist estimated the TBSA of the same wounds using the rule of nines and palm method. RESULTS: Three-dimensional imaging showed excellent inter-observer reliability, with an intra-class correlation coefficient (ICC) of 0.99, standard error of measurement (SEM) of 0.054, and limits of agreement (LoA) of +/-0.15*the mean TBSA (between the measurements of two researchers). The inter-observer reliability of the methods used in current clinical practice was less reliable, with an ICC of 0.91, SEM of 0.300 and LoA of +/-0.78*the mean TBSA. The inter observer reliability was least reliable between three-dimensional imaging and the residents compared with the burn specialists for the estimated TBSA, with an ICC of 0.68, SEM of 0.69 and LoA of +/-1.49*the mean TBSA. CONCLUSION: The inter observer reliability of three-dimensional imaging was superior compared with the rule of nines and palm method. PMID- 29395394 TI - Women's recovery, negotiation of appearance, and social reintegration following a burn. AB - The gendered nature of postburn coping has received scant research attention in South Africa, a country that has a high rate of burns with significant concentrations among women. In this study, narratives that emerged from in-depth interviews with seven women were examined. The narratives emphasized essential needs of these burn survivors for personal support, the complexities of negotiating intimate relationships, struggles with the humiliation from family and friends, in some instances strained relationships with children, the support found through religious beliefs and institutions, and often frustratingly slow psychological acceptance of scars. These difficulties faced by women survivors of burns have highlighted the need to include religion/spirituality, intimate male partners, and women's children into the psychological recovery process, in an attempt to assist women's journey to psychological and emotional healing after burn. PMID- 29395395 TI - Burns and fires in South Africa's informal settlements: Have approved kerosene stoves improved safety? AB - This study is a follow-on to an intervention project that implemented South African Bureau of Standards approved kerosene stoves and safety education in 150 households of a Johannesburg informal settlement. An investigation conducted 12 months later established that 43 stoves had operational defects, yet 23 households continued using the faulty appliances. This study focuses on (1) the psychological and behavioural factors associated with continued use of faulty stoves by the 23 households, and (2), the specific technical failures of these stoves. The study involved one-on-one recall interviews with the households using defective stoves (N=21) and laboratory-based stove tests for seven of the affected appliances. The results indicate that the stoves had defects in critical safety features such as flame control and the self-extinguishing mechanism. Four stove malfunctions of minor burn affect were reported in the study. Continued use of the damaged stoves was significantly associated with the time from receipt of the stove to detection of first failure: stoves that failed later on were more significantly likely to remain in use as compared to those that failed sooner. The findings point to the need for strengthening enforcement of appliance standards, public education on kerosene stove use, and structural change for the energy-poor. PMID- 29395396 TI - Measuring serum albumin levels at 0 and 24h: Effect on the accuracy of clinical evaluations in the prediction of burn-related mortality. AB - OBJECTIVES: To evaluate whether measuring serum albumin levels in clinical assessments affects the accuracy of mortality predictions in large burns and to compare patients' serum albumin levels at hour 0(Alb0h) and hour 24(Alb24h) following their admission. METHODS: This prospective observational study was performed at an academic burn unit. Aged between 16 and 65, patients who presented with burns on more than 20% of total body surface area (%TBSA) were included. Patients with severe comorbidities, concomitant trauma or referred from other centres were excluded from the study. The main variables in the study were Alb0h, Alb24h and Abbreviated Burn Severity Index (ABSI) scores. The primary outcome was in-hospital mortality. RESULTS: In a population of 105 patients, %TBSA, being female, inhalational injury, Alb0h, Alb24h and ABSI score (p<0.001) and the presence of a full thickness injury (p=0.008) were associated with mortality. In the multivariable analysis, ABSI scores and Alb24h remained in the model (OR, 2.32 and 0.06, respectively). The area under curves (AUCs) were 0.94, 0.97 and 0.97 for ABSI, ABSI+Alb0h and ABSI+Alb24h, respectively. No significant difference among the AUCs was seen, but adding Alb0h and Alb24h improved the mortality predictions of ABSI by 5 (4.7%) and 4 (3.8%) patients, respectively. Alb0h (at 3.5g/dL) and Alb24h (at 2.4g/dL) showed 84-85% and 88-85% sensitivity specificity for mortality, respectively. CONCLUSION: Measuring serum albumin levels in clinical assessments slightly increases the accuracy of mortality predictions; however, different cut-off points for Alb0h and Alb24h needs to be considered to avoid interpretation errors. PMID- 29395397 TI - Response to Letter to the Editor: 'Comments on procalcitonin for the early diagnosis of sepsis in burn patients: A retrospective study'. PMID- 29395398 TI - Comment on "Accelerant-related burns and drug abuse: Challenging combination". PMID- 29395399 TI - Platelet count: A predictor of sepsis and mortality in severe burns; Methodological issues. PMID- 29395400 TI - Virtual Reality in the treatment of burn patients: A systematic review. AB - AIM: To identify studies that approach immersive virtual realities and its main effects in the treatment of burn patients in the context of the scientific world of literature. METHODS: A systematic review following the steps of Cochrane. The search was conducted in eight databases between May and August 2016. RESULTS: 34 studies were analyzed, including 23 randomized clinical trials. VR was applied using three-dimensional features and video games. The findings demonstrate the association of this technology with increased enjoyment and the reduction of pain, anxiety and stress during dressing changes and also during physical rehabilitation and physiotherapy. Few side effects have been reported. CONCLUSION: VR is a complementary drug strategy that has proven beneficial results in the treatment of burn patients. PMID- 29395401 TI - Comments on procalcitonin for the early diagnosis of sepsis in burn patients: A retrospective study. PMID- 29395402 TI - Stem cell enriched dermal substitutes for the treatment of late burn contractures in patients with major burns. PMID- 29395403 TI - The value of WhatsApp communication in paediatric burn care. AB - BACKGROUND: Telemedicine is increasingly applied in developed settings to facilitate transfer of information to and from burn surgeons across vast geographic areas. WhatsApp is a widely available and extremely user-friendly encrypted smartphone application that does not require the expensive physical and personnel infrastructure that characterizes many of these telemedicine systems. The aim of this study was to review the use of WhatsApp to facilitate paediatric burn injury consultations to a regional burn centre in a developing country, where burn care continues to be thwarted by administrative apathy, poor resource allocation and lack of attention to medical and nursing education at all levels. METHODS: A retrospective review was undertaken of all consultations using WhatsApp over an 18-month period, received by the burn centre's two senior medical practitioners. The specific origin and nature of the telemedicine requests for advice, transfer or follow-up were collected, as were data relating to the demographics of the patients, the aetiology, mechanism and extent of the burn injury. The impact of the system of communication in terms of reductions in admissions and clinic visits was assessed, and a cost analysis was undertaken. Feedback was also obtained from those health practitioners regularly using the service. RESULTS: 838 communications occurred during the study period, which included 1562 distinct clinical queries. 486 interactions (58%) originated from within the hospital, the majority of which were initiated by surgeons in training or burn nurse practitioners. 352 (42%) consultations were from outside the hospital. Queries related to the full spectrum of burn care, including emergency management and stabilization, triage and transfer, the need for escharotomy, fluid resuscitation, wound care, the timing and nature of surgical intervention, as well as follow-up and rehabilitation. While no significant changes in the number of surgical interventions or admissions were observed when compared to the five years prior to the intervention, outpatient visits reduced significantly during the study period. It was estimated that over 150 unnecessary admissions were also avoided as a result of the triage made possible by WhatsApp, which translated into considerable cost saving for the institution. DISCUSSION: Incorporating WhatsApp technology into the daily processes of burn care has significantly improved the quality of paediatric burn care referrals to specialist burn services. Specifically, WhatsApp has contributed to reductions in unnecessary referrals and outpatient visits, facilitated opportunities for continuing medical education, improved the care of major burn injuries through more effective prehospital communication, and enabled greater allocation of scarce specialist resources at the burn centre. This study motivates for the wider application of WhatsApp for burn care referrals, especially in developing countries. PMID- 29395404 TI - A survey of learning methods used by Plastic Surgery and Anaesthetics trainees in burn care. PMID- 29395405 TI - Matrix metalloproteinase-2 and its correlation with basal membrane components laminin-5 and collagen type IV in paediatric burn patients measured with Surface Plasmon Resonance Imaging (SPRI) biosensors. AB - : The purpose of this study was the determination of matrix metalloproteinase-2 and its correlation with basal membrane components laminin-5 and collagen type IV in the blood plasma of burn patients measured with Surface Plasmon Resonance Imaging (SPRI) biosensors. MATERIAL AND METHODS: 31 children scalded by hot water who were managed at the Department of Paediatric Surgery between 2014-2015, after primarily presenting with burns in 4-20% TBSA were included into the study (age 9 months up to 14 years, mean age 2,5+1 years). There were 10 girls and 21 boys. Venous blood samples were drawn 2-6h, and 12-16h after the thermal injury, and on the subsequent days 3, 5 and 7. The matrix metalloproteinase-2, collagen type IV and laminin-5 concentrations were assessed using Surface Plasmon Resonance Imaging by the investigators blinded to the other data. RESULTS: The MMP-2, laminin-5 and collagen type IV concentrations in the blood plasma of patients with burns, were highest 12-16h after thermal injury, the difference was statistically significant. The MMP-2, laminin-5 and collagen type IV concentrations measured 3 days, 5 days and 7 days after the thermal injury, slowly decreased over time, and on the 7th day reached the normal range, when compared with the concentration measured in controls. CONCLUSION: Current work is the first follow-up study regarding MMP-2 in burns. MMP-2, laminin-5 and collagen type IV levels were elevated early after burn injury in the plasma of studied patients, and were highest 12-16h after the injury. MMP-2, laminin-5 and collagen type IV levels were not proportional to the severity of the burn. We believe in the possibility that the gradual decrease of MMP-2, collagen type IV and laminin 5 concentrations could be connected with the process of healing, but to prove it, more investigation is needed in this area. The SPR imaging biosensor is a good diagnostic tool for determination of MMP-2, laminin-5 and collagen type IV in blood plasma of patients with burns. PMID- 29395406 TI - Hyperkalemia in electrical burns: A retrospective study in Colombia. AB - INTRODUCTION: Classically, hyperkalemia has been regarded as a complication in patients with electrical burns. The etiology of hyperkalemia includes metabolic acidosis, destruction of red blood cells, rhabdomyolysis and the development of renal failure. The purpose of this study was to determine the prevalence of hyperkalemia within the first 24h after electrical burn injury and to evaluate the possible association of serum potassium concentration with cutaneous burn size (%TBSA) and serum creatine phosphokinase (CPK) concentration. METHODS: A retrospective, cross-sectional study was conducted, based on review of medical records of adult patients hospitalized in the first 24h post electrical injury. Serum potassium (K+) levels were divided into low, normal, and high groups, with breakpoints at 3.5mmol/L and 5.0mmol/L and normal 3.6-4.9mmol/L. To assess potential differences according to the time elapsed between the time of the injury and the sampling time, data were grouped as follows: t1: samples obtained in the first 6h post-injury; t2: samples taken at 6-12h; t3: samples taken at 12 24h. RESULTS: 336 patients were studied. The median age was 32 years old (IQR: 25 43). 95.2% of patients were men. Low and normal values of K+ were observed in 13.7% and 85.1%, respectively. The prevalence of hyperkalemia was only 1.2%, and was not related to previously-administered medications or to simple blood gas pH value during admission. CPK>10,000IU/L was observed in 22.6%. No association was found between the serum potassium concentration and either %TBSA burned or the highest CPK value. CONCLUSIONS: First, patients admitted to our burn unit with electrical injury accompanied by significant skin and muscle injury rarely exhibit hyperkalemia. Secondly, the presence of hyperkalemia is independent of the severity of rhabdomyolysis or the extent of the burn. PMID- 29395407 TI - Can live music therapy reduce distress and pain in children with burns after wound care procedures? A randomized controlled trial. AB - OBJECTIVE: Burn wound care procedures are very painful and lead to distress. Live music therapy has shown beneficial effects on distress and pain in specific pediatric patient populations. In this study we measured whether live music therapy has beneficial effects in terms of less distress and pain in children with burns after wound care procedures. METHODS: This randomized assessor-blinded controlled trial (RCT) took place at the burns unit of the Red Cross War Memorial Children's Hospital, Cape Town, South Africa. It included newly admitted inpatients between the ages of 0 and 13 years undergoing their first or second wound care procedures. Excluded were children with a hearing impairment or low level of consciousness. The intervention group received one live music therapy session directly after wound care in addition to standard care. The control group received standard care only. The primary outcome was distress measured with the Observational Scale of Behavioral Distress-revised (OSBD-r). The secondary outcome was pain measured with the COMFORT-behavioral scale (COMFORT-B). In addition, in children older than 5 years self-reported distress with the validated Wong-Baker scale (FACES) and pain with the Faces Pain Scale-Revised (FPS-R) were measured. Patients in both groups were videotaped for three minutes before wound care; during the music therapy or the control condition; and for two minutes thereafter. Two researchers, blinded to the study condition, independently scored the OSBD-r and the COMFORT-B from the video footage before and after music therapy. RESULTS: We included 135 patients, median age 22.6 months (IQR 15.4-40.7 months). Change scores did not significantly differ between the intervention and the control groups for either distress (p=0.53; d=0.11; 95% CI -0.23 to 0.45) or pain (p=0.99; d=0.04; 95% CI -0.30 to 0.38). Self-reported distress in a small group of children (n=18) older than 5 years indicated a significant reduction in distress after live music therapy (p=0.05). CONCLUSIONS: Live music therapy was not found effective in reducing distress and pain in young children after burn wound care. Older children might be more responsive to this intervention. PMID- 29395408 TI - Incidence of risk factors for bloodstream infections in patients with major burns receiving intensive care: A retrospective single-center cohort study. AB - OBJECTIVES: The objective was primarily to identify risk factors for bloodstream infections (BSI) caused by different pathogens. METHODS: A retrospective single center cohort study was performed on 472 burn patients with an abbreviated burn severity index (ABSI)>=3, a total burn surface area (TBSA)>=10%, and an ICU stay of at least 24h. Risk factors for different BSI pathogens were analyzed by competing risks regression model of Fine and Gray. RESULTS: A total of 114 burn patients developed 171 episodes of BSIs caused by gram-negative bacteria (n=78;46%), gram-positive bacteria (n=69;40%), and fungi (n=24;14%) median after 14days (range, 1-164), 16days (range, 1-170), and 16days (range, 0-89), respectively. A total of 24/114 patients (21%) had fatal outcomes. Isolation of the most common bloodstream isolates Enterococcus sp. (n=26), followed by Candida sp. and Pseudomonas sp. (n=22 for both) was significantly associated with increased TBSA (p<=0.006) and ABSI (p<0.0001) and need for fasciotomy (p<0.01). The death risk of patients with MDR gram-negative bacteremia was significantly increased by a hazard ratio of 12.6 (95% CI:4.8-32.8; p<0.0001). CONCLUSIONS: A greater TBSA and ABSI were associated with a significantly higher incidence of BSIs caused by Pseudomonas sp., Enterococcus sp. and Candida sp. PMID- 29395409 TI - Physical, functional, and psychosocial recovery from burn injury are related and their relationship changes over time: A Burn Model System study. AB - OBJECTIVE: While burn injuries can have dramatic effect on patients' physical health, they can also lead to intense psychological distress, loss of important social and role functioning, and alterations in outward appearance. We aimed to identify potential leading indicators of recovery in the post-discharge period following acute burn injury and hospitalization. METHOD: Using data derived from the Burn Model System National Database, we identified five outcomes of interest measured at four time points (Pre-burn/Discharge, 6 months, 12 months, and 24 months post-discharge), including mental health, physical functioning, community integration, life satisfaction, and satisfaction with appearance. We applied cross-lagged panel analysis to the sample of 1052 injured patients admitted to burn intensive care units. RESULTS: Overall, there was little mean change in the five measures after the 6-month assessment. A time-varying panel model was superior to a time-invariant model, showing that the process of recovery itself may change over the course of two years post-burn. Physical functioning is an important predictor throughout this period, while satisfaction with appearance is quite predictive of other factors at discharge, but somewhat less predictive later. Overall mental health functioning is less predictive at discharge but at later intervals was a meaningful leading predictor of the other outcomes. CONCLUSIONS: Recovery from burn injury is complex and the most important facets of recovery change over time. Future research should focus on developing treatments to help patients adjust to post-burn appearance in the early post discharge period, and mental health interventions may be effective as patients progress in recovery. PMID- 29395410 TI - Risk factors for burn injuries and fire safety awareness among patients hospitalized at a public hospital in Nairobi, Kenya: A case control study. AB - INTRODUCTION: Burn injuries are some of the most physically and psychologically devastating forms of trauma and most common injuries affecting children, especially in the home environment. They are more prevalent and are a public health problem in developing countries mainly because of poor socio-economic conditions. Effective prevention programs should be guided by the results of well designed studies aimed at investigating risk factors for burns. STUDY OBJECTIVE: To establish the risk factors for burn injuries among patients hospitalized at the Kenyatta National Hospital (KNH). METHODOLOGY: This was an age and gender matched case-control study comprising 202 patients admitted with burns (cases) and 202 non-surgical patients (controls) admitted into the pediatric and medical wards. The study site was KNH, a 1800-bed national referral and teaching hospital in Kenya. DATA ANALYTICAL METHODS: SPSS version 17 was used for data analysis, with descriptive statistics used for demographic data, whereas in the analysis for risk factors chi square test and odds ratio (OR) were used to determine the relationship between the predictive (risk factors) and outcome variables (burn injury). Logistic regression was used to determine the strength of association between risk factors and burn injury. RESULTS: The risk factors found to be significant for burn injuries were: low level of education (p=0.043), use of kerosene as fuel for cooking (OR=2.027; 95% CI: 1.361-3.019, p=0.000) and lack of knowledge of burn injury prevention and fire safety (OR=4.009; CI: 2.603-6.172, p=0.000). CONCLUSION: Low level of education, use of kerosene for cooking and lack of knowledge of burn injury prevention and fire safety were identified as risk factors for burn injury among patients hospitalized at KNH. These risk factors should be addressed in burn injury prevention programs for Kenya. PMID- 29395411 TI - Are we headed for a shortage of burn care providers in Canada? AB - INTRODUCTION: Specialized burn care is categorized as an essential component in the criteria for provincial/state and regional trauma systems. Studies in the United States and New Zealand found a need for more burn surgeons and anticipated a severe shortage in the future. The purpose of this study is to describe the current active workforce of burn surgeons in Canada and forecast any perceived shortages in the future. METHODS: Burn care providers were identified from each metropolitan area across Canada. A survey was modified from a previous study and distributed electronically via SurveyMonkeyTM to representatives from 26 centres. RESULTS: Twenty-six centres responded to the questionnaire (response rate=100%). Four of these centres self-identified as providing dedicated burn care, 19 identified themselves as being integrated into surgical programs at their institution, and two stated they no longer treated burn injuries. The mean number of acute burn admissions per year was 67.2 (range 2-290). Of the centres admitting over 75 burns per year, 44% (4/9) are currently looking for a surgeon, 56% (5/9) will be looking for another surgeon in five years, and 44% (4/9) are having or feel they will have trouble finding a surgeon to manage burns. DISCUSSION: Canada is facing a shortage of burn care specialists similar to other developed nations. Active mentorship of surgical trainees is essential to maintain the delivery of high quality of burn care in Canada. PMID- 29395412 TI - Influence on clinical parameters of depressomassage (part I): The effects of depressomassage on color and transepidermal water loss rate in burn scars: A pilot comparative controlled study. AB - OBJECTIVE: Depressomassage is a non-invasive massage technique using a mechanical suction device that is used in the treatment of traumatic or burn scars. Since color and transepidermal water loss (TEWL) are respectively the most important physical and physiological characteristic of hypertrophic scar formation, we wanted to investigate the effects of depressomassage on the recovery of color and TEWL in burn scars compared to the traditional physiotherapy. METHODS: In this pilot comparative controlled study a total 43 burn patients were included and allocated into 2 groups. All patients received standard physical therapy, and the test group received additional depressomassage during 6 months. Color was assessed using the POSAS questionnaire (for color, vascularity and pigmentation) and the Minolta Chromameter. TEWL was measured using DermaLab. RESULTS: Patients of both groups were evaluated at baseline, after 1, 3 and 6 months and after 1year. The evidence for a difference in evolution of color and TEWL between both groups in our study was minimal. CONCLUSIONS: In practice, precise indications to begin depressomassage have to be kept in mind. Perhaps other scar abnormalities such as decreased elasticity, increased thickness, excessive pain or itching could be sufficient reasons to begin depressomassage and should be assessed. PMID- 29395413 TI - Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta analysis. AB - AIMS: Diabetes is associated with adverse cancer outcomes. However, the effect of hyperglycaemia in non-diabetic cancer patients is unclear. MATERIALS AND METHODS: A systematic search of electronic databases identified publications exploring the effect of hyperglycaemia on overall survival, disease-free survival (DFS) or progression-free survival (PFS). Data from studies reporting a hazard ratio and 95% confidence interval and/or a P-value were pooled in a meta-analysis using generic inverse-variance and random effects modelling. Subgroup analyses were conducted based on method of hyperglycaemia measurement (HbA1c, other) and stage (early, advanced, mixed). Meta-regression was performed to evaluate the influence of clinical characteristics including baseline diabetes status on the hazard ratio for overall survival. RESULTS: Twelve studies comprising a total of 9872 patients were included. All studies reported hazard ratios for overall survival. Three studies reported DFS; two reported PFS outcomes. Definitions of hyperglycaemia and cut-offs varied between studies. Hyperglycaemia was associated with worse overall survival (hazard ratio 2.05, 95% confidence interval 1.67 2.51; P < 0.001) and DFS (hazard ratio 1.98, 95% confidence interval 1.20-3.27; P = 0.007), but did not affect PFS (hazard ratio 1.08, 95% confidence interval 0.72 1.62; P = 0.71). The association with worse overall survival was maintained in subgroups based on method of hyperglycaemia measurement (subgroup difference P = 0.46) and stage (P = 0.14). Meta-regression showed a significantly greater magnitude of association between hyperglycaemia and decreased overall survival in studies with higher proportions of women and diabetic patients. CONCLUSIONS: Hyperglycaemia is associated with adverse overall survival and DFS in patients with cancer. The therapeutic role of glycaemic control in cancer patients warrants further investigation. PMID- 29395414 TI - High Levels of Patient Satisfaction in Joint Uro-oncology Clinics to Assist Patient Choice in Early Prostate Cancer and Muscle-invasive Bladder Cancer. PMID- 29395415 TI - The Brugada pattern in a patient treated with amitriptyline. PMID- 29395416 TI - Insights into insulin resistance, lifestyle, and anthropometric measures of patients with prior colorectal cancer compared to controls: A National Health and Nutrition Examination Survey (NHANES) Study. AB - BACKGROUND: Insulin resistance (IR) increases the risk of index colorectal cancer (CRC) development. Limited data exist on IR values, lifestyle, and anthropometric alterations of patients after CRC diagnosis, a population at high risk for CRC recurrence. METHODS: This is a retrospective cohort study using the National Health and Nutrition Examination Survey (NHANES), 1999-2010. We identified patients with and without prior CRC above age 50. Our outcomes were lifestyle, anthropometric measures, and IR measured using the triglyceride to high-density lipoprotein ratio and the homeostasis model assessment IR. RESULTS: There were 146,841 patients with prior CRC and 26,979,507 without prior cancer (controls) in our cohort. Prior patients with CRC were significantly older than controls (75.8 vs 62.3, P < 0.01), however, there were no significant differences in gender, ethnicity, income, caloric intake, tobacco use or alcohol consumption between both groups. Multivariate analysis revealed no difference between prior patients with CRC and controls in triglyceride to high-density lipoprotein ratio (adjusted percentage change = -2.17; 95% CI: -27.96 to 18.43) or homeostasis model assessment IR (adjusted percentage change = -6.85; 95% CI: -35.74 to 15.90). Despite similar weight at age 25, prior CRC subjects had lower weights compared to controls (at time of NHANES survey, one and 10 years before survey and greatest weight). Furthermore prior CRC subjects gained less weight in the 10 years before survey. CONCLUSION: Patients with prior CRC above age 50 have no conclusive evidence of increased IR compared to non-CRC controls. This is possibly due to lesser weight gain in the peri-CRC diagnosis or treatment period. Future efforts should focus on alternate etiologies for the increased CRC recurrence in this high-risk group. PMID- 29395417 TI - Retroperitoneal follicular dendritic cell sarcoma in a young woman: Diagnosis and treatment challenges. AB - INTRODUCTION: Follicular dendritic cell sarcoma (FDCS) is an uncommon tumor that usually arises in lymph nodes, especially in the cervical, mediastinal, or axillary areas, but rarely in extranodal sites. Few cases have been reported in English literature so far. The scarcity may be partially due to under-recognition of this entity. Through this case report we analyzed the difficulties of clinical and pathological diagnosis of this rare tumor with its unusual location mistaken it with gynecological cancer's iliac lymph nodes metastases. We also discussed its systemic treatment options. CASE REPORT: A 48-year-old woman presented with a loss of weight and epigastralgia. Computed tomography (CT) showed a mass of 5cm of diameter, located close to iliac vessels. Investigation for gynecologic cancers was negative and a partial tumor resection was performed. Pathological examination readdressed the diagnosis of FDCS. Microscopically, the tumor was composed of a proliferation of spindle to ovoid cells arranged in fascicles, whorls and storiform pattern, accompanied by sprinkling of small lymphocytes. The nuclei of the tumor cells were elongated spindled or ovoid shape with vesicular chromatin and distinct small nuclei. Immunohistochemically, the tumor cells were positive for CD21, CD23 but negative for any type of cytokeratin. Even pathological diagnosis was misleading, therapeutic management was more challenging with this unusual location particularly associated with an aggressive clinical course. Two lines of chemotherapy gave different responses. CONCLUSION: Clinical and pathological diagnosis of retroperitoneal FDCS needs vigilance. Both lymphoma and sarcoma chemotherapy regimens are effective. Due to this pathology's rareness we highlighted a lack of treatment consensus and proposed options. PMID- 29395418 TI - RIFM FRAGRANCE INGREDIENT SAFETY ASSESSMENT phenylethyl 2-methylbutyrate, CAS Registry Number 24817-51-4. PMID- 29395419 TI - RIFM FRAGRANCE INGREDIENT SAFETY ASSESSMENT p-Methylanisole, CAS Registry Number 104-93-8. PMID- 29395420 TI - Patient characteristics and in-hospital outcomes of emergency carotid endarterectomy and carotid stenting after stroke in evolution. AB - OBJECTIVE: The objective of this study was to describe characteristics and in hospital outcomes of patients treated with carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke in evolution (SIE) under routine conditions in Germany. METHODS: This secondary data analysis is based on the German statutory quality assurance database for carotid revascularization procedures. Patients with SIE who had undergone CEA or CAS were included. The primary outcome was any new stroke or all-cause death until hospital discharge. Descriptive statistics were calculated using statistical standard methods. To identify factors that are associated with the primary or secondary outcomes, a multilevel multivariable regression analysis was performed (exploratory approach). RESULTS: Between 2009 and 2014, a total of 5058 patients (mean age, 70 +/- 11 years; 68% male) with SIE were treated with CEA (n = 3176) or percutaneous transluminal angioplasty/CAS (n = 1882). The primary outcome occurred in 9.0% and 11.7% after CEA and CAS, respectively. The multivariable regression analysis revealed that age (per 10-year increase: risk ratio [RR], 1.30; 95% confidence interval [CI], 1.12-1.50), American Society of Anesthesiologists (ASA) class (ASA class 4 and 5 vs ASA class 3: RR, 2.34; 95% CI, 1.65-3.32), ipsilateral degree of stenosis (occlusion vs severe stenosis: RR, 1.90; 95% CI, 1.29-2.79; low grade vs severe stenosis: RR, 3.06; 95% CI, 1.55-6.02), and neurologic deficit on admission (modified Rankin scale score of 3-5 vs 0-2: RR, 1.48; 95% CI, 1.04 2.10) are significantly associated with the risk of stroke or death after emergency CEA for SIE. In patients treated with CAS, only age (per 10-year increase: RR, 1.58; 95% CI, 1.37-1.82), ASA class (ASA class 1 and 2 vs ASA class 3: RR, 0.66; 95% CI, 0.46-0.95; ASA class 4 and class 5 vs ASA class 3: RR, 1.91; 95% CI, 1.31-2.78), and ipsilateral degree of stenosis (moderate vs severe stenosis: RR, 0.19; 95% CI, 0.04-0.77; occlusion vs severe stenosis: RR, 1.63; 95% CI, 1.18-2.25) were significantly associated with the primary outcome rate. CONCLUSIONS: Emergency carotid revascularization is associated with a combined stroke or death rate of about 10% under routine conditions in Germany. Lower age, lower ASA class, moderate to high-grade stenosis, and less severe neurologic deficit preceding CEA potentially serve as protective factors. PMID- 29395421 TI - Preoperative antihypertensive medication intake and acute kidney injury after major vascular surgery. AB - OBJECTIVE: Postoperative acute kidney injury (AKI) is frequent after major vascular surgery and is associated with significant morbidity and mortality. It remains unclear whether the administration of combined oral antihypertensive medications on the day of surgery can increase the risk of postoperative AKI. METHODS: We performed a retrospective cohort study of hypertensive patients undergoing elective major vascular surgery to determine the association between the number of antihypertensive medications continued on the morning of surgery and AKI at 48 hours postoperatively. RESULTS: A total of 406 patients who had undergone suprainguinal vascular surgery were included, and 10.3% suffered postoperative AKI. In multivariable analysis, the number of antihypertensive medications taken on the morning of surgery was independently associated with AKI (P = .026). Compared with patients who took no medication, taking one medication (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 0.68-3.75) and taking two or more medications (aOR, 2.70; 95% CI, 1.13-6.44) were associated with a 1.6-fold and 2.7-fold increased risk of postoperative AKI, respectively. Other predictors of AKI were suprarenal surgery (aOR, 3.37; 95% CI, 1.53-7.44), age (aOR, 2.29 per 10 years; 95% CI, 1.40-3.74), length of surgery (aOR, 1.40 per 1 hour; 95% CI, 1.10-1.76), hemoglobin drop (aOR, 1.37 per 10 g/L; 95% CI, 1.10 1.74), and history of coronary artery disease (aOR, 2.33; 95% CI, 1.08-5.00). CONCLUSIONS: In patients undergoing major vascular surgery who are treated with chronic antihypertensive therapy, the administration of antihypertensive drugs on the morning of surgery is independently associated with an increased risk of postoperative AKI. Further prospective studies are needed to confirm this finding. PMID- 29395422 TI - Effects of C1 inhibitor on endothelial cell activation in a rat hind limb ischemia-reperfusion injury model. AB - OBJECTIVE: Ischemia-reperfusion (I/R) injury is a major clinical problem linked to vascular surgery. Currently, no drugs to prevent or to treat I/R injury are approved for clinical use. C1 inhibitor (C1 INH) is known to reduce activation of the plasma cascade systems that are involved in the pathophysiologic process of I/R injury. The aim of this study was therefore to investigate the effect of C1 INH on complement deposition and endothelial cell activation in a rat model of hind limb I/R injury. METHODS: Male Wistar rats (wild type, bred at the central animal facility, University of Bern), weighing 250 to 320 g, were used. The rats underwent 2-hour ischemia and 24-hour reperfusion by unilateral clamping of the femoral artery and additional use of a tourniquet. Five groups were divided according to intravenous treatment 5 minutes before ischemia: 50 IU/kg C1 INH (n = 5); 100 IU/kg C1 INH (n = 7); vehicle control (n = 5); nontreated control (n = 7); and normal, healthy control without intervention (n = 4). At the end, muscle edema, tissue viability, and histologic features were assessed. Deposition of immunoglobulin M, C1r, C4d, and fibrin and expression of plasminogen activator inhibitor 1, heparan sulfate (HS), E-selectin, and vascular cell adhesion molecule 1 were evaluated by fluorescence staining. In addition, high-mobility group box 1 protein was measured in plasma. RESULTS: Edema formation was reduced by C1 INH at two dosages, mirrored by improved histologic injury scores and preserved muscle viability. Deposition of immunoglobulin M, C4d, and fibrin was significantly decreased by 100 IU/kg C1 INH compared with nontreated controls. Pretreatment with 100 IU/kg C1 INH also significantly reduced HS shedding and expression of plasminogen activator inhibitor 1 as well as plasma levels of high mobility group box 1 protein. CONCLUSIONS: Pretreatment with both 50 and 100 IU/kg C1 INH attenuated reperfusion injury of rat hind limbs. Pretreatment with 100 IU/kg also preserved the endothelial HS layer as well as the natural, profibrinolytic phenotype of the endothelium. Prevention of endothelial cell activation by C1 INH may therefore be a promising strategy to prevent I/R injury in the clinical setting of peripheral vascular diseases and elective surgery on extremities. PMID- 29395423 TI - Identification of optimal device combinations for the chimney endovascular aneurysm repair technique within the PERICLES registry. AB - OBJECTIVE: The ideal stent combination for chimney endovascular aneurysm repair remains undetermined. Therefore, we sought to identify optimal aortic and chimney stent combinations that are associated with the best outcomes by analyzing the worldwide collected experience in the PERformance of chImney technique for the treatment of Complex aortic pathoLogiES (PERICLES) registry. METHODS: The PERICLES registry was reviewed for patients with pararenal aortic disease electively treated from 2008 to 2014. Eleven different aortic devices were identified with three distinct subgroups: group A (n = 224), nitinol/polyester; group B (n = 105), stainless steel/polyester; and group C (n = 69), nitinol/expanded polytetrafluoroethylene. The various chimney stent subtypes included the balloon-expandable covered stent (BECS), self-expanding covered stent, and bare-metal stent. Deidentified aortic and chimney device combinations were compared for risk of chimney occlusion, type IA endoleak, and survival. Effects of high-volume centers (>100 cases), use of an internal lining chimney stent, number of chimney stents, and number of chimney stent subtypes deployed were also considered. We considered demographics, comorbidities, and aortic anatomic features as potential confounders in all models. RESULTS: The 1- and 3 year freedom from BECS chimney occlusion was not different between groups (group A, 96% +/- 2% and 87% +/- 5%; groups B and C, 93% +/- 3% and 76% +/- 10%; Cox model, P = .33). Similarly, when non-BECS chimney stents were used, no difference in occlusion risk was noted for the three aortic device groupings; however, group C patients receiving BECS did have a trend toward higher occlusion risk relative to group C patients not receiving a BECS chimney stent (hazard ratio [HR], 4.0; 95% confidence interval [CI], 0.85-18.84; P = .08). Patients receiving multiple chimney stents, irrespective of stent subtype, had a 1.8-fold increased risk of occlusion for each additional stent (HR, 1.8; 95% CI, 1.2-2.9; P = .01). Use of a bare-metal endolining stent doubled the occlusion hazard (HR, 2.1; 95% CI, 1.0 4.5; P = .05). Risk of type IA endoleak (intraoperatively and postoperatively) did not significantly differ for the aortic devices with BECS use; however, group C patients had higher risk relative to groups A/B without BECS (C vs B: odds ratio [OR], 3.2 [95% CI, 1-11; P = .05]; C vs A/B: OR, 2.4 [95% CI, 0.9-6.4; P = .08]). Patients treated at high-volume centers had significantly lower odds for development of type IA endoleak (OR, 0.2; 95% CI, 0.1-0.7; P = .01) irrespective of aortic or chimney device combination. Mortality risk was significantly higher in group C + BECS vs group A + BECS (HR, 5.3; 95% CI, 1.6-17.5; P = .006). The 1- and 3-year survival for groups A, B, and C (+BECS) was as follows: group A, 97% +/- 1% and 92% +/- 3%; group B, 93% +/- 3% and 83% +/- 7%; and group C, 84% +/- 7% and 63% +/- 14%. Use of more than one chimney subtype was associated with increased mortality (HR, 3.2; 95% CI, 1.4-7.5; P = .006). CONCLUSIONS: Within the PERICLES registry, use of nitinol/polyester stent graft devices with BECS during chimney endovascular aneurysm repair is associated with improved survival compared with other aortic endografts. However, this advantage was not observed for non-BECS repairs. Repairs incorporating multiple chimney subtypes were also associated with increased mortality risk. Importantly, increasing chimney stent number and bare-metal endolining stents increase chimney occlusion risk, whereas patients treated at low-volume centers have higher risk of type IA endoleak. PMID- 29395424 TI - Rationale and design of the Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial investigating the therapeutic mechanism of mesenchymal stromal cells in the treatment of critical limb ischemia. AB - OBJECTIVE: Currently, there are no accepted nonsurgical therapies that improve the delivery of blood-derived nutrients to patients with critical limb ischemia. Here, we describe the ongoing phase 1/2 Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial, which will provide crucial evidence of the safety profile of mesenchymal stromal cells (MSCs) and explore their therapeutic mechanisms in the setting of critical limb ischemia requiring below-knee amputation (BKA). METHODS: In the CHAMP and the parallel marrowCHAMP trials (hereafter grouped together as CHAMP), a total of 32 extremities with rest pain or tissue loss requiring BKA will be enrolled to receive intramuscular injections of allogeneic MSCs (CHAMP; n = 16) or autogenous concentrated bone marrow aspirate (marrowCHAMP; n = 16) along the distribution of the BKA myocutaneous flap and proximal tibialis anterior. After treatment, subjects are randomized to BKA at four time points after injection (days 3, 7, 14, and 21). At the time of amputation, skeletal muscle is collected at 2-cm increments from the tibialis injection site and used to determine proangiogenic cytokine description, MSC retention, quantification of proangiogenic hematopoietic progenitor cells, and histologic description. Clinical limb perfusion before and after treatment will be quantified using transcutaneous oximetry, toe-brachial index, ankle-brachial index, and indocyanine angiography. Additional clinical end points include all-cause mortality, need for amputation revision, and gangrene incidence during the 6-month post-treatment follow-up. RESULTS: Enrollment is under way, with 10 patients treated per protocol thus far. We anticipate full conclusion of follow-up within the next 24 months. CONCLUSIONS: CHAMP will be pivotal in characterizing the safety, efficacy, and, most important, therapeutic mechanism of allogeneic MSCs and autogenous concentrated bone marrow aspirate in ischemic skeletal muscle. PMID- 29395425 TI - Improved mortality in treatment of patients with endovascular interventions for chronic mesenteric ischemia. AB - OBJECTIVE: Chronic mesenteric ischemia (CMI) continues to be a devastating diagnosis. There is a national trend toward increased use of endovascular procedures with improved survival for the treatment of these patients. Our aim was to evaluate whether this trend has changed CMI patients' length of hospitalization and health care cost. METHODS: We identified all patients admitted for CMI from the National Inpatient Sample (NIS) from 2000 to 2014. Our primary end points included length of hospital stay (LOS) and cost of hospitalization (COH). Our secondary end points included mortality assessment of the CMI hospitalization. RESULTS: There were 15,475 patients admitted for CMI. The mean age of patients was 71 years, and 4022 (26.0%) were male. There were 10,920 (70.6%) patients treated endovascularly (ENDO) and 4555 (29.4%) patients treated in an open fashion (OPEN). Although a higher proportion of patients in the ENDO (43.3%) group vs OPEN (33.1%) had a Charlson Comorbidity Index score of >=2 (P < .0001), they had a lower mortality rate (2.4% vs 8.7%; P < .0001), lower mean LOS (6.3 vs 14.0 days; P < .0001), and lower COH ($21,686 vs $42,974; P < .0001). After adjusting for clinical and hospital factors, OPEN continued to demonstrate higher mortality than ENDO (odds ratio, 7.2; 95% confidence interval, 4.9-10.6; P < .0001), longer LOS (mean, +9.7 days; P < .0001), and higher COH (mean, +$25,834; P < .0001). CONCLUSIONS: The rate of ENDO continues to rise nationally in the treatment of CMI patients. After adjusting for clinical and hospital factors, patients in the ENDO group tend to have lower in-hospital mortality of 2.4% and lower LOS by 10 days, and they incur a cost saving of >$25,000 compared with patients in the OPEN group. ENDO should be considered first line of therapy for patients with CMI. PMID- 29395426 TI - Prediction of advanced endovascular stent graft rotation and its associated morbidity and mortality. AB - OBJECTIVE: Advanced endovascular aneurysm repair (EVAR) with fenestrated and branched stent grafts is increasingly being used to repair complex aortic aneurysms; however, these devices can rotate unpredictably during deployment, leading to device misalignment. The objectives of this study were to quantify the short-term clinical outcomes in patients with intraoperative stent graft rotation and to identify quantitative anatomic markers of the arterial geometry that can predict stent graft rotation preoperatively. METHODS: A prospective study evaluating all patients undergoing advanced EVAR was conducted at two university affiliated hospitals between November 2015 and December 2016. Stent graft rotation (defined as >=10 degrees) was measured on intraoperative fluoroscopic video of the deployment sequence. Standard preoperative computed tomography angiography imaging was used to calculate the geometric properties of the arterial anatomy. Any in-hospital and 30-day complications were prospectively documented, and a composite outcome of any end-organ ischemia or death was used as the primary end point. RESULTS: Thirty-nine patients undergoing advanced EVAR were enrolled in the study with a mean age of 75 years (interquartile range [IQR], 71-80 years) and a mean aneurysm diameter of 64 mm (IQR, 59-65 mm). The incidence of stent graft rotation was 37% (n = 14), with a mean rotation of 25 degrees (IQR, 21-28 degrees). A nominal logistic regression model identified iliac artery torsion, volume of iliac artery calcification, and stent graft length as the primary predictive factors. The total net torsion and the total volume of calcific plaque were higher in patients with stent graft rotation, 8.9 +/- 0.8 mm-1 vs 4.1 +/- 0.5 mm-1 (P < .0001) and 1054 +/- 144 mm3 vs 525 +/- 83 mm3 (P < .01), respectively. The length of the implanted stent grafts was also higher in patients with intraoperative rotation, 172 +/- 9 mm vs 156 +/- 8 mm (P < .01). The composite outcome of any end-organ ischemia or death was also substantially higher in patients with stent graft rotation (36% vs 0%; P = .004). In addition, patients with stent graft rotation had significantly higher combined rates of type Ib and type III endoleaks (43% vs 8%; P = .03). CONCLUSIONS: Patients with intraoperative stent graft rotation have a significantly higher rate of severe postoperative complications, and this is strongly associated with higher levels of iliac artery torsion, calcification, and stent graft length. These findings suggest that preoperative quantitative analysis of iliac artery torsion and calcification may improve risk stratification of patients before advanced EVAR. PMID- 29395427 TI - Computed tomography angiography-fluoroscopy image fusion allows visceral vessel cannulation without angiography during fenestrated endovascular aneurysm repair. AB - BACKGROUND: Fenestrated endovascular aneurysm repair (FEVAR) is an evolving technique to treat juxtarenal abdominal aortic aneurysms (AAAs). Catheterization of visceral and renal vessels after the deployment of the fenestrated main body device is often challenging, usually requiring additional fluoroscopy and multiple digital subtraction angiograms. The aim of this study was to assess the clinical utility and accuracy of a computed tomography angiography (CTA) fluoroscopy image fusion technique in guiding visceral vessel cannulation during FEVAR. METHODS: Between August 2014 and September 2016, all consecutive patients who underwent FEVAR at our institution using image fusion guidance were included. Preoperative CTA images were fused with intraoperative fluoroscopy after coregistering with non-contrast-enhanced cone beam computed tomography (syngo 3D3D image fusion; Siemens Healthcare, Forchheim, Germany). The ostia of the visceral vessels were electronically marked on CTA images (syngo iGuide Toolbox) and overlaid on live fluoroscopy to guide vessel cannulation after fenestrated device deployment. Clinical utility of image fusion was evaluated by assessing the number of dedicated angiograms required for each visceral or renal vessel cannulation and the use of optimized C-arm angulation. Accuracy of image fusion was evaluated from video recordings by three raters using a binary qualitative assessment scale. RESULTS: A total of 26 patients (17 men; mean age, 73.8 years) underwent FEVAR during the study period for juxtarenal AAA (17), pararenal AAA (6), and thoracoabdominal aortic aneurysm (3). Video recordings of fluoroscopy from 19 cases were available for review and assessment. A total of 46 vessels were cannulated; 38 of 46 (83%) of these vessels were cannulated without angiography but based only on image fusion guidance: 9 of 11 superior mesenteric artery cannulations and 29 of 35 renal artery cannulations. Binary qualitative assessment showed that 90% (36/40) of the virtual ostia overlaid on live fluoroscopy were accurate. Optimized C-arm angulations were achieved in 35% of vessel cannulations (0/9 for superior mesenteric artery cannulation, 12/25 for renal arteries). CONCLUSIONS: Preoperative CTA-fluoroscopy image fusion guidance during FEVAR is a valuable and accurate tool that allows visceral and renal vessel cannulation without the need of dedicated angiograms, thus avoiding additional injection of contrast material and radiation exposure. Further refinements, such as accounting for device-induced aortic deformation and automating the image fusion workflow, will bolster this technology toward optimal routine clinical use. PMID- 29395428 TI - Institutional experience with the Zenith Fenestrated aortic stent graft. AB - OBJECTIVE: The Zenith Fenestrated (ZFEN; Cook Medical, Bloomington, Ind) aortic stent graft system was approved for commercial use by the Food and Drug Administration in April 2012. We report our single-center experience of 100 consecutive patients treated with the ZFEN platform from October 2012 to March 2017. METHODS: A retrospective review of our prospectively maintained fenestrated endovascular aneurysm repair (FEVAR) database at a tertiary care academic institution located in the Midwest United States was performed for descriptive analysis. All continuous variables are reported as a mean +/- standard deviation and compared using two-sided Student t-tests. Categorical variables were compared using two-sided Fisher exact tests. RESULTS: All but one of the procedures were elective in nature. Overall intraoperative characteristics included a mean blood loss (estimated blood loss) of 388 +/- 385 mL, fluoroscopy time of 63 +/- 30 minutes, radiation dose of 437 +/- 272 rad, contrast material volume of 99 +/- 36 mL, and operative time of 236 +/- 87 minutes. Average number of visceral arteries stented was 2.1 +/- 0.5. Technical success was achieved in 98% of the patients. Statistically significant (P < .05) improvement in estimated blood loss (2.1 fold) was observed in the second half of our series. Interestingly, no improvements were made in terms of fluoroscopy time, radiation exposure, contrast material use, or operative time. However, procedural difficulty increased in the last half by number of visceral arteries stented as a surrogate (1.9 vs 2.2; P < .05). Mean length of stay was 3.6 +/- 4.3 days. Perioperative mortality at 30 days was 2%. Perioperative morbidity included a 5% incidence of any bowel ischemia, 1% of spinal cord ischemia, 3% of renal failure requiring hemodialysis, 1% of stroke, and 4% of myocardial infarction. Average follow-up was 1.7 +/- 1.4 years. Reintervention during the follow-up phase was 20%. Of the 209 visceral arteries stented, we noted 6 instances of stent thrombosis, 6 of kinking or stenosis, and 1 of stent fracture in follow-up. Endoleak, most commonly type II, was present or could not be excluded in 15% of all FEVARs at last available computed tomography angiography. CONCLUSIONS: In our experience, FEVAR with the ZFEN system continues to be safe and effective. There is a significant rate of reintervention observed, and close monitoring is fundamental to maintaining good clinical results. PMID- 29395429 TI - Current trauma care system and trauma care training in China. AB - Trauma is a life-threatening "modern disease". The outcomes could only be optimized by cost-efficient and prompt trauma care, which embarks on the improvement of essential capacities and conceptual revolution in addition to the disruptive innovation of the trauma care system. According to experiences from the developed countries, systematic trauma care training is the cornerstone of the generalization and the improvement on the trauma care, such as the Advance Trauma Life Support (ATLS). Currently, the pre-hospital emergency medical services (EMS) has been one of the essential elements of infrastructure of health services in China, which is also fundamental to the trauma care system. Hereby, the China Trauma Care Training (CTCT) with independent intellectual property rights has been initiated and launched by the Chinese Trauma Surgeon Association to extend the up-to-date concepts and techniques in the field of trauma care as well to reinforce the generally well-accepted standardized protocols in the practices. This article reviews the current status of the trauma care system as well as the trauma care training. PMID- 29395430 TI - Locking plate versus external fixation for type C distal radius fractures: A meta analysis of randomized controlled trials. AB - PURPOSE: Distal radial fracture is one of the most common fractures. Up to now, locking plates (LP) and external fixation (EF) are two conventional surgical approaches to type C radius fracture. Which method is superior has not yet reached a consensus. We try to assess the clinical effectiveness of the two interventions by this meta-analysis. METHODS: We used network to search the PubMed, Embase, and Cochrane Medical Library of randomized controlled clinical trials about the type C distal radius fractures performed according to the search strategy mentioned in Cochrane Handbook 5.1.0 from Jan. 2005 to Jan. 2016. Patients in the experimental group were used LP, in the control group were included EF and other surgical approaches. Publication language was restricted to English. Studies that patient population and surgical indication did not define had been excluded. Studies must report at least one of the outcomes as follow: radial inclination, palmar tilt, ulnar variance, range of wrist flexion and extension, and range of wrist supination and pronation. The trials in which participants included children were excluded. We used Jadad study scores to appraise the study. RESULTS: Seven studies included 162 patients (LP group) and 190 patients (EF group). We compared the radial inclination, palmar tilt, ulnar variance, range of wrist flexion and extension, and range of wrist supination and pronation. The radial inclination were revealed a difference favoring LP over EF [WMD = 1.84, 95% CI (0.17, 3.50), p = 0.03] and the palmar tilt and ulnar variance was no significant difference between the two groups [(WMD = 3.61, 95% CI (0.00, 7.23), p = 0.05; WMD = 0.05, 95% CI (-0.99, 1.09), p = 0.93]. The functional activities of range of flexion and extension and range of supination and pronation between the two groups was no difference [WMD = 10.04, 95% CI ( 6.88, 26.96), p = 0.24; WMD = 12.53, 95% CI (-9.99, 35.06), p = 0.28]. CONCLUSION: Locking plate and external fixation is feasible to heal radius type C fracture. We found the small difference between the two groups on imaging examination. The locking plate has the advantage on maintaining reduction, however no significant difference regarding outcomes has been found between the two groups. PMID- 29395431 TI - ATP Citrate Lyase: A New Player Linking Skeletal Muscle Metabolism and Epigenetics. AB - Intermediates generated in several metabolic processes are used to regulate transcription through covalent histone and DNA modifications. In Cell Reports, Das et al. show that acetyl-coenzyme A (acetyl-CoA) generated by ATP citrate lyase (ACL) is utilized to acetylate histone H3 at MyoD regulatory regions, resulting in increased MyoD expression and improved muscle regeneration after injury. PMID- 29395432 TI - Ramie (Boehmeria nivea)'s uranium bioconcentration and tolerance attributes. AB - The authors sampled and analyzed 15 species of dominant wild plants in Huanan uranium tailings pond in China, whose tailings' uranium contents were 3.21-120.52 MUg/g. Among the 15 species of wild plants, ramie (Boehmeria nivea) had the strongest uranium bioconcentration and transfer capacities. In order to study the uranium bioconcentration and tolerance attributes of ramie in detail, and provide a reference for the screening remediation plants to phytoremedy on a large scale in uranium tailings pond, a ramie cultivar Xiangzhu No. 7 pot experiment was carried out. We found that both wild ramie and Xiangzhu No. 7 could bioconcentrate uranium, but there were two differences. One was wild ramie's shoots bioconcentrated uranium up to 20 MUg/g (which can be regarded as the critical content value of the shoot of uranium hyperaccumulator) even the soil uranium content was as low as 5.874 MUg/g while Xiangzhu No. 7's shoots could reach 20 MUg/g only when the uranium treatment concentrations were 275 MUg/g or more; the other was that all the transfer factors of 3 wild samples were >1, and the transfer factors of 27 out of 28 pot experiment samples were <1. Probably wild ramie was a uranium hyperaccumulator. Xiangzhu No. 7 satisfied the needs of uranium hyperaccumulator on accumulation capability, tolerance capability, bioconcentration factor, but not transfer capability, so Xiangzhu No. 7 was not a uranium hyperaccumulator. We analyzed the possible reasons why there were differences in the uranium bioconcentration and transfer attributes between wild ramie and Xiangzhu No. 7., and proposed the direction for further research. In our opinion, both the plants which bioconcentrate contaminants in the shoots and roots can act as phytoextractors. Although Xiangzhu No. 7's biomass and accumulation of uranium were concentrated on the roots, the roots were small in volume and easy to harvest. And Xiangzhu No. 7's cultivating skills and protection measures had been developed very well. Xiangzhu No. 7's whole bioconcentration factors and the roots' bioconcentration factors, which were 1.200-1.834 and 1.460-2.341, respectively, increased with the increases of uranium contents of pot soil when the soil's uranium contents are 25-175 MUg/g, so it can act as a potential phytoextractor when Huanan uranium tailings pond is phytoremediated. PMID- 29395433 TI - Reply letter to: Role of endocrine therapy in weak estrogen/progesterone receptor expression in HER2 negative breast cancer. PMID- 29395434 TI - Selective neck dissection in surgically treated head and neck squamous cell carcinoma patients with a clinically positive neck: Systematic review. AB - Adequate treatment of lymph node metastases is essential for patients with head and neck squamous cell carcinoma (HNSCC). However, there is still no consensus on the optimal surgical treatment of the neck for patients with a clinically positive (cN+) neck. In this review, we analyzed current literature about the feasibility of selective neck dissection (SND) in surgically treated HNSCC patients with cN + neck using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. From the reviewed literature, it seems that SND is a valid option in patients with cN1 and selected cN2 neck disease (non-fixed nodes, absence of palpable metastases at level IV or V, or large volume ->3 cm-multiple lymph nodes at multiple levels). Adjuvant (chemo) radiotherapy is fundamental to achieve good control rates in pN2 cases. The use of SND instead a comprehensive neck dissection (CND) could result in reduced morbidity and better functional results. We conclude that SND could replace a CND without compromising oncologic efficacy in cN1 and cN2 cases with the above mentioned characteristics. PMID- 29395435 TI - The new Epstein gleason score classification significantly reduces upgrading in prostate cancer patients. AB - PURPOSE: To evaluate the differences between the old and the new Gleason score classification systems in upgrading and downgrading rates. MATERIALS AND METHODS: Between 2012 and 2015, we identified 9703 patients treated with retropubic radical prostatectomy (RP) in four tertiary centers. Biopsy specimens as well as radical prostatectomy specimens were graded according to both 2005 Gleason and 2014 ISUP five-tier Gleason grading system (five-tier GG system). Upgrading and downgrading rates on radical prostatectomy were first recorded for both classifications and then compared. The accuracy of the biopsy for each histological classification was determined by using the kappa coefficient of agreement and by assessing sensitivity, specificity, positive and negative predictive value. RESULTS: The five-tier GG system presented a lower clinically significant upgrading rate (1895/9703: 19,5% vs 2332/9703:24.0%; p = .001) and a similar clinically significant downgrading rate (756/9703: 7,7% vs 779/9703: 8%; p = .267) when compared to the 2005 ISUP classification. When evaluating their accuracy, the new five-tier GG system presented a better specificity (91% vs 83%) and a better negative predictive value (78% vs 60%). The kappa-statistics measures of agreement between needle biopsy and radical prostatectomy specimens were poor and good respectively for the five-tier GG system and for the 2005 Gleason score (k = 0.360 +/- 0.007 vs k = 0.426 +/- 0.007). CONCLUSIONS: The new Epstein classification significantly reduces upgrading events. The implementation of this new classification could better define prostate cancer aggressiveness with important clinical implications, particularly in prostate cancer management. PMID- 29395436 TI - Evidence basis for sentinel node biopsy post neoadjuvant chemotherapy - Bias is a 4-letter word. PMID- 29395437 TI - Centers of excellence or excellence networks: The surgical challenge and quality issues in rare cancers. AB - There are several suggestions that centralization of care improves outcome for rare cancers, particularly when optimal treatment requires complex surgery or high-technology radiotherapy equipment. Diagnosis and treatment in reference centers are expected to be more accurate because they benefit from large numbers of cases discussed in a multidisciplinary tumor board with a well-run pathway. However, centralization is sometimes moderately perceived by oncologists as a solution to be endorsed for rare cancer patients; disadvantages of centralization are the need for patients to move and the risk of a longer waiting list, with discomfort and possible negative effects on outcome. It is difficult to find single experts on rare cancers: all the more it will be difficult to find a multidisciplinary panel of experts, and the role of the surgeon is to be a functional part of it. On the other side, from a surgical point of view, the quality of the initial management of many rare cancers directly impacts the final outcome; surgery of rare cancers may not necessarily be more demanding than the average from a technical point of view, but the lack of cultural knowledge about the disease can well lead to inappropriateness even in the lack of major technical challenges. Care for rare cancer patients must be organized in pathways that cover the patient's journey from their point of view rather than that of the healthcare system, and pathways must follow the best evidence on diagnosis, treatment and follow-up. PMID- 29395438 TI - Comparison of preoperative concurrent chemoradiotherapy with chemotherapy alone in patients with locally advanced siewert II and III adenocarcinoma of the esophagogastric junction. AB - PURPOSE: Preoperative therapy improves overall survival (OS) after surgery in patients with adenocarcinoma of the esophagogastric junction (AEG). We aimed to retrospectively analyze whether preoperative chemoradiotherapy (CRT) could improve the prognosis of patients with locally advanced Siewert II and III AEG comparing with preoperative chemotherapy alone (CT). PATIENTS AND METHODS: From March 2012 to December 2015, 170 patients with locally advanced (cT3-4NxM0) Siewert II and III AEG were treated with preoperative CRT or CT in Hebei Medical University Fourth Hospital, and 123 patients were included in this study to compare the effects of preoperative CRT with CT. RESULTS: R0 resection rate was 96.7% in CRT group and 82.5% in CT group (P = .016). The pathological complete response was 16.7% after CRT group and 3.2% after CT (P = .015). The median follow-up time was 20 months. The 1- and 3-year OS were 89.4%, 79.2% in CRT group and 88.2%, 58.0% in CT group (P = .016; HR = 0.40, 95% confidence interval 0.21 0.76). The 1- and 3-year PFS were 87.3%, 73.5% in CRT group and 72.8%, 42.8% in CT group (P = .014; HR = 0.46, 95% confidence interval 0.24-0.86). Multivariate analysis showed that clinical T stage, adjuvant chemotherapy cycles and histologic differentiation were shown to be the independent prognostic factors for OS, and postoperative pathologic N stage was shown to be the independent prognostic factor for PFS. CONCLUSION: For the patients with locally advanced AEG, the addition of radiotherapy to preoperative chemotherapy can improve survival with safety, but is not an independent prognostic factor for OS and PFS. PMID- 29395439 TI - Mycobacterium lentiflavum as the main cause of lymphadenitis in pediatric population. AB - INTRODUCTION: Cervical lymphadenitis is the most common nontuberculous mycobacteria (NTM) infection in immunocompetent children, mainly in those under 5years. For many years Mycobacterium lentiflavum (M. lentiflavum) has been considered a rare NTM causing lymphadenitis. METHODS: A restrospective study was performed in pediatric patients with microbiologically confirmed NTM cervical lympahdenitis at the Nino Jesus Hospital in Madrid during 2009-2016. RESULTS: During the period studied, 28 cases of cervical lymphadenitis were recorded. In 23 (82.14%) and in 5 (17,85%) cases, M. lentiflavum and Mycobacterium avium were isolated, respectively. In those patients infected with M. lentiflavum, the most frequent location was sub-maxilar (43.47%); 15 (65.21%) were boys, global median age was 30,8 months and all cases showed a satisfactory evolution. CONCLUSION: We propose that M. lentiflavum should be considered an important emergent pathogen cause of cervical lymphadenitis in the pediatric population. PMID- 29395440 TI - Natural products for the treatment of type 2 diabetes mellitus: Pharmacology and mechanisms. AB - Epidemiological studies have implied that diabetes mellitus (DM) will become an epidemic accompany with metabolic and endocrine disorders worldwide. Most of DM patients are affected by type 2 diabetes mellitus (T2DM) with insulin resistance and insulin secretion defect. Generally, the strategies to treat T2DM are diet control, moderate exercise, hypoglycemic and lipid-lowing agents. Despite the therapeutic benefits for the treatment of T2DM, most of the drugs can produce some undesirable side effects. Considering the pathogenesis of T2DM, natural products (NPs) have become the important resources of bioactive agents for anti T2DM drug discovery. Recently, more and more natural components have been elucidated to possess anti-T2DM properties, and many efforts have been carried out to elucidate the possible mechanisms. The aim of this paper was to overview the activities and underlying mechanisms of NPs against T2DM. Developments of anti-T2DM agents will be greatly promoted with the increasing comprehensions of NPs for their multiple regulating effects on various targets and signal pathways. PMID- 29395441 TI - Pine nut allergy in Korean children: Clinical characteristics and diagnostic values of specific IgE against pine nuts. AB - BACKGROUND: Hypersensitivity reactions to pine nuts in children have been occasionally encountered recently, although reports on pine nut allergy cases are rare worldwide. The study aimed to feature clinical and laboratory findings pertaining to pine nut allergy in Korean children. METHODS: Forty-two subjects were enrolled through a retrospective review of medical records, from September 2010 to December 2015, at the Department of Pediatrics in Ajou University Hospital. The demographic profiles, clinical characteristics, and laboratory findings were evaluated. RESULTS: Twenty-four patients showed immediate-type reactions after exposure to pine nuts (the allergic group), while the remaining 18 were atopic controls, who exhibited no allergic symptoms (the tolerant group). The median age of the subjects in the allergic group was three years. More than half of the subjects in this group experienced allergic symptoms within 5min, and seven of them experienced anaphylaxis. The median level of pine nut-specific immunoglobulin E (sIgE) in the allergic group (1.62kUA/L) was significantly higher (p=0.014) than that in the tolerant group (0.11kUA/L), with an optimal cut off level of 0.40kUA/L (sensitivity, 66.7% and specificity, 77.8%). The positive decision point of pine nut-sIgE (specificity, 100%) to distinguish the allergic and tolerant groups was 2.84kUA/L. However, there was no difference in pine nut sIgE levels between the anaphylaxis and non-anaphylaxis cases. CONCLUSION: About 30% of children with pine nut allergy experienced anaphylaxis. The optimal cut off level of pine nut-sIgE to distinguish the allergic and tolerant groups was 0.40kUA/L and the positive decision point was 2.84kUA/L. PMID- 29395442 TI - RNA interference technology to improve the baculovirus-insect cell expression system. AB - The baculovirus expression vector system (BEVS) is a popular manufacturing platform for the production of recombinant proteins, antiviral vaccines, gene therapy vectors, and biopesticides. Besides its successful applications in the industrial sector, the system has also played a significant role within the academic community given its extensive use in the production of hard-to-express eukaryotic multiprotein complexes for structural characterization for example. However, as other expression platforms, BEVS has to be continually improved to overcome its limitation and adapt to the constant demand for manufacturing processes that provide recombinant products with improved quality at higher yields and lower production cost. RNA interference, or RNAi, is a relatively recent technology that has revolutionized how scientist study gene function. Originally introduced as a tool to study biological and disease-related processes it has recently been applied to improve the yield and quality of recombinant proteins produced in several expression systems. In this review, we provide a comprehensive summary of the impact that RNAi-mediated silencing of cellular or viral genes in the BEVS has on the production of recombinant products. We also propose a critical analysis of several aspects of the methodologies described in the literature for the use of RNAi technology in the BEVS with the intent to provide the reader with eventually useful guidance for designing experiments. PMID- 29395443 TI - Structured review of the patient-reported outcome instruments used in clinical trials in head and neck surgery. AB - The number of clinical trials that relate to patients with cancer of the head and neck is growing. Patient-reported outcomes, which are rarely the primary outcome, are now an important component, and in this structured review to identify and report the characteristics of the questionnaires that have been used in these trials, we summarise the findings reported. We searched several online databases using the key terms: head and neck oncology, head and neck surgery, reconstruction, clinical trials patient-reported outcomes, questionnaires, quality of life (QoL), validated instruments, and patients' satisfaction. We screened 1342 papers to collect information about the topic of the paper, sample size, selection criteria, main advantages and disadvantages of the patient reported outcome used, and if it was used in conjunction with another measure. A total of 54 were eligible, and from them we identified 22 questionnaires. The primary reason for using a questionnaire was its relevance to the focus of the paper, such as xerostomia, pain, or swallowing. To allow the experience of patients to be the focus of the primary outcome in a clinical trial, we recommend that the measures used should be appropriate, reliable, valid, responsive, precise, interpretable, acceptable, and feasible. The trials used validated questionnaires, but the patient-reported outcome measures tended not to be the focus. There is merit in such measures being the primary outcomes in future trials and these should be designed around an explicit hypothesis. PMID- 29395444 TI - Assessment of the anterior loop of the inferior alveolar nerve using reformatted computed tomography: a retrospective study. AB - The anterior loop of the inferior alveolar nerve (IAN) is an important landmark in the anterior mandible that must be considered during the placement of dental implants. We measured the length and prevalence of loops of the IAN in 188 consecutive, dentate patients using reformatted computed tomography (CT). A total of 158/188 (84%) had at least one anterior loop; 111/188 (59%) had bilateral loops. The mean (SD) length of the loops in the third quadrant was 1.4 (0.7)mm; 95% CI 1.3 to 1.6; (range 0.3 - 4.0mm). The mean (SD) length of the loops in the fourth quadrant was 1.5 (0.9)mm; 95% CI 1.4 to 1.6; range 0.3 - 5.5mm. In total 42/188 (22%) had loops that were longer than 2mm in quadrants three and four. CT images that have been reformatted with specialised software may be useful to identify loops in the IAN, particularly when recent cone-beam CT images are not freely available. The prevalence of these loops is high while their length varies, which makes meticulous assessment necessary before the placement of implants. PMID- 29395445 TI - Tuberculosis: the great imitator in the head and neck - our experience of 24 cases in 22 years. AB - This retrospective study covered over two decades, during which an individual head and neck surgeon treated 24 patients with cervicofacial lymphadenitis that was related to both Mycobacterium tuberculosis complex (n=17, made up of M tuberculosis (n=16) and M bovis (n=1)), and non-tuberculous mycobacteria. The seven cases of non-tuberculous mycobacteria were caused by M avium complex (n=3), M malmoense (n=3), and M kansaii (n=1). By using a tailored management approach, at times selective combined surgical and antimycobacterial treatment, he achieved a success rate of 23/24 cases, with only one recurrence and no major complications. The results suggest that patients with tuberculosis confined to the head and neck rarely develop constitutional symptoms, so the absence of such symptoms may not exclude tuberculosis. There was also a good correlation between predictive variables (immune state, inflammatory markers on admission, causative mycobacterium, and the antimycobacterial regimen used) and time spent under follow-up at the head and neck outpatient clinic. PMID- 29395446 TI - Management of self-inflicted gunshot wounds to the face: retrospective review from a single tertiary care trauma centre. AB - There are limited published data about the surgical management of self-inflicted facial gunshot wounds. The aim of this retrospective study was to review our management of subjects who initially survive such a wound and were admitted to a tertiary care trauma centre between 2002 and 2012. Only subjects with definitive evidence of a self-inflicted facial gunshot wound and who were admitted alive were included. Data collected included personal and clinical details, characteristics of the gunshot wound, and medical and surgical management. Types of operations and their duration were recorded, and primary reconstruction was divided into early (within the first 48hours after presentation) or delayed (longer than 48hours). Determinants of infection were assessed with univariate analysis. Seventy-six subjects (65 male and 11 female, mean (range) age 44 (18 83) years) were included in the study. Twenty-five patients needed an early surgical airway and five needed emergency intervention to control haemorrhage. Forty-five patients had primary reconstructions (28 early and 17 delayed) and 12 who were treated by delayed repair had a submental entry site to the wound. There were no significant differences in infection rates between those who had early, compared with those who had late, reconstructions. Early primary reconstruction can be successful for patients with self-inflicted facial gunshot wounds, particularly when the entry point of the bullet is in the upper and midface area. Delayed primary reconstruction was more common when the bullet entered the lower face. PMID- 29395447 TI - Hard lumps in the neck: diagnostic essentials. PMID- 29395448 TI - Buccal fat pad and subperiosteal midface lifts in conjunction with open reduction and internal fixation to treat fractures of the zygomaticomaxillary complex. PMID- 29395449 TI - Do signs of an effusion of the temporomandibular joint on magnetic resonance imaging correlate with signs and symptoms of temporomandibular joint disease? AB - Effusions are common among patients with disorders of the temporomandibular joint (TMJ), but publications are limited and results inconsistent about the correlation between them and important clinical variables, in particular severity of pain and degenerative disease. We organised a retrospective study of patients who presented for the evaluation and management of arthralgia of the TMJ and myofascial pain at the University of Michigan between 2011 and 2014. Inclusion criteria were: patients who had pain that was primarily arthrogenous, and coexisting myogenous pain, who had had initial non-surgical treatment, and arthroscopy of the TMJ with or without intramuscular injection of onabotulinumtoxinA (Botox,(r) Allegan, Weston, Fl, USA). The primary outcome variables were pain at rest as measured by visual analogue score (VAS) and the presence of degenerative disease of the joint. The secondary outcome variables included the position of the disc and whether it was perforated, signs of synovitis, maximal interincisal opening (MIO), and duration of symptoms. We studied 47 patients (94 TMJ) who met the inclusion criteria. We found no significant differences in pain at rest before or after arthroscopy, between patients with and without effusions, or in maximal MIO or duration of symptoms between the two groups. There was, however, a significant relation between effusions and degenerative joint disease. Effusions were also associated with a lower probability of the disc being in a normal position and a higher probability of anterior disc displacement without reduction. PMID- 29395450 TI - Reconstruction after resection of carcinoma of the lower lip. PMID- 29395451 TI - Quality of life after reconstruction with a free forearm flap in patients who have survived oral cancer for more than five years. PMID- 29395452 TI - Evaluation of stress by finite element analysis of the midface and skull base at the time of midpalatal osteotomy in models with or without pterygomaxillary dysjunction. AB - Surgically-assisted rapid maxillary expansion (SARME) is commonly used to treat skeletally mature patients with transverse discrepancies. Some osteotomies are made in areas that resist expansion, but there is no clear consensus about the sequence in which the osteotomies are made. Some clinicians do the pterygomaxillary osteotomy last, while others do it before the midpalatal osteotomy. We used the finite element method to measure the stresses on the midface, cranial base and pterygoid plates at the time of midpalatal osteotomy in two models, one with and one without pterygomaxillary dysjunction (PMD). In both, SARME consisted of maxillary bilateral osteotomy from the piriform rim to the pterygoid plate. Midpalatal osteotomy was also done in both. In the PMD model, minimum principal stresses increased on the midface, and maximum principal and von Mises stresses increased at the cranial base and on the pterygoid plates. Our results suggest that the stresses on the midface and cranial base can be reduced during midpalatal osteotomy in adults if the pterygomaxillary osteotomy is done last. PMID- 29395453 TI - Genomic analysis to assess disease progression and recurrence in patients with oral squamous cell carcinoma: - a preliminary study. AB - We studied the progression from dysplasia to invasive carcinoma and subsequent second primaries or locoregional recurrences in 11 patients with recurrent squamous cell carcinoma (SCC). Between one and six samples were sequenced/patient. DNA samples were prepared, and libraries multiplexed to between 40 and 80 samples/lane of an Illumina HiSeq 3000 and sequenced with 2*100bp paired end sequencing. Copy number data were generated by CNAnorm (Bioconductor package). Samples of recurrent SCC showed unique patterns of descent when compared with earlier samples from the primary tumour, and three main patterns emerged. In four patients there was convincing evidence that the later lesion was descended directly from cells from the first, and in a further four there were no detectable genomic events between the two lesions. Three patients had some shared events between the early and later lesions, but although there were enough differences to deduce that the two lesions had a shared ancestor, they were not directly descended from each other. We present the patients' characteristics in detail, including the overall survival in each group. There was a distinct genomic pattern after a second episode of SCC in all the groups. A larger study that uses similar methods and a longer duration could provide reliable conclusions with respect to survival. With the use of new techniques, genomic data can be available to clinical teams during the planning of treatment. PMID- 29395454 TI - Outcomes of treatment for intracapsular fractures of the mandibular condyle: recommendation for a new classification. AB - We know of no universally accepted classification for intracapsular condylar fractures. We propose here a new classification based on the concept of a "disc condyle" unit, and validate the classification based on outcomes of treatment. From 1 January 2010 - 31 December 2014, 55 patients with unilateral intracapsular condylar fractures were classified into three types: type A has no reduction in mandibular height or displacement of the disc (n=7); type B has displacement of the disc with no reduction in mandibular height (n=17); and type C has reduced mandibular height with or without displacement of the disc (n=31). We treated types B and C by open reduction and fixation, while type A fractures were managed non-surgically. At six month follow-up, we found no significant differences in the vertical height of the ramus, mandibular deviation, protrusion, or lateral protrusion between the fractured and healthy sides. All patients had normal occlusion postoperatively and only one patient (type C) reported pain. Magnetic resonance imaging and computed tomography showed good osseous healing and disc condylar relations in all cases. Our results show that this new classification of intracapsular condylar fractures is a safe and easy way to obtain satisfactory outcomes of treatment. However, it needs further independent validation. PMID- 29395455 TI - General Data Protection Regulation (GDPR) and implications for research. PMID- 29395456 TI - Managing excessive alcohol consumption at a population level: The earlier the better. PMID- 29395457 TI - Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life. AB - BACKGROUND & AIMS: High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease. METHODS: We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied. RESULTS: During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01 1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day. CONCLUSION: Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised. LAY SUMMARY: We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more. PMID- 29395458 TI - Corrigendum to "Alfapump(r) system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study" [J Hepatol 67 (2017) 940 949]. PMID- 29395459 TI - Dosimetric comparison of sector-blocked and non-sector-blocked Gamma Knife Perfexion treatment plans for trigeminal neuralgia. AB - The purpose of this study is to compare the quality of trigeminal neuralgia (TN) treatment plans with and without utilizing sector blocking. Twelve patients with 13 cases of TN were evaluated in this retrospective study. Identical magnetic resonance imaging (MRI) contour sets and prescription doses used in treatments were reused for all plans. Treatment plans were compared on the basis of the amount of dose received by critical structures (i.e., brainstem, ipsilateral temporal lobe, optic chiasm, optic nerves, cochlea) and the estimated total treatment time. The use of sector blocking resulted in a statistically significant decrease in the radiation dose to the brainstem but increased doses to the cerebellum and temporal lobe regions. The magnitude of these differences was small and individual patient anatomy specific. The use of sector blocking also resulted in a statistically significant increase in the treatment time. The magnitude of the change in treatment time was dependent on the number of sectors blocked. Our study suggests some potential benefits, as well as disadvantages, to the use of sector blocking in the treatment of TN. Treatment decision needs to be individualized based on the patient's anatomy and overall condition. PMID- 29395460 TI - Risk factors for radiotherapy incidents: a single institutional experience. AB - We aimed to analyze risk factors for incidents occurring during the practice of external beam radiotherapy (EBRT) at a single Japanese center. Treatment data for EBRT from June 2014 to March 2017 were collected. Data from incident reports submitted during this period were reviewed. Near-miss cases were not included. Risk factors for incidents, including patient characteristics and treatment related factors, were explored using uni- and multivariate analyses. Factors contributing to each incident were also retrospectively categorized according to the recommendations of the American Association of Physicists in Medicine (AAPM). A total of 2887 patients were treated during the study period, and 26 incidents occurred (0.90% per patient). Previous history of radiotherapy and large fraction size were identified as risk factors for incidents by univariate analysis. Only previous history of radiotherapy was detected as a risk factor in multivariate analysis. Identified categories of contributing factors were human behavior (50.0%), communication (40.6%), and technical (9.4%). The incident rate of EBRT was 0.90% per patient in our institution. Previous history of radiotherapy and large fraction size were detected as risk factors for incidents. Human behavior and communication errors were identified as contributing factors for most incidents. PMID- 29395461 TI - Comparison of the verification performance and radiation dose between ExacTrac x ray system and On-Board Imager-A phantom study. AB - Recently, On-Board Imager (OBI) and ExacTrac x-ray 6 degree-of-freedom system (ExacTrac) are increasingly used verification systems in local radiotherapy centers. This study aimed to compare the differences between these two systems in terms of verification accuracy, organ doses, and verification time for head-and neck (H&N) and pelvic cases. Rando anthropomorphic phantoms of H&N and pelvic regions were positioned with known set-up deviations from the reference position in the linear accelerator. x-Ray verification images were then acquired using both systems. Verification accuracy was evaluated based on the residual positioning error (deltaD) after image registration. Thermoluminescence dose meters (TLD-100s) were placed in specific locations of the phantoms for the measurement of imaging doses at the organs of interest. Besides, the verification time was also recorded for comparison. Most average detection errors for both systems were within 1 mm. The detection error of ExacTrac was significantly larger than OBI in the H&N region in all directions (p < 0.05), but was significantly lower in the pelvis (p < 0.05). The mean imaging doses to all organs of interest from ExacTrac were significantly lower than OBI (p < 0.05). The mean verification time for ExacTrac was about 10 seconds, which was significantly shorter than the 100 seconds in OBI (p < 0.001). Both verification systems achieved satisfactory performance in the H&N and pelvic regions despite ExacTrac being better in terms of verification time and organ dose. The verification accuracy of Exactrac was better in pelvic region than the H&N region when compared with OBI. PMID- 29395462 TI - A feasibility study of independent verification of dose calculation for Vero4DRT using a Clarkson-based algorithm. AB - Dose verification for a gimbal-mounted image-guided radiotherapy system, Vero4DRT (Mitsubishi Heavy Industries Ltd., Tokyo, Japan) is usually carried out by pretreatment measurement. Independent verification calculations using Monte Carlo methods for Vero4DRT have been published. As the Clarkson method is faster and easier to use than measurement and Monte Carlo methods, we evaluated the accuracy of an independent calculation verification program and its feasibility as a secondary check for Vero4DRT. Computed tomography (CT)-based dose calculation was performed using a modified Clarkson-based algorithm. In this study, 120 patients' treatment plans were collected in our institute. The treatments were performed using conventional irradiation for lung and prostate, 3-dimensional (3D) conformal stereotactic body radiotherapy (SBRT) for the lung, and intensity modulated radiation therapy (IMRT) for the prostate. Differences between the treatment planning system (TPS) and the Clarkson-based independent dose verification software were computed, and confidence limits (CLs, mean +/- 2 standard deviation %) for Vero4DRT were compared with the CLs for the C-arms linear accelerators in the previous study. The results of the CLs, the conventional irradiation, SBRT, and IMRT showed 2.2 +/- 3.5% (CL of the C-arms linear accelerators: 2.4 +/- 5.3%), 1.1 +/- 1.7% (-0.3 +/- 2.0%), 4.8 +/- 3.7% (5.4 +/- 5.3%), and -0.5 +/- 2.5% (-0.1 +/- 3.6%) differences, respectively. The dose disagreement between the TPS and CT-based independent dose verification software was less than the 5% action level of American Association of Physicists in Medicine (AAPM) Task Group 114 (TG114). The CLs for the gimbal-mounted Vero4DRT were similar to the deviations for C-arms linear accelerators. PMID- 29395463 TI - Uncovering Hereditary Tumor Syndromes: Emerging Role of Surgical Pathology. AB - With the increased use of modern next generation sequencing technologies in routine molecular pathology practice, the proportion of cancer cases with a definite or probable hereditary background seems to be steadily increasing. Currently, it is assumed that >=10% of all malignancies develop in the setting of germline predisposition. Diagnosis and recognition of cancer predisposition syndromes relies not rarely on distinctive histopathological features that proved to be highly valuable and reproducible in uncovering those diseases that would otherwise have gone undetected by clinicians as being hereditary in nature. This is especially true in case of new mutations without suspicious family history. Example of such entities are fumarate hydratase-deficient renal cell carcinoma (RCC), succinate dehydrogenase-deficient RCC, hereditary gastrointestinal stromal tumor syndromes and many other diseases. It is remarkable that many of these inherited cancer syndromes do present as unifocal disease with highly variable age of onset so that many of them are misinterpreted as sporadic on clinical grounds. Availability of specialized cancer screening programs and disease specific follow-up schemes for several hereditary cancer syndromes encourages the recognition of such disorders, so that "at risk patients" can be enrolled in such programs for early detection and timely intervention/ treatment of these malignancies which are in the majority of cases aggressive. In several conditions, as in familial adenomatous polyposis coli (FAP), well established prophylactic surgical interventions may be adopted to prevent the disease manifestations, highlighting the importance of the timely recognition of these potentially life-limiting neoplasms. In this review, the clinicopathological, demographic and histological features that are considered highly suggestive of a hereditary basis of "a neoplasm under consideration" are highlighted and discussed briefly. The details of some of these entities are in addition dealt with in reviews devoted to them in this special issue. PMID- 29395464 TI - In vivo automated quantification of thermally damaged human tissue using polarization sensitive optical coherence tomography. AB - Over the decades numerous technologies have been performed for the quantification of skin injuries, but their poor sensitivity, specificity and accuracy limits their applications. Optical coherence tomography (OCT) can be potential tool for the identification but the modern high-speed OCT system acquires huge amount of data, which will be very time-consuming and tedious process for human interpretation. Our proposed method opens the possibility of fully automated quantitative analysis based on morphological features of thermally damaged tissue, which will become biomarker for the removal of non-viable skin. The proposed method is based on multi-level ensemble classifier by dissociating morphological features (A-line, B-scan, phase images) extracted from Polarization Sensitive Optical Coherence Tomography (PS-OCT) images. Our proposed classifier attained the average sensitivity, specificity and accuracy is 92.22%, 87.2% and 92.5%, respectively, in detecting the thermally damaged human skin. Moreover, we show that our classifier is one of the best possible classifier based on features extracted from PS-OCT images, which demonstrates the significance of PS-OCT data in detecting abnormality in human skin. PMID- 29395465 TI - Corrigendum to "Beyond war and PTSD: The crucial role of transition stress in the lives of military veterans" [Clin. Psychol. Rev. 59 (2018) 137-144]. PMID- 29395466 TI - Diagnostic difficulties in cases of papillary urothelial neoplasm of low malignant potential, urothelial proliferation of uncertain malignant potential, urothelial dysplasia and urothelial papilloma: A review of current literature. AB - Tumours of the urinary tract are the fifth most frequent type of cancer. The most common types are urothelial tumours, among which, non-invasive urothelial neoplasms represent 45% of all cases. The 2016 WHO classification of urinary tract tumours introduced new classifications of non-invasive lesions. Besides urothelial papilloma (UP) and papillary urothelial neoplasm of low malignant potential (PUNLMP), as described in the former classification, the new classification also includes new entities such as urothelial proliferation of uncertain malignant potential (UPUMP) and urothelial dysplasia (UD). Of the aforementioned, UPUMP is the lesion that most commonly progresses, but solely to non-invasive carcinomas. UD is associated with a high risk of progression to invasive carcinoma. Understanding the biological character, and establishing the correct differential diagnosis in cases of non-invasive, non-cancerous lesions of the urinary bladder, will be of importance in establishing outcome predictions for future patients. A systematic review of the current literature allows us to systematize genetic, morphologic and prognostic factors of such lesions. Moreover, the collected data provide the basis for a proposed diagnostic algorithm which facilitates quick and effective differential diagnoses in cases of non-invasive non-cancerous urinary bladder lesions. PMID- 29395467 TI - Zirconia toughened mica glass ceramics for dental restorations. AB - OBJECTIVE: The objective of the present study is to understand the role of yttria stabilized zirconia (YSZ) in achieving the desired spectrum of clinically relevant mechanical properties (hardness, elastic modulus, fracture toughness and brittleness index) and chemical solubility of mica glass ceramics. METHODS: The glass-zirconia mixtures with varying amounts of YSZ (0, 5, 10, 15 and 20wt.%) were ball milled, compacted and sintered to obtain pellets of glass ceramic-YSZ composites. Phase analysis was carried out using X-ray diffraction and microstructural characterization with SEM revealed the crystal morphology of the composites. Mechanical properties such as Vickers hardness, elastic modulus, indentation fracture toughness and chemical solubility were assessed. RESULTS: Phase analysis of sintered pellets of glass ceramic-YSZ composites revealed the characteristic peaks of fluorophlogopite (FPP) and tetragonal zirconia. Microstructural investigation showed plate and lath-like interlocking mica crystals with embedded zirconia. Vickers hardness of 9.2GPa, elastic modulus of 125GPa, indentation toughness of 3.6MPa.m1/2, and chemical solubility of 30MUg/cm2 (well below the permissible limit) were recorded with mica glass ceramics containing 20wt.% YSZ. SIGNIFICANCE: An increase in hardness and toughness of the glass ceramic-YSZ composites with no compromise on their brittleness index and chemical solubility has been observed. Such spectrum of properties can be utilised for developing a machinable ceramic for low stress bearing inlays, onlays and veneers. PMID- 29395468 TI - Development of a novel dental resin cement incorporating FGF-2-loaded polymer particles with the ability to promote tissue regeneration. AB - OBJECTIVE: Aiming to achieve bioactive dental resins that promote healing of surrounding tissues, we developed novel poly(2-hydroxyethyl methacrylate/trimethylolpropane trimethacrylate) (polyHEMA/TMPT) particles. These particles have been reported to be useful as a non-biodegradable carrier for fibroblast growth factor-2 (FGF-2) in vitro. The aim of this study was to evaluate the ability of an adhesive resin incorporating FGF-2-loaded polymer particles to promote tissue regeneration in vitro and in vivo. METHODS: Experimental adhesive resins were prepared by incorporating FGF-2-loaded polyHEMA/TMPT particles into a 4-META/MMA-based adhesive resin, and the release profiles of FGF-2 were evaluated. The proliferation of osteoblast-like cells in the eluate from cured experimental resin was assessed. When the experimental resin was implanted into rat calvaria defects, bone regeneration was evaluated by microcomputed tomography and histological observations. RESULTS: Sustained release of FGF-2 from the experimental resin was observed for 14 days. Eluate from the cured experimental resin significantly promoted the proliferation of osteoblast-like cells. Significantly greater bone regeneration was observed using the experimental resin compared with the control resin without FGF-2. SIGNIFICANCE: 4-META/MMA-based adhesive resin incorporating FGF-2-loaded polymer particles is useful to promote tissue regeneration, suggesting that its application would be beneficial for root-end filling or the repair of fractured roots in cases with severely damaged periodontal tissue. PMID- 29395469 TI - 8DSS peptide induced effective dentinal tubule occlusion in vitro. AB - OBJECTIVE: Eight repetitive nucleotide sequences of aspartate-serine-serine (8DSS) derived from dentin phosphoprotein (DPP) has been proved to be a good remineralization agency. In this study, 8DSS peptide was employed to induce dentinal tubule occlusion. METHODS: Dentin samples were acid-etched, and then the samples were coated with 8DSS solution. The binding capacity of 8DSS to acid etched dentin was tested by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Subsequently, the 8DSS-treated dentin samples were immersed in artificial saliva for 1, 2 and 4 weeks. After 4 weeks, the remineralized dentin was treated with 6wt% citric acid (pH 1.5) solution for 1min. Dentin permeability measurement and scanning electron microscopy (SEM) were carried out after different periods. Energy dispersive spectroscopy (EDS) and X ray diffraction (XRD) were used to identify the mineral phase of the regenerated minerals. RESULTS: The results showed that 8DSS had a good binding capacity to the acid-etched dentin, and significantly reduced the dentin permeability by inducing minerals deposited within the dentinal tubules. After 4 weeks, all the dentinal tubules were occluded by large bulk of regenerated minerals, which largely decreased the diameters of the tubules. The regenerated minerals deposited with a deep depth within the dentinal tubules, ensuring an effective occlusion even after an acid challenge. The results of XRD and EDS confirmed that the regenerated minerals were mainly hydroxyapatite (HA). SIGNIFICANCE: 8DSS peptide induced strong dentinal tubule occlusion. 8DSS have a great potential to be used in the treatment of dentin hypersensitivity in the future. PMID- 29395470 TI - Influence of thread shape and inclination on the biomechanical behaviour of plateau implant systems. AB - OBJECTIVE: To assess the influence of implant thread shape and inclination on the mechanical behaviour of bone-implant systems. The study assesses which factors influence the initial and full osseointegration stages. METHODS: Point clouds of the original implant were created using a non-contact reverse engineering technique. A 3D tessellated surface was created using Geomagic Studio(r) software. From cross-section curves, generated by intersecting the tessellated model and cutting-planes, a 3D parametric CAD model was created using SolidWorks(r) 2017. By the permutation of three thread shapes (rectangular, 30 degrees trapezoidal, 45 degrees trapezoidal) and three thread inclinations (0 degrees , 3 degrees or 6 degrees ), nine geometric configurations were obtained. Two different osseointegration stages were analysed: the initial osseointegration and a full osseointegration. In total, 18 different FE models were analysed and two load conditions were applied to each model. The mechanical behaviour of the models was analysed by Finite Element (FE) Analysis using ANSYS(r) v. 17.0. Static linear analyses were also carried out. RESULTS: ANOVA was used to assess the influence of each factor. Models with a rectangular thread and 6 degrees inclination provided the best results and reduced displacement in the initial osseointegration stages up to 4.58%. This configuration also reduced equivalent VM stress peaks up to 54%. The same effect was confirmed for the full osseointegration stage, where 6 degrees inclination reduced stress peaks by up to 62%. SIGNIFICANCE: The FE analysis confirmed the beneficial effect of thread inclination, reducing the displacement in immediate post-operative conditions and equivalent VM stress peaks. Thread shape does not significantly influence the mechanical behaviour of bone-implant systems but contributes to reducing stress peaks in the trabecular bone in both the initial and full osseointegration stages. PMID- 29395471 TI - Multitechnique characterization of conventional and experimental Ag-based brazing alloys for orthodontic applications. AB - OBJECTIVES: To characterize the microstructure, mechanical properties, ionic release and tarnish resistance of conventional and experimental Ag-based soldering alloys for orthodontic applications. METHODS: Disk shaped specimens were prepared from four commercial Ag based soldering alloys [Dentaurum Universal Silver Solder (DEN), Orthodontic Solders (LEO), Ortho Dental Universal Solder (NOB), and Silver Solder (ORT)] and four experimental alloys Ag12Ga, Ag10Ga5Sn, Ag20In and Ag7Sn. The elemental composition and microstructure was determined by SEM/EDX and XRD analysis, while the mechanical properties were determined by Instrumented Indentation Testing. Ionic release of Ag, Cu, Zn, Ga, In and Sn was determined by ICP-EAS in 0.9% NaCl and Ringer's solutions after 28, 49 and 70 days. Tarnish resistance was also tested and colorimetry was applied to quantify the differences in color (DE) before and after immersion in testing media. DSC was used to determine the melting range of the experimental alloys. Mechanical properties, ionic release and DE were statistically compared by ANOVA and Holm Sidak multiple comparison test (a=0.05). RESULTS: All commercially alloys belong to the Ag-Zn-Cu ternary system and consist a Ag rich face centered cubic (FCC) and Cu (FCC) phase. The former is the predominant phase also in experimental alloys. Conventional alloys demonstrated higherhardness, less ductility and lower melting rangers compared to experimental alloys. Immersion testing revealed the release of Cu and Zn ions from the commercially alloys and Ga ions from AgGa and AgGaSn while no ionic release was identified for AgIn and AgSn. All alloys failed tarnish testing according to ISO 10271 showing DE values much higher than the clinical acceptable limit (3.7). SIGNIFICANCE: The conventional Ag based soldering alloys showed substantial differences in their microstructure, mechanical properties and ionic release, and thus different clinical performance is anticipated. Ga, Sn and In might be employed as alloying addition to modify the properties of Ag brazing alloys. PMID- 29395472 TI - Strength and fracture toughness of zirconia dental ceramics. AB - OBJECTIVE: The aim of the paper is to determine and discuss the correlation between the fracture toughness and the fracture stress in zirconia transforming ceramics with a small artificial crack. As an R-curve behaviour is usually present in transforming ceramics for both small and long cracks, predictions of the fracture stress can only be done with an accurate knowledge of the R-curve and crack dimensions. METHODS: First, basic concepts of fracture mechanics, strength and testing of ceramic materials are introduced. This is followed by a very brief introduction to zirconia dental ceramics and to strength degradation by hydrothermal ageing of 3Y-TZP. Fracture toughness of 3Y-TZP and 12Ce-TZP are then determined for a short (~50MUm) sharp edge crack produced by ultra short pulsed laser ablation on prismatic bending bars in four point bending. The crack size is small but large enough for controlling fracture and for applying elastic fracture mechanics. RESULTS: In both materials the determined fracture toughness is similar, in spite of their difference R-curves. The results of fracture toughness and fracture stress are analysed by using a simple function to represent the R-curve, but which contains the main ingredients of experimental R curves extracted from the literature either for short or long cracks in 12Ce-TZP. SIGNIFICANCE: It is concluded that the high R-curves reported in the literature for long and short cracks in 12Ce-TZP and 3Y-TZP might have only a marginal influence on the fracture resistance with cracks of the size studied. This effect is of more significance in 12Ce-TZP. The use of an ideal and simple model of R curve is presented as a useful guide to predict whether the fracture stress will be enhanced by an existent R-curve. PMID- 29395473 TI - Application of radiopaque micro-particle fillers for 3-D imaging of periodontal pocket analogues using cone beam CT. AB - BACKGROUND: Periodontitis is an infectious/inflammatory disease most often diagnosed by deepening of the gingival sulcus, which leads to periodontal pockets (PPs) conventional manual periodontal probing does not provide detailed information on the three-dimensional (3-D) nature of PPs. OBJECTIVES: To determine whether accurate 3-D analyses of the depths and volumes of calibrated PP analogues (PPAs) can be obtained by conventional cone beam computed tomography (CBCT) coupled with novel radiopaque micro-particle fillers (described in the companion paper) injected into the PPAs. METHODS: Two PPA models were employed: (1) a human skull model with artificial gingiva applied to teeth with alveolar bone loss and calibrated PPAs, and (2) a pig jaw model with alveolar bone loss and surgically-induced PPAs The PPAs were filled with controlled amounts of radiopaque micro-particle filler using volumetric pipetting Inter-method and intra-method agreement tests were then used to compare the PPA depths and volumes obtained from CBCT images with values obtained by masked examiners using calibrated manual methods. RESULTS: Significant inter-method agreement (0.938 0.991) and intra-method agreement (0.94-0.99) were obtained when comparing analog manual data to digital CBCT measurements enabled by the radiopaque filler. SIGNIFICANCE: CBCT imaging with radiopaque micro-particle fillers is a plausible means of visualizing and digitally assessing the depths, volumes, and 3-D shapes of PPs This approach could transform the diagnosis and treatment planning of periodontal disease, with particular initial utility in complex cases Efforts to confirm the clinical practicality of these fillers are currently in progress. PMID- 29395474 TI - Fatigue resistance of all-ceramic fixed partial dentures - Fatigue tests and finite element analysis. AB - OBJECTIVE: To estimate the fatigue resistance of a new translucent zirconia material in comparison to lithium disilicate for 3-unit fixed partial dentures (FPDs). METHODS: Eighteen 3-unit FPDs (replacement of first upper molar) with a connector size of 4mm*4mm were dry milled with a five-axis milling machine (Zenotec Select, Wieland, Germany) using discs made of a new translucent zirconia material (IPS e.max ZirCAD MT, Ivoclar Vivadent). Another 9 FPDs with a reduced connector size (3mm*4mm) were milled. The zirconia FPDs were sintered at 1500 degrees C. For a comparison, 9 FPDs were made of IPS e.max Press, using the same dimensions. These IPS e.max Press FPDs were ground from a wax disc (Wieland), invested and pressed at 920 degrees C. All FPDs were glazed twice. The FPDs were adhesively luted to PMMA dies with Multilink Automix. Dynamic cyclic loading was carried out on the molar pontic using Dyna-Mess testing machines (Stolberg, Germany) with 2*106 cycles at 2Hz in water (37 degrees C). Two specimens per group and load were subjected to decreasing load levels (at least 4) until the two specimens no longer showed any failures. Another third specimen was subjected to this load to confirm the result. All the specimens were evaluated under a stereo microscope (20* magnification). The number of cycles reached before observing a failure, and their dependence on the load and on the material, were modeled, using a Weibull model. This made it possible to estimate the fatigue resistance as the maximum load for which one would observe less than 1% failure after 2*106 cycles. In addition to the experimental study, Finite Element Modeling (FEM) simulations were conducted to predict the force to failure for IPS e.max ZirCAD MT and IPS e.max Press with a reduced cross-section of the connectors. RESULTS: The failure mode of the zirconia FPDs was mostly the fracture of the distal connector, whereas the failure mode of the lithium disilicate FPDs observed to be the fracture of the connectors or multiple cracks of the pontic. The fatigue resistance with 1% fracture probability was estimated to be 488N for the IPS e.max ZirCAD MT FPDs (453N for repeated test), 365N for IPS e.max ZirCAD MT FPDs with reduced connector size and 286N for the e.max Press FPDs. All three IPS e.max ZirCAD groups statistically performed significantly better than IPS e.max Press (p<0.001). On the other hand, no significant difference could be established between the two IPS e.max ZirCAD MT3 groups with a 4mm*4mm connector size (p>0.05). The allowable maximum principal stress (sigmamax) which did not lead to failure during fatigue testing for IPS e.max ZirCAD MT3 was calculated between 208MPa and 223MPa for FPDs with 4mm*4mm connectors for 2*106 cycles. This value could also be verified for the FPDs of the same material with 3mm*4mm connectors. On the other hand fatigue strength in terms of sigmamax at 2*106 cycles of IPS e.max Press was calculated to be between 78 and 90MPa. SIGNIFICANCE: The fatigue resistance of the translucent zirconia 3 unit FPDs was about 60-70% higher than that of the lithium disilicate 3-unit FPDs, which may justify their use for molar replacements, provided that a minimal connector size of 4mm*4mm is observed. Even with a limited number of specimens (n=9) per group it was possible to statistically differentiate between the tested groups. PMID- 29395475 TI - A systematic review of parents' experiences and information needs related to their child's urinary tract infection. AB - OBJECTIVE: As a first step toward the development of an animated video and infographic to increase parents' knowledge of pediatric urinary tract infections (UTIs), we conducted a systematic review of their experiences and information needs. METHODS: We searched Ovid Medline, Ovid PsycINFO, CINAHL, and ProQuest Dissertations and Theses Global for studies published in 2000 or thereafter. We appraised quality using the Mixed Methods Appraisal Tool. We summarised the quantitative data narratively and the qualitative data thematically. RESULTS: We identified 1493 records and included four. Sample size ranged from 20 to 2726 parents. The children ranged from <1 to 12 years old and had experienced one to >10 UTIs. Parents were not always aware of UTI symptoms and generally received little information. Parents sought information online, and desired it via other means. Some parents were not confident in healthcare providers' (HCPs') knowledge of UTIs. Inadequate information about diagnostic tests sometimes resulted in fear and non-compliance. CONCLUSIONS: From the limited literature, it appears that parents would like information about prevention, diagnosis, treatment, and prognosis, but do not always consider HCPs good information sources. PRACTICE IMPLICATIONS: Care providers should communicate information in ways that suit parents' self-identified needs. PMID- 29395476 TI - Exploring patient-centeredness: The relationship between self-reported empathy and patient-centered communication in medical trainees. AB - OBJECTIVE: To explore the relationships between self-reported Empathy and the patient-centered communication patterns of physician trainees. METHODS: "Eighty four 3rd year medical students completed the Jefferson Scale of Empathy (JSE - student version) and had recordings of a single OSCE analyzed using the Roter Interactional Analysis System (RIAS). Correlation and regression were employed to explore the relationships among JSE total score, 3 JSE subscales, 10 composite codes of provider communication, and a summary 'patient centered communication' ratio, reflecting the balance of psychosocial and emotional to biomedical communication of the simulated patient and student. RESULTS: Results indicate that controlling for other elements of student communication, the RIAS composite of codes reflecting 'emotional responsiveness' (characterized by empathy statements, legitimization, showing concern, partnership statements and medically relevant provider self-disclosure) was positively related to the JSE Total Score while student 'question asking' and 'biomedical counseling' were negatively related to the JSE Score. RIAS-coded communication variables accounted for 32.4% of the JSE Total score. CONCLUSION: The relationship between student expressions of emotional responsiveness and predicted self-reported empathy provides concurrent validation evidence for the JSE. PRACTICE IMPLICATIONS: Further research is needed in order to elaborate and further explore a Patient Centeredness latent variable. PMID- 29395477 TI - WWW mesothelioma information: Surfing on unreliable waters. A cross-sectional study into the content and quality of online informational resources for mesothelioma patients. AB - OBJECTIVE: Malignant Mesothelioma (MM) is a rare asbestos related disease mostly diagnosed in low-skilled patients. The decision-making process for MM treatment is complicated, making an adequate provision of information necessary. The objective of this study is to assess the content and quality of online informational resources available for Dutch MM patients. METHODS: The first 100 hits of a Google search were studied using the JAMA benchmarks, the Modified Information Score (MIS) and the International Patient Decision Aid Standard Scoring (IPDAS). RESULTS: A total of 37 sources were included. Six of the 37 resources were published by hospitals. On average, the informational resources scored 37 points on the MIS (scale 0-100). The resources from a (bio)medical sources scored the best on this scale. However, on the domain of use of language, these resources scored the worst. CONCLUSIONS: The current level of medical content and quality of online informational resources for patient with MM is below average and cannot be used as decision-aids for patients. PRACTICE IMPLICATIONS: The criteria used in this article could be used for future improvements of online informational resources for patients, both online, offline and through health education in the care path. PMID- 29395478 TI - Understanding organellar protein folding capacities and assessing their pharmacological modulation by small molecules. AB - Dysfunctional organellar protein quality control machinery leads to protein misfolding associated cardiovascular, neurodegenerative, metabolic and secretory disorders. To understand organellar homeostasis, suitable tools are required which can sense changes in their respective protein folding capacity upon exposure to environmental and pharmacological perturbations. Herein, we have assessed protein folding capacity of cellular organelles using a metastable sensor selectively targeted to cytosol, nucleus, mitochondria, endoplasmic reticulum, golgi and peroxisomes. Microscopy and biochemical data revealed that these sensors report both acute and organelle-specific cellular insults. It also provided insights into contrasting refolding capacities of cellular organelles to recover from proteotoxic challenges. Further, we used these metastable sensors to evaluate pharmacological modulation of organellar protein folding capacity by small molecules. We observed pyrazole based scaffolds increased organellar protein folding capacity through upregulation of chaperones, mainly HSP90 and its co-chaperone HOP which coordinate refolding of misfolded/aggregated species. Overall, our data highlights the potential use of organelle-specific metastable sensors to understand protein folding capacity of sub-cellular compartments and assess pharmacological correction of their proteostasis imbalance. This study also provides additional avenue for use of these organelle-specific metastable sensors in drug discovery programs for identification of novel pharmacophores and drug repositioning of promising scaffolds for protein conformational diseases associated with different cellular organelles. PMID- 29395479 TI - Insufficient Apaf-1 expression in early stages of neural differentiation of human embryonic stem cells might protect them from apoptosis. AB - Recent evidence suggests that mitochondrial apoptosis regulators and executioners may regulate differentiation, without being involved in cell death. However, the involved factors and their roles in differentiation and apoptosis are still not fully determined. In the present study, we compared mitochondrial pathway of cell death during early neural differentiation from human embryonic stem cells (hESCs). Our results demonstrated that ROS generation, cytosolic cytochrome c release, caspases activation and rise in p53 protein level occurred upon either neural or apoptosis induction in hESCs. However, unlike apoptosis, no remarkable increase in apoptotic protease activating factor-1 (Apaf-1) level at early stages of differentiation was observed. Also the caspase-like activity of caspase-9 and caspase-3/7 were seen less than apoptosis. The results suggest that low levels of Apaf-1 as an adaptor protein might be considered as a possible regulatory barrier by which differentiating cells control cell death upon rise in ROS production and cytochrome c release from mitochondria. Better understanding of mechanisms via which mitochondria-mediated apoptotic pathway promote neural differentiation can result in development of novel therapeutic approaches. PMID- 29395480 TI - Melanopsin and rhodopsin mediate UVA-induced immediate pigment darkening: Unravelling the photosensitive system of the skin. AB - The mammalian skin has a photosensitive system comprised by several opsins, including rhodopsin (OPN2) and melanopsin (OPN4). Recently, our group showed that UVA (4.4 kJ/m2) leads to immediate pigment darkening (IPD) in murine normal and malignant melanocytes. We show the role of OPN2 and OPN4 as UVA sensors: UVA induced IPD was fully abolished when OPN4 was pharmacologically inhibited by AA9253 or when OPN2 and OPN4 were knocked down by siRNA in both cell lines. Our data, however, demonstrate that phospholipase C/protein kinase C pathway, a classical OPN4 pathway, is not involved in UVA-induced IPD in either cell line. Nonetheless, in both cell types we have shown that: a) intracellular calcium signal is necessary for UVA-induced IPD; b) the involvement of CaMK II, whose inhibition, abolished the UVA-induced IPD; c) the role of CAMK II/NOS/sGC/cGMP pathway in the process since inhibition of either NOS or sGC abolished the UVA induced IPD. Taken altogether, we show that OPN2 and OPN4 participate in IPD induced by UVA in murine normal and malignant melanocytes through a conserved common pathway. Interestingly, upon knockdown of OPN2 or OPN4, the UVA-driven IPD is completely lost, which suggests that both opsins are required and cooperatively signal in murine both cell lines. The participation of OPN2 and OPN4 system in UVA radiation-induced response, if proven to take place in human skin, may represent an interesting pharmacological target for the treatment of depigmentary disorders and skin-related cancer. PMID- 29395481 TI - Overexpression of the lamina proteins Lamin and Kugelkern induces specific ultrastructural alterations in the morphology of the nuclear envelope of intestinal stem cells and enterocytes. AB - The nuclear envelope has a stereotypic morphology consisting of a flat double layer of the inner and outer nuclear membrane, with interspersed nuclear pores. Underlying and tightly linked to the inner nuclear membrane is the nuclear lamina, a proteinous layer of intermediate filament proteins and associated proteins. Physiological, experimental or pathological alterations in the constitution of the lamina lead to changes in nuclear morphology, such as blebs and lobulations. It has so far remained unclear whether the morphological changes depend on the differentiation state and the specific lamina protein. Here we analysed the ultrastructural morphology of the nuclear envelope in intestinal stem cells and differentiated enterocytes in adult Drosophila flies, in which the proteins Lam, Kugelkern or a farnesylated variant of LamC were overexpressed. Surprisingly, we detected distinct morphological features specific for the respective protein. Lam induced envelopes with multiple layers of membrane and lamina, surrounding the whole nucleus whereas farnesylated LamC induced the formation of a thick fibrillary lamina. In contrast, Kugelkern induced single layered and double-layered intranuclear membrane structures, which are likely be derived from infoldings of the inner nuclear membrane or of the double layer of the envelope. PMID- 29395482 TI - Podocyte Infolding Glomerulopathy (PIG) in a Patient With Undifferentiated Connective Tissue Disease: A Case Report. AB - Podocyte infolding glomerulopathy (PIG) is a recently described pathologic entity characterized by diffuse podocyte infolding into the glomerular basement membrane (GBM) associated with ultrastructurally demonstrable microspherular aggregates. The clinical features, significance, and pathogenesis of this condition are still not well delineated because only a few cases have been documented to date, all from Japan. We report a case of PIG associated with undifferentiated connective tissue disease in an Indian woman who presented with nephrotic syndrome while undergoing treatment for an autoimmune disorder. Ultrastructural analysis of the kidney biopsy specimen revealed unusual subepithelial aggregates of microspherules admixed with few microtubules alongside extensive infolding of podocyte foot processes into the underlying GBMs. Characteristic clustering of these microparticles near the invaginated tips of podocyte foot processes in the GBM was observed on transmission electron microscopy. The patient's clinical condition responded favorably to immunosuppressive therapy. The clinical, light microscopic, and diagnostic electron microscopic features of this condition are highlighted in this report in an attempt to contribute some insights into the possible pathogenetic mechanisms of this obscure entity. PMID- 29395483 TI - One-Year Linear Trajectories of Symptoms, Physical Functioning, Cognitive Functioning, Emotional Well-being, and Spiritual Well-being Among Patients Receiving Dialysis. AB - BACKGROUND: This study evaluated 1-year linear trajectories of patient-reported dimensions of quality of life among patients receiving dialysis. STUDY DESIGN: Longitudinal observational study. SETTING & PARTICIPANTS: 227 patients recruited from 12 dialysis centers. FACTORS: Sociodemographic and clinical characteristics. MEASUREMENTS/OUTCOMES: Participants completed an hour-long interview monthly for 12 months. Each interview included patient-reported outcome measures of overall symptoms (Edmonton Symptom Assessment System), physical functioning (Activities of Daily Living/Instrumental Activities of Daily Living), cognitive functioning (Patient's Assessment of Own Functioning Inventory), emotional well-being (Center for Epidemiologic Studies Depression Scale, State Anxiety Inventory, and Positive and Negative Affect Schedule), and spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale). For each dimension, linear and generalized linear mixed-effects models were used. Linear trajectories of the 5 dimensions were jointly modeled as a multivariate outcome over time. RESULTS: Although dimension scores fluctuated greatly from month to month, overall symptoms, cognitive functioning, emotional well-being, and spiritual well-being improved over time. Older compared with younger participants reported higher scores across all dimensions (all P<0.05). Higher comorbidity scores were associated with worse scores in most dimensions (all P<0.01). Nonwhite participants reported better spiritual well-being compared with their white counterparts (P<0.01). Clustering analysis of dimension scores revealed 2 distinctive clusters. Cluster 1 was characterized by better scores than those of cluster 2 in nearly all dimensions at baseline and by gradual improvement over time. LIMITATIONS: Study was conducted in a single region of the United States and included mostly patients with high levels of function across the dimensions of quality of life studied. CONCLUSIONS: Multidimensional patient-reported quality of life varies widely from month to month regardless of whether overall trajectories improve or worsen over time. Additional research is needed to identify the best approaches to incorporate patient-reported outcome measures into dialysis care. PMID- 29395484 TI - Variation in Dialysis Exposure Prior to Nonpreemptive Living Donor Kidney Transplantation in the United States and Its Association With Allograft Outcomes. AB - BACKGROUND: The impact of dialysis exposure before nonpreemptive living donor kidney transplantation on allograft outcomes is uncertain. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult first-time recipients of kidney-only living donor transplants in the United States who were recorded within the Scientific Registry of Transplant Recipients for 2000 to 2016. FACTORS: Duration of pretransplantation dialysis exposure. OUTCOMES: Kidney transplant failure from any cause including death, death-censored transplant failure, and death with allograft function. RESULTS: Among the 77,607 living donor transplant recipients studied, longer pretransplantation dialysis exposure was independently associated with progressively higher risk for transplant failure from any cause, including death beginning 6 months after transplantation. Compared with patients with 0.1 to 3.0 months of dialysis exposure, the HR for transplant failure from any cause including death increased from 1.16 (95% CI, 1.07-1.31) among patients with 6.1 to 9.0 months of dialysis exposure to 1.60 (95% CI, 1.43-1.79) among patients with more than 60.0 months of dialysis exposure. Pretransplantation dialysis exposure varied markedly among centers; median exposures were 11.0 and 18.9 months for centers in the 10th and 90th percentiles of dialysis exposure, respectively. Centers with the highest proportions of living donor transplantations had the shortest pretransplantation dialysis exposures. In multivariable analysis, patients of black race, with low income, with nonprivate insurance, with less than high school education, and not working for income had longer pretransplantation dialysis exposures. Dialysis exposure in patients with these characteristics also varied 2-fold between transplantation centers. LIMITATIONS: Why longer dialysis exposure is associated with transplant failure could not be determined. CONCLUSIONS: Longer pretransplantation dialysis exposure in nonpreemptive living donor kidney transplantation is associated with increased risk for allograft failure. Pretransplantation dialysis exposure is associated with recipients' sociodemographic and transplantation centers' characteristics. Understanding whether limiting pretransplantation dialysis exposure could improve living donor transplant outcomes will require further study. PMID- 29395485 TI - Omega-3 Polyunsaturated Fatty Acid Supplementation to Prevent Arteriovenous Fistula and Graft Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Arteriovenous access failure frequently occurs in people on hemodialysis and is associated with morbidity, mortality and large healthcare expenditures. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) may improve access outcomes via pleiotropic effects on access maturation and function, but may cause bleeding complications. STUDY DESIGN: Systematic review with meta analysis. SETTING & POPULATION: Adults requiring hemodialysis via arteriovenous fistula or graft. SELECTION CRITERIA: Trials evaluating omega-3 PUFA for arteriovenous access outcomes identified by searches in CENTRAL, MEDLINE, and Embase to 24 January 2017. INTERVENTION: Omega-3 PUFA. OUTCOMES: Primary patency loss, dialysis suitability failure, access abandonment, interventions to maintain patency or assist maturation, bleeding, gastrointestinal side-effects, all-cause and cardiovascular mortality, hospitalization, and treatment adherence. Treatment effects were summarized as relative risks (RR) and 95% confidence intervals (CI). Evidence was assessed using GRADE. RESULTS: Five eligible trials (833 participants) with a median follow-up of 12 months compared peri-operative omega 3 PUFA supplementation with placebo. One trial (n=567) evaluated treatment for fistulae and four (n=266) for grafts. Omega-3 PUFA supplementation prevented primary patency loss with moderate certainty (761 participants, RR 0.81, CI 0.68 0.98). Low quality evidence suggested, that omega-3 PUFA may have had little or no effect on dialysis suitability failure (536 participants, RR 0.95, CI 0.73 1.23), access abandonment (732 participants, RR 0.78, CI 0.59-1.03), need for interventions (732 participants, RR 0.82, CI 0.64-1.04), or all-cause mortality (799 participants, RR 0.99, CI 0.51-1.92). Bleeding risk (793 participants, RR 1.40, CI 0.78-2.49) or gastrointestinal side-effects (816 participants, RR 1.22, CI 0.64-2.34) from treatment were uncertain. There was no evidence of different treatment effects for grafts and fistulae. LIMITATIONS: Small number and methodological limitations of included trials. CONCLUSIONS: Omega-3 PUFA supplementation probably protects against primary loss of arteriovenous access patency, but may have little or no effect on dialysis suitability failure, access interventions or access abandonment. Potential treatment harms are uncertain. PMID- 29395486 TI - The Value of Genetic Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and COL4A1 Mutations. AB - The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies on imaging criteria in the setting of a positive familial history. Molecular analysis, seldom used in clinical practice, identifies a causative mutation in >90% of cases in the genes PKD1, PKD2, or rarely GANAB. We report the clinical and genetic dissection of a 7-generation pedigree, resulting in the diagnosis of 2 different cystic disorders. Using targeted next-generation sequencing of 65 candidate genes in a patient with an ADPKD-like phenotype who lacked the familial PKD2 mutation, we identified a COL4A1 mutation (p.Gln247*) and made the diagnosis of HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome. While 4 individuals had ADPKD-PKD2, various COL4A1-related phenotypes were identified in 5 patients, and 3 individuals with likely digenic PKD2/COL4A1 disease reached end-stage renal disease at around 50 years of age, significantly earlier than observed for either monogenic disorder. Thus, using targeted next generation sequencing as part of the diagnostic approach in patients with cystic diseases provides differential diagnoses and identifies factors underlying disease variability. As specific therapies are rapidly developing for ADPKD, a precise etiologic diagnosis should be paramount for inclusion in therapeutic trials and optimal patient management. PMID- 29395487 TI - Co-variation of fatigue and psychobiological stress in couples' everyday life. AB - OBJECTIVE: There is limited knowledge about how fatigue develops and worsens and what influences fluctuations in daily fatigue. Stress was found to influence fatigue, and being in a relationship seems to either increase or decrease stress depending on the couple interaction. In this study, co-variation of fatigue, self reported stress, and biological stress markers in couples' everyday lives was investigated. Specifically, we examined a) whether momentary couple interactions moderated dyadic outcomes and b) whether and how stress and relationship measures influenced individual momentary fatigue. METHODS: Forty heterosexual couples (age: 28 +/- 5 years) reported subjective fatigue and stress levels 4 times a day for 5 consecutive days (1600 measures). Furthermore, participants reported whether they had interacted with their partner since the last data entry and, if so, they rated the valence of this interaction. Salivary cortisol (a measure of HPA axis activity) and alpha amylase (a measure of ANS activity) were analyzed as biological stress markers from saliva samples obtained at the same time points. Moment-to-moment data were analyzed using dyadic multilevel models to account for the nested design. RESULTS: Stress (women and men: p <= 0.001) and fatigue (women: p = .003, men: p = .020) showed patterns of co-variation within couples, especially if partners had interacted with each other since the previous data entry. Cortisol was also found to co-vary between partners (women: unstandardized coefficient (UC) = 0.12, p <= .001, men: UC = 0.18, p <= .001), whereas the regulation of alpha-amylase levels depending on the partner's levels was only present in women (UC = 0.11, p = .002). Valence of couple interaction was negatively associated with fatigue (women: UC = -0.13, p <= .001, men: UC = 0.06, p = .011). There was no momentary association of fatigue with an individual's own or the partner's subjective or biological stress markers. CONCLUSIONS: Fatigue and stress levels during the day seem to co-vary within couples. These associations were particularly strong when the partners had interacted with each other since the last measurement. These data underline the importance of social factors in fatigue and stress in everyday life. PMID- 29395489 TI - Multi-scale modeling of an upper respiratory airway: Effect of mucosal adhesion on Eustachian tube function in young children. AB - BACKGROUND: The Eustachian tube is a collapsible upper respiratory airway that is periodically opened to maintain a healthy middle ear. Young children, <10 years old, exhibit reduced Eustachian tube opening efficiency and are at risk for developing middle ear infections. Although these infections increase mucosal adhesion, it is not known how adhesion forces alters the biomechanics of Eustachian tube opening in young children. This study uses computational techniques to investigate how increased mucosal adhesion alters Eustachian tube function in young children. METHODS: Multi-scale finite element models were used to simulate the muscle-assisted opening of the Eustachian tube in healthy adults and young children. Airflow during opening was quantified as a function of adhesion strength, muscle forces and tissue mechanics. FINDINGS: Although Eustachian tube function was sensitive to increased mucosal adhesion in both adults and children, young children developed Eustachian tube dysfunction at significantly lower values of mucosal adhesion. Specifically, the critical adhesion value was 2 orders of magnitude lower in young children as compared to healthy adults. Although increased adhesion did not alter the sensitivity of Eustachian tube function to tensor and levator veli palatini muscles forces, increased adhesion in young children did reduced the sensitivity of Eustachian tube function to changes in cartilage and mucosal tissue stiffness. INTERPRETATIONS: These results indicate that increased mucosal adhesion can significantly alter the biomechanical mechanisms of Eustachian tube function in young children and that clinical assessment of adhesion levels may be important in therapy selection. PMID- 29395490 TI - Regional flow and deposition variability in adult female lungs: A numerical simulation pilot study. AB - BACKGROUND: Despite the promise of respiratory simulations improving diagnosis and treatment of pulmonary diseases, model predictions have yet to be translated into the clinical setting. Current state-of-the-art in silico models have not yet incorporated subject variability in their predictions of airflow distributions and extent of deposited particles. Until inter-subject variability is accounted for in lung modeling, it will remain impossible to translate model predictions into clinical practice. METHODS: Airflow and particle trajectories (dp=1,3,5MUm) are calculated in three subject-specific female adults by performing physiologically-based simulations. The computation framework features the ability to track air and particles throughout the respiration cycle and in the entire lung. Airway resistances, air velocities, and local deposition sites are correlated to airway anatomical features. FINDINGS: Smaller airway diameters are correlated to larger airway resistances and pressure gradients in one subject compared to the other two. Irregular shape of the airway and flow direction (e.g. inspiration or expiration) correspond with peak velocities and secondary flow motions. Largest subject variability in deposition between conducting and respiratory zones is seen for 1 MUm diameter particles. Little difference in total deposition is found among subjects. Localized deposited particle concentration hotspots are linked to airway anatomy and flow motion. INTERPRETATION: Simulation predictions provide a first look into the correlation of anatomical features with airflow characteristics and deposited particle concentrations. Global deposition percentages ranged (at most, by 20%) between subjects and variances in localized deposition hotspots are correlated to variances in flow characteristics. PMID- 29395488 TI - Anteroventral bed nuclei of the stria terminalis neurocircuitry: Towards an integration of HPA axis modulation with coping behaviors - Curt Richter Award Paper 2017. AB - A network of interconnected cell groups in the limbic forebrain regulates hypothalamic-pituitary-adrenal (HPA) axis activation and behavioral responses to emotionally stressful experiences, and chronic disruption of these systems chronically is implicated in the pathogenesis of psychiatric illnesses. A significant challenge has been to unravel the circuitry and mechanisms providing for regulation of HPA activity, as these limbic forebrain regions do not provide any direct innervation of HPA effector cell groups in the paraventricular hypothalamus (PVH). Moreover, information regarding how endocrine and behavioral responses are integrated has remained obscure. Here we summarize work from our laboratory showing that anteroventral (av) bed nuclei of the stria terminalis (BST) acts as a point of convergence between the limbic forebrain and PVH, receiving and coordinating upstream influences, and restraining HPA axis output in response to inescapable stressors. Recent studies highlight a more expansive modulatory role for avBST as one that coordinates HPA-inhibitory influences while concurrently suppressing passive behavioral responses via divergent pathways. avBST is uniquely positioned to convey endocrine and behavioral alterations resulting from chronic stress exposure, such as HPA axis hyperactivity and increased passive coping strategies, that may result from synaptic reorganization in upstream limbic cortical regions. We discuss how these studies give new insights into understanding the systems-level organization of stress response circuitry, the neurobiology of coping styles, and BST circuit dysfunction in stress-related psychiatric disorders. PMID- 29395491 TI - Epistasis analysis of metabolic genes polymorphisms associated with ischemic heart disease in Yucatan. AB - OBJECTIVE: Epistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischemic heart disease in Yucatan was determined. METHODS: Case control study in 79 Yucatecan patients with ischemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55M (paraoxonase 1; PON1), C677T, A1298C (methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (P<0.05), and cross validation consistency. RESULTS: We found an independent association of the null genotype GSTT1*0/0 (OR=3.39, CI: 1.29-8.87, P=0.017) and the null allele (OR=1.86, CI: 1.19-2.91, P=0.007) with ischemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene-environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR), and hypertension as the factors that best explain ischemic heart disease in the study population. CONCLUSIONS: The interaction of the MTHFR, GSTT1 and hypertension may constitute a predictive model of risk for early onset ischemic heart disease in the population of Yucatan. PMID- 29395492 TI - Evaluation of non-HDL cholesterol as a predictor of non-fatal cardiovascular events in a prospective population cohort. AB - INTRODUCTION: Non-HDL cholesterol (non-HDL-C) is becoming relevant both in its participation in cardiovascular risk assessment and as a therapeutic target. The objective of the present study was to assess the independent predictive capacity of both non-HDL-C and LDL-C (the main priority in dyslipidemias to reduce cardiovascular risk), in cardiovascular morbidity in a population-based sample. METHODS: A prospective cohort study involving 1186 individuals in the non-HDL-C group and 1177 in the LDL-C group, followed for 10.7years (SD=2.2), who had not had any previous cardiovascular event. The predictor variables included in the adjustment were: gender, age, arterial hypertension, diabetes mellitus, smoker status and non-HDL-C in one group. In the other group, consisting of patients presenting TG levels of 400mg/dL, non-HDL-C was replaced by LDL-C. Survival curves (Kaplan-Meier) were calculated and two Cox regression models were applied, one for each group. RESULTS: Non-HDL-C group presented 6.2% of non-fatal cardiovascular episodes during follow-up and the LDL-C group 6.0%. After adjustment, for each 30mg/dL increase in non-HDL-C, the incidence of new non fatal cardiovascular events increased by 31% (HR=1.31, 95%CI: 1.06-1.61; P=.018) and in the LDL-C group by 27% (HR=1.27, 95%CI: 0.97-1.61, P=.068). CONCLUSIONS: After a follow-up of 10.7years, non-HDL-C has been shown in our population as a prognostic factor of non-fatal cardiovascular disease, but not LDL-C, although its HR is close to statistical significance. PMID- 29395493 TI - Fibrates in the secondary prevention of cardiovascular disease (infarction and stroke). Results of a systematic review and meta-analysis of the Cochrane collaboration. AB - Fibrates are a group of drugs that are known mainly for reducing triglycerides, increasing high density lipoproteins (HDL), and reducing the fraction of small, dense LDL particles. The results of a Cochrane Collaboration study have recently been published on their efficacy and safety in the secondary prevention of severe cardiovascular accidents, including coronary and cerebrovascular disease. The study included randomised clinical trials in which the fibrate was compared with placebo or with no treatment. Clinical trials comparing two different fibrates were excluded. The clinical trials evaluated included a total of 16,112 patients (13 trials). The meta-analysis (including all the trials with fibrates) showed evidence of a protective effect of the fibrates compared with placebo as regards a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin (hazard ration of 0.88, with a 95% confidence interval of 0.83 to 0.94; in 16,064 individuals included in 12 studies). Thus, the results showed, with a moderate level of evidence, that fibrates could be effective in secondary prevention considering a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin. PMID- 29395494 TI - An increase in epicardial fat in women is associated with thrombotic risk. AB - INTRODUCTION: A decrease in fibrinolytic activity and an increase in the thickness of the epicardial adipose tissue have been observed in patients with coronary artery disease. The aim of this study was to determine the association between epicardial adipose tissue and fibrinolytic activity by measuring the concentration of plasminogen activator inhibitor-1 (PAI-1). METHODS: A cross sectional study was conducted on 56 apparently healthy women aged 45 to 60 years. Anthropometric measurements and biochemical determinations were performed on all participants. The fibrinolytic activity was determined by measuring PAI-1 by ELISA. Epicardial thickness was assessed by transthoracic echocardiography. RESULTS: The concentration of PAI-1 was directly associated with the thickness of the epicardial adipose tissue (r=0.475, P=.001), body mass index (BMI), visceral adipose tissue, insulin resistance, glucose, and HDL-cholesterol. The multivariate regression analysis indicated that epicardial fat independently predicts the concentrations of PAI-1. CONCLUSIONS: Women with thicker epicardial adipose tissue have reduced fibrinolytic activity, and consequently greater thrombotic risk. PMID- 29395495 TI - Influence of a physical exercise program on VO2max in adults with cardiovascular risk factors. AB - OBJECTIVE: The aim of the study was to assess the influence of a physical exercise program on VO2max in sedentary subjects with cardiovascular risk factors. MATERIALS AND METHODS: The sample was composed of 214 patients (80 males, 134 females) with an average age of 52 years, who were referred to a physical exercise program from 2 primary care centres of Spanish southeast. It was implemented a 10 week program (3 training*1h/week) combining strength with cardiorespiratory fitness. TheVO2max was analyzed through the Rockport Walk Test (RWT) comparing the pre and post program measurements. RESULTS: The results show significant improvements on VO2max for both genders (p<0,05). The most pronounced increase in VO2max was among males in the highest age band (56-73 years). CONCLUSIONS: Prescribing and referral exercise programs from primary care centers must be considered as a resource for improving cardiorespiratory fitness in the population studied. PMID- 29395496 TI - UGT polymorphisms and lamotrigine clearance during pregnancy. AB - OBJECTIVE: To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP). METHODS: Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus. RESULTS: Reductions in the LTG concentration-to dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between -53% and -74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: -53% (95%CI: -68% to -39%) versus -65% (95%CI: -69% to -60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were -64% in T2 (95%CI: -69% to -59%) and -67% in T3 (95%CI: -71% to -63%) in women who expected a female child compared to whose with a male child -58% in T2 (p = 0.002, 95%CI: 67% to -48%) and -57% in T3 (p < 0.001, 95%CI: -65% to -48%). CONCLUSION: Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance. PMID- 29395497 TI - Management of pregnant women with epilepsy who use lamotrigine. PMID- 29395498 TI - Teicoplanin-induced DRESS syndrome: The importance of skin tests. PMID- 29395499 TI - Reply to Mustafa Z. Temiz and Huseyin Besiroglu's Letter to the Editor re: Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur Urol 2017;72:910-7. PMID- 29395500 TI - Prostate Cancer Care and Practice Patterns: Low-quality Observations Miss the Benefits from High-quality Care. PMID- 29395501 TI - Genomic Classifiers in Renal Cell Carcinoma. PMID- 29395502 TI - Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial. AB - BACKGROUND: Adjuvant chemotherapy is standard treatment for other solid tumours, but to date has not proven effective in prostate cancer. OBJECTIVE: o evaluate whether six cycles of docetaxel alone improve biochemical disease-free survival after radical prostatectomy for high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomised multinational phase 3 trial. Enrolment of 459 patients after prostatectomy. INCLUSION CRITERIA: high-risk pT2 margin positive or pT3a Gleason score >=4+3, pT3b, or lymph node positive disease Gleason score >=3+4. Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75mg/m2 every 3 wk without daily prednisone (Arm A) or surveillance (Arm B) until endpoint was reached. Primary endpoint was prostate-specific antigen progression >=0.5 ng/ml. INTERVENTION: Docetaxel treatment after prostatectomy. RESULTS AND LIMITATIONS: Median time to progression, death, or last follow-up was 56.8 mo. Primary endpoint was reached in 190/459 patients-the risk of progression at 5 yr being 41% (45% in Arm A and 38% in Arm B). There was evidence of nonproportional hazards in Kaplan-Meier analysis, so we used the difference in restricted mean survival time as the primary estimate of effect. Restricted mean survival time to endpoint was 43 mo in Arm A versus 46 mo in Arm B (p=0.06), a nonsignificant difference of 3.2 mo (95% confidence interval: 6.7 to -1.5 mo). A total of 116 serious adverse events were recorded in Arm A and 41 in Arm B with no treatment-related deaths. Not all patients received docetaxel by protocol. The endpoint is biochemical progression and some patients received radiation treatment before the endpoint. CONCLUSIONS: Docetaxel without hormonal therapy did not significantly improve biochemical disease-free survival after radical prostatectomy. PATIENT SUMMARY: In this randomised trial, we tested whether chemotherapy after surgery for high-risk prostate cancer decreases the risk of a rising prostate-specific antigen. We found no benefit from docetaxel given after radical prostatectomy. PMID- 29395503 TI - Nail scissors and fingernails as reservoirs of hepatitis B virus DNA: Role of nail scissors in household transmission of hepatitis B virus. AB - BACKGROUND: No study in the current literature has scientifically clarified the transmission of hepatitis B virus (HBV) via personal hygiene tools. We determined risk of household transmission of HBV via nail scissors. Moreover, we assessed whether nails from HBV-infected people contained HBV, and evaluated correlations of HBV DNA levels of serum, nail specimens, and nail scissors. METHODS: Seventy patients testing positive for the surface antigen of the hepatitis B virus (63 positive for HBV DNA) treated for HBV infection and 27 healthy individuals were included. Real-time polymerase chain reaction method was used to detect HBV DNA levels in sera, nail, and nail scissors. RESULTS: HBV DNA was detected on 27% of nail scissors and in 50% of nail specimens from 63 serum HBV DNA-positive patients. Serum HBV DNA level >105 IU/mL was associated with 71.8% probability of nail scissors being HBV DNA-positive (P < .05). Serum HBV DNA level >107 IU/mL was associated with 71.5% probability of fingernails being HBV DNA-positive (P > .05). Shared-use of nail scissors was correlated with surface antigen of the hepatitis B virus positivity and total hepatitis B core antibody/immunoglobulin G positivity. A high HBV DNA level was detected in nail scissors and low level HBV DNA in the nails of persons with high serum HBV DNA levels. CONCLUSIONS: Nail scissors, shared-use of nail scissors, and duration of shared use play important roles in household transmission of HBV. Level of education within society in this regard should be increased via mass media. PMID- 29395504 TI - Infection prevention and control in outpatient settings in China-structure, resources, and basic practices. AB - BACKGROUND: More than 7 billion visits are made by patients to ambulatory services every year in mainland China. Healthcare-associated infections are becoming a new source of illness for outpatients. Little is known about infection prevention, control structure, resources available, and basic practices in outpatient settings. METHODS: In 2014, we conducted a multisite survey. Five provinces were invited to participate based on geographic dispersion. Self assessment questionnaires regarding the structure, infrastructure, apparatus and materials, and basic activities of infection prevention and control were issued to 25 hospitals and 5 community health centers in each province. A weight was assigned to each question according to its importance. RESULTS: Overall, 146 of 150 facilities (97.3%) participated in this study. The average survey score was 77.6 (95% confidence interval 75.7-79.5) and varied significantly between the different gross domestic product areas (P < .01), but scores were not significantly different between the 5 facility types (P = .07). The main lapse of infrastructure was in providing hand hygiene equipment (43.4%) and masks (38.7%) for patients in the waiting areas and main entrances. CONCLUSION: In a sample of ambulatory facilities in 5 provinces in China, infection prevention and control was practiced consistently, although there were lapses in some areas. PMID- 29395505 TI - Evaluation of the potential for electronic thermometers to contribute to spread of healthcare-associated pathogens. AB - In a point-prevalence culture survey, 24 of 300 (8%) handles of electronic thermometers in 3 hospitals were contaminated with 1 or more potential pathogens. A DNA marker inoculated onto the handles of electronic thermometers in hospital and long-term care facility settings spread to surfaces in patient rooms, to other types of portable equipment, and to patients' hands. Our findings suggest that effective strategies are needed to reduce the risk for pathogen transmission by electronic thermometers. PMID- 29395506 TI - A systematic review of adenosine triphosphate as a surrogate for bacterial contamination of duodenoscopes used for endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: Bacterial culture is the accepted standard to measure the adequacy of high-level disinfection (HLD) of duodenoscopes. Adenosine triphosphate (ATP) bioluminescence assays have been suggested as an alternative method of evaluating the quality of reprocessing. We systematically reviewed published research describing the correlation between ATP and bacterial cultures. METHODS: The primary outcome was the correlation or concordance between concomitantly sampled ATP and bacterial contamination obtained from the instrument channel and/or elevator mechanism of the duodenoscope. A secondary outcome included the reduction in ATP measurements between paired samples before and after stages of duodenoscope reprocessing. RESULTS: Ten studies were included in the analysis. Four studies reported the relationship between concomitantly sampled ATP and cultures. Three studies reported receiver operating characteristic curves (1 study additionally reported a Wilcoxon rank sum test), and 1 study reported Spearman correlation coefficients and paired dichotomous measurements of ATP and bacterial contamination. All analyses suggested a poor relationship between the 2 measures. Studies measuring ATP before and after manual cleaning and before and after HLD reported a reduction in ATP after the reprocessing stage. CONCLUSION: Current research does not support the direct substitution of ATP for bacterial culture surveillance of duodenoscopes. Serial ATP measurement may be a useful tool to evaluate the adequacy of manual cleaning and for training of endoscopic reprocessing staff. PMID- 29395507 TI - Understanding the patient experience of health care-associated infection: A qualitative systematic review. AB - BACKGROUND: The global burden of health care-associated infection (HAI) is well recognized; what is less well known is the impact HAI has on patients. To develop acceptable, effective interventions, greater understanding of patients' experience of HAI is needed. This qualitative systematic review sought to explore adult patients' experiences of common HAIs. METHODS: Five databases were searched. Search terms were combined for qualitative research, HAI terms, and patient experience. Study selection was conducted by 2 researchers using prespecified criteria. Critical Appraisal Skills Programme quality appraisal tools were used. Internationally recognized Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied. The Noblit and Hare (1988) approach to meta-synthesis was adopted. RESULTS: Seventeen studies (2001 2017) from 5 countries addressing 5 common types of HAI met the inclusion criteria. Four interrelated themes emerged: the continuum of physical and emotional responses, experiencing the response of health care professionals, adapting to life with an HAI, and the complex cultural context of HAI. CONCLUSIONS: The impact of different HAIs may vary; however, there are many similarities in the experience recounted by patients. The biosociocultural context of contagion was graphically expressed, with potential impact on social relationships and professional interactions highlighted. Further research to investigate contemporary patient experience in an era of antimicrobial resistance is warranted. PMID- 29395508 TI - Dynamics of intraoperative Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter transmission. AB - BACKGROUND: Our primary objective was to examine anesthesia work area reservoir isolation of Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter spp (KAPE) pathogens. This is a retrospective analysis of a randomized, prospective, and observational study involving 3 academic medical centers. METHODS: Patients included adults undergoing general anesthesia. Gram-negative isolates (N = 2,682) were collected from anesthesia work area reservoirs in 274 randomly selected operating room case pairs. Nine hundred and forty-five isolates were included in this study. Chi square tests were used to examine the association of anesthesia work area reservoirs with KAPE genera isolation. RESULTS: Acinetobacter pathogens were more likely to be isolated from anesthesia provider hands (risk ratio [RR], 1.07; 95% confidence interval [CI], 1.04-1.10; corrected P = .004) and less likely to be isolated from patients (RR, 0.2; 95% CI, 0.08-0.50; corrected P < .0001). Enterobacter pathogens were more likely to be isolated from patients (RR, 3.34; 95% CI, 1.92-5.81; corrected P = 0.001) and less likely to be isolated from provider hands (RR, 0.89; 95% CI, 0.83-0.97; corrected P = .007). CONCLUSIONS: Anesthesia provider hands are important reservoirs for Acinetobacter spp, whereas patient skin surfaces are key reservoirs for Enterobacter spp. Future work should examine the impact of a multimodal program in controlling the intraoperative spread of Acinetobacter and Enterobacter pathogens. PMID- 29395509 TI - Exploring the nurses' role in antibiotic stewardship: A multisite qualitative study of nurses and infection preventionists. AB - BACKGROUND: There is a growing recognition of the need to partner with nurses to promote effective antibiotic stewardship. In this study, we explored the attitudes of nurses and infection preventionists toward 5 nurse-driven antibiotic stewardship practices: 1) questioning the need for urine cultures; 2) ensuring proper culturing technique; 3) recording an accurate penicillin drug allergy history; 4) encouraging the prompt transition from intravenous (IV) to oral (PO) antibiotics; and 5) initiating an antibiotic timeout. METHODS: Nine focus groups and 4 interviews with 49 clinical nurses, 5 nurse managers, and 7 infection preventionists were conducted across 2 academic pediatric and adult hospitals. RESULTS: Nurse-driven antibiotic stewardship was perceived as an extension of the nurses' role as patient advocate. Three practices were perceived most favorably: questioning the necessity of urinary cultures, ensuring proper culturing techniques, and encouraging the prompt transition from IV to PO antibiotics. Remaining recommendations were perceived to lack relevance or to challenge traditionally held nursing responsibilities. Prescriber and family engagement were noted to assist the implementation of select recommendations. Infection preventionists welcomed the opportunity to assist in providing nurse stewardship education. CONCLUSIONS: Nurses appeared to be enthusiastic about participating in antibiotic stewardship. Efforts to engage nurses should address knowledge needs and consider the contexts in which nurse-driven antibiotic stewardship occurs. PMID- 29395510 TI - A prospective analysis of clinical detection of defective wrapping by operating room staff. AB - Surgical instrument trays are wrapped for sterilization, and these wraps are inspected by operating room personnel for defects before using the instruments. In this study, we intentionally damaged wraps, and these wraps were evaluated by operating room personnel. Examiners correctly identified a wrapper's sterile integrity with an overall 56.1% accuracy, with correct identification of 67.2% for defects between 2 and 5 cm. However, studies have shown bacterial contamination through defects as small as 1.1 mm. This study suggests that the current method for assessing sterility is inadequate. PMID- 29395511 TI - Healthcare-associated infections in the neurological intensive care unit: Results of a 6-year surveillance study at a major tertiary care center. AB - BACKGROUND: Healthcare-associated infections (HAIs) occur frequently in neurological intensive care units (neuro-ICUs); however, data differentiating associations with various diagnostic categories and resulting burdens are limited. This prospective cohort study reported incidence rates, pathogen distribution, and patient-related outcomes of HAIs in a neuro-ICU population from April 2010 to March 2016. METHODS: Laboratory results and specific clinical indicators were used to categorize infections as per National Healthcare Safety Network nosocomial infection surveillance definitions. Patient outcomes studied included length of stay and mortality. RESULTS: There were 6,033 neuro-ICU admissions resulting in 20,800 neuro-ICU days over the 6-year study period. A total of 227 HAIs were identified for a rate of 10.9/1,000 ICU days. Device associated infections accounted for 80.6% of HAIs, with incidence rates (per 1,000 device days) being 18.4 for ventilator-associated pneumonia; 4.9 for catheter-associated urinary tract infections (CAUTIs); 4.0 for ventriculostomy associated infections; and 0.6 for central line-associated blood stream infections (CLABSIs). Of the various diagnostic categories, subdural hematoma and intracerebral/intraventricular hemorrhage were associated with the highest pooled HAIs, with incidence rates of 21.3 and 21.1 per 1,000 neuro-ICU days, respectively. Prolonged neuro-ICU length of stay was strongly associated with all HAIs. CONCLUSIONS: This large-scale surveillance study provides estimates of the risk of common HAIs in neurocritical care patients and their effect on hospitalization. Preventive strategies kept rates of infection very low, in particular CAUTI, CLABSI, and Clostridium difficile infections, and inhibited the emergence of resistant organisms. PMID- 29395512 TI - A Final Warning to Planet Earth. PMID- 29395513 TI - Species' Distributions as a Coexistence Problem: A Response to Godsoe et al. PMID- 29395514 TI - From dead's will come life. PMID- 29395515 TI - Barriers to immunization among newcomers: A systematic review. AB - INTRODUCTION: Currently, there is a lack of comprehensive evidence exploring vaccine decision-making among newcomers. We conducted a systematic review of qualitative studies aimed at identifying factors that influence newcomers' decision-making with regards to vaccination. METHODS: We conducted a search of MEDLINE, EMBASE, CINAHL and Cochrane Central. To be included, studies needed to employ a qualitative methodology and address newcomer attitudes, beliefs, and/or perceptions regarding vaccination. Two independent reviewers screened the articles for relevant information and applied a content analysis methodology to code the identified barriers. RESULTS: Twenty-one studies were included in this review, and four types of barriers were identified: cultural factors, knowledge barriers, insufficient access to healthcare, and vaccine hesitancy. Insufficient knowledge about vaccination and the virus being prevented and concerns about safety were the most commonly reported barriers. A sub-analysis of barriers specific to HPV indicated that cultural beliefs about sexuality and incomplete knowledge about the role of HPV in the development of cervical cancer are major barriers to vaccine uptake. CONCLUSION: Strategies to improve vaccination uptake in newcomers should consider focusing on the barriers identified in this review while taking into account the unique opportunities for promoting uptake within newcomer populations. PMID- 29395516 TI - Haemophilus influenzae-protein D specific antibody correlate with protection against acute otitis media in young children. AB - BACKGROUND: Haemophilus influenzae (Hi) causes respiratory infections and pathogenesis of this microbe begins in the human nasopharynx (NP). The objective of this study was to assess the correlation of NP colonization-induced serum antibody levels to Hi protein D with risk of acute otitis media (AOM) in children <2 yr. METHODS: 455 sera from 213 children (age 6-24 months old) were collected when they were colonized with Hi and when the children developed AOM. Presence of Hi during AOM was confirmed by culture of middle ear fluid. Quantitative ELISA was used to determine serum IgG against protein D antigen. RESULTS: Asymptomatic Hi NP colonization reduced the risk of future AOM infections. Higher serum IgG titers against Hi protein D were correlated with reduced future AOM risk. CONCLUSION: Colonization by Hi reduces future AOM risk. Higher antibody levels against protein D correlates with lower risk of AOM caused by Hi. PMID- 29395517 TI - Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE): A vision for the vaccines of tomorrow. AB - A clear vision for vaccines research and development (R&D) is needed if Europe is to continue to lead the discovery of next generation vaccines. Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE) is a collaboration between leading vaccine experts to develop a roadmap setting out how Europe can best invest in the science and technology essential for vaccines innovation. This FP7 project, started in December 2013, brought together more than 130 key public and private stakeholders from academia, public health institutes, regulators, industry and small and medium-sized enterprises to determine and prioritise the gaps and challenges to be addressed to bolster innovation in vaccines and vaccination in Europe. The IPROVE consultation process was structured around seven themes: vaccine R&D, manufacturing and quality control, infrastructure, therapeutic vaccines, needs of small and medium-sized enterprises, vaccines acceptance and training needs. More than 80 recommendations were made by the consultation groups, mainly focused on the need for a multidisciplinary research approach to stimulate innovation, accelerated translation of scientific knowledge into technological innovation, and fostering of real collaboration within the European vaccine ecosystem. The consultation also reinforced the fact that vaccines are only as good as their vaccine implementation programmes, and that more must be done to understand and address vaccination hesitancy of both the general public and healthcare professionals. Bringing together a wide range of stakeholders to work on the IPROVE roadmap has increased mutual understanding of their different perspectives, needs and priorities. IPROVE is a first attempt to develop such a comprehensive view of the vaccine sector. This prioritisation effort, aims to help policy-makers and funders identify those vaccine-related areas and technologies where key investment is needed for short and medium-long term success. PMID- 29395518 TI - Influenza B virus reverse genetic backbones with improved growth properties in the EB66(r) cell line as basis for vaccine seed virus generation. AB - Vaccination remains the best available prophylaxis to prevent influenza virus infections, yet current inadequacies in influenza virus vaccine manufacturing often lead to vaccine shortages at times when the vaccine is most needed, as it was the case during the last influenza virus pandemic. Novel influenza virus vaccine production systems will be crucial to improve public health and safety. Here we report the optimization of influenza B virus growth in the proprietary EB66(r) cell line, currently in use for human vaccine production. To this end, we collected, curated and sequenced 71 influenza B viruses selected for high diversity in date of isolation and lineage. This viral collection was tested for ability to enter and replicate within EB66(r) cells in a single cycle assay and appears to readily infect these cells. When the collection was tested for viral progeny production in a multi-cycle assay, we found a large variation from strain to strain. The strains with the top growth characteristics from the B/Victoria and B/Yamagata lineages were selected for vaccine backbone generation using a reverse genetics system. We then showed that these backbones maintain their desirable growth within EB66(r) cells when the HA and NA from poorly growing strains were substituted for the parental segments, indicating that the selected backbones are viable options for vaccine production in EB66(r). Finally, we show that compounds previously reported to enhance influenza virus growth in cell culture also increase virus production in the EB66(r) cell line. PMID- 29395519 TI - Identification of suitable adjuvant for vaccine formulation with the Neospora caninum antigen NcSRS2. AB - The parasite Neospora caninum is the main cause of abortion in cattle in many countries around the world, so a vaccine is a rational approach method for the control of the disease. An effective vaccine should be able to prevent both, the horizontal and vertical transmission of N. caninum. In this study, the immune vaccinal response of the recombinant protein rNcSRS2 of N. caninum expressed in Pichia pastoris and formulated with water-in-oil emulsion, xanthan gum, and alum hydroxide was assessed in an experimental murine model. Groups of 10 Balb/c mice were subcutaneously inoculated with two doses of prNcSRS2 twenty-one days apart. After the second immunization, four mice from each group were euthanized, and splenocytes were stimulated ex vivo with recombinant protein. The IgG dynamics were evaluated by indirect ELISA, and the splenocytes cytokines transcription by qPCR. All groups elicited specific antibodies against prNcSRS2, with the water-in oil group showing significantly (p <= .05) elevated titers compared to the other groups. The prNcSRS2 protein alone did not induce a significant ex vivo splenic transcription level of IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-12 cytokines, except for IL-17A, and the adjuvant associations with the prNcSRS2 protein induced different cytokine transcription profiles. The water-in-oil emulsion modulated the expression of TNF-alpha; the xanthan gum modulated IL-4, IL-10, and IL-12; and alum hydroxide modulated IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-12. In conclusion, it was found that the association of the recombinant prNcSRS2 protein with different adjuvants induced different levels of specific antibody, and a distinct splenic cytokine profile in an adjuvant-dependent manner. The mechanisms of adjuvancity activity is complex, so adjuvant formulation may help in the design of efficient vaccine to control Neosporosis. PMID- 29395520 TI - Core pertussis transmission groups in England and Wales: A tale of two eras. AB - The recent resurgence of pertussis in England and Wales has been marked by infant deaths and rising cases in teens and adults. To understand which age cohorts are most responsible for these trends, we employed three separate statistical methods to analyze high-resolution pertussis reports from 1982 to 2012. The fine-grained nature of the time-series allowed us to describe the changes in age-specific incidence and contrast the transmission dynamics in the 1980s and during the resurgence era. Our results identified infants and school children younger than 10 years of age as a core group, prior to 2002: pertussis incidence in these populations was predictive of incidence in other age groups. After 2002, no core groups were identifiable. This conclusion is independent of methodology used. Because it is unlikely that the underlying contact patterns substantially changed over the study period, changes in predictability likely result from the introduction of more stringent diagnostics tests that may have inadvertently played a role in masking the relative contributions of core transmission groups. PMID- 29395521 TI - Hepatitis A and hepatitis B vaccination coverage among adults with chronic liver disease. AB - BACKGROUND: Infection with hepatitis A and hepatitis B virus can increase the risk of morbidity and mortality in persons with chronic liver disease (CLD). The Advisory Committee on Immunization Practices recommends hepatitis A (HepA) and hepatitis B (HepB) vaccination for persons with CLD. METHODS: Data from the 2014 and 2015 National Health Interview Surveys (NHIS), nationally representative, in person interview surveys of the non-institutionalized US civilian population, were used to assess self-reported HepA (>=1 and >=2 doses) and HepB vaccination (>=1 and >=3 doses) coverage among adults who reported a chronic or long-term liver condition. Multivariable logistic regression was used to identify factors independently associated with HepA and HepB vaccination among adults with CLD. RESULTS: Overall, 19.4% and 11.5% of adults aged >= 18 years with CLD reported receiving >=1 dose and >=2 doses of HepA vaccine, respectively, compared with 14.7% and 9.1% of adults without CLD (p < .05 comparing those with and without CLD, >=1dose). Age, education, geographic region, and international travel were associated with receipt of >=2 doses HepA vaccine among adults with CLD. Overall, 35.7% and 29.1% of adults with CLD reported receiving >=1 dose and >=3 doses of HepB vaccine, respectively, compared with 30.2% and 24.7% of adults without CLD (p < .05 comparing those with and without CLD, >=1 dose). Age, education, and receipt of influenza vaccination in the past 12 months were associated with receipt of >=3 doses HepB vaccine among adults with CLD. Among adults with CLD and >=10 provider visits, only 13.8% and 35.3% had received >=2 doses HepA and >=3 doses HepB vaccine, respectively. CONCLUSIONS: HepA and HepB vaccination among adults with CLD is suboptimal and missed opportunities to vaccinate occurred. Providers should adhere to recommendations to vaccinate persons with CLD to increase vaccination among this population. PMID- 29395522 TI - Reduced pathogenicity of fructose-1,6-bisphosphatase deficient Leishmania donovani and its use as an attenuated strain to induce protective immunogenicity. AB - Currently, there is no approved vaccine for visceral leishmaniasis (VL) caused by L. donovani. The ability to manipulate Leishmania genome by eliminating or introducing genes necessary for parasites' survival considered as the powerful strategy to generate the live attenuated vaccine. In the present study fructose 1,6-bisphosphatase (LdFBPase) gene deleted L. donovani (Deltafbpase) was generated using homologous gene replacement strategy. Though LdFBPase gene deletion (Deltafbpase) does not affect the growth of parasite in the promastigote form but axenic amastigotes display a marked reduction in their capacity to multiply in vitro inside macrophages and in vivo in Balb/c mice. Though Deltafbpase L. donovani parasite persisted in BALB/c mice up to 12 weeks but was unable to cause infection, we tested its ability to protect against a virulent L. donovani challenge. Notably, intraperitoneal immunisation with live Deltafbpase parasites displayed the reduction of parasites load in mice spleen and liver post challenge. Moreover, immunised BALB/c mice showed a reversal of T cell anergy and high levels of NO production that result in the killing of the parasite. A significant, correlation was found between parasite clearance and elevated IFNgamma, IL12, and IFNgamma/IL10 ratio compared to IL10 and TGFbeta in immunised and challenged mice. Results suggested the generation of protective Th1 type immune response which induced significant parasite clearance at 12-week, as well as 16 weeks post, challenged immunised mice, signifying sustained immunity. Therefore, we propose that Deltafbpase L. donovani parasites can be a live attenuated vaccine candidate for VL and a good model to understand the correlatives of protection in visceral leishmaniasis. PMID- 29395523 TI - Immunogenicity and protective efficacy of recombinant fiber-2 protein in protecting SPF chickens against fowl adenovirus 4. AB - Since a novel hyper-virulent fowl adenovirus serotype 4 (FAdV-4) infection occurred in 2015, the novel FAdV-4 has been widely spreading across China, causing significant economic losses to the poultry industry. As the urgency of the issue calls for effective and efficient solutions, the present study investigated the possibility of the fiber-2 protein of the FAdV-4 to serve as a vaccine candidate against the novel FAdV-4. In the research, fiber-2 proteins were expressed in Escherichia coli, and then purified. To evaluate the immunogenicity of the recombinant fiber-2 protein, we investigated both the humoral and cellular immune responses in chickens immunized with fiber-2. The humoral immunity was assessed by detecting IgY antibodies and virus-neutralizing antibodies in chicken serum at 7, 14, 21 days post-immunization (dpi). We examined cellular immune responses by detecting CD3+CD4+ and CD3+CD8+ changes in chickens' peripheral blood through using flow cytometry at 7, 14, 21 dpi. The cytokine production in the serum of the immunized chickens was detected by ELISA at 7, 14, 21 dpi to further explore the impact of the recombinant protein on the regulation of cytokines. The protective efficacy was determined by the survival rate of the immunized chickens challenged with the novel FAdV-4. The results show that the level of IgY antibodies of the chickens immunized with fiber-2 protein was significantly higher than that of the chickens immunized with an inactivated vaccine against FAdV-4. Moreover, 7 days after immunization, the CD4+ T-cell proliferative response of the chickens immunized with fiber-2 was significantly higher than that of the chickens immunized with the inactivated vaccine. Challenge experiment showed that the fiber-2 protein could provide full protection and the inactivated vaccine could provide 90 percent protection against the FAdV-4. These results suggest that the recombinant fiber-2 protein can be an ideal candidate for subunit vaccines against the disease. PMID- 29395524 TI - Recipient vaccine-associated paralytic poliomyelitis in China, 2010-2015. AB - INTRODUCTION: Vaccine-associated paralytic poliomyelitis (VAPP) is one of the most important adverse effects of vaccines that are in current use globally. The Chinese national adverse event following immunization information system (CNAEFIS) is a passive surveillance system which collects data on VAPP. AIMS: To describe the epidemiological characteristics of VAPP and estimate the risk of recipient VAPP in China. METHODS: We retrieved information from reported cases of recipient VAPP from CNAEFIS from 2010 to 2015, examined the demographic characteristics of the cases, and used administrative data on vaccination doses and the estimated number of births as denominators to calculate VAPP incidence. RESULTS: During 2010-2015, 157 cases of recipient VAPP were reported to CNAEFIS (male-to-female ratio, 8.2:1); 151 cases (96.2%) were less than six months old. All cases were associated with trivalent OPV (tOPV), and 89.8% occurred after the receipt of first dose. Of the 157 recipient VAPP cases, type II, type III, and type I poliovirus vaccine strains were isolated from 27 (17.2%) , 25 (15.9%) , and 16 (10.2%) cases, respectively. One case died and one case recovered completely; the other 155 cases had various physical disabilities, such as monolateral or bilateral limping. Using the administered doses of OPV as the denominator, the incidence of recipient VAPP during the study period was estimated at 0.4 per million doses. The estimated recipient VAPP per million births ranged from 1.0 to 2.4 during 2010-2015. CONCLUSION: The epidemiological characteristics of recipient VAPP cases in China, such as age distribution, were comparable to those in previous studies from other countries. The risk of recipient VAPP, using either estimated births or vaccination doses, was comparable to that in the US and Japan. We recommend using an inactive poliovirus vaccine to decrease the number of recipient VAPP cases in China. PMID- 29395525 TI - Vaccine failure and serologic response to live attenuated and inactivated influenza vaccines in children during the 2013-2014 season. AB - BACKGROUND: Recent observational studies in the United States indicated live attenuated influenza vaccine (LAIV) was less effective in children against clinical influenza infection caused by A(H1N1)pdm09 relative to inactivated influenza vaccine (IIV). During the 2013-2014 influenza season, we conducted an observational study among children aged 5-17 years to compare serologic responses to LAIV and IIV and explore factors associated with vaccine failure. METHODS: One hundred and sixty-one children received one dose of trivalent IIV or quadrivalent LAIV according to parental preference. Baseline and postvaccination serum samples were tested with hemagglutination inhibition (HI) assays against vaccine reference strains. Geometric mean titers (GMT), geometric mean fold rise (GMFR), seroconversion, and seroprotection (HI titer >= 40) were used to assess response to vaccine. Active surveillance for acute respiratory illness was conducted during the influenza season and influenza cases were confirmed by reverse transcription polymerase chain reaction (RT-PCR). Logistic regression was used to examine the association between vaccine type and vaccine failure. RESULTS: LAIV and IIV recipients were similar with respect to demographics and baseline GMT for each vaccine strain. RT-PCR confirmed influenza (vaccine failure) occurred in 8 (13%) of 62 LAIV recipients and 3 (3%) of 99 IIV recipients (p = .02). Postvaccination GMFR for A(H1N1)pdm09 was higher for IIV vs LAIV receipt (GMFR 3.3 vs. 0.8, p < .0001). Postvaccination titers against A(H1N1)pdm09 were >=40 for 91% and 44% of IIV and LAIV recipients, respectively (p < .0001). Among 13 IIV and 18 LAIV recipients with seronegative baseline titer against A(H1N1pdm09), 54% and 0% seroconverted, respectively. LAIV receipt was the only factor associated with A(H1N1)pdm09 vaccine failure in the age-adjusted multivariable model (odds ratio 4.5, 95% CI 1.1-18.2). CONCLUSION: Receipt of LAIV generated minimal HI antibody response in children, including among those seronegative at baseline. LAIV recipients had significant increased risk of A(H1N1)pdm09 infection compared to IIV recipients. PMID- 29395527 TI - Anti-vaccination and pro-CAM attitudes both reflect magical beliefs about health. AB - We examined the relationship between complementary and alternative medicine (CAM) use and vaccination scepticism; and specifically whether a person's more general health-related worldview might explain this relationship. A cross-sectional online survey of adult Australians (N = 2697) included demographic, CAM, and vaccination measures, as well as the holistic and magical health belief scales (HHB, MHB). HHB emphasises links between mind and body health, and the impact of general 'wellness' on specific ailments or resistance to disease, whilst MHB specifically taps ontological confusions and cognitive errors about health. CAM and anti-vaccination were found to be linked primarily at the attitudinal level (r = -0.437). We did not find evidence that this was due to CAM practitioners influencing their clients. Applying a path-analytic approach, we found that individuals' health worldview (HHB and MHB) accounted for a significant proportion (43.1%) of the covariance between CAM and vaccination attitudes. MHB was by far the strongest predictor of both CAM and vaccination attitudes in regressions including demographic predictors. We conclude that vaccination scepticism reflects part of a broader health worldview that discounts scientific knowledge in favour of magical or superstitious thinking. Therefore, persuasive messages reflecting this worldview may be more effective than fact-based campaigns in influencing vaccine sceptics. PMID- 29395526 TI - Immunogenicity and safety of measles-mumps-rubella vaccine delivered by disposable-syringe jet injector in India: A randomized, parallel group, non inferiority trial. AB - BACKGROUND: We conducted a randomized, non-inferiority, clinical study of MMR vaccine by a disposable-syringe jet injector (DSJI) in toddlers in India in comparison with the conventional administration. METHODS: MMR vaccine was administered subcutaneously by DSJI or needle-syringe (N-S) to toddlers (15-18 months) who had received a measles vaccine at 9 months. Seropositivity to measles, mumps, and rubella serum IgG antibodies was assessed 35 days after vaccination. Non-inferiority was concluded if the upper limit of the 95% CI for the difference in the percent of seropositive between groups was less than 10%. Solicited reactions were collected for 14 days after vaccination by using structured diaries. RESULTS: In each study group, 170 subjects received MMR vaccine. On day 35, seropositivity for measles was 97.5% [95% CI (93.8%, 99.3%)] in the DSJI group and 98.7% [95% CI (95.5%, 99.8%)] in the N-S group; for mumps, 98.8% [95% CI (95.6%, 99.8%)] and 98.7% [95% CI (95.5%, 99.8%)]; and for rubella, 98.8% [95% CI (95.6%, 99.8%)] and 100% [95% CI (97.7%, 100.0%)]; none of the differences were significant. The day 35 post-vaccination GMTs in DSJI and N-S groups were measles: 5.48 IU/ml [95% CI (3.71, 8.11)] and 5.94 IU/ml [95% CI (3.92, 9.01)], mumps: 3.83 ISR [95% CI (3.53, 4.14)] and 3.66 ISR [95% CI (3.39, 3.95)] and rubella: 95.27 IU/ml [95% CI (70.39, 128.95)] and 107.06 IU/ml [95% CI (79.02, 145.06)]; none of the differences were significant. The DSJI group reported 173 solicited local reactions and the N-S group reported 112; most were mild grade. Of the total of 156 solicited systemic adverse events, most were mild, and incidence between the two groups was similar. CONCLUSIONS: MMR vaccination via DSJI is as immunogenic as vaccination by N-S. Safety profile of DSJI method is similar to N-S except for injection site reactions which are more with DSJI and are well-tolerated. Registration US National Institutes of Health clinical trials identifier - NCT02253407. Clinical trial registry of India identifier - CTRI/2013/05/003702. PMID- 29395529 TI - Compliance to timely vaccination in an Expanded Program on Immunization center of Pakistan. AB - The importance of childhood immunization in prevention of highly fatal diseases and disability cannot be overemphasized. Pakistan has a national Expanded Program on Immunization but the compliance is far below the international benchmark for achieving a herd immunity. Monitoring the compliance to timely receipt of vaccinations is crucial to establishing and preventing disease and disability associated risk in children. There is little or no evidence that reports the timeliness of the vaccinations according to the EPI schedule in Peshawar. The primary objective of the study was to evaluate rate of Fully Immunized Children and to report compliance to the timeliness of vaccine specific schedule during the study period in the EPI center in the capital city of Peshawar, Khyber Pakhtunkhwa province of Pakistan. We collected consecutive retrospective data of the infants enrolled from June 2014 to December 2015 in one EPI center for our study. Out of the total 157 (n) children, fully immunized children (FIC) were 62 (39.5%) and only 19 (12.1%) were FIC with timely visits. Dropouts increased with successive vaccinations with highest for Measles 1 (42%). On-time vaccinations decreased over time, while the proportion of children receiving vaccination outside the ideal window period reaches as high as 46%. The study reports a low compliance to EPI schedule, and also highlights that immunization coverage is not a good indicator of age appropriate vaccinations. PMID- 29395528 TI - Substance use patterns of HVTN phase I clinical trial participants: Enrollment, risk reduction counseling and retention. AB - BACKGROUND: The primary objectives of HIV Vaccine Trials Network (HVTN) phase 1 preventive HIV vaccine clinical trials are to assess safety and immune response to study products. Participant alcohol and drug use may affect adherence, retention, and risk of HIV infection. Data on the effects of substance use are limited to medical care compliance and treatment adherence in HIV infected participants. To our knowledge, there are no data assessing substance use and retention in these vaccine trials. METHODS: We performed a meta-analysis on substance use and its impact on retention in HVTN phase I trials that recruited participants demonstrating lower risk profiles for HIV infection. Our analysis included data from 10 HVTN phase 1 clinical trials conducted between February 2009 and September 2014 in the Americas and Switzerland that utilized the identical interviewer-administered behavioral risk assessment questionnaire to capture participant self-report of substance use in the previous six months. Chi Square tests were used to assess statistical differences between variables. RESULTS: Among the 964 participants, 170 (18%) missed a clinic visit and 78 (8%) terminated early from clinic follow-up; 75/774 (10%) on studies with multiple vaccination timepoints did not complete their vaccinations. Neither frequency of alcohol use, binge drinking, marijuana, nor other drug use reported at screening visits were associated with the three adherence/retention measures. Binge drinking was associated with higher rates of unprotected sex while drunk (p < .001). CONCLUSIONS: Light to moderate alcohol use does not negatively impact adherence or retention in phase I clinical trials. Based on these screening data and the low infection rate of participants during the trial period, the screening process for participation in HVTN phase 1 trials has largely been successful in enrolling and retaining individuals with lower risk profiles. Focusing on binge drinking and increased HIV/STI risk during risk reduction counseling may be warranted. PMID- 29395530 TI - Impact of introduction of the 9-valent human papillomavirus vaccine on vaccination coverage of youth in North Carolina. AB - OBJECTIVES: The objective of this study was to evaluate the impact of introduction of 9vHPV vaccine on HPV vaccination uptake (doses per capita) and initiation (>=1 doses), completion (>=3 doses) and compliance (>=3 doses within 12 months) by adolescents. METHODS: We used a retrospective cohort analysis using North Carolina Immunization Registry (NCIR) data from January 2008 through October 2016. The sample included Vaccines for Children eligible adolescents aged 9 to 17 years in 2016, for whom the NCIR contains complete vaccination history. We applied an interrupted time series design to measure associations between ZIP Code Tabulation Area (ZCTA)-level HPV vaccination outcomes over time with the introduction of 9vHPV in North Carolina (NC) in July 2015. RESULTS: Each outcome displayed a linear upward trend over time with large seasonal spikes near August of each year, corresponding to the time when adolescents often receive other vaccines required for school entry. After accounting for these underlying trends, introduction of 9vHPV was not associated with a change in publicly funded HPV vaccination rates in NC. CONCLUSIONS: Our results indicate that 9vHPV substituted for 4vHPV in the first year after release in NC, but the release of 9vHPV was not associated with an overall change in HPV vaccination. PMID- 29395531 TI - Strategies to implement maternal vaccination: A comparison between standing orders for midwife delivery, a hospital based maternal immunisation service and primary care. AB - Maternal vaccination is a safe and effective strategy to reduce maternal and neonatal morbidity and mortality from pertussis and influenza. However, despite recommendations for maternal vaccination since 2010, uptake remains suboptimal. Barriers to uptake have been studied widely and include lack of integration of vaccination into routine pregnancy care and access to vaccination services. Standing orders for administration of vaccines without the need for a physician review or prescription have been demonstrated to improve uptake as part of multi model interventions to increase antenatal influenza and post-partum pertussis vaccination. Monash Health is a university-affiliated, public healthcare network in Melbourne, Australia providing maternity services across three hospitals. In this study we compared three different immunisation models - an immunisation nurse-led immunisation service, standing orders for midwife-administered pertussis vaccination within pregnancy care clinics, and delivery by general practitioners in primary care. Uptake of maternal pertussis vaccine was measured as recorded in the state-wide perinatal data collection tool. Uptake improved significantly at all three hospitals over the study period with the most significant change (39% to 91%, p < .001) noted at the hospital where standing orders were introduced. Our study highlights the diversity of immunisation service models available in maternity care settings. We demonstrated significant improvement in uptake of maternal pertussis vaccination with introduction of midwife-administered vaccination but each maternity service should consider the model best suited to their needs. PMID- 29395532 TI - Sharing knowledge about immunisation (SKAI): An exploration of parents' communication needs to inform development of a clinical communication support intervention. AB - INTRODUCTION: The SKAI (Sharing Knowledge About Immunisation) project aims to develop effective communication tools to support primary health care providers' consultations with parents who may be hesitant about vaccinating their children. AIM: This study explored parents' communication needs using a qualitative design. METHODS: Parents of at least one child less than five years old were recruited from two major cities and a regional town known for high prevalence of vaccine objection. Focus groups of parents who held similar vaccination attitudes and intentions were convened to discuss experiences of vaccination consultations and explore their communication needs, including preferences. Draft written communication support tools were used to stimulate discussion and gauge acceptability of the tools. RESULTS: Important differences in communication needs between group types emerged. The least hesitant parent groups reported feeling reassured upon reading resources designed to address commonly observed concerns about vaccination. As hesitancy of the group members increased, so did their accounts of the volume and detail of information they required. Trust appeared to be related to apparent or perceived transparency. More hesitant groups displayed increased sensitivity and resistance to persuasive language forms. PMID- 29395533 TI - Immunization with phage virus-like particles displaying Zika virus potential B cell epitopes neutralizes Zika virus infection of monkey kidney cells. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that has re-emerged and is associated with many debilitating clinical manifestations. Research is currently being conducted to develop a prophylactic vaccine against the virus; however, there has not been any licensed ZIKV vaccine. Recent studies have identified potential B-cell epitopes (amino acids 241-259, 294-315, 317-327, 346-361, 377 388 and 421-437) on the envelope protein of ZIKV, which could be explored to develop peptide vaccines against ZIKV infection. Nevertheless, the immunogenicity of these epitopes has never been assessed. Here, we displayed these epitopes on highly immunogenic bacteriophage virus-like particles (VLPs; MS2, PP7 and Qbeta) platforms and assessed their immunogenicity in mice. Mice immunized with a mixture of VLPs displaying ZIKV envelope B-cell epitopes elicited anti-ZIKV antibodies. Although, immunized mice were not protected against a high challenge dose of ZIKV, sera - albeit at low titers - from immunized mice neutralized (in vitro) a low dose of ZIKV. Taken together, these results show that these epitopes are B-cell epitopes and they are immunogenic when displayed on a Qbeta VLP platform. Furthermore, the results also show that immunization with VLPs displaying a single B-cell epitope minimally reduces ZIKV infection whereas immunization with a mixture of VLPs displaying a combination of the B-cell epitopes neutralizes ZIKV infection. Thus, immunization with a mixture of VLPs displaying multiple ZIKV B-cell epitopes is a good strategy to enhance ZIKV neutralization. PMID- 29395534 TI - The role of timeliness in the cost-effectiveness of older adult vaccination: A case study of pneumococcal conjugate vaccine in Australia. AB - While the impact of the timeliness of vaccine administration has been well studied for childhood vaccinations, there has been little detailed quantitative analysis on the potential impact of the timeliness of vaccinations in older adults. The aim of this study was to explore the impact of implementing more realistic observed uptake distributions, taking into the account reduced vaccine efficacy but higher pneumococcal disease burden with increasing age beyond 65 years. A multi-cohort Markov model was constructed to evaluate the cost effectiveness of a pneumococcal (PCV13) immunisation program in Australia, assuming two different uptake modelling approaches. The approach using an estimate of observed uptake was compared with a scenario in which the total cumulative uptake was delivered at the recommended age of vaccination. We found these two approaches produced different results both in terms of cases prevented and cost-effectiveness. The impact of the non-timely uptake in adult programs may sometimes have positive and other times negative effects, depending on several factors including the age-specific disease rates and the duration of vaccine protection. Our study highlights the importance of using realistic assumptions around uptake (including non-timely vaccination) when estimating the impact of vaccination in adults. PMID- 29395535 TI - Vaccine delivery to newly arrived refugees and estimated costs in selected U.S. clinics, 2015. AB - BACKGROUND: Newly arrived refugees are offered vaccinations during domestic medical examinations. Vaccination practices and costs for refugees have not been described with recent implementation of the overseas Vaccination Program for U.S. bound Refugees (VPR). We describe refugee vaccination during the domestic medical examination and the estimated vaccination costs from the US government perspective in selected U.S. clinics. METHODS: Site-specific vaccination processes and costs were collected from 16 clinics by refugee health partners in three states and one private academic institution. Vaccination costs were estimated from the U.S. Vaccines for Children Program and Medicaid reimbursement rates during fiscal year 2015. RESULTS: All clinics reviewed overseas vaccination records before vaccinating, but all records were not transferred into state immunization systems. Average vaccination costs per refugee varied from $120 to $211 by site. The total average cost of domestic vaccination was 15% less among refugees arriving from VPR- vs. nonVPR-participating countries during a single domestic visit. CONCLUSION: Our findings indicate that immunization practices and costs vary between clinics, and that clinics adapted their vaccination practices to accommodate VPR doses, yielding potential cost savings. PMID- 29395536 TI - Respiratory syncytial virus vaccine research and development: World Health Organization technological roadmap and preferred product characteristics. AB - The respiratory syncytial virus causes a considerable respiratory disease burden globally, most markedly in young infants, in low and middle income countries. A diverse product pipeline illustrates the recent intensification of research and development activities for vaccines and monoclonal antibodies against RSV. With the aim to ensure that product development activities are directed to address the public health needs, the World Health Organization has developed a research and development technical roadmap and articulated product characteristics preferences. PMID- 29395537 TI - Phylogenetic classification of six novel species belonging to the genus Bifidobacterium comprising Bifidobacterium anseris sp. nov., Bifidobacterium criceti sp. nov., Bifidobacterium imperatoris sp. nov., Bifidobacterium italicum sp. nov., Bifidobacterium margollesii sp. nov. and Bifidobacterium parmae sp. nov. AB - Six Bifidobacterium strains, i.e., Goo31D, Ham19E, Rab10A, Tam1G, Uis4E and Uis1B, were isolated from domestic goose (Anser domesticus), European hamster (Cricetus cricetus), European rabbit (Oryctolagus cuniculus), emperor tamarin (Saguinus imperator) and pygmy marmoset (Callithrix pygmaea). Cells are Gram positive, non-motile, non-sporulating, facultative anaerobic and fructose 6 phosphate phosphoketolase-positive. Phylogenetic analyses based on 16S rRNA, ITS , multilocus- sequences and the core genome revealed that bifidobacterial strains Goo31D, Ham19E, Rab10A, Tam1G, Uis4E and Uis1B exhibit close phylogenetic relatedness with Bifidobacterium choerinum LMG 10510, Bifidobacterium hapali DSM 100202, Bifidobacterium saguini DSM 23967 and Bifidobacterium stellenboschense DSM 23968. Genotyping based on the genome sequence of the isolated strains combined with phenotypic analyses, clearly show that these strains are distinct from each of the type strains of the so far recognized Bifidobacterium species. Thus, Bifidobacterium anseris sp. nov. (Goo31D=LMG 30189T=CCUG 70960T), Bifidobacterium criceti sp. nov. (Ham19E=LMG 30188T=CCUG 70962T), Bifidobacterium imperatoris sp. nov. (Tam1G=LMG 30297T=CCUG 70961T), Bifidobacterium italicum sp. nov. (Rab10A=LMG 30187T=CCUG 70963T), Bifidobacterium margollesii sp. nov. (Uis1B=LMG 30296T=CCUG 70959T) and Bifidobacterium parmae sp. nov. (Uis4E=LMG 30295T=CCUG 70964T) are proposed as novel Bifidobacterium species. PMID- 29395538 TI - Bacillus onubensis sp. nov., isolated from the air of two Andalusian caves. AB - Two Gram-positive, catalase-positive, oxidase-negative, motile, endospore forming, rod-shaped bacteria, designated as 0911MAR22V3T and 0911TES10J4, were isolated from air samples collected in two show caves, located in Andalusia, Southern Spain. Phylogenetic analysis based on 16S rRNA gene sequences indicated that both strains were indistinguishable and they were most closely related to Bacillus humi DSM 16318T (98%). DNA-DNA hybridization values of the strain 0911MAR22V3T with respect to strain 0911TES10J4 and B. humi DSM 16318T were 76.8% (73.9%, reciprocal) and 56.9% (63.3%, reciprocal analysis), respectively. Whole genome average nucleotide identity (ANI) values of both strains were in the threshold value for species delineation and less than 85% with B. humi. Strains 0911MAR22V3T and 0911TES10J4 grew at 10-47 degrees C (optimum 37 degrees C), at pH 6-9.5 and with 0-8% (w/v) NaCl (optimum 1%). In both strains the dominant isoprenoid quinone was MK-7, the major cellular polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and two more phospholipids, the predominant fatty acids were iso-C15:0 and anteiso-C15:0 and the DNA G+C content was 38mol%. On the basis of their phylogenetic relatedness and their phenotypic and genotypic features, the strains 0911MAR22V3T and 0911TES10J4 should be attributed to a novel species within the genus Bacillus, for which the name Bacillus onubensis sp. nov. is proposed. The type strain is 0911MAR22V3T (=LMG 27963T=CECT 8479T); and strain 0911TES10J4 (CECT 8478) is a reference strain. PMID- 29395539 TI - WASP (Write a Scientific Paper): "As we may think" - The internet and its research potential revisited. AB - This collection of papers includes a contribution that lists educational resources on the internet. It is thus salutary to look back at one of the earliest predictions as to how the internet might come to be, by a great scientist from the middle of the 1940s, Vannevar Bush (1890-1974). This engineer and inventor came up with the concept of the "memex", a hypothetical adjustable microfilm viewer with a structure and functionality analogous to that of today's hypertext, way back in 1945. This paper will describe the extremely prescient memex concept and its analogy with today's computers and the internet. PMID- 29395540 TI - Influence of birthweight on childhood balance: Evidence from two British birth cohorts. AB - BACKGROUND: Birthweight is an important predictor of various fundamental aspects of childhood health and development. AIM: To examine the impact of birthweight on childhood balance performance classification and verify if this is replicable and consistent in different populations. STUDY DESIGN: Prospective birth cohort study. SUBJECTS: To describe heterogeneity in balance skills, latent class analyses were conducted separately with data from the 1958 National Child Development Study - NCDS (n = 12,778), and the 1970 British Cohort Study - BCS (n = 12,115). OUTCOME MEASURES: Four balance tasks for NCDS and five balance tasks for BCS. RESULTS: Birthweight was assessed as a predictor of balance skills. In both cohorts, two latent classes (good and poor balance skills) were identified. In both cohorts, higher birthweight was associated with a higher likelihood of having good balance skills. Boys were less likely to have good balance compared to girls. CONCLUSIONS: The results establish the reproducibility and consistency of the effect of birthweight on balance skills and point to early intervention for individuals with lower birthweight to mitigate the impact of motor impairment. PMID- 29395541 TI - Ten Years after the Creation of the Portuguese National Network for Long-Term Care in 2006: Achievements and Challenges. AB - The Portuguese National Network for Long-term Integrated Care (Rede Nacional de Cuidados Continuados, RNCCI) was created in 2006 as a partnership between the Ministry of Health and the Ministry of Labour and Social Solidarity. The formal provision of care within the RNCCI is made up of non-profit and non-public institutions called Private Institutions of Social Solidarity, public institutions belonging to the National Health Service and for-profit institutions. These institutions are organized by type of care in two main settings: (i) Home and Community-Based Services and (ii) four types of Nursing Homes to account for different care needs. This is the first study that assess the RNCCI reform in Portugal since 2006 and takes into account several core dimensions: coordination, ownership, organizational structure, financing system and main features, as well as the challenges ahead. Evidence suggests that despite providing universal access, Portuguese policy-makers face the following challenges: multiple sources of financing, the existence of several care settings and the sustained increase of admissions at the RNCCI, the dominance of institutionalization, the existence of waiting lists, regional asymmetries, the absence of a financing model based on dependence levels, or the difficulty to use the instrument of needs assessment for international comparison. PMID- 29395542 TI - Extending' euthanasia to those 'tired of living' in the Netherlands could jeopardize a well-functioning practice of physicians' assessment of a patient's request for death. AB - The Dutch Euthanasia Act (EA) took effect in 2002 and regulates the ending of one's life by a physician at the request of a patient who is suffering unbearably. According to the Dutch Supreme Court, unbearable suffering is a state for which the presence of a medical condition is a strict prerequisite. As a consequence, the Dutch EA has attributed the assessment of unbearable suffering to physicians who evaluate the presence of a medical classifiable disorder. Currently, a debate within the Netherlands questions whether older people, without a medical condition, who value their life as completed, should be granted euthanasia. To concede the autonomy of such a person, the Dutch government intends to create a separate legal framework that regulates this tired of living euthanasia request. This debate is crucial for policy-makers and an international audience because it discusses if a self-directed death of older people, should be implemented in (the current Dutch) euthanasia practice. However, this article argues that the current legal proposal that regulates the tired of living euthanasia request ignores crucial jurisprudence on physicians' application of the unbearable suffering criterion in practice. Furthermore it points out that this proposal neglects physicians role in guaranteeing a euthanasia practice of due care and that its use of an ethic of absolute autonomy could jeopardize this well-established practice. PMID- 29395543 TI - Reconciling a "pleasant exchange" with evidence of information bias: A three country study on pharmaceutical sales visits in primary care. AB - OBJECTIVES: To examine and compare the experiences and attitudes of primary care physicians in three different regulatory environments (United States, Canada, and France) towards interactions with pharmaceutical sales representatives, particularly their perspectives on safety information provision and self-reported influences on prescribing. METHODS: We recruited primary care physicians for 12 focus groups in Montreal, Sacramento, Toulouse and Vancouver. A thematic analysis of the interview data followed a five-stage framework analysis approach. RESULTS: Fifty-seven family physicians (19 women, 38 men) participated. Physicians expected a commercial bias and generally considered themselves to be immune from influence. They also appreciated the exchange and the information on new drugs. Across all sites, physicians expressed concern about missing harm information; however, attitudes to increased regulation of sales visits in France and the US were generally negative. A common solution to inadequate harm information was to seek further commercially sourced information. Physicians at all sites also expressed sensitivity to critiques from medical students and residents about promotional interactions. CONCLUSIONS: Physicians have contradictory views on the inadequate harm information received from sales representatives, linked to their lack of awareness of the drugs' safety profiles. Commonly used strategies to mitigate information bias are unlikely to be effective. Alternate information sources to inform prescribing decisions, and changes in the way that physicians and sales representatives interact are needed. PMID- 29395544 TI - Sex assessment based on clavicular measurements in a modern Japanese population using multidetector computed tomography. AB - Accurate sex estimation from unknown human remains is crucial as an integral and foremost step toward individual identification. The aims of this study were to assess sexual dimorphism of the clavicle and develop discriminant equations for sex estimation in a modern adult Japanese population based on clavicular measurements using three-dimensional (3D) computed tomographic (CT) images. A total of 300 cadavers (150 males, 150 females) of known age and sex that underwent postmortem CT and subsequent forensic autopsy were obtained. Four measurements were performed using 3D CT reconstructed images that extracted only bones based on the CT values, as follows: the linear distances between the medial superior margins of the left and right sternal facets to the lateral points of the left and right acromial ends, and the linear distances between the medial superior margins of the left and right sternal facets to the tips of the left and right conoid tubercles. The mean values of all measurements were significantly greater for male subjects than female subjects. Univariate discriminant function analysis (DFA) provided correct sex prediction rates of 88.3-92.2%. Stepwise DFA for the left and right clavicles yielded sex classification accuracy rates of 92.2% and 91.0%, respectively. In conclusion, clavicular measurements using 3D CT images of a contemporary Japanese population may be useful for sex estimation in forensic contexts. PMID- 29395545 TI - Erratum to "Recovery of trace DNA and its application to DNA profiling of insoles" [Forensic Sci Int 145 (1) (2004) 7-12]. PMID- 29395546 TI - Visual and oxide analysis for identification of electrical fire scene. AB - Three aluminum wires with different melted mark, which were found inside a burned distribution board from the electrical fire debris in rural areas of Northeast China were characterized to determine the cause of fire. By visual and microstructure/metallographic analysis, one melted bead shows typical morphology (microstructure/characteristics) as a result of overheating or electric short circuit (ESC) arc beads which was identified as the most possible ignition source. The macro-/micro-structure of the metallic wire, the chemical composition of the beads surface and the state of the polymer insulating sheath combining the tension state of the electric wire provided solid evidence on the exposure temperature and time of each aluminum wire. Consequently, the fire source was identified. Therefore, the characterization on the macro-/micro-structure and chemical composition of metallic surface with scientific technique is greatly helpful in determining heating process of metallic parts and subsequently the cause of fire. PMID- 29395547 TI - Spinning, hurting, still, afraid: Living life spaces with Type I Chiari Malformation. AB - Human geography's varied engagement with the brain has involved considerations of the way people know and respond to their environments, and their place-based experiences with emotions, mental illnesses and disorders, intellectual disabilities and particular neurological conditions. This paper argues however that this scholarship could be augmented by, and existing expertise be directed towards, considering physical brain abnormalities and injuries. As a case in point it considers the spatial experience of living with Type 1 Chiari Malformation. Through interviews with four sufferers, the research articulates three domains that they have had to re-negotiate - home space, social space and medical space - emphasizing supportive and challenging aspects of each, as well as meaningful and affective qualities to encounters. The paper concludes with some pointers towards the future study of physical brain abnormalities and injuries and the kinds of knowledge it might create to increase awareness and inform care. PMID- 29395548 TI - Excision of Labral Amorphous Calcification as a Part of Hip Arthroscopy-Clinical Outcomes in a Matched-Controlled Study. AB - PURPOSE: To evaluate clinical outcomes, demographics, and radiographic findings for patients whose hip arthroscopies involved amorphous calcification (AC) excision and to compare them with a control group with no AC and with the general population regarding diabetes mellitus and hypothyroidism. METHODS: Patients who underwent primary hip arthroscopy involving surgical excision of AC deposit in the anterosuperior labralcapsular recess between October 2008 and July 2014 were reviewed. Demographics, radiographic findings, intraoperative findings, and procedures were reviewed. Minimum follow-up was 2 years and included visual analog scale for pain, patient satisfaction, and the following patient-reported outcome scores: modified Harris hip score, hip outcomes score sport-specific subscale, and nonarthritic hip score. These patients were matched (1:2 ratio) to patients who underwent hip arthroscopy with no AC using the following matching criteria: age at surgery +/- 5 years, body mass index +/- 5, gender, type of labral treatment, and type of capsular treatment. RESULTS: We reviewed 12 cases in 11 female patients. Mean latest follow-up scores improved from 64.0 to 83.4 (P = .003) for modified Harris hip score, from 57.6 to 80.6 (P < .001) for nonarthritic hip score, from 35.4 to 62.7 (P = .021) for hip outcomes score sport specific subscale, and from 6.4 to 2.8 (P = .016) for visual analog scale. The survivorship rate was 91.7%, with one hip converting to total hip arthroplasty. Mean patient satisfaction was 8.4 +/- 2.3. Six hips of the 12 (50%) had clock face localization of the AC. They were all between 11 and 12 with a mean of 12:30. Postoperative radiographic findings showed no subsequent AC in all 12 hips. No complications or revisions were reported. There were no significant differences between the AC group and the control group. CONCLUSIONS: The treatment of AC as part of hip arthroscopy for labral tear and femoro-acetabular impingement is safe and has favorable and similar outcomes compared with a control group at minimum 2-year follow-up. Female gender may be a risk factor for the development of AC. There is no strong evidence that AC should be debrided. LEVEL OF EVIDENCE: Level III, case control study. PMID- 29395549 TI - Patients With Concomitant Intra-articular Lesions at Index Surgery Deteriorate in Their Knee Injury and Osteoarthritis Outcome Score in the Long Term More Than Patients With Isolated Anterior Cruciate Ligament Rupture: A Study From the Swedish National Anterior Cruciate Ligament Register. AB - PURPOSE: To analyze and compare clinical outcomes after anterior cruciate ligament (ACL) reconstruction 5 and 10 years postsurgery between patients with concomitant intra-articular injuries and those with isolated ACL injury at reconstruction. METHODS: Registrations were made using a web-based protocol by physicians for baseline and surgical data. Patients registered their Knee Injury and Osteoarthritis Outcome Score (KOOS) preoperatively and at 5 and 10 years postsurgery. The exclusion criteria for the present study were revisions of previously unregistered ACL surgeries, non-ACL surgeries, patients for whom 10 year follow-up data had not yet been collected, and the proportion of index surgeries that were revision or contralateral interventions. RESULTS: There were 1,295 KOOS scores available for patients 5 years postsurgery, and 1,023 10 years postsurgery from a baseline of 2,751 index reconstructions. A deterioration between the 5- and 10-year scores was observed for patients with concomitant meniscus injury on the KOOS subscales for pain (P = .015), symptoms (P = .005), sport and recreation (P = .011), and knee-related quality of life (QoL) (P = .03) compared with patients with isolated ACL injury. Correspondingly, KOOS subscale score deterioration was seen for combined concomitant cartilage and meniscus injuries for pain (P = .005), symptoms (P = .009), sport and recreation (P = .006), and QoL (P < .001). The largest deteriorations were found in sport and recreation (-5.9 points; confidence interval [CI] -10.1, -1.1) and QoL (-6.5 points; CI -10.3, -2.8) subscale scores for patients with concomitant meniscal and cartilage injuries. A similar pattern was not seen between patients with concomitant cartilage injury and isolated ACL injury. CONCLUSIONS: The present study reveals that concomitant meniscus injuries at the index operation, either in isolation or in combination with cartilage lesions, render a deterioration of scores on the KOOS outcome subscales for pain, sport and recreation, and quality of life between 5- and 10-year postsurgery follow-up of ACL-reconstructed patients. No such deterioration was seen for patients who had isolated ACL injury. LEVEL OF EVIDENCE: Level III, retrospective analysis of prospectively collected data. PMID- 29395550 TI - The Relationship Between the Location of Uptake on Positron Emission Tomography/Computed Tomography and the Impingement Point by Computer Simulation in Femoroacetabular Impingement Syndrome With Cam Morphology. AB - PURPOSE: To clarify the concordance rate of the location of uptake on positron emission tomography/computed tomography (PET/CT) and the impingement point demonstrated in computer simulation in femoroacetabular impingement (FAI) syndrome with cam morphology. METHODS: We included hip joints with FAI syndrome that underwent 18F-fluoride PET/CT. We also excluded hips with SUVmax <6. Each hip was evaluated for the region of the SUVmax point on PET/CT as well as the impingement point by computer simulation. We used ZedHip software (Lexi, Tokyo, Japan) for impingement simulation analysis based on CT data. Bony impingement is identified if there is a mesh in acetabular and femoral side contact in at least one unit. We investigated the rate of concordance between these 2 regions for each 10 degrees flexion angle of the hip, ranging from 0 degrees to 90 degrees . RESULTS: Twenty-two hips of 22 patients were evaluated. The SUVmax region was most frequently distributed in the proximal middle region in 12 hips. In 18 of 22 hips (81.8%), the SUVmax region was concordant with the impingement region for at least one flexion angle. The concordance rates in 50 degrees (P = .034), 60 degrees (P = .007), 70 degrees (P = .011), and 80 degrees (P = .046) of flexion were significantly higher than in 90 degrees of flexion. CONCLUSIONS: It was possible to visualize and clarify the detailed location of abnormal uptake in FAI syndrome patients with cam morphology by applying 18F-fluoride PET/CT. The concordance rates in 50 degrees , 60 degrees , 70 degrees , and 80 degrees of flexion were significantly higher than in 90 degrees of flexion, which suggested that impingement may more frequently occur at less than 90 degrees of flexion in FAI syndrome with cam morphology. LEVEL OF EVIDENCE: Level III, cross-sectional diagnostic study. PMID- 29395551 TI - Quantitative Assessment of the Coracoacromial and the Coracoclavicular Ligaments With 3-Dimensional Mapping of the Coracoid Process Anatomy: A Cadaveric Study of Surgically Relevant Structures. AB - PURPOSE: To perform a quantitative anatomic evaluation of the (1) coracoid process, specifically the attachment sites of the conjoint tendon, the pectoralis minor, the coracoacromial ligament (CAL), and the coracoclavicular (CC) ligaments in relation to pertinent osseous and soft tissue landmarks; (2) CC ligaments' attachments on the clavicle; and (3) CAL attachment on the acromion in relation to surgically relevant anatomic landmarks to assist in planning of the Latarjet procedure, acromioclavicular (AC) joint reconstructions, and CAL resection distances avoiding iatrogenic injury to surrounding structures. METHODS: Ten nonpaired fresh-frozen human cadaveric shoulders (mean age 52 years, range 33-64 years) were included in this study. A 3-dimensional coordinate measuring device was used to quantify the location of pertinent bony landmarks and soft tissue attachment areas. The ligament and tendon attachment perimeters and center points on the coracoid, clavicle, and acromion were identified and subsequently dissected off the bone. Coordinates of points along the perimeters of attachment sites were used to calculate areas, whereas coordinates of center points were used to determine distances between surgically relevant attachment sites and pertinent bony landmarks. RESULTS: The CAL had a single consistent acromial attachment (mean area 77 mm [51.9, 102.2]) and then bifurcated into 2 bundles, anterior and posterior, that separately inserted on the lateral aspect of the coracoid. The footprint areas were 54.4 mm2 [31.7, 77.2] and 30.6 mm2 [23.4, 37.7] for the anterior and posterior CAL bundles, respectively. These anterior and posterior bundles attached 10.6 mm [8.4, 12.9] and 24.8 mm [12.3, 27.4] medial and proximal to the apex of the coracoid process, respectively. The minimum distance between the coracoid apex and the trapezoid ligament was 25.1 mm [22.1, 28.1] and was noted to be different in males (28.1 mm [25.1; 31.2]) and females (22.0 mm [18.2, 25.9]). The most lateral insertion of the CC ligaments on the clavicle the AC joint was 15.7 mm [13.1, 18.3]. The distance between the most medial to the most lateral point of the CC ligaments on the clavicle was 25.6 mm [22.3, 28.9], which accounted for 18.2% [15.8, 20.6] of the clavicle length. CONCLUSIONS: In contrast to previous findings, 2 different coracoid attachments (anterior and posterior bundles) of the CAL were consistently identified in all specimens. Moreover, a coracoid osteotomy for a bone graft for the Latarjet procedure should be performed at less than 28.1/22 mm from the apex of the coracoid in male/female patients, respectively. The CC ligaments' attachments on the clavicle were located 15.7 mm from the AC joint, which should be considered for reconstruction. CLINICAL RELEVANCE: During the Latarjet technique, to maintain the integrity of the CC ligaments, precise knowledge of differences between male and female anatomy is necessary during a coracoid osteotomy. Furthermore, when reconstructing the AC joint, the distance from the lateral aspect of the clavicle and the size of the attachments areas should be considered to better replicate the native anatomy. PMID- 29395552 TI - Patellofemoral Cartilage Lesions Treated With Particulated Juvenile Allograft Cartilage: A Prospective Study With Minimum 2-Year Clinical and Magnetic Resonance Imaging Outcomes. AB - PURPOSE: To analyze the functional outcomes of patients treated with particulated juvenile articular cartilage (PJAC) for symptomatic articular cartilage lesions in the patellofemoral joint, correlates clinical outcomes with magnetic resonance imaging (MRI) appearance of the repair tissue using cartilage-sensitive quantitative T2-mapping. METHODS: All patients treated with PJAC for patellofemoral lesions were identified and prospectively followed with clinical outcome scores (International Knee Documentation Committee [IKDC], Knee Outcome Survey-Activities of Daily Living [KOS-ADL], and Marx Activity Scale [MAS]). Postoperative MRI scans using quantitative T2 mapping were obtained and interpreted by an independent musculoskeletal radiologist. RESULTS: Twenty-seven patients treated with PJAC for 30 full-thickness patellofemoral cartilage lesions were identified; mean postoperative follow-up was 3.84 years. Improvements from pre- to postoperative mean IKDC (45.9 vs 71.2, P < .001) and KOS-ADL (60.7 vs 78.8, P < .001) scores were observed; no significant change in MAS was seen (7.04 vs 7.17, P = .97). Advanced age, history of previous surgery, lesion location (patella vs trochlea), or concomitant tibial tubercle osteotomy did not affect outcome scores. Greater body mass index was associated with less improvement in KOS-ADL score. No patients required reoperation for graft-related issues. Lesion fill exceeding 67% by MRI assessment was noted in 69.2% of lesions; depth of lesion fill did not correlate with clinical outcomes. Quantitative T2-mapping revealed prolonged relaxation time at the graft site compared with adjacent normal cartilage at both deep and superficial zones. CONCLUSIONS: This study found significantly improved pain and function in patients treated with PJAC for symptomatic patellofemoral articular cartilage defects. No patients required reoperation for graft-related issues. Postoperative MRI revealed majority lesion fill in more than 69% of patients, but persistent morphologic differences between graft site and normal adjacent cartilage remain. Though we support PJAC use in this setting to improve patient subjective outcomes, improved appearance on postoperative imaging was not found to provide additional clinical benefit. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29395553 TI - Arthroscopic Ankle Arthrodesis: A 2-15 Year Follow-up Study. AB - PURPOSE: The purpose of our study was to determine the results of arthroscopic ankle arthrodesis (AAA) and how the procedure affects adjoining joints and functional scores. METHODS: Between 1993 and 2013, 116 patients (120 ankles) underwent AAA. Nineteen ankles were lost to follow-up due to death, insufficient radiographic studies, or inability to contact, resulting in 97 patients (101 ankles). Mean age at surgery was 61.1 years (range, 35.8-79.6 years); mean follow up was 86 months (range, 24-247 months). Patients were assessed according to the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle and Hindfoot scale, Ankle Osteoarthritis Scale (AOS), and Foot and Ankle Outcome Score (FAOS) and underwent comprehensive clinical and radiographic examinations. RESULTS: A total of 94.6% of patients achieved ankle fusion on radiographs. Mean AOFAS score was 83.3 (standard deviation [SD], 13.2). Mean modified FAOS score was 87.4 (SD, 10.4). The AOS scoring system showed 75% good/excellent results. According to the Kellgren-Lawrence score and van Dijk osteoarthritis grading scale, 85% and 69% of patients had no change in talonavicular or subtalar grade of osteoarthritis, respectively. There were no cases of deep infection or other serious adverse events. All but 4 patients were able to return to work following AAA. CONCLUSIONS: AAA is an effective operation for treating degenerative ankle disease, even in cases of moderate tibiotalar coronal deformity. At a mean of 86 months postop, nearly three quarters of our patients had good/excellent functional outcomes. Arthritis found in the adjacent hindfoot joints at the time of tibiotalar fusion appears to be a function of preexisting arthritic change and not directly caused by the tibiotalar fusion. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 29395554 TI - Fundamentals of Arthroscopic Surgery Training Program Improves Knee Arthroscopy Simulator Performance in Arthroscopic Trainees. AB - PURPOSE: To determine the effectiveness of a nonanatomic simulator in developing basic arthroscopy motor skills transferable to an anatomic model. METHODS: Forty three arthroscopy novice individuals currently enrolled in medical school were recruited to perform a diagnostic knee arthroscopy using a high-fidelity virtual reality arthroscopic simulator providing haptic feedback after viewing a video of an expert performing an identical procedure. Students were then randomized into an experimental or control group. The experimental group then completed a series of self-guided training modules using the fundamentals of arthroscopy simulator training nonanatomic modules including camera centering, tracking, periscoping, palpation, and collecting stars in a three-dimensional space. Both groups completed another diagnostic knee arthroscopy between 1 and 2 weeks later. Camera path length, time, tibia and femur cartilage damage, as well as a composite score were recorded by the simulator on each attempt. RESULTS: The experimental group (n = 22) showed superior performance in composite score (30.09 vs 24, P = .046) and camera path length (71.51 cm vs 109.07 cm, P = .0274) at the time of the second diagnostic knee arthroscope compared with the control group (n = 21). The experimental group also showed significantly greater improvement in composite score between the first and second arthroscopes compared with the control group (14.27 vs 4.95, P < .01). Femoral and tibial cartilage damage were not significantly improved between arthroscopy attempts (-0.86% vs -1.45%, P = .40) and (-1.10 vs -1.27%, P = .83), respectively. CONCLUSIONS: The virtual reality based fundamentals of arthroscopy simulator training nonanatomic simulator is beneficial in developing basic motor skills in arthroscopy novice individuals resulting in significantly greater composite performance in an anatomic knee model. Based on the results of this study, it appears that there may be benefit from nonanatomic simulators in general as part of an arthroscopy training program. LEVEL OF EVIDENCE: Level II, randomized trial. PMID- 29395555 TI - Reporting Standards in Clinical Studies Evaluating Bone Marrow Aspirate Concentrate: A Systematic Review. AB - PURPOSE: To perform a systematic review of clinical studies evaluating bone marrow aspirate concentrate (BMAC) in the treatment of musculoskeletal pathology to compare levels of reporting with recently published minimum standards. METHODS: A systematic review of the clinical literature from August 2002 to August 2017 was performed. Human clinical studies published in English and involving the administration of BMAC for musculoskeletal applications were included. Studies evaluating non-concentrated preparations of bone marrow aspirate or preparations of laboratory cultured cells were excluded. Studies evaluating the treatment of dental or maxillofacial conditions were excluded. Similarly, in vitro studies, editorials, letters to the editor, and reviews were excluded. Levels of reporting were compared with previously published minimum standards agreed on through an international Delphi consensus process. RESULTS: Of 1,580 studies identified on the initial search, 46 satisfied the criteria for inclusion. Considerable deficiencies in reporting of key variables including the details of BMAC preparation and composition were noted. Studies reported information on only 42% (range, 25%-60%) of the variables included within established minimum reporting standards. No study provided adequate information to enable the precise replication of preparation protocols and accurate characterization of the BMAC formulation delivered. CONCLUSIONS: We found that all existing clinical studies in the literature evaluating BMAC for orthopaedic or sports medicine applications are limited by inadequate reporting of both preparation protocols and composition. Deficient reporting of the variables that may critically influence outcomes precludes interpretation, prevents other researchers from reproducing experimental conditions, and makes comparisons across studies difficult. We encourage the adoption of emerging minimum reporting standards for clinical studies evaluating the use of mesenchymal stem cells in orthopaedics. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies. PMID- 29395556 TI - Outcomes of Arthroscopic Management of Trochanteric Bursitis in Patients With Femoroacetabular Impingement: A Comparison of Two Matched Patient Groups. AB - PURPOSE: To determine the prevalence of chronic trochanteric bursitis (TB) in patient being treated for femoroacetabular impingement (FAI) and determine the effectiveness of arthroscopic bursectomy and iliotibial band lengthening (AB-ITB L) at the time of hip arthroscopy for FAI. METHODS: Patients diagnosed with primary FAI and chronic TB were included in the study. Patients were included if they underwent hip arthroscopy with labral repair, femoral and/or acetabular osteoplasty, and AB-ITB-L. Patients were matched by age and gender to patients without chronic TB. RESULTS: The prevalence of chronic TB with FAI was 7% (90/1,278). Females were 5.3 times more likely to have TB compared with males (95% confidence interval: 3.2-8.7). Patients more than 30 years of age were 2.5 times more likely to have TB (95% confidence interval: 1.48-4.4). Of the 90 patients diagnosed with TB, 72 (54 female, 18 male) with an average age of 36.7 years underwent AB-ITB-L at the time of their index hip arthroscopy for FAI. All 72 patients had associated intra-articular pathology consisting of a combined cam and pincer pathology. The TB (average follow-up = 42 +/- 9.9 months) and non-TB group (average follow-up = 42 +/- 9.1 months) both had significant improvement from preoperative to postoperative scores for Hip Outcome Score Activities Daily Living, Hip Outcome Score Sport, Modified Harris Hip Score, Western Ontario and McMaster Universities Arthritis Index, Short Form (SF)-12 Physical Component score, and SF-12 Mental Component Score. There was no significant difference between the 2 groups in postoperative patient reported outcome scores. CONCLUSIONS: The occurrence of chronic TB in the FAI population, which did not adequately respond to nonoperative management, for a single surgeon high volume hip arthroscopy practice was 7%, and was more commonly seen in women older than 30 years. Patients who undergo concomitant AB-ITB-L for chronic TB report excellent pain relief, and have equivalent results and outcome scores that are not inferior when compared with patients with primary FAI without chronic TB. LEVEL OF EVIDENCE: Level III, retrospective matched case control study. PMID- 29395557 TI - All-Epiphyseal Anterior Cruciate Ligament Femoral Tunnel Drilling: Avoiding Injury to the Physis, Lateral Collateral Ligament, Anterolateral Ligament, and Popliteus-A 3-Dimensional Computed Tomography Study. AB - PURPOSE: To investigate the relation of the at-risk structures (distal femoral physis, lateral collateral ligament, anterolateral ligament, popliteus, and articular cartilage) during all-epiphyseal femoral tunnel drilling. A second purpose was 2-fold: (1) to develop recommendations for tunnel placement and orientation that anatomically reconstruct the anterior cruciate ligament (ACL) while minimizing the risk of injury to these at-risk structures, and (2) to allow for maximal tunnel length to increase the amount of graft in the socket to facilitate healing. METHODS: Three-dimensional models of 6 skeletally immature knees (aged 7-11 years) were reconstructed from computed tomography and used to simulate all-epiphyseal femoral tunnels. Tunnels began within the ACL footprint and were directed laterally or anterolaterally, with the goal of avoiding injury to at-risk structures. The spatial relation between the ideal tunnel and these structures was evaluated. Full-length tunnels and partial length condyle sockets were simulated in the models using the same trajectories. RESULTS: An anterolateral tunnel could be placed to avoid direct injury to lateral structures. The safe zone on the anterolateral aspect of the femur was larger than that of a tunnel with a direct lateral trajectory (median 127 mm2 vs 83 mm2, P = .028). Anterolateral tunnels were longer than direct lateral tunnels (median 30 mm vs 24 mm, P = .041). Safe angles for anterolateral tunnels were 34 degrees to 40 degrees from the posterior condylar axis; direct lateral tunnels were drilled 4 degrees to 9 degrees from the posterior condylar axis. Sockets could be placed without direct injury to structures at risk with either orientation. CONCLUSIONS: An all-epiphyseal ACL femoral tunnel can be placed without causing direct injury to at-risk structures. A tunnel angled anterolaterally from the ACL origin is longer and has a larger safe zone compared with the direct lateral tunnel. CLINICAL RELEVANCE: The largest safe zone for femoral all-epiphyseal ACL drilling was (1) anterior to the lateral collateral ligament origin, (2) distal to the femoral physis, and (3) proximal to the popliteus tendon origin. A direct lateral tunnel may also be used, but has a smaller safe zone. Sockets or partial length tunnels may have a lower risk of injury to at-risk structures. PMID- 29395558 TI - [Vascular rehabilitation in lower-extremity artery diseasein 2018]. AB - WHAT WE KNEW: The vascular rehabilitation is an effective treatment for patients with an intermittent claudication linked to lower-extremity artery disease. This treatment increases the claudication distance of 180% with the Gardner's protocol (30 to 60 minutes of walking at least 3 times a week, walking until appearance of a mild pain) and allows also to control the vascular risk factors. This treatment is not enough prescribed for many reasons and often requires a hospitalization in a rehabilitation centre. WHAT WE KNOW NOW: Walking rehabilitation remains the base of the treatment of lower-extremity artery disease. Many walking protocols can be proposed. For a similar efficiency, patients are not obliged to walk until appearance of a pain but only until appearance of a discomfort. Exercises other than walking have been tested and can be used. Heart Rehabilitation Centres will propose more often vascular rehabilitation including hospitalisations for complex patients or out-management for non-complex patients. With a lower cost, the walking rehabilitation could be also realised at home by the patient himself with a certain degree of supervision with good results. Supervision means the use of a podometer, weekly advices given by phone by a Vascular Physician or a Physiotherapist, one walking session once a week in a rehabilitation centre. Connected devices could be also helpful allowing increasing of the patients' motivation. Simultaneously, it is necessary that the patients observe the recommendations of the World Health Organisation by performing weekly 150 minutes of mild-intensity endurance's activity in order to minimise their long-term vascular risk. Finally, the respective place of the revascularisations and walking rehabilitation remains to be clarify in case of intermittent claudication due to a superficial femoral artery lesion. PMID- 29395559 TI - [Neuroleptic malignant syndrome under amisulpride in a patient during a second acute psychotic episode]. PMID- 29395560 TI - [Effect of a surgical mask on six minute walking distance]. AB - INTRODUCTION: Six minutes walking test (6MWT) is regularly used in pulmonology. To minimize the risk of cross-infection, some patients must wear surgical mask at rest and sometimes during exercise. AIM OF THE STUDY: To evaluate the effect of wearing a surgical mask during 6MWT in healthy subjects. MATERIAL AND METHOD: It is a prospective study on 44 healthy subjects. After a first 6MWT for training, they performed randomly two 6MWT: with or without a surgical mask. Distance and dyspnea, heart rate and saturation variations were recorded. RESULTS: Distance was not modified by the mask (P=0.99). Dyspnea variation was significantly higher with surgical mask (+5.6 vs. +4.6; P<0.001) and the difference was clinically relevant. No difference was found for the variation of other parameters. CONCLUSION: Wearing a surgical mask modifies significantly and clinically dyspnea without influencing walked distance. PMID- 29395561 TI - [Tracheostomy performed in ICU: Professional practice assessment and patient outcome]. AB - INTRODUCTION: Tracheostomy is a commonly performed procedure. The aim of this study was to assess professional practice, describe patient characteristics and examine short and long-term outcomes. METHODS: All patients with CCAM GEPA004 code were retrospectively included. RESULTS: Two hundred and fourteen (7%) patients who were mecanically ventilated had a tracheostomy performed in intensive care unit (ICU). Median time to tracheostomy was 22 (14-28) days. In total, 95.3% of tracheostomy procedures were surgical. Median age was 58 (48-67) years. Eighty-three (38.8%) tracheostomies were performed for respiratory reasons. Twenty-eight-day and 90-day mortality were 4.2% and 35.5%. One-year mortality was 52.4%. Patients with tracheostomies performed for weaning from mechanical ventilation had a higher mortality rate. After ICU discharge, mortality rate was 29.8% and was higher in non-decannulated patients. Patient characteristics, timing, technique, indication and outcomes were stable over the years. CONCLUSION: Young patients weaning from mechanical ventilation were more likely to receive a tracheostomy. More than half died during the first year. Patients discharged from ICU with a tracheostomy tube in place had higher mortality rate. PMID- 29395562 TI - [Endobronchial ultrasound with transbronchial needle aspiration: Evaluation of clinical practice]. AB - INTRODUCTION: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has undergone a large increase in France since 2007. The aim is to study the evolution of the indications for EBUS-TBNA in our region during the period 2008-2013. MATERIAL AND METHODS: We conducted a retrospective observational study including all the patients who underwent an EBUS-TBNA procedure in Picardie from 2008 to 2013. The respective proportion for each indication was noted. RESULTS: During the study period, 1036 EBUS-TBNA procedures were performed with a continuous increase in number (86 in 2008 versus 275 in 2013). We observed an increase in the proportion of procedures performed for a suspected diagnosis of sarcoidosis (OR=1.31; IC 95% [1.09-1.58]; P=0.005) and for the simultaneous diagnosis and staging of lung cancer (OR=1.12; IC 95% [1.02 1.24]; P=0.022). For the diagnosis of sarcoidosis, we observed an improvement in the diagnostic yield between the periods [2008-2010] and [2011-2013] (42.9% versus 72.5%). CONCLUSION: A continuous increase in the number of EBUS-TBNA procedures was observed during the period 2008-2013. It was associated with a modification in practice with an increased proportion of procedures performed for the diagnosis of sarcoidosis. PMID- 29395563 TI - [Bacteriology of acute exacerbations of chronic obstructive pulmonary disease in Tunisia]. AB - INTRODUCTION: The role of bacteria, including atypical organisms, in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has been assessed in various ways in Tunisia. METHODS: This was a descriptive and analytical study of patients with a mean age of 68.3+/-10.5 years hospitalized for AECOPD. Bacteriological examination included a cytological sputum exam and serology for atypical organisms including Mycoplasma pneumoniae, Coxiella burnetii, Chlamydophila pneumoniae and Legionella pneumophila using standard techniques. RESULTS: Of the 240 patients enrolled, 175 sputum cultures (73%) were considered significant. Twenty-nine cultures were positive (16.5%) and 31 microorganisms were isolated of which the most frequent were P. aeruginosa (25.8%), K. pneumoniae (16.2%), H. influenzae (13%) and S. pneumoniae (9.7%). The prevalence of C. pneumoniae, M. pneumoniae and C. burnetii was 8.4%, 9% and 6.6%, respectively. No L. pneumophila infection was found. The Anthonisen criteria were associated with a positive culture (P=0.04). Almost half (40.9%) of the isolates were resistant to conventional first line antibiotics (43.7% to amoxicillin clavulanic acid). CONCLUSIONS: Awareness of the low positivity of quantitative sputum bacteriology and the large percentage of resistant strains with a predominance of exclusively multi-resistant Pseudomonas should help in the management of patients with AECOPD. PMID- 29395565 TI - [Rigid bronchoscopy]. PMID- 29395564 TI - [Cohort of patients initiated to home ventilation. Observational and prospective study]. AB - Cohort of patients initiated to home ventilation. Observational and prospective study. The effectiveness of home noninvasive ventilation (NIV) for chronic respiratory failure (CRF) is well established. However, few data are available about home NIV prescription and utilization according to the different etiologies of respiratory failure. The ANTADIR Federation, in partnership with the Ventilatory Support Group of the French Speaking Pulmonary Society, has set up a national, observational and multicenter cohort study. The main goal of this study is to analyze the clinical data justifying home NIV prescription in patients with chronic respiratory insufficiency. The secondary objectives will be to assess: the evolution of comorbidities or their occurrence, hospitalizations, NIV compliance, dropout and survival. The population includes patients with chronic respiratory failure newly initiated onto NIV, both in a stable state and following an acute exacerbation who qualify for long-term NIV. Data collected include: diagnosis and comorbidities, age, sex, BMI, biomarkers (hematocrit, arterial blood gases, total CO2) and functional data (FEV1, VC, TLC), nocturnal results (SaO2, PtcCO2), type of ventilator used, ventilator parameters and mask type. Follow-up data will be collected at 4 months, 1 year and 2 years and will include: hospitalizations, changes in prescription, adherence, dropouts and deaths. This work will make it possible to obtain new scientific information on long-term NIV use in France. PMID- 29395566 TI - [Clinical and radiological characteristics of pulmonary tuberculosis in tobacco smokers]. AB - INTRODUCTION: Tobacco smoke alters lung defense mechanisms against infections and so increases the risk of mycobacterium tuberculosis infection. OBJECTIVE: To determine the particular clinical features of tuberculosis in smokers and identify risk factors. METHODS AND PATIENTS: We conducted a prospective, cross sectional study over a period of nine months in Dakar, Senegal. The Chi-square test and multiple logistic regression were used to identify differences between smokers and non-smokers and to identify factors associated with clinical outcomes. RESULTS: We included 165 patients with active pulmonary tuberculosis (59 smokers versus 106 never-smokers). The average age of smokers was 43.8+/-12.7 versus 32.1+/-13.1 years (P<0.0001). Smokers were overwhelmingly male (98.3% versus 1.8%, P<0.0001). The average delay to consultation was longer among smokers (90 days [30-120] versus 60 days [30-90] ; P<0.0001). In multivariate analysis, alcohol abuse, increasing age, male sex, and an unknown retroviral status were independent risk factors for pulmonary tuberculosis. Haemoptysis was observed more frequently in smokers (49.1% versus 31.1%, P=0.017). With regards to chest X-ray features, smokers presented with more advanced, bilateral and cavitating lung lesions. CONCLUSION: Diagnostic delay and haemoptysis are important characteristics of the pulmonary tuberculosis in tobacco smokers. PMID- 29395567 TI - [Immune checkpoint inhibitors (antibodies to PD1 and PD-L1), a new therapeutic weapon against non-small cell bronchial carcinoma]. AB - INTRODUCTION: Classical therapeutic strategy for advanced and metastatic non small cell lung cancer, without activable oncogenic driver mutation, has been based mainly on cytotoxic chemotherapy with modest benefits in terms of increased survival. BACKGROUND: A better understanding of the mechanisms involved in the regulation of the immune system led to the development of antibodies directed against immune checkpoints such as PD-L1. The first encouraging clinical data from phase I studies assessing anti-PD1 and anti-PD-L1 antibodies have been confirmed in randomised phase III trials. CONCLUSIONS: These new drugs now constitute a standard second-line treatment for metastatic tumours and in the future, at least for pembrolizumab, in the first line. Their adjuvant role after locoregional treatment with curative intent is currently under investigation. PMID- 29395568 TI - [Pulmonary granuloma in an immunodepressed patient]. AB - INTRODUCTION: Pulmonary alveolar echinococcosis is a rare but potentially severe condition. CASE REPORT: We report the case of a 50-year-old woman suffering from pulmonary alveolar echinococcosis who had had a renal transplant for polycystic liver and kidney disease. A lung opacity was identified radiologically in May 2013. Both broncho-alveolar lavage and bronchial biopsy were uninformative. In January 2014, a follow up CT-scan showed the opacity to be enlarging. A surgical biopsy revealed a giant cell epithelioid granuloma with caseous necrosis suggesting a diagnosis of pulmonary tuberculosis. Antituberculous treatment was started but cultures remained negative. A histological revue was therefore requested in March 2014. This suggested bronchocentric granulmatosis, possibly associated with echinococcosis. This hypothesis was finally confirmed serologically. Treatment for alveolar echinococcosis was begun in June 2014 after consultation with the national reference centre for parasitology. CONCLUSION: Outside endemic areas and in the absence of hepatic involvement pulmonary alveolar echinococcosis can be difficult to diagnose. This case report focuses on the diagnostic criteria and treatment. PMID- 29395569 TI - Dilemmas in infection control in the intensive care unit. PMID- 29395570 TI - What was I thinking? Decision making and its impact on outcomes, quality improvement, and research. PMID- 29395571 TI - Nonfatal Injuries to Law Enforcement Officers: A Rise in Assaults. AB - INTRODUCTION: Limited studies exist that describe nonfatal work-related injuries to law enforcement officers. The aim of this study is to provide national estimates and trends of nonfatal injuries to law enforcement officers from 2003 through 2014. METHODS: Nonfatal injuries were obtained from the National Electronic Injury Surveillance System-Occupational Supplement. Data were obtained for injuries treated in U.S. emergency departments from 2003 to 2014. Nonfatal injury rates were calculated using denominators from the Current Population Survey. Negative binomial regression was used to analyze temporal trends. Data were analyzed in 2016-2017. RESULTS: Between 2003 and 2014, an estimated 669,100 law enforcement officers were treated in U.S. emergency departments for nonfatal injuries. The overall rate of 635 per 10,000 full-time equivalents was three times higher than all other U.S. workers rate (213 per 10,000 full-time equivalents). The three leading injury events were assaults and violent acts (35%), bodily reactions and exertion (15%), and transportation incidents (14%). Injury rates were highest for the youngest officers, aged 21-24 years. Male and female law enforcement officers had similar nonfatal injury rates. Rates for most injuries remained stable; however, rates for assault-related injuries grew among law enforcement officers between 2003 and 2011. CONCLUSIONS: National Electronic Injury Surveillance System-Occupational Supplement data demonstrate a significant upward trend in assault injuries among U.S. law enforcement officers and this warrants further investigation. Police-citizen interactions are dynamic social encounters and evidence-based policing is vital to the health and safety of both police and civilians. The law enforcement community should energize efforts toward the study of how policing tactics impact both officer and citizen injuries. PMID- 29395572 TI - Case Reports of Acupuncturists and Massage Therapists at Mayo Clinic: New Allies in Expediting Patient Diagnoses. AB - Acupuncturists and massage therapists practicing within hospital and clinic settings is a relatively new, but growing phenomenon. Many clinical trials have documented the therapeutic roles these professionals can play in caring for patients. However, to our knowledge, little emphasis has been placed on their ability to aid in the diagnostic process. We report here our experience with these providers playing a critical role in contributing novel diagnostic information, both in the outpatient and inpatient settings. These observations suggest that acupuncturists and massage therapists can play a strategic role in helping achieve timely diagnoses for many patients. Strategies on how to incorporate these professionals into the care flow in the clinic and hospital are discussed. PMID- 29395573 TI - Increased levels of lipocalin 2 in palmoplantar pustular psoriasis. AB - BACKGROUND: Palmoplantar pustular psoriasis (PPP) is a recalcitrant chronic skin disease affecting the palms and soles. OBJECTIVE: To identify and characterize pathogenetic players in PPP. METHODS: Clinical and anamnestic data as well as skin and blood samples of 60 PPP patients were collected. Healthy participants served as controls. Analysis of patient samples and cultured primary skin cells was performed by ELISA, qRT-PCR, and immunohistochemistry. RESULTS: Upon screening of blood mediators in PPP patients, lipocalin 2 (LCN2) emerged as being significantly upregulated compared to healthy participants. LCN2 blood levels were independent of age, sex, or concomitant psoriasis vulgaris. Keratinocytes in PPP skin lesions were important LCN2 producers. In vitro, LCN2 production of these cells was upregulated by IL-1beta and further enhanced by IL-17 and TNF alpha, while IL-22 had no effect. Accordingly, a positive relationship between blood IL-1beta and LCN2 levels was evident in PPP. LCN2 blood levels also showed a positive correlation with PPP pustule score, Dermatology Quality of Life Index and blood levels of the pro-atherogenic molecule resistin. CONCLUSIONS: In PPP, increased blood levels of LCN2 indicate an important activity of IL-1beta in the epidermis, may contribute to skin neutrophil infiltration, and may point to an increased pro- atherosclerosis risk. PMID- 29395574 TI - Up-regulated expression of CD86 on circulating intermediate monocytes correlated with disease severity in psoriasis. AB - BACKGROUND: The number of intermediate monocytes (CD14++CD16+) increases in many inflammatory conditions. However, it is not yet known which functional markers expressed by these populations are linked to the pathogenesis of psoriasis. OBJECTIVES: We evaluated the expression of functional markers on circulating intermediate monocytes. Our goal was to correlate specific populations and their markers with the clinical severity of psoriasis. METHODS: A cohort of 43 psoriatic patients was subjected to analysis. The proportion of intermediate monocytes with CD86 expression was evaluated by flow cytometry. Serum beta defensin-2 levels were measured by ELISA. Immunofluorescent staining was performed in order to identify the presence of CD14+CD16+ cells that co-expressed CD86 in affected skin tissues. RESULTS: Upregulated expression of CD86 on the intermediate subset (but not the number of intermediate monocytes) correlated with clinical severity as measured by PASI scores and serum beta defensin-2 levels. Immunostaining also showed the presence of CD86+CD14+CD16+ cells in the epidermis and dermis of psoriatic plaques, which was associated with increased epidermal proliferation. CONCLUSION: These results suggest that the expression of CD86 on circulating intermediate monocytes could be used as an index in clinical practice and provide novel insights into how these cells join a complex immune network under the pathological conditions of psoriasis. PMID- 29395575 TI - Age-dependent trigeminal and female-specific lumbosacral increase in herpes zoster distribution in the elderly. AB - BACKGROUND: Varicella-zoster virus causes herpes zoster (HZ) along specific dermatomes, but the effects of age and sex on HZ distribution are unclear. OBJECTIVE: We investigated the age- and sex-dependent distribution characteristics of HZ. METHODS: Patients with HZ were monitored by members of the Miyazaki Dermatologist Society. Questionnaires containing information on age, sex, and dermatome distribution and lesion specimens from 2730 patients were collected, and 2508 PCR-diagnosed cases were analyzed. RESULTS: The ratio of lesions in the thoracic area to lesions in the whole body decreased with age, whereas those of other areas increased. HZ incidence increased with age to about four times that of the basic incidence in the dermatome areas at age 0-29 years; the incidence in the trigeminal area in both sexes increased 11-fold, and the incidence in the thoracic and lumbosacral areas increased in females more than in males. Furthermore, the fact that the highest incidence was found along the first branch of the trigeminal nerve suggests an association with long-term ultraviolet ray exposure. Segmental dermatomes comprising thoracic 10-lumbar 1/sacral 2-4 and thoracic 5-6 were significantly more frequently affected in female patients at age 50-59 years and are consistent with areas of obstetric anesthesia for childbirth and of breastfeeding, respectively. CONCLUSIONS: HZ incidence increased with age; moreover, exposure to ultraviolet rays, childbirth, and breastfeeding might increase the incidence at specific dermatomes in older individuals. This study provides important information on the etiology of HZ. PMID- 29395576 TI - Reduced-HMGB1 suppresses poly(I:C)-induced inflammation in keratinocytes. AB - BACKGROUND: High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes DNA and facilitates gene transcription. Additionally, cell stress or death induces the release of HMGB1 outside the cell membrane, where HMGB1 functions as an alarmin, causing an inflammatory response in combination with other cytokines, damage-associated molecular patterns (DAMPs), and pathogen associated molecular patterns (PAMPs). OBJECTIVE: To evaluate the effect of reduced-HMGB1 (previously termed chemoattractive-HMGB1) on polyinosine polycytidylic acid [poly(I:C)]-induced inflammation in normal human keratinocytes (NHKs). METHODS: We focused on downstream components of the poly(I:C)-Toll-like receptor 3 (TLR3), retinoic acid-inducible gene-I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) pathways, including IkappaBalpha, nuclear factor (NF)-kappaB p65, mitogen-activated protein kinase (MAPK), and interferon regulatory factor 3 (IRF3), and assessed whether these pathways are involved in the suppression of poly(I:C)-induced inflammation in NHKs by HMGB1. An immunoprecipitation was performed to know whether HMGB1 could bind to poly(I:C), and immunofluorescence staining and flow cytometric analysis were performed to check whether reduced-HMGB interferes with cellular uptake of poly(I:C) translocation (possibly by endocytosis). RESULTS: Application of exogenous HMGB1 before, but not after, exerted a suppressive effect on poly(I:C) induced inflammation in NHKs. In addition, reduced-HMGB1, but not disulfide HMGB1, exerted a suppressive effect on poly(I:C)-induced inflammation in NHKs, suggesting the importance of the redox status of exogenous HMGB1. Pre-treatment with reduced-HMGB1 inhibited the phosphorylation of IkappaBalpha, NF-kappaB p65, and IRF3 induced by poly(I:C) stimulation in NHKs; however, phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) was unaffected. Disulfide-HMGB1 formed a complex with poly(I:C), as did reduced- and oxidized-HMGB1, albeit to a lesser extent. Immunofluorescence staining and flow cytometric analysis indicated that reduced-HMGB interferes with cellular uptake of poly(I:C) translocation (possibly by endocytosis). CONCLUSION: These findings suggest that pre-treatment with reduced-HMGB1 ameliorates poly(I:C)-mediated inflammation in NHKs. PMID- 29395578 TI - Suppression of autophagy perturbs turnover of sequestosome-1/p62 in Merkel cells but not in keratinocytes. PMID- 29395577 TI - HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. AB - BACKGROUND: The anticancer effects of histone deacetylase inhibitors (HDACi) vary between patients, and their molecular mechanisms remain poorly understood. Previously, we have identified heat shock 70 kDa protein 1A (HSPA1A, also known as HSP72) as the most overexpressed protein in valproic acid (VPA)-resistant cell lines. KNK437, an inhibitor of heat shock proteins, enhanced the cytotoxic effects of not only VPA but also vorinostat, another HDACi. However, the mechanisms underlying the role of HSP72 in resistance against HDACi remain largely unknown. OBJECTIVE: The purpose of this study was to identify the mechanisms underlying the role of HSP72 in HDACi resistance. METHODS: We established an HSP72-overexpressing Jurkat cell line and used it to assess the functional role of HSP72 following treatment with the HDACi vorinostat and VPA. RESULTS: HDACi-induced apoptosis, assessed using annexin V assays, sub-G1 fraction analysis, and PARP cleavage, was significantly lower in HSP72 overexpressing cells than in control cells. The HDACi-induced upregulation in caspase-3, -8, and -9 activity, as well as the HDACi-induced reduction in mitochondrial membrane potential, were also suppressed following HSP72 overexpression. The basal expression levels of Bcl-2, phosphorylated Bad, and XIAP increased in HSP72-overexpressing cells, whereas HDACi-induced Bid truncation and the suppression of Bad expression. Furthermore, vorinostat-induced histone hyperacetylation was also diminished in HSP72-overexpressing cells. CONCLUSION: These findings clearly demonstrate that HSP72 inhibits HDACi-induced apoptosis. PMID- 29395579 TI - Trans-cinnamic acid attenuates UVA-induced photoaging through inhibition of AP-1 activation and induction of Nrf2-mediated antioxidant genes in human skin fibroblasts. AB - BACKGROUND: UVA irradiation-induced skin damage/photoaging is associated with redox imbalance and collagen degradation. OBJECTIVE: Dermato-protective efficacies of trans-cinnamic acid (t-CA), a naturally occurring aromatic compound have been investigated against UVA irradiation, and elucidated underlying molecular mechanism. METHODS: Human foreskin fibroblast-derived (Hs68) cells and nude mice were treated with t-CA prior to UVA exposure, and assayed the anti photoaging effects of t-CA. RESULTS: We found t-CA (20-100 MUM) pretreatment substantially ameliorated UVA (3 J/cm2)-induced cytotoxicity, and inhibited intracellular ROS production in Hs68 cells. UVA-induced profound upregulation of metalloproteinase (MMP)-1/-3 and degradation of type I procollagen in dermal fibroblasts were remarkably reversed by t-CA, possibly through inhibition of AP-1 (c-Fos, but not c-Jun) translocation. The t-CA-mediated anti-photoaging properties are associated with increased nuclear translocation of Nrf2. Activation of Nrf2 signaling is accompanied with induction of HO-1 and gamma-GCLC expressions in t-CA-treated fibroblasts. Furthermore t-CA-induced Nrf2 translocation is mediated through PKC, AMPK, CKII or ROS signaling cascades. This phenomenon was confirmed with respective pharmacological inhibitors, GF109203X, Compound C, CKII inhibitor or NAC, which blockade t-CA-induced Nrf2 activation. Silencing of Nrf2 signaling with siRNA showed no anti-photoaging effects of t-CA against UVA-induced ROS production, loss of HO-1 and type I collagen degradation in fibroblasts. In vivo evidence on nude mice revealed that t-CA pretreatment (20 or 100 mM/day) significantly suppressed MMP-1/-3 activation and maintained sufficient type I procollagen levels in biopsied skin tissue against UVA irradiation (3 J/cm2/day for 10-day). CONCLUSION: t-CA treatment diminished UVA induced photoaging/collagen degradation, and protected structural integrity of the skin. PMID- 29395580 TI - A lamellar body mimetic system for the treatment of oxazolone-induced atopic dermatitis in hairless mice. AB - BACKGROUND: Atopic dermatitis is a common skin disease characterized by a Th2 cell-dominant inflammatory infiltrate, elevated serum IgE levels and impaired epidermal barrier function. It is associated to abnormal epidermal lamellar body secretion, producing alteration in lipid composition and extracellular lamellar membrane organization. OBJECTIVES: The oxazolone-induced atopic dermatitis in hairless mice was used to evaluate in vivo the effect of the application of a lipid system that mimics the morphology, structure and composition of epidermal lamellar bodies. METHODS: The skin barrier function was evaluated measuring TEWL and skin hydration in vivo. Inflammation was assessed by analysis of serum IgE levels and histological analysis. The microstructure of the intercellular lipid region was also evaluated before and after treatment. RESULTS: The skin condition was improved after 10 days of treatment indicated by decreased TEWL, decreased serum IgE levels, reduced epidermal thickness and reduced lymphocyte-dominated infiltrate. However, the treatment did no improve skin hydration. CONCLUSIONS: The treatment with this lipid system seems to improve the skin condition by reinforcing the barrier function and reducing the skin inflammation. Therefore, the present study provides evidence that this lipid system combining appropriate lipid composition and morphology could be of interest for the development of future treatments for atopic dermatitis. PMID- 29395581 TI - Association of elevated homocysteine levels and Methylenetetrahydrofolate reductase (MTHFR) 1298 A > C polymorphism with Vitiligo susceptibility in Gujarat. AB - BACKGROUND: Several studies have reported hyperhomocysteinemia in vitiligo patients, suggesting the potential role of elevated homocysteine levels in precipitating vitiligo. OBJECTIVES: We aimed to estimate homocysteine and vitamin B12 levels, and to investigate the role of MTHFR 677 C > T and 1298 A > C polymorphisms in vitiligo susceptibility in Gujarat population. METHODS: Homocysteine and vitamin B12 levels were estimated in plasma of 55 vitiligo patients and 60 controls by Electrochemiluminescence immunoassay (ECLIA). Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) techniques were used to genotype MTHFR 677 C > T and 1298 A > C polymorphisms in 520 vitiligo patients and 558 controls. RESULTS: Our results showed significantly elevated homocysteine levels (p = 0.0003) as well as significant decrease in vitamin B12 levels (p = 0.0102) in vitiligo patients, as compared to controls. No significant difference in genotype and allele frequencies of MTHFR 677 C > T polymorphism was observed among patients and controls, however, the frequency of 'CC' genotype of MTHFR 1298 A > Cpolymorphism was significantly increased in patients as compared to controls (p = 0.0151). Analysis based on the type of vitiligo revealed a significant increase in 'C' allele of MTHFR 1298 A > C polymorphism in patients with generalized (p = 0.003) and active (p = 0.007) vitiligo as compared to controls. Both the polymorphisms of MTHFR were in low linkage disequilibrium (LD) and susceptible 'TC' haplotype was more frequently observed (p = 0.008) in vitiligo patients. Interestingly, elevated homocysteine levels were also positively correlated with MTHFR 1298 A > C polymorphism in vitiligo patients. Structure based in silico prediction revealed structural perturbations in MTHFR protein due to Ala222Val and Glu429Ala amino acid substitution. CONCLUSIONS: The present findings suggest that MTHFR 1298 A > C polymorphism and, altered homocysteine and vitamin B12 levels might play a vital role in the precipitation of vitiligo. PMID- 29395582 TI - Gap Formation During Cyclic Testing of Flexor Tendon Repair. AB - PURPOSE: Substantial gap formation of a repaired finger flexor tendon is assumed to be harmful for tendon healing. The purpose of this study was to investigate the relationship between gap formation and the failure of the repair during cyclic loading. METHODS: Thirty-five porcine flexor tendons were repaired and tested cyclically using variable forces until failure or a maximum of 500 cycles. Depending on the biomechanical behavior during cyclic testing, specimens were divided into 3 groups: Sustained (no failure), Fatigued (failure after 50 cycles), and Disrupted (failure before 50 cycles). The relationships between the gap formations, time-extension curves, and group assignments of the samples were investigated. RESULTS: The time-extension curves of the Fatigued specimens showed a sudden onset of repair elongation-a fatigue point-which preluded the subsequent failure of the repair. This point coincides with the start of plastic deformation and, thereafter, cumulative injury of the repair consistently led to failure of the repair during subsequent cycles. None of the sustained repairs showed a fatigue point or substantial gapping during loading. CONCLUSIONS: We conclude that the emergence of a fatigue point and subsequent gap formation during loading will lead to failure of the repair if loading is continued. CLINICAL RELEVANCE: The results of this experimental study imply that an inadequate flexor tendon repair that is susceptible to gap formation is under risk of failure. PMID- 29395583 TI - Rotational Pedicle Myocutaneous Forearm Fillet Flap Used to Fill Forequarter Amputation Defect: Indications and Uses. AB - A full-thickness fourth-degree burn to a large area of the upper extremity may require a forequarter amputation. Whereas our case describes a burn injury, forequarter amputations may more commonly be done in oncological surgery. In addition to the challenge of providing well-vascularized tissue coverage, the burn patient may also pose the complication of respiratory compromise in a systemically ill person. Fillet flaps have often been utilized as "spare part" reconstruction. Although previous forequarter amputations have been covered with free myocutanous forearm fillet flaps, we devised a rotational pedicle myocutaneous forearm fillet flap that might be less complex than a microvascular reconstruction. This article describes the technique and advantages of the pedicle fillet flap of the upper limb. This technique eliminates the risks of delayed warm ischemia time and avoids additional morbidity of donor sites. Although we sought to find a simpler, more rapid procedure for a burn patient, the pedicle forearm fillet flap has applications for both burn and oncological forequarter amputation defects. It provides a good combination of large tissue coverage with maximum perfusion of muscle bulk. The pedicle flap also enabled us to keep the distal part vascularized and to "bank" it for later use when the recipient area was well vascularized and free of infection. PMID- 29395584 TI - Arthroscopic Diagnosis of the Triangular Fibrocartilage Complex Foveal Tear: A Cadaver Assessment. AB - PURPOSE: To determine whether the arthroscopic hook and trampoline tests are accurate and reliable diagnostic tests for foveal triangular fibrocartilage complex (TFCC) detachment. METHODS: Wrist arthroscopy was performed on 10 cadaveric upper extremities. Arthroscopic hook and trampoline tests were performed and videos recorded (baseline). The deep foveal TFCC insertion was then sharply detached. Arthroscopic hook and trampoline tests were repeated. Subsequently, the foveal detachment was repaired via an ulnar tunnel technique and the hook test was repeated for a third time. Videos were independently reviewed at 2 time points by 2 fellowship-trained hand surgeons and 1 hand surgery fellow in a randomized and blinded fashion. Hook and trampoline tests were graded as positive or negative. Proportions of categorical variables were compared via 2-tailed Fisher exact test. Inter- and intraobserver reliabilities were assessed via Cohen kappa coefficient. RESULTS: The sensitivity and specificity of the hook test for foveal detachment diagnosis were 90% and 90%, respectively. There was 90% agreement among all 3 observers for the baseline and foveal detachment hook tests. Cohen kappa coefficients for the inter- and intraobserver reliabilities of the hook test were 0.87 and 0.81, respectively. Seventeen percent of trampoline tests were positive at baseline versus 43% after foveal detachment. The trampoline test had 45% agreement between the 3 observers. Cohen kappa coefficients for the inter- and intraobserver reliabilities of the trampoline test were 0.16 and 0.63, respectively. Following ulnar tunnel repair, 20% of hook tests were positive. CONCLUSIONS: The hook test is highly sensitive, specific, and reliable for the diagnosis of isolated TFCC foveal detachment. The trampoline test has insufficient reliability to assess foveal detachment. A TFCC foveal repair using an ulnar tunnel technique returns the hook test to baseline. CLINICAL RELEVANCE: The hook test is a sensitive, specific, and reliable test for the diagnosis of isolated TFCC foveal detachment. PMID- 29395585 TI - Mechanics of Metacarpophalangeal Joint Extension. AB - PURPOSE: It is a common belief that extension of the metacarpophalangeal (MCP) joint of the finger is achieved via the sagittal bands acting as a sling or lasso to attach the extensor tendon to the base of the proximal phalanx. The aim of this study was to test the hypotheses that (1) division of the sagittal bands reduces extension force or torque of the MCP joint, and (2) division of the extensor tendon distal to the sagittal band will not affect the extension force or torque of the MCP joint. METHODS: Ten cadaver limbs were secured to a jig to allow for testing of the extension force of the MCP joints of the index, middle, and ring fingers. A 1-kg load was applied to the forearm extensor digitorum communis tendon and the extension force was measured with the MCP joint positioned at 0 degrees (neutral extension) and again at 45 degrees flexion. These measurements were repeated after the sagittal bands were divided in 15 specimens; in the other 15 specimens, the extensor tendon was divided just distal to the sagittal bands. RESULTS: After sagittal band division, extension force was similar in the 2 groups (0.11 N reduction after division with the MCP joints in neutral and 0.14 N in 45 degrees flexion). There was significantly less extension force after division of the extensor tendon in both joint positions (0.95 N reduction after division in neutral extension and 0.66 N in 45 degrees flexion). CONCLUSIONS: The sagittal bands do not primarily extend the MCP as a sling or lasso. The extensor tendon continuation to the extensor hood and middle phalanx is the major extension motor. The MCP joint is extended by the torque generated by the extensor tendon passing the joint carrying a force and possessing an extension moment arm. CLINICAL RELEVANCE: This principle should be correctly understood in the literature to ensure that clinical decisions related to injury and/or repair of the extensor tendon and sagittal bands are based on a sound understanding of their mechanics. PMID- 29395587 TI - Intramuscular Tendon of the Adductor Pollicis and Underlying Capsule of the Metacarpophalangeal Joint: An Anatomical Study With Possible Implications for the Stener Lesion. AB - PURPOSE: To identify the layered relationship anatomically between the musculotendinous structures of the adductor pollicis, the ulnar collateral ligament, and the capsule of the metacarpophalangeal joint in terms of understanding the pathomechanism of a Stener lesion. METHODS: We macroscopically analyzed 37 cadaveric thumbs to identify the intramuscular tendon of the adductor pollicis and bony attachments of the joint capsule including the ulnar collateral ligament. In addition, we histologically analyzed 3 thumbs and made a 3 dimensional image of 3 other thumbs, using micro-computed tomography. RESULTS: The adductor pollicis has 3 components of an intramuscular tendon (dorsal, palmar, and distal), which connect to form a lambda shape. The dorsal part inserts into the joint capsule dorsal to the ulnar sesamoid. The palmar part inserts into the ulnar sesamoid. The distal part inserts into the lateral tubercle of the proximal phalanx. The thickened and cord-like part of the joint capsule, which has generally been referred to as the proper ulnar collateral ligament, has a distinct bony attachment on the proximal slope of the lateral tubercle of the proximal phalanx separate from the adductor pollicis insertion. CONCLUSIONS: Of the 3 components of the intramuscular tendon of the adductor pollicis muscle, the dorsal part inserted into not only the aponeurosis but also the joint capsule. CLINICAL RELEVANCE: The results of the current study suggest the anatomic basis for a possible pathomechanism of the Stener lesion. PMID- 29395586 TI - A Prospective Observational Assessment of Unicortical Distal Screw Placement During Volar Plate Fixation of Distal Radius Fractures. AB - PURPOSE: Although volar plating of the distal radius is performed frequently, the necessity of distal bicortical fixation in the metaphyseal and epiphyseal areas of the distal radius has not been proven. This study aimed primarily to quantify the ability of unicortical distal screws to maintain operative reduction of adult distal radius fractures and secondarily to determine if unicortical screw lengths could be predicted based on anatomical measurements. METHODS: This prospective trial enrolled 75 adult patients undergoing volar locking plate fixation of a unilateral distal radius fracture at a tertiary center. Study inclusion required screw fixation in the distal rows of the plate performed with unicortical screw placement. The primary outcome was maintenance of operative reduction, according to predefined parameters, quantified by comparing initial operative reduction to final reduction after fracture healing. Repeated measures analysis of variance analyzed for systematic change in radiographic parameters between injury, operative, and healed images. Correlation coefficients quantified the relationship of screw lengths with lunate width and other anatomical measurements. RESULTS: Seventy-five patients (mean age, 54 years +/- 15 years; 79% women) were enrolled and followed to fracture union. Fracture severity varied and included AO type A (40%), B (12%), and C (48%) fractures. There was no significant change in mean lateral translation, intra-articular gap, intra articular stepoff, radial inclination, or lateral tilt of the radius between the time of fixation and union for the cohort. Two patients lost reduction (increased dorsal tilt, 10 degrees , 20 degrees , respectively), potentially attributable to provision of unicortical fixation (3%; 95% confidence interval [95% CI], 0%-9%). No extensor tenosynovitis or extensor tendon ruptures occurred. Eighty percent of screws were 18 mm or less and screw lengths were not correlated with lunate width or any other anatomical measurements. CONCLUSIONS: Unicortical distal fixation during volar locking plate fixation effectively maintains operative reductions of distal radius fractures while potentially minimizing the incidence of extensor tendon ruptures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29395588 TI - Retropharyngeal Contralateral C7 Nerve Transfer to the Lower Trunk for Brachial Plexus Birth Injury: Technique and Results. AB - PURPOSE: Brachial plexus birth injuries with multiple nerve root avulsions present a particularly difficult reconstructive challenge because of the limited availability of donor nerves. The contralateral C7 has been described for brachial plexus reconstruction in adults but has not been well-studied in the pediatric population. We present our technique and results for retropharyngeal contralateral C7 nerve transfer to the lower trunk for brachial plexus birth injury. METHODS: We performed a retrospective review. Any child aged less than 2 years was included. Charts were analyzed for patient demographic data, operative variables, functional outcomes, complications, and length of follow-up. RESULTS: We had a total of 5 patients. Average nerve graft length was 3 cm. All patients had return of hand sensation to the ulnar nerve distribution as evidenced by a pinch test, unprompted use of the recipient limb without mirror movement, and an Active Movement Scale (AMS) of at least 2/7 for finger and thumb flexion; one patient had an AMS of 7/7 for finger and thumb flexion. Only one patient had return of ulnar intrinsic hand function with an AMS of 3/7. Two patients had temporary triceps weakness in the donor limb and one had clinically insignificant temporary phrenic nerve paresis. No complications were related to the retropharyngeal nerve dissection in any patient. Average follow-up was 3.3 years. CONCLUSIONS: The retropharyngeal contralateral C7 nerve transfer is a safe way to supply extra axons to the severely injured arm in brachial plexus birth injuries with no permanent donor limb deficits. Early functional recovery in these patients, with regard to hand function and sensation, is promising. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 29395590 TI - [Transient monocular blindness following intra-oral local anesthesia: Case report]. PMID- 29395589 TI - Relative Prevalence of Anxiety and Depression in Patients With Upper Extremity Conditions. AB - PURPOSE: Prior research regarding the impact of mental health on upper extremity musculoskeletal function and recovery has frequently grouped catastrophizing, anxiety, and depression. This study was designed to define the relative prevalence of heightened anxiety versus depressive symptoms among a patient population seeking upper extremity care and to determine if those prevalences varied according to the symptomatic condition. METHODS: All adult patients presenting to a tertiary upper extremity orthopedic center between June 1, 2016 and November 30, 2016 (n = 3,315) completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety and Depression Computer Adaptive Tests. Descriptive statistics and multivariable linear regression assessed differences in average PROMIS scores between demographic and diagnostic groups. Patients were also analyzed according to crossing thresholds for heightened anxiety and depression scores based on established linkage tables with the Generalized Anxiety Disorder 7 and Patient Health Questionnaire-9 Depression scales, respectively. Pearson chi-square analysis and binary logistic regression were performed to determine if the proportion of patients crossing these thresholds varied according to the primary symptomatic condition while accounting for patient age, sex, and race. RESULTS: African American patients and those with carpal tunnel syndrome, trapeziometacarpal arthritis, or shoulder conditions reported significantly higher PROMIS Anxiety scores. Higher PROMIS Depression scores varied only by diagnosis. Seventeen percent of patients exceeded the Anxiety symptoms score threshold and 10% of patients exceeded the Depression symptom threshold. In logistic regression modeling, the likelihood of exceeding the Anxiety threshold varied by diagnosis and was increased in African American patients and females. African American race was associated with exceeding the Depression threshold while accounting for sex and diagnosis. CONCLUSIONS: Patients with upper extremity conditions more frequently report heightened anxiety than heightened depression. Patient race and diagnosis are independent predictors of anxiety among patients seeking care for upper extremity conditions. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 29395591 TI - [Nocardia keratitis: Case report]. PMID- 29395592 TI - [Accidental ocular instillation of superglue in a sleepwalker]. PMID- 29395593 TI - [What about tropical endemic vernal keratoconjunctivitis? Which relationship with intestinal parasites?] AB - : Given the causative parasite hypothesis for tropical endemic limbo conjunctivitis (TELC), we conducted an analytical case-control study of all children with tropical endemic limbo-conjunctivitis seen in the ophthalmology department of Laquintinie hospital in Douala during the period from January 2nd to April 30, 2015. RESULTS: We identified 64 cases of tropical endemic limbo conjunctivitis out of 550 children seen; a hospital prevalence of 11.6%; thirteen cases (eight boys and five girls) did not meet inclusion criteria, and 51 cases were included, 31 boys (60.8%) and 20 girls (39.2%) with a male/female (M/F) sex ratio of 1.41. For controls, we included 28 males (54.9%) and 23 girls (45.1%) for a M/F sex-ratio of 1.22. The prevalence of tropical endemic limbo conjunctivitis in boys was 12.1%, and for girls it was 7.1% in the case group. Stage II was the most frequent at 29 cases (56.9%), as well as the mixed form at 31 cases (60.8%). The frequency of intestinal parasites was 14 cases (27.5%) in the group of tropical endemic limbo-conjunctivitis patients and 6 cases (11.8%) in the control group (P=0.08). Entamoeba histolytica in its cystic form was the most intestinal parasite found in both groups, 10 cases for tropical endemic limbo-conjunctivitis (19.6%) and 6 cases in the control groups (11.8%). The mean serum IgE among cases was 81.2 IU/ml, while in the controls it was 15.6 IU/ml (P=0.001) CONCLUSION: There is no relationship between intestinal parasitic infection and the occurrence of tropical endemic limbo-conjunctivitis. PMID- 29395594 TI - [Migration of an intravitreal dexamethasone implant into the anterior chamber in contact with an anterior chamber intraocular lens]. PMID- 29395595 TI - Toric intraocular lens outcomes with a new protocol for IOL selection and implantation. AB - INTRODUCTION: The published literature on toric intraocular lenses (IOL) reports postoperative refractive cylinder less than or equal to 0.5 D in anywhere from 25% to 100% of implantations with both the Acrysof(r) Toric and Tecnis(r) Toric IOL, depending upon the article. However, the majority of articles tend to cite rates between 70% and 80%. PURPOSE: The purpose was to evaluate my personal outcomes for both models of toric IOL, in terms of one-month postoperative refractive cylinder, after implementation of new methods of IOL selection, calculation and implantation. MATERIALS AND METHODS: The new protocol included measurement of centroid surgically induced astigmatism by vector analysis; calculations using only the Barrett toric calculator, for which the keratometry values were obtained by optical biometry, while the keratometric axes were chosen by visual inspection of the axial topographic map; preoperative marking with the toriCAM cell phone appliance; and corneal incisions performed either manually or with a femtosecond laser. A prospective, observational study was conducted of all consecutive monofocal toric IOL implantations from September 2016 through April 2017. One-month postoperative refractive cylinder was recorded for each eye. RESULTS: Seventy eyes were implanted with monofocal toric IOL, 31 Acrysof(r) Toric and 39 Tecnis(r) Toric. Mean postoperative refractive cylinder was 0.48 D (0.00-1.50) for the Acrysof(r) Toric group and 0.46 D (0.00-1.00) for the Tecnis(r) Toric group. There were no statistically significant differences in postoperative refractive cylinder between IOL models or methods of incision. The percentage of eyes achieving postoperative refractive cylinder <=0.50 D ("success") was 77% for the Acrysof(r) Toric group (82% for laser-assisted and 75% for manual) and 72% for the Tecnis(r) Toric group (80% for laser-assisted and 69% for manual). CONCLUSION: The implementation of the new protocol resulted in an overall surgical success rate of 77% for Acrysof(r) Toric IOL and 72% for Tecnis(r) Toric IOL (P=0.7702). Femtosecond laser-assisted surgery resulted in higher success rates than manual surgery (82% vs. 75% for Acrysof(r) Toric and 80% vs. 69% for Tecnis(r) Toric), but these differences were not statistically significant (Acrysof(r) Toric P=0.7336; Tecnis(r) Toric P=0.8862). PMID- 29395596 TI - [Postoperative appearance of subretinal fibrosis in rhegmatogenous retinal detachment]. PMID- 29395597 TI - [Post-traumatic macular hematoma as presenting sign of angioid streaks: Role of spectral-domain optical coherence tomography (SD-OCT)]. PMID- 29395599 TI - [Anterior uveitis]. AB - Anterior uveitis is the most common form of uveitis. There are several known and many possible etiologies for anterior uveitis. After examining the posterior segment and ruling out masquerade syndromes, the main step of etiologic diagnosis is clinical characterization. It is essential to establish unilateral versus bilateral involvement and presence or absence of granulomatous features. Subsequently, a work-up may be obtained which then helps to confirm diagnostic hypotheses based on the detailed history and clinical examination. The priority is to rule out an infection, although less frequent, before starting steroid therapy, adapted to the severity of the clinical picture. Finally, biologics have greatly changed the management and prevention of some forms of anterior uveitis, in particular uveitis associated with HLA-B27 and juvenile idiopathic arthritis associated anterior uveitis. PMID- 29395598 TI - Treatment of cystoid macular edema in homozygous twins with glutathione synthetase deficiency and retinal dystrophy. AB - Monozygotic twins with glutathione synthetase deficiency, progressive retinal dystrophy and cystoid macular edema were followed for foveal changes on optical coherence tomography under different treatment modalities. The purpose of the study is to show the effect of topical dorzolamide in conjunction with systemic acetazolamide in terms of decreasing macular edema in this specific disease. The results showed that systemic acetazolamide alone or in combination with topical dorzolamide decreased CME in both patients for a certain period of time. The result can be temporary sustained after treatment discontinuation. In conclusion, topical dorzolamide, in conjunction with systemic acetazolamide, could reduce cystoid macular edema in GSSD. PMID- 29395600 TI - Ultrasound assessment of extensor pollicis brevis tendon excursion in different wrist positions in healthy people. AB - STUDY DESIGN: Cross-sectional, observational study. INTRODUCTION: There is little reported on the in vivo mechanics and behavior of extensor pollicis brevis (EPB) in relation to wrist position. Wrist position is known to significantly influence tendon excursion and therefore function of the digits. Ultrasound imaging (USI) can be used to assess in vivo tendon behavior and excursion. An improved knowledge of the excursion of the EPB tendon is important in understanding normal tendon mechanics and potentially pathological tendon disorders such as de Quervains tenosynovitis. PURPOSE OF THE STUDY: To assess the reliability of using USI to measure EPB tendon excursion and to quantify EPB tendon excursion in 3 wrist positions. METHODS: USI with speckle-tracking analysis were utilized to assess 49 normal EPB tendons (25 subjects). Tendon excursion was measured in wrist flexion (45 degrees ), wrist neutral and wrist extension (45 degrees ) on 2 different occasions. RESULTS: The within- and between-session reliability of using USI to quantify EPB tendon excursion was "excellent" and "high," respectively. Wrist position had a significant influence on EPB tendon excursion (P <= .05). EPB excursion in the neutral wrist position was statistically greater than the other 2 positions (P < .05). DISCUSSION: EPB tendon excursion has been shown to be dependent on the wrist positions of flexion and extension. The measures are notably lower than those found in cadaver studies; however, they follow a similar pattern with greatest excursion occurring in the neutral wrist position and least in flexion. This information is useful for EPB tendon rehabilitation and in consideration of biomechanics and pathogenesis of disorders that affect EPB tendon. CONCLUSION: In vivo EPB tendon excursion measures have been quantified, and wrist position has been found to have an influence on excursion. USI with speckle-tracking analysis are considered to be reliable methods for measuring EPB tendon excursion. PMID- 29395601 TI - Reliability and validity of the Brachial Plexus Outcome Measure in children with obstetric brachial plexus palsy. AB - STUDY DESIGN: Clinical measurement and cross-sectional study. INTRODUCTION: Numerous scales have been developed to examine activities of daily living and function in children with brachial plexus palsy. The Brachial Plexus Outcome Measure (BPOM) scale was developed in 2012 by Emily S. Ho and contains 14 items that measure activity and self-evaluation. PURPOSE OF THE STUDY: The aim of the study was to cross-culturally translate the BPOM scale into Turkish and test its measurement properties in children with brachial plexus palsy. METHODS: The scale was translated into Turkish using standard cross-cultural translation procedures. Forty-eight children with obstetric brachial plexus palsy (OBPP) were included in psychometric evaluations. Internal structure consistency and test-retest reliability were measured for reliability analyses. For each item on the scale, Cronbach alpha coefficient and item-total score correlations for all subscales were calculated. The scale was administered at baseline and 1 week later by 2 different physiotherapists to evaluate test-retest reliability. Concurrent construct validity was assessed using Pearson correlations between the OBPP and the Mallet classification system. RESULTS: Eighteen (37.5%) girls and 30 (62%) boys, in total 48 children, whose mean age was 8.7 +/- 2.4 (minimum-maximum = 5 14) years were included in the study; 9 (18.9%) have a history of both early microsurgery and tendon transfers and 39 (81.3%) have a history of only tendon transfer. Cronbach alpha ranged from 0.89 to 0.96, and for the whole scale, it was calculated as 0.938. DISCUSSION: Test-retest reliability was high. Moderate correlations were observed between the measures. CONCLUSION: The Turkish BPOM scale is a valid and reliable measurement for assessing function in children with OBPP in the Turkish population. PMID- 29395602 TI - An Observational Study of 3 Different Transfusion Medicine Teaching Methods for Medical Students. AB - Knowledge deficits of transfusion medicine are prevalent among learners and practicing physicians. In the past, the transfusion medicine community has thoughtfully defined the content of transfusion medicine curriculums through Transfusion Medicine Academic Award Group and The Academy of Clinical Laboratory Physicians and Scientists. The manner in which the curriculum should be delivered has been less carefully examined and defined. We completed an observational study in which we analyzed 3 different teaching techniques: in-person faculty-led simulation curriculum consisting of didactic session and simulation ("Simulation group"); hybrid education with a combination of online materials and short in person simulation ("Hybrid group"); and online-only education module, which delivered the whole curricular content through a variety of online materials and videos ("Online-only group"). Knowledge acquisition was assessed with a 10 question multiple-choice questionnaire, and satisfaction was assessed by a 9 question online student satisfaction survey. A total of 276second-year medical students participated in the study. There was statistically significant difference between pre- and posttest results and in knowledge gain favoring the Simulation group as compared with the Online-only group (P=.03, P<.0001) and favoring the Simulation group as compared with the Hybrid group (P=.004, P<.0001). The Simulation group and Hybrid group medical students were also more satisfied with the education activity as compared with the Online-only group (P<.0001, P<.001). Our study demonstrated that a faculty-run transfusion medicine simulation curriculum consisting of an in-person didactic session and simulation session for the second-year medical students produced greater immediate knowledge acquisition compared with an online only or a hybrid curriculum. Furthermore, any curriculum that contained in-person teaching by faculty was preferred over the online only education. PMID- 29395603 TI - Improving air quality in subway systems: An overview. AB - This article comments on the current reality of particulate matter (PM) concentrations breathed by commuters on subway train platforms and considers what can be done to improve air quality underground. We propose the introduction of a targeted, color-coded approach to the problem, based on the methodology of the World Health Organisation and designed to encourage transport authorities to aim for progressive PM reductions. The method defines thresholds that cascade down through bands of decreasing PM concentrations towards the ideal WHO Air Quality Guideline of PM2.5 annual mean level of 10 MUg m-3, where negative health effects of long term particle inhalation are minimal. PMID- 29395604 TI - Patterns and predictors of trajectories for social and occupational functioning in patients presenting with first-episode non-affective psychosis: A three-year follow-up study. AB - BACKGROUND: Functional impairment is prevalent in patients with first-episode psychosis (FEP). Longitudinal course of functioning in the early stage of psychotic illness is under-studied. In this report, we aimed to investigate the patterns and baseline predictors of social-occupational functional trajectories over 3 years, utilizing growth mixture modeling (GMM) analysis, in a large representative Chinese young FEP cohort in Hong Kong. METHOD: Six hundred seventeen consecutive patients aged 15-25 years presenting with first-episode non affective psychosis to a specialized early intervention service were studied. Data on demographic, pre-treatment and baseline clinical characteristics were collected. Individual class membership of functioning derived from GMM was based on ratings on Social and Occupational Functioning Scale (SOFAS) measured at five different time-points (baseline, 6, 12, 24 and 36 months) across 3-year follow up. RESULTS: Four distinct functional trajectories were identified including persistently poor (48.1%, n = 320), early improved (31.3%, n = 203), gradually improved (14.8%, n = 69) and improved-deteriorated (5.8%, n = 25) trajectories. Multinomial regression analysis revealed that male gender, lower educational attainment, a diagnosis of schizophrenia-spectrum disorder and a receipt of inpatient treatment upon initial presentation independently predicted persistently poor trajectory membership. CONCLUSION: The current study reveals a heterogeneous course of social-occupational functioning in FEP. Our finding that approximately half of the patients displaying persistently poor trajectory over 3 years indicates functional impairment as an unmet therapeutic need in early illness phase. Further research applying individual-based trajectory analysis in FEP is warranted to facilitate better characterization of longitudinal patterns of functioning and development of targeted intervention to promote early recovery. PMID- 29395605 TI - Association between frailty and its individual components with the risk of falls in patients with schizophrenia spectrum disorders. AB - Frailty is common among older people who carry an increased risk for poor outcomes, including falls, physical disabilities, infections, and mortality. However, the prevalence of frailty and the prognostic influence of frailty status are poorly understood in adults with schizophrenia. The present study aimed to assess the predictive ability of frailty and its individual components for the risk of falls in patients with chronic schizophrenia. Frailty status was assessed at baseline by using Fried frailty criteria after the enrollment of 561 patients with chronic schizophrenia. The patients were followed up for 18 months, and the outcome of the study was the incidence of falls. The mean age of the patients was 53.8 years, and a total of 35.3% were females. One-quarter (25.3%) of patients received typical antipsychotics. The prevalence of frailty was 10.2% at baseline. During follow-up, 40 patients (7.1%) experienced falls. Frailty status was associated with increased susceptibility to falling with an unadjusted hazard ratio of 5.27 (95% confidence interval: 2.75-10.10) and a hazard ratio of 4.65 (95% confidence interval: 1.88-11.54) after multivariate adjustment. Among the components of frailty, the most significant association was observed between low physical activity and falls (p < 0.05). In conclusion, frailty is highly prevalent in patients with chronic schizophrenia and is associated with the risk of adverse clinical events. Further studies are needed to explore the mechanisms underlying the relationship between schizophrenia and frailty in an attempt to develop an appropriate treatment plan for improving clinical outcomes for these patients. PMID- 29395606 TI - Response to concerns over Cantillon et al. dopamine serotonin stabilizer RP5063 clinical trial's design, analyses and findings (SCHRES-D-17-00455) by Ahmed S Aboraya, MD, DrPh. PMID- 29395607 TI - A quantitative systems pharmacology study on optimal scenarios for switching to paliperidone palmitate once-monthly. AB - Long-acting injectable (LAI) antipsychotic formulations are increasingly used for improving patient compliance and long-term outcomes. Transitioning to LAIs raises questions regarding how optimum efficacy can be rapidly achieved while minimizing potential efficacy and safety concerns related to overlapping plasma levels of prior treatments and the new LAI. Ideally, randomized clinical trials would provide guidance regarding transition algorithms, but the number of studies and sample size required to address relevant questions makes this approach unachievable. We have used quantitative systems pharmacology, a clinically calibrated, mechanism-based computer model for schizophrenia to identify optimal switching scenarios to injectable paliperidone palmitate once-monthly (PP1M) from oral antipsychotics. We show that starting PP1M 1day after the last oral medication dose or 4weeks after the last LAI injection provides optimal benefit risk compared to a delayed PP1M start after 1week with either a 1- or 2-week overlap with oral paliperidone. Although a similar or better therapeutic effect can be achieved within 2weeks for oral medications and LAI haloperidol decanoate and 8weeks for LAI aripiprazole, we identified a potential transient undertreatment liability in all cases except for risperidone. Switching from oral olanzapine may lead to a small reduction of antipsychotic efficacy in some patients. Switching to PP1M decreases extrapyramidal symptom liability in most cases, but increased dopamine D2 receptor inhibition (except for haloperidol) might potentially increase prolactin synthesis. Overall, these results suggest time-windows for which the treating clinician must be most vigilant for potential efficacy and safety signals when switching to PP1M. PMID- 29395608 TI - Leading causes of death among decedents with mention of schizophrenia on the death certificates in the United States. AB - BACKGROUND: Little is known about the changes in the ranking of leading cause of death (COD) among people died with schizophrenia across years in the United States (U.S.). This study aims to determine the ranking of leading COD among U.S. decedents with mention of schizophrenia by age from 2000 to 2015. METHODS: The mortality multiple COD files maintained by the National Center for Health Statistics were used to identify decedents aged 15 years old and above with mention of schizophrenia anywhere on the death certificates to determine the number and proportion of deaths attributed to various underlying CODs. RESULTS: Of 13,289, 13,655, 14,135, and 15,033 people who died in 2000-2003, 2004-2007, 2008-2011and 2012-2015 with mention of schizophrenia, similar to all decedents, heart disease and cancer was the first and the second leading COD throughout the study years. Schizophrenia ranked the third in most years except in 2004-2007. The first leading COD for decedents with mention of schizophrenia aged 15-24, 25 44, 45-64, 65-74, and 75+ years old in 2012-2015 was suicide, accidents, heart disease, heart disease, and Alzheimer's disease and related dementia, respectively. Nevertheless, it was accidents, accidents, cancer, cancer, and heart disease, respectively for all decedents. CONCLUSION: The ranking of leading CODs among U.S. decedents with mention of schizophrenia changed across years and differed from all decedents by age, which suggest that different interventions should be designed accordingly. PMID- 29395609 TI - Unraveling the insight paradox: One-year longitudinal study on the relationships between insight, self-stigma, and life satisfaction among people with schizophrenia spectrum disorders. AB - The promotion of insight among people with schizophrenia spectrum disorders has posed a dilemma to service providers as higher insight has been linked to positive clinical outcomes but negative psychological outcomes. The negative meaning that people attached to the illness (self-stigma content) and the recurrence of such stigmatizing thoughts (self-stigma process) may explain why increased insight is associated with negative outcomes. The present study examined how the presence of high self-stigma content and self-stigma process may contribute to the negative association between insight and life satisfaction. A total of 181 people with schizophrenia spectrum disorders were assessed at baseline. 130 and 110 participants were retained and completed questionnaire at 6 month and 1-year follow-up, respectively. Results showed that baseline insight was associated with lower life satisfaction at 6-month when self-stigma process or self-stigma content was high. Furthermore, baseline insight was predictive of better life satisfaction at 1-year follow-up when self-stigma process was low. Findings suggested that the detrimental effects of insight can be a result from both the presence of cognitive content and habitual process of self-stigma. Future insight promotion interventions should also address self-stigma content and process among people with schizophrenia spectrum disorders so as to maximize the beneficial effects of insight. PMID- 29395610 TI - Disrupted salience processing involved in motivational deficits for real-life activities in patients with schizophrenia. AB - Motivational deficits in patients with schizophrenia adversely affect various domains of daily living. This symptom in everyday life situations manifests in a complex behavioral pattern whose root cannot be simplified to an impaired reward motivation scheme. This study aimed to identify impairment of the salience network that underlies motivational deficits seen in patients with schizophrenia in real-life situations. During the functional magnetic resonance imaging scan, 20 patients with schizophrenia and 20 normal controls performed a task mimicking real-life situations, in which an avatar proposed participation in a daily activity with either an intrinsic or extrinsic reward. Group and type-of-reward effects were evaluated with respect to brain activity. Further, psychophysiological interactions were analyzed for the dorsal anterior cingulate cortex (dACC) and insula, which are the key nodes of the salience network. The acceptance of the proposal was significantly higher for intrinsic than for extrinsic rewards in controls, whereas patients showed no difference. The imaging results showed a group effect in the dACC, right insula, thalamus, and lingual gyrus. The dACC showed negative contrast interaction with regions of the left dorsolateral prefrontal cortex, and the right insula showed positive contrast interaction with the occipital gyrus and precentral gyrus. These results suggest that patients exhibit no different participation behavior between activities with intrinsic and extrinsic rewards, which can be explained by the floor effect. Disrupted salience processing in schizophrenia including aberrant salience network and a disconnection of the salience and reward networks may account for the lack of motivation for daily activities. PMID- 29395611 TI - Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta analysis of randomized, double-blind, placebo-controlled trials. AB - OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, has been used in treating postmenopausal women with schizophrenia with inconsistent results. This meta-analysis of randomized, double-blind, placebo-controlled trials (RCTs) examined its efficacy and safety for postmenopausal women with schizophrenia. METHOD: Standardized mean differences (SMDs) and risk ratio (RR) together with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: The meta-analysis included 5 RCTs (n = 240) comparing raloxifene (n = 125, 60 or 120 mg/day) with placebo (n = 115). Adjunctive raloxifene outperformed placebo with regard to the Positive and Negative Syndrome Scale (PANSS) total psychopathology [n = 240, SMD:-0.64 (95%CI:-0.90, -0.37), P < 0.00001; I2 = 0%], positive symptoms [n = 240, SMD:-0.49 (95%CI:-0.81, -0.16), P = 0.003; I2 = 29%], negative symptoms [n = 240, SMD:-0.43 (95%CI:-0.68, -0.17), P = 0.001; I2 = 0%], and general psychopathology scores [n = 240, SMD:-0.66 (95%CI: 0.92, -0.39), P < 0.00001; I2 = 0%]. Both groups had similar rates of adverse events and discontinuation (n = 159, RR: 1.32 (95%CI: 0.65, 2.70), P = 0.44, I2 = 0%). CONCLUSION: Adjunctive raloxifene appears to be effective and safe in improving psychotic symptoms for postmenopausal women with schizophrenia. Review registration: CRD 42017059946. PMID- 29395612 TI - Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome. AB - 22q11.2 deletion syndrome (22q11.2DS) is one of the most common copy number variants and confers a markedly increased risk for schizophrenia. As such, 22q11.2DS is a homogeneous genetic liability model which enables studies to delineate functional abnormalities that may precede disease onset. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia relative to healthy controls in MMN tasks. In the search for early risk-markers for schizophrenia we investigated the neural basis of change detection in a group with 22q11.2DS. We recorded high density EEG from 19 young non-psychotic 22q11.2 deletion carriers, as well as from 27 healthy non-carriers with comparable age distribution and sex ratio, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Despite finding no significant reduction in the MMN responses, whole scalp spatiotemporal analysis of responses to the tones revealed a greater fronto temporal N1 component in the 22q11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison. We discuss these findings in terms of reduced adaptation and a general increased sensitivity to tones in 22q11.2DS. PMID- 29395613 TI - Towards a comprehensive routine outcome monitoring program for people with psychotic disorders: The Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS). AB - BACKGROUND: Patients with psychotic disorders are at risk of developing mental health and social problems, and physical disorders. To monitor and treat these problems when indicated, an annual routine outcome monitoring program, Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS), was developed. This paper presents the background and content of PHAMOUS, implementation of PHAMOUS, characteristics of the patients screened in 2015, and the outcome of patients with three annual screenings between 2011 and 2015. METHODS: PHAMOUS was implemented in four mental health institutions in the Northern Netherlands in 2006. During the PHAMOUS screening, patients are assessed on socio-demographics, psychiatric symptoms, medication, physical parameters, lifestyle, (psycho)social functioning and quality of life, using internationally validated instruments. RESULTS: In 2015, 1955 patients with psychotic disorders were enrolled in the PHAMOUS screening. The majority (72%) was receiving mental healthcare for ten years or longer. A small group was hospitalized (10%) in the past year. Half of the patients were in symptomatic remission. Less than 10% had a paid job. More than half of the patients fulfilled the criteria for metabolic syndrome (54%). The subsample with three annual screenings from 2011 to 2015 (N = 1230) was stable, except the increasing prevalence of high glucose levels and satisfaction with social relationships (Cochran's Q = 16.33, p = .001 resp. Q = 14.79, p = .001). CONCLUSION: The annual PHAMOUS screening enables to follow the mental, physical and social health problems of patients, which offers a good basis for shared-decision making with regard to updating the annual treatment plan, next to a wealth of data for scientific research. PMID- 29395614 TI - Transcriptomic analysis of chicken cochleae after gentamicin damage and the involvement of four signaling pathways (Notch, FGF, Wnt and BMP) in hair cell regeneration. AB - Unlike mammalian hair cells, which are essentially unable to regenerate after damage, avian hair cells have a robust capacity for regeneration. The prerequisite for understanding the above difference is knowing the genetic programming of avian hair cell regeneration. Although the major processes have been known, the precise molecular signaling that induces regeneration remains unclear. To address this issue, we performed a high-throughput transcriptomic analysis of gene expression during hair cell regeneration in the chick cochlea after antibiotic injury in vivo. A total of 16,588 genes were found to be expressed in the cochlea, of which about 1000 genes were differentially expressed among the four groups studied, i.e., 2 days (d) or 3 d post-treatment with gentamicin or physiological saline. The differentially expressed genes were distributed across approximately one hundred signaling pathways, including the Notch, MAPK (FGF), Wnt and TGF-beta (BMP) pathways that have been shown to play important roles in embryonic development. Some differentially expressed genes (2 3 in each pathway) were further verified by qRT-PCR. After blocking Notch, FGF or BMP signaling, the number of regenerating hair cells and mitotic supporting cells increased. However, the opposite effect was observed after suppressing the Wnt pathway or enhancing BMP signaling. To our knowledge, the present study provided a relatively complete dataset of candidate genes and signaling pathways most likely involved in hair cell regeneration and should be a useful start in deciphering the genetic circuitry for inducing hair cell regeneration in the chick cochlea. PMID- 29395616 TI - A phenomenological model of the synapse between the inner hair cell and auditory nerve: Implications of limited neurotransmitter release sites. AB - Peterson and Heil [Hear. Res., In Press] have argued that the statistics of spontaneous spiking in auditory nerve fibers (ANFs) can be best explained by a model with a limited number of synaptic vesicle docking (release) sites (~4) and a relatively-long average redocking time (~16-17 ms) for each of the sites. In this paper we demonstrate how their model can be: i) generalized to also describe sound-driven ANF responses and ii) incorporated into a well-established and widely-used model of the entire auditory periphery [Zilany et al., J. Acoust. Soc. Am. 135, 283-286, 2014]. The responses of the new model exhibit substantial improvement in several measures of ANF spiking statistics, and predicted physiological forward-masking and rate-level functions from the new model structure are shown to also better match published physiological data. PMID- 29395617 TI - Unilateral congenital hearing loss in children: Challenges and potentials. AB - The estimated incidence of sensorineural hearing impairment (>40 dB HL) at birth is 1.86 per 1000 newborns in developed countries and 30-40% of these are unilateral. Profound sensorineural unilateral hearing impairment or single sided deafness (SSD) can be treated with a cochlear implant. However, this treatment is costly and invasive and unnecessary in the eyes of many. Very young children with SSD often do not exhibit language and cognitive delays and it is hard to imagine that neurocognitive skills will present difficulties with one good ear. In the current paper we review the most recent evidence on the consequences of unilateral hearing impairment for auditory and neurocognitive factors. While data of both adults and children are discussed, we focus on developmental factors, congenital deafness and a window of opportunity for intervention. We discuss which etiologies qualify for a cochlear implant and present our multi-center prospective study on cochlear implants in infants with one deaf ear. The large, state-of-the art body of research allows for evidence-based decisions regarding management of unilateral hearing loss in children. PMID- 29395615 TI - Subcortical pathways: Towards a better understanding of auditory disorders. AB - Hearing loss is a significant problem that affects at least 15% of the population. This percentage, however, is likely significantly higher because of a variety of auditory disorders that are not identifiable through traditional tests of peripheral hearing ability. In these disorders, individuals have difficulty understanding speech, particularly in noisy environments, even though the sounds are loud enough to hear. The underlying mechanisms leading to such deficits are not well understood. To enable the development of suitable treatments to alleviate or prevent such disorders, the affected processing pathways must be identified. Historically, mechanisms underlying speech processing have been thought to be a property of the auditory cortex and thus the study of auditory disorders has largely focused on cortical impairments and/or cognitive processes. As we review here, however, there is strong evidence to suggest that, in fact, deficits in subcortical pathways play a significant role in auditory disorders. In this review, we highlight the role of the auditory brainstem and midbrain in processing complex sounds and discuss how deficits in these regions may contribute to auditory dysfunction. We discuss current research with animal models of human hearing and then consider human studies that implicate impairments in subcortical processing that may contribute to auditory disorders. PMID- 29395618 TI - Re: Diagnostic performance of contrast-enhanced CT-scan in sinusoidal obstruction syndrome induced by chemotherapy of colorectal liver metastases: Radio pathological correlation. PMID- 29395619 TI - Development and validation of a multivariate prediction model for patients with acute pancreatitis in Intensive Care Medicine. AB - BACKGROUND/OBJECTIVES: Development and validation of a multivariate prediction model for patients with acute pancreatitis (AP) admitted in Intensive Care Units (ICU). METHODS: A prospective multicenter observational study, in 1 year period, in 46 international ICUs (EPAMI study). PATIENTS: adults admitted to an ICU with AP and at least one organ failure. INTERVENTIONS: Development of a multivariate prediction model, using the worst data of the stay in ICU, based in multivariate analysis, simple imputation in a development cohort. The model was validated in another cohort. RESULTS: 374 patients were included (mortality of 28.9%). Variables with statistical significance in multivariate analysis were age, no alcoholic and no biliary etiology, development of shock, development of respiratory failure, need of continuous renal replacement therapy, and intra abdominal pressure. The model created with these variables presented an AUC of ROC curve of 0.90 (CI 95% 0.81-0.94) in the validation cohort. We developed a multivariable prediction model, and AP cases could be classified as low mortality risk (between 2 and 9.5 points, mortality of 1.35%), moderate mortality risk (between 10 and 12.5 points, 28.92% of mortality), and high mortality risk (13 points of more, mortality of 88.37%). Our model presented better AUC of ROC curve than APACHE II (0.91 vs 0.80) and SOFA in the first 24 h (0.91 vs 0.79). CONCLUSIONS: We developed and validated a multivariate prediction model, which can be applied in any moment of the stay in ICU, with better discriminatory power than APACHE II and SOFA in the first 24 h. PMID- 29395621 TI - Current practices in clinical neurofeedback with functional MRI-Analysis of a survey using the TIDieR checklist. AB - BACKGROUND: A core principle of creating a scientific evidence base is that results can be replicated in independent experiments and in health intervention research. The TIDieR (Template for Intervention Description and Replication) checklist has been developed to aid in summarising key items needed when reporting clinical trials and other well designed evaluations of complex interventions in order that findings can be replicated or built on reliably. Neurofeedback (NF) using functional MRI (fMRI) is a multicomponent intervention that should be considered a complex intervention. The TIDieR checklist (with minor modification to increase applicability in this context) was distributed to NF researchers as a survey of current practice in the design and conduct of clinical studies. The aim was to document practice and convergence between research groups, highlighting areas for discussion and providing a basis for recommendations for harmonisation and standardisation. METHODS: The TIDieR checklist was interpreted and expanded (21 questions) to make it applicable to neurofeedback research studies. Using the web-based Bristol Online Survey (BOS) tool, the revised checklist was disseminated to researchers in the BRAINTRAIN European research collaborative network (supported by the European Commission) and others in the fMRI-neurofeedback community. RESULTS: There were 16 responses to the survey. Responses were reported under eight main headings which covered the six domains of the TIDieR checklist: What, Why, When, How, Where and Who. CONCLUSIONS: This piece of work provides encouraging insight into the ability to be able to map neuroimaging interventions to a structured framework for reporting purposes. Regardless of the considerable variability of design components, all studies could be described in standard terms of diagnostic groups, dose/duration, targeted areas/signals, and psychological strategies and learning models. Recommendations are made which include providing detailed rationale of intervention design in study protocols. PMID- 29395620 TI - High throughput gene sequencing reveals altered landscape in DNA damage responses and chromatin remodeling in sporadic pancreatic neuroendocrine tumors. AB - PURPOSE: The main objectives of this retrospective study were to survey the genetic landscape of PNETs in a clinical cohort by using the high throughput gene sequencing method and to determine cellular signaling networks affected by the uncovered gene mutations. MATERIALS AND METHODS: We retrieved the demographics and tumor characteristics of 13 patients. Cellular DNA was extracted from fresh snap frozen tumor tissues and was subject to high throughput gene sequencing analysis using the Illumina NextSeq500 System. Furthermore, the interaction network was constructed from the input gene set by Reactome and performed gene set enrichment analysis was performed with a cutoff FDR of <=0.01. RESULTS: Totally 74 mutated genes and 93 mutations were identified. The median number of mutations was 7 (range 1-20) and that of mutated genes was 6 (range 1-17). Among these mutations, 48 (51.6%) were substitution mutations, nine (9.7%) were duplication mutations, 28 (30.1%) were deletion mutations and eight (8.6%) were deletion/insertion mutations. Gene set enrichment analysis generated a network of 21 interactions, 10 of which were associated with DNA repair like the Fanconi anemia pathway, nucleotide excision repair, and homologous recombination repair, or chromosome maintenance. Moreover, 9 patients had one or more mutations in DNA repair genes including the mismatch repair genes MSH2/MSH6. CONCLUSIONS: The study has uncovered genetic alterations of genes implicated in DNA damage responses and chromatin remodeling. Our findings will prompt further studies into the role of these mutated genes in the oncogenesis and molecular stratification of PNETs. PMID- 29395622 TI - Prediction of a peptidome for the ecotoxicological model Hyalella azteca (Crustacea; Amphipoda) using a de novo assembled transcriptome. AB - Due to its sensitivity to many environmental and anthropogenic stressors, including a wide range of chemical compounds, Hyalella azteca, a freshwater amphipod, has emerged as one of the most commonly used invertebrates for ecotoxicological assessment.Peptidergic signaling systems are key components in the control of organism-environment interactions, and there is a growing literature suggesting that they are targets of a number of aquatic toxicants.Interestingly, and despite its model species status in the field of ecotoxicology, little is known about the peptide hormones of H. azteca.Here, a transcriptome was produced for this species using the de novo assembler Trinity and mined for sequences encoding putative peptide precursors; the transcriptome was assembled from 460,291,636 raw reads and consists of 133,486 unique transcripts.Seventy-six sequences encoding peptide pre/preprohormones were identified from this transcriptome, allowing for the prediction of 202 distinct peptides, which included members of the allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/molt-inhibiting hormone, ecdysis-triggering hormone, eclosion hormone, elevenin, FMRFamide-like peptide, glycoprotein hormone, GSEFLamide, inotocin, leucokinin, myosuppressin, neuropeptide F, orcokinin, orcomyotropin, pigment dispersing hormone, proctolin, pyrokinin, red pigment concentrating hormone, RYamide, short neuropeptide F, SIFamide, sulfakinin, tachykinin-related peptide and trissin families.These peptides expand the known peptidome for H. azteca approximately nine-fold, forming a strong foundation for future studies of peptidergic control, including disruption by aquatic toxicants, in this important ecotoxicological model. PMID- 29395623 TI - Muscle and liver transcriptome characterization and genetic marker discovery in the farmed meagre, Argyrosomus regius. AB - Meagre (Argyrosomus regius), a teleost fish of the family Sciaenidae, is part of a group of marine fish species considered new for Mediterranean aquaculture representing the larger fish cultured in the region. Meagre aquaculture started ~25years ago in West Mediterranean, and the supply of juveniles has been dominated by few hatcheries. This fact has raised concerns on possible inbreeding, urging the need for genetic information on the species and for an assessment of the polymorphisms found in the genome. To that end we characterized the muscle and liver transcriptome of a pool of meagre individuals, from different families and phenotypic size, to obtain a backbone that can support future studies regarding physiology, immunology and genetics of the species. The assembled transcripts were assigned to a wide range of biological processes including growth, reproduction, metabolism, development, stress and behavior. Then, to infer its genetic diversity and provide a catalogue of markers for future use, we scanned the reconstructed transcripts for polymorphic genetic markers. Our search revealed a total of 42,933 high quality SNP and 20,581 STR markers. We found a relatively low rate of polymorphism in the transcriptome that may indicate that inbreeding has taken place. This study has led to a catalogue of genetic markers at the expressed part of the genome and has set the ground for understanding growth and other traits of interest in meagre. PMID- 29395624 TI - Anterior cingulate cortex glutamate and its association with striatal functioning during cognitive control. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by structural, functional and neurochemical alterations of the fronto-striatal circuits and by deficits in cognitive control. In particular, ADHD has been associated with impairments in top-down fronto-striatal glutamate signalling. However, it is unknown whether fronto-striatal glutamate is related to cognitive control dysfunction. Here we explored whether and how anterior cingulate cortex (ACC) glutamate relates to striatal BOLD-responses during cognitive control. We used proton magnetic resonance spectroscopy to evaluate glutamate-to-creatine ratios in 62 participants (probands with ADHD n=19, unaffected siblings n=24 and typical controls n=19, mean age=20.4). Spectra were collected from the ACC and the dorsal striatum and glutamate-to-creatine ratios were extracted. Thirty-two participants additionally took part in a functional magnetic resonance imaging (fMRI) Stroop task to investigate neural responses during cognitive control. Given small sample sizes we report all effects with p<0.10 along with effect sizes. ADHD subjects showed decreased glutamate-to creatine ratios in the ACC (F=3.81, p=0.059, etap2=0.104; medium to large effect size) compared with controls. Importantly, decreased ACC glutamate-to-creatine ratios were associated with increased striatal BOLD-responses during cognitive control (rho=-0.41, p=0.019; medium effect-size), independent of diagnosis. Increased striatal responses tended to be associated with more errors during the task and more hyperactivity/impulsivity symptoms (rho=0.34, p=0.058 and rho=0.33, p=0.068, respectively); the latter two being correlated too (rho=0.37, p=0.037), all with medium effect sizes. Our results suggest that ACC glutamate in ADHD might be associated with striatal (dys)functioning during the Stroop task, supporting the role of fronto-striatal glutamate in cognitive control. PMID- 29395625 TI - Mitral Effective Regurgitant Orifice Area Predicts Pulmonary Artery Pressure Level in Patients with Aortic Valve Stenosis. AB - BACKGROUND: Mitral regurgitation (MR) and elevated pulmonary artery pressure are common findings in patients with aortic valve stenosis (AS). The pathophysiologic role of quantitatively defined MR as a determinant of pulmonary hypertension (PH) is incompletely characterized across the whole spectrum of AS degrees. The purpose of the study was to investigate whether the quantification of MR reveals a link to PH in patients with AS. METHODS: Consecutive patients undergoing comprehensive echocardiography and presenting peak aortic velocity >= 2.5 m/sec were prospectively enrolled. Effective regurgitant orifice area (ERO) and regurgitant volume were obtained using the proximal isovelocity surface area method. Systolic pulmonary artery pressure was calculated by adding right atrial pressure to the tricuspid regurgitation pressure gradient. RESULTS: A total of 642 patients were enrolled between 2008 and 2013 (mean age, 79 +/- 11 years; mean ejection fraction, 62 +/- 10%; mean aortic valve area, 1.09 +/- 0.39 cm2); MR was present in 187 (29%). Of note, 154 of 187 patients (82%) showed ERO < 0.20 cm2. ERO and regurgitant volume had the most significant associations with systolic pulmonary artery pressure (R2 = 0.30 and R2 = 0.35, respectively, P < .0001). This relationship persisted after multivariate adjustment and in the subgroups of patients with severe AS or reduced ejection fraction (P < .0001). For each 0.10 cm2 increase, the odds ratio for PH was 3.56 (95% CI, 2.65-4.86; P < .0001). CONCLUSIONS: In patients with MR and a wide range of AS severity, ERO is independently associated with PH. Also, the role of MR quantification appears stronger than other continuous variables commonly associated with left ventricular diastolic dysfunction, such as E/e' ratio and left atrial volume. PMID- 29395627 TI - Challenges and Promises of PET Radiomics. AB - PURPOSE: Radiomics describes the extraction of multiple, otherwise invisible, features from medical images that, with bioinformatic approaches, can be used to provide additional information that can predict underlying tumor biology and behavior. METHODS AND MATERIALS: Radiomic signatures can be used alone or with other patient-specific data to improve tumor phenotyping, treatment response prediction, and prognosis, noninvasively. The data describing 18F fluorodeoxyglucose positron emission tomography radiomics, often using texture or heterogeneity parameters, are increasing rapidly. RESULTS: In relation to radiation therapy practice, early data have reported the use of radiomic approaches to better define tumor volumes and predict radiation toxicity and treatment response. CONCLUSIONS: Although at an early stage of development, with many technical challenges remaining and a need for standardization, promise nevertheless exists that PET radiomics will contribute to personalized medicine, especially with the availability of increased computing power and the development of machine-learning approaches for imaging. PMID- 29395626 TI - Echocardiography Core Laboratory Reproducibility of Cardiac Safety Assessments in Cardio-Oncology. AB - BACKGROUND: As the potential for cancer therapy-related cardiac dysfunction is increasingly recognized, there is a need for the standardization of echocardiographic measurements and cut points to guide treatment. The aim of this study was to determine the reproducibility of cardiac safety assessments across two academic echocardiography core laboratories (ECLs) at the University of Pennsylvania and the Duke Clinical Research Institute. METHODS: To harmonize the application of guideline-recommended measurement conventions, the ECLs conducted multiple training sessions to align measurement practices for traditional and emerging assessments of left ventricular (LV) function. Subsequently, 25 echocardiograms taken from patients with breast cancer treated with doxorubicin with or without trastuzumab were independently analyzed by each laboratory. Agreement was determined by the proportion (coverage probability [CP]) of all pairwise comparisons between readers that were within a prespecified minimum acceptable difference. Persistent differences in measurement techniques between laboratories triggered retraining and reassessment of reproducibility. RESULTS: There was robust reproducibility within each ECL but differences between ECLs on calculated LV ejection fraction and mitral inflow velocities (all CPs < 0.80); four-chamber global longitudinal strain bordered acceptable reproducibility (CP = 0.805). Calculated LV ejection fraction and four-chamber global longitudinal strain were sensitive to small but systematic interlaboratory differences in endocardial border definition that influenced measured LV volumes and the speckle tracking region of interest, respectively. On repeat analyses, reproducibility for mitral velocities (CP = 0.940-0.990) was improved after incorporating multiple-beat measurements and homogeneous image selection. Reproducibility for four-chamber global longitudinal strain was unchanged after efforts to develop consensus between ECLs on endocardial border determinations were limited primarily by a lack of established reference standards. CONCLUSIONS: High-quality quantitative echocardiographic research is feasible but requires a commitment to reproducibility, adherence to guideline recommendations, and the time, care, and attention to detail to establish agreement on measurement conventions. These findings have important implications for research design and clinical care. PMID- 29395628 TI - External Beam Radiation Therapy and Brachytherapy for Cervical Cancer: The Experience of the National Centre for Radiotherapy in Accra, Ghana. AB - PURPOSE: Most women with cervical cancer in Sub-Saharan Africa present with locally advanced disease. These women require external beam radiation therapy and brachytherapy for curative treatment, but data on their outcomes remain sparse. We report data on treatment characteristics, follow-up, toxicity, and cancer outcomes in a large population of patients from the National Centre for Radiotherapy in Accra, Ghana. METHODS AND MATERIALS: The charts of patients treated from 2006 to 2011 were reviewed. Patients treated without brachytherapy or with palliative intent were excluded. Staging computed tomography scans were not routinely performed. Cobalt 60 external beam radiation therapy was followed by 2 low-dose-rate brachytherapy insertions. Concurrent weekly cisplatin was recommended. Because many patients experienced delays from diagnosis to treatment, we calculated overall survival and locoregional recurrence from the date of first radiation therapy to the event date-or last follow-up when no event recurred-using the Kaplan-Meier (product-limit) method. RESULTS: We included 250 patients with a median age at diagnosis of 55 years. The International Federation of Gynecology and Obstetrics stage was IIB or lower in 63% of patients. The median dose to point A was 83 Gy (range, 60-97.5 Gy). The median doses to the bladder and rectal points were 71 Gy and 65 Gy, respectively. Of the patients, 69% received >=4 cycles of concurrent cisplatin. The median overall treatment time was 73 days. The median follow-up period was 2.4 years, with 3-year overall survival and locoregional recurrence rates of 86% and 19%, respectively. The most commonly reported late side effect was vaginal stenosis and shortening, occurring in 32% of patients. We also identified nearly 300 patients who were offered curative treatment but never returned to start treatment. CONCLUSIONS: We report promising outcomes in a population of women with cervical cancer treated with concurrent chemoradiation therapy and brachytherapy in Ghana. To our knowledge, this is the largest series of its kind, and it demonstrates what can be achieved with a well-established cancer program in Sub-Saharan Africa. PMID- 29395630 TI - Failure of Further Validation for Survival Nomograms in Oropharyngeal Cancer: Issues and Challenges. AB - PURPOSE: To retrospectively test 2 nomograms recently validated as prognostic tools for patients with oropharyngeal cancer treated with curative radiation based therapy, in 184 consecutive subjects treated from April 2004 to January 2016. PATIENT AND METHODS: Complete information regarding disease, survival status, and nomogram covariates was retrieved for 174 patients, with a median follow-up of 51 months. Calibration of the nomograms was obtained by evaluating the ability to accurately predict the absolute risk level; discriminative ability estimated by the Harrell C statistic was tested by assessing the ability of the nomograms to rank the patients from low risk to high risk. RESULTS: The outcome predicted by the nomograms was worse than observed, especially for progression free survival. This may be due to several factors: geographic and genetic background, smoking, alcohol use, the different national health system organization, which provides universal and free-of-charge coverage to all individuals, and the setting of treatment in clinical practice, outside of clinical trials. CONCLUSIONS: Our results show that the usefulness of nomograms to predict outcome of oropharyngeal cancer may not be generalizable to patients of different countries. Further studies are needed to clarify whether sociodemographic, epidemiologic, and cultural scenarios may seriously affect the prognostic ability of newly developed predictive tools. PMID- 29395629 TI - Local Control After Stereotactic Body Radiation Therapy for Liver Tumors. AB - PURPOSE: To quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and to examine whether outcomes are affected by SBRT dosing regimen. METHODS AND MATERIALS: We identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy10 vs >100 Gy10). Comparisons were made using log-rank testing. RESULTS: Thirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, log-rank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs of <=100 Gy10 (3-year local control 65%, P < .001). CONCLUSIONS: Stereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy10 are utilized. PMID- 29395631 TI - Trapezius viscoelastic properties are heterogeneously affected by eccentric exercise. AB - OBJECTIVES: The aim of this study was to investigate the influence of eccentric exercise (ECC) on the spatial mapping of muscle stiffness and creep of the upper trapezius, using a quantitative myotonometry device. DESIGN: Two groups of 16 subjects participated in the experimental sessions. In part A, the test-retest reliabilities of muscle stiffness and creep were assessed. In part B, muscle stiffness and muscle creep were mapped before, immediately after and 24h after ECC when post-exercise soreness had developed. METHODS: The ECC protocol consisted of 50 eccentric contractions divided into 5 bouts of 10 contractions at maximum force level. RESULTS: The relative reliabilities of stiffness and creep measurements were found to be substantial to almost perfect. Muscle stiffness for musculotendinous sites increased at 24h after ECC while it decreased for muscle belly immediately after and 24h after ECC. Muscle creep for musculotendinous sites decreased, and for muscle belly sites increased, immediately after and 24h after ECC. CONCLUSIONS: For the first time, the present study showed sign of discrepancies in the effects of ECC on muscle stiffness and creep, underlining opposite changes in the musculotendinous and muscle belly viscoelastic properties of upper trapezius. PMID- 29395632 TI - Predictors of clinical success in runners with patellofemoral pain: Secondary analyses of a randomized clinical trial. AB - OBJECTIVES: To identify predictors of outcome to a rehabilitation program focused on education and management of training loads in runners with patellofemoral pain (PFP). DESIGN: Secondary analyses of a randomized clinical trial. METHODS: Fifty eight runners with PFP (62% female, aged 31.2+/-6.6years, running 20.3+/ 5.6km/week) were included in analyses. Following baseline collection of demographics, anthropometry, symptomatology, isometric strength, running mechanics and radiological data, runners were randomized to one of the three 8 week intervention program: (1) Education on symptoms management and training modifications; (2) Education+Exercise program; (3) Education+Gait retraining. Clinical success was defined as an increase >=13.6% on the Knee Outcome Survey - Activities of Daily Living Scale (KOS-ADLS) at 3 months following program completion. Potential predictors were entered into logistic regression analyses. RESULTS: Forty-five runners (78%) were categorized as Success. Together, KOS-ADLS score (<70%), knee extension isometric strength (<70% bodyweight), presence of patellar tendinopathy (Grade >0) and level of usual pain (>2/10) at baseline predicted treatment outcome with 87.9% accuracy. The model provided sensitivity of 0.93 (95% C.I. 0.82-0.98), specificity of 0.69 (95% C.I. 0.42-0.87), positive likelihood ratio of 3.0 (95% C.I. 1.3-6.9), and negative likelihood ratio of 0.1 (95% C.I. 0-0.3). The best individual predictors were KOS-ADLS score and knee extension strength. CONCLUSIONS: The combination of KOS-ADLS, knee extensors strength, patellar tendon integrity and usual pain best predicted clinical outcome of runners with PFP following an intervention that had a common education component. Further testing is needed before a clinical prediction rule can be recommended to clinicians. PMID- 29395633 TI - The reproducibility of 10 and 20km time trial cycling performance in recreational cyclists, runners and team sport athletes. AB - OBJECTIVES: This study aimed to determine the reliability of 10 and 20km cycling time trial (TT) performance on the Velotron Pro in recreational cyclists, runners and intermittent-sprint based team sport athletes, with and without a familiarisation. DESIGN: Thirty-one male, recreationally active athletes completed four 10 or 20km cycling TTs on different days. METHODS: During cycling, power output, speed and cadence were recorded at 23Hz, and heart rate and rating of perceived exertion (RPE) were recorded every km. Multiple statistical methods were used to ensure a comprehensive assessment of reliability. Intraclass correlations, standard error of the measurement, minimum difference required for a worthwhile change and coefficient of variation were determined for completion time and mean trial variables (power output, speed, cadence, heart rate, RPE, session RPE). RESULTS: A meaningful change in performance for cyclists, runners, team sport athletes would be represented by 7.5, 3.6 and 12.9% improvement for 10km and a 4.9, 4.0 and 5.6% for 20km completion time. After a familiarisation, a 4.0, 3.7 and 6.4% improvement for 10km and a 4.1, 3.0 and 4.4% would be required for 20km. CONCLUSIONS: Data from this study suggest not all athletic subgroups require a familiarisation to produce substantially reliable 10 and 20km cycling performance. However, a familiarisation considerably improves the reliability of pacing strategy adopted by recreational runners and team sport athletes across these distances. PMID- 29395634 TI - Does drug-induced sleep endoscopy predict surgical success of limited palatal muscle resection in patients with obstructive sleep apnea? AB - OBJECTIVE: The aims of this study were to determine the associated factors affecting the success rate of limited palatal muscle resection (LPMR), and to investigate whether drug-induced sleep endoscopy (DISE) could predict the therapeutic response to LPMR in patients with obstructive sleep apnea obstructive sleep apnea (OSA). METHODS: Twenty-one consecutive OSA patients underwent LPMR were enrolled. All patients received routine ENT examination, preoperative DISE, and polysomnography (PSG). Clinical, polysomnographic, cephalometric variables, and DISE findings were evaluated. The measurements were related to the success or failure of LPMR based on the results of preoperative and postoperative PSG. RESULTS: The overall success rate of LPMR was 66.6%. Postoperative AHI and minimal oxygen saturation were significantly decreased after LPMR (p<0.001). Comparison between success and failure groups revealed no significant differences in BMI, Friedman stage, preoperative AHI, minimal oxygen saturation, and all cephalometric parameters. However, the success of LPMR was significantly correlated with site, degree, and configuration of obstruction in DISE. In the velopharynx, complete obstruction (p=0.006) with anterolateral or concentric pattern (p=0.044) had significantly better success rate than partial obstruction with lateral pattern. CONCLUSION: DISE was only predictive method for identifying the success in OSA patients undergoing LPMR. Patients with anteroposterior or concentric total obstruction in the velopharynx might be suitable candidate for LPMR. PMID- 29395635 TI - Bordetella Pertussis in hajj pilgrims. PMID- 29395636 TI - Letter to the editor: Increased levels of serum Wisteria floribunda agglutinin positive Mac-2 binding protein in idiopathic pulmonary fibrosis. PMID- 29395637 TI - Effect of adding B-vitamins to vitamin D and calcium supplementation on CpG methylation of epigenetic aging markers. AB - BACKGROUND AND AIM: B-vitamins may influence DNA methylation. We studied the effects of vitamin D + Ca + B versus D + Ca on epigenetic age markers and biological age. METHODS AND RESULTS: Participants (mean +/- SD of age = 68.4 +/- 10.1 years) were randomized to receive 1200 IE vitamin D3 plus 800 mg Ca carbonate alone (n = 31) or with 0.5 mg B9, 50 mg B6, and 0.5 mg B12 (n = 32). The CpG methylation of 3 genes (ASPA, ITGA2B, and PDE4C) and the changes in methylation were compared between the groups after 1 year. The changes of ASPA methylation from baseline were higher in the D + Ca + B than in the D + Ca group (1.40 +/- 4.02 vs. -0.96 +/- 5.12, respectively; p = 0.046, adjusted for age, sex, and baseline methylation). The changes in PDE4C from baseline were slightly higher in the D + Ca + B group (1.95 +/- 3.57 vs. 0.22 +/- 3.57; adjusted p = 0.062). Methylation of ITGA2B and its changes from baseline were not different between the intervention groups. Sex-adjusted odds ratio of accelerated aging (chronological age < biological age at 1 year) was 5.26 (95% confidence interval 1.51-18.28) in the D + Ca + B compared with the D + Ca group. Accelerated aging in both groups was associated with younger age. In the D + Ca + B group, it was additionally associated with lower baseline homocysteine. CONCLUSIONS: Vitamin D + Ca + B and D + Ca differentially affected epigenetic age markers, although the effect size appeared to be small after 1 year. B-vitamins effect in young subjects with low homocysteine requires further investigation. ClinicalTrials.gov ID: NCT02586181. PMID- 29395638 TI - Lenalidomide-Induced Ischemic Cerebrovascular Disease in Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome. AB - We describe the case of a 34-year-old woman with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. She developed transient ischemic attack after the introduction of lenalidomide plus dexamethasone (Rd) therapy despite no vascular risk factors. Magnetic resonance and computed tomography angiographies showed bilateral internal carotid artery stenosis. Rd therapy was suspended because of its thromboembolic risk. She had been neurologically stable during the suspension of Rd therapy. After Rd therapy was restarted, however, she repeated ischemic cerebrovascular disease. Rd therapy was switched to carfilzomib plus dexamethasone therapy. Thereafter, she had been neurologically stable. Multivessel stenosis is infrequently seen in POEMS syndrome. Therefore, magnetic resonance angiography should be performed before introducing Rd therapy in POEMS syndrome. PMID- 29395639 TI - Safety and Feasibility of Carotid Artery Stenting with Dual-Echo Technique to Minimize Iodinated Contrast Dose. AB - BACKGROUND: The aim of this study was to evaluate the safety and feasibility of carotid artery stenting (CAS) employing dual-ultrasound technique and administering a minimal contrast agent in patients with renal insufficiency. METHODS: Between September 2009 and July 2013, 63 consecutive patients underwent CAS at our institution: dual-echo carotid artery stenting (DECAS) in 7 patients with renal insufficiency and standard carotid artery stenting (STCAS) in the remaining 56 patients. Periprocedural adverse events and outcomes were compared between the 2 groups. RESULTS: Technical success was achieved in all cases. The 3 procedure-related complications were 1 case of transient hemiparesis in the DECAS group and 1 transient and 1 permanent case of hemiparesis in the STCAS group. The rate of positive diffusion-weighted-imaging lesions did not differ significantly between the 2 groups (28.6% versus 12.5%, P = .26). A significantly smaller volume of contrast was used in DECAS (15 versus 163 mL, P < .01). The change in creatinine level remained stable after CAS and did not differ between the 2 groups (.02 versus .03 mg/dL, P = .96). CONCLUSIONS: DECAS is safe and feasible for patients with pre-existing renal insufficiency and can provide an alternative for patients with carotid stenosis and renal insufficiency. PMID- 29395640 TI - Disseminated Microinfarctions with Cerebral Microbleeds. AB - Disseminated microinfarctions are uncommonly encountered in clinical practice. Here we describe a patient with long-standing cerebral microbleeds who developed acute cognitive decline in the setting of acute hypotension. Magnetic resonance imaging showed acute disseminated microinfarctions, with no change in microbleeds. This case emphasizes the important relationship between ischemic and hemorrhagic microvascular disease of the brain, especially in the setting of acute blood pressure changes compounding preexisting microvascular injury. PMID- 29395641 TI - The Burden of Diabetes and the Chance of a Previous Stroke: Thrombolysis for Recurrent Stroke in Diabetics. AB - BACKGROUND: Intravenous thrombolysis with recombinant tissue plasminogen activator is still not approved by the European Medicines Agency for patients with diabetes mellitus and previous stroke. We assessed functional benefit and potential risk of thrombolysis in patients with diabetes and previous stroke and the influence of age, preexisting diabetic damage, as well as acute and chronic hyperglycemia on outcome, symptomatic intracranial hemorrhage, and in-hospital mortality. METHODS: We analyzed 527 consecutive patients treated with thrombolysis for acute stroke. Poor outcome was defined as deterioration of prestroke modified Rankin Scale (mRS) to 3 or greater at discharge. Symptomatic intracranial hemorrhage was defined according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria. RESULTS: Of the patients, 35.9% were diabetic and 33.2% had previous stroke. Of these patients, 14.4% were diabetics with previous stroke (index group). The rate of patients with poor functional outcome at discharge, symptomatic intracranial hemorrhage, or mortality did not differ between the index group and patients with either diabetes or previous stroke in 2 * 2 comparisons. Diabetics with first-ever stroke showed significantly more symptomatic intracranial hemorrhage (9.7%, P < .001) than the other groups, poorer functional recovery (P = .036), and the highest rate of mortality (12.4%, P < .001). Significant predictors for poor outcome were age (P < .001) and HbA1c (P = .013), for symptomatic intracranial hemorrhage HbA1c (P = .006) and for mortality acute hyperglycemia (P = .001) and age (P = .004). CONCLUSION: Diabetics with previous stroke should not be withheld from intravenous thrombolysis. The risk of complications derives primarily from poor long-term metabolic control rather than from acute hyperglycemia or from previous stroke. PMID- 29395642 TI - One-Year Risk of Pneumonia and Mortality in Patients with Poststroke Dysphagia: A Nationwide Population-Based Study. AB - BACKGROUND: In the early stages of stroke, the use of a nasogastric tube can reduce complications such as malnutrition, dehydration, and pneumonia. However, its long-term efficacy is controversial. METHODS: This retrospective cohort study used Taiwan's National Health Insurance Research Database to investigate associations among dysphagia, rate of readmission due to pneumonia, and mortality 1 year after stroke. Patients who had received their first stroke diagnosis and inpatient rehabilitation from January 1, 2006, to December 31, 2010, were enrolled. The presence of dysphagia was determined by the number of nasogastric tubes received (>=2 was classified as dysphagia, <2 as control). Kaplan-Meier plots with log-rank tests revealed differences between the 2 groups, and a Cox regression model was used to estimate the hazard ratio. RESULTS: There were 5032 patients in the dysphagia group and 52,323 patients in the control group. The dysphagia group had a higher probability and incidence of pneumonia (18.78% versus 6.52%, P < .001 and adjusted hazard ratio [AHR] = 2.00, 95% confidence interval [CI] = 1.84-2.16) and a higher mortality rate (10.45% versus 4.77%, P < .001; AHR = 1.61, 95% CI = 1.46-1.79) 1 year after stroke. CONCLUSIONS: The association persisted until the 5-year poststroke time point. Our results suggest that prolonged nasogastric tube use has negative effects. Intensive evaluation of dysphagia and removal of the nasogastric tube in the early stages of stroke might reduce pneumonia incidence and mortality. PMID- 29395643 TI - Ideal Cardiovascular Health and Arterial Stiffness in Spanish Adults-The EVIDENT Study. AB - BACKGROUND: Studies concerning ideal cardiovascular (CV) health and its relationship with arterial stiffness are lacking. This study examined the association between arterial stiffness with ideal CV health as defined by the American Heart Association, across age groups and gender. METHODS: The cross sectional study included 1365 adults. Ideal CV health was defined as meeting ideal levels of the following components: 4 behaviors (smoking, body mass index, physical activity, and Mediterranean diet adherence) and 3 factors (total cholesterol, blood pressure, and glycated hemoglobin). Patients were grouped into 3 categories according to their number of ideal CV health metrics: ideal (5-7 metrics), intermediate (3-4 metrics), and poor (0-2 metrics). We analyzed the pulse wave velocity (PWV), the central and radial augmentation indexes, and the ambulatory arterial stiffness index (AASI). RESULTS: The ideal CV health profile was inversely associated with lower arterial radial augmentation index and AASI in both genders, particularly in middle-aged (45-65 years) and in elderly subjects (>65 years). Also in elderly subjects, adjusted models showed that adults with at least 3 health metrics at ideal levels had significantly lower PWV than those with 2 or fewer ideal health metrics. CONCLUSIONS: An association was found between a favorable level of ideal CV health metrics and lower arterial stiffness across age groups. PMID- 29395644 TI - Risk of Recurrent Ischemic Stroke with Unintended Low-Dose Oral Anticoagulant Therapy and Optimal Timing of Review. AB - BACKGROUND: Direct oral anticoagulant (DOAC) dose is adjusted according to manufacturer's recommendations when introduced. However, subsequent changes from appropriate DOAC doses to "unintended" inappropriate low-dose DOAC (ILD) due to increased body weight (BW) or decreased serum creatinine concentration might be overlooked. We investigated outcomes in patients receiving appropriate DOAC, "intended" ILD, or unintended ILD, to determine the optimal review time for DOAC doses and associated factors. METHODS: This single-center, retrospective cohort study included inpatients receiving apixaban for stroke prevention between August 2015 and July 2017. Primary outcome was whether starting DOAC dose was selected according to manufacturer's recommendations and whether that dose remained appropriate thereafter. Secondary outcome was the incidence of recurrent ischemic stroke and intracranial bleeding during therapy. Average rates of change in BW, creatinine, and creatinine clearance (CrCl) were evaluated after hospitalization every 10 +/- 3 days. RESULTS: During the study period, 120 patients received apixaban; 112 (93.3%) commenced appropriate DOAC doses, and 8 (6.7%) commenced intended ILD doses. Of the 112 patients on appropriate DOAC doses, 7 (6.3%) changed to unintended ILD doses because of increased BW (n = 4) or decreased creatinine (n = 3). The rate of recurrent ischemic stroke differed significantly between the appropriate DOAC dose and the intended or unintended ILD dose group (1.9% [2 of 105] versus 20.0% [3 of 15], P = .014). BW and renal function had stabilized after 20 +/- 3 days posthospitalization. CONCLUSIONS: Receiving ILD doses, especially unintended, might be a risk factor for recurrent ischemic stroke and DOAC dose should be reviewed around 20 +/- 3 days posthospitalization. PMID- 29395645 TI - Injury of the Precommissural Fornix in a Patient with Subarachnoid Hemorrhage: A Case Report. AB - OBJECTIVES: We investigated injury of the pre- or postcommissural fornix in a patient with subarachnoid hemorrhage (SAH) using diffusion tensor imaging. CASE DESCRIPTION: A 48-year-old male patient was diagnosed as SAH due to rupture of the right middle cerebral artery bifurcation aneurysm. After 9 weeks from onset, he was transferred to the rehabilitation department and he showed memory impairment. The whole fornix was reconstructed using single-tract fornix model based on a fiber assignment by continuous tracking, and separated fornices (pre- and postcommissural fornices) were reconstructed using 2-tract fornix model based on a probabilistic tractography method. The fractional anisotropy (FA), mean diffusivity, and fiber volume were measured in the patient and 6 normal control subjects. The integrities of both reconstructed whole fornices that were reconstructed using probabilistic tractography method were preserved. By contrast, in the results of 2-tract fornix model, the precommissural fornices showed discontinuations in both fornical cruses. In addition, the FA and fiber volume of both precommissural fornices in the patient were decreased by more than 2 standard deviations of those of normal control subjects. CONCLUSIONS: Separate evaluations of the pre- and postcommissural fornices using 2-tract fornix model would be useful for diagnosis in patients with memory impairment following SAH. PMID- 29395646 TI - Amnesia due to the Injury of Papez Circuit Following Isolated Fornix Column Infarction. PMID- 29395647 TI - Expression of Connexin43 in Cerebral Arteries of Patients with Moyamoya Disease. AB - BACKGROUND AND PURPOSE: Moyamoya disease has a high incidence of cerebral vascular accident in children and adolescents, which can endanger the physical and mental health of children and adults seriously. However, the etiology and the pathogenesis of moyamoya disease remain unclear. Connexin43 (Cx43) is a predominant intercellular gap junction protein that plays an important role in the normal function of arteries and the development of several cardiovascular diseases. We aimed to preliminarily investigate pathological changes and the expression of Cx43 in cerebral arteries of patients with moyamoya disease. MATERIALS AND METHODS: This study collected 10 experimental cerebral artery specimens from patients with moyamoya disease and 10 control cerebral artery specimens from patients without moyamoya disease during surgery, then pathological changes and change in Cx43 expression of cerebral artery specimens were investigated in the 2 groups by hematoxylin and eosin staining and immunofluorescence. RESULTS: The intima of cerebral arteries was thin with monolayer endothelial cells in the control group but had asymmetrical thickening for the cerebral arteries in the experimental group. The mean +/- standard deviation of the mean optical density of Cx43 in the experimental group was .065 +/- .011 (range, .045-.081), whereas that in the control group was .035 +/- .005 (range, .028-.042). The expression of Cx43 in the experimental group was statistically significantly higher in comparison with the control group (P < .01). CONCLUSION: The abnormal expression of Cx43 in the cerebral arteries may play an important role in the formation of vascular intima thickening in patients with moyamoya disease. PMID- 29395648 TI - Delayed Administration of the Glucagon-Like Peptide 1 Analog Liraglutide Promoting Angiogenesis after Focal Cerebral Ischemia in Mice. AB - BACKGROUND: Glucagon-like peptide 1 (GLP-1) analogs administered before or after cerebral ischemia have been shown to provide neuroprotection. Here, we explored whether delayed administration of a GLP-1 analog, liraglutide, could improve long term functional recovery and promote angiogenesis after stroke. MATERIALS AND METHODS: In the present study, mice were established as a focal cerebral cortical ischemia model and were intraperitoneally administered liraglutide or normal saline (NS) daily for 14 consecutive days, starting 1 day after cerebral ischemia. The neurological deficits were evaluated using rotarod test. The microvessel density (MVD) and endothelial cell (EC) proliferation were assessed by immunohistochemical staining. The expression of vascular endothelial growth factor (VEGF) was assessed by Western blot analysis. RESULTS: Liraglutide significantly reduced infarct volume and improved the rotarod test scores, compared with mice treated with NS. Liraglutide also greatly increased the MVD and EC proliferation and simultaneously upregulated the expression of VEGF in the cerebral ischemic area. CONCLUSIONS: These results demonstrated that liraglutide promoted angiogenesis and long-term recovery of cerebral ischemia through increasing the expression of VEGF. PMID- 29395649 TI - Adductor Pollicis Muscle Thickness and Obesity Are Associated with Poor Outcome after Stroke: A Cohort Study. AB - BACKGROUND: Nutritional status may influence outcome after stroke. It is possible that some obese individuals present reduced fat-free mass. AIMS: We aimed to determine if bedside evaluation of body composition by the body mass index (BMI), adductor pollicis muscle thickness (APMT) and arm muscle area (AMA), and the combination of low APMT or AMA with obesity are associated with disability 90 days after stroke. METHODS: A cohort study evaluating 120 patients hospitalized at the Stroke Unit was carried out. Data were expressed as average +/- standard deviation or median and percentiles. Obesity was evaluated by BMI and fat-free mass by the APMT and AMA. Receiver operating characteristic (ROC) curves and multivariate logistic regression analysis were used to measure whether APMT and obesity were associated with modified Rankin Scale (mRS) >=3 (disability) within 90 days of stroke. The data were adjusted for National Institutes of Health Stroke Scale (NIHSS), sex, age, type of stroke, and thrombolysis. The significance level was 5%. RESULTS: Of 120 patients, we came up with the following demographics: men: 66 (55.0%); mean age: 66.6 +/- 13.2 years; ischemic stroke: 109 (90.8%); mean NIHSS: 4 (2-10); thrombolysis: 18 (16.5%). Considering mRS >=3, ROC curve analysis showed that the value of the cutoff for APMT was <12.5 mm. In multivariate analysis adjusted for the above factors, each 1 mm of increase in APTM reduced the chance of disability by 31%. The intersection of obesity with APMT <12.5 mm increased by 37-fold the risk of disability. AMA was not associated with mRS >=3. CONCLUSION: Lower APMT alone or in combination with obesity was associated with poor functional status. PMID- 29395650 TI - Remote Limb Ischemic Conditioning during Cerebral Ischemia Reduces Infarct Size through Enhanced Collateral Circulation in Murine Focal Cerebral Ischemia. AB - BACKGROUND: Remote ischemic conditioning (RIC) induces protection in focal cerebral ischemia. The conditioning is divided into pre-, per-, and postconditioning. However, the mechanisms of RIC remain unknown. OBJECTIVES: This study aimed to determine the most effective subtype of RIC. We also examined involvement of collateral circulation on RIC. METHODS: Transient middle cerebral artery occlusion (MCAO) was performed with nylon sutures in adult C57BL/6 mice under the monitoring of cerebral blood flow (CBF). Fifty mice were divided into 5 groups: MCAO control group, delayed pre-RIC group (RIC 24 hours before MCAO), early pre-RIC group (RIC 5 minutes before MCAO), per-RIC group (RIC during MCAO), and post-RIC group (RIC 5 minutes after MCAO). In other middle cerebral artery (MCA) control and per-RIC groups, collateral circulation was visualized with latex compound perfusion. RESULTS: After MCAO, CBF was reduced by 80% in all groups. At the end of MCAO, relative increase in CBF in per-RIC group was significantly greater than that in MCA control, whereas the infarct volume in per RIC group was significantly smaller than that in other groups. The diameter of leptomeningeal anastomosis was larger in the per-RIC group than that in the control group. CONCLUSIONS: Among the 4 RIC procedures, only the per-RIC group showed clear brain protection. Enhancement of collateral circulation could play a role in the protective effect of per-RIC. PMID- 29395651 TI - In Response to: De Bernardo, M and Rosa, N. "Transorbital Sonography to Evaluate Optic Nerve in Hypertensive Encephalopathy". PMID- 29395652 TI - Sigmoid-weighted linear units for neural network function approximation in reinforcement learning. AB - In recent years, neural networks have enjoyed a renaissance as function approximators in reinforcement learning. Two decades after Tesauro's TD-Gammon achieved near top-level human performance in backgammon, the deep reinforcement learning algorithm DQN achieved human-level performance in many Atari 2600 games. The purpose of this study is twofold. First, we propose two activation functions for neural network function approximation in reinforcement learning: the sigmoid weighted linear unit (SiLU) and its derivative function (dSiLU). The activation of the SiLU is computed by the sigmoid function multiplied by its input. Second, we suggest that the more traditional approach of using on-policy learning with eligibility traces, instead of experience replay, and softmax action selection can be competitive with DQN, without the need for a separate target network. We validate our proposed approach by, first, achieving new state-of-the-art results in both stochastic SZ-Tetris and Tetris with a small 10 * 10 board, using TD(lambda) learning and shallow dSiLU network agents, and, then, by outperforming DQN in the Atari 2600 domain by using a deep Sarsa(lambda) agent with SiLU and dSiLU hidden units. PMID- 29395653 TI - Mind the Organelle Gap - Peroxisome Contact Sites in Disease. AB - The eukaryotic cell is organized as a complex grid system where membrane-bound cellular compartments, organelles, must be localized to the right place at the right time. One way to facilitate correct organelle localization and organelle cooperation is through membrane contact sites, areas of close proximity between two organelles that are bridged by protein/lipid complexes. It is now clear that all organelles physically contact each other. The main focus of this review is contact sites of peroxisomes, central metabolic hubs whose defects lead to a variety of diseases. New peroxisome contacts, their tethering complexes and functions have been recently discovered. However, if and how peroxisome contacts contribute to the development of peroxisome-related diseases is still a mystery. PMID- 29395655 TI - RNA Selection by PIWI Proteins. AB - Gene regulation by PIWI-piRNA complexes is determined by the selection of cognate target RNAs by PIWI-piRNA. What are the mechanisms for this selection? There is a rigorous multistep control in identifying target RNAs by PIWI-piRNA structures, and RNA helicases play a potentially crucial role in this process. PMID- 29395654 TI - Protein Tertiary Structure by Crosslinking/Mass Spectrometry. AB - Observing the structures of proteins within the cell and tracking structural changes under different cellular conditions are the ultimate challenges for structural biology. This, however, requires an experimental technique that can generate sufficient data for structure determination and is applicable in the native environment of proteins. Crosslinking/mass spectrometry (CLMS) and protein structure determination have recently advanced to meet these requirements and crosslinking-driven de novo structure determination in native environments is now possible. In this opinion article, we highlight recent successes in the field of CLMS with protein structure modeling and challenges it still holds. PMID- 29395656 TI - Serum protein marker panel for predicting preeclampsia. AB - BACKGROUND: Preeclampsia is a multi-system disorder in pregnancy which has no effective treatment. The diagnosis of preeclampsia is based on clinical presentation and routine laboratory tests. OBJECTIVE: This study aimed at identifying serum protein markers for diagnosis of preeclampsia and predicting its severe features. STUDY DESIGN: In total, 172 pregnant women were enrolled in this study including 110 subjects with preeclampsia and 62 normotensive subjects. Eleven serum proteins (VEGF, sFlt-1, sEndoglin, PlGF, sEGFR, prolactin, PTX3, PAI 1, NGAL, IL-27, COX-2) were assessed using Luminex multiplex immunoassay and ELISA. RESULTS: The levels of seven proteins (sFlt-1, VEGF, sEndoglin, sEGFR, PlGF, NGAL, COX-2) correlated with preeclampsia, and 4 proteins (VEGF, sEndoglin, PlGF, sEGFR) were identified as independent factors associated with preeclampsia. The levels of three proteins (sEndoglin, PTX3, sFlt-1) correlated with severe features of preeclampsia, and three variables (serum creatinine, platelet count and sEndoglin) were identified as independent factors in predicting severe features of preeclampsia. CONCLUSIONS: A combination of serum protein markers (VEGF, sEndoglin, PlGF, sEGFR) and clinical variables (serum creatinine, platelet count and sEndoglin) could be used as analytical tool in diagnosis of preeclampsia and its severe features, respectively. Serum sEGFR, a novel biomarker in preeclampsia, may be involved in the pathogenesis of preeclampsia. PMID- 29395657 TI - Compositional dynamics and codon usage pattern of BRCA1 gene across nine mammalian species. AB - The BRCA1 gene is located on the human chromosome 17q21.31 and plays important role in biological processes. The aminoacyl-tRNA synthetases (AARS) are a family of heterogenous enzymes responsible protein synthesis and whose secondary functions include a role in autoimmune myositis. Our findings reveal that the compositional constraint and the preference of more A/T -ending codons determine the codon usage patterns in BRCA1 gene while more G/C-ending codons influence the codon usage pattern of AARS gene among mammals. The codon usage bias in BRCA1 and AARS genes is low. The codon CGC encoding arginine amino acid and the codon TTA encoding leucine were uniformly distributed in BRCA1 and AARS genes, respectively in mammals including human. Natural selection might have played a major role while mutation pressure might have played a minor role in shaping the codon usage pattern of BRCA1 and AARS genes. PMID- 29395658 TI - Dermal fibroblasts-A heterogeneous population with regulatory function in wound healing. AB - Dermal fibroblasts, which make up the major cell type in the dermis, have, historically, been considered to be relatively 'passive' cells which are responsible for the synthesis and remodeling of extracellular matrix proteins. However, the dermal fibroblast population is composed of heterogeneous and distinct cell types, and it has been established that, under the stress conditions of healing wound environments, dermal fibroblasts participate in the regulation of ongoing inflammation and cell proliferation by secreting a variety of signaling molecules that modulate the functions of immune cells, keratinocyte, endothelial cells and mast cells via both direct cell to cell communication and autocrine and paracrine interactions. This review describes the capacity of dermal fibroblasts to sense and respond to signals from the micro-environment and to communicate with surrounding cells during cutaneous wound healing. The review further emphasizes the, to date, poorly understood roles of heterogeneous dermal fibroblast populations in the wound healing process. PMID- 29395659 TI - Adiponectin: A potential therapeutic target for metabolic syndrome. AB - Adiponectin is an important adipocytokine secreted chiefly by fat containing adipocytes, and plays a crucial role in glucose and lipid metabolism, inflammation and oxidative stress. Alterations in adiponectin levels have been shown to directly affect lipid and glucose metabolism that further increase the synthesis of lipids, free fatty acids and inflammatory cytokines. Changes in adiponectin levels also contribute to insulin resistance, obesity, cardiovascular diseases and type 2 diabetes. In the present review, we provide a comprehensive evaluation of the role of adiponectin and its molecular mechanisms in metabolic syndrome. Clinical improvement in adiponectin levels have been shown to positively modulate lipid and glucose metabolism, thus further substantiating its role in regulation of lipid and glucose metabolism. Currently adiponectin is being investigated as a potential therapeutic target for metabolic syndrome, although more research is required to understand the underlying mechanisms controlling adiponectin levels, including dietary and lifestyle interventions, that may target adiponectin as a therapeutic intervention in metabolic syndrome. PMID- 29395660 TI - New quantitative method for evaluation of motor functions applicable to spinal muscular atrophy. AB - OBJECTIVE: The aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity. METHODS: The movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed. RESULTS: In the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patient's doctors. CONCLUSION: We have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders. PMID- 29395661 TI - Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma. AB - Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4 55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored. PMID- 29395662 TI - Detection of fast (40-150 Hz) oscillations from the ictal scalp EEG data of myoclonic seizures in pediatric patients. AB - OBJECTIVE: We explored fast (40-150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures. SUBJECTS AND METHODS: The participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis. RESULTS: We identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019). CONCLUSION: FOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system. PMID- 29395663 TI - ATP1A3-related epileptic encephalopathy responding to ketogenic diet. AB - BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na+-K+ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported. CASE REPORT: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development. CONCLUSIONS: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary. PMID- 29395664 TI - Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation. AB - Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature. PMID- 29395665 TI - Ethnicity, length of residence, and prospective trends in body mass index in a national sample of Australian adults (2006-2014). AB - PURPOSE: Increasing global migration, high obesity in developed countries, and ethnic health inequalities are compelling reasons to monitor immigrant obesity trends. Longitudinal studies of ethnicity, length of residence, and adiposity in contexts outside of the United States are lacking. METHODS: Nine waves (2006 2014) of the Household Income and Labour Dynamics in Australia survey were analyzed (n = 20,934; 52% women; 101,717 person-year observations) using random effects modeling to assess average annual change in body mass index (BMI) by ethnic group. A second analysis used an immigrant only cohort (n = 4583; 52% women; 22,301 person-year observations) to examine BMI change by length of residence. RESULTS: Over 9 years, mean BMI increased significantly in all ethnic and Australian-born groups, and by the final wave, mean BMI exceeded 25 kg m-2 for all groups. Trajectories of change did not vary between groups, with the exception of slower BMI increases for North-West European men compared with Australian born. Immigrants residing in Australia for 10-19 years had significantly faster annual increases in BMI compared with long-term immigrants (>=30 years). CONCLUSIONS: Immigrants to Australia, regardless of ethnicity, are at risk of obesity over time. Obesity prevention policy should prioritize immigrants in the early-mid settlement period. PMID- 29395666 TI - "It's a Long-Term Process": Description of Daily Family Life When a Child Has a Feeding Disorder. AB - Pediatric feeding problems occur in 25% of the general pediatric population and up to 80% of those who have developmental delays. When feeding problems place the child at nutritional risk, families are typically encouraged to increase their child's intake. Family mealtime can become a battle, which further reinforces problematic feeding behaviors from the child and intensifies well-intentioned but unguided parental mealtime efforts. Family has an essential influence on feeding; however, studies to date neglect to address the family context of feeding difficulty. In this study we describe, in the context of everyday life, family management of feeding when a child had a significant feeding problem. Parents of children with feeding problems were interviewed with the Family Management Style Framework components as a guide. Twelve parents participated, representing nine families of children with feeding disorder. Description of family management of feeding provides a foundation for development of family feeding interventions. PMID- 29395667 TI - Four new hybrid polyketide-terpenoid metabolites from the Penicillium sp. SYPF7381 in the rhizosphere soil of Pulsatilla chinensis. AB - A search for cytotoxic agents from cultures of the Penicillium sp., isolated from the rhizosphere soil of Pulsatilla chinensis, led to the isolation of four new hybrid polyketide-terpenoid metabolites (1-4), together with fourteen known compounds (5-18). Using a bioassay-guided fractionation approach, eighteen compounds were obtained from the ethyl acetate extract of this fungus. Structure elucidation was achieved by extensive analysis of spectroscopic data (1D/2D NMR, HRESIMS and IR). The absolute configurations of compounds 1-4 were determined by means of electronic circular dichroism (ECD) calculation. Compounds 1-4, 7-9, 11, 12, 14 and 17 were tested for their cytotoxicity against HL-60, THP-1 and Caco2 cell lines. Compound 1 showed potent cytotoxic capability against HL-60, THP-1 and Caco2 cell with IC50 values of 3.4MUM, 4.3MUM, 10.5MUM, and compound 2 showed significant inhibiting activities against HL-60 cell line and THP-1 cell line (IC50=7.9MUM, 11.3MUM, respectively), using 5-fluorouracil as the positive drug with IC50 values of 6.4MUM, 4.4MUM, 56.6MUM for HL-60, THP-1 and Caco2 cells, respectively. And compound 1 showed antibacterial activity toward Bacillus cereus (IC50=49MUg/mL, IC90=111MUg/mL) and Bacillus subtilis (IC50=10MUg/mL, IC90=85MUg/mL). PMID- 29395668 TI - EGFR amplification and expression in oral squamous cell carcinoma in young adults. AB - The aim of this study was to investigate epidermal growth factor receptor (EGFR) gene alterations in two groups of patients with oral squamous cell carcinoma (OSCC) (a test group of subjects aged <=40 years and a control group of subjects aged >=50 years) and to associate the results with EGFR immunostaining, clinicopathological features, and the prognosis. Sixty cases of OSCC were selected (test group, n=21; control group, n=39). The tissue microarray technique was applied to ensure the uniformity of results. Gene amplification was analyzed by fluorescence in situ hybridization (FISH), and immunohistochemical staining for EGFR was analyzed using an automated imaging system. EGFR amplification was higher in the test group than in the control group (P=0.018) and was associated with advanced clinical stage (P=0.013), regardless of age. Patients with EGFR overexpression had worse survival rates, as did patients who had T3-T4 tumours and positive margins. EGFR overexpression has a negative impact on disease progression. Despite the higher amplification of EGFR in young adults, it does not significantly impact the survival rates of affected patients. PMID- 29395669 TI - Significant association of increased PD-L1 and PD-1 expression with nodal metastasis and a poor prognosis in oral squamous cell carcinoma. AB - Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD 1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9% of OSCC cases and increased expression of PD-1 was found in 61.9%. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response. PMID- 29395670 TI - One versus two venous anastomoses in microsurgical head and neck reconstruction: a cumulative meta-analysis. AB - Venous compromise is still the most common cause of free flap failure. The use of two venous anastomoses has been advocated to reduce venous compromise. However, the effectiveness of this approach remains controversial. A systematic review and cumulative meta-analysis was performed to assess the effect of one versus two venous anastomoses on venous compromise and free flap failure in head and neck microsurgical reconstruction. A total of 27 articles reporting 7389 flaps were included in this study. On comparison of one versus two venous anastomoses, the odds ratio (OR) for flap failure was 1.66 (95% confidence interval 1.11-2.50; P=0.014) and for venous compromise was 1.50 (95% confidence interval 1.10-2.05; P=0.011), suggesting a significant increase in the flap failure rate and venous compromise rate in the single venous anastomosis group. These results show that the execution of two venous anastomoses has significant effects on reducing the vascular compromise and free flap failure rate in head and neck reconstruction. PMID- 29395672 TI - DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine. AB - DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS. PMID- 29395671 TI - A database for screening and registering late onset Pompe disease in Turkey. AB - The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe. PMID- 29395673 TI - 228th ENMC International Workshop:: Airway clearance techniques in neuromuscular disorders Naarden, The Netherlands, 3-5 March, 2017. PMID- 29395674 TI - Specific muscle strength is reduced in facioscapulohumeral dystrophy: An MRI based musculoskeletal analysis. AB - The aim was to test whether strength per unit of muscle area (specific muscle strength) is affected in facioscapulohumeral dystrophy (FSHD) patients, as compared to healthy controls. Ten patients and ten healthy volunteers underwent an MRI examination and maximum voluntary isometric contraction measurements (MVICs) of the quadriceps muscles. Contractile muscle volume, as obtained from the MR images, was combined with the MVICs to calculate the physiological cross sectional area (PCSA) and muscle strength using a musculoskeletal model. Subsequently, specific strength was calculated for each subject as muscle strength divided by total PCSA. FSHD patients had a reduced quadriceps muscle strength (median(1st quartile-3rd quartile): 2011 (905.4-2775) N vs. 5510 (4727 8321) N, p <0.001) and total PCSA (83.6 (62.3-124.8) cm2vs. 140.1(97.1-189.9) cm2, p = 0.015) compared to healthy controls. Furthermore, the specific strength of the quadriceps was significantly lower in patients compared to healthy controls (20.9 (14.7-24.0) N/cm2vs. 41.9 (38.3-49.0) N/cm2, p <0.001). Thus, even when correcting for atrophy and fatty infiltration, patients with FSHD generated less force per unit area of residual muscle tissue than healthy controls. Possible explanations include impaired force propagation due to fatty infiltration, reduced intrinsic force-generating capacity of the muscle fibers, or mitochondrial abnormalities leading to impaired energy metabolism. PMID- 29395676 TI - Quantitative Evaluation of Combretastatin A4 Phosphate Early Efficacy in a Tumor Model with Dynamic Contrast-Enhanced Ultrasound. AB - Combretastatin A4 phosphate (CA4P) is a vascular disrupting agent that rapidly shuts down blood supply to tumors. Early monitoring of tumor perfusion plays a crucial role in determining the optimal strategy to managing treatment and guiding future therapy. The aim of this study was to investigate the potential value of dynamic contrast-enhanced ultrasound (CEUS) in quantitative evaluation of tumor perfusion at an early stage in CA4P therapy. Central and peripheral perfusion of tumors was detected by CEUS pre-treatment (0 h) and 2, 12 and 48 h after CA4P injection. Two perfusion parameters, maximum intensity (IMAX) and time to peak (TTP), were calculated from the time-intensity curve. After CEUS, the efficacy of CA4P was immediately confirmed by immunofluorescence assay and hematoxylin and eosin, Hoechst 33342 and fluorescein isothiocyanate-lectin staining. In CEUS of the center region of tumors, IMAX gradually decreased from 0 to 12 h and regrew at 48 h (p < 0.01). TTP increased only at 2 h. In the peripheral regions, IMAX did not change obviously from 0 to 12 h (p > 0.05) and just increased at 48 h (p < 0.01). The TTP of peripheral regions had the same tendency to vary tendency as that of center regions. In addition, microvascular density (MVD), vascular perfusion and necrotic area of the tumor were quantitatively analyzed. A close correlation between IMAX and MVD was observed in the center areas of tumors (r = 0.72, p < 0.01), whereas the correlation between IMAX and MVD in peripheral areas was weak (r = 0.37, p < 0.01). However, IMAX was positively correlated with tumor perfusion in both center and peripheral areas of tumors (r = 0.82, p < 0.01, and r = 0.63, p < 0.01, respectively). Consequently, IMAX was a reliable indicator of tumor perfusion evaluation by CEUS. The use of CEUS to quantify tumor perfusion could a promising method for the early detection of tumor responses in anti-vascular treatment. PMID- 29395675 TI - Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up. AB - Congenital myasthenic syndromes (CMS) are a group of hereditary disorders affecting the neuromuscular junction. Here, we present clinical, electrophysiological and genetic findings of 69 patients from 51 unrelated kinships from Turkey. Genetic tests of 60 patients were performed at Mayo Clinic. Median follow-up time was 9.8 years (range 1-22 years). The most common CMS was primary acetylcholine receptor (AChR) deficiency (31/51) and the most common mutations in AChR were c.1219 + 2T > G (12/51) and c.1327delG (6/51) in CHRNE. Four of our 5 kinships with AChE deficiency carried p.W148X that truncates the collagen domain of COLQ, and was previously reported only in patients from Turkey. These were followed by GFPT1 deficiency (4/51), DOK7 deficiency (3/51), slow channel CMS (3/51), fast channel CMS (3/51), choline acetyltransferase deficiency (1/51) and a CMS associated with desmin deficiency (1/51). Distribution of muscle weakness was sometimes useful in giving a clue to the CMS subtype. Presence of repetitive compound muscle action potentials pointed to AChE deficiency or slow channel CMS. Our experience confirms that one needs to be cautious using pyridostigmine, since it can worsen some types of CMS. Ephedrine/salbutamol were very effective in AChE and DOK7 deficiencies and were useful as adjuncts in other types of CMS. Long follow-up gave us a chance to assess progression of the disease, and to witness 12 mainly uneventful pregnancies in 8 patients. In this study, we describe some new phenotypes and detail the clinical features of the well-known CMS. PMID- 29395677 TI - Microembolic Signals Predict Recurrence of Ischemic Events in Symptomatic Patients with Middle Cerebral Artery Stenosis. AB - Middle cerebral artery (MCA) stenosis is a common cause of ischemic stroke in Asian populations. We sought to determine whether microembolic signals (MESs) can predict the occurrence or recurrence of ischemia in symptomatic and asymptomatic patients with MCA stenosis. The symptomatic group had a significantly higher incidence of MES (30% vs. 16.2%, p < 0.05), as well as higher incidences of cerebral infarction and transient ischemic attack (TIA) (infarction, 13.0% vs. 4.4%, OR 3.123 [95% CI, 1.049-9.294], p < 0.05; TIA, 21.0% vs. 2.9%, OR = 7.108 [95% CI, 1.808-27.949], p < 0.001) than the asymptomatic group. After a follow-up period of 0.5-4.5 y, the subgroup of MES-positive (MES+) symptomatic patients had a significantly higher incidence of TIA (36.7% vs. 14.3%, OR = 1.623 [95% CI, 1.166-2.258]; p < 0.001) than the subgroup of MES-negative (MES-) symptomatic patients. The likelihood of the early occurrence of an endpoint event was also higher in the subgroup of MES+ symptomatic patients. In the group of asymptomatic patients with MCA stenosis, no significant differences were identified between the MES+ and MES- subgroups. PMID- 29395678 TI - 3-D Quantitative Dynamic Contrast Ultrasound for Prostate Cancer Localization. AB - To investigate quantitative 3-D dynamic contrast-enhanced ultrasound (DCE-US) and, in particular 3-D contrast-ultrasound dispersion imaging (CUDI), for prostate cancer detection and localization, 43 patients referred for 10-12-core systematic biopsy underwent 3-D DCE-US. For each 3-D DCE-US recording, parametric maps of CUDI-based and perfusion-based parameters were computed. The parametric maps were divided in regions, each corresponding to a biopsy core. The obtained parameters were validated per biopsy location and after combining two or more adjacent regions. For CUDI by correlation (r) and for the wash-in time (WIT), a significant difference in parameter values between benign and malignant biopsy cores was found (p < 0.001). In a per-prostate analysis, sensitivity and specificity were 94% and 50% for r, and 53% and 81% for WIT. Based on these results, it can be concluded that quantitative 3-D DCE-US could aid in localizing prostate cancer. Therefore, we recommend follow-up studies to investigate its value for targeting biopsies. PMID- 29395679 TI - High Intensity Focused Ultrasound (HIFU) Heating Improves Perfusion and Antimicrobial Efficacy in Mouse Staphylococcus Abscess. AB - Chronic wounds typically require long-duration treatment with a combination of antibiotics administered systemically. This incurs adverse side effects and can require aversive surgical treatments and limb amputations. To improve non invasive antimicrobial therapy, the objective of this study was to investigate antimicrobial chemotherapy combined with high-intensity focused ultrasound (HIFU) heating (HT). A Staphylococcus aureus abscess (80 +/- 30 mm3) was generated in the mouse flank region. Once the average temperature (~42 degrees C-46 degrees C) in the abscess was reached with HIFU-HT, a broad-spectrum antimicrobial (ciprofloxacin, 10 mg/kg) and perfusion marker (Evans blue dye, 40 mg/kg wt) were administered intravenously via the tail vein. Four hours later, mean abscess perfusion and colony-forming units (CFUs) per gram of abscess were determined. HIFU-HT increased abscess perfusion by ~2.5-fold (4 +/- 0.6 ug/mL Evans blue) compared with control (1.5 +/- 0.7 ug/mL), and improved antimicrobial efficacy to decrease percentage average survival of S. aureus by ~20% (46 +/- 7 CFUs/g of abscess) versus that seen with ciprofloxacin alone (61 +/- 4 CFU/g). Our in vivo data suggest that HIFU-HT can improve antimicrobial treatment responses against deep-seated bacteria in abscess wounds via enhanced perfusion. PMID- 29395680 TI - Mesenchymal-myeloid interaction in the regulation of immunity. AB - Several studies have demonstrated how different cell types of mesenchymal and myeloid origin can independently exhibit immunoregulatory activities. In response to inflammatory cues, they transcribe a molecular repertoire that restores the tissue microenvironment to what it was before the injury. There is accumulating evidence that stromal and myeloid-derived cells do not act independently but that the establishment of a cross-talk between them is a fundamental requirement. Stromal cells, prompted by inflammatory molecules, orchestrate and initiate myeloid cell recruitment and their functional reprogramming. Once instructed, myeloid cells effect the anti-inflammatory activity or, if alternatively required, enhance immune responses. The cross-talk plays a fundamental role in tissue homeostasis, not only to regulate inflammation, but also to promote tissue regeneration and cancer progression. PMID- 29395681 TI - Complement involvement in bone homeostasis and bone disorders. AB - An integral part of innate immunity is the complement system, a defence system, consisting of fluid-phase and cell surface-bound proteins. Its role to ensure adequate responses to danger factors and thus promoting host defence against pathogens has been well described already for decades. Recently, numerous further reaching functions of complement have been discovered, among these are tissue homeostasis and regeneration, also with respect to the skeletal system. The influence of complement activation on bone was recognised first in pathological conditions of inflamed bone tissue and surrounding areas, observed, for example, in rheumatoid arthritis and osteoarthritis. Greatly enhanced levels of complement proteins were detected in synovial fluids and sera of arthritic patients compared to healthy individuals. Additionally, complement-mediated signalling was shown to modulate periodontitis disease development and progression. Periodontitis is an infectious condition of the periodontium, which involves severe bone loss. Moreover, the complement system critically modulates bone regeneration and healing outcome after fracture. This is seen in uneventful fracture healing, but particularly under severe inflammatory conditions induced by an additional traumatic injury. Therefore, complement activation plays an important role in both sterile and non-sterile inflammatory conditions of the bone, which will be addressed here in respect of findings in bone fractures, arthritides, periodontitis and osteomyelitis. Importantly, complement proteins are thought to be critical not simply in the states of an activated immune system, but also for bone growth during physiological development and bone homeostasis, given for example their presence in long-bone growth-plate cartilage. Furthermore, bone cell development from precursor cells and bone-cell metabolism and communication, for example, between bone-forming osteoblasts and bone-resorbing osteoclasts, are dependent on or even critically influenced by the presence of complement proteins and complement-mediated signalling. The present review summarises the current view on the role of the complement cascade on bone, both under homeostatic physiological conditions and under inflammatory and infectious conditions, which strongly affect the bone and skeletal health. Furthermore, this review addresses the potential and the feasibility of therapeutic interventions involving the complement cascade, derived from experimental and clinical data. Modulating the complement system could help in the future to reduce bone infections, ensure a balanced bone turnover and to generally improve skeletal health. PMID- 29395682 TI - Response by Sarfo and Ovbiagele to letter regarding "Post-stroke depression: Risk assessment". PMID- 29395683 TI - Three synchronous malignancies in a patient with DICER1 syndrome. PMID- 29395685 TI - When and how to use carboplatin in metastatic castration-resistant prostate cancer? PMID- 29395686 TI - Comparison of 3 anesthetic protocols for the elective cesarean-section in the dog: Effects on the bitch and the newborn puppies. AB - This study assessed the influence of 3 different anesthetic protocols based on the quality of anesthesia induction and maintenance in four dog breeds (French Bulldog, n = 13; Yorkshire terrier, n = 12; Chihuahua, n = 10; Bull Terrier, n = 10) subjected to cesarean section. Neonatal mortality, birth defects and newborn viability were assessed. All females were pre-medicated with morphine (IM), and then were assigned to three different anesthetic protocols: group P (n = 17), anesthesia was induced with propofol (IV) and then also maintained with propofol until the complete delivery of puppies and then anesthesia was maintained afterwards with sevoflurane; group PS (n = 14), anesthesia was induced with IV propofol, and maintenance of the anesthesic plan was performed with sevoflurane; group PES (n = 14) the females were induced by propofol and an epidural anesthesia was then performed, anesthesia was then maintained with propofol until the complete extraction of all puppies and then anesthesia was maintained afterwards with sevoflurane. Throughout the surgery, group PES required a lower concentration of sevoflurane (p < 0.05), and extra doses of propofol or fentanyl during inhalatory anesthesia were not required. Mean values of heart rate (p < 0.01) were higher in females from groups P and PS. Mean values of blood pressure values were lower (p < 0.01) in group PES as compared with the other two groups. Birth defects were detected in 3.1% (5/162) of the neonates, with a significantly higher incidence (p < 0.05) in French bulldog puppies. Neonatal viability was assessed using a modified Apgar score model; Apgar score was defined immediately after delivery (Apgar0) and a second score was assessed 60 min after delivery (Apgar60). Apgar0 scores were significantly different between the groups, showing neonates of group PES the highest values (p < 0.05). In Apgar60, more than 94% of puppies were already classified as normal viability neonates (7-10 score) and no differences were observed between groups. This study confirmed that females of group PES showed a higher quality of anesthesia during surgery and a vitality of puppies immediately after delivery. Regardless of the anesthetic protocol used, French bulldog females and puppies required more clinical care than other breeds. PMID- 29395684 TI - Trends in incidence of thick, thin and in situ melanoma in Europe. AB - BACKGROUND: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness. MATERIAL AND METHODS: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. RESULTS: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. DISCUSSION: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia. PMID- 29395687 TI - Changes in external osmolality and ionic composition affect Megaleporinus obtusidens sperm motility. AB - Understanding the effects of environmental factors on sperm motility characteristics can increase artificial reproduction efficiency in species that do not spawn naturally in captivity, such as Megaleporinus obtusidens. This study evaluated the effects of the osmolality (25, 85, 145, 205, 265, and 325 mOsm kg 1) and composition of activating solutions (NaCl, KCl, or fructose) on the percentage of motile sperm, and the swimming velocity and path straightness of M. obtusidens spermatozoa. The concentrations of major ions in the seminal fluid were also assessed and Na+ (74.46 mmol L-1), K+ (37.24 mmol L-1), and Cl- (114.29 mmol L-1) were the most abundant. When the activating solution was hypertonic (325 mOsm kg-1) compared to the seminal fluid (293 mOsm kg-1), sperm motility was completely inhibited. A wide range of osmolalities that initiated sperm motility were identified for all three solutions. Both, the percentage of motile sperm and the motility duration were reduced (P < .05) at extreme osmolalities. At 145 mOsm kg-1, the percentage of motile sperm remained high (>50%) up to 40 s after activation and the motile phase lasted for >50 s, regardless of the activating solution composition. Over the postactivation time, the curvilinear velocity and straightness were similar (P > .05) for fructose and NaCl solutions, whereas KCl solutions induced a higher (P < .05) curvilinear velocity, lower (P < .05) straight-line velocity, and a circular swimming motion in spermatozoa. Our results suggest that a reduction in osmolality, using both non-electrolyte and electrolyte solutions, is the main trigger for the onset of spermatic movement in M. obtusidens sperm. PMID- 29395688 TI - Culture of somatic cells isolated from frozen-thawed equine semen using fluorescence-assisted cell sorting. AB - Nuclear transfer using somatic cells from frozen semen (FzSC) would allow cloning of animals for which no other genetic material is available. Horses are one of the few species for which cloning is commercially feasible; despite this, there is no information available on the culture of equine FzSC. After preliminary trials on equine FzSC, recovered by density-gradient centrifugation, resulted in no growth, we hypothesized that sperm in the culture system negatively affected cell proliferation. Therefore, we evaluated culture of FzSC isolated using fluorescence-assisted cell sorting. In Exp. 1, sperm were labeled using antibodies to a sperm-specific antigen, SP17, and unlabeled cells were collected. This resulted in high sperm contamination. In Exp. 2, FzSC were labeled using an anti-MHC class I antibody. This resulted in an essentially pure population of FzSC, 13-25% of which were nucleated. Culture yielded no proliferation in any of nine replicates. In Exp. 3, 5 * 103 viable fresh, cultured horse fibroblasts were added to the frozen-thawed, washed semen, then this suspension was labeled and sorted as for Exp. 2. The enriched population had a mean of five sperm per recovered somatic cell; culture yielded formation of monolayers. In conclusion, an essentially pure population of equine FzSC could be obtained using sorting for presence of MHC class I antigens. No equine FzSC grew in culture; however, the proliferation of fibroblasts subjected to the same processing demonstrated that the labeling and sorting methods, and the presence of few sperm in culture, were compatible with cell viability. PMID- 29395689 TI - Effect of GnRH analogue administration on Day 7 after natural mating on formation accessory corpus luteum, progesterone concentration and conception rate in llamas (Lama glama). AB - The objectives of the present study were to determine the effects of exogenous GnRH administered 7 days after breeding on the formation of an accessory corpus luteum (ACL), plasma progesterone (P4) concentrations and pregnancy rates. Adult females (n = 71) having a follicle >= 7 mm in diameter in the ovary were naturally mated (Day 0). On Day 7, ultrasonic examination was performed to confirm the occurrence of ovulation as evidenced by presence of an induced corpus luteum (ICL). Females with an ICL plus a dominant follicle >= 7 mm (n = 56) were treated with saline solution (SS, n = 29) or GnRH analogue (n = 27). On Day 14, the formation of an ACL was observed by ultrasonography. Blood samples were collected on Days 7 and 14 to quantify plasma P4 concentrations. On Day 14, 21 of 27 (77.8%) females in the GnRH group developed an ACL, whereas females in the SS group did not. Progesterone concentrations on Day 7 and 14 in those llamas diagnosed as pregnant on Day 30 were not different (P > 0.05) between groups. In addition, P4 concentration was similar for GnRH-treated females having two CL to those with a single CL. Pregnancy rates were similar (P > 0.05) between SS and GnRH groups (55.2% compared with 74.1% respectively) and the pregnancy rate for the GnRH group was not affected (P > 0.05) by the number of CL observed at Day 14 (66.6% and 75.6% for females with one and two CL respectively). In conclusion, GnRH administration on Day 7 after breeding leads to ACL formation; however, neither the plasma P4 concentration nor pregnancy rate was affected by having an ACL. PMID- 29395690 TI - Benign Headache Management in the Emergency Department. AB - BACKGROUND: Headache is a common complaint managed in the emergency department (ED), with emergency physicians focusing on evaluation for life-threatening conditions while treating pain and nausea. OBJECTIVE: This review evaluates the treatment of benign, primary headaches in the ED, with recommendations provided based on the literature. DISCUSSION: Headaches are a major cause of disability in the United States and a common condition managed in the ED. The primary objectives of emergency evaluation of these patients include evaluation for a life-threatening, secondary cause of headache, with treatment of primary headaches. Close evaluation for a secondary cause of headache include consideration of red flags and focused neurologic examination. The diagnosis of primary headaches is clinical. Literature has evaluated medication efficacy in headache treatment, with antidopaminergic medications demonstrating high rates of efficacy when used in combination with nonsteroidal inflammatory drugs or acetaminophen. Dexamethasone can be used for the reduction of headache recurrence. If dehydration is present, intravenous fluids should be provided. Diphenhydramine is not recommended for analgesia but may reduce akathisia associated with prochlorperazine. Ketamine, propofol, and nerve blocks demonstrate promise. Triptan agents are also efficacious, provided absence of contraindications. Most patients are appropriate for discharge with pain improvement. CONCLUSIONS: A variety of medications is available for the treatment of primary headaches in the ED. Antidopaminergic agents demonstrate the highest efficacy and should be provided with acetaminophen and nonsteroidal inflammatory drugs. Dexamethasone may reduce headache recurrence. Other treatments include ketamine, propofol, and nerve blocks. PMID- 29395691 TI - Pott's Disease in a Patient with Subtle Red Flags. AB - BACKGROUND: Tuberculosis (TB) is now rare in developed countries; however, it is an important diagnosis for the Emergency Physician to be able to make. Classically thought of as a respiratory disease, TB can present in other ways, making it more challenging to recognize. CASE REPORT: We report the case of a 41 year-old woman who presented to the Emergency Department with a 4-week history of back pain. A diagnosis of T12 osteomyelitis and right psoas muscle abscess was made after magnetic resonance imaging. The concurrent finding raised concern for TB as psoas muscle abscess is usually found along with spinal TB. A computed tomography-guided fine-needle aspiration confirmed the diagnosis. This patient's social history was negative for many of the classic predisposing factors associated with TB: immunosuppression, personal travel, crowded living conditions. Repeated investigation into the patient's history revealed a visit several months prior from a family member from Vietnam who had been treated for TB. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important for Emergency Physicians to be aware of the relatively high incidence of TB as a cause for concurrent psoas abscess and vertebral osteomyelitis. PMID- 29395692 TI - Approach to the Agitated Emergency Department Patient. AB - BACKGROUND: Acute agitation is a common occurrence in the emergency department (ED) that requires rapid assessment and management. OBJECTIVE: This review provides an evidence-based summary of the current ED evaluation and management of acute agitation. DISCUSSION: Acute agitation is an increasingly common presentation to the ED and has a broad differential diagnosis including metabolic, neurologic, infectious, toxicologic, and psychiatric etiologies. Missed diagnosis of a dangerous etiology of the patient's agitation may result in severe morbidity and mortality. Assessment and management of the agitated patient should occur concurrently. Focused history and physical examination are recommended, though control of the patient's agitation may be required. All patients should receive a point-of-care glucose test, with additional testing depending upon the specific patient presentation. Initial management should involve verbal de-escalation techniques, followed by pharmacologic interventions, with physical restraints reserved as a last resort. Pharmacologic options include first-generation antipsychotics, second-generation antipsychotics, benzodiazepines, and ketamine. Finally, the management of pediatric, pregnant, and elderly patients warrants special consideration. CONCLUSION: Acute agitation is an important presentation that requires prompt recognition and treatment. A focused and thorough examination coupled with appropriate management strategies can assist emergency clinicians to safely and effectively manage these patients. PMID- 29395693 TI - Disaster Training in 24 Hours: Evaluation of a Novel Medical Student Curriculum in Disaster Medicine. AB - BACKGROUND: Over a decade ago, the Association of American Medical Colleges called for incorporation of disaster medicine training into the education of medical students in the United States. Despite this recommendation, similar suggestions by other professional organizations, and significant interest from medical students and educators, few medical schools explicitly include robust disaster training in their curricula. OBJECTIVES: This study describes the results of the implementation of a novel medical student curriculum in disaster response at an allopathic U.S. medical school. Specifically, this study evaluates the effectiveness of a voluntary training program in increasing the knowledge of medical students to respond to disasters. METHODS: Over 2 years, 24 hours of training consisting of didactics and hands-on exercises was delivered to medical students by volunteers from the Department of Emergency Medicine. Student knowledge was tested prior to and after each training session through a multiple choice questionnaire and evaluated using a paired t-test. RESULTS: Consistent with previous studies, this voluntary disaster curriculum improved students' knowledge of emergency preparedness. The mean test score for all students participating in the training increased from 5.30 +/- 1.05 (with a maximum score of 10), to 7.98+/-0.96 post course. CONCLUSION: This intervention represents a low-cost, high-impact mechanism for improving the capacity of an underutilized segment of the health care team to respond to public health emergencies. PMID- 29395694 TI - A Rare Airway Obstruction Caused by Dissection of a Reinforced Endotracheal Tube. AB - BACKGROUND: Endotracheal tube (ETT) obstruction or narrowing in patients undergoing general anesthesia due to dissection of reinforced ETT is unusual. CASE REPORT: A 26-year-old woman was transferred to the emergency department due to drowsy mental status after surgery. She was intubated by reinforced ETT with grossly normal external appearance, but the inner layer of ETT was dissected, the inner diameter was narrowed, and the extent of protrusion of inner layer of ETT was more severe at the distal end. Therefore, the patient had to breathe through a very small diameter ETT, and hypercapnia and CO2 narcosis developed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although rare, obstruction by dissection of ETT can be life-threatening if diagnosis is delayed. Therefore, emergency physicians should keep in mind the possibility of ETT dissection when peak airway pressures or EtCO2 values are elevated in intubated patients. PMID- 29395696 TI - Client experiences with perinatal healthcare for high-risk and low-risk women. AB - PROBLEM: It is unknown if client experiences with perinatal healthcare differ between low-risk and high-risk women. BACKGROUND: In the Netherlands, risk selection divides pregnant women into low- and high-risk groups. Receiving news that a pregnancy or childbirth has an increased likelihood of complications can cause elevated levels of emotional distress. AIM: The purpose of this study is to describe client experiences with perinatal healthcare and to determine which, if any, background characteristics, pregnancy circumstances, childbirth or follow-up care characteristics are explaining variables of differences in client experiences between high-risk and low-risk women. METHODS: Client experiences were measured with a validated questionnaire completed by 1388 women within 12 weeks after childbirth. FINDINGS: Women rated their experiences with perinatal healthcare with a mean score of 3.78 on a scale of 1-4; 5.5% of the women rated their experiences as "notably bad". Client experiences with perinatal healthcare show small variations, with a lower mean score for women who were at high risk (3.75) compared to low-risk women (3.84). This difference is partially due to more unplanned medical interventions and pain relief during childbirth in the high-risk group. Also, single mothers and non-Dutch women were more susceptible to less positive experiences. CONCLUSION: Given the potential negative impact of adverse client experiences, this study highlights the need for healthcare professionals to be aware of what women are susceptible for having had negative experiences. It is advised that healthcare provision be altered to tailor to the needs of these women. PMID- 29395697 TI - Sexual dysfunction predicts depressive symptoms during the first 2 years postpartum. AB - BACKGROUND: The association between sexual function and depression has yet to be examined in a prospective cohort study with prolonged postpartum follow-up. AIM: We investigated whether sexual dysfunction predicted depressive symptoms during the 24-month postpartum period and examined the influence of obstetric factors. METHODS: This prospective 2-year cohort study with repeated measures included 196 participants who were recruited in a medical center in Taipei, Taiwan (2010 2011). Data on participants' personal characteristics, sexual function, and depression symptoms at 4-6 weeks and at 3, 6, 12, and 24 months postpartum were collected and then assessed using the Female Sexual Function Index and the Center for Epidemiologic Studies Depression Scale. RESULTS: After adjusting for time and covariates, women with sexual dysfunction had a 1.62-fold (95% confidence interval [CI]: 1.05-2.50-fold) higher estimated odds ratio (OR) for depressive symptoms during the entire 24 months after childbirth than did women without sexual dysfunction. Risk factors for depressive symptoms were a higher pain score (OR: 1.33, 95% CI: 1.13-1.57), a medical condition (OR: 1.65, 95% CI: 1.00-2.73), and severe perineal laceration (OR: 4.67, 95% CI: 1.37-15.92). Sexual satisfaction during the entire 24 months after childbirth (OR: 0.81, 95% CI: 0.70 0.95) and the highest personal income level (OR: 0.33, 95% CI: 0.11-0.99) were factors protecting against higher-scoring depressive symptoms. CONCLUSIONS: Our study provides robust evidence that sexual dysfunction and poor satisfaction, together with severe perineal laceration, greater pain, and a medical condition, predict depressive symptoms during the 24-month postpartum period. PMID- 29395695 TI - A New Diagnostic Approach to the Adult Patient with Acute Dizziness. AB - BACKGROUND: Dizziness, a common chief complaint, has an extensive differential diagnosis that includes both benign and serious conditions. Emergency physicians must distinguish the majority of patients with self-limiting conditions from those with serious illnesses that require acute treatment. OBJECTIVE OF THE REVIEW: This article presents a new approach to diagnosis of the acutely dizzy patient that emphasizes different aspects of the history to guide a focused physical examination with the goal of differentiating benign peripheral vestibular conditions from dangerous posterior circulation strokes in the emergency department. DISCUSSION: Currently, misdiagnoses are frequent and diagnostic testing costs are high. This relates in part to use of an outdated, prevalent, diagnostic paradigm. The traditional approach, which relies on dizziness symptom quality or type (i.e., vertigo, presyncope, or disequilibrium) to guide inquiry, does not distinguish benign from dangerous causes, and is inconsistent with current best evidence. A new approach divides patients into three key categories using timing and triggers, guiding a differential diagnosis and targeted bedside examination protocol: 1) acute vestibular syndrome, where bedside physical examination differentiates vestibular neuritis from stroke; 2) spontaneous episodic vestibular syndrome, where associated symptoms help differentiate vestibular migraine from transient ischemic attack; and 3) triggered episodic vestibular syndrome, where the Dix-Hallpike and supine roll test help differentiate benign paroxysmal positional vertigo from posterior fossa structural lesions. CONCLUSIONS: The timing and triggers diagnostic approach for the acutely dizzy patient derives from current best evidence and offers the potential to reduce misdiagnosis while simultaneously decreases diagnostic test overuse, unnecessary hospitalization, and incorrect treatments. PMID- 29395698 TI - Response to the Hammoud et al paper on 'the new MTV generation'. PMID- 29395699 TI - Problematising LGBTIQ drug use, governing sexuality and gender: A critical analysis of LGBTIQ health policy in Australia. AB - It is well-established that a high prevalence of substance use is found in lesbian, gay, bisexual, transgender, intersex and queer (LGBTIQ) populations; a finding that researchers attribute to the stigmatised status of non-normative sexual and gender expression, and the role of illicit drug use in the collective production of socio-sexual pleasures, expressivity and disclosure in LGBTIQ communities. Despite the connections between sexual experimentation and substance use, LGBTIQ consumption practices have rarely received the attention they deserve within the alcohol and other drug (AOD) field. In this paper, we draw on concepts from post-structuralist policy analysis to analyse how AOD consumption among sexual and gender minorities is constituted in the policies of three Australian LGBTIQ health organisations. Following Carol Bacchi's (2009, p. xi) observation that we are "governed through problematisations rather than policies", we consider how substance use in LGBTIQ populations has been formulated as a policy problem requiring intervention. Doing so allows us to identify the normative assumptions about minority sexual and gender identities that underpin dominant problematisations of LGBTIQ substance use. These include: a) high rates of AOD use in LGBTIQ populations constitute problems in and of themselves, regardless of individual patterns of use; b) LGBTIQ people are a vulnerable population with specialised needs; and c) sexualised drug use is associated with "disinhibition" and a range of risks (including HIV transmission, drug dependence and mental health issues). Addressing the implications of these assumptions for how LGBTIQ communities are governed, we suggest that problematisation is an embodied, situated process, and that there is much to be gained by reframing dominant problematisations of AOD consumption so that this process is better informed by the inventive practices of LGBTIQ consumers themselves. PMID- 29395700 TI - Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis in Women: Clinical Characteristics and Outcomes. AB - Aortic stenosis (AS), 1 of the most common valve diseases in developed countries, carries a poor prognosis if left untreated. Transcatheter aortic valve replacement (TAVR) has become the standard of care for high-risk and inoperable patients with severe aortic stenosis (AS). Women represent a significant proportion of patients with severe AS and demonstrate specific clinical, anatomic, and pathophysiological features that are evident both before and after valve replacement. In this review, we discuss these features as well as the outcomes of women undergoing TAVR for AS. PMID- 29395701 TI - Radiotherapy for Patients with Cardiovascular Implantable Electronic Devices: A Review. AB - Because cardiovascular implantable electronic devices are increasingly indicated in older patients, and the burden of cancer is rising with the growth and aging of the world population, the management of patients with cardiac devices who require radiotherapy for cancer treatment is a timely concern. Device malfunctions might occur in as high as 3% of radiotherapy courses, posing a substantial issue in clinical practice. A nonsystematic comprehensive review was undertaken. We searched PubMed and the MEDLINE database for randomized controlled trials, meta-analyses, systematic reviews, observational studies, in vitro/in vivo studies, and case reports. Articles were selected by 2 independent reviewers, and emphasis was given to information of interest to a general medical readership. The pathophysiology and predictors of cardiovascular implantable electronic device malfunction due to radiotherapy are reviewed, recommendations for the management of patients with such devices undergoing radiotherapy are summarized, and the clinical significance and future directions of this field are discussed. Radiotherapy-induced device malfunctions are rare, but because of the potential complications, the development of evidence-based guidelines for the management of patients with cardiovascular implantable electronic devices undergoing radiotherapy is a timely concern. PMID- 29395702 TI - Left Ventricular Strain in Chemotherapy-Naive and Radiotherapy-Naive Patients With Cancer. AB - BACKGROUND: We sought to investigate left ventricular (LV) function and mechanics in patients with cancer before they received chemotherapy or radiotherapy, as well as the relationship between cancer and reduced LV multidirectional strain in the whole study population. METHODS: The retrospective study involved 122 chemotherapy- and radiotherapy-naive patients with cancer and 45 age- and sex matched controls with a cardiovascular risk profile similar to that of the patients with cancer. All the patients underwent echocardiographic examination before introduction of chemotherapy or radiotherapy. RESULTS: LV longitudinal ( 19.1% +/- 2.1% vs -17.8% +/- 3.5%; P = 0.022), circumferential (-22.9% +/- 3.5% vs -20.1% +/- 4.1%; P < 0.001), and radial (40.5% +/- 8.8% vs 35.2% +/- 10.7%; P = 0.004) strain was significantly lower in the patients with cancer than in the control group. Endocardial and midmyocardial longitudinal LV strain was significantly reduced in the patients with cancer compared with the controls, whereas epicardial longitudinal strain was similar between these groups. Endocardial, midmyocardial, and epicardial circumferential strain was significantly lower in the chemotherapy- or radiotherapy-naive patients with cancer than in the controls. Cancer was associated with reduced longitudinal (odds ratio [OR], 9.0; 95% confidence interval [CI], 2.20-23.50; P < 0.001), reduced circumferential (OR, 7.1; 95% CI, 3.80-20.40; P < 0.001), and reduced radial strain (OR, 7.2; 95% CI, 3.41-25.10; P < 0.001) independent of age, sex, body mass index, diabetes, and hypertension. CONCLUSIONS: LV mechanics was impaired in the patients with cancer compared with the controls even before initiation of chemotherapy and radiotherapy. Cancer and hypertension were associated with reduced LV multidirectional strain independent of other clinical parameters. The present results indicate that cancer itself potentially induces cardiac remodelling independent of chemotherapy and radiotherapy. PMID- 29395704 TI - Personalized Anticoagulation: Guided Apixaban Dose Adjustment to Compensate for Pharmacokinetic Abnormalities Related to Short-Bowel Syndrome. AB - A 45-year-old woman who required lifelong anticoagulation for recurrent thrombosis had her therapeutic choices limited by heparin-induced thrombocytopenia and abnormal pharmacokinetics (greatly reduced absorption) resulting from short gut syndrome from extensive gut resection after mesenteric thrombosis. As an alternative to inconvenient and expensive injections of fondaparinux, personalized dosing of a direct oral anticoagulant was sought using clinical pharmacology techniques. Enteral absorption was ascertained with small test doses of apixaban, and the ability of supraconventional doses to deliver effective concentrations was verified. PMID- 29395703 TI - Long-Term Outcomes of Percutaneous Coronary Intervention for Chronic Total Occlusion in Patients Who Have Undergone Coronary Artery Bypass Grafting vs Those Who Have Not. AB - BACKGROUND: We aimed to investigate the procedural and long-term outcomes of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) in patients who had undergone previous coronary artery bypass grafting (CABG) vs those who had not, and to evaluate the role of the Registry of CrossBoss and Hybrid procedures in France, the Netherlands, Belgium, and United Kingdom (RECHARGE) score in predicting acute and long-term outcomes. METHODS: We compiled a multicentre registry of consecutive patients undergoing CTO PCI at 7 centres between January 2009 and April 2017. The primary end point was target-vessel failure (TVF), a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization on follow-up. RESULTS: Overall, 2058 patients were included (patients who underwent CABG, n = 401; CABG-naive patients, n = 1657). Patients who had undergone CABG were older and had a higher prevalence of comorbidities and higher occlusion complexity (RECHARGE score, 3.6 +/- 1.3 vs 1.8 +/- 1.2; P < 0.001). Antegrade dissection/re-entry techniques and the retrograde approach were used more frequently in patients who had undergone CABG. Procedural metrics were worse, and technical (82% vs 88%; P = 0.001) and procedural (81% vs 87%; P = 0.001) success was lower in patients who had undergone CABG. They also experienced a higher rate of major complications (3.7% vs 1.5%; P = 0.004). The RECHARGE score was inversely associated with technical success (P < 0.001). Median follow-up was 377 days (interquartile range, 277-766 days). The 24-month TVF rate was higher in patients who had undergone CABG than in CABG-naive patients (16.1% vs 9.0%; P < 0.001). On multivariable analysis, the RECHARGE score (hazard ratio, 1.61; P < 0.001) remained an independent predictor of TVF, together with longer total stent length and not using a drug-eluting stent. CONCLUSIONS: Compared with CABG-naive patients, CTO PCI in patients who had undergone CABG shows higher procedural complexity, worse success rates, and higher adjusted risk of TVF on follow-up. PMID- 29395705 TI - Assessment and Management of the Left Atrial Appendage Thrombus in Patients With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Intracardiac thrombi arising in the left atrial appendage (LAA) are the principal cause of stroke in nonvalvular atrial fibrillation (AF). Predicting the presence of LAA thrombi is of vital importance in stratifying patients that would need further LAA imaging prior to cardioversion or AF ablation. METHODS: We comprehensively searched PubMed from its inception to November 2017 for randomized controlled trials, cohort and case control studies, as well as for case series on LAA thrombi risk factors, imaging, prevention, and anticoagulation management in atrial fibrillation. RESULTS: A systematic review of the literature identified 106 articles that investigated the presence of LAA thrombi in AF patients. We classified the articles according to topic and reported on: (1) risk factors; (2) diagnostic imaging modalities; (3) prevention strategies before cardioversion; (4) prevention strategies before AF ablation; and (5) management of detected LAA thrombi. CONCLUSIONS: Integration of clinical, biomarker, and imaging risk factors can improve overall prediction for the presence of LAA thrombi, translating into improved patient selection for imaging. The gold standard for the diagnosis of LAA thrombi remains transesophageal echocardiography, although intracardiac ultrasound, cardiac computed tomography, and cardiovascular magnetic imaging are promising alternative modalities. When LAA thrombi are discovered, the treatment regimen remains variable, although direct oral anticoagulants might have efficacy similar to vitamin K antagonists. Future trials will help further elucidate direct oral anticoagulant use for the treatment of LAA thrombi. PMID- 29395706 TI - Epidemiology of Kawasaki Disease in Canada 2004 to 2014: Comparison of Surveillance Using Administrative Data vs Periodic Medical Record Review. AB - BACKGROUND: We have previously documented an increase in the incidence of Kawasaki disease (KD) in Ontario followed by a stabilization from 1995 to 2006. We sought to validate the estimation of incidence of KD using administrative data and to describe the epidemiology of KD across Canada from 2004 to 2014. METHODS: We queried the Canadian Hospital Discharge Database for hospital admissions associated with a discharge diagnosis of KD. The data set was manually curated and estimates of incidence were compared with those obtained from the retrospective triennial surveillances of KD performed in 2007 and 2010. RESULTS: The average number of cases per year identified through administrative data was 245 +/- 45 vs 229 +/- 33 from retrospective surveillance. This overestimation, representing 7 +/- 6%, is similar to the historical percentage of patients originally diagnosed with KD in whom the diagnosis is subsequently excluded. The annual incidence of KD in Canada was 19.6, 6.4, and 1.3 cases per 100,000 children younger than 5 years, 5-9 years, and 10-14 years old, respectively, with important regional and seasonal differences. The incidence remained stable over the study period in the youngest age group but increased in both older age categories. Coronary artery aneurysms affected 3.5% of all patients, and 0.8% experienced associated major cardiac complications. CONCLUSIONS: Reliance on administrative data to determine incidence of KD is feasible and accurate with manual curation of the data. The incidence of KD in Canada seems to have plateaued for younger children. Differences in annual incidence observed between provinces remain to be explained, and might reflect genetic or environmental differences. PMID- 29395707 TI - Optical Coherence Tomography Image of Coronary Spasm in a Bioresorbable Vascular Scaffold. PMID- 29395708 TI - Successful Treatment of Type 1 Cryoglobulinemic Vasculitis With Cardiac Involvement. AB - Cryoglobulinemic vasculitis is a rare and frequently fatal type of myocarditis. Cardiac manifestations in type 1 cryoglobulinemic vasculitis have never been reported to our knowledge. We report a rare case of type 1 cryoglobulinemic vasculitis with cardiac involvement in a patient who experienced progressive heart failure during the diagnosis. The diagnosis was made by the presence of cryoglobulins and endomyocardial biopsy results. After bortezomib-containing treatments, plasma cryoglobulin levels returned to normal, and the patient's clinical condition gradually improved. PMID- 29395709 TI - Aortic Arch Reconstructive Surgery With Conventional Techniques vs Frozen Elephant Trunk: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Frozen elephant trunk (FET) surgery offers a new alternative in the management of complex thoracic aortic aneurysms and dissections. We performed a systematic review and meta-analysis of comparator observational studies evaluating the efficacy of FET compared with conventional aortic arch surgery, primarily focusing on mortality and stroke as well as the secondary outcomes of spinal cord ischemia, major bleeding, and operative time. METHODS: We searched MEDLINE, EMBASE, PubMed, and the Cochrane Library for trials and studies comparing the FET technique with conventional surgery in patients with aortic aneurysms or dissections, or both. The overall quality of evidence was low, as assessed by Grading of Recommendations, Assessment, Development, and Evaluation, based primarily on the risk of bias secondary to study design, plausible confounding, and imprecision. RESULTS: Meta-analysis revealed a significant reduction in mortality (12 studies, 1803 patients: odds ratio [OR], 0.55; 95% CI, 0.39-0.78) and a nonsignificant reduction in stroke (12 studies, 1803 patients: OR, 0.78; 95% CI, 0.52-1.15) favouring FET; however, FET was associated with a significant increase in spinal cord ischemia (9 studies, 1476 patients: OR, 2.20; 95% CI, 1.10-4.37). No significant differences between groups were observed regarding major bleeding, cardiopulmonary bypass time, or cross-clamp time. CONCLUSIONS: Current evidence suggests that FET surgery is associated with lower mortality in patients with thoracic aneurysmal disease and dissections, without a significant increase in stroke, bleeding, or operative times. However, the risk of spinal cord ischemia is increased in patients who undergo FET. A well-powered randomized trial is needed to evaluate this evolving field. PMID- 29395710 TI - An Invasive vs a Conservative Approach in Elderly Patients with Non-ST-Segment Elevation Myocardial Infarction: Systematic Review and Meta-Analysis. AB - BACKGROUND: Elderly (>= 75 years) patients form a large sub-group of non-ST segment elevation myocardial infarction (NSTEMI) population but are vastly under represented in trials. Thus, the benefits of an early angiography in the elderly remain unclear. In this systematic review, we compared outcomes of "invasive" and "conservative" strategies of NSTEMI management in elderly patients. METHODS: A comprehensive search of major databases was performed. We included comparative studies of any design that enrolled patients >= 75 years, and where outcomes of both strategies of NSTEMI management were available. RESULTS: Among the included studies (3 randomized and 6 observational), there were 6340 patients in the "invasive" group and 13,358 patients in the "conservative" group. The 12-month mortality rate (odds ration [OR], 0.45; p < 0.00001), the 30-day mortality (OR, 0.50; p = 0.0009), and events of stroke (OR, 0.42; p < 0.00001) were significantly lower in the invasive group. Major bleeding was higher in the invasive cohort (OR, 1.63; p = 0.03). Analysis of randomised studies showed lower reinfarction with invasive approach at 12 months (p = 0.0001). Significant heterogeneity was noted among studies according to study design. CONCLUSION: The overall benefit with invasive strategy comes from the data of observational studies that are prone to selection bias. We believe that there is a need for a large randomized study in the elderly patients regarding management of NSTEMI. PMID- 29395711 TI - The prevalence of mcr-1 and resistance characteristics of Escherichia coli isolates from diseased and healthy pigs. AB - Colistin has been used as the last-line antibiotic for Escherichia coli infections. Herein, we collected 102 E. coli isolates from diseased pigs and 204 from healthy ones in Henan province of China. Then, we screened antimicrobial resistance and mcr-1 of bacteria. There was 25.5% (78/306) mcr-1-positive porcine E. coli, in which 46 isolates (45.1%, 46/102) were obtained from diseased pigs; the others (15.7%, 32/204) were collected from healthy pigs (45.1% versus 15.7%, P=0.000). Meanwhile, the former presented more serious resistance to colistin, ceftiofur, cefquinome, gentamicin, amikacin, doxycycline, florfenicol, enrofloxacin, and olaquindox than those from healthy pigs, which were similar to the relations between isolates with or without mcr-1, except for amikacin and doxycycline. Also, the resistance profiles of mcr-1-positive E. coli were more extensive than those of mcr-1-negative isolates. PMID- 29395712 TI - Differences in suppression of regrowth and resistance despite similar initial bacterial killing for meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. AB - We described bacterial killing and resistance emergence at various fixed concentrations of meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. Time-kill studies were conducted utilizing nine isolates and a large range of concentrations. Within each strain and antibiotic, initial killing was similar, with concentrations >=2*MIC. At many (strain specific) concentrations causing substantial initial killing, regrowth occurred at 24-48h. For remaining concentrations, growth typically remained suppressed (<5 log10 cfu/mL). The concentrations of meropenem required to suppress regrowth ranged from 2-8*MIC for P. aeruginosa and 2-64*MIC for E. coli. For piperacillin/tazobactam, the equivalent concentrations ranged from 8-16*MIC for P. aeruginosa and 4-16*MIC for E. coli. The number of less-susceptible bacteria increased with rising concentrations before decreasing at even higher concentrations. Suppression of regrowth and resistance was substantially improved with higher concentrations (typically >=8*MIC), suggesting a benefit of higher beta-lactam concentrations beyond those required for maximum initial killing. PMID- 29395713 TI - Antimicrobial activity of ceftobiprole and comparator agents when tested against contemporary Gram-positive and -negative organisms collected from Europe (2015). AB - Susceptibility testing of ceftobiprole and comparators against 12,240 isolates was performed following CLSI/EUCAST guidelines. The percentage of susceptible MRSA isolates was higher for ceftobiprole (96.5% susceptible) than for ceftaroline (86.2% susceptible). Both ceftobiprole (MIC50/90, 0.5/2 mg/L) and ceftaroline (MIC50/90, 0.25/1 mg/L) demonstrated potent activity against coagulase-negative staphylococci. Ceftobiprole demonstrated good potency against Enterococcus faecalis (MIC50/90 values of 0.5/2 mg/L); ceftaroline (MIC50/90, 2/8 mg/L) was 4-fold less active against these strains. Ceftobiprole activity was comparable to that of the other beta-lactam agents tested against S. pneumoniae (MIC90, 0.5 mg/L vs 0.12-2 mg/L [other beta-lactams]), viridans-group streptococci (MIC90,0.25 mg/L vs 0.006-1 mg/L [other beta-lactams]), and beta hemolytic streptococci (MIC90,0.03 mg/L vs 0.015-0.06 mg/L [other beta-lactams]). Overall, 73.8% of Enterobacteriaceae isolates tested were susceptible to ceftobiprole. Ceftobiprole inhibited 70.4% of P. aeruginosa at <=4 mg/L and all isolates of Haemophilus influenzae and Moraxella catarrhalis at <= 0.5 mg/L. Ceftobiprole was active in vitro against a broad range of clinically-relevant contemporary Gram-positive and Gram-negative bacterial isolates. PMID- 29395714 TI - Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae. AB - Breakpoint changes may impact cephalosporin susceptibility rates in uncomplicated urinary tract infections (uUTIs). Applying the <=16-mg/L breakpoint to urine cultures from adult women in an academic health system resulted in cefazolin being the most active uUTI antimicrobial, with 86.9% susceptibility, compared to levofloxacin (80%), nitrofurantoin (76.5%), and sulfamethoxazole-trimethoprim (72.6%). PMID- 29395715 TI - Changes in shape and astigmatism of total, anterior, and posterior cornea after long versus short clear corneal incision cataract surgery. AB - PURPOSE: To compare changes in the shape and astigmatism of the total, anterior, and posterior cornea between eyes with long-length clear corneal incisions (CCIs) and eyes with short-length CCIs in cataract surgery. SETTING: Hayashi Eye Hospital, Fukuoka, Japan. DESIGN: Prospective case series. METHODS: Both eyes of patients having phacoemulsification with temporal CCIs were randomized to have a long-length (>=1.75 mm) or short-length (<1.75 mm) CCI. Corneal astigmatic changes were decomposed to vertical/horizontal (Jackson cross-cylinder, axes at 180 degrees and 90 degrees [J0]) and oblique changes (Jackson cross-cylinder, axes at 45 degrees and 135 degrees [J45]) using power vector analysis. Corneal shape changes were assessed using the average of the difference map on videokeratography 2 days and 2, 4, and 8 weeks postoperatively. RESULTS: The mean J0 and J45 values of the total cornea in the 120 eyes evaluated were significantly greater in the long CCI group than in the short CCI group at all follow-ups (P <= .0290). The videokeratography showed a wedge-shaped flattening in the total and anterior cornea and a steepening in the posterior cornea around the CCI 2 days postoperatively in both groups. This wound-related flattening of the total and anterior cornea rapidly reduced but persisted until 8 weeks, whereas the steepening of the posterior cornea disappeared within 4 weeks. These changes extended closer to the central cornea in the long CCI group than in the short CCI group. CONCLUSIONS: Corneal astigmatic changes were significantly greater after long CCI than after short CCI. The wound-related shape changes occurred immediately postoperatively but rapidly diminished. PMID- 29395716 TI - Autophagy in Neurodegeneration: Can't Digest It, Spit It Out! AB - The autophagy-lysosome pathway maintains cellular homeostasis and protects against neurodegenerative disorders. Recent findings show that autophagy can be impaired in these diseases, and that the cell activates an alternative Golgi mediated degradation pathway, leading to expulsion of toxic protein aggregates. Ultimately this process leads to nuclear breakdown and neuronal cell death. PMID- 29395717 TI - Novel Insights into NDP52 Autophagy Receptor Functioning. AB - NDP52/CALCOCO2 makes multiple contributions to selective autophagy. By interacting with cargos and LC3, NDP52 directs autophagy targets to autophagosomes. In addition, NDP52 promotes autophagosomes fusion with endolysosomes by connecting autophagosomes to MYOSIN VI. Recent studies reveal that Rab35 GTPase controls NDP52 recruitment to its targets and that NDP52 triggers MYOSIN VI (MYO6) motility. PMID- 29395718 TI - Risk Factors for Early Dislocation Following Primary Elective Total Hip Arthroplasty. AB - BACKGROUND: Dislocation following total hip arthroplasty (THA) continues to be one of the most common reasons for revision THA. The purpose of this study is to measure the current rate of dislocation following THA in the United States. A secondary goal is to identify patients at highest risk of instability after THA. METHODS: The Nationwide Readmissions Database was used to identify cases of elective primary THA between 2012 and 2014. All readmissions associated with dislocations were identified. Kaplan-Meier curves were used to assess the time to dislocation in the study population. A multivariate logistic regression was modeled to assess risk factors associated with readmission for dislocation. RESULTS: A total of 207,285 THAs were identified between 2012 and 2014. Of the total, 2842 dislocation-associated readmissions (1.4%) were identified, at a median of 40 days post-THA. A history of spinal fusion was the strongest independent predictor of dislocation (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.97-3.04; P < .0001). Parkinson's disease was also significantly associated with dislocation (OR, 1.63; 95% CI, 1.05-2.51; P = .03), as well as dementia (OR, 1.96; 95% CI, 1.13-3.39; P = .02), depression (OR, 1.28; 95% CI, 1.13-1.43; P < .0001), and chronic lung disease (OR, 1.2; 95% CI, 1.07-1.33; P = .001). Inflammatory arthritis and avascular necrosis were independent risk factors for dislocation (OR, 1.56; 95% CI, 1.25-1.97; P < .0001; OR, 1.67; 95% CI, 1.45-1.93; P < .0001). CONCLUSION: THA is a highly effective procedure with a low overall rate of instability. A history of spinal fusion was the most significant independent risk factor for dislocation within the first 6 months following THA. PMID- 29395719 TI - Utility of Serological Markers for Detecting Persistent Infection in Two-Stage Revision Arthroplasty in Patients With Inflammatory Arthritis. AB - BACKGROUND: Serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly used for the diagnosis of persistence of infection after the first stage of 2-stage revision arthroplasty for periprosthetic joint infection (PJI). As both ESR and CRP are markers of systemic inflammation, the utility of these tests to monitor infection clearance in patients with inflammatory arthritis is unclear. METHODS: From 2001 to 2016, 44 two-stage revision total hip or knee arthroplasties in patients with an inflammatory arthritis diagnosed by a rheumatologist were identified. Persistence of infection at the time of planned second stage was defined as satisfying the Musculoskeletal Infection Society criteria for PJI (14 infected, 30 noninfected). ESR and CRP values were compared between the stages using nonparametric tests. Receiver operating characteristic analysis was performed to obtain the diagnostic parameters. RESULTS: ESR and CRP decreased between the stages in the noninfected group (ESR: mean decrease = 31.6 mm/h [19.2-44.0], P < .001; CRP: mean decrease = 5.2 mg/dL [2.1-8.2], P < .001), but remained elevated in the infected group (ESR: mean decrease = 7.7 [-23.1 to 36.6], P = .572; CRP: mean decrease = 1.5 [-2.2 to 5.1], P = .258). Optimal thresholds for persistent infection were 29.5 mm/h and 2.8 mg/dL, respectively, for ESR and CRP. The sensitivity and specificity at the optimal thresholds were 64% and 77% for ESR, and 64% and 90% for CRP. CONCLUSION: ESR and CRP responded to the treatment of PJI in patients with inflammatory arthritis and had reasonably high specificities with moderate sensitivities. ESR and CRP appear to be useful tools in diagnosing persistent infection even in patients with inflammatory arthritis. PMID- 29395720 TI - Distal Femoral Rotation Correlates With Proximal Tibial Joint Line Obliquity: A Consideration for Kinematic Total Knee Arthroplasty. AB - BACKGROUND: We hypothesized that there is a correlation between the distal femoral rotation and proximal tibial joint line obliquity in nonarthritic knees. This has significance for kinematic knee arthroplasty, in which the target knee alignment desired approximates the knee before disease. METHODS: Fifty computed tomography scans of nonarthritic knees were evaluated using three-dimensional image processing software. Four distal femoral rotational axes were determined in the axial plane: the transepicondylar axis (TEA), transcondylar axis (TCA), posterior condylar axis (PCA), and a line perpendicular to Whiteside's anterior posterior axis. Then, angles were measured relative to the TEA. Tibial joint line obliquity was measured as the angle between the proximal tibial plane and a line perpendicular to the axis of the tibia. RESULTS: There was a strong positive correlation between PCA-TEA and tibial joint line obliquity (r = 0.68, P < .001) as well as TCA-TEA and tibial joint line obliquity (r = 0.69, P < .001). In addition, the tibial joint line obliquity and TCA-TEA angles were similar, 3.7 degrees +/- 2.2 degrees (mean +/- standard deviation) and 3.5 degrees +/- 1.7 degrees , respectively (mean difference, 0.2 degrees +/- 0.2 degrees ; P = .369). CONCLUSION: Both PCA-TEA and TCA-TEA strongly correlated with proximal tibial joint line obliquity indicating a relationship between distal femoral rotational geometry and proximal tibial inclination. These findings could imply that the native knee in flexion attempts to balance the collateral ligaments toward a rectangular flexion space. A higher tibial varus inclination is matched with a more internally rotated distal femur relative to the TEA. PMID- 29395721 TI - Can Total Knee Arthroplasty Be Performed Safely as an Outpatient in the Medicare Population? AB - BACKGROUND: The Centers for Medicare and Medicaid Services has solicited public comments for the 2017 Proposed Rule to consider removing total knee arthroplasty (TKA) from the Inpatient Only List. The purpose of this study is to compare the complication rates between outpatient (same-day discharge), short-stay (discharge within 1 day), and inpatient TKA and to identify the ideal candidates for a short stay or outpatient procedure. METHODS: We queried the American College of Surgeons-National Surgical Quality Improvement Program database for patients over age 65 years who underwent TKA from 2014 to 2015. Demographics, comorbidities, 30 day complications, and readmission rates were compared between patients after outpatient, short-stay, and inpatient procedures. A multivariate regression analysis was then performed to identify at-risk patients who should not be candidates for outpatient or short-stay TKA. RESULTS: Of the 49,136 Medicare-aged TKA patients, 365 (0.7%) were outpatient, 3033 (6%) were short-stay and 45,738 (93%) were inpatient. Short-stay patients had a lower complication rate than both the outpatient and inpatient groups (2% vs. 8% vs. 8%, P < .001). Independent risk factors (all P < .05) for experiencing a complication or requiring an inpatient stay include female gender (odds ratio [OR] 1.655), general anesthesia (OR 1.282), diabetes mellitus (OR 1.171), chronic obstructive pulmonary disease (OR 1.579, P < .001), hypertension (OR 1.144), kidney disease (OR 1.425), American Society of Anesthesiologists Score 4 (OR 1.748), body mass index >35 kg/m2 (OR 1.265), and age >75 years (OR 1.429). CONCLUSION: TKA can be performed safely as an outpatient in a subset of healthy Medicare patients with a complication rate similar to an inpatient stay. A 23-hour stay, however, may be the "sweet spot" that minimizes complications in this population. PMID- 29395722 TI - Satisfaction Rates and Quality of Life Changes Following Total Knee Arthroplasty in Age-Differentiated Cohorts. AB - BACKGROUND: Comparisons of satisfaction rates following total knee arthroplasty (TKA) among large, age-differentiated, rigorously matched cohorts are lacking. Therefore, we compared satisfaction rates following TKA in large, age differentiated, propensity score-matched cohorts. METHODS: We identified primary TKAs performed for non-inflammatory arthritis in patients of ages 18-55 or 65-75, yielding 529 younger and 2001 older patients. Patient-reported outcomes were recorded pre-operatively and 2 years post-operatively. 1:1 propensity score matching between groups yielded 529 patient pairs. Matching was based on gender, body mass index, American Society of Anesthesiologists grade, Charlson Comorbidity Index, and Short Form 12 Mental Health Component score. Outcomes were compared between matched groups using t-test and Wilcoxon rank-sum test. RESULTS: Satisfaction with knee surgery was 86% among younger patients and 91% among older patients. Distribution of satisfaction responses was shifted toward greater satisfaction in older patients (P < .001). Overall quality of life (QOL) improvement was 91% among younger patients and 96% among older patients. Pre operative and post-operative knee-related QOL was better among older patients (P < .0001). Post-operative global health-related QOL was equivalent between groups based on Short Form 12 Physical Component Score and Mental Health Component score (P = .6646 and P = .5705, respectively) and QOL improvement questionnaires (P = .181). Younger patients reported greater knee-related dysfunction and higher activity levels pre-operatively and post-operatively (P <= .0002). CONCLUSION: Satisfaction with knee surgery was over 85% regardless of age. Younger patients perceived more knee-related dysfunction and dissatisfaction after surgery despite higher levels of self-reported activity pre-operatively and post-operatively. PMID- 29395723 TI - Short Stems Versus Conventional Stems in Cementless Total Hip Arthroplasty: A Long-Term Registry Study. AB - BACKGROUND: Short stems in total hip arthroplasty (THA) have recently gained increasing popularity, allowing mini-invasive exposures and bone-sparing approaches. However, long-term studies and recommendations for the routine use are not available. The aim of this report was to compare the survival rates and the reasons for revision of short stems versus conventional stems in cementless THAs, in a registry-based population. METHODS: The Registry of Prosthetic Orthopedic Implants (RIPO) was inquired about cementless THAs performed since 2000 to 2016. The stems were divided into short (<12 cm) and conventional ones, and then, classified according to the classification by Feyen and Shimmin: short stems with neck-retaining osteotomy (group A: 1684 hips), short stems with standard osteotomy (group B: 2727 THAs), and conventional stems (group C: 57,359 cases). Demographics, survivorships, and reasons for revision were investigated and compared. RESULTS: Short stems were preferentially implanted in younger patients and normal morphologies. Short and conventional stems showed comparable survival rates at long-term follow-up (>90% at 15 years). The rates of stem aseptic loosening, intraoperative fractures, and periprosthetic fractures were similar in the 3 groups. Group B had higher rates of revisions due to primary instability (early dislocations and impingement-related events; P < .05). Revisions due to pain were nonsignificantly higher in group B. CONCLUSION: Short stems are reliable implants at long-term follow-up. The comparison with conventional stems showed no additional risk of premature aseptic loosening and intraoperative and periprosthetic fractures. However, the high rate of revisions due to pain and, mostly, primary instability should be investigated in clinical trials. PMID- 29395724 TI - Risk Factors for Staphylococcus aureus Nasal Colonization in Joint Arthroplasty Patients. AB - BACKGROUND: Several studies have shown that Staphylococcus aureus (S aureus) nasal colonization is associated with surgical site infection and that preoperative decolonization can reduce infection rates. Up to 30% of joint arthroplasty patients have positive S aureus nasal swabs. Patient risk factors for colonization remain largely unknown. The aim of this study was to determine whether there is a specific patient population at increased risk of S aureus nasal colonization. METHODS: This study is a retrospective review of 716 patients undergoing hip or knee arthroplasty beginning in 2011. All patients were screened preoperatively for nasal colonization. Univariate and multivariate analyses were used to assess risk factors for nasal colonization. RESULTS: A total of 716 patients undergoing joint arthroplasty had preoperative nasal screening. One hundred twenty-five (17.50%) nasal swabs were positive for methicillin susceptible S aureus (MSSA), 13 (1.80%) were positive for methicillin-resistant S aureus (MRSA), and 84 (11.70%) were positive for other organisms. In bivariate analysis, diabetes (P = .04), renal insufficiency (P = .03), and immunosuppression (P = .02) were predictors of nasal colonization with MSSA/MRSA. In multivariate analysis, immunosuppression (P = .04; odds ratio, 2.0; 95% confidence interval, 1.03-3.71) and renal insufficiency (P = .04; odds ratio, 2.5; 95% confidence interval, 1.01-6.18) were independent predictors of nasal colonization with MSSA/MRSA. CONCLUSION: Overall, 17.5% of patients undergoing primary hip or knee arthroplasty screened positive for S aureus. Diabetes, renal insufficiency, and immunosuppression are risk factors for such colonization. Given that these comorbidities are already known independent risk factors for periprosthetic joint infection, these patients should be particularly screened and when necessary, decolonized. PMID- 29395725 TI - Recurrent Focal Seizures and Transient Hemiparesis: Think About Alternating Hemiplegia of Childhood. PMID- 29395726 TI - Renal scintigraphy for post-transplant monitoring after kidney transplantation. AB - BACKGROUND: Clinicians use several diagnostic modalities to recognize post transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities. METHODS: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391. RESULTS: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes. CONCLUSIONS: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results. PMID- 29395727 TI - Foal Diarrhea: Established and Postulated Causes, Prevention, Diagnostics, and Treatments. AB - Diarrhea is one of the most important diseases in young foals and may occur in more than half of foals until weaning age. Several infectious and noninfectious underlying causes have been implicated but scientific evidence of pathogenesis is evolving. It is important to investigate all known potential causes and identify infectious agents to avoid outbreaks, evaluate the level of systemic compromise, and establish adequate therapy. It is crucial to differentiate foals that can be managed in field conditions from those that should be sent to a referral center. This article reviews these aspects and recent developments in the diagnostic and therapeutic approaches. PMID- 29395728 TI - Rise of a Cereal Killer: The Biology of Magnaporthe oryzae Biotrophic Growth. AB - The rice blast fungus, Magnaporthe oryzae, causes one of the most destructive diseases of cultivated rice in the world. Infections caused by this recalcitrant pathogen lead to the annual destruction of approximately 10-30% of the rice harvested globally. The fungus undergoes extensive developmental changes to be able to break into plant cells, build elaborate infection structures, and proliferate inside host cells without causing visible disease symptoms. From a molecular standpoint, we are still in the infancy of understanding how M. oryzae manipulates the host during this complex multifaceted infection. Here, we describe recent advances in our understanding of the cell biology of M. oryzae biotrophic interaction and key molecular factors required for the disease establishment in rice cells. PMID- 29395730 TI - Legionella Effectors Explored with INSeq: New Functional Insights. AB - Legionella pneumophila secretes over 300 effector proteins that manipulate host cells. This multiplicity of effectors hampers the characterization of their individual roles. Shames et al. report a new approach to solve the enigma of Legionella effector function by using INSeq to analyse effector functions in the context of infection. PMID- 29395731 TI - Evolutionary Transition of GAL Regulatory Circuit from Generalist to Specialist Function in Ascomycetes. AB - The Gal4 transcription factor (TF) controls gene expression by binding the DNA sequence motif CGG(N11)CCG. Well studied versions regulate metabolism of glucose in Candida albicans and galactose in Saccharomyces cerevisiae. Gal4 is also found within Aspergillus species and shows a wide range of potential binding targets. Members of the CTG clade that reassigned CUG codons from leucine to serine lack the Gal80 binding domain of Gal4, and they use the TF to regulate only glycolytic genes. In this clade, the galactose catabolic pathway (also known as the Leloir pathway) genes are regulated by Rtg1/Rtg3. In the WGD species, the complete Gal4/Gal80 module is limited to regulation of the Leloir pathway, while glycolysis is controlled by Gcr1/Gcr2. This shows a switch of Gal4 from a generalist to a specialist within the ascomycetes, and the split of glucose and galactose metabolism into distinct regulatory circuits. PMID- 29395729 TI - Antiviral Immunity and Virus-Mediated Antagonism in Disease Vector Mosquitoes. AB - More than 100 pathogens, spanning multiple virus families, broadly termed 'arthropod-borne viruses (arboviruses)' have been associated with human and/or animal diseases. These viruses persist in nature through transmission cycles that involve alternating replication in susceptible vertebrate and invertebrate hosts. Collectively, these viruses are among the greatest burdens to global health, due to their widespread prevalence, and the severe morbidity and mortality they cause in human and animal hosts. Specific examples of mosquito-borne pathogens include Zika virus (ZIKV), West Nile virus (WNV), dengue virus serotypes 1-4 (DENV 1-4), Japanese encephalitis virus (JEV), yellow fever virus (YFV), chikungunya virus (CHIKV), and Rift Valley fever virus (RVFV). Interactions between arboviruses and the immune pathways of vertebrate hosts have been extensively reviewed. In this review we focus on the antiviral immune pathways present in mosquitoes. We also discuss mechanisms by which mosquito-borne viruses may antagonize antiviral pathways in disease vectors. Finally, we elaborate on the possibility that mosquito-borne viruses may be engaged in an evolutionary arms race with their invertebrate vector hosts, and the possible implications of this for understanding the transmission of mosquito-borne viruses. PMID- 29395732 TI - Storage potential and residual emissions from fresh and stabilized waste samples from a landfill simulation experiment. AB - The storage capacity and the potentially residual emissions of a stabilized waste coming from a landfill simulation experiment were evaluated. The evolution in time of the potential emissions and the mobility of some selected elements or compounds were determined, comparing the results of the stabilized waste samples with the values detected in the related fresh waste samples. Analyses were conducted for the total bulk waste and also for each identified category (under sieve, kitchen residues, green and wooden materials, plastics, cellulosic material and textiles) to highlight the contribution of the different waste fractions in the total emission potential. The waste characterization was performed through analyses on solids and on leaching test eluates; the chemical speciation of carbon, nitrogen, chlorine and sulfur together with the partitioning of heavy metals through a SCE procedure were carried out. Results showed that the under-sieve is the most environmentally relevant fraction, hosting a consistent part of mobile compounds in fresh waste (40.7% of carbon, 44.0% of nitrogen, 47.6% of chloride and 40.0% of sulfur) and the greater part of potentially residual emissions in stabilized waste (88.4% of carbon, 90.9% of nitrogen, 98.4% of chloride and 91.1% of sulfur). Landfilled Municipal Solid Waste (MSW) proved to be an effective sink, finally storing more than 55% of carbon, 53% of nitrogen, 33% of sulfur and 90% of heavy metals (HM) which were initially present in fresh waste samples. A general decrease in leachable fractions from fresh to stabilized waste was observed for each category. Tests showed that solid waste is not a good sink for chlorine, whose residual non mobile fraction amounts to 12.3% only. PMID- 29395733 TI - Heavy metal behavior in "Washing-Calcination-Changing with Bottom Ash" system for recycling of four types of fly ashes. AB - The Washing-Calcination-Changing with Bottom Ash (WCCB) system, effective at reducing chloride, was proposed to treat fly ash (FA) from a municipal solid waste incinerator (MSWI) before recycling FA in cement kiln as raw material. This study analyzed the behavior of heavy metals in four types of FA during WCCB treatment via Tessier and X-ray absorption fine structure (XANES) method. One FA was from the bag filter of a typical MSWI in Beijing, China (CFA), and the other three were from Japan (RFA, CaFA, and NaFA). All the metals were reduced especially Pb, Cd, and Hg (38.4-82.4%, 21.8-34.7%, and 100%, respectively). Besides Cr almost all heavy metals were stabilized according to Tessier analysis. Cr should be given more attention in WCCB as the formation of exchangeable Cr in the final residue. XANES result indicated that PbCl2 could be the main species of Pb in FA, while CaFA contains some PbO. The treated FAs contain PbCO3 and PbO besides PbCl2. The Tessier results of Ni, Pb, Cd, Cr, and Cu showed that NaFA was better at heavy metal stabilization than the other FA, so NaHCO3 is a more suitable neutralizer in WCCB. PMID- 29395734 TI - Converting inert plastic waste into energetic materials: A study on the light accelerated decomposition of plastic waste with the Fenton reaction. AB - Better treatment and management strategies than landfilling are needed to address the large quantities of unrecycled plastic waste generated by daily human activities. Waste-to-energy conversion is an ideal benchmark for developing future large-scale waste management technologies. The present study explores a new approach for producing energetic materials by converting inert plastic waste into energy (thermal and mechanical energies) via a light-controlled process through the simple chemical activation of plastic waste, including polyethylene, polypropylene, and polyvinyl chloride. The inert and non-polar polymer surfaces of the plastics were modified by generating a number of sulfonic groups (SO3-) using chlorosulfuric acid, followed by grafting of Fe(III) catalyst onto the polymer chains to obtain activated polymer. Elemental analyses of these activated materials showed that the carbon-to-sulfur ratio ranged from 3:1 to 5:1. The FTIR spectra indicated the presence of CC bonds (vC=C: 1615-1630 cm-1) and SO bonds (vS=O: 1151-1167 cm-1) in the activated polymers after chemical reaction. These activated materials were energetic, as light could be used to convert them into thermal (1800-3200 J/g) and mechanical energies (380-560 kPa/g) using hydrogen peroxide as the oxidant under ambient conditions within 1 h. PMID- 29395735 TI - Extractability and crop transfer of potentially toxic elements from mediterranean agricultural soils following long-term sewage sludge applications as a fertilizer replacement to barley and maize crops. AB - Sewage sludge is used as a fertilizer replacement in agricultural soils for its chemical properties, such as organic matter content, and for its capability to improve physical soil characteristics like porosity. This is also an appealing disposal option for residue whose production is increasing worldwide. However, there is some concern about the presence of potentially toxic elements (PTEs) that can accumulate in soils and become available for crops. In this work, a study was conducted to evaluate the extractability and crops transfer of thirteen PTEs from soils that had been amended with biosolids each year for 15 years as a regular agricultural practice. The study was conducted with barley (winter cereal) and maize (spring cereal) crops. After this long period, an increase in the amount of Pb, Hg, Zn and Ag in soils amended by biosolids was confirmed. However, it is important to emphasize that the PTE total content in croplands was still far below the thresholds established by US and European regulations. Statistically significant differences were also found between the soils fertilized with biosolids and other treatments compared with the potential phytoavailable amount of Cu, Se, Sb and especially for As and Zn, by a DTPA leaching test. Despite these results, the concentration of PTEs in the barley and maize grains grown in fields repeatedly amended with biosolids was not statistically different from those grown with chemical fertilization, except for As in barley grains. In this case, a significant correlation was found between the DTPA-extractable As content in soils and the total content in grains (r = 0.83). PMID- 29395736 TI - Ultrasound-enhanced electrokinetic remediation for removal of Zn, Pb, Cu and Cd in municipal solid waste incineration fly ashes. AB - Low-frequency ultrasound generated by a transducer was investigated to activate the raw municipal solid waste incineration (MSWI) fly ashes in the electrokinetic process, aiming at enhancing heavy metal (HM) removal and achieving better remedial efficacy. The maximum removal efficiencies of 69.84%, 64.24%, 67.74% and 59.93% were obtained in the orthogonal tests of ultrasonication for Zn, Pb, Cu and Cd, respectively. The acoustic time of 30 min and controlling temperature of 45 degrees C in the operating parameters were quantitatively determined to optimize the ultrasonication of the MSWI fly ash matrices. The changes of acoustic time had a significant effect on the extraction efficiencies of all the four heavy metal elements in the sonication optimal experiments. The longer running time was preferred for the pretreatment of the fly ashes in according to the marginal mean removal results. The voltage gradient of 2 V/cm was most likely to improve the removals of four HMs during the electrokinetics in the range of 0.5-2 V/cm. The synergetic application of acidification and ultrasonication for the media treatment was demonstrated to be most effective in enhancing the remedial efficiencies in the further electrokinetic experiments compared with the other activation systems. Correspondingly, the leaching concentrations of Zn, Pb, Cu and Cd in the samples were reduced by 85.92%, 98.22%, 88.53% and 98.34%, respectively. The contaminants were continuously extracted from the solid grains of the fly ashes by the protonic attack and bubble implosion. The obtained risk assessment-code values indicated the adoption of AUS-EKR system reduced the environmental toxicity for the fly ashes to the maximum extent. PMID- 29395737 TI - Corrigendum to "The Biological Foundation of the Genetic Association of TOMM40 with Late-onset Alzheimer's disease" [Biochim. Biophys. Acta 1863/11 (2017) 2973 2986]. PMID- 29395738 TI - Th17 cells, gammadelta T cells and their interplay in EAE and multiple sclerosis. AB - Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting CD4 and gammadelta T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convincing evidence that IL-17-secreting CD4 T cells (Th17 cells) and IL 17-secreting gammadelta T cells play a critical pathogenic role in central nervous system (CNS) inflammation in EAE and MS. Indeed a significant number of the major discoveries on the pathogenic role of IL-17-secreting T cells in autoimmunity were made in the EAE model. These included the first demonstration that IL-23-activated IL-17-secreting T cells are the key T cells in driving autoimmune disease pathology. Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that gammadelta T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases. Furthermore, it emerged that Th1 cells can also have encephalitogenic activity and that there was considerable plasticity in these T cell responses, with Th17 cells reverting to a Th1 phenotype in vivo. This questioned the pathogenic role of IL-17 and suggested that other cytokines, such as IFN-gamma, GM-CSF and TNF, may be important. Nevertheless, biological drugs that target the IL-23-IL-17 pathway are highly effective in treating human psoriasis and are showing promise in the treatment of relapsing remitting MS and other T-cell mediated autoimmune diseases. PMID- 29395739 TI - Predicting progression to diabetes in islet autoantibody positive children. AB - While full oral glucose tolerance test (OGTT) helps improve prediction, it requires intravenous access with 6 sample collections for glucose and C-peptide. The objective of this study was to explore less costly and less time-consuming options. All children being prospectively followed by the Diabetes Autoimmunity Study in the Young (DAISY) who had a complete baseline OGTT and at least one confirmed islet autoantibody (Ab+) were included in this study (n = 68). Of 68 Ab+ subjects with a baseline OGTT, 25 developed diabetes after a mean follow-up 5.7 yrs, at a mean age of 12.4 yrs. Univariate proportional hazards (PH) models suggested that age at seroconversion, number of Ab+, IA-2A levels, HbA1c and metabolic variables from the OGTT predicted progression to diabetes, while HLA DR3/4, BMI, levels of IAA or GADA did not. Five multivariate PH predictive models were similar (p = 0.32). All five models included age at seroconversion, number of Ab+, IA-2A levels and HbA1c, and in addition included: model 1 - 1 h glucose and 1 h C-peptide; model 2 - 2 h glucose and 2 h C-peptide; model 3 - glucose sum and C-peptide sum; model 4 - glucose AUC and C-peptide AUC; and model 5: index 60. A model containing age at seroconversion, number of Ab+, IA-2A levels, HbA1c, 1 h glucose and 1 h C-peptide was as predictive for type 1 diabetes progression as models including all sum or AUC values for glucose and C-peptide from full OGTT. The performance of this model should be confirmed in an independent population of Ab+ children. PMID- 29395740 TI - Start-up of the completely autotrophic nitrogen removal over nitrite process with a submerged aerated biological filter and the effect of inorganic carbon on nitrogen removal and microbial activity. AB - Good start-up and performance are essential for the completely autotrophic nitrogen removal over nitrite (CANON) process, and inorganic carbon (IC) is also important for this process. In this study, a lab-scale submerged aerated biological filter (SABF) was adopted for the CANON process. A 16S rRNA gene high throughput sequencing analysis showed that the phyla Proteobacteria and Planctomycetes were the dominant microorganisms and that the genus Candidatus Brocadia functioned as the nitrogen remover. The effect of IC on the nitrogen removal was analyzed. The results showed that the optimum concentration ratio of IC to nitrogen (IC/N) was 1.2, which produced the highest average ammonium nitrogen removal rate (ANR) and total nitrogen removal rate (TNR) values of 95.5% and 80.3%, respectively. The average AOB and AnAOB activities were 2.45 mg.L-1.h 1 and 3.57 mg.L-1.h-1, respectively. This research could promote the nitrogen removal ability of the CANON process with a SABF in the future. PMID- 29395741 TI - Towards developing a representative biochemical methane potential (BMP) assay for landfilled municipal solid waste - A review. AB - The applicability of slurry-based (semi-liquids) BMP assay in determining biodegradation kinetic parameters of landfilled waste is critically reviewed. Factors affecting the amount and rate of methane (CH4) production during anaerobic degradation of municipal solid waste (MSW) and optimal values of these factors specific to landfill conditions are presented. The history of conventional BMP, and some existing procedures are reviewed. A landfill BMP (LBMP) assay is proposed that manipulates some of the key factors, such as moisture content, particle and sample size, that affects the rate of CH4 production and the CH4 generation potential of landfilled MSW (LMSW). By selecting proper conditions for these factors, a representative BMP assay could be conducted to ensure accurate determinations of CH4 potential and the kinetic parameters k; first order rate coefficient and Lo; methane generation potential. PMID- 29395742 TI - Electric field-based technologies for valorization of bioresources. AB - This review provides an overview of recent research on electrotechnologies applied to the valorization of bioresources. Following a comprehensive summary of the current status of the application of well-known electric-based processing technologies, such as pulsed electric fields (PEF) and high voltage electrical discharges (HVED), the application of moderate electric fields (MEF) as an extraction or valorization technology will be considered in detail. MEF, known by its improved energy efficiency and claimed electroporation effects (allowing enhanced extraction yields), may also originate high heating rates - ohmic heating (OH) effect - allowing thermal stabilization of waste stream for other added-value applications. MEF is a simple technology that mostly makes use of green solvents (mainly water) and that can be used on functionalization of compounds of biological origin broadening their application range. The substantial increase of MEF-based plants installed in industries worldwide suggests its straightforward application for waste recovery. PMID- 29395743 TI - Mild and efficient extraction of hardwood hemicellulose using recyclable formic acid/water binary solvent. AB - Formic acid/water binary solvent extraction with formic acid fraction lower than 77.5% (w/w) of azeotrope was used to extract hemicellulose-derived saccharides from poplar wood at various levels of severity. The highest xylose yield of 77.8% and arabinose yield of 93.5% were obtained at 120 degrees C and 1 h. To reduce cellulose hydrolysis and facilitate downstream xylose crystallization, mild conditions at 90 degrees C and 4 h was chosen as optimum severity, which led to the highest xylose fraction of 81.7% in all saccharides extracted, with a remarkable xylose yield of 73.1%. Mass balance analysis showed that 5.84% of xylan was degraded, but only 0.25% of xylan ended up as furfural at optimum severity. The proposed extraction process has high feasibility for industrial application since the low formic acid fraction in solvent allows simple recovery and concentration of used solvent. PMID- 29395744 TI - Tourniquet time in total knee arthroplasty. AB - BACKGROUND: Whether the arterial tourniquet in total knee arthroplasty (TKA) is a friend or a foe is still debated. Longer ischemia causes hypoxic damage; yet short duration of a tourniquet may influence outcome. Understanding the time dependent influence of the tourniquet in TKA patients could improve the overall outcome and safety. The purpose of the study was to measure the tourniquet induced time-dependent alterations in skeletal muscle metabolism in TKA to establish a 'safe tourniquet time.' METHODS: In the femoral quadriceps muscle of 12 patients undergoing a total knee arthroplasty with a tourniquet (TKA) we measured the ischemic response using microdialysis. Lactate, pyruvate, glucose and glycerol were measured in the muscle underneath the tourniquet, in the ischemic muscle distally to the tourniquet and in the opposite muscle as a reference. RESULTS: Lactate pyruvate ratio (L/P ratio) increased time-dependently after 15min of ischemia. L/P ratio increased faster underneath the tourniquet compared to ischemic tissue distal to the tourniquet. Glycerol was elevated underneath the tourniquet compared to ischemic tissue distal to the tourniquet and correlated to the individual ischemic response. Only minor increases in creatine-kinase, asparagine-aminotransferase, and lactate-dehydrogenase were observed. Thirty minutes of reperfusion normalized lactate levels. CONCLUSIONS: The muscle underneath the tourniquet suffered more from ischemia than the ischemic tissue distal to the tourniquet. Less than 15min of ischemia did not increase ischemic markers. If any muscle damage occurs from longer tourniquet time, it is likely reversible and occurs mainly underneath the tourniquet. Fifteen minutes of ischemia appears safe. PMID- 29395745 TI - Early quadriceps tendon rupture after primary total knee arthroplasty. AB - BACKGROUND: Extensor mechanism disruption following total knee arthroplasty (TKA) is a rare complication and results in significant morbidity and severe functional limitations. Quadriceps tendon rupture in the early postoperative period after TKA is one limitation about which there is a significant paucity of available information. METHODS: In this retrospective study of 2404 patients who underwent primary TKA between June 2015 to May 2016, there were 10 quadriceps tendon ruptures in seven patients (three bilateral, four unilateral) presented within 3 months after surgery. The rupture was due to a sudden fall while walking or getting up from a chair. All seven patients presented with haematoma formation around the knee, inability to get up and inability to walk. Diagnosis was confirmed by ultrasonography and managed by exploration and end-to-end tendon repair by suturing. RESULTS: In our study, incidence of quadriceps tendon tear in the early postoperative period (within 3 months) after TKA is 0.29% (seven of 2404). All patients had rupture within 90days of primary TKA; early primary repair was performed in all cases. All patients achieved preoperative range of motion without extension lag or restriction in range of movement within 6 months of repair of the quadriceps tendon. CONCLUSION: Early identification and prompt treatment of quadriceps tendon injury followed by controlled postoperative rehabilitation results in excellent short-term and mid-term outcomes. PMID- 29395746 TI - Reinterventions after dynamic intraligamentary stabilization in primary anterior cruciate ligament repair. AB - BACKGROUND: The goal of this study was to perform an in-depth analysis of the frequency and cause of secondary interventions subsequent to primary anterior cruciate ligament (ACL) repair with dynamic intraligamentary stabilization (DIS). METHODS: Between July 2009 and June 2014, 455 patients underwent DIS treatment. The minimum follow-up was 21months (mean 28months, range 21-64months). RESULTS: A total of 215 (48.2%) reinterventions were performed in 190 (42.6%) patients. One hundred and seventy-six (39.4%) were non-revision reinterventions, and 39 (8.7%) were revision ACL reconstructions. Re-arthroscopies included 26 (5.8%) scar tissue debridements with hardware removal due to range of motion deficits, 14 (3.1%) partial meniscectomies, four (0.9%) meniscal sutures, and four (0.9%) arthroscopies due to crepitation or knee pain. Minor non-revision reinterventions performed under analgosedation consisted of 97 (21.7%) hardware removals, 20 (4.5%) hardware removals with manipulations under anesthesia, and four manipulations under anesthesia alone (0.9%). CONCLUSIONS: In our study, the revision rate was within the range of published results after ACL reconstructions. In over 90% of patients, the native ACL was preserved with no need for a secondary reconstruction. Most of the non-revision reinterventions were minor and included hardware removals and manipulations under anesthesia. The re-arthroscopy rate was lower than that after ACL reconstruction with fewer secondary meniscal sutures and partial meniscectomies. Early treatment of meniscal tears may be one crucial benefit of ACL repair with DIS. PMID- 29395747 TI - A preliminary modeling investigation into the safe correction zone for high tibial osteotomy. AB - BACKGROUND: High tibial osteotomy (HTO) re-aligns the weight-bearing axis (WBA) of the lower limb. The surgery reduces medial load (reducing pain and slowing progression of cartilage damage) while avoiding overloading the lateral compartment. The optimal correction has not been established. This study investigated how different WBA re-alignments affected load distribution in the knee, to consider the optimal post-surgery re-alignment. METHODS: We collected motion analysis and seven Tesla MRI data from three healthy subjects, and combined this data to create sets of subject-specific finite element models (total=45 models). Each set of models simulated a range of potential post-HTO knee re-alignments. We shifted the WBA from its native alignment to between 40% and 80% medial-lateral tibial width (corresponding to 2.8 degrees -3.1 degrees varus and 8.5 degrees -9.3 degrees valgus), in three percent increments. We then compared stress/pressure distributions in the models. RESULTS: Correcting the WBA to 50% tibial width (0 degrees varus-valgus) approximately halved medial compartment stresses, with minimal changes to lateral stress levels, but provided little margin for error in undercorrection. Correcting the WBA to a more commonly used 62%-65% tibial width (3.4 degrees -4.6 degrees valgus) further reduced medial stresses but introduced the danger of damaging lateral compartment tissues. To balance optimal loading environment with that of the historical risk of under-correction, we propose a new target: WBA correction to 55% tibial width (1.7 degrees -1.9 degrees valgus), which anatomically represented the apex of the lateral tibial spine. CONCLUSIONS: Finite element models can successfully simulate a variety of HTO re-alignments. Correcting the WBA to 55% tibial width (1.7 degrees -1.9 degrees valgus) optimally distributes medial and lateral stresses/pressures. PMID- 29395748 TI - Does different duration of non-operative immobilization have an effect on the redislocation rate of primary patellar dislocation? A retrospective multicenter cohort study. AB - BACKGROUND: Immobilization devices such as plaster splints, casts and braces have been used for first time patellar dislocation (FTPD) in order to prevent redislocation. This study evaluates different non-operative immobilization regimes upon rates of redislocation. METHODS: A retrospective cohort study with a study population of 1366 in which 601 subjects under 30years with FTPD were included from three hospitals. Exclusion criteria were osteochondral fracture, ligament injury and subluxation. Subjects were divided into five groups; unknown/none, two weeks of brace, two weeks of brace followed by bandage, four weeks of brace and six weeks of brace with increasing of range of motion. Radiographs were evaluated for trochlear dysplasia (TD), patella alta, trochlear depth and growth zone. Crude analysis and logistic regression adjusted for radiographic assessments, age, gender and rehabilitation was done in STATA(r) with significance p<=0.05. RESULTS: Forty-five point eight percent were between 15 and 19years and 51.4% were male. One hundred sixty-three experienced redislocation (27.1%). Logistic regression was performed at 404 subjects and showed that rehabilitation, gender, TD, patella alta, and growth zone had no significant odds ratio (OR) on redislocation. The duration of brace demonstrated no significant OR in reducing redislocation. Subjects between 20 and 29years showed lower OR in redislocation (95% CI) of 0.27 (0.11; 0.64, p=0.003). CONCLUSION: This study demonstrated no difference in duration of brace treatment in reducing patella redislocation after FTPD. Rehabilitation and predisposal factors such as TD, trochlear depth, patella alta and open growth zone did not influence the redislocation rate. Increasing age reduced risk of redislocation. PMID- 29395749 TI - Reduced white matter connectivity associated with auditory verbal hallucinations in first-episode and chronic schizophrenia: A diffusion tensor imaging study. AB - This study aims to explore whether auditory verbal hallucinations (AVH) in schizophrenia are associated with the white matter abnormalities in tracts connecting language, auditory and memory/limbic networks in first-episode and chronic schizophrenia patients. 21 first-episode (FE-AVH) and 12 chronic (chronic AVH group) patients who suffered from auditory verbal hallucinations and 26 healthy controls (HC group) were enrolled. Diffusion tensor imaging with tract based spatial statistics was performed to assess the white matter changes between the two patient groups and HC group. Decreased fractional anisotropy and increased radial diffusivity were found in the patient groups compared to the HC group in multiple white matter tracts including the corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, cingulum, external capsule and anterior limb of the internal capsule. The chronic-AVH group showed more widespread white matter impairment than the FE AVH group. Furthermore, increased axial diffusivity was also observed in some discrete regions of the chronic-AVH group. Auditory verbal hallucinations in schizophrenia are accompanied by white matter abnormalities in tracts connecting the language, auditory and memory/limbic networks. Chronic-AVH schizophrenia patients may present with more severe neurodegeneration relative to first-episode patients. PMID- 29395751 TI - Early stroke post-heart transplant is associated with decreased survival in children. AB - BACKGROUND: Major neurologic events (MNEs) after heart transplantation (HTx) and their effect on survival have not been well described in children. In this study we aimed to characterize early MNEs (stroke, isolated seizures not from stroke and posterior reversible leukoencephalopathy [PRES] within 1 year after primary pediatric HTx) and evaluate their impact on 1-year post-HTx survival. We hypothesized that early an MNE after HTx is associated with decreased 1-year patient survival. METHODS: We performed a pediatric, single-center, retrospective analysis of 345 consecutive patients aged 0 to 22 years who underwent primary HTx during the period from November 1, 1994 to October 31, 2015. Characteristics were compared between patients with and without early MNEs. RESULTS: Nineteen percent (65 of 345) of patients had an MNE within 1 year after HTx (median 9 days, interquartile range [IQR] 4 to 23 days). Freedom from early MNE was 97%, 85% and 80% at 1, 6 and 12 months, respectively. Of the total 65 events, stroke comprised 55.4% (n = 36), isolated seizure 29.2% (n = 19) and PRES 15.4% (n = 10). With multiple logistic regression, previous neurologic disease, infection requiring intravenous antibiotic therapy and post-operative drug-treated hypertension were found to be significant risk factors for early MNEs. Stroke (hazard ratio 4.1, IQR 2.3 to 7.6, p < 0.0001), but not seizures and PRES, was associated with decreased 1-year patient survival. CONCLUSIONS: Major neurologic events are common after pediatric HTx and usually occur within the first few weeks. Early stroke was associated with decreased 1-year survival. Potentially modifiable factors, including prior neurologic event, drug-treated hypertension and infection, were associated with increased risk of developing early MNEs. PMID- 29395752 TI - Disclosure of infectious risk to heart transplant candidates: Shared decision making is here to stay. AB - The Public Health Service has defined 12 criteria of increased-risk (PHS-IR) for transmissible viral infections in potential organ donors where clinicians are required to document informed consent. Over the last decade, there has been a near tripling of PHS-IR donor organs in the United States. In light of the paucity in guidelines and consensus statements to guide clinicians on how to provide informed consent to potential recipients, using a typical case, we provide an overview including: how to effectively communicate infectious risk, whether clinicians should decline PHS-IR organs, the need to standardize disclosure practice across centers and finally how much information about the donor should be communicated to the transplant candidate. Many patients can be empowered by involving them in shared decision making to understand the minimal risk associated with the use of PHS-IR organs; an important step in improving donor utilization. PMID- 29395753 TI - Authors' reply to Hadid and colleagues' comment on "Catheter Ablation of Atrial Flutter Following Orthotopic Heart Transplantation". PMID- 29395750 TI - Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples. AB - Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5-75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3-7) in an IUI programme for subfertile couples. A cost-effectiveness analysis was conducted using the results of a randomized trial, including 620 IUI cycles. The primary outcome was the incremental cost-effectiveness ratio (ICER) of using HMG versus clomiphene citrate. Results are presented from the healthcare payer perspective. The total cost per patient associated with one IUI treatment with HMG is ?764, whereas it is ?558 if clomiphene citrate is used, resulting in an incremental cost of ?206 for HMG per treatment. The incremental clinical pregnancy rate of using HMG instead of clomiphene citrate, however, is also 5.7 percentage points higher, resulting in an ICER of HMG versus clomiphene citrate of ?3615 per additional clinical pregnancy achieved. On average, HMG was found to be more cost-effective than clomiphene citrate. PMID- 29395754 TI - Constipation in children: NICE guidance in practice in two emergency departments. PMID- 29395755 TI - Emergency department evaluation of patient satisfaction. Does physician gender impact Press Ganey scores? A multicenter study. PMID- 29395756 TI - Lawn mower injuries presenting to the emergency department: 2005 to 2015. AB - OBJECTIVE: The objective of this study was to describe recent trends in the epidemiology of lawn mower injuries presenting to the Emergency Department in the United States using nationally representative data for all ages. METHODS: Data for this retrospective analysis were obtained from the U.S. Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS), for the years 2005-2015. We queried the system using all product codes under "lawn mowers" in the NEISS Coding Manual. We examined body part injured, types of injuries, gender and age distribution, and disposition. RESULTS: There were an estimated 934,394 lawn mower injuries treated in U.S. ED's from 2005 to 2015, with an average of 84,944 injuries annually. The most commonly injured body parts were the hand/finger (22.3%), followed by the lower extremity (16.2%). The most common type of injury was laceration (23.1%), followed by sprain/strain (18.8%). The mean age of individuals injured was 46.5 years, and men were more than three times as likely to be injured as women. Patients presenting to the ED were far more likely to be discharged home after treatment (90.5%) than to be admitted (8.5%). CONCLUSION: Lawn mowers continue to account for a large number of injuries every year in the United States. The incidence of lawn mower injuries showed no decrease during the period of 2005-2015. Preventative measures should take into account the epidemiology of these injuries. PMID- 29395757 TI - Standardized model of porcine resuscitation using a custom-made resuscitation board results in optimal hemodynamic management. AB - AIM: Standardized modeling of cardiac arrest and cardiopulmonary resuscitation (CPR) is crucial to evaluate new treatment options. Experimental porcine models are ideal, closely mimicking human-like physiology. However, anteroposterior chest diameter differs significantly, being larger in pigs and thus poses a challenge to achieve adequate perfusion pressures and consequently hemodynamics during CPR, which are commonly achieved during human resuscitation. The aim was to prove that standardized resuscitation is feasible and renders adequate hemodynamics and perfusion in pigs, using a specifically designed resuscitation board for a pneumatic chest compression device. METHODS AND RESULTS: A "porcine fit" resuscitation board was designed for our experiments to optimally use a pneumatic compression device (LUCAS(r) II, Physio-Control Inc.), which is widely employed in emergency medicine and ideal in an experimental setting due to its high standardization. Asphyxial cardiac arrest was induced in 10 German hybrid landrace pigs and cardiopulmonary resuscitation was performed according to ERC/AHA 2015 guidelines with mechanical chest compressions. Hemodynamics were measured in the carotid and pulmonary artery. Furthermore, arterial blood gas was drawn to assess oxygenation and tissue perfusion. The custom-designed resuscitation board in combination with the LUCAS(r) device demonstrated highly sufficient performance regarding hemodynamics during CPR (mean arterial blood pressure, MAP 46 +/- 1 mmHg and mean pulmonary artery pressure, mPAP of 36 +/- 1 mmHg over the course of CPR). MAP returned to baseline values at 2 h after ROSC (80 +/- 4 mmHg), requiring moderate doses of vasopressors. Furthermore, stroke volume and contractility were analyzed using pulse contour analysis (106 +/- 3 ml and 1097 +/- 22 mmHg/s during CPR). Blood gas analysis revealed CPR-typical changes, normalizing in the due course. Thermodilution parameters did not show persistent intravascular volume shift. CONCLUSION: Standardized cardiopulmonary resuscitation is feasible in a porcine model, achieving adequate hemodynamics and consecutive tissue perfusion of consistent quality. PMID- 29395758 TI - What's going wrong with this postpartum woman? AB - Peripartum cardiomyopathy (PPCM) is a left ventricular systolic dysfunction failure emerges during the antepartum or puerperal period, and can result in maternal death. Reported incidences are increasing and differing globally. Echocardiography is the cornerstone for the diagnosis. The immediate goals in acute management are the stabilization of the hemodynamic state, providing symptomatic relief, and ensuring fetal wellbeing. Emergency physicians should be aware of PPCM at the differential diagnosis of dyspnea in pregnancy related emergencies and play role in early diagnosis. PMID- 29395759 TI - Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity. AB - AIM: Reducing or reversing the toxicity effects of new oral anticoagulants is an important question.The purpose of the present study is to evaluate the effect of lipid emulsion (LE) and Activated Charcoal (AC) therapy on the intoxication of rivaroxaban, on mice. METHODS: Adult male Balb/c mice weighing approximately 30g were used in the study. Seven groups were assigned, with six mice in each group. Groups were defined; given only rivaroxaban, given only LE, given only AC, after the administration of rivaroxaban LE applied group in the 1st hour, after the administration of rivaroxaban LE applied group in the 3rd hour, after the administration of rivaroxaban AC applied group in the1st hour, after the administration of rivaroxaban AC applied group in the 1st hour and LE applied group in the 3rd hour. PT and Anti-Factor Xa activity were measured in all blood samples from subjects. RESULTS: A statistically significant difference was found when all groups were compared in terms of mean PT values and Anti-FactorXa values. However, no statistically significant difference was found in the mean PT and Anti-FactorXa values when only rivaroxaban administrated group and after the administration of rivaroxaban LE and/or AC applied groups were compared one to one. No deaths occurred in groups during the observation. CONCLUSION: Although the administration of either AC or LE alone or in combination resulted in a decrease in the mean values of PT and anti-Factor Xa, in case of rivaroxaban toxicity, but one-to-one comparison of the groups was not statistically significant. PMID- 29395760 TI - Shortened preprocedural fasting in the pediatric emergency department. AB - BACKGROUND: There is no evidence of an association between fasting time and the incidence of adverse events during procedural sedation and analgesia. Pediatric and adult emergency medicine guidelines support avoiding delaying procedures based on fasting time. General pediatric guidelines outside emergent care settings continue to be vague and do not support a set fasting period for urgent and emergent procedures. OBJECTIVE: To describe shortened preprocedural fasting and vomiting event rates during the implementation of a shortened fasting protocol. METHODS: This was a prospective study of patients undergoing procedural sedation and analgesia (PSA) in an urban, tertiary care children's hospital emergency center from March 2010-February 2012. All consecutive patients had documentation of preprocedural fasting time and adverse events recorded on a standardized data collection form. RESULTS: PSA occurred in 2426 patients with fasting data available for 2188 (90.2%); 1472 were fasted >=6 h for solids and 716 patients were in the shortened fasting group (<6 h). There is no evidence of an association between emesis at any time and shortened fasting time unadjusted (OR = 1.18 (95% CI 0.75-1.84) or adjusted for known risk factors including age >12 years, initial ketamine dose >2.5 mg/kg or total dose >5.0 mg/kg (OR = 1.14 (95% CI 0.74-1.75). CONCLUSION: Analysis of a large prospective cohort study failed to find evidence of an association between emesis and shortened fasting time upon implementation of a shortened fasting protocol for procedural sedation and analgesia. PMID- 29395761 TI - Cyanide poisoning is a possible cause of cardiac arrest among fire victims, and empiric antidote treatment may improve outcomes. AB - BACKGROUND: Carbon monoxide and cyanide poisoning are important causes of death due to fire. Carbon monoxide is more regularly assessed than cyanide at the site of burn or smoke inhalation treatment due to its ease in assessment and simplicity to treat. Although several forensic studies have demonstrated the significance of cyanide poisoning in fire victims using blood cyanide levels, the association between the cause of cardiac arrest and the concentration of cyanide among fire victims has not been sufficiently investigated. This study aimed to investigate the frequency of cyanide-induced cardiac arrest in fire victims and to assess the necessity of early empiric treatment for cyanide poisoning. METHODS: This study was a retrospective analysis of fire victims with cardiac arrest at the scene who were transported to a trauma and critical care center, Kyorin University Hospital, from January 2014 to June 2017. Patients whose concentration of cyanide was measured were included. RESULTS: Five patients were included in the study; all died despite cardiopulmonary resuscitation. Three of these victims were later found to have lethal cyanide levels (>3 MUg/ml). Two of the patients had non-lethal carboxyhemoglobin levels under 50% and might have been saved if hydroxocobalamin had been administered during resuscitation. CONCLUSION: According to our results, cyanide-induced cardiac arrest may be more frequently present among fire victims than previously believed, and early empiric treatment with hydroxocobalamin may improve outcomes for these victims in cases where cardiac arrest is of short duration. PMID- 29395762 TI - Emergency department sepsis screening tool decreases time to antibiotics in patients with sepsis. AB - Recent literature has highlighted the importance of early identification and treatment of sepsis; however, limited data exists to help recognize sepsis in the emergency department (ED) through use of a screening tool. The purpose of this study was to evaluate the impact of a sepsis screening tool implemented in an academic medical center ED on compliance with the 3-hour sepsis bundle. This was a retrospective cohort study that included a total of 115 patients, of which 58 were in the pre-tool group and 57 were in the post-tool group. There was no difference in 3-hour bundle compliance between groups (36.2% vs. 47.4%, P = 0.26). There was no difference in the following bundle components: lactate (79.3% vs. 80.7%, P = 0.85), blood cultures (86.2% vs. 96.5%, P = 0.09), blood cultures before administering antibiotics (91.4% vs. 100%, P = 0.57) and adequate fluids administration (44.7% vs. 41.9%, P = 0.820). A significantly higher number of patients received antibiotics within 3 h in the post-tool group (58.6% vs. 89.5%, P < 0.001). Statistically significant secondary outcomes included average time to antibiotics (P = 0.04), administering antibiotics within an hour (P > 0.001), and ICU length of stay (P = 0.03). There was no difference in 30-day mortality, however mortality was numerically lower in the post-tool group (36.2% vs. 26.3%, P = 0.25). Although implementation of an ED sepsis screening tool did not increase 3-hour bundle compliance, it did increase the proportion of patients receiving timely antimicrobial therapy and demonstrated a trend towards decreased mortality. PMID- 29395763 TI - Challenge of intravascular volume assessment in acute ischemic stroke. AB - INTRODUCTION: Retrospective data indicates that dehydration in acute ischemic stroke patients may be common, even though these patients frequently have elevated blood pressure. We sought to evaluate clinical and laboratory measures of intravascular volume status compared to more objective measures using ultrasound measurements of the inferior vena cava (IVC). METHODS: This was a prospective observation study of acute ischemic stroke patients in the emergency department. Patients with NIH stroke scale >=4 within 12 h of symptom onset were included. A trained ultrasonographer performed bi-dimensional imaging of the IVC with passive respiration to determine the percent inspiratory collapse and maximum diameter. We defined low intravascular volume as >50% IVC collapse and a maximal diameter < 2.1 cm. Analysis was limited to patients with confirmed ischemic stroke. RESULTS: There were 42 patients, of whom 31 had confirmed acute ischemic stroke. The mean age was 65 +/- 15 years, 52% were female, and 71% were hypertensive. The median NIH stroke scale score was 7 (IQR 5-15). Based on IVC ultrasound, low intravascular volume was present in 63% (95% CI 44-80%) of patients. A higher proportion of hypertensive patients had low intrasvascular volume (72% vs. 33%). There was poor correlation between IVC assessment of intrasvascular volume and blinded clinician assessment or laboratory markers of dehydration. CONCLUSION: The majority of ED acute ischemic stroke patients in this sample were hypertensive and demonstrated low intravascular volume based on IVC ultrasound. PMID- 29395764 TI - The authors respond: The ED diagnostic workup of constipation in children. PMID- 29395765 TI - Emergency medicine considerations in atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is an abnormal heart rhythm which may lead to stroke, heart failure, and death. Emergency physicians play a role in diagnosing AF, managing symptoms, and lessening complications from this dysrhythmia. OBJECTIVE: This review evaluates recent literature and addresses ED considerations in the management of AF. DISCUSSION: Emergency physicians should first assess patient clinical stability and evaluate and treat reversible causes. Immediate cardioversion is indicated in the hemodynamically unstable patient. The American Heart Association/American College of Cardiology, the European Society of Cardiology, and the Canadian Cardiovascular Society provide recommendations for management of AF. If hemodynamically stable, rate or rhythm control are options for management of AF. Physicians may opt for rate control with medications, with beta blockers and calcium channel blockers the predominant medications utilized in the ED. Patients with intact left ventricular function should be rate controlled to <110 beats per minute. Rhythm control is an option for patients who possess longer life expectancy and those with AF onset <48 h before presentation, anticoagulated for 3-4 weeks, or with transesophageal echocardiography demonstrating no intracardiac thrombus. Direct oral anticoagulants are a safe and reliable option for anticoagulation. Clinical judgment regarding disposition is recommended, but literature supports discharging stable patients who do not have certain comorbidities. CONCLUSION: Proper diagnosis and treatment of AF is essential to reduce complications. Treatment and overall management of AF include rate or rhythm control, cardioversion, anticoagulation, and admission versus discharge. This review discusses ED considerations regarding AF management. PMID- 29395766 TI - A time trend analysis of CT and MRI scan imaging in acute pancreatitis patients presenting to US emergency departments. PMID- 29395767 TI - Palpebral emphysema following a dental procedure. AB - Palpebral emphysema is a rare occurrence after a dental procedure. However, it can be associated with severe complications, such as soft tissue infection, pneumomediastinum, pneumothorax, optic nerve ischemia or even blindness. Early diagnosis and prompt management are mandatory for emergency physicians. PMID- 29395768 TI - Comparison of sitting and standing position for central venous catheter insertion: A crossover simulation trial. PMID- 29395769 TI - Implications of language barrier on the diagnostic yield of computed tomography in pulmonary embolism. AB - OBJECTIVES: To determine if a physician-patient language barrier impacts the diagnostic accuracy of pulmonary embolism (PE) evaluation. METHODS: A retrospective chart review, conducted between June 2015 and December 2016, of a consecutive sample of diagnostic computed tomography pulmonary angiogram (CTPA) studies performed on adult patients. Positive and negative CTPA scans were further categorized by patient language and the positive diagnostic yield was determined for each language group. A post collection sub-analysis was performed to determine the yield when interpreter services were identified as necessary. RESULTS: The yield for English speaking patients was 10.24% (92/898, 95% CI 8.39% to 12.36%), similar to the yield in Spanish speaking patients of 9.40% (25/266, 95% CI 6.31% to 13.37%, P=0.69). This contrasted with the yield in patients who identified as bilingual, which was significantly lower at 1.41% (1/71, 95% CI 0.07% to 6.75%) compared to both English-(P<0.02) and Spanish-only speakers (P<0.03). The yield for non-English speaking patients who requested an interpreter was 7.37% (14/190, 95% CI 4.26% to 11.77%) versus 3.23% (2/62, 95% CI 0.54% to 10.25%, P=0.25) in those who did not. CONCLUSIONS: The diagnostic yield in English- and Spanish-only speaking patients was similar, however, the yield in those that self-identified as bilingual was significantly lower. In patient groups in which a language barrier existed and an interpreter was not utilized, there was a trend toward a lower diagnostic yield. This suggests an increased propensity to order diagnostic imaging when potential communication barriers exist. PMID- 29395770 TI - The efficacy of endotracheal intubation utilizing INTUBRITE laryngoscope during cardiopulmonary resuscitation. PMID- 29395771 TI - Fluid resuscitation in pre-hospital management of septic shock. PMID- 29395772 TI - Effectiveness of prehospital trauma triage systems in selecting severely injured patients: Is comparative analysis possible? AB - INTRODUCTION: In an optimal trauma system, prehospital trauma triage ensures transport of the right patient to the right hospital. Incorrect triage results in undertriage and overtriage. The aim of this systematic review is to evaluate and compare prehospital trauma triage system quality worldwide and determine effectiveness in terms of undertriage and overtriage for trauma patients. METHODS: A systematic search of Pubmed/MEDLINE, Embase, and Cochrane Library databases was performed, using "trauma", "trauma center," or "trauma system", combined with "triage", "undertriage," or "overtriage", as search terms. All studies describing ground transport and actual destination hospital of patients with and without severe injuries, using prehospital triage, published before November 2017, were eligible for inclusion. To assess the quality of these studies, a critical appraisal tool was developed. RESULTS: A total of 33 articles were included. The percentage of undertriage ranged from 1% to 68%; overtriage from 5% to 99%. Older age and increased geographical distance were associated with undertriage. Mortality was lower for severely injured patients transferred to a higher-level trauma center. The majority of the included studies were of poor methodological quality. The studies of good quality showed poor performance of the triage protocol, but additional value of EMS provider judgment in the identification of severely injured patients. CONCLUSION: In most of the evaluated trauma systems, a substantial part of the severely injured patients is not transported to the appropriate level trauma center. Future research should come up with new innovative ways to improve the quality of prehospital triage in trauma patients. PMID- 29395773 TI - Pre-hospital times and clinical characteristics of severe trauma patients: A comparison between mountain and urban/suburban areas. PMID- 29395774 TI - A mathematical model for efficient emergency transportation in a disaster situation. AB - This work focuses on a real-life patient transportation problem derived from emergency medical services (EMS), whereby providing ambulatory service for emergency requests during disaster situations. Transportation of patients in congested traffic compounds already time sensitive treatment. An urgent situation is defined as individuals with major or minor injuries requiring EMS assistance simultaneously. Patients are either (1) slightly injured and treated on site or (2) are seriously injured and require transfer to points of care (PoCs). This paper will discuss enhancing the response-time of EMS providers by improving the ambulance routing problem (ARP). A genetic based algorithm is proposed to efficiently guide the ARP while simultaneously solving two scenarios. PMID- 29395775 TI - A randomized, cross-over, pilot study comparing the standard cricothyrotomy to a novel trochar-based cricothyrotomy device. PMID- 29395776 TI - How can we administer high-quality chest compressions to a cardiac arrest patient on a bed? PMID- 29395777 TI - Which option for ventilation is optimal for resuscitation performed by nurses? Pilot data. PMID- 29395778 TI - Minocycline blocks traumatic brain injury-induced alcohol consumption and nucleus accumbens inflammation in adolescent male mice. AB - Alcohol use is a well characterized risk factor for traumatic brain injury (TBI); however, emerging clinical and experimental research suggests that TBI may also be an independent risk factor for the development of alcohol use disorders. In particular, TBIs incurred early in life predict the development of problem alcohol use and increase vulnerability to neuroinflammation as a consequence of alcohol use. Critically, the neuroinflammatory response to alcohol, mediated in large part by microglia, may also function as a driver of further alcohol use. Here, we tested the hypothesis that TBI increases alcohol consumption through microglia-mediated neuroinflammation. Mice were injured as juveniles and alcohol consumption and preference were assessed in a free-choice voluntary drinking paradigm in adolescence. TBI increased alcohol consumption; however, treatment with minocycline, an inhibitor of microglial activation, reduced alcohol intake in TBI mice to sham levels. Moreover, a single injection of ethanol (2 g/kg) significantly increased microglial activation in the nucleus accumbens and microglial expression of the proinflammatory cytokine IL-1beta in TBI, but not sham or minocycline-treated, mice. Our data implicate TBI-induced microglial activation as a possible mechanism for the development of alcohol use disorders. PMID- 29395779 TI - Moving Forward with Physical Activity: Self-Management of Chronic Pain among Women. PMID- 29395781 TI - Editorial commentary: Novel developments in revascularization for left main coronary artery disease. PMID- 29395780 TI - Interest in Over-the-Counter Access to a Progestin-Only Pill among Women in the United States. AB - BACKGROUND: A progestin-only pill may be the first pill formulation to become available over the counter in the United States; however, no research on over-the counter (OTC) pill interest has focused on progestin-only pills or a representative sample of teens. The objective of this study was to assess U.S. women and teens' interest in OTC progestin-only pill use. METHODS: In October 2015, we conducted a nationally representative, cross-sectional, online survey with 2,026 sexually active adult women aged 18 to 44 not currently desiring pregnancy, and 513 female teens aged 15 to 17. Logistic regression was used to identify characteristics associated with likely OTC progestin-only pill use. We also assessed reasons for use or nonuse, duration of use, and willingness to pay. RESULTS: Thirty-nine percent of adults and 29% of teens reported likely use, with a greater likelihood if covered by insurance. Adults were willing to pay $15 per month and teens $10 per month on average. Among adults, women who were never married or living alone (vs. married), uninsured (vs. privately insured), current pill or less effective method users (vs. ring, patch, injectable, or intrauterine device), tried to get a birth control prescription in the past year, or ever used an oral contraceptive pill or progestin-only pill had higher odds of likely use. Among teens, Spanish speakers and those who ever had sex had higher odds of likely use; Black teens (vs. White) had lower odds. CONCLUSIONS: Teens and adults are interested in using an OTC progestin-only pill. These findings indicate a large pool of interested users and the potential for improved contraceptive access by making an OTC progestin-only pill available. PMID- 29395782 TI - Editorial commentary: Beta blockers and the inertia of evidence-based medicine. PMID- 29395783 TI - Characterization of Caco-2 cells stably expressing the protein-based zinc probe eCalwy-5 as a model system for investigating intestinal zinc transport. AB - Intestinal zinc resorption, in particular its regulation and mechanisms, are not yet fully understood. Suitable intestinal cell models are needed to investigate zinc uptake kinetics and the role of labile zinc in enterocytes in vitro. Therefore, a Caco-2 cell clone was produced, stably expressing the genetically encoded zinc biosensor eCalwy-5. The aim of the present study was to reassure the presence of characteristic enterocyte-specific properties in the Caco-2-eCalwy clone. Comparison of Caco-2-WT and Caco-2-eCalwy cells revealed only slight differences regarding subcellular localization of the tight junction protein occludin and alkaline phosphatase activity, which did not affect basic integrity of the intestinal barrier or the characteristic brush border membrane morphology. Furthermore, introduction of the additional zinc-binding protein in Caco-2 cells did not alter mRNA expression of the major intestinal zinc transporters (zip4, zip5, znt-1 and znt-5), but increased metallothionein 1a-expression and cellular resistance to higher zinc concentrations. Moreover, this study examines the effect of sensor expression level on its saturation with zinc. Fluorescence cell imaging indicated considerable intercellular heterogeneity in biosensor expression. However, FRET-measurements confirmed that these differences in expression levels have no effect on fractional zinc-saturation of the probe. PMID- 29395785 TI - Structural Architecture of the Nucleosome Remodeler ISWI Determined from Cross Linking, Mass Spectrometry, SAXS, and Modeling. AB - Chromatin remodeling factors assume critical roles by regulating access to nucleosomal DNA. To determine the architecture of the Drosophila ISWI remodeling enzyme, we developed an integrative structural approach that combines protein cross-linking, mass spectrometry, small-angle X-ray scattering, and computational modeling. The resulting structural model shows the ATPase module in a resting state with both ATPase lobes twisted against each other, providing support for a conformation that was recently trapped by crystallography. The autoinhibiting NegC region does not protrude from the ATPase module as suggested previously. The regulatory NTR domain is located near both ATPase lobes. The full-length enzyme is flexible and can adopt a compact structure in solution with the C-terminal HSS domain packing against the ATPase module. Our data imply a series of conformational changes upon activation of the enzyme and illustrate how the NTR, NegC, and HSS domains contribute to regulation of the ATPase module. PMID- 29395784 TI - Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling. AB - Sodium ions are endogenous allosteric modulators of many G-protein-coupled receptors (GPCRs). Mutation of key residues in the sodium binding motif causes a striking effect on G-protein signaling. We report the crystal structures of agonist complexes for two variants in the first sodium coordination shell of the human A2A adenosine receptor, D522.50N and S913.39A. Both structures present an overall active-like conformation; however, the variants show key changes in the activation motif NPxxY. Changes in the hydrogen bonding network in this microswitch suggest a possible mechanism for modified G-protein signaling and enhanced thermal stability. These structures, signaling data, and thermal stability analysis with a panel of pharmacological ligands provide a basis for understanding the role of the sodium-coordinating residues on stability and G protein signaling. Utilizing the D2.50N variant is a promising method for stabilizing class A GPCRs to accelerate structural efforts and drug discovery. PMID- 29395786 TI - An Intramolecular Interaction of UHRF1 Reveals Dual Control for Its Histone Association. AB - UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) is one of the essential components of mammalian DNA methylation machinery. Chromatin association of UHRF1 is controlled via an interplay between its intramolecular interaction and dual recognition of histone H3 trimethylated at lysine 9 (H3K9me3) and hemimethylated DNA. Here, we report the crystal structure of the N terminal tandem Tudor domain (TTD) of UHRF1 in complex with the C-terminal polybasic region (PBR). Structural analysis reveals that PBR binding leads to displacement of the TTD-plant homeodomain (PHD) linker, as well as blockage of the H3K9me3-engaging cage, both of which contribute to a chromatin-occluded UHRF1 conformation. Disruption of the TTD-PBR interaction, which is facilitated by the binding of UHRF1 to hemimethylated DNA or regulatory protein USP7, shifts the UHRF1 conformation toward an open state, allowing for efficient H3K9me3 binding. Together, this study provides structural basis for the allosteric regulation of UHRF1. PMID- 29395788 TI - MonoRes: Automatic and Accurate Estimation of Local Resolution for Electron Microscopy Maps. AB - Since the beginning of electron microscopy, resolution has been a critical parameter. In this article, we propose a fully automatic, accurate method for determining the local resolution of a 3D map (MonoRes). The foundation of this algorithm is an extension of the concept of analytic signal, termed monogenic signal. The map is filtered at different frequencies and the amplitude of the monogenic signal is calculated, after which a criterion is applied to determine the resolution at each voxel. MonoRes is fully automatic without compulsory user parameters, with great accuracy in all tests, and is computationally more rapid than existing methods in the field. In addition, MonoRes offers the option of local filtering of the original map based on the calculated local resolution. PMID- 29395787 TI - Structure of the Deactive State of Mammalian Respiratory Complex I. AB - Complex I (NADH:ubiquinone oxidoreductase) is central to energy metabolism in mammalian mitochondria. It couples NADH oxidation by ubiquinone to proton transport across the energy-conserving inner membrane, catalyzing respiration and driving ATP synthesis. In the absence of substrates, active complex I gradually enters a pronounced resting or deactive state. The active-deactive transition occurs during ischemia and is crucial for controlling how respiration recovers upon reperfusion. Here, we set a highly active preparation of Bos taurus complex I into the biochemically defined deactive state, and used single-particle electron cryomicroscopy to determine its structure to 4.1 A resolution. We show that the deactive state arises when critical structural elements that form the ubiquinone-binding site become disordered, and we propose reactivation is induced when substrate binding to the NADH-reduced enzyme templates their reordering. Our structure both rationalizes biochemical data on the deactive state and offers new insights into its physiological and cellular roles. PMID- 29395789 TI - Structural Basis of Formation of the Microtubule Minus-End-Regulating CAMSAP Katanin Complex. AB - CAMSAP/Patronin family members regulate the organization and stability of microtubule minus ends in various systems ranging from mitotic spindles to differentiated epithelial cells and neurons. Mammalian CAMSAP2 and CAMSAP3 bind to growing microtubule minus ends, where they form stretches of stabilized microtubule lattice. The microtubule-severing ATPase katanin interacts with CAMSAPs and limits the length of CAMSAP-decorated microtubule stretches. Here, by using biochemical, biophysical, and structural approaches, we reveal that a short helical motif conserved in CAMSAP2 and CAMSAP3 binds to the heterodimer formed by the N- and C-terminal domains of katanin subunits p60 and p80, respectively. The identified CAMSAP-katanin binding mode is supported by mutational analysis and genome-editing experiments. It is strikingly similar to the one seen in the ASPM katanin complex, which is responsible for microtubule minus-end regulation in mitotic spindles. Our work provides a general molecular mechanism for the cooperation of katanin with major microtubule minus-end regulators. PMID- 29395790 TI - The Impact of a Nursing Coping Kit and a Nursing Coping Bouncy Castle on the Medical Fear Levels of Uzbek Refugee Children. PMID- 29395791 TI - Use of Electronic Visibility Boards to Improve Patient Care Quality, Safety, and Flow on Inpatient Pediatric Acute Care Units. AB - PURPOSE: Effective information exchange among healthcare providers is critical to the delivery of high quality care. Electronic visibility boards (EVB) are an established tool for improving health care efficiency and promoting communication between healthcare team members. DESIGN AND METHODS: Seattle Children's Hospital (SCH) sought to evaluate the use of EVBs as a tool to improve patient care quality, safety and flow in a pediatric inpatient setting. EVBs were placed on the cancer and surgical patient care units at SCH, and displayed data flowing directly from the electronic health record. RESULTS: This paper describes the conceptual framework used for designing these boards, and details on the design methodology, testing approach, and successful deployment of the boards. CONCLUSIONS: The close collaboration between development analysts and clinical nursing is highlighted as a key to successful EVB implementation. Initial metrics indicate improvements in incentive spirometry compliance, nursing documentation of care plans, and flow awareness on the units. PRACTICE IMPLICATIONS: These results suggest that with appropriate design, EVBs can effectively enhance patient safety and care, and may be a useful tool for implementation on other pediatric inpatient units. PMID- 29395792 TI - Play Within the Pre-registration Children's Nursing Curriculum Within the United Kingdom: A Content Analysis of Programme Specifications. AB - PURPOSE: To determine the number of programme specifications which cite play within the curriculum and in what context. Play is an essential part of childhood. Therefore we might expect nurses caring for children to be trained in how to facilitate play within their clinical areas. Programme specifications provide information on course aims, the intended learning outcomes and what the learner is expected to achieve. DESIGN AND METHOD: Inductive qualitative content analysis. RESULTS: Only 13% (seven out of 54) programme specifications published by Higher Education Institutions cite play. Where play is mentioned there is a clear link made to use play as a communication tool. Also distraction figured prominently within the same sentence as play, despite these two terms being quite distinct. The availability of the programme specifications was also noted with 49% (28 out of 57) were easily accessible from the university web sites. A further 16% (9 out of 57) provided web links when access was requested. 35% were not publicly accessible without requesting access. Three Universities declined to be involved. CONCLUSION: It is clear that even if play is embedded within the child field nursing curriculum, it is not clearly stated as a priority within 87% of universities programme specifications which make no mention of it. PRACTICE IMPLICATIONS: If play is not part of programme specifications its importance could be lost to educators already delivering a full curriculum. Nurses could be qualifying with little or no knowledge around their role in facilitating play for their patients. PMID- 29395793 TI - Case: A Second Victim Support Program in Pediatrics: Successes and Challenges to Implementation. AB - PURPOSE: While there is growing attention to making health care safer, there has been less emphasis on helping health care workers to cope with stressful patient related events (these workers are commonly referred to as second victims). We used the RISE (Resilience In Stressful Events) peer support program at the Johns Hopkins Hospital as a case study for evaluating effectiveness, and identifying barriers to addressing the needs of second victims. DESIGN AND METHODS: The study used a mixed-method approach that included: 1) quantitative analysis of surveys of health care workers in the Department of Pediatrics before RISE implementation and four years after, and 2) content analysis of open-ended commentaries about respondents' experience with seeking second victim support, as well as feedback on RISE. RESULTS: Survey response rates were 22.4% and 23.3% respectively. Quantitative analysis showed that respondents at the later time point were more likely to contact an organizational support structure, and had greater awareness of the availability of support. Respondents were very likely (93%) to recommend RISE to others. Content analysis identified barriers to using RISE: overcoming blame culture, need to promote the initiative, and need for more staff time to handle adverse events. Respondents reported varied preferences for the support format and specific support interventions. CONCLUSIONS: The mixed-method approach allowed a comprehensive evaluation of RISE and provided some evidence for its effectiveness in supporting pediatric health care workers. PRACTICE IMPLICATIONS: The findings suggest an important role of organizational culture in second victim support program implementation and evaluation. PMID- 29395794 TI - Folate receptor alpha is associated with poor clinicopathological perspectives in breast carcinoma. AB - BACKGROUND: Breast carcinoma is the commonest malignancy in females. Folate is required for the biosynthesis of nucleotide bases, amino acids, and other cellular methylation reactions in proteins and phospholipids. The high affinity folate receptor alpha (FRalpha) has been shown to be expressed in several kinds of human cancers. METHODS: In this descriptive-analytic study, sections from formalin-fixed paraffin-embedded tissue blocks of 50 cases of invasive ductal breast carcinoma (IDC) as well as 15 cases of non-neoplastic breast specimens were immunohistochemically stained with FRalpha antibody. Histopathological evaluation for various clinicopathological parameters was done and was correlated with FRalpha expression. RESULTS: Positive FRalpha expression was more frequently detected in IDC (64%) compared to non-neoplastic breast specimens (20%). In IDC, Positive FRalpha expression was significantly associated with high tumor grade (p = 0.007), large tumor size (p < 0.001), high lymph node stage (p = 0.004), presence of angiolymphatic emboli (p = 0.001), presence of perineural invasion (p = 0.001). Significant association between FRalpha positivity and negative hormone receptors (estrogen and progesterone) (p < 0.001) and triple negative cases (p = 0.0021). CONCLUSION: Our work demonstrates that FRalpha is over expressed in IDC compared to non-neoplastic breast tissue. Folate receptor alpha expression was associated with poor clinicopathological perspective. This work suggests that FRalpha may be an independent prognostic factor and supports the possibility of using FRalpha-targeted therapies of breast carcinoma. However, our work requires validation on larger cohort with correlation with survival data of patients. PMID- 29395795 TI - Comparison of Interobserver Agreement and Diagnostic Accuracy for IASLC/ITMIG Thymic Epithelial Tumor Staging Among Co-registered FDG-PET/MRI, Whole-body MRI, Integrated FDG-PET/CT, and Conventional Imaging Examination with and without Contrast Media Administrations. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare the interobserver agreements and diagnostic accuracies for IASLC/ITMIG (International Association for the Study of Lung Cancer/International Thymic Malignancies Interest Group) thymic epithelial tumor staging of co-registered fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (FDG PET/MRI), MRI, integrated fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and conventional imaging examination. MATERIALS AND METHODS: Prospective whole-body MRI including diffusion-weighted imaging, integrated PET/CTs, conventional imaging examinations, pathological examinations, and surgical reports, as well as follow up examinations, were performed for 64 consecutive patients with thymic epithelial tumor. All FDG-PET/MRIs were co-registered PET data with MRI. TNM staging was evaluated by two radiologists on the basis of the IASLC/ITMIG thymic epithelial tumor staging system. Kappa statistics were determined for evaluations of agreements of all factors between each of the methods and final diagnosis. Finally, the diagnostic accuracy of each factor and of determination of the clinical stage was statistically compared to each other using McNemar test. RESULTS: Agreements for all factors between each method and final diagnosis were assessed as fair, moderate, substantial, or almost perfect (0.28 <= kappa value <= 0.80; P < .0001). Diagnostic accuracy for N factor of PET/MRI (93.8% [60/64]) and MRI (93.8% [60/64]) was significantly higher than that of conventional imaging examination (81.3% [52/64] vs PET/MRI and MRI; P = .008). In addition, diagnostic accuracy for staging of PET/MRI (84.4% [54/64]) and MRI (84.4 [54/64]) was significantly higher than that of conventional imaging examination (71.9% [46/64] vs PET/MRI and MRI; P = .008). CONCLUSIONS: Whole-body PET/MRI, MRI, and PET/CT have better interobserver agreements and accuracies than conventional imaging examination for the new IASLC/ITMIG thymic epithelial tumor staging. PMID- 29395796 TI - Adaptive Iterative Dose Reduction 3D Integrated with Automatic Tube Current Modulation for CT Coronary Artery Calcium Quantification: Comparison to Traditional Filtered Back Projection in an Anthropomorphic Phantom and Patients. AB - RATIONALE AND OBJECTIVES: We aimed to evaluate integrated adaptive iterative dose reduction 3D (AIDR 3D) algorithm in automatic tube current modulation (ATCM) for the quantification of coronary artery calcium score (CACS) and cardiac risk stratification. MATERIALS AND METHODS: A thoracic phantom with calcium inserts of known densities was scanned with filtered back projection (FBP) and AIDR 3D algorithms in small- and medium-sized phantoms. Twenty-four patients underwent two consecutive scans of CACS with FBP and AIDR 3D algorithms. The absolute Agatston score, Agatston score risk, volume score, and Agatston score percentile based risk were compared, and concordance coefficients and agreement plots were made. RESULTS: Agatston and volume scores were significantly different between the phantom sizes (P < .01). There were no significant differences in the Agatston scores between FBP and AIDR 3D for the medium phantoms (P = .25). In the patients, there were no significant differences in Agatston and volume scores between FBP and AIDR 3D (P = .06 and P = .09, respectively). The correlation coefficients of Agatston and volume scores with AIDR 3D were excellent compared to those of FBP. There were no significant differences in Agatston score risk and Agatston score percentile-based risk between FBP and AIDR 3D (P = .74 and P = 1, respectively). There was mean dose reduction of 57.8% +/- 18.6% for AIDR 3D. CONCLUSION: The absolute Agatston score differed between FBP and AIDR 3D reconstructions. However, the cardiac risk categorizations of the two methods were comparable. An integrated AIDR 3D algorithm with automatic tube current modulation enables radiation dose savings at a consistent noise level without sacrificing CACS. PMID- 29395797 TI - Has the Objective Quality of Evidence in Imaging Papers Changed Over the Last 20 Years? AB - RATIONALE AND OBJECTIVES: We aimed to determine if both evidence level (EL) as well as clinical efficacy (CE) of imaging manuscripts have changed over the last 20 years. MATERIALS AND METHODS: With our review of medical literature, Institutional Review Board approval was waived, and no informed consent was required. Using Web of Science, we determined the 10 highest impact factor imaging journals. For each journal the 10 most cited and 10 average cited papers were compared for the following years: 1994, 1998, 2002, 2006, 2010, and 2014. EL was graded using the same criteria as the Journal of Bone and Joint Surgery (Wright et al., 2003). CE was graded using the criteria of Thornbury and Fryback (1991). Statistical software R and package lme4 were used to fit mixed regression models with fixed effects for group, year, and a random effect for journal. RESULTS: EL has improved -0.03 every year on average (P < .001). The more cited papers had better ELs (group effect = -0.23, SE 0.09, P = .011). CE is lower in top cited compared to average cited articles, although the differences were not statistically significant (group effect = -0.14, SE = 0.09, P = .16). CE level increased modestly in both groups over this 20-year time period (0.06 per year, SE = 0.007, P < .001). CONCLUSION: Over the last 20 years, imaging journal articles have improved modestly in quality of evidence, as measured by EL and CE. PMID- 29395798 TI - Using Convolutional Neural Networks for Enhanced Capture of Breast Parenchymal Complexity Patterns Associated with Breast Cancer Risk. AB - RATIONALE AND OBJECTIVES: We evaluate utilizing convolutional neural networks (CNNs) to optimally fuse parenchymal complexity measurements generated by texture analysis into discriminative meta-features relevant for breast cancer risk prediction. MATERIALS AND METHODS: With Institutional Review Board approval and Health Insurance Portability and Accountability Act compliance, we retrospectively analyzed "For Processing" contralateral digital mammograms (GE Healthcare 2000D/DS) from 106 women with unilateral invasive breast cancer and 318 age-matched controls. We coupled established texture features (histogram, co occurrence, run-length, structural), extracted using a previously validated lattice-based strategy, with a multichannel CNN into a hybrid framework in which a multitude of texture feature maps are reduced to meta-features predicting the case or control status. We evaluated the framework in a randomized split-sample setting, using the area under the curve (AUC) of the receiver operating characteristic (ROC) to assess case-control discriminatory capacity. We also compared the framework to CNNs directly fed with mammographic images, as well as to conventional texture analysis, where texture feature maps are summarized via simple statistical measures that are then used as inputs to a logistic regression model. RESULTS: Strong case-control discriminatory capacity was demonstrated on the basis of the meta-features generated by the hybrid framework (AUC = 0.90), outperforming both CNNs applied directly to raw image data (AUC = 0.63, P <.05) and conventional texture analysis (AUC = 0.79, P <.05). CONCLUSIONS: Our results suggest that informative interactions between patterns exist in texture feature maps derived from mammographic images, which can be extracted and summarized via a multichannel CNN architecture toward leveraging the associations of textural measurements to breast cancer risk. PMID- 29395799 TI - Low-dose Lung Cancer Screening at an Academic Medical Center: Initial Experience and Dose Reduction Strategies. AB - RATIONALE AND OBJECTIVES: Implementation of low dose computed tomography (LDCT) lung cancer screening programs has followed the demonstration of reduced lung cancer mortality in the National Lung Screening Trial and subsequent consensus screening recommendations. Here we aim to assess the initial results of a screening program at an academic medical center, to discuss the challenges of implementing such a program, and suggest strategies for reducing patient dose. MATERIALS AND METHODS: Retrospective review of all patients who underwent LDCT lung cancer screening at our institution between March 2015 and July 2016 was performed to assess the lung cancer detection rate, the spectrum of imaging findings (nodule or mass characteristics, degree of emphysema, etc.), and patient radiation dose indices. RESULTS: A total of 272 patients were screened during the study period. Approximately 50% (n = 135) were women. The lung cancer detection rate was 2.2% (n = 6). One patient underwent chemoradiation therapy, whereas the remainder underwent uneventful thoracoscopic resection. Approximately, 80% of screened patients met United States Preventative Services Task Force criteria for LDCT screening. The median pack-years of smoking was 42 pack-years. The mean volume CT dose index for the screening CTs was 3.12 mGy. Utilizing tube current modulation and iterative reconstruction, where available, resulted in lower patient doses. CONCLUSION: Initial LDCT lung cancer screening at our institution yielded results similar to those of the National Lung Screening Trial. Thorough prescreening evaluation, joint decision-making, centralized coordination of screening-related care, and patient size conscious scanning protocols are critical elements of a safe and successful lung cancer screening program. PMID- 29395800 TI - Educating Radiologists for Self-governance. PMID- 29395801 TI - Synthesized Mammography: The New Standard of Care When Screening for Breast Cancer with Digital Breast Tomosynthesis? AB - RATIONALE AND OBJECTIVES: This study aims to evaluate the screening performance of digital breast tomosynthesis (DBT) combined with synthesized mammography (SM) vs combined with full-field digital mammography (FFDM). MATERIALS AND METHODS: We retrospectively reviewed all screening studies utilizing FFDM + DBT (n = 7845) and SM + DBT (n = 14,776) between April 1, 2013, and February 15, 2016. Recall rate, biopsy rate, positive predictive value 1 (PPV1), positive predictive value 3 (PPV3), and cancer detection rate (CDR) were compared between the two groups. A generalized linear mixed model specifying the reading radiologist as the random effect and controlling for age was used to compare clinical outcomes between the two groups. RESULTS: The overall recall rate was significantly lower in the SM + DBT cohort compared to the FFDM + DBT cohort (7.06% vs 7.63%, P = .04). There was no difference in biopsy rate, PPV1, PPV3, or CDR between the two groups. CONCLUSIONS: When DBT is performed for screening, the use of SM rather than acquiring an additional FFDM has no significant effect on biopsy rate, PPV1, PPV3, or CDR. We found a decrease in recall rate in the SM + DBT group, which may be related to the learning curve of interpreting DBT. These findings support the use of SM for patients undergoing screening with DBT. PMID- 29395802 TI - [Deliberations of the expert advisory council on innovation fund applications]. AB - The "Innovation Fund" provides incentives for the development and testing of healthcare innovations in the area of the statutory health insurance with the aim to improve the quality of care in Germany. Over a period of initially four years (2016-19), 300 million Euro will be allocated annually to projects on "innovative forms of healthcare provision" and "health services research". Using a formalized procedure, the ten-member expert advisory board appointed by the German Federal Ministry of Health (BMG) assess all applications on the basis of various criteria for scientific quality, potential of innovation, relevance for health service delivery, and implementability. The present discussion paper sets out important considerations for submission and assessment and puts them up for discussion. (As supplied by the authors). PMID- 29395803 TI - Design, synthesis and fungicidal evaluation of novel pyraclostrobin analogues. AB - A series of novel pyraclostrobin derivatives were designed and prepared as antifungal agents. Their antifungal activities were tested in vitro with five important phytopathogenic fungi, namely, Batrylis cinerea, Phytophthora capsici, Fusarium sulphureum, Gloeosporium pestis and Sclerotinia sclerotiorum using the mycelium growth inhibition method. Among these compounds, 5s displayed IC50 value of 0.57 MUg/mL against Batrylis cinerea and 5k-II displayed IC50 value of 0.43 MUg/mL against Sclerotinia sclerotiorum, which were close to that of the positive control pyraclostrobin (0.18 MUg/mL and 0.15 MUg/mL). Other compounds 5f, 5k-II, 5j, 5m and 5s also exhibited strong antifungal activity. Further enzymatic assay demonstrated compound 5s inhibited porcine bc1 complex with IC50 value of 0.95 MUM. The statistical results from an integrated computational pipeline demonstrated the predicted total binding free energy for compound 5s is the highest. Consequently, compound 5s with the biphenyl-4-methoxyl side chain could serve as a new motif as inhibitors of bc1 complex and deserve to be further investigated. PMID- 29395804 TI - Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics. AB - The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market. PMID- 29395805 TI - Contribution to the aged society: Prevention of osteoporotic fragility fractures in the elderly. PMID- 29395806 TI - A comparative study of 2-year follow-up outcomes in lumbar spinal stenosis patients treated with physical therapy alone and those with surgical intervention after less successful physical therapy. AB - BACKGROUND: The efficacy of physical therapy for patients with lumbar spinal stenosis (LSS) has been reported only for the short term, and few reports have compared outcomes of surgical treatment with nonsurgical treatment after physical therapy. The purpose of this study was to assess 2-year outcomes of LSS patients treated with surgery or under follow-up observation after physical therapy for 6 weeks. METHODS: Patients presenting with neurogenic claudication, radiologically confirmed central LSS affecting both legs and refractory symptoms to pharmacotherapy of more than 3 months were enrolled. Patients were treated with manual therapy, stretching and strengthening exercises, and body weight-supported treadmill walking once a week for 6 weeks. Clinical outcomes were measured using the Zurich Claudication Questionnaire (ZCQ), visual analog scale of low back pain, leg pain, and numbness, the Japanese Orthopedic Association Back Pain Evaluation Questionnaire and the SF-36. Two years after physical therapy, patients were classified into the observation group (Group I) or the surgery group (Group II), whose patients failed to respond to physical therapy and wanted to undergo surgery. RESULTS: Thirty-eight patients were enrolled; 28 had complete data at 2 years: 21 and 7 in Groups I and II, respectively. Group II had a higher body mass index (BMI) than Group I. There were no significant differences in clinical outcomes at baseline. Six weeks after physical therapy, Group I had significantly better outcomes for symptom severity and physical function on the ZCQ subscales, physical functioning and bodily pain on the SF-36 subscales. These outcomes in Group I were maintained or improved and did not differ significantly between groups at 2-years. However, the physical function on the ZCQ subscales was improved in Group II more than those in Group I (mean difference -0.6; 95% CI: -1.2 to -0.03, P < 0.05) at 2 years. CONCLUSIONS: At 2 years, the outcomes except for the change in physical function score in the ZCQ subscale did not differ significantly between patients who had undergone surgery and those who avoided surgery. PMID- 29395807 TI - The distal margin of the lateral malleolus visible under ankle arthroscopy (articular tip) from the anteromedial portal, is separate from the ATFL attachment site of the fibula: A cadaver study. AB - PURPOSE: The purpose of this study was to evaluate the relationship between the lateral malleolus view under ankle arthroscopy and the anterior talofibular ligament (ATFL) attachment site. METHODS: Seven normal ankles from Thiel-embalmed cadavers were investigated. Ankle arthroscopy was performed using a 2.7 mm diameter, 30-degree, oblique-viewing endoscope. An antero-medial portal (AM), a medial midline portal (MML), and an antero-central portal (AC) were created in order, and the ankle arthroscope was inserted. The lateral malleolus was visualized as distally as possible, and the site that appeared to be the distal margin was marked with a 1.5 mm-diameter K-wire. Visualization with arthroscopy was carried out from all portals to mark the distal margin, and the ankle was subsequently exposed to directly measure the distance from the center of the ATFL attachment site at the fibula to each marking. RESULTS: The distances from the ATFL attachment site to the markings made under arthroscopy from the AM, MML, and AC portals were 10.4 +/- 2.6 mm, 7.4 +/- 1.9 mm, and 7.3 +/- 1.9 mm, respectively. Compared to markings made from the MML or AC portal, the marking made from the AM portal was significantly further away from the ATFL attachment site. CONCLUSIONS: A typical ankle arthroscopy portal may not allow complete visualization of the tip of the lateral malleolus, indicating that it may not be feasible to thoroughly observe the ATFL attachment site. It is necessary to perform arthroscopic surgeries with the understanding that the distal margin of the lateral malleolus that appears under ankle arthroscopy is 7-10 mm proximal to the ATFL attachment site. PMID- 29395808 TI - Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes. AB - AIMS: Short-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes. METHODS: In this study, 63 patients (age 59+/-8.3 years, baseline A1c 6.8+/-0.7%, diabetes duration 3.0+/-2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR). RESULTS: As expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P=0.02), decreased HOMA-IR (P<0.001), and reduced AUCglucagon (P<0.001). Of note, however, IIT had no significant impact on AUCGLP 1 (P=0.24) and reduced AUCGIP (P=0.02). CONCLUSION: Despite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP 1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion. PMID- 29395809 TI - Metabolomics signatures associated with an oral glucose challenge in pregnant women. AB - AIM: The oral glucose tolerance test (OGTT), widely used as a gold standard for gestational diabetes mellitus (GDM) diagnosis, provides a broad view of glucose pathophysiology in response to a glucose challenge. We conducted the present study to evaluate metabolite changes before and after an oral glucose challenge in pregnancy; and to examine the extent to which metabolites may serve to predict GDM diagnosis in pregnant women. METHODS: Peruvian pregnant women (n=100) attending prenatal clinics (mean gestation 25 weeks) participated in the study with 23% of them having GDM diagnosis. Serum samples were collected immediately prior to and 2-hours after administration of a 75-g OGTT. Targeted metabolic profiling was performed using a LC-MS based metabolomics platform. Changes in metabolite levels were evaluated using paired Student's t-tests and the change patterns were examined at the level of pathways. Multivariate regression procedures were used to examine metabolite pairwise differences associated with subsequent GDM diagnosis. RESULTS: Of the 306 metabolites detected, the relative concentration of 127 metabolites were statistically significantly increased or decreased 2-hours after the oral glucose load (false discovery rate [FDR] corrected P-value<0.001). We identified relative decreases in metabolites in acylcarnitines, fatty acids, and diacylglycerols while relative increases were noted among bile acids. In addition, we found that C58:10 triacylglycerol (beta= 0.08, SE=0.04), C58:9 triacylglycerol (beta=-0.07, SE=0.03), adenosine (beta=0.70, SE=0.32), methionine sulfoxide (beta=0.36, SE=0.13) were significantly associated with GDM diagnosis even after adjusting for age and body mass index. CONCLUSIONS: We identified alterations in maternal serum metabolites, representing distinct cellular and metabolic pathways including fatty acid metabolism, in response to an oral glucose challenge. These findings offer novel perspectives on the pathophysiological mechanisms underlying GDM. PMID- 29395810 TI - Role of fatty liver in the association between obesity and reduced hepatic insulin clearance. AB - AIM: Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD: Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS: HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION: HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER: These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351. PMID- 29395811 TI - Can persistent organic pollutants distinguish between two opposite metabolic phenotypes in lean Koreans? AB - AIMS: This study investigated the association of persistent organic pollutants (POPs), an emerging new risk factor for type 2 diabetes and the metabolic syndrome, with the presence of opposite phenotypes of glucose and lipid metabolism among normal-weight Koreans of similar body composition. METHODS: Fifty subjects, randomly selected from an ongoing community-based cohort study, from two opposite phenotype groups - metabolically unhealthy normal weight (MUHNW) and metabolically healthy normal weight (MHNW) - were matched for waist circumference, visceral fat mass and demographic variables, then compared for serum concentrations of POPs. RESULTS: Most POPs (10 out of 13 compounds) were present in higher serum concentrations in the MUHNW than in the MHNW. In particular, serum concentrations of all compounds of the organochlorine pesticide class were 2.2 to 4.7 times higher in cases than in controls. Compared with the lowest tertile of summary measures of POPs, Odds ratios (95% confidence interval) for the second and third tertiles were 7.4 (1.9-29.4) and 10.4 (2.6-41.2), respectively. Adjusting for possible confounders did not change the results. CONCLUSION: Taken altogether, these findings from the present and previous studies suggest that increased serum POP concentrations may play an important role in the development of unhealthy metabolic phenotypes in lean people. PMID- 29395812 TI - The prognostic significance of glutamic acid decarboxylase antibodies in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation. AB - AIM: Islet autotransplantation (IAT) is considered a 'non-immune' model of islet transplant, with no risk for autoimmune-mediated beta cell loss, but we have previously observed de novo type 1 diabetes in one total pancreatectomy with islet autotransplantation (TPIAT) recipient. We aimed to investigate the clinical significance of glutamic acid decarboxylase antibodies (GADA), as a sensitive marker for autoimmune diabetes mellitus (DM), in patients with chronic pancreatitis undergoing TPIAT. METHODS: We identified 9 patients undergoing TPIAT with elevated GADA pre-TPIAT (8 non-diabetic and 1 with C-peptide positive DM), otherwise demographically similar to GADA negative TPIAT recipients (n=341). Metabolic and clinical measures related to islet cell function were recorded both before and after TPIAT. RESULTS: None of the 9 TPIAT patients achieved insulin independence after surgery, vs. 33% of GADA negative patients (n=318 with 1-yr follow-up). The two patients with the highest titters of GADA (>250 IU/mL) both experienced islet graft failure, despite normoglycaemia pre-TPIAT and high islet mass transplanted (5276 and 9378 IEQ per kg), with elevated HbA1c levels post TPIAT (8.3%, 9.6%). The remaining 7 seven were insulin dependent with partial graft function and HbA1c levels <7%. CONCLUSION: Insulin dependence was more frequent in 9 patients with elevated GADA prior to TPIAT than in GADA negative TPIAT recipients, with graft failure in 2 cases. We speculate that beta-cell autoimmunity may occur in a small subset of TPIAT recipients and that beta cell antibody testing prior to TPIAT may be warranted to identify individuals at higher risk for insulin dependence. PMID- 29395813 TI - Ghrelin concentration as an indicator of eating-disorder risk in obese women. AB - AIM: Eating disorders (EDs), disordered eating (DE) and obesity are thought to have overlapping aetiological processes. DE in obesity can jeopardize weight-loss results, and acyl ghrelin (AG) is a hormone that stimulates food intake and reward processes. The main study objective was to determine whether higher-than expected concentrations of AG in common obesity are associated with DE symptoms. METHODS: The study population included 84 women, aged 20-55 years, free of established EDs: 55 were severely obese (OB) and 29 were of normal weight (NW). OB participants were stratified into two groups according to their median concentration of fasting AG distribution. The OB women with a high fasting plasma ghrelin concentration (HGC) were compared with both OB women with a low fasting plasma ghrelin concentration (LGC) and NW women. Participants were assessed by the Eating Disorder Inventory (EDI-2), Three-Factor Eating Questionnaire (TFEQ) and Hospital Anxiety and Depression Scale (HADS). Fasting glucose, insulin, leptin and ghrelin plasma concentrations were also quantified. RESULTS: Between the two AG groups of OB women, there was no statistical difference in either anthropometric or metabolic parameters, HADS, TFEQ or fasting hunger scores. However, the HGC group scored significantly higher than the LGC group on the drive-for-thinness subscale of EDI-2 (9.30+/-0.99 vs. 6.46+/-0.83, respectively; P=0.033). CONCLUSION: Results support the hypothesis of a potential relationship between fasting plasma AG concentrations and ED risk, regardless of mood and anxiety. AG may be considered a potential biomarker of vulnerability for developing EDs. PMID- 29395814 TI - Low normal fasting glucose and risk of accidental death in Korean adults: A prospective cohort study. AB - AIM: This study aimed to prospectively examine whether low normal glucose levels and hypoglycaemia are associated with increased mortality due to external causes, especially unintentional accidents. METHODS: A total of 345,318 normoglycaemic Korean adults who had undergone health examinations during 2002-2003 were followed-up to 2013. To avoid potential biases related to glucose-lowering medication use, those with known diabetes or hyperglycaemia were excluded. RESULTS: During 3.6 million person-years of follow-up, 1293 participants died because of unintentional accidents. Hazard ratios (HRs) for these accidental deaths were 1.26 (95% CI: 1.11-1.42), 1.60 (1.21-2.11) and 3.07 (1.37-6.85) for fasting serum glucose (FSG) levels of 70-79, 55-69 and <55mg/dL (3.9-4.4, 3.05 3.83 and <3.05mmol/L), respectively, compared with 80-99mg/dL (4.44-5.5mmol/L). FSG levels<80mg/dL were associated with an approximately 30% higher mortality due to accidents: specifically, 40% were non-fall-related injury; 50% were automobile related; and 80% were motorcycle-related. The associations were weak (approximately 10% higher mortality, with P>0.05 for each cause) for deaths due to traffic accidents (pedestrians, pedal cyclists), falls, intentional self-harm and physical assault. The population attributable risks for FSG levels <80mg/dL were 10% (95% CI: 2-18%) for non-fall-related injury, 11% (6-17%) for car accidents and 17% (6-27%) for motorcycle accidents. CONCLUSION: FSG levels of 70 79mg/dL (3.9-4.4mmol/L) as well as <70mg/dL are risk factors for accidental death. Appropriate management of the impact of FSG levels <80mg/dL might reduce unintended deaths due to non-fall-related injury, and automobile and motorcycle accidents, by >=10%. PMID- 29395815 TI - Association of Oral Intake and Transient Mixed Venous Oxygen Desaturation in Patients Undergoing Fast-Track Postoperative Care After Open-Heart Surgery. AB - OBJECTIVE: The impact of early resumption of oral intake after cardiac surgery on hemodynamics has not been characterized. The authors examined the effects of early oral intake on the oxygen supply-demand relationship in patients undergoing on-pump cardiac surgery in an early recovery after surgery program. DESIGN: Prospective data were collected in postcardiac surgical patients in a multidisciplinary intensive care unit (ICU) during an 18-month period. SETTING: Single institution study. PARTICIPANTS: Forty-three patients who underwent either mitral or aortic valve repair and were successfully liberated from ventilatory support within 10 hours after surgery. INTERVENTIONS: Patients were either allowed to resume oral intake on the morning of the first postoperative day or not at the discretion of the surgical team after extubation. MEASUREMENTS AND MAIN RESULTS: The oxygen supply-demand relationship was assessed continuously with cardiac index and mixed venous oxygen saturation (SvO2). Among the subjects, 22 patients were allowed to eat, and transient SvO2 decrease was noted in 13 patients. All transient SvO2 decreases occurred in the patients with early oral intake. The hemodynamic status and oxygen supply-demand relationship did not differ between the patients with and without transient SvO2 decrease. All the subjects were discharged successfully from the ICU on the first postoperative day, and the length of hospital stay was similar irrespective of SvO2 decrease after early oral intake. CONCLUSIONS: Early oral intake shortly after extubation was associated with transient but significant SvO2 decrease in patients who underwent fast-track recovery after open-heart surgery. Because this phenomenon did not negatively affect the postoperative outcome, early oral intake may not be harmful. PMID- 29395816 TI - A Comparative Study of Point-of-Care Prothrombin Time in Cardiopulmonary Bypass Surgery. AB - OBJECTIVE: Point-of-care (POC) devices allow for prothrombin time/international normalized ratio (PT/INR) testing in whole blood (WB) and timely administration of plasma or prothrombin complex concentrate during cardiopulmonary bypass surgery. This study evaluated the sensitivities of a new POC PT test, a dry hematology method with heparin neutralization technology (DRIHEMATO PT-S [DRI PT S]; A&T Corporation, Kanagawa, Japan), and compared it with other POC tests currently available. DESIGN: Prospective, observational study. SETTING: University hospital, single center. PARTICIPANTS: Healthy volunteers and warfarin treated and cardiac surgical patients. MEASUREMENT AND MAIN RESULTS: In WB samples obtained from 6 healthy volunteers, PT-INR results of DRI PT-S were not affected by an in vitro addition of heparin <6.0 U/mL. In warfarin-treated samples (n = 88, PT/INR 0.98-3.87), PT-INR with DRI PT-S showed acceptable correlation with the laboratory method (r2 = 0.85, p < 0.001). In blood samples obtained from cardiac surgical patients (n = 72), heparin prolonged the PT/INR with the laboratory assay, dry-hematology method with non heparin neutralization technology (DRI PT), Coaguchek XS (Roche Diagnostics, Basel, Switzerland), and Hemochron Jr. (Accriva Diagnostics, Edison, NJ), but DRI PT-S was not affected by heparin anticoagulation. In nonheparinized samples, different methods between DRI PT-S and the laboratory method yielded acceptable correlations (r2 = 0.76, p < 0.0001). There was a moderate correlation between factor levels and the PT-INR with DRI PT-S (factor [F]II: r2 = 0.63, FVII: r2 = 0.47, FX: r2 = 0.67; p < 0.0001). CONCLUSIONS: This study demonstrated that PT/INR can be accurately assessed using the dry-hematology method in WB under therapeutic heparin levels. Currently available other POC PT/INR tests are affected by heparin, and thus they are not recommended for coagulation monitoring during cardiopulmonary bypass. PMID- 29395817 TI - Transapical Ablation of Symptomatic Premature Ventricular Contractions in a Patient With Mechanical Mitral and Aortic Valves. PMID- 29395818 TI - A Recipe for Success in Echocardiography Training: The University of Utah Experience. PMID- 29395819 TI - Successful Rescue Utilization of Intraoperative Tissue Plasminogen Activator in the Setting of Massive Thrombosis of Avalon Catheter and Patient in Extremis with Refractory Hypoxemia. PMID- 29395820 TI - Pro: Routine Use of Embolic Protection Devices in Transcatheter Aortic Valve Replacement Should Be Considered. PMID- 29395821 TI - Early Extubation After Cardiac Surgery: A Better Predictor of Outcome than Metric of Quality? PMID- 29395822 TI - Utilization of Transverse Abdominis Plexus Block for Treatment of HeartMate II Left Ventricular Assist Device-Associated Pain. PMID- 29395823 TI - Cardiopulmonary Bypass and Malaria Relapse. PMID- 29395824 TI - When Cardiopulmonary Bypass Is Not An Option-A Case of Massive Retrosternal Goiter With Severe Tracheal Compression in an Extremely Obese Patient. PMID- 29395825 TI - Alkaptonuric Ochronosis and the Failure of Regional Cerebral Tissue Oxygen Saturation Monitoring by Two Different Near-infrared Spectroscopy Devices. PMID- 29395826 TI - Systemic Inflammation after Transcatheter Aortic Valve Implantation: A Prospective Exploratory Study. PMID- 29395827 TI - Pediatric Patients with High Pulmonary Arterial Pressure in Congenital Heart Disease Have Increased Tracheal Diameters Measured by Computed Tomography. AB - OBJECTIVES: Determination of the appropriate tracheal tube size using formulas based on age or height often is inaccurate in pediatric patients with congenital heart disease (CHD), particularly in those with high pulmonary arterial pressure (PAP). Here, the authors compared tracheal diameters between pediatric patients with CHD with high PAP and low PAP. DESIGN: Retrospective clinical study. SETTING: Hospital. PARTICIPANTS: Pediatric patients, from birth to 6 months of age, requiring general anesthesia and tracheal intubation who underwent computed tomography were included. Patients with mean pulmonary artery pressure >25 mmHg were allocated to the high PAP group, and the remaining patients were allocated to the low PAP group. The primary outcome was the tracheal diameter at the cricoid cartilage level, and the secondary goal was to observe whether the size of the tracheal tube was appropriate compared with that obtained using predictable formulas based on age or height. MEASUREMENTS AND MAIN RESULTS: The mean tracheal diameter was significantly larger in the high PAP group than in the low PAP group (p < 0.01). Pediatric patients with high PAP required a larger tracheal tube size than predicted by formulas based on age or height (p = 0.04 for age and height). CONCLUSIONS: Pediatric patients with high PAP had larger tracheal diameters than those with low PAP and required larger tracheal tubes compared with the size predicted using formulas based on age or height. PMID- 29395828 TI - 4-Valve Heart Disease and Right Heart Failure. AB - Carcinoid heart disease is a rare form of heart disease due to secretion of vasoactive compounds, including serotonin, from gastrointestinal tumors. This E challenge examines the case of a patient with advanced carcinoid heart disease who presented to the operating room (OR) for a tricuspid valve replacement. Once the patient was in the OR, intraoperative transesophageal echocardiography was used to discover a patent foramen ovale and involvement of all 4 valves with regurgitant lesions. The patient underwent tricuspid valve replacement, pulmonic valve replacement, right ventricular outflow tract reconstruction, and patent foramen closure in the OR and experienced subsequent fulminant right heart failure. Mechanical circulatory support was required to separate the patient from cardiopulmonary bypass, which was first attempted with an intra-aortic balloon pump and subsequently achieved with implantation of a right ventricular assist device. Multiple reports of acute right heart failure are available in the literature; however, this case helps illustrate several important considerations for the anesthesiologist. The effects of chronic circulating vasoactive compounds on the heart valves are well documented; however, it is likely that advanced carcinoid heart disease also will trigger pre-existing myocardial dysfunction, which may be underappreciated. Identifying patients who are at high risk for intraoperative right heart failure and considering what constitutes an adequate preoperative assessment of right heart function aid in preparing for OR management. In addition, reviewing the potential options for managing these patients when the traditional therapies are inadequate, including mechanical support and extracorporeal circulation, is a useful exercise in preparation. This case also highlights the contributions of intraoperative transesophageal echocardiography in the diagnosis and management of carcinoid heart disease, the need for additional preoperative optimization of these patients, and the management and potential complications of mechanical support. PMID- 29395829 TI - Intraoperative Transesophageal Echocardiographic Findings in Surgical Resection of a Giant Right Atrial Diverticulum That Severely Compressed the Right Ventricle. PMID- 29395830 TI - Labile plasma iron as an indicator of patient adherence to iron chelation treatment. AB - Poor adherence of transfusion-dependent patients to chelation treatment is often the cause of persistent iron overload and ensuing morbidity. However, a tool to assess patient compliance with therapy is lacking in clinical practice. Labile plasma iron (LPI, the redox-active component of non-transferrin bound iron) has been studied as an indicator of systemic iron overload and of chelation efficacy, and may particularly reflect recent iron equilibrium. We considered the use of LPI as a potential indicator for recent chelation treatment in 18 transfusion dependent pediatric patients. Samples were collected under chelation treatment or after a short interruption of the treatment, and LPI was measured by the FeROS assay (Aferrix, Tel Aviv, Israel). LPI was significantly higher after a short term interruption of the chelation (median of 0.4 MUM off-therapy [range:0-4] vs 0 MUM on-therapy [range:0-2.8] (p < .001)). Conversely, serum iron, serum ferritin and calculated transferrin saturation were not significantly higher in the "off-therapy" samples compared to "on-therapy". In addition, in multivariate logistic regression analysis LPI was the variable most significantly associated with recent chelation treatment (p = .001). We conclude that LPI could serve as a useful indicator of compliance to chelation therapy. PMID- 29395831 TI - lncRNAs in Plant and Animal Sexual Reproduction. AB - Long noncoding RNAs (lncRNAs) are transcripts over 200 base pairs in length with no discernible protein-coding potential. Multiple lines of evidence point to lncRNAs as master regulators, controlling the expression of protein-coding genes. Studies in plants and animals consistently show high expression of lncRNAs in reproductive organs in a cell- and tissue-specific manner. Sexual reproduction is a complex process that involves cell fate specification and specialized cell division requiring precise coordination of gene expression in response to intrinsic and extrinsic signals. The roles of lncRNAs as master regulators of gene expression and chromatin organization might make them particularly suited for coordination and control of molecular processes involved in sexual reproduction. PMID- 29395832 TI - Combinatorial Transcriptional Control of Plant Specialized Metabolism. AB - Plants produce countless specialized compounds of diverse chemical nature and biological activities. Their biosynthesis often exclusively occurs either in response to environmental stresses or is limited to dedicated anatomical structures. In both scenarios, regulation of biosynthesis appears to be mainly controlled at the transcriptional level, which is generally dependent on a combined interplay of DNA-related mechanisms and the activity of transcription factors that may act in a combinatorial manner. How environmental and developmental cues are integrated into a coordinated cell type-specific stress response has only partially been unraveled so far. Building on the available examples from (metabolic) gene expression, here we propose theoretical models of how this integration of signals may occur at the level of transcriptional control. PMID- 29395833 TI - Molecular identification of Candida species from urinary infections in Honduras. AB - BACKGROUND: Candiduria is a common infection among hospitalised patients. Although the clinical relevance of yeasts in urine is not clearly defined, fungal urinary tract infections have increased significantly in the last decades, becoming a growing public health problem. Candida albicans is the most commonly reported species in urinary infections, although other species of the genus are becoming particularly important, because some of them are linked with resistance to antifungal drugs. AIMS: This study aimed to evaluate the frequency of Candida species causing candiduria in a hospital in Honduras. METHODS: A simple and cost effective PCR-RFLP approach was used, by amplifying a partial sequence of the ribosomal ITS1-ITS2 region and a subsequent digestion with the enzyme MspI. RESULTS: During 2016, an analysis was performed on 73 urine samples from patients of different ages. Seven species were found. Candida albicans/dubliniensis was the most frequent species (30%); Candida glabrata (28.8%) was the most isolated among the rest of the species. Candida kefyr was the least frequent species found (2.5%). CONCLUSIONS: This study shows, for the first time in Honduras, the frequency of the Candida species isolated from urine using PCR-RFLP for their identification. This approach could be applied in future epidemiological studies at local and national level. PMID- 29395834 TI - Corrigendum to "Co-delivery of sorafenib and siVEGF based on mesoporous silica nanoparticles for ASGPR mediated targeted HCC therapy" [Eur. J. Pharm. Sci. 111 (1 January 2018) 492-502]. PMID- 29395835 TI - Colonization of preservation solution in kidney transplantation: Clinical impact and risk of secondary acute graft pyelonephritis. AB - INTRODUCTION: Bacterial colonization of preservative solutions (PS) remains poorly described in renal transplantation. We investigated the bacterial colonization of the PS and its influence on graft pyelonephritis within one year from the renal transplantation. PATIENTS AND METHODS: We cultured 2 samples of PS from 424 patients who underwent a renal transplantation. The follow-up period was one year. An acute graft pyelonephritis was defined as a positive bacteriological urine analysis, with temperature higher than 38.5 degrees C or graft pain. RESULTS: In total, 424 samples of PS were tested and 195 were positive for colonization (46%). Forty-five patients developed an acute graft pyelonephritis during the follow-up period (10.6%), of which, 21 (46.7%) showed a colonization of their PS. Twenty-four had no colonization (53.3%). This difference was not significant (P=0.697). DISCUSSION: Our data suggest that the bacterial colonization of PS samples does not seem to increase the risk of acute graft pyelonephritis in renal transplant recipients. LEVEL OF EVIDENCE: -3. PMID- 29395836 TI - Reshaping the deep brain stimulation trial for treatment-resistant depression. PMID- 29395837 TI - Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States. AB - BACKGROUND: In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival. PATIENTS AND METHODS: Adults with NDMM from January 2008 to June 2015 were followed up to identify their second line therapy. The duration of therapy (DOT) and time to next therapy (TTNT), as a proxy for progression-free survival, were estimated using the Kaplan-Meier method. The relationship between the duration of second-line therapy and overall survival was evaluated with a logistic marginal structural model to mitigate the risk of treatment selection and survival bias. RESULTS: A total of 628 NDMM patients developed a relapse after initial therapy. The median DOT for second line therapy was 6.9 months (95% confidence interval [CI], 5.9-7.7 months), which was shorter than the corresponding TTNT (median, 15.1 months; 95% CI, 13.4-17.3 months). Each additional month of second-line therapy was associated with a reduced adjusted risk of death at 1 year (odds ratio, 0.78; 95% CI, 0.77-0.83; P < .001). CONCLUSION: In a large database capturing a heterogeneous patient population and varied treatment patterns reflecting routine clinical care, we found a clinical benefit for continued longer DOT at first relapse. Despite the emerging paradigm favoring continuous therapy, second-line progression-free survival (utilizing TTNT as the proxy) was more than twofold longer than the DOT. Understanding the barriers to extended DOT could help to improve the outcomes for RRMM patients. PMID- 29395838 TI - Recommendations of the VAC2VAC workshop on the design of multi-centre validation studies. AB - Within the Innovative Medicines Initiative 2 (IMI 2) project VAC2VAC (Vaccine batch to vaccine batch comparison by consistency testing), a workshop has been organised to discuss ways of improving the design of multi-centre validation studies and use the data generated for product-specific validation purposes. Moreover, aspects of validation within the consistency approach context were addressed. This report summarises the discussions and outlines the conclusions and recommendations agreed on by the workshop participants. PMID- 29395839 TI - Lipid accumulation product and triglycerides/glucose index are useful predictors of insulin resistance. AB - OBJECTIVES: To investigate the association of triglycerides/glucose index (TyG index), anthropometrically predicted visceral adipose tissue (apVAT), lipid accumulation product (LAP), visceral adiposity index (VAI) and triglycerides (TG):high density lipoprotein-cholesterol (HDL-C) ratio with insulin resistance (IR) in adult Americans. METHODS: This study was based on data from three NHANES cycles (2005 to 2010). The TyG index was calculated as ln [TG*fasting glucose/2]. VAI was calculated using gender-specific formulas: men [waist circumference (WC)/39.68+(1.88*body mass index (BMI)]*(TG/1.03)*(1.31/HDL-C); women: [WC/36.58+(1.89*BMI)]*(TG/0.81)*(1.52/HDL-C). LAP index was calculated as [WC 65]*[TG] in men, and [WC-58]*[TG] in women. Correlation and regression analyses accounted for the complex sampling of database. RESULTS: A total of 18,318 subjects was included in this analysis [mean age 47.6Years]; 48.7% (n=8918) men]. The homeostatic model assessment of insulin resistance (HOMA-IR) had a significant positive correlation with the TyG index (r=0.502), LAP (r=0.551), apVAT (r=0.454), TG:HDL-C ratio (r=0.441) and VAI (r=451) (p<0.001 for all comparisons). Bland-Altman plots showed no systematic errors. The optimal cut-off to predict HOMA-diagnosed IR was 0.473 (sensitivity=74.5% and specificity=72.7%) for LAP, 0.478 (75.9%, 71.9%) for TyG, 0.391 (70.4%, 67.1%) for VAI, 0.392 (77.1% and 62.0%) for TG:HDL-C ratio and 0.381 (63.8%, 74.8%) for apVAT. CONCLUSIONS: The LAP index is a simple, cheap and accurate although not perfect, surrogate marker of HOMA-diagnosed IR among adult Americans. Moreover, it has higher predictability than other screening tools which traditionally applied. Among the markers, apVAT had the highest specificity and the TG:HDL-C ratio had the highest sensitivity. PMID- 29395840 TI - TAp63 is correlated with chronic inflammation in patients with newly diagnosed type 2 diabetes mellitus. AB - AIMS: To investigate TAp63 expression in patients with type 2 diabetes mellitus (T2DM) and the potential correlations between TAp63 and proinflammatory cytokines production and other clinical parameters. METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma were collected from 72 T2DM (cases) and 72 healthy subjects (controls). Fasting blood glucose (FBG), fasting insulin (FIN) and a blood lipid profile were measured. The homeostasis model assessment (HOMA) was used to estimate insulin resistance (IR). Plasma tumor necrosis factor-alpha (TNF alpha) and interleukin (IL)-6 were determined. PBMCs isolated from healthy subjects were cultured with or without 33.3 mmol/l glucose or 0.5 mmol/l palmitic acid (PA) for 6 h, 24 h, 48 h, and 72 h. The expression of TAp63 at mRNA and protein levels in PBMCs was analyzed using real-time qRT-PCR and western blots, respectively. RESULTS: TAp63 expression was significantly lower in T2DM patients compared with that of the controls. In addition, TAp63 expression showed a negative correlation with FBG, FIN, HbA1c, HOMA-IR, FFAs, TNF-alpha, and IL-6 levels. Treatment with 33.3 mmol/l glucose or 0.5 mmol/l PA increased TAp63 expression in the cultured PBMCs. CONCLUSIONS: TAp63 level may be correlated with chronic inflammatory state and perturbed glucose and lipid metabolism in T2DM. PMID- 29395841 TI - Associations between advanced glycation endproducts and matrix metalloproteinases and its inhibitor in individuals with type 1 diabetes. AB - AIMS: Advanced glycation endproducts (AGEs) and altered extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) are associated with vascular complications in type 1 diabetes. Experimental studies have shown that AGEs regulate the production of MMPs and/or TIMP-1. Therefore, we investigated associations between specific AGEs and MMP-1, -2, -3, -9, and -10, and TIMP-1 in individuals with type 1 diabetes. METHODS: In 670 type 1 diabetic individuals we determined serum levels of protein bound AGEs Nepsilon-(carboxymethyl)lysine (CML), Nepsilon-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1) and pentosidine, and MMP-1, -2, -3, 9, and -10, and TIMP-1. We performed linear regression analyses to investigate associations between AGEs and markers of the MMP-TIMP system. Analyses were adjusted for age, sex, HbA1c and duration of diabetes, and additionally for other potential confounders and presence of vascular complication. RESULTS: After full adjustment, levels of CML were positively associated with levels of MMP-2 and inversely with MMP-9. CEL was positively associated with MMP-3 and TIMP-1. MG-H1 was only associated with TIMP-1, whereas pentosidine was not associated with MMPs or TIMP-1. CONCLUSIONS: We showed independent associations between several AGEs and markers of the MMP-TIMP system, which indicate specific AGE-MMP/TIMP-1 interactions potentially contributing to vascular complications in patients with type 1 diabetes. PMID- 29395842 TI - Heterogeneity in effects of genetically determined adiposity on insulin resistance and type 2 diabetes: The atherosclerosis risk in communities study. AB - BACKGROUND: A recent genome-wide association study has identified 12 genetic variants robustly associated with body fat percentage (BF%) with diverse cardiometabolic consequences. We developed three genetic risk scores (GRSs) according to the associations of the 12 individual variants with type 2 diabetes (T2D) and test the GRSs' associations with insulin resistance and T2D in the Atherosclerosis Risk in Communities Study. METHODS: In 6895 European-American participants, we calculated GRS-I as the number of BF%-increasing alleles from variants associated with increased risk of T2D, GRS-D from variants associated with decreased risk of T2D, and GRS-ALL from all 12 variants. Linear and logistic regression models were used to evaluate associations of the GRSs with insulin resistance and risk of T2D, respectively, adjusted for age, sex, smoking, and drinking, and additionally for body mass index (BMI). RESULTS: GRS-D was significantly associated with decreased levels of fasting insulin (P = 0.014) and homeostasis assessment of insulin resistance (P = 0.023). While GRS-I was not associated with insulin resistance measures, it was with T2D (P = 0.002). Further adjustment for BMI did not substantially change the above associations. GRS-ALL was inversely associated with insulin resistance after controlling for covariates including BMI; GRS-ALL was not associated with T2D. CONCLUSION: Genetically determined BF% has differential effects on cardiometabolic risk, which may partly explain the heterogeneity in obesity-induced cardiometabolic risk and have implications for developing new strategies mitigating obesity-induced cardiometabolic consequences. PMID- 29395843 TI - Where is the fracture? Penetrating injury with a foreign bone. AB - Injuries in the explosion scenarios are usually hollow organ injuries including rapid gas expansion, thermal injuries, penetrating injuries due to secondary projectiles and secondary injuries like falls and burns. Our case is a penetrating injury that was considered open knee fracture (Gustilo Anderson Type 3A) and peroneal nerve palsy in the emergency service after bomb attack but later it was seen that the secondary projectile was a foreign bone and the patient's bone integrity was intact. Our aim is to show that specific human tissues must be considered as a factor in the secondary injuries. PMID- 29395844 TI - The Prevalence and Risk for Herpes Zoster Infection in Adult Patients With Diabetes Mellitus in the Canadian Primary Care Sentinel Surveillance Network. AB - OBJECTIVES: Herpes zoster (HZ) is a common infection in Canada that can result in serious and long-term complications. People with diabetes may be at an increased risk for HZ. The objectives of this study were to develop and validate a case definition of HZ diagnosis based on electronic medical records; determine a prevalence estimate for HZ in adult patients in the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and assess the association between HZ and diabetes. METHODS: This was a retrospective cross-sectional study. Patients 18 years of age or older who had made at least 1 visit to their primary health-care providers within the past 2 years in the CPCSSN were included. These data came from a 2015 extract of CPCSSN data, and a subsample of 289 patients was used to validate our case definition. Prevalences were estimated for the overall population and for people with diabetes, chronic obstructive pulmonary disease, cancer or HIV. Risk ratios were modelled for these conditions. RESULTS: The sensitivity, specificity, positive predictive value and negative predictive values for HZ were 100%, 73.8%, 83.9% and 100%, respectively. The 1-year prevalence of HZ in the CPCSSN data was 0.32%. The prevalence of HZ was higher in females (0.35%) than in males (0.28%). People with diabetes have an increased risk for HZ infection (RR 2.64, 95% CI 2.34, 2.99). CONCLUSIONS: People with diabetes have an increased risk for the diagnosis of HZ infection in the primary care setting in Canada. Women over the age of 65 years with diabetes and/or other chronic conditions are at greatest risk for developing HZ. PMID- 29395845 TI - Qualitative Evaluation of the Barriers and Facilitators Influencing the Use of an Electronic Basal Bolus Insulin Therapy Protocol to Improve the Care of Adult Inpatients With Diabetes. AB - OBJECTIVES: A qualitative evaluation of the perceived impact of a new evidence informed electronic basal bolus insulin therapy order set on clinical workflow and practice, and exploration of potential barriers and facilitators to electronic basal bolus insulin order set uptake and use in acute care facilities for various acute care team members. METHODS: We conducted 9 semistructured focus groups with multidisciplinary nursing staff (n=22), resident trainees (n=24) and attending physicians (n=23) involved in the delivery of inpatient diabetes care at 3 adult acute care facilities. The domains of inquiry included impact on workload, perceived impact on patient care and discipline-specific barriers and facilitators to use, including care-providers' needs, comfort and competencies, contributions from the clinical environment and efficacy of communication. The interviews were transcribed and analyzed using a content analysis approach. RESULTS: Several major themes emerged from the focus group discussions, including impact of education, information technology/user interface, workflow, organizational issues and practices, and perceived outcomes. Barriers and facilitators were identified relating to each theme. CONCLUSIONS: The outcomes highlight the complex interplay between educational, organizational and technical themes and the significance of employing a systemic approach to support the implementation of electronic inpatient glycemic-management protocols within complex social organizations. PMID- 29395846 TI - Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort. AB - Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naive CD4+CD45RA+CD27+ T-lymphocyte values at 3, 6, 9, 12months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p=0.002, p<0.001, p<0.001, p=0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery. PMID- 29395847 TI - Restoration of somatosensory perception via electrical stimulation of peripheral nerves. PMID- 29395848 TI - Sleep patterns open the window into disorders of consciousness. PMID- 29395849 TI - Is it significant? Is it relevant? PMID- 29395850 TI - Sensorimotor integration is problematic in amyotrophic lateral sclerosis. PMID- 29395851 TI - Corrigendum to "Ultrasound in polyneuropathies - Is size or structure all that matters?" [Clin. Neurophysiol. 128 (2017) 2519-2520]. PMID- 29395852 TI - Movement-related neural processing in people with congenital mirror movements beyond the (cortical) surface. PMID- 29395853 TI - Bronchiolitis obliterans organizing pneumonia after stereotactic ablative radiation therapy for lung cancer: A case report. AB - Bronchiolitis obliterans organizing pneumonia is an interstitial lung disease rarely occurring after radiotherapy probably due to an activation of autoimmune processes. Most cases have been described after postoperative radiotherapy for breast cancer. Corticosteroids represent the main treatment, prognosis is generally favorable. We described a case of bronchiolitis obliterans organizing pneumonia after stereotactic ablative radiation therapy for a recurrent lung cancer. Antibiotics and steroids were administered to solve the clinical picture. After three years, a new lesion at the right lung was found and treated with stereotactic ablative radiation therapy and concomitant long course of steroids with no recurrence of bronchiolitis obliterans organizing pneumonia. Bronchiolitis obliterans organizing pneumonia is a rare event after radiotherapy with undefined risk factors. In our case, steroids played an important role in management and, maybe, in preventing bronchiolitis obliterans organizing pneumonia recurrence after second course of stereotactic ablative radiation therapy. PMID- 29395854 TI - Total body irradiation using Helical Tomotherapy(r): Treatment technique, dosimetric results and initial clinical experience. AB - PURPOSE: Helical TomoTherapy(r) allows precise and homogeneous tumour coverage and excellent sparing of organs at risk. We present here our treatment technique, dosimetric results, and our first clinical data for patients receiving total body irradiation as part of the conditioning regimen before hematopoietic stem cell transplantation. PATIENTS AND METHODS: The cohort consisted of 11 patients who were treated in our institution between August 2014 and January 2016. The total dose was 12Gy in six fractions in three days. We collected the dose distribution information in the treatment volumes, organs at risk and area of junction. We report retrospectively the clinical events during the first 6 months after the procedure. RESULTS: Median age was 31 years (range, 18-57 years). Median D98% was 11.5Gy (range: 6.6-11.9Gy). The median of the mean doses to the lungs was 8.7Gy (range: 8.5-9.3Gy). The mean dose for the junction area was 12Gy (range: 11.9 12.1Gy). All patients had the total procedure, and all underwent successful engraftment. During the first six months, nine patients had at least one grade 3 or 4 toxicity that was due essentially to graft versus host disease. No patient had radiation pneumonitis. The toxicities were both more frequent and of higher grade during the first three months. CONCLUSION: Total body irradiation using helical TomoTherapy(r) is feasible. It allows a very good homogeneity of dose and conformity with an acceptable tolerance. It could deliver higher doses to sites at high risk of recurrence (bone marrow, sanctuary sites), while sparing major normal organs like lungs, liver, and kidneys. This reduction of dose could lead to reduced severity and frequency of late complications. PMID- 29395855 TI - Walking Tests: Are They Sensitive Enough to Detect Cognitive Decline in Older Adults? PMID- 29395856 TI - Walking While Talking and Risk of Incident Dementia. AB - INTRODUCTION: Walking while talking (WWT) is a performance-based test of divided attention that examines cognitive-motor interactions. The purpose of this study is to examine the predictive validity of WWT for dementia and dementia subtypes. METHODS: We prospectively studied the associations of WWT performance at baseline with risk of developing incident dementia in 1,156 older adults (mean age: 78.28 +/- 5.27 years, 60.7% female) enrolled in the Einstein Aging Study using Cox proportional hazard models. Associations were reported as hazard ratio (HR) with 95% confidence intervals (CI). RESULTS: Over a median follow-up of 1.90 years (interquartile range: 4.70 years), 85 participants developed incident dementia (53 Alzheimer dementia [AD] and 26 vascular dementia [VaD]). Three gait domains were derived using principal component analysis. Only variability, which loaded heavily for swing time standard deviation (SD) and step time SD, was associated with an increased risk of incident dementia per 1 point increase (HR: 1.24, 95% CI: 1.02-1.54) and VaD (HR: 1.50, 95% CI: 1.06-2.12) after adjusting for demographics, disease burden, mental status, and normal walking velocity. Among eight individual gait variables, only swing time variability SD was associated with increased risk for both incident dementia (HR: 1.35, 95% CI: 1.03-1.77) and VaD (HR: 1.78, 95% CI: 1.12-2.83). Variability and swing time SD were not significantly associated with risk of incident AD. CONCLUSIONS: Complex walking as assessed by the WWT task is a simple and pragmatic tool for assessing risk of developing dementia, especially VaD, in older adults. PMID- 29395857 TI - Turmeric for Prevention of Dementia: Food for Thought. PMID- 29395859 TI - Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone? AB - In recent years, multiple strategies for eliciting anti-tumor immunity have been developed in different clinical studies. Currently, immunotherapy was clinically validated as effective treatment option for many tumors such as melanoma, non small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Some surface receptors of immune cells, called immune checkpoint receptors, may inhibit activity of proinflammatory lymphocytes, following binding with specific ligands. Cancer cells exploit these mechanisms to inactivate tumor-infiltrating lymphocytes (TILs) to escape from immunosurveillance. Among the different tumor infiltrating immune cell populations, including leucocytes, macrophages, dendritic cells and mast cells, TILs are considered a selected population of T cells with a higher specific immunological reactivity against tumor cells than the non-infiltrating lymphocytes. In this review we will discuss the promising role of TILs as biomarkers reflecting the immune response to the tumor, describing their potential ability to predict the prognosis and clinical outcome of immunotherapy in some solid tumors. PMID- 29395858 TI - Cognitive Reappraisal Intervention for Suicide Prevention (CRISP) for Middle-Aged and Older Adults Hospitalized for Suicidality. AB - Middle-aged and older adults constitute a high suicide-risk group. Among adults aged 50 years old and older, suicide rates increased and suicide deaths almost doubled during the period from 2000 to 2015. Suicide rates are elevated for patients hospitalized for suicidality (i.e., active suicidal ideation or suicide attempt) and the 3 months post-hospitalization is the time of the highest suicide risk. Psychosocial interventions for middle-aged and older adults hospitalized for suicidality are sparse. In this article, we present the main aspects, stages, techniques and a clinical case study of Cognitive Reappraisal Intervention for Suicide Prevention (CRISP), a psychosocial intervention targeting cognitive reappraisal to reduce suicide risk in middle-aged and older adults who have been recently hospitalized for suicidal ideation or a suicide attempt. CRISP is based on the theory that hospitalization for suicidality is preceded by an emotional crisis ("perfect storm"); this emotional crisis is related to personalized (patient- and situation-specific) triggers; and identifying these personalized triggers and the associated negative emotions and providing strategies for an adaptive response to these triggers and negative emotions will reduce suicidal ideation and improve suicide prevention. CRISP therapists identify these triggers of negative emotions and use cognitive reappraisal techniques to reduce these negative emotions. The cognitive reappraisal techniques have been selected from different psychosocial interventions and the affective neuroscience literature and have been simplified for use with middle-aged and older adults. CRISP may fill a treatment need for the post-discharge high-risk period for middle-aged and older adults hospitalized for suicidality. PMID- 29395861 TI - Nivolumab plus ipilimumab in metastatic colorectal cancer. PMID- 29395860 TI - Some news from the unknown soldier, the Peyer's patch macrophage. AB - In mammals, macrophages (MF) are present in virtually all tissues where they serve many different functions linked primarily to the maintenance of homeostasis, innate defense against pathogens, tissue repair and metabolism. Although some of these functions appear common to all tissues, others are specific to the homing tissue. Thus, MF become adapted to perform particular functions in a given tissue. Accordingly, MF express common markers but also sets of tissue-specific markers linked to dedicated functions. One of the largest pool of MF in the body lines up the wall of the gut. Located in the small intestine, Peyer's patches (PP) are primary antigen sampling and mucosal immune response inductive sites. Surprisingly, although markers of intestinal MF, such as F4/80, have been identified more than 30 years ago, MF of PP escaped any kind of phenotypic description and remained "unknown" for decades. In absence of MF identification, the characterization of the PP mononuclear phagocyte system (MPS) functions has been impaired. However, taking into account that PP are privileged sites of entry for pathogens, it is important to understand how the latter are handled by and/or escape the PP MPS, especially MF, which role in killing invaders is well known. This review focuses on recent advances on the PP MPS, which have allowed, through new criteria of PP phagocyte subset identification, the characterization of PP MF origin, diversity, specificity, location and functions. PMID- 29395862 TI - Cancer in pregnancy: evidence, or still empiricism? PMID- 29395864 TI - HIPEC improves survival in stage III epithelial ovarian cancer. PMID- 29395863 TI - Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. AB - BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14 26). The proportion of patients who achieved a response was 22.5% (95% CI 10.8 38.5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co. PMID- 29395865 TI - Immune checkpoint inhibitors: the next step for thymic carcinomas. PMID- 29395866 TI - New cancer blood test developed. PMID- 29395867 TI - Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients. AB - BACKGROUND: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. METHODS: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. FINDINGS: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1.10, 95% CI 1.05-1.15), mainly related to an increase of chemotherapeutic treatment (1.31, 1.20-1.43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1.04, 95% CI 1.01-1.06) and fewer iatrogenic preterm deliveries (0.91, 0.84-0.98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3.12, 95% CI 1.45 6.70), and between taxane chemotherapy and NICU admission (OR 2.37, 95% CI 1.31 4.28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7.13, 95% CI 2.86-17.7) and thyroid cancers having lowest risk (0.14, 0.02-0.90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0.30, 95% CI 0.17 0.55). Other associations between treatment or cancer type and outcomes were less clear. INTERPRETATION: Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients. FUNDING: Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic. PMID- 29395868 TI - Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma. AB - Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh+/Notch+ suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh+++/Notch- basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch. PMID- 29395869 TI - c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. AB - A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers. PMID- 29395870 TI - Tobacco use does not influence the response to non-pharmacologic depression treatment: A secondary analysis of the Regassa randomized controlled trial. AB - Behavioural interventions show promising results among patients with mild- to moderate depression. However, whether tobacco use moderates the effects of these interventions is not known. In the present study, we examined whether patients suffering from mild-to-moderate depression differed in their response to prescribed physical exercise or internet-based cognitive behavioural therapy (ICBT) according to their current tobacco use. We conducted a secondary analysis of data from 740 participants in a multicentre randomised controlled trial comparing physical exercise, internet-based cognitive behavioural therapy and treatment as usual (Regassa study). Information on current daily tobacco use was self-reported at baseline. Linear and logistic regression were used to examine the treatments' effect (reduction in depression score) in the subgroups of tobacco users (n=154) and non-users (n=586). We found that baseline tobacco use did not significantly moderate the association between treatment type and post treatment depression severity. Both interventions (exercise and ICBT) resulted in a reduction of depression scores that was similar among non-users and users of tobacco, albeit formally statistically significant only among non-users. Physical exercise on prescription and ICBT can be used in the clinical management of depressed patients, with similar prognostic advantage among tobacco users and non users. PMID- 29395871 TI - Clinically significant personality traits in individuals at high risk of developing psychosis. AB - It is still unclear to what extent personality may influence the development of psychosis. We aimed to explore significant personality traits in individuals at high-risk (HR) for psychosis. Personalities of forty HR individuals and a matched sample of 40 healthy volunteers (HVs) were evaluated with the Millon Multiaxial Inventory (MCMI-III). They were also assessed with the Positive and Negative Symptoms Scale (PANSS), Beck Depression and Anxiety Inventories (BDI-II and BAI), Global Assessment of Functioning (GAF) and Mini-International Neuropsychiatric Interview (MINI 6.0.0). Fisher's exact test was employed to compare frequency of traits. Mann-Whitney U test and logistic regression were used to establish relationships between traits and symptoms, and the effect of age, sex and symptoms on such traits. Most HR individuals (97.5%) had at least one significant trait; 75% had personality disorders, mainly depressive, borderline or schizotypal. Only histrionic and narcissistic traits were more prevalent in HVs. Negative symptoms were related to schizoid and paranoid traits. Depression was more severe with borderline traits. Most HR individuals (67.6%) had more than one DSM-IV Axis I diagnosis, mainly depressive/anxiety disorders. Transition rate was low (5%). Certain personality profiles may not be markers for conversions to psychosis but contribute to high morbidity in HR individuals. PMID- 29395872 TI - 27 ways to meet PTSD: Using the PTSD-checklist for DSM-5 to examine PTSD core criteria. AB - Posttraumatic stress disorder (PTSD) has been criticized for including symptoms that substantially overlap with other depression and anxiety disorders. To address this concern, Brewin et al. (2009) reformulated the diagnosis around a core symptom set. Although several studies have examined the utility of the core criteria in predicting diagnostic status, none have done so using a self-report screening instrument. The sample included 617 veterans presenting for outpatient psychological services. As a part of the intake process, veterans completed the PTSD Checklist for DSM-5 (PCL-5) and were assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). Veterans meeting core criteria on the PCL-5 were over 22 times more likely to meet PCL-5 diagnosed PTSD than veterans who met the core criteria on the PCL-5 but did not meet PCL-5 diagnosed PTSD (OR = 22.94; CI [12.76, 41.25]). Further, veterans who met core criteria on the PCL-5 were over 2 times more likely (OR = 2.34; 95.0% CI [1.53, 3.59]) to meet CAPS-5 diagnosed PTSD than veterans who met the core criteria on the PCL-5 but did not meet CAPS-5 diagnosed PTSD. Findings from the current study have implications for the assessment and classification of PTSD. PMID- 29395873 TI - A meta-analytic approach to genes that are associated with impaired and elevated spatial memory performance. AB - Spatial memory deficits are a common hallmark of psychiatric conditions, possibly due to a genetic predisposition. Thus, unravelling the relationship between genes and memory might suggest novel therapeutic targets and pathogenetic pathways. Genetic deletions are known to lead to memory deficits (post-deletion "forgetfulness" genes, PDF), or, in few instances to improve spatial memory (post deletion "hypermnesic" genes, PDH). To assess this topic, we performed a meta analytic approach on memory behavior in knock-out mice. We screened 300 studies from PubMed and retrieved 87 genes tested for possible effects on spatial memory. This database was crossed with the Allen Brain Atlas (brain distribution) and the Enrichr (gene function) databases. The results show that PDF genes have higher expression level in several ventral brain structures, particularly the encephalic trunk and in the hypothalamus. Moreover, part of these genes are implicated in synaptic functions. Conversely, the PDH genes are associated to G-protein coupled receptors downstream signalling. Some candidate drugs were also found to interfere with some of the PDH genes, further suggesting that this approach might help in identifying drugs to improve memory performance in psychiatric conditions. PMID- 29395874 TI - Association between bipolar disorder and subsequent traumatic brain injury in patients who received inpatient treatment. AB - Mental disorders may confer a high risk of traumatic brain injury, but only rare studies have investigated mood disorders. This nationwide cohort study compared the risk of traumatic brain injury in patients with and without bipolar disorder. We compared 1017 patients with bipolar disorder who received inpatient treatment and 9080 compared patients. The annual incidence rate of traumatic brain injury was calculated as the number of new cases divided by the total number of person years in the available records. The incidence of subsequent traumatic brain injury was significantly higher in the bipolar group than in control group. The adjusted hazard ratio for those with multiple hospitalizations was higher than the counterpart. Except for patients in the 50-59-year age group, those in all other age groups had higher risks of traumatic brain injury. Our findings reveal a higher risk of traumatic brain injury in patients with bipolar disorder. Patients with recurrent hospitalization and multiple psychotropic use had an increased risk of traumatic brain injury. Age may modify the risk of traumatic brain injury, with a higher risk in middle-aged patients. PMID- 29395875 TI - Motives for physical activity in the adoption and maintenance of physical activity in men with alcohol use disorders. AB - Within the self-determination theory and the trans-theoretical model (stages of change) frameworks, we investigated motives for physical activity adoption and maintenance in men with alcohol use disorder (AUD). Fifty Ugandan patients completed the Behavioral Regulation in Exercise Questionnaire-3 (BREQ-3) to assess exercise motives, the Patient-centred Assessment and Counselling for Exercise (PACE) to determine stage of change and the Alcohol Use Disorders Identification Test. The relationship between motives for physical activity and stage of change was investigated using ANOVA with post-hoc Scheffe tests. Multivariate analyses found significantly higher levels of introjected, identified and integrated motivation in the action and maintenance stage versus the pre-action stage. There were no differences in intrinsic motivation between the stages of change. Our results suggest that in order to adopt and maintain an active lifestyle the most important source of motivation comes from the benefits that may be obtained rather than from the inherent pleasure or challenge associated with it. The study provides a platform for future research to investigate the importance of autonomous motivation within physical activity interventions for people with AUD. PMID- 29395876 TI - Motivation deficits in individuals with social anhedonia. AB - Patients with schizophrenia have been reported to exhibit anhedonia, a reduced hedonic capacity and deficits in motivation for reward pursuit. However, it is unclear whether these deficits also exist in at-risk individuals prone to psychosis or not. The present study compared 26 individuals with social anhedonia and 28 healthy controls using a grip Effort-based Pleasure Experience Task (E PET). The findings showed that individuals with social anhedonia did not increase their hard task choices with the elevation of reward magnitude and probability while healthy controls did. Higher reward probability and magnitude did not lead to more anticipatory pleasure in individuals with social anhedonia. The mean anticipatory pleasure experience ratings in individuals with social anhedonia were significantly lower than controls. Our results suggest that individuals with social anhedonia already exhibit motivational deficits during reward pursuit. PMID- 29395877 TI - Musical scaffolding and the pleasure of sad music: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29395878 TI - Six degrees of depolarization: Comment on "Network science of biological systems at different scales: A review" by Marko Gosak et al. PMID- 29395879 TI - Mind the physics: Physics of mind: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by Felix Schoeller, Leonid Perlovsky, and Dmitry Arseniev. PMID- 29395880 TI - Does the Kids Cafe Program's Nutrition Education Improve Children's Dietary Intake? A Pilot Evaluation Study. AB - OBJECTIVE: To evaluate the Kids Cafe Program (KCP) nutrition education and assess its impact on children's diet quality and body mass index (BMI) percentile. DESIGN: An experimental design consisting of pretest-posttest comparison groups using mixed methods to evaluate a 6-session nutrition education intervention. SETTING: Four Boys and Girls Club sites PARTICIPANTS: A total of 120 9- to 12 year-old children in the KCP (60 intervention and 60 comparison); 89% completed posttest evaluations. INTERVENTION: Trained KCP site staff taught the nutrition education curriculum at intervention sites. MAIN OUTCOME MEASURES: Healthy Eating Index-2010 using 24-hour dietary recall data (primary) and BMI percentile (secondary) ANALYSIS: Repeated-measures mixed-effects modeling RESULTS: Mean age of children was 10.2 years; mean BMI percentile was about 79; 95% were from food insecure households. The total Healthy Eating Index-2010 score for both groups at baseline and posttest ranged from 50 to 60. At posttest, compared with baseline scores, children from both groups scored significantly lower for total vegetables, and greens and beans; the intervention group children had significantly higher sodium scores. Process evaluation indicated that 60-minute lecture-based sessions were too long after children were in school all day. CONCLUSION: This pilot study suggests that the KCP nutrition education curriculum needs improvement. Further research based on behavioral constructs is needed to refine the curriculum to encourage healthier food choices among children and using the MyPlate and the 2015-2020 Dietary Guidelines for Americans. PMID- 29395882 TI - Bowel obstruction due to ingestion of a water-absorbing bead. AB - Foreign body ingestion is a common pediatric complaint. Most foreign bodies pass spontaneously through the gastrointestinal tract, but bowel obstruction is a rare complication that can occur. We report a case of a 14-month-old infant with complete bowel obstruction due to ingestion of a polymer bead used for botanical arrangements. A laparotomy was performed to remove the object, resolving the symptoms. Polymer beads are brightly coloured and are of a size that is easy to swallow by very young children, increasing the risk of accidental ingestion. They increase in size over a short period of time during their passage through the gastrointestinal tract, causing significant morbidity. PMID- 29395881 TI - Postdiarrheal hemolytic and uremic syndrome with severe multiorgan involvement and associated early risk factors. AB - AIM: Identifying early clinical and biological factors associated with severe forms of postdiarrheal hemolytic uremic syndrome (D+HUS) that may help practitioners determine appropriate treatment. METHODS: This retrospective study was conducted in 49 children with D+HUS between 2001 and 2011. Severe forms were defined as occurrence of one of the following conditions: death, major neurological involvement, cardiovascular involvement, and/or the presence of sequelae (neurological, cardiovascular, pancreatic, or renal). RESULTS: During the acute phase, 35 children exhibited at least one type of extrarenal involvement including 13 severe forms with a median delayed occurrence after admission of 4.5 days (range: 1-8) for comatose children and 5 days (range: 2-6) for cardiovascular involvement; 32 children required dialysis and three died. In multivariate analysis, (i) major neurological involvement (n=13), (ii) dialysis (n=32), and (iii) sequelae (n=12) were associated with (i) fever during the prodromal phase requiring dialysis at admission, (ii) C-reactive protein level (CRP) >22mg/L at admission, and (iii) major neurological involvement and a white blood cell count (WBC)>20*103/mm3 during the acute stage, respectively. CONCLUSIONS: D+HUS is a multiorgan disease with a delayed occurrence of life threatening extrarenal organ involvement. Severe forms appear to be associated with early biological and clinical inflammatory parameters. PMID- 29395883 TI - [Investigation of tall stature in children: Diagnostic work-up, review of the main causes]. AB - Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than+2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents' height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes. PMID- 29395884 TI - [Changes in clinical practice related to the arrival of next-generation sequencing in the genetic diagnosis of developmental diseases]. AB - INTRODUCTION: The arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses. METHODS: Geneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken. RESULTS: Of those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures. DISCUSSION: The survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort? CONCLUSION: It is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine. PMID- 29395885 TI - [Dermatological features of auto-inflammatory recurrent fevers]. AB - Auto-inflammatory diseases are characterized by unexplained and recurrent attacks of systemic inflammation often involving the skin, joints, or serosal membranes. They are due to a dysfunction or dysregulation of the innate immunity, which is the first line of defense against pathogens. Early recognition of these diseases by the clinician, especially by pediatricians encountering such pathologies in pediatric patients, is primordial to avoid complications. Skin manifestations, common in most auto-inflammatory diseases, are helpful for prompt diagnosis. After a brief physiopathological review, we will describe auto-inflammatory recurrent fevers by their main dermatological presentations: urticarial lesions, neutrophilic dermatoses, panniculitis, other maculopapular eruptions, dyskeratosis, skin vasculitis, and oral aphthous. We finally suggest a decision tree to help clinicians better target genetic exams in patients with recurrent fevers and dermatological manifestations. PMID- 29395886 TI - [Drug administration to pediatric patients: Evaluation of the nurses' preparation habits in pediatric units]. AB - In hospitals, the nursing staff is often confronted with the problem of the preparation and administration of drugs for their pediatric patients because of the lack of indication, pediatric dosage, and appropriate galenic form. The goal of this study was to give an overview of the nurses' preparation habits in pediatric units and highlight their daily problems. This single-center prospective study was conducted through an observation of the nursing staff during the drug preparation process in medicine, surgery and intensive care units. We included 91 patients (55 boys and 36 girls), with an average age of 6.3 years (youngest child, 10 days old; oldest child, 18 years old). We observed a mean 2.16 drug preparations per patient [1-5]. We collected 197 observation reports regarding 66 injectable drugs and 131 oral drugs (71 liquid forms and 60 solid forms). The majority of these reports concerned central nervous system drugs (63/197), metabolism and digestive system drugs (50/197), and anti infective drugs (46/197). The study highlights the nurses' difficulties: modification of the solid galenic forms, lack of knowledge on oral liquid form preservation or reconstitution methods, withdrawal of small volumes, and vague and noncompliant labeling. This study led to the creation of a specific working group for pediatrics. This multidisciplinary team meets on a regular basis to work toward improving the current habits to both simplify and secure drug administration to hospitalized children. PMID- 29395887 TI - Palivizumab administration in preterm infants in France: EPIPAGE-2 cohort study. AB - BACKGROUND: Several countries, including France, have restricted the indications for monoclonal antibodies directed against respiratory syncytial virus (RSV) compared to the marketing authorization (MA). No new data concerning use of palivizumab on a national scale have been published since the 2007 update of the national guidelines. OBJECTIVES: To describe palivizumab administration for RSV prophylaxis during the first RSV season in infants born prematurely in France in 2011. METHODS: Infants from the national population-based cohort EPIPAGE-2 born at<=34 weeks' gestation, discharged home before 31 March 2012 and followed-up at 1year were included. The RSV season ran from 1 October 2011 to 31 March 2012. Prophylaxis was deemed "initiated" if the infant had received at least one dose of palivizumab during this period and "complete" if it had received at least five doses or as many doses as the number of exposed months. The reference documents were the MA and French Transparency Committee guidelines (TC). RESULTS: Prophylaxis was indicated in 3586 of 3608 infants (99.7%) according to the MA and 1315 of 3608 (16.7%) according to the TC. A total of 1906 infants (26.6%) received at least one dose of palivizumab. The overall rate of conformity with TC indications was 85%, but was lower for infants born at 27-32 weeks' gestation. The rate of complete prophylaxis was 77.2%. The factors associated with prophylaxis initiation were low gestational age, low birthweight, high maternal educational level, type of neonatal unit, and date at discharge. Factors associated with complete prophylaxis were respiratory impairment, high educational level, and characteristics related to living conditions (absence of siblings at home, type of childcare). CONCLUSIONS: Palivizumab administration in France generally conformed with TC guidelines, but could be further improved for infants born at 27-32 weeks' gestation without bronchopulmonary dysplasia. PMID- 29395888 TI - HIV infection in children as an example of chronic disease management in French speaking Africa. PMID- 29395889 TI - Sudden unexpected infant death: Time for integrative national registries. PMID- 29395890 TI - Newborn follow-up after discharge from the maternity unit: Compliance with national guidelines. AB - BACKGROUND: In the context of shorter hospital stays in maternity units, in 2014 the French health authorities issued guidelines for newborn follow-up after discharge from maternity units. A medical visit is recommended between the 6th and 10th day of life, as are home visits from midwives. This study was designed to evaluate compliance with these guidelines. METHODS: The study was observational, prospective, multicenter, and was conducted in March and April 2015 in three maternity units in northern France that participate in the Baby Friendly Hospital Initiative (BFHI). Follow-up practices (medical visit between the 6th and 10th day, home visits from a midwife) and demographic, social, and medical data were recorded during the stay in the maternity unit, and through a phone interview 1 month later, in singleton term-born infants. RESULTS: The study population included 108 mother-infant pairs. The recommended medical visit was effectively performed by a physician between the 6th and 10th day of life for 20 newborns (19%) (95% CI: [11; 26]). During the 1st month, at least one home visit from a midwife was recorded for 96 mother-infant pairs (89%). The only factor positively correlated with a medical visit between the 6th and 10th day was the mother's choice, made early during the hospital stay and independently of the real length of stay, for early discharge from the maternity unit. CONCLUSION: Compliance with national guidelines was poor for the recommended medical visit between the 6th and 10th day of life. Information needs to be improved. PMID- 29395891 TI - Hemodynamic support of a 15-year-old waiting for a heart transplant: Is there a role for levosimendan in pediatric heart failure? AB - Decompensated heart failure in children requires rapid and aggressive support. In refractory cases, invasive supportive care is essential to ensure cardiac output. This results in lengthy pediatric intensive care unit (PICU) stays, secondary morbidity, and high cost. Levosimendan may help palliate the pitfalls encountered with the usual treatment. It has been shown to improve hemodynamics and decrease morbidity and mortality from heart failure in adult trials and pediatric cohorts. We report the case of a 15-year-old boy with dilated cardiomyopathy and refractory ventricular dysfunction who was weaned from continuous inotropes and discharged from the PICU with levosimendan while waiting for heart transplantation. PMID- 29395892 TI - Toxicological and pharmacological profiling of organically and non-organically cultivated Cymbopogon citratus. AB - BACKGROUND: With the rapid depletion of forests, impairing the availability of raw drugs, Ayurveda, has reached a very critical phase. Consequently, cultivation of medicinal plants is essential to ensure their availability to the industry. In view of the above concept, organic farming of medicinal plants needs scientific validity. OBJECTIVES: The present study includes the organic and non-organic cultivation of Cymbopogon citratus, followed by toxicological and pharmacological profiling of extracts. MATERIALS AND METHODS: C. citratus was simultaneously cultivated organically (OCC) and non-organically (NCC). Toxicity profile of aqueous extracts was recorded on prokaryotes using bioluminescent bacteria, Vibrio harveyi and evaluated its type 2 anti-diabetic activity. RESULTS: OCC have shown the higher mean values of height, number of germplasms and root lengths compared to NCC. The higher level of toxicity was shown by NCC with decrease in bioluminescence with increasing concentration of extract. In acute type 2 anti diabetic study, OCC showed prominent decrease in blood glucose at postprandial condition (6th h) (48.86% OCC-200). The order of sub-chronic anti-diabetic activity was observed as positive control > OCC-200 > NCC-200, while OCC at 200 mg/kg corrected the altered lipid profile and antioxidant status with significant increase in body weights of animals. Histopathological examination of pancreas showed the enlargement of pancreatic islets and formation of neo islets with degenerative changes in OCC treated animals. CONCLUSION: The study confirms that organically grown C. citratus is better in terms of nourishment, biological activity and safety measures. PMID- 29395893 TI - Effect of Nadi svedana with simultaneous passive stretching on correction of sandhijadya. AB - Severe knee flexion contracture greater than 80 degrees is rare and challenging to manage. It is a common complication which occurs after a prolonged course of the rheumatoid arthritis. The case was a 45 year old female patient of Ama vata (rheumatoid arthritis) with sandhijadya and sankoca (contracture deformity) who was hospitalized for 2 months. She was unable to walk since 1 year due to contracture of both knee joints. The patient came on a wheel chair and was unable to walk even with support. She was advised for contracture repair surgery which she refused. After hospitalization she was treated with Nadi svedana twice a day for 20 min each. Simultaneously, passive stretching for 45 s in every 5 min interval was done. She was treated for 2 months. The patient was instructed to continue other Ayurvedic remedies given as the Ama vata (rheumatoid arthritis) treatment. After Nadi svedana, goniometric assessment of the knees contracture was performed every week. She got satisfactory result in stiffness and pain and has been able to walk with support. Extension of both knee joints has improved up to 20 degrees with increased range of motion. Her height has also been increased up to 1.5 cm due to improvement in the extension of the knee joints with better feeling in daily activities during 3 months of follow-up period. PMID- 29395894 TI - Effects of yogic breath regulation: A narrative review of scientific evidence. AB - Pranayama or breath regulation is considered as an essential component of Yoga, which is said to influence the physiological systems. We present a comprehensive overview of scientific literature in the field of yogic breathing. We searched PubMed, PubMed Central and IndMed for citations for keywords "Pranayama" and "Yogic Breathing". The search yielded a total of 1400 references. Experimental papers, case studies and case series in English, revealing the effects of yogic breathing were included in the review. The preponderance of literature points to beneficial effects of yogic breathing techniques in both physiological and clinical setups. Advantageous effects of yogic breathing on the neurocognitive, psychophysiological, respiratory, biochemical and metabolic functions in healthy individuals were elicited. They were also found useful in management of various clinical conditions. Overall, yogic breathing could be considered safe, when practiced under guidance of a trained teacher. Considering the positive effects of yogic breathing, further large scale studies with rigorous designs to understand the mechanisms involved with yogic breathing are warranted. PMID- 29395895 TI - Melioration of anti-hepatotoxic effect by Lichen rangiferinus against alcohol induced liver damage in rats. AB - BACKGROUND: Reindeer lichen, Lichen rangiferinus syn. or Cladonia rangiferina (L.) F. H. Wigg. (Cladoniaceae) has been traditionally reported as a remedy to treat fever, colds, arthritis as well as convulsions, liver infections, coughs, constipation, and tuberculosis. The current study is aimed at rectification of alcohol induced liver damage by the use of L. rangiferinus extract. OBJECTIVES: The aim of the study was to compare some biochemical markers for liver injury and hematological indices in normal untreated rats and treated rats. MATERIAL AND METHODS: The study was performed using male Wistar rats. Animals were categorized into five groups, negative control group (normal diet only), treated groups (2 groups were lichen treated along with 10% ethanol & 1 group was only ethanol treated) and positive control group (Silymarin+10% ethanol) of six animals in each group. Biochemical markers for liver injury and hematological indices of all animals were measured using standard diagnostic tools. The animals were then sacrificed and livers were sent to the pathology lab for histopathological analysis. RESULTS: Lichen extract showed a significant restoration of altered biochemical parameters towards normal in both in vitro and in vivo conditions. The total phenolic and flavonoid content of the LRE was found to be 21.78 MUg PE/mg of extract and 5.13 MUg RE/mg of extract respectively. The IC50 values for atranorin and fumarprotocetraric acid were found to be 128.48 and 218.46 mg/mL respectively. Reducing power of the extract was found to be quite significant. After administration of lichen extract, endothelial cells were less injured around central vein and number of fat vacuoles was also lesser in hepatocytes. CONCLUSIONS: Conclusively, treatment with lichen extract assuages alcohol-related damage and guards hepatic tissue from alcohol-induced toxicity. PMID- 29395896 TI - Pilot Study of the Safety and Efficacy of Gallbladder Cryoablation in a Porcine Model: Midterm Results. AB - PURPOSE: To investigate the midterm safety and efficacy of computed tomography (CT)-guided percutaneous gallbladder cryoablation in swine. MATERIALS AND METHODS: Three swine underwent gallbladder cryoablation. Cryoprobes were positioned percutaneously at the gallbladder margins or within the gallbladder lumen under CT guidance. Two freeze/thaw cycles were performed. One animal was euthanized on postprocedure day 4 as a result of hematemesis unrelated to the ablation. The other 2 animals were euthanized at postprocedure days 30 and 48, respectively. The gallbladder and bile ducts were resected and examined microscopically. RESULTS: Gallbladder cryoablation was completed with freeze/thaw cycle durations of 7.5-10 minutes (mean, 9.4 min +/- 1.3) and ablation margins of 5.8-11.5 mm (mean, 7.8 mm +/- 1.9). No nontarget ablation was observed. Laboratory values at postprocedure day 4 and the time of euthanasia were within normal limits. Two of 3 animals thrived and exhibited appropriate activity and weight gain. Contrast-enhanced CT immediately before euthanasia demonstrated delayed linear enhancement of the gallbladder wall. Gross inspection at autopsy revealed fibrotic-appearing gallbladders. Cholecystography revealed no communication to the biliary tree. Histologic examination demonstrated complete gallbladder wall fibrosis. Autopsy of the animal euthanized on day 4 revealed a gastric mucosal ulcer distant from the ablation site with no gastric serosal injury. CONCLUSIONS: Gallbladder cryoablation is a promising alternative to surgical cholecystectomy, with complete transmural gallbladder wall fibrosis and cystic duct occlusion seen at 30 and 48 days in swine. Further studies are required to establish procedural safety and long-term efficacy. PMID- 29395897 TI - #InterventionalRadiology. AB - PURPOSE: To characterize the interventional radiology Twitter network by analyzing tweets bearing the #IRad hashtag. MATERIALS AND METHODS: A total of 61,055 consecutive tweets bearing the hashtag #IRad composed by 5,704 Twitter users from January 8, 2015 to October 13, 2017 were analyzed. Twitter analytics, including activity metrics, content analysis, user characteristics, engagement, and network analysis, were obtained with the use of Symplur Signals, a health care social media analytics platform. RESULTS: The number of tweets bearing the #IRad hashtag, the number of users, and the number of impressions increased by 124%, 76%, and 102%, respectively, over the past year. Regarding tweet content, 4,571 tweets (7.5%) reported new or innovative topics and 4,040 tweets (6.6%) pertained to patients; 19,409 (31.8%) tweets contained at least 1 image and 15,245 tweets (25.0%) included links to websites or journals. Embolization, ablation, and stent placement were commonly discussed topics. Endoscopy, transarterial chemoembolization, uterine artery embolization, and prostate artery embolization discussions were trending more commonly. As for engagement, there were 39,953 retweets (65.4%), 50,452 mentions (82.6%), and 1,704 replies (2.8%). Physicians and patients authored 29,182 (47.8%) and 127 (0.8%) tweets, respectively. Network analysis demonstrated advocate, provider, and media organizations, and physicians as the most active participants using the #IRad hashtag on Twitter. CONCLUSIONS: The use of the #IRad hashtag by interventional radiologists is growing rapidly, with the majority of discussions involving medical professionals and medical-related organizations. PMID- 29395899 TI - Fistulography of a Patent Hemodialysis Access: When Not to Treat and Implications for Establishing a Nontreatment Rate. AB - PURPOSE: To establish a rate of nonintervention in patients referred for hemodialysis access fistulography and to report clinical and fistulographic variables associated with nonintervention. MATERIALS AND METHODS: Encounters for fistulography were reviewed from 2001 to 2016 to determine annual rates of nontreatment over 15 years. Next, an access database was used to retrospectively identify patients undergoing fistulography from 2010 to 2016. Patients who underwent fistulography without intervention (angioplasty or stent placement) served as the nontreatment group (NTG; n = 76). Patients who underwent fistulography with intervention served as the control group (CG; n = 77). Patients with thrombosed accesses were excluded. Clinical indications for intervention and physical examination findings were correlated with fistulography. Need for subsequent percutaneous intervention was recorded. RESULTS: Annual nontreatment rates ranged from 3% to 14% (median, 10%). Preprocedure thrill was encountered in 45 patients in the NTG (59%) vs 6 in the CG (7.8%; P < .01). Aneurysm as indication for fistulography was more common in the NTG than the CG (19 [25%] vs 4 [5%]; P < .01). The NTG had a higher proportion of aneurysms noted on fistulography as well (38 [50%] vs 19 [25%]; P < .01). The CG had a higher proportion of patients needing subsequent percutaneous intervention vs the NTG (73 [96%] vs 38 [50%]; P < .001). CONCLUSIONS: A suggested nonintervention rate for hemodialysis access fistulography is 10%. Patients in the NTG were more likely to have a thrill on physical examination or to present with aneurysms as the clinical indicator. NTG patients were less likely to require subsequent percutaneous intervention. PMID- 29395898 TI - Impact of Prior Hepatectomy History on Local Tumor Progression after Percutaneous Ablation of Colorectal Liver Metastases. AB - PURPOSE: To test the hypothesis that, given the current resection eligibility criteria for colorectal liver metastasis (CLM), prior hepatectomy would be associated with improved local tumor control and survival after percutaneous ablation of CLMs. MATERIALS AND METHODS: This single-institution retrospective study included 82 consecutive patients with 97 CLMs treated with ablation (radiofrequency ablation, microwave ablation, or cryoablation) from January 2005 to December 2014. Local tumor progression-free survival (LTPFS), recurrence-free survival (RFS) at any organ, and overall survival (OS) were calculated using the Kaplan-Meier method from the time of ablation and compared between patients with (n = 49) and without (n = 33) prior hepatectomy. Cox regression models were used to identify LTPFS predictors. RESULTS: Median overall follow-up period was 28 months (range, 4.5-132 months). Three-year actuarial LTPFS (patient level: 73% vs 34%, P < .001) was significantly higher in patients with than without prior hepatectomy, respectively. Similarly, 3-year RFS (23% vs 9.1%, P = .026) and OS (78% vs 48%, P = .003) were improved in patients with prior hepatectomy. At multivariate analysis, predictors of worse LTPFS were: no prior hepatectomy (hazard ratio [HR] 2.35, 95% confidence interval [CI] 1.02-5.45; P = .045), minimal ablation margin < 5 mm (HR 2.4, 95% CI 1.18-4.87; P = .016), and RAS mutant tumor (HR 2.65, 95% CI 1.18-5.94; P = .019). CONCLUSIONS: Prior hepatectomy for CLMs is associated with improved local tumor control after percutaneous ablation of post-resection-developed CLMs. PMID- 29395900 TI - Perceptions of Quality in Interventional Oncology. AB - PURPOSE: To inductively characterize perceptions of quality in interventional oncology (IO) based on values and experiences of patients and referring providers. MATERIALS AND METHODS: Brief ethnographic interviews were completed with referring providers and patients before and after a variety of liver directed procedures about their experiences, concerns, and perceptions of IO services at a single institution. Constructivist grounded theory was used to systematically analyze interview transcripts for themes until thematic saturation was achieved. All transcripts were analyzed by a reviewer with 3-years of experience performing such analyses, and 50% were randomly selected to be coded by 2 additional blinded reviewers. Interreviewer agreement was assessed via Cohen kappa. RESULTS: Interviews with 22 patients (mean age, 65 y +/- 13; 9 women) and 12 providers (mean age, 54 y +/- 9; 6 women) were required to reach and confirm thematic saturation. Interreviewer agreement for interview themes was excellent (kappa = 0.78; P < .001). Perceptions of high-quality IO care relied on interventional radiologists being responsive, friendly, and open; engaging in multidisciplinary collaboration; having thoughtful, dedicated support staff; and facilitating well-coordinated care after procedures and follow-up more than technical expertise and periprocedural comfort. Patient and provider perceptions of quality differed, but disjointed care after procedures was the most common critique among both groups. CONCLUSIONS: An inductive qualitative approach effectively characterized specific aspects of perceptions of high-quality IO care among patients and referring providers. PMID- 29395901 TI - Interventional Radiology-Operated Cholecystoscopy and Cholecystolithotripsy: A Guide for Interventionalists. PMID- 29395902 TI - Safety and Outcomes of Transradial Access in Patients with International Normalized Ratio 1.5 or above. AB - PURPOSE: To examine the safety and outcomes for patients undergoing transradial noncoronary interventions with international normalized ratio (INR) >=1.5. MATERIALS AND METHODS: A retrospective review of 2,271 transradial access (TRA) cases performed from July 2012 to July 2016 was conducted. Criteria for inclusion were moderate bleeding risk cases with preprocedure INR >=1.5. Within the study period, there were 176 moderate bleeding risk procedures (transarterial chemoembolization: 70/176 [39.8%]; Barbeau B: 121/176 [68.8%]; 5-F sheath: 157/176 [89.2%]) performed on 122 patients (age 61.6 +/- 12.1 years, 68.9% male, body mass index 28.0 kg/m2) with INR >=1.5. RESULTS: Technical success was achieved in 98.9% of cases. Grade 1/2 hematomas developed in 10 cases (5.7%). Age >=65 years (P = .042) and female sex (P = .046) were predictive of access site bleeding complications. Fresh frozen plasma (FFP) transfusion was administered in 11.4% of cases (n = 20). Baseline INR and creatinine were significantly different between transfused and nontransfused cases (P values .006 and .028, respectively). Minor access site bleeding occurred in 3/20 cases (15%) receiving prior FFP transfusion and 7/156 nontransfused cases (4.5%), with no significant difference between these 2 groups (P = .072). CONCLUSIONS: TRA in patients with elevated INR appears to be safe in our experience. Age >=65 years and female sex were associated with increased incidence of access site bleeding. Although INR correction was not standardized in this cohort, preprocedure FFP transfusion did not decrease bleeding complications. PMID- 29395903 TI - Pharmacists' views on the development of asthma pharmaceutical care model in Indonesia: A needs analysis study. AB - BACKGROUND: Over recent years the pharmacy profession in Indonesia has adopted a stance of pharmaceutical care to expand their scope of practice. Asthma management presents a key opportunity for pharmacists to test expanded roles in health service provision. There is however no exploratory work on the willingness, experience or future practice needs of Indonesian pharmacists in the realm of specialised asthma service provision. OBJECTIVES: The objectives of this study were to explore Indonesian pharmacists' experiences, perspectives, and needs regarding the provision of pharmaceutical care for asthma patients in Indonesia. METHODS: The study utilised conventional qualitative content analyses with two stages, i.e.: deductive analyses and inductive concept development. Data were collected using Focus Group Discussion (FGD) Method. FGDs were conducted using a topic guide and by facilitators trained in FGD conduct. FGDs were audio recorded and transcribed verbatim prior to analysis. A maximum variation sampling methods targeted pharmacist across various settings of practice within Yogyakarta Indonesia. RESULTS: Nine focus groups with 103 pharmacist participants were conducted, with an average of 11 participants in each group. Inductively derived concepts that emerged included: willingness to adopt asthma service provision roles, pragmatism in recognising essential barriers/facilitators in adopting such roles, reflections regarding practice gaps and barriers to interprofessional collaboration mainly in relation to doctors. Inductive data analysis indicated clear differences in responses between hospital and non-hospital pharmacists. Key barriers to service provision included lack of training, lack of supportive professional frameworks, time and lack of reimbursement channels for services. Participants urged for a visionary leadership to facilitate pharmacists' role expansion into health services provision in Indonesia. CONCLUSIONS: Indonesian pharmacists were willing to adopt change and reported universally recognised barriers and facilitators to changing roles, especially in the provision of asthma care. Given this universality of pharmacists expressions, it may be suggested that the experience of researchers and academics who have expended time and effort in developing and implementing asthma care models in other countries should be, to some extent, transplanted to regions where pharmacy organisations are now considering adopting roles additional to medicines supply. PMID- 29395904 TI - Design of an automated staff scheduling system for an independent pharmacy. AB - BACKGROUND: In service industries, employee salaries and wages often constitute the largest portion of the costs to the company. This is very true in the case of an independent pharmacy, which employs pharmacists and pharmacy technicians. Thus, for pharmacies to cost effectively meet the increasing demand for pharmaceuticals, it is crucial that pharmacy managers efficiently allocate the pharmacy staff's time. METHOD: Through a case study, this paper demonstrates the use of an Excel VBA based on a mathematical model to schedule the staff of an independent pharmacy. The whole year data was used in this study. After collection of whole year's data, the number of prescriptions to be filled for each day by hour of hour of the day were sourced and classified. RESULTS: It is indicated that the pharmacy employees' time could be more efficiently assigned to meet the demand of the pharmacy. The benefit of modeling the pharmacy employees at this pharmacy is based on the data (the number of total prescriptions filled on Friday in March) with the following results; 12 h shifts are covered where one employee must be between 04:00-16:00, two employees between 06:00-18:00, one employee between 07:00-19:00 and one employee between 15:00-03:00. CONCLUSION: In this study a basic model was presented that can be used schedule pharmacy employees in an independent pharmacy and solved by Excel VBA. This model can be further extended to meet the needs of a specific pharmacy. PMID- 29395905 TI - High resolution in-vivo diffusion imaging of the human hippocampus. AB - The human hippocampus is a key target of many imaging studies given its capacity for neurogenesis, role in long term potentiation and memory, and nearly ubiquitous involvement in neurological and psychiatric conditions. Diffusion tensor imaging (DTI) has detected microstructural abnormalities of the human hippocampus associated with various disorders, but acquisitions have typically been limited to low spatial resolution protocols designed for whole brain (e.g. > 2 mm isotropic, >8 mm3 voxels), limiting regional specificity and worsening partial volume effects. The purpose here was to develop a simple DTI protocol using readily available standard single-shot EPI at 3T, capable of yielding much higher spatial resolution images (1 x 1 x 1 mm3) of the human hippocampus in a 'clinically feasible' scan time of ~6 min. A thin slab of twenty 1 mm slices oriented along the long axis of the hippocampus enabled efficient coverage and a shorter repetition time, allowing more diffusion weighted images (DWIs) per slice per unit time. In combination with this strategy, a low b value of 500 s/mm2 was chosen to help overcome the very low SNR of a 1 x 1 x 1 mm3 EPI acquisition. 1 mm isotropic mean DWIs (averaged over 120-128 DWIs) showed excellent detail of the hippocampal architecture (e.g. morphology and digitations, sub-regions, stratum lacunosum moleculare - SLM) that was not readily visible on 2 mm isotropic diffusion images. Diffusion parameters within the hippocampus were consistent across subjects and fairly homogenous across sub-regions of the hippocampus (with the exception of the SLM and tail). However, it is expected that DTI parameters will be sensitive to microstructural changes associated with a number of clinical disorders (e.g. epilepsy, dementia) and that this practical, translatable approach for high resolution acquisition will facilitate localized detection of hippocampal pathology. PMID- 29395906 TI - A Neuronal piRNA Pathway Inhibits Axon Regeneration in C. elegans. AB - The PIWI-interacting RNA (piRNA) pathway has long been thought to function solely in the germline, but evidence for its functions in somatic cells is emerging. Here we report an unexpected role for the piRNA pathway in Caenorhabditis elegans sensory axon regeneration after injury. Loss of function in a subset of components of the piRNA pathway results in enhanced axon regrowth. Two essential piRNA factors, PRDE-1 and PRG-1/PIWI, inhibit axon regeneration in a gonad independent and cell-autonomous manner. By smFISH analysis we find that prde-1 transcripts are present in neurons, as well as germ cells. The piRNA pathway inhibits axon regrowth independent of nuclear transcriptional silencing but dependent on the slicer domain of PRG-1/PIWI, suggesting that post transcriptional gene silencing is involved. Our results reveal the neuronal piRNA pathway as a novel intrinsic repressor of axon regeneration. PMID- 29395907 TI - A Translational Repression Complex in Developing Mammalian Neural Stem Cells that Regulates Neuronal Specification. AB - The mechanisms instructing genesis of neuronal subtypes from mammalian neural precursors are not well understood. To address this issue, we have characterized the transcriptional landscape of radial glial precursors (RPs) in the embryonic murine cortex. We show that individual RPs express mRNA, but not protein, for transcriptional specifiers of both deep and superficial layer cortical neurons. Some of these mRNAs, including the superficial versus deep layer neuron transcriptional regulators Brn1 and Tle4, are translationally repressed by their association with the RNA-binding protein Pumilio2 (Pum2) and the 4E-T protein. Disruption of these repressive complexes in RPs mid-neurogenesis by knocking down 4E-T or Pum2 causes aberrant co-expression of deep layer neuron specification proteins in newborn superficial layer neurons. Thus, cortical RPs are transcriptionally primed to generate diverse types of neurons, and a Pum2/4E-T complex represses translation of some of these neuronal identity mRNAs to ensure appropriate temporal specification of daughter neurons. PMID- 29395908 TI - Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila. AB - In vertebrates and invertebrates, neurons and glia are generated in a stereotyped manner from neural stem cells, but the purpose of invariant lineages is not understood. We show that two stem cells that produce leg motor neurons in Drosophila also generate neuropil glia, which wrap and send processes into the neuropil where motor neuron dendrites arborize. The development of the neuropil glia and leg motor neurons is highly coordinated. However, although motor neurons have a stereotyped birth order and transcription factor code, the number and individual morphologies of the glia born from these lineages are highly plastic, yet the final structure they contribute to is highly stereotyped. We suggest that the shared lineages of these two cell types facilitate the assembly of complex neural circuits and that the two birth order strategies-hardwired for motor neurons and flexible for glia-are important for robust nervous system development, homeostasis, and evolution. PMID- 29395910 TI - TMC Proteins Modulate Egg Laying and Membrane Excitability through a Background Leak Conductance in C. elegans. AB - Membrane excitability is a fundamentally important feature for all excitable cells including both neurons and muscle cells. However, the background depolarizing conductances in excitable cells, especially in muscle cells, are not well characterized. Although mutations in transmembrane channel-like (TMC) proteins TMC1 and TMC2 cause deafness and vestibular defects in mammals, their precise action modes are elusive. Here, we discover that both TMC-1 and TMC-2 are required for normal egg laying in C. elegans. Mutations in these TMC proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg laying. Mechanistically, TMC proteins enhance membrane depolarization through background leak currents and ectopic expression of both C. elegans and mammalian TMC proteins results in membrane depolarization. Therefore, we have identified an unexpected role of TMC proteins in modulating membrane excitability. Our results may provide mechanistic insights into the functions of TMC proteins in hearing loss and other diseases. PMID- 29395909 TI - Localized Myosin II Activity Regulates Assembly and Plasticity of the Axon Initial Segment. AB - The axon initial segment (AIS) is the site of action potential generation and a locus of activity-dependent homeostatic plasticity. A multimeric complex of sodium channels, linked via a cytoskeletal scaffold of ankyrin G and beta IV spectrin to submembranous actin rings, mediates these functions. The mechanisms that specify the AIS complex to the proximal axon and underlie its plasticity remain poorly understood. Here we show phosphorylated myosin light chain (pMLC), an activator of contractile myosin II, is highly enriched in the assembling and mature AIS, where it associates with actin rings. MLC phosphorylation and myosin II contractile activity are required for AIS assembly, and they regulate the distribution of AIS components along the axon. pMLC is rapidly lost during depolarization, destabilizing actin and thereby providing a mechanism for activity-dependent structural plasticity of the AIS. Together, these results identify pMLC/myosin II activity as a common link between AIS assembly and plasticity. PMID- 29395911 TI - Thermal Excitation of the Mechanotransduction Apparatus of Hair Cells. AB - Although a hair bundle is normally deflected by mechanical stimuli, we found that irradiation of a hair cell from the bullfrog's sacculus with ultraviolet light causes rapid motion of the hair bundle toward its tall edge. This movement is associated with opening of mechanotransduction channels and disappears when tip links are disrupted. We localized the absorptive element responsible for the motion to the region directly below the hair bundle and measured an action spectrum similar to the absorption spectra of mitochondrial constituents. Temperature measurements revealed heating around the site of absorption; direct heating of the hair bundle confirmed that the response to light is mediated through heat. Although mechanical offsets of the hair bundle revealed that heat softens gating springs, it also acts directly to open transduction channels. This study identifies an unconventional method of hair-cell stimulation and clarifies the previously unexplained sensitivity of auditory organs to thermal stimulation. PMID- 29395912 TI - Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. AB - In contrast with numerous studies of glutamate receptor-associated proteins and their involvement in the modulation of excitatory synapses, much less is known about mechanisms controlling postsynaptic GABAA receptor (GABAAR) numbers. Using tandem affinity purification from tagged GABAAR gamma2 subunit transgenic mice and proteomic analysis, we isolated several GABAAR-associated proteins, including Cleft lip and palate transmembrane protein 1 (Clptm1). Clptm1 interacted with all GABAAR subunits tested and promoted GABAAR trapping in the endoplasmic reticulum. Overexpression of Clptm1 reduced GABAAR-mediated currents in a recombinant system, in cultured hippocampal neurons, and in brain, with no effect on glycine or AMPA receptor-mediated currents. Conversely, knockdown of Clptm1 increased phasic and tonic inhibitory transmission with no effect on excitatory synaptic transmission. Furthermore, altering the expression level of Clptm1 mimicked activity-induced inhibitory synaptic scaling. Thus, in complement to other GABAAR associated proteins that promote receptor surface expression, Clptm1 limits GABAAR forward trafficking and regulates inhibitory homeostatic plasticity. PMID- 29395913 TI - Supralinear and Supramodal Integration of Visual and Tactile Signals in Rats: Psychophysics and Neuronal Mechanisms. AB - To better understand how object recognition can be triggered independently of the sensory channel through which information is acquired, we devised a task in which rats judged the orientation of a raised, black and white grating. They learned to recognize two categories of orientation: 0 degrees +/- 45 degrees ("horizontal") and 90 degrees +/- 45 degrees ("vertical"). Each trial required a visual (V), a tactile (T), or a visual-tactile (VT) discrimination; VT performance was better than that predicted by optimal linear combination of V and T signals, indicating synergy between sensory channels. We examined posterior parietal cortex (PPC) and uncovered key neuronal correlates of the behavioral findings: PPC carried both graded information about object orientation and categorical information about the rat's upcoming choice; single neurons exhibited identical responses under the three modality conditions. Finally, a linear classifier of neuronal population firing replicated the behavioral findings. Taken together, these findings suggest that PPC is involved in the supramodal processing of shape. PMID- 29395914 TI - Integration of Visual Information in Auditory Cortex Promotes Auditory Scene Analysis through Multisensory Binding. AB - How and where in the brain audio-visual signals are bound to create multimodal objects remains unknown. One hypothesis is that temporal coherence between dynamic multisensory signals provides a mechanism for binding stimulus features across sensory modalities. Here, we report that when the luminance of a visual stimulus is temporally coherent with the amplitude fluctuations of one sound in a mixture, the representation of that sound is enhanced in auditory cortex. Critically, this enhancement extends to include both binding and non-binding features of the sound. We demonstrate that visual information conveyed from visual cortex via the phase of the local field potential is combined with auditory information within auditory cortex. These data provide evidence that early cross-sensory binding provides a bottom-up mechanism for the formation of cross-sensory objects and that one role for multisensory binding in auditory cortex is to support auditory scene analysis. PMID- 29395916 TI - Reversible Silencing of the Frontopolar Cortex Selectively Impairs Metacognitive Judgment on Non-experience in Primates. AB - Self-evaluation of one's own ignorance requires us to peer into our own mind retrospectively. Here, we found that only the bilateral frontopolar cortices (area 10) are recruited for metacognitive evaluation of non-experienced events in macaque monkeys performing metacognitive confidence judgment on memory under fMRI scanning and that targeted reversible inactivation of the localized spots in area 10 selectively impaired the confidence judgment of non-experienced events. In contrast, fMRI experiments revealed that area 10 was not recruited for metacognition of experienced events like the way that the dorsal prefrontal cortex (area 9) was and, correspondingly, the inactivation of area 10 did not impair confidence judgment of experienced events. Notably, this inactivation did not impair the ability to identify novel events by distinguishing from repetitive events. Our findings elucidate that the frontopolar cortex plays a causal role to confer not awareness of past experience in general but awareness of one's own ignorance. PMID- 29395915 TI - Different Levels of Category Abstraction by Different Dynamics in Different Prefrontal Areas. AB - Categories can be grouped by shared sensory attributes (i.e., cats) or a more abstract rule (i.e., animals). We explored the neural basis of abstraction by recording from multi-electrode arrays in prefrontal cortex (PFC) while monkeys performed a dot-pattern categorization task. Category abstraction was varied by the degree of exemplar distortion from the prototype pattern. Different dynamics in different PFC regions processed different levels of category abstraction. Bottom-up dynamics (stimulus-locked gamma power and spiking) in the ventral PFC processed more low-level abstractions, whereas top-down dynamics (beta power and beta spike-LFP coherence) in the dorsal PFC processed more high-level abstractions. Our results suggest a two-stage, rhythm-based model for abstracting categories. PMID- 29395917 TI - Modulation of Host Learning in Aedes aegypti Mosquitoes. AB - How mosquitoes determine which individuals to bite has important epidemiological consequences. This choice is not random; most mosquitoes specialize in one or a few vertebrate host species, and some individuals in a host population are preferred over others. Mosquitoes will also blood feed from other hosts when their preferred is no longer abundant, but the mechanisms mediating these shifts between hosts, and preferences for certain individuals within a host species, remain unclear. Here, we show that olfactory learning may contribute to Aedes aegypti mosquito biting preferences and host shifts. Training and testing to scents of humans and other host species showed that mosquitoes can aversively learn the scent of specific humans and single odorants and learn to avoid the scent of rats (but not chickens). Using pharmacological interventions, RNAi, and CRISPR gene editing, we found that modification of the dopamine-1 receptor suppressed their learning abilities. We further show through combined electrophysiological and behavioral recordings from tethered flying mosquitoes that these odors evoke changes in both behavior and antennal lobe (AL) neuronal responses and that dopamine strongly modulates odor-evoked responses in AL neurons. Not only do these results provide direct experimental evidence that olfactory learning in mosquitoes can play an epidemiological role, but collectively, they also provide neuroanatomical and functional demonstration of the role of dopamine in mediating this learning-induced plasticity, for the first time in a disease vector insect. PMID- 29395918 TI - Bacteria Use Collective Behavior to Generate Diverse Combat Strategies. AB - Animals have evolved a wide diversity of aggressive behavior often based upon the careful monitoring of other individuals. Bacteria are also capable of aggression, with many species using toxins to kill or inhibit their competitors. Like animals, bacteria also have systems to monitor others during antagonistic encounters, but how this translates into behavior remains poorly understood. Here, we use colonies of Escherichia coli carrying colicin-encoding plasmids as a model for studying antagonistic behavior. We show that in the absence of threat, dispersed cells with low reproductive value produce colicin toxins spontaneously, generating efficient pre-emptive attacks. Cells can also respond conditionally to toxins released by clonemates via autoinduction or other genotypes via competition sensing. The strength of both pre-emptive and responsive attacks varies widely between strains. We demonstrate that this variability occurs easily through mutation by rationally engineering strains to recapitulate the diversity in naturally occurring strategies. Finally, we discover that strains that can detect both competitors and clonemates are capable of massive coordinated attacks on competing colonies. This collective behavior protects established colonies from competitors, mirroring the evolution of alarm calling in the animal world. PMID- 29395919 TI - Form and Function in Human Song. AB - Humans use music for a variety of social functions: we sing to accompany dance, to soothe babies, to heal illness, to communicate love, and so on. Across animal taxa, vocalization forms are shaped by their functions, including in humans. Here, we show that vocal music exhibits recurrent, distinct, and cross-culturally robust form-function relations that are detectable by listeners across the globe. In Experiment 1, internet users (n = 750) in 60 countries listened to brief excerpts of songs, rating each song's function on six dimensions (e.g., "used to soothe a baby"). Excerpts were drawn from a geographically stratified pseudorandom sample of dance songs, lullabies, healing songs, and love songs recorded in 86 mostly small-scale societies, including hunter-gatherers, pastoralists, and subsistence farmers. Experiment 1 and its analysis plan were pre-registered. Despite participants' unfamiliarity with the societies represented, the random sampling of each excerpt, their very short duration (14 s), and the enormous diversity of this music, the ratings demonstrated accurate and cross-culturally reliable inferences about song functions on the basis of song forms alone. In Experiment 2, internet users (n = 1,000) in the United States and India rated three contextual features (e.g., gender of singer) and seven musical features (e.g., melodic complexity) of each excerpt. The songs' contextual features were predictive of Experiment 1 function ratings, but musical features and the songs' actual functions explained unique variance in function ratings. These findings are consistent with the existence of universal links between form and function in vocal music. PMID- 29395920 TI - TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer. AB - The mitochondrial translocase of the outer membrane (TOM) is a protein complex that is essential for the post-translational import of nuclear-encoded mitochondrial proteins. Among its subunits, TOM70 and TOM20 are only transiently associated with the core complex, suggesting their possible additional roles within the outer mitochondrial membrane (OMM). Here, by using different mammalian cell lines, we demonstrate that TOM70, but not TOM20, clusters in distinct OMM foci, frequently overlapping with sites in which the endoplasmic reticulum (ER) contacts mitochondria. Functionally, TOM70 depletion specifically impairs inositol trisphosphates (IP3)-linked ER to mitochondria Ca2+ transfer. This phenomenon is dependent on the capacity of TOM70 to interact with IP3-receptors and favor their functional recruitment close to mitochondria. Importantly, the reduced constitutive Ca2+ transfer to mitochondria, observed in TOM70-depleted cells, dampens mitochondrial respiration, affects cell bioenergetics, induces autophagy, and inhibits proliferation. Our data reveal a hitherto unexpected role for TOM70 in pro-survival ER-mitochondria communication, reinforcing the view that the ER-mitochondria signaling platform is a key regulator of cell fate. PMID- 29395921 TI - Repression of Cell Differentiation by a cis-Acting lincRNA in Fission Yeast. AB - The cell fate decision leading to gametogenesis requires the convergence of multiple signals on the promoter of a master regulator. In fission yeast, starvation-induced signaling leads to the transcriptional induction of the ste11 gene, which encodes the central inducer of mating and gametogenesis, known as sporulation. We find that the long intergenic non-coding (linc) RNA rse1 is transcribed divergently upstream of the ste11 gene. During vegetative growth, rse1 directly recruits a Mug187-Lid2-Set1 complex that mediates cis repression at the ste11 promoter through SET3C-dependent histone deacetylation. The absence of rse1 bypasses the starvation-induced signaling and induces gametogenesis in the presence of nutrients. Our data reveal that the remodeling of chromatin through ncRNA scaffolding of repressive complexes that is observed in higher eukaryotes is a conserved, likely very ancient mechanism for tight control of cell differentiation. PMID- 29395922 TI - TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes. AB - The Toll/interleukin-1 receptor (TIR) domain is the signature signaling domain of Toll-like receptors (TLRs) and their adaptors, serving as a scaffold for the assembly of protein complexes for innate immune signaling [1, 2]. TIR domain proteins are also expressed in plants, where they mediate disease resistance [3, 4], and in bacteria, where they have been associated with virulence [5-9]. In pursuing our work on axon degeneration [10], we made the surprising discovery that the TIR domain of SARM1 (sterile alpha and TIR motif containing 1), a TLR adaptor protein, has enzymatic activity [11]. Upon axon injury, the SARM1 TIR domain cleaves nicotinamide adenine dinucleotide (NAD+), destroying this essential metabolic co-factor to trigger axon destruction [11, 12]. Whereas current studies of TIR domains focus on their scaffolding function, our findings with SARM1 inspired us to ask whether this enzymatic activity is the primordial function of the TIR domain. Here we show that ancestral prokaryotic TIR domains constitute a new family of NADase enzymes. Using purified proteins from a cell free translation system, we find that TIR domain proteins from both bacteria and archaea cleave NAD+ into nicotinamide and ADP-ribose (ADPR), with catalytic cleavage executed by a conserved glutamic acid. A subset of bacterial and archaeal TIR domains generates a non-canonical variant cyclic ADPR (cADPR) molecule, and the full-length TIR domain protein from pathogenic Staphylococcus aureus induces NAD+ loss in mammalian cells. These findings suggest that the primordial function of the TIR domain is the enzymatic cleavage of NAD+ and establish TIR domain proteins as a new class of metabolic regulatory enzymes. PMID- 29395923 TI - A New Cretaceous Insect with a Unique Cephalo-thoracic Scissor Device. AB - Insects use different parts of their body to cling to mating partners, to catch prey, or to defend themselves, in most cases the mouthparts or the legs. However, in 400 million years of evolution [1, 2], specialized devices were independently acquired in several groups to adopt these tasks, as for instance modified legs in mantids, assassin bugs or stick insects [3-5], or clasping antennae of the globular springtails [6]. So far, no known species used the neck region between the head and thorax in one of these functional contexts. Here we describe females of ?Caputoraptor elegans, a very unusual, presumably predacious insect discovered in approximately 100-million-year-old [7] Burmese amber. Based on several morphological features, we conclude that this species lived in the foliage of trees or bushes. A unique feature of the new taxon is a scissor-like mechanism formed by wing-like extensions on the posterior head and corresponding serrated edges of the dorsal sclerite of the first thoracic segment. Based on the specific structure of the apparatus, we conclude that it was probably used by females to hold on to males during copulation. A defensive or prey-catching function appears less likely. A similar mechanism did not evolve in any other known known group of extant or extinct insects. PMID- 29395924 TI - Visual Features in the Perception of Liquids. AB - Perceptual constancy-identifying surfaces and objects across large image changes remains an important challenge for visual neuroscience [1-8]. Liquids are particularly challenging because they respond to external forces in complex, highly variable ways, presenting an enormous range of images to the visual system. To achieve constancy, the brain must perform a causal inference [9-11] that disentangles the liquid's viscosity from external factors-like gravity and object interactions-that also affect the liquid's behavior. Here, we tested whether the visual system estimates viscosity using "midlevel" features [12-14] that respond more to viscosity than other factors. Observers reported the perceived viscosity of simulated liquids ranging from water to molten glass exhibiting diverse behaviors (e.g., pouring, stirring). A separate group of observers rated the same animations for 20 midlevel 3D shape and motion features. Applying factor analysis to the feature ratings reveals that a weighted combination of four underlying factors (distribution, irregularity, rectilinearity, and dynamics) predicted perceived viscosity very well across this wide range of contexts (R2 = 0.93). Interestingly, observers unknowingly ordered their midlevel judgments according to the one common factor across contexts: variation in viscosity. Principal component analysis reveals that across the features, the first component lines up almost perfectly with the viscosity (R2 = 0.96). Our findings demonstrate that the visual system achieves constancy by representing stimuli in a multidimensional feature space-based on complementary, midlevel features-which successfully cluster very different stimuli together and tease similar stimuli apart, so that viscosity can be read out easily. PMID- 29395925 TI - Maternal Inheritance of a Single Somatic Animal Cell Displayed by the Bacteriocyte in the Whitefly Bemisia tabaci. AB - Bacteriocytes are insect cells harboring symbiotic bacteria that are required by their insect host and are transmitted vertically via the female ovary [1]. In most insect groups, the bacteria are released from the bacteriocytes and transferred to the ovary [2, 3], but in whiteflies, maternal bacteriocytes migrate to each egg [4-6], where they have been reported to lyse, releasing the symbionts [1]. To investigate bacteriocyte inheritance in whiteflies further, we applied microsatellite genotyping and genomic analysis to a genetically diverse population of Bemisia tabaci, and we observed the fate of the bacteriocyte in embryos. Surprisingly, the microsatellite profile of the bacteriocytes was uniform, and insect cross experiments demonstrated that the bacteriocytes have a stable genotype that differs from the genotype of the insect head (which lacks bacteriocytes). Comparative genomic analysis indicates that genomes of the bacteriocyte and whitefly head are distinct. Interestingly, the bacterioyte genome contains the canonical arthropod telomere repeats TTAGG, and the bacteriocytes express telomere maintenance genes that may underlie cellular immortality in animal cells [7]. Microscopy observations confirmed that a single bacteriocyte transmitted to each egg is retained and divides once just before egg hatch, yielding two bacteriocytes in the neonate insect. These data demonstrate the maternal inheritance of an absolutely required somatic insect cell, violating the developmental separation of germline and soma [8, 9]. Future investigation on the mechanism and phylogenetic distribution of maternally inherited bacteriocytes will shed light on the developmental origins and evolutionary diversification of bacteriocytes [10] and the processes underlying cellular immortality [11]. PMID- 29395926 TI - KIN7 Kinase Regulates the Vacuolar TPK1 K+ Channel during Stomatal Closure. AB - Stomata are leaf pores that regulate CO2 uptake and evapotranspirational water loss. By controlling CO2 uptake, stomata impact on photosynthesis and dry matter accumulation. The regulation of evapotranspiration is equally important because it impacts on nutrient accumulation and leaf cooling and enables the plant to limit water loss during drought [1]. Our work centers on stomatal closure [2-6]. This involves loss of potassium from the guard cell by a two-step process. Salt is released across the plasma membrane via anion channels such as SLAC1 [7-9] and depolarization-activated channels such as GORK [10, 11], with the net result that cations and anions exit guard cells. However, this critically depends on K+ release from the vacuole; with ~160 and 100 mM K+ in cytoplasm and vacuole of open guard cells [12], vacuolar K+ efflux is driven by the negative tonoplast potential, and this expels K+ from the vacuole via tonoplast K+ channels like TPK1. In all, guard cell salt release leads to a loss of turgor that brings about stomatal closure. First, we show that the TPK1 vacuolar K+ channel is important for abscisic acid (ABA)- and CO2-mediated stomatal closure. Second, we reveal that, during ABA- and CO2-mediated closure, TPK1 is phosphorylated and activated by the KIN7 receptor-like protein kinase (RLK), which co-expresses in the tonoplast and plasma membrane. The net result is K+ release from the vacuole. Taken together, our work reveals new components involved in guard cell signaling and describes a new mechanism potentially involved in fine-tuning ABA- and CO2 induced stomatal closure. PMID- 29395927 TI - Genetic Regulation of the 2D to 3D Growth Transition in the Moss Physcomitrella patens. AB - One of the most important events in the history of life on earth was the colonization of land by plants; this transition coincided with and was most likely enabled by the evolution of 3-dimensional (3D) growth. Today, the diverse morphologies exhibited across the terrestrial biosphere arise from the differential regulation of 3D growth processes during development. In many plants, 3D growth is initiated during the first few divisions of the zygote, and therefore, the genetic basis cannot be dissected because mutants do not survive. However, in mosses, which are representatives of the earliest land plants, 3D shoot growth is preceded by a 2D filamentous phase that can be maintained indefinitely. Here, we used the moss Physcomitrella patens to identify genetic regulators of the 2D to 3D transition. Mutant screens yielded individuals that could only grow in 2D, and through an innovative strategy that combined somatic hybridization with bulk segregant analysis and genome sequencing, the causative mutation was identified in one of them. The NO GAMETOPHORES 1 (NOG1) gene, which encodes a ubiquitin-associated protein, is present only in land plant genomes. In mutants that lack PpNOG1 function, transcripts encoding 3D-promoting PpAPB transcription factors [1] are significantly reduced, and apical initial cells specified for 3D growth are not formed. PpNOG1 acts at the earliest identified stage of the 2D to 3D transition, possibly through degradation of proteins that suppress 3D growth. The acquisition of NOG1 function in land plants could thus have enabled the evolution and development of 3D morphology. PMID- 29395928 TI - Generative Cell Specification Requires Transcription Factors Evolutionarily Conserved in Land Plants. AB - Land plants differentiate germ cells in the haploid gametophyte. In flowering plants, a generative cell is specified as a precursor that subsequently divides into two sperm cells in the developing male gametophyte, pollen. Generative cell specification requires cell-cycle control and microtubule-dependent nuclear relocation (reviewed in [1-3]). However, the generative cell fate determinant and its evolutionary origin are still unknown. In bryophytes, gametophytes produce eggs and sperm in multicellular reproductive organs called archegonia and antheridia, respectively, or collectively called gametangia. Given the monophyletic origin of land plants [4-6], evolutionarily conserved mechanisms may play key roles in these diverse reproductive processes. Here, we showed that a single member of the subfamily VIIIa of basic helix-loop-helix (bHLH) transcription factors in the liverwort Marchantia polymorpha primarily accumulated in the initial cells and controlled their development into gametangia. We then demonstrated that an Arabidopsis thaliana VIIIa bHLH transiently accumulated in the smaller daughter cell after an asymmetric division of the meiosis-derived microspore and was required for generative cell specification redundantly with its paralog. Furthermore, these A. thaliana VIIIa bHLHs were functionally replaceable by the M. polymorpha VIIIa bHLH. These findings suggest the VIIIa bHLH proteins as core regulators for reproductive development, including germ cell differentiation, since an early stage of land plant evolution. PMID- 29395929 TI - Spectroscopic study of uracil, 1-methyluracil and 1-methyl-4-thiouracil: Hydrogen bond interactions in crystals and ab-initio molecular dynamics. AB - Hydrogen bond networks in uracil, 1-methyluracil and 1-methyl-4-thiouracil were studied by ab initio molecular dynamics as well as analysis of the orbital interactions. The power spectra calculated by ab initio molecular dynamics for atoms involved in hydrogen bonds were analyzed. We calculated spectra by using anharmonic approximation based on the autocorrelation function of the atom positions obtained from the Born-Oppenheimer simulations. Our results show the differences between hydrogen bond networks in uracil and its methylated derivatives. The studied methylated derivatives, 1-methyluracil as well as 1 methyl-4-thiouracil, form dimeric structures in the crystal phase, while uracil does not form that kind of structures. The presence of sulfur atom instead oxygen atom reflects weakness of the hydrogen bonds that build dimers. PMID- 29395930 TI - Micro-nano zinc oxide film fabricated by biomimetic mineralization: Designed architectures for SERS substrates. AB - In this study, we have investigated the effect of the surface morphologies of the zinc oxide (ZnO) substrates on surface enhanced Raman spectroscopy (SERS). During synthetic process, the self-assembly monolayers (SAMs) with different terminal groups are used as templates to induce the nucleation and growth of Zn(NO3)2.6H2O crystals, then different morphologies micro-nano ZnO powders are obtained by annealing Zn(NO3)2.6H2O crystals at 450 degrees C. The products obtained at different conditions are characterized by means of X-ray diffraction (XRD) patterns, scanning electron microscopy (SEM) and Raman spectra. The as-prepared ZnO micro-sized particles have been used the efficient Surface enhanced Raman scattering (SERS) substrates, and the SERS signals of 4-mercaptopyridine (Mpy) probe molecules are much influenced by the morphologies of the ZnO structures. Results indicated that the more (0001) facets appear in the of ZnO morphology, the greater degree of charge-transfer (PCT) for the SERS enhancement on the surface of semiconductors is achieved. The chemical interaction between ZnO structures and Mpy molecules plays a very important role in the SERS enhancement. PMID- 29395931 TI - Elucidation of the electronic states in polyethylene glycol by attenuated Total reflectance spectroscopy in the far-ultraviolet region. AB - We measured the attenuated total reflectance-far ultraviolet (ATR-FUV) spectra of poly(ethylene glycol) (PEG; average molecular weights of 200, 300, and 400) and related materials in the liquid state in the 145-200-nm wavelength region. For appropriately assigning the absorption bands, we also performed theoretical simulation of the unit-number dependent electronic spectra. The FUV spectra of PEGs contain three bands, which are assigned to the transitions between n(CH2OCH2)-3s Rydberg state (176 nm), n(CH2OCH2)-3p Rydberg state (163 nm), and n(OH)-3p Rydberg state (153 nm). Since the contribution of n(OH) decreases compared to n(CH2OCH2) with increase in the number of units, the ratios of the molar absorption coefficients, epsilon, at 153 nm relative to 163 nm, decrease. On the other hand, the ratio of epsilon at 176 nm to that at 163 nm increases with increase in the number of units, because of the difference in the number of unoccupied orbitals in the transitions. The calculated results suggest that n orbitals form two electronic bands. In the upper band, the electrons expand over the ether chain, whereas in the lower band, the electrons are localized in the terminal OH in the PEGs. PMID- 29395932 TI - Label-free SERS in biological and biomedical applications: Recent progress, current challenges and opportunities. AB - To achieve an insightful look within biomolecular processes on the cellular level, the development of diseases as well as the reliable detection of metabolites and pathogens, a modern analytical tool is needed that is highly sensitive, molecular-specific and exhibits fast detection. Surface-enhanced Raman spectroscopy (SERS) is known to meet these requirements and, within this review article, the recent progress of label-free SERS in biological and biomedical applications is summarized and discussed. This includes the detection of biomolecules such as metabolites, nucleic acids and proteins. Further, the characterization and identification of microorganisms has been achieved by label free SERS-based approaches. Eukaryotic cells can be characterized by SERS in order to gain information about the outer cell wall or to detect intracellular molecules and metabolites. The potential of SERS for medically relevant detection schemes is emphasized by the label-free detection of tissue, the investigation of body fluids as well as applications for therapeutic and illicit drug monitoring. The review article is concluded with an evaluation of the recent progress and current challenges in order to highlight the direction of label-free SERS in the future. PMID- 29395933 TI - Microheterogeneity in binary mixtures of water with CH3OH and CD3OH: ATR-IR spectroscopic, chemometric and DFT studies. AB - Here we report ATR-IR spectroscopic study on the separation at a molecular level (microheterogeneity) and the degree of deviation of H2O/CH3OH and H2O/CD3OH mixtures from the ideal mixture. Of particular interest is the effect of isotopic substitution in methyl group on molecular structure and interactions in both mixtures. To obtain comprehensive information from the multivariate data we applied the excess molar absorptivity spectra together with two-dimensional correlation analysis (2DCOS) and chemometric methods. In addition, the experimental results were compared and discussed with the structures of various model clusters obtained from theoretical (DFT) calculations. Our results evidence the presence of separation at a molecular level and deviation from the ideal mixture for both mixtures. The experimental and theoretical results show that the maximum of these deviations appears at equimolar mixture. Both mixtures consist of three kinds of species: homoclusters of water and methanol and mixed clusters (heteroclusters). The heteroclusters exist in the whole range of mole fractions with the maximum close to the equimolar mixture. At this mixture composition near 55-60% of molecules are involved in heteroclusters. In contrast, the homoclusters of water occur in a limited range of mole fractions (XME < 0.85-0.9). Upon mixing the molecules of methanol form weaker hydrogen bonding as compared with the pure alcohol. In contrast, the molecules of water in the mixture are involved in stronger hydrogen bonding than those in bulk water. All these results indicate that both mixtures have similar degree of deviation from the ideal mixture. PMID- 29395934 TI - Violence against doctors: A pandemic in the making. PMID- 29395935 TI - Factors reducing omalizumab response in severe asthma. AB - BACKGROUND: Despite adding Omalizumab to conventional therapy, several severe asthmatics still show poor disease control. We investigated the factors that may affect a reduced Omalizumab response in a large population of severe asthmatics. METHODS: 340 patients were retrospectively evaluated. FEV1%, FVC%, Asthma Control Test (ACT), fractional exhaled nitric oxide (FENO), possible step-downs/step-ups of concomitant therapies, exacerbations, disease control levels, ICS doses and SABA use, observed at the end of treatment, were considered as a response to Omalizumab. RESULTS: Age was an independent risk factor for a reduced response concerning FEV1%, FVC%, ACT and for a lower asthma control. Obesity (vs normal weight) was a determinant condition for exacerbations (OR:3.114[1.509-6.424], p = 0.002), for a disease partial/no control (OR:2.665[1.064-6.680], p = 0.036), for excessive SABA use (OR:4.448[1.837-10.768], p = 0.002) and for an unchanged/increased level of concomitant asthma medications. Furthermore, obesity also reduced the response in FEV1 (beta = -6.981,p = 0.04), FVC (beta = -11.689,p = 0.014) and ACT (beta = -2.585, p = 0.027) and was associated with a higher FENO level (beta = 49.045,p = 0.040). Having at least one comorbidity was a risk factor for exacerbations (OR:1.383[1.128-1.697], p = 0.008) and for an ACT <20 (OR:2.410[1.071-3.690], p = 0.008). Specifically, chronic heart disease was associated with both a lower ACT and FVC% whereas gastroesophageal reflux with a partial/no asthma control. Nasal polyps were a predisposing factor leading both to exacerbations and to the use of higher inhaled corticosteroids doses. Moreover, smoking habits, pollen or dog/cat dander co-sensitizations may negatively influence Omalizumab response. CONCLUSION: Age, obesity, comorbidities, smoking habits, nasal polyps, allergic poly-sensitization might reduce Omalizumab effectiveness independently to other asthma-influencing factors. PMID- 29395936 TI - A proposed Oxford classification-based clinicopathological nomogram for predicting short-term renal outcomes in IgA nephropathy after acute kidney injury. AB - BACKGROUND: This study aimed to investigate the effect of acute kidney injury (AKI) on the progression of renal disease and to develop a clinico-pathological nomogram to predict the renal outcome of IgA nephropathy (IgAN) patients, based on Oxford classification score. METHODS: This is a retrospective observational study. A total of 988 IgAN patients treated at our hospital between 2006 and 2011 were included and divided into AKI (n = 82) and non-AKI group (n = 906). The primary outcome measure was the composite renal endpoint. The secondary outcome measure was all-cause mortality. Clinical and pathologic features were assessed with multivariable Cox regression to predict the outcome in IgAN patients. A nomogram was developed to predict the renal outcome. RESULTS: The median follow up time was 48.6 months (range: 34.4 to 62.7). The incidence of AKI was 8.30%. The AKI group had more severe pathological characteristics and a significantly poor survival outcome than the non-AKI group. The multivariate Cox regression analysis showed that the AKI group had a 2.84 times higher risk of the composite renal endpoint as compared with the non-AKI group (P < 0.001). A clinico pathological nomogram was developed using the seven predictors for the primary renal composite endpoint. The AUC for the nomogram model was 0.81 (sensitivity = 0.78, specificity = 0.85), and the C-index was 0.91 (95% CI = 0.85-0.97). CONCLUSIONS: For IgAN patients, AKI is an independent risk factor for the progression of renal disease. Our nomogram model has good prediction power for the renal outcome of IgAN patients. PMID- 29395937 TI - Are there ways to improve the citations of a scientific paper? AB - BACKGROUND: The expansion of scientific publications makes more difficult the mining of relevant information necessary for a productive appraisal of authors' work, scientific interaction and exchange. Papers over-citation is unproductive, under-citation of innovative research generates delay and inefficiency. The extraction of information from the literature is mostly based on keywords (KWs). METHODS: I computed the chances of citation of one paper as 1/number of papers retrieved by the KWs published in that paper, and compared them with the chances obtained by selecting different KWs. RESULTS: Using generic KWs the chances are smaller, at times practically nil, as compared to those calculated with more specific KWs and their association. CONCLUSIONS: Selecting scientifically analyzed KWs, specific for the message conveyed by a paper and computing beforehand the theoretical chances of citation, might increase the citations obtained, the retrieval of important scientific and innovative information, optimize scientific exchange and qualitative productivity. LEARNING POINTS. PMID- 29395939 TI - Longitudinal modeling in developmental neuroimaging research: Common challenges, and solutions from developmental psychology. AB - Hypotheses about change over time are central to informing our understanding of development. Developmental neuroscience is at critical juncture: although the majority of longitudinal imaging studies have observations with two time points, researchers are increasingly obtaining three or more observations of the same individuals. The goals of the proposed manuscript are to draw upon the long history of methodological and applied literature on longitudinal statistical models to summarize common problems and issues that arise in their use. We also provide suggestions and solutions to improve the design, analysis and interpretation of longitudinal data, and discuss the importance of matching the theory of change with the appropriate statistical model used to test the theory. Researchers should articulate a clear theory of change and to design studies to capture that change and use appropriately sensitive measures to assess that change during development. Simulated data are used to demonstrate several common analytic approaches to longitudinal analyses. We provide the code for our simulations and figures in an online supplement to aid researchers in exploring and plotting their data. We provide brief examples of best practices for reporting such models. Finally, we clarify common misunderstandings in the application and interpretation of these analytic approaches. PMID- 29395938 TI - Geriatrician-performed comprehensive geriatric care in older adults referred to an outpatient community rehabilitation unit: A randomized controlled trial. AB - BACKGROUND: Older adults make increasing demands on all sectors of the healthcare system. We investigated the effect of geriatrician-performed comprehensive geriatric care (CGC) in older adults referred to an outpatient community rehabilitation unit. DESIGN: Randomized controlled trial. SETTING: Two Danish non hospital based rehabilitation units. PARTICIPANTS: Persons aged 65 or older admitted from home or hospital. INTERVENTION: CGC performed by a geriatrician at the rehabilitation unit. OUTCOMES: Primary outcome was number of hospital admissions and emergency department (ED) visits. Secondary outcomes were number of ambulatory contacts, general practitioner (GP) contacts, activities of daily living (ADL) and overall quality of life (OQoL). Outcomes were measured within 90 days of admission to the rehabilitation units. RESULTS: 368 persons were randomized: 185 to the intervention group (IG) vs 183 to the control group (CG). Groups were comparable at baseline. The number of hospital admissions and ED visits, ambulatory contacts and out of hour GP visits or phone calls did not differ between the groups. The number of daytime GP consultations and visits or phone and email consultations was lower in the IG (P < 0.001). There were no differences in the mean between the groups for ADL and OQoL, but more participants in the IG improved their OQoL (OR 1.63, 95% CI: 1.07-2.48, P = 0.023). CONCLUSION: Geriatrician-performed CGC in older adults in an outpatient community rehabilitation unit had no effect on the secondary healthcare utilization, but may reduce primary healthcare utilization and improve OQoL during the 90-day follow-up period. TRIAL REGISTRATION: ClinicalTrials.govNCT01506219. PMID- 29395940 TI - Two-dimensional speckle tracking echocardiography in calves: feasibility and repeatability study. AB - OBJECTIVES: To assess the feasibility and repeatability of two-dimensional speckle tracking echocardiography for the evaluation of left ventricular function in healthy calves. ANIMALS: 12 Holstein calves, 62 +/- 11.6 days old; 75.25 +/- 5.4 Kg. METHODS: Observational study. Right parasternal short-axis views at papillary muscle level were recorded in standing calves and subsequently analyzed by two-dimensional speckle tracking for global and regional radial and circumferential strains and strain rates and radial displacement. Echocardiographic examinations were performed by 2 observers to evaluate intra- and interobserver repeatability and variability. RESULTS: Two-dimensional speckle tracking was feasible in all calves. Automated tracking was better in systole than in diastole. Repeatability of the technique was good in calves. Systolic radial strain and strain rate peak values showed little variability compared with systolic circumferential strain and strain rate and to all diastolic measurements. Variability of the interobserver measurements was greater than the intraobserver measurements. CONCLUSIONS: Two-dimensional speckle tracking is feasible in calves. As in other species, evaluation of systolic radial left ventricular function is more reliable than circumferential and diastolic left ventricular function. PMID- 29395941 TI - Vardenafil inhibiting parasympathetic function of tracheal smooth muscle. AB - BACKGROUND: Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. METHODS: This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10-6 M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. RESULTS: The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10-5 M or above elicited a significant relaxation response to 10-6 M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. CONCLUSION: High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle. PMID- 29395942 TI - Reference equations for predicting standing height of children by using arm span or forearm length as an index. AB - BACKGROUND: Standing height (SH) is the most reliable parameter used to predict spirometric values in children, but measurement of this parameter may be difficult in children with thoracic or spinal abnormalities. This study was designed to establish reference equations to estimate SHs of children using their arm span length (ASL) or forearm ulnar length (UL) as an index. METHODS: Children aged 1-17 years were enrolled to measure their SH, body weight, ASL, and UL. Sex and age were also recorded. The relationship between SH and children's weight, age, ASL, and UL were analyzed. Regression equations using different indexes for SH of enrolled cases were used, and adults aged 18-64 years were also enrolled for comparison. RESULTS: A total of 512 children and 144 adults were enrolled. There was a strong linear relationship between SH and both ASL and UL in children and adults. Pearson's correlation coefficients of SH for ASL and UL were 0.989 and 0.968 (p < 0.001) in children and 0.933 and 0.845 (p < 0.001) in adults. The linear regression equations for estimating SH in children were calculated as SH = 9.363 + 0.943 ASL (r2 = 0.978, p < 0.001) and SH = 14.542 + 5.570 UL (r2 = 0.936, p < 0.001). In adults, age and sex were also added as indexes: SH = 59.849 + 0.642 ASL-0.047 Age +3.431 Sex (male = 1; female = 0) (r2 = 0.887, p < 0.001) and SH = 102.824 + 2.317 UL -0.049 age + 6.739 sex (r2 = 0.773, p < 0.001). CONCLUSION: Both ASL and UL have a significant linear relationship with SHs of children and adults. True SH can be estimated using regression equations with ASL or UL as a single index for situations where direct measurement of SH is difficult. PMID- 29395943 TI - Warfarin accelerated vascular calcification and worsened cardiac dysfunction in remnant kidney mice. AB - BACKGROUND: Vascular calcification is highly prevalent in end-stage renal disease (ESRD) and is a significant risk factor for future cardiovascular events and death. Warfarin use results in dysfunction of matrix Gla protein, an inhibitor of vascular calcification. However, the effect of warfarin on vascular calcification in patients with ESRD is still not well characterized. Thus we investigated whether arterial calcification can be accelerated by warfarin treatment both in vitro and in vivo using a mouse remnant kidney model. METHODS: Human aortic smooth muscle cells (HASMC) were cultured in medium supplemented with warfarin and phosphate to investigate the potential role of this drug in osteoblast transdifferentiation. For in vivo study, adult male C57BL/6 mice underwent 5/6 nephrectomy were treated with active vitamin D3 plus warfarin to determine the extent of vascular calcification and parameters of cardiovascular function. RESULTS: We found that the expressions of Runx2 and osteocalcin in HASMC were markedly enhanced in the culture medium containing warfarin and high phosphate concentration. Warfarin induced calcification of cultured HASMC in the presence of high phosphate levels, and this effect is inhibited by vitamin K2. Severe aortic calcification and reduced left ventricular ejection fractions were also noted in 5/6 nephrectomy mice treated with warfarin and active vitamin D3. CONCLUSION: Warfarin treatment contributes to the accelerated vascular calcification in animal models of advanced chronic kidney disease. Clinicians should therefore be aware of the profound risk of warfarin use on vascular calcification and cardiac dysfunction in patients with ESRD and atrial fibrillation. PMID- 29395944 TI - Comparing the reliability and accuracy of clinical measurements using plaster model and the digital model system based on crowding severity. AB - BACKGROUND: This study aims to clarify whether 3ShapeTM digital model system could be applied in orthodontic diagnostic analysis with certainty, especially under different crowding condition. Reliability, accuracy and efficiency of 3ShapeTM digital model system were assessed by comparing them with traditional plaster cast. METHODS: 29 plaster casts with permanent dentition were transformed into digital models by 3ShapeTM D800 scanner. All 29 models were categorized into mild-crowding (arch length discrepancy <3 mm), moderate-crowding (arch length discrepancy >3 mm and <8 mm), and severe-crowding group (arch length discrepancy >8 mm). Fourteen linear measurements were made manually using a digital caliper on plaster casts and virtually using the 3ShapeTM Ortho Analyzer software by two examiners. Intra-class Correlation Coefficient (ICC) was used to evaluate intra examiner reliability, inter-examiner reliability and reliability between two model systems. Paired t test was used to evaluate accuracy between two model systems. Kruskal-Wallis test followed by Mann-Whitney U test was used to evaluate the measurement differences between 3 groups in two model systems. RESULTS: Both intra-examiner and inter-examiner reliability were generally excellent for all measurements made on 3ShapeTM digital model and plaster cast (ICC: 0.752-0.993). Reliability between different model systems was also excellent (ICC: 0.897 0.998). Half of the accuracy test showed statistically significant differences (p < 0.05) when digital models were compared with plaster casts. Furthermore, while assessing measurement differences between 3 groups in two model systems, the mandibular required space showed significant difference (p = 0.012) between mild crowding group (0.27 + 0.01 mm) and severe crowding group (0.20 + 0.09 mm). However, the differences were less than 0.5 mm and would not affect clinical decision. CONCLUSION: Using 3ShapeTM digital model system instead of plaster casts for orthodontic diagnostic measurements is clinically acceptable. PMID- 29395945 TI - Pattern of non-trauma emergency department resource utilization in older adults: An 8-year experience in Taiwan. AB - BACKGROUND: To describe the patterns of non-trauma emergency department (ED) resource utilization, cost of visit, acuity level, and admission rate in older adult patients in Taiwan. METHODS: This is a retrospective observational cohort study conducted at the Taipei Veterans General Hospital with an annual ED population of 80,000 patients. Patients aged >=20 years with non-trauma ED visits from 2005 to 2012 were included in the study. RESULTS: We analyzed 441,665 ED visits. Older adult patients had higher ED usage, with the ratio of their ED visit and population being 3.56, 8.34, and 7.64 in the age groups 70-79, 80-89, and >=90 years, respectively. ED cost, acuity level, and risks of intensive care unit (ICU) admission increased with increasing age. Compared with patients aged 20-29 years, patients aged >=90 years required almost twice as much ED resources per visit [adjusted risk ratio (aRR), 1.98]. aRRs for high acuity in the age groups 70-79, 80-89, and >=90 years were 1.96, 1.87, and 1.91, respectively. The risk of ICU admission in the age groups 40-49, 50-59, 70-79, and >=90 years also increased by 3-fold (aRR, 2.99), 4-fold (aRR, 4.09), >6-fold (aRR, 6.66), and almost 10-fold (aRR, 9.84), respectively, compared with that in the age group 20 29 years. Among patients aged >=90 years, 2.9% with low acuity still required ICU admission, whereas 25.1% with high acuity required ICU admission. CONCLUSION: Our study shows that older adult patients are associated with more ED visits and higher acuity, higher ED costs, and higher risks of admission to both the ordinary ward and ICU than younger adult patients. PMID- 29395946 TI - Real-world Outcomes in Advanced Urothelial Cancer and the Role of Neutrophil to Lymphocyte Ratio. AB - INTRODUCTION: In the first- and second-line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real-world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR). METHODS: A retrospective analysis was performed on patients with mUC treated with systemic therapy. Overall response rates (ORRs), median time to treatment failure (mTTF), and median overall survival (mOS) were calculated. The association between baseline NLR (using a literature-derived cut-off of 3, as well as the best cut-off NLR value of 5.45 as identified by X-Tile software from this dataset) and mTTF and mOS were evaluated using Cox regression analysis. RESULTS: We evaluated 233 patients. In the first-line, the ORR was 25%. mTTF and mOS were 6.9 months and 9.0 months, respectively. Low baseline NLR was significantly associated with improved 8.3-month mTTF, in contrast to 5.8 months for patients with high NLR (P = .046). Low NLR was significantly correlated with a longer mOS of 13.1 months, compared with high NLR (8.2 months; P = .007). In the second-line, an ORR of 22%, an mTTF of 4.1 months, and an mOS of 8 months were observed. Low NLR in the second-line was significantly associated with improved mTTF at 7.9 months versus high NLR patients (3.3 months; P = .023). Second-line low NLR was significantly associated with a longer mOS of 12.2 months, in comparison to 6.8 months with high NLR (P = .003). CONCLUSION: In this real-world analysis of patients with mUC, first-line outcomes were lower than expected. Low NLR in the first- and second-line is associated with improved mTTF and mOS. PMID- 29395947 TI - Placental Site Trophoblastic Tumor in Nonseminomatous Mixed Germ Cell Tumors of the Testis: a Case Report and Review of the Literature. PMID- 29395948 TI - Changing Trends for Suicidal Death in Patients With Bladder Cancer: A 40+ Year Population-level Analysis. AB - BACKGROUND: Previous studies suggest that patients with bladder cancer (BCa) are at increased risk of suicide compared with the general population. The objective of this study is to improve our understanding of patients at high risk for suicidal death and to better characterize patients at risk of delayed suicide years after diagnosis. PATIENTS AND METHODS: Patients with bladder urothelial carcinoma were identified between 1973 and 2013 using the Surveillance, Epidemiology, and End Results (SEER) database (n = 333,679). Competing risks models were performed to generate hazard ratios (HRs) to identify variables associated with suicidal death. Among patients dying of suicide, logistic regression modelling was used to generate odds ratios (ORs) for factors associated with suicide > 36 months after diagnosis. RESULTS: There were 794 patients (0.24%) that died of suicide, 190,734 patients (57.2%) that died from other causes, and 142,151 patients (42.6%) that were alive. Significant factors associated with suicide included diagnosis between 1973 and 1983 (HR, 2.22), unmarried (HR, 1.74), white race (HR, 2.22), male (HR, 6.91), regional disease (HR, 2.49), living in the Southeast United States (HR, 2.43), and not undergoing a radical cystectomy (HR, 1.42). Older age was associated with suicide, whereas younger age was protective. No radical cystectomy (OR, 0.45), older age (OR, 0.32), unmarried status (OR, 0.65), and regional disease (OR, 0.19) were significantly associated with decreased odds of suicidal death > 36 months after diagnosis. CONCLUSIONS: Those at highest risk for suicidal death include male gender, the elderly, white, unmarried, and patients with nonlocalized disease. These patients may benefit from targeted survivorship care plans. PMID- 29395949 TI - Treatments, Outcomes, and Validity of Prognostic Scores in Patients With Sarcomatoid Renal Cell Carcinoma: A 20-Year Single-Institution Experience. AB - INTRODUCTION: Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC. PATIENTS AND METHODS: Patients were retrospectively identified from the database of the pathology department of the University Hospital of Strasbourg. We enrolled all patients with RCC with a sarcomatoid component diagnosed between 1995 and 2016. Patients with nonmetastatic RCC were excluded. Recorded variables included: clinical stage, metastatic sites, pathologic stage, type of treatments, prognostic group, and survival data. The primary end point was overall survival. The institutional ethical committee approved the study protocol. RESULTS: Of 104 patients with SRCC, 47 patients with metastatic SRCC were included. The median age was 60 years (range, 41-77 years). Median length of follow-up was 34 months (range, 1-180 months). Fifty-five percent of patients had known metastases at diagnosis. Lung represented the first metastatic site (70%) followed by glandular (28%), bone (23%), liver (21%), and brain (6%). Fifteen percent of patients received immunotherapy including cytokine-based therapy (n = 7), or checkpoint inhibitors (n = 2). Moreover, 7 patients received chemotherapy. Five patients received no systemic treatment because of their poor performance status. Of 42 treated patients, 2 patients achieved complete response and 9 partial response (24%). Median overall survival was 13.3 months. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups were valid in this subset of SRCC patients. A sarcomatoid percentage cutoff of 30% had the strongest influence on overall survival. CONCLUSION: Despite the arrival of tyrosine kinase inhibitors 10 years ago, metastatic SRCC remains a disease of poor prognosis and difficult to treat. Chemotherapy regimen and targeted therapies showed little activity in SRCC. IMDC score is a relevant prognostic factor in SRCC patients. Additionally, the MSKCC score, the sarcomatoid percentage, the necrotic fraction, and the vascular invasion could prove useful in identifying patients with a more favorable prognosis. These findings could help toward better patient stratification in clinical trials. Prospective trials assessing new drugs including immune checkpoint inhibitors are currently ongoing to improve SRCC survival. PMID- 29395950 TI - Diarrhea and flatulence are major bowel disorders after radical cystectomy: Results from a cross-sectional study in bladder cancer patients. AB - OBJECTIVES: We had previously demonstrated changes in defecation after radical cystectomy (RC). Reports addressing long-term bowel disorders following RC are rare. This cross-sectional study evaluates long-term bowel issues in a large cohort. MATERIAL AND METHODS: A questionnaire assessing changes in bowel function (diarrhea, constipation, urge to defecate, sensation of incomplete defecation, and flatulence) and its effect on quality of life was developed based on the gastrointestinal quality of life index and distributed in collaboration with the German bladder cancer support group. There were 431 evaluable questionnaires. For the analyses, we focused on patients that had the RC>1 year ago (n = 324). RESULTS: Current bowel problems were reported by 42.6% of patients. The most frequent bowel problems were flatulence (48.8%), diarrhea (29.6%), and sensation of incomplete defecation (22.5%). In cases of bowel problems, 39.7% and 59.8% of the patients indicated life restriction and dissatisfaction, respectively. Prevalence of diarrhea and flatulence were significantly higher>12 (vs. <=12) months following RC. Both symptoms significantly correlated with younger age at RC, life restriction, lower quality of life, lower health state, and lower energy level. Additionally, diarrhea significantly correlated with pouches as urinary diversion (vs. ileal conduit or ureterocutaneostomy) and higher dissatisfaction level. CONCLUSIONS: To our knowledge this is the largest cohort evaluating long term bowel symptoms after RC. Diarrhea is a prominent symptom after RC with a high impact on daily life that leads to dissatisfaction. A better understanding of long-term bowel symptoms could be translated into optimized surgical procedures, postoperative medication/nutrition, and patient education. PMID- 29395951 TI - Epigenetic reprogramming: A key mechanism driving therapeutic resistance. AB - Prostate cancer initiation, development and progression is driven by androgen receptor (AR) signaling. Androgen deprivation therapy is the primary treatment for patients that present with locally advanced or metastatic disease. However, androgen deprivation therapy is not curative, and patients will progress to castrate-resistant disease (CRPC). Although most patient's progress to CRPC via restoration of AR signaling (CRPC-Ad), approximately a quarter of patients will progress via mechanisms independent of AR signaling. This highly lethal phenotype is termed aggressive variant prostate cancer (AVPC). Data from clinical and preclinical studies demonstrate that AVPC involves combinatorial loss-of-function mutations in key tumor suppressor genes, low to absent AR levels, and re expression of reprogramming, stem, and neuroendocrine related gene signatures. Further, AVPC is shown to evolve from a CRPC-Ad phenotype. Overall, lineage plasticity underlying progression to AVPC is thought to be provoked by genome wide chromatin remodeling. Here, we will discuss an emerging focus on key drivers of chromatin remodeling in AVPC, and how their identification could provide noninvasive biomarkers to predict or detect AVPC emergence, and therapeutic targets to prevent or reverse progression to AVPC. PMID- 29395952 TI - Recent developments in the treatment of advanced bladder cancer. AB - Urothelial carcinoma of the bladder is a common malignancy which has historically been difficult to treat in its advanced stages. Clinically effective treatment options for locally advanced/inoperable or metastatic urothelial carcinoma (mUC) consisted of cisplatin-based chemotherapy regimens, with few other impactful therapeutic options. The past 2 years have seen a remarkable shift in the therapeutic landscape of mUC, with 5 novel immunotherapy agents receiving FDA approval for mUC, including first-line and second-line postplatinum settings. There are now many important clinical trials ongoing seeking to answer how best to use chemotherapy, immunotherapy, and targeted therapy agents in patients with mUC. Here we review the current standard of care for patients with mUC based on published data from the past 2 years, and look forward toward future research directions. PMID- 29395953 TI - Organizing a clinical trial for the new investigator. AB - BACKGROUND AND PURPOSE: Clinical trials organization can be daunting especially when orienting to a new system. The steps to a successful clinical trial are not concrete and vary based on the system. METHODS: In this section the discussion centers on how to shape the question for the clinical trial which is rational and feasible to answer within the planned study design. FINDINGS: Senior mentorship, collaboration and early involvement of stakeholders can help shape a successful clinical trial. Keeping in mind ethics and the processes within a system will make planning easier. Questions about key elements of the trial should be answered early to prevent delays of study initiation. CONCLUSION: Clinical trial development and implementation can be very rewarding, but successful outcomes require careful planning and considerations. PMID- 29395955 TI - Contribution of bladder cancer pathology assessment in planning clinical trials. AB - Bladder cancer is a heterogeneous disease that demonstrates a wide spectrum of histologic features. The modern classification of bladder cancer is largely based on pathologic analysis, which assesses tumor grade, stage, type, size, and other features that are essential for understanding the biological behavior of bladder cancer. Bladder cancers with similar histologic features are likely to show comparable responses to a new therapeutic agent in clinical trial. Furthermore, pathologic analysis also evaluates the quality of tissue samples in clinical trial to ensure the integrity of various molecular tests. In spite of the emerging role of genomic and molecular studies, pathology remains the cornerstone in the diagnosis, prognosis, and treatment of bladder cancer. Herein, the pathologic considerations for bladder cancer clinical trial planning are reviewed. PMID- 29395954 TI - Perioperative and long-term outcomes after radical cystectomy in hemodialysis patients. AB - PURPOSE: Patients on hemodialysis have an increased risk of developing advanced stage bladder cancer. They also have a significant risk of noncancer-related mortality. Radical cystectomy (RC) is the standard of care for nonmetastatic muscle-invasive bladder cancer, however little is known regarding outcomes in this population. MATERIALS AND METHODS: The United States Renal Disease System database was used to identify all patients on hemodialysis who underwent RC for bladder cancer in the United States between 1984 and 2013. A total of 985 patients were identified for analysis. Perioperative outcomes were evaluated. Competing risks analysis was used to estimate overall and cancer-specific mortality along with factors associated with death. RESULTS: Median hospital length of stay was 10 days and 43.1% of patients experienced a complication. Mortality within 30 days was 9.3%. Overall mortality at 1, 3, and 5 years was 51.7%, 77.3%, and 87.9%, respectively. Cancer-specific mortality at 1, 3, and 5 years was 12.3%, 18.4%, and 19.7%, respectively. Age, diabetes, and cerebrovascular disease were independently associated with overall mortality, while performance of urinary diversion was associated with a protective effect. Active smoking was the sole risk factor for cancer-specific mortality. CONCLUSIONS: RC in dialysis patients is associated with significant morbidity and mortality, with less than 15% overall survival at 5 years. Older patients, and those with a history of diabetes or cerebrovascular disease, are at an increased risk of mortality. PMID- 29395956 TI - Furan and p-xylene as candidate biomarkers for prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed noncutaneous malignant tumor among males in the Western world. Prostate-specific antigen has been considered the most important biomarker for PCa detection; however, it lacks specificity, leading to the search for alternative biomarkers. Volatile organic compounds (VOCs) are released during cell metabolism and can be found in exhaled breath, urine, and other fluids. VOCs have been used in the diagnosis of lung, breast, ovarian, and colorectal cancers, among others. The objective of this study was to identify urinary VOCs that may be sensitive and specific biomarkers for PCa. METHODS: The study included 29 patients with PCa and 21 with benign prostatic hyperplasia. Urine samples were obtained from all participants before and after prostate massage. VOCs were identified by gas chromatography-mass spectrometry. IBM SPSS Statistics v.20 was used for statistical analysis. Sample normality and homogeneity of variances were studied and, according to the distribution normality, ANOVA or the Kruskal-Wallis test was applied to evaluate significant differences between groups. The Pearson test was used to establish correlations. RESULTS: Fifty-seven VOCs were identified. Samples gathered before prostate massage showed significant between-group differences in urinary levels of furan (P<= 0.001), 2-ethylhexanol (P = 0.032), 3,5-dimethylbenzaldehyde (P = 0.027), santolin triene (P = 0.032), and 2,6-dimethyl-7-octen-2-ol (P = 0.003). Samples gathered after prostate massage showed significant differences in urinary levels of furan (P<= 0.001), 3- methylphenol (P = 0.014), p-xylene (P = 0.002), phenol (P<= 0.001), and 2-butanone (P = 0.001). CONCLUSIONS: Significant differences between PCa and BPH patients were found in urinary levels of certain VOCs both before and after prostate massage, supporting the proposal that VOCs may serve as PCa-specific biomarkers. PMID- 29395958 TI - Antioxidant and hypoglycemic effects of Diospyros lotus fruit fermented with Microbacterium flavum and Lactobacillus plantarum. AB - Diospyros lotus, a member of the Ebenaceae family, has long been used as a traditional sedative in China. In this study, the antioxidant and hypoglycemic effects of non-fermented and microorganism-fermented D. lotus were explored. The total phenolic and vitamin C contents of microorganism-fermented D. lotus for 24 72 h were less than those of non-fermented. High-performance liquid chromatography showed that the tannic, catechinic, and ellagic acid contents increased significantly upon fermentation for 24 h. D. lotus fermented with Microbacterium flavum for 24 h exhibited the highest DPPH radical scavenging activity (IC50 = 4.18 MUg mL-1), and the highest ABTS radical scavenging activity was exhibited at 72 h of fermentation (IC50 = 29.18 MUg mL-1). The anti-alpha glucosidase activity of fermented D. lotus was higher (2.06-4.73-fold) than that of non-fermented one. Thus, fermented D. lotus is a useful source of natural antioxidants, and a valuable food, exhibiting antioxidant and hypoglycemic properties. PMID- 29395957 TI - Implementing risk-aligned bladder cancer surveillance care. AB - Implementation science is a rapidly developing field dedicated to the scientific investigation of strategies to facilitate improvements in healthcare delivery. These strategies have been shown in several settings to lead to more complete and sustained change. In this essay, we discuss how refined surveillance recommendations for non-muscle-invasive bladder cancer, which involve a complex interplay between providers, healthcare facilities, and patients, could benefit from use of implementation strategies derived from the growing literature of implementation science. These surveillance recommendations are based on international consensus and indicate that the frequency of surveillance cystoscopy should be aligned with each patient's risk for recurrence and progression of disease. Risk-aligned surveillance entails cystoscopy at 3 and 12 months followed by annual surveillance for low-risk cancers, with surveillance every 3 months reserved for high-risk cancers. However, risk-aligned care is not the norm. Implementing risk-aligned surveillance could curtail overuse among low risk patients, while curbing underuse among high-risk patients. Despite clear direction from respected and readily available clinical guidelines, there are multiple challenges to implementing risk-aligned surveillance in a busy clinical setting. Here, we describe how implementation science methods can be systematically used to understand determinants of care and to develop strategies to improve care. We discuss how the tailored implementation for chronic diseases framework can facilitate systematic assessment and how intervention mapping can be used to develop implementation strategies to improve care. Taken together, these implementation science methods can help facilitate practice transformation to improve risk-aligned surveillance for bladder cancer. PMID- 29395959 TI - Identification of EayjjPB encoding a dicarboxylate transporter important for succinate production under aerobic and anaerobic conditions in Enterobacter aerogenes. AB - Enterobacter aerogenes, a gram-negative, rod-shaped bacterium, is an effective producer of succinate from glucose via the reductive tricarboxylic acid cycle under anaerobic conditions. However, to date, succinate-exporter genes have not been identified in E. aerogenes, although succinate exporters have a large impact on fermentative succinate production. Recently, we genetically identified yjjP and yjjB, as genes encoding a succinate transporter in Escherichia coli. Evaluation of the yjjPB homologs in E. aerogenes (EayjjPB genes) showed that succinate accumulation increased from 4.1 g L-1 to 9.1 g L-1 when the EayjjPB genes were expressed under aerobic conditions. Under anaerobic conditions, succinate yield increased from 53% to 60% by EayjjPB expression and decreased to 48% by deletion of EayjjPB. Furthermore, the production levels of fumarate and malate, which are intermediates of the succinate-biosynthesis pathway, were also increased by EayjjPB expression. A complementation assay conducted in Corynebacterium glutamicum strain AJ110655DeltasucE1 demonstrated that both EaYjjP and EaYjjB are required for the restoration of succinate production. Taken together, these results suggest that EaYjjPB function as a dicarboxylate transporter in E. aerogenes and that the products of both genes are required for dicarboxylate transport. PMID- 29395960 TI - Application of microalgae hydrolysate as a fermentation medium for microbial production of 2-pyrone 4,6-dicarboxylic acid. AB - Actual biomass of microalgae was tested as a fermentation substrate for microbial production of 2-pyrone 4,6-dicarboxylic acid (PDC). Acid-hydrolyzed green microalgae Chlorella emersonii (algae hydrolysate) was diluted to adjust the glucose concentration to 2 g/L and supplemented with the nutrients of Luria Bertani (LB) medium (tryptone 10 g/L and yeast extract 5 g/L). When the algae hydrolysate was used as a fermentation source for recombinant Escherichia coli producing PDC, 0.43 g/L PDC was produced with a yield of 20.1% (mol PDC/mol glucose), whereas 0.19 g/L PDC was produced with a yield of 8.6% when LB medium supplemented with glucose was used. To evaluate the potential of algae hydrolysate alone as a fermentation medium for E. coli growth and PDC production, the nutrients of LB medium were reduced from the algae hydrolysate medium. Interestingly, 0.17 g/L PDC was produced even without additional nutrient, which was comparable to the case using pure glucose medium with nutrients of LB medium. When using a high concentration of hydrolysate without additional nutrients, 1.22 g/L PDC was produced after a 24-h cultivation with the yield of 16.1%. Overall, C. emersonii has high potential as cost-effective fermentation substrate for the microbial production of PDC. PMID- 29395962 TI - Potential Environmental and Ecological Effects of Global Climate Change on Venomous Terrestrial Species in the Wilderness. AB - INTRODUCTION: Climate change has been scientifically documented, and its effects on wildlife have been prognosticated. We sought to predict the overall impact of climate change on venomous terrestrial species. We hypothesize that given the close relationship between terrestrial venomous species and climate, a changing global environment may result in increased species migration, geographical redistribution, and longer seasons for envenomation, which would have repercussions on human health. METHODS: A retrospective analysis of environmental, ecological, and medical literature was performed with a focus on climate change, toxinology, and future modeling specific to venomous terrestrial creatures. Species included venomous reptiles, snakes, arthropods, spiders, and Hymenoptera (ants and bees). Animals that are vectors of hemorrhagic infectious disease (eg, mosquitos, ticks) were excluded. RESULTS: Our review of the literature indicates that changes to climatic norms will have a potentially dramatic effect on terrestrial venomous creatures. Empirical evidence demonstrates that geographic distributions of many species have already shifted due to changing climatic conditions. Given that most terrestrial venomous species are ectotherms closely tied to ambient temperature, and that climate change is shifting temperature zones away from the equator, further significant distribution and population changes should be anticipated. For those species able to migrate to match the changing temperatures, new geographical locations may open. For those species with limited distribution capabilities, the rate of climate change may accelerate faster than species can adapt, causing population declines. Specifically, poisonous snakes and spiders will likely maintain their population numbers but will shift their geographic distribution to traditionally temperate zones more often inhabited by humans. Fire ants and Africanized honey bees are expected to have an expanded range distribution due to predicted warming trends. Human encounters with these types of creatures are likely to increase, resulting in potential human morbidity and mortality. CONCLUSIONS: Temperature extremes and changes to climatic norms may have a dramatic effect on venomous terrestrial species. As climate change affects the distribution, populations, and life histories of these organisms, the chance of encounters could be altered, thus affecting human health and the survivability of these creatures. PMID- 29395963 TI - What do patients want from their asthma care doctors? AB - One of the most important causes of asthma morbidity, hospital admissions, and death is non-adherence to prescribed therapy. It is generally assumed that adherence rates can be increased with asthma education, although well conducted studies have not always supported this assumption. Education can be achieved, or can fail, in many ways and no two patients have the same needs or perceived needs. In order to better understand what children with asthma and their parents or caregivers would desire as support from their physician providers, we conducted a survey of nearly 1000 parents of asthmatic children affiliated with the Asthma and Allergy Network. Most of those who responded wanted convenient access to their doctor, more time spent in office visits with greater attention paid to the patient, help in navigating insurance and prescription costs and paperwork, and a partnership in developing care plans. Although most patients were well insured for medical coverage (not a given in the USA), half were dissatisfied with their self-reported asthma control, many were concerned about medication side effects, 60% were not cared for by an asthma specialist, and nearly half did not have an asthma action plan. These results are consistent with data from other published studies and suggest that we still can do much more to meet the needs of children for whom we provide asthma care. PMID- 29395964 TI - A case of contact dermatitis and contact urticaria syndrome due to multiple allergens observed in a professional baseball player. PMID- 29395965 TI - Efficacy and safety of the emedastine patch, a novel transdermal drug delivery system for allergic rhinitis: Phase III, multicenter, randomized, double-blinded, placebo-controlled, parallel-group comparative study in patients with seasonal allergic rhinitis. AB - BACKGROUND: The emedastine patch was developed in Japan as the first transdermal drug delivery system of emedastine difumarate for allergic rhinitis. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison was conducted in patients with seasonal allergic rhinitis. Patients were administered Emedastine patches (4 or 8 mg), placebo, or levocetirizine hydrochloride (5 mg tablet) once daily for 2 weeks (double-dummy technique). The primary objective was superiority to placebo by the change of the total nasal symptom score (sneezing, rhinorrhea, and nasal congestion) in Week 2. Levocetirizine was a reference drug and not a comparator in this study. RESULTS: A total of 1276 patients were randomized to receive the 4 mg emedastine patch (n = 384), 8 mg emedastine patch (n = 382), placebo (n = 384), or levocetirizine (n = 126). The least squares mean (LSM) of the change from baseline of the total nasal symptom score (TNSS) in Week 2 was significantly larger in both emedastine patch groups than in the placebo group (adjusted p < 0.0001). In secondary analysis, LSM of the change in the TNSS was -1.20, -1.49, -0.44, and -1.32 in the 4 mg emedastine patch, 8 mg patch, placebo, and levocetirizine, respectively. Reductions in the number of episodes and scores of individual nasal symptoms were all significantly larger throughout the day in the emedastine patch groups than the placebo group (all p < 0.05). No clinically significant safety problems occurred. CONCLUSIONS: The emedastine patch (4 and 8 mg) effectively and safely controlled symptoms of seasonal allergic rhinitis with sustained action throughout the day. STUDY REGISTRATION: JapicCTI-153092. PMID- 29395966 TI - Long-term management and persistent impairment of pulmonary function in chronic eosinophilic pneumonia: A review of the previous literature. AB - Chronic eosinophilic pneumonia (CEP) is an inflammatory disease characterized by accumulations of eosinophils in the lung with unknown etiology. Although corticosteroid treatment dramatically resolves these inflammations, relapse is common during the course of the disease. Approximately 50% of patients with CEP experience relapse. Subsequent to persistent disease and repeated relapse, and in cases of combined severe asthma, some CEP patients are administered corticosteroids indefinitely. Similar to patients with severe asthma who are often steroid dependent, a number of CEP patients exhibit prolonged persistent impairment of pulmonary function. Thus, CEP should be considered a potentially chronic disease requiring long-term management, rather than an acute or sub-acute disease requiring short-time therapy only. This review summarizes previous CEP studies, as well as our own cohort data, and discusses the long-term management of CEP with a particular focus on relapse, the prevalence of maintenance therapy, and persistent impairment of pulmonary function. PMID- 29395968 TI - GH and GHR signaling in human disease. AB - Along with its inherent properties in growth promotion, cell division and regeneration, growth hormone (GH) exerts a variety of miscellaneous and widespread actions on the human body after binding to its receptor (GHR). Indeed, GH influences the metabolism of carbohydrates, lipids and proteins; shapes body composition, influences cardiovascular profile, quality of life, and induces other direct and indirect physiologic effects. Besides this salutary actions, GH and its derived peptide insulin-like growth factor-I (IGF-I), main product of the GH/GHR interaction, have been implicated in the genesis of diseases such as cancer and insulin-resistant diabetes. The effects of these peptides are difficult to discern in healthy individuals but can be better evaluated in disease states in which their action in target tissues is abnormal. In consequence, we selected acromegaly and Laron syndrome due to GH receptor deficiency (GHRD) as models for excess and absence of GH action, and focused in the role of GH/GHR signaling in the genesis of cancer and diabetes. Considering that malignancy has been linked at epidemiological level to type 2 diabetes and high body mass index, suggesting that hyperinsulinemia is an independent contributor to cancer genesis and progression, we propose that the GH-derived IGF I is also an independent influence for progression to neoplasia since its absence associates with less DNA damage, diminished mutagenesis and efficient apoptosis. Regarding development of type 2 diabetes, we support the notion that GH, by influencing insulin sensitivity via its counter-regulatory properties on carbohydrate metabolism, is an important contributor for development of this disease. PMID- 29395967 TI - Factors correlated with serum insulin-like growth factor-I levels in health check up subjects. AB - BACKGROUND: Most of circulating IGF-I is derived from the liver and circulating IGF-I levels are decreased in several pathological conditions, such as liver cirrhosis, uncontrolled diabetes, renal failure, and malnutrition. However, it has not fully been elucidated which factors modify IGF-I level in a physiological condition. OBJECTIVE: To identify the factors which are associated with circulating IGF-I levels. DESIGN: Cross-sectional study. METHODS: This study included 428 subjects who undertook health check-up. Subjects diagnosed with non alcoholic fatty liver disease (NAFLD) by ultrasonography were analyzed separately. Univariate and multivariate regression analyses were conducted to identify the factors associated with circulating IGF-I levels. RESULTS: Regression analyses revealed that serum albumin levels, total-bilirubin levels, calcium levels, and HOMA-IR were positively correlated with IGF-I levels. Serum transaminase levels and habitual drinking (ethanol intake >20 g/day) were negatively correlated with serum IGF-I levels. Although serum IGF-I standard deviation scores (SDS) in subjects with and without NAFLD were comparable, after adjusting confounding factors clarified by multivariate regression analysis, IGF I SDS negatively correlated with the presence of NAFLD. CONCLUSION: In this study, we demonstrated that serum bilirubin and calcium levels are correlated with serum IGF-I levels. Although further study is necessary, these data suggest a presence of interaction between GH-IGF-I axis and bilirubin and calcium metabolism. PMID- 29395969 TI - Design, synthesis and biological evaluation of novel pyrazolo-oxothiazolidine derivatives as antiproliferative agents against human lung cancer cell line A549. AB - An efficient, one-pot multicomponent reaction of novel pyrazolo-oxothiazolidine derivatives was achieved by condensation of 1-(benzofuran-2-yl)-3-(substituted arylprop-2-en-1-ones, thiosemicarbazide and dialkyl acetylenedicarboxylates under the optimized reaction conditions. Synthesised compounds were evaluated for their antiproliferative activity against A549 human lung cancer cell line. Among all the tested compounds, 4a (IC50 - 0.930 MUg/mL), 4e (IC50 - 1.207 MUg/mL), 4f (IC50 - 0.808 MUg/mL), 4g (IC50 - 1.078 MUg/mL), 4h (IC50 - 0.967 MUg/mL) and 4j (IC50 - 2.445 MUg/mL) showed promising activity compared with standard drug Sorafenib (IC50 - 3.779 MUg/mL). Molecular docking studies indicated that compound 4f had the greatest affinity for catalytic site of receptors EGFR (PDB ID code: 1 M17) and VEGFR2 (PDB ID code: 4AGD, 4ASD). These novel pyrazolo oxothiazolidine derivatives can be promising therapeutic agents for A549 human lung cancer cell line. PMID- 29395970 TI - Selective inhibition of monoamine oxidase A by hispidol. AB - Hispidol, an aurone, isolated from Glycine max Merrill, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A), with an IC50 value of 0.26 uM, and to inhibit MAO-B, but with lower potency (IC50 = 2.45 uM). Hispidol reversibly and competitively inhibited MAO-A with a Ki value of 0.10 uM with a potency much greater than toloxatone (IC50 = 1.10 uM), a marketed drug. It also reversibly and competitively inhibited MAO-B (Ki = 0.51 uM). Sulfuretin, an analog of hispidol, effectively inhibited MAO-A (IC50 = 4.16 uM) but not MAO-B (IC50 > 80 uM). A comparison of their chemical structures showed that the 3'-hydroxyl group of sulfuretin might reduce its inhibitory activities against MAO-A and MAO-B. Flexible docking simulation revealed that the binding affinity of hispidol for MAO-A (-9.1 kcal/mol) was greater than its affinity for MAO-B (-8.7 kcal/mol). The docking simulation showed hispidol binds to the major pocket of MAO-A or MAO-B. The findings suggest hispidol is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a novel lead compound for development of novel reversible inhibitors of MAO-A. PMID- 29395971 TI - Novel (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H) dione derivatives: Selective inhibition of MV-4-11 biphenotypic B myelomonocytic leukemia cells' growth is accompanied by reactive oxygen species overproduction and apoptosis. AB - A series of optically pure (R)- and (S)-1,3,4,12a-tetrahydropyrazino[2,1 c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives was designed and synthesized as novel anthramycin analogues in a three-step, one-pot procedure, and tested for their antiproliferative activity on nine following cell lines: MV-4-11, UMUC-3, MDA-MB-231, MCF7, LoVo, HT-29, A-549, A2780 and BALB/3T3. The key structural features responsible for exhibition of cytotoxic effect were determined: the (S) configuration of chiral center and the presence of hydrophobic 4-biphenyl substituent in the side chain. Introduction of bromine atom into the 8 position (8g) or substitution of dilactam ring with benzyl group (8m) further improved the activity and selectivity of investigated compounds. Among others, compound 8g exhibited selective cytotoxic effect against MV-4-11 (IC50 = 8.7 MUM) and HT-29 (IC50 = 17.8 MUM) cell lines, while 8m showed noticeable anticancer activity against MV-4-11 (IC50 = 10.8 MUM) and LoVo (IC50 = 11.0 MUM) cell lines. The cell cycle arrest in G1/S checkpoint and apoptosis associated with overproduction of reactive oxygen species was also observed for 8e and 8m. PMID- 29395972 TI - Docetaxel prodrug self-assembled nanosystem: Synthesis, formulation and cytotoxicity. AB - Conventional drug delivery systems of docetaxel (DTX) are challenged with low drug loading efficiency and potential carriers-induced toxicity. In this work, a docetaxel prodrug self-assembled nanosystem was designed and synthesized by conjugating docetaxel with oleic acid (OA) exploring a thioether as the linker, which is redox-sensitive to the redox environment within tumor cells. Notably, the carrier-free nanomedicine which does not need any carrier has obviously high drug loading that reaches 58%. Moreover, the cytotoxicity of DTX-S-OA maintains an equal level with DTX. The novel prodrug conjugate therefore has a promising perspective as carrier-free nanomedicine for cancer therapy due to its high drug loading property, redox-sensitive release and long circulation mechanism. PMID- 29395973 TI - Design and synthesis of novel dasatinib derivatives as inhibitors of leukemia stem cells. AB - We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC50 = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC50 = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d-15f and oxadiazole compounds 24a-24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC50 = 0.14 MUM and 0.05 MUM vs. 8.98 MUM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo. PMID- 29395974 TI - Synthesis of novel (-)-epicatechin derivatives as potential endothelial GPER agonists: Evaluation of biological effects. AB - To potentially identify proteins that interact (i.e. bind) and may contribute to mediate (-)-epicatechin (Epi) responses in endothelial cells we implemented the following strategy: 1) synthesis of novel Epi derivatives amenable to affinity column use, 2) in silico molecular docking studies of the novel derivatives on G protein-coupled estrogen receptor (GPER), 3) biological assessment of the derivatives on NO production, 4) implementation of an immobilized Epi derivative affinity column and, 5) affinity column based isolation of Epi interacting proteins from endothelial cell protein extracts. For these purposes, the Epi phenol and C3 hydroxyl groups were chemically modified with propargyl or mesyl groups. Docking studies of the novel Epi derivatives on GPER conformers at 14 ns and 70 ns demostrated favorable thermodynamic interactions reaching the binding site. Cultures of bovine coronary artery endothelial cells (BCAEC) treated with Epi derivatives stimulated NO production via Ser1179 phosphorylation of eNOS, effects that were attenuated by the use of the GPER blocker, G15. Epi derivative affinity columns yielded multiple proteins from BCAEC. Proteins were electrophoretically separated and inmmunoblotting analysis revealed GPER as an Epi derivative binding protein. Altogether, these results validate the proposed strategy to potentially isolate and identify novel Epi receptors that may account for its biological activity. PMID- 29395975 TI - Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1. AB - Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a-d, 5f-n, and 7a b) exhibited Zmp1 inhibition with IC50 values in the range 1.3-43.9 uM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 uM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 ug/ml. This work represents a step forward in targeting Zmp1 by small molecules. PMID- 29395976 TI - Screening one bead one compound libraries against serum using a flow cytometer: Determination of the minimum antibody concentration required for ligand discovery. AB - One bead one compound (OBOC) libraries can be screened against serum samples to identify ligands to antibodies in this mixture. In this protocol, hit beads are identified by staining with a fluorescent labeled secondary antibody. When screens are conducted against two different sets of serum, antibodies, and ligands to them, can be discovered that distinguish the two populations. The application of DNA-encoding technology to OBOC libraries has allowed the use of 10 um beads for library preparation and screening, which pass through a standard flow cytometer, allowing the fluorescent hit beads to be separated from beads displaying non-ligands easily. An important issue in using this approach for the discovery of antibody biomarkers is its analytical sensitivity. In other words, how abundant must an IgG be to allow it to be pulled out of serum in an unbiased screen using a flow cytometer? We report here a model study in which monoclonal antibodies with known ligands of varying affinities are doped into serum. We find that for antibody ligands typical of what one isolates from an unbiased combinatorial library, the target antibody must be present at 10-50 nM. True antigens, which bind with significantly higher affinity, can detect much less abundant serum antibodies. PMID- 29395977 TI - Corrigendum to "Synthesis and biological evaluations of new nitric oxide-anti inflammatory drug hybrids" [Bioorg Med Chem Lett (2017) 4358-4369]. PMID- 29395978 TI - Design, synthesis and biological evaluation of matrine derivatives as potential anticancer agents. AB - Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2 pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by 1H NMR, 13C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC50 values in range of 3.42-8.05 MUM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC 7721 and CNE2 cells at G2/M phase. PMID- 29395979 TI - Cytotoxic oligophenols from the rhizome of Wikstroemia indica. AB - A new tricoumarin glycoside, triumbelletin-7-O-beta-d-glucoside (1) and a new biflavonoid, wikstroflavone A (2), together with two known compounds, wikstaiwanone A (3) and wikstaiwanone B (4), were isolated from the rhizome of Wikstroemia indica. The structures of new compounds were elucidated by extensive spectroscopic techniques (UV, IR, HRESIMS, 1D, 2D NMR and CD), in combination with quantum chemical calculations of 13C NMR and ECD spectra. All isolates were tested for their antineoplastic activities against cancer-derived cell lines HCT116, SW480, U87 and T98G. Compounds 2-4 exhibited moderate cytotoxic activities to the four cell lines. The flow cytometry assay and western blot analysis revealed that the cytotoxic effects were possibly attributed to the induced apoptotic cell death. PMID- 29395980 TI - Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs. AB - In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for alpha1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold. PMID- 29395981 TI - Therapeutic effects of isothiocyanate prodrugs on rheumatoid arthritis. AB - Isothiocyanates 7a and 7b have poor stability and aqueous solubility. To address these problems, prodrugs 8a and 8b were synthesized. Prodrugs 8a and 8b were stable in HEPES buffer at pH 4.4, but released the active compounds 7a and 7b in HEPES buffer at pH 7.4 and in mouse plasma, respectively. Compound 8a and especially compound 8b showed anti-inflammatory effects. Compound 8b demonstrated significant efficacy in animal models of traumatic inflammation, acute inflammation and rheumatoid arthritis. Compound 8b also did not cause appreciable toxicity in mice after 5 weeks at a daily dose of 200 mg/kg. PMID- 29395982 TI - Reconstructive surgery and persistent postsurgical pain after mastectomy. PMID- 29395983 TI - Reply to Kendall and Castro-Alves: Reconstructive surgery and persistent postsurgical pain after mastectomy. PMID- 29395984 TI - Sleep and emotional processing. AB - A growing body of literature suggests that sleep plays a critical role in emotional processing. This review aims at synthesizing current evidence on the role of sleep and sleep loss in the modulation of emotional reactivity, emotional memory formation, empathic behavior, fear conditioning, threat generalization and extinction memory. Behavioral and neurophysiological evidence suggesting that rapid-eye movement (REM) sleep plays an important role in emotional processing is also discussed. Furthermore, we examine the relations between sleep and emotions by reviewing the functional neuroimaging studies that elucidated the brain mechanisms underlying these relations. It is shown that sleep supports the formation of emotional episodic memories throughout all the stages that compose memory processing. On the contrary, sleep loss deteriorates both the encoding of emotional information and the emotional memory consolidation processes. Research is also progressively providing new insights into the protective role of sleep in human emotional homeostasis and regulation, promoting adaptive next-day emotional reactivity. In this respect, evidence converges in indicating that lack of sleep significantly influences emotional reactivity. Moreover, notwithstanding some contradictory findings, the processing of emotionally salient information could mainly benefit from REM sleep. However, some crucial aspects of sleep-dependent emotional modulation remain unclear. PMID- 29395986 TI - Sleep and plasticity: Waking from a fevered dream. PMID- 29395985 TI - Feeling validated yet? A scoping review of the use of consumer-targeted wearable and mobile technology to measure and improve sleep. AB - The objectives of this review were to evaluate the use of consumer-targeted wearable and mobile sleep monitoring technology, identify gaps in the literature and determine the potential for use in behavioral interventions. We undertook a scoping review of studies conducted in adult populations using consumer-targeted wearable technology or mobile devices designed to measure and/or improve sleep. After screening for inclusion/exclusion criteria, data were extracted from the articles by two co-authors. Articles included in the search were using wearable or mobile technology to estimate or evaluate sleep, published in English and conducted in adult populations. Our search returned 3897 articles and 43 met our inclusion criteria. Results indicated that the majority of studies focused on validating technology to measure sleep (n = 23) or were observational studies (n = 10). Few studies were used to identify sleep disorders (n = 2), evaluate response to interventions (n = 3) or deliver interventions (n = 5). In conclusion, the use of consumer-targeted wearable and mobile sleep monitoring technology has largely focused on validation of devices and applications compared with polysomnography (PSG) but opportunities exist for observational research and for delivery of behavioral interventions. Multidisciplinary research is needed to determine the uses of these technologies in interventions as well as the use in more diverse populations including sleep disorders and other patient populations. PMID- 29395987 TI - Humanitarian health computing using artificial intelligence and social media: A narrative literature review. AB - INTRODUCTION: According to the World Health Organization (WHO), over 130 million people are in constant need of humanitarian assistance due to natural disasters, disease outbreaks, and conflicts, among other factors. These health crises can compromise the resilience of healthcare systems, which are essential for achieving the health objectives of the sustainable development goals (SDGs) of the United Nations (UN). During a humanitarian health crisis, rapid and informed decision making is required. This is often challenging due to information scarcity, limited resources, and strict time constraints. Moreover, the traditional approach to digital health development, which involves a substantial requirement analysis, a feasibility study, and deployment of technology, is ill suited for many crisis contexts. The emergence of Web 2.0 technologies and social media platforms in the past decade, such as Twitter, has created a new paradigm of massive information and misinformation, in which new technologies need to be developed to aid rapid decision making during humanitarian health crises. OBJECTIVE: Humanitarian health crises increasingly require the analysis of massive amounts of information produced by different sources, such as social media content, and, hence, they are a prime case for the use of artificial intelligence (AI) techniques to help identify relevant information and make it actionable. To identify challenges and opportunities for using AI in humanitarian health crises, we reviewed the literature on the use of AI techniques to process social media. METHODOLOGY: We performed a narrative literature review aimed at identifying examples of the use of AI in humanitarian health crises. Our search strategy was designed to get a broad overview of the different applications of AI in a humanitarian health crisis and their challenges. A total of 1459 articles were screened, and 24 articles were included in the final analysis. RESULTS: Successful case studies of AI applications in a humanitarian health crisis have been reported, such as for outbreak detection. A commonly shared concern in the reviewed literature is the technical challenge of analyzing large amounts of data in real time. Data interoperability, which is essential to data sharing, is also a barrier with regard to the integration of online and traditional data sources. Human and organizational aspects that might be key factors for the adoption of AI and social media remain understudied. There is also a publication bias toward high-income countries, as we identified few examples in low-income countries. Further, we did not identify any examples of certain types of major crisis, such armed conflicts, in which misinformation might be more common. CONCLUSIONS: The feasibility of using AI to extract valuable information during a humanitarian health crisis is proven in many cases. There is a lack of research on how to integrate the use of AI into the work-flow and large-scale deployments of humanitarian aid during a health crisis. PMID- 29395988 TI - Profiling insomnia using subjective measures: where are we and where are we going. PMID- 29395991 TI - Effect of different doses and durations of teriparatide therapy on resolution of medication-related osteonecrosis of the jaw: A randomized, controlled preclinical study in rats. AB - OBJECTIVE: To evaluate the effects of different doses and durations of teriparatide therapy on MRONJ resolution in rats. SUBJECTS AND METHODS: A total of 120 rats that had been affected with MRONJ (after six weekly zoledronate injections and tooth extraction) were randomly divided into eight subgroups: 2, 10, and 20 MUg/kg/day teriparatide were administered to L4, M4, and H4 for 4 weeks, and to L8, M8, and H8 for 8 weeks, respectively. C4 and C8 received saline for 4 and 8 weeks, respectively. One week after the final injection, rats were sacrificed and assessed clinically (bone exposure/fistula) and histologically (number of osteocytes in extraction socket and empty lacunae in alveolar bone). RESULTS: MRONJ was clinically improved in 72.2%, 61.5%, and 40% of stage I, II, and III experimental rats, respectively. In the control rats, the results were 20.8% for stage I and no improvement for stages II and III. Aside from L4 and L8, the experimental subgroups had a significantly higher rate of clinical and histological improvement compared with their corresponding controls. There was a significantly higher number of osteocytes and lower number of empty lacunae in M4 and H4 compared with C4, in H4 compared with L4, in M8 and H8 compared with C8, and in H8 compared with L8. CONCLUSION: Teriparatide therapy improved clinical and histological features of MRONJ in a dose-dependent manner, but clinically relevant doses of teriparatide might not be sufficient for MRONJ resolution in rats. Extending the duration of teriparatide therapy from 4 to 8 weeks did not affect treatment outcomes. PMID- 29395989 TI - Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. AB - Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management. PMID- 29395992 TI - Bioabsorbable plates versus metal miniplate systems for use in endoscope-assisted open reduction and internal fixation of mandibular subcondylar fractures. AB - PURPOSE: To compare bioabsorbable plates with metal miniplate systems for use in endoscope-assisted open reduction and internal fixation (EAORIF) of mandibular subcondylar fractures. MATERIALS AND METHODS: This retrospective cohort study included patients with mandibular subcondylar fractures treated with EAORIF using bioabsorbable unsintered hydroxyapatite/poly l-lactide composite plates or titanium miniplate systems. The outcome variables included preoperative fracture conditions, postoperative stability during fracture healing, and complications during the follow-up period. Other variables included clinical characteristics (age, sex, fracture site, and total follow-up duration) and intra- and postoperative data (surgical duration, duration of intermaxillary fixation/elastic band guidance). Variables were evaluated using descriptive statistics and compared between groups using the Mann-Whitney test and the chi square test or Fisher's exact test, as appropriate. RESULTS: In total, 28 patients were analyzed, including 13 who underwent EAORIF using bioabsorbable plates and 15 who underwent EAORIF using titanium miniplates. With the exception of second surgery for plate removal, none of the assessed variables showed significant differences between the two groups (p < 0.05). CONCLUSIONS: Our results suggest that EAORIF using biodegradable plates is a stable and reliable method for the management of mandibular subcondylar fractures and eliminates the need for secondary surgery for plate removal. PMID- 29395990 TI - Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. AB - A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease causing mutation. The new care considerations acknowledge the effects of long term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available. PMID- 29395993 TI - A worldwide comparison of the management of surgical treatment of advanced oral cancer. AB - INTRODUCTION: Microvascular surgery following tumor resection has become an important field of oral and maxillofacial surgery (OMFS). Following the results from management of T1/T2 floor-of-mouth and tongue squamous cell carcinoma (SCC) in German-speaking countries, Europe, and worldwide, this paper presents specific concepts for the management of resection and reconstruction of T3/T4 SCC of the maxillary and mandibular alveolar process and tongue. METHODS: The DOSAK questionnaire was distributed in three different phases to a growing number of maxillofacial units worldwide. Within this survey, clinical patient settings were presented to participants and center-specific treatment strategies were evaluated. RESULTS: A total of 188 OMFS units from 36 different countries documented their treatment strategies for T3/T4 maxillary and mandibular alveolar process and tongue SCC. The extent of surgical resections and subsequent reconstructions is more consistent than with T1/T2 tumors, although the controversy surrounding continuity resections and mandible-sparing procedures remains. For continuity resection of the mandible the fibula free flap is the most frequently used bone replacement, whereas maxilla reconstruction concepts are less consistent, ranging from locoregional coverage concepts and different microvascular reconstruction options to treatment via obturator prosthesis. CONCLUSION: Results from treatment strategies for T3/T4 tumors underline the limited evidence for the appropriate amount of resection and subsequent reconstruction process, especially in cases involving the mandible. Prospective randomized trials will be necessary in the long term to establish valid treatment guidelines. PMID- 29395994 TI - Alveolar corticotomies for accelerated orthodontics: A systematic review. AB - INTRODUCTION: It has been suggested that alveolar corticotomies may accelerate tooth movement, broaden the scope of malocclusion types that can be treated orthodontically, decrease the need for extractions, and support long-term stability. Several techniques have been proposed, although the indications, ideal design and technical characteristics, potential complications, and objective clinician and patient satisfaction remain unclear. This systematic review aimed to provide scientific support to validate alveolar corticotomies as a reliable approach to accelerated orthodontics. MATERIAL & METHODS: A literature search was conducted using MEDLINE (via PubMed), Cochrane, and EMBASE electronic databases until December, 2016. Articles written in any language other than English, Spanish, French, German, and Portuguese were excluded. Randomized controlled trials, controlled clinical trials, and case series involving healthy adult patients, with a sample size of at least 5 patients, and using alveolar corticotomy techniques were included. Two reviewers extracted the data independently. RESULTS: Three randomized clinical trials, 2 prospective randomized clinical trials, 6 case series and 1 randomized controlled split-mouth study were included. No clinical trials were retrieved. Mean total treatment time in corticotomy-facilitated orthodontic cases was 8.85 months (range, 4-20 months); control groups treatment duration was 16.4 months (range, 7.8-28.3 months). Complications such as pain, swelling, and dentin hypersensitivity were reported. Few studies mentioned patient/clinician satisfaction. The faster and less invasive procedures appeared to be well tolerated. However, the methodological quality of the selected studies was low, with only low to moderate scientific evidence. CONCLUSIONS: Corticotomy-facilitated orthodontics resulted in decreased treatment time. Few complications and low morbidity were found. More solid evidence-based research is required to support these results. PMID- 29395995 TI - National trends in tongue reduction surgery for macroglossia in children. AB - OBJECTIVES: To examine the frequency of partial glossectomy performed for the indication of macroglossia in children within the United States, assessing for differences in rates of intervention across various demographics. To identify potential morbidities associated with partial glossectomy in this population and determine how such factors may influence length of stay and cost of admission following tongue reduction surgery. STUDY DESIGN: Retrospective cross-sectional study. SETTING: The Kids' Inpatient Database 2003, 2006, 2009, and 2012. SUBJECTS: Patients under age 5 diagnosed with macroglossia who underwent partial glossectomy. METHODS: Demographics were analyzed and cross tabulations, linear regression modeling, and multivariate analysis were performed. RESULTS: During the four-years studied, partial glossectomy was performed in 196 children under age 5 with macroglossia. A disproportionately higher rate of intervention was seen in white children (p = 0.001), patients undergoing surgery in the mid-west (p < 0.001) and patients in the highest socioeconomic quartile (p = 0.015). Most patients underwent glossectomy in their second year of life. The average length of stay in patients who underwent partial glossectomy for macroglossia was 9.59 days (Range 1-211 days, median 3.45 days) and the average cost was $56,602 (median $16,330). CONCLUSION: Partial glossectomy for macroglossia is typically performed prior to age 2 in the United States. A higher rate of intervention is seen in white children, those who have surgery in the mid-west and affluent children even when controlling for confounding variables. LEVEL OF EVIDENCE: III. PMID- 29395996 TI - Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study. AB - BACKGROUND: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality. METHODS: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we measured 425 metabolites using liquid chromatography-mass spectrometry in CSF and serum from 33 HIV-negative Indonesian patients with confirmed or probable tuberculous meningitis and 22 control participants with complete clinical data between March 12, 2009, and Oct 27, 2013. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients. FINDINGS: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association of low CSF tryptophan with patient survival was confirmed in the validation cohort (hazard ratio 0.73; 95% CI 0.64-0.83; p<0.0001; per each halving). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0.00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0.0083). INTERPRETATION: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis. FUNDING: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health. PMID- 29395997 TI - Prevention of malaria in pregnancy. AB - Malaria remains one of the most preventable causes of adverse birth outcomes. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine pyrimethamine is used to prevent malaria, but resistance to this drug combination has decreased its efficacy and new alternatives are needed. In Africa, a meta analysis showed three-course or monthly IPTp with sulfadoxine-pyrimethamine to be safe and more effective than the original two-course sulfadoxine-pyrimethamine strategy, prompting WHO to update its policy in 2012. Although resistance to sulfadoxine-pyrimethamine reduces the parasitological efficacy of IPTp, this drug combination remains associated with reduced incidence of low birthweight in areas where prevalence of parasites with quintuple Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps) mutations is greater than 90%. Nevertheless, its effectiveness is compromised in women infected with sextuple mutant parasites. Six trials of IPTp showed that neither amodiaquine, mefloquine, nor chloroquine-azithromycin are suitable replacements for sulfadoxine-pyrimethamine because of poor tolerability. Furthermore, four trials showed that intermittent screening and treatment with the current generation of malaria rapid diagnostic tests was not a suitable alternative strategy to IPTp with sulfadoxine-pyrimethamine, even in areas with high prevalence of quintuple mutations. Two trials showed that IPTp with dihydroartemisinin-piperaquine was well tolerated, effective, and acceptable for IPTp, with monthly regimens being the most effective. Coverage of IPTp and insecticide-treated nets continues to lag behind targets. The key barriers to uptake are well documented, and many are open to intervention. Outside of Africa, a single trial suggests a potential role for integrated approaches that combine sulfadoxine-pyrimethamine with azithromycin for IPTp in areas of Papua New Guinea where malaria transmission is high. Modelling analysis suggests the importance of the prevention of malaria early in pregnancy and the need to protect pregnant women declines more slowly than the rate at which transmission declines. Improved funding has led to an increase in the number of prevention trials in the past decade, showing the value of more sustained protection with monthly IPTp regimens. There is a need for confirmatory trials of the safety, efficacy, and feasibility of IPTp with dihydroartemisinin-piperaquine, for studies of intermittent screening and treatment with more sensitive rapid diagnostic tests, for studies of integrated strategies for malaria and other co-infections, and for studies of prevention strategies for malaria in pregnant women who are HIV-positive and living outside of Africa. Additional research is required on how to improve uptake of WHO's updated policy on IPTp with sulfadoxine-pyrimethamine and insecticide-treated nets. PMID- 29395998 TI - Treatment of uncomplicated and severe malaria during pregnancy. AB - Over the past 10 years, the available evidence on the treatment of malaria during pregnancy has increased substantially. Owing to their relative ease of use, good sensitivity and specificity, histidine rich protein 2 based rapid diagnostic tests are appropriate for symptomatic pregnant women; however, such tests are less appropriate for systematic screening because they will not detect an important proportion of infections among asymptomatic women. The effect of pregnancy on the pharmacokinetics of antimalarial drugs varies greatly between studies and class of antimalarial drugs, emphasising the need for prospective studies in pregnant and non-pregnant women. For the treatment of malaria during the first trimester, international guidelines are being reviewed by WHO. For the second and third trimester of pregnancy, results from several trials have confirmed that artemisinin-based combination treatments are safe and efficacious, although tolerability and efficacy might vary by treatment. It is now essential to translate such evidence into policies and clinical practice that benefit pregnant women in countries where malaria is endemic. Access to parasitological diagnosis or appropriate antimalarial treatment remains low in many countries and regions. Therefore, there is a pressing need for research to identify quality improvement interventions targeting pregnant women and health providers. In addition, efficient and practical systems for pharmacovigilance are needed to further expand knowledge on the safety of antimalarial drugs, particularly in the first trimester of pregnancy. PMID- 29395999 TI - Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study. AB - BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have substantially reduced the incidence of invasive pneumococcal disease caused by vaccine serotypes; however, replacement disease with non-PCV serotypes remains a concern. We describe the population effect of the seven-valent and 13-valent PCVs (PCV7 and PCV13) on invasive pneumococcal disease in England and Wales. METHODS: Using national invasive pneumococcal disease surveillance data for 2016/17, we compared incidence rate ratios (IRRs) against pre-PCV13 (2008/09-2009/10) and pre-PCV7 (2000/01-2005/06) baselines. We also estimated the number of invasive pneumococcal disease cases prevented since the introduction of PCVs. FINDINGS: In 2016/17, overall invasive pneumococcal disease incidence (9.87 cases per 100 000; 5450 cases) across all age groups was 37% lower (IRR 0.63, 95% CI 0.60-0.65) than pre-PCV7 incidence (14.79 per 100 000; 8167 cases) and 7% lower (0.93; 0.89-0.97) than pre-PCV13 incidence (10.13 per 100 000; 5595 cases). By 2016/17, PCV7-type invasive pneumococcal disease incidence across all age groups had decreased by 97% (0.24 per 100 000; 0.03, 0.02-0.04) compared with the pre-PCV7 period, whereas additional PCV13-type invasive pneumococcal disease decreased by 64% (1.66 per 100 000; 0.36, 0.32-0.40) since the introduction of PCV13. Invasive pneumococcal disease incidence due to non-PCV13 serotypes doubled (7.97 per 100 000; 1.97, 1.86-2.09) since the introduction of PCV7, and accelerated since 2013/14-especially serotypes 8, 12F, and 9N, which were responsible for more than 40% of invasive pneumococcal disease cases by 2016/17. Invasive pneumococcal disease incidence in children younger than 5 years remained stable since 2013/14, with nearly all replacement disease occurring in adults. We estimated 38 366 invasive pneumococcal disease cases were prevented in the 11 years since the introduction of PCV7. INTERPRETATION: Both PCV7 and PCV13 have had a major effect in reducing the burden of invasive pneumococcal disease in England and Wales; however, rapid increases in some non-PCV13 serotypes are compromising the benefits of the programme. FUNDING: Public Health England. PMID- 29396000 TI - The effects of antibiotic cycling and mixing on antibiotic resistance in intensive care units: a cluster-randomised crossover trial. AB - BACKGROUND: Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs). METHODS: In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin-tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram negative bacteria as Enterobacteriaceae with extended-spectrum beta-lactamase production or piperacillin-tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin-tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071. FINDINGS: Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0.64), yielding an adjusted incidence rate ratio during mixing of 1.039 (95% CI 0.837-1.291; p=0.73). There was no difference in all-cause in ICU mortality between intervention periods. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme. PMID- 29396002 TI - Use of data to drive pneumococcal conjugate vaccine policy. PMID- 29396001 TI - Molecular surveillance of norovirus, 2005-16: an epidemiological analysis of data collected from the NoroNet network. AB - BACKGROUND: The development of a vaccine for norovirus requires a detailed understanding of global genetic diversity of noroviruses. We analysed their epidemiology and diversity using surveillance data from the NoroNet network. METHODS: We included genetic sequences of norovirus specimens obtained from outbreak investigations and sporadic gastroenteritis cases between 2005 and 2016 in Europe, Asia, Oceania, and Africa. We genotyped norovirus sequences and analysed sequences that overlapped at open reading frame (ORF) 1 and ORF2. Additionally, we assessed the sampling date and country of origin of the first reported sequence to assess when and where novel drift variants originated. FINDINGS: We analysed 16 635 norovirus sequences submitted between Jan 1, 2005, to Nov 17, 2016, of which 1372 (8.2%) sequences belonged to genotype GI, 15 256 (91.7%) to GII, and seven (<0.1%) to GIV.1. During this period, 26 different norovirus capsid genotypes circulated and 22 different recombinant genomes were found. GII.4 drift variants emerged with 2-3-year periodicity up to 2012, but not afterwards. Instead, the GII.4 Sydney capsid seems to persist through recombination, with a novel recombinant of GII.P16-GII.4 Sydney 2012 variant detected in 2014 in Germany (n=1) and the Netherlands (n=1), and again in 2016 in Japan (n=2), China (n=8), and the Netherlands (n=3). The novel GII.P17-GII.17, first reported in Asia in 2014, has circulated widely in Europe in 2015-16 (GII.P17 made up a highly variable proportion of all sequences in each country [median 11.3%, range 4.2-53.9], as did GII.17 [median 6.3%, range 0-44.5]). GII.4 viruses were more common in outbreaks in health-care settings (2239 [37.2%] of 6022 entries) compared with other genotypes (101 [12.5%] of 809 entries for GI and 263 [13.5%] of 1941 entries for GII non-GII.Pe-GII.4 or GII.P4-GII.4). INTERPRETATION: Continuous changes in the global norovirus genetic diversity highlight the need for sustained global norovirus surveillance, including assessment of possible immune escape and evolution by recombination, to provide a full overview of norovirus epidemiology for future vaccine policy decisions. FUNDING: European Union's Horizon 2020 grant COMPARE, ZonMw TOP grant, the Virgo Consortium funded by the Dutch Government, and the Hungarian Scientific Research Fund. PMID- 29396003 TI - Norovirus surveillance comes of age: the impact of NoroNet. PMID- 29396004 TI - Development of vaccines against Zika virus. AB - Zika virus is an emerging pathogen of substantial public health concern to human beings. Although most infections are asymptomatic or present with benign, self limited symptoms, a small percentage of patients have complications, such as congenital anomalies in the developing fetus of pregnant women infected with the virus and neurological complications (eg, Guillain-Barre syndrome). To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. In this Review, we examine vaccine development efforts for Zika virus to date and research gaps in the development of candidate vaccines against Zika virus. Top research priorities should include development of a better understanding of immunity to Zika virus to establish clear correlates of protection; determination of what effect, if any, Zika vaccine-induced immune responses will have on subsequent dengue virus infection; evaluation of vaccine immunogenicity and efficacy in healthy adults and in the various subpopulations affected by Zika virus infection (children, pregnant women, women of childbearing age, and eldery people); and identification of the molecular mechanisms that underlie birth defects and neurological sequelae related to Zika virus. PMID- 29396005 TI - Vaginal microbes, inflammation, and HIV risk in African women. PMID- 29396007 TI - WHO Global Antimicrobial Resistance Surveillance System early implementation 2016 17. PMID- 29396006 TI - Evaluation of the association between the concentrations of key vaginal bacteria and the increased risk of HIV acquisition in African women from five cohorts: a nested case-control study. AB - BACKGROUND: Disruptions of vaginal microbiota might increase women's susceptibility to HIV infection. Advances in molecular microbiology have enabled detailed examination of associations between vaginal bacteria and HIV acquisition. Therefore, this study aimed to evaluate the association between the concentrations of specific vaginal bacteria and increased risk of HIV acquisition in African women. METHODS: We did a nested case-control study of participants from eastern and southern Africa. Data from five cohorts of African women (female sex workers, pregnant and post-partum women, and women in serodiscordant relationships) were used to form a nested case-control analysis between women who acquired HIV infection versus those who remained seronegative. Deep sequence analysis of broad-range 16S rRNA gene PCR products was applied to a subset of 55 cases and 55 controls. From these data, 20 taxa were selected for bacterium specific real-time PCR assays, which were examined in the full cohort as a four category exposure (undetectable, first tertile, second tertile, and third tertile of concentrations). Conditional logistic regression was used to generate odds ratios (ORs) and 95% CIs. Regression models were stratified by cohort, and adjusted ORs (aORs) were generated from a multivariable model controlling for confounding variables. The Shannon Diversity Index was used to measure bacterial diversity. The primary analyses were the associations between bacterial concentrations and risk of HIV acquisition. FINDINGS: Between November, 2004, and August, 2014, we identified 87 women who acquired HIV infection (cases) and 262 controls who did not acquire HIV infection. Vaginal bacterial community diversity was higher in women who acquired HIV infection (median 1.3, IQR 0.4-2.3) than in seronegative controls (0.7, 0.1-1.5; p=0.03). Seven of the 20 taxa showed significant concentration-dependent associations with increased odds of HIV acquisition: Parvimonas species type 1 (first tertile aOR 1.67, 95% CI 0.61-4.57; second tertile 3.01, 1.13-7.99; third tertile 4.64, 1.73-12.46; p=0.005) and type 2 (first tertile 3.52, 1.63-7.61; second tertile 0.85, 0.36-2.02; third tertile 2.18, 1.01-4.72; p=0.004), Gemella asaccharolytica (first tertile 2.09, 1.01 4.36; second tertile 2.02, 0.98-4.17; third tertile 3.03, 1.46-6.30; p=0.010), Mycoplasma hominis (first tertile 1.46, 0.69-3.11; second tertile 1.40, 0.66 2.98; third tertile 2.76, 1.36-5.63; p=0.048), Leptotrichia/Sneathia (first tertile 2.04, 1.02-4.10; second tertile 1.45, 0.70-3.00; third tertile 2.59, 1.26 5.34; p=0.046), Eggerthella species type 1 (first tertile 1.79, 0.88-3.64; second tertile 2.62, 1.31-5.22; third tertile 1.53, 0.72-3.28; p=0.041), and vaginal Megasphaera species (first tertile 3.15, 1.45-6.81; second tertile 1.43, 0.65 3.14; third tertile 1.32, 0.57-3.05; p=0.038). INTERPRETATION: Differences in the vaginal microbial diversity and concentrations of key bacteria were associated with greater risk of HIV acquisition in women. Defining vaginal bacterial taxa associated with HIV risk could point to mechanisms that influence HIV susceptibility and provide important targets for future prevention research. FUNDING: National Institute of Child Health and Human Development. PMID- 29396008 TI - Putting malaria in pregnancy back in the spotlight. PMID- 29396009 TI - A colistin crisis in India. PMID- 29396010 TI - Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. AB - Over the past 10 years, knowledge of the burden, economic costs, and consequences of malaria in pregnancy has improved, and the prevalence of malaria caused by Plasmodium falciparum has declined substantially in some geographical areas. In particular, studies outside of Africa have increased the evidence base of Plasmodium vivax in pregnancy. Rapid diagnostic tests have been poor at detecting malaria in pregnant women, while PCR has shown a high prevalence of low density infection, the clinical importance of which is unknown. Erythrocytes infected with P falciparum that express the surface protein VAR2CSA accumulate in the placenta, and VAR2CSA is an important target of protective immunity. Clinical trials for a VAR2CSA vaccine are ongoing, but sequence variation needs to be carefully studied. Health system and household costs still limit access to prevention and treatment services. Within the context of malaria elimination, pregnant women could be used to monitor malaria transmission. This Series paper summarises recent progress and highlights unresolved issues related to the burden of malaria in pregnancy. PMID- 29396011 TI - Antibiotic strategies in critical care: back to square one? PMID- 29396012 TI - Utility of single-photon emission computed tomography and computed tomography imaging in bone infarction. PMID- 29396013 TI - Coexistence of anti-Jo1 and anti-signal recognition particle antibodies in a polymyositis patient. AB - Idiopathic inflammatory myopathies are a heterogeneous group of potentially treatable myopathies. They are classified, on the basis of clinical and histopathological features, into four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis and inclusion-body myositis. Myositis-associated antibodies and myositis-specific autoantibodies are frequently found in patients with idiopathic inflammatory myopathies, and are useful in the diagnosis and classification. Anti-histidyl transfer RNA synthetase antibody is the most widely prevalent and is highly specific for polymyositis. Signal recognition particle antibody is also a specific autoantibody for polymyositis, but it is infrequent and rarely found in patients having other myositis-specific autoantibodies. We present a man with polymyositis who had both antibodies in serum, which is considered an extremely rare clinical situation. Here we analyze the clinical course and findings, and examine the effect of the coexistence and possible interaction on prognosis. PMID- 29396015 TI - Heavy Water Shedding Light on Antigen-Specific T Cell Responses. AB - CD8 T cells are crucial for long-term immunity. Nevertheless, the in vivo differentiation of human naive CD8 T cells into effector and memory populations remains ill-defined. A recent study assesses the in vivo turnover of human antigen-specific CD8 T cells and suggests that long-lived memory cells arise from effector cells. PMID- 29396014 TI - Generalists and Specialists: A New View of How MHC Class I Molecules Fight Infectious Pathogens. AB - In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems. This review discusses the new concept that poorly expressed promiscuous class I alleles act as generalists to protect against a wide variety of infectious pathogens, while highly expressed fastidious class I alleles can act as specialists to protect against new and dangerous pathogens. PMID- 29396016 TI - Effect of TENS on Postoperative Pain and Pulmonary Function in Patients Undergoing Coronary Artery Bypass Surgery. AB - BACKGROUND: The aim of this study was to determine the effect of electrical nerve stimulation on pain intensity and pulmonary function in patients undergoing coronary artery bypass surgery. MATERIALS AND METHODS: In a randomized clinical trial, a total of 100 patients undergoing coronary artery bypass surgery at Masih Daneshvari Hospital, Tehran, Iran, from February to May 2014, were divided into two groups. In the intervention group (n = 50), patients received routine care along with transcutaneous electrical nerve stimulation (TENS) immediately after admission to the intensive care unit (ICU). In the placebo group (n = 50), patients only received routine care. The pain intensity was measured using a visual analog scale (VAS) every 6 hours for 72 hours after surgery in two conditions of rest and coughing. Pulmonary function was assessed through forced expiratory volume in 1 second (FEV1) and forced volume capacity (FVC) at 24, 48, and 72 hours after surgery. Age, gender, body mass index, narcotic consumption, ICU length of stay, and requests for chest radiographs were recorded. The statistical level of significance was set at p < .05. RESULTS: There were no significant differences between the two groups in terms of age, gender, and body mass index (p > .05). Pain intensity was significantly lower in the TENS group than the placebo group in both resting and coughing condition (p < .05). FVC and FEV1 were significantly better and faster in the TENS group than in the placebo group at 24, 48, and 72 hours after surgery (p < .05). Patients in the TENS group had significantly lower narcotic use and requests for chest radiographs compared with placebo group. CONCLUSIONS: TENS may reduce postoperative pain in resting and coughing conditions, improve pulmonary function, and reduce narcotic use in patients undergoing coronary artery bypass surgery. PMID- 29396017 TI - Numerical validation of a subject-specific parameter identification approach of a quadriceps femoris EMG-driven model. AB - Muscle models can be used to estimate muscle forces in motor tasks. Muscle model parameters can be estimated by optimizing cost functions based on error between measured and model-estimated joint torques. This paper is a numerical simulation study addressing whether this approach can accurately identify the parameters of the quadriceps femoris. The simulated identification task is a single joint maximum voluntary knee concentric-eccentric extension in an isokinetic dynamometer, keeping the hip fixed at a neutral position. A curve considered as the nominal torque was obtained by simulating the quadriceps femoris model exerting a maximum knee extension torque using a set of known parameter values. Three parameters, with different expected sensitivities of force estimations by Hill-type muscle models, were studied: very sensitive, sensitive and not sensitive, corresponding to slack tendon length, maximum isometric force, and pennation angle, respectively. The initial values of the parameters were randomly changed, simulating an ignorance of nominal values. EMG generation and torque measurement error models were used to obtain realistic simulated data corrupted by noise. Simulated annealing was chosen as the optimization algorithm. Different sequences of parameter identification and cost functions were tested. The best nominal torque curve reconstruction was obtained by optimizing the parameters sequentially, starting from slack tendon length using the Euclidean norm cost function. However, the simultaneous estimation of all parameters resulted in the most accurate values for the parameters, although dispersion was relatively large. In conclusion, in the present simulation study using realistic synthetic torque and EMG data, the optimization approach based on torque error curve was able to closely approximate the parameter values of the model's quadriceps femoris muscle. PMID- 29396018 TI - Mechanical properties of cancellous bone from the acetabulum in relation to acetabular shell fixation and compared with the corresponding femoral head. AB - To gain initial stability for cementless fixation the acetabular components of a total hip replacement are press-fit into the acetabulum. Uneven stiffness of the acetabular bone will result in irregular deformation of the shell which may hinder insertion of the liner or lead to premature loosening. To investigate this, we removed bone cores from the ilium, ischium and pubis within each acetabulum and from selected sites in corresponding femoral heads from four cadavers for mechanical testing in unconfined compression. From a stress relaxation test over 300 s, the residual stress, its percentage of the initial stress and the stress half-life were calculated. Maximum modulus, yield stress and energy to yield (resilience) were calculated from a load-displacement test. Acetabular bone had a modulus about 10-20%, yield stress about 25% and resilience about 40% of the values for the femoral head. The stress half-life was typically between 2-4 s and the residual stress was about 60% of peak stress in both acetabulum and femur. Pubic bone was mechanically the poorest. These results may explain uneven deformation of press-fit acetabular shells as they are inserted. The measured half-life of stress-relaxation indicates that waiting a few minutes between insertion of the shell and the liner may allow seating of a poorly congruent liner. PMID- 29396019 TI - Constitutive modeling of compressible type-I collagen hydrogels. AB - Collagen hydrogels have been used ubiquitously as engineering biomaterials with a biphasic network of fibrillar collagen and aqueous-filled voids that contribute to a complex, compressible, and nonlinear mechanical behavior - not well captured within the infinitesimal strain theory. In this study, type-I collagen, processed from a bovine corium, was fabricated into disks at 2, 3, and 4% (w/w) and exposed to 0, 105, 106, and 107 microjoules of ultraviolet light or enzymatic degradation via matrix metalloproteinase-2. Fully hydrated gels were subjected to unconfined, aqueous, compression testing with experimental data modeled within a continuum mechanics framework by employing the uncommon Blatz-Ko material model for porous elastic materials and a nonlinear form of the Poisson's ratio. From the Generalized form, the Special Blatz-Ko, compressible Neo-Hookean, and incompressible Mooney-Rivlin models were derived and the best-fit material parameters reported for each. The average root-mean-squared (RMS) error for the General (RMS = 0.13 +/- 0.07) and Special Blatz-Ko (RMS = 0.13 +/- 0.07) were lower than the Neo-Hookean (RMS = 0.23 +/- 0.10) and Mooney-Rivlin (RMS = 0.18 +/ 0.08) models. We conclude that, with a single fitted-parameter, the Special Blatz-Ko sufficiently captured the salient features of collagen hydrogel compression over most examined formulations and treatments. PMID- 29396020 TI - Low-Intensity Shockwave Therapy for Erectile Dysfunction: A Randomized Clinical Trial Comparing 2 Treatment Protocols and the Impact of Repeating Treatment. AB - BACKGROUND: There is lack of evidence-based optimization of the protocol for low intensity shockwave therapy for erectile dysfunction. Furthermore, the safety and efficacy of repeating shockwave therapy have not been explored. AIM: To compare the efficacy and safety of 6 and 12 treatment sessions within a 6-week treatment period and investigate the effect of repeat treatment after a 6-month period in a 2-phase study. METHODS: Patients with vasculogenic erectile dysfunction that responded to phosphodiesterase type 5 inhibitors were randomized into 2 groups: low-intensity shockwave therapy sessions once (group A, n = 21) or twice (group B, n = 21) per week for 6 consecutive weeks (phase 1). Patients who completed 6 month follow-up were offered 6 additional sessions (phase 2); group A received 2 sessions per week and group B received 1 session per week. Patients were followed for 6 months. OUTCOMES: International Index for Erectile Function erectile function domain (IIEF-EF) score, minimally clinical important differences (MCIDs), Sexual Encounter Profile question 3 (SEP3) score, and triplex ultrasonographic parameters. RESULTS: In phase 1, groups A and B showed improvement in IIEF-EF score, MCID, SEP3 score, and mean peak systolic velocity compared with baseline. MCIDs were achieved in 62% of group A and 71% of group B, and the percentage of yes responses to SEP3 was 47% in group A and 65% in group B (P = .02). Mean peak systolic velocity at baseline and at 3-month follow-up were 29.5 and 33.4 cm/s for group A and 29.6 and 35.4 cm/s for group B (P = .06). In phase 2, group A showed a greater increase in the percentage of yes responses to SEP3 (group A = +14.9; group B = +0.3). When the impact of the total number of sessions received was examined, MCIDs in IIEF-EF score from baseline were achieved in 62%, 74%, and 83% of patients after 6, 12, and 18 sessions, respectively. No treatment-related side effects were reported. CLINICAL IMPLICATIONS: The total number of low-intensity shockwave therapy sessions affects the efficacy of erectile dysfunction treatment. Retreating patients after 6 months could further improve erectile function without side effects. 12 sessions can be delivered within 6 weeks without a 3-week break period. STRENGTHS AND LIMITATIONS: This study lacked a sham-controlled arm. However, all patients were randomized to different groups, and baseline characteristics were similar between groups. Also, all patients were confirmed by triplex ultrasonography to have arterial insufficiency. CONCLUSION: Patients can benefit more in sexual performance from 12 sessions twice per week compared with 6 sessions once a week. Shockwave therapy can be repeated up to a total of 18 sessions. Kalyvianakis D, Memmos E, Mykoniatis I, et al. Low-Intensity Shockwave Therapy for Erectile Dysfunction: A Randomized Clinical Trial Comparing 2 Treatment Protocols and the Impact of Repeating Treatment. J Sex Med 2018;15:334-345. PMID- 29396021 TI - Sexual Inhibition is a Vulnerability Factor for Orgasm Problems in Women. AB - BACKGROUND: The differential role of psychological traits in the etiology and maintenance of female orgasm difficulties is yet to be consistently established. AIM: To investigate the contribution of different psychological trait features (personality, sexual inhibition and excitation, and sexual beliefs) to predict female orgasm and to assess the degree to which these dispositional factors moderate the association between sexual activity and orgasm occurrence in a large community sample of Portuguese women. METHODS: 1,002 women (18-72 years, mean age = 26.27, SD = 8.74) completed questionnaires assessing personality traits (NEO Five Factor Inventory), sexual inhibition and sexual excitation (Sexual Inhibition/Sexual Excitation Scales-Short Form [SIS/SES]), sexual beliefs (Sexual Dysfunctional Beliefs Questionnaire), sexual behavior (frequency of sexual activities and frequency of orgasm occurrence), and social desirability (Socially Desirable Response Set). Hierarchical multiple regression and moderation analyses were conducted while controlling for the effect of covariates such as social desirability, sociodemographic and medical characteristics, and relationship factors. OUTCOMES: The main outcome measurement was orgasm frequency as predicted and moderated by personality, SIS/SES dimensions, and sexual beliefs. RESULTS: Results of the hierarchical multiple regression analysis indicated a significant predictive role for sexual inhibition (associated with fear of performance failure [SIS1] and related to the threat of performance consequences) and body image beliefs in female orgasm occurrence. The significant predictive effect of extraversion and of sexual excitation on orgasm frequency ceased to be significant with the insertion of all trait predictors in the final model. Furthermore, SIS1 significantly moderated the relation between sexual activity and orgasm occurrence. CLINICAL IMPLICATIONS: Attention should be given to individual factors impairing orgasmic response in women, particularly sexual inhibition processes. The development of clinical strategies to address and regulate them is recommended. STRENGTHS AND LIMITATIONS: Although this study investigated a large community sample, this sample was composed of heterosexual, relatively young women and thus generalization of the present results demands some caution. Social desirability was controlled for in the analyses and questionnaires were not collected face to face, which constitutes a strength of this study because social desirability is lower in self-administered online questionnaires compared with paper-and-pencil questionnaires, particularly for more sensitive sexual issues. CONCLUSION: SIS1 was found to be a vulnerability factor for female orgasmic difficulties. Future research should test these findings with different samples, particularly clinical samples of women with orgasmic problems, preferably with the use of longitudinal designs. Tavares IM, Laan ETM, Nobre PJ. Sexual Inhibition is a Vulnerability Factor for Orgasm Problems in Women. J Sex Med 2018;15:361-372. PMID- 29396022 TI - Ignorance Is Not Bliss: If We Don't Understand Hypoactive Sexual Desire Disorder, How Can Flibanserin Treat It? Commentary. AB - BACKGROUND: Female sexual dysfunction (FSD) affects as many as 1 in every 3 women, with a significant portion of these with hypoactive sexual desire disorder (HSDD). These figures alone present significant psychological and pharmacologic challenges. Partly in response to this situation, in 2015 the US Food and Drug Administration approved flibanserin for the treatment of HSDD. This approval has drawn criticism on the grounds of efficacy and necessity. AIM: To better inform potential consumers about FSD, flibanserin and other interventions for the treatment of HSDD, the importance of understanding the mechanism of FSD, and the efficacy of flibanserin and to review existing relevant knowledge. METHODS: A literature review of extant clinic studies and theoretical discussion articles was performed. OUTCOMES: Efficacy of flibanserin for addressing symptoms associated with HSDD in premenopausal women. RESULTS: Extant literature and empirical evidence suggest that the efficacy of flibanserin for the treatment of HSDD in premenopausal women is at least questionable. CLINICAL TRANSLATION: Clinicians considering the prescription of flibanserin would be well advised to appreciate some of the controversies concerning the efficacy of the drug. STRENGTHS AND LIMITATIONS: The prohibitive usage guidelines, tenuous risk-benefit profile, and considerable cost of use of flibanserin are each worthy of consideration. Flibanserin thus far has been trialed in only a narrow patient range: premenopausal women in long-term relationships with acquired or generalized HSDD. CONCLUSIONS: Although we acknowledge that the discovery and use of flibanserin constitute a compelling narrative, we conclude by questioning the specific efficacy and necessity of flibanserin in providing a treatment for HSDD in women. Anderson R, Moffatt CE. Ignorance Is Not Bliss: If We Don't Understand Hypoactive Sexual Desire Disorder, How Can Flibanserin Treat It? COMMENTARY: J Sex Med 2018;15:273-283. PMID- 29396023 TI - Sexual Modes Questionnaire (SMQ): Translation and Psychometric Properties of the Italian Version of the Automatic Thought Scale. AB - BACKGROUND: The Sexual Modes Questionnaire (SMQ) is a validated and widespread used tool to assess the association among negative automatic thoughts, emotions, and sexual response during sexual activity in men and women. AIM: To test the psychometric characteristics of the Italian version of the SMQ focusing on the Automatic Thoughts subscale (SMQ-AT). METHODS: After linguistic translation, the psychometric properties (internal consistency, construct, and discriminant validity) were evaluated. 1,051 participants (425 men and 626 women, 776 healthy and 275 clinical groups complaining about sexual problems) participated in the present study. OUTCOMES: 2 confirmatory factor analyses were conducted to test the fit of the original factor structures of the SMQ versions. In addition, 2 principal component analyses were performed to highlight 2 new factorial structures that were further validated with confirmatory factor analyses. Cronbach alpha and composite reliability were used as internal consistency measures and differences between clinical and control groups were run to test the discriminant validity for the male and female versions. The associations with emotions and sexual functioning measures also are reported. RESULTS: Principal component analyses identified 5 factors in the male version: erection concerns thoughts, lack of erotic thoughts, age- and body-related thoughts, negative thoughts toward sex, and worries about partner's evaluation and failure anticipation thoughts. In the female version 6 factors were found: sexual abuse thoughts, lack of erotic thoughts, low self-body image thoughts, failure and disengagement thoughts, sexual passivity and control, and partner's lack of affection. Confirmatory factor analysis supported the adequacy of the factor structure for men and women. Moreover, the SMQ showed a strong association with emotional response and sexual functioning, differentiating between clinical and control groups. CLINICAL TRANSLATION: This measure is useful to evaluate patients and design interventions focused on negative automatic thoughts during sexual activity and to develop multicultural research. STRENGTHS AND LIMITATIONS: This study reports on the translation and validation of the Italian version of a clinically useful and widely used measure (assessing automatic thoughts during sexual activity). Limits regarding sampling technique and use of the Automatic Thoughts subscale are discussed in the article. CONCLUSION: The present findings support the validity and the internal consistency of the Italian version of the SMQ-AT and allow the assessment of negative automatic thoughts during sexual activity for clinical and research purposes. Nimbi FM, Tripodi F, Simonelli C, Nobre P. Sexual Modes Questionnaire (SMQ): Translation and Psychometric Properties of the Italian Version of the Automatic Thought Scale. J Sex Med 2018;15:396-409. PMID- 29396024 TI - In statistics we trust: Towards the careful derivation and interpretation of meaningful survival estimates in cystic fibrosis. PMID- 29396026 TI - The effect of enteral tube feeding in cystic fibrosis: A registry based study. AB - BACKGROUND: Long-term effect of enteral tube feeding (ETF) in cystic fibrosis (CF) remains equivocal. METHODS: A Belgian CF registry based, retrospective, longitudinal study, evaluated the pre- and post- ETF (n = 113) clinical evolution and compared each patient with 2 age, gender, pancreatic status and genotype class-matched controls. RESULTS: At baseline ETF had a worse BMI z-score (p < 0.0001) and FEV1% (p < 0.0001) compared to controls. Patients eventually receiving ETF, had already a significant worse nutritional status and pulmonary function at first entry in the registry. Both parameters displayed a significant decline before ETF-introduction. ETF had more hospitalization and intravenous antibiotic (IVAB) treatment days (p < 0.0001). After ETF introduction hospitalizations and IVAB decreased significantly. After ETF-introduction BMI z score recuperated towards the original curve before the decline, but remained below the controls. Starting ETF had no effect on rate of height gain in children. The pre-index FEV1 decline (-1.52%/year (p = 0.002)) stabilized to +0.39%/year afterwards. Controls displayed decline of -0.48%/year (p < 0.0001). CONCLUSION: ETF introduction improved BMI z-score and stabilized FEV1, associated with less hospitalizations and IVAB treatments. Higher mortality and transplantation in the ETF cases, leading to drop-outs, made determination of the effect size difficult. PMID- 29396025 TI - Early life growth patterns persist for 12 years and impact pulmonary outcomes in cystic fibrosis. AB - BACKGROUND: In children with cystic fibrosis (CF), recovery from growth faltering within 2 years of diagnosis (Responders) is associated with better growth and less lung disease at age 6 years. This study examined whether these benefits are sustained through 12 years of age. METHODS: Longitudinal growth from 76 children with CF enrolled in the Wisconsin CF Neonatal Screening Project was examined and categorized into 5 groups: R12, R6, and R2, representing Responders who maintained growth improvement to age 12, 6, and 2 years, respectively, and I6 and N6, representing Non-responders whose growth did and did not improve during ages 2-6 years, respectively. Lung disease was evaluated by % predicted forced expiratory volume in one second (FEV1) and chest radiograph (CXR) scores. RESULTS: Sixty-two percent were Responders. Within this group, 47% were R12, 28% were R6, and 25% were R2. Among Non-responders, 76% were N6. CF children with meconium ileus (MI) had worse lung function and CXR scores compared to other CF children. Among 53 children with pancreatic insufficiency without MI, R12 had significantly better FEV1 (97-99% predicted) and CXR scores during ages 6-12 years than N6 (89-93% predicted). Both R6 and R2 experienced a decline in FEV1 by ages 10-12 years. CONCLUSIONS: Early growth recovery in CF is critical, as malnutrition during infancy tends to persist and catch-up growth after age 2 years is difficult. The longer adequate growth was maintained after early growth recovery, the better the pulmonary outcomes at age 12 years. PMID- 29396027 TI - High levels of faecal contamination in drinking groundwater and recreational water due to poor sanitation, in the sub-rural neighbourhoods of Kinshasa, Democratic Republic of the Congo. AB - In many urban and peri-urban areas of developing countries, shallow wells and untreated water from urban rivers are used for domestic purposes, including drinking water supply, population bathing and irrigation for urban agriculture. The evaluation and monitoring of water quality are therefore necessary for preventing potential human risk associated with the exposure to contaminated water. In this study, physicochemical and bacteriological parameters were assessed in an urban river (named Kokolo Canal/Jerusalem River) draining the municipality of Lingwala (City of Kinshasa, Democratic Republic of the Congo) and in two shallow wells used as drinking water supplies, during the wet and dry seasons in order to estimate the seasonal variation of contamination. The faecal indicator bacteria (FIB) isolated strains (Escherichia coli (E. coli) and Enterococcus (ENT)) from water and surface sediment, were characterized for human specific bacteroides by molecular approach. The results revealed very high faecal contamination of water from the shallow wells, and of water and sediments from the river, during both wet and dry seasons. During the wet season, E. coli reached the values of 18.6 * 105 and 4.9 * 105 CFU 100 mL-1 in Kokolo Canal and shallow wells, respectively; and Enterococcus reached the values of 7.4 * 104 and 2.7 * 104 CFU 100 mL-1. Strong mutually positive correlation was observed between E. coli and ENT, with the range of R-value being 0.93 < r < 0.97 (p-value < 0.001, n = 15). The PCR assays for human-specific Bacteroides indicated that more than 98% of 500 isolated FIB strains were of human origin, pointing out the effect of poor household sanitation practices on surface water but also on groundwater contamination. The water samples from the shallow wells and Kokolo Canal were highly polluted with faecal matter in both seasons. However, the pollution level was significantly higher during the wet season compared to the dry season. Physicochemical analysis revealed also very high water electrical conductivity, with values much higher than the recommended limits of the World Health Organization guideline for drinking water. These results highlight the potential human health risk associated with the exposure to water contamination from shallow wells and Kokolo Canal, due to the very high level of human FIB. Rapid, unplanned and uncontrolled population growth in the city of Kinshasa is increasing considerably the water demand, whereas there is a dramatic lack of appropriate sanitation and wastewater facilities, as well as of faecal sludge (and solid waste) management and treatment. The lack of hygiene and the practice of open defecation is leading to the degradation of water quality, consequently the persistence of waterborne diseases in the neighbourhoods of sub-rural municipalities, and there is a growing threat to the sustainability to water resources and water quality. The results of this study should encourage municipality policy and strategy on increasing the access to safely managed sanitation services; in order to better protect surface water and groundwater sources, and limit the proliferation of epidemics touching regularly the city. PMID- 29396028 TI - Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG. AB - Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X linked ATP6AP1, an accessory protein of the mammalian vacuolar H+-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1 dependent impact on the beta-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient. PMID- 29396029 TI - Prenatal treatment of ornithine transcarbamylase deficiency. AB - PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul(r)) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome. PMID- 29396031 TI - Environmental sensing and plant development. PMID- 29396030 TI - DNAJC12: A molecular chaperone involved in proteostasis, PKU, biogenic amines metabolism and beyond? PMID- 29396032 TI - Pound foolish and penny wise-when will dosing of rifampicin be optimised? PMID- 29396033 TI - New insights into functional dyspepsia: further evidence for postprandial distress syndrome as a distinct disease. PMID- 29396034 TI - Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross sectional population-based study. AB - BACKGROUND: The population prevalence, clinical characteristics, and associations for Rome IV functional dyspepsia are not known. Following the publication of the Rome IV criteria for functional gastrointestinal disorders, we aimed to assess the prevalence, characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults across the USA, Canada, and the UK. METHODS: We sent an internet-based cross-sectional health survey to adults in the general population of three English-speaking countries: the USA, Canada, and the UK. We used quota-based sampling to generate demographically balanced and population representative samples. Individuals were invited to complete an online questionnaire on general health, without mention that the purpose of this survey was to examine gastrointestinal symptoms. We excluded participants who failed two attention-test questions or were excessively inconsistent on the three gastrointestinal questions that were presented twice in the survey for this particular purpose. The survey enquired about demographics, health-care visits, medications, somatisation, quality of life, and symptom-based criteria for Rome IV functional dyspepsia as well as for irritable bowel syndrome (IBS) and functional heartburn. We made subsequent comparisons between participants with Rome IV functional dyspepsia and controls without dyspepsia. The primary objective was to identify participants who fulfilled symptom-based criteria for Rome IV functional dyspepsia and categorise them into postprandial distress syndrome, epigastric pain syndrome, or overlapping subtypes. FINDINGS: 6300 general population adults completed the health survey; 2100 each from the USA, Canada, and the UK. 369 responses were deemed inconsistent, leaving data for 5931 adults. Rome IV functional dyspepsia was significantly more prevalent in the USA (232 [12%] of 1949) than in Canada (167 [8%] of 1988) and the UK (152 [8%] of 1994; p<0.0001). The subtype distribution was 61% postprandial distress syndrome, 18% epigastric pain syndrome, and 21% overlapping variant with both syndromes; this pattern was similar across the countries. Participants with functional dyspepsia had significantly greater health impairment and health-care usage than those without dyspepsia. Participants with the overlapping variant showed greater somatisation and poorer quality-of-life scores than did individuals with either postprandial distress syndrome or epigastric pain syndrome alone. In multivariate analysis, independent factors associated with all functional dyspepsia subtypes included worsening quality of life and the presence of symptoms compatible with functional heartburn and IBS, with functional heartburn and IBS having the strongest association with overlapping postprandial distress syndrome and epigastric pain syndrome. Notably, somatisation showed a positive association with postprandial distress syndrome and the overlapping variant, and use of antidepressants showed a negative association with postprandial distress syndrome. INTERPRETATION: Approximately 10% of the adult population fulfils symptom-based criteria for Rome IV functional dyspepsia and incurs considerable associated health impairment. The functional dyspepsia subtypes show differing associations, suggesting differences in pathophysiological processes or influences. FUNDING: The Rome Foundation, the US National Institute of Diabetes and Digestive and Kidney Diseases, the Swedish Medical Research Council, AFA Insurance, Ferring Pharmaceuticals, and the Faculty of Medicine, University of Gothenburg, Gothenburg, Sweden. PMID- 29396035 TI - Demonstration of simulated annealing optimization for permanent breast seed implant treatment planning. AB - PURPOSE: Permanent breast seed implant (PBSI) is a developing brachytherapy technique for the treatment of early-stage breast cancer. In current practice, PBSI uses manual planning strategies to generate clinical treatment plans. In this work, a simulated annealing-based algorithm is developed to demonstrate the first application of inverse optimization for PBSI. METHODS AND MATERIALS: Target, skin, and chest wall muscle contours, exported from a treatment planning system in digital imaging and communications in medicine format, are used as inputs. To optimize, the user defines the dose-volume histogram objectives for the target and specifies a relative weighting for target and skin constraints. A 10-patient cohort of previously treated patients was planned by using the inverse optimization algorithm. Plan quality was compared to the clinically treated manually generated plans using the V90%, V100%, V150%, and V200% for the planning target volume (PTV), V90% and D0.2 cc for skin dose, and PTV conformity indices. RESULTS: For each of the 10 patients, patient-wise paired differences between inverse and manual plans were analyzed and presented in box plots. Comparing inverse and manual planning techniques, a statistical difference was not observed (p > 0.05) in PTV coverage criteria (V90%, V100%) and dose to skin2mm. A statistical difference was observed in the inverse plans as a reduction of the V150% (mean of 6.2%) and increase in conformity index of the 20%, 50%, 90%, and 100% isodose lines. CONCLUSIONS: This work presents the first application of inverse optimization used to generate PBSI treatment plans. A 10-patient cohort previously treated with PBSI was retrospectively planned for comparison with the clinically treated manually generated plans. PMID- 29396036 TI - Progress Toward Precisely Diagnosing Autoimmune Retinopathy. PMID- 29396037 TI - Evaluation of Goldmann applanation tonometry, rebound tonometry and dynamic contour tonometry in keratoconus. PMID- 29396038 TI - Long-term experience with perampanel in refractory epilepsy: Experience at tertiary epilepsy care center in Tours. PMID- 29396039 TI - A Tyrosine Phosphorylation Cycle Regulates Fungal Activation of a Plant Receptor Ser/Thr Kinase. AB - Plants initiate immunity by cell-surface pattern-recognition receptors (PRRs), which perceive non-self molecules. PRRs are predominantly receptor serine/threonine (Ser/Thr) kinases that are evolutionarily related to animal interleukin-1 receptor-associated kinase (IRAK)/Pelle-soluble kinases. However, how the activity of these receptor kinases is modulated remains poorly understood. We report that the Arabidopsis PRR chitin elicitor receptor kinase 1 (CERK1) is autophosphorylated in unstimulated cells at tyrosine428 (Tyr428), a modification that is required for CERK1 activation upon binding to the fungal cell wall component chitin. Upon chitin activation, CERK1 recruits the CERK1 interacting protein phosphatase 1 (CIPP1), a predicted Ser/Thr phosphatase, to dephosphorylate Tyr428 and dampen CERK1 signaling. CIPP1 subsequently dissociates from Tyr428-dephosphorylated CERK1, allowing CERK1 to regain Tyr428 autophosphorylation and return to a standby state. This work sheds light onto plant chitin signaling and shows that a receptor kinase and phosphatase can coordinately regulate signal transduction of a receptor kinase through a phosphorylation cycle. PMID- 29396041 TI - Oxidative and endoplasmic reticulum stress defense mechanisms of bovine granulosa cells exposed to heat stress. AB - In most mammalian species including cattle, heat stress has detrimental effects on ovarian function through disturbing estradiol production and viability of granulosa cells. However, effect of heat stress and underlying cellular defense mechanisms of bovine granulosa cells is not fully understood. Here, we aimed to investigate the effect of heat stress on granulosa cells function and the associated defense mechanism. For this an in vitro granulosa cell model was used to investigate the role of elevated temperature (41 degrees C) on granulosa cell functions at 24 h and 48 h exposure compared to the control cultured at 37 degrees C. The results showed that reactive oxygen species level was higher in cells under 41 degrees C at 24 h compared to control. In response to increased reactive oxygen species level, the expression of NRF2 and its antioxidant genes, CAT and PRDX1 were higher in bovine granulosa cells exposed to heat stress. Interestingly, heat stress markedly increased expression of endoplasmic reticulum stress marker genes; GRP78 and GRP94, in cultured bovine granulosa cells at 24 h, and higher protein accumulation of GRP78 accompanied by increased expression of apoptotic genes, BAX and CASPASE-3. Moreover, heat stress significantly decreased the bovine granulosa cells proliferation, which was supported by decreased in the expression of proliferation marker gene PCNA. All in all heat stress induce reactive oxygen species accumulation, apoptosis and reduced proliferation, which trigger the NRF2 mediated oxidative stress and endoplasmic reticulum stress response by bovine granulosa cells. PMID- 29396040 TI - Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium. AB - Botulinum neurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster. PMID- 29396042 TI - Cow body condition affects the hormonal release of ovarian cells and their responses to gonadotropic and metabolic hormones. AB - The body condition score (BCS) of cows affects their reproductive efficiency, but the underlying mechanism is unclear. We examined the effect of BCS on the basic ovarian cell functions and their responses to gonadotropic and metabolic hormones. We isolated ovarian cells from cows with a tendency toward emaciation (BCS2) and those with an average body condition (BCS3), and we compared their hormonal release and responses to FSH, leptin, ghrelin, and neuropeptide Y (NPY) added at doses of 0, 1, 10, or 100 ng/mL. Progesterone, testosterone, estradiol, and insulin-like growth factor I (IGF-I) release were evaluated by RIA. No differences were found in progesterone or testosterone release between BCS2 and BCS3 cells; however, ovarian cells from BCS2 cows released more estradiol and IGF I than cells from BCS3 cows. FSH, ghrelin, and NPY promoted progesterone release in BCS2 cells but had no stimulatory or inhibitory effect on BCS3 cells. In contrast, leptin promoted progesterone release in BCS3 cells and inhibited progesterone release in BCS2 cells. FSH also promoted testosterone release in both BCS2 and BCS3 cells but inhibited progesterone at a low dose in BCS3 cells. Leptin inhibited testosterone release in BCS3 cells but not in BCS2 cells. Estradiol release was promoted by leptin and ghrelin in BCS3 cells; however, it was unaffected by leptin and inhibited by ghrelin in BCS2 cells. IGF-I production was promoted by FSH and inhibited by leptin in both groups. Ghrelin suppressed IGF-I release in BCS2 cells and increased IGF-I release in BCS3 cells. NPY promoted IGF-I release in BCS2 cells but not in BCS3 cells. Our results demonstrate the effects of BCS on ovarian cell estradiol and IGF-I (but not progesterone or testosterone) release, as well as on the responses of ovarian cells to FSH, leptin, ghrelin, and NPY. PMID- 29396043 TI - Characteristics and fertility of domestic cat epididymal spermatozoa cryopreserved with two different freezing media. AB - The study represents a comparison of cryopreservation of domestic cat epididymal spermatozoa with two commercially available freezing media: CaniPlus Freeze (CPF) and SpermFreeze (SF). The viability of nonfrozen spermatozoa evaluated by the VitalScreen test was 68.7 +/- 3.0%. These figures were lower for the frozen thawed spermatozoa: 51.2 +/- 6.3% for CPF group and 54.4 +/- 3.1% for SF group. The motility of nonfrozen spermatozoa was 57.2 +/- 4.5%. These figures were reduced in both frozen-thawed groups; however, there was no significant difference in these parameters between CPF (30.8 +/- 7.1%) and SF (27.4 +/- 8.1%) groups. The percentage of nonprogressively moving motile spermatozoa after freezing-thawing was decreased in both frozen-thawed groups (23.5 +/- 5.9 and 12.0 +/- 2.4 for CPF and SF frozen correspondingly) as compared with nonfrozen controls (42.1 +/- 4.1%). Morphology of spermatozoa was assessed by light microscopy. The mean percentages of normal spermatozoa were 28.5 +/- 4.1% for nonfrozen group, 26.0 +/- 2.3% for CPF frozen group, and 23.9 +/- 1.9% for SF frozen group. The most frequent anomalies in all the three groups were flagella and combined defects. In vitro fertilization (IVF) of domestic cat oocytes with nonfrozen and frozen-thawed spermatozoa produced developing embryos. The percentage of in-vitro-derived embryos was 43.6% after using nonfrozen spermatozoa. Frozen-thawed spermatozoa developed at a similar rate (44.0%) after using SF. However, the rate of embryo development was lower (20.1%) when CPF was used. The in-vitro-derived embryos in the nonfrozen group consisted of 46.9 +/- 2.5 cells after 5-day culturing. After cryopreservation with SF and CPF the cell numbers per embryo were 39.9 +/- 2.7 and 31.8 +/- 3.4 correspondingly. In CPF group these numbers were lower than in nonfrozen controls. Cryopreservation of spermatozoa with either of two freezing media led to a decrease in post-thaw viability and motility of spermatozoa but did not affect the rate or spectrum of their morphological anomalies. The use of CPF, but not SF led to a decrease of sperm fertilizing abilities. PMID- 29396044 TI - Frequencies of IL-15Ralpha+ cells in patients with Behcet's disease and the effects of overexpressing IL-15Ralpha+ on disease symptoms in mice. AB - It has been suggested higher serum levels of IL-15 and lower expression levels of IL-15 receptor alpha (IL-15Ralpha) are correlated with pathogenesis of Behcet's disease (BD). However, whether overexpressing IL-15Ralpha could be used as a therapeutic candidate for BD is currently unclear. Therefore, the purpose of this study was to determine whether overexpressing IL-15Ralpha could affect BD symptoms in a mouse model. IL-15/IL-15Ralpha complex expressing vector or protein complex of IL-15/IL-15Ralpha-Fc was used to treat BD mice. Frequencies of IL 15Ralpha+ cells in peripheral blood leukocytes (PBL) and lymph node cells were determined using a flow cytometer. BD symptoms in mice improved after treatment with IL-15/15Ralpha expression vector or IL-15/IL-15Ralpha-Fc protein complex. In addition, treatment with pIL-15/15Ralpha significantly (p = .016) decreased disease severity score of BD mice compared to treatment with control vector. Frequencies of IL-15Ralpha+ cells were also significantly (p = .01) higher in peritoneal macrophages of pIL-15/15Ralpha treated BD mice than those of mice treated with control vector. Frequencies of IL-15Ralpha+ PBL were also significantly higher in BD mice treated with IL-15/IL-15Ralpha-Fc protein complex than those in the control group. These results suggest up-regulating IL-15Ralpha+ cells could be used as novel therapeutic strategies to control BD in the future. PMID- 29396045 TI - Expression of the B cell differentiation factor BAFF and chemokine CXCL13 in a murine model of Respiratory Syncytial Virus infection. AB - Innate immune responses are known to influence the subsequent development of adaptive immunity. We have previously shown that RSV infection of human airway epithelial cells results in production of the B cell growth factor, BAFF. To better understand how the airway responds to RSV infection by production of this and other factors to support or enhance local B cell responses to infection, we analysed the lung expression of BAFF and B cell homeostatic chemokines CXCL12, CXCL13, CCL19 and CCL21 in a murine model of RSV infection. Following infection with A2 strain RSV, the highest RSV N gene expression was observed at day 4 after challenge with virus. In contrast, two peaks of elevated BAFF expression at days 2 and 7 were observed. CXCL13 was significantly elevated at days 1, 2 and 7. CXCL12, CCL19 and CCL21 were expressed within lung tissue from control and RSV challenged animals but no significant difference in expression was found. Immunofluorescence showed BAFF to be present throughout the tissue however CXCL13 expression was localized to cell rich areas probably constituting lymphoid aggregates. Our results define the kinetics of B cell chemoattractant and growth factor expression during RSV infection and indicate an important role for these cytokines in the airway response to RSV infection. PMID- 29396046 TI - Simultaneous presence of hypercoagulation and increased clot lysis time due to IL 1beta, IL-6 and IL-8. AB - Circulating cytokines, and particularly the interleukin (IL)-family are known to play an important role in inflammation. These molecules circulate in the blood and therefore have a direct effect on the plasma molecules and the formed elements like the erythrocytes and platelets. Aberrant coagulation (hypercoagulation or blood clots that form too easily) and clot lyses (hypofibrinolysis, where clots do not dissolve properly, with an abnormally low rate of clot lysis time), are usually the hallmarks of many inflammatory conditions. However, the mechanism by which cross-linking augments clot stiffness remains undetermined. IL-1beta; IL-6 and IL-8 has been found to be involved in most chronic and acute inflammatory diseases. In the present study, we investigate clot structure of healthy blood, with the addition of these 3 interleukins, to determine the individual effects at concentrations that mimic low-grade, chronic inflammation. Previous studies showed that clot rheological behavior is regulated by at least the following three factors, fibrinogen concentration, fibrin network architecture and FXIIIa-induced ligation. We investigated clot formation and lysis using thromboelastography (TEG), before and after exposure, and created clots by adding thrombin to whole blood. This allowed us to look at extensive fibrin fiber formation and their interactions with particularly the erythrocytes, using scanning electron microscopy (SEM). Our results showed that IL-1beta; IL-6 and IL-8 causes hypercoagulation and results in a disheveled fibrin clot, with trapped RBCs. IL-8 showed eryptosis (a type of apoptosis in erythrocytes). Our lysis results showed that both clot lysis time and maximum rate of lysis are decreased, with the addition of the interleukins. This is a novel finding and the observations reported in this paper, therefore points to the importance of looking at the effects of individual circulating inflammagens, to better understand the role that each play in the expression of disease. These methods can be used for an individualized patient-orientated approach in healthcare to track blood viscosity in conditions with acute and chronic inflammation. PMID- 29396047 TI - Fisetin inhibits TNF-alpha/NF-kappaB-induced IL-8 expression by targeting PKCdelta in human airway epithelial cells. AB - Fisetin (3,7,3',4'-tetrahydroxyflavone), a natural flavonoid, is a therapeutic agent for respiratory inflammatory diseases such as chronic obstructive pulmonary disease (COPD). However, detailed molecular mechanisms regarding the target protein of fisetin remain unknown. Fisetin significantly reduces tumour necrosis factor alpha (TNF-alpha)-induced interleukin (IL)-8 levels by inhibiting both nuclear factor kappa B (NF-kappaB) transcriptional activity and the phosphorylation of its upstream effectors. We show that fisetin prevents interactions between protein kinase C (PKC)delta and TNF receptor-associated factor 2 (TRAF2), thereby inhibiting the inhibitor of kappa B kinase (IKK)/NF kappaB downstream signalling cascade. Furthermore, we found that fisetin directly binds to PKCdelta in vitro. Our findings provide evidence that fisetin inhibits the TNF-alpha-activated IKK/NF-kappaB cascade by targeting PKCdelta, thereby mediating inflammatory diseases such as COPD. These data suggest that fisetin is a good therapeutic drug for the treatment of inflammatory lung diseases, such as COPD, by inhibiting the TNF-alpha/NF-kappaB signalling pathway. PMID- 29396048 TI - Pro- and anti-inflammatory biomarkers and traumatic brain injury outcomes: A review. AB - Traumatic Brain Injury (TBI) triggers a cascade of secondary biological and physiological effects that are variable, depending on the severity, location, and complexity of the injury. Improved diagnosis and prognosis of brain injury may be possible by examining changes in protein biomarker concentrations and, determining their role in long-term outcomes may improve treatment. One promising direction for biomarker research surrounds pro- and anti-inflammatory cytokines which may have utility for predicting short and long-term prognosis after TBI, and may also be therapeutic targets in shaping neuronal recovery following a TBI. The purpose of this review is to examine the relationship between TBI symptoms and changes in pro- and anti- inflammatory biomarkers. Eighteen (18) published articles met criteria for inclusion. Fourteen studies focused on individuals with severe TBI. Increased levels of interleukin (IL)-6, IL-1, IL-8, IL-10 and tumor necrosis factor alpha (TNFalpha) were associated with worse outcomes, with most studies focusing on morbidity and mortality. It is important to identify the biochemical changes that may influence or initiate the presentation of health outcomes after a TBI. Earlier identification of symptoms associated with these biochemical changes can be used to support better treatment planning, targeted interventions and ultimately, improvement in patient outcomes. PMID- 29396049 TI - Increased expression of angiogenic cytokines in CD56+ uterine natural killer cells from women with recurrent miscarriage. AB - OBJECTIVE: To compare the expression pattern of angiogenic cytokines in CD56+ uNK cells from peri-implantation endometrium in women with a history of recurrent miscarriage and fertile controls. METHODS: 28 women were recruited, from which 18 women were diagnosed as recurrent miscarriage and 10 women were of proven fertility. Endometrial biopsy samples were obtained precisely 7 days after luteinization hormone surge in a natural cycle. The angiogenic profile of isolated CD56+ uNK cells was determined by RayBio human angiogenesis antibody array G Series 1000. Differentially expressed angiogenic cytokines between groups were validated by ELISA kits. RESULTS: CD56+ uNK cells freshly isolated from peri implantation endometrium were determined to be >90% pure. Angiogenic cytokine array demonstrated that CD56+ uNK cells are one of the angiogenic factors producers in endometrium around the time of embryo implantation. A differential angiogenic cytokine expression profile was found between two groups, with significantly higher expressions of angiogenin, VEGF-A and bFGF in CD56+ uNK cells from women with recurrent miscarriage, compared with fertile controls. CONCLUSIONS: Differential angiogenic cytokine profile of isolated CD56+ uNK cells suggested the role of uNK cells in the altered endometrial vascularity at the time of implantation, which may account for the endometrial contribution to recurrent miscarriage. PMID- 29396050 TI - Association of interleukin (IL)-4 variable number of tandem repeats (VNTRs) and IL-4-590 promoter polymorphisms with susceptibility to pediatric autoimmune hepatitis type 1. AB - OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease mediated by an autoimmune reaction to hepatocytes, the present study aimed to assess the possible associations between interleukin-4 (IL-4) variable number of tandem repeats (VNTRs) and IL-4-590 promoter polymorphisms and susceptibility to autoimmune hepatitis type 1 in children. SUBJECTS AND METHODS: The study was performed on 101 children diagnosed with AIH and 104 apparently healthy, age and sex-matched control children, diagnosis of AIH was based on the simplified score for the diagnosis of AIH. Genotyping for the IL-4 VNTR and IL-4-590 were performed using PCR-RFLP. RESULTS: The distribution of genotype frequencies of IL 4 gene intron 3 VNTR polymorphism were not significantly different between AIH patients and controls for 3R/2R and 2R/2R genotypes, while the 2R allele distribution was significantly higher among AIH patients than the control group. The frequency of IL-4-590 single nucleotide polymorphism (SNP) CT and TT genotypes was statistically higher among AIH patients than controls. CONCLUSION: This study revealed the presence of an association between IL-4 -590 TT genotype and T alleles with increased AIH risk in pediatric patients, also assess its severity as they were detected with Child Plugh scores B and C. PMID- 29396051 TI - Expression analysis of cytokine coding genes in epileptic patients. AB - Epilepsy is a chronic disorder in which immune dysregulation is shown to be involved. Imbalances in the cytokine levels both in serum and brain tissue have been demonstrated in epileptic patients. In the present study, we assessed mRNA expression of TNF-alpha, TGF-beta, IFN-gamma, CXCL8, IL-1beta, IL-2, 1L-4, IL-6, IL-17 and CXCL8 in blood samples of 40 epileptic patients compared with age- and sex-matched healthy controls by means of quantitative real time PCR. The relative levels of CXCL8 transcripts were significantly higher in total epileptic patients compared with healthy subjects (P = .023). Relative mRNA expression of IFN-gamma was significantly higher in female patients compared with female healthy subject (P = .048). In addition, significant correlations have been found between the mRNA levels of mentioned cytokines. Such imbalance between expression of pro inflammatory and anti-inflammatory cytokines might be implicated in the pathogenesis of epilepsy. PMID- 29396053 TI - How well does qSOFA correspond to underlying systemic inflammatory response? AB - Need for prompt recognition and management of sepsis recently led to the introduction of qSOFA score. However, its association with underlying host inflammatory response remains unclear, while previous studies have challenged its performance in non - intensive care unit (ICU) patients comparing to previously used systemic inflammatory response syndrome (SIRS) criteria. Between June 2016 and April 2017, we performed a prospective observational study in the medical ward of a tertiary hospital to explore the relation of qSOFA >= 2 and <2 to underlying inflammatory response, as this is mirrored in levels of serum pro- and anti-inflammatory mediators i.e. IL-6, IL-10 and TNF-alpha. A total of 100 consecutive patients were finally included in this study. Comparable levels [(pg/ml) median (IQR)] of IL-6 [200 (53-200) vs 65.1 (17.3-200)], IL-10 [ 7 (2.3 170.6) vs 2.3 (2.3-27.7)], and TNF-alpha [4 (4-46.1) vs 46.06 (4-227.2)] were noted between group of patients with qSOFA >= 2 or <2. Nevertheless, prognosis was worse in patients with qSOFA >= 2 showing longer length of stay [10 (7-25) vs 5 (3-7) days, p = .03] and lower recovery rates (41 vs 93%, p < .0001). Our results underline the need for prompt management of critically ill patients in presence of systemic inflammatory response regardless of qSOFA score, partly reflecting its low sensitivity comparing to previously used SIRS criteria. PMID- 29396054 TI - Could the inhibition of IL-17 or IL-18 be a potential therapeutic opportunity for gastric cancer? AB - Chronic inflammation is recognized as a key tumor-promoting factor in a number of epithelial cancers, including gastric cancer (GC). The production of pro inflammatory cytokines in the tumor microenvironment by both the innate and the adaptive immune response can activate signaling pathways that are associated with increased cell survival and proliferation of cancer cells. Among the cytokines that have most commonly been linked to inflammation-associated cancers, are the Th17 cell-associated cytokines IL-17A, IL-23, IL-22, and the IL-1 family members IL-1beta and IL-18. However, whether their contribution to inflammation associated cancers is universal, or specific to individual types of cancers, remains to be elucidated. This review will explore our current understanding of the known roles of these cytokines in gastritis and discuss how their therapeutic inhibition may be useful for GC. PMID- 29396052 TI - TGF-beta signaling in cancer: post-transcriptional regulation of EMT via hnRNP E1. AB - The TGFbeta signaling pathway is a critical regulator of cancer progression in part through induction of the epithelial to mesenchymal transition (EMT). This process is aberrantly activated in cancer cells, facilitating invasion of the basement membrane, survival in the circulatory system, and dissemination to distant organs. The mechanisms through which epithelial cells transition to a mesenchymal state involve coordinated transcriptional and post-transcriptional control of gene expression. One such mechanism of control is through the RNA binding protein hnRNP E1, which regulates splicing and translation of a cohort of EMT and stemness-associated transcripts. A growing body of evidence indicates a major role for hnRNP E1 in the control of epithelial cell plasticity, especially in the context of carcinoma progression. Here, we review the multiple mechanisms through which hnRNP E1 functions to control EMT and metastatic progression. PMID- 29396055 TI - The twin peg Oxford knee - Medium term survivorship and surgical principles. AB - BACKGROUND: A multicentre study of single peg Oxford knees reported failure associated with osteoarthritis progression, femoral component loosening, unexplained pain and meniscal bearing dislocation. Suboptimally positioned femoral components and intraoperative MCL damage could explain these problems. We hypothesised that modifying implantation technique to optimise femoral component positioning and MCL preservation, and introducing the twin peg Oxford knee would address these problems and improve longer term survival. Moreover, its better congruency in high flexion could reduce wear. This study aims to investigate this hypothesis by asking 1) Is the 98% survivorship up to nine years found in an earlier study sustained at longer term (up to 13 years)? 2) What are the remaining causes of failure? METHODS: We described our modified implantation technique. A cohort of all patients treated by the senior author using this modified technique and the Oxford twin peg cemented knee replacement between September 2003 and August 2013 was investigated. A survival analysis was performed and the causes of failure were analysed. RESULTS: The cohort consisted of 468 patients with 554 medial cemented implants. In all, 16 implants were revised and the 12-year survivorship was 95%. Patients with extended indications had a lower survivorship than those with anteromedial osteoarthritis (10-year survival rate 78% vs 97%, p<0.001). There were no failures due to femoral loosening. CONCLUSIONS: Using our surgical principles the cemented twin peg Oxford knee can result in good medium to long-term implant survival, comparable to those obtained by the originating centre for the single peg Oxford knee. PMID- 29396056 TI - Inflammation in human carotid atheroma plaques. AB - Inflammation in carotid atherosclerotic plaque is linked to plaque rupture and cerebrovascular accidents. The balance between pro- and anti-inflammatory mediators governs development of the plaque, and may mediate enhancement of lesion broadening or, on the contrary, delay progression. In addition to macrophages and endothelial cells, smooth muscle cells (SMCs), which are the dominant cell subset in advanced plaques, are crucial players in carotid atherosclerosis development given their ability to differentiate into distinct phenotypes in reponse to specific signals received from the environment of the lesion. Carotid atheroma SMCs actively contribute to the inflammation in the lesion because of their acquired capacity to produce inflammatory mediators. We review the successive stages of carotid atheroma plaque formation via fatty streak early-stage toward more advanced rupture-prone lesions and document involvement of cytokines and chemokines and their cellular sources and targets in plaque progression and rupture. PMID- 29396057 TI - Cerebrovascular disorders and Fahr's disease: Report of two cases and literature review. AB - Fahr's disease is a rare idiopathic nosological entity, characterized by calcification of the basal ganglia and dentate nuclei of the cerebellum. Sometimes it may be associated to other diseases like cerebrovascular disorders. However, this link remains unclear and it needs to be further validated. We report two cases of patients with cerebrovascular disorders and Fahr's disease. In the first case, a 69-years-old woman with right internal capsule-basal ganglia haemorrhage. In the second case, a 72-years-old woman with ischemic stroke and pericallosal artery aneurysm. The physiopathology is discussed and concerning literature is reviewed. PMID- 29396058 TI - Stuttering in Parkinson's disease after deep brain stimulation: A note on dystonia and low-frequency stimulation. AB - Stuttering, a speech fluency disorder, is a rare complication of Deep Brain Stimulation (DBS) in Parkinson's Disease (PD). We report a 61 years-old patient with PD, afflicted by severe On and Off dystonia, treated with Subthalamic Nucleus DBS that developed post-DBS stuttering while on 130 Hz stimulation. Stuttering reduction was noted when frequency was changed to 80 Hz, but the previously observed dystonia improvement was lost. There are no reports in literature on patients developing stuttering with low-frequency stimulation. We question if low-frequency stimulation could have a role for managing PD's post DBS stuttering, and notice that stuttering improvement was associated with dystonia worsening suggesting that they are distinct phenomena. PMID- 29396059 TI - Flunarizine and the risk of parkinsonism in a newly diagnosed type 2 diabetic population in Taiwan: A nested case-control study. AB - Previous studies demonstrated that both diabetes and flunarizine use can increase the risk of parkinsonism. The aim of the current study was to investigate the risk of developing parkinsonism after flunarizine treatment, in a cohort of patients newly diagnosed with type 2 diabetes. We conducted a nested case-control study of a type 2 diabetic cohort from the Taiwan Longitudinal Health Insurance Database 2005 (LHID 2005). Each incident case of parkinsonism, during the period from 2001 to 2013, was randomly matched with 3-10 controls, according to age, sex, calendar year of cohort entry, and the duration of follow-up. Conditional logistic regression was used to estimate the odds ratio (OR) of parkinsonism associated with flunarizine use. The cohort consisted of 44,644 patients with newly diagnosed type 2 diabetes from 2001 to 2013, of whom 464 patients had a parkinsonism event during the follow-up period. The adjusted OR of parkinsonism with relation to flunarizine use was 2.75 (95% confidence interval: 2.26-3.36). There were also duration- and dose-response effects. Compared to those who had not used it, the OR for developing parkinsonism was 1.77 for patients who used flunarizine for less than 1 month. When the exposure period expanded over 3 months, the OR increased to 7.03. Our findings suggested that flunarizine use is a potential risk factor for parkinsonism in patients with newly diagnosed type 2 diabetes, especially when the drug is persistently used for over 3 months. PMID- 29396060 TI - Prognostic analysis of patients who underwent gross total resection of newly diagnosed glioblastoma. AB - Despite cumulative evidence supporting the idea that gross total resection (GTR) contributes to prolonged survival of patients with glioblastoma (GBM), the survival outcome of such patients remains unsatisfactory. To develop more effective postoperative therapeutic strategies for patients who underwent GTR, identification of prognostic factors influencing survival is urgently needed. Here we retrospectively analyzed prognostic factors for patients who underwent GTR of newly diagnosed GBM, with a particular focus on the influence of the subventricular zone (SVZ) as the tumor location. Forty-eight consecutive patients with newly diagnosed GBM who underwent GTR during the initial operation were investigated. Tumor involvement of the SVZ was significantly associated with overall survival (OS). The SVZ-positive group had a significantly shorter median OS of 12.2 months, compared to 34.9 months for the SVZ-negative group. The occurrence of leptomeningeal dissemination was significantly influenced by tumor involvement of the SVZ, but was not significantly influenced by ventricular opening during surgery. We observed a statistically significant difference in OS according to radiation modality. The median OS was 36.9 months for patients treated with high-dose proton beam therapy, compared with 26.2 months for patients treated with conventional radiotherapy. We demonstrated that tumor involvement of the SVZ was associated with poor survival of patients who underwent GTR of newly diagnosed GBM, suggesting the potential need for therapeutic strategies that specifically target tumors in the SVZ. Further prospective studies to evaluate whether radiotherapy targeting the SVZ improves survival of patients with tumor involvement of the SVZ who had undergone GTR are warranted. PMID- 29396061 TI - Anaerobic bacterial meningitis in adults. AB - Anaerobic infection is a very uncommon condition in adult bacterial meningitis (ABM), and its clinical characteristics have yet to be clarified. We enrolled 540 patients with culture-proven bacterial meningitis during a study period of 30 years (1986-2015), of whom 13 (2.4%) had anaerobic infections. These 13 patients were eight men and five women, aged 22-77 years. Among them, 53.8% (7/13) had a postneurosurgical state as the preceding event, and 79.6% (10/13) had underlying medical conditions including diabetes mellitus, malignancy, liver cirrhosis, cerebral infarct and alcoholism. Nosocomial and mixed infections were found in 15.5% (2/13) and 46.1% (6/13) of the patients, respectively. A total of 14 anaerobic strains were isolated from cerebrospinal fluid specimens, including nine Gram-negative (G(-)) strains: Fusobacterium nucleatum (3), Prevotella species (3) and Bacteroides fragilis (3), and five Gram-positive (G(+)) strains: Propionibacterium acnes (3) and Peptostreptococcus micros (also known as Parvimonas micra) (2). All of the implicated G(+) anaerobic bacteria were susceptible to penicillin, and no multiple drug-resistant strains were found among the implicated G(-) anaerobic bacteria. Despite treatment, 30.8% (4/13) of the patients died. Of the nine survivors, 22.2% (2/9) had a full recovery, while the other 77.8% (7/9) had varying degrees of neurological deficits. Compared with the good outcome group (n = 6, modified Rankin scale (mRS) scores: 0-2), the poor outcome group (n = 7, mRS scores ?3) had higher incidence of seizure. These results may offer a preliminary view of the clinical characteristics of anaerobic ABM. PMID- 29396062 TI - Sellar plasmacytomas masquerading as pituitary adenomas: A systematic review. AB - Given the rarity of intracranial plasmacytomas, these lesions are frequently misdiagnosed as pituitary adenomas. We report on the distinguishing characteristics of sellar plasmacytomas from cases in the literature and our experience. A literature search was conducted to collect all documented cases of a plasmacytoma originating in the sellar region. Patient characteristics, medical history, presentation, tumor characteristics, and survival data were collected. An additional case from our institution not previously reported was included. Thirty-one patients with sellar plasmacytomas were studied. Presenting symptoms were most commonly headache (68%), diplopia (65%) and visual field disturbances (10%). Fifteen patients (48%) were initially suspected of having a pituitary adenoma. Pathologic diagnosis of plasmacytoma preceded a finding of multiple myeloma in 14 cases (45%). Thirty patients (90%) had surgical intervention. Adjuvant therapy consisted of radiotherapy for twenty-five patients (81%) and chemotherapy for sixteen (52%). Tumor recurrence was reported for 7 cases (23%). Nine deaths were reported (23%). We demonstrate that cranial nerve involvement is far more common in sellar plasmacytomas than conventional pituitary adenomas. Given the successful management of these tumors with radiotherapy, such deficits, particularly in patients with known multiple myeloma, should impact the diagnostic workup and treatment considerations. PMID- 29396063 TI - Forgetting the fundoscope - A case of fulminant idiopathic intracranial hypertension causing rapid visual loss. AB - Idiopathic intracranial hypertension (IIH) is a syndrome of elevated intracranial pressure without evidence of intracranial mass lesion or venous thrombosis, and bland cerebrospinal fluid examination. It mostly affects overweight women of childbearing age and if left untreated, can lead to permanent visual loss. Visual decline in this condition is generally slow, over months to years. However, a small proportion of patients develop rapidly progressive visual loss within days or weeks of onset of headaches. We describe a 29 year-old patient with fulminant IIH in whom inadequate fundoscopy and assessment of vision contributed to a delay in diagnosis and poor outcome. Unfortunately, competence with the bedside examination technique of fundoscopy is declining. We emphasise the importance of thorough assessment of vision and fundi in patients presenting with new-onset headache. PMID- 29396064 TI - Methodological issues on reliability of noncontrast-enhancing tumor as a biomarker of IDH1 mutation status in glioblastoma. PMID- 29396065 TI - Variable response of CNS hemangioblastomas to Pazopanib in a single patient with von Hippel-Lindau disease: Case report. AB - Von Hippel-Lindau (VHL) disease is a multisystem genetic disease, the cardinal manifestations of which include central nervous system hemangioblastomas (CNS HB), renal cell carcinomas (RCC), and pheochromocytoma. Tumorigenesis in VHL of both RCC and CNS HB occurs secondary to downstream effects of a mutated or absent VHL protein. Treatment of RCCs with tyrosine kinase inhibitors (TKIs) such as Pazopanib is now first line therapy, but their effect on VHL-associated CNS HBs remains unknown. We report the use of Pazopanib in a patient with VHL disease for treatment of RCC who also harbored multiple CNS HBs. Following initiation of treatment, a large cervical and a lumbar spinal HB regressed in size while the remaining CNS HBs exhibited stable or progressive disease. These findings highlight the multiplicity of factors contributing to hemangioblastoma development, even among tumors with a common germline mutation, and the potential limitations of TKIs, but additionally this report supports the conservative management of asymptomatic VHL patients with spinal HBs whereby tumor response to TKI treatment may alleviate or postpone the need for surgery. PMID- 29396066 TI - Successful deep brain stimulation for central post-stroke pain and dystonia in a single operation. AB - BACKGROUND: Central post-stroke pain is known to be refractory to medications and difficult to manage. We present a case of central post-stroke pain associated with dystonia. Both conditions were successfully treated with a single deep brain stimulation (DBS) operation. CASE DESCRIPTION: A 60-year-old female suffered a right posterior cerebral artery stroke following emergent clipping of a ruptured posterior cerebral artery aneurysm resulting in central post-stroke pain. This manifested as delayed left face and hemibody allodynia and hyperesthesia. The patient also developed marked left-sided dystonia. These progressive symptoms were disabling and refractory to conservative management. The patient underwent a single-stage DBS surgery with stereotactic targeting and implantation of two leads. One lead was placed in the right-sided ventral capsule/ventral striatum for treatment of pain and a second lead in the right-sided globus pallidus interna for treatment of dystonia. The surgical implantation proceeded without complication. The patient's dystonia markedly improved following surgery. While her pain improved, she required multiple, meticulous programing sessions to achieve significant pain relief and decrease in pain medication use. Overall, the patient was satisfied with the results of her intervention. She did, however, have occasional intermittent spells of severe pain on top of her residual discomfort throughout her treatment course. Unfortunately, she died from small cell lung carcinoma a year after her DBS surgery. CONCLUSIONS: Deep brain stimulation targeting multiple brain networks in one operation is feasible and safe. Deep brain stimulation may be considered in some refractory cases of central post-stroke pain; however, it requires meticulous programming. PMID- 29396067 TI - Low serum vitamin D levels in patients with myasthenia gravis. AB - Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease. Vitamin D has important roles both in the autoimmune response and in skeletal muscles. We investigated the levels of 1,25-dihydroxy vitamin D [1,25(OH)2D] and 25-hydroxy vitamin D [25(OH)D] in patients with MG and healthy subjects. MG patients were classified by disease stage, age of onset and treatment status whether or not to taking immunosuppressive agents. MG patients had lower plasma 25(OH)D levels (mean, 18.8 +/- 8.4 ng/mL) than healthy controls (26.3 +/- 6.1 ng/mL) (p < .05). 1,25(OH)2D levels showed slightly high in MG patients than healthy controls, but had no significant difference between two groups. In addition, no significant differences were observed between two groups divided by clinical characteristics. Serum 25(OH)D levels significantly lower in patients with MG compared with healthy controls. We recommend monitoring of vitamin D status in patients with MG to avoid direct negative effects on the muscles or autoimmune response. PMID- 29396068 TI - Significance of fatigue in patients with migraine. AB - Fatigue is often stated as a headache trigger or migraine-specific symptom. We investigated predictors of fatigue and its impact on quality of life (QOL) in patients with migraine. Patients with migraine were recruited from a headache clinic and completed psychosomatic instruments, including the 12-item Allodynia Symptom Checklist (ASC-12), the Migraine Disability Assessment Scale (MIDAS), the Patients Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD 7), the Epworth Sleepiness Scale (ESS), the Insomnia Severity Index (ISI), the Fatigue Severity Scale (FSS), and Migraine-Specific Quality of Life Questionnaire (MSQ). Two hundreds twenty-six patients with migraine were eligible for the study. Pathologic fatigue was manifested in 133 patients (58.8%). The FSS score was significantly associated with age, age of onset, the Visual Analog Scale (VAS) depicting headache intensity, photophobia, phonophobia, and the scores of the ASC-12, the MIDAS, the ESS, the ISI, the PHQ-9 and the GAD-7. The strongest predictor for the FSS was the PHQ-9 (beta = 0.432, p < .001), followed by age (beta = -0.169, p = .002), the ISI (beta = 0.151, p = .016), and the VAS (beta = 0.139, p = .018). There was an inverse correlation between the FSS score and three dimensional scores of the MSQ (p < .001). Appropriate interventions for depression, insomnia, and headache intensity are likely to lessen fatigue and improve QOL. PMID- 29396069 TI - Cytomegalovirus associated longitudinally extensive transverse myelitis and acute hepatitis in an immunocompetent adult. AB - Cytomegalovirus can cause severe disease in immunocompromised patients including encephalomyelitis, hepatitis, pneumonitis, colitis and retinitis. CMV induced myelitis and hepatitis are rare in immunocompetent patients. Following a thorough search on the literature using pubmed, there were only 10 well documented CMV induced transverse myelitis cases reported worldwide. We report a healthy young male who developed longitudinal extensive transverse myelitis and acute hepatitis secondary to CMV infection. Our case is different from the other cases as our patient had concurrent acute hepatitis and received plasma exchange therapy (PLEX) in addition to pulsed steroids and antivirals. The patient recovered well and had an excellent outcome. PMID- 29396070 TI - Cognitive performance of 20 healthy humans supplemented with L-homoarginine for 4 weeks. AB - l-homoarginine (l-hArg) is an endogenous non-proteinogenic amino acid. Low l-hArg concentrations are associated with increased all-cause mortality, fatal strokes, and worse outcome after stroke. On the other hand, oral supplementation with l hArg in mice improved neurological deficits and preserved cardiac function in experimental models of stroke and heart failure, respectively. Recently, oral supplementation with 125 mg daily l-hArg capsules in healthy volunteers demonstrated increased l-hArg plasma levels. Therefore, oral l-hArg supplementation could represent a potential treatment for patients with cerebrovascular disease. In addition to vascular physiology, animal studies have suggested that l-hArg might play a role in synapse function, neurotransmitter metabolism and cognitive training. However the direct influence of l-hArg on cognitive function has not been studied so far. In this study, cognitive performance in healthy humans was analyzed concerning memory, learning, and attention following supplementation with placebo or l-hArg for 4 weeks. Our results did not reveal any effects on cognition, neither impairment nor improvement, upon l-hArg supplementation. Therefore, potential l-hArg treatment is not expected to cause any acute neurocognitive or behavioral side effects. PMID- 29396071 TI - Surfer's myelopathy: A rare presentation in a teenage gymnast and review of the literature. AB - This article describes a novel setting for a rare nontraumatic spinal cord injury referred to as Surfer's myelopathy. The patient is a 16 year-old female cheerleader who presented following a gymnastics practice where she was repeatedly performing back handsprings. She demonstrated progressively worsening midthoracic back pain and evolving paraplegia and hypesthesia of the lower extremities. Magnetic resonance imaging findings were consistent with T5-T7 spinal cord ischemia at 8 h and 16 h after symptom onset. The clinical and radiologic findings for this patient are consistent with previous case reports of Surfer's myelopathy. The authors also provide a summary of the current literature describing Surfer's myelopathy, which to date includes 64 reported cases. The diagnosis of nontraumatic spinal cord injury, referred to as Surfer's myelopathy, in a gymnast highlights the importance of greater physician and patient awareness of this rare condition. PMID- 29396072 TI - Muscle strength and psychiatric symptoms influence health-related quality of life in patients with myasthenia gravis. AB - : Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by skeletal muscle weakness which can impact motor function and, furthermore, produce negative impact on the health-related quality of life (HRQOL). OBJECTIVE: To evaluate the predictors for HRQOL in patients with MG. METHODS: Eighty patients were evaluated with the MG Foundation of America classification and the MG Composite scale. HRQOL was estimated by the MGQOL15, while anxious and depressive symptoms were evaluated with the Hospital Anxiety and Depression Scale (HAD). RESULTS: The mean age of patients was 41.9 years with mean illness duration of 13.5 years. Almost half of the patients (43.75%) had significant anxiety and more than a quarter (27.50%) had depressive symptoms. Factors that influenced the HRQOL in MG were skeletal muscle weakness and anxiety and depressive symptoms (p < .001 in logistic regression model). CONCLUSION: Anxiety and depressive symptoms, besides motor symptoms, influence HRQOL in MG. Mental health must be a clinical focus in addition to the treatment of somatic symptoms during the course of MG. PMID- 29396073 TI - Microelectrode accuracy in deep brain stimulation surgery. AB - Microelectrode recording (MER) provides vital neurophysiological information about target nuclei during deep brain stimulation (DBS). There have been extensive studies looking at the accuracy of DBS lead placement; however, to date, no large series have assessed the accuracy of the microelectrode. In this study, we report the accuracy of microelectrode tip placement in comparison to preoperatively planned radiographic target. Patients who underwent DBS with MER from 2014 to 2016 were included in the study. At the authors' institution, intra operative CT (iCT) is routinely performed after the first microelectrode track to confirm tip accuracy. Retrospective analysis of microelectrode track error was calculated between the planned trajectory and the microelectrode tip. The radial error was calculated on the same axial plane using the Euclidian distance formula, and multivariate analysis was performed to ascertain any directional bias of error. A total of 227 microelectrode tracks were analyzed, (150 STN, 50 ViM, 27 GPi) yielding a total radial error of 1.2 mm +/- 0.2 SEM across all targets. Analysis of vector error distribution revealed lack of directional bias. MER is an accurate electrophysiological representation of the planned target. PMID- 29396074 TI - Direct oral anticoagulant and antiplatelet combination therapy: Hemorrhagic events in coronary artery stent recipients. AB - Direct oral anticoagulant (DOAC) use is growing as monotherapy and combined with platelet inhibitors. The safety of such combination therapy, especially in comparison to regimens including warfarin, in real world populations remains uncertain. We investigated hemorrhage associated with DOAC and antiplatelet combination therapy in a cohort of elderly coronary artery stent recipients. We employed Medicare data 2010-2013 for a 40% random sample of beneficiaries enrolled in inpatient, outpatient and prescription benefits. We used Cox proportional hazards models to examine the association of the combination anticoagulant (DOAC or warfarin) plus antiplatelets with major hemorrhage events (upper gastrointestinal or intracranial) in the 12 months following stent placement. We identified 70,900 stent recipients. 14.4% had atrial fibrillation (AF) diagnosis preoperatively. Among the 24.5 million observation days, exposure distribution was: 73.8% antiplatelets only, 4.7% antiplatelets plus warfarin, 0.6% antiplatelets plus DOAC, 2.2% warfarin only, 0.3% DOAC only and 18.4% no observed antiplatelets or anticoagulant. Overall, 8,029 patients (11.3%) experienced major hemorrhage. Among AF patients, compared to antiplatelets only, DOAC plus antiplatelets was associated with increased hemorrhage risk (HR, 1.94; 95%CI, 1.48-2.54); warfarin plus antiplatelets conferred comparable bleed risk (HR, 1.69; 95%CI, 1.47-1.94). In the non-AF group, compared to antiplatelets alone, combination DOAC plus antiplatelets (HR, 3.09; 95%CI, 2.15-4.46), and warfarin plus antiplatelets (HR, 2.21; 95%CI, 1.97-2.48) conferred greater bleed risk. Among elderly coronary artery stent recipients with AF, the two drug combinations, DOAC plus antiplatelets and warfarin plus antiplatelets, were associated with similarly increased risk of major hemorrhage compared to antiplatelets alone. PMID- 29396075 TI - Beasley's 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention. AB - The 1981 Lancet paper by Beasley et al., "Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan" is a seminal publication that clearly demonstrated that chronic infection with hepatitis B virus (HBV), as measured by seropositivity for the hepatitis B surface antigen (HBsAg), preceded the development of hepatocellular carcinoma (HCC). In doing so, this study paved the way for liver cancer prevention efforts through the implementation of hepatitis B vaccination programs. In this commentary, we will describe the discovery of HBV, which led to the study by Beasley et al.; summarize the major findings of the Beasley paper and its implications; discuss the importance of well-designed cohort studies for prevention activities; and consider the ramifications of the Beasley study and the work that has followed since. PMID- 29396076 TI - [What are the real purpose and scope of screening for aneuploidy?] AB - In France, the recommended method for Down syndrome screening is the first trimester combined test, the risk assessment, based on maternal age, ultrasound measurement of fetal nuchal translucency and maternal serum markers (free beta hCG and PAPP-A). The Down syndrome detection rate is 78.7% at a screen positive rate of 5%. However, the best screening test is the integrated test using a combination of first trimester combined test and second trimester quadruple test (serum alpha-fetoprotein, human chorionic gonadotropin, unconjugated E3, and dimeric inhibin-A) and being able to achieve a detection rate for Down syndrome of approximately 96% at a screen-positive rate of 5%. In recent years, the isolation of small fragments of "fetal" cell-free DNA in the maternal blood dramatically changed the screening strategy paradigm allowing a Down syndrome detection rate and false positive rate of 99.2 and 0.09%, respectively. However, aneuploidy screening based on cell-free DNA presents two major limitations which must be taken into account because they considerably limit its benefit: (i) not every woman will receive an interpretable result and that those who fail to receive a result are at increased risk for fetal aneuploidy: whether an inconclusive result is treated as screen positive or screen negative affects the overall detection rate (sensitivity) and false-positive rate (specificity) of the test; (ii) the limited number of targeted aneuploidies (trisomies 21, 18, 13 and common sex chromosome aneuploidies) in contrast to conventional noninvasive screening which is also able to detect rare aneuploidies, duplications, deletions, and other structural rearrangements. Of course, genetic counseling has to include a discussion about benefits and limitations of aneuploidy screening based on cell-free DNA. However, it should not be considered as a new screening test to substitute for conventional noninvasive screening. Moreover, if the ultimate goal is to deliver the most information about potential risk of various chromosomal abnormalities associated with adverse perinatal outcomes, then current cell-free DNA screening strategies may not be the best approach. These data highlight the limitations of cell-free DNA screening and the importance of a clear and fair information during pretest genetic counseling about benefits and limitations of any prenatal noninvasive screening (whether conventional or by cell-free DNA), but also about risks and benefits of invasive diagnostic procedures (in first- or second-line), especially since the cytogenetic analysis with chromosomal microarray analysis has improved the detection of genome microdeletions and microduplications (variants of the copy number) that can not be detected by standard cytogenetic analysis. PMID- 29396077 TI - [Are we heading towards a "freeze all for all" strategy?] PMID- 29396078 TI - Detection of Human Cytomegalovirus in Malignant and Benign Breast Tumors in Egyptian Women. AB - INTRODUCTION: Previous studies have reported a role for human cytomegalovirus (HCMV) in breast carcinogenesis. We sought to assess the role of HCMV infection in the development and/or progression of breast cancer (BC) among Egyptian patients. PATIENTS AND METHODS: The study included 61 patients with BC cases. Of these 61 patients, 40 had been assessed for HCMV in the blood, BC tissue samples, and adjacent non-neoplastic tissue samples, and 21 had been assessed for HCMV in the tissue only. Tissue samples from 20 patients with fibroadenoma (FA) were also included. As a control group, 41 blood samples obtained from healthy women with no history of cancer were used as a blood control group. HCMV was assessed using enzyme-linked immunosorbent assay, real-time polymerase chain reaction (PCR), and immunohistochemistry (IHC). RESULTS: A significant difference was found in the index value for the anti-CMV IgG antibodies between the BC patients and the control group (P = .001). Using real-time PCR, HCMV DNA was detected in 11 of 61 BC tissues (18%) compared with 1 of 20 FA tissues (5%). HCMV DNA was present in 8 of the 40 plasma samples (20%). Regarding the viral proteins, 21 of 61 samples (34.4%) were positive for early/immediate early (E/IE) and 49 (80.3%) were positive for PP65 expression by IHC. The concordance between the results obtained by the different assays was low. CMVPP65 expression was significantly associated with E/IE protein expression in the malignant and FA groups (P < .001). CONCLUSION: The presence of CMV proteins and DNA in BC tissues suggests a role for this virus. However, the basic criteria to support a causal association of HCMV with BC were not fulfilled. PMID- 29396079 TI - Review of Factors Influencing Women's Choice of Mastectomy Versus Breast Conserving Therapy in Early Stage Breast Cancer: A Systematic Review. AB - We have performed a narrative synthesis. A literature search was conducted between January 2000 and June 2014 in 7 databases. The initial search identified 2717 articles; 319 underwent abstract screening, 67 underwent full-text screening, and 25 final articles were included. This review looked at early stage breast cancer in women only, excluding ductal carcinoma in situ and advanced breast cancer. A conceptual framework was created to organize the central constructs underlying women's choices: clinicopathologic factors, physician factors, and individual factors with subgroups of sociodemographic, geographic, and personal beliefs and preferences. This framework guided our review's synthesis and analysis. We found that larger tumor size and increasing stage was associated with increased rates of mastectomy. The results for age varied, but suggested that old and young extremes of diagnostic age were associated with an increased likelihood of mastectomy. Higher socioeconomic status was associated with higher breast conservation therapy (BCT) rates. Resident rural location and increasing distance from radiation treatment facilities were associated with lower rates of BCT. Individual belief factors influencing women's choice of mastectomy (mastectomy being reassuring, avoiding radiation, an expedient treatment) differed from factors influencing choice of BCT (body image and femininity, physician recommendation, survival equivalence, less surgery). Surgeon factors, including female gender, higher case numbers, and individual surgeon practice, were associated with increased BCT rates. The decision-making process for women with early stage breast cancer is complicated and affected by multiple factors. Organizing these factors into central constructs of clinicopathologic, individual, and physician factors may aid health-care professionals to better understand this process. PMID- 29396080 TI - Pediatrician and Behavioral Clinician-Delivered Screening, Brief Intervention and Referral to Treatment: Substance Use and Depression Outcomes. AB - PURPOSE: Early intervention for adolescent substance use and mental health problems may mitigate potential harm. We examined patient outcomes from a pragmatic trial of two modalities of delivering screening, brief intervention, and referral to treatment (SBIRT) and usual care (UC) in pediatric primary care. METHODS: All clinic pediatricians (n = 52) were randomized to three arms: (1) pediatrician-only, in which pediatricians were trained to deliver SBIRT; (2) embedded behavioral clinician (BC), in which pediatricians were trained to refer eligible adolescents to a BC who administered SBIRT; and (3) UC. Using electronic health record data, changes in past year substance use and depression symptoms between the index visit and next screening visit were examined across treatment arms. RESULTS: Among patients who endorsed substance use and/or depression symptoms or were eligible for further assessments, brief interventions, and referrals based on clinician assessment at the index visit, 648 patients (mean age = 15.2 [standard deviation = 1.2]) were rescreened at a follow-up visit between 6 months and 2 years later. Among all patients, self-reported substance use rates did not differ over time or across arms, and depression symptoms increased over time. The embedded BC arm had lower odds of having depression symptoms at follow-up than the physician-only arm, and lower odds than the UC arm although not significant; we found no differences between the pediatrician-only and UC arms. CONCLUSIONS: The increase in depression symptoms over time highlights this population's vulnerability and the importance of developing appropriate interventions. An embedded BC in pediatric primary care trained in SBIRT may benefit patients with depression symptoms. PMID- 29396081 TI - Girls' Sleep Trajectories Across the Pubertal Transition: Emerging Racial/Ethnic Differences. AB - PURPOSE: This study aims to examine the longitudinal association between puberty and sleep in a diverse sample of girls and explore racial/ethnic differences in this association. METHODS: Using latent growth curve modeling, the present study measured pubertal development (timing and rate) and sleep (wake time and bedtime) in 1,239 socioeconomically and ethnically diverse girls starting when they were 6 8 years old and followed longitudinally for up to 8 years. Pubertal assessment was conducted annually in clinic by physical examination, classified by sexual maturation stage for breast and pubic hair development by trained raters. RESULTS: In line with previous research, black girls had the earliest pubertal development, followed by Hispanic, white, and Asian girls. Black girls, on average, reported significantly shorter sleep duration than Hispanic (beta = .20, p < .001), Asian (beta = -.29, p = .002), and white (beta = -.35, p < .001) girls. In a series of dual-process models, we found that early pubertal timing predicted shorter sleep duration for early-maturing black girls (breast development: beta = .13, p = .005; pubic hair development: beta = .14, p = .012). There was no evidence of any association between pubertal rate and sleep. All models controlled for family socioeconomic status and body mass index. CONCLUSION: Sleep is essential for many aspects of youth development, including emotional, cognitive, and physical functioning. Developmental changes associated with puberty may put some early maturing girls at risk of shorter sleep duration in adolescence and exacerbate racial/ethnic disparities in health and well-being. PMID- 29396082 TI - Linking Patterns of Substance Use With Sexual Risk-Taking Among Female Adolescents With and Without Histories of Maltreatment. AB - PURPOSE: This study aimed to determine the associations between patterns of substance use and sexual risk-taking among female adolescents with and without histories of maltreatment. METHODS: Data are from a prospective cohort study examining the impact of maltreatment on subsequent female adolescent sexual health (N = 504). Participants averaged 18.24 years in age (SD = 1.12), and approximately 63% had substantiated incidences of maltreatment filed with Child Protective Services prior to age 18. The present study used latent class analysis to examine patterns in adolescent substance use, and negative binomial regression models to examine the links between patterns of substance use and sexual risk taking and to determine whether these associations were moderated by adolescents' maltreatment status. RESULTS: Six classes emerged from latent class analysis labeled as follows: abstainers (25% of sample); polysubstance users-early initiators (13%); polysubstance users-late initiators (23%); alcohol and cannabis users-late initiators (9%); alcohol users-late initiators (18%); and tobacco users (12%). Patterns of adolescent polysubstance use were associated with the highest levels of sexual risk-taking, and patterns of late-initiated polysubstance use, late-initiated alcohol use, and tobacco use were more strongly related to sexual risk-taking for female adolescents with histories of maltreatment. CONCLUSIONS: This study is the first to determine the specific patterns of substance use that are more strongly related to sexual risk-taking for maltreated female adolescents. By doing so, this study demonstrates how a person-centered approach can facilitate our understanding of how to best leverage sexual risk-taking prevention efforts. PMID- 29396084 TI - Spontaneous and rapid healing of massive symptomatic postoperative right-sided infarction of the greater omentum. PMID- 29396083 TI - Concurrent and Prospective Associations Between Substance-Specific Parenting Practices and Child Cigarette, Alcohol, and Marijuana Use. AB - PURPOSE: The current study aimed to understand whether substance-specific parenting practices predicted the probability of child alcohol, cigarette, or marijuana use beyond known family factors like family management and parental substance use and norms. METHODS: Data were drawn from the Intergenerational Project, which used an accelerated longitudinal design and included 383 families surveyed seven times between 2002 and 2011. Analyses included 224 families with children ages 10-18 years (49% female). Multilevel models tested both concurrent and lagged (predictors at time t - 1, outcomes at time t) associations between child past year use of alcohol, cigarettes, and marijuana and time-varying measures of substance-specific parenting practices, including permitting child use of alcohol or cigarettes; family rules about alcohol, cigarette, and drug use; and child involvement in family member alcohol or cigarette use (getting, opening, or pouring alcoholic drinks; getting or lighting cigarettes for family members). Demographic controls were included. RESULTS: Child involvement in family member substance use predicted an increased probability of child substance use both concurrently and 1 year later, even when controlling parent substance use, pro-substance norms, and family management. Family rules about substance use and parent provision of alcohol or cigarettes were not consistently related to child alcohol, cigarette, or marijuana use. CONCLUSIONS: Family-based preventive interventions to reduce youth substance use should continue to focus on family management and include messaging discouraging parents from allowing children to get, open, or pour drinks or get or light cigarettes for family members. PMID- 29396085 TI - Detection and characterization of focal liver lesions with ultra-low dose computed tomography in neoplastic patients. AB - PURPOSE: The purpose of this study was to evaluate and compare the diagnostic accuracy of ultra-low dose (ULD) computed tomography (CT) with that of standard dose (STD) CT in the detection and characterization of focal liver lesions in neoplastic patients. MATERIALS AND METHODS: A total of 177 neoplastic patients who underwent two abdominopelvic CT examinations (one with STD and one with ULD protocol) for suspected focal liver lesions were included. There were 103 men and 74 women with a mean age of 64.6+/-14.4 (SD) (range: 19-93 years). Raw data images were reconstructed with iterative reconstruction. Dose length product (DLP) and effective dose for both protocols were compared. Images were independently evaluated by two radiologists for image-quality, diagnostic quality, and confidence level. RESULTS: DLP for STD and ULD were respectively 215.4+/-92.0 (SD) mGy.cm (range: 76-599mGy.cm) and 90.7+/-37.2 (SD) mGy.cm (range: 32-254mGy.cm). Effective dose for STD and ULD CT were 3.2+/-1.4 (SD) mSv (range: 1.1-9.0mSv) and 1.4+/-0.6 (SD) mSv (range: 0.5 to 3.8mSv). A significant 58% dose reduction was found between the two protocols (P<0.05). Noise, signal-to noise ratio and contrast-to-noise ratio were higher with the ULD protocol compared to the STD protocol. No differences in subjective image quality were found between the two protocols. STD CT revealed focal liver lesions in 80 patients and ULD CT in 70 patients (P<0.05). ULD protocol resulted in a sensitivity of 83.8% and a specificity of 96.9% for the diagnosis of focal liver lesions although it was not able to characterize them properly (Se 62.5%). CONCLUSION: STD CT helps detect and characterize focal liver lesions. ULD CT offers good performance to detect focal liver lesions but with lower performances for lesion characterization. PMID- 29396086 TI - MR imaging of catecholamine-mediated myocarditis complicated by left ventricular thrombus. PMID- 29396087 TI - Assessment of patient's peak skin dose during abdominopelvic embolization using radiochromic (Gafchromic) films. AB - PURPOSE: To assess the value of the routine use of radiochromic films in abdominopelvic embolization procedures to improve patient follow-up. METHODS: A total of 55 patients who underwent transcatheter abdominopelvic embolization were prospectively included. Six types of procedures were evaluated including hepatic chemoembolization (HCE), gonadal veins embolization (GVE), uterine elective embolization (UEE), uterine urgent embolization (UUE), abdominal elective embolization (AEE), and abdominal urgent embolization (AUE). Dosimetric indicators (DIs) such as air-kerma (AK) and kerma-area-product (KAP) were collected and peak skin dose (PSD) was measured with radiochromic films. Correlations between PSD and DIs were searched for. RESULTS: The mean (+/ standard deviation [SD]) PSD for the various procedures were: 1033+/-502 mGy for HCE; 476+/-271 mGy for GVE; 460+/-171 mGy for UEE; 531+/-263 mGy for UUE; 708+/ 896 mGy for AEE; 683+/-392 mGy for AUE. Strong correlations were observed between PSD and DIs (r=0.974 for AK and r=0.925 for KAP). PSD was>2Gy in one procedure and all procedures (7/132) procedures resulted in AK>2Gy, mostly for HCE and AEE. CONCLUSION: Dosimetry using radiochromic film is only appropriate for HCE, AEE and AUE, whereas dose-mapping systems present a more suitable solution for all embolizations including those with AK that occasionally exceed 2Gy. PMID- 29396088 TI - Magnetic resonance imaging (MRI) of the knee: Identification of difficult-to diagnose meniscal lesions. AB - This article characterizes common meniscal pathologies, reviews magnetic resonance imaging (MRI) diagnostic criteria for meniscal tears, and identifies difficult-to-detect tears and fragments and the best MRI sequences and practices for recognizing these lesions. These difficult-to-diagnose meniscal lesions that radiologists should consider include tears, meniscocapsular separation lesions, and displaced meniscal fragments. Meniscus tears are either vertical, which are generally associated with traumatic injury, horizontal, which are associated with degenerative injury, or combinations of both. MRI has a high sensitivity for tears but not for fragments; MRI performance is also better for medial than lateral meniscal lesions. Fragment detection can be improved by recognizing signs secondary to migration, especially signs of epiphyseal irritation and mechanical impingement. Radial and peripheral tears, as well as those close to the posterior horn insertion, have been traditionally difficult to detect, but improvements in arthroscopic knowledge, identification of common lesion patterns, and selection of the proper MRI sequence and plane for each lesion type mean that, when properly used, MRI is an invaluable tool in detecting all types of meniscal tears. PMID- 29396089 TI - Intraoperative Diagnosis of Major Aortopulmonary Collateral Arteries by Transesophageal Echocardiography. PMID- 29396090 TI - Generalized dystonia associated with mutation in the histone methyltransferase gene KMT2B (DYT28) and white matter abnormalities. PMID- 29396091 TI - Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. AB - BACKGROUND: Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. METHODS: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m2) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-to treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. FINDINGS: Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17.8 months (IQR 14.7-20.9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3 4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. INTERPRETATION: Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial. FUNDING: Janssen and Celgene. PMID- 29396093 TI - Can we improve on ibrutinib in mantle cell lymphoma? PMID- 29396092 TI - Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. AB - BACKGROUND: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0.0001) and increased International Working Group-defined haematological improvement-platelet rates (p<0.0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2.5; the subsequent 58-week acute myeloid leukaemia HR was 1.2 (95% CI 0.4-3.8). METHODS: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18-90 years, and had platelets of 20 * 109 per L or less with or without a history of bleeding or 50 * 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (>=20 * 109 per L or <20 * 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 MUg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. FINDINGS: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1.06 [95% CI 0.48-2.33]; p=0.88) and proportions who died (93 [56%] vs 54 [54%]; HR 1.03 [0.72-1.47]; p=0.89) were not significantly different between the two groups. INTERPRETATION: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. FUNDING: Amgen Inc. PMID- 29396095 TI - Consolidation and maintenance in follicular lymphoma: radioimmunotherapy revisited? PMID- 29396094 TI - R-CHOP, radioimmunotherapy, and maintenance rituximab in untreated follicular lymphoma (SWOG S0801): a single-arm, phase 2, multicentre study. AB - BACKGROUND: Despite an abundance of therapeutic options, advanced-stage follicular lymphoma remains incurable. Furthermore, the ideal sequence and absolute benefit of post-induction therapy is unclear. We designed SWOG S0801 to assess the efficacy and safety of consolidative radioimmunotherapy and sequential maintenance rituximab following chemoimmunotherapy. METHODS: For this single-arm, phase 2, multicentre study, we enrolled patients aged 18 years and older with a diagnosis of stage III, IV, or bulky stage II follicular lymphoma, grades 1, 2, or 3a, who had not received previous therapy, from from 20 institutions within the United States National Cancer Institute Clinical Trials Network. Patients were assigned to a 5-year treatment plan consisting of R-CHOP (rituximab plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1.4 mg/m2], and prednisone or prednisolone [100 mg]) every 21 days for up to six cycles, with rituximab 375 mg/m2 given on day 1 of cycles 1-4, followed by 131iodine tositumomab radioimmunotherapy and subsequent maintenance rituximab 375 mg/m2 within 12 weeks after the sixth cycle of R-CHOP, every 3 months for up to 4 years. The primary endpoint was 3-year progression-free survival in the intention to-treat population. Efficacy and safety analyses were done in the intention-to treat population and the per-protocol population. This trial was registered with ClinicalTrials.gov, number NCT00770224. FINDINGS: Between April 1, 2009, and Dec 15, 2010, we enrolled 84 evaluable patients, of whom 73 completed R-CHOP and radioimmunotherapy. Of 69 patients who registered to maintenance therapy, only 41 completed the 4-year rituximab maintenance treatment. Progression-free survival at 3 years was 90% (95% CI 82-95). The most common grade 3 or worse adverse events included neutropenia in 48 (57%) patients, leucopenia in 34 (40%) patients, thrombocytopenia in 17 (20%) patients, and febrile neutropenia in 14 (17%) patients. Nine patients had possible treatment-related deaths during the study from secondary or unknown causes (n=3), cirrhosis (n=1), cardiac arrest (n=1), and secondary malignancies (n=4). Secondary malignancies occurred in seven patients, including two sarcomas, two colorectal carcinomas, two acute myelogenous leukaemias, and one case of renal-cell carcinoma. INTERPRETATION: SWOG S0801 showed near universal responses following chemoimmunotherapy and radioimmunotherapy. However, most discontinuations occurred during maintenance therapy, suggesting that rituximab over a 4-year span is not feasible for many patients. Nonetheless, this sequential therapeutic strategy resulted in good overall outcomes for patients, including a low incidence of early disease progression. FUNDING: The National Cancer Institute and GlaxoSmithKline. PMID- 29396096 TI - Good news for patients with myelodysplastic syndromes and thrombocytopenia. PMID- 29396097 TI - The effectiveness of cerebral oxygenation monitoring during arthroscopic shoulder surgery in the beach chair position: a randomized blinded study. AB - BACKGROUND: Beach chair positioning for shoulder surgery is associated with measurable cerebral desaturation events (CDEs) in up to 80% of patients. Near infrared spectroscopy (NIRS) technology allows real-time measurement of cerebral oxygenation and may minimize the frequency of CDEs. The purpose of this study was to investigate the incidence of CDEs when anesthetists were aware of and blinded to NIRS monitoring and to determine the short-term cognitive effects of surgery in the beach chair position. METHODS: NIRS was used to monitor cerebral oxygenation saturation in 41 consecutive patients undergoing arthroscopic shoulder surgery in the beach chair position. Patients were randomized to 2 groups, anesthetists aware of or blinded to NIRS data. The Montreal Cognitive Assessment (MoCA) was used to assess cognitive function preoperatively, immediately postoperatively, and at 2 and 6 weeks postoperatively. RESULTS: Overall, 7 (17.5%) patients experienced a CDE, 5 (25%) in the aware group and 2 (10%) in the blinded group. There was no significant difference in MoCA scores between the aware and blinded groups preoperatively (27.9.1 vs. 28.2; P = .436), immediately postoperatively (26.1 vs. 26.2; P = .778), 2 weeks postoperatively (28.0 vs. 28.1; P = .737), or 6 weeks postoperatively (28.5 vs. 28.4; P = .779). There was a correlation of NIRS with systolic blood pressure (r = 0.448), diastolic blood pressure (r = 0.708), and mean arterial pressure (r = 0.608). CONCLUSION: In our series, the incidence of CDEs was much lower than previously reported and was not lowered by use of NIRS. Patients did not have significant cognitive deficits after arthroscopic surgery in the beach chair position, and there was a correlation between NIRS and intraoperative brachial blood pressure. PMID- 29396098 TI - Sonographic assessment of the subscapularis after reverse shoulder arthroplasty: impact of tendon integrity on shoulder function. AB - BACKGROUND: The deltopectoral approach for reverse shoulder arthroplasty (RSA) requires subscapularis tenotomy or lesser tuberosity osteotomy. Whether the subscapularis should be repaired at the conclusion of the procedure remains controversial. The present study sonographically assessed the subscapularis after RSA and evaluated the effect of tendon integrity on functional outcome. METHODS: All patients who had undergone RSA in the Gold Coast University Hospital between 2005 and 2016 were included. Sonography was performed by a blinded examiner. Function was assessed using the Disabilities of the Arm, Shoulder and Hand, the Constant-Murley, and Oxford Shoulder scores. Internal rotation ability was recorded on a 6-point scale. RESULTS: The study included 43 patients (48 shoulders). Median length of follow-up was 19 months (range, 4-132 months). On sonography, the subscapularis was graded intact in 6 shoulders (13%), intact with mild attenuation in 16 (33%), severely attenuated in 15 (31%), and not intact or absent in 11 (23%). Differences in Disabilities of the Arm, Shoulder and Hand, Constant-Murley, or Oxford Shoulder scores between intact and attenuated or absent subscapularis shoulders were not significant. Internal rotation scores were significantly higher in the intact and mildly attenuated tendon group than in the absent tendon group (U = 1.0, P = .001 and U = 28.5, P = .007, respectively). CONCLUSIONS: The present work is the first long-term outcome study of RSA using sonography to assess the subscapularis. Subscapularis integrity did not appear to have a measurable effect on patient outcome as measured by standard scores but was important for internal rotation ability after RSA. PMID- 29396099 TI - A new local muscle flap for elbow coverage-the medial triceps brachii flap: anatomy, surgical technique, and preliminary outcomes. AB - BACKGROUND: The medial triceps brachii is vascularized by the middle collateral artery and the arterial circle of the elbow. This vascularization allows a distal pedicled use to cover soft tissue defects of the elbow. We report our experience using this flap to cover traumatic and postsurgical wounds. METHODS: Patients who underwent a pedicled medial triceps brachii flap procedure between 2008 and 2015 were included. Data concerning characteristics of the patients, wound size, surgical technique, and complications were retrospectively reviewed. An independent observer examined patients and assessed outcome of the coverage procedure: wound healing, scar length, range of elbow motion, and patient satisfaction. RESULTS: Eight patients were included (70.6 +/- 17.7 years old at the time of surgery). All patients had serious comorbidities and risk factors of poor wound healing. Defects were due to postoperative healing complications (5 patients), skin necrosis secondary to an underlying olecranon fracture (1 patient), and direct open fractures (2 patients). Soft tissue defects had a median surface of 17 (14-22) cm2. The olecranon was exposed in 7 cases and the medial humeral epicondyle in 1 case. Mean procedure duration was 83 +/- 14 minutes. There was no intraoperative or postoperative complication. All patients healed properly at 3 weeks of follow-up. No wound recurrence or surgery-related complication was reported after a median follow-up of 40.5 (21.5-69.5) months. CONCLUSION: Favorable outcomes in all of our 8 patients make this flap an interesting option to cover small to medium-sized defects of the posterior aspect of the elbow. PMID- 29396100 TI - Is nonoperative management of partial distal biceps tears really successful? AB - BACKGROUND: The current treatment of partial distal biceps tears is a period of nonoperative management, followed by surgery, if symptoms persist. Little is known about the success rate and outcomes of nonoperative management of this illness. METHODS: We identified 132 patients with partial distal biceps tears through an International Classification of Diseases, Ninth Revision code query of our institution's database. Patient records were reviewed to abstract demographic information and confirm partial tears of the distal biceps tendon based on clinical examination findings and confirmatory magnetic resonance imaging (MRI). Seventy-four patients completed an outcome survey. RESULTS: In our study, 55.7% of the contacted patients who tried a nonoperative course (34 of 61 patients) ultimately underwent surgery, and 13 patients underwent immediate surgery. High need patients, as defined by occupation, were more likely to report that they recovered ideally if they underwent surgery, as compared with those who did not undergo surgery (odds ratio, 11.58; P = .0138). For low-need patients, the same analysis was not statistically significant (P = .139). There was no difference in satisfaction scores between patients who tried a nonoperative course before surgery and those who underwent immediate surgery (P = .854). An MRI-diagnosed tear of greater than 50% was a predictor of needing surgery (odds ratio, 3.0; P = .006). CONCLUSIONS: This study has identified clinically relevant information for the treatment of partial distal biceps tears, including the following: the failure rate of nonoperative treatment, the establishment of MRI percent tear as a predictor of failing nonoperative management, the benefit of surgery for the high-need occupational group, and the finding that nonoperative management does not negatively affect outcome if subsequent surgery is necessary. PMID- 29396101 TI - Outcomes of lesser tuberosity osteotomy in revision anatomic shoulder arthroplasty. AB - BACKGROUND: Lesser tuberosity osteotomy (LTO) is a common surgical approach during anatomic shoulder arthroplasty. Outcomes of LTO have been shown to be similar to subscapularis tenotomy and peel techniques, but little is known about the outcomes of LTO during revision arthroplasty. METHODS: This retrospective case series included 10 consecutive patients who underwent LTO during revision shoulder arthroplasty at a single institution from 2012 to 2016. Patients underwent a preoperative computed tomography scan to evaluate the lesser tuberosity bone stock. Demographic information, radiographic evidence of LTO healing, outcomes of range of motion, subscapularis strength, and visual analog scale pain scores were analyzed. RESULTS: Revision total shoulder arthroplasty with LTO was performed for glenoid arthritis after hemiarthroplasty in 10 patients. Average age at surgery was 59.8 years, and no humeral stems were revised. Eight of 10 patients had prior subscapularis tenotomy. Average follow-up after revision surgery was 9.2 months. LTO union was documented in 80% and nondisplaced nonunion in 20%. At follow-up, 50% reported mild pain. Subscapularis strength testing was graded normal in 80% and weak in 20%. Average visual analog scale pain improved from 9.4 prerevision to 4.8 postrevision (P < .05). On average, range of motion improved in active forward elevation from 123 degrees to 141 degrees and remained unchanged in active external rotation from 42 degrees to 42 degrees . CONCLUSION: Patients undergoing LTO during revision anatomic shoulder arthroplasty demonstrate successful LTO bony healing, improvement in pain, and improved forward elevation. In select patients not requiring humeral stem revision, LTO is a safe and effective surgical approach to subscapularis management during revision anatomic shoulder arthroplasty. PMID- 29396102 TI - The accelerated effect of recombinant human bone morphogenetic protein 2 delivered by beta-tricalcium phosphate on tendon-to-bone repair process in rabbit models. AB - BACKGROUND: Bone morphogenetic protein 2 (BMP-2) plays an important role in the tendon-to-bone repair process. However, there is no previous literature on acceleration of the tendon-to-bone repair process by BMP-2 delivered by beta tricalcium phosphate (beta-TCP). The aim of this study was to investigate the accelerated effect of recombinant human BMP-2 (rhBMP-2) delivered by beta-TCP on the tendon-to-bone repair process. METHODS: The infraspinatus tendon of elderly female Japanese white rabbits was detached from its insertion site on the humerus. A bone tunnel (4.2 mm) was created at the original insertion site of the tendon, which was repaired using the McLaughlin procedure after filling in beta TCP (porosity 75%) without BMP-2 (control group) or with 10 ug rhBMP-2 (BMP group). The rabbits were sacrificed at the second, fourth, and eighth weeks after surgery for histologic analysis and biomechanical testing. We also evaluated the maturity of the tendon-to-bone junction using the tendon-to-bone maturity score. RESULTS: Histologic analysis revealed no significant difference between the groups at 2 and 8 weeks but a more abundant organized fibrocartilage at the tendon-to-bone junction in the BMP group at 4 weeks. The tendon-to-bone maturity score improved sequentially. The interface of the BMP group at 4 weeks had significantly improved biomechanical properties than that of the control group. CONCLUSION: The tendon-to-bone repair process was facilitated by the use of rhBMP 2 delivered by beta-TCP at 4 weeks. PMID- 29396103 TI - Antihypertensive therapy in nondiabetic chronic kidney disease: a review and update. AB - Hypertension is an important contributor to progression of nondiabetic chronic kidney disease (CKD). Compelling observational evidence indicates that the divergence of blood pressure (BP) away from an ideal range in either direction is associated with a progressive rise in the risk of mortality and cardiovascular and renal disease progression. To date, various clinical trials and meta-analyses examining strict versus less intensive BP control in nondiabetic CKD have not conclusively demonstrated a renal advantage of one BP-lowering approach over another, except in certain subgroups such as proteinuric patients where evidence is circumstantial. As recent data have come to light suggesting that intensive BP control yields superior survival and cardiovascular outcomes in patients at high risk for cardiovascular disease, interest in the prospect of whether such benefit extends to individuals with CKD has surged. This review is a comprehensive analysis of antihypertensive literature in nondiabetic renal disease, with a particular emphasis on BP target. PMID- 29396104 TI - 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 29396105 TI - Ambulatory blood pressure variability within the first 24 hours after admission and outcomes of acute ischemic stroke. AB - Our purpose was to evaluate the value of blood pressure variability within the first 24 hours after admission in predicting outcomes of patients with acute ischemic stroke (AIS). A greater variability in systolic blood pressure (adjusted odds ratio [OR] = 1.801, 95% confidence interval [CI] = 1.167-2.779) was associated with poor discharge outcome, especially for nondiabetics (adjusted OR = 1.948, 95% CI = 1.184-3.205) and cardioembolism-related patients with AIS (OR = 7.650, 95% CI = 1.370-42.713). However, this correlation was not observed with a long-term (3-month or 6-month) outcome in patients with AIS. There was no association between diastolic blood pressure variability within the first 24 hours after admission and outcome. In conclusion, systolic blood pressure variability within the first 24 hours after admission is a critical predictor for short-term outcome of patients with AIS. PMID- 29396106 TI - The prevalence of central hypertension defined by a central blood pressure type I device and its association with target organ damage in the community-dwelling elderly Chinese: The Northern Shanghai Study. AB - We aimed to investigate the prevalence of central hypertension and its association with target organ damage (TOD). 1983 community-dwelling elderly Chinese people were recruited for this analysis. Brachial and central blood pressure (BP) were measured by an oscillometric device and SphygmoCor (type I device), respectively. Brachial hypertension was defined by brachial systolic BP/diastolic BP >=140/90 mmHg or using antihypertensive medications. Central hypertension was defined by central systolic BP/diastolic BP >=130/90 mmHg or using antihypertensive medications. TOD included left ventricular hypertrophy and diastolic dysfunction, carotid-femoral pulse wave velocity, and urinary albumin creatinine ratio. In this cohort, there were 563 (28.4%) brachial and central consistent normotension, 46 (2.3%) isolated brachial hypertension, 27 (1.4%) isolated central hypertension, and 1347 (67.9%) brachial and central combined hypertension (BCCH). In analysis of variance, BCCH showed significantly higher levels in all TOD than brachial and central consistent normotension. In multiple logistic regression, all TOD were significantly associated with BCCH (left ventricular hypertrophy: adjusted odds ratios [95% confidence interval] = 2.03 [1.55, 2.68]; left ventricular diastolic dysfunction: 2.29 [1.53, 3.43]; carotid femoral pulse wave velocity >10 m/s: 3.41 [2.55, 4.58]; urinary albumin creatinine ratio >30 mg/g: 1.97 [1.58, 2.44]), rather than isolated brachial hypertension or isolated central hypertension. In conclusion, central hypertension was prevalent (69.3%) in this elderly cohort. BCCH was independently and significantly associated with cardiac, arterial, and renal damage. This finding implies that both brachial and central BPs need to be considered for managing hypertension. PMID- 29396107 TI - Oligomeric amyloid beta preferentially targets neuronal and not glial mitochondrial-encoded mRNAs. AB - INTRODUCTION: Our laboratories have demonstrated that accumulation of oligomeric amyloid beta (OAbeta) in neurons is an essential step leading to OAbeta-mediated mitochondrial dysfunction. METHODS: Alzheimer's disease (AD) and matching control hippocampal neurons, astrocytes, and microglia were isolated by laser-captured microdissection from the same subjects, followed by whole-transcriptome sequencing. Complementary in vitro work was performed in OAbeta-treated differentiated SH-SY5Y, followed by the use of a novel CoQ10 analogue for protection. This compound is believed to be effective both in suppressing reactive oxygen species and also functioning in mitochondrial electron transport. RESULTS: We report decreases in the same mitochondrial-encoded mRNAs in Alzheimer's disease laser-captured CA1 neurons and in OAbeta-treated SH-SY5Y cells, but not in laser-captured microglia and astrocytes. Pretreatment with a novel CoQ10 analogue, protects neuronal mitochondria from OAbeta-induced mitochondrial changes. DISCUSSION: Similarity of expression changes in neurons from Alzheimer's disease brain and neuronal cells treated with OAbeta, and the effect of a CoQ10 analogue on the latter, suggests a pretreatment option to prevent OAbeta toxicity, long before the damage is apparent. PMID- 29396108 TI - Transitions across cognitive states and death among older adults in relation to education: A multistate survival model using data from six longitudinal studies. AB - INTRODUCTION: This study examines the role of educational attainment, an indicator of cognitive reserve, on transitions in later life between cognitive states (normal Mini-Mental State Examination (MMSE), mild MMSE impairment, and severe MMSE impairment) and death. METHODS: Analysis of six international longitudinal studies was performed using a coordinated approach. Multistate survival models were used to estimate the transition patterns via different cognitive states. Life expectancies were estimated. RESULTS: Across most studies, a higher level of education was associated with a lower risk of transitioning from normal MMSE to mild MMSE impairment but was not associated with other transitions. Those with higher levels of education and socioeconomic status had longer nonimpaired life expectancies. DISCUSSION: This study highlights the importance of education in later life and that early life experiences can delay later compromised cognitive health. This study also demonstrates the feasibility and benefit in conducting coordinated analysis across multiple studies to validate findings. PMID- 29396110 TI - Operative technique: Transperitoneal robotic adrenalectomy. PMID- 29396109 TI - Neighborhoods, sleep quality, and cognitive decline: Does where you live and how well you sleep matter? AB - INTRODUCTION: We evaluated the association between neighborhood socioeconomic status (NSES) and sleep quality on cognitive decline in the Health and Retirement Study. METHODS: Health and Retirement Study participants (n = 8090), aged 65+ with DNA and multiple biennial cognitive observations (abbreviated Telephone Interview for Cognitive Status), were included. Participants were grouped into quartiles of NSES and sleep quality scores. We adjusted for apolipoprotein E epsilon4, demographic, and cardiovascular risk factors. Random effects modeling evaluated cognitive change over time. RESULTS: NSES and sleep were significantly associated with cognitive decline, and there was a significant interaction between them (P = .02). Significant differences between high/low NSES and high/low sleep quality (P < .0001) were found. DISCUSSION: Sleep and NSES were associated with cognitive decline; the association between sleep and cognition appeared stronger among those with low NSES. The association between low NSES, poor sleep quality, and cognitive decline was roughly equivalent to the association between apolipoprotein E epsilon4 and cognitive decline. PMID- 29396111 TI - Pelvic tumor fed by the superior mesenteric artery. What is your diagnosis? GIST complicating Meckel's diverticulum. PMID- 29396112 TI - Risk factors of exocrine and endocrine pancreatic insufficiency after pancreatic resection: A multi-center prospective study. AB - : Management of functional consequences after pancreatic resection has become a new therapeutic challenge. The goal of our study is to evaluate the risk factors for exocrine (ExoPI) and endocrine (EndoPI) pancreatic insufficiency after pancreatic surgery and to establish a predictive model for their onset. PATIENTS AND METHODS: Between January 1, 2014 and June 19, 2015, 91 consecutive patients undergoing pancreatoduodenectomy (PD) or left pancreatectomy (LP) (72% and 28%, respectively) were followed prospectively. ExoPI was defined as fecal elastase content<200MUg per gram of feces while EndoPI was defined as fasting glucose>126mg/dL or aggravation of preexisting diabetes. The volume of residual pancreas was measured according to the same principles as liver volumetry. RESULTS: The ExoPI and EndoPI rates at 6 months were 75.9% and 30.8%, respectively. The rate of ExoPI after PD was statistically significantly higher than after LP (98% vs. 21%; P<0.001), while the rate of EndoPI was lower after PD vs. LP, but this difference did not reach statistical significance (28% vs. 38.5%; P=0.412). There was no statistically significant difference in ExoPI found between pancreatico-gastrostomy (PG) and pancreatico-jejunostomy (PJ) (100% vs. 98%; P=1.000). Remnant pancreatic volume less than 39.5% was predictive of ExoPI. CONCLUSION: ExoPI occurs quasi-systematically after PD irrespective of the reconstruction scheme. The rate of EndoPI did not differ between PD and LP. PMID- 29396113 TI - Early experience with ambulatory robotic ventral rectopexy. AB - OBJECTIVE OF THE STUDY: Ventral rectopexy can be performed robotically with only limited trauma for the patient, making its performance in an ambulatory setting potentially interesting. The aim of this study is to report our preliminary experience with ambulatory robotic ventral rectopexy in consecutive patients. PATIENTS AND METHODS: Ten consecutive patients underwent robotic ventral rectopexy for total rectal prolapse (n=8) or symptomatic enterocele (n=2) between February 2014 and April 2015. Patients were selected for outpatient treatment based on criteria of patient motivation, favorable social conditions, and satisfactory general condition. Patient characteristics, technical results and cost were reported. RESULTS: The mean operating time was 94minutes (range: 78 150). The average operating room occupancy time was 254minutes (222-339). There were no operative complications, conversion to laparotomy, or postoperative complication. The average duration of hospital stay was 11 (8-32) hours. Two patients required hospitalization: one for persistent pain and the other for urinary retention. The average maximum pain score recorded on postoperative day 1 was 2/10 on a visual analog scale (range: 0-5/10). Estimated average cost (excluding amortization of the purchase of the robot) was ?9088 per procedure. CONCLUSIONS: Ambulatory management of robotic ventral rectopexy is feasible and safe. PMID- 29396115 TI - A Lipid Transfer Protein Signaling Axis Exerts Dual Control of Cell-Cycle and Membrane Trafficking Systems. AB - Kes1/Osh4 is a member of the conserved, but functionally enigmatic, oxysterol binding protein-related protein (ORP) superfamily that inhibits phosphatidylinositol transfer protein (Sec14)-dependent membrane trafficking through the trans-Golgi (TGN)/endosomal network. We now report that Kes1, and select other ORPs, execute cell-cycle control activities as functionally non redundant inhibitors of the G1/S transition when cells confront nutrient-poor environments and promote replicative aging. Kes1-dependent cell-cycle regulation requires the Greatwall/MASTL kinase ortholog Rim15, and is opposed by Sec14 activity in a mechanism independent of Kes1/Sec14 bulk membrane-trafficking functions. Moreover, the data identify Kes1 as a non-histone target for NuA4 through which this lysine acetyltransferase co-modulates membrane-trafficking and cell-cycle activities. We propose the Sec14/Kes1 lipid-exchange protein pair constitutes part of the mechanism for integrating TGN/endosomal lipid signaling with cell-cycle progression and hypothesize that ORPs define a family of stage specific cell-cycle control factors that execute tumor-suppressor-like functions. PMID- 29396114 TI - Cardiomyocytes Sense Matrix Rigidity through a Combination of Muscle and Non muscle Myosin Contractions. AB - Mechanical properties are cues for many biological processes in health or disease. In the heart, changes to the extracellular matrix composition and cross linking result in stiffening of the cellular microenvironment during development. Moreover, myocardial infarction and cardiomyopathies lead to fibrosis and a stiffer environment, affecting cardiomyocyte behavior. Here, we identify that single cardiomyocyte adhesions sense simultaneous (fast oscillating) cardiac and (slow) non-muscle myosin contractions. Together, these lead to oscillating tension on the mechanosensitive adaptor protein talin on substrates with a stiffness of healthy adult heart tissue, compared with no tension on embryonic heart stiffness and continuous stretching on fibrotic stiffness. Moreover, we show that activation of PKC leads to the induction of cardiomyocyte hypertrophy in a stiffness-dependent way, through activation of non-muscle myosin. Finally, PKC and non-muscle myosin are upregulated at the costameres in heart disease, indicating aberrant mechanosensing as a contributing factor to long-term remodeling and heart failure. PMID- 29396117 TI - Concerted Action of Evolutionarily Ancient and Novel SNARE Complexes in Flowering Plant Cytokinesis. AB - Membrane vesicles delivered to the cell-division plane fuse with one another to form the partitioning membrane during plant cytokinesis, starting in the cell center. In Arabidopsis, this requires SNARE complexes involving the cytokinesis specific Qa-SNARE KNOLLE. However, cytokinesis still occurs in knolle mutant embryos, suggesting contributions from KNOLLE-independent SNARE complexes. Here we show that Qa-SNARE SYP132, having counterparts in lower plants, functionally overlaps with the flowering plant-specific KNOLLE. SYP132 mutation causes cytokinesis defects, knolle syp132 double mutants consist of only one or a few multi-nucleate cells, and SYP132 has the same SNARE partners as KNOLLE. SYP132 and KNOLLE also have non-overlapping functions in secretion and in cellularization of the embryo-nourishing endosperm resulting from double fertilization unique to flowering plants. Evolutionarily ancient non-specialized SNARE complexes originating in algae were thus amended by the appearance of cytokinesis-specific SNARE complexes, meeting the high demand for membrane-fusion capacity during endosperm cellularization in angiosperms. PMID- 29396119 TI - Managing cardiovascular disease risk in patients with severe mental illness. PMID- 29396118 TI - Clinical and cost-effectiveness of an intervention for reducing cholesterol and cardiovascular risk for people with severe mental illness in English primary care: a cluster randomised controlled trial. AB - BACKGROUND: People with severe mental illnesses, including psychosis, have an increased risk of cardiovascular disease. We aimed to evaluate the effects of a primary care intervention on decreasing total cholesterol concentrations and cardiovascular disease risk in people with severe mental illnesses. METHODS: We did this cluster randomised trial in general practices across England, with general practices as the cluster unit. We randomly assigned general practices (1:1) with 40 or more patients with severe mental illnesses using a computer generated random sequence with a block size of four. Researchers were masked to allocation, but patients and general practice staff were not. We included participants aged 30-75 years with severe mental illnesses (schizophrenia, bipolar disorder, or psychosis), who had raised cholesterol concentrations (5.0 mmol/L) or a total:HDL cholesterol ratio of 4.0 mmol/L or more and one or more modifiable cardiovascular disease risk factors. Eligible participants were recruited within each practice before randomisation. The Primrose intervention consisted of appointments (<=12) with a trained primary care professional involving manualised interventions for cardiovascular disease prevention (ie, adhering to statins, improving diet or physical activity levels, reducing alcohol, or quitting smoking). Treatment as usual involved feedback of screening results only. The primary outcome was total cholesterol at 12 months and the primary economic analysis outcome was health-care costs. We used intention-to treat analysis. The trial is registered with Current Controlled Trials, number ISRCTN13762819. FINDINGS: Between Dec 10, 2013, and Sept 30, 2015, we recruited general practices and between May 9, 2014, and Feb 10, 2016, we recruited participants and randomly assigned 76 general practices with 327 participants to the Primrose intervention (n=38 with 155 patients) or treatment as usual (n=38 with 172 patients). Total cholesterol concentration data were available at 12 months for 137 (88%) participants in the Primrose intervention group and 152 (88%) participants in the treatment-as-usual group. The mean total cholesterol concentration did not differ at 12 months between the two groups (5.4 mmol/L [SD 1.1] for Primrose vs 5.5 mmol/L [1.1] for treatment as usual; mean difference estimate 0.03, 95% CI -0.22 to 0.29; p=0.788). This result was unchanged by pre agreed supportive analyses. Mean cholesterol decreased over 12 months (-0.22 mmol/L [1.1] for Primrose vs -0.36 mmol/L [1.1] for treatment as usual). Total health-care costs (L1286 [SE 178] in the Primrose intervention group vs L2182 [328] in the treatment-as-usual group; mean difference -L895, 95% CI -1631 to 160; p=0.012) and psychiatric inpatient costs (L157 [135] vs L956 [313]; -L799, 1480 to -117; p=0.018) were lower in the Primrose intervention group than the treatment-as-usual group. Six serious adverse events of hospital admission and one death occurred in the Primrose group (n=7) and 23, including three deaths, occurred in the treatment-as-usual group (n=18). INTERPRETATION: Total cholesterol concentration at 12 months did not differ between the Primrose and treatment-as-usual groups, possibly because of the cluster design, good care in the treatment-as-usual group, short duration of the intervention, or suboptimal focus on statin prescribing. The association between the Primrose intervention and fewer psychiatric admissions, with potential cost-effectiveness, might be important. FUNDING: National Institute of Health Research Programme Grants for Applied Research. PMID- 29396116 TI - The WAVE Regulatory Complex and Branched F-Actin Counterbalance Contractile Force to Control Cell Shape and Packing in the Drosophila Eye. AB - Contractile forces eliminate cell contacts in many morphogenetic processes. However, mechanisms that balance contractile forces to promote subtler remodeling remain unknown. To address this gap, we investigated remodeling of Drosophila eye lattice cells (LCs), which preserve cell contacts as they narrow to form the edges of a multicellular hexagonal lattice. We found that during narrowing, LC-LC contacts dynamically constrict and expand. Similar to other systems, actomyosin based contractile forces promote pulses of constriction. Conversely, we found that WAVE-dependent branched F-actin accumulates at LC-LC contacts during expansion and functions to expand the cell apical area, promote shape changes, and prevent elimination of LC-LC contacts. Finally, we found that small Rho GTPases regulate the balance of contractile and protrusive dynamics. These data suggest a mechanism by which WAVE regulatory complex-based F-actin dynamics antagonize contractile forces to regulate cell shape and tissue topology during remodeling and thus contribute to the robustness and precision of the process. PMID- 29396120 TI - Deep Learning in Radiology: Does One Size Fit All? AB - Deep learning (DL) is a popular method that is used to perform many important tasks in radiology and medical imaging. Some forms of DL are able to accurately segment organs (essentially, trace the boundaries, enabling volume measurements or calculation of other properties). Other DL networks are able to predict important properties from regions of an image-for instance, whether something is malignant, molecular markers for tissue in a region, even prognostic markers. DL is easier to train than traditional machine learning methods, but requires more data and much more care in analyzing results. It will automatically find the features of importance, but understanding what those features are can be a challenge. This article describes the basic concepts of DL systems and some of the traps that exist in building DL systems and how to identify those traps. PMID- 29396121 TI - Optimizing Recruitment Into Radiology: Some Simple Approaches to Controlling Bias. PMID- 29396122 TI - Re: "ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee". PMID- 29396123 TI - Evaluating Report Text Variation and Informativeness: Natural Language Processing of CT Chest Imaging for Pulmonary Embolism. AB - OBJECTIVE: The aim of this study was to quantify the variability of language in free text reports of pulmonary embolus (PE) studies and to gauge the informativeness of free text to predict PE diagnosis using machine learning as proxy for human understanding. MATERIALS AND METHODS: All 1,133 consecutive chest CTs with contrast studies performed under a PE protocol and ordered in the emergency department in 2016 were selected from our departmental electronic workflow system. We used commercial text-mining and predictive analytics software to parse and describe all report text and to generate a suite of machine learning rules that sought to predict the "gold standard" radiological diagnosis of PE. RESULTS: There was extensive variation in the length of Findings section and Impression section texts across the reports, only marginally associated with a positive PE diagnosis. A marked concentration of terms was found: for example, 20 words were used in the Findings section of 93% of the reports, and 896 of 2,296 distinct words were each used in only one report's Impression section. In the validation set, machine learning rules had perfect sensitivity but imperfect specificity, a low positive predictive value of 73%, and a misclassification rate of 3%. CONCLUSION: Use of free text reporting was associated with extensive variability in report length and report terms used. Interpretation of the free text was a difficult machine learning task and suggests potential difficulty for human recipients in fully understanding such reports. These results support the prospective assessment of the impact of a fully structured report template with at least some mandatory discrete fields on ease of use of reports and their understanding. PMID- 29396124 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria Sinonasal Disease. PMID- 29396125 TI - Performing an Informatics Consult: Methods and Challenges. AB - Our health care system is plagued by missed opportunities, waste, and harm. Data generated in the course of care are often underutilized, scientific insight goes untranslated, and evidence is overlooked. To address these problems, we envisioned a system where aggregate patient data can be used at the bedside to provide practice-based evidence. To create that system, we directly connect practicing physicians to clinical researchers and data scientists through an informatics consult. Our team processes and classifies questions posed by clinicians, identifies the appropriate patient data to use, runs the appropriate analyses, and returns an answer, ideally in a 48-hour time window. Here, we discuss the methods that are used for data extraction, processing, and analysis in our consult. We continue to refine our informatics consult service, moving closer to a learning health care system. PMID- 29396126 TI - Use of the REVERT(r) total protein stain as a loading control demonstrates significant benefits over the use of housekeeping proteins when analyzing brain homogenates by Western blot: An analysis of samples representing different gonadal hormone states. AB - Western blot is routinely used to quantify differences in the levels of target proteins in tissues. Standard methods typically use measurements of housekeeping proteins to control for variations in loading and protein transfer. This is problematic, however, when housekeeping proteins also are affected by experimental conditions such as injury, disease, and/or gonadal hormone manipulations. Our goal was to evaluate an alternative and perhaps superior method for conducting Western blot analysis of brain tissue homogenates from rats with distinct physiologically relevant gonadal hormone states. Tissues were collected from the hippocampus, frontal cortex, and striatum of young adult female rats that either were ovariectomized to model surgical menopause, or were treated with the ovatotoxin 4-vinylcyclohexene diepoxide (VCD) to model transitional menopause. Tissues also were collected from rats with a normal estrous cycle killed at proestrus when estradiol levels are high, and at diestrus when estradiol levels are low. Western blot detection of alpha-tubulin, beta actin, and GAPDH was performed and were compared for sensitivity and reliability with a fluorescent total protein stain (REVERT(r)). Results show that the total protein stain was much less variable across samples and had a greater linear range than alpha-tubulin, beta-actin, or GAPDH. The stain was stable and easy to use, and did not interfere with the immunodetection or multiplexed detection of the housekeeping proteins. In addition, we show that normalization of our data to total protein, but not to GAPDH, revealed significant differences in alpha tubulin expression in the hippocampus as a function of treatment, and that gel-to gel consistency in measuring differences between paired samples run on multiple gels was significantly better when data were normalized to total protein than when normalized to GAPDH. These results demonstrate that the REVERT(r) total protein stain can be used in Western blot analysis of brain tissue homogenates to control for variations in loading and protein transfer, and provides significant advantages over the use of housekeeping proteins for quantifying changes in the levels of multiple target proteins. PMID- 29396128 TI - Irritable bowel syndrome and endometriosis: New insights for old diseases. AB - Irritable bowel syndrome and endometriosis are two diseases affecting a significant part of the female population, either together or individually, with remarkable consequences in the quality of life. Several studies suggest an epidemiological association between them. Their association may not be just an epidemiological phenomenon, but the manifestation of a pathophysiological correlation, which probably generates a mutual promotion phenomenon. In particular, both clinical entities share the presence of a chronic low-grade inflammatory state at the basis of the disease persistence. Recognizing this association is highly significant due to their prevalence and the common clinical manifestation occurring with a chronic abdominal pain. A further multi disciplinary approach is suggested in these patients' management in order to achieve an adequate diagnostic work up and a targeted therapy. This paper analyses some common pathophysiological mechanisms, such as activation of mast cell line, neuronal inflammation, dysbiosis and impaired intestinal permeability. The aim was to investigate their presence in both IBS and endometriosis, and to show the complexity of their relationship in the generation and maintenance of chronic inflammation. PMID- 29396127 TI - RAS mutation testing in patients with metastatic colorectal cancer in French clinical practice: A status report in 2014. AB - BACKGROUND: RAS (NRAS + KRAS) mutation testing is required in addition to simple KRAS testing prior to initiating anti-epidermal-growth-factor-receptor (EGFR) antibodies (MAb) as in metastatic colorectal cancer (mCRC). AIMS: To assess prescription and implementation rates of RAS/KRAS mutation testing. To describe the RAS/KRAS mutation test procedure and its impact on therapeutic strategy. PATIENTS AND METHODS: Observational retrospective study conducted from June to September 2014 in all consecutive patients with newly diagnosed mCRC. RESULTS: Data from 375 patients (male: 57.8%; mean age, 65.7 +/- 11.7 years) were analysed. RAS/KRAS mutation testing was prescribed in 90.1% of patients (338/375). The test was prescribed within 1 month around mCRC diagnosis and prior to first-line therapy in 73.1% (242/331) and 85.4% (280/328) of patients, respectively. Time from test request to receipt of results was 24.6 +/- 17.2 days. 59.7% of patients (190/318) had a mutation, mainly KRAS (47.9%; 152/317). Anti-EGFR MAb was prescribed in 90.9% of RAS-wild-type cases (60/66), consistent with the goal of genotyping-testing in this population. CONCLUSION: In 2014, RAS genotyping-testing in addition to KRAS testing was routinely prescribed and performed in mCRC patients in France. Time to receive results remains long and must be reduced so as to match clinical practice. PMID- 29396129 TI - Accuracy of fecal calprotectin for the prediction of endoscopic activity in patients with inflammatory bowel disease. AB - BACKGROUND: Fecal calprotectin is a noninvasive marker of inflammatory bowel disease. AIM: To evaluate the accuracy of calprotectin for prediction of endoscopic activity in inflammatory bowel disease. METHODS: One-hundred patients were prospectively included. Quantum Blue(r) (Buhlmann) kits were used to determine calprotectin. Endoscopic activity was calculated. Various serum markers (platelets, leukocytes, C-reactive protein, and albumin) were recorded. RESULTS: Calprotectin was higher in patients with endoscopic activity than in those without activity: in ulcerative colitis, with the low- (29 +/- 14 vs. 301 +/- 174, p < 0.001) and high- (99 +/- 727 vs. 617 +/- 801, p < 0.001); and in Crohn's disease, with the low- (29 +/- 59 vs. 124 +/- 268, p < 0.01) and high-range kit (99 +/- 37 vs. 287 +/- 607, p < 0.01). Serological marker concentrations did not vary with endoscopic activity. The area under the ROC curve of calprotectin for the prediction of endoscopic activity was 0.9 in ulcerative colitis and 0.8 in Crohn's disease. The best cut-off points for the detection of activity in ulcerative colitis were 50 for the low- (sensitivity 85%, specificity 79%) and 102 for the high- (sensitivity 85%, specificity 79%); in Crohn's disease, 54 for the low- (sensitivity 71%, specificity 75%) and 122 for the high-range kit (sensitivity 71%, specificity 75%). CONCLUSIONS: Fecal calprotectin concentration has good diagnostic accuracy for the detection of endoscopic activity in inflammatory bowel disease and performs better in ulcerative colitis than in Crohn's disease. PMID- 29396130 TI - Meta-analysis shows similar re-bleeding rates among Western and Eastern populations after index video capsule endoscopy. AB - BACKGROUND & AIMS: Video capsule endoscopy (VCE) is the first-line diagnostic procedure for investigating obscure gastrointestinal bleeding (OGIB). Different re-bleeding rates following index VCE have been reported among Western and Eastern studies. METHODS: We conducted a comprehensive literature search to identify studies examining re-bleeding rates after VCE for OGIB. Meta-analysis assessed the pooled proportion of re-bleeding events after VCE for OGIB according to study's origin (Western vs. Eastern) and according to the length of follow-up (>=24 months vs. <24 months). We also calculated the re-bleeding odds ratios (OR; 95% CI) after positive vs. negative index VCE, overt vs. occult initial presentation of bleeding and after interventional treatment for positive index cases, according to the study's origin. RESULTS: We included 46 (30 Western and 16 Eastern) studies with 5796 patients. Significant heterogeneity was detected among meta-analyzed studies. Overall, the pooled re-bleeding rate was similar between Western (29%; 95% CI: 23-34) and Eastern (21%; 95% CI: 15-27) populations, irrespective of the length of follow-up. The odds of re-bleeding was significantly higher after positive as compared to negative index VCE in Eastern studies (OR: 1.77; 95% CI: 1.07-2.94). Application of specific treatment after positive index VCE was associated with lower re-bleeding odds in both Western (OR: 0.37; 95% CI: 0.16-0.87) and Eastern (OR: 0.39; 95% CI: 0.21-0.72) populations. CONCLUSIONS: Patients undergoing VCE for OGIB have similar re bleeding rates in the East and the West, regardless of the length of follow-up. However, increased re-bleeding odds after positive index VCE is observed in Eastern studies. PMID- 29396131 TI - Donor PNPLA3 rs738409 genotype is a risk factor for graft steatosis. A post transplant biopsy-based study. AB - BACKGROUND & AIMS: The rs738409 c.444C > G (p.I148M) polymorphism in PNPLA3 is a major factor predisposing to non-alcoholic fatty liver disease. The aim of the study was to clarify the impact of liver and extrahepatic expression of the PNPLA3 p.148M variant on liver graft steatosis after liver transplantation. METHODS: Fat content was assessed in liver biopsies from 176 transplant recipients. During a period of 4 +/- 1 years after transplantation, 17 patients developed grade 3 steatosis, 14 patients grade 2 steatosis, 56 patients grade 1 steatosis, and 89 patients grade 0 steatosis. The influence of the recipient and donor rs738409 genotype and clinical and laboratory data on liver fat content were analyzed using ordinal logistic regression. RESULTS: The PNPLA3 rs738409 CC/CG/GG genotype frequencies, respectively, were 0.494/0.449/0.057 in the graft donors and 0.545/0.330/0.125 in the graft recipients. In the multivariate analysis, the presence of the PNPLA3 c.444G allele in donor (OR 1.62; 95%CI 1.12 2.33), post-transplant BMI (OR 1.14; 95%CI 1.07-1.22), diabetes mellitus (OR 1.99; 95%CI 1.22-3.22), and serum triglycerides (OR 1.40; 95%CI 1.11-1.76) were independent risk factors for increased liver graft fat content. CONCLUSIONS: These data indicate that the liver expression of the PNPLA3 p.148M variant confers a genetic predisposition to liver graft steatosis along with nutritional status and diabetes. PMID- 29396132 TI - Successful endoscopic transmural drainage of septate walled off necrosis by fracturing the septum under EUS guidance. PMID- 29396133 TI - Efficacy and safety of SIC-8000 (Eleview(r)) for submucosal injection for endoscopic mucosal resection and endoscopic submucosal dissection in an in vivo porcine model. AB - BACKGROUND: Submucosal injection is generally required for both endoscopic mucosal resection (EMR) and submucosal dissection (ESD). SIC-8000 (EleviewTM) is a new FDA 510(k) cleared and CE marked liquid composition for submucosal injection, containing a biocompatible polymer as a cushioning agent. AIMS: The aim of this randomized study was to compare Eleview with saline solution when performing upper- and lower-GI EMR/ESD in a porcine model. METHODS: EMR/ESD procedures were performed in a total of 10 white domestic pigs comparing Eleview vs. NaCl 0.9% containing methylene blue at 0.001% (control solution) as submucosal solution to be injected. Animals were randomized between EMR (22 procedures) and ESD (22 procedures) and between upper- (8 animals) and lower-(2 animals) GI procedures. All procedures were performed aiming for a resection size of 1 cm * 1 cm for EMR and 2 cm * 2 cm for ESD. Volume of injected fluid, number of injections, time of resection, technical success, en-bloc resection, and adverse events were collected. Endoscopic surveillance was conducted each week for 4 weeks after the EMR/ESD, including biopsies on the margins of resection sites at week-1 of follow-up. After four weeks, pigs were sacrificed and necropsy performed. RESULTS: Overall, 22 EMR and 22 ESD were performed in 10 live pigs. The average total volume needed for EMR and ESD was statistically significantly lower with Eleview as compared with control solution for both of the techniques (EMR: 5.6 +/- 3.4 ml vs. 11.5 +/- 6.7 ml; p = 0.02; ESD: 19.0 +/- 10.0 ml vs. 36.3 +/- 16.9 ml; p = 0.02). The rate of adverse events was statistically significantly lower in the Eleview than in the control group (2/26, 7.7% vs. 6/18, 33.3%; p = 0.03), but most of them were minor. No difference between Eleview and control solution was found in the rate of technical success (EMR: 11/13, 84.6% vs. 7/9, 77.8%; p = 0.7; ESD: 13/13, 100% vs. 9/9, 100%; p = 1), en bloc resection (EMR: 6/13, 46.2% vs. NaCl: 5/9, 55.6%; p = 0.06; ESD: 12/13, 92.3% vs. 8/9, 88.9%; p = 0.8), and time of resection (EMR: 9.1 +/- 7.75 min vs. 9.4 +/- 9.6 min; p = NS; ESD: 38.4 +/- 17.2 min vs. 40.2 +/- 19.1 min; p = NS). At endoscopic follow up and necropsy, no difference in the process of healing of post-endoscopic ulcer and in the histological inflammation at the site of resection was shown between the two groups. CONCLUSIONS: The new submucosal injection composition Eleview appeared to be an effective alternative to saline solution for submucosal injection for EMR/ESD, resulting in a substantial reduction of the volume administered to achieve an adequate lifting. No signs of adverse local or distant tissue reaction to Eleview were found at long-term follow up. PMID- 29396135 TI - Novel TGM1 mutation in a Pakistani family affected with severe lamellar ichthyosis. PMID- 29396134 TI - A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients. AB - BACKGROUNDS: The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB). AIMS: To develop and validate a novel noninvasive index for moderate to severe fibrosis (>=S2) in CHB patients. METHODS: A total of 401 CHB patients who underwent liver biopsy were divided into the training (n = 300) and validation (n = 101) cohort. Histological severity was scored using a modified Scheuer system. Clinical and laboratory assessments were collected. RESULTS: In the training cohort, PACG, a novel index combining the quantitative hepatitis B core antibody (qAnti-HBc), platelet count (PLT), and albumin globulin ratio (A/G), presented better diagnostic performance (AUROC = 0.814) than that of APRI (0.735, p = 0.007) and FIB-4 (0.749, p = 0.014). In the validation cohort, the AUROC of the PACG, APRI, FIB-4 and Fibroscan were 0.834, 0.806, 0.791 and 0.810, respectively. More importantly, a higher and lower cutoff of PACG for predicting >=S2 fibrosis or not had a >90% sensitivity and specificity, with a diagnostic accuracy of 85.9%. CONCLUSION: PACG is a promising noninvasive alternative to liver biopsy in CHB patients for the evaluation of moderate to severe fibrosis. PMID- 29396136 TI - Renal replacement therapy in the neonatal intensive care unit. AB - BACKGROUND: Renal replacement therapy (RRT) is becoming increasingly necessary for supporting critically ill neonates. Few studies have reported the use of RRT in the neonatal intensive care unit (NICU). Therefore, we performed a retrospective study to describe the use of RRT in our NICU and its associated efficacy, complications, and outcomes. METHODS: We identified patients requiring RRT between January 2009 and January 2017. Demographic data, mode of RRT, and associated factors were recorded. Efficacy was calculated as the percentage reduction in the blood urea nitrogen (BUN) or toxic metabolite level after 24 h of RRT. Complications including hypotension, electrolyte disturbance, and technical and catheter-related complications were documented. Measures of clinical outcome included in-hospital survival, presence of neurological sequelae, and chronic kidney disease. The chi-square test and Mann-Whitney U test were used for categorical and continuous variables, respectively. RESULTS: We included 17 neonates in our study. The median gestational age at birth was 37 weeks (32-39 weeks), and the median birth weight was 2.7 kg (1.5-3.6 kg). Twelve neonates, including three with inborn errors of metabolism (IEM), received continuous RRT (CRRT), and five neonates underwent peritoneal dialysis (PD). The percentage reduction in ammonia in neonates with IEM who received CRRT was 87.2% at 24 h. The percentage reductions in BUN in the non-IEM neonates in the CRRT and PD groups were 33.7% and 23.7% at 24 h, respectively. The main complication was electrolyte disturbance including hypokalemia, hypocalcemia, and hypophosphatemia. All neonates with IEM survived, whereas the mortality rates for the non-IEM neonates in the CRRT and PD groups were 78% and 80%, respectively. CONCLUSION: Our study findings reveal RRT to be feasible, even in preterm neonates with low birth weight. CRRT had a higher efficacy level, particularly in neonates with IEM, and the complications encountered were transient and correctable. PMID- 29396137 TI - Awareness of attenuated mucopolysaccharidoses in a pediatric orthopedic clinic. PMID- 29396139 TI - Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis. PMID- 29396138 TI - RIFM fragrance ingredient safety assessment, octanal dimethyl acetal, CAS Registry Number 10022-28-3. PMID- 29396140 TI - Arabidopsis ENOR3 regulates RNAi-mediated antiviral defense. AB - Viruses can infect host plants to cause severe diseases and substantial agricultural loss, while plants have evolved RNA interference (RNAi) strategy to defend against viral infection. Despite enormous efforts, only a few host proteins in RNAi pathway were shown to mediate antiviral defense, including RNA dependent RNA polymerase 1 (RDR1), RDR6, DICER-LIKE 2 (DCL2) and DCL4. In this study, we carried out a genetic screen for antiviral factors of RNAi pathway in Arabidopsis rdr6 background via inoculation with a 2b-deficient Cucumber Mosaic Virus (CMV-Delta2b). We identified a mutant susceptible to CMV-Delta2b, referred to as enhancer of rdr6 (enor) 3-1 rdr6, and found that ENOR3 encodes a functionally unknown protein with high homology to the mammalian Non Imprinted in Prader-Willi/Angelman (NIPA) magnesium transporters. ENOR3 inhibits accumulation of CMV-Delta2b and acts additively with RDR1, RDR6, DCL2 and DCL4 in antiviral defense. These results uncover that ENOR3 is a key component in antiviral RNAi pathway, and provide new insights into antiviral immunity. PMID- 29396141 TI - Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment. AB - In eukaryotic cells, protein synthesis is a complex and multi-step process that has several mechanisms to start the translation including cap-dependent and cap independent initiation. The translation control of eukaryotic gene expression occurs principally at the initiation step. In this context, it is critical that the eukaryotic translation initiation factor eIF4E bind to the 7-methylguanosine (m7G) cap present at the 5'-UTRs of most eukaryotic mRNAs. Combined with other initiation factors, eIF4E mediates the mRNA recruitment on ribosomes to start the translation. Moreover, the eIF4E nuclear bodies are involved in the export of specific mRNAs from the nucleus to the cytoplasm. In this review, we focus on the eIF4E structure and its physiological functions, and describe the role of eIF4E in cancer development and progression and the current therapeutic strategies to target eIF4E. PMID- 29396142 TI - Generation of ApoE deficient dogs via combination of embryo injection of CRISPR/Cas9 with somatic cell nuclear transfer. PMID- 29396143 TI - Clinical significance of germline copy number variation in susceptibility of human diseases. AB - Germline copy number variation (CNV) is considered to be an important form of human genetic polymorphisms. Previous studies have identified amounts of CNVs in human genome by advanced technologies, such as comparative genomic hybridization, single nucleotide genotyping, and high-throughput sequencing. CNV is speculated to be derived from multiple mechanisms, such as nonallelic homologous recombination (NAHR) and nonhomologous end-joining (NHEJ). CNVs cover a much larger genome scale than single nucleotide polymorphisms (SNPs), and may alter gene expression levels by means of gene dosage, gene fusion, gene disruption, and long-range regulation effects, thus affecting individual phenotypes and playing crucial roles in human pathogenesis. The number of studies linking CNVs with common complex diseases has increased dramatically in recent years. Here, we provide a comprehensive review of the current understanding of germline CNVs, and summarize the association of germline CNVs with the susceptibility to a wide variety of human diseases that were identified in recent years. We also propose potential issues that should be addressed in future studies. PMID- 29396144 TI - Mouse macrophage specific knockout of SIRT1 influences macrophage polarization and promotes angiotensin II-induced abdominal aortic aneurysm formation. AB - Abdominal aortic aneurysm (AAA) is a vascular degenerative disease. Macrophage polarization and the balance between classically activated macrophages (M1) and alternatively activated macrophages (M2) are crucial for AAA pathogenesis. The present study aims to investigate the roles of macrophage SIRT1 in AAA formation and macrophage polarization. We found that in mouse peritoneal macrophages, SIRT1 expression was decreased after M1 stimulation, but was enhanced after M2 stimulation. Results from SIRT1flox/flox mice and macrophage specific SIRT1 knockout mice with treatment of angiotensin II (Ang II) for 4 weeks showed that macrophage specific deficiency of SIRT1 increased the incidence of AAA and exacerbated the severity, including more severe aneurysm types, enlarged diameter of the aneurysm and increased degradation of elastin. In mouse aortas, SIRT1 deficiency increased the pro-inflammatory M1 molecule inducible nitric oxide synthase (iNOS), and decreased M2 molecules such as arginase 1 (Arg1) and mannose receptor (MR). Furthermore, in peritoneal macrophages, SIRT1 deficiency increased the expression of M1 inflammatory molecules, but decreased the expression of M2 molecules. Overexpression of SIRT1 had the opposite effects. Thus, macrophage specific knockout of SIRT1 influences macrophage polarization and accelerates Ang II-induced AAA formation. PMID- 29396145 TI - HDAC5 Regulates the Formation of Drug Memories. AB - Cocaine-associated environmental cues can precipitate craving and relapse in addicted individuals even after years of abstinence, but the molecular mechanisms by which maladaptive drug memories are generated remain unclear. New findings suggest that histone deacetylase 5 (HDAC5) plays a key role in this process. PMID- 29396146 TI - Defining Substance Use Disorders: The Need for Peripheral Biomarkers. AB - Addiction is a brain disease, and current diagnostic criteria for substance use disorders (SUDs) are qualitative. Nevertheless, scientific advances are beginning to characterize neurobiological domains. Combining multiple units of measure may provide an opportunity to deconstruct the heterogeneities of a SUD and define endophenotypes by using peripheral biospecimens. There are several recent examples of potential biomarker types that can be examined, together with their categorical applications for SUDs. We propose that, in conjunction with rapidly advancing statistical and mathematical modeling techniques, there is now a unique opportunity for the discovery of composite biomarkers within specific domains of addiction; these may lay the foundation for future biomarker qualification, with important implications for drug development and medical care. PMID- 29396147 TI - Focusing on the Opioid System for Addiction Biomarker Discovery. AB - Substance use disorders (SUD) and behavioral addictions are devastating conditions that impose a severe burden on all societies, and represent difficult challenges for clinicians. Therefore, biomarkers are urgently needed to help predict vulnerability, clinical course, and response to treatment. Here, we elaborate on the potential for addiction biomarker discovery of the opioid system, particularly within the emerging framework aiming to probe opioid function in peripheral tissues. Mu, delta, and kappa opioid receptors all critically regulate neurobiological and behavioral processes that define addiction, and are also targeted by major pharmacotherapies used in the management of patients with SUD. We propose that opioid biomarkers may have the potential to improve and guide diagnosis and therapeutic decisions in the addiction field. PMID- 29396148 TI - Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability. AB - Substance use disorders (SUDs) are marked by heterogeneity in clinical symptomatology and high relapse rates following treatment. Here, we describe specific peripheral and central stress responses associated with the pathophysiology of SUDs. We outline potential stress response measures, including hypothalamus-pituitary-adrenal axis markers, autonomic responses, and central structural and functional brain alterations that could be exploited as putative biomarkers in SUDs. We posit that stress responses can be predictive of both the development of SUDs and their high relapsing nature. We examine their potential as candidate biomarkers, as well as the remaining challenges in developing and implementing their application for the prevention and treatment of SUDs. PMID- 29396149 TI - Finding the Roots: Molecularly Tracking Substance Addiction. PMID- 29396150 TI - Usefulness of ultrasound for the diagnosis of pyogenic flexor tenosynovitis: A prospective single-center study of 57 cases. AB - Pyogenic flexor tenosynovitis (PFT) is a functional emergency in hand surgery; however, its diagnosis can be difficult to make. It should always be considered when a patient presents with an inflamed finger. The goal of this study was to investigate the usefulness of ultrasound in the diagnosis of early PFT. Seventy three patients with suspected pyogenic flexor tenosynovitis were candidates for the study. Since the diagnosis of PFT was obvious in 16 patients, they were excluded from the study and immediately underwent surgery. The remaining 57 patients underwent a clinical examination by a senior surgeon, a blood test for C reactive protein levels and an ultrasound (US). The US results were compared to the intraoperative findings if the patients were operated or to the clinical outcome in non-operated patients. Seventeen patients had the US diagnosis of PFT confirmed intraoperatively. In 10 patients, the US diagnosis of PFT was not confirmed intraoperatively. In 29 other patients, the diagnosis of PFT was ruled out by US; they all had good outcomes after being treated with antibiotics. In one patient for whom the diagnosis of PFT had been ruled out by US, PFT was actually present. Ultrasound had 94% sensitivity, 65% specificity, 63% positive predictive value, and 95% negative predictive value. Ultrasound is useful as a diagnostic tool for managing early PFT thanks to its excellent negative predictive value and specificity. This objective examination complements the surgeon's subjective clinical examination. PMID- 29396151 TI - "Snapping triceps": A rare and misleading condition - a clinical case report. AB - Snapping triceps corresponds to subluxation of the medial head of the triceps brachii over the medial epicondyle during active elbow flexion. It is a rare and misleading condition that is often associated with ulnar nerve instability. The latter can result in the snapping triceps being missed. Diagnosis requires a detailed clinical examination. Surgical treatment consists of anterior translocation of the nerve with an adipose flap to stabilize it and transfer of the distal attachment of the medial head of triceps brachii. PMID- 29396152 TI - Treatment of defects in the tip and palmar surface of the fingers. AB - Defects on the palmar surface of the fingers are an important part of hand emergencies, especially fingertip wounds. Luckily, many coverage methods are available. We will review the anatomy of this area and the thought process for treating these defects. We will also propose an algorithm that can be used to select the best technique based on the type of injury present. PMID- 29396153 TI - No Improvements in Postnatal Dietary Outcomes Were Observed in a Two-Arm, Randomized, Controlled, Comparative Impact Trial among Rural, Southern, African American Women. AB - BACKGROUND: Suboptimal diet quality, prevalent among postpartum women, is troubling for mothers and their children because positive relationships between maternal and child diet quality exist. OBJECTIVE: The primary objective was to determine whether postnatal diet quality scores of participants in the two treatment arms differed or changed over time. DESIGN: Delta Healthy Sprouts was a two-arm, randomized, controlled, comparative impact trial. PARTICIPANTS AND SETTING: Pregnant women at least 18 years of age, less than 19 weeks pregnant, and residing in three Mississippi counties were recruited between March 2013 and December 2014. Postnatal data was collected from 54 participants between September 2013 and May 2016. The postnatal attrition rates were 17% and 13% for the control and experimental arms. INTERVENTION: The control arm received the Parents as Teachers curriculum, and the experimental arm received a nutrition- and physical activity-enhanced Parents as Teachers curriculum. MAIN OUTCOME MEASURES: Multiple-pass 24-hour dietary recalls were collected from participants at the postnatal month 1, 4, 6, 8, and 12 visits. Healthy Eating Index-2010 was used to calculate diet quality. STATISTICAL ANALYSIS PERFORMED: Linear mixed models were used to test for treatment, time, and treatment by time (interaction) effects on postnatal dietary outcomes. RESULTS: Control arm mean (95% confidence limits) total Healthy Eating Index-2010 scores were 36.8 (range=32.5 to 41.1), 36.5 (range=31.9 to 41.1), 40.2 (range=35.7 to 44.8), 39.3 (range=34.7 to 43.9), and 36.4 (range=31.8 to 41.0) at postnatal months 1, 4, 6, 8, and 12, respectively. Corresponding experimental arm scores were 42.3 (range=37.5 to 47.0), 41.6 (range=36.3 to 46.9), 40.2 (range=34.8 to 45.7), 45.8 (range=40.5 to 51.1), and 37.6 (range=32.6 to 42.7), respectively. Experimental scores were significantly higher than control scores across time. No other effects were significant. CONCLUSIONS: Neither the standard Parents as Teachers curriculum nor the enhanced Parents as Teachers curriculum was effective at improving the poor diet quality of this cohort of rural, Southern, African-American women during the 12 months following the birth of their infant. PMID- 29396154 TI - Association of Individual and Neighborhood Factors with Home Food Availability: Evidence from the National Health and Nutrition Examination Survey. AB - BACKGROUND: Accumulating evidence suggests the important role of the home food environment in an individual's dietary intake. OBJECTIVE: This study examined the associations of individual and neighborhood-level factors with the availability of healthy and unhealthy foods in the home using a nationally representative sample from the 2007 to 2008 and 2009 to 2010 National Health and Nutrition Examination Surveys (NHANES). DESIGN: A cross-sectional study design was used with NHANES merged with the 2000 census data. Food availability was measured through self-report questionnaire regarding the frequency of foods or drinks available in the home. PARTICIPANTS: The analysis included 8,975 participants aged 19 to 65 years. STATISTICAL ANALYSES PERFORMED: Associations of individual and neighborhood factors with home food availability (always or most of the time available) were assessed using logistic regression modeling accounting for NHANES' complex survey design and weights. Individual-level and neighborhood level factors were simultaneously included in the analysis. RESULTS: Family income-to-needs ratio was positively associated with the availability of dark green vegetables (odds ratio [OR]=1.07; 95% CI=1.00 to 1.13), fat-free or low-fat milk (OR=1.16; 95% CI=1.07 to 1.25), and salty snacks (OR=1.12; 95% CI=1.04 to 1.20) in the home. College graduates were more likely to have fruits (OR=1.96, 95% CI=1.48 to 2.60), vegetables (OR=1.48; 95% CI=1.16 to 1.88), and fat-free or low-fat milk (OR=1.81; 95% CI=1.55 to 2.12) and less likely to have salty snacks (OR=0.77; 95% CI=0.63 to 0.95) and sugary drinks (OR=0.46, 95% CI=0.37 to 0.57) available compared with non-college graduates. Tract socioeconomic status (SES) scores were positively associated with fruit (OR=1.15; 95% CI=1.02 to 1.29), vegetable (OR=1.14; 95% CI=1.03 to 1.26), and fat-free or low-fat milk (OR=1.25; 95% CI=1.10 to 1.42) availability. Urban residents were associated with greater availability of fruits (OR=1.47; 95% CI=1.05 to 2.08) and fat-free or low-fat milk (OR=1.33; 95% CI=1.02 to 1.73) in the home compared with rural residents. Food desert status was not associated with home food availability. CONCLUSIONS: The results show that SES at both individual (education, income) and neighborhood level was linked to home food availability, suggesting a need to improve the home food environment for socioeconomically disadvantaged individuals and neighborhoods. PMID- 29396155 TI - Genetically distinct lineages of Salmonella Typhimurium ST313 and ST19 are present in Brazil. AB - In sub-Saharan Africa, two genetically distinct lineages of multi-drug resistant non-typhoidal Salmonella (NTS) serovar Typhimurium sequence type 313 (ST313) are known to cause invasive disease among people. S. Typhimurium ST313 has evolved to become more human-adapted and is commonly isolated from systemic sites (eg., blood) from febrile patients in sub-Saharan Africa. Epidemiological studies indicate that S. Typhimurium is frequently isolated from systemic sites from human patients in Brazil, however, it is currently unknown if this pathogen has also evolved to become more invasive and human-adapted in this country. Here we determined genotypic and phenotypic divergence among clinical S. Typhimurium strains isolated from systemic and non-systemic sites from human patients in Brazil. We report that a subset (8/38, 20%) of epidemiologically diverse human clinical strains of S. Typhimurium recovered from systemic sites in Brazil show significantly higher intra-macrophage survival, indicating that this subset is likely more invasive. Using the whole genome sequencing and phylogenetic approaches, we identified S. Typhimurium ST313-lineage in Brazil that is genetically and phenotypically distinct from the known African ST313-lineages. We also report the identification of S. Typhimurium ST19-lineage in Brazil that is evolving similar to ST313 lineages from Africa but is genetically and phenotypically distinct from ST19-lineage commonly associated with the gastrointestinal disease worldwide. The identification of new S. Typhimurium ST313 and ST19 lineages responsible for human illnesses in Brazil warrants further epidemiological investigations to determine the incidence and spread of a genetically divergent population of this important human pathogen. PMID- 29396156 TI - Patency rates and clinical outcomes in a cohort of 200 patients treated with a dedicated venous stent. AB - OBJECTIVE: Minimally invasive interventions by recanalization, percutaneous transluminal angioplasty, and stenting in post-thrombotic syndrome (PTS) obstructions and iliac vein compression syndrome (IVCS) have shown good results. Until recently, no dedicated venous stents were available, and stent-related issues accounted for a decrease in patency scores. The introduction of dedicated stents with more flexibility and higher radial forces could result in higher patency scores. This study focused on the outcomes of patients treated by a dedicated sinus-Venous stent (OptiMed GmbH, Ettlingen, Germany). Patency rates and clinical evaluation are described for both PTS and IVCS patients. METHODS: A total of 200 patients treated at a tertiary university referral center were analyzed. A percutaneous procedure was performed in 103 (51%) PTS patients and 48 (24%) IVCS patients. In 49 (25%) patients, a hybrid procedure was executed. Patency rates and complications were analyzed by duplex ultrasound. Clinical improvement was scored by Venous Clinical Severity Score, Villalta scale, and venous claudication rates. RESULTS: The mean age was 43.2 +/- 14.5 (17-81) years, and 66% were female. Mean Villalta score decreased from 10.5 +/- 4.2 (3-24) to 5.3 +/- 3.8 (0-14) at the latest follow-up (P < .001). Venous Clinical Severity Score decreased by a total of 3 points (P < .001). At baseline, venous claudication was present in 132 patients, which subsided in 115 (87%). Overall patency scores revealed a primary patency of 68%, assisted primary patency of 83%, and secondary patency of 90% with a median follow-up of 12 (11-12) months. Of all included patients, 122 (61%) did not have a complication during follow-up; the most frequent complications were in-stent restenosis (n = 23) and occlusion (n = 25) of the stented tract. CONCLUSIONS: Short-term clinical results using the sinus-Venous stent are comparable to previous research. Loss of stent patency due to stent-related issues like kinking or tapering is hardly ever seen in this short-term follow-up. PMID- 29396157 TI - Differences in radial expansion force among inferior vena cava filter models support documented perforation rates. AB - OBJECTIVE: Inferior vena cava (IVC) filters are used in patients at risk for pulmonary embolism who cannot be anticoagulated. Unfortunately, these filters are not without risk, and complications include perforation, migration, and filter fracture. The most prevalent complication is filter perforation of the IVC, with incidence varying among filter models. To our knowledge, the mechanical properties of IVC filters have not been evaluated and are not readily available through the manufacturer. This study sought to determine whether differences in mechanical properties are similar to differences in documented perforation rates. METHODS: The radial expansion forces of Greenfield (Boston Scientific, Marlborough, Mass), Cook Celect (Cook Medical, Bloomington, Ind), and Cook Platinum filters were analyzed with three replicates per group. The intrinsic force exerted by the filter on the measuring device was collected in real time during controlled expansion. Replicates were averaged and significance was determined by calculating analysis of covariance using SAS software (SAS Institute, Cary, NC). RESULTS: Each filter model generated a significantly different radial expansion force (P < .001), and force was distributed at significantly different rates (P < .001) during expansion. The largest radial expansion force at minimal caval diameter was seen in the Cook Platinum filter, followed by the Cook Celect and Greenfield filters. Radial force dispersion during expansion was greatest in the Cook Celect, followed by the Cook Platinum and Greenfield filters. CONCLUSIONS: Differences in radial expansion forces among IVC filter models are consistent with documented perforation rates. Cook Celect IVC filters have a higher incidence of perforation compared with Greenfield filters when they are left in place for >90 days. Evaluation of Cook Celect filters yielded a significantly higher radial expansion force at minimum caval diameter, with greater force dispersion during expansion. PMID- 29396158 TI - An institution-wide algorithm for direct-stick embolization of peripheral venous malformations. AB - OBJECTIVE: No standardized therapeutic algorithm or embolic agent of choice has yet been identified for management of congenital peripheral venous malformations (VMs). Treatment options and reported outcomes therefore vary widely. Herein, we present an institution-wide algorithm for management of symptomatic congenital peripheral VMs using a single embolotherapeutic modality. METHODS: During 36 months, patients with symptomatic congenital peripheral VMs underwent contrast enhanced magnetic resonance imaging. Hematologic monitoring for localized intravascular coagulopathy was performed in all. Perioperative anticoagulation was administered accordingly. When applicable, venous duplex ultrasound was performed to assess for presence and patency of a deep venous system and superficial venous reflux. If superficial venous reflux was identified, radiofrequency ablation was performed per standard protocol before or at the time of initial embolization. Direct-stick embolizations (DSEs) were performed by a single operator using two concentrations (1% and 3%) of sodium tetradecyl sulfate (STS; Sotradecol; AngioDynamics, Latham, NY) without foam preparation. Patients were followed up clinically for resolution of symptoms, coagulopathic monitoring, and development of complications. All data were prospectively maintained and retrospectively reviewed. RESULTS: There were 71 DSEs performed in 40 patients (1.8 procedures per patient [range, 1-8]; 12 male patients; mean age, 22 years [range, 2-53 years]). Mean follow-up was 17.1 months (range, 0.8-31.6 months). Presenting symptoms included pain (n = 40 [100%]), swelling (n = 36 [90%]), and cosmetic disfigurement (n = 32 [80%]). Anatomic distribution was upper extremity (n = 16 [23%]), lower extremity (n = 37 [52%]), head and neck (n = 7 [10%]), trunk (n = 10 [14%]), and visceral (n = 1 [1%]). There were 33 sporadic cases, 4 (10%) Klippel-Trenaunay syndrome cases, 2 (5%) blue rubber bleb nevus syndrome cases, and 1 (2.5%) CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, and skeletal deformities) syndrome case. Four patients presented with localized intravascular coagulopathy, two of whom required perioperative enoxaparin. Twenty-six patients (65%) required a single DSE session with complete symptom relief. Fourteen patients (35%) required repeated DSE. Two patients (5%) required adjunctive surgical excision. There was one postoperative death (1.4%) secondary to massive pulmonary embolism. Complications were otherwise limited to skin necrosis (n = 2 [3%]). Mean volume of sclerosant per session was 7 mL of 1% STS (range, 3-14 mL), and 15 mL of 3% STS (range, 3-42.5 mL). CONCLUSIONS: In the absence of allergic reactions, most congenital peripheral VMs can be safely embolized with liquid STS, thereby avoiding the well-documented toxicity of ethanol. Venous thromboembolism remains a major source of morbidity and mortality in this population of patients despite close hematologic scrutiny. Prospective randomized trials are needed for embolotherapeutic standardization. PMID- 29396159 TI - Patterns of age-specific socioeconomic inequalities in net survival for common cancers in Taiwan, a country with universal health coverage. AB - INTRODUCTION: In high-income countries, advances in early diagnosis and treatment have improved cancer survival. However, socioeconomic inequalities in survival have persisted or increased for some adult cancers. MATERIALS AND METHODS: We assessed net survival for the 20 most common adult cancers in Taiwan. They were stratified into six age groups and three socioeconomic groups. RESULTS: Out of 120 cancer site and age group combinations, 49 showed improvements in 5-year net survival from 2000-2004 to 2005-2010. Only cervix uteri cancer in the 35-49-year age group showed a deterioration. During 2000-2010, 13 of the 20 cancer cases experienced socioeconomic inequalities for all age groups combined, and the deprivation gaps varied with cancer site and age at diagnosis. For the five most common cancers - liver, colon and rectum, lung, breast, and oral - there were socioeconomic inequalities, and 5-year net survival improved for most or all of the six age groups from 2000-2004 to 2005-2010. CONCLUSION: Reducing socioeconomic inequality in survival may lead to improvements in survival overall. We should focus on the age groups with large deprivation gaps. Our results are useful for prioritizing cancer sites and age groups for in-depth socioeconomic disparity studies and for proposing interventions for health disparity reductions and net cancer survival improvements. PMID- 29396160 TI - Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity. AB - Chronic viral infections remain a global health concern. The early events that facilitate viral persistence have been linked to the activity of the immunoregulatory cytokine IL-10. However, the mechanisms by which IL-10 facilitates the establishment of chronic infection are not fully understood. Herein, we demonstrated that the antigen sensitivity of CD8+ T cells was decreased during chronic infection and that this was directly mediated by IL-10. Mechanistically, we showed that IL-10 induced the expression of Mgat5, a glycosyltransferase that enhances N-glycan branching on surface glycoproteins. Increased N-glycan branching on CD8+ T cells promoted the formation of a galectin 3-mediated membrane lattice, which restricted the interaction of key glycoproteins, ultimately increasing the antigenic threshold required for T cell activation. Our study identified a regulatory loop in which IL-10 directly restricts CD8+ T cell activation and function through modification of cell surface glycosylation allowing the establishment of chronic infection. PMID- 29396161 TI - B Cell Receptor and CD40 Signaling Are Rewired for Synergistic Induction of the c Myc Transcription Factor in Germinal Center B Cells. AB - Positive selection of germinal center (GC) B cells is driven by B cell receptor (BCR) affinity and requires help from follicular T helper cells. The transcription factors c-Myc and Foxo1 are critical for GC B cell selection and survival. However, how different affinity-related signaling events control these transcription factors in a manner that links to selection is unknown. Here we showed that GC B cells reprogram CD40 and BCR signaling to transduce via NF kappaB and Foxo1, respectively, whereas naive B cells propagate both signals downstream of either receptor. Although either BCR or CD40 ligation induced c-Myc in naive B cells, both signals were required to highly induce c-Myc, a critical mediator of GC B cell survival and cell cycle reentry. Thus, GC B cells rewire their signaling to enhance selection stringency via a requirement for both antigen receptor- and T cell-mediated signals to induce mediators of positive selection. PMID- 29396162 TI - Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4. AB - Glucocorticoids are steroid hormones with strong anti-inflammatory and immunosuppressive effects that are produced in a diurnal fashion. Although glucocorticoids have the potential to induce interleukin-7 receptor (IL-7R) expression in T cells, whether they control T cell homeostasis and responses at physiological concentrations remains unclear. We found that glucocorticoid receptor signaling induces IL-7R expression in mouse T cells by binding to an enhancer of the IL-7Ralpha locus, with a peak at midnight and a trough at midday. This diurnal induction of IL-7R supported the survival of T cells and their redistribution between lymph nodes, spleen, and blood by controlling expression of the chemokine receptor CXCR4. In mice, T cell accumulation in the spleen at night enhanced immune responses against soluble antigens and systemic bacterial infection. Our results reveal the immunoenhancing role of glucocorticoids in adaptive immunity and provide insight into how immune function is regulated by the diurnal rhythm. PMID- 29396164 TI - Wideband acoustic absorbance in children with Down syndrome. AB - INTRODUCTION: Tympanometry is currently the most frequently used tool for assessing the status of the middle ear, commonly assessed using a single 226Hz tone. However, the use of the Acoustic Immittance Measures with a wideband stimulus is a promising high-resolution evaluation, especially in individuals known to have middle ear alterations, such as Down syndrome patients. OBJECTIVE: The aim of this study was to analyze the acoustic absorbance measurements in children with Down syndrome. METHODS: Cross-sectional study, approved by the institution's ethics committee. Data were collected from 30 children, with a mean age of 8.4 years, 15 with Down syndrome (DS-study group) and 15 children with typical development and no hearing complaints (control group). Energy absorbance was measured at frequencies of 226-8000Hz at ambient pressure and at peak pressure as a function of frequency using TITAN equipment. Statistical analysis was performed using the established level of statistical significance of 5%. RESULTS: With the 226Hz probe tone, 30 ears of the control group and 22 of the study group exhibited Type A tympanograms, whereas Type B was observed in eight children in the study group. The mean acoustic absorbance ratio of the study group was lower than that of the control group at frequencies centered at 2520Hz (p=0.008) for those with normal tympanometry results, and 226-4000Hz (p<0.03) for those with a Type B tympanometry curve. CONCLUSION: The low energy absorption in the presence of normal tympanograms in children with Down syndrome may suggest middle ear abnormalities. PMID- 29396165 TI - Sustainability of a nurse-driven early progressive mobility protocol and patient clinical and psychological health outcomes in a neurological intensive care unit. AB - OBJECTIVES: To determine sustainable impact of an early progressive mobility protocol on mobility level and clinical outcomes. DESIGN/METHODS: Prospective, longitudinal, comparative study using three time points (pre-, immediate post intervention and 12-month post-intervention sustainability). Analyses included comparative statistics and multivariable modelling. Data were collected by clinical nurses, from administrative databases. Psychological health data were collected using a valid, reliable tool. SETTING: Patients treated in a 22-bed Neurological Intensive Care Unit of a quaternary-care medical centre. OUTCOME MEASURES: Highest mobility level, length of stay, mortality, discharge disposition, quality metrics and psychological profile including depression, anxiety, and hostility. RESULTS: Amongst 260 pre-intervention, 377 post implementation, and 480 twelve-month post-implementation patients (N = 1117) walking increased post-implementation and was sustained at the eight-month assessment, p < .001. After multivariable adjustment, unit and hospital length of stay and psychological distress were reduced compared to the pre-early mobility programmes (all p < .001). There were no differences in discharge disposition (i.e., home vs skilled nursing facility), mortality or quality metrics. CONCLUSION: Ongoing implementation of an early mobility programme in a neurological intensive care environment led to sustained improvement in patients' level of mobility, length of unit and hospital stay, depression, anxiety and hostility levels. PMID- 29396163 TI - Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation. AB - Respiratory syncytial virus (RSV) is a leading cause of infant mortality, and there are currently no licensed vaccines to protect this vulnerable population. A comprehensive understanding of infant antibody responses to natural RSV infection would facilitate vaccine development. Here, we isolated more than 450 RSV fusion glycoprotein (F)-specific antibodies from 7 RSV-infected infants and found that half of the antibodies recognized only two antigenic sites. Antibodies targeting both sites showed convergent sequence features, and structural studies revealed the molecular basis for their recognition of RSV F. A subset of antibodies targeting one of these sites displayed potent neutralizing activity despite lacking somatic mutations, and similar antibodies were detected in RSV-naive B cell repertoires, suggesting that expansion of these B cells in infants may be possible with suitably designed vaccine antigens. Collectively, our results provide fundamental insights into infant antibody responses and a framework for the rational design of age-specific RSV vaccines. PMID- 29396166 TI - Postpartum Depression Screening Tools: A Review. AB - OBJECTIVE: The purpose of this study was to analyze the accuracy of screening tools in detecting postpartum depression (PPD). METHODS: A review of the literature was conducted using PubMed, Clinical Key, and Google Scholar from the years 2001-2016 with a modified PRISMA method. The keywords, "postnatal depression screening," "antenatal depression screening," and "maternal depression" were used in the search. Sixty-eight articles were reviewed, and 36 further analyzed. RESULTS: The accuracy of screening tools was dependent upon a number of factors. The studies reviewed differed in the types of screening tools tested, the combination of screening tools administered, the timing in which screening tools were administered, the geographic location of patients screened, and the reference standard(s) used. CONCLUSIONS: No tool could be deemed best at accurately detecting PPD on the basis of sensitivity and specificity. Additionally, there was no recommended time duration in which screening should be done. Thus, further research is needed to elucidate the accuracy of PPD screening tools, and the best criteria to determine this. PMID- 29396168 TI - Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. METHODS: In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7 +/- 3.5 years at diagnosis, median 2.5 years after therapy; males: 28). INCLUSION CRITERIA: >=6 years of age, >=3 months after last administration of Vincristine, and cumulative dose of Vincristine 12 mg/m2. We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment of small- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large fiber neuropathy. RESULTS: Fifteen survivors (33%) had abnormal rPed-mTNS values (>=4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p < 0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. CONCLUSION: QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival. PMID- 29396169 TI - Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders. AB - Anti-N-Methyl-d-aspartate-receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in pediatric age. This retrospective observational study was aimed at describing the clinical characteristics of the disease in a cohort of children and teenagers. Eighteen patients (10 females and 8 males), with a median age of 12.4 years at symptom onset were enrolled. The clinical presentation of the disease was marked by neurological manifestations in 13 patients and by severe psychiatric and behavioral symptoms in 5. The symptoms at onset varied according to the age: all the children presented with prominent neurological symptoms, whereas psychiatric symptoms were prominent in teenagers. Regardless the age, movement disorders (MDs) were distinctive symptoms during the acute stage of the disease. Several MDs might coexist in a given patient, and persist during sleep. The complexity, and the oddness of MDs often challenged their definition and the differential diagnosis with psychiatric manifestations and epileptic seizures. Stereotyped motor phenomena were the most typical MDs, and were recorded in all patients. Among them, perseveration, reproduction of acquired complex motor activities, and orofacial dyskinesia were the most distinctive features. In children, hyperkinetic MDs dominate; in teenagers, by contrast, a constellation of symptoms consistent with catatonia was the most frequent syndrome observed. The management of the several symptoms requires their accurate recognition, definition and assessment, and the knowledge of the potential side effects of antiepileptic and psychotropic drugs which could either mimic or worsen symptoms of encephalitis. PMID- 29396167 TI - Challenges in vascular tissue engineering for diabetic patients. AB - : Hyperglycemia and dyslipidemia coexist in diabetes and result in inflammation, degeneration, and impaired tissue remodeling, processes which are not conducive to the desired integration of tissue engineered products into the surrounding tissues. There are several challenges for vascular tissue engineering such as non thrombogenicity, adequate burst pressure and compliance, suturability, appropriate remodeling responses, and vasoactivity, but, under diabetic conditions, an additional challenge needs to be considered: the aggressive oxidative environment generated by the high glucose and lipid concentrations that lead to the formation of advanced glycation end products (AGEs) in the vascular wall. Extracellular matrix-based scaffolds have adequate physical properties and are biocompatible, however, these scaffolds are altered in diabetes by the formation AGEs and impaired collagen degradation, consequently increasing vascular wall stiffness. In addition, vascular cells detect and respond to altered stimuli from the matrix by pathological remodeling of the vascular wall. Due to the immunomodulatory effects of mesenchymal stem cells (MSCs), they are frequently used in tissue engineering in order to protect the scaffolds from inflammation. MSCs together with antioxidant treatments of the scaffolds are expected to protect the vascular grafts from diabetes-induced alterations. In conclusion, as one of the most daunting environments that could damage the ECM and its interaction with cells is progressively built in diabetes, we recommend that cells and scaffolds used in vascular tissue engineering for diabetic patients are tested in diabetic animal models, in order to obtain valuable results regarding their resistance to diabetic adversities. STATEMENT OF SIGNIFICANCE: Almost 25 million Americans have diabetes, characterized by high levels of blood sugar that binds to tissues and disturbs the function of cardiovascular structures. Therefore, patients with diabetes have a high risk of cardiovascular diseases. Surgery is required to replace diseased arteries with implants, but these fail after 5-10 years because they are made of non-living materials, not resistant to diabetes. New tissue engineering materials are developed, based on the patients' own stem cells, isolated from fat, and added to extracellular matrix-based scaffolds. Our main concern is that diabetes could damage the tissue-like implants. Thus we review studies related to the effect of diabetes on tissue components and recommend antioxidant treatments to increase the resistance of implants to diabetes. PMID- 29396170 TI - Deep brain stimulation for dystonia due to cerebral palsy: A review. AB - Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies. PMID- 29396171 TI - ATP1A3 spectrum disorders: A video-documented history of 7 genetically confirmed early onset cases. AB - Mutations in the ATP1A3 gene, which encodes the alpha3-subunit of sodium potassium ATPase, are related to a spectrum of neurological diseases including Rapid onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome. Moreover, an increasing number of patients with intermediate and non classical phenotypes have been reported. Herein we describe 7 patients with 6 different de novo ATP1A3 mutations, and we focus on paroxysmal and chronic movement disorders with the help of video documentation. Our cases confirm that ATP1A3-related neurological disorders make up a phenotypic continuum rather than overlapping syndromes, in which early onset dystonia, ataxia and paroxysmal episodes with triggering or worsening factors are key diagnostic clues. Moreover, our experience suggests that ATP1A3 gene analysis should be extended both to children with channelopathy-like spells and to patients with early onset, fever-related encephalopathy. PMID- 29396172 TI - Severe GABAA receptor encephalitis without seizures: A paediatric case successfully treated with early immunomodulation. AB - BACKGROUND: Autoimmune-mediated processes are the driving force behind many neurological diseases. Autoimmune encephalitis, a group of syndromes, mediated by or at least associated with autoantibodies against neuronal tissue, have gained increasing importance especially in paediatric neurology. Since the first NMDAR encephalitis was described a growing number of patients with encephalopathy, seizures and psychiatric symptoms were found to suffer from treatable autoimmune disorders. Recently a severe form of encephalitis associated with GABAAR antibodies was described showing extensive MRI abnormalities and refractory seizures. CASE: We now describe a child with catatonia and encephalopathy due to antibodies against the GABAA receptor. It is a rare paediatric case without the development of seizures despite severe encephalopathy. RELEVANCE: The report extends the phenotype of this rare disease. It demonstrates a favourable outcome after introduction of an early and aggressive immunomodulatory therapy. Due to the child's history of previous viral meningitis, the case raises questions about the unrevealed mechanisms leading to autoimmune encephalitis, including the model of a viral trigger as discussed in Herpes infection and NMDAR encephalitis. Finally, it describes in detail the neuropsychological symptoms and cognitive functions during disease flare and recovery. PMID- 29396173 TI - The neuropsychology of basal ganglia. AB - Basal ganglia are subcortical structures specialized at very early age, functionally different according to the right or left side. They are part of complex distributed network composed by parallel segregated loops where specific information are processed and open loops where different information are integrated. These loops are connected to specialized cortical areas thus entering into distributed processing of higher order cognitive functions and behaviours. Lesion or malfunction of basal ganglia nuclei cause deficits in different neuropsychological functions and neurobehavioural diseases, such Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, Tourette syndrome, etc., for the reciprocal connections from and to the limbic system and the frontal system. Basal ganglia have a computational functioning, working by activation and inhibition sequences, coded in time and space and regulated by inhibitory and excitatory mechanisms, with such accuracy to guarantee an effective and elegant product. PMID- 29396174 TI - Diagnosis and treatment of pediatric onset isolated dystonia. AB - Isolated dystonia refers to a genetic heterogeneous group of progressive conditions with onset of symptoms during childhood or adolescence, progressive course with frequent generalization and marked functional impairment. There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance. Genetic findings of the past years have widened the etiological spectrum and the phenotype. The recently discovered genes (GNAL, ANO-3, KTM2B) or variant of already known diseases, such as Ataxia-Teleangectasia, are emerging as another causes of pediatric onset dystonia, sometimes with a more complex phenotype, but their incidence is unknown and still a considerable number of cases remains genetically undetermined. Due to the severe disability of pediatric onset dystonia treatment remains unsatisfactory and still mainly based upon oral pharmacological agents. However, deep brain stimulation is now extensively applied with good to excellent results especially when patients are treated early during the course of the disease. PMID- 29396176 TI - The relevance of gene panels in movement disorders diagnosis: A lab perspective. AB - Next-Generation Sequencing (NGS) is a group of new methods that allow sequencing a variable number of known genes (targeted resequencing) or even the whole human genome (whole genome sequencing-WGS) and have contributed to an exponential genetic knowledge growth, especially in rare diseases, in the past few years. Since 2015, in the Molecular Neurogenetics Unit of Neurological Institute "Carlo Besta", some gene panels have become available to screen all the known genes associated with Movement Disorders (MD) in children and adults as a diagnostic package. Over 221 patients analyzed (part of the Telethon Network of Genetic Biobanks - TNGB), pathogenic variants were found in 25 (11.31%), allowing a definitive genetic diagnosis. Among them, we found mutations in 10/114 patients with dystonia (8.8%); 10/59 patients with Parkinson's disease (16.9%); 1/25 patients with Neurodegeneration with Brain Iron Accumulation (NBIA) (4%) and 4/23 patients with neurotransmitter and biopterin metabolism synthesis defect (17.4%). Our results are in line with those published in literature; targeted resequencing does not replace Sanger sequencing totally, but its usage needs to be discussed with clinicians taking into account both the patient's clinical picture and radiological and neurophysiological data. PMID- 29396175 TI - Basal ganglia mechanisms in action selection, plasticity, and dystonia. AB - Basal ganglia circuits are organized to selected desired actions and to inhibit potentially competing unwanted actions. This is accomplished through a complex circuitry that is modified through development and learning. Mechanisms of neural plasticity underlying these modifications are increasingly understood, but new mechanisms continue to be discovered. Dystonia, a movement disorder characterized by involuntary muscle contractions that cause abnormal postures and movements. Emerging evidence points to important links between mechanisms of plasticity and the manifestations of dystonia. Investigation of these mechanisms has improved understanding of the action of currently used medication and is informing the development of new treatments. PMID- 29396177 TI - Early-onset movement disorder as diagnostic marker in genetic syndromes: Three cases of FOXG1-related syndrome. AB - FOXG1-related syndrome is a developmental encephalopathy with a high phenotypic variability. A movement disorder presenting at onset is one of the main features, along with microcephaly and severe psychomotor delay without regression. Specific brain MRI findings facilitate the diagnosis. We report three cases of FOXG1 related syndrome, focusing on clinical onset, brain MRI and evolution over time in order to identify common features despite the three different underlying genotypes (14q12 deletion including the FOXG1 gene, FOXG1 intragenic mutation, 14q12 deletion including PRKD1 and a region regulating FOXG1 expression). In conclusion, we stress the importance of considering genetic syndromes in the differential diagnosis of early-onset movement disorders. PMID- 29396178 TI - Pharmacy technician involvement in community pharmacy medication therapy management. AB - OBJECTIVES: To assess the impact of technician involvement on the completion of medication therapy management (MTM) services in a community pharmacy setting and to describe pharmacists' and technicians' perceptions of technician involvement in MTM-related tasks and their satisfaction with the technician's role in MTM. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: In the fall of 2015, pharmacists and selected technicians from 32 grocery store-based community pharmacies were trained to use technicians within MTM services. MAIN OUTCOME MEASURES: Completed MTM claims were evaluated at all pharmacies for 3 months before training and 3 months after training. An electronic survey, developed with the use of competencies taught in the training and relevant published literature, was distributed via e-mail to trained employees 3 months after training. RESULTS: The total number of completed MTM claims at the 32 pharmacy sites was higher during the posttraining time period (2687 claims) versus the pretraining period (1735 claims). Of the 182 trained participants, 112 (61.5%) completed the survey. Overall, perceived technician involvement was lower than expected. However, identifying MTM opportunities was the most commonly reported technician MTM task, with 62.5% of technicians and 47.2% of pharmacists reporting technician involvement. Nearly one-half of technicians (42.5%) and pharmacists (44.0%) agreed or strongly agreed they were satisfied with the technician's role in MTM services, and 40.0% of technicians agreed that they were more satisfied with their work in the pharmacy after involvement in MTM. CONCLUSION: Three months after initial training of technicians in MTM, participation of technicians was lower than expected. However, the technicians involved most often reported identifying MTM opportunities for pharmacists, which may be a focus for future technician trainings. In addition, technician involvement in MTM services may increase satisfaction with many aspects of work for actively involved technicians. PMID- 29396179 TI - Corrigendum to "Oral cancer-derived exosomal NAP1 enhances cytotoxicity of natural killer cells via the IRF-3 pathway" [Oral Oncol. 76 (2018) 34-41]. PMID- 29396180 TI - Transport of silver nanoparticles in single fractured sandstone. AB - Silver nanoparticles (Ag-NP) are used in various consumer products and are one of the most prevalent metallic nanoparticle in commodities and are released into the environment. Transport behavior of Ag-NP in groundwater is one important aspect for the assessment of environmental impact and protection of drinking water resources in particular. Ag-NP transport processes in saturated single-fractured sandstones using triaxial flow cell experiments with different kind of sandstones is investigated. Ag-NP concentration and size are analyzed using flow field-flow fractionation and coupled SEM-EDX analysis. Results indicate that Ag-NP are more mobile and show generally lower attachment on rock surface compared to experiments in undisturbed sandstone matrix and partially fractured sandstones. Ag-NP transport is controlled by the characteristics of matrix porosity, time depending blocking of attachment sites and solute chemistry. Where Ag-NP attachment occur, it is heterogeneously distributed on the fracture surface. PMID- 29396181 TI - Argonaute 2 Is Required for Extra-embryonic Endoderm Differentiation of Mouse Embryonic Stem Cells. AB - In mouse, although four Argonaute (AGO) proteins with partly overlapping functions in small-RNA pathways exist, only Ago2 deficiency causes embryonic lethality. To investigate the role of AGO2 during mouse early development, we generated Ago2-deficient mouse embryonic stem cells (mESCs) and performed a detailed characterization of their differentiation potential. Ago2 disruption caused a global reduction of microRNAs, which resulted in the misregulation of only a limited number of transcripts. We demonstrated, both in vivo and in vitro, that AGO2 is dispensable for the embryonic germ-layer formation. However, Ago2 deficient mESCs showed a specific defect during conversion into extra-embryonic endoderm cells. We proved that this defect is cell autonomous and can be rescued by both a catalytically active and an inactive Ago2, but not by Ago2 deprived of its RNA binding capacity or by Ago1 overexpression. Overall, our results suggest a role for AGO2 in stem cell differentiation. PMID- 29396182 TI - Primary Cilia Are Dysfunctional in Obese Adipose-Derived Mesenchymal Stem Cells. AB - Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases. PMID- 29396183 TI - Astrocytes Attenuate Mitochondrial Dysfunctions in Human Dopaminergic Neurons Derived from iPSC. AB - Astrocytes, the most populous glial cell type in the brain, are critical for regulating the brain microenvironment. In various neurodegenerative diseases, astrocytes determine the progression and outcome of the neuropathological process. We have recently revealed the direct involvement of mitochondrial function in human pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neuronal differentiation. Using the astroglial-neuronal co-culture system, we show here that astrocytes effectively rescue defects in neurogenesis of DA neurons with mitochondrial respiratory chain disruption. Co-culture of astrocytes with defective DA neurons completely restored mitochondrial functions and dynamics insulted by mitochondrial toxins. These results suggest the significance of astroglia in maintaining mitochondrial development and bioenergetics during differentiation of hiPSC-derived DA neurons. Our study also provides an active astroglial-neuronal interaction model for future investigation of mitochondrial involvement in neurogenesis and neurodegenerative diseases. PMID- 29396185 TI - Hearing Loss: Why Does It Matter for Nursing Homes? AB - Over the past decade, hearing loss has emerged as a key issue for aging and health. We describe why hearing loss may be especially disabling in nursing home settings and provide an estimate of prevalence using the Minimum Data Set (MDS v.3.0). We outline steps to mitigate hearing loss. Many solutions are inexpensive and low-tech, but require significant awareness and institutional commitment. PMID- 29396184 TI - Reduced Self-Diploidization and Improved Survival of Semi-cloned Mice Produced from Androgenetic Haploid Embryonic Stem Cells through Overexpression of Dnmt3b. AB - Androgenetic haploid embryonic stem cells (AG-haESCs) hold great promise for exploring gene functions and generating gene-edited semi-cloned (SC) mice. However, the high incidence of self-diploidization and low efficiency of SC mouse production are major obstacles preventing widespread use of these cells. Moreover, although SC mice generation could be greatly improved by knocking out the differentially methylated regions of two imprinted genes, 50% of the SC mice did not survive into adulthood. Here, we found that the genome-wide DNA methylation level in AG-haESCs is extremely low. Subsequently, downregulation of both de novo methyltransferase Dnmt3b and other methylation-related genes was determined to be responsible for DNA hypomethylation. We further demonstrated that ectopic expression of Dnmt3b in AG-haESCs could effectively improve DNA methylation level, and the high incidence of self-diploidization could be markedly rescued. More importantly, the developmental potential of SC embryos was improved, and most SC mice could survive into adulthood. PMID- 29396186 TI - Receptive Music Therapy Is More Effective than Interactive Music Therapy to Relieve Behavioral and Psychological Symptoms of Dementia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Music therapy is demonstrated to be effective to relieve the agitation among people with dementia, but the comparative effectiveness of methods of music engagement for people with dementia is uncertain. OBJECTIVE: To evaluate the effects on cognitive functions and behavioral symptoms between interactive and receptive music therapies for people with dementia. METHODS: Prospective studies evaluating interactive and receptive music therapies were identified from the OVID databases, included MEDLINE, EMBASE, PsycINFO, and CINAHL. Supplementary search was conducted in Google Scholar. The primary outcome focused on cognitive function; the secondary outcomes were apathy, anxiety, depressive symptoms, agitation, and other behavioral problems. All outcomes were measured by the standard assessment tools. The heterogeneity of studies was examined, and the effects were pooled by meta-analysis. Quality of studies and risk of bias were assessed. RESULTS: Thirty-eight trials involving 1418 participants with dementia were included. The mean age ranged from 75 to 90 years, and the percentage of male participants ranged from 6% to 83%. No significant difference was found between participants receiving interactive or receptive music therapy and usual care in cognitive function; the mean difference (MD) of Mini-Mental State Examination was 0.18 [95% confidence interval (CI) 1.34 to 1.69], and -0.15 (95% CI -0.55 to 0.25), respectively. Participants with receptive music therapy had significant decrease in agitation (Cohen-Mansfield Agitation Inventory: MD = -7.99, 95% CI -5.11 to -0.87) and behavioral problems (Neuropsychiatric Inventory: MD = -3.02 95% CI -5.90 to -0.15) compared to usual care, while no significant difference was found between interactive music therapy and usual care in behavioral problems and psychiatric symptoms. CONCLUSIONS: This study demonstrated that receptive music therapy could reduce agitation, behavioral problems, and anxiety in older people with dementia, and appears to be more effective than interactive music therapy. It is easy and convenient to implement receptive music therapy; therefore, we recommended the use of receptive music therapy in nursing homes, day care centers, and client homes. PMID- 29396188 TI - Erratum. PMID- 29396187 TI - Diabetes Care and Dementia Among Older Adults: A Nationwide 3-Year Longitudinal Study. AB - OBJECTIVES: To compare diabetes monitoring and the incidence of acute diabetic complications between patients with and without incident Alzheimer's Disease and Related Syndromes (ADRS). DESIGN: Longitudinal observational study from 2010 to 2014. SETTING: Data from the French national health system database. PARTICIPANTS: The France-Demence cohort: individuals aged 65 years or older suffering from incident ADRS, based on long-term disease registry, hospitalization for dementia, or antidementia drug delivery. They were matched (1:1) to a pair free of ADRS on age, sex, residence area, and insurance scheme. This study included France-Demence population with known diabetes for at least 2 years. MEASUREMENTS: Data related to diabetes control and complications: biological monitoring such as glycated hemoglobin A1c (HbA1c, >=1/y, >=2/y), lipid profile, microalbuminuria; eye examination; hospitalization for diabetes related complications such as coma with ketoacidosis; and hospitalization for hypoglycemia were studied between the year prior to ADRS identification (Y-1) and the 2 following years (Y0; Y1). Incidences between the 2 groups (ADRS/non-ADRS) were compared using age-standardized incidence ratios (SIR). RESULTS: The studied population included 87,816 individuals. HbA1c determination was less frequent in ADRS group, no matter the study period and the minimal annual threshold used. Respectively, 82.6% and 88.5% of ADRS and non-ADRS group had at least 1 HbA1c testing during Y-1 [SIR = 0.94, 95% confidence interval (CI) 0.93-0.95], 73.4% and 89.0% during Y0 (SIR = 0.83, 95% CI 0.82-0.84), and 75.4% and 89.3% during Y1 (SIR = 0.85, 95% CI 0.83-0.86). Subjects with ADRS were also consistently more hospitalized than non-ADRS peers. The gap was maximal in the year following the diagnosis, as observed for hospitalizations for any cause related to diabetes (SIR Y-1: 2.04, Y0: 3.14, Y1: 1.67), diabetes mellitus with coma (SIR Y-1: 3.84, Y0: 9.30, Y1: 3.06), and hypoglycemia (SIR Y-1: 4.20, Y0: 5.25, Y1: 2.27). CONCLUSIONS: Incident ADRS is associated with a less frequent diabetes monitoring and an increased risk of diabetes complications compared with older people without ADRS. Our study questions healthcare quality offered to participants with ADRS in comorbidity control. Further investigations are required to explain the mechanisms underlying our results and to propose actions to improve care of patients with ADRS. PMID- 29396189 TI - Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: I. Cardiovascular Drugs. AB - BACKGROUND AND OBJECTIVE: Use of certain medications is recognized as a major and modifiable risk factor for falls. Although the literature on psychotropic drugs is compelling, the literature on cardiovascular drugs as potential fall-risk increasing drugs is conflicting. The aim of this systematic review and meta analysis is to provide a comprehensive overview of the associations between cardiovascular medications and fall risk in older adults. METHODS: Design: A systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and PsycINFO. Key search concepts were "fall," "aged," "causality," and "medication." Studies that investigated cardiovascular medications as risk factors for falls in participants >=60 years old or participants with a mean age of 70 or older were included. A meta-analysis was performed using the generic inverse variance method, pooling unadjusted and adjusted odds ratios (ORs) separately. RESULTS: In total, 131 studies were included in the qualitative synthesis. Meta-analysis using adjusted ORs showed significant results (pooled OR [95% confidence interval]) for loop diuretics, OR 1.36 (1.17, 1.57), and beta-blocking agents, OR 0.88 (0.80, 0.97). Meta-analysis using unadjusted ORs showed significant results for digitalis, OR 1.60 (1.08, 2.36); digoxin, OR 2.06 (1.56, 2.74); and statins, OR 0.80 (0.65, 0.98). Most of the meta-analyses resulted in substantial heterogeneity that mostly did not disappear after stratification for population and setting. In a descriptive synthesis, consistent associations were not observed. CONCLUSION: Loop diuretics were significantly associated with increased fall risk, whereas beta-blockers were significantly associated with decreased fall risk. Digitalis and digoxin may increase the risk of falling, and statins may reduce it. For the majority of cardiovascular medication groups, outcomes were inconsistent. Furthermore, recent studies indicate that specific drug properties, such as selectivity of beta-blockers, may affect fall risk, and drug disease interaction also may play a role. Thus, studies addressing these issues are warranted to obtain a better understanding of drug-related falls. PMID- 29396190 TI - El Intercambio Cultural - A Hispanic Culture and Language Immersion Project in a Nursing Home. PMID- 29396191 TI - Sarcopenia in Parkinson Disease: Comparison of Different Criteria and Association With Disease Severity. AB - OBJECTIVES: In Parkinson disease (PD), sarcopenia may represent the common downstream pathway that from motor and nonmotor symptoms leads to the progressive loss of resilience, frailty, and disability. Here we (1) assessed the prevalence of sarcopenia in older adults with PD using 3 different criteria, testing their agreement, and (2) evaluated the association between PD severity and sarcopenia. DESIGN: Cross-sectional, observation study. SETTING: Geriatric day hospital. PARTICIPANTS: Older adults with idiopathic PD. MEASUREMENTS: Body composition was evaluated through dual energy x-ray absorptiometry. Handgrip strength and walking speed were measured. Sarcopenia was operationalized according to the Foundation for the National Institutes of Health, the European Working Group on Sarcopenia in Older Persons, and the International Working Group. Cohen k statistics was used to test the agreement among criteria. RESULTS: Among the 210 participants (mean age 73 years; 38% women), the prevalence of sarcopenia was 28.5%-40.7% in men and 17.5%-32.5% in women. The prevalence of severe sarcopenia was 16.8%-20.0% in men and 11.3%-18.8% in women. The agreement among criteria was poor. The highest agreement was obtained between the European Working Group on Sarcopenia in Older Persons (severe sarcopenia) and International Working Group criteria (k = 0.52 in men; k = 0.65 in women; P < .01 for both). Finally, severe sarcopenia was associated with PD severity (odds ratio 2.30; 95% confidence interval 1.15 4.58). CONCLUSIONS: Sarcopenia is common in PD, with severe sarcopenia being diagnosed in 1 in every 5 patients with PD. We found a significant disagreement among the 3 criteria evaluated, in detecting sarcopenia more than in ruling it out. Finally, sarcopenia is associated with PD severity. Considering its massive prevalence, further studies should address the prognosis of sarcopenia in PD. PMID- 29396192 TI - Management of Nursing Home Residents Following Acute Hospitalization: Efficacy of the "Regular Early Assessment Post-Discharge (REAP)" Intervention. AB - OBJECTIVES: Rehospitalization of nursing home (NH) residents is frequent, costly, potentially avoidable and associated with diminished quality of life and poor survival. This study aims to evaluate the impact and cost-effectiveness of the Regular Early Assessment Post-Discharge (REAP) protocol of coordinated specialist geriatrician and nurse practitioner visits on rates of rehospitalization, hospital length of stay, and emergency department presentations for NH residents recently discharged from hospital. DESIGN: Prospective randomized controlled study of recently hospitalized NH residents. SETTING: Twenty-one of 24 eligible NHs within the geographical catchment area of St George Hospital, a 650-bed university hospital in Sydney, Australia. PARTICIPANTS: NH residents from eligible facilities admitted to St George Hospital's geriatric service were enrolled prior to hospital discharge. INTERVENTION: REAP intervention of monthly coordinated specialist geriatrician and nurse practitioner assessments within participants' NHs for 6 months following hospital discharge. MEASUREMENTS: Impact of the REAP intervention on hospital readmissions, hospital inpatient days, emergency department utilization, general practitioner visits, investigations and associated costs during the study intervention period. RESULTS: Forty-three NH residents were randomly allocated to REAP intervention (n = 22) or control (n = 21) groups. The REAP intervention group had almost two-thirds fewer hospital readmissions (P = .03; Cohen's d = 0.73) and half as many emergency department visits than controls. Total costs were 50% lower in the REAP intervention group, with lower total hospital inpatient (P = .04; Cohen's d = 0.63) and total emergency department (P = .04; Cohen's d = 0.65) costs. CONCLUSION: Cost effective reductions in the utilization of hospital-related services were demonstrated following implementation of the REAP intervention for NH residents recently discharged from hospital. PMID- 29396193 TI - Prone patient positioning to exclude left atrial appendage thrombus using cardiac CT. PMID- 29396195 TI - Re: ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee. PMID- 29396194 TI - Low thigh muscle mass is associated with coronary artery stenosis among HIV infected and HIV-uninfected men: The Multicenter AIDS Cohort Study (MACS). AB - BACKGROUND: HIV-infected individuals are at increased risk for both sarcopenia and cardiovascular disease. Whether an association between low muscle mass and subclinical coronary artery disease (CAD) exists, and if it is modified by HIV serostatus, are unknown. METHODS: We performed cross-sectional analysis of 513 male MACS participants (72% HIV-infected) who underwent mid-thigh computed tomography (CT) and non-contrast cardiac CT for coronary artery calcium (CAC) during 2010-2013. Of these, 379 also underwent coronary CT angiography for non calcified coronary plaque (NCP) and obstructive coronary stenosis >=50%. Multivariable-adjusted Poisson regression was used to estimate prevalence risk ratios of associations between low muscle mass (<20th percentile of the HIV uninfected individuals in the sample) and CAC, NCP and obstructive stenosis. RESULTS: The prevalence of low thigh muscle mass was similar by HIV serostatus (20%). There was no association of low muscle mass with CAC or NCP. However, low thigh muscle mass was significantly associated with a 2.5-fold higher prevalence of obstructive coronary stenosis, after adjustment for demographics and traditional CAD risk factors [PR 2.46 (95% CI 1.51, 4.01)]. This association remained significant after adjustment for adiposity, inflammation, and physical activity. There was no significant interaction by HIV serostatus (p-interaction = 0.90). CONCLUSIONS: In this exploratory analysis, low thigh muscle mass was significantly associated with subclinical obstructive coronary stenosis. Additional studies involving larger sample sizes and prospective analyses are needed to confirm the potential utility of measuring mid-thigh muscle mass for identifying individuals at increased risk for obstructive CAD who might benefit from more aggressive risk factor management. PMID- 29396197 TI - Ticks (Acari: Ixodidae) of Nepal: First record of Amblyomma varanense (Supino), with an update of species list. AB - Males and females specimens of Amblyomma were collected from Orthriophis hodgsoni (Squamata: Colubridae) caught during routine herpetological work in Kathmandu. Morphological characteristics led to the diagnosis of A. varanense, constituting the second Nepalese species for the genus after the collection of Amblyomma gervaisi, also from a colubrid snake, almost 100 years ago. Amblyomma varanense is the 55th species found in the country, and preceded for the collection of 21 species of Haemaphysalis, 14 Ixodes, 6 Rhipicephalus, 6 Hyalomma, 4 Dermacentor, 1 Amblyomma, 1 Anomalohimalaya and 1 species of Nosomma. Eleven and 19 species have been found on humans and domestic mammals, respectively, evidencing the medical and economic importance of Nepalese Ixodidae. PMID- 29396196 TI - Disruption of blood meal-responsive serpins prevents Ixodes scapularis from feeding to repletion. AB - Serine protease inhibitors (serpins) are thought to mediate the tick's evasion of the host's serine protease-mediated defense pathways such as inflammation and blood clotting. This study describes characterization and target validation of 11 blood meal-responsive serpins that are associated with nymph and adult Ixodes scapularis tick feeding as revealed by quantitative (q)RT-PCR and RNAi silencing analyses. Given the high number of targets, we used combinatorial (co) RNAi silencing to disrupt candidate serpins in two groups (G): seven highly identical and four non-identical serpins based on amino acid identities, here after called GI and GII respectively. We show that injection of both GI and GII co-dsRNA into unfed nymph and adult I. scapularis ticks triggered suppression of cognate serpin mRNA. We show that disruption of GII, but not GI serpins significantly reduced feeding efficiency of both nymph and adult I. scapularis ticks. Knockdown of GII serpin transcripts caused significant respective mortalities of <=40 and 71% of nymphal and adult ticks that occurred within 24-48 h of attachment. This is significant, as the observed lethality preceded the tick feeding period when transmission of tick borne pathogens is predominant. We suspect that some of the GII serpins (S9, S17, S19 and S32) play roles in the tick detachment process in that upon detachment, mouthparts of GII co-dsRNA injected were covered with a whitish gel-like tissue that could be the tick cement cone. Normally, ticks do not retain tissue on their mouthparts upon detachment. Furthermore, disruption of GII serpins reduced tick blood meal sizes and the adult tick's ability to convert the blood meal to eggs. We discuss our data with reference to tick feeding physiology and conclude that some of the GII serpins are potential targets for anti-tick vaccine development. PMID- 29396198 TI - Morphodifferentiation of Gene's organ in engorged Amblyomma sculptum Berlese, 1888 female ticks (Acari: Ixodidae). AB - The Gene's organ (GO) secretes a waxy substance on eggs that reduces water loss and has antimicrobial properties. The current study evaluated morphological and histochemical aspects of GO in Amblyomma sculptum from the period of post-feeding - when ticks detach from the host - to the stage just before oviposition. In this species, GO is composed of a corpus and two pairs of glands, namely, cranial and caudal. Glandular cells are joined laterally by a system of interdigitating membranes with junctional complexes. Histochemistry showed that lipid droplets became more evident as GO developed, while glycogen gradually disappeared, and proteins were detected only near the onset of oviposition. The ultrastructural results revealed a marked distension of the cuticle filled with an amorphous material. Glandular cells showed poor endoplasmatic reticulum, many mitochondria mainly in the basal cell poles and a very developed basal labyrinth. We concluded that the development of GO in A. sculptum ticks was continuous and progressive, and it started after detachment from the host. Additionally, the ultrastructure study suggests that gland cells have an important absorption ability and a low synthetic activity, which indicates that the majority of wax precursors are derived from haemolymph. PMID- 29396199 TI - Clinical management of non-faecium non-faecalis vancomycin-resistant enterococci infection. Focus on Enterococcus gallinarum and Enterococcus casseliflavus/flavescens. AB - Enterococcus gallinarum and Enterococcus casseliflavus/flavescens are enterococci intrinsically resistant to vancomycin belonging to the E. gallinarum group. They are responsible mainly for healthcare-associated infections, in particular bloodstream, urinary tract and surgical wound infections. Diseases due to these bacteria are significantly increasing worldwide, as they are prone to cause infection in patients with concurrent hepatobiliary or oncohematological disorders. Along with their distinguishing vancomycin resistance, due to a chromosomally-encoded VanC operon, their additional intrinsic resistance to many antibiotics other than glycopeptides limits the therapeutic choices. In addition, their intrinsic vancomycin resistance, unlike the vancomycin resistance of Enterococcus faecalis and Enterococcus faecium caused by transmissible plasmids, poses different infection control issues. We focused on the therapeutic and infection control issues of clinical syndromes caused by E. gallinarum and E. casseliflavus/flavescens. We propose therapeutic algorithms on bloodstream infections, endocarditis, central nervous system infections, endophthalmitis and urinary tract infections. The implementation of infection control measures in cases of E. gallinarum and E. casseliflavus/flavescens infection or colonization should be evaluated on a case-by-case basis, especially for epidemic outbreaks or for isolates supposed to harbor a potential transmissible vancomycin-resistance phenotype. PMID- 29396201 TI - Mission Accomplished? We Need a Guide to the 'Post Release' World of Wolbachia for Aedes-borne Disease Control. AB - Historically, sustained control of Aedes aegypti, the vector of dengue, chikungunya, yellow fever, and Zika viruses, has been largely ineffective. Subsequently, two novel 'rear and release' control strategies utilizing mosquitoes infected with Wolbachia are currently being developed and deployed widely. In the incompatible insect technique, male Aedes mosquitoes, infected with Wolbachia, suppress populations through unproductive mating. In the transinfection strategy, both male and female Wolbachia-infected Ae. aegypti mosquitoes rapidly infect the wild population with Wolbachia, blocking virus transmission. It is critical to monitor the long-term stability of Wolbachia in host populations, and also the ability of this bacterium to continually inhibit virus transmission. Ongoing release and monitoring programs must be future proofed should political support weaken when these vectors are successfully controlled. PMID- 29396202 TI - Novel Entamoeba Findings in Nonhuman Primates. AB - In addition to well-known human-infecting species, Entamoeba species not found in humans have been identified recently in nonhuman primates (NHPs). Importantly, it has become clear that the organism identified as Entamoeba histolytica in NHPs is usually a distinct species, Entamoeba nuttalli. Many DNA-based stool surveys use species-specific detection methods and so may miss the full range of Entamoeba species present. In addition, authors may be using the same species name to describe distinct organisms. These various shortcomings may not be obvious to readers. In this review, we clarify the relationships between Entamoeba species' names based on morphological and molecular data, and highlight gaps in recently published data on Entamoeba species in wild NHPs resulting from the use of variable methodology. PMID- 29396200 TI - Do Cryptic Reservoirs Threaten Gambiense-Sleeping Sickness Elimination? AB - Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations at risk, drug donations, and efforts by national and international stakeholders have brought the epidemic under control with <2200 cases in 2016. The World Health Organization (WHO) has set the goals of gambiense-HAT elimination as a public health problem for 2020, and of interruption of transmission to humans for 2030. Latent human infections and possible animal reservoirs may challenge these goals. It remains largely unknown whether, and to what extend, they have an impact on gambiense-HAT transmission. We argue that a better understanding of the contribution of human and putative animal reservoirs to gambiense-HAT epidemiology is mandatory to inform elimination strategies. PMID- 29396203 TI - Evolutionary ARMS Race: Antimalarial Resistance Molecular Surveillance. AB - Molecular surveillance of antimalarial drug resistance markers has become an important part of resistance detection and containment. In the current climate of multidrug resistance, including resistance to the global front-line drug artemisinin, there is a consensus to upscale molecular surveillance. The most salient limitation to current surveillance efforts is that skill and infrastructure requirements preclude many regions. This includes sub-Saharan Africa, where Plasmodium falciparum is responsible for most of the global malaria disease burden. New molecular and data technologies have emerged with an emphasis on accessibility. These may allow surveillance to be conducted in broad settings where it is most needed, including at the primary healthcare level in endemic countries, and extending to the village health worker. PMID- 29396204 TI - Mismatch between ADA and AGS recommendations for glycated hemoglobin targets for older adults. AB - In recent years, modified glycemic targets have been defined for older adults with diabetes mellitus. In a sample of elderly patients, we have identified several inconsistencies between the real life applicability of glycated hemoglobin goals recommended by the American Diabetes Association and the American Geriatrics Society. PMID- 29396205 TI - The identification of higher forefoot temperatures associated with peripheral arterial disease in type 2 diabetes mellitus as detected by thermography. AB - AIMS: The purpose of this study was to investigate whether heat emitted from the feet of patients with type 2 diabetes (DM) and peripheral arterial disease (PAD) differed from those with type 2 diabetes without complications (DM). METHODS: A non-experimental, comparative prospective study design was employed in a tertiary referral hospital. Out of 223 randomly selected participants (430 limbs) who were initially tested, 62 limbs were categorized as DM+PAD and 22 limbs as DM without PAD. Subjects with evidence of peripheral neuropathy were excluded. Participants underwent thermographic imaging. Automatic segmentation of regions of interest extracted the temperature data. RESULTS: A significant difference in temperature in all the toes between the two groups was found (p=0.005, p=0.033, p=0.015, p=0.038 and p=0.02 for toes 1-5 respectively). The mean forefoot temperature in DM+PAD was significantly higher than that in DM (p=.019), with DM+PAD having a higher mean temperature (28.3 degrees C) compared to DM (26.2 degrees C). Similarly, the toes of subjects with DM+PAD were significantly warmer than those of subjects with DM only. CONCLUSIONS: Contrary to expectations the mean toe and forefoot temperatures in DM patients with PAD is higher than in those with DM only. This unexpected result could be attributed to disruption of noradrenergic vasoconstrictor thermoregulatory mechanisms with resulting increased flow through cutaneous vessels and subsequent increased heat emissivity. These results demonstrate that thermography may have potential in detecting PAD and associated temperature differences. PMID- 29396206 TI - Estimating transition probability of different states of type 2 diabetes and its associated factors using Markov model. AB - AIMS: Type 2 diabetes is a chronic metabolic disorder and one of the most common non-contagious diseases which is on the rise all over the world. The present study aims to assess the trend of change in fasting blood sugar (FBS) and factors associated with the progression and regression of type 2 diabetes. Moreover, this study estimates transition intensities and transition probabilities among various states using the multi-state Markov model. METHODS: In this study Multi-Ethnic Study of Atherosclerosis (MESA) dataset, from a longitudinal study, was used. The study, at the beginning, included 6814 individuals who were followed during the five phases of the study. FBS, serving as the criterion to assess the progression of diabetes, was classified into four states including (a) normal (FBS<100mg/dl), (b) impaired fasting glucose I (IFG I) (100mg/dl126mg/dl). A continuous-time Markov process was used to describe the evaluation of disease changes over the four states. The model estimated the mean sojourn time for each state. RESULTS: Based on the results obtained from fitting the Markov model, the transition probability for a normal individual to remain in the same status over a 10-year period was 0.63, while the probability for a person in the diabetes state was 0.40. The mean sojourn time for the normal and diabetic individuals aged 45-84 years was 6.26 and 5.20 respectively. The covariates of age, race, body mass index (BMI), physical activity, waist-to-hip ratio (WHR) and blood pressure, significantly affected the progression and regression of diabetes. CONCLUSION: An increase in physical activity could be the most important factor in the regression of diabetes, while an increase in WHR and BMI could be the most significant factors in progression of the disease. PMID- 29396207 TI - A seven-year study on an integrated hospital-community diabetes management program in Chinese patients with diabetes. AB - AIMS: To assess whether an integrated hospital-community diabetes management program could improve major cardiovascular risk factor control among patients with diabetes in real-world clinical settings. METHODS: 985 adults with diabetes in the Shanghai Taopu community health service center were enrolled at baseline and 907 subjects completed the follow-up. The follow-up levels of the metabolic profiles were assessed by their averages during the follow up period. RESULTS: After a mean 7-year follow-up period, heamoglobin A1c, systolic and diastolic blood pressure levels decreased by 0.6%, 5.7mmHg, and 1.5mmHg, respectively (all P<0.001). There was a non-significant difference in low-density lipoprotein cholesterol, while high-density lipoprotein cholesterol increased 1.9mg/dL and triglycerides decreased 28.3mg/dL, respectively (all P<0.001). The percentage of patients with diabetes who met any one of three Chinese Diabetes Society goals (heamoglobin A1c <7.0%, blood pressure <140/80mmHg, and low-density lipoprotein cholesterol <100mg/dL) increased from 58.2% to 70.1%. The chronic diabetes complication screening rates (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) have significantly increased, from almost zero to 12-78%. CONCLUSIONS: This long-term program has increased the proportions of attaining major cardiovascular risk factors control goals and diabetic chronic complication screening rates among patients with diabetes. PMID- 29396208 TI - The impact of perceptual changes to studied items on ERP correlates of familiarity and recollection is subject to hemispheric asymmetries. AB - It is still unclear which role the right hemisphere (RH) preference for perceptually specific and the left hemisphere (LH) bias towards abstract memory representations play at the level of episodic memory retrieval. When stimulus characteristics hampered the retrieval of abstract memory representations, these hemispheric asymmetries have previously only modulated event-related potential (ERP) correlates of recollection (late positive complex, LPC), but not of familiarity (FN400). In the present experiment, we used stimuli which facilitated the retrieval of abstract memory representations. With the divided visual field technique, new items, identical repetitions and color-modified versions of incidentally studied object pictures were presented in either the right (RVF) or the left visual field (LVF). Participants performed a memory inclusion task, in which they had to categorize both identically repeated and color-modified study items as 'old'. Only ERP, but not behavioral data showed hemispheric asymmetries: Compared to identical repetitions, FN400 and LPC old/new effects for color modified items were equivalent with RVF/LH presentation, but reduced with LVF/RH presentation. By promoting the use of abstract stimulus information for memory retrieval, we were thus able to show that hemispheric asymmetries in accessing abstract or specific memory representations can modulate ERP correlates of familiarity as well as recollection processes. PMID- 29396209 TI - Chromatic and achromatic visual fields in relation to choroidal thickness in patients with high myopia: A pilot study. AB - PURPOSE: To analyse the relationship between the choroidal thickness and the visual perception of patients with high myopia but without retinal damage. METHODS: All patients underwent ophthalmic evaluation including a slit lamp examination and dilated ophthalmoscopy, subjective refraction, best corrected visual acuity, axial length, optical coherence tomography, contrast sensitivity function and sensitivity of the visual pathways. RESULTS: We included eleven eyes of subjects with high myopia. There are statistical correlations between choroidal thickness and almost all the contrast sensitivity values. The sensitivity of magnocellular and koniocellular pathways is the most affected, and the homogeneity of the sensibility of the magnocellular pathway depends on the choroidal thickness; when the thickness decreases, the sensitivity impairment extends from the center to the periphery of the visual field. CONCLUSIONS: Patients with high myopia without any fundus changes have visual impairments. We have found that choroidal thickness correlates with perceptual parameters such as contrast sensitivity or mean defect and pattern standard deviation of the visual fields of some visual pathways. Our study shows that the magnocellular and koniocellular pathways are the most affected, so that these patients have impairment in motion perception and blue-yellow contrast perception. PMID- 29396210 TI - [Mucoepidermoid carcinoma of the conjunctiva. Case report]. PMID- 29396211 TI - Effect of charge on the current-voltage characteristics of silicon pin structures with and without getter annealing under beta irradiation of Ni-63. AB - The charge model for efficiency of betavoltaics effect is proposed. It allows calculating the charge value for pin structures under irradiation of Ni-63. We approximated the current-voltage characteristics of the structures using an equivalent diode circuit with a charge on the barrier capacitance. We calculated the charge function from current-voltage characteristics for two types of silicon pin structures - with and without getter annealing. The charging on the surface of pin structure decreases the efficiency of betavoltaics effect. Value of charge for our structures is changed in the range from -50 to +15mC/cm2 and depends on the applied potential. The getter annealing allows getting the structures with a higher efficiency of betavoltaic effect, but it does not exclude the surface charging under beta irradiation from Ni-63. PMID- 29396212 TI - Multi-element detection in sea water using preconcentration procedure and EDXRF technique. AB - A method was optimized for detecting trace elements in sea water using Energy dispersive X-ray fluorescence (EDXRF) technique. Sea water samples were pre concentrated using ammonium pyrrolidinedithiocarbamate (APDC) as chelating agent and methyl isobutyl ketone (MIBK) as organic phase. The preconcentrated samples were dried to form thin films on mylar substrate and analysed using EDXRF spectrometer. The multi-element standard samples prepared in synthetic sea water were used for EDXRF instrument calibration. The instrument was calibrated for 11 elements namely As, Cd, Co, Cr, Fe, Ga, Pb, Se, Sc, V and Zn using linear regression method for concentration up to 200 ppb. The detection limits achieved for As, Cd, Co, Cr, Fe, Ga, Pb, Se, Sc, V and Zn were 13, 70, 5.1, 36, 15, 36, 23, 11, 20, 13 and 40 ppb respectively. The optimized method was used for determination of elements in sea water collected from the Thane creek, Mumbai, India. The results were checked for accuracy by comparing it with inductively coupled plasma atomic emission spectroscopy (ICP AES) technique. The comparison showed the discrepancy of results to be insignificant at 95% confidence level. PMID- 29396213 TI - Study of activation cross sections of deuteron induced reactions on erbium in the 32-50MeV energy range. AB - Activation cross sections of the natEr(d,x)163,165,166,167,168,170Tm and natEr(d,x)171,161Er nuclear reactions have been measured in the 32-50MeV energy range, above 40MeV for the first time. The activation method with stacked foil irradiation technique and gamma-ray spectroscopy were used. The experimental cross sections were compared with the theoretical predictions in the TENDL-2015 library. PMID- 29396214 TI - Hypothyroidism during pregnancy and its association to perinatal and obstetric morbidity: a review. AB - There is currently no consensus among the different scientific societies on screening for thyroid dysfunction in the first trimester of pregnancy. Indeed, diagnosis and treatment of subclinical hypothyroidism during pregnancy are controversial, as no cut-off value for thyrotropin (TSH) is universally accepted. TSH measurement may be influenced by different factors throughout pregnancy, but especially during the first trimester. The association between overt hypothyroidism during pregnancy and obstetric and perinatal complications is well established. It is also accepted that thyroid hormones are important for neurodevelopment of the offspring. However, there is no scientific evidence available about the impact of subclinical hypothyroidism and its treatment during the first trimester of pregnancy on children's neurodevelopment. In recent years, studies conducted in the offspring of mothers with subclinical hypothyroidism have reported new biochemical parameters which may eventually serve as biomarkers of offspring neurodevelopment and which are more reproducible and are measured at an earlier time than the conventional clinical tests. PMID- 29396215 TI - Validation of equations and proposed reference values to estimate fat mass in Chilean university students. AB - OBJECTIVES: (i) To propose regression equations based on anthropometric measures to estimate fat mass (FM) using dual energy X-ray absorptiometry (DXA) as reference method, and (ii)to establish population reference standards for equation-derived FM. MATERIAL AND METHODS: A cross-sectional study on 6,713 university students (3,354 males and 3,359 females) from Chile aged 17.0 to 27.0years. Anthropometric measures (weight, height, waist circumference) were taken in all participants. Whole body DXA was performed in 683 subjects. A total of 478 subjects were selected to develop regression equations, and 205 for their cross-validation. Data from 6,030 participants were used to develop reference standards for FM. Equations were generated using stepwise multiple regression analysis. Percentiles were developed using the LMS method. RESULTS: Equations for men were: (i) FM=-35,997.486 +232.285 *Weight +432.216 *CC (R2=0.73, SEE=4.1); (ii)FM=-37,671.303 +309.539 *Weight +66,028.109 *ICE (R2=0.76, SEE=3.8), while equations for women were: (iii)FM=-13,216.917 +461,302 *Weight+91.898 *CC (R2=0.70, SEE=4.6), and (iv) FM=-14,144.220 +464.061 *Weight +16,189.297 *ICE (R2=0.70, SEE=4.6). Percentiles proposed included p10, p50, p85, and p95. CONCLUSION: The developed equations provide valid and accurate estimation of FM in both sexes. The values obtained using the equations may be analyzed from percentiles that allow for categorizing body fat levels by age and sex. PMID- 29396216 TI - New WHO classification of thyroid tumors: a pragmatic categorization of thyroid gland neoplasms. PMID- 29396217 TI - Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Bangladesh: a cluster randomised controlled trial. AB - BACKGROUND: Diarrhoea and growth faltering in early childhood are associated with subsequent adverse outcomes. We aimed to assess whether water quality, sanitation, and handwashing interventions alone or combined with nutrition interventions reduced diarrhoea or growth faltering. METHODS: The WASH Benefits Bangladesh cluster-randomised trial enrolled pregnant women from villages in rural Bangladesh and evaluated outcomes at 1-year and 2-years' follow-up. Pregnant women in geographically adjacent clusters were block-randomised to one of seven clusters: chlorinated drinking water (water); upgraded sanitation (sanitation); promotion of handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate child nutrition plus lipid-based nutrient supplements (nutrition); combined water, sanitation, handwashing, and nutrition; and control (data collection only). Primary outcomes were caregiver-reported diarrhoea in the past 7 days among children who were in utero or younger than 3 years at enrolment and length-for-age Z score among children born to enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCC01590095. FINDINGS: Between May 31, 2012, and July 7, 2013, 5551 pregnant women in 720 clusters were randomly allocated to one of seven groups. 1382 women were assigned to the control group; 698 to water; 696 to sanitation; 688 to handwashing; 702 to water, sanitation, and handwashing; 699 to nutrition; and 686 to water, sanitation, handwashing, and nutrition. 331 (6%) women were lost to follow-up. Data on diarrhoea at year 1 or year 2 (combined) were available for 14 425 children (7331 in year 1, 7094 in year 2) and data on length-for-age Z score in year 2 were available for 4584 children (92% of living children were measured at year 2). All interventions had high adherence. Compared with a prevalence of 5.7% (200 of 3517 child weeks) in the control group, 7-day diarrhoea prevalence was lower among index children and children under 3 years at enrolment who received sanitation (61 [3.5%] of 1760; prevalence ratio 0.61, 95% CI 0.46-0.81), handwashing (62 [3.5%] of 1795; 0.60, 0.45-0.80), combined water, sanitation, and handwashing (74 [3.9%] of 1902; 0.69, 0.53-0.90), nutrition (62 [3.5%] of 1766; 0.64, 0.49-0.85), and combined water, sanitation, handwashing, and nutrition (66 [3.5%] of 1861; 0.62, 0.47-0.81); diarrhoea prevalence was not significantly lower in children receiving water treatment (90 [4.9%] of 1824; 0.89, 0.70-1.13). Compared with control (mean length-for-age Z score -1.79), children were taller by year 2 in the nutrition group (mean difference 0.25 [95% CI 0.15-0.36]) and in the combined water, sanitation, handwashing, and nutrition group (0.13 [0.02-0.24]). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth. INTERPRETATION: Nutrient supplementation and counselling modestly improved linear growth, but there was no benefit to the integration of water, sanitation, and handwashing with nutrition. Adherence was high in all groups and diarrhoea prevalence was reduced in all intervention groups except water treatment. Combined water, sanitation, and handwashing interventions provided no additive benefit over single interventions. FUNDING: Bill & Melinda Gates Foundation. PMID- 29396218 TI - Gaps in physical access to emergency care in sub-Saharan Africa. PMID- 29396219 TI - Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Kenya: a cluster-randomised controlled trial. AB - BACKGROUND: Poor nutrition and exposure to faecal contamination are associated with diarrhoea and growth faltering, both of which have long-term consequences for child health. We aimed to assess whether water, sanitation, handwashing, and nutrition interventions reduced diarrhoea or growth faltering. METHODS: The WASH Benefits cluster-randomised trial enrolled pregnant women from villages in rural Kenya and evaluated outcomes at 1 year and 2 years of follow-up. Geographically adjacent clusters were block-randomised to active control (household visits to measure mid-upper-arm circumference), passive control (data collection only), or compound-level interventions including household visits to promote target behaviours: drinking chlorinated water (water); safe sanitation consisting of disposing faeces in an improved latrine (sanitation); handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate maternal, infant, and young child feeding plus small-quantity lipid based nutrient supplements from 6-24 months (nutrition); and combined water, sanitation, handwashing, and nutrition. Primary outcomes were caregiver-reported diarrhoea in the past 7 days and length-for-age Z score at year 2 in index children born to the enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704105. FINDINGS: Between Nov 27, 2012, and May 21, 2014, 8246 women in 702 clusters were enrolled and randomly assigned an intervention or control group. 1919 women were assigned to the active control group; 938 to passive control; 904 to water; 892 to sanitation; 917 to handwashing; 912 to combined water, sanitation, and handwashing; 843 to nutrition; and 921 to combined water, sanitation, handwashing, and nutrition. Data on diarrhoea at year 1 or year 2 were available for 6494 children and data on length-for-age Z score in year 2 were available for 6583 children (86% of living children were measured at year 2). Adherence indicators for sanitation, handwashing, and nutrition were more than 70% at year 1, handwashing fell to less than 25% at year 2, and for water was less than 45% at year 1 and less than 25% at year 2; combined groups were comparable to single groups. None of the interventions reduced diarrhoea prevalence compared with the active control. Compared with active control (length-for-age Z score -1.54) children in nutrition and combined water, sanitation, handwashing, and nutrition were taller by year 2 (mean difference 0.13 [95% CI 0.01-0.25] in the nutrition group; 0.16 [0.05-0.27] in the combined water, sanitation, handwashing, and nutrition group). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth. INTERPRETATION: Behaviour change messaging combined with technologically simple interventions such as water treatment, household sanitation upgrades from unimproved to improved latrines, and handwashing stations did not reduce childhood diarrhoea or improve growth, even when adherence was at least as high as has been achieved by other programmes. Counselling and supplementation in the nutrition group and combined water, sanitation, handwashing, and nutrition interventions led to small growth benefits, but there was no advantage to integrating water, sanitation, and handwashing with nutrition. The interventions might have been more efficacious with higher adherence or in an environment with lower baseline sanitation coverage, especially in this context of high diarrhoea prevalence. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development. PMID- 29396220 TI - Access to emergency hospital care provided by the public sector in sub-Saharan Africa in 2015: a geocoded inventory and spatial analysis. AB - BACKGROUND: Timely access to emergency care can substantially reduce mortality. International benchmarks for access to emergency hospital care have been established to guide ambitions for universal health care by 2030. However, no Pan African database of where hospitals are located exists; therefore, we aimed to complete a geocoded inventory of hospital services in Africa in relation to how populations might access these services in 2015, with focus on women of child bearing age. METHODS: We assembled a geocoded inventory of public hospitals across 48 countries and islands of sub-Saharan Africa, including Zanzibar, using data from various sources. We only included public hospitals with emergency services that were managed by governments at national or local levels and faith based or non-governmental organisations. For hospital listings without geographical coordinates, we geocoded each facility using Microsoft Encarta (version 2009), Google Earth (version 7.3), Geonames, Fallingrain, OpenStreetMap, and other national digital gazetteers. We obtained estimates for total population and women of child bearing age (15-49 years) at a 1 km2 spatial resolution from the WorldPop database for 2015. Additionally, we assembled road network data from Google Map Maker Project and OpenStreetMap using ArcMap (version 10.5). We then combined the road network and the population locations to form a travel impedance surface. Subsequently, we formulated a cost distance algorithm based on the location of public hospitals and the travel impedance surface in AccessMod (version 5) to compute the proportion of populations living within a combined walking and motorised travel time of 2 h to emergency hospital services. FINDINGS: We consulted 100 databases from 48 sub-Saharan countries and islands, including Zanzibar, and identified 4908 public hospitals. 2701 hospitals had either full or partial information about their geographical coordinates. We estimated that 287 282 013 (29.0%) people and 64 495 526 (28.2%) women of child bearing age are located more than 2-h travel time from the nearest hospital. Marked differences were observed within and between countries, ranging from less than 25% of the population within 2-h travel time of a public hospital in South Sudan to more than 90% in Nigeria, Kenya, Cape Verde, Swaziland, South Africa, Burundi, Comoros, Sao Tome and Principe, and Zanzibar. Only 16 countries reached the international benchmark of more than 80% of their populations living within a 2-h travel time of the nearest hospital. INTERPRETATION: Physical access to emergency hospital care provided by the public sector in Africa remains poor and varies substantially within and between countries. Innovative targeting of emergency care services is necessary to reduce these inequities. This study provides the first spatial census of public hospital services in Africa. FUNDING: Wellcome Trust and the UK Department for International Development. PMID- 29396221 TI - Can integrated interventions create the conditions that support caregiving for better child growth? PMID- 29396222 TI - Reply letter to: Letter to the editor on the article "Endoscopic resection versus radical gastrectomy for early gastric cancer in Asia: A meta-analysis. PMID- 29396223 TI - International consensus (ICON) on functional and aesthetic rhinoplasty. AB - During the 2017 IFOS international congress in Paris, a roundtable discussion on the topic of functional and aesthetic rhinoplasty was organised. Five experts, from the five continents and renown in the field of rhinoplasty, were brought together to discuss the issue from an international perspective and to put forward a consensus or on the contrary practical differences. Five questions were put to the experts beforehand to guarantee independent answers, which were then discussed during the roundtable. The questions were the following: - What are the age limits for achieving a rhinoplasty? - Do you use objective measurements before, during and after surgery? (facial landmarks, airflow, peroperative measurements) - How do you manage the preoperative general information and computer imaging of the patient? - What are the indications in your practice to perform a CT-scan or endoscopic examination before doing a rhinoplasty? - What kind of graft or prosthesis do you use for an augmentation rhinoplasty? This paper offers a synthesis of the roundtable based on the experts' answers to the different questions. PMID- 29396224 TI - Laryngeal papillomatosis in Senegal: A ten-year experience. AB - OBJECTIVES: The objectives of this study were to describe the epidemiological, clinical and therapeutic characteristics of laryngeal papillomatosis in the Fann teaching hospital ENT department in Dakar, Senegal. PATIENTS AND METHODS: We retrospectively reviewed all cases of laryngeal papillomatosis managed in the Fann teaching hospital ENT department between 1st January 2006 and 31st December 2015. Epidemiological, clinical and therapeutic characteristics of laryngeal papillomatosis were studied. Statistical analysis was performed with SPSS 18 software. RESULTS: The median age at diagnosis was 11 years and the sex ratio was 1.88. The mean time to consultation was 4.5 years. The predominant symptom was dysphonia, present in all cases, followed by laryngeal dyspnoea in 64.6% of cases. The glottic area was involved in all patients. Tracheostomy was performed in 20.8% of cases. All patients in our study underwent endoscopic excision of the lesions. CONCLUSION: Laryngeal papillomatosis is the most common benign tumor in children, but it can also occur in adults. Treatment has been revolutionized by progress in endoscopy and antiviral therapy. However, tracheostomy still occupies an important place in our practice. PMID- 29396225 TI - International consensus (ICON) on assessment of oropharyngeal dysphagia. AB - OBJECTIVE: To present international recommendations regarding the proper evaluation of oropharyngeal dysphagia (OD), both objectively and subjectively (self-evaluation). METHODS: Following a thorough review of the literature, 5 experts in the field from 4 different continents answered separately a questionnaire regarding the work-up of OD. Individual answers were presented and discussed during the world ENT conference that was held in Paris in June 2017. This article will present the recommendations issued from that meeting. RESULTS: For the initial objective assessment of OD, it is recommended to perform either a functional endoscopic evaluation of swallowing (FEES) or a videofluoroscopic swallowing study (VFSS). FEES is the more popular investigation given its increased ease of use and accessibility. When evaluating for the presence of aspiration during the objective evaluation of OD, it is recommended to perform either a FEES or a VFSS. In this case, FEES is the favored investigation given its likely increased sensitivity. In order to highlight the presence of oropharyngeal food residue following the deglutition process, it is recommended to perform either a FEES or a VFSS; FEES likely being the more sensitive investigation while VFSS allows a better quantification of the amount of pharyngeal residue. Is it also recommended to objectify the quality of the deglutition process by means of a score during the objective evaluation of OD. Finally, it is recommended to utilize a self-evaluation questionnaire during research studies exploring the deglutition process. PMID- 29396226 TI - International consensus (ICON) on treatment of sudden sensorineural hearing loss. AB - Sudden sensorineural hearing loss (SSNHL) is a common and alarming symptom that often prompts an urgent visit to an ENT specialist. Treatment of SSNHL remains one of the most problematic issues for contemporary otorhinolaryngology: although many meta-analyses and national guidelines have been issued, management is not standardized in terms of medical treatment, and duration and route of administration. We present several methodological suggestions for the study of treatments for SSNHL. These were developed from the existing level of evidence of the main treatments used in SSNHL by experts who convened at the IFOS 2017 ENT World Congress in Paris, France. All panelists agreed that one of the main limitations present in studies on SSNHL is related to the wide heterogeneity, which characterizes both the initial hearing deficit and the amount of hearing recovery. Although evidence of the efficacy of systemic steroids cannot be considered as strong enough to recommend their use, it is still the most widespread primary therapy and can be considered as the current standard of care. Therefore, systemic steroids stand as an adequate control for any innovative treatment. To reduce the number of subjects we suggest that the inclusion criteria should be restricted to moderate to profound levels of hearing loss. The efficacy of trans-tympanic steroids as a salvage therapy was suggested in several reports on small populations and needs to be confirmed with larger randomized controlled trials. PMID- 29396227 TI - An unusual neck tumor. PMID- 29396228 TI - Is there a role for shared decision-making in pediatric weight management? AB - Shared decision-making (SDM) is central to personalising health and medical decisions. This decisional model encourages patients to act as managers of their own care while maintaining a partnership with health professionals. Although applied to some conditions, SDM has been used infrequently in pediatric weight management (PWM). Herein, we highlight the applicability and usefulness of SDM in making several important decisions related to PWM, including referral-making to different levels of care and treatment initiation and implementation. We conclude by describing possible challenges that may arise when implementing this model and suggest strategies to optimise the use of SDM in PWM. PMID- 29396229 TI - Exclusive breastfeeding and partial breastfeeding reduce the risk of overweight in childhood: A nationwide longitudinal study in Korea. AB - OBJECTIVE: Breastfeeding is generally known to reduce the risk of childhood overweight and obesity. However, the results are controversial between countries, and nationwide data are rare. This study assessed the relationship between breastfeeding types and overweight incidence using nationwide longitudinal data in Korea. METHODS: We analysed 774,764 infants who participated in the longitudinal nationwide data from the Korea National Children's Health Examination 2007-2013. Childhood overweight was defined by a Z-score>=1.64 (95th centile) for infants under 24 months and Z-scores>=1.04 (85th centile) for children over 24 months. Cox proportional hazard model was used to analyse the relationship between breastfeeding types and overweight incidence. RESULTS: Infants who were exclusively breastfed at 4-6 months of age had the multivariate adjusted hazard ratio (HRs) for overweight of 0.78 (95% CI 0.77-0.79) and infants who were partially breastfed had the HRs for overweight of 0.96 (95% CI 0.94 0.98), which was lower compared to that of the exclusively formula fed group. Similar results were obtained for stratified analysis by boys and girls. CONCLUSIONS: Exclusive and partial breastfeeding have preventive effect on childhood overweight in Korea. Therefore, it is necessary to encourage breastfeeding to prevent childhood obesity and its consequences in developed Asian countries. PMID- 29396230 TI - Nonlinear dose-response association between body mass index and risk of all-cause and cardiovascular mortality in patients with hypertension: A meta-analysis. AB - OBJECTIVE: The present study examined the dose-response association of body mass index (BMI) and risk of all-cause and cardiovascular mortality in patients with existing hypertension. METHOD: A systematic search was done using PubMed and Scopus, from their inception up to January 25, 2017. Prospective and retrospective cohort studies reporting risk estimates of all-cause and cardiovascular mortality for three or more quantitative categories of BMI were included. Studies which reported results as continuous also were included. Pooled relative risks (RRs) were calculated using random effects models. RESULTS: Of initial 34,938 identified studies, 14 studies with a total of 489,222 hypertensive patients, involving 41,872 cases of all-cause mortality and 2,123 cases of cardiovascular mortality were included. A five-unit increment in BMI was associated with an 8% reduction in the risk of all-cause mortality (Pooled RR: 0.92, 95% CI: 0.87, 0.97, P=0.003; I2=95.7%, n=13), and marginally and inversely associated with the risk of cardiovascular mortality (Pooled RR: 0.95, 95% CI: 0.88, 1.02, P=0.15; I2=90.3%, n=5). Nonlinear dose-response meta-analysis suggested a reverse J-shaped association between BMI and risk of all-cause and cardiovascular mortality, with a nadir at BMI of ~27.5-30kg/m2. Subgroup analysis indicated that the strength and shape of the association between BMI and all cause mortality might be influenced by age. CONCLUSION: There is strong evidence which confirms existence of obesity paradox in patients with hypertension. However, owing to the observational nature of included studies, these findings should be interpreted with caution. PMID- 29396231 TI - Abnormal of inter-hemispheric functional connectivity in elderly subjects with overweight/obesity. AB - BACKGROUND: There is a growing literature documenting a variety of brain abnormalities associated with obesity. However, little is known about the effects of obesity on inter-hemispheric connectivity in aging people. METHODS: Participants included 61 cognitively intact elderly (including people with obesity, overweight, and lean controls) who underwent structural MRI, resting state functional magnetic resonance imaging (rsfMRI) and standard neuropsychological batteries. Techniques including FreeSurfer and Voxel-mirrored Homotopic Connectivity (VMHC) were employed to evaluate inter-hemispheric structural and functional connectivity respectively. RESULTS: There were no differences of cognitive abilities and vascular risks among groups. When compared to lean controls, obese group had greater VMHC in fusiform gyrus (FG); while overweight group had greater VMHC in FG, calcarine gyrus, inferior temporal gyrus (ITG), and postcentral gyrus (PCG). Moreover, the obesity group had lower VMHC in calcarine gyrus and PCG than overweight group (p<0.05, corrected). CONCLUSIONS: The present study suggested, increased inter-hemispheric information transmission in networks supporting visual and sensorimotor function may lead to gain in weight, by possibly mediating diet behaviours of individuals. PMID- 29396232 TI - The engagement pathway: A conceptual framework of engagement-related terms in weight management. AB - Engagement denotes the extent to which, and how, individuals participate in weight management (WM) services. Effective WM services should generate meaningful outcomes and promote high participant engagement; however, research is predominantly focused on the former. Given that engagement is a poorly understood phenomenon, and that engagement-related concepts are often used synonymously (e.g., dropout and attrition), the engagement pathway is hereby introduced. This pathway defines key concepts (e.g., recruitment, adherence, attrition) and their relationships in the enrolment, intervention, and maintenance stages of treatment. The pathway will help researchers and practitioners better understand engagement-related concepts whilst encouraging greater conceptual consistency between studies. PMID- 29396234 TI - Nutritional management of older adults with gastrointestinal cancers: An International Society of Geriatric Oncology (SIOG) review paper. AB - Malnutrition is one of the most common physical manifestations of gastrointestinal (GI) cancers and is often under-diagnosed and under-treated. Like cancers, malnutrition occurs more commonly in older adults, with potential negative consequences to quality of life, functional status, tolerance to treatment, and prognosis. Nutritional assessment and management require a proactive and systematic, multi-disciplinary approach. Early assessment, detection, and prompt intervention of cancer-associated malnutrition and cachexia are equally essential to achieve better quality nutritional care for older oncology patients. This article aims to provide an overview of the evidence associated with poor nutrition and outcomes in older adults with GI cancers, and recommends a management approach from a geriatric oncologist's perspective. PMID- 29396233 TI - In Vivo Evaluation of the Synergic Effect of Metformin and mTOR Inhibitors on the Endothelial Healing of Drug-eluting Stents in Diabetic Patients. AB - INTRODUCTION AND OBJECTIVES: Recent animal studies have shown metformin (MF) to impair endothelialization of drug-eluting stents (DES). The aim of this study was to evaluate the effect of MF on the healing of DES in human coronary arteries of patients with diabetes mellitus by optical coherence tomography (OCT). METHODS: The RESERVOIR trial randomized 116 lesions in 112 patients with diabetes mellitus to amphilimus- or everolimus-eluting stents and included mandatory OCT at 9 months of follow-up. Patients were divided in 3 groups according to the glucose lowering agents received: a) no MF; b) MF in noninsulin treated patients, and c) MF in insulin-treated patients. The primary safety endpoint was the rate of uncovered stents. RESULTS: Seventeen patients with 19 lesions did not receive MF, whereas MF was administered to 53 noninsulin treated patients (54 lesions) and 28 insulin-treated patients (28 lesions). Baseline characteristics were comparable, although noninsulin treated patients who received MF had better glycemic control (P < .01). By OCT, rates of uncovered struts were comparable between groups (3.07+/-4.80% vs 2.23+/-4.73% vs 3.43+/-6.69%, respectively; P = .48). Multivariate models confirmed that MF had no effect on the healing of DES (OR, 1.49, 95%CI, 0.71-3.08; P = .29). Similarly, quantitative angiography showed no effect of MF on late lumen loss, whereas patients treated with exogenous insulin had greater late lumen loss (P = .02). CONCLUSIONS: Metformin use does not impair endothelial healing of DES in patients with both insulin- and noninsulin-treated diabetes mellitus. According to these results, MF should not be discouraged in these patients. PMID- 29396235 TI - Investigation of treatment pattern, medical resource utilization and demographic prognostic factors in older patients with non-Hodgkin lymphoma: A nationwide population-based study. AB - BACKGROUND: This nationwide population study aimed to investigate treatment patterns, medical resource utilization and demographic prognostic factors in older Taiwanese patients with non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: This study was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. The older patients (65years or older) diagnosed with NHL between 1997 and 2008 were identified for analysis. RESULTS: A total of 5136 patients (3049 males and 2087 females) with a median age of 74.1years were identified for analysis. Among these patients, 3267 patients (63.6%) received various combinations of systemic therapies. The older the patient, the less likely it was for intensive curative treatment to be given. Regarding medical resource usage, younger patients or patients living in more urbanized areas were more likely to receive NHL treatment in medical centers. The median overall survival of all patients with NHL was 49.41months (range, 0.03 to 143.97). The investigation for prognostic factors by multivariate analysis revealed that more advanced age, treatment in non-medical centers and living in less urbanized areas were associated with poorer outcomes. CONCLUSION: Treatment of older patients with NHL is still a challenge. For better outcomes, it is very important to evaluate the patient and tailor treatment modalities. Additionally, health policy makers should help to narrow discrepancies in survival based on demographics. PMID- 29396236 TI - Update in geriatrics: What geriatric oncology can learn from general geriatric research. AB - Life expectancy has been steadily increasing for decades and this trend is likely to continue in coming years. In fact, there is more than a 50% probability that by 2030 female life expectancy could break the 90 year barrier, with more than half of the expected gains due to enhanced longevity above the age of 65 years. The resultant aging of societies means that health care will be faced with a rising number of increasingly older patients, who are also likely to have higher levels of multimorbidity. Most issues regarding assessment, prognostication and, management of older patients are not unique to geriatric oncology and thus there is opportunity to learn from progress in other fields. The purpose of this paper is to provide an update on research, reviews, and debate in general geriatrics that may be relevant to clinicians and researchers active in geriatric oncology. The selection of topics was based on a general search of the table of contents of widely read geriatrics and internal medicine journals, and includes geriatric co management, improving research for older patients, caregiver issues, eliciting patient preferences, and shared-decision making. PMID- 29396237 TI - Second-Line Treatment Options in Non-Small-Cell Lung Cancer: Report From an International Experts Panel Meeting of the Italian Association of Thoracic Oncology. AB - Non-small-cell lung cancer (NSCLC) patients inevitably progress to first-line therapy and further active treatments are warranted. In the past few years, new second-line therapies, beyond chemotherapy agents, have become available in clinical practice. To date, several options for the second-line treatment of non oncogene-addicted NSCLC patients ranging from chemotherapy in combination with antivascular endothelial growth factor receptor to immunotherapeutics are available. In oncogene-driven tumors, the better knowledge of mechanisms of acquired resistance to earlier tyrosine kinase inhibitors is leading to novel active inhibitors now available/in development. The second-line algorithm treatment of NSCLC becomes very intricate and the selection of proper patients with one of the new available therapeutic options is of paramount importance to personalize and optimize the treatment. In this review we discuss the second-line treatment opportunities of addicted as well as not-addicted NSCLC. PMID- 29396238 TI - LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival. AB - BACKGROUND: Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non-small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3+ tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification. MATERIALS AND METHODS: Primary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected. The expression of LAG-3 was evaluated by immunohistochemistry on tissue microarrays. RESULTS: On univariate analysis, LAG-3+ TILs in the intraepithelial and stromal compartments of primary tumors and in the intraepithelial and extraepithelial compartments of metastatic lymph nodes were associated with improved disease-specific survival (DSS). On multivariate analysis, stromal LAG-3+ TILs were a significant independent predictor of improved DSS (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.43-0.82; P = .002). Stromal LAG-3+ TILs did not have prognostic impact across all pathologic stages. In the metastatic lymph nodes, intraepithelial (HR, 0.61; 95% CI, 0.38-0.99; P = .049) and extraepithelial (HR, 0.54; 95% CI, 0.29-0.70; P < .001) LAG-3+ TILs were independently associated with favorable DSS. CONCLUSION: LAG-3+ TILs are an independent positive prognostic factor in stage I-IIIB NSCLC. LAG-3 in metastatic lymph nodes is a candidate marker for an immunoscore in NSCLC. PMID- 29396239 TI - Long term outcomes of new generation drug eluting stents versus coronary artery bypass grafting for multivessel and/or left main coronary artery disease. A Bayesian network meta-analysis of randomized controlled trials. AB - BACKGROUND: Most data guiding revascularization of multivessel disease (MVD) and/or left main disease (LMD) favor coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI). However, those data are based on trials comparing CABG to bare metal stents (BMS) or old generation drug eluting stents (OG-DES). Hence, it is essential to outcomes of CABG to those of new generation drug eluting stents (NG-DES). METHODS: We searched PUBMED and Cochrane database for trials evaluating revascularization of MVD and/or LMD with CABG and/or PCI. A Bayesian network meta-analysis was performed to calculate odds ratios (OR) and 95% credible intervals (CrI). Primary outcome was major adverse cardiovascular events (MACE) at 3-5 years. Secondary outcomes were mortality, cerebrovascular accidents (CVA), myocardial infarction (MI) and repeat revascularization. RESULTS: We included 10 trials with a total of 9287 patients. CABG was associated with lower MACE when compared to BMS or OG-DES. However, MACE was not significantly different between CABG and NG-DES (OR 0.79, CrI 0.45-1.40). Moreover, there were no significant differences between CABG and NG-DES in mortality (OR 0.78, CrI 0.45-1.37), CVA (OR 0.93 CrI 0.35-2.2) or MI (OR 0.6, CrI 0.17-2.0). On the other hand, CABG was associated with lower repeat revascularization (OR 0.55, CrI 0.36-0.84). CONCLUSIONS: Our study suggests that NG-DES is an acceptable alternative to CABG in patients with MVD and/or LMD. However, repeat revascularization remains to be lower with CABG than with PCI. PMID- 29396240 TI - Discussing Conservative Management With Older Patients With CKD: An Interview Study of Nephrologists. AB - BACKGROUND: Although dialysis may not provide a large survival benefit for older patients with kidney failure, few are informed about conservative management. Barriers and facilitators to discussions about conservative management and nephrologists' decisions to present the option of conservative management may vary within the nephrology provider community. STUDY DESIGN: Interview study of nephrologists. SETTING & PARTICIPANTS: National sample of US nephrologists sampled based on sex, years in practice, practice type, and region. METHODOLOGY: Qualitative semistructured interviews continued until thematic saturation. ANALYTICAL APPROACH: Thematic and narrative analysis of recorded and transcribed interviews. RESULTS: Among 35 semistructured interviews with nephrologists from 18 practices, 37% described routinely discussing conservative management ("early adopters"). 5 themes and related subthemes reflected issues that influence nephrologists' decisions to discuss conservative management and their approaches to these discussions: struggling to define nephrologists' roles (determining treatment, instilling hope, and improving patient symptoms), circumventing end-of life conversations (contending with prognostic uncertainty, fearing emotional backlash, jeopardizing relationships, and tailoring information), confronting institutional barriers (time constraints, care coordination, incentives for dialysis, and discomfort with varied conservative management approaches), conservative management as "no care," and moral distress. Nephrologists' approaches to conservative management discussions were shaped by perceptions of their roles and by a common view of conservative management as no care. Their willingness to pursue conservative management was influenced by provider- and institutional-level barriers and experiences with older patients who regretted or had been harmed by dialysis (moral distress). Early adopters routinely discussed conservative management as a way of relieving moral distress, whereas others who were more selective in discussing conservative management experienced greater distress. LIMITATIONS: Participants' views are likely most transferable to large academic medical centers, due to oversampling of academic clinicians. CONCLUSIONS: Our findings clarify how moral distress serves as a catalyst for conservative management discussion and highlight points of intervention and mechanisms potentially underlying low conservative management use in the United States. PMID- 29396241 TI - [Delayed recurrence of a phaechromocytoma with metastasis as a cause of severe hypertension in a woman with a surgically intervened retroperitoneal tumour]. AB - We present the case of a woman with a previous history of hypertension and retroperitoneal tumour. The histology was reported as a paraganglioma. There was no clinical follow-up. Years later, there was a recurrence of the phaeochromocytoma after presenting with a difficult to control hypertension, along with elevation of urinary catecholamines. The case aims to highlight the importance of performing a clinical follow-up in these patients, due to the risk of recurrence. PMID- 29396242 TI - Lupus nephritis with preserved kidney function associated with poorer cardiovascular risk control: A call for more awareness. AB - BACKGROUND: Despite the improvement in the prognosis of lupus nephritis (LN), the cardiovascular morbimortality remains high. The early recognition and remission of flares, while trying to avoid the metabolic adverse effects of medication, must be mandatory. AIM: The aim of our study was to assess the cardiovascular (CV) risk profile in a cohort of lupus patients with preserved kidney function after a nephritis episode, compared to patients without a nephritis flare. METHODS: 130 patients diagnosed of SLE (32 with previous nephritis flare and 98 without) were studied in order to evaluate the CV risk profile, despite the preserved kidney function. RESULTS: The most prevalent risk factors were sedentary lifestyle (57.6%), overweight/obesity (38.3%) and dyslipidemia (36%), followed by smoking (32%) and hypertension (16%). Though more than a half (53.1%) was taking CV medication, a high percentage did not reach a therapeutic target value, especially regarding obesity (11.5%) and cholesterol levels (LDL-C of 16%). The prevalence of dyslipidemia (53.1% vs 30.6%), smoking (46.6% vs 27.5%), left ventricular hypertrophy (LVH) (21.4% vs 6.4%) and lower HDL-C (48.6mg/dL vs 55.4mg/dL) were significantly different in the group with previous nephritis flare. Moreover, young patients with lupus nephritis, received more pulses of corticosteroids and cyclophosphamide, had higher prevalence of hypertension, LVH, higher proteinuria, hospital admissions and waist circumference, constituting the subgroup of patients with greater aggregation of CV risk factors. CONCLUSIONS: Patients with previous nephritis flare showed a poor control of CV risk factors despite the preserved renal function, these patients would require a closer therapeutic management. PMID- 29396243 TI - [Menopause: Hypertension and vascular disease]. AB - Hypertension is the main cardiovascular risk factor affecting 25% of women. Hormone changes and hypertension after menopause may lead to higher target organ damage and cardiovascular disease such as increased arterial stiffness, coronary diseases, chronic heart failure and stroke. The physiopathological mechanisms involved in the development of hypertension and cardiovascular diseases in menopausal women are controversial. There are pharmacokinetic and pharmacodynamic differences in both sexes, the women have more coughing when using the converting enzyme inhibitors, more cramps when using thiazide diuretics and more oedema in the inferior limbs when using calcium antagonists. The aim of this review is to analyse possible physiopathological mechanisms involved in hypertension after menopause and to gain a better understanding of the biological effects mediated by vascular ageing in women when the level of oestrogen protective effect decreases over the vascular system. PMID- 29396244 TI - [Hypertension in adolescents: Diagnostic approach through ambulatory blood pressure monitoring]. PMID- 29396245 TI - Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 * 2 factorial, double-blind, randomised controlled trial. AB - BACKGROUND: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. METHODS: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 * 2 factorial design done at six centres in the UK. Adults with active moderate-to severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 * 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for >=80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. FINDINGS: Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0.86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2.56 (95% CI 0.98-6.66, p=0.054) for azathioprine and 0.89 (0.36-2.23, p=0.80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6.83 (1.66-28.1, p=0.008) for azathioprine and 1.32 (0.30-4.84, p=0.67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. INTERPRETATION: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. FUNDING: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity. PMID- 29396247 TI - Personalised blood pressure ranges in type 2 diabetes? PMID- 29396246 TI - Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. AB - BACKGROUND: European guidelines recommend intravenous methylprednisolone as first line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. METHODS: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. FINDINGS: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1.76 (95% CI 0.92-3.39, p=0.089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2.16, 1.09-4.25, p=0.026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0.71, 0.17-3.03, p=0.72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0.65, 0.12-3.44, p=0.61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2.44, 1.23-4.82, p=0.011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1-2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0.48). INTERPRETATION: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. FUNDING: Novartis, Germany. PMID- 29396248 TI - Graves' orbitopathy: the ongoing search for new treatment strategies. PMID- 29396249 TI - Optimisation of follow-up after metabolic surgery. AB - Bariatric surgery has many benefits beyond weight loss, including improved control of glycaemia, blood pressure, and dyslipidaemia; hence, such surgery has been rebranded as metabolic surgery. The operations are, unfortunately, also associated with major surgical and medical complications. The medical complications include gastro-oesophageal reflux disease, malnutrition, and metabolic complications deriving from vitamin and mineral malabsorption. The benefits of surgery can be optimised by implementing specific protocols before and after surgery. In this Review, we discuss the assessment of the risk of major cardiac complications and severe obstructive sleep apnoea before surgery, and the provision of adequate lifelong postsurgery nutritional, vitamin, and mineral supplementation to reduce complications. Additionally, we examine the best antidiabetic medications to reduce the risk of hypoglycaemia after gastric bypass and sleeve gastrectomy, and the strategies to improve weight loss or reduce weight regain. Although optimising clinical pathways is possible to maximise metabolic benefits and reduce the risks of complications and micronutrient deficiencies, evolution of these strategies can further improve the risk-to benefit ratio of metabolic surgery. PMID- 29396250 TI - Relationship of Polycystic Ovarian Syndrome with Cardiovascular Risk Factors. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. The two main documented pathogenic mechanisms are hyperinsulinemia and hyperandrogenemia but there is growing evidence for increased predisposition to cardiovascular disease, dyslipidemia, and type 2 diabetes mellitus. Our study aims to analyze the association of PCOS with cardiovascular risk factors. METHODS: This is a prospective study which targeted 100 PCOS patients from Civil Hospital Karachi over a period of one year (July 2016 to July 2017). An equal number of age-matched healthy control participants were also included in the study. The student's t-test was used to assess the significance of differences using SPSS version (19). The statistical significance was set at a p-value of <.05. RESULTS: The most frequently presented feature associated with PCOS was primary infertility seen in 72% of the patients. Mean arterial pressure, fasting glucose and insulin levels and insulin resistance was found to be significantly different in PCOS patients as compared to their controls. A classic atherosclerotic lipid profile demonstrating elevated total cholesterol and low-density lipoprotein-C (LDL-C) levels and decreased serum high density lipoprotein-C(HDL-C) was observed in our study. CONCLUSION: This study established a significant yet independent association of PCOS with major cardiovascular risk factors. This association can effectively progress into CVD outcomes which necessitates early intervention programs and preventative strategies to reduce mortality from cardiovascular events. This study lays out the framework for conducting further researches on the PCOS women while exploring novel cardiovascular risk factors. PMID- 29396251 TI - Glycated albumin in chronic kidney disease: Pathophysiologic connections. AB - Nephropathy in diabetes patients is the most common etiology of end-stage kidney disease (ESKD). Strict glycemic control reduces the development and progression of diabetes-related complications, and there is evidence that improved metabolic control improves outcomes in subjects having diabetes mellitus with advanced chronic kidney disease (CKD). Glycemic control in people with kidney disease is complex. Changes in glucose and insulin homoeostasis may occur as a consequence of loss of kidney function and dialysis. The reliability of measures of long-term glycemic control is affected by CKD and the accuracy of glycated haemoglobin (HbA1c) in the setting of CKD and ESKD is questioned. Despite the altered character of diabetes in CKD, current guidelines for diabetes management are not specifically adjusted for this patient group. The validity of indicators of long term glycemic control has been the focus of increased recent research. This review discusses the current understanding of commonly used indicators of metabolic control (HbA1c, fructosamine, glycated albumin) in the setting of advanced CKD. PMID- 29396252 TI - Glycated albumin and the risk of chronic kidney disease in subjects with Type 2 Diabetes: A study in North Indian Population. AB - AIM: Glycated albumin (GA) suggested being alternative glycemic marker than haemoglobin A1C (HbA1c) in patients with chronic kidney diseases (CKD). We investigated the association between GA and the progression of diabetic nephropathy (DN) in T2DM subjects. METHODS: We recruited T2DM subjects with different stages of CKD who had regularly measured serum creatinine and estimated glomerular filtration rates (eGFR) according to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, HbA1c consecutively every 3 months along with GA levels and other anthropometric and demographic measurements. We grouped age and sex matched subjects into the CKD progression, Group I healthy subjects (n = 100, M: F;50:50). Group II T2DM subjects with eGFR >=90 mL/min (n = 167, M:F; 76:91). Group III of T2DM patients with eGFR 60-89 mL/min (n = 91, M:F; 44:47). Group IV T2DM subjects with eGFR 30-59 mL/min (n = 68, M:F;31:37). Group V T2DM with eGFR <= 29 mL/min (n = 21, M:F; 13:8). RESULTS: Pearson's correlation analysis between glycated albumin and biochemical parameters were established in all subjects. GA/HbA1c ratio increases with poor glycemic control except for nephrosis state. CONCLUSION: Mean GA levels were more closely associated with DN progression than mean HbA1c in subjects with T2DM and can be implemented as an alternative diagnostic marker in nephropathy. PMID- 29396253 TI - Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. AB - CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain. PMID- 29396255 TI - The doubling potential of T lymphocytes allows clinical-grade production of a bank of genetically modified monoclonal T-cell populations. AB - BACKGROUND AIMS: To produce an anti-leukemic effect after hematopoietic stem cell transplantation we have long considered the theoretical possibility of using banks of HLA-DP specific T-cell clones transduced with a suicide gene. For that application as for any others, a clonal strategy is constrained by the population doubling (PD) potential of T cells, which has been rarely explored or exploited. METHODS: We used clinical-grade conditions and two donors who were homozygous and identical for all HLA-alleles except HLA-DP. After mixed lymphocyte culture and transduction, we obtained 14 HLA-DP-specific T-cell clones transduced with the HSV-TK suicide gene. Clones were then selected on the basis of their specificity and functional characteristics and evaluated for their doubling potential. RESULTS: After these steps of selection the clone NAT-DP4(TK), specific for HLA DPB1*04:01/04:02, which produced high levels of interferon-gamma (IFNgamma), tumor necrosis factor (TNF), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was fully sequenced. It has two copies of the HSV-TK suicide transgene whose localizations were determined. Four billion NAT DP4(TK) cells were frozen after 50 PDs. Thawed NAT-DP4(TK) cells retain the potential to undergo 50 additional PDs, a potential very far beyond that required to produce a biological effect. This PD potential was confirmed on 6/16 additional different T-cell clones. This type of well-defined clone can also support a second genetic modification with CAR constructs. CONCLUSION: The possibility of choosing rare donors and exploiting the natural proliferative potential of T lymphocytes may dramatically reduce the clinical and immunologic complexity of adoptive transfer protocols that rely on the use of third-party T cell populations. PMID- 29396254 TI - Variation in primary and culture-expanded cells derived from connective tissue progenitors in human bone marrow space, bone trabecular surface and adipose tissue. AB - BACKGROUND AIMS: Connective tissue progenitors (CTPs) embody the heterogeneous stem and progenitor cell populations present in native tissue. CTPs are essential to the formation and remodeling of connective tissue and represent key targets for tissue-engineering and cell-based therapies. To better understand and characterize CTPs, we aimed to compare the (i) concentration and prevalence, (ii) early in vitro biological behavior and (iii) expression of surface-markers and transcription factors among cells derived from marrow space (MS), trabecular surface (TS), and adipose tissues (AT). METHODS: Cancellous-bone and subcutaneous adipose tissues were collected from 8 patients. Cells were isolated and cultured. Colony formation was assayed using Colonyze software based on ASTM standards. Cell concentration ([Cell]), CTP concentration ([CTP]) and CTP prevalence (PCTP) were determined. Attributes of culture-expanded cells were compared based on (i) effective proliferation rate and (ii) expression of surface-markers CD73, CD90, CD105, SSEA-4, SSEA-3, SSEA-1/CD15, Cripto-1, E-Cadherin/CD324, Ep-CAM/CD326, CD146, hyaluronan and transcription factors Oct3/4, Sox-2 and Nanog using flow cytometry. RESULTS: Mean [Cell], [CTP] and PCTP were significantly different between MS and TS samples (P = 0.03, P = 0.008 and P= 0.0003), respectively. AT derived cells generated the highest mean total cell yield at day 6 of culture-4 fold greater than TS and more than 40-fold greater than MS per million cells plated. TS colonies grew with higher mean density than MS colonies (290 +/- 11 versus 150 +/- 11 cell per mm2; P = 0.0002). Expression of classical-mesenchymal stromal cell (MSC) markers was consistently recorded (>95%) from all tissue sources, whereas all the other markers were highly variable. CONCLUSIONS: The prevalence and biological potential of CTPs are different between patients and tissue sources and lack variation in classical MSC markers. Other markers are more likely to discriminate differences between cell populations in biological performance. Understanding the underlying reasons for variation in the concentration, prevalence, marker expression and biological potential of CTPs between patients and source tissues and determining the means of managing this variation will contribute to the rational development of cell-based clinical diagnostics and targeted cell-based therapies. PMID- 29396256 TI - School closure during novel influenza: A systematic review. AB - BACKGROUND: School closure as a non-pharmaceutical measure appeared as an efficient strategy in previous epidemics. We investigated the impact of school closure on the epidemic peak whether implemented before or after the epidemic reaches its peak. We also investigated the optimal duration of closure. METHODS: Data sources included Medline-PubMed, ProQuest and Cochrane databases. The inclusion criteria were all articles that reported a quantified effect on school closure on an influenza epidemic. Exclusion criteria were non-English articles that have no translation and articles that only reported school closure effect as a combination with another measure. Out of 668 articles, we included 31 articles. RESULTS: The mean reduction of the peak of the epidemic was M=29.65%. Implementing school closure before or after the epidemic reaches its peak reduced the overall influenza epidemic. School closure reduced and delayed the epidemic peak especially if implemented earlier. The longer the duration of closure the more the epidemic peak delayed. Additionally, closure containment effect also correlated with organisms having high attack rate and longer infectiveness duration. CONCLUSION: We conclude with several implications for school closure taking into consideration the feasibility and the cost. PMID- 29396257 TI - The prevalence of Middle East respiratory Syndrome coronavirus (MERS-CoV) infection in livestock and temporal relation to locations and seasons. AB - BACKGROUND: The Middle East respiratory syndrome (MERS) has been reported for the first time infecting a human being since 2012. The WHO was notified of 27 countries have reported cases of MERS, the majority of these cases occur in the Arabian Peninsula, particularly in Saudi Arabia. Dromedary camels are likely to be the main source of Middle East respiratory syndrome virus (MERS-CoV) infection in humans. METHODS: MERS-CoV infection rates among camels in livestock markets and slaughterhouses were investigated in Saudi Arabia. A total of 698 nasal swabs were collected and examined with Rapid assay and rtRT-PCR. Ten MERS-CoV positive samples were subjected to full genomic sequencing. In addition, the sensitivity and specificity of the Rapid immunochromatographic assay (BioNote, South Korea) was evaluated as a diagnostic tool for MERS-CoV compared to rtRT-PCR. RESULTS: The results showed a high percentage of dromedaries (56.4%) had evidence for nasal MERS-CoV infection. Phylogenetic analysis of the ten MERS-CoV isolates showed that the sequences were closely related to the other MERS-CoV strains recovered from camels and human cases. Moreover, the results showed that 195 samples were positive for MERS-CoV by rapid assay compared to 394 positive samples of rtRT-PCR, which showed low rapid assay sensitivity (49.49%) while, the specificity were found to be 100%. CONCLUSION: These findings indicate that these sites are a highly-hazardous to zoonotic diseases. PMID- 29396258 TI - Parental supply and alcohol-related harm in adolescence: emerging but incomplete evidence. PMID- 29396259 TI - Association of parental supply of alcohol with adolescent drinking, alcohol related harms, and alcohol use disorder symptoms: a prospective cohort study. AB - BACKGROUND: Some parents supply alcohol to their children, reportedly to reduce harm, yet longitudinal research on risks associated with such supply is compromised by short periods of observation and potential confounding. We aimed to investigate associations between parental supply and supply from other (non parental) sources, with subsequent drinking outcomes over a 6-year period of adolescence, adjusting for child, parent, family, and peer variables. METHODS: We did this prospective cohort study using data from the Australian Parental Supply of Alcohol Longitudinal Study cohort of adolescents. Children in grade 7 (mean age 12 years), and their parents, were recruited between 2010 and 2011 from secondary schools in Sydney, Perth, and Hobart, Australia, and were surveyed annually between 2010 and 2016. We examined the association of exposure to parental supply and other sources of alcohol in 1 year with five outcomes in the subsequent year: binge drinking (more than four standard drinks on a drinking occasion); alcohol-related harms; and symptoms of alcohol abuse (as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]), alcohol dependence, and alcohol use disorder (as defined by DSM-5). This trial is registered with ClinicalTrials.gov, number NCT02280551. FINDINGS: Between September, 2010, and June, 2011, we recruited 1927 eligible parents and adolescents (mean age 12.9 years [SD 0.52]). Participants were followed up until 2016, during which time binge drinking and experience of alcohol-related harms increased. Adolescents who were supplied alcohol only by parents had higher odds of subsequent binge consumption (odds ratio [OR] 2.58, 95% CI 1.96-3.41; p<0.0001), alcohol-related harm (2.53, 1.99-3.24; p<0.0001), and symptoms of alcohol use disorder (2.51, 1.46-4.29; p=0.0008) than did those reporting no supply. Parental supply of alcohol was not significantly associated with the odds of reporting symptoms of either alcohol abuse or dependence, compared with no supply from any source. Supply from other sources was associated with significant risks of all adverse outcomes, compared with no supply, with an even greater increased risk of adverse outcomes. INTERPRETATION: Providing alcohol to children is associated with alcohol-related harms. There is no evidence to support the view that parental supply protects from adverse drinking outcomes by providing alcohol to their child. Parents should be advised that this practice is associated with risk, both directly and indirectly through increased access to alcohol from other sources. FUNDING: Australian Research Council, Australian Rotary Health, Foundation for Alcohol Research and Education, National Drug and Alcohol Research Centre. PMID- 29396260 TI - Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia. AB - BACKGROUND: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). OBJECTIVE: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. METHODS: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. RESULTS: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of >=15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. CONCLUSION: Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH. PMID- 29396261 TI - Maternal lipid profile 6 years after a gestational hypertensive disorder. AB - BACKGROUND: Gestational hypertensive disorders (GHDs), including gestational hypertension and preeclampsia, are associated with an increased risk of cardiovascular disease in later life, possibly through an atherogenic lipid profile. OBJECTIVE: The objective of this study is to assess if women with a previous GHD have a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. METHODS: In a population-based prospective cohort study, we included 4933 women during pregnancy, including 302 women with a GHD. Six years after pregnancy, we determined maternal lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein[a], and apolipoprotein B) and glucose levels. RESULTS: Women with a previous GHD had a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. These atherogenic lipid profiles were a result of higher levels of triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B and lower levels of high-density lipoprotein cholesterol. Differences in lipid profile between women with a previous GHD and women with a previous normotensive pregnancy were attenuated after adjustment for prepregnancy body mass index. Between women from both groups, no differences were observed in total cholesterol, lipoprotein[a], and glucose levels. CONCLUSION: Women with a previous GHD show a more atherogenic lipid profile 6 years after pregnancy than women with a previous normotensive pregnancy. The increased risk of cardiovascular disease after a GHD might result from an atherogenic lipid profile after pregnancy, primarily driven by prepregnancy body mass index. PMID- 29396262 TI - A case of apolipoprotein A-I deficiency due to carboxyl-terminal truncation. AB - Apolipoprotein A-I deficiency is a rare metabolic disease characterized by an impaired reverse cholesterol transport system resulting in excessive cholesterol accumulation. Here, we discuss a case of apolipoprotein A-I deficiency caused by a carboxyl-terminal truncation mutation p.His186ProfsX46 in APOA1, which might result in increased catabolism of the mutant protein. PMID- 29396263 TI - Modeling Unique Patients in Humanized Mice: Toward a Curative Strategy for HIV. PMID- 29396264 TI - Boosting, Not Breaking: CRISPR Activators Treat Disease Models. PMID- 29396265 TI - Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis. AB - Most of the peptides used for promoting cellular uptake bear positive charges. In our previous study, we reported an example of taurine (bearing negative charges in physiological conditions) promoting cellular uptake of D-peptides. Taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide. Particularly, intracellular carboxylesterase (CES) instructs the D-peptide to self-assemble and to form nanofibers, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide, as supported by that the addition of CES inhibitors partially impaired cellular uptake of this molecule in mammalian cell lines. Using dynamin 1, 2, and 3 triple knockout (TKO) mouse fibroblasts, we demonstrated that cells took up this molecule via macropinocytosis and dynamin-dependent endocytosis. Imaging of Drosophila larval blood cells derived from endocytic mutants confirmed the involvement of multiple endocytosis pathways. Electron microscopy (EM) indicated that the precursors can form aggregates on the cell surface to facilitate the cellular uptake via macropinocytosis. EM also revealed significantly increased numbers of vesicles in the cytosol. This work provides new insights into the cellular uptake of taurine derivative for intracellular delivery and self assembly of D-peptides. PMID- 29396266 TI - Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression. AB - Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease. PMID- 29396267 TI - A New Role for the Mitochondrial Pro-apoptotic Protein SMAC/Diablo in Phospholipid Synthesis Associated with Tumorigenesis. AB - The mitochondrial pro-apoptotic protein SMAC/Diablo participates in apoptosis by negatively regulating IAPs and activating caspases, thus encouraging apoptosis. Unexpectedly, we found that SMAC/Diablo is overexpressed in cancer. This paradox was addressed here by silencing SMAC/Diablo expression using specific siRNA (si hSMAC). In cancer cell lines and subcutaneous lung cancer xenografts in mice, such silencing reduced cell and tumor growth. Immunohistochemistry and electron microscopy of the si-hSMAC-treated residual tumor demonstrated morphological changes, including cell differentiation and reorganization into glandular/alveoli like structures and elimination of lamellar bodies, surfactant-producing organs. Next-generation sequencing of non-targeted or si-hSMAC-treated tumors revealed altered expression of genes associated with the cellular membrane and extracellular matrix, of genes found in the ER and Golgi lumen and in exosomal networks, of genes involved in lipid metabolism, and of lipid, metabolite, and ion transporters. SMAC/Diablo silencing decreased the levels of phospholipids, including phosphatidylcholine. These findings suggest that SMAC/Diablo possesses additional non-apoptotic functions related to regulating lipid synthesis essential for cancer growth and development and that this may explain SMAC/Diablo overexpression in cancer. The new lipid synthesis-related function of the pro apoptotic protein SMAC/Diablo in cancer cells makes SMAC/Diablo a promising therapeutic target. PMID- 29396268 TI - Clinical survey over the past 35 years at the clinic for maxillofacial prosthetics Tokyo Medical and Dental University. AB - PURPOSE: The purpose of this survey was to examine the overview of maxillofacial prosthetic treatment at our department, in order to ascertain the actual status of patients and discuss future needs. METHODS: Subjects were all patients who visited Clinic for Maxillofacial Prosthetics, Dental Hospital, Tokyo Medical and Dental University (TMDU) in the period from January 1, 1980 to December 31, 2014. Using medical records of the Clinic for Maxillofacial Prosthetics, Dental Hospital, TMDU, patients' data including sex, address, referring institution, and primary condition were analyzed throughout the period. RESULTS: The number of patients over 35 years was 6219, with a man-to-woman ratio of 6:4. The number of patients in their 60s, 70s, and 80s showed an increasing trend. Patients with tumors accounted for about 50 % of cases in 1980-1984 and increased to 80 % in 2010-2014. CONCLUSIONS: The survey showed an increasing number of elderly patients and patients with tumors. This suggests that more awareness and education about maxillofacial prosthetics are needed. PMID- 29396269 TI - Acidified seawater increases accumulation of cobalt but not cesium in manila clam Ruditapes philippinarum. AB - The pH of seawater around the world is expected to continue its decline in the near future in response to ocean acidification that is driven by heightened atmospheric CO2 emissions. Concomitantly, economically-important molluscs that live in coastal waters including estuaries and embayments, may be exposed to a wide assortment of contaminants, including trace metals and radionuclides. Seawater acidification may alter both the chemical speciation of select elements as well as the physiology of organisms, and may thus pose at risk to many shellfish species, including the manila clam Ruditapes philippinarum. The bioconcentration efficiency of two common radionuclides associated with the nuclear fuel cycle, 134Cs and 57Co, were investigated by exposing live clams to dissolved 134Cs and 57Co at control (pH = 8.1) and two lowered pH (pH = 7.8 and 7.5) levels using controlled aquaria. The uptake and depuration kinetics of the two radionuclides in the whole-body clam were followed for 21 and 35 days, respectively. At steady-state equilibrium, the concentration factor (CFss) for 57Co increased as the pH decreased (i.e. 130 +/- 5, 194 +/- 6, and 258 +/- 10 at pH levels 8.1, 7.8 and 7.5, respectively), whereas the 134Cs uptake was not influenced by a change in pH conditions. During depuration, the lowest depuration rate constant of 57Co by the manila clam was observed at the intermediate pH of 7.8. An increase in the accumulation of 57Co at the intermediate pH value was thought to be caused mainly by the aragonitic shell of the clam, as well as the low salinity and alkalinity of seawater used in the experiment. Considering that accumulation consists of uptake and depuration, among the three pH conditions moderately acidified seawater enhanced most the accumulation of 57Co. Accumulation of 134Cs was not strongly influenced by a reduced pH condition, as represented by an analogous uptake constant rate and CFss in each treatment. Such results suggest that future seawater pH values that are projected to be lower in the next decades, may pose a risk for calcium-bearing organisms such as shellfish. PMID- 29396270 TI - Radionuclide transport in the "sediments - water - plants" system of the water bodies at the Semipalatinsk test site. AB - This paper provides research data on levels and character of radionuclide contamination distribution in the "sediments- water - plants " system of objects of the Semipalatinsk test site (STS). As the research objects there were chosen water bodies of man-made origin which located at the territory of "Experimental Field", "Balapan", "Telkem" and "Sary-Uzen" testing sites. For research the sampling of bottom sediments, water, lakeside and water plants was taken. Collected samples were used to determine concentration of anthropogenic radionuclides 90Sr, 239+240Pu, 241Am, 137Cs. The distribution coefficient (Kd) was calculated as the ratio of the content of radionuclides in the sediments to the content in water, and the concentration ratio (FV) was calculated as the ratio of radionuclide content in plants to the content in sediments or soil. PMID- 29396272 TI - Ethical issues and dentists' practices with children with intellectual disability: A qualitative inquiry into a local French health network. AB - BACKGROUND: The provision of dental care for children with intellectual disability raises many ethical questions. OBJECTIVE: The aim of this qualitative study was to explore approaches to dental treatment in an anxious child with intellectual disability and the ethical dilemmas that ensue. METHODS: Semi structured interviews were conducted between February and May 2012. A clinical scenario was used to establish a starting point for a discussion of the clinical approach and lead to an ethical reflection. Four topics were discussed: first contact with the patient, information, attitude towards the patient and outcome from the practitioner's viewpoint. The coding procedure used thematic content analysis. RESULTS: Most practitioners fetched the patient from the waiting room personally, greeted them, gave them special attention, and either began the consultation at once, or used distraction to relax the patient. Verbal language and tell-show-do were most often used to provide information. Anxiety and pain were evaluated using parental assessment and standardized scales. A reassuring attitude was adopted. An ethical dilemma arose if the patient refused care or had to be restrained. Practitioners reported sacrificing ethical values (patient autonomy, beneficence and non-maleficence) when making a clinical decision. CONCLUSIONS: There is a wide range of practices but no consensus. This study shed some light on the different perspectives of dentists, most of whom adopted a utilitarianist viewpoint. In this context, ethical reflection is necessary to avoid a detached attitude or, worse, abuse. Further study would enrich this reflection. PMID- 29396273 TI - The American Board Style Practice In-Training Examination as a Predictor of Performance on the American Board of Surgery In-Training Examination. AB - BACKGROUND: The American Board of Surgery In-Training Examination (ABSITE), is an annual 250 question, multiple-choice test that assesses residents' surgical knowledge in preparation for board examinations. At our program, we developed a Surgical Council on Resident Education-based American Board Style Practice In Training Examination: The ABSPITE. The 40-question examination was designed to help with test preparation. The purpose of this study was to evaluate the ABSPITE's predictive value on ABSITE performance. METHODS: From 2013 to 2016, the ABSPITE was administered to residents at our program. Performances (N = 134) were graded based on a standardized scale to determine resident percent and percentile performance, then compared to average ABSITE performance. RESULTS: Combined analysis showed a statistically significant positive correlation between average ABSITE and ABSPITE percentages and percentiles. This held true when categorical and preliminary residents were compared. When stratified by resident PGY level, the same results were seen for PGY 1 and PGY 2 residents but correlations failed to reach statistical significance for higher resident training levels. CONCLUSIONS: The practice ABSPITE examination strongly correlates with ABSITE performance among junior residents at our program, and may be a valuable tool to predict ABSITE performance and guide review efforts. PMID- 29396271 TI - At the intersection of chronic disease, disability and health services research: A scoping literature review. AB - BACKGROUND: There is a concerted effort underway to evaluate and reform our nation's approach to the health of people with ongoing or elevated needs for care, particularly persons with chronic conditions and/or disabilities. OBJECTIVE: This literature review characterizes the current state of knowledge on the measurement of chronic disease and disability in population-based health services research on working age adults (age 18-64). METHODS: Scoping review methods were used to scan the health services research literature published since the year 2000, including medline, psycINFO and manual searches. The guiding question was: "How are chronic conditions and disability defined and measured in studies of healthcare access, quality, utilization or cost?" RESULTS: Fifty-five studies met the stated inclusion criteria. Chronic conditions were variously defined by brief lists of conditions, broader criteria-based lists, two or more (multiple) chronic conditions, or other constructs. Disability was generally assessed through ADLs/IADLs, functional limitations, activity limitations or program eligibility. A smaller subset of studies used information from both domains to identify a study population or to stratify it by subgroup. CONCLUSIONS: There remains a divide in this literature between studies that rely upon diagnostically-oriented measures and studies that instead rely on functional, activity or other constructs of disability to identify the population of interest. This leads to wide ranging differences in population prevalence and outcome estimates. However, there is also a growing effort to develop methods that account for the overlap between chronic disease and disability and to "segment" this heterogeneous population into policy or practice relevant subgroups. PMID- 29396274 TI - Case Reporting, Competence, and Confidence: A Discrepancy in the Numbers. AB - PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) continues to play an integral role in accreditation of surgical programs. The institution of case logs to demonstrate competency of graduating residents is a key component of evaluation. This study compared the number of vascular cases a surgical resident has completed according to the ACGME operative log to their operative proficiency, quality of anastomosis, operative experience, and confidence in both a simulation and operative setting. MATERIALS AND METHODS: General surgery residents ranging from PGY 1 to 5 participated in a simulation laboratory in which they completed an end-to-side vascular anastomosis. Each participant was given a weighted score based on technical proficiency and anastomosis quality using a previously validated Global Rating Scale (Duran et al, 2014). These scores were correlated to the General Surgery Milestones. Participants completed preoperative and postoperative surveys assessing resident operative experience using the 4-level Zwisch scale (DaRosa et al., 2013), confidence with vascular procedures and confidence performing simulated anastomoses. Confidence was assessed on a scale from 1 to 9 (not confident to extremely confident). Case logs were recorded for each participant. An IRB approved questionnaire was distributed to assess preoperative and postoperative roles of both the resident physician and faculty, with a defined goal. Univariate and multivariate analysis was performed. RESULTS: Twenty-one general surgery residents were evaluated in the simulation laboratory and 8 residents were assessed intraoperatively. The residents were evenly distributed throughout clinical years. Groups of residents were divided into quartiles based upon the number of vascular cases recorded in the ACGME database. No correlation was found between number of cases, Milestones score and the weighted score (p = 0.94). No statistical significance was found between confidence and quality of anastomosis (p = 0.1). Resident operative experience per the Zwisch scale was categorized most commonly as "Smart Help" by both the trainee and attending surgeon, despite mean resident confidence ratings of 6.67 (+/- 1.61) with vascular procedures. CONCLUSIONS: ACGME case logs, which are utilized to assess readiness for completion of general surgery residency, may not be indicative of a resident's operative competency and technical proficiency. Confidence is not correlated with technical ability. Faculty and resident insight as to their role in a procedure differ, as faculty feel that they are providing less help than the resident perceives. Careful examination of resident operative technique is the best measure of competency. PMID- 29396275 TI - Transpedicular Approach on a Novel Spine Simulator: A Validation Study. AB - OBJECTIVE: The popularity of simulation in the medical field has increased dramatically over the last decades. However, the majority of studies focused on laparoscopic or other endoscopic procedures. In this study, participants performed an image-guided surgery task on a novel spine simulator. Face, content, construct, and concurrent validity were examined. DESIGN: A surgical access through both pedicles (transpedicular) into the vertebral body of artificial L3 vertebrae was performed. Questionnaires, a simulation-based performance score, and a specialist rating were used to evaluate the various forms of validity. SETTING: Klinikum Wels-Grieskirchen, Wels, Austria; tertiary hospital PARTICIPANTS: According to their expertise in image-guided surgery and pedicle tool insertions, 43 participants were subdivided into 3 groups: 22 novices, 12 intermediates, and 9 experts. RESULTS: Of the novice group, the vast majorities were impressed with the attractiveness and the general appearance of the simulator. The majority of intermediates (92%) and experts (89%) would recommend the simulator to others. According to a simulation-based performance score, experts performed significantly better than novices (p = 0.001, d = 1.52) and intermediates (p = 0.01, d = 1.26). The association between the simulation-based performance score and the specialist rating was strong (R = 0.86, p < 0.01). CONCLUSIONS: The novel spine simulator provides an applicable tool for the training of image-guided surgery skills in a realistic design. Its simulation based assessment score classifies different levels of expertise accurately. PMID- 29396276 TI - Evaluating Fitness to Perform in Surgical Residents after Night Shifts and Alcohol Intoxication: The development of a "Fit-to-Perform" test. AB - OBJECTIVE: To develop a self-test to measure clinical fitness to perform in surgical residents, with alcohol-induced impairment as reference. DESIGN: Observational, exploratory study to evaluate night shift-induced impaired performance in surgical residents followed by a randomized blinded, placebo controlled, crossover study to evaluate impaired performance as a result of ethanol intoxication. Impairment was quantified using the Mini-NeuroCart, a psychomotor and cognitive test battery for assessment of subjective and objective measures of alertness, concentration, eye-hand coordination, mood, and self assessed ability to perform. Surgical performance was tested in the randomized study with a laparoscopy surgical trainer. SETTINGS: Level-I trauma hospital and a clinical research unit. PARTICIPANTS: Surgical residents (n = 12 for the observational study, n = 18 for the randomized study). RESULTS: High alcohol levels (0.6gL-1) impaired adaptive tracking, reduced objective and subjective alertness, and increased slowness. Moreover, laparoscopy depth perception was impaired in the 0.6gL-1 group. No significant within-subject correlation between subjective and objective measures of alertness was found. Performance of postcall surgeons was similar to, or even worse than, the performance of intoxicated surgeons. CONCLUSIONS: The Mini-NeuroCart detected ethanol-induced performance effects that were similar to the effects of working a 14-hour night shift. Social (ethanol), personal (mood), and professional (laparoscopic skills) standards of fitness can in this manner be related to accepted deleterious effects of alcohol. The Mini-NeuroCart is, therefore, a potential noninvasive test for assessing "fitntness to perform" in healthcare professionals. PMID- 29396277 TI - Simulation-Based Testing of Pager Interruptions During Laparoscopic Cholecystectomy. AB - OBJECTIVE: To determine if pager interruptions affect operative time, safety, or complications and management of pager issues during a simulated laparoscopic cholecystectomy. DESIGN: Twelve surgery resident volunteers were tested on a Simbionix Lap Mentor II simulator. Each resident performed 6 randomized simulated laparoscopic cholecystectomies; 3 with pager interruptions (INT) and 3 without pager interruptions (NO-INT). The pager interruptions were sent in the form of standardized patient vignettes and timed to distract the resident during dissection of the critical view of safety and clipping of the cystic duct. The residents were graded on a pass/fail scale for eliciting appropriate patient history and management of the pager issue. Data was extracted from the simulator for the following endpoints: operative time, safety metrics, and incidence of operative complications. The Mann-Whitney U test and contingency table analysis were used to compare the 2 groups (INT vs. NO-INT). SETTING: Level I trauma center; Simulation laboratory. PARTICIPANTS: Twelve general surgery residents. RESULTS: There was no significant difference between the 2 groups in any of the operative endpoints as measured by the simulator. However, in the INT group, only 25% of the time did the surgery residents both adequately address the issue and provide effective patient management in response to the pager interruption. CONCLUSION: Pager interruptions did not affect operative time, safety, or complications during the simulated procedure. However, there were significant failures in the appropriate evaluations and management of pager issues. Consideration for diversion of patient care issues to fellow residents not operating to improve quality and safety of patient care outside the operating room requires further study. PMID- 29396278 TI - Internet-Based Digital Simulation for Cleft Surgery Education: A 5-Year Assessment of Demographics, Usage, and Global Effect. AB - BACKGROUND: In October 2012, a freely available, internet-based cleft simulator was created in partnership between academic, nonprofit, and industry sectors. The purpose of this educational resource was to address global disparities in cleft surgery education. This report assesses demographics, usage, and global effect of our simulator, in its fifth year since inception. OBJECTIVE: Evaluate the global effect, usage, and demographics of an internet-based educational digital simulation cleft surgery software. SETTING AND PARTICIPANTS: Simulator modules, available in five languages demonstrate surgical anatomy, markings, detailed procedures, and intraoperative footage to supplement digital animation. Available data regarding number of users, sessions, countries reached, and content access were recorded. Surveys evaluating the demographic characteristics of registered users and simulator use were collected by direct e-mail. RESULTS: The total number of simulator new and active users reached 2865 and 4086 in June 2017, respectively. By June 2017, users from 136 countries had accessed the simulator. From 2015 to 2017, the number of sessions was 11,176 with a monthly average of 399.0 +/- 190.0. Developing countries accounted for 35% of sessions and the average session duration was 9.0 +/- 7.3 minutes. This yields a total simulator screen time of 100,584 minutes (1676 hours). Most survey respondents were surgeons or trainees (87%) specializing in plastic, maxillofacial, or general surgery (89%). Most users found the simulator to be useful (88%), at least equivalent or more useful than other resources (83%), and used it for teaching (58%). CONCLUSIONS: Our internet-based interactive cleft surgery platform reaches its intended target audience, is not restricted by socioeconomic barriers to access, and is judged to be useful by surgeons. More than 4000 active users have been reached since inception. The total screen time over approximately 2 years exceeded 1600 hours. This suggests that future surgical simulators of this kind may be sustainable by stakeholders interested in reaching this target audience. PMID- 29396279 TI - Comment on: medium to long-term outcomes of bariatric surgery in older adults with super obesity. PMID- 29396280 TI - Effect of bariatric surgery on urinary sphingolipids in adolescents with severe obesity. AB - BACKGROUND: Untreated severe obesity of adolescents is associated with abnormal kidney function and development of chronic kidney disease. Lipotoxicity due to lipid accumulation in glomeruli might be an important mechanism in the progression of kidney disease in obesity. OBJECTIVE: To assess subclinical glomerular injury by measuring urinary sphingolipids in adolescents with severe obesity before and after weight loss surgery. We hypothesized that the levels of urinary sphingolipids would be elevated at baseline and improve after weight reduction. SETTING: Cincinnati Children's Hospital Medical Center, University of Cincinnati. METHODS: Ten adolescents undergoing bariatric surgery with no microalbuminuria and normal kidney function were selected. Urinary sphingolipids (ceramides, glycosphingolipids, and sphingomyelins) were quantified using ultra performance liquid chromatography electrospray ionization tandem mass spectrometry at baseline and 1 year postoperatively. The levels of sphingolipids were compared with lean and moderately obese controls. RESULTS: Participants with severe obesity had a mean baseline body mass index of 50 kg/m2 that decreased to 36 kg/m2 at 1 year postsurgery (28% reduction). Almost all urinary ceramides, glycosphingolipids, and sphingomyelin species were significantly elevated in participants with severe obesity compared with controls at baseline (P<.01). One year after weight loss surgery, levels of urinary sphingolipids improved but were still significantly elevated compared with controls. CONCLUSIONS: Our study indicates that severe obesity is associated with increased urinary excretion of sphingolipids despite the absence of microalbuminuria or decreased kidney function. Urinary sphingolipids may therefore represent a marker of early (subclinical) glomerular injury in adolescents with severe obesity. PMID- 29396281 TI - Erectile Dysfunction and Subclinical Cardiovascular Disease. AB - BACKGROUND: An association between erectile dysfunction (ED) and cardiovascular (CV) disease (CVD) has long been recognized, and studies suggest that ED is an independent marker of CVD risk. More significantly, ED is a marker for both obstructive and non-obstructive coronary artery disease (CAD) and may reveal the presence of subclinical CAD in otherwise asymptomatic men. AIM: To discuss the role of ED as an early marker of subclinical CVD; describe an approach to quantifying that burden; and propose an algorithm for the evaluation and management of CV risk in men 40-60 years of age with vasculogenic ED, those presumed to have the highest risk for a CV event. METHODS: A comprehensive review of original literature and expert consensus documents was conducted and incorporated into clinical recommendations for ED management in the context of CV risk. OUTCOMES: Assessment and management of ED may help identify and reduce the risk of future CV events. Initial evaluation should distinguish between vasculogenic ED and ED of other etiologies. RESULTS: For men with predominantly vasculogenic ED, we recommend that initial CV risk stratification be based on the 2013 American College of Cardiology/American Heart Association atherosclerotic CV disease risk score. Management of men with ED who are at low risk for CVD should focus on risk factor control; men at high risk, including those with CV symptoms, should be referred to a cardiologist. Intermediate-risk men should undergo non invasive evaluation for subclinical atherosclerosis. Evidence supports use of a prognostic markers, particularly coronary calcium score, to further understand CV risk in men with ED. CONCLUSIONS: Clinicians must assess the presence or absence of ED in every man >40 years of age, especially those men who are asymptomatic for signs and symptoms of CAD. We support CV risk stratification and CVD risk factor reduction in all men with vasculogenic ED. Miner M, Parish SJ, Billups KL, et al. Erectile Dysfunction and Subclinical Cardiovascular Disease. Sex Med Rev 2018;XX:XXX-XXX. PMID- 29396282 TI - Male Orgasmic Dysfunction Post-Radical Pelvic Surgery. AB - BACKGROUND: Pelvic surgeries are recognized to cause dysfunction of the male sexual response, which consists of erection, emission, expulsion, and orgasm. However, the least attention has been paid to male orgasmic dysfunction after invasive pelvic surgery. AIM: To describe the available literature on post-pelvic surgery orgasmic dysfunction disorders. METHODS: A literature search was performed on PubMed using the search strings related to dysfunction of the male sexual cycle and orgasm after pelvic surgery. OUTCOMES: Orgasmic dysfunction after pelvic procedures in urologic, colorectal, and vascular surgeries was assessed. RESULTS: Radical prostatectomy was the most common procedure where orgasmic dysfunction was quantified. Anorgasmia post-operatively occurred in patients in a range of 5-70%. Dysorgasmia occurred less frequently from 7-14%. The prevalence of climacturia was highly variable occurring in 20-93% of patients. Radical cystectomy resulted in anorgasmia 33-62% of the time and climacturia ranged from 6-45%. Studies involving colorectal surgeries were less likely to assess for dysorgasmia and climacturia, but anorgasmia rates ranged from 0-52%. Most current studies do not differentiate between ejaculatory and orgasmic dysfunction. However, more recent studies have started to distinguish between the 2 disorders and publish more specific data on what components of the male sexual response has been affected by the specific surgery. CONCLUSIONS: The male sexual response, specifically the male orgasm, is difficult to quantify in a non-obtrusive setting and can exhibit variability between patients and between sexual encounters in the same patient. Data involving the outcome of male orgasmic dysfunction after pelvic surgery are sparse, limiting health professionals' ability to appropriately counsel patients. Future work needs to standardize outcome assessment for orgasmic disorders, which, in turn, can be used across all surgical specialties. Haney NM, Alzweri LM, Hellstrom WJG. Male Orgasmic Dysfunction Post-Radical Pelvic Surgery. Sex Med Rev 2018;6:429-437. PMID- 29396283 TI - Urological Survivorship Issues Among Adolescent Boys and Young Men Who Are Cancer Survivors. AB - BACKGROUND: Urological survivorship issues encompass an area that may potentially be overlooked after treatment of childhood cancer in adolescent boys and young men. Side effects of cancer therapy may include subsequent development of erectile dysfunction (ED), hypogonadism, and infertility in adulthood. AIM: The purpose of this review is to focus on the etiology and prevalence of the range of sexual and gonadal dysfunction in adolescent boys and young men who are cancer survivors, while discussing current recommendations for evaluation and treatment. METHODS: We performed a literature review of articles evaluating hypogonadism, sexual dysfunction, ED, and infertility in young men cancer survivors. OUTCOMES: There is compelling evidence that significant survivorship issues are faced by boys entering adulthood after completing cancer therapy. RESULTS: Overall, young men cancer survivors are much more likely to report symptoms of sexual dysfunction than the general population of men. These patients can develop ED due to physiologic and psychological changes that take place with diagnosis of a malignancy and subsequent treatment. Primary hypogonadism can arise due to pelvic radiation or chemotherapy, and central hypogonadism may arise from pituitary insufficiency after brain radiation or surgery. Infertility develops from direct damage to the Sertoli cells and germinal epithelium from radiotherapy or chemotherapy. Cancer survivors who are men should therefore be screened for these important urological survivorship issues, although exact surveillance strategies remain unclear. CONCLUSIONS: Urological survivorship issues including ED, hypogonadism, and infertility are common among cancer survivors and result in significant morbidity. Due to the medical complexity of cancer survivorship, the population of adolescent and young adult survivors would benefit from a network of multidisciplinary survivorship experts to aid the transition into adulthood. Improved research efforts may help to clarify risk factors and to develop enhanced strategies for evaluation and treatment. Sukhu T, Ross S, Coward RM. Urological Survivorship Issues Among Adolescent Boys and Young Men Who Are Cancer Survivors. Sex Med Rev 2018;6:396-409. PMID- 29396284 TI - Green tea extract affects porcine ovarian cell apoptosis. AB - Green tea is a commonly used beverage and green tea extract is a common dietary herbal supplement manufactured into different over-the-counter products. The aim of this in vitro study was to examine the steroid hormone secretion (progesterone and 17-beta estradiol), proliferation and apoptosis of porcine ovarian granulosa cells after addition of green tea extract. Granulosa cells were incubated with green tea extract at five doses (0.1, 1, 10, 100 and 200 MUg/ml) and the release of hormones by granulosa cells was assessed by EIA after 24 h exposure. The presence of proliferation and apoptotic markers was assessed by immunocytochemistry. Secretion of steroid hormones was not affected by green tea extract at all the doses in comparison to control. Also, markers of proliferation (PCNA and cyclin B1) were not affected by green tea extract. However, the highest dose (200 MUg/ml) of green tea extract used in this study increased the accumulation of apoptotic markers caspase-3 and p53 in granulosa cells. In conclusion, our results indicate the impact of green tea extract at the highest dose used in this study on ovarian apoptosis through pathway that includes activation of caspase-3 and p53. Potential stimulation of these intracellular regulators could induce the process of apoptosis in ovarian cells. PMID- 29396285 TI - Uterine artery flow velocity waveform, arterial flow indices, follicular dynamics, and sex hormones during preovulatory period in synchronized ovulatory cycle of Bos indicus beef cows. AB - A greater understanding of the uterine artery's (UtA) biology is essential to the increase in female reproductive abilities. The UtA flow velocity waveform, blood flow volume (BFV), pulsatility and resistance indices (PI and RI), blood flow velocities, dynamics of the dominant follicle (DF), and estradiol (E2) and progesterone (P4) levels in an induced ovulatory cycle were evaluated in Thai native cattle. Twenty cows were induced with synchronized ovulation through a P4 releasing device, from Day -9 to Day -4, concurrent with the administration of two doses of a gonadotropin-releasing hormone on Day -9 and Day -1, and two doses of prostaglandin F2alpha on Day -4 and 8 h later. Day 0 was designated as the day of ovulation. The cows underwent Doppler sonographic determination and blood collection from Day -4 to Day 0. The cows were classified in the non-ovulating (n = 5) and ovulating groups (n = 15). The ovulating cows presented higher BFV values, blood flow velocities, DF growth rates, and E2 levels; yet lower PI values and P4 concentrations, than those of the non-ovulating cows. The BFV values and the blood flow velocities were greater, but the RI and PI values were lower in the ovulatory side UtA than in the contraovulatory side UtA. The BFV values were positively correlated with blood flow velocities, DF growth rates and E2 concentrations in the ovulating cows; confirming the importance of UtA blood flow, follicular growth, and E2-vasodilation during preovulatory phase in the induced ovulatory cycle of Bos indicus beef cows. PMID- 29396286 TI - Genetic variants in post myocardial infarction patients presenting with electrical storm of unstable ventricular tachycardia. AB - Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm. These genes have been previously reported to be associated with inherited syndromes of Sudden Cardiac Death. The present study suggests that the genetic architecture in patients with remote MI and ES of unstable ventricular tachycardia may be similar to that of Ion channelopathies. Identification of these variants may identify post MI patients who are predisposed to develop electrical storm and help in risk stratification. PMID- 29396287 TI - Fads and facts. PMID- 29396288 TI - Directed Evolution to Engineer Monobody for FRET Biosensor Assembly and Imaging at Live-Cell Surface. AB - Monitoring enzymatic activities at the cell surface is challenging due to the poor efficiency of transport and membrane integration of fluorescence resonance energy transfer (FRET)-based biosensors. Therefore, we developed a hybrid biosensor with separate donor and acceptor that assemble in situ. The directed evolution and sequence-function analysis technologies were integrated to engineer a monobody variant (PEbody) that binds to R-phycoerythrin (R-PE) dye. PEbody was used for visualizing the dynamic formation/separation of intercellular junctions. We further fused PEbody with the enhanced CFP and an enzyme-specific peptide at the extracellular surface to create a hybrid FRET biosensor upon R-PE capture for monitoring membrane-type-1 matrix metalloproteinase (MT1-MMP) activities. This biosensor revealed asymmetric distribution of MT1-MMP activities, which were high and low at loose and stable cell-cell contacts, respectively. Therefore, directed evolution and rational design are promising tools to engineer molecular binders and hybrid FRET biosensors for monitoring molecular regulations at the surface of living cells. PMID- 29396289 TI - Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. AB - Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system. PMID- 29396290 TI - Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria. AB - Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding. Nuclear magnetic resonance solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively drug-resistant (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria. In vivo efficacy was demonstrated in a murine bacteremia model with a colistin-resistant P. aeruginosa clinical isolate. PMID- 29396291 TI - Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite. AB - Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide. This fragment functions as an effective natural inhibitor of mature IrCD1 that operates in a pH-dependent manner through a unique allosteric inhibition mechanism. The study uncovers the propeptide binding exosite as a target for the regulation of pepsin-family aspartic peptidases and defines the structural requirements for exosite inhibition. PMID- 29396292 TI - Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein. AB - Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay. Dynarrestin reversibly inhibits cytoplasmic dynein 2 dependent intraflagellar transport (IFT) of the cargo IFT88 and flux of Smo within cilia without interfering with ciliogenesis and suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. As such, dynarrestin is a valuable tool for probing cytoplasmic dynein-dependent cellular processes and a promising compound for medicinal chemistry programs aimed at development of anti cancer drugs. PMID- 29396293 TI - Genomic Profile of Urothelial Carcinoma of the Upper Tract from Ureteroscopic Biopsy: Feasibility and Validation Using Matched Radical Nephroureterectomy Specimens. AB - : Urothelial carcinoma of the upper tract (UTUC) presents specific challenges regarding accurate staging and tumor sampling. We aimed to assess the feasibility of applying next-generation sequencing to biopsy specimens and gauged the concordance of their genetic profiles with matched radical nephroureterectomy (RNU) specimens. Of the 39 biopsy specimens collected, 36 (92%) had adequate material for sequencing using a hybridization-based exon capture assay (MSK IMPACT). The most frequently altered genes across the patient cohort were consistent with the urothelial carcinoma-associated alterations identified in a cohort of 130 RNU specimens previously sequenced at our center, including mutations in the TERT promoter (64%), hotspot activating mutations in FGFR3 (64%), and frequent mutations in chromatin remodeling genes. For 12 patients, a matching tumor sample from a subsequent RNU was sequenced. We found a high level of concordance between matched biopsy and RNU specimens, up to 92% for the likely pathogenic alterations. PATIENT SUMMARY: We evaluated the feasibility of genomic characterization of tumor tissue collected at the time of ureteroscopic biopsy and found high concordance with subsequent radical nephroureterectomy specimens. Molecular characterization of urothelial carcinoma of the upper tract biopsies could guide treatment decision-making and identify high-risk patients who could benefit from neoadjuvant chemotherapy and low-risk patients who could benefit from conservative or organ-sparing strategies. PMID- 29396294 TI - PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations. AB - Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas. PD-L1, PD-L2, and CTLA-4 mRNA expression levels showed a significant inverse correlation with promoter methylation (PD-L1: p=0.005; PD-L2: p<0.001; CTLA-4: p<0.001). Furthermore, immune checkpoint methylation was significantly associated with age (PD-L2: p=0.003; PD-1: p=0.015), molecular alterations, i.e. MGMT methylation (PD-L1: p<0.001; PD-L2: p<0.001), ATRX mutations (PD-L2: p<0.001, PD-1: p=0.001), and TERT mutations (PD-L1: p=0.035, PD L2: p<0.001, PD-1: p<0.001, CTLA4: p<0.001) as well as methylation subgroups and immune cell infiltrates. In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR=0.51 [0.34-0.76], p=0.001). Our findings suggest an epigenetic regulation of immune checkpoint genes via DNA methylation in LGG. PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies. PMID- 29396295 TI - Metabolomic Profiling Reveals Cellular Reprogramming of B-Cell Lymphoma by a Lysine Deacetylase Inhibitor through the Choline Pathway. AB - Despite the proven clinical antineoplastic activity of histone deacetylase inhibitors (HDACI), their effect has been reported to be lower than expected in B cell lymphomas. Traditionally considered as "epigenetic drugs", HDACI modify the acetylation status of an extensive proteome, acting as general lysine deacetylase inhibitors (KDACI), and thus potentially impacting various branches of cellular metabolism. Here, we demonstrate through metabolomic profiling of patient plasma and cell lines that the KDACI panobinostat alters lipid metabolism and downstream survival signaling in diffuse large B-cell lymphomas (DLBCL). Specifically, panobinostat induces metabolic adaptations resulting in newly acquired dependency on the choline pathway and activation of PI3K signaling. This metabolic reprogramming decreased the antineoplastic effect of panobinostat. Conversely, inhibition of these metabolic adaptations resulted in superior anti-lymphoma effect as demonstrated by the combination of panobinostat with a choline pathway inhibitor. In conclusion, our study demonstrates the power of metabolomics in identifying unknown effects of KDACI, and emphasizes the need for a better understanding of these drugs in order to achieve successful clinical implementation. PMID- 29396296 TI - Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease. AB - We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16+/-2.824ng/ml vs 35.07+/-2.099ng/ml, p<0.001). Similar to CHIT1, serum CHI3L1 was also significantly increased in GD patients compared with healthy controls (1736+/-152.1pg/ml vs 684.7+/-68.20pg/ml, p<0.001). Whereas the PGRN level is significantly reduced in GD patients as compared to the healthy control (91.56+/-3.986ng/ml vs 150.6+/-4.501, p<0.001). Collectively, these results indicate that CHI3L1 may be a previously unrecognized biomarker for diagnosing GD and for evaluating the therapeutic effects of new GD drug(s). PMID- 29396298 TI - Losmapimod: A Novel Clinical Drug to Overcome Gefitinib-Resistance. PMID- 29396297 TI - In Vitro Regeneration of Patient-specific Ear-shaped Cartilage and Its First Clinical Application for Auricular Reconstruction. AB - Microtia is a congenital external ear malformation that can seriously influence the psychological and physiological well-being of affected children. The successful regeneration of human ear-shaped cartilage using a tissue engineering approach in a nude mouse represents a promising approach for auricular reconstruction. However, owing to technical issues in cell source, shape control, mechanical strength, biosafety, and long-term stability of the regenerated cartilage, human tissue engineered ear-shaped cartilage is yet to be applied clinically. Using expanded microtia chondrocytes, compound biodegradable scaffold, and in vitro culture technique, we engineered patient-specific ear shaped cartilage in vitro. Moreover, the cartilage was used for auricle reconstruction of five microtia patients and achieved satisfactory aesthetical outcome with mature cartilage formation during 2.5years follow-up in the first conducted case. Different surgical procedures were also employed to find the optimal approach for handling tissue engineered grafts. In conclusion, the results represent a significant breakthrough in clinical translation of tissue engineered human ear-shaped cartilage given the established in vitro engineering technique and suitable surgical procedure. This study was registered in Chinese Clinical Trial Registry (ChiCTR-ICN-14005469). PMID- 29396299 TI - Radiotherapy Upregulates Programmed Death Ligand-1 through the Pathways Downstream of Epidermal Growth Factor Receptor in Glioma. AB - BACKGROUND: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). MATERIALS AND METHODS: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT upregulated PD-L1 expression using human glioma cell lines U87 and U251. RESULTS: Our data demonstrated that the PD-L1 expression was significantly correlated with EGFR expression in glioma specimens (chi2=5.00, P=0.025). The expressions of PD L1 at the protein and mRNA levels were both significantly up-regulated by RT (P<0.05). The expressions of phosphorylated EGFR and janus kinase 2 (JAK2) were also induced by RT (P<0.05). Besides, inhibition of EGFR pathway could abrogate the RT-triggered PD-L1 up-regulation (P>0.05). The combination of RT with EGFR inhibitor exhibited the same effect on antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). CONCLUSIONS: RT could up-regulate the PD-L1 expression through the pathways downstream of EGFR in glioma. PMID- 29396300 TI - Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. AB - Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent a mechanistic link between Abeta/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid beta (Abeta) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Abeta-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop. We postulate that TBI can initiate cerebrovascular pathology, which is causally involved in the development of multiple forms of neurodegeneration including AD-like dementias. In this review, we will explore how novel biomarkers, animal and human studies with a focus on cerebrovascular dysfunction are contributing to the understanding of the consequences of TBI on the development of AD-like pathology. PMID- 29396301 TI - Glucagon and/or IGF-1 Production Regulates Resetting of the Liver Circadian Clock in Response to a Protein or Amino Acid-only Diet. AB - The circadian system controls the behavior and multiple physiological functions. In mammals, the suprachiasmatic nucleus (SCN) acts as the master pacemaker and regulates the circadian clocks of peripheral tissues. The SCN receives information regarding the light-dark cycle and is thus synchronized to the external 24-hour environment. In contrast, peripheral clocks, such as the liver clock, receive information from the SCN and other factors; in particular, food intake which leads to insulin secretion induces strong entrainment of the liver clock. On the other hand, the liver clock of insulin-depleted mice treated with streptozotocin (STZ) has been shown to be entrained by scheduled feeding, suggesting that insulin is not necessary for entrainment of the liver clock by feeding. In this study, we aimed to elucidate additional mechanism on entraining liver clock by feeding a protein-only diet and/or amino-acid administration which does not increase insulin levels. We demonstrated that protein-only diet and cysteine administration elicit entrainment of the liver clock via glucagon secretion and/or insulin-like growth factors (IGF-1) production. Our findings suggest that glucagon and/or IGF-1 production are additional key factors in food induced entrainment. PMID- 29396303 TI - The Comeback of Scarlet Fever. PMID- 29396302 TI - SATB2 is a Promising Biomarker for Identifying a Colorectal Origin for Liver Metastatic Adenocarcinomas. AB - SATB2 (Special AT-rich sequence-binding protein 2) has recently been shown to be a specific biomarker of colorectal cancer (CRC). The aim of this study was to investigate the diagnostic potential of SATB2 as a means of detecting a CRC origin for liver metastases. SATB2 expression was examined in a resection cohort of 101 CRC and 273 non-CRC adenocarcinoma samples using immunohistochemistry (IHC). The diagnostic accuracy of CRC origins of liver metastases based on SATB2 and a three marker panel of SATB2, CK20 and CDX2 was evaluated using an independent cohort of 192 liver biopsies. IHC showed 97 of the 101 (96.0%) primary CRC samples were SATB2 positive, compared to only 6 of the 273 (2.1%) samples of other cancer types. The sensitivity, specificity and AUC values of SATB2 expression in resection samples were 97%, 97.1% and 0.977, respectively. Meanwhile, for the liver biopsy samples, the sensitivity, specificity and AUC values of a CRC liver metastases was 92.2%, 97.8% and 0.948 for SATB2, 95.1%, 91.0% and 0.959 for CK20, and 100%, 85.4% and 0.976 for CDX2, respectively. Further analysis demonstrated that all three-marker positivity was detected in 92/103 (89.3%) CRC and 2/89 (2.2%) non-CRC liver metastases sampled by biopsy. Our findings suggest that SATB2, as measured by IHC, could serve as a promising diagnostic biomarker of CRC metastases. Combining evaluation of SATB2 with CK20 and CDX2 to form a three marker panel further improved the detection of metastatic CRCs in liver biopsy tissues. PMID- 29396304 TI - LDL Receptor Gene-Ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia with Dominant Inheritance and Diet-Induced Coronary Atherosclerosis. PMID- 29396305 TI - Disconnect Between Genes Associated With Ischemic Heart Disease and Targets of Ischemic Heart Disease Treatments. AB - BACKGROUND: Development of pharmacological treatments to mitigate ischemic heart disease (IHD) has encompassed disappointing results and expensive failures, which has discouraged investment in new approaches to prevention and control. New treatments are most likely to be successful if they act on genetically validated targets. We assessed whether existing pharmacological treatments for IHD reduction are acting on genetically validated targets and whether all such targets for IHD are currently being exploited. METHODS: Genes associated with IHD were obtained from the loci of single nucleotide polymorphisms reported in either of two recent genome wide association studies supplemented by a gene-based analysis (accounting for linkage disequilibrium) of CARDIoGRAMplusC4D 1000 Genomes, a large IHD case (n=60,801)-control (n=123,504) study. Treatments targeting the products of these IHD genes and genes with products targeted by current IHD treatments were obtained from Kyoto Encyclopedia of Genes and Genomes and Drugbank. Cohen's kappa was used to assess agreement. RESULTS: We identified 173 autosomal genes associated with IHD and 236 autosomal genes with products targeted by current IHD treatments, only 8 genes (PCSK9, EDNRA, PLG, LPL, CXCL12, LRP1, CETP and ADORA2A) overlapped, i.e. were both associated with IHD and had products targeted by current IHD treatments. The Cohen's kappa was 0.03. Interventions related to another 29 IHD genes exist, including dietary factors, environmental exposures and existing treatments for other indications. CONCLUSIONS: Closer alignment of IHD treatments with genetically validated physiological targets may represent a major opportunity for combating a leading cause of global morbidity and mortality through repurposing existing interventions. PMID- 29396307 TI - Editorial overview: Intraspecies transmission of viruses. PMID- 29396306 TI - A 30-Min Nucleic Acid Amplification Point-of-Care Test for Genital Chlamydia trachomatis Infection in Women: A Prospective, Multi-center Study of Diagnostic Accuracy. AB - BACKGROUND: Rapid Point-Of-Care Tests for Chlamydia trachomatis (CT) may reduce onward transmission and reproductive sexual health (RSH) sequelae by reducing turnaround times between diagnosis and treatment. The io(r) single module system (Atlas Genetics Ltd.) runs clinical samples through a nucleic acid amplification test (NAAT)-based CT cartridge, delivering results in 30min. METHODS: Prospective diagnostic accuracy study of the io(r) CT-assay in four UK Genito-Urinary Medicine (GUM)/RSH clinics on additional-to-routine self-collected vulvovaginal swabs. Samples were tested "fresh" within 10days of collection, or "frozen" at 80 degrees C for later testing. Participant characteristics were collected to assess risk factors associated with CT infection. RESULTS: CT prevalence was 7.2% (51/709) overall. Sensitivity, specificity, positive and negative predictive values of the io(r) CT assay were, respectively, 96.1% (95% Confidence Interval (CI): 86.5-99.5), 97.7% (95%CI: 96.3-98.7), 76.6% (95%CI: 64.3-86.2) and 99.7% (95%CI: 98.9-100). The only risk factor associated with CT infection was being a sexual contact of an individual with CT. CONCLUSIONS: The io(r) CT-assay is a 30 min, fully automated, high-performing NAAT currently CE-marked for CT diagnosis in women, making it a highly promising diagnostic to enable specific treatment, initiation of partner notification and appropriately intensive health promotion at the point of care. PMID- 29396308 TI - Variation in treatment of low energy gunshot injuries - A survey of OTA members. AB - The purpose of this study was to determine current practice patterns in the treatment of low energy gunshot wounds involving bones and joints. One hundred seventy-three Orthopaedic Trauma Association (OTA) members completed a web-based survey. The survey included practices for antibiotic therapy and operative treatment for different types of low-energy gunshot injuries. Six different scenarios of soft tissue injury, intra-articular injury, and fractures were described. Several permutations of antibiotic therapy and operative or non operative management options were given as choices on the survey. Survey responses had a high degree of heterogeneity with only two treatment options receiving more than 50% agreement among responders: 54% agreed on joint exploration with perioperative antibiotics for gunshot wounds (GSWs) traversing a joint and 55% agreed on treating operative tibial shaft fractures from GSWs with fixation, along with debridement and irrigation of the GSW tract, and perioperative antibiotics. The majority of participants (69%) were either not aware of or not sure of an established protocol for treatment of GSW to bones and joints at their institution. Moreover, there is still wide variation in treatments among 31% of the participants who reported a protocol in place at their institutions. We conclude there is wide variation among orthopaedic surgeons in the antimicrobial prophylaxis and treatment of GSWs. Opportunity exists to develop standardized practices to minimize related infections, other complications, and costs. PMID- 29396309 TI - Persistent light to moderate alcohol intake and lung function: A longitudinal study. AB - Alcohol intake has been inconsistently associated with lung function levels in cross-sectional studies. The goal of our study was to determine whether longitudinally assessed light-to-moderate alcohol intake is associated with levels and decline of lung function. We examined data from 1333 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease. Alcohol intake was assessed with four surveys between 1972 and 1992. Subjects who completed at least two surveys were classified into longitudinal drinking categories ("never", "inconsistent", or "persistent drinker"). Spirometric lung function was measured in up to 11 surveys between 1972 and 1992. Random coefficient models were used to test for differences in lung function by drinking categories. After adjustment for sex, age, height, education, BMI categories, smoking status, and pack-years, as compared to never drinkers, persistent drinkers had higher FVC (coefficient: 157 mL, p < 0.001), but lower FEV1/FVC ratio (-2.3%, p < 0.001). Differences were due to a slower decline of FVC among persistent than among never-drinkers (p = 0.003), and these trends were present independent of smoking status. Inconsistent drinking showed similar, but weaker associations. After adjustment for potential confounders, light-to-moderate alcohol consumption was associated with a significantly decreased rate of FVC decline over adult life. PMID- 29396310 TI - Parent's Perspectives on How They Cope With the Impact on Their Family of a Child With Heart Disease. AB - PURPOSE: Studies of familial coping with a child's chronic condition have highlighted psychological distress; family functioning; and quality of life; as issues that demand coping strategies. There are conflicting findings on impact and coping and a paucity of information about the specific coping challenges for parents of a child with heart disease, with few qualitative studies in this area. The purpose of the study was to explore the way parents coped with their child's heart condition as it impacted on different domains of family functioning. DESIGN AND METHOD: In this qualitative study, interviews were held with 17 parents attending a pediatric hospital-based family support program in 2015. Fifteen of the 17 children's conditions were classified as "major". Domains covered in the interviews included: coping challenges posed at different stages of the illness trajectory, parenting, condition management, transitions, psychological impact, social support and coping strategies. Interview transcripts were coded thematically. RESULTS: Multiple points of stress and challenges to coping were identified: coping with the diagnosis, including consideration of termination; dealing with the challenges facing their child; coping with parenting including co-parenting issues; the role of social support in coping; and identification of adaptive and maladaptive coping behaviours. CONCLUSION: A large range of positive coping strategies were identified, as was the need for coping-focused psychological support throughout the parents' and children's journey. PRACTICE IMPLICATIONS: The strategies identified have formed the basis of a manualised intervention for these parents. PMID- 29396311 TI - Electrodiagnostic Grade and Carpal Tunnel Release Outcomes: A Prospective Analysis. AB - PURPOSE: The value of electrodiagnostic (EDX) study grades as a prognostic indicator of clinical results after carpal tunnel release (CTR) remains controversial. In this study, we tested the primary null hypothesis that symptom relief after CTR would not differ based on EDX grade. Secondarily, we evaluated the degree of symptomatic and functional postoperative improvement relative to preoperative EDX grade. METHODS: We prospectively evaluated 199 consecutive patients with 256 hands after CTR confirmed with EDX. Data were collected before surgery and patients were observed at 2 weeks and 3 months after surgery. There were 20 hands with mild, 126 with moderate, and 110 with severe involvement in the preoperative EDX. Demographic, EDX grade (mild, moderate, or severe); surgical parameters; Quick-Disabilities of the Arm, Shoulder, and Hand questionnaire; symptom severity scale, functional status scale, pain catastrophizing scale, and visual analog scale data were collected and analyzed. RESULTS: There was significant improvement in Quick-Disabilities of the Arm, Shoulder, and Hand, symptom severity scale, and functional status scale scores from the preoperative to 2-week and 3-month postoperative visits in all categories of EDX grade. There was no significant difference in the extent of recovery by the 2-week and 3-month visits relative to EDX grade. Catastrophic thinking did not have a significant effect on any of the 3 groups. Pain decreased dramatically at 2 weeks after surgery but there was no additional significant difference in visual analog scale scores between the 2-week and 3-month postoperative visits. Postoperative pain improvement occurred regardless of EDX grade. There were no major complications or reoperations in any group. CONCLUSIONS: Carpal tunnel release demonstrated consistently significant improvement in outcomes regardless of EDX grade at initial and final follow-up. The extent of postoperative improvement after CTR overall was also not statistically different between groups with differing EDX severity. Older patients with severe CTS achieved more modest gains. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 29396312 TI - Volumetric comparison of maxillofacial soft tissue morphology: computed tomography in the supine position versus three-dimensional optical scanning in the sitting position. AB - OBJECTIVE: Three-dimensional (3-D) surgical simulation has become popular, but the accuracy of such simulation is difficult to assess. Because maxillofacial soft tissue profiles vary with posture, we compared such profiles obtained in the supine and sitting positions. STUDY DESIGN: In total, 28 patients with skeletal Class III jaw deformities underwent computed tomography in the supine position and 3-D optical scanning in the sitting position. The 2 sets of 3-D data were superimposed, and linear and volumetric differences were calculated. We evaluated the cheeks, the subauricular and infraorbital regions, the nose, the lips, and the chin. Statistical analyses were performed by using paired Student's t tests. Differences with P < .05 were considered significant. RESULTS: Patients were divided into 3 groups based on body mass index. The facial profiles of the cheeks and subauricular areas differed significantly between the sitting and supine positions. The extent of variation increased with body mass index. CONCLUSIONS: When a patient moves from the sitting position to the supine position, maxillofacial soft tissue migrates from the cheeks to the subauricular regions. Thus, simulations for surgery based on supine computed tomography alone do not accurately model the cheeks and subauricular areas. PMID- 29396313 TI - Mandibular pain, trismus, and weight loss in a 75-year-old man. PMID- 29396314 TI - Comments on the clinicopathologic conference case report entitled: "Submucosal nodule in buccal mucosa". PMID- 29396315 TI - Historical perspective and nomenclature of potentially malignant or potentially premalignant oral epithelial lesions with emphasis on leukoplakia-some suggestions for modifications. AB - Of the potentially (pre)maligant oral epithelial lesions, leukoplakia is the most common. A brief overview of the various definitions of leukoplakia that have been used in the past is presented here. A proposal has been made to modify the current definition. Clinically, for decades, leukoplakias have been divided into homogeneous and nonhomogeneous leukoplakias and further into different subtypes. A proposal has been made to slightly rearrange these subtypes. Furthermore, attention has been paid to a number of keratotic lesions that have been reported in the literature. It is expected that the increasing knowledge on carcinogenesis, including various genetic aspects, will be reflected in the definition of oral potentially (pre)malignant lesions in the near future. PMID- 29396317 TI - OOOO and related journals: an opportunity to guide the dental school curriculum and reinforce the relationship between biomedical science education and dental practice? PMID- 29396316 TI - Clinical significance of preoperative imaging in oral squamous cell carcinoma compared with lymph node status: a comparative retrospective study. AB - OBJECTIVE: The accuracy and sensitivity of commonly used imaging modalities in evaluating oral cavity cancer was evaluated by comparing the preoperative radiologic findings and the postoperative pathology report. STUDY DESIGN: Patients with oral squamous cell carcinoma, who had undergone at least 1 imaging test 2 weeks before surgery were included. Radiologic findings were compared with the dissected neck findings to assess the lymph node status. Sensitivity and specificity of the imaging modalities were calculated by using the chi2 test. RESULTS: Sensitivities for detecting metastatic neck lymph nodes at a threshold of 1 cm were 48% (P = .02) and 43.8% (P = .3) for computed tomography (CT) and magnetic resonance imaging respectively. Specificities were 76.3% and 70%, respectively. As for the 1.5 cm threshold, sensitivities were 36% (P = .002) and 31.3% (P = .5), respectively, and specificities were 91.5% and 76.7%, respectively. PET-CT was the most sensitive modality in the present study, with a P value of .02. CONCLUSIONS: The different studied imaging modalities used for preoperative neck staging are not sensitive enough and would lead to underdiagnoses of a significant proportion of patients. Thus, prophylactic neck dissection for occult neck disease is of extreme importance and remains the gold standard for oral cancer treatment. PMID- 29396318 TI - Treatment of enucleated odontogenic jaw cysts: a systematic review. AB - OBJECTIVES: In this systematic review, we aimed to assess the impact of filling or not filling enucleated odontogenic jaw cysts on bony defect consolidation. In terms of filling, we aimed to assess which is the best filling material based on current evidence. STUDY DESIGN: An electronic search was performed using PubMed, Embase, and MEDLINE databases with the logical operators: "odontogenic cysts" AND "jaw cysts" AND "treatment AND therapy." RESULTS: Thirteen studies with primary enucleation (6 with filling and 7 without filling) were included. In terms of filling, either synthetic bone substitutes or autologous bone were used. The primary outcome was bony regeneration judged by radiographic follow-up measurements. Two-dimensional (2-D) radiographic follow-up measurements (densitometry) revealed a bone density increase and comparable bone regeneration in both groups. CONCLUSIONS: Because of the low number of studies and the heterogeneity of the included data, evidence-based treatment recommendations cannot be given at this time. Also, outcomes based on 2-D measurements should be interpreted with caution. However, the following factors are suggested as having an impact on bony defect consolidation: defect size, defect configuration, the preservation of the periosteum, and localization (upper or lower jaw). Prospective comparable clinical studies with a 3-dimensional follow-up are needed. PMID- 29396319 TI - Oral potentially malignant disorders: risk of progression to malignancy. AB - Oral potentially malignant disorders (OPMDs) have a statistically increased risk of progressing to cancer, but the risk varies according to a range of patient- or lesion-related factors. It is difficult to predict the risk of progression in any individual patient, and the clinician must make a judgment based on assessment of each case. The most commonly encountered OPMD is leukoplakia, but others, including lichen planus, oral submucous fibrosis, and erythroplakia, may also be seen. Factors associated with an increased risk of malignant transformation include sex; site and type of lesion; habits, such as smoking and alcohol consumption; and the presence of epithelial dysplasia on histologic examination. In this review, we attempt to identify important risk factors and present a simple algorithm that can be used as a guide for risk assessment at each stage of the clinical evaluation of a patient. PMID- 29396320 TI - Pain exposure associates with telomere length erosion in very preterm infants. AB - Very preterm (VPT) infants (gestational age < 32 weeks) require long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU), even in absence of severe morbidities. During NICU stay, life-saving interventions occur and include invasive and painful skin-breaking procedures (NICU-related stress), which constitute a major early adverse experience for VPT infants. Telomeres are repeat sequence at the end of chromosomes, which shorten with age and are highly susceptible to life adversities: the exposure to early adverse experiences is associated with shorter telomere length (TL). Nonetheless, previous research did not assess longitudinally the association between NICU-related stress and TL in VPT infants. In the present study, leukocyte TL was assessed from cord blood at birth in 46 VPT infants and in a group of 31 full-term (FT) infants, as well as at NICU discharge in VPTs only. NICU-related stress was measured as the number of skin-breaking procedures occurring throughout the NICU stay. A significant difference emerged for TL between VPT infants and FT counterparts at birth. TL decreased from birth to discharge in VPT infants, although the change was not significant in the group as a whole. The amount of NICU-related stress emerged as the primary predictor of TL erosion in VPT infants, even controlling for neonatal and clinical confounders. Furthermore, VPT infants exposed to high NICU-related stress exhibited a marked and significant decrease in TL, whereas VPT exposed to low NICU-related stress exhibited a non-significant increase. The present study confirms previous evidence of longer telomeres in VPT infants at birth compared to FT controls. Moreover, NICU-related stress emerged as a key regulator of TL erosion from birth to discharge in VPT infants. Future research is warranted to further explore TL erosion in VPT infants and the factors associated with individual differences in NICU-related stress susceptibility at the epigenetic level. PMID- 29396321 TI - Conceptual endophenotypes: A strategy to advance the impact of psychoneuroendocrinology in precision medicine. AB - Psychobiological research has generated a tremendous amount of findings on the psychological, neuroendocrine, molecular and environmental processes that are directly relevant for mental and physical health, but have overwhelmed our capacity to meaningfully absorb, integrate, and utilize this knowledge base. Here, we reflect about suitable strategies to improve the translational success of psychoneuroendocrinological research in the era of precision medicine. Following a strategy advocated by the National Research Council and the tradition of endophenotype-based research, we advance here a new approach, termed "conceptual endophenotypes". We define the contextual and formal criteria of conceptual endophenotypes, outline criteria for filtering and selecting information, and describe how conceptual endophenotypes can be validated and implemented at the bedside. As proof-of-concept, we describe some of our findings from research that has adopted this approach in the context of stress-related disorders. We argue that conceptual endophenotypes engineer a bridge between the bench and the bedside. This approach readily lends itself to being continuously developed and implemented. Recent methodological advances, including digital phenotyping, machine learning, grassroots collaboration, and a learning healthcare system, may accelerate the development and implementation of this conceptual endophenotype approach. PMID- 29396323 TI - Universal Alternative Splicing of Noncoding Exons. AB - The human transcriptome is so large, diverse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed targeted single molecule and short-read RNA-seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome, identifying a fundamental distinction between protein-coding and noncoding gene content: almost every noncoding exon undergoes alternative splicing, producing a seemingly limitless variety of isoforms. Analysis of syntenic regions of the mouse genome shows that few noncoding exons are shared between human and mouse, yet human splicing profiles are recapitulated on Hsa21 in mouse cells, indicative of regulation by a deeply conserved splicing code. We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution. PMID- 29396324 TI - An endotracheal tube mounted camera for intubation during cardiopulmonary resuscitation. Preliminary data. PMID- 29396322 TI - A Landscape of Metabolic Variation across Tumor Types. AB - Tumor metabolism is reorganized to support proliferation in the face of growth related stress. Unlike the widespread profiling of changes to metabolic enzyme levels in cancer, comparatively less attention has been paid to the substrates/products of enzyme-catalyzed reactions, small-molecule metabolites. We developed an informatic pipeline to concurrently analyze metabolomics data from over 900 tissue samples spanning seven cancer types, revealing extensive heterogeneity in metabolic changes relative to normal tissue across cancers of different tissues of origin. Despite this heterogeneity, a number of metabolites were recurrently differentially abundant across many cancers, such as lactate and acyl-carnitine species. Through joint analysis of metabolomic data alongside clinical features of patient samples, we also identified a small number of metabolites, including several polyamines and kynurenine, which were associated with aggressive tumors across several tumor types. Our findings offer a glimpse onto common patterns of metabolic reprogramming across cancers, and the work serves as a large-scale resource accessible via a web application (http://www.sanderlab.org/pancanmet). PMID- 29396326 TI - Taking memory beyond the brain: Does tobacco dream of the mosaic virus? AB - Memory is typically defined through animal behavior, but this point of view may limit our understanding of many related processes in diverse biological systems. The concept of memory can be broadened meaningfully by considering it from the perspective of time and homeostasis. On the one hand, this theoretical angle can help explain and predict the behavior of various non-neural systems such as insulin-secreting cells, plants, or signaling cascades. On the other hand, it emphasizes biological continuity between neural phenomena, such as synaptic plasticity, and their evolutionary precursors in cellular signaling. PMID- 29396325 TI - The response of C19- and some C21-steroids during Synacthen and insulin tolerance test. AB - Testing of the adrenal function with ACTH 1-24 (Synacthen test) or insulin (insulin tolerance test-ITT) is commonly used. The question of ongoing debate is the dose of Synacthen. Moreover, it may be important from the physiological point of view besides measurement of cortisol levels and 17alpha-hydroxy-progesterone to know also the response of other steroids to these test. The plasma levels of 24 free steroids and their polar conjugates were followed after stimulation of 1 MUg, 10 MUg and 250 MUg of ACTH 1-24 and after insulin administration in thirteen healthy subjects. The study aimed to describe a response of steroid metabolome to various doses of ACTH 1-24 and to find the equivalency of these tests. The additional ambition was to contribute to understanding of physiology of these stimulation tests and suggest an additional marker for HPA axis evaluation. No increase of most conjugated steroids and even decrease of some of them during all of the Synacthen tests and ITT at 60th min were observed. The levels of steroid conjugates decreased in ITT but did not during all of the Synacthen tests by 20 min of each test. Testosterone and estradiol did not increase during the Synacthen tests or ITT as expected. The results suggest that the conjugated steroids in the circulation can serve as reserve stock for rapid conversion into free steroids in the first minutes of the stress situation. Various doses of ACTH 1-24 used in the Synacthen tests implicate earlier or later occurrence of maximal response of stimulated steroids. The equivalent dose to ITT and standard 250 MUg of ACTH 1-24 seemed to be dose of 10 MUg ACTH 1-24 producing the similar response in all of the steroids in the 60th min of the test. PMID- 29396327 TI - Prognostic impact of anastomotic leakage after elective colon resection for cancer - A propensity score matched analysis of 628 patients. AB - BACKGROUND: There is limited information regarding the impact of anastomotic leakage on oncologic outcome in exclusively colon cancer patients. METHODS: The colorectal database of the Department of Surgery of the University of Heidelberg was used to assess the impact of anastomotic leakage on oncologic outcome in patients undergoing curative resection for Stage I-III colon cancer. Risk adjusted Cox regression analysis and propensity score methods were used to assess overall, disease-free, and relative survival. RESULTS: 628 patients of which 26 (4.1%) experienced anastomotic leakage were analysed. Anastomotic leakage was associated with significantly worse overall, disease-free and relative survival in univariate and multivariate analysis. The analysis after exact propensity score matching confirmed the negative impact of anastomotic leakage on overall (HR 2.62, 95% CI 1.33-5.18, p = .011), disease-free (HR 2.28, 95% CI 1.16-4.47, p = .027) and relative survival (HR 3.70, 95% CI 1.82-7.52, p < .001). 5-year overall survival was 51.6% (95% CI 34.5-77.2%) for patients with anastomotic leakage compared to 77.7% (95% CI 73.0-82.8%) for patients without anastomotic leakage. CONCLUSIONS: All conceivable efforts should be made to avoid anastomotic leakage after colon resection for cancer not only to evade short-term consequences but also to allow for adequate long-term outcome. PMID- 29396328 TI - Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in operable breast cancer: A prospective cohort study. AB - PURPOSE: Diagnostic methods to evaluate the response to neoadjuvant chemotherapy (NAC) for breast cancer have not been established. Dedicated breast PET (DbPET) is a high-resolution molecular breast imaging method, and we investigated the capability of DbPET to predict residual primary tumors after NAC compared with whole-body PET (WBPET). METHODS: Forty-five patients (47 tumors) underwent WBPET and ring-type DbPET after NAC, and the tumors were completely resected between January 2016 and March 2017. The pathological response was classified as complete remission (ypT0), residual intraductal disease (ypTis), or residual invasive disease (ypT >= 1). Standardized uptake value (SUV) and tumor-to-normal tissue ratio (TNR) were assessed. RESULTS: Twelve patients achieved ypT0 and five developed ypTis. DbPET detected all cases of ypTis, and WBPET detected only one case of ypTis. The sensitivity, specificity, and accuracy of WBPET for ypTis and/or ypT >= 1 were 54.3%, 83.3%, and 61.7%, respectively, and those of DbPET were 77.1%, 83.3%, and 78.7%, respectively. In the ypT0/ypTis/ypT >= 1 groups, the median WBPET-SUV, DbPET-SUV, and DbPET-TNR was 1.0/0.9/1.1, 1.7/1.8/2.2, and 1.0/1.6/1.7 (P = .134, .077, and 0.008), respectively. Areas under the curves of WBPET-SUV, DbPET-SUV, and DbPET-TNR for predicting ypTis and/or ypT >= 1 were 0.610, 0.648, and 0.807, respectively. CONCLUSIONS: DbPET was more accurate than WBPET in detecting residual primary tumors after NAC, particularly intraductal carcinoma. TNR was the better parameter for pathological evaluation compared with SUV. PMID- 29396329 TI - The dutch national clinical audit for lung cancer: A tool to improve clinical practice? An analysis of unforeseen ipsilateral mediastinal lymph node involvement in the Dutch Lung Surgery Audit (DLSA). AB - OBJECTIVE: Optimal treatment selection for patients with non-small cell lung cancer (NSCLC) depends on the clinical stage of the disease. Particularly patients with mediastinal lymph node involvement (stage IIIA-N2) should be identified since they generally do not benefit from upfront surgery. Although the standardized preoperative use of PET-CT, EUS/EBUS and/or mediastinoscopy identifies most patients with mediastinal lymph node metastasis, a proportion of these patients is only diagnosed after surgery. The objective of this study was to identify all patients with unforeseen N2 disease after surgical resection for NSCLC in a large nationwide database and to evaluate the preoperative clinical staging process. METHODS: Data was derived from the Dutch Lung Surgery Audit. Patients with pathological stage IIIA NSCLC after an anatomical resection between 2013 and 2015 were evaluated. Clinical and pathological TNM-stage were compared and an analysis was performed on the diagnostic work-up of patients with unforeseen N2 disease. RESULTS: From 3585 patients undergoing surgery for NSCLC between 2013 and 2015, a total of 527 patients with pathological stage IIIA NSCLC were included. Of all 527 patients, 254 patients were upstaged from a clinical N0 (n = 186) or N1 (n = 68) disease to a pathological N2 disease (7.1% unforeseen N2). In these 254 patients, 18 endoscopic ultrasounds, 62 endobronchial ultrasounds and 67 mediastinoscopies were performed preoperatively. CONCLUSIONS: In real world clinical practice in The Netherlands, the percentage of unforeseen N2 disease in patients undergoing surgery for NSCLC is seven percent. To further reduce this percentage, optimization of the standardized preoperative workup is necessary. PMID- 29396330 TI - Diagnosing climate change impacts and identifying adaptation strategies by involving key stakeholder organisations and farmers in Sikkim, India: Challenges and opportunities. AB - Narrowing the gap between research, policy making and implementing adaptation remains a challenge in many parts of the world where climate change is likely to severely impact water security. This research aims to narrow this gap by matching the adaptation strategies being framed by policy makers to that of the perspectives of development agencies, researchers and farmers in the Himalayan state of Sikkim in India. Our case study examined the perspectives of various stakeholders for climate change impacts, current adaptation strategies, knowledge gaps and adaptation barriers, particularly in the context of implementing the Sikkim State Action Plan on Climate Change through semi-structured interviews carried out with decision makers in the Sikkim State Government, researchers, consultants, local academia, development agencies and farmers. Using Stakeholders Network Analysis tools, this research unravels the complexities of perceiving climate change impacts, identifying strategies, and implementing adaptation. While farmers are less aware about the global phenomenon of climate change impacts for water security, their knowledge of the local conditions and their close interaction with the State Government Agriculture Department provides them opportunities. Although important steps are being initiated through the Sikkim State Action Plan on Climate Change it is yet to deliver effective means of adaptation implementation and hence, strengthening the networks of close coordination between the various implementing agencies will pay dividends. Knowledge gaps and the need for capacity building identified in this research, based on the understandings of key stakeholders are highly relevant to both the research community and for informing policy. PMID- 29396331 TI - The influence of air cleaners on indoor particulate matter components and oxidative potential in residential households in Beijing. AB - In many developing regions with poor air quality, the use of air filtration devices to clean indoor air is growing rapidly. In this study, we collected indoor, outdoor and personal exposure filter-based samples of fine particulate matter (PM2.5) with both properly operating, and sham air cleaners in six Beijing residences from July 24th to August 17th, 2016. Mass concentrations of PM2.5 and several health relevant components of PM2.5 including organic carbon, elemental carbon, sulfate, nitrate, ammonium, and 21 selected metals, were analyzed to evaluate the effectiveness of air cleaners. The effect of air purification on PM2.5 reactive oxygen species (ROS) activity, a metric of the oxidative potential of the aerosol, was also evaluated. The average indoor PM2.5 concentration during true filtration was 8.47MUg/m3, compared to 49.0MUg/m3 during sham filtration; thus, air cleaners can significantly reduce the indoor PM2.5 concentration to well below WHO guideline levels and significantly lower all major components of PM2.5. However, the utility of air cleaners in reducing overall personal exposure to PM2.5 and its components was marginal in this study: the average personal exposure PM2.5 concentration was 67.8 and 51.1MUg/m3 during true and sham filtration respectively, and it is likely due to the activity patterns of the subjects. Short-term exposure contributions from environments with high PM2.5 concentrations, including exposure to traffic related emissions as well as uncharacterized indoor microenvironments, likely add substantially to the total PM2.5 exposure burden. The toxicity assay indicates that the air cleaners can also significantly reduce ROS activity in the indoor environment; however, this decrease did not translate to a reduction in personal exposure. Elemental carbon, lead, and arsenic were well-correlated with the ROS activity, thus adding to the knowledge base of drivers for ROS activity. PMID- 29396332 TI - Association between floods and infectious diarrhea and their effect modifiers in Hunan province, China: A two-stage model. AB - BACKGROUND: Understanding the potential links between floods and infectious diarrhea is important under the context of climate change. However, little is known about the risk of infectious diarrhea after floods and what factors could modify these effects in China. OBJECTIVES: This study aims to quantitatively examine the relationship between floods and infectious diarrhea and their effect modifiers. METHODS: Weekly number of infectious diarrhea cases from 2004 to 2011 during flood season in Hunan province were supplied by the National Notifiable Disease Surveillance System. Flood and meteorological data over the same period were obtained. A two-stage model was used to estimate a provincial average association and their effect modifiers between floods and infectious diarrhea, accounting for other confounders. RESULTS: A total of 134,571 cases of infectious diarrhea were notified from 2004 to 2011. After controlling for seasonality, long term trends, and meteorological factors, floods were significantly associated with infectious diarrhea in the provincial level with a cumulative RR of 1.22 (95% CI: 1.05, 1.43) with a lagged effect of 0-1 week. Geographic locations and economic levels were identified as effect modifiers, with a higher impact of floods on infectious diarrhea in the western and regions with a low economic level of Hunan. CONCLUSIONS: Our study provides strong evidence of a positive association between floods and infectious diarrhea in the study area. Local control strategies for public health should be taken in time to prevent and reduce the risk of infectious diarrhea after floods, especially for the vulnerable regions identified. PMID- 29396334 TI - Total systemic failure? AB - While the world argues about whether climate change is real, what if all systems are failing? This paper seeks to ignite further discussion concerning human impact on all aspects of our environment as we move further into the Anthropocene, not only in terms of the pressure we produce, but also how our activity changes the nature of the relationships between Earth's systems. The paper suggests that we currently lack the tools and analytical capacity to understand the significance of these changes and therefore we cannot answer the question, "are all systems failing?". We discuss how complexity theory, complex networks, and Artificial Intelligence, could contribute part of a solution. PMID- 29396333 TI - Spatial variation of mercury bioaccumulation in bats of Canada linked to atmospheric mercury deposition. AB - Wildlife are exposed to neurotoxic mercury at locations distant from anthropogenic emission sources because of long-range atmospheric transport of this metal. In this study, mercury bioaccumulation in insectivorous bat species (Mammalia: Chiroptera) was investigated on a broad geographic scale in Canada. Fur was analyzed (n=1178) for total mercury from 43 locations spanning 20 degrees latitude and 77 degrees longitude. Total mercury and methylmercury concentrations in fur were positively correlated with concentrations in internal tissues (brain, liver, kidney) for a small subset (n=21) of little brown bats (Myotis lucifugus) and big brown bats (Eptesicus fuscus), validating the use of fur to indicate internal mercury exposure. Brain methylmercury concentrations were approximately 10% of total mercury concentrations in fur. Three bat species were mainly collected (little brown bats, big brown bats, and northern long-eared bats [M. septentrionalis]), with little brown bats having lower total mercury concentrations in their fur than the other two species at sites where both species were sampled. On average, juvenile bats had lower total mercury concentrations than adults but no differences were found between males and females of a species. Combining our dataset with previously published data for eastern Canada, median total mercury concentrations in fur of little brown bats ranged from 0.88-12.78MUg/g among 11 provinces and territories. Highest concentrations were found in eastern Canada where bats are most endangered from introduced disease. Model estimates of atmospheric mercury deposition indicated that eastern Canada was exposed to greater mercury deposition than central and western sites. Further, mean total mercury concentrations in fur of adult little brown bats were positively correlated with site-specific estimates of atmospheric mercury deposition. This study provides the largest geographic coverage of mercury measurements in bats to date and indicates that atmospheric mercury deposition is important in determining spatial patterns of mercury accumulation in a mammalian species. PMID- 29396335 TI - A study of the in-situ CO2 removal pyrolysis of Chinese herb residue for syngas production. AB - The in-situ CO2 removal pyrolysis of Chinese herb residue was studied by thermodynamic equilibrium simulation and experimental methods. The effects of temperature, pressure, and CaO loading on the gas composition, heating value and yield were determined. The simulation results indicate that the heating value of product gas increases with the increase of Ca/H and pressure, and slightly decreases with the increase of temperature. The simulation results were verified by the experiments conducted with a micro fixed-bed reactor. Under the simulated reaction conditions including atmospheric pressure, reaction temperature of 700 degrees C and the Ca/H of 0.65, the CO2 in the product gas was effectively removed, resulting the syngas with a high heating value. The product gas was mainly composed of H2, CO, CO2 and CH4 with the contents of 47.52, 22.04, 9.01 and 14.02 respectively by experiment. And the lower heating value of the product gas reached 18.1 MJ/Nm3. PMID- 29396336 TI - Alteration parameters affecting the Luxor Avenue of the Sphinxes-Egypt. AB - Stone alteration in the environment is caused by various extrinsic disintegration agents, besides, their intrinsic properties "mineralogical composition, textures and internal structure". Therefore, the purpose of the current study was to evaluate the weathering state affecting the Luxor Avenue of the Sphinxes by studying its chemical, mineralogical and physio-mechanical characteristics, in addition to morphological features. Scientific techniques, such as X-ray fluorescence (XRF), X-ray diffraction (XRD), Petrographical microscopy (PM), Cathodoluminescence (CL), Environmental Scanning Electron Microscope (ESEM) and micro energy-dispersive X-ray fluorescence (MU-EDXRF) were used. The results showed that quartz represents more than 96% of the sandstones and the main cement of the grains is quartz overgrowth. Alteration and formation of kaolinite was clearly observed. Halite, sylvite and bischofite were the main salts that affected the statues representing approx. 78.40%. The study also provided information about the different deterioration factors affected the Avenue of the Sphinxes namely; burial environment, solar effects, soil moisture and groundwater. These caused some deterioration forms such as soiling & crusting, breaking down most of the statues heads, saturation forms, salt crystallizations and stone abrasion. Cleaning, desalination and consolidation using different materials and techniques, in addition to reducing the human anthropogenic impacts are recommended for future conservation of the Luxor Avenue of the Sphinxes. PMID- 29396337 TI - A critical perspective on early communications concerning human health aspects of microplastics. AB - Microplastic research in recent years has shown that small plastic particles are found almost everywhere we look. Besides aquatic and terrestrial environments, this also includes aquatic species intended for human consumption and several studies have reported their prevalence in other food products and beverages. The scientific as well as public debate has therefore increasingly focused on human health implications of microplastic exposure. However, there is a big discrepancy between the magnitude of this debate and actual scientific findings, which have merely shown the presence of microplastics in certain products. While plastics can undoubtedly be hazardous to human health due to toxicity of associated chemicals or as a consequence of particle toxicity, the extent to which microplastics in individual food products and beverages contribute to this is debatable. Considering the enormous use of plastic materials in our everyday lives, microplastics from food products and beverages likely only constitute a minor exposure pathway for plastic particles and associated chemicals to humans. But as this is rarely put into perspective, the recent debate has created a skewed picture of human plastic exposure. We risk pulling the focus away from the root of the problem: the way in which we consume, use and dispose of plastics leading to their widespread presence in our everyday life and in the environment. Therefore we urge for a more careful and balanced discussion which includes these aspects. PMID- 29396338 TI - Life cycle assessment of pyrolysis, gasification and incineration waste-to-energy technologies: Theoretical analysis and case study of commercial plants. AB - Municipal solid waste (MSW) pyrolysis and gasification are in development, stimulated by a more sustainable waste-to-energy (WtE) option. Since comprehensive comparisons of the existing WtE technologies are fairly rare, this study aims to conduct a life cycle assessment (LCA) using two sets of data: theoretical analysis, and case studies of large-scale commercial plants. Seven systems involving thermal conversion (pyrolysis, gasification, incineration) and energy utilization (steam cycle, gas turbine/combined cycle, internal combustion engine) are modeled. Theoretical analysis results show that pyrolysis and gasification, in particular coupled with a gas turbine/combined cycle, have the potential to lessen the environmental loadings. The benefits derive from an improved energy efficiency leading to less fossil-based energy consumption, and the reduced process emissions by syngas combustion. Comparison among the four operating plants (incineration, pyrolysis, gasification, gasification-melting) confirms a preferable performance of the gasification plant attributed to syngas cleaning. The modern incineration is superior over pyrolysis and gasification melting at present, due to the effectiveness of modern flue gas cleaning, use of combined heat and power (CHP) cycle, and ash recycling. The sensitivity analysis highlights a crucial role of the plant efficiency and pyrolysis char land utilization. The study indicates that the heterogeneity of MSW and syngas purification technologies are the most relevant impediments for the current pyrolysis/gasification-based WtE. Potential development should incorporate into all process aspects to boost the energy efficiency, improve incoming waste quality, and achieve efficient residues management. PMID- 29396339 TI - Environmental assessments on schools located on or near former industrial facilities: Feedback on attenuation factors for the prediction of indoor air quality. AB - One of the goals of the French national campaign called "Etablissements Sensibles (Sensitive Establishments)" is to evaluate indoor air degradation in schools because of vapor intrusion of volatile compounds from soil gases towards the indoor air, related to the presence of former industrial sites on or near the establishment. During this campaign, as recommended by the United States of Environmental Protection Agency (US EPA), indoor air quality was evaluated from soil gas concentrations using generic attenuation factors, and extra investigations into soil gases and indoor air were performed when the estimated values exceeded target indoor air concentrations. This study exploits matched data on subsurface soil gases and indoor air that came from the "Sensitive Establishments" campaign. It aims to consolidate and refine the use of attenuation factors as a function of environmental variables acquired routinely during environmental assessments. We have been able to select the measured environmental variables that have the most influence on vapor intrusion using Principal Components Analysis and hypotheses tests. Since the collected data are mainly related to weak sources (only 15% schools required risk management measures related to vapor intrusion), halogenated volatile organic compounds (HVOC) were selected as tracer compounds for vapor intrusion for this study. This choice enables the exclusion or minimization of background sources contributions. From the results we have calculated the descriptive statistics of the attenuation factors distribution for the subslab-to-indoor air pathway and refined the attenuation factors for this pathway through an easily obtained parameter, building age. Qualitative comparison of attenuation factors according to the building age shows that attenuation factors observed for building less than 50 years are lower than attenuation factors for buildings 50 years old and above. These results show the utility of creating databases for consolidating and refining attenuation factors and therefore improving their use. PMID- 29396340 TI - Fluvial dissolved organic carbon composition varies spatially and seasonally in a small catchment draining a wind farm and felled forestry. AB - Assessing whether land use, from activities such as wind farm construction and tree-felling, impacts on terrestrial C delivery to rivers has focused on quantifying the loss of dissolved organic carbon (DOC), and not the composition changes. Here we explore how land use influences DOC composition by considering fluvial DOC concentration, [DOC], and spectrophotometric composition of a river draining a peat-rich catchment. We find that in this 5.7km2 catchment differences occur in both the concentration and composition of the DOC in its sub-catchments. This is attributed to differences in how land was used: one tributary (D-WF) drains an area with wind farm construction and forestry in the headwaters, and one tributary (D-FF) drains an area with felled plantation trees. Generally, [DOC] in both streams showed similar seasonal variation, and autumn maxima. However, the felled catchment had greater mean [DOC] than the wind farm catchment. The SUVA254 and E4/E6 indicated DOC in both streams had similar aromaticity and fulvic:humic acid for most of the time, but SUVA410 and E2/E4 indicated less DOC humification in the felled catchment. This may be due to young DOC from the breakdown of residual branches and roots, or more humification in soils in the wind farm area. During the dry months, DOC composition showed more spatial variation: the D-WF DOC had smaller SUVA254 (less total aromatic material) and SUVA410 (fewer humic substances). The decreased E2/E4 in both streams indicated the total aromatic carbon decreased more than humic substances content. Moreover, the larger E4/E6 for D-WF in summer indicated that the humic substances were richer in fulvic acids than humic acids. Soil disturbance associated with forestry-felling likely contributed to the higher [DOC] and release of less-humified material in D-FF. This research indicates drivers of different DOC concentration and composition can exist even in small catchments. PMID- 29396341 TI - Environmental impacts of the Chennai oil spill accident - A case study. AB - Chennai, a coastal city in India with a population of over 7 million people, was impacted by a major oil spill on January 28th 2017. The spill occurred when two cargo ships collided about two miles away from the Chennai shoreline. The accident released about 75 metric tons of heavy fuel oil into the Bay of Bengal. This case study provides field observations and laboratory characterization data for this oil spill accident. Our field observations show that the seawalls and groins, which were installed along the Chennai shoreline to manage coastal erosion problems, played a significant role in controlling the oil deposition patterns. A large amount of oil was trapped within the relatively stagnant zone near the seawall-groin intersection region. The initial cleanup efforts used manual methods to skim the trapped oil and these efforts indeed helped recover large amount of oil. Our laboratory data show that the Chennai oil spill residues have unique fingerprints of hopanes and steranes which can be used to track the spill. Our weathering experiments show that volatilization processes should have played a significant role in degrading the oil during initial hours. The characterization data show that the source oil contained about 503,000 mg/kg of total petroleum hydrocarbons (TPH) and 17,586 mg/kg of total polycyclic aromatic hydrocarbons (PAHs). The field samples collected 6 and 62 days after the spill contained about 71,000 and 28,000 mg/kg of TPH and 4854 and 4016 mg/kg of total PAHs, respectively. The field samples had a relatively large percentage of heavy PAHs, and most of these PAHs are highly toxic compounds that are difficult to weather and their long-term effects on coastal ecosystems are largely unknown. Therefore, more detailed studies are needed to monitor and track the long term environmental impacts of the Chennai oil spill residues on the Bay of Bengal coastal ecosystem. PMID- 29396342 TI - Modeling individual exposures to ambient PM2.5 in the diabetes and the environment panel study (DEPS). AB - Air pollution epidemiology studies of ambient fine particulate matter (PM2.5) often use outdoor concentrations as exposure surrogates, which can induce exposure error. The goal of this study was to improve ambient PM2.5 exposure assessments for a repeated measurements study with 22 diabetic individuals in central North Carolina called the Diabetes and Environment Panel Study (DEPS) by applying the Exposure Model for Individuals (EMI), which predicts five tiers of individual-level exposure metrics for ambient PM2.5 using outdoor concentrations, questionnaires, weather, and time-location information. Using EMI, we linked a mechanistic air exchange rate (AER) model to a mass-balance PM2.5 infiltration model to predict residential AER (Tier 1), infiltration factors (Finf_home, Tier 2), indoor concentrations (Cin, Tier 3), personal exposure factors (Fpex, Tier 4), and personal exposures (E, Tier 5) for ambient PM2.5. We applied EMI to predict daily PM2.5 exposure metrics (Tiers 1-5) for 174 participant-days across the 13 months of DEPS. Individual model predictions were compared to a subset of daily measurements of Fpex and E (Tiers 4-5) from the DEPS participants. Model predicted Fpex and E corresponded well to daily measurements with a median difference of 14% and 23%; respectively. Daily model predictions for all 174 days showed considerable temporal and house-to-house variability of AER, Finf_home, and Cin (Tiers 1-3), and person-to-person variability of Fpex and E (Tiers 4-5). Our study demonstrates the capability of predicting individual-level ambient PM2.5 exposure metrics for an epidemiological study, in support of improving risk estimation. PMID- 29396343 TI - Seasonal changes impact soil bacterial communities in a rubber plantation on Hainan Island, China. AB - Rubber plantations have expanded rapidly over the past 20 years in tropical Asia and their impacts on regional ecosystems have garnered much concern. While much attention has been given to the negative impacts on aboveground diversity and function, the belowground bacterial soil community has received much less attention. Here, we investigated the community composition and diversity of soil bacteria of rubber plantations on Hainan Island in south China. The goals of the study were to describe changes in bacterial compositions and diversity across seasons. We found that seasonality defined by differences in rainfall amount strongly influenced bacterial communities. At both the Phylum and Family levels, we found significant differences in the total number of taxa, as well as the composition of the community as a function of season. Diversity of soil samples in the dry-rainy season was highest of three seasons, suggesting that bacterial structure was more sensitive in alternate periods of season. Diversity in the rainy season was substantial lower than in dry season. Results from a redundancy analysis showed that seasonal changes explained the largest part (31.9%) of the total variance of bacterial community composition. In conclusion, seasonal change had the greatest influence on bacterial communities, which overshadowed the effects of soil nutrient as well as other factors, and controls the bacterial communities in soils of RP in tropical region of Hainan. PMID- 29396344 TI - Prevalence of antibiotic resistance genes in bacteriophage DNA fraction from Funan River water in Sichuan, China. AB - To better understand the role that bacteriophages play in antibiotic resistance genes (ARGs) dissemination in the aquatic environment, 36 water samples were collected from the Funan River in Sichuan, China. The occurrence of 15 clinically relevant ARGs and one class 1 integron gene int1 in phage-particle DNA were evaluated by PCR. The abundance of ARGs (blaCTX-M, sul1, and aac-(6')-1b-cr) was determined by quantitative PCR (qPCR). High prevalence of the int1 gene (66.7%) was found in the phage-particle DNA of tested samples, followed by sul1 (41.7%), sul2 (33.3%), blaCTX-M (33.3%), aac-(6')-lb-cr (25%), aph(3')-IIIa (16.7%), and ermF (8.3%). The qPCR data showed higher gene copy (GC) numbers in samples collected near a hospital (site 7) and a wastewater treatment plant (WWTP) (site 10) (P < .05). Particularly the absolute abundance of aac-(6')-lb-cr gene was significantly higher than the blaCTX-M and sul1 genes with the gene copy (GC) numbers of 5.73 log10 copy/mL for site 7 and 4.99 log10 copy/mL for site 10. To our best knowledge, this is the first study to report the presence of sul2, aac (6')-lb-cr, ermF and aph(3')-IIIa genes in bacteriophage DNA derived from aquatic environments. Our findings highlight the potential of ARGs to be transmitted via bacteriophages in the aquatic environment. PMID- 29396345 TI - Beryllium-7 in vegetation, soil, sediment and runoff on the northern Loess Plateau. AB - Beryllium-7 (7Be), as a potentially powerful tracer, was widely used to document soil redistribution and identify sediment sources in recent decades, but the quantity and distribution of 7Be in vegetation, soil, sediment and runoff on the Loess Plateau have not been fully described. In this study, we measured 7Be in vegetation, soil, sediment and runoff on the northern Loess Plateau of China and analyzed its variations during the rainy season to assess the potential of the 7Be method for documenting soil redistribution and identifying sediment sources in a wide range of environments. The results indicated that vegetation, soil, and sediment samples showed higher levels and larger variations of 7Be activities during the rainy season. The drying plants showed 7Be mass activity that was more than three times higher than that of living and semi-decomposed plants. 7Be mass activity in plants and sediment was much higher than in the soil. 7Be activity in runoff water with a few submicron suspended particles varied slightly and was far lower than in plant, soil and sediment samples. The cumulative precipitation generally determined 7Be inventory held by plants and soil. An inverse relationship was found between the 7Be mass activity in sediment and the sediment amount. Globally, approximate 30% of the total 7Be was held by plants in both the herbaceous and subshrub plots. Approximate 10% of the total 7Be was lost with sediment from the bare plot. A very small proportion of 7Be (1.18%-3.20%) was lost with runoff, and the vast majority of 7Be was retained in the slope soil at the end of rainy season. Vegetation cover and soil erosion significantly affected the spatial distribution and variations of the 7Be inventory in soil, providing a necessary condition for the development of a 7Be method to document soil erosion on slopes with vegetation. PMID- 29396346 TI - Beneficial effects of restoration practices can be thwarted by climate extremes. AB - The impacts of climate extremes on species, communities and ecosystems have become critical concerns to science and society. Under a changing climate, how restoration outcomes are affected by extreme climate variables is a largely unknown topic. We analyzed the effects of experimental factors (grazing and sowing of native species), extreme climate events (intense precipitation and extreme temperatures indexes) and their combination on the restoration progress of a dry, calcareous grassland in Tuscany (Italy) with a 1 year before/15 years continuous annual monitoring after, control/impact (BACI) experiment. Grazing had a beneficial effect on the diversity of the grassland, while sowing had a limited impact. The climatic index that most affected the entire plant community composition was the number of very heavy precipitation days. The interaction of grazing and extreme climatic indexes had a significant detrimental effect on restoration outcomes, increasing the cover of synanthropic and Cosmopolitan Subcosmopolitan generalist species and decreasing the cover of more valuable species such endemic species. In the richest grazed plots, species richness showed a lower sensitivity to the average precipitation per wet day but in grazed site, restoration outcomes can be negatively influenced by the intensification of precipitation and temperature extremes. In a context of progressive tropicalization of the Mediterranean area, to assist managers setting achievable restoration goals, restoration practitioners should consider that climate extremes might interfere with the beneficial effects of restoration practices. PMID- 29396347 TI - Enantioselective effects of chiral amide herbicides napropamide, acetochlor and propisochlor: The more efficient R-enantiomer and its environmental friendly. AB - Amide herbicides, which are used extensively worldwide, are often chiral. Enantiomeric selectivity comes from the different effects of the enantiomers on target and non-target organisms. In this study, the enantiomers of three amide herbicides were purified by the semi-preparative column and were used to investigate the enantioselective effects on target Echinochloa crusgalli (lowland rice weeds), and non-target Microcystis aeruginosa, and the yeast transformed with the human TRbeta plasmid organisms. The results showed that (i) the R enantiomers of the three amide herbicides exhibited the strongest activity toward weed inhibition and the lowest toxicity toward non-target organisms; (ii) napropamide was better suited for controlling root growth, while acetochlor and propisochlor were better for leaves control; (iii) herbicides at certain low concentrations (0.01 mg L-1 for acetochlor and propisochlor) could be utilized to promote plant growth. These findings encourage the use of R-amide herbicides instead of their racemates to increase the efficiency of weed control and reduce the risk to non-target organisms. On the other hand, the adverse effects are caused mostly by S-enantiomer, using R-enantiomer-enriched products may offer great environmental/ecological benefits. PMID- 29396348 TI - Risk assessment of human exposure to Ra-226 in oil produced water from the Bakken Shale. AB - Unconventional oil production in North Dakota (ND) and other states in the United States uses large amounts of water for hydraulic fracturing to stimulate oil flow. Most of the water used returns to the surface as produced water (PW) containing different constituents. Some of these contents are total dissolved solids and radionuclides. The most predominant radionuclide in PW is radium-226 (Ra-226) of which level depends on several factors including the content of certain cations. A multivariate regression model was developed to predict Ra-226 in PW from the Bakken Shale based on the levels of barium, strontium, and calcium. The simulated Ra-226 activity concentration in PW was 535 pCi/L supporting extremely limited actual data based on three PW samples from the Bakken (527, 816, and 1210 pCi/L). The simulated activity concentration was further analyzed by studying its impact in the event of a PW spill reaching a surface water body that provides drinking water, irrigation water for crops, and recreational fishing. Using food transfer factors found in the literature, the final annual effective dose rate for an adult in ND was estimated. The global average annual effective dose rate via food and drinking water is 0.30 mSv, while the predicted dose rate in this study was 0.49 mSv indicating that there is potential risk to human health in ND due to Ra-226 in PW spills. This predicted dose rate is considered the best case scenario as it is based on the simulated Ra 226 activity concentration in PW of 535 pCi/L which is close to the low end actual activity concentration of 527 pCi/L. PMID- 29396349 TI - Assessing the efficiency of a coastal Managed Aquifer Recharge (MAR) system in Cyprus. AB - Managed Aquifer Recharge (MAR) is becoming an attractive water management option, with more than 223 sites operating in European countries. The quality of the produced water, available for drinking or irrigation processes is strongly depended on the aquifer's hydrogeochemical characteristics and on the MAR system design and operation. The objective of this project is the assessment of the operation efficiency of a MAR system in Cyprus. The coupling of alternative methodologies is used such as water quality monitoring, micro-scale sediment sorption experiments, simulation of groundwater flow and phosphate and copper transport in the subsurface using the FEFLOW model and evaluation of the observed change in the chemical composition of water due to mixing using the geochemical model PHREEQC. The above methodology is tested in the Ezousa MAR project in Cyprus, where treated effluent from the Paphos Waste Water Treatment Plant, is recharged into the aquifer through five sets of artificial ponds along the riverbed. Additionally, groundwater is pumped for irrigation purposes from wells located nearby. A slight attenuation of nutrients is observed, whereas copper in groundwater is overcoming the EPA standards. The FEFLOW simulations reveal no effective mixing in some intermediate infiltration ponds, which is validated by the inverse modeling simulation of the PHREEQC model. Based on the results, better control of the infiltration capacity of some of the ponds and increased travel times are some suggestions that could improve the efficiency of the system. PMID- 29396350 TI - Anthropogenic contribution and influencing factors on metal features in fluvial sediments from a semi-arid Mediterranean river basin (Tafna River, Algeria): A multi-indices approach. AB - Metals in river sediments from a semi-arid Mediterranean basin were investigated from upstream to downstream during contrasting hydrological conditions in 2014 and 2015. The level and origin of the contamination were evaluated using several geochemical and isotopic indicators. Elements were grouped by their level of contamination: high (Pb > Cd > Zn > Cu) and low (Al, Fe, Cr, Co, Ni). Multiple local sources of contamination were identified (industrial, agricultural and domestic waste), as well as very specific ones (gasoline station) and diffuse pollution from atmospheric deposition (gasoline, ores, aerosols). During storm events, the upstream dams can either be secondary sources of contamination or dilutors through particles derived from natural erosion. The contamination was slowed downstream due to the river geomorphology, but eventually washed into the Mediterranean Sea by intense storm events. Naturally derived elements (Co, Ni, Cr, As) were associated with Al, Fe and Mn oxides or clays, and anthropogenic originated metals with phosphorus (Cd and Zn), sulphur (Cu) and POC (Pb enrichment). Cadmium and Pb were the most available metals upstream and at the outlet, but their availability was not strictly related to their degree of contamination. These conclusions could be drawn thanks to an approach by multiple indicators. PMID- 29396351 TI - Spatial and temporal variability of carbon budgets of shallow South African subtropical estuaries. AB - Estuarine carbon fluxes constitute a significant component of coastal CO2 emissions and nutrients recycling, but high uncertainty is still present due to the heterogeneity of these areas. Although South Africa has nearly 300 estuaries, very little is known about their contribution to carbon emissions or sequestration. This study aims to provide a first estimation of the carbon emissions and nutrient fluxes of South African sub-tropical estuaries through a direct quantification of respiration, primary production and nutrient regeneration of benthic and planktonic communities. In order to account for the extreme variability in subtropical estuarine areas, due to seasonality in rainfall, two estuaries with opposite characteristics were studied; the temporarily open/closed Mdloti Estuary subjected to strong anthropic pressure, and the permanently open Mlalazi Estuary located in a natural reserve. Field deployment of benthic chambers and clear/dark bottles assessed oxygen, ammonia and phosphate fluxes of both benthic and planktonic communities. An inverse pattern between benthic and pelagic primary production was found in both estuaries. Different drivers related to mouth status and sediment characteristics were identified in the two estuaries. The annual average carbon emission indicates that the two systems are heterotrophic over the year releasing substantial CO2 emissions into the atmosphere. Results show that carbon fluxes in subtropical estuaries are extremely variable in space and time. Future up-scaling carbon estimations need to account for those small scale and regional dynamics. PMID- 29396352 TI - Risk of high-risk human papillomavirus infection and cervical precancerous lesions with past or current trichomonas infection: a pooled analysis of 25,054 women in rural China. AB - BACKGROUND: Trichomonas vaginitis (TV) infection has obviously been implicated in gynecological morbidity but still unclear in cervical lesions. OBJECTIVE: To evaluate the risk of hr-HPV infection and cervical intraepithelial neoplasia grade 2 or worse (CIN2 + ) by TV infection. STUDY DESIGN: The pooled study was conducted among 12 population-based, cervical cancer screening studies throughout China (N = 24,054). HPV was detected by Hybrid Capture(r)2 (HC2) test. Past TV infection was measured by self-reporting, current TV infection was diagnosed by liquid-based cytology (LBC), cervical lesions was diagnosed by histopathology. RESULTS: Respective prevalence of hr-HPV and CIN2+ were 17.4% and 3.3%. Out of 24,054 women, 14.6% reported past TV infection, and out of 11,853 women, 9.9% had current TV infection. Current TV-positive women had an increased risk for hr-HPV (OR 1.31, 95%CI: 1.11-1.56). The risk of CIN2+ decreased for hr-HPV positive women with current TV infection (adjusted OR 0.50, 95% CI: 0.30-0.84) and past TV infection (adjusted OR 0.68, 95% CI: 0.54-0.86). Among hr-HPV negative women, no significant associations were observed between past or current TV infection and risk of CIN2+. CONCLUSIONS: Women infected with HPV are more likely to be infected by other types of sexually transmitted diseases. Current TV-positive women had an increased risk for hr-HPV infection compared to currently TV negative women. Both past and current TV-positive women had a decreased risk for CIN2+, especially among high-risk HPV positive women. More direct investigation into the interaction between TV, HPV, inflammatory signals, and risk of carcinogenesis are further needed. PMID- 29396353 TI - Enterovirus-D68 (EV-D68) in pediatric patients with respiratory infection: The circulation of a new B3 clade in Italy. AB - BACKGROUND: In recent years, several outbreaks due to Enterovirus D-68 (EV-D68) have been reported, and it was confirmed that the virus can cause upper and lower respiratory tract diseases and be associated with the development of neurological problems. OBJECTIVES: The main aim of this research was to study the genetic characteristics of EV-D68 strains that were circulating in Italy identified during an outbreak of an EV-D68 infection that occurred in Italy during the period March-October 2016. STUDY DESIGN: A retrospective study of the circulation of different types and subtypes of EV-D68 was performed. Nasopharyngeal swabs were collected from March 2016 through October 2016 in children admitted to the Emergency Room with respiratory diseases. RESULTS: Among 390 children, 22 (59.1% males; mean age 47 months) were found to be infected by EV-D68 and most of them were immunocompetent (72.7%). Pneumonia was diagnosed in 12 (54.5%) children. Phylogenetic analysis of the VP1 region showed that all the strains identified in this study belonged to clade B3. Within B3 subclade, the Italian EV-D68 strains were most closely related to strains detected in Southern China in 2015 as well as to strains detected in US and the Netherlands in 2016. CONCLUSIONS: These results showed that EV-D68 infections are a common cause of lower respiratory illness in pediatric age. The circulation of one EV-D68 lineage has been proven in Italy and in the European region during 2016. However, further studies are required to investigate whether some strains or lineages may possess a higher affinity for the lower airway or central nervous system. PMID- 29396354 TI - Utility of the Abbott RealTime HCV Genotype Plus RUO assay used in combination with the Abbott RealTime HCV Genotype II assay. AB - BACKGROUND: Hepatitis virus C (HCV) genotype (GT) determination and subtype (ST) differentiation (1a versus 1b) remain important for the selection of appropriate direct-acting antiviral (DAA) therapy. OBJECTIVES: This study is a retrospective comparison of HCV GT and ST result distribution when using the Abbott RealTime HCV Genotype II assay (HCVGT II) alone and in combination with the Abbott RealTime HCV Genotype Plus RUO assay (HCVGT Plus) for routine testing of clinical serum specimens at a reference laboratory. STUDY DESIGN: HCVGT II results of specimens tested from June 2014 through January 2016 (period 1) were compared with combined results from HCVGT II and HCVGT Plus (HCVGT II/Plus) performed from January 2016 through January 2017 (period 2). RESULTS: A total of 44,127 and 25,361 specimens were tested during periods 1 and 2, respectively. Use of HCVGT II/Plus significantly reduced the frequency of GT 1 results without ST (0.4%) when compared to preliminary HCVGT II results during period 2 (5.3%; p < 0.01) and final HCVGT II results in period 1 (5.5%; p < 0.01). HCVGT II/Plus also resulted in GT 6 reactivity in 38 specimens with results of "HCV detected" (n = 17) or GT 1 (n = 21) following initial HCVGT II testing during period 2. CONCLUSIONS: When compared to the use of HCVGT II alone, HCVGT II/Plus significantly reduced the frequency of GT 1 without ST results observed in a large reference laboratory, while also enabling the identification of HCV GT 6. PMID- 29396355 TI - Development of the perceived stigma scale and the concealment of epilepsy scale for the Turkish population. AB - The aim of this study was to develop two culture-specific scales to measure the level of felt stigma, and level of concealment of Turkish adult people with epilepsy (PWE). For this purpose, a 10-item felt-stigma scale and a 17-item disclosure of epilepsy scale were developed and then applied to 200 adult PWE. After item and factor analyses of the stigma scale, the 10 items with a one factor solution explained 45.6% of the variance with a 0.86 internal consistency value. Higher scores represent higher felt stigma. The concealment of epilepsy scale has 17 items loaded on one factor, which explained 45.1% of the variance. Cronbach's alpha coefficient was found to be 0.92. The higher the score, the higher the concealment of illness by the participant. For convergent validity, the relationship between stigma and disclosure scales was examined, and a positive significant relation (r=0.64, p<0.000) was found. PMID- 29396356 TI - SPECT perfusion changes during ictal automatisms with preserved responsiveness in patients with right temporal lobe epilepsy. AB - Ictal automatism with preserved responsiveness (APR) has been reported, particularly in nondominant temporal lobe epilepsy (TLE), but its pathophysiology remains poorly understood. This study sought to investigate the relationship between APRs and increased cerebral blood flow (CBF) using ictal single photon emission computed tomography (SPECT) in TLE. Forty-seven subjects with right mesial TLE (15 with and 32 without APR) were enrolled. Patients with APR (APR+) were subdivided into four groups according to degree of responsiveness during seizures. Cerebral blood flow changes during these seizures were semiquantitatively assessed by subtraction ictal SPECT coregistered to MRI (SISCOM). Hyperperfusion in temporal regions did not vary significantly between the APR+ and APR- groups. Cerebral blood flow changes in the frontal area, insula, cingulum, and occipital area were also nonsignificant. However, hyperperfusion in the ipsilateral parietal areas was more frequent in the APR- group than in the APR+ group. Furthermore, hyperperfusion of the contralateral basal ganglia showed an inclination to be more common in the APR- group, but without statistical significance. The study suggested that the involvement of the parietal association cortex during seizure may play an important role in ictal loss of consciousness in TLE. Further studies will be needed to elucidate the pathophysiology of changes in consciousness during temporal lobe seizures. PMID- 29396357 TI - Quality of life in Malaysian children with epilepsy. AB - BACKGROUND: Children with epilepsy (CWE) are at risk of impaired quality of life (QOL), and achieving a good QOL is an important treatment goal among CWE. To date, there are no published multiethnic QOL studies in Asia. Our study aimed to: i) investigate the QOL of multiethnic CWE in Malaysia as reported by both the child and parent; ii) determine the level of agreement between child-self report and parent-proxy report QOL; and iii) explore potential correlates of sociodemographic, epilepsy characteristics, and family functioning with QOL in CWE. METHODS: Cross-sectional study of all CWE aged 8-18years old with at least 6months' duration of epilepsy, minimum reading level of primary school education Year 1, and attending mainstream education. Quality of life was measured using the parent-proxy and child self-report of Quality of Life Measurement for Children with Epilepsy (CHEQOL-25) questionnaire. Total and subscale CHEQOL-25 scores were obtained. The levels of parent-child agreement were determined using intraclass correlation coefficients (ICC). Family functioning was assessed using the General functioning subscale (GF-12). RESULTS: A total of 115 CWE and their parents participated in the study. In general, Malaysian parents rated children's total CHEQOL-25 scores poorer than the children themselves [mean total parent score: 68.56 (SD: 10.86); mean total child score: 71.82 (SD: 9.55)]. Agreement between child and parent on the CHEQOL-25 was poor to moderate (ICC ranged from 0.31-0.54), with greatest discordance in the epilepsy secrecy domain (ICC=0.31, p=0.026). Parent and child were more likely to agree on more external domains: intrapersonal/social (ICC=0.54, p<0.001) and interpersonal/emotional (ICC=0.50, p<0.001). Malay ethnicity, focal seizure and high seizure frequency (>=1 seizure per month) were associated with lower CHEQOL-25 scores. There was a significant but weak correlation between GF-12 and parent-proxy CHEQOL-25 Total Scores (r= 0.186, p=0.046). CONCLUSION: Our results emphasize the importance to have the child's perspective of their QOL as the level of agreement between the parent and child reported scores were poor to moderate. Malaysian CWE of Malay ethnicity, those with focal seizures or high seizure frequency are at risk of poorer QOL. PMID- 29396358 TI - Impact of sleep disorders on the risk of seizure recurrence in juvenile myoclonic epilepsy. AB - OBJECTIVE: The aim of this study was to investigate the presence of sleep disturbances in patients with juvenile myoclonic epilepsy (JME) using sleep questionnaires. Further, we tried to evaluate whether alterations in sleep quality may influence the clinical expression of JME. METHODS: Sixty-two patients with JME treated with levetiracetam were included. Demographic and clinical variables were collected. Moreover, all patients submitted the Pittsburgh Sleep Quality index (PSQI) and the Epworth Sleepiness Scale (ESS) in order to respectively assess sleep quality during the last month and daytime sleepiness. All patients were followed up for a 6-month period and divided in two groups: seizure-free (Group 1) and seizure recurrence (Group 2). The PSQI and ESS scores were synthesized as binary variables <5/>=5 and <10/>=10, respectively. A comprehensive analysis was performed to evaluate the independent effect of the sleep quality and daytime sleepiness on the risk of having seizures during the follow-up. RESULTS: Both reduced sleep quality during the last month and daytime sleepiness were associated with an increased risk of suffering from seizures during the follow-up period. In fact, a PSQI score<5 or an ESS score<10 resulted significantly associated with the absence of seizure recurrence (p<0.004 and p<0.001, respectively). Increasing age had a significantly protective effect in the risk of seizure relapse. CONCLUSIONS: Our findings show that reduced sleep quality and daytime sleepiness in patients with JME increase the risk of seizure occurrence in spite of an appropriate pharmacological treatment. This negative effect seems to be more relevant in younger patients. Sleep disorders and their specific correction should be taken into consideration for the management of patients with JME. PMID- 29396359 TI - Efficacy and tolerability of adjuvant lacosamide: The role of clinical characteristics and mechanisms of action of concomitant AEDs. AB - OBJECTIVE: The objective of this study was to analyze the effectiveness and long term tolerability of adjuvant lacosamide (LCM) in a multicenter cohort. We aim to assess outcomes of LCM-containing antiepileptic drug (AED) combinations based upon 'mechanism of action' (MoA) and patient's clinical features. METHODS: Consecutive patients commenced on LCM, with focal epilepsy were identified from three Australian hospitals. The 12-month efficacy endpoints were greater than 50% reduction in seizure frequency (responders) and seizure freedom. Tolerability endpoints were cessation of LCM for any reason, cessation due to side-effects and censoring due to inefficacy. Outcomes were assessed according to concomitant AEDs according to their MoA and the clinical risk factor profile. RESULTS: Three hundred ten patients were analyzed and followed for median 17.3months. Two hundred ninety-nine (97%) had drug-resistant epilepsy, and 155 (50%) had tried more than 7 AEDs at LCM commencement. Adjuvant LCM was associated with responder and seizure freedom rate of 29% and 9% respectively at 12months. Lower baseline seizure frequency, a prior 6-month period of seizure freedom at any time since epilepsy diagnosis and being on fewer concomitant AEDs were predictive of 12 month seizure freedom. Previous focal to bilateral tonic-clonic seizures (FBTCS), lower baseline seizure frequency, and concomitant AED reduction after LCM commencement were associated with improved LCM tolerability. No specific MoA AED combinations offered any efficacy or tolerability advantage. SIGNIFICANCE: Adjuvant LCM is associated with seizure freedom rates of 9% at 12months after commencement and is predicted by lower prior seizure frequency, a period of 6months or longer of seizure freedom since diagnosis and fewer concomitant AEDs. While the broad MoA of concomitant AEDs did not influence efficacy or tolerability outcomes, we have provided a framework that may be utilized in future studies to help identify optimal synergistic AED combinations. PMID- 29396360 TI - Effect of repetitive transcranial magnetic stimulation on action myoclonus: A pilot study in patients with EPM1. AB - OBJECTIVE: The objective of this study was to explore the short-term effects of repetitive transcranial magnetic stimulation (rTMS) on action myoclonus. METHODS: Nine patients with Unverricht-Lundborg (EPM1) progressive myoclonus epilepsy type underwent two series of 500 stimuli at 0.3Hz through round coil twice a day for five consecutive days. Clinical and neurophysiological examinations were performed two hours before starting the first rTMS session and two hours after the end of the last rTMS session. RESULTS: Eight patients completed the protocol; one discontinued because of a transient increase in spontaneous jerks. The unified myoclonus rating scale indicated a 25% reduction in posttreatment myoclonus with action score associated with an increase in the cortical motor threshold and lengthening of the cortical silent period (CSP). The decrease in the myoclonus with action scores correlated with the prolongation of CSP. CONCLUSIONS: Repetitive transcranial magnetic stimulation can be safely used in patients with EPM1, improves action myoclonus, and partially restores deficient cortical inhibition. PMID- 29396361 TI - Pattern of executive functioning in adolescents with epilepsy: A multimethod measurement approach. AB - Youth with epilepsy demonstrate deficits in executive functioning (EF), the skills necessary for goal-directed behavior (e.g., problem-solving, initiating, monitoring, organization, planning, and working memory). Despite 30-50% of youth with epilepsy demonstrating EF deficits, no extant studies have utilized both performance and questionnaire-based measures to examine the pattern of EF deficits in adolescents with epilepsy. Study aims were to 1) identify the pattern of EF deficits in adolescents with epilepsy and 2) identify which assessment tools are most sensitive to EF deficits in this population (adolescents, ages 13 17, with epilepsy). An exploratory aim was to examine group differences on measures of EF by epilepsy type. Standard performance-based neuropsychological measures (Wechsler Intelligence Scale for Children - Version V or Wechsler Adult Intelligence Scale Working Memory Index-Version IV, Delis Kaplan Executive Functioning System, NIH Toolbox, Test of Everyday Attention for Children) and the Behavior Rating Inventory of Executive Functioning (BRIEF) comprised the multimethod assessment battery. Depending on the measure, 30% of adolescents with epilepsy had deficits in working memory, 17% in cognitive flexibility/problem solving, 6% in inhibition, and 18% in planning/organization. Attention was a significant problem for 15% of adolescents with epilepsy. Correlations among the various EF measures were quite poor. Across various EF domains, results indicated that adolescents with localization-related epilepsy demonstrated better EF skills compared to adolescents with unclassified epilepsy. Overall, our findings suggest that executive functioning deficits are selective and different from those observed in other neurological populations (e.g., attention deficit hyperactivity disorder (ADHD), traumatic brain injury) where problems with self-regulation (i.e., inhibition, planning/organization) are more pronounced. These findings support utilizing multiple measures, including both performance-based neuropsychological tests and parent- and self-reports, to assess executive functioning difficulties in adolescents with epilepsy as they are uniquely sensitive to executive functioning domains. Adolescents with unclassified epilepsy also appear to be at higher risk for EF deficits and thus represent an important group to target for intervention. PMID- 29396362 TI - Discovery of 2-aminothiazolyl berberine derivatives as effectively antibacterial agents toward clinically drug-resistant Gram-negative Acinetobacter baumanii. AB - Aminothiazolyl berberine derivatives as potentially antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens, and the aminothiazole and Schiff base moieties were helpful structural fragments for aqueous solubility and antibacterial activity. Especially, aminothiazolyl 9-hexyl berberine 9c and 2,4-dichlorobenzyl derivative 18a exhibited good activities (MIC = 2 nmol/mL) against clinically drug-resistant Gram-negative Acinetobacter baumanii with low cytotoxicity to hepatocyte LO2 cells, rapidly bactericidal effects and quite slow development of bacterial resistance toward A. baumanii. Molecular modeling indicated that compounds 9c and 18a could bind with GLY-102, ARG-136 and/or ALA-100 residues of DNA gyrase through hydrogen bonds. It was found that compounds 9c and 18a were able to disturb the drug-resistant A. baumanii membrane effectively, and molecule 9c could not only intercalate but also cleave bacterial DNA isolated from resistant A. baumanii, which might be the preliminary antibacterial action mechanism of inhibiting the growth of A. baumanii strain. In particular, the combination use of compound 9c with norfloxacin could enhance the antibacterial activity, broaden antibacterial spectrum and overcome the drug resistance. PMID- 29396363 TI - Novel inhibitors of the rRNA ErmC' methyltransferase to block resistance to macrolides, lincosamides, streptogramine B antibiotics. AB - In erythromycin-resistant bacteria, the N6 position of A2058 in 23S rRNA is mono- or dimethylated by Erm family methyltransferases. This modification results in cross-resistance to macrolides, lincosamides and streptogramin B. Most inhibitors of Erm methyltransferases developed up-to-date target the cofactor-binding pocket, resulting in a lack of selectivity whereas inhibitors that bind the substrate-binding pocket demonstrate low in vitro activity. In this study, a molecular docking approach followed by biochemical screening was applied to search for inhibitors targeting both cofactor- and substrate-binding pockets of ErmC' methyltransferase. Based on the results of the molecular docking-based virtual screening of the clean-leads subset of the ZINC database, 29 compounds were chosen for experimental verification. Among them inhibitor 28 (ZINC code 32747906), with an IC50 of 100 MUM, decreased the minimal inhibitory concentration of erythromycin in the Escherichia coli strain overexpressing ErmC'. Docking analysis of 28 to the ErmC' structure and the competitive ligand binding assay revealed a non-competitive model of inhibition. Inhibitor 28 served as a template for similarity-based virtual screening, which resulted in the identification of two derivatives 3s (ZINC code 62022572) and 4s (ZINC code 49032257) with an IC50 of 116 MUM and 110 MUM, respectively. Our results provide a basis for the development of inhibitors against the Erm-family of enzymes. PMID- 29396364 TI - Spirohydantoins and 1,2,4-triazole-3-carboxamide derivatives as inhibitors of histone deacetylase: Design, synthesis, and biological evaluation. AB - Two structurally novel series of histone deacetylase inhibitors (HDACIs) involving two potential surface recognition moieties; 3',4'-dihydro-2'H spiro[imidazolidine-4,1'-naphthalene]-2,5-dione (in series I) and 1-(3 methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide (in series II) were designed, synthesized, and evaluated for their anti-proliferative activities, HDAC inhibitory activities, and their binding modes to HDAC protein. Compounds 5f and 10e showed comparable HDAC inhibitory activity to SAHA. Series II have been also demonstrated as potential HDAC-tubulin dual inhibitors, promoted with structural similarities between (1-(3-methoxyphenyl)-5-(3,4,5 trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide) nucleus, of series II, and Combretastatin A4. The tubulin inhibitory activities of series II members, together with their docking into colchicine binding site of beta-tubulin were performed. Compound 9a showed remarkable cytotoxicity. Hybrid 10e behaved as potent HDAC-tubulin dual inhibitor. It showed better tubulin inhibition than CA4 as well as its effectiveness against HDAC. PMID- 29396365 TI - Monitoring of selected skin- and breath-borne volatile organic compounds emitted from the human body using gas chromatography ion mobility spectrometry (GC-IMS). AB - Human smuggling and associated cross-border crimes have evolved as a major challenge for the European Union in recent years. Of particular concern is the increasing trend of smuggling migrants hidden inside shipping containers or trucks. Therefore, there is a growing demand for portable security devices for the non-intrusive and rapid monitoring of containers to detect people hiding inside. In this context, chemical analysis of volatiles organic compounds (VOCs) emitted from the human body is proposed as a locating tool. In the present study, an in-house made ion mobility spectrometer coupled with gas chromatography (GC IMS) was used to monitor the volatile moieties released from the human body under conditions that mimic entrapment. A total of 17 omnipresent volatile compounds were identified and quantified from 35 ion mobility peaks corresponding to human presence. These are 7 aldehydes (acrolein, 2-methylpropanal, 3-methylbutanal, 2 ethacrolein, n-hexanal, n-heptanal, benzaldehyde), 3 ketones (acetone, 2 pentanone, 4-methyl-2-pentanone), 5 esters (ethyl formate, ethyl propionate, vinyl butyrate, butyl acetate, ethyl isovalerate), one alcohol (2-methyl-1 propanol) and one organic acid (acetic acid). The limits of detection (0.05-7.2 ppb) and relative standard deviations (0.6-11%) should be sufficient for detecting these markers of human presence in field conditions. This study shows that GC-IMS can be used as a portable field detector of hidden or entrapped people. PMID- 29396366 TI - Quantitation of trans-fatty acids in human blood via isotope dilution-gas chromatography-negative chemical ionization-mass spectrometry. AB - Trans-fatty acids (TFA) are geometric isomers of naturally occurring cis-fatty acids. High dietary TFA intake has been associated with risk factors for cardiovascular disease. However, little is known about TFA levels in humans. To address this data need, we developed and validated a new isotope dilution-gas chromatography-negative chemical ionization-mass spectrometry (ID-GC-NCI-MS) method for quantitation of 27 fatty acids (FA) including 4 major TFA in human plasma, serum, and red blood cells (RBC) from 66 donors. Quantitation was performed with 18 isotope labeled internal standards and results are presented in MUM and % of total FA. This method has high sensitivity and specificity due to use of pentafluorobenzyl-bromide derivatization combined with NCI-MS and a 200m column to optimize positional and geometric FA isomer separation. The four major TFA, palmitelaidic acid, elaidic acid, trans-vaccenic acid, and linoelaidic acid, were detected in all samples, with median total TFA concentrations of 17.7MUM in plasma, 19.6MUM in serum, and 21.5MUM in RBC. The % of total FA for the TFA was 0.20% in plasma, 0.20% in serum, and 0.30% in RBC. Patterns for % FA are similar to those reported in other studies. We developed a highly specific, ID-GC-NCI-MS method to quantitate TFA and other FA in humans. PMID- 29396367 TI - RP-HPLC method for simultaneous estimation of vigabatrin, gamma-aminobutyric acid and taurine in biological samples. AB - Vigabatrin is used as first line drug in treatment of infantile spasms for its potential benefit overweighing risk of causing permanent peripheral visual field defects and retinal damage. Chronic administration of vigabatrin in rats has demonstrated these ocular events are result of GABA accumulation and depletion of taurine levels in retinal tissues. In vigabatrin clinical studies taurine plasma level is considered as biomarker for studying structure and function of retina. The analytical method is essential to monitor taurine levels along with vigabatrin and GABA. A RP-HPLC method has been developed and validated for simultaneous estimation of vigabatrin, GABA and taurine using surrogate matrix. Analytes were extracted from human plasma, rat plasma, retina and brain by simple protein precipitation method and derivatized by naphthalene 2, 3-dicarboxaldehyde to produce stable fluorescent active isoindole derivatives. The chromatographic analysis was performed on Zorbax Eclipse AAA column using gradient elution profile and eluent was monitored using fluorescence detector. A linear plot of calibration curve was observed in concentration range of 64.6 to 6458, 51.5 to 5150 and 62.5 to 6258 ng/mL for vigabatrin, GABA and taurine, respectively with r2 >= 0.997 for all analytes. The method was successfully applied for estimating levels of vigabatrin and its modulator effect on GABA and taurine levels in rat plasma, brain and retinal tissue. This RP-HPLC method can be applied in clinical and preclinical studies to explore the effect of taurine deficiency and to investigate novel approaches for alleviating vigabatrin induced ocular toxicity. PMID- 29396368 TI - Liver-specific rescuing of CEACAM1 reverses endothelial and cardiovascular abnormalities in male mice with null deletion of Ceacam1 gene. AB - OBJECTIVE: Mice with global null mutation of Ceacam1 (Cc1-/-), display impairment of insulin clearance that causes hyperinsulinemia followed by insulin resistance, elevated hepatic de novo lipogenesis, and visceral obesity. In addition, they manifest abnormal vascular permeability and elevated blood pressure. Liver specific rescuing of Ceacam1 reversed all of the metabolic abnormalities in Cc1-/ liver+ mice. The current study examined whether Cc1-/- male mice develop endothelial and cardiac dysfunction and whether this relates to the metabolic abnormalities caused by defective insulin extraction. METHODS AND RESULTS: Myography studies showed reduction of agonist-stimulated nitric oxide production in resistance arterioles in Cc1-/-, but not Cc1-/-liver+ mice. Liver-based rescuing of CEACAM1 also attenuated the abnormal endothelial adhesiveness to circulating leukocytes in parallel to reducing plasma endothelin-1 and recovering plasma nitric oxide levels. Echocardiography studies revealed increased septal wall thickness, cardiac hypertrophy and reduced cardiac performance in Cc1-/-, but not Cc1-/-xliver+ mice. Insulin signaling experiments indicated compromised IRS1/Akt/eNOS pathway leading to lower nitric oxide level, and activated Shc/MAPK pathway leading to more endothelin-1 production in the aortae and hearts of Cc1-/ , but not Cc1-/-xliver+ mice. The increase in the ratio of endothelin-1 receptor A/B indicated an imbalance in the vasomotor activity of Cc1-/- mice, which was normalized in Cc1-/-xliver+ mice. CONCLUSIONS: The data underscore a critical role for impaired CEACAM1-dependent hepatic insulin clearance pathways and resulting hyperinsulinemia and lipid accumulation in aortae and heart in regulating the cardiovascular function. PMID- 29396369 TI - Cardiac natriuretic peptides promote adipose 'browning' through mTOR complex-1. AB - OBJECTIVE: Activation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed 'browning'), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. beta-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose 'browning' as well as proper development of the interscapular BAT. In addition to cAMP-PKA signaling pathways, cGMP-PKG signaling also promotes this browning process; however, it is unclear whether or not mTORC1 is also necessary for cGMP-PKG induced browning. METHOD: Activation of mTORC1 by natriuretic peptides (NP), which bind to and activate the membrane-bound guanylyl cyclase, NP receptor A (NPRA), was assessed in mouse and human adipocytes in vitro and mouse adipose tissue in vivo. RESULTS: Activation of mTORC1 by NP-cGMP signaling was observed in both mouse and human adipocytes. We show that NP-NPRA-PKG signaling activate mTORC1 by direct PKG phosphorylation of Raptor at Serine 791. Administration of B type natriuretic peptide (BNP) to mice induced Ucp1 expression in inguinal adipose tissue in vivo, which was completely blocked by the mTORC1 inhibitor rapamycin. CONCLUSION: Our results demonstrate that NP-cGMP signaling activates mTORC1 via PKG, which is a component in the mechanism of adipose browning. PMID- 29396370 TI - Distinct adipocyte progenitor cells are associated with regional phenotypes of perivascular aortic fat in mice. AB - OBJECTIVE: Perivascular adipose tissue depots around the aorta are regionally distinct and have specific functional properties. Thoracic aorta perivascular adipose tissue (tPVAT) expresses higher levels of thermogenic genes and lower levels of inflammatory genes than abdominal aorta perivascular adipose tissue (aPVAT). It is not known whether this distinction is due to the in-vivo functional environment or to cell-autonomous traits that persist outside the in vivo setting. In this study, we asked whether the progenitor cells in tPVAT and aPVAT have cell-autonomous traits that lead to formation of regionally distinct PVAT. METHODS: We performed microarray analysis of thoracic and abdominal peri aortic adipose tissues of C57Bl/6J mice to define gene expression profile of each depot. To derive adipocyte progenitor cells, C57Bl/6J mice were sacrificed and thoracic and abdominal aorta fragments were embedded in Matrigel and cultured under pro-angiogenic conditions. Adipogenesis was induced using the Ppar-gamma agonist rosiglitazone, a thiazolidinedione (TZD). TZD-induced adipocyte populations were analyzed using immunofluorescence and qRT-PCR. RESULTS: Microarray analysis showed that tPVAT expressed higher levels of transcription factors related brown adipose tissue development compared to aPVAT. Classic brown adipose tissue (BAT) genes such as Ucp-1, Prdm16, Dio2, Slc27a displayed a concordant trend of higher level expression in tPVAT, while white adipose tissue (WAT) genes such as Hoxc8, Nnat, Sncg, and Mest were expressed at a higher level in aPVAT. The adipokines resistin and retinol binding protein 4 were also higher in aPVAT. Furthermore, adipocyte progenitors from abdominal and thoracic aortic rings responded to TZD with expression of canonical adipocyte genes Acrp30, Plin1, and Glut4. Adipocytes differentiated from thoracic aorta progenitors displayed markedly higher induction of Ucp-1 and Cidea. CONCLUSIONS: Thoracic aorta PVAT expresses higher levels of brown adipocyte transcription factors than aPVAT. Precursor cells from the thoracic aorta give rise to adipocytes that express significantly higher levels of Ucp-1 and Cidea ex vivo, suggesting that progenitor cells in tPVAT and aPVAT have cell-autonomous properties that dictate adipocyte phenotype. PMID- 29396371 TI - Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. AB - OBJECTIVE: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing beta-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult beta-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. METHODS: In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. RESULTS: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult beta-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes. CONCLUSIONS: Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a beta-cell developmental program. PMID- 29396373 TI - Circular RNAs as novel regulators of beta-cell functions in normal and disease conditions. AB - OBJECTIVE: There is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of beta-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of beta-cells functions. METHODS: We used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, beta-cell proliferation, and apoptosis. RESULTS: We identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced beta-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key beta-cell genes, such as Slc2a2, Akt1, and Mtpn. CONCLUSIONS: Our findings point to circular RNAs as novel regulators of beta-cell activities and suggest an involvement of this novel class of non-coding RNAs in beta-cell dysfunction under diabetic conditions. PMID- 29396372 TI - Ghrelin mediates exercise endurance and the feeding response post-exercise. AB - OBJECTIVE: Exercise training has several well-established health benefits, including many related to body weight, appetite control, and blood glucose homeostasis. However, the molecular mechanisms and, in particular, the hormonal systems that mediate and integrate these beneficial effects are poorly understood. In the current study, we aimed to investigate the role of the hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), in mediating the effects of exercise on food intake and blood glucose following exercise as well as in regulating exercise endurance capacity. METHODS: We used two mouse models of treadmill running to characterize the changes in plasma ghrelin with exercise. We also assessed the role of the ghrelin system to influence food intake and blood glucose after exercise, exercise endurance, and parameters potentially linked to responses to exercise. Mice lacking GHSRs (GHSR null mice) and wild-type littermates were studied. RESULTS: An acute bout of exercise transiently elevated plasma acyl-ghrelin. Without the action of this increased ghrelin on GHSRs (as in GHSR-null mice), high intensity interval exercise markedly reduced food intake compared to control mice. The effect of exercise to acutely raise blood glucose remained unmodified in GHSR-null mice. Exercise-induced increases in plasma ghrelin positively correlated with endurance capacity, and time to exhaustion was reduced in GHSR-null mice as compared to wild-type littermates. In an effort to mechanistically explain their reduced exercise endurance, exercised GHSR-null mice exhibited an abrogated sympathoadrenal response, lower overall insulin-like growth factor-1 levels, and altered glycogen utilization. CONCLUSIONS: Exercise transiently increases plasma ghrelin. GHSR-null mice exhibit decreased food intake following high intensity interval exercise and decreased endurance when submitted to an exercise endurance protocol. These data suggest that an intact ghrelin system limits the capacity of exercise to restrict food intake following exercise, although it enhances exercise endurance. PMID- 29396375 TI - Corrigendum to "Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha" [Mol Metab 7 (2018) 80-89]. PMID- 29396374 TI - Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. METHODS: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12 month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). RESULTS: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. CONCLUSIONS: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and beta-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602. PMID- 29396376 TI - Calcitonin-gene related peptide is a potent inducer of oedema in rat orofacial tissue. AB - BACKGROUND AND AIMS: This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. EXPERIMENTAL APPROACH: Wistar rats (150-200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 MUl; 8-33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before (T = 0) and up to 24 h following injection of CGRP. Pretreatment with antagonists (CGRP8-37, 10 nmol; pizotifen, 2 mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30 min, respectively, before the inflammatory stimulus. CGRP and CGRP8-37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (+/-SEM) difference in thickness between the right and the left sides at each time. RESULTS: Following intra-oral injection, CGRP induced a rapidly developing (5-15 min) and long-lasting (6 h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP8-37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16 pmol) potentiated the oedema induced by co-injected substance P (3.7 nmol) and contributed to the oedema following intraoral injection of carrageenan (100 MUg). Injection of CGRP8-37 alone induced an early but short-lasting oedema. CONCLUSION: Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP8-37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues. PMID- 29396377 TI - The determination of 5-methoxytryptophan in human plasma. AB - Methoxyindoles have been of continued interest due to their biological effects. Recent studies using enzyme-linked immunosorbent assays (ELISAs) have reported micromolar levels of 5-methoxytryptophan (MeOTRP) in human plasma. This prompted our development of a method for the determination of MeOTRP in human plasma that involved solid phase extraction (SPE) followed by HPLC. The identity of a putative MeOTRP peak was confirmed through chromatographic, voltammometric and fluorometric characterization. Using a standard addition approach, actual mean human plasma MeOTRP levels were found to be approximately 2ng/mL, 20 to 100 times lower than previously reported. Prior studies on the physiological and possible biomarker roles of MeOTRP need to be reconsidered and future studies of MeOTRP need to take the present findings into consideration. PMID- 29396378 TI - Cloud point extraction coupled with microwave-assisted back-extraction (CPE-MABE) for determination of Eszopiclone (Z-drug) using UV-Visible, HPLC and mass spectroscopic (MS) techniques: Spiked and in vivo analysis. AB - A procedure for the determination of Eszopiclone (ESZ) from complex matrices i.e. in vitro (spiked matrices), as well as in vivo (mice model) was developed using cloud point extraction coupled with microwave-assisted back-extraction (CPE MABE). Analytical measurements have been carried using UV-Visible, HPLC and MS techniques. The proposed method has been validated according to ICH guidelines and legitimate reproducible and reliability of protocol is assessed through intraday and inter-day precision <3.61% and <4.70%, respectively. Limit of detection has been obtained as 0.083MUg/mL and 0.472MUg/mL respectively, for HPLC and UV-Visible techniques, corresponding to assessed linearity range. The coaservate phase in CPE was back extracted under microwaves exposure, with isooctane at pre-concentration factor ~50 when 5mL of sample solution was pre concentrated to 0.1mL. Under optimized conditions i.e. Aqueous-Triton X-114 4% (w/v), pH4.0, NaCl 4% (w/v) and equilibrium temperature of 45 degrees C for 20min, average extraction recovery has been obtained between 89.8 and 99.2% and 84.0-99.2% from UV-Visible and HPLC analysis, respectively. The method has been successfully applied to the pharmacokinetic estimation (post intraperitoneal administration) of ESZ in mice. MS analysis precisely depicted the presence of active N-desmethyl zopiclone in impales as well as in mice plasma. PMID- 29396379 TI - Therapeutic effects of gefitinib-encapsulated thermosensitive injectable hydrogel in intervertebral disc degeneration. AB - Intervertebral disc (IVD) degeneration is one of the most widespread musculoskeletal diseases worldwide, which remains an intractable clinical challenge. The aim of this study is to investigate the therapeutic potential of the small molecule gefitinib (an epidermal growth factor receptor (EGFR) inhibitor) in ameliorating IVD degeneration. Aberrant EGFR activation levels were detected in both human and rat degenerative IVDs, which prompted us to investigate the functional roles of EGFR by utilizing inducible cartilage specific EGFR-deficient mice. We demonstrated that conditional EGFR deletion in mice increased nucleus pulposus (NP) extracellular matrix (ECM) production and autophagy marker activation while MMP13 expression decreased. These outcomes are comparable to the use of a controlled-release injectable thermosensitive hydrogel of gefitinib to block EGFR activity in a puncture-induced rat model. We also conducted a case series study involving patients with non-small cell lung cancer and IVD degeneration who received gefitinib treatment from 2010 to 2015. Gefitinib-treated patients displayed a relative slower disc degenerating progression, in contrast to control subjects. These findings thus provide evidence that suppression of EGFR by the FDA-approved drug gefitinib can protect IVD degeneration in rats, implying the potential application of gefitinib as a small molecule drug for treating IVD degeneration. PMID- 29396380 TI - An injectable conductive hydrogel encapsulating plasmid DNA-eNOs and ADSCs for treating myocardial infarction. AB - Myocardial infarction (MI) leads to the mass death of cardiomyocytes accompanying with the unfavorable alternation of microenvironment, a fibrosis scar deprived of electrical communications, and the lack of blood supply in the infarcted myocardium. The three factors are inextricably intertwined and thus result in a conservative MI therapy efficacy in clinic. A holistic approach pertinently targeted to these three key points would be favorable to rebuild the heart functions. Here, an injectable conductive hydrogel was constructed via in situ Michael addition reaction between multi-armed conductive crosslinker tetraaniline polyethylene glycol diacrylate (TA-PEG) and thiolated hyaluronic acid (HA-SH). The resultant soft conductive hydrogel with equivalent myocardial conductivity and anti-fatigue performance was loaded with plasmid DNA encoding eNOs (endothelial nitric oxide synthase) nanocomplexes and adipose derived stem cells (ADSCs) for treating MI. The TA-PEG/HA-SH/ADSCs/Gene hydrogel-based holistic system was injected into the infarcted myocardium of SD rats. We demonstrated an increased expression of eNOs in myocardial tissue the heightening of nitrite concentration, accompanied with upregulation of proangiogenic growth factors and myocardium related mRNA. The results of electrocardiography, cardiogram, and histological analysis convincingly revealed a distinct increase of ejection fraction (EF), shortened QRS interval, smaller infarction size, less fibrosis area, and higher vessel density, indicating a significant improvement of heart functions. This conception of combination approach by a conductive injectable hydrogel loaded with stem cells and gene-encoding eNOs nanoparticles will become a robust therapeutic strategy for the treatment of MI. PMID- 29396381 TI - Perceptions of pregnancy preparation in women with a low to intermediate educational attainment: A qualitative study. AB - OBJECTIVE: in the promotion of periconceptional health, appropriate attention has to be given to the perceptions of those who are most vulnerable, such as women with a relatively low socioeconomic status based on their educational attainment. The aim of this study was to explore these women's perceptions of pregnancy preparation and the role they attribute to healthcare professionals. DESIGN: we conducted semi-structured interviews with women with a low to intermediate educational attainment and with a desire to conceive, of which a subgroup had experience with preconception care. Thematic content analysis was applied on the interview transcripts. FINDINGS: the final sample consisted of 28 women. We identified four themes of pregnancy preparation perceptions: (i)"How to prepare for pregnancy?", which included health promotion and seeking healthcare; (ii) "Why prepare for pregnancy?", which mostly related to fertility and health concerns; (iii) "Barriers and facilitators regarding pregnancy preparation", such as having limited control over becoming pregnant as well as the health of the unborn; (iv) "The added value of preconception care", reported by women who had visited a consultation, which consisted mainly of reassurance and receiving information. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the attained insights into the perceptions of women with a low to intermediate education are valuable for adapting the provision of preconception care to their views. We recommend the proactive offering of preconception care, including information on fertility, to stimulate adequate preparation for pregnancy and contribute to improving perinatal health among women who are socioeconomically more vulnerable. PMID- 29396382 TI - Exploring young pregnant smokers' experiences with a self-nominated non-smoking buddy. AB - INTRODUCTION: psychosocial interventions can increase the proportion of women who stop smoking in pregnancy. There is limited research exploring self-nominated, non-smoking buddy support, to assist young pregnant smokers to quit. METHODS: this qualitative descriptive study was embedded within a randomised controlled study assisting young (16 to 24 years) pregnant smokers to quit. Women were recruited from two public maternity hospitals in Western Australia. Interviews were performed every two weeks from recruitment to six weeks post birth. The study aim was to explore women's experiences with a self-nominated non-smoking buddy. Thematic analysis was utilised to identify common themes. FINDINGS: a total of 204 interviews were performed with 36 women, who had a mean of six interviews, with four conducted in pregnancy and two post birth. Two themes were revealed. The first 'Challenges of finding the right buddy' reflected the experiences women had in finding a non-smoking buddy to provide support and encompassed three sub themes; 'The only non-smoker I know', 'Reluctance to alter the existing relationship' and 'Limited discussion around expectations of buddy support'. The second theme 'Sustaining the buddy relationship' centred on the continuing relationship the woman had with her buddy and encompassed three sub themes; 'Consistent relationship', 'Changeable buddies' and 'Unofficial buddies'. CONCLUSION: our findings reveal the complexity of incorporating non-smoking buddy support into smoking cessation programs for young pregnant smokers. The characteristics and social environment of individual women may have the capacity to influence their ability to engage and sustain a relationship with a non smoking buddy. PMID- 29396383 TI - Developing a work/study programme for midwifery education in East Africa. AB - BACKGROUND: there is extensive evidence to show that skilled midwifery care is crucial in reducing maternal deaths; however, in East Africa, the midwifery profession has been subsumed within the nursing role. This paper highlights issues in the preparation of skilled midwives in three East African countries, specifically, Uganda, Kenya and Tanzania and provides a case study description of a flexible work/study programme designed to develop skilled midwives to meet internationally regarded ICM competency standards in midwifery education and practice. THE MODEL: a flexible, competency-based Bachelor's of Science in Midwifery programme (BScM) has been developed based on fifteen years' experience of running a Bachelor of Science in nursing programme. The new BSCM programme allows licensed diploma midwives the opportunity to study for two days a week towards a bachelor's degree in midwifery, whilst continuing to work and support their families. The model also provides education at degree level thus providing a sound platform for ongoing development of a cadre of midwifery leaders. CONCLUSION: the BScM education model for working midwives builds on the success of the BScN work/study model in developing strong leadership, clinical and critical thinking competencies. The newly developed midwifery programme provides a pathway by which to increase the availability of skilled East African midwives educated to the Global Standards for Midwifery Education. PMID- 29396384 TI - Midwifery education: Challenges for the future in a dynamic environment. AB - Iceland and the Netherlands both have a long history of midwifery education and midwifery practice. Starting as a midwife requires a direct entry BSc program in midwifery in The Netherlands, where Iceland requires a nurse-midwife model. This paper presents an overview of midwifery education and its dynamic in these countries. Subsequently, we explore two most notable components that were identified as important for the future of midwifery education. In the concluding section, we reflect how these components support the scope of practice as presented in the Lancet framework for quality maternal and newborn care. PMID- 29396385 TI - How Knowledge Is Constructed and Exchanged in Virtual Communities of Physicians: Qualitative Study of Mindlines Online. AB - BACKGROUND: As a response to the criticisms evidence-based practice currently faces, groups of health care researchers and guideline makers have started to call for the appraisal and inclusion of different kinds of knowledge in guideline production (other than randomized controlled trials [RCTs]) to better link with the informal knowledge used in clinical practice. In an ethnographic study, Gabbay and Le May showed that clinicians in everyday practice situations do not explicitly or consciously use guidelines. Instead, they use mindlines: collectively shared, mostly tacit knowledge that is shaped by many sources, including accumulated personal experiences, education (formal and informal), guidance, and the narratives about patients that are shared among colleagues. In this study on informal knowledge, we consider virtual networks of clinicians as representative of the mindlines in the wider medical community, as holders of knowledge, as well as catalysts of knowing. OBJECTIVE: The aim of this study was to explore how informal knowledge and its creation in communities of clinicians can be characterized as opposed to the more structured knowledge produced in guideline development. METHODS: This study included a qualitative study of postings on three large virtual networks for physicians in the United Kingdom, the Netherlands, and Norway, taking the topic of statins as a case study and covering more than 1400 posts. Data were analyzed thematically with reference to theories of collaborative knowledge construction and communities of practice. RESULTS: The dataset showed very few postings referring to, or seeking to adhere to, explicit guidance and recommendations. Participants presented many instances of individual case narratives that highlighted quantitative test results and clinical examination findings. There was an emphasis on outliers and the material, regulatory, and practical constraints on knowledge use by clinicians. Participants conveyed not-so-explicit knowledge as tacit and practical knowledge and used a prevailing style of pragmatic reasoning focusing on what was likely to work in a particular case. Throughout the discussions, a collective conceptualization of statins was generated and reinforced in many contexts through stories, jokes, and imagery. CONCLUSIONS: Informal knowledge and knowing in clinical communities entail an inherently collective dynamic practice that includes explicit and nonexplicit components. It can be characterized as knowledge-in-context in practice, with a strong focus on casuistry. Validity of knowledge appears not to be based on criteria of consensus, coherence, or correspondence but on a more polyphonic understanding of truth. We contend that our findings give enough ground for further research on how exploring mindlines of clinicians online could help improve guideline development processes. PMID- 29396386 TI - Open Notes in Swedish Psychiatric Care (Part 1): Survey Among Psychiatric Care Professionals. AB - BACKGROUND: When the Swedish version of Open Notes, an electronic health record (EHR) service that allows patients online access, was introduced in hospitals, primary care, and specialized care in 2012, psychiatric care was exempt. This was because psychiatric notes were considered too sensitive for patient access. However, as the first region in Sweden, Region Skane added adult psychiatry to its Open Notes service in 2015. This made it possible to carry out a unique baseline study to investigate how different health care professionals (HCPs) in adult psychiatric care in the region expect Open Notes to impact their patients and their practice. This is the first of two papers about the implementation of Open Notes in adult psychiatric care in Region Skane. OBJECTIVE: The objective of this study was to describe, compare, and discuss how different HCPs in adult psychiatric care in Region Skane expect Open Notes to impact their patients and their own practice. METHODS: A full population Web-based questionnaire was distributed to psychiatric care professionals in Region Skane in late 2015. The response rate was 28.86% (871/3017). Analyses show that the respondents were representative of the staff as a whole. A statistical analysis examined the relationships between different professionals and attitudes to the Open Notes service. RESULTS: The results show that the psychiatric HCPs are generally of the opinion that the service would affect their own practice and their patients negatively. The most striking result was that more than 60% of both doctors (80/132, 60.6%) and psychologists (55/90, 61%) were concerned that they would be less candid in their documentation in the future. CONCLUSIONS: Open Notes can increase the transparency between patients and psychiatric HCPs because patients are able to access their EHRs online without delay and thus, can read notes that have not yet been approved by the responsible HCP. This may be one explanation as to why HCPs are concerned that the service will affect both their own work and their patients. PMID- 29396387 TI - Telehealth Interventions Delivering Home-based Support Group Videoconferencing: Systematic Review. AB - BACKGROUND: Group therapy and education and support sessions are used within health care across a range of disciplines such as chronic disease self-management and psychotherapy interventions. However, there are barriers that constrain group attendance, such as mobility, time, and distance. Using videoconferencing may overcome known barriers and improve the accessibility of group-based interventions. OBJECTIVE: The aim of this study was to review the literature to determine the feasibility, acceptability, effectiveness, and implementation of health professional-led group videoconferencing to provide education or social support or both, into the home setting. METHODS: Electronic databases were searched using predefined search terms for primary interventions for patient education and/or social support. The quality of studies was assessed using the Mixed Methods Appraisal Tool. We developed an analysis framework using hierarchical terms feasibility, acceptability, effectiveness, and implementation, which were informed by subheadings. RESULTS: Of the 1634 records identified, 17 were included in this review. Home-based groups by videoconferencing are feasible even for those with limited digital literacy. Overall acceptability was high with access from the home highly valued and little concern of privacy issues. Some participants reported preferring face-to-face groups. Good information technology (IT) support and training is required for facilitators and participants. Communication can be adapted for the Web environment and would be enhanced by clear communication strategies and protocols. A range of improved outcomes were reported but because of the heterogeneity of studies, comparison of these across studies was not possible. There was a trend for improvement in mental health outcomes. Benefits highlighted in the qualitative data included engaging with others with similar problems; improved accessibility to groups; and development of health knowledge, insights, and skills. Videoconference groups were able to replicate group processes such as bonding and cohesiveness. Similar outcomes were reported for those comparing face-to-face groups and videoconference groups. CONCLUSIONS: Groups delivered by videoconference are feasible and potentially can improve the accessibility of group interventions. This may be particularly useful for those who live in rural areas, have limited mobility, are socially isolated, or fear meeting new people. Outcomes are similar to in-person groups, but future research on facilitation process in videoconferencing-mediated groups and large scale studies are required to develop the evidence base. PMID- 29396388 TI - The Significance of Witness Sensors for Mass Casualty Incidents and Epidemic Outbreaks. AB - Due to the increasing number of natural and man-made disasters, mass casualty incidents occur more often than ever before. As a result, health care providers need to adapt in order to cope with the overwhelming patient surge. To ensure quality and safety in health care, accurate information in pandemic disease control, death reduction, and health quality promotion should be highlighted. However, obtaining precise information in real time is an enormous challenge to all researchers of the field. In this paper, innovative strategies are presented to develop a sound information network using the concept of "witness sensors." To overcome the reliability and quality limitations of information obtained through social media, researchers must focus on developing solutions that secure the authenticity of social media messages, especially for matters related to health. To address this challenge, we introduce a novel concept based on the two elements of "witness" and "sensor." Witness sensors can be key players designated to minimize limitations to quality of information and to distinguish fact from fiction during critical events. In order to enhance health communication practices and deliver valid information to end users, the education and management of witness sensors should be further investigated, especially for implementation during mass casualty incidents and epidemic outbreaks. PMID- 29396389 TI - Mobile Diabetes Intervention Study of Patient Engagement and Impact on Blood Glucose: Mixed Methods Analysis. AB - BACKGROUND: Successful treatment of diabetes includes patient self-management behaviors to prevent or delay complications and comorbid diseases. On the basis of findings from large clinical trials and professional guidelines, diabetes education programs and health providers prescribe daily regimens of glucose monitoring, healthy eating, stress management, medication adherence, and physical activity. Consistent, long-term commitment to regimens is challenging. Mobile health is increasingly being used to assist patients with lifestyle changes and self-management behaviors between provider visits. The effectiveness of mobile health to improve diabetes outcomes depends on patient engagement with a technology, content, or interactions with providers. OBJECTIVES: In the current analysis, we aimed to identify patient engagement themes in diabetes messaging with diabetes providers and determine if differences in engagement in the Mobile Diabetes Intervention Study (MDIS) influenced changes in glycated hemoglobin A1c (HbA1c) over a 1-year treatment period (1.9% absolute decrease in the parent study). METHODS: In the primary MDIS study, 163 patients were enrolled into 1 of 3 mobile intervention groups or a usual care control group based on their physician cluster randomization assignment. The control group received care from their physicians as usual. Participants in each intervention group had access to a patient portal where they could record monitoring values for blood glucose, blood pressure, medication changes, or other self-management information while also assigned to varying levels of physician access to patient data. Intervention participants could choose to send and receive messages to assigned certified diabetes educators with questions or updates through the secure Web portal. For this secondary analysis, patient engagement was measured using qualitative methods to identify self-care themes in 4109 patient messages. Mixed methods were used to determine the impact of patient engagement on change in HbA1c over 1 year. RESULTS: Self-care behavior themes that received the highest engagement for participants were glucose monitoring (75/107, 70.1%), medication management (71/107, 66.4%), and reducing risks (71/107, 66.4%). The average number of messages sent per patient were highest for glucose monitoring (9.2, SD 14.0) and healthy eating (6.9, SD 13.2). Compared to sending no messages, sending any messages about glucose monitoring (P=.03) or medication (P=.01) led to a decrease in HbA1c of 0.62 and 0.72 percentage points, respectively. Sending any messages about healthy eating, glucose monitoring, or medication combined led to a decrease in HbA1c of 0.54 percentage points compared to not sending messages in these themes (P=.045). CONCLUSIONS: The findings from this study help validate the efficacy of the mobile diabetes intervention. The next step is to determine differences between patients who engage in mobile interventions and those who do not engage and identify methods to enhance patient engagement. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01107015; https://clinicaltrials.gov/ct2/show/NCT01107015 (Archived by WebCite at http://www.webcitation.org/6wh4ekP4R). PMID- 29396390 TI - Diagnostic Function of 3D Optical Coherence Tomography Images in Diagnosis of Vogt-Koyanagi-Harada Disease at Acute Uveitis Stage. AB - BACKGROUND This study analyzed the macular 3D-OCT images of Vogt-Koyanagi-Harada disease (VKH) in uveitis, explored the characteristics of 3D-OCT images of the macular region of VKH, and assessed which characteristics contribute most to VKH diagnosis. MATERIAL AND METHODS The 3D-OCT examination of 25 cases of VKH was performed on the macular area, and the image characteristics were analyzed. RESULTS Our study included a total of 50 eyes from 25 cases of VKH patients, 10 males and 15 females, aged 17 to 64 years, mean (39.44+/-11.60) years old. According to OCT B-scan images, 49 (98%) eyes had ERD, 49 (98%) eyes had nerve retinal edema, 36 (72%) eyes had endometrium-like structure (including cysts), 5 (10%) eyes had RPE folds, 35 (70%) eyes had changes in the internal septum, 49 (98%) eyes had RPE monolayer structure outside the ERD region. In ILM-RPE thickness, 49 (98%) eyes had retinal irregular thickening and 31 (62%) eyes had radial stripe changes. In ILM contour figure, 50 eyes (100%) showed exceptional uplift, 5 (10%) eyes had small focal uplift for PED on the RPE surface, and 48 (96%) eyes had wavy ups and downs. CONCLUSIONS In OCT B-scan imaging, the ERT, retinal edema of the retina, and the RPE monolayer structure outside the range are most likely to occur in VKH. The ILM-RPE thickness chart in 3D reconstruction showed irregular thickening of the retina. The ILM contour graph showed abnormal uplift, and RPE surface wavy ups and downs in VKH most likely to occur. PMID- 29396391 TI - Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe. AB - Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling. PMID- 29396392 TI - Upregulation of kinesin family member 4A enhanced cell proliferation via activation of Akt signaling and predicted a poor prognosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death worldwide, and the molecular pathogenesis and development of HCC are largely unknown. In the present study, we found that KIF4A expression was upregulated in HCC (678 samples, P = 2.03E-8) based on a meta-analysis of Oncomine database. We further confirmed that both KIF4A mRNA and protein expressions were overexpressed in human HCC tumour tissues as well as cancer cell lines. Higher KIF4A expression was correlated with poorer overall survival (P < 0.0001) and disease-free survival (P < 0.0337) in HCC patients. We constructed in vitro KIF4A overexpression and depletion HCC cell models. KIF4A overexpression significantly enhanced cellular proliferation and clonogenic abilities, whereas KIF4A depletion caused a dramatic increase of cells with abnormal chromosome segregation and subsequently resulted in augmentation of apoptosis in HCC cells. In addition, we demonstrated that KIF4A depletion was related to inhibition of Akt kinase activity and induction of intrinsic apoptosis signaling pathway. Taken together, KIF4A may act as a prognostic biomarker and potential therapeutic target in human HCC. PMID- 29396393 TI - UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins. AB - Muscle development requires the coordinated activities of specific protein folding and degradation factors. UFD-2, a U-box ubiquitin ligase, has been reported to play a central role in this orchestra regulating the myosin chaperone UNC-45. Here, we apply an integrative in vitro and in vivo approach to delineate the substrate-targeting mechanism of UFD-2 and elucidate its distinct mechanistic features as an E3/E4 enzyme. Using Caenorhabditis elegans as model system, we demonstrate that UFD-2 is not regulating the protein levels of UNC-45 in muscle cells, but rather shows the characteristic properties of a bona fide E3 ligase involved in protein quality control. Our data demonstrate that UFD-2 preferentially targets unfolded protein segments. Moreover, the UNC-45 chaperone can serve as an adaptor protein of UFD-2 to poly-ubiquitinate unfolded myosin, pointing to a possible role of the UFD-2/UNC-45 pair in maintaining proteostasis in muscle cells. PMID- 29396394 TI - Author Correction: The F-box protein FKF1 inhibits dimerization of COP1 in the control of photoperiodic flowering. AB - The previously published version of this Article contained errors in Figure 5. In panel c, the second and fourth blot images were incorrectly labeled 'alpha-Myc' and should have been labelled 'alpha-HA'. These errors have been corrected in both the PDF and HTML versions of the Article. PMID- 29396395 TI - Replication confers beta cell immaturity. AB - Pancreatic beta cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in beta-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal beta cells that are functionally immature as defined by a lower set point for glucose stimulated insulin secretion. Here we show that beta-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non oncogenic levels of c-Myc. Adult beta cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal beta that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the beta cell reverts to a less functional one in response to proliferative cues. PMID- 29396396 TI - Revealing hole trapping in zinc oxide nanoparticles by time-resolved X-ray spectroscopy. AB - Nanostructures of transition metal oxides, such as zinc oxide, have attracted considerable interest for solar-energy conversion and photocatalysis. Both applications are sensitive to the transport and trapping of photoexcited charge carriers. The probing of electron trapping has recently become possible using time-resolved element-sensitive methods, such as X-ray spectroscopy. However, valence-band-trapped holes have so far escaped observation. Herein we use X-ray absorption spectroscopy combined with a dispersive X-ray emission spectrometer to probe the charge carrier relaxation and trapping processes in zinc oxide nanoparticles after above band-gap photoexcitation. Our results, supported by simulations, demonstrate that within 80 ps, photoexcited holes are trapped at singly charged oxygen vacancies, which causes an outward displacement by ~15% of the four surrounding zinc atoms away from the doubly charged vacancy. This identification of the hole traps provides insight for future developments of transition metal oxide-based nanodevices. PMID- 29396397 TI - Ants improve the reproduction of inferior morphs to maintain a polymorphism in symbiont aphids. AB - Identifying stable polymorphisms is essential for understanding biodiversity. Distinctive polymorphisms are rare in nature because a superior morph should dominate a population. In addition to the three known mechanisms for polymorphism persistence, we recently reported a fourth mechanism: protection of the polymorphism by symbionts. Attending ants preferentially protect polymorphic aphid colonies consisting of green and red morphs. Here, we show that attending ants manipulate the reproductive rate of their preferred green morphs to equal that of the red morphs, leading to the persistence of the polymorphism within the colonies. We could not, however, explain how the ants maintained the polymorphism in aphid colonies regardless of inter-morph competition. Manipulation by symbionts may be important for the maintenance of polymorphisms and the resulting biodiversity in certain symbiotic systems. PMID- 29396399 TI - Author Correction: Deep Learning for Fully-Automated Localization and Segmentation of Rectal Cancer on Multiparametric MR. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396398 TI - Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts. AB - Most cases of early onset torsion dystonia (DYT1) are caused by a 3-base pair deletion in one allele of the TOR1A gene causing loss of a glutamate in torsinA, a luminal protein in the nuclear envelope. This dominantly inherited neurologic disease has reduced penetrance and no other medical manifestations. It has been challenging to understand the neuronal abnormalities as cells and mouse models which are heterozygous (Het) for the mutant allele are quite similar to wild-type (WT) controls. Here we found that patient fibroblasts and mouse neurons Het for this mutation showed significant differences from WT cells in several parameters revealed by infection with herpes simplex virus type 1 (HSV) which replicates in the nucleus and egresses out through the nuclear envelope. Using a red fluorescent protein capsid to monitor HSV infection, patient fibroblasts showed decreased viral plaque formation as compared to controls. Mouse Het neurons had a decrease in cytoplasmic, but not nuclear HSV fluorescence, and reduced numbers of capsids entering axons as compared to infected WT neurons. These findings point to altered dynamics of the nuclear envelope in cells with the patient genotype, which can provide assays to screen for therapeutic agents that can normalize these cells. PMID- 29396400 TI - Diffraction based Hanbury Brown and Twiss interferometry at a hard x-ray free electron laser. AB - X-ray free-electron lasers (XFELs) provide extremely bright and highly spatially coherent x-ray radiation with femtosecond pulse duration. Currently, they are widely used in biology and material science. Knowledge of the XFEL statistical properties during an experiment may be vitally important for the accurate interpretation of the results. Here, for the first time, we demonstrate Hanbury Brown and Twiss (HBT) interferometry performed in diffraction mode at an XFEL source. It allowed us to determine the XFEL statistical properties directly from the Bragg peaks originating from colloidal crystals. This approach is different from the traditional one when HBT interferometry is performed in the direct beam without a sample. Our analysis has demonstrated nearly full (80%) global spatial coherence of the XFEL pulses and an average pulse duration on the order of ten femtoseconds for the monochromatized beam, which is significantly shorter than expected from the electron bunch measurements. PMID- 29396401 TI - Abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions in cervical dystonia. AB - The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway. Previous TMS studies showed that cerebellar cortex excitation can block the increase in M1 excitability induced by a paired-associative stimulation (PAS), while cerebellar cortex inhibition would enhance it. Since cerebellum is known to be affected in many types of dystonia, this bidirectional modulation was assessed in 22 patients with cervical dystonia and 23 healthy controls. Exactly opposite effects were found in patients: cerebellar inhibition suppressed the effects of PAS, while cerebellar excitation enhanced them. Another experiment comparing healthy subjects maintaining the head straight with subjects maintaining the head turned as the patients found that turning the head is enough to invert the cerebellar modulation of M1 plasticity. A third control experiment in healthy subjects showed that proprioceptive perturbation of the sterno-cleido-mastoid muscle had the same effects as turning the head. We discuss these finding in the light of the recent model of a mesencephalic head integrator. We also suggest that abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions of the integrator in cervical dystonia. PMID- 29396402 TI - Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. AB - Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy. PMID- 29396403 TI - Electrophilic fatty acid nitroalkenes regulate Nrf2 and NF-kappaB signaling:A medicinal chemistry investigation of structure-function relationships. AB - Fatty acid nitroalkene derivatives (NO2-FA) activate Nrf2-regulated antioxidant gene expression and inhibit NF-kappaB-dependent cytokine expression. To better define NO2-FA structure-function relationships, a series of 22 new chemical entities (NCEs) containing an electrophilic nitroalkene functional group were synthesized and screened for both Nrf2- and NF-kappaB activities using luciferase based assays. The structural variables were acyl chain length (11 to 24 carbons) and position of the electrophilic nitroalkene group. In luciferase-based reporter assays, Nrf2 was maximally activated by omega-12 nitroalkene fatty acids while TNFalpha stimulated NF-kappaB-inhibition was maximal for omega-5 nitroalkenes. The top pathway-modulating NO2-FAs were a) evaluated for an ability to activate Nrf2-dependent signaling and inhibit NF-kappaB-dependent inflammatory responses of RAW264.7 cells and b) compared to electrophilic compounds in clinical development. These findings revealed that 8/9-nitro-eicos-8-enoic acid (NCE-10) was collectively the most effective NCE and that both the alpha and omega acyl chain lengths influence nitroalkene activation of Nrf2 and inhibition of NF kappaB signaling. This insight will guide development of more effective non natural homologs of endogenously-detectable fatty acid nitroalkenes as anti inflammatory and anti-fibrotic drug candidates. PMID- 29396404 TI - The ciliopathy protein TALPID3/KIAA0586 acts upstream of Rab8 activation in zebrafish photoreceptor outer segment formation and maintenance. AB - Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in signal transduction. Cilia are anchored inside the cell through basal bodies (BBs), modified centrioles also acting as microtubule-organization centers. Photoreceptors (PRs) are sensory neurons, whose primary cilium forms a highly specialized compartment called the outer segment (OS) responsible for sensing incoming light. Thus, ciliopathies often present with retinal degeneration. Mutations in KIAA0586/TALPID3 (TA3) cause Joubert syndrome, in which 30% of affected individuals develop retinal involvement. To elucidate the function of TALPID3 in PRs, we studied talpid3 zebrafish mutants and identified a progressive retinal degeneration phenotype. The majority of PRs lack OS development due to defects in BB positioning and docking at the apical cell surface. Intracellular accumulation of the photopigment opsin leads to PR cell death of moderate severity. Electroretinograms demonstrate severe visual impairement. A small subset of PRs display normally docked BBs and extended OSs through rescue by maternally deposited Talpid3. While localization of the small GTPase Rab8a, which plays an important role in BB docking, appears unaffected in talpid3-/- PRs, overexpression of constitutively active Rab8a rescues OS formation, indicating that the role of Ta3 in early ciliogenesis lies upstream of Rab8a activation in PRs. PMID- 29396405 TI - The association of telomere attrition with first-onset stroke in Southern Chinese: a case-control study and meta-analysis. AB - The relationship between telomere length and stroke was inconsistent mostly due to different pathogenesis of subtypes, environment and genetics. We aimed to assess whether leukocyte telomere contributes to stroke in Southern Chinese by investigating a case-control study comprising 543 cases (224 atherothrombotic stroke, 94 hemorrhagic stroke and 225 lacunar infraction) and 616 controls and replicated the investigation in an independent study comprising 773 cases and 875 controls with the same diagnostic criteria. Telomere was inversely correlated with increasing age in controls (correlation coefficient gamma = -0.28, P < 0.001) and in cases with atherothrombotic stroke (gamma = -0.17, P = 0.012). Individuals within the lowest tertile of telomere showed a higher risk for atherothrombotic stroke [odds ratio 2.33, 95% confidence (CI) 1.42-3.83; P = 0.003], whereas had a lower presence of lacunar infarction (OR 0.49, 95% CI 0.30 0.81; P = 0.007). Similar results were obtained in the second replication study. A further meta-analysis showed a 12% increased pooled risk of ischemic stroke (95% CI 1.04-1.18) in relation to shorter telomere, but this association was stronger in the retrospective studies and in Asians when stratified by study design and ethnicity. Our data provided the first evidence that in Southern Chinese stroke population, leukocyte telomere is independently associated with atherothrombotic stroke and lacunar infarction. PMID- 29396406 TI - Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability. AB - The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD. PMID- 29396407 TI - High Density Lipoproteins Inhibit Oxidative Stress-Induced Prostate Cancer Cell Proliferation. AB - Recent evidence suggests that oxidative stress can play a role in the pathogenesis and the progression of prostate cancer (PCa). Reactive oxygen species (ROS) generation is higher in PCa cells compared to normal prostate epithelial cells and this increase is proportional to the aggressiveness of the phenotype. Since high density lipoproteins (HDL) are known to exert antioxidant activities, their ability to reduce ROS levels and the consequent impact on cell proliferation was tested in normal and PCa cell lines. HDL significantly reduced basal and H2O2-induced oxidative stress in normal, androgen receptor (AR) positive and AR-null PCa cell lines. AR, scavenger receptor BI and ATP binding cassette G1 transporter were not involved. In addition, HDL completely blunted H2O2-induced increase of cell proliferation, through their capacity to prevent the H2O2-induced shift of cell cycle distribution from G0/G1 towards G2/M phase. Synthetic HDL, made of the two main components of plasma-derived HDL (apoA-I and phosphatidylcholine) and which are under clinical development as anti atherosclerotic agents, retained the ability of HDL to inhibit ROS production in PCa cells. Collectively, HDL antioxidant activity limits cell proliferation induced by ROS in AR-positive and AR-null PCa cell lines, thus supporting a possible role of HDL against PCa progression. PMID- 29396408 TI - Jacalin capped platinum nanoparticles confer persistent immunity against multiple Aeromonas infection in zebrafish. AB - Bacterial resistance is a major clinical problem, which is compounded by both a lack of new antibiotics and emergence of multi- and extremely-drug resistant microbes. In this context, non-toxic nanoparticles could play an important role in conferring protection against bacterial infections and in this study we have made an attempt to show the usefulness of jacalin capped platinum nanoparticles in protecting zebrafish against multiple infections with Aeromonas hydrophila. Our results also indicate that use of nanoparticles promotes adaptive immune response against the pathogen, so much so that zebrafish is able to survive repetitive infection even after twenty one days of being treated with jacalin capped platinum nanoparticles. This is significant given that platinum salt is not antibacterial and jacalin is non-immunogenic. Our study for the first time reveals a novel mechanism of action of nanoparticles, which could form an alternate antibacterial strategy with minimal bacterial resistance. PMID- 29396409 TI - Sensitive detection of mitochondrial DNA variants for analysis of mitochondrial DNA-enriched extracts from frozen tumor tissue. AB - Large variation exists in mitochondrial DNA (mtDNA) not only between but also within individuals. Also in human cancer, tumor-specific mtDNA variation exists. In this work, we describe the comparison of four methods to extract mtDNA as pure as possible from frozen tumor tissue. Also, three state-of-the-art methods for sensitive detection of mtDNA variants were evaluated. The main aim was to develop a procedure to detect low-frequent single-nucleotide mtDNA-specific variants in frozen tumor tissue. We show that of the methods evaluated, DNA extracted from cytosol fractions following exonuclease treatment results in highest mtDNA yield and purity from frozen tumor tissue (270-fold mtDNA enrichment). Next, we demonstrate the sensitivity of detection of low-frequent single-nucleotide mtDNA variants (<=1% allele frequency) in breast cancer cell lines MDA-MB-231 and MCF-7 by single-molecule real-time (SMRT) sequencing, UltraSEEK chemistry based mass spectrometry, and digital PCR. We also show de novo detection and allelic phasing of variants by SMRT sequencing. We conclude that our sensitive procedure to detect low-frequent single-nucleotide mtDNA variants from frozen tumor tissue is based on extraction of DNA from cytosol fractions followed by exonuclease treatment to obtain high mtDNA purity, and subsequent SMRT sequencing for (de novo) detection and allelic phasing of variants. PMID- 29396411 TI - Clinorotation-induced autophagy via HDM2-p53-mTOR pathway enhances cell migration in vascular endothelial cells. AB - Individuals exposed to long-term spaceflight often experience cardiovascular dysfunctions characterized by orthostatic intolerance, disability on physical exercise, and even frank syncope. Recent studies have showed that the alterations of cardiovascular system are closely related to the functional changes of endothelial cells. We have shown previously that autophagy can be induced by simulated microgravity in human umbilical vein endothelial cells (HUVECs). However, the mechanism of enhanced autophagy induced by simulated microgravity and its role in the regulation of endothelial function still remain unclear. We report here that 48 h clinorotation promoted cell migration in HUVECs by induction of autophagy. Furthermore, clinorotation enhanced autophagy by the mechanism of human murine double minute 2 (HDM2)-dependent degradation of cytoplasmic p53 at 26S proteasome, which results in the suppression of mechanistic target of rapamycin (mTOR), but not via activation of AMPK in HUVECs. These results support the key role of HDM2-p53 in direct downregulation of mTOR, but not through AMPK in microgravity-induced autophagy in HUVECs. PMID- 29396410 TI - Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells. AB - Congenital Zika syndrome (CZS) causes early brain development impairment by affecting neural progenitor cells (NPCs). Here, we analyze NPCs from three pairs of dizygotic twins discordant for CZS. We compare by RNA-Seq the NPCs derived from CZS-affected and CZS-unaffected twins. Prior to Zika virus (ZIKV) infection the NPCs from CZS babies show a significantly different gene expression signature of mTOR and Wnt pathway regulators, key to a neurodevelopmental program. Following ZIKV in vitro infection, cells from affected individuals have significantly higher ZIKV replication and reduced cell growth. Whole-exome analysis in 18 affected CZS babies as compared to 5 unaffected twins and 609 controls excludes a monogenic model to explain resistance or increased susceptibility to CZS development. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to oligogenic and/or epigenetic mechanisms. PMID- 29396412 TI - DNA damage in leukocytes after internal ex-vivo irradiation of blood with the alpha-emitter Ra-223. AB - Irradiation with high linear energy transfer alpha-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all alpha- and beta-particles of the decay, ranging from 0 to 142 mGy. gamma-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of alpha-induced DNA damage tracks and small gamma-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of alpha-induced gamma-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small gamma-H2AX + 53BP1 DSB foci indicative of beta-irradiation was similar to baseline values, being in agreement with a negligible beta-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223 treated patients and early after incorporation of alpha-emitters. PMID- 29396413 TI - A sequence polymorphism on 8q24 is associated with survival in hepatocellular carcinoma patients who received radiation therapy. AB - There is a growing consensus that genetic variation in candidate genes can influence cancer progression and treatment effects. In this study, we genotyped the rs9642880 G > T polymorphism using DNA isolated from blood samples of 271 hepatocellular carcinoma (HCC) patients who received radiotherapy treatment. We found that patients who carried the GT or TT genotypes had significantly shorter median survival times (MSTs) compared to patients with the GG genotype (14.6 vs.21.4 months). The multivariate P value was 0.027, the hazard ratio (HR) was 1.38, and the 95% confidence interval was 1.04-1.84. Further analysis revealed that patients with the variant genotypes had an increased risk of poor tumour response to radiotherapy (P = 0.036 and 0.002 for stable disease and progressive disease, respectively) and higher incidence of multiple intrahepatic lesions (P = 0.026) and BCLC C stage (P = 0.027). Moreover, further stratified survival analyses revealed that at least radioresponse and BCLC stage contributed to the association between the rs9642880 G > T polymorphism and survival of HCC patients in this study (P value, 0.017 vs 0.053 for BCLC C stage vs B stage; 0.011 vs 0.531 for radioresponse SD + PD vs CR + PR). These results illustrate the potential association between rs9642880 G > T and survival in HCC patients who received radiotherapy treatment. PMID- 29396414 TI - Comparing the Intramedullary Nail and Extramedullary Fixation in Treatment of Unstable Intertrochanteric Fractures. AB - Treatment options for unstable intertrochanteric fractures include intramedullary nail and extramedullary fixation, although evidence regarding the most appropriate treatment for such fractures remains controversial. Our hypothesis was that there would be no obvious differences in mortality rates, functional outcomes and complications between the two groups. We therefore conducted a meta analysis to compare the relative advantages of intramedullary nail and extramedullary fixation. A total of 10 randomized controlled trials including only patients with unstable intertrochanteric fractures were included in the final analysis. We found that no statistically significant difference in one-year mortality was observed between the two groups (RR: 0.78, 95% CI: 0.55-1.10, p = 0.160). Analysis of exact p values from five included studies indicated that functional outcomes were markedly better for patients of the intramedullary nail group when compared with those of the extramedullary fixation group (p = 0.0028), although evidence remains controversial. Higher incidences of all complications were noted for extramedullary fixation (RR:1.48, 95% CI: 1.12-1.96, p = 0.006). However, no significant differences in implant-related complications were observed between the two groups (RR:1.20, 95% CI: 0.73-1.97, p = 0.475). Therefore, comparing with extramedullary fixation, the intramedullary nail method would be more reliable and should be encouraging for unstable intertrochanteric fractures. PMID- 29396416 TI - Plasma Modification of Poly Lactic Acid Solutions to Generate High Quality Electrospun PLA Nanofibers. AB - Physical properties of pre-electrospinning polymer solutions play a key role in electrospinning as they strongly determine the morphology of the obtained electrospun nanofibers. In this work, an atmospheric-pressure argon plasma directly submerged in the liquid-phase was used to modify the physical properties of poly lactic acid (PLA) spinning solutions in an effort to improve their electrospinnability. The electrical characteristics of the plasma were investigated by two methods; V-I waveforms and Q-V Lissajous plots while the optical emission characteristics of the plasma were also determined using optical emission spectroscopy (OES). To perform a complete physical characterization of the plasma-modified polymer solutions, measurements of viscosity, surface tension, and electrical conductivity were performed for various PLA concentrations, plasma exposure times, gas flow rates, and applied voltages. Moreover, a fast intensified charge-couple device (ICCD) camera was used to image the bubble dynamics during the plasma treatments. In addition, morphological changes of PLA nanofibers generated from plasma-treated PLA solutions were observed by scanning electron microscopy (SEM). The performed plasma treatments were found to induce significant changes to the main physical properties of the PLA solutions, leading to an enhancement of electrospinnability and an improvement of PLA nanofiber formation. PMID- 29396415 TI - Inter-subject synchrony as an index of functional specialization in early childhood. AB - Early childhood is a time of significant change within multiple cognitive domains including social cognition, memory, executive function, and language; however, the corresponding neural changes remain poorly understood. This is likely due to the difficulty in acquiring artifact-free functional MRI data during complex task based or unconstrained resting-state experiments in young children. In addition, task-based and resting state experiments may not capture dynamic real-world processing. Here we overcome both of these challenges through use of naturalistic viewing (i.e., passively watching a movie in the scanner) combined with inter subject neural synchrony to examine functional specialization within 4- and 6 year old children. Using a novel and stringent crossed random effect statistical analysis, we find that children show more variable patterns of activation compared to adults, particularly within regions of the default mode network (DMN). In addition, we found partial evidence that child-to-adult synchrony increased as a function of age within a DMN region: the temporoparietal junction. Our results suggest age-related differences in functional brain organization within a cross-sectional sample during an ecologically valid context and demonstrate that neural synchrony during naturalistic viewing fMRI can be used to examine functional specialization during early childhood - a time when neural and cognitive systems are in flux. PMID- 29396417 TI - Implementation of a Talbot-Lau interferometer in a clinical-like c-arm setup: A feasibility study. AB - X-ray grating-based phase-contrast imaging has raised interest regarding a variety of potential clinical applications, whereas the method is feasible using a medical x-ray tube. Yet, the transition towards a clinical setup remains challenging due to the requirement of mechanical robustness of the interferometer and high demands applying to medical equipment in clinical use. We demonstrate the successful implementation of a Talbot-Lau interferometer in an interventional c-arm setup. The consequence of vibrations induced by the rotating anode of the tube is discussed and the prototype is shown to provide a visibility of 21.4% at a tube voltage of 60 kV despite the vibrations. Regarding clinical application, the prototype is mainly set back due to the limited size of the field of view covering an area of 17 mm * 46 mm. A c-arm offers the possibility to change the optical axis according to the requirements of the medical examination. We provide a method to correct for artifacts that result from the angulation of the c-arm. Finally, the images of a series of measurements with the c-arm in different angulated positions are shown. Thereby, it is sufficient to perform a single reference measurement in parking position that is valid for the complete series despite angulation. PMID- 29396418 TI - Structural insights into the design of novel anti-influenza therapies. AB - A limited arsenal of therapies is currently available to tackle the emergence of a future influenza pandemic or even to deal effectively with the continual outbreaks of seasonal influenza. However, recent findings hold great promise for the design of novel vaccines and therapeutics, including the possibility of more universal treatments. Structural biology has been a major contributor to those advances, in particular through the many studies on influenza hemagglutinin (HA), the major surface antigen. HA's primary function is to enable the virus to enter host cells, and structural work has revealed the various HA conformational forms generated during the entry process. Other studies have explored how human broadly neutralizing antibodies (bnAbs), designed proteins, peptides and small molecules, can inhibit and neutralize the virus. Here we review milestones in HA structural biology and how the recent insights from bnAbs are paving the way to design novel vaccines and therapeutics. PMID- 29396419 TI - Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene. AB - Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450-42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS. PMID- 29396420 TI - Universal route to optimal few- to single-cycle pulse generation in hollow-core fiber compressors. AB - Gas-filled hollow-core fiber (HCF) pulse post-compressors generating few- to single-cycle pulses are a key enabling tool for attosecond science and ultrafast spectroscopy. Achieving optimum performance in this regime can be extremely challenging due to the ultra-broad bandwidth of the pulses and the need of an adequate temporal diagnostic. These difficulties have hindered the full exploitation of HCF post-compressors, namely the generation of stable and high quality near-Fourier-transform-limited pulses. Here we show that, independently of conditions such as the type of gas or the laser system used, there is a universal route to obtain the shortest stable output pulse down to the single cycle regime. Numerical simulations and experimental measurements performed with the dispersion-scan technique reveal that, in quite general conditions, post compressed pulses exhibit a residual third-order dispersion intrinsic to optimum nonlinear propagation within the fiber, in agreement with measurements independently performed in several laboratories around the world. The understanding of this effect and its adequate correction, e.g. using simple transparent optical media, enables achieving high-quality post-compressed pulses with only minor changes in existing setups. These optimized sources have impact in many fields of science and technology and should enable new and exciting applications in the few- to single-cycle pulse regime. PMID- 29396421 TI - Conserved noncoding sequences conserve biological networks and influence genome evolution. AB - Comparative genomics approaches have identified numerous conserved cis-regulatory sequences near genes in plant genomes. Despite the identification of these conserved noncoding sequences (CNSs), our knowledge of their functional importance and selection remains limited. Here, we used a combination of DNA methylome analysis, microarray expression analyses, and functional annotation to study these sequences in the model tree Populus trichocarpa. Methylation in CG contexts and non-CG contexts was lower in CNSs, particularly CNSs in the 5' upstream regions of genes, compared with other sites in the genome. We observed that CNSs are enriched in genes with transcription and binding functions, and this also associated with syntenic genes and those from whole-genome duplications, suggesting that cis-regulatory sequences play a key role in genome evolution. We detected a significant positive correlation between CNS number and protein interactions, suggesting that CNSs may have roles in the evolution and maintenance of biological networks. The divergence of CNSs indicates that duplication-degeneration-complementation drives the subfunctionalization of a proportion of duplicated genes from whole-genome duplication. Furthermore, population genomics confirmed that most CNSs are under strong purifying selection and only a small subset of CNSs shows evidence of adaptive evolution. These findings provide a foundation for future studies exploring these key genomic features in the maintenance of biological networks, local adaptation, and transcription. PMID- 29396423 TI - Publisher Correction: Task-Correlated Cortical Asymmetry and Intra- and Inter Hemispheric Separation. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396422 TI - EPEC NleH1 is significantly more effective in reversing colitis and reducing mortality than NleH2 via differential effects on host signaling pathways. AB - Enteropathogenic Escherichia coli (EPEC) is a foodborne pathogen that uses a type III secretion system to translocate effector molecules into host intestinal epithelial cells (IECs) subverting several host cell processes and signaling cascades. Interestingly, EPEC infection induces only modest intestinal inflammation in the host. The homologous EPEC effector proteins, NleH1 and NleH2, suppress the nuclear factor-kappaB (NF-kappaB) pathway and apoptosis in vitro. Increased apoptosis and activation of NF-kappaB and MAP kinases (MAPK) contribute to the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to determine if NleH1 and NleH2 also block MAPK pathways in vitro and in vivo, and to compare the effects of these bacterial proteins on a murine model of colitis. Cultured IECs were infected with various strains of EPEC expressing NleH1 and NleH2, or not, and the activation of ERK1/2 and p38 was determined. In addition, the impact of infection with various strains of EPEC on murine DSS colitis was assessed by change in body weight, colon length, histology, and survival. Activation of apoptosis and MAPK signaling were also evaluated. Our data show that NleH1, but not NleH2, suppresses ERK1/2 and p38 activation in vitro. Interestingly, NleH1 affords significantly greater protection against and hastens recovery from dextran sodium sulfate (DSS)-induced colitis compared to NleH2. Strikingly, colitis-associated mortality was abolished by infection with EPEC strains expressing NleH1. Interestingly, in vivo NleH1 suppresses activation of ERK1/2 and p38 and blocks apoptosis independent of the kinase domain that inhibits NF-kappaB. In contrast, NleH2 suppresses only caspase-3 and p38, but not ERK1/2. We conclude that NleH1 affords greater protection against and improves recovery from DSS colitis compared to NleH2 due to its ability to suppress ERK1/2 in addition to NF-kappaB, p38, and apoptosis. These findings warrant further investigation of anti-inflammatory bacterial proteins as novel treatments for IBD. PMID- 29396424 TI - Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2 p53 and Mdm2-MRN-ATM axes. AB - RPS27L (ribosomal protein S27-like) is an evolutionarily conserved ribosomal protein and a direct p53 target. We recently reported that Rps27l disruption triggers ribosomal stress to induce p53, causing postnatal death, which can be rescued by Trp53 +/- . Whether and how Rps27l modulates radiosensitivity is unknown. Here we report that Rps27l -/- ; Trp53 +/- mice are extremely sensitive to radiation due to reduced proliferation and massive induction of apoptosis in radiation-sensitive organs. Mechanistically, the radiation sensitivity is mediated by two signaling pathways: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) reduced DNA damage response due to reduced MRN/Atm signal as a result of elevated Mdm2 binding of Nbs1 to inhibit Nbs1-Atm binding and subsequent Atm activation. Indeed, heterozygous deletion of Mdm2 restores the MRN/Atm signal. Collectively, our study revealed a physiological condition under which Rps27l regulates the Mdm2/p53 and MRN/Atm axes to maintain DNA damage response and to confer radioprotection in vivo. PMID- 29396425 TI - Recent inner ear specialization for high-speed hunting in cheetahs. AB - The cheetah, Acinonyx jubatus, is the fastest living land mammal. Because of its specialized hunting strategy, this species evolved a series of specialized morphological and functional body features to increase its exceptional predatory performance during high-speed hunting. Using high-resolution X-ray computed micro tomography (MUCT), we provide the first analyses of the size and shape of the vestibular system of the inner ear in cats, an organ essential for maintaining body balance and adapting head posture and gaze direction during movement in most vertebrates. We demonstrate that the vestibular system of modern cheetahs is extremely different in shape and proportions relative to other cats analysed (12 modern and two fossil felid species), including a closely-related fossil cheetah species. These distinctive attributes (i.e., one of the greatest volumes of the vestibular system, dorsal extension of the anterior and posterior semicircular canals) correlate with a greater afferent sensitivity of the inner ear to head motions, facilitating postural and visual stability during high-speed prey pursuit and capture. These features are not present in the fossil cheetah A. pardinensis, that went extinct about 126,000 years ago, demonstrating that the unique and highly specialized inner ear of the sole living species of cheetah likely evolved extremely recently, possibly later than the middle Pleistocene. PMID- 29396426 TI - The peroxisome biogenesis factors posttranslationally target reticulon homology domain-containing proteins to the endoplasmic reticulum membrane. AB - The endoplasmic reticulum (ER) is shaped by a class of membrane proteins containing reticulon homology domain (RHD), the conserved hydrophobic domain encompassing two short hairpin transmembrane domains. RHD resides in the outer leaflet of the ER membrane, generating high-curvature ER membrane. While most of the membrane proteins destined to enter the secretory pathway are cotranslationally targeted and inserted into ER membrane, the molecular mechanism how the RHD-containing proteins are targeted and inserted into the ER membrane remains to be clarified. Here we show that RHD-containing proteins can be posttranslationally targeted to the ER membrane. PEX19, a cytosolic peroxin, selectively recognizes the nascent RHD-containing proteins and mediates their posttranslational targeting in cooperation with PEX3, a membrane peroxin. Thus, these peroxisome biogenesis factors provide an alternative posttranslational route for membrane insertion of the RHD-containing proteins, implying that ER membrane shaping and peroxisome biogenesis may be coordinated by the posttranslational membrane insertion. PMID- 29396427 TI - 10Be-inferred paleo-denudation rates imply that the mid-Miocene western central Andes eroded as slowly as today. AB - Terrestrial cosmogenic nuclide concentrations of detrital minerals yield catchment-wide rates at which hillslopes erode. These estimates are commonly used to infer millennial scale denudation patterns and to identify the main controls on mass-balance and landscape evolution at orogenic scale. The same approach can be applied to minerals preserved in stratigraphic records of rivers, although extracting reliable paleo-denudation rates from Ma-old archives can be limited by the target nuclide's half-life and by exposure to cosmic radiations after deposition. Slowly eroding landscapes, however, are characterized by the highest cosmogenic radionuclide concentrations; a condition that potentially allows pushing the method's limits further back in time, provided that independent constraints on the geological evolution are available. Here, we report 13-10 million-year-old paleo-denudation rates from northernmost Chile, the oldest 10Be inferred rates ever reported. We find that at 13-10 Ma the western Andean Altiplano has been eroding at 1-10 m/Ma, consistent with modern paces in the same setting, and it experienced a period with rates above 10 m/Ma at ~11 Ma. We suggest that the background tectono-geomorphic state of the western margin of the Altiplano has remained stable since the mid-Miocene, whereas intensified runoff since ~11 Ma might explain the transient increase in denudation. PMID- 29396428 TI - YAP triggers the Wnt/beta-catenin signalling pathway and promotes enterocyte self renewal, regeneration and tumorigenesis after DSS-induced injury. AB - Impaired epithelial regeneration is a crucial pathophysiological feature of ulcerative colitis (UC). Yes-associated protein (YAP1) appears to control cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in intestinal epithelial cell (IEC) self-renewal, regeneration and tumorigenesis. We first observed that YAP was significantly reduced in 62.5% (45/72) of human UC tissues and it was dramatically enhanced during epithelial regeneration in a murine colitis model. Using lentiviral infection, we established a YAP-overexpression (YAPWT) mouse model. We then found that after tissue injury, YAPWT mice had increased epithelial cell self-renewal capacity and drastically restored intestinal crypt structure. Strikingly, these mice were more susceptible to colitis-associated cancer (CAC) in chemically induced carcinoma. Mechanistically, YAP and beta-catenin showed increased nuclear co-localization during regeneration after inflammation. Overexpressing YAP significantly improved IEC 'wound-healing' ability and increased the expression of both beta-catenin and the transcriptional targets of Wnt signalling Lgr5 and cyclin D1, whereas silencing beta-catenin in YAPWT cells attenuated this effect. Remarkably, we observed that YAP could directly interact with beta-catenin in the nucleus and formed a transcriptional YAP/beta-catenin/TCF4 complex; Lgr5 and cyclin D1 were confirmed to be the target genes of this complex. In contrast, cancer cell proliferation and tumour development were suppressed by the phospho-mimetic YAP mutant. In summary, nuclear YAP-driven IEC proliferation could control epithelial regeneration after inflammation and may serve as a potential therapeutic target in UC. However, excessive YAP activation promoted CAC development. PMID- 29396430 TI - Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers. AB - p53 mutations are frequently detected in malignant gastric cancers. However, the molecular mechanisms by which loss of p53 function promotes gastric cancer are not clear. We utilized Gan mice (K19-Wnt1/C2mE), which have functional p53 and develop intestinal-type gastric tumors, to investigate the role of p53 in gastric cancer progression by knocking out p53. We found that gastric epithelial cells acquire tumorigenicity in the subcutis of C57BL/6 mice as a result of Wnt activation, COX-2 activation and p53 deficiency. With repeated allograft transfers, these gastric epithelial cells gradually acquired the properties of malignant gastric cancer. Loss of p53 conferred cell stemness and induced epithelial to mesenchymal transition (EMT) in gastric epithelial cells, and these properties were further enhanced by the in vivo microenvironment, ultimately leading to gastric cancer formation and metastasis. We also found that the in vivo microenvironment enhanced activation of the COX-2 pathway, which further contributed to cancer progression. With this system, we have succeeded in recapitulating the development of malignant gastric cancer from gastric epithelial cells in a normal immune environment. PMID- 29396429 TI - Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of origin of HO in an accurate genetic mouse model of FOP (Acvr1 tnR206H ). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP. PMID- 29396431 TI - Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis. AB - An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFkappaB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy. PMID- 29396432 TI - Simultaneous detection of nucleotide excision repair events and apoptosis-induced DNA fragmentation in genotoxin-treated cells. AB - Novel in vivo excision assays for monitoring the excised oligonucleotide products of nucleotide excision repair in UV-irradiated cells have provided unprecedented views of the kinetics and genomic distribution of repair events. However, an unresolved issue is the fate of the excised oligonucleotide products of repair and their mechanism of degradation. Based on our observation that decreases in excised oligonucleotide abundance coincide with the induction of apoptotic signaling in UV-irradiated cells, we considered the possibility that caspase mediated apoptotic signaling contributes to excised oligonucleotide degradation or to a general inhibition of the excision repair system. However, genetic and pharmacological approaches to inhibit apoptotic signaling demonstrated that caspase-mediated apoptotic signaling does not affect excision repair or excised oligonucleotide stability. Nonetheless, our assay for detecting soluble DNAs produced by repair also revealed the production of larger DNAs following DNA damage induction that was dependent on caspase activation. We therefore further exploited the versatility of this assay by showing that soluble DNAs produced by both nucleotide excision repair and apoptotic signaling can be monitored simultaneously with a diverse set of DNA damaging agents. Thus, our in vivo excision repair assay provides a sensitive measure of both repair kinetics and apoptotic signaling in genotoxin-treated cells. PMID- 29396433 TI - Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1. AB - Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes. PMID- 29396434 TI - Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9. AB - Cancer cells are commonly more resistant to cell death activated by the membranolytic protein complex C5b-9. Several surface-expressed and intracellular proteins that protect cells from complement-dependent cytotoxicity (CDC) have been identified. In this study, we investigated the function of heat shock protein 90 (Hsp90), an essential and ubiquitously expressed chaperone, overexpressed in cancer cells, in C5b-9-induced cell death. As shown, inhibition of Hsp90 with geldanamycin or radicicol is enhancing sensitivity of K562 erythroleukemia cells to CDC. Similarly, Hsp90 inhibition confers in Ramos B cell lymphoma cells elevated sensitivity to treatment with rituximab and complement. C5b-9 deposition is elevated on geldanamycin-treated cells. Purified Hsp90 binds directly to C9 and inhibits zinc-induced C9 polymerization, indicating that Hsp90 may act directly on the C5b-9 complex. Mortalin, also known as stress protein 70 or GRP75, is a mitochondrial chaperone that confers resistance to CDC. The postulated cooperation between Hsp90 and mortalin in protection from CDC was tested. Geldanamycin failed to sensitize toward CDC cells with knocked down mortalin. Direct binding of Hsp90 to mortalin was shown by co-immunoprecipitation in cell extracts after triggering with complement as well as by using purified recombinant proteins. These results provide an insight into the protective mechanisms utilized by cancer cells to evade CDC. They suggest that Hsp90 protects cells from CDC by inhibiting, together with mortalin, C5b-9 assembly and/or stability at the plasma membrane. PMID- 29396435 TI - Identification of influenza polymerase inhibitors targeting C-terminal domain of PA through surface plasmon resonance screening. AB - Currently, many strains of influenza A virus have developed resistance against anti-influenza drugs, and it is essential to find new chemicals to combat this virus. The influenza polymerase with three proteins, PA, PB1 and PB2, is a crucial component of the viral ribonucleoprotein (RNP) complex. Here, we report the identification of a hit compound 221 by surface plasmon resonance (SPR) direct binding screening on the C-terminal of PA (PAC). Compound 221 can subdue influenza RNP activities and attenuate influenza virus replication. Its analogs were subsequently investigated and twelve of them could attenuate RNP activities. One of the analogs, compound 312, impeded influenza A virus replication in Madin Darby canine kidney cells with IC50 of 27.0 +/- 16.8 MUM. In vitro interaction assays showed that compound 312 bound directly to PAC with Kd of about 40 MUM. Overall, the identification of novel PAC-targeting compounds provides new ground for drug design against influenza virus in the future. PMID- 29396436 TI - Effects of elastic band exercise on lean mass and physical capacity in older women with sarcopenic obesity: A randomized controlled trial. AB - Sarcopenia is associated with loss of muscle mass as well as an increased risk of physical disability in elderly people. This study was aimed to investigate the effect of elastic band resistance training (ERT) on muscle mass and physical function in older women with sarcopenic obesity. A randomized controlled trial with an intention-to-treat analysis was conducted. A total of 56 women (mean +/- SD age 67.3 +/- 5.1 years) were randomly assigned to the experimental group receiving 12 weeks of ERT and to the control group receiving no exercise intervention. Lean mass (measured using a dual-energy X-ray absorptiometer), physical capacity (assessed using the global physical capacity score), and a 36 item short form questionnaire were conducted at the baseline examination (T0), as well as the 3-month (T1) and 9-month followups (T2). At T1 and T2, the between group difference was measured in total skeletal mass relative to T0, with mean differences of 0.70 kg (95% CI 0.12-1.28; P < 0.05) and 0.72 kg (95% CI 0.21 1.23; P < 0.01), respectively. Similar results were found in muscle quality, physical capacity, and physical function outcomes. The ERT exerted a significant beneficial effect on muscle mass, muscle quality, and physical function in older women with sarcopenic obesity. PMID- 29396437 TI - Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector. AB - Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a short period of survival even with recent multimodality treatment. The neurotropic JC polyomavirus (JCPyV) infects glial cells and oligodendrocytes and causes fatal progressive multifocal leukoencephalopathy in patients with AIDS. In this study, a possible gene therapy strategy for GBM using JCPyV virus-like particles (VLPs) as a gene delivery vector was investigated. We found that JCPyV VLPs were able to deliver the GFP reporter gene into tumor cells (U87-MG) for expression. In an orthotopic xenograft model, nude mice implanted with U87 cells expressing the near-infrared fluorescent protein and then treated by intratumoral injection of JCPyV VLPs carrying the thymidine kinase suicide gene, combined with ganciclovir administration, exhibited significantly prolonged survival and less tumor fluorescence during the experiment compared with controls. Furthermore, JCPyV VLPs were able to protect and deliver a suicide gene to distal subcutaneously implanted U87 cells in nude mice via blood circulation and inhibit tumor growth. These findings show that metastatic brain tumors can be targeted by JCPyV VLPs carrying a therapeutic gene, thus demonstrating the potential of JCPyV VLPs to serve as a gene therapy vector for the far highly treatment-refractory GBM. PMID- 29396438 TI - Publisher Correction: A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. AB - The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. PMID- 29396439 TI - Characterization of avian influenza H9N2 viruses isolated from ostriches (Struthio camelus). AB - H9N2 subtype avian influenza viruses (AIVs) have been isolated from various species of wild birds and domestic poultry in the world, and occasionally transmitted to humans. Although H9N2 AIVs are seldom isolated from ostriches, seven such strains were isolated from sick ostriches in China between 2013 and 2014. Sequence analysis showed several amino acid changes relating to viral adaptation in mammals were identified. The phylogenetic analyses indicated that these isolates were quadruple reassortant viruses, which are different from the early ostrich isolates from South Africa or Israel. Most of the ostrich virus carried a human-type receptor-binding property. The chicken experiments showed the ostrich strains displayed low pathogenicity, while they could cause mild to severe symptoms in chicken. Theses strains could efficiently transmit among chickens, and one strain showed higher transmissibility. The virus could not kill mice, and merely replicated in the lung of mice. The ostrich strains could not efficiently transmit between guinea pigs in the direct contact model. These results suggested we should pay attention to the interface between ostrich and other domestic fowl, and keep an eye on this population when monitoring of influenza virus. PMID- 29396441 TI - Unusually warm Indian Ocean sea surface temperatures help to arrest development of El Nino in 2014. AB - In early 2014, strong westerly wind bursts (WWBs) and high heat content in the equatorial Pacific favored development of a major El Nino. However, significant coupling between the Pacific Ocean and atmosphere failed to take hold during boreal summer of 2014 such that only borderline El Nino conditions were evident by the end of the year. Observational analysis suggests that warm sea surface temperatures (SSTs) in the Indian Ocean in 2014 weakened westerly wind anomalies in the Pacific and may have helped to arrest the development of the El Nino. We test this hypothesis using an ensemble of coupled numerical experiments in which observed Indian Ocean SST anomalies in 2014-15 are prescribed but the Pacific Ocean-atmosphere system is free to evolve. Results confirm that warm SST anomalies in the Indian Ocean created conditions that would have favored a weakening of El Nino by suppressing the Bjerknes feedback in boreal summer of 2014. This process does not preclude others that have been proposed in the unusual evolution of El Nino SSTs in 2014, but it adds to the list a forcing mechanism external to the Pacific basin. PMID- 29396440 TI - Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression. AB - ZAK, a mixed lineage kinase, is often described as a positive or negative regulator of cell growth. We identified it as one of the top hits in our kinome cDNA screen for potent regulators of epithelial mesenchymal transition (EMT). Ectopic expression of ZAK promoted EMT phenotypes and apoptosis resistance in multiple epithelial cell lines, while having different impacts on cell growth in different cell lines. Conversely, depletion of ZAK in aggressive mesenchymal cancer cells reversed EMT phenotypes, increased sensitivity to conventional cytotoxic drugs, and attenuated bone metastasis potential, with little impact on primary tumor growth. Mechanistically, ZAK-mediated EMT is associated with activation of ZEB1 and suppression of epithelial splicing regulatory proteins (ESRPs), which results in a switch in CD44 expression from the epithelial CD44v8 9 isoform to the mesenchymal CD44s isoform. Of note, transcriptomic analysis showed that ZAK overexpression is significantly associated with poor survival in a number of human cancer types. Tissue microarray analysis on breast invasive carcinoma further supported that ZAK overexpression is an independent poor prognostic factor for overall survival in breast cancer. Through combination with ZAK, prognostic accuracy of other common clinicopathological markers in breast cancer is improved by up to 21%. Taken together, these results suggest that promoting EMT is the primary role for ZAK in cancer progression. They also highlight its potential as a biomarker to identify high-risk patients, and suggest its promise as a therapeutic target for inhibiting metastasis and overcoming drug resistance. PMID- 29396442 TI - Nonthermal plasma treated solution inhibits adipocyte differentiation and lipogenesis in 3T3-L1 preadipocytes via ER stress signal suppression. AB - The accumulation and differentiation of adipocytes contribute to the development of obesity and metabolic diseases. It is well-known that interactions of transcription factors such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer binding protein alpha (C/EBPalpha), and endoplasmic reticulum (ER) stress are required for adipogenesis. Recently, use of nonthermal atmospheric plasma (NTP) is expanding from the biomedical field into various other fields. In this study, we investigated whether nonthermal plasma-treated solution (NTS) has an inhibitory effect on adipogenesis and elucidated its mechanisms. Our results demonstrated that NTS significantly inhibited pre adipocyte differentiation into adipocytes based on Oil Red O staining and triglyceride accumulation. Moreover, NTS treatment suppressed the mRNA and protein expression levels of key adipogenic transcription factors, and adipocyte specific genes. NTS also down-regulated endoplasmic reticulum stress-related proteins. Consistent with in vitro studies, an animal study using a mouse model of diet-induced obesity showed that NTS treatment reduced body weight and fat, ER stress/UPR, triglyceride, and adipogenic marker level without altering food intake. These findings indicate that NTS inhibits adipogenic differentiation, and provide a mechanistic explanation of the inhibitory effect of NTS on adipogenesis. Taken together, our results suggest that NTS might be useful to treat obesity and obesity-related diseases. PMID- 29396443 TI - Signatures of Plexitonic States in Molecular Electroluminescence. AB - We develop a quantum master equation (QME) approach to investigate the electroluminesence (EL) of molecules confined between metallic electrodes and coupled to quantum plasmonic modes. Within our general state-based framework, we describe electronic tunneling, vibrational damping, environmental dephasing, and the quantum coherent dynamics of coupled quantum electromagnetic field modes. As an example, we calculate the STM-induced spontaneous emission of a tetraphenylporphyrin (TPP) molecule coupled to a nanocavity plasmon. In the weak molecular exciton-plasmon coupling regime we find excellent agreement with experiments, including above-threshold hot luminescence, an effect not described by previous semiclassical calculations. In the strong coupling regime, we analyze the spectral features indicative of the formation of plexitonic states. PMID- 29396445 TI - Positive relationship between species richness and aboveground biomass across forest strata in a primary Pinus kesiya forest. AB - Both biodiversity and biomass are important variables in forest ecosystems, and the relationship between them is critical for ecosystem functioning and management. The primary Pinus kesiya forest is increasingly threatened by human disturbance in Yunnan Province. We observed that species richness had a positive impact on aboveground biomass across all forest vegetation layers, and this relationship was strongest in the herb layer. The asymptotic relationship between cumulative species number and aboveground biomass suggested that individual of Pinus kesiya trees with relatively large diameters contributed the majority of the aboveground biomass in the tall tree strata due to their strong competitive advantage over other tree species. Although aboveground biomass increased with stand age in the tall tree strata, climate factors and the soil nutrient regime affected the magnitude of the diversity-productivity relationship. Stand age had no significant effect on species richness and aboveground biomass in the forest understory. The effect of the positive diversity-productivity relationship of the tall trees on the shrub layer was negligible; the diversity-productivity relationship in the forest understory was significantly affected by the tall tree aboveground biomass. The tall trees have increased the strength of the positive diversity-productivity relationship in the forest understory. PMID- 29396444 TI - Differential long non-coding RNA expression profiles in human oocytes and cumulus cells. AB - Progress in assisted reproductive technologies strongly relies on understanding the regulation of the dialogue between oocyte and cumulus cells (CCs). Little is known about the role of long non-coding RNAs (lncRNAs) in the human cumulus oocyte complex (COC). To this aim, publicly available RNA-sequencing data were analyzed to identify lncRNAs that were abundant in metaphase II (MII) oocytes (BCAR4, C3orf56, TUNAR, OOEP-AS1, CASC18, and LINC01118) and CCs (NEAT1, MALAT1, ANXA2P2, MEG3, IL6STP1, and VIM-AS1). These data were validated by RT-qPCR analysis using independent oocytes and CC samples. The functions of the identified lncRNAs were then predicted by constructing lncRNA-mRNA co-expression networks. This analysis suggested that MII oocyte lncRNAs could be involved in chromatin remodeling, cell pluripotency and in driving early embryonic development. CC lncRNAs were co-expressed with genes involved in apoptosis and extracellular matrix-related functions. A bioinformatic analysis of RNA sequencing data to identify CC lncRNAs that are affected by maternal age showed that lncRNAs with age-related altered expression in CCs are essential for oocyte growth. This comprehensive analysis of lncRNAs expressed in human MII oocytes and CCs could provide biomarkers of oocyte quality for the development of non invasive tests to identify embryos with high developmental potential. PMID- 29396446 TI - SMAD4 feedback regulates the canonical TGF-beta signaling pathway to control granulosa cell apoptosis. AB - Canonical TGF-beta signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF beta1), receptors (TGFBR2/1), receptor-activated SMADs (SMAD2/3), and the common SMAD (SMAD4). Here we provide evidence that SMAD4, a core component of the canonical TGF-beta signaling pathway, regulates the canonical TGF-beta signaling pathway in porcine granulosa cells (GCs) through a feedback mechanism. Genome wide analysis and qRT-PCR revealed that SMAD4 affected miRNA biogenesis in GCs. Interestingly, TGFBR2, the type II receptor of the canonical TGF-beta signaling pathway, was downregulated in SMAD4-silenced GCs and found to be a common target of SMAD4-inhibited miRNAs. miR-425, the most significantly elevated miRNA in SMAD4-silenced GCs, mediated the SMAD4 feedback regulation of the TGF-beta signaling pathway. This was accomplished through a direct interaction between the transcription factor SMAD4 and the miR-425 promoter, and a direct interaction between miR-425 and the TGFBR2 3'-UTR. Furthermore, miR-425 enhanced GC apoptosis by targeting TGFBR2 and the canonical TGF-beta signaling pathway, which was rescued by SMAD4 and TGF-beta1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-beta signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-beta signaling pathway, which regulates GC function and follicular development. PMID- 29396447 TI - Associations between serum polybrominated diphenyl ethers and thyroid hormones in a cross sectional study of a remote Alaska Native population. AB - Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants. Arctic indigenous peoples are exposed to PBDEs through a traditional diet high in marine mammals. PBDEs disrupt thyroid homeostasis. The aim of this study was to assess the relationship between serum PBDEs and thyroid function in a remote population of St. Lawrence Island Yupik. Serum samples were collected from 85 individuals from St. Lawrence Island, Alaska and measured for concentrations of PBDEs, free and total thyroxine (T4), free and total triiodothyronine (T3), and thyroid stimulating hormone (TSH). The relationships between PBDEs and thyroid hormones were assessed using multiple linear regression fit with generalized estimating equations. Serum concentrations of several Penta-BDE congeners (BDE 28/33, 47, and 100) were positively associated with concentrations of TSH and free T3, while serum concentration of BDE-153 was negatively associated with total T3 concentrations. Both BDE-47 and 153 remained significantly associated with thyroid hormones when BDE-47, BDE-153, and BDE-209 were covariates in the same model. There were no significant relationships between serum concentrations of PBDEs and either free or total T4. Individual PBDEs are associated with thyroid hormones in serum from a remote population of Alaska Natives, and directions of effect differ by congener. PMID- 29396448 TI - Ventromedial prefrontal cortex mediates sex differences in persistent cognitive drive for food. AB - Contemporary environments are saturated with food cues that stimulate appetites in the absence of hunger, which leads to maladaptive eating. These settings can induce persistent drive to eat, as learned behaviors can reappear after extinction. Behavioral paradigms of responding renewal provide a valuable framework to study how food cues contribute to the inability to resist palatable foods and change maladaptive eating habits. Using a rat model for this persistent food motivation, we determined sex differences in the causal function for the ventromedial prefrontal cortex (vmPFC) during context-mediated renewal of responding to food cues. Previously, we found behavioral sex differences (only males exhibited renewal) and differential recruitment within the vmPFC (increased Fos induction in males but decreased in females). Here, we used DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to silence vmPFC neurons in males and to stimulate vmPFC neurons in females specifically during renewal. Silencing vmPFC neurons in males disrupted renewal of responding to a food cue, while stimulating vmPFC neurons in females induced this behavior. These findings demonstrate sex differences in the vmPFC function in a model of food seeking relevant to environmentally driven appetites contributing to obesity and eating disorders. PMID- 29396450 TI - Publisher Correction: Ambipolar field role in formation of electron distribution function in gas discharge plasma. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396449 TI - Comparative phosphoproteomic analysis reveals signaling networks regulating monopolar and bipolar cytokinesis. AB - The successful completion of cytokinesis requires the coordinated activities of diverse cellular components including membranes, cytoskeletal elements and chromosomes that together form partly redundant pathways, depending on the cell type. The biochemical analysis of this process is challenging due to its dynamic and rapid nature. Here, we systematically compared monopolar and bipolar cytokinesis and demonstrated that monopolar cytokinesis is a good surrogate for cytokinesis and it is a well-suited system for global biochemical analysis in mammalian cells. Based on this, we established a phosphoproteomic signature of cytokinesis. More than 10,000 phosphorylation sites were systematically monitored; around 800 of those were up-regulated during cytokinesis. Reconstructing the kinase-substrate interaction network revealed 31 potentially active kinases during cytokinesis. The kinase-substrate network connects proteins between cytoskeleton, membrane and cell cycle machinery. We also found consensus motifs of phosphorylation sites that can serve as biochemical markers specific to cytokinesis. Beyond the kinase-substrate network, our reconstructed signaling network suggests that combination of sumoylation and phosphorylation may regulate monopolar cytokinesis specific signaling pathways. Our analysis provides a systematic approach to the comparison of different cytokinesis types to reveal alternative ways and a global overview, in which conserved genes work together and organize chromatin and cytoplasm during cytokinesis. PMID- 29396451 TI - Tiny timekeepers witnessing high-rate exhumation processes. AB - Tectonic forces and surface erosion lead to the exhumation of rocks from the Earth's interior. Those rocks can be characterized by many variables including peak pressure and temperature, composition and exhumation duration. Among them, the duration of exhumation in different geological settings can vary by more than ten orders of magnitude (from hours to billion years). Constraining the duration is critical and often challenging in geological studies particularly for rapid magma ascent. Here, we show that the time information can be reconstructed using a simple combination of laser Raman spectroscopic data from mineral inclusions with mechanical solutions for viscous relaxation of the host. The application of our model to several representative geological settings yields best results for short events such as kimberlite magma ascent (less than ~4,500 hours) and a decompression lasting up to ~17 million years for high-pressure metamorphic rocks. This is the first precise time information obtained from direct microstructural observations applying a purely mechanical perspective. We show an unprecedented geological value of tiny mineral inclusions as timekeepers that contributes to a better understanding on the large-scale tectonic history and thus has significant implications for a new generation of geodynamic models. PMID- 29396452 TI - Polymerization-Induced Phase Separation Formation of Structured Hydrogel Particles via Microfluidics for Scar Therapeutics. AB - Excessive scar formation can form disabling contractures that result in a debilitating psychological outcome. Sustainable hydrophobic corticosteroid release in vivo is essential to regulate the wound healing process. Functional hydrogel particles are widely applied for sustainable release. However, due to the limited aqueous solubility of hydrophobic compounds, most of the corticosteroid is released from the hydrogels within seconds, causing undesirable scar formation and recurrence. In this study, a novel polymerization-induced phase separation is investigated to form well-defined polyethylene glycol diacrylate (PEGDA) core/alginate shell structured hydrogel particles using microfluidics without toxic organic solvents. Based on their wettability preference, hydrophobic corticosteroid-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles are compartmentalized in the PEGDA core during polymerization to control the corticosteroid release. The distribution of the PLGA nanoparticles is precisely regulated by the phase separation boundary and characterized using a fluorescent dye. The thickness of the shell and partition coefficients are determined using the UV intensity and irradiation period. Upon encapsulation of the PLGA nanoparticles within the poly(PEGDA) core, a long-term corticosteroid treatment is developed and effective scar therapeutic outcomes are evaluated using both in vitro and in vivo models. PMID- 29396453 TI - SMRT sequencing of full-length transcriptome of flea beetle Agasicles hygrophila (Selman and Vogt). AB - This study was aimed at generating the full-length transcriptome of flea beetle Agasicles hygrophila (Selman and Vogt) using single-molecule real-time (SMRT) sequencing. Four developmental stages of A. hygrophila, including eggs, larvae, pupae, and adults were harvested for isolating total RNA. The mixed samples were used for SMRT sequencing to generate the full-length transcriptome. Based on the obtained transcriptome data, alternative splicing event, simple sequence repeat (SSR) analysis, coding sequence prediction, transcript functional annotation, and lncRNA prediction were performed. Total 9.45 Gb of clean reads were generated, including 335,045 reads of insert (ROI) and 158,085 full-length non-chimeric (FLNC) reads. Transcript clustering analysis of FLNC reads identified 40,004 consensus isoforms, including 31,015 high-quality ones. After removing redundant reads, 28,982 transcripts were obtained. Total 145 alternative splicing events were predicted. Additionally, 12,753 SSRs and 16,205 coding sequences were identified based on SSR analysis. Furthermore, 24,031 transcripts were annotated in eight functional databases, and 4,198 lncRNAs were predicted. This is the first study to perform SMRT sequencing of the full-length transcriptome of A. hygrophila. The obtained transcriptome may facilitate further exploration of the genetic data of A. hygrophila and uncover the interactions between this insect and the ecosystem. PMID- 29396454 TI - Floquet Topological Superfluid and Majorana Zero Modes in Two-Dimensional Periodically Driven Fermi Systems. AB - We propose a simple approach to realize two-dimensional Floquet topological superfluid by periodically tuning the depth of square optical lattice potentials. We show that the periodic driving can induce topological phase transitions between trivial superfluid and Floquet topological superfluid. For this systems we verify the anomalous bulk-boundary correspondence, namely that the robust chiral Floquet edge states can appear even when the winding number of all the bulk Floquet bands is zero. We establish the existence of two Floquet Majorana zero modes separated in the quasienergy space, with epsilon0,pi = 0,pi/T at the topological defects. PMID- 29396455 TI - Non quasi-Hemispherical Seismological Pattern of the Earth's Uppermost Inner Core. AB - We assembled a database consisting of 5,404 PKIKP/PKiKP observations from 555 events, where PKIKP is the phase sampling the inner core (IC) and PKiKP is the phase reflected at the inner core boundary (ICB). Around 138 degrees distances, their differential arrival times and amplitude ratio are mostly sensitive to the seismic velocity and attenuation structure in the uppermost IC (UIC), respectively. Our observations do not support a large-scale anisotropy in the UIC, but do not exclude its presence in some restricted areas. A robust inversion for the isotropic P-wave velocity perturbations shows a higher velocity cap with a radius of ~60 degrees , approximately centered beneath the Northern Sumatra, with a local low velocity zone beneath the central Indian Ocean. The rest of the UIC, including the Northern part of Eurasia and of the Atlantic Ocean, exhibits mostly lower velocity. Amplitude ratio values of PKIKIP/PKiKP (observed vs. computed) from 548 high signal-to-noise (>5) recordings show a large variance, suggesting only a faint correlation between higher velocity and lower attenuation in the UIC. Our results provide better constraints to the models invoking a heat transfer in the UIC, with a complex temperature pattern near ICB. PMID- 29396456 TI - Nanodiamonds-induced effects on neuronal firing of mouse hippocampal microcircuits. AB - Fluorescent nanodiamonds (FND) are carbon-based nanomaterials that can efficiently incorporate optically active photoluminescent centers such as the nitrogen-vacancy complex, thus making them promising candidates as optical biolabels and drug-delivery agents. FNDs exhibit bright fluorescence without photobleaching combined with high uptake rate and low cytotoxicity. Focusing on FNDs interference with neuronal function, here we examined their effect on cultured hippocampal neurons, monitoring the whole network development as well as the electrophysiological properties of single neurons. We observed that FNDs drastically decreased the frequency of inhibitory (from 1.81 Hz to 0.86 Hz) and excitatory (from 1.61 to 0.68 Hz) miniature postsynaptic currents, and consistently reduced action potential (AP) firing frequency (by 36%), as measured by microelectrode arrays. On the contrary, bursts synchronization was preserved, as well as the amplitude of spontaneous inhibitory and excitatory events. Current clamp recordings revealed that the ratio of neurons responding with AP trains of high-frequency (fast-spiking) versus neurons responding with trains of low frequency (slow-spiking) was unaltered, suggesting that FNDs exerted a comparable action on neuronal subpopulations. At the single cell level, rapid onset of the somatic AP ("kink") was drastically reduced in FND-treated neurons, suggesting a reduced contribution of axonal and dendritic components while preserving neuronal excitability. PMID- 29396457 TI - Nondestructive Measurement of Hemoglobin in Blood Bags Based on Multi-Pathlength VIS-NIR Spectroscopy. AB - Hemoglobin concentration is an indicator for assessing blood product quality. To measure hemoglobin concentration in blood products without damaging blood bags, we proposed a method based on visible-near infrared transmission spectroscopy. Complex optical properties of blood bag walls result in measurement irregularities. Analyses showed that the slope of the light intensity-pathlength curve was more robust to the influence of the blood bag wall. In this study, the transmission spectra of red blood cell suspensions at multiple optical pathlengths were obtained, and the slopes of logarithmic light intensity pathlength curves were calculated through curve fitting. A nondestructive measurement of hemoglobin content was achieved by using a regression model correlating slope spectra and hemoglobin concentration. Sixty samples with hemoglobin concentrations ranging from 72 to 161 g/L were prepared. Among them, 40 samples were used as a calibration set, and the remaining 20 samples were used as a prediction set. The determination coefficient of the prediction set was 0.97, with a mean square error of 2.78 g/L. This result demonstrates that a non destructive measurement of hemoglobin levels in blood bags can be achieved by multiple-pathlength transmission spectroscopy. PMID- 29396458 TI - Mossbauer spectroscopy of a monolayer of single molecule magnets. AB - The use of single molecule magnets (SMMs) as cornerstone elements in spintronics and quantum computing applications demands that magnetic bistability is retained when molecules are interfaced with solid conducting surfaces. Here, we employ synchrotron Mossbauer spectroscopy to investigate a monolayer of a tetrairon(III) (Fe4) SMM chemically grafted on a gold substrate. At low temperature and zero magnetic field, we observe the magnetic pattern of the Fe4 molecule, indicating slow spin fluctuations compared to the Mossbauer timescale. Significant structural deformations of the magnetic core, induced by the interaction with the substrate, as predicted by ab initio molecular dynamics, are also observed. However, the effects of the modifications occurring at the individual iron sites partially compensate each other, so that slow magnetic relaxation is retained on the surface. Interestingly, these deformations escaped detection by conventional synchrotron-based techniques, like X-ray magnetic circular dichroism, thus highlighting the power of synchrotron Mossbauer spectroscopy for the investigation of hybrid interfaces. PMID- 29396459 TI - Water Resistant Cellulose - Titanium Dioxide Composites for Photocatalysis. AB - Novel water resistant photocatalytic composites of microfibrillated cellulose (MFC)-polyamide-amine-epichlorohydrin (PAE)-TiO2 nanoparticles (NPs) were prepared by a simple two-step mixing process. The composites produced are flexible, uniform, reproducible and reusable; they can readily be removed from the pollutant once used. Small amount of TiO2 NPs are required for the loaded composites to exhibit a remarkable photocatalytic activity which is quantified here as achieving at least 95% of methyl orange degradation under 150 min of UV light irradiation for the composite with best combination. The cellulose network combined with PAE strongly retains NPs and hinders their release in the environment. PAE dosage (10 and 50 mg/g MFC) controls the NP retention in the cellulose fibrous matrix. As TiO2 content increases, the photocatalytic activity of the composites levels off to a constant; this is reached at 2wt% TiO2 NPs for 10 mg/g PAE and 20wt% for 50 mg/g PAE. SEM and SAXS analysis confirms the uniform distribution of NPs and their formation of aggregates in the cellulose fibre network. These economical and water resistant photocatalytic paper composites made by a simple, robust and easily scalable process are ideal for applications such as waste water treatment where efficiency, reusability and recyclability are important. PMID- 29396462 TI - VO2-dispersed glass: A new class of phase change material. AB - Energy storage technology is crucial for a sustainable society, and its realisation strongly depends on the development of materials. Oxide glass exhibits high durability. Moreover, the amorphous structure of the glass without periodic ordering demonstrates excellent formability and controllability, thus enabling a large-scale production. These factors provide impetus for the development of new materials for thermal management applications. As vanadium dioxide (VO2) with a strongly correlated electron system exhibits a structural phase transition, leading to a large heat of transition. Therefore, VO2 demonstrates immense potential as a phase change material (PCM). This study reports the fabrication of VO2-dispersed glass and examines its potential as a new latent heat storage material, which can be applied for massive PCM heat storage applications. PMID- 29396461 TI - The anillin-related Int1 protein and the Sep7 septin collaborate to maintain cellular ploidy in Candida albicans. AB - Variation in cell ploidy is a common feature of Candida albicans clinical isolates that are resistant to the antifungal drug fluconazole. Here, we report that the anillin-related protein Int1 interacts with septins for coupling cytokinesis with nuclear segregation. Loss of Int1 results in a rapid disassembly of duplicated septin rings from the bud neck at the onset of actomyosin ring contraction. Strikingly, this has no major impact on cytokinesis and septum formation. However, Int1 genetically interacts with the Sep7 septin, maintaining the diffusion barrier at the bud neck and guarantying a faithful nuclear segregation. Indeed, int1DeltaDelta sep7DeltaDelta mutant cells, in contrast to int1DeltaDelta cdc10DeltaDelta, undergo a premature activation of mitotic exit prior to the alignment of the mitotic spindle with the division axis, producing large multinucleated cells. Some of these multinucleated cells arise from trimeras similar to those observed upon fluconazole exposure. Finally, the defects in nuclear segregation could be in part due to the inability to maintain the Lte1 mitotic exit activator at the cortex of the daughter cell. These results suggest that Int1 and Sep7 play a role in maintaining genome stability by acting as a diffusion barrier for Lte1. PMID- 29396460 TI - Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. AB - Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants. PMID- 29396463 TI - The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance. AB - Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3'-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a 'miR-135b-BMAL1-YY1' loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance. PMID- 29396464 TI - Predicting optimum crop designs using crop models and seasonal climate forecasts. AB - Expected increases in food demand and the need to limit the incorporation of new lands into agriculture to curtail emissions, highlight the urgency to bridge productivity gaps, increase farmers profits and manage risks in dryland cropping. A way to bridge those gaps is to identify optimum combination of genetics (G), and agronomic managements (M) i.e. crop designs (GxM), for the prevailing and expected growing environment (E). Our understanding of crop stress physiology indicates that in hindsight, those optimum crop designs should be known, while the main problem is to predict relevant attributes of the E, at the time of sowing, so that optimum GxM combinations could be informed. Here we test our capacity to inform that "hindsight", by linking a tested crop model (APSIM) with a skillful seasonal climate forecasting system, to answer "What is the value of the skill in seasonal climate forecasting, to inform crop designs?" Results showed that the GCM POAMA-2 was reliable and skillful, and that when linked with APSIM, optimum crop designs could be informed. We conclude that reliable and skillful GCMs that are easily interfaced with crop simulation models, can be used to inform optimum crop designs, increase farmers profits and reduce risks. PMID- 29396465 TI - The rolB plant oncogene affects multiple signaling protein modules related to hormone signaling and plant defense. AB - The rolB plant oncogene of Agrobacterium rhizogenes perturbs many biochemical processes in transformed plant cells, thereby causing their neoplastic reprogramming. The oncogene renders the cells more tolerant to environmental stresses and herbicides and inhibits ROS elevation and programmed cell death. In the present work, we performed a proteomic analysis of Arabidopsis thaliana rolB expressing callus line AtB-2, which represents a line with moderate expression of the oncogene. Our results show that under these conditions rolB greatly perturbs the expression of some chaperone-type proteins such as heat-shock proteins and cyclophilins. Heat-shock proteins of the DnaK subfamily were overexpressed in rolB-transformed calli, whereas the abundance of cyclophilins, members of the closely related single-domain cyclophilin family was decreased. Real-time PCR analysis of corresponding genes confirmed the reliability of proteomics data because gene expression correlated well with the expression of proteins. Bioinformatics analysis indicates that rolB can potentially affect several levels of signaling protein modules, including effector-triggered immunity (via the RPM1 RPS2 signaling module), the miRNA processing machinery, auxin and cytokinin signaling, the calcium signaling system and secondary metabolism. PMID- 29396467 TI - Surface temperatures in New York City: Geospatial data enables the accurate prediction of radiative heat transfer. AB - Despite decades of research seeking to derive the urban energy budget, the dynamics of thermal exchange in the densely constructed environment is not yet well understood. Using New York City as a study site, we present a novel hybrid experimental-computational approach for a better understanding of the radiative heat transfer in complex urban environments. The aim of this work is to contribute to the calculation of the urban energy budget, particularly the stored energy. We will focus our attention on surface thermal radiation. Improved understanding of urban thermodynamics incorporating the interaction of various bodies, particularly in high rise cities, will have implications on energy conservation at the building scale, and for human health and comfort at the urban scale. The platform presented is based on longwave hyperspectral imaging of nearly 100 blocks of Manhattan, in addition to a geospatial radiosity model that describes the collective radiative heat exchange between multiple buildings. Despite assumptions in surface emissivity and thermal conductivity of buildings walls, the close comparison of temperatures derived from measurements and computations is promising. Results imply that the presented geospatial thermodynamic model of urban structures can enable accurate and high resolution analysis of instantaneous urban surface temperatures. PMID- 29396466 TI - The effect of constitutive representations and structural constituents of ligaments on knee joint mechanics. AB - Ligaments provide stability to the human knee joint and play an essential role in restraining motion during daily activities. Compression-tension nonlinearity is a well-known characteristic of ligaments. Moreover, simpler material representations without this feature might give reasonable results because ligaments are primarily in tension during loading. However, the biomechanical role of different constitutive representations and their fibril-reinforced poroelastic properties is unknown. A numerical knee model which considers geometric and material nonlinearities of meniscus and cartilages was applied. Five different constitutive models for the ligaments (spring, elastic, hyperelastic, porohyperelastic, and fibril-reinforced porohyperelastic (FRPHE)) were implemented. Knee joint forces for the models with elastic, hyperelastic and porohyperelastic properties showed similar behavior throughout the stance, while the model with FRPHE properties exhibited lower joint forces during the last 50% of the stance phase. The model with ligaments as springs produced the lowest joint forces at this same stance phase. The results also showed that the fibril network contributed substantially to the knee joint forces, while the nonfibrillar matrix and fluid had small effects. Our results indicate that simpler material models of ligaments with similar properties in compression and tension can be used when the loading is directed primarily along the ligament axis in tension. PMID- 29396468 TI - Alterations of Pregnant Gait during Pregnancy and Post-Partum. AB - Physique changes during pregnancy lead to gait characteristic variations. This study aimed to analyse gait of pregnant individuals throughout pregnancy and post partum. Sixteen healthy pregnant women volunteered as participants and had their lower limb kinematics analysed through a VICON three-dimensional motion system and plantar pressure measured with a Novel EMED force plate. Significant changes were observed in pelvic anterior motion, hip and ankle joint kinematics. Mean pressure distribution and COP trajectory deviation altered accordingly with increased pregnancy time, compared with post-partum. This longitudinal study of pregnant gait biomechanics in T2, T3 and PP reveals lower extremity kinematic and foot pressure alterations to adapt to pregnancy related changes, and the COP trajectory highlights a falling risk during pregnancy, particularly in T3. PMID- 29396469 TI - The exchange bias behavior of BiFeO3 nanoparticles with natural core-shell structure. AB - The surface and interface effects of small antiferromagnetic nanostructures are important on the modulation of their magnetic properties. In this report, temperature and particle size dependent magnetic exchange bias effect was investigated in BiFeO3 (BFO) nanoparticles that possess natural core-shell structure. Nonmonotonic variation of exchange bias field, interesting surface spin-glass state and improved exchange bias training effect are only obtained in 18 nm BFO particles. Based on comparative experiments on particles with different sizes, we found that the surface spins and the interaction among them show great effect on the interfacial exchange coupling of the core-shell structure, and thus are responsible for the peculiar exchange bias behavior in small BFO nanoparticles. Our work provides the effect of surface spin state on the magnetic characteristics of nanomaterials and will favor their applications on spintronic devices. PMID- 29396470 TI - Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking. AB - CD134 (OX40) is a member of the tumour necrosis factor receptor superfamily (TNFRSF). It acts as a costimulatory receptor on T cells, but its role on NK cells is poorly understood. CD137, another TNFRSF member has been shown to enhance the anti-tumour activity of NK cells in various malignancies. Here, we examine the expression and function of CD134 on human and mouse NK cells in B cell lymphoma. CD134 was transiently upregulated upon activation of NK cells in both species. In contrast to CD137, induction of CD134 on human NK cells was dependent on close proximity to, or cell-to-cell contact with, monocytes or T cells. Stimulation with an agonistic anti-CD134 mAb but not CD134 ligand, increased IFNgamma production and cytotoxicity of human NK cells, but this was dependent on simultaneous antibody:Fcgamma receptor binding. In complementary murine studies, intravenous inoculation with BCL1 lymphoma into immunocompetent syngeneic mice resulted in transient upregulation of CD134 on NK cells. Combination treatment with anti-CD20 and anti-CD134 mAb produced a synergistic effect with durable remissions. This therapeutic benefit was abrogated by NK cell depletion and in Fcgamma chain -/- mice. Hence, anti-CD134 agonists may enhance NK-mediated anti-tumour activity in an Fcgamma receptor dependent fashion. PMID- 29396471 TI - Publisher Correction: Crystal Orientation Dependence of Gallium Nitride Wear. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396472 TI - Propagation-based phase-contrast synchrotron imaging of aortic dissection in mice: from individual elastic lamella to 3D analysis. AB - In order to show the advantage and potential of propagation-based phase-contrast synchrotron imaging in vascular pathology research, we analyzed aortic medial ruptures in BAPN/AngII-infused mice, a mouse model for aortic dissection. Ascending and thoraco-abdominal samples from n = 3 control animals and n = 10 BAPN/AngII-infused mice (after 3, 7 and 14 days of infusion, total of 24 samples) were scanned. A steep increase in the number of ruptures was already noted after 3 days of BAPN/AngII-infusion. The largest ruptures were found at the latest time points. 133 ruptures affected only the first lamella while 135 ruptures affected multiple layers. Medial ruptures through all lamellar layers, leading to false channel formation and intramural hematoma, occurred only in the thoraco-abdominal aorta and interlamellar hematoma formation in the ascending aorta could be directly related to ruptures of the innermost lamellae. The advantages of this technique are (i) ultra-high resolution that allows to visualize the individual elastic lamellae in the aorta; (ii) quantitative and qualitative analysis of medial ruptures; (iii) 3D analysis of the complete aorta; (iv) high contrast for qualitative information extraction, reducing the need for histology coupes; (v) earlier detection of (micro-) ruptures. PMID- 29396473 TI - Decreased TESK1-mediated cofilin 1 phosphorylation in the jejunum of IBS-D patients may explain increased female predisposition to epithelial dysfunction. AB - Disturbed intestinal epithelial barrier and mucosal micro-inflammation characterize irritable bowel syndrome (IBS). Despite intensive research demonstrating ovarian hormones modulation of IBS severity, there is still limited knowledge on the mechanisms underlying female predominance in this disorder. Our aim was to identify molecular pathways involved in epithelial barrier dysfunction and female predominance in diarrhea-predominant IBS (IBS-D) patients. Total RNA and protein were obtained from jejunal mucosal biopsies from healthy controls and IBS-D patients meeting the Rome III criteria. IBS severity was recorded based on validated questionnaires. Gene and protein expression profiles were obtained and data integrated to explore biological and molecular functions. Results were validated by western blot. Tight junction signaling, mitochondrial dysfunction, regulation of actin-based motility by Rho, and cytoskeleton signaling were differentially expressed in IBS-D. Decreased TESK1-dependent cofilin 1 phosphorylation (pCFL1) was confirmed in IBS-D, which negatively correlated with bowel movements only in female participants. In conclusion, deregulation of cytoskeleton dynamics through TESK1/CFL1 pathway underlies epithelial intestinal dysfunction in the small bowel mucosa of IBS-D, particularly in female patients. Further understanding of the mechanisms involving sex-mediated regulation of mucosal epithelial integrity may have significant preventive, diagnostic, and therapeutic implications for IBS. PMID- 29396474 TI - Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA. AB - Recent studies show substantial growth-promoting properties of nicotine (NIC) in cancer, which is a combined outcome of genetic and epigenetic alterations. However, the role of epigenetic modifiers in response to NIC in breast cancer is less studied. In the present study, for the first time we have shown NIC-induced enhanced EZH2 expression. Six pairs of smoking-associated breast cancer patient tissues were analyzed. Samples from smoking breast cancer patients showed distinguished enhanced EZH2 expression in comparison to non-smoking ones. The upregulation in EZH2, which is due to NIC, was further confirmed in breast carcinoma cell lines using 10 uM NIC, 1 uM DZNepA, and EZH2si. The upregulation of EZH2 was concomitant with upregulation in Myc and alpha9-nAChR. The xenograft of breast cancer cells in BALB/c nude mice in the presence or absence of NIC showed significantly higher tumor uptake in the NIC injected group, which clearly demonstrates the effect of NIC in breast cancer progression. Interestingly, DZNepA considerably suppressed the NIC-mediated tumor growth. CHIP-qPCR assay confirmed the increased Myc enrichment on EZH2 promoter upon NIC treatment, thereby strengthening our findings that there exists an association between NIC, Myc, and EZH2. Overall, the present study identifies a strong association between NIC and EZH2 particularly in the progression of breast cancer in smokers through a novel axis involving nAChR and Myc. Moreover, the findings provide preliminary evidence suggesting potential of high level of EZH2 expression as a prognostic marker in smoking-associated breast cancer. PMID- 29396475 TI - Visible light sensitizer-catalyzed highly selective photo oxidation from thioethers into sulfoxides under aerobic condition. AB - We report herein a visible light sensitizer-catalyzed aerobic oxidation of thioethers, affording sulfoxides in good to excellent yields. The loading of the catalyst was as low as 0.1 mol%. The selectivity was excellent. Mechanism studies showed both singlet oxygen and superoxide radical anion were likely involved in this transformation. PMID- 29396476 TI - Molecular and Functional Characterization of pheromone binding protein 1 from the Oriental Fruit Moth, Grapholita molesta (Busck). AB - Pheromone binding protein (PBP) is thought primarily to bind and transport the sex pheromone in moths. The accumulated studies suggest that three PBPs were identified in moth species. In Grapholita molesta, the functions of GmolPBP2 and GmolPBP3 have been previously studied. However, the function of GmolPBP1 is still unclear. Furthermore, the Cydia pomonella sex pheromone Codlemone can act as a sex pheromone synergist of G. molesta. In C. pomonella, CpomPBP1 specifically bind the Codlemone. CpomPBP1 displays high identity with GmolPBP1 (70%), indicating that the two PBPs may share a similar 3D structure thus can bind the similar or same ligands. In this study, we explored the molecular and functional characterization of GmolPBP1. GmolPBP1, bearing the typical characteristics of Lepidopteran odorant binding proteins, was closest phylogenetically to CpomPBP1. Binding studies demonstrated that GmolPBP1 exhibited strong binding affinities with (Z)-8-dodecenyl alcohol, 1-dodecanol and Codlemone. Molecular docking showed that GmolPBP1 has different ligand recognition mechanism for the three ligands. Our results suggest that GmolPBP1 functions as recognizer of (Z)-8-dodecenyl alcohol and 1-dodecanol of the female sex pheromone blend, and may be the potential transporter of Codlemone, which contributes to the synergism of the pheromone response of G. molesta by Codlemone. PMID- 29396477 TI - The odd one out: Arabidopsis reticulon 20 does not bend ER membranes but has a role in lipid regulation. AB - Reticulons are integral ER membrane proteins characterised by a reticulon homology domain comprising four transmembrane domains which results in the proteins sitting in the membrane in a W-topology. Here we report on a novel subgroup of reticulons with an extended N-terminal domain and in particular on arabidopsis reticulon 20. Using high resolution confocal microscopy we show that reticulon 20 is located in a unique punctate pattern on the ER membrane. Its closest homologue reticulon 19 labels the whole ER. Other than demonstrated for the other members of the reticulon protein family RTN20 and 19 do not display ER constriction phenotypes on over expression. We show that mutants in RTN20 or RTN19, respectively, display a significant change in sterol composition in roots indicating a role in lipid regulation. A third homologue in this family 3BETAHSD/D1- is unexpectedly localised to ER exit sites resulting in an intriguing location difference for the three proteins. PMID- 29396478 TI - Direct effects of transcranial electric stimulation on brain circuits in rats and humans. AB - Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an 'intersectional short pulse' stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols. PMID- 29396479 TI - Evolving affinity between Coulombic reversibility and hysteretic phase transformations in nano-structured silicon-based lithium-ion batteries. AB - Nano-structured silicon is an attractive alternative anode material to conventional graphite in lithium-ion batteries. However, the anode designs with higher silicon concentrations remain to be commercialized despite recent remarkable progress. One of the most critical issues is the fundamental understanding of the lithium-silicon Coulombic efficiency. Particularly, this is the key to resolve subtle yet accumulatively significant alterations of Coulombic efficiency by various paths of lithium-silicon processes over cycles. Here, we provide quantitative and qualitative insight into how the irreversible behaviors are altered by the processes under amorphous volume changes and hysteretic amorphous-crystalline phase transformations. Repeated latter transformations over cycles, typically featured as a degradation factor, can govern the reversibility behaviors, improving the irreversibility and eventually minimizing cumulative irreversible lithium consumption. This is clearly different from repeated amorphous volume changes with different lithiation depths. The mechanism behind the correlations is elucidated by electrochemical and structural probing. PMID- 29396480 TI - Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. AB - Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers. PMID- 29396481 TI - Conserved DNA Methylation Signatures in Early Maternal Separation and in Twins Discordant for CO2 Sensitivity. AB - Respiratory and emotional responses to blood-acidifying inhalation of CO2 are markers of some human anxiety disorders, and can be enhanced by repeatedly cross fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO2 sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO2 challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO2 hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO2 hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field. PMID- 29396482 TI - Gasoline particle filter reduces oxidative DNA damage in bronchial epithelial cells after whole gasoline exhaust exposure in vitro. AB - A substantial amount of traffic-related particle emissions is released by gasoline cars, since most diesel cars are now equipped with particle filters that reduce particle emissions. Little is known about adverse health effects of gasoline particles, and particularly, whether a gasoline particle filter (GPF) influences the toxicity of gasoline exhaust emissions. We drove a dynamic test cycle with a gasoline car and studied the effect of a GPF on exhaust composition and airway toxicity. We exposed human bronchial epithelial cells (ECs) for 6 hours, and compared results with and without GPF. Two hours later, primary human natural killer cells (NKs) were added to ECs to form cocultures, while some ECs were grown as monocultures. The following day, cells were analyzed for cytotoxicity, cell surface receptor expression, intracellular markers, oxidative DNA damage, gene expression, and oxidative stress. The particle amount was significantly reduced due to GPF application. While most biological endpoints did not differ, oxidative DNA damage was significantly reduced in EC monocultures exposed to GPF compared to reference exhaust. Our findings indicate that a GPF has beneficial effects on exhaust composition and airway toxicity. Further studies are needed to assess long-term effects, also in other cell types of the lung. PMID- 29396483 TI - Contractile Skeletal Muscle Cells Cultured with a Conducting Soft Wire for Effective, Selective Stimulation. AB - Contractile skeletal muscle cells were cultured so as to wrap around an electrode wire to enable their selective stimulation even when they were co-cultured with other electrically-excitable cells. Since the electrode wire was composed of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and polyurethane (PU), which is soft and highly capacitive (~10 mF cm-2), non-faradaic electrical stimulation with charge/discharge currents could be applied to the surrounding cells without causing significant damage even for longer periods (more than a week). The advantage of this new culture system was demonstrated in the study of chemotactic interaction of monocytes and skeletal muscle cells via myokines. PMID- 29396484 TI - The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4-dependent migration of cancer cells. AB - We have earlier found abnormal expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2, S18-2) in endometrial cancer, compared to the expression in hyperplasia and in normal endometrium. Here we report that expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer (PCa). The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in PCa cell lines. Moreover, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. Neutralizing CXCR4 protein or abrogating S18-2 expression in cells significantly reduced their migratory ability directed toward CXCL12. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level. Together, these data suggest that the S18-2 protein induces EMT through the TWIST2/E-cadherin signalling and, consequently, CXCR4 mediated migration of PCa cells. PMID- 29396485 TI - hnRNP A1/A2 and Sam68 collaborate with SRSF10 to control the alternative splicing response to oxaliplatin-mediated DNA damage. AB - Little is known about how RNA binding proteins cooperate to control splicing, and how stress pathways reconfigure these assemblies to alter splice site selection. We have shown previously that SRSF10 plays an important role in the Bcl-x splicing response to DNA damage elicited by oxaliplatin in 293 cells. Here, RNA affinity assays using a portion of the Bcl-x transcript required for this response led to the recovery of the SRSF10-interacting protein 14-3-3epsilon and the Sam68-interacting protein hnRNP A1. Although SRSF10, 14-3-3epsilon, hnRNP A1/A2 and Sam68 do not make major contributions to the regulation of Bcl-x splicing under normal growth conditions, upon DNA damage they become important to activate the 5' splice site of pro-apoptotic Bcl-xS. Our results indicate that DNA damage reconfigures the binding and activity of several regulatory RNA binding proteins on the Bcl-x pre-mRNA. Moreover, SRSF10, hnRNP A1/A2 and Sam68 collaborate to drive the DNA damage-induced splicing response of several transcripts that produce components implicated in apoptosis, cell-cycle control and DNA repair. Our study reveals how the circuitry of splicing factors is rewired to produce partnerships that coordinate alternative splicing across processes crucial for cell fate. PMID- 29396486 TI - In vivo microbiome and associated immune markers: New insights into the pathogenesis of vaginal dysbiosis. AB - The microbiota fulfils a key role in the training and function of the immune system, which contributes to the symbiosis between the host and complex microbial communities. In this study, we characterized the interplay between vaginal bacteria and local immune mediators during dysbiosis in selected women of reproductive age who were grouped according to Nugent's criteria. The abundance of Gardnerella vaginalis and Bifidobacterium breve was increased in the intermediate dysbiotic status, while the presence of a plethora of non-resident bacteria characterized the group with overt vaginosis. In response to these increases, the anti-inflammatory IL1ra and pro-inflammatory IL2 increased, while the embryo trophic factors FGFbeta and GMCSF decreased compared to the healthy milieu. A specific pattern, including IL1alpha, IL1beta, IL8, MIG, MIP1alpha and RANTES, distinguished the intermediate group from the vaginosis group, while IL5 and IL13, which are secreted by Th2 cells, were significantly associated with the perturbation of the commensals Lactobacilli, Gardnerella and Ureaplasma. Summarizing, we postulate that although the dysbiotic condition triggers a pro inflammatory process, the presence of a steady state level of Th2 may influence clinical manifestations. These results raise clinically relevant questions regarding the use of vaginal immunological markers as efficacious tools to monitor microbial alterations. PMID- 29396487 TI - 3D auxetic single material periodic structure with ultra-wide tunable bandgap. AB - The design and the combination of innovative metamaterials are attracting increasing interest in the scientific community because of their unique properties that go beyond the ones of natural materials. In particular, auxetic materials and phononic crystals are widely studied for their negative Poisson's ratio and their bandgap opening properties, respectively. In this work, auxeticity and phononic crystals bandgap properties are properly combined to obtain a single phase periodic structure with a tridimensional wide tunable bandgap. When an external tensile load is applied to the structure, the auxetic unit cells change their configurations by exploiting the negative Poisson's ratio and this results in the tuning, either hardening or softening, of the frequencies of the modes limiting the 3D bandgap. Moreover, the expansion of the unit cell in all the directions, due to the auxeticity property, guarantees a fully 3D bandgap tunability of the proposed structure. Numerical simulations and analytical models are proposed to prove the claimed properties. The first experimental evidence of the tunability of a wide 3D bandgap is then shown thanks to the fabrication of a prototype by means of additive manufacturing. PMID- 29396488 TI - Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers. AB - Signal crosstalk between distinct G protein-coupled receptors (GPCRs) is one mechanism that underlies pleiotropic signalling. Such crosstalk is also pertinent for GPCRs activated by gonadotrophic hormones; follicle-stimulating hormone (FSH) and luteinising hormone (LH), with specific relevance to female reproduction. Here, we demonstrate that gonadotrophin receptor crosstalk alters LH-induced Galphaq/11-calcium profiles. LH-induced calcium signals in both heterologous and primary human granulosa cells were prolonged by FSHR coexpression via influx of extracellular calcium in a receptor specific manner. LHR/FSHR crosstalk involves Galphaq/11 activation as a Galphaq/11 inhibitor abolished calcium responses. Interestingly, the enhanced LH-mediated calcium signalling induced by FSHR co expression was dependent on intracellular calcium store release and involved Gbetagamma. Biophysical analysis of receptor and Galphaq interactions indicated that ligand-dependent association between LHR and Galphaq was rearranged in the presence of FSHR, enabling FSHR to closely associate with Galphaq following LHR activation. This suggests that crosstalk may occur via close associations as heteromers. Super-resolution imaging revealed that LHR and FSHR formed constitutive heteromers at the plasma membrane. Intriguingly, the ratio of LHR:FSHR in heterotetramers was specifically altered following LH treatment. We propose that functionally significant FSHR/LHR crosstalk reprograms LH-mediated calcium signalling at the interface of receptor-G protein via formation of asymmetric complexes. PMID- 29396489 TI - Increased risk of coronary heart disease among patients with primary Sjogren's syndrome: a nationwide population-based cohort study. AB - To investigate the association between primary Sjogren's syndrome (pSS) and coronary heart disease (CHD), and the influence of medications for pSS patients on risk of CHD. The authors identified 4175 patients with a new diagnosis of pSS between 2002 and 2013 from the National Health Insurance Research database. The control-to-case ratio was 4:1. The risk and cumulative incidences of CHD were calculated. The adjusted hazard ratio (HR) of CHD for pSS patients was 1.17 (1.03 1.34) after adjusting for age, sex, comorbidities, and medications. The cumulative incidence for CHD in the pSS group was significantly higher than that in the control group (log-rank p < 0.0001). The risk of CHD in pSS patients was increased with age by 4% per year, and 45- to 59-year-olds were at the highest risk (HR = 1.464, 1.195-1.794). The application of corticosteroids (HR = 1.45, 1.07-1.97) as well as NSAIDs (HR = 1.31, 1.05-1.65) both increased the risk of CHD among pSS patients. pSS is associated with an increased risk of subsequent CHD in Taiwan. Primary Sjogren's syndrome might be an independent risk factor for CHD. Use of corticosteroids and NSAIDs in the treatment of pSS patients increased the risk of developing CHD. PMID- 29396490 TI - Fast modification on wheat straw outer surface by water vapor plasma and its application on composite material. AB - The presence of non-poplar extracts, cutin, and wax layer in the wheat straw outer surface (WOS) greatly limit its application in bio-composite preparation. In this study, a dielectric-barrier-discharge plasma using water vapor as feeding gas was used to fast modify the WOS. The morphology, free radical concentrations, surface chemical components, and contact angles of WOS before and after plasma modification were investigated. Wheat straw was further prepared into wheat straw based composites (WSC) and its bonding strength was evaluated by a paper tension meter. The results showed that water vapor plasma leads to the appearance of surface roughness, the generation of massive free radicals, and the introduction of oxygen-containing groups. In addition, both initial and equilibrium contact angle and the surface total free energy were significantly increased after plasma modification. These results synergistically facilitate the spread and permeation of adhesive onto the WOS and thus improve the bonding strength of all prepared WSCs. A good linear relationship between bonding strength and surface roughness parameters, contact angles, and total free energy were observed. In general, this study provided a time-saving and cost-effective modification method to realize WSC manufacture. PMID- 29396491 TI - Most species are not limited by an Amazonian river postulated to be a border between endemism areas. AB - At broad scales in the Amazon, it is often hypothesized that species distributions are limited by geographical barriers, such as large rivers (river barrier hypothesis). This hypothesis has been used to explain the spatial distribution limits of species and to indicate endemism areas for several phylogenetic lineages. We tested the ability of the river-barrier hypothesis to explain patterns of species diversity and spatial-distribution limits for 1952 easily-detected species in 14 taxonomic groups that occur around the Madeira River, and our results indicate that the hypothesis that the Madeira River is the border between endemism areas and explains much of the diversity found in the region is inappropriate for >99% of species. This indicates that alternative hypotheses should be proposed to explain the limits of distributions of species around the Madeira River, as well as a revision of the criteria that are used to determine species-endemism areas. PMID- 29396492 TI - Early Detection of Apathetic Phenotypes in Huntington's Disease Knock-in Mice Using Open Source Tools. AB - Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington's disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test HttQ111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, HttQ111/+ mice exhibit reduced PR performance at 9-11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies. PMID- 29396494 TI - Broadband single-phase hyperbolic elastic metamaterials for super-resolution imaging. AB - Hyperbolic metamaterials, the highly anisotropic subwavelength media, immensely widen the engineering feasibilities for wave manipulation. However, limited by the empirical structural topologies, the reported hyperbolic elastic metamaterials (HEMMs) suffer from the limitations of the relatively narrow frequency width, inflexible adjustable operating subwavelength scale and difficulty to further improve the imaging resolution. Here, we show an inverse design strategy for HEMMs by topology optimization. We design broadband single phase HEMMs supporting multipolar resonances at different prescribed deep subwavelength scales, and demonstrate the super-resolution imaging for longitudinal waves. Benefiting from the extreme enhancement of the evanescent waves, an optimized HEMM at an ultra-low frequency can yield an imaging resolution of ~lambda/64, representing the record in the field of elastic metamaterials. The present research provides a novel and general design methodology for exploring the HEMMs with unrevealed mechanisms and guides the ultrasonography and general biomedical applications. PMID- 29396495 TI - Structure-guided design of Serratia marcescens short-chain dehydrogenase/reductase for stereoselective synthesis of (R)-phenylephrine. AB - Bioconversion is useful to produce optically pure enantiomers in the pharmaceutical industry, thereby avoiding problems with side reactions during organic synthesis processes. A short-chain dehydrogenase/reductase from Serratia marcescens BCRC 10948 (SmSDR) can stereoselectively convert 1-(3-hydroxyphenyl)-2 (methylamino) ethanone (HPMAE) into (R)-phenylephrine [(R)-PE], which is marketed medically as a nasal decongestant agent. The whole-cell conversion process for the synthesis of (R)-PE using SmSDR was reported to have an unexpectedly low conversion rate. We reported the crystal structure of the SmSDR and designed profitable variants to improve the enzymatic activity by structure-guided approach. Several important residues in the structure were observed to form hydrophobic clusters that stabilize the mobile loops surrounding the pocket. Of these, Phe98 and Phe202 face toward each other and connect the upper curvature from the two arms (i.e., the alpha7 helix and loopbeta4-alpha4). The mutant structure of the double substitutions (F98YF202Y) exhibited a hydrogen bond between the curvatures that stabilizes the flexible arms. Site-directed mutagenesis characterization revealed that the mutations (F98Y, F98YF202Y, and F98YF202L) of the flexible loops that stabilize the region exhibited a higher transformation activity toward HPMAE. Together, our results suggest a robust structure-guided approach that can be used to generate a valuable engineered variant for pharmaceutical applications. PMID- 29396496 TI - Metals Enhance the Killing of Bacteria by Bacteriophage in Human Blood. AB - Multidrug-resistant bacterial pathogens are a major medical concern. E. coli, particularly the pathotype extraintestinal pathogenic E. coli (ExPEC), is a leading cause of bloodstream infections. As natural parasites of bacteria, bacteriophages are considered a possible solution to treat patients infected with antibiotic resistant strains of bacteria. However, the development of phage as an anti-infective therapeutic is hampered by limited knowledge of the physiologic factors that influence their properties in complex mammalian environments such as blood. To address this barrier, we tested the ability of phage to kill ExPEC in human blood. Phages are effective at killing ExPEC in conventional media but are substantially restricted in this ability in blood. This phage killing effect is dependent on the levels of free metals and is inhibited by the anticoagulant EDTA. The EDTA-dependent inhibition of ExPEC killing is overcome by exogenous iron, magnesium, and calcium. Metal-enhanced killing of ExPEC by phage was observed for several strains of ExPEC, suggesting a common mechanism. The addition of metals to a murine host infected with ExPEC stimulated a phage dependent reduction in ExPEC levels. This work defines a role for circulating metals as a major factor that is essential for the phage-based killing of bacteria in blood. PMID- 29396497 TI - Multiplex model of mental lexicon reveals explosive learning in humans. AB - Word similarities affect language acquisition and use in a multi-relational way barely accounted for in the literature. We propose a multiplex network representation of this mental lexicon of word similarities as a natural framework for investigating large-scale cognitive patterns. Our representation accounts for semantic, taxonomic, and phonological interactions and it identifies a cluster of words which are used with greater frequency, are identified, memorised, and learned more easily, and have more meanings than expected at random. This cluster emerges around age 7 through an explosive transition not reproduced by null models. We relate this explosive emergence to polysemy - redundancy in word meanings. Results indicate that the word cluster acts as a core for the lexicon, increasing both lexical navigability and robustness to linguistic degradation. Our findings provide quantitative confirmation of existing conjectures about core structure in the mental lexicon and the importance of integrating multi relational word-word interactions in psycholinguistic frameworks. PMID- 29396493 TI - Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer. AB - Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERalpha), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERalpha, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients. PMID- 29396498 TI - Oscillatory interlayer coupling in spin Hall systems. AB - Many spintronics applications consist of ultrathin magnetic and nonmagnetic multilayers and require an in-depth understanding of interfacial magnetism and spin transport. Here, we study permalloy/copper/platinum multilayer systems. We find that magnetic damping, perpendicular anisotropy, and proximity magnetization exhibit correlated oscillations as a function of the copper thickness. We ascribe these observations to an oscillatory interlayer coupling between permalloy and platinum. Such interlayer coupling may have a significant impact on the performance of spintronics applications. PMID- 29396499 TI - Movement Strategies for Countermovement Jumping are Potentially Influenced by Elastic Energy Stored and Released from Tendons. AB - The preferred movement strategies that humans choose to produce work for movement are not fully understood. Previous studies have demonstrated an important contribution of elastic energy stored within the Achilles tendon (AT) during jumping. This study aimed to alter energy available for storage in the AT to examine changes in how jumpers distribute work among lower limb joints. Participants (n = 16) performed maximal and sub-maximal jumps under two paradigms, matched for increasing total work output by manipulating jump height or adding body mass. Motion capture and ground reaction force data were combined in an inverse dynamics analysis to compute ankle, knee and hip joint kinetics. Results demonstrated higher peak moments about the ankle joint with added body mass (+26 Nm), likely resulting in additional energy storage in the AT. Work at the ankle joint increased proportionally with added mass, maintaining a constant contribution (~64%) to total work that was not matched with increasing jump height (-14%). This implies greater energy storage and return by the AT with added mass but not with increased height. When total work during jumping is constant but energy stored in tendons is not, humans prioritise the use of stored elastic energy over muscle work. PMID- 29396500 TI - Hepatocellular carcinoma-targeting oncolytic adenovirus overcomes hypoxic tumor microenvironment and effectively disperses through both central and peripheral tumor regions. AB - Cancer-specific promoter driven replication of oncolytic adenovirus (Ad) is cancer-specific, but shows low transcriptional activity. Thus, we generated several chimeric alpha-fetoprotein (AFP) promoter variants, containing reconstituted enhancer and silencer regions, to preferentially drive Ad replication in hepatocellular carcinoma (HCC). Modified AFP promoter, containing 2 enhancer A regions and a single enhancer B region (a2bm), showed strong and HCC specific transcription. In AFP-positive HCCs, gene expression was 43- to 456-fold higher than those of control AFP promoter lacking enhancers. a2bm promoter was further modified by inserting multiple hypoxia-responsive elements (HRE) to generate Ha2bm promoter, which showed stronger transcriptional activity than a2bm promoter under hypoxic conditions. Ha2bm promoter-regulated oncolytic Ad (Ha2bm d19) showed a stronger antitumor and proapoptotic effect than did a2bm promoter regulated oncolytic Ad (a2bm-d19) in HCC xenograft tumors. Systemically administered Ha2bm-d19 caused no observable hepatotoxicity, whereas control replication-competent Ad, lacking cancer specificity (d19), induced significant hepatic damage. Ha2bm-d19 caused significantly lower expression of interleukin-6 than d19, showing that HCC-targeted delivery of Ad attenuates induction of the innate immune response against Ad. This chimeric AFP promoter enabled Ad to overcome the hypoxic tumor microenvironment and target HCC with high specificity, rendering it a promising candidate for the treatment of aggressive HCCs. PMID- 29396501 TI - AhGLK1 affects chlorophyll biosynthesis and photosynthesis in peanut leaves during recovery from drought. AB - Peanut is an important edible oil crop plant whose quality and yield are greatly affected by drought. The process and molecular mechanisms of recovery from drought are also critical to its productivity, but are currently poorly characterized. Here, we investigate the involvement of peanut AhGLK1 in recovery from drought, and in particular its relationship with AhPORA, which encodes a key enzyme in chlorophyll biosynthesis. We found that chlorophyll content, chlorophyll fluorescence, AhPORA protein level and genes related to chlorophyll biosynthesis and photosynthesis declined markedly under drought conditions, but all increased during recovery. Consistent with this, AhGLK1 expression decreased during water stress and increased when the stress was removed. When AhGLK1 was transformed into Arabidopsis glk1glk2 mutant, it increased the survival rate of the mutant during recovery from drought and fully rescued the mutant's pale-green phenotype. In addition, chlorophyll content and fluorescence, and the expression of genes related to chlorophyll biosynthesis and photosynthesis, were all increased. Bioinformatics analysis and experimental evidence suggested that AhGLK1 augments the expression of AhPORA by binding to its promoter. Our findings confirm that AhGLK1 plays a role as a transcription factor that upregulates expression of AhPORA during post-drought recovery, thereby stimulating chlorophyll biosynthesis and photosynthesis. PMID- 29396502 TI - Three Dimensional Polarimetric Neutron Tomography of Magnetic Fields. AB - Through the use of Time-of-Flight Three Dimensional Polarimetric Neutron Tomography (ToF 3DPNT) we have for the first time successfully demonstrated a technique capable of measuring and reconstructing three dimensional magnetic field strengths and directions unobtrusively and non-destructively with the potential to probe the interior of bulk samples which is not amenable otherwise. Using a pioneering polarimetric set-up for ToF neutron instrumentation in combination with a newly developed tailored reconstruction algorithm, the magnetic field generated by a current carrying solenoid has been measured and reconstructed, thereby providing the proof-of-principle of a technique able to reveal hitherto unobtainable information on the magnetic fields in the bulk of materials and devices, due to a high degree of penetration into many materials, including metals, and the sensitivity of neutron polarisation to magnetic fields. The technique puts the potential of the ToF time structure of pulsed neutron sources to full use in order to optimise the recorded information quality and reduce measurement time. PMID- 29396503 TI - Third-order transport coefficients for localised and delocalised charged-particle transport. AB - We derive third-order transport coefficients of skewness for a phase-space kinetic model that considers the processes of scattering collisions, trapping, detrapping and recombination losses. The resulting expression for the skewness tensor provides an extension to Fick's law which is in turn applied to yield a corresponding generalised advection-diffusion-skewness equation. A physical interpretation of trap-induced skewness is presented and used to describe an observed negative skewness due to traps. A relationship between skewness, diffusion, mobility and temperature is formed by analogy with Einstein's relation. Fractional transport is explored and its effects on the flux transport coefficients are also outlined. PMID- 29396504 TI - Publisher Correction: A novel miRNA analysis framework to analyze differential biological networks. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396505 TI - Genetic background dominates the susceptibility to ventricular arrhythmias in a murine model of beta-adrenergic stimulation. AB - In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the beta-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to beta-adrenergic blockade (metoprolol) and beta-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal beta-adrenergic tone, with the response to beta-adrenergic stimulation or with the absolute heart rates during beta-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of beta-adrenergic stimulation. PMID- 29396506 TI - Ormeloxifene-induced unfolded protein response contributes to autophagy associated apoptosis via disruption of Akt/mTOR and activation of JNK. AB - Autophagy, a regulated nutrient recycling program can affect both cell survival and cell death. Here, we show that Ormeloxifene (ORM), a selective estrogen receptor modulator approved for oral contraceptive use induces autophagic flux in ovarian cancer cells, which is activated by an ER stress response upstream of autophagy. The ER stress response is characterized by activation of IRE1alpha, PERK and ATF6 and is under regulation of JNK. Pharmacological inhibition of either autophagy or ER stress increased cell survival, as did silencing of autophagy proteins LC3 and Beclin 1, implying that ORM-induced autophagy is pro death in nature. Ultrastructural observations of treated cells confirmed stages of autophagic maturation. Caspase-dependent apoptosis succeeded these events and was characterized by generation of reactive oxygen species and disruption of mitochondrial membrane potential. A concomitant inhibition of the Akt/mTOR axis was also observed with possible regulation of Akt by ORM. ORM inhibited tumor growth in ovarian xenograft model and displayed autophagic activity. In summary, in vitro and in vivo results reveal that ORM induces autophagy-associated cell death to attenuate proliferation of ovarian cancer cells. Our results demonstrate that using ORM in combination with ER stress and autophagy modulators could offer better therapeutic outcome in ovarian cancer. PMID- 29396507 TI - First identification of marine diatoms with anti-tuberculosis activity. AB - Marine microalgae are considered a potentially new and valuable source of biologically active compounds for applications in several biotechnology sectors. They can be easily cultured, have short generation times and enable an environmentally-friendly approach to drug discovery by overcoming problems associated with the over-utilization of marine resources and the use of destructive collection practices. Considering the increasing rate of antibiotic resistance bacteria and infections by fungi, 46 microalgae have been screened in this study for possible antibacterial and antifungal activities. Two different extraction methods have been used in order to increase the probability of finding positive hits. In particular, we screened microalgae in both control and nutrient stress conditions. We also tested different strains for 7 species in order to study potentially different bioactivities due to strain diversity. Results showed that extracts of two diatoms, Skeletonema tropicum and Chaetoceros pseudocurvisetus, had anti-tuberculosis activity and were active only when cultured in the control and phosphate-starvation conditions, while the nitrogen starvation condition showed no activity. In addition, we tested both the organic and water extracts and found that only the organic extracts for both diatoms were active. The organic extracts of these two diatom species were not toxic on normal human cell lines. PMID- 29396508 TI - Elevated miR-301a expression indicates a poor prognosis for breast cancer patients. AB - Although microRNA-301a (miR-301a) has been reported to function as an oncogene in many human cancers, there are limited data regarding miR-301a and breast tumours. In this study, we first detected the expression of miR-301a using an in situ hybridization (ISH) -based classification system in 380 samples of BC tissue, including both non-TNBC (triple-negative breast cancer) and TNBC specimens. Our results suggest that analysing miR-301a expression in breast tissue biopsy specimens at the time of diagnosis could have the potential to identify patients who might be candidates for active surveillance. We validated our results that higher expression of miR-301a is associated with a decreased OS in independent public breast cancer databases, such as TCGA and METABRIC, using the online webtool Kaplan-Meier Plotter, which provided additional powerful evidence to confirm the prognostic value of miR-301a. MiR-301a may serve as a potential therapeutic target for patients with breast cancer. According to our results, miR 301a should be considered, and novel therapeutic options are needed to target this aggressive miR-301a-positive type of breast cancer to reduce recurrence and the mortality rate. PMID- 29396509 TI - Stationary gaze entropy predicts lane departure events in sleep-deprived drivers. AB - Performance decrement associated with sleep deprivation is a leading contributor to traffic accidents and fatalities. While current research has focused on eye blink parameters as physiological indicators of driver drowsiness, little is understood of how gaze behaviour alters as a result of sleep deprivation. In particular, the effect of sleep deprivation on gaze entropy has not been previously examined. In this randomised, repeated measures study, 9 (4 male, 5 female) healthy participants completed two driving sessions in a fully instrumented vehicle (1 after a night of sleep deprivation and 1 after normal sleep) on a closed track, during which eye movement activity and lane departure events were recorded. Following sleep deprivation, the rate of fixations reduced while blink rate and duration as well as saccade amplitude increased. In addition, stationary and transition entropy of gaze also increased following sleep deprivation as well as with amount of time driven. An increase in stationary gaze entropy in particular was associated with higher odds of a lane departure event occurrence. These results highlight how fatigue induced by sleep deprivation and time-on-task effects can impair drivers' visual awareness through disruption of gaze distribution and scanning patterns. PMID- 29396510 TI - Nitrogen supply influences photosynthesis establishment along the sugarcane leaf. AB - Nitrogen (N) is a major component of the photosynthetic apparatus and is widely used as a fertilizer in crops. However, to the best of our knowledge, the dynamic of photosynthesis establishment due to differential N supply in the bioenergy crop sugarcane has not been reported to date. To address this question, we evaluated physiological and metabolic alterations along the sugarcane leaf in two contrasting genotypes, responsive (R) and nonresponsive (NR), grown under high- and low-N conditions. We found that the N supply and the responsiveness of the genotype determined the degree of senescence, the carboxylation process mediated by phosphoenolpyruvate carboxylase (PEPcase) and differential accumulation of soluble sugars. The metabolite profiles indicated that the NR genotype had a higher respiration rate in the youngest tissues after exposure to high N. We observed elevated levels of metabolites related to photosynthesis in almost all leaf segments from the R genotype under high-N conditions, suggesting that N supply and the ability to respond to N influenced photosynthesis. Therefore, we observed that N influence on photosynthesis and other pathways is dependent on the genotype and the leaf region. PMID- 29396511 TI - Reducing antibiotic utilization rate in preterm infants: a quality improvement initiative. AB - BACKGROUND: Judicious use of antibiotic therapy in preterm infants is necessary as prolonged and unwarranted use of antibiotics have been associated with adverse short-term and long-term outcomes. LOCAL PROBLEM: Our baseline data review revealed overuse and unnecessary prolonged antibiotic exposure among preterm infants despite a low suspicion for sepsis. METHODS AND INTERVENTIONS: The baseline overall AUR was calculated retrospectively from our pharmacy database for a period of 4 months prior to the quality improvement (QI) initiative (pre-QI phase). The principal QI intervention included the development and implementation of guidance algorithms for evaluation and management of suspected sepsis incorporating key QI measures, such as an emphasis on early discontinuation of antibiotics by 36 h if blood culture remained negative and the introduction of multiplex polymerase chain reaction assay for early identification of causative organisms. This QI initiative was implemented through multiple Plan-Do-Study-Act cycles, starting in February 2016 (QI phase), with an objective to achieve a 10% reduction in the baseline overall AUR by December 2016, in preterm infants with gestational ages between 250/7 and 336/7 weeks. Data for the QI phase of the study were collected prospectively. RESULT: The overall AUR (outcome measure) decreased from 154.8 to 138.4 days of treatment per 1000 hospital days (10.6% decrease, p < 0.05) over the 11-month period. However, the overall rate of adherence to guidance algorithm (process measure) remained below the target goal of 90%. CONCLUSION: This multiphase QI initiative was able to reduce the overall AUR at our NICU. The beneficial impact of this decrease in AUR in preterm infants remains to be determined. PMID- 29396512 TI - Geometric isotope effect of deuteration in a hydrogen-bonded host-guest crystal. AB - Deuteration of a hydrogen bond by replacing protium (H) with deuterium (D) can cause geometric changes in the hydrogen bond, known as the geometric H/D isotope effect (GIE). Understanding the GIEs on global structures and bulk properties is of great importance to study structure-property relationships of hydrogen-bonded systems. Here, we report a hydrogen-bonded host-guest crystal, imidazolium hydrogen terephthalate, that exemplifies striking GIEs on its hydrogen bonds, phases, and bulk dielectric transition property. Upon deuteration, the donor acceptor distance in the O-H...O hydrogen bonds in the host structure is found to increase, which results in a change in the global hydrogen-bonded supramolecular structure and the emergence of a new phase (i.e., isotopic polymorphism). Consequently, the dynamics of the confined guest, which depend on the internal pressure exerted by the host framework, are substantially altered, showing a downward shift of the dielectric switching temperature. PMID- 29396513 TI - PCSK9 induces a pro-inflammatory response in macrophages. AB - Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP 1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 / 2.5 ug/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 ug/ml PCSK9, a significant induction of IL-1beta, IL-6, TNF alpha, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP 1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF alpha (2.4 +/- 0.5 fold) and IL-1beta (8.6 +/- 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-alpha mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 +/- 1.6 fold vs 31.1 +/- 6.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-alpha plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 / 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR. PMID- 29396514 TI - Tunable phonon blockade in quadratically coupled optomechanical systems. AB - We theoretically investigate the phonon statistics of a quadratically coupled optomechanical system, in which an effective second-order nonlinear interaction between an optical mode and a mechanical mode is induced by a strong optical driving field on two-phonon red-sideband resonance. We show that strong phonon antibunching can be observed even if the strength of the effective second-order nonlinear interaction is much weaker than the decay rates of the system, by driving the optical and mechanical modes with weak driving fields respectively. Moreover, the phonon statistics can be dynamically controlled by tuning the strengths and the phase difference of the weak driving fields. The scheme proposed here can be used to realize tunable single-phonon sources with quadratically optomechanical coupling. PMID- 29396515 TI - Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro. AB - Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A2A receptor (A2AR) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A2AR in microglia protects against the pathological features of AMD. Herein, we show that an A2AR antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A2AR in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE 19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A2AR in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A2AR antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors. PMID- 29396517 TI - Percutaneous Coronary Intervention versus Coronary Artery Bypass Graft in Acute Coronary Syndrome patients with Renal Dysfunction. AB - ACS patients with renal dysfunction tend to have a poorer prognosis than those with normal renal function. This retrospective cohort study was performed using The Second Drug-Eluting Stent Impact on Revascularization Registry, a retrospective registry, to evaluate the time-dependent relative risk of revascularization strategies in ACS patients with renal dysfunction. The study demonstrated that the short-term MACCE rate was lower after PCI than CABG. However, there was no significant difference in long-term MACCE rate. Subgroup analyses based on the degree of renal dysfunction resulted in similar findings. The revascularization strategy was identified as a time-dependent covariate by the time-dependent Cox model, and the regression coefficient was '-1.124 + 0.344 * ln (time + 1)'. For the entire object group and the separate subgroups, PCI was initially associated with a lower hazard for MACCE than CABG after revascularization, then the hazard ratio increases with time. In conclusion, the hazard ratio for MACCE in PCI relative to CABG is time-dependent. PCI tends to have a lower risk for MACCE than CABG in the short-term, then the hazard ratio increases with time. PMID- 29396516 TI - RAP80 is an independent prognosis biomarker for the outcome of patients with esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues. Moreover, the RAP80 mRNA level was validated to be an independent prognosis biomarker for the overall survival time of ESCC patients. The following biological assays revealed that it promoted cell proliferation both in vitro and in vivo, inhibited cell apoptosis at both early and late stages, and participated in G2/M checkpoint regulation. Even though studies have reported that ATM phosphorylates RAP80 at different serine sites upon DNA damage, the reversal regulation of RAP80 on the activity of ATM has never been investigated. In the study, mechanism explorations revealed that RAP80 positively regulated the ATM activity via proteasome-ubiquitination pathway to promote the transition of G2/M phase in cell cycle. By examining a number of E3 ubiquitination ligases (Ub) and deubiquitination (DUb) enzymes, we found that RAP80 positively regulated the stability of USP13 to promote cell proliferation of EC cells. Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians. PMID- 29396518 TI - Atomistic evolution during the phase transition on a metastable single NaYF4:Yb,Er upconversion nanoparticle. AB - The phase evolution of as-prepared NaYF4:Yb,Er upconversion nanoparticles (UCNPs) with a metastable cubic structure is studied based on in situ heating experiments via transmission electron microscopy (TEM). The atomistic behavior on the single NaYF4:Yb,Er UCNP is observed during the phase transition. The formation and evolution of voids on the NaYF4:Yb,Er UCNP appear at a temperature below 420 degrees C. Small circular voids are transformed at the initial stage to a large, hexagonal-pillar shaped single void. Two different routes to reach the stable alpha-phase from the metastable cubic structure are identified on a single NaYF4:Yb,Er UCNP. The first is via a stable beta-phase and the second is a direct change via a liquid-like phase. The specific orientation relationships, [110]cubic//[11[Formula: see text]0]hexagonal and {002}cubic//{2[Formula: see text]00}hexagonal, between the cubic and hexagonal structures are confirmed. Additionally, a few extra-half planes terminated in the cubic structures are also observed at the cubic/hexagonal interface. PMID- 29396519 TI - An Accord of Nuclear Receptor Expression in M. tuberculosis Infected Macrophages and Dendritic Cells. AB - Mycobacterium tuberculosis instigates interactions with host factors to promote its survival within the host inimical conditions. Among such factors, nuclear receptors (NRs) seem to be promising candidates owing to their role in bacterial pathogenesis. However, only few members of NR superfamily have been implicated in M. tuberculosis infection and there is a dearth of comprehensive knowledge about expression or function of the entire superfamily. In this study, we performed detailed expression analysis and identified key NRs getting differentially regulated in murine macrophages and dendritic cells (DC) upon infection with H37Rv. The murine macrophages and DCs infected with H37Rv entailed overlapping changes in the expression of certain NRs which reflect upon the possibility that both cells might utilize similar transcriptional programs upon M. tuberculosis infection. We identified Nr4a3 and Rora, which have not been implicated in M. tuberculosis pathogenesis, undergo similar changes in expression in macrophages and DCs upon H37Rv infection. Interestingly, a similar pattern in their expression was also observed in infected human monocyte derived macrophages and the findings corroborated well with PBMCs obtained from TB patients. This all inclusive analysis provides the basis for a precise approach in identifying NRs that can be targeted therapeutically in intracellular bacterial infections. PMID- 29396521 TI - Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus. AB - Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20-180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target. PMID- 29396520 TI - Demonstration of ion channel synthesis by isolated squid giant axon provides functional evidence for localized axonal membrane protein translation. AB - Local translation of membrane proteins in neuronal subcellular domains like soma, dendrites and axon termini is well-documented. In this study, we isolated the electrical signaling unit of an axon by dissecting giant axons from mature squids (Dosidicus gigas). Axoplasm extracted from these axons was found to contain ribosomal RNAs, ~8000 messenger RNA species, many encoding the translation machinery, membrane proteins, translocon and signal recognition particle (SRP) subunits, endomembrane-associated proteins, and unprecedented proportions of SRP RNA (~68% identical to human homolog). While these components support endoplasmic reticulum-dependent protein synthesis, functional assessment of a newly synthesized membrane protein in axolemma of an isolated axon is technically challenging. Ion channels are ideal proteins for this purpose because their functional dynamics can be directly evaluated by applying voltage clamp across the axon membrane. We delivered in vitro transcribed RNA encoding native or Drosophila voltage-activated Shaker KV channel into excised squid giant axons. We found that total K+ currents increased in both cases; with added inactivation kinetics on those axons injected with RNA encoding the Shaker channel. These results provide unambiguous evidence that isolated axons can exhibit de novo synthesis, assembly and membrane incorporation of fully functional oligomeric membrane proteins. PMID- 29396522 TI - Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody. AB - Assisted Design of Antibody and Protein Therapeutics (ADAPT) is an affinity maturation platform interleaving predictions and testing that was previously validated on monoclonal antibodies (mAbs). This study expands the applicability of ADAPT to single-domain antibodies (sdAbs), a promising class of recombinant antibody-based biologics. As a test case, we used the camelid sdAb A26.8, a VHH that binds Clostridium difficile toxin A (TcdA) relatively weakly but displays a reasonable level of TcdA neutralization. ADAPT-guided A26.8 affinity maturation resulted in an improvement of one order of magnitude by point mutations only, reaching an equilibrium dissociation constant (KD) of 2 nM, with the best binding mutants having similar or improved stabilities relative to the parent sdAb. This affinity improvement generated a 6-fold enhancement of efficacy at the cellular level; the A26.8 double-mutant T56R,T103R neutralizes TcdA cytotoxicity with an IC50 of 12 nM. The designed mutants with increased affinities are predicted to establish novel electrostatic interactions with the antigen. Almost full additivity of mutation effects is observed, except for positively charged residues introduced at adjacent positions. Furthermore, analysis of false positive predictions points to general directions for improving the ADAPT platform. ADAPT guided the efficacy enhancement of an anti-toxin sdAb, an alternative therapeutic modality for C. difficile. PMID- 29396524 TI - Identifying musical pieces from fMRI data using encoding and decoding models. AB - Encoding models can reveal and decode neural representations in the visual and semantic domains. However, a thorough understanding of how distributed information in auditory cortices and temporal evolution of music contribute to model performance is still lacking in the musical domain. We measured fMRI responses during naturalistic music listening and constructed a two-stage approach that first mapped musical features in auditory cortices and then decoded novel musical pieces. We then probed the influence of stimuli duration (number of time points) and spatial extent (number of voxels) on decoding accuracy. Our approach revealed a linear increase in accuracy with duration and a point of optimal model performance for the spatial extent. We further showed that Shannon entropy is a driving factor, boosting accuracy up to 95% for music with highest information content. These findings provide key insights for future decoding and reconstruction algorithms and open new venues for possible clinical applications. PMID- 29396523 TI - Focused shockwave induced blood-brain barrier opening and transfection. AB - Despite extensive efforts in recent years, the blood-brain barrier (BBB) remains a significant obstacle for drug delivery. This study proposes using a clinical extracorporeal shockwave instrument to open the BBB, combined with a laser assisted bi-axial locating platform to achieve non-invasive, controllable-focus and reversible BBB opening in the brains of rats. Under shockwave treatment with an intensity level of 5 (P-9.79 MPa, energy flux density (EFD) 0.21 mJ/mm2) and a pulse repetition frequency of 5 Hz, the BBB could be opened after 50 shocks without the use of an ultrasound contrast agent. With the proposed method, the BBB opening can be precisely controlled in terms of depth, size and location. Moreover, a shockwave based gene transfection was demonstrated using a luciferase gene. PMID- 29396525 TI - The first identification of genomic loci in plants associated with resistance to galling insects: a case study in Eucalyptus L'Her. (Myrtaceae). AB - Genomic loci related with resistance to gall-inducing insects have not been identified in any plants. Here, association mapping was used to identify molecular markers for resistance to the gall wasp Leptocybe invasa in two Eucalyptus species. A total of 86 simple sequence repeats (SSR) markers were screened out from 839 SSRs and used for association mapping in E. grandis. By applying the mixed linear model, seven markers were identified to be associated significantly (P <= 0.05) with the gall wasp resistance in E. grandis, including two validated with a correction of permutation test (P <= 0.008). The proportion of the variance in resistance explained by a significant marker ranged from 3.3% to 37.8%. Four out of the seven significant associations in E. grandis were verified and also validated (P <= 0.073 in a permutation test) in E. tereticornis, with the variation explained ranging from 24.3% to 48.5%. Favourable alleles with positive effect were also mined from the significant markers in both species. These results provide insight into the genetic control of gall wasp resistance in plants and have great potential for marker-assisted selection for resistance to L. invasa in the important tree genus Eucalyptus. PMID- 29396526 TI - Broad impact of extracellular DNA on biofilm formation by clinically isolated Methicillin-resistant and -sensitive strains of Staphylococcus aureus. AB - Staphylococcus aureus is a major causative agent for biofilm-associated infections. Inside biofilms, S. aureus cells are embedded in an extracellular matrix (ECM) composed of polysaccharide-intercellular adhesins (PIA), proteins, and/or extracellular DNA (eDNA). However, the importance of each component and the relationship among them in biofilms of diverse strains are largely unclear. Here, we characterised biofilms formed by 47 S. aureus clinical isolates. In most (42/47) of the strains, biofilm formation was augmented by glucose supplementation. Sodium chloride (NaCl)-triggered biofilm formation was more prevalent in methicillin-sensitive S. aureus (15/24) than in methicillin resistant strain (1/23). DNase I most effectively inhibited and disrupted massive biofilms, and Proteinase K was also effective. Anti-biofilm effects of Dispersin B, which cleaves PIA, were restricted to PIA-dependent biofilms formed by specific strains and showed significant negative correlations with those of Proteinase K, suggesting independent roles of PIA and proteins in each biofilm. ECM profiling demonstrated that eDNA was present in all strains, although its level differed among strains and culture conditions. These results indicate that eDNA is the most common component in S. aureus biofilms, whereas PIA is important for a small number of isolates. Therefore, eDNA can be a primary target for developing eradication strategies against S. aureus biofilms. PMID- 29396527 TI - Climate Based Predictability of Oil Palm Tree Yield in Malaysia. AB - The influence of local conditions and remote climate modes on the interannual variability of oil palm fresh fruit bunches (FFB) total yields in Malaysia and two major regions (Peninsular Malaysia and Sabah/Sarawak) is explored. On a country scale, the state of sea-surface temperatures (SST) in the tropical Pacific Ocean during the previous boreal winter is found to influence the regional climate. When El Nino occurs in the Pacific Ocean, rainfall in Malaysia reduces but air temperature increases, generating a high level of water stress for palm trees. As a result, the yearly production of FFB becomes lower than that of a normal year since the water stress during the boreal spring has an important impact on the total annual yields of FFB. Conversely, La Nina sets favorable conditions for palm trees to produce more FFB by reducing chances of water stress risk. The region of the Leeuwin current also seems to play a secondary role through the Ningaloo Nino/ Nina in the interannual variability of FFB yields. Based on these findings, a linear model is constructed and its ability to reproduce the interannual signal is assessed. This model has shown some skills in predicting the total FFB yield. PMID- 29396528 TI - A missing link in the estuarine nitrogen cycle?: Coupled nitrification denitrification mediated by suspended particulate matter. AB - In estuarine and coastal ecosystems, the majority of previous studies have considered coupled nitrification-denitrification (CND) processes to be exclusively sediment based, with little focus on suspended particulate matter (SPM) in the water column. Here, we present evidence of CND processes in the water column of Hangzhou Bay, one of the largest macrotidal embayments in the world. Spearman's correlation analysis showed that SPM was negatively correlated with nitrate (rho = -0.372, P = 0.018) and marker genes for nitrification and denitrification in the water column were detected by quantitative PCR analysis. The results showed that amoA and nir gene abundances strongly correlated with SPM (all P < 0.01) and the ratio of amoA/nir strongly correlated with nitrate (rho = 0.454, P = 0.003). Furthermore, aggregates consisting of nitrifiers and denitrifiers on SPM were also detected by fluorescence in situ hybridization. Illumina MiSeq sequencing further showed that ammonia oxidizers mainly belonged to the genus Nitrosomonas, while the potential denitrifying genera Bradyrhizobium, Comamonas, Thauera, Stenotrophomonas, Acinetobacter, Anaeromyxobacter, Sulfurimonas, Paenibacillus and Sphingobacterium showed significant correlations with SPM (all P < 0.01). This study suggests that SPM may provide a niche for CND processes to occur, which has largely been missing from our understanding of nitrogen cycling in estuarine waters. PMID- 29396529 TI - Sustainable manufacture of insect repellents derived from Nepeta cataria. AB - Malaria devastates sub-Saharan Africa; the World Health Organization (WHO) estimates that 212 million people contract malaria annually and that the plasmodium virus will kill 419 000 in 2017. The disease affects rural populations who have the least economic means to fight it. Impregnated mosquito nets have reduced the mortality rate but the Anopheles mosquitoes are changing their feeding patterns and have become more active at dusk and early morning rather than after 22h00 as an adaptation to the nets. Everyone is susceptible to the Anopheles at these times but infants and pregnant women are the most vulnerable to the disease. Plant-based mosquito repellents are as effective as synthetic repellents that protect people from bites. They are sustainable preventative measures against malaria not only because of their efficacy but because the local population can produce and distribute them, which represents a source of economic growth for rural areas. Here, we extract and test the essential oil nepetalactone from Nepeta cataria via steam distillation. Families in endemic areas of Burundi found them effective against bites but commented that the odor was pungent. An epidemiological study is required to establish its clinical efficacy. PMID- 29396530 TI - Structural characterisation of high-mobility Cd3As2 films crystallised on SrTiO3. AB - Cd3As2 has long been known as a high-mobility semiconductor. The recent finding of a topological semimetal state in this compound has demanded growth of epitaxial films with high crystallinity and controlled thickness. Here we report the structural characterisation of Cd3As2 films grown on SrTiO3 substrates by solid-phase epitaxy at high temperatures up to 600 degrees C by employing optimised capping layers and substrates. The As triangular lattice is epitaxially stacked on the Ti square lattice of the (001) SrTiO3 substrate, producing (112) oriented Cd3As2 films exhibiting high crystallinity with a rocking-curve width of 0.02 degrees and a high electron mobility exceeding 30,000 cm2/Vs. The systematic characterisation of films annealed at various temperatures allowed us to identify two-step crystallisation processes in which out-of-plane and subsequently in-plane directions occur with increasing annealing temperature. Our findings on the high-temperature crystallisation process of Cd3As2 enable a unique approach for fabricating high-quality Cd3As2 films and elucidating quantum transport by back gating through the SrTiO3 substrate. PMID- 29396531 TI - Theory of frequency response of mechanically driven cardiomyocytes. AB - We theoretically predict and compare with experiments, transitions from spontaneous beating to dynamical entrainment of cardiomyocytes induced by an oscillating, external mechanical probe. In accord with recent experiments, we predict the dynamical behavior as a function of the probe amplitude and frequency. The theory is based on a phenomenological model for a non-linear oscillator, motivated by acto-myosin contractility. The generic behavior is independent of the detailed, molecular origins of the dynamics and, consistent with experiment, we find three regimes: spontaneous beating with the natural frequency of the cell, entrained beating with the frequency of the probe, and a "bursting" regime where the two frequencies alternate in time. We quantitatively predict the properties of the "bursting" regime as a function of the amplitude and frequency of the probe. Furthermore, we examine the pacing process in the presence of weak noise and explain how this might relate to cardiomyocyte physiology. PMID- 29396532 TI - Chloroplast genomes of Byrsonima species (Malpighiaceae): comparative analysis and screening of high divergence sequences. AB - Byrsonima is the third largest genus (about 200 species) in the Malpighiaceae family, and one of the most common in Brazilian savannas. However, there is no molecular phylogeny available for the genus and taxonomic uncertainties at the generic and family level still remain. Herein, we sequenced the complete chloroplast genome of B. coccolobifolia and B. crassifolia, the first ones described for Malpighiaceae, and performed comparative analyses with sequences previously published for other families in the order Malpighiales. The chloroplast genomes assembled had a similar structure, gene content and organization, even when compared with species from other families. Chloroplast genomes ranged between 160,212 bp in B. crassifolia and 160,329 bp in B. coccolobifolia, both containing 115 genes (four ribosomal RNA genes, 28 tRNA genes and 83 protein-coding genes). We also identified sequences with high divergence that might be informative for phylogenetic inferences in the Malpighiales order, Malpighiaceae family and within the genus Byrsonima. The phylogenetic reconstruction of Malpighiales with these regions highlighted their utility for phylogenetic studies. The comparative analyses among species in Malpighiales provided insights into the chloroplast genome evolution in this order, including the presence/absence of three genes (infA, rpl32 and rps16) and two pseudogenes (ycf1 and rps19). PMID- 29396533 TI - Temperature, Crystalline Phase and Influence of Substrate Properties in Intense Pulsed Light Sintering of Copper Sulfide Nanoparticle Thin Films. AB - Intense Pulsed Light sintering (IPL) uses pulsed, visible light to sinter nanoparticles (NPs) into films used in functional devices. While IPL of chalcogenide NPs is demonstrated, there is limited work on prediction of crystalline phase of the film and the impact of optical properties of the substrate. Here we characterize and model the evolution of film temperature and crystalline phase during IPL of chalcogenide copper sulfide NP films on glass. Recrystallization of the film to crystalline covellite and digenite phases occurs at 126 degrees C and 155 degrees C respectively within 2-7 seconds. Post-IPL films exhibit p-type behavior, lower resistivity (~10-3-10-4 Omega-cm), similar visible transmission and lower near-infrared transmission as compared to the as deposited film. A thermal model is experimentally validated, and extended by combining it with a thermodynamic approach for crystal phase prediction and via incorporating the influence of film transmittivity and optical properties of the substrate on heating during IPL. The model is used to show the need to a-priori control IPL parameters to concurrently account for both the thermal and optical properties of the film and substrate in order to obtain a desired crystalline phase during IPL of such thin films on paper and polycarbonate substrates. PMID- 29396535 TI - Publisher Correction: Real-time Acute Stress Facilitates Allocentric Spatial Processing in a Virtual Fire Disaster. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396534 TI - Targeted plasma proteomics identifies a novel, robust association between cornulin and Swedish moist snuff. AB - Lifestyle behaviors are believed to influence the body's inflammatory state. Chronic low-grade inflammation contributes to the development of major non communicable diseases such as diabetes, cardiovascular disease and cancer. Inflammation may thus be an important link between lifestyle and disease. We evaluated self-reported physical activity, tobacco use and alcohol consumption in relation to plasma levels of 160 validated inflammatory and cancer biomarkers. The study included 138 participants from a population-based cohort, all with repeated sampling of plasma and data ten years apart, allowing consideration of both intra- and inter-individual variation. Of 17 relationships identified, the strongest was an independent, positive association between cornulin (CRNN) and Swedish moist snuff (snus) use. We replicated the finding in a second cohort of 501 individuals, in which a dose-response relationship was also observed. Snus explained approximately one fifth of the variance in CRNN levels in both sample sets (18% and 23%). In conclusion, we identified a novel, independent, dose dependent association between CRNN and snus use. Further study is warranted, to evaluate the performance of CRNN as a potential snus biomarker. The putative importance of lifestyle behaviors on a wide range of protein biomarkers illustrates the need for more personalized biomarker cut-offs. PMID- 29396537 TI - Impacts of warming on phytoplankton abundance and phenology in a typical tropical marine ecosystem. AB - In the tropics, thermal stratification (during warm conditions) may contribute to a shallowing of the mixed layer above the nutricline and a reduction in the transfer of nutrients to the surface lit-layer, ultimately limiting phytoplankton growth. Using remotely sensed observations and modelled datasets, we study such linkages in the northern Red Sea (NRS) - a typical tropical marine ecosystem. We assess the interannual variability (1998-2015) of both phytoplankton biomass and phenological indices (timing of bloom initiation, duration and termination) in relation to regional warming. We demonstrate that warmer conditions in the NRS are associated with substantially weaker winter phytoplankton blooms, which initiate later, terminate earlier and are shorter in their overall duration (~ 4 weeks). These alterations are directly linked with the strength of atmospheric forcing (air-sea heat fluxes) and vertical stratification (mixed layer depth [MLD]). The interannual variability of sea surface temperature (SST) is found to be a good indicator of phytoplankton abundance, but appears to be less important for predicting bloom timing. These findings suggest that future climate warming scenarios may have a two-fold impact on phytoplankton growth in tropical marine ecosystems: 1) a reduction in phytoplankton abundance and 2) alterations in the timing of seasonal phytoplankton blooms. PMID- 29396536 TI - A multidrug ABC transporter with a taste for GTP. AB - During the evolution of cellular bioenergetics, many protein families have been fashioned to match the availability and replenishment in energy supply. Molecular motors and primary transporters essentially need ATP to function while proteins involved in cell signaling or translation consume GTP. ATP-Binding Cassette (ABC) transporters are one of the largest families of membrane proteins gathering several medically relevant members that are typically powered by ATP hydrolysis. Here, a Streptococcus pneumoniae ABC transporter responsible for fluoroquinolones resistance in clinical settings, PatA/PatB, is shown to challenge this concept. It clearly favors GTP as the energy supply to expel drugs. This preference is correlated to its ability to hydrolyze GTP more efficiently than ATP, as found with PatA/PatB reconstituted in proteoliposomes or nanodiscs. Importantly, the ATP and GTP concentrations are similar in S. pneumoniae supporting the physiological relevance of GTP as the energy source of this bacterial transporter. PMID- 29396538 TI - Repeated five-day administration of L-BMAA, microcystin-LR, or as mixture, in adult C57BL/6 mice - lack of adverse cognitive effects. AB - The cyanobacterial toxins beta-methylamino-L-alanine (L-BMAA) and microcystin-LR (MC-LR; a potent liver toxin) are suspected to cause neurological disorders. Adult male C57BL/6JOlaHsd mice aged approximately 11 months were subcutaneously injected for five consecutive days with L-BMAA and microcystin-LR alone, or as a mixture. A dose-range study determined a tolerable daily dose to be ~31 ug MC LR/kg BW/day based on survival, serum liver status enzymes, and relative liver and kidney weight. Mice tolerating the first one-two doses also tolerated the subsequent three-four doses indicating adaptation. The LD50 was 43-50 MUg MC LR/kg BW. Long-term effects (up to 10 weeks) on spatial learning and memory performance was investigated using a Barnes maze, were mice were given 30 ug MC LR/kg BW and/or 30 mg L-BMAA/kg BW either alone or in mixture for five consecutive days. Anxiety, general locomotor activity, willingness to explore, hippocampal and peri-postrhinal cortex dependent memory was investigated after eight weeks using Open field combined with Novel location/Novel object recognition tests. Toxin exposed animals did not perform worse than controls, and MC-LR exposed animals performed somewhat better during the first Barnes maze re test session. MC-LR exposed mice rapidly lost up to ~5% body weight, but regained weight from day eight. PMID- 29396539 TI - Spin-orbit coupling and electric-dipole spin resonance in a nanowire double quantum dot. AB - We study the electric-dipole transitions for a single electron in a double quantum dot located in a semiconductor nanowire. Enabled by spin-orbit coupling (SOC), electric-dipole spin resonance (EDSR) for such an electron can be generated via two mechanisms: the SOC-induced intradot pseudospin states mixing and the interdot spin-flipped tunneling. The EDSR frequency and strength are determined by these mechanisms together. For both mechanisms the electric-dipole transition rates are strongly dependent on the external magnetic field. Their competition can be revealed by increasing the magnetic field and/or the interdot distance for the double dot. To clarify whether the strong SOC significantly impact the electron state coherence, we also calculate relaxations from excited levels via phonon emission. We show that spin-flip relaxations can be effectively suppressed by the phonon bottleneck effect even at relatively low magnetic fields because of the very large g-factor of strong SOC materials such as InSb. PMID- 29396540 TI - Genome-scale analysis of Methicillin-resistant Staphylococcus aureus USA300 reveals a tradeoff between pathogenesis and drug resistance. AB - Staphylococcus aureus infection is a rising public health care threat. S. aureus is believed to have elaborate regulatory networks that orchestrate its virulence. Despite its importance, the systematic understanding of the transcriptional landscape of S. aureus is limited. Here, we describe the primary transcriptome landscape of an epidemic USA300 isolate of community-acquired methicillin resistant S. aureus. We experimentally determined 1,861 transcription start sites with their principal promoter elements, including well-conserved -35 and -10 elements and weakly conserved -16 element and 5' untranslated regions containing AG-rich Shine-Dalgarno sequence. In addition, we identified 225 genes whose transcription was initiated from multiple transcription start sites, suggesting potential regulatory functions at transcription level. Along with the transcription unit architecture derived by integrating the primary transcriptome analysis with operon prediction, the measurement of differential gene expression revealed the regulatory framework of the virulence regulator Agr, the SarA-family transcriptional regulators, and beta-lactam resistance regulators. Interestingly, we observed a complex interplay between virulence regulation, beta-lactam resistance, and metabolism, suggesting a possible tradeoff between pathogenesis and drug resistance in the USA300 strain. Our results provide platform resource for the location of transcription initiation and an in-depth understanding of transcriptional regulation of pathogenesis, virulence, and antibiotic resistance in S. aureus. PMID- 29396541 TI - TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole. AB - Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates. In this study, we established the NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners. A screen of pharmacologically active compounds from the LOPAC(r)1280 library identified auranofin, chelerythrine and riluzole as dose-dependent inhibitors of TDP-43 self-interaction. Further analysis of drug action of the gold-containing thioredoxin reductase inhibitor auranofin revealed a redistribution from insoluble TDP-43 protein pool to PBS-soluble protein pool in N2a cells. In addition, auranofin treatment diminished reduced glutathione as a sign for oxidative modulation. PMID- 29396542 TI - Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. AB - Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFbeta family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain. Specific modulation of myostatin and GDF11 activity by targeting growth factor receptor interactions has traditionally been challenging. Here we demonstrate that a novel strategy for blocking myostatin and GDF11, inhibition of growth factor release, specifically and potently inhibits signaling both in vitro and in vivo. We developed human monoclonal antibodies that selectively bind the myostatin and GDF11 precursor forms, including a subset that inhibit myostatin proteolytic activation and prevent muscle atrophy in vivo. The most potent myostatin activation-blocking antibodies promoted robust muscle growth and resulted in significant gains in muscle performance in healthy mice. Altogether, we show that blocking the extracellular activation of growth factors is a potent method for preventing signaling, serving as proof of concept for a novel therapeutic strategy that can be applied to other members of the TGFbeta family of growth factors. PMID- 29396544 TI - Effect of nanograin-boundary networks generation on corrosion of carburized martensitic stainless steel. AB - Martensitic stainless steel parts used in carbonaceous atmosphere at high temperature are subject to corrosion which results in a large amount of lost energy and high repair and maintenance costs. This work therefore proposes a model for surface development and corrosion mechanism as a solution to reduce corrosion costs. The morphology, phase, and corrosion behavior of steel are investigated using GIXRD, XANES, and EIS. The results show formation of nanograin boundary networks in the protective layer of martensitic stainless steel. This Cr2O3-Cr7C3 nanograin mixture on the FeCr2O4 layer causes ion transport which is the main reason for the corrosion reaction during carburizing of the steel. The results reveal the rate determining steps in the corrosion mechanism during carburizing of steel. These steps are the diffusion of uncharged active gases in the stagnant-gas layer over the steel surface followed by the conversion of C into C4- and O into O2- at the gas-oxide interface simultaneously with the migration of Cr3+ from the metal-oxide interface to the gas-oxide interface. It is proposed that previous research on Al2O3 coatings may be the solution to producing effective coatings that overcome the corrosion challenges discussed in this work. PMID- 29396543 TI - Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect. AB - Ouabagenin (OBG) is an aglycone of the cardiotonic steroid ouabain and until now was considered a biologically inactive biosynthetic precursor. Herein, we revealed that OBG functions as a novel class of ligand for the liver X receptor (LXR). Luciferase reporter assays and in silico docking studies suggested that OBG has LXR-selective agonistic activity. In addition, OBG repressed the expression of epithelial sodium channel (ENaC), a LXR target gene, without causing hepatic steatosis, a typical side effect of conventional LXR ligands. This remarkable biological activity can be attributed to a unique mode of action; the LXR agonist activity mainly proceeds through the LXRbeta subtype without affecting LXRalpha, unlike conventional LXR ligands. Thus, OBG is a novel class of LXR ligand that does not cause severe side effects, with potential for use as an antihypertensive diuretic or a tool compound for exploring LXR subtype specific biological functions. PMID- 29396545 TI - Cold-induced metabolic conversion of haptophyte di- to tri-unsaturated C37 alkenones used as palaeothermometer molecules. AB - The cosmopolitan marine haptophyte alga Emiliania huxleyi accumulates very long chain (C37-C40) alkyl ketones with two to four trans-type carbon-carbon double bonds (alkenones). These compounds are used as biomarkers of haptophytes and as palaeothermometers for estimating sea-surface temperatures in biogeochemistry. However, the biosynthetic pathway of alkenones in algal cells remains enigmatic, although it is well known that the C37 tri-unsaturated alkenone (K37:3) becomes dominant at low temperatures, either by desaturation of K37:2 or by a separate pathway involving the elongation of tri-unsaturated alkenone precursors. Here, we present experimental evidence regarding K37:3 synthesis. Using the well-known cosmopolitan alkenone producer E. huxleyi, we labelled K37:2 with 13C by incubating cells with 13C-bicarbonate in the light at 25 degrees C under conditions of little if any K37:3 production. After stabilisation of the 13C K37:2 level by depleting 13C-bicarbonate from the medium, the temperature was suddenly reduced to 15 degrees C. The 13C-K37:2 level rapidly decreased, and the 13C-K37:3 level increased, whereas the total 13C-K37 level-namely [K37:2 + K37:3] remained constant. These 13C-pulse-chase-like experimental results indicate that 13C-K37:2 is converted directly to 13C-K37:3 by a desaturation reaction that is promoted by a cold signal. This clear-cut experimental evidence is indicative of the existence of a cold-signal-triggered desaturation reaction in alkenone biosynthesis. PMID- 29396546 TI - Microbial ecology of full-scale wastewater treatment systems in the Polar Arctic Circle: Archaea, Bacteria and Fungi. AB - Seven full-scale biological wastewater treatment systems located in the Polar Arctic Circle region in Finland were investigated to determine their Archaea, Bacteria and Fungi community structure, and their relationship with the operational conditions of the bioreactors by the means of quantitative PCR, massive parallel sequencing and multivariate redundancy analysis. The results showed dominance of Archaea and Bacteria members in the bioreactors. The activated sludge systems showed strong selection of Bacteria but not for Archaea and Fungi, as suggested by diversity analyses. Core OTUs in influent and bioreactors were classified as Methanobrevibacter, Methanosarcina, Terrestrial Group Thaumarchaeota and unclassified Euryarchaeota member for Archaea; Trichococcus, Leptotrichiaceae and Comamonadaceae family, and Methylorosula for Bacteria and Trichosporonaceae family for Fungi. All influents shared core OTUs in all domains, but in bioreactors this did not occur for Bacteria. Oligotype structure of core OTUs showed several ubiquitous Fungi oligotypes as dominant in sewage and bioreactors. Multivariate redundancy analyses showed that the majority of core OTUs were related to organic matter and nutrients removal. Also, there was evidence of competition among Archaea and Fungi core OTUs, while all Bacteria OTUs were positively correlated among them. The results obtained highlighted interesting features of extremely cold temperature bioreactors. PMID- 29396547 TI - Three-dimensional imaging of KNDy neurons in the mammalian brain using optical tissue clearing and multiple-label immunocytochemistry. AB - Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in the regulation of fertility. The ability to detect features of KNDy neurons that are essential for fertility may require three-dimensional (3D) imaging of the complete population. Recently developed protocols for optical tissue clearing permits 3D imaging of neuronal populations in un-sectioned brains. However, these techniques have largely been described in the mouse brain. We report 3D imaging of the KNDy cell population in the whole rat brain and sheep hypothalamus using immunolabelling and modification of a solvent-based clearing protocol, iDISCO. This study expands the use of optical tissue clearing for multiple mammalian models and provides versatile analysis of KNDy neurons across species. Additionally, we detected a small population of previously unreported kisspeptin neurons in the lateral region of the ovine mediobasal hypothalamus, demonstrating the ability of this technique to detect novel features of the kisspeptin system. PMID- 29396548 TI - beta-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer. AB - Aberrant expression of FOXN2, a member of the Forkhead box transcription factors, has been found in several types of cancer. However, the underlying mechanisms of FOXN2 deregulation in tumorigenesis remain largely unknown. Here, we find that FOXN2 binds to and is ubiquitinated by beta-Trcp ubiquitin ligase and RSK2 kinase for degradation. Furthermore, we demonstrate that the Ser365 and Ser369 sites in a conserved DSGYAS motif are critical for the degradation of FOXN2 by beta-Trcp and RSK2. Moreover, gain-of-function and loss-of-function studies show that FOXN2 impairs cell proliferation in vitro and in vivo and enhances the radiosensitivity of lung cancer. Importantly, beta-Trcp-mediated and RSK2-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer cells. Collectively, our study reveals a novel post-translational modification of FOXN2 and suggests that FOXN2 may be a potential therapeutic and radiosensitization target for lung cancer. PMID- 29396549 TI - RGMa mediates reactive astrogliosis and glial scar formation through TGFbeta1/Smad2/3 signaling after stroke. AB - In response to stroke, astrocytes become reactive astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor beta1 (TGFbeta1) stimulated RGMa expression through TGFbeta1 receptor activin like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive astrogliosis and glial scar formation induced by TGFbeta1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co immunoprecipitated with ALK5 and Smad2/3. TGFbeta1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFbeta1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke. PMID- 29396550 TI - IL-6 potentiates BMP-2-induced osteogenesis and adipogenesis via two different BMPR1A-mediated pathways. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used in the clinic for bone defect reconstruction because of its powerful osteoinductive capacity. However, commercially available rhBMP-2 requires a high concentration in the clinical setting for consistent bone formation. A high dose of rhBMP-2 induces a promising bone formation yield but also leads to inflammation-related events, deteriorated bone quality, and fatty tissue formation. We hypothesize that the seemingly contradictory phenomenon of coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids may be associated with interleukin-6 (IL-6), which is significantly elevated after application of rhBMP 2/absorbable collagen sponge (rhBMP-2/ACS). Here, we show that IL-6 injection enhances new bone regeneration and induces excessive adipose tissue formation in an rhBMP-2/ACS-induced ectopic bone formation model in rats. In vitro data further show that IL-6 and its soluble receptor sIL-6R synergistically augment rhBMP-2-induced osteogenic and adipogenic differentiation of human BMSCs (hBMSCs) by promoting cell surface translocation of BMPR1A and then amplifying BMPR1A mediated BMP/Smad and p38 MAPK pathways, respectively. Our study suggests elevated IL-6 may be responsible for coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids. PMID- 29396551 TI - Lateral heterogeneity of soil physicochemical properties in riparian zones after agricultural abandonment. AB - The study aimed to identify the lateral heterogeneity of soil physicochemical properties in riparian zones, and its underlying drivers during natural restoration after agricultural abandonment. Abandoned farmlands, after 5-year natural restoration, within 500 m from the edges on both sides of Liaohe River were selected as the study area. Soil physicochemical properties of four lateral buffers (<10 m, 10~100 m, 100~300 m, and >300 m from river edge, respectively) along riparian zones were measured. The results showed that riparian soils were characterized by high sand content (78.88%~96.52%) and poor soil nutrients. Soil silt content, organic carbon (OC), cation exchange capacity (CEC), total nitrogen (TN), and available nitrogen (AN) increased laterally with increasing distance from river edge, while soil sand content decreased. Total phosphorus (TP) and available phosphorus (AP) are not spatially autocorrelated. Soil OC, TN, AN, and CEC along upstream and midstream reaches showed negative spatial autocorrelation along the lateral gradients, and positive along downstream reach. Altitude, distance from river edge and distance from nearest farmland were the pronounced factors affecting soil physicochemical properties in this study. PMID- 29396552 TI - New type of highly active chromium(III) catalysts containing both organic cations and anions designed for polymerization of beta-olefin derivatives. AB - The new type of catalysts designed for the olefin derivatives polymerization has been synthetized. The novel catalysts are chromium(III) salt type complexes composed of both organic cation and anion, i.e. [Cr(dipic)2][Cr(bipy)(dipic)H2O]?2H2O and [Cr(dipic)2]Hdmbipy?2.5 H2O. The compositions of these complexes have been confirmed by a number of instrumental methods including NMR, IR, UV-Vis, MS and elemental analysis ones. Moreover, the crystal structures of these novel catalysts were determined and reported. Furthermore, the [Cr(dipic)2][Cr(bipy)(dipic)H2O]?2H2O and [Cr(dipic)2]Hdmbipy?2.5H2O complexes have been studied towards their catalytic activity, after the activation by MMAO (modified methylaluminoxane), in the case of 2-chloro-2-propen-1-ol polymerization at 21 degrees C and atmospheric pressure. It has been found that novel catalysts, [Cr(dipic)2][Cr(bipy)(dipic)H2O]?2H2O and [Cr(dipic)2]Hdmbipy?2.5 H2O, exhibit a very high catalytic activity in the process of the polymerization of the beta olefin derivatives. The products of a such catalyzed polymerization are the poly(allyl alcohol) derivatives. PMID- 29396553 TI - Determining the Rate of Carbonic Anhydrase Reaction in the Human Brain. AB - Carbonic anhydrase plays important role in life. This study sought to demonstrate the feasibility of detecting carbonic anhydrase activity in the human brain in vivo. After oral administration of [U-13C6]glucose, 13C saturation transfer experiments were performed with interleaved control spectra and carbon dioxide saturation spectra. Proton nuclear Overhauser effect pulses were used to increase signal to noise ratio; no proton decoupling was applied. Results showed that the 13C signal of bicarbonate was reduced by 72% +/- 0.03 upon saturating carbon dioxide. The unidirectional dehydration rate constant of the carbonic anhydrase reaction was found to be 0.28 +/- 0.02 sec-1 in the human brain. These findings demonstrate the feasibility of measuring carbonic anhydrase activity in vivo in the human brain, which makes it possible to characterize this important enzyme in patients with brain disorders. PMID- 29396554 TI - Lactobacillus plantarum Restores Intestinal Permeability Disrupted by Salmonella Infection in Newly-hatched Chicks. AB - Salmonella infections in newly hatched chicks result in enteric and systemic diseases with a high mortality. Probiotics can improve the health of a host. The purpose of the present study was to investigate the effect of Lactobacillus plantarum LTC-113 on the gut permeability in the presence or absence of Salmonella (Salmonella Typhimurium) infection. Newly hatched chicks were randomly allocated to 4 treatments (i) NC (negative control); (ii) LAC (the L. plantarum LTC-113-treated group); (iii) SAL (the Salmonella-infected group), and (iv) LAC + SAL (the L. plantarum LTC-113-treated and Salmonella-infected group). Compared with the NC group, the intestinal permeability and claudin-2 (CLDN-2) were significantly increased, while mRNA levels of zonula occludens-1 (ZO-1) and claudin-5 (CLDN-5) were significantly decreased in the SAL group. However, these changes were eliminated in the LAC + SAL group. Additionally, numbers of Salmonella in liver, spleen and ceca were significantly reduced in the LAC + SAL group compared with the SAL group. Moreover, L. plantarum LTC-113 prevented the increase of inflammatory meditators myeloperoxidase (MPO), LITAF, IL-1beta, IL-6 and inflammation scores induced by Salmonella. These findings indicate that L. plantarum LTC-113 can protect hosts from Salmonella induced intestinal barrier disruption by regulating expression of tight junction genes and inflammatory meditators and decreasing Salmonella colonization. PMID- 29396555 TI - Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination. AB - Ubiquitin-specific protease 4 (USP4) is a member of the deubiquitinating enzyme family, which plays an important role in human tumor diseases. However, the mechanisms by which USP4 facilitates tumor development, especially in hepatocellular carcinoma (HCC), remain unclear. Clinically, we found that USP4 is overexpressed in human HCC tissues compared with adjacent non-tumoral tissues and is significantly correlated with malignant phenotype characteristics, including tumor size, tumor number, differentiation, serum alpha-fetoprotein level, and vascular invasion. Moreover, Kaplan-Meier survival analysis showed a poor overall survival rate in patients with USP4-overexpressing tumors. Analyses of univariate and multivariate Cox proportional hazard models indicated that USP4 is a prognostic biomarker for poor outcome. Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion. Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC. We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells. Subsequently, the USP4/CypA complex activated the MAPK signaling pathway and prevented CrkII phosphorylation. These data suggest that USP4 acts as a novel prognostic marker, offering potential therapeutic opportunities for HCC. PMID- 29396556 TI - Author Correction: Hippocampal oxytocin receptors are necessary for discrimination of social stimuli. AB - The original version of this Article contained an error in the spelling of the author Alexa H. Veenema, which was incorrectly given as Alexa Veenema. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29396557 TI - Magnetization reversal in trilayer structures consisting of GaMnAs layers with opposite signs of anisotropic magnetoresistance. AB - Magnetization reversal in a GaMnAs trilayer system consisting of two GaMnAs layers separated by a Be-doped GaAs spacer was investigated by magnetotransport measurements. The rotation of magnetization in the two GaMnAs layers is observed as two abrupt independent transitions in planar Hall resistance (PHR). Interestingly, one GaMnAs layer manifests a positive change in PHR, while the other layer shows a negative change for the same rotation of magnetization. Such opposite behavior of the two layers indicates that anisotropic magnetoresistance (AMR) has opposite signs in the two GaMnAs layers. Owing to this opposite behavior of AMR, we are able to identify the sequence of magnetic alignments in the two GaMnAs layers during magnetization reversal. The PHR signal can then be decomposed into two independent contributions, which reveal that the magnetic anisotropy of the GaMnAs layer with negative AMR is predominantly cubic, while it is predominantly uniaxial in the layer with positive AMR. This investigation suggests the ability of engineering the sign of AMR in GaMnAs multilayers, thus making it possible to obtain structures with multi-valued PHR, that can be used as multinary magnetic memory devices. PMID- 29396558 TI - Publisher Correction: Dietary arginine affects the insulin signaling pathway, glucose metabolism and lipogenesis in juvenile blunt snout bream Megalobrama amblycephala. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29396559 TI - Early skeletal colonization of the coral holobiont by the microboring Ulvophyceae Ostreobium sp. AB - Ostreobium sp. (Bryopsidales, Ulvophyceae) is a major microboring alga involved in tropical reef dissolution, with a proposed symbiotic lifestyle in living corals. However, its diversity and colonization dynamics in host's early life stages remained unknown. Here, we mapped microborer distribution and abundance in skeletons of the branching coral Pocillopora damicornis from the onset of calcification in primary polyps (7 days) to budding juvenile colonies (1 and 3 months) growing on carbonate and non-carbonate substrates pre-colonized by natural biofilms, and compared them to adult colonies (in aquarium settings). Primary polyps were surprisingly already colonized by microboring filaments and their level of invasion depended on the nature of settlement substrate and the extent of its pre-colonization by microborers. Growth of early coral recruits was unaffected even when microborers were in close vicinity to the polyp tissue. In addition to morphotype observations, chloroplast-encoded rbcL gene sequence analyses revealed nine new Ostreobium clades (OTU99%) in Pocillopora coral. Recruits and adults shared one dominant rbcL clade, undetected in larvae, but also present in aquarium seawater, carbonate and non-carbonate settlement substrates, and in corals from reef settings. Our results show a substratum dependent colonization by Ostreobium clades, and indicate horizontal transmission of Ostreobium-coral associations. PMID- 29396562 TI - Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage. AB - In response to Ravera et al. "Fanconi anemia: from DNA repair to metabolism" commenting on our recent publication by Abu-Libdeh, Douiev et al., describing a pathogenic variant in the COX 4I1 gene simulating Fanconi anemia, we wish to add supplementary, pertinent information linking cytochrome c oxidase (COX, mitochondrial respiratory chain complex IV) dysfunction to oxidative stress and nuclear DNA damage. Elevated production of reactive oxygen species (ROS) in COX 4I1 deficient fibroblasts was detected in cells grown in glucose free medium and normalized by ascorbate or N-acetylcysteine supplementation. A pilot study shows positive nuclear staining with antibodies against Phospho-Histone H2A.X (Ser 139) indicating double-stranded DNA breaks (DBSs) both in COX 4I1 and in COX6B1 deficient fibroblasts. Additional investigation is required, and ongoing, to elucidate the precise mechanism of DNA damage in mitochondrial respiratory chain dysfunction and how it could be prevented. PMID- 29396560 TI - Dynamic changes of phenotypically different circulating tumor cells sub populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib. AB - The aim of the study was to investigate the effect of 2nd-line pazopanib on the different CTCs subpopulations in SCLC patients and evaluate the clinical relevance of their changes. Different CTCs subpopulations were evaluated before pazopanib initiation (n = 56 patients), after one-cycle (n = 35) and on disease progression (n = 45) by CellSearch and double immunofluorescence using anti-CKs and anti-Ki67, anti-M30 or anti-Vimentin antibodies. Before treatment, CTCs were detected in 50% of patients by CellSearch whereas 53.4%, 15.5% and 74.1% patients had CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs, respectively. One pazopanib cycle significantly decreased the number of CTCs as detected by CellSearch (p = 0.043) as well as the number of CK+/Ki67+ (p < 0.001), CK+/M30+ (p = 0.015) and CK+/Vim+ (p < 0.001) cells. On disease progression, both the incidence and CTC numbers were significantly increased (CellSearch, p = 0.027; CK+/Ki67+, p < 0.001; CK+/M30+, p = 0.001 and CK+/Vim+, p < 0.001). In multivariate analysis, the detection of CK+/Vim+ CTCs after one treatment cycle (HR: 7.9, 95% CI: 2.9-21.8; p < 0.001) and CTCs number on disease progression, as assessed by CellSearch, (HR: 2.0, 95% CI: 1.0-6.0; p = 0.005) were emerged as independent factors associated with decreased OS. In conclusion, pazopanib can eliminate different CTC subpopulations in patients with relapsed SCLC. The analysis of CTCs could be used as a dynamic biomarker of treatment efficacy. PMID- 29396561 TI - Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes. AB - Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling. PMID- 29396564 TI - Fanconi anemia: from DNA repair to metabolism. PMID- 29396563 TI - The RD-Connect Registry & Biobank Finder: a tool for sharing aggregated data and metadata among rare disease researchers. AB - In rare disease (RD) research, there is a huge need to systematically collect biomaterials, phenotypic, and genomic data in a standardized way and to make them findable, accessible, interoperable and reusable (FAIR). RD-Connect is a 6 years global infrastructure project initiated in November 2012 that links genomic data with patient registries, biobanks, and clinical bioinformatics tools to create a central research resource for RDs. Here, we present RD-Connect Registry & Biobank Finder, a tool that helps RD researchers to find RD biobanks and registries and provide information on the availability and accessibility of content in each database. The finder concentrates information that is currently sparse on different repositories (inventories, websites, scientific journals, technical reports, etc.), including aggregated data and metadata from participating databases. Aggregated data provided by the finder, if appropriately checked, can be used by researchers who are trying to estimate the prevalence of a RD, to organize a clinical trial on a RD, or to estimate the volume of patients seen by different clinical centers. The finder is also a portal to other RD-Connect tools, providing a link to the RD-Connect Sample Catalogue, a large inventory of RD biological samples available in participating biobanks for RD research. There are several kinds of users and potential uses for the RD-Connect Registry & Biobank Finder, including researchers collaborating with academia and the industry, dealing with the questions of basic, translational, and/or clinical research. As of November 2017, the finder is populated with aggregated data for 222 registries and 21 biobanks. PMID- 29396565 TI - TRPA1-dependent reversible opening of tight junction by natural compounds with an alpha,beta-unsaturated moiety and capsaicin. AB - The delivery of hydrophilic macromolecules runs into difficulties such as penetration of the cell membrane lipid bilayer. Our prior experiment demonstrated that capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. Herein, we screened paracellular permeability enhancers other than capsaicin. As TJ opening by capsaicin is associated with Ca2+ influx, we first screened the compounds that induce Ca2+ influx in layered MDCK II cells, and then we determined the compounds' abilities to open TJs. Our results identified several natural compounds with alpha,beta-unsaturated moiety. A structure-activity relationship (SAR) analysis and the results of pretreatment with reducing reagent DTT suggested the importance of alpha,beta-unsaturated moiety. We also examined the underlying mechanisms, and our findings suggest that the actin reorganization seen in capsaicin treatment is important for the reversibility of TJ opening. Furthermore, our analyses revealed that TRPA1 is involved in the Ca2+ influx and TJ permeability increase not only by an alpha,beta-unsaturated compound but also by capsaicin. Our results indicate that the alpha,beta-unsaturated moiety can be a potent pharmacophore for TJ opening. PMID- 29396566 TI - A computationally driven analysis of the polyphenol-protein interactome. AB - Polyphenol-rich foods are part of many nutritional interventions aimed at improving health and preventing cardiometabolic diseases (CMDs). Polyphenols have oxidative, inflammatory, and/or metabolic effects. Research into the chemistry and biology of polyphenol bioactives is prolific but knowledge of their molecular interactions with proteins is limited. We mined public data to (i) identify proteins that interact with or metabolize polyphenols, (ii) mapped these proteins to pathways and networks, and (iii) annotated functions enriched within the resulting polyphenol-protein interactome. A total of 1,395 polyphenols and their metabolites were retrieved (using Phenol-Explorer and Dictionary of Natural Products) of which 369 polyphenols interacted with 5,699 unique proteins in 11,987 interactions as annotated in STITCH, Pathway Commons, and BindingDB. Pathway enrichment analysis using the KEGG repository identified a broad coverage of significant pathways of low specificity to particular polyphenol (sub)classes. When compared to drugs or micronutrients, polyphenols have pleiotropic effects across many biological processes related to metabolism and CMDs. These systems wide effects were also found in the protein interactome of the polyphenol-rich citrus fruits, used as a case study. In sum, these findings provide a knowledgebase for identifying polyphenol classes (and polyphenol-rich foods) that individually or in combination influence metabolism. PMID- 29396567 TI - Brain Region-dependent Heterogeneity and Dose-dependent Difference in Transient Microglia Population Increase during Lipopolysaccharide-induced Inflammation. AB - Numerous studies have reported the importance of microglial activation in various pathological conditions, whereas little attention has been given to the point for dynamics of microglial population under infection-induced inflammation. In the present study, the single systemic stimulation of 100 MUg/kg lipopolysaccharide (LPS) induced robust microglial proliferation only in the circumventricular organs (CVOs) and their neighboring brain regions. More than half of microglia similarly showed proliferative activity in the CVOs and their neighboring brain regions after 1 mg/kg LPS stimulation, while this stimulation expanded microglia proliferating brain regions including the hypothalamus, medulla oblongata, and limbic system. Microglia proliferation resulted in a transient increase of microglial density, since their density almost returned to basal levels within 3 weeks. Divided microglia survived at the same rate as non-divided ones. Proliferating microglia frequently expressed a resident microglia marker Tmem119, indicating that increase of microglia density is due to the proliferation of resident microglia. Thus, the present study demonstrates that transient increase in microglia density depends on the brain region and dose of LPS during infection induced inflammation and could provide a new insight on microglia functions in inflammation and pathogenesis of brain diseases. PMID- 29396568 TI - Co-administration of iRGD with peptide HPRP-A1 to improve anticancer activity and membrane penetrability. AB - To improve the specificity and penetration of anticancer peptides against tumors, in this study, we examined the effects of co-administration of the membrane active peptide HPRP-A1 and the tumor homing/penetrating peptide iRGD. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide targeting to alphavbeta3 integrins and neuropilin-1 (NRP-1) receptors, which show high expression in many tumor cells. The anticancer activity, cancer specificity and penetration activity in vitro and in vivo of the co-administered peptides were examined on 2D monolayer cells, 3D multi-cellular spheroids (MCS) and xenograft nude mice. Co-administration of iRGD and HPRP-A1 exhibited stronger anticancer activity and tumor specificity against A549 non-small cell lung cancer cells with NRP-1 receptor overexpression compared with HPRP-A1 alone. A549 cells showed uptake of the peptide combination and destruction of the integrity of the cell membrane, as well as adherence to the mitochondrial net, resulting in induction of apoptosis by a caspase-dependent pathway. The iRGD peptide dramatically increased the penetration depth of HPRP-A1 on A549 MCS and anticancer efficacy in an A549 xenograft mouse model. Our results suggest that the co-administration strategy of anticancer and penetrating peptides could be a potential therapeutic approach for cancer treatment in clinical practice. PMID- 29396569 TI - Controlled Information Transfer Through An In Vivo Nervous System. AB - The nervous system holds a central position among the major in-body networks. It comprises of cells known as neurons that are responsible to carry messages between different parts of the body and make decisions based on those messages. In this work, further to the extensive theoretical studies, we demonstrate the first controlled information transfer through an in vivo nervous system by modulating digital data from macro-scale devices onto the nervous system of common earthworms and conducting successful transmissions. The results and analysis of our experiments provide a method to model networks of neurons, calculate the channel propagation delay, create their simulation models, indicate optimum parameters such as frequency, amplitude and modulation schemes for such networks, and identify average nerve spikes per input pulse as the nervous information coding scheme. Future studies on neuron characterization and artificial neurons may benefit from the results of our work. PMID- 29396575 TI - Age Differences in Voice Evaluation: From Auditory-Perceptual Evaluation to Social Interactions. AB - Purpose: The factors that influence the evaluation of voice in adulthood, as well as the consequences of such evaluation on social interactions, are not well understood. Here, we examined the effect of listeners' age and the effect of talker age, sex, and smoking status on the auditory-perceptual evaluation of voice, voice-related psychosocial attributions, and perceived speech tempo. We also examined the voice dimensions affecting the propensity to engage in social interactions. Method: Twenty-five younger (age 19-37 years) and 25 older (age 51 74 years) healthy adults participated in this cross-sectional study. Their task was to evaluate the voice of 80 talkers. Results: Statistical analyses revealed limited effects of the age of the listener on voice evaluation. Specifically, older listeners provided relatively more favorable voice ratings than younger listeners, mainly in terms of roughness. In contrast, the age of the talker had a broader impact on voice evaluation, affecting auditory-perceptual evaluations, psychosocial attributions, and perceived speech tempo. Some of these talker differences were dependent upon the sex of the talker and his or her smoking status. Finally, the results also show that voice-related psychosocial attribution was more strongly associated with the propensity of the listener to engage in social interactions with a person than auditory-perceptual dimensions and perceived speech tempo, especially for the younger adults. Conclusions: These results suggest that age has a broad influence on voice evaluation, with a stronger impact for talker age compared with listener age. While voice-related psychosocial attributions may be an important determinant of social interactions, perceived voice quality and speech tempo appear to be less influential. Supplemental Materials: https://doi.org/10.23641/asha.5844102. PMID- 29396576 TI - Lingual Pressure as a Clinical Indicator of Swallowing Function in Parkinson's Disease. AB - Purpose: Swallowing impairment, or dysphagia, is a known contributor to reduced quality of life, pneumonia, and mortality in Parkinson's disease (PD). However, the contribution of tongue dysfunction, specifically inadequate pressure generation, to dysphagia in PD remains unclear. Our purpose was to determine whether lingual pressures in PD are (a) reduced, (b) reflect medication state, or are (c) consistent with self-reported diet and swallowing function. Method: Twenty-eight persons with idiopathic PD (PwPD) and 28 age- and sex-matched controls completed lingual pressure tasks with the Iowa Oral Performance Instrument. PwPD were tested during practically defined ON and OFF dopaminergic medication states. Participants were also stratified into three sex- and age matched cohorts (7 men, 5 women): (a) controls, (b) PwPD without self-reported dysphagia symptoms or diet restrictions, and (c) PwPD with self-reported dysphagia symptoms with or without diet restrictions. Results: PwPD exhibited reduced tongue strength and used elevated proportions of tongue strength during swallowing compared with controls (p < .05) without an effect of medication state (p > .05). Reduced tongue strength distinguished PwPD with self-reported dysphagia symptoms from PwPD without reported symptoms or diet restrictions (p = .045) and controls (p = .002). Conclusion: Tongue strength was significantly reduced in PwPD and did not differ by medication state. Tongue strength differentiated between PwPD with and without self-reported swallowing symptoms. Therefore, measures of tongue strength and swallowing pressures may serve as clinical indicators for further dysphagia evaluation and may promote early diagnosis and management of dysphagia in PD. PMID- 29396577 TI - A Priori Assessment of Adipose Tissue Mechanical Testing by Global Sensitivity Analysis. AB - In modeling the mechanical behavior of soft tissues, the proper choice of an experiment for identifying material parameters is not an easy task. In this study, a finite element computational framework is used to virtually simulate and assess commonly used experimental setups: rotational rheometer tests, confined- and unconfined-compression tests, and indentation tests. Variance-based global sensitivity analysis is employed to identify which parameters in different experimental setups govern model prediction and are thus more likely to be determined through parameter identification processes. Therefore, a priori assessment of experimental setups provides a base for systematic and reliable parameter identification. It is found that in indentation tests and unconfined compression tests, incompressibility of soft tissues (adipose tissue in this study) plays an important role at high strain rates. That means bulk stiffness constitutes the main part of the mechanism of tissue response; thus, these experimental setups may not be appropriate for identifying shear stiffness. Also, identified material parameters through loading-unloading shear tests at a certain rate might not be reliable for other rates, since adipose tissue shows highly strain rate dependent behavior. Frequency sweep tests at a wide-enough frequency range seem to be the best setup to capture the strain rate behavior. Moreover, analyzing the sensitivity of model parameters in the different experimental setups provides further insight about the model itself. PMID- 29396578 TI - CONFIRM-Comparing Colonoscopy and Fecal Occult Testing. PMID- 29396579 TI - The Effect of Remote Masking on the Reception of Speech by Young School-Age Children. AB - Purpose: Psychoacoustic data indicate that infants and children are less likely than adults to focus on a spectral region containing an anticipated signal and are more susceptible to remote masking of a signal. These detection tasks suggest that infants and children, unlike adults, do not listen selectively. However, less is known about children's ability to listen selectively during speech recognition. Accordingly, the current study examines remote masking during speech recognition in children and adults. Method: Adults and 7- and 5-year-old children performed sentence recognition in the presence of various spectrally remote maskers. Intelligibility was determined for each remote-masker condition, and performance was compared across age groups. Results: It was found that speech recognition for 5-year-olds was reduced in the presence of spectrally remote noise, whereas the maskers had no effect on the 7-year-olds or adults. Maskers of different bandwidth and remoteness had similar effects. Conclusions: In accord with psychoacoustic data, young children do not appear to focus on a spectral region of interest and ignore other regions during speech recognition. This tendency may help account for their typically poorer speech perception in noise. This study also appears to capture an important developmental stage, during which a substantial refinement in spectral listening occurs. PMID- 29396580 TI - Listeners Experience Linguistic Masking Release in Noise-Vocoded Speech-in-Speech Recognition. AB - Purpose: The purpose of this study was to evaluate whether listeners with normal hearing perceiving noise-vocoded speech-in-speech demonstrate better intelligibility of target speech when the background speech was mismatched in language (linguistic release from masking [LRM]) and/or location (spatial release from masking [SRM]) relative to the target. We also assessed whether the spectral resolution of the noise-vocoded stimuli affected the presence of LRM and SRM under these conditions. Method: In Experiment 1, a mixed factorial design was used to simultaneously manipulate the masker language (within-subject, English vs. Dutch), the simulated masker location (within-subject, right, center, left), and the spectral resolution (between-subjects, 6 vs. 12 channels) of noise vocoded target-masker combinations presented at +25 dB signal-to-noise ratio (SNR). In Experiment 2, the study was repeated using a spectral resolution of 12 channels at +15 dB SNR. Results: In both experiments, listeners' intelligibility of noise-vocoded targets was better when the background masker was Dutch, demonstrating reliable LRM in all conditions. The pattern of results in Experiment 1 was not reliably different across the 6- and 12-channel noise vocoded speech. Finally, a reliable spatial benefit (SRM) was detected only in the more challenging SNR condition (Experiment 2). Conclusion: The current study is the first to report a clear LRM benefit in noise-vocoded speech-in-speech recognition. Our results indicate that this benefit is available even under spectrally degraded conditions and that it may augment the benefit due to spatial separation of target speech and competing backgrounds. PMID- 29396581 TI - Routine Cardiac Catheterization Prior to Fontan Operation: Is It a Necessity? AB - Prior to the Fontan procedure, patients with single ventricle physiology with Glenn shunt are typically referred for cardiac catheterization to assess hemodynamics and potentially provide interventional measures. Currently, echocardiography provides detailed information which together with other non invasive imaging such as CT scan and MRI may obviate the need for routine cardiac catheterization prior to the Fontan procedure. In this study, we examine the findings in cardiac catheterization in this population to determine: (a) the accuracy of echocardiography in providing adequate information prior to the Fontan procedure, particularly in identifying those in need of per-catheter intervention, and (b) the percentage of patients requiring interventional procedures during cardiac catheterization. We performed a retrospective chart review of echocardiographic and cardiac catheterization data for patients who underwent pre-Fontan cardiac catheterization at our center in the period from 02/01/2008 to 02/28/2017. We aimed to re-examine the necessity of routine cardiac catheterization in all single ventricle patients. This was performed through examining pre-catheterization echocardiography reports and comparing them to findings of the subsequent cardiac catheterization reports. Echocardiography reports were evaluated for accuracy in identifying significant anatomical or hemodynamic findings, which may impact success of Fontan procedure as well as the ability of echocardiography to predict findings important to know prior to the Fontan procedure. In this cohort of 40 children, 3 patients were found to have significant hemodynamic findings through cardiac catheterization which were not previously known by echocardiography. In addition, 28 out of 40 patients (70%) required interventional procedures to address significant abnormalities (systemic to pulmonary arterial collaterals, pulmonary artery stenosis, aortic arch stenosis, etc.). All cases of aortic arch stenosis were detected by echocardiography, however, all patients who required systemic to pulmonary arterial or left SVC embolization were not detected by echocardiography. Furthermore, echocardiography did not detect the need for branch pulmonary artery stenosis in 50% of cases. Cardiac catheterization appears to be an essential part of patient assessment prior to Fontan completion in patients with single ventricle physiology. This current practice may change in the future if a non invasive screening tool is found to have high positive and negative predictive values in identifying the subset of patients who require potential intervention in pre-Fontan cardiac catheterization. PMID- 29396582 TI - Comparative Noninvasive Measurement of Cardiac Output Based on the Inert Gas Rebreathing Method (Innocor(r)) and MRI in Patients with Univentricular Hearts. AB - There are many complex cardiac malformations that are characterized by a functionally univentricular physiology. Staged surgical repair according to the Fontan principle separates the systemic and pulmonary circulations by connecting the systemic venous return to the pulmonary arteries. However, long-term follow up studies demonstrate a gradual deterioration of cardiac function, particularly from the second or third decade. Noninvasive evaluation of the cardiac function is, therefore, important in the follow-up of these patients. The cardiac index (CI) is a reliable hemodynamic parameter and represents an important marker of cardiac function. We compared CI values determined by cardiac MRI (CMRI) with values obtained by noninvasive inert gas rebreathing (IGR; Innocor(r) system). Sixteen patients (age range: 7.2-32.7 years) with functionally univentricular hearts (UVH) following total cavopulmonary connection (TCPC) were compared with 12 healthy subjects (age range: 8.5-18.6 years). The standard treadmill protocol of the German Society of Pediatric Cardiology was used for exercise testing. CI was determined at rest and at two standardized submaximal exercise levels. In all subjects, CI increased under exercise conditions, but the values were significantly lower in patients with UVH. There was no significant difference between patients with UVH and predominantly right- or left-ventricular morphology. In comparison with CMRI measurements, the CI values obtained by the IGR method tended to be lower, with a mean difference of 1.02 l/min/m2. Noninvasive measurement of CI with the IGR method is feasible at rest and during exercise, and appears to be suited for routine determination of CI in patients with UVH following TCPC. PMID- 29396583 TI - Determination of hexachlorobutadiene, pentachlorobenzene, and hexachlorobenzene in waste incineration fly ash using ultrasonic extraction followed by column cleanup and GC-MS analysis. AB - Hexachlorobutadiene (HCBD) was listed as a new controlling persistent organic pollutant in the Stockholm Convention because of its wide industrial applications and potential genotoxicity and carcinogenicity. However, only limited information exists on the release of HCBD from unintentional sources, such as waste incineration. Identification and quantification of HCBD in fly ash, one of the major outputs of waste incineration, is imperative. This work presents a simple method for determining HCBD in waste incineration fly ash based on ultrasonic extraction coupled with a silica gel-Florisil column cleanup followed by gas chromatography-mass spectrometry detection. Two typical persistent organic pollutants, pentachlorobenzene (PeCB) and hexachlorobenzene (HCB), were measured simultaneously. The parameters that influence the extraction efficiency and the quality of instrument detection were studied. Under the optimum experimental conditions, high sensitivity (detection limit 0.25-0.53 ng g-1), acceptable recoveries (64.0-71.4%) at spiking levels of 5-500 ng g-1, and good repeatability [relative standard deviation (n = 3) of 14% or less] were achieved for all target analytes. The validation of this method was performed by analysis of six real fly ash samples from different waste incinerators in eastern China. The concentrations of HCBD detected in these samples (1.39-97.6 ng g-1) were comparable to those of PeCB (1.22-150 ng g-1) and HCB (0.82-120 ng g-1), indicating that the residual HCBD as well as PeCB and HCB in waste incineration fly ash should not be ignored. The results confirm for the first time that waste incineration is an unintentional source of HCBD in China. Graphical abstract An analytical method for hexachlorobutadiene, pentachlorobenzene, and hexachlorobenzene in fly ash from waste incineration. GC-MS gas chromatography mass spectrometry, Ph-d10 phenanthrene-d10. PMID- 29396584 TI - Facile synthesis of terminal-alkyne bioorthogonal molecules for live -cell surface-enhanced Raman scattering imaging through Au-core and silver/dopamine shell nanotags. AB - Alkyne is unique, specific and biocompatible in the Raman-silent region of the cell, but there still remains a challenge to achieve ultrasensitive detection in living systems due to its weak Raman scattering. Herein, a terminal alkyne ((E)-2 [4-(ethynylbenzylidene)amino]ethane-1-thiol (EBAE)) with surface-enhanced Raman scattering is synthesized. The EBAE molecule possesses S- and C-termini, which can be directly bonded to gold nanoparticles and dopamine/silver by forming the Au-S chemical bond and the carbon-metal bond, respectively. The distance between Raman reporter and AuNPs/AgNPs can be reduced, contributing to forming hot-spot based SERS substrate. The alkyne functionalized nanoparticles are based on Au core and encapsulating polydopamine shell, defined as Au-core and dopamine/Ag shell (ACDS). The bimetallic ACDS induce strong SERS signals for molecular imaging that arise from the strong electromagnetic field. Furthermore, the EBAE provides a distinct peak in the cellular Raman-silent region with nearly zero background interference. The EBAE Raman signals could be tremendously enhanced when the Raman reporter is located at the middle of the Au-core and dopamine/Ag shell. Therefore, this work could have huge potential benefits for the highly sensitive detection of intercellular information delivery by connecting the recognition molecules in biomedical diagnostics. Graphical abstract Terminal alkyne-functionalized Au-core and silver/dopamine-shell nanotags for live-cell surface-enhanced Raman scattering imaging. PMID- 29396585 TI - Dynamic augmentation restores anterior tibial translation in ACL suture repair: a biomechanical comparison of non-, static and dynamic augmentation techniques. AB - PURPOSE: There is a lack of objective evidence investigating how previous non augmented ACL suture repair techniques and contemporary augmentation techniques in ACL suture repair restrain anterior tibial translation (ATT) across the arc of flexion, and after cyclic loading of the knee. The purpose of this work was to test the null hypotheses that there would be no statistically significant difference in ATT after non-, static- and dynamic-augmented ACL suture repair, and they will not restore ATT to normal values across the arc of flexion of the knee after cyclic loading. METHODS: Eleven human cadaveric knees were mounted in a test rig, and knee kinematics from 0 degrees to 90 degrees of flexion were recorded by use of an optical tracking system. Measurements were recorded without load and with 89-N tibial anterior force. The knees were tested in the following states: ACL-intact, ACL-deficient, non-augmented suture repair, static tape augmentation and dynamic augmentation after 10 and 300 loading cycles. RESULTS: Only static tape augmentation and dynamic augmentation restored ATT to values similar to the ACL-intact state directly postoperation, and maintained this after cyclic loading. However, contrary to dynamic augmentation, the ATT after static tape augmentation failed to remain statistically less than for the ACL-deficient state after cyclic loading. Moreover, after cyclic loading, ATT was significantly less with dynamic augmentation when compared to static tape augmentation. CONCLUSION: In contrast to non-augmented ACL suture repair and static tape augmentation, only dynamic augmentation resulted in restoration of ATT values similar to the ACL-intact knee and decreased ATT values when compared to the ACL deficient knee immediately post-operation and also after cyclic loading, across the arc of flexion, thus allowing the null hypotheses to be rejected. This may assist healing of the ruptured ACL. Therefore, this study would support further clinical evaluation of dynamic augmentation of ACL repair. PMID- 29396586 TI - Free-living bacteria and potential bacterial pathogens in sewage treatment plants. AB - To comprehensively understand the profile of free-living bacteria and potential bacterial pathogens in sewage treatment plants (STPs), this study applied high throughput sequencing-based metagenomics approaches to investigate the effects of activated sludge (AS) treatment process and ultraviolet (UV) disinfection on the community of bacterial pathogens in two full-scale STPs. A total of 23 bacterial genera were identified as free-living bacteria, and 243 species/OTU97% were identified as potential bacterial pathogens, 6 of which were confidently detected in the STPs (with the total abundances ranging from 0.02 to 14.19%). Both diversity and relative abundance of the detected bacterial pathogens decreased obviously after AS treatment process (p < 0.05), and increased slightly after sedimentation (p < 0.05). UV disinfection shows no obvious effects on the total relative abundance of the free-living pathogenic bacteria in sewage. Although large amounts of the particle-bound pathogens were eliminated through the sewage treatment process, the STPs could not effectively remove the free-living bacterial pathogens, and some pathogenic bacteria (e.g., Pseudomonas aeruginosa) present in the effluent had higher relative abundance after UV disinfection. Overall, the results extend our knowledge regarding the community of potential pathogens (especially free-living pathogens) in STPs. PMID- 29396587 TI - Impact of gut-associated bifidobacteria and their phages on health: two sides of the same coin? AB - Bifidobacteria are among the first microbial colonisers of the human infant gut post-partum. Their early appearance and dominance in the human infant gut and the reported health-promoting or probiotic status of several bifidobacterial strains has culminated in intensive research efforts that focus on their activities as part of the gut microbiota and the concomitant implications for human health. In this mini-review, we evaluate current knowledge on the genomics of this diverse bacterial genus, and on the genetic and functional adaptations that have underpinned the success of bifidobacteria in colonising the infant gut. The growing interest in functional genomics of bifidobacteria has also created interest in the interactions of bifidobacteria and their (bacterio)phages. While virulent phages of bifidobacteria have yet to be isolated, the incidence of integrated (pro)phages in bifidobacterial genomes are widely reported and this mini-review considers the role of these so-called bifidoprophages in modulating bifidobacterial populations in the human gastrointestinal tract and the implications for existing and future development of probiotic therapies. PMID- 29396589 TI - A new leaf rust resistance gene Lr79 mapped in chromosome 3BL from the durum wheat landrace Aus26582. AB - KEY MESSAGE: A new leaf rust resistance gene Lr79 has been mapped in the long arm of chromosome 3B and a linked marker was identified for marker-assisted selection. Aus26582, a durum wheat landrace from the A. E. Watkins Collection, showed seedling resistance against durum-specific and common wheat-specific Puccinia triticina (Pt) pathotypes. Genetic analysis using a recombinant inbred line (RIL) population developed from a cross between Aus26582 and the susceptible parent Bansi with Australian Pt pathotype showed digenic inheritance and the underlying loci were temporarily named LrAW2 and LrAW3. LrAW2 was located in chromosome 6BS and this study focused on characterisation of LrAW3 using RILs lacking LrAW2. LrAW3 was incorporated into the DArTseq map of Aus26582/Bansi and was located in chromosome 3BL. Markers linked with LrAW3 were developed from the chromosome survey sequence contig 3B_10474240 in which closely-linked DArTseq markers 1128708 and 3948563 were located. Although bulk segregant analysis (BSA) with the 90 K Infinium array identified 51 SNPs associated with LrAW3, only one SNP-derived KASP marker mapped close to the locus. Deletion bin mapping of LrAW3 linked markers located LrAW3 between bins 3BL11-0.85-0.90 and 3BL7-0.63. Since no other all stage leaf rust resistance gene is located in chromosome 3BL, LrAW3 represented a new locus and was designated Lr79. Marker sun786 mapped 1.8 cM distal to Lr79 and Aus26582 was null for this locus. However, the marker can be reliably scored as it also amplifies a monomorphic fragment that serves as an internal control to differentiate the null status of Aus26582 from reaction failure. This marker was validated among a set of durum and common wheat cultivars and was shown to be useful for marker-assisted selection of Lr79 at both ploidy levels. PMID- 29396590 TI - [Evaluation of a simple screening tool for ambulant fall prevention]. AB - BACKGROUND: An individual's risk of falling is generally difficult to detect and it is likely to be underestimated. Thus, preventive measures are challenging and they demand sufficient integration and implementation into aftercare and outpatient management. The Aachen Falls Prevention Scale (AFPS) is a quick and easy tool for patient-driven fall risk assessment. Older adults' risk of falling is identified in a suitable manner and they then have the opportunity to independently assess and monitor their risk of falling. OBJECTIVES: The aim of the current study was to evaluate the AFPS as a simple screening tool in geriatric trauma patients via the identification of influencing factors, e.g. objective or subjective fall risk, fear of falling (FOF) and demographic data. In this context, we investigated older adults' willingness to take part in special activities concerning fall prevention. METHODS: Retrospectively, all patients over 70 years of age who received in-hospital fracture treatment between July 2014 and April 2016 were analyzed at a level I trauma center. After identification of 884 patients, participants completed a short questionnaire (47 questions, yes/no, Likert scale) comprising the AFPS. A history of falls in the past year was considered an indicator of a balance disorder. In addition, ambulant patients were invited to participate between July and August 2016. RESULTS: In total, 201 patients (mean 80.4 years, range 63-97 years) performed a self-assessment based on the AFPS. After steps 1 and 2 of the AFPS had been completed, 95 (47%) participants rated their subjective risk of falling as high (more than 5 points). Of the participants 84 (42%) were objectively classified as "fallers" with significant effects on their AFPS evaluation and rating of their subjective risk of falling. Furthermore, 67% of the participants identified a general practitioner as their main contact person, and 43% of the respondents viewed the AFPS as a beneficial screening tool in fall risk evaluation (8% negative attitudes). Only 12% of the participants could imagine using the AFPS app version as a feasible option. CONCLUSION: It would be advantageous to pretest at-risk individuals in their environment using a simple self-assessment approach, with the main purpose of identifying potential balance problems. With this approach, cost savings in the healthcare system are possible, combined with a higher health-related quality of life in the geriatric population. PMID- 29396588 TI - Identification of cyclosporin C from Amphichorda felina using a Cryptococcus neoformans differential temperature sensitivity assay. AB - We used a temperature differential assay with the opportunistic fungal pathogen Cryptococcus neoformans as a simple screening platform to detect small molecules with antifungal activity in natural product extracts. By screening of a collection extracts from two different strains of the coprophilous fungus, Amphichorda felina, we detected strong, temperature-dependent antifungal activity using a two-plate agar zone of inhibition assay at 25 and 37 degrees C. Bioassay guided fractionation of the crude extract followed by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR) identified cyclosporin C (CsC) as the main component of the crude extract responsible for growth inhibition of C. neoformans at 37 degrees C. The presence of CsC was confirmed by comparison with a commercial standard. We sequenced the genome of A. felina to identify and annotate the CsC biosynthetic gene cluster. The only previously characterized gene cluster for the biosynthesis of similar compounds is that of the related immunosuppressant drug cyclosporine A (CsA). The CsA and CsC gene clusters share a high degree of synteny and sequence similarity. Amino acid changes in the adenylation domain of the CsC nonribosomal peptide synthase's sixth module may be responsible for the substitution of L-threonine compared to L alpha-aminobutyric acid in the CsA peptide core. This screening strategy promises to yield additional antifungal natural products with a focused spectrum of antimicrobial activity. PMID- 29396591 TI - Clinical Application of Platelet-Rich Fibrin in Plastic and Reconstructive Surgery: A Systematic Review. AB - BACKGROUND: Platelet-rich fibrin (PRF) has been applied in the clinical field for more than a decade, but largely in oral surgery and implant dentistry. Its utilization in plastic and reconstructive surgery is limited and lacking a comprehensive review. Hence, this article focuses on the various clinical applications of PRF pertaining to the plastic and reconstructive field through a systematic review. METHODS: In this review, articles describing the clinical application of PRF in plastic and reconstructive surgery were screened using predetermined inclusion and exclusion criteria. The articles were summarized and divided into groups based on the utilization of PRF. The effects and complications of PRF were analyzed and concluded. RESULTS: Among the 634 articles searched, 7 articles describing 151 cases are eligible. PRF was applied on 116 (76.8%) wounds to facilitate tissue healing, and the complete wound closure rate was 91.4% (106/116). Otherwise, PRF was applied in 10 (6.6%) cases of zygomaticomaxillary fracture to reconstruct orbital floor defects and in 25 (16.6%) cases of facial autologous fat grafts to increase the fat retention rate successfully. There is no report of PRF-related complications. CONCLUSIONS: PRF could facilitate wound healing, including the healing of soft tissues and bony tissues, and facilitate fat survival rate. Further studies are needed to test the mechanism of PRF and expand its scope of application in plastic and reconstructive surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29396592 TI - Correction to: Epigenetic regulation of neuroblastoma development. AB - The authorship names of this paper are incorrect. PMID- 29396593 TI - Impact of opioid use on health care utilization and survival in patients with newly diagnosed stage IV malignancies. AB - PURPOSE: Patients with advanced cancers frequently experience pain. Opioids are commonly prescribed to treat cancer-related pain, but their use might be associated with undesirable consequences including adverse effects and tumor progression, resulting in increased heath care utilization and shorter survival. We examined these possibilities in a large cohort of patients diagnosed with ten common advanced malignancies. METHODS: We identified 1386 newly diagnosed patients with stage IV non-hematologic malignancies from 2005 to 2013 and ascertained opioid utilization within 90 days of starting anti-cancer treatment using electronic medical record and tumor registry data. Opioid utilization was stratified into low opioid (LO; < 5 mg oral morphine equivalents (OME)/day) and high opioid (HO; >= 5 mg OME/day). Health care utilization included tallies of emergency room, urgent care, and inpatient visits. The association of opioid use, tumor type prognosis, age, and gender with overall survival was analyzed in univariate and multivariate models. RESULTS: HO use patients (n = 624) had greater health care utilization compared to LO use patients (n = 762; p < 0.05). HO use patients also had shorter survival (median survival, 5.5 vs 12.4 months; p < 0.0001). On multivariate analysis, HO use remained associated with shorter overall survival (HR 1.4; 95% CI, 1.3-1.6; p < 0.0001) after adjusting for age, gender, and prognostic group. CONCLUSIONS: In advanced cancer patients, HO use is associated with greater health care utilization and shorter survival. Prospective studies using opioid-sparing approaches are indicated, to confirm these retrospective findings and to evaluate if these undesirable effects associated with opioid use can be mitigated. PMID- 29396595 TI - Correction to: Atrial thrombogenesis in atrial fibrillation : Results from atrial fibrillation models and AF-patients. AB - Correction to: Herzschr Elektrophys 2017 https://doi.org/10.1007/s00399-017-0543 x Please accept the Publisher's apologies for the following mistake:In the first online version of this contribution the title was incomplete. The correct version reads: "Atrial thrombogenesis in atrial fibrillation. Results from atrial fibrillation models and AF-patients".The .... PMID- 29396594 TI - Integrative medicine and the oncology patient: options and benefits. AB - Cancer is a major public health problem, and cancer patients and survivors face many physical and emotional challenges after the initial diagnosis, through treatment, and in the post-treatment period. Different integrative medicine (IM) modalities can be used to mitigate some of the physical issues that originate from the cancer itself or the treatment and to promote well-being and emotional health. Here, we discuss how an IM Department can function in a hospital system, particularly with regard to oncology patients, the modalities appropriate for oncology patients, how these modalities can benefit this patient population, and the role of IM in cancer survivorship. A dedicated IM Department that works with oncologists provides support and care for the whole person. These different modalities work together to reduce pain, anxiety, and chemotherapy-induced nausea and peripheral neuropathy, while promoting immune function and improving sleep, range of motion, and an overall sense of well-being. However, each modality has different contraindications for the oncology patient, and proper training is required for safe and effective care. We illustrate how IM can be a valuable component of the care of the oncology patient. PMID- 29396596 TI - Subcutaneous injection of multipotent mesenchymal stromal cells admixed with melanoma cells in mice favors tumor incidence and growth: a systematic review and meta-analysis. AB - Multipotent mesenchymal stem/stromal cells (MSCs) have strong tropism towards cancer cells, thus being tested as tools for the targeted delivery of therapeutic substances for the treatment of melanoma. However, different experimental approaches for melanoma induction and MSC treatment can have a direct impact on the outcomes. Systematic search was carried out in three databases (PubMed, Scopus, and Web of Science) to include all studies, where stem cells were used as intervention for animal models for melanoma. Selected articles were classified according to SYRCLE's risk of bias tool for animals' studies. Experimental variables and published data for tumor incidence and growth were extracted from the eligible articles and standardized using Hedge's G for random effects meta analysis and meta-regression. From 627 entries, 11 articles were eligible for meta-analysis. All studies tested the effects of a single injection of mesenchymal stem/stromal cells (MSCs) (from bone marrow or adipose tissue) admixed with B16 mouse melanoma cells (B16-F0 or B16-F10) or with human melanoma cells (A375 or M4Beu) in mice. Mean SYRCLE score was 3.09 out of 10. Results from random effects meta-analysis indicate that MSCs favored both tumor incidence and tumor growth (p = 0.001) in melanoma. Our results show that MSCs are protumorigenic in co-injection mice models for melanoma, increasing both tumor incidence and growth. PMID- 29396597 TI - Effect of EMD on the orthodontically induced root resorption repair process in rats. AB - BACKGROUND: While different levels of root resorption may occur in orthodontic treatment, several preventive approaches have been reported. Nevertheless, little is known about the effect of enamel matrix derivative (EMD) on root repair during orthodontic tooth movement. OBJECTIVE: To evaluate the effect of EMD on root resorption repair following the application of orthodontic force. MATERIALS AND METHODS: A force of 100 g was exerted for 14 days on the left maxillary first molars of twenty 10-week-old Sprague-Dawley rats divided into the EMD and control groups (n = 10 per group). In the EMD group, repeatedly injection of Emdogain(r) was administered after the appliance was removed, while phosphate-buffered saline was administered in the control group. In vivo microcomputed tomography (CT), haematoxylin and eosin (H&E) staining, and immunohistochemistry were then used to evaluate the effect of EMD on the process of root repair. RESULTS: In the EMD group, the observed decrease in root resorption crater volume and increase in both the bone volume fraction and trabecular thickness were significantly greater than those in the control group. H&E staining showed that the periodontal fibres were relatively regular in arrangement and that the surface of the cementum was smooth in the EMD group. Immunohistochemical analysis showed higher bone morphogenetic protein 2 (BMP-2) and bone sialoprotein (BSP) expression levels in the EMD group than in the control group. In addition, the osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) expression levels were similar in both groups. CONCLUSION: EMD enhanced the repair process following orthodontically induced root resorption in rats. PMID- 29396598 TI - Genomic Alterations in Sporadic Pituitary Tumors. AB - PURPOSE OF REVIEW: Pituitary tumors are undergoing a transformation in histopathologic and molecular classification, coincident with the continued refinement of increasingly powerful methods of genomic annotation and discovery. We highlight novel genomic alterations identified in pituitary adenomas and craniopharyngiomas and discuss their clinical implications. RECENT FINDINGS: Sporadic pituitary adenomas are associated with relatively few recurrent somatic mutations. Recurrent mutations occur largely in subsets of hormone-producing tumors, including GNAS and GPR101 in somatotroph adenomas and USP8 in corticotroph adenomas. Additionally, they manifest with a dichotomous signature of copy number alterations, ranging from almost none to widespread genome instability, while microduplication of chromosome Xq26.3, containing the GNAS gene, defines X-linked acrogigantism. Papillary craniopharyngiomas are defined by BRAF V600E mutations while beta-catenin alterations characterize adamantinomatous craniopharyngiomas. Genomic annotation of pituitary tumors is defining increasing subsets of neuroendocrine adenohypophyseal tumors and craniopharyngiomas, offering rationale-based pharmacologic targets and potential biomarkers for clinical outcome. PMID- 29396599 TI - Sorption and mobility of 14C-fenamiphos in Brazilian soils. AB - Although fenamiphos is widely used as an insecticide and nematicide in bowling greens and agriculture, information on its sorption in tropical soils is limited. In this study, mobility, sorption, and desorption dynamics of 14C-fenamiphos in three contrasting Brazilian soils were examined both in batch and column experiments. Fenamiphos sorption coefficients (K d ) were 2.33, 3.86, and 3.9 L kg-1 for the three soils tested. The insecticide exhibited linear adsorption isotherms in all the three soils, and desorption was in a range of 30-40% during a 72-h period. With its low mobility, fenamiphos did not percolate through the soil profile even after 48 h. However, there is a risk of leaching to water bodies due to runoff because of its high solubility in water. In view of the fact that fenamiphos and its oxidation products are highly toxic to aquatic invertebrates and could affect the soil microbial activities even at low concentrations, the present information is of great importance in risk assessment of fenamiphos in the environment. PMID- 29396600 TI - Benthic macroinvertebrate community structure in Napoleon Gulf, Lake Victoria: effects of cage aquaculture in eutrophic lake. AB - An investigation was conducted on the macro-benthic fauna of the Napoleon Gulf in the northern part of Lake Victoria from March 2011 to December 2016 at the cage fish farm. The aim was to examine the likely impact of cage aquaculture on macro benthic invertebrates. Cage aquaculture is now a common practice on Lake Victoria yet little is known about its long-term effect on macro-benthic faunal assemblages. Temporal variation indicated a general decline in annual faunal density at the farm area with corresponding stability at upstream (control) and downstream sites. Arthropods remained numerically dominant at the control and downstream sites. The percentage abundance of EPT (Ephemeroptera, Plecoptera, and Trichoptera) and Malacostraca was highest at the upstream and lowest at the farm area. The farm area which initially was dominated by molluscs became dominated by arthropods after 3 years. The decrease in density of molluscs at the farm area was attributed to the general decrease in density of two species: Bellamya unicolor (Gastropoda) and Corbicula africana (Bivalvia). These two species were initially abundant but showed decline within the farm area with corresponding stability at the upstream and downstream areas. Oligochaete annelids were more abundant within the farm area than at the upstream and downstream sites. These findings suggested that molluscs offered better prediction of the impact of cages on the environment than arthropods. Besides that, in a community dominated by pollution-tolerant organisms, the impact of aquaculture may not be immediate especially when organic loading from aquaculture is moderate. PMID- 29396602 TI - Subthalamic deep brain stimulation under general anesthesia and neurophysiological guidance while on dopaminergic medication: comparative cohort study. AB - OBJECTIVES: The authors have previously reported on the technical feasibility of subthalamic nucleus deep brain stimulation (STN DBS) under general anesthesia (GA) with microelectrode recording (MER) guidance in Parkinsonian patients who continued dopaminergic therapy until surgery. This paper presents the results of a prospective cohort analysis to verify the outcome of the initial study, and report on wider aspects of clinical outcome and postoperative recovery. METHODS: All patients in the study group continued dopaminergic therapy until GA was administered. Baseline characteristics, intraoperative neurophysiological markers, and perioperative complications were recorded. Long-term outcome was assessed using selective aspects of the unified Parkinson's disease rating scale motor score. Immediate postoperative recovery from GA was assessed using the "time needed for extubation" and "total time of recovery." Data for the "study group" was collected prospectively. Examined variables were compared between the "study group" and "historical control group" who stopped dopaminergic therapy preoperatively. RESULTS: The study group, n = 30 (May 2014-Jan 2016), were slightly younger than the "control group," 60 (51-64) vs. 64 (56-69) years respectively, p = 0.043. Both groups were comparable for the recorded intraoperative neurophysiological parameters; "number of MER tracks": 60% of the "study group" had single track vs. 58% in the "control" group, p = 1.0. Length of STN MER detected was 9 vs. 7 mm (median) respectively, p = 0.037. A trend towards better recovery from GA in the study group was noted, with shorter "total recovery time": 60 (50-84) vs. 89 (62-120) min, p = 0.09. Long-term improvement in motor scores and reduction in L-dopa daily equivalent dose were equally comparable between both groups. No cases of dopamine withdrawal or problems with immediate postop dyskinesia were recorded in the "on medications group." The observed rate of dopamine-withdrawal side effects in the "off-medications" group was 15%. CONCLUSIONS: The continuation of dopaminergic treatment for patients with PD does not affect the feasibility/outcome of the STN DBS surgery. This strategy appears to reduce the risk of dopamine-withdrawal adverse effects and may improve the recovery in the immediate postoperative period, which would help enhance patients' perioperative experience. PMID- 29396601 TI - Rad5 coordinates translesion DNA synthesis pathway by recognizing specific DNA structures in saccharomyces cerevisiae. AB - DNA repair is essential to maintain genome integrity. In addition to various DNA repair pathways dealing with specific types of DNA lesions, DNA damage tolerance (DDT) promotes the bypass of DNA replication blocks encountered by the replication fork to prevent cell death. Budding yeast Rad5 plays an essential role in the DDT pathway and its structure indicates that Rad5 recognizes damaged DNA or stalled replication forks, suggesting that Rad5 plays an important role in the DDT pathway choice. It has been reported that Rad5 forms subnuclear foci in the presence of methyl methanesulfonate (MMS) during the S phase. By analyzing the formation of Rad5 foci after MMS treatment, we showed that some specific DNA structures rather than mono-ubiquitination of proliferating cell nuclear antigen are required for the recruitment of Rad5 to the damaged site. Moreover, inactivation of the base excision repair (BER) pathway greatly decreased the Rad5 focus formation, suggesting that Rad5 recognizes specific DNA structures generated by BER. We also identified a negative role of overexpressed translesion synthesis polymerase Poleta in the formation of Rad5 foci. Based on these data, we propose a modified DDT pathway model in which Rad5 plays a role in activating the DDT pathway. PMID- 29396603 TI - Endplate changes after lumbar discectomy with and without implantation of an annular closure device. AB - BACKGROUND: The implantation of a bone-anchored annular closure device (ACD) might be associated with the developed new endplate changes (EPC) after surgery. METHODS: A post hoc analysis has been done in patients from a prospective randomized multicenter study. All patients underwent limited lumbar discectomy with intraoperative randomization into the groups limited lumbar discectomy alone or additional ACD implantation. Low-dose lumbar computed tomography (CT) and clinical investigations were performed preoperatively and 12 months after the operation. RESULTS: A total of 554 patients were randomized. After exclusion of dropouts, the per-protocol population included 493 patients (251 in the control group and 242 in the ACD group); the follow-up rate was >= 90%. The number of patients showing EPC at baseline was similar in both groups. The number of patients showing EPC and the total EPC lesion area significantly increased in both groups over time, but significantly increased more in the EPC group for the superior and inferior endplate (all P < 0.0001). There was no association of pre existing number and size of EPC with sex, age, or smoking habits. Correlation of clinical variables showed no relation with number, size, and increase of EPC area after surgery. CONCLUSIONS: Patients with primary lumbar disc herniation show EPC in the corresponding segments. There is a significant increase of lesion number and size within 12 months after discectomy. This increase is significantly more pronounced in the ACD group. Presence and growth of EPC is not correlated with low-back pain or ODI. PMID- 29396604 TI - Socioeconomic position and occupational social class and their association with risky alcohol consumption among adolescents. AB - OBJECTIVES: To compare different measures of socioeconomic position (SEP) and occupational social class (OSC) and to evaluate their association with risky alcohol consumption among adolescents attending the last mandatory secondary school (ages 15-17 years). METHODS: This was a cross-sectional study. 1268 adolescents in Catalonia (Spain) participated in the study. Family affluence scale (FAS), parents' OSC, parents' level of education and monthly familiar income were used to compare socioeconomic indicators. Logistic regression analyses were conducted to evaluate socioeconomic variables and missing associated factors, and to observe the relation between each SEP variable and OSC adjusting by sociodemographic variables. RESULTS: Familiar income had more than 30% of missing values. OSC had the fewest missing values associated factors. Being immigrant was associated with all SEP missing values. All SEP measures were positively associated with risky alcohol consumption, yet the strength of these associations diminished after adjustment for sociodemographic variables. Weekly available money was the variable with the strongest association with risky alcohol consumption. CONCLUSIONS: OSC seems to be as good as the other indicators to assess adolescents' SEP. Adolescents with high SEP and those belonging to upper social classes reported higher levels of risky alcohol consumption. PMID- 29396605 TI - Composting of Sewage Sludge with a Simple Aeration Method and its Utilization as a Soil Fertilizer. AB - The objective of this study was to examine the feasibility of sewage sludge composting using a simple aeration method. Two consecutive composting trials (run A and run B) using Japanese sludge and woodchips (1:1, v/v) were conducted in cubic boxes (0.45 * 0.45 * 0.45 m3) made by plywood at Okayama University. Air was forced up through small holes perforated on two open-ended parallel PVC pipes (o 16 mm, 0.25 m apart) laid at the base. The results show that compost temperatures were rapidly increased to the peak points of 47.4 degrees C (run A) and 74.8 degrees C (run B) within the first 2-3 days and varied depending on each composting run and vertical locations. The changes in physicochemical properties with particular attention to inorganic nitrogen (NH4-N, NO3-N) and free amino acid nitrogen (FAA-N) indicated that the biodegradation took place by different mineralization pathways during the composting process. The degradation of organic matter into amino acids followed by ammonification was predominant in run B, whereas the nitrification was greater in run A. A pot experiment using the two finished composts and their raw materials was carried out to study their effectiveness as fertilizer to Komatsuna (Brassica rapa var. perviridis). The total plant biomass produced by the composts was similar to chemical fertilizer. The lowering proportions of FAA-N/T-N, NH4-N/NO3-N, and C/N ratios in the composts compared to those in raw materials was found to correlate with the increase in plant biomass. PMID- 29396606 TI - 3D printed models in mandibular reconstruction with bony free flaps. AB - The aim of the study was to compare two types of mandible reconstructive operations with scapula and fibula free flaps: procedures with 3-D models from thermoplastic materials and conventional planning surgeries. 8 patients were treated due to an advanced oral cavity squamous cell carcinoma. In four patients with a mandibular defect, a physical 3-D model consisting of the reconstructed and unaffected sites was prepared for a reconstruction protocol. The 3-D models were designed based to high resolution CT scans. Assessment of comparative functionality (stability of junction, mobility, mastication ability) and cosmetics was examined in both groups, following a 8 weeks healing period with better results in group with 3D model. 3-D models for mandible and donor bones allow to obtain better functionality of restored mandible in comparison to the traditional method also significantly decreases time of the operation and allows to achieve the desired shape and esthetic effect within the 1/3 of the lower face. PMID- 29396607 TI - [Sinonasal tumors : News from the WHO with special reference to mesenchymal entities]. AB - The last two decades have seen significant advances in the pathology of sinonasal tract neoplasms. This was the consequence of the availability of several innovative diagnostic tools, which resulted in a dynamic evolution of entities and splitting of newly defined or conceptualized entities and subtypes that have been included in the spectrum of old heterogeneous diseases. Most of these new tumor subtypes have distinctive demographic, clinicopathologic, and biological characteristics with prognostic and therapeutic implications for individual patients. NUT carcinoma (NUT midline carcinoma) was separated from the spectrum of sinonasal undifferentiated carcinoma (SNUC) and is defined by specific recurrent translocation. On the other hand, the recently described SMARCB1 deficient carcinoma (while probably representing a distinctive clinicopathologic entity) remained as a variant in the SNUC spectrum. A new neoplasm in the spectrum of non-keratinizing carcinomas is the human papillomavirus(HPV)-related adenoid-cystic-like sinonasal carcinoma with its distinctive, albeit diverse, morphology. In the group of small round-cell malignancies, adamantinoma-like Ewing sarcoma has been delineated as an important diagnostic pitfall given its prominent epithelial differentiation. Inclusion of the biphenotypic (myoneural) sinonasal sarcoma (BSS) as a low-grade malignancy defined by recurrent PAX3/MAML3 translocation represents an important feature of the new WHO classification given the distinctive biological behavior of this low-grade non-metastasizing rare entity, which has been uniformly misclassified as a peripheral nerve sheath tumor or leiomyosarcoma in the past. Recognition of CTNNB1 mutations and STAT6/NAB2 gene fusions as defining genetic markers for sinonasal hemangio /glomangiopericytoma and solitary fibrous tumors, respectively, represents another important achievement in recent years. This review summarizes the new aspects in the WHO classification and also addresses recently described entities that have not been included in the WHO classification. PMID- 29396608 TI - Signal transduction in L-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression. AB - A large number of signaling abnormalities have been implicated in the emergence and expression of L-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of L-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of L-DOPA leads to intermittent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifications of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. Enhanced levels of multiple effector targets, including several transcription factors have been implicated in LID and associated changes in synaptic plasticity and morphology. This article provides an overview of the intracellular modifications occurring in SPN and associated with LID. PMID- 29396611 TI - [Handling of retrieved implants in orthopedic surgery : Results of a survey within the framework of the EndoCert initiative]. AB - BACKGROUND: Although investigations of retrieved medical implants can provide valuable information about the cause of the revision, there is a lack of information, which could be avoided by consequent failure analyses. In the framework of the EndoCert certification system it is obligatory to record and report incidents. OBJECTIVES: The present work examines how the willingness to report has developed in certified arthroplasty centers and which method of handling retrievals is preferred and actually used. MATERIALS AND METHODS: On the basis of a questionnaire for handling retrievals, all 508 arthroplasty centers that were certified till June 1, 2016, were included (return rate = 97.2%). RESULTS: A total of 93.3% of the centers have established an algorithm for handling of retrievals and 83.0% of the centers prefer to hand out the retrieval to the patient, while only 25.7% wish to store it in the center for research purposes. In the case of a potential incident as the cause of revision, centers prefer to forward the retrieval to damage analysis, whereby the centers act in different ways, depending on the case. An implant fracture is, e.g., considered a reportable event in most cases without temporal limitation. On the other hand, breakage or failure of surgical instruments is considered not to be reported in the case of more than half of the centers. In 2014 and 2015, approximately 71% of EPZs reported no incidents. CONCLUSIONS: According to our survey, many certified arthroplasty centers are sensitized to careful handling of retrievals. The treatment of the explanted components is conducted in different ways. The assessment of whether an incident is to be reported shows large differences. In view of the relatively high number of revision surgeries, the number of reports to the authorities appears to be low. PMID- 29396609 TI - Role of adenosine A2A receptors in motor control: relevance to Parkinson's disease and dyskinesia. AB - Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson's disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia. PMID- 29396612 TI - Older Brothers and Older Sisters Odds Ratios in 36 Samples of Homosexual Males. PMID- 29396610 TI - Arsenic trioxide: insights into its evolution to an anticancer agent. AB - Arsenic and its various forms have been in use in ancient Chinese medicine for more than 2000 years. Arsenicals have gained importance for having remedial effects for various diseases from syphilis to cancer thus highlighting its role as a therapeutic agent even though it has been labelled as a potential 'poison'. The ability of arsenic, specifically arsenic trioxide, to treat acute promyelocytic leukaemia has radically changed the perception of this poison and has been the main factor for the re-emergence of this candidate to Western medicine for the treatment of leukaemia and other solid tumours. This review highlights the glorious history of arsenic and its various forms with major emphasis on arsenic trioxide as a therapeutic agent. The mechanism of action, pathogenesis, pharmacokinetic profile, safety concerns, ongoing clinical trials and various new forms of arsenic trioxide are discussed. The review also outlines the therapeutic ability of this drug, discusses the latest developments and recent investigations and potential advancement of arsenic trioxide as nanoformulations that has made it emerge as a potential remedial agent. PMID- 29396613 TI - A Compensatory Effect on Mate Selection? Importance of Auditory, Olfactory, and Tactile Cues in Partner Choice among Blind and Sighted Individuals. AB - Human attractiveness is a potent social variable, and people assess their potential partners based on input from a range of sensory modalities. Among all sensory cues, visual signals are typically considered to be the most important and most salient source of information. However, it remains unclear how people without sight assess others. In the current study, we explored the relative importance of sensory modalities other than vision (smell, touch, and audition) in the assessment of same- and opposite-sex strangers. We specifically focused on possible sensory compensation in mate selection, defined as enhanced importance of modalities other than vision among blind individuals in their choice of potential partners. Data were obtained from a total of 119 participants, of whom 78 were blind people aged between 16 and 65 years (M = 42.4, SD = 12.6; 38 females) and a control sample of 41 sighted people aged between 20 and 64. As hypothesized, we observed a compensatory effect of blindness on auditory perception. Our data indicate that visual impairment increases the importance of audition in different types of social assessments for both sexes and in mate choice for blind men. PMID- 29396614 TI - Safety and Feasibility of a Ketamine Package to Support Emergency and Essential Surgery in Kenya When No Anesthetist is Available: Reply. PMID- 29396615 TI - Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Trading Six for a Risky Half Dozen: Reply. PMID- 29396616 TI - The hidden therapist: evidence for a central role of music in psychedelic therapy. AB - RATIONALE: Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. OBJECTIVES: The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. METHODS: Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience). RESULTS: Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. CONCLUSIONS: This study indicates that music plays a central therapeutic function in psychedelic therapy. PMID- 29396618 TI - Bradyrhizobium forestalis sp. nov., an efficient nitrogen-fixing bacterium isolated from nodules of forest legume species in the Amazon. AB - Three strains of nitrogen-fixing bacteria isolated from nodules of Inga sp. (INPA54BT) and Swartzia sp. (INPA86A and INPA01-91A) in soils under native forest in the Brazilian Amazon were previously identified as belonging to the Bradyrhizobium genus. In this study, these strains were characterized using a polyphasic approach to establish their taxonomic position. The three strains shared more than 99.5% sequence similarity of the 16S rRNA gene with the type strains of five Bradyrhizobium species (B. japonicum USDA 6T, B. liaoningense LMG 18230T, B. ottawaense OO99T, B. subterraneum 58 2-1T and B. yuanmingense LMG 21827T). However, multilocus sequence analysis of two (recA and glnII) or three (atpD, gyrB, and recA) housekeeping genes indicated that these three strains represent a new Bradyrhizobium species, which is closely related to B. subterraneum 58 2-1T and B. yuanmingense LMG 21827T. DNA-DNA hybridization values between INPA54BT and B. subterraneum 58 2-1T and B. yuanmingense LMG 21827T were only 41.5 and 30.9%, respectively. Phenotypic characterization also allowed the differentiation of the novel species from B. subterraneum 58 2-1T and B. yuanmingense LMG 21827T. In the phylogenetic analysis of the nodC and nifH genes, the three strains showed similar sequences that were divergent from those of type strains of all Bradyrhizobium species. We concluded that these strains represent a novel species, for which the name Bradyrhizobium forestalis is proposed, with INPA54BT (= LMG 10044T) as type strain. The G+C content in the DNA of INPA54BT is 63.7 mol%. PMID- 29396617 TI - Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats. AB - RATIONALE: Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity. OBJECTIVES: The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats. METHODS: Female rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing. RESULTS: Resistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core. CONCLUSIONS: These data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats. PMID- 29396619 TI - Untapped bacterial diversity and metabolic potential within Unkeshwar hot springs, India. AB - Hot springs support diverse and interesting groups of microorganisms adapted to extreme conditions and gaining attention in biotechnological applications. However, due to limitations of cultivation methods, a majority of such extremophiles remain uncultivated and unexplored. The advent of multiple cultivation conditions and specialized culture media could possibly aid to access the unexplored microbial portion of hot springs. In the present study, different media and isolation strategies were applied to isolate hitherto unexplored bacterial taxa in the water samples collected from Unkeshwar hot springs, India. Molecular, phylogenetic and predictive functional characterization of the isolated bacterial population was done using 16S rRNA sequencing coupled with Tax4Fun tools. Furthermore, representative isolates were screened for important enzymes (cellulase, xylanase, amylase, and protease) and heavy metal tolerance (chromium, arsenic) properties. A total of 454 bacterial isolates obtained were mapped into 57 unique bacterial genera and 4 different bacterial phyla. Interestingly, 37 genera not previously isolated from Indian hot springs, were isolated for the first time in the present study. However, most of these genera (23 out of 37) were reported only in metagenomics studies from Indian and global hot springs. Furthermore, around 14 genera not previously cultivated and not detected in metagenomics studies of hot springs are documented here. The metabolic potential was ascertained by determining the abundance of specific genes using in silico based Tax4Fun tool, which identified around 315 metabolic pathways for metabolism of carbohydrates, synthesis of secondary metabolites and degradation of xenobiotic compounds. Bioprospection study revealed that 33 and 25 bacterial genera were positive for enzyme production and resistance to the heavy metals, respectively. The present study revealed the advantages of cultivation methods using a comprehensive multiple isolation approach for exploring untapped and unique bacterial diversity, and also utilities for various biotechnological and environmental applications. PMID- 29396620 TI - Polarization-Insensitive Surface Plasmon Polarization Electro-Absorption Modulator Based on Epsilon-Near-Zero Indium Tin Oxide. AB - CMOS-compatible plasmonic modulators operating at the telecom wavelength are significant for a variety of on-chip applications. Relying on the manipulation of the transverse magnetic (TM) mode excited on the metal-dielectric interface, most of the previous demonstrations are designed to response only for specific polarization state. In this case, it will lead to a high polarization dependent loss, when the polarization-sensitive modulator integrates to a fiber with random polarization state. Herein, we propose a plasmonic modulator utilizing a metal oxide indium tin oxide (ITO) wrapped around the silicon waveguide and investigate its optical modulation ability for both the vertical and horizontal polarized guiding light by tuning electro-absorption of ITO with the field-induced carrier injection. The electrically biased modulator with electron accumulated at the ITO/oxide interface allows for epsilon-near-zero (ENZ) mode to be excited at the top or lateral portion of the interface depending on the polarization state of the guiding light. Because of the high localized feature of ENZ mode, efficient electro-absorption can be achieved under the "OFF" state of the device, thus leading to large extinction ratio (ER) for both polarizations in our proposed modulator. Further, the polarization-insensitive modulation is realized by properly tailoring the thickness of oxide in two different stacking directions and therefore matching the ER values for device operating at vertical and horizontal polarized modes. For the optimized geometry configuration, the difference between the ER values of two polarization modes, i.e., the DeltaER, as small as 0.01 dB/MUm is demonstrated and, simultaneously with coupling efficiency above 74%, is obtained for both polarizations at a wavelength of 1.55 MUm. The proposed plasmonic-combined modulator has a potential application in guiding and processing of light from a fiber with a random polarization state. PMID- 29396621 TI - Progressive kidney disease may not alter the association of hyponatremia with mortality. AB - BACKGROUND: Hyponatremia is a common electrolyte disorder and a prognostic marker for mortality. We hypothesize that in advanced chronic or acute kidney disease, hyponatremia is not independently associated with mortality because of the contribution of kidney failure to its pathophysiology. METHODS: Clinical Looking Glass, Montefiore's clinical database, was used to build a cohort of all patients hospitalized between January of 2009 and December of 2011. A chronic kidney disease (CKD) group and an acute kidney injury (AKI) group were defined based on GFR measurements during and before index hospitalization. Cox regression models assessed the hazard for death for those with community acquired hyponatremia as compared to those without hyponatremia, stratified by stage of kidney disease within each cohort. RESULTS: Forty-four thousand four hundred and seventy-six patients were studied. Forty six percent (46.2%) of subjects were in the CKD cohort and 53.8% were in the AKI cohort. Hyponatremic patients were older, and had a higher prevalence of CKD and AKI. A total of 7,934 subjects died (17.8%) during 22 months of follow-up. In CKD and AKI cohorts, hyponatremia, age, race, illness severity and Charlson score were associated with mortality. Hyponatremia had similar hazard ratios (HR) across kidney disease stages despite loss of statistical significance in later stages due to smaller sample size. CONCLUSIONS: The association between community acquired hyponatremia and mortality showed consistent HRs across progressive stages of CKD and AKI suggesting that the contribution of tubular dysfunction to hyponatremia in advanced kidney disease does not alter this association. PMID- 29396623 TI - Advancing the grading for drug-induced sleep endoscopy-a useful modification of the Croft-Pringle Grading System. PMID- 29396622 TI - AQP2 in human urine is predominantly localized to exosomes with preserved water channel activities. AB - BACKGROUND: AQP2 water channel is critical for urinary concentration in the kidney. Interestingly, AQP2 is abundantly excreted in the urine as extracellular vesicles (EVs), which is known to be a useful biomarker for water-balance disorders although the character of AQP2-enriched EVs is poorly understood including water channel function. METHODS: Human urine EVs were obtained by a differential centrifugation method. AQP2-bearing EVs were isolated by immunoprecipitation with an AQP2-specific antibody, and the proteins in the EVs were analyzed by LC-MS/MS proteomic analysis. Osmotic water permeability (Pf) of the AQP2-rich EVs was measured by a stopped-flow method monitoring scattered light intensity in response to outwardly directed osmotic gradient. RESULTS: Sequential centrifugation of human urine showed that AQP2 was present predominantly (80%) in low-density EVs (160,000 g), whereas negligible amount in high-density EVs (17,000 g). Proteomic analysis of the AQP2-bearing EVs identified 137 proteins, mostly in the endosome pathway, including the components of ESCRT (endosomal sorting complex required transporter)-I, II, III. Pf value of the 160,000 g EVs was 4.75 +/- 0.38 * 10-4 cm s-1 (mean +/- SE) with the activation energy of 3.51 kcal mol-1 which was inhibited with 0.3 mM HgCl2 by 63%, suggesting a channel-mediated water transport. Moreover, Pf value showed a significant correlation with the abundance of AQP2 protein in EVs. CONCLUSION: Taken together, AQP2 is localized predominantly to urinary exosomes with preserved water channel activities. PMID- 29396624 TI - Is the 1298A>C polymorphism in the MTHFR gene a risk factor for arterial ischaemic stroke in children? The results of meta-analysis. AB - An elevated level of homocysteine is a risk factor for vascular diseases, brain atrophy and several other disorders. The 1298A>C polymorphism (rs1801131) leads to mildly decreased MTHFR activity. Previously, it was observed that the MTHFR 1298A>C polymorphism in combined analysis with the MTHFR 677C>T polymorphism increases homocysteine levels. However, conflicting results on its relation to ischaemic stroke in children can be found. We conducted a meta-analysis to analyse possible connections between the MTHFR 1298A>C polymorphism and ischaemic stroke in paediatric patients. We identified available data published before December 2016 using appropriate keywords and searching PubMed as well as the references cited in the found articles. Eight case-control studies were included in the meta-analysis (426 children with stroke and 778 controls). Statistical analyses were made using R and Comprehensive Meta-Analysis softwares to investigate the impact of polymorphism in four models: dominant, recessive, additive and allelic. No publication bias was observed in the meta-analysis. We demonstrated no relationship between the 1298A>C polymorphism and ischaemic stroke in children in the case of recessive, additive and allelic models. However, the results of the dominant model analysis should be treated with caution due to the sensitivity analysis results. After omitting one of the included study, we observed a significant association between the carriers of the MTHFR C allele (cases with AC + CC genotypes) and ischaemic stroke in children (OR 1.35 95% CI 1.02-1.79, p = 0.035 in a fixed effects model). In conclusion, the 1298A>C polymorphism in the MTHFR gene is not a risk factor for ischaemic stroke in paediatric patients. PMID- 29396625 TI - TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. AB - Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-beta (TGF-beta) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Complex proteins 1 and 2 (TSC1/2) negatively regulate protein synthesis by inactivating the mTOR complex 1 (mTORC1) at energy limiting states. Here we report that TSC1 and TSC2 regulate Smoothened (SMO)-dependent HH signaling in mouse embryonic fibroblasts (MEFs). Reduced SMO-dependent expression of Gli1 was demonstrated in both Tsc1-/- and Tsc2-/- cells, and we found that Tsc1 is required for TGF-beta induced phosphorylation of SMAD2/3 and subsequent expression of the HH signaling effector and transcription factor GLI2. Hedgehog signaling was restored in Tsc1-/- cells after exogenous expression of Gli2, whereas rapamycin restored HH signaling in Tsc2-/- cells. Furthermore, we observed that Tsc1-/- MEFs display significantly elongated cilia, whereas cilia in Tsc2-/- MEFs were shorter than normal. The elongated cilium phenotype of Tsc1-/- MEFs is likely due to increased mTORC1 dependent autophagic flux observed in these cells, as both the autophagic flux and the cilia length phenotype was restored by rapamycin. In addition, ciliary length control in Tsc1-/- MEFs was also influenced by reduced expression of Gli2, which compromised expression of Wnt5a that normally promotes cilia disassembly. In summary, our results support distinct functions of Tsc1 and Tsc2 in cellular signaling as the two genes affect ciliary length control and HH signaling via different mechanisms. PMID- 29396626 TI - [Ablative therapy of small renal masses]. AB - Renal cell cancer is nowadays predominantly diagnosed in early stages due to the widespread use of sectional imaging for unrelated symptoms. Small renal masses (<4 cm) feature a largely indolent biology with a very low risk for metastasis or even a benign biology in up to 30% of the cases. Consequently, there is a need for less invasive therapeutic alternatives to nephron-sparing surgery. Meanwhile, there is a broad portfolio of local ablation techniques to treat small renal tumors. These include the extensively studied radiofrequency ablation and cryoablation techniques as well as newer modalities like microwave ablation and irreversible electroporation as more experimental techniques. Tumor ablation can be performed percutaneously under image guidance or laparoscopically. In particular, the percutaneous approach is a less invasive alternative to nephron sparing surgery with lower risk for complications. Comparative studies and meta analyses report a higher risk for local recurrence after renal tumor ablation compared to surgery. However, long-term oncological results after treatment of small renal masses are promising and do not seem to differ from partial nephrectomy. The possibility for salvage therapy in case of recurrence also accounts for this finding. Especially old patients with an increased risk of surgical and anesthesiological complications as well as patients with recurrent and multiple hereditary renal cell carcinomas may benefit from tumor ablation. Tumor biopsy prior to intervention is associated with very low morbidity rates and is oncologically safe. It can help to assess the biology of the renal mass and prevent therapy of benign lesions. PMID- 29396627 TI - [Alvimopan for recovery of bowel function after radical cystectomy]. PMID- 29396628 TI - Iron status and its association with HbA1c levels in Dutch children with diabetes mellitus type 1. AB - : Children with diabetes mellitus (DM) type 1 may be at risk for iron deficiency (ID) although this has been little studied. ID is either an absolute (depleted iron stores) or a functional (restricted iron stores due to chronic inflammation) deficiency each requiring a different therapeutic approach. Unfortunately, absolute ID is often not distinguished from functional ID. Furthermore, iron deficient anemia may influence hemoglobin A1c (HbA1c) levels. We aimed to determine the prevalence and type of ID and investigate its association with HbA1c levels in pediatric DM type 1 patients. We performed a two-center prospective observational study in which the iron status of Dutch children with DM type 1 was determined during a regular check-up. Absolute ID and functional ID were found in 13/227 (5.7%) and 100/214 (47%) patients, respectively, while only 15/113 (13%) patients also had anemia. HbA1c levels in patients with and without a deprived iron status (absolute or functional) were not significantly different (65 +/- 17 vs. 65 +/- 16 mmol/mol, p = 0.815). CONCLUSION: Functional, but not absolute, ID was common in Dutch pediatric DM type 1 patients. HbA1c levels were not associated with ID, which can be explained by the relatively mild deprived iron status in our patients. TRIAL REGISTRATION: NTR4642 What is Known: * Iron deficiency is either an absolute (depleted iron stores) or a functional (restricted iron stores due to chronic inflammation) deficiency each requiring a different therapeutic approach. * Children with diabetes mellitus type 1 may be at risk for both types of iron deficiency and this can influence their hemoglobin A1c levels although this has been little studied. What is New: * In Dutch children with diabetes mellitus type 1, functional, but not absolute iron deficiency, is common and should not be treated with iron replacement therapy. * Hemoglobin A1c levels were not associated with iron deficiency, probably due to the relatively mild deprived iron status in our patients. PMID- 29396630 TI - The HSP90 inhibitor NVP-AUY922 inhibits growth of HER2 positive and trastuzumab resistant breast cancer cells. AB - As HER2 is a client protein of the molecular chaperone Hsp90, targeting Hsp90 may be beneficial in HER2-positive breast cancer. In this study, the activity of the Hsp90 inhibitor NVP-AUY922 was assessed in HER2 overexpressing breast cancer cell lines, including two cell line models of acquired trastuzumab-resistance. The seven HER2-positive breast cancer cell lines tested showed significant sensitivity to NVP-AUY922 in vitro, with IC50 values between 6 and 17 nM. Combining NVP-AUY922 with chemotherapy did not improve response. NVP-AUY922 in combination with trastuzumab, significantly enhanced growth inhibition in three of the seven cell lines tested. In conclusion, our data shows that NVP-AUY922 displays potent anti-cancer activity in HER2-positive and trastuzumab-resistant breast cancer cells, and supports further testing of NVP-AUY922 in patients with HER2-positive breast cancer. PMID- 29396631 TI - Fractional anisotropy of white matter, disability and blood iron parameters in multiple sclerosis. AB - : Multiple sclerosis (MS) is a disorder related to myelin damage, which can be investigated by neuroimaging techniques such as fractional anisotropy (FA), a measure of microstructural white matter properties. The objectives of this study were to investigate (1) the relationship between FA and disability using an extremes of outcome approach, and (2) whether blood iron parameters were associated with FA and/or disability. Patients diagnosed with MS (n = 107; 14 males and 93 females) had iron parameter tests and disability determinations using the Expanded Disability Status Scale (EDSS). FA was recorded in 48 white matter tracts in 11 of the female patients with MS and 12 female controls. RESULTS: In patients with high disability scores the mean FA was significantly lower (0.34 +/- 0.067) than in the control group (0.45 +/- 0.036; p = 0.04), while patients with low disability had mean FA values (0.44 +/- 0.014) similar to controls (p = 0.5). Positive associations were found between FA and the iron parameters serum iron, ferritin and percentage transferrin saturation (%Tfsat) in all the white matter tracts. For % Tfsat, the associations were highly significant in 14 tracts (p < 0.01; r-values 0.74-0.84) and p < 0.001 (r = 0.83) in the superior fronto occipital fasciculus (LH). In the whole patient group a trend was found towards an inverse association between the EDSS and the %Tfsat (r = -0.26, p = 0.05) after excluding male gender and smoking as confounders, suggesting reduced disability in the presence of higher blood iron parameters. Additionally, significant inverse associations between disease duration and haemoglobin (p = 0.04) as well as %Tfsat (p = 0.02) suggested that patients with MS may experience a decrease in blood iron concentrations over time. PMID- 29396633 TI - Project ACCEPT: Evaluation of a Group-Based Intervention to Improve Engagement in Care for Youth Newly Diagnosed with HIV. AB - ACCEPT is a gender-specific, group-based intervention aimed at addressing factors that impact engagement in care for youth newly diagnosed with HIV, including stigma, disclosure, healthy relationships, substance use, and future life planning. To test the efficacy of ACCEPT, we enrolled 103 youth and randomly assigned 57 to the ACCEPT condition and 46 to a health education control condition (HEALTH). Acceptability ratings were very high for both conditions. Over the 12 months post-intervention, the ACCEPT group was associated with an odds ratio of 2.33 greater likelihood of self-reported use of HIV medications compared to the HEALTH group (OR = 2.33 95% CI 1.29-4.21, p = 0.005) as well as declining viral load over time (- 0.14 (0.07), p = 0.041). The group-based ACCEPT intervention can improve engagement in care with corresponding positive health outcomes among HIV + youth. Despite the efficacy of ARV treatment, behavioral interventions are still valuable to promote engagement in care as well as adherence to medication. PMID- 29396632 TI - Commonality of Risk Factors for Mothers' Poor Oral Health and General Health: Baseline Analysis of a Population-Based Birth Cohort Study. AB - Objective The association between and commonality of risk factors for poor self rated oral health (SROH) and general health (SRGH) among new mothers has not been reported. The purpose of this paper is to assess the commonality of risk factors for poor SROH and SRGH, and self-reported obesity and dental pain, among a population-based sample of new mothers in Australia. It also investigated health conditions affecting new mothers' general health. Methods Data collected at baseline of a population-based birth cohort was used. Mothers of newborns in Adelaide were approached to participate. Mothers completed a questionnaire collecting data on socioeconomic status (SES), health behaviours, dental pain, SROH, self-reported height and weight and SRGH. Analysis was conducted sequentially from bivariate to multivariable regression to estimate prevalence rate (PR) of reporting poor/fair SROH and SRGH. Results of the 1895 new mothers, some 21 and 6% rated their SROH and SRGH as poor/fair respectively. Dental pain was associated with low income and smoking status, while being obese was associated with low SES, low education and infrequent tooth brushing. SROH and SRGH was associated with low SES, smoking, and dental pain. SROH was also associated with SRGH [PR: 3.06 (2.42-3.88)]. Conclusion for practice There was a commonality of factors associated with self-rated oral health and general health. Strong associations between OH and GH were also observed. Given the importance of maternal health for future generations, there would be long-term societal benefit from addressing common risk factors for OH and GH in integrated programs. PMID- 29396634 TI - Cementless total hip arthroplasty for severely dislocated hips previously treated with Schanz osteotomy of the proximal femur. AB - INTRODUCTION: We report the short-term outcomes of total hip arthroplasty(THA) in patients previously treated with Schanz osteotomy (SO). MATERIALS AND METHODS: Eighteen patients [2 male, 16 female; mean age, 55.4 (range, 50-66) years] who had undergone THA after SO were retrospectively evaluated. Clinical evaluation was performed based on the Harris hip score. Radiological evaluation was performed using full-length radiographs of the lower extremities, pelvis, and hip. RESULTS: The mean follow-up period was 30.8 (range, 18-56) months. Mean femoral shortening was 3.7 (range, 2-5) cm. Perioperative complications occurred in 4 (22.2%) patients. Nonunion was not found at the osteotomy sites. No dislocation was observed. The Trendelenburg sign was positive for five (27.7%) patients, postoperatively. The mean Harris hip score improved from 42.7 to 78.7 (p < 0.05). CONCLUSION: THA for hips previously treated with SO is technically demanding. If careful preoperative planning is performed, successful treatment can be achieved. PMID- 29396635 TI - Short stem survival after osteonecrosis of the femoral head. AB - INTRODUCTION: Short stems were developed as a bone-conserving alternative especially for the young hip arthroplasty patient. Patients suffering from osteonecrosis of the femoral head are frequently younger than primary arthritis patients. The outcome of short stems in these patients remains unclear. The aim of our study was to compare mid-term survival of short stems after osteonecrosis of the femoral head (ONFH) and primary arthritis. MATERIALS AND METHODS: Data on short stem implantations over a 10-year period were collected. Demographic data and X-ray measurements before and after surgery were recorded. Indication for operation was determined from medical records and X-rays. Patients were asked by post about any revision. Reason for revision was identified by analysis of operation protocols. Short stem revision rates were analyzed using Kaplan-Meier charts, comparing 212 ONFH patients (231 operations) and 1284 primary arthritis patients (1455 operations). RESULTS: Follow-up time averaged 5.3 and 6 years and was complete for 92% (ONFH) and 94% (primary arthritis) of the patients. ONFH patients were significantly younger (53 years vs. 59 years, p < 0.001) and more frequently male (55 vs. 42%, p < 0.001). The total revision rate did not differ between the two groups (8 years: 4.2 vs. 5.6%, p = ns). A trend towards more stem revisions was detected for ONFH patients (3 vs. 1.8%, p = ns). The aseptic stem loosening rate was significantly elevated for osteonecrosis patients (8 years: 2.6 vs. 0.7%, p = 0.013). CONCLUSIONS: Our study showed elevated short stem loosening rates after ONFH. Similar results are published for classic cementless stems. The question of which stem is best for the young osteonecrosis patient cannot be answered yet. Consecutive studies directly comparing loosening rates of short and classic cementless stems in young osteonecrosis patients are required. PMID- 29396636 TI - Imaging alphavbeta3 integrin expression in skeletal metastases with 99mTc maraciclatide single-photon emission computed tomography: detection and therapy response assessment. AB - PURPOSE: Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of 99mTc-maraciclatide, a radiopharmaceutical targeting alphavbeta3 integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy. METHODS: The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with 99mTc-maraciclatide before (n = 17) and 12 weeks after (n = 11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria. RESULTS: Before treatment, metastases showed specific 99mTc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389-740 HU) showed lower T:M ratios (4.22 vs. 7.04, p = 0.02) than less sclerotic/lytic lesions (46-381 HU). Patients with progressive disease (PD; n = 5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and -8.0%, p = 1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (-21.9, and -27.2%, p = 0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r = -0.59, p = 0.006). CONCLUSIONS: 99mTc-maraciclatide accumulates in PCa bone metastases in keeping with increased alphavbeta3 integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and 99mTc-maraciclatide imaging may be a potential method for assessing early response. PMID- 29396638 TI - [Current aspects in the prognosis of advanced melanoma]. AB - The therapy of metastatic melanoma has changed rapidly in recent years. Immune checkpoint blockade and targeted therapy have replaced less effective chemotherapies. New clinical studies also point towards a substantial benefit of these drugs for the adjuvant treatment of high-risk patients. Thus, the prognosis of advanced melanoma has improved. Nevertheless, it remains a life-threatening condition due to frequent relapses and progression of the disease. This article aims at providing an overview of current treatment strategies for metastasized melanoma and their impact on prognosis of the disease. In addition, changes in the recently published American Joint Committee of Cancer (AJCC) classification identifying groups at risk will be highlighted. PMID- 29396639 TI - [Necrotizing exanthema, mucous membrane alterations and atypical pneumonia in an Indonesian priest]. PMID- 29396637 TI - Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease. AB - PURPOSE: We aimed to determine the amyloid (Abeta) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals. METHODS: A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [18F]fluorodeoxyglucose ([18F]FDG) as a function of [18F]florbetapir Abeta positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel. RESULTS: The combination of [18F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years. CONCLUSIONS: These results highlight the new concept that combined Abeta and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease modifying therapies on [18F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD. PMID- 29396640 TI - [Neurophysiology of atopic pruritus]. AB - Pruritus is one of the major symptoms of inflammatory skin diseases and strongly affects the quality of life in patients. Although the perception of pruritus and pain are closely intertwined, pruritus represents a distinct sensation, which is also significantly different to pain at a neurophysiological level. The pathophysiological basis of chronic and acute pruritus is not fully understood. Besides histamine, a plethora of different neuromediators of itch, including neurotrophins, neuropeptides and their corresponding receptors, have been identified. In atopic dermatitis the release of these mediators leads to an activation of immune cells, such as mast cells and eosinophilic granulocytes, which in turn release neuromediators and cytokines that activate peripheral neurons. This review focuses on the neurophysiological interactions which regulate pruritus and summarizes the function of neurological and inflammatory mediators in atopic pruritus. PMID- 29396641 TI - [Information services for melanoma patients and awareness among those affected]. AB - BACKGROUND: Besides medical consultations, various sources of information and support are available for melanoma patients (MP) in Germany from commercial and non-commercial providers; however, little is known about how they are perceived and accepted by MPs. MATERIAL AND METHODS: Between July and October 2016 a total of 529 melanoma patients were surveyed at 27 accredited German skin cancer centers by means of a standardized questionnaire. Their awareness and satisfaction with 12 given sources of information and counseling services (print, online and by telephone) were surveyed. The sources were recommended by renowned providers from the field of (dermatological) oncology for use by MPs. RESULTS: The MPs reported that the booklets called The blue advisor - skin cancer (Die Blauen Ratgeber - Hautkrebs, 43%) and Patient guidelines melanoma (Patientenleitlinie Melanom 24%) and the online domain www.hautkrebs-screening.de (23%) were the best known sources. These also met the information needs of the majority of users (65-80%). Booklets from commercial providers (between 8-16% known) were satisfactory for 42-56% of users. At 14% and 11%, respectively, the cancer counseling services (Krebsinformationsdienst) and INFONETZ Krebs as mainly telephone advisory offers were less well known. Few MPs were familiar with the skin cancer or melanoma booklets of the Austrian Cancer Aid and the Swiss Cancer League (2% each). CONCLUSION: The increased awareness and acceptance of booklets as well as information from principally non-commercial providers suggest that they are more often mediated to MPs and more frequently used and accepted by those affected. PMID- 29396642 TI - The effect of statins on periodontal treatment-a systematic review with meta analyses and meta-regression. AB - OBJECTIVE: This study aimed to systematically review clinical trials about the effect of statins as adjunct to mechanical periodontal therapy, on probing pocket depth, clinical attachment level, and intrabony defects, in comparison to mechanical periodontal therapy alone or in association with placebo. MATERIAL AND METHODS: Three databases were searched for controlled clinical trials that used any locally delivered or systemically statin as a sole adjunctive therapy to mechanical periodontal treatment. Weighted mean differences between baseline and 6 months after periodontal treatment for clinical attachment level (CAL), probing pocket depth (PPD), and intrabony defect (IBD) were calculated. A high heterogeneity was detected. Therefore, a meta-regression adjusted for type of statin and year of publication was performed. RESULTS: Fifteen studies were included in the systematic review, and ten studies were included in the meta analysis. In the meta-regression, the adjunct use of simvastatin, rosuvastatin, and atorvastatin additionally reduced PPD in comparison to mechanical periodontal therapy and a placebo gel (2.90 +/- 0.35, 3.90 +/- 0.77, 3.06 +/- 0.71 mm, respectively; p < 0.05). Regarding the resolution of IBD, simvastatin and rosuvastatin significantly improved in comparison to control group (0.89 +/- 0.35 and 1.93 +/- 0.77 mm, respectively; p < 0.05). No statistically significant difference was found between the statins for both PPD and IBD (p < 0.05). Regarding CAL gain, simvastatin provided a statistically significant improvement as compared to the control group (2.02 +/- 0.79 mm; p = 0.043). CONCLUSIONS: The use of statins, used as sole adjuncts to mechanical periodontal treatment, improved the periodontal parameters. In the quantitative analyses, simvastatin was the only drug that showed additional benefits in all evaluated parameters. CLINICAL RELEVANCE: Statins promote significantly clinical periodontal improvements when administered in association with non-surgical scaling and root planning (SRP), when compared to SRP alone or in association with a placebo. PMID- 29396643 TI - A randomized controlled clinical trial on the effectiveness of three different mouthrinses (chlorhexidine with or without alcohol and C31G), adjunct to periodontal surgery, in early wound healing. AB - OBJECTIVES: The use of chlorhexidine (CHX) with or without alcohol has been recommended for a number of clinical applications. On the other hand, there is a plethora of widely subscribed antiseptics, such as agent C31G (alkyl dimethyl glycine/alkyl dimethyl amine oxide), which has not yet been evaluated postsurgically. The effectiveness of three different mouthrinses (CHX with and without alcohol, C31G) in plaque control and early wound healing was compared postoperatively. MATERIALS AND METHODS: In this, randomized, double-blind, controlled clinical trial 42 patients were allocated to three groups assigned to 2 weeks rinsing after non-regenerative periodontal flap surgery with or without osseous surgery with C31G (group A), alcohol-free CHX 0.12% (group B) or alcohol based CHX 0.12% (group C). At days 7 and 14, plaque and early wound healing indices were recorded. At day 14, total bacterial counts were estimated utilizing real-time quantitative polymerase chain reaction (qPCR). Statistics included linear and generalized linear mixed models. RESULTS: At day 7, healing response was not significantly different among groups. At day 14, group A revealed the highest while group C demonstrated the lowest plaque index values (B vs A, odds ratio-OR = 0.18, p = 0.012; C vs A, OR = 0.01, p < 0.001; C vs B, OR = 0.06, p < 0.001). Group C demonstrated the lowest bacterial counts levels at day 14 (38.470 * 106, 48.190 * 106, and 3.020 * 106 for groups A, B, and C, respectively). At day 14, healing was significantly better in group C compared to B (p = 0.007). Group A showed no significant differences compared to other groups. CONCLUSIONS: (1) The presence of alcohol may increase the effectiveness of CHX in early wound healing, (2) C31G might be an alternative solution prescribed during early postoperative period after non-regenerative periodontal flap surgery. CLINICAL RELEVANCE: The present study found that active agent C31G displayed no significant differences to CHX formulations regarding periodontal wound healing improvement and might be used alternatively after non-regenerative periodontal flap surgery. In addition, an alcohol based 0.12% CHX mouthwash was more effective than an alcohol-free 0.12% CHX and C31G mouthrinse on plaque control in the absence of mechanical oral hygiene. PMID- 29396644 TI - Expression and localization of CRAMP in rat tooth germ and during reparative dentin formation. AB - OBJECTIVES: Cathelicidin-related antimicrobial peptide (CRAMP) is an antimicrobial peptide in mice and rats homologous to LL-37 in humans. In addition to its antibacterial activity, CRAMP has various physiological functions by binding to formyl peptide receptor 2 (FPR2). However, the role of these peptides in teeth is unknown. Therefore, we investigated the role of CRAMP and FPR2 in tooth development, reparative dentin formation, and defense response. MATERIAL AND METHODS: First, we examined the localization of CRAMP and FPR2 during tooth development by immunohistochemical analysis. Next, we investigated the localization of CRAMP, FPR2, and CD68-positive macrophages by immunohistochemical analysis during pulp inflammation and reparative dentin formation after cavity preparation. Finally, we analyzed the effect of lipopolysaccharide (LPS) on the expression of CRAMP and FPR2 in dental pulp cells by real-time reverse transcription PCR. RESULTS: At the late bell stage in tooth development, CRAMP was detected in odontoblasts, and FPR2 was observed in the sub-odontoblastic layer. In mature teeth, CRAMP was not detected, but FPR2 continued to be localized in the sub-odontoblastic layer. After cavity preparation, CRAMP positive cells and macrophages were found in dental pulp tissues below the cavity at an early stage of repair. At subsequent stages of reparative dentin formation, CRAMP was observed in odontoblast-like cells that contacted reparative dentin. FPR2 immunoreactivity was also detected in odontoblast-like cells and neighboring cells. LPS stimulated the expression of CRAMP mRNA in dental pulp cells in vitro. CONCLUSIONS: Localization of CRAMP and its receptor FPR2-positive cells were observed during physiological and reparative dentin formation. CLINICAL RELEVANCE: CRAMP/LL-37 has a possibility that induce reparative dentin formation. PMID- 29396645 TI - Postoperative pain after removal of gutta-percha from root canals in endodontic retreatment using rotary or reciprocating instruments: a prospective clinical study. AB - OBJECTIVES: The aim of this clinical study was to evaluate and compare the incidence and intensity of postoperative pain following removal of gutta-percha from root canals using rotary and reciprocating instruments. MATERIALS AND METHODS: One hundred and sixty patients scheduled for a non-surgical endodontic retreatment were included for evaluation. Preoperative pain was recorded with using a questionnaire with a 10-cm visual analogical scale (VAS). Endodontic filling material was removed with Reciproc (VDW, Munich, Germany) or ProFile (Dentsply Tulsa Dental Specialties, Tulsa, OK) instruments. Patients then recorded their postoperative pain in a VAS pain scale at 4, 8, 16, 24, 48, and 72 h post-treatment. Results were analyzed using the Mann-Whitney U, Kruskal-Wallis, and Chi-square tests. Multivariate logistic and a multiple regression analysis were used to detect the effect of confounding factors. RESULTS: Results showed a direct relation between the intensity of pre-operative pain and that of postoperative pain (P < .05). No significant differences were observed between the two groups regarding postoperative pain (P > .05) as a qualitative variable. As numerical values, statistically significant differences were found regarding sex and the system used (P < .05). CONCLUSIONS: The method for pain evaluation was determinant in postoperative pain findings. Endodontic retreatment preparation with Reciproc results in lower values of postoperative pain compared with ProFile. Women are more susceptible to postoperative pain than are men. CLINICAL RELEVANCE: One of the most significant contributions of this research is the importance given to the method used for pain evaluation. The present study analyzed postoperative pain resulting from the use of reciprocating or continuous rotary instruments during removal of gutta-percha in retreatment procedures. PMID- 29396646 TI - The Headache-Attributed Lost Time (HALT) Indices: measures of burden for clinical management and population-based research. AB - BACKGROUND: The burden attributable to headache disorders has multiple components: a simple measure summarising them all does not exist. The Migraine Disability Assessment (MIDAS) instrument has proved useful, estimating productive time lost in the preceding 3 months due to the disabling effect of headache. We developed adaptations of MIDAS for purposes of the Global Campaign against Headache, embracing epidemiological studies and the provision of clinical management aids. METHODS: We reviewed the structure, content, wording and scoring of MIDAS and made revisions, developing the Headache-Attributed Lost Time (HALT) Indices in three versions. Over 10 years, these were employed in multiple epidemiological and clinical studies in countries worldwide. RESULTS: In the original HALT-90, we made no changes to the structure and scoring of MIDAS, but used wording in questions 1-4 that we believed would be more widely understood and more easily translated into other languages. Of the two alternative versions, HALT-30 kept the same structure, question format and wording except that "3 months" was replaced by "1 month". HALT-7/30 was a variant of HALT-30: focusing only on lost work time for population-based studies of headache-attributed burden, it enquired into lost days in the preceding month (30 days) and week (7 days). CONCLUSIONS: Three versions of the HALT Indices serve different purposes as measures of headache-attributed burden, and offer different means of scoring. In studies using HALT as a population measure, there is no need to reflect the states of individuals, whereas a measure over shorter periods than 3 months is likely to be more reliable through better recall. Assessment of individual patients prior to treatment may best estimate impact if enquiry is made into the preceding 90 days, except in cases where headache is highly frequent. Follow-up in clinical management may be better served by assessments over 30 rather than 90 days. PMID- 29396647 TI - Cocrystal Solubility Product Prediction Using an in combo Model and Simulations to Improve Design of Experiments. AB - PURPOSE: To predict the aqueous solubility product (K sp ) and the solubility enhancement of cocrystals (CCs), using an approach based on measured drug and coformer intrinsic solubility (S 0API , S 0cof ), combined with in silico H-bond descriptors. METHOD: A regression model was constructed, assuming that the concentration of the uncharged drug (API) can be nearly equated to drug intrinsic solubility (S 0API ) and that the concentration of the uncharged coformer can be estimated from a linear combination of the log of the coformer intrinsic solubility, S 0cof , plus in silico H-bond descriptors (Abraham acidities, alpha, and basicities, beta). RESULTS: The optimal model found for n:1 CCs (-log10 form) is pK sp = 1.12 n pS 0API + 1.07 pS 0cof + 1.01 + 0.74 alphaAPI.betacof - 0.61 betaAPI; r 2 = 0.95, SD = 0.62, N = 38. In illustrative CC systems with unknown K sp , predicted K sp was used in simulation of speciation-pH profiles. The extent and pH dependence of solubility enhancement due to CC formation were examined. Suggestions to improve assay design were made. CONCLUSION: The predicted CC K sp can be used to simulate pH-dependent solution characteristics of saturated systems containing CCs, with the aim of ranking the selection of coformers, and of optimizing the design of experiments. PMID- 29396648 TI - Characterization of bone morphology in CCN5/WISP5 knockout mice. AB - CCN5/WISP2 is part of the CCN family of matricellular proteins, but is distinct in that it lacks the C-terminal (CT) domain. Although CCN5 has been shown to impact cell proliferation and differentiation in vitro, its role in vivo is unclear. We therefore generated mice using ES cells developed by the Knockout Mouse Project (KOMP) in which exons 2-5, which encode the all of the conserved protein coding regions, are replaced by a lacZ cassette. Ccn5 LacZ/LacZ mice were viable and apparently normal. Based on previous studies showing that CCN5 impacts osteoblast proliferation and differentiation, we performed an analysis of adult bone phenotype. LacZ expression was examined in adult bone, and was found to be strong within the periosteum, but not in trabecular bone or bone marrow. Micro-CT analysis revealed no apparent changes in bone mineral density (BMD) or bone tissue volume (BV/TV) in Ccn5 LacZ/LacZ mice. These studies indicate that CCN5 is not required for normal bone formation, but they do not rule out a role in mechanotransduction or repair processes. The availability of Ccn5 LacZ mice enables studies of CCN5 expression and function in multiple tissues. PMID- 29396650 TI - [Lobectomy vs. radiotherapy for non-small-cell lung cancer patients]. PMID- 29396651 TI - [Primary treatment of anal cancer]. PMID- 29396649 TI - Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex. AB - Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and gamma-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and alpha ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system. PMID- 29396652 TI - Activity pacing: moving beyond taking breaks and slowing down. AB - This brief communication responds to the paper by Jeong and Cho (Qual Life Res 26(4):903-911, 2017) that has described activity pacing in limited terms of adjusting activities through going at a slower rate and taking breaks. Activity pacing was reported as not involving goal setting, in comparison to other strategies for long-term conditions such as Acceptance and Commitment Therapy. This brief communication aims to challenge this limited perception of activity pacing in light of numerous studies that recognise pacing to be a more complex strategy. Pacing is considered to be a multifaceted coping strategy, including broad themes of not only adjusting activities, but also planning activities, having consistent activity levels, acceptance of current abilities and gradually increasing activities, and one that includes goal setting as a key facet. It is essential that pacing is both defined and measured as a multifaceted strategy in order to assess the outcomes of pacing, and for meaningful comparisons with other strategies regarding efficacy for the management of long-term conditions. PMID- 29396653 TI - Measurement properties of depression questionnaires in patients with diabetes: a systematic review. AB - PURPOSE: To conduct a systematic review on measurement properties of questionnaires measuring depressive symptoms in adult patients with type 1 or type 2 diabetes. METHODS: A systematic review of the literature in MEDLINE, EMbase and PsycINFO was performed. Full text, original articles, published in any language up to October 2016 were included. Eligibility for inclusion was independently assessed by three reviewers who worked in pairs. Methodological quality of the studies was evaluated by two independent reviewers using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Quality of the questionnaires was rated per measurement property, based on the number and quality of the included studies and the reported results. RESULTS: Of 6286 unique hits, 21 studies met our criteria evaluating nine different questionnaires in multiple settings and languages. The methodological quality of the included studies was variable for the different measurement properties: 9/15 studies scored 'good' or 'excellent' on internal consistency, 2/5 on reliability, 0/1 on content validity, 10/10 on structural validity, 8/11 on hypothesis testing, 1/5 on cross-cultural validity, and 4/9 on criterion validity. For the CES-D, there was strong evidence for good internal consistency, structural validity, and construct validity; moderate evidence for good criterion validity; and limited evidence for good cross-cultural validity. The PHQ-9 and WHO-5 also performed well on several measurement properties. However, the evidence for structural validity of the PHQ-9 was inconclusive. The WHO-5 was less extensively researched and originally not developed to measure depression. CONCLUSION: Currently, the CES-D is best supported for measuring depressive symptoms in diabetes patients. PMID- 29396654 TI - Confounders for interpreting the benefit of a biomarker-based strategy in early discontinuation of empirical antifungal therapy. PMID- 29396655 TI - A hospital-wide intervention replacing ceftriaxone with cefotaxime to reduce rate of healthcare-associated infections caused by extended-spectrum beta-lactamase producing Enterobacteriaceae in the intensive care unit. PMID- 29396656 TI - PtNi Alloy Cocatalyst Modification of Eosin Y-Sensitized g-C3N4/GO Hybrid for Efficient Visible-Light Photocatalytic Hydrogen Evolution. AB - An economic and effective Pt-based alloy cocatalyst has attracted considerable attention due to their excellent catalytic activity and reducing Pt usage. In this study, PtNi alloy cocatalyst was successfully decorated on the g-C3N4/GO hybrid photocatalyst via a facile chemical reduction method. The Eosin Y sensitized g-C3N4/PtNi/GO-0.5% composite photocatalyst yields about 1.54 and 1178 times higher hydrogen evolution rate than the Eosin Y-sensitized g-C3N4/Pt/GO 0.5% and g-C3N4/Ni/GO-0.5% samples, respectively. Mechanism of enhanced performance for the g-C3N4/PtNi/GO composite was also investigated by different characterization, such as photoluminescence, transient photocurrent response, and TEM. These results indicated that enhanced charge separation efficiency and more reactive sites are responsible for the improved hydrogen evolution performance due to the positive synergetic effect between Pt and Ni. This study suggests that PtNi alloy can be used as an economic and effective cocatalyst for hydrogen evolution reaction. Graphical abstract A significant enhancement of photocatalytic H2 evolution is realized over the Eosin Y-sensitized g C3N4/PtNi/GO composite with PtNi alloy as an efficient cocatalyst. PMID- 29396657 TI - Twenty-year experience with the Konno operation: Konno incision does not impair LV function. AB - BACKGROUND: There has been no report observing the LV function of Konno incision. We examined the outcomes of the Konno operations over 20 years. METHODS: We investigated 63 Konno operations with mechanical valves performed from 1984. This study aimed to evaluate the effects of Konno incision including LV function changes and the long-term outcomes of patient survival and reoperation rate (RVOT and LVOT complications). RESULTS: The postoperative follow-up period was 20.6 +/- 6.2 years. Early death occurred in 1 case and late death occurred in 9 cases. The cumulative survival rate was 89.6, 87.5, and 84.5% in the 5th, 10th, and 20th follow-up years. Five patients required reoperation for the aortic valve. The recurrence avoidance rate for LVOT reoperation was 96.6, 94.7, and 92% in the 5th, 10th, and 20th follow-up years of the Konno operation. Konno incision did not show significant decline in postoperative LV ejection fraction. (Pre, 62% vs 20 years later, 58%; P = 0.052.) There were no cases requiring intervention at the event of ventricular arrhythmia, but 13 cases were Complete Right bundle branch block, and 11 cases were Left bundle branch block. CONCLUSIONS: The survival rate associated with Konno operation throughout 20 years was excellent. Konno incision can secure sufficient LV outflow tract and is a safe treatment for complex LVOTO without deteriorating LV ejection fraction. PMID- 29396658 TI - Systemic inflammation and functional capacity in elderly heart failure patients. AB - BACKGROUND: Elevated C-reactive protein (CRP) is associated with adverse outcomes in heart failure (HF) patients. Beta-blocker therapy may lower CRP levels. METHODS AND RESULTS: To assess if the changes of high-sensitivity (hs) CRP levels in HF patients over 12-week titration with beta-blockers correlate with functional capacity, plasma hs-CRP levels were measured in 488 HF patients [72.1 +/- 5.31 years, LVEF 40% (33/50)]. Hs-CRP, NT-proBNP and 6-min-walk-test (6MWT) were assessed at baseline and at week 12. Patients were divided based on hs-CRP changes (cut-off > 0.3 mg/dl) into low-low (N = 225), high-high (N = 132), low high (N = 54), high-low (N = 77) groups. At baseline, median hs-CRP concentration was 0.25 (0.12/0.53) mg/dl, NT-proBNP 551 (235/1455) pg/ml and average 6MWT distance 334 +/- 105 m. NT-proBNP changes were significantly different between the four hs-CRP groups (P = 0.011). NT-proBNP increased in the low-high group by 30 (- 14/88) pg/ml and decreased in the high-low group by - 8 (- 42/32) pg/ml. 6MWT changes significantly differed between groups [P = 0.002; decrease in the low-high group (- 18 +/- 90 m) and improvement in the low-low group (24 +/- 62 m)]. CONCLUSION: After beta-blocker treatment, hs-CRP levels are associated with functional capacity in HF patients. Whether this represents a potential target for intervention needs further study. PMID- 29396659 TI - A criteria and indicators monitoring framework for food forestry embedded in the principles of ecological restoration. AB - Food forestry is a burgeoning practice in North America, representing a strong multifunctional approach that combines agriculture, forestry, and ecological restoration. The Galiano Conservancy Association (GCA), a community conservation, restoration, and educational organization on Galiano Island, British Columbia in Canada, recently has created two food forests on their protected forested lands: one with primarily non-native species and the other comprising native species. These projects, aimed at food production, education, and promotion of local food security and sustainability, are also intended to contribute to the overall ecological integrity of the landscape. Monitoring is essential for assessing how effectively a project is meeting its goal and thus informing its adaptive management. Yet, presently, there are no comprehensive monitoring frameworks for food forestry available. To fill this need, this study developed a generic Criteria and Indicators (C&I) monitoring framework for food forestry, embedded in ecological restoration principles, by employing qualitative content analysis of 61 literature resources and semi-structured interviews with 16 experts in the fields of food forestry and ecological restoration. The generic C&I framework comprises 14 criteria, 39 indicators, and 109 measures and is intended to guide a comprehensive and systematic assessment for food forest projects. The GCA adapted the generic C&I framework to develop a customized monitoring framework. The Galiano C&I monitoring framework has comprehensive suite of monitoring parameters, which are collectively address multiple values and goals. PMID- 29396660 TI - Hospital Pharmacists in Europe: Between Warehouse and Prescription Pad? PMID- 29396661 TI - Utilization and Expenditure of Anti-cancer Medicines in Kosovo: Findings and Implications. AB - BACKGROUND AND OBJECTIVE: The Ministry of Health (MoH) leads and organizes health policy in Kosovo, which includes procurement and provision of medicines, including anti-cancer medicines, which compose a special group of medicines. However, there has been limited analysis of the utilization and expenditure on anti-cancer medicines in Kosovo; consequently, the objective of this study is to undertake research to provide future guidance on the use of anti-cancer medicines. METHOD: National drug utilization data is available in Kosovo. Utilization and expenditure on anti-cancer medicines [Anatomical Therapeutic Chemical (ATC) code L], initially from 2011 to 2013, especially for anti-cancer medicines on the essential medicines list was analysed from national data. In addition, current systems for procuring and managing anti-cancer medicines in Kosovo was documented. RESULTS: There was appreciable variability in the utilization of anti-cancer medicines over the years, with low or limited use of some anti-cancer medicines on the Essential Medicine List. This is a concern in view of their essential medicine status. From 2011 to 2013, ?16.49 million was spent on anti-cancer medicines (ATC L). The process of selection of new medicines begins with suggestions from doctors at the University Clinical Centre in Kosovo. CONCLUSION: The analysis has shown appreciable variation with current utilization patterns for anti-cancer medicines in Kosovo. This needs to be addressed as part of improving the drug management process to optimize patient care within available resources. Future years and reforms need to be assessed to improve current utilization and expenditure patterns. PMID- 29396663 TI - The VIII International Congress on Stress Proteins in Biology and Medicine: taynna henkea. AB - About 150 international scientists gathered in Turku, Finland, in August of 2017 for the eighth in a series of international congresses about the roles of stress proteins in biology and medicine. The scientific theme and title of the 2017 Congress was "Stress Management Mechanisms and Pathways." The meeting covered a broad range of topics, reflecting the wide scope of the Cell Stress Society International (CSSI) and highlighting the numerous recent breakthroughs in stress response biology and medicine. The keynote lecturers included Marja Jaattela, Richard Morimoto, Anne Bertolotti, and Peter Walter. The Executive Council of the CSSI elected new Fellows and Senior Fellows. The Spirit of Budapest Award was presented to Peter Csermely, Wolfgang Schumann, and Subhash Lakhotia in recognition of pioneering service contributions to the CSSI. The CSSI Medallion for Career Achievement was awarded to Larry Hightower and CSSI president Gabriella Santoro proclaimed Tuesday, August 15, 2017, Robert M. Tanguay Day at the congress in recognition of Robert's many years of scientific accomplishment and work on behalf of the CSSI. Additional special events were the awarding of the Ferruccio Ritossa Early Career Award to Serena Carra and the Alfred Tissieres Young Investigator Award to Ayesha Murshid. As is the tradition at CSSI congresses, there were social events that included an exciting piano performance by a trio of young Finnish pianists, at the Sibelius Museum. PMID- 29396662 TI - MiSight Assessment Study Spain (MASS). A 2-year randomized clinical trial. AB - PURPOSE: To compare myopia progression in children randomized to MiSight contact lenses (CLs) versus children corrected with single-vision spectacles (SV) over a 2-year period. METHODS: Subjects aged 8 to 12 with myopia (-0.75 to -4.00 D sphere) and astigmatism (< -1.00 D cylinder) were assigned to the lens study group (MiSight) or the control group (single vision). Measurements of visual acuity and subjective refraction were taken at 6-month intervals, and axial length, anterior chamber, corneal power, and cycloplegic autorefraction were measured at the baseline, 12-month, and 24-month visits. RESULTS: Eighty-nine subjects were recruited. Forty-fix children were assigned to the MiSight group, and 33 to the single-vision spectacle group. In total, 74 children completed the clinical trial, with the following parameters at the beginning of the study: n = 41 in the MiSight group (age: 11.01 +/- 1.23 years, spherical equivalent: -2.16 +/- 0.94 D, gender: male: 21, female: 20) and n = 33 in the single-vision group (age: 10.12 +/- 1.38 years, spherical equivalent: -1.75 +/- 0.94 D, gender: male: 12, female: 21). After 2 years of follow-up, myopia progressed slowly in the MiSight group compared to the control group (0.45 D vs 0.74 D, p < 0.001) and there was less axial elongation in the MiSight group compared to the single vision group (0.28 mm vs 0.44 mm, p < 0.001). Therefore, use of MiSight CLs produced lower myopia progression (39.32%) and lower axial growth of the eye (36.04%) at 2 years compared to spectacle use. CONCLUSIONS: MiSight contact lens wear reduces axial elongation and myopia progression in comparison to distance single-vision spectacles in children. ClinicalTrials.gov Identifier: NCT01917110. PMID- 29396664 TI - Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I-III HER2-positive breast cancer. AB - PURPOSE: The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy. METHODS: The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon's two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-'negative cohorts, respectively. RESULTS: The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60-91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13-46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had >= 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases. CONCLUSIONS: Eighty percent of HR negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2 targeted therapy during the taxane phase only of sequential taxane-anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2 targeted therapies combined with chemotherapy in the neoadjuvant setting. PMID- 29396665 TI - Rapid review: radiomics and breast cancer. AB - PURPOSE: To perform a rapid review of the recent literature on radiomics and breast cancer (BC). METHODS: A rapid review, a streamlined approach to systematically identify and summarize emerging studies was done (updated 27 September 2017). Clinical studies eligible for inclusion were those that evaluated BC using a radiomics approach and provided data on BC diagnosis (detection or characterization) or BC prognosis (response to therapy, morbidity, mortality), or provided data on technical challenges (software application: open source, repeatability of results). Descriptive statistics, results, and radiomics quality score (RQS) are presented. RESULTS: N = 17 retrospective studies, all published after 2015, provided BC-related radiomics data on 3928 patients evaluated with a radiomics approach. Most studies were done for diagnosis and/or characterization (65%, 11/17) or to aid in prognosis (41%, 7/17). The mean number of radiomics features considered was 100. Mean RQS score was 11.88 +/- 5.8 (maximum value 36). The RQS criteria related to validation, gold standard, potential clinical utility, cost analysis, and open science data had the lowest scores. The majority of studies n = 16/17 (94%) provided correlation with histological outcomes and staging variables or biomarkers. Only 4/17 (23%) studies provided evidence of correlation with genomic data. Magnetic resonance imaging (MRI) was used in most studies n = 14/17 (82%); however, ultrasound (US), mammography, or positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D glucose integrated with computed tomography (18F FDG PET/CT) was also used. Much heterogeneity was found for software usage. CONCLUSIONS: The study of radiomics in BC patients is a new and emerging translational research topic. Radiomics in BC is frequently done to potentially improve diagnosis and characterization, mostly using MRI. Substantial quality limitations were found; high-quality prospective and reproducible studies are needed to further potential application. PMID- 29396666 TI - Cross-reactivity between MUC1 antigen and MCA: false elevation of serum CA 15-3 level in pregnant and lactating women by Ma695-Ma552-based assay. AB - PURPOSE: Cancer antigen 153 (CA 15-3) is one of the most commonly used biomarkers of breast cancer. However, elevated CA 15-3 is reported in pregnant and lactating women more frequently on Beckman DxI 800 immunoassay system (Ma695-Ma552 antibody pair) than on Abbott ARCHITECT system (115D8-DF3 antibody pair) in laboratory methodological evaluation. We conducted this study in order to figure out the reason behind this phenomenon. METHODS: Serum CA 15-3 concentration was analyzed in 426 subjects, including 180 patients with breast cancer, 121 patients with benign breast disease, and 125 healthy volunteers (45 pregnant and 80 non pregnant women). CA 15-3 assay was further validated using another cohort of 112 pregnant or postpartum women. Immunological cross reaction was analyzed by Western blotting and immunoprecipitation. RESULTS: The serum CA 15-3 level was abnormally higher in almost 95% of the pregnant and lactating women detected using Ma695-Ma552 antibody pair (median: 71.4 U/mL) than that detected using 115D8-DF3 antibody pair (median: 16.5 U/mL). Western blotting and immunoprecipitation indicated that such a significant difference was mainly due to the cross reaction between monoclonal antibody Ma552 and mucin-like carcinoma associated antigen (MCA). CONCLUSIONS: The CA 15-3 assay using 115D8-DF3 antibody pair is more suitable for monitoring therapy in pregnancy-associated breast cancer. PMID- 29396667 TI - The heterogeneity of cancer. PMID- 29396668 TI - Targeting ataxia telangiectasia-mutated- and Rad3-related kinase (ATR) in PTEN deficient breast cancers for personalized therapy. AB - PURPOSE: Phosphate and tensin homolog (PTEN), a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN-deficient triple-negative breast cancer (TNBC). METHODS: PTEN, ATR and pCHK1Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient- (MDA-MB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell proliferation assay, FACS (cell cycle progression & gammaH2AX accumulation) and FITC-annexin V flow cytometry analysis. RESULTS: Low nuclear PTEN was associated with higher grade, pleomorphism, de-differentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values < 0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values < 0.05). VE-821 was selectively toxic in PTEN-deficient TNBC cells and resulted in accumulation of double-strand DNA breaks, cell cycle arrest, and increased apoptosis. CONCLUSION: ATR signalling adversely impact survival in PTEN-deficient breast cancers. ATR inhibition is synthetically lethal in PTEN-deficient TNBC cells. PMID- 29396669 TI - Application of open-path Fourier transform infrared spectroscopy for atmospheric monitoring of a CO2 back-production experiment at the Ketzin pilot site (Germany). AB - During a controlled "back-production experiment" in October 2014 at the Ketzin pilot site, formerly injected CO2 was retrieved from the storage formation and directly released to the atmosphere via a vent-off stack. Open-path Fourier transform infrared (OP FTIR) spectrometers, on-site meteorological parameter acquisition systems, and distributed CO2 point sensors monitored gas dispersion processes in the near-surface part of the atmospheric boundary layer. The test site provides a complex and challenging mosaic-like surface setting for atmospheric monitoring which can also be found at other storage sites. The main aims of the atmospheric monitoring of this experiment were (1) to quantify temporal and spatial variations in atmospheric CO2 concentrations around the emitting vent-off stack and (2) to test if and how atmospheric monitoring can cope with typical environmental and operational challenges. A low environmental risk was encountered during the whole CO2 back-production experiment. The study confirms that turbulent wind conditions favor atmospheric mixing processes and are responsible for rapid dilution of the released CO2 leading to decreased detectability at all sensors. In contrast, calm and extremely stable wind conditions (especially occurring during the night) caused an accumulation of gases in the near-ground atmospheric layer with the highest amplitudes in measured gas concentration. As an important benefit of OP FTIR spectroscopic measurements and their ability to detect multiple gas species simultaneously, emission sources could be identified to a much higher certainty. Moreover, even simulation models using simplified assumptions help to find suitable monitoring network designs and support data analysis for certain wind conditions in such a complex environment. PMID- 29396670 TI - Hierarchically Macroporous Graphitic Nanowebs Exhibiting Ultra-fast and Stable Charge Storage Performance. AB - The macro/microstructures of carbon-based electrode materials for supercapacitor applications play a key role in their electrochemical performance. In this study, hierarchically macroporous graphitic nanowebs (HM-GNWs) were prepared from bacterial cellulose by high-temperature heating at 2400 degrees C. The HM-GNWs were composed of well-developed graphitic nanobuilding blocks with a high aspect ratio, which was entangled as a nanoweb structure. The morphological and microstructural characteristics of the HM-GNWs resulted in remarkable charge storage performance. In particular, the HM-GNWs exhibited very fast charge storage behaviors at scan rates ranging from 5 to 100 V s-1, in which area capacitances ranging from ~ 8.9 to 3.8 mF cm-2 were achieved. In addition, ~ 97% capacitance retention was observed after long-term cycling for more than 1,000,000 cycles. PMID- 29396671 TI - Endocarditis associated with vertebral osteomyelitis and septic arthritis of the axial skeleton. AB - PURPOSE: The relationship between infective endocarditis (IE) and osteoarticular infections (OAIs) are not well known. We aimed to study the characteristics of patients with IE and OAIs, and the interactions between these two infections. METHODS: An observational study (1993-2014) which includes two cohorts: (1) patients with IE (n = 607) and (2) patients with bacteremic OAIs (n = 458; septic arthritis of peripheral and axial skeleton, and vertebral and peripheral osteomyelitis). These two cohorts were prospectively collected, and we retrospectively reviewed the clinical and microbiological variables. RESULTS: There were 70 cases of IE with concomitant OAIs, representing 11.5% of IE cases and 15% of bacteremic OAI cases. Among cases with IE, the associated OAIs mainly involved the axial skeleton (n = 54, 77%): 43 were vertebral osteomyelitis (61%), mainly caused by "less virulent" bacteria (viridans and bovis streptococci, enterococci, and coagulase-negative staphylococci), and 15 were septic arthritis of the axial skeleton (21%), which were mainly caused by Staphylococcus aureus. OAIs with involvement of the axial skeleton were associated with IE (adjusted OR = 2.2; 95% CI 1.1-4.3) independently of age, sex, and microorganisms. CONCLUSIONS: Among patients with IE, the associated OAIs mainly involve the axial skeleton. Transesophageal echocardiography should be carefully considered in patients presenting with these bacteremic OAIs. PMID- 29396672 TI - Copper influence on bank vole's (Myodes glareolus) sexual behavior. AB - The impact of human activity on the environment has led to a steady increase of the amounts of copper in the ecosystems. This element accumulates in plants and water, potentially exposing rodents to its harmful effects. In industrial districts, a decrease in the density of small rodent populations has been observed. This decline may be caused by many factors, including mortality, decreased fertility, or impaired sexual behavior. The decline in the reproductive abilities of small rodents after copper exposure was demonstrated in our previous work (Miska-Schramm A, Kruczek M, Kapusta J, Ecotoxicology 23:1546-1554, 2014). The aim of the presented research was to determine how copper administered at concentrations similar to those recorded in industrial districts (Cu I-150 mg/kg, Cu II-600 mg/kg, C-control) affects the sexual behavior of small rodents. The model species was the bank vole (Myodes glareolus). The behavior and vocalizations of male-female pairs were recorded during open-field tests: ?C vs. ?C; ?Cu I vs. ?C; ?Cu II vs. ?C while in preference tests, female behavior was assessed in the following combinations: ?C vs. ?C & ?Cu I; ?C vs. ?C & ?Cu II. In the presented work, we show that copper decreased the males' sexual attractiveness. Females showed suppressed preference towards males treated with 600 mg/kg copper. The number of sniffs and a number of approaches towards Cu II males was significantly lower than towards control individuals. Also, in preference test with 150 mg/kg treated animals, total activity was lower towards copper treated animals. At the same time, copper did not influence intra-sexual interactions. PMID- 29396673 TI - Changes in metallothionein transcription levels in the mussel Mytilus galloprovincialis exposed to CdTe quantum dots. AB - Quantum dots (QDs) are a class of engineered nanoparticles (ENPs) with several biomedical, industrial and commercial applications. However, their metabolism and detoxification process in aquatic invertebrates and environmental health hazards remain unclear. This study investigate the transcriptional changes of metallothioneins (MTs) isoforms (mt10IIIa and mt20IV) induced by CdTe QDs, in comparison with its dissolved counterpart, in the marine mussel Mytilus galloprovincialis. Mussels were exposed to CdTe QDs and to the same Cd concentration (10 ug Cd L-1) of dissolved Cd for 14 days and mt transcription levels were measured by real time quantitative PCR (qPCR). Tissue specific mt transcription patterns were observed in mussels exposed to both Cd forms, wherein the gills were a more sensitive organ compared to the digestive gland. No significant changes were observed in mt10IIIa transcription levels in mussels exposed to both Cd forms. In contrast, transcription of mt20IV was tissue and exposure time dependent, with higher mt20IV mRNA levels in mussels exposed to QDs and dissolved Cd when compared to unexposed mussels. Multivariate analysis indicates particle-specific effects after 14 days of exposure and a dual role of MTs in the QD metabolism and in the protection against oxidative stress in mussels exposed to Cd-based ENPs. PMID- 29396674 TI - An optimized DNA extraction method for molecular identification of coccidian species. AB - Molecular identification of Eimeria parasites infecting poultry and livestock has been commonly used for more than 20 years. An important step of the molecular identification technique is the rupturing of the oocyst wall for DNA extraction. Previously, DNA extraction methods included pre-treatment with sodium hypochlorite and osmotic shock with saturated salt solution. Here, we present a modification of this technique for a more sensitive and efficient identification of Eimeria spp. in field samples. The disruption extent of the oocyst walls, yield of DNA extraction, and identification of species-specific DNA sequences by PCR were used to evaluate this optimized method. Incubation of oocysts in sodium hypochlorite for 1.5 h at 4 degrees C followed by treatment with a saturated salt solution for 1 h at 55 degrees C broke up the walls of most Eimeria tenella oocysts, as well as other coccidian species of chicken and rabbit, such as Eimeria intestinalis and even Cryptosporidium cuniculus. Notably, polymerase chain reaction (PCR) amplification of the intervening transcribed sequence 1 (ITS 1) was successfully performed with genomic DNA extracted from just 50 oocysts using this optimized method. Our findings will greatly promote the development of molecular diagnosis methods of coccidiosis and simplify coccidian species identification and categorization as well as infection prevalence, providing a significant advancement in the development of techniques for coccidiosis control and prevention. PMID- 29396675 TI - Diet assimilation trends and host-parasite relationships in two species of sunfish (Lepomis) revealed by stable isotope analyses of multiple tissues. AB - White grub flukes, Posthodiplostomum minimum centrarchi (Trematoda), and hookworms Pomphorhynchus bulbocolli (Acanthocephala) are common internal parasites for many North American freshwater fishes. P. minimum are found as cysts in internal organ tissues, while P. bulbocolli are found as sexually mature adults in gastrointestinal (GI) tracts. Stable isotopes of carbon and nitrogen (delta13C and delta15N) are commonly used to infer food web relationships in freshwater lakes. To see if delta13C and delta15N could be used to analyze parasite-host relationships, we analyzed the stable isotopes of the two species of parasites and various tissue types of their fish hosts (bluegill and pumpkinseed sunfish) from different host tissues. The samples delta13C and delta15N demonstrated that P. minimum and P. bulbocolli fed on the fish hosts livers and intestines, respectively. It is also corroborated by correlations in C/N ratios of those fish parasites and their fish host tissues. This study highlights the importance of identifying the specific host tissues parasites feed on in stable isotope analysis. PMID- 29396677 TI - Downbeat nystagmus and lower motor neuron disease: 14 years follow-up. PMID- 29396676 TI - The Canary Islands as a model of risk of pulmonary dirofilariasis in a hyperendemic area. AB - We assessed the risk of human pulmonary dirofilariasis in the Canary Islands, hyperendemic for canine heartworm (Dirofilaria immitis), a zoonotic vector-borne infection. For this purpose, 1479 inhabitants were tested for anti-D. immitis antibodies. Four of the 7 islands presented high seroprevalences (from 6.2 to 12.7%), therefore high exposure to the parasite and risk of zoonotic infection. These corresponded to those islands with high canine prevalences of dirofilariasis and favourable climatic conditions for the development of mosquito vectors. The lowest prevalences (from 0 to 1.6%) were found in the desert islands and those with low canine prevalences of heartworm. Seroprevalences were very variable inside each island as well, being related to the climate and demographic factors. Human pulmonary dirofilariasis is an emerging zoonosis worldwide which frequently goes undiagnosed. Serological studies could be useful for the correct evaluation of the risk of infection among the human population, and study of the health implications of the continuous contact with the parasite in endemic areas. Sanitary authorities should be aware of the current epidemiological data, and physicians should include human dirofilariasis in the differential diagnosis of pulmonary nodules. PMID- 29396678 TI - Longitudinal predictors of caregiver burden in amyotrophic lateral sclerosis: a population-based cohort of patient-caregiver dyads. AB - OBJECTIVE: Caregiver burden is a recognised consequence of caring for a patient with neurodegeneration. Amyotrophic lateral sclerosis (ALS) differs from other neurodegenerations by its rapid progression and impairment of motor, cognitive, and behavioural function, which contribute to caregiver burden. However, longitudinal factors that determine the extent of caregiver burden, and in particular the impact of psychological distress among caregivers, have not been fully established. METHODS: Patients with ALS (n = 85) and their primary caregivers (n = 85) completed three serial evaluations. Caregiver burden was measured using the Zarit Burden Interview (ZBI). Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS). The Edinburgh Cognitive-Behavioural ALS Screen (ECAS) was used to determine cognitive function in patients. The ALS Functional Rating Scale (ALSFRS-R) measured disease progression. RESULTS: Using the ZBI, caregivers were categorised as high or low burden. In the low burden group, anxiety scores from the HADS predicted caregiver burden (r = 0.410, F = 3.73, p = 0.033), whereas the depression sub-score from the HADS was predictive of caregiver burden in the high burden group (r = 0.501, F = 5.87, p = 0.006) for cross-sectional analyses. Longitudinally, an elevated score on the HADS at Time 1 was the largest predictor of caregiver burden across serial assessments. CONCLUSION: In a patient cohort with relatively preserved cognitive function (65%), anxiety and depression at Time 1, as measured by the HADS, were the best predictors of caregiver burden at Time 3. This observation provides a mechanism by which caregiver burden can be identified by health-care professionals and a stepped care programme of intervention initiated. PMID- 29396679 TI - Cerebellum and cognition in multiple sclerosis: the fall status matters. AB - Cerebellar volume has been linked with cognitive performances in MS; however, the association in terms of fall status has never been compared. Therefore, the objective of the current study was to compare cognitive performance with cerebellar volume between MS fallers and non-fallers. The cross-sectional study included 140 PwMS (96 women). MRI volumetric analysis was based on the FreeSurfer image analysis suite. Volumes of the cerebellar gray and white matter were identified as the region of interest. Cognitive function included scores obtained from a computerized cognitive battery of tests. The sample was divided into fallers and non-fallers. MS fallers demonstrated a lower global cognitive performance and reduced gray and white matter cerebellar volumes compared to non fallers. A significant association was found between total gray and white matter cerebellar volume and visual spatial subdomain (P value = 0.044 and 0.032, respectively) in the non-fallers group. The association remained significant after controlling for the total cranial volume and neurological disability (P value = 0.026 and 0.047, respectively). A relationship was found between the visual spatial score and the left gray matter cerebellum volume; R2 = 0.44, P value = 0.021. We believe that a unique relationship exists between the cerebellum structure and cognitive processing according to fall history in PwMS and should be considered when investigating the association between brain functioning and cognitive performances in MS. PMID- 29396680 TI - Detection of Distant Metastases in Head and Neck Cancer: Changing Landscape. AB - As head and neck squamous cell carcinoma (HNSCC) patients with distant metastases (DM) were generally treated only palliatively, the value of screening for DM was usually limited to attempts to avoid extensive locoregional treatment when DM were present pretreatment. Recently, the concept of treating oligometastases, e.g., by metastatectomy or stereotactic body radiotherapy, has been reintroduced for HNSCC and may cause a change in the treatment paradigm. Although whole body 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computed tomography (CT; WB-FDG-PET/CT) is still the mainstay diagnostic technique, there is a growing body of evidence supporting implementation of whole body magnetic resonance imaging (WB-MRI) as an important diagnostic technique for screening for DM. Also, FDG-PET/MRI may become a valuable technique for the detection of DM in HNSCC patients. Because the yield of examinations for detection of DM is too low to warrant routine screening of all HNSCC patients, only patients with high risk factors should be selected for intense screening for DM. Clinical and histopathological risk factors are mainly related to the extent of lymph node metastases. Risk for development of DM may also be assessed by molecular characterization of the primary tumor using genomic and proteomic technologies and radiomics. More research is needed to develop a new protocol for screening for DM after introduction of the concept of treating oligometastases in HNSCC. PMID- 29396681 TI - Head and Neck Cancer: A Review of the Impact of Treatment Delay on Outcome. AB - Delay between the initial symptoms, diagnosis, and the definitive treatment of head and neck cancers is associated with tumor progression and upstaging. These delays may lead to poor outcomes and may mandate more aggressive treatments with unnecessary morbidity and even mortality. The multidisciplinary team approach for the treatment of patients with head and neck cancers has improved organization of standard clinical guidelines, but this development has yet to translate into a demonstrable impact on survival. We review the association between waiting times (time between diagnosis and initiation of treatment) and clinical outcomes in patients with head and neck squamous cell carcinoma (HNSCC). PMID- 29396682 TI - Causality Assessment of Olfactory and Gustatory Dysfunction Associated with Intranasal Fluticasone Propionate: Application of the Bradford Hill Criteria. AB - Causality assessment is crucial to post-marketing pharmacovigilance and helps optimize safe and appropriate use of medicines by patients in the real world. Self-reported olfactory and gustatory dysfunction are common in the general population as well as in patients with allergic rhinitis and nasal polyposis. Intranasal corticosteroids, including intranasal fluticasone propionate (INFP), are amongst the most effective drugs indicated in the treatment of allergic rhinitis and nasal polyposis. While intranasal corticosteroids are associated with olfactory and gustatory dysfunction and are currently labeled for these adverse events, causality assessment has not been performed to date. Although there is no single widely accepted method to assess causality in pharmacovigilance, the Bradford Hill criteria offer a robust and comprehensive approach because nine distinct aspects of an observed potential drug-event association are assessed. In this literature-based narrative review, Hill's criteria were applied to determine causal inference between INFP and olfactory and gustatory dysfunction. PMID- 29396683 TI - Alginate membranes loaded with hyaluronic acid and silver nanoparticles to foster tissue healing and to control bacterial contamination of non-healing wounds. AB - Chronic non-healing wounds are a clinically important problem in terms of number of patients and costs. Wound dressings such as hydrogels, hydrocolloids, polyurethane films and foams are commonly used to manage these wounds since they tend to maintain a moist environment which is shown to accelerate re epithelialization. The use of antibacterial compounds is important in the management of wound infections. A novel wound-dressing material based on a blended matrix of the polysaccharides alginate, hyaluronic acid and Chitlac silver nanoparticles is here proposed and its application for wound healing is examined. The manufacturing approach to obtain membranes is based on gelling, foaming and freeze-casting of alginate, hyaluronic acid and Chitlac-silver nanoparticles mixtures using calcium ions as the cross-linking agent. Comprehensive evaluations of the morphology, swelling kinetics, permeability, mechanical characteristics, cytotoxicity, capability to inhibit metalloproteinases and of antibacterial property were conducted. Biological in vitro studies demonstrated that hyaluronic acid released by the membrane is able to stimulate the wound healing meanwhile the metal silver exploits an efficient antibacterial activity against both planktonic bacteria and biofilms. Overall, the experimental data evidence that the studied material could be used as antibacterial wound dressing for wound healing promotion. PMID- 29396684 TI - Genetic characterization and diversity of circulating influenza A/H1N1pdm09 viruses isolated in Jeddah, Saudi Arabia between 2014 and 2015. AB - The emerged influenza A/H1N1pdm09 viruses have replaced the previously circulating seasonal H1N1 viruses. The close antigenic properties of these viruses to the 1918 H1N1 pandemic viruses and their post-pandemic evolution pattern could further enhance their adaptation and pathogenicity in humans representing a major public health threat. Given that data on the dynamics and evolution of these viruses in Saudi Arabia is sparse we investigated the genetic diversity of circulating influenza A/H1N1pdm09 viruses from Jeddah, Saudi Arabia, by analyzing 39 full genomes from isolates obtained between 2014-2015, from patients with varying symptoms. Phylogenetic analysis of all gene segments and concatenated genomes showed similar topologies and co-circulation of clades 6b, 6b.1 and 6b.2, with clade 6b.1 being the most predominate since 2015. Most viruses were more closely related to the vaccine strain (Michigan/45/2015) recommended for the 2017/2018 season, than to the California/07/2009 strain. Low sequence variability was observed in the haemagglutinin protein compared to the neuraminidase protein. Resistance to neuraminidase inhibitors was limited as only one isolate had the H275Y substitution. Interestingly, two isolates had short PA X proteins of 206 amino acids compared to the 232 amino acid protein found in most influenza A/H1N1pdm09 viruses. Together, the co-circulation of several clades and the predominance of clade 6b.1, despite its low circulation in Asia in 2015, suggests multiple introductions most probably during the mass gathering events of Hajj and Umrah. Jeddah represents the main port of entry to the holy cities of Makkah and Al-Madinah, emphasizing the need for vigilant surveillance in the kingdom. PMID- 29396685 TI - The role of exposure time in computerized training of prostate cryosurgery: performance comparison of surgical residents with engineering students. AB - PURPOSE: This study aims at the evaluation of a prototype of a computerized trainer for cryosurgery-the controlled destruction of cancer tumors by freezing. The hypothesis in this study is that computer-based cryosurgery training for an optimal cryoprobe layout is essentially a matter of exposure time, rather than trainee background or the specific computer-generated planning target. Key geometric features under considerations are associated with spatial limitations on cryoprobes placement and the match between the resulted thermal field and the unique anatomy of the prostate. METHODS: All experiments in this study were performed on the cryosurgery trainer-a prototype platform for computerized cryosurgery training, which has been presented previously. Among its key features, the cryosurgery trainer displays the prostate shape and its contours and provides a distance measurement tool on demand, in order to address spatial constraints during ultrasound imaging guidance. Another unique feature of the cryosurgery trainer is an output movie, displaying the simulated thermal field at the end of the cryoprocedure. RESULTS: The current study was performed on graduate engineering students having no formal background in medicine, and the results were benchmarked against data obtained on surgical residents having no experience with cryosurgery. Despite fundamental differences in background and experience, neither group displayed superior performance when it comes to cryoprobe layout planning. CONCLUSIONS: This study demonstrates that computer based training of an optimal cryoprobe layout is feasible. This study demonstrates that the training quality is essentially related to the training exposure time, rather than to a specific planning strategy from those investigated. PMID- 29396687 TI - Efficacy and safety of pop-titrated versus fixed-energy trans-scleral diode laser cyclophotocoagulation for refractory glaucoma. AB - PURPOSE: To compare the efficacy and safety of pop-titrated versus fixed-energy diode laser trans-scleral cyclophotocoagulation (DLTSC) for refractory glaucoma. METHODS: This is a prospective, interventional, longitudinal, and comparative case-control study. Patients with refractory glaucoma treated with pop-titrated DLTSC were compared to a fixed-energy DLTSC control group. Variables analyzed included: age, gender, diagnosis, pre- and post-treatment intraocular pressure (IOP). Success rate, anti-glaucoma medications reduction, and complications were analyzed at day 90 post-treatment. Primary success criterion consisted of eyes with a postoperative IOP <= 22 mmHg or a 30% reduction of pre-treatment IOP and managed with topical anti-glaucoma medications only. RESULTS: A total of 68 eyes from 67 patients were included for analysis: 30 in the pop-titrated group and 38 in the fixed-energy group. Therapeutic success was achieved in 56-72% of the pop titrated group versus 47-52% in the fixed-energy group considering the 3 different criteria analyzed (p = 0.23-0.4). There was a 22% (from 4.1 to 3.2 drugs) reduction of anti-glaucoma medications in the pop-titrated group, compared to 32% (from 3.5 to 2.4 drugs) in the fixed-energy group (p = 0.42). Five eyes (13.1%) developed hypotony, all of which belonged to the fixed-energy group (p = 0.048). CONCLUSIONS: Pop-titrated DLTSC represents an effective and safe option for the management of refractory glaucoma. We found no statistically significant difference in success rates among both groups. However, there was a significantly higher risk of hypotony in eyes treated with the fixed-energy protocol. PMID- 29396686 TI - Measurement of wire deflection on loading may indicate union in Ilizarov constructs, an in vitro model. AB - No entirely reliable method exists for assessing union during Ilizarov treatment. Premature removal results in potential treatment failure; hence, alternative methods warrant investigation. Wire deflection might provide an indication of fracture site deformation on weight bearing, indicating progress towards union. This study aimed to test a method for assessing wire deflection within an Ilizarov frame. (1) To assess the repeatability of our novel measurement method in measuring wire deflection within an Ilizarov frame in vitro. (2) To compare the amount of wire deflection in an unstable model with that in an intact bone model. (3) To assess accuracy of this method by comparing wire deflection measured with overall machine extension. Tests were performed on clinical grade tensioned fine wire 4-ring Ilizarov constructs stabilising a simulated fracture, with and without an unstable defect. Models were sequentially loaded to 700 N using an Instron testing machine. A digital depth gauge attached to the superior ring measured relative wire displacement at the ring closest to the fracture. Tests were repeated 3 times. (1) Both unstable and stable bone models produced highly repeatable load deformation curves (R2 = 0.98 and 0.99). (2) In the unstable model, wires tensioned at 882 and 1274 N produced mean maximum deflections of 2.41 and 2.69 mm compared with 0.05 and 0.04 mm in the intact bone model (significant p < 0.0001). (3) Wire deflection and machine extension results were strongly correlated (r = 0.99). A measurable difference in wire deflection between stable and unstable situations exists using this method which appears accurate and repeatable, with clear correlation between displacement and load and displacement and machine extension. This approach might be clinically applicable, and further clinical testing is required. PMID- 29396688 TI - Validation of the structure-function correlation report from the heidelberg edge perimeter and spectral-domain optical coherence tomography. AB - PURPOSE: To compare the diagnostic assessment of glaucoma specialists with an automated structure-function correlation report combining visual field (VF) and spectral-domain optical coherence tomography (SD-OCT) imagining in subjects with glaucoma. METHODS: This prospective, cross-sectional study was conducted at Wills Eye Hospital, Philadelphia, PA, USA. Subjects with glaucoma received ophthalmic examination, VF testing, and SD-OCT imaging. An automated report was generated describing structure-function correlations between the two structural elements [retinal nerve fiber layer (RNFL) and Bruch's membrane opening-minimum rim width (MRW)] and VF sectors. Three glaucoma specialists masked to the automated report and to each other identified clinically significant structure-function correlations between the VF and SD-OCT reports. Raw agreement and chance corrected agreement (kappa statistics) between the automated report and the clinical assessments were compared. RESULTS: A total of 53 eyes from 45 subjects with glaucoma were included in this study. The overall agreement between the automated report and clinical assessment comparing MRW and VF was good at 74.8% with a kappa of 0.62 (95% CI 0.55-0.69). Agreements for the six different MRW sections were moderate to good with kappa values ranging from 0.54 to 0.69. For mean RNFL thickness and VF comparisons, agreement between the automated report and clinical assessment was 75.4% with a kappa of 0.62 (95% CI 0.54-0.70). For different RNFL sectors, kappa values ranged from 0.47 (moderate agreement) to 0.80 (good agreement). CONCLUSIONS: This study suggests that the automated structure-function report combining results from the SD-OCT and the HEP may assist in the evaluation and management of glaucoma. PMID- 29396689 TI - [Arthroscopic suprapectoral tenodesis of the long head of the biceps tendon]. AB - OBJECTIVE: The aim of a tenotomy of the long biceps tendon is to remedy a painful pathology in the proximal region of the tendon. Tenodesis of the tendon can restore the motor and cosmetic function of the biceps brachii muscle. INDICATIONS: Partial rupture or tendopathy of the long biceps tendon, injuries of the anchor of the long biceps tendon (SLAP lesions; SLAP: superior labrum anterior posterior), lesions of the pulley system. CONTRAINDICATIONS: Infections or tumors, loss of the long head biceps tendon from the intertubercular groove. SURGICAL TECHNIQUE: Shoulder arthroscopy via a posterior standard portal in beach chair position. Anteroinferior portal. Standard diagnostic arthroscopy. Checking the stability of the biceps anchor and the pulley system with a probe. Testing the extra-articular portion of the long biceps tendon with the hook. By pulling the tendon into the joint, the course of the tendon can be assessed. Anterolateral portal superior of the intertubercular groove. Pulling the tendon out of the anterolateral portal. Arming of the tendon with Krackow stitches. Fixation of the tendon in the intertubercle groove with a knotless suture anchor. POSTOPERATIVE MANAGEMENT: Three weeks immobilization with an arm sling, 6 weeks no forced elbow flexion and forearm supination, 2 weeks active-assisted mobilization of the shoulder up to horizontal, 30 degrees external rotation, internal rotation free. RESULTS: The results published in the literature show that epiossal anchor tenodisis improves the clinical scores (preoperative vs. postoperative) and leads to a better cosmetic result and a lower rerupture rate than soft tissue tenodesis. PMID- 29396690 TI - [Correction of kyphotic fixed lumbar segments and hypolordosis with the transforaminal lumbar interbody fusion technique]. AB - OBJECTIVE: Correction of a segmental or global lumbar hypolordosis to improve a sagittal imbalance. INDICATIONS: Lumbar segments fixed in kyphosis; degenerative or posttraumatic hypolordotic deformity of the lumbar spine with sagittal imbalance. CONTRAINDICATIONS: Bechterew disease; extended adhesions in the retroperitoneum. SURGICAL TECHNIQUE: Segmental correction of a kyphotic fixed segment using a unilateral transforaminal approach to release the annulus and anterior longitudinal ligament. With an additional posterior V-shaped osteotomy, a segmental correction of more than 20 degrees could be achieved to improve a global sagittal imbalance. POSTOPERATIVE MANAGEMENT: Back-friendly mobilisation starting the first day after surgery with support of a physiotherapist. No sports for 3-4 months. RESULTS: In all, 25 patients with 33 kyphotic fixed lumbar segments were treated using a complete anterior release of the annulus and anterior longitudinal ligament via a unilateral transforaminal approach. This enabled a lordosizing correction of the segment between 5 degrees and 29 degrees (mean 11.4 degrees ) without any neurological or vascular complications. A total of 10 patients treated with an additional posterior osteotomy were corrected 14 29 degrees (mean 19 degrees ). There was a loss of reduction of the lordotic correction (mean 1 degrees ; range 0-3 degrees ) in the X-ray control at a minimum follow-up of 6 months (range 6-33 months). PMID- 29396691 TI - The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes. AB - AIMS/HYPOTHESIS: We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. METHODS: A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 +/- 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as 'high-risk' for future albuminuria and the lower two tertiles were deemed 'low-risk'. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1-Q5) for associations with log10 ACR and ACR risk groups. RESULTS: Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2-Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1-Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. CONCLUSIONS/INTERPRETATION: Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications. PMID- 29396692 TI - Characterisation of manganese peroxidase and laccase producing bacteria capable for degradation of sucrose glutamic acid-Maillard reaction products at different nutritional and environmental conditions. AB - Maillard reactions products (MRPs) are a major colorant of distillery effluent. It is major source of environmental pollution due to its complex structure and recalcitrant nature. This study has revealed that sucrose glutamic acid-Maillard reaction products (SGA-MRPs) showed many absorption peaks between 200 and 450 nm. The absorption maximum peak was noted at 250 nm in spectrophotometric detection. This indicated the formation of variable molecular weight Maillard products during the SGA-MRPs formation at high temperature. The identified aerobic bacterial consortium consisting Klebsiella pneumoniae (KU726953), Salmonella enterica (KU726954), Enterobacter aerogenes (KU726955), Enterobacter cloaceae (KU726957) showed optimum production of MnP and laccase at 120 and 144 h of growth, respectively. The potential bacterial consortium showed decolourisation of Maillard product up to 70% in presence of glucose (1%), peptone (0.1%) at optimum pH (8.1), temperature (37 degrees C) and shaking speed (180 rpm) within 192 h of incubation. The reduction of colour of Maillard product correlated with shifting of absorption peaks in UV-Vis spectrophotometry analysis. Further, the changing of functional group in FT-IR data showed appearance of new peaks and GC MS analysis of degraded sample revealed the depolymerisation of complex MRPs. The toxicity evaluation using seed of Phaseolus mungo L. showed reduction of toxicity of MRPs after bacterial treatment. Hence, this study concluded that developed bacterial consortium have capability for decolourisation of MRPs due to high content of MnP and laccase. PMID- 29396693 TI - Efficacy and outcome predictors of fluoroscopy-guided facet joint injection for spondylolysis. AB - OBJECTIVE: To assess the efficacy of fluoroscopy-guided facet joint injection for symptomatic spondylolysis and to analyze the outcome predictors. MATERIALS AND METHODS: This study included 108 patients who underwent fluoroscopy-guided facet joint steroid injection for symptomatic spondylolysis with follow-up medical records from January 2013 to December 2016. Among them, 47 patients underwent concomitant epidural steroid injection. Response to injection was assessed at the initial follow-up. The symptom-free interval was analyzed using the Kaplan-Meier method. Outcome predictors were statistically analyzed using independent t test and Chi-square test. RESULTS: The facet joint injection was effective in 52 of 108 (48.1%) patients at initial follow-up. Recurrence was reported in 21 of these 52 (40.4%) patients. For the 52 patients in whom facet joint injection was effective, the median symptom-free interval was 298 days (95% confidence interval, 29-567 days). No significant difference was found in the response between the group with facet joint injection only (n = 61) and the group with facet joint injection and additional ESI (n = 47). Additionally, no significant outcome predictors were detected. CONCLUSIONS: Fluoroscopy-guided facet joint injection may potentially be an effective therapy for providing prolonged pain relief and avoiding unnecessary surgery for symptomatic spondylolysis without significant outcome predictors. PMID- 29396696 TI - Clavicle pain. PMID- 29396695 TI - Prevalence of vitamin D insufficiency in radiologists: a cross-sectional study. AB - OBJECTIVE: To compare the prevalence of vitamin D insufficiency between radiologists and a control group of non-radiologists. MATERIALS AND METHODS: This prospective cross-sectional study was conducted at the Swiss Congress of Radiology in May of 2016. Attendees (radiologists and non-radiologists) were asked to give a venous blood sample to measure vitamin D (25-hydroxyvitamin D) blood serum level. Vitamin D insufficiency was defined as < 50 nmol/l (30 ng/ml). We collected information on profession, age, gender, vitamin D supplements, recent sunny vacation, and eating fish. We compared vitamin D between radiologists and non-radiologists. RESULTS: A total of 137 radiologists (mean age, 38 +/- 10 years) and 164 non-radiologists (mean age, 40 +/- 12 years) participated in the study. Prevalence of vitamin D insufficiency in both groups was similar (58.4% (80/137) vs. 53.7% (88/164); p = 0.240). Forty-three participants were under vitamin D supplementation. In those without supplementation, we found no difference in vitamin D between groups (44.0 +/- 16.2 nmol/l (17.6 +/- 6.5 ng/ml) vs. 44.4 +/- 16.9 nmol/l (17.8 +/- 6.8 ng/ml); p = 0.757). Average vitamin D levels for radiologists were slightly lower (-0.98 nmol/l (0.39 ng/ml), 95% confidence interval - 5.96 to 4.00 (- 2.38 to 1.6 ng/ml); p = 0.699), when adjusting for the potential confounders, but not statistically significant. The odds ratio of vitamin D insufficiency for radiologists versus non-radiologists was 1.7 (95% CI = 0.94-3.06; p = 0.078) after adjusting for the other independent variables. CONCLUSIONS: The prevalence of vitamin D insufficiency in radiologists was high (58.4%), but not substantially higher than in non-radiologists. PMID- 29396694 TI - Feasibility of using an inversion-recovery ultrashort echo time (UTE) sequence for quantification of glenoid bone loss. AB - OBJECTIVE: To utilize the 3D inversion recovery prepared ultrashort echo time with cones readout (IR-UTE-Cones) MRI technique for direct imaging of lamellar bone with comparison to the gold standard of computed tomography (CT). MATERIALS AND METHODS: CT and MRI was performed on 11 shoulder specimens and three patients. Five specimens had imaging performed before and after glenoid fracture (osteotomy). 2D and 3D volume-rendered CT images were reconstructed and conventional T1-weighted and 3D IR-UTE-Cones MRI techniques were performed. Glenoid widths and defects were independently measured by two readers using the circle method. Measurements were compared with those made from 3D CT datasets. Paired-sample Student's t tests and intraclass correlation coefficients were performed. In addition, 2D CT and 3D IR-UTE-Cones MRI datasets were linearly registered, digitally overlaid, and compared in consensus by these two readers. RESULTS: Compared with the reference standard (3D CT), glenoid bone diameter measurements made on 2D CT and 3D IR-UTE-Cones were not significantly different for either reader, whereas T1-weighted images underestimated the diameter (mean difference of 0.18 cm, p = 0.003 and 0.16 cm, p = 0.022 for readers 1 and 2, respectively). However, mean margin of error for measuring glenoid bone loss was small for all modalities (range, 1.46-3.92%). All measured ICCs were near perfect. Digitally registered 2D CT and 3D IR-UTE-Cones MRI datasets yielded essentially perfect congruity between the two modalities. CONCLUSIONS: The 3D IR UTE-Cones MRI technique selectively visualizes lamellar bone, produces similar contrast to 2D CT imaging, and compares favorably to measurements made using 2D and 3D CT. PMID- 29396697 TI - Multicentric carpotarsal osteolysis syndrome: long-term follow-up of three patients. AB - Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal disorder characterized by progressive carpal and tarsal destruction. The upper and lower limbs may be involved, leading to deformities and joint limitation. These anatomic features may be associated with progressive renal failure. The radiographs obtained during childhood showed a carpal and tarsal osteolysis and an asymmetrical involvement. Here, we report on the long-term clinical and radiological findings of three patients with skeletal manifestations of MCTO. PMID- 29396698 TI - Vertebral Fractures Following Denosumab Discontinuation in Patients with Prolonged Exposure to Bisphosphonates. AB - Denosumab (DMAB) efficacy for treatment of osteoporosis was demonstrated in a pivotal trial with a reduction in vertebral and hip fractures during 3 years, and fracture risk reduction was sustained up to 10 years in an extension study. DMAB causes potent yet reversible inhibition of bone resorption. Bone density declines rapidly upon discontinuation and bone turnover markers increase above baseline in a rebound fashion. Spontaneous multiple vertebral fractures after DMAB discontinuation were recently reported. Prior treatment with bisphosphonates (BP) was postulated to decrease the risk for this alarming phenomenon. We aimed to describe our experience of fractures following DMAB withdrawal with special attention to past history of osteoporosis treatment. A phone survey of physicians engaged in bone metabolism from nine hospitals in Israel was performed. Clinical data of the patients presenting with vertebral fractures upon DMAB discontinuation were summarized and compared to the previously published cases. Nine elderly (74.2 +/- 5.3 years) female patients were identified. Most patients had a prolonged prior exposure to BP (7.4 +/- 3.2 years). All but one sustained osteoporotic fractures prior to DMAB initiation and their FRAX scores were high. Thirty-six vertebral fractures were identified in nine patients. Eight patients presented with multiple fractures, and most fractures were spontaneous. In line with the previous reports, the timing and severity of the fractures raise concern of DMAB discontinuation effect. Prolonged BP exposure in most of our patients challenges the protective effect hypothesis. Care providers, patients, and regulatory authorities should be aware of the possible risk of DMAB treatment interruption. PMID- 29396699 TI - [Complications instead of improved survival and local freedom from recurrence after early radical cystectomy in muscle-invasive bladder cancer compared to multimodal maintenance therapy]. PMID- 29396700 TI - Dual delivery of hydrophilic and hydrophobic drugs from chitosan/diatomaceous earth composite membranes. AB - Oral administration of drugs presents important limitations, which are frequently not granted the importance that they really have. For instance, hepatic metabolism means an important drug loss, while some patients have their ability to swell highly compromised (i.e. unconsciousness, cancer...). Sublingual placement of an accurate Pharmaceutical Dosage Form is an attractive alternative. This work explores the use of the beta-chitosan membranes, from marine industry residues, composed with marine sediments for dual sublingual drug delivery. As proof of concept, the membranes were loaded with a hydrophilic (gentamicin) and a hydrophobic (dexamethasone) drug. The physico-chemical and morphological characterization indicated the successful incorporated of diatomaceous earth within the chitosan membranes. Drug delivery studies showed the potential of all formulations for the immediate release of hydrophilic drugs, while diatomaceous earth improved the loading and release of the hydrophobic drug. These results highlight the interest of the herein developed membranes for dual drug delivery. PMID- 29396702 TI - A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea. AB - OBJECTIVE: Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. METHODS: This was a phase II, randomized, double blind, multicenter study. Healthy subjects aged >= 18 years with moderate-to severe rosacea that had been diagnosed >= 6 months previously and with >= 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator's Global Assessment (IGA) improvement, IGA "clear" or "almost clear" (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. RESULTS: A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of "clear" or "almost clear." Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n = 3; vehicle, n = 1). CONCLUSION: Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. CLINICALTRIALS. GOV IDENTIFIER: NCT02601963. PMID- 29396701 TI - Cartilage turnover and intra-articular corticosteroid injections in knee osteoarthritis. AB - Intra-articular corticosteroid injections (IACI) are commonly used interventions for pain relief in patients with knee osteoarthritis (OA). Biomarkers may be helpful in further elucidating how IACI exert their effect. The aim of this study is to look at the response of biomarkers of cartilage and bone metabolism after IACI in knee OA. Eighty subjects with symptomatic knee OA [45% male, mean age (SD) 64 (11) years] underwent routine knee joint injection with 40 mg triamcinolone acetonide and 4 ml 1% lignocaine. Knee pain (as pain subscale of WOMAC VAS) and biomarkers [C-telopeptides of type-II collagen (uCTX-II), and N telopeptides of type-I collagen in urine; cartilage oligomeric matrix protein (COMP), hyaluronic acid, N-terminal propeptide of type-IIA collagen, and human cartilage glycoprotein-39 (YKL-40) in serum] were measured at baseline and 3 weeks after IACI. Radiographic severity of disease was evaluated using knee radiographs. Median uCTX-II, a cartilage degradation marker, was lower at 3 weeks post IACI compared with baseline: 306.3 and 349.9 ng/mmol, respectively (p < 0.01), which remained significant after Bonferroni correction. Apart from a weak trend of lower sCOMP post IACI (p = 0.089), other biomarkers showed no change after IACI. Both baseline uCTX-II values and the change in uCTX-II from baseline to 3 weeks post injection correlated with radiographic severity of joint space narrowing, but not osteophyte grade. No association between uCTX-II and pain was observed. This observational study suggests that IACI in knee OA may reduce cartilage degradation in the short term. PMID- 29396705 TI - Biokinetics, dosimetry, and radiation risk in infants after 99mTc-MAG3 scans. AB - BACKGROUND: Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing 99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data. Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing 99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool. RESULTS: The mean age of the patients was 7.0 +/- 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of 99mTc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 +/- 0.03 mGy/MBq for the kidneys and 0.27 +/ 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 +/- 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified). CONCLUSION: In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with 99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the 99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer. PMID- 29396703 TI - Immunologic Milieu of Mature T-Cell and NK-Cell Lymphomas-Implications for Therapy. AB - PURPOSE OF THE REVIEW: T-cells and natural killer (NK) cells share the same ontogeny, and lymphomas derived from them are clinically diverse, occurring in nodal and extranodal sites. In addition to inherent properties of these lymphomas, their microenvironment also impacts on pathogenesis and response to therapy. An understanding of the milieu of T-cell and NK cell lymphomas has important implications on treatment. RECENT FINDINGS: Components of the microenvironment include tumour-associated macrophages (TAM), non-neoplastic T cells and B-cells, eosinophils, dendritic cells, endothelial cells and blood vessels. TAM typically undergoes M2 polarization, promoting angiogenesis and inhibiting anti-tumour cellular immunity. In lymphomas of follicular helper T cell derivation, increased B-cell proliferation occurs, which may in turn enhance neoplastic T-cell growth. The expression of immune checkpoint ligands on TAM, dendritic cells or lymphoma cells induces an immunosuppressive environment conducive to neoplastic proliferation. Strategies against this complex cellular and immunologic microenvironment have shown promises. These include the use of signal transduction inhibitors, monoclonal antibodies against chemokines or non neoplastic microenvironmental cells, immunomodulatory drugs and immune checkpoint blockade. As T-cell and NK cell lymphomas are highly heterogeneous, clinical trials to demonstrate efficacy of a given therapeutic approach requires careful design aiming at enriching patient populations who will best respond. Targeting of the immunologic milieu in T-cell and NK-cell lymphomas offers exciting challenges and opportunities. PMID- 29396706 TI - Polarization Converter with Controllable Birefringence Based on Hybrid All Dielectric-Graphene Metasurface. AB - Previous studies on hybrid dielectric-graphene metasurfaces have been used to implement induced transparency devices, while exhibiting high Q-factors based on trapped magnetic resonances. Typically, the transparency windows are single wavelength and less appropriate for polarization conversion structures. In this work, a quarter-wave plate based on a hybrid silicon-graphene metasurface with controllable birefringence is numerically designed. The phenomena of trapped magnetic mode resonance and high Q-factors are modulated by inserting graphene between silicon and silica. This results in a broader transmission wavelength in comparison to the all-dielectric structure without graphene. The birefringence tunability is based on the dimensions of silicon and the Fermi energy of graphene. Consequently, a linear-to-circular polarization conversion is achieved at a high degree of 96%, in the near-infrared. Moreover, the polarization state of the scattered light is switchable between right and left hand circular polarizations, based on an external gate biasing voltage. Unlike in plasmonic metasurfaces, these achievements demonstrate an efficient structure that is free from radiative and ohmic losses. Furthermore, the ultrathin thickness and the compactness of the structure are demonstrated as key components in realizing integrable and CMOS compatible photonic sensors. PMID- 29396707 TI - Metabolic modelling and flux analysis of microorganisms from the Atacama Desert used in biotechnological processes. AB - Metabolic modelling is a useful tool that enables the rational design of metabolic engineering experiments and the study of the unique capabilities of biotechnologically important microorganisms. The extreme abiotic conditions of the Atacama Desert have selected microbial diversity with exceptional characteristics that can be applied in the mining industry for bioleaching processes and for production of specialised metabolites with antimicrobial, antifungal, antiviral, antitumoral, among other activities. In this review we summarise the scientific data available of the use of metabolic modelling and flux analysis to improve the performance of Atacama Desert microorganisms in biotechnological applications. PMID- 29396708 TI - Real-time monitoring of a microbial electrolysis cell using an electrical equivalent circuit model. AB - Efforts in developing microbial electrolysis cells (MECs) resulted in several novel approaches for wastewater treatment and bioelectrosynthesis. Practical implementation of these approaches necessitates the development of an adequate system for real-time (on-line) monitoring and diagnostics of MEC performance. This study describes a simple MEC equivalent electrical circuit (EEC) model and a parameter estimation procedure, which enable such real-time monitoring. The proposed approach involves MEC voltage and current measurements during its operation with periodic power supply connection/disconnection (on/off operation) followed by parameter estimation using either numerical or analytical solution of the model. The proposed monitoring approach is demonstrated using a membraneless MEC with flow-through porous electrodes. Laboratory tests showed that changes in the influent carbon source concentration and composition significantly affect MEC total internal resistance and capacitance estimated by the model. Fast response of these EEC model parameters to changes in operating conditions enables the development of a model-based approach for real-time monitoring and fault detection. PMID- 29396709 TI - Genome-wide identification and comparative analysis of phosphate starvation responsive transcription factors in maize and three other gramineous plants. AB - KEY MESSAGE: The present study identified several important candidate Pi regulation genes of maize and provides a better understanding on the generation of PHR genes in gramineous plants. Plants have evolved adaptive responses to cope with low phosphate (Pi) soils. The previous studies have indicated that phosphate starvation response (PHR) genes play central roles in regulating plant Pi starvation responses. However, the investigation of PHR family in gramineous plants is limited. In this study, we identified 64 PHR genes in four gramineous plants, including maize, rice, sorghum, and brachypodium, and conducted systematical analyses on phylogenetic, structure, collinearity, and expression pattern of these PHR genes. Genome synteny analysis revealed that a number of PHR genes were present in the corresponding syntenic blocks of maize, rice, sorghum, and brachypodium, indicating that large-scale duplication events contributed significantly to the expansion and evolution of PHR genes in these gramineous plants. Gene expression analysis showed that many PHR genes were expressed in various tissues, suggesting that these genes are involved in Pi redistribution and allocation. In addition, the expression levels of PHR genes from maize and rice under low Pi stress conditions revealed that some PHRs may play an important role in Pi starvation response. Our results provided a better understanding on the generation of PHR genes in gramineous plants and identified several important candidate Pi regulation genes of maize. PMID- 29396710 TI - N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner. AB - Therapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppresses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that impact the quality of TCR-transduced T cells and suggest that the addition of NAC to current clinical protocols should be considered. PMID- 29396711 TI - Prevalence of suicide attempts and their risk factors in school-aged patients with epilepsy: a population-based study. AB - Suicide prevention is a critical issue for young people. However, no large body of representative data on the risk of suicide attempts in school-aged patients with epilepsy in Taiwan or other developing countries is available. Patients aged <= 18 years who received a diagnosis of epilepsy between 2000 and 2012 were included in the epilepsy cohort (N = 9801). The comparison cohort was matched to the epilepsy cohort at a ratio of 4:1. We calculated the adjusted hazard ratio and 95% confidence intervals (CIs) for suicide attempts after adjustment for age, sex, urbanization level, parental occupation category, comorbidities, and follow up time. Further analysis was performed to assess the dose-response effect on the risk of attempting suicide based on the average frequency of medical visits for epilepsy. The overall incidence rates of suicide attempts in the epilepsy and comparison cohorts were 15.7 and 5.89 per 100,000 people per year, respectively. The epilepsy cohort had a 2.34-fold higher risk of suicide being attempted (95% CI 2.17-2.52) than did the comparison cohort. Male sex, over 12 years of age, and parental occupation of office work were found to be the major risk factors for suicide attempts. Epilepsy might be an independent factor predisposing school aged patients to suicide attempts. The results of this study could provide clinicians and governments with vital information on suicide prevention for young people with epilepsy in Taiwan and other developing countries. PMID- 29396712 TI - Informant-related effects of neurofeedback and cognitive training in children with ADHD including a waiting control phase: a randomized-controlled trial. AB - There is controversy regarding the clinical efficacy of neurofeedback (NF) and computerized cognitive training (CogT) as treatments for ADHD. Meta-analyses claim that probably blinded teachers observe smaller effects than parents, because they are less biased. We investigated informant-specific effects by manipulating the involvement of informants, by controlling for waiting time effects, and by adding a blinded outcome measure. Seventy-seven children with ADHD were randomly allocated to slow cortical potential NF or to individualized CogT (of attention, working memory or inhibition). The training was conducted in schools (NF: n = 19, CogT: n = 19) or in outpatient clinics (NF: n = 19, CogT: n = 20). Three assessments were scheduled: baseline, followed by a waiting period, pre-training, and post-training. Multivariate Analyses of Variance were conducted to assess parent- and teacher-rated changes in ADHD symptoms and executive functions (EF), and changes according to standardized classroom observations. Both treatments resulted in significant improvements according to informants, with larger effects for parents (ADHD symptoms: parent eta p2 = .32; teacher eta p2 = .10), and according to observations (eta p2 = .19). The setting had no effect on outcome. Considerable waiting time effects were revealed for ADHD symptom ratings by both informants, for EF ratings only by teachers. Changed classroom behavior was uncorrelated with teacher-rated changes. Overall, the results do not support the notion that teachers are more objective while being as sensitive to change as parents. The three sources seem to contribute differential and mostly unrelated pieces of information to the evaluation of treatments. PMID- 29396713 TI - Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies. AB - Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov . PMID- 29396714 TI - Prognostic risk models for transplant decision-making in myelofibrosis. AB - Prognostic models are widely used in clinical practice for transplant decision making in myelofibrosis (MF). We have compared the performance of the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS plus in a series of 544 patients with primary or secondary MF aged <= 70 years at the time of diagnosis. The median projected survival of the overall series was 9.46 years (95% confidence interval 7.44-10.59). Median survival for the highest risk groups was less than 4 years in the three prognostic models. By contrast, the projected survival for patients in the intermediate-2 categories by the IPSS, DIPSS, and DIPSS-plus was 6.6, 5.6, and 6.5 years, respectively. The number of patients in the intermediate-2 and high-risk categories was smaller in the DIPSS than in the IPSS or the DIPSS-plus. The IPSS and DIPSS-plus were the best models to discriminate between the intermediate-1 and intermediate-2 risk categories, which is a critical cut-off point for patient selection to transplant. Among patients assigned at diagnosis to the intermediate-2 or high-risk groups by the IPSS, DIPSS, and DIPSS-plus, only 17, 21, and 20%, respectively, were subsequently transplanted. In conclusion, in our contemporary series of younger MF patients only the highest risk categories of the current prognostication systems have a median survival below the 5-year threshold recommended for considering transplantation. Patient selection for transplantation can significantly differ depending on which prognostication model is used for disease risk stratification. PMID- 29396715 TI - Effects of a Medication Review on Delirium in Older Hospitalised Patients: A Comparative Retrospective Cohort Study. AB - BACKGROUND: Delirium in older hospitalised patients is a common and serious disorder. Polypharmacy and certain medications are risk factors for developing delirium. A medication review could benefit older hospitalised patients with delirium. OBJECTIVES: (1) Evaluate the effects of medication review on length of delirium, length of hospital stay, mortality, and discharge destination; and (2) describe and analyse the proposed changes to medication and its implementation by the treating physician. SETTING: The study was conducted at Maastricht University Medical Centre+. METHODS: We compared two cohorts of older patients with delirium: the first cohort from before introducing the medication review, and a second cohort 5 months after introduction of the medication review. Data were extracted from the patients' digital medical records. RESULTS: A significant interaction effect of cohort and number of medications taken by the patient was found for duration of delirium: patients from the second cohort taking between zero and six medications had significantly shorter delirious episodes than patients in the first cohort. This effect bordered on significance for patients taking between seven and 11 medications, but disappeared for patients taking 12 or more medications. No other statistically significant differences were found between the cohorts. The proposed changes in medication were implemented for 71% of the patients. CONCLUSION: A medication review seems to significantly decrease the length of an older patient's delirious episode. Given the clinical relevance of these findings, we advise medication reviews for all older patients who are delirious or are at risk of developing delirium. PMID- 29396717 TI - Management of exposed ventriculoperitoneal shunt on the scalp in pediatric patients. AB - PURPOSE: The exposure of a ventriculoperitoneal shunt on the scalp is a serious complication. There are limited studies evaluating this complication's management in the literature. The aim of this study is to define the management of shunt salvage and the reconstruction of the scalp. METHODS: This retrospective study included seven pediatric patients with ventriculoperitoneal shunts that were exposed on the scalp for various reasons. The demographic characteristics of the patients and the medical and surgical treatments used were recorded. The patient follow-up durations and complications associated with these methods were determined. RESULTS: Four female and three male patients with an average age of 5.7 were followed for an average of 9.4 months. All but one of these patients were treated without removing the shunt. While one skin flap was used in one patient, successful repairs were made with double skin flaps in five patients. There were no complications during follow-up for the patients treated with these methods. CONCLUSION: In this study, the appropriate management of shunt exposure, which is common in pediatric cases, has been revealed. Given appropriate infection prevention, the reconstruction of the scalp is possible without the removal of the shunt. PMID- 29396718 TI - Chiari type I malformation of infants and toddlers. AB - OBJECTIVES: Chiari I malformation has been a well-recognized clinical entity; however, its occurrence among infants and toddlers is unusual. Their clinical presentations may be different from other age groups due to their lack of effective verbal communication. The authors analyze their personal series of patients focusing on symptomatology and MRI characteristics. Treatment methods, results, and outcome are analyzed in order to identify appropriate surgical management among infants and toddlers with Chiari I malformation. METHODS: The authors retrospectively reviewed 16 patients who were diagnosed and surgically treated between 2007 and 2014 during the first 3 years of life with minimum follow-up of 3 years. We focused on the presenting symptoms, magnetic resonance imaging findings, and surgical techniques used for posterior fossa decompression (PFD) and their postoperative outcome. RESULTS: Twelve patients (75%) presented with signs of headaches such as irritability, inconsolable crying, head grabbing, and/or arching back. Ten patients (62.5%) presented with oropharyngeal and/or respiratory symptoms such as emesis, choking, gagging, snoring, sleep apnea, breathing pause, and/or vocal cord palsy. Only one patient had segmental cervical hydromyelia. At the first surgery, ten patients had PFD with dural scoring (Type 1 procedure), while six others had PFD with duraplasty (Type 2 procedure) with thermal reduction of the cerebellar tonsils in four. Following the first operation, all initially had varying degrees of symptomatic improvement; however, seven patients subsequently had symptomatic recurrence. Persistent crowding at the PFD site on the postoperative imaging indicated greater risk of recurrences in both Type 1 procedure and Type 2 procedure groups. Of seven patients who needed a second operation, fivewere after Type 1 procedure and the two were after Type 2 procedure. The difference of recurrence rates between these two groups is not significant. CSF-related complications occurred in 4 out of 11 patients who had Type 2 procedure (one after primary decompression and three after the second decompression for recurrence). CONCLUSION: Young patients lacking effective verbal communication often present their Chiari I malformation differently from olderage groups. Behavioral changes indicative of headaches/irritability and oropharyngeal/respiratory symptoms are the primary presenting symptoms. The recurrence rate tends to be higher among the patients after Type 1 procedure (particularly those younger than 18 months) than after Type 2 procedure. We observed that duraplasty at primary or at redo PFD provides for better decompression and long-term outcome. However, one should keep it in mind that there is risk of CSF-related complications following duraplasty, particularly higher tendency after redo PFD. PMID- 29396719 TI - Challenges in the management of childhood low-grade glioma in a developing country. AB - BACKGROUND: Treatment modality impacts outcome of childhood low-grade glioma (LGG). Optimizing management in developing countries can be challenging. This study evaluates the clinical characteristics, treatment, and factors influencing outcome of childhood LGG in Saudi Arabia. PATIENTS AND METHODS: This study retrospectively evaluated 59 children consecutively diagnosed with LGG between January 2001 and June 2016. RESULTS: Median age at diagnosis was 6.0 years. Pilocytic astrocytoma represented 64.9% of cases. The anatomic site was cerebellar in 23.7%, cerebral in 18.6%, hypothalamic-optic pathway in 33.9%, and midline in 23.7%. The 5-year overall survival (OS) and progression-free survival (PFS) were 90.6 +/- 4.7 and 54.3 +/- 8.4%, respectively. Initial treatment was observation in 28.8%, surgery alone in 35.6%, chemotherapy in 13.6%, radiotherapy in 5.1%, and combined in 16.9% of cases. The corresponding 5-year PFS was 56.3 +/ 15.6, 53.3 +/- 14.0, 22.9 +/- 19.7, 33.3 +/- 27.2, and 88.9 +/- 10.5%, respectively (p = 0.006). Among the 61% who had surgical intervention (either alone or in combination with other therapies), 22% achieved complete resection with 5-year radiation/progression-free survival (RPFS) of 87.5 +/- 11.7% compared to 27.6 +/- 10.8% for subtotal resection/biopsy and 62.2 +/- 17.0% for no surgery (p = 0.013). Adjuvant therapy for residual tumor improved survival with 5-year PFS of 66.7 +/- 19.2% for chemotherapy and 100% for radiotherapy compared to 12.5 +/- 11.4% for observation (p = 0.033). CONCLUSIONS: We identified variability in the outcomes of LGG. Fewer surgeries with lower rates of total resection were noted, compared to reports from international cooperative groups. The extent of resection was predictive of RPFS. Adjuvant therapy improved the outcome of patients with residual disease, resulting in PFS rates comparable to international data. PMID- 29396720 TI - Cervicothoracic epidural hematoma in a toddler with miosis, ptosis, nonspecific symptoms, and no history of major trauma: case report. AB - INTRODUCTION: Spinal epidural hematomas are uncommon in children. The diagnosis can be elusive as most cases present without a history of trauma, while symptoms can be atypical. CASE REPORT: We encountered a 35-month-old male presenting with nonspecific symptoms and no history of trauma. He later developed unilateral miosis and ptosis; MRI discovered a subacute cervicothoracic epidural which was promptly evacuated. The patient made an excellent recovery. COCLUSIONS: We emphasize the frequent absence of identifiable trauma and the importance of thorough imaging when this entity is suspected. Miosis and ptosis, likely representing a partial Horner syndrome, is an extremely rare presentation, this being one of the only reported cases. PMID- 29396721 TI - Relationships between serum leptin levels and bone mineral parameters in school aged children: a 3-year follow-up study. AB - Leptin regulates bone cell differentiation and functions via direct and indirect actions in experimental settings. Epidemiologically, however, the impact of leptin on the regulation of bone metabolism remains unclear. While some studies have reported a positive relationship between leptin and bone mineral parameters, other studies found an inverse or no association. We analyzed data from a population-based follow-up survey of community-dwelling children in Hamamatsu, Japan, to investigate relationships between leptin levels and bone mineral parameters. Multiple regression analysis was performed. Multicollinearity was quantified using the variance infiltration factor (VIF). Among 408 children who participated in the baseline survey (at age 11.2 years), 254 (121 boys and 133 girls) completed the follow-up survey (at age 14.2 years). Leptin levels were strongly related to fat mass (r = 0.87 in boys, r = 0.80 in girls). Leptin levels at baseline were significantly (P < 0.05) positively related to total body less head (TBLH) areal bone mineral density (aBMD) at follow-up in girls (standardized partial regression coefficient: beta = 0.302, VIF = 2.246), after adjusting for body fat percentage (%). On the other hand, leptin levels were inversely related to TBLH aBMD in boys (beta = - 0.395, VIF = 4.116), after adjusting for body fat mass (kg). Positive relationships between leptin levels and bone mineral parameters were observed with VIF values < 4.0, whereas inverse relationships were observed with VIF values >= 4.0. These findings suggest that positive relationships between leptin levels and bone mineral parameters are weak, or not always observed, due to statistical problems (i.e., multicollinearity) and other factors derived from adipose tissue. PMID- 29396722 TI - Increased expression of the gene encoding stearoyl-CoA desaturase 1 in human bladder cancer. AB - Bladder cancer is a common disease and a significant cause of death worldwide. There is thus great interest in identifying a diagnostic and prognostic biomarker, as well as gaining an understanding of the molecular basis of bladder cancer. Stearoyl-CoA desaturase 1 gene (SCD1) is highly overexpressed in many human cancers. However, the expression of SCD1 has not yet been investigated in patients with bladder cancer. Here, we document that (a) the SCD1 is highly overexpressed in human bladder cancer; (b) high expression of SCD1 is more frequently observed in the late stage of disease and patients with lymph node metastasis; (c) bladder cancer patients with a higher SCD1 mRNA level have a poorer survival rate than those with normal SCD1 expression. Overall, this is the first report to indicate an association between SCD1 mRNA level and clinical indicators of human bladder cancer. Our study has provided evidence supporting the potential role of SCD1 as a biomarker for human bladder cancer prognosis. PMID- 29396724 TI - Rise and fall: two sides of a coin of middle aged women's perceptions of reproductive: a qualitative study. AB - The present study was conducted to determine the perceptions of middle-aged women of reproductive changes. The present study was a qualitative research with a content analysis approach. The participants were 30 middle-aged women whose perceptions of reproductive changes had been collected on in-depth semi structured interviews. The data were analyzed using the Graneheim and Lundman's inductive content analysis method. The main themes extracted from the data were a sense of "fall" and "the beginning of a new life cycle." A feeling of fall was formed from the subthemes "deterioration of youth," "the dusk of femininity," and "fade-out of the gender roles." The theme "beginning of a new life cycle" was formed from the subthemes of "acceptance," "sophistication," and "maturity." Middle-aged women had a wide range of emotions experienced from the reproductive changes ranging from a feeling of decline to that of excellence and rise. PMID- 29396723 TI - Duration-dependent effects of nicotine exposure on growth and AKT activation in human kidney epithelial cells. AB - Exposure to nicotine is known to cause adverse effects in many target organs including kidney. Epidemiological studies suggest that nicotine-induced kidney diseases are prevalent worldwide. However, the impact of duration of exposure on the nicotine-induced adverse effects in normal kidney cells and the underlying molecular mechanism is still unclear. Hence, the objective of this study was to evaluate both acute and long-term effects of nicotine in normal human kidney epithelial cells (HK-2). Cells were treated with 1 and 10 uM nicotine for acute and long-term duration. The result of cell viability showed that the acute exposure to 1 uM nicotine has no significant effect on growth. However, the 10 uM nicotine caused significant decrease in the growth of HK-2 cells. The long-term exposure resulted in significantly increased cell growth in both 1 and 10 uM nicotine-treated groups. Analysis of cell cycle and expression of marker genes related to proliferation and apoptosis further confirmed the effects of nicotine. Additionally, the analysis of growth signaling pathway revealed the decreased level of pAKT in cells with acute exposure whereas the increased level of pAKT in long-term nicotine-exposed cells. This suggests that nicotine, through modulating the AKT pathway, controls the duration-dependent effects on the growth of HK-2 cells. In summary, this is the first report showing long-duration exposure to nicotine causes increased proliferation of human kidney epithelial cells through activation of AKT pathway. PMID- 29396725 TI - Expression of gremlin1 in gastric cancer and its clinical significance. AB - As an antagonist of bone morphogenetic proteins (BMPs), 2, 4 and 7, gremlin1 plays a role in regulating organogenesis, tissue differentiation and angiogenesis. However, there is little information regarding gremlin1 in gastrointestinal cancer. We attempted to clarify how gremlin1 expression affects the clinical features and biological properties of gastric cancer. A total of 232 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were enrolled. Gremlin1 expression in gastric cancer was detected by immunohistochemical and western blotting methods. Correlations between clinicopathological parameters and gremlin1 expression were analyzed. Gremlin1 was identified in the cytoplasm and nucleus of all gastric cancer cell lines and some regions of surgical specimens of gastric cancer. One hundred and seventeen of the 232 patients (50.4%) were classified as gremlin1-positive based on gremlin1 expression. Gremlin1 positivity was correlated with shallower tumor depth, smaller tumor size, less nodal involvement and vessel invasion (p < 0.05). The 5-year survival rate of the gremlin1-positive group was 81%, which was significantly higher than the gremlin1-negative group (p < 0.01). Multivariate analysis revealed that gremlin1 was not selected as an independent prognostic marker. Gremlin1 expression in gastric cancer may be a useful prognostic marker that is involved with the BMP signaling pathway. Furthermore, gremlin1 may have clinical use as a diagnostic and treatment tool. PMID- 29396726 TI - Effects of substituting concentrate mix with water hyacinth (Eichhornia crassipes) leaves on feed intake, digestibility and growth performance of Washera sheep fed rice straw-based diet. AB - The objective of this experiment was to determine effects of substituting concentrate mixture (CM) with water hyacinth (Eichhornia crassipes) leaves (WHL) at different inclusion levels of feed and nutrient intake, digestibility, and growth performance of Washera sheep. Twenty yearlings intact male sheep with initial body weight of 24.1 +/- 1.68 kg (mean +/- SD) were used in both 90 days of feeding and 7 days of digestibility trials. The experimental animals were arranged into four blocks of five animals based on their initial body weight. The dietary treatments used in the experiment were 100% concentrate mix (0WHL-T1), 50% WHL and 50% CM (50WHL-T2), 75% WHL and 25% concentrate mix (75WHL-T3), and 100% WHL (100WHL-T4). Rice straw was given ad libitum. The crude protein (CP) content of water hyacinth leaf is 14.4%. Dry matter digestibility was greater (p < 0.001) for 0WHL and 50WHL followed by 75WHL. The average daily weight gain was higher for 100% concentrate mix followed by 50 and 75% water hyacinth leave supplemented sheep. Therefore, wilted water hyacinth leave can safely substitute concentrate mix up to 75% and result in the optimum growth of Washera sheep from the feeding regime employed in this study. PMID- 29396727 TI - From 'Parent' to 'Expert': How Parents of Children with Autism Spectrum Disorder Make Decisions About Which Intervention Approaches to Access. AB - Parents of children with Autism Spectrum Disorder are responsible for deciding which interventions to implement with their child. There is limited research examining parental decision-making with regards to intervention approaches. A constructivist grounded theory methodology was implemented in this study. Semi structured interviews were undertaken with 14 participants from 12 family units. Data collection and analysis occurred concurrently, allowing a grounded theory to be constructed. Parental decision-making was influenced by many factors, arranged into seven core categories (values, experience, information, motivation, understanding, needs and logistics). Decision-making evolved over time, as parents transformed from 'parent' to 'expert'. The results of this study provide an insight into parental decision-making, which has implications for the support provided to parents by health professionals. PMID- 29396729 TI - Influence of meteorological parameters on the soil radon (Rn222) emanation in Kutch, Gujarat, India. AB - The soil radon (Rn222) and thoron (Rn220) concentrations recorded at Badargadh and Desalpar observatories in the Kutch region of Gujarat, India, have been analyzed to study the sources of the radon emissions, earthquake precursors, and the influence of meteorological parameters on radon emission. Radon and meteorological parameters were recorded using Radon Monitor RMT 1688-2 at these two stations. We used the radon data during February 21, 2011 to June 8, 2011, for Badargadh and March 2, 2011 to May 19, 2011, for the Desalpar station with a sampling interval of 10 min. It is observed that the radon concentrations at Desalpar varies between 781 and 4320 Bq m-3with an average value of 2499 Bq m-3, whereas thoron varies between 191 and 2017 Bq m-3with an average value of 1433.69 Bq m-3. The radon concentration at Badargadh varies between 264 and 2221 Bq m 3with an average value of 1135.4 Bq m-3, whereas thoron varies between 97 and 556 Bq m-3. To understand how the meteorological parameters influence radon emanation, the radon and other meteorological parameters were correlated with linear regression analysis. Here, it was observed that radon and temperature are negatively correlated whereas radon and other two parameters, i.e., humidity and pressure are positively correlated. The cross correlogram also ascertains similar relationships between radon and other parameters. Further, the ratio between radon and thoron has been analyzed to determine the deep or shallow source of the radon emanation in the study area. These results revealed that the ratio radon/thoron enhanced during this period which indicates the deeper source contribution is prominent. Incidentally, all the local earthquakes occurred with a focal depth of 18-25 km at the lower crust in this region. We observed the rise in the concentrations of radon and the ratio radon/thoron at Badargadh station before the occurrence of the local earthquakes on 29th March 2011 (M 3.7) and 17th May 2011 (M 4.2). We clearly observed the radon level crossing the mean + 2*sigma level before the occurrence of these events. We conclude that these enhanced radon emissions are linked with alteration of the crustal stress/strain in this region as this observing station is near the epicenters of the earthquakes. We did not observe considerable variations in radon at the Desalpar station which is far from the earthquake location. PMID- 29396728 TI - Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1alpha (HIF 1alpha) in pancreatic adenocarcinoma. AB - HIF-1alpha is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1alpha is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1alpha stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1alpha by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1alpha did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P AscH- suppresses the levels of HIF-1alpha protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment. PMID- 29396730 TI - Nerve detection during surgery: optical spectroscopy for peripheral nerve localization. AB - Precise nerve localization is of major importance in both surgery and regional anesthesia. Optically based techniques can identify tissue through differences in optical properties, like absorption and scattering. The aim of this study was to evaluate the potential of optical spectroscopy (diffuse reflectance spectroscopy) for clinical nerve identification in vivo. Eighteen patients (8 male, 10 female, age 53 +/- 13 years) undergoing inguinal lymph node resection or resection or a soft tissue tumor in the groin were included to measure the femoral or sciatic nerve and the surrounding tissues. In vivo optical measurements were performed using Diffuse Reflectance Spectroscopy (400-1600 nm) on nerve, near nerve adipose tissue, muscle, and subcutaneous fat using a needle-shaped probe. Model-based analyses were used to derive verified quantitative parameters as concentrations of optical absorbers and several parameters describing scattering. A total of 628 optical spectra were recorded. Measured spectra reveal noticeable tissue specific characteristics. Optical absorption of water, fat, and oxy- and deoxyhemoglobin was manifested in the measured spectra. The parameters water and fat content showed significant differences (P < 0.005) between nerve and all surrounding tissues. Classification using k-Nearest Neighbor based on the derived parameters revealed a sensitivity of 85% and a specificity of 79%, for identifying nerve from surrounding tissues. Diffuse Reflectance Spectroscopy identifies peripheral nerve bundles. The differences found between tissue groups are assignable to the tissue composition and structure. PMID- 29396731 TI - Stage-specific approaches promote in vitro induction for spermatogenesis. AB - Spermatogenesis in vitro has been demonstrated using spermatogonial stem cells (SSCs) in monolayer culture or testis tissue fragments in agarose-constructed three-dimensional (3-D) conditions. However, the low efficiency of gamete maturation and the lack of a novel induction platform have limited the progress of its use in further research and clinical applications. Here, we provide modified stage-specific induction approaches for spermatogenesis in in vitro culture with cells possessing a totipotent status. With this stage-specific propagation in a monolayer condition and a changing cytokine combination, we obtained spermatogenic cells in the forward to late meiosis stages with haploid features. Based on this technical platform, we refined a novel serum-free culture system with various cytokines in 3-D Matrigel for spermatogenesis that promote totipotent embryonic stem cells to meiosis stage with distinct SCP3 expression. And we also explored the effects of coculture with fibroblasts, the mutual interactions in the induction conditions promote the mouse embryonic fibroblasts underwent stromal cells differentiation. In further overexpression of spermatogenic gene Dazl in mouse embryonic fibroblasts, we found early stage initiation for spermatogenesis, and that will enhanced if cocultured with embryonic stem cells in the induction condition. Our results provide alternative approaches for effective spermatogenesis and support the development of promising avenues for infertility therapies. PMID- 29396732 TI - Primary prophylaxis of variceal bleeding. PMID- 29396733 TI - Vector and Cell Line Engineering Technologies Toward Recombinant Protein Expression in Mammalian Cell Lines. AB - The rapid growth of global biopharmaceutical market in the recent years has been a good indication of its significance in biotechnology industry. During a long period of time in recombinant protein production from 1980s, optimizations in both upstream and downstream processes were launched. In this regard, one of the most promising strategies is expression vector engineering technology based on incorporation of DNA opening elements found in the chromatin border regions of vectors as well as targeting gene integration. Along with these approaches, cell line engineering has revealed convenient outcomes in isolating high-producing clones. According to the fact that more than 50% of the approved therapeutic proteins is being manufactured in mammalian cell lines, in this review, we focus on several approaches and developments in vector and cell line engineering technologies in mammalian cell culture. PMID- 29396734 TI - Formulation and Characterization of Fast-Dissolving Sublingual Film of Iloperidone Using Box-Behnken Design for Enhancement of Oral Bioavailability. AB - Iloperidone is a second-generation antipsychotic drug which is used for the treatment of schizophrenia and has very low aqueous solubility and bioavailability. This drug also undergoes first-pass metabolism. The aim of this work is to formulate fast-dissolving sublingual films of iloperidone to improve its bioavailability. Sublingual films were prepared by solvent casting method. Hydroxypropyl methyl cellulose E5, propylene glycol 400, and transcutol HP were optimized using Box-Behnken three-level statistical design on the basis of disintegration time and folding endurance of films. Iloperidone:hydroxypropyl beta-cyclodextrin kneaded complex was used in films instead of plain drug due to its low solubility. Optimized film was further evaluated for drug content, pH, dissolution studies, ex vivo permeation studies, and pharmacokinetic studies in rats. The optimized film disintegrated within 30 s. The in vitro dissolution of the film showed 80.3 +/- 3.4% drug dissolved within first 5 min. In ex vivo permeation studies using sublingual tissue, flux achieved within first 15 min by film was around 117.1 +/- 0.35 (mcg/cm2/h) which was ten times more than that of plain drug. This formulation showed excellent uniformity. AUC and Cmax of film were significantly higher (p < 0.001) as compared to plain drug and relative bioavailability of the films was 148% when compared to the plain drug. Thus, this study showed optimized fast-dissolving sublingual film to improve permeation and bioavailability of iloperidone. Fast-dissolving films will be customer-friendly approach for geadiatric schizophrenic patients. PMID- 29396736 TI - Editor's Note: Special Issue on the Life and Work of Donald Capps (1939-2015). PMID- 29396735 TI - Study of Nanoscale Friction Behaviors of Graphene on Gold Substrates Using Molecular Dynamics. AB - In this paper, we investigate the friction behaviors of graphene flakes sliding on a gold substrate using molecular dynamics simulations. The effects of flake size, flake shape, relative rotation angle between flake and substrate, and crystal orientation of substrate on the friction process are thoroughly studied. It is found that under the same load, the average friction forces per atom are smaller for a bigger graphene flake, which exhibits an obvious size effect. It is also shown that flake shape is critical in determining the friction in the sliding process. The average friction forces per atom for the square flake are much bigger than those for the triangular and round flakes. Moreover, the average friction forces per atom for the triangular flake are the smallest. We also find that the orientation of graphene flake relative to gold substrate plays a vital role in the friction process. The friction forces for the graphene flake sliding along the armchair direction are much bigger than those for the flakes with rotation. In addition, it is also found that single crystalline gold substrate exhibits a significant anisotropic effect of friction, which is attributed to the anisotropic effect of potential energy corrugation. These understandings not only shed light on the underlying mechanisms of graphene flake sliding on the gold substrates but also may guide the design and fabrication of nanoscale graphene based devices. PMID- 29396737 TI - Prenatal diagnosis of funisitis: two case reports. AB - Acute funisitis is characterized by the infiltration of fetal neutrophils from the umbilical vessels into Wharton's jelly and presents as fetal inflammation. However, no reports about its prenatal diagnosis using ultrasonography have been published. We encountered one case of oligohydramnios at 26 weeks and another case of threatened premature delivery at 27 weeks of gestation with ultrasonographic findings of non-uniform thickening of Wharton's jelly, a heterogeneous internal echo, and a high echoic line of the umbilical vessel wall. Acute funisitis was diagnosed, and the postpartum histopathological examination revealed severe funisitis in both cases. To our knowledge, this is the first case report of prenatal diagnosis of funisitis determined using ultrasonography. When we find such ultrasonographic features under the circumstances of intrauterine infection, severe funisitis should be included in the differential diagnosis. PMID- 29396739 TI - Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly. AB - The apolipoprotein E (APOE) epsilon4 and epsilon2 alleles are acknowledged genetic factors modulating Alzheimer's disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE epsilon2, epsilon3, and epsilon4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 epsilon2 carriers, 44 epsilon3 homozygotes, and 49 epsilon4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the epsilon3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the epsilon4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the epsilon2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the epsilon4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles. PMID- 29396738 TI - Pharmacokinetic and pharmacodynamic re-evaluation of a genetic-guided warfarin trial. AB - PURPOSE: A previous trial failed to demonstrate the superiority of a demographic genetic algorithm in predicting warfarin (W) dose over a standard clinical approach. The purpose of the present study is to re-analyse the results in subgroups of patients with differing baseline sensitivity to W, integrated with additional pharmacokinetic data. METHODS: The original trial allocated 180 treatment-naive patients with non-valvular atrial fibrillation to a control arm (CTL, n = 92) or a genetic-guided arm (GEN, n = 88). Before starting anticoagulation treatment, all patients were genotyped for CYP2C9, VKORC1 and CYP4F2 variants and classified into four quartiles (Q1, Q2, Q3, Q4) according to the algorithm-predicted W maintenance dose. International normalised ratios (INR) and plasma concentrations of S-warfarin [S-W]s and R-warfarin [R-W]s were measured at baseline and on days 5, 7, 9, 12, 15 and 19 of therapy. RESULTS: In the lowest dose quartile (Q1), the number of INRs > 3 and mean INR values on days 5 and 7 were significantly higher in CTL than in GEN. In Q3 and Q4, the mean INR values reached therapeutic level (> 2) 2 days later in CTL than in GEN. During follow-up, the mean time courses of INRs and [S-W]s in GEN were remarkably stable in all dose quartiles. Thus, mean changes from starting to final doses were significantly smaller in GEN than in CTL. Plasma concentrations of R-W (a partially active enantiomer) steadily increased from day 5 to day 19 in all Qs in both CTL and GEN, except in the Q1 CTL group, due to the marked dose reduction required. CONCLUSIONS: This analysis showed that the demographic-genetic algorithm used to predict the W dose can identify patients with differing degrees of sensitivity to W and to 'normalise' their average anticoagulant responses. The progressive rise in [R-W]s throughout the 19-day follow-up indicates that the (partial) contribution of R-W to the W anticoagulant effect changes continually during the early phase of treatment. PMID- 29396740 TI - The first records of human infestation by the hard tick Ixodes (Endopalpiger) australiensis (Acari: Ixodidae), with a review of human infestation by ticks in Australia. AB - The first record of human infestation and feeding by the native tick species Ixodes australiensis is reported in Australia based on a specimen collected from an adult male. Human infestation by ticks in Australia is reviewed and a concise list of anthropophagic ticks occurring in Australia is presented. PMID- 29396741 TI - Postdural puncture headache at Sylvanus Olympio University Hospital of Lome in Togo: incidence and risk factors. PMID- 29396742 TI - A review of diagnostic accuracy and clinical impact from the focused use of perioperative ultrasound. AB - PURPOSE: To perform a narrative review of the current trials examining the use of perioperative ultrasound to diagnose common issues related to the heart, lungs, stomach, and airway. METHOD: A review of the current literature was conducted in June 2017 on all trials involving ultrasound, including both surface and transesophageal ultrasound, in the perioperative period. The search included the terms 'ultrasonography', 'perioperative care', 'point-of-care', and 'bedside'. Trials were limited to human subjects with no language or time restrictions being applied. The results were then collected and a narrative review was completed with the available information. RESULTS: In total 1,176 reports of original investigation or systematic reviews were collected and reviewed. Of those 1,176 reports and reviews, a total of 80 original articles met the inclusion criteria for this review. Topics were broadly defined based on common themes emerging from the literature including cardiac disease, lung pathology (pneumothorax, pleural effusion, pulmonary edema, and pulmonary consolidation), volume and contents of the stomach, confirmation of endotracheal tube position, confirmation of lung isolation, and the application of ultrasound for guiding cricothyroidotomy. Where possible, the sensitivity and specificity of the trials are presented. Few trials reported on patient outcomes, although several discussed provider outcomes such as a change in anesthesia practice. In addition, trials reporting outcomes, although few in number, were included. CONCLUSION: Perioperative point-of-care ultrasound is a useful method for the diagnosis of many important perioperative conditions. The impact of this diagnostic approach on patient outcomes however remains to be determined. PMID- 29396743 TI - Price Transparency for Whom? In Search of Out-of-Pocket Cost Estimates to Facilitate Cost Communication in Cancer Care. PMID- 29396744 TI - Economic Evaluation of Direct-Acting Antivirals for Hepatitis C in Norway. AB - PURPOSE: New direct-acting antiviral (DAA) drugs have revolutionized the treatment of hepatitis C in recent years. OBJECTIVE: Our objective was to analyse the cost effectiveness of combinations of different DAAs compared with ribavirin and peginterferon-alpha-2a, taking into account rebates from tender negotiations. METHODS: We used a compartmental model specifically developed for Norway to simulate hepatitis C and complications with and without different DAAs. All costs were based on Norwegian fees and estimates, estimating healthcare sector costs for the year 2016. We performed Monte Carlo simulations on uncertain input parameters to facilitate probabilistic sensitivity analyses. RESULTS: For patients diagnosed with genotype 1, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost effective compared with eight other available alternatives, given a cost-effectiveness threshold of ?70,000 per quality adjusted life-year. For genotype 2, the combination of sofosbuvir and ribavirin was the most effective and cost-effective alternative for all patients. Among available alternatives for patients with genotype 3, sofosbuvir in combination with peginterferon and ribavirin was the most cost-effective alternative, although the combination of daclatasvir and sofosbuvir was somewhat more effective. CONCLUSIONS: For each of the hepatitis C genotypes 1, 2 and 3, there were combinations of DAAs that were cost effective in a Norwegian setting. As a result of recent tender negotiations in Norway, treating all diagnosed patients with hepatitis C with the most cost-effective DAAs will result in lower total expenditure on these medications compared with 2015. PMID- 29396745 TI - High-level recombinant production of squalene using selected Saccharomyces cerevisiae strains. AB - For recombinant production of squalene, which is a triterpenoid compound with increasing industrial applications, in microorganisms generally recognized as safe, we screened Saccharomyces cerevisiae strains to determine their suitability. A strong strain dependence was observed in squalene productivity among Saccharomyces cerevisiae strains upon overexpression of genes important for isoprenoid biosynthesis. In particular, a high level of squalene production (400 +/- 45 mg/L) was obtained in shake flasks with the Y2805 strain overexpressing genes encoding a bacterial farnesyl diphosphate synthase (ispA) and a truncated form of hydroxyl-3-methylglutaryl-CoA reductase (tHMG1). Partial inhibition of squalene epoxidase by terbinafine further increased squalene production by up to 1.9-fold (756 +/- 36 mg/L). Furthermore, squalene production of 2011 +/- 75 or 1026 +/- 37 mg/L was obtained from 5-L fed-batch fermentations in the presence or absence of terbinafine supplementation, respectively. These results suggest that the Y2805 strain has potential as a new alternative source of squalene production. PMID- 29396746 TI - Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234. AB - Tiancimycin (TNM) A, a recently discovered enediyne natural product from Streptomyces sp. CB03234, showed rapid and complete killing of cancer cells and could be used as a payload in antibody drug conjugates. The low yield of TNM A in the wild-type strain promoted us to use ribosome engineering and fermentation optimization for its yield improvement. The Streptomyces sp. CB03234-R-16 mutant strain with a L422P mutation in RpoB, the RNA polymerase beta-subunit, was obtained from the rifamycin-resistant screening. After fermentation optimization, the titers of TNM A in Streptomyces sp. CB03234-R-16 reached to 22.5 +/- 3.1 mg L 1 in shaking flasks, and 13 +/- 1 mg L-1 in 15 L fermentors, which were at least 40-fold higher than that in the wild-type strain (~ 0.3 mg L-1). Quantitative real-time RT-PCR revealed markedly enhanced expression of key genes encoding TNM A biosynthetic enzymes and regulators in Streptomyces sp. CB03234-R-16. Our study should greatly facilitate the future efforts to develop TNM A into a clinical anticancer drug. PMID- 29396748 TI - A decision support system for real-time scheduling of multiple patient classes in outpatient services. AB - We propose a methodology to provide real-time assistance for outpatient scheduling involving multiple patient types. Schedulers are shown how each prospective placement in the appointment book would impact a day's operational performance for patients and providers. Rooted in prior literature and analytical findings, the information provided to schedulers about vacant slots is based on the probabilities that the calling patient, the already-existing appointments, and the session-end time will be unduly delayed. The information is updated in real-time before and after every new booking; calculations are driven by each patient type's historical consultation times and no-show data, and implemented via a simulation tool based on the underlying analytical methodology. Our findings lead to practical guidelines for dynamically constructing templates that provide allowances for different consultation durations, service time variability, no-show rates, and provider-driven performance targets for patient waiting and provider overtime. Extensions to healthcare batch scheduling applications such as radiology, surgery, or chemotherapy-where patient mixes may be known in advance-are suggested as future research opportunities since avoiding session overtime and procedures' completion time delays involve similar considerations. PMID- 29396747 TI - Cook Your Samples: The Application of Microwave Irradiation in Speeding Up Biological Processes. AB - Classic and conventional procedures in molecular cloning are inherent compositions in modern molecular biological experiments and are frequently involved in daily laboratory activities. They take up the majority of the total time input in spite of the availability of well-designed specialized commercial kits. A similar situation is also in the field of biotechnology. Fortunately, microwave/ultrasonic irradiation has been found to be capable of speeding up these processes, such as proteolysis in sample preparation for proteomics research, and digestion, ligation, (de)phosphorylation of DNA with the corresponding enzymes, even the introduction of DNA samples to recipient cells, and biotransformation (e.g., the production of biodiesel). Microwave/ultrasonic irradiation, when used solely or in combination with other existing operations, makes it possible to finish these time-consuming processes in as short as 1 min with comparable or even improved efficiency, and there is no need of reagent upgradation. The adoption of irradiation is ideal because it eliminates any possible side effects of the chemicals used as performance enhancer(s) that will inevitably make the system more complicated at least. More notably, the needed irradiation in the laboratory can be generated by a common microwave oven or ultrasonic cleaner. Taken together, microwave/ultrasonic irradiation provides an accessible method to make the procedures mentioned above time- and cost- efficient. In this article, we reviewed the relevant literature and discussed the experiment and mechanism details. PMID- 29396749 TI - Neuroticism Magnifies the Detrimental Association between Social Media Addiction Symptoms and Wellbeing in Women, but Not in Men: a three-Way Moderation Model. AB - Addiction symptoms in relation to the use of social networking sites (SNS) can be associated with reduced wellbeing. However, the mechanisms that can control this association have not been fully characterized, despite their relevance to effective treatment of individuals presenting SNS addiction symptoms. In this study we hypothesize that sex and neuroticism, which are important determinants of how people evaluate and respond to addiction symptoms, moderate this association. To examine these assertions, we employed hierarchical linear and logistic regression techniques to analyze data collected with a cross-sectional survey of 215 Israeli college students who use SNS. Results lend support to the hypothesized negative association between SNS addiction symptoms and wellbeing (as well as potentially being at-risk for low mood/ mild depression), and the ideas that (1) this association is augmented by neuroticism, and (2) that the augmentation is stronger for women than for men. They demonstrated that the sexes may differ in their SNS addiction-wellbeing associations: while men had similar addiction symptoms -wellbeing associations across neuroticism levels, women with high levels of neuroticism presented much steeper associations compared to women with low neuroticism. This provides an interesting account of possible "telescoping effect", the idea that addicted women present a more severe clinical profile compared to men, in the case of technology-"addictions". PMID- 29396750 TI - Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography. AB - PURPOSE: Manganese ion has been extensively used as a magnetic resonance imaging (MRI) contrast agent in preclinical studies to assess tissue anatomy, function, and neuronal connectivity. Unfortunately, its use in human studies has been limited by cellular toxicity and the need to use a very low dose. The much higher sensitivity of positron emission tomography (PET) over MRI enables the use of lower concentrations of manganese, potentially expanding the methodology to humans. PROCEDURES: PET tracers manganese-51 (Mn-51, t1/2 = 46 min) and manganese 52 (Mn-52, t1/2 = 5.6 days) were used in this study. The biodistribution of manganese in animals in the brain and other tissues was studied as well as the uptake in the pancreas after glucose stimulation as a functional assay. Finally, neuronal connectivity in the olfactory pathway following nasal administration of the divalent radioactive Mn-52 ([52Mn]Mn2+) was imaged. RESULTS: PET imaging with the divalent radioactive Mn-51 ([51Mn]Mn2+) and [52Mn]Mn2+ in both rodents and monkeys demonstrates that the accumulation of activity in different organs is similar to that observed in rodent MRI studies following systemic administration. Furthermore, we demonstrated the ability of manganese to enter excitable cells. We followed activity-induced [51Mn]Mn2+ accumulation in the pancreas after glucose stimulation and showed that [52Mn]Mn2+ can be used to trace neuronal connections analogous to manganese-enhanced MRI neuronal tracing studies. CONCLUSIONS: The results were consistent with manganese-enhanced MRI studies, despite the much lower manganese concentration used for PET (100 mM Mn2+ for MRI compared to ~ 0.05 mM for PET). This indicates that uptake and transport mechanisms are comparable even at low PET doses. This helps establish the use of manganese-based radiotracers in both preclinical and clinical studies to assess anatomy, function, and connectivity. PMID- 29396751 TI - Cue quality and criterion setting in recognition memory. AB - Previous studies on how people set and modify decision criteria in old-new recognition tasks (in which they have to decide whether or not a stimulus was seen in a study phase) have almost exclusively focused on properties of the study items, such as presentation frequency or study list length. In contrast, in the three studies reported here, we manipulated the quality of the test cues in a scene-recognition task, either by degrading through Gaussian blurring (Experiment 1) or by limiting presentation duration (Experiment 2 and 3). In Experiments 1 and 2, degradation of the test cue led to worse old-new discrimination. Most importantly, however, participants were more liberal in their responses to degraded cues (i.e., more likely to call the cue "old"), demonstrating strong within-list, item-by-item, criterion shifts. This liberal response bias toward degraded stimuli came at the cost of increasing the false alarm rate while maintaining a constant hit rate. Experiment 3 replicated Experiment 2 with additional stimulus types (words and faces) but did not provide accuracy feedback to participants. The criterion shifts in Experiment 3 were smaller in magnitude than Experiments 1 and 2 and varied in consistency across stimulus type, suggesting, in line with previous studies, that feedback is important for participants to shift their criteria. PMID- 29396752 TI - Topography of activation deficits in schizophrenia during P300 task related to cognition and structural connectivity. AB - BACKGROUND: The study of cerebral underpinnings of schizophrenia may benefit from the high temporal resolution of electromagnetic techniques, but its spatial resolution is low. However, source imaging approaches such as low-resolution brain electromagnetic tomography (LORETA) allow for an acceptable compromise between spatial and temporal resolutions. METHODS: We combined LORETA with 32 channels and 3-Tesla diffusion magnetic resonance (Dmr) to study cerebral dysfunction in 38 schizophrenia patients (17 first episodes, FE), compared to 53 healthy controls. The EEG was acquired with subjects performing an odd-ball task. Analyses included an adaptive window of interest to take into account the interindividual variability of P300 latency. We compared source activation patters to distractor (P3a) and target (P3b) tones within- and between-groups. RESULTS: Patients showed a reduced activation in anterior cingulate and lateral and medial prefrontal cortices, as well as inferior/orbital frontal regions. This was also found in the FE patients alone. The activation was directly related to IQ in the patients and controls and to working memory performance in controls. Symptoms were unrelated to source activation. Fractional anisotropy in the tracts connecting lateral prefrontal and anterior cingulate regions predicted source activation in these regions in the patients. CONCLUSIONS: These results replicate the source activation deficit found in a previous study with smaller sample size and a lower number of sensors and suggest an association between structural connectivity deficits and functional alterations. PMID- 29396755 TI - New perspectives to improve critical care benchmarking. PMID- 29396754 TI - Robotic versus laparoscopic distal pancreatectomy: a French prospective single center experience and cost-effectiveness analysis. AB - BACKGROUND: Benefits and cost-effectiveness of robotic approach for distal pancreatectomy (DP) remain debated. In this prospective study, we aim to compare the short-term results and real costs of robotic (RDP) and laparoscopic distal pancreatectomy (LDP). METHODS: From 2011 until 2016, all consecutive patients underwent minimally invasive DP were included and data were prospectively collected. Patients were assigned in two groups, RDP and LDP, according to the availability of the Da Vinci(r) Surgical System for our Surgical Unit. RESULTS: A minimally invasive DP was performed in 38 patients with a median age of 61 years old (44-83 years old) and a BMI of 26 kg/m2 (20-31 kg/m2). RDP group (n = 15) and LDP group (n = 23) were comparable concerning demographic data, BMI, ASA score, comorbidities, malignant lesions, lesion size, and indication of spleen preservation. Median operative time was longer in RDP (207 min) compared to LDP (187 min) (p = 0.047). Conversion rate, spleen preservation failure, and perioperative transfusion rates were nil in both groups. Pancreatic fistula was diagnosed in 40 and 43% (p = 0.832) of patients and was grade A in 83 and 80% (p = 1.000) in RDP and LDP groups, respectively. Median postoperative hospital stay was similar in both groups (RDP: 8 days vs. LDP: 9 days, p = 0.310). Major complication occurred in 7% in RDP group and 13% in LDP group (p = 1.000). Ninety days mortality was nil in both groups. No difference was found concerning R0 resection rate and median number of retrieved lymph nodes. Total cost of RDP was higher than LDP (13611 vs. 12509 ?, p < 0.001). The difference between mean hospital incomes and costs was negative in RDP group contrary to LDP group (- 1269 vs. 1395 ?, p = 0.040). CONCLUSION: Short-term results of RDP seem to be similar to LDP but the high cost of RDP makes this approach not cost-effective actually. PMID- 29396753 TI - Tobacco smoking is associated with antipsychotic medication, physical aggressiveness, and alcohol use disorder in schizophrenia: results from the FACE SZ national cohort. AB - Tobacco smoking is common in schizophrenia and is one of the main causes of premature mortality in this disorder. Little is known about clinical correlates and treatments associated with tobacco smoking in patients with schizophrenia. Still, a better characterization of these patients is necessary, in a personalized care approach. Aggressiveness and childhood trauma have been associated with tobacco smoking in general population, but this association has never been explored in schizophrenia. Our study examines the clinical and therapeutic characteristics of tobacco smoking in schizophrenia. 474 stabilized patients (mean age = 32.2; 75.7% male gender; smokers n = 207, 54.6%) were consecutively included in the network of the FondaMental Expert centers for Schizophrenia and assessed with valid scales. Current tobacco status was self declared. Aggressiveness was self-reported with Buss-Perry Aggressiveness Questionnaire and Childhood Trauma with Childhood Trauma Questionnaire. Ongoing treatment was reported. In univariate analysis, tobacco smoking was associated with lower education level (p < 0.01), positive syndrome (p < 0.01), higher physical aggressiveness (p < 0.001), alcohol dependence (p < 0.001), and First Generation Antipsychotics (FGAs) use (p = 0.018). In a multivariate model, tobacco smoking remained associated with physical aggressiveness (p < 0.05), current alcohol dependence (p < 0.01) and FGA use (p < 0.05). No association was observed with childhood trauma history, mood disorder, suicidal behavior, psychotic symptom, global functioning or medication adherence. Patients with tobacco use present clinical and therapeutic specificities, questioning the neurobiological links between tobacco and schizophrenia. They could represent a specific phenotype, with specific clinical and therapeutic specificities that may involve interactions between cholinergic-nicotinic system and dopaminergic system. Further longitudinal studies are needed to confirm the potential efficacy of second generation antipsychotics (SGAs) on tobacco use in schizophrenia and to develop effective strategies for tobacco cessation in this population. PMID- 29396756 TI - Pre-hospital management of pediatric polytrauma during modern conflict: experience and limits of the French military health service. AB - BACKGROUND: French military physicians serving in deployment are confronted with pediatric polytrauma patients (PPP) during the provision of medical aid to civilian populations. The objectives of this study were to describe the current care of PPPs during these missions, to report difficulties encountered and to evaluate the training of doctors for management of PPPs in the field. METHODS: A descriptive epidemiological study based on a questionnaire sent to physicians who had been deployed overseas. RESULTS: 91 doctors participated. Their mean age was 35 years. 86% of the doctors managed children whilst serving overseas, of which 54% were PPPs. The incidence of pediatric polytrauma varied according to the country, but overall from 1129 emergencies reported during overseas missions, 11% were PPPs. Penetrating traumas represented 37% of cases; 24% were circulatory distress and 19% were massive bleeding. 80% of the doctors reported a lack of pediatric trauma experience, less than 5% had received appropriate in-service training and only 9% had worked in pediatric emergency facilities in France. The equipment available for PPPs in the field was often poorly understood and frequently considered to be insufficient. CONCLUSIONS: The occurrence of PPPs of war is rare and complex, but care of older children it is similar to that required for adults. Preparation for PPP management, it could be optimized by identifying risks which alter depending on the country of deployment, such as the logistical organization of the battlefield chain of care. Improvements in doctors' pediatric trauma training should be individualized, based on their mission needs. LEVEL OF EVIDENCE: III. PMID- 29396757 TI - Epidemiology of open tibia fractures in a population-based database: update on current risk factors and clinical implications. AB - BACKGROUND: Open tibia fractures usually occur in high-energy mechanisms and are commonly associated with multiple traumas. The purposes of this study were to define the epidemiology of open tibia fractures in severely injured patients and to evaluate risk factors for major complications. METHODS: A cohort from a nationwide population-based prospective database was analyzed (TraumaRegister DGU(r)). Inclusion criteria were: (1) open or closed tibia fracture, (2) Injury Severity Score (ISS) >= 16 points, (3) age >= 16 years, and (4) survival until primary admission. According to the soft tissue status, patients were divided either in the closed (CTF) or into the open fracture (OTF) group. The OTF group was subdivided according to the Gustilo/Anderson classification. Demographic data, injury mechanisms, injury severity, surgical fracture management, hospital and ICU length of stay and systemic complications (e.g., multiple organ failure (MOF), sepsis, mortality) were collected and analyzed by SPSS (Version 23, IBM Inc., NY, USA). RESULTS: Out of 148.498 registered patients between 1/2002 and 12/2013; a total of 4.940 met the inclusion criteria (mean age 46.2 +/- 19.4 years, ISS 30.4 +/- 12.6 points). The CTF group included 2000 patients (40.5%), whereas 2940 patients (59.5%) sustained open tibia fractures (I degrees : 49.3%, II degrees : 27.5%, III degrees : 23.2%). High-energy trauma was the leading mechanism in case of open fractures. Despite comparable ISS and NISS values in patients with closed and open tibia fractures, open fractures were significantly associated with higher volume resuscitation (p < 0.001), more blood (p < 0.001), and mass transfusions (p = 0.006). While the rate of external fixation increased with the severity of soft tissue injury (37.6 to 76.5%), no major effect on mortality and other major complications was observed. CONCLUSION: Open tibia fractures are common in multiple trauma patients and are therefore associated with increased resuscitation requirements, more surgical procedures and increased in-hospital length of stay. However, increased systemic complications are not observed if a soft tissue adapted surgical protocol is applied. PMID- 29396758 TI - Insulin sensitivity and secretion and adipokine profile in patients with Cushing's disease treated with pasireotide. AB - PURPOSE: To evaluate the effect of pasireotide on beta-cell and adipose function in patients with Cushing's disease (CD). METHODS: Clinical and hormonal parameters, insulin secretion evaluated by HOMA-beta and by the area under the curve (AUC2h) of C-peptide during a mixed meal tolerance test and insulin sensitivity, evaluated by the euglycaemic hyperinsulinaemic clamp, were evaluated in 12 patients with active CD, before and after 6 and 12 months of pasireotide. In addition, a panel of adipokines including leptin (Ob), leptin/leptin receptor ratio (Ob/Ob-R ratio), adiponectin, resistin, visfatin, adipocyte fatty acid binding protein (AFABP) and non-esterified fatty acids (NEFAs) was evaluated at baseline and after 12 months of pasireotide. RESULTS: During 12 months of pasireotide treatment, a significant decrease in weight (p = 0.004), BMI (p = 0.008), waist circumference (p = 0.009), urinary free cortisol (p = 0.007), fasting insulinaemia (p = 0.007), HOMA-beta (p = 0.015) and AUC2h c-peptide (p = 0.017), concomitance with an increase in fasting glycaemia (p = 0.015) and HbA1c (p = 0.030), was found. With regard to adipokines, a significant decrease in Ob (p = 0.039), Ob/Ob-R ratio (p = 0.017) and AFABP (p = 0.036) was observed concomitant with a significant increase in Ob-R (p = 0.028) after 12 months of pasireotide. CONCLUSIONS: 12 months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity. PMID- 29396759 TI - Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect. AB - PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 +/- 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect. PMID- 29396760 TI - Interventions to improve endocrine therapy adherence in breast cancer survivors: what is the evidence? AB - PURPOSE: Endocrine therapy reduces the risk of breast cancer recurrences and mortality in hormone receptor-positive (HR+) breast cancer survivors. However, non-adherence to treatment remains a significant problem. The aim of this study was to review current literature and ongoing trials to identify interventions employed to improve adherence to adjuvant endocrine therapy (AET) in breast cancer survivors. METHODS: We searched PubMed and the National Library of Medicine registry of clinical trials using the terms "breast cancer" and "adherence" or "compliance" and "intervention" and "medication" or "endocrine therapy" or "hormone therapy" to identify published studies as well as ongoing clinical trials. RESULTS: Three hundred and sixty-three studies were identified; five studies met the inclusion criteria. Most studies enrolled postmenopausal women diagnosed with early stage HR+ breast cancer. Providing educational materials was the most common intervention implemented to improve adherence to one or more aromatase inhibitors. None of the studies found a significant improvement in adherence with the intervention evaluated. Twelve clinical trials investigating various interventions, mostly based on technology, to improve AET adherence were also identified. CONCLUSIONS: Improving adherence to AET in HR+ breast cancer survivors is an urgent medical need. While newer clinical trials are overcoming some of the limitations seen with published studies, tailored interventions led by clinicians need further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Our study highlights the unmet clinical need to develop and test feasible interventions to improve AET adherence in HR+ breast cancer survivors to extend their long-term survival. PMID- 29396761 TI - Integrative Data Analysis of Gender and Ethnic Measurement Invariance in Nicotine Dependence Symptoms. AB - Little research has evaluated whether conflicting evidence for gender and racial/ethnic differences in nicotine dependence (ND) may be attributed to differences in psychometric properties of ND symptoms, particularly for young Hispanic smokers. Inadequate racial/ethnic diversity and limited smoking exposure variability has hampered research in young smokers. We used integrative data analysis (IDA) to pool DSM-IV ND symptom data for current smokers aged 12-25 (N = 20,328) from three nationally representative surveys (1999, 2000 National Surveys on Drug Use and Health (NSDUH) and Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Moderated nonlinear factor analysis (MNLFA) tested symptom measurement invariance in the pooled sample containing greater ethnic and smoking exposure variability. There was study noninvariance for most symptoms. NESARC participants were more likely to report tolerance, using larger amounts or for longer periods, inability to cut down/quit, and more time spent smoking at higher levels of ND severity, but reported emotional/physical health problems at lower ND severity. Four symptoms showed gender or race/ethnicity noninvariance, but observed differences were small. An ND severity factor score adjusting for symptom noninvariance related to study membership, gender, and race/ethnicity did not differ substantively from traditional DSM-IV diagnosis and number of endorsed symptoms in estimated gender and race/ethnicity differences in ND. Results were consistent with studies finding minimal gender and racial/ethnic differences in ND, and suggest that symptom noninvariance is not a major contributor to observed differences. Results support IDA as a potentially promising approach for testing novel ND hypotheses not possible in independent studies. PMID- 29396762 TI - Stable Single-Mode Operation of Distributed Feedback Quantum Cascade Laser by Optimized Reflectivity Facet Coatings. AB - In this work, quantum cascade lasers (QCLs) based on strain compensation combined with two-phonon resonance design are presented. Distributed feedback (DFB) laser emitting at ~ 4.76 MUm was fabricated through a standard buried first-order grating and buried heterostructure (BH) processing. Stable single-mode emission is achieved under all injection currents and temperature conditions without any mode hop by the optimized antireflection (AR) coating on the front facet. The AR coating consists of a double layer dielectric of Al2O3 and Ge. For a 2-mm laser cavity, the maximum output power of the AR-coated DFB-QCL was more than 170 mW at 20 degrees C with a high wall-plug efficiency (WPE) of 4.7% in a continuous-wave (CW) mode. PMID- 29396763 TI - Dose-dependent effect of fluoride on clinical and subclinical indices of fluorosis in school going children and its mitigation by supply of safe drinking water for 5 years: an Indian study. AB - Fluorosis is a public health problem in India; to know its prevalence and severity along with its mitigation measures is very important. The present study has been undertaken with the aim to assess the F dose-dependent clinical and subclinical symptoms of fluorosis and reversal of the disease by providing safe drinking water. For this purpose, a cross-sectional study was undertaken in 1934 schoolgoing children, Nalgonda district. Study villages were categorized into control (category I, F = 0.87 mg/L), affected (category II, F = 2.53 mg/L, and category III, F = 3.77 mg/L), and intervention categories (category IV, F = < 1.0 mg/L). School children were enrolled for dental grading by modified Dean Index criteria. Anthropometric measurements (height and weight) were used to assess nutritional status of the children. The biochemical parameters like serum T3, T4, TSH, PTH, ALP, 25-OH vitamin D, and 1,25-(OH)2 vitamin D were analyzed. The results showed a positive correlation between the drinking water and urinary fluoride (UF) in different categories. However, there was a significant decrease in the UF levels in the intervention category IV compared to affected group (category III). Fluoride altered the clinical (dental fluorosis and stunting) and subclinical indices (urine and blood) of fluorosis in a dose-dependent manner. In conclusion, the biochemical indices were altered in a dose-dependent manner and intervention with safe drinking water for 5 years in intervention group-mitigated clinical and subclinical symptoms of fluorosis. PMID- 29396764 TI - Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients. AB - BACKGROUND: Elf5 is a transcription factor previously shown to be involved in regulating cell differentiation in both normal and pathological breast tissues. Pertinently, Elf5 was reported to interact with the FOXA1 transcription factor, a pivotal regulatory factor in a subset of AR overexpressing triple negative cancer (TNBC) cases. METHODS: We examined the correlation among AR, FOXA1, and Elf5 expression in a series of TNBC cases. The cases were retrieved from surgical pathological files of Tohoku University Hospital Japan and consisted of 60 cases operated between the year 1999 and 2007. An additional cohort cases of 51 TNBC ductal carcinoma in situ was used to compare invasive and non-invasive TNBC. RESULTS: In our cohort, 47% of all carcinomas were positive for Elf5, with a significantly higher proportion of Elf5 positive cases occurring in the younger age groups (p = 0.0061). Elf5 immunoreactivity was not associated with any other clinicopathological factors examined in this study. However, Elf5 expression was associated with decreased overall and disease-free survival of the patients (Peto Peto modification of Gehan-Wilcoxon test, OS p = 0.132, DFS p = 0.1 (LI cutoff 10%); OS p = 0.038, DFS p = 0.021 (LI cutoff 50%)). Of particular interest, its effects on survival were more pronounced in the EGFR-/CK5/6- (non-basal surrogate) than the EGFR+ and/or CK5/6+ (basal-surrogate) subtype of TNBC. CONCLUSIONS: Elf5 is present in TNBC and its status was significantly correlated with overall survival of the patients. Further studies examining possible interactions between Elf5 and other factors in TNBC could contribute to disentangling TNBC biology. PMID- 29396765 TI - The evaluation of lumbar paraspinal muscle quantity and quality using the Goutallier classification and lumbar indentation value. AB - PURPOSE: The cross-sectional area and fat infiltration are accepted as standard parameters for quantitative and qualitative evaluation of muscle degeneration. However, they are time-consuming, which prevents them from being used in a clinical setting. The aim of this study was to analyze the relationship between lumbar muscle degeneration and spinal degenerative disorders, using lumbar indentation value (LIV) as quantitative and Goutallier classification as qualitative measures. METHODS: This is a retrospective analysis of kinematic magnetic resonance images (kMRI). Two-hundred and thirty patients with kMRIs taken in weight-bearing positions were selected randomly. The LIV and Goutallier classification were evaluated at L4-5. The correlation of these two parameters with patients' age, gender, lumbar lordosis (LL), range of motion, disc degeneration, disc height, and Modic change were analyzed. RESULTS: There was no significant trend of LIV among the different grades of Goutallier classification (p = 0.943). There was a significant increase in age with higher grades of Goutallier classification (p < 0.001). In contrast, there was no correlation between LIV and age (p = 0.799). The Goutallier classification positively correlated with LL (r = 0.377) and severe disc degeneration (r = 0.249). The LIV positively correlated with LL (r = 0.476) and degenerative spondylolisthesis (r = 0.184). Multinomial logistic regression analysis showed that age (p = 0.026), gender (p = 0.003), and LIV (p < 0.001) were significant predictors for patients with low LL (< 10 degrees ). CONCLUSION: Lumbar muscle quantity and quality showed specific correlation with age and spine disorders. Additionally, LL can be predicted by the muscle quantity, but not the quality. These time-saving evaluation tools potentially accelerate the study of lumbar muscles. These slides can be retrieved under Electronic Supplementary Material. PMID- 29396767 TI - Correction to: A method to quantify the "cone of economy". AB - Unfortunately, in the abstract at the results section units have been published incorrectly. PMID- 29396766 TI - Analysis of cervical sagittal alignment variations after lumbar pedicle subtraction osteotomy for severe imbalance: study of 59 cases. AB - OBJECTIVE: To evaluate postoperative changes within the cervical alignment following surgical lumbar correction by pedicle subtraction osteotomy (PSO) in patients affected with sagittal global malalignment disease. METHODS: This was a monocentric, radiographic, and prospective study. 79 patients, who underwent sagittal correction by PSO, performed an EOS imaging pre- and postoperatively between January 2008 and December 2013 at the University Hospital of Bordeaux. Inclusion criteria were a performed pre- and postoperative EOS imaging and a preoperative C7SVA > 5 cm. Were excluded patients who did not allow EOS with a viewable cervical spine due to hyperkyphosis. The study involved the analysis of pelvic, lumbar, thoracic, cervical, and cranial parameters before and after the surgery. RESULTS: 59 patients met the criteria. Mean follow-up was 38 months. The lumbar PSO significantly improved sagittal alignment including L1S1 lordosis, T1T12 kyphosis, and C7SVA (p < 0.001). We did not reported a significant change within cervical parameters after PSO (C2C7 lordosis 22.7 degrees -21.5 degrees p = 0.64, C1C7 lordosis 50.6 degrees -48.8 degrees p = 0.56, C1C2 angle 28.2 degrees -27.9 degrees p = 0.82, C7 slope stayed constant 32.3 degrees -30.5 degrees p = 0.47, OC2 angle 15.54 degrees -15.56 degrees p = 0.99). However, cranial slope decreased significantly (p < 0.05). We did not find correlation between lumbar lordosis and cervical lordosis variations (R = 0.265). Cervical lordosis was highly correlated with the C7 slope (R = 0.597) and with the Spino Cranial Angle (R = - 0.867). CONCLUSION: Reciprocal changes in cervical spine after PSO are difficult to approach. Maintaining a horizontal gaze involves locoregional mechanisms of compensation adapting to the slope of C7. The cranial system by decreasing the cranial slope allows the gaze alignment and is the first compensation mechanism to get involved after a loss of lumbar lordosis. Restoring optimal C7SVA is necessary to prevent the development of secondary cervical painful symptomatology when the cranial compensation is outdated. PMID- 29396768 TI - The relationship between medical expenses and the severity of peripheral arterial disease in Japan. AB - The main objective is to examine whether the severity of peripheral arterial disease (PAD) affects the expenses and hospital stay of the patients who undergo bypass surgery below the inguinal ligament for PAD. Eighty consecutive patients who underwent infrainguinal bypass surgery for PAD between January 2012 and December 2014 were included in the study. Patients were divided into groups according to their critical limb ischemia (CLI) symptoms and the Wound, Ischemia, and Foot Infection (WIfI) classification. As endpoints, we assessed the duration of postoperative hospital stay and expenses during hospitalization. CLI was a significant factor for longer hospital stay and increased medical expenses (p = 0.009 and p = 0.001). In the patients with CLI, significant factors for longer hospital stay and increased medical expenses were (1) history of distal bypass (p = 0.33 and p = 0.003, respectively) and stage 4 local lower limb status in WIfI classification (p = 0.0007 and p = 0.053). PAD severity was associated with prolonged postoperative hospital stay and increased medical expenses. The presence or absence of CLI and its severity according to the WIfI classification correlated with medical expenses and hospital stay duration between the milder and severe groups. PMID- 29396769 TI - Right minithoracotomy versus conventional median sternotomy for patients undergoing mitral valve surgery and Cox-maze IV ablation with entirely bipolar radiofrequency clamp. AB - Cox-maze IV ablation by bipolar radiofrequency clamp was considered to be only performed through median sternotomy (MS), but impossible through right minithoracotomy (RM). Now, we developed a novel technique of performing Cox-maze IV ablation entirely by bipolar clamp through RM. To compare the outcomes of RM or MS for patients undergoing mitral valve surgery and concomitant Cox-maze IV ablation with entirely bipolar clamp. All 152 patients underwent mitral valve surgery and concomitant Cox-maze IV ablation with bipolar clamp through RM (n = 69) or MS (n = 83) were analyzed for outcome differences. The etiology of mitral valve disease was rheumatic (n = 97) and degenerative (n = 55). All patients had long-standing persistent atrial fibrillation (AF). Diameter of left atrium ranged from 42 to 60 mm. All patients successfully underwent Cox-maze IV ablation by bipolar clamp. RM group had longer cardiopulmonary bypass time (130.3 +/- 17.7 vs 115.3 +/- 14.4 min; P < 0.001) and aortic cross-clamp time (91.8 +/- 12.7 vs 74.6 +/- 9.3 min; P < 0.001). But mechanical ventilation time (14.2 +/- 6.6 vs 21.3 +/ 9.0 h; P < 0.001) and hospital length of stay (9.3 +/- 2.6 vs 11.7 +/- 3.0 days; P < 0.001) were shorter in RM group. At discharge, the maintenance of normal sinus rhythm (NSR) was 94.2% in RM group and 95.1% in MS group (P = 1.000). Cumulative maintenance of NSR at 2 years postoperatively was 85.1 +/- 5.8% in RM group and 88.6 +/- 3.6% in MS group (P = 0.767). RM can achieve similar therapeutic effect to MS for patients undergoing mitral valve surgery and concomitant Cox-maze IV ablation with entirely bipolar clamp. In addition, patients through RM had faster recovery. PMID- 29396770 TI - Simultaneous detection of intra- and inter-molecular paramagnetic relaxation enhancements in protein complexes. AB - Paramagnetic relaxation enhancement (PRE) measurements constitute a powerful approach for detecting both permanent and transient protein-protein interactions. Typical PRE experiments require an intrinsic or engineered paramagnetic site on one of the two interacting partners; while a second, diamagnetic binding partner is labeled with stable isotopes (15N or 13C). Multiple paramagnetic labeled centers or reversed labeling schemes are often necessary to obtain sufficient distance restraints to model protein-protein complexes, making this approach time consuming and expensive. Here, we show a new strategy that combines a modified pulse sequence (1HN-Gamma2-CCLS) with an asymmetric labeling scheme to enable the detection of both intra- and inter-molecular PREs simultaneously using only one sample preparation. We applied this strategy to the non-covalent dimer of ubiquitin. Our method confirmed the previously identified binding interface for the transient di-ubiquitin complex, and at the same time, unveiled the internal structural dynamics rearrangements of ubiquitin upon interaction. In addition to reducing the cost of sample preparation and speed up PRE measurements, by detecting the intra-molecular PRE this new strategy will make it possible to measure and calibrate inter-molecular distances more accurately for both symmetric and asymmetric protein-protein complexes. PMID- 29396772 TI - Identification of Characteristic Macromolecules of Escherichia coli Genotypes by Atomic Force Microscope Nanoscale Mechanical Mapping. AB - The categorization of microbial strains is conventionally based on the molecular method, and seldom are the morphological characteristics in the bacterial strains studied. In this research, we revealed the macromolecular structures of the bacterial surface via AFM mechanical mapping, whose resolution was not only determined by the nanoscale tip size but also the mechanical properties of the specimen. This technique enabled the nanoscale study of membranous structures of microbial strains with simple specimen preparation and flexible working environments, which overcame the multiple restrictions in electron microscopy and label-enable biochemical analytical methods. The characteristic macromolecules located among cellular surface were considered as surface layer proteins and were found to be specific to the Escherichia coli genotypes, from which the averaged molecular sizes were characterized with diameters ranging from 38 to 66 nm, and the molecular shapes were kidney-like or round. In conclusion, the surface macromolecular structures have unique characteristics that link to the E. coli genotype, which suggests that the genomic effects on cellular morphologies can be rapidly identified using AFM mechanical mapping. Graphical Abstract Quantification of surface macromolecules of E. coli cells using AFM mechanical mapping. Surface macromolecules of cellular surface of three E. coli genotypes, MG1655, CFT073, and RS218, were characterized with the sizes ranging from 38 to 66 nm and with round or kidney-like shapes. The topography images were colored with adhesion mapping with the scale bars = 200 nm. PMID- 29396771 TI - Effect of Atmospheric PM2.5 on Expression Levels of NF-kappaB Genes and Inflammatory Cytokines Regulated by NF-kappaB in Human Macrophage. AB - Exposure to PM2.5 induces systemic inflammation, and the NF-kappaB signaling pathway plays an important role in the inflammation process. We aim to clarify whether the expression of NF-kappaB gene family affects inflammation caused by PM2.5. Human monocytic cells (THP-1) were induced to differentiate into macrophages using phorbol myristate acetate. The macrophages were then treated with 100, 200, and 400 MUg/ml of PM2.5 for 12, 24, and 48 h, respectively. Then, we determined the survival rate of macrophages through the MTT assay. The TNF alpha and CRP levels in the cell culture medium were measured through enzyme linked immunosorbent assay. The NF-kappaB1, NF-kappaB2, RelA, RelB, and Rel mRNA levels in macrophages were measured with reverse transcriptase-polymerase chain reaction. As a consequence, the survival rate of macrophages decreased with increasing PM2.5 exposure time and dose. The TNF-alpha levels in PM2.5-treated groups were lower as compared with the control group and in contrast to the NF kappaB mRNA levels at all exposure times. The TNF-alpha level in the 400-MUg/ml group and the NF-kappaB1, NF-kappaB2, RelB, and Rel mRNA levels in all PM2.5 treated groups were found to be higher at 24 h than at 12 h. Furthermore, the TNF alpha, CRP, and NF-kappaB2 mRNA levels in the group treated with 400 MUg/ml PM2.5 were higher at 48 h that at 12 and 24 h. On the other hand, the NF-kappaB1, RelA, RelB, and Rel mRNA levels in all PM2.5-treated groups were lower as compared to levels of TNF-alpha, CRP, and NF-kappaB2 mRNA. The levels of NF-kappaB genes and inflammatory cytokines demonstrated different correlations at different exposure times. Therefore, we conclude that PM2.5 reduces the survival rate of macrophages. As macrophages are exposed to PM2.5, the NF-kappaB gene family expression is increased, which subsequently affects inflammatory factor levels. PMID- 29396773 TI - Dolutegravir in pregnancy-effects on HIV-positive women and their infants. AB - The development of new drugs for treatment of HIV has increased the efficacy and the quality of life together with decreased unwanted side-effect for people living with HIV. The integrase inhibitor dolutegravir has in short time become part of the first-line treatment in many countries, but is not a recommended first-line drug in pregnancy. As there are few publications of dolutegravir use during pregnancy, we found it valuable to analyze the Stockholm pregnancy cohort. A retrospective analysis of all pregnant women and their infants exposed to dolutegravir at Karolinska University Hospital, 2014-August 2017. Information about maternal health, treatment, pregnancy, and child outcome were collected. Thirty-six women with singleton pregnancies were included. Four early spontaneous abortions occurred. One late termination was performed and one was lost to follow up. Fourteen were on dolutegravir before and 22 started during pregnancy. Eighteen delivered by caesarean section, three of them because of HIV RNA > 50 copies/mL. The preeclampsia rate and the maternal liver function were normal. One infant was delivered in GW 34 on maternal indication and the rest in full term. No gross malformations were noted. All infants received antiretroviral prophylaxis and have tested negative on follow-up. No increased maternal or infant morbidity was detected in this retrospective study of dolutegravir during pregnancy. This is so far one of the largest observational studies of dolutegravir treatment during pregnancy, but the number is indeed small, and further studies are needed to evaluate the safety and efficacy. PMID- 29396775 TI - New Biomarkers to Diagnose Ventilator Associated Pneumonia: Pentraxin 3 and Surfactant Protein D. AB - OBJECTIVE: To detect the most effective biomarker to confirm ventilator associated pneumonia (VAP). METHODS: Fifty patients with VAP suspicious diagnosis and 30 healthy patients were recruited. Suspicion of VAP was established if patients met the modified CPIS score >= 6 points. The confirmation of VAP was defined by the quantitative culture of nonbronchoscopic bronchoalveolar lavage (BAL) >105 CFU/ml of pathogenic microorganism. Serum samples for determination of C-reactive protein (CRP), procalcitonin (PCT), pentraxin 3 (PTX3), surfactant protein D (SPD) were collected on suspected VAP. RESULTS: Twenty seven of 50 patients were accepted as confirmed VAP group whose nonbronchoscopic BAL cultures were positive and rest of them were accepted as unconfirmed VAP group. PTX3, PCT and SPD levels were significantly higher in confirmed VAP group, (P = 0.021, P = 0.007, P < 0.001 respectively). There were no significant differences in CRP levels between the two groups (P = 0.062). The most sensitive marker for diagnosing VAP was SPD (P < 0.001). Receiver operating characteristic (ROC) curve for modified clinical pulmonary infection score (CPIS) to confirm VAP was evaluated (AUC 0.741 +/- 0.07, P < 0.001) and the optimal cutoff value was >7 with a sensitivity of 51.85% and a specificity of 91.3%. SPD levels were significantly higher in Acinetobacter baumannii and Pseudomonas aeruginosa infected patients than culture negative patients (P < 0.001). CONCLUSIONS: The index findings suggest that serum SPD is the most sensitive biomarker in diagnosis of VAP and it can be used as an early and organism specific marker for Acinetobacter baumannii and Pseudomonas aeruginosa. PMID- 29396777 TI - Bone Strength in Growing Rats Treated with Fluoride: a Multi-dose Histomorphometric, Biomechanical and Densitometric Study. AB - Bone deformation and fragility are common signs of skeletal fluorosis. Disorganisation of bone tissue and presence of inflammatory foci were observed after fluoride (F-) administration. Most information about F- effects on bone has been obtained in adult individuals. However, in fluorosis areas, children are a population very exposed to F- and prone to develop not only dental but also skeletal fluoroses. The aim of this work was to evaluate the bone parameters responsible for the effect of different doses of F- on fracture load of the trabecular and cortical bones using multivariate analysis in growing rats. Twenty four 21-day-old Sprague-Dawley rats were divided into four groups: F0, F20, F40 and F80, which received orally 0, 20, 40 or 80 MUmol F-/100 g bw/day, respectively, for 30 days. After treatment, tibiae were used for measuring bone histomorphometric and connectivity parameters, bone mineral density (BMD) and bone cortical parameters. The femurs were used for biomechanical tests and bone F content. Trabecular bone volume was significantly decreased by F-. Consistently, we observed a significant decrease in fracture load and Young's modulus (YM) of the trabecular bone in F--treated groups. However, cortical bone parameters were not significantly affected by F-. Moreover, there were no significant differences in cortical nor trabecular BMD. Multivariate analysis revealed a significant correlation between the trabecular fracture load and YM but not with bone volume or BMD. It is concluded that when F- is administered as a single daily dose, it produces significant decrease in trabecular bone strength by changing the elasticity of the trabecular bone. PMID- 29396776 TI - DFT studies of hydrocarbon combustion on metal surfaces. AB - Catalytic combustion of hydrocarbons is an important technology to produce energy. Compared to conventional flame combustion, the catalyst enables this process to operate at lower temperatures; hence, reducing the energy required for efficient combustion. The reaction and activation energies of direct combustion of hydrocarbons (CH -> C + H) on a series of metal surfaces were investigated using density functional theory (DFT). The data obtained for the Ag, Au, Al, Cu, Rh, Pt, and Pd surfaces were used to investigate the validity of the Bronsted Evans-Polanyi (BEP) and transition state scaling (TSS) relations for this reaction on these surfaces. These relations were found to be valid (R2 = 0.94 for the BEP correlation and R2 = 1.0 for the TSS correlation) and were therefore used to estimate the energetics of the combustion reaction on Ni, Co, and Fe surfaces. It was found that the estimated transition state and activation energies (ETS = 69.70 eV and Ea = 1.20 eV for Ni, ETS = -87.93 eV and Ea = 1.08 eV for Co and ETS = -92.45 eV and Ea = 0.83 eV for Fe) are in agreement with those obtained by DFT calculations (ETS = -69.98 eV and Ea = 1.23 eV for Ni, ETS = -87.88 eV and Ea = 1.08 eV for Co and ETS = -92.57 eV and Ea = 0.79 eV for Fe). Therefore, these relations can be used to predict energetics of this reaction on these surfaces without doing the time consuming transition state calculations. Also, the calculations show that the activation barrier for CH dissociation decreases in the order Ag ? Au ? Al ? Cu ? Pt ? Pd ? Ni > Co > Rh > Fe. PMID- 29396778 TI - Fetal valproate syndrome: the Irish experience. AB - INTRODUCTION: Fetal valproate syndrome was first described in 1984. Valproic acid crosses the placenta and can potentially lead to major congenital malformation, dysmorphism and neurodevelopmental disorder. METHODS: A retrospective study of 29 cases of FVS diagnosed by geneticists from 1995 to 2016. The cases were diagnosed based on criteria of fetal anticonvulsant syndrome. RESULTS: A total of 29 cases reported in the last 21 years. Features commonly described are prominent metopic ridge, midface hypoplasia, epicanthic folds, micrognathia and broad and flat nasal bridge. Four (13.7%) had cleft palate, three (10%) had neural tube defect, four (13.7%) with cardiac malformation, 15 (52%) experienced developmental delay including six (40%) with speech delay, 11 (38%) with limb defects, four (13.7%) reported with neurodevelopmental disorder and two (7%) had hypospadias. CONCLUSION: FVS is still seen in the Irish population even though the teratogenicity of the VPA has been known for over 32 years. It is very important to create public and professional awareness to prevent FVS whenever possible. PMID- 29396780 TI - Structural identifiability for mathematical pharmacology: models of myelosuppression. AB - Structural identifiability is an often overlooked, but essential, prerequisite to the experiment design stage. The application of structural identifiability analysis to models of myelosuppression is used to demonstrate the importance of its considerations. It is shown that, under certain assumptions, these models are structurally identifiable and so drug and system specific parameters can truly be separated. Further it is shown via a meta-analysis of the literature that because of this the reported system parameter estimates for the "Friberg" or "Uppsala" model are consistent in the literature. PMID- 29396779 TI - Protein tyrosine phosphatases in cardiac physiology and pathophysiology. AB - More than any other organ, the heart is particularly sensitive to gene expression deregulation, often leading in the long run to impaired contractile performances and excessive fibrosis deposition progressing to heart failure. Recent investigations provide evidences that the protein phosphatases (PPs), as their counterpart protein kinases, are important regulators of cardiac physiology and development. Two main groups, the protein serine/threonine phosphatases and the protein tyrosine phosphatases (PTPs), constitute the PPs family. Here, we provide an overview of the role of PTP subfamily in the development of the heart and in cardiac pathophysiology. Based on recent in silico studies, we highlight the importance of PTPs as therapeutic targets for the development of new drugs to restore PTPs signaling in the early and late events of heart failure. PMID- 29396781 TI - The Effects of Postprandial Exercise on Glucose Control in Individuals with Type 2 Diabetes: A Systematic Review. AB - BACKGROUND: Regulation of postprandial hyperglycemia is a major concern for individuals with type 2 diabetes. Exercise can reduce postprandial hyperglycemia by increasing contraction-mediated glucose uptake. However, there is no consensus with which to develop guidelines for optimal postprandial exercise timing and prescription. OBJECTIVE: The current systematic review was conducted to consolidate the literature surrounding the effects of postprandial exercise on glucose regulation in individuals with type 2 diabetes. METHODS: Electronic databases were searched on 17 February 2017. Inclusion criteria were: (1) trial was a randomized crossover trial; (2) subjects were diagnosed with type 2 diabetes; (3) a standardized meal was given; (4) exercise was initiated within three hours of the meal; (5) subjects were not treated with insulin. RESULTS: Twelve studies met the inclusion criteria, involving 135 participants (108 males, 20 females, seven unknown). The included studies varied greatly in their timing, duration, intensity, modality, and glucose measures. Postprandial aerobic exercise (11 studies) decreased short-term glucose area under the curve by 3.4 26.6% and 24-h prevalence of hyperglycemia by 11.9-65%. Resistance exercise (two studies) decreased the short-term glucose area under the curve by 30% and 24-h prevalence of hyperglycemia by 35%. CONCLUSION: Postprandial exercise may be an effective way to improve glucose control in individuals with type 2 diabetes. The most consistent benefits were seen in long-duration (>= 45 min), moderate intensity aerobic exercise. Resistance training also appears to be an effective modality. We recommend that individuals with type 2 diabetes focus on increasing energy expenditure after the largest meal of the day. More research is needed in this area to confirm the results of this systematic review and to provide clinicians with specific exercise recommendations. PMID- 29396782 TI - Author's Reply to Souza et al: Comment on: "Volume for Muscle Hypertrophy and Health Outcomes: The Most Effective Variable in Resistance Training". PMID- 29396783 TI - Comment on: Volume for Muscle Hypertrophy and Health Outcomes: The Most Effective Variable in Resistance Training. PMID- 29396784 TI - Tactile recovery assessment with shortened Semmes-Weinstein monofilaments in patients with buccinator myomucosal flap oral cavity reconstructions. AB - BACKGROUND: The sensitive restoration is a primary aim of oral reconstructive surgery. The Semmes-Weinstein monofilament test is the "Gold Standard" to assess the threshold of tactile sensitivity on the skin but its use in the oral cavity is limited due to the size of the tools. We adopted half-cut Semmes-Weinstein monofilaments to evaluate the threshold of tactile sensitivity in oral reconstructions with buccinator myomucosal flaps. MATERIALS AND METHODS: Monofilaments were half-cut and recalibrated. Fifty-seven oral reconstructions were considered at 4-year minimum follow-up. Test was conducted both on the reconstructive flap and on the non-operated contralateral side. RESULTS: All of the considered flaps (100%) showed a recovery of tactile sensitivity. The overall average tactile threshold value assessed on this sample was 0.76 +/- 1.58 g/mm2 overall. CONCLUSIONS: Shortened monofilaments allow easily assessment of tactile sensitivity in all the oral cavity areas, even in operated patients which often present lockjaw or microstomia. PMID- 29396785 TI - A randomized, prospective study of laparoendoscopic single-site plus one-port versus mini laparoscopic technique for live donor nephrectomy. AB - PURPOSE: To compare the clinical outcomes of laparoendoscopic single-site plus one-port donor nephrectomy (LESSOP-DN) and mini laparoscopic donor nephrectomy (MLDN). METHODS: A prospective randomized controlled trial was conducted from December 2014 to February 2016 in donors scheduled for left donor nephrectomy. Donor and recipient demographics and clinical outcomes including pain scores and questionnaires (BIQ: body image questionnaire, SF-36, patient-reported overall convalescence) were also compared. RESULTS: A total of 121 eligible donors were recruited, of which 99 donors who were scheduled to undergo an operation on their left side were randomized into LESSOP-DN (n = 50) and MLDN (n = 49) groups. There were no significant demographic differences between the two groups. The renal extraction time in the LESS-DN group was shorter than that in the MLDN group (75.89 +/- 13.01 vs. 87.31 +/- 11.38 min, p < 0.001). Other perioperative parameters and complication rates were comparable between the two groups. The LESSOP-DN group had a smaller incision length than the MLDN group (4.89 +/- 0.68 vs. 6.21 +/- 1.11 cm, p < 0.001), but cosmetic scores and body image scores were similar in the two groups (p = 0.905, 0.217). Donor quality of life (SF-36) and recovery and satisfaction data were comparable between the two groups. Delayed graft function (DGF) occurred in one recipient undergoing MLDN procedure (2.1%) and progressed to graft failure. CONCLUSIONS: There were no differences in cosmetic satisfaction between groups despite the smaller incision size of LESSOP DN. Safety parameters and subjective measures of postoperative morbidity were similar between the two groups. PMID- 29396786 TI - Histopathology: ditch the slides, because digital and 3D are on show. AB - Due to the growing field of digital pathology, more and more digital histology slides are becoming available. This improves the accessibility, allows teleconsultations from specialized pathologists, improves education, and might give urologist the possibility to review the slides in patient management systems. Moreover, by stacking multiple two-dimensional (2D) digital slides, three-dimensional volumes can be created, allowing improved insight in the growth pattern of a tumor. With the addition of computer-aided diagnosis systems, pathologist can be guided to regions of interest, potentially reducing the workload and interobserver variation. Digital (3D) pathology has the potential to improve dialog between the pathologist and urologist, and, therefore, results in a better treatment selection for urologic patients. PMID- 29396787 TI - The effect of corticosteroid on postoperative early pain, renal colic and total analgesic consumption after uncomplicated and unstented ureteroscopy: a matched pair analysis. AB - PURPOSE: To evaluate the effect of corticosteroid (CS) on early postoperative pain, renal colic and total analgesic consumption after uncomplicated and unstented ureteroscopy (URS). METHODS: Data of 397 patients who underwent URS and stone fragmentation for symptomatic distal ureteral stone (<= 15 mm) were retrospectively evaluated. After exclusion, 72 patients who received methylprednisolone (Group I) after non-stenting uncomplicated URS were matched with another 72 patients who did not receive CS (Group II). Cases were matched 1:1 ratio and the matched-pair criteria were age, stone diameter, and duration of surgery. RESULTS: Both groups were statistically similar in terms of mean age, operative time, stone size and preoperative pain score. However, the mean postoperative pain score was statistically significantly lower in group I than group II on the day of surgery (3.3 +/- 1.7 vs. 3.9 +/- 1.3, p = 0.012) and postoperative day 1 (2.8 +/- 1.8 vs. 3.4 +/- 1.3, p = 0.02), respectively. Renal colic episode development rate (4.2 vs. 13.2%, p = 0.036), parenteral analgesic requirement rate (18.1 vs. 33.3%, p = 0.001) and total parenteral analgesic consumption per patient (18 vs. 36mg, p = 0.009) were statistically lower in group I than group II on the day of surgery; however, there were no statistically significant differences on postoperative day 1. There were no statistically significant differences between groups in terms of ureteral stenting requirement and late unplanned urgent room visit rates. CONCLUSIONS: Corticosteroid after uncomplicated URS can be offered to reduce early postoperative pain, renal colic episode and total analgesic consumption. PMID- 29396788 TI - Cilostazol induced migraine does not respond to sumatriptan in a double blind trial. AB - BACKGROUND: Cilostazol is an inhibitor of phosphodiesterase 3 and thus causes accumulation of cAMP. It induces migraine-like attacks in migraine patients. Whether the cilostazol model responds to sumatriptan in migraine patients and therefore is valid for testing of future anti-migraine medications has never been investigated. METHODS: In a cross-over study, 30 patients received cilostazol (200 mg p.o.) on two separate days each day followed by oral self-administered placebo or sumatriptan 50 mg. We recorded headache characteristics and associated symptoms using a questionnaire. The 30 participants were asked to subsequently treat their spontaneous attacks with sumatriptan (50 mg) or placebo in a double blind cross-over design and 15 participants did so. RESULTS: Cilostazol induced headache with some migraine characteristics in all participants; 18 patients on the sumatriptan day and 19 patients on the placebo day fulfilled criteria for a migraine-like attack. The difference in median headache intensity between sumatriptan and placebo at 2 h was not significant (p = 0.09), but it was at 4 h (p = 0.017). During spontaneous attacks, the difference between placebo and sumatriptan was not significant at 2 h (p = 0.26), but it was highly significant at 4 h (p = 0.006). CONCLUSION: The cilostazol model in migraine patients could not be validated by a sufficient sumatriptan response. The model may perhaps respond to new drugs that act intracellularly or directly on ion channels. TRIAL REGISTRATION: The study is registered on clinicaltrials.gov ( NCT02486276 ). PMID- 29396789 TI - Enhanced Photocatalytic Hydrogen Evolution by Loading Cd0.5Zn0.5S QDs onto Ni2P Porous Nanosheets. AB - Ni2P has been decorated on CdS nanowires or nanorods for efficient photocatalytic H2 production, whereas the specific surface area remains limited because of the large size. Here, the composites of Cd0.5Zn0.5S quantum dots (QDs) on thin Ni2P porous nanosheets with high specific surface area were constructed for noble metal-free photocatalytic H2 generation. The porous Ni2P nanosheets, which were formed by the interconnection of 15-30 nm-sized Ni2P nanoparticles, allowed the uniform loading of 7 nm-sized Cd0.5Zn0.5S QDs and the loading density being controllable. By tuning the content of Ni2P, H2 generation rates of 43.3 MUM h- 1 (1 mg photocatalyst) and 700 MUM h- 1 (100 mg photocatalyst) and a solar to hydrogen efficiency of 1.5% were achieved for the Ni2P-Cd0.5Zn0.5S composites. The effect of Ni2P content on the light absorption, photoluminescence, and electrochemical property of the composite was systematically studied. Together with the band structure calculation based on density functional theory, the promotion of Ni2P in charge transfer and HER activity together with the shading effect on light absorption were revealed. Such a strategy can be applied to other photocatalysts toward efficient solar hydrogen generation. PMID- 29396790 TI - State-Dependent Plasticity in Response to Host-Plant Volatiles in a Long-Lived Moth, Caloptilia fraxinella (Lepidoptera: Gracillariidae). AB - Volatile chemicals produced by plants mediate host location, mate-finding and oviposition behavior in insects. State-dependent response to plant cues allows for timing of foraging, mating and oviposition on ephemeral host plants or plant parts. Caloptilia fraxinella is a herbivorous specialist on the foliage of ash trees (Fraxinus). Adults are long-lived and undergo a nine-month reproductive diapause over the fall and winter. Mating and oviposition occur in the spring when volatile chemicals released by ash leaves mediate host location. This study tested the plasticity of olfactory response of C. fraxinella to host plant volatiles using both electroantennogram and behavioral bioassays. The effect of moth physiological state on olfactory response was tested on male and female moths in different nutritional, mating, and diapause states. Antennal responses to host plant volatiles were plastic and depended on moth physiological state, and were highest when moths were reproductively active and would be seeking oviposition hosts. Moth sex and nutritional status also impacted antennal response to host plant volatiles. Oriented flight of females to ash seedlings varied with physiological state and nutritional status, with fed, reproductively active females having the highest response. Physiological state impacted oriented flight of males to female-produced sex pheromone signals whether or not a host plant was present, and there was no increase in behavioral response to sex pheromone in the presence of an ash host. PMID- 29396791 TI - Quality and readability of online patient information regarding sclerotherapy for venous malformations. AB - BACKGROUND: Patients often use the internet as a source of information about their condition and treatments. However, this information is unregulated and varies in quality. OBJECTIVE: To evaluate the readability and quality of online information for pediatric and adult patients and caregivers regarding sclerotherapy for venous malformations. MATERIALS AND METHODS: "Venous malformation sclerotherapy" was entered into Google, and results were reviewed until 20 sites that satisfied predefined inclusion criteria were identified. Scientific and non-patient-focused web pages were excluded. Readability was assessed using the Flesch Reading Ease Score and American Medical Association reading difficulty recommendations and quality was assessed using Journal of the American Medical Association standards and assessing if the site displayed HONcode (Health on the Net Code) certification. Assessment of the breadth of relevant information was made using a predefined checklist. RESULTS: Forty-nine search engine results were reviewed before 20 sites were identified for analysis. Average Flesch Reading Ease Score was 44 (range: 24.2-70.1), representing a "fairly difficult" reading level. None of the sites had a Flesch Reading Ease Score meeting the American Medical Association recommendation of 80-90. Only one site met all four Journal of the American Medical Association quality criteria (average: 2.1). None of the sites displayed a HONcode seal. The information most frequently found was: sclerotherapy is performed by radiologists, multiple treatments may be needed and surgery is an alternative treatment. CONCLUSION: Online information regarding sclerotherapy for venous malformations is heterogeneous in quality and breadth of information, and does not meet readability recommendations for patient information. Radiologists should be aware of and account for this when meeting patients. PMID- 29396794 TI - Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure. AB - OBJECTIVE: Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients. METHODS: Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA). RESULTS: MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH. CONCLUSIONS: Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases. PMID- 29396792 TI - Role of interventional radiology in managing pediatric liver tumors : Part 2: percutaneous interventions. AB - Hepatoblastoma and hepatocellular carcinoma (HCC) are the most common pediatric liver malignancies, with hepatoblastoma occurring more commonly in younger children and HCC occurring more commonly in older children and adolescents. Although surgical resection (including transplant when necessary) and systemic chemotherapy have improved overall survival rate for hepatoblastoma to approximately 80% from 30%, a number of children with this tumor type are not eligible for operative treatment. In contradistinction, pediatric HCC continues to carry a dismal prognosis with an overall 5-year survival rate of 30%. The Paediatric Hepatic International Tumour Trial (PHITT) is an international trial aimed at evaluating both existing and emerging oncologic therapies for primary pediatric liver tumors. Interventional radiology offers a number of minimally invasive procedures that aid in diagnosis and therapy of pediatric liver tumors. For diagnosis, the PHITT biopsy guidelines emphasize and recommend percutaneous image-guided tumor biopsy. Additionally, both percutaneous and endovascular procedures provide therapeutic alternatives that have been, to this point, only minimally utilized in the pediatric population. Specifically, percutaneous ablation offers a number of cytotoxic technologies that can potentially eradicate disease or downstage children with unresectable disease. Percutaneous portal vein embolization is an additional minimally invasive procedure that might be useful to induce remnant liver hypertrophy prior to extended liver resection in the setting of a primary liver tumor. PHITT offers an opportunity to collect data from children treated with these emerging therapeutic options across the world. The purpose of this manuscript is to describe the potential role of minimally invasive percutaneous transhepatic procedures, as well as review the existing data largely stemming from the adult HCC experience. PMID- 29396795 TI - The Clinical Autonomic Research journal 2018 and onward. PMID- 29396793 TI - Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases. AB - Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within double-stranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes. PMID- 29396796 TI - A New Community-Based Model for Training in Evidence-Based Psychotherapy Practice. AB - It is critical that evidence-based practices (EBP's) be provided to patients. Efforts to train clinicians in the community in EBP's, however, has been hindered by a lack of resources and rigid and resource intensive models of training. We describe efforts to overcome these barriers in a large scale community-based training program for Interpersonal Psychotherapy implemented with over 1400 clinicians in Los Angeles working within the Los Angeles County Department of Mental Health public system of care. The program, described in detail, is a potential template for training for community-based clinicians in evidence-based psychotherapy practices. PMID- 29396797 TI - A Study on Tobacco Use Among School Children. AB - Tobacco use among school children is becoming a serious problem. The early age of initiation underscores the urgent need to intervene and protect this vulnerable group from falling prey to this addiction. The present study was undertaken to assess (i) the prevalence and pattern of tobacco use among school children in India (ii) relation of tobacco use prevalence and pattern with socio-economic status (SES) of student's family. This is a cross sectional 16 months study done in school going Indian students aged >= 6 years with sample size of 1460. The prevalence of tobacco use in children from lower SES families was 9.4% compared to 5.7% in children from middle SES families (p = 0.017). Among children who used tobacco, mean age of onset was younger among children from lower SES (9.97 year vs 11.85 year, p = < 0.01) and they were more likely to use smokeless tobacco only (79.1% vs 61.3%, p = .0.006). However there was no significant difference between two groups in factors which motivated them towards first experience of tobacco. Also there was no significant difference between family histories of two groups in terms of tobacco use. The high prevalence of tobacco consumption, especially smokeless tobacco among children highlights the need for early intervention like regular screening at school level. Also tobacco use cases need to be followed up with intensive treatment. PMID- 29396798 TI - The Involvement of Cytochrome c Oxidase in Mitochondrial Fusion in Primary Cultures of Neonatal Rat Cardiomyocytes. AB - Cytochrome c oxidase (CCO) is a copper-dependent enzyme of mitochondrial respiratory chain. In pressure overload-induced cardiac hypertrophy, copper level and CCO activity are both depressed, along with disturbance in mitochondrial fusion and fission dynamics. Copper repletion leads to recovery of CCO activity and normalized mitochondrial dynamics. The present study was undertaken to define the link between CCO activity and mitochondrial dynamic changes. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine to induce cell hypertrophy. Hypertrophic cardiomyocytes were then treated with copper to reverse hypertrophy. In the hypertrophic cardiomyocytes, CCO activity was depressed and mitochondrial fusion was suppressed. Upon copper repletion, CCO activity was recovered and mitochondrial fusion was reestablished. Depression of CCO activity by siRNA targeting CCO assembly homolog 17 (COX17), a copper chaperone for CCO, led to fragmentation of mitochondria, which was not recoverable by copper supplementation. This study thus demonstrates that copper-dependent CCO is critical for mitochondrial fusion in the regression of cardiomyocyte hypertrophy. PMID- 29396799 TI - Comparing Non-Medical Sex Selection and Saviour Sibling Selection in the Case of JS and LS v Patient Review Panel: Beyond the Welfare of the Child? AB - The national ethical guidelines relevant to assisted reproductive technology (ART) have recently been reviewed by the National Health and Medical Research Council (NHMRC). The review process paid particular attention to the issue of non medical sex selection, although ultimately, the updated ethical guidelines maintain the pre-consultation position of a prohibition on non-medical sex selection. Whilst this recent review process provided a public forum for debate and discussion of this ethically contentious issue, the Victorian case of JS and LS v Patient Review Panel (Health and Privacy) [2011] VCAT 856 provides a rare instance where the prohibition on non-medical sex selection has been explored by a court or tribunal in Australia. This paper analyses the reasoning in that decision, focusing specifically on how the Victorian Civil and Administrative Tribunal applied the statutory framework relevant to ART and its comparison to other uses of embryo selection technologies. The Tribunal relied heavily upon the welfare-of-the-child principle under the Assisted Reproductive Treatment Act 2008 (Vic). The Tribunal also compared non-medical sex selection with saviour sibling selection (that is, where a child is purposely conceived as a matched tissue donor for an existing child of the family). Our analysis leads us to conclude that the Tribunal's reasoning fails to adequately justify the denial of the applicants' request to utilize ART services to select the sex of their prospective child. PMID- 29396800 TI - High liver density on CT imaging due to amiodarone toxicity. PMID- 29396801 TI - In regard to the letter by Li and Yang on the article "Which immobilization is better for distal radius fracture? A prospective randomized trial". PMID- 29396802 TI - Safe placement of pedicle screw in lumbar spine with minimum three year follow up: a case series and technical note. AB - PURPOSE: This study aims to find a safe and easy-to-perform strategy for lumbar pedicle screw insertion based on anatomical landmarks. METHODS: From March 2011 to January 2012, 74 patients underwent posterior lumbar interbody fusion or transforaminal lumbar interbody fusion using the new-designed screw insertion technique. During the operation, the entry site for screw insertion was on the outer edge of the superior facet joint, 4 mm downward from upper border of processus transversus. A connecting line between superior and inferior facet joints was used to determine the direction of screw insertion. Postoperative radiograph and computed tomography (CT) were taken routinely to show the position of the screws. Functional outcomes were evaluated using Oswestry Disability Index score, Japanese Orthopedic Association score, and Visual Analogue Scale, respectively. RESULTS: Sixty-two patients (27 males and 35 females, average age 58.95 +/- 8.45) finished the follow-up visit with an average of 46.03 months (36 60). The mean operation time and the blood loss were 169.60 +/- 41.21 min and 489.52 +/- 189.38 ml, respectively. A total of 274 pedicle screws were inserted following the new technique. According to Lothar Wiesner's classification, 11 screws (4.01%) caused minor violation into wall, two screws (0.73%) caused moderate violation, and other screws were in proper position. CONCLUSION: A new designed surgical strategy for pedicle screw insertion of lumbar spine was introduced and performed, which featured a series of original and easily distinguished landmarks. Clinical application demonstrated the safety and effectiveness of this novel technique for pedicle screw insertion. PMID- 29396803 TI - Prospective comparative study of knee laxity with four different methods in anterior cruciate ligament tears. AB - BACKGROUND AND PURPOSE: Anterior knee laxity can be evaluated using different devices, the most commonly used being the Telos(r), KT1000(r), Rolimeter(r), and GNRB(r). However, the laxity values obtained with these devices have never been compared to one another. As such, the outcomes of studies using these different knee laxity measurement devices may not be comparable. The primary purpose of this study was to determine the side-to-side laxity difference in patients with one ACL-injured knee, using each of these devices, and to compare the values obtained from each. We hypothesized that the measurements of laxity would vary depending on the device used. METHODS: This was a prospective study. All patients with an ACL injury, in which surgical reconstruction was planned, underwent pre operative knee laxity measurements using four different devices. The concordance correlation coefficient (CCC) of the results was compared between the four devices. RESULTS: The study enrolled 52 patients. With regard to the values of the side-to-side differences, the KT1000(r) and the GNRB(r) obtained the most similar values (CCC = 0.51, 95% CI 0.37-0.63). The two devices with the lowest correlation were the Telos(r) and the Rolimeter(r) (CCC = 0.04, 95% CI - 0.14 0.23). The comparability was considered average for the KT1000(r) and GNRB(r) and poor for the other devices. CONCLUSIONS: The knee laxity devices used in regular practice are not comparable to one another. As a result, caution must be taken when comparing results from studies using these different devices. PMID- 29396804 TI - The role of suture cutout in the failure of meniscal root repair during the early post-operative period: a biomechanical study. AB - PURPOSE: To assess the role of suture cutout in the mechanics of failure of the repaired posterior meniscal root during the early post-operative period when using sutures of different shape. METHODS: Twenty medial porcine menisci were randomized in two groups depending on the suture shape used to repair the posterior root: thread or tape. The sutured menisci were subjected to cyclic loading (1000 cycles, (10, 30) N) followed by load-to-failure testing. Residual displacements, stiffness, and ultimate failure load were determined. During tests, the tissue-suture interface was recorded using a high-resolution camera. RESULTS: In cyclic tests, cutout progression at the suture insertion points was not observed for any specimen of either group and no differences in residual displacements were found between use of thread or tape. In load-to-failure tests, suture cutout started in all menisci at a load close to the ultimate failure and all specimens failed by suture pullout. Suture tape had a greater ultimate load with no other differences. CONCLUSIONS: In a porcine model of a repaired posterior meniscal root subjected to cyclic loads representative of current rehabilitation protocols in the early post-operative period under restricted loading conditions, suture cutout was not found as a main source of permanent root displacement when using suture thread or tape. Suture cutout progression started at high loading levels close to the ultimate load of the construct. Tape, with a meniscus-suture contact area larger than thread, produced higher ultimate load. PMID- 29396805 TI - Standardized three dimensional computerised tomography scanner reconstructions increase the accuracy of acetabular fracture classification. AB - PURPOSE: Evaluate the role of four standardized 3D reconstruction views in the accurate diagnosis of acetabular fractures. MATERIALS AND METHODS: Thirty-five acetabular fracture cases were selected from a tertiary centre database. Fourteen reviewers with different experience level evaluated this set of images which were provided in axial 2D views and multiplanar reconstruction (MPR) without 3D views in the first two readings then the standardized 3D views were added for the subsequent two readings. The primary outcome was the accuracy of diagnosis while inter-observer reliability and reading time as well as time needed for accurate diagnosis were evaluated. RESULTS: Accuracy of classification was 56.7% using the 2D and 73% using the described 3D (p < 0.001). Improvement was noted in all groups even though the expert group showed the least improvement (6.7% (p = 0.04)) and the least experience group showed the most improvement (35.7% (p < 0.001)). Average time of interpretation was 96 minutes for the 2D sets and 47 minutes for the 3D sets. Finally, the adding of the four standardized views increased the inter-observer reliability in all groups compared to the standard 2D sets with MPR. CONCLUSION: Acetabular fracture diagnosis according to Letournel classification is difficult and depends greatly on the experience of the reader. The described set of 3D images yields better accuracy and renders the diagnosis more repeatable and faster. We recommend the use of these images in classifying acetabular fractures. PMID- 29396806 TI - Effect of knee flexion position and combined application of tranexamic acid on blood loss following primary total knee arthroplasty: a prospective randomized controlled trial. AB - PURPOSE: The aim of this study was to demonstrate the association between tranexamic acid (TXA)-combined application and knee flexion in the first 24 hour post-operatively that could reduce total blood loss and transfusion need in patients undergoing total knee arthroplasty (TKA), without sacrificing safety. METHODS: Ninety TKA patients were divided into three groups randomly: the flexion group: the knee was in 90 degrees flexion position for the first 12 hour post surgery and kept at 60 degrees for the next 12 hour, combined with 1 g TXA topical and 1 g TXA intravenous application. The extension group: the knee was in fully extension position post-operatively, combined with topical and intravenous TXA application. The controlled group: the knee was in fully extension position post-operatively combined with single intravenous TXA application. The primary outcomes included blood loss variables and transfusion values. The secondary outcomes included post-operative hospital stay, knee flexion degree, complication rate, and hospital charge. RESULTS: The total blood loss and transfusion needs in the flexion group were significantly reduced in comparison with that in the extension group and controlled group. The post-operative knee flexion motion was significant higher in the flexion group than the other two groups. There was no difference among the three groups with regard to the rates of complications. CONCLUSIONS: Keeping the knee in flexion position combined with topical and intravenous TXA application in patients undergoing primary unilateral TKA significantly reduced post-operative bleeding and the transfusion rate compared with what was found after treatment with extension knee position or single intravenous TXA application. LEVEL OF EVIDENCE: Therapeutic Level I. PMID- 29396808 TI - Histologic Outcome of Indeterminate Thyroid Nodules Classified at Low or High Risk. AB - The revised Italian consensus for the classification and reporting of thyroid cytology (ICCRTC) was published in 2014. Very recently, a high reliability of ICCRTC in classifying low and high risk indeterminate nodules (Tir 3A and Tir 3B, respectively) was demonstrated. This finding prompted us to review our case series of thyroid indeterminate lesions to verify these data. Only lesions undergone FNAC from December 2014 to October 2017 with subsequent histology at our institutions were eligible for the study. All cytologic samples had originally been classified according to ICCRTC in the subcategories of indeterminate lesion, such as Tir 3A and Tir 3B by three cytopathologists and another one with more than 10 years experience, when necessary. Sixty-three indeterminate FNAC were diagnosed during the study period, of which 51 were subsequently surgically treated. Overall, 9 carcinomas (7 follicular and 2 papillary) and 42 benign lesions were found at histology. The cancer rate observed in the Tir 3A category (3/40, 7.5%) was significantly (p = 0.0015) lower than that found in Tir 3B (6/11, 54.5%). No significant differences were found in age and size of the sampled nodules between the two subcategories. We can confirm in our series that the Italian reporting system for thyroid cytology shows high reliability in discriminating low risk indeterminate lesions from those at high risk of malignancy. PMID- 29396807 TI - The CNS penetrating taxane TPI 287 and the AURKA inhibitor alisertib induce synergistic apoptosis in glioblastoma cells. AB - Glioblastoma is a highly malignant disease in critical need of expanded treatment options. The AURKA inhibitor alisertib exhibits antiproliferative activity against glioblastoma in vitro and in vivo. Unlike current clinically used taxane drugs, the novel taxane TPI 287 penetrates the CNS. We tested for interactions between three selective AURKA inhibitors and TPI 287 against standard U87 and U1242 cells and primary glioblastoma neurospheres using colony formation assays. Bliss and Chou-Talalay analyses were utilized to statistically test for synergism. Morphological analysis, flow cytometry and annexin V binding were employed to examine cell cycle and apoptotic effects of these drug combinations. TPI 287 not only potentiated the cytotoxicity of the AURKA inhibitors alisertib, MLN8054 and TC-A2317, but was often potently synergistic. Morphologic and biochemical analysis of the combined effects of alisertib and TPI 287 consistently revealed synergistic induction of apoptosis. While each agent alone induces a mitotic block, slippage occurs allowing some tumor cells to avoid apoptosis. Combination treatment greatly attenuated mitotic slippage, committing the majority of cells to apoptosis. Alisertib and TPI 287 demonstrate significant synergism against glioblastoma cells largely attributable to a synergistic effect in inducing apoptosis. These results provide compelling rationale for clinical testing of alisertib and/or other AURKA inhibitors for potential combination use with TPI 287 against glioblastoma and other CNS neoplasms. PMID- 29396809 TI - Molecular Testing of Nodules with a Suspicious or Malignant Cytologic Diagnosis in the Setting of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP). AB - Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor characterized by frequent RAS mutations and an absence of the BRAF V600E mutation commonly seen in classical papillary thyroid carcinoma (cPTC). The ability to differentiate potential NIFTP/follicular variant of papillary thyroid carcinoma (FVPTC) from cPTC at the time of fine needle aspiration (FNA) can facilitate conservative management of NIFTP. The aim of the current study was to investigate how molecular testing may add to cytologic assessment in the pre-operative differentiation of potential NIFTP/FVPTC and cPTC. We had previously evaluated cytologists' ability to prospectively distinguish potential NIFTP/FVPTC from cPTC in a cohort of 56 consecutive FNAs diagnosed as malignant or suspicious for malignancy. We utilized this cohort to perform molecular analysis. Detected molecular abnormalities were stratified into two groups: (1) those supporting malignancy and (2) those supporting a diagnosis of potential NIFTP/FVPTC. The cytologists' characterization of cases and the detected molecular alterations were correlated with the final histologic diagnoses. Molecular testing was performed in 52 (93%) of the 56 cases. For the 37 cases cytologists favored to be cPTC, 31 (84%) had a molecular result that supported malignancy (28 BRAF V600E mutations, 2 NTRK1 fusions, 1 AGK-BRAF fusion). For the 8 cases that were favored to be NIFTP/FVPTC by cytologists, 7 (88%) had a molecular result that supported conservative management (1 NRAS mutation, 6 wild-type result). Seven cases were designated as cytomorphologically indeterminate for NIFTP/FVPTC or cPTC, of which 6 (86%) had a molecular result that would have aided in the pre-operative assessment of potential NIFTP/FVPTC or cPTC/malignancy. These included 3 BRAF V600E mutations in nodules that were cPTC on resection, an HRAS mutation, and a wild-type result in the 2 nodules that were NIFTP, and a TERT promoter mutation along with an NRAS mutation in a poorly differentiated thyroid carcinoma. For nodules with an FNA diagnosis of suspicious for malignancy or malignant, cytologists can differentiate most cases of potential NIFTP/FVPTC from cPTC. However, molecular testing may be valuable for a subset of cases, especially those that are indeterminate for potential NIFTP/FVPTC versus cPTC based on cytologic features alone. PMID- 29396810 TI - The Prevalence of Extranodal Extension in Papillary Thyroid Cancer Based on the Size of the Metastatic Node: Adverse Histologic Features Are Not Limited to Larger Lymph Nodes. AB - Extranodal extension (ENE) is a prognostic indicator of aggressiveness for papillary thyroid cancer (PTC). The association between the size of metastatic nodes and the prevalence of ENE has not been previously explored. However, there is a common belief that small lymph nodes with metastatic disease do not significantly impact patient outcome. This study investigates the relationship between the prevalence of ENE and the size of a positive lymph node. Linear dimensions and malignant histological characteristics of 979 metastatic lymph nodes from 152 thyroid cancer patients were retrospectively analyzed. Data was analyzed using chi-square tests and multilevel logistic regression modeling. ENE was present in 144 of 979 lymph nodes; the sizes of the involved lymph nodes ranged from 0.9 to 44 mm. ENE was identified in 7.8% of lymph nodes measuring <= 5 mm, 18.9% between 6 and 10 mm, 23.1% between 11 and 15 mm, 25.0% between 16 and 20 mm, and 14.0% between 21 and 25 mm in size. The association between node size and ENE status was significant (odds ratio (OR) = 1.07, confidence interval (CI) = [1.04, 1.11]). The size of the metastatic focus directly correlated with ENE (OR = 1.07, 95% CI = [1.07, 1.14], p value < 0.001). Increasing lymph node size increases the likelihood of ENE for metastatic PTC. Importantly, small positive lymph nodes can also harbor ENE to a significant extent. Further studies are required to determine the clinical and prognostic significance of lymph node size and the presence of ENE. PMID- 29396811 TI - Successful treatment of a venous pseudoaneurysm in a brachiobasilic fistula using ultrasound-guided manual compression: two case reports. AB - A pseudoaneurysm or a false aneurysm is the consequence of a persistent blood leak caused generally by iatrogenic rupture of a vessel wall. In hemodialysis fistula, pseudoaneurysm results from repeated puncturing of the vein at the same site. Surgery and endovascular treatment stay widely used as the treatment of pseudoaneurysm compared to the ultrasound-guided manual compression (UGMC). UGMC is a non-invasive and effective procedure which could be attempted before invasive procedures. We reported two cases of successful treatment of pseudoaneurysm by ultrasound-guided compression. A total thrombosed cavity has been obtained and fistulas could be cannulated in the next session. PMID- 29396812 TI - Replay to: Phenotypic spectrum of POLG1 mutations. PMID- 29396813 TI - Association between CLU gene rs11136000 polymorphism and Alzheimer's disease: an updated meta-analysis. AB - Large-scale genome-wide association studies (GWAS) identified that the single nucleotide polymorphism rs11136000 in Clusterin (CLU) gene was associated with risk of Alzheimer's disease (AD) in Caucasian ancestry. However, recent studies reported either a weak association or no association between rs11136000 polymorphism and AD in Asian populations. Therefore, we performed a meta-analysis to explore whether rs11136000 polymorphism is associated with susceptibility to AD in Asian populations. A total of 17 articles including 26 studies with 19,829 cases and 30,900 controls, which were identified by searching PubMed, MEDLINE, and AlzGene up to Nov 2016, were collected for this meta-analysis. The significant association between rs11136000 and AD in the pooled population was found under all the models. In subgroup analysis, we identified significant association in Asian population under the additive mode (OR = 0.90, 95% CI = 0.85 0.96) but not in the recessive model (OR = 0.80, 95% CI = 0.53-1.21) and the dominant model (OR = 0.94, 95% CI = 0.86-1.03). Our analysis further supports previous findings that the rs11136000 polymorphism C allele is associated with AD susceptibility. To our knowledge, this is the new largest meta-analysis to access to the association of CLU rs11136000 polymorphism with AD risk. PMID- 29396815 TI - Reply to: "Patients' Expectations Are Important for Success in Bariatric Surgery". PMID- 29396814 TI - Intraoperative radiation exposure in spinal scoliosis surgery for pediatric patients using the O-arm(r) imaging system. AB - PURPOSE: The O-arm(r) navigation system allows intraoperative CT imaging that can facilitate highly accurate instrumentation surgery, but radiation exposure is higher than with X-ray radiography. This is a particular concern in pediatric surgery. The purpose of this study is to examine intraoperative radiation exposure in pediatric spinal scoliosis surgery using O-arm. METHODS: The subjects were 38 consecutive patients (mean age 12.9 years, range 10-17) with scoliosis who underwent spinal surgery with posterior instrumentation using O-arm. The mean number of fused vertebral levels was 11.0 (6-15). O-arm was performed before and after screw insertion, using an original protocol for the cervical, thoracic, and lumbar spine doses. RESULTS: The average scanning range was 6.9 (5-9) intervertebral levels per scan, with 2-7 scans per patient (mean 4.0 scans). Using O-arm, the dose per scan was 92.5 (44-130) mGy, and the mean total dose was 401 (170-826) mGy. This dose was 80.2% of the mean preoperative CT dose of 460 (231-736) mGy (P = 0.11). The total exposure dose and number of scans using intraoperative O-arm correlated strongly and significantly with the number of fused levels; however, there was no correlation with the patient's height. CONCLUSIONS: As the fused range became wider, several scans were required for O arm, and the total radiation exposure became roughly the same as that in preoperative CT. Use of O-arm in our original protocol can contribute to reduction in radiation exposure. PMID- 29396816 TI - Overcoming the Racial Hierarchy: the History and Medical Consequences of "Caucasian". AB - The term Caucasian is ubiquitous in the medical field. It is used without a significant consideration of its history or medical necessity. First, the term Caucasian has racist historical origins in a beauty-based hierarchy with implied superiority. It is derived from a 1700's historical scheme which places Caucasians above the other, degenerated racial groups. Second, the pseudo scientific justification for this hierarchy has been co-opted to legally justify discrimination against minority groups in the USA. Third, the unnecessary and incorrect application of antiquated racial identifiers negatively impacts patient care. Disentangling real, clinically meaningful genetic differences from superficial racial determinations remains an ongoing challenge. Framing patient care through Caucasian or white lens leads to the unequal care and the otherization of minority groups. Fourth, we must develop a more appropriate, racially sensitive system for patient identification in clinical practice and research. This demands intentionality, precision, and consistency. PMID- 29396817 TI - Renal medullary carcinoma: a nearly fatal malignancy specifically affecting patients with a so-called benign condition. AB - Renal medullary carcinoma (RMC) is a highly aggressive and rare malignancy found almost exclusively in young patients with sickle cell trait (SCT). Metastatic disease is commonly present at diagnosis. There is very limited experience treating disseminated disease and the prognosis is dismal. We report the case of a young 9-year-old boy with SCT, who presented with 4 months' progression of abdominal pain, nausea and vomiting associated with cough spells, dysphagia, and weight loss. Upon evaluation, he was underweight, pale, and in mild respiratory distress. Cervical lymphadenopathy was evident and abdomen was diffusely tender. A whole-body CT scan showed a left kidney lesion with associated cervical, mediastinal, and retroperitoneal lymphadenopathy. Biopsy of a cervical lymph node revealed metastatic RMC. Patient was started on combination chemotherapy with paclitaxel, carboplatin, and gemcitabine followed by left adrenalectomy. In spite of having advanced disease, our patient achieved an excellent response with a progression-free survival of 17 months. Although SCT is thought to be a "benign" condition, RMC is one devastating complication associated with it. Considering its rarity, the near uniform associated fatality should prompt the question of whether clinical practice should change regarding proper counseling of these patients and raise awareness in the medical community. PMID- 29396818 TI - Health-Promoting Behavior and Influencing Factors in Young North Korean Refugees (NKRs) Living in South Korea. AB - The number of young North Korean refugees (NKRs) entering South Korea to escape famine and poverty and improve their quality of life is drastically increasing. The aims of this study were to identify and compare health promoting lifestyle behaviors (HPLBs) of young NKRs, compared to South Koreans, and to investigate influencing factors related to HPLBs in young NKRs. Data were obtained from 150 NKRs residing in South Korea and 161 South Koreans. Respondents provided their psychological status (depression, stress, and life satisfaction) and HPLBs. The NKRs reported lower interpersonal relations scores and higher spiritual growth scores compared to the control group. Attendance in religious services, stress, and life satisfaction were significantly associated with HPLBs in young NKRs. Health education and/or promotion programs focusing interpersonal relations and spiritual growth may be beneficial. In addition, regular psychological health screening is proposed as part of health-checkup programs, potentially improving adjustment to South Korean society. PMID- 29396819 TI - Severe Secondary Polycythemia in a Female-to-Male Transgender Patient While Using Lifelong Hormonal Therapy: A Patient's Perspective. AB - After a registered drug is available on the market and used in everyday circumstances, hitherto unknown adverse drug reactions (ADRs) may occur. Furthermore, the patient can experience a previously unknown course of a known ADR. Voluntary reports by patients play an important role in gaining knowledge about ADRs in daily practice. The Netherlands Pharmacovigilance Centre Lareb received a report from a 55-year-old female-to-male transgender patient who experiences secondary polycythemia while using lifelong testosterone therapy. The onset age of the symptoms was 38 years. The symptoms appeared gradually and after approximately 1 year it was clear that the patient's hemoglobin and hematocrit had started to increase. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's polycythemia and use of the suspect drug. Polycythemia is a known ADR in testosterone treatment, but little attention has been paid to the possible severity and complications of these symptoms as well as the impact on the patient's well-being. PMID- 29396820 TI - Arsenic hyperaccumulation in Pityrogramma calomelanos L. (Link): adaptive traits to deal with high metalloid concentrations. AB - Pityrogramma calomelanos is interestingly the single non-Pteris arsenic (As) hyperaccumulating fern. It has been pointed as a potential species for phytoremediation and a model plant to study the As toxicity and its mechanisms of action. In order to investigate the morphoanatomical traits associated to As tolerance, P. calomelanos plants were exposed to different As concentrations in hydroponic solution. At low As dose (1 mM As), 90% of the As accumulated in plants was allocated in shoots, and no symptoms of As stress were observed in fronds and roots. Under higher As exposure (10 and 30 mM As), 81-74% of the total As in plants was present in shoots, and apical and marginal necroses on pinnae were observed. Anatomical observations showed that As induces damages mainly in the secondary veins and adjacent cells. High amounts of phenols were observed in pinna tissues of control and treated plants. In the roots, As promoted slight alterations as detachment of border-like cells and accumulation of granular substances in cortical cells. The high root-to-shoot As translocation and the constitutive presence of phenols and border-like cells protecting the root tips showed to be adaptive traits that allow P. calomelanos to survive in contaminated sites. PMID- 29396821 TI - Ecotoxicity of the nonsteroidal ecdysone mimic RH-5849 to Daphnia magna. AB - The nonsteroidal ecdysone mimic 1,2-dibenzoyl-1-tert-butylhydrazine (RH-5849), a novel insect growth regulator, is mainly registered for use in rice fields. So far, its toxicity and ecological risks towards aquatic cladoceran invertebrates remain unclear. In this study, RH-5849 was evaluated for its acute and 21-day chronic toxicity towards Daphnia magna. The viability, morphology, growth, and reproduction of D. magna were observed to establish a concentration-toxicity relationship associated with the RH-5849 exposure. In addition, the relationship between the changes of physiological and biochemical indices and the chronic indices was analyzed in order to find potential early warning indicators in D. magna to the chronic risk of RH-5849 exposure. The results showed that the 48-h EC50 of acute immobilization and EC50 of 21-day survival of RH-5849 on D. magna were 45.3 and 1.34 mg/L, respectively. Chronic exposure to RH-5849 mainly affected the reproductive parameters of D. magna and the no observed effect concentration (NOEC) and the EC50 were 0.050 and 0.5423 mg/L, respectively. The number of offspring per female reduced significantly after 21-day exposure to 0.10 mg/L of RH-5849. The morphological changes, manifested in head width and body length, the length of the helmet or apical spine, and the curvature and transparency of the body, were observed in RH-5849-treated groups. Moreover, it was found that the alkaline phosphatase activity in D. magna after 5-7-day exposure was positively correlated with the number of offspring per female after 21 days. These results indicate the potential risk of RH-5849 towards aquatic crustaceans should be taken into consideration when applied to rice fields. PMID- 29396822 TI - Combined Fe/P and Fe/S ratios as a practicable index for estimating the release potential of internal-P in freshwater sediment. AB - Release of phosphorus (P) from sediment is a major source of P in many freshwater lakes. Currently, assessing the ability of sediment to release P, which is valuable to the management of water eutrophication, remains a challenge. Thus, the purpose of this study was to find effective indexes for predicting the release potential of internal-P. In this study, high-resolution diffusive gradients in thin films (DGT) and conventional sequential extraction were used to characterize the distribution and speciation of P, iron (Fe), and sulfur (S) in the surface sediment of a mildly eutrophic reservoir in southwestern China. Sediment samples exhibited large variations in Fe, S, and P, thereby providing favorable conditions for investigating the effects of Fe and S on sediment P mobilization. In contrast to traditional knowledge, our results show that total P (TP) and redox-sensitive P(BD-P) are poorly correlated with releasable P(DGT-P). This implies that high levels of sedimentary TP and BD-P do not necessarily result in an elevated release of internal-P under anaerobic conditions. Sedimentary P release was greatly suppressed at ratios of Fe/P > 30 and Fe/S > 6. Significant positive correlations between DGT-P and DGT-Fe or DGT-S suggest that Fe and S play an important role in governing the mobility of sedimentary P. These results support the combined Fe/P and Fe/S ratios as an effective and practicable index for assessing the ability of sediment to release P. Thus, our study provides a new and simple method for assessing sedimentary P pollution in freshwater ecosystems. PMID- 29396823 TI - Effects of lanthanum and silicon stress on bio-sequestration of lanthanum in phytoliths in rice seedlings. AB - Plant phytoliths are important for silicon (Si) cycling in natural ecosystems; however, their role in lanthanum (La) sequestration in plants is still unclear. In the present study, we elucidated the mechanism of La-induced damage to the growth of rice (Oryza sativa L.) seedling from the viewpoint of the La sequestration by phytoliths (PhytLa). The phytoliths were extracted by using the microwave digestion method. La concentrations within the plants and phytoliths were determined by a modified lithium metaborate fusion method. Analysis showed that pretreatment with low La concentration not only promoted photosynthesis and transpiration in rice but also enhanced the sequestration ability of phytoliths on La. Conversely, high La concentration inhibited photosynthesis and transpiration in rice and the ability of phytoliths to sequester La. Moreover, high Si concentrations promoted the sequestration ability of phytoliths during these processes. Promotion of combined stress of La and Si on the ability of rice seedling was stronger than that of the single La stress. The sequestration ability of phytoliths in different parts of rice varied significantly, following the order: stem > leaf > root. This pattern could be attributed to factors such as the production of various phytolith morphotypes (such as tubes) and PhytLa, PhytLa efficiency, La accumulation, and the rate of photosynthesis and transpiration in different parts of rice seedlings. This study demonstrated that La uptake in rice seedlings was affected by the presence of Si in the medium, and phytolith played a crucial role in the bio-sequestration of La and assuaged the damage caused by La in rice seedlings. Graphical abstract ?. PMID- 29396824 TI - Distribution and mobility of exogenous copper as influenced by aging and components interactions in three Chinese soils. AB - Copper contamination of soils is a global environmental problem. Soil components (organic matter, clay minerals, and microorganisms) and retention time can govern the adsorption, fixation, and distribution of copper. This study evaluated the interaction effects of soil components and aging on the distribution of exogenous copper. Three typical Chinese soils (Ultisol, Alfisol, and Histosol) were collected from Hunan, Henan, and Heilongjiang Provinces. Soils were incubated with rice straw (RS) and engineered bacteria (Pseudomonas putida X4/pIME) in the presence of exogenous copper for 12 months. Sequential extraction was employed to obtain the distribution of Cu species in soils, and the mobility factors of Cu were calculated. The relationships between soil properties and Cu fractions were analyzed with stepwise multiple linear regression. The results show that organic carbon plays a more important role in shaping the distribution of relatively mobile Cu, and iron oxides can be more critical in stabilizing Cu species in soils. Our results suggest that organic matter is the most important factor influencing copper partitioning in Ultisols, while iron oxides are more significant in Alfisols. The mobility of exogenous Cu in soils depends largely on organic carbon, amorphous Fe, and aging. The introduction of both rice straw and rice straw + engineered bacteria enhanced the stabilization of Cu in all the three soils during aging process. The introduction of bacteria could reduce copper mobility, which was indicated by the lowest mobility factors of Cu for the treatment with bacteria in Black, Red, and Cinnamon soils at the first 4, 8, and 8 months, respectively. Different measures should be taken into account regarding the content of organic matter and iron oxides depending on soil types for the risk assessment and remediation of Cu-contaminated soils. PMID- 29396825 TI - Performance of A2NO-MBR process in treating synthetic and municipal wastewater. AB - In this study, a novel anaerobic-anoxic/nitrification (A2N) two-sludge sequencing batch reactor (SBR) configured with post-aeration (A2NO-membrane bioreactor process) was conducted to evaluate the operational efficiency, process characteristics, and microbial community structure in treating synthetic and municipal wastewater. When influent C/N ratios were 4.2-8.6, the removal efficiencies of COD, NH4+-N, TN, and TP were 86.4-90.0, 85.2-93.6, 61.8-76.0, and 97.6-99.3%, respectively, and the effluent concentrations met the first level A criteria of GB18918-2002. Phosphorus removal was mainly in anoxic phase with a removal rate of 0.54-1.30 mgP/(gMLSS h), accounting for 75.9-99.7%. Enhanced phosphorus removal was observed during post-aeration phase with a removal rate of 0.06-0.55 mgP/(gMLSS h). Additionally, Oxidation-Reduction Potential (ORP) and pH could reflect the process of anaerobic phosphorus release and anoxic denitrifying phosphorus removal. DO and pH could indicate the end of nitrification. Moreover, Candidatus Accumulibacter and Dechloromonas related to biological nitrogen and phosphorus removal were enriched effectively with total proportions of 15.9 and 11.5% in treating synthetic and municipal wastewater, respectively. PMID- 29396826 TI - Impact of humic acid on the accumulation of metals by microalgae. AB - Indirect impact of humic acid (HA) on metal accumulation and toxicity (Cd, Ni, Pb, and Hg; 100 MUM; 24 h of exposure) in Scenedesmus quadricauda was studied. Algae were pre-cultured on solid (10 and 100 mg HA/L) or in liquid media (1, 5, and 10 mg HA/L) over 30 days and then exposed to metals mentioned above. Accumulation of applied metals irrespective of pre-culture increased in the order Ni < Cd < Pb < Hg. Algae pre-cultured on solid HA-enriched media accumulated more Cd (+ 46% at 10 mg HA/L), Ni (+ 50 and + 81% at 10 and 100 mg HA/L, respectively), and Pb (+ 15% at 100 mg HA/L) but the impact on Hg amount was not detected. Potassium and calcium decreased in response to all metals (K strongly under Hg excess) and HA had negligible impact. Interestingly, fluorescence microscopy detection of reactive oxygen species/nitric oxide (ROS/NO) balance showed that HA pre-culture suppressed ROS signal and stimulated NO signal in response to Cd (indicating positive impact of HA) while ROS signal in Ni and Pb treatments rather increased but NO signal decreased as expected from elevated Ni and Pb accumulation. Hg had clearly the most toxic impact on the ROS/NO balance. Algae pre-cultured in liquid HA-enriched media showed significantly increased Ni accumulation only (+ 14% at a dose 10 mg HA/L). Present study for the first time showed that humic acid may indirectly affect accumulation of metals and that solid HA-enriched medium used for pre-culture is more suitable to increase accumulation of metals by algae. PMID- 29396827 TI - Sorption of pentachlorophenol (PCP) in the marine bottom sediments-batch sorption experiment at varying pressure. AB - Study was undertaken to determine the effect of hydrostatic pressure on the sorption of pentachlorophenol (PCP). The experiment was conducted at atmospheric pressure (1000 hPa) and at increased pressure (6000 hPa) simulating conditions at the water depth of 50 m. The sorption of PCP was examined in an artificial environment (microcosm) consisting of the marine water and the bottom sediments from a Polish harbor and the southern Baltic Sea. The first part of the experiment comprised the determination of PCP sorption parameters in the microcosms and parameters of the sediments (organic matter content, conductivity) and of the overlying water (pH, ion concentration) at 1000 hPa. The second part of the experiment was conducted at 6000 hPa inside the hyperbaric chamber. The hyperbaric exposure affected parameters of the harbor sediments and the overlying water but had little influence on the concentration of PCP in the microcosms containing the southern Baltic Sea sediments. Considering the specific characteristics of the harbor sediments, it can be assumed that the impact of hydrostatic pressure on the sorption process of PCP at 50-m depth appears to be negligible. PMID- 29396828 TI - UV modification of biochar for enhanced hexavalent chromium removal from aqueous solution. AB - This study was conducted to understand the effects of ultraviolet (UV) irradiation on the physicochemical properties and the hexavalent chromium (Cr(VI)) removal ability of biochar. Structural and morphological analysis showed that UV irradiation increased the specific surface area of biochar and added a large amount of oxygen-containing functional groups (e.g., carboxyl, lactonic, and hydroxyl) to biochar's surface. Batch sorption experimental results showed that UV-modified biochar (UVBC) produced at the pyrolysis temperature of 300 degrees C, the irradiated time of 24 h, and the irradiation distance of 40 mm exhibited excellent Cr(VI) removal ability (from 1.11 mg/g for BC to 20.04 mg/g for UVBC, a 18.1-fold increase). The adsorption kinetics and adsorption isotherm data agreed well with the pseudo-second-order model and Freundlich model, respectively. Experimental and modeling results suggest that the oxygen containing functional groups and specific surface areas of biochars were notably increased by UV irradiation, which enhanced Cr(VI) adsorption by surface complexation. X-ray photoelectron spectroscopy (XPS) analysis of UVBC before and after reaction with Cr(VI) showed that reduction occurred during Cr(VI) adsorption. The energy consumption of UV modification is 2.7 MJ per gram of UVBC produced, which is comparable to that in activated carbon. The results showed that the method of UV modification of biochar is a very novel and effective method for the adsorption of Cr(VI) in solution. PMID- 29396829 TI - Characteristics of aorto-iliofemoral arterial tree according to aortic valve morphology in chinese patients considered for TAVR. AB - To characterize the anatomy of aorto-iliofemoral arterial tree according to aortic valve phenotype by CT in patients referred for transcatheter aortic valve replacement (TAVR). We retrospectively enrolled 215 patients screened for TAVR who underwent CT. Dimensions, calcification, vascular tortuosity index score and other putative risk features of 13 different regions were evaluated for bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) morphology. The study consisted of 44% BAVs with younger age than TAVs. The dimensions of the annulus, sinus of Valsalva, ascending aorta and aortic arch were consistently larger in BAVs. The prevalence of calcification of aortic arch was significantly higher in TAVs even after adjustment for atherosclerotic risk factors. BAVs was associated with two-fold higher odds of having over I degree AA calcification (odds ratio 2.02; 95% CI 1.60-5.31; p < 0.001). The prevalence of severe iliac tortuosity was higher among BAVs (11.7 vs. 2.5%, p = 0.015). BAVs had a trend to more atheroma than TAVs in the abdominal aortic artery and iliofemoral artery. BAV anatomy is common in Chinese AS patients screened for TAVR. Aorto-iliofemoral pathology varies according to aortic valve phenotype, which may contribute to technical challenges in BAV vs. TAV anatomy and support the need for the integrated risk assessment for each valve phenotype. PMID- 29396831 TI - Outcomes, Access, and Cost Issues Involving PCSK9 Inhibitors to Lower LDL Cholesterol. AB - The clinical importance and benefit of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appears well established for the high-risk cardiovascular (CV) patient. This applies especially to the statin-intolerant patient or the patient who does not attain an appropriate low-density lipoprotein cholesterol (LDL-C) target. Therefore, the barriers to appropriate clinical use of the PCSK9 inhibitors involve cost and not the documented CV benefit or LDL-C lowering. Multiple roadblocks affect many high-risk CV patients in arranging approval of a PCSK9 inhibitor. Overcoming these roadblocks may require legal pressures, some increased regulation, and facilitation by competitive forces. PMID- 29396832 TI - Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND AND AIMS: Ezetimibe reduces plasma low-density lipoprotein cholesterol (LDL-C) levels by up to 20%. However, its effect on plasma lipoprotein(a) [Lp(a)] concentrations in patients with primary hypercholesterolemia has not been defined. OBJECTIVE: Therefore, we performed a systematic review and meta-analysis to assess this effect based on the available randomized controlled trials (RCTs). METHODS: We searched the PubMed and SCOPUS databases from inception until 28 February 2017 to identify RCTs that investigated the effect of ezetimibe monotherapy on plasma Lp(a) concentrations in patients with primary hypercholesterolemia. We pooled mean percentage changes in plasma Lp(a) concentrations as a mean difference (MD) with a 95% confidence interval (CI). RESULTS: Seven RCTs with 2337 patients met the selection criteria and were included in the analysis. Overall pooled analysis suggested that ezetimibe 10 mg significantly reduced plasma Lp(a) concentrations in patients with primary hypercholesterolemia by - 7.06% (95% CI - 11.95 to - 2.18; p = 0.005) compared with placebo. No significant heterogeneity was observed (chi2 = 5.34; p = 0.5). Excluding one study from the analysis resulted in insignificant differences between the two groups (p = 0.2). Meta-regression did not find a significant association between the mean percentage changes in Lp(a) and other potential moderator variables, which included the mean percentage changes of LDL-C concentrations (p = 0.06) and baseline Lp(a) mean values (p = 0.46). CONCLUSIONS: Ezetimibe monotherapy (10 mg/day) showed a small (7.06%) but statistically significant reduction in the plasma levels of Lp(a) in patients with primary hypercholesterolemia. According to current literature, this magnitude of reduction seems to have no clinical relevance. However, further studies are warranted to clarify the mechanism mediating this effect of ezetimibe and to investigate its efficacy in combination with other drugs that have shown promise in lowering Lp(a) levels. PMID- 29396830 TI - Novel Dual Mitochondrial and CD44 Receptor Targeting Nanoparticles for Redox Stimuli-Triggered Release. AB - In this work, novel mitochondrial and CD44 receptor dual-targeting redox sensitive multifunctional nanoparticles (micelles) based on oligomeric hyaluronic acid (oHA) were proposed. The amphiphilic nanocarrier was prepared by (5 carboxypentyl)triphenylphosphonium bromide (TPP), oligomeric hyaluronic acid (oHA), disulfide bond, and curcumin (Cur), named as TPP-oHA-S-S-Cur. The TPP targeted the mitochondria, the antitumor drug Cur served as a hydrophobic core, the CD44 receptor targeting oHA worked as a hydrophilic shell, and the disulfide bond acted as a connecting arm. The chemical structure of TPP-oHA-S-S-Cur was characterized by 1HNMR technology. Cur was loaded into the TPP-oHA-S-S-Cur micelles by self-assembly. Some properties, including the preparation of micelles, morphology, redox sensitivity, and mitochondrial targeting, were studied. The results showed that TPP-oHA-S-S-Cur micelles had a mean diameter of 122.4 +/- 23.4 nm, zeta potential - 26.55 +/- 4.99 mV. In vitro release study and cellular uptake test showed that TPP-oHA-S-S-Cur micelles had redox sensibility, dual targeting to mitochondrial and CD44 receptor. This work provided a promising smart multifunctional nanocarrier platform to enhance the solubility, decrease the side effects, and improve the therapeutic efficacy of anticancer drugs. PMID- 29396833 TI - Belimumab: A Review in Systemic Lupus Erythematosus. AB - Belimumab (Benlysta(r)) is a human immunoglobulin G1lambda monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells. It is the only biological agent currently approved for the treatment of non-renal systemic lupus erythematosus (SLE). Belimumab is approved in the EU, the USA and other countries as add-on therapy in adult patients with active, autoantibody positive SLE despite standard therapy. In phase III trials, treatment with IV or SC belimumab plus standard therapy was effective in terms of reducing overall disease activity and reducing the incidence and severity of flares, without worsening of patients' overall condition or the development of significant disease activity in new organ systems. Sustained disease control was maintained during longer-term (up to 10 years) treatment with IV belimumab. Belimumab also demonstrated steroid-sparing effects and was associated with clinically meaningful improvements in health-related quality of life and fatigue. Belimumab was generally well tolerated in clinical trials, with low rates of immunogenicity. In view of the flexibility regarding the route of administration and the convenience of the once-weekly, self-administered, SC regimen, add-on therapy with belimumab is a useful treatment option for patients with active, autoantibody-positive SLE despite standard therapy. PMID- 29396835 TI - Successful endoscopic sphincterotomy for choledocholithiasis in a patient with severe hemophilia A and inhibitors. AB - Endoscopic sphincterotomy (ES) is a standard procedure for bile duct stone removal. However, the safety of ES in patients with hemophilia remains unknown. We treated a 46-year-old man who had choledocholithiasis and severe hemophilia A with high-responding inhibitors during immune tolerance induction therapy. Since coagulation factor VIII inhibitors neutralize and inactivate endogenous and exogenous factor VIII, bleeding risk is higher in hemophilia A patients with inhibitors than in those without inhibitors. With adequate pre- and post procedure monitoring of the clotting factor and supplemented clotting factor, the patient could safely undergo ES without bleeding complications. ES can be also an effective and safe first-line therapy for choledocholithiasis in patients with hemophilia and inhibitors under the condition of appropriate management. PMID- 29396836 TI - WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon. AB - Charcot-Marie-Tooth disease (CMT) refers to a group of clinically and genetically heterogeneous inherited neuropathies. Ganglioside-induced differentiation associated protein 1 GDAP1-related CMT has been reported in an autosomal dominant or recessive form in patients presenting either axonal or demyelinating neuropathy. We report two Sri Lankan sisters born to consanguineous parents and presenting with a severe axonal sensorimotor neuropathy. The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT. However, sequencing of the coding regions of the gene was normal. Whole-exome sequencing (WES) was performed and revealed that the largest region of homozygosity was around GDAP1 with several variants, mostly in non-coding regions. In view of the high clinical suspicion of GDAP1 gene involvement, we examined the variants in this gene and this, along with functional studies, allowed us to identify an alternative splicing site revealing a cryptic in-frame stop codon in intron 4 responsible for a severe loss of wild-type GDAP1. This work is the first to describe a deleterious mutation in GDAP1 gene outside of coding sequences or intronic junctions and emphasizes the importance of interpreting molecular analysis, and in particular WES results, in light of the clinical and electrophysiological phenotype. PMID- 29396837 TI - Examining Burnout, Depression, and Attitudes Regarding Drug Use Among Lebanese Medical Students During the 4 Years of Medical School. AB - OBJECTIVES: This study aims to evaluate the prevalence of burnout, depressive symptoms, and anxiety symptoms and attitudes toward substance use in medical students as well as their evolution during the 4 years of medical school. METHODS: A cross-sectional study was carried out at the American University of Beirut Medical Center (AUBMC) between September and December 2016. In total, 176 out of 412 eligible medical students responded. The survey was anonymous and administered via e-mail link to an electronic form. The study included general socio-demographic questions and standardized validated tools to measure depressive symptomatology (PHQ-9), burnout (Burnout Measure), anxiety (GAD-7), alcohol use (AUDIT), and substance abuse (DAST-10) as well as questions pertaining to attitudes toward recreational substance use. RESULTS: Overall, 23.8% of medical students reported depressive symptomatology, with 14.5% having suicidal ideations. Forty-three percent were found to have burnout. Those who screened positive for burnout were more likely to be males, to be living away from their parents, and to have experienced a stressful life event during the last year. With the exception of burnout, there was no significant difference in the prevalence of depression or anxiety among the 4 years of medical school. There was a significant difference in alcohol use, illicit substance use, and marijuana use during the four medical school years. CONCLUSIONS: The results of this study show high rates of depression, burnout, and suicidal ideation among medical students from the Middle East region. Increased rates of substance use were detected as well as a more tolerant attitude toward substance use in general, specifically cannabis. It is crucial that medical educators and policymakers keep tackling the complex multifactorial mental health issues affecting medical students and design effective solutions and support systems. PMID- 29396838 TI - Preparticipation screening-the way forward is smart screening. AB - The image of a young athlete collapsing on the pitch, followed by resuscitation, leaves an unforgettable impression. However, this impression should not seduce us into resuscitating the debate for large-scale preparticipation screening without doing the smart thing: taking a step back to review what we know to be effective, and what has been shown not to be effective. What we should do is use this momentum to focus on what we still need to know. PMID- 29396834 TI - Recent Advances in Pharmacotherapy for Migraine Prevention: From Pathophysiology to New Drugs. AB - Migraine is a common and disabling neurological disorder, with a significant socioeconomic burden. Its pathophysiology involves abnormalities in complex neuronal networks, interacting at different levels of the central and peripheral nervous system, resulting in the constellation of symptoms characteristic of a migraine attack. Management of migraine is individualised and often necessitates the commencement of preventive medication. Recent advancements in the understanding of the neurobiology of migraine have begun to account for some parts of the symptomatology, which has led to the development of novel target based therapies that may revolutionise how migraine is treated in the future. This review will explore recent advances in the understanding of migraine pathophysiology, and pharmacotherapeutic developments for migraine prevention, with particular emphasis on novel treatments targeted at the calcitonin gene related peptide (CGRP) pathway. PMID- 29396839 TI - What the elite athlete does not want to know. PMID- 29396840 TI - The Promise and Pitfalls of Facebook Advertising: a Genetic Counselor's Perspective. AB - Facebook advertising is a powerful tool for increasing the outreach and recruitment of research participants. We describe our experience as genetic counselors within the context of an internet-based research study, recruiting subjects for a Parkinson disease (PD) biomarker study. PMID- 29396842 TI - Associations between age and 50 trace element contents and relationships in intact thyroid of males. AB - BACKGROUND: It is unclear why a prevalence of thyroid dysfunction is higher in the elderly as compared to the younger population. An excess or deficiency of trace element contents in thyroid may play important role in goitre- and carcinogenesis of gland. AIM: To examine the variation with age of the mass fraction of 50 trace elements in intact (normal) male thyroid. METHOD: Samples of thyroid parenchyma obtained from 72 healthy males (mean age 37.8 years, range 2 80 years) was investigated. Measurements were performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma mass spectrometry, respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for trace element analysis. RESULTS: There is a statistically significant increase in Cd and Se mass fraction, as well as a decrease in Al, Be, Dy, Ga, Gd, Li, Mn, U, and Y mass fraction in the normal thyroid of male during a lifespan. Moreover, a disturbance of intra-thyroidal chemical element relationships (correlations) with increasing age was found. DISCUSSION: Our findings suggest that, at least, a goitrogenic and carcinogenic effect of Cd overload and Mn deficiency in the thyroid of old males may be assumed. Many trace elements in human thyroid behave themselves as antagonists or synergists. Therefore, an age-related disturbance in correlations between Mn and other trace element mass fractions in thyroid parenchyma may also contribute to harmful effects on the gland. CONCLUSION: Age-related changes in intra-thyroidal trace element contents and disturbances in trace element relationships are involved in goitre- and carcinogenesis. PMID- 29396841 TI - Metabolic phenotype of male obesity-related secondary hypogonadism pre replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. AB - AIM: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU). METHODS: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD). RESULTS: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR). CONCLUSION: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition. PMID- 29396843 TI - Use of electromagnetic navigational bronchoscopy in robotic pulmonary resection. AB - Robotic resection of pulmonary lesions has become a more common approach in the field of thoracic surgery. The greatest drawback of robotic resection is the lack of tactile feedback as compared to open approaches, making identification of intrapulmonary lesion difficult. Electromagnetic navigational bronchoscopy (navibronch) enables pre-incisional marking of pulmonary lesions for intraoperative identification. We sought to determine how effective navibronch was in our institution's robotic cases. Thirty-one patients underwent robotically assisted resection of 35 lesions with the assistance of navibronch from 7/2014 to 9/2015. Retrospective demographic and operative data were collected on these patients, and statistical analysis was conducted using ANOVA means testing, Chi square, and non-parametric tests. The average age in this patient population was 63.7 +/- 13.5 years. Eight patients (25.8%) were male. Twenty-five (80.6%) of the patients had pathology involving one lobe, with six (19.4%) in two lobes. 34 of the resections (97.1%) resulted in dye being localized to the first specimen; 34 (97.1%) were found to have the target pathology in the initial specimen. Further resection was carried out in 22 (62.9%) cases, with the final resection resulting in a segment in 2 (5.7%) and a lobe in 14 (40.0%). The mean number of lung specimens collected was 1.94 +/- 0.13. The mean number of tumors in each target resection was 1.46 +/- 0.66 in final pathology. Malignancy was found in 19 (54.3%) of final specimens. There were no complications related to navibronch. Navibronch is an effective technique in the identification and localization of pulmonary lesions in robotically assisted lung resections. PMID- 29396844 TI - Evaluation of Probiotic Potential of Bacteriocinogenic Lactic Acid Bacteria Strains Isolated from Meat Products. AB - In this study, the probiotic potential of five bacteriocin-producing lactic acid bacteria (LAB) strains, isolated from meat products, was investigated. They were presumptively identified as Lactococcus lactis subsp. cremoris CTC 204 and CTC 483, L. lactis subsp. hordinae CTC 484, and Lactobacillus plantarum CTC 368 and CTC 469 according to morphological, biochemical, and physiological characteristics. Analysis of genetic variability (random amplified polymorphic (RAPD)-PCR) and whole-cell proteins (SDS-PAGE) revealed similarity between Lactobacillus strains and variability among Lactococcus strains. The evaluation of the probiotic potential showed that the five LAB strains were tolerant to pH 2.0, and only strain CTC 469 was tolerant to the lowest concentration of the bile salts evaluated (0.1%). All strains showed survival or growth ability at 4, 25, and 37 degrees C, and tolerance at - 20 degrees C. Although strain CTC 204 in TSB Broth supplemented with MgSO4 showed the highest intensity of biofilm production, this compound was produced by all of them. The safety assessment showed that no thermonuclease, hemolytic, or gelatinase activities were detected. All strains were resistant to erythromycin and sensitive to amoxicillin and phenoxymethylpenicillin; furthermore, CTC 204 was resistant to chloramphenicol, CTC 368 and CTC 469 to chloramphenicol and vancomycin, CTC 483 to tetracycline and vancomycin, and CTC 484 to clindamycin and chloramphenicol. The evaluated strains showed biogenic amine production; the lowest levels were produced by CTC 204 and CTC 368 strains. It was concluded that CTC 204 and CTC 368 strains have the greatest potential for becoming probiotics. PMID- 29396845 TI - Resistance of Collard Green Genotypes to Bemisia tabaci Biotype B: Characterization of Antixenosis. AB - Bemisia tabaci (Genn.) biotype B (Hemiptera: Aleyrodidae) is an important pest of vegetable crops, including collard greens Brassica oleracea var. acephala (Brassicaceae). The use of resistant genotypes is an interesting option to reduce insect populations and can be used as an important tool for integrated pest management (IPM). This study evaluated 32 genotypes of collard greens against the attack of silver leaf whitefly, with the aim to characterize antixenosis. Initially, a multiple-choice trial was conducted using all genotypes, in which the adult attractiveness was assessed on two leaves per genotype at 24 and 48 h after infestation. After 48 h, one leaf of each genotype was randomly selected for the determination of the number of eggs per square centimeter. From the results of the multiple-choice trial, 13 genotypes were selected for a no-choice oviposition test, following the same method of the previous test. Colorimetric analyses were also performed to establish possible correlations between leaf color and insect colonization. Genotypes HS-20, OE, and VA were less attractive, demonstrating antixenosis. Genotypes LG, VE, J, MG, MOP, HS-20, VA, and MT had less oviposition in the multiple-choice test, which indicated expression of antixenosis. In the no-choice test, genotypes VE, P1C, CCB, RI-919, H, and J had less oviposition, which also characterized antixenosis. Therefore, genotypes VE and J showed the highest resistance stability because both had less oviposition in both test modalities. Thus, the resistance to B. tabaci biotype B indicates the genotypes HS-20, OE, VA, VE, and J are promising for use in breeding programs to develop resistance to whitefly. PMID- 29396846 TI - Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. AB - Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond-Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted-NGS panel, including 34 and 71 genes, respectively. Seventy-four probands from 62 unrelated families were investigated. Our study includes the most comprehensive gene set for these anemias and the largest cohort of patients described so far. We obtained an overall diagnostic yield of 64.9%. Despite 54.2% of cases showed conclusive diagnosis fitting well to the clinical suspicion, the multi-gene analysis modified the original clinical diagnosis in 45.8% of patients (nonmatched phenotype-genotype). Of note, 81.8% of nonmatched patients were clinically suspected to suffer from CDA. Particularly, 45.5% of the probands originally classified as CDA exhibited a conclusive diagnosis of chronic anemia due to enzymatic defects, mainly due to mutations in PKLR gene. Interestingly, we also identified a syndromic CDA patient with mild anemia and epilepsy, showing a homozygous mutation in CAD gene, recently associated to early infantile epileptic encephalopathy-50 and CDA-like anemia. Finally, we described a patient showing marked iron overload due to the coinheritance of PIEZO1 and SEC23B mutations, demonstrating that the multi-gene approach is valuable not only for achieving a correct and definitive diagnosis, but also for guiding treatment. PMID- 29396847 TI - Extension of the QuickFF force field protocol for an improved accuracy of structural, vibrational, mechanical and thermal properties of metal-organic frameworks. AB - QuickFF was originally launched in 2015 to derive accurate force fields for isolated and complex molecular systems in a quick and easy way. Apart from the general applicability, the functionality was especially tested for metal-organic frameworks (MOFs), a class of hybrid materials consisting of organic and inorganic building blocks. Herein, we launch a new release of the QuickFF protocol which includes new major features to predict structural, vibrational, mechanical and thermal properties with greater accuracy, without compromising its robustness and transparent workflow. First, the ab initio data necessary for the fitting procedure may now also be derived from periodic models for the molecular system, as opposed to the earlier cluster-based models. This is essential for an accurate description of MOFs with one-dimensional metal-oxide chains. Second, cross terms that couple internal coordinates (ICs) and anharmonic contributions for bond and bend terms are implemented. These features are essential for a proper description of vibrational and thermal properties. Third, the fitting scheme was modified to improve robustness and accuracy. The new features are tested on MIL-53(Al), MOF-5, CAU-13 and NOTT-300. As expected, periodic input data are proven to be essential for a correct description of structural, vibrational and thermodynamic properties of MIL-53(Al). Bulk moduli and thermal expansion coefficients of MOF-5 are very accurately reproduced by static and dynamic simulations using the newly derived force fields which include cross terms and anharmonic corrections. For the flexible materials CAU-13 and NOTT-300, the transition pressure is accurately predicted provided cross terms are taken into account. (c) 2018 Wiley Periodicals, Inc. PMID- 29396848 TI - Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. AB - Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. PMID- 29396849 TI - SAAMP 2.0: An algorithm to predict genotype-phenotype correlation of lysosomal storage diseases. AB - Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino-acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAAMP 2.0 was developed by excluding 3 tools with worst performance, yielding a sensitivity of 94% and a specificity of 90%. To generalize the guideline to proteins without known structures, we built the three-dimensional model of iduronate-2-sulfatase by homology modeling. Further, we investigated the phenotype severity of known disease-causing mutations of the GLB1 gene, which lead to 2 LSDs (GM1 gangliosidosis and Morquio disease type B). Based on the previous literature and structural analysis, we associated these mutations with disease subtypes and proposed a theory to explain the complicated genotype-phenotype correlation. Collectively, an updated guideline for phenotype prediction with SAAMP 2.0 was proposed, which will provide essential information for early diagnosis and proper treatment allocation, and they may be generalized to many monogenic diseases. PMID- 29396850 TI - Phenotypes and survival in Erdheim-Chester disease: Results from a 165-patient cohort. PMID- 29396851 TI - Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases. AB - Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, beta2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from beta2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from beta2 agonists. This increased cancer risk in beta2 agonist users merits further investigation. PMID- 29396852 TI - Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling. AB - While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32 5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4 shRNA or miR-32-5p may help to develop a new therapy to better suppress the ccRCC metastasis. PMID- 29396853 TI - Sweet syndrome associated with ipilimumab in a patient with metastatic melanoma. PMID- 29396854 TI - Current and potential use of pathological targets in the treatment of Hodgkin lymphoma. PMID- 29396855 TI - Use of a novel 1-hour protocol for rapid frozen section immunocytochemistry, in a case of squamous cell carcinoma treated with Mohs micrographic surgery. AB - For squamous cell carcinoma (SCC) treated using Mohs micrographic surgery (MMS), interpretation of haematoxylin and eosin-stained frozen sections can be challenging. In these situations, ancillary use of immunostaining is a useful tool for the Mohs surgeon. However, use of immunostaining in MMS laboratories is limited, mainly because current manual immunostaining platforms are subject to operator error, and automated immunostaining, albeit accurate, is too slow for inclusion in MMS. In this report, we describe a novel 1-hour protocol for rapid frozen section immunocytochemistry, using the pancytokeratin markers AE1/AE3. This protocol has been specifically designed to integrate the speed of manual techniques and the accuracy of automated platforms, making it a valuable addition to the MMS laboratory. We propose that in selected or histologically challenging cases, there is a role for the use of this novel protocol, allowing the Mohs surgeon to more confidently declare tumour clearance, thus preventing further unnecessary surgery and preserving healthy tissue. PMID- 29396856 TI - The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population. AB - Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM) treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease-free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5-year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients. PMID- 29396857 TI - Flai (fludarabine, cytarabine, idarubicin) plus low-dose Gemtuzumab Ozogamicin as induction therapy in CD33-positive AML: Final results and long term outcome of a phase II multicenter clinical trial. AB - The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab-Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first-line therapy in CD33 positive AML. We treated 130 patients, aged <65, with a median age of 52 years. FLAI-GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (2 g/sqm) on days 1-5; idarubicin (10 mg/sqm) on days 1, 3, and 5; and GO (3 mg/sqm) on day 6. SCT was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of MRD by WT1 expression, feasibility and outcome of consolidation with SCT, overall survival (OS) and disease-free survival (DFS). After induction with FLAI-GO, complete remission (CR) rate was 82%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337+/-9936 copies/104 ABL (diagnosis) to 182 +/- 436 copies after induction therapy (p = 0.0001) showing a very good disease debulking. After a median follow-up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5-year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5-year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged <= 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow-up, support the reintroduction of GO in clinical practice. PMID- 29396858 TI - Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre clinical models. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naive and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naive to treatments; (2) stable-genome naive to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD genome PDX, naive to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naive to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs. PMID- 29396859 TI - N-acetyl-L-cysteine improves bone marrow endothelial progenitor cells in prolonged isolated thrombocytopenia patients post allogeneic hematopoietic stem cell transplantation. AB - Prolonged isolated thrombocytopenia (PT) is a serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to murine studies, endothelial progenitor cells (EPCs) play a crucial role in the regulation of hematopoiesis and thrombopoiesis in the bone marrow (BM) microenvironment. We previously showed that the reduced frequency of BM EPCs was an independent risk factor for the occurrence of PT following allo-HSCT. However, the functional role of BM EPCs and methods to improve the impaired BM EPCs in PT patients are unknown. In the current case-control study, we investigated whether the BM EPCs in PT patients differed from those in good graft function patients. Moreover, we evaluated whether N-acetyl-L-cysteine (NAC, a reactive oxygen species [ROS] scavenger) could enhance BM EPCs from PT patients in vitro and in vivo. The PT patients exhibited dysfunctional BM EPCs characterized by high levels of ROS and apoptosis and decreased migration and angiogenesis capabilities. In vitro treatment with NAC improved the quantity and function of the BM EPCs cultivated from the PT patients by downregulating the p38 MAPK pathway and rescued the impaired BM EPCs to support megakaryocytopoiesis. Furthermore, according to the results of a preliminary clinical study, NAC is safe and effective in PT patients. In summary, these results suggested that the reduced and dysfunctional BM EPCs are involved in the occurrence of PT. The defective BM EPCs in the PT patients can be quantitatively and functionally improved by NAC, indicating that NAC is a promising therapeutic approach for PT patients following allo-HSCT. PMID- 29396860 TI - Trapped like a butterfly in a spider's web: Experiences of female spousal caregivers in the care of husbands with severe mental illness. AB - AIMS AND OBJECTIVES: To explore the experiences of female spousal caregivers in the care of husbands with severe mental illness. BACKGROUND: Family involvement in the care of patients with chronic illness is essential to provide a backbone of support for them. However, little is known about how female spousal caregivers are confronted with challenges while taking care of their husbands with severe mental illness. DESIGN: An exploratory qualitative study. METHODS: Fourteen female spousal caregivers of people with severe mental illness (defined here as schizophrenia, schizoaffective disorders and bipolar affective disorders) were recruited using purposive sampling and were interviewed using a semistructured in depth interview method. Data were analysed by conventional content analysis until data saturation was achieved. RESULTS: Care of a husband with severe mental illness had a disruptive influence on the emotional relationships of the family and resulted in emotional detachment over time. Despite the caregivers' struggle to protect their families, the lack of supportive resources caused emotional exhaustion. Caregiving tasks interfering with their many other responsibilities, along with being a reference for family matters, led to loss of self. Consequently, they experienced psychological distress because of the transition to a caregiver role without any supportive resources. CONCLUSION: Constant caring, without supportive resources, forced them to do various roles and manage other issues within the family. Being unprepared for a caregiving role led to the psychological distress of female spousal caregivers. Therefore, adequate information, education and supportive resources must be provided for spouses to facilitate their transition to caregiving roles. RELEVANCE TO CLINICAL PRACTICE: It is necessary to pay close attention to the spousal caregivers' own mental health problems while they care for their mentally ill husbands. Mental health professionals should adopt a new approach to the prioritisation and planning of policies that support both family caregivers and patients. PMID- 29396861 TI - Opposite impact of Methylene tetrahydrofolate reductase C677T and Methylene tetrahydrofolate reductase A1298C gene polymorphisms on systemic inflammation. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been found to be related with many diseases. Systemic inflammation is now considered as a major predisposition factor for diseases including diabetes mellitus (DM), coronary arterial disease (CAD), stroke, and cancer. This study aimed to investigate whether systemic inflammation is a possible underlying pathogenesis for MTHFR gene polymorphism-related disease. METHODS: A total of 292 patients were enrolled, and single nucleotide polymorphisms for MTHFR C667T and A1298C were genotyped. Systemic inflammation markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were collected. RESULTS: In our study population, MTHFR 677 variants had significant higher NLR level than MTHFR 677 wild type (3.77 +/- 0.26 vs 3.06 +/- 0.18, P = .028). Logistic regression analysis showed that MTHFR 677 variants were significantly associated with increased NLR level. MTHFR 1298 variants showed the opposite effects which tended to have lower level of NLR (3.21 +/- 0.16 vs 3.79 +/- 0.34, P = .087) and PLR (137.0 +/- 4.8 vs 157.7 +/- 9.4, P = .052) than MTHFR 1298 wild type. General linear model showed that there was no statistically significant interaction between MTHFR C667T and A1298C gene polymorphism on NLR or PLR. CONCLUSIONS: This study indicates that MTHFR C677T and MTHFR A1298C gene polymorphisms have opposite effect on systemic inflammation, and systemic inflammation may contribute to the pathogenesis for diseases associated with MTHFR C667T gene polymorphism. PMID- 29396862 TI - Maternal thyroid-stimulating hormone reference ranges for first trimester screening from 11 to 14 weeks of gestation. AB - BACKGROUND: To establish maternal thyroid-stimulating hormone (TSH) reference ranges for first trimester screening from 11 + 0 to 13 + 6 weeks of gestation. METHODS: A total of 10 592 singleton and 201 twin consecutive Caucasian pregnant women who underwent simultaneously prenatal first trimester Down's syndrome screening and thyroid function screening from January 2010 to November 2017 were included in the study. Women with positive antithyroid peroxidase antibody (TPOAb) and positive personal history of thyroid disease were previously excluded. TSH was measured by immunochemiluminescent assay on ci 16200 Abbott Architect analyzer. Nonparametric percentile method (also known as CLSI C28.A3) was used for the determination of reference ranges. RESULTS: We established reference ranges of TSH for the period of gestation from 11 + 0 to 13 + 6 weeks of pregnancy as 0.16-3.43 mU/L for singleton Caucasian pregnancies and 0.02-2.95 mU/L for twin Caucasian pregnancies. The median (IQR) of TSH for singleton pregnancies was higher than that for twin pregnancies (1.25 mU/L (0.83-1.81) vs 0.84 (0.37-1.47), respectively; P < .0001). CONCLUSIONS: Each first trimester screening center should be aware of which type of immunoassay their laboratory uses. TSH reference ranges in women during the first trimester of pregnancy are lower than those for general population. Twin pregnancies have lower TSH than singleton pregnancies. PMID- 29396863 TI - Crystal structure of peptidoglycan recognition protein SA in Apis mellifera (Hymenoptera: Apidae). AB - Peptidoglycan recognition protein SA (PGRP-SA) is a key pattern recognition receptor in the insect innate immune system. PGRP-SA can bind to bacterial PGN and activate the Toll pathway, which triggers the expression and release of antimicrobial peptides to prevent bacterial infection. Here, we report the first structure of Apis mellifera PGRP-SA from Hymenoptera at 1.86 A resolution. The overall architecture of Am-PGRP-SA was similar to the Drosophila PGRP-SA; however, the residues involved in PGN binding groove were not conserved, and the binding pocket was narrower. This structure gives insight into PGN binding characteristics in honeybees. PMID- 29396864 TI - Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. AB - Anticoagulation is used to treat venous thromboembolism (VTE) in cancer patients, but may be associated with an increased risk of bleeding. VTE recurrence and major bleeding were assessed in cancer patients treated for VTE with the most currently prescribed anticoagulants in clinical practice. Newly diagnosed cancer patients (first VTE 1/1/2013-05/31/2015) who initiated rivaroxaban, low-molecular weight heparin (LMWH), or warfarin were identified from Humana claims data and observed until end of eligibility or end of data availability. VTE recurrence was a hospitalization with a primary diagnosis of VTE >=7 days after first VTE. Major bleeding events on treatment were identified using validated criteria. Cohorts were compared using Kaplan-Meier rates at 6 and 12 months and Cox proportional hazards models. Cohorts were adjusted for their differences at baseline. A total of 2428 patients (rivaroxaban: 707; LMWH: 660; warfarin: 1061) met inclusion criteria. Patient characteristics were well balanced after weighting. There was a trend for lower VTE recurrence rates in rivaroxaban users compared to LMWH users at 6 months (13.2% vs. 17.1%; P = .060) and significantly lower at 12 months (16.5% vs. 22.2%; P = .030) [HR: 0.72, 95% CI: (0.52-0.95); P = .024]. VTE recurrence rates were also lower for rivaroxaban than warfarin users at 6 months (13.2% vs. 17.5%; P = .014) and 12 months (15.7% vs. 19.9%; P = .017) [HR: 0.74, 95% CI: (0.56-0.96); P = .028]. Major bleeding rates were similar across cohorts. This real-world analysis suggests cancer patients with VTE treated with rivaroxaban had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with LMWH or warfarin. PMID- 29396865 TI - Comparison between characteristics of severe and very severe aortic stenosis. AB - OBJECTIVES: Patients with very severe aortic stenosis (AS) have extremely poor clinical outcomes even if they are asymptomatic compared to those with severe AS, but the clinical and echocardiographic characteristics of patients with very severe AS remain unclear. METHODS: The Asian Valve Registry is a prospective, multicenter, multinational registry for the study and identification of the incidence, natural course, clinical outcomes, and prognostic factors for patients with significant AS at 9 centers in Asian countries. Severe AS was observed in 367 of 1066 patients with AS, and 212 were classified as very severe AS, defined as a peak aortic valve velocity >=5.0 m/s or a mean aortic valve gradient >=60 mm Hg. RESULTS: The prevalence of NYHA functional class II-IV among patients with very severe AS was significantly higher than that among patients with severe AS (67.9% vs 51.5%, P < .001). As for echocardiographic parameters, it was noteworthy that left ventricular mass index (LVMI) and left atrial volume index (LAVI) for patients with very severe AS were significantly larger than those for patients with severe AS (LVMI: 145.1 +/- 36.4 g/m2 vs 119.2 +/- 32.1 g/m2 , P < .0001; LAVI: 56.1 +/- 24.6 mL/m2 vs 49.8 +/- 22.6 mL/m2 , P = .002). Moreover, multivariate logistic regression analysis showed that LVMI was the only independently associated with NYHA functional class II-IV in patients with very severe AS. CONCLUSIONS: Our findings may well have clinical implications for better management of patients with AS and lead to better understanding of poor outcomes for patients with very severe AS. PMID- 29396866 TI - Genetic and phenotypic characterizations of drug-resistant Mycobacterium tuberculosis isolates in Cheonan, Korea. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) causes tuberculosis (TB), which is a fatal disease. Cases of drug-resistant MTB have increased in recent years. In this study, we analyzed 7 sites of MTB DNA sequences, including the rpoB and inhA gene, to investigate the relationship between gene mutations and drug resistance in MTB. METHODS: Mycobacterium tuberculosis liquid culture samples (197 specimens from 74 cases) were collected between June 2015 and May 2016 and sequenced. The results were compared with those obtained from antibiotic susceptibility tests. RESULTS: In 65 (87.8%) cases, the antibiotic-resistant phenotype was consistent with genotyping results, whereas in 9 (12.2%) cases, there was no match. Eight mutations were detected in the rpoB gene, which showed the highest mutation rate. Sequencing results indicated that these mutations were present in 12 cases. CONCLUSION: Previously published data on antibiotic resistance genes are insufficient for effective prevention of multidrug- or extensive drug-resistant TB. Additional studies are needed to characterize the complement of antibiotic resistance genes in MTB. PMID- 29396868 TI - An innovative method to quantitate tissue integration of hyaluronic acid-based dermal fillers. AB - BACKGROUND/PURPOSE: Following intradermal injection, hyaluronic acid (HA)-based fillers tend to spread within the reticular dermis and to distribute between the dermal fibers. This biointegration is commonly measured qualitatively using histological methods. We developed a "toolbox" consisting of a visual scoring and a semi-automatic image analysis method using internal developed algorithm to quantitate the biointegration of Restylane(r) in histological sections. METHODS: Restylane(r) was injected intradermally in the abdominal skin of 10 healthy human subjects scheduled for abdominoplasty. The injections were performed either in vivo before surgery or ex vivo on samples taken post-surgery at different time points. The samples were processed for histology by visual scoring and image analysis using algorithms developed in Definiens to assess biointegration. RESULTS: The image analysis segmentation was accurate with <5% manual changes. Furthermore, the results calculated with the semi-automatic method were consistent with the visual scores obtained on injected human skin samples by means of a 5-grade photographic scale. A modified hematoxylin-eosin staining was found adequate to visualize both, the filler and the general morphology, on the same section. An excellent correlation was observed between the integration results obtained with PAS/Alcian Blue and HE-stained slides, allowing for a single staining in future studies. CONCLUSION: We developed a modified HE staining histological method and a new histomorphometric image analysis tool to quantitate biointegration of HA-based fillers in human skin. The results obtained in this study confirmed the known intermediate biointegration properties of Restylane(r), thus validating these innovative methods. PMID- 29396867 TI - The GNAT: A new tool for processing NMR data. AB - The GNAT (General NMR Analysis Toolbox) is a free and open-source software package for processing, visualising, and analysing NMR data. It supersedes the popular DOSY Toolbox, which has a narrower focus on diffusion NMR. Data import of most common formats from the major NMR platforms is supported, as well as a GNAT generic format. Key basic processing of NMR data (e.g., Fourier transformation, baseline correction, and phasing) is catered for within the program, as well as more advanced techniques (e.g., reference deconvolution and pure shift FID reconstruction). Analysis tools include DOSY and SCORE for diffusion data, ROSY T1 /T2 estimation for relaxation data, and PARAFAC for multilinear analysis. The GNAT is written for the MATLAB(r) language and comes with a user-friendly graphical user interface. The standard version is intended to run with a MATLAB installation, but completely free-standing compiled versions for Windows, Mac, and Linux are also freely available. PMID- 29396869 TI - Ethnocultural influences in how people prefer to obtain and receive health information. AB - AIMS AND OBJECTIVES: To develop an understanding of south Asian and Chinese people's preferences about where to find health information and how best to receive health information, relative to their white counterparts. BACKGROUND: South Asian and Chinese ethnic groups represent the largest proportion of Canada's growing visible minorities. There may be challenges to ensuring that south Asian and Chinese people have access to health information in the same way that others do. DESIGN: Qualitative descriptive. METHODS: Fifty-two participants (12 white, 16 south Asian and 24 Chinese) engaged in six focus groups (two for each ethnocultural group). Focus groups were conducted in English, Punjabi and Cantonese, with the assistance of Punjabi and Cantonese interpreters. Questions were focused on how participants have preferred or would prefer to receive health information (e.g., when, where, what format, from whom), as well as the facilitators and barriers to understanding the health information. RESULTS: Participants agreed that although physicians were their primary source for health information, they also used written materials, media and the Internet to glean information. Participants identified concerns regarding the use of technical jargon by healthcare providers. South Asians and Chinese referred to their English language fluency and the lack of ethnoculturally specific information as additional challenges to understanding information they were offered. Whether and how family members were included in the communication process, also varied by ethnocultural group. CONCLUSIONS: As Canada welcomes immigrants from other countries, and its population becomes more diverse, healthcare providers need to have an understanding of the potential diversity in how to approach offering health information. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers need to consider what people of different ethnocultural backgrounds need when developing effective health communication strategies. PMID- 29396870 TI - Trajectories of change in cognitive function in people with chronic obstructive pulmonary disease. AB - AIMS AND OBJECTIVES: To describe changes in cognitive function, as measured by the trail making test; to identify distinct patterns of change in cognitive function; and to examine predictors of change in cognitive function in people with severe chronic obstructive pulmonary disease. BACKGROUND: How cognitive function changes in people with chronic obstructive pulmonary disease and what factors influence those changes over time is not well known, despite the fact that it declines rapidly in this population and significantly impacts functional decline in healthy older adults. DESIGN: A secondary analysis and longitudinal study with a follow-up period of 3 years. METHODS: A data set from the National Emphysema Treatment Trial provided participant data. Patients with severe chronic obstructive pulmonary disease (n = 307) were recruited at a clinical site. Several demographic and clinical measures were assessed at baseline. Trail making test scores were measured at baseline, 1, 2 and 3 years. RESULTS: Cognitive function was stable for 3 years in people with chronic obstructive pulmonary disease. However, four distinct patterns of change in cognitive function were identified. Age, education, 6-min walk distance and cognitive impairment scores at baseline on the trail making test Part B were significant predictors of worsening cognitive function and below-average cognitive function over 3 years. CONCLUSIONS: These findings suggest that increasing exercise capacity improves cognitive function and delays deterioration of cognitive function in people with COPD. RELEVANCE TO CLINICAL PRACTICE: Understanding the trajectories of change in cognitive function and predictors of change in cognitive function over 3 years may enable health care providers to identify patients at greatest risk of developing mental deterioration and those who might benefit from interventions to improve cognitive function. Health care providers should periodically assess and frequently screen people with COPD for cognitive function. PMID- 29396871 TI - Supported Porous Nanomaterials as Efficient Heterogeneous Catalysts for CO2 Fixation Reactions. AB - CO2 is a major greenhouse gas responsible for global warming and can act as an abundant and inexpensive C1 source for enhancing the chain length/functionalization of a wide range of reactive organic molecules. It is moderately reactive, nontoxic and renewable. Thus, CO2 fixation reactions are important to meet the global challenges, that is, to mitigate the concentration of CO2 in the atmosphere through its fruitful utilization, which is of great interest from economic and environmental perspectives. Various metallic nanoparticles as well as metal oxides can be supported over high surface area porous materials and the resulting nanomaterial can act as heterogeneous and reusable solid catalyst for CO2 fixation reactions for the synthesis of a large number of fuels, natural products agrochemicals, and pharmaceutical compounds. Here we present an overview of the recent progress as well as promising future of metal/metal oxide nanoparticles supported over porous nanomaterials as heterogeneous catalysts for a wide spectrum of these CO2 fixation reactions. PMID- 29396872 TI - Anatomical considerations on transposition of the lateral femoral cutaneous nerve. PMID- 29396873 TI - Clinical and molecular features of treatment-related neuroendocrine prostate cancer. AB - Treatment-related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration-resistant prostate cancer treatment. Treatment-related neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment-related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment-related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers. Clinically, it manifests with predominantly visceral or lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels or a short response duration to androgen deprivation therapy. Furthermore, although the tumor initially responds to platinum-based chemotherapy, the duration of the response is short. Based on the poor prognosis, it is imperative to identify novel molecular targets for treatment-related neuroendocrine prostate cancer. Recent advances in genomic and molecular research, supported by novel in vivo models, have identified some of the key molecular characteristics of treatment-related neuroendocrine prostate cancer. The gain of MYCN and AURKA oncogenes, along with the loss of tumor suppressor genes TP53 and RB1 are key genomic alterations associated with treatment-related neuroendocrine prostate cancer. Androgen receptor repressed genes, such as BRN2 and PEG10, are also necessary for treatment-related neuroendocrine prostate cancer. These genetic changes converge on pathways upregulating genes, such as SOX2 and EZH2, that facilitate lineage plasticity and neuroendocrine differentiation. As a result, on potent androgen receptor pathway inhibition, castration-resistant prostate cancer transdifferentiates to treatment related neuroendocrine prostate cancer in a clonally divergent manner. Further understanding of the disease biology is required to develop novel drugs and biomarkers that would help treat this aggressive prostate cancer variant. PMID- 29396874 TI - Gross anatomy examination performances in relation to medical students' knowledge of classical latin and greek. AB - The ability of medical students to acquire anatomical and medical terminologies could be influenced by their knowledge of classical Greek and Latin. In a previous study (Stephens and Moxham , Clin. Anat. 29:696at. ), it was reported that, while newly recruited medical students have a very favorable attitude toward the need to understand these classical languages, final year students see no benefit. In this study, we tested the hypothesis that, regardless of attitude, students in the initial stages of their medical education perform better at both summative and formative anatomy examinations if they have prior knowledge of Greek and Latin. First year medical students at Cardiff University who had been involved in the previous study concerning attitudes toward the relevance of the classical languages to medical education were evaluated in terms of their examination results in anatomy. Two hundred and twenty-seven students responded to a questionnaire (83% of the class) that categorized students into their linguistic knowledge and skills and their performances in formative and summative examinations were analyzed. For medical students with prior knowledge of classical Greek and Latin performed better in both summative and formative anatomy examinations. The results are therefore consistent with our hypothesis. Clin. Anat. 31:501-506, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29396875 TI - Interference of in vitro hemolysis complete blood count. AB - BACKGROUND: Hemolysis may occur in vivo, under pathological conditions, or in vitro, related to pre-analytical errors. Hemolyzed samples may produce unreliable results, leading to errors in diagnostic and monitoring evaluations. This study aims to evaluate the interference of in vitro hemolysis on the interpretation of the parameters of the blood cell-counting performed by the impedance method. METHODS: Peripheral blood samples were collected in anticoagulant K2-EDTA and subsequently divided into three 1.0 mL aliquots. The first aliquot was not subjected to any intervention, and the second and third aliquots were passed 5 and 10 times through a small-gauge needle to produce scalar amounts of hemolysis. Hematological tests were performed by Hemacounter 60-RT 7600(r) . RESULTS: Comparison of the samples with different degrees of hemolysis showed a decrease in red blood cells count and hematocrit counts and increase in mean corpuscular hemoglobin concentration and platelet count in samples with a high degree of hemolysis. According to the accepted clinical point of view, the samples with a high degree of hemolysis exceeded the desirable bias, presenting decrease in red blood cells count, hematocrit and mean corpuscular volume, and increase in red cell distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet counts. However, samples with a mild degree of hemolysis showed only a slight increase in mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count. CONCLUSION: This study demonstrated that in vitro hemolysis can decrease the clinical and analytical reliability of the assessment of the blood count. PMID- 29396876 TI - Neuronal oscillations on an ultra-slow timescale: daily rhythms in electrical activity and gene expression in the mammalian master circadian clockwork. AB - Neuronal oscillations of the brain, such as those observed in the cortices and hippocampi of behaving animals and humans, span across wide frequency bands, from slow delta waves (0.1 Hz) to ultra-fast ripples (600 Hz). Here, we focus on ultra slow neuronal oscillators in the hypothalamic suprachiasmatic nuclei (SCN), the master daily clock that operates on interlocking transcription-translation feedback loops to produce circadian rhythms in clock gene expression with a period of near 24 h (< 0.001 Hz). This intracellular molecular clock interacts with the cell's membrane through poorly understood mechanisms to drive the daily pattern in the electrical excitability of SCN neurons, exhibiting an up-state during the day and a down-state at night. In turn, the membrane activity feeds back to regulate the oscillatory activity of clock gene programs. In this review, we emphasise the circadian processes that drive daily electrical oscillations in SCN neurons, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication within this hypothalamic region and across other brain circuits. PMID- 29396877 TI - Stable Nitrogen-Centered Bis(imino)rylene Diradicaloids. AB - The synthesis of stable open-shell singlet diradicaloids is critical for their practical material application. So far, most reported examples are based on carbon-centered radicals, which are intrinsically reactive, and there are very few examples of stable nitrogen-centered diradicaloids. In this full paper, a series of soluble and stable bis(imino)rylenes up to octarylene were synthesized on the basis of newly developed dibromorylene intermediates. It was found that from hexarylene onward, these quinoidal rylenes showed open-shell singlet ground states and could be thermally populated to paramagnetic triplet aminyl diradicals. They are stable due to efficient spin delocalization onto the rylene backbone as well as kinetic blocking of the aminyl sites by the bulky and electron-deficient 2,4,6-trichlorophenyl groups. They exhibited very different electronic structures, diradical character, excited-state dynamics, one-photon absorption, two-photon absorption, and electrochemical properties from their respective aromatic rylene counterparts. These bis(imino)rylenes represent a rare class of stable, neutral, nitrogen-centered aminyl diradicaloids. PMID- 29396878 TI - "It's about fitting in with the organisation": A qualitative study of employers of nurse practitioners. AB - AIMS AND OBJECTIVES: To explore the views of employers about the value nurse practitioners (NPs) add to health services, enablers and barriers to employing NPs, and intentions to employ NPs or expand NP services in the future. BACKGROUND: Research on Australian NPs has focused on NPs' experiences or patient related factors like waiting times. Few studies have explored NP roles from the perspective of employers. Australian NPs employed by the private sector are eligible for reimbursement by the national health insurance scheme (Medicare Australia), potentially generating revenue for employers and broadening their career opportunities. We aimed to explore private sector employers' views on the barriers and facilitators to employing NPs and to identify factors affecting NP employability. DESIGN: A qualitative descriptive exploratory study. METHOD: Employers of NPs from 23 private and nonprofit health services in Western Australia were interviewed. Inductive content analysis was used to explore the data. RESULTS: Enablers to employing an NP included enhanced customer service and improved health outcomes. Barriers to employing an NP included lack of financial benefit and inadequate experience or qualifications. Employers also identified future directions for NP employability, such as filling a gap that added value to the health service. CONCLUSIONS: Employers wanted NPs to work towards a shared vision of patient care that aligned with organisational needs. RELEVANCE TO CLINICAL PRACTICE: Findings can inform NP education and workforce planning to optimally meet employer and patient health needs. PMID- 29396879 TI - Impacts of licensed premises trading hour policies on alcohol-related harms. AB - BACKGROUND AND AIM: Evaluations of alcohol policy changes demonstrate that restriction of trading hours of both 'on'- and 'off'-licence venues can be an effective means of reducing rates of alcohol-related harm. Despite this, the effects of different trading hour policy options over time, accounting for different contexts and demographic characteristics, and the common co-occurrence of other harm reduction strategies in trading hour policy initiatives, are difficult to estimate. The aim of this study was to use dynamic simulation modelling to compare estimated impacts over time of a range of trading hour policy options on various indicators of acute alcohol-related harm. METHODS: An agent-based model of alcohol consumption in New South Wales, Australia was developed using existing research evidence, analysis of available data and a structured approach to incorporating expert opinion. Five policy scenarios were simulated, including restrictions to trading hours of on-licence venues and extensions to trading hours of bottle shops. The impact of the scenarios on four measures of alcohol-related harm were considered: total acute harms, alcohol related violence, emergency department (ED) presentations and hospitalizations. RESULTS: Simulation of a 3 a.m. (rather than 5 a.m.) closing time resulted in an estimated 12.3 +/- 2.4% reduction in total acute alcohol-related harms, a 7.9 +/- 0.8% reduction in violence, an 11.9 +/- 2.1% reduction in ED presentations and a 9.5 +/- 1.8% reduction in hospitalizations. Further reductions were achieved simulating a 1 a.m. closing time, including a 17.5 +/- 1.1% reduction in alcohol related violence. Simulated extensions to bottle shop trading hours resulted in increases in rates of all four measures of harm, although most of the effects came from increasing operating hours from 10 p.m. to 11 p.m. CONCLUSIONS: An agent-based simulation model suggests that restricting trading hours of licensed venues reduces rates of alcohol-related harm and extending trading hours of bottle shops increases rates of alcohol-related harm. The model can estimate the effects of a range of policy options. PMID- 29396880 TI - Effects of perioperative warm socks-wearing in maintaining core body temperature of patients undergoing spinal surgery. AB - AIMS AND OBJECTIVES: To investigate whether warming the feet with socks would prevent hypothermia among patients undergoing spinal surgery. BACKGROUND: Perioperative hypothermia is a common health problem among spinal surgery patients. RESEARCH DESIGN: This study used a quasi-experimental design. METHODS: Seventy-two patients were assigned to two groups. The control group (n = 36) received usual care without the warmed socks. The intervention group (n = 36) received usual care plus warmed socks during operation and recovery period. Data were collected during (180 min) and after the surgery (30 min) during the period of 7 February-10 April 2015. Core body temperature, shivering response and subjective thermal comfort of the two groups were compared over time using the repeated-measures ANOVA. RESULTS: The oesophageal temperature of the socks wearing group was maintained between 36.36-36.45 degrees C during surgery (mean = 36.41 +/- 0.03, 95% CI = 36.34-36.47), whereas that of the control was between 35.75-35.97 degrees C (mean = 35.98 +/- 0.03, 95% CI = 35.92-36.04). The tympanic temperature in the recovery room of the socks-wearing group was between 36.28 36.38 degrees C (mean = 36.37 +/- 0.04, 95% CI = 36.29-36.45) and that of the control group was 35.90-36.04 degrees C (mean = 35.95 +/- 0.04, 95% CI = 35.88 36.05). Shivering response of the intervention group (mean = 0.04 +/- 0.08, 95% CI = -0.13 to 0.21) was significantly lower than that of the control group (mean = 0.47 +/- 0.08, 95% CI = 0.30-0.64) in the recovery room (F = 4.28, p < .001). As for subjective thermal comfort, the intervention group (mean = 4.86 +/- 0.13, 95% CI = 4.62-5.13) was significantly lower than that of the control group (mean = 3.08 +/- 0.13, 95% CI = 2.82-3.33) in the recovery room (F = 98.13, p < .001). As for the frequency of pethidine medication, the intervention group was significantly lower than that of the control (chi2 = 5.14, p = .023). CONCLUSION: The use of perioperative warmed socks for spinal surgery patients was effective in maintaining perioperative core temperature, preventing shivering and maintaining subjective thermal comfort. RELEVANCE TO CLINICAL PRACTICE: Considering cost-effectiveness of warmed socks, it might be worth trying option for the maintenance of core temperature in spinal surgery patients. PMID- 29396881 TI - Jean St. Germain, M.S. PMID- 29396882 TI - The impact of care practices and health demographics on the prevalence of skin tears and pressure injuries in aged care. AB - AIMS AND OBJECTIVES: To determine whether differences in care practices and demographics between two long-term aged care facilities affected the incidence of residents' skin wounds. METHODS: A retrospective analysis of care plans and clinical outcomes was conducted for a 6-month period in 2016 at two aged care facilities, N = 39 Home 1 and N = 45 Home 2. Skin tears, pressure injuries and usual care practices and associated health demographics were recorded. RESULTS: Over the 6-month period, 84 residents were found to have a total of 206 aged care acquired skin wounds (skin tears, pressure injuries, haematomas, rashes, infections). The frequency of skin tears or total wounds did not differ between the homes. Several factors were identified that influenced the skin wounds. A reduction in skin tears was associated with the use of heel protectors and antiembolic stockings, whilst a diagnosis of vascular dementia was associated with increased prevalence of skin wounds. Pressure injuries were significantly higher at Home 2. Increased use of strategies to moderate-risk activities, such as tray tables and bed rails, and impaired cognitive function were associated with higher pressure injury prevalence. CONCLUSION: A number of care factors and health demographics influenced the rate of skin wounds. A holistic approach to skin management is needed. RELEVANCE TO CLINICAL PRACTICE: Practices, such as repositioning and skin hygiene, are well known to reduce the incidence of pressure injuries and skin tears; however, there are other care practices that take place in homes as part of usual care that also impact skin wounds that have been largely ignored. This study highlights those care practices, as well as resident characteristics and comorbidities that may increase the risk of skin wounds, requiring further monitoring/mitigating strategies. PMID- 29396883 TI - Experiences of giving and receiving care in traumatic brain injury: An integrative review. AB - AIMS AND OBJECTIVES: To synthesise the literature on the experiences of giving or receiving care for traumatic brain injury for people with traumatic brain injury, their family members and nurses in hospital and rehabilitation settings. BACKGROUND: Traumatic brain injury represents a major source of physical, social and economic burden. In the hospital setting, people with traumatic brain injury feel excluded from decision-making processes and perceive impatient care. Families describe inadequate information and support for psychological distress. Nurses find the care of people with traumatic brain injury challenging particularly when experiencing heavy workloads. To date, a contemporary synthesis of the literature on people with traumatic brain injury, family and nurse experiences of traumatic brain injury care has not been conducted. DESIGN: Integrative literature review. METHODS: A systematic search strategy guided by the PRISMA statement was conducted in CINAHL, PubMed, Proquest, EMBASE and Google Scholar. Whittemore and Knafl's (Journal of Advanced Nursing, 52, 2005, 546) integrative review framework guided data reduction, data display, data comparison and conclusion verification. RESULTS: Across the three participant categories (people with traumatic brain injury/family members/nurses) and sixteen subcategories, six cross-cutting themes emerged: seeking personhood, navigating challenging behaviour, valuing skills and competence, struggling with changed family responsibilities, maintaining productive partnerships and reflecting on workplace culture. CONCLUSIONS: Traumatic brain injury creates changes in physical, cognitive and emotional function that challenge known ways of being in the world for people. This alters relationship dynamics within families and requires a specific skill set among nurses. RELEVANCE TO CLINICAL PRACTICE: Recommendations include the following: (i) formal inclusion of people with traumatic brain injury and families in care planning, (ii) routine risk screening for falls and challenging behaviour to ensure that controls are based on accurate assessment, (iii) formal orientation and training for novice nurses in the management of challenging behaviour, (iv) professional case management to guide access to services and funding and (v) personal skill development to optimise family functioning. PMID- 29396884 TI - Recognition and assessment of resident' deterioration in the nursing home setting: A critical ethnography. AB - AIMS AND OBJECTIVES: To explore the recognition and assessment of resident deterioration in the nursing home setting. BACKGROUND: There is a dearth of research exploring how nurses and personal-care-assistants manage a deteriorating nursing home resident. DESIGN: Critical ethnography. METHODS: Observation and semi-structured interviews with 66 participants (general medical practitioners, nurses, personal-care-assistants, residents and family members) in two Australian nursing homes. The study has been reported in accordance with the Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: The value of nursing assessment is poorly recognised in the nursing home setting. A lack of clarity regarding the importance of nursing assessments associated with resident care has contributed to a decreasing presence of registered nurses and an increasing reliance on personal-care-assistants who had inadequate skills and knowledge to recognise signs of deterioration. Registered nurses experienced limited organisational support for autonomous decision-making and were often expected to undertake protocol-driven decisions that contributed to potentially avoidable hospital transfers. CONCLUSIONS: Nurses need to demonstrate the importance of assessment, in association with day-to-day resident care and demand standardised, regulated, educational preparation of an appropriate workforce who are competent in undertaking this role. Workforce structures that enhance familiarity between nursing home staff and residents could result in improved resident outcomes. The value of nursing assessment, in guiding decisions at the point of resident deterioration, warrants further consideration. PMID- 29396885 TI - "Dignity": A central construct in nursing home staff understandings of quality continence care. AB - AIMS AND OBJECTIVES: To explore nursing home staff members' beliefs and expectations about what constitutes "quality continence care" for people living in nursing homes. BACKGROUND: Most nursing home residents require assistance to maintain continence or manage incontinence. Best practice guidelines promote active investigation of incontinence, treatment of underlying potentially reversible causes, and initial conservative interventions to prevent, minimise and/or treat incontinence. Despite research showing the positive benefits of implementing active interventions, translating the findings of research into practice in nursing homes has been modest. Understanding the perspectives of individuals who provide continence care may help bridge the gap between evidence and practice. DESIGN: A qualitative exploratory descriptive design. METHODS: Qualitative interviews were conducted with 19 nursing home staff: eight registered nurses, four enrolled nurses and seven personal care workers working in a nursing home in Australia between 2014-2015. Data were analysed inductively to identify themes and subthemes that described and explained staff beliefs about quality continence care in nursing homes. FINDINGS: Participants' understanding and expectations about quality continence care were linked to beliefs about incontinence being an intractable and undignified condition in nursing homes. The key theme to emerge was "protecting residents' dignity" which was supported by the following six subthemes: (i) using pads, ii) providing privacy, (iii) knowing how to "manage" incontinence, (iv) providing timely continence care, (v) considering residents' continence care preferences and (vi) communicating sensitively. CONCLUSION: The findings provide new insight into the basis for continence care practices in nursing homes. Education about continence care should challenge beliefs that limit continence care practice to cleaning, containing and concealing incontinence. There is a need for a multidimensional framework that is informed by social, psychological and biomedical research about incontinence, research about the fundamental elements of care, care-dependent individuals' expectations about care, and values about dignity and care. RELEVANCE TO CLINICAL PRACTICE: The in-depth exploration led to an understanding of the basis for continence care practices that centre on cleaning, containing and concealing residents' incontinence in some nursing homes. There is a need to review the quality of education for the aged care workforce about incontinence to ensure it equips them with a broad understanding of the fundamentals of care and how to enact dignity in continence care through a resident-centred approach. PMID- 29396886 TI - Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial-mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti-inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF-kappaB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF-kappaB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF-kappaB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E-cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E-cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF-kappaB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC. PMID- 29396887 TI - A staging table for the embryonic development of the brownbanded bamboo shark (Chiloscyllium punctatum). AB - BACKGROUND: Studying cartilaginous fishes (chondrichthyans) has helped us understand vertebrate evolution and diversity. However, resources such as genome sequences, embryos, and detailed staging tables are limited for species within this clade. To overcome these limitations, we have focused on a species, the brownbanded bamboo shark (Chiloscyllium punctatum), which is a relatively common aquarium species that lays eggs continuously throughout the year. In addition, because of its relatively small genome size, this species is promising for molecular studies. RESULTS: To enhance biological studies of cartilaginous fishes, we establish a normal staging table for the embryonic development of the brownbanded bamboo shark. Bamboo shark embryos take around 118 days to reach the hatching period at 25 degrees C, which is approximately 1.5 times as fast as the small-spotted catshark (Scyliorhinus canicula) takes. Our staging table divides the embryonic period into 38 stages. Furthermore, we found culture conditions that allow early embryos to grow in partially opened egg cases. CONCLUSIONS: In addition to the embryonic staging table, we show that bamboo shark embryos exhibit relatively fast embryonic growth and are amenable to culture, key characteristics that enhance their experimental utility. Therefore, the present study is a foundation for cartilaginous fish research. Developmental Dynamics 247:712-723, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29396888 TI - Challenges in the transition to clinical training in dentistry: An ADEE special interest group initial report. AB - INTRODUCTION: Curricular integration in higher education has been widely supported in the educational literature. As a result, several health care and specifically dental curricula have evolved from compartmentalised disciplinary training to integrated modalities; however, in many courses, a pre-clinical clinical watershed remains a barrier to integration in dental education. This article introduces a general description of the pre-clinical-clinical transition in dentistry according to the outcomes of the discussion held during the first working group session of the "Transition to Clinical Training" Special Interest Group during the 2016 annual meeting of the Association for Dental Education in Europe. MATERIALS AND METHODS: An online questionnaire was made available before the meeting to survey the curricular characteristics of the participants' schools. During the meeting, a working session related to the pre-clinical clinical transition occurred. Conclusions from the discussion are summarised in this article. RESULTS: Fourteen dental schools from 12 countries participated in the online survey. The included programmes had an average duration of 5.3 years (SD = 0.48), with high school or the local equivalent as the required entrance level for dentistry. The hybrid curriculum was the leading curriculum design (n = 9) followed by competence-based curricula (n = 3), with patient treatment as the core of clinical training in every included programme. CONCLUSION: The pre clinical-clinical transition in dentistry is a recognisable matter in dental education that requires assessment and research to ease the management of a stage with relevant influence on educational outcomes. This article presents an initial framework for further research and educational intervention. PMID- 29396889 TI - Inertia in nursing care of hospitalised patients with urinary incontinence. AB - AIMS AND OBJECTIVES: To assess the existence of therapeutic inertia in the nursing care of patients with urinary incontinence during the patient's time in hospital, together with the sociodemographic and professional variables involved. BACKGROUND: Inertia in care is a problem which appears in the nursing care process. Actions related to inertia can be attributed to not adhering to protocols, clinical guidelines and the lack of prevention measures which have undesirable effects on the efficiency of care. DESIGN: This was a prospective observational study. METHODS: A total of 132 nursing professionals participated over two consecutive months. Data were collected randomly through the method of systematic, nonparticipative observation of medical practice units and patients' medical records. RESULTS: The results showed a pattern of severely compromised action in the assessment of the pattern of urinary elimination, in actions related to urinary continence, in therapeutic behaviour and in patient satisfaction and were found to be consistent with professional experience (p < .05). In the 600 records analysed, no statistically significant differences were found between gender and the use of records. In 50% (n = 301), the use of a rating scale was not reflected. In over 90% (n = 560) of cases, the type of incontinence was not recorded. In no continuity of care report were recommendations regarding incontinence included, nor was the type of continence products recommended indicated. CONCLUSION: It is clear that inertia exists in nursing care in the hospital environment while the patient is hospitalised, in prevention care, in the treatment of urinary incontinence and in the management of records. RELEVANCE TO CLINICAL PRACTICE: Contributing to the understanding of the existence of inertia in nursing care raises questions regarding its causes and interventions to predict or monitor it. PMID- 29396890 TI - Duplicated FoxA genes in the leech Helobdella: Insights into the evolution of direct development in clitellate annelids. AB - BACKGROUND: As an adaptation to the land, the clitellate annelid had reorganized its embryogenesis to develop "directly" without the ancestral planktonic larval stage. To study the evolution of gut development in the directly developing clitellates, we characterized the expression pattern of the conserved gut gene, FoxA, in the embryonic development of the leech. RESULTS: The leech has three FoxA paralogs. Hau-FoxA1 is first expressed in a subset of endoderm cells and then in the foregut and the midgut. Hau-FoxA2 is expressed in the stomodeum, which is secondarily derived from the anterior ectoderm in the clitellates rather than the tissue around the blastopore, the ancestral site of mouth formation in Phylum Annelida. Hau-FoxA3 is expressed during the morphogenesis of segmental ganglia from the ectodermal teloblast lineages, a clitellate-specific trait. Hau FoxA1 and Hau-FoxA2 are also expressed during the morphogenesis of the leech specific front sucker. CONCLUSIONS: The expression patterns suggested that Hau FoxA1 carries out most of the conserved function in the endoderm and gut development, while the other two duplicates appear to have evolved unique novel functions in the directly developing clitellate embryos. Therefore, neofunctionalization and co-option of FoxA might have made a significant contribution to the evolution of direct development in Clitellata. Developmental Dynamics 247:763-778, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29396892 TI - Diastolic pressure indices offer a novel approach to predicting risk of graft loss after pediatric heart transplant. AB - PH is a risk factor for GL after HTx. However, traditional parameters are not reliable predictors of risk in children. We hypothesized that DPI (dPAP and DPG) are predictive of GL in pediatric HTx recipients. The UNOS/SRTR database was reviewed to identify pediatric HTx recipients (age <18 years) between 1994 and 2013. Recipients with pretransplant hemodynamic data were grouped by diagnosis (CMP or CHD), and the groups were analyzed separately. Bivariate Cox regression analysis examined the association between hemodynamic variables and GL. DPI showed the strongest association with early GL in recipients with CMP (dPAP: HR = 1.25 [1.09-1.42]; DPG: 1.24 [1.11-1.38]). Among CHD recipients, DPI were associated with early GL in those with preexisting PH (dPAP: HR = 1.16 [1.01 1.33]; DPG: HR = 1.10 [1.00-1.21]). No cutoff values for "high-risk" DPI were identified, but a continuous relationship between higher DPI and risk of early GL was observed. DPI are associated with early GL in select pediatric HTx recipients. Our findings suggest that DPI should be considered as part of routine hemodynamic assessment for pediatric HTx candidates. PMID- 29396893 TI - Aging-related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes. AB - Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl-insoluble fractions reveal a pattern of phospho-tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen in AD. Phosphoproteomics of dissected vulnerable regions identifies an increase of phosphorylation marks in a large number of proteins in ARTAG compared with controls. GFAP, aquaporin 4, several serine-threonine kinases, microtubule associated proteins and other neuronal proteins are among the differentially phosphorylated proteins in ARTAG thus suggesting a hyper-phosphorylation background that affects several molecules, including many kinases and proteins from several cell compartments and various cell types. Finally, present results show for the first time that tau seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type mice of sarkosyl insoluble fractions enriched in hyper-phosphorylated tau from selected ARTAG cases. These findings show astrocytes as crucial players of tau seeding in tauopathies. PMID- 29396891 TI - The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. AB - Bone marrow derived mesenchymal stromal cells have been shown to have significant therapeutic effects in experimental models of pneumonia and lung injury. The current study examined the roles of the toll like receptor 4 (TLR4) and protease activated receptor 1 (PAR1) pathways on mesenchymal stromal cell (MSC) survival and therapeutic activity in a murine model of pneumonia. MSCs from TLR4 -/- and R41Q-PAR1 mutated mice were isolated to test the effect of mutating these specific pathways on MSC survival when exposed to cytotoxic stimuli in vitro. An Escherichia coli pneumonia model was used to assess the effect of these specific pathways on MSC therapeutic activity in vivo. Our results showed that mutation of either the TLR4 or PAR1 pathways in MSCs impaired cell survival under conditions of inflammatory stress in vitro, and eliminated their therapeutic efficacy in vivo. Also, stimulation of the TLR4 pathway on MSCs led to secretion of low levels of prothrombin by MSCs, while disrupting the TLR4 pathway impaired canonical signaling through PAR1 in response to thrombin. Therefore, this study demonstrates that both TLR4 and PAR1 are required for MSC survival under inflammatory conditions in vitro and therapeutic capacity in vivo, and that the TLR4 pathway regulates signaling through PAR1 on MSCs. Stem Cells 2018;36:796 806. PMID- 29396894 TI - Convolution-based modified Clarkson integration (CMCI) for electron cutout factor calculation. AB - Electron therapy is widely used to treat shallow tumors because of its characteristic sharp dose fall-off beyond a certain range. A customized cutout is typically applied to block radiation to normal tissues. Determining the final monitor unit (MU) for electron treatment requires an output factor for the cutout, which is usually generated by measurement, especially for highly irregular cutouts. However, manual measurement requires a lengthy quality assurance process with possible errors. This work presents an accurate and efficient cutout output factor prediction model, convolution-based modified Clarkson integration (CMCI), to replace patient-specific output factor measurement. Like the Clarkson method, we decompose the field into basic sectors. Unlike the Clarkson integration method, we use annular sectors for output factor estimation. This decomposition method allows calculation via convolution. A 2D distribution of fluence is generated, and the output factor at any given point can be obtained. We applied our method to 10 irregularly shaped cutouts for breast patients for 6E, 9E, and 15E beams and compared the results with measurements and the electron Monte Carlo (eMC) calculation using the Eclipse planning system. While both the CMCI and eMC methods showed good agreement with chamber measurements and film measurements in relative distributions at the nominal source to surface distance (SSD) of 100 cm, eMC generated larger errors than the CMCI method at extended SSDs, with up to -9.28% deviations from the measurement for 6E beam. At extended SSD, the mean absolute errors of our method relative to measurements were 0.92 and 1.14, while the errors of eMC were 1.42 and 1.79 for SSD 105 cm and 110 cm, respectively. These results indicate that our method is more accurate than eMC, especially for low-energy beams, and can be used for MU calculation and as a QA tool for electron therapy. PMID- 29396895 TI - Spin-orbit effects on magnetically induced current densities in the M5- (M = N,P,As,Sb,Bi,Mc) clusters. AB - This study reports the spin-orbit effects on the aromaticity of the N5-, P5-, As5 , Sb5-, Bi5-, and Mc5- anionic clusters via the magnetically induced current density method. All-electron density functional theory (DFT) calculations were carried out using the four-component Dirac-Coulomb (DC) hamiltonian, including scalar and spin-orbit relativistic effects. The magnetic index of aromaticity was calculated by numerical integration over the current flow between two atoms in the pentagonal ring. These values were compared to the spin-free values (spin orbit coupling switched off), in order to assess the spin-orbit effect on aromaticity. It was found that in the heavy anions, Bi5- and Mc5-, there is a significant influence of the spin-orbit coupling. (c) 2018 Wiley Periodicals, Inc. PMID- 29396896 TI - A new discussion of the cutaneous vascular reactivity in sensitive skin: A sub group of SS? AB - BACKGROUND: Sensitive skin (SS) seems not to be a one-dimensional condition and many scholars concentrate on skin barrier disruption or sensorineural change, but few focus on its increased vascular reactivity. This study explored the possibility of using the different selection methods and measurement methods to verify a high vascular reactivity in SS without an impaired cutaneous barrier function. METHODS: Sixty "self-perceived sensitive skin" volunteers were enlisted and each one completed three kinds of screening tests: assess cutaneous sensory using questionnaire survey and Lactic Acid Sting Test (LAST); assess barrier function using Sodium lauryl sulphate (SLS) skin irritation test and assess cutaneous vascular reactivity using 98% DMSO test and non-invasive measurement. Volunteers were divided into different groups based on response to SLS. The DMSO clinical score and the biophysical parameters obtained by non-invasive measurement were subsequently analysed. RESULTS: (1) The positive correlations could be seen between sum LAST score and sum DMSO score regardless of the observation time; (2) The biological parameters (CBF,a*values and L* values) are all keeping with DMSO score; (3) If the participants were divided into SLS reactors and non-reactors, a composition ratio of DMSO score was significant difference in these two groups and in SLS non-reactors, there were still seven participants showed high reaction to DMSO. CONCLUSIONS: There is a sub-group of SS for characteristics of a high vascular reactivity without an impaired cutaneous barrier function. The DMSO test and novel non-invasive measurements which are conducive to assess cutaneous vascular reactivity, combined with SLS skin irritation test could help us to screen this kind of SS. PMID- 29396897 TI - Four-year follow-up of an internet-based brief intervention for unhealthy alcohol use in young men. AB - AIM: To estimate the long-term efficacy of an internet-based brief intervention (IBI) in decreasing alcohol use among men on (1) number of drinks/week and (2) monthly or more binge drinking prevalence. In addition, overall changes in alcohol use were assessed. DESIGN: Participants in a cohort study were recruited in a two parallel-group randomized controlled trial of an IBI versus no intervention control condition, showing a positive intervention effect at 6 months. As part of the regular cohort assessments, participants were re-assessed 47 months after the initial trial, offering an opportunity to determine long-term efficacy. SETTING: Young Swiss men from the general population. PARTICIPANTS: Of 737 randomized trial participants with unhealthy alcohol use (> 14 drinks/week or >= 6 drinks/occasion at least monthly, or Alcohol Use Disorders Identification Test (AUDIT) >= 8), 626 completed a cohort assessment at mean +/- standard deviation (SD) = 47.4 +/- 2.6) months after their randomized trial baseline assessment. INTERVENTION: IBI included normative and personalized feedback on alcohol use, risk indicators, information about alcohol and health and recommendations; controls: assessment only. MEASUREMENTS: Self-reported number of drinks/week and monthly or more binge drinking prevalence. FINDINGS: Comparisons at follow-up were adjusted for baseline drinking. Missing values were replaced with the last observation carried forward. There was no evidence of differences between the IBI and control group on either the number of drinks/week [IBI: 10.8 (14.2); control: 10.7 (14.1), P = 0.8] or monthly or more binge drinking prevalence (IBI: 65.1%; control: 63.5%, P = 0.5). Although there was no evidence of overall change from baseline in number of drinks/week [9.8 (7.9) at baseline, 10.8 (14.1) at 47 months, P = 0.051], there was evidence that monthly or more binge drinking prevalence had decreased during the follow-up time (84.9% at baseline, 64.3% at 47 months, P < 0.001). CONCLUSIONS: An internet-based brief intervention directed at unhealthy alcohol use among young men does not appear to reduce drinking over the long-term. PMID- 29396898 TI - Quantitative estimation of progression of chronic liver disease using gadoxetate disodium-enhanced magnetic resonance imaging. AB - AIM: The purpose of this study was to determine whether the liver stiffness (LS) measured on magnetic resonance (MR) elastography can be estimated by a combination of gadoxetate disodium-enhanced MR imaging (EOB-MRI) and ordinary blood tests. METHODS: We evaluated 33 consecutive patients with suspected liver disease who underwent EOB-MRI using a Differential Subsampling with Cartesian Ordering MR sequence and MR elastography using a 1.5-T MR system in this prospective study. A stepwise multiple linear regression model analysis of LS was performed using various predictive values obtained from two-in-one-uptake, two compartment model analysis of EOB-MRI (velocity constants of arterial inflow [K1a ], portal venous inflow [K1p ], hepatocellular uptake [Ki ]), and ordinary blood test results (blood platelet count, serum albumin level [ALB], total serum bilirubin level [T-BIL], and prothrombin time [PT%]). RESULTS: Multiple linear regression model analysis revealed that hepatic perfusion-uptake index (HPUI = K1a + K1p + Ki ) (P < 0.0001), albumin-bilirubin linear predictor (ALBI-LP = 0.66 * log10 T-BIL - 0.085 * ALB) (P = 0.034), and blood platelet count (P = 0.046) were significant independent predictors of LS (r = 0.863). The area under receiver operator characteristics curve of multiple linear regression model in prediction of the liver stiffness corresponding to higher (LS > 5.0 kPa) and lower (LS < 4.2 kPa) risk for developing hepatocellular carcinoma were 0.956 and 0.938, respectively. CONCLUSION: LS can be estimated quantitatively with the use of HPUI obtained from compartment model analysis of EOB-MRI combined with ALBI-LP and blood platelet count. PMID- 29396899 TI - Predictive factors of satisfaction and quality of life after immediate breast reconstruction using the BREAST-Q(c). AB - AIMS AND OBJECTIVES: To analyse quality of life and satisfaction after immediate breast reconstruction due to cancer and its determining factors. BACKGROUND: Studying breast reconstruction is important because of its frequency and variability. In addition to the surgical results, it is necessary to analyse the quality of life and patient satisfaction using a specific tool. DESIGN METHODS: An ambispective design was used (n = 101; alpha = 0.05; precision = 10%), studying anthropometric, sociocultural data, Fagerstrom test and the BREAST-Q(c) questionnaire. A logistic regression analysis was performed to identify variables associated with quality of life and satisfaction. RESULTS: Mean age of the patients on diagnosis was 44.87 +/- 8.5 years. Forty-one of the patients were carried out a skin-sparing mastectomy (42.7%). Immediate reconstruction was performed with implant in 73 (74.5%). The domains on the BREAST-Q(c) for quality of life with the lowest scores were physical well-being chest (74) and sexual well-being (61.5). The satisfaction domain with the lowest score was with the breast (59). The variables associated with the worst quality of life in the physical well-being chest domain were the skin-sparing mastectomy (OR, 4.2; 95% confidence interval (CI), 1.2-14.1) and lymphedema (OR, 12.9; 95% CI, 1.0-159.9). Antibody treatment was associated with a worse score on the psychosocial well being domain (OR, 4.25; 95% CI, 1.0-18.0) and sexual well-being domain (OR, 7.34; 95% CI, 0.9-54.6). Satisfaction was associated with nicotine dependence on the breast and outcome scale. The higher the dependence on nicotine, the greater the dissatisfaction with the breasts (OR, 2.41; 95% CI, 1.1-5.3) and with the result (OR, 2.45; 95% CI, 1.0-5.9). CONCLUSIONS: The type of treatment and lymphedema modify the patients' quality of life. Nicotine dependence is associated with lower satisfaction with the breast and with the outcome. RELEVANCE TO CLINICAL PRACTICE: This study suggests the need for multidisciplinary attention during the first year of adjuvant treatment despite the benefits of immediate reconstruction. It shows the need for preoperative assessment of the level of nicotine dependence, anxiety and depression of smoking patients before preoperative counselling. PMID- 29396900 TI - Effects of early antiplatelet therapy after splenectomy with gastro-oesophageal devascularization. AB - BACKGROUND: This study aimed to explore the effects of early antiplatelet therapy (APT) for portal vein thrombosis (PVT) in patients with cirrhotic portal hypertension after splenectomy with gastro-oesophageal devascularization. METHODS: We retrospectively analysed 139 patients who underwent splenectomy with gastro-oesophageal devascularization for portal hypertension due to cirrhosis between April 2010 and December 2016. Based on the post-operative platelet values, we used two different APT regimens: APT was started when platelet counts were increased to 200 * 109 /L or above (group A, n = 64) or 300 * 109 /L or above (group B, n = 75). We took note of the patients' clinical symptoms, operative factors and biochemical indicators. RESULTS: Platelet count, mean platelet volume, D-dimer and pancreatic fistula were closely related to the development of PVT. Early APT was an independent protective factor for PVT. The incidence of post-operative PVT was 15.1% (21/139) overall, 4.7% (3/64) in group A and 24% (18/75) in group B; there was a significant difference between groups A and B (chi2 = 10.042, P = 0.002). CONCLUSION: Platelet count, mean platelet volume, D-dimer and pancreatic fistula were independent risk factors for the development of PVT after splenectomy with gastro-oesophageal devascularization. Selection of the appropriate timing for early APT according to the post-operative platelet count was feasible. Moreover, the use of aspirin combined with dipyridamole was safe and effective for early prevention of PVT. PMID- 29396901 TI - Fine Tuning of Canonical Wnt Stimulation Enhances Differentiation of Pluripotent Stem Cells Independent of beta-Catenin-Mediated T-Cell Factor Signaling. AB - The canonical Wnt/beta-catenin pathway is crucial for early embryonic patterning, tissue homeostasis, and regeneration. While canonical Wnt/beta-catenin stimulation has been used extensively to modulate pluripotency and differentiation of pluripotent stem cells (PSCs), the mechanism of these two seemingly opposing roles has not been fully characterized and is currently largely attributed to activation of nuclear Wnt target genes. Here, we show that low levels of Wnt stimulation via ectopic expression of Wnt1 or administration of glycogen synthase kinase-3 inhibitor CHIR99021 significantly increases PSC differentiation into neurons, cardiomyocytes and early endodermal intermediates. Our data indicate that enhanced differentiation outcomes are not mediated through activation of traditional Wnt target genes but by beta-catenin's secondary role as a binding partner of membrane bound cadherins ultimately leading to the activation of developmental genes. In summary, fine-tuning of Wnt signaling to subthreshold levels for detectable nuclear beta-catenin function appears to act as a switch to enhance differentiation of PSCs into multiple lineages. Our observations highlight a mechanism by which Wnt/beta-catenin signaling can achieve dosage dependent dual roles in regulating self-renewal and differentiation. Stem Cells 2018;36:822-833. PMID- 29396902 TI - Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells. AB - Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL 17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17 expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914. PMID- 29396903 TI - Topical fluoride use: Knowledge, attitudes and practices of undergraduate dental students of three Dental Colleges in South India. AB - OBJECTIVES: For effective utilisation of topical fluorides in caries prevention, dental professionals should have adequate knowledge regarding its appropriate use. The decision regarding preventive treatments like topical fluorides is influenced by knowledge acquired during undergraduate training. The aim of this study was to assess the knowledge, attitudes and practices of undergraduate dental students in the use of topical fluorides. METHODOLOGY: A descriptive cross sectional questionnaire study was conducted from June to August 2015 following ethical clearance. Three willing Dental Colleges from 3 states of South India participated. Information regarding the knowledge, attitudes and practices of students in the use of topical fluorides was collected using a validated questionnaire. RESULTS: Nine hundred and seventy-two dental students (79.6% females, 20.4% males) participated. Freshers and preclinical batches had poor overall knowledge of fluorides, which did not show substantial improvement by internship. Self-applied topical fluoride use (fluoridated toothpaste) was seen in more than 90% of interns, and majority had "positive fluoride attitude." Having knowledge of topical fluorides and positive attitudes to topical fluorides did not result in "good oral self-care behaviour" nor appropriate clinical use of topical fluorides. Students who used topical fluorides for persons with history of caries had highest odds of brushing twice a day (OR = 2.7, 95% CI = 1.54, 4.12) and a "positive fluoride attitude" (OR = 1.2, 95% CI = 0.21, 1.57). CONCLUSION: Dental students showed deficiencies in their knowledge and understanding of topical fluorides. Dental education in India needs emphasis on topical fluorides across all years, with a special focus on caries risk-based topical fluoride use. PMID- 29396905 TI - Transplant-related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis. AB - The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant-related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high-risk group (P = .006). High-risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies. PMID- 29396906 TI - Surface sulfonamide modification of poly(N-isopropylacrylamide)-based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake. AB - Two different surface sulfonamide-functionalized poly(N-isopropylacrylamide) based polymeric micelles were designed as pH-/temperature-responsive vehicles. Both sulfadimethoxine- and sulfamethazine-surface functionalized micelles were characterized to determine physicochemical properties, hydrodynamic diameters, zeta potentials, temperature-dependent size changes, and lower critical solution temperatures (LCST) in both pH 7.4 and 6.8 solutions (simulating both physiological and mild low pH conditions), and tested in the incorporation of a proof-of-concept hydrophobic antiproliferative drug, paclitaxel. Cellular uptake studies were conducted using bovine carotid endothelial cells and fluorescently labeled micelles to evaluate if there was enhanced cellular uptake of the micelles in a low pH environment. Both variations of micelles showed enhanced intracellular uptake under mildly acidic (pH 6.8) conditions at temperatures slightly above their LCST and minimal uptake at physiological (pH 7.4) conditions. Due to the less negative zeta potential of the sulfamethazine-surface micelles compared to sulfadimethoxine-surface micelles, and the proximity of their LCST to physiological temperature (37 degrees C), the sulfamethazine variation was deemed more amenable for clinically relevant temperature and pH stimulated applications. Nevertheless, we believe both polymeric micelle variations have the capacity to be implemented as an intracellular drug or gene delivery system in response to mildly acidic conditions. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1552-1560, 2018. PMID- 29396904 TI - A Lucifer-Based Environment-Sensitive Fluorescent PNA Probe for Imaging Poly(A) RNAs. AB - Fluorescence-based oligonucleotide (ON) hybridization probes greatly aid the detection and profiling of RNA sequences in cells. However, certain limitations such as target accessibility and hybridization efficiency in cellular environments hamper their broad application because RNAs can form complex and stable structures. In this context, we have developed a robust hybridization probe suitable for imaging RNA in cells by combining the properties of 1) a new microenvironment-sensitive fluorescent nucleobase analogue, obtained by attaching the Lucifer chromophore (1,8-naphthalimide) at the 5-position of uracil, and 2) a peptide nucleic acid (PNA) capable of forming stable hybrids with RNA. The fluorescence of the PNA base analogue labeled with the Lucifer chromophore, when incorporated into PNA oligomers and hybridized to complementary and mismatched ONs, is highly responsive to its neighboring base environment. Notably, the PNA base reports the presence of an adenine repeat in an RNA ON with reasonable enhancement in fluorescence. This feature of the emissive analogue enabled the construction of a poly(T) PNA probe for the efficient visualization of polyadenylated [poly(A)] RNAs in cells-poly(A) being an important motif that plays vital roles in the lifecycle of many types of RNA. Our results demonstrate that such responsive fluorescent nucleobase analogues, when judiciously placed in PNA oligomers, could generate useful hybridization probes to detect nucleic acid sequences in cells and also to image them. PMID- 29396907 TI - Direct and Regioselective Amination of beta-Unsubstituted 5,15-Diazaporphyrins with Amines: A Convenient Route to Near-Infrared-Responsive Diazaporphyrin Sensitizers. AB - We have established a convenient method for the base-promoted direct amination of beta-unsubstituted 5,15-diazaporphyrins (DAPs) with secondary and primary amines to produce 3,7,13,17-tetraamino- and 3-amino-DAPs, respectively, regioselectively. The amino groups attached at the periphery cause significant red shifts of the absorption bands as a result of their perturbation of the HOMO and/or LUMO in the DAP pi-system. The palladium complex of a 3,7,13,17 tetrakis(diphenylamino)-DAP generated singlet oxygen in high yield under irradiation with near-infrared light. PMID- 29396908 TI - Mice Fed a High-Cholesterol Diet Supplemented with Quercetin-3-Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas. AB - SCOPE: Hepatic LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) regulate the clearance of plasma LDL-cholesterol (LDL-C): LDLR promotes it, and PCSK9 opposes it. These proteins also express in pancreatic beta cells. Using cultured hepatocytes, we previously showed that the plant flavonoid quercetin-3-glucoside (Q3G) inhibits PCSK9 secretion, stimulated LDLR expression, and enhanced LDL-C uptake. Here, we examine whether Q3G supplementation could reverse the hyperlipidemia and hyperinsulinemia of mice fed a high-cholesterol diet, and how it affects hepatic and pancreatic LDLR and PCSK9 expression. METHODS AND RESULTS: For 12 weeks, mice are fed a low- (0%) or high- (1%) cholesterol diet (LCD or HCD), supplemented or not with Q3G at 0.05 or 0.1% (w/w). Tissue LDLR and PCSK9 is analyzed by immunoblotting, plasma PCSK9 and insulin by ELISA, and plasma cholesterol and glucose by colorimetry. In LCD-fed mice, Q3G has no effect. In HCD-fed mice, it attenuates the increase in plasma cholesterol and insulin, accentuates the decrease in plasma PCSK9, and increases hepatic and pancreatic LDLR and PCSK9. In cultured pancreatic beta cells, however, it stimulates PCSK9 secretion. CONCLUSION: In mice, dietary Q3G could counter HCD-induced hyperlipidemia and hyperinsulinemia, in part by oppositely modulating hepatic and pancreatic PCSK9 secretion. PMID- 29396909 TI - Comparative Study of Different Polar Groups of EPA-Enriched Phospholipids on Ameliorating Memory Loss and Cognitive Deficiency in Aged SAMP8 Mice. AB - SCOPE: Recent studies have shown that omega-3 PUFAs enriched phospholipids (n-3 PUFA-PLs) have beneficial effects on memory and cognition. However, most reports only attribute the benefit to docosahexaenoic acid (DHA) and pay little attention to eicosapentaenoic acid (EPA). METHODS AND RESULTS: We investigate the effect of EPA-enriched phospholipids on cognitive deficiency in senescence-accelerated prone 8 (SAMP8) mouse. Ten-month-old SAMP8 mice are fed with 2% (w/w) EPA enriched phosphatidylcholine/phosphatidyl ethanolamine (EPA-PC/PE; EPA:DHA = 46.8:3.01) or 2% EPA-enriched phosphatidylserine (EPA-PS; biosynthesized from EPA PC/PE) for 8 weeks; we then test the behavioral performances in the Barnes maze test and Morris maze test; the changes of oxidative stress, apoptosis, neurotrophic factors, tau phosphorylation, and Abeta pathology are also measured. The results of behavior tests indicate that both EPA-PC/PE and EPA-PS significantly improve memory and cognitive deficiency. It is found that remarkable amelioration of oxidative stress and apoptosis occurs in both EPA PC/PE and EPA-PS groups. EPA-PS shows more ameliorative effects than EPA-PC/PE on neurotrophic activity by decreasing hyper-phosphorylation of tau and depressing the generation and accumulation of beta-amyloid peptide (Abeta). CONCLUSION: These data suggest that EPA-PS exhibits better effects than EPA-PC/PE on ameliorating memory and cognitive function, which might be attributed to the phospholipid polar groups. PMID- 29396910 TI - Superior bone-inducing potential of rhBMP9 compared to rhBMP2. AB - Recombinant human bone morphogenic protein (rhBMP) 9 has recently been reported to have more osteopromotive potential in vitro when compared to rhBMP2. The aim of the present study was to investigate the bone-inducing potential of rhBMP2 and rhBMP9. We compared rhBMP2, rhBMP7, and rhBMP9 at five different concentrations and showed convincingly that rhBMP9 possesses much greater potential for osteoblast differentiation even at 20 times lower concentrations in vitro. We further show that Noggin, an inhibitor for rhBMP2-induced osteogenesis, did not alter rhBMP9-induced osteogenesis. Thereafter, we show for the first time that rhBMP9 loaded onto atelo-collagen membranes is osteoinductive and has greater potential to form ectopic bone formation when compared to rhBMP2 even at four times lower doses. Similarly new bone formation of rhBMP2 and 9 when loaded on deproteinized bovine bone mineral (DBBM) was investigated in a rabbit calvarial defect. At 8 weeks, both rhBMP2 and rhBMP9 induced significantly higher new bone formation when compared to DBBM alone samples. Interestingly, once again four times lower dose of rhBMP9 group induced comparable or even greater levels of new bone height and new bone area when compared to the rhBMP2 group. The present study revealed that (1) rhBMP9 is capable of inducing ectopic new bone formation in vivo and (2) up to four times lower doses of rhBMP9 may be utilized to regenerate same-size bone defects when compared to rhBMP2. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1561-1574, 2018. PMID- 29396911 TI - Combining pure shift and J-edited spectroscopies: A strategy for extracting chemical shifts and scalar couplings from highly crowded proton spectra of oligomeric saccharides. AB - We report the application of pure shift and J-edited nuclear magnetic resonance spectroscopies to the structural analysis of a protected maltotrioside synthetic intermediate whose crowded 1 H spectrum displays highly crowded regions. The analytical strategy is based on the implementation of J-edited and TOCSY experiments whose resolution is optimized by the use of broadband homonuclear decoupling and selective refocusing techniques, to assign and measure chemical shifts and homonuclear scalar couplings with high accuracy. The resulting data show a high level of complementarity, providing a detailed insight into each subunit of this oligomeric saccharide, even for proton sites whose nuclear magnetic resonance signals strongly overlap. This approach allowed for fully assigning proton chemical shifts and extracting 80% of the 3 JHH couplings that are in excellent agreement with those expected for D-gluco-pyranosyl units in 4 C1 conformations. PMID- 29396912 TI - Three-dimensional plotted alginate fibers embedded with diclofenac and bone cells coated with chitosan for bone regeneration during inflammation. AB - Alginate hydrogel fibers embedded with bone cells and diclofenac were coated with a layer of chitosan hydrogel and made into a porous scaffold by three-dimensional (3D) printing for drug release and bone regeneration. It was hypothesized that the chitosan coating could improve the scaffold's drug retention and release properties and biocompatibility. Macrophage cells were stimulated and cocultured with the scaffold. Tests were conducted to show how the chitosan coating affected the scaffold's drug release efficacy and how the release efficacy affected the cellular activities of stimulated macrophages and bone cells. The bone cells encapsulated in the coated scaffold demonstrated good viability after the acidic/basic coating process. The coating improved the retention and release efficacy of diclofenac and hence significantly inhibited interleukin-6 and tumor necrosis factor-alpha secretion from macrophages (p < 0.05). The bone cells in the coated sample mineralized more extensively than the control (p < 0.01). They also more actively expressed genes that produce proteins for extracellular matrix remodeling, MMP13, and interacting with the mineral matrix, OPN (both p < 0.01). It is believed that on days 7 and 10, when diclofenac was depleted and the concentrations of inflammatory compounds surged, the coating effectively blocked the harmful compounds and protected the bone cells within the fibers. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1511-1521, 2018. PMID- 29396914 TI - The surgical treatment of intramedullary spinal cord tumors: A retrospective analysis of 76 patients. PMID- 29396913 TI - DNA gyrase activity regulates DnaA-dependent replication initiation in Bacillus subtilis. AB - In bacteria, initiation of DNA replication requires the DnaA protein. Regulation of DnaA association and activity at the origin of replication, oriC, is the predominant mechanism of replication initiation control. One key feature known to be generally important for replication is DNA topology. Although there have been some suggestions that topology may impact replication initiation, whether this mechanism regulates DnaA-mediated replication initiation is unclear. We found that the essential topoisomerase, DNA gyrase, is required for both proper binding of DnaA to oriC as well as control of initiation frequency in Bacillus subtilis. Furthermore, we found that the regulatory activity of gyrase in initiation is specific to DnaA and oriC. Cells initiating replication from a DnaA-independent origin, oriN, are largely resistant to gyrase inhibition by novobiocin, even at concentrations that compromise survival by up to four orders of magnitude in oriC cells. Furthermore, inhibition of gyrase does not impact initiation frequency in oriN cells. Additionally, deletion or overexpression of the DnaA regulator, YabA, significantly modulates sensitivity to gyrase inhibition, but only in oriC and not oriN cells. We propose that gyrase is a negative regulator of DnaA-dependent replication initiation from oriC, and that this regulatory mechanism is required for cell survival. PMID- 29396915 TI - P63 expression plays a role in developmental rate, embryo size, and local morphogenesis. AB - BACKGROUND: The p63 gene is integral to the development of many body parts including limb, palate, teeth, and urogenital tract. Loss of p63 expression may alter developmental rate, which is crucial to normal morphogenesis. To validate a novel, unbiased embryo phenotyping software tool, we tested whether delayed development contributes to the pathological phenotype of a p63 mouse mutant (p63 /- ). We quantified dysmorphology in p63-/- embryos and tested for universal growth delay relative to wild-type (WT) embryos. Fixed embryos (n = 6; p63-/- ) aged day (E) 15.5 were micro-CT scanned and quantitatively analyzed using a digital WT atlas that defined volumetric differences between p63-/- and WT embryos. RESULTS: p63-/- embryos showed a growth delay of approximately 22 hr (0.9 days). Among the E15.5 mutants, overall size was closest to WT E14.6 mice but shape was closest to WT E14.0. The atlas clearly identified in p63-/- embryos malformations of epithelial derivatives including limbs, tail, urogenital structures, brain, face, and tooth. CONCLUSIONS: The software atlas technique described the p63-/- phenotype as a combination of developmental delay (i.e., heterochrony) and malformation (i.e., pathological shape; failed organogenesis). This study identifies for the first time global and local roles for p63 in prenatal growth and development. Developmental Dynamics 247:779-787, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29396916 TI - Coping with interruptions in clinical nursing-A qualitative study. AB - AIMS AND OBJECTIVES: To gain knowledge on how nurses' cope with interruptions in clinical practice. BACKGROUND: Interruptions may delay work routines and result in wasted time, disorganised planning and ineffective working procedures, affecting nurses' focus and overview in different ways. Research has identified a growing problem linking errors or adverse events with interruptions. It may affect patient safety if nurses are not paying attention to interruptions. Little is known about how nurses cope with interruptions DESIGN: The study was inspired by ethnographic fieldwork with a hermeneutical phenomenological approach. METHODS: Observations were performed combined with semi-structured qualitative interviews. RESULTS: Managing interruptions depend on level of competence, working environment, dialogue and matching of expectations, collegial roles and implicit rules. Working procedures impact on how nurses are exposed to unnecessary interruptions. The latter affects overview and the ability to put the foot down and decline being interrupted. Professional competencies for example prioritising, keeping focus and collaborating across disciplines are needed to cope with interruptions. CONCLUSION: Culture work and matching of expectations are important to reflect on and discuss personal- and group behaviour caused by interruptions. We need to focus on the role of each nurse in the professional team, types of personality and unspoken rules. Professional competencies for example prioritising, keeping focus and cooperating across disciplines are needed to cope with interruptions. RELEVANCE TO CLINICAL PRACTICE: Coping with interruptions is important for the nursing profession, quality of care and patient safety. Changing practice requires multidisciplinary cooperation accepting different agendas at personal, group and organisational levels. Nurses must understand the meaning and nature of different types of interruptions to develop coping strategies and maintain quality in care and patient safety in multidisciplinary teamwork. PMID- 29396917 TI - Practical tool for sampling and fast analysis of large cocaine seizures. AB - Large quantities of illicit drugs are frequently seized by law enforcement. In such cases, a representative number of samples needs to be quickly examined prior to destruction. No procedure has yet been set up which rapidly provides information regarding the homogeneity of the samples, the presence of controlled substances, and the degree of purity. This study establishes a protocol for fast analysis of cocaine and its most common cutting agent, levamisole, in large seizures. The protocol is based on a hypergeometric sampling approach combined with Fourier-transform infrared (FTIR) spectrometry and support vector machines (SVM) algorithms as analysis methods. To demonstrate the practical use of this approach, 5 large cocaine seizures (consisting between 45 and 85 units) were analysed simultaneously with gas chromatography-mass spectrometry (GC-MS), gas chromatography-flame ionisation detector (GC-FID), and a portable FTIR spectrometer using attenuated total reflectance (ATR) sampling combined with SVM models. According to the hypergeometric sampling plan of the guidelines of the Drugs Working Group (DWG) of the European Network of Forensic Science Institutes (ENFSI), the required number of subsamples ranged between 19 and 23. Considering the identification analyses, the SVM models detected cocaine and levamisole in all subsamples of Cases 1 to 5 (100% correct classification), which was confirmed by GC-MS analysis. Considering the quantification analyses, the SVM models were able to estimate the cocaine and levamisole content in each subsample, compared to GC-FID data. The developed strategy is easy, cost effective, and provides immediate information about both the presence and concentration of cocaine and levamisole. By using this new strategy, the number of confirmation analyses with laborious and expensive chromatographic techniques could be significantly reduced. PMID- 29396918 TI - Nancy A. Moran - Recipient of the 2017 Molecular Ecology Prize. PMID- 29396919 TI - Does introgression of crop alleles into wild and weedy living populations create cryptic in situ germplasm banks? AB - Natural gene flow often delivers alleles from cultivated species into unmanaged populations of weedy or wild relatives. Unmanaged populations with introgressed crop alleles may become the unintended repositories of crop alleles that are no longer available to breeders. Descriptive studies have confirmed the introgression of alleles from 17 crop species into free-living populations. Multigeneration experimental studies allowing hybrid-derived individuals to evolve under natural conditions are informative, but remain few. A study in this issue of Molecular Ecology (Molecular Ecology, 26, 2017) documents genomewide crop allele evolution in experimental populations of crop-wild hybrid-derived sunflowers. Approximately, three-quarters of the wild alleles increased in frequency;-however, 5% of the crop alleles in each of the two sites increased (Molecular Ecology, 26, 2017; Figure ). The remainder behaved as if they were neutral. This study's results plus those of prior studies demonstrate that introgressed populations of crop-wild relatives contain a mixture of wild and crop alleles and thereby can be valued as a distinct kind of in situ germplasm resource relative to nonintrogressed populations. [Figure: see text]. PMID- 29396920 TI - Editorial 2018. PMID- 29396922 TI - Simultaneous determination and qualitative analysis of six types of components in Naoxintong capsule by miniaturized matrix solid-phase dispersion extraction coupled with ultra high-performance liquid chromatography with photodiode array detection and quadrupole time-of-flight mass spectrometry. AB - A simple and effective sample preparation process based on miniaturized matrix solid-phase dispersion was developed for simultaneous determination of phenolic acids (gallic acid, chlorogenic acid, ferulic acid, 3,5-dicaffeoylqunic acid, 1,5 dicaffeoylqunic acid, rosmarinic acid, lithospermic acid, and salvianolic acid B), flavonoids (kaempferol-3-O-rutinoside, calycosin, and formononetin), lactones (ligustilide and butyllidephthalide), monoterpenoids (paeoniflorin), phenanthraquinones (cryptotanshinone), and furans (5-hydroxymethylfurfural) in Naoxintong capsule by ultra high-performance liquid chromatography. The optimized condition was that 25 mg Naoxintong powder was blended homogeneously with 100 mg Florisil PR for 4 min. One milliliter of methanol/water (75:25, v/v) acidified by 0.05% formic acid was selected to elute all components. It was found that the recoveries of the six types of components ranged from 61.36 to 96.94%. The proposed miniaturized matrix solid-phase dispersion coupled with ultra high performance liquid chromatography was successfully applied to simultaneous determination of the six types of components in Naoxintong capsules. The results demonstrated that the proposed miniaturized matrix solid-phase dispersion coupled with ultra high-performance liquid chromatography could be used as an environmentally friendly tool for the extraction and determination of multiple bioactive components in natural products. PMID- 29396921 TI - A thermoresponsive, citrate-based macromolecule for bone regenerative engineering. AB - There is a need in orthopaedic and craniomaxillofacial surgeries for materials that are easy to handle and apply to a surgical site, can fill and fully conform to the bone defect, and can promote the formation of new bone tissue. Thermoresponsive polymers that undergo liquid to gel transition at physiological temperature can potentially be used to meet these handling and shape-conforming requirements. However, there are no reports on their capacity to induce in vivo bone formation. The objective of this research was to investigate whether the functionalization of the thermoresponsive, antioxidant macromolecule poly(poly ethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN), with strontium, phosphate, and/or the cyclic RGD peptide would render it a hydrogel with osteoinductive properties. We show that all formulations of functionalized PPCN retain thermoresponsive properties and can induce osteodifferentiation of human mesenchymal stem cells without the need for exogenous osteogenic supplements. PPCN-Sr was the most osteoinductive formulation in vitro and produced robust localized mineralization and osteogenesis in subcutaneous and intramuscular tissue in a mouse model. Strontium was not detected in any of the major organs. Our results support the use of functionalized PPCN as a valuable tool for the recruitment, survival, and differentiation of cells critical to the development of new bone and the induction of bone formation in vivo. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1743-1752, 2018. PMID- 29396923 TI - Frequency and immunological consequences of Helicobacter pylori and intestinal parasite co-infections: a brief review AB - Helicobacter pylori is a Gram-negative, spiral bacterium capable of colonizing the gastric mucosa. Infections caused by this microorganism often lead to the development of various gastrointestinal complaints. Simultaneous human colonization by H. pylori and intestinal parasites is a common phenomenon. Moreover, the two groups of pathogens share the similar predisposing factors. The presence of parasites together with H. pylori cansignificantly influence the modulation of the host immune response. During H. pylori infection, strong polarization of Th1 cells is observed. The presence of protozoa, also contributing to the recruitment of Th1 cells, may well aggravate this response and exacerbate gastric mucosal damage. In contrast, intestinal helminth infection is associated with the polarization of lymphocytes towards Th2; their presence enhances the regenerative processes within the digestive tract and lowers the host overresponse. A literature review suggests that co-infection with intestinal helminths may serve as a buffering mechanism against the effects of H. pylori and/or protozoan infection, alleviating the Th1-dependent response and protecting against inflammations within the gastrointestinal tract. PMID- 29396924 TI - Wildlife as an environmental reservoir of Enterocytozoon bieneusi (Microsporidia) - analyses of data based on molecular methods AB - Enterocytozoon bieneusi is the most commonly identified Microsporidia in humans and has also been detected worldwide in a large group of wild living and domestic animals. The identification of E. bieneusi in wildlife has raised the question of the importance of animal reservoirs in the epidemiology of microsporidiosis and the implications of the infection with this pathogen in hosts. This review summarizes the available molecular data on the variety of E. bieneusi genotypes, both potentially zoonotic and host-specific isolated from wild living mammals and birds. In contrast to microsporidial infections of humans and domestic animals, wildlife deserves attention as a source of significant environmental reservoir of E. bieneusi. PMID- 29396925 TI - Endoparasites of the grey wolf (Canis lupus) in protected areas of Slovakia AB - Although the grey wolf was on the brink of extinction in Central Europe in the last century, it never became extinct in Slovakia and nowadays its population is considered stable. The wolf population in Slovakia is estimated to be around 400 individuals with seasonal variations, and due to these small numbers, studies on the parasite fauna of wolf are scarce. Of the 35 parasitic species recorded worldwide in grey wolves in temperate and mountain zones of the Palearctic region, 15 were detected in Slovakia. In our study, 256 grey wolf faeces samples taken from three protected areas in Slovakia were examined using the modified flotation method with a zinc sulphate solution. In total,169 samples (66%) displayed propagative stages belonging to ten parasitic taxa (Isospora spp., Alaria alata, Taenia spp., Strongyloides stercoralis, Ancylostomatidae, Trichuridae, Toxocara canis, Toxascaris leonina, Spirocerca lupi, Angiostrongylus vasorum). The Trichuridae was the most prevalent group, with a prevalence of 17.7 60.3%. Theparasitic species Isospora spp. (3.5%) and A. vasorum (0.8%) are reported for the first time in wolves in Slovakia. Considering the zoonotic potential of some parasites, and the increasing co-existence of human and wildlife in protected areas, the present study provides important findings for further epidemiology research in the grey wolf population. PMID- 29396926 TI - Parasitological surveillance in a rat (Rattus norvegicus) colony in Sao Paulo Zoo animal house AB - Rattus norvegicus (Mammalia: Rodentia) is a widespread and synanthropic rodent, broadly used in medical experiments. It can also be used for feeding captive animals in zoos. Parasitological surveys are important to guarantee the health of both the animals and the staff responsible for their management. The aim of this study was to identify intestinal parasites of Rattus norvegicus offered as food to captive animals from Sao Paulo Zoo, anddemonstrate the importance of sanitary hurdling, disease control and biosecurity. The identified protozoan parasites were Eimeria sp., Entamoeba sp., Spironucleus sp., Giardia sp., Tritrichomonas sp., Chilomastix sp., unidentified cysts and non-sporulated coccidians oocysts (Isospora/Eimeria). The following helminths were found: Syphacia muris, Rodentolepis nana and Aspiculuris tetraptera. PMID- 29396927 TI - Serum cytokines and activation ex vivo of CD4+ and CD8+ T cells in chagasic chronic Mexican patients AB - The clinical manifestations of human Chagas disease are associated with several factors, including immunological alterations, in this regard, many studies propose that tissue damage might be more severe in the absence of immune regulatory mechanisms, other factors are the genetic background of host and parasite. Trypanosoma cruzi population is genetically, biochemistry and pathogenic diverse along the Latin-America continent and phylogenetic ally are divided into six intra-species lineages TcI-VI. The TcI lineage has a wide distribution with heterogeneous virulence and pathogenesis within strains. In Mexico, the main circulating lineage is TcI in human infections. We analyzed intracytoplasmic cytokines of unstimulated peripheral T lymphocytes, and the level of cytokines (IL-2, IL-4, IL-12, IL-10, IFN-gamma and sIL-2R) in the serum of Mexican chagasic subjects. The population studied consisted of 15 asymptomatic individuals, 17 patients with chronic chagasic cardiopathy (CCC), 20 patients with cardiopathy butnegative serology for T. cruzi, and 10 healthy subjects. The analysis of CD4+ cells revealed that CCC and asymptomatic patients have higher CD25+ and CD69 activation markers than controls. The Th1 subset (CD4+/IFN- gamma +) was higher in CCC than in asymptomatic and control subjects, whereas Th2 subset was markedly high in asymptomatic subjects. Circulating cytokines were below level detection with the exception of IL-2 and sIL-2R. Infection with Mexican Trypanosoma cruzi strains in asymptomatic chagasic subjects have a tendency for a Th2 response with higher CD8+/IFN-gamma T cells. In contrast, CCC patients have low levels of intracellular IFN- gamma and IL-2 cytokines. In both groups circulating serum cytokines are below the detectable level. PMID- 29396928 TI - Crouching Tiger, Hidden Dragon. PMID- 29396929 TI - Is Less Noise, Light and Parental/Caregiver Stress in the Neonatal Intensive Care Unit Better for Neonates? AB - In utero sensory stimuli and interaction with the environment strongly influence early phases of fetal and infant development. Extremely premature infants are subjected to noxious procedures and routine monitoring, in addition to exposure to excessive light and noise, which disturb the natural sleep cycle and induce stress. Non-invasive ventilation, measures to prevent sepsis, and human milk feeding improve short-term and long-term neurodevelopmental outcomes in premature infants. To preserve brain function, and to improve quality of life and long-term neurodevelopmental outcomes, the focus now is on the neonatal intensive care unit (NICU) environment and its impact on the infant during hospital stay. The objectives of this write-up are to understand the effects of environmental factors, including lighting and noise in the NICU, on sensory development of the infant, the need to decrease parental and caregiver stress, and to review existing literature, local policies and recommendations. PMID- 29396930 TI - Celiac Disease and Anemia. PMID- 29396931 TI - Scrub Typhus Meningitis Versus Acute Bacterial Meningitis and Tuberculous Meningitis. PMID- 29396932 TI - Celiac Disease in Children with Moderate-to-Severe Iron-deficiency Anemia. AB - OBJECTIVE: To evaluate the proportion of children with moderate to severe iron deficiency anemia who have associated celiac disease. METHODS: This cross sectional analytical study was conducted among children aged 1 to 12 years of age with moderate-to-severe iron deficiency anemia and control children without anemia. Serum IgA-tissue trans-glutaminase levels were assessed in both cases and controls. All children with positive celiac serology underwent upper gastrointestinal endoscopy and duodenal biopsy; biopsy finding of Marsh grade 3 was considered positive for celiac disease. RESULTS: There were 152 anemic children and 152 controls with mean (SD) hemoglobinof 7.7 (1.8) and 12.2 (0.74) g/dL, respectively. 16 (10.5%) cases and 3 (2%) control patients had positive serology for celiac disease [OR (95% CI) 5.33 (1.52-18.67), P=0.007]. Six (3.9%) children with iron-deficiency anemia and none of the controls had biopsy features diagnostic of celiac disease. CONCLUSION: In the Northern Indian tertiary-care hospital outpatient setting, Celiac disease was associated with 4% of children presenting with moderate-to-severe anemia. PMID- 29396933 TI - Comparison of Scrub Typhus Meningitis with Acute Bacterial Meningitis and Tuberculous Meningitis. AB - OBJECTIVE: To compare scrub typhus meningitis with bacterial and tuberculous meningitis. METHODS: Children aged <15 years admitted with meningitis were screened and those who fit criteria for diagnosis of scrub typhus meningitis (n=48), bacterial meningitis (n=44) and tuberculous meningitis (n=31) were included for analysis. Clinical features, investigations and outcomes were compared between the three types of meningitis. RESULTS: Mean age, duration of fever at presentation, presence of headache and, altered sensorium and presence of hepatomegaly/splenomegaly were statistically significantly different between the groups. Scrub typhus had statistically significant thrombocytopenia, shorter hospital stay and a better neurological and mortality outcome. CONCLUSION: Sub acute presentation of meningitis in older age group children, and good outcome is associated with scrub typhus when compared to bacterial and tuberculous meningitis. PMID- 29396934 TI - Long-term Protection Against the Hepatitis B Virus Detected Through an Early Response to a Booster Dose Injection. AB - OBJECTIVE: To determine the duration of protection conferred by the hepatitis B (HB) vaccination and the necessity of a booster dose. METHODS: Immediately after the initial blood sampling, 252 youths (aged 18.8-20.5 years, 52% females) with a history of neonatal HB vaccination with one dose of the HB vaccine received a booster. Serum concentrations of antibodies against the HB surface antigen were assessed in samples collected before and 10-14 days after the booster. Seroconversion from concentrations <10 to >=10 IU/L were defined as a positive immune response. RESULTS: Of the 252 participants, 131 were sero-susceptible and 114 responded. CONCLUSION: Nearly 90% of young people preserved their long-term protection; the results of this study do not support the use of an HB booster vaccination. PMID- 29396935 TI - Blowing Your Own Trumpet: How to Increase the Online Visibility of Your Publication? AB - After seeing one's manuscript in the print form in a journal, the author feels a sense of elation which is indescribable. However, if one really want peers and other researchers to take note of the work, some more effort is needed. With the massive increase in the number of biomedical journals in print - supplemented by another large chunk online - quite a few published papers remain unread by majority of the readers. The availability of social sites, persistent identifiers, and manuscript-sharing sites has simplified the job of increasing the impact of an article. We herein share some of these tricks-of-the-trade. PMID- 29396936 TI - Flow Cytometry in Pediatric Malignancies. AB - The utility of flow cytometry as a useful diagnostic modality for the assessment of hematopoietic neoplasms has been established beyond doubt. In fact, it is now an integral part of the diagnosis and classification of various diseases like leukemias and lymphomas along with molecular studies and cytogenetics. Prognostication and disease monitoring by flow cytometry is also being recognized increasingly as one of the important fortes. This is evident by the number of articles in the published in literature on the minimal residual disease detection by flow cytometry especially in the last decade or so. To add to this, ever growing list of utilities in hematopoietic malignancies, many non-hematopoietic neoplasms can also be analyzed by flow cytometry. The examples include fluid specimens from serous cavity effusions and samples from solid tissues like lymph nodes, reticulo-endothelial tissue, central nervous system tissue, etc. Flow cytometry technique provides a unique blend of rapidity, high sensitivity and specificity compared to cyto-morphology and conventional immunohistochemical staining. It is also remarkable for simultaneous analysis of more than one marker on the cells. Evaluation of limited samples such as cerebrospinal fluid or fine needle aspiration samples makes Flow cytometry a valuable tool. DNA ploidy analysis and assessment of pediatric non-hematopoietic neoplasms by Flow cytometry has envisaged the utility vista of this technique. This review is aimed at providing an insight into the applications of flow cytometry in pediatric malignancies. PMID- 29396937 TI - Management of Diarrhea - Changing Trends in Last 50 Years. PMID- 29396938 TI - Phone A Friend, When In Need! PMID- 29396939 TI - Creatine Transporter Deficiency in Two Brothers with Autism Spectrum Disorder. AB - BACKGROUND: Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. CASE CHARACTERISTICS: Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. OUTCOME: Both patients were given creatine monohydrate, L arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems. MESSAGE: Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify CTD in children with autistic behavior and language disorders. PMID- 29396940 TI - Trypanosomiasis in a Young Infant from Rural Gujarat, India. AB - BACKGROUND: Human trypansomiasis due to infection by animal trypanosomes is rarely reported from India. CASE CHARACTERISTICS: We describe clinical presentation of a 2-month-old boyfrom a rat infested house in rural Gujarat who was diagnosed to be havinginfection with the rodent parasite Trypanosoma lewisi. OBSERVATION: The fever and parasitemia resolved on treatment with liposomal amphotericin B, Ceftriaxone and Amikacin, and there was no recurrence of parasitemia over a 2 month follow-up. MESSAGE: The case highlights the need for increased awareness and heightened surveillance for this rare zoonotic infection. PMID- 29396941 TI - Etiology of Fever of Unknown Origin in Children from Mumbai, India. AB - This descriptive study evaluated 49 children with fever lasting for more than 7 days at a tertiary hospital in urban Mumbai. Etiologic diagnosis could be established in 88% of the cases. Infections were the causein 34 (79%)patients, 6 (14%) were diagnosed as collagen vascular diseases, and 3 (7%) had other cause. PMID- 29396942 TI - Hypoferremic State in Overweight and Obese Children. AB - Children with high body mass index (BMI) are at risk of iron deficiency. In present study, 71 children with overweight or obesity were screened for iron deficiency. Mean BMI, ferritin and plasma soluble transferrin receptor (sTrfR) levels were 26.1 kg/m2, 41.9 ug/L and 0.375 mg/L, respectively. Twenty (28%) children had anemia, and 44 (62%) had an underlying hypoferraemic state. PMID- 29396943 TI - Paroxysmal Kinesigenic Dyskinesia. PMID- 29396944 TI - Malnutrition and Health Program. PMID- 29396945 TI - Malnutrition and Health Program: Authors Reply. PMID- 29396946 TI - Endotracheal Aspirate Microscopy and Culture in Early Prediction of Ventilator associated Pneumonia in Neonates. PMID- 29396947 TI - Endotracheal Aspirate Microscopy and Culture in Early Prediction of Ventilator associated Pneumonia in Neonates: Authors Reply. PMID- 29396948 TI - Primary Hypothyroidism Presenting as Bilateral Ovarian Torsion. PMID- 29396949 TI - Indian Children need Higher Vitamin D Supplementation. PMID- 29396950 TI - Indian Children need Higher Vitamin D Supplementation: Authors Reply. PMID- 29396951 TI - Transcutaneous Bilirubin Measurement in Preterm Neonates Receiving Phototherapy. PMID- 29396952 TI - Transcutaneous Bilirubin Measurement in Preterm Neonates Receiving Phototherapy: Authors Reply. PMID- 29396953 TI - Neonatal Endocrine Labomas: Few Concerns. PMID- 29396954 TI - Neonatal Endocrine Labomas: Few Concerns: Authors Reply. PMID- 29396955 TI - E-Learning in Medical Education: Indian Working Model in Practice. PMID- 29396956 TI - Kindler Syndrome. PMID- 29396957 TI - Study of the relation between medial orbitofrontal artery and anterior skull base performed by computed tomography angiography. AB - BACKGROUND: The aims of this study were to analyze the relationships between the medial orbitofrontal artery (MOFA) and the anterior skull base (ASB) including anatomical endonasal landmarks using computed tomography angiography (CTA). METHODS: We studied 52 CTAs using OsiriX software. All CTAs were placed in the same anatomical position. MOFA was identified in the sagittal and coronal plane and its correlation with ASB was analyzed. The distance between the MOFA and landmarks for endonasal surgery were obtained, determining the high risk areas for its injury. RESULTS: After arising from the anterior cerebral artery, the MOFA dives inferiorly towards the ASB, close to the midline (average distance of 1.5 mm), approaching the planum sphenoidale (average distance of 1.8 mm) and then ascends away from the ASB as it runs anteriorly, with an average distance of 4.4 mm in the region of the anterior wall of the sphenoid sinus and 12 mm in the region of the anterior ethmoid artery. CONCLUSIONS: The MOFA has an intimate relationship with the ASB and nasal cavity; the regions with the highest risk of surgical trauma are between the posterior ethmoid and the planum sphenoidale. PMID- 29396958 TI - Higher prevalence of nasal polyposis among textile workers: an endoscopic based and controlled study. AB - BACKGROUND: There is a deficit of reliable epidemiologic studies exploring the prevalence of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). Recent data suggests that occupational dust exposure may be involved in its physiopathology. OBJECTIVES: To compare the prevalence of nasal polyposis (NP) in a group of workers with occupational dust exposure (textile workers) and in a control group (retail store workers). METHODS: Cross-sectional study with a random sample of textile and retail store employees. Clinical data was gathered through a systematic interview, which included RhinoQOL and CAT questionnaires. A systematic endoscopic nasal examination was performed using a 0 degree rigid endoscope. Lund-Kennedy endoscopic score was determined for each participant. Statistical analysis was performed with SPSS. RESULTS: 316 participants were included in the study, i.e. 215 textile workers and 101 retail store workers. NP was found in 19 subjects among textile workers and none in the control group. The prevalence of NP increased by age strata and by years of dust exposition. Polypoid degeneration of the middle turbinate was more prevalent in the exposed group with Lund-Kennedy scoring also higher. RhinoQOL and CAT questionnaires had both significantly higher scores among textile employees. Previous medical diagnosis of atopic diseases or chronic lower airway diseases did not differ between exposed and control groups or even between subjects with and without NP. CONCLUSIONS: These results point to an important correlation between occupational dust exposure and NP occurrence. PMID- 29396959 TI - Mucocele formation after frontal sinus obliteration. AB - BACKGROUND: A possible complication of frontal sinus obliteration with fat is the formation of mucoceles. We studied the prevalence of mucoceles as well as and the need for revision surgery. METHODS: Retrospective case review of forty consecutive patients undergoing frontal sinus obliteration from September 1995 to February 2012 for chronic rhinosinusitis (26), frontal mucocele (12) or frontal osteoma (2) with an average follow up of 80 months (range 15-218). MRI of the paranasal sinuses was performed in all. Outcome measures included MRI signs of mucocele formation in the obliterated frontal sinus, revision surgery, symptom burden. RESULTS: Magnetic resonance imaging (MRI) showed potential postoperative frontal sinus mucoceles in 6/40 patients. In 3 patients (7.5%) a revision operation was performed, revealing mucoceles in two cases. A wait and scan-policy in the other 3 patients confirmed the presence of a mucocele in 1 of these patients. The majority of patients (33/40, 83%) was asymptomatic at the last follow up. CONCLUSION: The prevalence of mucoceles and revision rate in this series was 7.5% (3/40). MRI can improve detection rate and reduce / avoid unnecessary revision surgery after frontal sinus obliteration. PMID- 29396961 TI - [Outpatient Psychosocial Cancer Care at a University Medical Center - Study Results Concerning Patient Characteristics and Care Needs]. AB - BACKGROUND: Psychosocial care for cancer patients has gained importance in recent years and psycho-oncological counselling centers (POCC's) offer a wide range of services in this area. We investigated the scope and content of a POCC at a university medical center. METHODS: The presented data were collected at the POCC at University Medical Center Leipzig in 2014. In total, 469 cancer patients participated (mean age 60 years, 67% female, 36% breast cancer). Psychosocial distress and psychopathology were assessed with the PHQ-9, GAD-7 and the NCCN Distress Thermometer. Descriptive statistics were analyzed. RESULTS: 1 in 4 patients (24%) reported at least moderate levels of depressive symptoms. Patients with hematological malignancies and head and neck tumors showed stronger depressive symptoms. 15% of patients suffered from elevated levels of anxiety. The average number of reported problems on the Distress Thermometer and Problem List was 14 out of 39. Physical and psychosocial problems were most prevalent (e. g. fatigue, problems getting around, anxiety). Supportive care needs were less common than reported problems. CONCLUSIONS: We found that a close network of POCS, oncological inpatient and outpatient care can help direct patients toward psychosocial care at an early stage. Psychosocial screening enables psycho oncologists to identify problem areas and offer tailored counselling services. PMID- 29396960 TI - Monoclonal antibodies for the treatment of chronic rhinosinusitis with nasal polyposis: a systematic review. AB - BACKGROUND: Monoclonal antibodies have been proposed as a novel therapy in patients suffering from chronic rhinosinusitis with nasal polyposis (CRSwNP). The purpose of this systematic review was to evaluate their efficacy and safety. METHODOLOGY: A literature search was performed in MEDLINE, Web of Science, the Cochrane Library and multiple trial registries followed by extensive hand searching for the identification of relevant studies. Only randomized controlled trials (RCTs) comparing the use of monoclonal antibodies with placebo or another therapy in adult patients with CRSwNP were included. RESULTS: Anti-immunoglobin E (IgE) therapy with omalizumab was assessed in two studies, anti-interleukin (IL) 5 therapy in three studies (1 reslizumab, 2 mepolizumab) and finally anti-IL-4 and anti-IL-13 therapy in only one. With the exception of one study, biologic therapy was proved to be effective in reducing total nasal endoscopic polyp score (TPS) in treatment as compared to placebo groups. Monoclonal antibodies brought about improvement in several other outcomes, such as opacification in computed tomography (CT), quality of life measures, nasal airflow, olfaction and type 2 helper T-cell (Th2) associated biomarkers. Overall, the use of these agents was deemed safe and well-tolerated. CONCLUSIONS: This is the first systematic review showing encouraging results for the use of all three main categories of monoclonal antibodies in CRSwNP patients and highlights the need for further well designed and with larger sample sizes RCTs. PMID- 29396962 TI - Hoofbeats, Zebras, and a Child with Vomiting. PMID- 29396963 TI - Cartilage Restoration: Microfracture and Osteochondral Autograft Transplantation. AB - The treatment of patellofemoral cartilage defects presents several distinct challenges when compared with cartilage restoration techniques used for other compartments of the knee due to the unique anatomy and distribution of forces. The etiologies of patellofemoral articular cartilage lesions include acute traumatic instability injuries, such as dislocation and subluxation, osteochondritis dissecans, and chronic degenerative changes. Regardless of the etiology, untreated patellofemoral cartilage lesions can contribute to activity limiting anterior knee pain. The goal of patellofemoral cartilage restoration procedures is to impart symptomatic relief and improve quality of life by repairing the articular cartilage surface and any comorbid malalignment or maltracking.Microfracture and osteochondral autograft transplantation (OAT) are two cartilage restoration procedures to consider when treating full-thickness patellofemoral chondral defects. Considered by some experts to be the gold standard therapy, microfracture is one of the most common procedures used for cartilage restoration. The technique involves the perforation of the subchondral bone plate for the release of marrow elements, filling the defect with a fibrocartilage clot repair. Though less commonly used, OAT allows defect replacement with native hyaline cartilage via autologous transplantation from a non-weight bearing area. The purpose of this article is to discuss the indication, technical considerations, and outcomes of microfracture and OAT when used for treating chondral lesions of the patellofemoral joint. PMID- 29396964 TI - Elevated Levels of Estrogen Suppress Hepcidin Synthesis and Enhance Serum Iron Availability in Premenopausal Women. AB - Clinical and experimental observations have long suggested that elevated levels of estrogen associate with increased serum iron availability. Additionally, recent work has shown that estrogen can downregulate hepcidin synthesis in vitro. This study aims at assessing whether the ability of estrogen to downregulate hepcidin synthesis translates into changes in serum iron status. Hepcidin synthesis was evaluated in MCF-7, Hep-G2 and SKOV-3 cells treated with increasing concentrations of estrogen and cultured for up to 24 h post treatment. The correlation between levels of serum estrogen, hepcidin and iron was assessed using serum samples collected from 153 premenopausal women at random and samples collected from 6 women at days 1, 5, 10, 16, 21 and 28 of the monthly cycle. Estrogen-treated MCF-7 cells showed a significant reduction in hepcidin synthesis, especially at 20 nM/24 h E2 treatment. Hepcidin synthesis was also significantly reduced in Hep-G2 and SKOV-3 cells at 20 nM/24 h E2 treatment. In serum samples collected at random, estrogen (P=0.022; R=-0.213) and iron (P=0.028; R=-0.316) correlated negatively with hepcidin and positively with each other (P=0.033; R=0.319). An overall similar pattern was also observed in monthly cycle-timed samples. These findings suggest that elevated levels of estrogen reduce hepcidin synthesis as means of enhancing serum iron content in menstruating women. PMID- 29396965 TI - Risk factors for patients with diabetes who have abnormal toe-brachial index and normal ankle-brachial index. AB - AIM: To investigate the association of ankle-brachial index (ABI) and toe brachial index (TBI) with metabolic parameters and the risk factors causing a divergence between ABI and TBI in patients with diabetes. METHODS: Outpatients who were simultaneously examined for both ABI and TBI were included. Multiple regression analysis was performed to assess the association of ABI and TBI with metabolic parameters. Furthermore, logistic regression analysis was performed to detect the risk factors causing a divergence between ABI and TBI. RESULTS: Of the 307 patients that were enrolled, 77 had normal ABI but decreased TBI. ABI was inversely associated with plasma glucose and triglycerides and positively associated with high-density lipoprotein cholesterol. In contrast, TBI was inversely associated with the duration of diabetes, plasma glucose and haemoglobin A1c. Logistic regression analysis showed that smoking history and a history of cardiovascular disease were associated with an increased risk of the divergence between ABI and TBI. CONCLUSION: Our findings suggest that smoking history and a history of cardiovascular disease are important risk factors in patients with diabetes who had normal ABI but decreased TBI. Patients with multiple vascular complications are at a high risk of coexisting peripheral artery disease, even if their ABI is normal. PMID- 29396966 TI - Search for Pharmacoepigenetic Correlations in Type 2 Diabetes Under Sulfonylurea Treatment. AB - Sulfonylureas are insulin secretagogues which act in pancreatic beta cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR. KCNJ11 methylation was detected in 19/88 (21.6%) of hypoglycemic and in 23/83 (27.7%) of non-hypoglycemic patients (p=0.353), while ABCC8 methylation in 6/83 (7.2%) of non-hypoglycemic and none (0/88) of the hypoglycemic patients (p=0.012). Methylation in at least one promoter (KCNJ11 or ABCC8) was significantly associated with non-hypoglycemic patients who are carriers of KCNJ11 EK allele (p=0.030). Our data suggest that ABCC8 but not KCNJ11 methylation is associated to hypoglycemic events in sulfonylureas-treated T2DM patients. Furthermore, it is demonstrated that the KCNJ11 E23K polymorphism in association to either of the two genes' DNA methylation may have protective role against sulfonylurea-induced hypoglycemia. PMID- 29396967 TI - Frequency of Thyroid-Stimulating Hormone Monitoring in Patients After Thyroidectomy: A Retrospective Study in Primary Care Practices in Germany. AB - AIM: The goal of this study was to analyze the frequency of thyroid-stimulating hormone (TSH) monitoring in thyroidectomy patients followed by general practitioners in Germany. METHODS: This study included all individuals >=18 years who had undergone a thyroidectomy between 2000 and 2015 in 258 general practices in Germany. Another inclusion criterion was a minimum of three medical visits between 2015 and 2016, following thyroidectomy. The primary outcome was the annual frequency of TSH monitoring in thyroidectomy patients in 2015. Demographic data included age, sex, and type of health insurance coverage (private versus statutory). Clinical and therapeutic data included the amount of time since the first thyroidectomy, thyroidectomy-associated diagnosis (thyroid cancer, noncancerous enlargement of the thyroid (goiter), or hyperthyroidism), type of thyroidectomy (total or hemithyroidectomy), the Charlson Comorbidity Index score, and the prescription of levothyroxine therapy in 2015. A multivariable logistic regression model was performed to identify variables potentially associated with the likelihood of having been tested at least once for TSH in the year 2015. RESULTS: The present study included 1,135 thyroidectomy patients. The mean age was 60.1 years (SD=14.3 years), and 75.8% of the patients were women. TSH was measured at least once in 42.3% of patients. In addition, 31.5% of individuals after thyroidectomy had mean TSH values between 0.25 and 1 mIU/L in 2015. No variable was significantly associated with the frequency of TSH monitoring. However, there was a tendency toward a lower TSH monitoring frequency in the groups which had undergone thyroidectomy years ago (OR=0.77 (95% CI: 0.53-1.11) for 1-5 years and OR=0.67 (95% CI: 0.45-0.99) for>5 years compared to<=1 year). CONCLUSIONS: Only 40% of thyroidectomy patients followed by general practitioners in Germany were monitored at least once for TSH in 2015. PMID- 29396968 TI - Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. AB - AIM: Patients on levothyroxine-treatment frequently have complaints although TSH is within the reference range. Moreover, FT3 is often low in these patients. The clinical significance of this disequilibrium is studied here. PATIENTS, METHODS: We conducted a retrospective longitudinal study including 319 patients with differentiated thyroid carcinoma on LT4-medication (1.8 [1.6,2.1] ug/kg body weight). Patients were followed at 2309 visits for at median 63 [46,81] months. Association of reported complaints during follow-up with changes in thyroid parameters were analysed using a generalised linear mixed model accounting for within-variability and intra-subject correlations. RESULTS: 26% of patients expressed hypothyroid and 9.7% hyperthyroid complaints at any one visit, rates per visit being 6.5% and 2%, respectively. During follow-up, median changes in spans were as follows, LT4-dose 0.49 [IQR 0.29,0.72] ug/kg, FT3 1.77 [1.25,2.32] pmol/l, FT4 9.80 [6.70,12.8] pmol/l and TSH 1.25 [0.42,2.36] mIU/l. While rates of both hypothyroid or hyperthyroid symptoms were significantly related to all three thyroid parameters, the relationship of hypothyroid symptoms with FT3 extended to a below reference TSH range. Hypothyroid symptom relief was associated with both a T4 dose giving TSH-suppression below the lower reference limit and FT3 elevated further into the upper half of its reference range. In multivariable analysis, relationships between complaints and FT3 concentrations remained significant after adjusting for gender, age and BMI. CONCLUSION: Residual hypothyroid complaints in LT4-treated patients are specifically related to low FT3 concentrations. This supports an important role of FT3 for clinical decision making on dose adequacy, particularly in symptomatic athyreotic patients. PMID- 29396969 TI - Impact of type 2 Diabetes and Metformin use on Vitamin B12 Associated Biomarkers an Observational Study. AB - AIMS: Assessment of the impact of type 2 diabetes (T2DM) and metformin use on vitamin B12 (VB12) associated biomarkers and their suitability to represent VB12 supply. METHODS: Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction (%AB12)=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with (DMMet+ ) and without metformin use (DMMet-) and ii) in comparison to an external non-diabetic reference group with low VB12 (<200 pmol/L). RESULTS: VB12 associated biomarkers were distributed equally between DMMet+ (n=29, 58%) and DMMet- (n=21, 42%). Significant differences in %AB12 in diabetic patients with low VB12 (n=19) compared to the non-diabetic reference group (n=31) were found. Higher %AB12 was associated with diabetes. Hcy levels were significantly associated with age, folic acid level, renal function and HoloTc but not with VB12. CONCLUSIONS: In T2DM patients with low VB12, %AB12 was confirmed as being higher in comparison to nondiabetic patients. The effect was not clearly attributable to metformin use. HoloTc was unaffected by the lowering of VB12 and significantly associated with the functional marker Hcy. Both findings support the use of HoloTc for the assessment of VB12 supply in diabetic patients. PMID- 29396970 TI - Oxidized cellulose as hemostatic agent to prevent bleeding after high-risk endoscopic resection of rectal laterally spreading tumor overlying hemorrhoids. PMID- 29396971 TI - Intrabiliary resection of metastasis originating from colorectal carcinoma during direct peroral cholangioscopy: a new tool for biliary palliation. PMID- 29396972 TI - Successful closure of a refractory rectal anastomotic fistula using endoscopic submucosal dissection combined with an over-the-scope clip. PMID- 29396973 TI - New closure method for a mucosal defect after endoscopic submucosal dissection: the clip-on-clip closure method. PMID- 29396974 TI - Gastric endoscopic submucosal dissection using the "pulley clip with elastic line" method. PMID- 29396975 TI - Endoscopic removal of a proximally migrated pancreatic stent. PMID- 29396976 TI - Re-intervention with endoscopic ultrasound-guided hepaticogastrostomy for unresectable hilar biliary drainage using a multipath occlusion balloon. PMID- 29396977 TI - Thoracic Endovascular Repair for Acute Traumatic Transection of the Descending Thoracic Aorta and Postendovascular Remodeling Change. AB - BACKGROUND: The recently developed thoracic endovascular repair (TEVAR) technique seems to offer a good alternative for treating acute traumatic transection of the thoracic aorta (TTA). We reviewed our experience of TEVAR in cases of acute traumatic transection and analyzed the subsequent remodeling changes. METHODS: The medical records of 17 patients who underwent TEVAR for TTA were reviewed. The trauma mechanisms, anatomical characteristics of the transected aortas, technical details of TEVAR, and postprocedural results were reviewed. RESULTS: The overall mean injury severity score was 53 +/- 12. On three-dimensional computed tomography (CT), the mean distance of transection from the left subclavian artery was 14 +/- 9 (0-31) mm. Fifteen patients presented an aortic pseudoaneurysm and two patients had impending rupture. TEVAR was performed emergently under general endotracheal induction. Technical success was achieved and complete pseudoaneurysm sealing was confirmed with aortography in all 17 patients. Two patients (12%) died of hypovolemic shock and hyperkalemia; however, no late death or stent-related complication occurred during the 45 +/- 32 (6-102) months of follow-up. During a mean CT follow-up of 35 months, the mean aortic diameter increased by 2 (0-5) mm and pseudoaneurysm lesions completely disappeared in all patients. CONCLUSIONS: TEVAR resulted in good early survival in patients with TTA. No late or stent graft-related event was encountered up to a maximum of 9 years after surgery. We recommend that patients with grade III or higher TTA should undergo emergency surgery. Moreover, we consider that long-term follow-up and blood pressure management are essential when the proximal aortic diameter is found to increase slightly after TEVAR on follow-up CT. PMID- 29396978 TI - High-intensity Interval Training Frequency: Cardiometabolic Effects and Quality of Life. AB - The effects of high intensity interval training (HIIT) frequency on cardiometabolic health and quality of life were examined in 35 healthy inactive adults (age: 31.7+/-2.6 yrs, VO2peak: 32.7+/-7.4 ml.: kg-1 .: min-1). Participants were randomly assigned to a control (CON) and two training groups, which performed 10*60-s cycling at ~83% of peak power, two (HIIT-2) or three times per week (HIIT-3) for eight weeks. Compared with CON, both training regimes resulted in similar improvements in VO2peak (HIIT-2: 10.8%, p=0.048, HIIT-3: 13.6%, p=0.017), waist circumference (HIIT-2: -1.4 cm, p=0.048, HIIT-3: -2.4 cm, p=0.028), thigh cross-sectional area (HIIT-2: 11.4 cm2, p=0.001, HIIT-3: 9.3 cm2, p=0.001) and the physical health component of quality of life (HIIT-2: 8.4, p=0.001, HIIT-3: 12.2, p=0.001). However, HIIT-3 conferred additional health related benefits by reducing total body and trunk fat percentage (p<0.05, compared with CON), total cholesterol and low-density lipoprotein-cholesterol (p<0.02, compared with CON) and by improving the mental component of quality of life (p=0.045, compared with CON). In conclusion, performing HIIT only twice per week is effective in promoting cardiometabolic health-related adaptations and quality of life in inactive adults. However, higher HIIT frequency is required for an effect on fat deposits, cholesterol and mental component of well-being. PMID- 29396979 TI - Reply to a Letter to the Editor: Anatomical Study of the Fingertip Artery in Tamai Zone I: Clinical Significance in Fingertip Replantation. PMID- 29396980 TI - Anatomical Study of the Fingertip Artery in Tamai Zone I: Clinical Significance in Fingertip Replantation. PMID- 29396981 TI - Novel Surgical Approach for Decompression of the Scalene Triangle in Neurogenic Thoracic Outlet Syndrome. AB - Thoracic outlet syndrome (TOS) is a cause of upper extremity and shoulder dysfunction. TOS can present with a wide range of symptoms due to compression of the brachial plexus or its branches during their passage through the cervicothoracobrachial region or scalene triangle. There are three types of TOS: arterial, venous, and neurogenic. Neurogenic TOS (nTOS) is by far the most frequent type and represents more than 95% of all cases. Historically, surgical intervention for all types of TOS has evolved based on the treatment for a vascular etiology and has typically included a first rib resection. Despite nTOS being by far the more common type, most previous interventions have not considered treatment via peripheral nerve decompression.We describe surgical treatment of nTOS, performed on an outpatient basis, which focuses on the surgical decompression of the structures associated with the scalene triangle in conjunction with release of the pectoralis minor insertion through limited incisions. The procedure avoids the morbidity associated with first rib resection and is successful in ameliorating nTOS symptoms. Further, we propose a nomenclature shift to scalene triangle syndrome (STS) to reflect the nerve and arterial compressions needing to be addressed. PMID- 29396982 TI - Use of Social Media and an Online Survey to Discuss Complex Reconstructive Surgery: A Case of Upper Lip Reconstruction with 402 Responses from International Microsurgeons. AB - BACKGROUND: The best reconstructive strategy for upper lip defects is still in debate. The purpose of this study was to analyze the decisions made by international microsurgeons, who were participated through online questionnaire, distributed by email and social media network. MATERIALS AND METHODS: A case of a two-thirds upper lip oncologic defect was presented via an online questionnaire and 402 microsurgeons replied their treatment options. The data were then analyzed according to the geographic area, microsurgical fellowship, seniority, and subspecialty. All the data were analyzed using SPSS 22. RESULTS: A total of 27.7% of microsurgeons chose a free flap, while 72.3% chose a local/pedicle flap as their preferred method for reconstruction. The most common choice of free and local/pedicle flaps was radial forearm (73.6%) and Abbe (36.2%), respectively. The microsurgeons in Europe preferred local/pedicle flaps than free flap when compared with Middle/South America, Asia-Pacific, Africa and South Asia/Middle East (11.6% versus 50%, 43.4%, 29.3% and 27.3%, respectively, multivariant p < 0.05). The microsurgeons with microsurgical fellowships preferred to use free flaps (32.9% versus 17.5%, multivariant p = 0.021). There was no difference for the seniority and specialty of the microsurgeons. CONCLUSIONS: The online questionnaire is valuable and feasible for obtaining experts' opinions. This study provides a current global overview of surgical preferences for this common complicated clinical scenario. PMID- 29396983 TI - Stable Rat Model of Mechanical Allodynia in Diabetic Peripheral Neuropathy: The Role of Nerve Compression. AB - BACKGROUND: Preclinical studies involving animal models are essential for understanding the underlying mechanisms of diabetic neuropathic pain. METHODS: Rats were divided into four groups: two controls and two experimental. Diabetes mellitus was induced by streptozotocin (STZ) injection in two experimental groups. The first group involved one sham operation. The second group involved one latex tube encircling the sciatic nerve. The vehicle-injection rats were used as two corresponding control groups: sham operation and encircled nerves. By the third week, STZ-injected rats with encircled nerves were further divided into three subgroups: one involving continuing observation and the other two involving decompression (removal of the latex tube) at different time points (third week and fifth week). Weight and blood glucose were monitored, and behavioral analysis, including paw withdrawal threshold (PWT) and latency, was performed every week during the experimental period (7 weeks). RESULTS: Hyperglycemia was induced in all STZ-injected rats. A significant increase in weight was observed in the control groups when compared with the experimental groups. By the third week, more STZ-injected rats with encircled nerves developed mechanical allodynia than those without (P < 0.05), while no significant difference was noted (P > 0.05) on the incidence of thermal hyperalgesia. Mechanical allodynia, but not thermal hyperalgesia, could be ameliorated by the removal of the latex tube at an early stage (third week). CONCLUSION: With the combined use of a latex tube and STZ injection, a stable rat model of painful diabetic peripheral neuropathy (DPN) manifesting both thermal hyperalgesia and mechanical allodynia has been established. PMID- 29396984 TI - The glycan-dependent ERAD machinery degrades topologically diverse misfolded proteins. AB - Many soluble and integral membrane proteins fold in the endoplasmic reticulum (ER) with the help of chaperones and folding factors. Despite these efforts, protein folding is intrinsically error prone and amino acid changes, alterations in post-translational modifications or cellular stress can cause protein misfolding. Folding-defective non-native proteins are cleared from the ER and typically undergo ER-associated degradation (ERAD). Here, we investigated whether different misfolded glycoproteins require the same set of ERAD factors and are directed to HRD1 complex-mediated degradation in plants. We generated a series of glycoprotein ERAD substrates harboring a misfolded domain from Arabidopsis STRUBBELIG or the BRASSINOSTEROID INSENSITVE 1 receptor fused to different membrane anchoring regions. We show that single pass and multispanning ERAD substrates are subjected to glycan-dependent degradation by the HRD1 complex. However, the presence of a powerful ER exit signal in the multispanning ERAD substrates causes competition with ER quality control and targeting of misfolded glycoproteins to the vacuole. Our results demonstrate that the same machinery is used for degradation of topologically different misfolded glycoproteins in the ER of plants. PMID- 29396986 TI - S-Nitrosoglutathione works downstream of nitric oxide to mediate iron-deficiency signaling in Arabidopsis. AB - Iron (Fe) is essential for plant growth and development. Knowledge of Fe signaling, from the beginning of perception to activation of the uptake process, is critical for crop improvement. Here, by using chemical screening, we identified a small molecule 3-amino-N-(3-methylphenyl)thieno[2,3-b]pyridine-2 carboxamide named R7 ('R' denoting repressor of IRON-REGULATED TRANSPORTER 1), that modulates Fe homeostasis of Arabidopsis. R7 treatment led to reduced Fe levels in plants, thus causing severe chlorosis under Fe deficiency. Expression analysis of central transcription factors, FER-LIKE IRON DEFICIENCY INDUCED TRANSCRIPTION FACTOR (FIT) and subgroup Ib basic helix-loop-helix (Ib bHLH) genes bHLH38/39/100/101, revealed that R7 targets the FIT-dependent transcriptional pathway. Exogenously supplying S-nitrosoglutathione (GSNO), but not other nitric oxide (NO) donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl-dl penicillamine (SANP), alleviated the inhibitory effects of R7 on Fe homeostasis. R7 did not inhibit cellular levels of NO or glutathione but decreased GSNO level in roots. We demonstrate that NO is involved in regulating not only the FIT transcriptional network but also the Ib bHLH networks. In addition, GSNO, from S nitrosylation of glutathione, specifically mediates the Fe-starvation signal to FIT, which is distinct from the NO to Ib bHLH signal. Our work dissects the molecular connection between NO and the Fe-starvation response. We present a new signaling route whereby GSNO acts downstream of NO to trigger the Fe-deficiency response in Arabidopsis. PMID- 29396985 TI - Extended-release injectable naltrexone for opioid use disorder: a systematic review. AB - AIMS: To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol(r) ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined. METHODS: We searched PubMed and used Google Scholar for forward citation searches of peer-reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR-NTX were included. RESULTS: We identified and included 34 studies. Pooled estimates showed that XR-NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5-70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0 90.1%); 44.2% (95% CI = 33.1-55.9%) of individuals took all scheduled injections of XR-NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6-month rates: 46.7%, 95% CI = 34.5-59.2% versus 10.5%, 95% CI = 4.6-22.4%, respectively). Compared with referral to treatment, XR-NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR-NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR-NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification. CONCLUSIONS: Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most who do start XR-NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect. PMID- 29396987 TI - The effects of flexibility training on exercise-induced muscle damage in young men with limited hamstrings flexibility. AB - Adaptations to 6 weeks of supervised hamstring stretching training and its potential impact on symptoms of eccentric exercise-induced muscle damage (EIMD) were studied in 10 young, untrained men with limited hamstrings flexibility. Participants performed unilateral flexibility training (experimental leg; EL) on an isokinetic dynamometer, while the contralateral limb acted as control (CL). Hip range of motion (ROM), passive, isometric, and concentric torques, active optimum angle, and biceps femoris and semitendinosus muscle thickness and ultrasound echo intensity were assessed both before and after the training. Additionally, muscle soreness was assessed before and after an acute eccentric exercise bout in both legs (EL and CL) at post-training only. Hip ROM increased (P < .001) only in EL after the training (EL = 10.6 degrees vs CL = 1.6 degrees ), but no changes (P > .05) in other criterion measurements were observed. After a bout of eccentric exercise at the end of the program, isometric and dynamic peak torques and muscle soreness ratings were significantly altered at all time points equally in EL and CL. Also, active optimum angle was reduced immediately, 48 and 72 hours post-exercise, and hip ROM was reduced at 48 and 72 hours equally in EL and CL. Finally, biceps femoris muscle thickness was significantly increased at all time points, and semitendinosus thickness and echo intensity significantly increased at 72 hours, with no significant differences between legs. The stretching training protocol significantly increased hip ROM; however, it did not induce a protective effect on EIMD in men with tight hamstrings. PMID- 29396988 TI - RAF2 is a RuBisCO assembly factor in Arabidopsis thaliana. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) catalyzes the reaction between gaseous carbon dioxide (CO2 ) and ribulose-1,5-bisphosphate. Although it is one of the most studied enzymes, the assembly mechanisms of the large hexadecameric RuBisCO is still emerging. In bacteria and in the C4 plant Zea mays, a protein with distant homology to pterin-4alpha-carbinolamine dehydratase (PCD) has recently been shown to be involved in RuBisCO assembly. However, studies of the homologous PCD-like protein (RAF2, RuBisCO assembly factor 2) in the C3 plant Arabidopsis thaliana (A. thaliana) have so far focused on its role in hormone and stress signaling. We investigated whether A. thalianaRAF2 is also involved in RuBisCO assembly. We localized RAF2 to the soluble chloroplast stroma and demonstrated that raf2 A. thaliana mutant plants display a severe pale green phenotype with reduced levels of stromal RuBisCO. We concluded that the RAF2 protein is probably involved in RuBisCO assembly in the C3 plant A. thaliana. PMID- 29396989 TI - Organization of the TC and TE cellular T-DNA regions in Nicotiana otophora and functional analysis of three diverged TE-6b genes. AB - Nicotiana otophora contains Agrobacterium-derived T-DNA sequences introduced by horizontal gene transfer (Chen et al., 2014). Sixty-nine contigs were assembled into four different cellular T-DNAs (cT-DNAs) totalling 83 kb. TC and TE result from two successive transformation events, each followed by duplication, yielding two TC and two TE inserts. TC is also found in other Nicotiana species, whereas TE is unique to N. otophora. Both cT-DNA regions are partially duplicated inverted repeats. Analysis of the cT-DNA divergence patterns allowed reconstruction of the evolution of the TC and TE regions. TC and TE carry 10 intact open reading frames. Three of these are TE-6b genes, derived from a single 6b gene carried by the Agrobacterium strain which inserted TE in the N. otophora ancestor. 6b genes have so far only been found in Agrobacterium tumefaciens or Agrobacterium vitis T-DNAs and strongly modify plant growth (Chen and Otten, 2016). The TE-6b genes were expressed in Nicotiana tabacum under the constitutive 2 * 35S promoter. TE-1-6b-R and TE-2-6b led to shorter plants, dark-green leaves, a strong increase in leaf vein development and modified petiole wings. TE-1-6b-L expression led to a similar phenotype, but in addition leaves show outgrowths at the margins, flowers were modified and plants became viviparous, i.e. embryos germinated in the capsules at an early stage of their development. Embryos could be rescued by culture in vitro. The TE-6b phenotypes are very different from the earlier described 6b phenotypes and could provide new insight into the mode of action of the 6b genes. PMID- 29396990 TI - Determination of the speciation and bioavailability of samarium to Chlamydomonas reinhardtii in the presence of natural organic matter. AB - As technological interest and environmental emissions of the rare earth elements increase, it is becoming more important to assess their potential environmental impact. Samarium (Sm) is a lanthanide of intermediate molar mass that is used in numerous high-technology applications including wind turbines, solar panels, and electric vehicles. The present study relates the speciation of Sm determined in the presence of natural organic matter (NOM) to its bioavailability to the unicellular green alga Chlamydomonas reinhardtii. The free ion concentration was determined using a cation exchange resin (ion exchange technique) in dynamic mode and compared with thermodynamic modeling. Short-term biouptake experiments were performed in the presence of 4 types of NOM: Suwannee River fulvic acids, Pahokee Peat fulvic acids, Suwannee River humic acids, and a Luther Marsh dissolved organic matter isolate (90-95% humic acids). It was clearly shown that even a small amount of NOM (0.5 mg C L-1 ) resulted in a significant decrease (10 times) in the Sm internalization fluxes. Furthermore, complexation with humic acids (and the corresponding reduction in Sm bioavailability) was stronger than that with fulvic acids. The results showed that the experimentally measured (free) Sm was a better predictor of Sm internalization than either the total concentrations or the free ion concentrations obtained using thermodynamic modeling. Environ Toxicol Chem 2018;37:1623-1631. (c) 2018 SETAC. PMID- 29396991 TI - Alterations in natural killer and dendritic cell subsets in individuals with HIV associated neurotuberculosis. AB - One of the commonest HIV-associated opportunistic infections of the central nervous system is neurotuberculosis. Interaction between HIV, Mycobacterium tuberculosis and host immune system in co-infected individuals may result in altered frequencies of immune cells, thereby modulating dissemination and disease progression. We examined the frequencies of natural killer (NK) cell and dendritic cell (DC) subsets in HIV infected individuals with neurotuberculosis (HIVNTB) as compared to individuals with HIV associated systemic TB (HIVSTB), asymptomatic HIV, non-HIV NTB, non-HIV STB, and healthy controls. Peripheral blood mononuclear cells (PBMC) were stained with fluorochrome-conjugated monoclonal antibodies- Lineage cocktail (containing CD3, CD14, CD19, and CD20), HLA-DR, CD16, CD56, CD11c, and CD123, fixed with 2% paraformaldehyde and analyzed on the flow cytometer. The pDCs were significantly reduced in all HIV infected groups, with a marked reduction in HIVNTB cases as compared to healthy controls. While the CD56- CD16bt NK cell subset displayed a significant increase in frequency in all three HIV infected groups compared the three HIV negative groups, the CD56dim CD16bt subset was significantly lower in frequency in the HIVNTB compared to healthy controls. The decreased frequencies of plasmacytoid DCs and cytotoxic NK cells, which are crucial for innate immune defence against HIV, may result in ineffective virus control and lead to an exacerbated course of disease in HIVNTB individuals. PMID- 29396992 TI - Recombinant type Human mastadenovirus D85 associated with epidemic keratoconjunctivitis since 2015 in Japan. AB - The aim of this study was to report the emergence of a recombinant human mastadenovirus (HAdV) type 85 (HAdV-85) and to describe its genomic and clinical characteristics. The strains were detected and identified in Japan in cases of adenoviral conjunctivitis including epidemic keratoconjunctivitis (EKC). The type was designated as HAdV-85 based on the novel combination of penton base (P = HAdV 37), hexon (H = HAdV-19), and fiber (F = HAdV-8). The whole genome sequence determined for HAdV-85 was compared against sequences of other types in the same species. The results of the phylogenetic analysis suggested a recombinant origin between HAdV-53 and HAdV-64, which have been two major causes of adenoviral EKC in Japan over the past decade. During the period between 2008 and 2016 in Kumamoto city, southwest of Japan, 311 cases diagnosed with conjunctivitis were diagnosed as being the consequence of adenoviral infections. Among them, 11 cases were determined to have been caused by HAdV-85 since 2015. Thus, HAdV-85 could be an emerging causative agent of adenoviral conjunctivitis. PMID- 29396993 TI - Electron affinities of substituted nitrobenzenes from negative ion mass spectrometry lifetimes and literature electron affinities. PMID- 29396994 TI - Strategic Design and Fabrication of Nerve Guidance Conduits for Peripheral Nerve Regeneration. AB - Nerve guidance conduits (NGCs) have been drawing considerable attention as an aid to promote regeneration of injured axons across damaged peripheral nerves. Ideally, NGCs should include physical and topographic axon guidance cues embedded as part of their composition. Over the past decades, much progress has been made in the development of NGCs that promote directional axonal regrowth so as to repair severed nerves. This paper briefly reviews the recent designs and fabrication techniques of NGCs for peripheral nerve regeneration. Studies associated with versatile design and preparation of NGCs fabricated with either conventional or rapid prototyping (RP) techniques have been examined and reviewed. The effect of topographic features of the filler material as well as porous structure of NGCs on axonal regeneration has also been examined from the previous studies. While such strategies as macroscale channels, lumen size, groove geometry, use of hydrogel/matrix, and unidirectional freeze-dried surface are seen to promote nerve regeneration, shortcomings such as axonal dispersion and wrong target reinnervation still remain unsolved. On this basis, future research directions are identified and discussed. PMID- 29396995 TI - Twenty-year analysis of implant treatment in an Australian public dental clinic. AB - BACKGROUND: This retrospective cohort study reviewed dental implant treatment completed at the Adelaide Dental Hospital over a 20-year period. METHODS: The database of implant treatment completed between 1996 and 2015 was analysed for patient, implant, prosthesis and operator specifics together with known implant status. RESULTS: Three hundred and twenty patients (mean age, 51.50 years) were treated with 527 implants. One hundred and eighty-four female patients received 296 implants and 136 males received 231 implants. Three hundred implants were restored with single crowns, 147 implants were restored with 63 mandibular implant overdentures, five implants were restored with two maxillary implant overdentures and 67 implants were restored with 20 full-arch fixed prostheses. The overall known implant survival rate was 87.67%. Mandibular implant overdentures had a risk of implant failure four times that of single implant retained crowns that was statistically significant (P = 0.0100). CONCLUSIONS: Implant treatment completed in this public sector clinic using finite resources and a defined system of patient and restorative selection criteria demonstrated a high known implant survival rate. Utilizing a structured and maintained patient recall protocol, it would be ideal to investigate further parameters of interest, particularly those that could improve treatment delivery and longevity. PMID- 29396996 TI - Intranasal Ketamine and Its Potential Role in Cancer-Related Pain. AB - Cancer-related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment using a tiered approach of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N-methyl-d-aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations but has also been investigated for depression, bipolar disorder, and general and postoperative pain management. As an analgesic, low-dose ketamine decreases morphine requirements and rates of nausea and vomiting, suggesting a potentially beneficial role in cancer-related pain. Ketamine is typically administered intravenously and has a rapid onset of action with a relatively short half-life (2-3 hours) but is inconvenient for use in an ambulatory setting. Oral bioavailability is low and erratic, limiting application of this route for chronic use. Intranasal administration has a number of potential advantages, including avoidance of first-pass hepatic metabolism, no need for venous access, ability to repeat doses quickly, and rapid absorption. Although early studies of intranasal ketamine are promising in a number of indications, information is more limited in its use as an adjunct in cancer-related pain. We review the background, rationale, pharmacokinetics, and clinical and safety data using intranasal ketamine as an adjunctive agent and its potential in cancer-related pain. PMID- 29396997 TI - Potential use of stable isotope and fatty acid analyses for traceability of geographic origins of jumbo squid (Dosidicus gigas). AB - RATIONALE: Squid is an important seafood resource for Asian and European countries. With the continuous development of processed squid products, an effective traceability system has become increasingly prominent. Here, we attempt to trace the fishery products of the main target species, jumbo squid (Dosidicus gigas), by using biochemical tracers. METHODS: Carbon and nitrogen isotope ratios (delta13 C and delta15 N values) and fatty acid profiles were identified in squid from three harvest locations in the eastern Pacific Ocean by isotope ratio mass spectrometry and gas chromatography/mass spectrometry, respectively. Comparative analysis was used to evaluate the geographic variations in tracers and to identify the suitable discriminatory variables among origins. RESULTS: Significant spatial variations were found in isotopic values and fatty acid profiles in squid muscle tissues, possibly because of different food availability and/or oceanographic conditions that each group experiences at a given location. The stepwise discriminant analysis indicated that delta15 N, C16:1n7, C17:1n7, C18:2n6, C20:1 and C20:4n6 were effective variables at differentiating origin. CONCLUSIONS: Combined use of stable isotope ratios and fatty acid analyses could trace geographic origins of jumbo squid. This study provides an alternative approach for improving authenticity evaluation of commercial squid products. PMID- 29396998 TI - Four Arabidopsis berberine bridge enzyme-like proteins are specific oxidases that inactivate the elicitor-active oligogalacturonides. AB - Recognition of endogenous molecules acting as 'damage-associated molecular patterns' (DAMPs) is a key feature of immunity in both animals and plants. Oligogalacturonides (OGs), i.e. fragments derived from the hydrolysis of homogalacturonan, a major component of pectin are a well known class of DAMPs that activate immunity and protect plants against several microbes. However, hyper-accumulation of OGs severely affects growth, eventually leading to cell death and clearly pointing to OGs as players in the growth-defence trade-off. Here we report a mechanism that may control the homeostasis of OGs avoiding their deleterious hyper-accumulation. By combining affinity chromatography on acrylamide-trapped OGs and other procedures, an Arabidopsis thaliana enzyme that specifically oxidizes OGs was purified and identified. The enzyme was named OG OXIDASE 1 (OGOX1) and shown to be encoded by the gene At4g20830. As a typical flavo-protein, OGOX1 is a sulphite-sensitive H2 O2 -producing enzyme that displays maximal activity on OGs with a degree of polymerization >4. OGOX1 belongs to a large gene family of mainly apoplastic putative FAD-binding proteins [Berberine Bridge Enzyme-like (BBE-like); 27 members], whose biochemical and biological function is largely unexplored. We have found that at least four BBE like enzymes in Arabidopsis are OG oxidases (OGOX1-4). Oxidized OGs display a reduced capability of activating the immune responses and are less hydrolysable by fungal polygalacturonases. Plants overexpressing OGOX1 are more resistant to Botrytis cinerea, pointing to a crucial role of OGOX enzymes in plant immunity. PMID- 29396999 TI - Progress of CRISPR-Cas Based Genome Editing in Photosynthetic Microbes. AB - The carbon footprint caused by unsustainable development and its environmental and economic impact has become a major concern in the past few decades. Photosynthetic microbes such as microalgae and cyanobacteria are capable of accumulating value-added compounds from carbon dioxide, and have been regarded as environmentally friendly alternatives to reduce the usage of fossil fuels, thereby contributing to reducing the carbon footprint. This light-driven generation of green chemicals and biofuels has triggered the research for metabolic engineering of these photosynthetic microbes. CRISPR-Cas systems are successfully implemented across a wide range of prokaryotic and eukaryotic species for efficient genome editing. However, the inception of this genome editing tool in microalgal and cyanobacterial species took off rather slowly due to various complications. In this review, we elaborate on the established CRISPR Cas based genome editing in various microalgal and cyanobacterial species. The complications associated with CRISPR-Cas based genome editing in these species are addressed along with possible strategies to overcome these issues. It is anticipated that in the near future this will result in improving and expanding the microalgal and cyanobacterial genome engineering toolbox. PMID- 29397000 TI - Estimating the health-care costs of children born to pregnant smokers in England: cohort study using primary and secondary health-care data. AB - BACKGROUND AND AIMS: Little is known about the long-term economic consequences of smoking during pregnancy. We estimated the association between smoking in pregnancy and the costs of delivering health-care to infants and children in England, and investigated which aspects of care are the key drivers of these costs. METHODS: We used Hospital Episode Statistics (HES) linked with Clinical Practice Research Datalink (CPRD) data in England from January 2003 to January 2015 in children with longitudinal data for at least 1, 5 and 10 years after birth. Poisson regression provided rate ratios (RR) and 95% confidence intervals (CIs) comparing health-care episode rates between those exposed and not exposed to smoking during pregnancy. Linear regression was used to compare estimated costs between groups (L sterling, 2015 prices) and generalized linear multivariable (GLM) models adjusted for potentially moderating factors. RESULTS: A total of 93 152 singleton pregnancies with the required data were identified. Maternal smoking in pregnancy was associated with higher primary care, prescription and hospital in-patient episode rates, but lower out-patient visit and diagnostic test rates. Adjusting for year of birth, socio-economic deprivation, parity, sex of child and delivery method showed that maternal smoking in pregnancy was associated with increased child health-care costs at 1 year [average cost difference for children of smokers, beta = L91.18, 95% confidence interval (CI) = L47.52-134.83 and 5 years of age (beta = L221.80, 95% CI = L17.78-425.83], but not at 10 years of age (beta = L365.94, 95% CI = L192.72 to L924.60). CONCLUSION: In England, maternal smoking in pregnancy is associated with increased child health-care costs over the first 5 years of life; these costs are driven primarily by greater hospital in-patient care. PMID- 29397001 TI - The relationship between methamphetamine use and heterosexual behaviour: evidence from a prospective longitudinal study. AB - AIMS: To estimate the extent to which specific sexual behaviours (being sexually active, having multiple sex partners, casual sex, condomless casual sex, anal sex and condomless anal sex) change during periods of methamphetamine use. DESIGN: Within-person estimates for the relationship between methamphetamine use and sexual behaviour were derived from longitudinal panel data from the Methamphetamine Treatment Evaluation Study (MATES) cohort (2006-10). SETTING: Sydney and Brisbane, Australia. PARTICIPANTS: Participants (n = 319) were recruited through treatment and other health services, self-identified as heterosexual, were aged 17-51 years, 74% were male and all were dependent on methamphetamine on study entry. MEASUREMENTS: Days of methamphetamine use in the past month and sexual behaviour in the past month were both assessed using the Opiate Treatment Index. FINDINGS: When using methamphetamine, participants had double the odds of being sexually active compared with when they were not using, after adjustment for demographics and other substance use [adjusted odds ratio (aOR) = 1.9, P = 0.010]. When participants were sexually active, they were more likely to have multiple sex partners (aOR = 3.3, P = 0.001), casual sex partners (aOR = 3.9, P < 0.001) and condomless casual sex (aOR = 2.6, P = 0.012) when using methamphetamine than when they were not using. During months when participants had a casual sex partner, there was no significant reduction in their likelihood of condom use when they were using methamphetamine. There was no significant change in the likelihood of having anal sex or condomless anal sex during months of methamphetamine use. CONCLUSIONS: Methamphetamine use is associated with an increase in being sexually active, having multiple sex partners and casual sex partners and having condomless sex with casual partners, but it is not associated with a change in condom use per se. PMID- 29397002 TI - Contemporary surgical management of renal oncocytoma: a nation's outcome. AB - OBJECTIVE: To report on the contemporary UK experience of surgical management of renal oncocytomas. PATIENTS AND METHODS: Descriptive analysis of practice and postoperative outcomes of patients with a final histological diagnosis of oncocytoma included in The British Association of Urological Surgeons (BAUS) nephrectomy registry from 01/01/2013 to 31/12/2016. Short-term outcomes were assessed over a follow-up of 60 days. RESULTS: Over 4 years, 32 130 renal surgical cases were recorded in the UK, of which 1202 were oncocytomas (3.7%). Most patients were male (756; 62.9%), the median (interquartile range [IQR]) age was 66.8 (13) years. The median (IQR; range) lesion size was 4.1 (3; 1-25) cm, 43.5% were <=4 cm and 30.3% were 4-7 cm lesions. In all, 35 patients (2.9%) had preoperative renal tumour biopsy. Most patients had minimally invasive surgery, either radical nephrectomy (683 patients; 56.8%), partial nephrectomy (483; 40.2%) or other procedures (36; 3%). One in five patients (243 patients; 20.2%) had in-hospital complications: 48 were Clavien-Dindo classification grade >=III (4% of the total cohort), including three deaths. Two additional deaths occurred within 60 days of surgery. The analysis is limited by the study's observational nature, not capturing lesions on surveillance or ablated after biopsy, possible underreporting, short follow-up, and lack of central histology review. CONCLUSION: We report on the largest surgical series of renal oncocytomas. In the UK, the complication rate associated with surgical removal of a renal oncocytoma was not negligible. Centralisation of specialist services and increased utilisation of biopsy may inform management, reduce overtreatment, and change patient outcomes for this benign tumour. PMID- 29397003 TI - Outcome of full pulpotomy using Biodentine in adult patients with symptoms indicative of irreversible pulpitis. AB - AIM: To assess the outcome of full pulpotomy using Biodentine in permanent teeth with carious exposures and symptoms indicative of irreversible pulpitis. METHODOLOGY: Sixty-four permanent molar teeth with symptomatic vital pulps in 52 patients aged 19-69 years were included. Preoperative pulpal and periapical diagnosis was established. After informed consent, the tooth was anaesthetized, isolated using rubber dam and disinfected with 5% NaOCl before caries excavation; subsequently, the pulp was amputated to the level of the canal orifices. Haemostasis was achieved, and a 3-mm layer of Biodentine (Septodont, Saint-Maur des-Fosses, France) was placed as the pulpotomy agent. Resin-modified glass ionomer liner was placed and the tooth restored with either resin composite or amalgam, and a postoperative periapical radiograph exposed. Clinical and radiographic evaluation was completed at 6 months and 1 year postoperatively. Pain levels were scored preoperatively and 2 days post-treatment. RESULTS: Clinical signs and symptoms indicative of irreversible pulpitis were established in all teeth, and periapical rarefaction was present in nine teeth. After 2 days, 93.8% reported complete relief of pain. At 6 months, 63 of 64 attended recall with 98.4% clinical and radiographic success. At 1 year, 59 of 63 attended recall, with 100% clinical and 98.4 radiographic success. Seven of eight cases with periapical rarefaction who attended recall had improvement in the periapical index (PAI) score. A hard tissue barrier was detected radiographically in four cases. CONCLUSION: Full pulpotomy using Biodentine was a successful treatment option for cariously exposed pulps in mature permanent molar teeth with clinical signs and symptoms indicative of irreversible pulpitis, up to 1 year. PMID- 29397004 TI - Detection of the iron complexes with hydrolysis products of cephalexin and cefradine upon high-performance liquid chromatography/electrospray ionization mass spectrometry analysis. AB - RATIONALE: Cephalosporins (e.g. cephalexin, cefradine) are a major group of widely used beta-lactam antibiotics. Hydrolysis of the beta-lactam ring is an important reaction (often undesired) which leads to deactivation of beta-lactams. To the best of our knowledge there is no electrospray ionization mass spectrometry (ESI-MS) data reported concerning the products of hydrolysis of cephalosporins. METHODS: The hydrolysis of cephalexin and cefradine was performed in aqueous NaOH solutions. After the process the solutions were analyzed by high performance liquid chromatography (HPLC)/ESI-MS. The elemental compositions of the ions discussed were confirmed by the accurate mass measurements on a quadrupole time-of-flight (QTOF) mass spectrometer. RESULTS: Unexpectedly, complexes between the hydrolysis products of cephalexin and cefradine (CFLh and CFRh ) and iron cation were detected upon HPLC/ESI-MS analysis, namely the ions [(CFLh -H)2 +Fe]+ and [(CFRh -H)2 +Fe]+ , although iron was not added to the analyzed solutions or to the mobile phase. These ions were found to be very stable in the gas phase. CONCLUSIONS: The detection of the complexes between the hydrolysis products of cephalosporins and iron may have a positive impact on the sensitivity and specificity of HPLC/ESI-MS analyses of the hydrolysis products of some cephalosporins. PMID- 29397005 TI - Antibacterial properties of silver nanoparticles as a root canal irrigant against Enterococcus faecalis biofilm and infected dentinal tubules. AB - AIM: To evaluate the antimicrobial action of an irrigant containing silver nanoparticles in an aqueous vehicle (AgNp), sodium hypochlorite and chlorhexidine against Enterococcus faecalis biofilm and infected dentinal tubules. METHODOLOGY: Bovine dentine blocks were used for E. faecalis biofilm development for 21 days and irrigated with 94 ppm AgNp solution, 2.5% NaOCl and 2% chlorhexidine for 5, 15 and 30 min. For infection of dentinal tubules with E. faecalis, dentine specimens from bovine incisors were submitted to a contamination protocol over 5 days, with eight centrifugation cycles on every alternate day, and irrigated with the same solutions and time intervals used for the biofilm. The specimens were stained with the Live/Dead technique and evaluated using a confocal laser scanning microscope (CLSM). The bioImage_L software was used for measurement of the total biovolume of biofilm in MUm3 and percentage of viable bacteria (green cells) in biofilm and in dentinal tubules found after the irrigation. Statistical analyses were performed using Kruskal-Wallis and Dunn's tests for quantification of viable cells in biofilm, the Friedman test for comparisons of viable bacteria in dentinal tubules in different areas of the root canal and the Mann-Whitney U test to compare the action of the irrigants between the two methods (P < 0.05). RESULTS: The AgNp solution eliminated fewer bacteria, but was able to dissolve more biofilm compared with chlorhexidine (P < 0.05). NaOCl had the greatest antimicrobial activity and biofilm dissolution capacity. AgNp solution had less antimicrobial action in infected dentinal tubules compared with NaOCl (P < 0.05). The AgNp solution after 5 min was more effective in eliminating planktonic bacteria in dentinal tubules than in biofilm, but at 30 min fewer viable bacteria were observed in the biofilm compared with intratubular dentine (P < 0.05). CONCLUSIONS: AgNp irrigant was not as effective against E. faecalis compared to solutions commonly used in root canal treatment. NaOCl is appropriate as an irrigant because it was effective in disrupting biofilm and in eliminating bacteria in biofilms and in dentinal tubules. PMID- 29397006 TI - Quantification of dsRNA using stable isotope labeling dilution liquid chromatography/mass spectrometry. AB - RATIONALE: Recent developments in RNA interference (RNAi) have created a need for cost-effective and large-scale synthesis of double-stranded RNA (dsRNA), in conjunction with high-throughput analytical techniques to fully characterise and accurately quantify dsRNA prior to downstream RNAi applications. METHODS: Stable isotope labeled dsRNA was synthesised both in vivo (15 N) and in vitro (13 C,15 N guanosine-containing dsRNA) prior to purification and quantification. The stable isotope labeled dsRNA standards were subsequently spiked into total RNA extracted from E. coli engineered to express dsRNA. RNase mass mapping approaches were subsequently performed using liquid chromatography/electrospray ionisation mass spectrometry (LC/ESI-MS) for both the identification and absolute quantification of the dsRNA using the ratios of the light and heavy oligonucleotide pairs. RESULTS: Absolute quantification was performed based on the resulting light and heavy oligoribonucleotides identified using MS. Using this approach we determined that 624.6 ng/MUL and 466.5 ng/MUL of dsRNA was present in 80 MUL total RNA extracted from 108 E. coli cells expressing 765 bp and 401 bp dsRNAs, respectively. CONCLUSIONS: Stable isotope labeling of dsRNA in conjunction with MS enabled the characterisation and quantification of dsRNA in complex total RNA mixtures. PMID- 29397007 TI - Commentary: IARC Monographs Program and public health under siege by corporate interests. AB - The International Agency for Research on Cancer (IARC) evaluates causes of cancer with help from independent international experts in an open and transparent manner. Countries, research and regulatory agencies, and other organizations adopt IARC evaluations for communication of human cancer hazards, and for strategies to prevent cancer. Scientists worldwide endorse IARC cancer evaluations and process. Those with economic interests, however, challenge IARC's cancer evaluations, most recently for glyphosate and red and processed meats, and are conducting a campaign including intervention from US Congressional Representatives to discredit IARC's review process and to undermine financial support-a campaign intimidating to IARC and Working Group members. Challenges to scientific interpretations serve to advance science and should be resolved by scientific experts who do not have conflicts of interest. Such interference does not bode well for the free flow of scientific information that informs and protects the public from risks of cancer. PMID- 29397008 TI - Synthesis and Electronic Structure of Boron-Graphdiyne with an sp-Hybridized Carbon Skeleton and Its Application in Sodium Storage. AB - Boron-graphdiyne (BGDY), which has a unique pi-conjugated structure comprising an sp-hybridized carbon skeleton and evenlydistributed boron heteroatoms in a well organized 2D molecular plane, is prepared through a bottom-up synthetic strategy. Excellent conductivity, a relatively low band gap and a packing mode of the planar BGDY are observed. Notably, the unusual bonding environment of the all sp carbon framework and the electron-deficient boron centers generates affinity to metal atoms, and thus provides extra binding sites. Furthermore, the expanded molecule pores of the BGDY molecular plane can also facilitate the transfer of metal ions in the perpendicular direction. The practical effect of the all sp carbon structure and boron heteroatoms on the properties of BGDY are demonstrated in its performance as the anode in sodium-ion batteries. PMID- 29397009 TI - speed-ne: Software to simulate and estimate genetic effective population size (Ne ) from linkage disequilibrium observed in single samples. AB - The genetic effective population size, Ne , can be estimated from the average gametic disequilibrium (r2^) between pairs of loci, but such estimates require evaluation of assumptions and currently have few methods to estimate confidence intervals. speed-ne is a suite of matlab computer code functions to estimate Ne^ from r2^ with a graphical user interface and a rich set of outputs that aid in understanding data patterns and comparing multiple estimators. speed-ne includes functions to either generate or input simulated genotype data to facilitate comparative studies of Ne^ estimators under various population genetic scenarios. speed-ne was validated with data simulated under both time-forward and time backward coalescent models of genetic drift. Three classes of estimators were compared with simulated data to examine several general questions: what are the impacts of microsatellite null alleles on Ne^, how should missing data be treated, and does disequilibrium contributed by reduced recombination among some loci in a sample impact Ne^. Estimators differed greatly in precision in the scenarios examined, and a widely employed Ne^ estimator exhibited the largest variances among replicate data sets. speed-ne implements several jackknife approaches to estimate confidence intervals, and simulated data showed that jackknifing over loci and jackknifing over individuals provided ~95% confidence interval coverage for some estimators and should be useful for empirical studies. speed-ne provides an open-source extensible tool for estimation of Ne^ from empirical genotype data and to conduct simulations of both microsatellite and single nucleotide polymorphism (SNP) data types to develop expectations and to compare Ne^ estimators. PMID- 29397010 TI - Nitrogen-Based Lewis Acids: Synthesis and Reactivity of a Cyclic (Alkyl)(Amino)Nitrenium Cation. AB - A room-temperature-stable crystalline cyclic (alkyl)(amino)nitrenium cation 2 features cationic nitrogen atom with a smaller HOMO-LUMO gap compared to that of a 1,2,3-triazolium 5 (an N-heterocyclic nitrenium cation). The low-lying LUMO of 2 results in an enhanced electrophilicity, which allowed for the formation of Lewis adducts with neutral Lewis bases, such as Me3 P, nBu3 P, and IiPr. The N based Lewis acid 2 also forms an FLP with tBu3 P but subsequently reacts with (PrS)2 to cleave the S-S bond. Both experimental and theoretical results suggest that the Lewis acidity of 2 is stronger than its N3 analogues. PMID- 29397011 TI - Dual-Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors. AB - A combination of chemo- and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual target (RC-12 and PG-6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as-synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self-immolated cleavage under irradiation from a near-IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo-photothermal combination. PMID- 29397012 TI - Evaluation of the bioactivity of fluoride-enriched mineral trioxide aggregate on osteoblasts. AB - AIM: To investigate whether a combination of mineral trioxide aggregate (MTA) and fluoride compounds affects bone cells. METHODOLOGY: Mineral trioxide aggregate (MTA) discs (ProRoot(r) , Dentsply Sirona, Ballaigues, Switzerland) with and without the addition of 0.1%, 0.25% and 0.5% sodium fluoride were characterized for their surface roughness by laser scanning microscopy and for the adhesion of human alveolar osteoblasts by scanning electron microscopy. Using eluates from fluoride-enriched MTA discs, the cell proliferation was measured by monitoring the DNA incorporation of 5-bromo-2'-deoxyuridine. Further, gene expression was evaluated by qPCR arrays, extracellular matrix mineralization was quantified by absorption measurement of Alizarin red stains, and effects were calculated with repeated measures analysis and post hoc P-value adjustment. RESULTS: Irrespective of fluoride addition, cell adhesion was similar on MTA discs, of which the surface roughness was comparable. Control osteoblasts had a curvilinear proliferation pattern peaking at d5, which was levelled out by incubation with MTA. The addition of fluoride partly restored the MTA-related reduction in the cellular proliferation rate in a dose-dependent manner. At the mRNA level, both fluoride and MTA modulated a number of genes involved in osteogenesis, bone mineral metabolism and extracellular matrix formation. Although MTA significantly impaired extracellular matrix mineralization, the addition of fluoride supported the formation of mineralized nodules in a dose-dependent manner. CONCLUSION: The addition of fluoride modulated the biocompatibility of MTA in terms of supporting bone cell proliferation and hard tissue formation. Hence, fluoride enrichment is a trend-setting advancement for MTA-based endodontic therapies. PMID- 29397013 TI - Supramolecular Nanostructures of Structurally Defined Graphene Nanoribbons in the Aqueous Phase. AB - Structurally well-defined graphene nanoribbons (GNRs) have attracted great interest because of their unique optical, electronic, and magnetic properties. However, strong pi-pi interactions within GNRs result in poor liquid-phase dispersibility, which impedes further investigation of these materials in numerous research areas, including supramolecular self-assembly. Structurally defined GNRs were synthesized by a bottom-up strategy, involving grafting of hydrophilic poly(ethylene oxide) (PEO) chains of different lengths (GNR-PEO). PEO grafting of 42-51 % percent produces GNR-PEO materials with excellent dispersibility in water with high GNR concentrations of up to 0.5 mg mL-1 . The "rod-coil" brush-like architecture of GNR-PEO resulted in 1D hierarchical self assembly behavior in the aqueous phase, leading to the formation of ultralong nanobelts, or spring-like helices, with tunable mean diameters and pitches. In aqueous dispersions the superstructures absorbed in the near-infrared range, which enabled highly efficient conversion of photon energy into thermal energy. PMID- 29397014 TI - Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review. AB - Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF alpha and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients. PMID- 29397015 TI - Differential virus-specific CD8+ T-cell epitope repertoire in hepatitis C virus genotype 1 versus 4. AB - Virus-specific CD8+ T-cell responses play an important role in the outcome of hepatitis C virus (HCV) infection. To date, most HCV-specific CD8+ T-cell epitopes have been defined in HCV genotype 1 infection. In contrast, the HCV genotype 4-specific CD8+ T-cell response is poorly defined. Here, we analysed whether known HCV-specific CD8+ T-cell epitopes are also recognized in HCV genotype 4-infected patients and set out to identify the first HCV genotype 4 specific CD8+ T-cell epitopes. We studied patients chronically infected with HCV genotype 1 (n = 20) or 4 (n = 21) using 91 well-described HCV-specific epitope peptides. In addition, we analysed 24 genotype 4-infected patients using 40 epitope candidates predicted using an in silico approach. HCV-specific CD8+ T cell responses targeting previously described epitopes were detectable in the majority of genotype 1-infected patients (11 of 20). In contrast, patients infected with HCV genotype 4 rarely targeted these epitopes (4 of 21; P = .0247). Importantly, we were able to identify eight novel HCV genotype 4-specific CD8+ T cell epitopes. Only one of these epitopes was shared between genotype 1 and genotype 4. These results indicate that there is little overlap between CD8+ T cell repertoires targeting HCV genotype 1 and 4. Prophylactic vaccination studies based on HCV genotype 1 are currently underway. However, in countries with the highest prevalence of HCV infection, such as Egypt, most patients are infected with HCV genotype 4. Thus, prophylactic vaccination strategies need to be adapted to HCV genotype 4 before their application to regions where HCV genotype 4 is endemic. PMID- 29397016 TI - Risk of hepatitis B virus reactivation in hepatitis B virus + hepatitis C virus co-infected patients with compensated liver cirrhosis treated with ombitasvir, paritaprevir/r + dasabuvir + ribavirin. AB - Hepatitis B virus may reactivate in patients with chronic hepatitis C treated with direct-acting antivirals. The aim of this study was to investigate the risk of hepatitis B virus (HBV) reactivation in HBV + hepatitis C virus (HCV)-co infected patients with compensated liver cirrhosis treated with paritaprevir/ombitasvir/ritonavir, dasabuvir with ribavirin. We reviewed prospectively gathered data from a national cohort of 2070 hepatitis C virus patients with compensated liver cirrhosis who received reimbursed paritaprevir/ombitasvir/r, dasabuvir with ribavirin for 12 weeks from the Romanian National Health Agency during 2015-2016. Twenty-five patients in this cohort were HBs antigen positive (1.2%); 15 untreated with nucleotide analogues agreed to enter the study. These patients were followed up: ALT monthly, serology for HBV and DNA viral load at baseline, EOT and SVR at 12 weeks. Hepatitis B virus (HBV)-co-infected patients were all genotype 1b and 52% females, with a median age of 60 years (51 / 74); 76% were pretreated with peginterferon + ribavirin; 72% were with severe necroinflammatory activity on FibroMax assessment; 40% presented comorbidities; and all were HBe antigen negative. Hepatitis C virus (HCV) SVR response rate was 100%. Hepatitis B virus (HBV)-DNA viral load was undetectable in 7/15 (47%) before therapy, and for the other 8 patients, it varied between below 20 and 867 IU/mL. Five patients (33%) presented virological reactivation (>2 log increase in HBV-DNA levels) during therapy. One patient presented with hepatitis associated with HBV reactivation, and two started anti-HBV therapy with entecavir. Hepatitis B virus (HBV) virological reactivation was present in 33% in our patients. Generally, HBV-DNA elevations were mild (<20 000 IU/mL); however, we report one case of hepatitis associated with HBV reactivation. PMID- 29397018 TI - From SOMDA to application - integration strategies in the OR.NET demonstration sites. AB - The effective development and dissemination of the open integration for the next generation of operating rooms require a comprehensive testing environment. In this paper, we present the various challenges to be addressed in demonstration applications, and we discuss the implementation approach, the foci of the demonstration sites and the evaluation efforts. Overall, the demonstrator setups have proven the feasibility of the service-oriented medical device architecture (SOMDA) and real-time approaches with a large variety of example applications. The applications demonstrate the potentials of open device interoperability. The demonstrator implementations were technically evaluated as well as discussed with many clinicians from various disciplines. However, the evaluation is still an ongoing research at the demonstration sites. Technical evaluation focused on the properties of a network of medical devices, latencies in data transmission and stability. A careful evaluation of the SOMDA design decisions and implementations are essential to a safe and reliable interoperability of integrated medical devices and information technology (IT) system in the especially critical working environment. The clinical evaluation addressed the demands of future users and stakeholders, especially surgeons, anesthesiologists, scrub nurses and hospital operators. The opinions were carefully collected to gain further insights into the potential benefits of the technology and pitfalls in future work. PMID- 29397017 TI - Steroid therapy in children with fulminant hepatitis A. AB - Fulminant hepatic failure is a life-threatening disease. Hepatitis A virus (HAV) can cause fulminant hepatic failure and death in about 0.2% of cases. Extensive destruction of infected hepatocytes by immune-mediated lysis is thought to be the cause. We aimed to evaluate the use of steroid therapy in children with fulminant HAV. This study included 33 children with fulminant HAV in two groups. Steroid group: comprised of 18 children who received prednisolone (1 mg/kg/d) or its equivalent dose of methylprednisolone, and the nonsteroid group: comprised another 15 children who did not receive steroid therapy. Age and sex were matched for both groups (P > .05), and they were comparable regarding baseline clinical and laboratory characteristics. Of the steroid group, 15 patients survived and 3 died, while in the nonsteroid group, 4 patients survived and 11 died (P = .001). Of the living patients, 15 of 19 (78.9%) received steroids while only 3 of 14 (21.4%) of the dead patients received steroids (P = .001). Stepwise regression analysis showed that steroid therapy was the only independent variable associated with recovery (P = .001). Steroid therapy in children with fulminant HAV associated significantly with improved outcome and survival. Future studies on a larger population size are strongly recommended. PMID- 29397019 TI - Use of circulating tumor cells in prospective clinical trials for NSCLC patients standardization of the pre-analytical conditions. AB - BACKGROUND: Circulating tumor cells (CTCs) hold potential for noninvasive diagnosis, prognosis and prediction testing in non-small cell lung cancer (NSCLC) patients. Minimizing degradation or loss of CTCs is pivotal for detection and profiling of the low abundance and fragile CTCs, particularly in clinical trials. We prospectively investigated (NCT02372448) whether a new blood collection device performed better compared to commonly used K3EDTA tubes, when subjected to long term sample storage. METHODS: Blood samples were drawn into K3EDTA and blood collection tubes (BCT) (Streck), and filtered by the Isolation by SizE of Tumor/Trophoblastic Cells (ISET(r) system), for CTC detection in two study populations of NSCLC patients; the training set of 14 patients with stage II/IV NSCLC, and the validation set of 36 patients with stage IV NSCLC). MET expression was evaluated by immunocytochemistry (ICC) and anaplastic lymphoma kinase (ALK) gene rearrangement by break-apart fluorescence in situ hybridization (FISH) on ISET-enriched CTCs. RESULTS: Blood processed after 24 h and 48 h in BCT tubes showed stable CTCs counts and integrity, whereas CTCs in K3EDTA tubes showed an altered morphology in all patients. CTCs recovered in BCT or K3EDTA tubes at 24 and 48 h were evaluable by ICC for MET expression and by FISH for ALK rearrangement. CONCLUSIONS: The BCT tubes gave a high yield and preserved the integrity of CTCs after 24 and 48 h of storage at room temperature, which facilitate their molecular characterization in NSCLC patients entering clinical trials. PMID- 29397020 TI - Platelet serotonin is not elevated in patients with benign head and neck paragangliomas. PMID- 29397021 TI - "Send & hold" clinical decision support rules improvement to reduce unnecessary testing of vitamins A, E, K, B1, B2, B3, B6 and C. AB - BACKGROUND: We assessed the impact of several "send & hold" clinical decision support rules (CDSRs) within the electronical request system for vitamins A, E, K, B1, B2, B3, B6 and C for all outpatients at a large health department. METHODS: When ordered through electronical request, providers (except for all our primary care physicians who worked as a non-intervention control group) were always asked to answer several compulsory questions regarding main indication, symptomatology, suspected diagnosis, vitamin active treatments, etc., for each vitamin test using a drop-down list format. After samples arrival, tests were later put on hold internally by our laboratory information system (LIS) until review for their appropriateness was made by two staff pathologists according to the provided answers and LIS records (i.e. "send & hold"). The number of tests for each analyte was compared between the 10-month period before and after CDSRs implementation in both groups. RESULTS: After implementation, vitamins test volumes decreased by 40% for vitamin A, 29% for vitamin E, 42% for vitamin K, 37% for vitamin B1, 85% for vitamin B2, 68% for vitamin B3, 65% for vitamin B6 and 59% for vitamin C (all p values 0.03 or lower except for vitamin B3), whereas in control group, the majority increased or remained stable. In patients with rejected vitamins, no new requests and/or adverse clinical outcome comments due to this fact were identified. CONCLUSIONS: "Send & hold" CDSRs are a promising informatics tool that can support in utilization management and enhance the pathologist's leadership role as tests specialist. PMID- 29397022 TI - Current state and recommendations for harmonization of serum/plasma 17 hydroxyprogesterone mass spectrometry methods. PMID- 29397023 TI - Cellular markers of eryptosis are altered in type 2 diabetes. PMID- 29397024 TI - Pseudomonas and Burkholderia inhibit growth and asexual development of Phytophthora capsici. AB - The objective of this study was to isolate and characterize antagonistic rhizobacteria from chili against a notorious phytopathogen Phytophthora capsici. Among the 48 bacteria isolated, BTLbbc-02, BTLbbc-03, and BTLbbc-05 were selected based on their inhibitory activity against P. capsici. They were tentatively identified as Burkholderia metallica BTLbbc-02, Burkholderia cepacia BTLbbc-03, and Pseudomonas aeruginosa BTLbbc-05, respectively, based on their 16S rRNA gene sequencing. All inhibited the growth of P. capsici at varying levels by inducing characteristic morphological alterations of P. capsici hyphae. The cell-free culture supernatant of all three isolates impaired motility (up to 100%) and caused lysis (up to 50%) of the halted zoospores. Bioassays revealed that Pseudomonas sp. had higher antagonism and zoospore motility-inhibitory effects against P. capsici compared with two other isolates, Burkholderia spp. and B. metallica, which caused vacuolation in mycelium. All three bacteria suppressed sporangium formation and zoosporogenesis of P. capsici, and improved the seed germination and growth of cucumber. Our findings suggest that epiphytic bacteria, B. metallica, B. cepacia, and P. aeruginosa, could be used as potential biocontrol agents against P. capsici. A further study is required to ensure conformity with the existing regulations for soil, plant, and human health. PMID- 29397025 TI - CCNO mutations in NPH? PMID- 29397026 TI - Overexpression of Coiled-Coil Domain-Containing Protein 34 (CCDC34) and its Correlation with Angiogenesis in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND The coiled-coil domain-containing proteins have been shown to have a series of functions in biological synthesis. Recent studies have found that CCDC34 is highly expressed in bladder cancer, but the underlying molecular mechanisms still remain unclear. Therefore, we performed the present study to assess the expression of the coiled-coil domain-containing protein 34 (CCDC34) in esophageal squamous cell carcinoma (ESCC) patients. We also explored the relationships between CCDC34 expression and clinicopathologic characteristics, tumor angiogenesis, and prognosis. MATERIAL AND METHODS We detected the expressions of CCDC34, VEGF, and MVD by immunohistochemical technique in 100 cases of ESCC and 80 cases of corresponding paracarcinomatous normal tissues. The relationship between CCDC34 expression and clinicopathologic characteristics, tumor angiogenesis, and prognosis were also explored. RESULTS The expression of CCDC34 protein was obviously increased in ESCC tissues, which was significantly correlated with sex (p=0.038), TNM stage (p=0.003), and lymphatic metastasis (p=0.024). In addition, we found that the expression of CCDC34 was an independent prognostic factor for ESCC patients. The overexpression of CCDC34 protein in ESCC was associated with tumor progression, angiogenesis, and poor survival. CONCLUSIONS Our results demonstrate that CCDC34 is overexpressed in ESCC and can be used as an independent parameter for indicating the poor prognosis of ESCC patients, suggesting that CCDC34 might be a new potential therapeutic target for ESCC patients in the future. PMID- 29397027 TI - Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas - Diagnostic algorithm and principles of therapy. AB - Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development. Other genetic diseases, which may show palmoplantar involvement, such as selected subtypes of hereditary epidermolysis bullosa, various hereditary ichthyoses and other keratinization disorders, several ectodermal dysplasias and some multisystem genetic disorders, are also briefly summarized. PPK diagnosis is based on inheritance pattern, age at onset, morphology, distribution and severity of hyperkeratosis, pattern of additional dermatological and systemic manifestations and laboratory findings. Molecular analysis is at present the gold standard to confirm the diagnosis in PPK forms due to mutations in known causative genes. No specific and curative therapy is currently available for PPKs which highly impair patients' quality of life. Topical treatments are symptomatic and offer only temporary relief. Among systemic treatments, retinoids improve disease symptoms in the majority of patients. PMID- 29397029 TI - Nitrogen deposition drives loss of moss cover in alpine moss-sedge heath via lowered C : N ratio and accelerated decomposition. AB - In alpine ecosystems, nitrogen (N) deposition has been linked to plant community composition change, including loss of bryophytes and increase of graminoids. Since bryophyte growth is stimulated by increased N availability, it has been hypothesized that loss of bryophyte cover is driven by enhanced decomposition. As bryophyte mats are a significant carbon (C) store, their loss may impact C storage in these ecosystems. We used an N deposition gradient across 15 sites in the UK to examine effects of N deposition on bryophyte litter quality, decomposition and C and N stocks in Racomitrium moss-sedge heath. Increasing N deposition reduced C : N in bryophyte litter, which in turn enhanced decomposition. Soil N stocks increased significantly in response to increased N deposition, and soil C : N declined. However, depletion of the bryophyte mat and its replacement by graminoids under high N deposition was not associated with a change in total ecosystem C stocks. We conclude that decomposition processes in Racomitrium heath are very sensitive to N deposition and provide a mechanism by which N deposition drives depletion of the bryophyte mat. Nitrogen deposition did not measurably alter C stocks, but changes in soil N stocks and C : N suggest the ecosystem is becoming N saturated. PMID- 29397028 TI - Drought stress and tree size determine stem CO2 efflux in a tropical forest. AB - CO2 efflux from stems (CO2_stem ) accounts for a substantial fraction of tropical forest gross primary productivity, but the climate sensitivity of this flux remains poorly understood. We present a study of tropical forest CO2_stem from 215 trees across wet and dry seasons, at the world's longest running tropical forest drought experiment site. We show a 27% increase in wet season CO2_stem in the droughted forest relative to a control forest. This was driven by increasing CO2_stem in trees 10-40 cm diameter. Furthermore, we show that drought increases the proportion of maintenance to growth respiration in trees > 20 cm diameter, including large increases in maintenance respiration in the largest droughted trees, > 40 cm diameter. However, we found no clear taxonomic influence on CO2_stem and were unable to accurately predict how drought sensitivity altered ecosystem scale CO2_stem , due to substantial uncertainty introduced by contrasting methods previously employed to scale CO2_stem fluxes. Our findings indicate that under future scenarios of elevated drought, increases in CO2_stem may augment carbon losses, weakening or potentially reversing the tropical forest carbon sink. However, due to substantial uncertainties in scaling CO2_stem fluxes, stand-scale future estimates of changes in stem CO2 emissions remain highly uncertain. PMID- 29397030 TI - Sensitive skin in France: a study on prevalence, relationship with age and skin type and impact on quality of life. AB - BACKGROUND: Many epidemiological studies have been performed, but a potential increase in the prevalence of sensitive skin, its relationship with age and skin type and the impact of sensitive skin on quality of life are still debated. OBJECTIVE: To answer these unresolved questions. METHODS: An opinion poll was conducted on a representative French 5000 person sample. RESULTS: Fifty-nine per cent of the people declared very sensitive or fairly sensitive skin (together: sensitive skin), and women (66%) declared sensitive skin more frequently than men (51.9%). The results also showed that sensitive skin is more common (more than 60%) in younger people (<35 years old), and there was a decrease in the following age groups. The univariate analysis demonstrated that sensitive skin was more likely to be reported by people with fair skin (OR = 1.83) and by people with an atopic predisposition (OR = 2.51). The risk of sensitive skin is higher for people with dry skin (OR = 6.18 compared with normal skin), but sensitive skin can occur in other skin types (OR = 2.45 for mixed skin and OR = 2.16 for greasy skin). Quality of life was clearly altered in patients with sensitive skin, as assessed by SF-12 and DLQI. CONCLUSION: This large study demonstrates that sensitive skin can alter quality of life and is more common in young people and in women as well as patients with dry skin or fair skin or an atopic predisposition. It also suggests that there is an increase in the prevalence of sensitive skin. PMID- 29397031 TI - Comparative genome analysis and characterization of the Salmonella Typhimurium strain CCRJ_26 isolated from swine carcasses using whole-genome sequencing approach. AB - : Salmonella pathogenicity relies on virulence factors many of which are clustered within the Salmonella pathogenicity islands. Salmonella also harbours mobile genetic elements such as virulence plasmids, prophage-like elements and antimicrobial resistance genes which can contribute to increase its pathogenicity. Here, we have genetically characterized a selected S. Typhimurium strain (CCRJ_26) from our previous study with Multiple Drugs Resistant profile and high-frequency PFGE clonal profile which apparently persists in the pork production centre of Rio de Janeiro State, Brazil. By whole-genome sequencing, we described the strain's genome virulent content and characterized the repertoire of bacterial plasmids, antibiotic resistance genes and prophage-like elements. Here, we have shown evidence that strain CCRJ_26 genome possible represent a virulence-associated phenotype which may be potentially virulent in human infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Whole-genome sequencing technologies are still costly and remain underexplored for applied microbiology in Brazil. Hence, this genomic description of S. Typhimurium strain CCRJ_26 will provide help in future molecular epidemiological studies. The analysis described here reveals a quick and useful pipeline for bacterial virulence characterization using whole-genome sequencing approach. PMID- 29397032 TI - Impact of Gastrostomy Feeding Tube Placement on the 1-Year Trajectory of Care in Patients After Stroke. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) feeding tubes are commonly placed in acute stroke patients with a need for enteral nutrition. However, PEG tubes are associated with medical complications and a decrease in quality of life. We compared the 1-year care trajectory of stroke patients with and without PEG tube placement to enhance knowledge about the long-term impact of PEG tube placement. METHODS: We conducted a retrospective analysis of commercially insured stroke patients included in the Truven Health MarketScan Research Databases of 2011. We analyzed their index hospital stay and conducted 1-month, 3-months, 6 months, and 1-year follow-ups. We compared admissions to inpatient rehabilitation facilities, acute hospitals, skilled nursing facilities, outpatient hospital visits, and home visits for stroke patients with and without PEG tube placement using unadjusted and adjusted modelling. RESULTS: Of the 8911 included stroke patients, 148 patients (1.7%) had a PEG tube placed during their index hospital stay. After controlling for age, gender, stroke severity, comorbidities, and stroke type, PEG tube placement was an independent predictor for admissions to inpatient rehabilitation facilities and skilled nursing facilities. Furthermore, PEG tube placement was an independent predictor for all-cause, unplanned hospital readmissions in a multivariable logistic model (area under the receiver operating characteristic curve was .84). CONCLUSION: Stroke patients who receive a PEG tube can expect a significantly different care trajectory after being discharged from the acute hospital. Our findings can aide in predicting recovery and planning resources and identifying gaps and points for improvement in stroke care for patients with PEG tube placement. PMID- 29397033 TI - Interactions between the Newly Described Small- and Fast-Swimming Mixotrophic Dinoflagellate Yihiella yeosuensis and Common Heterotrophic Protists. AB - The mixotroph Yihiella yeosuensis is a small- and fast-swimming dinoflagellate. To investigate its protistan predators, interactions between Y. yeosuensis and 11 heterotrophic protists were explored. No potential predators were able to feed on actively swimming Y. yeosuensis cells, which escaped via rapid jumps, whereas Aduncodinium glandula, Oxyrrhis marina, and Strombidinopsis sp. (approximately 150 MUm in cell length) were able to feed on weakly swimming cells that could not jump. Furthermore, Gyrodinium dominans, Luciella masanensis, and Pfiesteria piscicida were able to feed on heat-killed Yihiella cells, whereas Gyrodinium moestrupii, Noctiluca scintillans, Oblea rotunda, Polykrikos kofoidii, and Strombidium sp. (20 MUm) did not feed on them. Thus, the jumping behavior of Y. yeosuensis might be primarily responsible for the observed lack of predation. With increasing Yihiella concentration, the growth rate of O. marina decreased, whereas that of Strombidinopsis did not change. However, with increasing Yihiella concentration (up to 530 ng C/ml), the ingestion rate of Strombidinopsis on Yihiella increased linearly. The highest ingestion rate was 24.1 ng C per predator per d. The low daily carbon acquisition from Yihiella relative to the body carbon content of Strombidinopsis might be responsible for its negligible growth. Thus, Y. yeosuensis might have an advantage over its competitors due to its low mortality rate. PMID- 29397034 TI - Lipid droplet-mediated lipid and protein homeostasis in budding yeast. AB - Lipid droplets are conserved specialized organelles that store neutral lipids. Our view on this unique organelle has evolved from a simple fat deposit to a highly dynamic and functionally diverse hub-one that mediates the buffering of fatty acid stress and the adaptive reshaping of lipid metabolism to promote membrane and organelle homeostasis and the integrity of central proteostasis pathways, including autophagy, which ensure stress resistance and cell survival. This Review will summarize the recent developments in the budding yeast Saccharomyces cerevisiae, as this model organism has been instrumental in deciphering the fundamental mechanisms and principles of lipid droplet biology and interconnecting lipid droplets with many unanticipated cellular functions applicable to many other cell systems. PMID- 29397035 TI - Psoriasis and cardiovascular disease risk factors: the HUNT Study, Norway. AB - BACKGROUND: Studies have examined the associations between psoriasis and cardiovascular diseases and their risk factors, but the results are conflicting, especially in the general population. OBJECTIVES: To investigate the association of psoriasis, and in particular psoriasis severity, with objectively measured cardiovascular disease risk factors and cardiovascular morbidity in a large population-based cross-sectional study. METHODS: We linked data on 50 245 persons in the HUNT3 Study, Norway, with information from the National Prescription Database to obtain information on use of psoriasis medication. A total of 2894 persons reported to have psoriasis; 2643 were classified as mild; and 251 as moderate/severe psoriasis. We used linear and logistic regression to estimate adjusted associations with 95% confidence intervals (CIs) between psoriasis and cardiovascular disease risk factors and morbidity. RESULTS: We observed a positive association between psoriasis and objective measures of body mass index (BMI), waist circumference and high-sensitivity C-reactive protein, but no clear association with blood pressure and blood lipids. People with moderate/severe psoriasis had an odds ratio for being overweight of 1.94 (95% CI 1.42, 2.67), whereas the odds ratio for metabolic syndrome was 1.91 (95% CI 1.47, 2.49). Psoriasis was also positively associated with self-reported diabetes, myocardial infarction and angina pectoris. CONCLUSIONS: In this population-based study, we found that psoriasis was positively associated with measures of adiposity, as well as with a clustering of cardiovascular disease risk factors. Overall, these associations were strongest for people with moderate/severe psoriasis. PMID- 29397036 TI - Antibody-mediated rejection in pediatric small bowel transplantation: Capillaritis is a major determinant of C4d positivity in intestinal transplant biopsies. AB - The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome. PMID- 29397037 TI - Morphology, Morphogenesis, and Molecular Phylogeny of a New Soil Ciliate, Sterkiella multicirrata sp. nov. (Ciliophora, Hypotrichia) from China. AB - The morphology and morphogenesis of a new soil hypotrich ciliate, Sterkiella multicirrata sp. nov., was investigated using live observation and protargol staining. The new species is characterised by: body elliptical, 110-180 * 45-75 MUm in vivo, an average of 35 adoral membranelles; usually 19 frontoventral transverse cirri, consisting of three frontal, five frontoventral, one buccal, four postoral ventral, two pretransverse, and four transverse cirri; four macronuclear nodules, and 2-5 micronuclei. S. multicirrata sp. nov. differs from its congeners mainly in the number of frontoventral-transverse cirri and macronuclear nodules. Morphogenesis of the new species is similar to its congeners; the primary difference exists in the segmentation of the frontoventral transverse cirral anlagen, which is usually generated in a 1:2:3:3:5:5 pattern. Based on the small subunit ribosomal DNA sequence, the phylogenetic position of the new species is discussed. PMID- 29397038 TI - Program-specific transplant rate ratios: Association with allocation priority at listing and posttransplant outcomes. AB - The Scientific Registry of Transplant Recipients (SRTR) is considering more prominent reporting of program-specific adjusted transplant rate ratios (TRRs). To enable more useful reporting of TRRs, SRTR updated the transplant rate models to adjust explicitly for components of allocation priority. We evaluated potential associations between TRRs and components of allocation priority that could indicate programs' ability to manipulate TRRs by denying or delaying access to low-priority candidates. Despite a strong association with unadjusted TRRs, we found no candidate-level association between the components of allocation priority and adjusted TRRs. We found a strong program-level association between median laboratory Model for End-stage Liver Disease (MELD) score at listing and program-specific adjusted TRRs (r = .37; P < .001). The program-level association was likely confounded by regional differences in donor supply/demand and listing practices. In kidney transplantation, higher program-specific adjusted TRRs were weakly associated with better adjusted posttransplant outcomes (r = -.14; P = .035) and lower adjusted waitlist mortality rate ratios (r = -.15; P = .022), but these associations were absent in liver, lung, and heart transplantation. Program specific adjusted TRRs were unlikely to be improved by listing candidates with high allocation priority and can provide useful information for transplant candidates and programs. PMID- 29397039 TI - Nutrition Status Among HIV-Positive and HIV-Negative Inpatients with Pulmonary Tuberculosis. AB - BACKGROUND: The association between tuberculosis (TB) and malnutrition is well recognized. Considering the risk of mortality due to malnutrition in patients with TB, it is necessary to conduct a thorough nutrition assessment to identify individuals at nutrition risk. The study objective was to assess the nutrition status of hospitalized patients with TB, co-infected or not by human immunodeficiency virus (HIV). METHODS: Patients with confirmed diagnosis of TB were included using a cross-sectional design. Nutrition assessment parameters included: body mass index (BMI), triceps skin-fold thickness (TSF), bioelectrical impedance analysis (BIA), mid-upper-arm circumference (MUAC), mid-arm muscle circumference (MAMC), food frequency questionnaire, Malnutrition Screening Tool (MST), Subjective Global Assessment (SGA), and serum levels of hemoglobin. RESULTS: A total 108 patients completed the study. Forty-four patients (40.7%) were HIV positive. Considering the BMI, 36.1% of the patients met the criteria for nutrition deficiency. Body fat percentage was low in 27.8% of patients. In addition, more than half of the participants met criteria for malnutrition according to MUAC, MAMC, TSF, SGA, or MST. Malnutrition measured by MAMC was more frequent in HIV-positive patients (n=33, 75.0%) than in HIV-negative patients (n=31, 48.4%) (P = 0.010). Regarding the components of diet, selenium and vitamin C intake among HIV-positive patients was significantly lower than in HIV-negative patients. CONCLUSIONS: We identified a high prevalence of malnutrition in hospitalized patients with pulmonary TB, regardless of the method used to assess nutrition status. In HIV-positive patients, malnutrition measured by MAMC was more frequent than in HIV-negative patients. PMID- 29397040 TI - Phase Angle as a Sarcopenia Marker in Hospitalized Elderly Patients. AB - BACKGROUND: Phase angle (PhA) has been proposed as a parameter to predict clinical outcomes and mortality for various diseases. Several studies have considered it an important nutrition assessment tool. However, the usefulness of this parameter as a sarcopenia marker has not yet been evaluated. This study was developed to evaluate the performance of PhA as a sarcopenia marker in hospitalized elderly patients. MATERIALS AND METHODS: This was a cross-sectional study involving elderly patients admitted to a hospital in northeastern Brazil. The PhA was obtained from resistance and reactance measurements by bioelectrical impedance. Sarcopenia was defined as a decrease in muscle mass associated with a reduced muscle strength or physical performance. RESULTS: The sample consisted of 148 patients with a mean age of 71.6 (+/-7.6) years and a 62.8% prevalence of sarcopenia. The average PhA was 5.9 +/- 2.0 degrees , similar for men and women (5.9 +/- 2.3 vs 5.9 +/- 1.8; P = .946). In men, sarcopenic patients had a lower average PhA (5.6 +/- 2.3 degrees ) when compared with patients without this condition (6.8 +/- 1.9 degrees ; P = .024). When comparing the value of PhA regarding the degree of sarcopenia, it was found that patients from both sexes with severe sarcopenia had lower averages. The PhA had a low predictive capacity in relation to the diagnostic components of sarcopenia (physical performance, muscle mass, and strength). CONCLUSION: PhA was an inaccurate marker to identify sarcopenia and presented low predictive capacity to explain muscle mass, muscle strength, and functional capacity, components involved in the diagnosis of sarcopenia. PMID- 29397042 TI - Corrigendum. PMID- 29397041 TI - Cell cycle-related and expression-elevated protein in tumor overexpression is associated with proliferation behaviors and poor prognosis in non-small-cell lung cancer. AB - The cell cycle-related and expression-elevated protein in tumor (CREPT) is overexpressed in several human malignancies. However, the clinical relevance of CREPT expression and its biological role in non-small-cell lung cancer (NSCLC) remains unclear. In this study, we detected the expression of CREPT in both NSCLC tissues and cell lines by immunohistochemistry, Western blot analysis, and RT PCR. The correlation between CREPT expression and clinicopathologic features was analyzed in 271 NSCLC patients. The prognostic value of CREPT expression was evaluated by Kaplan-Meier analysis and Cox regression analysis. CREPT was overexpressed in Calu-1 cell lines by using plasmid vector and its biological function was explored both in vitro and in vivo. We found that CREPT was significantly overexpressed in NSCLC compared with paired adjacent non-tumor tissues, and the expression level of CREPT was correlated with tumor differentiation, lymph node metastasis, and clinical stage. Kaplan-Meier analysis showed that the recurrence-free survival and overall survival of high CREPT expression groups were significantly shorter than those of the low CREPT expression group. Multivariate analysis identified that CREPT might be an independent biomarker for the prediction of NSCLC prognosis. Overexpression of CREPT increased cell proliferation and enhanced the migration and invasion ability of Calu-1 cells (a human NSCLC cell line with relative low CRPET expression) in vitro. Moreover, CREPT overexpression promoted tumor growth in a nude mice model. These results suggest that CREPT is closely relevant to the proliferation of NSCLC cells and it might be a potential prognostic marker in NSCLC patients. PMID- 29397044 TI - SCIENTISTS and SCIENCE ADVOCATES: Professor David W. Denning, An Extraordinary High Achiever in Clinical and Translational Science PMID- 29397043 TI - Study of Tnp1, Tekt1, and Plzf Genes Expression During an in vitro Three Dimensional Neonatal Male Mice Testis Culture AB - Background: In vitro spermatogenesis has a long research history beginning in the early 20th century. This organ culture method was therefore abandoned, and alternative cell culture methods were chosen by many researchers. Here, whether Tnp1, Tekt1, and Plzf, which play a crucial role in spermatogenesis, can be expressed during testis organ culture was assessed. Methods: Testes of 10 mouse pups were first removed, and the testis tissue was then separated into smaller pieces of seminiferous tubules. The size of the pieces was arbitrary; approximately 1 mg in weight or 1 mm3 in size when compacted. Afterwards, the testis tissue fragments (1-3) were transferred to the hexahedrons, incubated in a culture incubator and cultured for 12 weeks. Histological assessment and molecular evaluation were carried out at the end of the study. Results: The results showed that the expression of Tekt1 as a mitotic gene in mouse pups decreased significantly (p <= 0.05) in comparison to adult mouse testis. Meanwhile, the expression of Tnp1 as a meiotic gene increased significantly (p <= 0.05) as compared to neonate mouse testis at the beginning of the culture. The expression of Plzf showed no significant difference during the 12 weeks of culture (p >= 0.05). Based on histological study, different types of spermatocytes and post-meiotic stages of germ cells could not be detected. Conclusion: This kind of three-dimensional culture can induce expression of post meiotic gene, Tnp1, but only at the molecular level and not beyond meiosis. PMID- 29397045 TI - An experiment in using open-text comments from the Australian Rural Mental Health Study on health service priorities. AB - INTRODUCTION: Conducting research in rural and remote areas is compounded by challenges associated with accessing relatively small populations spread over large geographical areas. Open-ended questions provided in a postal survey format are an advantageous way of including rural and remote residents in research studies. This method means that it is possible to ask for in-depth perspectives, from a large sample, in a relatively resource-efficient way. Such questions are frequently included in population-based surveys; however, they are rarely analysed. The aim of this article is to explore word cloud analysis, to evaluate the utility of automated programs to supplement the analysis of open-ended survey responses. METHODS: Participants from the Australian Rural Mental Health Study completed the open-ended question 'What health services would you like to see the local health district providing that are currently not available in your area?' A word cloud analysis was then undertaken using the program Wordle; the size of the word in the cloud illustrates how many times, in proportion to other words, a word has appeared in responses, and provides an easily interpretable visual illustration of research results. RESULTS: In total, 388 participants provided a response to the free-text question. Using the word cloud as a visual guide, key words were identified and used to locate relevant quotes from the full open-text responses. ?'Mental health?' was the most frequent request, cited by 81 people (20.8%). Following mental health, requests for more ?'specialists?' (n=59) and ?'services?' (n=53) were the second and third most frequent responses respectively. Visiting specialists were requested by multiple respondents (n=14). Less frequent requests illustrated in the word cloud are important when considering representatives from smaller population groups such as those with specific health needs or conditions including ?'maternity?' services (n=13), ?'cancer?' (n=10), ?'drug and alcohol?' services (n=8), and ?'aged care?' (n=7) services are all core services even though they were being called for by fewer people. This lesser frequency may suggest that these services are already considered as available in some rural and remote communities. CONCLUSIONS: This research aimed to determine whether meaningful and informative data could be obtained from short responses from open-ended survey questions using an automated data analysis technique to supplement a more in-depth analysis. The findings showed that, while not as detailed as interview responses, the open-ended survey questions provided sufficient information to develop a broad overview of the health service priorities identified by this large rural sample. Such automated data analysis techniques are rarely employed; however, the current research provides valuable support for their utility in rural and remote health research. This research has implications for researchers interested in engaging rural and remote residents, demonstrating that meaningful information can be extracted from short survey response data, contributing a resource-efficient supplement to a more detailed analysis. Open-ended questions are often asked in population-based studies yet they are rarely analysed, posing both an opportunity and a challenge for researchers using such participant-driven responses. The lessons learned from the methodology applied can be transferred to other population-based survey studies more widely. PMID- 29397046 TI - Application of antimicrobial drugs in perioperative surgical incision. AB - Infection in surgical incision often results in poor wound healing, and one of the main factors for wound infection is the use of antimicrobial agents. Rational use of antibiotics is one of the key factors to prevent incision infection in general surgery. The number of current clinical studies on antibiotic use before and during surgery is greater than that of systematic studies on antibiotic use after surgery. For the rational use of antibiotics and improvement of wound healing rate, researchers around the world have gradually focused on the use of antibiotics after surgery. Despite the familiarity on the concept of "rational use of antibiotics", few clear and systematic studies were conducted to elucidate the effect of different antibiotics on wound healing. Therefore, this review focuses on the use of different types of antimicrobial agents in surgical wounds. PMID- 29397047 TI - Metabolic correlates of health-related quality of life among overweight and obese adolescents. AB - BACKGROUND: Little is known about the metabolic factors associated with the health-related quality of life (HRQOL) among obese youths. The aim of this study is to assess metabolic correlates of HRQOL in a clinical sample of Taiwanese overweight and obese (OW/OB) adolescents. METHODS: OW/OB adolescents (age 11-19 years) were recruited and compared to their normal-weight counterparts in a tertiary hospital. HRQOL was assessed by the Pediatric Quality of Life Inventory (PedsQL). Student t tests and Cohen's d were used to compare the differences in the PedsQL scores between normal-weight and OW/OB participants who were stratified by their cumulative number of cardiometabolic risk factors (CRF). Pearson's correlation and multivariate linear regression analyses were applied to identify predictors of PedsQL. RESULTS: OW/OB adolescents (n = 60) reported lower PedsQL scores than those of normal-weight peers. The negative effects were even larger in OW/OB participants with more than one CRF. Body mass index z-scores and serum alanine aminotransferase (ALT) levels were negatively correlated with overall and subscales of PedsQL (r = - 0.283 to - 0.431). Multivariate linear models showed ALT to be the most salient factor associated with poor obesity related HRQOL. CONCLUSION: Taiwanese OW/OB adolescents, particularly those having additional CRF, reported worse HRQOL. Impaired liver functions may predispose OW/OB subjects to even worse HRQOL. PMID- 29397048 TI - Pyogenic spondylitis and paravertebral abscess caused by Salmonella Saintpaul in an immunocompetent 13-year-old child: a case report. AB - BACKGROUND: Salmonella spondylitis is an uncommon complication of Salmonella infection in immunocompetent children. To prevent treatment failure and neurological deficits, it needs prompt diagnosis and sufficient effort to identify the causative organism. There are some options to identify the causative organism such as Computed Tomography (CT) guided biopsy or surgical debridement, however when to perform these invasive interventions remains controversial. CASE PRESENTATION: A 13-year-old boy presented with occasional high fever and lower back pain. He was diagnosed with spondylitis of the L4-5 vertebral bodies and paravertebral abscess. Initial blood cultures were negative, therefore empirical antibiotic treatment was started. He responded well to conservative management, and was discharged after clinical improvement. However, he was re-hospitalized 2 weeks after discharge, and surgical debridement was performed which led to the detection of Salmonella Saintpaul as the causative pathogen. It was revealed that the possible source of infection was consumption of raw poultry eggs, or contact with poultry. Definitive antibiotic therapy was started. He was discharged with good recovery after a 6-week hospitalization. CONCLUSIONS: This is the very first case report of pyogenic spondylitis caused by Salmonella Saintpaul. Salmonella should be considered as a causative pathogen of pyogenic spondylitis in immunocompetent children. Identifying the causative organism is essential to prevent treatment failure, and a high index of suspicion is needed for prompt diagnosis especially when blood cultures are negative. Invasive interventions such as CT-guided biopsy should be considered even if the clinical course seems to be uncomplicated. PMID- 29397050 TI - Bronchoalveolar lavage for diagnosis of tuberculosis infection in elephants. AB - Tuberculosis (TB) has been known to affect elephants for thousands of years. It was put into spotlight when few circus elephants were diagnosed carrying Mycobacterium (M.) tuberculosis. Because of the zoonotic risk and high susceptibility to M. tuberculosis, periodic testing was enacted since, in captive breeding programmes. Presently, trunk wash is the recommended diagnostic procedure for TB. Trunk wash, however, puts the operator at risk, has low sensitivity, and is prone to contamination. Here, bronchoalveolar lavage is described for the first time for TB diagnosis in elephants. Bronchial, trunk and mouth fluids were investigated using bacterial culture, M. tuberculosis complex (MTC)-specific real-time quantitative PCR (qPCR) and mycobacterial genus-specific qPCR for overall presence of mycobacteria or mycobacterial DNA including bacteria or DNA of closely related genera, respectively, in 14 elephants. Neither bacteria of the MTC nor their DNA were identified in any of the elephants. Yet, 25% of the cultures grew non-tuberculous mycobacteria (NTM) or closely related bacterial species. Furthermore, 85% of the samples contained DNA of NTM or closely related bacterial genera. This finding might explain continued false-positive results from various serological tests. From a zoonotic point of view, bronchoalveolar lavage is safer for the testing personal, has higher probability of capturing MTC and, through PCR, identifies DNA NTM in elephants. Yet, necessary endoscopic equipment, animal sedation and access to a TB reference laboratory might pose challenging requirements in remote conditions in some elephant range countries. PMID- 29397051 TI - Support needs of caregivers of patients with amyotrophic lateral sclerosis: A qualitative study. AB - OBJECTIVE: The aim of this study was to explore the support needs of Dutch informal caregivers of patients with amyotrophic lateral sclerosis (ALS). METHOD: Individual semi-structured interviews were conducted with 21 caregivers of ALS patients. Audio-taped interviews were transcribed and data were analyzed thematically. Result A total of four global support needs emerged: "more personal time", "assistance in applying for resources", "counseling", and "peer contact". Despite their needs, caregivers are reluctant to apply for and accept support. They saw their own needs as secondary to the needs of the patients. Significance of results ALS seems to lead to an intensive caregiving situation with multiple needs emerging in a short period. This study offers targets for the development of supportive interventions. A proactive approach seems essential, acknowledging the importance of the role of the caregivers in the care process at an early stage, informing them about the risk of burden, monitoring their wellbeing, and repeatedly offering support opportunities. Using e-health may help tailor interventions to the caregivers' support needs. PMID- 29397049 TI - Web survey-based selection of controls for epidemiological analyses of a multi prefectural outbreak of enterohaemorrhagic Escherichia coli O157 in Japan associated with consumption of self-grilled beef hanging tender. AB - An outbreak of enterohaemorrhagic Escherichia coli O157 occurred in multiple prefectures of Japan in November 2009. We conducted two case-control studies with trace-back and trace-forward investigations to determine the source. The case definition was met by 21 individuals; 14 (66.7%) were hospitalised, but no haemolytic uraemic syndrome, acute encephalopathy or deaths occurred. Median age was 23 (range 12-48) years and 14 cases were male (66.7%). No significant associations with food were found in a case-control study by local public health centres, but our matched case-control study using Internet surveys found that beef hanging tender (or hanger steak), derived from the diaphragm of the cattle, was significantly associated with illness (odds ratio = 15.77; 95% confidence interval, 2.00-124.11). Pulsed-field gel electrophoresis analysis of isolates from patients and the suspected food showed five different patterns: two in faecal and food samples, and another three in patient faecal samples only, although there were epidemiological links to the meat consumed at the restaurants. Trace-back investigation implicated a common food processing company from outside Japan. Examination of the logistics of the meat processing company suggested that contamination did not occur in Japan. We concluded that the source of the outbreak was imported hanging tender. This investigation revealed that Internet surveys could be useful for outbreak investigations. PMID- 29397052 TI - Intrauterine growth restriction combined with a maternal high-fat diet increased adiposity and serum corticosterone levels in adult rat offspring. AB - Intrauterine growth restriction (IUGR) and fetal exposure to a maternal high-fat diet (HFD) independently increase the risk of developing obesity in adulthood. Excess glucocorticoids increase obesity. We hypothesized that surgically induced IUGR combined with an HFD would increase adiposity and glucocorticoids more than in non-IUGR offspring combined with the same HFD, findings that would persist despite weaning to a regular diet. Non-IUGR (N) and IUGR (I) rat offspring from dams fed either regular rat chow (R) or an HFD (H) were weaned to either a regular rat chow or an HFD. For non-IUGR and IUGR rats, this study design resulted in three diet groups: offspring from dams fed a regular diet and weaned to a regular diet (NRR and IRR), offspring rats from dams fed an HFD and weaned to a regular diet (NHR and IHR) and offspring from dams fed an HFD and weaned to an HFD (NHH and IHH). Magnetic resonance imaging or fasting visceral and subcutaneous adipose tissue collection occurred at postnatal day 60. IHH male rats had greater adiposity than NHH males, findings that were only partly normalized by weaning to a regular chow. IHH male rats had a 10-fold increase in serum corticosterone levels. IHH female rats had increased adiposity and serum triglycerides. We conclude that IUGR combined with an HFD throughout life increased adiposity, glucocorticoids and triglycerides in a sex-specific manner. Our data suggest that one mechanism through which the perinatal environment programs increased adiposity in IHH male rats may be via increased systemic glucocorticoids. PMID- 29397053 TI - Parental effect of diapause in relation to photoperiod and temperature in the cabbage beetle, Colaphellus bowringi (Coleoptera: Chrysomelidae). AB - Increasing evidence has demonstrated that the environmental conditions experienced by parents can shape offspring phenotypes. Here, we examined the effects of the photoperiod and temperature experienced by parents on the incidence of diapause in their progeny in the cabbage beetle, Colaphellus bowringi, using three experiments. The first experiment examined parental diapause incidence under different photoperiods at 25 degrees C and the incidence of diapause in progeny from both non-diapausing and diapausing parents under the same rearing conditions. The results revealed that the incidence of diapause among progeny was exactly opposite to that of their parents, i.e., higher parental diapause incidence led to lower progeny diapause incidence, showing a negative relationship in diapause incidence between the parental generation and the progeny generation. The incidence of diapause among progeny produced by diapausing parents was higher than that in progeny produced by non-diapausing parents. The second experiment examined parental diapause incidence at different temperatures under LD 12:12 and the incidence of diapause in progeny from both non-diapausing and diapausing parents under the same rearing conditions. Similarly, the incidence of diapause in progeny was also opposite to that of their parents. However, the incidence of diapause in progeny produced by non diapausing parents was different from that in progeny produced by diapausing parents. In the third experiment, naturally diapausing adults were maintained at a constant temperature of 9, 28 degrees C or the mean daily summer temperature of 27.84 degrees C under continuous darkness for 3 months of dormancy. After dormancy, the progeny of these post-diapause parents were reared under different photoperiods at 25 degrees C. The results showed that the incidence of diapause among progeny was higher when their parents experienced high temperatures than when they experienced low temperatures. All results demonstrate that the photoperiod and temperature experienced by parents may significantly affect the diapause incidence among progeny. PMID- 29397054 TI - The intestinal protist Blastocystis is not a common member of the healthy infant gut microbiota in a Westernized country (Ireland). AB - Research into the gut microbiota of human infants is necessary in order to better understand how inter-species interactions and ecological succession shape the diversity of the gut microbiota, and in turn, how the specific composition of the gut microbiota impacts on host health both during infancy and in later years. Blastocystis is a ubiquitous intestinal protist that has been linked to a number of intestinal and extra-intestinal diseases. However, emerging data show that asymptomatic carriage is common and that Blastocystis is prevalent in the healthy adult gut microbiota. Nonetheless, little is known about the prevalence and diversity of this microorganism in the healthy infant gut, including when and how individuals become colonized by Blastocystis. Here, we surveyed the prevalence and diversity of Blastocystis in an infant population (n = 59) from an industrialized country (Ireland) using Blastocystis-specific primers at three or more time-points up to 24 months old. Only three infants were positive for Blastocystis (prevalence = 5%) and this was only noted for samples collected at month 24. This rate is comparatively low relative to previously reported prevalence rates in the contemporaneous adult population. These data suggest that infants in Westernized countries that are successfully colonized by Blastocystis most likely acquire this microorganism via horizontal transfer. PMID- 29397055 TI - A cross-sectional pilot study of compassion fatigue, burnout, and compassion satisfaction in pediatric palliative care providers in the United States. AB - OBJECTIVE: Compassion fatigue (CF) is secondary traumatic distress experienced by providers from contact with patients' suffering. Burnout (BO) is job-related distress resulting from uncontrollable workplace factors that manifest in career dissatisfaction. Compassion satisfaction (CS) is emotional fulfillment derived from caring for others. The literature on BO in healthcare providers is extensive, whereas CF and CS have not been comprehensively studied. Because of ongoing exposure to patient and family distress, pediatric palliative care (PPC) providers may be at particular risk for CF. We conducted a cross-sectional pilot study of CF, BO, and CS among PPC providers across the United States. METHOD: The Compassion Fatigue and Satisfaction Self-Test for Helpers and a questionnaire of professional and personal characteristics were distributed electronically and anonymously to PPC physicians and nurses. Logistic and linear regression models for CF, BO, and CS as a function of potential risk factors were constructed. RESULTS: The survey response rate was 39%, primarily consisting of female, Caucasian providers. The prevalence of CF, BO, and CS was 18%, 12%, and 25%, respectively. Distress about a "clinical situation," physical exhaustion, and personal loss were identified as significant determinants of CF. Distress about "coworkers," emotional depletion, social isolation, and "recent involvement in a clinical situation in which life-prolonging activities were not introduced" were significant determinants of BO. Physical exhaustion, personal history of trauma, "recent involvement in a clinical situation in which life-prolonging activities were not introduced," and not discussing distressing issues were significant predictors of lower CS scores. Significance of results CF and BO directly influence the well-being and professional performance of PPC providers. To provide effective compassionate care to patients, PPC providers must be attentive to predictors of these phenomena. Further work is needed to explore additional causes of CF, BO, and CS in PPC providers as well as potential interventions. PMID- 29397056 TI - Identification and tissue expression profiling of candidate UDP glycosyltransferase genes expressed in Holotrichia parallela motschulsky antennae. AB - It is difficult to control Holotrichia parallela Motschulsky with chemical insecticides due to the larvae's soil-living habit, thus the pest has caused great economic losses in agriculture. In addition, uridine diphosphate glycosyltransferases (UGTs) catalyze the glycosylation process of a variety of small lipophilic molecules with sugars to produce water-soluble glycosides, and play multiple roles in detoxification, endobiotic modulation, and sequestration in an insect. Some UGTs were found specifically expressed in antennae of Drosophila melanogaster and Spodoptera littoralis, and glucurono-conjugated odorants could not elicit any olfactory signals, suggesting that the UGTs may play roles in odorant inactivation by biotransformation. In the current study, we performed a genome-wide analysis of the candidate UGT family in the dark black chafer, H. parallela. Based on a UGT gene signature and the similarity of these genes to UGT homologs from other organisms, 20 putative H. parallela UGT genes were identified. Bioinformatics analysis was used to predict sequence and structural features of H. parallela UGT proteins, and revealed important domains and residues involved in sugar donor binding and catalysis by comparison with human UGT2B7. Phylogenetic analysis of these 20 UGT protein sequences revealed eight major groups, including both order-specific and conserved groups, which are common to more than one order. Of these 20 UGT genes, HparUGT1265-1, HparUGT3119, and HparUGT8312 were highly (>100-fold change) expressed in antennae, suggesting a possible role in olfactory tissue, and most likely in odorant inactivation and olfactory processing. The remaining UGT genes were expressed in all tissues (head, thorax, abdomen, leg, and wing), indicating that these UGTs likely have different biological functions. This study provides the fundamental basis for determining the function of UGTs in a highly specialized olfactory organ, the H. parallela antenna. PMID- 29397057 TI - Role of A-kinase anchoring protein 95 in the regulation of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) in human ovarian granulosa cells. AB - Irregular expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) is involved in the development of polycystic ovary syndrome (PCOS). Activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway plays a crucial role in FSH regulation of CYP19A1 in human ovarian granulosa cells. A-Kinase anchor protein 95 (AKAP95) is known to confine PKA to the nucleus. However, it is unclear whether anchoring PKA to the nucleus is essential for the induction of CYP19A1 by FSH in human ovarian granulosa cells. Using the human granulosa cell line KGN and primary cultured human luteinised granulosa cells (hLGCs), we found that knockdown of AKAP8, the gene encoding AKAP95, or inhibition of AKAP95 reduced the amount of PKA anchored in the nucleus and attenuated the phosphorylation of CREB by either FSH or activation of the cAMP/PKA pathway. Moreover, knockdown of AKAP8 or inhibition of AKAP95 also significantly attenuated FSH-induced CYP19A1 expression and oestrogen synthesis. Furthermore, significant decreases in AKAP95 and CYP19A1 were observed in hLGCs obtained from PCOS patients. The results of the present study demonstrate a crucial role for AKAP95 in CYP19A1 expression and oestrogen synthesis in hLGCs, which implies that AKAP95 may be involved in the pathogenesis of PCOS. PMID- 29397058 TI - Nonagenarians in Internal Medicine: Another 21st century epidemic. PMID- 29397059 TI - Modeling when and where a secondary accident occurs. AB - The occurrence of secondary accidents leads to traffic congestion and road safety issues. Secondary accident prevention has become a major consideration in traffic incident management. This paper investigates the location and time of a potential secondary accident after the occurrence of an initial traffic accident. With accident data and traffic loop data collected over three years from California interstate freeways, a shock wave-based method was introduced to identify secondary accidents. A linear regression model and two machine learning algorithms, including a back-propagation neural network (BPNN) and a least squares support vector machine (LSSVM), were implemented to explore the distance and time gap between the initial and secondary accidents using inputs of crash severity, violation category, weather condition, tow away, road surface condition, lighting, parties involved, traffic volume, duration, and shock wave speed generated by the primary accident. From the results, the linear regression model was inadequate in describing the effect of most variables and its goodness of-fit and accuracy in prediction was relatively poor. In the training programs, the BPNN and LSSVM demonstrated adequate goodness-of-fit, though the BPNN was superior with a higher CORR and lower MSE. The BPNN model also outperformed the LSSVM in time prediction, while both failed to provide adequate distance prediction. Therefore, the BPNN model could be used to forecast the time gap between initial and secondary accidents, which could be used by decision makers and incident management agencies to prevent or reduce secondary collisions. PMID- 29397060 TI - Supercritical water-treated fused silica capillaries in analytical separations: Status review. AB - Near- and supercritical water (SCW) has recently been shown to provide an unusual but effective tool to roughen the inner surface or manipulate the internal diameter of fused silica capillaries for analytical separation methods In this review, the to-date existing variants of instrumental arrangement for etching the fused silica capillaries with SCW are described, the currently accessible morphologies of SCW-etched capillaries are outlined, and both existing and prospective applications of the SCW-etched capillaries in analytical separations are briefly discussed. Relative merits of SCW and other agents to treat the inner surfaces of fused silica capillaries are also mentioned. PMID- 29397061 TI - Determination of steroid hormones and their metabolite in several types of meat samples by ultra high performance liquid chromatography-Orbitrap high resolution mass spectrometry. AB - A new analytical method based on ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high resolution mass spectrometry (Orbitrap-HRMS) has been developed for the determination of steroid hormones (hydrocortisone, cortisone, progesterone, prednisone, prednisolone, testosterone, melengesterol acetate, hydrocortisone-21-acetate, cortisone-21-acetate, testosterone propionate, 17alpha-methyltestosterone, 6alpha-methylprednisolone and medroxyprogesterone) and their metabolite (17alpha-hydroxyprogesterone) in three meat samples (chicken, pork and beef). Two different extraction approaches were tested (QuEChERS "quick, easy, cheap, effective, rugged and safe" and "dilute and shoot"), observing that the QuEChERS method provided the best results in terms of recovery. A clean-up step was applied comparing several sorbents, obtaining the best results when florisil and aluminum oxide were used. The optimized method was validated, obtaining suitable results for all validation parameters in the three meat matrices evaluated. Recovery values ranged from 70% to 103% (except for prednisone in beef samples), meanwhile repeatability and reproducibility were obtained at values lower than 18% and 21%, respectively. The limit of quantification (LOQ) was established for most of the compounds at 1.0 MUg/kg, except for testosterone in chicken and hydrocortisone-21-acetate and cortisone-21 acetate in pork at 2.0 MUg/kg. Decision limit (CCalpha) and detection capability (CCbeta) values ranged from 1.0-2.7 MUg/kg and 1.9-5.5 MUg/kg, respectively, in the three matrices. Finally, thirty one meat samples were analyzed and two hormones, progesterone and hydrocortisone, were detected in a beef and pork sample at 1.7 and 2.8 MUg/kg respectively. PMID- 29397062 TI - How I do colonoscopy. PMID- 29397063 TI - Speech outcomes following Sommerlad primary palatoplasty: Results of the Ghent University Hospital. AB - OBJECTIVE AND SUBJECTS: Speech outcomes were described for 16 patients with cleft palate (mean age: 5.4 years) following Sommerlad primary palatoplasty performed by a single surgeon of the Ghent University Hospital. These speech outcomes were compared with those of an age and gender matched control group without cleft palate (mean age: 5.3 years). METHODS: Speech intelligibility/distinctiveness, resonance, nasal airflow and articulation, were perceptually evaluated. Additionally, nasalance values and the NSI 2.0 were determined. RESULTS: In seven patients, speech intelligibility/distinctiveness was disordered. Hypernasality was present in twelve participants, whereas nasal emission and nasal turbulence were perceived in thirteen and five patients respectively. Both perceptual and instrumental speech evaluations were significantly poorer in the patient group in comparison to the control group. CONCLUSIONS: Patients still present with both obligatory and compensatory speech disorders following Sommerlad's palatoplasty. In the future, a Dutch speech assessment protocol will be developed in order to standardize follow-up of these patients and to allow for within-center and inter center comparisons. PMID- 29397064 TI - Cues, corticosterone and departure decisions in a partial migrant. AB - Most migrating birds make multiple stopovers to fuel and/or rest. The decision to resume migration from stopover is based on various cues, such as time within the season and wind conditions. There are hints that the strength of these departure cues shapes corticosterone level, which in its turn appears to regulate the timing of departure. We here provide results that very strongly indicate that indeed departure cues jointly shape corticosterone level of migrants at stopover. We compared corticosterone level between migrating and sedentary common blackbirds (Turdus merula) sampled simultaneously at the same location during autumn migration. As expected, in migrating individuals corticosterone level was positively associated with time within the season and with current wind conditions. The latter was only apparent in adult birds and not in 1st year migrants, thus matching the observation that 1st year autumnal migrants are less wind selective than adults. In contrast to the migrants, in sedentary blackbirds these "cues" did not explain variation in corticosterone level. Furthermore, stopover departure seemed more likely and to occur earlier in the night in migrants with high corticosterone level. Our unique comparative study thus supports the newly developed concept that corticosterone mediates between departure cues and stopover departure timing in avian migrants. PMID- 29397065 TI - The biology of serous cavity macrophages. AB - For decades, it has been known that the serous cavities, which include the peritoneal, pleural and pericardial cavities, harbour large numbers of macrophages. In particular, due to the ease of isolating these cells, the peritoneal cavity has been used as a convenient source of macrophages to examine many facets of macrophage biology over the last 50-60 years. Despite this, it is only recently that the true heterogeneity of serous cavity mononuclear phagocyte compartment, which includes macrophages and dendritic cells, has been revealed. Advances in technologies such as multi-parameter flow cytometry and the 'OMICs' revolution have uncovered the presence of distinct populations of mononuclear phagocytes in the serous cavities. Given that peritoneal macrophages have been implicated in many pathologies, including peritonitis, pancreatitis, endometriosis and acute liver injury, it is imperative to understand the biology of these cells. Here, we review the recent advances in understanding the identity, origin and function of discrete serous cavity mononuclear phagocyte subsets in homeostasis and how these may change when homeostasis is perturbed, focusing on peritoneal and pleural cavities and highlighting differences in the mononuclear phagocytes found in each. PMID- 29397066 TI - Cancer-associated fibroblasts in tumor microenvironment - Accomplices in tumor malignancy. AB - There is much cellular heterogeneity in the tumor microenvironment. The tumor epithelia and stromal cells co-evolve, and this reciprocal relationship dictates almost every step of cancer development and progression. Despite this, many anticancer therapies are designed around druggable features of tumor epithelia, ignoring the supportive role of stromal cells. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of many tumor types. Numerous previous studies have highlighted a pro-tumorigenic role for CAFs via secretion of various growth factors, cytokines, chemokines, and the degradation of extracellular matrix. Recent works showed that CAFs secrete H2O2 to effect stromal-mediated field cancerization, transform primary epithelial cells, and aggravate cancer cell aggressiveness, in addition to inflammatory and mitogenic factors. Molecular characterization of CAFs also underscores the importance of Notch and specific nuclear receptor signaling in the activation of CAFs. This review consolidates recent findings of CAFs and highlights areas for future investigations. PMID- 29397067 TI - Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington's disease. AB - Mitochondrial dysfunction is a major cytopathology in Huntington's disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determine the role that Mitogen-activated protein kinase 1 (MAPK1) plays in the over-activation of Dynamin-related protein 1 (Drp1), the mitochondrial fission protein, which leads to mitochondrial dysfunction and neurodegeneration seen in HD. We show that MAPK1 binds to and phosphorylates Drp1 in vitro. Drp1 phosphorylation at serine 616 is increased in HD knock-in mouse derived striatal cells, which is abolished by treatment with U0126, a potent inhibitor of MEK1/2. A phosphorylation-deficient mutant of Drp1, Drp1S616A, corrects mitochondrial fragmentation associated with HD. Treatment with U0126 also reduces mitochondrial fragmentation, but has no additional effect in correcting aberrant mitochondrial morphology in cells expressing Drp1S616A. Finally, treatment with U0126 reduces mitochondrial depolarization and mitochondrial superoxide production in HD mutant striatal cells when compared to wildtype cells. This study suggests that in HD, MAPK1 activation leads to the aberrant mitochondrial fission and mitochondrial function by phosphorylating Drp1. Therefore, inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for development of therapy for treating HD. PMID- 29397068 TI - A mechanism for agonist activation of the glucagon-like peptide-1 (GLP-1) receptor through modelling & molecular dynamics. AB - The receptor for glucagon-like peptide 1 (GLP-1R) is a validated drug target for the treatment of type 2 diabetes and obesity. Recently the first three structures of GLP-1R were published - an X-ray structure of the apo transmembrane domain in the inactive conformation; an X-ray structure of the full-length receptor bound to a truncated peptide agonist; and a cryo-EM structure of the full-length receptor bound with GLP-1 and coupled to the G protein Gs. Since the inactive structure was incomplete, and the two active-state structures shared significant differences, we utilised all available knowledge to build hybrid models of the full length active and inactive state receptors. The two models were simulated using molecular dynamics and the output trajectories analysed and compared to reveal insights into the mechanism for agonist-mediated receptor activation. His 7, Glu-9 and Asp-15 of GLP-1 act together to destabilise transmembrane helix 6 and extracellular loop 3 in order to generate an active conformation of GLP-1R. PMID- 29397069 TI - Characterisation of the biological response of Saccharomyces cerevisiae to the loss of an allele of the eukaryotic initiation factor 4A. AB - The translation initiation machinery is emerging as an important target for therapeutic intervention, with potential in the treatment of cancer, viral infections, and muscle wasting. Amongst the targets for pharmacological control of translation initiation is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is essential for cap-dependent translation initiation. We set out to explore the system-wide impact of a reduction of functional eIF4A. To this end, we investigated the effect of deletion of TIF1, one of the duplicate genes that produce eIF4A in yeast, through synthetic genetic array interactions and system-wide changes in GFP-tagged protein abundances. We show that there is a biological response to deletion of the TIF1 gene that extends through the proteostasis network. Effects of the deletion are apparent in processes as distributed as chromatin remodelling, ribosome biogenesis, amino acid metabolism, and protein trafficking. The results from this study identify protein complexes and pathways that will make ideal targets for combination therapies with eIF4A inhibitors. PMID- 29397070 TI - microRNA-181a downregulates deptor for TGFbeta-induced glomerular mesangial cell hypertrophy and matrix protein expression. AB - TGFbeta contributes to mesangial cell hypertrophy and matrix protein increase in various kidney diseases including diabetic nephropathy. Deptor is an mTOR interacting protein and suppresses mTORC1 and mTORC2 activities. We have recently shown that TGFbeta-induced inhibition of deptor increases the mTOR activity. The mechanism by which TGFbeta regulates deptor expression is not known. Here we identify deptor as a target of the microRNA-181a. We show that in mesangial cells, TGFbeta increases the expression of miR-181a to downregulate deptor. Decrease in deptor augments mTORC2 activity, resulting in phosphorylation/activation of Akt kinase. Akt promotes inactivating phosphorylation of PRAS40 and tuberin, leading to stimulation of mTORC1. miR-181a mimic increased mTORC1 and C2 activities, while anti-miR-181a inhibited them. mTORC1 controls protein synthesis via phosphorylation of translation initiation and elongation suppressors 4EBP-1 and eEF2 kinase. TGFbeta-stimulated miR-181a increased the phosphorylation of 4EBP-1 and eEF2 kinase, resulting in their inactivation. miR-181a-dependent inactivation of eEF2 kinase caused dephosphorylation of eEF2. Consequently, miR-181a-mimic increased protein synthesis and hypertrophy of mesangial cells similar to TGFbeta. Anti-miR-181a blocked these events in a deptor-dependent manner. Finally, TGFbeta-miR-181a driven deptor downregulation increased the expression of fibronectin. Our results identify a novel mechanism involving miR-181a-driven deptor downregulation, which contributes to mesangial cell pathologies in renal complications. PMID- 29397071 TI - DN604: A platinum(II) drug candidate with classic SAR can induce apoptosis via suppressing CK2-mediated p-cdc25C subcellular localization in cancer cells. AB - DN604, a carboplatin analogue with a functional dicarboxylato ligand, was deeply investigated to explore its ability to induce apoptosis as well as its antitumor mechanism of action. Both in vitro and in vivo assays indicated that DN604 could effectively inhibit cell viability of SGC-7901 gastric cancer cells and exhibited stronger antitumor activity than carboplatin and comparable activity to cisplatin. Significantly in contrast to cisplatin, DN604 resulted in negligible toxic effects in vivo with the same tumor growth inhibition effect as cisplatin. The mechanism study indicated that DN604 inhibited CK2-phosphorylated cdc25C activation to decrease p-cdc25C subcellular localization, leading to the inactivation of cdc2/Cyclin B and G2/M cell cycle arrest and apoptosis in SGC 7901 cancer cells. Our research revealed for the first time that the dicarboxylato ligand containing a suitable functional moiety as the leaving group in the platinum(II) complex can effectively induce cell cycle arrest and apoptosis via inhibiting key checkpoint proteins. PMID- 29397075 TI - Clusters, Dimensions, and Hierarchies: Finding a Path Forward for the Neuroscience of Mental Disorders? PMID- 29397074 TI - Aberrant Modulation of Brain Oscillatory Activity and Attentional Impairment in Attention-Deficit/Hyperactivity Disorder. AB - Electroencephalography and magnetoencephalography are noninvasive neuroimaging techniques that have been used extensively to study various resting-state and cognitive processes in the brain. The purpose of this review is to highlight a number of recent studies that have investigated the alpha band (8-12 Hz) oscillatory activity present in magnetoencephalography and electroencephalography, to provide new insights into the maladaptive network activity underlying attentional impairments in attention-deficit/hyperactivity disorder (ADHD). Studies reviewed demonstrate that event-related decrease in alpha is attenuated during visual selective attention, primarily in ADHD inattentive type, and is often significantly associated with accuracy and reaction time during task performance. Furthermore, aberrant modulation of alpha activity has been reported across development and may have abnormal or atypical lateralization patterns in ADHD. Modulations in the alpha band thus represent a robust, relatively unexplored putative biomarker of attentional impairment and a strong prospect for future studies aimed at examining underlying neural mechanisms and treatment response among individuals with ADHD. Potential limitations of its use as a diagnostic biomarker and directions for future research are discussed. PMID- 29397077 TI - High Temporal Resolution Measurement of Cognitive and Affective Processes in Psychopathology: What Electroencephalography and Magnetoencephalography Can Tell Us About Mental Illness. PMID- 29397073 TI - Using Event-Related Potentials and Startle to Evaluate Time Course in Anxiety and Depression. AB - The National Institute of Mental Health's Research Domain Criteria initiative is a research framework designed toward understanding psychopathology as abnormalities of dimensional neurobehavioral constructs rather than in terms of DSM-defined categories. Research Domain Criteria constructs within the negative valence domain are particularly relevant for understanding anxiety and depressive disorders, which are pervasive, debilitating, and characterized by negative processing bias. One important direction for Research Domain Criteria research is investigating processes and parameters related to the time course (or chronometry) of negative valenced constructs. Two reliable methods for assessing chronometry are event-related potentials (ERPs) and startle blink. In this qualitative review, we examine ERP and startle studies of individuals with anxiety or depression or individuals vulnerable to affective disorders. The aim of the review is to highlight how these methods can inform the role of chronometry in the spectrum of anxiety and depression. ERP studies examining different chronometry facets of negative valenced responses have shown that transdiagnostic groups of individuals with internalizing psychopathologies exhibit abnormalities at early stages of processing. Startle reactivity studies have robustly differentiated fear-based disorders (e.g., panic disorder, social phobia) from other anxiety disorders (e.g., generalized anxiety disorder) and have also shown that different internalizing phenotypes exhibit different patterns of habituation. Findings lend support to the value of ERP and startle measures in identifying groups that cut across conventional classification systems. We also highlight methodological issues that can aid in the validity and reproducibility of ERP and startle findings and, ultimately, in the goal of developing more precise models of anxiety and depression. PMID- 29397076 TI - Event-Related Potentials as Biomarkers of Behavior Change Mechanisms in Substance Use Disorder Treatment. AB - Substance use disorders (SUDs) are one of the most prevalent psychiatric conditions and represent a significant public health concern. Substantial research has identified key processes related to reinforcement and cognition for the development and maintenance of SUDs, and these processes represent viable treatment targets for psychosocial and pharmacological interventions. Research on SUD treatments has suggested that most approaches are comparable in effectiveness. As a result, recent work has focused on delineating the underlying mechanisms of behavior change that drive SUD treatment outcome. Given the rapid fluctuations associated with the key neurocognitive processes associated with SUDs, high-temporal-resolution measures of human brain processing, namely event related potentials (ERPs), are uniquely suited to expand our understanding of the underlying neural mechanisms of change during and after SUD treatment. The value of ERPs in the context of SUD treatment are discussed along with work demonstrating the predictive validity of ERPs as biomarkers of SUD treatment response. Example associations between multiple ERP components and psychosocial and/or pharmacological treatment outcome include the P3a and P3b (in response to neutral and substance-related cues), the attention-related negativities (e.g., N170, N200), the late positive potential, and the error-related negativity. Also addressed are limitations of the biomarker approach to underscore the need for research programs evaluating mechanisms of change. Finally, we emphasize the advantages of ERPs as indices of behavior change in SUD treatment and outline issues relevant for future directions in this context. PMID- 29397080 TI - Distinct Associations Between Low Positive Affect, Panic, and Neural Responses to Reward and Threat During Late Stages of Affective Picture Processing. AB - BACKGROUND: Abnormal patterns of attention to threat and reward have been proposed as potential mechanisms of dysfunction in anxiety and mood disorders. However, research on this topic has been inconsistent, perhaps because of both clinical heterogeneity in the samples assessed and measurement of attentional biases that is temporally imprecise. METHODS: The present study measured transdiagnostic symptoms of anxiety and depression in 205 young adults and recorded affect-modulated event-related potentials in response to task-irrelevant pictures in a speeded response task. RESULTS: Low positive affect was uniquely associated with reduced modulation of later event-related potentials (i.e., the P300 and the late positive potential) by rewarding images, suggesting deficits in sustained attention to reward. Low positive affect was also associated with a blunted threat-elicited late positive potential. Symptoms of panic were associated with an increased N1 to rewarding images, as well as an increased late positive potential to all picture types. CONCLUSIONS: These data suggest that dysfunction in neural markers of sustained attention to threat and reward relate in specific ways to transdiagnostic symptom dimensions of anxiety and depression. Moreover, event-related potentials are likely to be useful in investigations of the time course of attentional abnormalities associated with these symptom dimensions. PMID- 29397078 TI - Time-Frequency Reward-Related Delta Prospectively Predicts the Development of Adolescent-Onset Depression. AB - BACKGROUND: A blunted reward positivity (RewP), an event-related potential elicited by feedback indicating monetary gain relative to loss, was recently shown to prospectively predict the development of adolescent-onset depression. Time-frequency-based representations of this activity (e.g., reward-related delta) have also been associated with depression. This study is a reanalysis of the time-domain RewP investigation to examine the incremental value of time frequency indices in the prediction of adolescent-onset depression. METHODS: The sample included 444 13- to 15-year-old girls with no lifetime history of a depressive disorder. At baseline, adolescents completed a monetary guessing task, and both time-domain and time-frequency analyses were conducted on the event related potential response to gain and loss feedback. Lifetime psychiatric history in the adolescent and a biological parent were evaluated with diagnostic interviews, and adolescents' current depressive symptoms were assessed using a self-report questionnaire. Adolescents were interviewed again approximately 18 months later to identify first-onset depressive disorder. RESULTS: Blunted reward related delta predicted first-onset depressive disorder 18 months later, independent of the time-domain RewP and psychosocial risk factors (i.e., adolescent baseline depressive symptoms, adolescent and parental psychiatric history). In contrast, loss-related theta did not predict the development of depression. Reward-related delta increased sensitivity (73.8% to 82.8%) and positive predictive value (45.0% to 70.9%) for first-onset depressive disorder when applied in parallel and in series, respectively, with baseline depressive symptoms and the time-domain RewP. CONCLUSIONS: This study provides evidence that frequency-based representations of event-related potentials provide incremental value in the prediction of psychiatric disorders. PMID- 29397081 TI - Phase-Amplitude Coupling of the Electroencephalogram in the Auditory Cortex in Schizophrenia. AB - BACKGROUND: Cross-frequency interactions may coordinate neural circuits operating at different frequencies. While neural oscillations associated with particular circuits in schizophrenia (SZ) are impaired, few studies have examined cross frequency interactions. Here we examined phase-amplitude coupling (PAC) in the electroencephalograms of individuals with SZ and healthy control subjects (HCs). We computed PAC during the baseline period of 40-Hz auditory steady-state stimulation and rest. We hypothesized that subjects with SZ would show abnormal theta/gamma coupling during stimulation, especially in the left auditory cortex, and coupling with high frequencies would be higher during stimulation than during rest. METHODS: We reanalyzed data from 18 subjects with SZ and 18 HCs. Auditory cortex electroencephalogram activity was estimated using dipole source localization. PAC was computed using the debiased PAC measure, calculated with the generalized Morse wavelet transform. PAC clusters were identified using cluster-corrected permutation testing and interrogated in analyses of variance with correction for multiple tests. RESULTS: Overall, coupling of high beta and gamma amplitude was higher during the auditory steady-state response, while alpha/beta PAC was higher during rest. Theta/alpha PAC was higher in subjects with SZ than in HCs. Theta/gamma PAC was lateralized to the left hemisphere in HCs but was not lateralized in subjects with SZ. CONCLUSIONS: PAC involving high frequencies was state dependent and not abnormal in SZ. Increased theta/alpha PAC in subjects with SZ was consistent with other evidence of increased low-frequency activity. Hemispheric lateralization of theta/gamma PAC was reduced in subjects with SZ, consistent with evidence for left hemisphere auditory cortex abnormalities in subjects with SZ. PAC may reveal new insights into neural circuitry abnormalities in SZ and other neuropsychiatric disorders. PMID- 29397079 TI - Electroencephalography Source Functional Connectivity Reveals Abnormal High Frequency Communication Among Large-Scale Functional Networks in Depression. AB - BACKGROUND: Functional magnetic resonance imaging studies of resting-state functional connectivity have shown that major depressive disorder (MDD) is characterized by increased connectivity within the default mode network (DMN) and between the DMN and the frontoparietal network (FPN). However, much remains unknown about abnormalities in higher frequency (>1 Hz) synchronization. Findings of abnormal synchronization in specific frequencies would contribute to a better understanding of the potential neurophysiological origins of disrupted functional connectivity in MDD. METHODS: We used the high temporal resolution of electroencephalography to compare the spectral properties of resting-state functional connectivity in individuals with MDD (n = 65) with healthy control subjects (n = 79) and examined the extent to which connectivity disturbances were evident in a third sample of individuals in remission from depression (n = 30). Exact low resolution electromagnetic tomography was used to compute intracortical activity from regions within the DMN and FPN, and functional connectivity was computed using lagged phase synchronization. RESULTS: Compared to control subjects, the MDD group showed greater within-DMN beta 2 band (18.5-21 Hz) connectivity and greater beta 1 band (12.5-18 Hz) connectivity between the DMN and FPN. This hyperconnectivity was not observed in the remitted MDD group. However, greater beta 1 band DMN-FPN connectivity was associated with more frequent depressive episodes since first depression onset, even after controlling for current symptom severity. CONCLUSIONS: These findings extend our understanding of the neurophysiological basis of abnormal resting-state functional connectivity in MDD and indicate that elevations in high-frequency DMN FPN connectivity may be a neural marker linked to a more recurrent illness course. PMID- 29397082 TI - The Promise of Electroencephalography for Advancing Diagnosis and Treatment in Neurodevelopmental Disorders. PMID- 29397084 TI - Altered Brain Network Dynamics in Schizophrenia: A Cognitive Electroencephalography Study. AB - BACKGROUND: Alterations in the dynamic coordination of widespread brain networks are proposed to underlie cognitive symptoms of schizophrenia. However, there is limited understanding of the temporal evolution of these networks and how they relate to cognitive impairment. The current study was designed to explore dynamic patterns of network connectivity underlying cognitive features of schizophrenia. METHODS: In total, 21 inpatients with schizophrenia and 28 healthy control participants completed a cognitive task while electroencephalography data were simultaneously acquired. For each participant, Pearson cross-correlation was applied to electroencephalography data to construct correlation matrices that represent the static network (averaged over 1200 ms) and dynamic network (1200 ms divided into four windows of 300 ms) in response to cognitive stimuli. Global and regional network measures were extracted for comparison between groups. RESULTS: Dynamic network analysis identified increased global efficiency; decreased clustering (globally and locally); reduced strength (weighted connectivity) around the frontal, parietal, and sensory-motor areas; and increased strength around the occipital lobes (a peripheral hub) in patients with schizophrenia. Regional network measures also correlated with clinical features of schizophrenia. Network differences were prominent 900 ms following the cognitive stimuli before returning to levels comparable to those of healthy control participants. CONCLUSIONS: Patients with schizophrenia exhibited altered dynamic patterns of network connectivity across both global and regional measures. These network differences were time sensitive and may reflect abnormalities in the flexibility of the network that underlies aspects of cognitive function. Further research into network dynamics is critical to better understanding cognitive features of schizophrenia and identification of network biomarkers to improve diagnosis and treatment models. PMID- 29397083 TI - When Proactivity Fails: An Electrophysiological Study of Establishing Reference in Schizophrenia. AB - BACKGROUND: Schizophrenia is characterized by abnormalities in referential communication, which may be linked to more general deficits in proactive cognitive control. We used event-related potentials to probe the timing and nature of the neural mechanisms engaged as people with schizophrenia linked pronouns to their preceding referents during word-by-word sentence comprehension. METHODS: We measured event-related potentials to pronouns in two-clause sentences in 16 people with schizophrenia and 20 demographically matched control participants. Our design crossed the number of potential referents (1-referent, 2 referent) with whether the pronoun matched the gender of its preceding referent(s) (matching, mismatching). This gave rise to four conditions: 1) 1 referent matching ("Edward took courses in accounting but he . . ."); 2) 2 referent matching ("Edward and Phillip took courses but he . . . "); 3) 1 referent mismatching ("Edward took courses in accounting but she . . ."); and 4) 2-referent mismatching ("Edward and Phillip took courses but she . . ."). RESULTS: Consistent with previous findings, healthy control participants produced a larger left anteriorly distributed negativity between 400 and 600 ms to 2 referent matching than to 1-referent matching pronouns (the "Nref effect"). In contrast, people with schizophrenia produced a larger centroposterior positivity effect between 600 and 800 ms. Both patient and control groups produced a larger positivity between 400 and 800 ms to mismatching than to matching pronouns. CONCLUSIONS: These findings suggest that proactive mechanisms of referential processing, reflected by the Nref effect, are impaired in schizophrenia, while reactive mechanisms, reflected by the positivity effects, are relatively spared. Indeed, patients may compensate for proactive deficits by retroactively engaging with context to influence the processing of inputs at a later stage of analysis. PMID- 29397085 TI - Erratum to " Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review " [Rev. Neurol. 173 (5) (2017) 300-307]. PMID- 29397086 TI - Distribution of licensed acupuncturists and educational institutions in the United States in early 2015. AB - In recent decades, acupuncture has been used more widely and extensively in the United States (U.S.). However, there have been no national surveys or analyses reported in academic journals on the number of practicing or licensed acupuncturists. This study was conducted to identify the approximate number of licensed acupuncturists active in 2015. The Board of Acupuncture or Board of Medicine in each state or U.S. territory was contacted to collect data. Online license information searching was also performed in order to get accurate numbers of licensed acupuncturists for those states in which a board was unable to be contacted. The study found that the number of licensed acupuncturists in 2015 in the U.S. was 34,481. Of this, more than 50% were licensed in three states alone: California (32.39%), New York (11.89%) and Florida (7.06%). The number of licensed acupuncturists increased 23.30% and 52.09%, compared to the year 2009 (n = 27,965) and 2004 (n = 22,671), respectively; increasing about 1,266 per year. There were 62 and 10 accredited acupuncture institutions providing master and doctoral degrees, respectively. The West Coast comprised 51.39% of degree granting programs, while the East Coast comprised 29.17%; together the coastal states housed more than 80% of all programs, with the remainder sprinkled across the southern (9.72%), northern (8.33%), and the middle/central states (1.39%). Forty-four states and the District of Columbia regulated acupuncture practice by law at the time of data collection. Acupuncture continues to be a quickly growing profession in the U.S. PMID- 29397087 TI - The benefits of yoga in children. AB - The number of children suffering from stress and anxiety in Malaysia is on the rise. Evidence shows that mind-body therapies such as mindfulness therapy, meditation and yoga have been practiced in many other countries to reduce and/or manage the psychological effects of stress and anxiety. This review article looks at the intervention of yoga as a meditative movement practice in helping school children manage stress and anxiety. Articles were retrieved using a combination of databases including PubMed/MEDLINE, and PsycINFO. Not only peer-reviewed articles, but also those written in English language were included in this review. All studies reviewed had incorporated some form of meditative movement exercise. The intervention encompassed asanas (postures), pranayama (expansion of life force), dharana (concentration) and dhyana (meditation), which are the different paths in yoga. A total of eight articles met the inclusion criteria and were reviewed. The findings of this review reveal that the practice of yoga has brought about, among other things, improvement in managing and reducing stress and anxiety. Despite the limitations in most, if not all of the studies reviewed, in terms of heterogeneity and sample size, yoga appears to be an effective modality for helping children cope with stress and anxiety. It appears that if schools in Malaysia can incorporate yoga as part of the physical education curriculum, it will definitely benefit the students. PMID- 29397088 TI - Management of acute cough by Zataria multiflora Boiss as an alternative treatment. AB - Cough, as a defensive reflux mechanism, removes foreign objects and secretions from bronchi and bronchioles of airways. Zataria multiflora is a popular plant for treatment of cough in Iranian traditional medicine. The aim of this review was to evaluate the potency of Z. multiflora as an alternative treatment in management of acute cough and its possible mechanisms of action. Here the authors compiled information about Z. multiflora in the treatment of cough from all accessible resources and books. The results of this investigation showed that there were five clinical studies that evaluated the efficacy of Z. multiflora essential oil or extract alone (n = 1), in combination with Althaea officinalis (n = 2) or Foeniculum vulgare essential oil (n = 1), in the form of syrup (n = 3), oral drop (n = 1) and soft capsule (n = 1), for the treatment of acute cough in comparison with placebo or synthetic drugs (bromhexine, dextromethorphan and clobutinol). All clinical studies confirmed the efficacy of Z. multiflora in the amelioration of acute cough in pediatric (n = 1) and adult patients (n = 4) without any adverse effects. Different mechanisms, such as anti-inflammatory, analgesic, antimicrobial, relaxant and immune-enhancement, may be responsible for the efficacy of Z. multiflora in cough relief. Other clinical trials can be performed with Z. multiflora in combination with ivy leaf extract or primrose root extract on patients with cough. PMID- 29397089 TI - Brain functional connectivity network studies of acupuncture: a systematic review on resting-state fMRI. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is a novel method for studying the changes of brain networks due to acupuncture treatment. In recent years, more and more studies have focused on the brain functional connectivity network of acupuncture stimulation. OBJECTIVE: To offer an overview of the different influences of acupuncture on the brain functional connectivity network from studies using resting-state fMRI. SEARCH STRATEGY: The authors performed a systematic search according to PRISMA guidelines. The database PubMed was searched from January 1, 2006 to December 31, 2016 with restriction to human studies in English language. INCLUSION CRITERIA: Electronic searches were conducted in PubMed using the keywords "acupuncture" and "neuroimaging" or "resting-state fMRI" or "functional connectivity". DATA EXTRACTION AND ANALYSIS: Selection of included articles, data extraction and methodological quality assessments were respectively conducted by two review authors. RESULTS: Forty four resting-state fMRI studies were included in this systematic review according to inclusion criteria. Thirteen studies applied manual acupuncture vs. sham, four studies applied electro-acupuncture vs. sham, two studies also compared transcutaneous electrical acupoint stimulation vs. sham, and nine applied sham acupoint as control. Nineteen studies with a total number of 574 healthy subjects selected to perform fMRI only considered healthy adult volunteers. The brain functional connectivity of the patients had varying degrees of change. Compared with sham acupuncture, verum acupuncture could increase default mode network and sensorimotor network connectivity with pain-, affective- and memory-related brain areas. It has significantly greater connectivity of genuine acupuncture between the periaqueductal gray, anterior cingulate cortex, left posterior cingulate cortex, right anterior insula, limbic/paralimbic and precuneus compared with sham acupuncture. Some research had also shown that acupuncture could adjust the limbic-paralimbic-neocortical network, brainstem, cerebellum, subcortical and hippocampus brain areas. CONCLUSION: It can be presumed that the functional connectivity network is closely related to the mechanism of acupuncture, and central integration plays a critical role in the acupuncture mechanism. PMID- 29397090 TI - Determination of symptoms associated with hiesho among young females using hie rating surveys. AB - OBJECTIVE: Hie (cold sensation) is one of the most well-known health complaints in Japan and elsewhere in East Asia. Those who suffer from severe hie are considered to have hiesho (cold disorder). This study was conducted to determine symptoms associated with hie in young females using a survey consisting of the hie scale and hie diary. METHODS: Two hundred and seventy-one participants were included for the analysis. Survey forms were distributed to the participants. Diagnosis of hiesho was determined by using the hie scale. A discriminant score of over -0.38 was considered hiesho. The Short Form-8 Health Survey Standard Version (SF-8) was used to measure health-related quality of life (QOL). The participants were also asked to respond to the questionnaire evaluating 14 physical and emotional symptoms, utilizing a six-level Likert scale item. RESULTS: The 1st factor (hie factor) was correlated with hie (r = 0.546), dry mouth (r = 0.332), lower-extremity edema (r = 0.450), headrushes (r = 0.470), shoulder stiffness (r = 0.311), headrushes with chills (r = 0.726), and fatigue (r = 0.359). Cronbach's alpha of the 1st factor was 0.748, which indicated reliability between the items. When hie factor was the dependent variable, standardized partial regression coefficient was beta = -0.387 for physical component score (P < 0.001) and beta = -0.243 for mental component score (P < 0.001). CONCLUSION: This study indicated that hiesho symptoms among young female adults were associated with bodily pain and general health perceptions of the SF 8 QOL survey. PMID- 29397091 TI - Efficacy and safety of herbal steam bath in allergic rhinitis: a randomized controlled trial. AB - BACKGROUND: Allergic rhinitis is a nasal mucosa inflammatory disorder that is induced by exposure to an allergen which results in four major symptoms, including anterior or posterior rhinorrhea, sneezing, nasal itching and nasal congestion. Allergic rhinitis may result in sleep disturbance, fatigue, depression of mood-cognitive function and quality of life impairment. OBJECTIVE: This study examined the efficacy and safety of herbal steam bath used for the reduction of allergic rhinitis symptoms, and evaluated treatment satisfaction and improvements in quality of life among participating patients with allergic rhinitis. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A single-blind randomized controlled trial was conducted at Thai Traditional and Alternative Medicine Hospital between June and December 2016, using 64 subjects, equally divided into two groups. The treatment group received herbal steam bath and the control group received steam bath without herbs for 30 min 3 times a week for 4 consecutive weeks. MAIN OUTCOME MEASURES: Allergic rhinitis symptoms, such as itchy nose, runny nose, sneezing, nasal congestion and watery eyes, were measured using the visual analog scale at weeks 0, 1, 2, 3 and 4. Quality of life was assessed at week 0 and week 4. RESULTS: The characteristics (sex, age, marital status, education, allergic rhinitis symptoms and frequency of symptoms) at the baseline were not statistically different (P > 0.05) between the two test groups. Anterior or posterior rhinorrhea symptoms, including sneezing, nasal itching and nasal congestion, were statistically reduced over the course of the treatment, but reductions were not significantly different between the control and treatment groups. The treatment group, however, was shown to be significantly more satisfied with the treatment than the control group (P < 0.05). CONCLUSION: Both treatments appear to be able to significantly reduce the symptoms of allergic rhinitis. However, there was no difference in the effectiveness of steam bath with herbs and steam bath without herbs. TRIAL REGISTRATION: This trial was registered in the Thai Clinical Trial Registry with the identifier TCTR20170712002. PMID- 29397092 TI - Rhus coriaria L. increases serum apolipoprotein-A1 and high-density lipoprotein cholesterol levels: a double-blind placebo-controlled randomized clinical trial. AB - BACKGROUND: Lipid-lowering effect of Rhus coriaria L. (Rhus) has been investigated in multiple animal studies with promising results. Nonetheless, its clinical efficacy has not been adequately examined. OBJECTIVE: The aim of this study was to evaluate the lipid-lowering effects of Rhus among patients with hyperlipidemia. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: The study was designed as a two-arm, double-blind placebo-controlled randomized clinical trial, using a parallel design. Eighty patients with primary hyperlipidemia were randomly assigned to receive Rhus capsules or placebo for 6 weeks. MAIN OUTCOME MEASURES: The serum lipid levels, apolipoprotein-A1 (Apo-A1) and apolipoprotein-B (Apo-B) were measured. RESULTS: Mean serum high-density lipoprotein cholesterol (HDL-C) and Apo-A1 levels were significantly increased in the Rhus group, compared with the placebo group, after 6 weeks of intervention (P = 0.001). The analysis of covariance test including age, gender, body mass index (BMI), and smoking as co-variables revealed that the increase in HDL-C and Apo-A1 levels remained significant, and increases in HDL-C were dependent on the increase in Apo-A1 levels. No significant difference was observed between Rhus and placebo groups in terms of mean reductions in total cholesterol, low-density lipoprotein cholesterol and triglyceride levels; however, more significant improvement was observed among obese patients (BMI >= 30 kg/m2). CONCLUSION: The study showed significant increases in HDL-C and Apo-A1 levels in response to Rhus supplementation in patients with hyperlipidemia. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02295293. PMID- 29397093 TI - Effects of aqueous leaf extract of Tridax procumbens on contractile activity of corpus cavernosum in N-nitro-l-arginine methyl ester-induced hypertensive male rats. AB - OBJECTIVE: This study investigated the effects of aqueous leaf extract of Tridax procumbens (ALETP) on contractile activity of corpus cavernosum in N-nitro-l arginine methyl ester (l-NAME)-induced hypertensive male rats. METHODS: Twenty normal, adult male rats (130-150 g) were divided into four groups of five rats each. Group I (control) was given normal saline (0.6 mL/kg) and group II was given l-NAME (40 mg/kg) for 6 weeks. Groups III and IV also received l-NAME (40 mg/kg) for 6 weeks but were further co-treated with 100 and 200 mg/kg of ALETP, respectively, from week 4 to week 6. All treatments were given orally. Strips of corpus cavernosum from each of the four groups were exposed to increasing concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP) (10-9-10 5mol/L) after contraction with phenylephrine (10-7 mol/L) to test for a dose response effect. Response to potassium and calcium was also measured after cumulatively adding potassium and calcium (10-50 mmol/L) to potassium- and calcium-free organ chamber. Isometric contractions were recorded through an Ugo Basile data capsule acquisition system. RESULTS: Mean arterial blood pressure was significantly reduced in the ALETP co-treated group compared to the control and l NAME-only groups (P < 0.05). Cavernosa strips from ALETP co-treated rats exhibited significant inhibition of contraction in response to phenylephrine, potassium chloride, and calcium chloride (P < 0.05). Relaxation in response to Ach and SNP was also significantly impaired in cavernosa strips from the l-NAME only treated group (P < 0.05), while ALETP co-treated groups showed enhanced percentage relaxation. CONCLUSION: ALETP treatment of l-NAME-induced hypertensive rats promotes a relaxant effect on isolated cavernosa strips. ALETP shows potential in correcting erectile dysfunction in hypertension. PMID- 29397094 TI - Cytotoxic activity of the chemical constituents of Clerodendrum indicum and Clerodendrum villosum roots. AB - OBJECTIVE: The roots of two Thai medicinal plants, Clerodendrum indicum and Clerodendrum villosum are found in traditional medicine practices. The aim of this research was to preliminarily study the cytotoxicity of extracts of their roots, and the parts that possessed cytotoxic activity were separated on a chromatograph to identify their active compounds. METHODS: The extracts of both plants were screened for cytotoxicity on the SW620 cell line and the compounds isolated from the active extracts were further evaluated for their cytotoxic activity against five human cancer cell lines, including SW620, ChaGo-K-1, HepG2, KATO-III and BT-474 using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H tetrazolium bromide (MTT) assay. RESULTS: Dichloromethane extracts of C. indicum and C. villosum were active against the SW620 cell line. Triterpenoids were mostly obtained from the extracts of these plants (0.28% and 1.02%, respectively) and exhibited varying degrees of cytotoxicity and specificity against the tested cell lines. Two triterpenoids, oleanolic acid 3-acetate and betulinic acid, displayed moderate to strong cytotoxicity toward all cancer cell lines, with 50% inhibitory concentration (IC50) values of 1.66-20.49 umol/L, whereas 3beta hydroxy-D:B-friedo-olean-5-ene and taraxerol were cytotoxic to only the SW620 cell line (IC50 = 23.39 and 2.09 umol/L, respectively). Triterpenoid, lupeol, showed potent cytotoxicity on both SW620 (IC50 = 1.99 umol/L) and KATO-III cell lines (IC50 = 1.95 umol/L), while a flavonoid, pectolinarigenin, displayed moderate cytotoxicity against these cells (IC50 = 13.05 and 24.31 umol/L, respectively). Although the widely distributed steroid, stigmasterol, was effective against the SW620 cell line (IC50 = 2.79 umol/L) and beta-sitosterol was also active against SW620 (IC50 = 11.26 umol/L), BT-474 (IC50 = 14.11 umol/L) and HepG2 cancer cells (IC50 = 20.47 umol/L), none of the characteristic 24beta ethylsteroids of either Clerodendrum species were shown to be cytotoxic. CONCLUSION: This study is the first report on the presence of cytotoxic triterpenoids from the roots of these medicinal plants, which have been used in herbal formulas as an antipyretic. Our findings support further in-depth study of this pharmacological activity as an anticancer agent. PMID- 29397095 TI - Research methods in complementary and alternative medicine: an integrative review. AB - The scientific literature presents a modest amount of evidence in the use of complementary and alternative medicine (CAM). On the other hand, in practice, relevant results are common. The debates among CAM practitioners about the quality and execution of scientific research are important. Therefore, the aim of this review is to gather, synthesize and describe the differentiated methodological models that encompass the complexity of therapeutic interventions. The process of bringing evidence-based medicine into clinical practice in CAM is essential for the growth and strengthening of complementary medicines worldwide. PMID- 29397097 TI - 3beta-hydroxyesteroid dehydrogenase deficiency detected through increased serum levels of 17-hydroxyprogesterone in the neonatal screening. PMID- 29397096 TI - Anti-inflammatory and bronchodilatory constituents of leaf extracts of Anacardium occidentale L. in animal models. AB - OBJECTIVE: Anacardium occidentale L. leaf is useful in the treatment of inflammation and asthma, but the bioactive constituents responsible for these activities have not been characterized. Therefore, this study was aimed at identifying the bioactive constituent(s) of A. occidentale ethanolic leaf extract (AOEL) and its solvent-soluble portions, and evaluating their effects on histamine-induced paw edema and bronchoconstriction. METHODS: The bronchodilatory effect was determined by measuring the percentage protection provided by plant extracts in the histamine-induced bronchoconstriction model in guinea pigs. The anti-inflammatory effect of the extracts on histamine-induced paw edema in rats was determined by measuring the increase in paw diameter, after which the percent edema inhibition was calculated. The extracts were analyzed using gas chromatography-mass spectrometry to identify the bioactive constituents. Column chromatography and Fourier transform infrared spectroscopy were used respectively to isolate and characterize the constituents. The bronchodilatory and anti inflammatory activities of the isolated bioactive constituent were evaluated. RESULTS: Histamine induced bronchoconstriction in the guinea pigs and edema in the rat paw. AOEL, hexane-soluble portion of AOEL, ethyl acetate-soluble portion of AOEL, and chloroform-soluble portion of AOEL significantly increased bronchodilatory and anti-inflammatory activities (P < 0.05). Oleamide (9 octadecenamide) was identified as the most abundant compound in the extracts and was isolated. Oleamide significantly increased bronchodilatory and anti inflammatory activities by 32.97% and 98.41%, respectively (P < 0.05). CONCLUSION: These results indicate that oleamide is one of the bioactive constituents responsible for the bronchodilatory and anti-inflammatory activity of A. occidentale leaf, and can therefore be employed in the management of bronchoconstriction and inflammation. PMID- 29397098 TI - Look more carefully: Even your data show sleep makes memories more accessible. A reply to Schreiner and Rasch (2018). PMID- 29397099 TI - Underperformance of Mediastinal Lymph Node Evaluation in Resectable Non-Small Cell Lung Cancer. AB - BACKGROUND: Mediastinal lymph node evaluation (MLNE) is considered to be the standard of care in curative lung cancer surgery although it is not always performed. This study identifies factors associated with patients not being evaluated (non-MLNE) in cases of resectable non-small cell lung cancer. METHODS: A retrospective observational study using the Surveillance, Epidemiology, and End Results Program database was conducted. Adult patients diagnosed with non-small cell lung cancer stage I to IIIA (2004 to 2013) were included. Multilevel logistic regression analysis was performed to identify factors that were associated with non-MLNE. RESULTS: There were 86,721 patients included in this study: 73,034 (84.2%) with MLNE and 13,687 (15.8%) without. The use of MLNE gradually increased from 82.7% in 2004 to 85.8% in 2013. In multivariable analysis, factors associated with non-MLNE included the following: age more than 75 years (adjusted odds ratio [ORadj] 1.20, 95% confidence interval [CI]: 1.13 to 1.27); black (ORadj 1.11, 95% CI: 1.32 to 1.20); Native American/Alaskan (ORadj 1.63, 95% CI: 1.15 to 2.31); uninsured (ORadj 1.28, 95% CI: 1.05 to 1.56); residing in a low-income county (ORadj 1.12, 95% CI: 1.04 to 1.21); lesion at the middle lobe (ORadj 1.42, 95% CI: 1.29 to 1.56); lower lobe (ORadj 1.06, 95% CI: 1.01 to 1.11) or main bronchus (ORadj 2.38, 95% CI: 1.93 to 2.94); stage IA (ORadj 1.24, 95% CI: 1.17 to 1.32); sublobar resection (ORadj 11.08, 95% CI: 11.30 to 12.33); and preoperative treatment (ORadj 1.21, 95% CI: 1.08 to 1.36). Non-MLNE was less likely to occur in patients with adenocarcinoma (ORadj 0.88, 95% CI: 0.83 to 0.92) and more likely in other cell types (ORadj 1.23, 95% CI: 1.15 to 1.32), compared with squamous cell carcinoma. CONCLUSIONS: Patient demographics and socioeconomic status are associated with the decision to perform MLNE. Thoracic surgeons should access these factors and perform MLNE to accurately determine tumor stage and improve survival. PMID- 29397100 TI - Advancing the Legislative Priorities of Cardiothoracic Surgeons: The Society of Thoracic Surgeons Political Action Committee. AB - In the late 1990s, several federal government health policy decisions threatened the viability of thoracic surgery as a specialty. To respond to such decisions, active participation in political processes was given extremely high priority by the Executive Committee of The Society of Thoracic Surgeons (STS). Creation of the STS Political Action Committee (STS-PAC) in 1997 was a part of the platform of participation. The purpose of the STS-PAC is to enhance the Society's voice and stature in health care policymaking. Although the STS-PAC receives voluntary contributions from STS members, on average, only 10% of STS members contribute to the STS-PAC. For the 2015-2016 election cycle, there were 542 contributors to the STS-PAC totaling $273,000. An annual contribution of $100 from every STS member would put the STS-PAC into the top 10 for medical PACs (whereas currently it is ranked 22nd of 28 in the group of physician and dental association PACs). Despite the relatively small dollar amount the STS-PAC directs, its strategic disbursement of these dollars has yielded impressive results. For example, the STS-PAC was able to use its influence to effectively stop the Centers for Medicare and Medicaid Services from implementing a potentially calamitous rule that would effectively end traditional global surgical payments. Other advocacy successes include providing guidance to the Centers for Medicare and Medicaid Services in developing the national coverage determination for transcatheter aortic valve replacement and structuring its complex reimbursement schedule, and ensuring that a provision was included in the bill that would give the STS National Database access to claims data. The STS-PAC is a principal component of the STS' advocacy armamentarium. Despite the many successes of the STS-PAC, with even modest contributions by more STS members, the STS-PAC could become a leading medical PAC, and would give the STS an even stronger presence and voice in Washington, DC. Clearly, contributing to the STS-PAC provides STS members the opportunity to have a voice and an impact on health policy and the care of their patients. PMID- 29397101 TI - Outcomes for Thoracoscopy Versus Thoracotomy Not Just Technique Dependent: A Study of 9,787 Patients. AB - BACKGROUND: Studies reporting the benefits of video-assisted thoracoscopic surgery (VATS) lung cancer resection over thoracotomy have been subject to selection bias. We evaluated patient and hospital characteristics associated with type of surgery and the independent effect of VATS on outcomes. METHODS: The Statewide Planning and Research Cooperative System of New York State database was queried to identify all lung cancer patients undergoing lobectomy or sublobar resection between 2007 and 2012. Multivariable logistic regression was performed to identify patient (age, sex, race, comorbidities, year, and insurance) and hospital (urban, teaching, and total lung surgery volume) cofactors associated with surgical technique and propensity scores were used to evaluate whether technique was independently associated with complications or in-hospital mortality. RESULTS: There were 5,505 lobectomy and 4,282 sublobar resection patients, with 2,318 (42%) and 2,416 (56%) undergoing VATS, respectively. For lobectomy, VATS was associated with being female, lower comorbidity index, private insurance, older age, surgery in recent year, nonteaching hospital, and higher annual lung surgery volume. For sublobar resection, VATS was associated with black race, lower comorbidity index, Medicaid or other insurance, surgery in recent year, rural hospital, and higher annual lung surgery volume. Complication rate was significantly lower for VATS lobectomy and not sublobar resection, whereas in-hospital mortality was lower for VATS in both resection groups. CONCLUSIONS: Numerous patient- and hospital-related variables that affect morbidity and mortality also affect whether a patient undergoes VATS or open lung resection. Studies evaluating VATS must account more accurately for selection bias and adjust for these confounders. PMID- 29397102 TI - Predictors of Failure to Rescue After Esophagectomy. AB - BACKGROUND: Failure to rescue (FTR), defined as death after a major complication, is a metric increasingly being used to assess quality of care. Risk factors associated with FTR after esophagectomy have not been previously studied. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent esophagectomy with gastric conduit between 2010 and 2014. Patients with at least one major postoperative complication were grouped according to inhospital mortality (FTR group) and survival to discharge (SUR group). A stepwise logistic regression model was used to identify predictors of FTR. RESULTS: A total of 1,730 patients comprised the study group, with 102 (5.9%) in the FTR group and 1,628 (94.1%) in the SUR group. The FTR patients were older (69.0 versus 64.0 years, p < 0.0001) compared with the SUR patients. There were no differences in sex, body mass index, preoperative weight loss, smoking status, operation type, or surgeon specialty between the two groups. Age greater than 75 years (adjusted odds ratio 2.68, p < 0.0001), black race (adjusted odds ratio 2.75, p = 0.001), American Society of Anesthesiologists class 4 or 5 (adjusted odds ratio 1.82, p = 0.02), and the occurrence of pneumonia, respiratory failure, acute renal failure, sepsis, or acute myocardial infarction were predictive of FTR based on multivariable logistic regression. CONCLUSIONS: Nearly 6% of patients who have a major complication after esophagectomy do not survive to discharge. Age greater than 75 years, black race, American Society of Anesthesiologists class 4 or 5, and complications related to major infection or organ failure predict FTR. Further research is necessary to investigate how these factors affect survival after complications in order to improve rescue efforts. PMID- 29397103 TI - Caprini Risk Model Decreases Venous Thromboembolism Rates in Thoracic Surgery Cancer Patients. AB - BACKGROUND: Extended postoperative chemoprophylaxis is effective in reducing venous thromboembolism (VTE) among general surgical patients. We hypothesized that implementation of the Caprini risk assessment model (RAM) would reduce VTE rates among patients undergoing lung and esophageal cancer surgery. METHODS: The Caprini RAM, consisting of patient risk stratification and extended postoperative chemoprophylaxis with low molecular weight heparin, was implemented on the thoracic surgery service at Boston Medical Center in July 2014. Patients undergoing lung and esophageal cancer resections were enrolled in the postintervention group beginning in July 2014. Provider and patient adherence to treatment protocol was audited. Venous thromboembolism and adverse bleeding events were monitored for 60 days postoperatively. A preintervention control group including esophagectomy and lung cancer resection patients (January 2005 to June 2013) was used for VTE rate comparison. Exclusion criteria included chronic anticoagulation and presence of filters. RESULTS: There were 302 lung and esophageal cancer resection patients in the preintervention cohort, and 64 thoracic cancer resections in the postintervention group. The overall VTE rates for preintervention and postintervention cohorts were 7.3% (22 of 302) and 3.1% (2 of 64), respectively (p = 0.28). Provider adherence to Caprini RAM score assignment was 100%, whereas patient adherence to treatment was 97.4%. There were no adverse bleeding events. CONCLUSIONS: This study demonstrates a trend toward decreased symptomatic VTE after Caprini RAM implementation, as demonstrated among high-risk cancer patients. The absence of bleeding complications and high provider and patient adherence to VTE RAM support the safety and feasibility of a VTE prevention protocol in thoracic surgery patients. PMID- 29397104 TI - Impact of Selective Aspiration Thrombectomy on Mortality in Patients With ST Segment Elevation Myocardial Infarction. AB - Although routine aspiration thrombectomy (AT) is not recommended by the current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guideline, for selected cases, a class IIb indication is given because of lack of data. We studied the impact of selective AT on mortality in patients with ST-segment elevation myocardial infarction using a prospective registry. We analyzed data of 1,255 patients, of whom 535 underwent AT based on operator's decision. Separate propensity score matching procedures were performed including all patients and only those with initial TIMI (Thrombolysis In Myocardial Infarction) 0 to 1 flow, indicating the highest thrombus burden. Primary outcome measure was time to all-cause death at 1 year. Both studies were sufficiently powered to detect the hazard ratio (HR) of 0.52 seen in the TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study) trial. In the study with open inclusion criteria, 1-year mortality rates were 15.5% and 14.5% in the AT and conventional percutaneous coronary intervention arm, respectively (p = 0.77). The unadjusted HR was 1.05 (95% CI 0.73 to 1.51), p = 0.80, whereas the adjusted HR was 0.97 (95% CI 0.66 to 1.41), p = 0.87. In patients with initial TIMI 0 to 1 flow, mortality rate at 1 year was 15.6% in the AT and 16.7% in the standard percutaneous coronary intervention group (p = 0.76). The unadjusted and adjusted HRs were similar: 0.91 (95% CI 0.62 to 1.34), p = 0.65 and 0.93 (95% CI 0.62 to 1.37), p = 0.70, respectively. In conclusion, selective AT based on operator's discretion offers no mortality benefit of the magnitude detected in the TAPAS trial, even for patients with initial TIMI 0 to 1 flow grade. PMID- 29397105 TI - Effect of Electrophysiology Assessment on Mortality and Hospitalizations in Patients With New-Onset Atrial Fibrillation. AB - Few patients with atrial fibrillation (AF) receive care by cardiac electrophysiologists. Although previous work has highlighted differential care for patients with AF treated by electrophysiologists, it is unclear whether this is associated with improved clinical outcomes. This retrospective population level propensity score-matched cohort study included patients aged 20 to 80 years with new-onset AF presenting to an emergency department (ED) in Ontario, Canada, between 2010 and 2012. Patients were followed until March 31, 2015. Patients who saw an electrophysiologist within 1 year of the index ED visit were matched to patients who did not see an electrophysiologist. Linked administrative databases were used for cohort construction and allow 1-year follow-up to assess for the clinical end points of all-cause mortality and hospitalization for AF, heart failure, bleeding, and stroke. A total of 5,221 unique pairs of patients were matched. One hundred seventeen patients (2.2%) in the electrophysiologist cohort underwent an AF ablation procedure during the 1-year follow-up period. All-cause mortality (hazard ratio [HR] = 1.1, p = 0.17) and stroke (HR = 1.4, p = 0.09) were not significantly different between the 2 groups. Hospitalization for AF (HR = 1.4, p <0.001), bleeding (HR = 1.5, p = 0.0001), and congestive heart failure (HR = 1.5, p <0.0001) was increased in the group that saw an electrophysiologist. In conclusion, electrophysiologist care was not associated with improved clinical outcomes in patients with new-onset AF. PMID- 29397106 TI - Comparison of Baseline Characteristics and Outcomes in Men Versus Women With Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation. AB - Female gender has been linked to increased risk of adverse events after surgical aortic valve replacement; however, the evidence regarding the role of gender differences on clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI) is still debated. This retrospective study included 910 consecutive patients with severe, symptomatic aortic stenosis who underwent TAVI in 2 institutions from January 2012 to July 2016. The primary end point was all cause mortality at 1 year after TAVI in women versus men. Women had a higher incidence of in-hospital vascular complications (7.8% vs 4.1%) and major or life threatening bleeding (4.0% vs 1.6%) than men. At 1 year, women showed a lower mortality rate than men (7.0% vs 12.7%, adjusted hazard ratio [HR] 0.42, 95% confidence interval [CI] [0.23 to 0.76], p = 0.004). When stratifying by specific subgroups of interest, the survival benefit in women persisted in (1) patients with a Society of Thoracic Surgery risk score <= 8 (adjusted HR 0.35, 95% CI [0.14 to 0.88], p = 0.026); (2) patients treated with first-generation devices (adjusted HR 0.46, 95% CI [0.24 to 0.86], p = 0.016); and (3) patients treated with balloon-expandable valves (adjusted HR 0.40, 95% CI [0.19 to 0.86], p = 0.019). In conclusion, in this large patient cohort, women had lower 1-year mortality after TAVI than men, particularly with an STS score <= 8, or treated with first-generation and balloon-expandable devices. PMID- 29397107 TI - Platelet Function Analyzer 100 and Brain Natriuretic Peptide as Biomarkers in Obstructive Hypertrophic Cardiomyopathy. AB - To test dual blood biomarkers compared with electrocardiogram (ECG) for hypertrophic cardiomyopathy (HC) screening, we performed 3 analyses and cut-point assessments. First, we measured platelet function analyzer (PFA)-100 (n = 99) and normalized B-type natriuretic peptide (BNP) or NT-proBNP (BNP/upper limit of normal [ULN], n = 92) in 64 patients with HC and 29 normal controls (NCs). Second, from the regression equation between PFA and gradient (r = 0.77), we derived estimated PFA in a population of 189 patients with functional class I HC in whom measured BNP/ULN and ECG were available, and calculated single and dual biomarker sensitivity and specificity compared with ECG. Finally, we compared BNP/ULN in class I patients based on mutation and familial history status. In 42 patients with obstructive HC versus NCs, there was a slight overlap of PFA and BNP/ULN, but for the product of PFA * BNP/ULN, there was near-complete separation of values. Among patients with class I obstructive HC, estimated PFA * BNP/ULN had a sensitivity of 93% and a specificity of 100%; in latent and nonobstructive HC, sensitivity dropped to 61% and 72%; for ECG in obstructive, latent, and nonobstructive HC, sensitivity was 71%, 34%, and 67%. Functional class I patients with positive (n = 28) and negative (n = 36) sarcomere mutations and a positive (n = 71) or a negative (n = 109) family history had significant elevations of BNP/ULN versus NC, with no between-group differences. In conclusion, PFA and BNP were highly associated with obstructive HC and could potentially be used for screening; BNP was not uniquely elevated in patients with familial versus nonfamilial or mutation-positive versus mutation-negative HC. PMID- 29397108 TI - Knee medial and lateral contact forces in a musculoskeletal model with subject specific contact point trajectories. AB - Contact point (CP) trajectory is a crucial parameter in estimating medial/lateral tibio-femoral contact forces from the musculoskeletal (MSK) models. The objective of the present study was to develop a method to incorporate the subject-specific CP trajectories into the MSK model. Ten healthy subjects performed 45 s treadmill gait trials. The subject-specific CP trajectories were constructed on the tibia and femur as a function of extension-flexion using low-dose bi-plane X-ray images during a quasi-static squat. At each extension-flexion position, the tibia and femur CPs were superimposed in the three directions on the medial side, and in the anterior-posterior and proximal-distal directions on the lateral side to form the five kinematic constraints of the knee joint. The Lagrange multipliers associated to these constraints directly yielded the medial/lateral contact forces. The results from the personalized CP trajectory model were compared against the linear CP trajectory and sphere-on-plane CP trajectory models which were adapted from the commonly used MSK models. Changing the CP trajectory had a remarkable impact on the knee kinematics and changed the medial and lateral contact forces by 1.03 BW and 0.65 BW respectively, in certain subjects. The direction and magnitude of the medial/lateral contact force were highly variable among the subjects and the medial-lateral shift of the CPs alone could not determine the increase/decrease pattern of the contact forces. The suggested kinematic constraints are adaptable to the CP trajectories derived from a variety of joint models and those experimentally measured from the 3D imaging techniques. PMID- 29397109 TI - Adaptation of a clinical fixation device for biomechanical testing of the lumbar spine. AB - In-vitro biomechanical testing is widely performed for characterizing the load displacement characteristics of intact, injured, degenerated, and surgically repaired osteoligamentous spine specimens. Traditional specimen fixture devices offer an unspecified rigidity of fixation, while varying in the associated amounts and reversibility of damage to and "coverage" of a specimen - factors that can limit surgical access to structures of interest during testing as well as preclude the possibility of testing certain segments of a specimen. Therefore, the objective of this study was to develop a specimen fixture system for spine biomechanical testing that uses components of clinically available spinal fixation hardware and determine whether the new system provides sufficient rigidity for spine biomechanical testing. Custom testing blocks were mounted into a robotic testing system and the angular deflection of the upper fixture was measured indirectly using linear variable differential transformers. The fixture system had an overall stiffness 37.0, 16.7 and 13.3 times greater than a typical human functional spine unit for the flexion/extension, axial rotation and lateral bending directions respectively - sufficient rigidity for biomechanical testing. Fixture motion when mounted to a lumbar spine specimen revealed average motion of 0.6, 0.6, and 1.5 degrees in each direction. This specimen fixture method causes only minimal damage to a specimen, permits testing of all levels of a specimen, and provides for surgical access during testing. PMID- 29397110 TI - Validation of an ambient system for the measurement of gait parameters. AB - Fall risk in elderly people is usually assessed using clinical tests. These tests consist in a subjective evaluation of gait performed by healthcare professionals, most of the time shortly after the first fall occurrence. We propose to complement this one-time, subjective evaluation, by a more quantitative analysis of the gait pattern using a Microsoft Kinect. To evaluate the potential of the Kinect sensor for such a quantitative gait analysis, we benchmarked its performance against that of a gold-standard motion capture system, namely the OptiTrack. The "Kinect" analysis relied on a home-made algorithm specifically developed for this sensor, whereas the OptiTrack analysis relied on the "built in" OptiTrack algorithm. We measured different gait parameters as step length, step duration, cadence, and gait speed in twenty-five subjects, and compared the results respectively provided by the Kinect and OptiTrack systems. These comparisons were performed using Bland-Altman plot (95% bias and limits of agreement), percentage error, Spearman's correlation coefficient, concordance correlation coefficient and intra-class correlation. The agreement between the measurements made with the two motion capture systems was very high, demonstrating that associated with the right algorithm, the Kinect is a very reliable and valuable tool to analyze gait. Importantly, the measured spatio temporal parameters varied significantly between age groups, step length and gait speed proving the most effective discriminating parameters. Kinect-monitoring and quantitative gait pattern analysis could therefore be routinely used to complete subjective clinical evaluation in order to improve fall risk assessment during rehabilitation. PMID- 29397111 TI - Biomechanical response of intact, degenerated and repaired intervertebral discs under impact loading - Ex-vivo and In-Silico investigation. AB - Understanding the effect of impact loading on the mechanical response of the intervertebral disc (IVD) is valuable for investigating injury mechanisms and devising effective therapeutic modalities. This study used 24 porcine thoracic motion segments to characterize the mechanical response of intact (N = 8), degenerated (Trypsin-denatured, N = 8), and repaired (Genepin-treated, N = 8) IVDs subject to impact loading. A meta-model analysis of poroelastic finite element simulations was used in combination with ex-vivo creep and impact tests to extract the material properties. Forward analyses using updated specimen specific FE models were performed to evaluate the effect of impact duration. The maximum axial stress in the IVDs, Von-Mises stress in the endplates, and intradiscal pore pressure (IDP) were calculated, under a 400 N preload, subject to a sequence of impact loads for 10 impact durations (10-100 ms). The results were in good agreement with both creep and impact experiments (error < 10%). A significant difference was found in the maximum axial stress between the intact and degenerated disc groups. The IDP was also significantly lower in the degenerated disc group. The Von Mises stress in the adjacent endplates significantly increased with degeneration. It is concluded that the disc time dependent response significantly changes with disc degeneration. Cross-linker Genipin has the potential to recover the hydraulic permeability and can potentially change the time dependent response, particularly in the IDP. This is the first study, to our best knowledge, which explores the effect of impact loading on the healthy, degenerated and repaired IVD using both creep and impact validation tests. PMID- 29397112 TI - A finite nonlinear hyper-viscoelastic model for soft biological tissues. AB - Soft tissues exhibit highly nonlinear rate and time-dependent stress-strain behaviour. Strain and strain rate dependencies are often modelled using a hyperelastic model and a discrete (standard linear solid) or continuous spectrum (quasi-linear) viscoelastic model, respectively. However, these models are unable to properly capture the materials characteristics because hyperelastic models are unsuited for time-dependent events, whereas the common viscoelastic models are insufficient for the nonlinear and finite strain viscoelastic tissue responses. The convolution integral based models can demonstrate a finite viscoelastic response; however, their derivations are not consistent with the laws of thermodynamics. The aim of this work was to develop a three-dimensional finite hyper-viscoelastic model for soft tissues using a thermodynamically consistent approach. In addition, a nonlinear function, dependent on strain and strain rate, was adopted to capture the nonlinear variation of viscosity during a loading process. To demonstrate the efficacy and versatility of this approach, the model was used to recreate the experimental results performed on different types of soft tissues. In all the cases, the simulation results were well matched (R2?0.99) with the experimental data. PMID- 29397113 TI - Prevention and Management of Complications in Otosclerosis Surgery. AB - Surgical management of otosclerosis is a relatively safe and effective procedure, with a high rate of hearing improvement and a low rate of undesirable outcomes and complications. Many of these potential complications are common to any middle ear surgery, but many are unique to surgery involving the stapes footplate. Preventing complications with stapes surgery and minimizing their impact may be achieved by preparation as well as surgical experience. PMID- 29397114 TI - Special Anatomic Considerations in Otosclerosis Surgery. AB - The anatomy of the vestibular organs together with considerations of the middle and inner ear anatomy relevant to stapes surgery is discussed. An archival collection of macerated and freshly frozen human temporal bones underwent micro computed tomography (CT) with subsequent volume-rendering. Three-dimensional (3D) reconstructions and the topographic anatomy of the oval window were considered. Micro-CT and 3D rendering revealed the relationship between the otolith organs and the oval window. Anatomic variations were extensive and included the distance between the footplate and the reconstructed macula margins. A "no-go" zone is suggested for the surgeon to avoid injury during stapes surgery. PMID- 29397115 TI - 2017: A year of change for British Journal of Anaesthesia. PMID- 29397116 TI - Prevention of arterial hypotension after spinal anaesthesia using vena cava ultrasound to guide fluid management. AB - BACKGROUND: Significant hypotension is frequent after spinal anaesthesia and fluid administration as therapy is usually empirical. Inferior vena cava (IVC) ultrasound (US) is effective to assess fluid responsiveness in critical care patients. The aim of this study was to evaluate the IVCUS-guided volume optimization to prevent post-spinal hypotension. METHODS: In this prospective, randomized, cohort study, 160 patients scheduled for surgery under spinal anaesthesia were randomized into a study group (IVCUS-group), consisting of an IVCUS analysis before spinal anaesthesia with IVCUS-guided volume management and a control group (group C) with no IVCUS assessment. The primary outcome was a relative risk reduction in the incidence of hypotension between the groups; secondary outcomes were the need for vasoactive drugs and the amounts of fluids required after spinal anaesthesia. We also tested the hypothesis of a correlation between IVC collapsibility index and hypotension after spinal anaesthesia. RESULTS: The relative risk reduction of hypotension between the groups was 35% (IVCUS-group 27.5%, Group C 42.5%, P=0.044, CI=95%). The need for vasoactive drugs in the IVCUS-group was significantly lower compared to the C-group (P=0.015), while the total amount of fluids was significantly superior higher in the IVCUS group (P<0.0001) compared to Group C. IVC collapsibility index was correlated with the amount of fluid administered (r2=0.32), but could not be used to predict postspinal anaesthesia hypotension. CONCLUSIONS: IVCUS is an effective method to prevent postspinal anaesthesia hypotension by IVCUS-guided fluid administration before spinal anaesthesia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov - NCT02271477. PMID- 29397117 TI - The association between obesity and disability in survivors of joint surgery: analysis of the health and retirement study. AB - BACKGROUND: Obesity is associated with osteoarthritis and the need for joint surgery. Obese patients who undergo joint surgery may have a higher risk of morbidity compared with normal or overweight patients but less is known about their risk of postoperative disability. The primary objective of our study was to determine the association between obesity and the development of new dependence in activities of daily living within 2 years after joint surgery. METHODS: We obtained data from the Health and Retirement Study, a longitudinal survey of older Americans. We included participants who indicated having joint surgery for arthritis. We defined obesity as a BMI >=30 kg m-2. Our outcome was a new or increased dependence in one or more activities of daily living after surgery. RESULTS: We analysed data on 2519 respondents who underwent joint surgery for arthritis. Respondents had a median age of 69yr, 65.5% were female, 66.6% had joint replacement surgery and 45.3% were obese. The overall incidence of a new dependence within 2years was 22.1%. Obese respondents had a higher incidence of new dependence compared with non-obese respondents (25.4% vs 19.4%, P<0.001). In adjusted analysis, obese respondents had increased odds of developing dependence [odds ratio 1.35 (95% CI 1.09-1.68), P=0.007]. CONCLUSIONS: Obesity is associated with an increased risk of developing dependence in the 2 years after joint surgery. Our study findings identify a high-risk group that may benefit from targeted interventions and allocation of perioperative resources to optimize recovery and minimize longer-term disability. PMID- 29397118 TI - Supplemental oxygen and surgical-site infections: an alternating intervention controlled trial. AB - BACKGROUND: The main defence against bacterial infection is oxidative killing by neutrophils, which requires molecular oxygen in wounded tissues. High inspired oxygen fractions increase tissue oxygenation. But, whether improving tissue oxygenation actually reduces surgical-site infection (SSI) remains controversial. We therefore tested the primary hypothesis that supplemental oxygen (80% vs 30%) reduces the risk of a 30-day composite of deep tissue or organ-space SSI, healing related wound complications, and mortality. METHODS: In an isolated suite of operating rooms, the inspired-oxygen concentration was alternated between 30% and 80% at 2-week intervals for 39 months. The analysis was restricted to patients who had major intestinal surgery lasting at least 2 h. Qualifying operations (5749) were analysed, including 2843 (49%) colorectal resections, 1866 (32%) lower gastrointestinal therapeutic procedures, 373 (6%) small-bowel resections, and 667 (13%) other colorectal procedures. RESULTS: The 80% and 30% oxygen groups were well balanced on all of the demographic, baseline, and procedural variables. The oxygen intervention had no effect on the composite primary outcome or any of its components. The overall observed incidence of the composite outcome was 10.8% (314/2896) in the 80% oxygen group and 11.0% (314/2853) in the 30% group. The estimated relative risk was 0.99 (95% CI: 0.85, 1.14) for 80% vs 30%, P=0.85. CONCLUSIONS: Supplemental oxygen does not prevent major infection and healing related complications after major intestinal surgery. CLINICAL TRIAL REGISTRATION: NCT01777568. PMID- 29397120 TI - Implementing universal videolaryngoscopy: how to do it and what to expect. PMID- 29397121 TI - Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations. AB - Patients with severe grades of life-threatening brain injury are commonly characterized as having devastating brain injury (DBI), which we have defined as: 'any neurological condition that is assessed at the time of hospital admission as an immediate threat to life or incompatible with good functional recovery AND where early limitation or withdrawal of therapy is being considered'. The outcome in patients with DBI is often death or severe disability, and as a consequence rapid withdrawal of life sustaining therapies is commonly contemplated or undertaken. However, accurate prognostication in life-threatening brain injury is difficult, particularly at an early stage. Evidence from controlled studies to guide decision-making is limited, and there is a risk of a 'self-fulfilling prophecy', with early prognostication leading to early withdrawal of life sustaining therapies and death. The Joint Professional Standards committee of the Faculty of Intensive Care Medicine and the Intensive Care Society convened a consensus group with representation from stakeholder professional organizations to develop clear professional guidance in this area. It recognized that the weak evidence base makes GRADE guidelines difficult to justify. We have made 12 practical, pragmatic recommendations to help clinicians deliver safe, effective, equitable, and justifiable care within resource constrained healthcare systems. In the situation where patient-centred outcomes are recognized to be unacceptable, regardless of the extent of neurological improvement, then early transition to palliative care is appropriate. These recommendations are intended to apply where the primary pathology is DBI, rather than where DBI has compounded a progressive and irreversible deterioration in other life-threatening comorbidities. PMID- 29397119 TI - The hip fracture surgery in elderly patients (HIPELD) study to evaluate xenon anaesthesia for the prevention of postoperative delirium: a multicentre, randomized clinical trial. AB - BACKGROUND: Postoperative delirium occurs frequently in elderly hip fracture surgery patients and is associated with poorer overall outcomes. Because xenon anaesthesia has neuroprotective properties, we evaluated its effect on the incidence of delirium and other outcomes after hip fracture surgery. METHODS: This was a phase II, multicentre, randomized, double-blind, parallel-group, controlled clinical trial conducted in hospitals in six European countries (September 2010 to October 2014). Elderly (>=75yr-old) and mentally functional hip fracture patients were randomly assigned 1:1 to receive either xenon- or sevoflurane-based general anaesthesia during surgery. The primary outcome was postoperative delirium diagnosed through postoperative day 4. Secondary outcomes were delirium diagnosed anytime after surgery, postoperative sequential organ failure assessment (SOFA) scores, and adverse events (AEs). RESULTS: Of 256 enrolled patients, 124 were treated with xenon and 132 with sevoflurane. The incidence of delirium with xenon (9.7% [95% CI: 4.5 -14.9]) or with sevoflurane (13.6% [95% CI: 7.8 -19.5]) were not significantly different (P=0.33). Overall SOFA scores were significantly lower with xenon (least-squares mean difference: 0.33 [95% CI: -0.60 to -0.06]; P=0.017). For xenon and sevoflurane, the incidence of serious AEs and fatal AEs was 8.0% vs 15.9% (P=0.05) and 0% vs 3.8% (P=0.06), respectively. CONCLUSIONS: Xenon anaesthesia did not significantly reduce the incidence of postoperative delirium after hip fracture surgery. Nevertheless, exploratory observations concerning postoperative SOFA-scores, serious AEs, and deaths warrant further study of the potential benefits of xenon anaesthesia in elderly hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: EudraCT 2009 017153-35; ClinicalTrials.gov NCT01199276. PMID- 29397123 TI - Modelling the effects of perioperative interventions on cancer outcome: lessons from dexmedetomidine. PMID- 29397124 TI - Simplified algorithm for the prevention of postoperative nausea and vomiting: a before-and-after study. AB - BACKGROUND: Poor adherence to guidelines aimed at reducing the incidence of postoperative nausea and vomiting (PONV) is well known. In a before-and-after study, we tested the effectiveness of a simplified algorithm for PONV prophylaxis on the incidence of PONV. METHODS: In the first audit, we examined the adherence to our institutional guidelines for PONV prevention. In response to the results of this audit, we introduced a simplified algorithm for PONV prevention [female patients receiving triple prophylaxis (dexamethasone and ondansetron plus either a target-controlled infusion with propofol or droperidol) and male patients receiving double prophylaxis, dexamethasone, and ondansetron]. The impact of the simplification of the PONV algorithm was evaluated in a second audit. In both audits, we reviewed the medical records of all adult patients undergoing elective non-cardiac non-day-case surgery under general anaesthesia and being admitted to our post-anaesthesia care unit during two arbitrarily chosen weeks. We assessed the incidence of nausea, vomiting, and PONV after 1 and 24 h, and the compliance with the departmental algorithm for PONV prophylaxis. RESULTS: After simplification of the PONV algorithm, the overall incidence of PONV within 24 h after surgery was significantly lower than before the implementation of the simplified PONV algorithm (22% vs 33%, P=0.02). The PONV incidence within 1 h was comparable between the audits (11% vs 14%, P=0.45). The adherence to departmental guidelines for PONV prophylaxis was significantly higher after the implementation of the simplified PONV algorithm (46% vs 18%, P=0.0001). CONCLUSIONS: A simplified algorithm for PONV prophylaxis resulted in a significant reduction in the PONV incidence and better compliance with the PONV algorithm. PMID- 29397125 TI - Tracking and Reporting Outcomes Of Procedural Sedation (TROOPS): Standardized Quality Improvement and Research Tools from the International Committee for the Advancement of Procedural Sedation. AB - Many hospitals, and medical and dental clinics and offices, routinely monitor their procedural-sedation practices-tracking adverse events, outcomes, and efficacy in order to optimize the sedation delivery and practice. Currently, there exist substantial differences between settings in the content, collection, definition, and interpretation of such sedation outcomes, with resulting widespread reporting variation. With the objective of reducing such disparities, the International Committee for the Advancement of Procedural Sedation has herein developed a multidisciplinary, consensus-based, standardized tool intended to be applicable for all types of sedation providers in all locations worldwide. This tool is amenable for inclusion in either a paper or an electronic medical record. An additional, parallel research tool is presented to promote consistency and standardized data collection for procedural-sedation investigations. PMID- 29397126 TI - Universal videolaryngoscopy: a structured approach to conversion to videolaryngoscopy for all intubations in an anaesthetic and intensive care department. AB - BACKGROUND: Videolaryngoscopy (VL) is increasingly used, but not yet routine practice, for tracheal intubation. Few departments formally trial equipment before adopting it into practice. We describe the decision-making and implementation processes that our department used when introducing universal VL, with the C-MAC(c) (Karl Storz, Germany), throughout our anaesthesia and intensive care departments. METHODS: We used a structured process to assess the feasibility of a change to universal VL. After departmental training, we undertook a 2 month trial period of mandating VL for all adult in-theatre intubations. Thereafter, VL remained widely available, but not mandated. We regularly surveyed anaesthetists and anaesthetic assistants to evaluate departmental opinion regarding the introduction of universal VL. RESULTS: Before the trial period, one-third of anaesthetists judged that universal VL would be of overall benefit to patient safety, team dynamics, and quality of care. Reservations from both junior and senior anaesthetists focused on training concerns. Support for a changeover to VL, amongst both anaesthetists and anaesthetic assistants, increased throughout the trial period. Six months after the 2 month trial, support had grown further and was almost unanimous. Anaesthetists reported significant benefits in clinical performance, teaching, and human factors, especially teamwork and situation awareness. CONCLUSIONS: Performing a formal and prolonged trial of mandatory VL in theatre led to changes in perceptions and departmental consensus. As a result of the trial, the department agreed to the use of C-MAC(c) videolaryngoscopy as the default intubation technique throughout theatres and intensive care, with removal of standard Macintosh laryngoscopes from routine use. PMID- 29397127 TI - High-flow nasal oxygen therapy in intensive care and anaesthesia. AB - Oxygen therapy is first-line treatment for hypoxaemic acute respiratory failure (ARF). High-flow nasal oxygen therapy (HFNO) represents an alternative to conventional oxygen therapy. HFNO provides humidified, titrated oxygen therapy matching or even exceeding the patients' inspiratory demand. The application of HFNO is becoming widespread in Intensive Care Units (ICUs), favoured by increasing evidence based on numerous studies supporting its efficacy. The mechanisms of action and physiological effects of HFNO are not yet fully understood. Pharyngeal dead space washout, decrease in airway resistance, generation of a positive end-expiratory pressure, and enhanced delivery of oxygen are all alleged to be potential mechanisms. The emerging evidence suggests that HFNO is effective in improving oxygenation in most patients with hypoxaemic ARF of different aetiologies. Notwithstanding the potential benefit of HFNO in the management of hypoxaemia, further large cohort studies are necessary to clarify the indications, contraindications and factors associated with HFNO failure. HFNO may also be valuable in reducing the need for tracheal intubation in the management of post-extubation ARF. In addition, HFNO has been proposed to limit oxygen desaturation by prolonging apnoeic oxygenation during intubation both in ICUs and operating theatres. PMID- 29397128 TI - Dynamic behaviour of the soft palate during nasal positive pressure ventilation under anaesthesia and paralysis: comparison between patients with and without obstructive sleep-disordered breathing. AB - BACKGROUND: Difficult mask ventilation is common and is known to be associated with sleep-disordered breathing (SDB). It is our hypothesis that the incidence of expiratory retropalatal (RP) airway closure (primary outcome) during nasal positive pressure ventilation (PPV) is more frequent in patients with SDB (apnea hypopnea index >=5 h-1) than non-SDB subjects. METHODS: The severity of SDB was assessed before surgery using a portable sleep monitor. In anaesthetized and paralysed patients with (n=11) and without SDB (n=9), we observed the behaviour of the RP airway endoscopically during nasal PPV with the mouth closed and determined the dynamic RP closing pressure, which was defined as the highest airway pressure above which the RP airway closure was reversed. The static RP closing pressure was obtained during cessation of mechanical ventilation in patients with dynamic RP closure during nasal PPV. RESULTS: The expiratory RP airway closure accompanied by expiratory flow limitation occurred more frequently in SDB patients (9/11, 82%) than in non-SDB subjects (2/9, 22%; exact logistic regression analysis: P=0.022, odds ratio 3.6, 95% confidence interval 1.1-15.4). Receiver operating characteristic curve analyses indicated AHI >10h-1 and presence of habitual snoring as clinically useful predictors for the occurrence of RP closure during PPV. Dynamic RP closing pressure was greater than the static RP closing pressure by approximately 4-5 cm H2O. CONCLUSIONS: Valve-like dynamic RP closure that limits expiratory flow during nasal PPV occurs more frequently in SDB patients. PMID- 29397130 TI - High intraoperative oxygen use-context matters. PMID- 29397129 TI - Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. AB - BACKGROUND: Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an alpha2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression. METHODS: Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6-12 h, and its effects on metastasis formation, using various cancer types, were studied in naive animals and in the context of stress and surgery. RESULTS: Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through alpha2-adrenergic, but not alpha1 adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors. CONCLUSIONS: The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients. PMID- 29397131 TI - Effect of remote ischaemic preconditioning in patients with ischaemic heart disease undergoing orthopaedic surgery: a randomized controlled trial. PMID- 29397132 TI - Anaesthesia quality metrics: do they achieve the goals of evidence to improve patient care? PMID- 29397133 TI - Online and app-based access for the ACTA-PORT score. PMID- 29397134 TI - Systematic review of the QoR-15 score, a patient- reported outcome measure measuring quality of recovery after surgery and anaesthesia. AB - BACKGROUND: The QoR-15 is a patient-reported outcome questionnaire that measures the quality of recovery after surgery and anaesthesia. We aimed to perform a systematic review and meta-analysis of the measurement properties of the QoR-15. METHODS: Studies reporting measurement properties or interpretability of the QoR 15 after surgery were eligible for inclusion. All languages were included in the PubMed and Embase search. The COSMIN guidelines for systematic reviews of patient reported outcome measurements were followed. Criteria for good measurement properties outlined in the consensus-based guidelines for selecting outcome measurement instruments for clinical trials were applied. A metaanalysis and synthesis of data across studies was performed. RESULTS: Nine hundred and thirty three titles were identified, and six articles were included in the study. The study population comprised 1548 patients undergoing a variety of surgical elective procedures. The QoR-15 was validated in English, Danish, Chinese, and Portuguese. High-quality evidence for good content validity, good internal consistency (Cronbach's alpha of 0.836), and essential unidimensionality of the QoR-15 as a measurement of postoperative quality of recovery was found. There was at least moderate-quality evidence of good reliability of the QoR-15 (intraclass correlation of 0.989) and good error of measurement (standard error of measurement of 1.85). The upper 95% confidence limit of the smallest detectable change was 3.63, and the minimal clinical important difference was 8.0. CONCLUSIONS: The QoR-15 fulfils requirements for outcome measurement instruments in clinical trials and is the first measurement instrument of postoperative quality of recovery to undergo a systematic review according to the COSMIN checklist. PMID- 29397135 TI - Perioperative outcomes in the context of mode of anaesthesia for patients undergoing hip fracture surgery: systematic review and meta-analysis. AB - BACKGROUND: Previous meta-analyses on the anaesthetic management of patients undergoing surgery for hip fracture have focused on randomized trials. Furthermore, heterogeneity in outcome reporting across the studies has made it difficult to inform best practice guidelines for patient care. METHODS: This systematic review examined how perioperative outcomes were reported and defined in the context of comparing modes of anaesthesia for hip fracture surgery. Outcomes were included from randomised and non-randomised studies published between January 2000 and July 2017. Meta-analyses were performed for regional versus general anaesthesia, with sensitivity analyses performed for spinal versus general anaesthesia. RESULTS: By including data from 15 large observational studies in this meta-analysis, we have increased the number of patients for whom outcomes were assessed from approximately 3000 to 202 000. There was no significant difference in 30-day mortality [Odds ratio (OR) 1.15; 95% confidence interval (CI) 1.01, 1.32; I2 87%; n=200 464], prevalence of pneumonia (OR 1.10; 95% CI 0.93, 1.30; I2 43%; n=65 011), acute myocardial infarction (OR 0.96; 95% CI 0.88, 1.05; I2 0%, n=64 904), delirium (OR 1.07; 95% CI 0.72, 1.58; I2 93%, n=19 923) or renal failure (OR 0.94; 95% CI 0.54, 1.64; I2 0%, n=27 873) for regional compared to general anaesthesia. There was a small statistically significant difference for length of stay (standardized mean difference -0.03; 95% CI -0.05, -0.02; I2 0%; n=78 711) favouring regional anaesthesia, which is unlikely to be clinically significant. Sensitivity analyses for the same outcomes examining spinal only vs general anaesthesia showed minor statistical significance for length of stay favouring spinal. We also present data highlighting the scale of the inconsistencies in reported outcomes across 32 studies, making evaluation in a standardized manner very difficult. As an example, mortality was reported in nine different ways throughout the studies. CONCLUSIONS: We highlight the need for agreement on outcome definitions and for a minimum core outcome set to be measured and reported in hip fracture studies. This would strengthen the evidence-based approach to delivering optimal care. PMID- 29397136 TI - Postoperative hypotension and troponin elevation: association or causation? PMID- 29397137 TI - Decision making in perceived devastating brain injury: a call to explore the impact of cognitive biases. PMID- 29397138 TI - Perioperative structure and process quality and safety indicators: a systematic review. AB - BACKGROUND: Clinical indicators assess healthcare structures, processes, and outcomes. While used widely, the exact number and level of scientific evidence of these indicators remains unclear. The aim of this study was to evaluate the number, type, and evidence base of clinical process and structure indicators currently available for quality and safety measurement in perioperative care. METHODS: We performed a systematic review searching Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, Google Scholar, and System for Information in Grey Literature in Europe databases for English language human studies in adults (age >18) published in the past 10 years (January 2005-January 2016). We also included professional and governmental body publications and guidelines describing the development, validation, and use of structure and process indicators in perioperative care. RESULTS: We identified 43 860 journal articles and 43 relevant indicator program publications. From these, we identified a total of 1282 clinical indicators, split into structure (36%, n=463) and process indicators (64%, n=819). The dimensions of quality most frequently addressed were effectiveness (38%, n=475) and patient safety (29%, n=363). The majority of indicators (53%, n=675) did not have a level of evidence ascribed in their literature. Patient-centred metrics accounted for the fewest published clinical indicators. CONCLUSIONS: Despite widespread use, the majority of clinical indicators are not based on a strong level of scientific evidence. There may be scope in setting standards for the development and validation process of clinical indicators. Most indicators focus on the effectiveness, safety, and efficiency of care. PROSPERO DATABASE: CRD4201501277. PMID- 29397139 TI - Management of antiplatelet therapy in patients with coronary stents undergoing noncardiac surgery: association with adverse events. AB - BACKGROUND: Perioperative discontinuation of antiplatelet therapy (APT) in patients with coronary stents has been associated with major adverse cardiac events. Our aim was to analyse the perioperative management of APT in such patients and its relationship to the incidence of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding events (MBE) in noncardiac surgery. METHODS: We completed a prospective multicentre observational study of patients with coronary stents undergoing noncardiac surgery in 11 hospitals in Spain. The main objectives were to record perioperative events and prospectively analyse the management of APT, and to assess whether the different preoperative APT regimens were associated with MACCE and MBE. RESULTS: Of 432 surgical procedures studied, 15% experienced a perioperative MACCE and 37% a MBE. Overall mortality was 3.0%. Presurgical APT was prescribed in 95% of procedures, and was preoperatively discontinued in 15%. Surgery was urgent or emergent in 22% of patients, 31% were ASA IV, and 38% had a Revised Cardiac Risk Index of IV. MACCE were related to recent myocardial infarction (P=0.038), chronic kidney disease (P<0.001), insulin-dependent diabetes (P=0.006) and no preoperative APT (P=0.018). MBE also increased MACCE risk (P<0.001). We found statin therapy (P=0.049) and obesity (P=0.016) to be protective factors for MACCE. CONCLUSIONS: Patients with coronary stents undergoing noncardiac surgery suffer a high incidence of perioperative adverse events, even with perioperative APT. Major adverse cardiac and cerebrovascular events are mainly related to previous medical conditions and perioperative major bleeingn events. Our findings should be treated with caution when applied to an elective surgery population. CLINICAL TRIAL REGISTRATION: NCT01171612. PMID- 29397140 TI - Association between postoperative mean arterial blood pressure and myocardial injury after noncardiac surgery. AB - BACKGROUND: Myocardial injury after noncardiac surgery is common, although the exact pathophysiology is unknown. It is plausible that hypotension after surgery is relevant for the development of myocardial injury. The authors evaluated whether low mean arterial pressures (MAPs) after surgery are related to an increased incidence in postoperative cardiac-troponin elevation. METHODS: A prospective cohort of 2211 patients aged >=60 yr, undergoing major or moderate noncardiac surgery in The Netherlands, was retrospectively analysed for the occurrence of postoperative cardiac-troponin elevation [high-sensitive troponin T (hsTnT) >14 ng L-1]. Blood pressures after surgery were recorded and divided into quartiles based on the lowest MAP prior to peak troponin recording. The association between MAP and extent of postoperative cardiac-troponin elevation was analysed. RESULTS: The patients were divided into quartiles based on their lowest MAP in the period preceding the peak hsTnT, ranging from a median of 62 in the lowest quartile to 94 in the highest quartile. Postoperative hsTnT elevation was present in 53.2% of the population. An association between MAP quartile and postoperative peak hsTnT was predominantly observed in the lowest quartile (P<0.001): median hsTnT 17.6 (10.3-37.3), 14.9 (9.4-24.6), 13.8 (9.1-22.5), and 14.0 (9.2-22.4). The multivariable logistic-regression analysis showed an increased risk for postoperative cardiac-troponin elevation with decreasing MAP thresholds. CONCLUSIONS: Lower postoperative blood pressure is associated with an increased incidence of postoperative cardiac hsTnT elevation, irrespective of pre and intraoperative variables. PMID- 29397141 TI - Prognostic value of postoperative high-sensitivity troponin T in patients with different stages of kidney disease undergoing noncardiac surgery. AB - BACKGROUND: Emerging evidence suggests that postoperative troponin release is a strong and independent predictor of short-term mortality. However, evaluating elevated troponins in patients with chronic kidney disease (CKD) is still controversial and is often disregarded. This study examines morbidity along with short- and long-term mortality risk associated with elevated high-sensitivity troponin T (hsTnT) in patients with different stages CKD undergoing noncardiac surgery. METHODS: This observational cohort comprised 3262 patients aged >=60 yr who underwent noncardiac surgery. Postoperative hsTnT concentrations were divided into normal [<14 ng l-1 (reference)], low (14-49 ng l-1), moderate (50-149 ng l 1), and high (>=150 ng l-1) groups. A threshold of 50 ng l-1 was used to dichotomize hsTnT. The study endpoints were 30-day and long-term all-cause mortality, and postoperative myocardial infarction. RESULTS: Postoperative hsTnT was associated with a stepwise increase in 30-day and long-term mortality risk: low hsTnT adjusted hazard ratio (HR) 1.4 [95% confidence interval (CI): 1.1-1.7], moderate hsTnT adjusted HR 3.1 (95% CI: 2.3-4.3), high hsTnT adjusted HR 5.5 (95% CI: 3.6-8.4). Postoperative hsTnT >=50 ng l-1 was associated with 30-day and long term mortality risk for each stage of CKD. Elevated troponin concentrations in severe CKD (estimated glomerular filtration rate <30 mL min-1 1.73 m-2), however, did not predict short-term death. CONCLUSIONS: Elevated postoperative hsTnT is associated with a dose-dependent increase in 30-day and long-term mortality risk in each stage of CKD with an estimated glomerular filtration rate >=30 ml min-1 1.73 m-2. PMID- 29397142 TI - Risk-tailored prophylaxis for postoperative nausea and vomiting: has the big little problem gotten any smaller? PMID- 29397143 TI - Arterial pulse pressure and postoperative morbidity in high-risk surgical patients. AB - BACKGROUND: Systemic arterial pulse pressure (systolic minus diastolic pressure) <=53 mm Hg in patients with cardiac failure is correlated with reduced stroke volume and is independently associated with accelerated morbidity and mortality. Given that deconditioned surgical and heart failure patients share similar cardiopulmonary physiology, we examined whether lower pulse pressure is associated with excess morbidity after major surgery. METHODS: This was a prospective observational cohort study of patients deemed by their preoperative assessors to be at higher risk of postoperative morbidity. Preoperative pulse pressure was calculated before cardiopulmonary exercise testing. The primary outcome was any morbidity (PostOperative Morbidity Survey) occurring within 5 days of surgery, stratified by pulse pressure threshold <=53 mm Hg. The relationship between pulse pressure, postoperative morbidity, and oxygen pulse (a robust surrogate for left ventricular stroke volume) was examined using logistic regression analysis (accounting for age, sex, BMI, cardiometabolic co-morbidity, and operation type). RESULTS: The primary outcome occurred in 578/660 (87.6%) patients, but postoperative morbidity was more common in 243/ 660 patients with preoperative pulse pressure <=53 mm Hg{odds ratio (OR): 2.24 [95% confidence interval (CI): 1.29-3.38]; P<0.001). Pulse pressure <=53 mm Hg [OR:1.23 (95% CI: 1.03-1.46); P=0.02] and type of surgery were independently associated with all cause postoperative morbidity (multivariate analysis). Oxygen pulse <90% of population-predicted normal values was associated with pulse pressure <= 53 mm Hg [OR: 1.93 (95% CI: 1.32-2.84); P=0.007]. CONCLUSIONS: In deconditioned surgical patients, lower preoperative systemic arterial pulse pressure is associated with excess morbidity. These data are strikingly similar to meta-analyses identifying low pulse pressure as an independent risk factor for adverse outcomes in cardiac failure. Low preoperative pulse pressure is a readily available measure, indicating that detailed physiological assessment may be warranted. CLINICAL TRIAL REGISTRATION: ISRCT registry, ISRCTN88456378. PMID- 29397144 TI - Individual Significance of Olfaction: A Comparison Between Normosmic and Dysosmic People. AB - BACKGROUND: Olfactory dysfunction is common in older individuals. The importance of such dysfunction to individuals is highly variable: many people do not seem to care about their olfactory dysfunction, others suffer and complain about problems in daily life, a reduced quality of life, or symptoms of depression. OBJECTIVE: Understanding the importance of olfaction for different age groups in normosmic as well as in smell-disordered subjects may help to find reasons for insufficient coping with olfactory dysfunction. METHODS: We used a questionnaire to capture the individual importance of olfaction in a sample of 433 normosmic and 172 dysosmic people from 15-82 years of age. Furthermore, all participants underwent standardized assessment of olfactory function. RESULTS: The importance of olfaction was highest in the group of young (<=25-year-old) normosmic women. Dysosmia was associated with a decreased importance of olfaction, irrespective of age. However, 18 % of the dysosmic patients showed a tendency to aggravate their symptoms. This high degree of aggravation could not be explained by sex, age, or severity of olfactory dysfunction. CONCLUSIONS: The high importance of olfaction observed in young women may reflect the specific needs of this group, such as mate selection and child care. The strongly reduced importance of olfaction in dysosmic subjects seems to serve as an adaptive coping mechanism. A tendency to aggravate symptoms may indicate insufficient coping. Hence, detecting high aggravation could be a first step to recognizing high psychological strain and the need for psychotherapeutic treatment. PMID- 29397145 TI - Access to Paid Parental Leave for Academic Surgeons. AB - BACKGROUND: Parental leave is linked to health benefits for both child and parent. It is unclear whether surgeons at academic centers have access to paid parental leave. The aim of this study was to determine parental leave policies at the top academic medical centers in the United States to identify trends among institutions. METHODS: The top academic medical centers were identified (US News & World Report 2016). Institutional websites were reviewed, or human resource departments were contacted to determine parental leave policies. "Paid leave" was defined as leave without the mandated use of personal time off. Institutions were categorized based on geographical region, funding, and ranking to determine trends regarding availability and duration of paid parental leave. RESULTS: Among the top 91 ranked medical schools, 48 (53%) offer paid parental leave. Availability of a paid leave policy differed based on private versus public institutions (70% versus 38%, P < 0.01) and on medical center ranking (top third = 77%; middle third = 53%; and bottom third = 29%; P < 0.01) but not based on region (P = 0.06). Private institutions were more likely to offer longer paid leaves (>6 wk) than public institutions (67% versus 33%; P = 0.02). No difference in paid leave duration was noted based on region (P = 0.60) or rank (P = 0.81). CONCLUSIONS: Approximately, 50% of top academic medical centers offer paid parental leave. Private institutions are more likely to offer paid leave and leave of longer duration. There is considerable variability in access to paid parenteral leave for academic surgeons. PMID- 29397146 TI - Effects of a randomized intervention promoting healthy children's meals on children's ordering and dietary intake in a quick-service restaurant. AB - BACKGROUND: Children's consumption of restaurant foods is associated with higher energy intake and lower nutritional quality compared to foods prepared at home. The aim of this pilot study was to test whether an in-restaurant intervention promoting healthy children's meals (i.e. two meals that met nutrition recommendations and were thus healthier than typical children's meal offerings across leading restaurants) affected children's meal selection and intake. METHODS: Families with 4-to-8-year-old children were recruited from one location of Anderson's Frozen Custard, a regional quick-service restaurant chain. Families were randomly assigned to return to the restaurant during an intervention or control period and were blinded to group assignment. All families received free meals. During the intervention period families also received placemats featuring two healthy "Kids' Meals of the Day" upon restaurant entry. After families finished dining, researchers recorded children's orders and collected leftovers for quantifying dietary intake via weighed plate waste. Poisson regression and chi-square tests were used to compare children's orders between study groups, and t-tests were used to test for differences in dietary intake among children ordering a promoted healthy entree (main dish) versus those who did not. RESULTS: Fifty-eight families participated. Children who were exposed to the study placemats prior to ordering ordered a significantly greater number of healthy food components compared to controls (p = 0.03). Overall, in the intervention group, 21% of children ordered a healthy entree or side dish, versus 7% of controls. Children who ordered one of the promoted healthy entrees consumed less saturated fat across the total meal compared to those who did not (p = 0.04). CONCLUSIONS: Manipulating the prominence of healthy choices in restaurants may shift children's meal selections. Future research should build on these initial promising results, aiming to increase the potency of the intervention to achieve more widespread effects. PMID- 29397147 TI - A simplified insertion technique for tracheal T-tube. PMID- 29397148 TI - Coronary computed tomography angiography: Star of the show or supporting act? PMID- 29397149 TI - Disseminated Mycobacterium chimaera infection associated with heater-cooler units after aortic valve surgery without endocarditis. PMID- 29397150 TI - The good, the bad, and the uncertain: Can matrix metalloproteinase 12 simultaneously be protumorigenic and antitumorigenic? PMID- 29397151 TI - Primum non nocere when the treatment is worse than the disease. PMID- 29397152 TI - Zone zero thoracic endovascular aortic repair is all about "location, location, location". PMID- 29397153 TI - Cardiac stem cell trials and the new world of cellular reprogramming: Time to move on. PMID- 29397154 TI - The modern mission of the innovator: Data, data, and more data. PMID- 29397155 TI - Will cardiac surgeons even turn pumpkins into carriages? PMID- 29397156 TI - Good hearts for bad kidneys? PMID- 29397157 TI - Development of quantitative suspension array assays for six immunoglobulin isotypes and subclasses to multiple Plasmodium falciparum antigens. AB - BACKGROUND: Quantitative suspension arrays are powerful immunoassays to measure antibodies against multiple antigens in large numbers of samples in a short time and using few microliters. To identify antigen targets of immunity for vaccine development against complex microbes like Plasmodium falciparum, such technology allows the characterization of the magnitude and antigenic specificity of Ig isotypes and subclasses that are important for functional responses. However, standardized assays are not widely available. METHODS: We developed six quantitative suspension array assays to measure IgG1, IgG2, IgG3, IgG4, IgM and IgE specific to multiple P. falciparum antigens. Secondary and tertiary antibodies, as well as human purified antibodies for standard curves, were tested among several commercially available sources. Positive and negative controls included plasmas from malaria hyper-immune African adults and from malaria-naive European adults, respectively. Reagents were selected and optimal antibody and test sample dilutions established according to sensitivity, specificity and performance of the standard curves. The variability between replicates and plates was assessed with 30 test samples and controls. RESULTS: Assays were able to detect P. falciparum antigen-specific antibodies for all isotypes and subclasses in samples from malaria-exposed individuals, with low background signal in blank wells. Levels detected in malaria-naive individuals were overall low except for IgM. For the IgG2 and IgE assays, a triple sandwich was required for sensitivity. Standard curves with 5-parameter logistic fit were successfully obtained in all assays. The coefficients of variation for measurements performed in different days were all <30%, and <5% when comparing duplicates from the same plate. CONCLUSION: The isotype/subclass assays developed here were sensitive, specific, reproducible and of adequate quantification dynamic range. They allow performing detailed immuno-profiling to large panels of P. falciparum antigens to address naturally- and vaccine-induced Ig responses and elucidate correlates of malaria protection, and could also be applied to other antigenic panels. PMID- 29397158 TI - Prospective Cohort Study of Breastfeeding and the Risk of Childhood Asthma. AB - OBJECTIVES: To study whether the duration of breastfeeding and time for introduction of complementary foods was associated with the risk of childhood asthma. STUDY DESIGN: We used data from the Norwegian Mother and Child Study, a nationwide prospective cohort study that recruited pregnant women from across Norway between 1999 and 2008. Children with complete data of breastfeeding up to 18 months and current age >7 years were eligible (n = 41 020). Asthma as the primary outcome was defined based on >=2 dispensed asthma medications at age 7 years registered in the Norwegian Prescription Database. We used log-binomial regression models to obtain crude relative risks (RRs) in the main analysis, and adjusted for selected confounders in multivariable analyses. RESULTS: For duration of any breastfeeding, 5.9% of infants breastfed <6 months (adjusted RR [aRR] 1.05, 0.93-1.19) and 4.6% breastfed 6-11 months (aRR 0.96, 0.87-1.07) had dispensed asthma medications at age 7 years compared with 4.6% of infants breastfed >=12 months (Ptrend .62). Infants still breastfed at 6 months, but introduced to complementary foods <4 months and 4-6 months, had an aRR of 1.15 (0.98-1.36) and 1.09 (0.94-1.27) respectively, compared with infants fully breastfed for 6 months (Ptrend .09). Ages at introduction of solids or formula separately were not significant predictors (Ptrend .16 and .08, respectively). CONCLUSIONS: We found no association between duration of breastfeeding or age of introduction to complementary foods and asthma at age 7 years. PMID- 29397159 TI - Placental Pathology in Neonatal Stroke: A Retrospective Case-Control Study. AB - OBJECTIVE: To assess the association of placental abnormalities with neonatal stroke. STUDY DESIGN: This retrospective case-control study at 3 academic medical centers examined placental specimens for 46 children with neonatal arterial or venous ischemic stroke and 99 control children without stroke, using a standard protocol. Between-group comparisons used chi2 and Fisher exact t test. Correlations used Spearman correlation coefficient. RESULTS: Case placentas were more likely than controls to meet criteria for >=1 of 5 major categories of pathologic abnormality (89% vs 62%; OR, 5.1; 95% CI, 1.9-14.0; P = .0007) and for >=2 categories (38% vs 8%; OR, 7.3; 95% CI, 2.9-19.0; P < .0001). Fetal vascular malperfusion occurred in 50% of cases and 17% of controls (OR, 4.8; 95% CI, 2.2 10.5; P = .0001). Amniotic fluid inflammation occurred in 46% of cases with arterial ischemic stroke vs 25% of controls (OR, 2.6; 95% CI, 1.1-6.1; P = .037). There was evidence of a "stress response" (meconium plus elevated nucleated red blood cells) in 24% of cases compared with 1% of controls (OR, 31; 95% CI, 3.8 247.0; P < .0001). CONCLUSIONS: Placental abnormality was more common in children with neonatal stroke compared with controls. All placental findings represent subacute-to-chronic intrauterine stressors. Placental thrombotic processes were associated with both arterial and venous stroke. Our findings provide evidence for specific mechanisms that may predispose to acute perinatal stroke. Amniotic fluid inflammation associated with neonatal arterial ischemic stroke deserves further investigation. PMID- 29397160 TI - Effect of Dietary Counseling on a Comprehensive Metabolic Profile from Childhood to Adulthood. AB - OBJECTIVES: To study the effects of repeated, infancy-onset dietary counseling on a detailed metabolic profile. Effects of dietary saturated fat replacement on circulating concentrations of metabolic biomarkers still remain unknown. STUDY DESIGN: The Special Turku Coronary Risk Factor Intervention Project (STRIP) study is a longitudinal, randomized atherosclerosis prevention trial in which repeated dietary counseling aimed at reducing the proportion of saturated fat intake. Nuclear magnetic resonance metabolomics quantified circulating metabolites from serum samples assessed at age 9 (n = 554), 11 (n = 553), 13 (n = 508), 15 (n = 517), 17 (n = 457), and 19 (n = 417) years. RESULTS: The intervention reduced dietary intake of saturated fat (mean difference in daily percentage of total energy intake: -2.1 [95% CI -1.9 to -2.3]) and increased intake of polyunsaturated fat (0.6 [0.5-0.7]). The dietary counseling intervention led to greater serum proportions of polyunsaturated fatty acids (P < .001), with greater proportions of both circulating omega-3 (P = .02) and omega-6 (P < .001) fatty acids. The proportion of saturated fatty acids in serum was lower for both boys and girls in the intervention group (P < .001), whereas the serum proportion of monounsaturated fat was lower for boys in the intervention group only (P < .001). The intervention also reduced circulating intermediate-density lipoprotein and low-density lipoprotein lipid concentrations (P < .01). Dietary intervention effects on nonlipid biomarkers were minor except from greater concentrations of glutamine in the intervention group. CONCLUSIONS: Repeated dietary counseling from infancy to early adulthood yielded favorable effects on multiple circulating fatty acids and lipoprotein subclass lipids, particularly in boys. These molecular effects substantiate the beneficial role of saturated fat replacement on the metabolic risk profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00223600. PMID- 29397161 TI - Phenotypic and genotypic characterization of antimicrobial resistance profiles in Streptococcus dysgalactiae isolated from bovine clinical mastitis in 5 provinces of China. AB - Bovine mastitis is among the most prevalent and costly diseases of dairy animals and is caused by a variety of bacterial pathogens including Streptococcus dysgalactiae. However, comprehensive studies reporting the prevalence and antimicrobial resistance profiles of S. dysgalactiae isolated from bovine mastitis are scarce. Therefore, this study was to investigate the occurrence of S. dysgalactiae associated with bovine clinical mastitis, to assess their antimicrobial resistance profiles, and to analyze the phenotypic and genotypic profiling of resistant isolates. In total, 1,180 milk samples were collected from dairy cows with clinical mastitis belonging to 74 commercial dairy herds located in 14 provinces of China from January 2014 to May 2016. Overall S. dysgalactiae isolates were recovered from 88 (7.5%) of the mastitic milk samples. The antimicrobial susceptibility of these isolates was tested against 8 antimicrobial agents by using minimum inhibitory concentrations. Results showed that 82 (93.2%) isolates expressed resistance to more than one antimicrobial agent. Antimicrobial resistance was highest against kanamycin (89.8%), sulfonamide (83.0%), and streptomycin (58.0%), which can be attributed to the intrinsic resistance for most of Streptococcus spp. against those antimicrobial substances. Strikingly, 30 (34.1%) and 12 (13.6%) isolates were found resistant to cephalexin and ceftriaxone, respectively. BlaTEM, ermB, and tetM were the most prevalent resistance genes. All isolates carried at least one of all tested resistance genes. Also, 1.1, 12.5, 18.2, 36.4, and 31.8% of isolates were positive for at least one tested resistance gene in 1, 2, 3, 4, or 5 classes of antimicrobials. Survival analysis showed a significant association between ermB and survival of the S. dysgalactiae isolates at increasing erythromycin concentrations. No other statistically significant associations were observed between the phenotypic and genotypic resistance profiles. This study concludes a considerable prevalence of S. dysgalactiae associated with bovine mastitis in dairy herds of China and these isolates exhibited high resistance rates to tested antimicrobials, coupled with high occurrence of resistance genes. Both the prevalence of S. dysgalactiae and their antimicrobial resistance profiles strongly varied among dairy herds, demonstrating the need for antimicrobial susceptibility surveillance at the herd level to ensure optimal therapeutic results. PMID- 29397162 TI - Detection of evaluation bias caused by genomic preselection. AB - The aim of this simulation study was to investigate whether it is possible to detect the effect of genomic preselection on Mendelian sampling (MS) means or variances obtained by the MS validation test. Genomic preselection of bull calves is 1 additional potential source of bias in international evaluations unless adequately accounted for in national evaluations. Selection creates no bias in traditional breeding value evaluation if the data of all animals are included. However, this is not the case with genomic preselection, as it excludes culled bulls. Genomic breeding values become biased if calculated using a multistep procedure instead of, for example, a single-step method. Currently, about 60% of the countries participating in international bull evaluations have already adopted genomic selection in their breeding schemes. The data sent for multiple across-country evaluation can, therefore, be very heterogeneous, and a proper validation method is needed to ensure a fair comparison of the bulls included in international genetic evaluations. To study the effect of genomic preselection, we generated a total of 50 replicates under control and genomic preselection schemes using the structures of the real data and pedigree from a medium-size cow population. A genetic trend of 15% of the genetic standard deviation was created for both schemes. In carrying out the analyses, we used 2 different heritabilities: 0.25 and 0.10. From the start of genomic preselection, all bulls were genomically preselected. Their MS deviations were inflated with a value corresponding to selection of the best 10% of genomically tested bull calves. For cows, the MS deviations were unaltered. The results revealed a clear underestimation of bulls' breeding values (BV) after genomic preselection started, as well as a notable deviation from zero both in true and estimated MS means. The software developed recently for the MS validation test already produces yearly MS means, and they can be used to devise an appropriate test. Mean squared true MS of genomically preselected bulls was clearly inflated. After correcting for the simulated preselection bias, the true genetic variance was smaller than the parametric value used to simulate BV, and also below the variance based on the estimated BV. Based on this study, the lower the trait's heritability, the stronger the bias in estimated BV and MS means and variances. Daughters of genomically preselected bulls had higher true and estimated BV compared with the control scheme and only slightly elevated MS means, but no effect on genetic variances was observed. PMID- 29397163 TI - Whole-genome sequencing reveals the mechanisms for evolution of streptomycin resistance in Lactobacillus plantarum. AB - In this research, we investigated the evolution of streptomycin resistance in Lactobacillus plantarum ATCC14917, which was passaged in medium containing a gradually increasing concentration of streptomycin. After 25 d, the minimum inhibitory concentration (MIC) of L. plantarum ATCC14917 had reached 131,072 ug/mL, which was 8,192-fold higher than the MIC of the original parent isolate. The highly resistant L. plantarum ATCC14917 isolate was then passaged in antibiotic-free medium to determine the stability of resistance. The MIC value of the L. plantarum ATCC14917 isolate decreased to 2,048 ug/mL after 35 d but remained constant thereafter, indicating that resistance was irreversible even in the absence of selection pressure. Whole-genome sequencing of parent isolates, control isolates, and isolates following passage was used to study the resistance mechanism of L. plantarum ATCC14917 to streptomycin and adaptation in the presence and absence of selection pressure. Five mutated genes (single nucleotide polymorphisms and structural variants) were verified in highly resistant L. plantarum ATCC14917 isolates, which were related to ribosomal protein S12, LPXTG motif cell wall anchor domain protein, LrgA family protein, Ser/Thr phosphatase family protein, and a hypothetical protein that may correlate with resistance to streptomycin. After passage in streptomycin-free medium, only the mutant gene encoding ribosomal protein S12 remained; the other 4 mutant genes had reverted to the wild type as found in the parent isolate. Although the MIC value of L. plantarum ATCC14917 was reduced in the absence of selection pressure, it remained 128-fold higher than the MIC value of the parent isolate, indicating that ribosomal protein S12 may play an important role in streptomycin resistance. Using the mobile elements database, we demonstrated that streptomycin resistance related genes in L. plantarum ATCC14917 were not located on mobile elements. This research offers a way of combining laboratory evolution techniques and whole genome sequencing for evaluating antibiotic resistance in probiotics. PMID- 29397164 TI - Effect of isoflurane alone or in combination with meloxicam on the behavior and physiology of goat kids following cautery disbudding. AB - Cautery disbudding of goat kids is painful, but may be alleviated with pain mitigation. We therefore evaluated the effect of administering general anesthesia (isoflurane) or a nonsteroidal anti-inflammatory drug (meloxicam) on goat kid behavior and physiology following cautery disbudding. Trial 1 (n = 12/treatment) evaluated behavioral responses in 72 female Saanen dairy goat kids (mean +/- standard error of the mean; 3.9 +/- 0.15 d old) and trial 2 (n = 10/treatment) evaluated physiological responses in 60 female Saanen dairy goat kids (4.3 +/- 0.14 d old). Goat kids were randomly assigned to 1 of 6 treatment groups that were either (1) sham-handled only (simulated disbudding; SHAM) or disbudded with (2) no pain relief (CAUT), (3) isoflurane gas (ISO), (4) isoflurane and s.c. meloxicam combined (ISO+MEL), (5) meloxicam s.c. (0.5 mg/kg of body weight; I MEL), or (6) oral meloxicam (0.2 mg/kg of body weight; O-MEL). Head shaking, head scratching, self-grooming, feeding, and body shaking were continuously video recorded for 24 h pre- and post-treatment. Lying behavior was recorded continuously for 24 h pre- and post-treatment using accelerometers. Plasma cortisol, glucose, and lactate concentrations were measured from blood samples collected immediately before treatment (baseline) and at 15, 60, and 120 min post treatment. Body temperature was measured immediately after blood sampling at all blood sampling time points. Head shaking and body shaking frequencies were 50% higher in CAUT than SHAM kids 5 min post-treatment; ISO+MEL and ISO kids performed 25% less body shakes than CAUT kids. Head scratching durations 1 h post treatment were higher in CAUT than SHAM kids, whereas O-MEL were similar to SHAM kids from 2 h post-treatment. Self-grooming, feeding, and lying did not differ between groups. Cortisol concentrations were higher in CAUT than SHAM kids (156.4 +/- 26.41 and 104.1 +/- 26.41 nmol/L, respectively), whereas ISO+MEL and ISO kids (88.3 +/- 26.41 and 113.2 +/- 26.41 nmol/L, respectively) had lower cortisol concentrations than CAUT kids over the 2-h sampling period. Moreover, O-MEL and I MEL kids (163.0 +/- 26.41 and 130.9 +/- 26.41 nmol/L, respectively) had similar cortisol concentrations to CAUT kids. We found no evidence that plasma glucose and lactate concentrations or body temperature were affected by treatment. The administration of isoflurane, with or without meloxicam, appeared to reduce pain associated with cautery disbudding. PMID- 29397165 TI - Plasma glucose and nonesterified fatty acids response to epinephrine challenges in dairy cows during a 670-d lactation. AB - This experiment investigated the metabolic response to a 2-dose epinephrine challenge of dairy cows undergoing an extended lactation. Twelve multiparous Holstein-Friesian cows that calved in late winter in a seasonally calving pasture based dairying system were managed for a 670-d lactation by delaying rebreeding. In each of four 40-d experimental periods commencing at 73, 217, 422, and 520 (+/ 9.1) d in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM), supplemented with 1 (CON; n = 6) or 6 kg of grain (GRN; n = 6) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with a jugular catheter during the final week of each experimental period. Two doses of epinephrine (0.1 and 1.6 ug/kg of body weight) were infused via the catheter 2 h apart to each cow at approximately 100, 250, 460, and 560 DIM. Blood plasma concentrations of glucose and nonesterified fatty acids (NEFA) were measured before and after infusions. Cows in the GRN treatment had greater milk yield, milk fat and protein yields, and body weight than cows in the CON treatment. The maximum plasma glucose concentration was observed at 100 DIM for both the low and high doses of epinephrine. Thus, sensitivity and responsiveness to exogenous epinephrine were greater during early lactation, coinciding with increased priority of milk synthesis. Both the sensitivity and responsiveness to epinephrine decreased with decreasing milk yield, as measured by the acute appearance of NEFA in the plasma. Increased plasma glucose and NEFA clearance rates before 300 DIM indicated greater uptake of these substrates by the mammary gland for milk synthesis in early and mid lactation. These results support previous findings that major changes occur in terms of adipose tissue metabolism during extended lactations. Overall, sensitivity to epinephrine was not affected by diet, but responsiveness was greater in cows fed the GRN diet. The endocrine regulation of nutrient partitioning throughout traditional and extended lactations is complex, with many interactions between stage of lactation, diet, and milk yield potential. PMID- 29397166 TI - Plane of nutrition before and after 6 months of age in Holstein-Friesian bulls: II. Effects on metabolic and reproductive endocrinology and identification of physiological markers of puberty and sexual maturation. AB - The aim of this study was (1) to examine the effect of plane of nutrition during the first and second 6 mo of life on systemic concentrations of reproductive hormones and metabolites in Holstein-Friesian dairy bulls, and (2) to establish relationships with age at puberty and postpubertal semen production potential. Holstein-Friesian bull calves (n = 83) with a mean (standard deviation) age and body weight of 17 (4.4) d and 52 (6.2) kg, respectively, were assigned to a high or low plane of nutrition for the first 6 mo of life. At 24 wk of age, bulls were reassigned, within treatment, either to remain on the same diet or to switch to the opposite diet until puberty, resulting in 4 treatment groups: high-high, high low, low-low, and low-high. Monthly blood samples were analyzed for metabolites (albumin, urea, total protein, beta-hydroxybutyrate, glucose, nonesterified fatty acid, triglycerides and creatinine), insulin, insulin-like growth factor-1, leptin, adiponectin, FSH, and testosterone. A GnRH challenge was carried out at 16 and 32 wk of age (n = 9 bulls per treatment). Blood was collected at 15-min intervals for 165 min, with GnRH administered (0.05 mg/kg of body weight, i.v.) immediately after the third blood sample. Blood samples were subsequently analyzed for LH, FSH, and testosterone. Stepwise regression was used to detect growth and blood measurements to identify putative predictors of age at puberty and subsequent semen quality traits. Metabolic hormones and metabolites, in general, reflected metabolic status of bulls. Although FSH was unaffected by diet, it decreased with age both in monthly samples and following GnRH administration. Testosterone was greater in bulls on the high diet before and after 6 mo of age. Testosterone concentrations increased dramatically after 6 mo of age. Luteinizing hormone was unaffected by diet following GnRH administration but basal serum LH was greater in bulls on a high diet before 6 mo of age. In conclusion, the plane of nutrition offered before 6 mo of age influenced metabolic profiles, which are important for promoting GnRH pulsatility, in young bulls. PMID- 29397167 TI - Incorporating white clover (Trifolium repens L.) into perennial ryegrass (Lolium perenne L.) swards receiving varying levels of nitrogen fertilizer: Effects on milk and herbage production. AB - White clover (Trifolium repens L.; clover) can offer a superior nutritional feed compared with perennial ryegrass (Lolium perenne L.; PRG) and offers an additional or alternative source (or both) of N for herbage production. The objective of this study was to investigate the effect of including clover into PRG swards receiving 150 (Cl150) or 250 kg of N/ha (Cl250) compared with a PRG only sward receiving 250 kg of N/ha (Gr250) on herbage production, milk production, and herbage dry matter intake (DMI) in an intensive grass-based spring calving milk production system over 2 full lactations. A farm systems experiment was established in February 2013, and conducted over 2 grazing seasons [2013 (yr 1) and 2014 (yr 2)]. In February 2013 (yr 1), 42 Holstein-Friesian spring-calving dairy cows, and in February 2014 (yr 2), 57 Holstein-Friesian spring-calving dairy cows were allocated to graze the Cl150, Cl250, and Gr250 swards (n = 14 in yr 1 and n = 19 in yr 2) from February to November, at a stocking rate of 2.74 cows/ha. Herbage DMI was estimated twice in yr 1 (May and September) and 3 times in yr 2 (May, July, and September). Treatment did not have a significant effect on annual herbage production. Sward clover content was greater on the Cl150 treatment than the Cl250 treatment. The cows grazing both clover treatments (Cl250 and Cl150) produced more milk than the cows grazing Gr250 from June until the end of the grazing season. A significant treatment by measurement period interaction was observed on total DMI. In May, the cows on the Cl250 treatment had the greatest DMI. In July, the cows on the clover treatments had greater DMI than those on the Gr250 treatment, whereas in September, the cows on the Cl150 treatment had the lowest DMI. In conclusion, including clover in a PRG sward grazed by spring-calving dairy cows can result in increased animal performance, particularly in the second half of lactation. Reducing N fertilizer application to 150 kg of N/ha on grass-clover swards did not reduce herbage production compared with grass-only swards receiving 250 kg of N/ha. White clover can play an integral role in intensive grazing systems in terms of animal performance and herbage production. PMID- 29397168 TI - Short communication: Comparison of a palmitic acid-enriched triglyceride supplement and calcium salts of palm fatty acids supplement on production responses of dairy cows. AB - The objective of our study was to evaluate the effects of feeding a palmitic acid enriched triglyceride supplement or a calcium salts of palm fatty acid (FA) supplement on nutrient digestibility and production responses of mid-lactation dairy cows. Fifteen Holstein cows (139 +/- 39 d in milk) were randomly assigned to treatment sequence in a 3 * 3 Latin square design. Treatments were a control diet (CON; no fat supplement) and 1.5% of FA added either as a palmitic acid enriched triglyceride supplement (PA-TG) or as calcium salts of palm FA supplement (Ca-FA). Fat-supplemented treatments did not affect dry matter intake (DMI) compared with CON, but Ca-FA reduced DMI compared with PA-TG. Compared with CON, fat-supplemented treatments increased 18-carbon FA digestibility by 2.0 percentage units but did not affect digestibility of total FA or 16-carbon FA. Compared with Ca-FA, PA-TG reduced total FA digestibility by 8.7 percentage units due to a decrease in 16-carbon FA digestibility (21.7 percentage units). Both fat supplements increased neutral detergent fiber (NDF) digestibility compared with CON (3.90 percentage units), and PA-TG tended to increase NDF digestibility by 1.60 percentage units compared with Ca-FA. Compared with CON, fat-supplemented treatments increased milk yield (1.05 kg/d), 3.5% fat-corrected milk yield (2.20 kg/d), and energy-corrected milk yield (1.80 kg/d). Also, PA-TG increased milk fat yield (50 g/d) and milk energy output (1.0 Mcal/d) and tended to increase milk fat content (0.07 percentage units) and energy-corrected milk yield (1.0 kg/d) compared with Ca-FA. Fat-supplemented treatments reduced the yield of de novo milk FA (23 g/d) and increased the yields of mixed (43 g/d) and preformed (52 g/d) milk FA compared with CON. The PA-TG treatment increased the yield of 16 carbon (66 g/d) milk FA compared with Ca-FA, whereas Ca-FA increased the yield of preformed (60 g/d) milk FA. Fat-supplemented treatments increased intake of net energy for lactation by 1.80 Mcal/d, milk energy output by 1.30 Mcal/d, and energy in body reserves by 0.30 Mcal/d compared with CON. The Ca-FA treatment increased energy allocated to body reserves (0.60 Mcal/d), energy partitioning toward body reserves (1.20 percentage units), and body condition score change (0.06 units), and tended to increase body weight change (0.16 kg/d) and body condition score (0.08 units) compared with PA-TG. In conclusion, feeding a palmitic acid-enriched triglyceride supplement increased milk energy output due to increased yields of milk and milk fat, whereas feeding a calcium salts of palm FA supplement increased FA digestibility and energy partitioned to body reserves. PMID- 29397169 TI - Inhibition of arginase via jugular infusion of Nomega-hydroxy-nor-l-arginine inhibits casein synthesis in lactating dairy cows. AB - A previous in vitro study revealed that Arg elicits positive effects on casein synthesis through alterations of the Arg-ornithine pathway in bovine mammary epithelial cells. The main purpose of this work was to determine the effects of arginase inhibition using Nomega-hydroxy-nor-l-arginine (nor-NOHA) on milk protein synthesis in vivo. Six healthy Chinese Holstein cows with similar body weight (550.0 +/- 20 kg; means +/- standard deviation), parity (4), body condition score (3.0), milk yield (21.0 +/- 1.0 kg), and days in milk (80 +/- 2) were selected and randomly assigned to 3 treatments in a replicated 3 * 3 Latin square design with 22 d for each period (7 d for infusion and 15 d for washout). The treatments were (1) control: saline infusion; (2) nor-NOHA: infusion of 125 mg/L of nor-NOHA; (3) nor-NOHA + Arg: infusion of 125 mg/L of nor-NOHA with 9.42 g/L of Arg. The activity of enzymes related to Arg metabolism, milk protein synthesis, and expression of AA transporters was determined. The infusion of nor NOHA decreased the activity of arginase but had no effect on the activity of ornithine decarboxylase and nitric oxide synthase in serum, and these responses were the same at the gene expression level in mammary gland. In addition, the infusion of nor-NOHA also reduced protein and fat synthesis in milk but had no effect on milk yield. When Arg was infused with nor-NOHA, the activity of total arginase, ornithine decarboxylase, and nitric oxide synthase, and the concentration of casein, protein, and fat in milk did not change compared with the nor-NOHA group, but the milk protein yield, the expression of some Arg transporters (SLC7A5 and SLC7A8), and milk yield increased. Overall, results verified previous in vitro findings indicating that synthesis of casein protein is closely regulated by the Arg-ornithine pathway in bovine mammary gland. PMID- 29397170 TI - Cross-sectional study to identify staphylococcal species isolated from teat and inguinal skin of different-aged dairy heifers. AB - The purpose of this study was to describe the prevalence and distribution of staphylococcal species on the teat and inguinal skin of dairy heifers across the various stages of the heifer life cycle. The cross-sectional study included 106 Holstein heifers with an age range of 0 d to 27 mo that were selected from 11 different groups, based on housing type and age, on a single dairy operation. A composite swabbing sample including all 4 teats and a second composite sample including both inguinal regions of each heifer were collected using gas sterilized electrostatic dusters (Swiffers; Procter and Gamble, Cincinnati, OH). Swabbing samples were mixed with 10 mL of sterile saline, agitated, and cultured on mannitol salt agar plates. At 24 h, plates were read and up to 10 staphylococcal colonies were saved for further analysis. Staphylococcal isolates were speciated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR amplification and partial sequencing of rpoB or tuf. The prevalence of staphylococci was compared between the inguinal and teat regions using the chi-squared or Fisher's exact test, as applicable. Logistic regression models were used to investigate the relationship between a heifer's age (treated as a quantitative continuous variable) and the probability of isolating a given staphylococcal species from a given body site (inguinal region or teats). Overall, the most common species identified were Staphylococcus haemolyticus followed by Staphylococcus chromogenes, Staphylococcus xylosus, Staphylococcus devriesei, and Staphylococcus sciuri. Staphylococcus aureus was more prevalent on the teat than in the inguinal region, whereas Staphylococcus arlettae was more prevalent in the inguinal region than on the teat. All other staphylococcal species were as likely to be found on the teat skin as the inguinal region skin. Isolation from the inguinal and teat skin was associated with age for Staphylococcus agnetis, S. chromogenes, S. devriesei, Staphylococcus equorum, S. haemolyticus, Staphylococcus lentus, S. sciuri, Staphylococcus vitulinus, and S. xylosus. The probability of finding S. chromogenes and S. agnetis on the teat and inguinal region increased with age, whereas the probability of S. devriesei and S. haemolyticus decreased with age. This study provides further insight into the ecology of staphylococcal species involved in heifer mastitis. PMID- 29397171 TI - Udder health in Canadian dairy heifers during early lactation. AB - Mastitis is the most prevalent and costly disease in dairy cattle worldwide, with implications for animal health and welfare as well as production and economics. Nonlactating heifers are an often-neglected group of animals concerning mastitis management, as they are assumed to be free of mastitis. An observational field study was conducted between 2007 and 2008 on 91 dairy herds across Canada, representative of provincial averages of bulk milk somatic cell count (BMSCC) and barn type. The aims of that study were to (1) estimate in early-lactating heifers overall and pathogen-specific incidence rate of clinical mastitis (IRCM), prevalence of intramammary infection (IMI), and prevalence of subclinical mastitis (SCM; defined as SCC >=200,000 cells/mL); (2) compare these udder health parameters between heifers and multiparous cows; and (3) determine regional patterns and variations in these udder health parameters across BMSCC categories. During the first day of lactation, IRCM was higher in heifers than in multiparous cows (99 vs. 48 cases per 10,000 quarter-days at risk, respectively). Clinical mastitis affected 4% of heifers (0.73 cases per 100 quarters) in the first 30 d after calving, with the most common pathogens isolated being Staphylococcus aureus and Escherichia coli, whereas S. aureus and non-aureus staphylococci were the most commonly isolated pathogens in multiparous cows. The IRCM in heifers was highest in Ontario heifers, but overall IRCM did not vary by BMSCC category and it was only higher in multiparous cows than heifers in high-BMSCC Ontario herds. Intramammary infections were present in 33% of heifer quarters, with non-aureus staphylococci the most commonly isolated group of bacteria in both heifers (26% of quarters) and multiparous cows (18% of quarters). Pathogen-specific prevalence of IMI did not differ between heifers and multiparous cows, but we noted regional differences and differences across BMSCC categories in pathogen-specific prevalence of IMI. Prevalence of SCM in heifers was 13.6% and was lowest in Alberta herds. In all regions, SCM prevalence was higher in multiparous cows than in heifers. In conclusion, udder health of Canadian dairy heifers was similar to that of other countries, demonstrating the importance of the issue. Differences between heifers and multiparous cows early in lactation highlighted the need for management practices to target the precalving period in heifers, when exposure to risk factors differs from that in lactating cows. PMID- 29397172 TI - Immobilization of whole cells of Lactococcus lactis containing high levels of a hyperthermostable beta-galactosidase enzyme in chitosan beads for efficient galacto-oligosaccharide production. AB - Galacto-oligosaccharides (GOS) are prebiotic food ingredients that are proposed to stimulate the growth of beneficial gut microorganisms, particularly bifidobacteria. Previously, we developed a method for efficient GOS production using whole cells of Lactococcus lactis containing high levels of a hyper thermostable beta-galactosidase enzyme from Sulfolobus solfataricus. In this study, a recombinant DNA removal and whole-cell enzyme immobilization process was developed to produce GOS from lactose before removal of the immobilized whole cell enzyme, which could be reused for subsequent applications. Chitosan was found to be a superior immobilization material compared with alginate, as it retained its bead structure during the high temperature (90 degrees C) used here for GOS production. Prior to immobilization, the recombinant DNA was degraded in the whole cells using UV treatment, resulting in an immobilized whole-cell enzyme that was free of recombinant DNA and with minimum effect on the efficiency of the enzyme. The optimum pH and temperature for GOS synthesis using the chitosan beads was pH = 5.5 and 90 degrees C. The highest GOS production using the chitosan beads occurred with 40% initial lactose resulting in 150 g/L of GOS (tri oligosaccharides and tetra-oligosaccharides) in addition to di-oligosaccharide GOS products that were not quantified. Notably, the highest lactose conversion rate was found using lower starting lactose concentrations, with more than 60% conversion into tri-oligosaccharides and tetra-oligosaccharides. The immobilized enzyme retained ~50% activity after 2 cycles of GOS production. In conclusion, the chitosan-immobilized whole-cell enzyme can be used for efficient GOS production that is free of the whole-cell enzyme as well as detectable recombinant DNA. PMID- 29397173 TI - Short communication: Associations of feeding behavior and milk production in dairy cows. AB - Identification of the associations of cow feeding behavior with productivity is important for supporting recommendations of strategies that optimize milk yield and composition. The objective of this study was to identify associations between measures of feeding behavior and milk production using data collated from studies of the feeding behavior of lactating dairy cows. A database containing behavior and production data for 132 dairy cow-week observations (mean of 7 d of consecutive data per cow) was assembled from 5 studies. Cows averaged (mean +/- standard deviation) 1.8 +/- 0.9 lactations, 108.4 +/- 42.7 d in milk, and 654.6 +/- 71.4 kg of body weight during each observation week. Production data included dry matter intake (27.0 +/- 3.1 kg/d), milk yield (43.0 +/- 7.0 kg/d), milk fat content (3.60 +/- 0.49%), and milk protein content (3.05 +/- 0.25%). Behavioral data included feeding time (230.4 +/- 35.5 min/d), feeding rate (0.13 +/- 0.03 kg/min), meal frequency (9.0 +/- 2.0 meals/d), meal size (3.2 +/- 0.9 kg/meal), daily mealtime (279.6 +/- 51.7 min/d), and rumination time (516.0 +/- 90.7 min/d). Data were analyzed in multivariable mixed-effect regression models to identify which behavioral variables, when accounting for other cow-level factors (days in milk, parity, and body weight) and dietary characteristics (forage level, nutrient content, and particle distribution), were associated with measures of production. Dry matter intake was associated with feeding time (+0.02 kg/min) and tended to be associated with rumination time (+0.003 kg/min) and meal frequency (+0.2 kg/meal). Similarly, milk yield was associated with feeding time (+0.03 kg/min) and rumination time (+0.02 kg/min), and tended to be associated with meal frequency (+0.3 kg/meal). Milk fat yield was associated with meal frequency (+0.02 kg/meal). Overall, our results suggest that milk yield and component production may be improved in situations where cows are able to increase their time spent feeding, in more frequent meals, and time spent ruminating. PMID- 29397174 TI - Short communication: Test of the relationship between prepartum milk leakage and blood calcium concentration in Holstein cows-An observational study. AB - Prepartum milk leakage happens in some pregnant dairy cows close to calving. It has been hypothesized that low blood Ca is a cause of this event. To investigate the possible reason(s) of milk leakage, 137 multiparous pregnant Holstein cows were enrolled in the experiment and categorized by the presence (72 cows; leak group) or lack (65 cows; control group) of milk leakage before calving. The concentrations of Ca and P and the length of the teat were measured for all cows. Data showed that Ca concentration was not different between cows in the leak group (7.90 mg/dL) and those in the control group (7.99 mg/dL). Moreover, neither P concentration (4.62 vs. 4.54 mg/dL) nor teat length (4.28 vs 4.10 cm) differed between leak and control groups. Milk yield was greater for the leak group (53.6 kg/d) compared with the control group (50.1 kg/d) through 4 mo in milk. The leakage did not affect the odds of postpartum disorders such as retained placenta, metritis, mastitis, displaced abomasum, or lameness occurrence. The current results show that hypocalcemia is not a reason for observed prepartum leakage and that cows in the leak group produced more milk in the subsequent lactation period. PMID- 29397175 TI - Short communication: Characterization of Staphylococcus aureus isolated along the raw milk cheese production process in artisan dairies in Italy. AB - Staphylococcus aureus is a common cause of food-borne intoxications. Several staphylococcal food poisoning outbreaks have been linked to consumption of raw milk cheeses and artisanal cheese production. However, information on Staph. aureus isolated from artisanal raw milk cheeses and small-scale dairy production environments is very limited. Therefore, we aimed to characterize Staph. aureus isolated along the artisanal raw milk production chain by determining (1) the population structure, and (2) the presence/absence of enterotoxin genes, mecA/C, and pvl. We collected 276 samples from different production stages (raw milk, whey, curd, brine, drying worktops, and cheese) at 36 artisan dairies in Italy. A total of 102 samples from 25 dairies tested positive for Staph. aureus, with 80% positive samples among the tested artisan cheeses. All isolates were further characterized by spa typing and PCR screening for staphylococcal enterotoxin genes, the mecA/mecC genes characteristic for methicillin-resistant Staph. aureus, and the pvl gene encoding Panton-Valentine leukocidin. The 102 isolates represented 15 different spa types and were assigned to 32 different Staph. aureus strains. The spa type most frequently detected was t2953 (30%), which is associated with genotype B strains causing high within-herd levels of bovine mastitis. In addition, 3 novel spa types (t13269, t13277, and t13278) were identified. Although none of the strains harbored mecA/mecC or pvl, 55% of the isolates exhibited at least one enterotoxin gene. Many strains were present in samples from multiple dairies from different regions and years, highlighting the spread of Staph. aureus in small-scale cheese production plants. Our findings demonstrate that enterotoxigenic Staph. aureus and in particular t2953 (genotype B) isolates commonly occur in artisanal dairies and raw milk cheeses in Italy. It is particularly alarming that 80% of the artisan cheeses sampled in our study were positive for Staph. aureus. These findings stress the need for effective measures preventing staphylococcal food poisoning by limiting Staph. aureus growth and enterotoxin formation along the production chain and in the final product. PMID- 29397176 TI - Imidazole decreases the ampicillin resistance of an Escherichia coli strain isolated from a cow with mastitis by inhibiting the function of autoinducer 2. AB - Extended-spectrum beta-lactamase-positive Escherichia coli is an important causative agent of mastitis in dairy cows that results in reduced milk production and quality, and is responsible for severe economic losses in the dairy industry worldwide. The quorum sensing signaling molecule autoinducer 2 (AI-2) is produced by many species of gram-negative and gram-positive bacteria, and might be a universal language for intraspecies and interspecies communication. Our previous work confirmed that exogenous AI-2 increases the antibiotic resistance of extended-spectrum beta-lactamase-positive E. coli to the beta-lactam group of antibiotics by upregulating the expression of the TEM-type beta-lactamase. In addition, this regulation relies on the function of the intracellular AI-2 receptor LsrR. In the present work, we reported that exogenous imidazole, a furan carbocyclic analog of AI-2, decreases the antibiotic resistance of a clinical E. coli strain to beta-lactam antibiotics by inhibiting the function of AI-2. PMID- 29397177 TI - Effects of microwave on extracellular vesicles and microRNA in milk. AB - This study demonstrates the effects of microwaves on the microRNA (miRNA) content of milk and milk extracellular vesicles (EV). We determined the miRNA concentration in milk subjected to different treatments using real-time PCR and a spectrophotometer. The miRNA expression and total RNA content of the microwaved milk samples were lower when compared with untreated milk. We measured the microstructure and the size distribution by scanning electron microscopy and dynamic light scattering to verify the loss of miRNA in microwaved milk due to damage to the EV. The results revealed that 2 different-sized EV were present and had an average size of 147.50 and 22.14 nm, respectively. Furthermore, acridine orange staining showed that the total RNA content in microwaved milk EV was lower than that in cow milk. These results suggest that EV may confer the protection and the stability of the miRNA in milk. PMID- 29397178 TI - Frequency of extended-spectrum beta-lactamase (ESBL)- and AmpC beta-lactamase producing Enterobacteriaceae in a cheese production process. AB - The aim of this study was to investigate the extended-spectrum beta-lactamase (ESBL) and AmpC beta-lactamase activities of Enterobacteriaceae isolated from raw milk and cheese production line and to determine the probability of transmitting these bacteria to consumers. One hundred seventy-three samples from raw milk and cheese production lines were analyzed; 64 isolates were confirmed as Enterobacteriaceae. Sixteen of 64 isolates (25%) were resistant to at least one cephalosporin according to European Committee on Antimicrobial Susceptibility Testing Standards (EUCAST) and Clinical and Laboratory Standards Institute criteria. Seven of the 16 resistant isolates (43.75%) had confirmed ESBL activity. Additionally, phenotypic AmpC beta-lactamase activity was observed in 31 (48.44%) of 64 Enterobacteriaceae isolates and confirmed in 27 of the 31 strains (89.1%). Overall, 3 isolates showed both ESBL activity and AmpC resistance, 28 isolates were only AmpC resistant, and 5 isolates had ESBL activity alone. Of the 173 samples, the proportions of samples that contained ESBL- and AmpC-producing isolates were 4.64 and 15.6%, respectively. Five of the ESBL-positive isolates (62.5%) and 11 of the AmpC-positive isolates (40.7%) were obtained from bulk milk tanks; therefore, the bulk tank plays a very important role in the spread of antibiotic-resistant bacteria. Periodic cleaning and maintenance of bulk tanks should be performed and recorded. Effective food safety and hygiene practices should significantly reduce cross-contamination in dairy plants. PMID- 29397179 TI - Effect of delaying colostrum feeding on passive transfer and intestinal bacterial colonization in neonatal male Holstein calves. AB - The objective of this study was to investigate the effect of time of first colostrum feeding on the passive transfer of IgG and on bacterial colonization in the intestine of neonatal dairy calves. Twenty-seven male Holstein calves were randomly assigned to 1 of 3 treatments at birth: calves were fed colostrum at 45 min (0 h, n = 9), 6 h (n = 9), or 12 h after birth (n = 9). Calves were fed pooled, heat-treated colostrum (62 g of IgG/L) at their respective feeding times at 7.5% of birth body weight and fed milk replacer at 2.5% of birth body weight per meal every 6 h thereafter. Blood samples were taken every 3 h using a jugular catheter and were analyzed for determination of serum IgG by radial immunodiffusion. At 51 h after birth, calves were euthanized for collection of tissue and digesta of the distal jejunum, ileum, and colon. Quantitative real time PCR was used to estimate the prevalence of Bifidobacterium spp., Lactobacillus spp., Fecalibacterium prausnitzii, Clostridium cluster XIVa, and total Escherichia coli. Delaying colostrum feeding by 6 h (35.6 +/- 1.88%) and 12 h (35.1 +/- 3.15%) decreased the maximum apparent efficiency of absorption of IgG compared with feeding colostrum immediately after birth (51.8 +/- 4.18%) and delayed the time to maximum serum IgG concentration (24 h vs. 15 h, respectively). Moreover, 12-h calves tended to have a lower prevalence of Bifidobacterium spp. (0.12 +/- 0.017%) and Lactobacillus spp. (0.07 +/- 0.019%) associated with the colon mucosa compared with 0-h calves (1.24 +/- 0.648% and 0.26 +/- 0.075%, respectively). In addition, 6-h (0.26 +/- 0.124%) and 12-h (0.49 +/- 0.233%) calves had a lower prevalence of total E. coli associated with ileum mucosa compared with 0-h calves (1.20 +/- 0.458%). These findings suggest that delaying colostrum feeding within 12 h of life decreases the passive transfer of IgG and may delay the colonization of bacteria in the intestine, possibly leaving the calf vulnerable to infections during the preweaning period. PMID- 29397180 TI - Invited review: Mineral absorption mechanisms, mineral interactions that affect acid-base and antioxidant status, and diet considerations to improve mineral status. AB - Several minerals are required for life to exist. In animals, 7 elements (Ca, P, Mg, Na, K, Cl, and S) are required to be present in the diet in fairly large amounts (grams to tens of grams each day for the dairy cow) and are termed macrominerals. Several other elements are termed microminerals or trace minerals because they are required in much smaller amounts (milligrams to micrograms each day). In most cases the mineral in the diet must be absorbed across the gastrointestinal mucosa and enter the blood if it is to be of value to the animal. The bulk of this review discusses the paracellular and transcellular mechanisms used by the gastrointestinal tract to absorb each of the various minerals needed. Unfortunately, particularly in ruminants, interactions between minerals and other substances within the diet can occur within the digestive tract that impair mineral absorption. The attributes of organic or chelated minerals that might permit diet minerals to circumvent factors that inhibit absorption of more traditional inorganic forms of these minerals are discussed. Once absorbed, minerals are used in many ways. One focus of this review is the effect macrominerals have on the acid-base status of the animal. Manipulation of dietary cation and anion content is commonly used as a tool in the dry period and during lactation to improve performance. A section on how the strong ion theory can be used to understand these effects is included. Many microminerals play a role in the body as cofactors of enzymes involved in controlling free radicals within the body and are vital to antioxidant capabilities. Those same minerals, when consumed in excess, can become pro-oxidants in the body, generating destructive free radicals. Complex interactions between minerals can compromise the effectiveness of a diet in promoting health and productivity of the cow. The objective of this review is to provide insight into some of these mechanisms. PMID- 29397181 TI - How benchmarking motivates farmers to improve dairy calf management. AB - Dairy calves often receive inadequate colostrum for successful transfer of passive immunity and inadequate milk to achieve their potential for growth and avoid hunger, but little is known about what motivates farmers to improve calf management around these concerns. Our aim was to assess if and how access to benchmarking reports, providing data on calf performance and peer comparison, would change the ways in which farmers think about calves and their management. During our study, 18 dairy farmers in the lower Fraser Valley (British Columbia, Canada) each received 2 benchmark reports that conveyed information on transfer of immunity and calf growth for their own calves and for other farms in the region. Farmers were interviewed before and after receiving their benchmarking reports to gain an understanding of how they perceived access to information in the reports. We conducted qualitative analysis to identify major themes. Respondents generally saw having access to these data and peer comparisons favorably, in part because the reports provided evidence of how their calves were performing. Benchmarking encouraged farmers to make changes in their calf management by identifying areas needing attention and promoting discussion about best practices. We conclude that some management problems can be addressed by providing farmers better access to data that they can use to judge their success and inform changes. PMID- 29397182 TI - Symposium review: Oxylipids and the regulation of bovine mammary inflammatory responses. AB - Inflammation is a critical aspect of the innate immune system that can determine the outcome of several economically important diseases of dairy cattle such as mastitis. The purpose of the inflammatory response is to eliminate the source of tissue injury and then return tissues to normal function. Aggressive or uncontrolled inflammatory responses, however, can damage host tissues and contribute significantly to the pathophysiology associated with mastitis. A precarious balance between pro-inflammatory and pro-resolving mechanisms is needed to ensure optimal pathogen clearance and a prompt return to immune homeostasis. Therefore, inflammatory responses must be tightly regulated to avoid bystander damage to the milk-synthesizing tissues of the mammary gland. Oxylipids are potent lipid mediators that can regulate all aspects of the inflammatory response. The biosynthetic profiles of oxylipids are dependent on both the availability of diverse polyunsaturated fatty acids substrates and their subsequent metabolism through various oxidizing pathways. Changes in lipid metabolism in dairy cows around parturition can profoundly change the composition and concentration of oxylipids in the mammary gland that may be responsible for dysfunctional inflammatory responses during this time. This review will provide a brief overview of the bovine inflammatory response and the role that oxylipids play in contributing to the onset and resolution of inflammation especially as it pertains to mastitis. Factors associated with periparturient cows that can contribute to dysfunctional regulation of inflammation as a function of altered oxylipid biosynthesis and metabolism also will be described. Understanding the role that oxylipids may play in the development of mastitis is key to developing novel prevention and control programs for the dairy industry. PMID- 29397183 TI - Short communication: Probiotic induction of interleukin-10 and interleukin-12 production by macrophages is modulated by co-stimulation with microbial components. AB - Probiotic lactobacilli stimulate macrophages and dendritic cells to secrete cytokines and thereby regulate the immune responses of the host. The balance of the IL-10 and IL-12 production induced by a probiotic is crucial for determining the direction of the immune response. In the present study, we examined the ability of microbial components to modify IL-10 and IL-12 production induced by a popular probiotic strain, Lactobacillus casei strain Shirota (LcS), which itself predominantly induces IL-12 production. Microbial ligands for toll-like receptor (TLR)3 and TLR5 further enhanced the IL-12 induction by LcS, whereas ligands for TLR2, TLR4, TLR7, and TLR9 converted the cytokine production pattern from IL-12 predominant to IL-10 predominant. These results indicate that the probiotic induction of IL-10 and IL-12 production can be flexibly modified by co stimulation with microbial components. This could explain the variety of immunomodulatory functions (immunoactivation or anti-inflammation) exerted by this probiotic strain. PMID- 29397184 TI - Hot topic: Holder pasteurization of human milk affects some bioactive proteins. AB - The aim of this research was to investigate the effect of Holder pasteurization (HoP; 62.5 degrees C, 30 min) on the protein profile and activities of glutathione peroxidase (GPx) and lysozyme (LZ) in human milk. Over 6 mo of lactation, human milk samples were analyzed before (raw) and after HoP for GPx and LZ activity and electrophoresis protein profile. Holder pasteurization reduced human milk lactoferrin, immunoglobulin fractions, and GPx activity. In addition, GPx activity, which is high in colostrum and transitional milk, was naturally reduced over the 6-mo lactation period. In contrast, HoP did not affect human milk LZ activity. Besides its critical cellular antioxidant role in protecting the organism from oxidative damage, GPx decreases the redox potential of milk, stimulating the growth of anaerobic microorganisms, such as the probiotic Bifidobacterium. Considering the role of lactoferrin in infant health, we conclude that an important part of its function has been inactivated by pasteurization. These compounds should be replaced by human milk banks after the HoP step to recover lost functionality. Otherwise, an alternative technology to HoP that better retains human milk properties should be used by milk banks to eliminate the risk of transmission of infectious agents. PMID- 29397185 TI - Biogenic magnetic nanoparticles in human organs and tissues. PMID- 29397186 TI - Emerging facets in the treatment of patients with hepatopancreaticobiliary malignancies. PMID- 29397187 TI - [Cutaneous leiomyoma: Correlation between dermatopathology and dermatoscopy]. PMID- 29397188 TI - Choroidal Nevi in the Singapore Epidemiology of Eye Disease Study. PMID- 29397189 TI - Dexamethasone Intracameral Drug-Delivery Suspension for Inflammation Associated with Cataract Surgery: A Randomized, Placebo-Controlled, Phase III Trial. AB - PURPOSE: To evaluate the safety and efficacy of an anterior chamber intracameral dexamethasone drug-delivery suspension (IBI-10090; DEXYCU; Icon Bioscience Inc., Newark, CA) that provides medication for up to 21 days with a single application in treating postoperative inflammation in patients undergoing cataract surgery. DESIGN: Prospective, randomized, double-masked, multicenter trial. PARTICIPANTS: Patients with preoperative best-corrected visual acuity of 20/30 to 20/200 undergoing unilateral cataract surgery by phacoemulsification were randomized to receive IBI-10090 or placebo. METHODS: Three hundred ninety-four patients were randomized 1:2:2 to receive 5-MUl injections of placebo or 5-MUl injections of 342 or 517 MUg IBI-10090 dexamethasone drug delivery suspension injected into the anterior chamber at the conclusion of cataract surgery. Patients were followed for 90 days after surgery. MAIN OUTCOME MEASURES: Primary outcome was anterior chamber cell (ACC) clearing (ACC score of 0) in the study eye at postoperative day (POD) 8. Secondary outcome measures were anterior chamber flare and ACC plus flare clearing in the study eye. Ocular and nonocular adverse events were assessed. RESULTS: Anterior chamber cell clearing at POD 8 was achieved in 25.0% of eyes in the placebo group and in 63.1% and 66.0% of eyes in the 342- and 517 MUg treatment groups, respectively (P < 0.001). Anterior chamber flare clearing at POD 8 was achieved by 63.8% of eyes in the placebo group and in 92.4% and 89.1% of eyes in the 342- and 517-MUg IBI-10090 treatment groups, respectively (P < 0.001). Anterior chamber cell plus flare clearing at POD 8 was achieved in 33.8% of eyes receiving placebo and in 63.1% and 67.3% of eyes receiving 342- and 517-MUg IBI-10090, respectively (P < 0.001). Adverse events among the 3 groups were similar, and no serious ocular adverse events were reported up to POD 90. CONCLUSIONS: The IBI-10090 dexamethasone drug-delivery suspension placed in the anterior chamber after cataract surgery at concentrations of 342 and 517 MUg was safe and effective in treating inflammation occurring after cataract surgery and may be an alternative to corticosteroid drop installation in this patient population. PMID- 29397190 TI - Neural correlates of sine-wave speech intelligibility in human frontal and temporal cortex. AB - Auditory speech comprehension is the result of neural computations that occur in a broad network that includes the temporal lobe auditory cortex and the left inferior frontal cortex. It remains unclear how representations in this network differentially contribute to speech comprehension. Here, we recorded high-density direct cortical activity during a sine-wave speech (SWS) listening task to examine detailed neural speech representations when the exact same acoustic input is comprehended versus not comprehended. Listeners heard SWS sentences (pre exposure), followed by clear versions of the same sentences, which revealed the content of the sounds (exposure), and then the same SWS sentences again (post exposure). Across all three task phases, high-gamma neural activity in the superior temporal gyrus was similar, distinguishing different words based on bottom-up acoustic features. In contrast, frontal regions showed a more pronounced and sudden increase in activity only when the input was comprehended, which corresponded with stronger representational separability among spatiotemporal activity patterns evoked by different words. We observed this effect only in participants who were not able to comprehend the stimuli during the pre-exposure phase, indicating a relationship between frontal high-gamma activity and speech understanding. Together, these results demonstrate that both frontal and temporal cortical networks are involved in spoken language understanding, and that under certain listening conditions, frontal regions are involved in discriminating speech sounds. PMID- 29397191 TI - Modulation of intra- and inter-hemispheric connectivity between primary and premotor cortex during speech perception. AB - Primary motor (M1) areas for speech production activate during speechperception. It has been suggested that such activation may be dependent upon modulatory inputs from premotor cortex (PMv). If and how PMv differentially modulates M1 activity during perception of speech that is easy or challenging to understand, however, is unclear. This study aimed to test the link between PMv and M1 during challenging speech perception in two experiments. The first experiment investigated intra-hemispheric connectivity between left hemisphere PMv and left M1 lip area during comprehension of speech under clear and distorted listening conditions. Continuous theta burst stimulation (cTBS) was applied to left PMv in eighteen participants (aged 18-35). Post-cTBS, participants performed a sentence verification task on distorted (imprecisely articulated), and clear speech, whilst also undergoing stimulation of the lip representation in the left M1 to elicit motor evoked potentials (MEPs). In a second, separate experiment, we investigated the role of inter-hemispheric connectivity between right hemisphere PMv and left hemisphere M1 lip area. Dual-coil transcranial magnetic stimulation was applied to right PMv and left M1 lip in fifteen participants (aged 18-35). Results indicated that disruption of PMv during speech perception affects comprehension of distorted speech specifically. Furthermore, our data suggest that listening to distorted speech modulates the balance of intra- and inter hemispheric interactions, with a larger sensorimotor network implicated during comprehension of distorted speech than when speech perception is optimal. The present results further understanding of PMv-M1 interactions during auditory motor integration. PMID- 29397192 TI - Removing small non-enzymatic molecules for biochemical assay of redox regulatory enzymes; An exemplary comments on "Antioxidant responses in gills and digestive gland of oyster Crassostrea madrasensis (Preston) under lead exposure. AB - For biochemical assay of every enzyme including redox regulatory enzymes, any interfering small molecules (ISM) that may cross react with substrates or indirectly influence the reaction, must be removed. Such ISM(s) if present, need to be either neutralized or filtered out both from the sample or from the reaction mixture. This is a standard protocol adapted worldwide and fundamental rule in biochemistry. Without such approach, results obtained from a study that includes enzymatic assays seem to be inaccurate. Such inaccuracy raises question on the use of such data in future, especially as ecotoxic biomarkers. Tissue specific seasonal variation in natural titre of such ISM(s) in organisms leads to give rise counterfeit results. Such a case is highlighted in this correspondence article in relation to assay of redox regulatory enzymes including superoxide dismutase, catalase, especially the enzymes of glutathione system in presence of glutathione (GSH) in sample. This fact is discussed considering a recent publication doi.org/10.1016/j.ecoenv.2017.03.056 in which the authors have measured glutathione enzymes in tissues without removing GSH, that acts as ISM, from the sample. It is inferred that logical and sound scientific practices need to be followed for measuring biochemical activity of all enzymes in general and enzymes of glutathione system in particular. The main objective of this article was to make an alert in scientific society to avoid such mistakes in future. PMID- 29397193 TI - The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. AB - Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA. Phase I and III studies have demonstrated activity and benefit of niraparib in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Phase I testing of niraparib established the maximally tolerated dose of 300mg by mouth (PO) daily, and the phase 3 ENGOT-OV16/NOVA study demonstrated the benefit of niraparib maintenance therapy compared to placebo after completion of and response to platinum-based chemotherapy in both BRCAm and BRCAwt ovarian cancer patient populations. Toxicities seen with niraparib include hematologic, gastrointestinal, fatigue, and cardiovascular. Hematologic toxicities include thrombocytopenia, anemia, neutropenia and leukopenia; upfront dose modification to 200mg niraparib for patients with baseline weight of <=77kg and/or baseline platelets of <=150,000K/uL should be considered to avoid significant hematologic toxicity, especially thrombocytopenia, based on recent analyses of the ENGOT OV16/NOVA study. Cardiovascular toxicities include hypertension, tachycardia, as well as palpitations, and patients should be monitored for hypertension. PARP inhibitors have been associated with low risks of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and the overall risk of AML and MDS is 0.9% of all patients treated with niraparib. Niraparib testing is ongoing in newly diagnosed ovarian cancer patients as maintenance therapy following completion of platinum-based chemotherapy, in BRCAwt cancers as treatment, as well as in combinations with other biologic drugs such as immunotherapy and anti angiogenic agents. PMID- 29397194 TI - Corrigendum to "First venom gland transcriptomic analysis of Iranian yellow scorpion "Odonthubuthus doriae" with some new findings" [Toxicon 120 (2016) 69 77]. PMID- 29397195 TI - Pyridostigmine for the treatment of gastrointestinal symptoms in systemic sclerosis. AB - BACKGROUND/PURPOSE: Symptoms of gastrointestinal dysmotility are common among patients with systemic sclerosis (SSc), and the management of severe cases is often limited by a relative lack of effective interventions. The objective of this case series was to review our experience with pyridostigmine as a treatment for patients with SSc and symptomatic gastrointestinal disease. METHODS: This study evaluated rates of symptom improvement, side effects, medication adherence, and dose ranges for SSc patients prescribed pyridostigmine for refractory gastrointestinal symptoms over a 10-year period at a quaternary referral center. Patients were defined as responders if they remained on pyridostigmine for at least 4 weeks and clinical benefit was documented by the recorded response of the patient or by the treating physician RESULTS: Of 31 patients treated with pyridostigmine for at least 4 weeks, 51.6% reported symptomatic improvement. Constipation was the most commonly improved symptom based on prevalence prior to therapy (noted by 6/20 patients suffering with constipation). Fifteen of 31 patients reported adverse effects, most commonly diarrhea. Throughout the duration of follow-up (median 126 days, range: 28-506 days), pyridostigmine was continued by 81.3% of patients who reported symptomatic benefit and 58.1% of patients overall. CONCLUSIONS: Pyridostigmine holds promise for the treatment of various gastrointestinal symptoms in SSc patients, particularly in patients with refractory constipation. Though side effects may limit its use, most patients who experienced benefit chose to continue therapy. PMID- 29397196 TI - The effect of hydrofluoric acid concentration on the fatigue failure load of adhesively cemented feldspathic ceramic discs. AB - OBJECTIVE: This study investigated the influence of hydrofluoric acid (HF) etching at different concentrations on the fatigue failure load of adhesively cemented feldspathic ceramic discs (Vita Mark II). Besides, their effect on the micromorphology of ceramic surface was investigated. METHODS: Eighty ceramic discs (phi=10 mm; thickness=1.5 mm) were cemented to epoxy supporting discs (phi=10 mm; thickness=2.0mm) using different surface conditioning methods (n=20): nonetched control (CTRL), or etched for 60s with different HF concentrations: 1% (HF1), 5% (HF5), or 10% (HF10). All the ceramic discs received a silane application (Monobond Plus). The epoxy discs were etched with 10% HF for 60s and received a primer coating (Multilink Primer A+B). Adhesively cementation was performed (Multilink Automix), and the assemblies (ceramic discs/epoxy discs) were subjected to cyclic loads in water by a staircase approach (500,000 cycles; 20Hz; initial load=290N; step size=30N). Fatigue failure load data were analyzed using 1-way ANOVA and post-hoc Tukey's tests (alpha=.05). RESULTS: Mean failure load of the HF5 group (255.0+/-23.0N) was significantly lower; HF1 group (301.7+/ 71.0N) presented intermediate values, and the highest values were achieved in CTRL (351.7+/-13.4N) and HF10 (341.7+/-20.6N) groups. All the failures were radial cracks starting from the bonding surface. SIGNIFICANCE: In terms of fatigue failure load, etching with 1% and 5% HF had a deleterious effect on the fatigue behavior of an adhesively cemented feldspathic ceramic, while 10% HF had no negative influence. PMID- 29397197 TI - Accurate Prediction of False ST-Segment Elevation Myocardial Infarction: Ready for Prime Time? AB - : The incidence of inappropriate cardiac catheterization lab activation for treatment of a false ST-segment elevation myocardial infarction (STEMI) has been reported to be 2.6%-36%. Excessive inappropriate catheterization lab activation may be associated with risks to patients, provider fatigue and improper resource usage. HYPOTHESIS: To derive and validate a prediction score to more accurately classify patients with STEMI. METHODS AND RESULTS: We conducted a retrospective cohort analysis of 1144 consecutive patients initially diagnosed with STEMI between September 2008 and January 2013. The incidence of catheterization laboratory activation for false STEMI was 21.4%. Multiple logistic regression identified 8 factors as important for prediction of false STEMI. Using a prediction rule derived from these factors, the area under the curve for differentiating false from true STEMI patients was 0.80 (95% CI: 0.75-0.84). Using objective standards, criteria were defined that had 95% specificity for detecting patients with an incorrect diagnosis of STEMI. IN CONCLUSION: A prediction rule has been derived and validated in a large, racially diverse group to identify false STEMI patients with an incorrect classification rate of 5%, which is an improvement over current clinical practice. Prediction rules may be particularly useful in patients with atypical presentations in which emergent catheterization cannot be achieved rapidly or carries significant patient risk. PMID- 29397199 TI - Viroj Tangcharoensathien: master carpenter of Thai health care. PMID- 29397198 TI - Valganciclovir Use Among Commercially and Medicaid-insured Infants With Congenital CMV Infection in the United States, 2009-2015. AB - PURPOSE: The aim of this study was to assess the clinical characteristics and trends in valganciclovir use among infants diagnosed with congenital cytomegalovirus (CMV) disease in the United States. METHODS: We analyzed data from medical claims dated 2009-2015 from the Truven Health MarketScan(r) Commercial Claims and Encounters and Medicaid databases. We identified infants with a live birth code in the first claim who were continuously enrolled for at least 45 days. Among infants diagnosed with congenital CMV disease, identified by an ICD-9-CM or ICD-10-CM code for congenital CMV infection or CMV disease within 45 days of birth, we assessed data from claims containing codes for any CMV associated clinical condition within the same period, and data from claims for hearing loss and/or valganciclovir within the first 180 days of life. FINDINGS: In the commercial and Medicaid databases, we identified 257 (2.5/10,000) and 445 (3.3/10,000) infants, respectively, diagnosed with congenital CMV disease, among whom 135 (53%) and 282 (63%) had >=1 CMV-associated condition, 30 (12%) and 32 (7%) had hearing loss, and 41 (16%) and 78 (18%) had a claim for valganciclovir. Among infants with congenital CMV disease who had a claim for valganciclovir, 37 (90%) among commercially insured infants and 68 (87%) among Medicaid-insured infants had >=1 CMV-associated condition and/or hearing loss. From 2009 to 2015, the percentages with a claim for valganciclovir increased from 0% to 29% among commercially insured infants and from 4% to 37% among Medicaid-insured infants (P < 0.0001). IMPLICATIONS: During 2009-2015, there was a strong upward trend in valganciclovir claims among insured infants who were diagnosed with congenital CMV disease, the majority of whom had CMV-associated conditions and/or hearing loss. PMID- 29397200 TI - Health systems development in Thailand: a solid platform for successful implementation of universal health coverage. AB - Thailand's health development since the 1970s has been focused on investment in the health delivery infrastructure at the district level and below and on training the health workforce. Deliberate policies increased domestic training capacities for all cadres of health personnel and distributed them to rural and underserved areas. Since 1975, targeted insurance schemes for different population groups have improved financial access to health care until universal health coverage was implemented in 2002. Despite its low gross national income per capita in Thailand, a bold decision was made to use general taxation to finance the Universal Health Coverage Scheme without relying on contributions from members. Empirical evidence shows substantial reduction in levels of out-of pocket payments, the incidence of catastrophic health spending, and in medical impoverishment. The scheme has also greatly reduced provincial gaps in child mortality. Certain interventions such as antiretroviral therapy and renal replacement therapy have saved the lives of adults. Well designed strategic purchasing contributed to efficiency, cost containment, and equity. Remaining challenges include preparing for an ageing society, primary prevention of non communicable diseases, law enforcement to prevent road traffic mortality, and effective coverage of diabetes and tuberculosis control. PMID- 29397201 TI - Are Foley catheters needed after minimally invasive repair of pectus excavatum? AB - BACKGROUND: High narcotic requirements after minimally invasive repair of pectus excavatum (MIRPE) can increase the risk of urinary retention. Placement of intraoperative Foley catheters to minimize this risk is variable. This study determines the rate of urinary retention in this population to guide future practice. MATERIALS AND METHODS: We reviewed retrospectively all patients who underwent MIRPE from January 2012 to July 2016 at 2 academic children's hospitals. Data collected included demographics, BMI, severity of the pectus defect, postoperative pain management, and the incidence of urinary retention and urinary tract infection (UTI). RESULTS: Of 360 total patients who underwent MIRPE, 218 had an intraoperative Foley catheter. Patients with epidural pain control were more likely to receive a Foley catheter. The urinary retention rate was 34% for patients without an intraoperative Foley, and 1% in patients after removal of an intraoperatively placed Foley. Urinary retention was greater with an epidural compared with patient-controlled anesthesia (55% vs 26%, P = .002) in the no intraoperative Foley group. No urinary tract infections were identified. Epidural pain control was the only risk factor on multivariate analysis for retention in patients without an intraoperatively Foley catheter. CONCLUSION: Intraoperative Foley catheters obviate urinary retention without increasing the risk of urinary tract infection after MIRPE. These results will allow surgeons to better counsel patients regarding Foley placement. PMID- 29397202 TI - Nonstructural protein 9 residues 586 and 592 are critical sites in determining the replication efficiency and fatal virulence of the Chinese highly pathogenic porcine reproductive and respiratory syndrome virus. AB - The highly pathogenic porcine reproductive and respiratory syndrome virus (HP PRRSV) has caused huge economic losses to the swine industry in China. Understanding the molecular basis in relation to the virulence of HP-PRRSV is essential for effectively controlling clinical infection and disease. In the current study, we constructed and rescued a serial of mutant viruses in nsp9 and nsp10 based on the differential amino acid sites between HP-PRRSV JXwn06 and LP PRRSV HB-1/3.9. The replication efficiency in pulmonary alveolar macrophages (PAMs) and the pathogenicity of the mutant viruses for piglets were analyzed. Our results showed that the mutation of Thr to Ala in 586 and Ser to Thr in 592 of nsp9 decreased the replication efficiency of HP-PRRSV in PAMs, and could attenuate its virulence for piglets, suggesting that the residues 586 and 592 of nsp9 are critical sites natively in determining the fatal virulence of the Chinese HP-PRRSV for piglets. PMID- 29397203 TI - Stable Intronic Sequence RNAs Engage in Feedback Loops. AB - Stable intronic sequence RNAs (sisRNAs) are conserved in various organisms. Recent observations in Drosophila suggest that sisRNAs often engage in regulatory feedback loops to control the expression of their parental genes. The use of sisRNAs as mediators for local feedback control may be a general phenomenon. PMID- 29397204 TI - Reply to "A negative LGE is inconclusive to exclude an early cardiac amyloidosis: It's the time for a T1 mapping in clinical practice". PMID- 29397205 TI - JDP2: A novel therapeutic thought in cardiac remodeling. PMID- 29397206 TI - Effects of Melatonin on Blood Pressure, Oxidative Stress and Placental Expressions of TNFalpha, IL-6, VEGF and sFlt-1 in RUPP Rat Model of Preeclampsia. PMID- 29397208 TI - Resource Supply and Demand Both Affect Metabolic Scaling: A Response to Harrison. PMID- 29397207 TI - Cholinergic imbalance in lumbar spinal cord of a rat model of multiple sclerosis. AB - Cholinergic dysfunction in the central nervous system is an important characteristic of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). By using a rat EAE model, upregulation of vesicular acetylcholine transporter (VAChT) level in the EAE rat lumbar spinal cord was detected by western blot and immunostaining, and was associated with lymphocyte filtration and glial activation. Ex vivo and in vitro autoradiography studies with [18F]VAT, a VAChT-specific radioligand, also revealed increased tracer uptake in EAE rat lumbar spinal cord compared with shams. These studies on VAChT expression suggest central cholinergic imbalance during EAE progression. PMID- 29397209 TI - Update of the systematic review of palliative radiation therapy fractionation for bone metastases. AB - PURPOSE: Radiation therapy is an effective modality for pain management of symptomatic bone metastases. We update the previous meta-analyses of randomized trials comparing single fraction to multiple fractions of radiation therapy in patients with uncomplicated bone metastases. METHODS: A literature search was conducted in Ovid Medline, Embase, and Cochrane Central Register. Ten new randomized trials were identified since 2010, five with adequate and appropriate data for inclusion, resulting in a total of 29 trials that were analyzed. Forest plots based on each study's odds ratios were computed using a random effects model and the Mantel-Haenszel statistic. RESULTS: In intention-to-treat analysis, the overall response rate was similar in patients for single fraction treatments (61%; 1867/3059) and those for multiple fraction treatments (62%; 1890/3040). Similarly, complete response rates were nearly identical in both groups (23% vs 24%, respectively). Re-treatment was significantly more frequent in the single fraction treatment arm, with 20% receiving additional treatment to the same site versus 8% in the multiple fraction treatment arm (p < 0.01). No significant difference was seen in the risk of pathological fracture at the treatment site, rate of spinal cord compression at the index site, or in the rate of acute toxicity. CONCLUSION: Single fraction and multiple fraction radiation treatment regimens continue to demonstrate similar outcomes in pain control and toxicities, but re-treatment is more common for single fraction treatment patients. PMID- 29397210 TI - Factors involved in the late failure of endoscopic treatment of vesicoureteral reflux. AB - INTRODUCTION: The short-term results of endoscopic treatment of vesicoureteral reflux (VUR) are excellent. Over time, however, a number of patients have been identified for whom VUR reappeared after being resolved with this technique. The aim of this study was to analyse the factors related to this event. MATERIAL AND METHODS: A retrospective, analytical, case-control study included 395 ureteral units with primary VUR treated successfully at our centre, with a minimum follow up of 3 years. We identified cases in which VUR reappeared and analysed the demographic variables, those related to VUR (grade, laterality, initial study) and those related to the operation (materials used). RESULTS: We identified 77 ureteral units with recurrence in the 395 included units (19.5%). The recurrence rate was 29.7% for the patients treated with dextranomer/hyaluronic acid (Dx/HA), 20.2% for those treated with polydimethylsiloxane (MP) and 12.2% for polytetrafluoroethylene (PTFE). The onset of recurrence rose to 35% for patients treated before 1 year of age and those with gradeV VUR. Urinary dysfunction symptoms also increased the recurrence rate to 34.9%. CONCLUSION: The use of resorbable dextranomer/hyaluronic acid material was related to recurrence in the endoscopic treatment of VUR. The high-grade reflux and treatment at an early age, as well as the presence of urinary dysfunction, are also factors associated with recurrence. PMID- 29397211 TI - Translating transdermal alcohol monitoring procedures for contingency management among adults recently arrested for DWI. AB - Recent developments in alcohol monitoring devices have made it more feasible to use contingency management (CM) procedures to reduce alcohol use. A growing body of literature is demonstrating the effectiveness of CM to reduce alcohol use among community recruited adults wearing transdermal alcohol concentration (TAC) monitoring devices. This article describes the quality improvement process aimed at adapting TAC-informed CM aimed at minimizing alcohol use and maximizing treatment completion. This extends literature to a high-risk population; adults arrested and awaiting trial (pretrial) for criminal charge of driving while intoxicated (DWI). Participants were enrolled during their orientation to pretrial supervision conditions of DWI bond release. At enrollment, participants completed a screening, brief intervention, and referral to treatment; those with high risk alcohol histories were enrolled in an 8-week CM procedure to avoid TAC readings. Four Plan-Do-Study-Act (PDSA) quality improvement cycles were conducted where the TAC cutoff for determining alcohol use, the quantity of reinforcer, and handling of tampers on the transdermal alcohol monitor were manipulated. Across four PDSA cycles, the retention for the full 8-weeks of treatment was increased. The proportion of weeks with alcohol use was not decreased across cycles, the peak TAC values observed during drinking weeks were significantly lower in Cycles 1 and 4 than 3. CM may be developed as a tool for pretrial supervision to be used to increase bond compliance of those arrested for DWI and for others as a method to identify the need for additional judicial services. PMID- 29397212 TI - Real-Time Whole-Brain Radiation Therapy: A Single-Institution Experience. AB - PURPOSE: To demonstrate the feasibility of a real-time whole-brain radiation therapy (WBRT) workflow, taking advantage of contemporary radiation therapy capabilities and seeking to optimize clinical workflow for WBRT. METHODS AND MATERIALS: We developed a method incorporating the linear accelerator's on-board imaging system for patient simulation, used cone-beam computed tomography (CBCT) data for treatment planning, and delivered the first fraction of prescribed therapy, all during the patient's initial appointment. Simulation was performed in the linear accelerator vault. An acquired CBCT data set was used for scripted treatment planning protocol, providing inversely planned, automated treatment plan generation. The osseous boundaries of the brain were auto-contoured to create a target volume. Two parallel-opposed beams using field-in-field intensity modulate radiation therapy covered this target to the user-defined inferior level (C1 or C2). The method was commissioned using an anthropomorphic head phantom and verified using 100 clinically treated patients. RESULTS: Whole-brain target heterogeneity was within 95%-107% of the prescription dose, and target coverage compared favorably to standard, manually created 3-dimensional plans. For the commissioning CBCT datasets, the secondary monitor unit verification and independent 3-dimensional dose distribution comparison for computed and delivered doses were within 2% agreement relative to the scripted auto-plans. On average, time needed to complete the entire process was 35.1 +/- 10.3 minutes from CBCT start to last beam delivered. CONCLUSIONS: The real-time WBRT workflow using integrated on-site imaging, planning, quality assurance, and delivery was tested and deemed clinically feasible. The design necessitates a synchronized team consisting of physician, physicist, dosimetrist, and therapists. This work serves as a proof of concept of real-time planning and delivery for other treatment sites. PMID- 29397213 TI - Enterococcus faecalis Hydrolyzes Dental Resin Composites and Adhesives. AB - INTRODUCTION: After root canal treatment, the dentin-sealer interface undergoes degradation, allowing for interfacial microbial biofilm proliferation and treatment failure. Saliva and cariogenic bacteria showed esterase-like activities (ie, cholesterol esterase [CE]-like and/or pseudocholinesterase [PCE]-like) that degrade methacrylate-based resin materials and/or the restoration-tooth interface, increasing microbial interfacial proliferation. Enterococcus faecalis is a gram-positive bacterium that is commonly detected in persistent endodontic infections. The aim of this study was to measure E. faecalis esterase-like, CE like, and PCE-like activities and to assess the ability of the bacterium to degrade methacrylate-based resin composite (RC) and total-etch (TE) and self-etch (SE) adhesives. METHODS: CE-like and PCE-like activities from E. faecalis were measured using nitrophenyl and butyrylthiocholine substrates, respectively. The ability of E. faecalis to degrade resin composite, total-etch and self-etch adhesives was examined by quantifying the release of a universal resin degradation by-product (ie, Bis[hydroxypropoxy]-phenyl propane [BisHPPP]) using high-performance liquid chromatography. RESULTS: E. faecalis showed CE-like (1.23 +/- 0.13 U/MUg dry bacteria) but no PCE-like activity. After 30 days and/or 14 days of incubation, the amount of BisHPPP released was significantly higher in the presence of bacteria versus media for TE and RC but not SE (P < .05). The amount of BisHPPP released after 30 days of incubation with bacteria was highest for TE (23.69 +/- 1.72 MUg/cm2) followed by RC (3.43 +/- 1.20 MUg/cm2) and lowest for SE (0.86 +/- 0.44 MUg/cm2) (P < .05). CONCLUSIONS: E. faecalis possesses esterase-like degradative activity toward dental methacrylate resin restoration materials, which could accelerate the degradation of the dentin-methacrylate resin interface, increasing bacterial biofilm proliferation and penetration into the root canal system. PMID- 29397214 TI - Efficacy of Articaine versus Lidocaine in Supplemental Infiltration for Mandibular First versus Second Molars with Irreversible Pulpitis: A Prospective, Randomized, Double-blind Clinical Trial. AB - INTRODUCTION: Profound pulpal anesthesia is difficult to achieve in mandibular molars with irreversible pulpitis (IP). However, there are no published randomized controlled clinical trials comparing the success of supplemental buccal infiltration (BI) in mandibular first versus second molars with IP. The purpose of this prospective, randomized, double-blind study was to compare the efficacy of 4% articaine with 2% lidocaine for supplemental BIs in mandibular first versus second molars with IP after a failed inferior alveolar nerve block (IANB). This study's sample was combined with data from a previous trial. METHODS: One hundred ninety-nine emergency subjects diagnosed with IP of a mandibular molar were selected and received an IANB with 4% articaine. Subjects who failed to achieve profound pulpal anesthesia, determined by a positive response to cold or pain upon access, randomly received 4% articaine or 2% lidocaine as a supplemental BI. Endodontic access was begun 5 minutes after infiltration. Success was defined as less than mild pain during endodontic access and instrumentation on the Heft-Parker visual analog scale. RESULTS: There was a 25% IANB success rate with 4% articaine. The success rate for articaine supplemental BI in first molars was 61% versus 63% for second molars (P > .05). The success of lidocaine in first molars was 66%, but for second molars it was 32% (P = .004). CONCLUSIONS: The success rate for IANB with 4% articaine was 25%. Articaine and lidocaine had similar success rates for supplemental infiltration in first molars, whereas articaine was significantly more successful for second molars. However, because BI often did not provide profound pulpal anesthesia, additional techniques including intraosseous anesthesia may still be required. PMID- 29397215 TI - Treatment Outcomes of 4 Vital Pulp Therapies in Mature Molars. AB - INTRODUCTION: Vital pulp therapy (VPT) is a biological approach to minimally invasive endodontics. This randomized clinical trial aimed to evaluate and compare clinical and radiographic success of 4 VPTs (indirect pulp capping [IPC], direct pulp capping [DPC], miniature pulpotomy [MP], and full pulpotomy [FP]) using calcium-enriched mixture cement for deep caries management of mature permanent molars including teeth with clinical signs of irreversible pulpitis and the presence of apical periodontitis. METHODS: Blinded participants (N = 302) were randomly allocated to 4 study arms. Random allocation was disregarded when visible pulp exposures did not happen after complete caries removal and the tooth was transferred to the IPC arm. Pre- and intraoperative data including vitality test results, pulpal/periapical status, and exposure type/location were recorded. Pain was measured using a numeric rating scale before treatment initiation up to 1 week postoperatively. Participants were followed up for 1 year. RESULTS: The groups were homogenous in terms of age, sex, marital status, education, and practitioner; pre- and intraoperative conditions were similar in all arms and did not affect the long-term success. Preoperative pain and apical periodontitis were significantly different among arms (P < .05); however, it was not the case when the IPC group was excluded. After baseline pain adjustment, pain relief was continuous with similar patterns in all treatment groups. The 3- and 12-month success rates of the VPT techniques were comparable in the IPC (98.7% and 100%, respectively), DPC (98.4% and 94.7%, respectively), MP (98.4% and 91.4%, respectively), and FP (93.5% and 95.5%, respectively) arms, respectively (P > .05). CONCLUSIONS: In deep caries management of mature permanent molars, the 4 VPTs were associated with favorable/comparable clinical and radiographic outcomes. The pulpal and periapical status as well as pulpal exposure type/location had no effect on treatment outcomes. PMID- 29397216 TI - Accuracy of Cone-beam Computed Tomographic Image Interpretation by Endodontists and Endodontic Residents. AB - INTRODUCTION: Limited field cone-beam computed tomography (CBCT) imaging has become a modality frequently used by endodontists to evaluate the teeth and surrounding tissues of their patients. Accurate image interpretation is vital to obtain needed treatment information as well as to discern coincidental findings that could be present. The goal of this study was to determine the accuracy of CBCT volume interpretation when performed by endodontists and endodontic residents. METHODS: Eighteen deidentified limited field CBCT scans were obtained and evaluated by an oral and maxillofacial radiologist and an endodontist experienced in reading CBCT images. Their collective findings were combined as the "gold standard" of interpretation for this investigation. Using standard CBCT software, 4 practicing endodontists and 5 second-year endodontic residents evaluated each scan and recorded any notable findings and whether or not each scan warranted referral to a radiology specialist. Their interpretations were then compared with the gold standard to determine accuracy and any significant differences among the groups. RESULTS: The overall accuracy was 58.3% for endodontists and 64.3% for residents. Paired t tests showed no statistically significant differences in accuracy between the 2 groups for findings in teeth or in bone, but residents were significantly better for maxillary sinus findings. Endodontists agreed with the gold standard 38.9% of the time and residents 49.8% of the time on necessity of referral. The Cohen kappa coefficient showed moderate agreement between the groups. CONCLUSIONS: Endodontists and residents had similar accuracy in CBCT scan evaluation. More training and experience are warranted for both groups in order to maximize image assessment accuracy. PMID- 29397217 TI - Omega-3 Fatty Acids Reduce Inflammation in Rat Apical Periodontitis. AB - INTRODUCTION: The effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) on pro- and anti-inflammatory mediators were evaluated in a rat model of pulp exposure-induced apical periodontitis (AP). METHODS: Twenty-eight male Wistar rats were divided into 4 groups: control, untreated rats (group C); control rats treated with omega-3 PUFAs (group C-O); rats with pulp exposure-induced AP (group AP); and rats with pulp exposure-induced AP treated with omega-3 PUFAs (group AP O). Omega-3 PUFAs were administered orally once a day for 15 days before pulp exposure; this treatment was continued for 30 days after pulp exposure. The rats were sacrificed 30 days after pulp exposure, and their dissected jaws were subjected to immunohistochemical analysis to detect immunoreactivity for tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-1beta, IL-17, and IL-10 on the periapical bone surface. The results were statistically evaluated using analysis of variance and the Tukey post-test. The significance level was set at 5%. RESULTS: Immunoreactivity for the proinflammatory cytokines TNF-alpha, IL-6, IL-1beta, and IL-17 was higher in the AP group than in the AP-O, C, and C-O groups (P < .05). Immunoreactivity for the anti-inflammatory cytokine IL-10 was lower in the AP group than in the AP-O group (P < .05). CONCLUSIONS: Supplementation with omega-3 PUFAs can modulate the inflammatory response in rat AP, decreasing levels of TNF-alpha, IL-6, IL-1beta, and IL-17 but increasing levels of IL-10. PMID- 29397218 TI - Cyclic Fatigue Resistance of Heat-treated Nickel-titanium Instruments after Immersion in Sodium Hypochlorite and/or Sterilization. AB - INTRODUCTION: The purpose of this study was to assess the effects of sodium hypochlorite (NaOCl) immersion and sterilization on the cyclic fatigue resistance of heat-treated nickel-titanium (NiTi) rotary instruments. METHODS: Two hundred ten new 25/.06 Twisted Files (TFs; SybronEndo, Orange, CA) and Hyflex CM (Coltene Whaledent, Cuyahoga Falls, OH) files were divided into 7 groups (n = 15) for each brand. Group 1 (control group) included new instruments that were not immersed in NaOCl or subjected to autoclave sterilization. Groups 2 and 3 were composed of instruments dynamically immersed for 3 minutes in 5% NaOCl solution 1 and 3 times, respectively. Groups 4 and 5 consisted of instruments only autoclaved 1 and 3 times, respectively. Groups 6 and 7 recruited instruments that received a cycle of both immersion in NaOCl and sterilization 1 and 3 times, respectively. Instruments were subsequently subjected to a fatigue test. The surface morphology of fractured instruments was studied by field-emission scanning electron microscopy and x-ray energy-dispersive spectrometric (EDS) analyses. The means and standard deviations of the number of cycles to failure (NCF) were calculated and statistically analyzed using 2-way analysis of variance (P < .05). RESULTS: Comparison among groups indicated no significant difference of NCF (P > .05) except for the groups of TFs sterilized 3 times without and with immersion in NaOCl (P < .05). HyFlex CM files exhibited higher cyclic fatigue resistance than TFs when files were sterilized 3 times, independently from immersion in NaOCl (P < .05). EDS analysis showed the presence of an oxide-rich layer on the Hyflex CM files' external surface. No morphologic or chemical differences were found between files of the same brand subjected to different treatments. CONCLUSIONS: Repeated cycles of sterilization did not influence the cyclic fatigue of NiTi files except for TFs, which showed a significant decrease of flexural resistance after 3 cycles of sterilization. Immersion in NaOCl did not reduce significantly the cyclic fatigue resistance of all heat-treated NiTi files tested. PMID- 29397219 TI - Leptin Induces Odontogenic Differentiation and Angiogenesis in Human Dental Pulp Cells via Activation of the Mitogen-activated Protein Kinase Signaling Pathway. AB - INTRODUCTION: Up-regulation of odontogenic differentiation, dentin formation, and angiogenesis in dental pulp are key factors in vital pulp therapy. The aim of this study was to investigate whether leptin could promote odontogenic differentiation and angiogenesis in human dental pulp cells (hDPCs). In addition, the involvement of the intracellular signaling pathway in these effects was determined. METHODS: The viability of hDPCs treated with leptin was examined using the water soluble tetrazolium salt-1 assay. Real-time polymerase chain reaction was performed to determine messenger RNA (mRNA) expression levels of odontogenic and angiogenic markers. Western blot analysis was used to measure odontogenic and angiogenic protein expression levels and assess mitogen-activated protein kinase (MAPK) pathway involvement. Alkaline phosphatase (ALP) and alizarin red staining were used to evaluate expression levels of ALP and calcified nodule formation after treatment with leptin and/or the presence of MAPK inhibitors. RESULTS: All concentrations of leptin used in this study did not significantly affect the viability of hDPCs. However, mRNA and protein levels of odontogenic and angiogenic markers, ALP activity, and calcified nodule formation were significantly increased in the leptin-treated group compared with those in the control group. Leptin enhanced phosphorylation of extracellular signal related kinases, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases within 5 minutes after treatment. However, leptin-induced dentin sialophosphoprotein and vascular endothelial growth factor protein expression and mineralization were appreciably blocked by the presence of MAPK inhibitors. CONCLUSIONS: Leptin can induce angiogenesis, odontogenic differentiation, and mineralization in hDPCs via activating the MAPK signaling pathway. PMID- 29397220 TI - Re: Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur Urol 2017;72:910-7. PMID- 29397221 TI - [A peculiar intra-uterine lesion: Inflammatory myofibroblastic tumor (IMT)]. AB - A 25-year-old woman presented with a spontaneous vaginal expulsion of a 4cm well circumscribed nodule a few weeks after delivery. An inflammatory myofibroblastic tumor diagnosis was made by morphologic, immunohistochemistry and FISH analysis of the nodule. PMID- 29397222 TI - Toxic Causes of Intestinal Disease in Horses. AB - Because most poisonings occur by toxin ingestion, the gastrointestinal system is the first exposed and, in most cases, it is exposed to the highest toxin concentrations. Consequently, enterocyte damage is common. However, because many toxins produce organ-specific damage, and enterocyte necrosis is easily confused with autolysis, many gastrointestinal lesions are overlooked or overshadowed by other clinical and pathologic changes. The objective of this work is to review several common toxins and poisonous plants that produce primarily gastrointestinal disease. PMID- 29397223 TI - FlaC supplemented with VAA, OmpK or OmpR as bivalent subunit vaccine candidates induce immune responses against Vibrio anguillarum in flounder (Paralichthys olivaceus). AB - In our previous study, ten candidate proteins have been identified with immunogenicity and protection against Vibrio anguillarum in flounder (Paralichthys olivaceus). Among them, FlaC is the important outer protein in the flagellum with immunogenicity; VAA, OmpK and OmpR are protection proteins against V. anguillarum. In this paper, FlaC supplemented with VAA, OmpK or OmpR as bivalent subunit vaccine candidates, and their immune response of flounder and protective effects were evaluated, respectively. Recombinant(r) proteins of FlaC were mixed with rVAA, rOmpK and rOmpR, respectively, rVAA + rFlaC (AF), rOmpK + rFlaC (KF) and rOmpR + rFlaC (RF); formalin-killed cells (FKC) or PBS were injected to flounder, respectively. After immunization, the percentages of CD3+ T lymphocytes and surface membrane immunoglobulin-positive (sIg+) B lymphocytes in peripheral blood lymphocytes (PBLs), total antibodies (TA), specific antibodies against V. anguillarum (VA), specific antibodies against bivalent recombinant proteins (PA), the expression of immune-related genes and relative percent survivals (RPS) were measured, respectively. The results showed that three bivalent vaccines candidates and FKC could induce the proliferation of sIg+ B lymphocytes and CD3+ T lymphocytes in PBLs. The TA, VA and PA induced in bivalent vaccines candidates and FKC groups were significantly higher than that of the control group. CD3, IgM, CD4-1, CD4-2, CD8alpha and CD8beta genes were up regulated. After challenge with V. anguillarum, RPS in AF, KF, RF and FKC groups exhibited 62.6 +/- 2.33%, 78.95 +/- 3.01%, 75.45 +/- 0.97%, and 56.71 +/- 2.15% respectively. The results revealed that three bivalent vaccines candidates and FKC could induce the immune response in flounder, and have good protection against V. anguillarum, and KF can be an efficient bivalent subunit vaccine candidate. PMID- 29397224 TI - Evidence of the impact of monovalent rotavirus vaccine on childhood acute gastroenteritis hospitalization in Togo. AB - BACKGROUND: Monovalent rotavirus vaccine (RV1) was introduced in the immunization schedule of Togo in June 2014. We evaluated the impact of rotavirus vaccines on acute gastroenteritis (AGE) and rotavirus-associated hospitalizations in Togolese children. METHODS: Sentinel surveillance for AGE (defined as >=3 liquid or semi liquid stools/24 h lasting <7 days) hospitalizations among children <5 years of age was conducted in two sites in the capital city, Lome. ELISA was used for diagnosis of rotavirus infection in children with AGE. Additionally, review of hospitalization registers was performed at five hospitals to assess trends in AGE hospitalizations among children aged <5 years. For the vaccine impact assessment, pre-rotavirus vaccine introduction (July 2010-June 2014) and post-rotavirus vaccine introduction (July 2014-June 2016) periods were compared for annual changes in proportions of hospitalizations associated with AGE and rotavirus. RESULTS: During the pre-vaccine period, sentinel surveillance showed that 1017 patients were enrolled and 57% (range, 53-62%) tested positive for rotavirus, declining to 42% (23% reduction) in the first post-vaccine year and to 26% (53% reduction) in the second post-vaccine year; declines were most marked among infants. The patient register review showed that, compared with pre-vaccine rotavirus seasons, declines in hospitalizations due to all-cause AGE during post vaccine rotavirus seasons were 48% among <1 year age-group in both first and second years following vaccine introduction. Among 1-4 year olds no reduction was noted in the first year and a 19% decline occurred in the second year. CONCLUSIONS: We report rapid and marked reduction in the number of AGE hospitalizations and the proportion of AGE hospitalizations attributable to rotavirus in the first two years post- RV1 implementation in Togo. It is necessary to monitor long-term vaccine impact on rotavirus disease burden through continued surveillance. PMID- 29397225 TI - Second five-year follow-up after a booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates at least 10 years antibody persistence. AB - BACKGROUND: Tick borne encephalitis (TBE) endemic zones are expanding. We previously evaluated long term persistence of antibody 5 years after the first booster immunization following different primary immunization schedules with the polygeline-free inactivated TBE vaccine (TBEvac) in adults and adolescents. Here, we report anti-TBE virus (TBEV) antibody persistence from 6 to 10 years post booster administration. METHODS: This was a phase IV, open-label, single-center, second extension study (NCT01562444), conducted in Czechia. Healthy adults and adolescents >=12 years who had received 3 different primary vaccination schedules (rapid, conventional and accelerated conventional) in the parent study and a booster dose before (12-18 months post-primary series completion) or at the beginning (3 years post-primary series completion) of the first extension study were screened and enrolled in this study. Blood samples were collected yearly and anti-TBEV antibody response was evaluated by neutralizing test (NT) antibody assays. Analysis was performed overall and per age strata: 15-49 years, >=50 years, and >=60 years. RESULTS: Of 206 screened individuals, 191 completed the study. Overall, 90-100% of participants in the all-screened set and >=97% in the per-protocol set had the clinically meaningful threshold of protection (NT titers >=10) across all timepoints, regardless of the primary vaccination schedule. Overall, antibody geometric mean titers (GMTs) varied from 134 to 343 in the all screened set. Older age groups showed overall lower GMTs, although GMTs remained higher than NT titers >=10 up to year 10 in all groups. CONCLUSION: This study showed long-term persistence of anti-TBEV NT antibodies for up to 10 years after the first booster dose of TBEvac in all age groups, regardless of the primary vaccination schedule. PMID- 29397226 TI - Natural immunity against capsular group X N. meningitidis following an outbreak in Togo, 2007. AB - BACKGROUND: Capsular group X N. meningitidis (MenX) has emerged as a cause of localized disease outbreaks in sub-Saharan Africa, but the human immune response following exposure to MenX antigens is poorly described. We therefore assessed the natural immunity against MenX in individuals who were living in an area affected by a MenX outbreak during 2007 in Togo, West Africa. During 2009, 300 healthy individuals (100 aged 3-5 years, 100 aged 13-19 years and 100 aged 20-25 years) were included in the study, and serum responses were compared with sera from age-matched controls from the U.K. and Burkina Faso. METHODS: MenX serum bactericidal antibody (SBA) was measured using rabbit complement, and antibodies against MenX polysaccharide (XPS) and outer membrane vesicles (XOMVs) were quantified by ELISA. RESULTS: The proportion of Togolese individuals with an SBA titer of >=8 against the MenX strain was 29% (95% confidence interval (CI) 18-41) among those aged 3-5 years, 34% (95% CI 9-60) among those aged 13-19 years and 32% (95% CI 24-40) among those aged 20-25 years. These were significantly higher than observed in the control populations from the U.K (range 13-16%) and Burkina Faso (range 2-6%). CONCLUSION: In Togolese individuals, the concentration of serum IgG against XPS was higher among the two older age groups as compared to the youngest age group. Antibody concentrations against MenX PS correlated significantly with SBA titers. This supports further development of a MenX PS based conjugate vaccine. Further studies are needed to verify the ability of MenX PS to induce SBA in humans. PMID- 29397227 TI - Cost-effectiveness of vaccination against cytomegalovirus (CMV) in adolescent girls to prevent infections in pregnant women living in France. AB - BACKGROUND: CMV infections are the most frequent congenital infections worldwide. AIM: Assess the cost-effectiveness of vaccination strategies of adolescent girls vs. current practice (hygiene counseling) to prevent CMV seroconversions during pregnancy in France. METHOD: A Markov decision-tree model simulated overtime the trajectory of a single fictive cohort of 390,000 adolescent women aged 14 years old, living in France. Impact of vaccination was explored until the end of their reproductive live 40 years later. STRATEGIES COMPARED: "S1: No vaccination" (current practice); "S2: Routine vaccination"; "S3: Screening and vaccination of the seronegative". MODEL PARAMETERS: Seroconversion rate without vaccination (0.035%/pregnant woman-week); fetal transmission risk (41%). Vaccine vs. no vaccination: a 50% decrease in maternal seroconversions. OUTCOMES: Quality Adjusted Life-Years (QALYs) of the cohort-born babies; discounted costs; Incremental Cost-Effectiveness Ratio (ICER). RESULTS: S2 was the most effective strategy (with 35,000 QALYs gained) and the most expensive (?211,533,000); S1 was the least effective and least costly (?75,423,000). ICERs of strategy S3 vs. S1, and S2 vs. S3 were 6,000?/QALY gained (95% uncertainty range [2700-13,300]) and 16,000?/QALY [negative ICER (S3 dominated by S2) - 94,000] gained, respectively; highly cost-effective because ICER < 1*France's GPD/capita = ?30,000. SENSITIVITY ANALYSIS: If the seroprevalence was >62% (vs. 20% in the base case), S3 would become the most efficient strategy. CONCLUSION: In France, systematic vaccination of adolescent girls was the most efficient strategy to prevent maternal seroconversions. If the population was less than 62% immune, systematic screening and vaccination of susceptibles would become the most cost-effective approach. PMID- 29397228 TI - SMART: Is saline on the tightrope? PMID- 29397229 TI - Asymmetric transfer efficiencies between fomites and fingers: Impact on model parameterization. AB - BACKGROUND: Healthcare-associated infections (HAIs) affect millions of patients every year. Pathogen transmission via fomites and healthcare workers (HCWs) contribute to the persistence of HAIs in hospitals. A critical parameter needed to assess risk of environmental transmission is the pathogen transfer efficiency between fomites and fingers. Recent studies have shown that pathogen transfer is not symmetric. In this study,we evaluated how the commonly used assumption of symmetry in transfer efficiency changes the dynamics of pathogen movement between patients and rooms and the exposures to uncolonized patients. METHODS: We developed and analyzed a deterministic compartmental model of Acinetobacter baumannii describing the contact-mediated process among HCWs, patients, and the environment. We compared a system using measured asymmetrical transfer efficiency to 2 symmetrical transfer efficiency systems. RESULTS: Symmetric models consistently overestimated contamination levels on fomites and underestimated contamination on patients and HCWs compared to the asymmetrical model. The magnitudes of these miscalculations can exceed 100%. Regardless of the model, relative percent reductions in contamination declined after hand hygiene compliance reached approximately 60% in the large fomite scenario and 70% in the small fomite scenario. CONCLUSIONS: This study demonstrates how healthcare facility-specific data can be used for decision-making processes. We show that the incorrect use of transfer efficiency data leads to biased effectiveness estimates for intervention strategies. More accurate exposure models are needed for more informed infection prevention strategies. PMID- 29397230 TI - Effectiveness of a bundled approach to reduce urinary catheters and infection rates in trauma patients. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are common nosocomial infections. In 2015, the Centers for Medicare and Medicaid Services began imposing financial penalties for institutions where CAUTI rates are higher than predicted. However, the surveillance definition for CAUTI is not a clinical diagnosis and may represent asymptomatic bacteriuria. The objective of this study was to compare rates of urinary catheterization and CAUTI before and after the implementation of a bundled intervention. METHODS: This retrospective review evaluated trauma patients from January 2013-January 2015. The bundled intervention optimized the urinary catheterization process and culturing practices to reduce false positives. The CAUTI rate was defined as a positive surveillance CAUTI divided by total catheter days multiplied by 1,000 days. RESULTS: A total of 6,236 patients were included (pre: n = 5,003; post: n = 1,233). Fewer patients in the post bundle group received a urinary catheter (pre: 25% vs post: 16%; P < .001). After bundle implementation, the CAUTI rate reduced over one third (pre: 4.07 vs post: 2.56; incidence rate ratio, 0.63; 95% confidence interval, 0.19-2.07). CONCLUSIONS: Although the number of patients exposed to urinary catheters and catheter days was decreased, optimization of culturing practices was essential to prevent the CAUTI rate from increasing from a reduced denominator. Implementation of a CAUTI prevention bundle works synergistically to improve patient safety and hospital performance. PMID- 29397231 TI - Management of a family outbreak of scabies with high risk of spread to other community and hospital facilities. AB - BACKGROUND: In developed countries, scabies is observed sporadically or as institutional outbreaks in hospitals and other health facilities. In the family context, outbreaks generally involve a limited number of cases. METHODS: A local health authority in Emilia-Romagna (Northern Italy) carried out an epidemiologic investigation on a family outbreak of scabies that included an unusually high number of cases. Its possible connection with a nosocomial case in a long-term care facility (LTCF) and outbreak management are discussed. RESULTS: Among the household members, 8 confirmed cases occurred (attack rate, 87.5%). Another case was reported in a patient of an LTCF where one of the family cases worked as a sociosanitary operator. In total, 244 contacts were placed under surveillance. The control strategy focused on a mass information campaign addressed to all contacts and the training of health care personnel. In addition, specific prophylaxis (permethrin 5%) was performed in 108 high-risk contacts and LTCF patients and staff. CONCLUSIONS: The control measures were successful in preventing the spread of the outbreak. However, misdiagnosis and the tendency of people to hide the symptoms caused the late recognition and underestimation of the cases, contributing to delayed control measures and increasing the economic and human resources required for outbreak management. PMID- 29397232 TI - Recurrent Spontaneous Pneumothorax as a Manifestation of Birt-Hogg-Dube Syndrome. PMID- 29397233 TI - [Hyper-IgE in internal medicine]. AB - Hyper-IgE may be found under many pathological conditions. The role of IgE is essentially associated with the occurrence of allergic manifestations, which may be accompanied by an increase of their serum levels. Elevation of total IgE has also been reported in association with certain rare genetic immune deficiencies called hyper-IgE syndromes. Other circumstances such as infectious diseases, tumors or autoimmune diseases may also be accompanied by an excessive synthesis of IgE. Considering the diversity of these situations, discussion of the prognostic value of total IgE is useful to the internist. PMID- 29397234 TI - [Authors' reply about " Impact diagnostique de l'eosinopenie aux urgences dans le sepsis : les donnees sont controversees ", Moussiegt et al.] PMID- 29397122 TI - The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis. AB - BACKGROUND: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. METHODS: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. RESULTS: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained >=1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32-0.77); P<0.01], but no difference in complication rates [OR 1.02 (0.88-1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62-0.92); P<0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61-0.88); P<0.01; I2=89%). CONCLUSIONS: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine. PMID- 29397235 TI - [It is necessary to quit smoking: Only reducing smoking does not decrease the risk of cardiovascular morbidity and mortality]. PMID- 29397236 TI - Response to 'Response to 'Chemical burns: Diphoterine untangled' by KS Alexander [Burns 2017]'. PMID- 29397237 TI - Response to 'Chemical burns: Diphoterine untangled' by KS Alexander [Burns 2017]. PMID- 29397240 TI - Helping Pet Owners Change Pet Behaviors: An Overview of the Science. AB - The predominant approach to training dogs and modifying their behavior has been steeped in antiquated theories of dominance and pack leadership that are not based in scientific evidence. Animals learn best through associative and consequential interactions. Using the most current evidence-based techniques, while acknowledging that each pet is an individual, results in more effective behavior modification. PMID- 29397241 TI - Separation, Confinement, or Noises: What Is Scaring That Dog? AB - Separation anxiety and noise aversions are 2 of the most common welfare issues affecting pet dogs. Despite the high prevalence of these conditions, many affected dogs do not receive treatment. Separation anxiety, noise aversions, and confinement distress may be comorbid with each other and with other behavioral issues. A behavioral history and video can help confirm the diagnosis. Treatment with psychopharmaceuticals and behavior modification is recommended to improve the affected dog's welfare. PMID- 29397238 TI - Hereditary SWI/SNF complex deficiency syndromes. AB - The SWItch Sucrose non-fermentable (SWI/SNF) complex is a highly conserved multi subunit complex of proteins encoded by numerous genes mapped to different chromosomal regions. The complex regulates the process of chromatin remodelling and hence plays a central role in the epigenetic regulation of gene expression, cell proliferation and differentiation. During the last three decades, the SWI/SNF complex has been increasingly recognized as a central molecular event driving the initiation and/or progression of several benign and malignant neoplasms of different anatomic origin and having diverse histomorphological appearance. Atypical teratoid/rhabdoid tumors (AT/RT) and renal/extrarenal malignant rhabdoid tumors of childhood, epithelioid sarcoma and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) represent the most commonly recognized SWI/SNF-driven neoplasms. Approximately one-third of pediatric malignant rhabdoid tumors are linked to germline SWI/SNF alterations (SMARCB1/INI1, rarely SMARCA4) resulting in occasional familial clustering of these highly aggressive malignancies (so-called rhabdoid tumor predisposition syndrome, RTPS, types 1 and 2, respectively). However, more recently, inherited SWI/SNF-deficiency has been linked to several benign syndromic tumors including a subset of familial schwannomatosis (linked to SMARCB1) and multiple meningiomas (linked to SMARCE1) as well as others. Beyond neoplasms, several congenital developmental functional disorders such as Coffin-Siris syndrome and intellectual disability are now known to be SWI/SNF-related. The latter are essentially not associated with SWI/SNF-driven neoplasms, although at least anecdotal cases have documented concurrence of both neoplastic and developmental disorders. This review summarizes the most important SWI/SNF-driven diseases with a main focus on neoplasms. PMID- 29397242 TI - A Rare Case of Acute Right-Sided Colonic Diverticulitis Presenting as Pancreatitis. AB - BACKGROUND: This case report highlights the clinical presentation, radiologic findings, and medical management of a case of right colonic diverticulitis (RCD) with concomitant pancreatitis, a rare and easily missed entity in the emergency department (ED) of Western hemisphere countries. In our report, we present and discuss a case of RCD that led to pancreatitis in a female Asian patient. We review the epidemiology, diagnosis, and management of this disorder, and also discuss some complications associated with RCD. The importance of considering this pathologic entity within the ED differential even in those patients presumed to be at low risk for this condition is also explained, as this can prevent inappropriate surgical intervention for this presentation. CASE REPORT: We describe a 40-year-old Asian woman presenting for evaluation of epigastric pain and vomiting. She was initially thought to have cholecystitis or food poisoning, but had a normal ultrasound evaluation and ultimately had co-presenting RCD and pancreatitis diagnosed after computed tomography scanning. The patient was admitted and made a full recovery after receiving medical therapy and maintaining bowel rest. This is, to our knowledge, the first reported case of RCD and concomitant pancreatitis found in the modern literature. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Severe epigastric pain in young Asian patients with minimal risk factors may be RCD. This condition presents much like appendicitis, cholecystitis, or food poisoning, but must be considered among early differential diagnoses and evaluated appropriately in order to prevent unnecessary interventions. PMID- 29397239 TI - Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing. AB - Recognition of hereditary forms of gastrointestinal cancer is of great importance for patients and their families and pathologists play a crucial role in this. This review recapitulates the clinical, pathological and molecular aspects of Hereditary Diffuse Gastric Cancer and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, as well as hereditary colorectal cancer syndromes such as Lynch syndrome and gastrointestinal polyposis syndromes (including Familial Adenomatous Polyposis, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome). Histopathological clues to recognize hereditary forms of gastrointestinal cancer and possible ancillary studies that can support an underlying syndrome and guide genetic testing are discussed. PMID- 29397243 TI - Bartholin's abscess due to Dialister micraerophilus in a woman presenting with repetitive bartholinitis episodes. PMID- 29397244 TI - Cataract in a patient with 47,XYY sex chromosome aneuploidy. AB - CASE REPORT: The case concerns a 16 year-old boy with a history of high myopia and unilateral congenital cataract, tall stature for age, facial dysmorphism, hypermobile metacarpal-phalangeal joints, as well as behavioural problems. The mother had a history of recurrent pregnancy loss. Chromosomal analysis of the peripheral blood lymphocytes reported 47,XYY. DISCUSSION: Patients with sex chromosome aneuploidy 47,XYY have higher risk of congenital malformations, although ophthalmological anomalies are unusual. Evaluation of patients with tall stature and behavioural problems should include a chromosomal analysis in order to determine the aetiology. PMID- 29397245 TI - Choroidal osteoma with choroidal excavation and associated neovascular membrane: An OCT-angiography study. AB - CLINICAL CASE: A case is presented of a unilateral choroidal osteoma with choroidal excavation and associated neovascular membrane that was studied using OCT-angiography. The OCT and OCT-angiography revealed an area of choroidal excavation and an active neovascular membrane. Three doses of aflibercept were administered to the patient, which stabilised the neovascularisation. DISCUSSION: OCT-angiography was used to analyse the morphology of the superficial vascular network of the osteoma, as well as to monitor the evolution of the neovascular membrane. PMID- 29397246 TI - Iris metastasis as first sign of lung adenocarcinoma. PMID- 29397247 TI - Discussion. PMID- 29397248 TI - Safety and feasibility of endovascular aortic aneurysm repair as day surgery. AB - OBJECTIVE: The adoption of endovascular aneurysm repair (EVAR) during the past two decades has led to significantly shorter length of stay as well as lower hospital resource use. Currently, most patients are admitted to the hospital after EVAR; however, there are no standard observation periods, and timing of discharge is based on clinical judgment. The aim of this study was to confirm the safety and feasibility of performing EVAR as outpatient surgery. METHODS: We developed criteria to identify patients for potential same-day discharge (infrarenal aneurysm, low perioperative risk, to be accompanied for first 24 hours). We then implemented a prospective trial that observed patients planned for same-day discharge and compared them with a historical control group (patients who had undergone EVAR during the previous 2 years and met same-day discharge criteria). Basic demographic and operative data as well as length of stay, inpatient and perioperative complications, emergency department visits, readmissions, reinterventions, and deaths were collected. The primary outcome was the 30-day complication rate, and the study was powered to assess noninferiority. RESULTS: Prospectively, we assessed 266 patients and planned 110 (41%) for outpatient EVAR (62% of historical controls met outpatient criteria). Demographic characteristics were similar between planned outpatients and historical controls. In planned outpatients, hospital stay was significantly shorter (0.7 +/- 2.6 days vs 2.5 +/- 6.9 days; P < .01), and 79% were discharged the same day of surgery. The 30-day follow-up was available for all study patients and 94% of control patients; there were no differences in complication (11% vs 9%), readmission (2% vs 4%), reintervention (4% vs 4%), or mortality (1% vs 1%) rates, but study patients had significantly more emergency department visits (15% vs 6%; P < .05). Unsuccessful same-day discharge was associated with longer operative times, increased blood loss, and use of general anesthesia. CONCLUSIONS: In selected patients undergoing elective EVAR, same-day discharge is feasible without increasing complication rates. Health resource utilization remains a challenge in transitioning to an outpatient model. PMID- 29397249 TI - Comparison of xerostomia incidence after three-dimensional conformal radiation therapy and contralateral superficial lobe parotid-sparing intensity-modulated radiotherapy for oropharyngeal and hypopharyngeal cancer. AB - OBJECTIVE: In the treatment of head-neck cancer, parotid-sparing intensity modulated radiotherapy (IMRT) could reduce the incidence of xerostomia. When the parotid glands cannot be sufficiently spared because of the widespread tumor, contralateral superficial lobe parotid-sparing (CSLPS)-IMRT could be used to reduce marginal recurrence, however the success of this approach remains to be determined. The primary purpose of this study was to compare the incidence of xerostomia between three-dimensional conformal radiotherapy (3D-CRT) and CSLPS IMRT for oropharyngeal and hypopharyngeal cancer. In a second aim, we also compared the clinical efficacy of 3D-CRT and CSLPS-IMRT. METHODS: We retrospectively reviewed the medical records of locally advanced oropharyngeal and hypopharyngeal cancer patients who were treated with definitive concurrent chemoradiotherapy between June 2007 and April 2014. We estimated the average mean dose delivered to the parotid glands, the incidence of xerostomia>=Grade 2, patterns of failure, and survival outcomes. RESULTS: Seventeen patients received 3D-CRT and 21 received CSLPS-IMRT. The average mean dose delivered to the superficial lobe of the contralateral parotid gland was 45.3Gy and 26.6Gy (p<0.001), and the incidence of xerostomia>=Grade 2 following treatment was 75% and 26% at 12 months (p=0.012) and 67% and 18% at 24 months (p=0.018) in the 3D CRT and CSLPS-IMRT groups, respectively. Patterns of failure did not differ between the two groups. The 2-year progression-free survival was 59% and 62% (p=0.73), and the 2-year overall survival rate was 71% and 71% in the 3D-CRT and CSLPS-IMRT groups, respectively (p=0.76). CONCLUSION: Incidence of xerostomia was significantly lower in patients receiving CSLPS-IMRT compared with 3D-CRT, while clinical efficacy did not differ between two treatment strategies. PMID- 29397250 TI - Endoscopic cartilage versus temporalis fascia grafting for anterior quadrant tympanic perforations - A prospective study in a tertiary care hospital. AB - OBJECTIVE: Management of anterior perforations of tympanic membrane is a surgical challenge. The objective of this study is to analyse and compare the results of composite cartilage perichondrium island (CCPI) graft and temporalis fascia graft by endoscopic technique in anterior quadrant perforations. METHODS: A prospective study was conducted in a tertiary care centre from 2012-16. A total of 187 ear drums(n) in 168 patients with perforations involving anterior quadrant were included in the study. All the patients were operated completely by endoscopic technique. Tragal Composite cartilage perichondrium island (CCPI) graft was used in 87 ears and temporalis fascia in 100. Each group was categorised into A and B depending on perforation size. The outcome parameters assessed include graft success with regard to perforation size, pre- and postoperative ABG, mean improvement in ABG, ABG closure ratio and graft medialisation/lateralisation status. RESULTS: Cartilage group had 91.95% (80/87) success rate overall, while fascia had 79% (79/100). In category 1, the success rate for cartilage and temporalis fascia were 89.6% (26/29) and 68.9% (20/29) respectively (p=0.51788). In category 2, the success rates were 93.1% (54/58) and 83.1% (59/71) respectively (p=0.86356). The mean improvement in ABG for both groups were 17.52+/-3.84dB and 15.26+/-5.56dB respectively (p=0.04). ABG closure ratio for both the groups were 62.84+/-11.87 % and 53.6+/-19.6 % respectively (p=0.0008). CONCLUSION: Endoscopic composite cartilage perichondrium island graft is an effective technique in managing perforations of anterior quadrant barring the expertise required for endoscopic ear surgeries. PMID- 29397251 TI - Effect of production management on semen quality during long-term storage in different European boar studs. AB - The processing of ejaculates is a fundamental step for the fertilizing capacity of boar spermatozoa. The aim of the present study was to identify factors that affect quality of boar semen doses. The production process during 1 day of semen processing in 26 European boar studs was monitored. In each boar stud, nine to 19 randomly selected ejaculates from 372 Pietrain boars were analyzed for sperm motility, acrosome and plasma membrane integrity, mitochondrial activity and thermo-resistance (TRT). Each ejaculate was monitored for production time and temperature for each step in semen processing using the special programmed software SEQU (version 1.7, Minitub, Tiefenbach, Germany). The dilution of ejaculates with a short-term extender was completed in one step in 10 AI centers (n = 135 ejaculates), in two steps in 11 AI centers (n = 158 ejaculates) and in three steps in five AI centers (n = 79 ejaculates). Results indicated there was a greater semen quality with one-step isothermal dilution compared with the multi step dilution of AI semen doses (total motility TRT d7: 71.1 +/- 19.2%, 64.6 +/- 20.0%, 47.1 +/- 27.1%; one-step compared with two-step compared with the three step dilution; P < .05). There was a marked advantage when using the one-step isothermal dilution regarding time management, preservation suitability, stability and stress resistance. One-step dilution caused significant lower holding times of raw ejaculates and reduced the possible risk of making mistakes due to a lower number of processing steps. These results lead to refined recommendations for boar semen processing. PMID- 29397252 TI - Freeze-dried spermatozoa: An alternative biobanking option for endangered species. AB - In addition to the iconic wild species, such as the pandas and Siberian tigers, an ever-increasing number of domestic species are also threatened with extinction. Biobanking of spermatozoa could preserve genetic heritages of extinct species, and maintain biodiversity of existing species. Because lyophilized spermatozoa retain fertilizing capacity, the aim was to assess whether freeze dried spermatozoa are an alternative option to save endangered sheep breeds. To achieve this objective, semen was collected from an Italian endangered sheep breed (Pagliarola), and a biobank of cryopreserved and freeze-dried spermatozoa was established, and evaluated using IVF (for frozen spermatozoa) and ICSI procedures (for frozen and freeze-dried spermatozoa). As expected, the fertilizing capacity of cryopreserved Pagliarola's spermatozoa was comparable to commercial semen stocks. To evaluate the activating capability of freeze-dried spermatozoa, 108 MII sheep oocytes were subjected to ICSI, and allocated to two groups: 56 oocytes were activated by incubation with ionomycin (ICSI-FDSa) and 52 were not activated (ICSI-FDSna). Pronuclear formation (2PN) was investigated at 14-16 h after ICSI in fixed presumptive zygotes. Only artificially activated oocytes developed into blastocysts after ICSI. In the present study, freeze-dried ram spermatozoa induced blastocyst development following ICSI at a relatively high proportion, providing evidence that sperm lyophilization is an alternative, low cost storage option for biodiversity preservation of domestic species. PMID- 29397253 TI - Hypertriglyceridemia and omega-3 fatty acids: Their often overlooked role in cardiovascular disease prevention. AB - AIMS: This review aims to describe the pathogenic role of triglycerides in cardiometabolic risk, and the potential role of omega-3 fatty acids in the management of hypertriglyceridemia and cardiovascular disease. DATA SYNTHESIS: In epidemiological studies, hypertriglyceridemia correlates with an increased risk of cardiovascular disease, even after adjustment for low density lipoprotein cholesterol (LDL-C) levels. This has been further supported by Mendelian randomization studies where triglyceride-raising common single nucleotide polymorphisms confer an increased risk of developing cardiovascular disease. Although guidelines vary in their definition of hypertriglyceridemia, they consistently define a normal triglyceride level as <150 mg/dL (or <1.7 mmol/L). For patients with moderately elevated triglyceride levels, LDL-C remains the primary target for treatment in both European and US guidelines. However, since any triglyceride level in excess of normal increases the risk of cardiovascular disease, even in patients with optimally managed LDL-C levels, triglycerides are an important secondary target in both assessment and treatment. Dietary changes are a key element of first-line lifestyle intervention, but pharmacological treatment including omega-3 fatty acids may be indicated in people with persistently high triglyceride levels. Moreover, in patients with pre-existing cardiovascular disease, omega-3 supplements significantly reduce the risk of sudden death, cardiac death and myocardial infarction and are generally well tolerated. CONCLUSIONS: Targeting resistant hypertriglyceridemia should be considered as a part of clinical management of cardiovascular risk. Omega-3 fatty acids may represent a valuable resource to this aim. PMID- 29397254 TI - Reply. PMID- 29397255 TI - Reply. PMID- 29397256 TI - How can we administer high-quality chest compressions to a cardiac arrest patient on a bed? PMID- 29397257 TI - Pyridoxine for the treatment of isoniazid-induced seizures in intentional ingestions: The experience of a national poison center. PMID- 29397258 TI - Propofol-fentanyl versus propofol-ketamine for procedural sedation and analgesia in patients with trauma. AB - OBJECTIVE: Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department. METHOD: This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded. RESULTS: Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15 min of PSA in the group PF was significantly higher than the group PK. CONCLUSION: It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments. PMID- 29397259 TI - Minimally invasive hepatopancreatobiliary surgery: Where do we go from here? PMID- 29397260 TI - Vibration-induced stress priming during seed culture increases microalgal biomass in high shear field-cultivation. AB - Vibrational wave treatment has been used to increase proliferation of microalgae. When directly applied at large scale, however, turbulence can offset positive effects of vibration on microalgae proliferation. Moreover, severe hydrodynamic shear fields in the bioreactor decrease cell viability that detrimentally influence maximum yieldable biomass. In this study, vibration pretreatment (between 10-30 Hz and 0.15-0.45 G) was used to prime the cells for enhanced biomass. When exposed to 10 Hz at 0.15 G for 72 h and inoculated in baffled flasks of large shear fields (0.292 Pa for the average wall shear force (aveWSF) and 184 s-1 for the average shear strain rate (aveSSR)), microalgae showed 27% increase in biomass as well as 39% increase in corresponding amount of heterologous protein (i.e. GFP-3HA). Our results show that stress primed microalgae with vibrations can lead to improved proliferation that results in increased biomass production at industrial scale bioprocesses. PMID- 29397261 TI - Using microfluidic platforms to develop CNS-targeted polymeric nanoparticles for HIV therapy. AB - The human immunodeficiency virus (HIV) uses the brain as reservoir, which turns it as a promising target to fight this pathology. Nanoparticles (NPs) of poly(lactic-co-glycolic) acid (PLGA) are potential carriers of anti-HIV drugs to the brain, since most of these antiretrovirals, as efavirenz (EFV), cannot surpass the blood-brain barrier (BBB). Forasmuch as the conventional production methods lack precise control over the final properties of particles, microfluidics emerged as a prospective alternative. This study aimed at developing EFV-loaded PLGA NPs through a conventional and microfluidic method, targeted to the BBB, in order to treat HIV neuropathology. Compared to the conventional method, NPs produced through microfluidics presented reduced size (73 nm versus 133 nm), comparable polydispersity (around 0.090), less negative zeta-potential (-14.1 mV versus -28.0 mV), higher EFV association efficiency (80.7% versus 32.7%) and higher drug loading (10.8% versus 3.2%). The microfluidics-produced NPs also demonstrated a sustained in vitro EFV release (50% released within the first 24 h). NPs functionalization with a transferrin receptor-binding peptide, envisaging BBB targeting, proved to be effective concerning nuclear magnetic resonance analysis (delta = -0.008 ppm; delta = 0.017 ppm). NPs demonstrated to be safe to BBB endothelial and neuron cells (metabolic activity above 70%), as well as non-hemolytic (1-2% of hemolysis, no morphological alterations on erythrocytes). Finally, functionalized nanosystems were able to interact more efficiently with BBB cells, and permeability of EFV associated with NPs through a BBB in vitro model was around 1.3-fold higher than the free drug. PMID- 29397262 TI - Consequences of dysregulated complement regulators on red blood cells. AB - The complement system represents the first line of defense that is involved in the clearance of pathogens, dying cells and immune complexes via opsonization, induction of an inflammatory response and the formation of a lytic pore. Red blood cells (RBCs) are very important for the delivery of oxygen to tissues and are continuously in contact with complement proteins in the blood plasma. To prevent complement activation on RBCs, various complement regulatory proteins can be found in plasma and on the cell membrane. RBCs are special cells without a nucleus and having a slightly different make-up of complement regulators than nucleated cells, as membrane cofactor protein (MCP) is not expressed and complement receptor 1 (CR1) is highly expressed. Decreased expression and/or function of complement regulatory proteins may result in unwanted complement activation and accelerated removal of RBCs. This review describes complement regulation on RBCs and the consequences when this regulation is out of balance. PMID- 29397263 TI - Proposal of a stage-specific surveillance strategy for colorectal cancer patients: A retrospective analysis of Japanese large cohort. AB - BACKGROUND: Frequency and duration of postoperative surveillance for colorectal cancer patients remain debatable, and follow-up data regarding stage I or resected stage IV patients are limited. METHOD: Cohort data from 22 institutions were retrospectively analyzed; 18,841 patients who underwent curative surgery for stage I to IV cancer were included. The cumulative incidence of recurrence, recurrence rate over surveillance period, and risk of recurrence each year after surgery were assessed. RESULTS: Recurrence rates in stages I, II, III, and IV were 4.2%, 14%, 32%, and 75%, respectively. Over 80% of recurrences occurred within the first 2 years in stage IV, and 3 years in stages II and III, whereas 86.8% of recurrences occurred in 5 years in stage I. Among patients with 5-year recurrence-free survival, 2.2% in stage III and 7.0% in stage IV still experienced recurrence after the 5-year postoperative period. When the duration is extended to 6 years in stage III and 8 years in stage IV, approximately 1% over the surveillance period would be achieved. In stage I, the risk of recurrence each year after surgery was consistently low, whereas the risks in stages II, III, and IV were high in the early postoperative phase. The risk of recurrence each year in stages III and IV patients were over 2-fold and 6-fold higher than that in stage II, respectively. CONCLUSIONS: Recurrence patterns were markedly different according to cancer stages. These results suggest that a stage specific approach to postoperative surveillance may improve the efficiency of detecting recurrences. PMID- 29397264 TI - Optimizing treatment for children and adolescents with papillary thyroid carcinoma in post-Chernobyl exposed region: The roles of lymph node dissections in the central and lateral neck compartments. AB - There is lack of data to predict lymph node metastases in pediatric thyroid cancer. The aims are to study (1) the factors affecting the lymph node metastases in children and adolescence with papillary thyroid carcinoma in region exposed to radiation and (2) to evaluate the predictive significance of these factors for lateral compartment lymphadenectomy. Five hundred and nine patients with papillary thyroid carcinoma underwent total thyroidectomy and lymph nodes resection (central and lateral compartments of the neck) surgery during the period of 1991-2010 in Belarus were recruited. The factors related to lymph node metastases were studied in these patients. In the patients with papillary thyroid carcinoma, increase number of cancer-positive lymph nodes in the central neck compartment were associated with a risk to develop lateral nodal disease as well as bilateral nodal disease. Futhermore, positive lateral compartment nodal metastases are associated with age and gender of the patients, tumour size, minimal extra-thyroidal extension, solid architectonic, extensive desmoplasia in carcinoma, presence of psammoma bodies, extensive involvement of the thyroid and metastatic ratio index revealed after examination of the central cervical chain lymph nodes. The presence of nodal disease, degree of lymph node involvement and the distribution of lymph node metastases significantly increase the recurrence rates of patients with papillary thyroid carcinoma. To conclude, the lymph nodes metastases in young patients with papillary thyroid carcinoma in post-Chernobyl exposed region are common and the pattern could be predicted by many clinical and pathological factors. PMID- 29397266 TI - Diffusion Tensor Imaging of the Ankle as a Possible Predictor of Chemotherapy Induced Peripheral Neuropathy: Pilot Study. AB - PURPOSE: Chemotherapy induced peripheral neuropathy (CIPN) is seen in up to 75% of treated cancer patients and can drastically limit their medical management and affect quality of life. Clinical and electrodiagnostic testing for CIPN have many pitfalls. Magnetic resonance neurography (MRN) is being increasingly used in the evaluation of peripheral nerves. Diffusion tensor imaging (DTI) shows promise in the workup of peripheral nerves. In this prospective pilot study, we investigated a possible relationship between DTI and peripheral neuropathy of the ankle and foot in cancer patients treated with chemotherapy. METHODS: Nine cancer patients with and without CIPN were clinically evaluated using vibratory perception threshold (VPT) testing. VPT score of >25Volts defined presence of CIPN. The posterior tibial nerve and branches in both feet were imaged using MRN and DTI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured at the posterior tibial, medial plantar, and lateral plantar nerves. Measurements for the CIPN group were compared to without CIPN by VPT cutoff. Correlations and possible relationships between DTI parameters and CIPN were analyzed. RESULTS: A total of 16feet of 9 enrolled patients were imaged (9feet with CIPN and 7feet without CIPN). Average age was 60.6 +/- 13.4 years (range: 33 74). Posterior tibial nerve ADC values were significantly lower than the medial plantar nerve ADC values in all feet (F = 3.50, P = 0.04). We found a correlation with FA and ADC values at specific nerve locations with CIPN, with the left medial plantar nerve FA value and left lateral plantar nerve ADC value demonstrating the strongest positive correlations (0.73 and 0.62, respectively). CONCLUSIONS: The use of DTI for assessing CIPN is challenging but promising. This pilot study provides preliminary data showing correlations between FA and ADC measurements with CIPN and potential utility of DTI as a predictive marker of onset and severity of CIPN in the ankle and foot, which could aid in preventive strategies. Larger, prospective DTI studies are needed to draw definitive conclusions. CLINICAL RELEVANCE: MRN with DTI shows promising results as a potential predictive marker of CIPN in the ankle and foot. PMID- 29397265 TI - The evaluation of circulating endothelial progenitor cells and related angiogenic markers as prognostic factors in soft-tissue tumors. AB - INTRODUCTION: Neovascularisation is a critical step in the progression of malignant tumors. Circulating endothelial progenitor cells (cEPC) have been proposed as surrogate markers of vasculogenesis in malignancies. In this project, we studied the impact of tumor-specific therapy on cEPC and associated angiogenic factors in patients with soft tissue tumors. MATERIALS AND METHODS: Fifty-three patients with soft tissue tumors (25 soft tissue sarcomas, 19 GIST, 9 desmoids) and 15 healthy controls were included. Blood samples were obtained at two time points, before and 8 weeks after start of tumor-specific therapy. Peripheral blood mononuclear cells (PBMCs) were isolated. cEPCs were characterised as CD34+, CD133+, CD45dim, CD31+ and vascular endothelial growth factor 2 (VEGFR-2) positive cells. Serum concentrations of VEGF-A and angiopoetin-2 were determined by enzyme-linked immunosorbent assay. RESULTS: VEGF-A and Ang-2 concentrations were significantly higher in tumor patients than in healthy controls in both samples (p < .01). Sarcoma patients with progressive disease developed a significant increase in cEPC levels between the two blood samples compared to those with stable disease (p = .002). GIST patients with progressive tumor or metastatic disease showed significant increase in VEGF-A values (p = .01). DISCUSSION: The pre-treatment values of the angiogenic markers did not correlate with the clinical course of the disease. However, cEPCs levels were significantly higher in sarcoma patients with progressive disease compared to those with stable disease and should be further evaluated as early markers of disease progression in sarcoma patients. VEGF-A and angiopoetin-2 clearly play a role as mediators of the vasculogenesis contributing to tumor progression. PMID- 29397267 TI - Customized Residency Leadership Tracks: A Review of What Works, What We're Doing and Ideas for the Future. AB - Effective leaders are essential to ensure the future of radiology. Radiologists often find themselves in leadership positions despite a lack of formal leadership training. The fourth year of residency is the ideal time to expose young physicians to leadership and extraclinical specialization, as such leadership development prior to fellowship may still impact academic career choice. In this manuscript, we discuss prior successes of leadership tracks within medicine and review the evidence supporting the saying that "leaders are made, not born". Finally, we describe the evolution of our institution's residency leadership tracks highlighting key components, challenges, early successes and future endeavors. PMID- 29397268 TI - Common Resident Errors When Interpreting Computed Tomography of the Abdomen and Pelvis: A Review of Types, Pitfalls, and Strategies for Improvement. AB - OBJECTIVE: The purpose of this study was to identify common errors that radiology residents make when interpreting abdominopelvic (AP) computed tomography (CT) while on call, to review the typical imaging findings of these cases, and to discuss strategies for improvement. MATERIALS AND METHODS: AP (or chest, abdomen, pelvis) CTs from 518 weekend senior call shifts (R3 or R4) were retrospectively reviewed. Discrepancies between preliminary and final reports were identified and then rated by whether the miss could impact short-term management. The imaging findings from the cases were reviewed. RESULTS: A total of 4695 CTs were reviewed, revealing a total of 145 discrepancies that could affect short-term clinical management (miss rate 3.1%). The most common misses were related to blood clots (13.8%), colitis (8.3%), misplaced lines or tubes (6.9%), or pyelonephritis (5.5%). Common pitfalls and strategies from improved detection are discussed using image examples. CONCLUSIONS: Through increased attention to the vasculature, colon, devices, and kidneys, trainees may improve their discrepancy rates and improve on-call reporting. PMID- 29397269 TI - Benefits of Integrated RIS/PACS/Reporting Due to Automatic Population of Templated Reports. AB - With integration of the Radiological Information Systems (RIS), Picture Archiving and Communication systems (PACS), and reporting systems, patient identifiers and examination information can automatically map into examination reports. There are many potential benefits of report automation to radiologists including improvements in efficiency, accuracy, and fatigue. In this article we describe a 2 part study, with the first part being an anonymous survey of radiologists concerning report automation. A total of 13 staff radiologists and 9 radiology residents at a single institution completed an anonymous survey. Respondents were asked if automatic population of examination description, comparison examination data, indications, computed tomography dose, technique, and copy to physician data saved time, decreased fatigue, and increased accuracy. Respondents were asked if a "copy findings" function saved time. The second objective part of the study was a mock examination experiment to assess time savings of report automation and to assess error rates. Of all, 9 radiologists were asked to dictate fields for 8 mock examinations. Subjects were timed and reporting errors monitored. Estimated daily time savings and error rates were calculated assuming a mix of 80 studies. A total of 95% surveyed responded that report automation saved time; 91% that report automation improved accuracy of dictations; 82% that report automation decreased fatigue. Furthermore, 83% of copy finding function users reported time savings. Average time to dictate these prepopulated fields was 51 seconds per study. Average error rate per report was 0.86, with an average of 0.26 errors remaining uncorrected upon report completion. Estimated average time per day saved per radiologist from report automation was 68 minutes. Estimated average corrected errors was 48 per day. Estimated average uncorrected or missed errors was 21 per day. These estimated benefits from report automation result from tight integration of RIS, PACS, and reporting systems. PMID- 29397270 TI - Device Related Pressure Ulcers Pre and Post Identification and Intervention. AB - PROBLEM: From 2014 to 2016, device related pressure injuries accounted for 62-81% of all hospital acquired pressure injuries. From January to June 2014, there were 5 BiPAP/CPAP pressure injuries noted, accounting for 3.579 injuries per 1000 ventilator days. In 2015, hospital data revealed that 26.5% of all hospital acquired pressure injuries occurred to prone surgical spine patients. METHODS: Collaborative teams including respiratory therapists and operating room staff were convened and crafted new strategies. INTERVENTIONS: Adhesive foam dressings on patient faces with BiPAP/CPAP masks and prior to orthopedic spinal surgery were used to prevent device and operating room positioning pressure injuries. RESULTS: From July to December 2014 there were 0 BiPAP/CPAP pressure injuries. After interventions in March of 2016 through the remainder of 2016, zero pressure injuries occurred when the adhesive foam dressings were applied to the potential pressure injury areas pre-operatively. CONCLUSIONS: We used real time patient data to drive efforts and create a new culture in the pediatric setting that honors critical airway maintenance, operative room positioning, and preventative skin protection. PMID- 29397271 TI - Effectiveness of Respiratory-gated Positron Emission Tomography/Computed Tomography for Radiotherapy Planning in Patients with Lung Carcinoma - A Systematic Review. AB - AIMS: A systematic review of the literature evaluating the clinical use of respiratory-gated (four-dimensional; 4D) fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) compared with non-gated (three dimensional; 3D) PET/CT for radiotherapy planning in lung cancer. MATERIALS AND METHODS: A search of MEDLINE, Cochrane, Web of Science, SCOPUS and clinicaltrials.gov databases was undertaken for articles comparing 3D and 4D PET/CT tumour volume or 4D PET/CT for radiotherapy planning. PRISMA guidelines were followed. RESULTS: Thirteen studies compared tumour volumes at 3D and 4D PET/CT; eight reported significantly smaller volumes (6.9-44.5%), three reported significantly larger volumes at 4D PET/CT (16-50%), one reported no significant difference and one reported mixed findings. Six studies, including two that reported differences in tumour volumes, compared target volumes or studied geographic misses. 4D PET/CT target volumes were significantly larger (19-40%) when compared with 3D PET/CT in all but one study, where they were smaller (3.8%). One study reported no significance in 4D PET/CT target volumes when compared with 4D CT, whereas another study reported significantly larger volumes (38.7%). CONCLUSION: The use of 4D PET/CT leads to differences in target volume delineation compared with 3D PET/CT. These differences vary depending upon technique and the clinical impact currently remains uncertain. Correlation of pretreatment target volumes generated at 3D and 4D PET/CT with postsurgical histology would be ideal but technically challenging. Evaluation of patient outcomes based on 3D versus 4D PET/CT derived treatment volumes warrants further investigation. PMID- 29397272 TI - Eosinophilic esophagitis and symptoms possibly related to eosinophilic esophagitis in oral immunotherapy. PMID- 29397274 TI - Enhanced coronary calcium visualization and detection from dual energy chest x rays with sliding organ registration. AB - We have developed a technique to image coronary calcium, an excellent biomarker for atherosclerotic disease, using low cost, low radiation dual energy (DE) chest radiography, with potential for widespread screening from an already ordered exam. Our dual energy coronary calcium (DECC) processing method included automatic heart silhouette segmentation, sliding organ registration and scatter removal to create a bone-image-like, coronary calcium image with significant reduction in motion artifacts and improved calcium conspicuity compared to standard, clinically available DE processing. Experiments with a physical dynamic cardiac phantom showed that DECC processing reduced 73% of misregistration error caused by cardiac motion over a wide range of heart rates and x-ray radiation exposures. Using the functional measurement test (FMT), we determined significant image quality improvement in clinical images with DECC processing (p < 0.0001), where DECC images were chosen best in 94% of human readings. Comparing DECC images to registered and projected CT calcium images, we found good correspondence between the size and location of calcification signals. In a very preliminary coronary calcium ROC study, we used CT Agatston calcium score >50 as the gold standard for an actual positive test result. AUC performance was significantly improved from 0.73 +/- 0.14 with standard DE to 0.87 +/- 0.10 with DECC (p = 0.0095) for this limited set of surgical patient data biased towards heavy calcifications. The proposed DECC processing shows good potential for coronary calcium detection in DE chest radiography, giving impetus for a larger clinical evaluation. PMID- 29397275 TI - Rotation-covariant tissue analysis for interstitial lung diseases using learned steerable filters: Performance evaluation and relevance for diagnostic aid. AB - A novel method to detect and classify several classes of diseased and healthy lung tissue of interstitial lung diseases is presented, as these diseases are hard to diagnose and differentiate. Local organizations of image directions at several scales drive the process of creating discriminative lung tissue texture signatures using spatial and Fourier domain information extracted from the images. The signatures are generated for four diseased tissue classes and healthy tissue, all of which appear in the Interstitial Lung Disease (ILD) database, using a novel one-versus-one approach for learning discriminative filter signatures. A multiclass tissue classification accuracy of 80.31% is observed using Radial Basis Function (RBF) Support Vector Machines (SVMs). The presented method compares well against a variety of state-of-the-art approaches. Another strong feature of our approach is the ability to access the individual class probabilities before a final classification decision is made. This enables an analysis of the causes of misclassification in this paper. We also make the case against total reliance on the accuracy of the ground truth given that the ILD database only contains a single label for a specific region and sometimes more than one pattern can be present, particularly for regions classified as healthy tissue. Measures to address misclassifications in this context are also proposed. PMID- 29397273 TI - Anxiety Cells in a Hippocampal-Hypothalamic Circuit. AB - The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA) but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA but not BA increased anxiety and avoidance, while activation of terminals in BA but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence-related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can rapidly influence innate anxiety behavior. PMID- 29397276 TI - Larval digestion of different manure types by the black soldier fly (Diptera: Stratiomyidae) impacts associated volatile emissions. AB - : Volatile emissions from decomposing animal waste are known environmental pollutants. The black soldier fly, Hermetia illucens (L.), is being evaluated for industrialization as a means to recycle wastes and produce protein for use as food and feed. We examined the ability of black soldier fly larvae to reduce odorous compounds associated with animal wastes. Black soldier fly larvae were reared under laboratory conditions on poultry, swine, and dairy manure at feed rates of 18.0 and 27.0 g every other day until 40% reached the prepupal stage. Volatile emissions were collected and analyzed from freshly thawed as well as the digested waste when 90% of the black soldier fly larvae reached the prepupal stage. Volatiles were also collected simultaneously from manure not inoculated with black soldier fly larvae (non-digested) and held under similar conditions. Manure samples were analyzed for relative amounts of nine select odorous volatile organic compounds: phenol, 4-methylphenol, indole, 3-methylindole, propanoic acid, 2-methylpropanoic acid, butanoic acid, 3-methylbutanoic acid and pentanoic acid. Black soldier fly larvae reduced emissions of all volatile organic compounds by 87% or greater. Complete reductions were observed for 2-methly propanoic acid in digested poultry manure, phenol, 4-methylphenol, indole and all five fatty acids in digested swine manure, and 4-methylphenol, indole, 3 methylindole and all five acids in digested dairy manure. This study is the first to identify volatile emissions from manure digested by black soldier fly larvae and compare to those found in non-digested manure. These data demonstrate additional benefits of using black soldier fly larvae as a cost-effective and environmentally friendly means of livestock manure management in comparison to current methods. CAPSULE: Black soldier fly larvae are capable of altering the overall profile of volatile organic compounds and reducing levels of targeted odorous compounds in livestock manure. PMID- 29397277 TI - Recovery of rare earths from spent NdFeB magnets of wind turbine: Leaching and kinetic aspects. AB - Increasing demands of rare earth (RE) metals for advanced technological applications coupled with the scarcity of primary resources have led to the development of processes to treat secondary resources like scraps or end of life products that are often rich in such metals. Spent NdFeB magnet may serve as a potential source of rare earths containing around ~30% of neodymium and other rare earths. In the present investigation, a pyro-hydrometallurgical process has been developed to recover rare earth elements (Nd, Pr and Dy) from the spent wind turbine magnet. The spent magnet is demagnetized and roasted at 1123 K to convert rare earths and iron to their respective oxides. Roasting of the magnet not only provides selectivity, but enhances the leaching efficiency also. The leaching of the roasted sample with 0.5 M hydrochloric acid at 368 K, 100 g/L pulp density and 500 rpm for 300 min selectively recovers the rare earth elements almost quantitatively leaving iron oxide in the residue. Leaching of rare earth elements with hydrochloric acid follows the mixed controlled kinetic model with activation energy (Ea) of 30.1 kJ/mol in the temperature range 348-368 K. The leaching mechanism is further established by characterizing the leach residues obtained at different time intervals by scanning electron microscopy- energy dispersive X-ray spectroscopy (SEM-EDS) and X-ray diffraction (XRD). Individual rare earth elements from the leach solution containing 16.8 g/L of Nd, 3.8 g/L Pr, 0.28 g/L of Dy and other minor impurity elements could be separated by solvent extraction. However, mixed rare earth oxide of 99% purity was produced by oxalate precipitation followed by roasting. The leach residue comprising of pure hematite has a potential to be used as pigment or can find other applications. PMID- 29397278 TI - Remote sensing of methane and nitrous oxide fluxes from waste incineration. AB - Incomplete combustion processes lead to the formation of many gaseous byproducts that can be challenging to monitor in flue gas released via chimneys. This study presents ground-based remote sensing approaches to make greenhouse gas (GHG) flux measurements of methane (CH4) and nitrous oxide (N2O) from a waste incineration chimney at distances of 150-200 m. The study found emission of N2O (corresponding to 30-40 t yr-1), which is a consequence of adding the reduction agent urea to decrease NOX emissions due to NOX regulation; a procedure that instead increases N2O emissions (which is approximately 300 times more potent as a GHG than CO2 on a 100-year time scale). CH4 emissions of 7-11 t yr-1 was also detected from the studied chimney despite the usage of a high incineration temperature. For this particular plant, local knowledge is high and emission estimates at corresponding levels have been reported previously. However, emissions of CH4 are often not included in GHG emission inventories for waste incineration. This study highlights the importance of monitoring combustion processes, and shows the possibility of surveying CH4 and N2O emissions from waste incineration at distances of several hundred meters. PMID- 29397279 TI - Cost of Tobacco-related Cancer Hospitalizations in the U.S., 2014. AB - INTRODUCTION: Smoking has been causally linked to 12 tobacco-related cancers: oral cavity and pharynx, esophagus, stomach, colon and rectum, liver, pancreas, larynx, lung, cervix, bladder, kidney, and acute myeloid leukemia. Tobacco related cancers-related morbidity and mortality have been well described, but little is known about the prevalence of tobacco-related cancer hospitalizations and associated costs. This study estimates the annual number of tobacco-related cancer hospitalizations and their associated direct medical costs in the U.S. METHODS: This study examined data from the 2014 National Inpatient Sample, the largest publicly available all-payer inpatient care database in the U.S. The authors calculated number of hospitalizations, total costs, length of stay, and cost per stay for tobacco-related cancer hospitalizations and cancer hospitalizations not related to tobacco. RESULTS: In 2014, there were an estimated 461,295 annual tobacco-related cancer hospitalizations at a cost of $8.2 billion in the U.S. Tobacco-related cancers accounted for 45% of total cancer hospitalizations and cancer hospitalization costs. Compared with cancer hospitalizations not related to tobacco, tobacco-related cancer hospitalizations had a longer mean length of stay (6.8 vs 5.7 days). CONCLUSIONS: The burden of tobacco-related cancer hospitalizations is substantial in the U.S. These findings highlight the importance of tobacco prevention and cessation efforts to decrease the burden of tobacco-related cancers in the U.S. PMID- 29397280 TI - The Affordability of Providing Sexually Transmitted Disease Services at a Safety net Clinic. AB - INTRODUCTION: Sexually transmitted diseases continue to increase in the U.S. There is a growing need for financially viable models to ensure the longevity of safety-net sexually transmitted disease clinics, which provide testing and treatment to high-risk populations. This micro-costing analysis estimated the number of visits required to balance cost and revenue of a sexually transmitted disease clinic in a Medicaid expansion state. METHODS: In 2017, actual and projected cost and revenues were estimated from the Rhode Island sexually transmitted disease clinic in 2015. Projected revenues for a hypothetical clinic offering a standard set of sexually transmitted disease services were based on Medicaid; private ("commercial") insurance; and institutional ("list price") reimbursement rates. The number of visits needed to cover clinic costs at each rate was assessed. RESULTS: Total operating cost for 2,153 clinic visits was estimated at $255,769, or $119 per visit. Laboratory testing and salaries each accounted for 44% of operating costs, medications for treatment 7%, supplies 5%, and 28% of visits used insurance. For a standard clinic offering a basic set of sexually transmitted disease services to break even, a projected 73% of visits need to be covered at the Medicaid rate, 38% at private rate, or 11% at institutional rate. CONCLUSIONS: Sexually transmitted disease clinics may be financially viable when a majority of visits are billed at a Medicaid rate; however, mixed private/public models may be needed if not all visits are billed. In this manner, sexually transmitted disease clinics can be solvent even if not all visits are billed to insurance, thus ensuring access to uninsured or underinsured patients. PMID- 29397281 TI - Demographic and socioenvironmental predictors of premorbid marijuana use among patients with first-episode psychosis. AB - OBJECTIVE: We identified, in subjects with first-episode psychosis, demographic and socioenvironmental predictors of three variables pertaining to premorbid marijuana use: age at initiation of marijuana use, trajectories of marijuana use in the five years prior to onset of psychosis, and the cumulative "dose" of marijuana intake in that same premorbid period. METHODS: We enrolled 247 first episode psychosis patients and collected data on lifetime marijuana/alcohol/tobacco use, age at onset of psychosis, diverse socioenvironmental variables, premorbid adjustment, past traumatic experiences, perceived neighborhood-level social disorder, and cannabis use experiences. Bivariate tests were used to examine associations between the three premorbid marijuana use variables and hypothesized predictors. Regression models determined which variables remained independently significantly associated. RESULTS: Age at initiation of cigarette smoking was linked to earlier initiation, faster escalation, and higher cumulative dose of premorbid marijuana use. During childhood, poorer academic performance was predictive of an earlier age at initiation of marijuana use, while poorer sociability was related to more rapid escalation to daily use and a higher cumulative dose. As expected, experiencing euphoric effects was positively correlated with trajectories and cumulative dose, but having negative experiences was unrelated. Traumatic childhood/adolescent experiences were correlated with rapid escalation and amount of marijuana used, but not with age at initiation of marijuana use. CONCLUSION: These data expand the very limited literature on predictors of premorbid marijuana use in first episode psychosis. Given its association with earlier age at onset of psychosis, and poorer outcomes among first-episode patients, prevention and treatment efforts should be further developed. PMID- 29397282 TI - Non-invasive brain stimulation for negative symptoms in schizophrenia: An updated systematic review and meta-analysis. AB - BACKGROUND: Schizophrenia is a mental disorder with significant socioeconomic burden. Although current pharmacological treatments are effective for treating positive symptoms, medications have little-to-no effect in the treatment of negative symptoms. OBJECTIVE: To assess the efficacy of non-invasive brain stimulation (NIBS) for negative symptoms in schizophrenia in randomized clinical trials (RCTs). METHODS: A systematic review in Medline and Cochrane Library databases was performed up to May 31, 2017. The primary outcome was Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I2 and chi2 tests. Publication bias was assessed using Begg's funnel plot. RESULTS: 31 RCTs (n = 1272) were included, most with small-to-modest sample sizes. Both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were superior to sham (Hedges' g = 0.19; 95% CI 0.07-0.32; and 0.5; 0.02-0.97, respectively). Only one study evaluated the use of transcutaneous auricular vagus nerve stimulation (taVNS). The funnel plot and Eggers test showed that the risk of publication bias was low. In relation to heterogeneity, we found an I2 of 0% (p = 0.749) and 51.3% (0.055) for rTMS and tDCS, respectively. CONCLUSION: Both rTMS and tDCS were superior to sham stimulation for ameliorating negative symptoms in schizophrenia. We found no considerable heterogeneity or publication bias in our analysis, corroborating the strength of our findings. Not enough studies on other NIBS techniques, such as taVNS, were found for an isolated analysis. Further RCTs with larger sample sizes are needed to clarify the specific impact of NIBS on negative symptoms in schizophrenia. PMID- 29397283 TI - The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats. AB - Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24 h before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24 h and 7 d after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK 801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24 h after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation. PMID- 29397284 TI - Preservation of conductive propagation after surgical repair of cardiac defects with a bio-engineered conductive patch. AB - BACKGROUND: Both stable and biodegradable biomaterials have been used to surgically repair congenital cardiac defects. However, neither type of biomaterial can conduct electrical activity. We evaluated the conductivity and efficacy of a newly synthesized conductive polypyrrole-chitosan (Ppy+Chi) gelfoam patch to support cardiomyocyte (CM) viability and function in vitro and to surgically repair a cardiac defect in vivo. METHODS: Ppy+Chi was incorporated into gelfoam (Gel) to form a 3-dimensional conductive patch. In vitro, patch characteristics were evaluated and biocompatibility and bioconductivity were investigated by culturing neonatal rat CMs on the patches. In vivo, a full thickness right ventricular outflow tract defect was created in rats and the patches were implanted. Four weeks after patch repair, cardiac electrical activation and conduction velocity were evaluated using an optical mapping system. RESULTS: In vitro, the Ppy+Chi+Gel patch had a higher mean breaking stress than the Gel or Chi+Gel patches, and the highest conductivity. None of the patches altered cell growth. The Ca2+ transient velocity of CMs cultured on the Ppy+Chi+Gel patch was 2.5-fold higher than that of CMs cultured on the Gel or Chi+Gel patches. In vivo, optical mapping at 4 weeks post-implantation demonstrated that Ppy+Chi+Gel patch-implanted hearts had faster conduction velocities, as measured on the epicardial surface. Continuous electrocardiographic telemetry did not reveal any pathologic arrhythmias after patch implantation. Ex-vivo patch conductivity testing also revealed that the Ppy+Chi+Gel patch was more conductive than the Gel and Chi+Gel patches. CONCLUSIONS: The Ppy+Chi+Gel patch was biocompatible, safe and conductive, making it an attractive candidate for a new biomaterial platform for cardiac surgical repair to preserve synchronous ventricular contraction. PMID- 29397285 TI - Correlation of Patient-Reported Outcome Measurement Information System Physical Function Upper Extremity Computer Adaptive Testing, With the American Shoulder and Elbow Surgeons Shoulder Assessment Form and Simple Shoulder Test in Patients With Shoulder Pain. AB - PURPOSE: To evaluate the Patient-Reported Outcome Measurement Information System Physical Function Upper Extremity Computer Adaptive Testing (PROMIS PFUE CAT) measurement tool against the already validated American Shoulder and Elbow Surgeons Shoulder Assessment Form (ASES) and the Simple Shoulder Test (SST) in patients presenting with shoulder pain and determine the responder burden for each of the 3 surveys. METHODS: Ninety patients presenting with shoulder pain were asked to fill out the ASES, SST, and PROMIS PFUE CAT. The time for completion of each survey was measured to determine responder burden, and the Pearson correlation between the 3 instruments was defined as excellent (r > 0.7), excellent-good (0.61 <= r <= 0.7), good (0.31 <= r <= 0.6), and poor (0.2 <= r <= 0.3). RESULTS: The PROMIS PFUE CAT showed an excellent correlation with the SST (r = 0.82, P < .001) and ASES (r = 0.72, P < .001). The average time to complete SST, ASES, and PROMIS PFUE CAT was 92.8 +/- 35.8, 142.3 +/- 60.1, and 61.3 +/- 28.8 seconds, respectively. The time to complete the PROMIS PFUE CAT was significantly less than both the SST (P < .001) and ASES (P < .001). CONCLUSIONS: The PROMIS PFUE CAT showed an excellent correlation with the previously validated ASES and SST in patients with shoulder pain. The time saving of the PROMIS PFUE CAT was found to be smaller than that of the ASES and SST but shows that moving forward, using the PROMIS PFUE CAT would not place any additional burden on the patient filling out the survey. The lack of ceiling or floor effects with the PROMIS PFUE CAT indicates its ability to differentiate both high and low functioning patients. All of these findings indicate that the PROMIS PFUE CAT is an adequate tool for the evaluation of patients with shoulder pain and should be used in these patients going forward. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29397286 TI - Arthroscopic Fixation of Tibial Eminence Fractures: A Biomechanical Comparative Study of Screw, Suture, and Suture Anchor. AB - PURPOSE: To compare biomechanical outcomes of 4 different arthroscopic techniques for fixation of tibial eminence fractures. METHODS: Twenty-four skeletally mature, fresh-frozen cadaveric knees were divided into 4 comparison groups based on the fixation method: screw fixation (group A), traditional sutures fixation with 2 FiberWire sutures (group B), a modified suture technique with 2 FiberWire sutures that created neckwear knots to firmly trap the fracture fragment (group C), or suture anchors which was based on the suture bridge technique primarily used in the shoulder for repair of rotator cuff tears and greater tuberosity fractures (group D). A tibial eminence fracture was created in each knee for subsequent fixation. After fixation, each knee underwent cyclic loading of 100 N to assess the displacement change after 500 cycles of the fixation construct. Afterward, a single tensile failure test load was performed to assess the ultimate failure load, stiffness, and failure mode for each specimen. RESULTS: All specimens survived cyclic testing and were subsequently loaded to failure. Group C had the highest ultimate failure load (P < .05) and group D had the lowest displacement compared with the other 3 groups (P < .05). Different failure modes were found among the 4 groups. CONCLUSIONS: Suture fixation using the neckwear knots technique provides superior fixation with regard to higher ultimate failure load, and absorbable suture anchor fixation with the suture bridge technique provides less displacement under cyclic loading conditions. Both techniques exhibited superior biomechanical properties compared with traditional screw and suture fixation. CLINICAL RELEVANCE: The new techniques showed satisfactory biomechanical properties and provided more choice for surgeons in the treatment of tibial eminence fractures. PMID- 29397287 TI - Clinical Outcomes After Arthroscopic Release of Patellofemoral Arthrofibrosis in Patients With Prior Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: The purpose of this study was to review our results of arthroscopic release in patients diagnosed with refractory patellofemoral arthrofibrosis (PFA) after having undergone anterior cruciate ligament (ACL) reconstruction. METHODS: From 2006 to 2016, all patients who underwent arthroscopic release for refractory PFA after ACL reconstruction were reviewed retrospectively. All patients then completed surveys containing the International Knee Documentation Committee (IKDC) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and were asked 2 subjective questions. Patients included in the study exhibited at least one finding of PFA and failed conservative treatment for at least 3 months. Included patients also had a minimum of 12 months of postoperative follow up after PFA release. Patients who underwent any other concomitant surgery in the same operative setting as arthroscopic release for PFA were excluded from the study. RESULTS: Thirty-two patients were included in the study. The mean age was 32.8 years (range, 19-58 years) with an average follow-up of 43.6 months (range, 16-98 months). There was a statistically significant increase preoperatively to postoperatively in the IKDC score from 49.6 to 69.4 (P < .00001), and 16 of 32 patients (50%) achieved a minimal clinically important difference (MCID). WOMAC scores also significantly increased from 74 to 85.3 (P < .00001), with 15 of 32 patients (47%) achieving MCID. Thirty-one patients (97%) reported that the procedure helped, and 25 patients (78%) said they would have the procedure again. CONCLUSIONS: Arthroscopic release, consisting of an extended lateral release, debridement of the notch/fat pad, and manual manipulation of the patella, results in significant increases in validated outcome measures and is well tolerated by patients. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29397288 TI - Contribution of the Ligamentum Teres to Hip Stability in the Presence of an Intact Capsule: A Cadaveric Study. AB - PURPOSE: To determine the contribution of the ligamentum teres (LT) to hip stability in the presence of an intact capsule with special attention to the change in range of motion and femoral head translation. METHODS: Seven fresh frozen cadaveric pelvises were used. Following visual inspection of the LT at different hip positions, internal rotation angles were measured at 10 degrees of extension and at 0 degrees of flexion, while external rotation was measured at 60 degrees , 90 degrees , and 110 degrees of flexion with different hip abduction angles using electromagnetic motion tracking sensor. Femoral head translations were measured simultaneously. The tests were repeated after resection of the LT. The capsule was left intact for all test conditions. The results were compared between intact and LT resected conditions when torque of 2 and 4 Nm was applied. RESULTS: Compared with the intact hip, the LT resected hip showed no significant difference when 2 Nm torque was applied in all scenarios. With 4 Nm torque application, significant increase in external rotation was found at 60 degrees and at 90 degrees of flexion (1.7 degrees +/- 0.8 degrees and 2.1 degrees +/- 1.0 degrees , respectively). Significant difference was also noted at 60 degrees , 90 degrees , and 110 degrees of flexion when the hip was in the adducted position while at 90 degrees in the abducted hip. However, LT resection did not show significant change in internal rotation. There was no significant difference in the translation distance of the femoral head in the intact hip compared with the LT resected hip (0.77-1.11 mm vs 0.79-1.29 mm). CONCLUSIONS: Our results indicate that within the physiologic range of motion, LT can minimally limit external rotation when the hip is in the flexed position but does not contribute to translation stability. CLINICAL RELEVANCE: In the hip with intact capsule, LT deficiency can result in a slight increase in range of motion, but its contribution to stability is questionable. PMID- 29397289 TI - Randomized Controlled Trials for Arthroscopy in Degenerative Knee Disease: Was Conservative Therapy Appropriately Tried Prior to Arthroscopy? AB - PURPOSE: We aimed to determine if the randomized controlled trials (RCTs) evaluated in the most recent meta-analysis on arthroscopic surgery for degenerative knee arthritis included documented trials of appropriate conservative treatment prior to randomization. METHODS: We selected all RCTs of the most recent meta-analysis by Brignardello-Petersen and recorded for each RCT, if physiotherapy prior to randomization was mandatory. We compared the treatment effect of arthroscopy in studies in which physiotherapy prior to randomization was mandatory versus studies in which it was not. This review was registered in the PROSPERO database (CRD42017070091). RESULTS: Of the 13 RCTs in the meta analysis, there were 2 in which physiotherapy prior to randomization was mandatory. In 1 additional multicenter RCT, prior conservative treatment was mentioned as mandatory in the publication, but not in the protocol. The treatment effects attributed to arthroscopy in terms of short-term pain (P = .0037), short term function (P = .0309), and long-term function (P = .0012) were larger in studies in which prior physiotherapy was mandatory. CONCLUSIONS: Although the most recent meta-analysis claims that it is based "on patients who do not respond to conservative treatment," physiotherapy was mandatory prior to randomization only in 2 of the 13 studies. As several orthopaedic guidelines recommend that the first line of treatment in patients with degenerative arthritis of the knee should be conservative, for instance with physiotherapy, and the question of performing arthroscopy arises once conservative treatment fails, 11 of the 13 RCTs failed to adhere to these accepted guidelines. Therefore, patient selection in these 11 studies may not represent the typical indications for arthroscopy, where patients have tried conservative management prior to being offered surgery. When comparing studies where prior physiotherapy was mandatory to studies in which it was not mandatory, there were statistically significant effects favoring arthroscopy in terms of pain in the short term, and for function both in the short and the long term. These findings suggest that the treatment effects attributed to arthroscopy were higher when prior physiotherapy was mandatory. Given these findings, the external validity of most of these RCTs, and the resulting "strong recommendation against the use of arthroscopy in nearly all patients with degenerative knee disease," is called into question. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. PMID- 29397290 TI - Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement. AB - Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD. PMID- 29397291 TI - A Randomized Controlled Trial Examining the Effect of the Addition of the Mandibular Block to Cervical Plexus Block for Carotid Endarterectomy. AB - OBJECTIVES: Although the cervical plexus block generally provides adequate analgesia for carotid endarterectomy, pain caused by metal retractors on the inferior surface of the mandible is not prevented by the cervical block. Different pain relief methods can be performed for patients who experience discomfort in these areas. In this study, the authors evaluated the effect of mandibular block in addition to cervical plexus block on pain scores in carotid endarterectomy. DESIGN: A prospective, randomized, controlled trial. SETTING: Training and research hospital. PARTICIPANTS: Patients who underwent a carotid endarterectomy. INTERVENTIONS: Patients scheduled for carotid endarterectomy under cervical plexus block were randomized into 2 groups: group 1 (those who did not receive a mandibular block) and group 2 (those who received a mandibular block). The main purpose of the study was to evaluate the mandibular block in addition to cervical plexus block in terms of intraoperative pain scores. MEASUREMENTS AND MAIN RESULTS: Intraoperative visual analog scale scores were significantly higher in group 1 (p = 0.001). The amounts of supplemental 1% lidocaine and intraoperative intravenous analgesic used were significantly higher in group 1 (p = 0.001 and p = 0.035, respectively). Patient satisfaction scores were significantly lower in group 1 (p = 0.044). The amount of postoperative analgesic used, time to first analgesic requirement, postoperative visual analog scale scores, and surgeon satisfaction scores were similar in both groups. There was no significant difference between the groups with respect to complications. No major neurologic deficits or perioperative mortality were observed. CONCLUSIONS: Mandibular block in addition to cervical plexus block provides better intraoperative pain control and greater patient satisfaction than cervical plexus block alone. PMID- 29397292 TI - ACGME Accreditation Guide for Adult Cardiothoracic Anesthesiology Fellowship. PMID- 29397293 TI - Report on Cardiac Anesthesia Progress and Challenges in China. PMID- 29397295 TI - Glenoid neck Hounsfield units on computed tomography can accurately identify patients with low bone mineral density. AB - BACKGROUND: Osteoporosis is a costly and morbid disease with the first presentation often with a fragility fracture. The purpose of this study was to assess whether Hounsfield unit (HU) measurements on shoulder computed tomography could identify patients at risk of osteoporosis and aid in its diagnosis. METHODS: We identified patients who had both a computed tomography scan of the glenoid and a dual-energy x-ray absorptiometry scan. Dual-energy x-ray absorptiometry results and HU measurements of the patients' glenoid were recorded. Differences in HU measurements between patients with normal and abnormal central bone mineral density (BMD) were assessed. Correlations were calculated, and receiver operating characteristics were examined. RESULTS: A total of 51 glenoids met the criteria. The mean glenoid HU measurement was 140.6 (95% confidence interval [CI], 120.1-161.1) in the osteoporotic group, 168.1 (95% CI, 152.7-183.5) in the osteopenic group, and 233.2 (95% CI, 210.1-256.4) in the normal BMD group (P < .001). There was a significant correlation between mean glenoid HU measurement and patients' t scores in the femoral neck (r = 0.581), total hip (r = 0.524), and lumbar spine (r = 0.345). The area under the receiver operating characteristic curve was 0.918. With 197 HUs used as the cutoff for diagnosis of abnormal BMD, the positive predictive value was 96.6%. With 257.1 HUs used as the cutoff, the negative predictive value was 100%. CONCLUSION: A patient with an HU measurement below 197 has a 97% chance of having low BMD, and a patient with a measurement over 257 likely has normal BMD. In patients with measurements between these values, a definitive diagnosis should be aggressively pursued. Opportunistic screening for a modifiable disease that has significant morbidity and mortality rates at no additional cost, radiation, or time is of great value. PMID- 29397294 TI - A prospective study of coracoclavicular ligament reconstruction with autogenous peroneus longus tendon for acromioclavicular joint dislocations. AB - BACKGROUND: Anatomic coracoclavicular (CC) ligament reconstruction (ACCR) provides good outcomes for Rockwood type III and VI acromioclavicular (AC) joint dislocations. Various grafts have been used, but complications from graft harvesting are not uncommon. This study examined the clinical and radiographic outcomes of patients with AC joint dislocations repaired with the autogenous anterior half of the peroneus longus tendon (AHPLT) to achieve ACCR. METHODS: Patients with a Rockwood type III to V AC joint dislocation and magnetic resonance imaging of the disruption of the CC ligaments, as well as the AC capsule, were prospectively recruited. Patients received ACCR using an autogenous AHPLT graft and were evaluated clinically and radiographically preoperatively and at 1, 3, 6, and 12 months postoperatively. RESULTS: A total of 18 patients (mean age, 51 years) were prospectively recruited and received an autogenous AHPLT graft ACCR. Fifteen patients completed clinical and radiographic follow-up examinations at 12 months. The mean Constant score (CS) was 51 preoperatively and 93 at 12 months (P <.005). No significant difference was noted at 12 months between the CS of the injured and contralateral shoulder. The mean American Orthopedic Foot and Ankle Society score at 12 months was 99, and this was not different from the value at any other time point. Loss of reduction occurred in 10 patients (56%), and tunnel widening was observed in 9 (50%), but neither was significantly correlated with functional outcome. CONCLUSION: Autogenous AHPLT appears to be a reliable tendon graft source for CC ligament reconstruction. PMID- 29397296 TI - Carmen Gerlach. PMID- 29397298 TI - Detection of respiratory bacterial pathogens causing atypical pneumonia by multiplex Lightmix(r) RT-PCR. AB - Pneumonia is a severe infectious disease. In addition to common viruses and bacterial pathogens (e.g. Streptococcus pneumoniae), fastidious respiratory pathogens like Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella spp. can cause severe atypical pneumonia. They do not respond to penicillin derivatives, which may cause failure of antibiotic empirical therapy. The same applies for infections with B. pertussis and B. parapertussis, the cause of pertussis disease, that may present atypically and need to be treated with macrolides. Moreover, these fastidious bacteria are difficult to identify by culture or serology, and therefore often remain undetected. Thus, rapid and accurate identification of bacterial pathogens causing atypical pneumonia is crucial. We performed a retrospective method evaluation study to evaluate the diagnostic performance of the new, commercially available Lightmix(r) multiplex RT-PCR assay that detects these fastidious bacterial pathogens causing atypical pneumonia. In this retrospective study, 368 clinical respiratory specimens, obtained from patients suffering from atypical pneumonia that have been tested negative for the presence of common agents of pneumonia by culture and viral PCR, were investigated. These clinical specimens have been previously characterized by singleplex RT-PCR assays in our diagnostic laboratory and were used to evaluate the diagnostic performance of the respiratory multiplex Lightmix(r) RT-PCR. The multiplex RT-PCR displayed a limit of detection between 5 and 10 DNA copies for different in-panel organisms and showed identical performance characteristics with respect to specificity and sensitivity as in-house singleplex RT-PCRs for pathogen detection. The Lightmix(r) multiplex RT-PCR assay represents a low-cost, time-saving and accurate diagnostic tool with high throughput potential. The time to-result using an automated DNA extraction device for respiratory specimens followed by multiplex RT-PCR detection was below 4 h, which is expected to significantly improve diagnostics for atypical pneumonia-associated bacterial pathogens. PMID- 29397299 TI - Transoral robotic surgery of parapharyngeal space tumours: a series of four cases. AB - Tumours arising from the parapharyngeal space (PPS) represent less than 1% of all head and neck tumours. Salivary gland tumours account for 40-50% of PPS lesions and are located in the pre-styloid parapharyngeal space. Pleomorphic adenomas represent 80-90% of salivary tumours in the PPS. Recently, transoral robotic surgery (TORS) has become common in head and neck surgery as a minimally invasive procedure. Four cases of benign PPS tumour treated with TORS are presented here. Preoperative diagnosis was conducted by fine needle aspiration biopsy and magnetic resonance imaging, and the results were used to plan the correct surgical approach. One case required a change of approach to conventional transoral blunt dissection. Patients required pain control and reported dysphagia symptoms for a period of weeks, but no nasogastric tube was needed at any time. This case series indicates that TORS is a safe surgical procedure for the excision of benign tumours of the PPS in selected cases. PMID- 29397300 TI - Effect of Helmet Use on Traumatic Brain Injuries and Other Head Injuries in Alpine Sport. AB - INTRODUCTION: Sport helmet effectiveness in preventing traumatic brain injury (TBI) has been repeatedly questioned. This study assesses the effect of helmet use on risk of TBI and other types of head injury (OTHI) in alpine sports. METHODS: From 2012 to 2014, data on the injured population were collected by physicians in on-mountain clinics in 30 French ski resorts, and interviews were conducted on the slope to sample a noninjured control population. Two sets of cases (1425 participants with TBI and 1386 with OTHI) were compared with 2 sets of controls (2145 participants without injury and 40,288 with an injury to a body part other than the head). The effect of helmet use on the risk of TBI and OTHI was evaluated with a multivariate logistic regression adjusted for age, sex, sport, skill level, crash type, and crash location. RESULTS: Using participants without injury as control, we found that helmet wearers were less likely to sustain any head injury (odds ratio [OR]TBI = 0.65; OROTHI = 0.42). When considering participants with an injury to another body part as control, the risk of OTHI was lower among helmet wearers (OROTHI: 0.61). However, no significant effect was found for the risk of TBI. Participants with low skill levels, those aged <26 and >50 years, snowboarders, and those involved in collision and in snowpark accidents were at higher risk of head injury. CONCLUSIONS: This study confirms the effectiveness of helmets in protecting users from head injuries but questions their effects on TBI, especially concussion. PMID- 29397297 TI - Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. AB - The functional capacities of natural killer (NK) cells differ within and between individuals, reflecting considerable genetic variation. 'Licensing/arming', 'disarming', and 'tuning' are models that have been proposed to explain how interactions between MHC class I molecules and their cognate inhibitory receptors - Ly49 in mice and KIR in humans - 'educate' NK cells for variable reactivity and sensitivity to inhibition. In this review we discuss recent progress toward understanding the genetic, epigenetic, and molecular features that titrate NK effector function and inhibition, and the impact of variable NK cell education on human health and disease. PMID- 29397301 TI - [Vocal cord dyskinesia and/or asthma]. AB - INTRODUCTION: Vocal cord dyskinesia or vocal cord dysfunction (VCD) is characterized by intermittent abnormal adduction of the vocal cords leading to airflow limitation at the level of the larynx, in the absence of local organic disease. It may occur in isolation or in association with asthma. The pathophysiology is complex and poorly understood. Wheeze, stridor or apparent upper airway obstruction are the most common symptoms. It occurs in a wide age range, more commonly in women, and diagnosis is often delayed and leads to unnecessary treatments (intubation, tracheostomy and high dose steroids). METHODS: A retrospective study of 15 cases of VCD (8 cases of isolated VCD and 7 cases of VCD with associated asthma) describing the main clinical features and the diagnosis strategy. RESULTS: Apparent upper airway obstruction, with or without associated asthma, requires an ear nose and throat examination with laryngoscopy to confirm the paradoxical adduction of the vocal cords during an acute episode of dyspnoea or during a provocation test with triggers like exercise or exposure to irritants, and for the purpose of differential diagnosis. CONCLUSIONS: VCD remains under-appreciated and misdiagnosed, often by mimicking asthma with which it can be associated. A delayed diagnosis by emergency specialists, pulmonologists and ear nose and throat surgeons leads to unnecessary treatments and morbidity before specific therapy can be given. PMID- 29397302 TI - [Smoking attitudes and behavior of the hospital staff Sahloul (Sousse, Tunisia)]. AB - BACKGROUND: Smoking is a major public health problem. Legislation banning smoking in public institutions exists but is not strictly enforced, particularly in health facilities. Therefore health workers have a crucial role to play in the control of smoking on account of their contact with patients and their credibility and moral authority in health matters. They can help patients by their advice and by abstaining from smoking in the hospital themselves. The aim of our study was to determine the prevalence of smoking among medical staff at the University Hospital of Sahloul in Sousse and their attitudes and behaviour with regard to smoking. METHODS: The data came from a descriptive cross-sectional study conducted during the year 2013-2014 using a self-administered questionnaire and included the health personnel of all services and laboratories of the University Hospital of Sahloul in Sousse. RESULTS: The participation rate was 71% (768/1081). Our study population was predominantly female (51%) with a mean age of 37.8 (+/-11.3) years. The overall prevalence of smoking was 21%. It was significantly higher among men (38.8%) than women (4.6%). This prevalence was higher among physicians/pharmacists (29.5%). More than half the smokers (58%) started smoking between the age of 19 and 25 years. Nicotine dependence was moderate among 27.4% and strong among 18.3% of smokers. The average dependence score was 4.1+/-2.4 [0-9] with a median of 4.0. Two-thirds of smokers (66.5%) reported smoking in the workplace. CONCLUSION: Confronted with the problem of tobacco, health institutions should find solutions for the prevention of smoking in hospitals. It seems necessary to train and involve hospital staff in anti tobacco measures and to help smokers to quit in order to make our hospital a tobacco smoke free space. PMID- 29397303 TI - [Impact of routine brain imaging in the initial management of lung cancer]. AB - INTRODUCTION: Brain metastases are a common complication of bronchial carcinoma (BC). There is no consensus as to the need to undertake a systematic search for these lesions during the initial assessment. The aim of this study was to evaluate the contribution of brain imaging in the initial evaluation of patients with CB. METHODS: We undertook a retrospective analysis of patients treated in the Thoracic Oncology Clinic at the Institute Jules-Bordet between 01/09/2008 and 31/08/2013, who were treatment-naive and were having a full diagnostic work-up including brain imaging. RESULTS: Four hundred and sixty-three patients consecutively diagnosed with BC were included. Brain magnetic resonance imaging and/or CT-scan showed brain metastases in 101 patients (21.8%), of whom 67 had no symptoms suggestive of brain metastatic disease. The addition of a brain imaging into the work-up procedure resulted in a stage migration for 30 patients (6.5%), mainly otherwise staged IIIA (n=10) or IIIB (n=14) without brain imaging. CONCLUSION: The addition of brain imaging in the initial assessment of bronchial carcinoma allows the identification of brain metastases in one case among 5, of which 2/3 are asymptomatic. This leads to a change in staging, primarily for disease otherwise considered to be stage III. PMID- 29397304 TI - Capturing the Alzheimer's disease pathological cascade. PMID- 29397306 TI - Anti-inflammatory roles of mesenchymal stromal cells during acute Streptococcus pneumoniae pulmonary infection in mice. AB - BACKGROUND: Pneumonia is the fourth leading cause of death worldwide, and Streptococcus pneumoniae is the most commonly associated pathogen. Increasing evidence suggests that mesenchymal stromal cells (MSCs) have anti-inflammatory roles during innate immune responses such as sepsis. However, little is known about the effect of MSCs on pneumococcal pneumonia. METHODS: Bone marrow-derived macrophages (BMDMs) were stimulated with various ligands in the presence or absence of MSC-conditioned medium. For in vivo studies, mice intranasally inoculated with S. pneumoniae were intravenously treated with MSCs or vehicle, and various parameters were assessed. RESULTS: After stimulation with toll-like receptor (TLR) 2, TLR9 or TLR4 ligands, or live S. pneumoniae, TNF-alpha and interleukin (IL)-6 levels were significantly decreased, whereas IL-10 was significantly increased in BMDMs cultured in MSC-conditioned medium. In mice, MSC treatment decreased the number of neutrophils in bronchoalveolar lavage fluid (BALF) after pneumococcal infection, and this was associated with a decrease in myeloperoxidase activity in the lungs. Levels of proinflammatory cytokines, including TNF-alpha, IL-6, GM-CSF and IFN-gamma, were significantly lower in MSC treated mice, and the bacterial load in the lung after pneumococcal infection was significantly reduced. In addition, histopathologic analysis confirmed a decrease in the number of cells recruited to the lungs; however, lung edema, protein leakage into the BALF and levels of the antibacterial protein lipocalin 2 in the BALF were comparable between the groups. CONCLUSIONS: These results indicate that MSCs could represent a potential therapeutic application for the treatment of pneumonia caused by S. pneumoniae. PMID- 29397307 TI - Human endometrial stem cells: High-yield isolation and characterization. AB - BACKGROUND: Menstrual blood is only recently and still poorly studied, but it is an abundant and noninvasive source of highly proliferative mesenchymal stromal cells (MSCs). However, no appropriate isolation method has been reported due to its high viscosity and high content of clots and desquamated epithelium. METHODS: We studied three different isolation approaches and their combinations: ammonium containing lysing buffer, distilled water and gradient-density centrifugation. We tested the proliferative capacity, morphology, surface markers and pluripotency of the resulting cells. RESULTS: Our isolation method yields up to four million nucleated cells per milliliter of initial blood, of which about 0.2-0.3% are colony-forming cells expressing standard mesenchymal markers CD90, CD105 and CD73, but not expressing CD45, CD34, CD117, CD133 or HLA-G. The cells have high proliferative potential (doubling in 26 h) and the ability to differentiate into adipocytes and osteocytes. Early endometrial MSCs (eMSCs) express epithelial marker cytokeratin 7 (CK7). CK7 is easily induced in later passages in a prohepatic environment. We show for the first time that a satisfactory and stable yield of eMSCs is observed throughout the whole menstrual period (5 consecutive days) of a healthy woman. DISCUSSION: The new cost/yield adequate method allows isolation from menstrual blood a relatively homogenous pool of highly proliferative MSCs, which seem to be the best candidates for internal organ therapy due to their proepithelial background (early expression of CK7 and its easy induction in later passages) and for mass cryobanking due to their high yield and availability. PMID- 29397305 TI - Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. AB - BACKGROUND: Models of Alzheimer's disease propose a sequence of amyloid beta (Abeta) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. METHODS: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Abeta deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18.9 years [SD 3.3] before expected onset), followed by hypometabolism (14.1 years [5.1] before expected onset), and lastly structural decline (4.7 years [4.2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22.2 years before expected onset for Abeta accumulation, 18.8 years before expected onset for hypometabolism, and 13.0 years before expected onset for cortical thinning). INTERPRETATION: Mutation carriers had elevations in Abeta deposition, reduced glucose metabolism, and cortical thinning compared with non carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Abeta, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. FUNDING: US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK. PMID- 29397308 TI - Derivation of male germ cells from induced pluripotent stem cells by inducers: A review. AB - Induced pluripotent stem cells (iPSCs) refer to stem cells that are artificially produced using a new technology known as cellular reprogramming, which can use gene transduction in somatic cells. There are numerous potential applications for iPSCs in the field of stem cell biology becauase they are able to give rise to several different cell features of lineages such as three-germ layers. Primordial germ cells, generated via in vitro differentiation of iPSCs, have been demonstrated to produce functional gametes. Therefore, in this review we discussed past and recent advances in the in vitro differentiation of germ cells using pluripotent stem cells with an emphasis on iPSCs. Although this domain of research is still in its infancy, exploring development mechanisms of germ cells is promising, especially in humans, to promote future reproductive and developmental engineering technologies. While few studies have evaluated the ability and efficiency of iPSCs to differentiate toward male germ cells in vitro by different inducers, the given effect was investigated in this review. PMID- 29397309 TI - Potentials and pitfalls of inverse fluorescence correlation spectroscopy. AB - Inverse Fluorescence Correlation Spectroscopy (iFCS) is a variant of FCS where unlabeled particles in solution, or domains in membranes, displace their surrounding, signal-generating molecules and thereby generate fluctuations. iFCS has to date been applied to unlabeled as well as labeled particles and protein molecules, using fluorescence as well as Raman scattering as a signal source, in diffraction-limited detection volumes as well as in nano-wells, and on fixed surfaces as well as in lipid bilayers. This review describes these applications and discusses the potentials and pitfalls when using iFCS. PMID- 29397310 TI - Characteristics of Symptomatic Intracerebral Hemorrhage in Patient Receiving Direct Oral Anticoagulants: Comparison with Warfarin. AB - BACKGROUND: Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated. METHODS: We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015. RESULTS: Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time. CONCLUSIONS: Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak. PMID- 29397311 TI - Cerebral Neuromonitoring during Carotid Endarterectomy and Impact of Contralateral Internal Carotid Occlusion. AB - BACKGROUND: The aim of this study was to identify the reliability of carotid artery stump pressure (SP) in predicting the neurologic changes and correlation with contralateral internal carotid artery (ICA) occlusion in patients undergoing eversion carotid endarterectomy (CEA). The optimal method for monitoring cerebral perfusion during CEA, performed under either local or general anesthesia, is still controversial. METHODS: We prospectively analyzed 118 consecutive patients undergoing eversion CEA under local anesthesia. We had 78 symptomatic (66%) and 40 asymptomatic patients (33.9%). Selective shunting was performed in patients who developed neurologic changes after carotid clamping regardless of SP. Correlation of preoperative symptom status, a degree of stenosis, status of contralateral ICA, arterial blood pressure, SP value, and the intraoperative need for shunting due to neurologic changes was evaluated for both groups: shunted and nonshunted. RESULTS: Selective shunting was performed in 12 patients (10%). There was no significant difference among the groups regarding the demographic characteristics. Mean carotid clamping time was 14.57 minutes. We had no perioperative mortality, stroke, or myocardial infarction. None of the patients required conversion to general anesthesia. We found a mean SP of 31 mm Hg as a reliable threshold for shunting (P < .001; sensitivity 92.3%; specificity 91.3%). Contralateral carotid occlusion was correlated with the significantly lower SP (27 +/- 13 mm Hg; P = .001) and the higher need for shunt (50%). CONCLUSIONS: SP measurement is a reliable and simple method for monitoring the collateral cerebral perfusion and can predict the need for shunting during CEA. Patients with the contralateral ICA occlusion showed significantly lower SP, although it did not have impact on the outcome. PMID- 29397312 TI - Late Transient Contrast-Induced Encephalopathy after Percutaneous Coronary Intervention. PMID- 29397313 TI - Ischemic and Hemorrhagic Stroke in Bahir Dar, Ethiopia: A Retrospective Hospital Based Study. AB - INTRODUCTION: The epidemiology of stroke in sub-Saharan countries is poorly characterized because of lack of population-based studies and national vital statistics systems with complete death registration. OBJECTIVE: To describe risk factors, clinical presentations, the pattern of brain insult, and outcomes of stroke patients admitted to a hospital in Ethiopia. METHOD: A retrospective hospital-based study was conducted on 508 patients, 303 of whom had computed tomography proven stroke, who were admitted to medical wards of Felege Hiwot Referral Hospital, Bahir Dar Ethiopia, from February 2014 to August 2016. RESULTS: From 508 patients with a clinical diagnosis of stroke, 303 patients had computed tomography and complete medical record. Of the latter, 63% were male and 32% were in the age group 61-70 years. The most common initial clinical presentation was hemiplegia (61%). Common risk factors documented with stroke were hypertension (36.3%), dyslipidemia (20.4%), atrial fibrillation (12.2%), and structural cardiac disease (9.2%). Ischemic stroke comprised 59.4%, whereas 40.6% were hemorrhagic stroke. Only 3.6% patients arrived at the hospital within 3 hours of onset of clinical symptoms. Among subjects with preexisting treated hypertension, 56% had discontinued antihypertensive medications. One third of patients with atrial fibrillation were on warfarin or aspirin. In-hospital mortality rate was 11%. The cerebral cortex was affected in 36.6%. CONCLUSION: Poor adherence to drugs and uncontrolled high blood pressure might have resulted in a high proportion of hemorrhagic stroke. Use of anticoagulants for atrial fibrillation should be standard in patient with risk factors for stroke in Ethiopia. PMID- 29397314 TI - Overload blunts baroreflex only in overreached athletes. AB - OBJECTIVES: Heart rate variability (HRV) is commonly used to diagnose overreaching and monitor athletes' responses to training. Baroreflex sensitivity (BRS) is modified by changes in training load and might be another means to detect overreaching. The goal of this study was to assess BRS and HRV changes in two groups of athletes responding either negatively (FOR) or positively (AF) to similar training overload. DESIGN: Fifteen athletes performed 2-week baseline (BSL) training followed by 3-week overload (+45%; OVL) and 2-week recovery (-20%; RCV). METHODS: HRV, training load and subjective fatigue were measured daily via questionnaires. BRS, salivary cortisol and testosterone, and submaximal exercise and maximal 3-km run performances were measured at the end of each period. RESULTS: Based on their performance change during OVL, 8 athletes were diagnosed as FOR and 7 as AF. Subjective fatigue was increased in FOR athletes during OVL. BRS increased in AF but not in FOR athletes during RCV. At the end of RCV, cortisol and testosterone were higher than BSL in both groups. CONCLUSIONS: Three weeks of similar training overload can induce either performance enhancement or overreaching. The changes in submaximal exercise and maximal performances and in subjective fatigue were the fastest-responding parameters that distinguished the two groups of athletes during OVL. Training overload blunted the increase in BRS in FOR only. Most of the differences in BRS were observed during the recovery period. BRS appears to be a more sensitive parameter than HRV for early monitoring of responses to training. PMID- 29397315 TI - Validation of the Barthel Index in the Spanish population. PMID- 29397316 TI - Leukaemia inhibitory factor in serum and follicular fluid of women with polycystic ovary syndrome and its correlation with IVF outcome. AB - Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian morphology. Leukaemia inhibitory factor (LIF) affects many reproductive activities, including follicular development, embryo implantation and growth. The aim of this study was to evaluate LIF concentrations in serum and follicular fluid of women with PCOS and controls who underwent IVF with embryo transfer (IVF-ET). Serum and follicular fluid LIF concentrations were lower in women with PCOS compared with controls. Oestradiol concentrations in follicular fluid were higher in PCOS subjects compared with controls. LIF concentrations in serum (r = 0.6263, P < 0.05) and follicular fluid (r = 0.7093, P < 0.05) were negatively correlated with oestradiol concentration in the PCOS group. LIF concentrations in follicular fluid showed no difference between women who conceived and women who did not in both PCOS and control groups. However, LIF concentrations in embryo culture medium were higher in women who conceived following IVF compared with women who did not, in combined PCOS and control groups. The findings indicate that low LIF concentrations in serum and follicular fluid may contribute to disordered folliculogenesis in PCOS. LIF concentrations in embryo culture medium may predict the outcome of IVF treatment. PMID- 29397317 TI - A finite element modeling study of peripheral nerve recruitment by percutaneous tibial nerve stimulation in the human lower leg. AB - Percutaneous tibial nerve stimulation (PTNS) is a clinical therapy for treating overactive bladder (OAB), where an un-insulated stainless steel needle electrode is used to target electrically the tibial nerve (TN) in the lower leg. Recent studies in anesthetized animals not only confirm that bladder-inhibitory reflexes can be evoked by stimulating the TN, but this reflex can also be evoked by stimulating the adjacent saphenous nerve (SAFN). Although cadaver studies indicate that the TN and major SAFN branch(es) overlap at the location of stimulation, the extent to which SAFN branches are co-activated is unknown. In this study, we constructed a finite element model of the human lower leg and applied a numeric axon model (MRG model) to simulate the electrical recruitment of TN and SAFN fibers during PTNS. The model showed that up to 80% of SAFN fibers (located at the level of the needle electrode) can be co-activated when electrical pulses are applied at the TN activation threshold, the standard therapeutic amplitude. Both the location of the inserted electrode and stimulation amplitude were important variables that affected the recruitment of SAFN branches. This study suggests further work is needed to investigate the potential therapeutic effects of SAFN stimulation in OAB patients. PMID- 29397318 TI - Highly efficient local delivery of endothelial progenitor cells significantly potentiates angiogenesis and full-thickness wound healing. AB - : Wound therapy with a rapid healing performance remains a critical clinical challenge. Cellular delivery is considered to be a promising approach to improve the efficiency of healing, yet problems such as compromised cell viability and functionality arise due to the inefficient delivery. Here, we report the efficient delivery of endothelial progenitor cells (EPCs) with a bioactive nanofibrous scaffold (composed of collagen and polycaprolactone and bioactive glass nanoparticles, CPB) for enhancing wound healing. Under the stimulation of CPB nanofibrous system, the viability and angiogenic ability of EPCs were significantly enhanced through the activation of Hif-1alpha/VEGF/SDF-1alpha signaling. In vivo, CPB/EPC constructs significantly enhanced the formation of high-density blood vessels by greatly upregulating the expressions of Hif-1alpha, VEGF, and SDF-1alpha. Moreover, owing to the increased local delivery of cells and fast neovascularization within the wound site, cell proliferative activity, granulation tissue formation, and collagen synthesis and deposition were greatly promoted by CPB/EPC constructs resulting in rapid re-epithelialization and regeneration of skin appendages. As a result, the synergistic enhancement of wound healing was observed from CPB/EPC constructs, which suggests the highly efficient delivery of EPCs. CPB/EPC constructs may become highly competitive cell based therapeutic products for efficient impaired wound healing application. This study may also provide a novel strategy to develop bioactive cell therapy constructs for angiogenesis-related regenerative medicine. STATEMENT OF SIGNIFICANCE: This paper reported a highly efficient local delivery of EPCs using bioactive glass-based CPB nanofibrous scaffold for enhancing angiogenesis and wound regeneration. In vitro study showed that CPB can promote the proliferation, migration, and tube formation of EPCs through upregulation of the Hif 1alpha/VEGF/SDF-1alpha signaling pathway, indicating that the bioactivity and angiogenic ability of EPCs can be highly maintained and promoted by the CPB scaffold. Moreover, CPB/EPC constructs effectively stimulated the regeneration of diabetic wounds with satisfactory vascularization and better healing outcomes in a full-thickness wound model, suggesting that the highly efficient delivery of EPCs to wound site facilitates angiogenesis and further leads to wound healing. The high angiogenic capacity and excellent healing ability make CPB/EPC constructs highly competitive in cell-based therapeutic products for efficient wound repair application. PMID- 29397319 TI - Influence of rice straw-derived dissolved organic matter on lactic acid fermentation by Rhizopus oryzae. AB - Rice straw can be used as carbon sources for lactic acid fermentation. However, only a small amount of lactic acid is produced even though Rhizopus oryzae can consume glucose in rice straw-derived hydrolysates. This study correlated the inhibitory effect of rice straw with rice straw-derived dissolved organic matter (DOM). Lactic acid fermentations with and without DOM were conducted to investigate the effect of DOM on lactic acid fermentation by R. oryzae. Fermentation using control medium with DOM showed a similar trend to fermentation with rice straw-derived hydrolysates, showing that DOM contained the major inhibitor of rice straw. DOM assay indicated that it mainly consisted of polyphenols and polysaccharides. The addition of polyphenols and polysaccharides derived from rice straw confirmed that lactic acid fermentation was promoted by polysaccharides and significantly inhibited by polyphenols. The removal of polyphenols also improved lactic acid production. However, the loss of polysaccharides during the removal of polyphenols resulted in low glucose consumption. This study is the first to investigate the effects of rice straw derived DOM on lactic acid fermentation by R. oryzae. The results may provide a theoretical basis for identifying inhibitors and promoters associated with lactic acid fermentation and for establishing suitable pretreatment methods. PMID- 29397320 TI - Deciphering defective amelogenesis using in vitro culture systems. AB - The conventional two-dimensional (2D) in vitro culture system is frequently used to analyze the gene expression with or without extracellular signals. However, the cells derived from primary culture and cell lines frequently deviate the gene expression profile compared to the corresponding in vivo samples, which sometimes misleads the actual gene regulation in vivo. To overcome this gap, we developed the comparative 2D and 3D in vitro culture systems and applied them to the genetic study of amelogenesis imperfecta (AI) as a model. Recently, we found specificity protein 6 (Sp6) mutation in an autosomal-recessive AI rat that was previously named AMI. We constructed 3D structure of ARE-B30 cells (AMI-derived rat dental epithelial cells) or G5 (control wild type cells) combined with RPC C2A cells (rat pulp cell line) separated by the collagen membrane, while in 2D structure, ARE-B30 or G5 was cultured with or without the collagen membrane. Comparative analysis of amelogenesis-related gene expression in ARE-B30 and G5 using our 2D and 3D in vitro systems revealed distinct expression profiles, showing the causative outcomes. Bone morphogenetic protein 2 and follistatin were reciprocally expressed in G5, but not in ARE-B30 cells. All-or-none expression of amelotin, kallikrein-related peptidase 4, and nerve growth factor receptor was observed in both cell types. In conclusion, our in vitro culture systems detected the phenotypical differences in the expression of the stage-specific amelogenesis related genes. Parallel analysis with 2D and 3D culture systems may provide a platform to understand the molecular basis for defective amelogenesis caused by Sp6 mutation. PMID- 29397321 TI - Using Metabolomics to Investigate Biomarkers of Drug Addiction. AB - Drug addiction has been associated with an increased risk for cancer, psychological complications, heart, liver, and lung disease, as well as infection. While genes have been identified that can mark individuals at risk for substance abuse, the initiation step of addiction is attributed to persistent metabolic disruptions occurring following the first instance of narcotic drug use. Advances in analytical technologies can enable the detection of thousands of signals in body fluids and excreta that can be used to define biochemical profiles of addiction. Today, these approaches hold promise for determining how exposure to drugs, in the absence or presence of other environmentally relevant factors, can impact human metabolism. We posit that these can lead to candidate biomarkers of drug dependence, treatment, withdrawal, or relapse. PMID- 29397322 TI - The rigid lens renaissance: A surge in sclerals. PMID- 29397323 TI - Combination therapy with cytapheresis plus vedolizumab in a corticosteroid dependent patient with ulcerative colitis and previous ANTI-TNF-alpha drug failure. PMID- 29397324 TI - Histologic features in pediatric ileitis: Is it possible to tip the balance towards Crohn's disease? PMID- 29397325 TI - Models of healthcare delivery for osteoarthritis. PMID- 29397326 TI - Neuropathic pain in Systemic Sclerosis patients: A cross-sectional study. AB - OBJECTIVES: To investigate if patients with Systemic Sclerosis (SSc) show a higher prevalence of neuropathic pain (NP) in comparison with controls. To study the relationship between clinical variables of the disease and NP among SSc patients. MATERIAL AND METHODS: 48 patients and 45 controls were included. Presence of NP was assessed applying the DN4 "Douleur Neuropathique en 4 Questions" questionnaire. Different clinical variables were also assessed in patients. Statistical analysis included parametric, nonparametric tests and multivariate logistic regression. RESULTS: NP was significantly higher in SSc patients (56.2% vs 13.3%, p<0.001). Mean Modified Rodnan Skin Score was independently associated with the presence of NP (p<0.05, OR 1.90). CONCLUSIONS: Peripheral nervous system involvement in SSc is not well studied and, as far as the authors are aware, this is the first study published evaluating NP in SSc patients and controls. These findings should raise the awareness of the clinician to recognize and address the presence of NP in these patients, especially in those with severe skin involvement. PMID- 29397327 TI - Fracture risk assessment tool (FRAX) re-aim framework. PMID- 29397328 TI - Cardiorespiratory Fitness and Body Composition Responses to Different Intensities and Frequencies of Exercise Training in Colorectal Cancer Survivors. AB - INTRODUCTION: Deteriorations in cardiorespiratory fitness (Vo2peak) and body composition are associated with poor prognosis after colorectal cancer treatment. However, the optimal intensity and frequency of aerobic exercise training to improve these outcomes in colorectal cancer survivors is unknown. PATIENTS AND METHODS: This trial compared 8 weeks of moderate-intensity continuous exercise (MICE; 50 minutes; 70% peak heart rate [HRpeak]; 24 sessions), with high intensity interval exercise (HIIE; 4 * 4 minutes; 85%-95% HRpeak) at an equivalent (HIIE; 24 sessions) and tapered frequency (HIIE-T; 16 sessions) on Vo2peak and on lean and fat mass, measured at baseline, 4, 8, and 12 weeks. RESULTS: Increases in Vo2peak were significantly greater after both 4 (+3.0 mL.kg 1.min-1, P = .008) and 8 (+2.3 mL.kg-1.min-1, P = .049) weeks of HIIE compared to MICE. After 8 weeks, there was a significantly greater reduction in fat mass after HIIE compared to MICE (-0.7 kg, P = .038). Four weeks after training, the HIIE group maintained elevated Vo2peak (+3.3 mL.kg-1.min-1, P = .006) and reduced fat mass (-0.7 kg, P = .045) compared to the MICE group, with Vo2peak in the HIIE T also being superior to the MICE group (+2.8 mL.kg-1.min-1, P = .013). CONCLUSION: Compared to MICE, HIIE promotes superior improvements and short-term maintenance of Vo2peak and fat mass improvements. HIIE training at a reduced frequency also promotes maintainable cardiorespiratory fitness improvements. In addition to promoting accelerated and superior benefits to the current aerobic exercise guidelines, HIIE promotes clinically relevant improvements even with a substantial reduction in exercise training and for a period after withdrawal. PMID- 29397329 TI - A systematic review and meta-analysis of cognitive and behavioral interventions to improve sleep health in adults without sleep disorders. AB - Many adults without a diagnosed sleep disorder report poor sleep health, which is defined by dissatisfactory levels of sleep duration, sleep quality, or the timing of sleep. No previous review has summarized and described interventions targeting poor sleep health in this population. This meta-analysis aimed to quantify the efficacy of behavioral and cognitive sleep interventions in adults with poor sleep health, who do not have a sleep disorder. Electronic databases (Medline, Embase, PsycInfo, Cinahl) were searched with restrictions for age (18-64 y) and English language full-text, resulting in 18,009 records being screened and 592 full-texts being assessed. Eleven studies met inclusion criteria, seven of which reported a measure of overall sleep health (Pittsburgh sleep quality index [PSQI]). Following appraisal for risk of bias, extracted data were meta-analyzed using random-effects models. Meta-analyses showed interventions had a medium effect on sleep quality (Hedge's g = -0.54, [95% confidence interval (CI)] -0.90 to -0.19, p < 0.01). Baseline sleep health was the only significant effect moderator (p = 0.01). The most frequently used intervention components were stress management and relaxation practice, stimulus control, sleep hygiene, and exercise. Interventions targeting cognitive and behavioral self-regulation improve sleep quality in adults without clinical sleep disorder. PMID- 29397331 TI - Fecal calprotectin and serum albumin as markers of gastrointestinal graft versus host disease. AB - BACKGROUND: Acute graft versus host disease (aGVHD) affects approximately 30-60% of patients after allogeneic hematopoietic stem cell transplantation (HCT) and our ability to predict who develops this complication and their response to treatment is limited. Fecal calprotectin has recently gained popularity as an effective marker of GI inflammation in patients with Inflammatory Bowel Disease (IBD). METHODS: Fecal calprotectin and albumin were evaluated as prognostic and predictive markers of aGVHD in 60 adult and pediatric HCT patients. Stool samples were sent for calprotectin quantification prior to starting conditioning, at day 14 post-HCT, at day 28 post-HCT, and at onset of aGVHD +/- 2 days. RESULTS: Fecal calprotectin did not differentiate patients with GI-GVHD and non-GI GVHD and did not vary based on severity. However, in patients with steroid-refractory GI aGVHD, significantly higher fecal calprotectin levels were noted. At onset of lower-GI symptoms, steroid refractory patients (n = 3) had a mean fecal calprotectin level of 449 ug/g (range 116-1111 ug/g) and a mean albumin of 1.93 g/dL (range 1.6-2.3 g/dL) compared with a mean fecal calprotectin of 24 ug/g (range 16-31 ug/g) and a mean albumin of 3.3 g/dL (range 2.3-3.9 g/dL) in steroid responsive patients (n = 9) (fecal calprotectin p = 0.032, albumin p = 0.027). CONCLUSION: Patients with steroid-refractory GI aGVHD had higher fecal calprotectin levels and lower albumin levels than patients with steroid responsive disease. We recommend further studies to evaluate non-invasive tests with fecal calprotectin in combination with albumin in predicting steroid refractory disease at onset of symptoms to potentially identify patients that may benefit from upfront escalation in GVHD treatment. PMID- 29397330 TI - La involvement in tRNA and other RNA processing events including differences among yeast and other eukaryotes. AB - The conserved nuclear RNA-binding factor known as La protein arose in an ancient eukaryote, phylogenetically associated with another eukaryotic hallmark, synthesis of tRNA by RNA polymerase III (RNAP III). Because 3'-oligo(U) is the sequence-specific signal for transcription termination by RNAP III as well as the high affinity binding site for La, the latter is linked to the intranuclear posttranscriptional processing of eukaryotic precursor-tRNAs. The pre-tRNA processing pathway must accommodate a variety of substrates that are destined for both common steps as well as tRNA-specific events. The order of intranuclear pre tRNA processing steps is mediated in part by three activities derived from interaction with La protein: 3'-end protection from untimely decay by 3' exonucleases, nuclear retention and chaperone activity that helps prevent pre tRNA misfolding and mischanneling into offline pathways. A focus of this perspective will be on differences between yeast and mammals in the subcellular partitioning of pre-tRNA intermediates and differential interactions with La. We review how this is most relevant to pre-tRNA splicing which occurs in the cytoplasm of yeasts but in nuclei of higher eukaryotes. Also divergent is La architecture, comprised of three RNA-binding domains in organisms in all examined branches of the eukaryal tree except yeast, which have lost the C-terminal RNA recognition motif-2alpha (RRM2alpha) domain. We also review emerging data that suggest mammalian La interacts with nuclear pre-tRNA splicing intermediates and may impact this branch of the tRNA maturation pathway. Finally, because La is involved in intranuclear tRNA biogenesis we review relevant aspects of tRNA associated neurodegenerative diseases. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena. PMID- 29397332 TI - Skin involvement in Burkitt's lymphoma. AB - Skin involvement in Burkitt's lymphoma (BL) is rare, more so in the pediatric age group. There are very few cases of BL involving skin either at presentation or relapse reported in literature. We report a case of a 9-years old boy with stage 4 Burkitt's lymphoma with skin involvement who tested negative for human immune deficiency virus. PMID- 29397333 TI - Beliefs about hydroxyurea in youth with sickle cell disease. AB - BACKGROUND: Hydroxyurea reduces complications and improves health-related quality of life (HRQOL) in sickle cell disease (SCD) patients, however adherence remains suboptimal. Understanding patients' views of hydroxyurea is critical to optimize adherence, particularly in adolescents and young adults (AYA). Study objectives were to assess beliefs about hydroxyurea using the Beliefs about Medicines Questionnaire (BMQ), and to examine the relationship of patients' beliefs to their hydroxyurea adherence and HRQOL. METHODS: Thirty-four AYA with SCD participated in a cross-sectional study January-December 2015. Study assessments included BMQ to examine beliefs about hydroxyurea; Visual Analogue Scale (VAS) to assess hydroxyurea adherence; and Patient Reported Outcomes Measurement Information System (PROMIS(r)) to evaluate HRQOL. RESULTS: Participants (41% female, 91% Black) had median age of 13.5 (IQR 12-18) years. Participants' concerns about overuse of medications correlated with concerns about hydroxyurea (rs = 0.36, p = 0.04) and overall harm of medications (rs = 0.5, p = 0.003). Participants' age positively correlated with the necessity of hydroxyurea (rs = 0.45, p = 0.007). Participants' concerns about hydroxyurea and overuse of medications positively correlated with anxiety (rs = 0.41, p = 0.02; rs = 0.44, p = 0.01) and depression (rs = 0.37, p = 0.04; rs = 0.54, p = 0.001), but inversely correlated with peer relationships (rs = -0.45, p = 0.03; rs = -0.44, p = 0.03), respectively, suggesting better HRQOL with concerns. Fifty percent of participants reported low hydroxyurea adherence (VAS < 80%), which was more seen in patients with higher concerns about hydroxyurea (p = 0.02). CONCLUSIONS: Beliefs about hydroxyurea correlated with HRQOL scores and adherence levels. Addressing patients' concern about hydroxyurea and medications overall as well as routine assessment of adherence and beliefs could help to overcome adherence barriers. PMID- 29397334 TI - Optimized energy of spectral coronary CT angiography for coronary plaque detection and quantification. AB - BACKGROUND: To optimize spectral coronary computed tomography angiography (CTA) for quantification of coronary artery plaque components. MATERIALS AND METHODS: Fifty-one subjects were prospectively enrolled (88.2% male) (NCT02740699). Dual energy coronary CTA was performed at 90/Sn150 kVp using a 3rd generation dual source CT scanner (SOMATOM Force, Siemens Healthcare). Dual energy images were reconstructed with a) linear mixed blending of 90 and Sn150 kVp data, b) virtual monoenergetic algorithm from 40 to 150 keV (at 10- keV intervals), and c) noise optimized virtual monoenergetic algorithm from 40 to 150 keV. Image noise, iodine signal-to-noise-ratio (SNR), and contrast-to-noise ratio (CNR) for calcified and non-calcified plaque were measured. Qualitative readings of image quality were performed. Semi-automated software (QAngioCT, Medis) was used to quantify coronary plaque. Linear mixed-models that account for within-subject correlation of plaques were used to compare the results. RESULTS: 100-150 keV noise-optimized virtual monoenergetic images had lower image noise than linear mixed images (all P < 0.05). The highest iodine SNR was achieved in 40 keV noise-optimized virtual monoenergetic images (33.3 +/- 0.6 vs 23.3 +/- 0.7 for linear mixed images, P < 0.001). 40-70 keV noise-optimized virtual monoenergetic images and 70 keV virtual monoenergetic images had superior coronary plaque CNR versus linear mixed images (all P < 0.01) with a maximum improvement of 20.1% and 22.7% for calcified plaque and non-calcified plaque (38.8 +/- 2.2 vs 32.3 +/- 2.3 and 17.3 +/- 1.3 vs 14.1 +/- 1.4, respectively). Using 90/Sn150 kVp linear mixed images as a reference, the plaque quantity was similar for 70 keV noise-optimized virtual monoenergetic images whereas low keV images (e.g. 40 keV) yielded significantly higher coronary plaque volumes (all P < 0.001). CONCLUSION: Spectral coronary CTA with low energy (40-70 keV) post-processing can improve the CNR of coronary plaque components. However, low energies (such as 40 keV) resulted in different absolute volumes of coronary plaque compared to "conventional" mixed 90/Sn150 kVp images. PMID- 29397335 TI - Proposed standards for reporting outcomes of treating biliary injuries. AB - BACKGROUND: There is no standard nor widely accepted way of reporting outcomes of treatment of biliary injuries. This hinders comparison of results among approaches and among centers. This paper presents a proposal to standardize terminology and reporting of results of treating biliary injuries. METHODS: The proposal was developed by an international group of surgeons, biliary endoscopists and interventional radiologists. The method is based on the concept of "patency" and is similar to the approach used to create reporting standards for arteriovenous hemodialysis access. RESULTS: The group considered definitions and gradings under the following headings: Definition of Patency, Definition of Index Treatment Periods, Grading of Severity of Biliary Injury, Grading of Patency, Metrics, Comparison of Surgical to Non Surgical Treatments and Presentation of Case Series. CONCLUSIONS: A standard procedure for reporting outcomes of treating biliary injuries has been produced. It is applicable to presenting results of treatment by surgery, endoscopy, and interventional radiology. PMID- 29397336 TI - Artesunate affords protection against aspirin-induced gastric injury by targeting oxidative stress and proinflammatory signaling. AB - BACKGROUND: Prolonged use of aspirin, a commonly prescribed non steroidal anti inflammatory drug, is well known to produce gastrointestinal toxicity which could be minimized by various anti-secretory agents. The present study was carried out to evaluate the protective effect of artesunate against aspirin induced gastric injury in rats. METHODS: Gastric injury was induced in fasted Wistar rats by oral administration of aspirin. The effect of 50 and 150mg/kg of artesunate was studied on macroscopic changes, gastric secretions, histology, oxidative stress and inflammatory markers in the stomach tissue after 5h of induction of gastric injury. Immunohistochemical analysis for the expression of IL-1beta, IL-6, NF kappaB(p65) and COX-2 was also carried out. The effect of artesunate was compared with that of standard anti-ulcer drug famotidine (20mg/kg). RESULTS: Artesunate pretreatment produced a dose-dependent reduction in aspirin induced gastric injury and restored the gastric juice parameters. It normalized the tissue levels of oxidative stress markers (glutathione, malondialdehyde and superoxide dismutase activity) and mediators of inflammation (myeloperoxidase and TNF alpha). The protection afforded by artesunate was evident from the histoarchitecture of stomach tissue and marked reduction in tissue expression of IL-1beta, IL-6, NF-kappaB(p65) and COX-2. The effect of artesunate was found to be comparable to that of standard drug famotidine. CONCLUSION: Artesunate markedly ameliorated aspirin induced gastric injury in rats by targeting oxidative stress and COX-2 dependent as well as COX-2 independent proinflammatory signaling pathways and could have a therapeutic potential in gastric ulcer disease. PMID- 29397337 TI - Meckel's diverticulum in the adult: Prophylactic surgery. PMID- 29397338 TI - Preoperative imaging and pathologic classification for pancreatic neuroendocrine tumors. AB - The management of patients with pancreatic neuroendocrine tumor (PNET), whether hormonally secretory or not, is multidisciplinary and often multimodal. Surgical treatment plays a central role because complete resection is the only potentially curative treatment. The choice of the therapeutic plan for a PNET requires precise localization of the primary tumor (which may sometimes be multiple in case of genetic predisposition), confirmation of the diagnosis of PNET, a search for metastases (mainly hepatic), and identification of the main histoprognostic factors. This update focuses on the WHO 2017 histological classification and recent innovations in the preoperative assessment of PNET using conventional and isotopic imaging. The aim is to not only allow the mapping of primary and metastatic lesions but also to predict tumor aggressiveness. PMID- 29397339 TI - Sleep, Snoring, and Surgery: OSA Screening Matters. AB - PURPOSE: This study was aimed to identify potential obstructive sleep apnea (OSA) in ambulatory surgical patients and create perianesthesia nursing protocols using a reliable and validated screening tool. DESIGN: Descriptive survey. METHODS: A nurse-initiated OSA survey was conducted in 1,118 preoperative ambulatory patients using the STOP-Bang Questionnaire to identify patients at risk for OSA. The findings resulted in the development of protocols, patient education, and interventions. FINDINGS: Ambulatory surgical patients were not routinely assessed for OSA before this study. The study verified that 10% of patients scheduled for ambulatory elective surgery had undiagnosed OSA and, because of the OSA identification, 16% of all scheduled surgeries were canceled. There were no unnecessary hospitalizations after the nurse-initiated OSA protocol. CONCLUSIONS: The STOP-Bang Questionnaire is a useful tool for screening patients with risks of OSA in the ambulatory surgical setting. This study supports using nursing best practices and safe patient care. PMID- 29397340 TI - Oral lymphangiectasias and Crohn's disease: two case reports. AB - Lymphangiectasias, or acquired lymphangiomas, are rare in the oral cavity, more typically occurring on the skin or the genital area and, to our knowledge, have not been reported previously in association with Crohn's disease. Lymphangiectasias can occur at any age and develop secondary to chronic obstruction of the lymphatics. This differentiates them from congenital lymphangiomas, which are congenital malformations of the lymphatic system. We present 2 cases of oral lymphangiectasias associated with Crohn's disease, one of which was treated successfully with cryotherapy. PMID- 29397341 TI - Patient morbidity among residents extracting third molars: does experience matter? AB - OBJECTIVE: The aim of this study was to evaluate the complication rates for third molar extractions, based on resident level within an oral and maxillofacial surgery program, and to identify the risk factors associated with postoperative complications following third molar extractions. STUDY DESIGN: Records of 1992 patients (5466 third molar extractions) over a 5-year period were reviewed. Data were collected by using appropriate Current Dental Terminology codes from July 1, 2011, to June 30, 2016. The cases were analyzed by using demographic statistics, Pearson chi2 test, and regression analysis. RESULTS: Of the total number of patients, 1855 had sufficient data available for analysis and inclusion in the study. There were 146 adverse outcomes. The common complication was alveolar osteitis. Nerve injuries and retained root tips were encountered less frequently. There was a significant association between the depth of impaction and developing a postoperative complication. There was a direct correlation between the level of resident training and the likelihood of an adverse outcome. CONCLUSIONS: The study indicates that there are identifiable risk factors associated with postoperative complications following third molar extraction in an oral and maxillofacial surgery residency program. These factors include location, depth of impaction, use of a surgical drill, and level of resident training, which are correlated directly with the development of negative outcomes following third molar extractions. PMID- 29397342 TI - High frequency of type 2 diabetes and impaired glucose tolerance in Japanese subjects with the angiopoietin-like protein 8 R59W variant. AB - BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is considered to be metabolically multifunctional. One notable function still to be elucidated definitively is a betatrophic role in protecting and preserving pancreatic beta cell function. There is, however, a paucity of data regarding the role of ANGPTL8 in the etiology of type 2 diabetes (T2D), but some findings of human research have suggested the potential for significant involvement. OBJECTIVE: To examine the frequency of T2D and impaired glucose tolerance (IGT) in Japanese subjects with the ANGPTL8 R59W variant. METHODS: ANGPTL8 R59W (Rs2278426, c.194C > T) was determined by polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme FokI in 797 consecutive Japanese individuals. Subjects with triglyceride levels greater than or equal to 150 mg/dL were considered to be hypertriglyceridemic. RESULTS: Genotype frequencies of ANGPTL8 R59W were as follows: wild-type RR (C/C) 53.5%, RW (C/T) 36.6%, and WW (T/T) 9.9%. T2D and IGT were significantly prevalent in WW and RW subjects relative to RR among all 797 subjects (P = .0138) and also in hypertriglyceridemic subjects (P = .0015). In multiple logistic regression models for the existence of T2D and IGT in hypertriglyceridemic subjects, the odds ratio for heterozygote RW and homozygote WW genotypes to wild-type RR was 2.406 (P = .0017) after controlling the risk factors of age, gender, and body mass index as covariates. CONCLUSIONS: The frequency of ANGPTL8 R59W is significantly higher in Japanese subjects than in other ethnic groups. The rates of T2D and IGT were greater in subjects with the R59W variant. These findings indicate that ANGPTL8 is a participant in diabetes and a potential therapeutic target for T2D prevention, especially in East Asians. PMID- 29397343 TI - Addressing meaningful use and maintaining an accurate medication list in primary care. AB - OBJECTIVES: The primary objective of this project was to determine the difference in medication list accuracy between an initial and follow-up medication reconciliation visit in a primary care office. Secondary objectives were to identify the difference in medication-related problems most commonly encountered during the visits, factors that may influence patient understanding of their medication regimen, and physician perceptions of the medication review visit. SETTING: Quasi-experimental study part of a larger pilot project to address the ability of how health information technology can be used to maintain an active medication list. PRACTICE DESCRIPTION: Three family medicine residency clinics in the Midwest. Adult patients with diabetes or chronic obstructive pulmonary disease who had 6 or more long-term medications listed in the electronic health record (EHR) were recruited to participate. PRACTICE INNOVATION: An initial comprehensive medication reconciliation visit was conducted by a resident physician and a pharmacist with the goal of ensuring an accurate, easy-to-follow, electronically developed medication list. A follow-up visit with the pharmacist occurred 3-6 months after the initial visit. EVALUATION: Medication list accuracy and medication-related problems were assessed at the initial and follow-up visits. Patient-related factors that could affect medication understanding were collected at the initial visit with status of enrollment in the EHR patient portal. RESULTS: Fifty-seven of 65 patients completed the study. The number of patients with an accurate medication list increased from 40% to 49% (P = 0.38). The number of medication-related problems decreased from 146 to 91 (P < 0.001). The use of special tools (e.g., pillboxes) was associated with fewer medication regimen errors (P = 0.036). Patients enrolled in the EHR patient portal were more likely to know the purpose of their medications as compared with those not enrolled (P = 0.019). CONCLUSION: An intentionally scheduled medication review with a primary care provider and pharmacist did not significantly improve the accuracy of the medication list, but it was associated with fewer drug-related problems. PMID- 29397345 TI - Variability of the hemodynamic response in infants: Influence of experimental design and stimulus complexity. AB - Measuring brain activity in developmental populations remains a major challenge despite great technological advances. Among the numerous available methods, functional near-infrared spectroscopy (fNIRS), an imaging modality that probes the hemodynamic response, is a powerful tool for recording brain activity in a great variety of situations and populations. Neurocognitive studies with infants have often reported inverted hemodynamic responses, i.e. a decrease instead of an increase in regional blood oxygenation, but the exact physiological explanation and cognitive interpretation of this response remain unclear. Here, we first provide an overview of the basic principles of NIRS and its use in cognitive developmental neuroscience. We then review the infant fNIRS literature to show that the hemodynamic response is modulated by experimental design and stimulus complexity, sometimes leading to hemodynamic responses with non-canonical shapes. We also argue that this effect is further modulated by the age of participants, the cortical regions involved, and the developmental stage of the tested cognitive process. We argue that this variability needs to be taken into account when designing and interpreting developmental studies measuring the hemodynamic response. PMID- 29397346 TI - Single-center Experience in Treating Patients With t(4;14) Multiple Myeloma With and Without Planned Frontline Autologous Stem Cell Transplantation. AB - BACKGROUND: Translocation t(4;14) has traditionally been classified as a high risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib. PATIENTS AND METHODS: We conducted a retrospective study on our patients with t(4;14) multiple myeloma treated with bortezomib-based induction between July 1, 2006 and June 30, 2014 to assess the real-world outcomes of these patients in a tertiary center. RESULTS: Among the 75 patients analyzed, the median PFS was 33.5 months, and the median OS was 69.6 months after a median follow-up of 41 months. Even in the era of novel agents, patients who received frontline autologous stem cell transplant had a better PFS than those who received chemotherapy alone (median PFS, 24.2 months vs. 41.5 months; P = .01). Hypercalcemia at the time of presentation was found to be a significant predictor of progression (hazard ratio [HR], 10.1; 95% confidence interval [CI], 4.0-26.0) and death (HR, 9.4; 95% CI, 3.2-27.8), and co harboring of del(17p) by fluorescent in situ hybridization with t(4;14) was associated with a significantly inferior OS (HR, 4.0; 95% CI, 1.4-11.4). CONCLUSION: Even in the era of novel agents, t(4;14) remains a negative prognostic marker. Frontline autologous stem cell transplant remains as an essential tool when treating these high-risk patients, but further prospective randomized studies are needed to determine the most effective strategy for this patient group. PMID- 29397347 TI - Outcome of Chronic Myeloid Leukemia-Chronic Phase Patients Treated With Imatinib: A Local Experience. AB - BACKGROUND: Imatinib was the first tyrosine kinase inhibitor that has revolutionized the therapy of chronic myeloid leukemia. It binds breakpoint cluster region-Abelson kinase domain inducing apoptosis of the leukemic cells. In this study, we assessed the efficacy and toxicity of imatinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) in our hospital. PATIENTS AND METHODS: We retrospectively analyzed the outcome of 17 patients with CML-CP treated with imatinib. RESULTS: The median age at the time of presentation was 35 years with male preponderance. The most common presenting clinical features were fatigue, abdominal distention, and discomfort. Forty-seven percent of patients had fever at presentation whereas 35.29% were referred to our hospital because of incidental findings of high blood cell counts. With a median follow-up of 8 years (range, 2-16 years) the overall survival is 100% and progression-free survival 85%. Two patients had acceptable adverse effects. CONCLUSION: After a median follow-up of 8 years, imatinib was found to induce long survival with manageable side effect in adult Saudi patients with CML-CP. PMID- 29397344 TI - Metabolic intermediates - Cellular messengers talking to chromatin modifiers. AB - BACKGROUND: To maintain homeostasis, cells need to coordinate the expression of their genes. Epigenetic mechanisms controlling transcription activation and repression include DNA methylation and post-translational modifications of histones, which can affect the architecture of chromatin and/or create 'docking platforms' for multiple binding proteins. These modifications can be dynamically set and removed by various enzymes that depend on the availability of key metabolites derived from different intracellular pathways. Therefore, small metabolites generated in anabolic and catabolic processes can integrate multiple external and internal stimuli and transfer information on the energetic state of a cell to the transcriptional machinery by regulating the activity of chromatin modifying enzymes. SCOPE OF REVIEW: This review provides an overview of the current literature and concepts on the connections and crosstalk between key cellular metabolites, enzymes responsible for their synthesis, recycling, and conversion and chromatin marks controlling gene expression. MAJOR CONCLUSIONS: Whereas current evidence indicates that many chromatin-modifying enzymes respond to alterations in the levels of their cofactors, cosubstrates, and inhibitors, the detailed molecular mechanisms and functional consequences of such processes are largely unresolved. A deeper investigation of mechanisms responsible for altering the total cellular concentration of particular metabolites, as well as their nuclear abundance and accessibility for chromatin-modifying enzymes, will be necessary to better understand the crosstalk between metabolism, chromatin marks, and gene expression. PMID- 29397348 TI - [Resistant hypertension: An update]. AB - An estimated 10% to 20% of hypertensive patients could be considered resistant to treatment (RH). These are patients who are not controlled using three drugs, at the maximum tolerated doses, including a diuretic, as well as those with high blood pressure controlled using four or more drugs. The term is used to identify patients that might benefit from special diagnostic and/or therapeutic consideration. The term 'refractory hypertension' has recently been proposed as a novel phenotype of antihypertensive failure. It refers to patients whose blood pressure cannot be controlled with maximum treatment. The first studies of this phenotype indicate that it is rare and affects less than 5% of patients with RH. Adherence to or compliance with medical treatment is key to defining resistant hypertension. Closer attention has been paid to clinical and experimental research since the first scientific statement for the diagnosis, assessment and treatment of RH from the American Heart Association, and in the European guidelines, was published in 2008. This review will set out the concepts relating to prevalence, prognosis and compliance and cover the latest developments on this subject. PMID- 29397350 TI - Corrections. PMID- 29397349 TI - Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. AB - Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease that results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homoeostasis. Identification of the granulocyte-macrophage colony-stimulating factor (GM-CSF) as an indispensable mediator of macrophage maturation and surfactant catabolism was the key discovery leading to the current understanding of the pathogenesis of most forms of PAP. Impaired GM-CSF bioavailability due to anti-GM-CSF autoimmunity is the cause of approximately 90% of adult PAP cases. Abnormal macrophage function due to endogenous or exogenous triggers, GM-CSF receptor defects, and other genetic abnormalities of surfactant production account for the remainder of causes. The usual physiological consequence of PAP is impairment of gas exchange, which can lead to dyspnoea, hypoxaemia, or even respiratory failure and death. Pulmonary fibrosis occurs occasionally in patients with PAP. For patients with moderate to severe disease, whole lung lavage is still the first-line treatment of choice. Supplemental GM-CSF is also useful, but details about indications, choice of agent, and dosing remain unclear. Other therapies, including rituximab, plasmapheresis, and lung transplantation have been described but should be reserved for refractory cases. PMID- 29397351 TI - Multidisciplinary coordinated care for Type 2 diabetes: A qualitative analysis of patient perspectives. AB - AIMS: To explore the patient perspective on coordinated multidisciplinary diabetes team care among a socioeconomically diverse group of adults with type 2 diabetes. METHODS: Qualitative research design using 8 focus groups (n=53). We randomly sampled primary care patients with type 2 diabetes and conducted focus groups at their primary care clinic. Discussion prompts queried current perceptions of team care. Each focus group was audio recorded, transcribed verbatim, and independently coded by three reviewers. Coding used an iterative process. Thematic saturation was achieved. Data were analyzed using content analysis. RESULTS: Most participants believed that coordinated multidisciplinary diabetes team care was a good approach, feeling that diabetes was too complicated for any one care team member to manage. Primary care physicians were seen as too busy to manage diabetes alone, and participants were content to be treated by other care team members, especially if there was a single point of contact and the care was coordinated. Participants suggested that an ideal multidisciplinary approach would additionally include support for exercise and managing socioeconomic challenges, components perceived to be missing from the existing approach to diabetes care. CONCLUSIONS: Coordinated, multidisciplinary diabetes team care is understood by and acceptable to patients with type 2 diabetes. PMID- 29397352 TI - The effect of warm air-blowing on the microtensile bond strength of one-step self etch adhesives to root canal dentin. AB - PURPOSE: The use of warm air-blowing to evaporate solvents of one-step self-etch adhesive systems (1-SEAs) has been reported to be a useful method. The purpose of this study was to evaluate the effect of warm air-blowing on root canal dentin. METHODS: Four 1-SEAs (Clearfil Bond SE ONE, Unifil Core EM self-etch bond, Estelink, BeautiDualbond EX) were used. Each 1-SEA was applied to root canal dentin according to the manufacturers' instructions. After the adhesives were applied, solvent was evaporated using either normal air (23+/-1 degrees C) or warm air (80+/-1 degrees C) for 20s, and resin composite was placed in the post spaces. The air from the dryer, which could be used in normal- or hot-air-mode, was applied at a distance of 5cm above the root canal cavity in the direction of tooth axis. The temperature of the stream of air from the dryer in the hot-air mode was 80+/-1 degrees C, and in the normal mode, 23+/-1 degrees C. After water storage of the specimens for 24h, the MUTBS were evaluated at the coronal and apical regions. The MUTBSs were statistically analyzed using three-way ANOVA and Student's t-test with Bonferroni correction (alpha=0.05). RESULTS: The warm air blowing significantly increased the MUTBS of all 1-SEAs at the apical regions, and also significantly increased the MUTBS of two adhesives (Estelink and BeautiDualBond EX) at coronal regions. CONCLUSIONS: The MUTBS of 1-SEAs to root canal dentin was improved by using warm air-blowing. PMID- 29397353 TI - Evaluating the influence of ambient light on scanning trueness, precision, and time of intra oral scanner. AB - PURPOSE: This study evaluated the influence of illuminance and color temperature of ambient light on the trueness, precision, and scanning time of a digital impression. METHODS: Master data were acquired with a high-accuracy coordinate measuring machine. The illuminance of ambient light was set at 0lux, 500lux, and 2500lux with a light-emitting diode (LED). Using a conversion filter, the color temperature was set at 3900 Kelvin (K) (yellow), 4100K (orange), 7500K (white), and 19,000K (blue). There were thus a total of 12 possible lighting conditions. The reference model was scanned five times under each condition by an intraoral scanner. Trueness was calculated as the mean difference between the master data and experimental data. Precision was calculated as the mean difference between the repeated scans in each test group. Statistical analysis was performed with two-way analysis of variance (ANOVA) and post hoc Tukey's multiple comparison test. The significance level was 0.05. RESULTS: For trueness, the mean deviation was significantly lower at 500lux than at 0lux and 2500lux. At 500lux, the mean deviation was significantly lower at 3900K than at other temperatures. Regardless of the color temperature, the scanning time was significantly longer at 2500lux than at other illuminance levels. CONCLUSIONS: The 3900K and 500lux condition is the most appropriate lighting condition for taking a digital impression. This condition is typical of clinical settings. High illuminance ambient light increased the scanning time. PMID- 29397355 TI - The Incidence of Overconfidence and Underconfidence Effects in Medical Student Examinations. AB - BACKGROUND: Overconfidence is the tendency to overestimate the knowledge, capacity, or performance one really possesses. This cognitive bias could be potentially dangerous in medical decision-making, considering the impact it could have on patient health care. The aim of this study was to evaluate the incidence of overconfidence and underconfidence in medical student knowledge on general surgery by using traditional and new statistical approaches. METHODS: During the application of a multiple-choice examination, 251 next-to-graduate medical students were invited to express the accuracy of their responses by choosing their own perceived confidence level for a set of questions. Analysis was done by comparing the difference between percentage of right answers (student's actual knowledge or accuracy) and self-estimated confidence level (student's perceived knowledge or confidence). Overconfidence was defined as a positive difference between confidence and accuracy, and underconfidence as a negative difference. RESULTS: Nearly 12% of students showed significant overconfidence regarding their actual knowledge or accuracy levels. Better students showed a lower overconfidence effect than students with poorer performance. On the other hand, underconfidence was less likely than overconfidence (8.3% of students), and that effect was most frequently found in students who performed better in examinations. CONCLUSIONS: The small proportion of our students exhibiting overconfidence or underconfidence behaviors moderates the need for educational interventions. Nevertheless, promoting prudence in individualized students manifesting overconfidence, and trust in those reporting significant underconfidence could increase the reliability of medical judgment during their future professional life. Overconfidence in individuals with lower scores in examinations may depend on a ceiling-like effect, since worst ranked students have a wider upper margin to manifest their confidence perceptions. The most confident students showed higher scores in examinations than the less confident ones. From this point of view, confidence could be considered an essential ingredient of success in examination performance. PMID- 29397356 TI - The Benefit of a Formal Plastic Surgery In-Service Conference. AB - INTRODUCTION: Annually, residents are expected to take an in-service examination to gauge their understanding of plastic surgery knowledge and prepare them for the American Board of Plastic Surgery written examination. In addition, in service score are now being used as an assessment tool for fellowship applicants. Because of the breadth of Plastic Surgery material, it is difficult to prepare a resident for such a comprehensive examination. At the University of Utah, a weekly conference was instituted to help prepare residents for the in-service and board examination with the goal of improving scores. MATERIALS AND METHODS: A weekly 90min review conference was initiated at the University of Utah in an effort to improve in-service scores. Residents along with a member of the faculty reviewed old in-service examination questions and discussed the selected topics in depth. The residents' examination score averages per PGY level were compared from years before and after initiation of the conference. In addition, examination scores for each individual were compared before and after initiation of the conference. Paired t-test comparisons were performed to analyze the results. RESULTS: Statistically significant improvement in residents examination scores averages were observed from years before and after initiation of the conference after the second year of training (42% vs 62%, p = 0.03). Furthermore, examination scores for each individual obtained the years before and the year after initiation of the conference significantly improved (31% vs 71%, p = 0.01). When comparing individuals in years prior to implementation of the conference there was no statistically significant improvement from year to year. CONCLUSION: Implementation of a formal weekly in-service conference significantly improved performance on the in-service examination. Improvement was found when comparing between PGY training level after the second year of training and individually for residents. These results advocate for a focused educational conference for preparation for the in-service examination. PMID- 29397354 TI - Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. AB - BACKGROUND: Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer. METHODS: This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0-1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621. FINDINGS: Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4.4 months (95% CI 3.7-4.9) in the napabucasin group and 4.8 months (4.0-5.3) in the placebo group (adjusted hazard ratio [HR] 1.13, 95% CI 0.88-1.46, p=0.34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5.1 months [95% CI 4.0-7.5] vs 3.0 months [1.7-4.1]; HR 0.41, 0.23-0.73, p=0.0025). INTERPRETATION: Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation. FUNDING: Canadian Cancer Society Research Institute and Boston Biomedical. PMID- 29397357 TI - Using Technological Advances to Improve Surgery Curriculum: Experience With a Mobile Application. AB - OBJECTIVE: Our previous home-video basic surgical skills curriculum required substantial faculty time and resources, and was limited by delayed feedback and technical difficulties. Consequently, we integrated that curriculum with a mobile application platform. Our purpose is to describe this application and learner satisfaction. MATERIALS AND METHODS: The mobile platform incorporates a patented pedagogical design based on Ericsson's deliberate practice and Bandura's social learning theory. Instructors built step-wise skills modules. During the challenge phase, learners watched a video of surgical tasks completed by experts and uploaded a video of themselves performing the same task. In the Peer Review phase, they used a grading rubric to provide feedback. In the Recap stage, learners received individual feedback and could review their own videos. Two groups of learners, graduating medical students and matriculating surgical residents, participated in this independent learning platform, along with 2 to 4 laboratory sessions, and completed a survey about their experience. Survey responses were summarized descriptively and comments analyzed using content analysis. RESULTS: Fifty learners submitted videos of assigned tasks and completed peer reviews. Learners reported positive experiences specifically for the Peer Review Stage, structured home practice, ease of mobile access to submit and review videos, and ongoing immediate feedback. Over half of the learners reported spending at least 10 to 30 minute practicing skills before recording their videos and over 80% rerecorded at least 2 times before submission. Content analysis revealed learners engaged with the educational concepts designed into the platform. CONCLUSION: Learners easily used and were satisfied with a mobile technology teaching platform that maintained the fundamental content, educational theories, and organizational structure of our previously effective surgical skills curriculum. Prior challenges were directly addressed through the mobile application's ease of use, support of deliberate practice, and improved timeliness of feedback. PMID- 29397358 TI - Feasibility of a bone and soft tissue chimeric anterolateral thigh free flap? Anatomic study and report of two cases for oral cavity reconstruction. AB - The anterolateral thigh flap (ALT) is a workhorse for a spectrum of reconstructive problems including head and neck defects. Its versatility as a chimeric flap employing a variety of soft tissues with a robust pedicle is useful for three-dimensional defects. The authors investigated the anatomical relationship between the vascular supply to the ALT and anterior femur. We studied 16 fresh cadaver limbs to identify the typical branching patterns to the femur off the descending branch of the lateral circumflex femoral artery. These patterns can facilitate dissection of this type of chimeric ALT. The authors have integrated a bone component of vascularised femur in this flap off the lateral circumflex femoral artery system to address oral cancer defects in two patients. A retrospective review of these cases correlating with the anatomic study was undertaken. Both patients had recurrent disease with limited donor site options. Both had extensive floor of mouth and tongue defects as well as small mandible defects of 2 cm. Both went on to heal at the donor and recipient sites at 32 months' follow-up. PMID- 29397359 TI - Operational Efficiency and Productivity Improvement Initiatives in a Large Cardiac Catheterization Laboratory. AB - OBJECTIVES: This study sought to report outcomes from an efficiency improvement project in a large cardiac cath lab. BACKGROUND: Operational inefficiencies are common in the cath lab, yet solutions are challenging. A detailed report describing and providing solutions for these inefficiencies may be valuable in guiding improvements in productivity. METHODS: In this observational study, the authors report metrics of efficiency before and after a cath lab quality improvement program in June 2014. Main outcomes included lab room start times, room turnaround times, laboratory use, and employee satisfaction. Time series analysis was used to assess trend over time. Chi-square testing and analysis of variance were used to assess change before and after the initiative. RESULTS: The principal changes included implementation of a pyramidal nursing schedule, increased use of an electronic scheduling system, and increased utilization of a preparation and recovery area. Comparing before with after the program, start times improved an average of 17 min, and on-time starts improved from 61.8% to 81.7% (p = 0.0024). Turnaround times improved from 20.5 min to 16.4 min (trend p < 0.0001), and the proportion of days at full lab utilization improved from 7.7% to 77.3% (p < 0.00001). There were no increases in overtime, night, or weekend cases. There was a reduction in full time employees from 36.1 in 2013 to 29.6 in 2016, with an improvement in employee satisfaction. CONCLUSIONS: A systematic approach to reducing inefficiencies can improve cath lab start times, turnaround times, and overall productivity. This knowledge may be helpful in assisting other cath labs in similar efficiency improvement initiatives. PMID- 29397360 TI - The Paradoxes of Transcatheter Aortic Valve Replacement Cardioembolic Protection Devices. PMID- 29397362 TI - Efficiency Improvements in the Catheterization Laboratory: It's All About the Team. PMID- 29397361 TI - Neurocognition and Cerebral Lesion Burden in High-Risk Patients Before Undergoing Transcatheter Aortic Valve Replacement: Insights From the SENTINEL Trial. AB - OBJECTIVES: The authors sought to determine baseline neurocognition before transcatheter aortic valve replacement (TAVR) and its correlations with pre-TAVR brain imaging. BACKGROUND: TAVR studies have not shown a correlation between diffusion-weighted image changes and neurocognition. The authors wanted to determine the extent to which there was already impairment at baseline that correlated with cerebrovascular disease. METHODS: SENTINEL (Cerebral Protection in Transcatheter Aortic Valve Replacement) trial patients had cognitive assessments of attention, processing speed, executive function, and verbal and visual memory. Z-scores were based on normative means and SDs, combined into a primary composite z-score. Brain magnetic resonance images were obtained pre-TAVR on 3-T scanners with a T2 fluid-attenuated inversion recovery (FLAIR) sequence. Scores <=-1.5 SD below the normative mean (7th percentile) were considered impairment. Paired t tests compared within-subject scores, and chi-square goodness-of-fit compared the percentage of subjects below -1.5 SD. Correlation and regression analyses assessed the relationship between neurocognitive z-scores and T2 lesion volume. RESULTS: Among 234 patients tested, the mean composite z score was -0.65 SD below the normative mean. Domain scores ranged from -0.15 SD for attention to -1.32 SD for executive function. On the basis of the >=1.5 SD normative reference, there were significantly greater percentages of impaired scores in the composite z-score (13.2%; p = 0.019), executive function (41.9%; p < 0.001), verbal memory (p < 0.001), and visual memory (p < 0.001). The regression model between FLAIR lesion volume and baseline cognition showed statistically significant negative correlations. CONCLUSIONS: There was a significant proportion of aortic stenosis patients with impaired cognition before TAVR, with a relationship between baseline cognitive function and lesion burden likely attributable to longstanding cerebrovascular disease. These findings underscore the importance of pre-interventional testing and magnetic resonance imaging in any research investigating post-surgical cognitive outcomes in patients with cardiovascular disease. PMID- 29397364 TI - It's the disease of not listening that I am troubled with (Henry IV). PMID- 29397363 TI - Unexpected Cardiac Tamponade Due to Bleeding From the Left Atrium During Transcatheter Aortic Valve Replacement. PMID- 29397365 TI - Validation of the cardiovascular risk model developed for Omanis with type 2 diabetes. AB - AIM: The first cardiovascular risk prediction model in the Arab world was recently developed for Omanis with type 2 diabetes mellitus. This study aims to validate the newly developed model. MATERIALS AND METHODS: A retrospective cohort study design was applied in this study. The model was validated in two samples; the model derivation sample and a separate validation sample, consisting of 1314 and 405 diabetics respectively. All patients were free of cardiovascular disease at the baseline (2009-2010) and were followed up until: the first cardiovascular event occurred; the patient died; or up to December 2015. All data were retrieved from the patients' medical records in a primary care setting. RESULTS: In both the derivation and validation samples, the model showed good discrimination, with an area under the receiver operating curve of 0.73 (95% CI; 0.69-0.77) and 0.70 (95% CI: 0.59-0.75) respectively. Calibration of the model was satisfactory and the actual difference between the mean predicted and observed risk in different risk groups ranged from 0.7%-3.1% and 0.1%-4.2% in the derivation and validation samples respectively. CONCLUSION: The recently developed cardiovascular disease risk assessment model for Omanis with type 2 diabetes achieved adequate overall validity. The model showed good discrimination and acceptable calibration; it therefore has the potential to be used in local clinical settings. However, further validation and comparison studies are needed to judge the generalizability and superiority of the model over other tools currently used in Oman. PMID- 29397367 TI - Can We Find Breast Cancer via Salivary Fluid Glycosylation Analyses? PMID- 29397366 TI - Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees. AB - Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A-/y fibroblasts. Bioinformatic analysis of ATP7A mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes. PMID- 29397370 TI - Food-dependent exercise-induced anaphylaxis due to almond in a PR-10-sensitized patient. PMID- 29397369 TI - Targetable Metabolic Vulnerability in Diffuse Large B-Cell Lymphoma. PMID- 29397368 TI - A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N=223,773). AB - BACKGROUND: Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. METHODS: We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. RESULTS: We identified 3343 SNPs which reached the genome-wide significance level of P<5*10-8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92*10-47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87*10-15 in the LINC02210-CRHR1 gene was the top SNP. Significant relationships between multiple brain tissues and genetic associations were identified through tissue expression analysis. We also identified significant positive genetic correlations between headache and many psychological traits. CONCLUSIONS: Our results suggest that brain function is closely related to broadly-defined headache. In addition, we found that many psychological traits have genetic correlations with headache. PMID- 29397371 TI - Should Younger Siblings of Peanut Allergic Children Be Screened for Peanut Allergy? AB - The role of screening younger siblings of peanut allergic children with allergy testing before peanut introduction is controversial. Although certain guidelines note some value in screening this population, it is not a direct indication in the recent National Institute of Allergy and Infectious Diseases guideline. Some studies suggest that siblings of peanut allergic children are at increased risk of peanut allergy, whereas others note that delayed ingestion or mislabeling of allergy in these children may be the main factors accounting for this increased risk. The low risk of severe reaction with first ingestion and risks of pre emptive testing must be balanced against data suggesting that families are reluctant to introduce peanut in siblings without testing. The goal of this article is to critically appraise the debated issues in this topic, providing a practical approach to this common clinical dilemma. PMID- 29397372 TI - Conducting an Integrative Health Interview. AB - Complementary medicine incorporates the use of non-evidence-based complementary modalities into conventional (Western) medicine. Alternative medicines are approaches that are used in place of conventional medicine. Integrative medicine is the synthesis of conventional medical treatments with "evidence-based" complementary medical practices. When complementary approaches are incorporated into mainstream health care, it is called integrative health (IH). Among children and adults, IH is common despite not all therapies being safe and/or effective. Clinicians have suboptimal knowledge of their patients' IH use because, in part, they do not know what questions to ask and/or do not have a standard intake form to collect an IH history, as recently demonstrated by an American Academy of Allergy, Asthma, and Immunology membership survey. To address this unmet need, a group of Complementary and Alternative Practice in Allergy Committee members and interprofessional collaborators reviewed the existing literature to locate IH history forms that could assist in identifying patients' IH use. When none was located, the group created 3 templates for the systematic collection and documentation of IH practices: 2 general screening surveys that could be given to patients to complete before an appointment and a third template that provides the clinician with open-ended questions to help uncover IH practices in culturally diverse patient populations. Specialists, already acknowledged as skillful interviewers, can expand their patient-centered expertise by developing their own IH competencies. PMID- 29397373 TI - The Journal of Allergy and Clinical Immunology: In Practice 2017 Year in Review. AB - An impressive number of clinically impactful studies and reviews were published in The Journal of Allergy and Clinical Immunology: In Practice in 2017. As a service to our readers, the editors provide this Year in Review article to highlight and contextualize the advances published over the past year. We include information from articles on asthma, allergic rhinitis, rhinosinusitis, immunotherapy, atopic dermatitis, contact dermatitis, food allergy, anaphylaxis, drug hypersensitivity, urticarial/angioedema, eosinophilic disorders, and immunodeficiency. Within each topic, epidemiologic findings are presented, relevant aspects of prevention are described, and diagnostic and therapeutic advances are enumerated. Treatments discussed include behavioral therapy, allergen avoidance therapy, positive and negative effects of pharmacologic therapy, and various forms of immunologic and desensitization management. We hope this review will help readers consolidate and use this extensive and practical knowledge for the benefit of patients. PMID- 29397374 TI - Risk Factors for Food Allergy in Early Adolescence: The SchoolNuts Study. AB - BACKGROUND: Despite the rising rates of anaphylaxis in older children and adolescents, risk factors for food allergy among this age group are understudied. OBJECTIVE: The objective of this study was to investigate the risk factors for current adolescent food allergy using a population-based sample. METHODS: The SchoolNuts study was a questionnaire survey among 10- to 14-year-old adolescents and their parents, followed by clinic evaluation including oral food challenge when food allergy was suspected from questionnaire response. We investigated the association between food allergy and demographic and environmental factors among a total of 4,991 adolescents using multiple logistic regression. RESULTS: Males and those with early-onset eczema had a higher risk of current food allergy in adolescence (adjusted odds ratio [aOR], 1.55; 95% confidence interval [CI], 1.12 2.15 and aOR, 14.08; 95% CI, 10.25-19.33). Those with Asian parents had increased risk compared with those with Caucasian parents (aOR, 2.82; 95% CI, 1.91-4.16), whereas being born in Asia compared with being born in Australia had decreased risk (aOR, 0.16; 95% CI, 0.04-0.67). Family history risk was higher for those with multiple members versus only 1 member (aOR, 4.62; 95% CI, 2.75-7.74 and aOR, 2.32; 95% CI, 1.36-3.97, respectively). Dog exposure during the first 5 years of life was associated with a decreased risk (aOR, 0.58; 95% CI, 0.38-0.91). CONCLUSIONS: Early-onset eczema, Asian background, and family history of allergic disease were associated with an increased risk of food allergy, whereas dog exposure in early life reduced the risk in 10- to14-year-old adolescents. Factors predicting food allergy risk in an adolescent population-based cohort appear remarkably similar to those predicting early-onset food allergy in infancy. PMID- 29397375 TI - Once-weekly GLP-1R agonists: moving the goal posts. PMID- 29397377 TI - A genetic approach to evaluation of short stature of undetermined cause. AB - Short stature is a common presentation to paediatric endocrinologists. After exclusion of major endocrine or systemic disease, most children with short stature are diagnosed based on a description of their growth pattern and the height of their parents (eg, familial short stature). Height is a polygenic trait and genome-wide association studies have identified many of the associated genetic loci. Here we review the application of genetic studies, including copy number variant analysis, targeted gene panels, and whole-exome sequencing in children with idiopathic short stature. We estimate 25-40% of children diagnosed with idiopathic short stature could receive a molecular diagnosis using these technologies. A molecular diagnosis for short stature is important for affected individuals and their families and might inform treatment decisions surrounding use of growth hormone or insulin-like growth factor 1 therapy. PMID- 29397376 TI - Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. AB - BACKGROUND: Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. METHODS: This was an open label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7.0-10.5% (53.0-91.0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0.5 mg, dulaglutide 0.75 mg, semaglutide 1.0 mg, or dulaglutide 1.5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA1c; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA1c non-inferiority (margin 0.4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204. FINDINGS: Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0.5 mg, 299 to dulaglutide 0.75 mg, 300 to semaglutide 1.0 mg, and 299 to dulaglutide 1.5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0.5 mg, 13 receiving dulaglutide 0.75 mg, 21 receiving semaglutide 1.0 mg, and 16 receiving dulaglutide 1.5 mg). From overall baseline mean, mean percentage HbA1c was reduced by 1.5 (SE 0.06) percentage points with semaglutide 0.5 mg versus 1.1 (0.05) percentage points with dulaglutide 0.75 mg (estimated treatment difference [ETD] -0.40 percentage points [95% CI -0.55 to -0.25]; p<0.0001) and by 1.8 (0.06) percentage points with semaglutide 1.0 mg versus 1.4 (0.06) percentage points with dulaglutide 1.5 mg (ETD -0.41 percentage points [ 0.57 to -0.25]; p<0.0001). From overall baseline mean, mean bodyweight was reduced by 4.6 kg (SE 0.28) with semaglutide 0.5 mg compared with 2.3 kg (0.27) with dulaglutide 0.75 mg (ETD -2.26 kg [-3.02 to -1.51]; p<0.0001) and by 6.5 kg (0.28) with semaglutide 1.0 mg compared with 3.0 kg (0.27) with dulaglutide 1.5 mg (ETD -3.55 kg [-4.32 to -2.78]; p<0.0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0.5 mg, 133 (44%) of 300 patients receiving semaglutide 1.0 mg, 100 (33%) of 299 patients receiving dulaglutide 0.75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1.5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group. INTERPRETATION: At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile. FUNDING: Novo Nordisk. PMID- 29397378 TI - Intraoperative optical imaging of metabolic changes after direct cortical stimulation - a clinical tool for guidance during tumor resection? AB - Brain tumor resection is even today one of the most challenging disciplines in neurosurgery. The current state of the art for the identification of tumor tissue during the surgical procedure comprises a wide variety of different tools, each with its own limitations and drawbacks. In this paper, we present a novel approach, the use of optical imaging in connection with direct electrical cortical stimulation (DCS), for identification of impaired tumor tissue and functional intact normal brain tissue under intraoperative conditions. Measurements with an optical imaging setup were performed as a proof of concept on three patients who underwent tumor resection of superficial gliomas. Direct electrical stimulations were applied on tumor tissue and surrounding brain tissue in each patient and characteristic features from the observed changes in the optical properties were compared between the different groups. The results reveal that in all patients a differentiation between non-functional tumor tissue and functional intact brain tissue was possible, and the technique might be a useful clinical tool in the future. PMID- 29397379 TI - Analytical validation of the Hevylite assays for M-protein quantification. AB - BACKGROUND: The heavy/light chain (HLC) immunoassay quantifies the different heavy chain/light chain combinations of each immunoglobulin (Ig) class. This makes the HLC assay suited to quantify monoclonal immunoglobulins (M-protein) and for monitoring of patients with monoclonal gammopathies. This method is particularly advantageous for those samples in which electrophoretic quantification of the M-protein is not possible. METHODS: In this study we tested the analytical performance of the HLC assay in 166 routine clinical samples and in 27 samples derived from the Dutch external quality assessment (EQA) for M protein diagnostics (74 participating laboratories). Analytical accuracy was assessed by verification that the sum of the HLC-pairs equaled total Ig concentration. Sensitivity of the HLC assay was determined in a direct method comparison with immunofixation electrophoresis (IFE). RESULTS: Comparison of HLC data with routine Ig diagnostics in 27 EQA samples showed very good correlation for both the quantification of polyclonal and monoclonal IgG, IgA and IgM (Pearson correlations [r] were 0.94, 0.99 and 0.99, respectively; slopes were 0.94, 1.07 and 0.98, respectively). The overall concordance between IFE and the HLC ratio was high (93%) with a Cohen kappa coefficient of 0.84. Discrepancies between both assays were mainly caused by the higher sensitivity of IFE to detect monoclonality. CONCLUSIONS: We conclude that the HLC assay is an accurate method to quantify M-proteins that can improve monitoring of M-proteins in the beta fraction that cannot be quantified using electrophoretic techniques. PMID- 29397380 TI - Glucose and total protein: unacceptable interference on Jaffe creatinine assays in patients. PMID- 29397381 TI - Investigation of the prevalence and causes and of legal abortion of teenage married mothers in Iran. AB - Background The therapeutic abortion law, in accordance with the fatwa issued by our Muslim jurisprudent approved by the parliament in 2005, has made major developments in dealing with cases of therapeutic abortions. Objective This study aimed at identifying the prevalence and causes of therapeutic abortion requests to the Legal Medicine Organization of Fars province, Shiraz, by pregnant teenager mothers. Methods This study was a retrospective, cross-sectional, descriptive survey. In this study, all documents related to therapeutic abortion requests from the Legal Medicine Organization of Fars province (southern Iran) from 2006 to 2013 were investigated. The total sample size included 1664, out of which 142 were teenagers. Sampling was carried out using Convenience method. Data were analyzed using SPSS statistical software, version 16, descriptive statistics and chi2. Results In this study, 142 mothers were under 20 years of age (8.5%). The prevalence of fetal abortion license requests was 110 (78.6%) and for maternal causes was 30 (21.4%). There was no significant statistical correlation between fetal causes in different years (p = 0.083). The most common causes of fetal abortion request were for thalassemia treatment in 78 cases (79.9%) followed by fetal malformations (20.9%); also, the most common maternal cause was thalassemia in 14 cases (51.9%) and depression in three cases (1.11%), respectively. Conclusion Our results showed that after approval of therapeutic abortion law, requests for therapeutic abortion due to fetal causes are extensively increasing. There is still a need for coordination of judicial, medical and legal authorities for prompt notification. PMID- 29397382 TI - Effect of communication skills based group counseling on mothers' sex dialogue with their adolescent daughters. AB - Background Sex dialogue is one of the most critical and challenging topics between mothers and adolescents. The knowledge and skills of mothers in sex dialogue with their daughters are essential. The purpose of this study is to determine the effect of group counseling based on communication skills on mothers through their sex dialogue with their daughters. Methods A randomized controlled field trial was conducted on 168 couples of mothers and their daughters selected by the stratified matching method and randomly divided into two control and intervention groups. The mothers in the intervention group participated in a communication-based consultation in groups consisting of 6-12 people for 6-7 weekly sessions, each one lasting 60 min. The data collection tool was a Persian translated questionnaire by Jaccard for sex dialogue between mother and daughter. The data were analyzed using Chi-square (chi2), ANOVA with repeated measures and modified post hoc Bonferroni tests. Results There was a significant difference in the mean score of mother-daughter sex dialogue 1 week after intervention between the intervention (34.48 +/- 8.74) and control (40.44 +/- 9.49) groups (p = 0.001) and 1 month after the intervention between the intervention (30.41 +/- 10.07) and control (42.47 +/- 9.62) groups (p < 0.001). Conclusion Through applying communication skills, an increase in mother-daughter sex dialogue frequency was observed after group counseling. Therefore, it is suggested to promote mother daughter communication skills by accessing the mothers via schools, health centers and with the aid of midwifery counselors, midwives and other trained caretakers. PMID- 29397383 TI - Facilitating factors of self-care among HIV-positive young women in Iran: a qualitative study. AB - Background Providing care for chronic disease such as HIV is a growing challenge in the world. In order to address the challenges of linkage and care in chronic disease management, we need to identify factors that can influence people to get more involved in self-care. This study was part of an extensive qualitative study conducted in Tehran, Iran in 2016. Methods The data were collected through semi structured interviews conducted on 25 women with HIV, and were analyzed using grounded theory. Four main themes were identified as facilitating self-care among participants: health system support, clinicians' support, family support and improved life expectancy. Sub-themes that emerged were free HIV tests; free medication; free membership in positive clubs; free psychological consultation; positive attitudes and friendly behavior from clinic staff; telephone follow up; support from husbands, mothers and peers; hope for recovery; hope for the future; and love for own children. Results Our results showed that, providing appropriate support and services, as well as a positive attitude of society towards HIV positive women, can contribute to adherence to self-care in young women with HIV. Conclusion Understanding the facilitating factors based on the patients' experiences can contribute to the development of new policies and procedures to improve the care of these patients. PMID- 29397384 TI - Predicting high school students' health-promoting lifestyle: a test of the information, motivation, behavioral skills model. AB - Background and aim Expenditure on adolescents' health promotion is critical to enhancing quality of life and fundamental for the prosperity of countries. This study tried to investigate the relationships between information-motivation behavioral skills (IMB) model constructs as predictors of high school student's health-promoting lifestyle (HPL) in Southwest Iran. Methods This cross-sectional descriptive-analytic study was conducted on 400 students in Southwest Iran. Sample size required for this study was obtained using Soper's structural equation modeling (SEM) calculator. The stratified random sampling method was used in this study. A path analysis was taken to evaluate the HPL main determinants utilizing SEM. Results Information only had a significant indirect relationship with adolescents' HPL. But, both motivation and behavioral skills constructs had significant direct and indirect relationship with adolescents' HPL. The behavioral skill construct was the most imperative predictor variable. In general, behavioral skills construct (75%), motivation (66%) and knowledge (50%) constructs had the highest impact on HPL. The IMB model was able to explain 71% of the variance in adolescents' HPL. Conclusion The findings of the study showed that the IMB model was appropriate for explaining adolescents' HPL. It is necessary that actions are taken to improve behavioral skills and promote adolescents' HPL. PMID- 29397385 TI - Faculty Experiences with Integrating Mandated High-Fidelity Human Patient Simulation (HF-HPS) Into Clinical Practice: A Phenomenological Study. AB - Background High fidelity human patient simulation (HF-HPS) is a teaching innovation in nursing education which may not be used to its full potential. This study seeks to understand the lived experiences of nurse faculty who are required to integrate HF-HPS into their teaching practice. Method A phenomenological methodology was used. Seventeen female nurse faculty teaching in the second year of a new collaborative bachelor of science in nursing program were interviewed about their experiences integrating mandated HF-HPS into their teaching practices. Results Six themes describing the participants' experiences were identified: striving for self-efficacy, struggling to maintain autonomy, being part of a community of practice, adopting HF-HPS as a teaching innovation, being an advocate, and being proud. An emerging theme, being an outsider, was discussed. Conclusion This research has implications for nurse faculty and educational administrators integrating a new teaching innovation. PMID- 29397386 TI - Blood troponin levels in acute cardiac events depends on space weather activity components (a correlative study). AB - BACKGROUND: Many biological processes are influenced by space weather activity components such as solar activity (SA), geomagnetic activity (GMA) and cosmic ray activity (CRA). Examples are total mortality, acute myocardial infarction (AMI), stroke (cerebrovascular accident), sudden cardiac death, some congenital maladies (congenital heart disease and Down syndrome), many events in neonatology, ophtalmology, blood pressure regulation, blood coagulation, inflammation, etc. The aim of this study was to check if the level of blood troponins (Tns) - markers of myocardial damage and recognized components of modern description of AMI - is connected with the mentioned space weather parameters. METHODS: Patients admitted to a 3000-bed tertiary university hospital in Kaunas, Lithuania, with suspected AMI were the object of the study. Data for the time between 2008 and 2013 - 72 consecutive months - were studied. Of the patients, 1896 (1398 male, 498 female) had elevated troponin I (Tn I) or troponin T (Tn T, sensitive Tn) levels. Normal values were 0.00-0.03 ng/mL for Tn I and 0.00-14.00 ng/mL for Tn T. Monthly means and standard deviation of Tn I and Tn T were compared with monthly markers of SA, GMA and CRA. Pearson correlation coefficients and their probabilities were established (in addition to the consecutive graphs of both comparing physical and biological data). The cosmophysical data came from space service institutions in the United States, Russia and Finland. RESULTS: AMI was diagnosed in 1188 patients (62.66%), and intermediate coronary syndrome in 698 patients (36.81%). There were significant links of the Tn blood levels with four SA indices and CRA (neutron activity in imp/min); there was no significant correlation with GMA indices Ap and Cp (p=0.27 and p=0.235). Tn T levels significantly correlated with the GMA indices and not with the SA and CRA levels (Ap: r=0.77, p=0.0021; Cp: r=0.729, p=0.0047). CONCLUSIONS: First, the monthly level of blood Tn I in ACS is significantly correlated with the indices of SA (inverse) and with CRA (neutron); second, no significant correlation with the GMA indices was found; and third, the Tn T levels showed significant links with the GMA indices and none with SA and CRA (neutron). PMID- 29397387 TI - Losartan improves renal function and pathology in obese ZSF-1 rats. AB - BACKGROUND: Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy. METHODS: The rats (7-10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks. RESULTS: Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP 1, L-FABP and KIM-1 were the only markers decreased by losartan. CONCLUSIONS: Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis. PMID- 29397389 TI - Recent studies on cellular and molecular mechanisms in Alzheimer's disease: focus on epigenetic factors and histone deacetylase. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes: ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, MS4A6A, MS4A4E, and PICALM, which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment. PMID- 29397388 TI - Vitamin D deficiency in childhood: old lessons and current challenges. AB - Hypovitaminosis D in childhood is a re-emerging public health problem in developed countries. New life style habits, current "epidemics" of obesity in children and adolescents worldwide, and other preventable risk factors may play a role in favoring the occurrence of vitamin D deficiency. In addition to skeletal consequences, hypovitaminosis D has been found to be involved in the development of serious health extra-skeletal problems in childhood, including atopy and autoimmunity. The increasing concerns about the global health impact of vitamin D deficiency make further research necessary to fill the gaps of knowledge in this field, and particularly to establish universally accepted "normal" serum 25(OH)D levels in the pediatric population, and to improve strategies for the screening, prevention and treatment of hypovitaminosis D. This review discusses the key points of hypovitaminosis D in childhood in the light of new knowledge, and highlights the limitations of current strategies to control this condition. PMID- 29397390 TI - Neuromuscular synergies in motor control in normal and poststroke individuals. AB - Muscle synergies are proposed to function as motor primitives that are modulated by frontal brain areas to construct a large repertoire of movement. This paper reviews the history of the development of our current theoretical understanding of nervous system-based motor control mechanisms and more specifically the concept of muscle synergies. Computational models of muscle synergies, especially the nonnegative matrix factorization algorithm, are discussed with specific reference to the changes in synergy control post-central nervous system (CNS) lesions. An alternative approach for motor control is suggested, exploiting a combination of synergies control or flexible muscle control used for gross motor skills and for individualized finger movements. Rehabilitation approaches, either supporting or inhibiting the use of basic movement patterns, are discussed in the context of muscle synergies. Applications are discussed for the use of advanced technologies that can promote the recovery and functioning of the human CNS after stroke. PMID- 29397391 TI - Gut microbiome and depression: what we know and what we need to know. AB - Gut microbiome diversity has been strongly associated with mood-relating behaviours, including major depressive disorder (MDD). This association stems from the recently characterised bi-directional communication system between the gut and the brain, mediated by neuroimmune, neuroendocrine and sensory neural pathways. While the link between gut microbiome and depression is well supported by research, a major question needing to be addressed is the causality in the connection between the two, which will support the understanding of the role that the gut microbiota play in depression. In this article, we address this question by examining a theoretical 'chronology', reviewing the evidence supporting two possible sequences of events. First, we discuss that alterations in the gut microbiota populations of specific species might contribute to depression, and secondly, that depressive states might induce modification of specific gut microbiota species and eventually contribute to more severe depression. The feasibility of both sequences is supported by pre-clinical trials. For instance, research in rodents has shown an onset of depressive behaviour following faecal transplantations from patients with MDD. On the other hand, mental induction of stress and depressive behaviour in rodents resulted in reduced gut microbiota richness and diversity. Synthesis of these chronology dynamics raises important research directions to further understand the role that gut microbiota play in mood-relating behaviours, which holds substantial potential clinical outcomes for persons who experience MDD or related depressive disorders. PMID- 29397392 TI - Experimental models of focal and multifocal cerebral ischemia: a review. AB - Rodent and rabbit stroke models have been instrumental in our current understanding of stroke pathophysiology; however, translational failure is a significant problem in preclinical ischemic stroke research today. There are a number of different focal cerebral ischemia models that vary in their utility, pathophysiology of causing disease, and their response to treatments. Unfortunately, despite active preclinical research using these models, treatment options for ischemic stroke have not significantly advanced since the food and drug administration approval of tissue plasminogen activator in 1996. This review aims to summarize current stroke therapies, the preclinical experimental models used to help develop stroke therapies, as well as their advantages and limitations. In addition, this review discusses the potential for naturally occurring canine ischemic stroke models to compliment current preclinical models and to help bridge the translational gap between small mammal models and human clinical trials. PMID- 29397393 TI - Distance-correlation based gene set analysis in longitudinal studies. AB - Longitudinal gene expression profiles of subjects are collected in some clinical studies to monitor disease progression and understand disease etiology. The identification of gene sets that have coordinated changes with relevant clinical outcomes over time from these data could provide significant insights into the molecular basis of disease progression and lead to better treatments. In this article, we propose a Distance-Correlation based Gene Set Analysis (dcGSA) method for longitudinal gene expression data. dcGSA is a non-parametric approach, statistically robust, and can capture both linear and nonlinear relationships between gene sets and clinical outcomes. In addition, dcGSA is able to identify related gene sets in cases where the effects of gene sets on clinical outcomes differ across subjects due to the subject heterogeneity, remove the confounding effects of some unobserved time-invariant covariates, and allow the assessment of associations between gene sets and multiple related outcomes simultaneously. Through extensive simulation studies, we demonstrate that dcGSA is more powerful of detecting relevant genes than other commonly used gene set analysis methods. When dcGSA is applied to a real dataset on systemic lupus erythematosus, we are able to identify more disease related gene sets than other methods. PMID- 29397394 TI - More than Ankylosing Spondylitis. PMID- 29397395 TI - The Expression of Calcium Sensing Receptor in Normal and Diabetic Rat Eyes. AB - BACKGROUND Calcium sensing receptor (CaSR) is widely expressed in many tissues of the body, but it is rarely reported to be expressed in the eyes. This research explored the expression and distribution of CaSR in eye tissues of normal and diabetic rats. MATERIAL AND METHODS Thirty male Sprague Dawley (SD) rats were randomly divided into a diabetic and a normal group. Diabetes mellitus (DM) models were successfully established by intraperitoneal injection of streptozotocin. The expression and distribution of CaSR in the rat eyeballs were detected by immunohistochemistry. Quantitative RT-PCR and western blotting were used to detect the presence of CaSR in normal and diabetic rats. RESULTS CaSR was detected in the cornea, lens epithelium, and retina. CaSR was expressed the most in the cornea, followed by the lens epithelium, and the retina (p<0.05). The expression of CaSR was decreased in the eye tissue of diabetic rats (p<0.05). CONCLUSIONS In this study, CaSR was detected in rat cornea, lens, and retina. It was significantly decreased in the eyes of diabetic rats. This indicated that the downregulated expression of CaSR was associated with diabetic oculopathy. PMID- 29397396 TI - Comparison of Unilateral Fasciocutaneous V-Y Flap Technique with Cleft Lift Procedure in the Treatment of Recurrent Pilonidal Sinus Disease: A Retrospective Clinical Study. AB - BACKGROUND This study aimed to assess treatment outcomes of the cleft lift procedure and V-Y flap technique in the treatment of recurrent pilonidal sinus disease (PSD). MATERIAL AND METHODS A total of 51 patients who underwent cleft lift procedure and 43 patients who underwent fasciocutaneous V-Y flap technique were evaluated. The demographic characteristics, previous operations, duration of symptoms, perioperative complications, duration of operation and hospital stay, duration of draining of all patients, and recurrence of PSD were recorded. RESULTS The mean operation time was 35.61+/-5.254 min in the cleft lift group (CLG) and 57.42+/-7.327 min in the V-Y flap group (VYFG) (p=0.001). No wound dehiscence was found in the VYFG and 5 patients (9.8%) had wound dehiscence in the CLG (p=0.035). Draining time was 1.39+/-0.603 days in the CLG and 2.79+/ 0.638 days in VYFG (p=0.001). The mean hospital stay was 1.75+/-0.523 days in the CLG and 3.77+/-1.02 days in the VYFG (p=0.001). Two patients (3.9%) in the CLG had recurrence and no recurrence was reported in the VYFG (p=0.189) in the given time interval. CONCLUSIONS Both methods in treatment of recurrent PSD can be preferred because of low complication and recurrence rates. Because no recurrence was found after the V-Y flap technique, it appears to be a preferable method despite some disadvantages. PMID- 29397397 TI - Nanos genes and their role in development and beyond. AB - The hallmark of Nanos proteins is their typical (CCHC)2 zinc finger motif (zf nanos). Animals have one to four nanos genes. For example, the fruit fly and demosponge have only one nanos gene, zebrafish and humans have three, and Fugu rubripes has four. Nanos genes are mainly known for their evolutionarily preserved role in germ cell survival and pluripotency. Nanos proteins have been reported to bind the C-terminal RNA-binding domain of Pumilio to form a post transcriptional repressor complex. Several observations point to a link between the miRNA-mediated repression complex and the Nanos/Pumilio complex. Repression of the E2F3 oncogene product is, indeed, mediated by cooperation between the Nanos/Pumilio complex and miRNAs. Another important interaction partner of Nanos is the CCR4-NOT deadenylase complex. Besides the tissue-specific contribution of Nanos proteins to normal development, their ectopic expression has been observed in several cancer cell lines and various human cancers. An inverse correlation between the expression levels of human Nanos1 and Nanos3 and E-cadherin was observed in several cancer cell lines. Loss of E-cadherin, an important cell-cell adhesion protein, contributes to tumor invasion and metastasis. Overexpression of Nanos3 induces epithelial-mesenchymal transition in lung cancer cell lines partly by repressing E-cadherin. Other than some most interesting data from Nanos knockout mice, little is known about mammalian Nanos proteins, and further research is needed. In this review, we summarize the main roles of Nanos proteins and discuss the emerging concept of Nanos proteins as oncofetal antigens. PMID- 29397399 TI - Longitudinal Effects of Supplemental Forage on the Honey Bee (Apis mellifera) Microbiota and Inter- and Intra-Colony Variability. AB - Honey bees (Apis mellifera) provide vital pollination services for a variety of agricultural crops around the world and are known to host a consistent core bacterial microbiome. This symbiotic microbial community is essential to many facets of bee health, including likely nutrient acquisition, disease prevention and optimal physiological function. Being that the bee microbiome is likely involved in the digestion of nutrients, we either provided or excluded honey bee colonies from supplemental floral forage before being used for almond pollination. We then used 16S rRNA gene sequencing to examine the effects of forage treatment on the bees' microbial gut communities over four months. In agreement with previous studies, we found that the honey bee gut microbiota is quite stable over time. Similarly, we compared the gut communities of bees from separate colonies and sisters sampled from within the same hive over four months. Surprisingly, we found that the gut microbial communities of individual sisters from the same colony can exhibit as much variation as bees from different colonies. Supplemental floral forage had a subtle effect on the composition of the microbiome during the month of March only, with strains of Gilliamella apicola, Lactobacillus, and Bartonella being less proportionally abundant in bees exposed to forage in the winter. Collectively, our findings show that there is unexpected longitudinal variation within the gut microbial communities of sister honey bees and that supplemental floral forage can subtly alter the microbiome of managed honey bees. PMID- 29397398 TI - Bidirectional motility of kinesin-5 motor proteins: structural determinants, cumulative functions and physiological roles. AB - Mitotic kinesin-5 bipolar motor proteins perform essential functions in mitotic spindle dynamics by crosslinking and sliding antiparallel microtubules (MTs) apart within the mitotic spindle. Two recent studies have indicated that single molecules of Cin8, the Saccharomyces cerevisiae kinesin-5 homolog, are minus end directed when moving on single MTs, yet switch directionality under certain experimental conditions (Gerson-Gurwitz et al., EMBO J 30:4942-4954, 2011; Roostalu et al., Science 332:94-99, 2011). This finding was unexpected since the Cin8 catalytic motor domain is located at the N-terminus of the protein, and such kinesins have been previously thought to be exclusively plus end-directed. In addition, the essential intracellular functions of kinesin-5 motors in separating spindle poles during mitosis can only be accomplished by plus end-directed motility during antiparallel sliding of the spindle MTs. Thus, the mechanism and possible physiological role of the minus end-directed motility of kinesin-5 motors remain unclear. Experimental and theoretical studies from several laboratories in recent years have identified additional kinesin-5 motors that are bidirectional, revealed structural determinants that regulate directionality, examined the possible mechanisms involved and have proposed physiological roles for the minus end-directed motility of kinesin-5 motors. Here, we summarize our current understanding of the remarkable ability of certain kinesin-5 motors to switch directionality when moving along MTs. PMID- 29397400 TI - Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. AB - Etoposide (ETP) and anthracyclines are applied for wide anti-cancer treatments. However, the ETP-induced cardiotoxicity remains to be a major safety issue and the underlying cardiotoxic mechanisms are not well understood. This study is aiming to unravel the cardiotoxicity profile of ETP in comparison to anthracyclines using physiologically relevant human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Using xCELLigence real-time cell analyser (RTCA), we found that single high dose of ETP induces irreversible increase in hPSC-CMs beating rate and decrease in beating amplitude. We also identified 58 deregulated genes consisting of 33 upregulated and 25 downregulated genes in hPSC-CMs after ETP treatment. Gene ontology (GO) and pathway analysis showed that most upregulated genes are enriched in GO categories like positive regulation of apoptotic process, regulation of cell death, and mitochondria organization, whereas most downregulated genes were enriched in GO categories like cytoskeletal organization, muscle contraction, and Ca2+ ion homeostasis. Moreover, we also found upregulation in 5 miRNAs (has-miR-486-3p, has-miR-34c-5p, has-miR-4423-3p, has-miR-182-5p, and has-miR-139-5p) which play role in muscle contraction, arginine and proline metabolism, and hypertrophic cardiomyopathy (HCM). Immunostaining and transmission electron microscopy also confirmed the cytoskeletal and mitochondrial damage in hPSC-CMs treated with ETP, as well as noticeable alterations in intracellular calcium handling and mitochondrial membrane potential were also observed. The apoptosis inhibitor, Pifithrin-alpha, found to protect hPSC-CMs from ETP-induced cardiotoxicity, whereas hPSC-CMs treated with ferroptosis inhibitor, Liproxstatin-1, showed significant recovery in hPSC-CMs functional properties like beating rate and amplitude after ETP treatment. We suggest that the damage to mitochondria is a major contributing factor involved in ETP-induced cardiotoxicity and the activation of the p53 mediated ferroptosis pathway by ETP is likely the critical pathway in ETP-induced cardiotoxicity. We also conclude that the genomic biomarkers identified in this study will significantly contribute to develop and predict potential cardiotoxic effects of novel anti-cancer drugs in vitro. PMID- 29397402 TI - Interim FDG PET/CT in primary mediastinal diffuse large B-cell lymphoma: really almost useless procedure? PMID- 29397401 TI - Absence of the tag polymorphism for the risk haplotype HLA-DR2 for multiple sclerosis in Wixarika subjects from Mexico. AB - The HLA-DRB1*15:01 allele has a demonstrated risk for the development of multiple sclerosis (MS) in most populations around the world. The single nucleotide polymorphism (SNP) rs3129934 is found in linkage disequilibrium with the risk haplotype formed by the HLA-DRB1*15:01 and HLA-DQB1*06:02 alleles, and it is considered a reliable marker of the presence of this haplotype. Native Americans have a null or low prevalence of MS. In this study, we sought to identify the frequency of rs3129934 in the Wixarika ethnic group as well as in Mestizo (mixed race) patients with MS and in controls from western Mexico. Through real-time polymerase chain reaction (PCR) using TaqMan probes, we analyzed the allele and genotype frequencies of rs3129934 in Mestizo individuals with and without MS and in 73 Wixarika subjects from the state of Jalisco, Mexico. The Wixarika subjects were homozygote for the C allele of rs3129934. The allele and genotype frequency in Mestizos with MS was similar to that of other MS populations with Caucasian ancestry. The absence of the T risk allele rs3129934 (associated with the haplotype HLA-DRB1*15:01, HLA-DQ1*06:02) in this sample of Wixarika subjects is consistent with the unreported MS in this Amerindian group, related to absence of such paramount genetic risk factor. PMID- 29397403 TI - Characterization of a new GmFAD3A allele in Brazilian CS303TNKCA soybean cultivar. AB - KEY MESSAGE: We molecularly characterized a new mutation in the GmFAD3A gene associated with low linolenic content in the Brazilian soybean cultivar CS303TNKCA and developed a molecular marker to select this mutation. Soybean is one of the most important crops cultivated worldwide. Soybean oil has 13% palmitic acid, 4% stearic acid, 20% oleic acid, 55% linoleic acid and 8% linolenic acid. Breeding programs are developing varieties with high oleic and low polyunsaturated fatty acids (linoleic and linolenic) to improve the oil oxidative stability and make the varieties more attractive for the soy industry. The main goal of this study was to characterize the low linoleic acid trait in CS303TNKCA cultivar. We sequenced CS303TNKCA GmFAD3A, GmFAD3B and GmFAD3C genes and identified an adenine point deletion in the GmFAD3A exon 5 (delA). This alteration creates a premature stop codon, leading to a truncated protein with just 207 residues that result in a non-functional enzyme. Analysis of enzymatic activity by heterologous expression in yeast support delA as the cause of low linolenic acid content in CS303TNKCA. Thus, we developed a TaqMan genotyping assay to associate delA with low linolenic acid content in segregating populations. Lines homozygous for delA had a linolenic acid content of 3.3 to 4.4%, and the variation at this locus accounted for 50.83 to 73.70% of the phenotypic variation. This molecular marker is a new tool to introgress the low linolenic acid trait into elite soybean cultivars and can be used to combine with high oleic trait markers to produce soybean with enhanced economic value. The advantage of using CS303TNKCA compared to other lines available in the literature is that this cultivar has good agronomic characteristics and is adapted to Brazilian conditions. PMID- 29397404 TI - Maximizing the expression of transgenic traits into elite alfalfa germplasm using a supertransgene configuration in heterozygous conditions. AB - KEY MESSAGE: A novel process for the production of transgenic alfalfa varieties. Numerous species of legumes, including alfalfa, are critical factors for agroecosystems due to their ability to grow without nitrogen fertilizers derived from non-renewable fossil fuels, their contribution of organic nitrogen to the soil, and their increased nutritional value. Alfalfa is the main source of vegetable proteins in meat and milk production systems worldwide. Despite the economic and ecological importance of this autotetraploid and allogamous forage crop, little progress has been made in the incorporation of transgenic traits into commercial alfalfa. This is mainly due to the unusually strong transgene silencing and complex reproductive behavior of alfalfa, which limit the production of events with high transgene expression and the introgression of selected events within heterogeneous synthetic populations, respectively. In this report, we describe a novel procedure, called supertransgene process, where a glufosinate-tolerant alfalfa variety was developed using a single event containing the BAR transgene associated with an inversion. This approach can be used to maximize the expression of transgenic traits into elite alfalfa germplasm and to reduce the cost of production of transgenic alfalfa cultivars, contributing to the public improvement of this legume forage and other polyploid and outcrossing crop species. PMID- 29397405 TI - Early differential diagnosis methods of biliary atresia: a meta-analysis. AB - PURPOSE: To evaluate the accuracy of early differential diagnosis methods of biliary atresia in patients with infantile cholestasis. METHODS: We searched PubMed, EMBASE and the Web of Science databases for articles evaluated the early differential diagnosis methods of biliary atresia. The methodological quality of each study was assessed with version 2 of the Quality Assessment of Diagnostic Accuracy Studies tool. Two reviewers extracted data independently. Pooled sensitivity, specificity, positive likelihood ratio (LR +), negative likelihood ratio (LR -), diagnostic odds ratio (DOR) with 95% CIs were calculated to assess each diagnosis method. RESULTS: A total of 38 articles were included. Summary sensitivity and specificity were 77% (95% CI 74-80%) and 93% (95% CI 91-94%), respectively, for B-US in 23 studies; 96% (95% CI 92-98%) and 58% (95% CI 51 65%), respectively, for MRCP in five studies; 87% (95% CI 82-91%) and 78% (95% CI 74-82%), respectively, for acholic stool in seven studies; 84% (95% CI 78-89%) and 97% (95% CI 97-98%), respectively, for serum liver function test in seven studies; 96% (95% CI 94-97%) and 73% (95% CI 70-76%), respectively, for hepatobiliary scintigraphy in 18 studies; 98% (95% CI 96-99%) and 93% (95% CI 89 95%), respectively, for percutaneous liver biopsy in 11 studies. CONCLUSION: The accuracy rate of percutaneous liver biopsy is better than all of the noninvasive methods. Take into consideration the advantages and disadvantages of the six methods, combination of multidisciplinary noninvasive diagnosis methods is the first choice for differential diagnosis of BA from other causes of neonatal cholestasis. PMID- 29397406 TI - Ultrasound-guided lumbar puncture in pediatric patients: technical success and safety. AB - BACKGROUND: Disadvantages of fluoroscopically guided lumbar puncture include delivery of ionizing radiation and limited resolution of incompletely ossified posterior elements. Ultrasound (US) allows visualization of critical soft tissues and the cerebrospinal fluid (CSF) space without ionizing radiation. OBJECTIVE: To determine the technical success and safety of US-guided lumbar puncture in pediatric patients. MATERIALS AND METHODS: A retrospective review identified all patients referred to interventional radiology for lumbar puncture between June 2010 and June 2017. Patients who underwent lumbar puncture with fluoroscopic guidance alone were excluded. For the remaining procedures, technical success and procedural complications were assessed. Two hundred and one image-guided lumbar punctures in 161 patients were included. Eighty patients (43%) had previously failed landmark-based attempts. RESULTS: One hundred ninety-six (97.5%) patients underwent lumbar puncture. Five procedures (2.5%) were not attempted after US assessment, either due to a paucity of CSF or unsafe window for needle placement. Technical success was achieved in 187 (95.4%) of lumbar punctures attempted with US guidance. One hundred seventy-seven (90.3%) were technically successful with US alone (age range: 2 days-15 years, weight range: 1.9-53.1 kg) and an additional 10 (5.1%) were successful with US-guided thecal access and subsequent fluoroscopic confirmation. Three (1.5%) cases were unsuccessful with US guidance but were subsequently successful with fluoroscopic guidance. Of the 80 previously failed landmark-based lumbar punctures, 77 (96.3%) were successful with US guidance alone. There were no reported complications. CONCLUSION: US guidance is safe and effective for lumbar punctures and has specific advantages over fluoroscopy in pediatric patients. PMID- 29397407 TI - Long non-coding RNA TUSC7 inhibits temozolomide resistance by targeting miR-10a in glioblastoma. AB - PURPOSE: Human glioblastoma multiforme (GBM) is the most malignant intracranial primary cancer and is associated with high mortality and poor prognosis. This study aimed to investigate the regulatory effects and mechanism of tumor suppressor candidate 7 (TUSC7) gene to malignant proliferation and chemotherapy resistance to temozolomide (TMZ) in glioma cells. METHODS: The expression of TUSC7 was detected by quantitative real-time PCR. CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry were used to detect cell cycle and cell apoptosis. The expression of MDR1 protein was examined by western blot. RNA pull-down assay was applied to confirm the specific combination between TUSC7 and miR-10a. RESULTS: In the present study, we detected low expression of TUSC7 in GBM cells and tissues resistant to TMZ. Upregulation of TUSC7 suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells. TUSC7 acted by directly targeting and silencing expression of miR-10a gene, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells. CONCLUSIONS: These findings suggest a negative correlation between TUSC7 expression and TMZ resistance and provide a mechanism and rationale for targeting TUSC7 in the treatment of GBM. PMID- 29397408 TI - Bisphosphonate use after clinical fracture and risk of new fracture. AB - : Among older adults with a previous fracture, treatment for osteoporosis was initially associated with a higher risk of new fracture. However, the relative risk of new fracture decreased over time, a trend that is consistent with a beneficial effect, as treatment for osteoporosis is prescribed to reduce high fracture risks. INTRODUCTION: The purpose of this study was to examine whether bisphosphonate use is associated with a lower risk of new fracture after a clinical fracture in older adults. METHODS: Data were available for 3,329,400 adults in Sweden who were aged >= 50 years between 2006 and 2011. During this period, 260,353 sustained a clinical fracture and were naive to bisphosphonates at the time. Those who subsequently received a bisphosphonate were matched to up to three others on sex, year of birth, and type and year of initial fracture. The final cohort comprised 83,104 adults (26.3% bisphosphonate users). RESULTS: During the period from initial fracture to initiation of bisphosphonate treatment, the incidence rate of any new clinical fracture was higher in those who later became bisphosphonate users than in those who remained nonusers (175.1 vs. 75.9 per 1000 person-years; hazard ratio 2.30, 95% confidence interval 2.19 to 2.41). Similarly, during the first 6 months of treatment, the incidence rate was higher in bisphosphonate users than in nonusers (128.8 vs. 90.2 per 1000 person-years; hazard ratio 1.41, 95% confidence interval 1.32 to 1.51). However, this difference decreased over time: by months 12 to 18, the incidence rate was similar in users and nonusers (59.3 vs. 55.3 per 1000 person-years; hazard ratio 1.03, 95% confidence interval 0.91 to 1.16). CONCLUSIONS: There was a decrease in the relative risk of new fracture during bisphosphonate treatment, a trend that is consistent with a beneficial treatment effect, as bisphosphonates are prescribed to reduce high fracture risks. PMID- 29397409 TI - FRAX calculated without BMD does not correctly identify Caucasian men with densitometric evidence of osteoporosis. AB - : The FRAX algorithm assesses the patient's probability of sustaining an osteoporotic fracture and can be calculated with or without densitometric data. This study seeks to determine whether in men, FRAX scores calculated without BMD, correctly identify patients with BMD-defined osteoporosis. INTRODUCTION: The diagnosis of osteoporosis is based on densitometric data, the presence of a fragility fracture or increased fracture risk. The FRAX algorithm estimates the patient's 10-year probability of sustaining an osteoporotic fracture and can be calculated with or without BMD data. The purpose of this study is to determine whether in men, FRAX calculated without BMD, can correctly identify patients with BMD-defined osteoporosis. METHODS: Retrospectively retrieved data from 726 consecutive Caucasian males, 50 to 70 years old referred to our Osteoporosis Center. RESULTS: In the population studied, 11.8 and 25.3% had BMD-defined osteoporosis when female and male reference populations were used respectively. When the National Osteoporosis Foundation thresholds to initiate treatment are used, only 27% of patients with BMD-defined osteoporosis, but 4% with normal BMD reached/exceeded these thresholds. Lowering the threshold increased sensitivity, but decreased specificity. CONCLUSIONS: Our results suggest that FRAX without BMD is not sensitive/specific enough to be used to identify Caucasian men 50 to 70 years old with BMD-defined osteoporosis. PMID- 29397410 TI - Behavioral and electrophysiological responses to fairness norm violations in antisocial offenders. AB - Antisocial personality disorder is characterized by a stable, lifelong pattern of disregard for and violation of others' rights. Disruptions in the representation of fairness norms may represent a key mechanism in the development and maintenance of this disorder. Here, we investigated fairness norm considerations and reactions to their violations. To examine electrophysiological correlates, we assessed the medial frontal negativity (MFN), an event-related potential previously linked to violations of social expectancy and norms. Incarcerated antisocial violent offenders (AVOs, n = 25) and healthy controls (CTLs, n = 24) acted as proposers in the dictator game (DG) and ultimatum game (UG) and received fair vs. unfair UG offers from either another human (social context) or a computer (non-social context). Results showed that AVOs made lower offers in the DG but not the UG, indicating more rational and strategic behavior. Most importantly, when acting as recipients in the UG, acceptance rates were modulated by social context in CTLs, while AVOs generally accepted more offers. Correspondingly, ERP data indicated pronounced MFN amplitudes following human offers in CTLs, whereas MFN amplitudes in AVOs were generally reduced. The current data suggest intact fairness norm representations but altered reactions to their violation in antisocial personality disorder. PMID- 29397411 TI - P2X7R: independent modulation of aquaporin 5 expression in CdCl2-injured alveolar epithelial cells. AB - The expression of aquaporin 5 in alveolar epithelial type I cells under conditions of cadmium-induced injury has not yet been discovered. We investigated the effect of the P2X7R agonist BzATP under this condition, since P2X7R is involved in altered regulation of aquaporin 5 in pulmonary fibrosis. CdCl2/TGF beta1 treatment of lung epithelial MLE-12 cells was leading to increasing P2X7R, and aquaporin 5 protein levels. The aquaporin 5 expression was P2X7R-independent in MLE-12 cells under cadmium, as was shown in blocking experiments with oxATP. Further, the expression of both proteins increased after 24 h CdCl2/TGF-beta1 treatment of precision-cut lung slices, but decreased after 72 h. Using immunohistochemistry, the activation of the P2X7R with the agonist BzATP modulated the aquaporin 5 immunoreactivity in the alveolar epithelium of precision-cut lung slices from wild-type but not from P2X7R knockout mice. Similarly, aquaporin 5 protein was reduced in BzATP-treated immortal lung epithelial E10 cells. Surprisingly, untreated alveolar epithelial type II cells of P2X7R knockouts exhibited a pronounced apical immunoreactivity in addition to the remaining alveolar epithelial type I cells. BzATP exposure did not alter this distribution pattern, but increased the number of apoptotic alveolar epithelial type II cells in wild-type lung slices. PMID- 29397412 TI - Resection arthrodesis using distraction osteogenesis then plating as a hybrid surgical technique for the management of bone sarcomas of the distal tibia. AB - PURPOSE: We report the oncological and functional results of limb salvage for bone sarcomas involving the distal tibia using hybrid surgical technique of resection arthrodesis by bone transport then plating. METHODS: Five patients (mean age 18.6 years) with primary distal tibial sarcomas (two Ewing's sarcomas and three osteosarcomas) were treated by this method. The average duration of follow-up is 53 months. All patients accepted distraction osteogenesis with a standard technique using external fixator after wide (four cases) or marginal (one case) resection in the first operation. They were re-admitted for the second surgical treatment (plate insertion and removal of the external fixator) one to two months after they achieved the necessary limb length and desired alignment. RESULTS: Solid union of the lengthening site and sound fusion of the ankle were achieved in all five patients with full and unassisted weight bearing. The mean lengthening was 11.8 cm (range 8-14 cm) and the external fixation index (EFI) was 29.3 days/cm (range 22.8-36.3 days/cm). The mean functional score according to the rating system of the Musculoskeletal Tumour Society was 88% (83-90%). One patient showed poor response to chemotherapy, had local recurrence of sarcoma one year after plating, and was treated with above-knee amputation. CONCLUSIONS: In carefully selected patients with primary distal tibial sarcomas, this hybrid method can effectively eliminate tumor lesion, reconstruct function, and shorten the length of wearing an external fixator by a meticulous conversion to internal fixator. PMID- 29397413 TI - Comparable outcome of culture-negative and culture-positive periprosthetic hip joint infection for patients undergoing two-stage revision. AB - PURPOSE: Lack of peri-operative microbiological evidence is an unfavourable factor in one-stage revision. The objective of this study was to figure out whether being culture-negative was an unfavourable factor for periprosthetic hip joint infection (PHJI) in patients undergoing two-stage revision. METHODS: Records of PHJI patients treated between October 2003 and December 2016 were reviewed at our institution. Information such as microbiological data, clinical outcomes, and other details of patients' clinical courses were recorded. RESULTS: A total of the 58 cases were reviewed. The median follow-up duration was 68.5 months. The infection control rate of PHJI was 93.1% after two-stage revision. Kaplan-Meier analysis showed no significant difference in infection control rates between culture-negative and culture-positive groups. Culture-positive sinus secretions were significantly associated with an increased rate of reinfection (P = 0.039). CONCLUSIONS: Two-stage revision had a high success rate for eradication of PHJI. Culture-negative PHJI had a comparable outcome with culture-positive PHJI. PMID- 29397414 TI - The antegrade angle-stable locking intramedullary nail for type-C distal femoral fractures: a thirty four case experience. AB - INTRODUCTION: This is a retrospective study that provides initial experience and verifies the effectiveness of the newly-designed antegrade interlocking angle stable intramedullary nail (IAIN) combined with half-threaded cancellous screws in the management of type-C (AO/OTA classification) distal femoral fractures. METHODS: During a period of 30 months, 34 patients (mean age 43.1 years) with type-C (AO/OTA classification) fractures of the distal femur were treated with IAIN and half-threaded cancellous screws were reviewed. Peri-operative and post operative parameters were analyzed. RESULTS: All of the fractures healed in a mean time of 12.6 weeks with no incidences of malunion, nonunion or infection. No secondary failure of fixation occurred. Partial weight bearing was initiated in an average of 7.4 weeks post-operatively, with full weight bearing initiated in 13.8 weeks. All of the patients, except for one, gained full extension. The mean flexion of the knee joint was 110.1 degrees , while the mean Hospital for Special Surgery (HSS) knee score was 85.2. CONCLUSION: The IAIN and half-threaded cancellous screws provided a reliable fixation that facilitated uncomplicated outcomes and uneventful early mobilization in treating type-C fractures of the distal femur. PMID- 29397415 TI - Arsenic-Iron Relationships in Aquifers of North East India: Implications for Public Health and the Environment. AB - Arsenic (As) contamination of groundwater in the Ganga-Brahmaputra-Meghna basin of India and Bangladesh poses severe risk to human health and the environment. Arsenic in the groundwater of this area is largely geogenic, derived from the microbial reductive dissolution of iron (Fe) oxyhydroxide and subsequent release of the sorbed As. The present study examined the correlation between As and Fe in groundwater sources in four districts of Manipur state, and in Cachar, Hailakandi, and Karimganj districts in the Barak Valley region of south Assam. Both the study areas are located in the northeastern region of India. The results reveal that As-Fe correlations in Manipur were more significant and positive, when compared to those in Barak Valley. The significance of these findings in the mobilization and transport of arsenic in the fluvial environment of these two areas of North East India, and in the prediction of arsenic-safe aquifers, are discussed and compared with existing literature. These findings, therefore, have implications in the sustainable management of groundwater resources in the study areas. PMID- 29397416 TI - Overexpression of ghr-miR166b generates resistance against Bemisia tabaci infestation in Gossypium hirsutum plants. AB - MAIN CONCLUSION: In silico identified Gossypium hirsutum ghr-miR166b shows multi compatible targets in mitochondrial ATP synthase of Bemisia tabaci. Its overexpression in planta has the potential to act as a biopesticide in reducing B. tabaci population, and consequently the spread of whitefly-transmitted plant viruses. Whiteflies (B. tabaci) are hemipterous insects that act as a vector to transmit plant viruses causing enormous losses to the plants. In the present study, G. hirsutum-encoded miRNAs targeting expressed sequence tags (ESTs) of B. tabaci, based on sequence complimentarity and miRNA-target mRNA thermodynamics, were in silico identified. Out of 108 G. hirsutum miRNAs, 55 targeted the protein encoding ESTs. Among them, ghr-miR166b was selected owing to its intrinsic affinity for ATP synthase. Its functional role was validated following expression of ghr-MIR166b (precursor) sequence in G. hirsutum cv. HS6 plants through Agrobacterium-mediated transformation. Total of seven independent transformed (T0) G. hirsutum lines were obtained. The transcript level of ghr-MIR166b in the transgenic lines was observed to be 2.0- to 17-fold higher as compared to non transformed plants. Northern-blot analysis of small RNAs isolated from the transgenic plants confirmed the presence of the ghr-miR166b. After feeding on the leaves of transgenic line (HS6-166-30) having highest level of ghr-miR166b expression, B. tabaci population was reduced up to 91% as compared to non transformed leaves. Further, in the whole plant assay, a maximum of 78% B. tabaci mortality was observed in the same line, while there was an increase in B. tabaci population on the non-transformed plants. Our results revealed that ghr-miR166b supposedly targeting ATP synthase gene of B. tabaci, and subsequently its overexpression in planta has potential to act as biopesticide for reducing B. tabaci population and consequently spread of whitefly transmitted viruses. PMID- 29397417 TI - Pediatric Crohn disease is characterized by Th1 in the terminal ileum and Th1/Th17 immune response in the colon. AB - : The aim of this study was to assess the expression of inflammatory mediators in the affected terminal ileum and colon in pediatric Crohn disease (CD) patients with different stages of disease. Additionally, we assessed the role of efflux transporters in disease pathogenesis and their correlation with immune response. The study included 26 CD patients (10 newly diagnosed (CD-new), 8 CD-treated, and 8 CD-remission) and 15 control subjects. The terminal ileum IFN-gamma, IL-6, and IL-1beta were elevated in CD-new, while in the colon, the IFN-gamma, IL-17A, and IL-6 were elevated in both CD-new and CD-treated subgroups. SOCS3 expression was elevated in both subgroups with active inflammation at both ileum and colon, while SOCS1 was elevated only in CD-new ileum and CD-treated colon. MDR1 expression in ileum was reduced in both subgroups with active inflammation, while BCRP was reduced only in CD-new subgroup. CONCLUSION: New onset pediatric CD is characterized by Th1 response in ileum and mixed Th1/Th17 response in the colon, with elevated expressions of innate IL-6 and IL-1beta. SOCS1/SOCS3 expressions seem to be insufficient for the regulation of the immune response. The reduction in MDR1 expression points to its role in the disease pathogenesis. What is Known: * CD is characterized by an aberrant immune response What is New: * The immune response in new onset pediatric CD differs between terminal ileum and colon * MDR1 expression is downregulated at both terminal ileum and colon irrespective of the disease activity. PMID- 29397418 TI - Characteristics of revisits of children at risk for serious infections in pediatric emergency care. AB - : In this study, we aimed to identify characteristics of (unscheduled) revisits and its optimal time frame after Emergency Department (ED) discharge. Children with fever, dyspnea, or vomiting/diarrhea (1 month-16 years) who attended the ED of Erasmus MC-Sophia, Rotterdam (2010-2013), the Netherlands, were prospectively included. Three days after ED discharge, we applied standardized telephonic questionnaires on disease course and revisits. Multivariable logistic regression analysis was used to identify independent characteristics of revisits. Young age, parental concern, and alarming signs and symptoms (chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea) were associated with revisits (n = 527) in children at risk for serious infections discharged from the ED (n = 1765). Children revisited the ED within a median of 2 days (IQR 1.0-3.0), but this was proven to be shorter in children with vomiting/diarrhea (1.0 day (IQR 1.0-2.0)) compared to children with fever or dyspnea (2.0 (IQR 1.0-3.0)). CONCLUSION: Young age, parental concern, and alarming signs and symptoms (chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea) were associated with emergency health care revisits in children with fever, dyspnea, and vomiting/diarrhea. These characteristics could help to define targeted review of children during post-discharge period. We observed a disease specific and differential timing of control revisits after ED discharge. What is Known * Fever, dyspnea, and vomiting/diarrhea are major causes of emergency care attendance in children. * As uncertainty remains on uneventful recovery, patients at risk need to be identified on order to improve safety netting after discharge from the ED. What is New * In children with fever, dyspnea, and vomiting/diarrhea, young age, parental concern and chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea help to define targeted review of children during the post-discharge period. * A revisit after ED discharge is disease-specific and seems to be shorter for children with vomiting/diarrhea than others. PMID- 29397420 TI - Cluster: barriers of the central nervous system. PMID- 29397419 TI - Quasispecies and virus. AB - Quasispecies theory has been instrumental in the understanding of RNA virus population dynamics because it considered for the first time mutation as an integral part of the replication process. The key influences of quasispecies theory on experimental virology have been: (1) to disclose the mutant spectrum nature of viral populations and to evaluate its consequences; (2) to unveil collective properties of genome ensembles that can render a mutant spectrum a unit of selection; and (3) to identify new vulnerability points of pathogenic RNA viruses on three fronts: the need to apply multiple selective constraints (in the form of drug combinations) to minimize selection of treatment-escape variants, to translate the error threshold concept into antiviral designs, and to construct attenuated vaccine viruses through alterations of viral polymerase copying fidelity or through displacements of viral genomes towards unfavorable regions of sequence space. These three major influences on the understanding of viral pathogens preceded extensions of quasispecies to non-viral systems such as bacterial and tumor cell collectivities and prions. These developments are summarized here. PMID- 29397422 TI - Periodic matrix models for seasonal dynamics of structured populations with application to a seabird population. AB - For structured populations with an annual breeding season, life-stage interactions and behavioral tactics may occur on a faster time scale than that of population dynamics. Motivated by recent field studies of the effect of rising sea surface temperature (SST) on within-breeding-season behaviors in colonial seabirds, we formulate and analyze a general class of discrete-time matrix models designed to account for changes in behavioral tactics within the breeding season and their dynamic consequences at the population level across breeding seasons. As a specific example, we focus on egg cannibalism and the daily reproductive synchrony observed in seabirds. Using the model, we investigate circumstances under which these life history tactics can be beneficial or non-beneficial at the population level in light of the expected continued rise in SST. Using bifurcation theoretic techniques, we study the nature of non-extinction, seasonal cycles as a function of environmental resource availability as they are created upon destabilization of the extinction state. Of particular interest are backward bifurcations in that they typically create strong Allee effects in population models which, in turn, lead to the benefit of possible (initial condition dependent) survival in adverse environments. We find that positive density effects (component Allee effects) due to increased adult survival from cannibalism and the propensity of females to synchronize daily egg laying can produce a strong Allee effect due to a backward bifurcation. PMID- 29397421 TI - Activin receptors regulate the oligodendrocyte lineage in health and disease. AB - The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan. PMID- 29397423 TI - The phosphorylation site T613 in the beta-subunit of rat epithelial Na+ channel (ENaC) modulates channel inhibition by Nedd4-2. AB - The epithelial Na+ channel (ENaC) is a heteromeric channel composed of three subunits (alpha, beta, gamma). At the C-terminus of each subunit, a PY-motif allows binding of the ubiquitin ligase Nedd4-2 which plays a key role in promoting ENaC retrieval from the plasma membrane. Phosphorylation of Nedd4-2 by the serum and glucocorticoid-inducible kinase 1 (Sgk1) reduces Nedd4-2 binding to the PY-motifs. In beta and gammaENaC, threonine residues (betaT613, gammaT623) belong to an extracellular signal-regulated kinase (ERK) motif and directly precede the PY-motifs. Thus, phosphorylation of these residues may modulate the interaction of their adjacent PY-motifs with Nedd4-2. In this study, a phosphospecific antibody was used to demonstrate phosphorylation of betaT613 in Xenopus laevis oocytes heterologously expressing rat alphabetagammaENaC. Treating the oocytes with progesterone to stimulate ERK increased phosphorylation of betaT613. Inactivation of the putative phosphorylation sites by mutating both threonine residues to alanine (betaT613A/gammaT623A) increased ENaC-mediated amiloride-sensitive whole-cell currents (DeltaIami) and expression of betaENaC at the cell surface. Co-expression of Nedd4-2 largely reduced DeltaIami in oocytes expressing alphabetagammaENaC or channels with mutated PY-motifs in alpha and gammaENaC or in alpha and betaENaC. Importantly, the inhibitory effect of co expressed Nedd4-2 was largely reduced in channels with mutated PY-motifs in alpha and gammaENaC when combined with the betaT613A mutation but conserved in channels with mutated PY-motifs in alpha and betaENaC combined with the gammaT623A mutation. These results suggest that phosphorylation and dephosphorylation of betaT613 play a prominent role in regulating Nedd4-2-mediated ENaC retrieval from the plasma membrane. PMID- 29397424 TI - Intracellular thermometry with fluorescent sensors for thermal biology. AB - Temperature influences the activities of living organisms at various levels. Cells not only detect environmental temperature changes through their unique temperature-sensitive molecular machineries but also muster an appropriate response to the temperature change to maintain their inherent functions. Despite the fundamental involvement of temperature in physiological phenomena, the mechanism by which cells produce and use heat is largely unknown. Recently, fluorescent thermosensors that function as thermometers in live cells have attracted much attention in biology. These new tools, made of various temperature sensitive molecules, have allowed for intracellular thermometry at the single cell level. Intriguing spatiotemporal temperature variations, including organelle specific thermogenesis, have been revealed with these fluorescent thermosensors, which suggest an intrinsic connection between temperature and cell functions. Moreover, fluorescent thermosensors have shown that intracellular temperature changes at the microscopic level are largely different from those assumed for a water environment at the macroscopic level. Thus, the employment of fluorescent thermosensors will uncover novel mechanisms of intracellular temperature-assisted physiological functions. PMID- 29397425 TI - Native tissue-based strategies for meniscus repair and regeneration. AB - Meniscus injuries appear to be becoming increasingly common and pose a challenge for orthopedic surgeons. However, there is no curative approach for dealing with defects in the inner meniscus region due to its avascular nature. Numerous strategies have been applied to regenerate and repair meniscus defects and native tissue-based strategies have received much attention. Native tissue usually has good biocompatibility, excellent mechanical properties and a suitable microenvironment for cellular growth, adhesion, redifferentiation, extracellular matrix deposition and remodeling. Classically, native tissue-based strategies for meniscus repair and regeneration are divided into autogenous and heterogeneous tissue transplantation. Autogenous tissue transplantation is performed more widely than heterogeneous tissue transplantation because there is no immunological rejection and the success rates are higher. This review first discusses the native meniscus structure and function and then focuses on the use of the autogenous tissue for meniscus repair and regeneration. Finally, it summarizes the advantages and disadvantages of heterogeneous tissue transplantation. We hope that this review provides some suggestions for the future design of meniscus repair and regeneration strategies. PMID- 29397426 TI - The role of neutrophils in equine laminitis. AB - Equine laminitis is a devastating disease in which failure of the adhesion between the digital dermal and epidermal laminae at the basement membrane results in crippling lameness and structural damage to the foot of the horse. Laminitis occurring secondary to sepsis is known to result from a significant inflammatory response that includes leukocyte emigration into the lamellar tissue. These leukocytes, in particular the neutrophil, have been extensively evaluated in experimental models of sepsis-related laminitis in the horse. This review will discuss the relevant findings elucidated from these models and how these findings have affected the development of therapies used to treat this crippling disease. PMID- 29397427 TI - Poly(I:C) adjuvant strongly enhances parasite-inhibitory antibodies and Th1 response against Plasmodium falciparum merozoite surface protein-1 (42-kDa fragment) in BALB/c mice. AB - Malaria vaccine development has been confronted with various challenges such as poor immunogenicity of malaria vaccine candidate antigens, which is considered as the main challenge. However, this problem can be managed using appropriate formulations of antigens and adjuvants. Poly(I:C) is a potent Th1 inducer and a human compatible adjuvant capable of stimulating both B- and T-cell immunity. Plasmodium falciparum merozoite surface protein 142 (PfMSP-142) is a promising vaccine candidate for blood stage of malaria that has faced several difficulties in clinical trials, mainly due to improper adjuvants. Therefore, in the current study, poly(I:C), as a potent Th1 inducer adjuvant, was evaluated to improve the immunogenicity of recombinant PfMSP-142, when compared to CFA/IFA, as reference adjuvant. Poly(I:C) produced high level and titers of anti-PfMSP-142 IgG antibodies in which was comparable to CFA/IFA adjuvant. In addition, PfMSP-142 formulated with poly(I:C) elicited a higher ratio of IFN-gamma/IL-4 (23.9) and IgG2a/IgG1 (3.77) with more persistent, higher avidity, and titer of IgG2a relative to CFA/IFA, indicating a potent Th1 immune response. Poly(I:C) could also help to induce anti-PfMSP-142 antibodies with higher growth-inhibitory activity than CFA/IFA. Altogether, the results of the current study demonstrated that poly(I:C) is a potent adjuvant that can be appropriate for being used in PfMSP-142-based vaccine formulations. PMID- 29397429 TI - Anaerobiosis revisited: growth of Saccharomyces cerevisiae under extremely low oxygen availability. AB - The budding yeast Saccharomyces cerevisiae plays an important role in biotechnological applications, ranging from fuel ethanol to recombinant protein production. It is also a model organism for studies on cell physiology and genetic regulation. Its ability to grow under anaerobic conditions is of interest in many industrial applications. Unlike industrial bioreactors with their low surface area relative to volume, ensuring a complete anaerobic atmosphere during microbial cultivations in the laboratory is rather difficult. Tiny amounts of O2 that enter the system can vastly influence product yields and microbial physiology. A common procedure in the laboratory is to sparge the culture vessel with ultrapure N2 gas; together with the use of butyl rubber stoppers and norprene tubing, O2 diffusion into the system can be strongly minimized. With insights from some studies conducted in our laboratory, we explore the question 'how anaerobic is anaerobiosis?'. We briefly discuss the role of O2 in non respiratory pathways in S. cerevisiae and provide a systematic survey of the attempts made thus far to cultivate yeast under anaerobic conditions. We conclude that very few data exist on the physiology of S. cerevisiae under anaerobiosis in the absence of the anaerobic growth factors ergosterol and unsaturated fatty acids. Anaerobicity should be treated as a relative condition since complete anaerobiosis is hardly achievable in the laboratory. Ideally, researchers should provide all the details of their anaerobic set-up, to ensure reproducibility of results among different laboratories. PMID- 29397428 TI - Halotolerant microbial consortia able to degrade highly recalcitrant plant biomass substrate. AB - The microbial degradation of plant-derived compounds under salinity stress remains largely underexplored. The pretreatment of lignocellulose material, which is often needed to improve the production of lignocellulose monomers, leads to high salt levels, generating a saline environment that raises technical considerations that influence subsequent downstream processes. Here, we constructed halotolerant lignocellulose degrading microbial consortia by enriching a salt marsh soil microbiome on a recalcitrant carbon and energy source, i.e., wheat straw. The consortia were obtained after six cycles of growth on fresh substrate (adaptation phase), which was followed by four cycles on pre digested (highly-recalcitrant) substrate (stabilization phase). The data indicated that typical salt-tolerant bacteria made up a large part of the selected consortia. These were "trained" to progressively perform better on fresh substrate, but a shift was observed when highly recalcitrant substrate was used. The most dominant bacteria in the consortia were Joostella marina, Flavobacterium beibuense, Algoriphagus ratkowskyi, Pseudomonas putida, and Halomonas meridiana. Interestingly, fungi were sparsely present and negatively affected by the change in the substrate composition. Sarocladium strictum was the single fungal strain recovered at the end of the adaptation phase, whereas it was deselected by the presence of recalcitrant substrate. Consortia selected in the latter substrate presented higher cellulose and lignin degradation than consortia selected on fresh substrate, indicating a specialization in transforming the recalcitrant regions of the substrate. Moreover, our results indicate that bacteria have a prime role in the degradation of recalcitrant lignocellulose under saline conditions, as compared to fungi. The final consortia constitute an interesting source of lignocellulolytic haloenzymes that can be used to increase the efficiency of the degradation process, while decreasing the associated costs. PMID- 29397430 TI - Long-term quality of life after conservative treatment versus surgery for different stages of acute sigmoid diverticulitis. AB - PURPOSE: It is controversial whether patients fare better with conservative or surgical treatment in certain stages of acute diverticulitis (AD), in particular when phlegmonous inflammation or covered micro- or macro-perforation are present. The aim of this study was to determine long-term quality of life (QoL) for AD patients who received either surgery or conservative treatment in different stages. METHODS: We included patients treated for AD at the University Hospital Grosshadern, Munich, Germany, between January 1, 2000, and December 31, 2010. Patients were classified by the Hansen and Stock (HS) classification, the modified Hinchey classification, and the German classification of diverticular disease (CDD). Pre-therapeutic staging was based on multidetector computed tomography. Long-term QoL was assessed by the Cleveland Global Quality of Life (CGQL) questionnaire, the Short Form 36 (SF-36), and the Gastrointestinal Quality of Life Index (GIQLI). Data are mean +/- SEM. RESULTS: Patients with phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) had a better long-term QoL on the GIQLI when they were operated (78.5 +/- 2.5 vs. 70.7 +/- 2.1; p < 0.05). Patients with micro-abscess (CDD 2a) had a better long-term QoL on the GIQLI, CGQL, and the "Role Physical" scale of the SF-36 when they were not operated (GIQLI 86.9 +/- 2.1 vs. 76.8 +/- 1.0; p = 0.10; CGQL 82.8 +/- 5.1 vs. 65.3 +/- 11.0; p = 0.08; SF-36/Role Physical 100 +/- 0.0 vs. 41.7 +/- 13.9; p < 0.001). Patients with macro-abscess (CDD 2b) had a better long-term QoL when they were operated (GIQLI 89.3 +/- 1.4 vs. 69.5 +/- 4.5; p < 0.01; CGQL 80.3 +/- 7.6 vs. 60.5 +/- 5.8; p < 0.05; SF-36/Role Physical 95.8 +/- 4.2 vs. 47.9 +/- 13.6; p < 0.001). CONCLUSION: Considering long-term QoL, phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) should be treated conservatively. In patients with covered perforation, abscess size should guide the decision on whether to perform surgery later on or not. In the light of long-term quality of life, patients fare better after elective sigmoid colectomy when abscess size exceeds 1 cm. PMID- 29397431 TI - Risk of colorectal cancer in patients with periodontal disease severity: a nationwide, population-based cohort study. AB - BACKGROUND: Periodontal disease (PD) and colorectal cancer (CRC) were associated with chronic inflammation. This retrospective cohort study examined the association between PD severity and CRC in a large-scale, population-based Chinese cohort. METHODS: A total of approximately 106,487 individuals with newly diagnosed PD and 106,487 age-matched and sex-matched patients without PD from 2000 to 2002 were identified from Taiwan's National Health Insurance Research Database (NHIRD). RESULTS: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with PD than in those without PD (log-rank test, P < 0.001). After adjustment for age, sex, and comorbidities, patients with PD were associated with a significantly higher risk of CRC compared with those without PD (adjusted HR = 1.64, 95% CI = 1.50-1.80). Further, the risk of CRC appeared to increase with increasing frequency of PD medical visits [adjusted HR (95% CI) was 1.78 (1.58-2.02) and 1.53 (1.35-1.74) for annual visits > 10 and < 4, respectively]. CONCLUSION: Based on our study, PD severity was associated with an increase in the risk of CRC. Further mechanistic research is needed. PMID- 29397432 TI - Spa therapy together with supervised self-mobilisation improves pain, function and quality of life in patients with chronic shoulder pain: a single-blind randomised controlled trial. AB - To determine whether spa therapy has a beneficial effect on pain and disability in patients with chronic shoulder pain, this single-blind randomised controlled clinical trial included patients with chronic shoulder pain due to miscellaneous conditions attending one of four spa centres as outpatients. Patients were randomised into two groups: spa therapy (18 days of standardised treatment combining thermal therapy together with supervised mobilisation in a thermal pool) and controls (spa therapy delayed for 6 months: 'immediate versus delayed treatment' paradigm). All patients continued usual treatments during the 6-month follow-up period. The main endpoint was the mean change in the French-Quick DASH (F-QD) score at 6 months. The effect size of spa therapy was calculated, and the proportion of patients reaching minimal clinically important improvement (MCII) was compared. Secondary endpoints were the mean change in SF-36, treatment use and tolerance. One hundred eighty-six patients were included (94 patients as controls, 92 in the spa group) and analysed by intention to treat. At 6 months, the mean change in the F-QD score was statistically significantly greater among spa therapy patients than controls (- 32.6 versus - 8.15%; p < 0.001) with an effect size of 1.32 (95%CI: 0.97-1.68). A significantly greater proportion of spa therapy patients reached MCII (59.3 versus 17.9%). Spa therapy was well tolerated with a significant impact on SF-36 components but not on drug intake. Spa therapy provided a statistically significant benefit on pain, function and quality of life in patients with chronic shoulder pain after 6 months compared with usual care. PMID- 29397433 TI - Periosteal mesenchymal chondrosarcoma of the tibia. PMID- 29397434 TI - Association between LCE gene polymorphisms and psoriasis vulgaris among Mongolians from Inner Mongolia. AB - The late cornified envelope (LCE) gene cluster is located on chromosome 1q21, including LCE1-LCE6. Several single nucleotide polymorphisms (SNPs) in the LCE cluster were associated with susceptibility to psoriasis in Chinese population. However, there is no report on the relationship in ethnic minority areas in China. This study aimed to investigate the association between the gene polymorphisms of LCE1B, LCE1C, LCE3A, LCE3D and psoriasis vulgaris among Mongolians from Inner Mongolia. Totally, 305 Mongolians with psoriasis vulgaris (PsV) and 383 healthy controls were enrolled in the study from 2006 to 2015. 7 SNPs including rs6701216, rs4112788, rs12023196, rs512208, rs4845454, rs4085613 and rs1886734, were selected for genotyping with ligase detection reaction (LDR). Statistical analysis was performed for comparisons of allele frequencies and genotype frequencies between the patient group and the control group. In this study, excluding rs4085613 and rs1886734, differences were detected in the allele frequencies of other 5 SNPs between the patients and controls. Genotype analysis showed that under the recessive inheritance model, the genotype frequencies of rs4845454, rs4112788 differed between the patients and controls (all p < 0.00 5).Under the dominant and the recessive model, the genotype frequencies of rs6701216, rs12023196 and rs512208 significantly differed between the patients and controls. The LD analysis showed that strong LD existed between rs6701216 and rs12023196, rs4845454 and rs4085613, rs4845454 and rs1886734, and rs4085613 and rs1886734. The SNPs rs6701216, rs4112788, rs12023196, rs512208 and rs4845454 in the LCE gene were associated with psoriasis vulgaris among Mongolians from Inner Mongolia. PMID- 29397435 TI - Autoantibody against aldehyde dehydrogenase 2 could be a biomarker to monitor progression of Graves' orbitopathy. AB - PURPOSE: This study surveyed the novel autoantigens expressed in the orbital fat tissue of patients with Graves' orbitopathy (GO) and explored the possibility of the autoantibodies against novel autoantigens as biomarkers for GO. METHODS: We used immuno-proteomic methods to survey novel autoantigens expressed in the orbit fat tissue of GO patients and confirmed by enzyme-linked immunosorbent assay (ELISA). RESULTS: One protein spot (aldehyde dehydrogenase 2 (ALDH2)) revealed high reactivity with the GO serum than did the healthy control serum and was further verified by ELISA. We found that the plasma anti-ALDH2 antibody level was increased in GO patients compared to healthy control donors. In addition, anti ALDH2 antibody level was correlated with GO activity classified by clinical activity score(r = 0.588, p < 0.001, using Pearson's correlation). CONCLUSIONS: These increased levels of anti-ALDH2 antibody in GO serum suggested that ALDH2 could attribute target autoantigen in GO, and anti-ALDH2 autoantibody might serve as a biomarker for GO and help to predict disease activity. PMID- 29397436 TI - The fate of eyes with wet AMD beyond four years of anti-VEGF therapy. AB - PURPOSE: Real-life studies on long-term functional outcome of anti-VEGF treatment for wet age-related macular degeneration (wAMD) are limited. We therefore assessed the 10-year outcomes in our patients. METHODS: In this retrospective study, all patients with newly diagnosed wAMD that had received minimally three intravitreal injections between 2007 and 2012 and a follow-up of >=48 months were included. Primary outcome measure was the evolution of best-corrected visual acuity (BCVA) over time. For qualitative, quantitative and longitudinal data, Pearson's chi2 test, the Mann-Whitney U-test and Wilcoxon's signed-rank test were applied at a significance level of p < 0.05. RESULTS: Of 267 eyes (219 patients) with newly diagnosed wAMD treated during this period, 104 eyes (104 patients) had been followed for at least 48 months and were included. Fifty-nine eyes (57.8%) after 7 years were still under active treatment, 29 eyes (25.0%) had interrupted treatment [mean follow-up 7.5 years (4.0-10.1; SD 1.6)], whereas 16 patients had died. BCVA stabilized at -7.3 to -11.9 letters after 3-10 years of follow-up with a mean of 2.8 injections (median; 3.0, SD 1.0; 1-5) and 5.1 visits per year. In two thirds of eyes, treatment was switched to aflibercept or corticosteroid combinations without bearing on functional outcomes. Thirty-seven percent (37%) of eyes maintained driving vision for up to 10 years. CONCLUSIONS: Beyond 3 years of treatment, functional stability was maintained for up to 10 years. Further improvement of long-term outcomes might have required a more intensive treatment in the early phase. PMID- 29397437 TI - Microphallus ochotensis sp. nov. (Digenea, Microphallidae) and relative merits of two-host microphallid life cycles. AB - A new digenean species, Microphallus ochotensis sp. nov., was described from the intestine of Pacific eiders (Somateria mollissima v-nigrum) from the north of the Sea of Okhotsk. It differs from other microphallids in the structure of the metraterm, which consists of two distinct parts: a sac with spicule-like structures and a short muscular duct opening into the genital atrium. Mi. ochotensis forms a monophyletic clade together with other congeneric species in phylograms derived from the 28S and ITS2 rRNA gene. Its dixenous life cycle was elucidated with the use of the same molecular markers. Encysted metacercariae infective for birds develop inside sporocysts in the first intermediate host, an intertidal mollusc Falsicingula kurilensis. The morphology of metacercariae and adults was described with an emphasis on the structure of terminal genitalia. Considering that Falsicingula occurs at the Pacific coast of North America and that the Pacific eider is capable of trans-continental flights, the distribution of Mi. ochotensis might span the Pacific coast of Alaska and Canada. The range of its final hosts may presumably include other benthos-feeding marine ducks as well as shorebirds. We suggest that a broad occurrence of two-host life cycles in microphallids is associated with parasitism in birds migrating along sea coasts. The chances that migrating birds would stop at a site where both first and second intermediate hosts occur are relatively low. The presence of a single molluscan host in the life cycle increases the probability of transmission. PMID- 29397438 TI - Parasites of skipjack, Katsuwonus pelamis, from Madeira, Eastern Atlantic. AB - Skipjack tuna, Katsuwonus pelamis, is a tropical species of economic importance for fisheries around the world. It occurs seasonally in subtropical waters around Madeira archipelago, in the warmer months. In this study, a parasitological analysis was carried out on a sample of 30 skipjack caught near Madeira Island. A total of 24 parasite taxa were found in this sample. The skipjack parasite community detected was characterized by a wide diversity of parasites, with a predominance of adult didymozoid trematodes, and high prevalences of Tentacularia coryphaenae cestode larvae and Anisakis sp. larvae. Microhabitat distribution of gill parasites was assessed for the most prevalent species, and correlations between parasite abundance and various host features such as size, condition, and fat content were investigated. Parasite taxa which might be useful as biological tags in future studies of skipjack migrations in the Eastern Atlantic were selected. PMID- 29397440 TI - Mutual exclusion of CDH1 and BRCA germline mutations in the pathway of hereditary breast cancer. PMID- 29397439 TI - Emergency department use during pregnancy: a prospective observational study in a single center institution. AB - PURPOSE: Gynecologists working in emergency department services in hospitals lately have the impression that the number of pregnant women who present themselves because of anxiety or uncertainty is increasing. Hence, the aim of this study was to assess reasons of pregnant women for presenting themselves to an emergency department. Of special interest was how far a diagnosis could be confirmed for the symptoms pregnant women complained about. METHODS: This is a prospective questionnaire-based study conducted between April 2015 and April 2016 in the Department of Gynecology and Obstetrics of the University Hospital of Cologne. The questionnaire was placed in the waiting area of the emergency department service for pregnant women. Pregnant patients were included with a gestational age of above 20 weeks of gestation. RESULTS: 331 patients were enrolled in this study. The most frequent reason for emergency department use was "pain" in 28.3% and cervical insufficiency in 19.7% of all cases. 45.6% (n = 151) of the patients had a recommendation of an outpatient practice for presentation to emergency department service. 36.3% (n = 120) of all patients were admitted to hospital for further treatment, 58.6% (n = 194) could be released from hospital. 3.3% (n = 11) of all patients rejected recommended further treatment in hospital. A trend was demonstrated concerning former abortion and hospital admission (p = 0.062). CONCLUSIONS: The high amount of patients making nonurgent use of emergency department services indicates potential uncertainty in interpretation of symptoms. Patients with former abortion history were admitted more often to hospital, and therefore need special attention during pregnancy. PMID- 29397441 TI - Evaluation of cesarean scar after single- and double-layer hysterotomy closure: a prospective cross-sectional study. AB - BACKGROUND: We aimed to determine if there is a difference in the size of the cesarean scar defect using saline infusion sonography (SIS) performed on the postoperative third month in patients who underwent single- or double-layered unlocked closure of their uterine incision during their first cesarean delivery. METHODS: This study was conducted as a prospective cross-sectional study between February 2015 and January 2016 in patients admitted to the labour ward of the Kanuni Sultan Suleyman Training and Research Hospital who subsequently underwent their first delivery by cesarean section. Patients with a previous history of cesarean delivery, preterm pregnancies less than 34 gestational weeks, patients lost to follow-up or those who had an IUD inserted after delivery were excluded from the study. Out of the 327 patients who underwent primary cesarean delivery, 280 were included into the study. Patients were divided into two groups according to the single- (n:126) or double-layered (n:156) closure of their uterine incision. The maternal age, height, weight, obstetric and gynecologic histories, medical histories, indications for their cesarean delivery, technique of uterine closure, birth weight of the baby, duration of the cesarean delivery, need for extra suturing and transfusion were recorded. A Saline infusion sonography (SIS) was performed 3 months postoperatively to determine the presence, depth and length of the cesarean scar. The residual myometrial thickness overlying the scar defect and the fundal myometrial thickness were recorded. RESULTS: No difference was detected between the groups with respect to patient characteristics, whether the operation was elective or emergent, the type of anesthesia used, need for extra suturing, incidence of bladder injuries or uterine atony, need for blood transfusions, duration of labour or cervical dilatation and effacement between the two groups. No statistically significant difference was detected between the two groups with respect to the length and depth of the scar defect. CONCLUSION: Single- or double-layered closure of the uterus does not seem to affect the size of the uterine scar defect detected on SIS 3 months following the first cesarean delivery. PMID- 29397442 TI - Efficacy of aromatherapy for reducing pain during labor: a randomized controlled trial. AB - BACKGROUND: Many strategies for labor pain management have been studied, including aromatherapy, which is a noninvasive, alternative medicine used as an adjunct for labor pain control. Nevertheless, the results were contradictory. Therefore, we conducted this study to determine the effectiveness of aromatherapy for reducing pain during labor. METHODS: A randomized controlled trial was carried out on Thai laboring primigravidae who were a low-risk singleton pregnancy undergoing vaginal delivery. All participants, both study and control group, received standard obstetric care. Aromatherapy was only provided to the study group during the first stage of labor. The women rated their pain intensity by rating scales at different stages of labor. The primary outcome was pain scores and the secondary outcomes were necessity of painkiller usage, labor time, aromatherapy-associated complications, route of delivery, and Apgar scores. RESULTS: A total of 104 women were recruited, 52 in each group. Baseline characteristics and baseline pain scores were comparable. The median pain score of latent and early active phase was lower in the aromatherapy group, 5 vs 6 and 7 vs 8, respectively. The mean differences of pain scores between latent and early active phase and the baseline were significantly lower in the aromatherapy group, 1.88 vs 2.6 (p = 0.010) and 3.82 vs 4.39 (p = 0.031), respectively. Late active phase pain scores and other perinatal outcomes were not significantly different. CONCLUSION: Aromatherapy is helpful in reducing pain in latent and early active phase, and can probably be used as an adjunctive method for labor pain control without serious side effects. PMID- 29397445 TI - Population attributable risk of factors associated with the repetition of self harm behaviour in young people presenting to clinical services: a systematic review and meta-analysis. AB - The repetition of hospital-treated self-harm by young people is common. However, little work has summarised the modifiable factors associated with this. A thorough understanding of those factors most strongly associated with repetition could guide the development of relevant clinical interventions. We systematically reviewed four databases (EMBASE, Medline, PubMed and PsycINFO) until 15 April 2016 to identify all observational studies of factors for the repetition of self harm or suicide reattempts (together referred to as 'self-harm behaviour') in young people. We quantified the magnitude of association with odds ratios (OR) and 95% confidence intervals (CIs) and calculated the population attributable risk (PAR) and population preventable fraction (PPF) for modifiable factors to provide an indication of the potential impact in reducing subsequent self-harm behaviour in this population. Seventeen studies were included comprising 10,726 participants. Borderline personality disorder (OR 3.47, 95% CI 1.84-6.53; PAR 42.4%), any personality disorder (OR 2.54, 95% CI 1.71-3.78; PAR 16.3%), and any mood disorder (OR 2.16, 95% CI 1.09-4.29; PAR 42.2%) are important modifiable risk factors. Severity of hopelessness (OR 2.95, 95% CI 1.74-5.01), suicidal ideation (OR 2.01, 95% CI 1.43-2.81), and previous sexual abuse (OR 1.52, 95% CI 1.02-2.28; PAR 12.8%) are also associated with repetition of self-harm. We recommend that clinical services should focus on identifying key modifiable risk factors at the individual patient level, whilst the reduction of exposure to child and adolescent sexual abuse would also be a useful goal for public health interventions. PMID- 29397444 TI - Surgical treatment of spinal disorders in Parkinson's disease. AB - PURPOSE: Most patients suffering from Parkinson's disease (PD) exhibit alterations in the posture, which can in several cases give rise to spine deformities, both in the sagittal and the coronal plane. In addition, degenerative disorders of the spine frequently associated to PD, such as spinal stenosis and sagittal instability, can further impact the quality of life of the patient. In recent years, spine surgery has been increasingly performed, with mixed results. The aim of this narrative review is to analyze the spinal disorders associated to PD, and the current evidence about their surgical treatment. METHODS: Narrative review. RESULTS: Camptocormia, i.e., a pronounced flexible forward bending of the trunk with 7% prevalence, is the most reported sagittal disorder of the spine. Pisa syndrome and scoliosis are both common and frequently associated. Disorders to the spinopelvic alignment were not widely investigated, but a tendency toward a lower ability of PD patients to compensate the sagittal malalignment with respect to non-PD elderly subjects with imbalance seems to emerge. Spine surgery in PD patients showed high rates of complications and re-operations. CONCLUSIONS: Disorders of the posture and spinal alignment, both in the sagittal and in the coronal planes, are common in PD patients, and have a major impact on the quality of life. Outcomes of spine surgery are generally not satisfactory, likely mostly due to muscle dystonia and poor bone quality. Knowledge in this field needs to be consolidated by further clinical and basic science studies. These slides can be retrieved under Electronic Supplementary Material. PMID- 29397446 TI - Marseille scoring system for empiric treatment of infective endocarditis. AB - Despite advances in medical, surgical, and critical care, infective endocarditis (IE) remains associated with considerable morbidity and mortality. We evaluated the performance of the Marseille score, including clinical data and biological tests obtained within 2 h, to identify patients at high risk of IE in order to initiate early antimicrobial treatment. This was secondarily confirmed using modified ESC criteria combined with molecular testing and (18)fluorodeoxyglucose positron emission tomography/computed tomography as diagnostic tools. In a prospective cohort study, we enrolled 484 patients with cardiovascular predisposition and clinical suspicion of IE from 2011 to 2013. The final diagnosis was definite IE in 123 patients and possible IE in 107. Marseille score was calculated adding one point for each present parameter (range 0-9). This score includes clinical, epidemiological (male, fever, splenomegaly, clubbing, vascular disease and stroke) and biological criteria (Leucocytes >10,000/mm3, sedimentation rate (SR) > 50/mm or C reactive protein >10 mg/L and hemoglobin <100 g/l). A score of 2 or more performed best in predicting IE in patients with predisposing heart lesions. Sensitivity was better on left-side heart lesions (94%) than on right-side heart lesions (85%) (p = 0.04) and better for valvulopathy (94%) than intra cardiac devices (84%) (p = 0.02). The predictive positive value of prosthetic valves was greater than that of native valves (p = 0.02). Using our simple Marseille score combined with our standardized diagnostic procedures would help improve IE management by focusing on early empiric treatment within 2 h of admission for patients with cardiac predisposition factors. PMID- 29397447 TI - Does ancestry influence health-related quality of life in type 1 diabetes patients? A nationwide study in Brazil. AB - AIMS: The aim of the present study was to evaluate the relationship between self reported color/race and genomic ancestry with HRQoL of patients with type 1 diabetes in a highly admixed population. METHODS: This was a nationwide, cross sectional study conducted with 1760 patients with type 1 diabetes from 2011 to 2014 at public clinics in all five Brazilian geographical regions. Information on HRQoL was obtained from two self-completed questionnaires: Short Form-6 Dimensions (SF-6D) and EuroQol-5 Dimensions (EQ-5D) with a visual analogue scale (EQ-VAS). Genomic ancestry was assessed using a Multiplex PCR methodology. Utility scores generated from the questionnaires were analyzed with multivariate logistic regression models. RESULTS: We included 1698 patients. Those patients who self-reported as black had lower EQ-VAS scores compared to the patients who self-reported as white (67.46 +/- 18.45; 72.37 +/- 16.44, respectively, p = 0.02). In a linear regression model, each 1% increase in African ancestry resulted in a 9.5 point decrease in EQ-VAS score (p < 0.001). In a multivariate logistic regression, after adjusting for demographic, socioeconomic status and diabetes-related variables, African ancestry remained associated with lower EQ VAS scores. CONCLUSION: A higher level of African ancestry implicates on lower quality of life even after adjustments for sociodemographic and diabetes-related data. Gender, physical activity and diabetes-related microvascular complications were strongly associated with low HRQoL in all three questionnaires used. This fact highlights the importance of social aspects when assessing quality of life, as well as the need for regular practice of physical activity and prevention of chronic complications to improve patients' quality of life. PMID- 29397448 TI - Letter to the editor: "Considerations in computer-aided design for inlay cranioplasty: technical note". PMID- 29397449 TI - The timing of stereotactic radiosurgery for medically refractory trigeminal neuralgia: the evidence from diffusion tractography images. AB - BACKGROUND: Diffusion tensor imaging (DTI) is a novel MRI technique that enables noninvasive evaluation of microstructural alterations in white matter of brain. Initially, DTI was used in intra- or inter-hemispheric association bundles. Recent technical advances are overcoming the challenges of imaging small white matter bundles, such as the cranial nerves. In this study, we use DTI to shed more light on the microstructure changes in long-standing trigeminal neuralgia. We also utilize DTI to study the effect of early stereotactic radiosurgery (SRS) on the microstructures of the trigeminal nerve and to predict the effectiveness of early SRS in the treatment of medically refractory trigeminal neuralgia (TN). METHODS: To analyze the presentation of trigeminal nerve, the DTI was reconstructed in 21 cases pre- and post-SRS. DTI parameters recorded include fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), linear anisotropy coefficient (Cl), planar anisotropy coefficient (Cp), and spherical anisotropy coefficient (Cs). Comparisons between ipsilateral (symptomatic) and contralateral (asymptomatic) trigeminal nerves and symptom durations of < 5 and ? 5 years were performed. RESULTS: The study cohort comprised 21 patients with TN with a median age of 66 years. Initial adequate facial pain relief (Barrow Neurological Institute facial pain scores I-IIIb) was achieved in 16 (76%) patients. For the pre-SRS DTI findings, ipsilateral trigeminal nerve was associated with higher baseline root entry zone (REZ) Cs compared to contralateral nerve (0.774 vs. 0.743, p = 0.04). Ipsilateral trigeminal nerve with symptoms of < 5 years was associated with higher baseline FA compared to trigeminal nerve with symptoms of ? 5 years (0.314 vs. 0.244, p = 0.02). For the post-SRS DTI findings, ipsilateral trigeminal nerves with symptoms of <5 years demonstrated decrease in Cl, while those with symptoms ? 5 years demonstrated increase in Cl after SRS at the ipsilateral REZ (- 0.025 vs. 0.018, p = 0.04). At the cisternal segment of ipsilateral trigeminal nerve, symptoms of < 5 years were associated with decreased FA and increased lambda2, while symptoms of ? 5 years were associated with increased FA and decreased lambda2 after SRS (FA - 0.068 vs. 0.031, p = 0.04, lambda2 0.0003 vs. - 0.0002, p = 0.02). CONCLUSIONS: SRS provides high rates of initial pain relief with moderate rates of facial hypoesthesia. Ipsilateral trigeminal nerve was associated with higher baseline REZ Cs, and baseline FA was associated with duration of symptoms. There were significant associations between duration of symptoms and changes in ipsilateral REZ Cl, cisternal segment FA, and cisternal segment lambda2 after SRS. These preliminary findings serve as comparisons for future studies investigating the use of DTI in radiosurgical planning for patients with TN. PMID- 29397450 TI - Segmentation and texture analysis of structural biomarkers using neighborhood clustering-based level set in MRI of the schizophrenic brain. AB - OBJECTIVE: Schizophrenia (SZ) is a psychiatric disorder that especially affects individuals during their adolescence. There is a need to study the subanatomical regions of SZ brain on magnetic resonance images (MRI) based on morphometry. In this work, an attempt was made to analyze alterations in structure and texture patterns in images of the SZ brain using the level-set method and Laws texture features. MATERIALS AND METHODS: T1-weighted MRI of the brain from Center of Biomedical Research Excellence (COBRE) database were considered for analysis. Segmentation was carried out using the level-set method. Geometrical and Laws texture features were extracted from the segmented brain stem, corpus callosum, cerebellum, and ventricle regions to analyze pattern changes in SZ. RESULTS: The level-set method segmented multiple brain regions, with higher similarity and correlation values compared with an optimized method. The geometric features obtained from regions of the corpus callosum and ventricle showed significant variation (p < 0.00001) between normal and SZ brain. Laws texture feature identified a heterogeneous appearance in the brain stem, corpus callosum and ventricular regions, and features from the brain stem were correlated with Positive and Negative Syndrome Scale (PANSS) score (p < 0.005). CONCLUSION: A framework of geometric and Laws texture features obtained from brain subregions can be used as a supplement for diagnosis of psychiatric disorders. PMID- 29397451 TI - The synergistic effect of calcium on organic carbon sequestration to ferrihydrite. AB - Sequestration of organic carbon (OC) in environmental systems is critical to mitigating climate change. Organo-mineral associations, especially those with iron (Fe) oxides, drive the chemistry of OC sequestration and stability in soils. Short-range-ordered Fe oxides, such as ferrihydrite, demonstrate a high affinity for OC in binary systems. Calcium commonly co-associates with OC and Fe oxides in soils, though the bonding mechanism (e.g., cation bridging) and implications of the co-association for OC sequestration remain unresolved. We explored the effect of calcium (Ca2+) on the sorption of dissolved OC to 2-line ferrihydrite. Sorption experiments were conducted between leaf litter-extractable OC and ferrihydrite at pH 4 to 9 with different initial C/Fe molar ratios and Ca2+ concentrations. The extent of OC sorption to ferrihydrite in the presence of Ca2+ increased across all tested pH values, especially at pH >= 7. Sorbed OC concentration at pH 9 increased from 8.72 +/- 0.16 to 13.3 +/- 0.20 mmol OC g-1 ferrihydrite between treatments of no added Ca2+ and 30 mM Ca2+ addition. Batch experiments were paired with spectroscopic studies to probe the speciation of sorbed OC and elucidate the sorption mechanism. ATR-FTIR spectroscopy analysis revealed that carboxylic functional moieties were the primary sorbed OC species that were preferentially bound to ferrihydrite and suggested an increase in Fe carboxylate ligand exchange in the presence of Ca at pH 9. Results from batch to spectroscopic experiments provide significant evidence for the enhancement of dissolved OC sequestration to 2-line ferrihydrite and suggest the formation of Fe Ca-OC ternary complexes. Findings of this research will inform modeling of environmental C cycling and have the potential to influence strategies for managing land to minimize OM stabilization. PMID- 29397453 TI - Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1. AB - In this study, a peptide-peptide co-administration therapy between hybrid peptide kla-TAT and cationic anticancer peptide HPRP-A1 was designed to increase the anticancer activity of the combination peptides through synergistic effect. kla is a pro-apoptotic peptide which could induce rapid cancer cell apoptosis by disruption the mitochondrial membrane when internalized the cells. To enhance more kla peptides pass through cell membrane, a double improvement strategy was designed by chemically conjugation with cell penetration peptide TAT as well as co-administration with cationic membrane active peptide HPRP-A1, and the double anticancer mechanism of the kla-TAT peptide and HPRP-A1 including membrane disruption and apoptosis induction was verified through in vitro experiments. The CompuSyn synergism/antagonism analysis showed that kla-TAT acted synergistically with HPRP-A1 against a non-small cell lung cancer (NSCLC) A549 cell line. The anticancer activities of the two peptides were dramatically increased by co administration, under the mechanism of cell membrane disruption, caspase dependent apoptosis induction, as well as cyclin-D1 down-regulation based G1 phase arrest. We believe that the synergic therapeutic strategy would be a meaningful method for the anticancer peptides used in cancer treatment. PMID- 29397452 TI - Update on the Treatment of Spontaneous Intraparenchymal Hemorrhage: Medical and Interventional Management. AB - PURPOSE OF REVIEW: Spontaneous intraparenchymal hemorrhage (IPH) is a prominent challenge faced globally by neurosurgeons, neurologists, and intensivists. Over the past few decades, basic and clinical research efforts have been undertaken with the goal of delineating biologically and evidence-based practices aimed at decreasing mortality and optimizing the likelihood of meaningful functional outcome for patients afflicted with this devastating condition. Here, the authors review the medical and surgical approaches available for the treatment of spontaneous intraparenchymal hemorrhage, identifying areas of recent progress and ongoing research to delineate the scope and scale of IPH as it is currently understood and treated. RECENT FINDINGS: The approaches to IPH have broadly focused on arresting expansion of hemorrhage using a number of approaches. Recent trials have addressed the effectiveness of rapid blood pressure lowering in hypertensive patients with IPH, with rapid lowering demonstrated to be safe and at least partially effective in preventing hematoma expansion. Hemostatic therapy with platelet transfusion in patients on anti-platelet medications has been recently demonstrated to have no benefit and may be harmful. Hemostasis with administration of clotting complexes has not been shown to be effective in reducing hematoma expansion or improving outcomes although correcting these abnormalities as soon as possible remains good practice until further data are available. Stereotactically guided drainage of IPH with intraventricular hemorrhage (IVH) has been shown to be safe and to improve outcomes. Research on new stereotactic surgical methods has begun to show promise. Patients with IPH should have rapid and accurate diagnosis with neuroimaging with computed tomography (CT) and computed tomography angiography (CTA). Early interventions should include control of hypertension to a systolic BP in the range of 140 mmHg for small hemorrhages without intracranial hypertension with beta blockers or calcium channel blockers, correction of any coagulopathy if present, and assessment of the need for surgical intervention. IPH and FUNC (Functional Outcome in Patients with Primary Intracerebral Hemorrhage) scores should be assessed. Patients should be dispositioned to a dedicated neurologic ICU if available. Patients should be monitored for seizures and intracranial pressure issues. Select patients, particularly those with intraventricular extension, may benefit from evacuation of hematoma with a ventriculostomy or stereotactically guided catheter. Once stabilized, patients should be reassessed with CT imaging and receive ongoing management of blood pressure, cerebral edema, ICP issues, and seizures as they arise. The goal of care for most patients is to regain capacity to receive multidisciplinary rehabilitation to optimize functional outcome. PMID- 29397454 TI - Reduced antigen presentation capability and modified inflammatory/immunosuppressive cytokine expression of induced monocyte-derived dendritic cells from peripheral blood of piglets infected with porcine circovirus type 2. AB - The efficiency of immune responses and host defense against pathogens largely depends on the function of dendritic cells (DCs). Porcine circovirus type 2 (PCV2) infection causes viremia and extensive modulation of immune activities in the blood. The objective of the present study was to investigate the effects of PCV2 infection in vivo on the immunological function of DCs induced from peripheral blood monocytes (MoDCs). At different points after infection with PCV2, peripheral blood monocytes from PCV2-infected pigs were used to induce differentiation of DCs in vitro. Flow cytometry and quantitative real-time reverse transcription PCR were conducted to detect mRNA expression of surface markers related to antigen presentation and inflammatory/immunosuppressive cytokines of the induced MoDCs. The ability of induced MoDCs to stimulate T cells was measured using an MTS assay. In the early phase of infection at 3 days post inoculation (DPI), IL-10, IL-8 and MIP-1beta in MoDCs were upregulated significantly. By the peak of virus proliferation at 7 DPI, antigen presentation molecules SLA-DR (MHC II) and CD80/86 together with cytokines IL-12 and IL-10 had decreased, accompanied by a rapid reduction of IL-8 and MIP-1beta. The T cell stimulation index of induced MoDCs in PCV2 groups after different infection times declined to some extent, with a significant difference at 7 DPI. PCV2 infection in vivo functionally reduced the antigen presentation capability of induced MoDCs from peripheral blood and modified expression of inflammatory/immunosuppressive cytokines that may be related to PCV2-induced immunosuppression. PMID- 29397455 TI - Molecular characterization and complete genome of a novel nepovirus from red clover. AB - During high throughput sequencing (HTS) of leaves from a symptomatic red clover plant, a new RNA virus, tentatively named red clover nepovirus A (RCNVA), was discovered. The complete genomic sequence was determined and characterized. Particularly noteworthy was that RCNVA shares high sequence identities in RNA1 with a group of phylogenetically related nepoviruses while homologies in the RNA2 segments are markedly lower. Based on the genomic organization and phylogenetic attributes, RCNVA should be classified as a novel virus of the genus Nepovirus (subfamily Comovirinae, family Secoviridae, order Picornavirales). PMID- 29397456 TI - Immune responses of mature chicken bone-marrow-derived dendritic cells infected with Newcastle disease virus strains with differing pathogenicity. AB - Infection of chickens with virulent Newcastle disease virus (NDV) is associated with severe pathology and increased morbidity and mortality. The innate immune response contributes to the pathogenicity of NDV. As professional antigen presenting cells, dendritic cells (DCs) play a unique role in innate immunity. However, the contribution of DCs to NDV infection has not been investigated in chickens. In this study, we selected two representative NDV strains, i.e., the velogenic NDV strain Chicken/Guangdong/GM/2014 (GM) and the lentogenic NDV strain La Sota, to investigate whether NDVs could infect LPS-activated chicken bone derived marrow DCs (mature chicken BM-DCs). We compared the viral titres and innate immune responses in mature chicken BM-DCs following infection with those strains. Both NDV strains could infect mature chicken BM-DC, but the GM strain showed stronger replication capacity than the La Sota strain in mature chicken BM DCs. Gene expression profiling showed that MDA5, LGP2, TLR3, TLR7, IFN-alpha, IFN beta, IFN-gamma, IL-1beta, IL-6, IL-18, IL-8, CCL5, IL-10, IL-12, MHC-I, and MHC II levels were altered in mature DCs after infection with NDVs at all evaluated times postinfection. Notably, the GM strain triggered stronger innate immune responses than the La Sota strain in chicken BM-DCs. However, both strains were able to suppress the expression of some cytokines, such as IL-6 and IFN-alpha, in mature chicken DCs at 24 hpi. These data provide a foundation for further investigation of the role of chicken DCs in NDV infection. PMID- 29397457 TI - Biodegradation of n-alkanes on oil-seawater interfaces at different temperatures and microbial communities associated with the degradation. AB - Oil biodegradation studies have mainly focused on microbial processes in dispersions, not specifically on the interfaces between the oil and the seawater in the dispersions. In this study, a hydrophobic adsorbent system, consisting of Fluortex fabrics, was used to investigate biodegradation of n-alkanes and microbial communities on oil-seawater interfaces in natural non-amended seawater. The study was performed over a temperature range from 0 to 20 degrees C, to determine how temperature affected biodegradation at the oil-seawater interfaces. Biodegradation of n-alkanes were influenced both by seawater temperature and chain-length. Biotransformation rates of n-alkanes decreased by reduced seawater temperature. Low rate coefficients at a seawater temperature of 0 degrees C were probably associated with changes in physical-chemical properties of alkanes. The primary bacterial colonization of the interfaces was predominated by the family Oceanospirillaceae at all temperatures, demonstrating the wide temperature range of these hydrocarbonoclastic bacteria. The mesophilic genus Oleibacter was predominant at the seawater temperature of 20 degrees C, and the psychrophilic genus Oleispira at 5 and 0 degrees C. Upon completion of n-alkane biotransformation, other oil-degrading and heterotrophic bacteria became abundant, including Piscirickettsiaceae (Cycloclasticus), Colwelliaceae (Colwellia), Altermonadaceae (Altermonas), and Rhodobacteraceae. This is one of a few studies that describe the biodegradation of oil, and the microbial communities associated with the degradation, directly at the oil-seawater interfaces over a large temperature interval. PMID- 29397458 TI - How medical technologies shape the experience of illness. AB - In this article we explore how diagnostic and therapeutic technologies shape the lived experiences of illness for patients. By analysing a wide range of examples, we identify six ways that technology can (trans)form the experience of illness (and health). First, technology may create awareness of disease by revealing asymptomatic signs or markers (imaging techniques, blood tests). Second, the technology can reveal risk factors for developing diseases (e.g., high blood pressure or genetic tests that reveal risks of falling ill in the future). Third, the technology can affect and change an already present illness experience (e.g., the way blood sugar measurement affects the perceived symptoms of diabetes). Fourth, therapeutic technologies may redefine our experiences of a certain condition as diseased rather than unfortunate (e.g. assisted reproductive technologies or symptom based diagnoses in psychiatry). Fifth, technology influences illness experiences through altering social-cultural norms and values regarding various diagnoses. Sixth, technology influences and changes our experiences of being healthy in contrast and relation to being diseased and ill. This typology of how technology forms illness and related conditions calls for reflection regarding the phenomenology of technology and health. How are medical technologies and their outcomes perceived and understood by patients? The phenomenological way of approaching illness as a lived, bodily being-in-the-world is an important approach for better understanding and evaluating the effects that medical technologies may have on our health, not only in defining, diagnosing, or treating diseases, but also in making us feel more vulnerable and less healthy in different regards. PMID- 29397459 TI - Tocilizumab for the treatment of birdshot uveitis that failed interferon alpha and anti-tumor necrosis factor-alpha therapy: two cases report and literature review. AB - Biotherapies appear as potential drugs for the treatment of inflammatory noninfectious uveitis. In this report, we show that tocilizumab, an anti-IL-6 agent, greatly improved two patients with birdshot chorioretinopathy refractory to conventional immunosuppressive drugs, interferon alpha2a, and anti-TNFalpha agents. After a follow-up of 22 months, patients exhibited an improvement of both visual acuity and macular edema. A corticosteroid-sparing effect was achieved in both cases. PMID- 29397460 TI - Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices. AB - BACKGROUND: Limited real-world research has investigated ramucirumab for the treatment of patients with gastric or gastroesophageal junction (GEJ) cancer. This study was designed to describe ramucirumab monotherapy or combination therapy use in a community oncology practice setting. METHODS: This was a retrospective observational cohort study to describe the treatment of adult patients with gastric or GEJ cancer who initiated ramucirumab treatment between 4/21/14 and 6/30/16 within the US Oncology Network. Kaplan-Meier method and Cox proportional hazards regression analyses were used to assess clinical outcomes. Multivariable logistic regression models were used to assess patient-level predictors of ramucirumab monotherapy or combination therapy. RESULTS: A total of 505 patients (mean age 64.4 years; 75.1% male) were included in the analysis; subgroups included: monotherapy (22.8%; n = 115), combination therapy (77.2%; n = 390). Monotherapy patients were significantly older (67.7 vs. 63.4 years; P = 0.0006), received ramucirumab approximately 3 months later after diagnosis (16.9 vs. 14.1 months; P = 0.0318) and more frequently initiated ramucirumab in the third or later lines of treatment (38.3 vs. 8.2%; P<0.0001) than patients receiving combination therapy. Median overall survival (OS) for monotherapy and combination therapy from the start of second-line therapy was 5.5 months (confidence interval [CI] 4.3, 7.8) and 7.4 months (CI 6.6, 8.8), respectively. CONCLUSIONS: The results showed that patients who received ramucirumab monotherapy started ramucirumab therapy later after diagnosis and were older than those who received ramucirumab in combination. Additionally, survival data suggest that outcomes observed in community oncology practices are similar to data from phase 3 clinical trials. PMID- 29397461 TI - Correlates of professional burnout in a sample of employees of cell and tissue banks in Poland. AB - Job Demands-Resources model proposes that the development of burnout follows excessive job demands and lack of job resources. Job demands are predictive of feeling of exhaustion, and lack of job resources-disengagement from work. This pilot study investigated professional burnout and its correlates in employees of Polish cell and tissue banks, many of whom were involved in procurement and processing of tissues from deceased donors, as it was hypothesized that job burnout in this population might influence the effectiveness of cell and tissue transplantation network in our country. This study utilized the Polish version of the Oldenburg Burnout Inventory (OLBI), which measures the two dimensions of burnout (exhaustion and disengagement), and the Psychosocial Working Conditions Questionnaire (PWC), a Polish instrument used for monitoring psychosocial stress at work. The study sample consisted of 31 participants. Their average time of working in a cell and tissue bank was 13.20 years. Majority of the PWC scales and subscales scores fell in the Average range, and the OLBI results for the Disengagement and the Exhaustion scales were in the Average range. A number of correlations between the Exhaustion or Disengagement and the PWC scales and subscales were detected, majority of which fell in the Moderate range. In spite of the limited number of participants, the results of this pilot study are consistent with the burnout literature reports. Among the detected correlates of professional burnout, it is job-related support which seems to be the most important factor which may influence the efficacy of transplantation network in Poland. PMID- 29397462 TI - Molecular testing of Klebsiella pneumoniae contaminating tissue allografts recovered from deceased donors. AB - Microbiological screening of tissue allografts is crucial to prevent the transmission of bacterial and fungal infections to transplant recipients. Klebsiella was the most prevalent and resistant contaminating microorganism observed in our setting in the Iranian Tissue Bank. This study was conducted to determine the presence of extended-spectrum beta-lactamase (ESBL) genes, antimicrobial resistance patterns of Klebsiella pneumoniae isolates, and their clonal relationships in allograft materials. K. pneumoniae contaminating bone and other tissue allografts recovered from deceased donors were identified and ESBL isolates were detected using a phenotypic confirmatory method. Antimicrobial susceptibility testing was carried out using the disk diffusion method. Distribution of ESBL genes and molecular typing were performed using polymerase chain reaction (PCR) and Repetitive-element (rep-PCR) methods. Of 3828 donated tissues, 51 (1.3%) were found contaminated by K. pneumoniae isolates. Compared to tissue allografts from brain-dead, heart-beating tissue donors, allografts from donors with circulatory cessation were associated with a higher risk of K. pneumoniae contamination [odds ratio (OR), 1.2 (CI 95% 0.9-2.3) (P value < 0.001)]. Half of the isolates produced ESBL, and the rate of susceptibility to cephalosporins was 51%. Among isolates, 22 (43.1%) harbored CTX-M, 31 (60.8%) SHV, and 9 (17.6%) harbored TEM types. The rep-dendrogram indicated that clones having identical or related strains with a similar antibiotype were isolated in the same period. This study provides evidence that a single clone of K. pneumoniae contaminated tissue allografts recovered from many different donors. A single clone found on tissues from several donors suggests contamination of tissues from a single source such as the tissue recovery process and environment. Genomic DNA testing and clonality of contaminating bacteria using molecular methods can focus the epidemiologic investigation on the tissue allograft recovery process including a search for contamination of the tissue recovery room environment, recovery staff, recovery equipment, reagents, solutions and supplies. PMID- 29397463 TI - Distal clavicle fracture radiography and treatment: a pictorial essay. AB - Fractures of the distal clavicle represent 15-30% of all clavicle fractures. The local osseoligamentous anatomy and deforming forces result in increased risk of delayed union and nonunion than fractures in other parts of the clavicle. These factors also contribute to challenges in fracture repair. Understanding these injuries and their imaging features enhances care and ensures patients are directed to appropriate management. We review the anatomy of the distal clavicle and surrounding ligaments, options for radiographic evaluation, relevant classification systems, and current concepts in management. Illustrative examples of specialized views are provided. Pediatric acromioclavicular joint pseudosubluxation is also reviewed, with findings specific to that injury. PMID- 29397464 TI - Recognizing intraventricular silicone. AB - Retinal detachment with subsequent silicone oil retinopexy is not uncommon. A known complication of silicone retinopexy is intraventricular migration of the intraocular silicone oil. While the oil itself does not result in direct pathology, misdiagnosis may lead to an unnecessary diagnostic workup and possibly predispose the patient to surgery intervention. Silicone oil typically appears hyperdense on computer tomography (CT) and hyperintense on T1-weighted magnetic resonance (MR). These imaging findings may mimic a mass or blood products. However, MR imaging of silicone results in chemical shift artifact which should help narrow the imaging differential. We present a patient with incidental CT and MRI findings which resulted in a prolonged hospital course following misidentification of intraventricular silicone oil. Although the imaging differential for an intraventricular lesion may include metastasis, lymphoma, hemorrhage, choroid plexus papilloma/carcinoma, meningioma, subependymoma, and ependymoma, secondary imaging findings should be noted to ensure an accurate diagnosis. In patients with evidence of prior silicone retinopexy, visualization of an intraventricular lesion with associated chemical shift artifact should raise the possibility of intraventricular silicone oil migration. PMID- 29397465 TI - 3D Printing Provides a Precise Approach in the Treatment of Tetralogy of Fallot, Pulmonary Atresia with Major Aortopulmonary Collateral Arteries. AB - Patients with tetralogy of Fallot, pulmonary atresia, and multiple aortopulmonary collateral arteries (Tet PA MAPCAs) have a wide spectrum of anatomy and disease severity. Management of these patients can be challenging and often require multiple high-risk surgical and interventional catheterization procedures. These interventions are made challenging by complex anatomy that require the proceduralist to mentally reconstruct three-dimensional anatomic relationships from two-dimensional images. Three-dimensional (3D) printing is an emerging medical technology that provides added benefits in the management of patients with Tet PA MAPCAs. When used in combination with current diagnostic modalities and procedures, 3D printing provides a precise approach to the management of these challenging, high-risk patients. Specifically, 3D printing enables detailed surgical and interventional planning prior to the procedure, which may improve procedural outcomes, decrease complications, and reduce procedure-related radiation dose and contrast load. PMID- 29397466 TI - Evaluation of mercury, lead, and cadmium in the waste material of crevalle jack fish from the Gulf of Uraba, Colombian Caribbean, as a possible raw material in the production of sub-products. AB - The Gulf of Uraba, currently considered a national strategic ecoregion, could be threatened by the presence of heavy metals such as mercury (Hg), lead (Pb), and cadmium (Cd), which directly affect the aquatic ecosystem. In Colombia, investigations on marine species pollution are scarce; however, their products are consumed. The aim of this study was to quantify the contents of Hg, Pb, and Cd in muscle and in waste material (head-gills, viscera, fins-tail), in one of one of the most commercialized resources, the crevalle jack (Caranx hippos), and to determine their presence in some of the body portions that are used in the production of sub-products. The concentrations of Hg, Pb, and Cd were compared between the waste material and muscle of the crevalle jack fish that were caught from each of the following sites the community usually uses to catch them: Bahia Candelaria, Bahia Marirrio, Bocas del Roto, and Bocas del Atrato. They were captured every 1 year in each climatic period. All body portions exceeded the maximum allowed limits for Pb (0.667-23.378 mg kg-1); the highest Hg concentrations were found in muscle (0.515-7.019 mg kg-1) and viscera (0.172 1.883 mg kg-1), and for Cd, the parts with the highest levels were the fins-tail (0.040-0.15 mg kg-1) and viscera (0.040-0.174 mg kg-1). Considering the obtained results, it is not recommended to use the waste material for the production of fish meal or fish silage due to the adverse effects it could cause on both animals and humans. PMID- 29397467 TI - Immediate provisionalization in the esthetic zone: 1-year interim results from a prospective single-cohort multicenter study evaluating 3.0-mm-diameter tapered implants. AB - OBJECTIVES: The aim of this interim analysis of a 5-year prospective multicenter study is to evaluate clinical and radiological performance of immediately provisionalized 3.0-mm-diameter tapered implants. MATERIALS AND METHODS: Patients needing implant rehabilitation of maxillary lateral incisors or mandibular lateral and central incisors were treated with 3.0-mm-diameter implants placed in extraction or healed sites and immediately provisionalized. Clinical and radiographic examinations were performed at implant insertion, 6 months thereafter, and are ongoing. Marginal bone levels and changes, complications, the papilla, plaque, and bleeding indices, and the pink esthetic score (PES) were evaluated at each follow-up visit. RESULTS: Of 112 enrolled patients, 77 patients (91 implants) met the inclusion criteria. Seventy-one patients with 82 implants completed the 1-year follow-up. Three implants failed yielding a CSR of 96.7%. All failures occurred within the first 3 months after implant insertion. Marginal bone level changes from insertion to 6 months was - 0.57 +/- 1.30 mm (n = 75) and from insertion to 12 months - 0.25 +/- 1.38 mm (n = 72). Fifteen non-serious complications were recorded. Papilla index score and PES improved at the 1-year follow-up. Plaque formation and bleeding-on-probing showed no statistically significant differences between the 6-month and the 1-year visit. CONCLUSIONS: This 1-year analysis demonstrated high survival, stable bone levels, and healthy soft tissue with 3.0-mm-diameter implants. CLINICAL IMPLICATIONS: Narrow diameter implants are a safe and predictable treatment option in patients with limited bone volume and/or limited interdental space and eligible for immediate loading protocols. PMID- 29397468 TI - The influence of management of tooth wear on oral health-related quality of life. AB - OBJECTIVE: The purpose of this study was to identify the level of oral health related quality of life and orofacial appearance in patients with moderate to severe tooth wear. Patients with and without a request for restorative treatment were included. METHODS: One hundred twenty-four patients (98 men, 26 women, mean age: 40.5 +/- 8.8 years) with moderate to severe tooth wear were included. Patients without a request for help received a non-restorative treatment of counseling and monitoring. Patients with a request for restorative treatment were treated with a full rehabilitation using composite resin restorations. Oral Health Impact Profile (OHIP-NL) and Orofacial Esthetic Scale (OES-NL) questionnaires were filled in at baseline and after 1 year. RESULTS: Counseling and monitoring group: baseline OHIP-NL score was 0.4 +/- 0.3, baseline summary score of OES-NL was 48 +/- 7.0, and baseline impression score was 7.1 +/- 1.2. Scores had not changed significantly after 1 year (p = 1.00 after Bonferroni correction).Restoration group: baseline OHIP-NL score was 0.8 +/- 0.6, baseline summary score of OES-NL was 38 +/- 10, and baseline impression score was 5.9 +/- 1.5. Scores had improved significantly after 1 year (p < 0.001 after Bonferroni correction). CONCLUSIONS: Counseling and monitoring did not result in a significant deterioration and restorative treatment resulted in a significant improvement of oral health-related quality of life (OHRQoL) and orofacial appearance in this patient group. CLINICAL SIGNIFICANCE: In patients with moderate to severe tooth wear, without functional and esthetical problems, counseling and monitoring may be an appropriate treatment option. Restorative treatment in patients with a need for treatment results in an improved OHRQoL. OHIP and OES questionnaires may be used to monitor changes in clinically relevant symptoms. PMID- 29397470 TI - Numbers in action: individual differences and interactivity in mental arithmetic. AB - Previous research indicates that interactive arithmetic tasks may alleviate the deleterious impact of maths anxiety on arithmetic performance. Our aim here was to further test the impact of interactivity on maths-anxious individuals and those with poorer numeracy skills. In the experiment reported here participants completed sums in two interactivity contexts. In a low-interactivity condition, sums were completed with hands down. In a second, high-interactivity condition, participants used moveable number tokens. As anticipated, accuracy and efficiency were greater in the high compared to the low-interactivity condition. Correlational analyses indicated that maths anxiety, objective numeracy, measures of maths expertise and working memory were stronger predictors of performance in the low- than in the high-interactivity conditions. Interactivity transformed the deployment of arithmetic skills, improved performance, and reduced the gap between high- and low-ability individuals. These findings suggest that traditional psychometric efforts that identify the cognitive capacities and dispositions involved in mental arithmetic should take into account the degree of interactivity afforded by the task environment. PMID- 29397471 TI - Animal transgenesis on the fast track in the era of evolving genome editing technologies: report for TT2017 the 14th Transgenic Technology Meeting in Snowbird, Utah. PMID- 29397469 TI - Efficacy of docetaxel in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate. AB - BACKGROUND: This study aimed to investigate the efficacy of docetaxel in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). PATIENTS AND METHODS: We retrospectively identified 79 CRPC patients with distant metastasis at initial diagnosis from June 2002 to January 2014. All patients received initial androgen deprivation therapy and 46 received docetaxel chemotherapy after progressing to CRPC. The primary outcome of interest was cancer-specific survival (CSS) from the time of CRPC diagnosis. The Cox regression model was used to confirm whether IDC-P and docetaxel would act as independent factors for prognosis. RESULTS: IDC-P was found in 62 of 79 patients. The median CSS in the IDC-P-present group was 18.2 versus 45.6 months in the IDC P-absent group (HR 2.67; 95% CI 1.18 to 6.06; P = 0.019). Docetaxel was administered to 36 patients with IDC-P and 10 patients without IDC-P, with a median CSS of 20.5 versus 53.2 months, respectively (HR 2.98; 95% CI 1.02 to 8.64; P = 0.044). Multivariate analysis demonstrated that the presence of IDC-P and docetaxel were independent prognostic factors for CSS (P = 0.026 and 0.005, respectively) and overall survival (OS) (P = 0.029 and 0.001, respectively). CONCLUSION: The presence of IDC-P is an independent prognostic factor in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. Docetaxel may prolong CSS and OS in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. PMID- 29397472 TI - Gastrointestinal Bleeding in Native and Prosthetic Valve Disease. AB - Gastrointestinal bleeding with severe aortic stenosis was originally described in the 1950s by Heyde, although for years, the association was debated. Further discovery of mechanisms and the ubiquity and severity of acquired von Willebrand syndrome in the left ventricular assist device therapy have removed any doubts. At this time, gastrointestinal bleeding from intestinal angiodysplasia in patients with turbulence-related proteolysis of the highest molecular weight multimers of von Willebrand factor is now known to occur in patients with aortic stenosis, and also subaortic obstruction and associated mitral insufficiency in hypertrophic cardiomyopathy, isolated mitral and aortic insufficiency, endocarditis, and in patients with prosthetic valve dysfunction, either from stenosis or insufficiency. The degree of loss of high molecular weight multimers correlates with lesion severity, and tests of von Willebrand factor function have been proposed as important biomarkers of the severity of valve dysfunction, including in-lab testing for paravalvular leak during transcatheter aortic valve replacement. Bleeding tends to recur after endoscopic or surgical therapy, but cardiac repair is curative in the great majority. PMID- 29397474 TI - Editor's note February 2018. PMID- 29397473 TI - Acute and chronic toxicity of pesticides on tadpoles of Physalaemus cuvieri (Anura, Leptodactylidae). AB - Brazil is the largest consumer of pesticides in the world. However, knowledge on how these pesticides affect wildlife is scarce. Among the vertebrates, amphibians are particularly important in research to assess the impact of pesticides because of the correlation between pesticide and the decline of these species. This study aimed to evaluate the acute and chronic toxicity of commercial formulations of pesticides, i.e., atrazine (herbicide), cypermethrin (insecticide), and tebuconazole (fungicide) in Physalaemus cuvieri tadpoles. Eggs were collected in nature and cultivated under controlled conditions in the laboratory. Toxicity tests were carried out under standard conditions to determine the lethal concentration (LC50) after 96 h of exposure and to determine the effect of sublethal concentrations after 7 days. In addition, we performed swimming activity tests on tadpoles exposed to sublethal concentrations. The lethal concentration (LC50) was 19.69 mg/L for atrazine, 0.24 mg/L for cypermethrin and 0.98 mg/L for tebuconazole. In the acute test, atrazine showed lower toxicity than cypermethrin and tebuconazole for P. cuvieri. Swimming activity was affected at sublethal doses of atrazine and cypermethrin, but was not after exposure to tebuconazole. Cypermethrin was the insecticide that most altered the swimming activity of the individuals tested. The risk evaluation analysis indicated risks for tadpoles exposed to three tested pesticides, specially cypermethrin. PMID- 29397475 TI - Assessment of superficial coronary vessel wall deformation and stress: validation of in silico models and human coronary arteries in vivo. AB - Cyclic biomechanical stress at the lumen-intima interface plays a crucial role in the rupture of coronary plaque. We performed a comprehensive assessment of a novel angiography-based method for four-dimensional (4D) dynamic assessment of superficial wall stress (SWS) and deformation with a total of 32 analyses in virtual stenosis models with equal lumen dimensions and 16 analyses in human coronary arteries in vivo. The in silico model analyses demonstrated that the SWS, derived by the proposed global displacement method without knowledge of plaque components or blood pressure, was comparable with the result calculated by traditional finite element method. Cardiac contraction-induced vessel deformation increased SWS. Softer plaque and positive arterial remodeling, associated with a greater plaque burden, showed more variation in mean lumen diameter within the cardiac cycle and resulted in higher SWS. In vivo patient analyses confirmed the accuracy of computed superficial wall deformation. The centerlines predicted by our method at random selected time instant matched well with the actual one in angiograms by Procrustes analysis (scaling: 0.995 +/- 0.018; dissimilarity: 0.007 +/- 0.014). Over 50% of the maximum SWS occurred at proximal plaque shoulders. This novel 4D approach could be successfully to predict superficial wall deformation of coronary artery in vivo. The dynamic SWS might be more realistic to evaluate the risk of plaque rupture. PMID- 29397476 TI - Local excision of a giant colonic lipoma. PMID- 29397478 TI - The future is now: cutting edge science and understanding toxicology. PMID- 29397477 TI - Involvement of Nuclear Receptor REV-ERBbeta in Formation of Neurites and Proliferation of Cultured Adult Neural Stem Cells. AB - Neural stem cells (NSCs) serve as the source of both neurons and support cells, and neurogenesis is reportedly linked to the circadian clock. This study aimed to clarify the functional role of the circadian rhythm-related nuclear receptor, REV ERBbeta, in neurogenesis of NSCs from adult brain. Accordingly, Rev-erbbeta expression and the effect of Rev-erbbeta gene-specific knockdown on neurogenesis in vitro was examined in adult rodent NSCs. Initial experiments confirmed REV ERBbeta expression in cultured adult NSCs, while subsequent gene expression and gene ontogeny analyses identified functional genes upregulated or downregulated by REV-ERBbeta. In particular, expression levels of factors associated with proliferation, stemness, and neural differentiation were affected. Knockdown of Rev-erbbeta showed involvement of REV-ERBbeta in regulation of cellular proliferation and self-renewal of cultured adult NSCs. Moreover, Rev-erbbeta knockdown cells formed neurons with a slightly shrunken morphology, fewer new primary neurites, and reduced length and branch formation of neurites. Altogether, this suggests that REV-ERBbeta is involved in neurite formation during neuronal differentiation of cultured adult NSCs. In summary, REV-ERBbeta is a known circadian regulatory protein that appears to be involved in neurogenesis via regulation of networks for cell proliferation and neural differentiation/maturation in adult NSCs. PMID- 29397479 TI - Identifying and Addressing Genetic Counseling Challenges among Indigenous People of Oaxaca-One Center's Experience with Two Immigrant Farmworker Families in the Central Valley of California. AB - An important aspect of genetic counseling is the recognition of and adaptation to the socio-cultural uniqueness of the different populations that a genetics clinic serves. The Central Valley of California is home to a large population from Mexico, with a significant proportion of indigenous ancestry originating from the state of Oaxaca. We report on our experience with two families of this community one extended family with an early lethal inborn error of metabolism and the other with a chronic disfiguring form of ichthyosis. We identified multiple important factors that needed to be considered, including the matching of language dialects, adaptation to different social interaction conventions, acknowledgement of traditional medicine beliefs, and effective transmission of genetic terms and concepts, all of which should be incorporated into the interactions with these families when aiming to provide comprehensive genetic counseling. PMID- 29397481 TI - Continuous Fluorescence Depletion Anisotropy Measurement of Protein Rotation. AB - Protein rotation in viscous environments can be measured by fluorescence depletion anisotropy (FDA) which combines long lifetimes of chromophore triplet states with the sensitivity of fluorescence excitation and detection. FDA achieves sensitivity well beyond that attainable by the more common technique of time-resolved phosphorescence anisotropy (TPA). We have now combined benefits of both time-domain and frequency-domain FDA into a single continuous technique (CFDA). Intensity and polarization of a single laser beam are modulated continuously according to a complex, repeating waveform. Fluorescence signals excited from triplet-forming fluorescent probes are digitized over recurring waveform periods by a high-speed signal averager. CFDA experiments typically involve substantial ground state depletion. Thus signals, unlike those of TPA, are not linear in the exciting light intensity and simple data analysis based on such linearity is not appropriate. An exact solution of the coupled diffusion and triplet production/decay equation describing CFDA within individual data points has been combined with simulated annealing optimization to extract triplet and anisotropy decay kinetics from experimental data. Related calculations compare possible excitation waveforms with respect to rotational information provided per fluorescence photon. We present CFDA results for the model system of eosin conjugates of carbonic anhydrase, BSA and immunoglobulin G in 90% glycerol at various temperatures and initial cellular results on eosin-IgE bound to 2H3 cell Type I Fcepsilon receptors. We explore how CFDA reflects rotational parameters of heterogeneous systems and discuss challenges of extending this method to single cell microscopic measurements. PMID- 29397480 TI - Factors Influencing Functional Outcomes and Return-to-Work After Amputation: A Review of the Literature. AB - Purpose Amputation is a life changing event that can significantly impact an individual's physical and mental well-being. Our objective was to review literature exploring the impact of amputation upon a person's functioning and inclusion in the workplace. Methods Medline, CINAHL, and PsycINFO were searched using keywords related to amputation, employment and community reintegration. Eligible studies were published since 2000 and one of the following study designs: randomized controlled trial, non-randomized controlled trial, retrospective study, prospective study, concurrent cohort study, or cross sectional study. Studies for civilians with amputation as well as service members and Veterans with amputation were considered for inclusion. Results The search identified 995 articles, 25 of which met inclusion/exclusion criteria and were included in the review. While strong evidence for correlations and predictors of outcomes after amputation were limited, multiple factors were identified as contributing to physical functioning and employment after amputation. Conclusions Outcomes after amputation can vary widely with many potentially inter-related factors contributing. The factors identified may also serve to inform the development of interventions aiming to improve functional performance and reintegration after amputation. Furthermore, the review highlights the need for more high quality prospective studies. PMID- 29397482 TI - Somatic NRAS mutation in patient with generalized lymphatic anomaly. AB - Generalized lymphatic anomaly (GLA or lymphangiomatosis) is a rare disease characterized by a diffuse proliferation of lymphatic vessels in skin and internal organs. It often leads to progressive respiratory failure and death, but its etiology is unknown. Here, we isolated lymphangiomatosis endothelial cells from GLA tissue. These cells were characterized by high proliferation and survival rates, but displayed impaired capacities for migration and tube formation. We employed whole exome sequencing to search for disease-causing genes and identified a somatic mutation in NRAS. We used mouse and zebrafish model systems to initially evaluate the role of this mutation in the development of the lymphatic system, and we studied the effect of drugs blocking the downstream effectors, mTOR and ERK, on this disease. PMID- 29397483 TI - Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling. AB - The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10DeltaEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10DeltaEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10DeltaEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10DeltaEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV 1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature. PMID- 29397484 TI - Higher Birthweight and Maternal Pre-pregnancy BMI Persist with Obesity Association at Age 9 in High Risk Latino Children. AB - Childhood obesity is increasing especially in Latinos and early intervention is essential to prevent later obesity complications. Latino children (n = 201) recruited at two San Francisco hospitals were assessed at birth including infant anthropometrics and feeding practices and followed to age 9 with annual anthropometric assessments. We evaluated the relationship between perinatal risk factors and obesity at age 9 and chronic obesity (obesity at both 5 and 9 years). Higher birthweight [odds ratio (OR) 2.48, 95% confidence interval (CI) 1.06-5.81] and maternal pre-pregnancy body mass index (BMI) (OR 1.09, 95% CI 1.00-1.18) were associated with increased risk for obesity at 9 years. Higher maternal pre pregnancy BMI (OR 1.10, 95% CI 1.01-1.20) was associated with chronic obesity. Additionally, prenatal depression symptoms were protective (OR 0.33, 95% CI 0.11 0.94) against chronic obesity. We found no association between maternal age and education, exclusive breastfeeding at 4-6 weeks, rapid infant weight gain, and obesity or chronic obesity. Perinatal risk factors for obesity including higher birthweight and maternal pre-pregnancy BMI persisted until age 9, whereas, other variables significant at age 5 in our cohort and other populations including exclusive breastfeeding and rapid infant weight gain were no longer associated with increased risk. PMID- 29397485 TI - Factors Influencing Trust in Agencies That Disseminate Tobacco Prevention Information. AB - Several health-related agencies administer national and targeted public education campaigns to provide health information and change health-related behaviors. The trust the public has in these agencies as the source of the message impacts the effectiveness of their communication campaigns. In this study, we explore the perceived trust of agencies that communicate health messages in the tobacco control field. As part of a larger tobacco regulatory science study, we conducted six 90-min focus groups comprising 41 participants. Five main themes emerged pertinent to the agency: (1) its integrity, (2) its competence, (3) its motives, (4) how it is portrayed in the media, and (5) skepticism and mistrust about it. Given the significant resources spent on health messaging to the public and potential benefits offered by this communication, an understanding of public trust in the agencies as the source of health messages is important. Findings suggest health information may be ignored or discounted when there is mistrust in the agency sending those messages. PMID- 29397486 TI - Usefulness of robot-assisted thoracoscopic esophagectomy. AB - OBJECTIVES: We started robot-assisted thoracoscopic esophagectomy using the da Vinci surgical system from June 2010 and operated on 30 cases by December 2013. Herein, we examined the usefulness of robot-assisted thoracoscopic esophagectomy and compared it with conventional esophagectomy by right thoracotomy. METHODS: Patients requiring an invasion depth of up to the muscularis propria with preoperative diagnosis were considered for surgical adaptation, excluding bulky lymph node metastasis or salvage surgery cases. The outcomes of 30 patients who underwent robot-assisted surgery (robot group) and 30 patients who underwent conventional esophagectomy by right thoracotomy (thoracotomy group) up to December 2013 were retrospectively examined. Five ports were used in the robot assisted thoracoscopic esophagectomy: 3rd intercostal (da Vinci right arm), 6th intercostal (da Vinci camera), 9th intercostal (da Vinci left arm), 4th and 8th intercostals (for assistance). RESULTS: There was no significant difference in patient characteristics. Robot group/right thoracotomy group: Operation time, 563/398 min; thoracic procedure bleeding volume, 21/135 ml; number of thoracic lymph node radical dissections, 25/23. Postoperative complications were recurrent nerve paralysis, 16.7/16.7%; pneumonia, 6.7%/10.0%; anastomotic leakage, 10.0/20.0%; surgical site infection, 0/10.0%; hospitalization, 17/30 days. For the robot group, the operation time was significantly longer, but the amount of intraoperative bleeding and postoperative hospitalization were significantly reduced. CONCLUSIONS: Robot-assisted thoracoscopic esophagectomy enables delicate surgical procedures owing to the 3D effect of the field of view and articulated forceps of the da Vinci. This procedure reduces bleeding and postoperative hospitalization and is less invasive than conventional esophagectomy by right thoracotomy. PMID- 29397487 TI - Bone metabolism markers and vitamin D in adolescent cyclists. AB - : This study aimed to describe bone metabolic activity in adolescent competitive cyclists compared to age-matched controls. The main result is that younger subjects present a higher bone turnover than the older ones. Moreover, cyclists under the age of 17 have higher scores on all markers than age-matched controls. PURPOSE: The purpose of this study was to describe bone metabolic activity in adolescent competitive cyclists compared to age-matched controls. METHODS: Twenty two male adolescent cyclists between 14 and 20 years (y) and 20 age-matched controls participated in this study. Serum osteocalcin (OC), aminoterminal propeptide of type I procollagen (PINP), and beta-isomerized C-telopeptides (beta CTX) were analyzed by electrochemiluminescence immunoassay (ECLIA); plasma 25 hydroxyvitamin D [25(OH)D] was analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Analysis of variance revealed no significant differences in bone metabolism markers and vitamin D between cyclists and controls. Cyclists over 17 y had a significantly lower concentration in bone formation and resorption biochemical markers compared to cyclists under 17 y (all P < 0.05). Moreover, controls over 17 y presented lower concentration for PINP (P < 0.05) compared to their peers under 17 y. Comparisons between cyclists and controls under 17 y revealed higher concentrations of OC and PINP (P < 0.05) in cyclists. Group interaction by age was found for OC, PINP, and beta-CTX (P < 0.01). Cyclists over 17 y had higher concentrations of [25(OH)D] (P < 0.05) than age matched controls. CONCLUSIONS: The present results support the idea that cycling during adolescence may be associated to a decrease in bone turnover that may affect bone health later in life. PMID- 29397488 TI - Lentibacillus alimentarius sp. nov., isolated from Myeolchi-jeotgal, a traditional Korean high-salt fermented anchovy. AB - A Gram-positive, motile, endospore-forming, rod-shaped bacterium, designated strain M2024T, was isolated from Myeolchi-jeotgal, a traditional Korean high-salt fermented anchovy and was characterised using a polyphasic taxonomic approach. Comparative 16S rRNA gene sequence analysis showed that strain M2024T belongs to the genus Lentibacillus in the family Bacillaceae of the Firmicutes. The 16S rRNA gene sequence analysis showed that strain M2024T is closely related to Lentibacillus populi WD4L-1T (95.5%), Lentibacillus garicola SL-MJ1T (95.2%) and Virgibacillus siamensis MS3-4T (95.1%). The chemotaxonomic properties of strain M2024T are consistent with those of members of the genus Lentibacillus: the quinone system has MK-7 as the predominant menaquinone and anteiso-C15:0 and anteiso-C17:0 are the predominant cellular fatty acids. The major polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The G+C content of the genomic DNA was determined to be 36.2 mol%. Differential phenotypic properties compared with closely related type strains support the conclusion that strain M2024T can be separated from previously described members of the genus Lentibacillus. The strain thus represents a novel species in this genus, for which the name Lentibacillus alimentarius sp. nov. is proposed. The type strain is M2024T (= KEMB 9001-124T = JCM 16521T). PMID- 29397489 TI - Effect of nicotine from tobacco root exudates on chemotaxis, growth, biocontrol efficiency, and colonization by Pseudomonas aeruginosa NXHG29. AB - Accumulated evidence suggests that root exudates have a major role in mediating plant-microbe interactions in the rhizosphere. Here, we characterized tobacco root exudates (TREs) by GC-MS and nicotine, scopoletin, and octadecane were identified as three main components of TREs. Qualitative and quantitative chemotaxis assays revealed that Pseudomonas aeruginosa NXHG29 with antagonistic activity displayed positive chemotactic responses towards TREs and their three main components (nicotine, scopoletin, octadecane) and its enhanced chemotaxis were induced by these substances in a concentration-dependent manner. Furthermore, following GC-MS and chemotaxis analysis, nicotine was selected as the target for evaluation of the effect on NXHG29 regarding antagonism, growth, root colonization and biocontrol efficiency. Results of in vitro studies showed that nicotine as a sole carbon source could enhance growth of NXHG29 and significantly increased the antagonism of NXHG29. We also demonstrated that nicotine exerted enhancing effects on the colonization ability of NXHG29 on tobacco roots by combining CLSM observations with investigation of population level dynamics by selective dilution plating method. Results from greenhouse experiments suggested nicotine exhibited stimulatory effects on the biocontrol efficiency of NXHG29 against bacterial wilt and black shank on tobacco. The stimulatory effect of nicotine was affected by the concentration and timing of nicotine application and further supported by the results of population level of NXHG29 on tobacco roots. This is the first report on the enhancement effect of nicotine from TREs on an antagonistic bacterium for its root colonization, control of soil-borne pathogens, regarding the chemotaxis and in vitro antagonism and growth. PMID- 29397490 TI - The 'gifted' actinomycete Streptomyces leeuwenhoekii. AB - Streptomyces leeuwenhoekii strains C34T, C38, C58 and C79 were isolated from a soil sample collected from the Chaxa Lagoon, located in the Salar de Atacama in northern Chile. These streptomycetes produce a variety of new specialised metabolites with antibiotic, anti-cancer and anti-inflammatory activities. Moreover, genome mining performed on two of these strains has revealed the presence of biosynthetic gene clusters with the potential to produce new specialised metabolites. This review focusses on this new clade of Streptomyces strains, summarises the literature and presents new information on strain C34T. PMID- 29397491 TI - Effect of Bifidobacterium infantis 35624 (Align) on the Lactulose Breath Test for Small Intestinal Bacterial Overgrowth. AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) may cause symptoms in patients with abdominal bloating, distension, and gas. SIBO can be assessed using the lactulose breath test (LBT). A commonly used probiotic supplement is Align containing Bifidobacterium infantis 35624. The aim of this study was to determine the effect of B. infantis 35624 on hydrogen and methane excretion during LBT. METHODS: Healthy subjects underwent LBT before and after 2 weeks of daily Align administration. Hydrogen and methane concentrations were measured for each breath sample. Results are expressed as mean +/- SE and analyzed using repeated measures ANCOVA. A breath test was considered positive if hydrogen and/or methane increased > 20 ppm above baseline by 90 min of the test or if a dual hydrogen peak was present. RESULTS: Nineteen healthy subjects were studied. Hydrogen levels were similar pre- and post-probiotic across the 3-h study (p = 0.768). In contrast, methane levels were significantly higher with probiotic administration (p = 0.012). A rise in methane > 20 ppm was seen in three subjects pre-probiotic but six post-probiotic. Of the 19 subjects, an "abnormal" LBT pre-probiotic was present in ten subjects and during the probiotic, 13 were abnormal. CONCLUSIONS: This study found that 2 weeks of B. infantis 35624 (Align) supplementation affects LBT assessment for SIBO by significantly increasing methane, but not hydrogen, excretion after lactulose administration. Methane levels reached values that would be considered positive for SIBO patients. This study suggests that patients undergoing LBT should discontinue probiotics prior to the test as these supplements may alter the test results. PMID- 29397492 TI - Epidemiology of Upper Gastrointestinal Hemorrhage in the USA: Is the Bleeding Slowing Down? PMID- 29397495 TI - Whiteboard Use in Labor and Delivery: A Tool to Improve Patient Knowledge of the Name of the Delivery Provider and Satisfaction with Care. AB - Introduction The impact of whiteboard use in labor rooms has not previously been studied. This quality improvement study aimed to evaluate patient knowledge of their delivering physician's name and the change in patient satisfaction after the implementation of a whiteboard in labor rooms. Methods A multidisciplinary team designed a dry-erase whiteboard prompting care providers to record their names, roles and patient care information. A questionnaire was administered to patients before and after the whiteboard implementation. Patients who had a planned cesarean or vaginal birth within 1 h of admission were excluded. Categorical variables were compared using Chi square and Fisher's exact tests. A multivariable logistic regression was performed to control for confounders. Results 191 patients completed the questionnaires. Although patients were not randomized, the pre-and post-intervention groups were similar. Post-intervention, we found a significant increase in recalling the delivery resident's name [21/101 (20.8%) vs. 33/90 (36.7%), p = 0.016] and a non-significant increase in recalling the name of the attending and nurse [19/101 (18.8%) vs. 23/90 (25.6%), p = 0.296; 46/101 (45.5%) vs. 53/90 (58.9%), p = 0.082]. Post-intervention, patient satisfaction with care was significantly higher [83/101 (82.2%) vs. 83/89 (93.3%), p = 0.028]. Knowledge of the delivery resident's name was associated with higher patient satisfaction [115/137 (84%) vs. 51/53 (96%), p = 0.03] and attendance of the postpartum care visit [50.4% (69/137) vs. 64.8% (35/54), p = 0.049]. Discussion The use of a well-designed whiteboard increases laboring patients' knowledge of their delivery physician's name and may improve patient satisfaction with care on Labor and Delivery. PMID- 29397493 TI - Clinicopathology and Survival in Patients with Gastroesophageal Reflux After Radical Surgery of Proximal Gastric Cancer. AB - BACKGROUND: Gastroesophageal reflux (GR) after radical resection of proximal gastric cancer (PGC) may influence survival; however, few studies have investigated survival in PGC patients who develop GR following radical resection. This study aimed to correlate the occurrence of GR after proximal gastrectomy (PG) and total gastrectomy (TG) with clinicopathological factors and long-term survival. METHODS: The PGC patient cohort was retrospectively grouped as follows: postoperative patients with and without GR (NGR). Clinicopathological characteristics and survival data were compared between the two groups. RESULTS: A total of 88 patients who underwent PG (53%) experienced postoperative GR; however, only 30 patients who underwent TG (14%) experienced GR (P = 0.000). The incidence of GR was significantly associated with surgical procedure (P < 0.01), tumor size (P < 0.01), infiltration depth (P < 0.01), lymph node metastasis (P = 0.018), postoperative distant metastasis (P < 0.01) and recurrence (P = 0.001). The 5-year overall survival of the GR group was significantly worse than that of the NGR group (39.3 vs. 46.5%, respectively; P = 0.046). The PG and TG groups had significantly different 5-year overall survival (45.2 vs. 50.9%, respectively; P = 0.047), and multivariate analysis revealed GR as an independent risk factor associated with poor overall survival. CONCLUSIONS: Patients who experienced GR after radical resection for PGC were more likely to develop recurrence and metastasis, leading to shorter survival. TG for PGC was associated with a more favorable 5-year overall survival than was PG. Thus, TG should be performed for PGC patients with tumors larger than 5 cm, T3/T4 disease or lymph node metastasis to improve their long-term survival. PMID- 29397494 TI - Adenoma Detection Rate Falls at the End of the Day in a Large Multi-site Sample. AB - BACKGROUND: There is concern that mental and physical fatigue among endoscopists over the course of the day will lead to lower adenoma detection rate (ADR). There are mixed findings in the prior literature on whether such an association exists. AIMS: The aim of this study was to measure the association between the number of colonoscopies performed in a day and ADR and withdrawal time. METHODS: We analyzed 86,624 colonoscopy and associated pathology reports between October 2013 and September 2015 from 131 physicians at two medical centers. A previously validated natural language processing program was used to abstract relevant data. We identified the order of colonoscopies performed in the physicians' schedule and calculated the ADR and withdrawal time for each colonoscopy position. RESULTS: The ADR for our overall sample was 29.9 (CI 29.6-30.2). The ADR for colonoscopies performed at the 9th + position was significantly lower than those at the 1st-4th or 5th-8th position, 27.2 (CI 25.8-28.6) versus 29.9 (CI 29.5 30.3), 30.2 (CI 29.6-30.9), respectively. Withdrawal time steadily decreased by colonoscopy position going from 11.6 (CI 11.4-11.9) min for the 1st colonoscopy to 9.6 (8.9-10.3) min for the 9th colonoscopy. CONCLUSION: In our study population, ADR and withdrawal time decrease by roughly 7 and 20%, respectively, by the end of the day. Our results imply that rather than mental or physical fatigue, lower ADR at the end of the day might be driven by endoscopists rushing. PMID- 29397496 TI - Feasibility and Psychometric Properties of the Infant Toddler Quality of Life (ITQOL) Questionnaire in a Community-Based Sample of Healthy Infants in China. AB - Objective Evaluate the feasibility and psychometric properties of the Infant Toddler Quality of Life (ITQOL) questionnaire as a measure of health-related quality of life (HRQOL) in a sample of Chinese infants. Methods The linguistically validated Simplified Chinese version of the ITQOL was used in a multicenter, observational study of healthy, term infants (N = 427), age 6 weeks at enrollment, in China. At Days 1 and 48, parents/guardians completed the ITQOL, the Short Form Health Survey (SF-12v2) and the Infant Gastrointestinal Symptom Questionnaire (IGSQ). ITQOL feasibility, reliability, ceiling/floor effects, concurrent validity and discriminatory validity were evaluated. Results Feasibility of administering the ITQOL was supported by strong response rates (> 97%) with < 1% missing items for all scales except physical abilities. Reliability was acceptable (Cronbach's alpha > 0.70) for all scales except Day 1 General Health (0.67). Floor effects were minimal (< 2%), except Day 1 physical abilities (7%). Ceiling effects increased from Days 1 to 48 across all scales. Concurrent validity was demonstrated by correlations between ITQOL infant-focused scales and IGSQ score (r = -0.20 to - 0.34, p < 0.001) and between parent-focused scales and SF-12v2 mental health composite (MCS) scores (r = 0.29-0.46, p < 0.001). ITQOL scales discriminated between infant subgroups based on illness related outcomes (sick visits, adverse events) and between parent subgroups based on SF-12v2 MCS scores. Conclusion The Simplified Chinese version of the ITQOL performed well in a community-based sample of Chinese infants, with evidence supporting the instrument's feasibility, reliability, and validity. These data support the ITQOL as a valuable tool to assess HRQOL in Chinese infants. PMID- 29397497 TI - Trends in Smoking and Smoking Cessation During Pregnancy from 1985 to 2014, Racial and Ethnic Disparity Observed from Multiple National Surveys. AB - Objective Current report assessed the trends in smoking prevalence and the percentage of smoking cessation during pregnancy among women from three major races/ethnicities. Methods Data were collected between 1999 and 2014 from the continuous National Health and Nutrition Examination Survey (NHANES). Smoking habits of women while pregnant with the child sampled by NHANES were assessed retrospectively. A total of 28,090 women who gave live birth between 1985 and 2014 were included. The prevalence ratios (PRs) of smoking and quitting smoking during pregnancy were calculated. The adjusted annual prevalence ratio (aaPR: the ratio associated with a 1-year increase in time) was estimated using logistic regression with the year of birth as a predictor. Results With child's race/ethnicity, gender, and mother's age controlled, the aaPR of smoking was 0.95 (95% confidence interval 0.92-0.97) for Hispanics, 0.96 (0.94-0.98) for whites, and 0.98 (0.94-1.00) for blacks. The aaPR of quitting smoking was 1.09 (1.02 1.16) for Hispanics, 1.01 (0.97-1.06) for whites, and 1.03 (0.95-1.12) for blacks. Compared with the counterparts aged 35 years or older, pregnant women younger than 20 years were more likely to smoke among whites [PR 1.56 (1.07 2.29)] but less likely among blacks [PR 0.37 (0.26-0.52)]. Conclusions for Practice Smoking prevalence has been declining continuously for all but at different rates among three major races/ethnicities. The risk profiles of smoking during pregnancy were race/ethnicity specific. Culturally appropriate programs should be developed to further reduce the maternal smoking during pregnancy. PMID- 29397498 TI - Genetic mapping of a novel recessive allele for non-glaucousness in wild diploid wheat Aegilops tauschii: implications for the evolution of common wheat. AB - Cuticular wax on the aerial surface of plants has a protective function against many environmental stresses. The bluish-whitish appearance of wheat leaves and stems is called glaucousness. Most modern cultivars of polyploid wheat species exhibit the glaucous phenotype, while in a wild wheat progenitor, Ae. tauschii, both glaucous and non-glaucous accessions exist. Iw2, a wax inhibitor locus on the short arm of chromosome 2D, is the main contributor to this phenotypic variation in Ae. tauschii, and the glaucous/non-glaucous phenotype of Ae. tauschii is usually inherited by synthetic hexaploid wheat. However, a few synthetic lines show the glaucous phenotype although the parental Ae. tauschii accessions are non-glaucous. Molecular marker genotypes indicate that the exceptional non-glaucous Ae. tauschii accessions share the same genotype in the Iw2 chromosomal region as glaucous accessions, suggesting that these accessions have a different causal locus for their phenotype. This locus was assigned to the long arm of chromosome 3D using an F2 mapping population and designated W4, a novel glaucous locus in Ae. tauschii. The dominant W4 allele confers glaucousness, consistent with phenotypic observation of Ae. tauschii accessions and the derived synthetic lines. These results implied that glaucous accessions of Ae. tauschii with the W2W2iw2iw2W4W4 genotype could have been the D-genome donor of common wheat. PMID- 29397499 TI - Testing the effect of paraquat exposure on genomic recombination rates in queens of the western honey bee, Apis mellifera. AB - The rate of genomic recombination displays evolutionary plasticity and can even vary in response to environmental factors. The western honey bee (Apis mellifera L.) has an extremely high genomic recombination rate but the mechanistic basis for this genome-wide upregulation is not understood. Based on the hypothesis that meiotic recombination and DNA damage repair share common mechanisms in honey bees as in other organisms, we predicted that oxidative stress leads to an increase in recombination rate in honey bees. To test this prediction, we subjected honey bee queens to oxidative stress by paraquat injection and measured the rates of genomic recombination in select genome intervals of offspring produced before and after injection. The evaluation of 26 genome intervals in a total of over 1750 offspring of 11 queens by microsatellite genotyping revealed several significant effects but no overall evidence for a mechanistic link between oxidative stress and increased recombination was found. The results weaken the notion that DNA repair enzymes have a regulatory function in the high rate of meiotic recombination of honey bees, but they do not provide evidence against functional overlap between meiotic recombination and DNA damage repair in honey bees and more mechanistic studies are needed. PMID- 29397500 TI - ITS2 sequence-structure phylogeny reveals diverse endophytic Pseudocercospora fungi on poplars. AB - For matching the new fungal nomenclature to abolish pleomorphic names for a fungus, a genus Pseudocercospora s. str. was suggested to host holomorphic Pseudocercosproa fungi. But the Pseudocercosproa fungi need extra phylogenetic loci to clarify their taxonomy and diversity for their existing and coming species. Internal transcribed spacer 2 (ITS2) secondary structures have been promising in charactering species phylogeny in plants, animals and fungi. In present study, a conserved model of ITS2 secondary structures was confirmed on fungi in Pseudocercospora s. str. genus using RNAshape program. The model has a typical eukaryotic four-helix ITS2 secondary structure. But a single U base occurred in conserved motif of U-U mismatch in Helix 2, and a UG emerged in UGGU motif in Helix 3 to Pseudocercospora fungi. The phylogeny analyses based on the ITS2 sequence-secondary structures with compensatory base change characterizations are able to delimit more species for Pseudocercospora s. str. than phylogenic inferences of traditional multi-loci alignments do. The model was employed to explore the diversity of endophytic Pseudocercospora fungi in poplar trees. The analysis results also showed that endophytic Pseudocercospora fungi were diverse in species and evolved a specific lineage in poplar trees. This work suggested that ITS2 sequence-structures could become as additionally significant loci for species phylogenetic and taxonomic studies on Pseudocerospora fungi, and that Pseudocercospora endophytes could be important roles to Pseudocercospora fungi's evolution and function in ecology. PMID- 29397501 TI - Detoxification of textile effluent by fungal treatment and its performance in agronomic usages. AB - Globally, scarcity of contaminant free water usages is increasing gradually; it might be solved after generation of any sustainable technology to detoxify contaminated waters. An attempt was undertaken to detoxify textile effluent with fungal strains Trichoderma harzianum and Mucor hiemalis. Fungal detoxified effluent and its performance on three crops (wheat, mungbean, and mustard) seed germination in petri dishes and seedlings establishment of mustard in polythene bag were evaluated. Fungal strains significantly detoxified textile effluent by removal of 76% total solids, 91.35% COD, 77.34% absorbance against optical density, and increased 87.31% DO. Studied heavy metals were reduced significantly (P <= 0.05) in treated effluent by both fungal strains but superior performance was achieved by Mucor hiemalis. Maximum 92.5, 88.7, 83, and 100% removal of Mn, Zn, Cu, and Fe were monitored in fungal-treated effluent, respectively. Seeds germination and seedling growth by fungal treated effluents were similar and insignificant with the results achieved in tap water but which was significant over raw textile effluent. Eighty and above percent seed germination in petri dishes was recorded at 48 h by Mucor hiemalis-treated textile effluent but conversely at the same period it was below 10% in raw effluent. Significant achievement of seedling establishment was noticed in poly bag with fungal-treated effluent. The applied technique might be a prospective way to detoxify and recycle the industrial effluents for beneficial purpose in the future. PMID- 29397502 TI - Effects of Spirulina platensis on DNA damage and chromosomal aberration against cadmium chloride-induced genotoxicity in rats. AB - Todays, bioactive compounds extracted from Spirulina platensis have been intensively studied for their therapeutical values. Therefore, in the present study, we aimed to evaluate the effects of S. platensis extract on DNA damage and chromosomal aberrations induced by cadmium in rats. Four groups of male albino rats (n = 7 rats) were used. The first group served as a control group and received distilled water. The second group was exposed intraperitoneally to cadmium chloride (CdCl2) (3.5 mg/kg body weight dissolved in 2 ml distilled water). The third group included the rats that were orally treated with S. platensis extract (1 g/kg dissolved in 5 ml distilled water, every other day for 30 days). The fourth group included the rats that were intraperitoneally and orally exposed to cadmium chloride and S. platensis, respectively. The experiment in all groups was extended for 60 days. The results of cadmium-mediated toxicity revealed significant genetic effects (DNA fragmentation, deletion or disappearance of some base pairs of DNA, and appearance of few base pairs according to ISSR-PCR analysis). Moreover, chromosomes showed structural aberrations such as reduction of chromosomal number, chromosomal ring, chromatid deletions, chromosomal fragmentations, and dicentric chromosomes. Surprisingly, S. platensis extract plus CdCl2-treated group showed less genetic effects compared with CdCl2 alone. Further, S. platensis extract upon CdCl2 toxicity was associated with less chromosomal aberration number and nearly normal appearance of DNA fragments as indicated by the bone marrow and ISSR-PCR analysis, respectively. In conclusion, the present novel study showed that co-treatment with S. platensis extract could reduce the genotoxic effects of CdCl2 in rats. PMID- 29397503 TI - Acute and single repeated dose effects of low concentrations of chlorpyrifos, diuron, and their combination on chicken. AB - This study investigated the acute and single repeated dose effects of low concentrations of chlorpyrifos, diuron, and their mixture to chicken. The effects were determined as biological response (chicken behavior); physiological response (body weight, gaining weight); and biochemical response such as reduction of acetylcholine esterase activity (ACHE), changes in liver biomarkers, such as (1) alkaline phosphatase (ALP), (2) aspartate aminotransferase (AST), and (3) alanine aminotransferase (ALP), and effects on kidney biomarkers such as total protein, creatinine, uric acid, and urea. Results showed abnormal behavior on chicken received 5 MUg/g and above from the tested compounds. A reduction in growth weight was observed in chicken received a single repeated dose of diuron and mixture. Enlargements in the liver and heart were observed in chicken received a single repeated dose of diuron. Percentage of serum ACHE inhibition increased linearly as the concentration of the tested compounds increased. The tested low concentration showed tremendous effects on liver enzymes and kidney functions. Similarly, a single repeated dose of the tested compounds caused severe inhibition on serum ACHE and affected the liver enzyme activities and kidney functions. It can be concluded that the low concentrations are not safe and may cause severe damage to the liver, heart, or kidney and disturb the life. PMID- 29397504 TI - Management of tannery wastewater for improving growth attributes and reducing chromium uptake in spinach through citric acid application. AB - The use of chromium (Cr)-contaminated tannery wastewater for irrigation is a common practice, especially in developing countries like Pakistan. This practice is due to the shortage of good quality irrigation water for crop growth as well as the issue of tannery wastewater disposal. The current study was done to evaluate the effect of citric acid (CA) (0, 1.0, and 2.0 mM) on the growth and Cr uptake by spinach irrigated with different mixtures of tap water and tannery wastewater (100:0, 50:50, and 0:100 tap water to wastewater ratio). Plants were grown for 8 weeks under ambient conditions. Results showed that 50:50% tap water and wastewater increased plant height, dry weights of shoots and roots, total chlorophyll contents, and gas exchange attributes than the plants treated with only tap water or only wastewater. Increasing wastewater ratio increased electrolyte leakage (EL) in plants and enhanced the leaf key antioxidant enzyme activities as well as increased Cr contents. Foliar application of CA increased the plant dry weights, photosynthesis, and enzyme activities, whereas reduced the EL and Cr concentrations in plants than respective treatments without CA application. It can be concluded that 50:50 tap water and wastewater irrigation along with foliar CA application might be an effective strategy for increasing vegetable growth with reduced metal concentrations. PMID- 29397505 TI - Temperature modulation of the health effects of particulate matter in Beijing, China. AB - Particulate matter (PM) has been proven to cause health risks and may result in hospital emergency room visits (ERVs), which might be complicated by extreme temperature events. However, it remains unclear how temperature modulates the effect of different-sized particles on ERVs. This study used three separate time series analyses (2009-2011) to explore such temperature modulation effect in Beijing, China. The analytical approaches included a bivariate response surface model, a non-stratification parametric model, and a stratification parametric model. Results showed that the average daily concentrations of PM10 and PM2.5 in Beijing were 110.16 and 67.89 MUg/m3, respectively, during the study period, which were higher than in most Western countries. Our findings indicated that the temperature modulation effects of PM2.5 were more evident than that of PM10. The effects of PM on morbidity depend on temperature. The effects were estimated for the increases in total, respiratory, and cardiovascular ERVs per 10 MUg/m3 increase in PM2.5 and PM10 concentrations at high temperature level (> 28 degrees C). The estimated increases in the three types of ERVs for PM2.5 were 0.15, 0.35, and 0.34%, respectively. For PM10, the increases were 0.12, 0.08, and 0.14%, respectively. In addition, the results showed that the elderly (age >= 65) and women are more vulnerable to PM at high temperatures. These findings may have implications for the health impact associated with both air pollution and global climate change. PMID- 29397506 TI - Agricultural technologies and carbon emissions: evidence from Jordanian economy. AB - Theoretically, agriculture can be the victim and the cause of climate change. Using annual data for the period of 1970-2014, this study examines the interaction between agriculture technology factors and the environment in terms of carbon emissions in Jordan. The results provide evidence for unidirectional causality running from machinery, subsidies, and other transfers, rural access to an improved water source and fertilizers to carbon emissions. The results also reveal the existence of bidirectional causality between the real income and carbon emissions. The variance error decompositions highlight the importance of subsidies and machinery in explaining carbon emissions. They also show that fertilizers, the crop and livestock production, the land under cereal production, the water access, the agricultural value added, and the real income have an increasing effect on carbon emissions over the forecast period. These results are important so that policy-makers can build up strategies and take in considerations the indicators in order to reduce carbon emissions in Jordan. PMID- 29397507 TI - Removal of chlorpyrifos, thiamethoxam, and tebuconazole from water using green synthesized metal hexacyanoferrate nanoparticles. AB - The low-cost and highly efficient pesticides are largely used in residential, agricultural, and commercial applications. Their prevalent occurrence, bioaccumulation, and chronic toxicity to living beings have raised environmental concern and call for their whole eradication, especially from water. By virtue of semiconducting nature and high surface area, nanomaterials have become efficient adsorbent and photocatalyst in removal of toxins. To confirm this, the potential of highly crystalline metal hexacyanoferrates (MHCFs) of Zn, Cu, Co, and Ni was evaluated in deprivation of selected hazardous pesticides, viz., chlorpyrifos (CP), thiamethoxam (TH), and tebuconazole (TEB). Sharp nanocubes of ZnHCF (~ 100 nm), distorted nanocubes of CuHCF (~ 100 nm), and nanospheres of CoHCF and NiHCF (< 10 nm) were synthesized via green route using Sapindus mukorossi (raw ritha). At 50 mg L-1 of pesticide, 15 mg of MHCF photocatalyst, neutral pH and sunlight irradiation, selected agrochemicals were degraded to maximum extent (91-98%) by ZnHCF followed by CuHCF (85-91%), NiHCF (73-85%), and CoHCF (70-83%). This might be because of highest zeta potential and BET surface area of ZnHCF. The highest adsorption of CP (83-98%) followed by TH (76-95%) and TEB (70-91%) on acidic surface of catalysts might be related to access of free electrons in their structures. On treatment with MHCF photocatalyst, targets underwent mineralization along with formation of some minor and non-toxic by-products such as (Z) but-2-enal, 3-aminopropanoic acid, and pyridin-3-ol, identified after mass spectrometric analysis of reaction mixture. Based on them, degradation pathways have been proposed to reveal the potential of MHCF for solar photocatalytic removal of organic pollutants in environment. PMID- 29397508 TI - Alteration of adaptive behaviors of progeny after maternal mobile phone exposure. AB - Exposure of pregnant women to radiofrequency (RF) devices raises questions on their possible health consequences for their progeny. We examined the hazard threshold of gestational RF on the progeny's glial homeostasis, sensory-motor gating, emotionality, and novelty seeking and tested whether maternal immune activation would increase RF toxicity. Pregnant dams were daily restrained with loop antennas adjoining the abdomen (fetus body specific absorption rates (SAR): 0, 0.7, or 2.6 W/kg) and received three lipopolysaccharide (LPS) intra-peritoneal injections (0 or 80 MUg/kg). Scores in the prepulse startle inhibition, fear conditioning, open field, and elevated plus maze were assessed at adolescence and adulthood. Glial fibrillary acidic protein (GFAP) and interleukines-1beta (ILs) were quantified. LPS induced a SAR-dependent reduction of the prepulse startle inhibition in adults. Activity in the open field was reduced at 2.6 W/kg at adolescence. GFAP and ILs, emotional memory, and anxiety-related behaviors were not modified. These data support the hypothesis that maternal immune activation increased the developmental RF exposure-induced long-term neurobiological impairments. These data support the fact that fetuses who receive combined environmental exposures with RF need special attention for protection. PMID- 29397509 TI - Essential oils from Foeniculum vulgare Miller as a safe environmental insecticide against the aphid Myzus persicae Sulzer. AB - Aphids are an important agricultural pest that not only damage plants by suction, but can also transmit a number of economically important plant viruses. Protection against aphids is based on the use of synthetic insecticides. However, these products can be dangerous for non-target organisms. Therefore, it is important to develop new, environmentally safe plant protection methods.In this study, we have tested an essential oil (EO) obtained from Foeniculum vulgare for the mortality of Myzus persicae, an important polyphagous pest, its natural predator Harmonia axyridis, and Eisenia fetida as a representative of soil organisms. The EO, with its major compounds trans-anethole (67.9%) and fenchone (25.5%), was found to provide excellent efficacy against M. persicae (LC50 = 0.6 and LC90 = 2.4 mL L-1) while not causing any significant mortality of the tested non-target organisms. On the contrary, application of an insecticide based on the active substance alpha-cypermethrin not only caused mortality in the aphids, but also had a fatal negative effect on both the non-target organisms we tested, resulting in their high mortality.Our results indicate very high prospects for using the essential oil from F. vulgare in the development of environmentally safe botanical insecticides designed for plant protection against aphids. PMID- 29397511 TI - Need of life cycle thinking for effective utilisation of resources based on developed and developing countries: a scenario for future generation. PMID- 29397510 TI - Sorption and recovery of platinum from simulated spent catalyst solution and refinery wastewater using chemically modified biomass as a novel sorbent. AB - In this study, Lagerstroemia speciosa biomass modified by polyethylenimine (PEI LS) was developed as a potential biosorbent for sorption and recovery of platinum(II) from platinum bearing waste solutions. Batch experiments were conducted to study the effect of various parameters on the sorption and recovery of platinum(II) using PEI-LS. The equilibrium time for platinum(II) sorption process was found to be 6 h. Both the sorption kinetics and sorption isotherm data fits pseudo second-order kinetic model and Langmuir isotherm, respectively. The maximum sorption capacity of platinum(II) onto PEI-LS at pH 2 for the studied temperature range (25-45 degrees C) is in the range of 122-154 mg/g. Evaluation of thermodynamic parameters suggests that the platinum(II) sorption is spontaneous and endothermic in nature. The regeneration of PEI-LS can be achieved using acidic thiourea as an eluent for recovery of platinum from the biosorbent. Fourier transform infrared (FT-IR) analysis suggests many functional groups were involved in platinum(II) sorption onto PEI-LS. Both the scanning electron microscope/energy dispersive spectroscopy (SEM/EDS) and X-ray photoelectron spectroscopy (XPS) analysis suggest a successful modification of raw biomass with PEI. The XPS analysis further concludes that platinum(II) sorption is governed by ion-exchange and co-ordination reaction. Finally, the PEI-LS was shown to recover >= 90% of platinum from two simulated solutions: the acid-leached spent catalyst solution and refinery wastewater. The biosorbent developed in this study is a low cost and eco-friendly media that can be effectively used for platinum recovery from industrial wastewater. PMID- 29397512 TI - Different calcification responses of two hermatypic corals to CO2-driven ocean acidification. AB - Understanding how calcification is influenced by the enhanced dissolution of CO2 in the oceans is the key to evaluating the effects of ocean acidification (OA) on coral reefs. In this study, two branching hermatypic corals widely distributed in the South China Sea, Pocillopora damicornis and Seriatopora caliendrum, were used to study the calcification responses to CO2-driven OA (7.77 +/- 0.07 vs. 8.15 +/- 0.12). Our results showed that the calcification rate (0.17 +/- 0.04%/day to 0.21 +/- 0.12%/day) in P. damicornis remained unchanged in the acidified seawaters, but that in S. caliendrum decreased significantly (0.62 +/- 0.21%/day to 0.44 +/- 0.11%/day). Our results suggested that reef corals with high calcification rates may be more susceptible to the enhanced dissolution of CO2. Differential calcified response to elevated CO2 may be closely attributed to coralline capacity of the upregulation at their site of calcification in acidified seawater. PMID- 29397513 TI - Contamination of estuaries from failing septic tank systems: difficulties in scaling up from monitored individual systems to cumulative impact. AB - Aquaculture in many coastal estuaries is threatened by diffuse sources of runoff from different land use activities. The poor performance of septic tank systems (STS), as well as runoff from agriculture, may contribute to the movement of contaminants through ground and surface waters to estuaries resulting in oyster contamination, and following their consumption, impacts to human health. In monitoring individual STS in sensitive locations, it is possible to show that nutrients and faecal contaminants are transported through the subsurface in sandy soils off-site with little attenuation. At the catchment scale however, there are always difficulties in discerning direct linkages between failing STS and water contamination due to processes such as effluent dilution, adsorption, precipitation and vegetative uptake. There is often substantial complexity in detecting and tracing effluent pathways from diffuse sources to water bodies in field studies. While source tracking as well as monitoring using tracers may assist in identifying potential pathways from STS to surface waters and estuaries, there are difficulties in scaling up from monitored individual systems to identify their contribution to the cumulative impact which may be apparent at the catchment scale. The processes which may be obvious through monitoring and dominate at the individual scale may be masked and not readily discernible at the catchment scale due to impacts from other land use activities. PMID- 29397514 TI - Toxicity comparison of the shoreline cleaners Accell Clean(r) and PES-51(r) in two life stages of the grass shrimp, Palaemonetes pugio. AB - Oil spills are a significant source of coastal pollution. Shoreline cleaners, used to remove oil from surfaces during spill response and remediation, may also act as toxins. Adult and larval grass shrimp, Palaemonetes pugio, were tested for lethal and sublethal impacts from two shoreline cleaners, Accell Clean SWA(r) and PES-51(r), alone and in combination with crude oil using Chemically Enhanced Water Accommodated Fractions (CEWAFs). Median lethal toxicity values determined for the individual cleaners were similar. However, when tested in mixture with oil as CEWAFs, Accell Clean SWA resulted in greater hydrocarbon concentrations in the water column and greater toxicity than PES-51. Increased glutathione levels were observed for adult shrimp exposed to Accell Clean SWA, and glutathione was elevated in shrimp exposed to both CEWAFs. Larval shrimp development was delayed after exposure to both CEWAFs. These findings may have implications for managing and mitigating oil spills. PMID- 29397515 TI - Biochar alleviates the toxicity of imidacloprid and silver nanoparticles (AgNPs) to Enchytraeus albidus (Oligochaeta). AB - The present study investigated the use of biochar for the alleviation of the toxic effects of a nanosilver colloidal dispersion and a chloronicotinyl insecticide. The survival and reproduction of the potworm Enchytraeus albidus were assessed after exposure to imidacloprid and silver nanoparticles (AgNPs). E. albidus was exposed to 0, 25, 50, 100, 200, and 400 mg imidacloprid/kg and 0, 5, 25, 125, and 625 mg Ag/kg for 21 days in 10% biochar amended and non-biochar amended OECD artificial soil. In both exposure substrates, the effects of imidacloprid on survival were significant in the two highest treatments (p < 0.01). No biochar effect was observed as survival was statistically similar in both soils after exposure to imidacloprid. In the case of AgNPs, significant mortality was only observed in the highest AgNP treatments in both the amended and non-amended soils (p < 0.05). Nevertheless, statistically greater survival occurred in the biochar-amended treatment (p < 0.05). Reproduction results showed a more pronounced biochar effect with an EC50 = 22.27 mg imidacloprid/kg in the non-amended soil and a higher EC50 = 46.23 mg imidacloprid/kg in the biochar amended soil. This indicated a 2-fold decrease in imidacloprid toxicity due to biochar amendment. A similar observation was made in the case of AgNPs where a reproduction EC50 = 166.70 mg Ag/kg soil in the non-amended soil increased to an EC50 > 625 mg Ag/kg soil (the highest AgNP treatment) in the amended soil. This indicated at least a 3.7-fold decrease in AgNPs toxicity due to biochar amendment. Although more studies may be needed to optimize the easing effects of biochar on the toxicity of these chemicals, the present results show that biochar could be useful for the alleviation of the toxic effects of imidacloprid and silver nanoparticles in the soil. PMID- 29397518 TI - Leaving us with fond memories, smiles, SMILES and, alas, tears: a tribute to David Weininger, 1952-2016. AB - David Weininger's career, accomplishments, genius, and friendship are warmly remembered by several of his colleagues, friends, and admirers. PMID- 29397516 TI - Role of polymorphic XRCC6 (Ku70)/XRCC7 (DNA-PKcs) genes towards susceptibility and prognosis of lung cancer patients undergoing platinum based doublet chemotherapy. AB - The DNA repair genes XRCC6 and XRCC7 formed an integral part of double strand break repair (DSBR) pathway. The two genes are thought to play an important role in the repair of lethal double strand damage on DNA. Polymorphic DSBR genes are studied to effect genomic stability. We intend to explore the association of DSBR genes i.e. XRCC6 and XRCC7 with susceptibility and survival in North Indian lung cancer patients. DNA isolation and genotyping was done for 320 controls and 330 lung cancer cases enrolled in the study. Each and every lung cancer study subjects were made a telephonic call and were followed for their health after administration of chemotherapy. Statistical analysis for susceptibility was done using logistic regression analysis. Survival analysis was done using Kaplan-Meier followed by Cox-regression. Small cell lung cancer (SCLC) subtype posed an amplified risk towards lung cancer in case of XRCC7 6721G>T (OR = 4.11, p = 0.0040). Gene-environment interaction analysis revealed that non-smokers with heterozygous genotype (CG) in case of XRCC6 61C>G showed a strong protective effect (OR = 0.38, p = 0.01) towards lung cancer. Survival analysis revealed poor prognosis in case of XRCC6 61C>G SCLC subtype. XRCC6 and XRCC7 were not involved in overall susceptibility and survival. However, in case of XRCC7 6721G>T subjects with SCLC subtype showed an increased susceptibility while poor prognosis in case of XRCC6 61C>G. PMID- 29397517 TI - Do MCF7 cells cope with metformin treatment under energetic stress in low glucose conditions? AB - There is a growing body of evidence about metformin being effective in cancer therapy. Despite controversies about the ways of its effectiveness, several ongoing clinical trials are evaluating the drug when used as an adjuvant or a neo adjuvant agent. We aimed to investigate metformin's effects on proliferation, metastasis, and hormone receptor expressions in breast cancer cell line MCF-7 incubated in two different glucose conditions. MCF-7 cells were incubated in high or low glucose media and treated with various doses of metformin. The cell viability was studied using MTT test. The Ki-67, estrogen and progesterone receptor expression were evaluated by ICC and galectin-3 expression was evaluated by ELISA or spectrophotometrically. The cell viability following consecutive metformin doses in either glucose condition for 24 and 48 h represented a significant decrease when compared to control. The proliferation detected in low glucose medium following metformin at doses < 20 mM was found significantly decreased when compared to high glucose medium at 48 h. In terms of galectin-3 levels, the increase in high glucose medium treated with metformin and the decrease in low glucose medium were found statistically significant when compared to control. Progesterone receptor staining demonstrated a significant increase in low glucose medium. Our findings represent better outcomes for cancer lines incubated in low glucose medium treated with metformin in terms of viability, receptor expression and metastatic activity, and highlight the potential benefit of metformin especially in restraining the cancer cell's ability to cope energetic stress in low glucose conditions. PMID- 29397519 TI - Impact of graphene-based nanomaterials (GBNMs) on the structural and functional conformations of hepcidin peptide. AB - Graphene-based nanomaterials (GBNMs) are widely used in various industrial and biomedical applications. GBNMs of different compositions, size and shapes are being introduced without thorough toxicity evaluation due to the unavailability of regulatory guidelines. Computational toxicity prediction methods are used by regulatory bodies to quickly assess health hazards caused by newer materials. Due to increasing demand of GBNMs in various size and functional groups in industrial and consumer based applications, rapid and reliable computational toxicity assessment methods are urgently needed. In the present work, we investigate the impact of graphene and graphene oxide nanomaterials on the structural conformations of small hepcidin peptide and compare the materials for their structural and conformational changes. Our molecular dynamics simulation studies revealed conformational changes in hepcidin due to its interaction with GBMNs, which results in a loss of its functional properties. Our results indicate that hepcidin peptide undergo severe structural deformations when superimposed on the graphene sheet in comparison to graphene oxide sheet. These observations suggest that graphene is more toxic than a graphene oxide nanosheet of similar area. Overall, this study indicates that computational methods based on structural deformation, using molecular dynamics (MD) simulations, can be used for the early evaluation of toxicity potential of novel nanomaterials. PMID- 29397520 TI - An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L?N?L PR mutant. AB - The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L?N?L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L?N?L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L?N?L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L?N?L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs. PMID- 29397521 TI - End-of-life care of children with diffuse intrinsic pontine glioma. AB - The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010. All patients died of disease progression, experiencing a significant symptom burden prior to death. Despite this, the majority of patient days at the end of life were spent at home. However, 60% of patients were hospitalized at least once in their final 3 months, often close to the time of death. A wide range of healthcare professionals were involved, providing a range of medicinal/non-medicinal interventions. Chemotherapy was given to 30% of patients in their final month. Thirty of 33 families approached (91%) agreed to a "Do not resuscitate" order. A small subset of families opted for intensive treatment towards the end of life including cardiopulmonary resuscitation, intensive care admission and mechanical ventilation. Children with DIPG have complex needs and require intensive multidisciplinary support. This paper describes the end-of-life choices made for these children and discusses how these choices influence our institutional model for palliative care. We believe this approach will be useful to clinicians caring for similar patients. PMID- 29397522 TI - Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental pathology characterized by an impairment in social interaction, communication difficulties, and repetitive behaviors. Glutamate signaling abnormalities are thought to be considered as major etiological mechanisms leading to ASD. The search for amino-acidic catabolytes related to glutamate in patients with different levels of ASD might help current research to clarify the mechanisms underlying glutamate signaling and its disorders, particularly in relation to ASD. In the present study, plasma levels of the amino acids and their derivatives glutamate, glutamine, and gamma aminobutyric acid (GABA), associated with their relative ratios, were evaluated using an enzyme-linked immunosorbent assay (ELISA) technique in 40 male children with ASD and in 38 age- and gender-matched neurotypical health controls. The Social Responsiveness Scale (SRS) was used to evaluate social cognition, and the Childhood Autism Rating Scale (CARS) was used to assess subjects' behaviors. Children with ASD exhibited a significant elevation of plasma GABA and glutamate/glutamine ratio, as well as significantly lower levels of plasma glutamine and glutamate/GABA ratios compared to controls. No significant correlation was found between glutamate levels and the severity of autism, measured by CARS and SRS. In receiver operating characteristic (ROC) curve analysis, the area under the curve for GABA compared to other parameters was close to one, indicating its potential use as a biomarker. Glutamine appeared as the best predictive prognostic markers in the present study. The results of the present study indicate a disturbed balance between GABAergic and glutamatergic neurotransmission in ASD. The study also indicates that an increased plasma level of GABA can be potentially used as an early diagnostic biomarker for ASD. PMID- 29397523 TI - ISCEV guide to visual electrodiagnostic procedures. AB - Clinical electrophysiological testing of the visual system incorporates a range of noninvasive tests and provides an objective indication of function relating to different locations and cell types within the visual system. This document developed by the International Society for Clinical Electrophysiology of Vision provides an introduction to standard visual electrodiagnostic procedures in widespread use including the full-field electroretinogram (ERG), the pattern electroretinogram (pattern ERG or PERG), the multifocal electroretinogram (multifocal ERG or mfERG), the electrooculogram (EOG) and the cortical-derived visual evoked potential (VEP). The guideline outlines the basic principles of testing. Common clinical presentations and symptoms are described with illustrative examples and suggested investigation strategies. PMID- 29397524 TI - Rationale and design of the TRICHAMPION trial: Triple Chamber Pacing in Hypertrophic Obstructive Cardiomyopathy Patients. AB - PURPOSE: Dual-chamber (DDD) pacing has been used for treatment of patients with hypertrophic obstructive cardiomyopathy (HOCM). Due to inconclusive results in prior trials, current guidelines assign DDD pacing a class IIb indication in selected patients. Prior observations indicate that lack of clinical improvement may result from suboptimal effect of DDD pacing with non-physiological AV intervals due to fusion of intrinsic and paced QRS complex. METHODS: The Triple Chamber Pacing in Hypertrophic Obstructive Cardiomyopathy Patients (TRICHAMPION) trial is a prospective, randomized, single-blinded, multicenter study to investigate the benefit of atrial synchronous biventricular pacing (CRT-P) in highly symptomatic HOCM patients with severe left ventricular outflow tract (LVOT) obstruction who are not candidates for ablative therapies. AV node ablation is used as key tool to optimize AV intervals in patients with QRS fusion. The primary endpoint is the percentage of patients with symptomatic improvement at 12 months, defined as improvement of New York Heart Association functional class, in the Minnesota Living with Heart Failure Questionnaire score and increased cardiopulmonary exercise endurance. CONCLUSIONS: The aim of the TRICHAMPION trial is to investigate the benefit of optimized atrial synchronous biventricular pacing in absence of QRS fusion in highly symptomatic HOCM patients with severe LVOT obstruction who are not candidates for ablative therapies. PMID- 29397525 TI - Coronary sinus morphology in pediatric patients with supraventricular tachycardia. AB - PURPOSE: The anatomic basis of atrioventricular node reentrant tachycardia (AVNRT) remains incompletely characterized in children. Differences in coronary sinus (CS) size and morphology have been observed in adults with AVNRT but have not been well characterized in children. METHODS: Children (< 18 years) brought to the EP lab with supraventricular tachycardia for ablation underwent CS venography. A blinded pediatric interventional cardiologist performed CS measurements, which were indexed to body surface area. Patients were excluded if they were < 25 kg or had significant congenital heart disease. RESULTS: Forty-six patients (age 14.2 +/- 3.3 years) met inclusion criteria, 17 with AVNRT and 32 with an accessory pathway (AP). CS ostium (LAO projection, end-systole) was 7.8 +/- 2.9 mm/m2 for the AVNRT group versus 6.0 +/- 2.5 mm/m2 for the AP group (p = 0.04). CS "windsock" morphology was more prevalent in the AVNRT group (16/17, 94.1%) than the AP group (11/32, 34.3%) (p < 0.001). Within the AVNRT group, there was no correlation between CS ostium size and tachycardia cycle length (R = 0.01, p = 0.96), fast-pathway ERP (FPERP) (R = 0.42, p = 0.12), or A2-H2 at the FPERP (R = 0.25, p = 0.39). CONCLUSIONS: Children with AVNRT have larger CS ostia and more prevalent windsock morphology. CS size/morphology did not correlate with EP properties of the AVNRT substrate. These features may explain the basis for the development of the electrophysiologic substrate for dual AV node physiology in children. PMID- 29397526 TI - Heterotopic ossifications: role of radiotherapy as prophylactic treatment. AB - BACKGROUND: Heterotopic ossification (HO) is abnormal formation of lamellar bone in soft tissue; the most frequent causes are total hip arthroplasty and trauma. Severe cases can lead to ankilosis with important impact on quality of life. Surgery is the elective treatment, but, especially in high-risk patients, it is important to prevent the re-formation of HO and, in these cases, radiotherapy (RT) can play an important role. MATERIALS AND METHODS: we retrospectively analyzed a mono-institutional casistic of 30 patients (31 sites) at high risk for HO development, treated with surgery and pre- or postoperative RT. The majority of patients received a single RT fraction of 7 Gy, median age was 62, with a prevalence of male and hip as most frequently involved site. Radiological studies and clinical examination were performed in all patients during the follow-up period to evaluate both treatment efficacy and acute or late toxicity. RESULTS: With a median follow up of 67 months, 23 patients had a complete response (CR) with excellent results in term of joint mobility. Two patients with CR showed a relapse of HO in the same site 19 and 12 months after treatment, respectively. Seven patients (22,6%) had a partial response (PR) to RT. One patient who reached CR had a history of previous irradiation in the same site 16 years before. No acute or late reactions have been reported. CONCLUSION: Our data confirm safety and efficacy of RT in preventing HO, especially in high-risk patients, preferring a single fraction of 7 Gy. PMID- 29397527 TI - Effect of roflumilast on chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - BACKGROUND: Randomized controlled trials (RCTs) of roflumilast effect on chronic obstructive pulmonary disease (COPD) have been reported in the last decade. The current meta-analysis was designed to systematically review and perform meta analysis of the RCTs of roflumilast treatment in COPD. METHODS: Electronic databases including PubMed, EMBASE, Web of Science, and Cochrane clinical trials database were searched to identify RCTs of roflumilast treatment on COPD. The primary outcomes were effect of roflumilast on pre-bronchodilator FEV1, post bronchodilator FEV1, and exacerbation rate. Secondary outcomes were effect of roflumilast on airway inflammation and adverse effect. RESULTS: A total of 11 RCTs were enrolled into the current analysis. Roflumilast significantly improved both pre-bronchodilator FEV1 (standardized difference in mean +/- SD was 0.621 +/ 0.161; 95% CI 0.306~0.936, p < 0.001) and post-bronchodilator FEV1 (standardized difference in mean +/- SD was 0.563 +/- 0.149, 95% CI 0.270~0.855, p < 0.001) compared with placebo. Roflumilast also significantly reduced exacerbation of COPD (standardized difference in mean +/- SD 0.099 +/- 0.020, 95% CI 0.061~0.138; p < 0.001) and suppressed airway inflammation (standardized difference in mean +/ SD 1.354 +/- 0.260, 95% CI 0.845~1.862, p < 0.001) compared with placebo. However, roflumilast significantly increased adverse effect such as diarrhea (rate ratio 2.945, 95% CI 2.453~3.536, p < 0.001) and weight loss (rate ratio 3.814, 95% CI 3.091~4.707, p < 0.001) compared with placebo. CONCLUSION: These findings indicated that roflumilast treatment could improve COPD patients' lung function and reduce exacerbation, and that inhibition of airway inflammation by roflumilast might contribute to the beneficial effect of PDE-4 inhibitors on COPD. PMID- 29397528 TI - The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL). AB - PURPOSE OF REVIEW: Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments. RECENT FINDINGS: With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future. PMID- 29397529 TI - Protein-Energy Malnutrition Exacerbates Stroke-Induced Forelimb Abnormalities and Dampens Neuroinflammation. AB - Protein-energy malnutrition (PEM) pre-existing at stroke onset is believed to worsen functional outcome, yet the underlying mechanisms are not fully understood. Since brain inflammation is an important modulator of neurological recovery after stroke, we explored the impact of PEM on neuroinflammation in the acute period in relation to stroke-initiated sensori-motor abnormalities. Adult rats were fed a low-protein (LP) or normal protein (NP) diet for 28 days before inducing photothrombotic stroke (St) in the forelimb region of the motor cortex or sham surgery; the diets continued for 3 days after the stroke. Protein-energy status was assessed by a combination of body weight, food intake, serum acute phase proteins and corticosterone, and liver lipid content. Deficits in motor function were evaluated in the horizontal ladder walking and cylinder tasks at 3 days after stroke. The glial response and brain elemental signature were investigated by immunohistochemistry and micro-X-ray fluorescence imaging, respectively. The LP-fed rats reduced food intake, resulting in PEM. Pre-existing PEM augmented stroke-induced abnormalities in forelimb placement accuracy on the ladder; LP-St rats made more errors (29 +/- 8%) than the NP-St rats (15 +/- 3%; P < 0.05). This was accompanied by attenuated astrogliosis in the peri-infarct area by 18% and reduced microglia activation by up to 41 and 21% in the peri-infarct area and the infarct rim, respectively (P < 0.05). The LP diet altered the cortical Zn, Ca, and Cl signatures (P < 0.05). Our data suggest that proactive treatment of pre-existing PEM could be essential for optimal post-stroke recovery. PMID- 29397530 TI - Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations. AB - ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model. PMID- 29397531 TI - A Simplified Method for Generating Purkinje Cells from Human-Induced Pluripotent Stem Cells. AB - The establishment of a reliable model for the study of Purkinje cells in vitro is of particular importance, given their central role in cerebellar function and pathology. Recent advances in induced pluripotent stem cell (iPSC) technology offer the opportunity to generate multiple neuronal subtypes for study in vitro. However, to date, only a handful of studies have generated Purkinje cells from human pluripotent stem cells, with most of these protocols proving challenging to reproduce. Here, we describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs. After 21 days of treatment with factors selected to mimic the self-inductive properties of the isthmic organiser-insulin, fibroblast growth factor 2 (FGF2), and the transforming growth factor beta (TGFbeta)-receptor blocker SB431542-hiPSCs could be induced to form En1-positive cerebellar progenitors at efficiencies of up to 90%. By day 35 of differentiation, subpopulations of cells representative of the two cerebellar germinal zones, the rhombic lip (Atoh1-positive) and ventricular zone (Ptf1a positive), could be identified, with the latter giving rise to cells positive for Purkinje cell progenitor-specific markers, including Lhx5, Kirrel2, Olig2 and Skor2. Further maturation was observed following dissociation and co-culture of these cerebellar progenitors with mouse cerebellar cells, with 10% of human cells staining positive for the Purkinje cell marker calbindin by day 70 of differentiation. This protocol, which incorporates modifications designed to enhance cell survival and maturation and improve the ease of handling, should serve to make existing models more accessible, in order to enable future advances in the field. PMID- 29397532 TI - Changes in Heart Rate Associated with Exenatide Once Weekly: Pooled Analysis of Clinical Data in Patients with Type 2 Diabetes. AB - INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed. METHODS: A pooled post hoc analysis of 11 randomized clinical trials (N = 4595) of 10-30 weeks' duration from the exenatide once-weekly (QW) development program evaluated heart rate with exenatide QW (intervention group) and exenatide twice daily (BID), liraglutide, and non-GLP-1RAs (insulin, metformin, pioglitazone, and sitagliptin) (comparison groups). The time course and size of heart rate changes from baseline and the relationship of heart rate change with baseline heart rate were studied. A multivariate analysis (9 studies; N = 3903) examined associations between patient characteristics or treatments and heart rate increases. RESULTS: Mean baseline heart rate +/- standard deviation was 75.0 +/- 8.5 beats per minute (bpm) with exenatide QW (n = 2096), 75.8 +/- 8.7 bpm with exenatide BID (n = 606), 75.2 +/- 8.9 bpm with liraglutide (n = 450), and 74.5 +/- 8.6 bpm with non-GLP-1RAs (n = 1443). Least-squares mean +/- standard error changes from baseline to final heart rate were + 2.7 +/- 0.2, + 1.0 +/- 0.3, and + 3.0 +/- 0.4 bpm with exenatide QW, exenatide BID, and liraglutide, respectively, and - 0.8 +/- 0.2 bpm with non-GLP-1RAs. The size and direction of heart rate changes in individual patients varied within each treatment group at all time points. At posttreatment follow-up, heart rate reverted to the baseline level after GLP-1RA discontinuation. Heart rate changes correlated negatively with baseline heart rate for all therapies (r = - 0.3 to - 0.4). Baseline heart rate was the strongest predictor of increased heart rate. CONCLUSIONS: Small increases in heart rate were associated with exenatide QW, exenatide BID, and liraglutide treatments but reverted to baseline after discontinuation. Increases were more likely in patients with a low baseline heart rate. The clinical relevance of these heart rate increases is unknown but will be clarified by several ongoing and recently completed cardiovascular outcome studies. PMID- 29397533 TI - Estrogen Receptors Are Involved in the Neuroprotective Effect of Silibinin in Abeta1-42-Treated Rats. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by a cascade of pathologic changes. A widely discussed theory indicates that amyloid beta (Abeta) peptides are the causative agents of AD. Silibinin, a flavonoid derived from milk thistle, is well known for its hepato protective activities and we have reported the neuroprotective effects of silibinin. In this study, we investigated the role of estrogen receptors (ERs) in silibinin's neuroprotective effect on Abeta1-42-injected rats. Results of Morris water maze and novel object-recognition tests demonstrated that silibinin significantly attenuated Abeta1-42-induced memory impairment. Silibinin attenuated ERs and PI3K-Akt pathways, as well as modulated mitogen-activated protein kinases in the hippocampus of Abeta1-42-injected rats. Taken together, silibinin is a potential candidate in the treatment of Alzheimer's disease. PMID- 29397534 TI - Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD. AB - Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD. PMID- 29397535 TI - The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents. AB - The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5 HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5 HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity. PMID- 29397536 TI - Rolipram Attenuates Early Brain Injury Following Experimental Subarachnoid Hemorrhage in Rats: Possibly via Regulating the SIRT1/NF-kappaB Pathway. AB - Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2 h after SAH with a dose of 10 mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-kappaB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-kappaB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment. PMID- 29397537 TI - Management of bloodstream infections by infection specialists in France and Germany: a cross-sectional survey. AB - INTRODUCTION: Bloodstream infections (BSI) are frequent infections worldwide. Our objective was to explore variation in the management of patients with BSI by infection specialists in France and Germany. METHODS: This work is part of an international ESCMID cross-sectional internet-based questionnaire survey that was opened from December 2016 to February 2017. All hospital-based infection specialists, senior or trainees, giving at least weekly advice on positive blood cultures could participate. Their practices were evaluated using six clinical vignettes presenting an uncomplicated BSI due to different pathogens. RESULTS: A hundred and ninety-six professionals (125 from Germany and 71 from France) participated. Systematic expert advice for positive blood cultures was more often available in Germany as compared with France (73 vs. 56%, p = 0.004). In Germany, the professional providing the expert advice was more often a microbiologist or a pharmacist as compared with France (p = 0.001 and p = 0.037, respectively) where it was more often an infectious diseases specialist. Fewer German respondents reported to advise systematic IV-oral switch of antibiotic therapy. German respondents also recommended less often combination therapy: for example for Enterococcus faecalis (64 vs. 43%, p = 0.015), ESBL E. coli (94 vs. 67%, p < 0.001) and Pseudomonas aeruginosa (76 vs. 37%, p < 0.001). Overall, management of candidaemia was more often compliant with the IDSA guidelines in France as compared with Germany, but no difference was noted for MRSA bacteraemia. CONCLUSION: Our survey shows that wide variations exist between two neighboring countries in the recommendations by infection specialists for the management of BSI. International guidelines are needed. PMID- 29397539 TI - Acquired myopia in Vogt-Koyanagi-Harada disease. AB - PURPOSE: To analyze the change in refractive error and the axial length of chronic Vogt-Koyanagi-Harada (VKH) disease. METHODS: Medical records of 106 eyes of 54 adult VKH patients were analyzed. The refractive error and the axial length were compared between the baseline (defined as the time point at least 2 weeks after acute stage of VKH) and the final visit. The rate of the eyes with significant myopia progression [defined as refraction change toward myopia > 1 diopter (D)] was examined. The correlation of the degree of sunset glow fundus/choroidal thickness with the change in refractive error was also evaluated. RESULTS: At the final visit, the mean refractive error was more myopic and the axial length was longer than at baseline. Seventeen of the 106 eyes (16.0%) showed significant myopia progression. The mean change in refractive error during a follow-up in these 17 eyes was - 2.7 D (range - 7.5 to - 1.1 D). The axial length data both at baseline and at the final visit were obtained only in 8 eyes. The mean change in axial length during a follow-up in these 8 eyes was 1.3 mm (range 0-3.7 mm). In the cases with myopia progression, sunset glow fundus was more frequent and subfoveal choroid was thinner than those without myopia progression. CONCLUSIONS: Myopia progression as well as increase in axial length occurs in VKH disease. The link between choroidal thinning and axial length elongation in VKH patients gives some insights into axial length increase of pathologic myopia. PMID- 29397538 TI - Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly. AB - PURPOSE: Acromegalic osteopathy is an emerging complication of acromegaly characterized by increase in bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). Somatostatin receptor ligands (SRLs) and pegvisomant (PegV) are used for treatment of acromegaly and there is evidence that both drugs may exert direct effects on peripheral targets regardless of biochemical control of disease. However, whether or not SRLs and PegV may directly influence skeletal health its is unknown. METHODS: In this longitudinal study, we evaluated the incidence of radiological VFs in 83 patients (48 females, 35 males; median age 47 years, range 18-80 years) who were treated with SRLs alone (42 cases), PegV alone (6 cases) or in combination with SRLs (35 cases) for median period of 82 months (range 36-126). PegV was given when acromegaly was not controlled by SRLs alone. RESULTS: During the follow-up, 29 patients (34.9%) developed incident VFs. In patients receiving PegV due to active disease during SRL therapy, incidence of VFs decreased significantly from 43.9 to 26.8% (p = 0.039). When acromegaly was controlled by PegV, the incidence of VFs was slightly but not significantly lower as compared to that observed in patients with biochemical control of disease by SRLs (10.0 vs. 26.7%; p = 0.09). In the multivariate logistic regression analysis, incident VFs were independently predicted by pre-existing VFs (odds ratio 61.0; p = 0.009), duration of active acromegaly (odds ratio 1.01; p = 0.05) and mean serum IGF-I during the follow-up (odds ratio 5.26; p = 0.03), regardless of the therapeutic regimen (odds ratio 1.05; p = 0.94). CONCLUSIONS: PegV and SRLs had comparable effects on VF risk in acromegaly. The activity of disease was the main determinant of VFs independently of the drug used to control acromegaly. PMID- 29397540 TI - Protective Effects of Quercetin Against Cadmium Chloride-Induced Oxidative Injury in Goat Sperm and Zygotes. AB - Quercetin, a plant-derived flavonoid, is frequently used as an antioxidant for efficient anti-oxidative capacity. However, whether quercetin has protective effects on goat sperm and preimplantation embryos against Cd2+-induced oxidative injury is still unclear. So, we researched the influence of quercetin on goat sperm and zygotes respectively under the oxidative stress induced by Cd2+. In our study, quercetin decreased the malonaldehyde (MDA) and reactive oxygen species (ROS) levels caused by Cd2+ in goat sperm (p < 0.05), which facilitated sperm characteristics including motility, survival rates, membrane integrity, and mitochondria activity during storage in vitro and subsequent embryo development (p < 0.05). Moreover, in goat zygotes, quercetin decreased peroxidation products including ROS, MDA, and carbonyl through preserving or maintaining mitochondrial function, gene expression, and anti-oxidative products such as glutathione peroxidase, superoxide dismutase, and catalase, which ameliorated subsequent embryo development and embryo quality (p < 0.05). Taken together, these results suggest that quercetin protects both goat sperm and preimplantation embryos from Cd2+-induced oxidative stress. PMID- 29397541 TI - Incidence and risk factors for acute kidney injury in patients with excessive anticoagulation on warfarin: a retrospective study. AB - Anticoagulant-related nephropathy is an acute kidney injury (AKI) associated with excessive anticoagulation. The nature of the association between excessive anticoagulation with warfarin and AKI and its incidence remain unclear. To evaluate the incidence of AKI in excessively anticoagulated patients taking warfarin and examine potential risk factors. A retrospective chart review was performed in patients on chronic warfarin. The primary outcome was AKI, defined as an acute increase in creatinine of > 26.5 umol/L within 7-14 days of an international normalized ratio (INR) >= 4.0. 292 patients with an INR >= 4.0 were included. 101 patients had CKD and 191 did not have CKD. Of the 292 patients with an INR >= 4.0, 38 (13%) had an AKI. In univariable analyses, CKD [odds ratio (OR) 2.1, 95% confidence interval (CI) 0.99-4.43] and use of renin-angiotensin system (RAS) blockers and/or diuretics (OR 3.85; 95% CI 1.15-20.15) were significantly associated with the risk of AKI. In a binomial logistic regression model, use of RAS blockers and/or diuretics was the only significant predictor of AKI (OR 3.4; 95% CI 1.02-11.76). Use of RAS blockers and/or diuretics significantly increased the risk of AKI in patients with warfarin-related excessive anticoagulation. Further prospective studies examining the association of high INRs and AKI are needed. PMID- 29397542 TI - Late Holocene wetland transgression and 500 years of vegetation and fire variability in the semi-arid Amboseli landscape, southern Kenya. AB - The semi-arid Amboseli landscape, southern Kenya, is characterised by intermittent groundwater-fed wetlands that form sedimentary geoarchives recording past ecosystem changes. We present a 5000-year environmental history of a radiocarbon dated sediment core from Esambu Swamp adjacent to Amboseli National Park. Although radiocarbon dates suggest an unconformity or sedimentary gap that spans between 3800 and 500 cal year BP, the record provides a unique insight into the long-term ecosystem history and wetland processes, particularly the past 500 years. Climatic shifts, fire activity and recent anthropogenic activity drive changes in ecosystem composition. Prior to 3800 cal year BP the pollen data suggest semi-arid savanna ecosystem persisted near the wetland. The wetland transgressed at some time between 3800 and 500 cal year BP and it is difficult to constrain this timing further, and palustrine peaty sediments have accumulated since 400 cal year BP. Increased abundance of Afromontane forest taxa from adjacent highlands of Kilimanjaro and the Chyulu Hills and local arboreal taxa reflect changes in regional moisture budgets. Particularly transformative changes occurred in the last five centuries, associated with increased local biomass burning coeval with the arrival of Maa-speaking pastoralists and intensification of the ivory trade. Cereal crops occurred consistently from around 300 cal year BP, indicative of further anthropogenic activity. The study provides unique insight in Amboseli ecosystem history and the link between ecosystem drivers of change. Such long-term perspectives are crucial for future climate change and associated livelihood impacts, so that suitable responses to ensure sustainable management practices can be developed in an important conservation landscape. PMID- 29397543 TI - The transboundariness approach and prioritization of transboundary aquifers between Mexico and Texas. AB - "Transboundariness" refers to a new approach that identifies and prioritizes transboundary aquifers using socio-economic and political criteria, improving their characterization by using other variables in addition to their mere physical boundaries. This approach is applied to the hydrogeological units/aquifers shared by Mexico and Texas, with the following results. First, the rankings agree with the current level of attention to transboundary aquifers in the region by both countries, providing a quantifiable system that could be tested in other transboundary aquifers. Second, this approach provides a holistic and integrative perspective for transboundary aquifer assessment and prioritization. Third, this prioritization exercise expands the criteria currently used into a more integrative regime of groundwater links to the community as a whole. Finally, the results reflect not only how the transboundary aquifers are being used (or neglected) but also the socio-political context of the populations that depend on these resources for current and future development. PMID- 29397544 TI - Factors driving collaboration in natural resource conflict management: Evidence from Romania. AB - A critical challenge in natural resource management is to bring all stakeholders together to negotiate solutions to critical problems. However, various collaborative approaches to heading off conflicts and resolving natural resource management disputes have been used. What drives these efforts, however, still needs further research. Our study provides a systematic look at the drivers likely to initiate collaborative problem-solving efforts in four cases in Romania. We use Emerson's et al. (2012) framework for collaborative governance and multi-value qualitative comparative analysis (mvQCA) to analyze cases involving endangered species, restrictions on forest harvest, conflicts associated with infrastructure development projects, and disputes over the management of environmentally sensitive areas. Our findings contribute to the already existing collaborative governance literature indicating which of the four factors: uncertainty, interdependence, consequential incentives, and leadership, in which combination, are necessary and sufficient to spur collaborative resource management efforts. Our results showed that in Romania the initiation of collaboration is best explained by positive consequential incentives (i.e., financial opportunities) which has determined leaders to take initiative. This study provides additional information for the complicated process of natural resource management which is often overriding collaboration by investigating what enables and constrains collaborative efforts in a country where natural resources were managed and used according to the principles of central planning. PMID- 29397545 TI - Coral reef aerosol emissions in response to irradiance stress in the Great Barrier Reef, Australia. AB - We investigate the correlation between stress-related compounds produced by corals of the Great Barrier Reef (GBR) and local atmospheric properties-an issue that goes to the core of the coral ecosystem's ability to survive climate change. We relate the variability in a satellite decadal time series of fine-mode aerosol optical depth (AOD) to a coral stress metric, formulated as a function of irradiance, water clarity, and tide, at Heron Island in the southern GBR. We found that AOD was correlated with the coral stress metric, and the correlation increased at low wind speeds, when horizontal advection of air masses was low and the production of non-biogenic aerosols was minimal. We posit that coral reefs may be able to protect themselves from irradiance stress during calm weather by affecting the optical properties of the atmosphere and local incident solar radiation. PMID- 29397546 TI - Limited capacity to retain phosphorus in the Baltic proper offshore sediments. PMID- 29397547 TI - A review of regulations and guidelines related to winter manure application. AB - Winter manure application elevates nutrient losses and impairment of water quality as compared to manure applications in other seasons. In conjunction with reviewing global distribution of animal densities, we reviewed worldwide mandatory regulations and voluntary guidelines on efforts to reduce off-site nutrient losses associated with winter manure applications. Most of the developed countries implement regulations or guidelines to restrict winter manure application, which range from a regulative ban to guidelines based upon weather and field management conditions. In contrast, developing countries lack such official directives, despite an increasing animal production industry and concern over water quality. An analysis of five case studies reveals that directives are derived from a common rationale to reduce off-site manure nutrient losses, but they are also affected by local socio-economic and biophysical considerations. Successful programs combine site-specific management strategies along with expansion of manure storage to offer farmers greater flexibility in winter manure management. PMID- 29397548 TI - Morphometry of the lower thoracic and lumbar pedicles and its relevance in pedicle fixation. AB - PURPOSE: To assess the pedicle morphology in the lower thoracic and lumbar spine in an Indian population and to determine the causes of pedicle wall violation by pedicle screws. METHODS: Computerised tomographic scans of 135 consecutive patients with thoracolumbar and lumbar spine fractures were prospectively analysed to determine the pedicle morphology. The transverse pedicle angle, pedicle diameter and screw path length at 527 uninjured levels were measured. Post-operative CT scans of 117 patients were analysed to determine the accuracy of 468 pedicle screws at 234 vertebrae. RESULTS: The lowest (mean +/- SD) transverse pedicle width in the lower thoracic spine was 5.4 +/- 0.70 mm, whereas in the lumbar spine it was 7.2 +/- 0.87 mm. The shortest (mean +/- SD) screw path length in lower thoracic pedicles was 35.8 +/- 2.10 and 41.9 +/- 2.18 mm in the lumbar spine. The mean transverse pedicle angle in the lower thoracic spine was consistently less than 5 degrees , whereas it gradually increased from L1 through L5 from 8.5 degrees to 30 degrees . Forty-one screws violated the pedicle wall, due to erroneous angle of screw insertion. CONCLUSIONS: In the current study, pedicle dimensions were smaller compared to the Western population. In Indian patients, pedicle screws of 5 mm diameter and 30 mm length, and 6 mm diameter and 35 mm length can safely be used in the lower thoracic and lumbar spine, respectively. However, it is important to assess the pedicle morphology on imaging prior to pedicle fixation. PMID- 29397550 TI - Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation, and structure-activity relationship studies. AB - In efforts to develop effective anticancer therapeutics with greater selectivity toward cancerous cell and reduced side-effects, such as emetic effects due to detrimental action of the drug toward the intestinal flora, a series of linear diarylheptanoids (LDHs) were designed and synthesized in 7 steps with good-to moderate yields. All synthesized compounds were evaluated for their antibacterial, antiproliferative, and topoisomerase-I and -IIalpha inhibitory activity. Overall, all compounds showed little to no activity against the bacterial strains tested. Most of the synthesized compounds showed good antiproliferative activity against human breast cancer cell lines (T47D); specifically, the IC50 values of compounds 6a, 6d, 7j, and 7e were 0.09, 0.64, 0.67, and 0.99 MUM, respectively. Among the tested compounds, 7b inhibited topo-I by 9.3% (camptothecin 68.8%), 7e and 7h inhibited topo-IIalpha by 38.4 and 47.4% (etoposide 76.9%), respectively, at the concentration of 100 MUM. These results suggest that a set of promising anticancer agents can be obtained by reducing inhibitory actions on different microbes to provide enhanced selectivity against cancerous cells. PMID- 29397549 TI - Visual internal urethrotomy for management of urethral strictures in boys: a comparison of short-term outcome of holmium laser versus cold knife. AB - PURPOSE: To compare efficacy and safety of visual internal urethrotomy (VIU) using holmium laser (Ho:YAG) (group A) versus cold knife (group B) in children with urethral strictures. It may be the first comparative study on this issue in children. METHODS: This study compared Ho:YAG group, which was evaluated prospectively from January 2014 till January 2016, versus cold knife group, which was a historical control performed from March 2008 till February 2010. Children <= 13 years old with urethral strictures <= 1.5 cm were included successively. Recurrent cases, congenital obstructions and cases with complete arrest of dye in voiding cystourethrography were excluded. Scar tissue was incised at twelve o'clock. Outcome was compared using Student's t, Mann-Whitney, Chi-square or Fisher exact tests as appropriate. RESULTS: Each group included 21 patients. Mean age was 6.27 +/- 3.23 (2-13) years old. Mean stricture length was 1.02 versus 1 cm in group A versus B, respectively (p = 0.862). Ten cases of penile/bulbous strictures and another 11 cases of membranous strictures were found in each group. There was no significant difference between both groups in preoperative data. Success rate for initial VIU was 66.7% in group A versus 38% in group B (p = 0.064). This was associated with significantly higher Qmax in group A (mean 16.52 vs 12.09 ml/s; p = 0.03). Success rate after two trials of VIU was 76.2% for group A and 47.61% for group B (p = 0.057). No complications were reported in both groups. CONCLUSION: Laser VIU has a higher success rate than cold knife VIU for urethral strictures <= 1.5 cm in children with significantly higher Qmax. Both are easy to perform, low invasive and safe. PMID- 29397552 TI - A New Method for a Virtue-Based Responsible Conduct of Research Curriculum: Pilot Test Results. AB - Drawing on Pennock's theory of scientific virtues, we are developing an alternative curriculum for training scientists in the responsible conduct of research (RCR) that emphasizes internal values rather than externally imposed rules. This approach focuses on the virtuous characteristics of scientists that lead to responsible and exemplary behavior. We have been pilot-testing one element of such a virtue-based approach to RCR training by conducting dialogue sessions, modeled upon the approach developed by Toolbox Dialogue Initiative, that focus on a specific virtue, e.g., curiosity and objectivity. During these structured discussions, small groups of scientists explore the roles they think the focus virtue plays and should play in the practice of science. Preliminary results have shown that participants strongly prefer this virtue-based model over traditional methods of RCR training. While we cannot yet definitively say that participation in these RCR sessions contributes to responsible conduct, these pilot results are encouraging and warrant continued development of this virtue based approach to RCR training. PMID- 29397551 TI - Finasteride inhibits melanogenesis through regulation of the adenylate cyclase in melanocytes and melanoma cells. AB - Finasteride is a well-known 5alpha-reductase inhibitor used for treatment of alopecia and prostate cancer. But the effect of finasteride in regulating melanogenesis is still unclear. In the present study the role of finasteride on melanogenesis was investigated. Finasteride decrease melanin level in melanocyte melan-a cells and B16F10 melanoma cells without inducing cytotoxicity. MC1R (melanocortin 1 receptor) protein expression was also inhibited by finasteride thereby decreasing the expression of adenylate cyclase, MITF (Melanogenesis associated transcription factor), tyrosinases, TRP (tyrosinase-related protein) 1 and -2. Thus our study suggest that finasteride inhibits melanogenesis in melanocyte and melanoma cells by inhibiting MC1R. PMID- 29397554 TI - The Role of Intralipid Emulsion in the Rat Model of Digoxin Intoxication. AB - Although the mechanism of action is not well known, intravenous lipid emulsion (ILE) has been shown to be effective in the treatment of lipophilic drug intoxications. It is thought that, ILE probably separates the lipophilic drugs from target tissue by creating a lipid-rich compartment in the plasma. The second theory is that ILE provides energy to myocardium with high-dose free fatty acids activating the voltage-gated calcium channels in the myocytes. In this study, effects of ILE treatment on digoxin overdose were searched in an animal model in terms of cardiac side effects and survival. Forty Sprague-Dawley rats were divided into five groups. As the pre-treatment, the groups were administered saline, ILE, DigiFab and DigiFab and ILE. Following that, digoxin was infused to all groups until death except the control group. First arrhythmia and cardiac arrest observation times were recorded. According to the results, there was no statistically significant difference among the group in terms of first arrhythmia time and cardiac arrest times. However, when the saline group compared with ILE treated group separately, significant difference was observed. DigiFab, ILE or ILE-DigiFab treatment make no significant difference in terms of the first arrhythmia and cardiac arrest duration in digoxin-intoxicated rats. However, it is not possible to say that at the given doses, ILE treatment might be successful at least as a known antidote. The fact that the statistical significance between the two groups is not observed in the subgroup analysis, the study should be repeated with larger groups. PMID- 29397553 TI - The Uncertainty of the Association Between Proton Pump Inhibitor Use and the Risk of Dementia: Prescription Sequence Symmetry Analysis Using a Korean Healthcare Database Between 2002 and 2013. AB - INTRODUCTION: Studies have found an association between the use of proton pump inhibitors (PPIs) and dementia, but these findings may have been confounded by selection biases. OBJECTIVE: We used prescription sequence symmetry analysis (PSSA) to estimate the sequence ratio (SR) between PPI use and dementia compared with an active comparator, the use of histamine-2 receptor antagonists (H2RAs). METHODS: We conducted a PSSA on a nationwide South Korean database between 2002 and 2013. Exposure was defined as new PPI users, and outcome was defined as a new dementia diagnosis (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10] codes F00-03, F05.1, G30, G31.1, G31.9, G31.82). In this study, we applied the 3-year time window. So the patients who initiated PPIs 3 years before or after their first diagnosis of dementia were included. The pairs with the time window < 6 months were excluded to minimize the potential protopathic bias. The SR was calculated as the number of patients first diagnosed with dementia after initiating PPI (causal group) divided by the number of patients first diagnosed with dementia before the initiation of PPI (non causal group). The SR was adjusted (aSR) to avoid the distortion of results due to underlying trends in PPI use and dementia diagnosis over time. We calculated 95% confidence intervals (CIs) for the aSR. The analysis was repeated for initiators of H2RAs. Sensitivity analyses were conducted using 1-, 2-, and 6-year time windows and using the initiation of medication for dementia treatment (Anatomical Therapeutic Chemical code: N06D). RESULTS: Our results showed that the aSR of dementia and PPIs (7342 pairs, aSR 1.21 [95% CI 1.16-1.27]) was not higher than that for dementia and H2RAs (6170 pairs, aSR 1.91 [95% CI 1.80 2.02]). When we used various time windows and restricted the findings to the use of medication for treating dementia, the results were consistent with the main results. CONCLUSION: The risk of PPIs being associated with dementia may be overestimated. Further pharmacoepidemiological studies are needed to identify the risk of dementia with PPI use. PMID- 29397555 TI - The incidence and risk factors of related lymphedema for breast cancer survivors post-operation: a 2-year follow-up prospective cohort study. AB - PURPOSE: To investigate the incidence rate, severity and risk factors of related lymphedema in breast cancer survivors. METHODS: A 2-year follow-up prospective study of 387 women who had operation from four hospitals from January 1, to December 31, 2014 was conducted. Limb volume was measured by circumference and symptoms were measured using questionnaires pre-treatment and 1, 3, 6, 12, 18, 24 months after surgery separately. The incidence rates and the severity of lymphedema were evaluated, respectively. Risk factors for the development of breast cancer-related lymphedema (BCRL) were analyzed using log-rank test and Cox regression. RESULTS: The incidences of BCRL were 4.4, 10.1, 15.2, 28.6, 31.2 and 32.5% at 1, 3, 6, 12, 18, 24 months after surgery, respectively, measured by Norman questionnaire. The rates measured by arm circumference were 2.5, 6.7, 13.4, 21.4, 26.3 and 29.4%, respectively. About 114 (29.4% of 387) women were diagnosed with BCRL, and 78 of them got mild lymphedema. Axillary lymph node dissection (ALND) (HR = 5.2, 95% CI 1.6-17.3), radiotherapy (HR = 3.9, 95% CI 2.0 7.5), modified radical mastectomy (MRM) (HR = 2.1, 95% CI 1.3-3.4), the number of positive lymph nodes (HR = 1.1, 95% CI 1.0-1.2) and body mass index (BMI) (HR = 1.1, 95% CI 1.0-1.1) were independent risk factors for BCRL. CONCLUSIONS: BCRL is a common complication for breast cancer patients after surgery. It can be fairly diagnosed only 1 month post-operation and the cumulative incidence of BCRL seems to be increasing over time, especially in the first year after surgery. ALND, radiotherapy, MRM, the number of positive axillary lymph nodes and BMI were found to be independent risk factors in the development of BCRL in this study. PMID- 29397556 TI - Whole-Transcriptome Analysis of Mouse Models with MPTP-Induced Early Stages of Parkinson's Disease Reveals Stage-Specific Response of Transcriptome and a Possible Role of Myelin-Linked Genes in Neurodegeneration. AB - Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons. A whole-transcriptome analysis of the substantia nigra and striatum of an MPTP-induced mouse models of the earliest stages of PD was performed. Functional clustering of differentially represented transcripts revealed processes associated with the functioning of synapses, dendrites, axons, and myelination of neuronal projections. All of these processes occur in both the substantia nigra and striatum, but they are aimed at the functioning of neuron terminals in the striatum. One cluster was identified at the earliest stage modeled, i.e., "neuron projection" in the substantia nigra and "transport" in the striatum, and their number increased at subsequent stages. The number of clusters in the striatum predominates over those in the substantia nigra and there is a pronounced increase in the number of clusters from the modeled early stages to the late stages. These findings indicate that the substantia nigra and striatum have unique patterns of changes at each stage. Considering the clustering of individual processes, it was seen that there is a set of hierarchical clusters that overlap only partially at different stages and in different tissues. The data indicate a consistent involvement of the transcriptome in the pathogenesis of PD and highlight the independent role of various brain structures and individual parts of nerve cells in the formation of a response to the development of neurodegeneration. Decreased myelination of neuronal projections may be associated with the development of PD in the models considered. PMID- 29397557 TI - Targeting Histone Deacetylase Activity to Arrest Cell Growth and Promote Neural Differentiation in Ewing Sarcoma. AB - There is an urgent need for advances in the treatment of Ewing sarcoma (EWS), an aggressive childhood tumor with possible neuroectodermal origin. Inhibition of histone deacetylases (HDAC) can revert aberrant epigenetic states and reduce growth in different experimental cancer types. Here, we investigated whether the potent HDAC inhibitor, sodium butyrate (NaB), has the ability to reprogram EWS cells towards a more differentiated state and affect their growth and survival. Exposure of two EWS cell lines to NaB resulted in rapid and potent inhibition of HDAC activity (1 h, IC50 1.5 mM) and a significant arrest of cell cycle progression (72 h, IC50 0.68-0.76 mM), marked by G0/G1 accumulation. Delayed cell proliferation and reduced colony formation ability were observed in EWS cells after long-term culture. NaB-induced effects included suppression of cell proliferation accompanied by reduced transcriptional expression of the EWS-FLI1 fusion oncogene, decreased expression of key survival and pluripotency-associated genes, and re-expression of the differentiation neuronal marker betaIII-tubulin. Finally, NaB reduced c-MYC levels and impaired survival in putative EWS cancer stem cells. Our findings support the use of HDAC inhibition as a strategy to impair cell growth and survival and to reprogram EWS tumors towards differentiation. These results are consistent with our previous studies indicating that HDis can inhibit the growth and modulate differentiation of cells from other types of childhood pediatric tumors possibly originating from neural stem cells. PMID- 29397558 TI - Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression. AB - Excitotoxic stress has been associated with several different neurological disorders, and it is one of the main causes of neuronal degeneration and death. To identify new potential proteins that could represent key factors in excitotoxic stress and to study the relationship between polyamine catabolism and excitotoxic damage, a novel transgenic mouse line overexpressing spermine oxidase enzyme in the neocortex (Dach-SMOX) has been engineered. These transgenic mice are more susceptible to excitotoxic injury and display a higher oxidative stress, highlighted by 8-Oxo-2'-deoxyguanosine increase and activation of defense mechanisms, as demonstrated by the increase of nuclear factor erythroid 2-related factor 2 (Nrf-2) in the nucleus. In Dach-SMOX astrocytes and neurons, an alteration of the phosphorylated and non-phosphorylated subunits of glutamate receptors increases the kainic acid response in these mice. Moreover, a decrease in excitatory amino acid transporters and an increase in the system xc- transporter, a Nrf-2 target, was observed. Sulfasalazine, a system xc- transporter inhibitor, was shown to revert the increased susceptibility of Dach SMOX mice treated with kainic acid. We demonstrated that astrocytes play a crucial role in this process: neuronal spermine oxidase overexpression resulted in an alteration of glutamate excitability, in glutamate uptake and efflux in astrocytes involved in the synapse. Considering the involvement of oxidative stress in many neurodegenerative diseases, Dach-SMOX transgenic mouse can be considered as a suitable in vivo genetic model to study the involvement of spermine oxidase in excitotoxicity, which can be considered as a possible therapeutic target. PMID- 29397560 TI - Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats. AB - Impaired glucose metabolism and mitochondrial decay greatly increase with age, when cognitive decline becomes rampant. No pharmacological or dietary intervention has proven effective, but proper diet and lifestyle do postpone the onset of neurodegeneration and some nutrients are being investigated. We studied insulin signaling, mitochondrial activity and biogenesis, and synaptic signaling in the hippocampus and cortex following dietary supplementation with bioactive phospholipid concentrates of krill oil (KOC), buttermilk fat globule membranes (BMFC), and a combination of both in aged rats. After 3 months of supplementation, although all groups of animals showed clear signs of peripheral insulin resistance, the combination of KOC and BMFC was able to improve peripheral insulin sensitivity. We also explored brain energy balance. Interestingly, the hippocampus of supplemented rats-mainly when supplemented with BMFC or the combination of KOC and BMFC-showed an increase in intracellular adenosine triphosphate (ATP) levels, whereas no difference was observed in the cerebral cortex. Moreover, we found a significant increase of brain-derived neurotrophic factor (BDNF) in the hippocampus of BMFC+KO animals. In summary, dietary supplementation with KOC and/or BMFC improves peripheral and central insulin resistance, suggesting that their administration could delay the onset of these phenomena. Moreover, n-3 fatty acids (FAs) ingested as phospholipids increase BDNF levels favoring an improvement in energy state within neurons and facilitating both mitochondrial and protein synthesis, which are necessary for synaptic plasticity. Thus, dietary supplementation with n-3 FAs could protect local protein synthesis and energy balance within dendrites, favoring neuronal health and delaying cognitive decline associated to age-related disrepair. PMID- 29397559 TI - Anti-Oxidative Effects of Melatonin Receptor Agonist and Omega-3 Polyunsaturated Fatty Acids in Neuronal SH-SY5Y Cells: Deciphering Synergic Effects on Anti Depressant Mechanisms. AB - Omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) and melatonin receptor agonist ramelteon (RMT) both display antidepressant effects, while their cellular effects on anti-oxidative and neuroprotective mechanisms might be different. In this study, we aimed to decipher the individual and synergistic actions of n-3 PUFAs and RMT, as compared with the conventional antidepressant fluoxetine (FLX), in a cellular model of oxidative stress, which might play an important role in the pathophysiology of depression and associated disorders. We investigated the rescue and prevention effects of FLX, RMT, and n-3 PUFAs, e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by using cell viability in SH-SY5Y cells under oxidative stress along with measurements of key cellular markers of oxidative stress, inflammatory, and neuroprotection. The results revealed that the RMT and EPA combination significantly increased the cell viability in a dose dependent manner. RMT showed preventive effects, FLX and DHA possessed rescue effects, while EPA showed both rescue and preventive effects. We observed the dose-dependent activation and translocation of nuclear factor-kappaB to the nucleus augmented by the expressions of peroxisome proliferator activator receptor-gamma, tyrosine hydroxylase, c-Fos expression, and reactive oxygen species, implying that RMT and EPA combination reversed oxidative and neuroinflammatory pathophysiology and protected the neuronal cells from further damage. The results demonstrated that RMT and EPA synergistically provide effective neuroprotective, anti-oxidative/inflammatory effect against oxidative stress. Our study provides pre-clinical evidence to conduct future clinical trials of using n-3 PUFAs/RMT combination in depressive disorders. PMID- 29397562 TI - Intimate stimuli result in fronto-parietal activation changes in anorexia nervosa. AB - BACKGROUND: Intimacy is a key psychological problem in anorexia nervosa (AN). Empirical evidence, including neurobiological underpinnings, is however, scarce. OBJECTIVE: In this study, we evaluated various emotional stimuli including intimate stimuli experienced in patients with AN and non-patients, as well as their cerebral response. METHODS: Functional magnetic resonance imaging was conducted using stimuli with positive, neutral, negative and intimate content. Participants (14 AN patients and 14 non-patients) alternated between passive viewing and explicit emotion regulation. RESULTS: Intimate stimuli were experienced less positively in AN patients compared to non-patients. AN patients showed decreased cerebral responses in superior parietal cortices in response to positive and intimate stimuli. Intimate stimuli led to stronger activation of the orbitofrontal cortex, and lower activation of the bilateral precuneus in AN patients. Orbitofrontal responses decreased in AN patients during explicit emotion regulation. CONCLUSIONS: These results show that intimate stimuli are of particular importance in AN patients, who show experiential differences compared to non-patients and altered activation of orbitofrontal and parietal brain structures. This supports that AN patients have difficulties with intimacy, attachment, self-referential processing and body perception. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 29397561 TI - Effect of ezetimibe on glycemic control: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: Given the increased risk of incident diabetes and the side effects on glycemic control with statin treatment, statin and ezetimibe combination therapy has been widely used. However, whether the same concern exists in ezetimibe remains uncertain. This meta-analysis aimed to investigate the influence of ezetimibe treatment on glycemic control. METHODS: Articles were searched from PubMed, EMBASE, and Cochrane Library. Randomized controlled trials (RCTs) were included if they compared the effects of ezetimibe with placebo, ezetimibe plus statin with the same statin, or low-dose stain plus ezetimibe with high-dose statin on FBG and glycosylated hemoglobin A1c (HbA1c). RESULTS: Of the 2440 articles retrieved, 16 RCTs were included. Ezetimibe did not cause side effects on FBG (WMD -0.62, 95% CI: -3.13 to 1.90) and HbA1c (WMD 0.07, 95% CI: -0.07 to 0.20%). No significant changes in FBG (WMD -1.78, 95% CI: -6.33 to 2.77%) and HbA1c (WMD -0.05, 95% CI: -0.14 to 0.05%) were observed in ezetimibe plus low dose statin treatment compared with high-dose statin. According to subgroup analysis, in comparison with high-dose statin, ezetimibe plus low-dose statin taken for more than 3 months showed a significant decrease in FBG (WMD -7.12, 95% CI: -13.86 to -0.38%) compared with that taken for less than 3 months (WMD 0.90, 95% CI: -2.91 to 4.71%). Nevertheless, this difference was invalid when the study conducted by Dagli et al. was removed. CONCLUSIONS: Compared with high-dose statin therapy, ezetimibe with low-dose statin for more than 3 months may have a beneficial tendency of effects on glycemic control. PMID- 29397564 TI - Orthorexic and restrained eating behaviour in vegans, vegetarians, and individuals on a diet. AB - PURPOSE: Orthorexic eating behaviour, restrained eating, and veganism/vegetarianism are food selection strategies sharing several characteristics. Since there are no studies investigating their interrelationships, aim of the present study was to analyse orthorexic and restrained eating behaviour in (1) a sample of vegans and vegetarians and (2) a sample of individuals on a diet to lose weight. METHOD: Division of samples according to pre-defined criteria in (1) vegans (n = 114), vegetarians (n = 63), individuals with rare meat consumption (n = 83) and individuals with frequent meat consumption (n = 91) and in (2) participants on a diet with dietary change (n = 104), without dietary change (n = 37) and a control group of individuals not on a diet (n = 258). Orthorexic eating behaviour was assessed with the Dusseldorfer Orthorexie Skala and restrained eating was assessed with the Restraint Eating Scale. RESULTS: Vegans and vegetarians do not differ in orthorexic eating behaviour, but both groups score higher in orthorexic eating behaviour than individuals consuming red meat. There are no differences regarding restrained eating. Individuals on a diet with dietary change score higher in both orthorexic and restrained eating, than individuals without dietary change and individuals not on a diet. CONCLUSIONS: Individuals who restrict their eating behaviour, either predominantly due to ethical reasons or with the intention to lose weight, display more orthorexic eating behaviour than individuals not limiting their food consumption. Further research is needed to investigate whether veganism, vegetarianism, or frequent dieting behaviour serve as risk factors for orthorexia. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 29397563 TI - Insulin resistance in obesity: an overview of fundamental alterations. AB - Obesity is a major health risk factor, and obesity-induced morbidity and complications account for huge costs for affected individuals, families, healthcare systems, and society at large. In particular, obesity is strongly associated with the development of insulin resistance, which in turn plays a key role in the pathogenesis of obesity-associated cardiometabolic complications, including metabolic syndrome components, type 2 diabetes, and cardiovascular diseases. Insulin sensitive tissues, including adipose tissue, skeletal muscle, and liver, are profoundly affected by obesity both at biomolecular and functional levels. Altered adipose organ function may play a fundamental pathogenetic role once fat accumulation has ensued. Modulation of insulin sensitivity appears to be, at least in part, related to changes in redox balance and oxidative stress as well as inflammation, with a relevant underlying role for mitochondrial dysfunction that may exacerbate these alterations. Nutrients and substrates as well as systems involved in host-nutrient interactions, including gut microbiota, have been also identified as modulators of metabolic pathways controlling insulin action. This review aims at providing an overview of these concepts and their potential inter-relationships in the development of insulin resistance, with particular regard to changes in adipose organ and skeletal muscle. PMID- 29397566 TI - Artificial Neural Network for the Prediction of Chromosomal Abnormalities in Azoospermic Males. AB - PURPOSE: To evaluate whether an artifical neural network helps to diagnose any chromosomal abnormalities in azoospermic males. MATERIALS AND METHODS: The data of azoospermic males attending to a tertiary academic referral center were evaluated retrospectively. Height, total testicular volume, follicle stimulating hormone, luteinising hormone, total testosterone and ejaculate volume of the patients were used for the analyses. In artificial neural network, the data of 310 azoospermics were used as the education and 115 as the test set. Logistic regression analyses and discriminant analyses were performed for statistical analyses. The tests were re-analysed with a neural network. RESULTS: Both logistic regression analyses and artificial neural network predicted the presence or absence of chromosomal abnormalities with more than 95% accuracy. CONCLUSION: The use of artificial neural network model has yielded satisfactory results in terms of distinguishing patients whether they have any chromosomal abnormality or not. PMID- 29397567 TI - Evaluation of PAWP and PLC? Expression in Infertile Men with Previous ICSI Fertilization Failure. AB - PURPOSE: The aim of this study was to evaluate postacrosomal sheet WW domain binding protein (PAWP) and phospholipase C ? (PLC?) protein expression in patients with fertilization failure. MATERIALS AND METHODS: Semen samples were collected from 15 fertile men (control group) and 15 patients with previous fertilization failure following ICSI (FF group) and were analyzed according to World Health Organization (WHO) criteria. The mean percentages of PAWP and PLC? positive sperm and the total level of PAWP and PLC? proteins were assessed using immunofluorescence staining. RESULTS: A significantly lower level and lower percentage of PAWP positive sperm in patients with fertilization failure was found compared to the control group (P = 0.01 and P = 0.03, respectively). The mean percentage ofPLC? positive sperm and level of PLC? protein were significantly lower in FF group compared to the control group (P = 0.0003 and P = 0.04, respectively). Significant positive correlations was observed between PAWP and PLC? positive sperms (r = 0.4, P = 0.008) and also total level of expression of PLC? and PAWP proteins (r = 0.4, P = 0.02) in all participants in the study. CONCLUSION: This is the first study that evaluates two main candidates for sperm borne oocyte activating factors (SOAFs) simultaneously in patients with fertilization failure. Considering lower expression of PAWP and PLC? proteins in such patients, it seems like both factors might have the potential to be considered as SOAFs and diagnostic markers for the oocyte activation ability. PMID- 29397565 TI - Myt1L Promotes Differentiation of Oligodendrocyte Precursor Cells and is Necessary for Remyelination After Lysolecithin-Induced Demyelination. AB - The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1L in neuron/glia antigen 2-positive (NG2+) OPCs was significantly higher than that in mature CC1+ oligodendrocytes. In primary cultured OPCs, overexpression of Myt1L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. ChIP assays showed that Myt1L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1L is an essential regulator of OPC differentiation, thereby supporting Myt1L as a potential therapeutic target for demyelinating diseases. PMID- 29397568 TI - CYP2C19 and ABCB1 genetic polymorphisms correlate with the recurrence of ischemic cardiovascular adverse events after clopidogrel treatment. AB - BACKGROUND: This study was aimed to investigate the correlation between CYP2C19 and ABCB1 polymorphisms and the recurrence of ischemic cardiovascular adverse events in patients with coronary artery disease treated with clopidogrel. METHODS: A total of 168 patients with coronary heart disease who underwent PCI operation and received clopidogrel treatment were enrolled. Dual antiplatelet therapy was applied to the treatment of patients for 2 years. Thromboelastography was used to test the efficiency of blood coagulation. Polymerase chain reaction (PCR) was used to detect CYP2C19 and ABCB1 3435CT polymorphisms. One-year follow up visit was carried out to record the incidence of cardiovascular adverse events after drug-eluting stent implantation was inset. RESULTS: Follow-up visit results suggested that the patients with high on-treatment platelet reactivity (HPR) had a higher recurrence rate of cardiovascular adverse events after PCI operation and clopidogrel treatment. Gene polymorphism testing results indicated that patients with CYP2C19*3 had a significantly higher incidence of HPR, whereas CYP2C19*2 and ABCB1 3435CT were not significantly correlated with HPR. Multivariable logistic regression analysis showed that CYP2C19*3 might be an independent predictive factor of post-PCI HPR. In addition, CYP2C19*3 as well as post-PCI HPR could function as independent predictive factors of cardiovascular adverse events. CONCLUSION: CYP2C19*3 polymorphism could be an important predictive factor of HPR and ischemic cardiovascular adverse events after clopidogrel treatment. PMID- 29397569 TI - Impact of age on quality of life in patients with localized prostate cancer treated with high-dose rate brachytherapy combined with external beam radiotherapy. AB - OBJECTIVES: To evaluate age-related quality of life changes in patients with localized prostate cancer treated by high-dose rate brachytherapy combined with external beam radiation therapy. METHODS: A total of 172 patients with clinically localized prostate cancer were categorized to age groups <75 years and >=75 years. Changes in their quality of life were evaluated using the Japanese version of Medical Outcome Study 8-Items Short Form Health Survey, Expanded Prostate Cancer Index Composite and International Index of Erectile Function-5 at baseline, and followed up to 24 months after treatment. RESULTS: There were no significant differences in Medical Outcome Study 8-Items Short Form Health Survey scores, and urinary and bowel scores of the Expanded Prostate Cancer Index Composite for older men after treatment. International Index of Erectile Function 5 summary scores were significantly decreased in both groups. Although sexual function and sexual bother scores were decreased in patients aged <75 years, these scores were maintained in patients aged >=75 years. CONCLUSIONS: Quality of life of prostate cancer patients undergoing high-dose rate brachytherapy combined with external beam radiation therapy does not seem to be significantly affected by age. PMID- 29397570 TI - Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression. AB - BACKGROUND: Atypical depression may show lowered rather than raised short-term cortisol levels. Atypical major depressive episodes (A-MDE) may also be more closely linked to environmental factors and show overlap with somatic symptom disorders. Hair specimens allow measuring long-term cortisol levels. METHODS: Twenty-seven A-MDE and 44 NA-MDE patients and 40 matched controls were tested. Measures of hair cortisol concentration [HCC] covering the previous 3 months and short-term cortisol parameters (six saliva specimens to assess the cortisol awakening response [CAR] and total daily cortisol output calculated as the area under the curve [AUCg]) were taken alongside measures of environmental factors and clinical variables. RESULTS: There were no differences in HCC between the three groups (P = 0.8), and no difference in the CAR (P = 0.95). However, A-MDE showed lowered short-term cortisol output (AUCg) compared to controls (P = 0.04). A-MDE patients also reported a higher number of daily hassles, and higher levels of fatigue and impaired concentration than NA-MDE. CONCLUSIONS: Normal long-term (HCC) and reduced short-term (AUCg) cortisol levels in A-MDE could suggest a disrupted long-term cortisol rhythm, perhaps affected by environmental factors or by certain symptoms, such as mid-nocturnal insomnia. However, other underlying explanations for these findings should also be investigated in the future. PMID- 29397571 TI - The Suicidal Narrative and Its Relationship to the Suicide Crisis Syndrome and Recent Suicidal Behavior. AB - In this study, we introduce the construct of the suicidal narrative, a hypothetical personal narrative linked to imminent suicide, and explore its relationship to near-term suicidal risk and the suicide crisis syndrome (SCS). Psychiatric outpatients (N = 289) were administered the Columbia Suicide-Severity Rating Scale (C-SSRS), Suicide Crisis Inventory (SCI), and Suicide Narrative Inventory (SNI), a novel instrument combining the documented risk factors of Thwarted Belongingness, Perceived Burdensomeness, Humiliation, Social Defeat, Goal Disengagement, and Goal Reengagement. Dimensional measures of past month, lifetime, and past suicidal phenomena, incorporating ideation and behavior, were calculated from the C-SSRS. Structural equation modeling was used to explore the interaction among variables. Factor analysis of the SNI yielded two orthogonal factors, termed Interpersonal and Goal Orientation. The former factor was comprised of Perceived Burdensomeness, Social Defeat, Humiliation, and Thwarted Belongingness, the latter of Goal Disengagement and Goal Reengagement. The Interpersonal factor correlated with both SCS severity and suicidal phenomena in each time frame and the Goal Orientation factor with no other variable. As hypothesized, the proposed model was significant for the past month only. Our findings support the construct of the suicidal narrative and its function as a near-term suicidal risk factor. PMID- 29397572 TI - Robot-assisted laparoscopic partial nephrectomy versus laparoscopic partial nephrectomy: A propensity score-matched comparative analysis of surgical outcomes and preserved renal parenchymal volume. AB - OBJECTIVES: To compare surgical outcomes, including renal function and the preserved renal parenchymal volume, between robot-assisted laparoscopic partial nephrectomy and laparoscopic partial nephrectomy using propensity score-matched analyses. METHODS: In total, 253 patients, with a normal contralateral kidney, who underwent laparoscopic partial nephrectomy (n = 131) or robot-assisted laparoscopic partial nephrectomy (n = 122) with renal arterial clamping between 2010 and 2015, were included. Patients' background and tumor factors were adjusted by propensity score matching. Surgical outcomes, including postoperative renal function, complications, warm ischemia time and preserved renal parenchymal volume, evaluated by volumetric analysis, were compared between the surgical procedures. RESULTS: After matching, 64 patients were assigned to each group. The mean age was 56-57 years, and the mean tumor size was 22 mm. Approximately 50% of patients had low complexity tumors (RENAL nephrometry score 4-7). The incidence rate of acute kidney failure was significantly lower in the robot-assisted laparoscopic partial nephrectomy (11%) than laparoscopic partial nephrectomy (23%) group (P = 0.049), and warm ischemia time shorter in the robot-assisted laparoscopic partial nephrectomy (17 min) than laparoscopic partial nephrectomy (25 min) group (P < 0.0001). The preservation rate of renal function, measured by the estimated glomerular filtration rate, at 6 months post-surgery was 96% for robot-assisted laparoscopic partial nephrectomy and 90% for laparoscopic partial nephrectomy (P < 0.0001). The preserved renal parenchymal volume was higher for robot-assisted laparoscopic partial nephrectomy (89%) than laparoscopic partial nephrectomy (77%; P < 0.0001). The rate of perioperative complications, surgical margin status and length of hospital stay were equivalent for both techniques. CONCLUSIONS: Robot-assisted laparoscopic partial nephrectomy allows to achieve better preservation of renal function and parenchymal volume than laparoscopic partial nephrectomy. PMID- 29397574 TI - Carotid intima-media thickness as a target-organ damage and treatment-target: Need for a major revision? PMID- 29397573 TI - Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities. AB - BACKGROUND: Dynamin 1 is a protein involved in the synaptic vesicle cycle, which facilitates the exocytosis of neurotransmitters necessary for normal signaling and development in the central nervous system. Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy. All previously reported DNM1 pathogenic variants causing this severe phenotype occur in the GTPase and Middle domains of the dynamin 1 protein. METHODS: We used whole-exome sequencing to characterize the molecular basis of DD and autistic symptoms in two identical siblings. RESULTS: The twin siblings exhibit mild to moderate ID and autistic symptoms but no epileptic encephalopathy. Exome sequencing revealed a genetic variant, c.1603A>G (p.Lys535Glu), in the PH domain of dynamin 1. Previous in vitro studies showed that mutations at Lys535 inhibit endocytosis and impair PH loop binding to PIP2. CONCLUSIONS: Our data suggest a previously undescribed milder phenotype associated with a missense genetic variant in the PH domain of dynamin 1. PMID- 29397576 TI - Threats to global antimicrobial resistance control: Centrally approved and unapproved antibiotic formulations sold in India. AB - AIMS: Rising antimicrobial resistance (AMR) is a global health crisis. India has among the highest resistance rates and antibiotic consumption internationally. Extensive use of fixed-dose combination (FDC) antibiotics and of unapproved formulations are claimed contributory factors but there has been no systematic examination of formulations or volumes sold. The aim of the present study was to investigate the regulatory approval status and sales volumes of systemic antibiotics marketed in India. METHODS: This was an ecological study using regulatory records in India, the UK and the US to determine the approval status in each country of systemic antibiotic FDCs and single-drug formulations (SDFs) sold in India. Pharmatrac(r) sales data were used to determine the formulations and volumes sold (2007-2012), branded-product numbers and manufacturers. RESULTS: Of 118 systemic antibiotic FDC formulations sold in India, 43 (36%) were approved but 75 (64%) had no record of regulatory approval; four (3%) formulations were approved in the UK and/or US. Almost half of formulations (58/118; 49%) comprised dual antimicrobials, most unapproved in India (43/58; 74%), and many were pharmacologically problematic. In contrast, 80/86 (93%) SDFs were approved in India and over two-thirds in the UK and/or US. Total antibiotic sales increased by 26%, from 2056 million units (2007-08) to 2583 million units (2011-12). FDC sales rose by 38% vs. 20% for SDFs. By 2011-12, FDCs comprised one-third of sales (872 million units). Over one-third of FDCs sold (300.26 million units; 34.5%) were of unapproved formulations. Multinational companies manufactured unapproved formulations and accounted for 19% of all FDC and SDF sales annually. CONCLUSIONS: Sales in India of antibiotic FDCs, including unapproved formulations, are rising. In the context of increasing AMR rates nationally and globally, unapproved antibiotic FDCs undermine India's national AMR strategy and should be banned from sale. PMID- 29397575 TI - Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. AB - BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations. RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene. CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis. PMID- 29397577 TI - Aging affects the in vivo regenerative potential of human mesoangioblasts. AB - Sarcopenia is the age-related loss of muscle mass, strength, and function. Although the role of human satellite cells (SCs) as adult skeletal muscle stem cells has been deeply investigated, little is known about the impact of aging on muscle interstitial stem cells. Here, we isolated the non-SC CD56- fraction from human muscle biopsies of young and elderly subjects. The elderly interstitial cell population contained a higher number of CD15+ and PDGFRalpha+ cells when compared to young samples. In addition, we found that the CD56- /ALP+ cells were well represented as a multipotent stem cell population inside the CD56- fraction. CD56- /ALP+ /CD15- cells were clonogenic, and since they were myogenic and expressed NG2, alpha-SMA and PDGFRbeta can be considered mesoangioblasts (MABs). Interestingly, elderly MABs displayed a dramatic impairment in the myogenic differentiation ability in vitro and when transplanted in dystrophic immunodeficient Sgcb-null Rag2-null gammac-null mice. In addition, elderly MABs proliferated less, but yet retained other multilineage capabilities. Overall, our results indicate that aging negatively impacted on the regenerative potential of MABs and this should be carefully considered for potential therapeutic applications of MABs. PMID- 29397578 TI - Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin. AB - Activation of hepatic stellate cells (HSCs) is an integral component of the wound healing process in liver injury/inflammation. However, uncontrolled activation of HSCs leads to constant secretion of collagen-rich extracellular matrix (ECM) proteins, resulting in liver fibrosis. The enhanced ECM synthesis/secretion demands an uninterrupted supply of intracellular energy; however, there is a paucity of data on the bioenergetics, particularly the mitochondrial (mito) metabolism of fibrogenic HSCs. Here, using human and rat HSCs in vitro, we show that the mito-respiration, mito-membrane potential (Deltapsim) and cellular 'bioenergetic signature' distinguish fibrogenic HSCs from normal, less-active HSCs. Ex vivo, HSCs from mouse and rat models of liver fibrosis further confirmed the altered 'bioenergetic signature' of fibrogenic HSCs. Importantly, the distinctive elevation in mito-Deltapsim sensitized fibrogenic HSCs for selective inhibition by mitotropic doxorubicin while normal, less-active HSCs and healthy human primary hepatocytes remained minimally affected if not, unaffected. Thus, the increased mito-Deltapsim may provide an opportunity to selectively target fibrogenic HSCs in liver fibrosis. PMID- 29397579 TI - alpha-Motor neurons are spared from aging while their synaptic inputs degenerate in monkeys and mice. AB - Motor function deteriorates with advancing age, increasing the risk of adverse health outcomes. While it is well established that skeletal muscles and neuromuscular junctions (NMJs) degenerate with increasing age, the effect of aging on alpha-motor neurons and their innervating synaptic inputs remains largely unknown. In this study, we examined the soma of alpha-motor neurons and innervating synaptic inputs in the spinal cord of aged rhesus monkeys and mice, two species with vastly different lifespans. We found that, in both species, alpha-motor neurons retain their soma size despite an accumulation of large amounts of cellular waste or lipofuscin. Interestingly, the lipofuscin profile varied considerably, indicating that alpha-motor neurons age at different rates. Although the rate of aging varies, alpha-motor neurons do not atrophy in old age. In fact, there is no difference in the number of motor axons populating ventral roots in old mice compared to adult mice. Moreover, the transcripts and proteins associated with alpha-motor neurons do not decrease in the spinal cord of old mice. However, in aged rhesus monkeys and mice, there were fewer cholinergic and glutamatergic synaptic inputs directly abutting alpha-motor neurons, evidence that aging causes alpha-motor neurons to shed synaptic inputs. Thus, the loss of synaptic inputs may contribute to age-related dysfunction of alpha-motor neurons. These findings broaden our understanding of the degeneration of the somatic motor system that precipitates motor dysfunction with advancing age. PMID- 29397580 TI - GDF-15 is a better complimentary marker for risk stratification of arrhythmic death in non-ischaemic, dilated cardiomyopathy than soluble ST2. AB - Growth differentiation factor (GDF)-15 and soluble ST2 (sST2) are established prognostic markers in acute and chronic heart failure. Assessment of these biomarkers might improve arrhythmic risk stratification of patients with non ischaemic, dilated cardiomyopathy (DCM) based on left ventricular ejection fraction (LVEF). We studied the prognostic value of GDF-15 and sST2 for prediction of arrhythmic death (AD) and all-cause mortality in patients with DCM. We prospectively enrolled 52 patients with DCM and LVEF <= 50%. Primary end points were time to AD or resuscitated cardiac arrest (RCA), and secondary end point was all-cause mortality. The median follow-up time was 7 years. A cardiac death was observed in 20 patients, where 10 patients had an AD and 2 patients had a RCA. One patient died a non-cardiac death. GDF-15, but not sST2, was associated with increased risk of the AD/RCA with a hazard ratio (HR) of 2.1 (95% CI = 1.1 4.3; P = .031). GDF-15 remained an independent predictor of AD/RCA after adjustment for LVEF with adjusted HR of 2.2 (95% CI = 1.1-4.5; P = .028). Both GDF-15 and sST2 were independent predictors of all-cause mortality (adjusted HR = 2.4; 95% CI = 1.4-4.2; P = .003 vs HR = 1.6; 95% CI = 1.05-2.7; P = .030). In a model including GDF-15, sST2, LVEF and NYHA functional class, only GDF-15 was significantly associated with the secondary end-point (adjusted HR = 2.2; 95% CI = 1.05-5.2; P = .038). GDF-15 is superior to sST2 in prediction of fatal arrhythmic events and all-cause mortality in DCM. Assessment of GDF-15 could provide additional information on top of LVEF and help identifying patients at risk of arrhythmic death. PMID- 29397581 TI - Impact of different antihypertensives on carotid arterial wall thickness. AB - Hypertension has been associated with atherosclerosis and cardiovascular disease. Carotid intima media thickness is increased in hypertensive patients. But, the correlation between carotid intima media thickness and antihypertensive agents is still uncertain. Therefore, we investigated carotid intima media thickness based on types of antihypertensive agents. 1809 patients were enrolled in this study and it showed that 1079 hypertensive patients had thicker carotid intima media thickness than non-hypertensive patients, with carotid intima media thicknesses of (0.72 +/- 17 mm vs 0.64 +/- 15 mm, P < .001), (0.31 +/- 0.07 mm vs 0.30 +/- 0.06 mm, P < .001), and (0.41 +/- 0.13 mm vs 0.35 +/- 0.12 mm, P < .001). Additionally, hypertensive patients on beta-blockers also had thicker carotid intima media thickness than the non-beta-blocker group, with carotid intima media thicknesses of (0.74 +/- 0.18 mm vs 0.71 +/- 0.16 mm, P = .018), (0.33 +/- 0.09 mm vs 0.31 +/- 0.07 mm, P = .029), and (0.43 +/- 0.13 mm vs 0.40 +/- 0.13 mm, P = .035). Multivariate analysis showed that carotid intima thickness was only correlated with beta-blockers (odds ratio = 2.489, confidence interval = 1.183 5.239, P = .016); however, this study showed that beta-blocker could be associated with increased carotid wall thickness as well. PMID- 29397582 TI - Use of strategies to improve antihypertensive medication adherence within United States outpatient health care practices, DocStyles 2015-2016. AB - Patients' adherence to antihypertensive medications is key to controlling high blood pressure. Evidence-based strategies to improve adherence exist, but their use, individually and in combination, has not been described. 2015-2016 DocStyles data were analyzed to describe health care professionals' and their practices' use of 10 strategies to improve antihypertensive medication adherence across 3 categories: prescribing, education, and tracking/encouragement. Among 1590 respondents, a mean of using 5 strategies was reported, with individual strategy use ranging from 17.2% (providing patients adherence-related rewards) to 69.4% (prescribing once-daily regimens). Those with higher odds of using >=7 strategies and strategies across all 3 categories included: (1) nurse practitioners compared to family practitioners/internists and (2) health care professionals in practices with standardized hypertension treatment protocols who routinely recommend home blood pressure monitor use compared to respondents without those characteristics. Despite using an array of evidence-based adherence-promoting strategies, additional opportunities exist for health care professionals to provide adherence support among hypertensive patients. PMID- 29397583 TI - Post-stroke hypertension control and receipt of health care services among veterans. AB - Many ischemic stroke patients do not achieve goal blood pressure (BP < 140/90 mm Hg). To identify barriers to post-stroke hypertension management, we examined healthcare utilization and BP control in the year after index ischemic stroke admission. This retrospective cohort study included patients admitted for acute ischemic stroke to a VA hospital in fiscal year 2011 and who were discharged with a BP >= 140/90 mm Hg. One-year post-discharge, BP trajectories, utilization of primary care, specialty and ancillary services were studied. Among 265 patients, 246 (92.8%) were seen by primary care (PC) during the 1-year post-discharge; a median time to the first PC visit was 32 days (interquartile range: 53). Among N = 245 patients with post-discharge BP data, 103 (42.0%) achieved a mean BP < 140/90 mm Hg in the year post-discharge. Provider follow-ups were: neurology (51.7%), cardiology (14.0%), nephrology (7.2%), endocrinology (3.8%), and geriatrics (2.6%) and ancillary services (BP monitor [30.6%], pharmacy [20.0%], nutrition [8.3%], and telehealth [8%]). Non-adherence to medications was documented in 21.9% of patients and was observed more commonly among patients with uncontrolled compared with controlled BP (28.7% vs 15.5%; P = .02). The recurrent stroke rate did not differ among patients with uncontrolled (4.2%) compared with controlled BP (3.8%; P = .89). Few patients achieved goal BP in the year post-stroke. Visits to primary care were not timely. Underuse of specialty as well as ancillary services and provider perception of medication non-adherence were common. Future intervention studies seeking to improve post-stroke hypertension management should address these observed gaps in care. PMID- 29397585 TI - [Fluid work and the prevention of occupational risks: a needed revisit of occupational health and safety in today's information society]. PMID- 29397586 TI - [Archivos 2017: 20 years with Archivos]. PMID- 29397584 TI - Mineralocorticoid receptor antagonists for heart failure: a real-life observational study. AB - AIMS: Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients. METHODS AND RESULTS: We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA treated group (P < 0.001). MRA-treated patients had more severe heart failure (higher New York Heart Association class and lower left ventricular ejection fraction, kidney function, and peak VO2 ). At a propensity-score-matching analysis performed on 1587 patients, MRA-treated and MRA-untreated patients showed similar study endpoint values. CONCLUSIONS: In conclusion, MRA treatment does not affect the composite of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation in a real-life setting. A meticulous patient follow-up, as performed in trials, is likely needed to match the positive MRA-related benefits observed in clinical trials. PMID- 29397587 TI - [Occupational diseases of musicians: the price of perfection]. AB - BACKGROUND: Musicians suffer from a wide range of health problems related to their profession. The aim of this paper was to assess whether work-related musician diseases are included into the Official Spanish List of Occupational Diseases and, if so, to describe and quantify those recognized in recent years. METHODS: The Official Spanish List of Occupational Diseases was searched to identify occupational diseases affecting musicians. We then conducted an incidence study of those occupational diseases recognized under code 29.32 Composers, musicians and singers (CNO-2011) for the period 2007 to 2014. Cases and rates were described and represented by disease type, gender and year of recognition. RESULTS: Ten entries were identified as musician diseases in the official occupational disease list; mostly involved musculoskeletal disorders (MSD) and hearing loss. Mental health disorders and focal dystonia are not included in the list. In the period 2007-2014, 213 cases were identified, 120 for men and 93 for women. Of these, 81% were MSD, 11% hearing loss and 7% vocal cord nodules. The average incidence rate per 100,000 was 18.3 (19.1 in men and 17.3 in women). CONCLUSIONS: The official Spanish List of Occupational Diseases allows the recognition of most occupational diseases affecting musicians with the exception of focal dystonia and mental health disorders. Their inclusion should be evaluated. The highest incidence corresponds to musculoskeletal disorders. PMID- 29397588 TI - [Technostress in Communication and Technology Society: Scoping Literature Review from the Web of Science]. AB - AIM: To perform a scoping review on the state of the art of technostress, an emerging risks associated with the growing use of Information and Communication Technologies (ICT) in society. METHODS: a scoping review on technostress at work was performed using the Web of Science (WoS), using the key term "technostress work". The search was completed with a literature review of the selected articles. RESULTS: A total of 58 articles were identified, of which 30 were selected for full-text in-depth review. The manual search of the bibliography allowed us to analyze an additional 14 articles. Most of articles focus on the analysis on the precipitating and alleviating factors of technostress in workers, as well as the main consequences of the materialization of this risk on worker performance. There is a lack of empirical studies that allow organizations to establish strategies to adequately manage technostress. CONCLUSIONS: there is a need to delve further into technostress through empirical studies that are not only focused on proposing theoretical models for its conceptualization or identifying its consequences in organizations, but on proposing management strategies that reduce the impact of this new labor reality. Future lines of research are proposed to understand and adequately manage technostress in workers. PMID- 29397589 TI - [Pesticides and heat stress in the global epidemic of chronic kidney disease of non-traditional origin]. PMID- 29397590 TI - [Author's response: Pesticides and heat stress in the global epidemic of chronic kidney disease of non-traditional origin]. PMID- 29397591 TI - [Current status and challenge of basic research and clinical translation for inflammatory bowel disease in China]. PMID- 29397592 TI - [Clinical guidelines for perioperative management of gastric endoscopic submucosal dissection]. AB - Gastric cancer has become one of the important public health issues endangering people's health in China. Currently, endoscopic submucosal dissection (ESD) has been used as the curative procedure of early gastric cancer without lymph node metastasis. Endoscopic resection has several advantages, including less invasiveness, permitting en bloc, histologically completed resection, accurate pathological diagnosis, lower recurrent rate and rapid recovery. The perioperative period of ESD is the time of a patient's endoscopic operative procedure; more specifically, it includes ward admission, indication, contraindication, preoperative preparation, endoscopic operation, postoperative complications, recovery and the disposal of specimen. The aim of this guideline is to assist endoscopists in providing standardized operation to patients, as well as managing perioperative complications. PMID- 29397593 TI - [Chinese expert consensus on the use of Xuezhikang (2017 revised edition)]. AB - Xuezhikang, a Chinese traditional medicine, contains natural statin and is effective on dyslipidemia by inhibiting cholesterol synthesis. Xuezhikang therapy for 8 weeks in patients with hyperlipidemia reduced total cholesterol (TC) by 23%, low density lipoprotein cholesterol (LDL-C) by 28.5% and triglyceride(TG) by 36.5%, and increased high density lipoprotein cholesterol (HDL-C) by 19.6%, respectively. Data from China Coronary Secondary Prevention Study (CCSPS) showed that treatment with Xuezhikang lowered the risks of major coronary events, death from coronary heart disease, and all cause death in patients with myocardial infarction, indicating that Xuezhikang can be used in the primary and secondary prevention of cardiovascular disease. PMID- 29397594 TI - [Efficacy of probiotics on the treatment of non-alcoholic fatty liver disease]. AB - Objective: To study the clinical effect of probiotics in the treatment of non alcoholic fatty liver disease (NAFLD). Methods: A total of 200 patients with NAFLD were randomly divided into 4 groups: control group (routine treatment group) and combined treatment group A, B and C. Each group had equal patients. The control group received orally polyene phosphatidylcholine capsules; whereas combined group A, B and C were given orally the live "combined Bifidobacterium Lactobacillus and Enterococcus powder" , "two live combined Bacillus subtilis and Enterococcus" , and the both probiotics respectively. The duration of treatment was 1 month. Laboratory parameters were evaluated before treatment and thirtieth day after treatment, including cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol(LDL-C), alanine aminotransferase(ALT), aspartate aminotransferase (AST), fasting blood glucose (FPG), serum high molecular weight adiponectin (HMW-APN) and serum TNFalpha. Meanwhile the faece sample was collected for routine test and bacterial culture. Liver ultrasound scan was done in all patients. Results: In terms of blood lipids and blood glucose, each group improved after treatment with significant differences (P<0.05) except for HDL-C. As for liver function, serum ALT and AST decreased after treatment in each group; especially in combined group C which were lower than those of control group [(33.7+/-7.6) U/L vs. (45.0+/-8.5) U/L; (22.0+/-1.6) U/L vs. (29.4+/-3.7) U/L; P<0.05]. TNFalpha levels decreased after treatment in each group, in addition the values in combined group C was significantly lower than that of control group[(0.51+/-0.27) ug/L vs. (0.82+/ 0.28) ug/L, P<0.05]. Serum HMW-APN increased after treatment in each group, and the HMW-APN in combined C group was significantly higher than that of control group[(9.28+/-3.72) ug/L vs. (7.87+/-3.96)ug/L, P<0.05]. (5) After treatment, all groups showed improvement of fatty liver by ultrasound, but the difference between groups was not statistically significant. (6) Compared with before treatment, fecal flora in combined groups was all reduced (P<0.01), but it was comparable before and after treatment in control group. Conclusions: Probiotics improve intestinal microecological system in NAFLD patients via inhibiting TNFalpha and enhancing adiponectin, possibly resulting in regulating blood glucose, lipid metabolism, and protecting liver injury from NAFLD. PMID- 29397595 TI - [The impact of stress and personality on resilience of patients with ulcerative colitis]. AB - Objective: To study relevant factors that influence psychological resilience in patients with ulcerative colitis(UC), especially the role of perceived stress and personality. Methods: Patients with UC were recruited from January 2015 to December 2016 in the First Hospital of Zhengzhou University. Education levels, income, duration of disease, Mayo score and disease phenotype according to Montreal classification were collected. Resilience was measured using Connor Davidson resilience scale (CD-RISC). Perceived stress was measured by perceived stress scale (PSS). Personality was evaluated using Eysenck personality questionnaire (EPQ). Univariate analyses were conducted to determine the correlation of variables with resilience and thereafter those statistically significant were reanalyzed via a multivariate regression model. Results: A total of 188 patients with UC were finally recruited. Univariate analyses demonstrated resilience was inversely associated with perceived stress, Mayo score and neuroticism. Extraversion, income, college education were positively related to resilience. However, multivariate analyses revealed that perceived stress(OR=0.901, 95%CI 0.833-0.975), extraversion (OR=1.257, 95%CI 1.087-1.454), neuroticism (OR=0.818, 95%CI 0.679-0.985), Mayo score (OR=0.856, 95%CI 0.742 0.988) and income (OR=6.411, 95%CI 2.136-9.244) were significantly related to resilience. Conclusions: Resilience of UC patients is not only associated with disease activity, but also with personality, perceived stress and income. PMID- 29397596 TI - [The clinical characteristics of patients with monomorphic epitheliotropic intestinal T-cell lymphoma characterized by minor endoscopic abnormalities]. AB - Objective: To clarify the clinical features of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) with minor endoscopic abnormalities. Methods: The clinical data of 6 patients with MEITL characterized by minor endoscopic abnormalities in Peking Union Medical College Hospital from 2012 to 2016 were retrospectively analyzed, including clinical manifestations, endoscopic, pathological features, medications and prognosis. Results: Five out of 6 patients were male, with an average age of 61.2 years old. The median disease duration was 4.5 months. All patients initially presented with diarrhea without specific findings for serologic testing. CT enterography showed continuous intestinal lesions, including symmetric thickening of the bowel wall, abnormal hyperenhancement of mucosal surface and lymphadenopathy. Endoscopic appearances were only mildly abnormal, including mucosal swelling, atrophy of villus, mosaic sign and shallow ulcers. Histopathologic findings revealed massive small to medium sized T lymphocytes infiltration with positive expression of CD(3) and CD(8). Chemotherapy and palliative treatment were administrated after diagnosis. Conclusions: Clinical presentations of MEITL are non-specific with minor endoscopic abnormalities. Therefore, biopsy is indispensable for patients with a relatively normal endoscopic result. PMID- 29397597 TI - [An analysis of clinical characteristic and related risk factors in 208 cirrhotic patients complicated with infections]. AB - Objective: To analyze the clinical features and risk factors of cirrhotic patients complicated with infections. Methods: The clinical and laboratory characteristics of cirrhotic patients complicated with infections hospitalized from April 2014 to June 2017 were retrospectively analyzed. Relevant risk factors for infection and mortality were explored. Results: The overall incidence of infections was 17.6% in 1 670 hospitalized cirrhotic patients. Among the recruited 208 patients in this study, alcoholic, viral hepatitis B or C and autoimmune liver diseases accounted for 29.8% (62/208), 26.0% (54/208), and 22.1% (46/208), respectively. The most common infection site was respiratory tract (70.2%), followed by urinary tract, intestinal and intra-abdomen. Forty-six pathogens were isolated from 32 patients, including 22 (47.8%) Gram negative bacteria, 16 (34.8%) Gram positive bacteria and 2(4.3%) mycobacterium tuberculosis, 5 (10.9%) fungi and 1 (2.2%) mycoplasma. The mortality in patients with nosocomial infections (16.7%,7/42) was higher than that in patients with community-acquired infections (6.0%,10/166, P=0.025). All 17 deaths occurred in decompensated cirrhosis. Multivariate analysis demonstrated that hepatic encephalopathy and prothrombin time were independent risk factors of mortality. Conclusions: Patients with decompensated cirrhosis are more susceptible to infections. Hepatic encephalopathy and prothrombin time are independent risk factors for death. PMID- 29397598 TI - [The clinical significance of microcirculation and oxygen metabolism evaluation in acute kidney injury assessment in patients with septic shock after resuscitation]. AB - Objective: To evaluate the value of microcirculation and oxygen metabolism evaluation (MicrOME) in acute kidney injury(AKI) evaluation in patients with septic shock after resuscitation. Methods: Consecutive patients with septic shock after resuscitation and mechanical ventilation were enrolled from October 2016 to February 2017 in ICU at Peking Union Medical College Hospital.Patients were divided into 3 groups based on 10 min transcutaneous oxygen challenge test transcutaneous partial pressure of oxygen(PtcO(2))and venoarterial pressure of carbon dioxide difference (Pv-aCO(2)) /arteriovenous O(2) content difference (Ca vO(2)) by blood gas analysis, i.e. group A [DeltaPtcO(2)>66 mmHg(1 mmHg=0.133 kPa) and Pv-aCO(2)/Ca-vO(2)<=1.23], group B (DeltaPtcO(2)<=66 mmHg), group C (DeltaPtcO(2)>66 mmHg and Pv-aCO(2)/Ca-vO(2)>1.23). Heart rate,mean arterial pressure,central venous pressure,noradrenaline dose,lactate,Pv-aCO(2),Ca-vO(2), lactate clearance, central venous oxygen saturation(ScvO(2)) and liquid equilibrium were assessed after resuscitation.AKI staging based on Kidney Disease Global Improving Outcomes (KDIGO) clinical practice guideline was analyzed. The predictive value of lactate, ScvO(2), Pv-aCO(2)/Ca-vO(2) to progression of AKI after resuscitation was determined using receiver operating characteristic(ROC)curve analysis. Results: A total of 49 septic shock patients were enrolled including 30 males and 19 females with mean age of (61.10+/ 17.10)years old.There were 19 patients in group A,21 patients in group B, and 9 patients in group C. Acute physiology and chronic health evaluation II score was 20.92+/-7.19 and sequential organ failure assessment score 12.02+/-3.28. There were 4 patients with AKI and 1 progressed in group A, 11 patients with AKI and 2 progressed in group B, 6 patients with AKI and 4 progressed in group C. The cutoff value of Pv-aCO(2)/Ca-vO(2) was equal or more than 2.20 for predicting progression of AKI, resulting in a sensitivity of 85.7% and a specificity of 73.8%. Conclusion: MicrOME is a significant parameter to predict the progression of AKI in patients with septic shock after resuscitation. Pv-aCO(2)/Ca-vO(2) is also a good predictive factor. PMID- 29397599 TI - [The clinical characteristics of Takayasu's arteritis with glomerulonephropathy]. AB - Objective: To investigate the clinical features of Takayasu's arteritis (TAK) with glomerulonephropathy and to improve physicians' understanding of this complication in patients with TAK. Methods: Clinical data were retrospectively collected including manifestations, laboratory tests, image findings and treatment of 8 patients diagnosed as Takayasu's arteritis with glomerulonephropathy from January 2002 to January 2017 in Peking Union Medical College Hospital. Results: Glomerulonephropathy was confirmed based on percutaneous renal biopsy. There were 6 women and 2 men. The median onset age and median disease duration were 24 (18-37) years and 42 (3-360) months, respectively. Five patients had hypertension. The 24 hour urinary protein was 0.18-14.91 g. Red blood cells and casts in urine were tested among 4 and 2 patients, respectively. Three patients had renal artery stenosis. Three patients demonstrated mesangial proliferative glomerulonephritis, two with IgA nephropathy, two with minimal change disease and one with membranoproliferative glomerulonephritis. Seven patients received glucocorticoid combined with cyclophosphamide therapy (glucocorticoid 40-60 mg/d, prednisone or equivalent; cyclophosphamide 0.4 g/week iv. or cyclophosphamide 0.1 g/d po.). Uninary blood cells removed and 24 hour urinary protein decreased from 1.65 g to 0.90 g after treatment for 12 months in one patient. The other 7 patients were missing. Conclusion: Glomerulonephropathy is occasionally observed among TAK patients. Mesangial proliferative glomerulonephritis is the most common pathological subtype. Glucocorticoid combined with cyclophosphamide therapy could be an optional therapy for Takayasu's arteritis with glomerulonephropathy. PMID- 29397600 TI - [A comparison of clinical characteristics between 2 pedigrees of multiple endocrine neoplasia type 2A with different RET mutations]. AB - Multiple endocrine neoplasia type 2A (MEN2A) is a hereditary syndrome. Here, two different RET proto-oncogen mutation were identified from family members of two MEN2A pedigrees by genetic screening. One RET mutations were found at codons 1893 and 1895 in exon 11 (1893-1895delCGA) from pedigree 1, which is a novel mutation, the other occurs at codon 634 (Cys634Arg) in exon 11 from pedigree 2. However, the clinical characteristics were similar in the patients of the two pedigrees. All the patients were in middle-age at onset. Most of them were firstly diagnosed with bilateral adrenal pheochromocytoma with different degrees of thyroid abnormalities (elevated serum calcitonin with or without thyroid mass, or had been diagnosed with medullary thyroid carcinoma). Some family members were with elevated serum parathyroid hormone but with no other evidences for hyperparathyroidism. PMID- 29397601 TI - [A case report of PPP syndrome]. PMID- 29397602 TI - [A pedigree report of a new gene mutation leading to HSD17B3 deficiency]. PMID- 29397603 TI - [A case report of afatinib-induced interstitial lung disease]. PMID- 29397604 TI - [The pitfall of early treatment for acute pancreatitis]. PMID- 29397605 TI - [The diagnosis and treatment of hypertriglyceridemic pancreatitis]. PMID- 29397606 TI - [What is a teaching clinic for resident?] PMID- 29397607 TI - [Advances in diagnosis and treatment of renal-related monoclonal gammopathy]. PMID- 29397608 TI - [Strengthen standardization of pharmacological clinical trials for chronic obstructive pulmonary disease in China]. PMID- 29397609 TI - [New strategy for the endocrinotherapy of breast cancer]. PMID- 29397610 TI - [Application of decision curve on evaluation of MRI predictive model for early assessing pathological complete response to neoadjuvant therapy in breast cancer]. AB - Objective: To construct a dynamic enhanced MR based predictive model for early assessing pathological complete response (pCR) to neoadjuvant therapy in breast cancer, and to evaluate the clinical benefit of the model by using decision curve. Methods: From December 2005 to December 2007, 170 patients with breast cancer treated with neoadjuvant therapy were identified and their MR images before neoadjuvant therapy and at the end of the first cycle of neoadjuvant therapy were collected. Logistic regression model was used to detect independent factors for predicting pCR and construct the predictive model accordingly, then receiver operating characteristic (ROC) curve and decision curve were used to evaluate the predictive model. Results: DeltaArea(max) and Deltaslope(max) were independent predictive factors for pCR, OR=0.942 (95%CI: 0.918-0.967) and 0.961 (95%CI: 0.940-0.987), respectively. The area under ROC curve (AUC) for the constructed model was 0.886 (95%CI: 0.820-0.951). Decision curve showed that in the range of the threshold probability above 0.4, the predictive model presented increased net benefit as the threshold probability increased. Conclusions: The constructed predictive model for pCR is of potential clinical value, with an AUC>0.85. Meanwhile, decision curve analysis indicates the constructed predictive model has net benefit from 3 to 8 percent in the likely range of probability threshold from 80% to 90%. PMID- 29397611 TI - [The expression of LTBP2 in breast cancer and its clinical significance]. AB - Objective: To explore the expression of latent transforming growth factor (TGF) beta binding protein 2 (LTBP2) in breast cancer and its clinical significance. Methods: Immunohistochemistry was used to detect the expression of LTBP2 in 125 cases of breast cancer tissue and normal breast tissue. Relationship between the expression of LTBP2 and estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, and its relationship with clinicopathological parameters of breast cancer were analyzed. Results: The positive expression of LTBP2 in breast cancer tissues (55.20%) was significantly higher than that in adjacent normal breast tissues (28.80%) (P<0.001). The expression of LTBP2 in breast cancer tissues was correlated with the clinical stage (chi(2)=4.516, P=0.034), over-expression of ER (chi(2)=7.112, P=0.008) and Ki67(chi(2)=4.024, P=0.045) and other adverse prognostic factors. Conclusion: Positive expression of LTBP2 in breast cancer plays an important role in the development and progression of breast cancer, and may be a marker of prognosis of patients. PMID- 29397612 TI - [Effect of HIF-2alpha on the biological characteristics of breast cancer stem cells]. AB - Objective: To explore the effect of hypoxia inducible factor (HIF)-2alpha on biological characteristics of breast cancer stem cells (BCSCs). Methods: Stem cells were isolated and purified from MCF-7 cells by using the immunomagnetic microbeads. HIF-2alpha ORF/shRNA lentiviral vectors were transduced into MCF-7 stem cells respectively, and then the stable stem cell lines were detected and gained. Using the method of Cell Counting Kit-8 (CCK-8) and flow cytometry, the effect of HIF-2alpha on cell vitality and apoptosis of MCF-7 cancer stem cells (CSCs) were tested. Serum-free suspension culture was used on MCF-7 cells to get breast CSCs microspheres. The expression of CD44(+) in different groups were detected by flow cytometry. Tumor-bearing nude mice model was established to compare tumor growth rate and pulmonary metastasis probability of MCF-7 CSC HIF 2alpha knock up/down in vivo. Results: Compared with MCF-7 CSC group, the apoptosis rate of MCF-7 CSCs HIF-2alpha knockup group decreased obviously and cell proliferation activity increased significantly (all P<0.05). However, the MCF-7 CSCs HIF-2alpha knock down group had the opposite trend. Results of flow cytometry showed that the proportion of CD44(+) cells in HIF-2alpha knock up group(93.0%)was much higher than MCF-7 group(83.8%)and MCF-7 HIF-2alpha knock down group(51.6%). The tumor growth rate, quality and lung metastasis rate of MCF 7 CSC HIF-2alpha knock up group were significantly higher than those in MCF-7 CSCs group and MCF-7 CSCs HIF-2alpha knock down group (P<0.01). Conclusions: In hypoxic microenvironment, up-regulation of HIF-2alphapromoted the formation of MCF-7 CSCs. Over-expression of HIF-2alpha can promote proliferation and inhibit apoptosis of MCF-7 CSCs, and thus increase the risk of tumorigenic ablility and pulmonary metastasis. PMID- 29397613 TI - [Prognosis and its risk factors in ANCA-associated glomerulonephritis patients treated with initial renal replacement therapy]. AB - Objective: To explore the prognosis and its risk factors in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) patients who needed initial renal replacement therapy (RRT). Methods: One hundred patients [54 females, 46 males, with a median age of 54(41, 60) years] with biopsy-proven AAGN and requiring initial RRT between January 1996 and December 2016 in Nanjing Jinling Hospital were included. Intensive immunotherapy indicated that the patients received corticosteroids in combination with cyclophosphamide or mycophenolate mofetil, or immunoadsorption (IA) or double filtration plasmapheresis (DFPP). The clinical and histological risk factors for renal survival were analyzed. Results: Forty-one patients were free of RRT after a median time of 1 (0.5, 2) month treatment (dialysis-independent group), and the remaining 59 patients were on maintenance dialysis (dialysis-dependent group). The multivariate logistic analysis revealed that the proportion of normal glomeruli <8% (OR=5.95, P=0.002) and global sclerotic glomeruli >=50% (OR=4.87, P=0.003), and not receiving intensive immunotherapy (OR=7.81, P=0.004) were the risk factors for the renal recovery in these patients. During a median follow-up time of 22 (10, 50) months, 15 patients(36.6%) in the dialysis-independent group progressed into maintenance dialysis, and the 1 and 3 year renal survival rate were 86% and 60%, respectively. During a median follow-up time of 6 (2, 24) months, 12 (12%) patients died, among whom four patients died of therapy. The multivariate Cox regression analysis revealed that IA/DFPP treatment (HR=10.85, P=0.034) and low albumin level (HR=1.26, P=0.009) significantly associated with a higher risk of therapy-related death. Conclusions: The renal recovery rate in AAGN patients with initial RRT was low. The proportion of normal and global sclerotic glomeruli, receiving intensive immunotherapy or not were associated with renal outcome, and IA/DFPP treatment as well as lower albumin level were independently associated with therapy-related death. PMID- 29397614 TI - [Analysis of clinical characteristics of paraganglioma in 42 patients]. AB - Objective: To summarize the clinical characteristics of paraganglioma. Methods: A total of 215 pheochromocytoma/ paraganglioma cases in Peking University First Hospital between January 1996 and December 2014 were retrospectively analyzed. The patients were divided into two groups according to the tumor position: pheochromacytoma group (173 patients) and paraganglioma group (42 patients). Then the clinical characteristics between the groups were compared. Results: There were 42 paraganglioma cases in the study, accounting for 19.5%. The most common position was retroperitoneum (66.7%, 28/42), followed by bladder (19.0%, 8/42), para-aorta (11.9%, 5/42) and pelvic cavity (2.4%, 1/42). Sixty-nine percent (29/42) of patients had different degree of hypertension, while up to 31.0% (13/42) was silent type. There was no statistical difference between the two groups in severity of hypertension, age, gender, duration, abnormal glucose metabolism, and the incidence of hypokalemia( all P>0.05). Adrenaline level was higher in pheochromocytoma group (13.4% vs 9.5%, P=0.004), while noradrenaline level was higher in paraganglioma group (80.8% vs 59.2%, P=0.001). Malignancy (21.4% vs 4.6%, P<0.001) and bigger tumor size [(6.67+/-3.24)cm vs (5.55+/ 2.76)cm, P=0.024] was more common in paraganglioma group. The maximum tumor volume was 18.0 cm*18.0 cm*10.5 cm vs 14.0 cm*13.0 cm*7.0 cm, while the minimum was 1.8 cm*1.3 cm*1.3 cm vs 1.2 cm*1.0 cm*1.0 cm. There was no significant difference in the pathological manifestations between the two groups. In the study, 11.9% (5/42) of patients in paraganglioma group was misdiagnosed or indefinite at the early diagnosis. Conclusion: Compared with pheochromocytoma, paraganglioma has the characteristics of widely distribution, more various clinical performance, more silent type and higher malignant rate. It is critical to put emphasis on its early diagnosis and treatment. PMID- 29397615 TI - [Clinical features and gene mutation analysis of patients with Niemann-Pick disease type C]. AB - Objective: To analyze the clinical manifestations, therapeutic efficacy, prognosis and characteristics of NPC1 mutation in Chinese patients with Niemann Pick disease type C(NPC). Methods: Ten unrelated Chinese NPC patients were diagnosed by NPC1 mutation analysis from July 2013 to February 2017 in Beijing Tian Tan Hospital of Capital Medical University. Clinical data of 10 cases were analyzed retrospectively which included clinical manifestations, laboratory results and NPC1 gene mutation features, and a series of follow-up were carried out about therapeutic efficacy and prognosis. Results: Ten patients suffering from NPC included 5 males and 5 females, aged from 42 days to 14 years when they presented to Tian Tan Hospital. According to their age of neurological onset, 4 were in early infantile period, 2 in late infantile period, 2 in juvenile periods, and the other 2 cases in neonatal period. They all presented with splenomegaly, 5 of 10 accompanied with hepatomegaly. Two cases of neonatal subtype presented mainly with delayed neonatal cholestatic jaundice and hepatosplenomegaly, accompanied with decreased muscle tone and slight psychomotor retardation. The other 8 cases presented with severe neurological involvement, such as progressive encephalopathy, ataxia and language impairment, 4 with dystonia, 3 with decreased muscle tension, 5 with vertical supranuclear gaze palsy, 5 with gelastic cataplexy, and 4 with epilepsy. Eight of 9 cases presented with foam cells in their bone marrow. Head MRI showed diffuse cerebral atrophy in 8 cases, thin corpus callosum in 2 cases, and brain white matter abnormal signals in 2 cases. Among 10 cases, 18 different mutations of NPC1 allelic genes were identified including 11 reported mutations, 3 novel missense mutations: c. 3683T>C (p.Met1128Thr), c.1926G>C (p.Met642Iie) and c. 3006C>G (p.Phe1002Leu), 2 novel nonsense mutation: c. 1142G>A(p.Trp381Ter ) and c. 3229C>T(p.Arg1077Ter), 1 novel minimal deletion mutation: c. 1385-1386del, and 1 novel intron mutation: c. 1757+ 5G>A. In 5 cases, the symptom of gelastic cataplexy was alleviated by imipramine, and the convulsion was relieved by valproate in 2 cases, by carbamazepine in 1 case at the beginning of seizure. During the 25 (3-66) months of follow-up, 4 cases died, the others' neurological symptoms were deteriorated progressively. Conclusions: The NPC1 gene mutation were high heterozygous in this group, and 7 novel mutations enriched the gene mutation spectrum of NPC1. The neurological manifestations were complicated in patients with NPC, and the symptomatology would be different according to their onset age of neurological symptoms. There might be effective symptomatic treatment for gelastic cataplexy by imipramine and for convulsion by valproate or carbamazepine. PMID- 29397616 TI - [Relationship between C-C chemokine receptor type 2 and P38 mitogen-activated protein kinase signaling pathway in the spinal cord of rats with bone cancer pain]. AB - Objective: To investigate the relationship between C-C chemokine receptor type 2(CCR2) and P38 mitogen-activated protein kinase (P38MAPK) signaling pathway in the spinal cord of rats and further clarify the mechanism of bone cancer pain (BCP). Methods: A total of 92 healthy female SD rats, of which 60 were subjected to behavioral tests using a ciliary mechanical stimulation needle. SD rats were randomly divided into six groups: sham operation group (group S), bone cancer pain group (group B), sham operation + DMSO solvent group (group SD), bone cancer pain + DMSO solvent group (group BD), sham operation + RS102895 CCR2 inhibitor group (group SR), bone cancer pain + RS102895 CCR2 inhibitor group (group BR), and Von Frey was used in the behavioral test. Another 32 SD rats were randomly divided into the following 8 groups (n=4): sham operation group (group S), bone cancer pain 5 d group (group B5), bone cancer pain 9 d group (group B9), bone cancer pain 14 d group (group B14), bone cancer pain + DMSO solvent group (group BD), bone cancer pain + RS102895 CCR2 inhibitor 0.5 h group (group BR0.5 h), bone cancer pain + RS102895 CCR2 inhibitor 4 h group (group BR4 h), bone cancer pain + RS102895 CCR2 inhibitor 12 h group (group BR12 h). Western blot was used to detect the expression of P38, p-P38 and CCR2 in spinal cord of rats. Results: At day 5, 7, 9, 14, 21 post-injection, mechanical withdrawal thresholds of group S were(30.9+/-1.5), (31.9+/-1.2), (32.0+/-1.1), (31.6+/-1.5), (32.2+/-1.4)g respectively, the mechanical withdrawal thresholds of group B were( 26.4+/-0.7), (24.4+/-0.8), (21.4+/-0.8), (13.5+/-0.4), (9.9+/-0.2)g respectively, the mechanical withdrawal thresholds in group B decreased obviously versus group S, and the differences were statistically significant(t=-13.177, -16.660, -23.778, 35.574, -48.401, all P<0.01). At day 9 post-injection, the mechanical withdrawal thresholds in SD, BD, SR and BR groups were (32.4+/-1.7), (19.4+/-1.1), (32.1+/ 1.3), (26.3+/-1.0) g respectively, the difference was statistically significant (F=224.681, P<0.01), and the mechanical withdrawal thresholds in group BD decreased obviously versus group SD, while the mechanical withdrawal thresholds in group BR increased obviously versus group BD. The expression levels of p-P38 in spinal cord of group S, group B5, group B9 and group B14 were(0.08+/-0.03), (0.20+/-0.05), (0.40+/-0.17), (0.65+/-0.14)respectively, the expression levels of CCR2 were(0.08+/-0.04), (0.18+/-0.05), (0.30+/-0.09), (0.58+/-0.07)respectively, the difference was statistically significant(F=19.123, 40.746, all P<0.01), and the expression of p-P38 and CCR2 in group B9 were showed a significant up regulation versus group S. The expression levels of p-P38 in spinal cord of group BD, group BR0.5 h, group BR4 h and group BR12 h were (0.57+/-0.06), (0.17+/ 0.11), (0.03+/-0.01), (0.25+/-0.11)respectively, and the difference was statistically significant(F=29.582, P<0.01). The expression of p-P38 in group BR0.5 h, BR4 h, BR12 h showed a significant down-regulation versus group BD. Conclusion: CCR2 in the spinal cord may be involved in the development of bone cancer pain by activating P38MAPK signaling pathway in rats. PMID- 29397617 TI - [The research of the innate defense regulator peptide on the effects of methicillin resistant staphylococcus aureus biofilm]. AB - Objective: To investigate the destruction of the mature biofilm and the inhibitory effect of the biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) by different concentrations of the innate defense regulatory peptide (IDR-1018). Methods: 1 *10(5)CFU /ml MRSA was inoculated uniformly into 96 well plates, the biofilm model would be completed after 48 h. Given the different concentration of IDR-1018 solution as the experimental group double diluted with tryptic soy broth (TSB), the concentration in bacteria suspension reached 3.75-1 000 mg/L respectively. Erythromycin is double diluted into different concentration gradient, combined with low concentration (15 mg/L) of IDR-1018 as the mixed group.The same amount of TSB treated as the blank control group. The growth of the biofilm was measured through the measurement of the value of absorbance (A)by the semi-quantitative method of crystal violet staining at 24 h. Using SPSS 18.0 as statistical software to analyze the data. Results: Compared with the control group (A(595)=1.764 +/- 0.026), IDR-1018 significantly damaged the mature MRSA biofilm, and function was worked in a dose dependent method. With decreasing drug concentration, the destruction of the biofilm decreased correspondingly. When the concentration was as low as 15 mg/L, A(595) = 0.946 +/- 0.047(t=32.955, P<0.01). When the concentration was 7.5 mg/L, A(595) = 1.211+/-0.054 (t=12.731, P<0.05). When the concentration was 3.75 mg/L, A(595)=1.360+/-0.066(t=4.843, P<0.05), the difference was still statistically significant compared with the control group. For the immature biofilm, compared with the control group(A(595)=1.689+/-0.068), IDR-1018 still had a significant inhibitory effect on the formation process of MRSA biofilm when the concentration was as low as 15 mg/L (A(595)=0.846+/-0.057, t=34.127, P<0.01). The inhibition of biofilm had a certain decline, when the concentration was 7.5 mg/L (A(595)=1.402 +/- 0.181, t=5.240, P<0.05). But the difference was still statistically significant compared with the control group. However, the inhibitory effect was significantly decreased when the concentration was 3.75 mg/L (A(595)=1.631+/ 0.190, t=0.913, P>0.05). When the low concentration (15 mg/L) of IDR-1018 and different concentrations of erythromycin were used together, the destruction and inhibition of MRSA biofilm was significantly higher than using erythromycin or IDR-1018 alone. Conclusion: IDR-1018 can play a good inhibitory role in the formation process of MRSA biofilm, and can play a good role in destroying MRSA biofilm. PMID- 29397618 TI - [The consensus on nutritional and multi-disciplinary management for bariatric surgery]. AB - Obesity is associated with many chronic diseases and has become a major public health problem all over the world. Although weight loss includes lifestyle modification, psychological and medical treatment, bariatric surgery remains an effective treatment for morbidly obese patients. Due to the lack of multidisciplinary management and long-term nutrition monitoring, some patients are suffering from malnutrition, functional impairment and other issues after bariatric surgery. This consensus is commissioned by the Nutrition and Metabolism Cooperation Group of Chinese Society for Parenteral and Enteral Nutrition and Bariatric Multidisciplinary Team of Peking Union Medical College Hospital. This consensus summarizes the latest research results and refers to some recommendations in guidelines both at home and abroad. The detailed evidence based recommendations allow for nuance-based clinical decision-making that addresses the multiple aspects of real-world medical care of patients with obesity to develop consensus on bariatric surgery and nutritional management among obese patients in multidisciplinary mode, including preoperative evaluation, perioperative management, postoperative long-term follow-up and nutritional management. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientifically based approach to management that optimizes health outcomes and safety. PMID- 29397619 TI - [Consensus of Chinese experts on the application of molecular imaging targeting prostate specific membrane antigen in prostate cancer patients]. AB - Recently, prostate cancer has become the most common male urological cancer worldwide. However, it was difficult for the currently widely available imaging modalities to precisely diagnose this disease. With the development of nuclear medical technology, molecular imaging targeting prostate specific membrane antigen has been introduced into China. To promote the standardization of this imaging modality, the experts consensus was published by Chinese Anticancer Association Genitourinary Oncology Committee and recommendations for its application in the diagnosis and treatment of prostate cancer were attached, which would be helpful for doctors who are conducting or preparing for this examination. PMID- 29397620 TI - [Ten hot issues of breast cancer in diagnosis and therapy in 2018]. AB - The rigorous randomized clinical trials and qualified real world evidence have improved the domestic standardized diagnosis and therapy. Meanwhile, the recent consensus and guideline integrated with Chinese realities have also promoted the breast cancer therapy. To expound our views and to provide suggestions for the revision of breast cancer guideline of Chinese Society of Clinical Oncology, we select ten hot issues to discuss with our experience. PMID- 29397621 TI - [Thoughts on optimizing the breast cancer screening strategies and implementation effects]. AB - Reasonable and effective breast cancer screening can make early diagnosis of breast cancer, improve the cure rate, prolong survival and improve the patients' quality of life. China has made preliminary exploration and attempt in breast cancer screening, however, there are still some problems that have not been solved in terms of the proportion of opportunistic screening, the selection of screening targets, methods and frequency, and the judgment of screening results. Therefore, this article analyzes the above problems in details, and presents some thoughts and recommendations on how to optimize the breast cancer screening strategies and implementation effects in China, from the experience of clinical practice, under the background of constantly emerging new research results and techniques and the rapid development of artificial intelligence, that is, to adjust measures to local conditions, provide personalized strategies, achieve precise screening, preach and educate, ensure health insurance coverage, improve quality control, offer technical support and employ artificial intelligence. PMID- 29397622 TI - [Current situation and prospect of breast cancer liquid biopsy]. AB - Liquid biopsy is a diagnostic approach by analyzing body fluid samples. Peripheral blood is the most common sample. Urine, saliva, pleural effusion and ascites are also used. Now liquid biopsy is mainly used in the area of neoplasm diagnosis and treatment. Compared with traditional tissue biopsy, liquid biopsy is minimally invasive, convenient to sample and easy to repeat. Liquid biopsy mainly includes circulating tumor cells and circulating tumor DNA (ctDNA) detection. Detection of ctDNA requires sensitive and accurate methods. The progression of next-generation sequencing (NGS) and digital PCR promote the process of studies in ctDNA. In 2016, Nature published the result of whole-genome sequencing study of breast cancer. The study found 1 628 mutations of 93 protein coding genes which may be driver mutations of breast cancer. The result of this study provided a new platform for breast cancer ctDNA studies. In recent years, there were many studies using ctDNA detection to monitor therapeutic effect and guide treatment. NGS is a promising technique in accessing genetic information and guiding targeted therapy. It must be emphasized that ctDNA detection using NGS is still at research stage. It is important to standardize ctDNA detection technique and perform prospective clinical researches. The time is not ripe for using ctDNA detection to guide large-scale breast cancer clinical practice at present. PMID- 29397623 TI - [Problems and reflections on the diagnosis and treatment of gallbladder cancer]. AB - Although more and more attention has been paid on the diagnosis and treatment of gallbladder cancer, the patients' survival were still unsatisfied.Increasing the early diagnosis rate, the raise of awareness and treatment of unexpected gallbladder cancer, performing radical surgery for early stage patients and utilizing comprehensive treatment with adjuvant therapy for aggressive T2 or higher stage cases were the key points to improve patients' prognosis of gallbladder cancer. PMID- 29397624 TI - [Retrospective analysis of diagnosis and treatment of breast cancer in pregnancy]. AB - Objective: To investigate the principles of diagnosis and treatment of breast cancer during pregnancy. Methods: Clinical data of patients with breast cancer during pregnancy admitted to Obstetrics and Gynecology Hospital of Fudan University between January 2012 to July 2017 were analyzed retrospectively. A total of 17 patients were diagnosed with breast cancer in pregnancy, the median age was 32 years (range from 25 to 45 years old), pathological staging revealed 2 patient with stage 0, 1 with stage IIa, 7 with stage IIb, 1 with stage IIIa, 2 with stage IIIc, 4 with stage IV. Results: Thirteen patients received surgical treatment in pregnancy, the gestational age at surgery was (27.7+/-4.6) weeks; 2 patients with ductal carcinoma in situ received mastectomy, 11 patients with breast cancer underwent modified radical mastectomy. In patients undergoing surgery during pregnancy, no prophylactic contractions were used in 4 patients who had been treated earlier, there were 2 patients with frequent contractions within 24 hours after operation in these patients. Follow-up 9 patients were given oral nifedipine to prevent contractions, no obvious contractions occurred after the operation. Seven patients received chemotherapy during pregnancy; the chemotherapy of 4 cases of triple negative breast cancer was weekly paclitaxel sequential epirubicin and cyclophosphamide, the chemotherapy of the other three patients was docetaxel sequential epirubicin and cyclophosphamide. Fifteen patients underwent cesarean section to terminate pregnancy, 2 patients underwent spontaneous labor. The gestational age of birth was (36.9 +/-1.3) weeks. Less than 35 weeks of termination of pregnancy occurred in one patient, the fetus was delivered to the neonatal intensive care unit due to neonatal respiratory distress syndrome, and suffered from congenital dysaudia. The prognosis of the other 16 survived infants was good. The median follow-up time was 10 months (range from 4 to 27) months, in 13 patients of stage 0 to IIIc, one patient were diagnosed with bone metastasis at 12 months after surgery, the remaining 12 patients had no disease progression, the progression free survival rate was 12/13, the overall survival rate was 13/13. Among the 4 patients with stage IV, one died in 7 months after delivery, one had new liver metastasis in 8 months after delivery. The remaining 2 patients were in stable condition. Conclusions: Breast cancer in pregnancy can be treated effectively, multidisciplinary cooperation and detailed assessment of maternal-fetal risks and benefits are necessary. Chemotherapy during pregnancy is safe for maternal-fetal, but it needed a large sample of clinical studies and long-term follow-up. The neonatal outcome was associated with gestational age, and therefore premature delivery was avoided as much as possible during treatment. PMID- 29397625 TI - [An analysis of 68 invasive lobular breast cancer cases in clinicopathological characteristics and the prognostic determinants]. AB - Objective: To study the clinicopathological characteristics and the prognostic determinants of the invasive lobular carcinoma breast cancer. Methods: This was a retrospective single-center study of invasive lobular breast cancer cases diagnosed from January 2008 to December 2014 at Peking University First Hospital Breast Disease Center. The study enrolled 68 invasive lobular breast cancer patients, which represented 3.64% (68/1 870) of total invasive breast cancer. The median age of all selected patients was 46 years ranging from 36 to 83 years. All patients were restaged based on the 8(th) edition of AJCC cancer staging system and follow-up data including disease-free survival (DFS) and overall survival (OS) were analyzed to explore the prognostic determinants. The 5-year OS and DFS were calculated using Kaplan-Meier method; the significance of correlations between clinicopathological features and prognostic factors was estimated using log-rank test. Results: There were significant differences in OS between patients with different anatomic stage, prognostic stage, lymph node metastasis, progesterone receptor (PR) expression, lymphvascular invasion and perineural invasion (chi(2:) 4.318 to 32.394, all P<0.05); significant differences in DFS were also observed between patients with different anatomic stage, prognostic stage, lymph node metastasis, PR expression, human epidermal growth factor receptor-2 expression, Ki-67 level, histological grade and lymphvascular invasion (chi(2:) 4.347 to 27.369, all P<0.05). Prognostic stages of 52.9% patients changed compared with anatomic stage, among which Luminal subtype mainly downstaged (22/30), however, triple negative subtype mainly upstaged (6/6). Conclusions: Anatomic stage, prognostic stage, lymph node metastasis, PR expression, lymphvascular invasion are the prognostic factors of invasive lobular breast cancer. Regard to invasive lobular breast cancer patients, clinicians should pay close attention to the differences between prognostic stage and anatomic stage. PMID- 29397626 TI - [The study of nomogram based on Ishak inflammation score for recurrence of hepatocellular carcinoma after curative resection]. AB - Objective: To investigate the correlation between Ishak inflammation score and the clinicopathological characteristics and recurrence of patients with hepatocellular carcinoma (HCC) after curative resection, and then set up a recurrence nomogram for HCC. Methods: A total of 326 patients with HCC after curative resection from January 2006 to December 2009 were studied retrospectively as training cohort and 110 HCC patients after surgery from January 2010 to December 2012 were used as validation cohort.Clinical follow-up data and peritumoral Ishak inflammation score in training cohort were used to set up a nomogram predicting recurrence of HCC, which was verified by validation cohort. Kaplan-Meier and Cox proportional hazard regression model were used to analyzed accuracy of model prediction. Results: According to Ishak inflammation score, patients were divided into four subgroups: Grade I(1-4 scores), Grade II(5 8 scores), Grade III (9-12 scores) and Grade IV(13-18 scores). Ishak inflammation score were associated with aspartate transaminase(median 36.0 U/L, P=0.011), gamma-glutamyl transpeptidase(median 54.5 U/L, P=0.005), HBV-DNA load(20.5%>10(6) copies/ml, P=0.015) and microvascular invasion(26.7% positive, P=0.021). Multivariate analysis showed that Ishak inflammation score(P=0.007), HBV-DNA load(P<0.01), tumor size(P=0.001) and microvascular invasion(P=0.001) were related with the recurrence of HCC patients.These four risk factors were incorporated into the nomogram.Calibration curves of the nomogram had good agreement between prediction and observation in the probability of recurrence.Both C-indexes and receiver operating characteristic curve analyses revealed that this nomogram had better predictive abilities than those of the AJCC and Barcelona Clinic Liver Cancer (BCLC) stage systems.These results were verified by the validation cohort. Conclusion: A nomogram based on Ishak inflammation score could accurately predict the recurrence of HCC and contribute to HCC relapse surveillance after curative hepatectomy. PMID- 29397627 TI - [Transcystic biliary drainage versus nasobiliary drainage during primary closure of the laparoscopic choledochotomy]. AB - Objective: To compare the clinical efficacy of transcystic biliary drainage with nasobiliary drainage during primary closure following laparoscopic choledochotomy. Methods: The clinical data of 106 patients with cholecystolithiasis and choledocholithiasis treated by laparoscopy at Department of General Surgery, Danyang People's Hospital from May 2014 to June 2017 were analyzed prospectively. The patients were divided into 2 groups by means of random number method: the study group was treated with transcystic biliary drainage, and the control group adopted nasobiliary drainage. The operation time, postoperative drainage volume, postoperative hospital stay and postoperative complications were compared between the 2 groups. Results: All patients in the two groups completed the operation successfully. Compared with nasobiliary drainage, the operation time of transcystic biliary drainage was shortened ((133.9+/-14.7) minutes vs. (143.3+/-21.7) minutes, t=-2.617, P<0.05). Postoperative hospital stay ((8.2+/-1.7) days vs. (7.7+/-2.5) days), the difference between the two groups was not statistically significant(P>0.05). The quantity of bile drainage was no significant difference in the two groups of patients. There were 1 case of duct obstruction and 2 cases of catheter slippage during transcystic biliary drainage, without causing bile leakage. During nasobiliary drainage, there were 3 cases of catheter obstruction, 1 case of catheter slippage, 2 cases of self extubation, 1 case of bile peritonitis caused by catheter blockage, transferred to laparotomy and T tube drainage. The patients were followed up for 1 month to 17 months, with an average of 8 months. B ultrasound showed no bile duct stenosis and hepatic function was normal. Conclusions: Transcystic biliary drainage could achieve the same biliary drainage as well as nasobiliary drainage during primary closure following laparoscopic choledochotomy. In addition, transcystic biliary drainage maintain the physiological function of bile duct, it is simple and minimally invasive under certain conditions. PMID- 29397628 TI - [A comparative study of endoscopic and traditional open surgery in the treatment of papillary thyroid carcinoma]. AB - Objective: To evaluate the feasibility, safety and efficacy of endoscopic thyroidectomy in the treatment of papillary thyroid carcinoma through clinical follow-up. Methods: Patients who underwent total thyroidectomy and had a final pathologic diagnosis of papillary thyroid carcinoma at Department of Thyroid Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine between February 2013 and April 2014 were enrolled in this study; those who had family history of thyroid cancer or a history of radiation of the neck area were excluded. There were 78 male and 228 female pantients, aging from 20 to 77 years with an age of (45.6+/-12.7) years. The patients were then divided into two groups: endoscopic surgery group (n=48) and traditional open surgery group (n=258). The clinical and pathological features and long-term follow-up data were collected and analyzed. The differences in surgical trauma, completeness, postoperative complications, and recurrence and metastasis risks between the two groups were compared by t test, rank-sum test, chi(2) test or Fisher exact test. Results: Compared to open surgery, endoscopic thyroidectomy had significant longer surgical time ((3.2+/-0.6) hours vs. (1.6+/-0.5) hours, t=17.904, P=0.000), two cases converted to open surgery because of tumor invasion of the recurrent laryngeal nerve, and one because of a false negative cell biology preopertively. The two groups showed no significant difference in surgical trauma which was measured by bleeding, white blood cell, C reactive protein, drainage, and et al. During follow up, the two groups had no significant difference in rate of Tg<1 MUg/L (97.9% vs. 91.9%, P=0.220). Recurrent rate showed no significant difference (4.1% in endoscopic group vs. 3.1% in open group, P=0.665) between the two groups after follow-up of (40.8+/-4.7) months. Recurrent time were either not significantly different ((23.5+/-21.9) months vs. (20.0+/-14.6) months, P=0.785) between the two groups. Conclusion: Compared with conventional open thyroidecomy, endoscopic thyroidectomy has the same safety, surgical completeness and long-term therapeutic effect. PMID- 29397629 TI - [Comparison of clinical outcome between utilized second sacral alar-iliac and iliac screw on kyphoscoliosis patients]. AB - Objective: To compare the clinical outcome and health related quality of life(HRQoL)of patients with degenerative spinal deformity who underwent spino pelvic fixation utilized second sacral alar-iliac(S(2)AI)with patient utilized traditional iliac screw(IS). Methods: Patients diagnosed as degenerative spinal deformity who underwent spino-pelvic fixation utilized either S(2)AI screw or Iliac screw at Department of Spine Surgery of Drum Tower hospital from January 2013 to January 2016 were retrospectively analyzed. Patients were divided into two groups according to the pelvic fixation technique. Cobb's angle, coronal balance distance(CBD), regional kyphosis(RK), sagittal vertical axis(SVA)were recorded at pre-operation, post-operation and last follow up. The MOS item short from the health survey(SF-36), visual analogue scale(VAS), Oswestry disability index(ODI) were also recorded at pre-operation and last follow up. Five physical examinations were administered to all patient at the last follow up to diagnose sacroiliac joint dysfunction, three tests resulting positive were regarded as dysfunction. Repeated measurement analysis of variance, t-test or non-parametric test was used to analyzed the data, respectively. Results: A total of 22 patients who met the inclusion were recruited in this study. Fourteen patients were utilized S(2)AI screw and 8 patients were utilized iliac screw.There were no significant differences in age, gender, follow up time between two groups. Cobb's angle, CBD, RK, SVA at pre- and post-operation and last follow up showed no significant difference between two groups.SF-36, ODI, VAS at pre-operation and last follow up showed no significant difference between two groups. Compared with baseline, Cobb's angle(44.4 degrees +/-14.0 degrees vs. 20.2 degrees +/-7.2 degrees vs. 18.3 degrees +/-7.1 degrees ), C(7)PL-CSVL((25.3+/-16.0)mm vs. (10.3+/-5.7)mm vs. (9.2+/-4.2)mm), RK(33.0 degrees (-12.0 degrees , 50.0 degrees ) vs. 20.0 degrees (-33.0 degrees , 8.5 degrees ) vs. -19.0 degrees (-29.0 degrees , 19.0 degrees )), SVA((31.5+/-34.4)mm vs. (12.1+/-8.4)mm vs. (10.9+/ 7.2)mm), SF36-physical function summary(PCS)(39.8+/-14.3 vs. 68.2+/-21.5), SF36 mental component summary(MCS)(44.9+/-14.8 vs. 73.9+/-19.9), ODI(37.7+/-16.9 vs. 19.8+/-15.8), VAS(4.8+/-2.1 vs. 1.8+/-0.9) were significantly improved postoperatively in S(2)AI group(P<0.05). In the IS group, compared with baseline, Cobb's angle(54.3 degrees +/-18.3 degrees vs. 26.1 degrees +/-13.2 degrees vs. 25.6 degrees +/-18.3 degrees ), C(7)PL-CSVL((31.0+/-16.0)mm vs. (13.9+/-7.0)mm vs. (12.4+/-6.6)mm), RK (47.0 degrees (15.0 degrees , 57.0 degrees ) vs. 4.0 degrees (-10.0 degrees , 16.0 degrees ) vs. 7.0 degrees (-9.0 degrees , 12.0 degrees )), SVA((27.1+/-23.9)mm vs.(13.1+/-7.5)mm vs. (13.6+/-6.0)mm), SF36 PCS(29.7+/-7.1 vs. 61.1+/-11.2), SF36-MCS(35.9+/-7.1 vs. 64.0+/-11.1), ODI(48.6+/ 13.4 vs. 19.0+/-10.7), VAS(4.9+/-1.8 vs. 2.6+/-1.3) were also significantly improved postoperatively(all P<0.05). There were two patients need revision surgery in the IS group due to the instrumentation-related complication. None of the patients in the S(2)AI group needed revision surgery. There were no instances of sacroiliac joint dysfunction in both groups at last follow up. Conclusion: Spino-pelvic fixation utilizing S(2)AI screw could provide similar correction rate to iliac screw and the sacroiliac joint penetration due to S(2)AI won't affect the HRQoL in patient with degenerative deformity who utilized S(2)AI. PMID- 29397630 TI - [Radiological analysis of coronal and sagittal spinopelvic parameters in patients with degenerative lumbar kyphoscoliosis]. AB - Objective: To review and compare radiological parameters between degenerative lumbar kyphoscoliosis (DLKS) and degenerative lumbar kyphosis (DLK), and analyze the relationships between coronal and sagittal deformities and compensatory mechanisms of sagittal balance. Methods: A total of 82 patients with lumbar degenerative deformities were enrolled for our radiographic study at Department of Spinal Surgery, Peking University People's Hospital from January 2016 to May 2017. These patients were divided into two groups: DLKS group (39 patients) with lumbar coronal and sagittal deformities, and DLK group (43 patients) just with lumbar sagittal deformity. Complete spinopelvic radiographic parameters were compared. Results: The Cobb angle and lumbar lordosis of DLKS group were (23.0+/ 11.8) degrees and (18.2+/-12.1) degrees , while the lumbar lordosis of DLK group was (20.4+/-10.2) degrees . In DLKS group, Cobb angle had correlations with lumbar lordosis(r=-0.338, P=0.035), and central sacral vertical line distance had significant correlations with thoracolumbar junctional angle (r=0.488, P=0.002) . Moreover, no significant differences of all sagittal spinopelvic parameters were found between two groups (P>0.05). In DLKS group, significant correlations between lumbar lordosis and sacral slope (r=0.617, P=0.000), and correlations between lumbar lordosis and thoracic kyphosis(r=-0.363, P=0.023) were observed. In DLK group, lumbar lordosis showed significant correlations with thoracic kyphosis(r=-0.341, P=0.025) and sacral slope (r=0.772, P=0.000). According to Nash-Moe grading scale of apical vertebral rotation, 10 patients were with I-II grade while 29 patients with III-V grade in DLKS group. Conclusions: Both as typical lumbar degenerative deformities, there are some correlations between scoliosis and kyphosis. However, coronal scoliosis may not influent sagittal morphological parameters for DLKS patients. Thoracic curve changes and pelvic backtilt are both important for maintaining the sagittal balance in patients with degenerative lumbar kyphoscoliosis. PMID- 29397631 TI - Development of epidermal growth factor receptor targeted therapy in pancreatic cancer. AB - The epidermal growth factor receptor (EGFR) family is a series of important cancer therapeutic targets involved in cancer biology. These genes play an important role in tumor biological characteristics including angiogenesis, cell survival, invasion and glucose metabolism. In recent years, progress has been achieved on the cellular and molecular biological characteristics of EGFR and its role in cancer development based on the study of tumor specimens and experimental animal model. EGFR (HER1/ErbB) is overexpressed in over sixty percent of triple negative breast cancers and occurs in pancreatic, bladder, lung and head-and-neck cancers. Up to now, EGFR inhibitors have been applied in various types of cancer, such as lung cancer, breast cancer, bladder cancer and head and neck cancers etc., in which the combination of EGFR inhibitors plus chemotherapeutic agents is now seen as the standard of cure for advanced/metastatic pancreatic cancer. For these reasons, EGFR inhibitors and their therapeutic effect for pancreatic cancer is becoming the focus in laboratory and clinical research. In this paper, research progress of the development of epidermal growth factor receptor targeted therapy in pancreatic cancer is introduced. PMID- 29397632 TI - Conventional cytology vs. immunocytochemistry of intraoperative peritoneal washes in gastric cancer patients subjected to gastrectomy: clinical correlates and association with overall survival. AB - BACKGROUND: The aim of this study was to verify if positive results yielded with conventional cytology and immunocytochemical analysis of peritoneal washes correlate with established prognostic factors and overall survival (OS) in gastric cancer patients. METHODS: The study included the data of 271 gastrectomized patients. Peritoneal washes of 131 (48.3%) patients were examined by means of conventional cytology, and material from 140 (51.7%) subjects treated surgically after this date was subjected to immunocytochemical analysis. RESULTS: Free cancer cells (FCCs) were detected significantly less often in patients from conventional cytology group than in those from immunocytochemistry group (4.6% vs. 12.1%). Positive result of immunocytochemical analysis was significantly more often associated with presence of pT3/4 tumor (94.1% vs. 60.2%), lymph node ratio >=0.2 (82.4% vs. 43.1%) and involvement of blood vessels (64.7% vs. 28.5%). Median OS in patients with immunocytochemical evidence of FCCs in peritoneal washes was significantly shorter than in those without (11 vs. 45 months). Moreover, the two groups differed significantly in terms of 5- (0% vs. 43.1%) and 10-year OS rates (0.0% vs. 29.3%). CONCLUSIONS: In contrast to conventional cytology, immunocytochemically documented presence of FCCs in peritoneal washes correlates with established prognostic factors and OS in gastric cancer patients. PMID- 29397633 TI - Analysis of patient selection policy and pattern of recurrence after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal carcinomatosis. AB - BACKGROUND: Actual cure rate and patterns of recurrence after cytoreductive surgery (CRS) associated to hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with colorectal peritoneal carcinomatosis (PC) are not yet well explored. Moreover, the selection policy to this resource-consuming treatment is still a matter of debate. METHODS: From a dataset of 400 CRS+HIPEC performed between October 1996 and December 2015, we selected 54 consecutive patients with colorectal PC. Exclusion criteria were age>70, PS>2, or disease progression during chemotherapy. From 2004, we also excluded patients with both PCI>16 and poor prognostic factors of primary tumor (i.e. T4, N2 and G3) and only proceeded to HIPEC in case of optimal cytoreduction. Prognostic factors, cure rate and patterns of recurrence were investigated, comparing the two time periods. RESULTS: After 2004, median overall survival was 52 months, with a 40% 5-year survival. Completeness of cytoreduction, primary tumor histology and time period were independent prognostic factors. Median recurrence-free survival was 16 months. A relapse was detected in 41 out of 46 patients with optimal cytoreduction. Main sites of first relapse were peritoneum (73%), and distant metastases (37%), mainly to liver and lungs. Peritoneal and liver/lung metastases presented as isolated recurrence in 73% and 58% of cases, respectively. CONCLUSIONS: By a selection policy based on patient, disease extension and primary tumor factors, a median survival higher than 50 months can be expected. Most patients will eventually recur, mainly in the peritoneum. The pattern of recurrence suggests a potential role for more effective intraperitoneal therapies and repeat surgical treatments. PMID- 29397634 TI - Comparing outcomes after treatment of rectal cancer over a long-lasting follow-up between patients who were offered surgery alone and surgery with neoadjuvant therapy. AB - BACKGROUND: To assess outcomes of patients operated on for rectal cancer (RC) by analysing the trends of disease free survival curves (DFSc) after a very long term follow-up. METHODS: All patients treated with curative intent for RC from 1986 to 2005 were retrospectively analyzed. Other than demographics, disease characteristics and treatment-related factors were considered. The DFSc were compared between patients who had neoadjuvant therapy (NAT) and those who had surgery alone. RESULTS: Median age of 319 patients included in the study was 66.3 years (range 23-89) and 140 (57.6%) of them were males. Moreover, NAT was given in 24 (11.8%) patients, and adjuvant therapy in 40 (19.7%) patients. Median follow-up was of 150 months (60-240). In patients who had NAT the mean age was higher (P=0.05), RC were located lower (P=0.009) and higher positive lymph-nodes were found (P=0.003), whereas the number of both local (P=0.4) and distant recurrences (P=0.7) was not significantly lower, compared to the other group. Comparing trends of DFSc a more progressive decrease was shown in patients treated with surgery alone. Even if the differences of DSFc between groups at the end of follow-up were not significant (95% CI: 0.609-2.963, P=0.46), patients who had NAT displayed better survival up to 180 months. CONCLUSIONS: Overall, these results showed comparable outcomes between both groups over such a long lasting follow-up. This time frame might be used more extensively for increasing our knowledge of RC biological behaviour as well. PMID- 29397635 TI - Ethical issues in surgical tele mentoring: challenges and dilemmas of an innovative technology. PMID- 29397636 TI - Use of pain medication before and after lumbar discectomy: longitudinal analysis of a nation-wide cohort. AB - BACKGROUND: Previous studies have suggested that variation in results of lumbar discectomy depends on careful selection of patients. Numerous factors have been suggested to explain this variation with no direct examinations on this issue. The objective was to examine the use of pain medication before and after lumbar discectomy in patients with back pain. METHODS: Prospective occupational cohort study (N.=151,618) with linkage to national registers. Of the cohort members, 1538 (age 44 years) underwent discectomy. Records from purchases of pain medication were obtained during a 3-year period before and after hospital discharge. RESULTS: Purchases of pain medication increased during the follow-up period from 9.7+/-28.7 to 17.3+/-17.3 defined daily doses. Three groups were identified: 1) with constant, relatively low pain medication use; 2) with high use combined with further increases in purchases until the time of surgery and only a slight decrease thereafter; and 3) with a sharp rise in medication use before surgery and a return to no pain medication use approximately six months after the discharge. Non-manual profession (OR=1.34, 95% CI: 1.06 to 1.69) and open surgery technique increased (OR=1.32, 95% CI: 1.04 to 1.67) the probability of being included into the third group. CONCLUSIONS: The greater decline in the use of pain medication after discectomy was associated with a sharp rise of that use within six months before surgery. This suggests that lumbar discectomy may benefit especially those with acute or subacute pain within the six-month window. PMID- 29397637 TI - Pringle maneuver in robotic liver surgery: preliminary study. AB - BACKGROUND: Liver resection may be complicated by unpredictable intraoperative bleeding. Pringle's maneuver was the first attempt to control bleeding, but the main problem is the duration of ischemia. Robotic surgery thanks to the magnified view, three-dimensional visualization associated and fine movement allow to perform good parenchymal dissection and identification of vascular structure. Aim of study is to evaluate blood loss and the need to perform Pringle maneuver in patients underwent robotic liver resection. METHODS: Thirty-three patients underwent robotic liver resections were analyzed, 16 (48%) male and 17 (52%) female, with median age of 64 years. Seven (21%) patients had benign lesions and twenty-six (79%) malignant tumor. RESULTS: Seventeen (52%) patients had anatomical resections, while sixteen (48%) patients had non anatomical resection. Operative time was 270 minutes. Estimated blood loss was 100 mL and Pringle maneuver was carried out on seven patients. Median hospital stay was 4 days. CONCLUSIONS: Our results show that liver resections with robotic technique can be performed safely even without systematic Pringle maneuver. PMID- 29397638 TI - OTSC(r) Proctology vs. fistulectomy and primary sphincter reconstruction as a treatment for low trans-sphincteric anal fistula in a randomized controlled pilot trial. AB - BACKGROUND: To compare OTSC(r) Proctology and fistulectomy with primary sphincter reconstruction results as treatment strategies for anorectal low trans sphincteric fistula. METHODS: Between February 2012 and March 2013, patients affected by trans-sphincteric anal fistula were consecutively enrolled in the trial. Patients were randomized to receive fistulectomy with primary sphincter reconstruction or OTSC(r) Proctology. Demographic characteristics, comorbodities, previous anorectal treatments, and recurrent fistula data were acquired. Postoperative therapy data and pain and Wexner scores (30 and 60 dd) were acquired during follow-up. Furthermore, patients were contacted by telephone after six months, and were visited both one year and three years after surgery. RESULTS: 30 consecutive patients were included in the study. 15 patients underwent the OTSC(r) Proctology procedure and 15 underwent the standard fistulectomy. The success rate was 93.3% in the OTSC group. The mean postoperative stay was 1.3 days in the OTSC(r) patients and 3.6 days in the fistulectomy group patients. The mean medications required for complete healing was 3.2 in the OTSC group and 8.9 in the FIPS group. CONCLUSIONS: Our results suggest that OTSC(r) Proctology is an effective and safe treatment in achieving permanent closure of the internal fistula opening in selected patients, with excellent results in terms of pain, postoperative incontinence, healing time, and days of hospitalization. PMID- 29397639 TI - Staple line reinforcement during sleeve gastrectomy with a new type of reinforced stapler. AB - BACKGROUND: Bleeding and staple-line leak, are the most common complications of laparoscopic sleeve gastrectomy. To decrease the incidence of this complications, a variety of intraoperative reinforcement of staple line is used. Reinforced GIATM is a new automatic suture device with pre-attached synthetic tissue reinforcement, but no study has evaluated its use in sleeve gastrectomy. The objective of this study is to evaluate the efficacy and safety of this new staple line reinforcement technique in laparoscopic sleeve gastrectomy. METHODS: We conducted a retrospective review of 290 patients who underwent laparoscopic sleeve gastrectomy between January 2013 and January 2016 in which reinforced GIATM or standard GIATM was used. Patients preoperative characteristics, Operative time, staple line leaks, staple line bleeds, stenosis, and complications requiring reoperation were collected. RESULTS: A total of 187 laparoscopic sleeve gastrectomy were performed with standard GIA and 103 with reinforced GIATM. Patient characteristics were not significantly different between the groups. The average operating time in the standard GIA group is 57.41+/-16.44 min against 50.9+/-14.12 min in the reinforced GIA group (P=0.006). Two staple line leaks developed in the standard GIA group and reoperated against no patients in the reinforced GIA group, without significant difference between the both groups (P=0.66). Staple line bleeds are less in the reinforced GIA group, only 23 (22.3%) against 78 (41.7%) cases in the standard GIA group (P=0.001). No patients of both groups developed gastric sleeve stenosis. CONCLUSIONS: During laparoscopic sleeve gastrectomy, the use of a reinforced stapler significantly reduces the operative time and staple line bleeding. No significant difference is evidenced in terms of reduction of staple line leaks with this reinforced stapler. PMID- 29397640 TI - The Role of Risk-sharing Mechanisms in Finance Health Care and Towards Universal Health Coverage in Low-and Middle-income Countries of World Health Organization Regions. PMID- 29397641 TI - Peer Smoking and Smoking-related Beliefs Among College Students in Bangladesh. AB - Objectives: Smoking is a significant public health issue in Bangladesh. The purpose of this study was to examine peer smoking and smoking-related beliefs among college students in Bangladesh. Methods: College students at two universities in Dhaka, Bangladesh participated in a self-administered survey in May and June 2017. Results: First, being a current or former smoker is associated with lower levels of beliefs among respondents that they would not smoke even with smoker friends or nervousness, and lower levels of intentions that they would not smoke, while current smokers and former smokers have different smoking related beliefs. Second, having smoker friends is associated with lower levels of intentions that they would not smoke. Third, higher levels of normative beliefs that it is important not to smoke are associated with higher levels of beliefs that they would not smoke even with smoker friends or nervousness, higher levels of intentions that they would not smoke, and higher levels of avoidance of smoking. Conclusions: Smoking-related beliefs and perceived norms in individuals' social networks are important components in promoting tobacco cessation in Bangladesh. But it is challenging to prevent or intervene in smoking because of the high rates of smoking in this country and the high prevalence of smokers in individuals' social networks. Future studies should examine the most effective interventions to combat smoking in high-smoking social networks, such as using mobile apps or social media, and evaluate the effectiveness of such interventions. PMID- 29397643 TI - Associations of the Neighborhood Environment With Substance Use: A Cross sectional Investigation Among Patients in Compulsory Drug Detention Centers in Thailand. AB - Objectives: To identify the associations of characteristics of the neighborhood environment with substance abuse among clients receiving treatment for drug abuse in Thailand. Methods: A cross-sectional study was conducted of 1128 drug addicts from 28 neighborhoods who were receiving treatment at all 7 compulsory drug detention centers in Thailand. A trained interviewer conducted structured interviews with the subjects about substance use and the perceived neighborhood environment in their community. A multilevel logistic regression model was applied to estimate the effects of the neighborhood environment on substance use. Results: The majority of participants, 53.8% only used methamphetamine pills, 31.3% used other illicit drugs as well as methamphetamine pills, and 14.9% used an illicit drug other than methamphetamine. Three neighborhood characteristics were associated with substance use. A 1-unit increase in the perceived neighborhood cohesion score was associated with a 15% reduction in methamphetamine pill use and an 11% reduction of the use of both methamphetamine pills and another illicit drug. Conversely, a 1-unit increase in perceived neighborhood crime predicted 19 and 14% increases in the use of methamphetamine pills and the use of both methamphetamine pills and another illicit drug, respectively. In addition, a 1-unit increase in the scores for stigma surrounding addiction corresponded to a 25% increase of the use of methamphetamine pills and a 12% increase in the use of both methamphetamine pills and another illicit drug. Conclusions: Substance use among drug addicts was influenced by characteristics of the neighborhood environment. Therefore, prevention and intervention strategies should be designed based on a consideration of the impact of neighborhood context on substance use behaviors. PMID- 29397642 TI - Identifying Adverse Events Using International Classification of Diseases, Tenth Revision Y Codes in Korea: A Cross-sectional Study. AB - Objectives: The use of administrative data is an affordable alternative to conducting a difficult large-scale medical-record review to estimate the scale of adverse events. We identified adverse events from 2002 to 2013 on the national level in Korea, using International Classification of Diseases, tenth revision (ICD-10) Y codes. Methods: We used data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC). We relied on medical treatment databases to extract information on ICD-10 Y codes from each participant in the NHIS-NSC. We classified adverse events in the ICD-10 Y codes into 6 types: those related to drugs, transfusions, and fluids; those related to vaccines and immunoglobulin; those related to surgery and procedures; those related to infections; those related to devices; and others. Results: Over 12 years, a total of 20 817 adverse events were identified using ICD-10 Y codes, and the estimated total adverse event rate was 0.20%. Between 2002 and 2013, the total number of such events increased by 131.3%, from 1366 in 2002 to 3159 in 2013. The total rate increased by 103.9%, from 0.17% in 2002 to 0.35% in 2013. Events related to drugs, transfusions, and fluids were the most common (19 446, 93.4%), followed by those related to surgery and procedures (1209, 5.8%) and those related to vaccines and immunoglobulin (72, 0.3%). Conclusions: Based on a comparison with the results of other studies, the total adverse event rate in this study was significantly underestimated. Improving coding practices for ICD-10 Y codes is necessary to precisely monitor the scale of adverse events in Korea. PMID- 29397644 TI - Spatial Inequalities in the Incidence of Colorectal Cancer and Associated Factors in the Neighborhoods of Tehran, Iran: Bayesian Spatial Models. AB - Objectives: The aim of this study was to determine the factors associated with the spatial distribution of the incidence of colorectal cancer (CRC) in the neighborhoods of Tehran, Iran using Bayesian spatial models. Methods: This ecological study was implemented in Tehran on the neighborhood level. Socioeconomic variables, risk factors, and health costs were extracted from the Equity Assessment Study conducted in Tehran. The data on CRC incidence were extracted from the Iranian population-based cancer registry. The Besag-York Mollie (BYM) model was used to identify factors associated with the spatial distribution of CRC incidence. The software programs OpenBUGS version 3.2.3, ArcGIS 10.3, and GeoDa were used for the analysis. Results: The Moran index was statistically significant for all the variables studied (p<0.05). The BYM model showed that having a women head of household (median standardized incidence ratio [SIR], 1.63; 95% confidence interval [CI], 1.06 to 2.53), living in a rental house (median SIR, 0.82; 95% CI, 0.71 to 0.96), not consuming milk daily (median SIR, 0.71; 95% CI, 0.55 to 0.94) and having greater household health expenditures (median SIR, 1.34; 95% CI, 1.06 to 1.68) were associated with a statistically significant elevation in the SIR of CRC. The median (interquartile range) and mean (standard deviation) values of the SIR of CRC, with the inclusion of all the variables studied in the model, were 0.57 (1.01) and 1.05 (1.31), respectively. Conclusions: Inequality was found in the spatial distribution of CRC incidence in Tehran on the neighborhood level. Paying attention to this inequality and the factors associated with it may be useful for resource allocation and developing preventive strategies in atrisk areas. PMID- 29397645 TI - Perceptions About Alcohol Harm and Alcohol-control Strategies Among People With High Risk of Alcohol Consumption in Alberta, Canada and Queensland, Australia. AB - Objectives: To explore alcohol perceptions and their association hazardous alcohol use in the populations of Alberta, Canada and Queensland, Australia. Methods: Data from 2500 participants of the 2013 Alberta Survey and the 2013 Queensland Social Survey was analyzed. Regression analyses were used to explore the association between alcohol perceptions and its association with hazardous alcohol use. Results: Greater hazardous alcohol use was found in Queenslanders than Albertans (p<0.001). Overall, people with hazardous alcohol were less likely to believe that alcohol use contributes to health problems (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.27 to 0.78; p<0.01) and to a higher risk of injuries (OR, 0.54; 95% CI, 0.33 to 0.90; p<0.05). Albertans with hazardous alcohol use were less likely to believe that alcohol contributes to health problems (OR, 0.48; 95% CI, 0.26 to 0.92; p<0.05) and were also less likely to choose a highly effective strategy as the best way for the government to reduce alcohol problems (OR, 0.63; 95% CI, 0.43 to 0.91; p=0.01). Queenslanders with hazardous alcohol use were less likely to believe that alcohol was a major contributor to injury (OR, 0.39; 95% CI, 0.20 to 0.77; p<0.01). Conclusions: Our results suggest that people with hazardous alcohol use tend to underestimate the negative effect of alcohol consumption on health and its contribution to injuries. In addition, Albertans with hazardous alcohol use were less in favor of strategies considered highly effective to reduce alcohol harm, probably because they perceive them as a potential threat to their own alcohol consumption. These findings represent valuable sources of information for local health authorities and policymakers when designing suitable strategies to target alcohol-related problems. PMID- 29397646 TI - Scientific Evidence for the Addictiveness of Tobacco and Smoking Cessation in Tobacco Litigation. AB - Smokers keep smoking despite knowing that tobacco claims many lives, including their own and others'. What makes it hard for them to quit smoking nonetheless? Tobacco companies insist that smokers choose to smoke, according to their right to self-determination. Moreover, they insist that with motivation and willpower to quit smoking, smokers can easily stop smoking. Against this backdrop, this paper aims to discuss the addictive disease called tobacco use disorder, with an assessment of the addictiveness of tobacco and the reasons why smoking cessation is challenging, based on neuroscientific research. Nicotine that enters the body via smoking is rapidly transmitted to the central nervous system and causes various effects, including an arousal response. The changes in the nicotine receptors in the brain due to continuous smoking lead to addiction symptoms such as tolerance, craving, and withdrawal. Compared with other addictive substances, including alcohol and opioids, tobacco is more likely to cause dependence in smokers, and smokers are less likely to recover from their dependence. Moreover, the thinning of the cerebral cortex and the decrease in cognitive functions that occur with aging accelerate with smoking. Such changes occur in the structure and functions of the brain in proportion to the amount and period of smoking. In particular, abnormalities in the neural circuits that control cognition and decision-making cause loss of the ability to exert self-control and autonomy. This initiates nicotine dependence and the continuation of addictive behaviors. Therefore, smoking is considered to be a behavior that is repeated due to dependence on an addictive substance, nicotine, instead of one's choice by free will. PMID- 29397647 TI - Concordance in the Health Behaviors of Couples by Age: A Cross-sectional Study. AB - Objectives: To investigate concordance in the health behaviors of women and their partners according to age and to investigate whether there was a stronger correlation between the health behaviors of housewives and those of their partners than between the health behaviors of non-housewives and those of their partners. Methods: We used data obtained from women participants in the 2015 Korea Community Health Survey who were living with their partners. The outcome variables were 4 health behaviors: smoking, drinking, eating salty food, and physical activity. The main independent variables were the partners' corresponding health behaviors. We categorized age into 4 groups (19-29, 30-49, 50-64, and >= 65 years) and utilized multivariate logistic regression analysis, stratifying by age group. Another logistic regression analysis was stratified by whether the participant identified as a housewife. Results: Data from 64 971 women older than 18 years of age were analyzed. Of the 4 health behaviors, the risk of smoking (adjusted odds ratio [aOR], 4.65; 95% confidence interval [CI], 3.93 to 5.49) was highest when the participant's partner was also a smoker. Similar results were found for an inactive lifestyle (aOR, 2.56; 95% CI, 2.45 to 2.66), eating salty food (aOR, 2.48; 95% CI, 2.36 to 2.62); and excessive drinking (aOR, 1.89; 95% CI, 1.80 to 1.98). In comparison to non-housewives, housewives had higher odds of eating salty food. Conclusions: The health behaviors of women were positively correlated with those of their partners. The magnitude of the concordance differed by age group. PMID- 29397648 TI - Gastric Peroral Endoscopic Myotomy. AB - Gastroparesis (GP) is a syndrome characterized by delayed gastric emptying in the absence of mechanical obstruction of the stomach or proximal small bowel. Currently available dietary and medical therapies are limited and have suboptimal efficacy. Pylorus-directed therapies have showed promising results. Gastric peroral endoscopic myotomy (G-POEM) has been reported for the treatment of GP refractory to standard therapy with promising results. This article reviews the current applications and results of G-POEM for the treatment of refractory GP. PMID- 29397649 TI - Quality is the Key for Emerging Issues of Population-Based Colonoscopy Screening. AB - Colonoscopy is currently regarded as the gold standard and preferred method of screening for colorectal cancer (CRC). However, the benefit of colonoscopy screening may be blunted by low participation rates in population-based screening programs. Harmful effects of population-based colonoscopy screening may include complications induced by colonoscopy itself and by sedation, psychosocial distress, potential over-diagnosis, and socioeconomic burden. In addition, harmful effects of colonoscopy may increase with age and comorbidities. As the risk of adverse events in population-based colonoscopy screening may offset the benefit, the adverse events should be managed and monitored. To adopt population based colonoscopy screening, consensus on the risks and benefits should be developed, focusing on potential harm, patient preference, socioeconomic considerations, and quality improvement of colonoscopy, as well as efficacy for CRC prevention. As suboptimal colonoscopy quality is a major pitfall of population-based screening, adequate training and regulation of screening colonoscopists should be the first step in minimizing variations in quality. Gastroenterologists should promote quality improvement, auditing, and training for colonoscopy in a population-based screening program. PMID- 29397650 TI - Can Contrast-Enhanced Harmonic Endoscopic Ultrasonography Differentiate Malignancy from Benign Disease? PMID- 29397651 TI - Balloon-Assisted Endoscopy: A Powerful Tool for Complete Colonoscopy. PMID- 29397652 TI - Is Percutaneous Endoscopic Gastrostomy Acceptable in Centenarian Patients? PMID- 29397653 TI - Endoscopic Treatment of Subepithelial Tumors. AB - Gastrointestinal subepithelial tumors (SETs) are generally found during endoscopy and their incidence has gradually increased. Although the indications for the endoscopic treatment of patients with SETs remain to be established, the feasibility and safety of endoscopic dissection, including the advantages of this method compared with surgical treatment, have been validated in many studies. The development of endoscopic techniques, such as endoscopic submucosal dissection, endoscopic enucleation, endoscopic excavation, endoscopic submucosal tunnel dissection, submucosal tunnel endoscopic resection, and endoscopic full-thickness resection has enabled the removal of SETs while reducing the occurrence of complications. Here, we discuss the endoscopic treatment of patients with SETs, outcomes for endoscopic treatment, and procedure-related complications. We also consider the advantages and disadvantages of the various endoscopic techniques. PMID- 29397654 TI - Full-Thickness Resection Device for Complex Colorectal Lesions in High-Risk Patients as a Last-Resort Endoscopic Treatment: Initial Clinical Experience and Review of the Current Literature. AB - The full-thickness resection device (FTRD) is a novel endoscopic device approved for the resection of colorectal lesions. This case-series describes the device and its use in high-risk patients with colorectal lesions and provides an overview of the potential indications in recently published data. Between December 2014 and September 2015, 3 patients underwent endoscopic full thickness resection using the FTRD for colorectal lesions: 1 case for a T1 adenocarcinoma in the region of a surgical anastomosis after recto-sigmoidectomy, 1 case for a non-lifting colonic adenoma with low-grade dysplasia in an 89-year old patient and 1 for a recurrent adenoma with high-grade dysplasia in a young patient with ulcerative rectocolitis who was under immunosuppression after renal transplantation. Both technical and clinical success rates were achieved in all cases. The size of removed lesions ranged from 9 to 30 mm. Overall, the most frequent indication in the literature has been for lifting or non-lifting adenoma, submucosal tumors, neuroendocrin tumors, incomplete endoscopic resection (R1) or T1 carcinoma. Colorectal FTRD is a feasible technique for the treatment of colorectal lesions and represents a minimally invasive alternative for either surgical or conventional endoscopic resection strategies. PMID- 29397655 TI - Colorectal Cancer Screening-Who, How, and When? AB - Colorectal cancer (CRC) is the third most common cancer worldwide. It is amenable to screening as it occurs in premalignant, latent, early, and curable stages. PubMed, Cochrane Database of Systematic Reviews, and national and international CRC screening guidelines were searched for CRC screening methods, populations, and timing. CRC screening can use direct or indirect tests, delivered opportunistically or via organized programs. Most CRCs are diagnosed after 60 years of age; most screening programs apply to individuals 50-75 years of age. Screening may reduce disease-specific mortality by detecting CRC in earlier stages, and CRC incidence by detecting premalignant polyps, which can subsequently be removed. In randomized controlled trials (RCTs) guaiac fecal occult blood testing (gFOBt) was found to reduce CRC mortality by 13%-33%. Fecal immunochemical testing (FIT) has no RCT data comparing it to no screening, but is superior to gFOBt. Flexible sigmoidoscopy (FS) trials demonstrated an 18% reduction in CRC incidence and a 28% reduction in CRC mortality. Currently, RCT evidence for colonoscopy screening is scarce. Although not yet corroborated by RCTs, it is likely that colonoscopy is the best screening modality for an individual. From a population perspective, organized programs are superior to opportunistic screening. However, no nation can offer organized population-wide colonoscopy screening. Thus, organized programs using cheaper modalities, such as FS/FIT, can be tailored to budget and capacity. PMID- 29397657 TI - Incremental Role of Pancreatic Magnetic Resonance Imaging after Staging Computed Tomography to Evaluate Patients with Pancreatic Ductal Adenocarcinoma. AB - Purpose: The purpose of this study was to investigate the impact of contrast enhanced pancreatic magnetic resonance imaging (MRI) in resectability and prognosis evaluation after staging computed tomography (CT) in patients with pancreatic ductal adenocarcinoma (PDA). Materials and Methods: From January 2005 to December 2012, 298 patients were diagnosed to have potentially resectable stage PDA on CT. Patients were divided into CT+MR (patients underwent both CT and MRI; n=216) and CT only groups (n=82). Changes in resectability staging in the CT+MR group were evaluated. The overall survival was compared between the two groups. The recurrence-free survival and median time to liver metastasis after curative surgery were compared between the two groups. Results: Staging was changed from resectable on CT to unresectable state on MRI in 14.4% of (31 of 216 patients) patients of the CT+MR group. The overall survival and recurrence-free survival rates were not significantly different between the two groups (p=0.162 and p=0.721, respectively). The median time to liver metastases after curative surgery in the CT+MR group (9.9 months) was significantly longer than that in the CT group (4.2 months) (p=0.011). Conclusion: Additional MRI resulted in changes of resectability and treatment modifications in a significant proportion of patients who have potentially resectable state at CT and in prolonged time to liver metastases in patients after curative surgery. Additional MRI to standard staging CT can be recommended for surgical candidates of PDA. PMID- 29397656 TI - Current Status of Peroral Endoscopic Myotomy. AB - Peroral endoscopic myotomy (POEM) has been established as an optional treatment for achalasia. POEM is an endoluminal procedure that involves dissection of esophageal muscle fibers followed by submucosal tunneling. Inoue first attempted to use POEM for the treatment of achalasia in humans. Expanded indications of POEM include classic indications such as type I, type II, type III achalasia, failed prior treatments, including Botulinum toxin injection, endoscopic balloon dilation, laparoscopic Heller myotomy, and hypertensive motor disorders such as diffuse esophageal spasm, jackhammer esophagus. Contraindications include prior radiation therapy to the esophagus and prior extensive esophageal mucosal resection/ablation involving the POEM field. Most of the complications are minor and self-limited and can be managed conservatively. As POEM emerged as the main treatment for achalasia, various adaptations to tunnel endoscopic surgery have been attempted. Tunnel endoscopic surgery includes POEM, peroral endoscopic tumor resection, gastric peroral endoscopic pyloromyotomy. POEM has been widely accepted as a treatment for all types of achalasia, even for specific cases such as achalasia with failed prior treatments, and hypertensive motor disorders. PMID- 29397658 TI - The Effect of Hospital Case Volume on Clinical Outcomes in Patients with Nasopharyngeal Carcinoma: A Multi-institutional Retrospective Analysis (KROG 1106). AB - Purpose: The purpose of this study was to investigate the effect of hospital case volume (HCV) on clinical outcomes in patients with nasopharyngeal carcinoma (NPC). Materials and Methods: Data on 1,073 patients with cT1-4N0-3M0 NPC were collected from a multi-institutional retrospective database (KROG 11-06). All patients received definitive radiotherapy (RT) either with three-dimensional conformal RT (3D-CRT) (n=576) or intensity-modulated RT (IMRT) (n=497). The patients were divided into two groups treated at high volume institution (HVI) (n=750) and low volume institution (LVI) (n=323), defined as patient volume >=10 (median, 13; range, 10 to 18) and < 10 patients per year (median, 3; range, 2 to 6), respectively. Endpoints were overall survival (OS) and loco-regional progression-free survival (LRPFS). Results: At a median follow up of 56.7 months, the outcomes were significantly better in those treated at HVI than at LVI. For the 614 patients of propensity score-matched cohort, 5-year OS and LRPFS were consistently higher in the HVI group than in the LVI group (OS: 78.4% vs. 62.7%, p < 0.001; LRPFS: 86.2% vs. 65.8%, p < 0.001, respectively). According to RT modality, significant difference in 5-year OS was observed in patients receiving 3D-CRT (78.7% for HVI vs. 58.9% for LVI; p < 0.001) and not in those receiving IMRT (77.3% for HVI vs. 75.5% for LVI; p=0.170). Conclusion: A significant relationship was observed between HVI and LVI for the clinical outcomes of patients with NPC. However, the difference in outcome becomes insignificant in the IMRT era, probably due to the standardization of practice by education. PMID- 29397659 TI - S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. AB - Purpose: We conducted a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as adjuvant chemotherapy for stage III gastric cancer patients. Patients and Methods Stage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of 8 cycles of DS (S-1 70 mg/m2/day on days 1-14 plus docetaxel 35 mg/m2 on days 1 and 8) every 3 weeks or SP (S-1 70 mg/m2/day on days 1-14 plus cisplatin 60 mg/m2 on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate. Results: Between November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, it was decided to close the study early. With a median follow up duration of 56.9 months, the 3-year DFS rate between two groups was not significantly different (49.14% in DS group vs. 52.5% in SP group). The most common grade 3-4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, P=0.351). SP group had more grade 3-4 anemia (1.3% vs. 11.5%, P=0.037), whereas grade 3-4 hand-foot syndrome (4.1% vs. 0%, P=0.025) and mucositis (10.7% vs. 2.6%, P=0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP group finished planned treatment. Conclusion: Our findings suggest that S-1 plus cisplatin or docetaxel is an effective and tolerable option for patients with curatively resected stage III gastric cancer. PMID- 29397660 TI - Delayed Terminal Ileal Perforation in a Relapsed/Refractory B-Cell Lymphoma Patient with Rapid Remission Following Chimeric Antigen Receptor T-Cell Therapy. AB - Chimeric antigen receptor T-cell strategy targeting CD19 (CART19) has prominent anti-tumor effect for relapsed/refractory B-cell lymphomas. CART19-associated complications have been gradually recognized, however, late-onset complications have not been extensively studied. Herein, for the first time we report a diffuse large B-cell lymphoma patient with terminal ileum involvement obtained rapid remission and developed spontaneous terminal ileal perforation 38 days following CART19 infusion. The late-onset perforation reminds us that, for the safety of CART treatment, more cautions are warranted for the management of delayed GI complications. PMID- 29397661 TI - The Present and Future of Precision Medicine in Psychiatry: Focus on Clinical Psychopharmacology of Antidepressants. AB - Precision medicine is a concept which is recently gaining momentum in all branches of medicine. In particular in psychiatry it is greatly needed given the huge societal costs of psychiatric disorders and given the long time needed to observe benefit from treatments and the response variability. The future will be based on biological determinants, however until such an interesting but still futuristic aim will be reached, at present we may only rely on clinical features to guide our individualized prescription which is currently still frequently based on personal opinion and subjective previous experiences. The aim of this review is to offer an overview of the main aspects to take into consideration when prescribing an antidepressant treatment to reach the best precision medicine using clinical information. More than 40 compounds are available for treating depression and a similar amount of compounds for other psychiatric disorders. The process of matching the profile of the patient with all different profiles of available compounds is therefore quite complex. Our everyday prescribing procedure should take into consideration a number of factors such as the knowledge of the profile of available compounds versus the symptomatology profile of the subject, previous efficacy, medical comorbidities, tolerability profile, individual preferences, and family history. While we are waiting more complex algorithms including biological or genetic measures, it is possible to optimize our current prescription practice by using all available information in order to obtain as much as possible an evidence based precision medicine prescription. PMID- 29397662 TI - Cognitive Deficits in Schizophrenia: Understanding the Biological Correlates and Remediation Strategies. AB - Cognitive deficits are one of the core symptoms of schizophrenia that evolve during the course of schizophrenia, after being originated even before the onset of illness. Existing pharmacological and biological treatment modalities fall short to meet the needs to improve the cognitive symptoms; hence, various cognitive remediation strategies have been adopted to address these deficits. Research evidences suggest that cognitive remediation measures improve the functioning, limit disability bettering the quality of life. The functional outcomes of cognitive remediation in schizophrenia are resultant of neurobiological changes in specific brain areas. Recent years witnessed significant innovations in cognitive remediation strategies in schizophrenia. This comprehensive review highlights the biological correlates of cognitive deficits in schizophrenia and the remedial measures with evidence base. PMID- 29397664 TI - Genotype-phenotype Analysis of Paraoxonase 1 in Schizophrenic Patients Treated with Atypical Antipsychotics. AB - Objective: Recent studies suggest a possible involvement of low paraoxonase 1 (PON1) enzyme activities in the association between schizophrenia, treatment with atypical antipsychotics and increased cardiovascular (CVD) risk. In the present study, we aimed at investigating the PON1 status in a group of schizophrenic patients treated with either olanzapine or other antipsychotic, as compared to a group of healthy control participants. Methods: We assessed the arylesterase (AREase) and paraoxonase (POase) activities of PON1, as well as three common polymorphisms of PON1 gene (Q192R, L55M, -108C>T). Results: We found significantly lower (-13.3%) AREase activity in schizophrenic patients, along with significantly lower (-18.2%) POase activity in olanzapine-treated patients with QQ genotype. Furthermore, we found a significant difference between groups in L55M polymorphism distribution, whereas Q192R and -108C>T polymorphisms distributions were similar. Conclusion: We identified the olanzapine-treated patients with QQ genotype as having the lowest PON1 (POase) activity, providing a possible way of identifying schizophrenic patients exposed to the greatest risk of CVD. PMID- 29397663 TI - From Neurons to Social Beings: Short Review of the Mirror Neuron System Research and Its Socio-Psychological and Psychiatric Implications. AB - The mirror neuron system (MNS) is a brain network activated when we move our body parts and when we observe the actions of other agent. Since the mirror neuron's discovery in research on monkeys, several studies have examined its network and properties in both animals and humans. This review discusses MNS studies of animals and human MNS studies related to high-order social cognitions such as emotion and empathy, as well as relations between MNS dysfunction and mental disorders. Finally, these evidences are understood from an evolutionary perspective. PMID- 29397665 TI - Thiol Disulfide Homeostasis in Schizophrenic Patients Using Atypical Antipsychotic Drugs. AB - Objective: Schizophrenia is a severe, debilitating mental disorder characterized by behavioral abnormalities. Although several studies have investigated the role of oxidative stress and the effects of antipsychotic drugs on oxidative markers in schizophrenia, adequate information is not available on these issues. The aim of this study is to determine the changes in oxidative status and thiol disulfide homeostasis in schizophrenic patients using atypical antipsychotic drugs. Methods: Thirteen schizophrenic patients using atypical antipsychotic drugs and 30 healthy controls were included this study. The concentrations of total oxidant status (TOS), total antioxidant status (TAS), native thiol, total thiol, and disulfide levels were determined in the study population. Results: The TAS (p=0.001), total thiol, and native thiol levels (p<0.001) were higher in the patients compared to the controls, whereas the TOS and disulfide levels were lower in the patients than in the controls (p<0.001). Conclusion: These results may suggest that atypical antipsychotic drugs have a useful therapeutic effect by reducing oxidative stress via the inhibition of the formation of disulfide bonds. The study population number was one of the limitations of this study. Therefore, further studies are needed to establish the association between thiol disulfide homeostasis in schizophrenic patients using atypical antipsychotic drugs. PMID- 29397667 TI - Efficacy and Safety Profile of Risperidone Long-acting Injection in Adolescents in a Real-life Setting. AB - Objective: Risperidone long-acting injection (RLAI) was shown to be an alternative option in adult patients, but there is not available data in child and adolescents about this medication. The aim of this study is to evaluate the safety and efficiency profile of RLAI in a group of adolescents. Methods: Eleven cases with conduct disorder and severe aggressive behaviors were initiated treatment with risperidone oral form. All cases were then shifted to RLAI 25 mg injection in each 15 days due to poor compliance to oral risperidone treatment. Efficiency of treatment included indicators of clinical severity and improvement, which were evaluated by Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I). Safety evaluation was performed by using Extrapyramidal Symptoms Rating Scale, and by monitoring body weight. Follow-up visits were done at the treatment initiation, and 8th, 16th, and 24th weeks of first injection. Results: Study included 9 girls, and 2 boys, with a mean age of 14.9+/-1.0 years. The CGI-S scores decreased from 6.6+/-0.5 at the beginning to 2.2+/-1.1 at the last visit (p<0.001), which is a very significant decrease through better clinical level. The CGI-I scores were also improved significantly from 2.4+/-0.5 to 1.9+/-0.5 at 24th week (p=0.001). Safety parameters were also showed favorable results, which there was no significant weight gain (p=0.076), and well-tolerated extrapyramidal adverse effects. Conclusion: Our results showed that RLAI is an efficient and safe medication option in the treatment of psychiatric disorders and severe behavioral problems in adolescents with low-compliance to oral treatment in our cases. PMID- 29397666 TI - Hippocampal Subfields Volume Reduction in High Schoolers with Previous Verbal Abuse Experiences. AB - Objective: Reduced hippocampal volume and alterations in white matter tracts have been frequently reported in adults having the history of emotional maltreatment. We investigated whether these structural change occur in adolescents with previous verbal abuse (VA) experiences. Methods: Hippocampal subfield volume and white matter structural connectivity measures were assessed in 31 first year male high school students with various degrees of exposure to parental and peer VA. Results: The high VA group showed significant volume reduction in the left cornu ammonis (CA) 1 and left subiculum compared to the low VA group (p<0.05). Volumes of left hippocampal subfields CA1 and subiculum were negatively correlated with previous VA experiences (p<0.05). Increased mean diffusivity (MD) of the splenium of the corpus callosum was related to high VA score across all subjects (p<0.05). There was an inverse relationship between volume of the CA1 and subiculum and MD of the splenium (p<0.05). Conclusion: Exposure to parental and peer VA may affect development of the left hippocampal subfields and the splenium of corpus callosum. These structural alterations can be discernible during adolescence. PMID- 29397668 TI - The Effects of Repetitive Transcranial Magnetic Stimulation at Dorsolateral Prefrontal Cortex in the Treatment of Migraine Comorbid with Depression: A Retrospective Open Study. AB - Objective: The literature on managing migraine non-responsive to pharmacological approaches and that co-occurring with depression is scanty. The comorbid condition predicts a poorer prognosis for migraine as well as depression. The present report assesses efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex as a treatment modality for migraine with comorbid depression. Methods: The current retrospective chart review assesses effectiveness of high frequency rTMS over left dorsolateral prefrontal cortex as a treatment modality to manage migraine occurring comorbid with depression in 14 subjects. Results: The mean scores on Migraine Disability Assessment Test (MIDAS) and depression rating scale reduced significantly from 21.14+/-3.01 and 20.71+/-3.95 at baseline to 13.93+/ 6.09 and 14.21+/-5.52 respectively, after rTMS. There was significant improvement in migraine frequency, severity and functional disability assessed using MIDAS scores (p<0.05) following high frequency rTMS compared to baseline. Conclusion: There is a role of applying rTMS as a potential therapeutic modality in the integrated management of a distinct subgroup of migraine patients with comorbid depression. PMID- 29397669 TI - Korean Medication Algorithm for Depressive Disorders 2017: Third Revision. AB - Objective: In 2002, the Korean Society for Affective Disorders developed the guidelines for the treatment of major depressive disorder (MDD), and revised it in 2006 and 2012. The third revision of these guidelines was undertaken to reflect advances in the field. Methods: Using a 44-item questionnaire, an expert consensus was obtained on pharmacological treatment strategies for MDD 1) without or 2) with psychotic features, 3) depression subtypes, 4) maintenance, 5) special populations, 6) the choice of an antidepressant (AD) regarding safety and adverse effects, and 7) non-pharmacological biological therapies. Recommended first, second, and third-line strategies were derived statistically. Results: AD monotherapy is recommended as the first-line strategy for non-psychotic depression in adults, children/adolescents, elderly adults, patient with persistent depressive disorder, and pregnant women or patients with postpartum depression or premenstrual dysphoric disorder. The combination of AD and atypical antipsychotics (AAP) was recommended for psychotic depression in adult, child/adolescent, postpartum depression, and mixed features or anxious distress. Most experts recommended stopping the ongoing initial AD and AAP after a certain period in patients with one or two depressive episodes. As an MDD treatment modality, 92% of experts are considering electroconvulsive therapy and 46.8% are applying it clinically, while 86% of experts are considering repetitive transcranial magnetic stimulation but only 31.6% are applying it clinically. Conclusion: The pharmacological treatment strategy in 2017 is similar to that of Korean Medication Algorithm for Depressive Disorder 2012. The preference of AAPs was more increased. PMID- 29397670 TI - The Diagnostic Value of Malondialdehyde, Superoxide Dismutase and Catalase Activity in Drug Naive, First Episode, Non-Smoker Generalized Anxiety Disorder Patients. AB - Objective: Generalized anxiety disorder (GAD) is a common anxiety disorder. Although lots of research done to reveal neurobiological basis of GAD, it is still unclear. Diagnosis of GAD depends on subjective complaints of patients, thus the need for a biological marker is constantly emerging. In this study, we aimed to investigate diagnostic value of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in GAD. Methods: We evaluated MDA, SOD, and CAT levels in peripheral blood of 46 patients and 45 controls. MDA was measured with Ohkawa's methods, SOD was measured with Fridovich method, and CAT was measured with Beutler's method. Results: MDA was significantly increased in patients than controls, medians 4.05 nmol/mg and 1.71 nmol/mg respectively, p<0.001; SOD and CAT activity was significantly decreased in patients than controls, medians of SOD were 159.07 U/mg and 301.87 U/mg, p<0.001 respectively, medians for CAT were 138.47 U/mg and 160.60 U/mg respectively. We found high correlation between Hamilton Anxiety Rating Scale and SOD, MDA r values were 0.723 and 0.715 respectively, p<0.001 for both. Receiver operator characteristic (ROC) curve analysis showed high diagnostic performance for MDA and SOD, low diagnostic performance for CAT, areas under curve were 1.0, 1.0, and 0.648 respectively. Conclusion: Our results reveal possible diagnostic value of MDA, less likely of SOD but not CAT. Future studies should investigate diagnostic value of oxidants and antioxidantn enzymes in larger samples and include diagnostic value of these parameters. PMID- 29397671 TI - The Association between Suicide Attempts and Toxoplasma gondii Infection. AB - Objective: Chronic 'latent' infection by Toxoplasma gondii is common and most of the hosts have minimal symptoms or they are even asymptomatic. However, there are possible mechanisms by which T. gondii may affect human behavior and it may also cause humans to attempt suicide. This article aimed to investigate the potential pathophysiological relationship between suicide attempts and T. gondii infection in Korea. Methods: One hundred fifty-five psychiatric patients with a history of suicide attempt and 135 healthy control individuals were examined with enzyme linked immunoassays and fluorescent antibody technique for T. gondii seropositivity and antibody titers. The group of suicide attempters was interviewed regarding the history of suicide attempt during lifetime and evaluated using 17-item Korean version of Hamilton Depression Scale (HAMD), Columbia Suicide Severity Rating Scale (C-SSRS), State-Trait Anxiety Inventory (STAI) and Korean-Barratt Impulsiveness Scale (BIS). Results: Immunoglobulin G antibodies were found in 21 of the 155 suicide attempters and in 8 of the 135 controls (p=0.011). The Toxoplasma-seropositive suicide attempters had a higher HAMD score on the depressed mood and feeling of guilt subscales and a higher total score than the seronegative suicide attempters. T. gondii seropositive status was associated with higher C-SSRS in the severity and lethality subscales. T. gondii IgG seropositivity was significantly associated with higher STAI-X1 scores in the suicide attempters group. Conclusion: Suicide attempters showed higher seroprevalence of T. gondii than healthy controls. Among the suicide attempters, the T. gondii seropositive and seronegative groups showed several differences in the aspects of suicide. These results suggested a significant association between T. gondii infection and psychiatric problems in suicidality. PMID- 29397672 TI - Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder. AB - Objective: Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. Methods: Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. Results: Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1beta (6.40+/-3.47 and 9.04+/-5.84 vs. 0.23+/-0.11; p<0.05) and tumor necrosis factor-alpha (2.23+/ 0.91 and 2.03+/-0.45 vs. 0.62+/-0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29+/-0.20 vs. 1.86+/-1.61; p=0.006) and CXCL10 expression (0.36+/-0.15 and 0.86+/-0.24 vs. 1.83+/-0.88; p<0.000 and p=0.04) compared to the euthymia group. Conclusion: Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD. PMID- 29397673 TI - Limbic Encephalitis Manifesting as Selective Amnesia and Seizure-like Activity: A Case Report. AB - Limbic encephalitis (LE) is characterized by short-term memory loss, disorientation, agitation, seizures, and histopathological evidence of medial temporal lobe inflammation. Leucine-rich, glioma inactivated 1 (LGI-1) is an auto antigen associated with LE. We report a 37-year-old male patient with LGI-1 related LE who presented with recurrent episodes of selective amnesia, seizure like activity, confusion, and personality change. His symptoms were significantly improved with steroid therapy. Thorough differential diagnosis with consideration for autoimmune encephalitis should be in patients with presentation of symptoms, such as memory impairment, personality change and seizure-like activity, especially when other neurological diagnoses are excluded. PMID- 29397674 TI - Polydipsia as a Precursor of Manic Episode in Bipolar Affective Disorder Patients with Alcohol Use Disorder. AB - Bipolar affective disorder (BD) diagnosis and initiation of appropriate treatment are often delayed, and this is associated with poorer outcomes, such as rapid cycling or cognitive decline. Therefore, identifying certain warning signs of a probable successive episode during the inter-episode phase is important for early intervention. We present the retrospective data of three cases of BD. Our first case had a history of alcohol use disorder (AUD), where he drank in a dipsomaniac manner, and the other two cases had dipsomaniac alcohol use before their manic attacks, and none of them had any AUD after the mood episode was over. Two brothers also had hypertensive episodes during the manic attacks. None of the cases reported increased fluid intake when they were euthymic. We suggest that polydipsia in BD may be a warning sign of an upcoming manic episode, especially in those patients with AUD. Polydipsia in BD may be caused or facilitated by a combination of hyperdopaminergic activity, hypothalamic dysfunction, and dysregulated renin-angiotensin system. To be able to prevent new episodes, a patient's drinking habits and change in fluid intake should be asked at every visit. Those patients with a history of alcohol abuse should especially be informed about polydipsia and manic episode association. PMID- 29397675 TI - Risperidone Related Raynaud's Phenomenon: An Adolescent Case. AB - Raynaud's phenomenon is a recurrent vasospastic condition with reducing in peripheral blood flow due to cold, or emotional stress. White, blue and red discolorations occur during the attacks. Serotonin reuptake inhibitors, psychostimulants, and aripiprazole are reported to be related with Raynaud's phenomenon. Risperidone is an atypical antipsychotic drug with dopaminergic and serotonergic effects. In children and adolescents, risperidone is used for bipolar disorder, tic disorders, conduct disorder, schizophrenia, symptoms of irritability and self-mutilation. Here we report a case of Raynaud's phenomenon associated with risperidone in a 12-year-old boy. Raynaud's phenomenon occurred two weeks after starting risperidone and disappeared after stopping risperidone. PMID- 29397677 TI - Abuse Liability of Baclofen. PMID- 29397676 TI - Combined Use of Duloxetine and Olanzapine in the Treatment of Urologic Chronic Pelvic Pain Syndromes Refractory to Conventional Treatment: A Case Report. AB - Patients with urologic chronic pelvic pain syndromes (UCPPS) report interstitial cystitis/bladder pain syndrome and/or chronic prostatitis/chronic pelvic pain syndrome. The pathogenesis of these syndromes remains unclear and there is currently no standard treatment. UCPPS is, therefore, often misdiagnosed and its management is complex. The present case report involves a 62-year-old male patient with UCPPS whose main presentation is painful bladder filling and painful urgency refractory to conventional treatment with medication, which was successfully treated with the combined use of duloxetine and olanzapine. The combined use of duloxetine and olanzapine may become a new therapeutic option in the management of UCPPS. PMID- 29397678 TI - The impact of assisted reproductive technologies in the human experience. PMID- 29397679 TI - Introduction of the contraceptive implant in South Africa: Successes, challenges and the way forward AB - In 2014, the contraceptive implant was introduced into public sectorfacilities in South Africa (SA). Several thousand healthcare workerswere trained, and demand was generated for the method, achievinghigh uptake. Use of the implant has since declined, but currentlyaccounts for ~7% of all contraceptive use - a not insignificantachievement for a 'new' method.[1,2] In this edition of SAMJ, threearticles[3-5] take stock of the early years of implant provision in SA.The articles, based on research in 2016, capture women's motivationsfor using the implant and their perspectives towards the method;and healthcare providers' competencies and experiences with serviceprovision. Insights may be generalisable to family planning servicesmore broadly, but are also relevant to the introduction of other newtechnologies, especially those related to HIV. PMID- 29397680 TI - User perspectives on Implanon NXT in South Africa: A survey of 12 public-sector facilities AB - Abstract: Background. Implanon NXT, a long-acting reversible contraceptive, was introduced in South Africa (SA) in early 2014, aiming to expand the method mix and increase its effectiveness. Initial uptake was high, but has since declined considerably. In these early years after the implant's introduction, it is important to identify reasons for the decline, and remedy gaps in services.Objectives. To determine periods of use, reasons for the use and early removal of the implant Implanon NXT.Methods. In 2016, we recruited 152 women from six clinics in the City of Johannesburg, and six in North West Province, SA. A semistructured interview was administered to 91 women currently using the implant and 61 previous users. We examined user perspectives, factors influencing women's experiences with the implant and reasons for discontinuation.Results. The participants' mean age was 30 years, with only 15% aged <25. Implant uptake was motivated by convenience (less frequent visits required than for short-acting methods) and by favourable views of the method among friends, family and healthcare providers. Only about a quarter of women recalled being counselled pre insertion about implant effectiveness, and half about side-effects pre-insertion. Among discontinuers, the median time to device removal was 8 months (interquartile range 6 - 12), and this was primarily as a result of side-effects (90%), especially bleeding-pattern changes and headaches. Removals were most common among married and cohabiting women, often ascribed to the effects of bleeding on their sexual relationships. Rumours and misinformation contributed to some removals. Overall, women's experiences with the implant were rated 'good' or 'very good' by 74% of those continuing use, many of whom reported not having experienced any side-effects or that these had diminished over time.Conclusion. Levels of acceptability among continuing users were high, mainly linked to the method's convenience. While early favourable views drove uptake, negative perceptions, if unaddressed, may now undermine services. Deficiencies in counselling around effectiveness and side-effects may extend to contraceptive services more generally. Women require more intensive support when experiencing sideeffects, including effective systematic approaches to ameliorating bleeding and headaches. Implant services could specifically target young women and first time contraceptive users. These actions together could reverse the persistent decline in implant use in SA. PMID- 29397681 TI - Uptake and early removals of Implanon NXT in South Africa: Perceptions and attitudes of healthcare workers AB - Background. The South African (SA) government introduced Implanon NXT, a long acting subdermal contraceptive implant, in 2014 to expand contraceptive choice. Following an initial high uptake, its use declined considerably amid reports of early removals and frequent side-effects. We examine providers' perceptions of training and attitudes towards Implanon NXT, as well as their views on the causes of early removals and the impact on the implant service.Objective. To assess healthcare providers' perceptions and attitudes towards implant services in SA.Methods. In-depth interviews were conducted with eight nurses providing implant services in public facilities in Gauteng and North West Province. Emerging themes were identified, manually coded and thematically analysed following an interpretivism approach.Results. Nurses lacked confidence in providing implant services effectively, particularly removals, which they ascribed to the brief, cascade-type training received. Nurses generally held negative views towards the method. They also reported that side-effects are the most common reason for early removals - particularly irregular bleeding - and that men often do not support their partners who use the method. Lastly, it was found that providers require guidance on counselling regarding the method and standardised guidelines on the management of side-effects.Conclusion. Retraining and support of providers are needed to address competency gaps and negative attitudes towards the method. Assessment of providers' readiness to perform removal procedures is also important. Finally, effective plans are necessary to improve implant continuation rates, especially among women whose partners are unsupportive. PMID- 29397683 TI - Synthesis of a Poly-l-Lysine/Black Phosphorus Hybrid for Biosensors. AB - A simple, noncovalent modification strategy was proposed to synthesize poly-l lysine-black phosphorus (pLL-BP) hybrid. BP nanoflakes were prepared with a water phase exfoliation method. pLL can adhere to the surface of BP via hydrophobic interaction between butyl chains of pLL and the BP surface as well as the electrostatic interaction between the protonated amino groups on pLL and the negative charge on deprotonated PxOy groups remaining on BP. The as-synthesized pLL-BP hybrid turns out to be an ideal matrix for hemoglobin immobilization and direct electron transfer. Good conductivity and biocompatibility of BP maintain the native structure and the bioactivity of hemoglobin (Hb), facilitating the direct electron transfer between the electroactive center of Hb and electrode. The rate constant ( kET) for direct electron transfer of Hb@pLL-BP is calculated to be 11.24 s-1. The constructed Hb-pLL-BP based enzymatic electrochemical biosensor displays excellent catalytic activity toward the reduction of oxygen and hydrogen peroxide. The electrochemical response toward H2O2 exhibits a linear dependence on hydrogen peroxide concentration ranging between 10 MUM and 700 MUM. The results demonstrate that the pLL-BP hybrid can act as a biocompatible building block for the construction of novel biofuel cells, bioelectronics, and biosensors. PMID- 29397682 TI - Label-Free Quantification of Small-Molecule Binding to Membrane Proteins on Single Cells by Tracking Nanometer-Scale Cellular Membrane Deformation. AB - Measuring molecular binding to membrane proteins is critical for understanding cellular functions, validating biomarkers, and screening drugs. Despite the importance, developing such a capability has been a difficult challenge, especially for small-molecule binding to membrane proteins in their native cellular environment. Here we show that the binding of both large and small molecules to membrane proteins can be quantified on single cells by trapping single cells with a microfluidic device and detecting binding-induced cellular membrane deformation on the nanometer scale with label-free optical imaging. We develop a thermodynamic model to describe the binding-induced membrane deformation, validate the model by examining the dependence of membrane deformation on cell stiffness, membrane protein expression level, and binding affinity, and study four major types of membrane proteins, including glycoproteins, ion channels, G-protein coupled receptors, and tyrosine kinase receptors. The single-cell detection capability reveals the importance of local membrane environment on molecular binding and variability in the binding kinetics of different cell lines and heterogeneity of different cells within the same cell line. PMID- 29397684 TI - Cardiovascular Small Heat Shock Protein HSPB7 Is a Kinetically Privileged Reactive Electrophilic Species (RES) Sensor. AB - Small heat shock protein (sHSP)-B7 (HSPB7) is a muscle-specific member of the non ATP-dependent sHSPs. The precise role of HSPB7 is enigmatic. Here, we disclose that zebrafish Hspb7 is a kinetically privileged sensor that is able to react rapidly with native reactive electrophilic species (RES), when only substoichiometric amounts of RES are available in proximity to Hspb7 expressed in living cells. Among the two Hspb7-cysteines, this RES sensing is fulfilled by a single cysteine (C117). Purification and characterizations in vitro reveal that the rate for RES adduction is among the most efficient reported for protein cysteines with native carbonyl-based RES. Covalent-ligand binding is accompanied by structural changes (increase in beta-sheet-content), based on circular dichroism analysis. Among the two cysteines, only C117 is conserved across vertebrates; we show that the human ortholog is also capable of RES sensing in cells. Furthermore, a cancer-relevant missense mutation reduces this RES-sensing property. This evolutionarily conserved cysteine-biosensor may play a redox regulatory role in cardioprotection. PMID- 29397685 TI - Heterologous Leader Sequences in Fusion Constructs Enhance Expression of Geranyl Diphosphate Synthase and Yield of beta-Phellandrene Production in Cyanobacteria ( Synechocystis). AB - Fusion constructs as protein overexpression vectors proved to be critical in the heterologous expression of terpene synthases in cyanobacteria. The concept was recently applied to the heterologous overexpression of the beta-phellandrene synthase (beta- PHLS) from plants, fused to the highly expressed endogenous cpcB gene encoding the beta-subunit of phycocyanin. Overexpressed CpcB*PHLS fusion proteins enhanced the heterologous yield of C10H16 beta-phellandrene hydrocarbons production in Synechocystis. This work extended the concept of fusion constructs as protein overexpression vectors by showing that highly expressed heterologous genes could also serve as leader sequences for protein overexpression in cyanobacteria. Examined are the kanamycin nptI and chloramphenicol cmR resistance cassettes, both of which are overexpressed in Synechocystis. Evidence showed a dual purpose of the nptI gene, as a leader sequence fused to a heterologous geranyl-diphosphate synthase ( GPPS), promoting its expression, while at the same time serving as a selectable marker for the screening of transformants. The work further showed that enhanced GPPS expression increased the yield of beta phellandrene in Synechocystis transformants harboring the beta- PHLS gene. Moreover, the research evaluated the expression efficacy of a DNA fragment comprising 87 nucleotides from the 5' end of the cmR gene in fusion with the GPPS gene. This short fusion construct substantially increased the intracellular geranyl-diphosphate synthase level, suggesting that "short-stretch" cmR leader sequences can be used to drive a higher expression level of heterologous biosynthetic genes, while avoiding undesirable internal recombinations, as these sequences are shorter than the threshold of 200 bp, commonly assumed to be the threshold of high efficiency recombinations. PMID- 29397686 TI - Identification of Different Bile Species and Fermentation Times of Bile Arisaema Based on an Intelligent Electronic Nose and Least Squares Support Vector Machine. AB - Fermentation is one of the most traditionally utilized methods to process the raw materials of traditional Chinese medicine (TCM). Bile Arisaema (BA) is produced by the fermentation of the roots of Arisaema heterophyllum with bile. Fermentation time and bile species are the key factors in producing BA. The study was aimed to develop a new and rapid method for the identification of different fermentation times and bile species of BA. The polysaccharide content (PC), protease activity (PA), and amylase activity (AC) of BA were determined. The changes of PC, PA, and AC were significant indicators for the evaluation of different fermentation times. On the basis of the odor data of BA obtained by electronic nose technology (E-nose), the principal component analysis (PCA) was used to identify bile species. The results were further verified by the least squares support vector machine (LS-SVM). The trained LS-SVM was also used to predict the PC, PA, and AC of the samples to identify fermentation time. The present study indicated that E-nose combined with LS-SVM could effectively predict the PC, PA, and AC of the samples and identify the bile species and fermentation time of BA, and it was proved to be a useful strategy for quality control of fermented products of TCMs. PMID- 29397687 TI - Transferability of MCR-1/2 Polymyxin Resistance: Complex Dissemination and Genetic Mechanism. AB - Polymyxins, a group of cationic antimicrobial polypeptides, act as a last-resort defense against lethal infections by carbapenem-resistant Gram-negative pathogens. Recent emergence and fast spread of mobilized colistin resistance determinant mcr-1 argue the renewed interest of colistin in clinical therapies, threatening global public health and agriculture production. This mini-review aims to present an updated overview of mcr-1, covering its global dissemination, the diversity of its hosts/plasmid reservoirs, the complexity in the genetic environment adjacent to mcr-1, the appearance of new mcr-like genes, and the molecular mechanisms for mobilized colistin resistance determinant 1/2 (MCR-1/2). PMID- 29397688 TI - Rational Synthesis and Assembly of Ni3S4 Nanorods for Enhanced Electrochemical Sodium-Ion Storage. AB - Even though advocated as the potential low-cost alternatives to current lithium ion technology, the practical viability of sodium-ion batteries remains illusive and depends on the development of high-performance electrode materials. Very few candidates available at present can simultaneously meet the requirements on capacity, rate capability, and cycle life. Herein, we report a high-temperature solution method to prepare Ni3S4 nanorods with uniform sizes. These colloidal nanorods readily self-assemble side by side and form microsized superstructures, which unfortunately negates the nanoscale feature of individual nanorods. To this end, we further introduce two-dimensional graphene nanosheets as the spacer to interrupt nanorod self-assembly. Resultant composite presents a marked advantage toward electrochemical storage of Na+ ions. We demonstrate that in half-cells it exhibits large reversible specific capacity in excess of 600 mAh/g, high rate capability with >300 mAh/g retained at 4 A/g, and great cycle life at different current rates. This anode material can also be combined with the NASICON-type Na3V2(PO4)3 cathode in full cells to enable large capacity and good cyclability. PMID- 29397689 TI - Dual Roles of Graphene Oxide To Attenuate Inflammation and Elicit Timely Polarization of Macrophage Phenotypes for Cardiac Repair. AB - Development of localized inflammatory environments by M1 macrophages in the cardiac infarction region exacerbates heart failure after myocardial infarction (MI). Therefore, the regulation of inflammation by M1 macrophages and their timely polarization toward regenerative M2 macrophages suggest an immunotherapy. Particularly, controlling cellular generation of reactive oxygen species (ROS), which cause M1 differentiation, and developing M2 macrophage phenotypes in macrophages propose a therapeutic approach. Previously, stem or dendritic cells were used in MI for their anti-inflammatory and cardioprotective potentials and showed inflammation modulation and M2 macrophage progression for cardiac repair. However, cell-based therapeutics are limited due to invasive cell isolation, time consuming cell expansion, labor-intensive and costly ex vivo cell manipulation, and low grafting efficiency. Here, we report that graphene oxide (GO) can serve as an antioxidant and attenuate inflammation and inflammatory polarization of macrophages via reduction in intracellular ROS. In addition, GO functions as a carrier for interleukin-4 plasmid DNA (IL-4 pDNA) that propagates M2 macrophages. We synthesized a macrophage-targeting/polarizing GO complex (MGC) and demonstrated that MGC decreased ROS in immune-stimulated macrophages. Furthermore, DNA-functionalized MGC (MGC/IL-4 pDNA) polarized M1 to M2 macrophages and enhanced the secretion of cardiac repair-favorable cytokines. Accordingly, injection of MGC/IL-4 pDNA into mouse MI models attenuated inflammation, elicited early polarization toward M2 macrophages, mitigated fibrosis, and improved heart function. Taken together, the present study highlights a biological application of GO in timely modulation of the immune environment in MI for cardiac repair. Current therapy using off-the-shelf material GO may overcome the shortcomings of cell therapies for MI. PMID- 29397690 TI - Terahertz Time-Domain Spectroscopy of Plasticized Poly(vinyl chloride). AB - Poly(vinyl chloride) (PVC) is today one of the most important commodity polymers. Its broad range of applications is due to the presence of plasticizers whose concentration largely impacts the microscopic and the macroscopic properties. Quantifying the concentration of plasticizer in PVC products is therefore of fundamental importance. Thus, in this paper, the applicability of terahertz (THz) time-domain spectroscopy for the characterization of plasticized PVC is for the first time evaluated in a systematic way. It could be demonstrated that the method is able to distinguish between PVC samples with different types and concentrations of plasticizers. Furthermore, a simple, fast, and efficient method is introduced to quantify the concentration of plasticizer in PVC samples of known plasticizer type but different thermal histories. The presented results are of key importance due to the need of reliable noninvasive and nondestructive analytical methods which can deliver onsite information about the remaining plasticizer concentration inside PVC products. Furthermore, it is expected that the proposed approach can be easily extended to other plasticized polymers. PMID- 29397691 TI - Parameter Optimization for Feature and Hit Generation in a General Unknown Screening Method-Proof of Concept Study Using a Design of Experiment Approach for a High Resolution Mass Spectrometry Procedure after Data Independent Acquisition. AB - High resolution mass spectrometry and modern data independent acquisition (DIA) methods enable the creation of general unknown screening (GUS) procedures. However, even when DIA is used, its potential is far from being exploited, because often, the untargeted acquisition is followed by a targeted search. Applying an actual GUS (including untargeted screening) produces an immense amount of data that must be dealt with. An optimization of the parameters regulating the feature detection and hit generation algorithms of the data processing software could significantly reduce the amount of unnecessary data and thereby the workload. Design of experiment (DoE) approaches allow a simultaneous optimization of multiple parameters. In a first step, parameters are evaluated (crucial or noncrucial). Second, crucial parameters are optimized. The aim in this study was to reduce the number of hits, without missing analytes. The obtained parameter settings from the optimization were compared to the standard settings by analyzing a test set of blood samples spiked with 22 relevant analytes as well as 62 authentic forensic cases. The optimization lead to a marked reduction of workload (12.3 to 1.1% and 3.8 to 1.1% hits for the test set and the authentic cases, respectively) while simultaneously increasing the identification rate (68.2 to 86.4% and 68.8 to 88.1%, respectively). This proof of concept study emphasizes the great potential of DoE approaches to master the data overload resulting from modern data independent acquisition methods used for general unknown screening procedures by optimizing software parameters. PMID- 29397692 TI - Tuning Electronic Structure of Single Layer MoS2 through Defect and Interface Engineering. AB - Transition-metal dichalcogenides (TMDs) have emerged in recent years as a special group of two-dimensional materials and have attracted tremendous attention. Among these TMD materials, molybdenum disulfide (MoS2) has shown promising applications in electronics, photonics, energy, and electrochemistry. In particular, the defects in MoS2 play an essential role in altering the electronic, magnetic, optical, and catalytic properties of MoS2, presenting a useful way to engineer the performance of MoS2. The mechanisms by which lattice defects affect the MoS2 properties are unsettled. In this work, we reveal systematically how lattice defects and substrate interface affect MoS2 electronic structure. We fabricated single-layer MoS2 by chemical vapor deposition and then transferred onto Au, single-layer graphene, hexagonal boron nitride, and CeO2 as substrates and created defects in MoS2 by ion irradiation. We assessed how these defects and substrates affect the electronic structure of MoS2 by performing X-ray photoelectron spectroscopy, Raman and photoluminescence spectroscopies, and scanning tunneling microscopy/spectroscopy measurements. Molecular dynamics and first-principles based simulations allowed us to conclude the predominant lattice defects upon ion irradiation and associate those with the experimentally obtained electronic structure. We found that the substrates can tune the electronic energy levels in MoS2 due to charge transfer at the interface. Furthermore, the reduction state of CeO2 as an oxide substrate affects the interface charge transfer with MoS2. The irradiated MoS2 had a faster hydrogen evolution kinetics compared to the as-prepared MoS2, demonstrating the concept of defect controlled reactivity in this phase. Our findings provide effective probes for energy band and defects in MoS2 and show the importance of defect engineering in tuning the functionalities of MoS2 and other TMDs in electronics, optoelectronics, and electrochemistry. PMID- 29397693 TI - Synthetic Control over Quantum Well Width Distribution and Carrier Migration in Low-Dimensional Perovskite Photovoltaics. AB - Metal halide perovskites have achieved photovoltaic efficiencies exceeding 22%, but their widespread use is hindered by their instability in the presence of water and oxygen. To bolster stability, researchers have developed low dimensional perovskites wherein bulky organic ligands terminate the perovskite lattice, forming quantum wells (QWs) that are protected by the organic layers. In thin films, the width of these QWs exhibits a distribution that results in a spread of bandgaps in the material arising due to varying degrees of quantum confinement across the population. Means to achieve refined control over this QW width distribution, and to examine and understand its influence on photovoltaic performance, are therefore of intense interest. Here we show that moving to the ligand allylammonium enables a narrower distribution of QW widths, creating a flattened energy landscape that leads to *1.4 and *1.9 longer diffusion lengths for electrons and holes, respectively. We attribute this to reduced ultrafast shallow hole trapping that originates from the most strongly confined QWs. We observe an increased PCE of 14.4% for allylammonium-based perovskite QW photovoltaics, compared to 11-12% PCEs obtained for analogous devices using phenethylammonium and butylammonium ligands. We then optimize the devices using mixed-cation strategies, achieving 16.5% PCE for allylammonium devices. The devices retain 90% of their initial PCEs after >650 h when stored under ambient atmospheric conditions. PMID- 29397694 TI - Pressure and Temperature Dependent Structural Studies on Hollandite Type Ferrotitanate and Crystal Structure of a High Pressure Phase. AB - The structural stability and phase transition behavior of tetragonal (I4/m) hollandite type K2Fe2Ti6O16 have been investigated by in situ high pressure X-ray diffraction using synchrotron radiation and a diamond anvil cell as well as by variable temperature powder neutron and X-ray diffraction. The tetragonal phase is found to be stable in a wider range of temperatures, while it reversibly transforms to a monoclinic (I2/m) structure at a moderate pressure, viz. 3.6 GPa. The pressure induced phase transition occurs with only a marginal change in structural arrangements. The unit cell parameters of ambient (t) and high pressure (m) phases can be related as am ~ at, bm ~ ct, and cm ~ bt. The pressure evolution of the unit cell parameters indicates anisotropic compression with betaa = betab >= betac in the tetragonal phase and becomes more anisotropic with betaa ? betab < betac in the monoclinic phase. The pressure-volume equations of state of both phases have been obtained by second order Birch-Murnaghan equations of state, and the bulk moduli are 122 and 127 GPa for tetragonal and monoclinic phases, respectively. The temperature dependent unit cell parameters show nearly isotropic expansion, with marginally higher expansion along the c-axis compared to the a- and b-axes. The tetragonal to monoclinic phase transition occurs with a reduction of unit cell volume of about 1.1% while the reduction of unit cell volume up to 6 K is only about 0.6%. The fitting of temperature dependent unit cell volume by using the Einstein model of phonons indicates the Einstein temperature is about 266(18) K. PMID- 29397695 TI - Temporal Changes and Stereoisomeric Compositions of 1,2,5,6,9,10 Hexabromocyclododecane and 1,2-Dibromo-4-(1,2-dibromoethyl)cyclohexane in Marine Mammals from the South China Sea. AB - Stereoisomeric compositions of 1,2,5,6,9,10-hexabromocyclododecane (HBCD) and 1,2 dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH) were investigated in the blubber of two species of marine mammals, finless porpoises ( Neophocaena phocaenoides) and Indo-Pacific humpback dolphins ( Sousa chinensis), from the South China Sea between 2005 and 2015. The concentrations of SigmaHBCD in samples of porpoise ( n = 59) and dolphin ( n = 32) ranged from 97.2 to 6,260 ng/g lipid weight (lw) and from 447 to 45,800 ng/g lw, respectively, while those of SigmaTBECH were both roughly 2 orders of magnitude lower. A significant increasing trend of SigmaHBCD was found in dolphin blubber over the past decade. The diastereomeric profiles exhibited an absolute predominance of alpha-HBCD (mostly >90%), while the proportions of four TBECH diastereomers in the samples appeared similar. A preferential enrichment of the (-)-enantiomers of alpha-, beta-, and gamma-HBCD was found in most blubber samples. Interestingly, the body lengths of porpoises showed a significant negative correlation with the enantiomer fractions of alpha HBCD. Significant racemic deviations were also observed for alpha-, gamma-, and delta-TBECH enantiomeric pairs. This is the first report of the presence of TBECH enantiomers in the environment. The estimated hazard quotient indicates that there is a potential risk to dolphins due to HBCD exposure. PMID- 29397696 TI - Isolation of Phytotoxic Phenols and Characterization of a New 5-Hydroxymethyl-2 isopropoxyphenol from Dothiorella vidmadera, a Causal Agent of Grapevine Trunk Disease. AB - Polyphenols were characterized from Dothiorella vidmadera (DAR78993), which was isolated from a grapevine in Australia. In total, six polyphenols were isolated including a new polyphenol characterized by a spectroscopic method (essentially NMR and HR ESIMS) as 5-hydroxymethyl-2-isopropoxyphenol. Tyrosol, benzene-1,2,4 triol, resorcinol, 3-(hydroxymethyl)phenol, and protocatechuic alcohol, the latter being the main metabolite, were also isolated. Although these are already known as naturally occurring compounds in microorganisms and plants, this is the first time they have been isolated from fungal organisms involved in grapevine trunk disease. When assayed on tomato seedlings, all the compounds show similar phytotoxic effects. However, when assayed on grapevine leaves (Vitis vinifera cv Shiraz), resorcinol was the most toxic compound, followed by protocatechuic alcohol and 5-hydroxymethyl-2-isopropoxyphenol. PMID- 29397697 TI - Oxygen Vacancy Engineering in Europia Clusters/Graphite-Like Carbon Nitride Nanostructures Induced Signal Amplification for Highly Efficient Electrochemiluminesce Aptasensing. AB - Oxygen vacancy is an intrinsic defect in metal oxide semiconductors and has a crucial influence on their physicochemical and electronic properties. To boost the electrochemiluminescence (ECL) efficiency of the graphite-like carbon nitride (g-C3N4), the wet-chemical-calcination method was developed to introduce an oxygen vacancy in Eu-doped g-C3N4 nanostructures for the first time. The morphology and structure characterization suggest that the Eu element was present in the matrix of the europia (Eu2O3) clusters. Because of the effect of oxygen vacancy promoting catalytic activity, the doping of Eu caused a great positive shift of onset potential and large signal amplification in cathodic ECL signals compared with pure g-C3N4. Furthermore, a novel and ultrasensitive ECL aptasensor was realized with 17beta-estradiol (E2) as a prototype target by adsorption of E2 aptamer onto the Eu2O3-doped g-C3N4 (Eu2O3- g-C3N4) surface via van der Waals force. Given the specific recognition between aptamer and E2, the ECL signal decreased with the increasing concentration of E2, because the formation of E2 aptamer complex impeded the diffusion of luminophor molecules and the electrons approaching the surface of the electrode. Under the optimal cases, the as prepared ECL aptasensor showed superior performances and also manifested outstanding selectivity toward E2. The present conceptual strategy offers a novel methodology to boost the sensitivity of the ECL sensor and promote the activity of ECL reagents. PMID- 29397698 TI - Comprehensive Screening Links Halogenated Organic Compounds with Testosterone Levels in Male Delphinus delphis from the Southern California Bight. AB - While environmental pollutants have been associated with changes in endocrine health in cetaceans, efforts to link contaminant exposure with hormones have largely been limited to a list of known, targeted contaminants, overlooking minimally characterized or unknown compounds of emerging concern. To address this gap, we analyzed a suite of potential endocrine disrupting halogenated organic compounds (HOCs) in blubber from 16 male short-beaked common dolphins ( Delphinus delphis) with known maturity status collected from fishery bycatch in the Southern California Bight. We employed a suspect screening mass spectrometry based method to investigate a wide range of HOCs that were previously observed in cetaceans from the same region. Potential endocrine effects were assessed through the measurement of blubber testosterone. We detected 167 HOCs, including 81 with known anthropogenic sources, 49 of unknown origin, and 37 with known natural sources. The sum of 11 anthropogenic and 4 unknown HOC classes were negatively correlated with blubber testosterone. Evidence suggests that elevated anthropogenic HOC load contributes to impaired testosterone production in mature male D. delphis. The application of this integrative analytical approach to cetacean contaminant analysis allows for inference of the biological consequences of accumulation of HOCs and prioritization of compounds for future environmental toxicology research. PMID- 29397699 TI - Double Transfer Voltammetry in Two-Polarizable Interface Systems: Effects of the Lipophilicity and Charge of the Target and Compensating Ions. AB - Analytical expressions are obtained for the study of the net current and individual fluxes across macro- and micro-liquid/liquid interfaces in series as those found in ion sensing with solvent polymeric membranes and in ion-transfer batteries. The mathematical solutions deduced are applicable to any voltammetric technique, independently of the lipophilicity and charge number of the target and compensating ions. When supporting electrolytes of semihydrophilic ions are employed, the so-called double transfer voltammograms have a tendency to merge into a single signal, which complicates notably the modeling and analysis of the electrochemical response. The present theoretical results point out that the appearance of one or two voltammetric waves is highly dependent on the size of the interfaces and on the viscosity of the organic solution. Hence, the two latter can be adjusted experimentally in order to "split" the voltammograms and extract information about the ions involved. This has been illustrated in this work with the experimental study in water | 1,2-dichloroethane | water cells of the transfer of the monovalent tetraethylammonium cation compensated by anions of different lipophilicity, and also of the divalent hexachloroplatinate anion. PMID- 29397700 TI - Synthesis of DNA Modified with Boronic Acid: Compatibility to Copper(I)-Catalyzed Azide-Alkyne Cycloaddition. AB - The postsynthetic and sequence-specific ligation chemistry of a phenylboronic acid to oligonucleotides using the amide bond formation was worked out. In the first coupling experiments with 4-carboxyphenylboronic acid, a 5'-hexylamino modified oligonucleotide was used to evaluate and optimize the reaction conditions. This postsynthetic modification works best in the presence of TBTU and triethanolamine and in a degassed DMF/carbonate buffer solvent mixture. The successful attachment of the boronic acid was evidenced by HPLC separation from phenol side products and clear identification via MALDI-TOF mass spectrometry as a citric acid derivative. This postsynthetic chemistry was further combined with the established Cu(I)-catalyzed azide-alkyne cycloaddition chemistry to allow the first orthogonal and postsynthetic incorporation of both the phenylboronic acid moiety and two different cyanine-styryl dyes. Because of the undesired reactivity of boronic acids by the presence of copper salts, the dye azides were first attached to the presynthesized oligonucleotides using the Cu(I)-catalyzed cycloaddition at the 2'-position of a propargylated uridine. After careful removal of all copper contaminants, the amide bond with the 4 carboxyphenylboronic acid at the propylamine linker of a 7-deaza-2' deoxyadenosine as anchor point was formed. These doubly modified oligonucleotides were characterized by their optical properties to elucidate the influence of the phenylboronic acid. The latter modification has only little influence on the fluorescence of the applied dyes. In conclusion, this postsynthetic and orthogonal chemistry opens the way to a broad variety of applications, in particular, saccharide detection based on fluorescent DNA aptamers. PMID- 29397701 TI - Developmental Effects and Estrogenicity of Bisphenol A Alternatives in a Zebrafish Embryo Model. AB - In order to understand the negative effects of bisphenol A (BPA) alternatives comprehensively, zebrafish embryos were used to assess the lethality, developmental effects, and estrogenic activity of bisphenol analogues. The in silico estrogenic activities of bisphenol analogues were assayed by binding simulation. According to our results, the lethality of bisphenol analogues decreased in order of bisphenol AF (BPAF) > BPA > bisphenol F (BPF) > bisphenol S (BPS). BPAF and BPF induced significant effects on zebrafish embryos, including decreased heart rate, hatching inhibition, and teratogenic effects. The binding potentials of bisphenol analogues toward zebrafish ERs (zfERS) decreased in the following order: BPAF > BPA > BPF > BPS. Among the three subtypes of zfERs, zfERbeta2 showed the highest binding activity toward the bisphenols, followed by zfERalpha and zfERbeta1. In vivo estrogenic activity tests showed that BPAF, BPA, and BPF significantly enhanced the protein levels of ERalpha along with the mRNA levels of esr1, esr2a, esr2b, and vtg1 in zebrafish embryos. Esr2b showed the strongest response to BPAF and BPA exposure among the three esrs. In contrast, BPS did not significantly regulate ER protein level or ER transcription. In conclusion, BPAF showed the highest lethality, developmental effects, and estrogenic activity (both in silico and in vivo) followed by BPA and BPF. BPS showed the weakest toxicity and estrogenic activity. zfERbeta2 might act as the main target among the three ER subtypes of zebrafish after exposure to BPAF and BPA. PMID- 29397702 TI - Plasmonic Enhancement Coupling with Defect-Engineered TiO2-x: A Mode for Sensitive Photoelectrochemical Biosensing. AB - This work demonstrates that the photoelectric response of defect-engineered TiO2 x modified with Au nanoparticles can be modulated by oxygen vacancy concentration and excitation wavelength. When strongly plasmonic Au nanoparticles are anchored to defect-engineered TiO2-x by DNA hybridization, several times plasmonic enhancement of photocurrent occurs under 585 nm excitation, and it is employed as a novel signaling mode for developing an improved photoelectrochemical sensing platform. This signaling mode combined with exonuclease III-assisted target recycling amplification exhibits excellent analytical performance, which provides a novel photoelectrochemical detection protocol. PMID- 29397703 TI - Impacts of Salinity and Temperature on the Thyroidogenic Effects of the Biocide Diuron in Menidia beryllina. AB - Diuron is a herbicide used in agricultural and urban settings and also as an antifouling agent. Recent studies have indicated sublethal responses of diuron in the endocrine system of fish and amphibians. Given the potential of climate change to also alter fish endocrinology, the combination of environmental stressors with diuron may contribute to its sublethal toxicity. In this study, the effects of temperature and salinity on thyroid targets of diuron were assessed in juveniles of the estuarine fish Menidia beryllina under different conditions of salinity (10 and 200/00) and temperature (10 and 20 degrees C). Environmentally relevant concentrations of diuron affected the growth, and the higher temperature reduced the condition factor of animals. Increased levels of T3 were observed in fish from all treatments, and at 10 degrees C, T4 levels were augmented at 100/00 but reduced at 200/00. Increased gene expression of deiodinases at 200/00 in both temperatures suggests the influence of salinity on the regulation of hormone imbalance via deiodination pathway activation. Decreased transcripts of thyroid and growth hormone receptors were also observed following diuron treatment. These results indicate that changes in environmental stressors may have significant impacts on the ecological risk of diuron in estuarine fish. PMID- 29397704 TI - UV/Nitrilotriacetic Acid Process as a Novel Strategy for Efficient Photoreductive Degradation of Perfluorooctanesulfonate. AB - Perfluorooctanesulfonate (PFOS) is a toxic, bioaccumulative, and highly persistent anthropogenic chemical. Hydrated electrons ( eaq-) are potent nucleophiles that can effectively decompose PFOS. In previous studies, eaq- are mainly produced by photoionization of aqueous anions or aromatic compounds. In this study, we proposed a new photolytic strategy to generate eaq- and in turn decompose PFOS, which utilizes nitrilotriacetic acid (NTA) as a photosensitizer to induce water photodissociation and photoionization, and subsequently as a scavenger of hydroxyl radical (*OH) to minimize the geminate recombination between *OH and eaq-. The net effect is to increase the amount of eaq- available for PFOS degradation. The UV/NTA process achieved a high PFOS degradation ratio of 85.4% and a defluorination ratio of 46.8% within 10 h. A pseudo-first-order rate constant ( k) of 0.27 h-1 was obtained. The laser flash photolysis study indicates that eaq- is the dominant reactive species responsible for PFOS decomposition. The generation of eaq- is greatly enhanced and its half-life is significantly prolonged in the presence of NTA. The electron spin resonance (ESR) measurement verified the photodissociation of water by detecting *OH. The model compound study indicates that the acetate and amine groups are the primary reactive sites. PMID- 29397705 TI - Conformational MU-Conotoxin PIIIA Isomers Revisited: Impact of Cysteine Pairing on Disulfide-Bond Assignment and Structure Elucidation. AB - Peptides and proteins carrying high numbers of cysteines can adopt various 3D structures depending on their disulfide connectivities. The unambiguous verification of such conformational isomers with more than two disulfide bonds is extremely challenging, and experimental strategies for their unequivocal structural analysis are largely lacking. We synthesized all 15 possible isomers of the 22mer conopeptide MU-PIIIA and applied 2D NMR spectroscopy and MS/MS for the elucidation of its structure. This study provides intriguing insights in how the disulfide connectivity alters the global fold of a toxin. We also show that analysis procedures involving comprehensive combinations of conventional methods are required for the unambiguous assignment of disulfides in cysteine-rich peptides and proteins and that standard compounds are crucially needed for the structural analysis of such complex molecules. PMID- 29397706 TI - Effect of Electric Field on Gas Hydrate Nucleation Kinetics: Evidence for the Enhanced Kinetics of Hydrate Nucleation by Negatively Charged Clay Surfaces. AB - Natural gas hydrates are found widely in oceanic clay-rich sediments, where clay water interactions have a profound effect on the formation behavior of gas hydrates. However, it remains unclear why and how natural gas hydrates are formed in clay-rich sediments in spite of factors that limit gas hydrate formation, such as small pore size and high salinity. Herein, we show that polarized water molecules on clay surfaces clearly promote gas hydrate nucleation kinetics. When water molecules were polarized with an electric field of 104 V/m, gas hydrate nucleation occurred significantly faster with an induction time reduced by 5.8 times. Further, the presence of strongly polarized water layers at the water-gas interface hindered gas uptake and thus hydrate formation, when the electric field was applied prior to gas dissolution. Our findings expand our understanding of the formation habits of naturally occurring gas hydrates in clay-rich sedimentary deposits and provide insights into gas production from natural hydrate deposits. PMID- 29397707 TI - Uptake and Depuration Kinetics Influence Microplastic Bioaccumulation and Toxicity in Antarctic Krill ( Euphausia superba). AB - The discarding of plastic products has led to the ubiquitous occurrence of microplastic particles in the marine environment. The uptake and depuration kinetics of ingested microplastics for many marine species still remain unknown despite its importance for understanding bioaccumulation potential to higher trophic level consumers. In this study, Antarctic krill ( Euphausia superba) were exposed to polyethylene microplastics to quantify acute toxicity and ingestion kinetics, providing insight into the bioaccumulation potential of microplastics at the first-order consumer level. In the 10 day acute toxicity assay, no mortality or dose-dependent weight loss occurred in exposed krill, at any of the exposure concentrations (0, 10, 20, 40, or 80% plastic diet). Krill exposed to a 20% plastic diet for 24 h displayed fast uptake (22 ng mg-1 h-1) and depuration (0.22 h-1) rates, but plastic uptake did not reach steady state. Efficient elimination also resulted in no bioaccumulation over an extended 25 day assay, with most individuals completely eliminating their microplastic burden in less than 5 days post exposure. Our results support recent findings of limited acute toxicity of ingested microplastics at this trophic level, and suggest sublethal chronic end points should be the focus of further ecotoxicological investigation. PMID- 29397708 TI - Electron Accumulative Molecules. AB - With the goal to produce molecules with high electron accepting capacity and low reorganization energy upon gaining one or more electrons, a synthesis procedure leading to the formation of a B-N(aromatic) bond in a cluster has been developed. The research was focused on the development of a molecular structure able to accept and release a specific number of electrons without decomposing or change in its structural arrangement. The synthetic procedure consists of a parallel decomposition reaction to generate a reactive electrophile and a synthesis reaction to generate the B-N(aromatic) bond. This procedure has paved the way to produce the metallacarboranylviologen [M(C2B9H11)(C2B9H10)-NC5H4-C5H4N M'(C2B9H11)(C2B9H10)] (M = M' = Co, Fe and M = Co and M' = Fe) and semi(metallacarboranyl)viologen [3,3'-M(8-(NC5H4-C5H4N-1,2-C2B9H10)(1',2' C2B9H11)] (M = Co, Fe) electron cumulative molecules. These molecules are able to accept up to five electrons and to donate one in single electron steps at accessible potentials and in a reversible way. By targeted synthesis and corresponding electrochemical tests each electron transfer (ET) step has been assigned to specific fragments of the molecules. The molecules have been carefully characterized, and the electronic communication between both metal centers (when this situation applies) has been definitely observed through the coplanarity of both pyridine fragments. The structural characteristics of these molecules imply a low reorganization energy that is a necessary requirement for low energy ET processes. This makes them electronically comparable to fullerenes, but on their side, they have a wide range of possible solvents. The ET from one molecule to another has been clearly demonstrated as well as their self organizing capacity. We consider that these molecules, thanks to their easy synthesis, ET, self-organizing capacity, wide range of solubility, and easy processability, can find important application in any area where ET is paramount. PMID- 29397709 TI - Absorbent Pads Containing N-Halamine Compound for Potential Antimicrobial Use for Chicken Breast and Ground Chicken. AB - N-Halamines are a group of compounds containing one or more nitrogen-halogen covalent bond(s), and the high-energy halide bond provides a strong oxidative state so that it is able to inactivate microorganisms effectively. In this study, the shelf life of chicken breast and ground chicken packed with 1-chloro-2,2,5,5 tetramethyl-4-imidazolidinone (MC, a member oft the N-halamines) treated absorbent pads was investigated during refrigerated storage. Fresh, processed chicken meat in packaging trays loaded with or without MC treated absorbent pads were stored at 4 degrees C for 11 days. The microbial counts in chicken meat as well as in the food pads were analyzed on days 1, 4, 7, and 11. MC treated pads reduced the levels of the main spoilage-related microorganisms (aerobic plate counts, lactic acid bacteria, Enterobacteriaceae, psychrotrophs, and Pseudomonas spp.) present in the absorbent pads by an average of 3.5 log CFU/g compared to the control. Microbial loads in chicken breast packed with MC coated absorbent pads were 0.3 log CFU/g lower than those in the control, and an approximate 0.2 log CFU/g reduction was observed for ground chicken. Neither the color nor the pH of the meat was negatively impacted by the presence of MC. The populations of inoculated Salmonella and Campylobacter in meat loaded with MC treated absorbent pads were on average lower than those in the controls. Pathogens in the control pads increased to 3.7 and 4.9 log CFU/g, while the MC treated absorbent pads lowered these two bacteria to under the detection limit (l.7 log CFU/g) throughout 11 days of storage. PMID- 29397710 TI - Analysis of Umami Taste Compounds in a Fermented Corn Sauce by Means of Sensory Guided Fractionation. AB - Corn sauce, an ingredient obtained from the fermentation of enzymatically hydrolyzed corn starch and used in culinary applications to provide savory taste, was investigated in this study. The links between its sensory properties and taste compounds were assessed using a combination of analytical and sensory approaches. The analyses revealed that glutamic acid, sodium chloride, and acetic acid were the most abundant compounds, but they could not explain entirely the savory taste. The addition of other compounds, found at subthreshold concentrations (alanine, glutamyl peptides, and one Amadori compound), contributed partly to close the sensory gap between the re-engineered sample and the original product. Further chemical breakdown, by a sensory-guided fractionation approach, led to the isolation of two fractions with taste modulating effects. Analyses by mass spectrometry and nuclear magnetic resonance showed that the fractions contained glutamyl peptides, pyroglutamic acid, glutamic acid, valine, N-formyl-glutamic acid, and N-acetyl-glutamine. PMID- 29397711 TI - Comprehensive Dissection of Metabolic Changes in Albino and Green Tea Cultivars. AB - Albino tea cultivars are special mutants of tea plants with white or yellow leaf color. In this study, three albino tea cultivars, including 'Anji Baicha', 'Huangjinya', and 'Baijiguan', and two green tea cultivars, 'Longjing 43' and 'Fuding Dabaicha', were applied to metabolite profiling by gas chromatography mass spectrometry and ultraperformance liquid chromatography-mass spectrometry. Multivariate analyses revealed significantly different metabolite phenotypes in leaves among albino cultivars and green cultivars. The differential metabolite related pathways included galactose metabolism, tryptophan metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis. For the young leaves of albino cultivars, the sugar (sorbitol and erythrose) and amino acid (mainly proline, isoleucine, ornithine, aspartic acid, threonine, and valine) concentrations increased, whereas gallocatechin and epigallocatechin gallate concentrations decreased. These results reveal the divergence in metabolic profiling between tea plant cultivars with different leaf colors. With the development of leaves, the concentrations of flavonoids increased largely in the older leaves of albino cultivars. PMID- 29397712 TI - GW100: Comparison of Methods and Accuracy of Results Obtained with the WEST Code. AB - The reproducibility of calculations carried out within many-body perturbation theory at the G0 W0 level is assessed for 100 closed shell molecules and compared to that of density functional theory. We consider vertical ionization potentials (VIP) and electron affinities (VEA) obtained with five different codes: BerkeleyGW, FHI-aims, TURBOMOLE, VASP, and WEST. We review the approximations and parameters that control the accuracy of G0 W0 results in each code, and we discuss in detail the effect of extrapolation techniques for the parameters entering the WEST code. Differences between the VIP and VEA computed with the various codes are within ~60 and ~120 meV, respectively, which is up to four times larger than in the case of the best results obtained with DFT codes. Vertical ionization potentials are validated against experiment and CCSD(T) quantum chemistry results showing a mean absolute relative error of ~4% for data obtained with WEST. Our analysis of the differences between localized orbitals and plane-wave implementations points out molecules containing Cu, I, Ga, and Xe as major sources of discrepancies, which call for a re-evaluation of the pseudopotentials used for these systems in G0 W0 calculations. PMID- 29397713 TI - Sunflower Oil and Nannochloropsis oculata Microalgae as Sources of Unsaturated Fatty Acids for Mitigation of Methane Production and Enhancing Diets' Nutritive Value. AB - The objective of this assay was to investigate the effect of adding sunflower oil, Nannochloropsis oculata microalgae and their mixture at 0, 1, 2, 3, 4, and 5% to three total mixed rations (TMRs) with different concentrate:forage ratios (40C:60F, 50C:50F, and 60C:40F) on in vitro gas production (GP), methane (CH4) production, and nutrient degradability. Asymptotic GP, GP rate, CH4 concentration/g acid detergent fiber (ADF), dry matter (DM) degradability (DMD), short chain fatty acids (SCFAs), and ruminal bacteria population increased, but neutral detergent fiber (NDF) degradability (NDFD), ADF degradability (ADFD), and protozoa count decreased with increasing concentrate level in the TMR. Methane production/g DM and NDF was higher for 50C:50F TMR. Sunflower oil reduced asymptotic GP, lag time, CH4 production/g ADF, ammonia-N (NH3-N), and SCFA. Compared to the control treatments, additives decreased GP rate, while sunflower oil/N. oculata mixture increased DMD and NDFD. All additives at 5% increased GP rate and lag time and decreased CH4 production/g DM, ADF, and NDF, ruminal NH3-N, and protozoa count. All additives at 2% increased DMD, NDFD and ADFD, SCFA, and bacteria population. Supplementation of TMR, containing different concentrate:forage ratios, with sunflower oil, N. oculata, and sunflower oil/N. oculata mixture at different doses modified in vitro GP, CH4 production, and nutrient degradability. PMID- 29397714 TI - Whey Peptide-Iron Complexes Increase the Oxidative Stability of Oil-in-Water Emulsions in Comparison to Iron Salts. AB - Food fortification with iron may favor lipid oxidation in both food matrices and the human body. This study aimed at evaluating the effect of peptide-iron complexation on lipid oxidation catalyzed by iron, using oil-in-water (O/W) emulsions as a model system. The extent of lipid oxidation of emulsions containing iron salts (FeSO4 or FeCl2) or iron complexes (peptide-iron complexes or ferrous bisglycinate) was evaluated during 7 days, measured as primary (peroxide value) and secondary products (TBARS and volatile compounds). Both salts catalyzed lipid oxidation, leading to peroxide values 2.6- to 4.6-fold higher than the values found for the peptide-iron complexes. The addition of the peptide-iron complexes resulted in the formation of lower amounts of secondary volatiles of lipid oxidation (up to 78-fold) than those of iron salts, possibly due to the antioxidant activity of the peptides and their capacity to keep iron apart from the lipid phase, since the iron atom is coordinated and takes part in a stable structure. The peptide-iron complexes showed potential to reduce the undesirable sensory changes in food products and to decrease the side effects related to free iron and the lipid damage of cell membranes in the organism, due to the lower reactivity of iron in the complexed form. PMID- 29397715 TI - Crispenes F and G, cis-Clerodane Furanoditerpenoids from Tinospora crispa, Inhibit STAT3 Dimerization. AB - Two new cis-clerodane-type furanoditerpenes, crispenes F and G (1 and 2), together with seven known compounds, were isolated from the stems of Tinospora crispa. Crispenes F and G (1 and 2) inhibited STAT3 dimerization in a cell-free fluorescent polarization assay and were found to have significant cytotoxicity against a STAT3-dependent MDA-MB 231 breast cancer cell line, while being inactive in a STAT3-null A4 cell line. These two compounds share structural similarities with a previously reported STAT3 inhibitor, crispene E, isolated from the same plant. Molecular docking studies suggested that the molecules inhibit STAT3 by interacting with its SH2 domain. PMID- 29397716 TI - Effects of Developmental Stages and Reduced UVB and Low UV Conditions on Plant Secondary Metabolite Profiles in Pak Choi (Brassica rapa subsp. chinensis). AB - Pak choi (Brassica rapa subsp. chinensis) is rich in secondary metabolites and contains numerous antioxidants, including flavonoids; hydroxycinnamic acids; carotenoids; chlorophylls; and glucosinolates, which can be hydrolyzed to epithionitriles, nitriles, or isothiocyanates. Here, we investigate the effect of reduced exposure to ultraviolet B (UVB) and UV (UVA and UVB) light at four different developmental stages of pak choi. We found that both the plant morphology and secondary metabolite profiles were affected by reduced exposure to UVB and UV, depending on the plant's developmental stage. In detail, mature 15- and 30-leaf plants had higher concentrations of flavonoids, hydroxycinnamic acids, carotenoids, and chlorophylls, whereas sprouts contained high concentrations of glucosinolates and their hydrolysis products. Dry weights and leaf areas increased as a result of reduced UVB and low UV. For the flavonoids and hydroxycinnamic acids in 30-leaf plants, less complex compounds were favored, for example, sinapic acid acylated kaempferol triglycoside instead of the corresponding tetraglycoside. Moreover, also in 30-leaf plants, zeaxanthin, a carotenoid linked to protection during photosynthesis, was increased under low UV conditions. Interestingly, most glucosinolates were not affected by reduced UVB and low UV conditions. However, this study underlines the importance of 4 (methylsulfinyl)butyl glucosinolate in response to UVA and UVB exposure. Further, reduced UVB and low UV conditions resulted in higher concentrations of glucosinolate-derived nitriles. In conclusion, exposure to low doses of UVB and UV from the early to late developmental stages did not result in overall lower concentrations of plant secondary metabolites. PMID- 29397717 TI - Determination of the Geographical and Botanical Origin of Hops (Humulus lupulus L.) Using Stable Isotopes of C, N, and S. AB - A need exists for a reliable method to determine the geographical and botanical origin of hops. For this study, three sets of samples were collected: the first set comprised 5 German samples; the second set comprised samples of hops from 10 of the world's major hop-growing regions; and the third comprised the 4 main Slovenian regions. The samples were analyzed using isotope ratio mass spectrometry (IRMS) to obtain delta13C, delta15N, and delta34S values. The delta15N (2.2 0/00 to 8.4 0/00) and delta34S (0.7 0/00 to 12.3 0/00) values were the most discriminating parameters for classifying hop according to geographical origin. ANOVA showed distinct groupings for 8 out of the 10 hop-growing regions. Although it was not possible to distinguish the geographical origin of hops based on delta13C (-28.9 0/00 to -24.7 0/00), in the case of botanical origin, delta13C values proved to be the most discriminative albeit with limited success. PMID- 29397718 TI - Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9 Deoxygenated 2,3-Difluoro- N-acetylneuraminic Acid Derivatives. AB - Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5- N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro beta-l-manno-2-nonulopyranosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency. PMID- 29397720 TI - Counterion-Regulated Dynamics of Water Confined in Lyotropic Liquid Crystalline Morphologies. AB - The dynamics of confined water is of fundamental and long-standing interest. In technologically important forms of confinement, such as proton-exchange membranes, electrostatic interactions with the confining matrix and counterions play significant roles on the properties of water. There has been recent interest on the dynamics of water confined to the lyotropic liquid crystalline (LLC) morphologies of Gemini dicarboxylate surfactants. These systems are exciting because the nature of confinement, for example, size and curvature of channels and surface functionality is dictated by the chemistry of the self-assembling surfactant molecules. Quasielastic neutron scattering experiments have shown an interesting dependence of the water self-diffusion constant, Dalpha, on the identity (denoted alpha) of the counterion: at high hydration, the magnitude of the water self-diffusion constant is in the order DTMA < DNa < DK, where TMA, Na, and K refer to tetramethyl ammonium, sodium, and potassium counterions, respectively. This sequence is similar to what is seen in bulk electrolyte solutions. At low hydrations, however, the order of water self-diffusion is different, that is, DNa < DTMA < DK. In this work, we present molecular dynamics simulations for the dynamics of water in the LLC phases of dicarboxylate Gemini surfactants. The simulations reproduce the trends seen in experiments. From an analysis of the trajectories, we hypothesize that two competing factors play a role: the volume accessible to the water molecules and the correlations between the water and the counterion. The excluded volume effect is the largest with TMA+, and the electrostatic correlation is the strongest with Na+. The observed trend is a result of which of these two effects is dominant at a given water to surfactant ratio. PMID- 29397719 TI - Phytosterol Profiles of Common Foods and Estimated Natural Intake of Different Structures and Forms in China. AB - Phytosterols are well-known for their cholesterol-lowering effects, and the structures and forms of phytosterols affect their bioactivity. We aimed to illustrate the phytosterol profiles in common foods and estimate their natural intake in five geographical regions and among different age groups in China. In total, 12 phytosterols in free and esterified forms of 119 foods from five regions across China were examined using gas chromatography-mass spectrometry. Then, the dietary intake of phytosterols was calculated combined with the dietary foods intake data of Chinese people. The total phytosterol content was highest in vegetable oils (150.4-1230.9 mg/100 g), followed by legumes (129.6-275.6 mg/100 g), nuts (18.9-255.2 mg/100 g), and cereals (11.9-93.8 mg/100 g). Vegetables and fruits contained lower contents of total phytosterols. Phytosterols were mainly esterified in most common foods except in nuts. The predominant phytosterols were beta-sitosterol, campesterol, and stigmasterol, all of which belonged to plant sterols and 4-desmethylsterols. Total phytosterol intake varied across different regions, ranging between 257.7 and 473.7 mg/standard-person (sp)/day, with the highest intake in Beijing, followed by Hangzhou, Wuhan, Chongqing, and Guangzhou. However, phytosterol proportion was similar across regions, with beta-sitosterol accounting for 46.5-50.3% of the natural intake. Phytosterol intake was mainly constituted by plant sterols and 4-desmethylsterols in esterified form (61.9 74.6%). At the age of 2-70 years, phytosterol intake ranged from 154.3 mg/day to 348.0 mg/day in the national scale. PMID- 29397721 TI - Reconstruction of Atomistic Structures from Coarse-Grained Models for Protein-DNA Complexes. AB - While coarse-grained (CG) simulations have widely been used to accelerate structure sampling of large biomolecular complexes, they are unavoidably less accurate and thus the reconstruction of all-atom (AA) structures and the subsequent refinement is desirable. In this study we developed an efficient method to reconstruct AA structures from sampled CG protein-DNA complex models, which attempts to model the protein-DNA interface accurately. First we developed a method to reconstruct atomic details of DNA structures from a three-site per nucleotide CG model, which uses a DNA fragment library. Next, for the protein-DNA interface, we referred to the side chain orientations in the known structure of the target interface when available. The other parts are modeled by existing tools. We confirmed the accuracy of the protocol in various aspects including the structure deviation in the self-reproduction, the base pair reproducibility, atomic contacts at the protein-DNA interface, and feasibility of the posterior AA simulations. PMID- 29397722 TI - Nonenzymatic Browning and Protein Aggregation in Royal Jelly during Room Temperature Storage. AB - Royal jelly possesses numerous functional properties. Improper storage usually causes bioactivity loss, especially queen differentiation activity. To determine changes in royal jelly, we investigated nonenzymatic browning and protein changes in royal jelly during room-temperature storage from 1 to 6 months. Our results indicate that royal jelly experiences nonenzymatic browning and protein aggregation. The products of nonenzymatic browning dramatically increased, especially Nepsilon-carboxymethyl lysine (CML) with growth of approximately 7 fold. We speculate that CML may be recognized as a freshness marker for royal jelly. Our results also demonstrate that the major royal jelly protein 1 (MRJP1) monomer gradually aggregated with MRJP1 oligomers into new oligomers of about 440 and 700 kDa. This suggests that the reduction of MRJP1 monomer may be attributable to aggregation. We provide the novel explanation that the differentiation loss of royal jelly may be due to the aggregation of MRJP1 limiting the honeybees' ability to digest and absorb royal jelly. PMID- 29397723 TI - Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites. AB - A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential. PMID- 29397724 TI - Learning about Biomolecular Solvation from Water in Protein Crystals. AB - Water occupies typically 50% of a protein crystal and thus significantly contributes to the diffraction signal in crystallography experiments. Separating its contribution from that of the protein is, however, challenging because most water molecules are not localized and are thus difficult to assign to specific density peaks. The intricateness of the protein-water interface compounds this difficulty. This information has, therefore, not often been used to study biomolecular solvation. Here, we develop a methodology to surmount in part this difficulty. More specifically, we compare the solvent structure obtained from diffraction data for which experimental phasing is available to that obtained from constrained molecular dynamics (MD) simulations. The resulting spatial density maps show that commonly used MD water models are only partially successful at reproducing the structural features of biomolecular solvation. The radial distribution of water is captured with only slightly higher accuracy than its angular distribution, and only a fraction of the water molecules assigned with high reliability to the crystal structure is recovered. These differences are likely due to shortcomings of both the water models and the protein force fields. Despite these limitations, we manage to infer protonation states of some of the side chains utilizing MD-derived densities. PMID- 29397725 TI - Temperature Dependence of Volumetric and Dynamic Properties of Imidazolium-Based Ionic Liquids. AB - Atomistically detailed molecular dynamics simulations were used to investigate the temperature dependence of the specific volume, dynamic properties, and viscosity of linear alkyl chain ([CnC1Im][NTf2], n = 3-7) and branched alkyl chain ([(n - 2)mCn-1C1Im][NTf2]) ionic liquids (ILs). The trend of the glass transition temperature (Tg) values obtained in the simulations as a function of the alkyl chain length of cations was similar to the trend seen in experiments. In addition, the system relaxation behavior as determined from the temperature dependence of the diffusion coefficient, rotational relaxation time, and viscosity close to Tg was observed to follow the Vogel-Fulcher-Tammann expression. Furthermore, the reciprocal of the diffusion coefficient of the anion and cation in both linear and branched IL systems showed a linear correlation with viscosity, thus confirming the validity of the Stokes-Einstein relationship for these systems. Similarly, the average rotational relaxation time of the ions was also found to correlate linearly with the viscosity of the ILs over a wide range of temperatures, thereby validating the Debye-Stokes-Einstein relationship for the ILs. These simulation findings suggest that the temperature dependence of the relaxation time of ILs is very similar to that of other glass-forming liquids. PMID- 29397726 TI - Atomistic and Coarse-Grained Modeling of the Adsorption of Graphene Nanoflakes at the Oil-Water Interface. AB - The high interfacial tension between two immiscible liquids can provide the necessary driving force for the self-assembly of nanoparticles at the interface. Particularly, the interface between water and oily liquids (hydrocarbon chains) has been exploited to prepare networks of highly interconnected graphene sheets of only a few layers thickness, which are well suited for industrial applications. Studying such complex systems through particle-based simulations could greatly enhance the understanding of the various driving forces in action and could possibly give more control over the self-assembly process. However, the interaction potentials used in particle-based simulations are typically derived by reproducing bulk properties and are therefore not suitable for describing systems dominated by interfaces. To address this issue, we introduce a methodology to derive solid-liquid interaction potentials that yield an accurate representation of the balance between interfacial interactions at atomistic and coarse-grained resolutions. Our approach is validated through its ability to lead to the adsorption of graphene nanoflakes at the interface between water and n hexane. The development of accurate coarse-grained potentials that our approach enables will allow us to perform large-scale simulations to study the assembly of graphene nanoparticles at the interface between immiscible liquids. Our methodology is illustrated through a simulation of many graphene nanoflakes adsorbing at the interface. PMID- 29397727 TI - Cation-pi Interactions between Quaternary Ammonium Ions and Amino Acid Aromatic Groups in Aqueous Solution. AB - Cation-pi interactions play important roles in the stabilization of protein structures and protein-ligand complexes. They contribute to the binding of quaternary ammonium ligands (mainly RNH3+ and RN(CH3)3+) to various protein receptors and are likely involved in the blockage of potassium channels by tetramethylammonium (TMA+) and tetraethylammonium (TEA+). Polarizable molecular models are calibrated for NH4+, TMA+, and TEA+ interacting with benzene, toluene, 4-methylphenol, and 3-methylindole (representing aromatic amino acid side chains) based on the ab initio MP2(full)/6-311++G(d,p) properties of the complexes. Whereas the gas-phase affinity of the ions with a given aromatic follows the trend NH4+ > TMA+ > TEA+, molecular dynamics simulations using the polarizable models show a reverse trend in water, likely due to a contribution from the hydrophobic effect. This reversed trend follows the solubility of aromatic hydrocarbons in quaternary ammonium salt solutions, which suggests a role for cation-pi interactions in the salting-in of aromatic compounds in solution. Simulations in water show that the complexes possess binding free energies ranging from -1.3 to -3.3 kcal/mol (compared to gas-phase binding energies between -8.5 and -25.0 kcal/mol). Interestingly, whereas the most stable complexes involve TEA+ (the largest ion), the most stable solvent-separated complexes involve TMA+ (the intermediate-size ion). PMID- 29397728 TI - A Lattice Model of Charge-Pattern-Dependent Polyampholyte Phase Separation. AB - In view of recent intense experimental and theoretical interests in the biophysics of liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs), heteropolymer models with chain molecules configured as self avoiding walks on the simple cubic lattice are constructed to study how phase behaviors depend on the sequence of monomers along the chains. To address pertinent general principles, we focus primarily on two fully charged 50-monomer sequences with significantly different charge patterns. Each monomer in our models occupies a single lattice site, and all monomers interact via a screened pairwise Coulomb potential. Phase diagrams are obtained by extensive Monte Carlo sampling performed at multiple temperatures on ensembles of 300 chains in boxes of sizes ranging from 52 * 52 * 52 to 246 * 246 * 246 to simulate a large number of different systems with the overall polymer volume fraction phi in each system varying from 0.001 to 0.1. Phase separation in the model systems is characterized by the emergence of a large cluster connected by intermonomer nearest-neighbor lattice contacts and by large fluctuations in local polymer density. The simulated critical temperatures, Tcr, of phase separation for the two sequences differ significantly, whereby the sequence with a more "blocky" charge pattern exhibits a substantially higher propensity to phase separate. The trend is consistent with our sequence-specific random-phase-approximation (RPA) polymer theory, but the variation of the simulated Tcr with a previously proposed "sequence charge decoration" pattern parameter is milder than that predicted by RPA. Ramifications of our findings for the development of analytical theory and simulation protocols of IDP LLPS are discussed. PMID- 29397730 TI - Formation of BixSey Phases Upon Annealing of the Topological Insulator Bi2Se3: Stabilization of In-Depth Bismuth Bilayers. AB - The goal of this work is to study transformations that occur upon heating Bi2Se3 to temperatures up to 623 K. X-ray diffraction (XRD) and scanning tunneling microscopy (STM) and spectroscopy (STS) techniques were used in our investigation. XRD was measured following the 00L and 01L truncation rods. These measurements revealed that upon heating there is a coexistence of a major Bi2Se3 phase and other ones that present structures of quintuple-layers intercalated with Bismuth bilayers. STM measurements of the surface of this material showed the presence of large hexagonal BixSey domains embedded in a Bi2Se3 matrix. STS experiments were employed to map the local electronic density of states and characterize the modifications imposed by the presence of the additional phases. Finally, density functional theory (DFT) calculations were performed to support these findings. PMID- 29397729 TI - How Detergent Impacts Membrane Proteins: Atomic-Level Views of Mitochondrial Carriers in Dodecylphosphocholine. AB - Characterizing the structure of membrane proteins (MPs) generally requires extraction from their native environment, most commonly with detergents. Yet, the physicochemical properties of detergent micelles and lipid bilayers differ markedly and could alter the structural organization of MPs, albeit without general rules. Dodecylphosphocholine (DPC) is the most widely used detergent for MP structure determination by NMR, but the physiological relevance of several prominent structures has been questioned, though indirectly, by other biophysical techniques, e.g., functional/thermostability assay (TSA) and molecular dynamics (MD) simulations. Here, we resolve unambiguously this controversy by probing the functional relevance of three different mitochondrial carriers (MCs) in DPC at the atomic level, using an exhaustive set of solution-NMR experiments, complemented by functional/TSA and MD data. Our results provide atomic-level insight into the structure, substrate interaction and dynamics of the detergent membrane protein complexes and demonstrates cogently that, while high-resolution NMR signals can be obtained for MCs in DPC, they systematically correspond to nonfunctional states. PMID- 29397731 TI - Ultrafast Crystallization Dynamics at an Organic-Inorganic Interface Revealed in Real Time by Grazing Incidence Fast Atom Diffraction. AB - The poor structural properties of organic-inorganic interfaces and their variability represent the main cause of device under-performance. Understanding and controlling the development of these properties in real time has been a difficult experimental challenge. Using a recent technique based on grazing incidence fast atom diffraction (GIFAD), we were able to directly observe during deposition structural transitions in a perylene monolayer on Ag(110). Crystallization from the liquid phase occurs into two distinct structures with drastically different dynamics. Transition to the most compact packing occurs by self-organization only after a second layer has started to build up; subsequent incorporation of molecules from second to first layer triggers an ultrafast crystallization on a macroscopic sale. The final compact crystalline structure shows a long-range order and superior stability, which opens good perspectives for producing in a controlled manner highly ordered hybrid interfaces for photovoltaics and molecular electronics. PMID- 29397732 TI - Silicene Quantum Dots: Synthesis, Spectroscopy, and Electrochemical Studies. AB - Organically functionalized silicene quantum dots (SiQDs) were synthesized by chemical exfoliation of calcium silicide and stabilized by hydrosilylation with olefin/acetylene derivatives forming Si-CH2-CH2- or Si-CH?CH- interfacial bonds. Transmission electron microscopy and atomic force microscopy measurements showed that the resultant SiQDs were ca. 2 nm in diameter and consisted of ca. four atomic layers of silicon. The structure was further characterized by 1H and 29Si NMR and X-ray photoelectron spectroscopic measurements. In photoluminescence measurements, the SiQDs exhibited a strong emission at 385 nm and the intensity varied with the interfacial linkage. In electrochemical measurements, both ethynylferrocene- and vinylferrocene-functionalized SiQDs exhibited a pair of well-defined voltammetric peaks at +0.15 V (vs Fc+/Fc) in the dark for the redox reaction of the ferrocene/ferrocenium couple; yet under UV photoirradiation, an additional pair of voltammetric peaks appeared at -0.41 V, most likely because of the redox reaction of ferrocene anions formed by photoinduced electron transfer from the SiQD to the ferrocene metal centers. PMID- 29397733 TI - Topical Administration of Spironolactone-Loaded Nanomicelles Prevents Glucocorticoid-Induced Delayed Corneal Wound Healing in Rabbits. AB - The objective was to investigate whether mineralocorticoid receptor antagonism using a novel topical micellar formulation of spironolactone could prevent glucocorticoid-induced delayed corneal wound healing in New Zealand white rabbits. Spironolactone micelles (0.1%, w/v) with a mean number weighted diameter of 20 nm were prepared using a pegylated copolymer (mPEG-dihexPLA) and showed a preliminary stability of at least 12 months at 5 degrees C. Preclinical studies in New Zealand white rabbits demonstrated that the 0.1% spironolactone micellar formulation was well-tolerated since no reaction was observed in the cornea following multiple daily instillation over 5 days. As expected, the preclinical studies also confirmed that dexamethasone significantly delayed epithelial wound healing as compared to untreated control (percentage re-epithelialization after day 4: 84.6 +/- 13.9% versus 99.5 +/- 1.0% for the control, p < 0.05). However, the addition of the 0.1% spironolactone micellar formulation significantly improved the extent of re-epithelialization, countering the dexamethasone induced delayed wound healing with a percentage re-epithelialization that was statistically equivalent to the control (96.9 +/- 7.3% versus 99.5 +/- 1.0%, p > 0.05). The biodistribution study provided insight into the ocular metabolism of spironolactone and hence the relative contributions of the parent molecule and its two principal metabolites, 7alpha-thiomethylspironolactone and canrenone, to the observed pharmacological effects. Comparison of the efficacies of spironolactone and potassium canrenoate (a water-soluble precursor of canrenone) in overcoming the dexamethasone-induced delayed wound healing confirmed that the former had greater efficacy. The results pointed to the greater potency of 7alpha thiomethylspironolactone over canrenone as a mineralocorticoid receptor antagonist, which explained its superior ability in countering the glucocorticoid induced overactivation that was responsible for the delayed wound healing. In conclusion, the preliminary results supported the above-mentioned hypothesis suggesting that coadministration of mineralocorticoid receptor antagonists to patients under glucocorticoid therapy might prevent the deleterious effects of glucocorticoids on complex corneal wound healing processes. PMID- 29397734 TI - Unique Features of Metformin: A Combined Experimental, Theoretical, and Simulation Study of Its Structure, Dynamics, and Interaction Energetics with DNA Grooves. AB - There are certain small molecules that exhibit extraordinarily diverse biological activities. Metformin is one of them. It is widely used as an antidiabetic drug for type-two diabetes. Recent lines of evidence of its role in antitumor activities and increasing the survival rates of cancer patients (namely, colorectal, breast, pancreas, and prostate cancer) are emerging. However, theoretical studies of the structure and dynamics of metformin have not yet been fully explored. In this work, we investigate the characteristic structural and dynamical features of three monoprotonated forms of metformin hydrochloride with the help of experiments, quantum chemical calculations, and atomistic molecular dynamics simulations. We validate our force field by comparing simulation results to those of the experimental findings. Energetics of proton transfer between two planar monoprotonated forms reveals a low energy barrier, which leads us to speculate a possible coexistence of them. Nevertheless, among the protonation states, we find that the nonplanar tautomeric form is the most stable. Our calculated values of the self-diffusion coefficient agree quantitatively with NMR results. Metformin forms strong hydrogen bonds with surrounding water molecules, and its solvation dynamics shows unique features. Because of an extended positive charge distribution, metformin possesses features of being a permanent cationic partner toward several targets. We study its interaction and binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry, and metadynamics simulation. We find a nonintercalative mode of interaction. Metformin feasibly forms a minor/major groove-bound state within a few tens of nanoseconds, preferably with AT-rich domains. A significant decrease in the free energy of binding is observed when it binds to a minor groove of DNA. PMID- 29397735 TI - Targeted Delivery and Redox Activity of Folic Acid-Functionalized Nanoceria in Tumor Cells. AB - Cerium oxide nanoparticles (nanoceria) are promising catalytic nanomaterials that are widely reported to modulate intracellular reactive oxygen species (ROS). In this study, nanoceria were synthesized by flame spray pyrolysis and functionalized with a cell-targeting ligand, folic acid (FA). The surface functionalization of nanoceria was stable, and FA enhanced the uptake of nanoceria via folate receptors. Internalized nanoceria and FA-nanoceria were localized predominantly in the cytoplasm. FA-nanoceria modulated intracellular ROS to a greater extent than the nanoceria in colon carcinoma cells, but induced ROS in ovarian cancer cells, likely due to their enhanced uptake. Together these data demonstrated that the functionalization of nanoceria with FA modulated their endocytosis and redox activity, and they may find application in the delivery of anticancer drugs in the future. PMID- 29397736 TI - Self-Adaptive Switch Enabling Complete Charge Separation in Molecular-Based Optoelectronic Conversion. AB - Achieving high charge recombination probability has been the major challenge for the practical utilization of molecule-based solar harvesting. Molecular switches were introduced to stabilize the charge separation state in donor-acceptor systems, but it is difficult to seamlessly incorporate the ON/OFF switching actions into the optoelectronic conversion cycle. Here we present a self-adaptive system in which the donor and acceptor are bridged by a switchable moiety that enables a complete charge separation repeatedly. Calculations are presented for a platinum(II) terpyridyl complex with an azobenzene bridge. The charge transfer induced by light extracts electrons from the azobenzene group, automatically triggering a trans -> cis isomerization. The resulting conformation suppresses charge recombination. Energized charges are trapped in the acceptor, ready for charge collection by electrodes. The bridge then goes through inverse isomerization to restore the conjugation and conductance. This self-adaptive design provides a novel way to improve the performance of optoelectronic conversion and realize practical solar-harvesting applications in organic molecular systems. PMID- 29397737 TI - Label-Free Confocal Raman Mapping of Transportan in Melanoma Cells. AB - Cell-penetrating peptides (CPPs) are promising vectors for the intracellular delivery of a variety of membrane-impermeable bioactive compounds. The mechanisms by which CPPs cross the cell membrane, and the effects that CPPs may have on cell function, still remain to be fully clarified. In this work, we employed confocal Raman microscopy (CRM) and atomic force microscopy (AFM) to study the infiltration and physiological effects of the amphipathic CPP transportan (Tp) on the metastatic melanoma cell line SK-Mel-2. CRM enabled the detection of label free Tp within the cells. Raman maps of live cells revealed rapid entry (within 5 min) and widespread distribution of the peptide throughout the cytoplasm and the presence of the peptide within the nucleus after ~20 min. Principal component analysis of the CRM data collected from Tp-treated and untreated cells showed that Tp Raman bands were not positively correlated with lipid Raman bands, indicating that Tp entered the cells via a nonendocytic mechanism. Analysis of intracellularly recovered Tp by mass spectrometry showed that Tp remained intact in SK-Mel-2 cells for up to 24 h. The Raman spectroscopic data also showed that, although Tp was predominantly unstructured (random coil) in aqueous solution, it accumulated to high densities within the cells with mostly beta-sheet and alpha helical structures. AFM was employed to measure the effect of Tp treatment on cell stiffness. These data showed that Tp induced a significant increase in cell stiffness within the first hour of treatment, which was partially abated after 2 h. It is hypothesized that the increase in cell stiffness was the result of cytoskeletal changes triggered by Tp. PMID- 29397738 TI - Carbon Nanotubes and Algal Polysaccharides To Enhance the Enzymatic Properties of Urease in Lipid Langmuir-Blodgett Films. AB - Algal polysaccharides (extracellular polysaccharides) and carbon nanotubes (CNTs) were adsorbed on dioctadecyldimethylammonium bromide Langmuir monolayers to serve as a matrix for the incorporation of urease. The physicochemical properties of the supramolecular system as a monolayer at the air-water interface were investigated by surface pressure-area isotherms, surface potential-area isotherms, interfacial shear rheology, vibrational spectroscopy, and Brewster angle microscopy. The floating monolayers were transferred to hydrophilic solid supports, quartz, mica, or capacitive electrolyte-insulator-semiconductor (EIS) devices, through the Langmuir-Blodgett (LB) technique, forming mixed films, which were investigated by quartz crystal microbalance, fluorescence spectroscopy, and field emission gun scanning electron microscopy. The enzyme activity was studied with UV-vis spectroscopy, and the feasibility of the thin film as a urea sensor was essayed in an EIS sensor device. The presence of CNT in the enzyme-lipid LB film not only tuned the catalytic activity of urease but also helped to conserve its enzyme activity. Viability as a urease sensor was demonstrated with capacitance-voltage and constant capacitance measurements, exhibiting regular and distinctive output signals over all concentrations used in this work. These results are related to the synergism between the compounds on the active layer, leading to a surface morphology that allowed fast analyte diffusion owing to an adequate molecular accommodation, which also preserved the urease activity. This work demonstrates the feasibility of employing LB films composed of lipids, CNT, algal polysaccharides, and enzymes as EIS devices for biosensing applications. PMID- 29397739 TI - ProForma: A Standard Proteoform Notation. AB - The Consortium for Top-Down Proteomics (CTDP) proposes a standardized notation, ProForma, for writing the sequence of fully characterized proteoforms. ProForma provides a means to communicate any proteoform by writing the amino acid sequence using standard one-letter notation and specifying modifications or unidentified mass shifts within brackets following certain amino acids. The notation is unambiguous, human-readable, and can easily be parsed and written by bioinformatic tools. This system uses seven rules and supports a wide range of possible use cases, ensuring compatibility and reproducibility of proteoform annotations. Standardizing proteoform sequences will simplify storage, comparison, and reanalysis of proteomic studies, and the Consortium welcomes input and contributions from the research community on the continued design and maintenance of this standard. PMID- 29397741 TI - Biomimetic Nanovesicles for Enhanced Antitumor Activity of Combinational Photothermal and Chemotherapy. AB - The combination of multiple modalities has shown great potential in cancer treatment with improved therapeutic effects and minimized side effects. Here, we fabricated a type of doxorubicin-encapsulated biomimetic nanovesicle (NV) by a facile method with near-infrared dye insertion in the membrane for combinatorial photothermal and chemotherapy. With innate biomimetic properties, NVs enhanced the uptake by tumor cells while reducing the phagocytosis of macrophages. Upon laser irradiation, NVs can convert the absorbed fluorescent energy into heat for effective tumor killing. Hyperthermia can further induce membrane ablation of NVs to accelerate the release of chemotherapeutic drug for potent cytotoxicity to tumor cells. The NVs improved drug accumulation and showed a more efficient in vivo photothermal effect with a rapid temperature increase in tumors. Moreover, the NV-based combinational photothermal and chemotherapy exhibited significant tumor growth suppression with a high inhibitory rate of 91.6% and negligible systemic toxicity. The results indicate that NVs could be an appealing vehicle for combinational cancer treatment. PMID- 29397740 TI - Comparative Proteomic Analysis of Exosomes and Microvesicles in Human Saliva for Lung Cancer. AB - Extracellular vesicles (EVs) are cell-derived microparticles present in most body fluids, mainly including microvesicles and exosomes. EV-harbored proteins have emerged as novel biomarkers for the diagnosis and prediction of different cancers. We successfully isolated microvesicles and exosomes from human saliva, which were further characterized comprehensively. Salivary EV protein profiling in normal subjects and lung cancer patients was systematically compared through utilizing LC-MS/MS-based label-free quantification. 785 and 910 proteins were identified from salivary exosomes and microvesicles, respectively. According to statistical analysis, 150 and 243 proteins were revealed as dysregulated candidates in exosomes and microvesicles for lung cancer. Among them, 25 and 40 proteins originally from distal organ cells were found in the salivary exosomes and microvesicles of lung cancer patients. In particular, 5 out of 25 and 9 out of 40 are lung-related proteins. Six potential candidates were selected for verification by Western blot, and four of them, namely, BPIFA1, CRNN, MUC5B, and IQGAP, were confirmed either in salivary microvesicles or in exosomes. Our data collectively demonstrate that salivary EVs harbor informative proteins that might be used for the detection of lung cancer through a noninvasive way. PMID- 29397742 TI - Tools and Functions of Reconfigurable Colloidal Assembly. AB - We review work in reconfigurable colloidal assembly, a field in which rapid, back and-forth transitions between the equilibrium states of colloidal self-assembly are accomplished by dynamic manipulation of the size, shape, and interaction potential of colloids, as well as the magnitude and direction of the fields applied to them. It is distinguished from the study of colloidal phase transitions by the centrality of thermodynamic variables and colloidal properties that are time switchable; by the applicability of these changes to generate transitions in assembled colloids that may be spatially localized; and by its incorporation of the effects of generalized potentials due to, for example, applied electric and magnetic fields. By drawing upon current progress in the field, we propose a matrix classification of reconfigurable colloidal systems based on the tool used and function performed by reconfiguration. The classification distinguishes between the multiple means by which reconfigurable assembly can be accomplished (i.e., the tools of reconfiguration) and the different kinds of structural transitions that can be achieved by it (i.e., the functions of reconfiguration). In the first case, the tools of reconfiguration can be broadly classed as (i) those that control the colloidal contribution to the system entropy-as through volumetric and/or shape changes of the particles; (ii) those that control the internal energy of the colloids-as through manipulation of colloidal interaction potentials; and (iii) those that control the spatially resolved potential energy that is imposed on the colloids-as through the introduction of field-induced phoretic mechanisms that yield colloidal displacement and accumulation. In the second case, the functions of reconfiguration include reversible: (i) transformation between different phases including fluid, cluster, gel, and crystal structures; (ii) manipulation of the spacing between colloids in crystals and clusters; and (iii) translation, rotation, or shape-change of finite-size objects self-assembled from colloids. With this classification in hand, we correlate the current limits on the spatiotemporal scales for reconfigurable colloidal assembly and identify a set of future research challenges. PMID- 29397743 TI - Multiple-Responsive Hierarchical Self-Assemblies of a Smart Supramolecular Complex: Regulation of Noncovalent Interactions. AB - We herein report a smart amphiphilic supramolecular complex ([MimA-EDA MimA]@[DBS]2) with stimuli-responsive self-assembly, constructed by 3-(3-formyl-4 hydroxybenzyl)-1-methylimidazolium chloride (MimACl), sodium dodecyl benzene sulfonate (SDBS), and ethylenediamine (EDA). The self-assembly of [MimA-EDA MimA]@[DBS]2 shows triple-sensitivities in response to pH, concentration, and salt. At a low pH, only micelles are formed, which can transform into vesicles spontaneously when the pH increases to 11.8. Vesicles can gradually fuse into vesicle clusters and elongated assemblies with increasing concentration of [MimA EDA-MimA]@[DBS]2. Chainlike aggregates, ringlike aggregates, or giant vesicles can be formed by adding inorganic salts (i.e., NaCl and NaNO3), which could be derived from the membrane fusion of vesicles. The noncovalent interactions, including pi-pi stacking, hydrogen bonding, and electrostatic interactions, were found to be responsible for the topology evolution of assemblies. Thus, it provides an opportunity to construct smart materials through the regulation of the role of noncovalent interactions in self-assembly. PMID- 29397744 TI - Heterostructured Copper-Ceria and Iron-Ceria Nanorods: Role of Morphology, Redox, and Acid Properties in Catalytic Diesel Soot Combustion. AB - This work reports the synthesis of heterostructured copper-ceria and iron-ceria nanorods and the role of their morphology, redox, and acid properties in catalytic diesel soot combustion. Microscopy images show the presence of nanocrystalline CuO (9.5 +/- 0.5 nm) and Fe2O3 (7.3 +/- 0.5 nm) particles on the surface of CeO2 nanorods (diameter is 8.5 +/- 2 nm and length within 16-89 nm). In addition to diffraction peaks of CuO and Fe2O3 nanocrystallites, X-ray diffraction (XRD) studies reveal doping of Cu2+ and Fe3+ ions into the fluorite lattice of CeO2, hence abundant oxygen vacancies in the Cu/CeO2 and Fe/CeO2 nanorods, as evidenced by Raman spectroscopy studies. XRD and Raman spectroscopy studies further show substantial perturbations in Cu/CeO2 rods, resulting in an improved reducibility of bulk cerium oxide and formation of abundant Lewis acid sites, as investigated by H2-temperature-programmed reduction and pyridine adsorbed Fourier transform infrared studies, respectively. The Cu/CeO2 rods catalyze the soot oxidation reaction at the lowest temperatures under both tight contact (Cu/CeO2; T50 = 358 degrees C, temperature at which 50% soot conversion is achieved, followed by Fe/CeO2; T50 = 368 degrees C and CeO2; T50 = 433 degrees C) and loose contact conditions (Cu/CeO2; T50 = 419 degrees C and Fe/CeO2; T50 = 435 degrees C). A possible mechanism based on the synergetic effect of redox and acid properties of Cu/CeO2 nanorods was proposed: acid sites can activate soot particles to form reactive carbon species, which are oxidized by gaseous oxygen/lattice oxygen activated in the oxygen vacancies (redox sites) of ceria rods. PMID- 29397745 TI - Highly Durable Na2V6O16.1.63H2O Nanowire Cathode for Aqueous Zinc-Ion Battery. AB - Rechargeable aqueous zinc-ion batteries are highly desirable for grid-scale applications due to their low cost and high safety; however, the poor cycling stability hinders their widespread application. Herein, a highly durable zinc-ion battery system with a Na2V6O16.1.63H2O nanowire cathode and an aqueous Zn(CF3SO3)2 electrolyte has been developed. The Na2V6O16.1.63H2O nanowires deliver a high specific capacity of 352 mAh g-1 at 50 mA g-1 and exhibit a capacity retention of 90% over 6000 cycles at 5000 mA g-1, which represents the best cycling performance compared with all previous reports. In contrast, the NaV3O8 nanowires maintain only 17% of the initial capacity after 4000 cycles at 5000 mA g-1. A single-nanowire-based zinc-ion battery is assembled, which reveals the intrinsic Zn2+ storage mechanism at nanoscale. The remarkable electrochemical performance especially the long-term cycling stability makes Na2V6O16.1.63H2O a promising cathode for a low-cost and safe aqueous zinc-ion battery. PMID- 29397746 TI - Solid-in-Oil Peptide Nanocarriers for Transcutaneous Cancer Vaccine Delivery against Melanoma. AB - Cancer vaccines represent a prophylactic or therapeutic method of suppressing cancer by activating the adaptive immune system. The immune response is initiated by the delivery of tumor antigens to antigen presenting cells (APCs). The use of peptides as vaccine antigens is advantageous, especially in the availability and productivity of pure and defined antigens. However, their limited immunogenicity remains a major drawback, and therefore, the utilization of nanocarriers as a means of delivering antigens to target cells and/or the addition of immune stimulants have been investigated as an efficient peptide-based cancer vaccine. We have developed a solid-in-oil (S/O) nanodispersion as a transcutaneous nanocarrier for hydrophilic molecules. This system has attractive features as a peptide nanocarrier for cancer vaccines, including transcutaneous targeting of professional APCs in the skin, high encapsulation efficacy of hydrophilic molecules, and capacity for coloading with a variety of immune stimulants such as adjuvants. We therefore sought to utilize the developed S/O nanodispersion for the delivery of the tyrosine-related protein 2 peptide, TRP-2180-188, as a peptide antigen against melanoma. Transcutaneous vaccination of the S/O nanodispersion coloaded with adjuvant R-848 was associated with a significant inhibition of melanoma growth and suppression of lung metastasis in tumor-bearing mice. Our findings indicate the potential of S/O nanodispersions as an endogenous peptide carrier for cancer vaccines. PMID- 29397747 TI - Hyaluronic Acid-Modified Micelles Encapsulating Gem-C12 and HNK for Glioblastoma Multiforme Chemotherapy. AB - Glioblastoma multiforme (GBM), a prevalent brain cancer with high mortality, is resistant to the conventional single-agent chemotherapy. In this study, we employed a combination chemotherapy strategy to inhibit GBM growth and addressed its possible beneficial effects. The synergistic effect of lauroyl-gemcitabine (Gem-C12) and honokiol (HNK) was first tested and optimized using U87 cells in vitro. Then, the hyaluronic acid-grafted micelles (HA-M), encapsulating the optimal mole ratio (1:1) of Gem-C12 and HNK, were prepared and characterized. Cell-based studies demonstrated that HA-M could be transported into cells by a CD44 receptor-mediated endocytosis, which could penetrate deeper into tumor spheroids and enhance the cytotoxicity of payloads to glioma cells. In vivo, drug loaded HA-M significantly increased the survival rate of mice bearing orthotopic xenograft GBM compared with the negative control (1.85-fold). Immunohistochemical analysis indicated that the enhanced efficacy of HA-M was attributed to the stronger inhibition of glioma proliferation and induction of apoptosis. Altogether, our findings showed advantages of combination chemotherapy of GBM using HA-grafted micelles. PMID- 29397748 TI - From Microparticles to Nanowires and Back: Radical Transformations in Plated Li Metal Morphology Revealed via in Situ Scanning Electron Microscopy. AB - Li metal is the preferred anode material for all-solid-state Li batteries. However, a stable plating and stripping of Li metal at the anode-solid electrolyte interface remains a significant challenge particularly at practically feasible current densities. This problem usually relates to high and/or inhomogeneous Li-electrode-electrolyte interfacial impedance and formation and growth of high-aspect-ratio dendritic Li deposits at the electrode-electrolyte interface, which eventually shunt the battery. To better understand details of Li metal plating, we use operando electron microscopy and Auger spectroscopy to probe nucleation, growth, and stripping of Li metal during cycling of a model solid-state Li battery as a function of current density and oxygen pressure. We find a linear correlation between the nucleation density of Li clusters and the charging rate in an ultrahigh vacuum, which agrees with a classical nucleation and growth model. Moreover, the trace amount of oxidizing gas (~10-6 Pa of O2) promotes the Li growth in a form of nanowires due to a fine balance between the ion current density and a growth rate of a thin lithium-oxide shell on the surface of the metallic Li. Interestingly, increasing the partial pressure of O2 to 10-5 Pa resumes Li plating in a form of 3D particles. Our results demonstrate the importance of trace amounts of preexisting or ambient oxidizing species on lithiation processes in solid-state batteries. PMID- 29397749 TI - Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis. AB - The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment. PMID- 29397750 TI - Visualization and Studies of Ion-Diffusion Kinetics in Cesium Lead Bromide Perovskite Nanowires. AB - The facile chemical transformation of metal halide perovskites via ion exchange has been attributed to their "soft" crystal lattices that enable fast ion migration. Kinetic studies of such processes could provide mechanistic insights on the ion migration dynamics. Herein, by using aligned single-crystal nanowires of cesium lead bromide (CsPbBr3) perovskite on epitaxial substrates as platforms, we visualize and investigate the cation or anion interdiffusion kinetics via spatially resolved photoluminescence measurement on heterostructures fabricated by stacking CsPbCl3, MAPbI3, or MAPbBr3 microplates on top of CsPbBr3 nanowires. Time-dependent confocal photoluminescence microscopy and energy-dispersive X-ray spectroscopy showed the solid-state anion interdiffusion readily occurs to result in halide concentration gradients along CsPbBr3-3 xCl3 x ( x = 0-1) nanowires. Quantitative analysis of such composition profiles using Fick's law allowed us, for the first time, to extract interdiffusion coefficients of the chloride bromide couple and an activation energy of 0.44 +/- 0.02 eV for ion diffusion from temperature-dependent studies. In contrast, iodide-bromide interdiffusion is limited, likely due to the complex phase behaviors of mixed alloys of CsPb(Br,I)3. In contrast to the relatively mobile anions, A-site cation interdiffusion across the MAPbBr3/CsPbBr3 junctions was barely observed at room temperature. Our results present a general method to investigate the kinetics of the solid-state ion migration, and the gained insights on ion diffusion can provide guidelines for rationally designing perovskite heterostructures that could lead to new properties for fundamental studies and technological applications. PMID- 29397751 TI - Ultrathin Au-Alloy Nanowires at the Liquid-Liquid Interface. AB - Ultrathin bimetallic nanowires are of importance and interest for applications in electronic devices such as sensors and heterogeneous catalysts. In this work, we have designed a new, highly reproducible and generalized wet chemical method to synthesize uniform and monodispersed Au-based alloy (AuCu, AuPd, and AuPt) nanowires with tunable composition using microwave-assisted reduction at the liquid-liquid interface. These ultrathin alloy nanowires are below 4 nm in diameter and about 2 MUm long. Detailed microstructural characterization shows that the wires have an face centred cubic (FCC) crystal structure, and they have low-energy twin-boundary and stacking-fault defects along the growth direction. The wires exhibit remarkable thermal and mechanical stability that is critical for important applications. The alloy wires exhibit excellent electrocatalytic activity for methanol oxidation in an alkaline medium. PMID- 29397752 TI - Nanosecond Laser-Induced Underwater Superoleophobic and Underoil Superhydrophobic Mesh for Oil/Water Separation. AB - Materials with special wettability have drawn considerable attention especially in the practical application for the separation and recovery of the oily wastewater, whereas there still remain challenges of the high-cost materials, significant time, and complicated production equipment. Here, a simple method to fabricate the underwater superoleophobic and underoil superhydrophobic brass mesh via the nanosecond laser ablation is reported for the first time, which provided the micro-/nanoscale hierarchical structures. This mesh is superhydrophilic and superoleophilic in air but superoleophobic under water and superhydrophobic under oil. On the basis of the special wettability of the as-fabricated mesh, we demonstrate a proof of the light or heavy oil/water separation, and the excellent separation efficiencies (>96%) and the superior water/oil breakthrough pressure coupled with the high water/oil flux are achieved. Moreover, the nanosecond laser technique is simple and economical, and it is advisable for the large-area and mass fabrication of the underwater superoleophobic and underoil superhydrophobic mesh in the large-scale oil/water separation. PMID- 29397753 TI - Synthesis of a Selective Estrogen Receptor Degrader via a Stereospecific Elimination Approach. AB - An efficient synthesis of a selective estrogen receptor degrader, GDC-0810, bearing a challenging stereodefined (E)-tetrasubstituted all-carbon olefin core, is reported. The described synthetic route involves a highly diastereoselective addition of an arylmagnesium reagent 3a to ketone 4, yielding the key tertiary alcohol 2a in >99:1 dr. The corresponding tert-butyl carbonate derivative was identified among other leaving groups to provide the desired olefin geometry in a 98:2 E/Z ratio via a concerted elimination. A four-step telescoped process was then developed starting from the tertiary alcohol 2a to produce GDC-0810 API as a pyrrolidine salt in 70% yield. PMID- 29397755 TI - The association between monetary and sexual delay discounting and risky sexual behavior in an online sample of men who have sex with men. AB - Delay discounting is a measure of impulsivity that has been found to be associated with numerous health-related outcomes. To the extent that delay discounting is associated with sexual risk-taking, it might serve as a marker for HIV risk or as the basis for novel HIV prevention interventions. The goal of the current study was to examine the association between monetary and sexual delay discounting and condomless anal intercourse (CAI) in a cross-sectional sample of men who have sex with men. Based on previous findings, we examined whether these associations were age-dependent. Sexual, but not monetary, delay discounting was found to be associated with CAI in the past 12 months. These results suggest that delay discounting is associated with sexual risk-taking. More high risk sexual behaviors and their associations with delay discounting should be investigated in the future. PMID- 29397759 TI - Familial silence surrounding HIV and non-disclosure of HIV status to older children and adolescents. AB - Increasing numbers of children with HIV are surviving to adolescence and beyond, many of whom are orphaned. Disclosure of childrens' and adolescents' HIV status has been shown to improve adherence and retention in HIV treatment programmes. We investigated caregiving arrangements and intra-familial experience of HIV and its relationship to HIV disclosure to older children and adolescents. Children aged 6 15 years, newly diagnosed with HIV infection or previously diagnosed but not engaged in HIV care, were recruited from seven primary care clinics in Harare, Zimbabwe. Their caregivers responded to a nurse-led questionnaire. Family history of HIV, disclosure of HIV status to the child and reasons for non-disclosure were ascertained. The association between sociodemographics, caregiving, family HIV history and other characteristics and non-disclosure of HIV status to the child was determined using univariate and multivariate logistic regression. We recruited 385 participants, median age = 11 years (IQR: 9-13); 52% were female. Disclosure had occurred in 79% of children aged 11-15 years and 19% of children aged 6-10 years. Age under 11 years (adjusted OR [aOR] = 18.89, 95% confidence interval [CI] = 10.64-33.55; p < 0.001), being male [aOR]= 2.56, 95% CI = 1.49 4.54; p = 0.001, being unaware of the parents' HIV status [aOR]= 32.42, 95% CI = 13.19-79.71; p < 0.001, and being newly diagnosed [aOR]= 2.52, 95% CI = 1.29 4.91; p = 0.007, were independently associated with non-disclosure. Disclosure outside of the family occurred infrequently and included friends of family (7%), school teacher (8%), school headmaster (4%) and church pastor (6%). High non disclosure rates were present as well as a lack of discussion about HIV within the family. Disclosure outside of family was low reflecting difficulty in caregivers' ability to discuss HIV with their child or surrounding community. HIV programmes need to support families in the disclosure process. PMID- 29397761 TI - Threats during sex work and association with mental health among young female sex workers in Hong Kong. AB - Young female sex workers (YFSWs) are confronted with significant threats during sex work. The present cross-sectional study examined different levels of threats (i.e., threats to life and health, threats to humanity, threats to control of work and financial security, and the threats to future) experienced by 87 YFSWs (age 16-25) in Hong Kong, and identified their association with mental health (i.e., psychological well-being) together with other factors, including childhood trauma, self-efficacy, hope, and social support. Results showed that the participants encountered a significant number of threats. More than half reported that they had a condom removed by clients during sex (51.7%); or have been humililated by clients (51.7%). Because of sex work, about a quarter (25.3%) have had sexually transmitted disease, and respectively 10.3% and 12.6% have had abortion and unplanned pregnancy. The majority have had friends found out that they engaged in sex work (72.4%). They also showed a high level of worry about the various threats. Multiple linear regression analysis showed that childhood trauma (beta = -.26) and worry about threats during sex work (beta = -.22) were significantly negative predictors, while self-efficacy (beta = .20) and hope (beta = .27) were significantly positive predictors of mental health. Future services should improve YFSWs' skills to minimize potential threats during female sex work, address the structural correlates and relieve their worries, and empower them with more hope and self-efficacy in choosing clients. PMID- 29397765 TI - Publish and Perish! PMID- 29397762 TI - Challenges with access to healthcare from the perspective of patients living with HIV: a scoping review & framework synthesis. AB - Accessing healthcare can be difficult but the barriers multiply for people living with HIV (PLHIV). To improve access and the health of PLHIV, we must consider their perspectives and use them to inform standard practice. A better understanding of the current literature related to healthcare access from the perspective of PLHIV, can help to identify evidence gaps and highlight research priorities and opportunities. To identify relevant peer-reviewed publications, search strategies were employed. Electronic and grey literature databases were explored. Articles were screened based on their title and abstract and those that met the screening criteria, were reviewed in full. Data analysis was conducted using a collaborative approach that included knowledge user consultation. Initial concepts were extracted, summarized and through framework synthesis, developed into emerging and final themes. From 20,678 articles, 326 articles met the initial screening criteria and 64 were reviewed in full. The final themes identified, in order of most to least frequent were: Acceptability, Availability, Accessibility, Affordability, Other Barriers, Communication, Satisfaction, Accommodation, Preferences and Equity in Access. The most frequently discussed concepts related to negative interactions with staff, followed by long wait times, limited household resources or inability to pay fees, and fear of one's serostatus being disclosed. Knowledge users were in agreement with the categorization of initial concepts and final themes; however, some gaps in the literature were identified. Specific changes are critical to improving access to healthcare for PLHIV. These include improving availability by ensuring staff and healthcare professionals have proper training, cultivating acceptability and reducing stigma through improving HIV awareness, increasing accessibility through increased HIV information for PLHIV and improved dissemination of this information to increase patient knowledge and health awareness. Finally, ensuring proper protocols are implemented and followed to guarantee patient confidentiality and overall satisfaction with healthcare services are recommended. PMID- 29397766 TI - Trends in discharges from the HIV/AIDS ward at a tertiary Canadian Hospital from 2005 to 2014. AB - Advances in HIV therapies have transformed HIV infection into a manageable chronic disease. Accordingly, hospital admission trends among people living with HIV may have evolved over time. This study describes discharge diagnoses from the dedicated HIV/AIDS ward at St. Paul's Hospital in Vancouver, Canada. A retrospective database review of admissions to the HIV/AIDS ward between 1 July 2005 and 30 June 2014 was conducted. Primary discharge diagnoses were manually categorized by condition and reviewed by two physicians. Data were analysed in 12 month intervals. Trends were fitted using generalized estimating equations. A total of 1595 individuals with 3919 admissions were included. The median age was 46 years, 77.1% identified as male, 63.6% had a history of injection drug use (IDU) and 61.8% had a history of hepatitis C virus exposure. The most common reasons for admission included non-opportunistic respiratory tract infections (18.2%), cellulitis (7.3%), gastroenteritis (6.0%), endocarditis/bacteremia (4.9%) and bone/joint infections (3.5%). The proportion of admissions attributable to opportunistic infections declined from 16.2% in 2005 to 5.5% in 2014. Over this period, the proportion of individuals on antiretroviral therapy and with virologic suppression increased (odds ratio 1.19 [95% confidence interval 1.16, 1.23] and 1.22 [95% confidence interval 1.17, 1.26], respectively). These results demonstrate a decline in admissions related to opportunistic infections but increased admissions due to other infections among people living with HIV. Preventive and outpatient care for respiratory infections and complications of IDU may further improve health care outcomes and decrease hospital admissions in this setting. PMID- 29397767 TI - Daedaleanols A and B, two new sesquiterpenes from cultures of the basidiomycete Daedalea incana. AB - Two new sesquiterpenes, daedaleanols A (1) and B (2), together with three known sesquiterpenes (3-5), were isolated from cultures of the basidiomycete Daedalea incana. Their structures were elucidated on the basis of extensive spectroscopic means. All compounds were tested for their cytotoxicities against three human cancer cell lines. PMID- 29397768 TI - Erratum. PMID- 29397769 TI - Erratum. PMID- 29397770 TI - Erratum. PMID- 29397771 TI - Dual HIV-1 reverse transcriptase and integrase inhibitors from Limonium morisianum Arrigoni, an endemic species of Sardinia (Italy). AB - During our search for potential templates of HIV-1 reverse transcriptase (RT) and integrase (IN) dual inhibitors, the methanolic extract obtained from aerial parts of Limonium morisianum was investigated. Repeated bioassay-guided chromatographic purifications led to the isolation of the following secondary metabolites: myricetin, myricetin 3-O-rutinoside, myricetin-3-O-(6"-O-galloyl)-beta-d galactopyranoside, (-)-epigallocatechin 3-O-gallate, tryptamine, ferulic and phloretic acids. The isolated compounds were tested on both HIV-1 RT-associated RNase H and IN activities. Interestingly, (-)-epigallocatechin-3-O-gallate and myricetin-3-O-(6"-O-galloyl)-beta-d-galactopyranoside potently inhibited both enzyme activities with IC50 values ranging from 0.21 to 10.9 MUM. Differently, tryptamine and ferulic acid exhibited a significant inhibition only on the IN strand transfer reaction, showing a selectivity for this viral enzyme. Taken together these results strongly support the potential of this plant as a valuable anti HIV-1 drugs source worthy of further investigations. PMID- 29397772 TI - A new polyketide purpurogenic acid: the activated production of polyketides by the diethyl sulphate mutagenesis of marine-derived Penicillium purpurogenum G59. AB - A new polyketide, purpurogenic acid (1), and two known polyketides, (-) mitorubrin (2) and (-)-mitorubrinol (3), were isolated from a fungal mutant derived from the diethyl sulphate (DES) mutagenesis of marine-derived Penicillium purpurogenum G59. The planar structure of new 1 was elucidated by spectroscopic methods and the absolute configuration was assigned on the basis of [alpha]D and CD data. In our preliminary MTT assay, 1 inhibited human cancer K562, HL-60, HeLa and BGC-823 cells with the inhibition rates of 52.7, 78.8, 38.4 and 35.3% at the 100 MUg/mL, respectively. PMID- 29397774 TI - A new coumarin from Juglans mandshurica Maxim induce apoptosis in hepatocarcinoma cells. AB - In this study, a new coumarin, juglansoside C (1) was isolated from the bark of Juglans mandshurica. Its chemical structure was identified by comprehensive spectroscopic analyses. The in vitro cytotoxicity assay showed that 1 exhibited moderate cytotoxicity against human hepatocellular carcinoma Hep3B cells with an IC50 value of 70.9 MUM. Furthermore, Annexin V-FITC/PI staining assay indicated that 1 markedly induced apoptosis in Hep3B cells. PMID- 29397775 TI - Acetylcholinesterase inhibitory active metabolites from the endophytic fungus Colletotrichum sp. YMF432. AB - An endophytic fungus, Chaetomium sp. YMF432, was isolated from Huperzia serrata (Thunb. ex Murray) Trev. and subjected to phytochemical investigation based on its special environment. From the extracts of fermentation solid of strain YMF 432, eight compounds including 1-O-methylemodin (1), 5-methoxy-2-methyl-3 tricosyl-1,4-benzoquinone (2), 4,8-dihydroxy-1-tetralone (3), (3beta,5alpha,6alpha, 22E)-3-hydroxy-5,6-epoxy-7-one-8(14),22-dien-ergosta (4), ergosta-4,6,8(14),22-tetraen-3-one (5), beta-sitostenone (6), beta-sitosterol (7) and (22E,24R)-ergosta-5,7,22 -trien-3beta-ol (8) were obtained. Their structures were elucidated on the basis of their spectroscopic data. These compounds were evaluated for acetylcholinesterase inhibitory activities in vitro. Compounds 1, 2, and 4 showed moderate acetylcholinesterase inhibitory activities (IC50 from 37.7 +/- 1.5 to 370.0 +/- 2.9 MUM). PMID- 29397776 TI - Perceptions of undergraduate pharmacy students on plagiarism in three major public universities in Egypt. AB - The survey aimed to capture the perceptions of undergraduate pharmacy students towards plagiarism in three major public universities in Cairo, Egypt: Helwan, Ain-Shams, and Cairo Universities. This was a paper-based self-administrated survey study. The questionnaire was validated by both content and face validation. The final survey form captured the knowledge of the students on plagiarism in terms of definitions, attitudes, and practices. Four hundred and fourteen students, 320 females and 94 males, participated in the study. There was a significant difference between the students who knew the definition of plagiarism among the three universities with p-value = .01. More than half of the participants (67%) claimed that they had no previous education or training on plagiarism. However, after being informed about plagiarism, most of them agreed that plagiarism should be regarded as stealing and a punishment. Additionally, poor study skills and the ease of copying and pasting from the Internet were identified by the majority of the students to be the leading causes of plagiarism. Pharmacy students need to be more educated on plagiarism and its consequences on research and educational ethics. Finally, more strict policies should be incorporated to monitor and control plagiarism in undergraduate sections. PMID- 29397777 TI - Impact of intimate partner violence on clinic attendance, viral suppression and CD4 cell count of women living with HIV in an urban clinic setting. AB - The substance abuse, violence and HIV/AIDS (SAVA) syndemic represents a complex set of social determinants of health that impacts the lives of women. Specifically, there is growing evidence that intimate partner violence (IPV) places women at risk for both HIV acquisition and poorer HIV-related outcomes. This study assessed prevalence of IPV in an HIV clinic setting, as well as the associations between IPV, symptoms of depression and PTSD on three HIV-related outcomes-CD4 count, viral load, and missed clinic visits. In total, 239 adult women attending an HIV-specialty clinic were included. Fifty-one percent (95% CI: 45%-58%) reported past year psychological, physical, or sexual intimate partner abuse. In unadjusted models, IPV was associated with having a CD4 count <200 (OR: 3.284, 95% CI: 1.251-8.619, p = 0.016) and having a detectable viral load (OR: 1.842, 95% CI: 1.006-3.371, p = 0.048). IPV was not associated with missing >33% of past year all type clinic visits (OR: 1.535, 95% CI: 0.920-2.560, p = 0.101) or HIV specialty clinic visits (OR: 1.251, 95% CI: 0.732-2.140). In multivariable regression, controlling for substance use, mental health symptoms and demographic covariates, IPV remained associated with CD4 count <200 (OR: 3.536, 95% CI: 1.114 11.224, p = 0.032), but not viral suppression. The association between IPV and lower CD4 counts, but not adherence markers such as viral suppression and missed visits, indicates a need to examine potential physiologic impacts of trauma that may alter the immune functioning of women living with HIV. Incorporating trauma informed approaches into current HIV care settings is one opportunity that begins to address IPV in this patient population. PMID- 29397778 TI - The clinical characteristics of Kleine-Levin syndrome according to ethnicity and geographic location. AB - PURPOSE: Kleine-Levin syndrome (KLS) is a rare, relapsing-remitting, debilitating sleep disorder. Examining KLS characteristics in different ethnic populations may help elucidate the genetic basis of the disorder. No studies have examined KLS in Arabs. Therefore, we compared the clinical characteristics of Saudi Arabian KLS patients to those in other published cohorts to determine whether Arab patients have a distinct phenotype. METHODS: This study included all patients who were diagnosed with KLS at our center between June 2003 and July 2016 (P = 12; Six familial cases). All participants completed the Stanford KLS questionnaire. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale; eating attitudes were assessed with the Eating Attitudes Test-26. We compared the clinical characteristics of our patients to those in other published cohorts. RESULTS: Saudi Arabian patients with KLS had similar features to those in patients from different countries and ethnic backgrounds, with only minor differences in sleep duration during disease episodes (2-3 h shorter). However, between episodes, Saudi Arabian KLS patients reported worse sleep, greater daytime sleepiness and higher levels of baseline depression, which may be related to KLS or to local cultural practices. Ankylosing spondylitis was present in five of the six familial patients. CONCLUSION: Saudi Arabian patients with KLS exhibited similar clinical characteristics during episodes compared to patients with KLS of different ethnicities. However, a new and interesting finding is that KLS patients may have inter-episode behavioral and pathophysiological changes, which may suggest that KLS is not necessarily a static disorder. PMID- 29397779 TI - Content comparison of guideline-recommended instruments used in treatment for alcohol use disorders. AB - PURPOSE: Practice guidelines recommend the use of standardized instruments in the treatment of alcohol use disorders (AUDs); however, the extent to which these instruments assess patients' functioning is unclear. The aim of this study was to examine the domains of functioning and contextual factors contained in guideline recommended instruments, using the International Classification of Functioning, Disability, and Health (ICF) as a reference. MATERIALS AND METHODS: We identified instruments by reviewing AUD treatment guidelines used in Germany, Canada, Australia and New Zealand, United Kingdom, and United States. We included instruments which were available in English free of charge, we excluded instruments developed solely for diagnostic or epidemiological purposes and those for children or adolescents. Following a standardized set of rules, two health care researchers identified the concepts contained in the items on the instruments and independently linked them to ICF categories. RESULTS: A total of 10 instruments were included. Among 517 items, 752 meaningful concepts (MCs) were derived, and 622 of them were linked to the ICF. Inter-rater agreement was kappa = 0.61. One hundred eighty eight MCs referred to personal factors, 175 to body functions, 168 to activity and participation, and 91 to environmental factors. The most frequently linked ICF chapter was b1 (mental functions). CONCLUSIONS: Instruments recommended in AUD treatment guidelines vary considerably in their assessment of patients' functioning and contextual factors. Within the investigated instruments, environmental factors are under-represented in comparison to body functions and personal factors. ICF linkage provides guidance for clinicians and researchers in the selection of appropriate instruments. Implications for rehabilitation Since instruments that are recommended in alcohol treatment guidelines vary considerably in respect the functioning domains and context factors they cover, it may be challenging for clinicians to select instruments relevant to their treatment context. Using the ICF as framework, our results provide guidance for clinicians in how to select appropriate instruments. Within the investigated instruments, environmental factors and activities and participation are under-represented in comparison to body functions and personal factors. Clinicians may employ AUD-unspecific or ICF-based instruments to cover these components if needed. PMID- 29397780 TI - Depressive symptoms affect outcomes of pessary use in postmenopausal women with uterine prolapse. AB - OBJECTIVE: This study aimed to investigate the impact of depressive symptoms on successful pessary treatment for postmenopausal women with symptomatic pelvic organ prolapse (POP). METHODS: We performed a prospective study involving postmenopausal women with POP who visited our clinic seeking pessary treatment. Demographic information and medical histories were collected. The participants completed the following questionnaires at baseline and after 3 months of successful pessary use: (1) the Pelvic Floor Impact Questionnaire-7 (PFIQ-7); (2) the Pelvic Floor Distress Inventory (PFDI-20); and (3) the Patient Health Questionnaire-9 (PHQ-9). The data were analyzed with the independent samples t test, Mann-Whitney U-test, chi2 test, Fisher's exact test, paired t-test or Wilcoxon signed-rank test as appropriate. RESULTS: In total, 102 (92.7%) participants who completed the entire study were included in the analysis. No significant differences were found in the sociodemographic or clinical characteristics between the 'positive' and 'negative' depressive symptom groups (p > 0.05). After 3 months of successful pessary treatment, the scores of the PFIQ-7 (including the Urinary Incontinence Questionnaire-7, the Colon Rectal Anal Impact Questionnaire-7 and the Pelvic Organ Prolapse Impact Questionnaire-7 subscales) and PFDI-20 (including the Pelvic Organ Prolapse Distress Inventory-6, the Colon Rectal Anal Distress Inventory-8 and the Urinary Distress Inventory-6 (UDI-6) subscales) were significantly decreased in all participants (p < 0.05). The PHQ-9 score was also significantly decreased (p < 0.001). However, the participants with depressive symptoms reported significantly less improvement post-treatment than those without depressive symptoms in the score of the PFDI-20 subscale UDI-6, which represented the degree of distress due to the lower urinary tract symptoms (p = 0.022). CONCLUSIONS: Both the quality of life and depressive symptom scores were significantly improved after 3 months of successful pessary use. We advocate making depressive symptom screening a regular indicator for assessing the effectiveness of conservative POP treatment. PMID- 29397781 TI - Ionizing Radiation Deregulates the MicroRNA Expression Profile in Differentiated Thyroid Cells. AB - BACKGROUND: Ionizing radiation (IR) is a well-known risk factor for papillary thyroid cancer, and it has been reported to deregulate microRNA expression, which is important to thyroid carcinogenesis. Therefore, this study investigated the impact of IR on microRNA expression profile of the normal thyroid cell line (FRTL 5 CL2), as well as its effect on radiosensitivity of thyroid cancer cell lines, especially the human anaplastic thyroid carcinoma cell line (8505c). METHODS: The global microRNA expression profile of irradiated FRTL-5 CL2 cells (5 Gy X-ray) was characterized, and data were confirmed by quantitative real-time polymerase chain reaction evaluating the expression of rno-miR-10b-5p, rno-miR-33-5p, rno miR-128-1-5p, rno-miR-199a-3p, rno-miR-296-5p, rno-miR-328a-3p, and rno-miR-541 5p in irradiated cells. The miR-199a-3p and miR-10b-5p targets were validated by quantitative real-time polymerase chain reaction, Western blot, and luciferase target assays. The effects of miR-199a-3p and miR-10b-5p on DNA repair were determined by evaluating the activation of the protein kinases ataxia telangiectasia mutated, ataxia telangiectasia, and Rad3-related and the serine 39 phosphorylation of variant histone H2AX as an indirect measure of double-strand DNA breaks in irradiated FRTL-5 CL2 cells. The impact of miR-10b-5p on radiosensitivity was analyzed by cell counting and MTT assays in FRTL-5 CL2, Kras transformed FRTL-5 CL2 (FRTL KiKi), and 8505c cell lines. RESULTS: The results reveal that miR-10b-5p and miR-199a-3p display the most pronounced alterations in expression in irradiated FRTL-5 CL2 cells. Dicer1 and Lin28b were validated as targets of miR-10b-5p and miR-199a-3p, respectively. Functional studies demonstrate that miR-10b-5p increases the growth rate of FRTL-5 CL2 cells, while miR-199a-3p inhibits their proliferation. Moreover, both of these microRNAs negatively affect homologous recombination repair, reducing activated ataxia telangiectasia mutated and Rad3-related protein levels, consequently leading to an accumulation of the serine 39 phosphorylation of variant histone H2AX. Interestingly, the overexpression of miR-10b-5p decreases the viability of the irradiated FRTL5-CL2 and 8505c cell lines. Consistent with this observation, its inhibition in FRTL KiKi cells, which display high basal expression levels of miR 10b-5p, leads to the opposite effect. CONCLUSIONS: These results demonstrate that IR deregulates microRNA expression, affecting the double-strand DNA breaks repair efficiency of irradiated thyroid cells, and suggest that miR-10b-5p overexpression may be an innovative approach for anaplastic thyroid cancer therapy by increasing cancer cell radiosensitivity. PMID- 29397782 TI - Impact of age on postoperative outcomes in bariatric surgery. AB - BACKGROUND: Age is often related to the increase of perioperative complications and reoperation rates. The authors aimed to determine the influence of age on outcomes of most commonly performed bariatric procedures. METHODS: The retrospective study included patients qualified for primary Laparoscopic Sleeve Gastrectomy (LSG) or Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) in two academic hospitals. Patients were divided into two groups: >=50 (21.2-26.9%) and <50 (57.6-73.1%) years old. Endpoints assessed the influence of patients' age on the perioperative and the one-year postoperative period. RESULTS: Operative time was longer in the >=50-year-old group, but only for LRYGB. There were no differences in the intraoperative adverse events, postoperative morbidity, reoperation and readmission rates between the groups. The risk of port site hernia was increased (OR: 4.23, CI: 1.49-12.06) in the >=50-year-old group. The mean % of total weight loss 12 months after the bariatric procedure was comparable, but % of excess weight loss and % of excess body mass index loss were lower in the >=50-year-old group (p = .033 and .032). CONCLUSIONS: Bariatric surgery is safe and feasible in patients over 50 years old. The weight loss effect can be worse among patients over 50 years old; nevertheless, the treatment should be considered as effective. PMID- 29397783 TI - Estimating Pressure Reactivity Using Noninvasive Doppler-Based Systolic Flow Index. AB - The study objective was to derive models that estimate the pressure reactivity index (PRx) using the noninvasive transcranial Doppler (TCD) based systolic flow index (Sx_a) and mean flow index (Mx_a), both based on mean arterial pressure, in traumatic brain injury (TBI). Using a retrospective database of 347 patients with TBI with intracranial pressure and TCD time series recordings, we derived PRx, Sx_a, and Mx_a. We first derived the autocorrelative structure of PRx based on: (A) autoregressive integrative moving average (ARIMA) modeling in representative patients, and (B) within sequential linear mixed effects (LME) models with various embedded ARIMA error structures for PRx for the entire population. Finally, we performed sequential LME models with embedded PRx ARIMA modeling to find the best model for estimating PRx using Sx_a and Mx_a. Model adequacy was assessed via normally distributed residual density. Model superiority was assessed via Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC), log likelihood (LL), and analysis of variance testing between models. The most appropriate ARIMA structure for PRx in this population was (2,0,2). This was applied in sequential LME modeling. Two models were superior (employing random effects in the independent variables and intercept): (A) PRx ~ Sx_a, and (B) PRx ~ Sx_a + Mx_a. Correlation between observed and estimated PRx with these two models was: (A) 0.794 (p < 0.0001, 95% confidence interval (CI) = 0.788-0.799), and (B) 0.814 (p < 0.0001, 95% CI = 0.809-0.819), with acceptable agreement on Bland-Altman analysis. Through using linear mixed effects modeling and accounting for the ARIMA structure of PRx, one can estimate PRx using noninvasive TCD-based indices. We have described our first attempts at such modeling and PRx estimation, establishing the strong link between two aspects of cerebral autoregulation: measures of cerebral blood flow and those of pulsatile cerebral blood volume. Further work is required to validate. PMID- 29397784 TI - Role of ultrasound for central catheter tip localization in neonates: a review of the current evidence. AB - Central catheters are known as "life lines" in intensive care units and are used frequently in neonatal intensive care unit (NICU) for multiple indications. The central catheters used in NICU includes umbilical venous catheter (UVC), umbilical arterial catheter (UAC) and peripherally inserted central catheter (PICC) lines. The tip of these central lines needs to be in a correct position as malpositioned central line tips lead to many neonatal complications. Radiograph either abdomen or chest is the most widely used modality for locating the tip of the central catheter. There are many disadvantages of radiographic confirmation of tip position and recently ultrasound (USG)/echocardiography has been used for localization of catheter tip. USG provides real-time assessment of the tip position with other added advantages like no radiation exposure, need for minimal training for performing USG, minimal handling of the neonate, identification of migration of central lines and making repositioning of central lines under USG guidance. The present evidence supports the use of USG/Echo for localization of central catheter tip and USG has shown to have good sensitivity, specificity, positive predictive value and negative predictive value when compared with a radiograph. In this review, we discuss about the role of USG/Echo in the identification of tip of central catheters in neonatal care. PMID- 29397785 TI - Reliability and validity of the de Morton Mobility Index in individuals with sub acute stroke. AB - PURPOSE: To establish the validity and reliability of the de Morton Mobility Index (DEMMI) in patients with sub-acute stroke. METHODS: This cross-sectional study was performed in a neurological rehabilitation hospital. We assessed unidimensionality, construct validity, internal consistency reliability, inter rater reliability, minimal detectable change and possible floor and ceiling effects of the DEMMI in adult patients with sub-acute stroke. RESULTS: The study included a total sample of 121 patients with sub-acute stroke. We analysed validity (n = 109) and reliability (n = 51) in two sub-samples. Rasch analysis indicated unidimensionality with an overall fit to the model (chi-square = 12.37, p = 0.577). All hypotheses on construct validity were confirmed. Internal consistency reliability (Cronbach's alpha = 0.94) and inter-rater reliability (intraclass correlation coefficient = 0.95; 95% confidence interval: 0.92-0.97) were excellent. The minimal detectable change with 90% confidence was 13 points. No floor or ceiling effects were evident. CONCLUSIONS: These results indicate unidimensionality, sufficient internal consistency reliability, inter-rater reliability, and construct validity of the DEMMI in patients with a sub-acute stroke. Advantages of the DEMMI in clinical application are the short administration time, no need for special equipment and interval level data. The de Morton Mobility Index, therefore, may be a useful performance-based bedside test to measure mobility in individuals with a sub-acute stroke across the whole mobility spectrum. Implications for Rehabilitation The de Morton Mobility Index (DEMMI) is an unidimensional measurement instrument of mobility in individuals with sub-acute stroke. The DEMMI has excellent internal consistency and inter rater reliability, and sufficient construct validity. The minimal detectable change of the DEMMI with 90% confidence in stroke rehabilitation is 13 points. The lack of any floor or ceiling effects on hospital admission indicates applicability across the whole mobility spectrum of patients with sub-acute stroke. PMID- 29397786 TI - Robotic Patterning a Superhydrophobic Surface for Collective Cell Migration Screening. AB - Collective cell migration, in which cells migrate as a group, is fundamental in many biological and pathological processes. There is increasing interest in studying the collective cell migration in high throughput. Cell scratching, insertion blocker, and gel-dissolving techniques are some methodologies used previously. However, these methods have the drawbacks of cell damage, substrate surface alteration, limitation in medium exchange, and solvent interference. The superhydrophobic surface, on which the water contact angle is greater than 150 degrees, has been recently utilized to generate patterned arrays. Independent cell culture areas can be generated on a substrate that functions the same as a conventional multiple well plate. However, so far there has been no report on superhydrophobic patterning for the study of cell migration. In this study, we report on the successful development of a robotically patterned superhydrophobic array for studying collective cell migration in high throughput. The array was developed on a rectangular single-well cell culture plate consisting of hydrophilic flat microwells separated by the superhydrophobic surface. The manufacturing process is robotic and includes patterning discrete protective masks to the substrate using 3D printing, robotic spray coating of silica nanoparticles, robotic mask removal, robotic mini silicone blocker patterning, automatic cell seeding, and liquid handling. Compared with a standard 96-well plate, our system increases the throughput by 2.25-fold and generates a cell-free area in each well non-destructively. Our system also demonstrates higher efficiency than conventional way of liquid handling using microwell plates, and shorter processing time than manual operating in migration assays. The superhydrophobic surface had no negative impact on cell viability. Using our system, we studied the collective migration of human umbilical vein endothelial cells and cancer cells using assays of endpoint quantification, dynamic cell tracking, and migration quantification following varied drug treatments. This system provides a versatile platform to study collective cell migration in high throughput for a broad range of applications. PMID- 29397787 TI - Gating of the neuroendocrine stress responses by stressor salience in early lactating female rats is independent of infralimbic cortex activation and plasticity. AB - In early lactation (EL), stressor salience modulates neuroendocrine stress responses, but it is unclear whether this persists throughout lactation and which neural structures are implicated. We hypothesized that this process is specific to EL and that the infralimbic (IL) medial prefrontal cortex (mPFC) might provide a critical link between assessment of threat and activation of the hypothalamo pituitary-adrenal (HPA) axis in EL. We measured neuroendocrine responses and neuronal Fos induction to a salient (predator odor) or non-salient (tail pinch) psychogenic stressor in EL and late lactation (LL) females. We found that EL females exhibited a large response to predator stress only in the presence of pups, while responses to tail pinch were reduced independently of pup presence. In LL, HPA axis responses were independent of pup presence for both stressors and only responses to tail pinch were modestly reduced compared to virgins. Intracerebral injection of the local anesthetic bupivacaine (BUP) (0.75%; 0.5 ul/side) in the IL mPFC did not differentially affect neuroendocrine responses to predator odor in virgin and EL females, suggesting that lactation-induced changes in this structure might not regulate stressor salience for the HPA axis. However, the IL mPFC displayed morphological changes in lactation, with significant increases in dendritic spine numbers and density in EL compared to LL and virgin females. EL females also showed improved performance in the attention set shifting task (AST), which could reflect early plasticity in the IL mPFC at a time when rapid adaptation of the maternal brain is necessary for pup survival. PMID- 29397788 TI - Effect of oral calcium bolus administration on milk production, concentrations of minerals and metabolites in serum, early-lactation health status, and reproductive performance of Holstein dairy cows. AB - AIMS: To determine the effects of oral Ca bolus administration in the early postpartum period of cows on milk yield and composition, blood metabolites, early lactation health status, and reproductive performance. METHODS: Multiparous Holstein dry cows (n=66) with a mean parity of 3.1 (SD 0.35) were fed a diet with a positive dietary cation-anion difference (DCAD) prior to calving. They were randomly assigned to receive no treatment (Control; n=33) or two oral Ca boluses (n=33, 45 g of Ca per bolus); one was administered immediately after calving (Day 0) and the second 24 hours (+/-30 minutes) later. Blood samples were collected at calving, and on Days 2 and 7 to determine concentrations in serum of Ca, P, Mg, glucose, non-esterified fatty acids (NEFA), and beta-hydroxybutyric acid (BHBA). Milk yield was recorded daily and milk composition was determined weekly from calving until 28 day postpartum. Health and outcomes were determined during the first 30 days postpartum and reproductive outcomes to 180 days postpartum. RESULTS: Mean milk yields and composition over the first month of lactation were similar between cows in the two treatment groups (p>0.1). Mean concentrations of Ca in serum were not different between treatment groups on Day 0, but were higher on Day 2 for cows that received oral Ca boluses (1.77 (SE 0.07)) compared with Control cows (1.54 (SE 0.08)) (p=0.04). Concentrations in serum of P, Mg, glucose, NEFA and BetaHBA did not differ between treatment groups on any day of measurement. Fewer cows that received oral Ca were diagnosed with hypocalcaemia (total concentrations of Ca in serum <1.5 mmol/L) by Day 2 (2/33; 6%) compared with Control cows (12/33; 36%) (p=0.01). There was no difference in the prevalence of other health outcomes between treatment groups. The proportion of cows conceiving to first insemination was greater in cows that received an oral Ca bolus (19/29; 65%) than Control cows (12/29; 41%) (p=0.01). CONCLUSIONS: Oral Ca bolus administration increased concentrations of Ca in serum on Day 2 postpartum, and increased first service conception rates, in cows fed a diet with a positive DCAD prior to calving compared to cows that received no oral Ca bolus supplementation. Because of the small number of cows used in this study, further studies in large-scale dairy farms should be carried out to confirm these findings. PMID- 29397789 TI - ROCK Inhibition Promotes the Development of Chondrogenic Tissue by Improved Mass Transport. AB - Human mesenchymal stem cell (hMSC)-based chondrogenesis is a key process used to develop tissue engineered cartilage constructs from stem cells, but the resulting constructs have inferior biochemical and biomechanical properties compared to native articular cartilage. Transforming growth factor beta containing medium is commonly applied to cell layers of hMSCs, which aggregate upon centrifugation to form 3-D constructs. The aggregation process leads to a high cell density condition, which can cause nutrient limitations during long-term culture and, subsequently, inferior quality of tissue engineered constructs. Our objective is to modulate the aggregation process by targeting RhoA/ROCK signaling pathway, the chief modulator of actomyosin contractility, to enhance the end quality of the engineered constructs. Through ROCK inhibition, repression of cytoskeletal tension in chondrogenic hMSCs was achieved along with less dense aggregates with enhanced transport properties. ROCK inhibition also led to significantly increased cartilaginous extracellular matrix accumulation. These findings can be used to create an improved microenvironment for hMSC-derived tissue engineered cartilage culture. We expect that these findings will ultimately lead to improved cartilaginous tissue development from hMSCs. PMID- 29397790 TI - Potential neuroprotective effect of Fingolimod in multiple sclerosis and its association with clinical variables. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti-inflammatory effect and/or to a direct effect on neuronal cells. Areas covered: In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS. Expert opinion: Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect. PMID- 29397791 TI - Glutaredoxin 3 promotes migration and invasion via the Notch signalling pathway in oral squamous cell carcinoma. AB - Substantial evidence indicates that the alteration of the cellular redox status is a critical factor involved in cell growth and death and results in tumourigenesis. Cancer cells have an efficient antioxidant system to counteract the increased generation of ROS. However, whether this ability to survive high levels of ROS has an important role in the growth and metastasis of tumours is not well understood. Glutaredoxin 3 (GLRX3), also known as TXNL2, Grx3 and PICOT, maintains a low level of ROS, thus contributing to the survival and metastasis of several types of cancer. However, little is known about the role of GLRX3 and the underlying mechanisms that suppress oral squamous cell carcinoma (OSCC) progression. Here, by using immunohistochemical staining, we demonstrated that GLRX3 was overexpressed in human OSCC, and enhanced GLRX3 expression correlated with metastasis and with decreased overall patient survival. Knockdown of GLRX3 in human OSCC cell lines reduced Notch activity by reversing the epithelial mesenchymal transition (EMT), resulting in the inhibition of in vitro migration and invasion. Importantly, knockdown of GLRX3 triggered the generation of ROS. Furthermore, N-acetyl cysteine (NAC), an ROS scavenger, enhanced the effects of GLRX3 knockdown on Notch-dependent EMT. Collectively, these findings suggested the vital roles of GLRX3 in OSCC progression through its relationship with EMT progression, and these data also suggest that a strategy of blocking ROS to enhance the activity of GLRX3 knockdown warrants further attention in the treatment of OSCC. PMID- 29397792 TI - Uterine artery Doppler ultrasound in second pregnancy with previous elective cesarean section. AB - OBJECTIVES: To assess the effects of previous cesarean delivery (CD) and placental location on second trimester uterine artery Doppler indices in subsequent pregnancy and to assess the predictive values of abnormal Doppler findings for adverse pregnancy outcomes in women with previous CD. STUDY DESIGN: This prospective cohort study evaluated 400 gravida two pregnant women (200 with previous none medically indicated CD and 200 with previous normal vaginal deliveries (NVD)) who were referred for second trimester fetal anatomic survey. Uterine artery Doppler studies were performed in all participants who were then followed until delivery. RESULTS: Compared with women having prior NVD, women with prior CD had significantly higher rates of abnormal uterine artery pulsatility index (PI) (p < .001), and significantly more adverse pregnancy outcomes (p = .01). Among women with previous CD, all the measured adverse pregnancy outcomes occurred significantly more often in women with abnormal uterine artery Doppler indices (p < .001). CONCLUSIONS: CD seems to be associated with increased risks of impaired placental function and circulation and adverse pregnancy outcomes in the subsequent pregnancy, particularly in women with anteriorly located placenta near the previous uterine scar. PMID- 29397793 TI - Loco-regional versus general anaesthesia for elective endovascular aneurysm repair - results of a cohort study and a meta-analysis. AB - BACKGROUND: The aim of this study was to investigate whether patients undergoing elective endovascular aneurysm repair (EVAR) with loco-regional anaesthetic techniques have better outcomes than those treated with general anaesthesia (GA). PATIENTS AND METHODS: We retrospectively evaluated outcomes of EVAR performed with regional anaesthesia (RA) or GA over a five-year period. Furthermore, we searched electronic bibliographic sources (MEDLINE, EMBASE, CINAHL, and CENTRAL) to identify studies comparing different anaesthetic methods in EVAR. We defined perioperative mortality and morbidity as well as length of hospital stay (LOS) as the primary outcome measures. Pooled effect estimates were calculated using fixed effect or random-effects models. Results are reported as the odds ratio (OR) or mean difference (MD) and 95 % confidence interval (CI). RESULTS: Three hundred and fifty-five patients underwent standard EVAR over the study period (RA, 215 patients; GA 140 patients). Patients in both groups had comparable baseline demographics and clinical characteristics. Perioperative mortality was significantly lower in the RA group (0.5 % vs. 4.3 %, P = 0.017). No difference was found in perioperative morbidity (P = 0.370), LOS (P = 0.146), postoperative destination (P = 0.799), reoperation (P = 0.355) or readmission within 30 days (P = 0.846). Meta-analysis of data on 15,472 patients from 15 observational studies found a significantly lower perioperative mortality (OR 0.70, 95 % CI 0.52-0.95, P = 0.02) and morbidity (OR 0.73, 95 % CI 0.55-0.96, P = 0.02) in patients treated with loco-regional anaesthetic techniques compared to those treated with GA. Our sub-group analysis demonstrated that both local anaesthesia (LA) (P = 0.003) and RA (P < 0.0001) were associated with a significantly shorter LOS compared to GA. CONCLUSIONS: Local and/or regional anaesthetic techniques may be advantageous over GA in elective EVAR, as indicated by reduced perioperative mortality and morbidity and a shorter hospital stay. Considering the current level of evidence, LA or RA should be considered in selected patients. Further clinical research is required to provide high level evidence on the optimal anaesthetic technique in EVAR. PMID- 29397795 TI - Global health trials methodological research agenda: results from a priority setting exercise. AB - BACKGROUND: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. METHODS: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. FINDINGS: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. CONCLUSION: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs. PMID- 29397796 TI - Primary purulent bacterial pericarditis due to Streptococcus intermedius in an immunocompetent adult: a case report. AB - BACKGROUND: Acute purulent bacterial pericarditis is of rare occurrence in this modern antibiotic era. Primary involvement of the pericardium without evidence of underlying infection elsewhere is even rarer. It is a rapidly progressive infection with high mortality. We present an extremely rare case of acute purulent bacterial pericarditis in an immunocompetent adult patient with no underlying chronic medical conditions. CASE PRESENTATION: A 33-year-old previously healthy white man presented with the complaints of chest pain and dyspnea. He was diagnosed as having acute pericarditis and was discharged home on indomethacin. Over a period of 2 weeks, his symptoms worsened gradually and he was readmitted to our hospital. He was found to have large pericardial effusion with cardiac tamponade. An urgent pericardiocentesis was done with drainage of 550 ml of purulent material. Cultures grew Streptococcus intermedius confirming the diagnosis of acute purulent bacterial pericarditis. No other focus of infection was identified on imaging workup suggesting primary infection of the pericardium. His clinical course was complicated by development of constrictive pericarditis for which he underwent surgical pericardiectomy. He received a total of 7 weeks of intravenously administered antibiotics with complete clinical recovery. CONCLUSIONS: Acute purulent bacterial pericarditis, although rare, should always be kept in mind as a possible cause of pericarditis. Early recognition and prompt intervention are important for a successful outcome. PMID- 29397797 TI - Tissue sterol composition in Atlantic salmon (Salmo salar L.) depends on the dietary cholesterol content and on the dietary phytosterol:cholesterol ratio, but not on the dietary phytosterol content. AB - The aim of the study was to investigate how the dietary sterol composition, including cholesterol, phytosterol:cholesterol ratio and phytosterols, affect the absorption, biliary excretion, retention, tissue storage and distribution of cholesterol and individual phytosterols in Atlantic salmon (Salmo salar L.). A feeding trial was conducted at two different temperatures (6 and 12 degrees C), using nine different diets with varying contents of phytosterols, cholesterol and phytosterol:cholesterol ratio. Cholesterol retention values were clearly dependent on dietary cholesterol, and showed that fish fed cholesterol levels <1000 mg/kg feed produced considerable quantities of cholesterol de novo. Despite this production, cholesterol content increased with increasing dietary cholesterol in liver, plasma, bile, muscle, adipose tissue and whole fish at 12 degrees C, and in plasma, bile and whole fish at 6 degrees C. The tissue sterol composition generally depended on the dietary cholesterol content and on the dietary phytosterol:cholesterol ratio, but not on the dietary phytosterol content in itself. Campesterol and brassicasterol appeared to be the phytosterols with the highest intestinal absorption in Atlantic salmon. There was a high biliary excretion of campesterol, but not of brassicasterol, which accumulated in tissues and particularly in adipose tissue, with 2-fold-higher retention at 12 degrees C compared with 6 degrees C. Campesterol had the second highest retention of the phytosterols in the fish, but with no difference between the two temperatures. Other phytosterols had very low retention. Although brassicasterol retention decreased with increasing dietary phytosterols, campesterol retention decreased with increasing dietary cholesterol, indicating differences in the uptake mechanisms for these two sterols. PMID- 29397798 TI - Population differentiation between Australian and Chinese Helicoverpa armigera occurs in distinct blocks on the Z-chromosome. AB - Over the last 40 years, many types of population genetic markers have been used to assess the population structure of the pest moth species Helicoverpa armigera. While this species is highly vagile, there is evidence of inter-continental population structure. Here, we examine Z-chromosome molecular markers within and between Chinese and Australian populations. Using 1352 polymorphic sites from 40 Z-linked loci, we compared two Chinese populations of moths separated by 700 km and found virtually no population structure (n = 41 and n = 54, with <1% of variation discriminating between populations). The levels of nucleotide diversity within these populations were consistent with previous estimates from introns in Z-linked genes of Australian samples (pi = 0.028 vs. 0.03). Furthermore, all loci surveyed in these Chinese populations showed a skew toward rare variants, with ten loci having a significant Tajima's D statistic, suggesting that this species could have undergone a population expansion. Eight of the 40 loci had been examined in a previous study of Australian moths, of which six revealed very little inter-continental population structure. However, the two markers associated with the Cyp303a1 locus that has previously been proposed to be a target of a selective sweep, exhibited allele structuring between countries. Using a separate dataset of 19 Australian and four Chinese moths, we scanned the molecular variation distributed across the entire Z-chromosome and found distinct blocks of differentiation that include the region containing Cyp303a1. We recommend some of these loci join those associated with insecticide resistance to form a set of genes best suited to analyzing population structure in this global pest. PMID- 29397794 TI - Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. AB - BACKGROUND: Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved. METHODS: An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure. RESULTS: Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre operative anxiety, prevention of agitation and risk of breast cancer. CONCLUSIONS: There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties. PMID- 29397799 TI - Gaps in monitoring systems for Implanon NXT services in South Africa: An assessment of 12 facilities in two districts AB - Background. Implanon NXT, a long-acting subdermal contraceptive implant, was introduced in South Africa (SA) in early 2014 as part of an expanded contraceptive method mix. After initial high levels of uptake, reports emerged of frequent early removals and declines in use. Monitoring of progress and challenges in implant service delivery could identify aspects of the programme that require strengthening.Objectives. To assess data management and record keeping within implant services at primary care facilities.Methods. We developed a checklist to assess the tools used for monitoring implant services and data reporting to district offices. The checklist was piloted in seven facilities. An additional six high-volume and six low-volume implant insertion clinics in the City of Johannesburg (CoJ), Gauteng Province, and the Dr Kenneth Kaunda District, North West Province, were selected for assessment.Results. All 12 facilities completed a Daily Head Count Register, which tallied the number of clients attending the clinic, but not information about implant use. A more detailed Tick Register recorded services that clinic attendees received, with nine documenting number of implant insertions and six implant removals. A more specific tool, an Insertion Checklist, collected data on insertion procedures and client characteristics, but was only used in CoJ (five of six facilities). Other registers, which were developed de novo by staff at individual facilities, captured more detailed information about insertions and removals, including reasons. Five of six low-volume insertion facilities used these registers, but only three of six high-volume facilities. No facilities used the form specifically developed by the National Department of Health for implant pharmacovigilance. Nine of 12 clinics reported data on numbers of insertions to the district office, six reported removals and none provided data on reasons for removals.Conclusion. For data to inform effective decision-making and quality improvement in implant services in SA, standardised reporting guidelines and data collection tools are needed, reinforced by staff training and quality assessment of data collection. Staff often took the initiative to fill gaps in reporting systems. Current systems are unable to accurately monitor uptake or discontinuation, or identify aspects of services requiring strengthening. Lack of pharmacovigilance data is especially concerning. Deficiencies noted in these monitoring systems may be common to family planning services more broadly, which warrants investigation. PMID- 29397801 TI - Comments on: A Model to Predict Central-Line-Associated Bloodstream Infection Among Patients With Peripherally Inserted Central Catheters: The MPC Score. PMID- 29397800 TI - Electronically Available Comorbid Conditions for Risk Prediction of Healthcare Associated Clostridium difficile Infection. AB - OBJECTIVE To analyze whether electronically available comorbid conditions are risk factors for Centers for Disease Control and Prevention (CDC)-defined, hospital-onset Clostridium difficile infection (CDI) after controlling for antibiotic and gastric acid suppression therapy use. PATIENTS Patients aged >=18 years admitted to the University of Maryland Medical Center between November 7, 2015, and May 31, 2017. METHODS Comorbid conditions were assessed using the Elixhauser comorbidity index. The Elixhauser comorbidity index and the comorbid condition components were calculated using the International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes extracted from electronic medical records. Bivariate associations between CDI and potential covariates for multivariable regression, including antibiotic use, gastric acid suppression therapy use, as well as comorbid conditions, were estimated using log binomial multivariable regression. RESULTS After controlling for antibiotic use, age, proton-pump inhibitor use, and histamine-blocker use, the Elixhauser comorbidity index was a significant risk factor for predicting CDI. There was an increased risk of 1.26 (95% CI, 1.19-1.32) of having CDI for each additional Elixhauser point added to the total Elixhauser score. CONCLUSIONS An increase in Elixhauser score is associated with CDI. Our study and other studies have shown that comorbid conditions are important risk factors for CDI. Electronically available comorbid conditions and scores like the Elixhauser index should be considered for risk-adjustment of CDC CDI rates. Infect Control Hosp Epidemiol 2018;39:297-301. PMID- 29397802 TI - Environmental Validation of Legionella Control in a VHA Facility Water System. AB - OBJECTIVES We conducted this study to determine what sample volume, concentration, and limit of detection (LOD) are adequate for environmental validation of Legionella control. We also sought to determine whether time required to obtain culture results can be reduced compared to spread-plate culture method. We also assessed whether polymerase chain reaction (PCR) and in field total heterotrophic aerobic bacteria (THAB) counts are reliable indicators of Legionella in water samples from buildings. DESIGN Comparative Legionella screening and diagnostics study for environmental validation of a healthcare building water system. SETTING Veterans Health Administration (VHA) facility water system in central Texas. METHODS We analyzed 50 water samples (26 hot, 24 cold) from 40 sinks and 10 showers using spread-plate cultures (International Standards Organization [ISO] 11731) on samples shipped overnight to the analytical lab. In-field, on-site cultures were obtained using the PVT (Phigenics Validation Test) culture dipslide-format sampler. A PCR assay for genus-level Legionella was performed on every sample. RESULTS No practical differences regardless of sample volume filtered were observed. Larger sample volumes yielded more detections of Legionella. No statistically significant differences at the 1 colony-forming unit (CFU)/mL or 10 CFU/mL LOD were observed. Approximately 75% less time was required when cultures were started in the field. The PCR results provided an early warning, which was confirmed by spread-plate cultures. The THAB results did not correlate with Legionella status. CONCLUSIONS For environmental validation at this facility, we confirmed that (1) 100 mL sample volumes were adequate, (2) 10* concentrations were adequate, (3) 10 CFU/mL LOD was adequate, (4) in-field cultures reliably reduced time to get results by 75%, (5) PCR provided a reliable early warning, and (6) THAB was not predictive of Legionella results. Infect Control Hosp Epidemiol 2018;39:259-266. PMID- 29397803 TI - Adolescents' Daily Perception of Internalizing Emotional States by Means of Smartphone-based Ecological Momentary Assessment - CORRIGENDUM. PMID- 29397804 TI - Pre-school nutrition-related behaviours at home and early childhood education services: findings from the Growing Up in New Zealand longitudinal study. AB - OBJECTIVE: Pre-school nutrition-related behaviours influence diet and development of lifelong eating habits. We examined the prevalence and congruence of recommended nutrition-related behaviours (RNB) in home and early childhood education (ECE) services, exploring differences by child and ECE characteristics. DESIGN: Telephone interviews with mothers. Online survey of ECE managers/head teachers. SETTING: New Zealand. SUBJECTS: Children (n 1181) aged 45 months in the Growing Up in New Zealand longitudinal study. RESULTS: A mean 5.3 of 8 RNB were followed at home, with statistical differences by gender and ethnic group, but not socio-economic position. ECE services followed a mean 4.8 of 8 RNB, with differences by type of service and health-promotion programme participation. No congruence between adherence at home and in ECE services was found; half of children with high adherence at home attended a service with low adherence. A greater proportion of children in deprived communities attended a service with high adherence, compared with children living in the least deprived communities (20 and 12 %, respectively). CONCLUSIONS: Children, across all socio-economic positions, may not experience RNB at home. ECE settings provide an opportunity to improve or support behaviours learned at home. Targeting of health-promotion programmes in high-deprivation areas has resulted in higher adherence to RNB at these ECE services. The lack of congruence between home and ECE behaviours suggests health-promotion messages may not be effectively communicated to parents/family. Greater support is required across the ECE sector to adhere to RNB and promote wider change that can reach into homes. PMID- 29397805 TI - Effects of infant formula composition on long-term metabolic health. AB - Early nutrition may have long-lasting metabolic impacts in adulthood. Even though breast milk is the gold standard, most infants are at least partly formula-fed. Despite obvious improvements, infant formulas remain perfectible to reduce the gap between breastfed and formula-fed infants. Improvements such as reducing the protein content, modulating the lipid matrix and adding prebiotics, probiotics and synbiotics, are discussed regarding metabolic health. Numerous questions remain to be answered on how impacting the infant formula composition may modulate the host metabolism and exert long-term benefits. Interactions between early nutrition (composition of human milk and infant formula) and the gut microbiota profile, as well as mechanisms connecting gut microbiota to metabolic health, are highlighted. Gut microbiota stands as a key actor in the nutritional programming but additional well-designed longitudinal human studies are needed. PMID- 29397806 TI - Something in the Water: Hospital Responds to Water Crisis. AB - Early on August 2, 2014, in the city of Toledo, Ohio, a media alert informed the public that traces of microcystin, a hazardous toxin, had been detected in the drinking water. The warning stated that residents should not drink, boil, or even touch the contaminated water. A water crisis of this magnitude was recognized to pose a potentially serious and significant impact on patient care and safety in health care environments. ProMedica Toledo Hospital's Emergency Operation Plan addressed 3 critical issues: safe water availability, alternate cleaning solutions, and preparations for a prolonged crisis. This report details some of the lessons learned throughout the response to the crisis: particularly, because the impact was county-wide which affected other hospitals who used the same vendors, alternate water sources should have been secured in advance; the courier service was vital to delivery of supplies and moving equipment to alternate areas for sterilization processes; and finally, communication with staff and patients was jeopardized by external media outlets. Changes to the emergency plan considering these unanticipated aspects proved useful in a later incident and should be considered by all health care facilities as water emergency policies and procedures are created and reviewed. (Disaster Med Public Health Preparedness. 2018;12:666-668). PMID- 29397807 TI - Older Adults' Health Care Utilization a Year After Experiencing Fear or Distress from Hurricane Sandy. AB - OBJECTIVE: To determine whether self-reports of disaster-related psychological distress predict older adults' health care utilization during the year after Hurricane Sandy, which hit New Jersey on October 29, 2012. METHODS: Respondents were from the ORANJ BOWL Study, a random-digit dialed sample from New Jersey recruited from 2006 to 2008. Medicare hospital, emergency department (ED) and outpatient claims data from 2012 and 2013 were matched to 1607 people age 65 and older in 2012 who responded to follow-up surveys conducted from July 2013 to July 2015 to determine their hurricane-related experiences. RESULTS: In total, 7% (107) of respondents reported they experienced a lot versus 93% (1493) respondents reported they experienced little or no fear and distress from Hurricane Sandy. Those who experienced a lot versus little or no fear and distress had higher probability of all-cause hospital admissions and more ED visits through 3 months (hazard ratio [HR]: 2.19, 95% CI: 1.03-4.63; incidence ratio [IR]: 2.57, 95% CI: 1.21-5.35), and ED and outpatient visits (IR: 2.20, 95% CI: 1.44-3.37; IR: 1.37, 95% CI: 1.02-1.87) through the year after the hurricane. CONCLUSIONS: A self-reported assessment of disaster-related psychological distress is a strong predictor of older adults' health care needs the year after the disaster. The results indicate that disaster preparedness should extend beyond acute health care needs to address longer-term health consequences of disasters. (Disaster Med Public Health Preparedness. 2018;12:578-581). PMID- 29397808 TI - Intentional overdose of liraglutide in a non-diabetic patient causing severe hypoglycemia. AB - ABSTRACTCases of liraglutide overdose are rare in the literature. Prior reports have not found hypoglycemia related to the medication overdose. We describe a case of a non-diabetic patient who intentionally overdosed on liraglutide leading to severe hypoglycemia. The patient required admission to the intensive care unit for a dextrose infusion and close monitoring. Glucagon-like protein-1 agonists are recognized for their safety and rarely causing hypoglycemia in diabetic patients. However, in this case the patient's non-diabetic status may have put him at risk for hypoglycemia in contrast to prior cases showing no hypoglycemia in diabetic patients. The case highlights the possible dangers of liraglutide overdose and need for blood glucose monitoring in the acute presentation. PMID- 29397809 TI - Mid-upper arm circumference in detection of weight-for-height Z-score below -3 in children aged 6-59 months. AB - OBJECTIVE: To evaluate the predictive ability of mid-upper arm circumference (MUAC) for detecting severe wasting (weight-for-height Z-score (WHZ) <-3) among children aged 6-59 months. DESIGN: Cross-sectional survey. SETTING: Rural Uttar Pradesh, India. SUBJECTS: Children (n 18 456) for whom both WHZ (n 18 463) and MUAC were available. RESULTS: The diagnostic test accuracy of MUAC for severe wasting was excellent (area under receiver-operating characteristic curve = 0.933). Across the lower range of MUAC cut-offs (110-120 mm), specificity was excellent (99.1-99.9 %) but sensitivity was poor (13.4-37.2 %); with higher cut offs (140-150 mm), sensitivity increased substantially (94.9-98.8 %) but at the expense of specificity (37.6-71.9 %). The optimal MUAC cut-off to detect severe wasting was 135 mm. Although the prevalence of severe wasting was constant at 2.2 %, the burden of severe acute malnutrition, defined as either severe wasting or low MUAC, increased from 2.46 to 17.26 % with cut-offs of <115 and <135 mm, respectively. An MUAC cut-off <115 mm preferentially selected children aged <=12 months (OR=11.8; 95 % CI 8.4, 16.6) or <=24 months (OR=23.4; 95 % CI 12.7, 43.4) and girls (OR=2.2; 95 % CI 1.6, 3.2). CONCLUSIONS: Based on important considerations for screening and case detection in the community, modification of the current WHO definition of severe acute malnutrition may not be warranted, especially in the Indian context. PMID- 29397810 TI - [Ultrastructure and Raman Spectral Characteristics of Two Kinds of Acute Myeloid Leukemia Cells]. AB - OBJECTIVE: To investigate the Raman spectral characteristics of leukemia cells from 4 patients with acute promyelocytic leukemia (M3) and 3 patients with acute monoblastic leukemia (M5), establish a novel Raman label-free method to distinguish 2 kinds of acute myeloid leukemia cells so as to provide basis for clinical research. METHODS: Leukemia cells were collected from bone marrow of above-mentioned patients. Raman spectra were acquired by Horiba Xplora Raman spectrometer and Raman spectra of 30-50 cells from each patient were recorded. The diagnostic model was established according to principle component analysis (PCA), discriminant function analysis (DFA) and cluster analysis, and the spectra of leukemia cells from 7 patients were analyzed and classified. Characteristics of Raman spectra were analyzed combining with ultrastructure of leukemia cells. RESULTS: There were significant differences between Raman spectra of 2 kinds of leukemia cells. Compared with acute monoblastic leukemia cells, the spectra of acute promyelocytic leukemia cells showed stronger peaks in 622, 643, 757, 852, 1003, 1033, 1117, 1157, 1173, 1208, 1340, 1551, 1581 cm-1. The diagnostic models established by PCA-DFA and cluster analysis could successfully classify these Raman spectra of different samples with a high accuracy of 100% (233/233). The model was evaluated by "Leave-one-out" cross-validation and reached a high accuracy of 97% (226/233). CONCLUSION: The level of macromolecules of M3 cells is higher than that of M5. The diagnostic models established by PCA-DFA can classify these Raman spectra of different cells with a high accuracy. Raman spectra shows consistent result with ultrastructure by TEM. PMID- 29397811 TI - [Detecting HB-1 Expression Level in Bone Marrow of Acute Leukemia Patients by Real-Time Fluorescence Quantitative RT-PCR]. AB - OBJECTIVE: To investigate the expression level of HB-1 gene in patients with acute lymphoblastic leukemia (ALL) and the significance of HB-1 gene in monitoring of minimal residual disease (MRD). METHODS: The method of real-time fluorescence quantitative RT-PCR (Taqman probe) was established to detect the expression levels of HB-1 gene; then the sensitivity, specificity and repeatability of this assay were evaluated and verified. The HB-1 gene expression levels in bone marrow of 183 cases of ALL, 70 cases of acute myeloid leukemias (AML), 52 cases of non-malignant hematologic diseases and 24 healthy hematopoietic stem cell donors were detected. The correlation of HB-1 level with diagnosis and relapse was analyzed by detecting bone marrow samples of 33 B-ALL. RESULTS: The sensitivity of this assay reached the 10-4 level. The coefficient of variation for inter-batch and inter-tube of HB-1 were 6.79% and 4.80%, respectively. It was found that HB-1 gene specifically expressed in acute B lymphoblastic leukemia. The median expression levels of HB-1 gene in newly diagnosed and relapsed B-ALL patients were statistically significantly higher than those in ALL in complete remission(CR), newly diagnosed T-ALL, newly diagnosed AML, non-malignant hematologic diseases, and healthy hematopoietic stem cell donors(33.0% vs 0.68%, 0.07%, 0.02%, 0.58% and 0, respectively) (P<0.01). No statistical differences were found between newly diagnosed T-ALL, newly diagnosed AML, non-malignant hematologic diseases and healthy donors (P>0.05). The expression level of HB-1 gene declined sharply when B-ALL patients reached complete remission (0-7.99%, with median level 0.68%), but increased when relapsed (7.69%, 8.08% and 484.0% in 3 relapsed samples), which was in accordance with results of flow cytometry. CONCLUSION: HB-1 gene specifically expressed in acute B lymphoblastic leukemia cells. The established real-time fluorescence quantitative RT-PCR assay shows good sensitivity, specificity and repeatability, thus, can be used as a biological marker in the clinical detection, monitoring MRD and predicting of early relapse for B-ALL patients. PMID- 29397812 TI - [CCL2 Protein Regulates Migration and Invasion of THP-1 cells by Autosecreting Inflammatory Chemokines]. AB - OBJECTIVE: To investigate the effects and mechanism of CCL2 on the migration and invasion of human leukemia cell THP-1. METHODS: The CCL2 gene was recombined with the transfer plasmid-PLVX and transfected into THP-1 cells. The CCL2 expression at RNA level was detected by RT-PCR, the CCL2 expression at protein level was determined by Western blot and ELISA, the influence of overexpression of CCL2 recombinant protein and THP-1 cells on the migration and invasion ability of THP 1 cells was analyzed by transwell migration and invasion tests, the PCR-array of migration-related cytokines was used to clarify the patential mechanism. RESULTS: With the Trans-Matrigel assay, the concentration of CCL2 in THP-1 transfected with CCL2 in the upper cells was higher than that in the lower cells, meanwhile, the invasion ability of CCL2-transfected THP-1 cells decreased. Increasing recombinant protein of CCL2 (rpCCL2) in the lower cells promoted migration of THP 1 cells. Migration RT2 profiler PCR array showed that the cells treated with rpCCL2 had higher levels of expression of CCL2, EPX, SPP1, CX3CL1 and CXCL13, as compared with control group. CONCLUSION: CCL2 affects the migration and invasion of THP-1 by autosecreting a series of inflammatory chemokines. PMID- 29397813 TI - [Correlation of Serum Albumin with Renal Function in Patients with Acute Leukemia]. AB - OBJECTIVE: To investigate the relationship between serum albumin and renal function in patients with acute leukemia (AL) and its clinical significance. METHODS: The clinical data and related test results of 267 newly diagnosed patients with acute leukemia from April 2015 to April 2017 were collected for retrospective cross-sectional analysis. Multivariate regression model was used for statistical analysis. RESULTS: The creatinine level in serum of newly diagnosed acute leukemia patients decreased with the increase of albumin level (the first quartile-the fourth quartile had an average creatinine level of 72.0 umol/L, 65.2 umol/L, 62.8 umol/L, 58.6 umol/L); Multiple regression model results showed that each elevated albumin 1 g/L, the serum creatinine level decreased 0.89 umol/L. The serum albumin was grouped into the model by quartile, and the first quartile was used as the reference group. With the increase of albunin, the beta value decreased steply (the second and fourth quartile beta values were 12.7, -14.81, -15.98), the trend line test p value was <0.05. CONCLUSION: Serum albumin negatively correlats with creatinine level in newly diagnosed acute leukemia patients, and its elevation shows protective effect on renal function. PMID- 29397814 TI - [Expression of Long-Chain Non-coding RNA RP11-87C12.5 in Acute Lymphocytic Leukemia and Its Cinical Significance]. AB - OBJECTIVE: To investigate the expression of long-chain non-coding RNA RP11 87C12.5 in acute lymphocytic leukemia and its clinical significance. METHODS: LncRNA RP11-87C12.5 expression was detected by RT-PCR in bone marrow samples from 17 control group, 33 newly diagnosed ALL patients and 26 complete remission ALL patients after chemotherapy, at the same time the clinical data were collected and the clinical significance of IncRNA RP11-87C12.5 expression was analyzed. RESULTS: Compared with control group, lncRNA RP11-87C12.5 expression increased in newly diagnosed ALL group (P=0.021); compared with newly diagnosed ALL group, IncRNA RP11-87C12.5 expression decreased in complete remission ALL group (P=0.039). lncRNA RP11-87C12.5 expression in newly diagnosed ALL group did not relate with sex, age, T or B type, WBC count, Hb level, Plt count, LDH level, bone marrow blast ratio, BCR/ABL fusion gene expression, chomosome karyotypes, WT1 gene, extrameanllary infiltration or no,complete remission or no after one chemotherapy and relapse or no. In 27 cases of ALL, IncRNA RP11-87C12.5 expression significantly increased in cCD79a low expression group, compared with cCD79a high expression group (P=0.004). IncRNA RP11-87C12.5 expression did not relate with other CD molecules of immunoclassification. CONCLUSION: The expression of LncRNA RP11-87C12.5 is high in newly diagnosed ALL group and low in complete remission ALL group. In B-ALL, the expression of IncRNA RP11-87C12.5 significantly enhances in cCD79a low expression group. In newly diagnosed ALL group, compared with low expression group, lncRNA RP11-87C12.5 high expression group have higer remission rate and relapse rate, but the difference was not statistically significant. PMID- 29397815 TI - [Relationship between High-Resolution HLA-A,-B,-DRB1 Alleles and Haplotype Polymorphisms with Myeloid Leukemia of Han People in North China]. AB - OBJECTIVE: To investigate the potential relationship between the high-resolution HLA-A,-B,-DRB1 alleles and haplotype polymorphism with actute myeloid leukemia (AML) and chronic myeloid leukemia (CML) of Han people in North China. METHODS: A total of 1241 healthy unrelated Han people's bone marrow donors in North China were used as a control group, 259 patients with myeloid leukemia were genotyped at high-resolution level by means of PCR-SBT, -SSO and -SSP typing methods for HLA-A,-B,-DRB1 loci. The frequencies of HLA allele and haplotype were calculated by software Arleguin 3.5.2. The different distribution of genes and haplotypes was analyzed by case control study, and the odd ratio (OR) of leukemia was also calculated. The structural difference of HLA alleles was analyzed 111by HLA three dimensional structure modeling and software Swiss-PdbViewer v4.1. RESULTS: chi2 test and correction showed that an increased frequency of A*02:07 (8.47% vs 5.28%, P' =0.013), A*29:01 (1.85% vs 0.68%, P=0.044), B*07:02 (5.29% vs 3.10%, P=0.029), B*07:05:01G (1.85% vs 0.68%, P=0.044) and B*35:02 (1.06% vs 0.20%, P=0.023) were found in AML patients (n=189) as compared with controls, respectively; whereas A*02:03 was less frequent in AML as compared with controls (0.79% vs 3.10%, P=0.011). The frequency of B*46:01 was lower in CML patients (n=70) as compared with controls (2.86% vs 7.82%, P=0.031). However, the above mentioned discrepancies were not statistically significant by Bonferroni correction. Through Fisher exact test and Bonferroni correction, the frequency of DRB1*11:28 and its haplotype A*24:02-B*15:01-DRB1*11:28 in CML group were very significantly higher than in controls (1.43% vs 0.00%, Pc=0.015; 1.43% vs 0.00%, P=0.003). Three-dimensional structure modeling of DRB1*11:28 and DRB1*11:01 presented significant structure differentiation (RMSD=0.09 nm) in peptide binding region of the backbone calculated by Swiss-PdbViewer v4.1. The haplotype A*03:01 B*50:01-DRB1*07:01 in AML and A*11:01-B*40:06-DRB1*09:01 in CML patients were significantly higher than that in controls (1.06% vs 0.00%, Pc=0.000; 2.86% vs 0.07%, Pc=0.000), and positively correlated with leukemia (OR=59.66, 95% CI=3.21 1110.39; OR=42.91, 95% CI=7.07-260.32). CONCLUSION: The relationship of HLA-A,-B, DRB1 alleles and haplotype polymorphism with leukemia at high-resolution level were obtained and unique in north Chinese Han population. AML and CML patients in Northern Han people carry particular susceptible haplotypes. DRB1*11:28, which might not actively present bcr-abl peptide to CD4+ T cells, and is a susceptibile gene for CML patients of Northern Han people, especially in Shaanxi Province (OR=89.62, 95% CI=4.28-1875.87), as well as correlated with its particular haplotype. PMID- 29397816 TI - [Effects of Four Renin-Angiotensin System' s Regulators on the Human Leukemia HEL Cell Growth]. AB - OBJECTIVE: To investigate the effects of 4 renin-angiotensin system's(RAS) regulators (losartan, telmisartan, aliskiren and angiotenisin) on the human leukemia HEL cell growth. METHODS: The HEL cells were treated with losartan, telmisartan, aliskiren and Angiotensin-(1-7) (Ang-(1-7)) for 12 days, respectively. The cell proliferation was measured by CCK-8 kit, the cell cycle and apoptosis were measured by flow cytometry. RESULTS: The 10-7 mol/L Ang-(1-7) markedly inhibited the growth of HEL cells, blocked cells at G0/G1 phase and markedly increased the late apoptotic cells (P< 0.001). The 10-5 mol/L losartan and telmisartan, 10-4 mol/L aliskiren had no effects on the proliferation, cell cycle and apoptosis of HEL cells (P>0.05). CONCLUSION: Ang-(1-7), one of renin angiotensin system's regulators, can inhibit the growth of HEL cells and promote the cell apoptosis. Ang-(1-7) may be one potential therapeutic drug for polycythemia vera with JAK2 mutation. PMID- 29397817 TI - [Effect of Hypoxia on the Proliferation and Hypoxia Inducible Factor-1alpha Expression in Human Leukemia K562 Cells]. AB - OBJECTIVE: To explore the effect of hypoxia on the cell proliferation and expression of hypoxia-inducible factor-1alpha(HIF-1alpha) of human leukemia K562 cells. METHODS: The leukemia cells were divided into 2 groups: hypoxia-treated group and conventional oxygen group as control. The K562 cells in hypoxia-treated group were treated with 50, 200, 400 and 800 umol/L of CoCl2, while the K562 cells in control group were cultured in conventional oxygen condition, then the K562 cells in 2 groups were colleted after treatment for 24, 48 and 72 hours. The morphological changes of cells were observed by the inverted phase-contrast microscopy, the proliferation-inhibitory rates of cells was detected by MTT method, the expression of HIF-1alpha at transcription level was detected by real time fluorescent quantitative PCR. RESULTS: The cell morphology was changed with increase of CoCl2 concentration and prolonging of treatment time of CoCl2. The MTT assay showed that the inhibitory rate of cell proliferation was enhanced also with increase of CoCl2 concentration and prolonging of treatment time of CoCl2(r=0.435, r=0.389, P<0.05). The real-time fluorescent quantitative PCR showed that the mRNA expression of HIF-1alpha in K562 cells of hypoxia group was up-regulated in concentration- and time- dependant manners. and displayed the positive correlation with concentration of CoCl2 and treatment time (r=0.954, r=0895). CONCLUSION: The hypoxia can inhibit the proliferation of K562 cells and up-requlate the expression of HIF-1alpha in cells, but does not induce cell differentiation. PMID- 29397818 TI - [Analysis of Early-Death and Factors Affecting Prognosis of Patients with Acute Promyelocytic Leukemia]. AB - OBJECTIVE: To investigate the factors affecting the early-death, overall survival (OS) and relapse-free survival (RFS) of acute promyelocytic leukemia (APL) patients. METHODS: The clinical and laboratorial charachteristics of 176 APL patients in our center were analyzed retrospectively during January 2002 to Mar 2016. The risk factors of early death and factors affecting OS and RFS of patients were analyzed. RESULTS: Among total of 176 patients, early death occured in 10 patients. Multivariate analysis showed both age >=60 years and fibrinogen<1.5 g/L (HR=6.4, 95%CI 1.4-28.2) (P=0.015), (HR=12.2, 95%CI 1.5-102.8) (P=0.021), respectively were the independent risk factors for the early death during the induction therapy. Among 154 patients with full follow-up data (median follow-up time was 101(2-262) months), the estimated 5-year OS and RFS rate were (98+/- 1)% and (77+/- 4)%, respectively. Cox regression analysis showed relapse during treatment as well as initial WBC count>=30* 109/L were independent prognostic indicators for OS. Accompanied psoriasis indicated higher relapse rate of APL(HR=4.8, 95%CI 1.8-12.5)(P=0.002), while the low-risk APL indicated lower relapse rate (HR=0.4, 95%CI 0.2-0.99)(P=0.048). CONCLUSION: Importance should be attached to the early-death events in elder and low-fibrinogen APL patients. As for patients with psoriasis or non low-risk group, emphasizing the intensified dynamic supervision during the treatment helps to detect the early-relapse events. For relapsed patients and patients with >=30* 109/L WBC count, seeking more optimized therapy strategy seems allow this cohorts to get better prognosis. PMID- 29397819 TI - [Effect of Heterozygosity Loss in HLA Region before Transplantation on HLA Typing in Patients with Leukemia]. AB - OBJECTIVE: To investigate the effect of loss of heterozygosity(LOH) in HLA region at initial diagnosis and remission of leukemia patient before transplantation on HLA typing. METHODS: The HLA typing was performed in DNA extracted from peripheral blood obtained at diagnosis (Sample 1 and Sample 2) and remission (Sample 3) in one pretransplant male patient with mixedphenotype acute leukemia (MPAL). HLA typing for HLA-A, B, C, DQB1, DRB1 was performed by Sequence-based typing (SBT), Sequence-specific oligonucleotide probe hybridization (SSO) and Sequence-specific primers (SSP). To define more precisely a cutoff limit for the detection of a heterozygous DNA present in a fraction of the cells by the SBT technology, DNA mixing experiments were performed. RESULTS: SBT results showed that Sample 1 and Sample 2 were both homozygous HLA results at five loci (lost one haplotype) although the sequencing background of Sample 1 was a little high. Except HLA-C locus was homozygous, Sample 3 was heterozygous HLA results at four loci. Based on DNA mixing experiments, a cutoff limit for the detection of heterozygous DNA was 20% by SBT technology, and a detection threshold for HLA-A, B, C, DQB1, DRB1 heterozygosity in blood samples was <75% blasts. CONCLUSION: Because LOH may be partial, any homozygous HLA result obtained during a blast crisis, especially >=75% blasts, would have to be confirmed by a second typing on a buccal swab or on peripheral blood from the patient in complete remission. PMID- 29397820 TI - [Effect of 4' -Hydroxywogonin on Proliferation and Apoptosis of Human Acute Lymphoblastic Leukemia Cells]. AB - OBJECTIVE: To investigate the effect of 4' -hydroxywogonin on proliferation and apoptosis of human acute lymphoblastic leukemia SUP-B15 and Jurkat cells, and to analyze its possible mechanism. METHODS: SUP-B15 and Jurkat cells were cultivated in vitro and treated with different concentrations of 4' -hydroxywogonin, the inhibitory effect of 4' -hydroxywogonin on the proliferation of SUP-B15 and Jurkat cells was detected by CCK-8 method; the cell apoptosis was examined by the flow cytometry with Annexin V-APC/7-AAD donble staining; the expression of C-MYC, BCL-2 and cleaved caspase 3 in SUP-B15 and Jurkat cells were measured with Western blot. RESULTS: 4' -hydroxywogonin inhibited the proliferation of SUP-B15 and Jurkat cells in a dose-dependent manner (r=0.78, r=0.89), with IC50 value of (6.32+/- 0.53) ug/ml in SUP-B15 cells and (12.04+/- 0.42) ug/ml in Jurkat cells at 24 h. The early apoptotic rate of cell was also enhanced with the increase of 4' -hydroxywogonin concentrations. The results of Western blot showed that 4' hydroxywogonin could down-regulate the expression of proliferation-related molecule C-MYC(P<0.01) and apoptosis-related molecule BCL-2(P<0.01), the expression of apoptosis-related molecule cleaved caspase 3 was up regulate(P<0.01). CONCLUSION: 4' -hydroxywogonin shows the effects of anti-tumor by inducing cell apoptosis and inhibiting cell proliferation, its molecular mechanism maybe relate with down-regulation of C-MYC and BCL-2 expression and up regulation of the cleaved caspase 3 expression. PMID- 29397821 TI - [Expression of Ki-67 in Adult and Children Acute Lymphoblastic Leukemia and Its Clinical Significance]. AB - OBJECTIVE: To investigate the relationship of Ki-67 level with clinical features, immunophenotype, gene mutation, curative efficacy and prognosis in patients with acute lymphoblastic leukemia(ALL). METHODS: Flow cytometry gated at CD45/SSC was used to detect the expression of Ki-67, and the correlation of Ki-67 expression with clinical manifestation, laboratorial indexes, curative efficacy and prognosis was analysed. RESULTS: Ki-67 expression level increased in ALL patients, the median expression rate was 29.22%, there was significant difference as compared with the healthy control (P<0.01). In adult ALL, the median expression rate of Ki-67 in the high-risk group was 31.49%, and the difference was statistically significant as compared with the low-risk group (P<0.05). In children ALL, the median expression rate of Ki-67 in high-risk group was 42.28%, and the difference was statistically significant (P<0.05). The results of unvariate analysis showed that the age, WBC count at newly diagnosed and extramedullary invasion were adverse factors affecting OS and DFS; the results of multivariate analysis showed that age and extramedullary invasion were independent risk factors for OS and DFS in patients. CONCLUSION: Age>=14 years old, intramedullary invasion are the poor factors for prognosis; the Ki-67 level is not an independent factor for the prognosis of patients. PMID- 29397822 TI - [ITRAQ Coupled with 2DLC-MS/MS to Screen and Identify Speci-fic Bio-markers of T Cell Acute Lymphoblastic Leukemia]. AB - OBJECTIVE: To screen and identify potential biomarkers specific for T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Sera were collected from 20 newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients and 20 T-ALL patients. Proteins were extracted, purified and digested with trypsin. All specimens were analyzed by isobaric tags for relative and absolute quantification (iTRAQ) and two-dimensional liquid chromatography-tandem mass spectrometry (2DLC MS/MS) in a data-dependent mode. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression of serum soluble L-selectin (sL-selectin). RESULTS: A total of 468 proteins were identified from distinct peptides. Compared with B-ALL group, 31 proteins were significantly differentially up-regulated while 7 proteins were significantly down-regulated in T-ALL group, sL-selectin was the higher up-regulated in these differential expression proteins. The overexpression of sL-selectin in T-ALL was verified by ELISA. CONCLUSION: There are the differentially expressed proteins between T-ALL and B-ALL, and the sL selectin is specific for T-ALL, which can not only become a new biomarker for the diagnosis and prognosis of T-ALL, but also can be used as a potential target for therapy of this leukemia. PMID- 29397823 TI - [Effect of Silencing Eps8 Gene Expression on the Biology Activity of Human Leukemia K562 Cells and Its Molecular Mechanism]. AB - OBJECTIVE: The study was to investigate the effect of silencing Eps8 gene expression on proliferation and apoptosis of human leukemia K562 cells and its molecular mechanism. METHODS: The expetriments were divided into 3 groups, including blank control group(K562 cells without treatment), K562-shRNA group(K562 cells transfected by specific Eps8-shRNA lenticiral vector) and K562 NC group(K562 cells transfected by negtive control lenticiral vector). K562 cells with stably-silenced Eps8 gene were constucted by lentibirus-mediated RNA technology. The efficacy of transfection was observed by fluorescence microscopy and the changes of Eps8 mRNA and protein level were detected by RT-PCR and Western blot respectively. Cell proliferation was confirmed by typan blue exclusion and MTT method. The apoptosis rate of cells was analysed by the flow cytometry, and colony forming was detected by methylcellulose colony forming assay. The protein level change of phosphrylated-AKT were detected by Western blot. RESULTS: Stably-silenced Eps8 gene K562 cells and the negative control cells were successfully constructed. Compared with the blank control group and the K562-NC group, the proliferation of K562-shRNA cells were siginificantly inhibited(P<0.05); the apoptosis of K562-shRNA cells increased(P<0.05). In addition, the methylcellulose colony forming assay showed that the colony forming was dramatically suppressed in K562-shRNA cells (P<0.05). Furthermore, knocking down Eps8 gene reduced the protein level of AKT phosphrylation at both residue Ser437 and Thr308(P<0.05), while there was no obvious change in the level of total-AKT(P>0.05). Knocking down Eps8 gene reduced the protein level of m-TOR phosphrylation and PRAS40 phosphrylation (P<0.05), while there was no obvious change in the level of total-mTOR and PRAS40 (P>0.05). CONCLUSION: Silencing Eps8 gene through lentvirus can inhibit the cell proliferation and promote the apoptosis of human leukemia K562 cells, which possibly relates with the inhibition of AKT/mTOR activation. PMID- 29397824 TI - [Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. AB - OBJECTIVE: To investigate the therapeutic effectiveness and side effects of decitabine combined with or without cytarabine-based low dose regimen for acute myeloid leukemia in geratic patients. METHODS: Clinical data of 8 geratic patients (aged over 70 years) suffered from acute myeloid leukemia from September 2009 to March 2012 were analyzed retrospectively, including age, sex, peripheral blood and bone marrow characteristics and so on. These patients were treated by an 1-hour intravenous infusion of decitabine 20 mg/m2 per day for 5 consecutive days every 4 weeks combined with or without low dose regimen dominantly consisting of cytarabine 20 mg per day as subcutaneous injection for seven consecutive days. The therapeutic effectiveness and side-effects were evaluated. RESULTS: Among 8 patients, incinding 3 males and 5 females aged between 71-84 years old, their median white blood cell count was 31.2(1.38-179)* 109/L, and median bone marrow blast cell ratio was 42.7(23-94)% at the initial diagnosis.The median treatment courses was 2.5 (1-20).After treatment by this protocol,2 patients achieved complete remission(CR) (25%), 2 patients achieved partial remission (PR)(25%), 3 were not relieved, and 1 died, thus the overall response rate reached to 50% (4/8). The median overall survival time was 9.5 (2-36) months, and the overall survival time of 3 patients reached 1 year or more. The main side-effects of treatment were grade III-IV of myelosuppression (87.5%) and pneumonia (50%). CONCLUSION: Decitabine combined with or without cytarabine-based low dose regimen is promising for the treatment of geriatric acute myeloid leukemia, thus improving the overall response rate, and prolonging overall survival time. PMID- 29397825 TI - [Detection of Novel Antigen MLAA-34 Gene Mutation in Acute Monocytic Leukemia and Its Correlation with Efficacy]. AB - OBJECTIVE: To investigate the correlation of all exone mutation in MLAA-34 gene with chemotherapeutic efficacy for leukemia. METHODS: The expression level of MLAA-34 gene in 40 patients with AML-M5 and 5 healthy volunteers as control was detected by RT-PCR and its effect on chemotherapeutic efficacy were analyzed by RT-PCR; the effect of MLAA-34 gene mutation on overall survival (OS) and progression-free survival (PFS) of AML-M5 patients was analyzed by sequencing of all 12 exoues in MLAA-34 gene, the correlation between the mutation of prognostic genes important to leukemia and the mutation of MLAA-34 gene was explored. RESULTS: The expression level of MLAA-34 gene was significantly up-regulated as compared with that of healthy volunteers, moreover this up-regulation was related with a C59T SNP site located in second exon of MLAA-34 gene, meanswhile this SNP site is affinitive to the well-known mdecular markers of AML, inclinding Fms-like tyrosine kinase (FLT-3) and DNA methyltransferase-3A(DNAMT3A). The AML-M5 patients with high expression of MLAA-34 gene poorly responded to chemotherapy, the AML-M5 patients with MLAA-34 C59T mulation had even more high expression of MLAA-34 gene and significantly short OS and PFS in comparison with those of patients without C59T mutation. CONCLUSION: The C59T mutation in MLAA-34 gene is a high risk factor for recurrence of AML, and may be a cadidate target for treatment of AML. PMID- 29397826 TI - [Mechanism of mTOR Pathway in K562 cell Apoptosis Induced by Homoharringtonine]. AB - OBJECTIVE: To investigate the effect of homoharringtonine (HHT) on proliferation and apoptosis of CML cell line K562 cells and to explore its possible mechanism through mTOR pathway. METHODS: K562 cells were cultured with different concentrations of HHT or in its combination with mTOR inhibitor rapamycin (RAPA) for 24 hours. The cell viability was analyzed by CCK-8 assay, the cell apoptosis was detected by flow cytometry, the expressions of BCL-6, Caspase-3 and mTOR signal pathway related proteins was assayed by Western blot, the expression of BCL-6 mRNA was determined by RT-PCR. RESULTS: The HHT inhibited proliferation and induced apoptosis of K562 cells in a concentration-dependent manner(r=0.970). With the increasing of HHT concentration, the expression level mTOR signal pathway related proteins increased(r=0.908), while the mRNA and protein expression levels of BCL-6 decreased(rmRNA=-0.961, rprotein =-0.981), as compared with the HHT alone, the combination of HHT with RAPA could down-regulate the expression of mTOR signal pathway related protein and caspase-3, and up-regulated expression of BCL-6. CONCLUSION: HHT induces apoptosis of K562 cells by inhibiting BCL-6 expression through mTOR signal pathway. PMID- 29397827 TI - [Value of CD, MPO, Ki-67 and C-MYC Positive Rate in the Pathological Tissues and C-MYC Gene of Patients with T-LBL/ALL for Predicting Prognosis]. AB - OBJECTIVE: To explore the value of of CD, MPO, Ki-67, C-MYC positive rates in the pathological tissues and C-MYC gene of patients with T-LBL/ALL for predicting Prognosis. METHODS: Ninty cases of T-LBL/ALL patients in our hospital were selected and included in the T-LBL/ALL group, and 30 cases of lymphnode reactive hyperplasia were selected as control group. Immunohistochemical staining was used to detect the changes of CD, MPO, Ki-67 and C-MYC positive rate in 2 groups, and the changes of C-MYC gene were detected by fluorescence in situ hybridization. RESULTS: In 90 patients with T-LBL/ALL, there were CD1a+ 34 cases (37.8%), CD3+ 67 cases (74.4%), epsilon CD3+ 47 cases (52.2%), CD7+ 85 cases (94.4%), CD10+ 33 cases (36.7%), CD34+ 22 cases (24.4%), CD43+ 48 cases (53.3%), CD45RO+ 46 cases (51.1%), CD99+ 88 cases (97.8%), TDT+ 85 cases (94.4%); and CD23, CD20, and MPO all were negative; Ki-67>80% 47 cases (52.2% cases), Ki-67<=80%, 43 cases (47.8%). In 90 T-LBL/ALL patients, the positive rate of C-MYC (66.7%) was significantly higher than the control group (positive rate 0.0%) (P< 0.05); the Ki-67 index, mediastinal widening of T-LBL/ALL patients and the positive rate of C-MYC positively were correlated (P< 0.05). The overall survival rate (44.0%) of C-MYC negative patients was significantly higher than that of C-MYC positive patients (0.0%). The overall survival rate of C-MYC negative patients was significantly higher than that of C-MYC positive patients (P< 0.05).Ann Arbor staging, LDH, bone marrow involvement, mediastinal widening, Ki-67 positive index, and C-MYC protein expression of patients with T-LBL/ALL did not correlated with increased C-MYC gene breakage and copy number (P> 0.05). CONCLUSION: The overall survival rate of C-MYC positive patients decreases, which positively correlates with Ki-67 positive index and mediastinal width, suggesting that the prognosis of the patients with C-MYC protein expression is poorer. PMID- 29397828 TI - [Correlation of Serum Concentration of Nilotinib with Clinical Efficacy in Patients with Chronic Myeloid Leukemia]. AB - OBJECTIVE: To investigate the correlation of the serum minimal concentrations (Cmins) of nilotinib(NIL) with the clinical efficacy and adverse events (AEs) in CML patients. METHODS: A total of 54 patients were divided into two groups according to the dosage of nilotinib. 44 cases received dose of 600-800 mg/d were classified as group A; while 10 cases received dose of 400 mg/d as group B. The Cmins of nilotinib were determmined by liquid chromatography-tandem mass spectrometry. RESULTS: Median Cmins of nilotinib in 54 patients was 1.71 (0.52 5.93) ug/ml. Cmins of nilotinib in group A and group B were 2.09+/- 1.21 ug/ml and 0.94+/- 0.27 ug/ml respectively, Cmins of group A was significantly higher than that of group B (P=0.001). In group A, 24 out of 44 cases obtained major molecular response (MMR) in 12 months, while 20 cases did not reach MMR in 12 months; the serum drug concentrations were 1.70+/- 0.75 ug/ml and 2.03+/- 0.82 ug/ml respectively, without statistically significant differences between these 2 subgroups(P=0.154). However, Cmins of nilotinib in patients with III-IV grade of adverse events were significantly higher than those in patients with 0-II grade of adverse events (3.09+/- 1.76 ug/ml vs 1.76+/- 0.68 ug/ml)(P=0.018). There was no statistic diffence in Cmins of nilotinib with MMR in 12 months of group A MMR 1.15+/- 0.27 ug/ml vs no MMR 0.83+/- 0.24 ug/ml(P=0.051). The MMR rate at 12 months in group A was 54.5%(24/44) and that in group B was 40%(4/10) (P=0.494). But the incidence of grade III-IV adverse events in group A was 29.5%(13/44), which was significantly higher than that of group B[0/10(0%)]. CONCLUSION: Cmins of nilotinib shows significant individual differences. The Cmins of nilotinib relate with the dosage and grade III-IV of adverse events. The lower dose of nilotinib may maintain a good therapeutic effect and significantly reduce the adverse events. PMID- 29397829 TI - [Expression and Significance of PTEN and BCL-2 in Acute Myeloid Leukemia]. AB - OBJECTIVE: To explore the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and B-cell lymphoma/leukemia-2 (BCL-2) in acute myeloid leukemia (AML) and its significance. METHODS: The expression levels of PTEN and BCL-2 mRNA and protein in bone marrow samples from 80 AML patients including 56 de novo patients, 16 patients in remission, 8 relapsed patients and 30 cases of non-hematologic diseases (as control) were detected by real-time PCR and Western blot, respectively, and the relationship between PTEN and BCL-2 expression and clinical pathological parameter was analyzed. RESULTS: The expression levels of both mRNA and protein of PTEN in newly diagnosed AML group and relapse group were significantly lower than those in the control and remission group (P<0.01). The expression levels of both mRNA and protein of BCL-2 in newly diagnosed group and relapse group were significantly higher than those in the control and remission group (P<0.01). The mRNA expression of PTEN and BCL-2 was did not related with the age, sex and white blood count in AML patients. The expression levels of PTEN negatively correlated with expression BCL-2 with AML(r=-0.432, r=-0.569). CONCLUSION: PTEN and BCL-2 participate in the occurrence and development of AML, and may be used as indicators for the evaluation of chemotheraeutic efficacy. PMID- 29397830 TI - [Effect of PKA Gene on Acute Lymphoblastic Leukemia in Children and Its Mechanism]. AB - OBJECTIVE: To explore the effect of PKA gene on acute T lymphocyte leukemia cells in children and its mechanism. METHODS: Jurkat and Sup-T1 cells were divided into 2 group: control group (Jurkat and Sup-T1 cells treated with non-specific siRNA) and transfected group (Jurkat and Sup-T1 cells transfected with PKA siRNA). The effects of down-regulating the expression of PKA gene on the viability, proliferotion, migration and cell cycle distribution of Jurkat and Sup-T1 cells in 2 groups were analyzed by CCK-8 assay, transwell experiment, cell colony formation test and flow cytometry; the cyclin-related protein levels after transfection with PKA siRNA were detected by Western blot. RESULTS: It was revealed that the expression of PKA in Jurkat and Sup-T1 cells decreased to different degree after siRNA transfection(P<0.05). CCK-8 assay showed that the proliferation of Jurkat and Sup-T1 cells in the transfected group was slower than that in the control group(P<0.05). Transwell experiment showed that the migration and invasion ability of Jurkat cells in the transfection group was weaker than that in the control group (P<0.05). The cell colong formation number of Jurkat and Sup-T1 cells in the transfection group decreased significantly (P<0.05). The cell level of Jurkat and Sup-T1 cells in G0/G1 phase increased after tansfection (P<0.05). Western blot assay revealed that the expression levels of CDK2, CyclinD1 and p-Rb in the Jurkat and Sup-T1 cells of the transfection group were suppressed (P<0.05). CONCLUSION: The down-regulating PKA gene expression can decrease the proliferation and migration of tumor cells, and also can restrict the cell proliferation through related cell cycle proteins. PMID- 29397831 TI - [Comparison of Diagnosis Values of CD64 Infection Index, CRP, PCT and NEU% in the Leukemia Complicated with Bacterial Infection]. AB - OBJECTIVE: To compare the diagnostic values of CD64 infection index, C-reactive protein (CRP), procalcitonin (PCT) and the percentage of neutrophils (NEU%) in leukemia patients complicated with bacterial infection. METHODS: Sixty cases of leukemia complicated with bacterial infection (combination with infection group), 60 cases of leukemia without bacterial infection (non-combination with infection group) and 60 cases of healthy persons (control group) were selected in our hospital. CD64 infection index, CRP, PCT and NEU% were detected in the 3 group. RESULTS: CD64 infection index, CRP, PCT and NEU% in combination with infection group were significantly higher than those in the non-combination with infection group and also significantly higher than those in the control group (all P<0.05). The CD64 infection index, CRP, PCT and NEU% in the non-combination with infection group were significantly higher than those in the control group (all P<0.05). The sensitivities of CD64, CRP, PCT and NEU% in the diagnosis of the leukemia with bacterial infection were 71.06%, 84.86%, 66.93% and 59.25% respectively, and the specificities of CD64, CRP, PCT and NEU% were 91.46%, 75.94%, 88.79% and 85.36% respectively. CONCLUSION: Compared with CRP, PCT and NEU%, CD64 infection index for diagnosis of leukemia complicated with bacterial infection has higher specificity, which is helpful for the early diagnosis of the disease. PMID- 29397832 TI - [Changes of T Lymphocyte Subsets and Immunoglobulin in Peripheral Blood of Patients with ALL and N-ALL before and after Treatment and their Value for Monitoring of Disease and Evaluation of Prognosis]. AB - OBJECTIVE: To study the changes of T lymphocyte subsets and immunoglobulin in peripheral blood of patients with acute lymphoblastic leukemia (ALL) and non acute lymphocytic leukemia (N-ALL) before and after treatment and their value for monitoring of disease and evaluation of prognosis. METHODS: One hundred and six cases of leukemia were selected in our hospital, including 48 cases of ALL (ALL group) and 58 cases of N-ALL (N-ALL group); 54 peoples of normal physical examination were selected as the normal control group in the same period. The IgA, IgG and IgM levels of peripheral blood were detected, and the absolute value of T lymphocyte subsets was determined by cell slide method. According to whether the patients' status was improved or not by treatment, the 106 patients were divided into the unimproved group (55 cases including 25 ALL, 30 N-ALL) and improved group (51 cases including 23 ALL, 28 N-ALL). RESULTS: The levels of IgA, IgG and IgM in 106 cases of leukemia were significantly lower than those in the control group (all P<0.05), and the CD3+ level, CD3+CD4+/CD3+CD8+ ratio and the absolute value of CD3+CD4+T cells in the peripheral blood were significantly lower than those in the control group(all P<0.05); the absolute value of CD3+CD8+T cells showed no significant difference in comparison with the control group (P >0.05). After treatment, IgA,IgG and IgM levels in the improved group were significantly higher than those before therapy (all P<0.05), while their levels were not significantly different from that in the control group (all P>0.05); the CD3+ level, CD3+CD4+/CD3+CD8+ ratio and the absolute value of CD3+CD4+T cells in the peripheral blood were significantly higher than those before therapy (all P<0.05), while those were not significantly different from the control group (all P>0.05). Compared with levels before treatment, the levels of above mentioned indicators in the unimproved group after treatment were not significantly different (all P>0.05); and the CD3+ level, CD3+CD4+/CD3+CD8+ ratio and the absolute value of CD3+CD4+T cells were significantly lower than those in the control group (all P<0.05), and the absolute value of CD3+CD8+T cells were higher than that in the control group (P<0.05). CONCLUSION: After the treatment, the T lymphocyte subsets (CD3+, CD3+CD4+T cells) and immunoglobulin (IgA, IgG, IgM) levels in peripheral blood of patients with ALL and N-ALL have been improved significantly, and the detection of these indexes is helpful for disease monitoring and prognosis evaluation. PMID- 29397833 TI - [C-MYC Gene and Protein Expression in Paraffin Wax of T Lymphoblastic Lymphoma and Leukemia Patients and Its Effect on the Prognosis]. AB - OBJECTIVE: To explore the relevance between the expression of C-MYC gene and protein of patients with T lymphoblastic lymphoma and leukemia(T-LBL/ALL) and its effect on the prognosis. METHODS: Paraffin specimens from 60 cases of T-LBL/ALL with detailed follow-up during May 2005 to May 2016 were selected as study group; at same time 20 cases of reactive hyperplasia (RH) of lymphonuedes were selected as control group. The immunohistochemical EnVision method was used to mark the terminal deoxynucleotidyl transferase (TDT), myeloperoxidase (MPO), Ki-67 and C MYC immune tissue. RESULTS: C-MYC gene rupture and copy number increase did not occur in 20 cases of RH.The expression of C-MYC protein did not correlate with C MYC gene copy number increase. The expression rate of C-MYC protein was 66.7% (40/60), and 20 cases of lymph node RH was all negative (0/20), as compared with the positive expression rate of protein C-MYC, the difference was statistically significant (P<0.05). The Ki-67 positive index and mediastinal bloadening had influence on the expression of C-MYC protein (P<0.05), the sex, primary site, symptoms, age, AnnArbor stage and lactate dehydrogenase (LDH) level and bone marrow involvement have no influence on it, there was no statistically significant difference (P>0.05). The 8q24 chromosome breakage occurred in 6 cases (10%), and the number of copies increased in 11 cases (18.3%). C-MYC gene copy number increase and C-MYC gene rupture in a total 20 cases of reactive hyperplasia of lymph nodes did not occur. CONCLUSION: C-MYC gene may play an important role on the development of T-LBL/ALL. It can be an independent prognosis factor. PMID- 29397834 TI - [Clinical Analysis of 10 Cases of AIDS Complicated with Lymphoma]. AB - OBJECTIVE: To investigate the clinical features and treatment of the patients with AIDS- related lymphoma (ARL). METHODS: The clinical data, pathology, treatment and prognosis of patients with ARL were retrospectively analyzed. RESULTS: Among 10 cases of ARL, 9 were male and 1 was female. The median age was 42 years old. Lymphoma occurred in 6 patients after diagnosis as AIDS, and treatment for 7-48 months, 1 case among which was diagnosed but not treated, then the lymphomatous symptions appeared after 48 months; 3 patients were found to have HIV infection during the diagnosis and treatment of lymphoma. Eight patients (8/10) had extranodal involvement. The count of CD4+ T cells was (69-601)* 106/L at presentation, the median count was 255* 106/L, HIV viral loads of 6 patients underwent antiretroviral therapy were lower than the lower-limit when diagnosed, while the RNA HIV copies of other patients were 0-45000 copies/ml. Four patients (4/10) displayed fever, 6 (6/10) with local mass, 2 with sore throat and throat ulcer. The pathological types of 7 cases were B cell-originated, including 5 cases of diffuse large B cell lymphomas (DLBCL), 1 case of Hodgkin's lymphoma and 1 cases of Burkitt' s lymphoma. The other 3 cases were T cell lymphomas. Nine patients received chemotherapy and antiretroviral therapy at the same time. There were no serious adverse reactions after chemotherapy. The CR rate was 67%, the median progression- free survival (PFS) was 14 months, the median survival time was 21 months. CONCLUSION: Clinical manifestations of ARL patients are diverse, chemotherapy combined with antiretroviral therapy may improve the prognosis. PMID- 29397835 TI - [Establishment of A20 Murine B Lymphoma Transplantation Model Labeled with Luciferase]. AB - OBJECTIVE: To establish the animal model of luciferase-transfected A20 murine B cell lymphoma, so as to provide experimental tools to explore the effect of graft versus tumor. METHODS: Luciferase- labeled A20 cells were cloned with puromycin selection. Transfected A20 cells and C57BL/6 bone marrow were inoculated into the irradiated BALB/c mice by injection in tailvein to establish the transplantation model. The bioluminescent imaging technique was used to monitor the tumor growth, and then the survival, body weight, tumor formation and pathological characteristics of target organs were observed. RESULTS: A20 cell line stably expressing luciferase gene was successfully obtained. The the bioluminicent imaging found that the tumor luminescence could be observed on day 8 of A20 cell inoculation, and the mean fluorescent intensity was increased along with the tumor growth. Compared with the BMT group, the survival rate and body weight of BMT+A20-Luc+ mice were decreased significantly. General anatomy showed the tumor mainly formed in the liver and spleen. CONCLUSION: A mouse transplantation model with luciferase- transfected A20 cells has been successfully established, thus laying a foundation for investigation of graft-versus-tumor. PMID- 29397836 TI - [Significance of H3K27me3 and EZH2 in Predicting the Therapeutic Efficacy of Diffuse Large B-Cell Lymphoma]. AB - OBJECTIVE: To investigate the significance of H3K27me3 and its methyltransferase EZH2 in predicting the short-term and long-term outcome of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The paraffin wax speciments of 102 DLBCL patients in Fujian Medical University Cancer Hospital were collected. The expression of H3K27me3, EZH2 and BCL-2 protein were detected using tissue array made by tissue microarray(TMA) technique and immunohistochemistry method. The evaluation data after clinical treatment and follow-up results were collected and combined with expression levels of H3K27me3, EZH2 and BCL-2 detected by tissue array, then on the basis of these data, the survival of patients was analyzed by Kaplan-Meier method, the correlation of EZH2 with H3K27me3 and BCL-2 was analyzed by pearson correlation test, the correlation of above mentioned indicators with different therapeutic efficacy was analyzed by spearman correlation test. The relationship of H3K27me3 and EZH2 expression as well as co-expression of H3K27me3 and EZH2 with the therapeutic efficacy and prognosis of patients were compared. RESULTS: A total of 61.8% patients showed EZH2 high expression which positively correlated with high expression of H3K27me3 and BCL-2. The complete remission (CR) and overall remission (OR) rates in H3K27me3 high expression and co-expression of H3K27me3 EZH2 groups were lower than those in low expression groups (P<0.001), moreover OS and PFS rates also were lower than those in low expression (P<0.001). In the RCHOP subgroup, the patients with EZH2 low expression showed significantly better CR, OR OS and PFS in comparison with those of patients with higher expression (P=0.003,P=0.019). CONCLUSION: Part of DLBCL patients with H3K27me3 high expression or coexpression of both H3K27me3 and EZH2 exhibit a worse prognosis in comparison with those patients with H3K27me3 low expression or without coexpression. The patients with EZH2 low expression usually responde well to RCHOP regimen in the short-term or long-term survival. PMID- 29397837 TI - [Expression and Clinical Prognostical Significance of RIP2 in Diffuse Large B Cell Lymphoma]. AB - OBJECTIVE: To investigate the expression and prognosis significance of receptor interacting protein 2 (RIP2) in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression of RIP2 in DLBCL GCB and non-GCB type was detected by immunohistochemistry, at same time the expressions of BCL-2 and C-MYC were detected. Then, the role of RIP2 in development of DLBCL was analyzed by related clinical and pathological parameters. RESULTS: The expression of RIP2 was related with middle-high risk group by IPI score, the An Arbor stage III+IV and intranodal lesions, and the differences were statistically significant (P<0.05). Besides, the single factor survival analysis suggested that GCB-type DLBCL showed a higher survival rate than that in non-GCB type(P<0.05). Patients with RIP2+ showed a lower survival rate as compared with patients with PIP2- (P<0.05), among which the patients receiving R-CHOP had a higher survival rate than that of those receiving CHOP (P<0.01). The expression of RIP2 in DLBCL cell lines was higher than that in peripheral mononuclear cells of normal subjects (P<0.01) and expressed differently in DLBCL of GCB and non-GCB type (P<0.01). CONCLUSION: The expression of RIP2 may relate with the poor prognosis and specific subtype of DLBCL. PMID- 29397838 TI - [Clinical Manifestations, Imaging Features and Pathological Diagnosis of Primary Central Nervous System Lymphoma]. AB - OBJECTIVE: To analyze the clinical manifestations, imaging features and pathological diagnosis of patients with primary central nervous system lymphoma. METHODS: The clinical data of 50 patients with primary central nervous system lymphoma admitted in our hospital from February 2016 to February 2008 were retrospectively analyzed. All the patients were examined by routine pathology and immunohistochemical staining. Among them 15 cases were examined by MVD and VEGF, and the other 15 glioma patients were taken as control group. RESULTS: In 50 patients, the disease was chronic, and the main clinical symptoms were numbness, cognitive disorder and disorder of consciousnessetc. Brain CT image of 33 cases (66%) mainly showed slightly higher density; 46 cases (92%) had head enhanced MRI lesions; 38 cases (76%) showed intracranial multiple lesions, 36 cases (72%) showed invasion of supratentorial, and 11 cases showed midline invasion (22%). Pathological diagnosis confirmed 47 cases (94%) with diffuse large B cell lymphoma, the proliferation index of the Ki-67(90%) in 41 case (82%) was higher. CONCLUSION: Primary central nervous system lymphoma is manifested with diffuse large B cell lymphoma as its main type, or with complicated clinical manifestations, lacks of features and certain imaging characteristics, but a few patients are easily pathologically misdiagnosed, therefore the biopsy is necessary for diagnosis of these patients. PMID- 29397839 TI - [ALC/AMC Value and Prognosis in Patients with Primary Follicular Lymphoma Treated with R-CHOP Chemotherapy]. AB - OBJECTIVE: To study the value of absolute lymphocyte count/absolute monocyte count (ALC/AMC) and its effect on prognosis in patients with primary follicular lymphoma treated with rituximab combined with cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP) chemotherapy. METHODS: Seventy patients with primary follicular lymphomawere in our hospital were treated with R-CHOP chemotherapy, the ALC/AMC value of peripheral blood was recorded, and the prognosis was assessed by the international prognostic index. RESULTS: According to the scores of the international prognostic index, 30 (42.86%) patients with score of 0-1 were enrolled in low-risk group, 21(30.00%), patients with score of 2 were enrolled in as the intermediate-risk group and 19 patients(27.14%) with score of 3-5 were enrolled in high-risk group. In the 3 group, the total effective rate of the low-risk group was the highest (95.24%), second was the intermediate-risk group (86.67%) and the total effective rate of the high-risk group was the lowest (78.95%), which showed that the difference was statistically significant (P<0.05); the progression-free survival(PFS) rate of 3 years in the low risk group was the highest (90%), followed by the intermediate-risk group (76.19%), and the PFS rate of the high-risk group was the lowest (52.63%)(P<0.05). The total effective rate of ALC/AMC<4.7 group was significantly lower than that of ALC/AMC >=4.7 group (68.63% vs 89.47%) (P<0.05), and the PFS rate of 3 years was lower than that of ALC/AMC>=4.7 group (70.59% vs 89.47%) (P<0.05). Multivariate analysis revealed that ALC/AMC value in the peripheral blood was an independent prognostic factor for patients with follicular lymphoma (P<0.05). CONCLUSION: The value of ALC/AMC in the peripheral blood may be an important marker for evaluation of prognosis in patients with primary follicular lymphoma treated with R-CHOP chemotherapy, which helps to assess the patient' s immune and tumor microenvironment. PMID- 29397840 TI - [Change of Neutrophils/ Lymphocyte Ratio in Patients with DLBCL before and after CHOP or R-CHOP Chemotherapy and Its Effect on Survival of Patients]. AB - OBJECTIVE: To analyze the change of neutrophil/lymphocyte ratio (NLR) in patients with diffuse large B cell lymphoma (DLBCL) patients before and after CHOP or R CHOP chemotherapy and its effect on survival of patients. METHODS: Clinical data of 60 patients with DLBCL were collected and were retrospectively analyzed. According to median NLR, 60 patients were divided into the group L in 33 cases (NLR< 2.27) and group H in 27 cases (NLR>= 2.27). The curative effect and survival rate by using CHOP or R-CHOP after chemotherapy were compared between the two groups. RESULTS: In the group H, the total effective rate after chemotherapy (55.56%) was significantly lower than that of group L (87.88%), which showed that the difference were statistically significant (P<0.05); the cumulative survival rate of 1,2,3 years in the group H (70.37%, 59.26%, 37.04%) were significantly lower than that in the group L (93.94%, 87.88%, 60.61%) (P<0.05). The NLR>= 2.27 before chemotherapy was the factor influencing the prognosis of patients with DLBCL (P<0.05). CONCLUSION: The NLR>= 2.27 before chemotherapy may be used as a factor influencing the prognosis of patients with DLBCL, and the high NLR may indicate poor clinical efficacy and worse prognosis. PMID- 29397841 TI - [Effects of Thalidomide on the Ratio of Th17 to Treg Cells in Peripheral Blood and Expression of IL-17 and IL-35 in Patients with Multiple Myeloma]. AB - OBJECTIVE: To explore the effects of thalidomide on the ratio of Th17 to Treg cells in peripheral blood and expression of IL-17 and IL-35 in patients with multiple myeloma(MM), so as to provide reference for the clinical treatment of patients with MM. METHODS: A total of 82 MM patients treated with thalidomide from January 2014 to December 2016 were enrolled in MM group, 30 healthy subjects were selected as control (control group). The ratio of T cell subsets and Treg cells accounted for CD4+T cell were detected by flow cytometer. The levels of IL 17 and IL-35 in serum were measured by ELISA, and the differences of various indexes were compared between 2 groups. RESULTS: Compared with the control group, the ratio of Th17 cells in peripheral blood and serum levels of IL-17 of MM patients were significantly increased, the ratio of Treg cells and the level of IL-35 were significantly decreased and the ratio of Th17/Treg cells was significantly increased in the patients with multiple myeloma before treatment (P<0.05). The ratio of Th17 cells in peripheral blood and serum levels of IL-17 in patients with multiple myeloma after treatment with thalidomide were significantly lower than those before treatment, and the ratio of Treg cells and levels of IL-35 were significantly higher than those before treatment, and the ratio of Th17 / Treg cells was higher than that before treatment (P<0.05). The indexes in ineffective treatment were not significantly changed (P> 0.05). CONCLUSION: The unbanlace of Th17/Treg cell ratio and abnormality of IL-17, IL-35 levels play an important role in the progression of multiple myeloma. The anti-MM mechanism of thalidomide may relate with the regulation of Th17 / Treg cell ratio and expression levels of IL-17 and IL-35. PMID- 29397842 TI - [Expression Level and Clinical Significance of VEGF, IL-17, beta2-MG and IL-35 in Patients with Multiple Myeloma]. AB - OBJECTIVE: To explore the expression and clinical significance of VEGF, IL-17, beta2-MG and IL-35 in patients with multiple myeloma. METHODS: A total of 83 patients with multiple myeloma (MM) from January 2012 to December 2016 were enrolled in MM group, 36 healthy subjects were enrolled in control group. The levels of IL-17, IL-35 and VEGF in serum were detected by ELISA. The levels of beta2-MG in serum were measured by radioimmunoassay. The differences of different indexes between 2 groups were compared. RESULTS: The serum levels of IL-17, VEGF and beta2-MG in serum of III stage were higher than that in II stage, which was higher than that in I stage and control group (P<0.05). The levels of IL-35 in the control group were significantly higher than those in the I,II,III stage group (P<0.05). The levels of IL-17, VEGF and beta2-MG in serum of progress period were higher than those in stable phase and control group, level of IL-35 in serum of control group was significantly higher than that in the stable phase and progress period group (P<0.05). The correlation analysis showed that the level of serum IL-17 positively correlated with VEGF, beta2-MG expression (r=0.65, 0.58, P<0.05); and the serum IL-17 levels were negatively correlated with IL-35 levels (r=-0.42, P<0.05). CONCLUSION: The anomalous levels of IL-17, IL-35, IVEGF and beta2-MG expressions correlate with the progression and prognosis of patients with multiple myeloma. PMID- 29397844 TI - [Clinical Study of Patients with Myelodysplastic Syndrome Transformed into Acute Myeloid Leukemia]. AB - OBJECTIVE: To study the biological characteristics and treatment response of patients with myelodysplastic syndrome (MDS) transformed into acute leukemia(AL). METHODS: Using WHO standard method, the clinical characteristics of patients with MDS into AML were retrospectively analyzed, the related factors influencing the MDS into AML and the treatment response of patients were analyzed. RESULTS: Twenty-six cases (17%) of MDS were transformed into AL among 153 cases of middle and high risk MDS, all of which were AML. The median time of transformation from MDS into AML was 4 months (1-29),and these cases transformed into AML-M2, M4, M5 and M6. In these 26 cases of AML patients, the varying degrees of anemia symptom appeared, 2 cases were with marrow infiltration, 18 cases (69.2%) were with abnormal chromosome karyotype. Compared with karyotype before transformation into AML, the abnormal karyotype in 9 cases had been conversed (new karyotype or disappear once of existing karyotype). Total efficiency of individualized treatment for MDS transformed into AML was 80%. This treatment could improve the patients quality of life. CONCLUSION: Middle and high risk MDS patients are prone to be tranformed into AML. Multiple factors are involved in the transformation of MDS into AML. These patients showed the special biological characteristics and poorer prognosis. Demethylation treatment is helpful to achieve a good near-term curative effect. PMID- 29397843 TI - [Comparison of Decitabine Rigimen and Traditional Chemotherapy Regimen in Treatment of Patients with Intermediate or High-Risk Myelodysplastic Syndrome]. AB - OBJECTIVE: To compare the clinical efficacy and relevant adverse reactions of homebred decitabine regimen and traditional chemotherapy regimen in treatment of patients with intermediate or high-risk myelodysplastic syndrome (MDS). METHODS: Forty-eight patients suffered from newly diagnosed intermediate or high-risk MDS from December 2011 to December 2016 were analyzed retrospectively. Among them 29 patients were treated by traditional chemotherapy regimen, and 19 patients were treated by decitabine regimen [15 mg/(m2.d), ivgtt, d1-5]. The clinical efficacy and relevant adverse reactions in two groups were compared. RESULTS: The overall response rate (ORR) of decitabine group was 78.9% (15/19), after 2 cycles of treatment, among them 5 achieved complete remission(CR), 5 achieved partial remission(PR), and 5 achieved hematologic improvement (HI); the ORR of traditional chemotherapy group was 65.9% (16/29), including 6 CR, 5 PR, 8 HI, the ORR and remission rate (PR+CR) in decitabine treatment group were not statistically significantly different from the that in traditional chemotherapy group (x2=0.458,P>0.05; x2=0.499, P>0.05). After 4 cycles of treatment, the ORR in decitabine group was 84.2% (16/19), including 5 CR, 9 PR and 2 HI. The ORR in traditional chemotherapy group was 68.9% (20/29), including 6 CR, 5 PR and 9 HI. The ORR of decitabine group was not statistically significantly different from the that in traditional chemotherapy (x2=0.726,P>0.05), but the remission rate was statistically significantly different(x2=4.534,P<0.05). The overall survival and progression-free survival in the decitabine group were different statistically significantly different from the traditional chemotherapy (P<0.05; P<0.01). The incidences of III-IV grades adverse reactions of hemoglobin, platelet and neutrophile in the patients treated with decitabine and traditional chemotherapy group were 52.6% and 79.3% (P>0.05), 57.9% and 86.2%(P>0.05), 84.2% and 96.6%(P>0.05), respectively. The infection rates were 26.3% and 79.3%(P<0.05), respectively. CONCLUSION: The homebred decitabine can effectively treat intermediate-or high-risk MDS, also can be well tolerated. So, it is worth to be clinically popularized. PMID- 29397845 TI - [Expressions of CD96 and CD123 and Their Relationship with Prognosis of Patients with Myelodysplastic Syndrome]. AB - OBJECTIVE: To explore the relationship between expression of CD96 and CD123 and prognosis of patients with myelodysplastic syndrome(MDS). METHODS: Eight-nine MDS patients(MDS group) and 20 persons without hematologic disease as controls(Control group) were enrolled. The patients were grouped by the risk. All participants received bone marrow biopsy. Mononuclear cells were extracted, CD34+CD38-CD123+ and CD34+CD38-CD96+ cells were counted by using flow cytometry. Expressions of 2 type cells in control group, MDS group and its subgroups were analyzed. RESULTS: The proportion of CD34+ cells and CD34+CD38- cells in mononuclear cells of patients in MDS group was higher than in control group (P<0.05). The proportions of CD34+CD38-CD123+ cells and CD34+CD38-CD96+ cells in CD34+CD38- cells were significantly higher than that in control group(P<0.05) and the proportion increased with the risk. In the low-and middle-risk group, the rates of complete remission(CR) and partial remission(PR) of patients with CD123- and CD96- were higher than those in patients with CD123+ and CD96+; in the middle 2 and high risk patients, the PR of patients with CD123- was higher than that in patients with CD123+(P<0.05). The CR rate of patients with CD96- was higher than that of patients with CD96+(P<0.05). CONCLUSION: The differentiation of CD34+ cells in bone marrow of MDS patients is abnormal, and the high expression of CD123 and CD96 cells existes. These findings may partially explain the cause of hematopoietic stem cell malignant clone in MDS patients. PMID- 29397846 TI - [Differential Expression Profiles of MicroRNAs between de novo and Complete Response Severe Aplastic Anemia]. AB - OBJECTIVE: To detect the expression of miRNA in de novo and complete response SAA patients and predict the targets of the miRNAs. METHODS: The expression profiles of miRNA from bone marrow mononuclear cells of the SAA patients with de novo and CR were detected by miRNA microarray. RESULTS: Totally 35 up-regulated and 37 down-regulated miRNA were identified in CR SAA patients in comparison with de novo SAA patients. Furthermore, by predicting the targets of the differentlly expressed miRNA, it was found that some targets associated with T cell receptor signaling pathway and cell adhesion molecules. CONCLUSION: Some miRNA may be involved in the pathogenesis of SAA. PMID- 29397847 TI - [Prevalence and Genotype Analysis of Newborn alpha-Thalassemia in Wuhan Area of China]. AB - OBJECTIVE: To investigate the genotypes of newborn alpha-thalassemia and to analyze its characteristics of molecular epidemiology in Wuhan area. METHODS: The newborn alpha-thalassemia gene in 1376 cases with positive confirmed in the primary screening in Wuhan area was detected by PCR, flow cytometry and FISH. RESULTS: The alpha-thalassemia in 436 newborns and alpha- beta-composite thalassemia in 10 newborns were confirmed by detection in Wuhan area. The majority of thalassemia cases [up to 92.20% (402/436)] were found to be minor and static type thalassemia including 237 cases of -SEAalphaalpha (54.36%), 135 cases of -alpha3.7 / alphaalpha (30.96%) and 30 case of -alpha4.2/alphaalpha (6.88%), however, the intermediate type -alpha3.7/-SEA was found in 1 newborn. The SEA/detetion, -alpha3.7/detetion and -alpha4.2/detetion were major in the detetion, the frequency was 54.12%, 32.29% and 7.13%, respectively; while the alphaCS mutation, alphaQS mutation and alphaWS mutation were less in the mutation, their frequency was 3.7%, 2.45% and 0.22% respectively. CONCLUSION: The minor and static type newborn thalassemia is most common, the incidence of detetion type -SEA/alphaalpha, -alpha3.7/alphaalpha and alpha4.2/alphaalpha is more high in Wuhan area of china. PMID- 29397848 TI - [Positive Distribution Rate of Coombs Test in Patients with Clinical Anemia and Blood Transfusion and Its Effect on Clinical Blood Transfusion]. AB - OBJECTIVE: To study the positive distribution rate of Coombs test in patients with clinical anemia and blood transfusion, and its effect on clinical blood transfusion. METHODS: Seventy patients with hemoglobin level in the normal range were enrolled into control group, while 130 patients with anemia or blood transfusion who' s hemoglobin level was lower comfirmed by micro-column gel antihuman globin detection card and 70 surgical patients with anemia or blood transfusion who' s hemoglobin level was lower comfirmed by micro-column gel anti human globin card were enrolled into anemia or blood transfusion (A or BT) group. And coomb' s test performed for all the patients, in which the positive patients in Department of Internal Medicine need to be re-typed. RESULTS: Among 70 surgical patients with anemia or blood transfusion, 14 cases were directly detected to be anti-human globine positive with detection rate 20%; among 130 internal medicine patients with anemia or blood transfusion, 54 cases were directly detected to be anti-human globine positive with detection rate 41.4%. Among 270 cases, the highest positive rate (66.7%) was observed in patients with 50-59 g/L of hemoglobin. According to type test, the samples of 54 patients with anemia in Department of Internal Medicine, who were directly selected to be anti human globin positive, could be divided into anti-C3d(7 cases, accounting for 13.0%), anti-IgG(12 cases accounting for, 22.2%) and anti-C3d+anti-IgG(35 cases, accounting for 64.8%), while according to diseases, the anti-human globin positive ratio was high in tumor cancer, hephropathy and gastroenteropathy patients, and patients in intensive care unit, moreover the blood transfusion frequency of these patients was higher than that of patients with anti-human globin negative(P<0.05). CONCLUSION: The important causes affecting the anemia in patients may relate with direct anti- human globulin positive test, therefore the interference of direct anti-human globin positive should be excluded in the course of blood transfusion, so as to ensure the effectiveness of blood transfusion. PMID- 29397849 TI - [Variation and Clinical Significance of LNK Gene in Essential Thrombocytosis]. AB - OBJECTIVE: To explore the mutation and single nucleotide polymorphism(SNP) of LNK gene in the patients with essential thrombocytosis (ET), and to analyze the relationship between LNK gene variation and the occurrence of ET. METHODS: JAK2V617F mutation was identified by allele-specific PCR. The whole exon of LNK gene was amplified by PCR. The amplified sequences included the Rs3184504 (C/T) and Rs78894077 (A/C/G/T) affecting the expression of amino acids in LNK gene, and the Rs7973120 (A/T) unaffecting the expression of amino acids. The mutation and SNP of LNK gene were analyzed by DNA sequencing. RESULTS: Six cases of ET had LNK mutation, including four types: A300V, R425C, V402L and R426Q. T allele distribution of SNP Rs78894077 Ser in ET group was statistically significantly higher than that in the control group (P<0.05). T allele frequency of SNP Rs3184504 Ser in ET group was higher than that in the control group(P<0.05). CONCLUSION: LNK mutations exist in ET patients, and the T allele gene carrying LNK SNP Rs78894077 Ser and Rs3184504 Ser in persons may increase the risk of ET. PMID- 29397850 TI - [Efficacy of Recombinant Human Thrombopoietin and Recombinant Human Interleukin 11 for Treatment of Chemotherapy Indu-ced Thrombocytopenia in Acute Myeloid Leukaemia Patients]. AB - OBJECTIVE: To evaluate and compare the clinical efficacy and safety of recombinant human thrombopoietin(rhTPO) and recombinant human interleukin11(rhIL 11) for the treatment of chemotherapy-induced thrombocytopenia in adult acute myeloid leukaemia patients. METHODS: Total of 96 adult acute myeloid leukaemia patients were divided into 3 groups according to randomized controlled method: rhTPO group, rhIL-11 group and control group, 32 cases in each group. The patients in rhTPO group and rhIL-11 received rhTPO of 15000 IU/d and rhIL-11 of 1.5 mg/d, respectively after the standard combined chemotherapy within 24 hours, and patients in control group, received nothing drugs to promote thrombocyte recovery. And rhTPO and rhIL-11 should be stopped when the Plt>=100* 109/L. After chemotherapy, the platelet recovery degree, duration of Plt<50* 109/L, >=50* 109/L and >=100* 109/L, the count of infusion thrombocytes, and incidence of adverse reactions all were compared. RESULTS: The duration of Plt<50* 109/L was obviously less than that in control group(P<0.01). The duration of rhIL-11 was less than that in control group, but there was no statistical significance(P>0.05). As compared with that in control group, the Plt count in rhTPO and rhIL-11 groups can faster increase to Plt>=50* 109/L (P<0.01, P<0.05), among them the Plt count in rhTPO group faster increase, but there was no statistical signiticance. As compared with that in control group, the Plt count in rhTPO group and rhIL-11 group can increase to Plt>=100* 109/L (P<0.01), the Plt count in rhTPO group was more obviously increase than that in rhIL-11 group(P<0.05). The count of infusion Plt in rhTPO and rhIL-11 groups was lese than that in control group(P<0.01, P<0.05), and the count of infusion Plt in rhTPO group was less than that in rhIL-11 group(P<0.05). After using rhTPO and rhIL-11, the adverse reactions, such as low fever, induration of injection site, athralgia, nausea and vomiting occured in rhTPO group and rhIL-11 group, but all can be tolerated. CONCLUSION: Both rhTPO and rhIL-11 can reduce the duration of thrombocytopenia and the amount of infused thrombocyte, promote platelet recovery in the patients with acute myeloid leukaemia after chemotherapy, to decreae the risk of bleeding, and reduce incidence of adverse reactions, both of them can be tolerated by patients, and rhTPO is more advantage than rhIL-11, worthy of clinical popularization and application. PMID- 29397851 TI - [Prognostic Analysis of Minimal Residual Disease from Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplant by Flow Cytometry]. AB - OBJECTIVE: To investigate the value of flow cytometry (FCM) detection in prognostic evaluation of minimal residual disease (MRD) of acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (allo HSCT). METHODS: Eighty-two cases of AML (except M3) after allo-HSCT who accord to enrolled condition (no MRD positive after allo-HSCT confirmed by regular flow cytometry detection and followed-up for 2 years) from April 2012 to September 2016 in our department were selected. Among 82 cases males were 50 and females were 32 with average age of 27.27 (2-57) years old. According to FAB classification, 2 cases were classified as M0/M1, 51 cases as M2, 24 cases as M4/M5 and 5 cases as M6. The antibody panels were selected accordingly to the initial leukemia associated immunophentype(LAIP) of patients. RESULTS: Twenty patients (24.39%) were identified as MRD+ (0.10%-4.91%, mean 1.64%) in 82 AML patients after allo-HSCT (all the patients were in complete remission phase based on bone marrow morphology). During follow-up, 16 cases relapsed (relapse rate 80%)in 20 MRD+ cases, including 1 case with extramedullary relapse; 4 out of 62 MRD- cases relapsed (relapse rate 6.45%)in bone marrow, and 2 cases extramedullary relapsed. The average survival time of leukemia- free survival (LFS) in group MRD+ was 15.19 +/- 3.99 months, median LFS was 10+/- 3.84 months. The average LFS time was 53.50 +/- 1.69 months in MRD- group (P<0.001). The average overall survival (OS) of the MRD+ group was 22.52 +/- 5.72 months, the median OS was 18 +/- 3.27 months; the average OS time was 42.86 +/- 2.83 months in MRD- group(P=0.008). CONCLUSION: For the patients with morphologically complete remission after allo-SCT, the FCM regular monitoring of bone marrow MRD closely relates with its relapse rate, LFS and OS. Compared with the MRD- group, the relapse rate of MRD+ group is significantly increases, and the LFS and OS significantly decreases. PMID- 29397852 TI - [Effects of IFN-gamma on Pulmonary GVHD after Allo-Hematopoietic Stem Cell Transplantation]. AB - OBJECTIVE: To explore the effects of IFN-gamma on pulmonary GVHD after hematopoietic stem cell transplantation (HSCT). METHODS: The mouse GVHD models were established by using C57BL/6J, B6D2F1 mice and different HSCT. According to HSCT modes, the mice were divided into 3 groups: syngeneic HSCT group(C57BL/6J >C57BL/6J), allogeneic HSCT group (C57BL/6J->B6D2F1) and IFN-gamma -/- allogeneic HSCT group (IFN-gamma -/-->C57BL/6J->B6D2F1). The survival time, GVHD clinical seore, pulmonary pathologic changes in 3 groups were compared and analyzed, and the total cell count in BALF and IFN-gamma level in serum were detected in 3 groups after transplantation. RESULTS: The mice in syngeneic HSCT group all survived at day 42 after transplantation without GVHD symptoms in lung, the GVHD clinical score was low. The mice in allogeneic HSCT group survived at day 24 after transplantation (survial rate >50%), the GVHD clinical score was higher than that in syngeneic HSCT group, the pathologic changes in lung did not serious, though the GVHD presentation was observed, but the olveola bleeding and lymphocyte infiltration in lung tissue were observed at day 28 after transplantation. The mice in IFN-gamma -/- allogeneic HSCT group all died of lethal GVHD within 14 days after transplantation, the GVHD clinical score reached to 6.7+/- 0.83 at 1st week after tansplantation, which was significantly higher than that in syngeneic and allogeneic HSCT groups. At 1st week after transplantation, the serious GVHD pathological changes occured in lung tissue, total cell count in BALF significanty increased, compared with syngeneic and allogeneic HSCT groups, but IFN-gamma level in serum was significantly lower than that in syngeneic and allogeneic HSCT groups (P<0.05). CONCLUSION: Donor-derived IFN-gamma plays an important immunoprotective role for lung tissue after HSCT. PMID- 29397853 TI - [MicroRNA-3963 Promotes Adipogenic Differentiation of Mouse-Derived Mesenchymal Stem Cells]. AB - OBJECTIVE: To investigate the effect of MicroRNA-3963(miR-3963) on the adipogenic differentiation of mouse bone-derived mesenchymal stem cells(MSC). METHODS: MSCs were isolated from C57BL/6 mice bone fragment and transfected with miR-3963 mimic, miR-3963 inhibitor and negative control. The expression of miR-3963 and transfection efficiency were detected by q-PCR. These transfected cells were induced to adipocytes and stained with oil red O after 14 days culture. q-PCR and Western blot were used to detect the expression of adipogenic differentiation marker genes C/EBPalpha and PPARgamma at transcriptional level and protein level. RESULTS: The results of q-PCR revealed that miR-3963 expression level was up regulated after transfection with miR-3963 mimic (P<0.0001), and down-regulated after transfection with miR-3963 inhibitor (P<0.0001). After oil red staining, overexpression of miR-3963 in MSCs could promote the formation of lipid droplet. The q-PCR and Western blot analyses showed the significant increase of expression of adipogenic marker genes C/EBPalpha and PPARgamma in MSC transfected with miR 3963 mimic. Additionally, compared with the control group, miR-3963 inhibitor could decrease adipogenic differentiation of MSC. CONCLUSION: miR-3963 can regulate and promote adipogenic differentiation of mouse bone-derived MSC. PMID- 29397854 TI - [Effect of G-CSF in vitro Stimulation on Distribution of Peripheral Lymphocyte Subsets in the Healthy Persons]. AB - OBJECTIVE: To investigate the effect of granulocyte-colony stimulating factor (G CSF) in vitro stimulation on the distribution of lymphocyte subset in healthy human. METHODS: Peripheral blood mononuclear cells (PBMNCs) were collected from 8 healthy volunteers by density gradient centrifugation on Ficoll-PaqueTM. In vitro 200 ng/ml G-CSF or 200 ng/ml G-CSF plus 10 ug/ml ConA directly act on PBMNCs, then the colleted cells were cultivated for 3 days. Lymphocyte subsets were stained with the corresponding fluoresce labeled antibodies and detected by flow cytometry. RESULTS: The levels of T cells in G-CSF group and G-CSF+ConA group were both higher than that in the control group (P<0.001, P<0.05). However, there were not significantly different in B cells and NK cells levels among the 3 groups. Furthermore, analysis of the effect of G-CSF on T cell subsets indicated that the levels of CD4+T cells and CD8+T cells in G-CSF group were both significantly higher than those in control group (P<0.01, P<0.05), Treg cells was not different between G-CSF and control group. Compared with the control group, the level of CD4+T cells, CD8+T cells and Treg cells in G-CSF+ConA group significantly increased (P<0.05, P<0.01, P<0.01). Analysis of G-CSF receptor (G CSFR) expression showed that G-CSFR expression on T cells in G-CSF+ConA group dramatically increased, as compared with control group (P<0.01). CONCLUSION: The levels of CD4+T cells and CD8+T cells in healthy human peripheral blood can be increased by G-CSF stimulation. ConA can enhance the level of T cells and induce G-CSFR expression on T cells. PMID- 29397855 TI - [Screening of HBV and Positive Population Distribution Characteristics of Voluntary Blood Donors in Qingyang]. AB - OBJECTIVE: To study and analyse the application of ELISA and nucleic acid test (NAT) to HBV detection of voluntary blood donors in Qingyang city and the characteristics and social attributes of HBV positive population. METHODS: The HBV of 70 659 blood donors in Qingyang city from January 2013 to December 2016 was detected by using ELISA and NAT, and the statistical analysis of results was performed by means of X2 detection and FIsher' s Exact test. RESULTS: The HBV positive rate detected by ELISA was 0.47% in 70 659 blood samples, and the HBV positive rate detected by NAT was 0.05% in 47 913 HBV negative samples detected by ELISA, moreover, the number of HBV negative by ELISA detection yet HBV positive by NAT detection increased year by year. The statistical analysis of positive population characteristics showed that the age distoibution was mainly between 26-45 years old, however the difference of detected rate between 26-45 years old and 18-25 years old gradually decreased on near 2 years, showing that the positive population tended to be younger. The distribution of blood type was B>O>A>AB, while the sex distribution was male> female, but this difference showed gradually nairowing trend due to increment of female voluntary donors with HBV positive; for marital status, HBV positive concentrated in married population. The regional distribution of HBV positive mainly concentrated in Xifeng region, mainly in jobless population; the HBV positive comparison betwwen anationalities showed Han natienatity was > minoring nationalitie. CONCLUSION: The application of ELISA combined with NAT for the HBV screaning of blood voluntary donors in Qiangyang city can prevent the detection failed and occult HBV, and reduce the potential risk of blood transfution. The characteristis analysis of HBV positive population provides practical basis for the safe use and transfution of blood. PMID- 29397856 TI - [Pathological Research of Splenic Extramedullary Hematopoiesis in Aged Rats]. AB - OBJECTIVE: To explore the occurrence and various influencing factors of the splenic extramedullary hematopoiesis in rats. METHODS: A total of 411 rats of different sex and species were assigned to this study. These rats were fed different feed in the same environment, and killed after 104 weeks. The spleen of all animals was embedded in paraffin, sectioned, stained with hematoxylin and eosin(H& E), then examined by optical microscopy to observe splenic extramedullary hematopoiesis. RESULTS: At the end of the study, it was found that the splenic extramedullary hematopoiesis occurred in 116 animals (28.22%). The splenic extramedullary hematopoiesis that included the erythroid, granulocytic and megakaryocytic lineages (23.11%); the inciderce of splenic extramedullary hematopoiesis in Wistar rats was higher than that in SD rats; the incidence of splenic extramedullary hematopoiesis in female was higher than that in male; the feed had no effect on splenic extramedullary hematopoiesis of all animals; different species and different feed were also did not involve in the level of splenic extramedullary hematopoiesis. CONCLUSION: Species and sex show effect on the incidence of splenic extramedullary hematopoiesis, but does not involve in the level of splenic extramedullary hematopoiesis; feed had no influences on all indexes of splenic extramedullary hematopoiesis. The results of this study may provide a reference for the study of the splenic extramedullary hematopoiesis of the aging human. PMID- 29397857 TI - [Research Progress on the Establishment of Animal Model with Immune Thrombocytopenic Purpura - Review]. AB - Immune thrombocytopenic purpura (ITP) is a chronic and recurrent autoimmune disease, which seriously affects the life quality of patients. At present, a series of new advances have been made in the pathogenesis of ITP, particularly, in the abnormal cellular immunity. However, in the medical studiess generally research of ITP cellular immunity was limited. Therefore, it is urgent to establish an ideal ITP model for the study of ITP pathogenesis, so as to contribute to promote the ITP new treatment progeamme. In this review, the passive modeling inclinding anti-platelet serum modeling, monoclonal antiboty modeling, and active modeling including NZW* BXSB rat modeling, antigenic mimicry modeling, immune splenic cell transplantation modeling, transgenic model, fetal and neonatal allsimmune thrombocytopenia modeling and so on, are summarized. PMID- 29397858 TI - [Application of Next Generation Sequencing in Genetic Diagnosis of Hereditary Platelet Disorders - Review]. AB - Hereditary platelet disorders are a heterogeneous group of disorders characterized by abnormal number or function of platelets, sometimes even involving other systems apart from blood abnormalities. The great clinical and genetic heterogeneity makes the diagnosis and treatment of hereditary platelet disorders as a huge challenge for clinicians. At present, only a small number of patients have received a clear molecular diagnosis of hereditary platelet diseases, and a lot of pathogenic genetic variations still remain unknown. The popularity of next generation sequencing (NGS) promotes the development of individualized gene sequencing. Researchers have made great progress in the field of hemostasis and thrombosis using whole genome sequencing (WGS), whole exone sequencing (WES) and target gene sequencing (TGS). The development of NGS has not only promoted the individualized molecular diagnosis of hereditary platelet diseases, but also laid a solid foundation for gene therapy in the future. In this review, the new progress of the diagnosis of platelet-related diseases by using next generation sequencing techniques, is summarized. PMID- 29397859 TI - [Research Progress on Effect of JAK Inhibitors on Myelofibrosis- Review]. AB - Myelofibrosis(MF) is a type of myeloprolifirative neoplasms which is difficult to be treated. With the discovery of V617F mutation site in Janus kinase 2 (JAK2), JAK inhibitor provides a new treatment strategy for patients with myelofibrosis. Since 2011 the FDA in USA approved the first generation of JAK inhibitor Ruxolitinib for marketing, a growing number of JAK inhibitors have been entering into the clinical trials and showed a certain clinical efficacy. On the one hand, some JAK inhibitors for single application can effectively relieve the clinical symptoms of patients with myelofibrosis, slow down disease progression, and prolong the survival; on the other hand, JAK inhibitor can also be applied in combination with traditional or other new targeted drugs for MF patients, even during the allogenetic hematopoietic stem cell transplantation, thus providing more choices for targeted therapy on the patients with myelofibrosis. This review focuses mainly on the latest advances of JAK inhibitors for the patients with myelofibrosis. PMID- 29397860 TI - [Advances in Pathogenesis of Essential Thrombocythemia - Review]. AB - Essential thrombocythemia(ET) is one of the Ph chromosome-negative myeloproliferative neoplasms. Some studies discovered that the mutation of JAK2 V617F existed in 50%-70% patients with ET. Recently, many significant advances in researches about pathogenesis of ET, such as mutations of JAK2V617F, MPL, CALR and other related mutation; the epigenetic abnomalities in incidence of ET; the changes of bone marrow microenvironment of ET and the regulation of related cytokines were obtained. In this article, the advances of above mentioned aspects of ET are summarized. PMID- 29397861 TI - [Research Progress on EB Virus and Its Related Lymphoma - Review]. AB - Epstein-Barr virus(EBV) closely relates with the occurrence, development and prognosis of multiple lymphomas, such as Burkitt' s lymphoma, diffuse large B cell lymphoma, Hodgkin' s lymphoma, angioimmunoblastic T cell lymphoma. The mechanism of EBV in tumorigenesis can be understanded through the research of EBV biological characteristics, EBV+ lymphoma and EBV- lymphoma. Based on traditional therapy, supplement of specific treatment for EBV, such as antiviral treatment, immunotherapy, can improve the curative rate of lymphoma. This review focuses on latest research progress about pathogenesis and treatment of EBV-related lymphoma. PMID- 29397862 TI - [Recent Research Advances on Signaling Pathway in B-cell Malignancy - Review]. AB - B-cell malignancy, a kind of malignant tumor of blood system, is characterized by heterogeneity and complexity of the pathogenesis. In this review, the recent advances of studies on B-cell malignancy and signaling pathways are briefly summarized. This review focuses on the role of signaling pathways, especially the NF-kappa B, Wnt, PI3K/Akt, Notch and JAK/STAT signaling pathway in the occurrence and development of B-cell malignancy, and discussed the influence of signaling pathways on the invasiveness and drug resistance of B-cell malignancy, and the clinical application of signaling pathway inhibitors. PMID- 29397863 TI - [Role of Intestinal Microbiota in Hematopoietic Stem Cell Transplantation - Review]. AB - Graft-versus-host disease (GVHD) and infection are the frequently encountered complications after hematopoietic stem cell transplantation (HSCT), which influence the outcome and limit the widespread application of HSCT. Intestinal microbiota plays an important role in maintaining intestinal immune balance. The diverse levels of intestinal microbiota associated with the incidences of GVHD, infection and the prognosis of HSCT, thus remodeling intestinal microbiota can alleviate GVHD and infection after HSCT. Herein, the recent research progress about the role and the involved mechanisms of intestinal microbiota in HSCT, and the novel manipulation strategies of intestinal microbiota are systematically reviewed. PMID- 29397864 TI - [MSC Senescence-related Signaling Pathway - Review]. AB - The replicative senescence of mesenchymal stem cells(MSC) during the in vitro expansion limits their use in the research and treatment of many disease. Also, MSC senescence may promote the individual senility, hypofunction of tissue and organ, and tumorigenesis. Thus, in order to better understand the senescent mechanism and delay the senescence, even reverse MSC senescence, the roles of signaling pathway, such as Wnt/beta-catenin, MAPK/ERK, PI3K/AKT and ROS-related signaling pathway during the MSC senescence all were reviewed, so as to can deepen the under-standing of MSC senescence and provide a new thinkings for delaying, even reversing the MSC senescence. PMID- 29397865 TI - The role of Purkinje cell-derived VEGF in cerebellar astrogliosis in Niemann-Pick type C mice. AB - Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative disorder caused by a deficiency of NPC1 gene function, which leads to severe neuroinflammation such as astrogliosis. While reports demonstrating neuroinflammation are prevalent in NP-C, information about the onset and progression of cerebellar astrogliosis in this disorder is lacking. Using gene targeting, we generated vascular endothelial growth factor (VEGF) conditional null mutant mice. Deletion of VEGF in cerebellar Purkinje neurons (PNs) led to a significant increase of astrogliosis in the brain of NP-C mice in addition to the loss of PNs, suggesting PN-derived VEGF as an important factor in NP-C pathology. Moreover, replenishment of VEGF in neurons improved brain pathology in NP-C mice. Overall, our data provide a new pathological perspective on cerebellar astrogliosis in NP-C and suggest the importance of VEGF as a therapeutic target for this disease. [BMB Reports 2018; 51(2): 79-84]. PMID- 29397866 TI - Drug resistance of bladder cancer cells through activation of ABCG2 by FOXM1. AB - Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer. [BMB Reports 2018; 51(2): 98-103]. PMID- 29397867 TI - Structure and function of vascular endothelial growth factor and its receptor system. AB - Vascular endothelial growth factor and its receptor (VEGF-VEGFR) system play a critical role in the regulation of angiogenesis and lymphangiogenesis in vertebrates. Each of the VEGF has specific receptors, which it activates by binding to the extracellular domain of the receptors, and, thus, regulates the angiogenic balance in the early embryonic and adult stages. However, de regulation of the VEGF-VEGFR implicates directly in various diseases, particularly cancer. Moreover, tumor growth needs a dedicated blood supply to provide oxygen and other essential nutrients. Tumor metastasis requires blood vessels to carry tumors to distant sites, where they can implant and begin the growth of secondary tumors. Thus, investigation of signaling systems related to the human disease, such as VEGF-VEGFR, will facilitate the development of treatments for such illnesses. [BMB Reports 2018; 51(2): 73-78]. PMID- 29397868 TI - SF3B4 as an early-stage diagnostic marker and driver of hepatocellular carcinoma. AB - An accurate diagnostic marker for detecting early-stage hepatocellular carcinoma (eHCC) is clinically important, since early detection of HCC remarkably improves patient survival. From the integrative analysis of the transcriptome and clinicopathologic data of human multi-stage HCC tissues, we were able to identify barrier-to-autointegration factor 1 (BANF1), procollagen-lysine, 2-oxoglutarate 5 dioxygenase 3 (PLOD3) and splicing factor 3b subunit 4 (SF3B4) as early HCC biomarkers which could be detected in precancerous lesions of HCC, with superior capabilities to diagnose eHCC compared to the currently popular HCC diagnostic biomarkers: GPC3, GS, and HSP70. We then showed that SF3B4 knockdown caused G1/S cell cycle arrest by recovering p27kip1 and simultaneously suppressing cyclins, and CDKs in liver cancer cells. Notably, we demonstrated that aberrant SF3B4 overexpression altered the progress of splicing progress of the tumor suppressor gene, kruppel like factor 4 (KLF4), and resulted in non-functional skipped exon transcripts. This contributes to liver tumorigenesis via transcriptional inactivation of p27Kip1 and simultaneous activation of Slug genes. Our results suggest that SF3B4 indicates early-stage HCC in precancerous lesions, and also functions as an early-stage driver in the development of liver cancer. [BMB Reports 2018; 51(2): 57-58]. PMID- 29397871 TI - Outbreak of bacterial endocarditis associated with an oral surgery practice: New Jersey public health surveillance, 2013 to 2014. AB - BACKGROUND: In October and November 2014, the New Jersey Department of Health received reports of 3 patients who developed Enterococcus faecalis endocarditis after undergoing surgical procedures at the same oral surgery practice in New Jersey. Bacterial endocarditis is an uncommon but life-threatening condition; 3 patients with enterococcal endocarditis associated with a single oral surgery practice is unusual. An investigation was initiated because of the potential ongoing public health risk. METHODS: Public health officials conducted retrospective surveillance to identify additional patients with endocarditis associated with the practice. They interviewed patients using a standardized questionnaire. An investigative public health team inspected the office environment, interviewed staff, and reviewed medical records. RESULTS: Public health officials identified 15 confirmed patients with enterococcal endocarditis of those patients who underwent procedures from December 2012 through August 2014. Among these patients, 12 (80%) underwent cardiac surgery. One (7%) patient died from complications of endocarditis and subsequent cardiac surgery. Breaches of recommended infection prevention practices were identified that might have resulted in transmission of enterococci during the administration of intravenous sedation, including failure to perform hand hygiene and failure to maintain aseptic technique when performing procedures and handling medications. CONCLUSIONS: This investigation highlights the importance of adhering to infection prevention recommendations in dental care settings. No additional patients with endocarditis were identified after infection prevention and control recommendations were implemented. PRACTICAL IMPLICATIONS: Infection prevention training should be emphasized at all levels of professional dental training. All dental health care personnel establishing intravenous treatment and administering intravenous medications should be trained in safe injection practices. PMID- 29397872 TI - Nutritional and dental issues in patients with intellectual and developmental disabilities. AB - BACKGROUND: People with intellectual and developmental disabilities are among the most disadvantaged and underserved groups of dental patients. Considerable health care disparities for this population have been identified, particularly oral and dental health as well as access to dental care services. People with Down syndrome and cerebral palsy have a variety of nutritional and dental considerations. CONCLUSIONS: These people have a higher prevalence of untreated caries and periodontal disease than the general population and may have higher rates of obesity, edentulism, and chronic oral and systemic diseases. Diet choices may affect the oral health and may play an important role in the systemic health of these people. Suggestions to improve and affect dietary intake are provided. CLINICAL IMPLICATIONS: Health issues within this population require a holistic approach to care. Concerns about oral health and diet must be addressed to support optimal health. PMID- 29397869 TI - The history and regulatory mechanism of the Hippo pathway. AB - How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. [BMB Reports 2018; 51(3): 106-118]. PMID- 29397870 TI - Upstream paths for Hippo signaling in Drosophila organ development. AB - Organ growth is fundamental to animal development. One of major mechanisms for growth control is mediated by the conserved Hippo signaling pathway initially identified in Drosophila. The core of this pathway in Drosophila consists of a cascade of protein kinases Hippo and Warts that negatively regulate transcriptional coactivator Yorkie (Yki). Activation of Yki promotes cell survival and proliferation to induce organ growth. A key issue in Hippo signaling is to understand how core kinase cascade is activated. Activation of Hippo kinase cascade is regulated in the upstream by at least two transmembrane proteins Crumbs and Fat that act in parallel. These membrane proteins interact with additional factors such as FERM-domain proteins Expanded and Merlin to modulate subcellular localization and function of the Hippo kinase cascade. Hippo signaling is also influenced by cytoskeletal networks and cell tension in epithelia of developing organs. These upstream events in the regulation of Hippo signaling are only partially understood. This review focuses on our current understanding of some upstream processes involved in Hippo signaling in developing Drosophila organs. [BMB Reports 2018; 51(3): 134-142]. PMID- 29397873 TI - Blisters Induced by PUVA: A Report of 5 Cases. AB - Blisters associated with PUVA treatments are an adverse effect of photochemotherapy that has been reported in the literature. Asymptomatic blisters appear spontaneously mainly on the lower limbs and resolve without treatment. The differential diagnoses to consider include a phototoxic reaction, pseudoporphyria, and PUVA-induced bullous pemphigoid. We describe the clinical and histologic features in 5 cases of blistering secondary to PUVA treatment. If this adverse effect is accurately diagnosed, photochemotherapy need not be interrupted, and unnecessary diagnostic procedures and additional treatments can be avoided. PMID- 29397874 TI - Prevalence of operator fatigue in winter maintenance operations. AB - Similar to commercial motor vehicle drivers, winter maintenance operators are likely to be at an increased risk of becoming fatigued while driving due to long, inconsistent shifts, environmental stressors, and limited opportunities for sleep. Despite this risk, there is little research concerning the prevalence of winter maintenance operator fatigue during winter emergencies. The purpose of this research was to investigate the prevalence, sources, and countermeasures of fatigue in winter maintenance operations. Questionnaires from 1043 winter maintenance operators and 453 managers were received from 29 Clear Road member states. Results confirmed that fatigue was prevalent in winter maintenance operations. Over 70% of the operators and managers believed that fatigue has a moderate to significant impact on winter maintenance operations. Approximately 75% of winter maintenance operators reported to at least sometimes drive while fatigued, and 96% of managers believed their winter maintenance operators drove while fatigued at least some of the time. Furthermore, winter maintenance operators and managers identified fatigue countermeasures and sources of fatigue related to winter maintenance equipment. However, the countermeasures believed to be the most effective at reducing fatigue during winter emergencies (i.e., naps) were underutilized. For example, winter maintenance operators reported to never use naps to eliminate fatigue. These results indicated winter maintenance operations are impacted by operator fatigue. These results support the increased need for research and effective countermeasures targeting winter maintenance operator fatigue. PMID- 29397875 TI - How shift scheduling practices contribute to fatigue amongst freight rail operating employees: Findings from Canadian accident investigations. AB - Canada's freight rail system moves 70% of the country's surface goods and almost half of all exports (RAC, 2016). These include dangerous goods. Anonymous survey of freight rail operating employees conducted by the Teamsters Canada Rail Conference (TCRC, 2014) revealed that many do not report getting enough sleep because of their work schedules, and that fatigue may be affecting their performance at work. Besides general impairments in attention and cognitive functioning, fatigue in railway operating employees slows reaction time to safety alarms and impairs conformance to train operating requirements. Shift scheduling practices can contribute to sleep-related fatigue by restricting sleep opportunities, requiring extended periods of wakefulness and by disrupting daily (circadian) rhythms. The primary goal of accident investigation is to identify causal and contributing factors so that similar occurrences can be prevented. A database search of Transportation Safety Board (TSB) rail investigation reports published in the 21-year period from 1995 to 2015 identified 18 that cited sleep related fatigue of freight rail operating employees as a causal, contributing, or risk finding. This number represents about 20% of TSB rail investigations from the same period in which a human factors aspect of freight train activities was a primary cause. Exploration of accident themes suggests that management of fatigue and shift scheduling in the freight rail industry is a complex issue that is often not conducive to employee circadian rhythms and sleep requirements. It also suggests that current shift scheduling and fatigue management practices may be insufficient to mitigate the associated safety risk. Railway fatigue management systems that are based on the principles of modern sleep science are needed to improve scheduling practices and mitigate the ongoing safety risk. PMID- 29397876 TI - How to Follow a Traveler with a Brownian Swagger. PMID- 29397877 TI - Arterial smooth muscle dynamics in development and repair. AB - Arterial vasculature distributes blood from early embryonic development and provides a nutrient highway to maintain tissue viability. Atherosclerosis, peripheral artery diseases, stroke and aortic aneurysm represent the most frequent causes of death and are all directly related to abnormalities in the function of arteries. Vascular intervention techniques have been established for the treatment of all of these pathologies, yet arterial surgery can itself lead to biological changes in which uncontrolled arterial wall cell proliferation leads to restricted blood flow. In this review we describe the intricate cellular composition of arteries, demonstrating how a variety of distinct cell types in the vascular walls regulate the function of arteries. We provide an overview of the developmental origin of arteries and perivascular cells and focus on cellular dynamics in arterial repair. We summarize the current knowledge of the molecular signaling pathways that regulate vascular smooth muscle differentiation in the embryo and in arterial injury response. Our review aims to highlight the similarities as well as differences between cellular and molecular mechanisms that control arterial development and repair. PMID- 29397879 TI - Systematic Second-look Surgery Plus HIPEC in Patients Without Evidence of Recurrence, at High Risk of Carcinomatosis After Colorectal Cancer Resection. AB - INTRODUCTION: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor, in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). METHODS: Between 2012-2016, 33 patients without any sign of peritoneal recurrence on imaging studies were prospectively included in the study and underwent second-look surgery aimed at treating limited PC earlier and were prospectively recorded. They were selected based on 5 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 10), synchronous ovarian metastases (n = 2), positive peritoneal cytology (n = 2), pT4 primary tumors (n = 15) and perforation (n = 4). RESULTS: PC was found and treated by cytoreduction plus HIPEC in 10 of the 33 (30.3%) patients, although it was detected in only 2/15 patients of the pT4 subgroup (13.3%). The patients without PC underwent complete abdominal exploration plus HIPEC. Median follow-up was 14.5 months. One patient died postoperatively at day 55. Severe morbidity rate (Clavien-Dindo III-V) was low (15.2%). The 3-year overall survival rate was 93% and the 3-year disease-free survival rate was 33%. Peritoneal recurrences occurred in 4 patients (12.1%), 2 of whom had macroscopic PC discovered at the second-look (20%), while the other 2 patients had no macroscopic PC (8.7%) (P = .04). CONCLUSIONS: The second look + HIPEC strategy in our series of patients at high risk of developing PC, allows its early detection and its treatment in 30.3% of cases, with a very low rate of peritoneal recurrence. It is important to continue evaluating the results to increase the accuracy of the inclusion criteria, especially the pT4 criterion that in this series has a low predictive power for the occurrence of PC. PMID- 29397878 TI - Neural tube closure depends on expression of Grainyhead-like 3 in multiple tissues. AB - Failure of neural tube closure leads to neural tube defects (NTDs), common congenital abnormalities in humans. Among the genes whose loss of function causes NTDs in mice, Grainyhead-like3 (Grhl3) is essential for spinal neural tube closure, with null mutants exhibiting fully penetrant spina bifida. During spinal neurulation Grhl3 is initially expressed in the surface (non-neural) ectoderm, subsequently in the neuroepithelial component of the neural folds and at the node streak border, and finally in the hindgut endoderm. Here, we show that endoderm specific knockout of Grhl3 causes late-arising spinal NTDs, preceded by increased ventral curvature of the caudal region which was shown previously to suppress closure of the spinal neural folds. This finding supports the hypothesis that diminished Grhl3 expression in the hindgut is the cause of spinal NTDs in the curly tail, carrying a hypomorphic Grhl3 allele. Complete loss of Grhl3 function produces a more severe phenotype in which closure fails earlier in neurulation, before the stage of onset of expression in the hindgut of wild-type embryos. This implicates additional tissues and NTD mechanisms in Grhl3 null embryos. Conditional knockout of Grhl3 in the neural plate and node-streak border has minimal effect on closure, suggesting that abnormal function of surface ectoderm, where Grhl3 transcripts are first detected, is primarily responsible for early failure of spinal neurulation in Grhl3 null embryos. PMID- 29397880 TI - Meta-Analysis Comparing Frequency of Overweight Versus Normal Weight in Patients With New-Onset Heart Failure. AB - Association between obesity and new-onset heart failure (HF) has repeatedly been established. Less is known about the risk of overweight with the development of HF. The aim of this systematic review and meta-analysis was to explore the association between overweight, obesity, and the incidence of new-onset HF. In this study, we systematically searched MEDLINE, MEDLINE In-Process & Other Non Indexed Citations, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from database inception through June 2017. Studies were included if they reported the association between overweight or obesity and new onset HF compared with normal weight. DerSimonian and Laird random effect meta analyses were used, and subgroup analyses were performed to explore the potential sources of heterogeneity. Of 2,184 retrieved articles, we identified 21 relevant studies with a total of 525,656 participants with 18,948 HF cases. Compared with the normal body weight index (body mass index < 25 kg/m2), overweight (body mass index 25 to 29.9 kg/m2) was associated with a 33% higher risk of developing HF (pooled risk ratios 1.33; 95% confidence interval 1.16 to 1.52; p <0.001), with substantial heterogeneity among studies (I2 = 83.6%). In addition, class I, II, and III obesity were stepwise-associated with an increase in the risk of developing HF as 73%, 85% and 189%, respectively (all p <.001) compared with normal weight. In conclusion, compared with healthy normal-weight patients, these results show that both overweight patients were independently associated with a significantly higher incidence of HF. These results highlight the need for a better understanding of the potential mechanisms of overweight and HF. PMID- 29397881 TI - Incidence, Predictors, and Impact on Six-Month Mortality of Three Different Definitions of Contrast-Induced Acute Kidney Injury After Coronary Angiography. AB - We assessed incidence, predictors, and impact on 6-month mortality of contrast induced acute kidney injury (CI-AKI) after coronary angiography with or without percutaneous coronary intervention in patients with acute coronary syndrome (ACS), according to 3 different CI-AKI definitions. Serum creatinine (sCr) was assessed at baseline and 48 to 72 hours after procedure to classify patients into 3 CI-AKI groups: Group 1: increase in sCR >=25% over baseline but absolute increase <0.5 mg/dl; Group 2: absolute increase >=0.5 mg/dl; Group 3: absolute increase >=0.3 mg/dl or >=50% over baseline. The association between CI-AKI and all-cause 6-month mortality was assessed using multivariate Cox regression. Among 1,002 patients included, median age was 68 [57 to 79] years. The sample had the following characteristics: 70% men, 25% diabetics, 22% had a history of myocardial infarction, 21% had baseline estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease) <60 ml/min/1.72 m2, 34% had ST-segment elevation myocardial infarction, 61% underwent percutaneous coronary intervention, and 43% had multivessel disease. Based on changes in sCr, 89 patients (8.9%) were classified in Group 1; 69 (6.9%) in Group 2; and 157 (15.7%) in Group 3, whereas sCr did not increase >25% in the remaining 844 (84.2%). CI-AKI was significantly associated with 6-month all-cause mortality using the definitions for Group 2 (hazard ratio 3.1, 95% confidence interval [CI] 1.5 to 6.6, p = 0.002) and Group 3 (hazard ratio 2.03, 95% CI 1.03 to 4.0, p = 0.04), but not Group 1. In conclusion, based on the definition used for CI-AKI, CI-AKI is observed in 6% to 15.7% of patients. An increase of 25% over baseline sCr does not identify high-risk patients. CI-AKI defined as an increase in sCr >0.3 mg/dl identifies 15.7% of the population at 2-fold higher risk of mortality. PMID- 29397882 TI - Effectiveness of Rescue Percutaneous Balloon Aortic Valvuloplasty in Patients With Severe Aortic Stenosis and Acute Heart Failure. AB - The prognosis of patients with cardiogenic shock (CS) or refractory pulmonary edema because of severe aortic stenosis remains poor. The purpose of this study was to assess the outcomes of rescue percutaneous balloon aortic valvuloplasty (PBAV) in the transcatheter aortic valve implantation (TAVI) era. Patients were consecutively included between 2008 and 2016. CS was defined as >=1 sign of systemic hypoperfusion and need of catecholamines. Refractory pulmonary edema was defined as not controlled by optimal medical treatment. A total of 40 patients, 22 men (55%), aged 79 +/- 9 years, were included: 17 with CS (42.5%), 23 with refractory pulmonary edema (57.5%). After PBAV, mean transaortic gradient decreased from 47 +/- 16 mm Hg to 32 +/- 10 mm Hg (p < 0.001), aortic valve area increased from 0.60 +/- 0.18 cm2 to 0.88 +/- 0.22 cm2 (p < 0.0001), left ventricular ejection fraction increased from 35 +/- 15 to 37 +/- 14% (p = 0.02), and systolic pulmonary artery pressure decreased from 61 +/- 15 to 48 +/- 12 mm Hg (p = 0.002). There was no procedural death. Early death occurred in 12 patients (30%). After PBAV, 16 of the 28 survivors (57%) were bridged to surgical aortic valve replacement (SAVR; n = 7) or TAVI (n = 9), and 12 (43%) were denied definitive therapy. The 2-year estimated survival rate was 71 +/- 17% after SAVR, 36 +/- 19% after TAVI, and 8 +/- 8% after PBAV alone. In conclusion, rescue PBAV is safe in patients with CS and high-risk aortic stenosis or refractory pulmonary edema and may improve their dismal prognosis when followed by TAVI or SAVR. PMID- 29397883 TI - Relation of the Brugada Phenocopy to Hyperkalemia (from the International Registry on Brugada Phenocopy). AB - Brugada phenocopies (BrPs) are clinical entities that differ in etiology from true congenital Brugada syndrome but have identical electrocardiographic (ECG) patterns. Hyperkalemia is known to be one of the causes of BrP. The aim of this study was to determine the clinical characteristics and evolution of hyperkalemia induced BrP. Data from 27 cases of hyperkalemia-induced BrP were collected from the International Registry at www.brugadaphenocopy.com. Data were extracted from publications. Of the 27 patients included in the analysis, 18 (67%) were male; mean age was 53 +/- 15 years (range 31 to 89). Mean serum potassium concentration was 7.45 +/- 0.89 mmol/L. Type-1 Brugada ECG pattern was observed in 21 cases (78%), whereas 6 cases (22%) showed a type-2 Brugada ECG pattern. The Brugada ECG pattern resolved once the hyperkalemia was corrected, with no arrhythmic events. Estimated time to resolution was 7 +/- 3 hours. In 4 cases (16%), a concurrent metabolic abnormality was detected: 3 (11%) presented with acidosis, 2 (7%) with hyponatremia, 1 (4%) with hypocalcaemia, 1 (4%) with hyperphosphatemia, and 1 (4%) with hyperglycemia. In 7 cases (26%), provocative testing using sodium channel blockers was performed, and all failed to reproduce a BrS ECG pattern (BrP class A). Additionally, no sudden cardiac death or malignant ventricular arrhythmias were detected. Hyperkalemia was found a common cause of BrP in our International Registry. The Brugada ECG pattern appears to occur at high serum potassium concentrations (>6.5 mmol/L). The ECG normalizes within hours of correcting the electrolyte imbalance. Importantly, hyperkalemia-induced BrP has not been associated with sudden cardiac death or ventricular arrhythmia. PMID- 29397884 TI - Comparison of Transcatheter Mitral Valve Repair Versus Surgical Mitral Valve Repair in Patients With Advanced Kidney Disease (from the National Inpatient Sample). AB - Transcatheter mitral valve repair (TMVR) is an emerging treatment modality that has been reserved for high-risk patients with multiple co-morbidities. We hypothesize that TMVR is a safe and effective procedure for patients with moderate to severe mitral regurgitation who are not surgical candidates. The National Inpatient Sample (2012 to 2014) using the International Classification of Diseases, 9th Revision, Clinical Modification procedure codes 35.97 for TMVR and 35.12 for surgical mitral valve repair (SMVR) were used. Patients with chronic kidney disease stage IV, Stage V, and end-stage renal disease (ESRD) were considered as patients with advanced kidney disease. A total of 2,123 patients were treated with SMVR and 74 patients were treated with TMVR. There were notably fewer patients treated with TMVR compared with patients treated with SMVR. The mean age was higher with the TMVR group (72.4 vs 61.7 years, p = <0.001). After performing multivariate regression analysis, the primary outcome of in-hospital mortality (13.8% vs 1.3%, adjusted p = 0.003) and all secondary outcomes, excluding dialysis requirement, cardiogenic shock, and cardiac arrest, were significantly lower with the TMVR approach. The average length of stay was lower with TMVR compared with SMVR (22.8 vs 12.6 days, adjusted p = <0.001), with reduced in-hospital costs ($98,165 vs $52,646, adjusted p = <0.001). This large, national study suggests TMVR is associated with significantly lower in-patient morbidity and mortality, with significant cost savings in patients with advanced kidney disease compared with SMVR. Hence, TMVR could be a safe and effective alternative for patients with advanced kidney disease who are not surgical candidates. PMID- 29397885 TI - Relation of Age and Health-Related Quality of Life to Invasive Versus Ischemia Guided Management of Patients with Non-ST Elevation Myocardial Infarction. AB - In older patients with non-ST-elevation myocardial infarction, an initial invasive strategy reduces cardiovascular events compared with an ischemia-guided approach; however its association with health status outcomes is unknown. Among patients with non-ST-elevation myocardial infarction from 2 multicenter US acute myocardial infarction (AMI) registries, health status was assessed at baseline and at 1, 6, and 12 months after AMI using the Seattle Angina Questionnaire (SAQ) and the 12-item Short-Form Health Survey (SF-12). Routine invasive management was defined as coronary angiography within 72 hours of admission without a preceding stress test. Among 3,559 patients with NSTEMI, 2,455 (69.0%) were treated with routine invasive treatment, which was more common in younger patients. In propensity-adjusted analyses, invasive treatment was associated with higher SAQ physical limitation, angina frequency, and summary scores over the year after AMI; however, the differences were small (<5 points, all p <0.05). Although there was a trend toward worse health status in patients aged >=85 years treated with an initial invasive treatment, the interaction between age and treatment for any health status measure (all p >=0.09) was not significant, except for SF-12 physical component score (p = 0.02), where worse scores were observed with invasive treatment in patients 85 years or older. In conclusion, an initial invasive treatment for patients with NSTEMI is associated with a small benefit in health status of marginal clinical significance, mainly in younger patients. The oldest old group trended toward less health status benefit from a routine invasive strategy-results that will need to be confirmed in a larger study. PMID- 29397886 TI - In response to the article entitled "The Parkland grading scale for cholecystitis" by Madni et al. In Madni TD, Leshikar DE, Minshall CT, Nakonezny PA, Cornelius CC, Imran JB, Clark AT, Williams BH, Eastman AL, Minei JP, Phelan HA. The Parkland grading scale for cholecystitis. In Am J Surg; 2017 Jun 6. doi.org/10.1016/j.amjsurg.2017.05.017. PMID- 29397887 TI - Ten-year trends in traumatic injury mechanisms and outcomes: A trauma registry analysis. AB - BACKGROUND: The Oklahoma Trauma Registry (OTR) collects data from all state licensed acute care hospitals. This study investigates trends and outcomes of trauma in Oklahoma using OTR. METHODS: 107,549 patients (2005-2014) with major severity and one of the following criteria were included: length of hospital stay >=48 h, dead on arrival or death in the hospital, hospital transfer, ICU admission, or surgery on the head, chest, abdomen, or vascular system. Patient characteristics, mechanisms of injury, and outcomes of trauma were analyzed. RESULTS: Hospital admissions due to falls increased with an annual percent change of 4.0% (95%CI: 3.1%-4.9%) while hospital admissions due to motor vehicle crashes decreased. The number of overall deaths per year remained stable except for the fall-related deaths, which increased proportionate to the increase in the incidence of fall. Fall-related mortality was 4.2% and intracranial bleeding was present in 60% in these patients. CONCLUSION: Falls are significantly increasing as a mechanism of trauma admissions and trauma-related deaths in Oklahoma. Analysis of state-based trauma registries can identify trends in etiologies of injuries and may indicate a reference point to prioritize preventive plans. PMID- 29397888 TI - Patients with sentinel lymph node positive melanoma: Who needs completion lymph node dissection? AB - INTRODUCTION: Completion lymph node dissection (CLND) for melanoma after positive sentinel lymph node biopsy (SLNB) was recently shown to improve regional but not overall survival, likely due to the majority of patients harboring no further nodal disease. We sought to determine predictors of non-sentinel node (NSN) positivity. METHODS: Retrospective review of prospectively collected data on melanoma patients undergoing SLNB. RESULTS: 116 patients underwent 119 CLNDs. The incidence of NSN positivity was 17.6%; the average number of positive NSNs in those cases was 1.5. Cervical and inguinofemoral location were most likely to yield positive NSN(s) (40% each). Conversely, the axilla was least likely at 18% (p < 0.001). The average number of nodes harvested was 13 for NSN negative cases and 20 for NSN positive cases (p = 0.005). Tumor thickness increased the probability of positive NSN(s) (OR 1.2, p = 0.02). CONCLUSIONS: Tumor thickness and nodal basin were predictors of NSN metastasis, factors that could help determine which patients may benefit from CLND. Further, CLNDs with fewer nodes may inadequately clear residual nodal disease. PMID- 29397889 TI - Routine shave margins are not necessary in early stage breast cancer treated with Breast Conserving Surgery. AB - INTRODUCTION: Breast Conserving Surgery (BCS) is considered standard of care for women with early stage breast cancer. Between 20 and 50% of women treated with BCS will require re-operation for positive or close margins and it has been suggested that routine cavity shave margins may reduce the frequency of positive margins. METHODS: Retrospective chart review of a prospectively maintained surgical database of patients undergoing BCS for early stage breast cancer, at a single institution, between January 2012 and December 2015. Cohort was followed until June 2016 to capture re-operations. RESULTS: Among 2096 patients with stage 0-III breast cancers, 872 (42%) underwent primary mastectomies and 1224 (58%) underwent primary BCS. Margins were positive in 128 (11%) and close in 442 (36%). Re-operation rate for patients after BCS was 19%. CONCLUSION: A lower than predicted positive margin rate suggests that routine shave margins are not warranted at our institution. PMID- 29397891 TI - Modified Appleby procedure for locally advanced pancreatic cancer. AB - Locally advanced pancreas cancer (LAPC) involving the celiac axis is typically considered unresectable and carries a poor prognosis. We present a case of a patient with LAPC who underwent a modified Appleby procedure for tumor clearance following neoadjuvant therapy. Technical aspects include diagnostic laparoscopy to exclude occult metastatic disease followed by complete mobilization of the pancreas and spleen, preservation of the left gastric artery, and resection and reconstruction of the common hepatic artery. With proper patient selection and preparation, LAPC with celiac axis involvement can be safely resected with favorable outcomes. PMID- 29397890 TI - Risk factors associated with missing post-esophagectomy hospital milestones. AB - BACKGROUND: Our institution utilizes an esophagectomy pathway to guide postoperative management. Our aim was to identify risk factors associated with missing pathway goals. METHODS: Retrospective review of esophagectomies from 2010 to 2015. Multivariate logistic regression models identified risk factors for missing postoperative milestones prior to discharge. Odds ratios of variables affecting goals were calculated. RESULTS: Of the195 esophagectomies, the most common risk factor for missing milestones was BMI, followed by operating room time, clinical stage, tobacco pack-years, and open surgical approach. Missing any milestone on the expected postoperative day significantly increase the odds of missing a future milestone, regardless of other risk factors. CONCLUSIONS: We have identified specific patient and operative factors that increase the risk of missing post-esophagectomy goals on time. Early identification of at-risk patients allows for pathway modification to avoid adverse outcomes and prolonged hospitalization. Analysis of meeting milestones early may allow for creation of accelerated pathways. PMID- 29397892 TI - Discussion of "Evaluation of a novel thoracic entry device versus needle decompression in a tension pneumothorax swine model". PMID- 29397893 TI - Response to the Discussion of "Open abdomen in liver transplantation". PMID- 29397894 TI - Prophylactic use of alpha-1 adrenergic blocking agents for prevention of postoperative urinary retention: A review & meta-analysis of randomized clinical trials. AB - BACKGROUND: Alpha-1 adrenergic blockers used to treat postoperative urinary retention (POUR) may also have a preventative role. Here we assess the evidence behind their prophylactic use on POUR prevention. STUDY DESIGN: PRISMA guidelines were followed. All studies reviewed for eligibility, data extraction, and risk of bias assessment. Pooled risk ratios with 95% confidence intervals calculated using a random effects model. Heterogeneity assessed using Forest plots, I2 statistic and Chi-squared Cochran's Q-statistic. RESULTS: Fifteen RCTs (1732 patients) included. Prophylactic alpha-1 adrenergic blockers significantly reduced risk of POUR, 13.16% vs 30.24%, RR = 0.48 (95%CI: 0.33; 0.70, p-value = .001), without a statistically significant increase in adverse events. Substantial heterogeneity found between included studies (I2 = 65.49% [95%CI:48.49; 95.01] & Q-statistic 43.46 (p-value<.001)). Subgroup analysis revealed strong risk reduction and little heterogeneity in males (RR:0.33, 95%CI:0.23; 0.47, p-value<.001, I2:10.58) and patients receiving spinal anesthesia (RR:0.26, 95%CI:0.14; 0.46, p-value<.0001, I2 = 0%). CONCLUSION: Prophylactic alpha-1 adrenergic blockers reduce risk of POUR in males and after spinal anesthesia. PMID- 29397895 TI - The evolving role of pre-pectoral ADM-assisted implant-based immediate breast reconstruction following skin-sparing mastectomy. AB - INTRODUCTION: The increasing use of acellular dermal matrix (ADM) and fat transfer in the context of breast reconstruction, following skin sparing mastectomy (SSM) for therapeutic and risk reducing purposes, combined with the need to eliminate animation deformities, reduce post-operative dysfunctional pain and the risk of capsular contracture, has prompted surgeons to investigate the possibility of placing the mammary implant over the pectoralis major muscle with complete coverage with ADM thus reviving the pre-pectoral approach which was previously abandoned due to high complications rates and poor aesthetics in the pre-ADM era. METHODS: We reviewed the literature regarding this evolving technique of muscle sparing ADM-assisted implant-based immediate breast reconstruction. RESULTS AND CONCLUSIONS: Several authors have recently reported positive early results confirming the potential benefits of eliminating breast animation and reducing postoperative pain, however, most of these reports contain insufficient numbers of patients (<100) and were retrospective in nature with a very short-term follow-up and lack of data regarding objective aesthetic assessment. Prospective data are required for more definitive recommendations. PMID- 29397896 TI - Single-incision laparoscopy versus standard laparoscopy for colorectal surgery: A systematic review and meta-analysis. PMID- 29397897 TI - Tele-mentored damage-control and emergency trauma surgery: A feasibility study using live-tissue models. AB - BACKGROUND: Damage-control and emergency surgical procedures in trauma have the potential to save lives. They may occasionally not be performed due to clinician inexperience or lack of comfort and knowledge. METHODS: Canadian Armed Forces (CAF) non-surgeon Medical Officers (MOs) participated in a live tissue training exercise. They received tele-mentoring assistance using a secure video conferencing application on a smartphone/tablet platform. Feasibility of tele mentored surgery was studied by measuring their effectiveness at completing a set series of tasks in this pilot study. Additionally, their comfort and willingness to perform studied procedures was gauged using pre- and post-study surveys. RESULTS: With no pre-procedural teaching, participants were able to complete surgical airway, chest tube insertion and resuscitative thoracotomy with 100% effectiveness with no noted complications. Comfort level and willingness to perform these procedures were improved with tele-mentoring. Participants felt that tele-mentored surgery would benefit their performance of resuscitative thoracotomy most. CONCLUSION: The use of tele-mentored surgery to assist non surgeon clinicians in the performance of damage-control and emergency surgical procedures is feasible. More study is required to validate its effectiveness. PMID- 29397898 TI - Outcomes in complex ventral hernia repair with anterior component separation in class III obesity patients. AB - BACKGROUND: Consensus guidelines recommend against elective ventral hernia repair (VHR) in patients with BMI >30 kg/m2 without preoperative weight loss intervention. We aim to compare hernia recurrence and perioperative complications in VHR utilizing anterior component separation (CS) in patients with class III obesity (BMI >40 kg/m2). METHODS: A retrospective review of patients undergoing VHR with CS was performed. The primary endpoint was hernia recurrence; secondary endpoints were wound complications, postoperative medical complications, mortality and length of stay. RESULTS: 185 consecutive patients were identified from 2008 to 2016. There were no significant differences between groups: hernia recurrence (6.9% BMI >40 kg/m2, 2.4% BMI <39.9 kg/m2, p = 0.21), wound complications (58.6% BMI >40 kg/m2, 47.2% BMI <39.9 kg/m2, p = 0.16), postoperative complications (39.7% BMI >40 kg/m2, 26% BMI <39.9 kg/m2, p = 0.08), mortality (1.6% BMI >40 kg/m2, 3.4% BMI <39.9 kg/m2, p = 0.59), and length of stay (10.6 days BMI >40 kg/m2, 11.2 days BMI <39.9 kg/m2, p = 0.5). CONCLUSION: This study demonstrates similar outcomes in class III obesity patients undergoing elective VHR compared to patients with BMI <39.9 kg/m2. PMID- 29397899 TI - Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks' add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured. RESULTS: Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group. CONCLUSIONS: Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia. PMID- 29397900 TI - Neural Mechanisms of Early-Life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders. AB - BACKGROUND: To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. METHODS: We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. RESULTS: Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. CONCLUSIONS: Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans. PMID- 29397901 TI - Transcription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing. AB - BACKGROUND: Lasting changes in gene expression in brain reward regions, including nucleus accumbens (NAc), contribute to persistent functional changes in the addicted brain. We and others have demonstrated that altered expression of several candidate transcription factors in NAc regulates drug responses. A recent large-scale genome-wide study from our group predicted transcription factor E2F3 (E2F3) as a prominent upstream regulator of cocaine-induced changes in gene expression and alternative splicing. METHODS: We studied expression of two E2F3 isoforms-E2F3a and E2F3b-in mouse NAc after repeated cocaine administration and assayed the effects of overexpression or depletion of E2f3 isoforms in NAc on cocaine behavioral responses. We then performed RNA sequencing to investigate the effect of E2f3a overexpression in this region on gene expression and alternative splicing and performed quantitative chromatin immunoprecipitation at downstream targets in NAc following E2f3a overexpression or repeated cocaine exposure. Sample sizes varied between experiments and are noted in the text. RESULTS: We showed that E2f3a, but not E2f3b, overexpression or knockdown in mouse NAc regulates cocaine-induced locomotor and place conditioning behavior. Furthermore, we demonstrated that E2f3a overexpression substantially recapitulates genome-wide transcriptional profiles and alternative splicing induced by cocaine. We further validated direct binding of E2F3a at key target genes following cocaine exposure. CONCLUSIONS: This study establishes E2F3a as a novel transcriptional regulator of cocaine action in NAc. The findings reveal a crucial role for E2F3a in the regulation of cocaine-elicited behavioral states. Moreover, the importance of this role is bolstered by the extensive recapitulation of cocaine's transcriptional effects in NAc by overexpression of E2f3a. PMID- 29397903 TI - Lymph node macrophages: Scavengers, immune sentinels and trophic effectors. AB - Lymph nodes (LN) are secondary lymphoid organs dispersed throughout the body that filter lymph and assist the immune system in mounting immune responses. These functions are supported by a complex stromal microarchitecture composed of mesenchymal and vascular elements. Different subsets of macrophages (MPhi) reside in the LN and are endowed with immune and trophic functions. Here we review these different subsets with particular emphasis on the recently described T cell zone MPhi. We also address the potential crosstalk between LN stromal cells and MPhi, proposing that the former constitute niches for the latter by supplying factors required for their specification, survival and turnover. In turn, MPhi could inform their stromal partners about the immune status of the LN and orchestrate the remodelling of its microanatomy during immune responses. PMID- 29397904 TI - MIF promotes a differential Th1/Th2/Th17 inflammatory response in human primary cell cultures: Predominance of Th17 cytokine profile in PBMC from healthy subjects and increase of IL-6 and TNF-alpha in PBMC from active SLE patients. AB - Macrophage migration Inhibitory Factor (MIF) is a cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive-feedback-loop with proinflammatory cytokines and could perpetuate the inflammatory process in Systemic Lupus Erythematosus (SLE).The aim of this study was to assess the effect of recombinant-human-MIF (rhMIF) on the expression of Th1, Th2 and Th17 cytokines in Peripheral Blood Mononuclear Cells (PBMC) from Healthy Subjects (HS) and SLE patients. The PBMC were isolated from SLE patients classified according to the 1997 SLE ACR criteria and HS donors; all subjects included were women from an unrelated Mexican-Mestizo population. The PBMC isolated were stimulated with rhMIF, LPS and ISO-1 in different combinations; Th1, Th2 and Th17cytokine profiles levels were determined by MAGPIX Bio-plex assay in supernatants from cell cultures. We observed in supernatants of PBMCs from HS treated with rhMIF a predominance of Th17 cytokine profile with an increase of IL-17A, IL-17F and IL-21 versus PBMCs from SLE patients, which showed an inflammatory profile represented by increase of IL-6 cytokine. According to SLE remission/activity presented at enrollment in the study (Mex-SLEDAI index), the PBMC from active SLE patients showed higher levels of TNF-alpha and IL-6 versus PBMC from remission SLE patients. In conclusion, our results suggest that MIF can induce a differential inflammatory response in physiological and pathological conditions with a predominance of a Th17 cytokine profile in PBMC from HS and an increase in TNF-alpha and IL-6 expression in PBMC from active SLE patients. PMID- 29397906 TI - December 2017 (vol. 217, no. 6, page 682). PMID- 29397902 TI - Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving. AB - BACKGROUND: Methamphetamine (meth) seeking progressively increases after withdrawal (incubation of meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in the rat dorsal striatum and incubation of meth craving. Here we used viral constructs to study the causal role of dorsal striatum HDAC5 in this incubation. METHODS: In experiment 1 (overexpression), we injected an adeno-associated virus bilaterally into dorsal striatum to express either green fluorescent protein (control) or a mutant form of HDAC5, which strongly localized to the nucleus. After training rats to self-administer meth (10 days, 9 hours/day), we tested the rats for relapse to meth seeking on withdrawal days 2 and 30. In experiment 2 (knockdown), we injected an adeno-associated virus bilaterally into the dorsal striatum to express a short hairpin RNA either against luciferase (control) or against HDAC5. After training rats to self-administer meth, we tested the rats for relapse on withdrawal days 2 and 30. We also measured gene expression of other HDACs and potential HDAC5 downstream targets. RESULTS: We found that HDAC5 overexpression in dorsal striatum increased meth seeking on withdrawal day 30 but not day 2. In contrast, HDAC5 knockdown in the dorsal striatum decreased meth seeking on withdrawal day 30 but not on day 2; this manipulation also altered other HDACs (Hdac1 and Hdac4) and potential HDAC5 targets (Gnb4 and Suv39h1). CONCLUSIONS: Results demonstrate a novel role of dorsal striatum HDAC5 in incubation of meth craving. These findings also set up future work to identify HDAC5 targets that mediate this incubation. PMID- 29397905 TI - C5a receptor targeting of partial non-structural protein 3 of dengue virus promotes antigen-specific IFN-gamma-producing T-cell responses in a mucosal dengue vaccine model. AB - Mucosal vaccination is an ideal strategy to induce protective immunity in both mucosal and parenteral areas. Successful induction of an antigen-specific immune response via mucosal administration essentially requires the effective delivery of antigen into a mucosal immune inductive site, which depends on antigen delivery into M cells. We previously reported that M cells specifically express C5aR, and antigen targeting to C5aR by using specific ligands, including Co1 peptide, promotes the antigen-specific immune response in both mucosal and systemic immune compartments. In this study, we found that application of the Co1 peptide to dengue virus antigen containing CD8 T cell epitopes effectively induced an antigen-specific IFN-gamma-producing CD8+ T cell response after oral mucosal administration of antigen. Consequently, we suggest that Co1 peptide mediated C5aR targeting of antigen into M cells can be used for the induction of an effective antigen-specific CD8+ T cell immune response in oral mucosal vaccine development. PMID- 29397907 TI - November 2017 (vol. 217, no. 5, page 586). PMID- 29397908 TI - October 2017 (vol. 217, no. 4, page B22). PMID- 29397909 TI - September 2017 (vol. 217, no. 3, page 346.e5). PMID- 29397910 TI - The importance of nutritional status in heart failure. PMID- 29397911 TI - Feasibility of a streamlined imaging protocol in technetium-99m-Tektrotyd somatostatin receptor SPECT/CT. AB - AIM: To assess the feasibility and efficacy of a streamlined single time-point 99mTc-HYNIC-Tyr3-octreotide (Tektrotyd) somatostatin receptor scintigraphy (SRS) protocol to differentiate pathological uptake by neuroendocrine tumours (NETs) from physiological activity. METHODS AND MATERIALS: Tektrotyd imaging in 50 consecutive patients with NETs was reviewed retrospectively. Imaging was independently assessed by two experienced reporters with dual-certification in radiology and nuclear medicine and agreed in consensus. The presence of physiological bowel activity and/or further sites of equivocal uptake on 4-hour planar imaging and whether combined single-photon-emission computed tomography (SPECT)/computed tomography (CT) assessment allowed accurate diagnosis was tabulated. A judgement was also made in each case on whether 2-hour planar imaging was necessary for accurate diagnostic interpretation. RESULTS: Thirty-six patients (72%) had positive findings on Tektrotyd SPECT/CT. Eight patients (16%) had bowel activity on 4-hour planar imaging, which could be considered to have hampered interpretation without access to SPECT/CT. Eleven studies in 10 patients (20%) demonstrated areas of indeterminate uptake on planar imaging; five in the uncinate process of the pancreas, three in the nasal cavity or paranasal sinuses, one in the adrenal glands, one in a focus of inflammation on the posterior abdominal wall, and one at the tip of a central venous line. In all cases, accurate interpretation of findings was possible with SPECT/CT, without the 2 hour planar image. CONCLUSION: Two-hour planar imaging could be safely omitted from Tektrotyd SRS incorporating SPECT/CT imaging without reducing the accuracy of diagnostic interpretation. Streamlined imaging has the potential to reduce patient inconvenience and improve scanner and staff efficiency. PMID- 29397912 TI - Selective duodenography for controlled first-pass bolus distention of the duodenum in neonates and young children with bile-stained vomiting. AB - AIM: To compare "selective duodenograms" performed through nasogastric tubes advanced into the proximal duodenum against traditional contrast studies regarding visualisation of a first-pass bolus distention of the duodenum and frequency of inconclusive results. MATERIALS AND METHODS: Retrospective comparison of "selective duodenograms" and traditional upper gastrointestinal contrast studies in neonates with bile-stained vomiting, regarding demonstration of the duodenal C-loop, first-pass bolus capture, degree of distention of the duodenum, and number of inconclusive studies. Statistical comparison was performed using the two-tailed Fishers exact and chi-squared tests. RESULTS: There were 31 "selective duodenograms" and 70 traditional studies. The C-loop was demonstrated in 93% of traditional studies versus 100% in "selective duodenograms" and was demonstrated significantly more often during the first-pass (94% versus 73%; p=0.018) and more often with distention of the duodenum for "selective duodenography" (94% versus 56%, p<0.001). There were more inconclusive traditional studies (7% versus 3%; non-significant). CONCLUSION: Emergency upper gastrointestinal tract studies performed in neonates using the "selective duodenogram" technique demonstrated the duodenum with 100% success, with significantly more frequent first-pass bolus visualisation and duodenal distention than traditional studies. The five (7%) inconclusive traditional studies, present a significant diagnostic conundrum in the emergency setting because emergency surgery must be contemplated without proof. PMID- 29397913 TI - CT quantitative parameters to predict the invasiveness of lung pure ground-glass nodules (pGGNs). AB - AIM: To investigate the value of computed tomography (CT) quantitative parameters in predicting the invasiveness of lung pure ground-glass nodules (pGGNs). MATERIALS AND METHODS: Chest CT images and pathological findings of 163 pGGNs in 154 consecutive patients were reviewed. According to the clinical management strategies, cases were divided into pre-invasive and MIA groups (atypical adenomatous hyperplasia [AAH], adenocarcinoma in situ [AIS], and minimally invasive adenocarcinoma [MIA]) and invasive group (invasive adenocarcinoma [IAC]). CT quantitative parameters including maximum diameter, largest diameter perpendicular to the maximum diameter, maximum cross-sectional area, volume, mass, and mean attenuation value were measured and compared between two groups. Their diagnostic performances were evaluated using receiver operating characteristic (ROC) and logistic regression analysis. RESULTS: Significant differences existed for all the CT quantitative parameters in both groups (p<0.01). The values of area under the curve (AUC) were 0.783 of maximum diameter (95% CI: 0.711-0.843), 0.779 of longest diameter perpendicular to maximum diameter (95% CI: 0.707-0.840), 0.796 of largest cross-sectional area (95% CI: 0.726-0.855), 0.781 of volume (95% CI: 0.710-0.842), 0.794 of mass (95% CI: 0.722 0.865) and 0.625 of mean attenuation value (95% CI: 0.546-0.700), respectively. A pairwise-manner comparison showed the AUC of mean attenuation value was the smallest (p<0.01). Logistic regression analysis showed the largest cross sectional area (OR=2.307, 95% CI: 1.689-3.150) was the independent predictor for IAC with a cut-off value of 2.22 cm2. CONCLUSIONS: CT quantitative parameters could predict the invasiveness of lung pGGNs. The largest cross-sectional area is the most valuable independent predictor and the mean attenuation value is less valuable. PMID- 29397914 TI - Non-interpretive radiology: an Irish perspective. AB - AIM: To describe and quantify the range of non-interpretive tasks engaged in by consultant radiologists in Ireland today. MATERIALS AND METHODS: A multiple choice electronic survey was circulated to over 200 Irish consultant radiologists and results were analysed. RESULTS: Responses were received from approximately 40% of the 267 full-time equivalent consultants in Ireland at the time of the survey. There was a wide sub-specialty mix, and responses from both clinical directors and those without designated administrative responsibility. Overall, the three most time-consuming activities were reported to be multidisciplinary meetings, vetting, and informal consultations. Non-interpretive tasks were estimated to account for 35% of the working week, with higher figures (up to 60%) for clinical directors. CONCLUSION: Consultant radiologists in Ireland spend a significant proportion of their time engaged in non-interpretive radiology; acknowledgement and scheduling of non-interpretive tasks will need to be supported by appropriate workforce planning. Non-interpretive skills will also need to be addressed during training to adequately prepare trainees for the reality of the workplace. PMID- 29397915 TI - [Gastrointestinal stromal tumors (GIST): The particularities aspects in African countries]. PMID- 29397917 TI - [Economic analysis of multinational clinical trials in oncology]. AB - In oncology, as in other fields of medicine, international multicentre clinical trials came into being so as to include a sufficient number of subjects to investigate a clinical situation. The existence of tight budgetary constraints and the desire to make the best use of the resources available have resulted in the development of economic evaluations associated with these trials, which, thanks to their level of evidence and their size, provide particularly relevant material. Nonetheless, economic evaluations alongside international clinical trials raise specific questions of methodology with regard to both the design and the analysis of the results. Indeed, the costs of goods and services consumed, the types and quantities of resources, and medical practices vary from one country to another and within an individual country. Economic data from the different countries involved must be available so as to study and to take into account this variability, and appropriate techniques for cost estimations and analysis must be implemented to aggregate the results from several countries. From a review of the literature, the aim of this work was to provide an overview of the specific methodological features of economic evaluations alongside international clinical trials: analysis of efficacy data from several countries, collection of resources and real costs, methods to establish the monetary value of resources, methods to aggregate results accounting for the trial effect. PMID- 29397918 TI - [Erratum to: "Reconstruction following shoulder resection for bone tumor" [Bull. Cancer 101 (2014) 951-957]]. PMID- 29397916 TI - [Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumors: Guidelines from the French national network dedicated to rare gynaecological cancer]. AB - INTRODUCTION: Rare ovarian tumors include complex borderline ovarian tumors, sex cord tumors, germ cell tumors, and rare epithelial tumors. Indications and modalities of fertility preservation, infertility management and contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and of experts in reproductive medicine and gynaecology have worked on guidelines about fertility preservation, contraception and menopause hormone therapy in women treated for ovarian rare tumors. METHODS: A panel of 39 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review, and then rated through two successive rounds. RESULTS: Thirty-five recommendations were selected, and concerned indications for fertility preservation, contraindications for ovarian stimulation (in the context of fertility preservation or for infertility management), contraceptive options (especially hormonal ones), and menopause hormone therapy for each tumor type. Overall, prudence has been recommended in the case of potentially hormone-sensitive tumors such as sex cord tumors, serous and endometrioid low-grade adenocarcinomas, as well as for high risk serous borderline ovarian tumors. DISCUSSION: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients. PMID- 29397919 TI - Assessment of slow wave propagation in multichannel electrogastrography by using noise-assisted multivariate empirical mode decomposition and cross-covariance analysis. AB - Electrogastrography (EGG) is a noninvasive technique for recording the myoelectrical activity of the stomach. An electrogastrographic signal recorded by using a four-channel system with electrodes placed on the surface of the skin is a mixture of a low-frequency gastric pacesetter potential known as a slow wave, electrical activity from other organs, and random noise. The aim of this work was to investigate the possibility of detecting the propagation of the gastric slow wave from multichannel EGG data. Noise-assisted multivariate empirical mode decomposition (NA-MEMD) and cross-covariance analysis (CCA) are proposed as new detection tools. NA-MEMD was applied to attenuate the noise and extract the EGG signal from four channels, while CCA was performed to assess the time shift between the EGG signal channels. Validation of the method was performed using synthetic EGG signals and the methodology was tested on four young, healthy adults. After validation, the proposed method was applied for two kinds of human EGG data: 10-min (short) EGG data from the preprandial phase and 90-120-min (long) EGG data from the preprandial phase as well as the postprandial phase. The results obtained for both synthetic and human EGG data confirm that the proposed method could be a useful tool for assessing the propagation of slow waves. The time shift calculation from the preprandial phase of the EGG examination yielded more consistent results than the postprandial phase. The mean value of the slow wave time lag between neighbouring channels for synthetic data was found to be 4.99+/-0.47 s. In addition, it was confirmed that the proposed method, that is, NA-MEMD and CCA together, are robust to noise. PMID- 29397920 TI - [Review of patient-specific instrumentation for total knee prosthesis]. AB - OBJECTIVES: Single use patient-specific instruments (PSI) for total knee prosthesis are introduced as a new alternative to conventional ancillaries and computer assisted surgery by improving implants positioning. An exhaustive review was carried out to identify their specific characteristics, with their advantages and disadvantages. METHODS: Medical devices suppliers were consulted in 2015 for reviewing their PSI. Their technical, clinical and economic data were compared. The results had been submitted to an orthopaedics expert commission of our university hospital for clinical and financial opinion. RESULTS: Ten companies have provided the documentation for the analysis. PSI are manufactured by suppliers using a three dimensional printing method based on CT scans or MRI images. PSI are produced according to the surgeon's preferences after a preliminary data check, which can be performed by the suppliers' engineers, the surgeon and automatic calculation. Five suppliers can produce sterile PSI with optional delivery of 3D bone models. According to the experts, the studies failed to demonstrate the superiority of a PSI or hospital economic gain. The prices listed remain high and operating room time is not always significantly reduced. CONCLUSIONS: With the development of personalized medicine, the role of PSI grows in importance. They facilitate the surgeon's work by fully respecting the anatomy. These systems offer an interesting perspective in their technical and pedagogical aspects. But it seems premature to take them into routine use given the low number of high-level studies that were currently done. PMID- 29397921 TI - High-capacity ice-recrystallization endpoint assay employing superhydrophobic coatings that is equivalent to the 'splat' assay. AB - We have developed an ice recrystallization inhibition (IRI) assay system that allows the side-by-side comparison of up to a dozen samples treated in an identical manner. This system is ideal for determining, by serial dilution, the IRI 'endpoint' where the concentration of a sample is reached that can no longer inhibit recrystallization. Samples can be an order of magnitude smaller in volume (<1 MUL) than those used for the conventional 'splat' assay. The samples are pipetted into wells cut out of a superhydrophobic coating on sapphire slides that are covered with a second slide and then snap-frozen in liquid nitrogen. Sapphire is greatly superior to glass in its ability to cool quickly without cracking. As a consequence, the samples freeze evenly as a multi-crystalline mass. The ice grain size is slightly larger than that obtained by the 'splat' assay but can be followed sufficiently well to assess IRI activity by changes in mean grain boundary size. The slides can be washed in detergent and reused with no carryover of IRI activity even from the highest protein concentrations. PMID- 29397922 TI - The effects of different preservation methods on ide (Leuciscus idus) sperm and the longevity of sperm movement. AB - The present study investigated the effects of chilled storage and cryopreservation on ide sperm motility and fertilizing capacity alongside the longevity of sperm movement. The parameters of motility (progressive motility pMOT, curvilinear velocity-VCL and straightness-STR) have been recorded during 48 h of chilled storage (4 degrees C) at 24-h intervals. The longevity of sperm movement was measured following activation for up to 120 s (in a range at 10-120 s) in freshly stripped and thawed sperm. A formerly established cryopreservation method was tested on ide sperm where motility parameters, hatching rate and larval malformation (according to 7 category groups) were investigated. Significant decrement of pMOT has already been observed after 24 h (6 +/- 5%) compared to the freshly stripped sperm (49 +/- 22%). pMOT and STR showed no significant changes for up to 120 s following activation in fresh sperm, whereas VCL showed significant difference between 10 (51 +/- 11 MUm/s), 90 (33 +/- 3 MUm/s) and 120 (31 +/- 4 MUm/s) seconds as well as between 20 (48 +/- 12 MUm/s), and 120 s. No negative effect of cryopreservation was recorded on pMOT (fresh: 49 +/- 19%, cryopreserved: 22 +/- 22%), VCL (fresh: 45 +/- 9 MUm/s and cryopreserved: 57 +/- 5 MUm/s), STR (fresh: 81 +/- 3% and cryopreserved: 92 +/- 1%) hatching rate (fresh: 22 +/- 15%, cryopreserved: 33 +/- 18%) or larval malformation (fresh: 12 +/- 4%, cryopreserved: 12 +/- 4%). No significant correlation was found between the three motility parameters and hatching rate. Cryopreservation had no effect on hatching and the prevalence of larval deformity. Furthermore craniofacial and eye deformities were characteristic in the group originating from fertilization with cryopreserved sperm, while edemas (pericardial, yolk) occurred more frequently in the control. The formerly developed cryopreservation protocol (method for cyprinids) was applicable to ide sperm. PMID- 29397923 TI - Improved cryosurvival of stallion spermatozoa after colloid centrifugation is independent of the addition of seminal plasma. AB - Addition of seminal plasma (SP) prior to cryopreservation may influence stallion sperm cryosurvival. The objective of this study was to investigate the addition of pooled SP from "good" or "bad" freezer stallions to spermatozoa selected by single layer centrifugation (SLC) prior to cryopreservation on post-thaw sperm quality. Semen from 12 stallions was collected; 5 mL was frozen as control (C) and the remainder was processed by SLC to remove SP and was divided into three aliquots: i) SLC sample without SP (SLC); ii) SLC plus pooled SP from "good freezer" stallions (SLC-GF); iii) SLC plus pooled SP from "bad freezer" stallions (SLC-BF). After thawing, the following parameters were evaluated: chromatin integrity (DNA fragmentation index; %DFI), mitochondrial membrane potential (MMP), membrane integrity (MI), reactive oxygen species (ROS) and sperm kinematics. The %DFI was reduced (P < 0.0001) in SLC samples compared to controls. The SLC group showed a lower proportion of spermatozoa with low MMP and a higher proportion of spermatozoa with high MMP than other groups (P < 0.0001), and had lower hydrogen peroxide content than control. Sperm kinematics were not different. In conclusion, selection by SLC prior to cryopreservation improved post-thaw sperm quality; inclusion of SP from "good" and "bad" freezer stallions did not have an additional beneficial effect. PMID- 29397924 TI - Dehydroepiandrosterone enhances decidualization in women of advanced reproductive age. AB - OBJECTIVE: To investigate the impact of the androgen precursor dehydroepiandrosterone (DHEA) on the decidualization of human endometrial stromal cells isolated from women of advanced reproductive age. DESIGN: In vitro study. SETTING: University research institute. PATIENT(S): Proliferative phase primary human endometrial stromal fibroblasts (hESFs) were isolated from women of advanced reproductive age (n = 16; mean age, 44.7 +/- 2.3). None of the women were receiving hormone therapy or had endometriosis. INTERVENTION(S): Isolated hESFs were decidualized in vitro by incubation with P (1 MUM) and cAMP (0.1 mg/mL) in the presence, or absence, of DHEA (10 nM, 100 nM). MAIN OUTCOME MEASURE(S): Secretion of androgens was assessed by ELISA. Expression of decidualization markers and endometrial receptivity markers was assessed by quantitative polymerase chain reaction and ELISA. RESULT(S): Decidualization responses were retained in hESF isolated from women of advanced reproductive age. Supplementation with DHEA increased androgen biosynthesis and concentrations of T and dihydrotestosterone were ~3* greater after coincubation with DHEA compared with hESF stimulated with decidualization alone. Addition of DHEA to decidualized hESF increased expression of the decidualization markers IGFBP1 and PRL and the endometrial receptivity marker SPP1. DHEA enhanced secretion of IGFBP1, PRL, and SPP1 proteins maximally by day 8 of the decidualization time course concomitant with peak androgen concentrations. CONCLUSION(S): These novel results demonstrate DHEA can enhance in vitro decidualization responses of hESF from women of advanced reproductive age. Supplementation with DHEA during the receptive phase may augment endometrial function and improve pregnancy rates in natural or assisted reproductive cycles. PMID- 29397925 TI - [Smartphone addiction: French validation of the Internet Addiction Test Smartphone version (IAT-smartphone) and associated psychopathological features]. AB - INTRODUCTION: Since their first appearance in 1992 smartphones have improved constantly, and their use, combined with the rapid spread of the Internet, has increased dramatically. The recent emergence of this technology raises new issues, at both individual and societal levels. Several studies have investigated the physical and psychological harm that may be caused by smartphones. The issue of excessive smartphone use as an addictive disorder is frequently raised and debated, although it is not acknowledged in international classifications. In France, there is no validated assessment tool for smartphone addiction. Therefore, the aims of this research were: to validate a French translation of the Internet Addiction Test-smartphone version (IAT-smartphone); to study the links between smartphone addiction, Internet addiction, depression, anxiety and impulsivity. METHOD: Two hundred and sixteen participants from the general population were included in the study (January to February 2016), which was available online using Sphinx software. We assessed smartphone addiction (French version of the Internet Addiction Scale - smartphone version, IAT-smartphone), specificity of smartphone use (time spent, types of activity), Internet addiction (Internet Addiction Test, IAT), impulsivity (UPPS Impulsiveness Behavior Scale), and anxiety and depression (Hospital Anxiety and Depression scale, HAD). We tested the construct validity of the IAT-smartphone (exploratory factor analysis, internal consistency, non-parametric correlation tests for convergent validity). We also carried out multiple linear regressions to determine the factors associated with IAT-smartphone. RESULTS: Mean age was 32.4+/-12.2 years; 75.5% of the participants were women. The IAT-smartphone had a one-factor structure (explaining 42 % of the variance), excellent internal consistency (alpha=0.93) and satisfactory convergent validity. Smartphone addiction was associated with Internet addiction (rho=0.85), depression (rho=0.31), anxiety (rho=0.14), and some impulsivity subscales, including "negative urgency" (rho=0.20; P<0.01), "positive urgency" (rho=0.20; P<0.01), and "lack of perseverance" (rho=0.16; P<0.05). Age was negatively associated with the IAT-S total score (rho=-0.25; P<0.001), and there was a non-significant difference between the IAT-S total scores of men and women (29.3+/-10.2 vs. 32.7+/-12.4; P=0.06). Multiple linear regression showed that age, anxiety, depression, average time spent on the smartphone, impulsivity and Internet addiction explained 71.4 % of the variance of IAT-smartphone scores. However, this score dropped to 13.2 % when Internet addiction was removed from the model. This variable alone explained 70.8 % of the IAT-smartphone scores. CONCLUSION: The French version of the IAT-smartphone is a reliable and valid questionnaire to assess smartphone addiction. This addiction appears to be strongly linked to anxiety, depression and impulsivity. The strong association between smartphone addiction and Internet addiction suggests that smartphone addiction is one of the many forms of Internet addiction. In fact, smartphones may not be the object of the addiction but rather a medium facilitating Internet access as it makes it possible to connect anywhere anytime. This raises the issue of the potential role of smartphones in speeding up and facilitating the development of Internet addiction. PMID- 29397926 TI - Bronchial Mismatch as a Predictor of Respiratory Failure After Congenital Tracheal Stenosis Repair. AB - BACKGROUND: The purpose of this study was to identify predictors of postoperative respiratory failure after surgical tracheoplasty for congenital tracheal stenosis. METHODS: Between February 2011 and April 2017, 16 infants underwent congenital tracheal stenosis repair. Preoperative computed tomography evaluation of the trachea and mainstem bronchi was performed. The primary outcome was midterm freedom from postoperative respiratory failure defined as persistent need for mechanical ventilation or surgical tracheobronchial reoperation. Bronchial mismatch, defined as [1 - (smaller bronchus diameter / larger bronchus diameter)] * 100, was analyzed in relation to the primary outcome. RESULTS: Median age was 106 days (range, 1 to 406) and median weight was 5.3 kg (range, 2.6 to 8 kg). Four patients were neonates (25%) and 6 had genetic abnormalities (37.5%). There were no early nor late deaths. Median ventilation time was 5.5 days (range, 3 to 45). Mean follow-up time was 2.2 years (range, 0.1 to 4.5). Four patients with bronchial mismatch greater than 20% had postoperative respiratory failure (p = 0.002). Two of them underwent tracheostomy and were discharged with ventilation home care support. One underwent successful reoperation consisting of bilateral bronchial plasty with autologous cartilage rib grafts, and the other underwent successful right bronchial and tracheal reconstruction. One patient with bilateral bronchial hypoplasia underwent slide tracheoplasty associated with preemptive bilateral bronchial plasty and made a full recovery. CONCLUSIONS: Surgical treatment of congenital tracheal stenosis in neonates and infants portends a good outcome. Bronchial mismatch greater than 20% can identify a subset of patients at increased risk for surgical reintervention and chronic respiratory failure. Slide tracheoplasty with preemptive bronchial reconstruction may prevent postoperative respiratory failure. PMID- 29397927 TI - Impact of Obesity on Readmission in Patients With Left Ventricular Assist Devices. AB - BACKGROUND: Hospital readmissions have an adverse effect on the quality of life in patients with end-stage heart failure. We examined the temporal pattern, predictors, and outcomes of readmission in continuous flow left ventricular assist device-supported patients. METHODS: We retrospectively reviewed inpatient data of 350 consecutive patients who received a continuous-flow left ventricular assist device at our center between May 2004 and December 2014. A total time restricted model was used to estimate hazard ratios for readmission, and the Nelson nonparametric method was used to estimate mean cumulative function for each cause of readmission. RESULTS: The mean age was 57 +/- 13 years, 82.6% received a HeartMate II (Abbott Laboratories, Chicago, IL), and 26.3% were destination therapy. The 30-day readmission rate was 21.7%, and 264 readmissions (41.1%) occurred within the first 6 months of support. The leading cause of readmission was bleeding (0.74 mean cumulative events per person), followed by infection (0.7), device failure (0.52), arrhythmia (0.3), and right heart failure (0.28) at 3 years. The number of readmissions did not have an adverse effect on survival (hazard ratio, 1.03; 95% confidence interval, 0.92 to 1.17; p = 0.58). Increase in each body mass index unit was associated with 1.029 times the rate of overall readmission (p = 0.041). Patients with a body mass index of 30 kg/m2 or higher had increased readmissions for device failure (p = 0.008) and right heart failure (p = 0.03). CONCLUSIONS: Readmission burden is highest during the first few months of continuous-flow left ventricular assist device support, but survival is not affected. Patients with an elevated body mass index are at increased risk for readmissions for device failure and right heart failure. PMID- 29397928 TI - Transcatheter Aortic Valve Replacement by a Novel Suprasternal Approach. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) provides therapy for patients with severe aortic stenosis at extreme, high, or intermediate surgical risk. Transfemoral access has been the preferred access route; however, this approach is not suitable for many TAVR candidates. A suprasternal approach may allow for earlier ambulation and shorter hospital stay as compared with other, nontransfemoral approaches. METHODS: A total of 11 patients with unsuitable transfemoral access underwent suprasternal TAVR. Propensity matching was used to compare suprasternal patients to patients undergoing transaortic, transapical, and trans-subclavian TAVR. RESULTS: Groups were well matched for baseline characteristics. A self-expanding valve device was used in 6 (54.5%) and a balloon-expandable valve in 5 (45.5%) of the 11 patients treated by the suprasternal route. Suprasternal and trans-subclavian patients were able to ambulate earlier than patients treated by the transaortic route, a median 1.6 days (interquartile range [IQR]: 0.9 to 1.8), 1.6 days (IQR: 0.9 to 2.7), and 3.9 days (IQR: 1.9 to 4.5) after the procedure for suprasternal, trans-subclavian, and transaortic patients, respectively (p = 0.001). Length of hospitalization was shorter for patients treated by suprasternal or trans-subclavian access in comparison with patients treated by the transaortic or transapical approach: median 4 days (IQR: 3 to 8) and 4 days (IQR: 4 to 8) versus 8 days (IQR: 6 to 14) and 6 days (IQR: 7 to 11) for suprasternal and trans-subclavian versus transaortic and transapical, respectively (p = 0.01). CONCLUSIONS: Suprasternal and trans-subclavian access are associated with earlier ambulation and shorter hospitalization than other nontransfemoral TAVR routes, without an increase in complications. Further study is required to determine if suprasternal is the alternative access of choice for TAVR patients with poor transfemoral vasculature. PMID- 29397929 TI - Analysis of Patients Discharged From the Hospital With a Chest Tube in Place. AB - BACKGROUND: Persistent air leak can complicate pulmonary resection, and one management option is dismissal with a chest tube in place. This study evaluated the rate of empyema and readmission after dismissal with a chest tube. METHODS: A retrospective review of our prospective database from January 2004 to December 2013 identified 236 patients who were discharged from our institution with an indwelling chest tube and attached one-way valve for air leak. Empyema was defined by leukocytosis or fever and undrained effusion on chest roentgenogram or computed tomography. Readmission was defined as readmission for any reason. Logistic regression analyses were performed to identify risk factors for empyema or readmission. RESULTS: Median age was 67 years (range, 18 to 91 years). Median chest tube duration was 18 days (range, 6 to 90 days). Empyema occurred in 40 patients (16.9%), and 62 patients (26.3%) were readmitted. Treatment required included antibiotics alone in 45% (18 of 40), further drainage in 30% (12 of 40), fibrinolytic therapy in 12.5% (5 of 40), and operative decortication in 12.5% (5 of 40). Predictors of empyema included male sex, coronary artery disease, and peripheral vascular disease. A secondary analysis grouping patients into an earlier era (2004 to 2008) vs a later era (2009 to 2013) revealed that the use of thoracoscopy increased from 34% to 48% of lung resections and dismissal with a chest tube increased from 3.4% to 4.5% (p = 0.03). CONCLUSIONS: Dismissal with an indwelling chest tube is not without consequence, having significant risk for further complications and potential need for additional interventions. PMID- 29397930 TI - Fontan Failure and Death in Contemporary Fontan Circulation: Analysis From the Last Two Decades. AB - BACKGROUND: We sought to evaluate the incidence of Fontan failure or complication and its relation to death in patients having contemporary Fontan strategies over 2 decades. METHODS: Five hundred patients who underwent Fontan completion (extracardiac, n = 326; lateral tunnel, n = 174) from 1985 to 2012 were reviewed. Patient characteristics, modes of Fontan failure/complication and death, and predictors for Fontan failure/complication and death were analyzed. RESULTS: There were 23 early deaths (4.6%) and 17 late deaths (3.4%), with no early death since 2000. Survival has improved over time (p < 0.001). Twenty-three of 40 patients who died were identified as Fontan failure before death, including ventricular dysfunction (n = 14), pulmonary vascular dysfunction (n = 4), thromboembolism (n = 2), and arrhythmia (n = 4). Mode of death was circulatory failure (n = 18), multiorgan failure (n = 6), pulmonary failure (n = 3), cerebral/renal (n = 5), and sudden death (n = 4). Modes of failure/complication were directly (65%) or conceivably (10%) related to death in 30 of 40 patients (75%). Forty-eight percent of survivors had late Fontan complication(s). Five year freedom from late Fontan complication was lower among patients who died compared with patients who survived (29.4% versus 53.3%, p < 0.001). Ventricular dysfunction (p = 0.001) and higher pulmonary artery pressures (p < 0.001) after Fontan were predictors for death. Longer cardiopulmonary bypass time (p = 0.032) and reinterventions (p < 0.001) were predictors for late Fontan complication. CONCLUSIONS: Early death in the early era has been overcome. Yet the incidence and causes of late death remain unchanged. There was a strong causative relationship between the mode of Fontan failure/complication and death, indicating the importance of early recognition and treatment of Fontan failure/complication. PMID- 29397931 TI - Operation and Chemotherapy: Prognostic Factors for Lung Cancer With One Synchronous Metastasis. AB - BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is considered incurable; however, some patients with only few metastases may benefit from treatment with a curative intent. We aimed to identify the prognostic factors for stage IV NSCLC with synchronous solitary M1. METHODS: A database constructed from our weekly multidisciplinary thoracic oncology meetings was retrospectively screened from 1993 to 2012. Consecutive patients with NSCLC stages I to IV were included. RESULTS: Of the 6,760 patients found, 4,832 patients were studied. Among the 1,592 patients (33%) with stage IV NSCLC, 109 (7%) had a synchronous solitary M1. Metastasis involved the brain in 64% of patients. Median overall survival was significantly longer in synchronous solitary M1 than in other stage IV (18.9 months, interquartile range [IQR]: 9.9 to 34.6 months versus 6.1 months, IQR: 2.3 to 13.7 months], respectively, p < 10-4). Among patients with synchronous solitary M1, 90 (83%) received a local treatment with curative intent at the primary and metastatic sites. Factors independently associated with survival were age older than 63 years (hazard ratio [HR] 1.63, 95% confidence interval [CI]: 1.01 to 2.63), Performance status of 3 or 4 (HR 7.91, 95% CI: 2.23 to 28.03), use of chemotherapy (HR 0.38, 95% CI: 0.23 to 0.64), and operation conducted at both sites (HR 0.35, 95% CI: 0.19 to 0.65). CONCLUSIONS: Synchronous solitary M1 treated with chemotherapy and operation at both sites resulted in better survival. Survival of NSCLC with synchronous solitary M1 was more similar to stage III than other stage IV NSCLCs. The eighth TNM classification takes this into account by distinguishing between stages M1b and M1c. PMID- 29397932 TI - A Phase I Clinical Trial of Targeted Intraoperative Molecular Imaging for Pulmonary Adenocarcinomas. AB - BACKGROUND: Intraoperative identification of pulmonary nodules, particularly small lesions, can be challenging. We hypothesize that folate receptor-targeted intraoperative molecular imagining can be safe and improve localization of pulmonary nodules during resection. METHODS: Twenty subjects with biopsy-proven pulmonary adenocarcinomas were enrolled in a phase I clinical trial to test the safety and feasibility of OTL38, a novel folate receptor-alpha (FRalpha) targeted optical contrast agent. During resection, tumors were imaged in situ and ex vivo and fluorescence was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemistry was utilized to quantify FRalpha expression. A multivariate analysis using clinical and tumor data was performed to determine variables impacting tumor fluorescence. RESULTS: Of the 20 subjects, three grade I adverse events were observed: all transient nausea/abdominal pain. All symptoms resolved after completing the infusion. Sixteen of 20 subjects (80%) had tumors with in situ fluorescence with a mean tumor-to-background fluorescence level of 2.9 (interquartile range, 2.1 to 4.2). The remaining 4 subjects' tumors fluoresced ex vivo. In situ fluorescence was dependent on depth from the pleural surface. Four subcentimeter nodules not identified on preoperative imaging were detected with intraoperative imaging. CONCLUSIONS: This phase I trial provides preliminary evidence suggesting that folate receptor-targeted molecular imaging with OTL38 is safe, with tolerable grade I toxicity. These data also suggest that OTL38 accumulates in known lung cancers and may improve identification of synchronous malignancies. Our group is initiating a five-center, phase II study to better understand the clinical implications of intraoperative molecular imaging using OTL38. PMID- 29397933 TI - Associations Between Unplanned Cardiac Reinterventions and Outcomes After Pediatric Cardiac Operations. AB - BACKGROUND: After pediatric heart operations, we sought to determine the incidence of unplanned cardiac reinterventions during the same hospitalization, assess risk factors for these reinterventions, and explore associations between reinterventions and outcomes. We hypothesized that younger patients undergoing more complex operations would be at greater risk for unplanned cardiac reinterventions and that operative mortality and postoperative length of stay (PLOS) would be greater in patients who undergo reintervention than in those who do not. METHODS: Patients aged 18 years or younger in The Society of Thoracic Surgeons Congenital Heart Surgery Database (January 2010 to June 2015) were included. We used multivariable regression to evaluate risk factors for unplanned cardiac reintervention (operation or therapeutic catheterization) and associations of reintervention with operative mortality and PLOS. RESULTS: Of 84,404 patients (117 centers), 21% were neonates and 36% infants. An unplanned cardiac reintervention was performed in 5.4% of patients, including 11.8% of neonates, 5.2% of infants, and 2.8% of children. Independent risk factors for unplanned reintervention included presence of noncardiac anomalies/genetic syndromes, nonwhite race, younger age, lower weight among neonates and infants, prior cardiothoracic operations, preoperative mechanical ventilation, other Society of Thoracic Surgeons preoperative risk factors, and higher Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery Mortality Category (adjusted p < 0.001 for all). Unplanned reintervention was a risk factor for operative mortality (adjusted odds ratio, 5.3; 95% confidence interval, 4.8 to 5.8; p < 0.001) and longer PLOS (adjusted relative risk, 2.3; 95% confidence interval, 2.2 to 2.4; p < 0.001). CONCLUSIONS: Unplanned cardiac reinterventions are not rare, particularly in neonates, and are independently associated with operative mortality and increased PLOS. Patients at greater risk may be identified preoperatively, presenting opportunities for quality improvement. PMID- 29397934 TI - Impact of Prothrombin Complex Concentrate on Blood Use, Cost, and Outcomes in Heart Transplantation. AB - BACKGROUND: Left ventricular assist device (LVAD) recipients undergoing heart transplantation have increased bleeding risk. We compared conventional warfarin reversal with fresh frozen plasma vs 4-factor prothrombin complex concentrate (PCC) and the effect on transfusion requirements, blood bank costs, and clinical outcomes. METHODS: A retrospective review identified 60 consecutive LVAD recipients undergoing heart transplantation divided into two groups: 30 (no PCC) received fresh frozen plasma and 30 (PCC) received PCC. Patient characteristics, intraoperative and postoperative transfusion requirements, short-term clinical outcomes, and blood bank costs were compared. PCC association with transfusion requirements was assessed by multivariate linear regression. RESULTS: Patients who received PCC were younger (50 +/- 11 vs 57 +/- 13 years, p = 0.02), fewer had ischemic cardiomyopathy (23% vs 60%, p = 0.01), had more than one prior sternotomy (7% vs 30%, p = 0.04), and had higher preoperative hemoglobin (11.8 +/ 1.8 vs 10.4 +/- 1.8 g/dL, p = 0.01). The PCC group had a significantly shorter bypass time (185 vs 217 minutes, p = 0.01), received less fresh frozen plasma (2 vs 5 units, p = 0.03), cryoprecipitate (0 vs 2 units, p = 0.05), and total blood products (9 vs 13.5 units, p = 0.03) intraoperatively, and was less likely to require delayed sternal closure (3% vs 23%, p = 0.05). On multivariate linear regression, PCC was significantly associated with decreased intraoperative transfusion (beta = -6.09, p = 0.02). There was no difference in thromboembolic events or in-hospital death. Total blood bank costs were $4,949 for PCC and $3,677 for no PCC (p = 0.01). CONCLUSIONS: Although more costly, PCC reduced transfusion requirements and delayed sternal closure in heart transplant recipients bridged with LVAD, justifying its use over traditional warfarin reversal. PMID- 29397936 TI - Characterization of human ATP-binding cassette protein subfamily D reconstituted into proteoliposomes. AB - In mammals, four ATP-binding cassette (ABC) proteins belonging to subfamily D have been identified. ABCD1-3 are located on peroxisomal membrane and play an important role in the transportation of various fatty acid-CoA derivatives, including very long chain fatty acid-CoA, into peroxisomes. ABCD4 is located on lysosomal membrane and is suggested to be involved in the transport of vitamin B12 from lysosomes to the cytosol. However, the precise transport mechanism by which these ABC transporters facilitate the import or export of substrate has yet to be well elucidated. In this study, the overexpression of human ABCD1-4 in the methylotrophic yeast Pichia pastoris and a purification procedure were developed. The detergent-solubilized proteins were reconstituted into liposomes. ABCD1-4 displayed stable ATPase activity, which was inhibited by AlF3. Furthermore, ABCD1 4 were found to possess an equal levels of acyl-CoA thioesterase activity. Proteoliposomes is expected to be an aid in the further biochemical characterization of ABCD transporters. PMID- 29397937 TI - General misincorporation frequency: Re-evaluation of the fidelity of DNA polymerases. AB - DNA replication in cells is performed in the presence of four dNTPs and four rNTPs. In this study, we re-evaluated the fidelity of DNA polymerases using the general misincorporation frequency consisting of three incorrect dNTPs and four rNTPs but not using the traditional special misincorporation frequency with only the three incorrect dNTPs. We analyzed both the general and special misincorporation frequencies of nucleotide incorporation opposite dG, rG, or 8 oxoG by Pseudomonas aeruginosa phage 1 (PaP1) DNA polymerase Gp90 or Sulfolobus solfataricus DNA polymerase Dpo4. Both misincorporation frequencies of other DNA polymerases published were also summarized and analyzed. The general misincorporation frequency is obviously higher than the special misincorporation frequency for many DNA polymerases, indicating the real fidelity of a DNA polymerase should be evaluated using the general misincorporation frequency. PMID- 29397938 TI - Intracellular localization and binding partners of death associated protein kinase-related apoptosis-inducing protein kinase 1. AB - Death associated protein kinase (DAPK)-related apoptosis-inducing protein kinase (DRAK)-1 is a positive apoptosis regulator. However, the molecular mechanisms underlying the DRAK1-mediated apoptotic pathway remain unclear. In this study, we demonstrated the intracellular localization and binding partners of DRAK1. In human osteosarcoma cell line U2OS cells, DRAK1 was mainly localized in the nucleus and translocated outside the nucleus through Ser395 phosphorylation by protein kinase C. In the nucleus, DRAK1 associated with tumor suppressor p53 and positively regulated p53 transcriptional activity in response to DNA-damaging agent cisplatin. On the other hand, DRAK1 interacted with the mitochondrial inner membrane protein, adenine nucleotide translocase (ANT)-2, an anti-apoptotic oncoprotein, outside the nucleus. These findings suggest that DRAK1 translocates in response to stimuli and induces apoptosis through its interaction with specific binding partners, p53 and/or ANT2. PMID- 29397939 TI - Hepatitis C virus regulates proprotein convertase subtilisin/kexin type 9 promoter activity. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease mainly expressed in liver. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, whether HCV regulates PCSK9 transcription has not been well studied. PCSK9 promoter activity is modulated by numerous transcription factors including sterol-regulatory element binding protein (SREBP)-1a, -1c, -2, hepatocyte nuclear factor-1 (HNF-1), and forkhead box O3 (FoxO3). Since they are differently regulated by HCV, we studied the effects of these transcription factors on PCSK9 promoter activity in the context of HCV infection and replication. We demonstrated that PCSK9 promoter activity was up-regulated after HCV infection and in HCV genomic replicon cells. We also studied the effects of HCV proteins on the PCSK9 promoter activity. While HCV structural proteins core, E1, and E2 had no effect, NS2, NS3, NS3-4A, NS5A and NS5B enhanced, and p7 and NS4B decreased PCSK9 promoter activity. Furthermore, we showed that transcription factors SREBP-1c, HNF-1alpha and specificity protein 1 increased PCSK9 promoter activity in HCV replicon cells, whereas SREBP-1a, HNF 1beta and FoxO3 had an inhibitory effect. These results demonstrated the molecular mechanisms of how HCV modulates PCSK9 promoter activity and advanced our understanding on the mutual interactions between HCV and PCSK9. PMID- 29397940 TI - KSHV vIRF4 enhances BCL6 transcription via downregulation of IRF4 expression. AB - Primary effusion lymphoma (PEL), strongly linked with latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), constitutively expresses cellular interferon regulatory factor 4 (IRF4) while suppressing the expression of B cell lymphoma 6 (BCL6). Recently, it was shown that IRF4, a key transcriptional repressor of BCL6, might be a pivotal regulator of KSHV for balancing between latency and its reactivation in PEL cells. However, the action of the BCL6-IRF4 transcription factor axis during KSHV's life cycle is not clear. Herein we found that the KSHV lytic protein viral interferon regulatory factor 4 (vIRF4) dramatically enhanced the transcriptional activity of the BCL6 through the inhibition of its negative regulator IRF4. Using a chromatin immunoprecipitation (ChIP) assay, we further showed that vIRF4 bound to the specific promoter region of IRF4, contributing to a dramatic suppression of IRF4 gene expression. Correspondingly, we also found BCL6 expression to be positively and inversely correlated with vIRF4 and IRF4 expression, respectively, during KSHV reactivation. Finally, we observed that these processes require efficient KSHV lytic replication. Thus, our findings suggest a crucial role of the BCL6-IRF4 axis in triggering the transition between KSHV latency and lytic reactivation. PMID- 29397941 TI - The protein J3 regulates flowering through directly interacting with the promoter of SOC1 in Brassica juncea. AB - DNA J HOMOLOG 3 (J3) is a special transcriptional regulator in flowering time control, but the molecular mechanism of J3 in regulating flowering time has not been thoroughly revealed in B. juncea which is one important oilseed and vegetable crop. In this study, J3 gene was cloned from B. juncea (BjuJ3). Phylogenetic relationship analysis showed that the BjuJ3 had high amino acid sequence similarity (>93%) with other Brassica plants. The BjuJ3-transgenic tobacco plants exhibited early flowering, suggesting that BjuJ3 was an activator of flowering time. The qRT-PCR analysis found that BjuJ3 could be ubiquitously induced by the long-day and vernalization treatments in all the tissues of B. juncea. Yeast two-hybrid assays and GST pull-down experiments revealed that BjuJ3 could not directly interact with BjuSOC1, BjuSVP and BjuAGL24. Whereas, yeast one hybrid and Dual-Glo(r) Luciferase assays found that BjuJ3 could not interact with BjuAGL24 promoter but could specifically bind to BjuSOC1-1 which is one of truncated fragments of BjuSOC1 promoter. Our research will provide valuable information for unraveling regulatory mechanisms of flowering time in B. juncea. PMID- 29397942 TI - Senescence-messaging secretome factors trigger premature senescence in human endometrium-derived stem cells. AB - Accumulating evidence suggests that the senescence-messaging secretome (SMS) factors released by senescent cells play a key role in cellular senescence and physiological aging. Phenomenon of the senescence induction in human endometrium derived mesenchymal stem cells (MESCs) in response to SMS factors has not yet been described. In present study, we examine a hypothesis whether the conditioned medium from senescent cells (CM-old) may promote premature senescence of young MESCs. In this case, we assume that SMS factors, containing in CM-old are capable to trigger senescence mechanism in a paracrine manner. A long-term cultivation MESCs in the presence of CM-old caused deceleration of cell proliferation along with emerging senescence phenotype, including increase in both the cell size and SA-beta-Gal activity. The phosphorylation of p53 and MAPKAPK-2, a direct target of p38MAPK, as well as the expression of p21Cip1 and p16Ink4a were increased in CM-old treated cells with senescence developing whereas the Rb phosphorylation was diminished. The senescence progression was accompanied by both enhanced ROS generation and persistent activation of DNA damage response, comprising protein kinase ATM, histone H2A.X, and adapter protein 53BP1. Thus, we suggest that a senescence inducing signal is transmitted through p16/MAPKAPK-2/Rb and DDR mediated p53/p21/Rb signaling pathways. This study is the first to demonstrate that the SMS factors secreted in conditioned medium of senescent MESCs trigger a paracrine mechanism of premature senescence in young cells. PMID- 29397935 TI - The dichotomous role of H2S in cancer cell biology? Deja vu all over again. AB - Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (H2S) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and H2S in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and H2S in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes. PMID- 29397943 TI - Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer. PMID- 29397944 TI - Expressed parental concern regarding childhood stuttering and the Test of Childhood Stuttering. AB - PURPOSE: The purpose of the present study was to determine whether the Test of Childhood Stuttering observational rating scales (TOCS; Gillam et al., 2009) (1) differed between parents who did versus did not express concern (independent from the TOCS) about their child's speech fluency; (2) correlated with children's frequency of stuttering measured during a child-examiner conversation; and (3) correlated with the length and complexity of children's utterances, as indexed by mean length of utterance (MLU). METHOD: Participants were 183 young children ages 3:0-5:11. Ninety-one had parents who reported concern about their child's stuttering (65 boys, 26 girls) and 92 had parents who reported no such concern (50 boys, 42 girls). Participants' conversational speech during a child-examiner conversation was analyzed for (a) frequency of occurrence of stuttered and non stuttered disfluencies, and (b) MLU. Besides expressing concern or lack thereof about their child's speech fluency, parents completed the TOCS observational rating scales documenting how often they observe different disfluency types in speech of their children, as well as disfluency-related consequences. RESULTS: There were three main findings. First, parents who expressed concern (independently from the TOCS) about their child's stuttering reported significantly higher scores on the TOCS Speech Fluency and Disfluency-Related Consequences rating scales. Second, children whose parents rated them higher on the TOCS Speech Fluency rating scale produced more stuttered disfluencies during a child-examiner conversation. Third, children with higher scores on the TOCS Disfluency-Related Consequences rating scale had shorter MLU during child examiner conversation, across age and level of language ability. CONCLUSIONS: Findings support the use of the TOCS observational rating scales as one documentable, objective means to determine parental perception of and concern about their child's stuttering. Findings also support the notion that parents are reasonably accurate, if not reliable, judges of the quantity and quality (i.e., stuttered vs. non-stuttered) of their child's speech disfluencies. Lastly, findings that some children may decrease their verbal output in attempts to minimize instances of stuttering - as indexed by relatively low MLU and a high TOCS Disfluency-Related Consequences scores - provides strong support for sampling young children's speech and language across various situations to obtain the most representative index possible of the child's MLU and associated instances of stuttering. PMID- 29397945 TI - Schoolbags and back pain: opinions strongest where the evidence is weakest. PMID- 29397946 TI - The Audiology of Otosclerosis. AB - Diagnostic audiologic procedures for otosclerosis are effective tools in identifying this condition. Audiometric data usually demonstrate a conductive hearing loss at the early stages of otosclerosis. Modern middle ear analysis procedures are becoming more popular in the better diagnosis of otosclerosis. In clinical practice, cochlear otosclerosis can also be observed. Audiologic rehabilitation of otosclerosis includes fitting of hearing aids and implantable hearing devices. Current hearing technology enables patients who do not pursue surgical correction to function well and significantly improve their communication and quality of life. Otosclerosis may also be associated with annoying tinnitus, and tinnitus management is important in the rehabilitation process. PMID- 29397947 TI - Otosclerosis: Temporal Bone Pathology. AB - Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. PMID- 29397948 TI - Stapedectomy Versus Stapedotomy. AB - Stapedectomy and stapedotomy represent the state-of-the-art surgical procedures in addressing the conductive hearing loss caused by otosclerosis. Their high rates of success and long-term stability have been demonstrated repeatedly in many studies. In comparing the short- and long-term results of the 2 procedures, it is evident that stapedotomy confers better hearing gain at high frequencies and lower complication rates. Modified stapes mobilization procedures may represent the next major development in stapes surgery in a selected patient population. PMID- 29397949 TI - A lymphedema surveillance program for breast cancer patients reveals the promise of surgical prevention. AB - BACKGROUND: Breast cancer-related lymphedema (BCRL) is one of the most significant survivorship issues in breast cancer management. Presently, there is no cure for BCRL. The single greatest risk factor for developing BCRL is an axillary lymph node dissection (ALND). Lymphatic Microsurgical Preventative Healing Approach (LYMPHA) is a surgical procedure to reduce the risk of lymphedema in patients undergoing an ALND. We present our single institution results after offering LYMPHA in the context of an established lymphedema surveillance program. MATERIALS AND METHODS: A retrospective review of our lymphedema surveillance program at the University of Florida was performed over a 2-year period (March 2014-March 2016). LYMPHA was offered to patients undergoing ALND beginning in March 2015. Patients who developed lymphedema were compared with those who did not. Demographics and potential risk factors for development of lymphedema such as age, body mass index, clinical stage, radiotherapy, and chemotherapy were reviewed. RESULTS: Eighty-seven patients participated in the surveillance program over the study period with an average age of 60 y (range 32 83) and body mass index of 30 kg/m2 (range 17-46). The single most significant risk factor for the development for lymphedema was an ALND (P < 0.001). One of 67 patients undergoing a sentinel lymph node biopsy developed lymphedema (1.5%). Four of 10 patients who underwent an ALND alone developed lymphedema (40%). One of 8 patients in the ALND + LYMPHA group developed transient lymphedema (12.5%). CONCLUSIONS: Offering LYMPHA with ALND decreased our institutional rate of lymphedema from 40% to 12.5%. Long-term follow-up and randomized control trials are necessary to further elucidate the promise of this surgical technique to reduce the incidence of BCRL. PMID- 29397950 TI - Triple Antithrombotic Therapy for Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention. AB - Dual antiplatelet therapy (DAPT) has been the cornerstone of antithrombotic management for patients undergoing percutaneous coronary intervention (PCI). However, approximately 10% of these patients have concomitant atrial fibrillation (AF) and require chronic oral anticoagulant (OAC) in addition to DAPT. This traditional "triple therapy" has been associated with a three to four-fold increased risk of bleeding. The safety of non-vitamin K OAC (NOAC)-based strategies, using a NOAC plus a P2Y12 inhibitor, has been compared to vitamin K antagonist (VKA)-based triple therapy in the PIONEER AF-PCI and REDUAL PCI randomized trials, both of which have demonstrated that NOAC-based strategies are safer and provide an attractive alternative to VKA-based triple therapy among AF patients who undergo PCI. This article reviews the rationale, evidence, and recent evaluation of triple antithrombotic therapy among AF patients undergoing PCI. PMID- 29397951 TI - Hydrocephalus combined with acute communicating syringomyelia resulting from aneurysmal subarachnoid hemorrhage: A case report. PMID- 29397952 TI - Proteasome accessory factor A (PafA) transferase activity makes sense in the light of its homology with glutamine synthetase. AB - The Pup-proteasome system (PPS) is a prokaryotic tagging and degradation system analogous in function to the ubiquitin-proteasome system (UPS). Like ubiquitin, Pup is conjugated to proteins, tagging them for proteasomal degradation. However, in the PPS, a single Pup-ligase, PafA, conjugates Pup to a wide variety of proteins. PafA couples ATP hydrolysis to formation of an isopeptide bond between Pup and a protein lysine via a mechanism similar to that used by glutamine synthetase (GS) to generate glutamine from ammonia and glutamate. GS can also transfer the glutamyl moiety from glutamine to a hydroxyl amine in an ATP independent manner. Recently, the ability of PafA to transfer Pup from one protein to another was demonstrated. Here, we report that such PafA activity mechanistically resembles the transferase activity of GS. Both PafA and GS transferase activities are ATP-independent and proceed in two catalytic steps. In the first step catalyzed by PafA, an inorganic phosphate is used by the enzyme to depupylate a Pup donor, while forming an acyl phosphate Pup intermediate. The second step consists of Pup conjugation to the new protein, alongside the release of an inorganic phosphate. Detailed experimental analysis, combined with kinetic modeling of PafA transferase activity, allowed us to correctly predict the kinetics and magnitude of Pup transfer between two targets, and analyze the effects of their affinity to PafA on the efficiency of transfer. By deciphering the mechanism of the PafA transferase reaction in kinetic detail, this work provides in-depth mechanistic understanding of PafA, a key PPS enzyme. PMID- 29397953 TI - Cardiac Compromise in Zika Virus Infection. PMID- 29397954 TI - Defining toxicological tipping points in neuronal network development. AB - Measuring electrical activity of neural networks by microelectrode array (MEA) has recently shown promise for screening level assessments of chemical toxicity on network development and function. Important aspects of interneuronal communication can be quantified from a single MEA recording, including individual firing rates, coordinated bursting, and measures of network synchrony, providing rich datasets to evaluate chemical effects. Further, multiple recordings can be made from the same network, including during the formation of these networks in vitro. The ability to perform multiple recording sessions over the in vitro development of network activity may provide further insight into developmental effects of neurotoxicants. In the current study, a recently described MEA-based screen of 86 compounds in primary rat cortical cultures over 12 days in vitro was revisited to establish a framework that integrates all available primary measures of electrical activity from MEA recordings into a composite metric for deviation from normal activity (total scalar perturbation). Examining scalar perturbations over time and increasing concentration of compound allowed for definition of critical concentrations or "tipping points" at which the neural networks switched from recovery to non-recovery trajectories for 42 compounds. These tipping point concentrations occurred at predominantly lower concentrations than those causing overt cell viability loss or disrupting individual network parameters, suggesting tipping points may be a more sensitive measure of network functional loss. Comparing tipping points for six compounds with plasma concentrations known to cause developmental neurotoxicity in vivo demonstrated strong concordance and suggests there is potential for using tipping points for chemical prioritization. PMID- 29397955 TI - Flocking of quad-rotor UAVs with fuzzy control. AB - This paper investigates the flocking problem of quad-rotor UAVs. Considering the actual situations, we derived a new simplified quad-rotor UAV model which is more reasonable. Based on the model, the T-S fuzzy model of attitude dynamic equation and the corresponding T-S fuzzy feedback controller are discussed. By introducing a double-loop control construction, we adjust its attitude to realize the position control. Then a flocking algorithm is proposed to achieve the flocking of the quad-rotor UAVs. Compared with the flocking algorithm of the mass point model, we dealt with the collision problem of the quad-rotor UAVs. In order to improve the airspace utilization, a more compact configuration called quasi e lattice is constructed to guarantee the compact flight of the quad-rotor UAVs. Finally, numerical simulations are provided to illustrate the effectiveness of the obtained theoretical results. PMID- 29397956 TI - Decentralized state estimation for a large-scale spatially interconnected system. AB - A decentralized state estimator is derived for the spatially interconnected systems composed of many subsystems with arbitrary connection relations. An optimization problem on the basis of linear matrix inequality (LMI) is constructed for the computations of improved subsystem parameter matrices. Several computationally effective approaches are derived which efficiently utilize the block-diagonal characteristic of system parameter matrices and the sparseness of subsystem connection matrix. Moreover, this decentralized state estimator is proved to converge to a stable system and obtain a bounded covariance matrix of estimation errors under certain conditions. Numerical simulations show that the obtained decentralized state estimator is attractive in the synthesis of a large-scale networked system. PMID- 29397957 TI - A novel dual closed-loop control scheme based on repetitive control for grid connected inverters with an LCL filter. AB - Grid-connected inverters with LCL filters need high steady-state control accuracy, fast dynamic response performance, and strong robustness to guarantee the power quality. However, there are many problems in traditional control strategies that restrict improvements to control system performance, such as poor dynamic performance of traditional single-repetitive control, large ripples, low steady-state accuracy of inverter current feedback based repetitive dual-loop control or grid-current feedback based single-loop proportional-integral control. In this paper, a novel dual closed-loop repetitive control strategy based on grid current feedback is proposed for single-phase grid-connected inverters with LCL filters. The proportional-integral inner loop is stabilized by using an inherent one-beat delay achieved by digital controller. Based on the inner loop system, a detailed design scheme of a repetitive controller is presented, through which direct control of the grid current is realized, the reference is tracked perfectly to a zero phase shift, and high-attenuation gain is achieved in the high frequency range. In particular, the gird-voltage feed forward control and current reference feedforward control are adopted to suppress grid-voltage disturbance and increase dynamic tracking performance. Finally, the simulation and experimental results show that the proposed method has the advantages of high steady-state accuracy, fast dynamic response, and anti-disturbance ability. PMID- 29397958 TI - Robust feedback linearization for nonlinear processes control. AB - In this research, a robust feedback linearization technique is studied for nonlinear processes control. The main contributions are described as follows: 1) Theory says that if a linearized controlled process is stable, then nonlinear process states are asymptotically stable, it is not satisfied in applications because some states converge to small values; therefore, a theorem based on Lyapunov theory is proposed to prove that if a linearized controlled process is stable, then nonlinear process states are uniformly stable. 2) Theory says that all the main and crossed states feedbacks should be considered for the nonlinear processes regulation, it makes more difficult to find the controller gains; consequently, only the main states feedbacks are utilized to obtain a satisfactory result in applications. This introduced strategy is applied in a fuel cell and a manipulator. PMID- 29397960 TI - Synergistic anti-proliferative effects of mTOR and MEK inhibitors in high-grade chondrosarcoma cell line OUMS-27. AB - Chondrosarcoma is a malignant bone tumor that produces cartilaginous neoplastic tissue. Owing to the absence of an effective adjuvant therapy, high-grade chondrosarcoma has a poor prognosis. Therefore, it is important to develop an effective adjuvant therapy to prevent the recurrence and metastasis. Mammalian target of rapamycin (mTOR), a central regulator of cell growth, metabolism, proliferation, and survival, is considered an important target for anticancer drug development. The mitogen activated protein kinase (MAPK) pathway is another highly implicated cellular pathway in cancer and is thought to have compensatory effects in response to the inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway. We investigated the mechanism of anti proliferative effect of the mTOR inhibitor rapamycin and MAPK/ERK (MEK) inhibitor PD 0325901, and the combined effect of rapamycin and PD 0325901 on human chondrosarcoma cell line (OUMS-27). Combination therapy with rapamycin and PD 0325901 showed a stronger anti-proliferative effect on OUMS-27 cells than rapamycin monotherapy. We confirmed that the dual inhibition of the PI3K/Akt/mTOR and RAF/MEK/ERK signaling pathways had synergistic anti-proliferative effects in OUMS-27. Our results suggest that combination therapy of mTOR and MEK inhibitor could be an effective therapeutic approach against chondrosarcoma. PMID- 29397959 TI - Neuromonitoring in the neonatal ECMO patient. AB - Utilization of extraocorporeal membrane oxygenation (ECMO) has become increasingly widespread as a bridging therapy for neonates with severe, reversible respiratory or cardiac diseases. While significant risks remain, due to advances in medical and surgical management, overall mortality has decreased. However, short and long-term neurological morbidity has remained high. Therefore, increasing attention has been focused on multimodal neuromonitoring to track and optimally, minimize or prevent intracranial injury. This review will explore the the indications, advantages, disadvantages, timing, frequency, duration, and any known correlation with neurodevelopmental outcomes of common types of neuromonitoring in the neonatal ECMO population. Investigational monitoring techniques such as NIRS will be briefly reviewed. PMID- 29397961 TI - The management of pediatric renovascular hypertension: a single center experience and review of the literature. AB - INTRODUCTION: Renal artery occlusive disease is poorly characterized in children; treatments include medications, endovascular techniques, and surgery. We aimed to describe the course of renovascular hypertension (RVH), its treatments and outcomes. METHODS: We performed literature review and retrospective review (1993 2014) of children with renovascular hypertension at our institution. Response to treatment was defined by National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents at most-recent follow up. RESULTS: We identified 39 patients with RVH. 54% (n=21) were male, with mean age of 6.93 +/- 5.27 years. Most underwent endovascular treatment (n=17), with medication alone (n=12) and surgery (n=10) less commonly utilized. Endovascular treatment resulted in 18% cure, 65% improvement and 18% failure; surgery resulted in 30% cure, 50% improvement and 20% failure. Medication alone resulted in 0% cure, 75% improvement and 25% failure. 24% with endovascular treatment required secondary endovascular intervention; 18% required secondary surgery. 20% of patients who underwent initial surgery required reoperation for re-stenosis. Mean follow-up was 52.2 +/- 58.4 months. CONCLUSIONS: RVH treatment in children includes medications, surgical or endovascular approaches, with all resulting in combined 79% improvement in or cure rates. A multidisciplinary approach and individualized patient management are critical to optimize outcomes. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: Level III. PMID- 29397963 TI - Corrigendum to "Effects of three veterinary antibiotics and their binary mixtures on two green alga species"[Chemosphere 194 (2018) 821-827]. PMID- 29397962 TI - Clearance of tunneled central venous catheter associated blood stream infections in children. AB - BACKGROUND: The optimal time to reinsert central venous catheters (tCVC) after a documented central line associated blood stream infection (CLABSI) is unclear. The goal of this study is to identify risk factors for children who develop persistent bacteremia after tCVC removal due to CLABSI. METHODS: We performed a retrospective cohort study from a tertiary children's hospital. Children who underwent removal of a tCVC due to CLABSI were included in our analysis. Our primary outcome was persistent bacteremia after tCVC removal defined by a persistently positive blood culture. Salient patient demographic and clinical factors were extracted from the medical record. RESULTS: A total of 140 patients met inclusion criteria and 27 (19%) had a persistent CLABSI after removal of the tCVC. There were no significant differences between the patients who cleared their bacteremia and those who develop persistent bacteremia. The median (IQR) time to positive blood culture after tCVC removal was 2.7 days (1.7- 4.0). CONCLUSIONS: We did not identify any patient risk factors distinguishing between a child who will clear a CLABSI versus develop a persistent CLABSI after tCVC removal. Blood stream infection clearance was rapid after tCVC removal, supporting a brief line holiday prior to tCVC reinsertion. LEVEL OF EVIDENCE: Level III Retrospective Case-Control Study. PMID- 29397964 TI - Mediastinal lymphangioma in an adult. PMID- 29397965 TI - Short-term outcomes of a simple and effective approach to aortic root and arch repair in acute type A aortic dissection. AB - OBJECTIVE: To evaluate short-term outcomes following direct aortic root and arch repair in patients with acute type A aortic dissection (ATAAD) without technical adjuncts. METHODS: Between 2012 and 2016, 94 consecutive patients with ATAAD underwent surgical repair, including aortic root repair (n = 45), root replacement (n = 39), or no root procedure (n = 10). Aortic root repair was achieved by running approximation of the dissected aortic wall circumferentially at the sinotubular junction and reinforcing the coronary ostia with 5-0 Prolene. The aortic root and arch were anastomosed to the Dacron graft with 5-0 Prolene without Teflon felt or biological glue. RESULTS: Postoperative new-onset myocardial infarction, stroke, renal failure, and complete heart block occurred in 0%, 4%, 13%, and 0% of patients, respectively, whereas 30-day mortality was 4%. The incidences of permanent neurologic deficit and renal failure were 1% and 2%, respectively. Up to 5 years, the aortic root repair group was free from residual or recurrent aortic root dissection, major change in the aortic root diameter, and moderate to severe aortic regurgitation; the entire cohort was free of anastomotic pseudoaneurysm and reoperation for proximal aortic pathology or significant change in diameter of the aortic arch and descending thoracic aorta. Overall survival was 85% at 4 years and was significantly enhanced in the aortic root repair group compared with the Bentall group (n = 24) (93% vs 57%; P = .035). CONCLUSIONS: Direct aortic root and arch repair with approximation of the aortic wall without use of technical adjuncts is safe and effective for patients with ATAAD. If warranted, preservation of the native aortic valve should be considered for a potential survival benefit. PMID- 29397966 TI - Blowing in a bottle. PMID- 29397967 TI - Snakes on a plan. PMID- 29397968 TI - The term "supportive care" is preferable to "palliative care" for consults in the cardiothoracic intensive care unit. PMID- 29397969 TI - Two roads diverged in the right ventricular outflow tract. PMID- 29397970 TI - "Intercostal artery reimplantation with saphenous vein during thoracoabdominal aortic replacement" Excellent idea, but.... PMID- 29397971 TI - Aortic valve replacement in patients with amyloidosis. AB - BACKGROUND: Outcome data on aortic valve replacement in patients with amyloidosis are limited. To address this issue, we reviewed our experience of patients with amyloidosis who underwent aortic valve replacement. METHODS: We retrospectively reviewed the records of 16 patients with amyloidosis who underwent aortic valve replacement between May 2000 and February 2017. RESULTS: The cohort comprised 11 males (69%) and 5 females (31%). The median patient age was 76 years (interquartile range [IQR], 71-82 years), and Society of Thoracic Surgeons predicted rate of mortality was 5.0% (IQR, 2.4%-8.7%). Amyloidosis type was immunoglobulin light chain in 6 patients (38%), age-related in 6 (38%), and localized in 4 (25%). The operation was surgical aortic valve replacement in 11 patients (69%) and balloon-expandable transfemoral transcatheter aortic valve insertion in the other 5. There was no procedure-related stroke, need for new onset dialysis or pacemaker, or death within 30 days of surgery. The median length of hospital stay was 1 day (IQR, 1-2 days) in the transcatheter valve insertion group and 6 days (IQR, 6-8 days) in the surgical group (P = .002). Follow-up was available for all patients at a median of 1.9 years (IQR, 1.2-4.8 years). During the follow-up period, there were 4 deaths, all occurring >1 year after surgery. CONCLUSIONS: Aortic valve replacement can be performed with low risk of operative morbidity and mortality in patients with amyloidosis. Transcatheter valve insertion has the advantage of reduced hospital length of stay. The 1-year survival is excellent. PMID- 29397972 TI - Correction of postpneumonectomy syndrome with tridimensional carbon fiber-printed implant. PMID- 29397973 TI - Pretreatment clinical stage predicts locoregional recurrence in patients with esophageal cancer who achieved a complete clinical response to chemoradiotherapy. AB - OBJECTIVE: Definitive chemoradiotherapy (dCRT) represents a curative nonsurgical treatment option for patients with esophageal cancer. However, tumor recurrence is common after dCRT, even when clinical complete response (cCR) is achieved. Here, we investigated the timing, patterns, and risk factors for recurrence in patients with esophageal squamous cell carcinoma (ESCC) who achieved cCR following dCRT. METHODS: We retrospectively examined the clinical records of patients with ESCC who achieved cCR following dCRT between 2001 and 2014. Locoregional recurrence (LR) was defined as a recurrence occurring in the esophageal lumen and/or locoregional lymph nodes. Recurrences at any other sites were considered as distant recurrences (DRs). RESULTS: A total of 102 patients who achieved cCR were included. After a mean follow-up of 54.5 months, 51 patients developed recurrences (34 LRs, 6 combined LR and DR, and 11 DRs). The cumulative 1-, 3-, and 5-year recurrence rates were 35%, 46%, and 50%, respectively. The mean time to recurrence for the 40 patients with LRs (including LRs plus LRs/DRs) was significantly shorter (281.4 days) compared with that of patients with DRs (643.6 days; P = .006), with 95% of the former being diagnosed within 2 years. Multivariate Cox regression analysis identified pretreatment clinical stage III as the only independent risk factor for LR (hazard ratio, 2.732; 95% confidence interval; 1.063-7.020; P = .037). CONCLUSIONS: Disease recurrence occurs in 50% of ESCC patients who achieve cCR following dCRT, with LR being the most common pattern. Advanced pretreatment clinical stage is an independent risk factor for LR. PMID- 29397974 TI - Four-dimensional flow magnetic resonance imaging: Just beautiful pictures or clinical relevant analysis? PMID- 29397975 TI - Remodeling the mitral valve: An outside-in strategy. PMID- 29397976 TI - Anatomy of the mitral subvalvular apparatus. AB - OBJECTIVES: To characterize morphologic variations in the papillary muscles and tendinous cords of the left ventricle and ventricular zones of the mitral valve leaflets. METHODS: A total of 100 autopsied human hearts from healthy donors with classical mitral valve type were investigated. RESULTS: In 1 heart, only 1 group of papillary muscles was found, and in the remaining 99%, we could distinguish 2 groups of muscles: Superolateral (SLPM) and inferoseptal papillary muscle (ISPM) groups. The SLPM group had 1 papillary muscle (75.8%), 2 in 20.2%, and >3 in 4.0%. In the ISPM group, the muscle percentages were 38.4%, 36.4%, and 25.2%, respectively. The apex of at least 1 papillary muscle was situated higher than the plane of the opened anterior leaflet (AML) in 47.5% and 50.5% for the SLPM and ISPM groups, respectively. The number of strut cords arising from the SLPM group was 0 (2.0%), 1 (50.5%), 2 (33.3%), 3 (12.1%), and 4 (2.0%), and from the ISPM group was 0 (6.1%), 1 (52.5%), 2 (35.4%), or 3 (6.1%). Cords to left ventricular outflow tract were present in 14 specimens. Muscular cords were found in eight hearts. In all hearts specimens AML had rough and clear zones. The classical zones (rough, clear, and basal) in the posterior mitral leaflet were observed in 38.4%. CONCLUSIONS: There is a high variability in the papillary muscles and tendinous cords in the mitral valve complex. Proper nomenclature, simple classification, and the most common variants for papillary muscle groups and tendinous cords were presented. PMID- 29397977 TI - Pleural mechanics and the pathophysiology of air leaks. PMID- 29397978 TI - Subacute mitral valve dysfunction after transcatheter aortic and mitral valve replacements. PMID- 29397979 TI - Extending the limits of size exclusion chromatography: Simultaneous separation of free payloads and related species from antibody drug conjugates and their aggregates. AB - Size exclusion chromatography (SEC) is commonly performed in isocratic conditions to separate partially excluded molecules from the pores of the stationary phase, based on their difference in hydrodynamic volume. In this work, a baseline resolution was obtained between the monomeric antibody drug conjugate (ADC) and high molecular weight species (HMWS). Besides HMWS, small free payloads, linkers and linker-payloads of ADCs, which would not be discriminated solely based on their size (MW < 1.5 kDa), were also separated on the same SEC column by applying sequentially an acetonitrile gradient after the elution of the largest species. Such an approach allowed a simultaneous i) measurement of the HMWS amount under native conditions, and ii) quantitation of the free payloads, within one generic SEC run. For this purpose, a state-of-the-art 150 * 4.6 mm SEC column packed with 2.0 MUm particles and 250 A pore size, was selected to achieve fast separations of the species within 10 min. A second dimension (RPLC) was also developed to further extend the possibility offered by this experimental setup. The SECxRPLC multiple heart cutting mode was operated by using a modern 2D-LC instrument containing twelve 120 MUL sampling loops. Repeatabilities (0.01% < RSD < 3.68%) and recoveries (between 82% and 107%) were found to be suitable with both approaches (SEC and SECxRPLC), whereas the LOQs remain similar. Finally, the SEC method was applied for the screening of ADC crude reaction mixtures, whereas the SEC x RPLC method facilitated separating some additional impurities. The streamlined methodology will further support the development and characterization of ADC products. PMID- 29397980 TI - Macrocyclic glycopeptide chiral selectors bonded to core-shell particles enables enantiopurity analysis of the entire verubecestat synthetic route. AB - Verubecestat is an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) being evaluated in clinical trials for the treatment of Alzheimer's disease. Synthetic route development involves diastereoselective transformations with a need for enantiomeric excess (ee) determination of each intermediate and final active pharmaceutical ingredient (API). The analytical technical package of validated methods relies on enantioselective SFC and RPLC separations using multiple 3 and 5 MUm coated polysaccharide-based chiral stationary phases (CSPs) and mobile phases combinations. Evaluation of recently developed chiral columns revealed a single chiral selector (Teicoplanin) bonded to 2.7 MUm core-shell particles using H3PO4 in H2O/ACN and triethylammonium acetate: methanol based eluents at different isocratic compositions allowed good enatioseparation of all verubecestat intermediates. EE determination of verubecestat is easily performed on NicoShell, another macrocyclic glycopeptide chiral selector bonded to 2.7 MUm superficially porous particles. This approach enables fast and reliable enantiopurity analysis of the entire verubecestat synthetic route using only two chiral columns and mobile phases on a conventional HPLC system, simplifying technical package preparation, method validation and transfer to manufacturing facilities. PMID- 29397981 TI - Liquid chromatography-tandem mass spectrometry detection of diclofenac and related compounds in water samples. AB - A frequently studied environmental contaminant is the active substance diclofenac, which is removed insufficiently in sewage treatment plants. Since its inclusion in the watch list of the EU Water Framework Directive, the concentrations in surface waters will be determined throughout Europe. For this, still, more precise analytical methods are needed. As a reference, HPLC-MS is frequently employed. One of the major metabolites is 4'-hydroxydiclofenac (4'-OH DCF). Also, diclofenac lactam is important for assessing degradation and transformation. Aceclofenac (ACF), the glycolic acid ester of diclofenac is used as a drug, too, and could potentially be cleaved to yield diclofenac again. In various sewage treatment plant influent samples, diclofenac, 4'-OH-DCF, DCF lactam and ACF could be determined with detection limits of 3 MUg/L, 0.2 MUg/L, 0.17 MUg/L and 10 ng/L, respectively. PMID- 29397982 TI - Ultra-high performance liquid chromatography tandem mass spectrometry for the determination of five glycopeptide antibiotics in food and biological samples using solid-phase extraction. AB - This paper demonstrated the development and validation of an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of five glycopeptide antibiotics in food and biological samples. The target glycopeptide antibiotics were isolated from the samples by solvent extraction, and the extracts were cleaned with a tandem solid phase extraction step using mixed strong cation exchange and hydrophilic/lipophilic balance cartridges. Subsequently, the analytes were eluted with different solvents, and then quantified by UHPLC-MS/MS in the positive ionization mode with multiple reaction monitoring. Under optimal conditions, good linear correlations were obtained for the five glycopeptide antibiotics in the concentration range of 1.0 MUg/L to 20.0 MUg/L, and with linear correlation coefficients >0.998. Employing this method, the target glycopeptide antibiotics in food and biological samples were identified with a recovery of 83.0-102%, and a low quantitation limit of 1.0 MUg/kg in food and 2.0 MUg/L in biological samples with low matrix effects. PMID- 29397983 TI - Chlorinated paraffin analysis by gas chromatography Orbitrap high-resolution mass spectrometry: Method performance, investigation of possible interferences and analysis of fish samples. AB - For decades, high quantities of short-chain chlorinated paraffins (SCCP) and medium-chain chlorinated paraffins (MCCP) have been widely used, for instance as plasticizers or flame retardants, leading to global pollution due to unintentional emissions from products or waste. Due to the high complexity of chlorinated paraffins with several thousand congeners there is no consensus on an analytical procedure for SCCPs and MCCPs in food samples. Amongst the multitude of methods currently in use, high-resolution mass spectrometry is particularly valuable for in-depth studies of homologue patterns. Here we analyse SCCPs and MCCPs with gas chromatography coupled to high-resolution Orbitrap mass spectrometry (GC-Orbitrap-HRMS) operated in full-scan acquisition in electron capture negative ion (ECNI) mode at 60,000 and 120,000 resolution (FWHM, m/z 200, equals roughly 30,000 and 60,000 at 5% peak height). Linear dynamic range, selectivity and sensitivity tests confirmed an excellent linearity in a concentration range of 25-15,000 pg/MUL with very low limits of detection (LODs) in the low pg/MUL range. Spiking experiments with high levels of native mono- and di-ortho-polychlorinated biphenyls (PCBs) and mixtures of MCCP and SCCP standards did not have a negative impact on isotope ratios of the examined homologues. Besides the [M-Cl]- fragment ions used for quantification, the mass spectra of homologues also featured [M-HCl]- ions whose abundance increased with decreasing chlorination degree. In addition, [M-HCl-Cl]- ions were detected with a relative abundance of 5-10%. Three salmon (Salmo salar) samples farmed in Norway showed a consistent CP homologue pattern which differed both from the CP pattern in a sample from Scottish aquaculture and a wild salmon sample. These measurements produce evidence that discretely different CP patterns may exist in different areas of origin. Our results demonstrate that GC/ECNI-Orbitrap-HRMS is well suited for the analysis of CPs by overcoming a range of mass interference problems and due to its thus far unmatched sensitivity. PMID- 29397984 TI - Use of a hypercrosslinked triphenylamine polymer as an efficient adsorbent for the enrichment of phenylurea herbicides. AB - A hypercrosslinked triphenylamine polymer (HCTPA) was prepared through a simple one-step Friedel-Crafts alkylation reaction. The HCTPA had an extended pi conjugated system, large specific surface area and high micropore volume. In order to evaluate its extraction performance, the HCTPA was used as the adsorbent for the solid-phase extraction of the phenylurea herbicides (monuron, chlortoluron, isoproturon, monolinuron and buturon) from watermelon, tomato and cucumber samples. The main parameters that could affect the extraction efficiency including the sample volume, sample solution pH, sample solution loading rate and desorption conditions were investigated and optimized. Under the optimized conditions, the HCTPA showed a good extraction performance for the target analytes. The linear range for the quantification of the analytes was in the range of 0.4-160.0 ng g-1 with the correlation coefficients of 0.9996-0.9999. The limits of detection (S/N = 3) of the analytes by the method ranged from 0.06 to 0.12 ng g-1 for watermelon and tomato, and 0.06-0.15 ng g-1 for cucumber samples. The recoveries of the analytes for the method were between 83.1% and 112.5% with the relative standard deviations below 5.5%. These results indicate that the HCTPA can be used for the enrichment of phenylurea herbicides from complex matrix samples like watermelon, tomato and cucumbers. PMID- 29397985 TI - Separation and quantitation of eight isomers in a molecule with three stereogenic centers by normal phase liquid chromatography. AB - A normal phase liquid chromatography method was developed for the separation and detection of eight stereoisomers of the key intermediate, CORE + OMe, having three chiral centers. The stereochemistry of this intermediate dictates the stereochemistry of the active pharmaceutical ingredient generated by an additional six synthetic steps. Multiple columns and mobile phases were screened during the development based on a platform approach. The use of dichloromethane as mobile phase additive and adjustment of flow rate and column temperature contributed in achieving resolution of these eight stereoisomers. The separation and detection of these stereoisomers was achieved using a Chiralcel OD-H, 4.6 * 250 mm, 5 MUm dp column with heptane: ethanol: dichloromethane in a ratio of 95:3:2 (v:v:v) as mobile phase at a flow rate of 0.7 mL/min. UV detection was carried out at 245 nm and the column temperature was maintained at 15 degrees C. The analytical method was phase appropriately validated. The limit of detection and limit of quantification were found to be 0.035 and 0.07 MUg, respectively. The newly developed method has been implemented for routine utilization to monitor the chiral control during process development and used as the quality control method for chiral purity of the desired compound. PMID- 29397986 TI - Experimental verification of the steric-entropic mode of retention in centrifugal field-flow fractionation using illite clay plates. AB - The commonly used theory to describe the normal Brownian mode of field-flow fractionation (FFF) assumes the particles to be point masses and hence the shape is ignored. Beckett and Giddings extended this theory to include the effect of thin rods and discs being forced very close to the accumulation wall. By including the decrease in the entropy this causes, they derived new expressions for the retention of such nonspherical particles in FFF. The steric-entropic theory predicts that when the sample cloud thickness is less than the major dimension of the rods or discs then particles elute earlier than predicted by the Brownian mode theory. This leads to an underestimation of the buoyant mass and equivalent spherical diameter calculated from FFF data. In this paper we report for the first time experimental data for the retention of thin illite particles in centrifugal FFF that agrees well with these steric-entropic predictions. Not only do the size distributions calculated using the Brownian mode theory shift to lower size when the field is increased but the shift in the retention ratio of the peak maxima of the FFF fractograms could be predicted fairly accurately by the steric-entropic equations. PMID- 29397987 TI - Fingerprinting and characterization of anthocyanins in 94 colored wheat varieties and blue aleurone and purple pericarp wheat crosses. AB - Colored wheat varieties and crosses were analyzed to figure out their anthocyanin profiles, and thus, their potential as health-related food. After method development, the obtained 94 anthocyanin fingerprints allowed the clear differentiation of the blue aleurone and purple pericarp genotypes as well as their breeding lines. The method was trimmed so that the complete analysis of the whole grain flour including sample preparation of up to 20 samples on one plate took less than 3 h (<9 min per sample) and total costs including sample preparation were <1.0 Euro/sample. Sample preparation of the complex wheat matrix was reduced to a minimum (only acidified methanol extraction of the ground whole wheat grain). Separation was well achieved on amino phases with a mixture of ethyl acetate, 2-butanone, water and formic acid. It was superior to the separation on either normal or reversed phases and more robust with regard to intrinsic pH variances of the sample extracts. Pattern recognition of anthocyanins was simply performed by visual detection (the image), a key feature of high-performance thin-layer chromatography. Wheat varieties and crosses with higher anthocyanin contents were easily selectable, and thus, successfully made out. Prominent anthocyanin zones were characterized by electrospray ionization mass spectrometry. Their sugar moiety was characterized via methanolysis and compared with the sugars available freely in the whole wheat grain. The developed profiling is a fast and efficient screening tool with option for quantification or identification on the same HPTLC plate. PMID- 29397988 TI - Nursing research in heart failure care: a position statement of the american association of heart failure nurses (AAHFN). AB - BACKGROUND: Heart Failure (HF) is a public health problem globally affecting approximately 6 million in the United States. OBJECTIVES: A tailored position statement was developed by the American Association of Heart Failure Nurses (AAHFN) and their Research Consortium to assist researchers, funding institutions and policymakers with improving HF clinical advancements and outcomes. METHODS: A comprehensive review was conducted using multiple search terms in various combinations to describe gaps in HF nursing science. Based on gaps described in the literature, the AAHFN made recommendations for future areas of research in HF. RESULTS: Nursing has made positive contributions through disease management interventions, however, quality, rigorous research is needed to improve the lives of patients and families while advancing nursing science. CONCLUSIONS: Advancing HF science is critical to managing and improving patient outcomes while promoting the nursing profession. Based on this review, the AAHFN is putting forth a call to action for research designs that promote validity, sustainability, and funding of future nursing research. PMID- 29397989 TI - Bioactive Glasses: Sprouting Angiogenesis in Tissue Engineering. AB - The biggest strategic challenge for tissue engineering is the development of efficient vascularized networks in engineered tissues and organs. Bioactive glasses (BGs) are potent biomaterials for inducing angiogenesis in hard and soft tissue engineering applications. Because tissue-healing processes strongly depend on angiogenesis, recent interest in BGs has increased dramatically. BGs with improved angiogenetic properties can be developed by adding a range of metallic ions (e.g., Cu2+, Co2+) into their structure, but further development of BGs with improved angiogenic activity is required, and many crucial questions remain to be answered. We introduce here the salient features, the hurdles that must be overcome, and the hopes and constraints for the development of this approach. PMID- 29397990 TI - The Circuit Motif as a Conceptual Tool for Multilevel Neuroscience. AB - Modern neuroscientific techniques that specifically manipulate and measure neuronal activity in behaving animals now allow bridging of the gap from the cellular to the behavioral level. However, in doing so, they also pose new challenges. Research using incompletely defined manipulations in a high dimensional space without clear hypotheses is likely to suffer from multiple well known conceptual and statistical problems. In this context it is essential to develop hypotheses with testable implications across levels. Here we propose that a focus on circuit motifs can help achieve this goal. Viewing neural structures as an assembly of circuit motif building blocks is not new. However, recent tool advances have made it possible to extensively map, specifically manipulate, and quantitatively investigate circuit motifs and thereby reexamine their relevance to brain function. PMID- 29397991 TI - The Many Worlds of Plasticity Rules. AB - Two recent papers have tackled the fundamental questions of how place fields are formed in a new environment and what plasticity mechanisms contribute to this process. Bittner et al., in their recent publication, discovered a novel plasticity rule that, in contrast to previous rules, spans the behavioral, seconds-long, timescale. Sheffield et al. have monitored, for the first time, dendritic activity during place field formation, and show the emergence of spatially tuned local NMDA spikes in basal dendrites of CA1 neurons. Together, these papers suggest that multiple complementary dendritic plasticity mechanisms may contribute to place field formation in changing environmental contexts. PMID- 29397992 TI - Combined effects of ocean acidification and warming on physiological response of the diatom Thalassiosira pseudonana to light challenges. AB - Diatoms are one of the most important groups of phytoplankton in terms of abundance and ecological functionality in the ocean. They usually dominate the phytoplankton communities in coastal waters and experience frequent and large fluctuations in light. In order to evaluate the combined effects of ocean warming and acidification on the diatom's exploitation of variable light environments, we grew a globally abundant diatom Thalassiosira pseudonana under two levels of temperature (18, 24 degrees C) and pCO2 (400, 1000 MUatm) to examine its physiological performance after light challenge. It showed that the higher temperature increased the photoinactivation rate in T. pseudonana at 400 MUatm pCO2, while the higher pCO2 alleviated the negative effect of the higher temperature on PSII photoinactivation. Higher pCO2 stimulated much faster PsbA removal, but it still lagged behind the photoinactivation of PSII under high light. Although the sustained phase of nonphotochemical quenching (NPQs) and activity of superoxide dismutase (SOD) were provoked during the high light exposure in T. pseudonana under the combined pCO2 and temperature conditions, it could not offset the damage caused by these multiple environmental changes, leading to decreased maximum photochemical yield. PMID- 29397993 TI - Effect of tidal environment on the trophic balance of mixotrophic hexacorals using biochemical profile and photochemical performance as indicators. AB - Fluctuations of environmental factors in intertidal habitats can disrupt the trophic balance of mixotrophic cnidarians. We investigated the effect of tidal environments (subtidal, tidal pools and emerged areas) on fatty acid (FA) content of Zoanthus sociatus and Siderastrea stellata. Effect on photophysiology was also accessed as an autotrophy proxy. There was a general tendency of a lower percentage of zooplankton-associated FAs in colonies from emerged areas or tidal pools when compared with colonies from the subtidal environment. Moreover, tidal environment significantly affected the photophysiology of both species. Colonies from the subtidal generally showed lower values of alpha, ETRmax and Ek when compared with their conspecifics from tidal pools or emerged areas. However, the absence of consistent patterns in Fv/Fm and in dinoflagellate-associated FAs, suggest that these corals are well adapted to intertidal conditions. This suggests that intertidal pressures may disturb the trophic balance, mainly by affecting heterotrophy of these species. PMID- 29397994 TI - Validation of water-borne steroid hormones in a tropical frog (Physalaemus pustulosus). AB - Minimally invasive methods for estimating hormone concentrations in wild vertebrates offer the opportunity to repeatedly measure behavior and hormone concentrations within individuals while minimizing experimenter interference during sample collection. We examined three steroid hormones (corticosterone, CORT; 17-beta estradiol, E2; progesterone, PROG) in tungara frogs (Physalaemus pustulosus) using non-invasive water-borne methods. Using solid-phase extraction of water samples and liquid extraction of plasma and homogenate samples, coupled with enzyme immunoassays, we complimented the conventional validation approaches (parallelism, recovery determination) with dose-response assays that incorporated pharmacological challenges with adrenocorticotropic hormone (ACTH) and human chorionic gonadotropin (HCG). We also compared steroid concentrations in water to those observed in plasma and whole body homogenates. Lastly, we identified the constituent steroids in each sample type with a panel targeting 30 steroid species using high performance liquid chromatography-mass spectrometry (HPLC-MS). We found that a 60-min water-bath captures physiologically relevant changes in concentrations of CORT, E2 and PROG. Peak levels of water-borne CORT were found at approximately 2 h after ACTH injection. Water-borne CORT and E2 concentrations were positively correlated with their plasma and homogenate equivalents, while water-borne PROG was uncorrelated with homogenate PROG concentrations but negatively correlated with homogenate E2 concentrations. Together, our findings indicate that sampling water-borne hormones presents a non-invasive and biologically informative approach that will be useful for behavioral endocrinologists and conservation physiologists. PMID- 29397995 TI - Letter to the editor concerning "Intraoperative lateral wall fractures during Dynamic Hip Screw fixation for intertrochanteric fractures-Incidence, causative factors and clinical outcome". PMID- 29397996 TI - Trochanteric fracture-implant motion during healing - A radiostereometry (RSA) study. AB - Cut-out complication remains a major unsolved problem in the treatment of trochanteric hip fractures. A better understanding of the three-dimensional fracture-implant motions is needed to enable further development of clinical strategies and countermeasures. The aim of this clinical study was to characterise and quantify three-dimensional motions between the implant and the bone and between the lag screw and nail of the Gamma nail. Radiostereometry Analysis (RSA) analysis was applied in 20 patients with trochanteric hip fractures treated with an intramedullary nail. The following three-dimensional motions were measured postoperatively, at 1 week, 3, 6 and 12 months: translations of the tip of the lag screw in the femoral head, motions of the lag screw in the nail, femoral head motions relative to the nail and nail movements in the femoral shaft. Cranial migration of the tip of the lag screw dominated over the other two translation components in the femoral head. In all fractures the lag screw slid laterally in the nail and the femoral head moved both laterally and inferiorly towards the nail. All femoral heads translated posteriorly relative to the nail, and rotations occurred in both directions with median values close to zero. The nail tended to retrovert in the femoral shaft. Adverse fracture-implant motions were detected in stable trochanteric hip fractures treated with intramedullary nails with high resolution. Therefore, RSA method can be used to evaluate new implant designs and clinical strategies, which aim to reduce cut-out complications. Future RSA studies should aim at more unstable fractures as these are more likely to fail with cut-out. PMID- 29397997 TI - Application of the advanced system for implant stability testing (ASIST) to natural teeth for noninvasive evaluation of the tooth root interface. AB - In this paper we present the development of the Advanced System for Implant Stability Testing (ASIST) for application to natural teeth. The ASIST uses an impact measurement combined with an analytical model of the system and surrounding support to provide a measure of the interface stiffness. In this study, an analytical model is developed for a single-rooted natural tooth allowing the ASIST to estimate the stiffness characteristics of the periodontal ligament (PDL). The geometry and inertia parameters of the tooth model are presented in two ways: (1) using full CT scans of the individual tooth and (2) using an approximate geometry model with estimates of only the tooth length and diameter. The developed system is evaluated with clinical data for patients undergoing orthodontic treatment. This study shows that ASIST technique can be applied to natural teeth to estimate the stiffness characteristics of the PDL. The developed system can provide a valuable clinical tool for assessment of tooth stability properties and PDL stiffness in a variety of clinical situations such as dental trauma, orthodontics, and periodontology. PMID- 29397998 TI - Comparison of lower limb kinetics, kinematics and muscle activation during drop jumping under shod and barefoot conditions. AB - This study was to investigate the acute effects of wearing shoes on lower limb kinetics, kinematics and muscle activation during a drop jump. Eighteen healthy men performed a drop jump under barefoot and shod conditions. Vertical ground reaction force (GRF) was measured on a force plate during the contact phase of a drop jump, and GRF valuables were calculated for each condition. The angles of the knee and ankle joints, and the foot strike angle (the angle between the plantar surface of the foot and the ground during ground contact) as well as the electromyography of 7 muscles were measured. The shod condition showed a significant larger first peak GRF, longer time to first peak GRF from the initial ground contact and lower initial loading rate than the barefoot condition. The shod condition showed a significant larger ankle joint angle at initial ground contact, smaller knee joint angle between the second peak GRF and take-off as well as smaller foot strike angle at both initial ground contact and take-off than the barefoot condition. There were significant correlations between relative differences in ankle joint at the initial ground contact and relative differences in the initial loading rate. The muscle activity of all muscles during foot ground contact did not differ between two conditions; however, in the shod condition, muscle activation of 150 ms before foot ground contact was significantly higher in the rectus femoris, whereas it was lower in the biceps femoris and tibialis anterior muscles than the barefoot condition. These results indicate that wearing shoes alternates the GRF variables at initial ground contact, joint kinematics at the ground contact and muscle activation before foot ground contact during a drop jump, suggesting that the effects of wearing shoes on drop jump training differ from being barefoot. PMID- 29397999 TI - Collective spreading of red blood cells flowing in a microchannel. AB - Due to recent advances in micro total analysis system technologies, microfluidics provides increased opportunities to manipulate, stimulate, and diagnose blood cells. Controlling the concentration of cells at a given position across the width of a channel is an important aspect in the design of microfluidic devices. Despite its biomedical importance, the collective spreading of red blood cells (RBCs) in a microchannel has not yet been fully clarified. In this study, we experimentally investigated the collective spreading of RBCs in a straight microchannel, and found that RBCs initially distributed in one side of the microchannel spread to the spanwise direction during downstream flow. Spreading increased considerably as the hematocrit increased, though the flow rate had a small effect. We proposed a scaling argument to show that this spreading phenomenon was diffusive and mainly induced by cell-cell interactions. The dispersion coefficient was approximately proportional to the flow rate and the hematocrit. These results are useful in understanding collective behaviors of RBCs in a microchannel and in microcirculation. PMID- 29398000 TI - An instrumental approach for monitoring physical exercises in a visual markerless scenario: A proof of concept. AB - This work proposes a real-time monitoring tool aimed to support clinicians for remote assessing exercise performances during home-based rehabilitation. The study relies on clinician indications to define kinematic features, that describe five motor tasks (i.e., the lateral tilt of the trunk, lifting of the arms, trunk rotation, pelvis rotation, squatting) usually adopted in the rehabilitation program for axial disorders. These features are extracted by the Kinect v2 skeleton tracking system and elaborated to return disaggregated scores, representing a measure of subjects performance. A bell-shaped function is used to rank the patient performances and to provide the scores. The proposed rehabilitation tool has been tested on 28 healthy subjects and on 29 patients suffering from different neurological and orthopedic diseases. The reliability of the study has been performed through a cross-sectional controlled design methodology, comparing algorithm scores with respect to blinded judgment provided by clinicians through filling a specific questionnaire. The use of task-specific features and the comparison between the clinical evaluation and the score provided by the instrumental approach constitute the novelty of the study. The proposed methodology is reliable for measuring subject's performance and able to discriminate between the pathological and healthy condition. PMID- 29398001 TI - A computer vision based method for 3D posture estimation of symmetrical lifting. AB - Work-related musculoskeletal disorders (WMSD) are commonly observed among the workers involved in material handling tasks such as lifting. To improve work place safety, it is necessary to assess musculoskeletal and biomechanical risk exposures associated with these tasks. Such an assessment has been mainly conducted using surface marker-based methods, which is time consuming and tedious. During the past decade, computer vision based pose estimation techniques have gained an increasing interest and may be a viable alternative for surface marker-based human movement analysis. The aim of this study is to develop and validate a computer vision based marker-less motion capture method to assess 3D joint kinematics of lifting tasks. Twelve subjects performing three types of symmetrical lifting tasks were filmed from two views using optical cameras. The joints kinematics were calculated by the proposed computer vision based motion capture method as well as a surface marker-based motion capture method. The joint kinematics estimated from the computer vision based method were practically comparable to the joint kinematics obtained by the surface marker-based method. The mean and standard deviation of the difference between the joint angles estimated by the computer vision based method and these obtained by the surface marker-based method was 2.31 +/- 4.00 degrees . One potential application of the proposed computer vision based marker-less method is to noninvasively assess 3D joint kinematics of industrial tasks such as lifting. PMID- 29398002 TI - The effect of prolonged level and uphill walking on the postural control of older adults. AB - Prolonged walking could alter postural control leading to an increased risk of falls in older adults. The aim of this study was to determine the effect of level and uphill prolonged walking on the postural control of older adults. Sixteen participants (64 +/- 5 years) attended 3 visits. Postural control was assessed during quiet standing and the limits of stability immediately pre, post and post 15 min rest a period of 30 min walking on level and uphill (5.25%) gradients on separate visits. Each 30 min walk was divided into 3 10 min blocks, the limits of stability were measured between each block. Postural sway elliptical area (PRE: 1.38 +/- 0.22 cm2, POST: 2.35 +/- 0.50 cm2, p = .01), medio-lateral (PRE: 1.33 +/ 0.03, POST: 1.40 +/- 0.03, p = .01) and anterio-posterior detrended fluctuation analysis alpha exponent (PRE: 1.43 +/- 0.02, POST: 1.46 +/- 0.02, p = .04) increased following walking. Medio-lateral alpha exponent decreased between post and post 15 min' rest (POST: 1.40 +/- 0.03, POST15: 1.36 +/- 0.03, p = .03). Forward limits of stability decreased between the second walking interval and post 15 min' rest (Interval 2: 28.1 +/- 1.6%, POST15: 25.6 +/- 1.6%, p = .01) and left limits of stability increased from pre-post 15 min' rest (PRE: 27.7 +/- 1.2%, POST15: 29.4 +/- 1.1%, p = .01). The neuromuscular alterations caused by prolonged walking decreased the anti-persistence of postural sway and altered the limits of stability in older adults. However, 15 min' rest was insufficient to return postural control to pre-exercise levels. PMID- 29398003 TI - The role of Snf5 in the osteogenic differentiation potential during replicative senescence of rat mesenchymal stromal cells. AB - The osteogenic capacities of bone marrow-derived stromal cells (BMSCs) diminish during replicative senescence, and these changes affect the success of therapeutic application of BMSCs. In this study, we sought to explore the molecular mechanisms underlying the osteogenic differentiation capacities that occur during replicative senescence. It is well known that Oct4 is a key transcription factor essential for maintaining differentiation capacities of the stem cells. In this study, we found that BMSCs at passage 6 (replicative senescent BMSCs) showed marked decreases in the osteogenic differentiation potential and the level of Oct4. These were accompanied by reduced levels of Snf5 and histone H3 lysine-4 trimethylation (H3K4me3) in the Oct4 promoter. In BMSCs at passage 2, knockdown of Snf5 diminished expression of Oct4 and disrupted the up-regulation of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) after osteogenic differentiation induction, which was accompanied by a reduction in Snf5 and H3K4me3 binding to the Oct4 promoter. These findings indicate that the decreased level of Snf5 binding to the promoter region of the Oct4 gene down-regulated the expression of Oct4, which may be the mechanism underlying the decline in osteogenic capacities in replicative senescent BMSCs. PMID- 29398005 TI - Kaposi sarcoma in an immunosuppressed young woman. PMID- 29398004 TI - Urticaria multiforme, an "erythema multiforme" simulator. PMID- 29398006 TI - Acute mastoiditis with subperiosteal abscess due to emerging infectious agents. PMID- 29398007 TI - More than a cyst in the head. PMID- 29398008 TI - Mediastinal cystic mass as atypical location of visceral leishmaniasis. PMID- 29398009 TI - Central sensitization syndrome: towards the structuring of a multidisciplinary concept. PMID- 29398010 TI - Deregulation of CRTCs in Aging and Age-Related Disease Risk: (Trends in Genetics, 33, 303-321, 2017). PMID- 29398011 TI - Feeding experiences of nursing aides for residents with dysphagia. AB - Dysphagia is a distressing symptom for residents in long-term care facilities, and nursing aides play an important role in feeding the residents with dysphagia. This study evaluated the perceptions of nursing aides about their feeding experiences for residents with dysphagia. This qualitative descriptive study used convenience sampling and recruited 16 nursing aides from six long-term care facilities in Central Taiwan. Data were collected through face-to-face interviews from November 2016 to March 2017. Participants were recruited until the findings reached saturation, and data were analyzed using qualitative content analysis. Analysis of participants' interview data on feeding experiences identified three main categories: recognizing dysphagia, making adjustments to adapt to the residents' dysphagia, and facing the dilemma of dysphagia management. The results may be useful in designing feeding training programs for nursing aides. PMID- 29398012 TI - Preferences of older inpatients and their family caregivers for life-sustaining treatments in South Korea. AB - This descriptive cross-sectional survey aimed to investigate the preferences of older inpatients and their family caregivers for life-sustaining treatments (LSTs) and their influential factors. Inpatients aged 60 and older and their family caregivers in three acute hospitals in Seoul, South Korea, were invited to participate in the study. A total of 180 surveys were returned from 90 pairs of patients and family caregivers with a response rate of 95%. Older inpatients expressed a significantly high desire for "not wanting to have cardiopulmonary resuscitation" (chi2 = 10.07, p = 0.007) and "mechanical ventilator" (chi2 = 10.35, p = 0.006) compared to their caregivers. Given that experiences of conversations about LSTs was a common factor in both groups and may prevent futile LSTs, it is important for nurses to initiate and support patients and family caregivers, helping them engage in formal and informal conversations about future healthcare preferences. PMID- 29398013 TI - Dietary acrylamide intake during pregnancy and postnatal growth and obesity: Results from the Norwegian Mother and Child Cohort Study (MoBa). AB - BACKGROUND: Prenatal acrylamide exposure has been negatively associated with fetal growth but the association with child growth is unknown. OBJECTIVES: We studied the association between prenatal acrylamide exposure and child postnatal growth up to 8 years in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: In 51,952 mother-child pairs from MoBa, acrylamide intake during pregnancy was estimated by combining maternal food intake with food concentrations of acrylamide. Mothers reported their child's weight and length/height up to 11 times between 6 weeks and 8 years. Weight and height growth trajectories were modelled using Jenss-Bayley's growth model. Logistic regression models were used to study the association with overweight/obese status at 3, 5 and 8 years, as identified using the International Obesity Task Force cut offs. Linear mixed-effect models were used to explore associations with overall growth. RESULTS: At 3 years, the adjusted odds ratios (95% Confidence Intervals (CI)) of being overweight/obese were 1.10 (1.02, 1.20), 1.12 (1.04, 1.22) and 1.21 (1.11, 1.31) by increasing prenatal acrylamide exposure quartile. Similar dose-response associations were found at 5 and 8 years. Acrylamide intake during pregnancy was associated with higher weight growth velocity in childhood. Children exposed at the highest level had 22 g (95% CI: 8, 37), 57 g (95% CI: 32, 81), and 194 g (95% CI: 110, 278) higher weight at 0.5, 2, and 8 years, respectively, compared to their low exposed peers. CONCLUSIONS: Children prenatally exposed to acrylamide in the highest quartile experienced a moderate increase in weight growth velocity during early childhood that resulted in a moderately increased prevalence of overweight/obesity compared to peers in the lowest quartile. Our study is the first to link prenatal acrylamide exposure and postnatal growth. PMID- 29398014 TI - IFPA meeting 2017. PMID- 29398015 TI - Mitochondrial oxidative stress and cardiac ageing. AB - According with different international organizations, cardiovascular diseases are becoming the first cause of death in western countries. Although exposure to different risk factors, particularly those related to lifestyle, contribute to the etiopathogenesis of cardiac disorders, the increase in average lifespan and aging are considered major determinants of cardiac diseases events. Mitochondria and oxidative stress have been pointed out as relevant factors both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy and diabetic cardiomyopathy. During aging, cellular processes related with mitochondrial function, such as bioenergetics, apoptosis and inflammation are altered leading to cardiac dysfunction. Increasing our knowledge about the mitochondrial mechanisms related with the aging process, will provide new strategies in order to improve this process, particularly the cardiovascular ones. PMID- 29398016 TI - Effect of mite allergenic components on innate immune response: Synergy of protease (Group 1 & 3) and non-protease (Group 2 & 7) allergens. AB - The major mite allergenic components of protease allergens (group 1,3) and non protease allergens (group 2,7) derived from Dermatophagoides peronyssinus (Dp) and D. farinae (Df) are reported to be capable of sensitizing 80-90% of mite allergic patients. Although protease and non-protease allergens have been demonstrated to trigger innate and adaptive immune responses through epithelium activation, the simultaneous or sequential effects of both groups of allergens has not been reported. Since all allergens are present in the mite crude extracts, it is important to determine whether these allergens can synergistically trigger the immune responses to cause airway inflammation. A total of 60 house dust mite (HDM)-allergic asthmatic patients were recruited to analyze their serum-specific IgE response to both groups of allergens. Recombinant protease allergen (Der p1 and Der p3) and non-protease allergens (Der p2 and Der p7) were used to activate the human airway epithelium cell (Beas-2B). The cells were analyzed for mRNA expression of IL-6/IL-8 and the culture supernatants were analyzed for neutrophil chemotactic activity (NCA). The results showed 48/60 (80%) HDM-allergic patients were sensitized to all allergenic components of Der p1, Der p2, Der f1, and Der f2. Most of the allergic patients were sensitized to both groups of allergens simultaneously. The associations of Der p1 with Der p2 were 83.3% (50/60) and Der f1 with Der f2 were 80% (48/60). When Beas-2B cells were cultured with Der p2 in conjunction with Der p1 and Der p3, the results showed that there was increased expression of IL-6/IL-8 in comparison with culture with allergen alone. There was only a trivial effect on IL-6/IL-8 expression when Der p2 was co-cultured with Der p7. Similar findings were obtained in the NCA measurement. When Beas-2B was cultured with Der p2 in conjunction with Der p1 and Der p3, there was increased NCA in comparison with culture with allergen alone. There were also trivial effects when Der p2 was co cultured with Der p7. The allergens (Der p2 and Der p3)-induced IL-6/IL-8 expression and NCA released from Beas-2B could be downregulated by dexamethasone and transcription factor inhibitor SP600125. The allergenic components derived from Dp and Df can sensitize allergic patients simultaneously and activate epithelium through protease allergens (group 1, 3) and non-protease allergen (group 2) synergistically. PMID- 29398017 TI - Fermentation and distillation of cheese whey: Carbon dioxide-equivalent emissions and water use in the production of whey spirits and white whiskey. AB - Whey disposal can be both an environmental and economic challenge for artisanal creameries. Lactose in whey can be fermented to produce ethanol and subsequently distilled. The objective of this study was to use a process-based life cycle analysis to compare carbon dioxide-equivalent (CO2e) emissions and water usage associated with the artisanal or craft production of clear, unaged spirits using whey or malted barley as fermentation substrate. Differences in production were assessed based on key process differences: energy used, water used, distillation by-product disposal, and mass of CO2 produced during fermentation. For this study, whey was assumed removed from the artisanal creamery waste stream. Quantifiable differences were evaluated per 750-mL (45% alcohol by volume) functional unit and expressed as mass-equivalent CO2 emissions (kg of CO2e) and mass of water (kg) used. The CO2e emissions and water usage were quantified using published data, thermodynamic calculations, and mass-balance calculations for a hypothetical distillation system. The process-based life cycle analysis estimated that distillation of fermented whey reduced overall CO2e emissions by 8.4 kg per functional unit and required 0.44 kg less water added into the production process compared with production of a similar clear, unaged spirit using malted barley as substrate. Our preliminary analysis suggests that conversion to distilled whey spirit is a more environmentally responsible approach compared with landfill disposal of whey. PMID- 29398018 TI - Short communication: A comparison of biofilm development on stainless steel and modified-surface plate heat exchangers during a 17-h milk pasteurization run. AB - Flow of milk through the plate heat exchanger (PHE) results in denaturation of proteins, resulting in fouling. This also accelerates bacterial adhesion on the PHE surface, eventually leading to the development of biofilms. During prolonged processing, these biofilms result in shedding of bacteria and cross-contaminate the milk being processed, thereby limiting the duration of production runs. Altering the surface properties of PHE, such as surface energy and hydrophobicity, could be an effective approach to reduce biofouling. This study was conducted to compare the extent of biofouling on native stainless steel (SS) and modified-surface [Ni-P-polytetrafluoroethylene (PTFE)] PHE during the pasteurization of raw milk for an uninterrupted processing run of 17 h. For microbial studies, raw and pasteurized milk samples were aseptically collected from inlets and outlets of both PHE at various time intervals to examine shedding of bacteria in the milk. At the end of the run, 3M quick swabs (3M, St. Paul, MN) and ATP swabs (Charm Sciences Inc., Lawrence, MA) were used to sample plates from different sections of the pasteurizers (regeneration, heating, and cooling) for biofilm screening and to estimate the efficiency of cleaning in place, respectively. The data were tested for ANOVA, and means were compared. Modified PHE experienced lower mesophilic and thermophilic bacterial attachment and biofilm formation (average log 1.0 and 0.99 cfu/cm2, respectively) in the regenerative section of the pasteurizer compared with SS PHE (average log 1.49 and 1.47, respectively). Similarly, higher relative light units were observed for SS PHE compared with the modified PHE, illustrating the presence of more organic matter on the surface of SS PHE at the end of the run. In addition, at h 17, milk collected from the outlet of SS PHE showed plate counts of 5.44 cfu/cm2, which were significantly higher than those for pasteurized milk collected from modified PHE (4.12 log cfu/cm2). This provided further evidence in favor of the modified PHE achieving better microbial quality of pasteurized milk in long process runs. Moreover, because cleaning SS PHE involves an acid treatment step, whereas an alkali treatment step is sufficient for the modified-surface PHE, use of the latter is both cost and time effective, making it a better surface for thermal processing of milk and other fluid dairy products. PMID- 29398019 TI - Addition of meloxicam to the treatment of bovine clinical mastitis results in a net economic benefit to the dairy farmer. AB - Recently, it has been shown that the addition of meloxicam to standard antimicrobial therapy for clinical mastitis (CM) improves the conception rate of dairy cows contracting CM in the first 120 d in milk. The objective of our study was to assess whether this improved reproduction through additional treatment with meloxicam would result in a positive net economic benefit for the farmer. We developed a stochastic bio-economic simulation model, in which a dairy cow with CM in the first 120 d in milk was simulated. Two scenarios were simulated in which CM cases were treated with meloxicam in conjunction with antimicrobial therapy or with antimicrobial therapy alone. The scenarios differed for conception rates (31% with meloxicam or 21% without meloxicam) and for the cost of CM treatment. Sensitivity analyses were undertaken for the biological and economic components of the model to assess the effects of a wide range of inputs on inferences about the cost effectiveness of meloxicam treatment. Model results showed an average net economic benefit of ?42 per CM case per year in favor of the meloxicam scenario. Cows in the no-meloxicam treatment scenario had higher returns on milk production, lower costs upon calving, and reduced costs of treatment. However, these did not outweigh the savings associated with lower feed intake, reduced number of inseminations, and the reduced culling rate. The net economic benefit favoring meloxicam therapy was a consequence of the better reproductive performance in the meloxicam scenario in which cows had a shorter calving to conception interval (132 vs. 143 d), a shorter intercalving interval (405 vs. 416 d), and fewer inseminations per conception (2.9 vs. 3.7) compared with cows in the no-meloxicam treatment scenario. This resulted in a shorter lactation, hence a lower lactational milk production (8,441 vs. 8,517 kg per lactation) with lower feeding costs in the meloxicam group. A lower culling rate (12 vs. 25%) resulted in lower replacement costs in the meloxicam treatment scenario. All of the scenarios evaluated in the sensitivity analyses favored meloxicam treatment over no meloxicam. This study demonstrated that improvements in conception rate achieved by the use of meloxicam, as additional therapy for mild to moderate CM in the first 120 d in milk, have positive economic benefits. This inference remained true over a wide range of technical and economic inputs, demonstrating that use of meloxicam is likely to be cost effective across many production systems. PMID- 29398020 TI - Effects of fat content, pasteurization method, homogenization pressure, and storage time on the mechanical and sensory properties of bovine milk. AB - Fluid milk may be pasteurized by high-temperature short-time pasteurization (HTST) or ultrapasteurization (UP). Literature suggests that UP increases milk astringency, but definitive studies have not demonstrated this effect. Thus, the objective of this study was to determine the effects of pasteurization method, fat content, homogenization pressure, and storage time on milk sensory and mechanical behaviors. Raw skim (<0.2% fat), 2%, and 5% fat milk was pasteurized in duplicate by indirect UP (140 degrees C, 2.3 s) or by HTST pasteurization (78 degrees C, 15 s), homogenized at 20.7 MPa, and stored at 4 degrees C for 8 wk. Additionally, 2% fat milk was processed by indirect UP and homogenized at 13.8, 20.7, and 27.6 MPa and stored at 4 degrees C for 8 wk. Sensory profiling, instrumental viscosity, and friction profiles of all milk were evaluated at 25 degrees C after storage times of 1, 4, and 8 wk. Sodium dodecyl sulfate PAGE and confocal laser scanning microscopy were used to determine protein structural changes in milk at these time points. Fresh HTST milk was processed at wk 7 for wk 8 evaluations. Ultrapasteurization increased milk sensory and instrumental viscosity compared with HTST pasteurization. Increased fat content increased sensory and instrumental viscosity, and decreased astringency and friction profiles. Astringency, mixed regimen friction profiles, and sensory viscosity also increased for UP versus HTST. Increased storage time showed no effect on sensory viscosity or mechanical viscosity. However, increased storage time generally resulted in increased friction profiles and astringency. Sodium dodecyl sulfate PAGE and confocal laser scanning microscopy showed increased denatured whey protein in UP milk compared with HTST milk. The aggregates or network formed by these proteins and casein micelles likely caused the increase in viscosity and friction profiles during storage. Homogenization pressure did not significantly affect friction behaviors, mechanical viscosity, or astringency; however, samples homogenized at 13.8 MPa versus 20.7 and 27.6 MPa showed higher sensory viscosity. Astringency was positively correlated with the friction coefficient at 100 m/s sliding speed (R2 = 0.71 for HTST milk and R2 = 0.74 for UP milk), and sensory viscosity was positively correlated with the mechanical viscosity at a shear rate of 50 s-1 (R2 = 0.90). Thus, instrumental testing can be used to indicate certain sensory behaviors of milk. PMID- 29398021 TI - Identification and proteolytic activity quantification of Pseudomonas spp. isolated from different raw milks at storage temperatures. AB - Commercial milk products worldwide come not only from cows, but also from goats, buffaloes, camels, and yaks. Milk from non-bovine animals is important culturally and economically. Pseudomonas spp. are frequently linked to milk spoilage under storage temperatures. The objectives of this study were to identify Pseudomonas spp. isolated from goat, buffalo, camel, and yak milks, and to measure proteolytic activity of Pseudomonas spp. under different storage temperatures. Raw milk samples of goat (n = 50), buffalo (n = 25), camel (n = 25), and yak (n = 25) were collected from 5 provinces in China. Pseudomonas spp. were analyzed by Pseudomonas-specific 16S, universal 16S rRNA, and rpoB gene sequence analyses. Proteolytic activity on milk agar, quantification via the trinitrobenzenesulfonic acid assay at 2 degrees C, 4 degrees C, 7 degrees C, 10 degrees C and 25 degrees C, as well as alkaline peptidase gene (aprX) identification were performed to ascertain the proteolytic activity of these isolates. Pseudomonas spp. were found in 46 samples out of total 125 samples. A total of 67 Pseudomonas spp. were identified. Of Pseudomonas isolates, we obtained extracellular peptidase activity in 7 (10.4%) at 2 degrees C, 17 (25.4%) at 4 degrees C, 24 (35.8%) at 7 degrees C, 39 (58.2%) at 10 degrees C, and 41 (61.2%) at 25 degrees C. The results revealed that a wide diversity of Pseudomonas spp. were present in different non bovine raw milks, with the ability to produce peptidases at storage temperatures. However, proteolytic activity varied widely among the peptidase-positive isolates. A majority of isolates from yak milk had high proteolytic activity. PMID- 29398022 TI - Establishing blood gas ranges in healthy bovine neonates differentiated by age, sex, and breed type. AB - Calf mortality and morbidity commonly occurs within the first month of life postpartum. Standard health ranges are invaluable aids in diagnostic veterinary medicine to confirm normal or the degree and nature of abnormal parameters in (sub)clinically ill animals. Extensive research has indicated significant differences between the physiologies of neonate and adult cattle, particularly for blood parameters such as pH, base excess, anion gap, and bicarbonate (HCO3-). The objective of this research was to determine the influence of age, sex, and breed type, in addition to environmental factors, on the normal blood gas profiles of neonatal calves, and thus develop a scientifically validated reference range accounting for any significant factors. The study was conducted on healthy neonatal calves (n = 288), and completed over a 2-yr period. Individual calf blood gas analysis was conducted for parameters of pH, base excess, Na+, K+, Ca2+, Cl-, glucose, total hemoglobin, HCO3-, pCO2, anion gap, strong ion difference, and hematocrit levels. Regression procedures examined the combined effect of year, farm, age, breed type, sex, and hours postfeeding on each variable. Significant effects were observed for age, sex, and breed type on several of the blood gas variables. Furthermore, year, farm, and hours postfeeding appeared to have less of an influence on neonatal bovine blood gas profiles. Consequently, specific ranges based on the neonate's age, sex, and breed type will allow for more detailed and accurate diagnosis of health and ill health in neonatal calves. PMID- 29398023 TI - Identification of biological traits associated with differences in residual energy intake among lactating Holstein cows. AB - Residual feed intake, which is usually used to estimate individual variation of feed efficiency, requires frequent and accurate measurements of individual feed intake to be carried out. Developing a breeding scheme based on residual feed intake in dairy cows is therefore complicated, especially because feed intake is not measurable for a large population. Another solution could be to focus on biological determinants of feed efficiency, which could potentially be directly and broadband measurable on farm. Several phenotypes have been identified in literature as being associated with differences in feed efficiency. The present study therefore aims to identify which biological mechanisms are associated with residual energy intake (REI) differences among dairy cows. Several candidate phenotypes were recorded frequently and simultaneously throughout the first 238 d in milk for 60 Holstein cows fed on a constant diet based on maize silage. A multiple linear regression of the 238 d in milk average of net energy intake was fitted on the 238 d in milk averages for milk energy output, metabolic body weight, the sum over the 238 d in milk of both, body condition score loss and gain, and the residuals were defined as REI. A partial least square regression was fitted over all biological traits to explain REI variability. Linear multiple regression explained 93.6% of net energy intake phenotypic variation, with 65.5% associated with lactation requirement, 23.2% with maintenance, and 4.9% with body reserves change; the 6.4% residuals represented REI. Overall, measured biological traits contributed to 58.9% of REI phenotypic variability, which were mainly explained by activity (26.5%) and feeding behavior (21.3%). However, apparent confounding was observed between behavior, activity, digestibility, and rumen temperature variables. Drawing a conclusion on biological traits that explain feed efficiency differences among dairy cows was not possible due to this apparent confounding between the measured variables. Further investigation is needed to validate these results and to characterize the causal relationship of feed efficiency with feeding behavior, digestibility, body reserves change, activity, and rumen temperature. PMID- 29398024 TI - The effect of rework content addition on the microstructure and viscoelastic properties of processed cheese. AB - The aim of this work was to add various amounts of rework (0.0 to 20.0% wt/wt) to processed cheeses with a dry matter content of 36% (wt/wt) and fat with a dry matter content of 45% (wt/wt). The effect of the rework addition on the viscoelastic properties and microstructure of the processed cheeses was observed. The addition of rework (in this case, to processed cheese with a spreadable consistency) in the amounts of 2.5, 5.0, and 10.0% (wt/wt) increased the firmness of the processed cheese. With the further addition of rework, the consistency of the processed cheeses no longer differed significantly. The conclusions obtained by the measurement of viscoelastic properties were supported by cryo-scanning electron microscopy, where fat droplets in samples with added rework of over 10.0% (wt/wt) were smaller than fat droplets in processed cheeses with lower additions of rework. PMID- 29398025 TI - Effect of temperature on the microstructure of fat globules and the immunoglobulin-mediated interactions between fat and bacteria in natural raw milk creaming. AB - Natural creaming of raw milk is the first step in production of Grana Padano and Parmigiano Reggiano Protected Denomination of Origin cheeses. This process decreases the fat content and plays an important role in the removal of clostridia species that may cause late-blowing defects in ripened cheeses. Partial coalescence of fat globules-that may influence fat behavior in cheese making and affect the microstructure of fat in the final cheese product-was observed at creaming temperatures higher than 22 degrees C by confocal laser scanning microscopy. The widespread practice of heating of milk at 37 degrees C before creaming at 8 degrees C resulted in important changes in the size distribution of fat globules in raw milk, potentially altering the ability of fat to entrap clostridia spores. We investigated the role of immunoglobulin classes in both the clustering of fat globules and the agglutination of Clostridium tyrobutyricum to fat globules during creaming. Immunogold labeling and transmission electron microscopy showed that IgA and IgM but not IgG were involved in both clustering and agglutination. Both vegetative cells and spores were clearly shown to agglutinate to fat droplets, a process that was suppressed by thermal denaturation of the immunoglobulins. The debacterization of raw milk through natural creaming was improved by the addition of purified immunoglobulins. Overall, these findings provide not only a better understanding of the phenomena occurring during the natural creaming but also practical insights into how the process of creaming may be optimized in cheese production plants. PMID- 29398026 TI - Antimicrobial consumption on dairy herds and its association with antimicrobial inhibition zone diameters of non-aureus staphylococci and Staphylococcus aureus isolated from subclinical mastitis. AB - The main objectives of this study were to quantify the consumption of antimicrobials on a convenience sample of dairy herds and to determine the association between herd-level antimicrobial consumption and inhibition zone diameters (IZD) of non-aureus staphylococci and Staphylococcus aureus isolates from subclinical mastitis cases. Also, the association between the IZD of non aureus staphylococci and Staph. aureus isolates within a herd was studied. Antimicrobial consumption data on 56 Flemish dairy farms were obtained between 2013 and 2014 by so-called garbage can audits and expressed as antimicrobial treatment incidence (ATI), with the unit of ATI being the number of defined daily doses animal (DDDA) used per 1,000 cow-days. The average total ATI in adult dairy cattle for all active substances was 18.73 DDDA per 1,000 cow-days and ranged from 6.28 to 42.13 DDDA between herds. The ATI of critically important (for human health) antimicrobials was 6.91 DDDA per 1,000 cow-days; that is, 37% of total antimicrobial consumption. The average ATI for intramammary therapy of (sub)clinical mastitis, intramammary dry-cow therapy, and systemically administered therapy was 5.20, 6.70, and 6.73 DDDA, respectively. The IZD of 239 non-aureus staphylococci and 88 Staph. aureus isolates originating from milk samples from cows with subclinical mastitis collected on selected dairy herds were determined using Kirby-Bauer disk diffusion and ranged between 6 and 42 mm. Because only a limited number of clinical breakpoints (Clinical and Laboratory Standards Institute) and epidemiological cut-off values (European Committee on Antimicrobial Susceptibility Testing) are available for mastitis-causing bacteria in bovine, IZD were used as a proxy for antimicrobial resistance. Inhibition zone diameters of non-aureus staphylococci for cefquinome, a critically important beta lactam antibiotic, were negatively associated with the ATI of critically important beta-lactam for systemically administered therapy and positively with the ATI for intramammary therapy of (sub)clinical mastitis of critically important beta-lactam antimicrobials. Only for neomycin was a positive association between the IZD of non-aureus staphylococci and Staph. aureus isolates within the same herd observed. PMID- 29398027 TI - Effects of acetic acid or sodium acetate infused into the rumen or abomasum on feeding behavior and metabolic response of cows in the postpartum period. AB - Effects of continuous isomolar infusions of acetic acid (AcA) or sodium acetate (NAc) infused into the rumen (RU) or into the abomasum (AB) on feeding behavior, dry matter intake (DMI), and metabolic response of cows in the early postpartum period were evaluated. Six rumen-cannulated multiparous Holstein cows (11.8 +/- 3.9 d in milk; mean +/- SD) were utilized in a 6 * 6 Latin square design experiment balanced for carryover effects with a 2 * 3 factorial arrangement of treatments. Treatments were AcA and NAc, with sodium chloride (CON) as a control, infused at a rate of ~0.75 mol/h (0.5 L/h) into the RU or AB for the first 8 h following feeding, with a rest day between infusion days. Treatment sequences were assigned randomly to cows. Feeding behavior was recorded by a computerized data acquisition system and blood was sampled at 0, 4, and 8 h relative to the start of infusion. We hypothesized that AcA is more hypophagic than NAc, and that infusion into the AB is more hypophagic than infusion into the RU. Dry matter intakes (DMI) for the CON treatments were similar at 6.2 kg/8 h for RU and 6.1 kg/8 h for AB, and the AcA and NAc treatments interacted with site of infusion to affect DMI. The NAc-RU treatment did not reduce DMI (7.0 kg/8 h), whereas AcA-RU (2.6 kg/8 h), AcA-AB (3.7 kg/8 h), and NAc-AB (4.0 kg/8 h) decreased DMI compared with CON. Following infusions of AcA compared with NAc, there was a residual effect on DMI for the remainder of the day, but treatments did not affect DMI during the rest day. Treatments increased plasma acetate and beta-hydroxybutyrate concentrations over time (interaction) and decreased plasma insulin concentration compared with CON. Plasma glucose concentration decreased over time after AcA-AB infusion compared with other treatments and CON. Plasma nonesterified fatty acid concentration increased over time for AcA compared with NAc and CON, suggesting an increase in lipolysis to compensate the decrease in DMI. In contrast to the other treatments, NAc-RU did not decrease DMI compared with control but we cannot determine the reason for this from the data available from the current study. PMID- 29398028 TI - Effect of dietary vitamin D3 and 25-hydroxyvitamin D3 supplementation on plasma and milk 25-hydroxyvitamin D3 concentration in dairy cows. AB - Milk enriched with vitamin D by supplementing dairy cow diets could provide a valuable dietary source of vitamin D, but information on the feasibility of this approach is limited. In the current study, the effects of supplementing dairy cows with either vitamin D3 or 25(OH)D3 over the transition/early lactation period on plasma and milk vitamin D concentrations were compared. Sixty dairy cows were randomly allocated to 1 of 4 dietary treatments from 14 d precalving to 56 d postcalving. Treatments were a control diet (control) for both precalving and postcalving periods containing 0.625 mg/d of vitamin D3; a precalving diet supplemented with 6 mg of 25(OH)D3/d, but with a postcalving diet matching that of the control diet [25(OH)D3 precalving]; the control diet precalving but with the postcalving diet supplemented with 2 mg of vitamin D3/d (D3max), and the control diet precalving but with the postcalving diet supplemented with 1.5 mg of 25(OH)D3/d [25(OH)D3 postcalving]. No treatment effect on milk yield, composition or 25(OH)D3 concentration was observed. However, an interaction was observed of treatment and time for plasma 25(OH)D3 concentration; this increased within 2 wk of supplementation for the 25(OH)D3 precalving treatment (peaking just after calving, 202 ng/mL), whereas that of the 25(OH)D3 postcalving group had a slower response following supplementation, continuing to increase at 56 d. Correlations were observed between plasma and milk 25(OH)D3 concentrations at d 4 and 14 of lactation, but not at later sampling times. The D3max treatment did not increase 25(OH)D3 concentration in plasma or milk. Overall, results from this study indicate that supplemental 25(OH)D3 is an effective means of enhancing dairy cow plasma 25(OH)D3 concentrations compared with vitamin D3 supplementation, but not necessarily milk concentrations. PMID- 29398029 TI - Estimating milk yield and value losses from increased somatic cell count on US dairy farms. AB - Milk loss due to increased somatic cell counts (SCC) results in economic losses for dairy producers. This research uses 10 mo of consecutive dairy herd improvement data from 2013 and 2014 to estimate milk yield loss using SCC as a proxy for clinical and subclinical mastitis. A fixed effects regression was used to examine factors that affected milk yield while controlling for herd-level management. Breed, milking frequency, days in milk, seasonality, SCC, cumulative months with SCC greater than 100,000 cells/mL, lactation, and herd size were variables included in the regression analysis. The cumulative months with SCC above a threshold was included as a proxy for chronic mastitis. Milk yield loss increased as the number of test days with SCC >=100,000 cells/mL increased. Results from the regression were used to estimate a monetary value of milk loss related to SCC as a function of cow and operation related explanatory variables for a representative dairy cow. The largest losses occurred from increased cumulative test days with a SCC >=100,000 cells/mL, with daily losses of $1.20/cow per day in the first month to $2.06/cow per day in mo 10. Results demonstrate the importance of including the duration of months above a threshold SCC when estimating milk yield losses. Cows with chronic mastitis, measured by increased consecutive test days with SCC >=100,000 cells/mL, resulted in higher milk losses than cows with a new infection. This provides farm managers with a method to evaluate the trade-off between treatment and culling decisions as it relates to mastitis control and early detection. PMID- 29398030 TI - High concentrations of fatty acids and beta-hydroxybutyrate impair the growth hormone-mediated hepatic JAK2-STAT5 pathway in clinically ketotic cows. AB - The hepatic growth hormone (GH)-insulin-like growth factor (IGF)-I axis is essential for regulating intrahepatic lipid metabolism. Ketotic cows are characterized by high blood concentrations of fatty acids and beta hydroxybutyrate (BHB), which display lipotoxicity. The aim of this study was to investigate changes in the hepatic GH-IGF-I axis in ketotic cows and to determine the effects of fatty acids and BHB on the GH-IGF-I axis in calf hepatocytes. Liver and blood samples were collected from healthy (n = 15) and clinically ketotic (n = 15) cows. Hepatocytes were isolated from calves and treated with various concentrations of GH, fatty acids, and BHB. The results showed that clinically ketotic cows displayed a high blood concentration of GH, a low blood concentration of IGF-I, and decreased hepatic GHR1A expression as well as impaired hepatic Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling. In vitro, GH treatment induced activation of the JAK2-STAT5 pathway to increase the mRNA expression and secretion of IGF-I in calf hepatocytes. More importantly, treatment with fatty acids or BHB significantly inhibited GHR1A mRNA and JAK2 protein expression, as well as the STAT5 phosphorylation level and phospho-STAT5 nuclear translocation; these effects markedly reduced IGF1 mRNA expression and secretion in calf hepatocytes. In summary, these results indicate that high blood concentrations of fatty acids or BHB can impair the intrahepatic GH-mediated JAK2-STAT5 pathway and downregulate IGF-I expression and secretion in ketotic cows. PMID- 29398031 TI - Does the number of parathyroid glands autotransplanted affect the incidence of hypoparathyroidism and recovery of parathyroid function? AB - BACKGROUND: The relationship between the number of parathyroid glands autotransplanted and hypoparathyroidism as well as recovery of parathyroid function is not understood fully. The aim was to ascertain whether the number of autotransplanted glands affected the incidence of hypoparathyroidism and recovery of parathyroid function in long-term follow-up after thyroidectomy. METHODS: A retrospective cohort study included all patients with papillary thyroid carcinoma who underwent first-time total thyroidectomy with central neck dissection between June 2012 and June 2015. The patients were divided into 4 groups (0, 1, 2, and 3) on the basis of the number of parathyroid glands autotransplanted. RESULTS: Of the 766 patients, 283 (36.9%) had no gland autotransplanted, and 373 (48.7%), 97 (12.7%), and 13 (1.7%) had 1, 2, and 3 glands autotransplanted, respectively. More lymph nodes and more metastatic ones in the central compartment were retrieved in groups 2 and 3 (P < .05). With increasing number of autotransplanted glands, the incidence of transient hypoparathyroidism was 26.1%, 36.2%, 52.6%, and 84.6% (P < .05), and the incidence of permanent hypoparathyroidism was 1.8%, 1.1%, 1.0%, and 0% (P > .05). The recovery rates of serum parathyroid hormone concentration were 84.7%, 82.2%, 82.0%, and 79.2% after 2-year follow-up (P > .05). CONCLUSION: Autotransplantation is an effective strategy for restoration of parathyroid function. Transient hypoparathyroidism is positively correlated to the number of autotransplanted parathyroid glands during total thyroidectomy with central neck dissection. There is no increase in permanent hypoparathyroidism in patients with a higher number of autotransplanted glands, despite more extensive lymph node disease. (Surgery 2018;161:XXX-XXX.). PMID- 29398032 TI - Invited commentary: databases for surgical health services research: collaborative quality improvement programs. PMID- 29398033 TI - Preoperative biliary colonization/infection caused by multidrug-resistant (MDR) pathogens in patients undergoing major hepatectomy with extrahepatic bile duct resection. AB - BACKGROUND: The aim of this study was to review the surgical outcomes of patients who underwent major hepatectomy with extrahepatic bile duct resection after preoperative biliary drainage with a particular focus on the impact of preoperative biliary colonization/infection caused by multidrug-resistant pathogens. METHODS: Medical records of patients who underwent hepatobiliary resection after preoperative external biliary drainage between 2001 and 2015 were reviewed retrospectively. Prophylactic antibiotics were selected according to the results of drug susceptibility tests of surveillance bile cultures. RESULTS: In total, 565 patients underwent surgical resection. Based on the results of bile cultures, the patients were classified into three groups: group A, patients with negative bile cultures (n = 113); group B, patients with positive bile cultures without multidrug-resistant pathogen growth (n = 416); and group C, patients with multidrug-resistant pathogen-positive bile culture (n = 36). The incidence of organ/space surgical site infection, bacteremia, median duration of postoperative hospital stay, and the mortality rate did not differ among the three groups. The incidence of incisional surgical site infection and infectious complications caused by multidrug-resistant pathogens was significantly higher in group C than in groups A and B. Fifty-two patients had postoperative infectious complications caused by multidrug-resistant pathogens. Multivariate analysis identified preoperative multidrug-resistant pathogen-positive bile culture as a significant independent risk factor for postoperative infectious complications caused by multidrug-resistant pathogens (P< .001). CONCLUSION: Major hepatectomy with extrahepatic bile duct resection after biliary drainage can be performed with acceptable rates of morbidity and mortality using appropriate antibiotic prophylaxis, even in patients with biliary colonization/infection caused by multidrug-resistant pathogens. PMID- 29398034 TI - Active surveillance for micro-papillary thyroid carcinoma: who are candidates, how should they be followed, when should they be treated, and what are the clinical and pathologic outcomes after delayed intervention. PMID- 29398035 TI - Perioperative and long-term outcome of intrahepatic cholangiocarcinoma involving the hepatic hilus after curative-intent resection: comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. AB - BACKGROUND: Intrahepatic cholangiocarcinoma with hepatic hilus involvement has been either classified as intrahepatic cholangiocarcinoma or hilar cholangiocarcinoma. The present study aimed to investigate the clinicopathologic characteristics and short- and long-term outcomes after curative resection for hilar type intrahepatic cholangiocarcinoma in comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. METHODS: A total of 912 patients with mass-forming peripheral intrahepatic cholangiocarcinoma, 101 patients with hilar type intrahepatic cholangiocarcinoma, and 159 patients with hilar cholangiocarcinoma undergoing curative resection from 2000 to 2015 were included from two multi-institutional databases. Clinicopathologic characteristics and short- and long-term outcomes were compared among the 3 groups. RESULTS: Patients with hilar type intrahepatic cholangiocarcinoma had more aggressive tumor characteristics (eg, higher frequency of vascular invasion and lymph nodes metastasis) and experienced more extensive resections in comparison with either peripheral intrahepatic cholangiocarcinoma or hilar cholangiocarcinoma patients. The odds of lymphadenectomy and R0 resection rate among patients with hilar type intrahepatic cholangiocarcinoma were comparable with hilar cholangiocarcinoma patients, but higher than peripheral intrahepatic cholangiocarcinoma patients (lymphadenectomy incidence, 85.1% vs 42.5%, P < .001; R0 rate, 75.2% vs 88.8%, P < .001). After curative surgery, patients with hilar type intrahepatic cholangiocarcinoma experienced a higher rate of technical related complications compared with peripheral intrahepatic cholangiocarcinoma patients. Of note, hilar type intrahepatic cholangiocarcinoma was associated with worse disease-specific survival and recurrence-free survival after curative resection versus peripheral intrahepatic cholangiocarcinoma (median disease specific survival, 26.0 vs 54.0 months, P < .001; median recurrence-free survival, 13.0 vs 18.0 months, P = .021) and hilar cholangiocarcinoma (median disease-specific survival, 26.0 vs 49.0 months, P = .003; median recurrence-free survival, 13.0 vs 33.4 months, P < .001). CONCLUSION: Mass-forming intrahepatic cholangiocarcinoma with hepatic hilus involvement is a more aggressive type of cholangiocarcinoma, which showed distinct clinicopathologic characteristics, worse long-term outcomes after curative resection, in comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. PMID- 29398036 TI - What matters after sleeve gastrectomy: patient characteristics or surgical technique? AB - BACKGROUND: The impact of operative technique on outcomes in laparoscopic sleeve gastrectomy has been explored previously; however, the relative importance of patient characteristics remains unknown. Our aim was to characterize national variability in operative technique for laparoscopic sleeve gastrectomy and determine whether patient-specific factors are more critical to predicting outcomes. METHODS: We queried the database of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program for laparoscopic sleeve gastrostomies performed in 2015 (n = 88,845). Logistic regression models were used to determine predictors of postoperative outcomes. RESULTS: In 2015, >460 variations of laparoscopic sleeve gastrectomy were performed based on combinations of bougie size, distance from the pylorus, use of staple line reinforcement, and oversewing of the staple line. Despite such substantial variability, technique variants were not predictive of outcomes, including perioperative morbidity, leak, or bleeding (all P >= .05). Instead, preoperative patient characteristics were found to be more predictive of these outcomes after laparoscopic sleeve gastrectomy. Only history of gastroesophageal disease (odds ratio 1.44, 95% confidence interval 1.08-1.91, P < .01) was associated with leak. CONCLUSION: Considerable variability exists in technique among surgeons nationally, but patient characteristics are more predictive of adverse outcomes after laparoscopic sleeve gastrectomy. Bundled payments and reimbursement policies should account for patient-specific factors in addition to current accreditation and volume thresholds when deciding risk-adjustment strategies. PMID- 29398038 TI - Discussion. PMID- 29398037 TI - The National Trauma Data Bank story for emergency department thoracotomy: How old is too old? AB - BACKGROUND: The fastest growing segment of the American population is the elderly (>65 years). This change in demographics also is being seen in trauma centers. Emergency department thoracotomy is utilized in an attempt to restore circulation for patients arriving in extremis. The purpose of this study was to investigate the relationship between clinical variables, particularly age, and outcomes for injured patients receiving an emergency department thoracotomy. METHODS: Using the National Trauma Data Bank for years 2008-2012, observations with International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes for exploratory thoracotomy were identified. Emergency department thoracotomy was defined as any observation that occurred at a time to thoracotomy less than the total time spent in the emergency department thoracotomy, and within 15 minutes of arrival. Mechanisms of injury, demographic data, and injuries were analyzed for predictors of survival and mortality rates. Mortality rates were determined for each decade and year of life. RESULTS: There were 11,380 observations for thoracotomy identified. Of these, 2,519 were emergency department thoracotomy, with the majority (n= 2,026, 80% observations) performed for penetrating wounds. Mortality rates ranged from 80% to 100% for each decade of life. Mortality was 100% for patients >57 years old with either penetrating or blunt mechanisms of injury. CONCLUSION: Emergency department thoracotomy offered no survival benefit for patients older than 57 years of age. These data suggest that emergency department thoracotomy performed in elderly patients may be futile. PMID- 29398040 TI - Discussion. PMID- 29398039 TI - Clinicopathologic score predicting lymph node metastasis in T1 gastric cancer. AB - BACKGROUND: Although gastrectomy with adequate regional nodal examination is considered the standard of care for invasive gastric adenocarcinoma, endoscopic resection has been adopted increasingly in select patients with T1 gastric cancer. The objective of this study was to identify preoperative predictors of lymph node metastasis in patients in the United States with T1 gastric cancer. METHODS: Patients who underwent operative resection for T1 gastric cancer between 2000 and 2012 were identified from a multi-institutional database. Clinicopathologic predictors of lymph node metastasis were determined using univariate and multivariate logistic regression. A preoperative score was created, assigning points based on each variable's regression coefficient. RESULTS: Among 835 patients with gastric cancer undergoing curative-intent surgical resection, 176 patients (20.5%) had T1 disease confirmed on final pathology. Of those, 38 patients (22%) had lymph node metastasis. Independent predictors of lymph node involvement on multivariate analysis were poor differentiation, T1b stage, lymphovascular invasion, and tumor size >2 cm. A clinicopathologic risk score composed of these 4 variables was created. Receiver operating curve analysis showed excellent discrimination (area under the curve = 0.79) and 100% sensitivity in detecting lymph node metastasis when only one of the aforementioned factors was present. CONCLUSIONS: In this cohort of U.S. patients with T1 gastric adenocarcinoma, the lack of lymph node involvement could be predicted by the absence of several unfavorable factors, including T stage, poor differentiation, lymphovascular invasion, and size >2 cm. PMID- 29398041 TI - The effect of prior upper abdominal surgery on outcomes after liver transplantation for hepatocellular carcinoma: An analysis of the database of the organ procurement transplant network. AB - OBJECTIVES: Orthotopic liver transplantation (OLT) is the preferred treatment for hepatocellular carcinoma (HCC) in select patients. Many patients listed for OLT have a history of prior upper abdominal surgery (UAS). Repeat abdominal surgery increases operative complexity and may cause a greater incidence of complication. This study sought to compare outcomes after liver transplantation for patients with and without prior UAS. METHODS: Adult HCC patients undergoing OLT were identified using the database from the Organ Procurement and Transplantation Network (1987-2015). Patients were separated by presence of prior UAS into 2 propensity-matched cohorts. Overall survival (OS) and graft survival (GS) were analyzed by log-rank test and graphed using Kaplan-Meier method. Recipient and donor demographic and clinical characteristics were also studied using Cox regression models. RESULTS: A total of 15,043 patients were identified, of whom 6,205 had prior UAS (41.2%). After 1:1 propensity score matching, cohorts (UAS versus no UAS) contained 4,669 patients. UAS patients experienced shorter GS (122 months vs 129 months; P < .001) and shorter OS (130 months vs 141 months; P < .001). Median duration of stay for both cohorts was 8 days. Multivariate Cox regression models revealed that prior UAS was associated with an increased hazard ratio (HR) for GS (HR 1.14; 95% confidence interval (CI) 1.06-1.22; P < .001) and OS (HR 1.14; 95% CI 1.06-1.23; P < .001). CONCLUSION: Prior UAS is an independent negative predictor of GS and OS after OLT for HCC. OLT performed in patients with UAS remains a well-tolerated and effective treatment for select HCC patients but may alter expected outcomes and influence follow-up protocols. PMID- 29398042 TI - Patient preference for time-saving telehealth postoperative visits after routine surgery in an urban setting. AB - BACKGROUND: Focusing on high-value delivery of health care, we describe our implementation of telephone postoperative visits as alternatives to in-person follow-up after routine, low-risk surgery in an urban setting. Our pilot program assessed telephone postoperative visit feasibility as well as patient satisfaction and clinical outcomes. METHODS: We offered telephone postoperative visits to all clinically eligible, in-state patients scheduled for appropriate low-risk operations. An advanced practitioner conducted the telephone postoperative visit within 2 weeks of the operation and discharged patients from routine follow-up if recovery was satisfactory. We reviewed the medical records to identify encounters and adverse events in the 30-day postoperative period. RESULTS: Telephone postoperative visits were opted for by 92/94 (98%) clinically eligible, in-state patients. Most patients cited convenience (55%), travel (34%), and time (22%) as their main motivations. The average patient opting in was 55 +/ 16 years old (range 23-88, 8% > 65) and lived 22 +/- 26 miles from our clinic (range 0.9-124). Of 50 patients completing telephone postoperative visits, 48 (96%, 2 were not asked) were satisfied with the telephone postoperative visit as their sole postoperative visit, 44 (88%) of whom required no additional follow up. On average, telephone postoperative visits lasted 8.6 +/- 3.9 minutes, compared with the 82.8 +/- 33.4 minutes for preintervention, postoperative visit time. Adding travel times, we estimate each patient saved an average of 139-199 minutes or 94-96% of the time they would have spent coming to clinic. No instances of major morbidity or mortality were identified on chart review. CONCLUSION: Many patients find telephone postoperative visits more convenient than in-clinic visits. Moreover, estimates of time saved are compelling. Amid changing regulations and reimbursement, our findings support the growing use of telehealth for postoperative care of routine, low risk operations. PMID- 29398043 TI - Preventive radioecological assessment of territory for optimization of monitoring and countermeasures after radiation accidents. AB - A methodology of a preventive radioecological assessment of the territory has been developed for optimizing post-emergency monitoring and countermeasure implementation in an event of a severe radiation accident. Approaches and main stages of integrated radioecological zoning of the territory are described. An algorithm for the assessment of the potential radioecological criticality (sensitivity) of the area is presented. The proposed approach is validated using data of the dosimetric passportization in Ukraine after the Chernobyl accident for the test site settlements. PMID- 29398044 TI - Mapping potassium and thorium concentrations in Belgian soils. AB - The European Atlas of Natural Radiation developed by the Joint Research Centre (JRC) of the European Commission includes maps of potassium K and thorium Th. With several different databases available, including data (albeit not calibrated) from an airborne survey, Belgium is a favourable case for exploring the methodology of mapping for these natural radionuclides. Harmonized databases of potassium and thorium in soil were built by radiological (not airborne) and geochemical data. Using this harmonized database it was possible to calibrate the data from the airborne survey. Several methods were used to perform spatial interpolation and to smooth the data: moving average (MA) without constraint, or constrained by soil class and by geological unit. Overall, there was a reasonable agreement between the maps on a 1 * 1 km2 grid obtained with the two datasets (airborne data and harmonized soil data) with all the methods. The agreement was better when the maps are reduced to a 10 km * 10 km grid used for the European Atlas of Natural Radiation. The best agreement was observed with the MA constrained by geological unit. PMID- 29398045 TI - [Management of orbital inflammation in internal medicine. Proposal for a diagnostic work-up]. AB - Inflammatory orbitopathies relate to an inflammatory state originating within the orbit and its adnexes, except the inner ocular globe. Orbital inflammation (OI) may be either localized manifestation of a proven or like autoimmune disease, or local response from immune system against infectious, structural or tumoral antigens. We review the clinical manifestations of OI, which provide helpful clues to the diagnosis and describe the inflammatory, infectious and neoplastic conditions classically associated with OI. Autoimmune diseases are probably the most common causes of OI associated with a bilateral dacryoadenitis (e.g., sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease). We focused on a major part of the IgG4-RD spectrum, the IgG4-related orbital disease which has been recently described and the idiopathic orbital inflammation syndrome that one should consider in patients 40 years of age or older with non specific inflammation OI on biopsy but without underlying local or systemic disease. An algorithm for the diagnostic approach of OI was proposed. If systemic explorations fail to diagnose an underlying disease, histopathologic control is required for distinguishing non-specific OI from other differential diagnosis, especially lymphoma. In the cases of pure myositic locations and posteriorly located tumours where biopsy could damage to the optic nerve, analysis of orbital lesions in T2W IRM sequence may be helpful to distinguish idiopathic OI (IOI) from lymphoma. When the diagnostic work-up fails, a corticosteroid trial could be used, but its beneficial effect has to be cautiously interpretated before definitively diagnosing IOI. Finally, treatments used in main infllammatory orbitopathies were also reviewed. PMID- 29398047 TI - Reply. PMID- 29398048 TI - Risk of Death in Infants Who Have Experienced a Brief Resolved Unexplained Event: A Meta-Analysis. AB - OBJECTIVE: To estimate an upper bound on the risk of death after a brief resolved unexplained event (BRUE), a sudden alteration in an infant's breathing, color, tone, or responsiveness, previously labeled "apparent life-threatening event" (ALTE). STUDY DESIGN: The meta-analysis incorporated observational studies of patients with ALTE that included data on in-hospital and post-discharge deaths with at least 1 week of follow-up after hospital discharge. Pertinent studies were identified from a published review of the literature from 1970 through 2014 and a supplementary PubMed query through February 2017. RESULTS: The 12 included studies (n = 3005) reported 12 deaths, of which 8 occurred within 4 months of the event. Applying a Poisson-normal random effects model to the 8 proximate deaths using a 4-month time horizon yielded a post-ALTE mortality rate of about 1 in 800, which constitutes an upper bound on the risk of death after a BRUE. CONCLUSIONS: This risk is about the same as the baseline risk of death during the first year of life. The meta-analysis therefore supports the return-home approach advocated in a recently published clinical practice guideline-not routine hospitalization-for BRUE patients who have been evaluated in the emergency department and determined to be at lower risk. PMID- 29398049 TI - Worth a Try? Describing the Experiences of Families during the Course of Care in the Neonatal Intensive Care Unit When the Prognosis is Poor. AB - OBJECTIVE: To determine how parents of infants in the neonatal intensive care unit with a poor or uncertain prognosis view their experience, and whether they view their choices as "worth it," regardless of outcome. STUDY DESIGN: Parents of eligible neonates at 2 institutions underwent audiotaped, semistructured interviews while their infants were still in the hospital and then again 6 months to 1 year after discharge or death. Interviews were transcribed and data were analyzed using thematic analysis. Two authors independently reviewed and coded each interview and discrepancies were resolved by consensus. RESULTS: Twenty-six families were interviewed in the initial group and 17 families were interviewed in the follow-up group. The most common themes identified included realism about death (24 families), appreciation for the infant's care team (23 families), and optimism and hope (22 families). Overall themes were very similar across both centers, and among parents of infants who died and those who survived. Themes of regret, futility, distrust of care team, and infant pain were brought up infrequently or not at all. CONCLUSIONS: No family believed that the care being provided to their infant was futile; rather, parents were grateful for the care provided to their infant, regardless of outcome. Even in the case of a poor prognosis or the death of an infant, families in our study viewed their infant's stay in the neonatal intensive care unit favorably. PMID- 29398051 TI - The Inverse Relationship between Digital Media Exposure and Childhood Flourishing. AB - OBJECTIVE: To describe the relationship between digital media exposure (DME) and parental perception of childhood flourishing, or overall positive well-being. It is hypothesized that there is an inverse association between parent-reported measures of childhood flourishing and increasing daily DME. STUDY DESIGN: Parental responses for children ages 6-17 years (N = 64 464) from the 2011-2012 National Survey of Children's Health were analyzed. Average weekday DME that was not school work related was categorized in 2-hour intervals: 0 to <2, 2 to < 4, 4 to < 6, and >=6 hours. Bivariate analyses and logistic regression models were used to examine the relationship between DME and parent-reported frequency of 5 childhood flourishing markers: completing homework, caring about academics, finishing tasks, staying calm when challenged, and showing interest in learning. RESULTS: Only 31% reported <2 hours of weekday DME. For the remaining children, daily DME was 2 to <4 hours (36%), 4 to <6 hours (17%), or >=6 hours (17%). In a model adjusted for age, sex, race, poverty level, primary language spoken at home, and highest maternal education level, there was a dose-dependent decrease in the odds of demonstrating all 5 markers of flourishing as weekday DME increased (test for trend for each outcome P < .001). In stratified analyses, this relationship held true regardless of the child's age group, sex, or poverty level. CONCLUSION: This study provides evidence that, among school-aged children, increasing weekday DME has an inverse dose-dependent relationship with multiple childhood flourishing markers. PMID- 29398052 TI - Risk Factors for Neonatal Venous and Arterial Thromboembolism in the Neonatal Intensive Care Unit-A Case Control Study. AB - OBJECTIVE: To identify risk factors associated with venous and arterial thrombosis in sick neonates admitted to the neonatal intensive care unit. STUDY DESIGN: A case-control study was conducted at 2 centers between January 2010 and March 2014 using the Children's Hospital Neonatal Database dataset. Cases were neonates diagnosed with either arterial or venous thrombosis during their neonatal intensive care unit stay; controls were matched in a 1:4 ratio by gestational age and presence or absence of central access devices. Bivariable and conditional logistic regression analyses for venous and arterial thrombosis were performed separately. RESULTS: The overall incidence of neonatal thrombosis was 15.0 per 1000 admissions. A higher proportion of neonates with thrombosis had presence of central vascular access devices (75% vs 49%; P < .01) were of extremely preterm gestational age (22-27 weeks; 26% vs 15.0%; P <.05) and stayed >=31 days in the neonatal intensive care unit (53% vs 32.9%; P <.01), when compared with neonates without thrombosis. A final group of 64 eligible patients with thrombosis and 4623 controls were analyzed. In a conditional multivariable logistic regression model, venous thrombosis was significantly associated with male sex (AOR, 2.12; 95% CI, 1.03-4.35; P = .04) and blood stream infection (AOR, 3.47; 95% CI, 1.30-9.24; P = .01). CONCLUSIONS: The incidence of thrombosis was higher in our neonatal population than in previous reports. After matching for central vascular access device and gestational age, male sex and blood stream infection represent independent risk factors of neonatal venous thrombosis. A larger cohort gleaned from multicenter data should be used to confirm the study results and to develop thrombosis prevention strategies. PMID- 29398055 TI - The Increasing Burden of Atopy and Allergy after Solid Organ Transplantation in Children. PMID- 29398053 TI - Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth. AB - We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth. PMID- 29398056 TI - Association of Health Insurance Status and Vaccination Coverage among Adolescents 13-17 Years of Age. AB - OBJECTIVE: To assess selected vaccination coverage among adolescents by health insurance status and other access-to-care characteristics. STUDY DESIGN: The 2015 National Immunization Survey-Teen data were used to assess vaccination coverage disparities among adolescents by health insurance status and other access-to-care variables. Multivariable logistic regression analysis and a predictive marginal modeling were conducted to evaluate associations between health insurance status and vaccination coverage. RESULTS: Overall, vaccination coverage was significantly lower among uninsured compared with insured adolescents for all vaccines assessed for except >=3 doses of human papillomavirus vaccine (HPV) among male adolescents. Among adolescents 13-17 years of age, vaccination of uninsured compared with insured adolescents, respectively, for tetanus toxoid, reduced content diphtheria toxoid, and acellular pertussis vaccine was 77.4% vs 86.8%; for >=1 dose of meningococcal conjugate vaccine was 72.9% vs 81.7%; for >=1 dose of HPV was 38.8% vs 50.2% among male and 42.9% vs 63.8% among female adolescents; for 3 doses of HPV was 24.9% vs 42.8% among female adolescents. In addition, vaccination coverage differed by the following: type of insurance among insured adolescents, having a well-child visit at 11-12 years of age, and number of healthcare provider contacts in the past year. Uninsured were less likely than insured adolescents to be vaccinated for HPV (female: >=1 dose and 3 doses; and male: >=1 doses) after adjusting for confounding variables. CONCLUSIONS: Overall, vaccination coverage was lower among uninsured adolescents. HPV vaccination coverage was lower than tetanus toxoid, reduced content diphtheria toxoid, and acellular pertussis vaccine Tdap and meningococcal conjugate vaccine in both insured and uninsured adolescents. Wider implementation of effective evidence based strategies is needed to help improve vaccination coverage among adolescents, particularly for those who are uninsured. Limitation of current federally funded vaccination programs or access to healthcare would be expected to erode vaccine coverage of adolescents. PMID- 29398054 TI - Severe Neurodevelopmental Impairment in Neonates Born Preterm: Impact of Varying Definitions in a Canadian Cohort. AB - OBJECTIVE: To assess the impact of variations in the definition of severe neurodevelopmental impairment (NDI) on the incidence of severe NDI and the association with risk factors using the Canadian Neonatal Follow-Up Network cohort. STUDY DESIGN: Literature review of severe NDI definitions and application of these definitions were performed in this database cohort study. Infants born at 23-28 completed weeks of gestation between 2009 and 2011 (n = 2187) admitted to a Canadian Neonatal Network neonatal intensive care unit and assessed at 21 months' corrected age were included. The incidence of severe NDI, aORs, and 95% CIs were calculated to express the relationship between risk factors and severe NDI using the definitions with the highest and the lowest incidence rates of severe NDI. RESULTS: The incidence of severe NDI ranged from 3.5% to 14.9% (highest vs lowest rate ratio 4.29; 95% CI 3.37-5.47). The associations between risk factors and severe NDI varied depending on the definition used. Maternal ethnicity, employment status, antenatal corticosteroid treatment, and gestational age were not associated consistently with severe NDI. Although maternal substance use, sex, score of neonatal acute physiology >20, late-onset sepsis, bronchopulmonary dysplasia, and brain injury were consistently associated with severe NDI irrespective of definition, the strength of the associations varied. CONCLUSIONS: The definition of severe NDI significantly influences the incidence and the associations between risk factors and severe NDI. A standardized definition would facilitate site comparisons and scientific communication. PMID- 29398057 TI - Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria. AB - OBJECTIVE: To assess the prevalence of functional gastrointestinal (GI) disorders in children 0-18 years old according to the newly established Rome IV diagnostic criteria as reported by parents in a representative community sample. STUDY DESIGN: A cross-sectional study in which mothers (n = 1255) of children aged 0-18 years old in the US were recruited to complete an online survey about their child's GI symptoms, quality of life (QoL), and other health conditions. RESULTS: Based on the Rome IV criteria, 24.7% of infants and toddlers aged 0-3 years and 25.0% of children and adolescents aged 4-18 years fulfilled symptom-based criteria for a functional GI disorder. The most common functional GI disorders were infant regurgitation among infants (24.1%) and functional constipation among both toddlers (18.5%) and children and adolescents (14.1%). QoL was diminished in pediatric patients with functional GI disorders (median = 71.69 vs median = 87.60; z = -11.41; P < .001). Children were more likely to qualify for a functional GI disorder if their parent qualified for a functional GI disorder (35.4% vs 23.0%; P < .001). CONCLUSIONS: Based on Rome IV criteria, functional GI disorders are common in pediatric populations of all ages and are associated with decreased QoL. PMID- 29398050 TI - Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes. AB - OBJECTIVES: Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes. STUDY DESIGN: In the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) multicenter trial, 285 participants failed to sustain glycemic control on randomized treatment (primary outcome, glycated hemoglobin A1c [HbA1c] at >=8% for 6 months); 363 maintained glycemic control (never reached primary outcome). Statins were used for a low-density lipoprotein cholesterol of >=130 mg/dL. Upon reaching the primary outcome, insulin was started. Changes in lipids and inflammatory markers (slopes over time) were examined. RESULTS: Progression of dyslipidemia was related to glycemic control. In those with the primary outcome, insulin therapy impacted HbA1c modestly, and dampened the increase in total cholesterol, low-density lipoprotein cholesterol, and total apolipoprotein B, although statin use increased from 8.6% to 22% year after the primary outcome. The increase in triglycerides and plasma nonesterified fatty acids stabilized after insulin was started, independent of HbA1c. There was an increase in high-sensitivity C-reactive protein that continued after insulin initiation, related to HbA1c and percent overweight. CONCLUSIONS: Worsening dyslipidemia and inflammation over time raise concern regarding premature development of atherosclerosis in youth with type 2 diabetes. Insulin therapy has a limited benefit in the absence of glycemic control. Strategies to achieve better glycemic control are needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00081328. PMID- 29398058 TI - Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy. AB - OBJECTIVE: To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. STUDY DESIGN: Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. RESULTS: Fifty-five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1-year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24-hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P < .001). Primary multivariable analyses showed that the hypertension group improved in scores of subtests of the Rey Auditory Verbal Learning Test, Grooved Pegboard, and Delis-Kaplan Executive Function System Tower Test (P < .05). However, the control group also improved in the same measures with similar effects sizes. Secondary analyses by effectiveness of antihypertensive therapy showed that subjects with persistent ambulatory hypertension at 1 year (n = 17) did not improve in subtests of Rey Auditory Verbal Learning Test and had limited improvement in Grooved Pegboard. CONCLUSIONS: Overall, children with hypertension did not improve in neurocognitive test performance after 1 year of antihypertensive therapy, beyond that also seen in normotensive controls, suggesting improvements with age or practice effects because of repeated neurocognitive testing. However, the degree to which antihypertensive therapy improves BP may affect its impact upon neurocognitive function. PMID- 29398059 TI - Cesarean Delivery and Childhood Malignancies: A Single-Center, Population-Based Cohort Study. AB - Rising rates of cesarean deliveries worldwide prompt the evaluation of long-term morbidity to the offspring. In this retrospective cohort study, we evaluated whether cesarean delivery influences the development of childhood malignancies. We identified an association of cesarean delivery with acute lymphoblastic leukemia in children, suggesting prudence in the recommendation of cesarean delivery for nonmedically indicated cases. PMID- 29398060 TI - Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder. AB - OBJECTIVE: To study the utility of genetic evaluation and testing in patients with suspected fetal alcohol spectrum disorder (FASD). STUDY DESIGN: We performed a retrospective chart review of all patients (n = 36) referred for evaluation for suspected FASD to the genetics clinic at Boston Children's Hospital between January 2006 and January 2013. Records of all patients were reviewed to obtain the medical history, family history, examination findings, and investigations, including genetic testing. RESULTS: Of the 36 patients, definite prenatal exposure was documented in 69%. Eight patients did not fulfill clinical criteria for FASD. Chromosomal microarray analysis (CMA) detected 19 copy number variants (CNVs) in 14 patients. Among patients who fulfilled criteria for FASD and underwent CMA, pathogenic CNVs were detected in 3 patients (2q37del, 22q11.22dup, and 4q31.21del syndromes), giving a yield of 14.3%. All 3 patients had overlapping features between FASD and the genetic syndrome. CONCLUSION: Genetic testing, especially CMA, should be considered in patients referred for evaluation of FASD, as a significant proportion have a clinically significant CNV even when they fulfill diagnostic criteria for FASD spectrum. PMID- 29398061 TI - The Maternal Nutritional Milieu and Neonatal Outcomes: Connecting the Dots. PMID- 29398046 TI - Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age. AB - OBJECTIVE: To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies. STUDY DESIGN: Infants <=26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression. RESULTS: Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively). CONCLUSIONS: Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia. PMID- 29398062 TI - How Adolescents Search for and Appraise Online Health Information: A Systematic Review. AB - OBJECTIVE: To conduct a systematic review of the evidence concerning whether and how adolescents search for online health information and the extent to which they appraise the credibility of information they retrieve. STUDY DESIGN: A systematic search of online databases (MEDLINE, EMBASE, PsycINFO, ERIC) was performed. Reference lists of included papers were searched manually for additional articles. Included were studies on whether and how adolescents searched for and appraised online health information, where adolescent participants were aged 13 18 years. Thematic analysis was used to synthesize the findings. RESULTS: Thirty four studies met the inclusion criteria. In line with the research questions, 2 key concepts were identified within the papers: whether and how adolescents search for online health information, and the extent to which adolescents appraise online health information. Four themes were identified regarding whether and how adolescents search for online health information: use of search engines, difficulties in selecting appropriate search strings, barriers to searching, and absence of searching. Four themes emerged concerning the extent to which adolescents appraise the credibility of online health information: evaluation based on Web site name and reputation, evaluation based on first impression of Web site, evaluation of Web site content, and absence of a sophisticated appraisal strategy. CONCLUSIONS: Adolescents are aware of the varying quality of online health information. Strategies used by individuals for searching and appraising online health information differ in their sophistication. It is important to develop resources to enhance search and appraisal skills and to collaborate with adolescents to ensure that such resources are appropriate for them. PMID- 29398063 TI - Multiple Postnatal Infections in Newborns Born Preterm Predict Delayed Maturation of Motor Pathways at Term-Equivalent Age with Poorer Motor Outcomes at 3 Years. AB - OBJECTIVES: To evaluate whether the number of postnatal infections is associated with abnormal white matter maturation and poorer motor neurodevelopmental outcomes at 36 months of corrected age. STUDY DESIGN: A prospective longitudinal cohort study was undertaken of 219 newborns born preterm at 24-32 weeks of gestational age recruited between 2006 and 2013 with magnetic resonance imaging of the brain both early in life and at term-equivalent age. Postnatal infection was defined as any clinical infection or positive culture >=72 hours after birth. White matter maturation was assessed by magnetic resonance spectroscopic imaging, magnetic resonance diffusion tensor imaging, and tract-based spatial statistics. Neurodevelopmental outcomes were assessed in 175 (82% of survivors) infants with Bayley Scales of Infant and Toddler Development-III composite scores and Peabody Developmental Motor Scales at 35 months of corrected age (IQR 34-37 months). Infection groups were compared via the Fisher exact test, Kruskal-Wallis test, and generalized estimating equations. RESULTS: Of 219 neonates born preterm (median gestational age 27.9 weeks), 109 (50%) had no postnatal infection, 83 (38%) had 1 or 2 infections, and 27 (12%) had >=3 infections. Infants with postnatal infections had more cerebellar hemorrhage. Infants with >=3 infections had lower N-acetylaspartate/choline in the white matter and basal ganglia regions, lower fractional anisotropy in the posterior limb of the internal capsule, and poorer maturation of the corpus callosum, optic radiations, and posterior limb of the internal capsule on tract-based spatial statistics analysis as well as poorer Bayley Scales of Infant and Toddler Development-III (P = .02) and Peabody Developmental Motor Scales, Second Edition, motor scores (P < .01). CONCLUSIONS: In newborns born preterm, >=3 postnatal infections predict impaired development of the motor pathways and poorer motor outcomes in early childhood. PMID- 29398064 TI - Numerical and experimental analysis of a focused reflected wave in a multi layered material based on a ray model. AB - A focal probe is used for the acoustic measurement of a thin layer of a material with unknown sound velocity. This is now possible, because an algorithm, based on the focused ray model, has been found. However, there are still several problems such as the assumption that the half-aperture angle equals the incident angle, the identification of the longitudinal-wave focus, and the composition of the signal. In this work, we study the multi-mode wave focus numerically and experimentally to identify the focused longitudinal waves. A theoretical multilayered focusing model has been introduced based on geometrical acoustics. In addition, a phase differentiation theory is proposed to find the incident angle for the focus of the tilted rays, which is referred to as maximum half aperture angle in other studies. The V(z,t) curve of a single layer, with a thickness of 1.5 mm and 2.0 mm, and a multi-layer are obtained using vertical translational movement. Both thickness and sound velocity are derived from the curve simultaneously. Our single layer experiments show that it is possible to focus multimode waves. The single and multi-layer experiments confirm the multi layered focused ray model and phase differentiation theory. Furthermore, experiments are conducted to analyze the measured results. PMID- 29398065 TI - Experimental evaluation of ultrasound higher-order harmonic imaging with Filtered Delay Multiply And Sum (F-DMAS) non-linear beamforming. AB - Tissue Harmonic Imaging (THI) mode is currently one of the preferred choices by the clinicians for its ability to provide enhanced ultrasound images, thanks to the use of the second harmonic component of backscattered echoes. This paper aims at investigating whether the combination of THI with Filtered-Delay Multiply And Sum (F-DMAS) beamforming can provide further improvements in image quality. F DMAS is a new non-linear beamformer, which, similarly to THI, is based on the use of the second harmonics of beamformed signals and is known to increase image contrast resolution and noise rejection. Thus, we have first compared the images obtained by using F-DMAS and the standard Delay And Sum (DAS) beamformers when only the second harmonics of the received signals was selected. Moreover, possible improvements brought about by other harmonic components generated by the combined use of the fundamental plus second harmonics and F-DMAS beamforming have been explored. Experimental results demonstrate that, as compared to standard harmonic imaging with DAS, THI and F-DMAS can be joined to improve the -20 dB lateral resolution up to 1 mm, the contrast ratio up to 12 dB on a cyst-phantom and up to 9 dB on in vivo images. PMID- 29398066 TI - Living tissues are more than cell clusters: The extracellular matrix as a driving force in morphogenesis. AB - In the study of morphogenesis, there is a general tendency to look at the extracellular matrix (ECM) as a mechanically passive agent that simply gives support to cells, and consequently, to place all the explanatory burden on cellular behaviors. Here we aimed to show that not only cells, but also the ECM may be an important force of morphogenesis. Understanding the mechanical role of the ECM broadens our view of morphogenesis and stresses the importance of considering embryonic tissues as a composite of cells and ECM. PMID- 29398068 TI - [Hydrochlorothiazide and skin cancer]. PMID- 29398067 TI - The use of ambulatory assessment in smoking cessation. AB - Ambulatory assessment of smoking behavior has greatly advanced our knowledge of the smoking cessation process. The current article first provides a brief overview of ecological momentary assessment for smoking cessation and highlights some of the primary advantages and scientific advancements made from this data collection method. Next, a discussion of how certain data collection tools (i.e., smoking topography and carbon monoxide detection) that have been traditionally used in lab-based settings are now being used to collect data in the real world. The second half of the paper focuses on the use of wearable wireless sensors to collect data during the smoking cessation process. Details regarding how these sensor-based technologies work, their application to newer tobacco products, and their potential to be used as intervention tools are discussed. Specific focus is placed on the opportunity to utilize novel intervention approaches, such as Just In-Time Adaptive Interventions, to intervene upon smoking behavior. Finally, a discussion of some of the current challenges and limitations related to using sensor-based tools for smoking cessation are presented, along with suggestions for future research in this area. PMID- 29398069 TI - Ovarian cancer screening with the Risk of Ovarian Cancer Algorithm (ROCA): Good, bad, or just expensive? AB - OBJECTIVES: To measure the effectiveness of ovarian cancer screening using the Risk of Ovarian Cancer Algorithm (ROCA). METHODS: A Markov model was constructed based on the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This model was used to predict the outcome of ovarian cancer screening with ROCA. RESULTS: The model predicted the ovarian cancer mortality from age 50 to age 85 to be 0.954% with a decrease in life expectancy of 0.178years (yrs) per person. Using data from the UKCTOCS the model predicted a similar reduction in mortality (11% vs. 10%), and similar curves for ovarian cancer mortality. Screening at age 50 for 20yrs reduced ovarian cancer mortality from 0.953% to 0.898%, an absolute decrease of 6%, yielding an increase in life expectancy of 0.0101yrs, preventing 55 deaths per 100,000 screened at a cost of $585,946 per life-yr. Screening for 30yrs reduced mortality from 0.954% to 0.872%, an absolute decrease of 9%, preventing 82 deaths at a cost of $763,970 per life-yr. CONCLUSION: The ROCA test can improve the detection of early ovarian cancer but is not practical for screening in an average-risk population. We predict the ROCA test will reduce overall ovarian cancer mortality by 6% to 9% but at a substantial cost. For ROCA to be practical, the cost would need to be reduced ten-fold and would have only a marginal impact on mortality from ovarian cancer. This model supports the FDA's criticism of the ROCA test. Ovarian cancer screening may reduce mortality from ovarian cancer but is not cost effective. PMID- 29398071 TI - Sodium hypochlorite is more effective than 70% ethanol against biofilms of clinical isolates of Staphylococcus aureus. AB - INTRODUCTION: Although disinfectants are used for eradication of bacteria from environmental surfaces, their antibiofilm efficacy is often not considered in determining the choice of disinfectant. AIM: This study aimed to compare the effectiveness of 2 commonly used disinfectants, sodium hypochlorite and ethanol, against the planktonic and biofilm state of Staphylococcus aureus clinical isolates. MATERIALS AND METHODS: Effect of 0.6% sodium hypochlorite and 70% ethanol was determined on the planktonic and biofilm states of 10 strong and weak biofilm formers through estimation of changes in colony forming unit counts and absorbance values. The morphologic changes were observed by scanning electron microscopy. RESULTS: Significant difference in the efficacy of sodium hypochlorite and ethanol was observed against the biofilm (P = .004) as well as planktonic (P = .000) states of S aureus. However, no significant difference was observed in their activity against strong and weak biofilm formers. On electron microscopy, sodium hypochlorite was found to induce significant formation of craters and irregular depressions on the surface of strong biofilm formers. CONCLUSIONS: Sodium hypochlorite demonstrated superior efficacy in controlling both planktonic and biofilm states of growth in S aureus. Furthermore, the characteristic morphologic changes observed in strong biofilm formers hint at its biofilm-specific activity. PMID- 29398072 TI - Nosocomial outbreaks caused by Acinetobacter baumannii and Pseudomonas aeruginosa: Results of a systematic review. AB - BACKGROUND: Large outbreaks of infection by Acinetobacter baumannii and Pseudomonas aeruginosa have been reported. This research compares characteristics of such outbreaks. OBJECTIVES: Determination of risk factors for the occurrence and appropriate infection control measures. DATA SOURCES: The Outbreak Database, PubMed, and reference lists of identified articles were used. Key words included nosocomial and (outbreak or epidemic) and (aeruginosa or baumannii). STUDY ELIGIBILITY CRITERIA: Articles were included if they describe distinct outbreak(s) caused by A baumannii or P aeruginosa and were published between 2000 and 2015. There were no further restrictions with respect to language or type of article. RESULTS: One hundred fifty outbreaks by A baumannii and 131 outbreaks by P aeruginosa were included, including multidrug-resistant strains in 113 Acinetobacter and 49 Pseudomonas outbreaks. Acinetobacter outbreaks were mainly reported from intensive care units, after use of antibiotics, during mechanical ventilation, and presented with a mortality rate of 47% compared with 23% by Pseudomonas. Resistance did not alter mortality by either species. Most infection control measures were implemented or enforced more often in Acinetobacter outbreaks. CONCLUSIONS: These findings should support staff in infection control departments and on wards if an outbreak is suspected. Better adherence to the Outbreak Reports and Intervention Studies of Nosocomial Infection guidelines in outbreak reporting is necessary. A precise definition of multidrug resistance for Acinetobacter and Pseudomonas is lacking. PMID- 29398070 TI - Intermediate-term results of trans-abdominal ultrasound (TAUS)-guided brachytherapy in cervical cancer. AB - OBJECTIVES: To report the intermediate-term results of trans-abdominal ultrasound (TAUS)-guided brachytherapy in cervical cancer. MATERIALS AND METHODS: Ninety-two patients with cervical cancer (stage IB-IVA, according to FIGO staging), were treated by curative radiotherapy from February 2012 to June 2015. All patients were treated with whole pelvic radiotherapy to 50 Gy in 25 fractions and central shielding after 44 Gy, in combination with TAUS-guided brachytherapy, in order to escalate the total dose (EQD2) to the minimal dose at cervical points (in EQD2 concepts) defined by TAUS, while maintaining low doses to ICRU bladder and rectal points. The treatment results and toxicity profiles were reported. RESULTS: At median follow-up time of 41.2 months (range 8 to 61 months) the pelvic control, disease-free survival, and overall survival rates were 84.8%, 75%, and 88%, respectively. The mean applied doses to cervix, bladder, and rectal points were 83.5, 72.3, and 76.5 Gy, respectively. Eight patients developed grade 2 Gastrointestinal toxicity. CONCLUSION: The 3-year results demonstrated that TAUS guided brachytherapy is feasible and associated with excellent tumor control/toxicity rates in cervical cancer. PMID- 29398073 TI - Thoracic aortic aneurism repair, during pregnancy, diagnosed thanks to heart examination at first antenatal visit, is a maternal and fetal safe option. PMID- 29398074 TI - Effect of knowledge on women's likely uptake of and willingness to pay for non invasive test (NIPT). PMID- 29398076 TI - Cardiac arrest while exercising on mountains. PMID- 29398075 TI - Assessment of second (I2M) and third (I3M) molar indices for establishing 14 and 16 legal ages and validation of the Cameriere's I3M cut-off for 18 years old in Chilean population. AB - This retrospective cross-sectional study has two-fold aims: the first is to assess new cut-offs at the legal age thresholds (LATs) of 14 and 16 years old and the second is to validate the cut-off of third molar index I3M=0.08 for 18 years of age in Chilean people. Orthopantomographs from 822 Chilean children aged from 11 to 22 (472 girls and 350 boys) were analysed. For LAT of 14 years, cut-offs were found using the ROC curves singly for boys and girls. The cut-offs for boys were I2M=0.16 and I3M=0.73 while for girls we obtained I2M=0.10 and I3M=0.77. For LAT of 16 years we obtained the same cut-offs regardless of gender, which were 0.06 and 0.36 for I2M and I3M respectively. Concerning the validity of I3M cut off for 18 years old in Chilean population, the proportion of correctly classified individuals was 83% and estimated post-test probability, PPV, was 93.2%, with a 95% confidence interval equals to 91.3%, 94.6%. Hence, the probability that a subject positive on the test was 18 years of age or older was 93.2%, confirming the validation of the I3M cut-off for Chilean population. PMID- 29398077 TI - Parendozoicomonas haliclonae gen. nov. sp. nov. isolated from a marine sponge of the genus Haliclona and description of the family Endozoicomonadaceae fam. nov. comprising the genera Endozoicomonas, Parendozoicomonas, and Kistimonas. AB - Two Gram-stain-negative, facultative anaerobic, motile, rod-shaped strains, S-B4 1UT and JOB-63a, forming small whitish transparent colonies on marine agar, were isolated from a sponge of the genus Haliclona. The strains shared 99.7% 16S rRNA gene sequence identity and a DNA-DNA hybridization value of 100%, but were differentiated by genomic fingerprinting using rep-PCRs. 16S rRNA gene sequence phylogeny placed the strains as a sister branch to the monophyletic genus Endozoicomonas (Oceanospirillales; Gammaproteobacteria) with 92.3-94.3% 16S rRNA gene sequence similarity to Endozoicomonas spp., 91.9 and 92.1% to Candidatus Endonucleobacter bathymodiolin, and 91.9 to 92.1% to the type strains of Kistimonas spp. Core genome based phylogeny of strain S-B4-1UT confirmed the phylogenetic placement. Major fatty acids were summed feature 3 (C16:1 omega7c/C16:1 omega6c) and 8 (C18:1 omega7c/C18:1 omega6c) followed by C10:0 3 OH, C16:0, and C18:0. The G+C content was 50.1-51.4mol%. The peptidoglycan diamino acid of strain S-B4-1UT was meso-diaminopimelic acid, the predominant polyamine spermidine, the major respiratory quinone ubiquinone Q-9; phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine were major polar lipids. Based on the clear phylogenetic distinction, the genus Parendozoicomonas gen. nov. is proposed, with Parendozoicomonas haliclonae sp. nov. as type species and strain S-B4-1UT (=CCM 8713T=DSM 103671T=LMG 29769T) as type strain and JOB-63a as a second strain of the species. Based on the 16S rRNA gene sequence phylogeny of the Oceanospirillales within the Gammaproteobacteria, the Endozoicomonaceae fam. nov. is proposed including the genera Endozoicomonas, Parendozoicomonas, and Kistimonas as well as the Candidatus genus Endonucleobacter. PMID- 29398078 TI - The diagnosis and management of inhalation injury: An evidence based approach. AB - INTRODUCTION: Smoke inhalation injury (II) is an independent risk factor for mortality in burns and its management is inherently complex. We aim to make recommendations for best practice in managing II and its sequelae by reviewing all available current evidence in order to provide an evidence-based approach. METHODS: We conducted a systematic search of the Cochrane database and Embase using PRISMA guidelines with no patient population exclusion criteria. Published work was reviewed and evidence levels graded. RESULTS: We identified 521 abstracts for inclusion. Of the 84 articles identified for secondary review, 28 papers were excluded leaving 56 papers suitable for final inclusion. CONCLUSIONS: We are able to identify a number of strategies in both diagnosis and treatment of II that have support in the published literature, including the role of bronchoscopy, permissive hypercapnia, nebulized heparin and hydroxycobalamin. Other strategies have not been shown to be harmful, but their efficacy is also not firmly established, such as high frequency oscillatory ventilation and exogenous surfactant. Prophylactic antibiotics and corticosteroids are not recommended. In general, published evidence for II is mostly Level 3 or below, due to a noticeable lack of large-scale human studies. This represents a challenge for evidence-based burns practice as a whole. PMID- 29398079 TI - Workforce planning to sustain UK burns services. PMID- 29398080 TI - Department of Error. PMID- 29398081 TI - Author Reply. PMID- 29398082 TI - Editorial Comment. PMID- 29398083 TI - Genome-Wide Association Study Reveals Variants in CFH and CFHR4 Associated with Systemic Complement Activation: Implications in Age-Related Macular Degeneration. AB - PURPOSE: To identify genetic variants associated with complement activation, which may help to select age-related macular degeneration (AMD) patients for complement-inhibiting therapies. DESIGN: Genome-wide association study (GWAS) followed by replication and meta-analysis. PARTICIPANTS: AMD patients and controls (n = 2245). METHODS: A GWAS on serum C3d-to-C3 ratio was performed in 1548 AMD patients and controls. For replication and meta-analysis, 697 additional individuals were genotyped. A model for complement activation including genetic and non-genetic factors was built, and the variance explained was estimated. Haplotype analysis was performed for 8 SNPs across the CFH/CFHR locus. Association with AMD was performed for the variants and haplotypes found to influence complement activation. MAIN OUTCOME MEASURES: Normalized C3d/C3 ratio as a measure of systemic complement activation. RESULTS: Complement activation was associated independently with rs3753396 located in CFH (Pdiscovery = 1.09 * 10-15; Pmeta = 3.66 * 10-21; beta = 0.141; standard error [SE] = 0.015) and rs6685931 located in CFHR4 (Pdiscovery = 8.18 * 10-7; Pmeta = 6.32 * 10-8; beta = 0.054; SE = 0.010). A model including age, AMD disease status, body mass index, triglycerides, rs3753396, rs6685931, and previously identified SNPs explained 18.7% of the variability in complement activation. Haplotype analysis revealed 3 haplotypes (H1-2 and H6 containing rs6685931 and H3 containing rs3753396) associated with complement activation. Haplotypes H3 and H6 conferred stronger effects on complement activation compared with the single variants (P = 2.53 * 10 14; beta = 0.183; SE = 0.024; and P = 4.28 * 10-4; beta = 0.144; SE = 0.041; respectively). Association analyses with AMD revealed that SNP rs6685931 and haplotype H1-2 containing rs6685931 were associated with a risk for AMD development, whereas SNP rs3753396 and haplotypes H3 and H6 were not. CONCLUSIONS: The SNP rs3753396 in CFH and SNP rs6685931 in CFHR4 are associated with systemic complement activation levels. The SNP rs6685931 in CFHR4 and its linked haplotype H1-2 also conferred a risk for AMD development, and therefore could be used to identify AMD patients who would benefit most from complement inhibiting therapies. PMID- 29398084 TI - Conservatively Treated Orbital Blowout Fractures: Spontaneous Radiologic Improvement. AB - PURPOSE: To determine if conservatively treated blowout fractures of the orbit undergo spontaneous improvement based on radiologic findings. DESIGN: Prospective, noncomparative series. PARTICIPANTS: Patients with conservatively treated orbital blowout fractures in a single tertiary institution from 2012 through 2016 with initial and follow-up computed tomography (CT) scans. METHODS: Comparison of initial and follow-up CT to assess for smoothening of bony contour, joining of bony edges, reduction in herniation of orbital contents, and new bone formation. Orbital and fracture volumes were calculated using a 3-dimensional reconstruction software program (3D Workstation; TeraRecon, Foster City, CA). MAIN OUTCOME MEASURES: Change in bony contour, new bone formation, and decrease in orbital and fracture volumes. RESULTS: Our study comprised 41 patients and 44 orbits, with 38 unilateral and 3 bilateral cases. Most were men (65.9%; n = 27), and the mean age was 34.3+/-13.5 years. The mean time from injury to follow-up scan was 4.6 months (range, 1-15 months). All orbits showed changes in bony contour from initial to follow up CT, including smoothening of the orbital contour (88.6%), joining of bony edges (90.9%), and reduction in herniation of orbital contents (65.9%). Most of the orbits (n = 41; 93.2%) showed features of neobone formation. Of the 44 orbits, 91.4% showed a decrease in orbital volume, whereas 94.3% showed a decrease in fracture volume. The reduction in volume was statistically significant for both orbital (from 23.7+/-4.0 to 21.8+/-3.9 ml) as well as fracture (from 1.2+/-0.8 to 0.7+/-0.6 ml) volumes from initial to follow up scans, respectively (P < 0.001). CONCLUSIONS: A large proportion of patients showed improvement in radiologic findings despite being treated conservatively. This highlights the spontaneous improvement that can occur in untreated blowout fractures not just clinically, but radiologically, in terms of soft tissue and bony findings. PMID- 29398085 TI - Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies. AB - PURPOSE: To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. DESIGN: Retrospective case series. PARTICIPANTS: Patients with mutations in CEP290 identified at a single UK referral center. METHODS: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. RESULTS: Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. CONCLUSIONS: Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches. PMID- 29398087 TI - Interfacial Characteristics and Cytocompatibility of Hydraulic Sealer Cements. AB - INTRODUCTION: The stability and long-term success of root canal obturation depends on the choice of sealer because the sealer bonds to the dentin and stabilizes the solid cone. Furthermore, the sealer needs to be nontoxic because sealer toxicity will certainly lead to treatment failure. The aim of this study was to assess the sealer-dentin interface of 3 hydraulic root canal sealers and to evaluate their cytocompatibility compared with AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany). METHODS: Four dental root canal sealers were assessed. AH Plus, MTA Fillapex (Angelus, Londrina, Brazil), BioRoot RCS (Septodont, Saint Maur-des-Fosses, France), and Endoseal (Maruchi, Wonju-si, Gangwon-do, South Korea) were characterized using scanning electron microscopy and energy dispersive spectroscopy. The sealer-tooth interface was assessed by confocal microscopy and scanning electron microscopy, and biocompatibility was measured by assessing the cell metabolic function using direct contact assays and alkaline phosphatase activity. RESULTS: The tricalcium silicate-based sealers presented a different microstructure and elemental composition despite their similar chemistry and classification. BioRoot RCS was free of aluminum, and all sealers presented different radiopacifying elements. The sealer penetration in the dentinal tubules and interfacial characteristics were different. The migration of silicon was evident from sealer to tooth for all sealers containing tricalcium silicate. MTA Fillapex and BioRoot RCS exhibited the best cytocompatibility in both the direct contact test and alkaline phosphatase activity. CONCLUSIONS: The use of hydraulic calcium silicate-based sealers has introduced a different material type to endodontics. These materials are different than other sealers mostly because of their hydraulic nature and their interaction with the environment. Although the sealers tested had a similar chemistry, their cytocompatibility and bonding mechanisms were diverse. PMID- 29398086 TI - Autolysin mediated adherence of Staphylococcus aureus with Fibronectin, Gelatin and Heparin. AB - Major autolysin (Atl) of Staphylococcus aureusis a cell surface associated peptidoglycan hydrolase with amidase and glucosaminidase domains. Atl enzymes (amidase and glucosaminidase) are known to participate in biofilm formation and also can bind with host matrices. Earlier studies demonstrated the binding of Atlwithfibronectin, thrombospondin 1, vitronectin and heat shock cognate protein Hsc70. Here, we have shown, Atl mediates attachment of S.aureus to heparin and gelatine as well. The atl mutant strain demonstrated around 2.5 fold decreased adherence with fibronectin, gelatin and heparin coated microtiter plates. The microscopic studies confirmed the reduced binding of atl mutant with them compared to its parental wild type and complemented mutant strains. Amidase and glucosaminidase were expressed as N-terminal histidine tagged proteins from Escherichia coli, purified and refolded. We found refolded amidase bind with fibronectin, gelatin and heparin; whereas refolded glucosaminidase binds with only fibronectin and heparin but not gelatin. These results reemphasize Atl as one of the crucial proteins from Staphylococcus that facilitate their binding with multiple host cellular components during colonization and infection. PMID- 29398088 TI - Root Canal Shaping Effect of Instruments with Offset Mass of Rotation in the Mandibular First Molar: A Micro-computed Tomographic Study. AB - INTRODUCTION: The aim of this study was to evaluate the root canal shaping effect of 2 nickel-titanium rotary instruments with offset mass of rotation compared with an instrument with a conventional centered mass of rotation. METHODS: Thirty six extracted human mandibular first molars with 2 independent mesial canals and 1 oval distal canal were selected and divided equally into 3 groups for instrumentation with ProTaper Next (PTN; Dentsply Maillefer, Ballaigues, Switzerland), Revo-S (RS; Micro-Mega, Besancon, France), and ProTaper Universal (PTU, Dentsply Maillefer) systems (n = 12). For apical preparation, PTN X2 (#25/0.06), RS SU (#25/0.06), and PTU F2 (#25/0.08) were used in the mesial canals and PTN X3 (#30/0.07), RS AS30 (#30/0.06), and PTU F3 (#30/0.09) were used in the distal canals. Specimens were scanned before and after instrumentation using a SkyScan 1272 scanner (Bruker micro-CT, Kontich, Belgium) at 10-MUm isotropic resolution. Changes in the canal area, volume, structure model index (SMI), and untouched canal area were evaluated. Canal transportation and centering ratio were measured at 1, 3, 5, and 7 mm from the apical foramen. Data were statistically analyzed using 1-way analysis of variance with the Tukey post hoc test. RESULTS: The PTN and RS systems showed significantly less transportation and better centering ability compared with the PTU system at 1 mm from the apical foramen (P < .05). All instrumentation increased the canal area, volume, and SMI values without significant differences among the 3 groups (P > .05). CONCLUSIONS: Regardless of the differences in the cross-sectional design, alloy type, and taper variation, instruments with offset mass of rotation showed better root canal shaping ability compared with an instrument with a centered mass of rotation. PMID- 29398089 TI - Tissue Response and Immunoexpression of Interleukin 6 Promoted by Tricalcium Silicate-based Repair Materials after Subcutaneous Implantation in Rats. AB - INTRODUCTION: The aim of the present study was to evaluate the inflammatory response induced by experimental tricalcium silicate cement with 20% zirconium oxide (TSC) and MTA Plus (MTAP; Avalon Biomed Inc, Bradenton, FL) in rat subcutaneous tissues. METHODS: Polyethylene tubes were filled with TSC (n = 20) and MTAP (n = 20) and implanted in the dorsal subcutaneous tissues of 32 rats. Empty tubes were used as the control (control group [CG], n = 20). After 7, 15, 30, and 60 days, the tubes with connective tissue were removed, and the inflammatory cells and immunolabeled cells for interleukin 6 (IL-6) were counted. Data were statistically analyzed using analysis of variance and the Tukey test (P <= .05). RESULTS: An increased number of inflammatory and immunolabeled cells for IL-6 were observed at 7 days. The number of inflammatory cells was higher for TSC and MTAP than the CG (P < .001) at 7 days; after 30 and 60 days, no significant differences were observed among the TSC, MTAP, and CG (P = .955). The number of immunolabeled cells for IL-6 was similar for TSC, MTAP, and CG at all evaluated periods. A gradual and significant decrease was observed in the number of inflammatory cells and IL-6-immunopositive cells. At 60 days, the capsules adjacent to TSC and MTAP exhibited fibroblasts and bundles of collagen fibers. CONCLUSIONS: TSC and MTAP caused a similar subcutaneous reaction in rats, suggesting that they are biocompatible and present similar immune responses. PMID- 29398090 TI - Effects of Various Cryotherapy Applications on Postoperative Pain in Molar Teeth with Symptomatic Apical Periodontitis: A Preliminary Randomized Prospective Clinical Trial. AB - INTRODUCTION: The purpose of the study was to evaluate the effects of intracanal, intraoral, and extraoral cryotherapy on postoperative pain in molar teeth with symptomatic apical periodontitis. METHODS: A total of 100 patients were randomly distributed into 4 groups: control (without cryotherapy application), intracanal cryotherapy application, intraoral cryotherapy application, and extraoral cryotherapy application. The postoperative pain of the patients was recorded at the first, third, fifth, and seventh days. The data were statistically analyzed by using linear regression, chi2, one-way analysis of variance, Tukey post hoc, and Kruskal-Wallis H tests (P = .05). RESULTS: There were no statistically significant differences among the groups in terms of demographic data (P > .05). The preoperative pain levels and preoperative visual analogue scale (VAS) scores of pain on percussion were similar among the groups (P > .05). The linear regression analysis demonstrated that group variable had the most significant effect on postoperative pain at day 1 (P < .001) among the other variables (group, age, gender, tooth number, preoperative pain levels, and VAS scores of pain on percussion). When compared with the control group, all the cryotherapy groups exhibited less percussion pain and less postoperative pain at the first, third, fifth, and seventh days (P < .05). CONCLUSIONS: Within the study limitations, all the cryotherapy applications (intracanal, intraoral, and extraoral) resulted in lower postoperative pain levels and lower VAS scores of pain on percussion versus those of the control group. PMID- 29398091 TI - Correlation between Temperature-dependent Fatigue Resistance and Differential Scanning Calorimetry Analysis for 2 Contemporary Rotary Instruments. AB - INTRODUCTION: The aim of this study was to assess differences in cyclic fatigue (CF) life of contemporary heat-treated nickel-titanium rotary instruments at room and body temperatures and to document corresponding phase transformations. METHODS: Forty Hyflex EDM (H-EDM) files (Coltene, Cuyahoga Falls, OH [#25/.08, manufactured by electrical discharge machining]) and 40 TRUShape (TS) files (Dentsply Tulsa Dental Specialties, Tulsa, OK [#25/.06v, manufactured by grinding and shape setting]) were divided into 2 groups (n = 20) for CF resistance tests in a water bath either at room (22 degrees C +/- 0.5 degrees C) or body temperature (37 degrees C +/- 0.5 degrees C). Instruments were rotated in a simulated canal (angle = 60 degrees , radius = 3 mm, and center of the curvature 5 mm from the tip) until fracture occurred. The motor was controlled by an electric circuit that was interrupted after instrument fracture. The mean half life and beta and eta Weibull parameters were determined and compared. Two instruments of each brand were subjected to differential scanning calorimetry (DSC). RESULTS: While TS instruments lasted significantly longer at room temperature (mean life = 234.7 seconds; 95% confidence interval [CI], 209-263.6) than at body temperature (mean life = 83.2 seconds; 95% CI, 76-91.1), temperature did not affect H-EDM behavior (room temperature mean life = 725.4 seconds; 95% CI, 658.8-798.8 and body temperature mean life = 717.9 seconds; 95% CI, 636.8 809.3). H-EDM instruments significantly outlasted TS instruments at both temperatures. At body temperature, TS was predominantly austenitic, whereas H-EDM was martensitic or in R-phase. TS was in a mixed austenitic/martensitic phase at 22 degrees C, whereas H-EDM was in the same state as at 37 degrees C. CONCLUSIONS: H-EDM had a longer fatigue life than TS, which showed a marked decrease in fatigue life at body temperature; neither the life span nor the state of the microstructure in the DSC differed for H-EDM between room or body temperature. PMID- 29398092 TI - Prenatal testosterone and theory of mind development: Findings from disorders of sex development. AB - Women on average perform better than men on the "Reading the Mind in the Eyes" test (RMET) which is a measure of Theory of Mind (ToM). The aim of this study was to assess whether these sex differences are influenced by differences in prenatal testosterone levels through a study on individuals with Disorders of Sex Development and matched controls. ToM performance was examined using the RMET in female-assigned-at-birth individuals with increased prenatal testosterone exposure (Congenital Adrenal Hyperplasia (CAH) and 5-alpha Reductase type-2 Deficiency (5alpha-RD-2)), female-assigned-at-birth individuals with testosterone insensitivity (Complete Androgen Insensitivity Syndrome (CAIS)), and their age matched unaffected male and female relatives. A total number of 158 individuals participated in the study; 19 with 5alpha-RD-2, 17 with CAH, 18 women with CAIS, 52 matched unaffected men and 52 matched unaffected women. All subgroups were around 20 years of age. Women with CAH scored significantly lower on RMET than control women and CAIS individuals. CAIS individuals scored significantly higher than control men and participants with 5alpha-RD. Statistically, CAIS individuals' performance on RMET was similar to control women's, women with CAH did not differ significantly from control men and 5alpha-RD-2 individuals scored significantly lower than control men. These results, which are in line with previous theories, illustrate that performance on the RMET, as an index of ToM, may be influenced by variations in prenatal androgens levels. PMID- 29398093 TI - Intraprostatic injectables for male lower urinary tract symptoms: Reality or fiction? PMID- 29398094 TI - National recommendations document on the follow-up of patients with renal cell carcinoma. AB - OBJECTIVES: This document was developed to establish directives for the follow-up of patients with renal cell carcinoma (RCC) based on the best available scientific evidence and on expert opinions, which can help urologists in the decision-making process and standardise the criteria at the national level. MATERIAL AND METHODS: The methodology is based on the RAND/UCLA method. A panel of 9 experts on RCC participated in designing a thematic index, identifying and reading the available evidence, formulating recommendations and drafting the content. A validating group of 25 experts, who did not participate in the previous phases, assessed the recommendations through anonymous voting in a face to-face consensus meeting. The recommendations that were agreed upon by 75% or more of the participants in this vote were accepted as consensus. The recommendations that did not achieve this consensus were rejected. RESULTS: A total of 25 recommendations were accepted as consensus. These recommendations cover the laboratory tests, clinical assessment tests and imaging tests that should be performed for patients with RCC. The presented recommendations have been adapted according to relapse risk. The current document also outlines the frequency and duration of follow-up for each patient profile. CONCLUSIONS: The current document enables standardisation of the follow-up criteria for patients with RCC treated in the Spanish healthcare setting, according to the patients' relapse risk. PMID- 29398095 TI - Comparison of experimental methods for estimating matrix diffusion coefficients for contaminant transport modeling. AB - Diffusion cell and diffusion wafer experiments were conducted to compare methods for estimating effective matrix diffusion coefficients in rock core samples from Pahute Mesa at the Nevada Nuclear Security Site (NNSS). A diffusion wafer method, in which a solute diffuses out of a rock matrix that is pre-saturated with water containing the solute, is presented as a simpler alternative to the traditional through-diffusion (diffusion cell) method. Both methods yielded estimates of effective matrix diffusion coefficients that were within the range of values previously reported for NNSS volcanic rocks. The difference between the estimates of the two methods ranged from 14 to 30%, and there was no systematic high or low bias of one method relative to the other. From a transport modeling perspective, these differences are relatively minor when one considers that other variables (e.g., fracture apertures, fracture spacings) influence matrix diffusion to a greater degree and tend to have greater uncertainty than effective matrix diffusion coefficients. For the same relative random errors in concentration measurements, the diffusion cell method yields effective matrix diffusion coefficient estimates that have less uncertainty than the wafer method. However, the wafer method is easier and less costly to implement and yields estimates more quickly, thus allowing a greater number of samples to be analyzed for the same cost and time. Given the relatively good agreement between the methods, and the lack of any apparent bias between the methods, the diffusion wafer method appears to offer advantages over the diffusion cell method if better statistical representation of a given set of rock samples is desired. PMID- 29398096 TI - Medical treatment of female overactive bladder syndrome and treatment-related effects. AB - The age-adjusted prevalence of overactive bladder syndrome (OAB) in Taiwan is approximately 16.9%. Currently, a variety of treatments are available for female OAB. However, different treatments have different treatment-related effects that may lead to significant adverse effects and ineffective treatment. In this article, we reviewed the tools that can be used to evaluate the efficacy of OAB treatments, such as a variety of questionnaires, serum or urine biomarkers, bladder diaries and urodynamic studies. In addition, we reviewed the medications used for female OAB treatment, such as antimuscarinics, beta-3 agonists, onabotulinumtoxinA intradetrusor injections, topical vaginal estrogen therapy and bladder instillation of liposome-encapsulated onabotulinumtoxinA. We focused on their efficacy and any treatment-related effects. The information in this review should be useful as a guide to the treatment of female OAB patients. PMID- 29398097 TI - 3D printing in orthognathic surgery - A literature review. AB - With the recent advances in three-dimensional (3D) imaging, computer-assisted surgical planning and simulation are now regularly used for analysis of craniofacial structures and improved prediction of surgical outcomes in orthognathic surgery. A variety of patient-specific surgical guides and devices have been designed and manufactured using 3D printing technology, which rapidly gained widespread popularity to improve the outcomes. The article presents an overview of 3D printing technology for state-of-the-art application in orthognathic surgery and discusses the impacts on treatment feasibility and patient outcome. The current available literature regarding the use of 3D printing methods in orthognathic surgery including 3D computer-aided design/computer-aided manufacturing, rapid prototyping, additive manufacturing, 3D printing, 3D printed models, surgical occlusal splints, custom-made guides, templates and fixation plates is reviewed. A Medline, PubMed, ProQuest and ScienceDirect search was performed to find relevant articles over the past 10 years. A total of 318 articles were found, out of which 69 were publications addressing the topic of this study. An additional 9 hand-searched articles were added. From the review, we can conclude that the use of 3D printing methods in orthognathic surgery provide the benefit of optimal functional and aesthetic results, patient satisfaction, and precise translation of the treatment plan. PMID- 29398098 TI - Wells syndrome (eosinophilic cellulitis) caused by adrenal insufficiency and relieved by cortisone supplementation. PMID- 29398099 TI - Developing a Plan to Treat Behavior Disorders. AB - When presented with a behavioral complaint, veterinarians must identify all contributing medical or behavioral disorders. Veterinarians can give valuable information regarding management and training tools. Owners should be directed to trainers or staff who are familiar with positive, reward-based training techniques. Psychotropic medication is prescribed to animals with a behavioral disorder (abnormal behavior), showing signs of anxiety and/or increased reactivity. Veterinarians need to collect a thorough behavioral history, understand the rationale behind the use of a drug class, and discuss expectations with pet owners. PMID- 29398100 TI - Vertical or Horizontal? Diagnosing and Treating Cats Who Urinate Outside the Box. AB - Feline elimination problems are commonly presented to general practitioners and behavioral medicine specialists. The correct diagnosis is often missed by veterinarians owing to individual variation and multifactorial cases. Three diagnostic umbrellas need to be considered: medical problems, toileting behavior outside of the litter box, and urine marking. The treatment plan for most cases, regardless of etiology, involves optimum litter box management, fulfilling cats' environmental needs, stress reduction, behavior therapy techniques, and trigger removal. Medical management with psychoactive medication might be necessary in cases where chronic stress, fear, and anxiety play a role in the feline patient's symptomatology. PMID- 29398101 TI - Corrigendum to "Refined assessment and perspectives on the cumulative risk resulting from the dietary exposure to pesticide residues in the Danish population"[Food and Chemical Toxicology 111 (2018) 207-267]. PMID- 29398102 TI - Reply to Glazier. PMID- 29398103 TI - Ecoevolutionary Dynamics of Carbon Cycling in the Anthropocene. AB - Climate change is altering natural selection globally, which could shift the evolutionary trajectories of traits central to the carbon (C) cycle. Here, we examine the components necessary for the evolution of C cycling traits to substantially drive changes in global C cycling and integrate these components into a framework of ecoevolutionary dynamics. Recent evidence points to the evolution of C cycling traits during the Anthropocene and the potential to significantly affect atmospheric CO2. We identify directions for further collaboration between evolutionary, ecosystem, and climate scientists to study these ecoevolutionary feedback dynamics and determine whether this evolution will ultimately accelerate or decelerate the current trend in rising atmospheric CO2. PMID- 29398104 TI - Human Virome. AB - The human virome is composed by the set of all viruses, eukaryotic and prokaryotic, present in the human body; as each body compartment constitutes a different microenvironment, the virome varies with the body part. Additionally, other factors influence the virome composition, such as age, diet, and the presence of other components of the microbiome. The study of the virome takes advantage of the development of next generation sequencing, and has allowed the discovery of novel viruses, and the characterization of the virome in healthy and diseased individuals, allowing the association of viruses with specific diseases. Perhaps the most interesting development of the study of the virome is the interplay that viruses can have with other components of the microbiome, specifically bacteria, that can either up- or down-regulate the antiviral immune response and can therefore modulate viral infectivity. This relationship is reciprocal since viruses can in turn modulate bacterial infections. The complex interactions of the virome with other members of the microbiome in the context of host genetics, and their influence in the health status of the patient have just begun to be investigated and are not completely understood, but the findings so far indicate that the regulation of the immune response by viruses and other members of the microbiome can affect the outcome of infections. PMID- 29398105 TI - [Unactivity of approaches in nursing activity]. PMID- 29398106 TI - [Resistance to change: nurse prescription]. PMID- 29398107 TI - Impact of an online training program in hospital workers' smoking cessation interventions in Bolivia, Guatemala and Paraguay. AB - OBJECTIVE: To examine changes in hospital workers' interventions before and after online training. METHOD: Pre-post evaluation of the self-reported performance of the 5A's by hospital workers from the three organizations involved. We assessed individual, behavioural, and organisational-level factors through a questionnaire that included 43 items (0 = none to 10 = most possible) completed before and 6 months after the training. Medians and interquartile ranges were calculated. To examine changes, the non-parametric test for paired data (Wilcoxon) was used. RESULTS: 202 professionals (76 in Bolivia, 79 in Guatemala, and 47 in Paraguay) finished the course, of these 99 (28, 42, and 29 respectively) completed both questionnaires before and after the training. Overall, there was an increase in the performance of each of the 5A components [Ask (7 to 9): Advise (7 to 9); Assess (6 to 8); Assist (2 to 7); and Arrange a follow up (0.52 to 5); all p <0.001]. Doctors, former smokers, and those from Paraguay obtained higher scores. The level of perception of the participants degree of preparedness, level of competence and familiarity with resources increased (p <0.001). CONCLUSION: The online training had a positive impact on the implementation of the brief intervention. Online education on smoking cessation is feasible and effective in improving smoking cessation interventions in these countries. PMID- 29398108 TI - [Health councils as an instrument of community participation: a qualitative research in La Rioja (Spain)]. AB - OBJECTIVE: To describe the functioning and regulations of health councils in La Rioja (Spain) as vehicles for citizen participation in health management. METHOD: A qualitative analysis was conducted triangulating the national and regional institutional framework reviews of health councils, the official minutes of 58 meetings, and 11 semi-structured interviews with related persons. RESULTS: The analysis revealed a predominantly biomedical-technological standpoint, a lack of training in community participation dynamics, and an absence of structure in council operations. The councils were also found to be over-powered by public healthcare administration and restricted to a role of simply transmitting information, thereby neglecting an opportunity for proactive community involvement. CONCLUSIONS: In spite of these shortcomings, community health councils can operate as efficient instruments in health management as long as the necessary political will and appropriate community awareness both exist. PMID- 29398109 TI - Long-term dentin remineralization by poly(amido amine) and rechargeable calcium phosphate nanocomposite after fluid challenges. AB - OBJECTIVE: Previous studies investigated short-term dentin remineralization; studies on long-term dentin remineralization after fluid challenges mimicking fluids in oral environment are lacking. The objective of this study was to develop a long-term remineralization method to via poly(amido amine) (PAMAM) and rechargeable composite containing nanoparticles of amorphous calcium phosphate (NACP) after fluid challenges for the first time. METHODS: NACP composite was immersed at pH 4 to exhaust its calcium (Ca) and phosphate (P) ions, and then recharged with Ca and P ions, to test the remineralization of the exhausted and recharged NACP composite. Dentin was acid-etched with 37% phosphoric acid. Four groups were prepared: (1) dentin control, (2) dentin with PAMAM, (3) dentin with the recharged NACP composite, and (4) dentin with PAMAM plus recharged NACP composite. PAMAM-coated dentin was immersed in phosphate-buffered saline with shaking for 72 days, because there is fluid flow in the mouth which could potentially detach the PAMAM from dentin. Specimens were treated with a cyclic artificial saliva/lactic acid regimen for 35 days. RESULTS: After 72days of immersion plus shaking, the PAMAM still successfully fulfilled its mineralization nucleation. The recharged NACP composite still provided acid-neutralization and ion re-release, which did not decrease with increasing the number of recharge cycles. The immersed-PAMAM plus NACP achieved complete dentin remineralization and restored the hardness to that of healthy dentin. SIGNIFIANCE: In conclusion, superior long-term remineralization of the PAMAM plus NACP method was demonstrated for the first time. The immersed-PAMAM plus recharged NACP completely remineralized the pre-demineralized dentin, even after prolonged fluid challenge similar to that in oral environment. The novel PAMAM plus NACP composite method is promising to provide long-term tooth protection and caries inhibition. PMID- 29398110 TI - Surface characteristics and biocompatibility of cranioplasty titanium implants following different surface treatments. AB - OBJECTIVE: Surface and mechanical properties of titanium alloys are integral for their use in restoring bone defects of skull and face regions. These properties are affected by the method of constructing and surface treatment of the titanium implant. This study aimed to investigate the effects of titanium finishing protocols on the surface morphology, hardness and biocompatibility of TiAl6V4. METHODS: Square shaped TiAl6V4 specimens (ASTM F68) (10*10*0.5mm) were divided into seven groups of different surface treatments (n=10). The treatments included mechanical polishing, sandblasting with AL2O3 (50MUm), immersion in different acids, and/or electro-chemical anodization. Weight loss %; 3D micro-roughness; Knoop micro-hardness, and osteoblast cell attachment and proliferation (after 3 days) were determined for each specimen. Data was analysed using one way ANOVA and Dunett T3 post-hoc tests, and t-test (p<0.05). RESULTS: Weight loss % was in the range of 1.70-5.60 as mechanical polishing produced the highest weight loss, followed by sandblasting, and combined protocol of mechanical polishing and acid treatment (p<0.05). Micro-roughness values (MUm) were in the range of 2.81-16.68. It was the highest for control specimens (p<0.05), and smoothest surfaces after combined mechanical polishing and acid treatment; or after electro-chemical treatment (p<0.05). Micro-hardness values (MPa) ranged 170.90-442.15 as sandblasting with/without acid treatment caused statically significantly the highest values (p<0.05) while control and mechanically polished specimens had the lowest values (p<0.05). All treatments produced equally biocompatible surfaces (p>0.05) after 1h or 3 days. Furthermore, osteoblast cell proliferation statistically significantly increased after 3days among each surface treatment (p<0.05). SIGNIFICANCE: Different finishing treatments have variable effect on cranioplasty titanium surface loss, micro-roughness and micro-hardness but constant improved biocompatibility effect. Electro-chemical treatment caused less material loss and produced biocompatible smoothest surface of comparable hardness; hence it can be suitable for cranioplasty titanium surface finishing. PMID- 29398111 TI - The two sides of the C-factor. AB - OBJECTIVE: The aim of this paper is to investigate the effects on shrinkage strain/stress development of the lateral constraints at the bonded surfaces of resin composite specimens used in laboratory measurement. METHODS: Using three dimensional (3D) Hooke's law, a recently developed shrinkage stress theory is extended to 3D to include the additional out-of-plane strain/stress induced by the lateral constraints at the bonded surfaces through the Poisson's ratio effect. The model contains a parameter that defines the relative thickness of the boundary layers, adjacent to the bonded surfaces, that are under such multiaxial stresses. The resulting differential equation is solved for the shrinkage stress under different boundary conditions. The accuracy of the model is assessed by comparing the numerical solutions with a wide range of experimental data, which include those from both shrinkage strain and shrinkage stress measurements. RESULTS: There is good agreement between theory and experiments. The model correctly predicts the different instrument-dependent effects that a specimen's configuration factor (C-factor) has on shrinkage stress. That is, for noncompliant stress-measuring instruments, shrinkage stress increases with the C factor of the cylindrical specimen; while the opposite is true for compliant instruments. The model also provides a correction factor, which is a function of the C-factor, Poisson's ratio and boundary layer thickness of the specimen, for shrinkage strain measured using the bonded-disc method. For the resin composite examined, the boundary layers have a combined thickness that is ~11.5% of the specimen's diameter. SIGNIFICANCE: The theory provides a physical and mechanical basis for the C-factor using principles of engineering mechanics. The correction factor it provides allows the linear shrinkage strain of a resin composite to be obtained more accurately from the bonded-disc method. PMID- 29398112 TI - 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. AB - Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A C receptor-selective inverse agonist ritanserin at resolutions of 3.0 A and 2.7 A, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. PMID- 29398113 TI - Circuit Design Features of a Stable Two-Cell System. AB - Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. Analytical screening of all possible two cell circuit topologies revealed the circuit features sufficient for stability, including environmental constraint and negative-feedback regulation. Moreover, we found that cell-cell contact is essential for the stability of the macrophage fibroblast circuit. These findings illustrate principles of cell circuit design and provide a quantitative perspective on cell interactions. PMID- 29398114 TI - Dopamine Secretion Is Mediated by Sparse Active Zone-like Release Sites. AB - Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in ~30% of dopamine varicosities. Conditional RIM knockout disrupted this scaffold and, unexpectedly, abolished dopamine release, while ELKS knockout had no effect. Optogenetic experiments revealed that dopamine release was fast and had a high release probability, indicating the presence of protein scaffolds for coupling Ca2+ influx to vesicle fusion. Hence, dopamine secretion is mediated by sparse, mechanistically specialized active zone-like release sites. This architecture supports spatially and temporally precise coding for dopamine and provides molecular machinery for regulation. PMID- 29398116 TI - Dynamic Ligand Discrimination in the Notch Signaling Pathway. AB - The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency modulated pulses that specifically upregulate the Notch target gene Hes1. By contrast, Dll4 activates Notch1 in a sustained, amplitude-modulated manner that predominantly upregulates Hey1 and HeyL. Ectopic expression of Dll1 or Dll4 in chick neural crest produced opposite effects on myogenic differentiation, showing that ligand discrimination can occur in vivo. Finally, analysis of chimeric ligands suggests that ligand-receptor clustering underlies dynamic encoding of ligand identity. The ability of the pathway to utilize ligands as distinct communication channels has implications for diverse Notch-dependent processes. PMID- 29398115 TI - In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. AB - Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes. PMID- 29398118 TI - Corrigendum to "Molecular signatures in breast cancer" [Methods 131 (2017) 135 146]. PMID- 29398117 TI - The roles of toll like receptor 3, 7 and 8 in allergic rhinitis pathogenesis. AB - Allergic rhinitis, as an allergic and nasal hypersensitivity disease, is associated with the inflammation of nasal mucosa. It appears that innate immune receptors are the important risk factors in the pathogenesis of the inflammatory disease. Toll-like receptors (TLRs) are the most important receptors of innate immunity; their crucial roles in the recognition of allergens and subsequently pathogenesis of allergic diseases have been evaluated recently. TLR3, 7 and 8 are the intracellular members of the innate immune receptors and recognize intracellular single and double strand RNAs. This review article collected the investigations regarding the roles of TLR3, 7 and 8 in the allergic rhinitis pathogenesis. PMID- 29398119 TI - Target-enriched sequencing of chromosome 17q21.31 in sporadic tauopathies reveals no candidate variants. AB - The main genetic risk factors for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are located at chromosome 17q21.31. The identification of risk H1 subhaplotypes suggests that disease-specific variants can be identified by resequencing the 17q21.31 region (1.4 Mb) in carriers of risk H1 subhaplotypes. We hypothesized that PSP/CBD H1 subhaplotype carriers could have undergone a mutational event absent among unaffected carriers leading to the disease risk. We performed this strategy in definite PSP subjects, definite CBD subjects, and healthy controls and tried to replicate the findings in a larger PSP/CBD case-control series. In the resequencing process, 40 candidate variants were identified, but an association between PSP and rs76970862 was replicated only using an unadjusted model. Gene expression association analysis of this variant suggested no potential functional effect. Although our results failed to identify disease-associated variants, it is still possible that the risk of PSP/CBD at chromosome 17 is driven by rare variants, even in PSP/CBD H1 cases or variants located outside the capture regions. PMID- 29398120 TI - Screening of GLE1 mutations in Chinese amyotrophic lateral sclerosis patients. AB - Amyotrophic lateral sclerosis (ALS) is a lethal neurological disease primarily involving the spinal cord, brainstem, and corticospinal tract. Recently, mutations in the GLE1 gene were reported in Caucasian ALS patients. To inquire whether Chinese ALS patients carried causal mutations in the gene, we screened all 16 coding exons of GLE1 with Sanger sequencing in a Han Chinese cohort of 250 ALS cases. No nonsynonymous coding variants were detected. Our results suggest that pathogenic variants in the GLE1 gene are rare in Chinese ALS patients. PMID- 29398121 TI - Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease. AB - SNCA missense mutations are a rare cause of autosomal dominant Parkinson's disease (PD). To date, 6 missense mutations in SNCA have been nominated as causal. Here, we assess the frequency of these 6 mutations in public population databases and PD case-control data sets to determine their true pathogenicity. We found that 1 of the 6 reported SNCA mutations, His50Gln, was consistently identified in large population databases, and no enrichment was evident in PD cases compared to controls. These results suggest that His50Gln is probably not a pathogenic variant. This information is important to provide counseling for His50Gln carriers and has implications for the interpretation of His50Gln alpha synuclein functional investigations. PMID- 29398123 TI - Association study of essential tremor genetic loci in Parkinson's disease. AB - A recent genome-wide association study identified variants associated with essential tremor (ET). The present study aimed to examine potential genetic overlap between ET and Parkinson's disease (PD). The top 22 variants identified by the ET genome-wide association study and 4 additional variants from previous studies were genotyped in a cohort of French and French-Canadian PD patients (n = 717) and controls (n = 595). Logistic regression analysis, adjusted for age and sex, was used to test for association between genotype and PD. None of the variants tested in the present study was significantly associated with PD. Our results do not support a role of ET-associated genetic variants in PD. PMID- 29398122 TI - Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients. PMID- 29398124 TI - Prevalence and incidence of psoriatic arthritis: A systematic review and meta analysis. AB - BACKGROUND: Psoriatic arthritis (PsA) is a specific form of inflammatory arthritis associated with psoriasis affecting in the same measure men and women but with a consistent geographic variability. Since the burden of PsA frequency has important implications in the definition of the healthcare policies, it is important to measure the frequency of disease in the general population. OBJECTIVE: To quantify the global health burden of PsA summarizing the data provided by the population-based available studies investigating prevalence and incidence of the disease. METHODS: A MEDLINE search was performed to identify all studies reporting the prevalence or incidence of PsA. Fixed- and random-effect models were fitted to estimate the prevalence and incidence pooled estimates. Between-study heterogeneity was evaluated using the Q statistic and the I2 index and Publication bias using Egger's asymmetry test. RESULTS: Twenty-eight studies were included in the meta-analysis, 17 retrieved from the literature search and 11 from the meta-analysis of Alamanos et al. The random effect pooled PsA prevalence and incidence rates are respectively 133 every 100,000 subjects (95% CI, 107-164 every 100,000 subjects) and 83 every 100,000 PY (95% CI, 41-167 every 100,000 PY). High between-study heterogeneity was found for both prevalence and incidence estimates. CONCLUSIONS: This study allowed the estimation of a global average prevalence and incidence rates of PsA and the evaluation of the geographic variability. The high between-study heterogeneity suggests the importance to look not only at the pooled estimates but also at the study specific estimate. PMID- 29398125 TI - Health-related quality of life in gout in primary care: Baseline findings from a cohort study. AB - OBJECTIVES: To examine gout-related, comorbid, and sociodemographic characteristics associated with generic and disease-specific health-related quality of life (HRQOL) in gout. METHODS: Adults with gout from 20 general practices were mailed a questionnaire containing the Health Assessment Questionnaire-Disability Index (HAQ-DI), Short-Form-36 Physical Function subscale (PF-10), Gout Impact Scale (GIS), and questions about gout-specific, comorbid and sociodemographic characteristics. Variables associated with HRQOL were examined using multivariable linear regression models. RESULTS: A total of 1184 completed questionnaires were received (response 65.9%). Worse generic and gout-specific HRQOL was associated with frequent gout attacks (>=5 attacks PF-10 beta = -4.90, HAQ-DI beta = 0.14, GIS subscales beta = 8.94, 33.26), current attack (HAQ-DI beta = 0.15, GIS beta = -1.94, 18.89), oligo/polyarticular attacks (HAQ-DI beta = 0.11, GIS beta = 0.78, 7.86), body pain (PF-10 beta = -10.68, HAQ-DI beta = 0.29, GIS beta = 2.61, 11.89), anxiety (PF-10 beta = -1.81, HAQ-DI beta = 0.06, GIS beta = 0.38, 1.70), depression (PF-10 beta = -1.98, HAQ-DI beta = 0.06, GIS 0.42, 1.47) and alcohol non-consumption (PF-10 beta = -16.10, HAQ-DI beta = 0.45). Gout specific HRQOL was better in Caucasians than non-Caucasians (GIS beta = -13.05, 13.48). Poorer generic HRQOL was associated with diabetes mellitus (PF-10 beta = 4.33, HAQ-DI beta = 0.14), stroke (PF-10 beta = -12.21, HAQ-DI beta = 0.37), renal failure (PF-10 beta = -9.43, HAQ-DI beta = 0.21), myocardial infarction (HAQ-DI beta = 0.17), female gender (PF-10 beta = -17.26, HAQ-DI beta = 0.43), deprivation (PF-10 beta = -7.80, HAQ-DI beta = 0.19), and body mass index >=35kg/m2 (PF-10 beta = -6.10, HAQ-DI beta = 0.21). CONCLUSIONS: HRQOL in gout is impaired by gout-specific, comorbid, and sociodemographic characteristics, highlighting the importance of comorbidity screening and early urate-lowering therapy. Both gout-specific and generic questionnaires identify the impact of disease-specific features on HRQOL but studies focusing on comorbidity should include generic instruments. PMID- 29398126 TI - An association of smoking with serum urate and gout: A health paradox. AB - BACKGROUND: The potential effect of cigarette smoking on levels of serum urate and risk of gout has been considered by a large number of studies, either as the primary variable of interest or as a covariate. METHODS: Here we systematically review the published evidence relating to the relationship of smoking with serum urate, hyperuricaemia, and gout. RESULTS: Many studies have reported that smoking reduces serum urate, however, the evidence has not been conclusive with other studies pointing to the opposite or no effect. It has also been suggested that smoking reduces the risk of gout, although there is some evidence to contradict this finding. CONCLUSION: A consensus has yet to be reached as to the effect of smoking on serum urate levels and the risk of gout. PMID- 29398127 TI - Carotid Dosimetry and the Risk of Carotid Blowout Syndrome After Reirradiation With Head and Neck Stereotactic Body Radiation Therapy. AB - PURPOSE: To correlate carotid dose and risk of carotid blowout syndrome (CBOS) after stereotactic body radiation therapy (SBRT), hypothesizing that carotid dose does not correlate with CBOS. METHODS AND MATERIALS: We retrospectively reviewed 186 patients with recurrent, previously irradiated head and neck cancer treated between January 2008 and March 2013. Patients treated early in our experience with incomplete dosimetry were excluded from analysis (n = 111). A total of 75 patients were identified, providing 150 carotid arteries for analysis. Median follow-up was 8 months (range, 1-91 months) for all patients, and 37 months for surviving patients (range, 31-91 months). Patients were treated with linear accelerator-based SBRT to a median dose up to 44 Gy (range, 40-50 Gy) in 5 fractions delivered on a twice-weekly basis. Concurrent cetuximab was used in 63 patients (84%). The bilateral common, internal, and external carotid arteries were delineated 2 cm above and below the planning target volume. The maximum dose to 0.1 cm3 (D0.1cc), 1 cm3 (D1cc), and 2 cm3 (D2cc) of the carotid and the mean carotid dose from SBRT were recorded and analyzed for association with carotid bleeding events, using binary logistic regression. RESULTS: Median reirradiation interval was 20 months (range, 3-423 months), and median prior radiation dose was 70 Gy (range, 52.5-140 Gy). Sixteen patients (21.3%) received more than 1 course of SBRT, and the cumulative carotid doses from fused summary plans were recorded. The overall median D0.1cc, D1cc, D2cc, and mean carotid doses were 40.8 Gy (interquartile range [IQR], 21.6-47.6 Gy), 26.8 Gy (IQR, 14.1-42.1 Gy), 15.4 Gy (IQR, 8.4-32.7 Gy), and 15.0 Gy (IQR, 8.9-23.3 Gy), respectively. There were a total of 4 bleeding events (5.3%): 2 patients (2.7%) had mucosal bleeds that resolved after embolization of carotid branches, and 2 patients (2.7%) died from complications of CBOS. In the 2 patients with CBOS the D0.1cc was 48.4 Gy and 47.6 Gy, respectively. There was no significant association between bleeding events and D1cc (P = .280), D2cc (P = .571), or mean dose (P = .568). There was a trend toward increased risk of bleeding and D0.1cc (P = .080). CONCLUSIONS: These results demonstrate a low risk of bleeding after reirradiation with SBRT when 5 fractions are delivered on nonconsecutive days, even when tumor is completely encasing the carotid artery. Although limited by the low number of events, no significant association was found between dose-volume parameters and the risk of carotid bleeding. No CBOS was noted when D0.1cc was <47.6 Gy. PMID- 29398128 TI - Health Care Disparities in Cancer Patients Receiving Radiation: Changes in Insurance Status After Medicaid Expansion Under the Affordable Care Act. AB - PURPOSE: To compare insurance status in cancer patients receiving radiation before and after Medicaid expansion under the Patient Protection and Affordable Care Act (ACA), in both expanded and non-expanded states. METHODS AND MATERIALS: Newly diagnosed cancer patients aged 18 to 64 years who received radiation from 2011 to 2014 were compiled from the Surveillance, Epidemiology, and End Results database. Patients with a prior cancer diagnosis or unknown insurance status were excluded. Insurance rates at diagnosis were examined before (2011-2013) and after Medicaid expansion (2014) and compared between states that fully or did not fully expand Medicaid. RESULTS: A total of 197,290 patients were analyzed. Of these, 73% lived in expanded states. After expansion, there was a 53% relative decrease in uninsured rates in expanded states (4.3%-2.1%) and a 5% relative decrease in non-expanded states (8.4%-8.0%) (P < .0001). In expanded states, the uninsured rate decreased regardless of race (whites: relative decrease 56%, 4.3% to 1.9%; blacks: relative decrease 50%, 6.0 to 3.0%; both P < .0001) or county poverty level (low poverty: relative decrease 46%, 3.9% to 2.1%; high poverty: relative decrease 60%, 4.5% to 1.8%; both P < .0001). In non-expanded states, a decrease in uninsured levels was seen primarily in whites (relative decrease 9%, 7.8% to 7.1%, P < .0001; blacks: relative increase 7%, 9.9% to 10.6%, P = .37) and those living in areas with the lowest poverty (relative decrease 27%, 4.8% to 3.5%, P = .04; high poverty: relative increase 2%, 10.9% to 11.1%, P = .17). Blacks and those living in the highest poverty areas had the greatest level of benefit from full expansion (absolute benefit 2.0%-2.3%, P = .0093 and P = .0029, respectively). CONCLUSIONS: Medicaid expansion in 2014 significantly decreased uninsured rates for cancer patients receiving radiation. Full expansion decreased rates of uninsurance to a greater degree and seemed to decrease racial and economic disparities. PMID- 29398130 TI - Sonodynamic Therapy Mediated by Emodin Induces the Oxidation of Microtubules to Facilitate the Sonodynamic Effect. AB - In previous studies, sonodynamic therapy mediated by emodin (emodin-SDT) induced cytoskeletal filament disruption and apoptosis of THP-1-derived macrophages. In this research, we investigated the underlying mechanism. THP-1-derived macrophages were incubated with emodin and exposed to ultrasound irradiation. After emodin-SDT, we measured the production of reactive oxygen species (ROS) and analyzed the level of amino acid oxidation in microtubules, the cleavage of microtubules and the mitochondrial membrane potential (MMP). We found that intracellular emodin accumulated mainly on microtubules. After emodin-SDT, generation of ROS was evident. Analysis of the carbonyl content of proteins suggested oxidation of microtubules. Microtubules were disrupted after emodin SDT, and the antioxidant N-acetyl-L-cysteine prevented this disruption. MMP decreased after emodin-SDT, and this effect could be prevented by N-acetyl-L cysteine. We conclude that emodin-SDT induces the generation of ROS. The oxidation of microtubules leads to its cleavage and the subsequent decline in MMP. PMID- 29398129 TI - Biophysical Modeling of In Vivo Glioma Response After Whole-Brain Radiation Therapy in a Murine Model of Brain Cancer. AB - PURPOSE: To develop and investigate a set of biophysical models based on a mechanically coupled reaction-diffusion model of the spatiotemporal evolution of tumor growth after radiation therapy. METHODS AND MATERIALS: Post-radiation therapy response is modeled using a cell death model (Md), a reduced proliferation rate model (Mp), and cell death and reduced proliferation model (Mdp). To evaluate each model, rats (n = 12) with C6 gliomas were imaged with diffusion-weighted magnetic resonance imaging (MRI) and contrast-enhanced MRI at 7 time points over 2 weeks. Rats received either 20 or 40 Gy between the third and fourth imaging time point. Diffusion-weighted MRI was used to estimate tumor cell number within enhancing regions in contrast-enhanced MRI data. Each model was fit to the spatiotemporal evolution of tumor cell number from time point 1 to time point 5 to estimate model parameters. The estimated model parameters were then used to predict tumor growth at the final 2 imaging time points. The model prediction was evaluated by calculating the error in tumor volume estimates, average surface distance, and voxel-based cell number. RESULTS: For both the rats treated with either 20 or 40 Gy, significantly lower error in tumor volume, average surface distance, and voxel-based cell number was observed for the Mdp and Mp models compared with the Md model. The Mdp model fit, however, had significantly lower sum squared error compared with the Mp and Md models. CONCLUSIONS: The results of this study indicate that for both doses, the Mp and Mdp models result in accurate predictions of tumor growth, whereas the Md model poorly describes response to radiation therapy. PMID- 29398131 TI - Quantitative Ultrasound Imaging to Assess the Biceps Brachii Muscle in Chronic Post-Stroke Spasticity: Preliminary Observation. AB - We prospectively investigated the feasibility of using quantitative ultrasound imaging (QUI) to assess the biceps brachii muscle (BBM) in individuals with chronic post-stroke spasticity. To quantify muscle echogenicity and stiffness, we measured QUI parameters (gray-scale pixel value and shear wave velocity [SWV, m/s]) of the BBM in three groups: 16 healthy BBMs; 12 post-stroke, non-spastic BBMs; and 12 post-stroke, spastic BBMs. The QUI results were compared with the Modified Ashworth Scale and Tardieu Scale. A total of 20 SWVs were measured in each BBM, once at elbow in 90 degrees flexion and again at maximally achievable extension using acoustic radiation force impulse imaging. BBM pixel value was measured in gray-scale images captured at 90 degrees elbow flexion using ImageJ software. Statistical analyses included analysis of variance for examining the difference in SWV and pixel values among the three groups; Bonferroni correction for testing the difference in SWV and pixel values in a paired group; t-test for examining the difference in SWV values measured at two elbow angles; and Pearson correlation coefficient for analyzing the correlation of QUI to Modified Ashworth Scale and Tardieu Scale. SWV significantly differed between spastic BBMs and non spastic or healthy BBMs. For pixel values, each of the three groups significantly differed from the others at elbow 90 degrees flexion. The difference in SWV measured between the two elbow angles was also significant (p <0.01). A strong negative correlation was found between SWV and passive range of motion (R2 = 0.88, p <0.0001) in spastic upper limbs. These results suggest that the use of QUI is feasible in quantitative assessment of spastic BBM. PMID- 29398132 TI - Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development. AB - To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM 1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting. PMID- 29398133 TI - Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies. AB - The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with nine multiplex PCR reactions. This kit produced 571 amplicons covering 37 genes associated with tubulopathies followed by massive parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, 384 index patients and 16 siblings were assessed. Most common clinical diagnoses were 174 patients with Bartter/Gitelman syndrome and 76 with distal renal tubular acidosis. A total of 269 different variants were identified in 27 genes, of which 95 variants were considered likely, 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 of the index patients. Genetic testing changed the clinical diagnosis in 16 cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic etiology in known disease genes. Thus, genetic testing helped establish a definitive diagnosis in almost two-thirds of patients thereby informing prognosis, management and genetic counseling. PMID- 29398136 TI - The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration. AB - Circulating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. First, it is roughly linked to urinary inorganic phosphate excretion. Second, expression of renal Npt2a and Npt2c, and intestinal Npt2b proteins also exhibit a dynamic daily oscillation. Analyses of Npt2a, Npt2b, and Npt2c knockout mice revealed the importance of renal inorganic phosphate reabsorption and cellular inorganic phosphate shifts in the daily oscillation. Third, experiments in which nicotinamide and a specific Nampt inhibitor (FK866) were administered in the active and rest phases revealed that the Nampt/NAD+ system is involved in renal inorganic phosphate excretion. Additionally, for cellular shifts, liver-specific Nampt deletion disturbed the daily oscillation of plasma phosphate during the rest but not the active phase. In systemic Nampt+/- mice, NAD levels were significantly reduced in the liver, kidney, and intestine, and the daily oscillation (active and rest phases) of the plasma phosphate concentration was attenuated. Thus, the Nampt/NAD+ system for Npt2 regulation and cellular shifts to tissues such as the liver play an important role in generating daily oscillation of plasma inorganic phosphate levels. PMID- 29398135 TI - Activation of podocyte Notch mediates early Wt1 glomerulopathy. AB - The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1 related glomerulosclerosis. PMID- 29398134 TI - Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. AB - HIV-positive individuals are at increased risk for kidney disease, including HIV associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals. PMID- 29398137 TI - Prognostic impact of leaflet-to-annulus index in patients treated with transapical off-pump echo-guided mitral valve repair with NeoChord implantation. AB - BACKGROUND: The transapical echo-guided NeoChord repair is a procedure to correct mitral regurgitation (MR) without the need for concomitant annuloplasty for degenerative mitral valve (MV) disease. Lacking strict criteria to define normal annular dimensions for patients undergoing MV repair, we consequently missed having precise selection criteria to identify patients who can benefit from a ringless procedure with respect to who would need a combined annular and leaflet repair. The aim of this study is to identify whether a new preoperative echocardiographic index may predict postoperative outcomes after NeoChord repair. METHODS: All consecutive patients with posterior leaflet disease who underwent NeoChord repair between November 2013 and January 2016 presenting complete postoperative echocardiographic assessment up to 1year were included. Leaflet-to Annulus Index (LAI) was defined as the ratio between the sum of anterior leaflet length (AML) and posterior leaflet length (PML) over antero-posterior length (AP; AML+PML/AP). Measurements were performed with 2D transesophageal echocardiography. RESULTS: Sixty-six patients were enrolled. At 1year MR was absent in (24) 38% of patients, mild in (28) 44%, moderate in (10) 16% and severe in (1) 2%. Logistic regression analysis identified LAI as positive prognostic predictor of MR<=mild for values >1.35 at 3months, 1.30 at 6months and 1.25 at 1year. At 30days LAI was not associated with the grade of residual MR. CONCLUSIONS: LAI is a positive postoperative predictor of MR<=mild at 1-year follow-up and can be used to identify patients who could benefit from a ringless NeoChord repair procedure for the absence of a leaflet-to-annulus mismatch. PMID- 29398140 TI - WASP (Write a Scientific Paper) using Excel - 6: Standard error and confidence interval. AB - The calculation of descriptive statistics includes the calculation of standard error and confidence interval, an inevitable component of data analysis in inferential statistics. This paper provides pointers as to how to do this in Microsoft ExcelTM. PMID- 29398141 TI - The relation between flocculus volume and tinnitus after cerebellopontine angle tumor surgery. AB - PURPOSE: Chronic tinnitus is a common symptom after cerebellopontine angle (CPA) tumor removal. Sometimes, the tinnitus is gaze-modulated. In that case, patients can change the loudness or pitch of their tinnitus by ocular movements. During tumor removal by a retrosigmoid craniotomy, the cerebellar flocculus is manipulated by the surgical approach to access the tumor. The flocculus has been associated with tinnitus in rats, and is involved in eye-gaze control. This suggests that the flocculus may have a role in gaze-modulated tinnitus after CPA tumor removal. In order to investigate this hypothesis, the relation between the flocculus volume and the characteristics of postoperative tinnitus was studied. RESULTS: A single-center cohort of 51 patients completed a questionnaire after CPA tumor removal. The questionnaire asked for the effect of eye movements on tinnitus and included the Tinnitus Functional Index (TFI). Tinnitus was present in 36 patients (71% of 51), of which 29 (81% of 36) described gaze-modulation. The median TFI was 22 (range 0-85). A postoperative MRI-scan of sufficient quality was available in 34 cases. The volumes of the (para)flocculi ipsilateral and contralateral to the surgery, and the ratio of these volumes were similar between patients with and without tinnitus. The TFI correlated with the volume of both ipsi- and contralateral (para)flocculus (rs(23) = .516, p = .008 and rs(23) = .430, p = .032). The ipsilateral-to-contralateral volume ratio of the (para)flocculi volumes was significantly lower in patients that could modulate the loudness of their tinnitus by eye gaze, compared to patients that could not (t(23) = 3.337, p = .003). CONCLUSIONS: The lack of a relation between flocculus volumes and the presence of tinnitus, combined with the significant correlation between tinnitus severity and flocculus volumes, suggests that the flocculus may not be the primary source of tinnitus, but is likely to mediate tinnitus severity. The reduced ipsi-to-contralateral volume ratio in patients with gaze modulated tinnitus suggests that atrophy of the flocculus on the surgery side triggers cross-modal interactions leading to modulation of tinnitus. PMID- 29398142 TI - Low- and high-frequency cortical brain oscillations reflect dissociable mechanisms of concurrent speech segregation in noise. AB - Parsing simultaneous speech requires listeners use pitch-guided segregation which can be affected by the signal-to-noise ratio (SNR) in the auditory scene. The interaction of these two cues may occur at multiple levels within the cortex. The aims of the current study were to assess the correspondence between oscillatory brain rhythms and determine how listeners exploit pitch and SNR cues to successfully segregate concurrent speech. We recorded electrical brain activity while participants heard double-vowel stimuli whose fundamental frequencies (F0s) differed by zero or four semitones (STs) presented in either clean or noise degraded (+5 dB SNR) conditions. We found that behavioral identification was more accurate for vowel mixtures with larger pitch separations but F0 benefit interacted with noise. Time-frequency analysis decomposed the EEG into different spectrotemporal frequency bands. Low-frequency (theta, beta) responses were elevated when speech did not contain pitch cues (0ST > 4ST) or was noisy, suggesting a correlate of increased listening effort and/or memory demands. Contrastively, gamma power increments were observed for changes in both pitch (0ST > 4ST) and SNR (clean > noise), suggesting high-frequency bands carry information related to acoustic features and the quality of speech representations. Brain-behavior associations corroborated these effects; modulations in low-frequency rhythms predicted the speed of listeners' perceptual decisions with higher bands predicting identification accuracy. Results are consistent with the notion that neural oscillations reflect both automatic (pre perceptual) and controlled (post-perceptual) mechanisms of speech processing that are largely divisible into high- and low-frequency bands of human brain rhythms. PMID- 29398139 TI - Cardiomyocyte-specific deletion of GSK-3beta leads to cardiac dysfunction in a diet induced obesity model. AB - BACKGROUND AND RATIONALE: Obesity, an independent risk factor for the development of myocardial diseases is a growing healthcare problem worldwide. It's well established that GSK-3beta is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3beta in diet-induced cardiac dysfunction is unknown. METHODS: CM-specific GSK-3beta knockout (CM-GSK-3beta-KO) and littermate controls (WT) mice were fed either a control diet (CD) or high-fat diet (HFD) for 55weeks. Cardiac function was assessed by transthoracic echocardiography. RESULTS: At baseline, body weights and cardiac function were comparable between the WT and CM GSK-3beta-KOs. However, HFD-fed CM-GSK-3beta-KO mice developed severe cardiac dysfunction. Consistently, both heart weight/tibia length and lung weight/tibia length were significantly elevated in the HFD-fed CM-GSK-3beta-KO mice. The impaired cardiac function and adverse ventricular remodeling in the CM-GSK-3beta KOs were independent of body weight or the lean/fat mass composition as HFD-fed CM-GSK-3beta-KO and controls demonstrated comparable body weight and body masses. At the molecular level, on a CD, CM-GSK-3alpha compensated for the loss of CM-GSK 3beta, as evident by significantly reduced GSK-3alphas21 phosphorylation (activation) resulting in a preserved canonical beta-catenin ubiquitination pathway and cardiac function. However, this protective compensatory mechanism is lost with HFD, leading to excessive accumulation of beta-catenin in HFD-fed CM GSK-3beta-KO hearts, resulting in adverse ventricular remodeling and cardiac dysfunction. CONCLUSION: In summary, these results suggest that cardiac GSK-3beta is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction. PMID- 29398138 TI - Corrigendum to "A predictive model for early mortality after surgical treatment of heart valve or prosthesis infective endocarditis. The EndoSCORE". [Int. J. Cardiol. 241 (Aug 15 2017) 97-102]. PMID- 29398144 TI - [Iris metastasis of prostatic adenocarcinoma: A case report]. PMID- 29398143 TI - [Persistence of Cloquet's canal: Multimodal imaging]. PMID- 29398145 TI - [A dramatic delay in diagnosis...]. PMID- 29398146 TI - [Endometrial carcinoma: An histopathological and histoprognotic study about 62 patients in a center in the Tunisian north]. AB - Endometrial cancer is the most prevalent genital tract cancer in occident and the third most common cancer among women in Tunisia. It is dominated by carcinoma. The identification of prognostic factors allows a better understanding of its outcome and guides its therapeutic approach. We propose to describe the clinicopathological features and identify the histoprognostic factors of this cancer. It is a retrospective analysis of a series of 62 total hysterectomy specimens with bilateral salpingo-oophorectomy from women with primary carcinoma of the endometrium, colligated in Anatomy Laboratory and Pathology Salah Azaiz Institute of Tunis over a period of 5 years, from January 2003 to December 2007. The median age was 60 years. At the time of diagnosis, 25% of patients were nulliparous and 86% were menopaused. The endometrioid adenocarcinoma was the most common, accounting for 84% of cases (5% of them were grade 3). A myometrial invasion superior or equal to 50% was observed in 40% of cases. 42% of cases were classified as stage IA, 14% in stage IB, 16% in stage II, 18% stage III and 10% in stage IV. 22% of patients had nodal involvement. Overall survival at 5 years was 81%. In multivariate analysis, stage IV, nodal involvement and brachytherapy have influenced this rate. Event-free survival at 5 years was 71%. It was directly related to stage and nodal involvement. Stage, histological type, tumor grade, invasion of more than half of the myometrium and lymph node involvement were the most important adverse prognostic factors, dictating an appropriate management of these tumors. PMID- 29398147 TI - [Ovarian Sertoli-Leydig tumor: A tricky tumor]. AB - We report the case of a 15 years old teenage girl presenting with a primary amenorrhea and hypervirilisation symptoms. The clinical assessement found a 16cm wide heterogenous ovarian mass testosteronemia and alpha-foeto protein levels were increased. On gross exam the tumor was solid and cystic, multilocular containing serous and mucinous liquids. Microscopically, there was a sertoli cells rich solid area in which the cells had a trabecular and nested organization with Leydig cells between them and there was also a cystic area made of glandular structures lined with an intestinal muco-secreting epithelium. Next to these area, there were Sertoli cells and an oedematous stroma. The immunostaining showed that the Sertoli cells expressed, among others, the inhibine and the glands expressed the cytokeratins 7 and 20. A Sertoli and Leydig cells tumor of intermediate differentiation with heterologous elements diagnostic was made. This is a rare tumor, representing less than 0.5% of ovary tumors. Well differentiated tumors are not frequent. In one third of the cases, there are hypervirilisation symptoms, the imaging exams will serve to narrow the diagnosis and to do a full work-up to establish an extension. There are several histologic sub types caracterised by the existence of retiforms structures or heterologous elements. There are no specific immunostainings, this will only help to narrow the diagnosis and rule out some hypothesis. There are no guidelines for the management of the patients, indeed each center has its own practices. Those tumors have quite a good prognosis thanks to their early diagnosis at a stade where they are still confined to the ovary. PMID- 29398148 TI - [A "four-leaf clover" case of colonic adenocarcinoma]. PMID- 29398149 TI - Evaluating Resident On-Call Performance: Does Volume Affect Discrepancy Rate? AB - OBJECTIVE: To examinehow study volume affects discrepancy rates for on-call radiology residents. Inparticular, we studied how both total shift volume and volume at a particularpoint in time might effect performance. MATERIALS/METHODS: Weretrospectively analyzed 518 weekend call shifts at our institution. The totalnumber of computed tomography (CT) studies per shift was recorded. For everyabdomen-pelvis (AP) or chest-abdomen-pelvis (CAP) CT, preliminary and finalreports were compared for possible discrepancy and rated (by effect on short termmanagement). We also developed "peristudy volume," defined as CTs read within +/-30minutes of a given CT, an estimate of how busy a resident might be at a giventime. We performed logistic regressions to determine whether overall shiftvolume or peristudy volume were predictors of discrepancies. RESULTS: CTvolume/day increased from 58.1 +/- 10.1 in 2011 to 75.3 +/- 12.5 in 2015(p<0.001). 4695 AP (or CAP) CTs were reviewed, with 145 discrepancies thatcould affect short-term management (3.1%). When reading a study during a shift with>=51 total CTs,residents had increased odds of an error compared to reading a study during ashift with <=30 studies (OR: 2.97, CI: 1.19-6.46) (p=0.01). When reading a CTwith a peristudy volume of >=6, residents had increased odds of an error comparedto reading a study with <=5 peristudy CTs (OR: 1.6, CI: 1.1-2.3) (p=0.01). CONCLUSION: Whenon-call residents interpret AP CT during high volume shiftsor during busy time-points, odds of discrepancies increase. Awareness of thesedata may inform residency programs in staffing decisions. PMID- 29398150 TI - Prognostic significance of pretreatment total lymphocyte count and neutrophil-to lymphocyte ratio in extensive-stage small-cell lung cancer. AB - BACKGROUND: We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC). METHODS: Pretreatment blood characteristics, age, sex, performance status, race, stage (M1a vs. M1b), number and location of metastases, weight loss, smoking status, chemotherapy cycles (<4 vs. >=4), thoracic radiotherapy dose (<45 vs. >=45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated in 252 patients with ES-SCLC treated in 1998-2015. Factors significant in univariate analysis were selected as covariates for a multivariate Cox model. RESULTS: Pretreatment TLC was below normal (<1.0 * 103/uL) in 58 patients (23%). Median OS time was 11.0 months and was worse for those with TLC <= 1.5 * 103/uL (9.8 vs. 12.0 months) and pretreatment NLR > 4.0 (9.4 vs. 13.9 months). Multivariate analysis identified low TLC (hazard ratio [HR] 0.734, 95% confidence interval [CI] 0.565-0.955, P = 0.021) and high NLR (HR 1.521, 95% CI 1.172-1.976, P = 0.002) as predicting inferior survival. Age (>63 y), sex (male), performance status (>=2), chemotherapy cycles (<4), radiation dose (<45 Gy), and no PCI also predicted worse OS (P < 0.05). CONCLUSIONS: Pretreatment TLC and NLR may be useful for stratifying patients with ES-SCLC for treatment approaches. PMID- 29398151 TI - Differentiation between radiation-induced brain injury and glioma recurrence using 3D pCASL and dynamic susceptibility contrast-enhanced perfusion-weighted imaging. AB - PURPOSE: This study was performed to validate the efficacy of three-dimensional pseudocontinuous arterial spin labeling (pCASL) compared with dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI) in distinguishing radiation-induced brain injury from glioma recurrence in patients with glioma. METHODS: Both 3D pCASL and DSC-PWI were performed using a 3.0 Tesla scanner in 69 patients with previously resected and irradiated glioma who displayed newly developed abnormal contrast-enhanced lesions. The included patients were classified into a radiation-induced brain injury group (n = 34) and a glioma recurrence group (n = 35) based on subsequent pathologic analysis or clinical-radiological follow-up. Lesion perfusion parameter values (CBF and nCBF on pCASL, nrCBV and nrCBF on DSC-PWI) were measured and compared between the two groups using Student's t test. Pearson correlation analysis was performed to evaluate the correlation between pCASL (CBF and nCBF) and DSC-PWI (nrCBV and nrCBF) values in the contrast-enhanced lesions and in the perifocal edema regions. RESULTS: For the contrast-enhanced lesions, the CBF, nCBF, nrCBV, and nrCBF (29.46 +/- 15.08 ml/100 g/min, 1.11 +/- 0.50, 1.39 +/- 1.15, and 1.30 +/- 0.74) in the radiation-induced brain injury group were significantly lower than those (64.52 +/- 33.92 ml/100 g/min, 2.73 +/- 1.71, 3.39 +/- 2.12, and 3.20 +/- 1.95) in the glioma recurrence group (P < 0.001). The CBF and nCBF demonstrated strong correlation with nrCBV and nrCBF in the contrast-enhanced lesions. CONCLUSION: Radiation-induced brain injury and glioma recurrence can be reliably distinguished using both 3D pCASL and DSC-PWI. Contrast-free 3D pCASL is a suitable alternative to DSC-PWI for long-term follow-up in glioma patients with postoperative radiotherapy. PMID- 29398152 TI - Radiotherapy for prostate cancer - Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial. AB - BACKGROUND: Novel cancer drugs are subject to strict scientific evaluation of safety and efficacy and usually undergo a cost effectiveness analysis before approval for use in clinical practice. For new techniques in radiotherapy (RT) such as image-guided radiotherapy (IGRT), this is often not the case. We performed a randomized controlled trial to compare daily cone beam computer tomography (CBCT) IGRT with reduced planning target volume (PTV) margins vs weekly orthogonal portal imaging with conventional PTV margins. The primary aim of the study was to investigate the effect of two different image guidance techniques on patient reported outcome (PRO) using early side effects as proxy outcome of late rectal side effects in patients receiving curative RT for prostate cancer. METHODS: This open label, phase 3 trial conducted at two RT centers in Norway enrolled men aged 18 years or older with previously untreated histologically proven intermediate or high-risk adenocarcinoma of the prostate. Patients eligible for radical RT received it after 3 months of total androgen blockage and were randomly assigned to 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging (15 mm margins to PTV) or by daily online CBCT IGRT (7 mm margins to PTV). Based on previous results indicating that acute rectal side effects are a valid proxy outcome for late rectal side effects, the primary outcome was acute rectal toxicity at end of RT as evaluated by rectal bother scale (five of the items from PRO's QUFW94). The RIC-trial is registered with ClinicalTrials.gov, number NCT01550237. FINDINGS: Between October 2012 and June 2015, 257 patients were randomly assigned to weekly offline portal imaging (n = 129) or daily online CBCT IGRT (n = 128). Out of 250 evaluable patients, 96% completed PROs at baseline and 97% at end of RT. Baseline analyses demonstrated balance between groups for baseline characteristics as well as for PROs. In general, patients reported a small degree of side effects at end of RT, and there was no difference between groups for primary outcome (rectal bother scale of QUFW94 1.871 vs 1.884, p = 0.804). In addition, there were no significant differences between groups for any other gastrointestinal or urinary symptom as reported by QUFW94. Health related quality of life analyses (EORTC QLQ 30) demonstrated no differences between groups. INTERPRETATION: In radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins. PMID- 29398153 TI - Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation. AB - BACKGROUND: Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases. MATERIALS/METHODS: We identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan-Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis. RESULTS: Among the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naive, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22-0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18 0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09-6.70, p = 0.03). CONCLUSIONS: Patients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study. PMID- 29398154 TI - Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study. AB - INTRODUCTION: The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity. MATERIAL AND METHODS: A brachytherapy dose finding study was performed in 38 inoperable/elderly patients with T2-T4N0-1 rectal cancer. Patients received EBRT (13 * 3 Gy) followed by three weekly HDREBT applications (5-8 Gy). Toxicity was assessed via three methods: patient and physician (CTCAEv3) reported rectal symptoms and endoscopically. Wilcoxon's signed rank test, paired t-test and Spearman's correlation were used. RESULTS: Patient reported bowel symptoms showed a marked increase at the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis occurred in 68.4% and 13.2% respectively while late grade 2 and >=3 proctitis occurred in 48% and 40%. Endoscopic evaluation mainly showed erythema and telangiectasia. In three patients frank haemorrhage or ulceration occurred. Most severe toxicity was observed 12-18 months after treatment. CONCLUSION: For elderly patients with rectal cancer, definitive radiotherapy can provide good tumour response but has a substantial risk of toxicity. The potential benefit and risks of a HDREBT boost above EBRT alone must be further evaluated. PMID- 29398155 TI - [Interstitial lung disease and pancreatic cancer: Series of two cases]. AB - INTRODUCTION: Pancreatic cancer is often not diagnosed until at a metastatic stage at which point the prognosis is very poor. Pulmonary metastases are pleomorphic, often present at the time of diagnosis and can lead to the discovery of an asymptomatic primary disease. CASE REPORT: We describe two cases aged 60 and 74 years, where imaging identified what was thought to be an interstitial lung disease but which was actually metastasis from pancreatic cancer. In the first case, CT showed multiple excavated pulmonary nodules but the presentation with medullary compression led rapidly to pathological diagnosis on bone lesions. In the second patient, a history of rheumatoid arthritis and the lack of abdominal symptoms led to an initial search for disease related to the rheumatoid disease. Histopathology, from lung and bone biopsies, enabled a correct diagnosis to be achieved. CONCLUSION: Where atypical interstitial lung disease occurs, biopsy should be considered in order not to delay a diagnosis of cancer, especially pancreatic cancer. PMID- 29398156 TI - [A history of chyle]. PMID- 29398157 TI - [Tuberculosis control: The U-shaped curve of public health decision makers]. PMID- 29398158 TI - Utilization and costs of HIV antiretroviral drugs in Europe during the last ten years: Impact of generic antiretroviral drugs on cost reduction. AB - INTRODUCTION: Simulation studies showed that generic antiretroviral (ARV) drug utilization could lead to significant cost reduction of HIV treatment in developed world. This study aimed to quantify ARV utilization and costs in European countries between 2006 and 2015. We also assessed the impact of generic ARV drug utilization on cost reduction in real-life. METHODS: ARV drug utilization in 14 European countries (France, Italy, Germany, Denmark, Netherlands, Norway, Sweden, Finland, Iceland, Croatia, Czech Republic, Estonia, Latvia, and Lithuania) were analysed using defined daily dose (DDD)/1000 inhabitants/year. ARV drug cost was estimated in million euro/year and euro/1000 inhabitants/year. The impact of generics on cost reduction was assessed in three countries: France, Denmark, and Czech Republic, using four parameters: expected savings, observed savings, brand price-reduction savings and overall savings. RESULTS: Between 2006 and 2015, median ARV drug utilization increased from 234 DDDs per 1000 inhabitants per year (IQR 124-388) to 385 (229-670). The median cost increased from ?3751/1000 inhabitants/year (1109-4681) to ?9158 (3269 10,646). Between 2013 and 2015, overall savings of ?0.9, ?1.6, and ?33.7 million were respectively observed in Denmark, Czech Republic, and France. CONCLUSION: Overall savings observed in real-life from generic ARV drugs in Denmark were related to high rate of low-price generic utilization, contrarily to France and Czech Republic where these were more related to brand price-reduction than generic utilization itself. PMID- 29398159 TI - Assessing the effect of standardized cost systems on financial performance. A difference-in-differences approach for hospitals according to their technological level. AB - Promoting the improvement of standardized cost systems (CS) is one of the measures available to health policy makers for the purpose of improving efficiency in hospitals over the long-term. Nevertheless, very few studies evaluate the relationship between alternative CS and the costs really incurred. We use data from 242 hospitals of the Spanish National Health Service (NHS) between 2010 and 2013 in order to explore the determinants of the cost per adjusted patient day, using a difference-in-differences approach where the treatment is the implementation of an advanced CS. We also investigate if the association between advanced CS and unit cost is different depending upon the technological level of the hospital. Results show that hospitals with more advanced CS contained their costs better. However, the latter effect of advanced CS is lower in hospitals with a greater endowment of high technology. Results suggest that health authorities should support the development of CS, particularly in high-tech hospitals, which are usually larger and more complex hospitals that tend to accumulate a greater portion of NHS hospital sector expenditure. PMID- 29398160 TI - Short-term Safety, Tolerability, and Pharmacokinetics of MRX-I, an Oxazolidinone Antibacterial Agent, in Healthy Chinese Subjects. AB - PURPOSE: This study was designed to evaluate the safety and pharmacokinetic profiles of MRX-I tablet, an oxazolidinone antibacterial agent, in healthy Chinese subjects. METHODS: The study was composed of 3 sequential periods. Period 1 was a randomized, double-blind, placebo-controlled, sequential ascending dose (50 to 1800 mg) study. Period 2 included one arm as a randomized, open-label, 3 period, 3 * 3 Latin square single-dose study of 300, 600, and 900 mg MRX-I administration and another arm as a crossover study to evaluate high-fat diet effect. Period 3 was a randomized, double-blind, placebo-controlled multiple-dose study with 600 or 800 mg, q12h regimens over 15 days. FINDINGS: MRX-I was rapidly absorbed and reached peak plasma concentration at about 2 hours post dose. The Cmax was 8.07, 12.24, and 15.25 mg/L and the corresponding AUC0-infinity 29.21, 48.27, and 59.60 mg/h/L, in 300-, 600-, and 900-mg dosing groups, respectively. High-fat diet increased the exposure of MRX-I. No discernable drug accumulation was observed after 15 days of continuous drug administration. About 2% of MRX-I was excreted via kidneys in unchanged form. No obvious hematologic toxicity by MRX-I was observed during the entire study. Based on Monte Carlo simulation, 600 or 800 mg BID can produce satisfactory efficacy against methicillin-resistant Staphylococcus aureus. IMPLICATIONS: MRX-I was well tolerated in healthy Chinese subjects (50-1800 mg). No serious or severe adverse effects were observed. MRX-I 600 or 800 mg BID up to 15 days can be recommended in future clinical trials. Chinese Clinical Trial Registration (http://www.chinadrugtrials.org.cn) identifier: CTR20131214. PMID- 29398161 TI - Analgesic Use and Risk for Acute Coronary Events in Patients With Osteoarthritis: A Population-based, Nested Case-control Study. AB - PURPOSE: Recent controversies on the safety profiles of opioids and paracetamol (acetaminophen) have led to changes in clinical guidance on osteoarthritis (OA) management. We studied the existing association between the use of different OA drug therapies and the risk for acute coronary events. METHODS: A cohort of patients with clinically diagnosed OA (according to ICD-10 codes) was identified in the SIDIAP database. Within the cohort, cases with incident acute coronary events (acute myocardial infarction or unstable angina) between 2008 and 2012 were identified using ICD-10 codes and data from hospital admission. Controls were matched 3:1 to acute coronary event-free patients matched by sex, age (+/-5 years), geographic area, and years since OA diagnosis (+/-2 years). Linked pharmacy dispensation data were used for assessing exposure to drug therapies. Multivariate conditional logistic regression models were fitted to estimate adjusted odds ratios of acute coronary events. FINDINGS: Totals of 5663 cases and 16,989 controls were studied. Previous morbidity and cardiovascular risk were higher in cases than in controls, with no significant differences in type or number of joints with OA. Multivariate adjusted analyses showed increased risks (odds ratio; 95% CI) related to the use of diclofenac (1.16; 1.06-1.27), naproxen (1.25; 1.04-1.48), and opioid analgesics (1.13; 1.03-1.24). No significant associations were observed with cyclooxygenase-2 selective NSAIDs, topical NSAIDs, glucosamine, chondroitin sulfate, paracetamol, or metamizole. IMPLICATIONS: In patients with clinically diagnosed OA, the use of nonselective NSAIDs or opioid analgesics is associated with an increased risk for acute coronary events. These risks should be considered when selecting treatments of OA in patients at high cardiovascular risk. PMID- 29398162 TI - Challenges Involved in the Development and Delivery of Abuse-deterrent Formulations of Opioid Analgesics. AB - PURPOSE: This commentary examines the development, regulatory, and reimbursement challenges facing abuse-deterrent formulation (ADF) products. METHODS: In January 2017, the Tufts Center for the Study of Drug Development convened a roundtable to explore clinical development, regulatory, and reimbursement challenges with respect to ADFs of opioid analgesics. Roundtable participants, who included a range of pharmaceutical industry and other experts, discussed multiple challenges. FINDINGS: First, several key clinical development challenges were identified and discussed. These challenges pertain to prodrug development and development of deterrents against oral abuse. Second, experts suggested that more clarity is needed from regulatory authorities regarding standards for proving ADF labeling claims and for being rewarded with 3-year data exclusivity. Similarly, given the substantial burdens associated with the development of postapproval evidence generation, experts raised the need for a consistent regulatory policy related to postapproval evidence generation for all ADFs (branded and generic). Third, despite the public health benefits of certain ADF products, current coverage and access policies impede patient access. Payer justification for restrictive policies appears to be based more on budget impact considerations than cost-effectiveness. Fourth, there remains a need to further expand the evidence base regarding clinical and cost-effectiveness as well as abuse deterrence in a real-world setting for all ADF products. IMPLICATIONS: Clinical development challenges need to be overcome with respect to novel ADF technologies, such as prodrugs and deterrents against oral abuse. More clarity is needed from regulatory authorities on labeling claims and data exclusivity eligibility with respect to ADFs. Ensuring prescriber training and awareness of various options for treating pain, including ADF products, is an important step, as is educating payers about the public health benefits of ADFs in appropriate subpopulations of pain patients. In addition, physicians may need to incorporate appropriate risk stratification methods. Finally, it is important to establish a level playing field between coverage of ADF and non-ADF products so that non-ADF products are not given preferred formulary placement. PMID- 29398163 TI - Descriptive Analysis and Profile of Health Care Transition Services Provided to Adolescents and Emerging Adults in the Movin' On Up Health Care Transition Program. AB - Global efforts are underway to develop, implement and test health care transition (HCT) models of care. Most studies have focused on the transfer of care models. In contrast, the nurse-led interdisciplinary HCT model, Movin' On Up, provides comprehensive HCT services beginning in early adolescence. A retrospective analysis was conducted of data extracted from HCT records of 146 adolescents and emerging adults with spina bifida (with a mean age of 13.91 years) who were provided services in the Movin' On Up HCT program. Data were categorized based on the Health Care Transition Research Consortium HCT model and the Omaha System framework and as to type of direct HCT services provided by the HCT Specialist and nurse-led interdisciplinary team conferences conducted. Findings revealed that the scope of services provided represented the scope of comprehensive needs beyond those associated with the transfer of care. PMID- 29398164 TI - Transitioning Pediatric Patients to Adult Health Care: A Quality Improvement Needs Assessment. PMID- 29398165 TI - An Infectious Masquerader. PMID- 29398166 TI - Encephalitis and Thalamic Injury From Neuroinvasive West Nile Virus in Children on Treatment for Acute Lymphoblastic Leukemia. PMID- 29398167 TI - Severity scores in trauma patients admitted to ICU. Physiological and anatomic models. AB - INTRODUCTION: The goals of this project were to compare both the anatomic and physiologic severity scores in trauma patients admitted to intensive care unit (ICU), and to elaborate mixed statistical models to improve the precision of the scores. METHODS: A prospective study of cohorts. The combined medical/surgical ICU in a secondary university hospital. Seven hundred and eighty trauma patients admitted to ICU older than 16 years of age. Anatomic models (ISS and NISS) were compared and combined with physiological models (T-RTS, APACHE II [APII], and MPM II). The probability of death was calculated following the TRISS method. The discrimination was assessed using ROC curves (ABC [CI 95%]), and the calibration using the Hosmer-Lemeshows H test. The mixed models were elaborated with the tree classification method type Chi Square Automatic Interaction Detection. RESULTS: A 14% global mortality was recorded. The physiological models presented the best discrimination values (APII of 0.87 [0.84-0.90]). All models were affected by bad calibration (P<.01). The best mixed model resulted from the combination of APII and ISS (0.88 [0.83-0.90]). This model was able to differentiate between a 7.5% mortality for elderly patients with pathological antecedents and a 25% mortality in patients presenting traumatic brain injury, from a pool of patients with APII values ranging from 10 to 17 and an ISS threshold of 22. CONCLUSIONS: The physiological models perform better than the anatomical models in traumatic patients admitted to the ICU. Patients with low scores in the physiological models require an anatomic analysis of the injuries to determine their severity. PMID- 29398168 TI - How much weight today doctor? Overconfidence or zeal excess. PMID- 29398169 TI - Efficacy of respiratory muscle training in weaning of mechanical ventilation in patients with mechanical ventilation for 48hours or more: A Randomized Controlled Clinical Trial. AB - OBJECTIVE: To evaluate the efficacy of respiratory muscular training in the weaning of mechanical ventilation and respiratory muscle strength in patients on mechanical ventilation of 48hours or more. DESIGN: Randomized controlled trial of parallel groups, double-blind. Ambit: Intensive Care Unit of a IV level clinic in the city of Cali. PATIENTS: 126 patients in mechanical ventilation for 48hours or more. INTERVENTIONS: The experimental group received daily a respiratory muscle training program with treshold, adjusted to 50% of maximal inspiratory pressure, additional to standard care, conventional received standard care of respiratory physiotherapy. MAIN INTEREST VARIABLES: weaning of mechanical ventilation. Other variables evaluated: respiratory muscle strength, requirement of non-invasive mechanical ventilation and frequency of reintubation. ANALYSIS: intention-to treat analysis was performed with all variables evaluated and analysis stratified by sepsis condition. RESULTS: There were no statistically significant differences in the median weaning time of the MV between the groups or in the probability of extubation between groups (HR: 0.82 95% CI: 0.55-1.20 P=.29). The maximum inspiratory pressure was increased in the experimental group on average 9.43 (17.48) cmsH20 and in the conventional 5.92 (11.90) cmsH20 (P=.48). The difference between the means of change in maximal inspiratory pressure was 0.46 (P=.83 95%CI -3.85 to -4.78). CONCLUSIONS: respiratory muscle training did not demonstrate efficacy in the reduction of the weaning period of mechanical ventilation nor in the increase of respiratory muscle strength in the study population. Registered study at ClinicalTrials.gov (NCT02469064). PMID- 29398170 TI - Corrigendum to "Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches" [Lung Cancer 106 (2017) 70-75]. PMID- 29398171 TI - [An "orthopedic" abdominal pain]. PMID- 29398172 TI - An innovative virtual reality training tool for orthognathic surgery. AB - Virtual reality (VR) surgery using Oculus Rift and Leap Motion devices is a multi sensory, holistic surgical training experience. A multimedia combination including 360 degrees videos, three-dimensional interaction, and stereoscopic videos in VR has been developed to enable trainees to experience a realistic surgery environment. The innovation allows trainees to interact with the individual components of the maxillofacial anatomy and apply surgical instruments while watching close-up stereoscopic three-dimensional videos of the surgery. In this study, a novel training tool for Le Fort I osteotomy based on immersive virtual reality (iVR) was developed and validated. Seven consultant oral and maxillofacial surgeons evaluated the application for face and content validity. Using a structured assessment process, the surgeons commented on the content of the developed training tool, its realism and usability, and the applicability of VR surgery for orthognathic surgical training. The results confirmed the clinical applicability of VR for delivering training in orthognathic surgery. Modifications were suggested to improve the user experience and interactions with the surgical instruments. This training tool is ready for testing with surgical trainees. PMID- 29398173 TI - Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE). AB - BACKGROUND: Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS. METHODS: The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients. RESULTS: The trial randomized 1754 patients between January 2013 and July 2017. Patients' mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants. CONCLUSION: MANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS. PMID- 29398174 TI - Does Cancer Affect Cardiac Function Prior to Cancer Therapy Exposure? PMID- 29398175 TI - High Leisure-Time Physical Activity Is Associated With Reduced Risk of Sudden Cardiac Death Among Men With Low Cardiorespiratory Fitness. AB - BACKGROUND: We studied the independent and joint associations of leisure-time physical activity (LTPA) and cardiorespiratory fitness (CRF) with the risk of sudden cardiac death (SCD) among middle-aged men. METHODS: The participants were 2656 randomly selected men aged 42-60 years at baseline who were followed for 19 years. LTPA was assessed using a questionnaire modified from the Minnesota LTPA Questionnaire and CRF using a respiratory gas exchange analyzer during maximal exercise test. The participants were divided into 4 groups according to the level of LTPA and CRF dichotomized at the lowest tertiles. RESULTS: Men with low CRF had a 1.6 (95% confidence interval [CI], 1.1-2.3; P = 0.011) times higher risk of SCD than men with high CRF after adjustment for conventional risk factors. Men with low LTPA had a 1.4 (95% CI, 1.0-2.0; P = 0.032) times higher SCD risk than men with high LTPA after these adjustments. Men with low CRF and low LTPA had a 2.2 (95% CI, 1.4-3.3) times higher SCD risk than men with high CRF and high LTPA adjusting for conventional risk factors (P = 0.044 for interaction). CONCLUSIONS: It seems that low LTPA increases the risk of SCD particularly among men with low CRF but the level of LTPA does not modify the incidence of SCD among men with high CRF. PMID- 29398177 TI - Percutaneous Fetal Atrial Balloon Septoplasty for Simple Transposition of the Great Arteries With an Intact Atrial Septum. AB - We report the first ultrasonographically guided percutaneous balloon atrial septoplasty (BAS), to our knowledge, in a fetus with transposition of the great arteries and an intact ventricular and atrial septum (37 + 2 weeks). After vaginal delivery at 38 weeks, the infant had an elective septostomy (day 1) and an arterial switch procedure (day 7), with an uneventful postoperative course. For centres with experience in fetal cardiac interventions, fetal BAS is a superior management option compared with the alternatives for this high-risk physiology. PMID- 29398176 TI - Profound Vasoplegia During Sacubitril/Valsartan Treatment After Heart Transplantation. AB - Vasoplegia occurs in up to 16% of patients who undergo heart transplantation (HT) and is associated with significant morbidity and mortality. We present a case of a 61-year-old man with ischemic cardiomyopathy receiving sacubitril/valsartan (Entresto; Novartis, Cambridge, MA) who developed profound hypotension after HT. He was treated with intravenous methylene blue and high-dose vasopressors, but developed acute kidney injury requiring dialysis and a prolonged stay in the intensive care unit. This case supports a potent vasodilatory effect of sacubitril/valsartan, and if confirmed by other studies, might warrant consideration for withholding treatment while awaiting HT, particularly in patients with risk factors for vasoplegia. PMID- 29398179 TI - Update on Diabetic Nephropathy: Core Curriculum 2018. AB - Diabetic kidney disease and diabetic nephropathy are the leading cause of end stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A1c concentration < 7% and blood pressure < 140/90mmHg with therapy anchored around the use of a RAS-blocking agent. The single best evidence-based therapy for diabetic nephropathy is therapy with a RAS-blocking medication. This Core Curriculum outlines and discusses in detail the epidemiology, pathophysiology, diagnosis, and management of diabetic nephropathy. PMID- 29398178 TI - Relationships Between Clinical Processes and Arteriovenous Fistula Cannulation and Maturation: A Multicenter Prospective Cohort Study. AB - BACKGROUND: Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation. STUDY DESIGN: Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study. SETTING & PARTICIPANTS: 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis. PREDICTORS: Postoperative care processes and complications. OUTCOMES: Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria. RESULTS: AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively). LIMITATIONS: Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution. CONCLUSIONS: Multiple processes of care and complications are associated with AVF maturation outcomes. PMID- 29398180 TI - Brain Magnetic Resonance Imaging Findings in Children and Young Adults With CKD. AB - BACKGROUND: The neuroanatomic basis for cognitive impairment in chronic kidney disease (CKD) is incompletely characterized. We performed advanced quantitative structural magnetic resonance imaging (MRI) to determine whether CKD affects brain structure and whether poorer neurocognitive performance in CKD is associated with structural brain differences. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 85 individuals with CKD stages 2 to 5 and 63 healthy controls, aged 8 to 25 years PREDICTORS: CKD versus control, estimated glomerular filtration rate (eGFR), and kidney transplant status were analyzed as predictors of MRI findings. MRI volumes in 19 prespecified regions of gray matter (GM), white matter (WM), and cerebrospinal fluid were analyzed as predictors of neurocognitive performance (median z scores) in 7 prespecified domains. OUTCOMES: 19 prespecified brain regions of interest (ROIs) in 7 prespecified domains. Neurocognitive performance in 7 prespecified domains. MEASUREMENTS: ROI volumes were compared in CKD versus controls using unadjusted t tests and analysis of covariance (ANCOVA). Associations of ROI volumes with eGFR and kidney transplant status in participants with CKD were analyzed using ANCOVA and linear regression. Associations of neurocognitive performance and ROI volumes were analyzed by linear regression. RESULTS: Participants with CKD had lower whole-brain, cortical, and left parietal GM volumes than controls in unadjusted analyses, but no differences were found in adjusted analysis. In participants with CKD, lower eGFR was associated with higher WM volume in whole-brain (P=0.05) and frontal (P=0.04) ROIs, but differences were not significant after multiple comparisons correction. Kidney transplant recipients had lower GM volumes in whole-brain (P=0.01; Q=0.06), frontal (P=0.02; Q=0.08), and left and right parietal (P=0.01; Q=0.06; and P=0.03; Q=0.1) ROIs and higher whole-brain WM volume (P=0.04; Q=0.1). Neurocognitive performance in the CKD group was not associated with ROI volumes. LIMITATIONS: Unable to assess changes in brain structure and kidney function over time; analysis limited to prespecified ROIs and neurocognitive domains. CONCLUSIONS: CKD in children and young adults may be associated with lower GM and higher WM volumes in some ROIs. Differences were relatively subtle in the CKD group as a whole, but were more prominent in recipients of a kidney transplant. However, neurocognitive performance was not explained by differences in brain ROI volumes, suggesting a functional rather than structural basis for neurocognitive impairment in CKD. PMID- 29398182 TI - Sustainability assessment for the transportation environment of Darjeeling, India. AB - Darjeeling is an important tourist hill town of West Bengal, India. It suffers from an acute problem of transportation, particularly during its peak tourist seasons due to limited road space, inadequate public transport facilities and indiscriminate use of automobiles. This hill town was originally designed for a population of 10,000, but over the years, it has come face-to-face with rapid urbanization, a rising population of both tourists and residents and intensifying motor vehicle usage. These factors together are posing a threat to its transport environment. This study identifies the Sustainable Transport Indicators (STIs) available in the existing literature to identify the critical stretches using Analytical Hierarchy Process (AHP) based on experts' consensus. It was found that the experts placed emphasis on the mobility of the town, talking about vehicular impact on air pollution and encroachment of roads as the main issues affecting the sustainability of the transport environment. Thereafter, policy-level interventions have been suggested in accordance with the identified sustainability issues. We trust that other tourist hill towns with issues similar to Darjeeling could easily emulate the study methodology to assess their transport environment sustainability, or replicate on the lines of the recommended policy interventions. PMID- 29398181 TI - Utility of additional dedicated high-resolution 3T MRI in children with medically refractory focal epilepsy. AB - PURPOSE: In patients with medically refractory epilepsy and normal magnetic resonance imaging (MRI), high-resolution dedicated MRI may identify cryptic lesions. The aim of this study was to assess improvement in lesion detection and its impact on clinical management, using additional high-resolution dedicated 3T MRI in children with medically refractory epilepsy who had normal 3T epilepsy protocol MRI. MATERIALS AND METHODS: Children who had resective epilepsy surgery and suspected focal cortical dysplasia (FCD) or normal 3T epilepsy protocol MRI were included. Those with other diagnosis on MRI including tumor and hippocampal sclerosis were excluded. Patients who had normal MRI on 3T epilepsy protocol underwent dedicated high-resolution 3T MRI through the epileptogenic zone, guided by video EEG, Magnetoencephalography and FDG-PET data. RESULTS: 101 patients with at least 1 year follow-up were included. Twenty-nine of 44 (66%) patients who had normal epilepsy protocol MRI had a lesion identified on dedicated high-resolution MRI. The addition of dedicated high-resolution MRI to standard epilepsy protocol increased sensitivity from 53.1% (95%CI: 40%-66%) to 85.9% (95%CI: 75%-93%). Identified lesions were concordant to surgical resection in all patients and guided depth/strip electrode insertion in 20/25 (80%) patients who underwent staged resection. Dedicated MRI detected small deep seated lesions in 10/20 (50%), and guided depth electrodes placement, without which it would not be feasible, as the lobar location of epileptogenic zone from other non-invasive tests were not sufficiently precise. CONCLUSION: Patients with non-lesional epilepsy on standard epilepsy protocol MR may benefit from high-resolution dedicated MRI to aid identification of an underlying lesion, which could impact surgical management and improve seizure control. PMID- 29398183 TI - Equine Dysautonomia. AB - Equine dysautonomia (ED; also known as equine grass sickness) is a neurological disease of unknown cause, which primarily affects grazing adult horses. The clinical signs reflect degeneration of specific neuronal populations, predominantly within the autonomic and enteric nervous systems, with disease severity and prognosis determined by the extent of neuronal loss. This review is primarily focused on the major clinical decision-making processes in relation to ED, namely, (1) clinical diagnosis, (2) selection of appropriate ancillary diagnostic tests, (3) obtaining diagnostic confirmation, (4) selection of treatment candidates, and (5) identifying appropriate criteria for euthanasia. PMID- 29398184 TI - Masculinity, emotion regulation, and psychopathology: A critical review and integrated model. AB - Relative to girls and women, boys and men experience disproportionate rates of "externalizing" problems (e.g., aggressive behavior, substance use disorders, and antisocial personality disorder). Unfortunately, relatively little is understood about how gender operates in the etiology, expression, and maintenance of men's psychopathology. We argue that this gap in knowledge reflects the challenge of accounting for the dynamic nature of masculinity (i.e., the fact that the influence of masculinity on men's lives varies across context, time, and individuals). Likewise, emotion regulation, the process by which individuals modify their emotions to respond to the varying demands of their environment, is itself an inherently dynamic construct. Difficulty regulating emotion has been identified as a transdiagnostic factor common to a range of psychiatric diagnoses and behavior problems. Integrating the literature on emotion regulation and masculinity, therefore, offers promise for enhancing our ability to understand the effects of gender on men's psychopathology and to alleviate its deleterious consequences. In keeping with this goal, we review and synthesize the available literature on masculinity and emotion regulation into a cross-cutting framework of masculinity and men's psychopathology. Implications are discussed in terms of recommendations for an integrated intervention approach. PMID- 29398186 TI - The treatment of vocal process granuloma. PMID- 29398185 TI - Preoperative laboratory data are associated with complications and surgical site infection in composite head and neck surgical resections. AB - OBJECTIVES: 1) Describe normal/abnormal preoperative laboratory testing incidence in head and neck (H&N) composite resections and 2) determine complication, surgical site infection (SSI), and transfusion predictors by laboratory test. METHODS: The 2006 to 2013 NSQIP databases were queried for H&N composite resections. Laboratory data was categorized within, under, or above the normal reference range according to NSQIP definitions. Overall complications and SSI were analyzed with multivariable logistic regression analysis. RESULTS: From 2006 to 2013, there were 1193H&N composite resections, of which 1135 (95.1%) underwent >=1 preoperative laboratory test. Complete blood counts were obtained in 92.3%, basic metabolic panels in 90.7%, coagulation studies in 56.2%, and liver function tests (LFTs) in 52.6%. Low sodium was found in 11.5%, increasing complication odds by 2.30 (p = 0.005). High AST comprised 10.0% and increased complication odds (OR = 2.93, p = 0.012). Additionally, 9.2% had a high white blood cell (WBC) count and 3.5% had high platelets, increasing complications by 1.92 (p = 0.030) and 3.13 (p = 0.015), respectively. BUN, creatinine, total bilirubin, albumin, alkaline phosphatase, INR, PT, and aPTT abnormal values did not affect postoperative complications. Increased SSI odds were appreciated with low sodium (OR: 2.83, p = 0.002), high AST (OR: 6.85, p < 0.001), and high alkaline phosphatase (OR: 5.46, p = 0.007). Importantly, INR had no effect on transfusion rates. High PT, aPTT, or low platelets did not change transfusion odds. CONCLUSION: Inflammatory markers are associated with complications but not SSI. High LFTs and low sodium are associated with complications and SSI. Coagulopathies did not increase transfusion rates. These findings identify laboratory studies to focus on during H&N resection preoperative assessments. PMID- 29398187 TI - Salvage of recurrence after surgery and adjuvant therapy: A systematic review. AB - PURPOSE: To determine the oncologic and functional outcomes of patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma after initial management with surgery and adjuvant therapy. DATA SOURCES: Ovid Medline, Embase, Scopus, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, and Clinicaltrials.gov. REVIEW METHODS: A structured search was performed of the literature to identify studies that included patients undergoing surgical salvage for local, regional, or locoregional recurrent head and neck squamous cell carcinoma without known distant metastases who had been treated with initial surgery and post-operative adjuvant radio- or chemoradiotherapy. Studies were excluded if they did not report at least 1-year survival estimates, included patients who underwent primary non-surgical management, or included those treated with non-surgical salvage therapies or supportive care alone. RESULTS: The search strategy yielded 3746 abstracts. After applying exclusion and inclusion criteria, 126 full-texts were reviewed and six studies were included with a total of 222 patients. All studies were retrospective in design and included diverse disease subsites and stages. Complications and functional outcomes were inconsistently reported. Five-year survival estimates ranged between 10% and 40% between studies. CONCLUSIONS: Patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma after initial surgery and adjuvant therapy may have a particularly poor prognosis. Future studies are needed to determine functional and quality of life outcomes in this patient population and to identify specific prognostic factors for re-recurrence and survival. PMID- 29398188 TI - In response to HMOX1 microsatellite polymorphism by Cao et al. PMID- 29398189 TI - Corrigendum to "Medial approach for minimally-invasive harvesting of a deep circumflex iliac artery flap for reconstruction of the jaw using virtual surgical planning and CAD/CAM technology" [Br J Oral Maxillofac Surg 2017;55(November (9)):946-51]. PMID- 29398190 TI - Monitoring of free flaps and reconstruction for oral cancer. PMID- 29398191 TI - Spinal hemangioma mimicking a dumbbell-shaped schwannoma: Case report and review of the literature. AB - Spinal hemangiomas are common, benign vascular lesions that involve the bony portion of vertebral bodies and are generally asymptomatic. Rarely, they can become aggressive and present with predominantly epidural extension, mimicking other neoplasms. We present the case of a fifty-one year old woman who presented with myelopathy and was discovered to have a large mass causing epidural spinal cord compression, thought to be due to a peripheral nerve sheath tumor. She underwent surgery for tumor debulking. Intraoperatively, the mass was found to be mostly epidural with minimal bone involvement. Final pathology demonstrated a cavernous hemangioma. The patient did well post-operatively, with resolution of symptoms and stable size of residual tumor on eighteen month follow-up imaging. PMID- 29398192 TI - Red man syndrome caused by vancomycin powder. AB - Red man syndrome (RMS) is a well-known hypersensitivity reaction caused by intravenous administration of vancomycin, with symptoms ranging from flushing, erythematous rash, pruritus, mild to profound hypotension, and even cardiac arrest. RMS has not previously been described from local application of vancomycin powder in a surgical wound, a technique increasingly utilized for infection prophylaxis in many surgical disciplines including neurosurgery. We describe the first reported case of RMS as a result of local intra-wound application of vancomycin powder for infection prophylaxis. A 73-year-old male with a history of Parkinson's disease underwent 2-stage deep brain stimulation implantation surgeries. Vancomycin powder was applied locally in the surgical wounds for infection prophylaxis during both of the surgeries. The patient developed a well-demarcated, geometric erythematous pruritic rash following the second surgery that was clinically diagnosed as RMS and resolved without sequelae. PMID- 29398193 TI - Outcome in chronic inflammatory demyelinating polyneuropathy from a Malaysian centre over sixteen years. AB - Long-term outcome in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is very limited, especially from Asian countries. We aimed to determine the outcome of our cohort of CIDP patients and to define the relevant clinical, electrophysiological and laboratory determinants of disease activity, progression and treatment response. We retrospectively reviewed records of 23 CIDP patients attending our Neurology service at Kuala Lumpur Hospital, Malaysia between January 2000 and December 2016. We analysed data on neurological deficits, electrophysiological and laboratory parameters to determine diagnostic characteristics, correlation with disease activity and clinical outcomes following treatment. Included were 15 (65%) males and 8 (35%) females with a mean age of 42.7 years (SD 14.4). Mean duration of follow-up visit was 66 months (range 6-134 months). The cohort consists of 19 classical (sensory-motor) CIDP and 4 MADSAM. Large majority of patients (66%) had either stable active disease (CDAS 3, 44%) or were in remission (CDAS class 2, 22%) following treatment with standard immunotherapies (Intravenous Immunoglobulins, steroids or immunosuppressants). The proportion of CIDP patients in each CDAS class was comparable to published cohorts from North America and Europe. Medical Research Council (MRC) sum score was the only clinical score that differed across CDAS classes (p = .010) with significant inverse correlation (Spearman's rho -0.664, p = .001). In conclusion, treatment outcomes of our CIDP cohort was comparable to those of published series. Further studies with larger cohort of patients from other parts of Asia are important to determine the long-term outcome of this heterogenous disease in this region. PMID- 29398194 TI - Vestibular symptoms as the presenting feature of progressive supranuclear palsy. AB - First described in 1964, progressive supranuclear palsy (PSP) is a chronic, sporadic, progressive neurodegenerative tauopathy. Substantial phenotypic variability inherent in PSP confers difficulty to diagnosis. Although the classic presentation, termed PSP-Richardson's syndrome, has been well described, additional variants of PSP are increasingly emerging. Phenotypes described to date include PSP-parkinsonism, PSP-pure akinesia with gait freezing, PSP corticobasal syndrome or PSP-progressive non-fluent aphasia. However, there has been scant description of vestibular features in PSP. Herein, we report three similar cases with 'probable PSP' who presented with a poorly defined vestibular syndrome and early falls, highlighting an uncommon and as yet under-recognised, vestibular presentation of PSP. Further description of the natural history of this unusual vestibular presentation of PSP may assist in earlier diagnosis and prevent mismanagement of such patients. PMID- 29398195 TI - Does epiaortic ultrasound screening reduce perioperative stroke in patients undergoing coronary surgery? A topical review. AB - Although the occurrence of stroke in patients undergoing coronary artery bypass grafting (CABG) is decreasing, it remains an important concern. Therefore, it is important to identify and adopt strategies that can decrease the incidence of stroke in these patients. One of the strategies that have demonstrated the potential to decrease the rate of post-CABG stroke is an assessment of aorta for atherosclerosis before surgery and changing the surgical plan accordingly to minimize the stroke risk. This assessment can be done through palpation of the aorta, transesophageal echocardiography (TEE), and epiaortic ultrasound scanning (EAS). EAS has shown superiority over both palpation and TEE for intraoperative evaluation of aorta. However, despite the evidence demonstrating reduced stroke rates with the EAS-guided approach, EAS is not yet the standard of care procedure in patients undergoing CABG. Therefore, we have reviewed the literature for evidence that supports the routine use of EAS in patients undergoing coronary surgery and have presented solutions to overcome the barriers to its routine use. PMID- 29398196 TI - Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials. AB - Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks. This study was undertaken to describe the use of multifocal visual evoked potentials (multifocal VEP, mfVEP) in the regular monitoring of NF2 patients with ONSM. This study involved three NF2 patients with ONSM who undertook mfVEP testing at an academic ophthalmic centre. Same day mfVEP and routine ophthalmic testing were undertaken. Topographical function of the optic nerve was assessed, utilising tools such as asymmetry deviation and accumap severity index. Results were assessed alongside MRI and visual acuity (VA). From the three patients, five eyes had ONSMs, of which two caused unilateral blindness. The remaining three affected eyes had initial VAs 6/6, 6/24, and 6/18. Over follow up, ranging from 5 to 12 years, all tumours progressed, and VA declined for all patients. Multifocal VEP detected optic nerve functional loss corresponding with visual decline. This case series suggests mfVEP is effective in the objective topographic monitoring of optic nerve function in NF2 patients with ONSM. Due also to its safety in a paediatric population, the test may be considered in the routine monitoring of these patients, to be used to assist regular ophthalmic review and MRI scans. PMID- 29398197 TI - Clinical presentation and treatment paradigms in patients with hereditary hemorrhagic telangiectasia and spinal vascular malformations. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that causes angiodysplasia and results in mucocutaneous telangiectasias and arteriovenous malformations of organs. Although central nervous system vascular malformations can occur anywhere along the neuraxis, spinal vascular malformations are rare. We present our experience with the presentation and management of spinal vascular malformations in patients with HHT. Of the more than 800 patients with the diagnosis of HHT screened at our institution from 1995 through 2017, four patients with spinal vascular malformations (age range 1 month 77 years; 2 male, 2 female) were identified, three of whom came to clinical attention after significant neurological deterioration from previously unknown malformations. A review of the literature including our patients demonstrated 29 total spinal arteriovenous fistulas (AVFs) in 28 HHT patients (69% male). The lesions were located predominantly in the thoracic spine (65.5%). Three lesions were not treated, 17 were treated with embolization, 6 were surgically resected, and 3 were treated with embolization and surgery. In 14 cases, the patients presented with hemorrhage of the AVF. Overall, 79% of patients achieved complete or near-complete occlusion, with 75% reporting improvement in neurological function. Discovery of spinal lesions often occurs after neurological decline because current screening protocols do not include evaluation of the patient for spinal lesions. Most patients benefit from intervention, which is tailored to the characteristics of the patient and their malformation. Given the often-severe neurological deficit encountered at presentation, we favor a protocol that screens HHT patients for spinal vascular malformations. PMID- 29398198 TI - Association of retinal nerve fibre layer thickness with quantitative magnetic resonance imaging data of the optic chiasm in pituitary adenoma patients. AB - To evaluate retinal nerve fibre layer (RNFL) thickness in patients with pituitary adenoma (PA) by optical coherence tomography and to compare it with magnetic resonance imaging (MRI) characteristics of pituitary extension. 154 eyes of 77 patients with PA were evaluated. Ophthalmologic evaluation was performed before surgical treatment. Average and per quadrant thickness of peripapillary RNFL (internal limiting membrane to nerve fiber layer/ganglion cell layer) were calculated. Optical coherence tomography was performed in a disc circle mode (layer distance 3.45 mm; 1024 scans). PA was confirmed by MRI scans. Characteristics of the optic chiasm in relation to the suprasellar adenoma were assessed. Suprasellar extension of PA was diagnosed in 55 patients (71.4%). The optic chiasm thickness differed significantly in the groups with and without suprasellar PA extension (p < .001). A weak positive correlation was found between the height of the optic chiasm right side, middle part, left side and visual acuity (r = 0.349; 0.276; 0.307) (p < .001). RNFL thickness around the optic nerve disc measured preoperatively was reduced significantly in all four quadrants in PA patients compared with the control group (p < .001). RNFL thickness was reduced significantly only in the temporal quadrant in PA patients with suprasellar extension compared with the patients without suprasellar extension (p = .009). The temporal RNFL thickness showed the strongest positive correlation with the distance between optic chiasm and PA (r = 0.401, p < .001), while the superior, nasal and, inferior RNFL quadrants showed a weak (r = 0.079; 0.074; 0.113) or not significant (r = 0.351; 0.380; 0.180) correlation with the distance between the optic chiasm and PA. The chiasmal right side, middle part, left side heights correlated significantly with RNFL thickness in all quadrants (p < .05). Our results indicate that suprasellar extension in PA patients causes visual disturbances. PMID- 29398199 TI - Letter to the editor: "Evaulation of radioisotopic and non-radioisotopic versions of local lymph node assays for subcategorization of skin sensitiers compliant to UN GHS rev 4" by Ha et al., 2017. PMID- 29398200 TI - Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 159 individuals from the Worcester region of the Western Cape province of South Africa. AB - DNA sequence-based typing at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, DRB1, and -DRB3/4/5 loci was performed on samples provided by 159 individuals from the Worcester region of the Western Cape province of South Africa. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, and -DRB1 loci. A minor deviation was detected at the HLA-DQB1 locus due to an excess of homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3425. PMID- 29398201 TI - Antimalarial polyoxygenated cyclohexene derivatives from the roots of Uvaria cherrevensis. AB - Three new polyoxygenated cyclohexene derivatives named cherrevenisyls A and B (1 and 2), and ellipeiopsol E (3), along with fifteen known compounds, were isolated from the roots of Uvaria cherrevensis. Their structures were determined by spectroscopic methods including 2D NMR techniques and mass spectrometry. The absolute configurations of 1 and 2 were assigned. Compounds 1, 2 and 5 showed antimalarial activity against Plasmodium falciparum with IC50 ranging from 3.34 7.34MUg/mL. Compounds 5-18 exhibited cytotoxicity against three cancer cell lines (KB, MCF-7 and NCI-H187) with IC50 values in ranging from 1.26-49.03MUg/mL. PMID- 29398202 TI - trans-Golgi network-bound cargo traffic. AB - Cargo following the retrograde trafficking are sorted at endosomes to be targeted the trans-Golgi network (TGN), a central receiving organelle. Though molecular requirements and their interaction networks have been somewhat established, the complete understanding of the intricate nature of their action mechanisms in every step of the retrograde traffic pathway remains unachieved. This review focuses on elucidating known functions of key regulators, including scission factors at the endosome and tethering/fusion mediators at the receiving dock, TGN, as well as a diverse range of cargo. PMID- 29398203 TI - Typology of drug use in United Kingdom men who have sex with men and associations with socio-sexual characteristics. AB - BACKGROUND: Analysis of specific drug use patterns in men who have sex with men (MSM) is important in targeting HIV prevention and harm reduction interventions and in developing a fuller picture of drug use in context beyond consideration of use of specific drugs in isolation. OBJECTIVES: We sought to develop a typology of recent drug use in MSM, and to explore how distribution of MSM across the classes in this typology differs by socio-sexual characteristics. METHODS: We examined last-year drug use reported by 16,814 MSM as part of a cross-sectional, internet-based survey of MSM living in the UK for which data were collected in late summer 2014. We tested models with between two and six classes for types of specific drug use, and related socio-sexual covariates to the classes in the best model using multinomial regression. RESULTS: Our five-class model described a range of drug use patterns, including minimal users, low-threshold users, old skool users, chemsex-plus users and diverse users. MSM identifying as gay were more likely to not be minimal users. HIV-positive MSM were more likely to be chemsex-plus users than HIV-negative MSM. Number and type of non-steady partners, ethnicity and education were each related to class membership, though trends were complex. CONCLUSIONS: Findings from associations between correlates and latent classes suggest avenues for service development beyond current attention to opiates or chemsex drugs. Our findings draw attention to heterogeneity in drug use patterns in MSM beyond what current discourse on chemsex drugs would suggest. PMID- 29398204 TI - Methylation of Elongation Factor 1A: Where, Who, and Why? AB - Eukaryotic elongation factor 1A (eEF1A) is an essential and highly conserved protein involved in diverse cellular processes, including translation, cytoskeleton organisation, nuclear export, and proteasomal degradation. Recently, nine novel and site-specific methyltransferases were discovered that target eEF1A, five in yeast and four in human, making it the eukaryotic protein with the highest number of independent methyltransferases. Some of these methyltransferases show striking evolutionary conservation. Yet, they come from diverse methyltransferase families, indicating they confer competitive advantage through independent origins. As might be expected, the first functional studies of specific methylation sites found them to have distinct effects, notably on eEF1A-related processes of translation and tRNA aminoacylation. Further functional studies of sites will likely reveal other unique roles for this interesting modification. PMID- 29398205 TI - Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances. AB - Changes in inflammatory cascades have been implicated in the underlying pathophysiology of psychosis. Translocator protein 18 kDa (TSPO) has been used to assess neuroinflammatory processes in psychotic disorders. Nonetheless, it is unclear whether TSPO, a mitochondrial protein, can be interpreted as a general marker for inflammation in diseases involving psychosis. To address this question, we investigated TSPO signaling in representative mouse models for psychosis with inflammatory disturbances. The maternal immune activation and cuprizone short-term exposure models show different TSPO signaling. Furthermore, we observed similarities and differences in their respective stress pathways including stress hormone signaling and oxidative stress that are functionally interconnected with the inflammatory responses. We propose that more careful studies of TSPO distribution in neuroinflammation and other stress cascades associated with psychotic symptoms will allow us to understand the biological mechanisms underlying psychosis-related behaviors. PMID- 29398206 TI - Paranoia and anxiety: A cluster analysis in a non-clinical sample and the relationship with worry processes. AB - BACKGROUND: Worry processes are implicated in paranoia and anxiety. However, clinical studies focused on patients with co-occurring paranoia and anxiety. As both paranoia and anxiety are distributed across clinical and non-clinical groups, an investigation on worry processes among non-clinical individuals will allow us to delineate the specific worry mechanisms in paranoia and anxiety respectively. AIMS: To identify clusters of non-clinical individuals who report varied levels of paranoia and anxiety, and to compare worry processes across clusters. METHOD: An online survey, consisting of self-report questionnaires on generalized anxiety, paranoia, and worry processes, was completed by 2796 undergraduate students. A multiple-step validity check procedure resulted in a subsample of 2291 students, upon which cluster analyses and multivariate analyses of variance were conducted. RESULTS: Four clusters of individuals were identified: (1) high paranoia/moderate anxiety, (2) average paranoia/high anxiety, (3) average paranoia/average anxiety, and (4) low paranoia/low anxiety. A unique cluster of individuals with high paranoia but low/average level of anxiety was not found. Cluster 1 reported a significantly higher intensity of day to-day worries, a higher level of meta-worry, and more extreme meta-cognitive beliefs about worry than other clusters. CONCLUSIONS: Individuals with high paranoia tended to report anxiety as well, but not vice versa. Our findings supported a hierarchical structure of anxiety and paranoia. All worry processes were exacerbated in individuals with paranoia and anxiety than those with anxiety alone. PMID- 29398207 TI - Effective connectivity within a triple network brain system discriminates schizophrenia spectrum disorders from psychotic bipolar disorder at the single subject level. AB - OBJECTIVE: Schizophrenia spectrum disorders (SSD) and psychotic bipolar disorder share a number of genetic and neurobiological features, despite a divergence in clinical course and outcome trajectories. We studied the diagnostic classification potential that can be achieved on the basis of the structure and connectivity within a triple network system (the default mode, salience and central executive network) in patients with SSD and psychotic bipolar disorder. METHODS: Directed static connectivity and its dynamic variance was estimated among 8 nodes of the three large-scale networks. Multivariate autoregressive models of deconvolved resting state functional magnetic resonance imaging time series were obtained from 57 patients (38 with SSD and 19 with bipolar disorder and psychosis). We used 2/3 of the patients for training and validation of the classifier and the remaining 1/3 as an independent hold-out test data for performance estimation. RESULTS: A high level of discrimination between bipolar disorder with psychosis and SSD (combined balanced accuracy = 96.2%; class accuracies 100% for bipolar and 92.3% for SSD) was achieved when effective connectivity and morphometry of the triple network nodes was combined with symptom scores. Patients with SSD were discriminated from patients with bipolar disorder and psychosis as showing higher clinical severity of disorganization and higher variability in the effective connectivity between salience and executive networks. CONCLUSIONS: Our results support the view that the study of network level connectivity patterns can not only clarify the pathophysiology of SSD but also provide a measure of excellent clinical utility to identify discrete diagnostic/prognostic groups among individuals with psychosis. PMID- 29398208 TI - Histo-morphologic characteristics of intra-osseous implants of WE43 Mg alloys with and without heat treatment in an in vivo cranial bone sheep model. AB - WE43 Mg alloy, composed of Mg, Yttrium, Rare Earth elements, and Zirconium, has proved to be a suitable candidate for production of resorbable osteosynthesis implants in both clinical and experimental settings. In a previous study we tested biocompatibility and degradation properties of untreated (as-cast) and artificially aged (T-5) WE43 Mg-alloys as subperiosteal implants on a maxillofacial sheep model. Both the alloy compositions showed excellent biocompatibility, however, with respect to degradation rate, the as-cast form showed increased degradability compared with the T-5. In the present study, we tested the same alloy composition (i.e. as-cast and T-5) to assess their biological behavior and degradation pattern when implanted as endosteal implants on a calvarial bone sheep model. Six implants in form of cylindrical discs were tested in 6 sheep, one per composition of each disc was placed in two monocortical cranial defect created with high speed trephine bur in the parietal bone. After euthanasia at 6 weeks histomorphological analysis of the bone/implant specimens was performed. WE43-as cast showed higher degradation rate, increased bone remodeling, gas pockets formation and osteolysis compared with the T5 alloy. WE43-T5 showed greater bone/implant interface stability, and seemed to be more suitable for fabrication of endosteal bone screws. PMID- 29398209 TI - Comparison of preseptal and retroseptal transconjunctival approaches in patients with isolated fractures of the orbital floor. AB - Transconjunctival approach has become a standard procedure to access fractures of orbit and the infraorbital rim. The transconjunctival incision can be performed pre- or retroseptally. Both approaches have been described combined with modifications such as transcaruncular or detachment of the lateral canthus for wider exposure of the orbital walls and rim. Particularly concerning aesthetics, the transconjunctival approach shows advantages compared to the transcutaneous incisions, such as the transciliary and infraorbital access. Moreover, transconjunctival approach is preferred in the literature regarding lid retraction. In this study the preseptal approach is compared with the retroseptal approach concerning en- or ectropion, foreign body sensation and formation of symblepharon. In our collective complication rates were lower in the retroseptal transconjunctival group, although this was not statistically significant. Whether the preseptal or the retroseptal transconjunctival approach is selected, is rather based on the surgeon's preferences. Nevertheless, the retroseptal approach must be considered as advantageous alternative to the preseptal approach because of simpler surgical technique and the safer distance to the vulnerable lid apparatus. PMID- 29398211 TI - Peripheral Nerve Injury After Elbow Arthroscopy: An Analysis of Risk Factors. AB - PURPOSE: To identify risk factors associated with peripheral nerve injury after elbow arthroscopy and provide an updated incidence of those complications. METHODS: The elbow arthroscopies that were performed at our institution between 2006 and 2016 were identified. Over a 10-year period, 253 elbow arthroscopies were performed at our institution. Two hundred twenty-seven cases had a minimum follow-up of 4 weeks, and were included in our analysis. Minor and major nerve related complications were recorded. The surgeon's experience and training, body max index of the patients, surgical tourniquet time, type of anesthesia or surgery, radiographic appearance of the elbow, diagnosis at the time of surgery, and presence of diabetes were analyzed. RESULTS: There were 12 reported peripheral nerve injuries, 10 minor (4.4%) and 2 major complications (0.9%). The risk factors examined in this study were not correlated with a higher rate of complications. CONCLUSIONS: The minor nerve-related complication rate was 4.4%, with a 0.9% incidence of major peripheral nerve injury. Based on these findings, we conclude that elbow arthroscopy is a relatively safe procedure. The risk factors examined in this study had no association with the rate of complications. This finding could be potentially related to type II or beta error in the analysis of risk factors for nerve injury. The exact reasons for nerve injury are not known from this study. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29398212 TI - Ankle Arthroscopy for Diagnosis of Full-thickness Talar Cartilage Lesions in the Setting of Acute Ankle Fractures. AB - PURPOSE: To delineate the prevalence of chondral lesions, in particular full thickness talar dome lesions, with concurrent arthroscopy in acute ankle fracture open reduction-internal fixation (ORIF) and evaluate the impact on clinical outcomes. METHODS: We conducted a retrospective chart review of prospectively collected registry data at our institution from 2012 to 2016. Consecutive patients who underwent acute ankle fracture ORIF with concurrent arthroscopy were identified. Charts were reviewed to determine the prevalence and grade of chondral lesions, fracture type, and associated factors. Clinical outcomes with a minimum of 1 year of follow-up were assessed using the Foot and Ankle Outcome Score. RESULTS: The study included 116 consecutive patients undergoing acute ankle fracture ORIF with concurrent arthroscopy. A chondral lesion was identified in 78% (90 of 116). A full-thickness talar dome chondral lesion was identified in 43% of these patients (39 of 90). Patient age was a significant predictor, with patients younger than 30 years being less likely to have a chondral injury than those aged 30 years or older (59% vs 85%, P = .0077). Of the patients who sustained a dislocation at the time of injury, 100% had a chondral lesion (P = .039). Patients with complete syndesmosis disruption and instability were also more likely to have a chondral lesion (96% vs 73%, P = .013). Patients with chondral lesions had statistically significantly worse clinical outcomes than those without them (Foot and Ankle Outcome Score, 81.2 vs 92.1; P = .009). CONCLUSIONS: Ankle arthroscopy performed concomitantly with ankle ORIF is a useful tool in diagnosing chondral injuries. Chondral lesions are common with ankle fractures. An ankle with a dislocation at presentation or a syndesmotic injury may be more likely to present with a chondral lesion and should thus prompt evaluation. The presence of a talar chondral injury may be associated with a negative impact on clinical outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 29398210 TI - Prospective, Observational Study of Opioid Use After Hip Arthroscopy for Femoroacetabular Impingement Syndrome. AB - PURPOSE: To provide estimates of postoperative opioid use after hip arthroscopy for femoroacetabular impingement (FAI) syndrome and to identify risk factors for increased postoperative opioid use. METHODS: All patients aged at least 18 years who were undergoing hip arthroscopy for FAI syndrome performed by 1 of 2 hip preservation surgeons between November 2015 and August 2016 were eligible for inclusion in this study. Target minimum enrollment was set at 30 patients per surgeon based on an a priori sample size calculation. Enrolled patients completed the International Hip Outcome Tool, visual analog pain scale, Pain Catastrophizing Scale, abbreviated Patient Health Questionnaire, and questions regarding demographic characteristics and opioid and anti-inflammatory use. Opioid consumption was assessed through pill counting at 2- and 6-week postoperative appointments. Of 80 patients enrolled, 67 had complete 2- and 6 week opioid use data. Patient and operative factors were correlated with outcomes in multivariate models. RESULTS: Opioid use in the 2 weeks before surgery was significantly associated with higher postoperative opioid use at 2 weeks postoperatively (253.8 additional oral morphine equivalents [OMEs]; 95% confidence interval [CI], 171.2-336.5 additional OMEs; P < .0001; n = 73) and 6 weeks postoperatively (385.3 additional OMEs; 95% CI, 241.6-529.0 additional OMEs; P < .0001; n = 67). By 6 weeks postoperatively, 41 of 52 patients (79%) without opioid use in the 2 weeks before surgery used 30 or fewer 5-mg oxycodone pills compared with only 2 of 15 patients (13%) with preoperative use (odds ratio, 24.9; 95% CI, 4.2-148.5; P < .0001). CONCLUSIONS: Among patients undergoing hip arthroscopy for FAI syndrome, any opioid use in the 2 weeks preceding surgery was the strongest predictor of opioid use after hip arthroscopy. The impact of preoperative opioid use far exceeded the impact of other baseline patient and operative factors. Assessment of preoperative opioid use could be an important factor in guiding postoperative opioid prescribing. LEVEL OF EVIDENCE: Level II, prospective observational study. PMID- 29398213 TI - Not All Patients With Diabetes Have the Same Risks: Perioperative Glycemic Control Is Associated With Postoperative Infection Following Knee Arthroscopy. AB - PURPOSE: To determine the association between glycemic control and infection following knee arthroscopy, and to determine the clinical utility of a threshold HbA1c level. METHODS: A national database identified patients who underwent knee arthroscopy from 2007 to 2016. Patients with concomitant open portions, more complex knee procedures, procedures performed for infection and patients with prior septic knee arthritis were excluded. Patients with an HbA1c level checked within 3 months of surgery were compared to control groups of nondiabetics and diabetics undergoing knee arthroscopy without a perioperative HbA1c. The study group was then stratified based on their HbA1c. The incidence of deep infection within 6 months was identified and compared to those in the control groups. A subgroup analysis was performed to investigate any trend in the timing of postoperative infection. A receiver operating characteristic (ROC) analysis was performed to determine and test a threshold value of HbA1c. RESULTS: 13,470 study patients were included, with an overall rate of infection of 0.33%. The rate of infection ranged from 0.25% to 1.03%. The rate of infection in study patients was greater than the nondiabetes control group's (P < .0001) and not significantly different from that in the nonstudy diabetes control (P = .765). The inflection point of the ROC curve corresponded to an HbA1c level of 8.0 mg/dL (P = .006, specificity = 76%, sensitivity = 44%, area under curve [AUC] = 0.619). CONCLUSIONS: The risk of infection following knee arthroscopy increases as the perioperative HbA1c increases. ROC analysis determined that an HbA1c above 8.0 mg/dL could serve as a threshold level; however, the AUC and low sensitivity reflected the poor utility of this test as an independent predictor for infection. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29398215 TI - Reciprocal Trading of Different Commodities in Norway Rats. AB - The prevalence of reciprocal cooperation in non-human animals is hotly debated [1, 2]. Part of this dispute rests on the assumption that reciprocity means paying like with like [3]. However, exchanges between social partners may involve different commodities and services. Hitherto, there is no experimental evidence that animals other than primates exchange different commodities among conspecifics based on the decision rules of direct reciprocity. Here, we show that Norway rats (Rattus norvegicus) apply direct reciprocity rules when exchanging two different social services: food provisioning and allogrooming. Focal rats were made to experience partners either cooperating or non-cooperating in one of the two commodities. Afterward, they had the opportunity to reciprocate favors by the alternative service. Test rats traded allogrooming against food provisioning, and vice versa, thereby acting by the rules of direct reciprocity. This might indicate that reciprocal altruism among non-human animals is much more widespread than currently assumed. PMID- 29398214 TI - A Localized Pseudomonas syringae Infection Triggers Systemic Clock Responses in Arabidopsis. AB - The circadian clock drives daily rhythms of many plant physiological responses, providing a competitive advantage that improves plant fitness and survival rates [1-5]. Whereas multiple environmental cues are predicted to regulate the plant clock function, most studies focused on understanding the effects of light and temperature [5-8]. Increasing evidence indicates a significant role of plant pathogen interactions on clock regulation [9, 10], but the underlying mechanisms remain elusive. In Arabidopsis, the clock function largely relies on a transcriptional feedback loop between morning (CCA1 and LHY)- and evening (TOC1) expressed transcription factors [6-8]. Here, we focused on these core components to investigate the Arabidopsis clock regulation using a unique biotic stress approach. We found that a single-leaf Pseudomonas syringae infection systemically lengthened the period and reduced the amplitude of circadian rhythms in distal uninfected tissues. Remarkably, the low-amplitude phenotype observed upon infection was recapitulated by a transient treatment with the defense-related phytohormone salicylic acid (SA), which also triggered a significant clock phase delay. Strikingly, despite SA-modulated circadian rhythms, we revealed that the master regulator of SA signaling, NPR1 [11, 12], antagonized clock responses triggered by both SA treatment and P. syringae. In contrast, we uncovered that the NADPH oxidase RBOHD [13] largely mediated the aforementioned clock responses after either SA treatment or the bacterial infection. Altogether, we demonstrated novel and unexpected roles for SA, NPR1, and redox signaling in clock regulation by P. syringae and revealed a previously unrecognized layer of systemic clock regulation by locally perceived environmental cues. PMID- 29398216 TI - Natural Infection of C. elegans by an Oomycete Reveals a New Pathogen-Specific Immune Response. AB - In its natural habitat, the nematode Caenorhabditis elegans encounters a plethora of other organisms, including many that are pathogenic [1, 2]. The study of interactions between C. elegans and various pathogens has contributed to characterizing key mechanisms of innate immunity [2-4]. However, how C. elegans recognizes different pathogens to mount pathogen-specific immune responses remains still largely unknown [3, 5-8]. Expanding the range of known C. elegans infecting pathogens and characterizing novel pathogen-specific immune responses are key steps toward answering this question. We report here that the oomycete Myzocytiopsis humicola is a natural pathogen of C. elegans, and we describe its infection strategy. We identify a new host immune response to pathogen exposure that involves induction of members of a previously uncharacterized gene family encoding chitinase-like (CHIL) proteins. We demonstrate that this response is highly specific against M. humicola and antagonizes the infection. We propose that CHIL proteins may diminish the ability of the oomycete to infect by hindering pathogen attachment to the host cuticle. This work expands our knowledge of natural eukaryotic pathogens of C. elegans and introduces a new pathosystem to address how animal hosts recognize and respond to oomycete infections. PMID- 29398217 TI - Excitatory Pathways from the Lateral Habenula Enable Propofol-Induced Sedation. AB - The lateral habenula has been widely studied for its contribution in generating reward-related behaviors [1, 2]. We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol. The lateral habenula is a glutamatergic, excitatory hub that projects to multiple targets throughout the brain, including GABAergic and aminergic nuclei that control arousal [3-5]. When glutamate release from the lateral habenula in mice was genetically blocked, the ability of propofol to induce sedation was greatly diminished. In addition to this reduced sensitivity to propofol, blocking output from the lateral habenula caused natural non-rapid eye movement (NREM) sleep to become highly fragmented, especially during the rest ("lights on") period. This fragmentation was largely reversed by the dual orexinergic antagonist almorexant. We conclude that the glutamatergic output from the lateral habenula is permissive for the sedative actions of propofol and is also necessary for the consolidation of natural sleep. PMID- 29398219 TI - Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells. AB - Natural killer (NK) cells are innate immune effectors that lyse virally infected and tumorigenic cells through the formation of an immunological synapse. Actin remodeling at the lytic immunological synapse is a critical requirement for multiple facets of cytotoxic function. Activating receptor and integrin signaling leads to the regulated turnover and remodeling of actin, which is required for adhesion, sustained receptor signaling, and ultimately exocytosis. NK cells undergo lytic granule exocytosis in hypodense regions of a pervasive actin network. Although these requirements have been well demonstrated, neither the dynamic regulation of synaptic actin nor its specific function, however, has been determined at a nanoscale level. Here, live-cell super-resolution microscopy demonstrates nanoscale filamentous actin dynamism in NK cell lytic granule secretion. Following cell spreading, the overall content of the branched actin network at an immune synapse is stable over time and contains branched actin fibers and discrete actin foci. Similar actin architecture is generated in cytolytic T cells, although the timescale differs from that of NK cells. Individual filament displacement leads to stochastic clearance formation and disappearance, which are independent of lytic granule positioning. Actin dynamism is dependent upon branched network formation mediated by Arp2/3 and contractility generated by myosin IIA. Importantly, the use of small-molecule inhibitors demonstrates that actin dynamism is ultimately needed for granule secretion. Thus, we describe a requirement for nanoscale actin fiber rearrangement in generating the complex actin architecture that enables lytic granule secretion. PMID- 29398221 TI - Nitrogen-Fixing Heterocystous Cyanobacteria in the Tonian Period. AB - Cyanobacteria were the ultimate ancestor of all plastids and, for much of Earth's history, the only source of biogenic oxygen and a major source of fixed carbon and nitrogen. One cyanobacterial clade, subsections IV+V, is characterized by multicellularity and cell differentiation, with many members bearing specialized nitrogen-fixing (or diazotrophic) heterocysts and encysting akinetes [1-3]. Molecular clock estimates of the divergence time of this clade are highly variable, ranging from ~2,000 Ma (mega-annum) [4-9] to ~500 Ma [10]. The older estimates are invariably calibrated by putative akinete fossils from Paleoproterozoic-Mesoproterozoic rocks around 2,100-1,400 Ma [3, 11, 12]. However, the interpretation of these fossils as akinetes has been questioned [13], and the next oldest akinete and heterocyst fossils are ~410 Ma [14]. Thus, the scarcity of reliable heterocystous cyanobacterial fossils significantly hampers our understanding of the evolution of complex multicellularity among cyanobacteria, their role in regulating geochemical cycles in the geological past, and our ability to calibrate cyanobacterial molecular clocks. Here, we report Tonian (~1,000-720 Ma) filamentous cyanobacteria that are characterized by large cells, binary fission (for filament elongation), hormogonia (for asexual reproduction and dispersal), probable akinetes (for survival in adverse conditions), and by implication, diazotrophic heterocysts. The new fossils provide a minimum age calibration on the divergence of subsections IV+V and place a firm constraint on the evolution of akinetes and heterocysts. PMID- 29398220 TI - Self-Organized Attractor Dynamics in the Developing Head Direction Circuit. AB - Head direction (HD) cells are neurons found in an extended cortical and subcortical network that signal the orientation of an animal's head relative to its environment [1-3]. They are a fundamental component of the wider circuit of spatially responsive hippocampal formation neurons that make up the neural cognitive map of space [4]. During post-natal development, HD cells are the first among spatially modulated neurons in the hippocampal circuit to exhibit mature firing properties [5, 6], but before eye opening, HD cell responses in rat pups have low directional information and are directionally unstable [7, 8]. Using Bayesian decoding of HD cell ensemble activity recorded in the anterodorsal thalamic nucleus (ADN), we characterize this instability and identify its source: under-signaling of angular head velocity, which incompletely shifts the directional signal in proportion to head turns. We find evidence that geometric cues (the corners of a square environment) can be used to mitigate this under signaling and, thereby, stabilize the directional signal even before eye opening. Crucially, even when directional firing cannot be stabilized, ensembles of unstable HD cells show short-timescale (1-10 s) temporal and spatial couplings consistent with an adult-like HD network. The HD network is widely modeled as a continuous attractor whose output is one coherent activity peak, updated during movement by angular head velocity signals and anchored by landmark cues [9-11]. Our findings present strong evidence for this model, and they demonstrate that the required network circuitry is in place and functional early during development, independent of reference to landmark information. PMID- 29398222 TI - Analysis of Evolutionarily Independent Protein-RNA Complexes Yields a Criterion to Evaluate the Relevance of Prebiotic Scenarios. AB - A central difficulty facing study of the origin of life on Earth is evaluating the relevance of different proposed prebiotic scenarios. Perhaps the most established feature of the origin of life was the progression through an RNA World, a prebiotic stage dominated by functional RNA. We use the appearance of proteins in the RNA World to understand the prebiotic milieu and develop a criterion to evaluate proposed synthetic scenarios. Current consensus suggests that the earliest amino acids of the genetic code were anionic or small hydrophobic or polar amino acids. However, the ability to interact with the RNA World would have been a crucial feature of early proteins. To determine which amino acids would be important for the RNA World, we analyze non-biological protein-aptamer complexes in which the RNA or DNA is the result of in vitro evolution. This approach avoids confounding effects of biological context and evolutionary history. We use bioinformatic analysis and molecular dynamics simulations to characterize these complexes. We find that positively charged and aromatic amino acids are over-represented whereas small hydrophobic amino acids are under-represented. Binding enthalpy is found to be primarily electrostatic, with positively charged amino acids contributing cooperatively to binding enthalpy. Arginine dominates all modes of interaction at the interface. These results suggest that proposed prebiotic syntheses must be compatible with cationic amino acids, particularly arginine or a biophysically similar amino acid, in order to be relevant to the invention of protein by the RNA World. PMID- 29398218 TI - A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine. AB - Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis. PMID- 29398223 TI - Offline adaptive radiation therapy in the treatment of prostate cancer: a case study. AB - The purpose of this case study is to develop a method to account for the difference in the daily volumes in the bladder, rectum, and targets in prostate radiotherapy and to compare the predicted dose to the actual dose to these organs. Five patients, both prospectively and retrospectively, were selected from 2 different cancer centers, with a biopsy-confirmed diagnosis of prostate cancer. The patients' planning target volume (PTV) and organs at risk (OAR) were contoured on the computed tomography (CT) dataset using either Eclipse or Monaco treatment planning systems (TPSs). Cone-beam computed tomography (CBCT) scans were collected before each daily treatment and exported to MIM software for analysis. The automatically generated reports evaluated the organ volume changes, the actual dose received during a single fraction, and the projected dose to each organ at the completion of the treatment course via comparative cumulative dose volume histograms (DVHs). Volume changes in the bladder and rectum can cause notable variations in the prescribed dose vs the actual dose received. MIM software was proven to have utility prospectively by tabulating daily dose and projecting final doses, potentially aiding physicians in decisions about the boost plans, thus making offline adaptive radiation therapy (ART) clinically manageable. PMID- 29398224 TI - Visual snow. PMID- 29398225 TI - Papillophlebitis in a young male patient with Buerger's disease. AB - CLINICAL CASE: A 27-year-old male with sudden visual loss of OD. He had a past history of heavy smoking, as well as a chronic ischaemia of his left lower limb of one-year onset. This led to a diagnosis of Buerger's disease, which is an inflammatory thrombotic disorder that affects small and medium vessels. The visual acuity (VA) of OD was 0.9, and in the funduscopy a very congestive papilla was observed, along with venous tortuosity, scattered retinal haemorrhages, but without macular oedema. He progressed favourably, with a complete recovery of VA. DISCUSSION: Papillophlebitis may be an ocular complication of Buerger's disease. PMID- 29398226 TI - Retinal macroaneurysm rupture. PMID- 29398227 TI - Straatsma syndrome: Satisfactory amblyopia treatment. Report of two cases. AB - CLINICAL CASES: The cases are presented on 2 female patients with Straatsma syndrome, with satisfactory treatment of amblyopia. DISCUSSION: The level of anisometropia and myelination of retinal nerve fibres were different in these two patients. However, both achieved 0.20 (logMAR) visual acuity with correction in both eyes following amblyopia treatment with ocular patching. Visual prognosis of amblyopia associated with myelination of retinal nerve fibres and anisometropia is poorer than anisometropic amblyopia without myelination. It is well known that the former is refractory to occlusive therapy. Despite having a poor prognosis, visual rehabilitation should be attempted. The two cases presented were successfully treated with eye-patching. PMID- 29398228 TI - Transient trochlear nerve palsy following percutaneous angioplasty. AB - CASE REPORT: A case is presented of a 63-year-old man who suffered a unilateral isolated trochlear nerve palsy with vertical diplopia following an elective radial coronary angiography and percutaneous coronary intervention, which resolved spontaneously within 2 months. DISCUSSION: Ophthalmoplegia following coronary percutaneous angioplasty is rare. Only internuclear ophthalmoplegia, III and VI cranial nerve palsy have been previously reported following percutaneous angioplasty. This is the first reported case of unilateral isolated trochlear nerve ophthalmoplegia following this procedure. PMID- 29398229 TI - Retino-choroidal coloboma: Study through retinography, fluorescence angiography, ecography and optical coherence tomography. PMID- 29398230 TI - Multimodal imaging in tubercular uveitis. PMID- 29398231 TI - Topical prostaglandin analogues and development of epiretinal membrane. AB - OBJECTIVES: To determine whether patients with glaucoma and epiretinal membrane (ERM) use a greater proportion of prostaglandin analogues (PA) than a control group of patients with glaucoma without ERM. METHOD: A retrospective study of cases and controls was conducted in order to determine whether patients with glaucoma and ERM used a greater proportion of PA than a control group of patients with glaucoma without ERM. The diagnosis of de ERM was made by clinical examination and optical coherence tomography. RESULTS: The mean age of the cases was 77 years (SD: 8.68; 95% CI: 74.3-79.4), compared to the controls with 63 years (SD: 16.6; 95% CI: 70.1-78.5). The cases included 50% (n=26) men and 50% women (n=26), whereas in the controls 25.4% (n=16) of the cases were men and 74.6% (n=47) women. PA treatment was used in 59.6% (n=31) and 60.3% (n=38) of the cases and controls, respectively. There was no statistically significant difference in PA use between the 2groups (P=.939). CONCLUSIONS: In this study, an association between the use of AP and the development of ERM could not be demonstrated. PMID- 29398232 TI - Identification of new candidate genes for retinopathy in type 2 diabetics. Valencia Study on Diabetic Retinopathy (VSDR). Report number 3. AB - OBJECTIVE: To identify genes involved in the pathogenic mechanisms of non proliferative diabetic retinopathy (NPDR), among which include oxidative stress, extracellular matrix changes, and/or apoptosis, in order to evaluate the risk of developing this retinal disease in a type2 diabetic (DM2) population. MATERIAL AND METHODS: A case-control study was carried out on 81 participants from the Valencia Study on Diabetic Retinopathy (VSDR) of both genders, with ages 25 85years. They were classified into: (i)DM2 group (n=49), with DR (+DR; n=14) and without DR (-DR; n=35), and (ii)control group (GC; n=32). The protocols included a personal interview, standardised ophthalmological examination, and blood collection (to analyse the DNA for determining the gene expression (TP53, MMP9, and SLC23A2) in the study groups. Statistical analyses were performed using the SPSS v22.0 program. RESULTS: The TP53 and MMP9 genes showed a higher expression in the DM2 group compared to the GC, although the difference was only significant for the MMP9 gene (TP53: 10.40+/-1.20 vs. 8.23+/-1.36, P=.084; MMP9: 1.45+/-0.16 vs. 0.95+/-0.16, P=.036), and the SLC23A2 gene showed a significant lower expression in the DM2 vs CG (5.58+/-0.64 vs. 11.66+/-1.90, P=.026). When sub dividing the DM2 group according to the presence of retinopathy, the expression of the TP53, MMP9 and SLC23A2 genes showed significant differences between the DM2-RD, DM2+RD and GC groups (TP53: 9.95+/-1.47 vs. 11.52+/-2.05 vs. 8.23+/-1.36, P=.038; MMP9: 1.47+/-0.20 vs. 1.41+/-0.27 vs. 0.95+/-0.16, P=.021; SLC23A2: 5.61+/-0.77 vs. 5.51+/-1.21 vs. 11.66+/-1.90, P=.018). CONCLUSIONS: Genes involved in extracellular matrix integrity (MMP9) and/or apoptosis (TP53), could be considered potential markers of susceptibility to the development/progression of NPDR. Interestingly, the SLC232A2 gene (ascorbic acid transporter) can be considered a protector of the risk of the development/progression of the retinopathy. PMID- 29398233 TI - Superdiluted atropine at 0.01% reduces progression in children and adolescents. A 5 year study of safety and effectiveness. AB - OBJECTIVE: To confirm the clinical security and effectiveness of the daily application of 0.01% superdiluted atropine eyedrops in the progression of myopia in children. MATERIAL AND METHODS: A total of 200 children 9-12 years of age were randomised into a treated group and a control without treatment. Refraction under cycloplegia was performed. RESULTS: Myopia progression of the treated group was 0.14+/-0.35 versus -0.65+/-0.54 in the control group without treatment. Only 2% of patients were forced to stop treatment due to side effects. CONCLUSION: Atropine superdiluted atropine 0.01% eyedrops is effective and well tolerated, and reduced myopia progression by 25%. PMID- 29398234 TI - Bilateral acute iris transillumination syndrome. A case report. AB - OBJECTIVE: To present a case report of a patient with a bilateral acute iris transillumination syndrome (BAIT). METHODS: BAIT syndrome is a new clinical condition characterised by severe transillumination of the iris, acute onset of pigment dispersion in the anterior chamber, and a medial mydriatic pupil that is unresponsive or poorly responsive to light, due to a sphincter paralysis. Patients with BAIT generally present with acute ocular pain, photophobia, and red eyes. DISCUSSION: The case is presented of a 53 year-old woman, who, after being treated with moxifloxacin for an upper respiratory tract infection, developed a BAIT syndrome, which was initially diagnosed as acute anterior uveitis. CONCLUSION: As far as is known this is the first case reported in Navarra, but more case reports are needed to establish clear patterns about this condition. PMID- 29398235 TI - Assessment of extraocular muscle thickness and correlation study using optical coherence tomography. AB - OBJECTIVE: To report reference values for the horizontal rectus muscles thickness using Spectral Domain optical coherence tomography (SD-OCT), and to evaluate whether there are any correlations between the muscle thickness and gender, age, or axial length (AL). MATERIAL AND METHODS: A cross-sectional study was conducted on 131 right eyes of healthy subjects. The gender and age were recorded, and axial length was measured using an optical biometer. The medial rectus (MR) muscle thickness was measured at 7.2 and 9.2mm from the limbus, and the lateral rectus (LR) at 8.5 and 10.5mm from the limbus using OCT. A multivariate model was adjusted to determine whether gender, age, and axial length could have an impact on the muscle thickness. RESULTS: Mean age was 43.3+/-20.9 years (range 6-86), and 59% were women. Mean AL was 24.9+/-2.7mm (range: 20.4-33.8). Mean thickness was 188.5+/-51.2MUm (range 69-342) for the LR at 8.5 and 186.5+/-45.9MUm (range 75-269) at 10.5mm, and for the MR, 158.1+/-39.1MUm (range 69-273) at 7.2mm and 193.7+/-55.9MUm (range 105-386) at 9.2mm. A correlation was observed between the AL and MR thickness (R=-.255; P=.023) while no correlation was observed for the LR (P>=0.203). No correlations were found between thickness and gender or thickness and age (P>=0.125). CONCLUSIONS: The reference ranges of the horizontal rectus muscles thickness was described using SD-OCT, observing an association between the AL and the MR thickness. PMID- 29398236 TI - Acute bilateral serous central chorioretinopathy after emergency contraceptive therapy with ulipristal acetate. AB - CASE REPORT: The case concerns a 31 year-old woman with no previous history who consulted due to decreased vision in both eyes. She mentioned taking 1 pill of ulipristal acetate (30mg) as an emergency contraceptive four days before the visual symptoms appeared. In the examination, a better corrected visual acuity of 0.6 was found in the right eye and 0.8 in left eye (by Snellen chart), and bilateral macular serous detachment. It was decided to observe, and 15 days later she showed a functional and anatomical improvement. DISCUSSION: Ulipristal acetate could lead to serous central chorioretinopathy due to its activity on the progesterone receptors present in choroidal and retinal pigment epithelium. PMID- 29398237 TI - Multimodal imaging in the characterisation of retinal arterial embolism. PMID- 29398238 TI - A meditation on technique. PMID- 29398239 TI - Unusual ocular clinical manifestation of leptospirosis. AB - CLINICAL CASE: An uncommon case is presented of a 15 year-old girl with bilateral, multiple serous detachments of retina and retinal pigment epithelium. With clinical and laboratory (IgG 1/160 and IgM 1/160, using an indirect immunofluorescence assay) diagnoses of leptospirosis, a complete ophthalmic examination, fluorescein angiography, autofluorescence and optical coherence tomography were performed, and the patient was followed for two years. DISCUSSION: Bilateral, multiple serous detachments of retina and retinal pigment epithelium can be a complication of systemic leptospirosis, a zoonotic disease caused by Leptospira. Without a detailed medical history it may be underdiagnosed, mainly because it can mimic other more common diseases. It may be prudent to ask patients regarding contact with pets. PMID- 29398240 TI - The joint 16th symposium on Trace Elements in Man and Animals (TEMA16), International Society for Trace Element Research in Humans (ISTERH-2017) and Nordic Trace Element Society (NTES), Saint-Petersburg, Russia, 26-29 June, 2017. PMID- 29398241 TI - The results of expanded-polytetrafluoroethylene mesh repair in difficult abdominal wall defects. AB - BACKGROUND: The repair of difficult abdominal wall defects (AWDs) continues to be a crucial and demanding issue for surgeons. This study aimed to present the risk factors and the long-term results of usage of an expanded-polytetrafluoroethylene (e-PTFE) synthetic mesh for the AWR of difficult abdominal wall defects. METHODS: This study included 156 adult patients who underwent difficult AWR with e-PTFE mesh for incisional hernia, ventral hernia, and created AWDs of various etiopathologies. The association between the risk factors and the postoperative complications of AWR was analyzed, and overall long-term outcomes of e-PTFE repair were assessed. RESULTS: The median follow-up duration was 119.1 (ranging from 2 to 206) months. In 70 (44.8%) patients, there were major co-morbidities. A surgical site infection developed in 17 (10.9%) patients. Of these, only 2 (1.3%) patients had e-PTFE mesh infection. Seven (4.4%) patients experienced recurrence. Recalcitrant seroma formation occurred in 8 (36.3%) patients. CONCLUSION: E-PTFE synthetic mesh usage for difficult abdominal wall hernias can help the hernia surgeon obtain safe and durable long-term results of sound repair. PMID- 29398242 TI - Utility of Neutrophil-to-Lymphocyte Ratio (NLR) as a Predictor of Acute Infarction in New-Onset Acute Vertigo Patients Without Neurologic and Computed Tomography Abnormalities. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been used as a predictive marker for various conditions. However, there are no previous studies about NLR as a prognostic marker for acute infarction. OBJECTIVE: To evaluate the potential utility of NLR as a predictor of acute infarction in acute vertigo patients without neurologic and computed tomography (CT) abnormalities. METHODS: We conducted a prospective, observational study in the Emergency Department (ED) between January 2015 and December 2016. All patients underwent physical examination, laboratory tests, CT, and magnetic resonance imaging (MRI). Results of the initial and follow-up MRI with clinical progress note were considered as the reference standard. Statistically, multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were used. RESULTS: Thirty-five (25.9%) patients were diagnosed with acute infarction and 100 (74.1%) patients were diagnosed with peripheral vertigo. Horizontal nystagmus (p = 0.03; odds ratio 0.22) and NLR (p = 0.03; odds ratio 5.4) were significant factors for the differential diagnosis of acute infarction and peripheral vertigo. NLR > 2.8 showed the greatest area under the ROC curve (AUC; 0.819), optimal sensitivity (85.7%), and specificity (78.0%). NLR > 1.4 showed the highest sensitivity (97.1%) and relatively low specificity (41%). The absence of horizontal nystagmus increased the specificity (81.0%) and AUC (0.844). CONCLUSIONS: A combination of NLR > 2.8 and the absence of horizontal nystagmus is sufficiently specific for acute infarction in an ED patient with acute vertigo; thus, further testing with MRI is indicated. NLR < 2.8 by itself or combined with the presence of horizontal nystagmus is not sufficiently sensitive to rule out the need for further testing. PMID- 29398243 TI - Global perspectives on food allergy: One size doesn't fit all. PMID- 29398244 TI - Race and ethnicity have significant influence on fractional exhaled nitric oxide. AB - BACKGROUND: Race and ethnicity have been shown to influence fractional exhaled nitric oxide (FeNO). There is a need to investigate cutoff points for different races and ethnicities to improve clinical application. OBJECTIVE: To investigate cutoff points for different races and ethnicities by analyzing the FeNO data collected by the National Health and Nutrition Examination Survey from 2007 to 2012. METHODS: This study included 23,433 participants. After excluding participants with confounding factors, 11,084 participants were eligible for data analysis. Based on age and the probability of having allergic airway inflammation, participants were divided into 4 groups. The geometric mean and 5th, 50th, and 95th percentiles of FeNO in Hispanic, white, black, and other races were analyzed in all groups. RESULTS: Compared with white participants, the geometric mean for FeNO in black participants was 36% to 41% higher in children and 5% to 8% higher in adults. Hispanic children had significantly higher FeNO values (14% to 19%) compared with non-Hispanic white children; however, those differences were not significant in adults. Other races had significantly higher FeNO values in children (24-54%) and adults (9-29%) compared with white participants. Further, for normal healthy black children, the 95th percentile was 40.2 parts per billion (ppb), which is significantly higher than the cutoff point recommended by current guidelines. CONCLUSION: Although there are significant differences in FeNO values among races and ethnicities, the current cutoff point at 50 ppb is sufficient to separate healthy from asthmatic populations in adults. However, for black children, we suggest increasing the cutoff point from 35 to 40 ppb to avoid unnecessary diagnosis and treatment. PMID- 29398245 TI - CANS: Childhood acute neuropsychiatric syndromes. AB - The terms Pediatric Autoimmune Neuropsychiatric disorders associated with streptococcal infections (PANDAS), Pediatric acute-onset neuropsychiatric Syndrome (PANS), and Childhood Acute Neuropsychiatric Symptoms (CANS) have been used to describe certain acute onset neuropsychiatric pediatric disorders. This clinical characteristic was unusually abrupt onset of obsessive compulsive symptoms and/or severe eating restrictions and concomitant cognitive, behavioral or neurological symptoms. Because the CANS/PANS criteria define a broad spectrum of neuropsychiatric conditions, the syndrome is presumed to result from a variety of disease mechanisms and to have multiple etiologies, ranging from postinfectious autoimmune and neuroinflammatory disorders to toxic, endocrine or metabolic disorders. We suggest a diagnostic flow-chart in case of acute onset neuropsychiatric syndrome to better define diagnostic criteria, identify possible subtypes and delineate treatment. PMID- 29398246 TI - Corrigendum to "miR-142-5p promotes development of colorectal cancer through targeting SDHB and facilitating generation of aerobic glycolysis" [Biomed. Pharmacother. 92 (2017) 1119-1127]. PMID- 29398247 TI - Comment on "Mild water restriction with or without urea for the longterm treatment of SIADH: Can urine osmolality help the choice?" by Decaux et al. PMID- 29398248 TI - Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. AB - INTRODUCTION: There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis is increasingly used by the elderly. We aimed to assess the characteristics of elderly people using medical cannabis and to evaluate the safety and efficacy of the treatment. METHODS: A prospective study that included all patients above 65 years of age who received medical cannabis from January 2015 to October 2017 in a specialized medical cannabis clinic and were willing to answer the initial questionnaire. Outcomes were pain intensity, quality of life and adverse events at six months. RESULTS: During the study period, 2736 patients above 65 years of age began cannabis treatment and answered the initial questionnaire. The mean age was 74.5 +/- 7.5 years. The most common indications for cannabis treatment were pain (66.6%) and cancer (60.8%). After six months of treatment, 93.7% of the respondents reported improvement in their condition and the reported pain level was reduced from a median of 8 on a scale of 0-10 to a median of 4. Most common adverse events were: dizziness (9.7%) and dry mouth (7.1%). After six months, 18.1% stopped using opioid analgesics or reduced their dose. CONCLUSION: Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids. Gathering more evidence-based data, including data from double-blind randomized-controlled trials, in this special population is imperative. PMID- 29398249 TI - Differential diagnosis of unexplained falls in dementia: Results of "Syncope & Dementia" registry. PMID- 29398250 TI - Designing a theory-based intervention to improve the guideline-concordant use of imaging to stage incident prostate cancer. AB - Among US men, most new prostate cancer cases are clinically localized and do not require imaging as part of staging workup according to guidelines. Two leading specialty societies promote stewardship of health resources by encouraging guideline-concordant care, thereby limiting inappropriate and obsolete imaging. However, imaging to stage low-risk prostate cancer remains high, as almost half of men with localized prostate cancer undergo wasteful imaging following diagnosis. We employed a theory-based approach, based on current evidence and data on existing practice patterns revealing that providers are the drivers to imaging decisions, to design an intervention to improve guideline -concordant prostate cancer staging imaging across populations. We conceptualized preliminary results using the theoretical domains framework and the behavior change wheel, frameworks used concurrently to investigate physicians' behaviors and intervention design in various clinical settings. Through these 2 frameworks, we designed a theory-based, physician-focused intervention to efficiently encourage guideline-concordant prostate cancer imaging, prostate cancer imaging stewardship (PCIS). Prostate cancer imaging stewardship consists of interventions (clinical order check, academic detailing, and audit and feedback) implemented at the individual, facility, and system level to enact provider behavior change by enabling facilitators and appealing to physician motivation. PMID- 29398251 TI - Metabolic inventory of Streptococcus pneumoniae growing in a chemical defined environment. AB - The Gram-positive bacterium Streptococcus pneumoniae can cause a broad range of severe diseases including pneumonia and septicemia. The pneumococcal pathophysiology is highly dependent on host nutrients such as purines, pyrimidines, amino acids and carbon sources. Therefore, we aimed to decipher the metabolome with a metabolomics approach that allows for the investigation of the basic metabolic characteristics during growth in a chemical defined medium composed of typical host metabolites. By using a combination of 1H-NMR, HPLC-MS and GC-MS methods we monitored extracellular uptake and secretion of metabolites as well as the intracellular metabolic composition. Employing our validated protocol for the pneumococcal intracellular metabolome analysis, a time resolved snapshot of the primary metabolism of pneumococci was obtained. The intracellular metabolic profile indicates a high glycolytic flux and displays high concentrated precursors of peptidoglycan synthesis probably to fuel cell-wall-metabolism in growing cells. Furthermore, our data reflect the biochemical dependency for S. pneumoniae on external host derived nutrients such as nucleosides. These essential pathways may serve as new targets in the drug development against S. pneumoniae. PMID- 29398252 TI - From the genome sequence via the proteome to cell physiology - Pathoproteomics and pathophysiology of Staphylococcus aureus. AB - While the genome sequence is the blueprint of life, functional genomics is required to transfer the genome sequence to cell physiology. Among the Omics technologies, proteomics holds a privileged position because it deals with the main players of life, the proteins. For the model organism Staphylococcus aureus comprehensive coverage of the proteome was accomplished and used to address physiological and pathophysiological questions. This review article demonstrates that the proteomic view of physiology and pathophysiology of S. aureus unveils cellular processes in an unprecedented manner. These new insights into bacterial adaptation are starting points for detailed follow-up studies aiming at a deep and comprehensive understanding of metabolism, stress responses and virulence of this dangerous pathogen. In vivo proteomics uncovered the life style of S. aureus under infection related conditions, namely after internalization by eukaryotic cells, and in infection settings. However, further analytical advances will improve capabilities for in vivo studies, particularly in murine and human tissue specimen and in this way support the identification of new targets for therapeutic interventions. Furthermore, a comprehensive set of cell surface associated proteins required for biofilm formation and host cell invasion as well as secreted proteins, among them many proteins of still unknown function, was described. The identification of the functions of these proteins will help to better understand the molecular mechanisms of the different diseases caused by S. aureus, thus leading to a more complete understanding of its pathogenicity. Finally, immunoproteomics can visualize the perception of the pathogen by the immune system and host defense mechanisms and may pave the way to the development of new vaccination approaches, which are urgently required. PMID- 29398253 TI - T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. AB - Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, type I diabetes, and inflammatory bowel disease. However, the functional consequences of these SNPs are poorly characterized. Herein, we show in blood cells that SNPs in the PTPN2 locus are highly correlated with DNA methylation levels at four CpG sites downstream of PTPN2 and expression levels of the long non-coding RNA (lncRNA) LINC01882 downstream of these CpG sites. We observed that LINC01882 is mainly expressed in T cells and that anti-CD3/CD28 activated naive CD4+ T cells downregulate the expression of LINC01882. RNA sequencing analysis of LINC01882 knockdown in Jurkat T cells, using a combination of antisense oligonucleotides and RNA interference, revealed the upregulation of the transcription factor ZEB1 and kinase MAP2K4, both involved in IL-2 regulation. Overall, our data suggests the involvement of LINC01882 in T cell activation and hints towards an auxiliary role of these non-coding SNPs in autoimmunity associated with the PTPN2 locus. PMID- 29398255 TI - Circulating soluble klotho is not associated with an elevated ankle-brachial index as a surrogate marker of early arterial calcification in patients with type 1 diabetes mellitus and no evidence of renal dysfunction. PMID- 29398254 TI - Intensive lifestyle modifications with or without liraglutide 3mg vs. sleeve gastrectomy: A three-arm non-randomised, controlled, pilot study. AB - BACKGROUND/OBJECTIVES: As only 1% of clinically eligible subjects choose to undergo surgical treatment for obesity, other options should be investigated. This study aimed to assess the effects of intensive lifestyle modification (ILM) with or without 3-mg liraglutide daily vs. sleeve gastrectomy (SG) on BMI after 1 year. SUBJECTS/METHODS: In this study performed at an Italian university hospital, non-diabetic patients eligible for bariatric surgery were recruited from a weight-loss clinic and had the option to choose from three possible weight loss programmes up to an allocation of 25 subjects in each arm matched by BMI and age. ILM consisted in 813kcal of a very low-calorie diet (VLCD) for 1 month, followed by a diet of 12kcal/kg body weight of high protein and high fat for 11 months plus 30min of brisk walking daily and at least 3h of aerobic exercise weekly. SG patients followed a VLCD for 1 month and a free diet thereafter. Patients were evaluated at baseline and at 1, 3, 6, 9 and 12 months. RESULTS: A total of 75 patients were enrolled; retention was 100% in the SG and 85% in the two medical arms. SG reduced BMI by 32% (P<0.001 vs. medical arm), while ILM+liraglutide and ILM led to BMI reductions of 24% and 14%, respectively (P<0.001). More women allocated themselves to the ILM+liraglutide group. Weight loss was 43kg with SG, 26kg with ILM+liraglutide and 15kg with ILM alone. Lean body mass reductions were -11.6kg with SG, -6.3kg with ILM and -8.3kg with ILM+liraglutide. Prevalence of prediabetes was significantly lower with ILM+liraglutide, and insulin resistance was reduced by about 70% by both ILM+liraglutide and SG vs. 39% by ILM alone. Cardiometabolic risk factors were greatly reduced in all three groups. DISCUSSION: At least in the short-term, liraglutide 3.0mg once daily associated with drastic calorie-intake restriction and intensive physical activity promoted a 24% weight loss, which was almost two times greater than ILM alone and only about 25% less than with SG, while preserving lean body mass. Although this study was non-randomised, it was designed to explore the efficacy of medical treatments for obesity in everyday clinical practice. PMID- 29398256 TI - Excess foetal growth and glycaemic control in type 1 diabetes and pregnancy. PMID- 29398257 TI - A Comparison of Mobile and Fixed-Bearing Unicompartmental Knee Arthroplasty at a Minimum 10-Year Follow-up. AB - BACKGROUND: The long-term survivorship and functional outcomes of the mobile bearing (MB) compared to the fixed-bearing (FB) unicompartmental knee arthroplasty (UKA) implant design remain a topic of debate. The aim of the current study was to compare the survivorship and functional outcomes of MB and FB UKA at a minimum 10-year follow-up. METHODS: We retrospectively reviewed 106 consecutive medial UKAs (89 patients) from our institution with a minimum 10-year follow-up. The 38 MB and 68 FB knees had follow-up of 14.2 years (12.9-15.5) and 11.5 years (10.2-15.1), respectively. Validated patient-reported outcomes and radiographs were evaluated as were etiology, timing, and complexity of revision. Kaplan-Meier 10-year survival was calculated with revision to total knee arthroplasty as the end point. RESULTS: The 10-year survival was 82.9% (95% confidence interval [CI] 65.8-91.9) for MB and 90.9% (95% CI 79.4-96.2) for FB UKA (P = .102), and 88.0% (95% CI 79.3-93.2) for the entire cohort. Patient outcomes were similar between groups, as were timing and etiologies for revision to total knee arthroplasty. One-third of revisions required either stems or tibial augments, and of these, all were of MB design. CONCLUSION: Survival and functional outcomes were similar between MB and FB designs. One-third of revisions required either stems or augments, all were of MB design. PMID- 29398258 TI - Different Factors Conduct Anterior Knee Pain Following Primary Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: A systematic review and meta-analysis was performed to investigate the risks associated with anterior knee pain (AKP) following primary total knee arthroplasty (TKA). METHODS: A computerized search was performed of the following databases: MEDLINE, Embase, and Cochrane Central (published prior to July 2017). A total of 37 studies, which included 1641 cases of AKP and 168,090 TKAs, were included in the meta-analysis. RESULTS: A subgroup analysis revealed that compared with those without the following medical conditions, patients who had an infrapatellar fat pad excision and more than 12 months of follow-up (odds ratio [OR] 12.58, 95% confidence interval [CI] 3.245-48.781) were more likely to have AKP after TKA. Circumpatellar electrocautery (>12 months: OR 0.50, 95% CI 0.326 0.760; <=12 months: OR 0.59, 95% CI 0.408-0.867) and patellar resurfacing (OR 0.25, 95% CI 0.131-0.485) may decrease the risk of AKP. Other factors, including the prosthesis bearing type (mobile bearing or fixed bearing) and the approach (midvastus compared with the medial parapatellar approach), were not significant risk factors for AKP. CONCLUSION: The use of strategies such as patellar denervation and patellar resurfacing in primary TKA is recommended because they are safe and result in good clinical outcomes in preventing AKP. Caution should be taken when using an infrapatellar fat pad excision, because there is an increased risk of AKP at long-term follow-up (>12 months). Future studies should investigate these different strategies to confirm the underlying mechanisms and help prevent the occurrence of AKP after TKA. The timing of AKP onset remains unclear and requires further research. PMID- 29398259 TI - Surgical Approaches and Hemiarthroplasty Outcomes for Femoral Neck Fractures: A Meta-Analysis. AB - BACKGROUND: The lateral approach (LA), posterior approach (PA), and anterior approach (AA) are conventional surgical access routes for hemiarthroplasty in proximal femoral fractures. This meta-analysis assesses and compares the outcomes and attempts to identify the best approach for hemiarthroplasty in the treatment of proximal femoral fractures. METHODS: An electronic search was performed from inception to October 25, 2017, for comparative studies including at least 2 of the conventional approaches. Outcomes including operation time, surgical blood loss, perioperative fractures, wound infections, dislocations, and hospital length of stay were plotted in forest plots. RESULTS: Twenty-one eligible studies were selected including 3 randomized, controlled trials, 7 prospective and 11 retrospective cohort studies. The odds ratio (OR) for dislocations was significantly higher for the PA compared with the AA (OR, 2.61; 95% confidence interval [CI], 1.26 to 5.43; P = .01) and the LA (OR, 2.90; 95% CI, 1.63 to 5.14; P = .0003). The PA had a higher risk of reoperation compared to the AA (OR, 1.25; 95% CI, 1.12 to 1.41; P < .0001). No significant differences were found concerning perioperative fractures, wound infections, and hospital length of stay. Some studies suggest a better short-term functional outcome using the AA compared to the PA. CONCLUSION: The PA for hemiarthroplasty in proximal femoral fractures poses an increased risk of dislocation and reoperation compared to the LA and AA. There are no evident advantages of the PA and its routine use for fracture-related hemiarthroplasty should be questioned. PMID- 29398260 TI - Infection Following Total Joint Arthroplasty Is the Main Cause of Litigation: Data From One Metropolitan Area. AB - BACKGROUND: A prior survey of members of the American Association of Hip and Knee Surgeons revealed that 78% of responding surgeons were named as a defendant in at least 1 lawsuit, and 69% of these lawsuits were dismissed or settled out of court. The most common sources of litigation were nerve injury, limb-length discrepancy, and infection. This study examined common reasons for lawsuits after total joint arthroplasty (TJA) in a single metropolitan area. METHODS: A retrospective review of lawsuits filed between 2009 and 2015 in a 5-county metropolitan area was performed, including 30 hospitals and 113 TJA surgeons. Complaints underwent a manual review to determine the number of lawsuits and the specific allegations filed against each surgeon. RESULTS: Thirty-one (27.4%) surgeons were named as a defendant in at least 1 lawsuit. Eighty-three total lawsuits were filed during the period, 50 of which were dismissed or settled outside of court. Top reasons for lawsuits were, in descending order, infection, nerve injury, chronic pain, vascular injury, periprosthetic fracture, retention of foreign body, dislocation, limb-length discrepancy, venous thromboembolism, loosening, compartment syndrome, and other medical complaints. CONCLUSION: Infection appears to be the basis of most lawsuits after TJA. Surgeons should be aware of the potential for a lawsuit for complications and should strive to better communicate with patients regarding preoperative informed consent and disclosure after adverse events. Surgeons should minimize performing surgery in patients at high risk of complications, such as patients with a higher likelihood of developing postoperative infection or patients on chronic pain medications. PMID- 29398261 TI - Prediction Models for 30-Day Mortality and Complications After Total Knee and Hip Arthroplasties for Veteran Health Administration Patients With Osteoarthritis. AB - BACKGROUND: Statistical models to preoperatively predict patients' risk of death and major complications after total joint arthroplasty (TJA) could improve the quality of preoperative management and informed consent. Although risk models for TJA exist, they have limitations including poor transparency and/or unknown or poor performance. Thus, it is currently impossible to know how well currently available models predict short-term complications after TJA, or if newly developed models are more accurate. We sought to develop and conduct cross validation of predictive risk models, and report details and performance metrics as benchmarks. METHODS: Over 90 preoperative variables were used as candidate predictors of death and major complications within 30 days for Veterans Health Administration patients with osteoarthritis who underwent TJA. Data were split into 3 samples-for selection of model tuning parameters, model development, and cross-validation. C-indexes (discrimination) and calibration plots were produced. RESULTS: A total of 70,569 patients diagnosed with osteoarthritis who received primary TJA were included. C-statistics and bootstrapped confidence intervals for the cross-validation of the boosted regression models were highest for cardiac complications (0.75; 0.71-0.79) and 30-day mortality (0.73; 0.66-0.79) and lowest for deep vein thrombosis (0.59; 0.55-0.64) and return to the operating room (0.60; 0.57-0.63). CONCLUSIONS: Moderately accurate predictive models of 30-day mortality and cardiac complications after TJA in Veterans Health Administration patients were developed and internally cross-validated. By reporting model coefficients and performance metrics, other model developers can test these models on new samples and have a procedure and indication-specific benchmark to surpass. PMID- 29398262 TI - EAU Guidelines on Assessment and Nonsurgical Management of Urinary Incontinence. AB - CONTEXT: The European Association of Urology guidelines on urinary incontinence (UI) have been updated in cyclical fashion with successive major chapters being revised each year. The sections on assessment, diagnosis, and nonsurgical treatment have been updated as of mid-2016. OBJECTIVE: We present a condensed version of the full guideline on assessment and nonsurgical management of UI, with the aim of improving accessibility and increasing their dissemination. EVIDENCE ACQUISITION: Our literature search was updated from the previous cut-off of July 2010 up to April 2016. Evidence synthesis was carried out by a pragmatic review of current systematic reviews and any newer subsequent high-quality studies, based on Population, Interevention, Comparator, and Outcome questions. Appraisal was conducted by an international panel of experts, working on a strictly nonprofit and voluntary basis, to develop concise evidence statements and action-based recommendations using modified Oxford and GRADE criteria. EVIDENCE SYNTHESIS: The guidelines include algorithms that summarise the suggested pathway for standard, uncomplicated patients with UI and are more useable in daily practice. The full version of the guideline is available at http://uroweb.org/guideline/urinary-incontinence/. CONCLUSIONS: These updated guidelines provide an evidence-based summary of the assessment and nonsurgical management of UI, together with a clear clinical algorithm and action-based recommendations. Although these guidelines are applicable to a standard patient, it must be remembered that therapy should always be tailored to individual patients' needs and circumstances. PATIENT SUMMARY: Urinary incontinence is a very common condition which negatively impacts patient's quality of life. Several types of incontinence exist and since the treatments will vary, it is important that the diagnostic evaluation establishes which type is present. The diagnosis should also identify patients who need rapid referral to an appropriate specialist. These guidelines aim to provide sensible and practical evidence-based guidance on the clinical problem of urinary incontinence. PMID- 29398263 TI - Expression of Androgen Receptor Splice Variant 7 or 9 in Whole Blood Does Not Predict Response to Androgen-Axis-targeting Agents in Metastatic Castration resistant Prostate Cancer. AB - : In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Of the patients, 24% (9/37) were AR-V-positive. Notably, prostate-specific antigen (PSA) response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs 64%, p=0.9). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 mo vs not reached; p=0.9). These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide. PATIENT SUMMARY: Detection of androgen receptor splice variants (AR-Vs) in circulating tumour cells of advanced prostate cancer patients has been linked to resistance to abiraterone and enzalutamide. We designed a blood test to detect AR-Vs that can be performed more routinely than tests involving circulating tumour cells and found that patients with AR-Vs still benefit from these effective treatments. PMID- 29398264 TI - Is Comparison of Robotic to Open Radical Prostatectomy Still Relevant? PMID- 29398265 TI - Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. AB - BACKGROUND: Predicting oncologic outcomes is important for patient counseling, clinical trial design, and biomarker study testing. OBJECTIVE: To develop prognostic models for progression-free (PFS) and cancer-specific survival (CSS) in patients with clear cell renal cell carcinoma (ccRCC), papillary RCC (papRCC), and chromophobe RCC (chrRCC). DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort review of the Mayo Clinic Nephrectomy registry from 1980 to 2010, for patients with nonmetastatic ccRCC, papRCC, and chrRCC. INTERVENTION: Partial or radical nephrectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PFS and CSS from date of surgery. Multivariable Cox proportional hazards regression was used to develop parsimonious models based on clinicopathologic features to predict oncologic outcomes and were evaluated with c-indexes. Models were converted into risk scores/groupings and used to predict PFS and CSS rates after accounting for competing risks. RESULTS AND LIMITATIONS: A total of 3633 patients were identified, of whom 2726 (75%) had ccRCC, 607 (17%) had papRCC, and 222 (6%) had chrRCC. Models were generated for each histologic subtype and a risk score/grouping was developed for each subtype and outcome (PFS/CSS). For PFS, the c-indexes were 0.83, 0.77, and 0.78 for ccRCC, papRCC, and chrRCC, respectively. For CSS, c-indexes were 0.86 and 0.83 for ccRCC and papRCC. Due to only 22 deaths from RCC, we did not assess a multivariable model for chrRCC. Limitations include the single institution study, lack of external validation, and its retrospective nature. CONCLUSIONS: Using a large institutional experience, we generated specific prognostic models for oncologic outcomes in ccRCC, papRCC, and chrRCC that rely on features previously shown-and validated-to be associated with survival. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment. PATIENT SUMMARY: We identified routinely available clinical and pathologic features that can accurately predict progression and death from renal cell carcinoma following surgery. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment. PMID- 29398266 TI - On the systematic underestimation of methane conversion factors in IPCC guidance. AB - This paper documents a systematic underestimation in how the Tier 2 methane conversion factors (MCF) are calculated in IPCC (2006) guidelines for liquid manure management. The first issue is the use of annual average temperature as an input to a non-linear function describing methane production. As expected based on Jensen's inequality, the MCF calculated based on annual average temperature is always an underestimate. In regions with large intra-annual temperature ranges, such as temperate climates, the underestimation can exceed 30%. A second issue is the lack of consideration for volatile solids retention time. Future updates to the IPCC methodology should therefore account for intra-annual temperature regime and retention time-not simply annual average temperature. PMID- 29398267 TI - Designing an agricultural vegetative waste-management system under uncertain prices of treatment-technology output products. AB - Setting up a sustainable agricultural vegetative waste-management system is a challenging investment task, particularly when markets for output products of waste-treatment technologies are not well established. We conduct an economic analysis of possible investments in treatment technologies of agricultural vegetative waste, while accounting for fluctuating output prices. Under a risk neutral approach, we find the range of output-product prices within which each considered technology becomes most profitable, using average final prices as the exclusive factor. Under a risk-averse perspective, we rank the treatment technologies based on their computed certainty-equivalent profits as functions of the coefficient of variation of the technologies' output prices. We find the ranking of treatment technologies based on average prices to be robust to output price fluctuations provided that the coefficient of variation of the output prices is below about 0.4, that is, approximately twice as high as that of well established recycled-material markets such as glass, paper and plastic. We discuss some policy implications that arise from our analysis regarding vegetative waste management and its associated risks. PMID- 29398268 TI - Downcycling versus recycling of construction and demolition waste: Combining LCA and LCC to support sustainable policy making. AB - Urgent solutions are needed in Europe to deal with construction and demolition waste (CDW). EU policy has contributed to significantly reducing the amount of CDW going to landfill, but most of the effort has been put in downcycling practices. Therefore, further policies are needed to stimulate high-quality recycling of CDW. The present paper presents a combined life cycle assessment (LCA) and life cycle costing (LCC) methodologies to analyse the environmental and the economic drivers in four alternative CDW end-of-life scenarios in the region of Flanders, in Belgium. The four analysed alternatives are (i) landfilling, (ii) downcycling, (iii) advanced recycling and (iv) recycling after selective demolition. LCA results show that landiflling is the scenario having the highest environmental impacts in terms of person equivalent (PE), followed by downcycling and recycling (-36%) and recycling after selective demolition (-59%). The decrease in environmental impacts is mostly due to the avoided landfilling of CDW and the recovery of materials from selective demolition. LCC results indicate that landfilling is the scenario bearing the highest total economic costs. This is due to the high landfill tax in Flanders. The recycling after selective demolition bears the second highest cost. The increase of high-quality CDW recycling can significantly reduce the overall environmental impact of the system. Implementing a high landfill tax, increasing the gate fee to the recycling plant, and boosting the sales price of recycled aggregates are the most effective drivers to facilitate a transition towards a more sustainable CDW management system. The paper demonstrates that the combined LCA and LCC results can highlight the environmental and economic drivers in CDW management. The results of the combined analysis can help policymakers to promote the aspects contributing to sustainability and to limit the ones creating a barrier. PMID- 29398269 TI - Dilute sulfuric acid fractionation of Korean food waste for ethanol and lactic acid production by yeast. AB - Fermentation of food waste biomass can be used to produce biochemicals such as lactic acid and ethanol in a cost-effective manner. Korean food waste (KFW) dewatered by a screw press contains 23.1% glucan on a dry basis and is a potential raw material for the production of ethanol and lactic acid through fermentation. This study was conducted to optimize the dilute acid fractionation conditions for KFW fermentation with respect to the H2SO4 concentration (0-0.8% w/v), temperature (130-190 degrees C), and residence time (1-128 min) using response surface methodology. Dilute sulfuric acid fractionation was carried out using a 30-mL stainless steel reactor under conditions, and then the dilute acid fractionation was scaled-up in 1-L and 7-L stainless steel reactors under the optimal conditions. The hydrolysate was concentrated, liquid-liquid extracted and neutralized for lactic acid and ethanol production. The highest concentration of glucose obtained from the KFW was 26.4 g/L using fractionation with 0.37% w/v H2SO4 at 156 degrees C for 123.6 min. Using recombinant Saccharomyces cerevisiae containing a codon-optimized lactate dehydrogenase, the yield of lactic acid and ethanol was 77% of the theoretical yield for 17.4 g/L of fermentable sugar at pH 5.5. Additionally, the yield of ethanol produced by Issatchenkia orientalis was 89% of the theoretical yield for 25 g/L of fermentable sugar at pH 3. PMID- 29398270 TI - Composition, production rate and characterization of Greek dental solid waste. AB - The overall objective of this work is to determine the composition, characterization and production rate of Greek dental solid waste (DSW). This information is important to design and cost management systems for DSW, for safety and health considerations and for assessing environmental impact. A total of 141 kg of DSW produced by a total of 2542 patients in 20 dental practices from Xanthi, Greece was collected, manually separated and weighed over a period of four working weeks. The waste was separated in 19 sub fractions, which were classified in 2 major categories, according to Greek regulations: Domestic-type waste comprising 8% and hazardous waste comprising 92% by weight of total DSW. The latter was further classified in infectious waste, toxic waste and mixed type waste (infectious and toxic together), accounting for 88.5%, 3.5% and 0.03% of total DSW by weight, respectively. The overall unit production rates (mean +/- standard error of the mean) were 381 +/- 15 g/practice/d and 53.3 +/- 1.4 g/patient/d for total DSW, 337 +/- 14 g/practice/d and 46.6 +/- 1.2 g/patient/d for total infectious DSW, 13.4 +/- 0.7 g/practice/d and 2.1 +/- 0.1 g/patient/d for total toxic DSW and 30.4 +/- 2.5 g/practice/d and 4.6 +/- 0.4 g/patient/d for domestic-type waste. Daily DSW production was correlated with daily number of patients and regression correlations were produced. DSW was subject to laboratory characterization in terms of bulk density, calorific value, moisture, ash and volatile solids content. Measured calorific values were compared to predictions from empirical models. PMID- 29398271 TI - Tread carefully: A functional variant in the human NADPH oxidase 4 (NOX4) is not disease causing. AB - In this study, we report a paediatric patient with a lethal phenotype of respiratory distress, failure to thrive, pancreatic insufficiency, liver dysfunction, hypertrophic cardiomyopathy, bone marrow suppression, humoral and cellular immune deficiency. To identify the genetic basis of this unusual clinical phenotype and potentially make available the option of future prenatal testing, whole exome sequencing (WES) was used followed by functional studies in a bid to confirm pathogenicity. The WES we identified a homozygous novel variant, AK298328; c.9_10insGAG; p.[Glu3dup], in NOX4 in the proband, and parental heterozygosity for the variant (confirmed by Sanger sequencing). NADPH Oxidase 4 NOX4 (OMIM 605261) encodes an enzyme that functions as the catalytic subunit of the NADPH oxidase complex. NOX4 acts as an oxygen sensor, catalysing the reduction of molecular oxygen, mainly to hydrogen peroxide (H2O2). However, although, our functional data including 60% reduction in NOX4 protein levels and a 75% reduction in the production of H2O2 in patient fibroblast extracts compared to controls was initially considered to be the likely cause of the phenotype in our patient, the potential contribution of the NOX4 variant as the primary cause of the disease was clearly excluded based on following pieces of evidence. First, Sanger sequencing of other family members revealed that two of the grandparents were also homozygous for the NOX4 variant, one of who has fibromuscular dysplasia. Second, re-evaluation of more recent variant databases revealed a high allele frequency for this variant. Our case highlights the need to re-interrogate bioinformatics resources as they are constantly evolving, and is reminiscent of the short-chain acyl-CoA dehydrogenase deficiency (SCADD) story, where a functional defect in fatty acid oxidation has doubtful clinical ramifications. PMID- 29398272 TI - Development of a high-growth enterovirus 71 vaccine candidate inducing cross reactive neutralizing antibody responses. AB - Although Enterovirus 71 (EV71) has only one serotype based on serum neutralization tests using hyperimmune animal antisera, three major genogroups (A, B and C) including eleven genotypes (A, B1-B2, and C1-C5) can be well classified based on phylogenetic analysis. Since 1997, large-scale EV71 epidemics occurred cyclically with different genotypes in the Asia-Pacific region. Therefore, development of EV71 vaccines is a national priority in several Asian countries. Currently, five vaccine candidates have been evaluated in clinical trials in China (three C4 candidates), Singapore (one B2 candidate), and Taiwan (one B4 candidate). Overall, the peak viral titers of these 5 vaccine candidates could only reach about 107 TCID50/mL. Moreover, genotypes of these 5 candidates are different from the current predominant genotype B5 in Taiwan and South Eastern Asia. We adapted a high-growth EV71 genotype B5 (HG-B5) virus after multiple passages and plaque selections in Vero cells and the HG-B5 virus could reach high titers (>108 TCID50/mL) in a microcarrier-based cell culture system. The viral particles were further purified and formulated with alum adjuvant. After two doses of intramuscular immunization in rabbits, the HG-B5 vaccine candidate could induce cross-reactive neutralizing antibodies against the three major EV71 genogroups. In conclusion, a high-growth EV71 virus was successfully adapted in Vero cells and could induce broad spectrum neutralizing antibody titers against three (A, B5, and C4) genotypes in rabbits. PMID- 29398274 TI - Strangvac: A recombinant fusion protein vaccine that protects against strangles, caused by Streptococcus equi. AB - The host-restricted pathogen Streptococcus equi causes strangles in the horse, which is characterised by abscessation of the lymph nodes of the head and neck. The disease is endemic throughout the world causing considerable welfare and economic cost to the horse industry. Here we report the results of three studies where ponies were vaccinated with combinations of recombinant fusion proteins to optimise vaccine production and the level of protection conferred. Optimal protection was conferred by a prototype multicomponent subunit vaccine, Strangvac 4, which contained eight proteins CNE, SclC, SclF, SclI, EAG (fused as CCE), SEQ_402, SEQ_0256 (fused as Eq85) and IdeE. Across the three experiments only three of 16 ponies vaccinated with Strangvac 4 became pyretic compared to all 16 placebo-vaccinated control ponies (P < .001). S. equi was recovered from the lymph nodes of eight Strangvac 4-vaccinated and 15 control ponies (P = .016). None of the ponies vaccinated with Strangvac 4, or the other prototype vaccines developed adverse reactions following vaccination. Our data provide evidence in support of the further clinical development of the Strangvac 4 vaccine. PMID- 29398273 TI - The choice of linker for conjugating R848 to inactivated influenza virus determines the stimulatory capacity for innate immune cells. AB - Inactivated influenza vaccines are not approved for use in infants less than 6 months of age due to poor immunogenicity in that population. While the live attenuated influenza vaccine has the potential to be more immunogenic, it is not an option for infants and other vulnerable populations, including the elderly and immunocompromised individuals due to safety concerns. In an effort to improve the immunogenicity of the inactivated vaccine for use in vulnerable populations, we have used an approach of chemically crosslinking the Toll-like receptor (TLR) 7/8 agonist R848 directly to virus particles. We have reported previously that an R848-conjugated, inactivated vaccine is more effective at inducing adaptive immune responses and protecting against lung pathology in influenza challenged neonatal African green monkeys than is the unmodified counterpart. In the current study, we describe a second generation vaccine that utilizes an amide-sulfhydryl crosslinker with different spacer chemistry and length to couple R848 to virions. The new vaccine has significantly enhanced immunostimulatory activity for murine macrophages and importantly for monocyte derived human dendritic cells. Demonstration of the significant differences in stimulatory activity afforded by modest changes in linker impacts our fundamental view of the design of TLR agonist-antigen vaccines. PMID- 29398275 TI - The impact of expanded program on immunization with live attenuated and inactivated Hepatitis A vaccines in China, 2004-2016. AB - INTRODUCTION: Since 2008, two types of hepatitis A (HepA) vaccines were integrated into the expanded program on immunization (EPI) in China. Children were given either one dose of live attenuated HepA (L-HepA) or two doses of inactivated HepA (I-HepA), depending on geographic regions. We sought to evaluate the impact of the EPI on HepA incidence in China. METHODS: We reviewed the epidemiology of HepA during 2004-2016 from National Notifiable Disease Reporting System (NNDRS). We collected data of L-HepA and I-HepA coverage from Children Immunization Information Management System (CIIMS). Based on the regions where two types of HepA vaccines were used, the coverage and incidence of HepA were compared over time. RESULTS: In 2008-2016, the HepA vaccine coverage was 98.8% among target children, with 99.6% in I-HepA region and 98.7% in L-HepA region. HepA incidence declined by 78.0% and 82.3% in L-HepA region and I-HepA region, respectively, without significant difference. Dramatic decline were seen in all age groups of both regions. CONCLUSION: The study suggests that the EPI, with high coverage for both I-HepA and L-HepA, had positive impact on HepA incidence in China. PMID- 29398276 TI - Waning of measles maternal antibody in infants in measles elimination settings - A systematic literature review. AB - INTRODUCTION: Most infants are born with immunity to measles through maternal antibodies transferred in pregnancy, which decay over time. However, in measles elimination settings, where measles does not circulate endemically and most immunity is from immunization rather than infection, maternal antibody levels are lower. This results in infant immunity that wanes earlier, and a wider susceptibility gap between maternal antibody decay and infant immunization than in non-eliminated settings. We aimed to systematically quantify the extent and duration of protection from measles in infants in settings that have sustained measles elimination. METHODS: We conducted a systematic review of studies of measles maternal antibody waning in infants in measles elimination settings. We searched MEDLINE, Embase, CINAHL, Scopus, BIOSIS Previews, and Global Health databases for relevant studies. Studies were included if they were set in countries that had eliminated measles for >=3 years, and if the study cohort included healthy, full-term, unvaccinated infants <=12 months, born to healthy mothers, and reported a relevant measure of measles maternal antibody in infants. We assessed study quality using the MetaQAT tool. RESULTS: We identified 4692 unique citations, eight of which met inclusion criteria. One study reported anti measles antibody in cord blood, six reported antibody in infant sera, and one reported both. Two studies reported that 80 and 100% of infants were protected from measles at birth. One study reported no protection amongst 3-7 month old infants, and another reported limited protection in infants >4 months. The remaining studies reported the proportion of infants with detected antibody, but not the proportion immune. CONCLUSION: Although limited, these data suggest that in settings that have sustained measles elimination, some infants are susceptible to measles well before the age of routine measles immunization. Setting-specific seroprevalence and vaccine effectiveness studies are required to evaluate this in different jurisdictions. PMID- 29398277 TI - Maternal immunization against Group B streptococcus: World Health Organization research and development technological roadmap and preferred product characteristics. AB - Group B streptococcus, found in the vagina or lower gastrointestinal tract of about 10-40% of women of reproductive age, is a leading cause of early life invasive bacterial disease, potentially amenable to prevention through maternal immunization during pregnancy. Following a consultation process with global stakeholders, the World Health Organization is herein proposing priority research and development pathways and preferred product characteristics for GBS vaccines, with the aim to facilitate and accelerate vaccine licensure, policy recommendation for wide scale use and implementation. PMID- 29398279 TI - The effects of glucose concentrations associated with lipopolysaccharide and interferon-gamma stimulus on mediators' production of RAW 264.7 cells. AB - Diabetes mellitus (DM) is a metabolic disorder that results in the impairment of the metabolism of carbohydrates, proteins and lipids. It can give rise to various complications, mainly caused by chronic exposure of cells to high glucose concentrations, including changes in the immune response processes. The aim of this study was to verify the chemokine and cytokines production profile in the presence of different glucose concentrations and infection/inflammatory stimuli. To this end, cell viability and the production of chemokines, cytokines and nitric oxide (NO) were analyzed in RAW 264.7 cell culture. Results demonstrated that there was no change in cell viability after 6, 24 and 72 h. Different stimuli were unable to modify the monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha production. Groups stimulated with lipopolysaccharides (LPS) and LPS and recombinant interferon (rIFN)-gamma down regulated interleukin (IL)-1alpha, IL-10 and IL-12 and up-regulated IL-6 production. NO production maintained a pattern of increase, according to the increase in glucose concentrations, reaching its peak at 72 h. In summary, the results demonstrated that high glucose concentrations alone may be sufficient to alter the in vitro mediators' production of RAW 264.7 cells. PMID- 29398280 TI - Cep120 promotes microtubule formation through a unique tubulin binding C2 domain. AB - Centrioles are microtubule-based structures that play essential roles in cell division and cilia biogenesis. Cep120 is an important protein for correct centriole formation and mutations in the Cep120 gene cause severe human diseases like Joubert syndrome and complex ciliopathies. Here, we show that Cep120 contains three consecutive C2 domains that are followed by a coiled-coil dimerization domain. Surprisingly, unlike the classical C2 domains, all three Cep120 C2 domains lack calcium- and phospholipid-binding activities. However, biophysical and biochemical assays revealed that the N-terminal Cep120 C2 domain (C2A) binds to both tubulin and microtubules, and promotes microtubule formation. Structural analyses coupled with mutagenesis identified a highly conserved, positively charged residue patch on the surface of Cep120 C2A, which mediates the interaction with tubulin and microtubules. Together, our results establish Cep120 C2A as a unique microtubule-binding domain. They further provide insights into the molecular mechanism of Cep120 during centriole biogenesis. PMID- 29398278 TI - Multisystem multitasking by CXCL12 and its receptors CXCR4 and ACKR3. AB - Chemokines are named and best known for their chemotactic cytokine activity in the hematopoietic system; however, their importance extends far beyond leukocytes, cell movement and immunoregulation. CXCL12, the most protean of chemokines, regulates development in multiple systems, including the hematopoietic, cardiovascular and nervous systems, and regulates diverse cell functions, including differentiation, distribution, activation, immune synapse formation, effector function, proliferation and survival in the immune system alone. The broad importance of CXCL12 is revealed by the complex lethal developmental phenotypes in mice lacking either Cxcl12 or either one of its two known 7-transmembrane domain receptors Cxcr4 and Ackr3, as well as by gain-of function mutations in human CXCR4, which cause WHIM syndrome, a multisystem and combined immunodeficiency disease and the only Mendelian condition caused by a chemokine system mutation. In addition, wild type CXCR4 is important in the pathogenesis of HIV/AIDS and cancer. Thus, CXCL12 and its receptors CXCR4 and ACKR3 provide extraordinary examples of multisystem multitasking in the chemokine system in both health and disease. PMID- 29398282 TI - Dr. Michael Peter Kaye. PMID- 29398281 TI - Neurocognitive outcomes after heart transplantation in early childhood. AB - BACKGROUND: Children requiring heart transplantation (HTx) for congenital heart disease (CHD) or failing anatomically normal hearts (CMP) face different challenges pre-HTx. We compared the neurocognitive capabilities in pre-school-age children receiving HTx for CHD vs CMP and determined factors predicting outcomes. METHODS: Data were collected within a prospective multi-provincial project from children who underwent HTx <=4 years of age between 1999 and 2011. At age 54 +/- 3 months, we obtained scores from the Wechsler Preschool and Primary Scales of Intelligence for full-scale intelligence quotient (FSIQ) verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), and from the Beery Buktenica Developmental Test for visual-motor integration (VMI). Possible predictive factors were collected prospectively from transplant listing. RESULTS: Of the 76 patients included in the study, 61 survived to assessment, 2 were lost to follow-up and 4 were excluded for genetic disorders or heart-lung transplant. The CHD patients (n = 32) had significantly more previous surgeries, more severe kidney injuries, more days on ventilator and in intensive care, broader human leukocyte antigen (HLA) sensitization, longer cardipulmonary bypass (CPB) times and higher inotropic scores than CMP patients (n = 23). Mean IQ scores for the HTx children were below population norms and significantly lower in children with CHD. Intellectual disability (FSIQ <70) was more common in the CHD group (p = 0.036). The lower VMI in CHD patients approached significance. Lower FSIQ and VMI were independently associated with higher pre-HTx creatinine and lactate, longer stay in intensive care and lower socioeconomic status. CONCLUSIONS: Children post HTx showed IQ and VMI scores within the borderline to low-average range, with CHD children ranging significantly lower. Low scores are associated with a more difficult pre- and peri-transplant course. Careful follow-up is required to warrant early detection of deficits and introduction of interventions and supportive measures. PMID- 29398283 TI - Hospitalizations due to exacerbations of COPD: A big data perspective. AB - BACKGROUND: Patients with Chronic Obstructive Pulmonary Disease (COPD) may suffer episodes of exacerbation (ECOPD) that require hospitalization and worsen their health status, and prognosis. We hypothesized that a detailed interrogation of health-care "big data" databases can provide valuable information to better understand the risk factors and outcomes of these episodes. MATERIAL AND METHODS: We interrogated four databases of the Catalan health-care system (>8,000,000 registries) to identify patients hospitalized because of ECOPD for the first time (index event) between 2010 and 2012. Analysis was carried forward since the index event until the end of 2014 or the death of the patient. The two years that preceded the index event were also investigated. RESULTS: We identified 17,555 patients, (>=50 years of age) hospitalized because of ECOPD (ICD9 v.9 codes at discharge) for the first time between 2010 and 2012. In this population we observed that: (1) 23% of patients die within a year after being discharged from their first ECOPD hospitalization; (2) in the remaining patients, all-cause mortality was related to the number of re-hospitalizations, particularly with early (<30 days) readmissions; (3) despite this being a 'respiratory' cohort, prescription and dispensation of drugs for cardiovascular diseases was higher than for obstructive airway diseases; and, finally, (4) lower winter ambient temperatures are associated with hospital admissions for ECOPD particularly in early re-admitters. CONCLUSIONS: Overall these results indicate under appreciation of the burden of COPD in patients hospitalized for the first time because ECOPD. PMID- 29398286 TI - Comment on: preoperative insulin therapy as a marker for type II diabetes remission in obese patients after bariatric surgery. PMID- 29398285 TI - Genetic biosensors for imaging nitric oxide in single cells. AB - : Over the last decades a broad collection of sophisticated fluorescent protein based probes was engineered with the aim to specifically monitor nitric oxide (NO), one of the most important signaling molecules in biology. Here we report and discuss the characteristics and fields of applications of currently available genetically encoded fluorescent sensors for the detection of NO and its metabolites in different cell types. LONG ABSTRACT: Because of its radical nature and short half-life, real-time imaging of NO on the level of single cells is challenging. Herein we review state-of-the-art genetically encoded fluorescent sensors for NO and its byproducts such as peroxynitrite, nitrite and nitrate. Such probes enable the real-time visualization of NO signals directly or indirectly on the level of single cells and cellular organelles and, hence, extend our understanding of the spatiotemporal dynamics of NO formation, diffusion and degradation. Here, we discuss the significance of NO detection in individual cells and on subcellular level with genetic biosensors. Currently available genetically encoded fluorescent probes for NO and nitrogen species are critically discussed in order to provide insights in the functionality and applicability of these promising tools. As an outlook we provide ideas for novel approaches for the design and application of improved NO probes and fluorescence imaging protocols. PMID- 29398284 TI - Circadian redox rhythms in the regulation of neuronal excitability. AB - Oxidation-reduction reactions are essential to life as the core mechanisms of energy transfer. A large body of evidence in recent years presents an extensive and complex network of interactions between the circadian and cellular redox systems. Recent advances show that cellular redox state undergoes a ~24-h (circadian) oscillation in most tissues and is conserved across the domains of life. In nucleated cells, the metabolic oscillation is dependent upon the circadian transcription-translation machinery and, vice versa, redox-active proteins and cofactors feed back into the molecular oscillator. In the suprachiasmatic nucleus (SCN), a hypothalamic region of the brain specialized for circadian timekeeping, redox oscillation was found to modulate neuronal membrane excitability. The SCN redox environment is relatively reduced in daytime when neuronal activity is highest and relatively oxidized in nighttime when activity is at its lowest. There is evidence that the redox environment directly modulates SCN K+ channels, tightly coupling metabolic rhythms to neuronal activity. Application of reducing or oxidizing agents produces rapid changes in membrane excitability in a time-of-day-dependent manner. We propose that this reciprocal interaction may not be unique to the SCN. In this review, we consider the evidence for circadian redox oscillation and its interdependencies with established circadian timekeeping mechanisms. Furthermore, we will investigate the effects of redox on ion-channel gating dynamics and membrane excitability. The susceptibility of many different ion channels to modulation by changes in the redox environment suggests that circadian redox rhythms may play a role in the regulation of all excitable cells. PMID- 29398287 TI - Comment on: decreased visceral fat area correlates with improved total testosterone levels after Roux-en-Y gastric bypass in obese Chinese males with type 2 diabetes: a 12-month follow-up. PMID- 29398288 TI - Direct interspecies electron transfer via conductive materials: A perspective for anaerobic digestion applications. AB - Anaerobic digestion (AD) is a microbial process that produces renewable energy in the form of methane by treating organic waste and high-strength wastewater. Recent studies have demonstrated that conductive materials can promote direct interspecies electron transfer (DIET) between exoelectrogenic bacteria and methanogenic archaea. DIET via conductive materials is more effective for methane production than interspecies electron transfer using electron carriers such as hydrogen, a principal route of methane production in conventional AD. This critical review presents the current understanding of DIET via conductive materials for methane production, summarizes the relevant studies published to date, and analyzes these studies with regard to conductive materials, substrates, inocula, performance, and microorganisms. Based on this analysis, possible future directions are suggested for practical DIET applications via conductive materials in AD. PMID- 29398289 TI - Tracking of Shewanella oneidensis MR-1 biofilm formation of a microbial electrochemical system via differential pulse voltammetry. AB - In this study, the electrochemical properties of a Shewanella oneidensis MR-1 biofilm were investigated using a mini-microbial electrochemical system. The performance of the biofilm was shown, using discharge test and cyclic voltammetry investigations, to improve over time. Differential pulse voltammograms were also acquired to determine the type of extracellular electron transfer that took place and to characterize the structure of the microbial biofilm formed on the electrode of the electrochemical system. These results indicated that extracellular electron transfer via a flavin-like mediator chemical predominated as the biofilm grew. The results, combined with a comparison of the measured current density with the calculated value of a seamless single-layered biofilm, also suggested that S. oneidensis MR-1 formed a multi-layered biofilm on the electrode. PMID- 29398290 TI - Assimilable organic carbon (AOC) variation in reclaimed water: Insight on biological stability evaluation and control for sustainable water reuse. AB - This review highlights the importance of conducting biological stability evaluation due to water reuse progression. Specifically, assimilable organic carbon (AOC) has been identified as a practical indicator for microbial occurrence and regrowth which ultimately influence biological stability. Newly modified AOC bioassays aimed for reclaimed water are introduced. Since elevated AOC levels are often detected after tertiary treatment, the review emphasizes that actions can be taken to either limit AOC levels prior to disinfection or conduct post-treatment (e.g. biological filtration) as a supplement to chemical oxidation based approaches (e.g. ozonation and chlorine disinfection). During subsequent distribution and storage, microbial community and possible microbial regrowth caused by complex interactions are discussed. It is suggested that microbial surveillance, AOC threshold values, real-time field applications and surrogate parameters could provide additional information. This review can be used to formulate regulatory plans and strategies, and to aid in deriving relevant control, management and operational guidance. PMID- 29398291 TI - Predictors for perioperative blood transfusion in elderly patients with extra capsular hip fractures treated with cephalo-medullary nailing. AB - PURPOSE: The aim of our study was to determine predictive factors and requirement for perioperative blood transfusion in elderly patients with extra capsular hip fractures treated with cephalo-medullary device. METHODS: Seventy-nine patients with extra capsular hip fractures treated with cephalo-medullary nailing were included in the study. Age, sex, ASA grade, timing of surgery, preoperative and postoperative haemoglobin, length of hospital stay, fracture type, number of units transfused and 30-day mortality were recorded. RESULTS: The mean age was 82.3 years. Forty-seven patients underwent a short nail and 32 patients a long nail; 53.4% patients required blood transfusion postoperatively. Transfusion was required in 71.8% of the long nails (p < 0.05), 65.8% patients above the age of 80 (p < 0.05), 100% of the patients with hemoglobin below 90 g/L and 20 patients with a ASA grade of 3 (p < 0.05). 78.5% patients with A2 fracture and 75% of A3 fractures needed blood transfusion (p > 0.05). Length of hospital stay in non transfusion group was 13 days and in transfusion group was 19 days (p < 0.05). 55.1% operated within 36 h and 47.6% operated after 36 h of admission needed transfusion (p > 0.05). Thirty-day mortality in patients needing blood transfusion was 5% and in non-transfusion group was 3.7% (p > 0.05). CONCLUSION: Patient age, ASA grade, preoperative haemoglobin and length of nail are reliable predictors for perioperative blood transfusion in extra capsular hip fractures in elderly patients treated with cephalo-medullary nailing and reinforce a selective transfusion policy. PMID- 29398293 TI - Pressure ulcer incidence and Braden subscales: Retrospective cohort analysis in general wards of a Portuguese hospital. AB - AIM: To study the influence of Braden subscales scores (at the first pressure ulcer risk assessment) on pressure ulcer incidence using a univariate and a multivariate time to event analysis. MATERIALS AND METHODS: Retrospective cohort analysis of electronic health record database from adult patients admitted without pressure ulcer(s) to medical and surgical wards of a Portuguese hospital during 2012. The hazard ratio of developing a pressure ulcer during the length of inpatient stay was calculated by univariate Cox regression for each variable of interest and by multivariate Cox regression for the Braden subscales that were statistically significant. RESULTS: This study included a sample of 6552 participants. During the length of stay, 153 participants developed (at least) one pressure ulcer, giving a pressure ulcer incidence of 2.3%. The univariate time to event analysis showed that all Braden subscales, except "nutrition", were associated with the development of pressure ulcer. By multivariate analysis the scores for "mobility" and "activity" were independently predictive of the development of pressure ulcer(s) for all participants. CONCLUSION: (Im)"mobility" (the lack of ability to change and control body position) and (in)"activity" (the limited degree of physical activity) were the major risk factors assessed by Braden Scale for pressure ulcer development during the length of inpatient stay. Thus, the greatest efforts in managing pressure ulcer risk should be on "mobility" and "activity", independently of the total Braden Scale score. PMID- 29398294 TI - Imaging of respiratory muscles in neuromuscular disease: A review. AB - Respiratory muscle weakness frequently occurs in patients with neuromuscular disease. Measuring respiratory function with standard pulmonary function tests provides information about the contribution of all respiratory muscles, the lungs and airways. Imaging potentially enables the study of different respiratory muscles, including the diaphragm, separately. In this review, we provide an overview of imaging techniques used to study respiratory muscles in neuromuscular disease. We identified 26 studies which included a total of 573 patients with neuromuscular disease. Imaging of respiratory muscles was divided into static and dynamic techniques. Static techniques comprise chest radiography, B-mode (brightness mode) ultrasound, CT and MRI, and are used to assess the position and thickness of the diaphragm and the other respiratory muscles. Dynamic techniques include fluoroscopy, M-mode (motion mode) ultrasound and MRI, used to assess diaphragm motion in one or more directions. We discuss how these imaging techniques relate with spirometric values and whether these can be used to study the contribution of the different respiratory muscles in patients with neuromuscular disease. PMID- 29398292 TI - Nephrogenic acute respiratory distress syndrome: A narrative review on pathophysiology and treatment. AB - The kidneys have a close functional relationship with other organs especially the lungs. This connection makes the kidney and the lungs as the most organs involved in the multi-organ failure syndrome. The combination of acute lung injury (ALI) and renal failure results a great clinical significance of 80% mortality rate. Acute kidney injury (AKI) leads to an increase in circulating cytokines, chemokines, activated innate immune cells and diffuse of these agents to other organs such as the lungs. These factors initiate pathological cascade that ultimately leads to ALI and acute respiratory distress syndrome (ARDS). We comprehensively searched the English medical literature focusing on AKI, ALI, organs cross talk, renal failure, multi organ failure and ARDS using the databases of PubMed, Embase, Scopus and directory of open access journals. In this narrative review, we summarized the pathophysiology and treatment of respiratory distress syndrome following AKI. This review promotes knowledge of the link between kidney and lung with mechanisms, diagnostic biomarkers, and treatment involved ARDS induced by AKI. PMID- 29398295 TI - Genotype and other determinants of respiratory function in myotonic dystrophy type 1. AB - New treatments are being developed for myotonic dystrophy type 1 (DM1). To evaluate their efficacy, knowledge about the natural history of respiratory dysfunction and its relationship with the genotype will be crucial. Also needed is information on factors predicting the time-course of respiratory function in DM1. Using data from 283 patients, we built a segmented linear mixed-effects regression model to assess respiratory function changes over time. Respiratory variables associated with the CTG repeat number were identified by multivariate linear regression analysis. Cox proportional-hazards regression was used to estimate hazard ratios (HRs) for starting non-invasive ventilation (NIV). Higher CTG repeat number was associated with peak cough flow impairment (p = 0.007) and with lower values for maximal inspiratory pressure (p <0.0001) and upright vital capacity. A vital capacity decline over time was associated with older age at first evaluation (p <0.0001), higher CTG repeat number (p <0.0001), and higher baseline body mass index (p = 0.0004). NIV initiation was associated with lower peak cough flow (p <0.001) after age and PaCO2 adjustment. Earlier and closer monitoring with routine peak cough flow determination in adults with congenital DM1, combined with weight control, may diminish the risk of respiratory complications and optimise other aspects of management. PMID- 29398296 TI - Ophthalmoplegia due to concurrent thyrotoxicosis and myasthenia gravis. PMID- 29398298 TI - New approach for the identification of implausible values and outliers in longitudinal childhood anthropometric data. AB - PURPOSE: We aimed to demonstrate the use of jackknife residuals to take advantage of the longitudinal nature of available growth data in assessing potential biologically implausible values and outliers. METHODS: Artificial errors were induced in 5% of length, weight, and head circumference measurements, measured on 1211 participants from the Maternal Vitamin D for Infant Growth (MDIG) trial from birth to 24 months of age. Each child's sex- and age-standardized z-score or raw measurements were regressed as a function of age in child-specific models. Each error responsible for a biologically implausible decrease between a consecutive pair of measurements was identified based on the higher of the two absolute values of jackknife residuals in each pair. In further analyses, outliers were identified as those values beyond fixed cutoffs of the jackknife residuals (e.g., greater than +5 or less than -5 in primary analyses). Kappa, sensitivity, and specificity were calculated over 1000 simulations to assess the ability of the jackknife residual method to detect induced errors and to compare these methods with the use of conditional growth percentiles and conventional cross-sectional methods. RESULTS: Among the induced errors that resulted in a biologically implausible decrease in measurement between two consecutive values, the jackknife residual method identified the correct value in 84.3%-91.5% of these instances when applied to the sex- and age-standardized z-scores, with kappa values ranging from 0.685 to 0.795. Sensitivity and specificity of the jackknife method were higher than those of the conditional growth percentile method, but specificity was lower than for conventional cross-sectional methods. CONCLUSIONS: Using jackknife residuals provides a simple method to identify biologically implausible values and outliers in longitudinal child growth data sets in which each child contributes at least 4 serial measurements. PMID- 29398297 TI - Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant. AB - Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the "common deletion" in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The "common mtDNA deletion" is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded. PMID- 29398299 TI - Racial differences in spatial patterns for poor glycemic control in the Southeastern United States. AB - PURPOSE: Evidence consistently shows poor outcomes in racial minorities, but there is limited understanding of differences that are explained by spatial variation. The goal of this analysis was to examine contribution of spatial patterns on disparities in diabetes outcomes in the Southeastern United States. METHODS: Data on 64,022 non-Hispanic black (NHB) and non-Hispanic white (NHW) veterans with diabetes living in Georgia, Alabama, and South Carolina were analyzed for 2014. Hemoglobin A1c (HbA1c) was categorized as controlled (less than 8%) and uncontrolled (greater than or equal to 8%). Logistic regression was used to understand the additional explanatory capability of spatial random effects over covariates such as demographics, service connectedness, and comorbidities. Data aggregated at the county level were used to identify hotspots in distribution of uncontrolled HbA1c and tested using local Moran's I test. RESULTS: Overall percent uncontrolled HbA1c was 36.5% (40.8% in NHB and 33.4% in NHW). In unadjusted analyses, NHB had 37% higher odds of uncontrolled HbA1c (odds ratio [OR]: 1.37, 95% confidence interval, 1.32, 1.41). After adjusting for demographics and comorbidities, the OR decreased to 1.09 but remained significant (95% confidence interval, 1.05, 1.13). The OR further decreased after incorporating spatial effects (OR: 1.07, 95% confidence interval, 1.03, 1.11) but remained statistically significant. Hotspots of high HbA1c were detected, and spatial patterns differed across racial groups. CONCLUSIONS: Differences in spatial patterns in glycemic control exists between NHB and NHW veterans with type 2 diabetes. Incorporating spatial effects helps explain more of the disparity in uncontrolled HbA1c than adjusting only for demographics and comorbidities, but significant differences in uncontrolled HbA1c remained. PMID- 29398300 TI - [Massive infestation with larva migrans]. PMID- 29398301 TI - Human and mouse artificial chromosome technologies for studies of pharmacokinetics and toxicokinetics. AB - In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human pharmacokinetics and toxicokinetics. Unfortunately, drugs under development are often discontinued because their nonclinical results do not extrapolate to human clinical studies in relation to either safety or efficacy. Therefore, it is important to improve the time- and cost-effectiveness of drug development. This might be achieved by developing new technologies including pharmacokinetics and toxicokinetics models that use human and mouse artificial chromosome vectors (HACs/MACs). HACs/MACs are unique vectors with several advantages: 1) independent maintenance, 2) defined copy number and mitotically stable, 3) no silencing of the transgene, and 4) no limitation of DNA insertion size. This review provides information on the advantages and examples of the utility of various models based on the recent advances in HAC/MAC technologies, including multifunctional cell-based models for assaying drug-drug interactions, bidirectional permeability, and cytotoxicity, as well as fully genetically humanized mouse models. We also discuss the future prospects of these technologies to advance drug discovery. In summary, these technologies offer advantages over current conventional models and should improve the success rate of drug development related to efficacy and safety for humans. PMID- 29398303 TI - Low mitochondrial activity within developing earthworm male germ-line cysts revealed by JC-1. AB - The male germ-line cysts that occur in annelids appear to be a very convenient model for spermatogenesis studies. Germ-line cysts in the studied earthworm are composed of two compartments: (1) germ cells, where each cell is connected via one intercellular bridge to (2) an anuclear central cytoplasmic mass, the cytophore. In the present paper, confocal and transmission electron microscopy were used to follow the changes in the mitochondrial activity and ultrastructure within the cysts during spermatogenesis. JC-1 was used to visualize the populations of mitochondria with a high and low membrane potential. We used the spot detection Imaris software module to obtain the quantitative data. We counted and compared the 'mitochondrial spots' - the smallest detectable signals from mitochondria. It was found that in all of the stages of cyst development, the majority of mitochondria spots showed a green fluorescence, thus indicating a low mitochondrial membrane potential (MMP). Moreover, the number of active mitochondria spots that were visualized by red JC-1 fluorescence (high MMP) drastically decreased as spermatogenesis progressed. As much as 26% of the total number of mitochondrial spots in the spermatogonial cysts showed a high MMP - 19% in the spermatocytes, 24% in the isodiametric spermatids and 3% and 6%, respectively, in the cysts that were holding early and late elongate spermatids. The mitochondria were usually thread-like and had an electron-dense matrix and lamellar cristae. Then, during spermiogenesis, the mitochondria within both the spermatids and the cytophore had a tendency to form aggregates in which the mitochondria were cemented by an electron-dense material. PMID- 29398302 TI - Organs-on-a-chip: Current applications and consideration points for in vitro ADME Tox studies. AB - Assay systems using in vitro cultured cells are increasingly applied for evaluation of the efficacy, safety, and toxicity of drug candidates. In vitro cell-based assays have two main applications in the drug discovery process: searching for a compound that is effective against the target disease (seed investigation) and confirmation of safety during use of the identified compounds (safety assessment). Currently available in vitro cell-based assays have been designed to evaluate the efficacy and toxicity in single organs, but the in vivo pharmacokinetics and pharmacodynamics of the administered drug candidates have not been considered. Thus, an evaluation system that interconnects cell culture units, one of which has appropriate drug metabolism activities and the other assesses the efficacy and toxicity of compounds, is needed. Accordingly, the in vitro ADME-Tox culture system known as organs-on-a-chip has been proposed. In this review, after introducing the organs-on-a-chip system, the evaluation of enterohepatic circulation and the gut-liver axis relationship will be presented as an example of the application of the organs-on-a-chip system for ADME studies based on inter-organ network. Additionally, the functions required for the organs on-a-chip system and the necessity of standardization of cells mounted on the chip system will be discussed. PMID- 29398304 TI - The Effect of Interactive Therapeutic Play Education Program on Anxiety Levels of Children Undergoing Cardiac Surgery and Their Mothers. AB - PURPOSE: This study was conducted to determine the effect of Interactive Therapeutic Play Education Program applied in preparing pediatric cardiac patients for surgery on the postoperative anxiety levels of such children and their mothers. DESIGN: This was a randomized controlled experimental trial. METHODS: The study was conducted on children aged 6 to 12 years, who underwent surgery for congenital heart disease, and their mothers (N = 43). FINDINGS: Anxiety levels of the children and their mothers were similar in the preoperative period, whereas postoperative anxiety levels were lower in the experimental group than in the control group (P < .05). CONCLUSIONS: As a result of this study it was determined that education provided using therapeutic play to preoperative patients aged 6 to 12 years to undergo surgery reduced the anxiety levels of children and their mothers in the postoperative period. PMID- 29398305 TI - Investigation of electron boost radiotherapy in patients with breast cancer: Is a direct electron field optimal? AB - PURPOSE: Historically, electron boost dose mainly was delivered by a direct field in adjuvant radiotherapy of breast cancer. In this prospective study, we investigated direct electron field, in terms of optimal coverage of tumour bed volume following localization using ultrasound and surgical clips. MATERIAL AND METHODS: First, for all 24 patients, a breast sonographer drew perimeter of tumour bed on the breast skin. Then an electron boost field was outlined on the demarcated territory, and a lead wire marker compatible with CT scan was placed on the field borders by a 2cm margin. After CT scan simulation, all patients underwent adjuvant whole breast irradiation with 3D-conformal radiotherapy to 50Gy in 25 fractions. Then for boost radiotherapy, lead wire in CT images was countoured as electron boost field. Also, the tumour bed was contoured based on surgical clips (true clinical target volume and true planning target volume). Electron treatment planning was done for electron boost field. Finally isodose coverages for true planning target volume investigated. RESULTS: On average, 16.68% of clips planning target volume (true planning target volume; range: 0.00 to 95%) received 90% oor more of the prescribed dose when the electron treatment plan was made. Isodose curves does not provide adequate coverage on the tumour bed (clips planning target volume) when electron boost treatment planning was generated for electron boost field (en face electron field). In fact, a part of target (planning target volume-c) is missed and more doses is absorbed in normal tissue. CONCLUSIONS: Electron boost treatment planning (an en face electron field) following tumour bed localization using ultrasonography does not provide an optimized coverage of tumour bed volume. PMID- 29398306 TI - Endovascular Management of a Left Subclavian Artery Pseudoaneurysm Secondary to Clavicular Fracture. PMID- 29398307 TI - Left Ovarian Vein Drainage Variant: An Exceptional Cause of Pelvic Congestion Syndrome. PMID- 29398309 TI - Percutaneous axillary artery access for endovascular interventions. AB - BACKGROUND: As endovascular therapy becomes increasingly complex, adjunct techniques such as upper extremity arterial access facilitate visceral branch interventions. The purpose of this study was to assess the viability of axillary artery percutaneous access in endovascular repair. METHODS: Records of all patients undergoing axillary artery percutaneous access as part of an endovascular intervention from December 2015 to December 2016 were examined. Demographics of the patients (age, sex, medical comorbidities, smoking status, and anticoagulation) were documented. Each case was examined for technical success and perioperative complications, including hematoma, brachial plexus injury, and return to the operating room. Early functional outcomes were assessed using clinic follow-up documentation. RESULTS: During the study interval, 25 axillary artery punctures in a total of 19 patients were performed for endovascular intervention. The mean age was 72 years; most patients were male (68%), and the cohort had a typical vascular comorbidity profile (hypertension in 84%, hyperlipidemia in 90%, diabetes in 21%, coronary artery disease in 58%, and chronic obstructive pulmonary disease in 47%; 90% were active or former smokers). Axillary access was obtained as part of complex endovascular aneurysm repair in 13 patients, mesenteric vessel intervention in 3 patients, and iliac intervention in 3 patients. Sheath size was most frequently 6F (6 punctures) or 7F (15 punctures). Closure devices included Perclose (Abbott Vascular, Santa Clara, Calif) in 36% and Angio-Seal (Terumo Interventional Systems, Somerset, NJ) in 64%. There were two perioperative deaths and one instance of return to the operating room for hematoma. There was no perioperative stroke, axillary occlusion, or severe brachial plexus injury. One patient had transient ipsilateral postoperative thumb numbness, and one patient had residual bleeding after closure requiring manual pressure. CONCLUSIONS: Percutaneous axillary artery access is a viable strategy to facilitate complex endovascular interventions. This technique avoids the need for brachial or axillary artery exposure and allows larger sheath sizes because of the caliber of the axillary artery. There were no major neurologic or ischemic complications. This technique is a relatively safe and practical alternative to approaches involving exclusively femoral and brachial access. PMID- 29398308 TI - Transthoracic Ultrasound Evaluation of Arch and Descending Thoracic Aortic Pathology. AB - BACKGROUND: Duplex ultrasonography (DUS) currently has limited applicability in the diagnosis and surveillance of thoracic aortic pathologies because of associated limitations. This study investigates the feasibility of using an optimised DUS protocol to detect descending thoracic aortic pathology. METHODS: This was a prospective, case control cohort study. Patients with computed tomography (CT) confirmed thoracic aortic pathology underwent DUS of the thoracic aorta. A control group known to have no thoracic pathology also underwent DUS. The sonographer performing DUS was blinded to the CT findings, and recorded the presence of pathology or any dilated aortic segment where visualised. Diameter cutoff points of 35 mm and 40 mm were compared. RESULTS: Forty patients were scanned (20 cases and 20 controls). All patients but one had a technically adequate assessment of the thoracic aorta (at least one view of the descending thoracic aorta). Using a size threshold of 40 mm, 16 out of 19 cases and two out of 20 control patients would have been recommended for definitive imaging. Using a cutoff of 35 mm, this became 18 out of 19 cases and six of 20 controls. Sensitivity and specificity were 100% and 70% for a threshold of 35 mm, and 84% and 90% for a threshold of 40 mm. CONCLUSIONS: DUS has the potential to be used as a diagnostic modality for thoracic aortic pathology, and may have a role in surveillance for some patients for whom CT scanning is contraindicated. Further validation and refinements to this technique are required. However, this study provides proof of concept. PMID- 29398311 TI - Natural history of spontaneous isolated celiac artery dissection after conservative treatment. AB - OBJECTIVE: Optimal treatment of spontaneous isolated celiac artery dissection (SICAD) is not well established because the natural history of this rare disease is poorly understood. We analyzed the natural history of patients who underwent conservative treatment. METHODS: The study included 28 patients with SICAD from December 2008 to January 2017. Our institutional policy of first-line treatment for SICAD patients was conservative, and invasive procedures were reserved for unstable complications such as severe persistent pain, significant organ malperfusion, rapid aneurysmal change, and rupture or concealed rupture. Demographics, clinical features, morphologic characteristics on computed tomography, treatment modalities, and follow-up results of these patients were retrospectively reviewed. RESULTS: Mean age was 52 years, and 89% of patients were male; 86% presented with pain, mostly abdominal, and 14% of cases were detected incidentally on abdominal imaging. None of these patients had unstable complications on admission, and all underwent initial conservative treatment. During the follow-up period (22 +/- 20 months), aneurysmal change and propagation of thrombosis were noted in one patient and two patients, respectively, all of whom were managed conservatively without adverse clinical events. No difference in clinical and morphologic outcomes was noted between patients who were treated with antihypertensive therapy and those who were not. Patients with intramural hematoma on initial images showed dynamic vascular remodeling (partial to complete resorption) during the follow-up period compared with patients who had dominant intimal flap on initial images. CONCLUSIONS: The clinical course of patients with SICAD was benign. Even progressive vascular changes during follow up did not require invasive treatment. Antihypertensive therapy might not modify the clinical course. The short-term results of conservative management are encouraging, but further evaluation with long-term follow-up in a large population is needed. PMID- 29398310 TI - Ethnic disparities in outcomes of patients with complicated type B aortic dissection. AB - OBJECTIVE: The objective of this study was to evaluate the difference in outcomes after endovascular intervention in patients with complicated type B aortic dissection (TBAD) based on ethnicity and blood pressure control. METHODS: Between 2012 and 2016, there were 126 patients who underwent endovascular procedures for complicated TBAD at a single-institution quaternary referral center. Patients self-identified as African American (n = 53), white (n = 70), and Asian (n = 3). African American and white patients were compared on a number of variables, including age, ethnicity, insurance type, blood pressure, comorbidities, number of previous interventions, and number of antihypertension medications they were taking before intervention. Primary outcomes were survival and need for reintervention. RESULTS: Kaplan-Meier estimates for survival for African Americans vs whites were 94% vs 89%, 91% vs 83%, 89% vs 79%, and 89% vs 76% at 30 days, 1 year, 3 years, and 5 years, respectively (P = .05). African Americans were younger overall (52.5 +/- 11 years) vs whites (63.7 +/- 14.7 years; P < .0001). African Americans required a significantly greater number of reinterventions (P = .007). They also had higher rates of chronic kidney disease (P = .01), smoking (P = .03), and cocaine use (P = .02) and were more likely to be on Medicaid (P = .02). Hypertension was poorly controlled in both groups, with the percentage of patients with uncontrolled hypertension (systolic >140 mm Hg) preoperatively, postoperatively, and 30 days after intervention at 32%, 32%, and 39%. There was no significant difference between the cohorts in uncontrolled hypertension preoperatively (P = .39) or postoperatively (P = .63). However, more African Americans had uncontrolled hypertension at 30 days (African Americans, 49%; whites, 31%; odds ratio, 2.1; P = .09). African Americans were taking a greater number of antihypertension medications at presentation than whites (P = .01) and specifically had higher use rates of beta blockers (P = .02), diuretics (P = .02), and angiotensin-converting enzyme inhibitors (P = .04). CONCLUSIONS: African Americans with TBAD present at a younger age than their white counterparts do and have a survival advantage up to at least 5 years. However, African Americans have a higher rate of reintervention that is probably associated with poor blood pressure control despite taking more antihypertension medications both before and after the repair. It appears that optimal medical therapy is difficult to achieve in all groups. More aggressive medical management is needed, particularly more so in African Americans, which may in turn decrease the number of interventions and potentially improve long-term survival. PMID- 29398312 TI - Implementation of a virtual vascular clinic with point-of-care ultrasound in an integrated health care system. AB - OBJECTIVE: Using secured videoconferencing technologies, telemedicine may replace traditional clinic visits, save patients' time and travel, and improve use of limited surgeon and facility resources. We report our initial experience of the remote clinical encounter (RCE) by evaluating vascular surgery patients. METHODS: In this proof-of-concept pilot study, we conducted telemedicine evaluations of vascular patients at a tertiary care institution from October 2015 to August 2016. Patients were offered synchronous virtual visits from a surgical provider in lieu of an in-person visit. We used Skype for Business (Microsoft, Redmond, Wash) over secured networks for patient-provider interaction, clinical data entry in the Epic electronic medical record (Epic Systems Corporation, Verona, Wisc) for documentation, and established satellite facilities with existing vascular laboratories for imaging and laboratory testing. We evaluated feasibility, demographics, encounter type, and satisfaction of the patient through web-based questionnaires. RESULTS: During a 10-month period, 41 women and 14 men with an average age of 57 years (range, 29-79 years) underwent 82 RCEs. There were 43 white (78.1%), 9 black (16.3%), 1 Asian (1.8%), and 2 Middle Eastern (3.6%) patients. Diagnoses included both arterial (aneurysm, carotid, and occlusive disease) and venous (deep venous thrombosis and varicose vein) disease. Among the 82 RCEs, visit types included 15 new patients, 30 postoperative visits, and 37 follow-up visits. Ultrasound imaging was performed in conjunction with the RCE in 74 patients (90.2%). Most patients (57%) had multiple RCEs during the study period. All 55 patients responded to the satisfaction questionnaire; 91% stated that they would highly recommend a virtual physician encounter to a friend or colleague, and all of the respondents found their encounter more convenient than having a traditional office visit. All patients thought that they were able to communicate clearly with the provider, and overall quality responses were overwhelmingly positive. CONCLUSIONS: Secured virtual visits can be conducted using commercially available hardware and software solutions. Synchronous telemedicine with point-of-care ultrasound is effective in evaluating common vascular conditions. Virtual care may be used for management of patients with chronic vascular disease. PMID- 29398313 TI - Natural history and management of renal artery aneurysms in a single tertiary referral center. AB - OBJECTIVE: Although renal artery aneurysms (RAAs) are uncommon, several large reports have been published indicating their benign natural history. The objective of our study was to review our single-center experience managing this disease entity. METHODS: A retrospective review of the Yale radiologic database from January 1999 to December 2016 was performed. Only patients with RAA and a computed tomography scan of the abdomen were selected for review. Demographics of the patients, aneurysm characteristics, management, postoperative complications, and follow-up data were collected. RESULTS: There were 241 patients with 259 RAAs identified, with a mean age of 69 years (range, 35-100 years); 147 were female (61%). On computed tomography, aneurysms were solitary and right sided in 224 (86%) and 159 (61%), respectively; 64 (27%) patients had aneurysms elsewhere. The breakdown of RAAs by location was as follows: renal bifurcation in 84 (32%), renal pelvis in 77 (30%), distal renal artery in 58 (22%), mid renal artery in 34 (13%), and proximal renal artery in 6 (2%). Five patients had symptoms that were attributed to the RAA and underwent operative repair; all others were observed without an operation. Symptoms in the operative repair group included flank pain in four and uncontrolled hypertension in one. The mean overall diameter of the RAAs was 1.22 +/- 0.49 cm. The diameter of operatively repaired and observed RAAs was 1.84 +/- 0.55 cm and 1.21 +/- 0.48 cm, respectively (P = .002). Operative repair included four coil embolizations and one open resection. There were no renal function changes in any of these patients after operation and no other complications. Mean follow-up was 41 +/- 35 months for patients in the group that was observed; 18 of these RAAs were >2 cm, and none ruptured. On multivariable regression analysis, female sex (P = .0001), smoking history (P = .00007), left sided RAA (P = .03), and main renal artery location (P = .03) were inversely related to growth, whereas a history of hypertension was directly related to growth rate (P = .01). The mean growth rate for RAAs was 0.017 +/- 0.052 cm/y. CONCLUSIONS: RAAs tend to have a benign natural history. Although previous reports have not identified any factors that contribute to RAA growth, we observed that RAA location, sex, smoking history, and hypertension may have an impact on growth rates. No ruptures were observed. Operative repair at our institution was rare, with no morbidity or mortality. Observation of RAAs over time seems feasible in the asymptomatic patient with a small RAA. PMID- 29398314 TI - Infrarenal aortic repair with or without false lumen intentional placement of endografts for hybrid management of complex aortic dissection. AB - OBJECTIVE: Aortic dissection (AD) often involves the infrarenal aorta. We review our experience with open infrarenal aortic repair with or without false lumen intentional placement (FLIP) of endografts in the proximal dissected aorta as part of a hybrid strategy to treat complex AD. METHODS: A prospectively maintained database of patients undergoing intervention for AD was reviewed. Data regarding diagnosis, imaging features, nature of the infrarenal repair (one- vs two-stage procedure), endoleaks, need for additional interventions, morbidity, and mortality were collected. RESULTS: Between 2006 and 2017, there were 16 patients with AD with thoracoabdominal aortic aneurysm (TAAA), malperfusion, or both who underwent open infrarenal aortic repair or replacement combined with endovascular repair in a single- or multiple-stage procedure. Fifteen patients had a chronic AD and one patient had an acute AD. The most common indication for intervention was absolute size or rapid growth of the abdominal, thoracic, or thoracoabdominal aortic aneurysm (65%). In four patients with AD, the infrarenal replacement surgical graft was used as a common distal seal zone, allowing FLIP of an endograft to treat the proximal AD. Ten (62%) cases were done in two or more stages. Three patients had infrarenal aortic replacement with debranching only. In two of these patients, the proximal dissected aorta has remained stable without aneurysmal degeneration. One patient died as a result of rupture of his aneurysm while awaiting the second stage (perioperative mortality, 6%). Patients were observed from 1 month to 7 years. One patient had a stable type II endoleak, and one patient required subsequent replacement of ascending aortic arch for aneurysmal disease. One patient died of unrelated causes on follow-up. CONCLUSIONS: Hybrid infrarenal aortic repair for treatment of complex AD can be performed with low morbidity and mortality and excellent medium-term results. This strategy can resolve malperfusion while simultaneously creating a landing zone using the false lumen as the conduit for the stent graft (FLIP) in selected patients. The FLIP technique allows full expansion of the endograft, potential preservation of lumbar and intercostal artery flow, and exclusion of the weaker false lumen while, in some cases, decompressing and thus stabilizing the proximal dissected aorta. PMID- 29398315 TI - Use of a primary carotid stenting technique does not affect perioperative outcomes. AB - BACKGROUND: Primary carotid stenting (PCS) has been shown to be feasible and safe in small series, but real-world outcomes in a large multicenter data set have yet to be explored. We aimed to compare outcomes for PCS (PCS+) vs conventional carotid artery stenting (CAS) with angioplasty (PCS-) using a national database. METHODS: We analyzed all CAS cases in the Vascular Quality Initiative (VQI) database (2005-2016) using univariable and multivariable logistic regression to assess the effect of PCS on outcomes. The primary end point was a composite of stroke/death occurring within 30 days. RESULTS: The study included 10,074 patients (mean age, 69.5 +/- 9.9 years; 64% male). The composite end point occurred in 3.5% of cases (stroke, 2.4%; death, 1.5%). PCS was used in 688 (6.8%) patients. On univariable analysis, stroke/death occurred more frequently with PCS+ vs PCS- (5.2% vs 3.4%; P = .01). However, this difference was mitigated after adjusting for baseline group differences (odds ratio [OR], 1.15; 95% confidence interval [CI], 0.72-1.83; P = .55). PCS also had no significant effect on the primary composite end point on adjusted analysis stratified by symptom status (asymptomatic: OR, 0.98 [95% CI, 0.39-2.48]; symptomatic: OR, 1.19 [95% CI 0.66-2.06]) or among patients undergoing CAS with embolic protection (OR, 1.54 [95% CI, 0.92-2.57]). Patients undergoing CAS without embolic protection had a significantly higher risk of stroke/death regardless of the stenting technique used (OR, 3.97 [95% CI, 2.47-6.37]). CONCLUSIONS: PCS is associated with a similar risk of stroke and death compared with conventional CAS with angioplasty. The use of an embolic protection device is essential to good outcomes with both techniques. PMID- 29398316 TI - Nurse-led Discharge in Pediatric Care: A Scoping Review. AB - PROBLEM: Patients and caregivers frequently report feeling ill-prepared during the transition from hospital to home. Given the privileged position nurses occupy within the health care setting, they are often an appropriate health care professional to lead the discharge process. We aimed to map what is currently known about nurse-led/facilitated discharge programs, interventions, models, or frameworks for the pediatric population. ELIGIBILITY CRITERIA: We conducted a scoping review following the Joanna Briggs Institute Methodology. Published literature targeting children 0-18 years old being discharged from acute care to home and describing a nurse leading the discharge planning/process was included. SAMPLE: A search strategy was developed and implemented in four electronic databases; CINAHL, MEDLINE, Embase, and Web of Science. We also hand searched three high impact journals and reviewed reference lists of relevant articles. This search resulted in 1485 records. Based on our eligibility criteria, 9 articles were included in this review. Two independent reviewers screened each eligible article and extracted relevant information. RESULTS: Terminology and program structure varied greatly across included studies. Critical appraisal revealed a lack of high quality research designs. CONCLUSIONS: We identified a paucity of nurse-led/facilitated discharge programs evaluated within the pediatric population. The majority of studies were inadequately reported, leaving it difficult to identify development, implementation, and evaluation strategies. IMPLICATIONS: Given the positive outcomes reported across all articles included in our review, future empirical research is warranted to explore this role within nursing practice. PMID- 29398317 TI - The Effects of a Humor Intervention on the Physiological, Physical, and Psychological Responses of School-aged Children With Atopic Dermatitis in South Korea: A Pilot Study. AB - PURPOSE: We examined the effects of a humor intervention on the physiological, physical, and psychological responses of school-aged children with atopic dermatitis. DESIGN AND METHODS: This quasi-experimental study used a nonequivalent control group and a pre- and post-test design. Forty-five schoolchildren participated. RESULTS: Children in the experimental group (n=26) received a humor intervention and reported significant differences in physiological response, which was evidenced by heightened salivary immunoglobulin A levels as compared to the control group (n=19). Additionally, the psychological response of the experimental group was significantly different from that of the control group as evidenced by decreased stress levels. CONCLUSION: Humor intervention may be an effective nursing intervention for children with atopic dermatitis. PMID- 29398318 TI - Association of Weight Control Behaviors with Body Mass Index in Korean Adolescents: A Quantile Regression Approach. AB - PURPOSE: Adolescents are interested in weight control but likely practice unhealthy weight control behaviors. This study aimed to examine weight control behaviors associated with body mass index (BMI) in Korean adolescents. DESIGN AND METHODS: In this descriptive cross-sectional study of 16- to 19-year-old adolescents (97 girls and 90 boys), analyses were conducted of physical activity, sedentary behaviors, dietary behaviors, and self-efficacy for physical activity and diet. Daily steps were measured using pedometers. Height and weight were self reported. We conducted descriptive statistics and quantile regression analysis using STATA 14.0. RESULTS: About 10% were underweight, and 8.6% overweight and obese. Average weekday and weekend steps/day were <10,000. Only 4.3% reported performing moderate-to-vigorous physical activity (MVPA) daily. Less than half (42.5%) reported that they had three meals/day every day. Most (89.3%) had milk less than once/day. Quantile regression showed that, for the 5th BMI percentile group, (1) age (beta = 0.941) and milk consumption (beta = 2.148) were significantly positively associated with BMI, whereas (2) dietary self-efficacy (beta = -0.083) was significantly negatively associated with BMI. For the 95th percentile group, having three meals/day (beta = 2.558) was significantly positively associated with BMI, whereas MVPA (beta = -5.440) and muscle strengthening exercise (beta = -3.392) were significantly negatively associated with BMI. CONCLUSIONS: Milk consumption was positively associated with BMI of underweight adolescents, whereas physical activities were negatively associated with BMI of overweight and obese adolescents. PRACTICE IMPLICATION: Weight control programs for adolescents may need to be tailored for differing BMI levels. PMID- 29398319 TI - PENS Position Statement on Bullying Prevention. PMID- 29398320 TI - The prognostic role of perioperative allogeneic blood transfusions in gastric cancer patients undergoing curative resection: A systematic review and meta analysis of non-randomized, adjusted studies. AB - The impact of allogeneic perioperative blood transfusions (APTs) on the prognosis of gastric cancer patients undergoing curative-intent gastrectomy is still a highly debated topic. Two meta-analyses were published in 2015, and new studies report conflicting results. A literature review was conducted using PubMed, Scopus, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews, updated to March 1, 2016. Thirty-eight non randomized studies reporting data on overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS) and postoperative complications (PCs) were included. An inverse variance random-effects meta-analysis was conducted. APTs showed an association with worse OS, DFS, DSS and an increased number of PCs. The hazard ratio (HR) for OS was 1.49, with a 95% confidence interval (95% CI) of 1.32-1.69 (p < .00001; Q-test p = .001, I-squared = 56%). After outlier exclusion, the HR for OS was 1.34 (95% CI = 1.23-1.45, p < .00001; Q-test p = .64, I-squared = 0%). The HR for DFS was 1.48 (95% CI = 1.18-1.86, p = .0007; Q test p = .31, I-squared = 16%), and the HR for DSS was 1.66 (95% CI = 1.5-2.19, p = .0004; Q-test p = .96, I-squared = 0%). The odds ratio for PCs was 3.33 (95% CI = 2.10-5.29, p < .00001; Q-test p = .14, I-squared = 42%). This meta-analysis showed a significant association between transfusions and OS, DFS, DSS and PCs. The quality of the evidence was low. Aggregation, selection and selective reporting bias were detected. The biases shifted the results towards significance. Further studies using accurate adjustment methods are needed. Until such additional studies are performed, caution in administering transfusions and optimization of cancer patient blood management are warranted. PMID- 29398321 TI - Navigating treatment controversies for DCIS in the era of genomic profiling and active surveillance trials. PMID- 29398322 TI - Perioperative nutrition and enhanced recovery after surgery in gastrointestinal cancer patients. A position paper by the ESSO task force in collaboration with the ERAS society (ERAS coalition). AB - Malnutrition in cancer patients - in both prevalence and degree - depends primarily on tumor stage and site. Preoperative malnutrition in surgical patients is a frequent problem and is associated with prolonged hospital stay, a higher rate of postoperative complications, higher re-admission rates, and a higher incidence of postoperative death. Given the focus on the cancer and its cure, nutrition is often neglected or under-evaluated, and this despite the availability of international guidelines for nutritional care in cancer patients and the evidence that nutritional deterioration negatively affects survival. Inadequate nutritional support for cancer patients should be considered ethically unacceptable; prompt nutritional support must be guaranteed to all cancer patients, as it can have many clinical and economic advantages. Patients undergoing multimodal oncological care are at particular risk of progressive nutritional decline, and it is essential to minimize the nutritional/metabolic impact of oncological treatments and to manage each surgical episode within the context of an enhanced recovery pathway. In Europe, enhanced recovery after surgery (ERAS) and routine nutritional assessment are only partially implemented because of insufficient awareness among health professionals of nutritional problems, a lack of structured collaboration between surgeons and clinical nutrition specialists, old dogmas, and the absence of dedicated resources. Collaboration between opinion leaders dedicated to ERAS from both the European Society of Surgical Oncology (ESSO) and the ERAS Society was born with the aim of promoting nutritional assessment and perioperative nutrition with and without an enhanced recovery program. The goal will be to improve awareness in the surgical oncology community and at institutional level to modify current clinical practice and identify optimal treatment options. PMID- 29398323 TI - Delaying surgery after neoadjuvant chemoradiotherapy in rectal cancer has no influence in surgical approach or short-term clinical outcomes. AB - AIMS: In rectal cancer, increasing the interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery could improve the pathological complete response (pCR) rates, allow full-dose neoadjuvant chemotherapy, and select patients with a clinical complete response (cCR) for inclusion in a "watch & wait" program (W&W). However, controversy arises from waiting more than 8-12 weeks after CRT, as it might increase fibrosis around the total mesorectal excision (TME) plane potentially leading to technical difficulties and higher surgical morbidity. This study evaluates the type of surgical approach and short term post-operative outcomes in patients with rectal cancer that were operated before and after 12 weeks post CRT. METHODS: Patients from three centres (two in the UK, one in Portugal) who received rectal cancer surgery following neoadjuvant CRT between 2007 and 2016 were identified from prospectively maintained databases. Preoperative CRT was given to patients with high risk for local recurrence (threatened CRM <=2 mm or T4 in staging MRI). The baseline characteristics and surgical outcomes of patients that were operated <12 weeks and >=12 weeks after finishing CRT were analysed. RESULTS: A total of 470 patients received rectal cancer surgery, of those 124 (26%) received neoadjuvant CRT. Seventy-six patients (61%) were operated >=12 weeks after end of neoadjuvant CRT and 48 < 12 weeks. Patients in the >=12 weeks cohort had a higher BMI (27 vs 25, p = 0.030) and lower lymph node yield (11 vs 14, p = 0.001). The remaining of the baseline characteristics were similar between the two groups (age, operating surgeon, gender, ASA grade, T stage, surgical approach, operation). Operation time, blood loss, conversion rate, length of stay, 30-day readmission rate, 30 day reoperation rate, anastomotic leak rate, 30-day mortality, CRM clearance, and ypT0 rates were similar between the two groups. Univariate and multivariate analysis showed that delaying surgery >=12 weeks did not affect morbidity and mortality. CONCLUSION: In our cohort, there was no difference in short term surgical outcomes between patients operated before or after 12 weeks following CRT. The type of surgical procedures and the proposed approach did not differ due to waiting after CRT. Delaying surgery by >= 12 weeks is safe, feasible and does not result in higher surgical morbidity. PMID- 29398325 TI - The risk/benefit ratio of differentiated thyroid cancer treatment: Exploring treatment de-escalation. PMID- 29398324 TI - Risk factors for the development of invasive cancer in unresected ductal carcinoma in situ. AB - BACKGROUND: The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. METHODS: Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for >=1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed. RESULTS: Eighty-nine women with DCIS diagnosed 1998-2010 were identified. The median age at diagnosis was 75 (range 44-94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12-180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12-144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades (p = .0016, log-rank test). Invasion was more frequent in lesions with calcification as the predominant feature (23/50 v. 5/25; p = .042) and in younger women (p = .0002). Endocrine therapy was associated with a lower rate of invasive breast cancer (p = .048). CONCLUSIONS: High cytonuclear grade, mammographic microcalcification, young age and lack of endocrine therapy were risk factors for DCIS progression to invasive cancer. Surgical excision of high grade DCIS remains the treatment of choice. Given the uncertain long-term natural history of non-high grade DCIS, the option of active surveillance of women with this condition should be offered within a clinical trial. PMID- 29398326 TI - The role of lnc-DC long non-coding RNA and SOCS1 in the regulation of STAT3 in coronary artery disease and type 2 diabetes mellitus. AB - AIMS: Coronary artery disease (CAD) can be classified as an inflammatory disease, which affected by type 2 diabetes mellitus (T2DM). Elevated levels of many inflammatory molecules were found in the serum of patients with CAD. STAT3 molecule as a transcription factor plays an important role in the cytokines expression. Here, we examined the expression levels of STAT3 and its important regulatory genes lnc-DC and SOCS1, in patients with CAD and T2DM. METHODS: Blood samples were obtained from 37 CAD+ and 36 CAD- patients. These patients were enrolled in this study based on angiography findings and categorized based on T2DM status. The expression levels of STAT3, lnc-DC and SOCS1 genes were examined with Real time PCR method. RESULTS: A significant increase was observed in expression of STAT3 and lnc-DC genes but not SOCS1 in CAD+ versus CAD- patients. These results replicated partially in some groups categorized based on T2DM and CAD status. However, severity of CAD had no effect on expressions of these genes. Moreover, we found some significant correlations between expressions of lnc-DC with SOCS1 and STAT3, which confirmed by in silico analysis. CONCLUSION: Our results shed further light to the inflammatory aspects of CAD and T2DM with emphasis to JAK/STAT pathway and the regulatory role of long non-coding RNAs in the physiopathology of these diseases. PMID- 29398327 TI - Differing clinical phenotype for higher alanine-aminotransferase (ALT) compared with high-risk NAFLD fibrosis score in type 2 diabetes mellitus. AB - AIMS: The impact of non-alcoholic fatty liver disease (NAFLD) presence and severity on the diabetes phenotype remains unclear. Our study aimed to explore and contrast the phenotypes associated with higher ALT and high-risk NAFLD fibrosis score (NFS) in type 2 diabetes. METHODS: 324 patients with type 2 diabetes mellitus who were seen at a diabetes centre for a complications assessment with data for NFS were available for study. Data regarding co morbidities and pathology were obtained at assessment and by file audit. Logistic regression was used to determine if there were significant relationships between pre-determined diabetes complications and co-morbidities and ALT or high-risk NFS (>0.675). RESULTS: Significant univariate associations with lower ALT included those of osteoporosis/osteopenia and inability to sense the monofilament. High risk NFS was associated with arrhythmia, VPT >= 25 V and albuminuria. The associations of high-risk NFS with albuminuria and VPT >= 25 V remained after adjustment. CONCLUSIONS: In type 2 diabetes, the clinical phenotype of those with higher ALT is dissimilar, sometimes inverse, to those with high-risk NFS. More emphasis should be placed on liver fibrosis risk rather than on liver enzymes alone. PMID- 29398328 TI - Relation of asymmetrical dimethylarginine levels with renal outcomes in hypertensive patients with and without type 2 diabetes mellitus. AB - AIM: The aim of the study was to evaluate the association between high plasma ADMA levels, a biomarker of endothelial dysfunction, with the progression of albuminuria and chronic kidney disease (CKD) in hypertensive patients, with and without type 2 diabetes mellitus. METHODS: We successfully contacted 213 of 644 patients who had been evaluated between 2004 and 2005 and for whom basal data were available. After the exclusion of 51 patients, 162 hypertensive patients who were free from albuminuria were stratified into the following 4 groups according to the presence of diabetes and plasma ADMA percentiles: general hypertensive patients with high levels of plasma ADMA (>P4 or ADMA > 0.61 MUmol/L), general hypertensive patients with low levels of plasma ADMA (<=P4), diabetic hypertensive patients with high levels of plasma ADMA (>P4), and diabetic hypertensive patients with low levels of plasma ADMA (<=P4). RESULTS: The patients were prospectively evaluated over 5.8 years. High ADMA levels were associated with the progression of albuminuria in hypertensive patients, with and without type 2 diabetes. Major increases in the ADMA value during follow-up were associated with the progression of CKD, and direct correlations between ADMA changes and GFR changes were observed in the whole group and in the subgroup of diabetic patients. CONCLUSIONS: We suggest that high plasma ADMA levels might be a biomarker of renal disease progression and might even be an early predictor of albuminuria and its progression to the late stages of renal disease in hypertensive and diabetic hypertensive patients. PMID- 29398329 TI - The Effect of Electronic Cigarettes on Hand Microcirculation. AB - PURPOSE: Smoking conventional cigarettes reduces peripheral microcirculation leading to worse outcomes after hand surgery. Patients are increasingly using electronic cigarettes (eCigarettes); however, there is no published research investigating the effects of eCigarettes on hand microcirculation. METHODS: Fifteen healthy subjects with a median age of 26 years were recruited: 7 smokers and 8 nonsmokers. A noninvasive O2C laser Doppler probe measured a baseline control reading at deep (7-mm) and superficial (3-mm) levels. Participants commenced a 5-minute smoking protocol of nonnicotine (0-mg) eCigarettes with continuous microcirculation measurements during smoking and for 20 minutes afterward. This was repeated with nicotine (24-mg) eCigarettes. Readings were averaged over 5-minute periods and standardized as a percentage of baseline. A linear mixed-effects model with an unstructured covariance structure was used to analyze the data. RESULTS: Smokers had a statistically significant reduction in hand microcirculation during and up to 20 minutes after smoking a 24-mg eCigarette. There was a maximum reduction of 77% in superficial flow and 29% in deep flow. After smoking a 0-mg eCigarette, smokers demonstrated an increase in superficial flow of up to 70% with no change in deep flow. Nonsmokers had no statistically significant change in superficial or deep flow after smoking either eCigarette. CONCLUSIONS: A 24-mg eCigarette significantly reduced smokers' hand microcirculation during and after smoking. Microcirculation increased in smokers after inhalation of a 0-mg eCigarette. CLINICAL RELEVANCE: We advise smokers undergoing hand surgery to avoid high-dose eCigarettes and, if necessary, to use 0-mg eCigarettes as an alternative. PMID- 29398330 TI - Perioperative Antibiotics for Clean Hand Surgery: A National Study. AB - PURPOSE: Given that surgical site infections remain a common performance metric in assessing the quality of health care, we hypothesized that prophylactic antibiotics are overutilized in soft tissue hand surgery when antimicrobials are not indicated. METHODS: We studied insurance claims from the Truven MarketScan Databases to identify patients who underwent 1 of 5 outpatient hand surgery procedures: open or endoscopic carpal tunnel release, trigger finger release, de Quervain release, and wrist ganglion excision between 2009 and 2015 (n = 305,946). Hospital payment claims for preoperative intravenous antibiotics and prescriptions filled for postoperative oral antibiotics were analyzed. We examined the rate and temporal trend of prophylactic antibiotics use and identified risk factors using multivariable logistic regression. We also calculated health care expenditures related to prophylaxis. RESULTS: Prior to surgery, 13.6% (2009-2015) of patients received prophylactic intravenous antibiotics and trend analysis showed a statistically significant increase from 2009 (10.6%) to 2015 (18.3%), an increase of 72.5%. Preoperative prophylaxis was used most often prior to trigger finger release (17.5%) and least often prior to endoscopic carpal tunnel release (11.2%). Younger age, male sex, lower income, and obese patients had higher odds of receiving antibiotics. The total charge of prophylactic antibiotics medication used in this study equaled $1.6 million. CONCLUSIONS: In 2015, prophylactic intravenous antibiotics were administered to nearly 1 in 5 patients prior to clean soft tissue hand surgery. Although consensus guidelines indicate prophylaxis is not indicated, their use has increased steadily in the United States from 2009 to 2015. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 29398331 TI - Hand Surgery Questions on the Orthopaedic In-Training Examination: Analysis of Content and Reference. AB - PURPOSE: To provide an updated analysis of the hand surgery section of the Orthopaedic In-Training Examination (OITE) from 2009 to 2015. The goal was to contribute to the existing literature on the analysis of OITE questions, to aid both residents and residency programs in preparation for the OITE and board examination. METHODS: The authors analyzed all OITE questions pertaining to hand surgery between 2009 and 2015. Hand questions were analyzed for category and subcategory of content, cited reference, treatment intervention, and imaging modality used. RESULTS: Hand-related questions comprised 157 of the 1,872 OITE questions (8.4%). Nine general topic areas were identified, the most common of which were fracture-dislocation, tendon/ligament, nerve, congenital, and amputation. Trends existed in the recommended references; the 5 journals and 2 textbooks that were consistently cited included the Journal of Hand Surgery (American Volume), the Journal of the American Academy of Orthopaedic Surgeons, the Journal of Bone and Joint Surgery (American Volume), the Journal of Hand Surgery (European Volume), Hand Clinics, Orthopaedic Knowledge Update, and Green's Operative Hand Surgery, respectively. CONCLUSIONS: Knowledge regarding topics and resources used for OITE hand questions could be mutually beneficial to both residents and residency programs. This information would consolidate resident OITE and board examination study time. Furthermore, this analysis could help residency programs develop or improve educational conferences and journal clubs. CLINICAL RELEVANCE: An understanding of question content and sources should enable efficient learning and improved scores on this section of the examination. PMID- 29398332 TI - Cannulated Self-Drilling, Self-Tapping Pins for Displaced Extra-articular Distal Radius Fractures. AB - Displaced unstable extra-articular radius fractures are common and frequently treated with open reduction and internal fixation with a fixed-angle volar plate. Although this treatment yields good results, it might be more invasive than necessary for management of this often relatively simple fracture. In this article, we present the technique of using a cannulated self-drilling, self tapping (CSDT) construct that can be employed in a minimally invasive fashion. The CSDT offers a minimally invasive alternative to volar fixed-angle plating for unstable extra-articular distal radius fractures. It also can be useful in isolated displaced radial styloid fractures. Placed appropriately, implants rarely have to be removed. The CSDT also allows for early motion and rapid return to activities with anticipated satisfactory range of motion and function. PMID- 29398333 TI - A Rare Manifestation of Primary Bone Lymphoma: Solitary Diffuse Large B-Cell Lymphoma of the Little Finger. AB - Solitary primary non-Hodgkin bone lymphoma of the hand is a rare entity with only 3 cases reported in the literature. We report the case of a 77-year-old patient with isolated large B-cell bone lymphoma of the proximal phalanx of the little finger without rheumatoid arthritis or methotrexate treatment. The patient was treated with digital amputation and at 6 months' follow-up showed no relapse or dissemination of the disease. PMID- 29398334 TI - Visual quality with corneo-scleral contact lenses for keratoconus management. AB - PURPOSE: To assess the visual quality achieved by fitting corneo-scleral contact lenses (CScL) for keratoconus management. METHODS: Thirty patients with keratoconus presented to have CScL fitted because of the unsatisfactory visual quality they experienced with their contact lenses or spectacles. The eye examination included visual acuity assessment, anterior eye biomicroscopy, ocular fundus examination, corneal topographic analysis, endothelial-cell count, contrast sensitivity and aberrometry. The fitting process was performed using a diagnostic trial set. Subjective visual quality and comfort, and contact lens wear time were also reported. Patients were monitored for one year. RESULTS: Three patients discontinued CScL wear before one year. Therefore, 27 eyes of 27 patients (19 male and 8 female) participated in this study. The mean age was 36.1 +/- 13.1 (mean +/- SD) years. Statistically significant differences were found in logMAR visual acuity between the best spectacle-corrected vision and after CScL fitting (mean +/- SD, 0.23 +/- 0.30 and 0.00 +/- 0.14, respectively; p < 0.001). The total high-order aberrations decreased significantly (55%), and the spatial frequencies of contrast sensitivity all improved to normal range values of the population. Furthermore, high subjective visual quality and comfort ratings, and prolonged usage times (mean +/- SD, 13.44 +/- 2.38 h a day) were reported. No adverse ocular effects or clinically relevant changes in corneal parameters, visual quality, comfort or usage time were found one year after wearing CScL. CONCLUSION: This CScL seems to be safe and healthy, providing optimal visual quality, comfort and prolonged usage times in patients with keratoconus. PMID- 29398336 TI - Exclusive enteral nutrition in Crohn's disease: Evidence and practicalities. AB - Exclusive enteral nutrition (EEN) is the first line therapy for paediatric Crohn's disease, providing a complete nutritional feed whilst simultaneously inducing remission in up to 80% of cases. The effect of EEN on systemic/local intestinal immune function and subsequent inflammation (including barrier permeability, direct anti-inflammatory effects and cytokine signalling pathways), alongside changes in the microbiome (specific species and broad taxonomic shifts, functional changes) are becoming clearer, however the exact mechanism for induction of remission in Crohn's disease remains uncertain. The evidence of efficacy in paediatric Crohn's disease is strong, with selected adult populations also benefiting from EEN. However despite recommendations from all major societies (ECCO, ESPGHAN, NASPGHAN and ESPEN) first-line use of EEN is varied and Europe/Australasia/Canada show significantly more routine use than other parts of North America. Growth and nutritional status are significantly improved with EEN compared to corticosteroids but long-term outcomes are sparse. This review discusses the evidence underlying the use of EEN, highlighting the mechanisms thought to underlie how EEN induces remission in Crohn's disease, when and how to use EEN, including practical issues in both paediatric and adult practice (formulation, compliance, volumes and administration), and summarises the ongoing research priorities. PMID- 29398335 TI - Association of geriatric nutritional risk index with infection-related mortality in patients undergoing hemodialysis: The Q-Cohort Study. AB - BACKGROUND & AIMS: The geriatric nutritional risk index (GNRI) is a simple but useful nutritional marker for all-cause mortality and cardiovascular mortality in patients undergoing hemodialysis (HD). However, whether the GNRI can predict infection-related mortality in patients undergoing HD remains unclear, and there is insufficient evidence regarding whether the GNRI improves the predictive value for risk assessment beyond the existing conventional nutritional markers. Here, we investigated the association between the GNRI and infection-related mortality in patients undergoing HD and evaluated the predictive value of GNRI. METHODS: A prospective cohort study was performed on a total of 3436 Japanese HD patients aged >=18 years. Patients were divided into four groups by quartiles of GNRI: (Quartile 1 [Q1], >100.2; Q2, 95.9-100.2; Q3, 90.8-95.8; Q4, <90.8). We estimated the relationship between GNRI and all-cause mortality and infection-related mortality using a Cox proportional hazards model. To assess the additional predictive value of the GNRI in risk assessment, we compared the c-statistic, net reclassification improvement, and integrated discrimination improvement among serum albumin, serum creatinine, and the GNRI. RESULTS: During follow-up period (median, 4.0 years), a total of 564 patients died; 120 of these patients died of infectious disease. All-cause mortality and infection-related mortality increased linearly with lower GNRI levels. After adjusting for confounding risk factors, the GNRI was an independent predictor of infection-related mortality as well as all-cause mortality (hazard ratio [HR], 5.89; 95% confidence interval [CI], 2.85 13.8; P < 0.001 for Q4 vs. Q1, HR, 2.62; 95% CI, 1.23-6.24; P = 0.01 for Q3 vs. Q1). Additionally, when the GNRI was incorporated into a model with potential risk factors instead of serum albumin, the c-statistic increased significantly (0.811 vs. 0.821, P = 0.03), and the net reclassification improvement and integrated discrimination improvement was 0.26 (P = 0.005) and 0.005 (P = 0.01). This association was more apparent in the older patients (0.739 vs. 0.760, P = 0.02) than in the younger patients (0.916 vs. 0.912, P = 0.35). Similar results were observed between serum creatinine and the GNRI, but the difference did not reach statistical significance. CONCLUSIONS: Lower GNRI levels are an independent risk factor for infection-related mortality in patients undergoing HD. Moreover, addition of the GNRI to models with standard risk factors significantly improves the predictive ability of infection-related mortality, especially in older patients. PMID- 29398337 TI - The effect of prunes on stool output, gut transit time and gastrointestinal microbiota: A randomised controlled trial. AB - BACKGROUND & AIM: Prunes (dried plums) are perceived to maintain healthy bowel function, however their effects on gastrointestinal (GI) function are poorly researched and potential mechanisms of action are not clear. We aimed to investigate the effect of prunes on stool output, whole gut transit time (WGTT), gut microbiota and short-chain fatty acids (SCFA) in healthy adults METHODS: We conducted a parallel group, randomised controlled trial with three treatment arms in 120 healthy adults with low fibre intakes and stool frequency of 3-6 stools/wk. Subjects were randomised to 80 g/d prunes (plus 300 ml/d water); 120 g/d prunes (plus 300 ml/d water) or control (300 ml/d water) for 4 weeks. Stool weight was the primary outcome and determined by 7-day stool collection. Secondary outcomes included stool frequency and consistency (stool diary), WGTT (radio-opaque markers), GI symptoms (diary), microbiota (quantitative PCR) and SCFA (gas liquid chromatography). Group assignment was concealed from the outcome assessors. RESULTS: There were significantly greater increases in stool weight in both the 80 g/d (mean + 22.2 g/d, 95% CI -1-45.3) and 120 g/d (+32.8 g/d, 95% CI 13.9-51.7) prune groups compared with control (-0.8 g/d, 95% CI -17.2 to 15.6, P = 0.026). Stool frequency was significantly greater following 80 g/d (mean 6.8 bowel movements/wk, SD 3.8) and 120 g/d (5.6, SD 1.9) prune consumption compared with control (5.4, SD 2.1) (P = 0.023), but WGTT was unchanged. The incidence of flatulence was significantly higher after prune consumption. There were no significant differences in any of the bacteria measured, except for a greater increase in Bifidobacteria across the groups (P = 0.046). Prunes had no effect on SCFA or stool pH. CONCLUSIONS: In healthy individuals with infrequent stool habits and low fibre intake, prunes significantly increased stool weight and frequency and were well tolerated. Prunes may have health benefits in populations with low stool weight. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ISRCTN42793297 http://www.isrctn.com/ISRCTN42793297. PMID- 29398339 TI - Sixteen years trends in reported undernutrition. AB - BACKGROUND & AIMS: How undernutrition is reported in hospital discharge data is not understood. To assess trends in reported undernutrition and its management among hospitalized patients in Switzerland, and the association between reported undernutrition and in-hospital mortality, acquired infection, intensive care unit stay (ICU), and length of hospital stay (LOS). METHODS: Data from the Swiss hospital discharge databases from 1998 to 2014 (n = 13,297,188 hospitalizations, 52.2% women, 48.4% aged 65+, and 85% Swiss national). Reported undernutrition was defined by the presence of any undernutrition-related International Classification of Diseases 10th revision code. Nutritional management was defined by the presence of any nutritional intervention code. RESULTS: Prevalence of reported undernutrition increased from 0.32% in 1998 to 3.97% in 2014 in Switzerland, and similar but varying trends were found for each of the seven Swiss administrative regions: ranging from 0.18% to 2.13% in Ticino and from 0.23% to 5.63% in Mittelland. Undernutrition management of hospitalizations with reported undernutrition increased from 0.6% in 1998 to 57.8% in 2014, with wide variations according to administrative region: from 0% to 32.9% in Ticino and from 0% to 68.9% in Central Switzerland. After multivariable adjustment, reported undernutrition was positively associated with in-hospital mortality: odds-ratio and (95% confidence interval): 2.30 (2.26-2.34); acquired infection: 3.57 (3.46 3.70); ICU stay: 1.65 (1.63-1.68) and longer LOS: 19.6 +/- 0.2 vs. 13.0 +/- 0.1 days. CONCLUSION: Undernutrition is increasingly reported in Switzerland; still, over 40% of undernourished hospitalizations don't benefit from nutritional support. Reported undernutrition is associated with increased in-hospital mortality, acquired infection, ICU stay, and LOS. PMID- 29398338 TI - Diagnostic accuracy of lip force and tongue strength for sarcopenic dysphagia in older inpatients: A cross-sectional observational study. AB - BACKGROUND & AIMS: Dysphagia can be caused by sarcopenia in older adults. Although sarcopenic dysphagia has been reported to be associated with low tongue strength, whether tongue strength can be useful as a diagnostic index for sarcopenic dysphagia remains unclear. In addition, the association between sarcopenic dysphagia and lip force is unknown. The aim of the present study was to clarify the association of lip force and tongue strength with sarcopenic dysphagia, and their diagnostic accuracy for sarcopenic dysphagia. METHODS: A cross-sectional study was conducted in consecutive 245 (166 women) inpatients aged >=65 years in the post-acute phase of illness. The presence of sarcopenic dysphagia, lip force, and tongue strength were assessed. Additional factors were also assessed: cognitive function, nutritional status, comorbidity, oral intake level, occlusion status, physical function, and inflammatory status. Multivariable logistic regression analysis was conducted with the presence of sarcopenic dysphagia as a dependent variable. Lip force and tongue strength were assessed with the area under the receiver operating characteristic curve (AUC) to clarify diagnostic accuracy for sarcopenic dysphagia. In addition, the cut-off values of lip force and tongue strength for identifying sarcopenic dysphagia were determined according to sex. RESULTS: In total, 86 patients (35.1%) had sarcopenic dysphagia. Both men and women with sarcopenic dysphagia had lower lip force and tongue strength than men and women without dysphagia or sarcopenic dysphagia (p < 0.001 for all). In multivariable logistic regression analysis, sarcopenic dysphagia was significantly associated with lip force (OR = 0.63, 95% CI 0.53-0.74, p < 0.001) and tongue strength (OR = 0.92, 95% CI 0.87-0.98, p = 0.011). The AUCs for lip force in patients with sarcopenic dysphagia were 0.88 (CI 0.81-0.95, p < 0.001) for men and 0.84 (CI 0.77-0.90, p < 0.001) for women. The AUCs for tongue strength were 0.79 (CI 0.69-0.89, p < 0.001) for men and 0.74 (CI 0.65-0.82, p < 0.001) for women. The cut-off values for sarcopenic dysphagia in men were 10.4 N for lip force and 24.3 kPa for tongue strength; the cut-off values in women were 8.5 N for lip force and 23.9 kPa for tongue strength. CONCLUSION: In older inpatients who are suspected as having dysfunction due to sarcopenia, lip force and tongue strength can be independently useful indices for diagnosing sarcopenic dysphagia, and may be factors that prevent and improve sarcopenic dysphagia. PMID- 29398340 TI - The relationship between behavioral factors, weight status and a dietary pattern in primary school aged children: The GRECO study. AB - BACKGROUND & AIMS: Numerous factors have been associated with the increase in childhood overweight and obesity, including environmental, dietary and behavioral. The latter have been associated with unhealthy eating behaviors but studies of their relation to dietary patterns are limited. Dietary patterns serve as a better means to evaluate children's diet and risk of obesity and therefore the aim of the study was to examine the relationship of behavioral factors with a specific dietary pattern developed for children (child derived Food Index (cdFI)), and to assess how behavioral and diet are related to children's weight status when addressed together in a model. METHODS: Study included school-aged children (n = 4434) from the Greek Childhood Obesity study (GRECO), a cross sectional survey. Participants self-reported behavioral habits and dietary intake, using a semi-quantitative food-frequency questionnaire (FFQ). A high dietary pattern-cdFI is related to a healthier dietary pattern. Anthropometric data were measured. Multiple linear and logistic regressions were performed, adjusting for age and gender. RESULTS: The dietary pattern was positively associated with sleep, family meals and study hours, and was inversely associated with total screen time, frequency of eating out and eating while on some screen. Overweight and obese children were more likely to have a lower cdFI score (2%), sleep less (8%) and report more study hours (6%). CONCLUSION: In order to reduce and prevent child overweight and obesity, interventions probably need to address specific behavioral and dietary patterns together. PMID- 29398341 TI - Inflammation and nutritional status assessment by malnutrition inflammation score and its outcome in pre-dialysis chronic kidney disease patients. AB - BACKGROUND: Malnutrition-inflammation complex syndrome (MICS), hyperhomocysteinemia, calcium and phosphate levels derangement have been predicted as important contributing factors for the progression of cardiovascular burden. Among patients with earlier stage of CKD, hypoalbuminaemia and inflammation deliberated as non-traditional cardiovascular risk factors, which add more burden to circulatory disease, mortality and rapid advancement to CKD stage 5. AIM: The aim of the study is to evaluate inflammation and nutritional status of CKD patients not on dialysis using Malnutrition inflammation score (MIS) and to verify the association with mortality in the follow-up period. METHODS AND MATERIAL: In this prospective cohort study 129 (66 males, 63 females) pre-dialysis CKD patients enrolled between June 2013 to August 2014 and censored until March 2017. Malnutrition and Inflammation assessed using Malnutrition inflammation score. Blood urea nitrogen, serum creatinine, albumin, Interleukin - 6, highly sensitive C reactive protein (hsCRP), total cholesterol and anthropometric data were analyzed. RESULTS: The Malnutrition inflammation score in pre-dialysis CKD patients ranged from 0 to 18 with the median score of two. During 36 or more months of follow-up, there were 30 (23.2%) deaths, 35 (27%) patients initiated on hemodialysis, one (0.7%) patient was initiated on peritoneal dialysis, two (1.4%) patients underwent renal transplantation and two (1.4%) patients were lost for follow-up. In this study, 33% had varying degree of malnutrition and inflammation. Patients who had MIS >=7 had significant increase in IL-6 (p = 0.003) and HsCRP levels (p < 0.001) when compared with other tertiles of MIS. ROC curve analysis of MIS showed 56.5% sensitivity and 81% specificity in predicting death rate (AUC 0.709; 95% CI 0.604-0.815, p < 0.001). Kaplan-Meier survival analysis showed MIS >=7 had a strong association (log rank test, p < 0.001) with mortality during 36 and more months of follow-up time. In unadjusted analyses, MIS (HR 1.140; 95% CI 1.054-1.233; p < 0.05) and HsCRP (HR 2.369; 95% CI 1.779-3.154; p < 0.001) found to be predictors of mortality. MIS and HsCRP remained predictors of mortality even after adjustments. CONCLUSIONS: This study shows MIS is an important factor that determines mortality in pre dialysis CKD patients during 36 and more months of follow-up time. Patients with MIS >=7 have high risk for mortality and needs close monitoring. In clinical setting application of MIS has a greater utilization in pre-dialysis CKD patients. Further research with longitudinal assessment of MIS and its association with outcomes are warranted. Pre-dialysis CKD patients should be assessed for their nutritional status and inflammation using MIS regularly to prevent malnutrition and its associated complications through appropriate medical and nutritional intervention. PMID- 29398342 TI - Source of stem cells in haploidentical transplantation. PMID- 29398343 TI - Cancer diagnosis distress eased through online intervention. PMID- 29398344 TI - Distinct effect of fetal bovine serum versus follicular fluid on multipotentiality of human granulosa cells in in vitro condition. AB - This study aimed to develop an appropriate medium for preservation of multipotentiality in human granulosa cells. To compare the possible effect of different media supplemented with follicular fluid or fetal bovine serum, granulosa cells were cultured in vitro over a period of 14 days. Stemness feature and any alteration in the cell phenotype were monitored using colony count assay and flow cytometry analysis by monitoring the expression of Oct3/4 and GATA-4 factors. Transcript expression level of Sox-2, Klf-4, and Nanog were investigated using quantitative real-time PCR analysis. Cells were cultured in the medium supplement with follicular fluid showed normal cell morphology and epithelial like appearance, however, cells treated with fetal bovine serum, exhibited the clonogenic potential of granulosa cells which was increased after exposure to follicular fluid after 14 days (p < 0.05). Flow cytometry analysis revealed a significant reduction in the protein level of GATA-4 in cells cultured in presence of follicular fluid compared with cells received fetal bovine serum (p < 0.001). Quantitative real-time PCR analysis disclosed reduction of Sox-2, Klf-4 and Nanog levels in cells exposed to fetal bovine serum. Our experiment showed the exposure of human granulosa cells to follicular fluid efficiently preserves the stemness characteristics of the cells. PMID- 29398345 TI - Comparison of reverse-transcriptase qPCR and droplet digital PCR for the quantification of dengue virus nucleic acid. AB - Polymerase chain reaction (PCR) is an important molecular biology technique for in vitro amplification of nucleic acids. Reverse transcriptase quantitative PCR (RT-qPCR) and more recently reverse transcriptase digital droplet PCR (RT-ddPCR) have been developed for the quantification of nucleic acids. We developed an RT ddPCR assay for the quantification of attenuated dengue virus serotype 2 nucleic acid and compared it with a routine RT-qPCR assay. While the routine RT-qPCR assay targets the NS5 gene, the E gene was selected for the optimization of the RT-ddPCR assay conditions. The specificity of the assay was demonstrated using the attenuated dengue virus serotype 2 alone and in the presence of the other three dengue serotypes. The results from both assays for 25 samples of the attenuated dengue virus serotype 2 were found to be comparable, with an R2 from the linear regression analysis of >0.98. A major advantage of the RT-ddPCR assay is that it allows quantification of nucleic acid, without the need of a standard curve. RT-ddPCR can be implemented for the absolute quantification of dengue vaccine virus nucleic acid during the vaccine manufacturing process. PMID- 29398346 TI - Measuring Acute Pain Over Time in the Critically Ill Using the Multidimensional Objective Pain Assessment Tool (MOPAT). AB - BACKGROUND: A valid and reliable instrument is needed to assess acute pain in critically ill patients unable to self-report and who may be transitioning between critical care and other settings. AIM: To examine the reliability, validity, and clinical utility of the Multidimensional Objective Pain Assessment Tool (MOPAT) when used over time by critical care nurses to assess acute pain in non-communicative critically ill patients. METHODS: Twenty-seven patients had pain assessed at two time points (T1 and T2) surrounding a painful event for up to 3 days. Twenty-one ICU nurses participated in pain assessments and completed the Clinical Utility Questionnaire. RESULTS: Internal consistency reliability coefficient alphas for the MOPAT were .68 at T1 and .72 at T2. Inter-rater agreement during painful procedures or turning was 68% for the behavioral dimension and 80% for the physiologic dimension. Validity was evidenced by decreases (p < .001) in the MOPAT total and behavioral and physiologic dimension scores when comparing T1 and T2. Nurses found the tool clinically useful. CONCLUSION: The MOPAT can be used in the critical care setting as a helpful tool to assess pain in non-communicative patients. The MOPAT is unique in that the instrument can be used over time and across settings. PMID- 29398347 TI - EPC/HPSG evidence-based guidelines for the management of pediatric pancreatitis. AB - BACKGROUND: Pediatric pancreatitis is an underdiagnosed disease with variable etiology. In the past 10-15 years the incidence of pediatric pancreatitis has increased, it is now 3.6-13.3 cases per 100,000 children. Up-to-date evidence based management guidelines are lacking for the pediatric pancreatitis. The European Pancreatic Club, in collaboration with the Hungarian Pancreatic Study Group organized a consensus guideline meeting on the diagnosis and management of pancreatitis in the pediatric population. METHODS: Pediatric Pancreatitis was divided into three main clinical categories: acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis. Fifteen relevant topics (acute pancreatitis: diagnosis; etiology; prognosis; imaging; complications; therapy; biliary tract management; acute recurrent pancreatitis: diagnosis; chronic pancreatitis: diagnosis, etiology, treatment, imaging, intervention, pain, complications; enzyme replacement) were defined. Ten experts from the USA and Europe reviewed and summarized the available literature. Evidence was classified according to the GRADE classification system. RESULTS: Within fifteen topics, forty-seven relevant clinical questions were defined. The draft of the updated guideline was presented and discussed at the consensus meeting held during the 49th Meeting of European Pancreatic Club, in Budapest, on July 1, 2017. CONCLUSIONS: These evidence-based guidelines provides the current state of the art of the diagnosis and management of pediatric pancreatitis. PMID- 29398348 TI - Evolution of the vertebrate corneal stroma. AB - Although the cornea is the major refractive element of the eye, the mechanisms controlling corneal shape and hence visual acuity remain unknown. To begin to address this question we have used multiphoton, non-linear optical microscopy to image second harmonic generated signals (SHG) from collagen to characterize the evolutionary and structural changes that occur in the collagen architecture of the corneal stroma. Our studies show that there is a progression in complexity of the stromal collagen organization from lower (fish and amphibians) to higher (birds and mammals) vertebrates, leading to increasing tissue stiffness that may control shape. In boney and cartilaginous fish, the cornea is composed of orthogonally arranged, rotating collagen sheets that extend from limbus to limbus with little or no interaction between adjacent sheets, a structural paradigm analogous to 'plywood'. In amphibians and reptiles, these sheets are broken down into broader lamellae that begin to show branching and anastomosing with adjacent lamellae, albeit maintaining their orthogonal, rotational organization. This paradigm is most complex in birds, which show the highest degree of lamellar branching and anastomosing, forming a 'chicken wire' like pattern most prominent in the midstroma. Mammals, on the other hand, diverged from the orthogonal, rotational organization and developed a random lamellar pattern with branching and anastomosing appearing highest in the anterior stroma, associated with higher mechanical stiffness compared to the posterior stroma. PMID- 29398349 TI - Dynamics of energy reserves and the cost of reproduction in female and male fiddler crabs. AB - The physiological costs of reproduction can be measured as the energy allocated to reproductive activities. In fiddler crabs, females allocate energy to vitellogenesis and brooding, whereas males perform expensive courtship behaviors. We evaluated in a large-scale study the reproduction cost of females and males of Leptuca uruguayensis in a temperate estuary, where their reproductive efforts are synchronized in a short reproductive season. The reproductive investments (vitellogenesis, spermatophore production, and male reproductive behaviors) were measured and related to the dynamics of storage and expenditure of energy reserves (glycogen, total lipids, and total protein) in the hepatopancreas, ovary, and muscle of the enlarged cheliped, throughout one annual cycle. Maximum energy storage occurred in winter, a period of low activity, whereas minimum energy storage occurred during the reproductive period, characterized by expensive activities. The glycogen reserves of the hepatopancreas decreased about 66% in females and 61% in males, suggesting high and similar physiological costs of reproduction between sexes, despite their different reproductive strategies to maximize their fitness. PMID- 29398350 TI - Morphological and immunohistochemical reactions of the larval epidermis in the Italian newt (Lissotriton italicus) after exposure to low pH. AB - Mounting evidence suggests that amphibians are globally and currently the most threatened group of vertebrates and different causes might be responsible for this phenomenon. Acidification of water bodies is a global environmental issue that has been proposed as a possible cause for amphibian populations decline. Indeed, it has been widely demonstrated that low pH may exert harmful effects on amphibians, either directly or by increasing the adverse effects of other stressors. Surprisingly only few studies documented the response of amphibian integument to acidic pH conditions and no data are available on the effects of a non-lethal level of pH onto the amphibian larval epidermis. The present study showed that acidic pH (4.5) condition has severe effects on the epidermis of the Italian newt (Lissotriton italicus, formerly Triturus italicus) inducing both morphological and functional alterations. The increase of mucus is the first evident effect of acid injury, followed by the flattening of the epithelium and the appearance of a keratinized shedding layer. The immunolabeling of cytokeratins substantially changes acquiring an adult-like pattern. Also aquaporin 3 and iNOS expression modify their distribution according to a change of the histological features of the epidermis. These results clearly indicate that a short-term exposure to a sub-lethal pH disrupts the epidermis morphology and function in L. italicus larvae. Since the skin exerts a prominent role in both respiration and osmoregulation, the described alterations may adversely affect the overall ionic balance, with a long chain of cascading effects significantly decreasing newts survival probabilities when environmental pH lowering occurs. PMID- 29398351 TI - Assessing the Decision-Making Capacity of Terminally Ill Patients with Cancer. AB - OBJECTIVE: Despite the clinical, ethical, and legal magnitude of end-of-life decision-making, the capacity of terminally ill patients to make the medical decisions they often face is largely unknown. In practice, clinicians are responsible for determining when their patients are no longer competent to make treatment decisions, yet the accuracy of these assessments is unclear. The purpose of this study was to explore decision-making capacity and its assessment in terminally ill cancer patients. METHODS: Fifty-five patients with advanced cancer receiving inpatient palliative care and 50 healthy adults were administered the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) to evaluate decision-making capacity with regard to the four most commonly used legal standards: Choice, Understanding, Appreciation, and Reasoning. Participants made a hypothetical treatment decision about whether to accept artificial nutrition and hydration for treatment of cachexia. Participants' physicians independently rated their decision-making capacity. RESULTS: Terminally ill participants were significantly more impaired than healthy adults on all MacCAT-T subscales. Most terminally ill participants were able to express a treatment choice (85.7%), but impairment was common on the Understanding (44.2%), Appreciation (49.0%), and Reasoning (85.4%) subscales. Agreement between physician-rated capacity and performance on the MacCAT-T subscales was poor. CONCLUSIONS: The use of the MacCAT-T revealed high rates of decisional impairment in terminally ill participants. Participants' physicians infrequently detected impairment identified by the MacCAT-T. The findings from the present study reinforce the need for engagement in advance care planning for patients with advanced cancer. PMID- 29398352 TI - Advanced Dementia in Long-Term Care: Avoiding the Pitfalls of Fall Prevention. PMID- 29398353 TI - Psychosis in Neurodegeneration: Relating Phenomenology to Pathology and Prognosis. PMID- 29398354 TI - A Machine Learning Approach to Identifying Placebo Responders in Late-Life Depression Trials. AB - OBJECTIVE: Despite efforts to identify characteristics associated with medication placebo differences in antidepressant trials, few consistent findings have emerged to guide participant selection in drug development settings and differential therapeutics in clinical practice. Limitations in the methodologies used, particularly searching for a single moderator while treating all other variables as noise, may partially explain the failure to generate consistent results. The present study tested whether interactions between pretreatment patient characteristics, rather than a single-variable solution, may better predict who is most likely to benefit from placebo versus medication. METHODS: Data were analyzed from 174 patients aged 75 years and older with unipolar depression who were randomly assigned to citalopram or placebo. Model-based recursive partitioning analysis was conducted to identify the most robust significant moderators of placebo versus citalopram response. RESULTS: The greatest signal detection between medication and placebo in favor of medication was among patients with fewer years of education (<=12) who suffered from a longer duration of depression since their first episode (>3.47 years) (B = 2.53, t(32) = 3.01, p = 0.004). Compared with medication, placebo had the greatest response for those who were more educated (>12 years), to the point where placebo almost outperformed medication (B = -0.57, t(96) = -1.90, p = 0.06). CONCLUSION: Machine learning approaches capable of evaluating the contributions of multiple predictor variables may be a promising methodology for identifying placebo versus medication responders. Duration of depression and education should be considered in the efforts to modulate placebo magnitude in drug development settings and in clinical practice. PMID- 29398355 TI - Prefrontal-Periaqueductal Gray-Projecting Neurons Mediate Context Fear Discrimination. AB - Survival critically depends on selecting appropriate defensive or exploratory behaviors and is strongly influenced by the surrounding environment. Contextual discrimination is a fundamental process that is thought to depend on the prefrontal cortex to integrate sensory information from the environment and regulate adaptive responses to threat during uncertainty. However, the precise prefrontal circuits necessary for discriminating a previously threatening context from a neutral context remain unknown. Using a combination of single-unit recordings and optogenetic manipulations, we identified a neuronal subpopulation in the dorsal medial prefrontal cortex (dmPFC) that projects to the lateral and ventrolateral periaqueductal gray (l/vlPAG) and is selectively activated during contextual fear discrimination. Moreover, optogenetic activation and inhibition of this neuronal population promoted contextual fear discrimination and generalization, respectively. Our results identify a subpopulation of dmPFC l/vlPAG-projecting neurons that control switching between different emotional states during contextual discrimination. PMID- 29398356 TI - A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia. AB - Parkinson's disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity and dyskinesia, we combine optogenetics and a method to manipulate dyskinesia-associated neurons, targeted recombination in active populations (TRAP). We find that TRAPed cells are a stable subset of sensorimotor striatal neurons, predominantly from the direct pathway, and that reactivation of TRAPed striatal neurons causes dyskinesia in the absence of levodopa. Inhibition of TRAPed cells, but not a nonspecific subset of direct pathway neurons, ameliorates LID. These results establish that a distinct subset of striatal neurons is causally involved in LID and indicate that successful therapeutic strategies for treating LID may require targeting functionally selective neuronal subtypes. PMID- 29398357 TI - Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum. AB - Elimination of redundant synapses formed early in development and strengthening of necessary connections are crucial for shaping functional neural circuits. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs) with similar strengths. A single CF is strengthened whereas the other CFs are eliminated in each PC during postnatal development. The underlying mechanisms, particularly for the strengthening of single CFs, are poorly understood. Here we report that progranulin, a multi-functional growth factor implicated in the pathogenesis of frontotemporal dementia, strengthens developing CF synaptic inputs and counteracts their elimination from postnatal day 11 to 16. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination. We propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single "winner" CFs that survive synapse elimination. PMID- 29398358 TI - Motor Cortex Embeds Muscle-like Commands in an Untangled Population Response. AB - Primate motor cortex projects to spinal interneurons and motoneurons, suggesting that motor cortex activity may be dominated by muscle-like commands. Observations during reaching lend support to this view, but evidence remains ambiguous and much debated. To provide a different perspective, we employed a novel behavioral paradigm that facilitates comparison between time-evolving neural and muscle activity. We found that single motor cortex neurons displayed many muscle-like properties, but the structure of population activity was not muscle-like. Unlike muscle activity, neural activity was structured to avoid "tangling": moments where similar activity patterns led to dissimilar future patterns. Avoidance of tangling was present across tasks and species. Network models revealed a potential reason for this consistent feature: low tangling confers noise robustness. Finally, we were able to predict motor cortex activity from muscle activity by leveraging the hypothesis that muscle-like commands are embedded in additional structure that yields low tangling. PMID- 29398360 TI - Working Memory Enhances Cortical Representations via Spatially Specific Coordination of Spike Times. AB - The online maintenance and manipulation of information in working memory (WM) is essential for guiding behavior based on our goals. Understanding how WM alters sensory processing in pursuit of different behavioral objectives is therefore crucial to establish the neural basis of our goal-directed behavior. Here we show that, in the middle temporal (MT) area of rhesus monkeys, the power of the local field potentials in the alphabeta band (8-25 Hz) increases, reflecting the remembered location and the animal's performance. Moreover, the content of WM determines how coherently MT sites oscillate and how synchronized spikes are relative to these oscillations. These changes in spike timing are not only sufficient to carry sensory and memory information, they can also account for WM induced sensory enhancement. These results provide a mechanistic-level understanding of how WM alters sensory processing by coordinating the timing of spikes across the neuronal population, enhancing the sensory representation of WM targets. PMID- 29398361 TI - Hypothalamic Circuits for Predation and Evasion. AB - The interactions between predator and prey represent some of the most dramatic events in nature and constitute a matter of life and death for both sides. The hypothalamus has been implicated in driving predation and evasion; however, the exact hypothalamic neural circuits underlying these behaviors remain poorly defined. Here, we demonstrate that inhibitory and excitatory projections from the mouse lateral hypothalamus (LH) to the periaqueductal gray (PAG) in the midbrain drive, respectively, predation and evasion. LH GABA neurons were activated during predation. Optogenetically stimulating PAG-projecting LH GABA neurons drove strong predatory attack, and inhibiting these cells reversibly blocked predation. In contrast, LH glutamate neurons were activated during evasion. Stimulating PAG projecting LH glutamate neurons drove evasion and inhibiting them impeded predictive evasion. Therefore, the seemingly opposite behaviors of predation and evasion are tightly regulated by two dissociable modular command systems within a single neural projection from the LH to the PAG. VIDEO ABSTRACT. PMID- 29398359 TI - Ultra-Slow Single-Vessel BOLD and CBV-Based fMRI Spatiotemporal Dynamics and Their Correlation with Neuronal Intracellular Calcium Signals. AB - Functional MRI has been used to map brain activity and functional connectivity based on the strength and temporal coherence of neurovascular-coupled hemodynamic signals. Here, single-vessel fMRI reveals vessel-specific correlation patterns in both rodents and humans. In anesthetized rats, fluctuations in the vessel specific fMRI signal are correlated with the intracellular calcium signal measured in neighboring neurons. Further, the blood-oxygen-level-dependent (BOLD) signal from individual venules and the cerebral-blood-volume signal from individual arterioles show correlations at ultra-slow (<0.1 Hz), anesthetic modulated rhythms. These data support a model that links neuronal activity to intrinsic oscillations in the cerebral vasculature, with a spatial correlation length of ~2 mm for arterioles. In complementary data from awake human subjects, the BOLD signal is spatially correlated among sulcus veins and specified intracortical veins of the visual cortex at similar ultra-slow rhythms. These data support the use of fMRI to resolve functional connectivity at the level of single vessels. PMID- 29398362 TI - Small Networks Encode Decision-Making in Primary Auditory Cortex. AB - Sensory detection tasks enhance representations of behaviorally meaningful stimuli in primary auditory cortex (A1). However, it remains unclear how A1 encodes decision-making. Neurons in A1 layer 2/3 (L2/3) show heterogeneous stimulus selectivity and complex anatomical connectivity, and receive input from prefrontal cortex. Thus, task-related modulation of activity in A1 L2/3 might differ across subpopulations. To study the neural coding of decision-making, we used two-photon imaging in A1 L2/3 of mice performing a tone-detection task. Neural responses to targets showed attentional gain and encoded behavioral choice. To characterize network representation of behavioral choice, we analyzed functional connectivity using Granger causality, pairwise noise correlations, and neural decoding. During task performance, small groups of four to five neurons became sparsely linked, locally clustered, and rostro-caudally oriented, while noise correlations both increased and decreased. Our results suggest that sensory based decision-making involves small neural networks driven by the sum of sensory input, attentional gain, and behavioral choice. PMID- 29398363 TI - Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. AB - Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer's disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer's disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau. PMID- 29398364 TI - Graded Arrays of Spinal and Supraspinal V2a Interneuron Subtypes Underlie Forelimb and Hindlimb Motor Control. AB - The spinal cord contains neural networks that enable regionally distinct motor outputs along the body axis. Nevertheless, it remains unclear how segment specific motor computations are processed because the cardinal interneuron classes that control motor neurons appear uniform at each level of the spinal cord. V2a interneurons are essential to both forelimb and hindlimb movements, and here we identify two major types that emerge during development: type I neurons marked by high Chx10 form recurrent networks with neighboring spinal neurons and type II neurons that downregulate Chx10 and project to supraspinal structures. Types I and II V2a interneurons are arrayed in counter-gradients, and this network activates different patterns of motor output at cervical and lumbar levels. Single-cell RNA sequencing (RNA-seq) revealed type I and II V2a neurons are each comprised of multiple subtypes. Our findings uncover a molecular and anatomical organization of V2a interneurons reminiscent of the orderly way motor neurons are divided into columns and pools. PMID- 29398365 TI - The Basal Forebrain Regulates Global Resting-State fMRI Fluctuations. AB - Patterns of spontaneous brain activity, typically measured in humans at rest with fMRI, are used routinely to assess the brain's functional organization. The mechanisms that generate and coordinate the underlying neural fluctuations are largely unknown. Here we investigate the hypothesis that the nucleus basalis of Meynert (NBM), the principal source of widespread cholinergic and GABAergic projections to the cortex, contributes critically to such activity. We reversibly inactivated two distinct sites of the NBM in macaques while measuring fMRI activity across the brain. We found that inactivation led to strong, regionalized suppression of shared or "global" signal components of cortical fluctuations ipsilateral to the injection. At the same time, the commonly studied resting state networks retained their spatial structure under this suppression. The results indicate that the NBM contributes selectively to the global component of functional connectivity but plays little if any role in the specific correlations that define resting-state networks. PMID- 29398366 TI - Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly. AB - Neuronal maturation requires dramatic morphological and functional changes, but the molecular mechanisms governing this process are not well understood. Here, we studied the role of Rbfox1, Rbfox2, and Rbfox3 proteins, a family of tissue specific splicing regulators mutated in multiple neurodevelopmental disorders. We generated Rbfox triple knockout (tKO) ventral spinal neurons to define a comprehensive network of alternative exons under Rbfox regulation and to investigate their functional importance in the developing neurons. Rbfox tKO neurons exhibit defects in alternative splicing of many cytoskeletal, membrane, and synaptic proteins, and display immature electrophysiological activity. The axon initial segment (AIS), a subcellular structure important for action potential initiation, is diminished upon Rbfox depletion. We identified an Rbfox regulated splicing switch in ankyrin G, the AIS "interaction hub" protein, that regulates ankyrin G-beta spectrin affinity and AIS assembly. Our data show that the Rbfox-regulated splicing program plays a crucial role in structural and functional maturation of postmitotic neurons. PMID- 29398367 TI - Linking diabetic vascular complications with LncRNAs. AB - Diabetes leads to markedly accelerated rates of many associated macrovascular complications like hypertension and atherosclerosis, and microvascular complications like nephropathy and retinopathy. High glucose, the hallmark of diabetes, drives changes in vascular and inflammatory cells that promote the development of these complications. Understanding the molecular processes involved in the development of diabetes and its debilitating complications can lead to much needed newer clinical therapies. Recently, long-noncoding RNAs (lncRNAs) have been shown to be important in the biology of vascular cells and there is growing evidence that lncRNAs are also involved in the cell biology relevant to diabetic vascular complications. In this review, we provide an overview of lncRNAs that function in vascular cells, and those that have been linked to diabetic complications. PMID- 29398369 TI - Transient Relative Age Effects across annual age groups in National level Australian Swimming. AB - OBJECTIVES: To determine the prevalence, magnitude and transient patterning of Relative Age Effects (RAEs) according to sex and stroke event across all age groups at the Australian National age swimming Championships. DESIGN: Repeated years of cross-sectional participation data were examined. METHODS: Participants were 6014 unique male (3185) and female (2829) swimmers (aged 12-18 years) who participated in Freestyle (50, 400m) and/or Breaststroke (100, 200m) at the National age swimming Championships between 2000-2014 (inclusive). RAE prevalence, magnitude and transience were determined using Chi-square tests and Cramer's V estimates for effect size. Odds Ratios (OR) and 95% Confidence Intervals (CI) examined relative age quartile discrepancies. These steps were applied across age-groups and according to sex and each stroke event. RESULTS: Consistent RAEs with large-medium effect sizes were evident for males at 12-15 years of age respectively, and with large-medium effects for females at 12-14 respectively across all four swimming strokes. RAE magnitude then consistently reduced with age across strokes (e.g., Q1 vs. Q4 OR range 16year old males=0.94 1.20; females=0.68-1.41). With few exceptions, by 15-16 years RAEs had typically dissipated; and by 17-18 years, descriptive and significant inverse RAEs emerged, reflecting overrepresentation of relatively younger swimmers. CONCLUSIONS: Performance advantages associated with relative age (and thereby likely growth and maturation) are transient. Greater consideration of transient performance and participation in athlete development systems is necessary. This may include revising the emphasis of sport programmes according to developmental stages and delaying forms of athlete selection to improve validity. PMID- 29398368 TI - Inhibition of miR-29b suppresses MAPK signaling pathway through targeting SPRY1 in atherosclerosis. AB - The treatment of atherosclerosis (AS), a severe condition associated with the pathogenesis of cardiovascular diseases (CVDs), is still not satisfactory worldwide. In this study, we aim to investigate whether protein sprout homologue 1 (SPRY1), a upstream mediator of MAPK signal pathway, is the target of miR-29b in vascular endothelium during the development of AS. ApoE-/- mice model was established, and an inverse correlation was noticed between level of miR-29b and SPRY1 expression in the aortic tissues. Meanwhile, the tumor necrosis factor alpha (TNF-alpha), reactive oxygen species (ROS) expression and NADPH oxidase activity were up-regulated in atherosclerotic tissues. In vitro experiments were carried out to investigate the roles of miR-29b in regulating the expression of SPRY1 in cultured human umbilical vein endothelial cells (HUVECs). We found that miR-29b mimic and antagomir could modulate the expression of SPRY1 protein in cultured HUVECs. However, the expression of SPRY1 mRNA showed no statistical difference when treating with miR-29b mimic or antagomir. These indicated that the modulation of SPRY1 induced by miR-29b was at the posttranslational level. Dural luciferase reporter assay was conducted to detect the potential interaction between miR-29b and the 3'UTR of SPRY1, which indicated that SPRY1 was a target of miR-29b. Besides, miR-29b antagomir induced decrease of TNF-alpha, ROS production and NADPH oxidase activity and down-regulated the expression of p-ERK and p-p38 in the presence of oxLDL. In conclusion, inhibition of miR-29b could attenuate AS by inhibiting the SPRY1/MAPK signaling pathway and inflammation in aorta. In future, treatment options based on miR-29b may be applicable for the treatment of AS. PMID- 29398370 TI - Depot-specific and GH-dependent regulation of IGF binding protein-4, pregnancy associated plasma protein-A, and stanniocalcin-2 in murine adipose tissue. AB - INTRODUCTION: Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin like growth factor (IGF)-I action through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. Most members of the IGF system are expressed in adipose tissue (AT), but there is a relative paucity of information on the distribution of IGFBP-4, PAPP-A, and STC2 in different AT depots. Since IGF-I expression in AT is highly GH-dependent, we used bovine GH transgenic (bGH) and GH receptor knockout (GHR-/-) mice to investigate AT depot-specific expression patterns of IGFBP-4, PAPP-A, and STC2, and whether the regulation is GH-dependent. METHODS: Seven-month-old male bGH, GHR-/- and wild type (WT) control mice were used. Body composition was determined, and subcutaneous, epididymal, retroperitoneal, mesenteric and brown adipose tissue (BAT) depots were collected. RNA expression of Igfbp4, Pappa, and Stc2 was assessed by reverse transcription quantitative PCR and IGFBP-4 protein by Western blotting. RESULTS: Igfbp4, Pappa, and Stc2 RNA levels were differentially expressed in an AT depot-dependent manner in WT mice. Igfbp4 RNA levels were significantly higher in all white AT depots than in BAT. Pappa was most highly expressed in the mesenteric depot: levels were 7.5-fold higher in mesenteric than in subcutaneous AT (p < .001). Although intraabdominal in origin, epididymal and retroperitoneal Pappa expression levels were 69% and 68% lower, respectively, as compared to mesenteric levels (p < .001). Stc2 RNA expression was significantly higher in all intraabdominal white AT as compared to subcutaneous AT and BAT; levels in epididymal, retroperitoneal, and mesenteric were all more than three-fold higher than in subcutaneous AT (p < .001) and 12 fold higher than in BAT (p < .001). Gene expression patterns in bGH and GHR-/- mice mimicked those in WT mice, suggesting that GH does not affect the transcription of the STC2-PAPP-A-IGFBP-4-axis in AT. However, proteins levels of intact IGFBP-4 were significantly increased in bGH mice and decreased in GHR-/- mice, whereas the PAPP-A-generated IGFBP-4 fragment level was unaltered. CONCLUSION: Expression of Igfbp4, Pappa, and Stc2 differ between AT depots and is generally higher in white AT than in BAT. The transcription appears to occur in a GH-independent manner, whereas IGFBP-4 protein levels are highly influenced by altered GH activity. PMID- 29398372 TI - Cardiac Surgery and the Low Hanging Fruit of Perioperative Nutritional Interventions. PMID- 29398371 TI - GH directly stimulates UCP3 expression. AB - OBJECTIVE: We evaluated the direct action of GH signaling in energy homeostasis in myocytes. DESIGN: We investigated the GH-induced expression of UCP3 in human embryonic kidney 293 cells, human H-EMC-SS chondrosarcoma cells, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal muscle cells, as well as its direct effect on the GHR/JAK/STAT5 pathway using a combination of a reporter assay, real-time quantitative polymerase chain reaction, and western blotting. RESULTS: We demonstrated that the regulation of energy metabolism by GH involves UCP3 via activated STAT5, a signal transducer downstream of GH. UCP3 expression increased with STAT5 in a dose-dependent manner and was higher than that of UCP2. We confirmed the functional STAT5 binding site consensus sequences at -861 and 507 bp in the UCP3 promoter region. CONCLUSION: The results suggest that GH stimulates UCP3 directly and that UCP2 and that UCP3 participate in the signal transduction pathway that functions downstream of the GHR/JAK/STAT. PMID- 29398373 TI - History of Cardiac Anesthesia in India. AB - Before the 19th century, the heart was considered as a "no-go" area, although minor and superficial procedures were performed in the early 1800s. It was only in the later part of the century that surgical repair of the wounds of the cardiac chambers was attempted. Cardiac surgery came to India in the mid-20th century and the operations performed were minor and extracardiac. Initially, the surgeries were performed at a select few centers located at Mumbai, Vellore, Delhi, Chennai, and Kolkata. The anesthesiologists of an earlier era in India worked with limited facilities, and with their interest and devotion contributed immensely to the growth of the specialty of cardiac anesthesia. The progress was somewhat modest until the 1980s, when it started increasing rapidly and India caught up with the Western world by the turn of century. The progress was seen not only in the clinical field, but also in technology, teaching, and academic fields. This article presents an account of the progress in the field of cardiac anesthesia in India, and highlights the contribution of some of the dedicated anesthesiologists because of whom the specialty has reached the present stature. PMID- 29398374 TI - Association Between Optic Nerve Head Blood Flow Measured Using Laser Speckle Flowgraphy and Radial Arterial Pressure During Aortic Arch Surgery. AB - OBJECTIVE: This study was designed to investigate the association between ocular blood flow measured using laser speckle flowgraphy (LSFG) and radial arterial pressure during aortic arch surgery. DESIGN: A prospective study. SETTING: A single university hospital. PARTICIPANTS: This study included 24 patients undergoing aortic arch surgery with cardiopulmonary bypass (CPB) using antegrade selective cerebral perfusion (SCP). INTERVENTIONS: Measurement of optic nerve head blood flow using LSFG and radial arterial pressure via a catheter in the radial artery METHODS AND MAIN RESULTS: Antegrade SCP was managed with 24C and 40 to-60 mmHg at the right radial artery, which usually corresponds to a flow rate of 10 mL/kg/min. Optic nerve head blood flow using LSFG and radial arterial blood pressure were evaluated simultaneously at the right side and recorded at the following 4 points: after the induction of anesthesia (phase 1), after the beginning of CPB (phase 2), after the beginning of antegrade SCP (phase 3), and after cessation of CPB (phase 4). A moderate positive correlation between %change of mean blur rate in the optic nerve head measured using LSFG and %change of radial mean arterial pressure was identified (r = 0.604, p < 0.001). Bland-Altman analysis showed that the bias (mean difference) was -1.2% (95% limits of agreement -47.4% to 45.0%), indicating good agreement between %changes of the values recorded using the 2 measurements. CONCLUSIONS: Intraoperative monitoring of optic nerve head blood flow using LSFG can be used as an additional cerebral perfusion parameter during aortic arch surgery with CPB using antegrade SCP. PMID- 29398375 TI - Anesthetic Preconditioning: Have We Found the Holy Grail of Perioperative Cardioprotection? PMID- 29398376 TI - Biventricular Epicardial Pacing: Is this Pacing Strategy Really Useful in High risk Patients Undergoing Cardiac Surgery? PMID- 29398377 TI - Hemodynamic Management in Aortic Root Replacement in a Patient With Coarctation of the Aorta. PMID- 29398378 TI - Systolic Anterior Motion of the Mitral Valve During Pulmonary Endarterectomy in a Patient with Chronic Thromboembolic Pulmonary Hypertension. PMID- 29398379 TI - The Discovery of Myocardial Preconditioning Using Volatile Anesthetics: A History and Contemporary Clinical Perspective. PMID- 29398380 TI - A Retrospective Analysis of the Variability in Case Duration for Aortic Valve Replacement and Association With Hospital Facility Types. AB - OBJECTIVE: Currently, there are no large-scale studies that compare differences in case duration of aortic valve replacements (AVRs). The primary objective of this study was to determine associations of hospital facility type, geographic location, case volume per year, and time of day with duration of valve replacement surgery. DESIGN: Retrospective. SETTING: Data from the National Anesthesia Clinical Outcomes Registry. PARTICIPANTS: National data from university and non-university hospitals. INTERVENTIONS: No interventions. MEASUREMENTS AND MAIN RESULTS: All AVRs from the National Anesthesia Clinical Outcomes Registry were identified from 2010 to 2014. Mean case duration for all AVRs was 360.8 +/- 95.8 minutes and was presented based on facility type (university hospital, large community hospital, medium-sized community hospital, and other); US geographic region; time of day (cases performed after 5 pm and before 7 am v day shift); and case volume per year. A multivariable linear regression model was built to determine the association of various patient, procedural, and facility characteristics with case duration. University hospitals were associated with increased case duration for AVRs (p < 0.0001). CONCLUSIONS: With this large national database, the authors demonstrated that academic hospitals, time of day of the surgery, US region, and case volume per year for a facility are related to the case duration of AVRs. PMID- 29398381 TI - Dual-antiplatelet Therapy Guidelines and Implications for Perioperative Management. PMID- 29398382 TI - Serratus Anterior Plane Block for Apical TAVR in an Awake Patient. PMID- 29398383 TI - Seizures After Adult Cardiac Surgery and Interventional Cardiac Procedures. AB - The aim of this narrative review is to evaluate the incidence of seizures after adult cardiac surgery or cardiac interventions, to describe risk factors, and to provide suggestions regarding diagnostic measures and proper management. Based on published peer-reviewed articles, the authors demonstrate specific procedure related risks for seizures. Early diagnosis, the identification of underlying causes, and avoidance of amenable risk factors are crucial to reduce associated long-term morbidity and mortality. Methods of early recognition of seizures, particularly focusing on the initiation of appropriate diagnostic measures, their management, and their timely treatment, are presented in the article. PMID- 29398384 TI - Ultra-Short-Acting beta-Blockers (Esmolol and Landiolol) in the Perioperative Period and in Critically Ill Patients. AB - beta-Blockers are useful drugs in several clinical cardiologic scenarios. Their use in the perioperative period and in critically ill patients is increasing, but their effect on clinically relevant outcomes remains controversial. Long-acting beta-blockers can have detrimental effects that are difficult to be counteracted in these settings. The authors describe the possible clinical uses of ultra-short acting beta-blockers (esmolol and landiolol) in the perioperative period and in critically ill patients because these drugs have the beneficial effects of beta blockers, but do not have the detrimental effects of long-acting agents. This narrative review focuses on ultra-short-acting beta-blockers in the following clinical settings: prevention and treatment of arrhythmias and myocardial ischemia in noncardiac and cardiac surgery, usage as cardioplegia adjuvants or to test the reversibility of systolic anterior motion of the mitral valve in cardiac surgery, medical treatment of aortic dissection before surgery, improvement of microcirculation and oxygenation in critically ill patients experiencing sepsis or undergoing extracorporeal membrane oxygenation, anesthesia induction, and coronary computed tomography angiography. PMID- 29398385 TI - Right Atrial Myxoma with Pulmonary Artery Hypertension: Role of Transesophageal Echocardiography in Detection of Cause and Perioperative Management. PMID- 29398386 TI - Embolization Using N-butyl Cyanoacrylate for Postoperative Lymphatic Leakage: A Case Report. PMID- 29398387 TI - Asymptomatic low-density malaria infections: a parasite survival strategy? PMID- 29398389 TI - Multidrug-resistant Plasmodium falciparum malaria in the Greater Mekong subregion. PMID- 29398388 TI - The persistence and oscillations of submicroscopic Plasmodium falciparum and Plasmodium vivax infections over time in Vietnam: an open cohort study. AB - BACKGROUND: A substantial proportion of Plasmodium species infections are asymptomatic with densities too low to be detectable with standard diagnostic techniques. The importance of such asymptomatic plasmodium infections in malaria transmission is probably related to their duration and density. To explore the duration of asymptomatic plasmodium infections and changes in parasite densities over time, a cohort of participants who were infected with Plasmodium parasites was observed over a 2-year follow-up period. METHODS: In this open cohort study, inhabitants of four villages in Vietnam were invited to participate in baseline and subsequent 3-monthly surveys up to 24 months, which included the collection of venous blood samples. Samples were batch-screened using ultra-sensitive (u)PCR (lower limit of detection of 22 parasites per mL). Participants found to be infected by uPCR during any of these surveys were invited to join a prospective cohort and provide monthly blood samples. We estimated the persistence of Plasmodium falciparum and Plasmodium vivax infections and changes in parasite densities over a study period of 24 months. FINDINGS: Between Dec 1, 2013, and Jan 8, 2016, 356 villagers participated in between one and 22 surveys. These study participants underwent 4248 uPCR evaluations (11.9 tests per participant). 1874 (32%) of 4248 uPCR tests indicated a plasmodium infection; 679 (36%) of 1874 tests were P falciparum monoinfections, 507 (27%) were P vivax monoinfections, 463 (25%) were co-infections with P falciparum and P vivax, and 225 (12%) were indeterminate species of Plasmodium. The median duration of P falciparum infection was 2 months (IQR 1-3); after accounting for censoring, participants had a 20% chance of having parasitaemia for 4 months or longer. The median duration of P vivax infection was 6 months (3-9), and participants had a 59% chance of having parasitaemia for 4 months or longer. The parasite densities of persistent infections oscillated; following ultralow-density infections, high density infections developed frequently. INTERPRETATION: Persistent largely asymptomatic P vivax and P falciparum infections are common in this area of low seasonal malaria transmission. Infections with low-density parasitaemias can develop into much higher density infections at a later time, which are likely to sustain malaria endemicity. FUNDING: The Wellcome Trust, Bill & Melinda Gates Foundation. PMID- 29398390 TI - Could omics unlock the secret of surviving tuberculous meningitis? PMID- 29398392 TI - Corrections. PMID- 29398391 TI - Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. AB - BACKGROUND: Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. METHODS: We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus. FINDINGS: We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. INTERPRETATION: The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. PMID- 29398393 TI - Utilisation of the snare technique for left ventricular lead placement in a patient with persistent left superior vena cava. AB - Persistence of the left superior vena cava occurs in about 0.3-0.7% of the general population. It is of particular importance in patients who need cardiac resynchronisation therapy. We present a unique case in which a snare system and tunnelling tool were used to place the left ventricular lead in a patient with persistence of the left superior vena cava. PMID- 29398394 TI - Outcomes of an anatomic total shoulder arthroplasty with a contralateral reverse total shoulder arthroplasty. AB - BACKGROUND: It is common for patients to require staged bilateral shoulder arthroplasties. There is a unique cohort of patients who require an anatomic total shoulder arthroplasty (TSA) and a contralateral reverse shoulder arthroplasty (RSA). This study compared the outcomes of patients with a TSA in 1 shoulder and an RSA in the contralateral shoulder. METHODS: Our institutional database was queried to identify all patients with a TSA and a contralateral RSA. Data collection included patient demographics, preoperative and latest follow-up shoulder range of motion, radiographic analysis, and postoperative complications. Identified patients were assessed at follow-up visits or contacted by phone for functional outcome scores. RESULTS: Nineteen patients met our inclusion/exclusion criteria. There was statistically significant greater internal rotation in the TSA shoulder (P= .044) but no significant difference in forward elevation (P = .573) or external rotation (P= .368). There was no radiographic evidence of humeral or glenoid component loosening of any arthroplasty implants. There were no significant differences between TSA and RSA shoulders for the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment (P= .381), Simple Shoulder Test (P = .352), Single Assessment Numerical Evaluation (P = .709), and visual analog scale satisfaction (P= .448) or pain scores (P= .305). Thirteen patients (68.4%) preferred the RSA side, 1 patient (5.3%; z = 4.04, P < .001) patient preferred the TSA side, and 5 patients expressed no preference. CONCLUSION: Despite known limitations and differences between TSA and RSA designs, patients who have received both implants are highly satisfied with both. The only parameter in which the TSA had superior outcomes was internal rotation. PMID- 29398395 TI - Quantifying success after total shoulder arthroplasty: the substantial clinical benefit. AB - BACKGROUND: An understanding of the substantial clinical benefit (SCB) after total shoulder arthroplasty (TSA) may help to gauge a minimum threshold beyond which a patient perceives his or her outcome as being substantially better. This study quantifies SCB for 7 outcome metrics and active motion measurements after shoulder arthroplasty and determines how these values vary based on prosthesis type, patient age at surgery, sex, and length of follow-up. METHODS: A total of 1,568 shoulder arthroplasties with 2-year minimum follow-up were performed by 13 shoulder surgeons and enrolled in a multicenter registry. The SCB for the American Shoulder and Elbow Surgeons Shoulder Assessment, Constant Score, University of California Los Angeles Shoulder Rating Scale, Simple Shoulder Test, Shoulder Pain and Disability Index, global shoulder function, and visual analog scale pain scores, as well as active abduction, flexion, and external rotation were calculated for different patient cohorts using an anchor-based method. RESULTS: The anchor-based SCB results were American Shoulder and Elbow Surgeons score, 31.5 +/- 2.0; Constant Score, 19.1 +/- 1.7; University of California Los Angeles Shoulder Rating Scale score, 12.6 +/- 0.5; Simple Shoulder Test score, 3.4 +/- 0.3; Shoulder Pain and Disability Index score, 45.4 +/- 2.2; global shoulder function, 3.1 +/- 0.2; visual analog scale, 3.2 +/- 0.3; active abduction, 28.5 degrees +/- 3.1 degrees ; active forward flexion, 35.4 degrees +/- 3.5 degrees ; and active external rotation, 11.7 degrees +/- 1.9 degrees . Anatomic TSA patients, male patients, and patients of longer follow-up duration were associated with higher SCB values than female patients, reverse TSA patients, and patients of shorter follow-up duration. CONCLUSION: Our analysis demonstrated two-thirds of patients achieved the SCB threshold after TSA. Generally, a change of 30% of the total possible score for each outcome metric approximates or exceeds this SCB threshold. PMID- 29398396 TI - Radiocapitellar prosthetic arthroplasty: short-term to midterm results of 19 elbows. AB - BACKGROUND: Few studies have discussed the short-term results of radiocapitellar (RC) prosthetic arthroplasty (PA). In this study, we assessed the short-term to midterm functional and radiographic results of elbows after RC PA. Our secondary aim was to assess the survival of the RC PA. METHODS: We included 19 elbows in 18 patients with a mean follow-up of 35 months (range, 12-88 months). Patients were examined for instability and range of motion and were assessed using Mayo Elbow Performance Index and Oxford Elbow Score at any subsequent visits. RC PA was the primary treatment in 16 elbows, and 3 were revision radial head arthroplasty with concomitant capitellar resurfacing. RESULTS: Range of motion, pain, and functional scores improved significantly from the preoperative to the final follow-up visit. Categoric grouping of the final Mayo Elbow Performance Index outcome scores showed 9 excellent, 5 good, 3 fair, 0 poor, and 2 missing data. However, stability of the elbow remained unchanged. There was no pain in 11 patients, mild pain in 5, and moderate pain in 3. Radiographic assessment showed no significant progress in ulnohumeral arthritis, although 3 elbows showed osteoarthritis progression to a higher grade. There were no major complications, including infection, revision, disassembly of the components, or conversion to total elbow arthroplasty. Survival of the RC PA was 100%. CONCLUSION: Elbow arthritis seems to become stationary after RC PA. Symptomatic RC osteoarthritis would probably benefit from RC PA regardless of the etiology. PMID- 29398397 TI - Latissimus dorsi transfer for irreparable subscapularis tendon tears. AB - BACKGROUND: There are several tendon transfers for reconstruction of irreparable subscapularis tears. The latissimus dorsi (LD) could be used because its direction and function are similar to those of the subscapularis. We performed LD transfers for irreparable subscapularis tears and evaluated clinical outcomes. METHODS: The study enrolled 24 consecutive patients who underwent LD transfers. Clinical and functional outcomes were evaluated using the Constant score, American Shoulder and Elbow Surgeons score, pain visual analog scale, and range of shoulder motion preoperatively and at last follow-up. The lift-off and belly press tests were performed to assess subscapularis integrity and function. Magnetic resonance imaging was performed preoperatively and 1 year postoperatively to evaluate tendon integrity. RESULTS: Mean Constant, American Shoulder and Elbow Surgeons, and pain scores improved from 46 +/- 6 to 69 +/- 5 (P < .001), from 40 +/- 3 to 70 +/- 5 (P < .001), and from 6 +/- 1 to 2 +/- 1 (P = .006), respectively. The mean range of motion for forward elevation and internal rotation increased from 135 degrees +/- 17 degrees to 166 degrees +/- 15 degrees (P = .016) and from L5 to L1 (P = .010), respectively. Improvement in the range of motion for external rotation was not significant (51 degrees +/- 7 degrees to 68 degrees +/- 7 degrees ; P = .062). At final follow-up, the belly press test results were negative for 18 of 24 patients, and the lift-off test results were negative for 16 of 20 patients. No complications related to tendon transfer, including axillary and radial nerve injuries, were found. No retearing of the transferred LD was observed. CONCLUSIONS: LD transfer resulted in pain relief and restoration of shoulder range of motion and function. LD transfer could be considered an effective and safe salvage treatment for irreparable subscapularis tears. PMID- 29398398 TI - Recurrent rotator cuff tear: is ultrasound imaging reliable? AB - BACKGROUND AND HYPOTHESIS: The diagnostic workup of the painful shoulder after rotator cuff repair (RCR) can be quite challenging. The aim of this study was to assess the reliability of ultrasonography (US) for the detection of recurrent rotator cuff tears in patients with shoulder pain after RCR. We hypothesized that US for the diagnosis of recurrent rotator cuff tear after RCR would not prove to be reliable when compared with surgical arthroscopic confirmation (gold standard). METHODS: In this cohort study (diagnosis), we retrospectively analyzed the data of 39 patients with shoulder pain after arthroscopic RCR who had subsequently undergone US, followed by revision arthroscopy. The rotator cuff was evaluated first using US for the presence of retears. Thereafter, revision arthroscopy was performed, and the diagnosis was either established or disproved. The sensitivity and specificity of US were assessed in reference to revision arthroscopy (gold standard). RESULTS: A rotator cuff retear was indicated by US in 21 patients (54%) and by revision arthroscopy in 26 patients (67%). US showed a sensitivity of 80.8% and specificity of 100% in the diagnosis of rotator cuff retears. Omission of partial rotator cuff retears resulted in a spike in sensitivity to 94.7%, with 100% specificity remaining. CONCLUSION: US imaging is a highly sensitive and specific test for the detection of recurrent rotator cuff tears, as confirmed by revision arthroscopy, in patients with a painful shoulder after primary RCR. PMID- 29398399 TI - Augmentation with a reinforced acellular fascia lata strip graft limits cyclic gapping of supraspinatus repairs in a human cadaveric model. AB - BACKGROUND: A reinforced biologic strip graft was designed to mechanically augment the repair of rotator cuff tears that are fully reparable by arthroscopic techniques yet have a likelihood of failure. This study assessed the extent to which augmentation of human supraspinatus repairs with a reinforced fascia strip can reduce gap formation during in vitro cyclic loading. METHODS: The supraspinatus tendon was sharply released from the proximal humerus and repaired back to its insertion with anchors in 9 matched pairs of human cadaveric shoulders. One repair from each pair was also augmented with a reinforced fascia strip. All repairs were subjected to cyclic mechanical loading of 5 to 180 N for 1000 cycles. RESULTS: All augmented and nonaugmented repair constructs completed 1000 cycles of loading. Augmentation with a reinforced fascia strip graft significantly decreased the amount of gap formation compared with nonaugmented repairs. The average gap formation of augmented repairs was 1.5 +/- 0.7 mm after the first cycle vs. 3.0 +/- 1.2 mm for nonaugmented repairs (P = .003) and 5.0 +/ 1.5 mm after 1000 cycles of loading, which averaged 24% +/- 21% less than the gap formation of nonaugmented repairs (7.0 +/- 2.8 mm, P = .014). CONCLUSION: Cadaveric human supraspinatus repairs augmented with a reinforced fascia strip have significantly less initial stroke elongation and gap formation than repairs without augmentation. Augmentation limited gap formation to the greatest extent early in the testing protocol. Human studies are necessary to confirm the appropriate indications and effectiveness of augmentation scaffolds for rotator cuff repair healing in the clinical setting. PMID- 29398400 TI - MicroRNAs link chronic inflammation in childhood to growth impairment and insulin resistance. AB - MicroRNAs are involved in multiple pathophysiological networks and in the pathogenesis of a broad spectrum of human disorders, including cancer and inflammatory diseases. Impaired linear growth is encountered in children with chronic inflammatory conditions such as cystic fibrosis, inflammatory bowel diseases, juvenile idiopathic arthritis, celiac disease and in subjects born intrauterine growth restricted/small for gestational age. Children with inflammatory conditions may also be at risk of developing insulin resistance as a result of the inflammatory process and concurrent therapy. Chronic inflammation may lead to a continuum of abnormalities in the Growth hormone/Insulin-like growth factor 1 (GH/IGF-I) axis, including relative GH insufficiency, GH/IGF-I resistance due to down regulation of GH and IGF-I receptors, changes in GH and IGF-I bioavailability due to modifications of binding proteins, and/or impaired GH/IGF-I signaling. The aim of this review is first to summarize the current knowledge concerning microRNAs involved in inflammation in the most relevant chronic inflammatory diseases in childhood, second to provide new insights into miRNA regulation of growth and insulin sensitivity mediated by the inflammatory processes. We evaluated single microRNAs involved in inflammation in the single conditions mentioned above and verified which had validated and predicted targets within the GH receptor, IGF-I type 1 receptor and insulin receptor interactomes. The findings show a new link among inflammation, growth and insulin sensitivity mediated by miRNAs that warrants further research in the future. PMID- 29398403 TI - Cannabinoid Markers in Biological Fluids and Tissues: Revealing Intake. AB - Understanding cannabis and synthetic cannabinoid intake history is vital for treating drug dependence, investigating cannabinoid effects, and providing information to healthcare personnel, medical examiners, and public health officials; this is particularly relevant today with cannabis medicalization and legalization. Required information includes identifying exposure, time of use, frequency of use, relapse, withdrawal, and predicting cannabinoid effects. Recent controlled cannabinoid administration studies enable the development of models and markers to better identify patterns of intake and exposure. Future challenges include developing behavioral markers of cannabis impairment, bringing to market breathalyzers for cannabinoid detection, and identifying markers of recent cannabis intake in diverse biological matrices. We posit that biological monitoring of cannabinoids and metabolites will improve the characterization of cannabis and synthetic cannabinoid intake history. PMID- 29398402 TI - Pulmonary Comorbidity in Lung Cancer. AB - Pulmonary hypertension (PH) is caused by many disorders that affect the pulmonary vasculature. A recent study has provided evidence that pulmonary vascular remodeling and PH can be observed in lung cancer, and this may be associated with tumor cell-immune cell inflammatory crosstalk. These findings highlight the pressing need to understand better and manage pulmonary vascular comorbidities in lung cancer. PMID- 29398401 TI - Functional Neurocircuits and Neuroimaging Biomarkers of Tobacco Use Disorder. AB - Drug abuse and addiction remain major public health issues, exemplified by the opioid epidemic currently devastating the United States. Treatment outcomes across substance use disorders remain unacceptably poor, wherein drug discovery/development for this multifaceted neuropsychiatric disorder focuses on single molecular-level targets. Rather, our opinion is that a systems-level neuroimaging perspective is crucial for identifying novel therapeutic targets, biomarkers to stratify patients, and individualized treatment strategies. Focusing on tobacco use disorder, we advocate a brain systems-level perspective linking two abuse-related facets (i.e., statelike withdrawal and traitlike addiction severity) with specific neurocircuitry (insula- and striatum-centered networks). To the extent that precise neurocircuits mediate distinct facets of abuse, treatment development must adopt not only a systems-level perspective, but also multi-intervention rather than mono-intervention practices. PMID- 29398404 TI - Recognizing pharmaceutical illiteracy in community pharmacy: Agreement between a practice-based interview guide and questionnaire based assessment. AB - BACKGROUND: Patients with limited pharmaceutical literacy are at increased risk of drug-related problems. Recognizing these patients in daily practice is difficult. The Recognition and Addressing of Limited Pharmaceutical Literacy (RALPH) interview guide was developed as practical set of questions to recognize patients with limited pharmaceutical literacy in daily pharmacy practice. OBJECTIVE: To compare agreement between pharmaceutical literacy measured with the RALPH guide and a validated general health literacy questionnaire. In addition, we provide insight into patients' pharmaceutical literacy using the RALPH interview guide. METHODS: Structured face-to-face interviews with patients who visited a community pharmacy to fill a prescription for themselves were conducted. The interview included the RALPH guide as well as the Functional Communicative Critical Health Literacy (FCCHL) questionnaire to measure general health literacy. Functional, communicative and critical skills were measured and agreement between two methods was calculated. RESULTS: Data were collected from 508 patients. Patients with limited pharmaceutical literacy, indicated by the RALPH questions, also had a lower general health literacy level according to FCCHL scores. Agreement between the RALPH guide and FCCHL questionnaire was moderate (~60%) for the three health literacy domains. Most patients (>90%) had correct understanding of frequency and timing of medication use, but 25% did not understand warnings or precautions correctly. Finding understandable information (39%), assessing information applicability (50%) and reliability (64%) were mentioned as difficult by patients. CONCLUSION: Patients experienced difficulties with more complex skills, e.g. interpretation of warnings or precautions when using a medicine, finding and analyzing medication information. Whereas the FCCHL questionnaire is useful to assess general health literacy, the RALPH interview guide provides insight in the level of skills needed for good medication use and is more suitable for use in a medication specific context such as community pharmacy. Context specific assessment of skills is important to provide tailored pharmaceutical care. PMID- 29398405 TI - Consumer willingness to pay for pharmacy services: An updated review of the literature. AB - BACKGROUND: Quantifying the value of pharmacy services is imperative for the profession as it works to establish an expanded role within evolving health care systems. The literature documents the work that many have contributed toward meeting this goal. To date, however, the preponderance of evidence evaluates the value of pharmacist services to third-party payers; few published studies address the value that consumers place on these services. OBJECTIVES: In 1999, a review of studies that used the contingent valuation method to value pharmacy services was published. The objective of this manuscript is to provide an update of that review. METHODS: Relevant studies published in the English language were identified searching MEDLINE, ECONLIT and International Pharmaceutical Abstracts databases from January 1999 to November 2017. Only studies that specifically elicited willingness to pay for a community pharmacist provided service from actual or potential consumers were included. RESULTS: Thirty-one studies using the contingent valuation method to value pharmacy services were identified using the search strategy outlined. These studies included surveys in different demographic and geographic populations and valuing various pharmacy services. CONCLUSIONS: Improving the quality of studies using contingent valuation to value pharmacy services will aid the profession in marketing pharmacy services to consumers, and may assist practitioners who wish to implement various pharmacy services in their practice settings. A limited number of studies have been conducted, but the quality of contingent valuation studies valuing pharmacist services is improving. Understanding the pharmacy services that consumers value, and understanding the level of their monetary willingness to pay for those services will be crucial as the profession continues to work toward establishing a sustainable and economically viable role within the evolving health care systems. PMID- 29398406 TI - Indoor air humidity, air quality, and health - An overview. AB - There is a long-standing dispute about indoor air humidity and perceived indoor air quality (IAQ) and associated health effects. Complaints about sensory irritation in eyes and upper airways are generally among top-two symptoms together with the perception "dry air" in office environments. This calls for an integrated analysis of indoor air humidity and eye and airway health effects. This overview has reviewed the literature about the effects of extended exposure to low humidity on perceived IAQ, sensory irritation symptoms in eyes and airways, work performance, sleep quality, virus survival, and voice disruption. Elevation of the indoor air humidity may positively impact perceived IAQ, eye symptomatology, and possibly work performance in the office environment; however, mice inhalation studies do not show exacerbation of sensory irritation in the airways by low humidity. Elevated humidified indoor air appears to reduce nasal symptoms in patients suffering from obstructive apnea syndrome, while no clear improvement on voice production has been identified, except for those with vocal fatigue. Both low and high RH, and perhaps even better absolute humidity (water vapor), favors transmission and survival of influenza virus in many studies, but the relationship between temperature, humidity, and the virus and aerosol dynamics is complex, which in the end depends on the individual virus type and its physical/chemical properties. Dry and humid air perception continues to be reported in offices and in residential areas, despite the IAQ parameter "dry air" (or "wet/humid air") is semantically misleading, because a sensory organ for humidity is non-existing in humans. This IAQ parameter appears to reflect different perceptions among other odor, dustiness, and possibly exacerbated by desiccation effect of low air humidity. It is salient to distinguish between indoor air humidity (relative or absolute) near the breathing and ocular zone and phenomena caused by moisture-damage of the building construction and emissions therefrom. Further, residential versus public environments should be considered as separate entities with different characteristics and demands of humidity. Research is needed about particle, bacteria and virus dynamics indoors for improvement of quality of life and with more focus on the impact of absolute humidity. "Dry (or wet) air" should be redefined to become a meaningful IAQ descriptor. PMID- 29398407 TI - Corrigendum to " Developing an easy-to-apply model for identifying relevant pathogen pathways into surface waters used for recreational purposes" [Int. J. Hyg. Environ. Health 219 (7, part B) (2016) 662-670]. PMID- 29398408 TI - Neighbourhood walkability and incidence of hypertension: Findings from the study of 429,334 UK Biobank participants. AB - BACKGROUND: With an estimated one billion hypertension cases worldwide, the role of the built environment in its prevention and control is still uncertain. The present study aims to examine the associations between neighbourhood walkability and hypertension in a large and diverse population-based cohort. MATERIALS AND METHODS: We examined the association between neighbourhood walkability and blood pressure outcomes for N = 429,334 participants drawn from the UK Biobank and aged 38-73 years. Neighbourhood walkability was objectively modelled from detailed building footprint-level data within multi-scale functional neighbourhoods (1.0-, 1.5- and 2.0-kilometer street catchments of geocoded dwelling). A series of linear and modified Poisson regression models were employed to examine the association between walkability and outcomes of diastolic blood pressure (DBP in mmHg), systolic blood pressure (SBP in mmHg) and prevalent hypertension adjusting for socio-demographic, lifestyle and related physical environmental covariates. We also examined the relationship between walkability and change in blood pressure for a sub-sample of participants with follow-up data and tested for interaction effects of age, sex, employment status, neighbourhood SES, residential density and green exposure. RESULTS: Neighbourhood walkability within one-kilometer street catchment was beneficially associated with all the three blood pressure outcomes, independent of all other factors. Each interquartile increment in walkability was associated with the lower blood pressure outcomes of DBP (beta = -0.358, 95% CI: -0.42, -0.29 mmHg), SBP (beta = -0.833, 95% CI: 0.95, -0.72 mmHg) as well as reduced hypertension risk (RR = 0.970, 95% CI: 0.96, 0.98). The results remained consistent across spatial and temporal scales and were sensitive to sub-groups, with pronounced protective effects among female participants, those aged between 50 and 60 years, in employment, residing in deprived, high density and greener areas. CONCLUSION: This large population-based cohort found evidence of protective association between neighbourhood walkability and blood pressure outcomes. Given the enduring public health impact of community design on individual behaviour and lifestyle, of particular interest, are the targetted upstream-level interventions in city design aimed at optimizing walkability. Further long term studies are required to assess its sustained effects upon hypertension prevention and control. PMID- 29398409 TI - Oroxylum indicum root bark extract prevents doxorubicin-induced cardiac damage by restoring redox balance. AB - BACKGROUND: Oroxylum indicum Vent., a Dasamula plant used in Ayurveda possesses antioxidant properties. OBJECTIVES: To evaluate the cardioprotective effect of 70% methanolic extract of O. indicum Vent. root bark (OIM) against doxorubicin induced cardiomyopathy in female Sprague Dawley rats. MATERIALS AND METHODS: Cardiotoxicity was induced by intra-peritoneal injection of doxorubicin 30 mg/kg body weight (b.w.) for 4 consecutive days after a ten-day pre-treatment of animals with OIM at 200 mg/kg b.w. and 400 mg/kg b.w (p.o.). Drug treatment continued up to day 14. Probucol, orally administered at a dose of 20 mg/kg b.w. served as standard. ECG was recorded. The animals were sacrificed on day 15 and comparative analysis of serum marker levels of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), tissue antioxidant status based on Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), reduced Glutathione (GSH) and lipid peroxidation (LPO) was carried out. Histopathological examination was carried out using hematoxylin-eosin staining. RESULTS: ECG records of OIM treated animals showed normal pattern, in comparison to the control with ST depression and arrhythmia in cardiogram. Tissue antioxidant profile (SOD, GSH and GPx) was significantly (p < 0.01) elevated in the cardiac tissue of treated group in dose-dependent manner; lipid peroxidation level was found to decrease with treatment. Comparative analysis of serum markers - CPK, LDH, SGOT and SGPT - among untreated control, standard and extract treated groups revealed that OIM extract at 400 mg/kg b.w. dose significantly reduced the levels (p < 0.01). Histological analysis revealed normal myocardial architecture in OIM treated groups. HPTLC fingerprint of OIM revealed 8 bands and detected the presence of chrysin, apigenin and quercetin. CONCLUSION: O. indicum Vent. root bark shows marked cardio-protective activity, possibly due to the presence of antioxidant compounds acting synergistically. PMID- 29398410 TI - Chemo-biological evaluation of antidiabetic activity of Mentha arvensis L. and it's role in inhibition of advanced glycation end products. AB - BACKGROUND: There has been enormous curiosity in the development of alternative plant based medicines to control diabetes, oxidative stress and related disorders. One of the therapeutic approaches is to reduce postprandial release of glucose in the blood. Two key enzymes that are involved in reducing postprandial glucose are alpha-amylase and alpha-glucosidase. Mentha arvensis L. has been traditionally used by several tribes as a medicinal plant to treat various disorders. OBJECTIVE: The present study was undertaken to test M. arvenisis L. for inhibition of postprandial hyperglycemia. MATERIAL AND METHOD: We performed various in vitro and in vivo tests to evaluate efficacy of M. arvenisis L. for antidiabetic activity (postprandial hyperglycemia). RESULTS: Methanolic extract of M. arvensis L. leaves showed DPPH free radical scavenging activity (more than 78% MUg/MUl) and high antiglycation potential (more than 90% inhibition of AGE formation). Methanolic extract also showed remarkable inhibitory effects on alpha amylase (more than 50% MUg/MUl) and alpha-glucosidase (68% MUg/MUl) and significant inhibition of postprandial hyperglycemia in starch induced diabetic Wistar rats. CONCLUSION: The non-insulin dependent antidiabetic or inhibition of postprandial hyperglycemic activity of methanolic extract of M. arvensis L. leaves was shown by using in vitro and in vivo approaches in the present study. PMID- 29398411 TI - The Utility of a Benign Biliary Stricture Protocol in Preventing Symptomatic Recurrence and Surgical Revision. AB - PURPOSE: To determine whether treating benign biliary strictures via a stricture protocol reduced the probability of developing symptomatic recurrence and requiring surgical revision compared to nonprotocol treatment. MATERIALS AND METHODS: A stricture protocol was designed to include serial upsizing of internal/external biliary drainage catheters to a target maximum dilation of 18 French, optional cholangioplasty at each upsizing, and maintenance of the largest catheter for at least 6 months. Patients were included in this retrospective analysis if they underwent biliary ductal dilation at a single institution from 2005 to 2016. Forty-two patients were included, 25 women and 17 men, with an average age of 51.9 years (standard deviation +/- 14.6). Logistic regression models were used to determine the probability of symptomatic recurrence and surgical revision by stricture treatment type. RESULTS: Twenty-two patients received nonprotocol treatment, while 20 received treatment on a stricture protocol. After treatment, 7 (32%) patients in the nonprotocol group experienced clinical or laboratory recurrence of a benign stricture, whereas only 1 patient in the stricture protocol group experienced symptom recurrence. Patients in the protocol group were 8.9 times (95% confidence interval [CI] = 1.4-175.3) more likely to remain symptom free than patients in the nonprotocol group. Moreover, patients in the protocol group had an estimated 89% reduction in the probability of undergoing surgical revision compared to patients receiving nonprotocol treatment (odds ratio = .11, 95% CI = .01-.73). CONCLUSIONS: Establishing a stricture protocol may decrease the risk of stricture recurrence and the need for surgical revision when compared to a nonprotocol treatment approach. PMID- 29398412 TI - Superselective Transcatheter Arterial Embolization for Large Unruptured Renal Angiomyolipoma in Lymphangioleiomyomatosis. AB - PURPOSE: To retrospectively evaluate therapeutic performance and complications of superselective transcatheter arterial embolization (TAE) for unruptured renal angiomyolipoma (AML) in patients with lymphangioleiomyomatosis (LAM) and to investigate the correlation between percentage reduction in tumor volume and intratumoral fat content. MATERIALS AND METHODS: Superselective TAE was performed in 14 consecutive patients with 15 large unruptured renal AMLs associated with LAM (mean age, 38 y; range, 21-57 y). Patients had renal AML with aneurysms >= 5 mm in diameter, tumor-related abdominal symptoms, or both. In all cases, embolization of 1 tumor was achieved in a single session by using multiporous gelatin sponge particles (GSPs) with additional metallic coils in all but 1 case. Tumor volume and fat content percentage were measured on CT or MR imaging before and after superselective TAE (median, 11 months; range, 6-14 months). RESULTS: Residual tumor staining declined by > 90% after all TAE sessions except 2, with embolization of all treated aneurysms. No nontarget embolization or severe complications were encountered. Mean percentage reduction in tumor volume after superselective TAE was 69% (range, 21%-95%). Percentage tumor volume reduction was negatively correlated with fat content before embolization (P < .01). CONCLUSIONS: Superselective TAE with multiporous GSPs and metallic coils for large unruptured renal AML in patients with LAM is useful for reducing tumor volume and treating intratumoral aneurysms without major pulmonary or renal complications. Extent of tumor reduction may be influenced by fat content before embolization. PMID- 29398413 TI - Best Practice Guidelines for CT-Guided Interventional Procedures. PMID- 29398414 TI - Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects. AB - BACKGROUND: Non alcoholic fatty liver disease (NAFLD) is associated with substantial cardiometabolic morbidity. AIMS: We evaluated the long-term extrahepatic complications of NAFLD and sought to evaluate NAFLD in non-obese subjects. METHODS: A total of 2920 participants were retrospectively selected from a health check-up center in 2000, and followed through to December 2010. NAFLD was diagnosed using ultrasonography. Subjects were stratified according to body mass index, NAFLD, and metabolic syndrome. RESULTS: The prevalence of non obese NAFLD subjects and metabolically unhealthy non-obese subjects was 14.4% and 8.7%, respectively. In the multivariate analysis, non-obese NAFLD subjects had a significantly higher risk for diabetes mellitus (DM; HR 2.69, 95% CI 1.72-4.20, P < 0.001); no increase was observed for hypertension or cardiovascular disease. Metabolically unhealthy non-obese subjects had a significantly higher risk for hypertension (HR 2.75, 95% CI 2.02-3.74, P < 0.001), DM (HR 5.72, 95% CI 3.68 8.89, P < 0.001), and cardiovascular disease (HR 2.93, 95% CI 1.53-5.63, P = 0.001). Subgroup analysis of non-obese subjects showed that NAFLD, without metabolic syndrome, conferred a higher risk for DM (HR 3.60, 95% CI 2.03-6.39, P < 0.001). CONCLUSION: Non-obese subjects with NAFLD are at a higher risk for DM independent of metabolic syndrome. PMID- 29398415 TI - A promising Forcep Strip Method for gastrointestinal subepithelial tumors originating from the muscularis propria. AB - BACKGROUND: Subepithelial tumors (SETs) originating from the muscularis propria layer are unlikely to be resected completely and safely. We developed the Forcep Strip Method (FSM) for the resection of SETs in the stomach. AIMS: This study aimed to evaluate the feasibility and safety of the FSM. METHODS: Endoscopic SET resection using electrical forceps was performed in 11 consecutive patients with clinical indications for lesion removal. Following injection around the tumor, the adjacent mucosa or submucosa was grasped with the hot forceps and pulled away to form a "tent". The tumor was dissected from the muscularis propria layer and carefully removed using coagulating forceps. RESULTS: The FSM was successful in 10 of the 11 patients in the series; one patient required surgery due to respiratory depression during the procedure. The complete resection rate was 100% and no major complications including bleeding and perforation occurred. Mean procedure time was 39.3 +/- 14.7 min, mean hospitalization time was 5.0 +/- 1.2 days, and mean tumor size was 17.1 +/- 4.7 mm. CONCLUSION: FSM was found to be an easy, safe, and effective procedure for the treatment of gastric SETs originating from the muscularis propria layer. PMID- 29398416 TI - Artificial cryopreserved embryo transfer cycle success depends on blastocyst developmental rate and progesterone timing. AB - This retrospective cohort analysis compared the developmental competence of cryopreserved day-4 and 5 blastocysts, and investigated the effect of progesterone administration duration on the success of artificial frozen embryo transfers. Between October 2015 and March 2016, 868 intracytoplasmic sperm injection blastocyst cryo-all cycles were carried out, with 586 subsequently undergoing frozen embryo transfer. Of these, 243 were day-5 single blastocyst transfers (SBT) and 152 were day-4 SBT. Day-4 blastocysts were transferred on day 5 progesterone (day-4 group) and day-5 blastocysts were transferred on day-5 (short-protocol day-5 sub-group, n = 104) or day-6 (standard-protocol day-5 sub group, n = 139) progesterone. Although more blastocysts were transferred in the standard-protocol day-5 sub-group (P = 0.009), pregnancy, clinical pregnancy and live birth rates were similar to those of the day-4 group, but were significantly lower in the short-protocol day-5 sub-group (P = 0.004, P = 0.008 and P = 0.02 respectively). For optimal outcomes, day-4 blastulating embryos should be prioritized for transfer on day 5 of progesterone and for day-5 blastocysts, transfer should be delayed by 1 day. The retrospective analysis and lack of adjustment for all known confounding variables limit the study. PMID- 29398417 TI - Time-lapse systems for ART. PMID- 29398418 TI - Luteal phase progesterone and oestradiol after ovarian stimulation: relation to response and prediction of pregnancy. AB - Research has focused on optimizing luteal phase support and endometrial receptivity in ovarian stimulation cycles. In this study, serial endocrine measurements were taken in 600 patients after a gonadotrophin-releasing hormone antagonist stimulation protocol. On the day of blastocyst transfer, serum progesterone and oestradiol were similar irrespective of a subsequent positive or negative pregnancy test (median 99 ng/ml versus 103 ng/ml for progesterone, respectively) or a subsequent live birth or pregnancy loss. Serum progesterone was significantly correlated to each ovarian response parameter (total number of follicles, number of oocytes retrieved and oestradiol concentration; r = 0.45, 0.57 and 0.54 respectively, all P < 0.0001). These correlations were consistent irrespective of clinical outcome. On the day of the pregnancy test, these correlations had vanished except in the live birth subgroup showing a weaker correlation (r = 0.22, 0.27 and 0.32 respectively, all P < 0.005). The lowest HCG and progesterone levels associated with live birth were 59.3 IU/l and 12.3 ng/ml, respectively. Fourteen out of 92 patients (15.2%) with pregnancy loss had normal HCG but low progesterone levels (above and below their respective 5th percentile), and miscarried before the end of the 7th week, when the luteal placental shift occurs. PMID- 29398419 TI - The endometrial stem cell markers notch-1 and numb are associated with endometriosis. AB - Previous studies reported increased expression of the notch pathway-associated protein Musashi-1 in endometriosis. This case-control study investigates an association of the endometrial stem cell markers notch-1 and numb with endometriosis. Fifty-one endometriosis patients and 76 controls were recruited in the IVF unit and tertiary endometriosis referral centre of a university hospital. All subjects underwent transcervical endometrial biopsy and diagnostic laparoscopy. Expression of endometrial notch-1 and numb was assessed by immunostaining and correlated with clinical data. Association of stem-cell-marker expression with the presence of endometriosis was evaluated. Numb expression in the luminal epithelium was significantly higher in eutopic endometrium of endometriosis patients compared with controls (20.5% versus 16.5%, P = 0.033). Numb-positive single stromal cells were less frequent in endometrioma patients compared with other forms of endometriosis (0.3 versus 0.5 cells/visual field; P = 0.028). Notch-1 expression in endometrial glands was significantly higher in patients with deep infiltrating endometriosis compared with controls (39.1% versus 21.8%; P = 0.045). We conclude that stem cell markers notch-1 and numb of eutopic endometrium are associated with endometriosis and its clinical presentations, supporting the stem cell hypothesis of endometriosis. These findings could help develop promising research strategies applying endometrial stem cells as novel tools. PMID- 29398420 TI - Response: time-lapse systems for ART. PMID- 29398421 TI - Can time-lapse parameters predict embryo ploidy? A systematic review. AB - Embryo morphology assessment performs relatively poorly in predicting implantation. Embryo aneuploidy screening (PGS) has recently improved, but its clinical value is still debated, and the development of a cheap non-invasive method for the assessment of embryo ploidy status is a highly desirable goal. The growing implementation of time-lapse devices led some teams to test the effectiveness of morphokinetic parameters as predictors of embryo ploidy, with conflicting results. The aim of this study was to conduct a comprehensive review of the literature on the predictive value of morphokinetic parameters for embryo ploidy status. A systematic search on PubMed was conducted using the following key words: time-lapse, morphokinetic, aneuploidy, IVF, preimplantation genetic screening, PGS, chromosomal status. A total of 13 studies were included in the analysis. They were heterogeneous in design, patients, day of embryo biopsy, statistical approach and outcome measures. No single or combined morphokinetic parameter was consistently identified as predictive of embryo ploidy status. In conclusion, the available studies are too heterogeneous for firm conclusions to be drawn on the predictive value of time-lapse analysis for embryo aneuploidy screening. Hence, morphokinetic parameters should not be used yet as a surrogate for PGS to determine embryo ploidy in vitro. PMID- 29398422 TI - Hormone Replacement Therapy and Colorectal Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. AB - INTRODUCTION: Hormone replacement therapy has been shown to reduce colorectal cancer incidence, but its effect on colorectal cancer mortality is controversial. The objective of this study was to determine the effect of hormone replacement therapy on survival from colorectal cancer. PATIENTS AND METHODS: We performed a secondary analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a large multicenter randomized trial run from 1993 to 2001, with follow-up data recently becoming mature. Participants were women aged 55 to 74 years, without recent colonoscopy. Data from the trial were analyzed to evaluate colorectal cancer incidence, disease-specific mortality, and all-cause mortality based on subjects' use of hormone replacement therapy at the time of randomization: never, current, or former users. RESULTS: A total of 75,587 women with 912 (1.21%) incident colorectal cancers and 239 associated deaths were analyzed, with median follow-up of 11.9 years. Overall, 88.6% were non-Hispanic white, and < 10% had not completed high school. The never-user group was slightly older than the current or former user groups (average, 63.8 vs. 61.4 vs. 63.3 years; P < .001). Almost one-half (47.1%) of the current users had undergone hysterectomy, compared with 21.6% of never-users and 34.0% of former users (P < .001). Adjusted colorectal cancer incidence in current users compared to never users was lower (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69 0.94; P = .005), as was death from colorectal cancer (HR, 0.63; 95% CI, 0.47 0.85; P = .002) and all-cause mortality (HR, 0.76; 95% CI, 0.72-0.80; P < .001). CONCLUSIONS: Hormone replacement therapy is associated with a reduced risk of colorectal cancer incidence and improved colorectal cancer-specific survival, as well as all-cause mortality. PMID- 29398423 TI - Frequency of Surveillance and Impact of Surveillance Colonoscopies in Patients With Ulcerative Colitis Who Developed Colorectal Cancer. AB - BACKGROUND: The risk of developing colorectal cancer (CRC) in patients with chronic ulcerative colitis (UC) is increased. The aim of this study was to evaluate if patients who developed CRC in the setting of UC were undergoing guideline-recommended surveillance colonoscopies and to determine the impact of surveillance on the staging of CRC. PATIENTS AND METHODS: Data was obtained from the Veterans Affairs healthcare system to identify patients with UC and CRC. Stage 0 and I were considered early-stage CRC, whereas stage >= II were considered advanced-stage CRC. Patients were considered to have adequate surveillance if they had a colonoscopy within 2 years before developing CRC. We conducted a case-case analysis using multivariable logistic regression to estimate the odds ratio for presenting with advanced-stage CRC associated with lack of adequate surveillance. RESULTS: Of the 48 patients, the majority were white (70.8%) and male (100%). Sixty-nine percent of patients had inadequate surveillance. In multivariable analysis, prior adherence to CRC surveillance was associated with a decreased risk of presenting with advanced-stage CRC (vs. early stage CRC) (adjusted odds ratio, 0.20; 95% confidence interval, 0.05-0.85; P = .029). CONCLUSION: The majority of patients who developed CRC in the setting of UC underwent inadequate surveillance, and they were more likely to present with advanced-stage CRC. PMID- 29398424 TI - Pasireotide does not prevent postoperative pancreatic fistula: a prospective study. AB - BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 MUg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula. PMID- 29398425 TI - Educating anesthesia residents to obtain and document informed consent for epidural labor analgesia: does simulation play a role? AB - BACKGROUND: Informed consent is required before placing an epidural. At our hospital, teaching of residents about this is done informally at the bedside. This study aimed to assess the ability of anesthesia residents to acquire and retain knowledge required when seeking informed consent for epidural labor analgesia. It assessed how well this knowledge was translated to clinical ability, by assessing the verbal consent process during an interaction with a standardized patient. METHODS: Twenty anesthesia residents were randomized to a 'didactic group' or a 'simulation group'. Each resident was presented with a written scenario and asked to document the informed consent process, as they normally would do (pre-test). The didactic group then had a presentation about informed consent, while the simulation group members interviewed a simulated patient, the scenarios focusing on different aspects of consent. All residents then read a scenario and documented their informed consent process (post-test). Six weeks later all residents interviewed a standardized patient in labor and documented the consent from this interaction (six-week test). RESULTS: There was no significant difference in the baseline performance of the two groups. Both groups showed significant improvement in their written consent documentation at the immediate time point, the improvement in the didactic group being greater. The didactic group performed better at both the immediate time point and the six week time point. CONCLUSIONS: In this small study, a didactic teaching method proved better than simulation-based teaching in helping residents to gain knowledge needed to obtain informed consent for epidural labor analgesia. PMID- 29398426 TI - The influence of fluid management on outcomes in preeclampsia: a systematic review and meta-analysis. AB - BACKGROUND: The optimal fluid management strategy to ensure best outcomes in preeclamptic patients remains a controversial issue, with little evidence to support any one approach. OBJECTIVE: The aim of this systematic review was to investigate the effect of various fluid management strategies on clinical outcomes, haemodynamic indices and biochemical markers in preeclamptic women and their babies. Primary outcome measures were the occurrence of pulmonary oedema and/or the development of renal impairment. METHODS: A systematic review of randomised fluid management strategies was conducted. Five electronic databases were searched using the expanded search terms: 'intravenous fluid', 'plasma substitutes', 'intravenous fluid management', 'intravenous fluid therapy', plasma volume expansion', 'fluid restriction', 'oncotic therapy', 'crystalloids', 'colloids', 'preeclampsia', 'toxemia of pregnancy', 'pregnancy-induced hypertension', 'eclampsia' and 'gestational proteinuric hypertension'. RESULTS: Six randomised controlled trials (RCTs), from nine publications, were included in the final analysis. There were no differences between groups with respect to the incidence of pulmonary oedema, perinatal mortality, preterm delivery and caesarean section. Colloid volume expansion was associated with a significantly lower systolic and diastolic blood pressure, but had no effect on heart rate or cardiac index. Data on systemic vascular resistance (SVR), serum atrial natriuretic peptide (ANP) and urine volume could not be aggregated. CONCLUSION: Data on the ideal fluid strategy in women with preeclampsia is limited, and insufficient to make any strong recommendations. Further randomised controlled studies are needed to provide more evidence for which fluid management strategies are best suited to this heterogeneous patient group. PMID- 29398428 TI - Field-Forwarding Leadership. PMID- 29398429 TI - Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis. AB - While the impact of very low concentrations of low-density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL LDL receptor (LDLR) activity reveal no safety issues. Patients achieving extremely low LDL levels in the IMPROVE-IT and FOURIER, and the PROFICIO and ODYSSEY programs seem not to have an increased prevalence of adverse effects. The main concern regarding extremely low LDL-C plasma concentrations is the adequacy of the supply of cholesterol, and other molecules, to peripheral tissues. However, LDL proteomic and kinetic studies reaffirm that LDL is the final product of endogenous lipoprotein metabolism. Four of 5 LDL particles are cleared through the LDL-LDLR pathway in the liver. Given that mammalian cells have no enzymatic systems to degrade cholesterol, the LDL-LDLR pathway is the main mechanism for removal of cholesterol from the body. Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that extremely low LDL-C levels due to increased LDLR activity may be a surrogate of adequate LDL-LDLR pathway function. PMID- 29398430 TI - Cardiovascular risk in patients with familial hypercholesterolemia using optimal lipid-lowering therapy. AB - BACKGROUND: Despite lipid-lowering therapy (LLT), some patients with familial hypercholesterolemia (FH) still develop cardiovascular events. Data about the quantification and factors contributing to this residual risk are lacking. OBJECTIVE: This study assessed how many patients with FH developed a cardiovascular event despite LLT and which factors contribute to this risk. METHODS: We performed a time-dependent analysis in a cohort of consecutive heterozygous FH patients using stable LLT to evaluate first and subsequent cardiovascular events. Univariate and multivariate regression analyses were conducted to study the association between clinical characteristics and cardiovascular events. RESULTS: Of 821 FH patients (median age 47.4 [interquartile range (IQR) 35.3-58.3] years) treated with LLT for a median period of 9.5 (IQR 5.1-14.2) years, 102 patients (12%) developed cardiovascular disease (CVD) in 8538 statin-treated person-years. Patients who developed a cardiovascular event had a median age of 52.0 (IQR 43.8-59.3) years. These patients more often had previous cardiovascular events (32% vs 9%, P < .001), a family history of premature CVD (58% vs 40%, P = .001), hypertension (70% vs 22%, P < .001), higher on-treatment low-density lipoprotein cholesterol (162 +/- 54 vs 135 +/- 58 mg/dL, P < .001), lower on-treatment high-density lipoprotein cholesterol (50 +/- 15 vs 54 +/- 15 mg/dL, P < .001), and were smokers (32% vs 14%, P < .001), compared to patients without cardiovascular events. In 31 patients (30%), a subsequent cardiovascular event occurred with a median interval of 5.7 (IQR 2.4-9.3) years between events. They were more often smokers (32% vs 10%, P = .01) compared to patients with a single cardiovascular event. CONCLUSIONS: Despite LLT, FH patients still develop cardiovascular events and especially subsequent events. Classical risk factors such as smoking and hypertension are driving factors for this risk, indicating the high priority of optimizing risk factor reduction in addition to maximum LLT. PMID- 29398431 TI - Dual regression physiological modeling of resting-state EPI power spectra: Effects of healthy aging. AB - Aging and disease-related changes in the arteriovasculature have been linked to elevated levels of cardiac cycle-induced pulsatility in the cerebral microcirculation. Functional magnetic resonance imaging (fMRI), acquired fast enough to unalias the cardiac frequency contributions, can be used to study these physiological signals in the brain. Here, we propose an iterative dual regression analysis in the frequency domain to model single voxel power spectra of echo planar imaging (EPI) data using external recordings of the cardiac and respiratory cycles as input. We further show that a data-driven variant, without external physiological traces, produces comparable results. We use this framework to map and quantify cardiac and respiratory contributions in healthy aging. We found a significant increase in the spatial extent of cardiac modulated white matter voxels with age, whereas the overall strength of cardiac-related EPI power did not show an age effect. PMID- 29398432 TI - Dual-phase Cone-beam CT-based Navigation Imaging Significantly Enhances Tumor Detectability and Aids Superselective Transarterial Chemoembolization of Liver Cancer. AB - RATIONALE AND OBJECTIVES: The objective of this study was to investigate the impact of a dual-phase cone-beam computed tomography (DP-CBCT)-based navigation imaging during transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) in a perspective randomized study. MATERIALS AND METHODS: Forty-two patients with HCC (39 men, 57 +/- 9 years, 13 first-time TACE) underwent TACE using three-dimensional image guidance with automatic detection of tumor-feeding vessels computed from DP-CBCT (early and delayed arterial phases). Forty-nine other patients with HCC (44 men, 55 +/- 12 years, 14 first-time TACE) were treated conventionally using digital subtraction angiography (DSA). Tumor detectability in DP-CBCT was compared to DSA and preoperative CT or magnetic resonance (MR) imaging. Tumor-feeding vessel visibility was rated (good, fair, and poor) intraoperatively by the operators. The superselective embolization success rate, the number of DSA acquisitions, fluoroscopy time, and patient radiation dose were collected and compared using paired t test and the Mann Whitney U test. RESULTS: Tumor detection of DP-CBCT was superior to DSA (100% vs 83%, P = .001) and comparable to CT-MR (96%, P = .456). Tumor and feeder visibilities were significantly enhanced by DP-CBCT (P < .001). Compared to using DSA, more superselective embolization was achieved (60% vs 49%) with less DSA acquisitions (n = 2.6 +/- 0.8 vs n = 3.4 +/- 0.7, P < .001) and shorter fluoroscopy time (4.1 +/- 2.6 vs 7.1 +/- 4.2 minutes, P < .001) with a slight increase in patient radiation exposure, that is, air kerma (median: 0.33, first to third quartiles: 0.24-0.48 vs 0.30, 0.24-0.44 Gy; P = .519) and dose-area product (134, 92-181 vs 97, 75-140 Gy?cm2, P = .048). CONCLUSIONS: DP-CBCT and navigation imaging improve tumor detectability and superselective embolization in TACE. PMID- 29398433 TI - Bridging the Gap: Identifying Global Trends in Gender Disparity Among the Radiology Physician Workforce. AB - RATIONALE AND OBJECTIVES: Women make up half of American medical school graduates, but remain underrepresented among radiologists. This study sought to determine whether workforce gender disparities exist in other countries, and to identify any country-specific indices associated with increased female representation. MATERIALS AND METHODS: In this cross-sectional study, 95 professional radiology organizations in 75 countries were contacted via email to provide membership statistics, including proportion of female members, female members aged 35 or under, and women in society leadership positions. Country specific metrics collected included gross domestic product, Gini index, percent female medical school enrollment, and Gender Development Index for the purposes of univariate multiple regression analysis. RESULTS: Twenty-nine organizations provided data on 184,888 radiologists, representing 26 countries from Europe (n = 12), North America (n = 2), Central/South America (n = 6), Oceania (n = 2), Asia (n = 3), and Africa (n = 1) for a response rate of 34.7% (26/75). Globally, 33.5% of radiologists are female. Women constitute a higher proportion of younger radiologists, with 48.5% of radiologists aged 35 or under being female. Female representation in radiology is lowest in the United States (27.2%), highest in Thailand (85.0%), and most variable in Europe (mean 40.1%, range 28.8%-68.9%). The proportion of female radiologists was positively associated with a country's Gender Development Index (P = .006), percent female medical student enrollment (P = .001), and Gini index (P = .002), and negatively associated with gross domestic product (P = .03). CONCLUSIONS: Women are underrepresented in radiology globally, most notably in the United States. Countries with greater representation of women had higher gender equality and percent female medical school enrollment, suggesting these factors may play a role in the gender gap. PMID- 29398434 TI - Effect of Implementing Community of Practice Modified Thyroid Imaging Reporting and Data System on Reporting Adherence and Number of Thyroid Biopsies. AB - RATIONALE AND OBJECTIVES: Thyroid nodules are common in the population, although the rate of malignancy is relatively low (5%-15%). The purpose of this study was to determine if introducing a modified standardized reporting format and management algorithm (Thyroid Imaging Reporting and Data System [TI-RADS]) affects radiologist reporting adherence, number of thyroid biopsies, and other measurable outcomes. MATERIALS AND METHODS: All thyroid biopsies performed over two 6-month periods were evaluated at a tertiary care hospital with Research Ethics Board approval. The first period was before implementation of TI-RADS and the second was several months after implementation of TI-RADS (using a modified version made through a multidisciplinary collaboration). The number of biopsies performed was determined in each of the two periods as well as the percent of positive malignancy, wait times, and rates of non-diagnostic/unsatisfactory and inconclusive biopsies, which included atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS). RESULTS: The average number of biopsies performed prior to implementing modified Kwak's TI-RADS was 74 thyroid biopsies per month and the average number of diagnostic ultrasounds was 271. After the introduction of modified Kwak's TI-RADS, the average number of thyroid biopsies decreased to 60 per month (an 18.9% reduction, P < .05), and the number of diagnostic ultrasound increased to 287 per month (a 5.9% increase from 2016 to 2017). The average wait time for a thyroid biopsy decreased from 5 to 3 weeks (P < .05). There was a slight increase in the rate of positive malignancy results (from 15% to 18%), although it was not statistically significant. The rate of non-diagnostic/unsatisfactory and inconclusive results (including AUS and FLUS) remained unchanged (18% AUS/FLUS/15% non-diagnostic/unsatisfactory before and 17% AUS/FLUS/15% non-diagnostic/unsatisfactory after TI-RADS introduction, P > .05). CONCLUSIONS: Introduction of a multidisciplinary-approved standardized reporting system with evidence-based management recommendations led to no statistically significant change in the number of diagnostic ultrasounds but a statistically significant reduction in the number of monthly thyroid biopsies and associated reduction in wait times. PMID- 29398435 TI - Gender Diversity in Academic Radiology Departments: Barriers and Best Practices to Optimizing Inclusion and Developing Women Leaders. AB - Gender diversity remains a challenge for radiology. As we aspire to embrace Diversity 3.0 and the goal of making diversity core to our organizations' mission, there must be increasing awareness of the barriers to achieving inclusion and to best practices for making diversity integral to achieving excellence. This article reviews the literature on gender diversity in radiology and in academic radiology leadership and discusses lessons learned from non health-care industry and from academic radiology departments that have been successful in developing and supporting female employees. PMID- 29398437 TI - Accuracy of Opposed-phase Magnetic Resonance Imaging for the Evaluation of Treated and Untreated Spinal Metastases. AB - RATIONALE AND OBJECTIVES: To assess whether the accuracy of opposed-phase magnetic resonance (MR) imaging to differentiate spinal metastases from benign lesions is influenced by treatment. MATERIALS AND METHODS: We retrospectively evaluated 25 benign lesions, 25 untreated spinal metastases, and 89 treated spinal metastases in 101 patients who underwent opposed-phase MR spine imaging at our institution. The largest possible region of interest was placed over the lesion in question on out-of-phase and in-phase MR sequences, and the signal intensity ratio (SIR) of the lesions was calculated. The SIRs were compared between benign, untreated, and treated lesions. Receiver operator characteristic (ROC) curves were used to identify the optimal threshold to differentiate benign lesions from untreated spinal metastases, and the accuracy of this threshold was assessed for treated spinal metastases, chemotherapy-treated spinal metastases, and radiated spinal metastases. RESULTS: Benign lesions had lower mean SIR than untreated (P = 2.4 * 10-8, 95% confidence interval [0.29, 0.51]) and treated spinal metastases (P = .51; 95% confidence interval [-0.13, 0.06]). A cutoff SIR of 0.856 had an accuracy of 88.00% for untreated lesions, 77.48% for previously treated lesions, and 70.45% for previously radiated lesions. The ROC curve to differentiate benign lesions from radiated spinal metastases was significantly different from the ROC curve to differentiate benign lesions from untreated spinal metastases (P = .0180). The ROC curve to differentiate benign lesions from lesions treated with chemotherapy only was significantly different from the ROC curve to differentiate between benign lesions and radiated spinal metastases (P = .041). CONCLUSIONS: Opposed-phase imaging is less accurate for treated spinal metastases, in particular after radiation. PMID- 29398436 TI - Image Quality on Dual-energy CTPA Virtual Monoenergetic Images: Quantitative and Qualitative Assessment. AB - RATIONALE AND OBJECTIVES: This study aims to determine the optimal photon energy for image quality of the pulmonary arteries (PAs) on dual-energy computed tomography (CT) pulmonary angiography (CTPA) utilizing low volumes of iodinated contrast. MATERIALS AND METHODS: The study received institutional review board exemption and was Health Insurance Portability and Accountability Act compliant. Adults (n = 56) who underwent dual-energy CTPA with 50-60 cc of iodinated contrast on a third-generation dual-source multidetector CT were retrospectively and consecutively identified. Twelve virtual monoenergetic kiloelectron volt (keV) image data sets (40-150 keV, 10-keV increments) were generated with a second-generation noise-reducing algorithm. Standard regions of interest were placed on main, right, left, and right interlobar pulmonary arteries; pectoralis muscle; and extrathoracic air. Attenuation [mean CT number (Hounsfield unit, HU)], noise [standard deviation (HU)], signal to noise (SNR), and contrast to noise ratio were evaluated. Three blinded chest radiologists rated (from 1 to 5, with 5 being the best) randomized monoenergetic and weighted-average images for attenuation and noise. P <.05 was considered significant. RESULTS: Region of interest mean CT number increased as keV decreased, with 40 keV having the highest value (P < .001). Mean SNR was highest for 40-60 keV (P <.05) (14.5-14.7) and was higher (P <.05) than all remaining energies (90-150 keV) for all vessel regions combined. Contrast to noise ratio was highest for 40 keV (P <.001) and decreased as keV increased. SNR was highest at 60 and 70 keV, only slightly higher than 40-50 keV (P <.05). Reader scores for 40-50 keV were greater than other energies and weighted-average images (P <.05). CONCLUSIONS: Kiloelectron volt images of 40-50 keV from the second-generation algorithm optimize attenuation on dual-energy CTPA and can potentially aid in interpretation and avoiding nondiagnostic examinations. PMID- 29398438 TI - Angiogenesis Research in Mouse Mammary Cancer Based on Contrast-enhanced Ultrasonography: Exploratory Study. AB - RATIONALE AND OBJECTIVES: The objective of this study was to investigate the contrast-enhanced ultrasound (CEUS) characteristics of tumor angiogenesis in mouse mammary cancer. MATERIALS AND METHODS: Twenty-four mice were examined with ultrasound and CEUS at 2-12 days after implantation. Four to five mice were assessed daily, and one to three mice were then sacrificed for histology. All of the histologic slides were reviewed and correlated with CEUS findings. RESULTS: A total of 46 cases of ultrasound examination had been performed in 24 mice. The mice were classified into three groups according to the tumor growth: group 1 (2~6 days after implantation, n = 20 cases), group 2 (7~9 days after implantation, n = 15 cases), and group 3 (10~12 days after implantation, n = 11 cases). In group 1, all tumors presented as a homogeneous hypoechoic mass with no color Doppler signals. However, three CEUS patterns were observed: 14 tumors presented as type I (peripheral ring enhancement with no enhancement within the tumor), 4 tumors presented as type II (peripheral ring enhancement with deep penetration), and 2 tumors presented as type III (homogeneous or heterogeneous enhancement in the entire tumor). In group 2, there was only difference in the echo (heterogeneous or not) and color Doppler signals (with or without) among the tumors in conventional ultrasound, but four CEUS patterns were observed and most presented as type III (53.3%, 8/15). In group 3, most tumors presented as a heterogeneous solid mass (81.8%, 9/11) with color signals (100%, 11/11), and almost all tumors presented as enhancement of type IV (peripheral ring enhancement with focal nodular enhancement) (90.9%, 10/11).The histologic results showed that the enhanced areas mainly corresponded to tumor cells, large tortuous vessels, and an inflammatory cell infiltrate. Nonenhanced areas corresponded to large areas of necrotic tissue or tumor cells, which arranged loosely with the small zone of necrosis. CONCLUSIONS: CEUS could image the progression of vessel formation. Moreover, most importantly, CEUS is able to identify angiogenesis before the change of tumor color Doppler, and presents different enhanced patterns at different tumor growth times, which corresponded to tumor histologic features. PMID- 29398439 TI - Radiologist Engagement as a Potential Barrier to the Clinical Translation of Quantitative Imaging for the Assessment of Tumor Heterogeneity. AB - RATIONALE AND OBJECTIVE: This study aims to identify potential barriers to the clinical implementation of quantitative imaging for the assessment of tumor heterogeneity. MATERIALS AND METHODS: An 18-month prospective observational study was undertaken in which the clinical implementation of computed tomography texture analysis (CTTA) as a technique for quantifying tumor heterogeneity in patients with non-small cell lung cancer was assessed using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RESULTS: Adopters of the technology comprised five specialists with dual accreditation in radiology and nuclear medicine supervising two trainees. Tumor heterogeneity information was extracted and reported in 190 of 322 eligible cases (59%) and presented at the multidisciplinary team meeting in 124 of 152 patients (82%) for whom CTTA had been performed. The maximum proportion of eligible cases in which heterogeneity information had been extracted and reported in any quarter was 80%, but fell in the latter half of the study. The maximum frequency with which available CTTA results were presented at the multidisciplinary team meeting in any quarter was 92% and was maintained in the latter part of the study. Significant differences in survival were observed for patients categorized using the two reported CTTA values (P = 0.004 and P = 0.0057, respectively). CONCLUSIONS: Radiologist engagement is a potential barrier to the effective translation of quantitative imaging assessments of tumor heterogeneity into clinical practice and will need to be addressed before tumor heterogeneity information can successfully contribute to clinical decision making in oncology. PMID- 29398440 TI - Combining Washout and Noncontrast Data From Adrenal Protocol CT: Improving Diagnostic Performance. AB - RATIONALE AND OBJECTIVES: To determine if combination of washout and noncontrast data from delayed adrenal computed tomography (CT) improves diagnostic performance, and demonstration of an optimizing analytical framework. MATERIALS AND METHODS: This retrospective study consisted of 97 adrenal lesions, in 96 patients, with pathologically proven adrenal lesions (75 benign; 22 malignant), who had undergone noncontrast, portal- and approximate 15-minute delayed-phase CT. Lesion CT attenuations (Hounsfield units [HU]) during each phase, and "absolute" and "relative" percent enhancement washouts (APEW and RPEW) were assessed. The optimum combination of sequential parameters and thresholds was determined by recursive partitioning analysis; resultant diagnostic performance was compared to commonly applied single-parameter criteria for malignancy (noncontrast > 10 HU, APEW < 60%, RPEW < 40%). RESULTS: The above single parameter criteria yielded sensitivities, specificities, and accuracies for malignancy of 100.0%, 41.3%, and 54.6%; 97.9%, 61.3%, and 69.1%; and 96.6%, 74.7%, and 78.4%, respectively. Recursive partitioning analysis identified noncontrast >=24.75 HU, with subsequent APEW <=63.49%, as the optimum sequential parameter-threshold combination, which yielded increased sensitivity, specificity, and accuracy of 100.0%, 85.3%, and 90.7%, respectively. Discrimination using the combined sequential classifier yielded statistically significant improvements in accuracy when compared to the above conventional single-parameter criteria (all P <= .039). CONCLUSION: Sequential application of noncontrast and washout criteria from delayed contrast-enhanced adrenal CT can improve diagnostic performance beyond that of commonly applied single-parameter criteria. Validation of the sequential ordering and refinement of the specific threshold values warrant further study. PMID- 29398441 TI - Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4. AB - We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib. PMID- 29398443 TI - 2-Formyl-komarovicine promotes adiponectin production in human mesenchymal stem cells through PPARgamma partial agonism. AB - Adiponectin is a major adipocytokine secreted from mammalian adipocytes. Relatively low expression of adiponectin is associated with various human metabolic diseases and some cancers. Adiponectin-secreting compounds have therapeutic potential for these diseases. Adipogenesis of human bone marrow mesenchymal stem cells (hBM-MSCs) has been used as a phenotypic assay to find adiponectin secreting compounds. In a phytochemical library screen, 2-formyl komarovicine, 1-(quinolin-8-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2 carbaldehyde, isolated from Nitraria komarovii was identified as a potential adiponectin-secreting compound. To validate the results of the impure phytochemical, we synthesized 2-formyl-komarovicine. The synthetic 2-formyl komarovicine significantly promoted adiponectin production during adipogenesis in hBM-MSCs. In a target identification experiment, 2-formyl-komarovicine bound to peroxisome proliferator-activated receptor gamma (PPARgamma) in a concentration dependent manner. Notably, 2-formyl-komarovicine competitively inhibited the adiponectin-promoting activity of a full PPARgamma agonist, troglitazone, in hBM MSCs, which is a pharmacological feature of a partial agonist. The ligand-docking model showed that 2-formyl-komarovicine interacted with the hydrophobic pocket of the PPARgamma ligand-binding domain, but lacked an interaction to stabilize helix H12, which is one of the major binding themes of PPARgamma partial agonists. We concluded that 2-formyl-komarovicine provides a novel pharmacophore for PPARgamma partial agonists to increase adiponectin production. PMID- 29398442 TI - Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region. AB - Pyroglutamate-modified amyloid beta peptides (pGlu-Abeta) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Abeta peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD. PMID- 29398444 TI - Synthesis and antibacterial studies of teixobactin analogues with non-isostere substitution of enduracididine. AB - Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0.25 to 1.0 uM. Structure-activity relationship is also established for further development of more promising teixobactin analogues. PMID- 29398445 TI - Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7 chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate. AB - Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7 chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of beta hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10 12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ? 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis. PMID- 29398446 TI - Toxins, Targets, and Triggers: An Overview of Toxin-Antitoxin Biology. AB - Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the toxin. The majority of toxins are enzymes that interfere with translation or DNA replication, but a wide variety of molecular activities and cellular targets have been described. Antitoxins are proteins or RNAs that often control their cognate toxins through direct interactions and, in conjunction with other signaling elements, through transcriptional and translational regulation of TA module expression. Three major biological functions of TA modules have been discovered, post-segregational killing ("plasmid addiction"), abortive infection (bacteriophage immunity through altruistic suicide), and persister formation (antibiotic tolerance through dormancy). In this review, we summarize the current state of the field and highlight how multiple levels of regulation shape the conditions of toxin activation to achieve the different biological functions of TA modules. PMID- 29398448 TI - Nucleo-cytosolic Shuttling of ARGONAUTE1 Prompts a Revised Model of the Plant MicroRNA Pathway. AB - Unlike in metazoans, plant microRNAs (miRNAs) undergo stepwise nuclear maturation before engaging cytosolic, sequence-complementary transcripts in association with the silencing effector protein ARGONAUTE1 (AGO1). Since their discovery, how and under which form plant miRNAs translocate to the cytosol has remained unclear, as has their sub-cellular AGO1 loading site(s). Here, we show that the N termini of all plant AGO1s contain a nuclear-localization (NLS) and nuclear-export signal (NES) that, in Arabidopsis thaliana (At), enables AtAGO1 nucleo-cytosolic shuttling in a Leptomycin-B-inhibited manner, diagnostic of CRM1(EXPO1)/NES dependent nuclear export. Nuclear-only AtAGO1 contains the same 2'O-methylated miRNA cohorts as its nucleo-cytosolic counterpart, but it preferentially interacts with the miRNA loading chaperone HSP90. Furthermore, mature miRNA translocation and miRNA-mediated silencing both require AtAGO1 nucleo-cytosolic shuttling. These findings lead us to propose a substantially revised view of the plant miRNA pathway in which miRNAs are matured, methylated, loaded into AGO1 in the nucleus, and exported to the cytosol as AGO1:miRNA complexes in a CRM1(EXPO1)/NES-dependent manner. PMID- 29398447 TI - Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP. AB - Regulation of RNA polymerase II (Pol II) elongation is a critical step in gene regulation. Here, we report that U1 snRNP recognition and transcription pausing at stable nucleosomes are linked through premature polyadenylation signal (PAS) termination. By generating RNA exosome conditional deletion mouse embryonic stem cells, we identified a large class of polyadenylated short transcripts in the sense direction destabilized by the RNA exosome. These PAS termination events are enriched at the first few stable nucleosomes flanking CpG islands and suppressed by U1 snRNP. Thus, promoter-proximal Pol II pausing consists of two processes: TSS-proximal and +1 stable nucleosome pausing, with PAS termination coinciding with the latter. While pausing factors NELF/DSIF only function in the former step, flavopiridol-sensitive mechanism(s) and Myc modulate both steps. We propose that premature PAS termination near the nucleosome-associated pause site represents a common transcriptional elongation checkpoint regulated by U1 snRNP recognition, nucleosome stability, and Myc activity. PMID- 29398451 TI - Editorial. PMID- 29398449 TI - RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis. AB - Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2-/-RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation. PMID- 29398450 TI - Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs. AB - Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs. PMID- 29398452 TI - Show and Tell: Video Modeling and Instruction Without Feedback Improves Performance but Is Not Sufficient for Retention of a Complex Voice Motor Skill. AB - PURPOSE: Modeling and instruction are frequent components of both traditional and technology-assisted voice therapy. This study investigated the value of video modeling and instruction in the early acquisition and short-term retention of a complex voice task without external feedback. METHOD: Thirty participants were randomized to two conditions and trained to produce a vocal siren over 40 trials. One group received a model and verbal instructions, the other group received a model only. Sirens were analyzed for phonation time, vocal intensity, cepstral peak prominence, peak-to-peak time, and root-mean-square error at five time points. RESULTS: The model and instruction group showed significant improvement on more outcome measures than the model-only group. There was an interaction effect for vocal intensity, which showed that instructions facilitated greater improvement when they were first introduced. However, neither group reproduced the model's siren performance across all parameters or retained the skill 1 day later. CONCLUSIONS: Providing verbal instruction with a model appears more beneficial than providing a model only in the prepractice phase of acquiring a complex voice skill. Improved performance was observed; however, the higher level of performance was not retained after 40 trials in both conditions. Other prepractice variables may need to be considered. Findings have implications for traditional and technology-assisted voice therapy. PMID- 29398453 TI - Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. AB - CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain. PMID- 29398454 TI - Melanoma in the very elderly, management in patients 85years of age and over. AB - OBJECTIVES: Melanoma treatment in the elderly can entail complex decision making. This study characterizes the presentation, management, and outcome of melanoma in the very elderly. METHOD: Retrospective review of all patients in their 85th year or older presenting to a tertiary referral cancer centre between 2000 and 2012 with American Joint Committee on Cancer stages 0-II cutaneous melanoma. RESULTS: 127 patients, 26 with in-situ disease and 101 with stages I-II disease, were included. For invasive primary disease, the median age was 87years (IRQ=86-89). Most patients had melanomas with poor prognoses at diagnosis: 49.5% were ulcerated, 68.3% mitotically active (mitotic rate>=1), and the median tumor thickness was 3.7mm (IQR=1.7-5.8). Nodular melanomas were the most frequent subtype (31.7%, 32/101). Only 66.3% received an excision margin>=10mm. Suboptimal excision margins were associated with increased risk of local recurrence (HR=6.87, 95% CI=5.53-8.20, p=0.0045) but not poorer disease specific survival (DSS, p=0.37) or overall survival (OS, p=0.19). Sentinel node biopsy (SNB) did not influence survival (DSS, p=0.39, OS, p=0.78). Median OS was 33months. Overall, one-third (34.7%) of patients died from causes other than melanoma during the follow up period. In patients aged >=90 only 1 patient (4.3%) died from melanoma, while 10 patients (43.5%) died of other causes. CONCLUSIONS: Older patients have thick, mitotically active and frequently ulcerated melanomas. An excision margin>=10mm should be considered to reduce risk of local recurrence. SNB did not impact on survival. With increasing age, patients will more commonly die of causes other than melanoma regardless of the extent of surgical care. PMID- 29398455 TI - Short course accelerated radiation therapy (SHARON) in palliative treatment of advanced solid cancer in older patients: A pooled analysis. AB - OBJECTIVES: To evaluate the efficacy and safety of a conformal Short Course Accelerated Radiation therapy (SHARON) for symptomatic palliation of locally advanced or metastatic cancers in older patients. MATERIALS AND METHODS: This is a pooled analysis on patients aged >=80 years selected between subjects enrolled in 3 phase I-II studies on a short course palliative treatment of advanced or metastatic cancer. The primary endpoint was to evaluate the symptoms response rate produced by accelerated radiotherapy delivered in 4 total fractions in twice a day. Total dose ranged between 14 Gy and 20 Gy while dose/fraction between 3.5 and 5 Gy. RESULTS: A total of 48 patients were included in this analysis. Twenty six patients (54.2%) had advanced primary or metastatic head and neck tumors, 11 (22.9%) locally advanced or metastatic thoracic cancers, 11 (22.9%) complicated bone metastases. The majority of patients presented pain (60.4%). With a median follow-up time of 5.5 months, no G4 acute and late toxicities were recorded. The overall palliative response rate was 91.7% with a median duration of palliation of 4 months. CONCLUSION: Short course accelerated radiotherapy in locally advanced or metastatic cancers is effective in terms of symptom relief and well tolerated even in older patients. PMID- 29398456 TI - Comparison of Partial Versus Radical Nephrectomy Effect on Other-cause Mortality, Cancer-specific Mortality, and 30-day Mortality in Patients Older Than 75 Years. AB - BACKGROUND: Historically, partial nephrectomy (PN) showed no benefit on other cause mortality (OCM) in elderly patients with small renal masses. OBJECTIVE: To test the effect of PN versus radical nephrectomy (RN) on OCM, cancer-specific mortality (CSM), as well as 30-d mortality in patients with nonmetastatic T1a renal cell carcinoma (RCC), aged >=75 yr old. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance, Epidemiology and End Results registry (2004-2014), we identified surgically treated patients with nonmetastatic pT1a RCC aged >=75 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We relied on propensity score (PS) matching to reduce the effect of inherent differences between PN and RN. After PS matching, cumulative incidence, multivariable competing-risks regression (CRR) and logistic regression models were used. LOESS plots graphically depicted the relation between nephrectomy type and OCM after adjustment for all the covariates. Landmark analyses at 6 mo tested for immortal time bias. RESULTS AND LIMITATIONS: Of all 4541 patients, 41.6% underwent PN. After 1:1 PS matching, 2826 patients remained. In multivariable CRR models, lower OCM rates were recorded in PN patients (hazard ratio [HR]: 0.67, confidence interval [CI]: 0.54 0.84; p<0.001). LOESS plots showed lower OCM rates after PN across all examined ages. Lower CSM rates were also recorded in PN patients (HR: 0.64, CI=0.44-0.92; p=0.02). Landmark analyses rejected the hypothesis of immortal time bias. Finally, PN did not result in different 30-d mortality rates (odds ratio: 1.87; CI: 0.79-4.47; p=0.2) versus RN. Data are retrospective. CONCLUSIONS: PN results in lower OCM in elderly patients with pT1a RCC. Moreover, PN does not contribute to higher CSM or 30-d mortality in patients aged >=75 yr. In consequence, PN should be given strong consideration, even in elderly patients. PATIENT SUMMARY: Partial nephrectomy (PN) may protect from renal insufficiency, hypertension, and other unfavorable health outcomes, even in elderly patients. This protective effect results in lower other-cause mortality. Moreover, PN benefits are not undermined by higher cancer-specific mortality or 30-d mortality. PMID- 29398457 TI - Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy. AB - BACKGROUND: Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. OBJECTIVE: To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Ten patients with treatment-naive prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. RESULTS AND LIMITATIONS: Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. CONCLUSIONS: Treatment-naive, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. PATIENT SUMMARY: Untreated patients' tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated. PMID- 29398458 TI - The Potential Role of MicroRNAs as Biomarkers in Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis. AB - CONTEXT: Benign prostate hyperplasia (BPH) is one of the most common urologic diseases. However, the molecular and cellular mechanisms involving the stromal and epithelial components of the prostate that lead to BPH remain unclear. OBJECTIVE: To review and evaluate the evidence implicating microRNAs (miRNAs) in the pathogenesis of BPH. EVIDENCE ACQUISITION: A systematic search of the PubMed and Embase databases was performed using the terms "benign prostate hypertrophy and miRNA" or ("benign prostate hypertrophy and microRNAs" or "miRNA" or "miR") on July 31, 2017. EVIDENCE SYNTHESIS: Sixty-four miRNAs from 37 selected articles were ranked according to p values (p<=0.05). To avoid false positive results, Benjamini-Hochberg correction of p values was performed. Application of the robust rank aggregation method identified miR-221 as significantly associated with BPH (p=0.013). The effect size (ES) was calculated for studies with miR-221 data to generate an estimate of the overall ES and its confidence interval. The ES for miR-221 was measured by the standardized mean difference obtained by dividing the difference in the average gene expression between the PCa and BPH groups by a pooled estimate of standard deviation. The random effects model was used to calculate the pooled ES due to the presence of heterogeneity among studies. Publication bias of the seven included studies was assessed by the Funnel plot and Egger's test and it was detected in the overall analysis of the seven studies (p<0.01). After the trim and fill procedure, Egger's test revealed no evidence of publication bias (p=0.76) CONCLUSIONS: miR-221 has the potential to be used both as a biomarker and novel target in the early diagnosis and therapy of BPH. Technological advances should enable the synthesis of pre-RNA or anti-RNA molecules within carrier vehicles that can be safely delivered into patients. The development of such new pharmacologic therapies should be lastly investigated as possible therapy of one of the most common urologic diseases among elderly men. PATIENT SUMMARY: miR-221 has the potential to be used both as a biomarker and novel target in the early diagnosis and therapy of benign prostate hyperplasia. The development of new pharmacologic therapies enabling the synthesis of anti-miR-221 should be lastly investigated as a possible therapy of one of the most common urologic diseases among elderly men. PMID- 29398459 TI - The importance of involving midwives before and during the implementation of an antenatal pertussis vaccination program in New South Wales, Australia. AB - PROBLEM: Typically there is limited opportunity for stakeholder engagement to determine service delivery gaps when implementing an outbreak or supplementary vaccination program. BACKGROUND: In response to increasing pertussis notifications in NSW, Australia, an antenatal pertussis vaccination program was introduced offering pertussis containing vaccine to all pregnant women in the third trimester. AIM: To explore the effectiveness of consulting with midwives prior to and during a new state-wide vaccination program. METHODS: A pre-program needs analysis was conducted through an online audit of the NSW Clinical Midwifery Consultants followed by a post-implementation audit at 18 months. FINDINGS: Information received from the midwives was utilised during program planning which facilitated program implementation without any major issues in all Local Health Districts. The post-implementation audit provided feedback to program planners that that implementation was continuing consistently and Midwives were found to be very supportive and engaged. DISCUSSION: Education and support of clinicians is vital for high vaccine uptake in new vaccination programs which can be enabled through appropriate educational packages and program resources. CONCLUSION: Consulting with the midwives in advance of a new vaccination program was a new initiative and highly recommended as it was time well spent gaining essential information on program resourcing and operational needs. Conducting a post-implementation audit is also strongly recommended as a check-point for issues and recommendations, to empower frontline staff and support consistent program implementation. Frontline staff engagement before and during implementation of a new vaccination program is a powerful mechanism for effective, efficient and consistent program delivery. PMID- 29398460 TI - A novel chemiluminescent immunoassay based on original acridinium ester labels as better solution for diagnosis of human toxoplasmosis than conventional ELISA test. AB - Toxoplasma gondii infection is one of the most common human zoonosis. Laboratory diagnosis of this disease is mainly based on the results of serological methods detecting specific antibodies in the patient's sera. In this study we aimed to evaluate the performance of a chemiluminescence immunoassay (CLIA) based on the use of a novel immunochemical reagent in the form of the conjugate of original acridinium label (AL) attached to secondary antibody (IgG-AL) and SAG2-GRA1-ROP1L chimeric antigen for T. gondii specific antibodies detection. The CLIA test was compared with conventional ELISA, which was based on the same recombinant antigen and differed only in terms of the detection methodology of immune complexes. The new CLIA assay proved to be more sensitive and better differentiated sera of patients with T. gondii infection from sera of healthy individuals, being a promising alternative to more labor, cost-demanding and less versatile ELISA as screening test in toxoplasmosis diagnostics. PMID- 29398461 TI - Presence of immune deficiency increases the risk of hospitalization in patients with norovirus infection. AB - Norovirus is an emerging pathogen causing gastroenteritis. We sought to identify factors associated with clinical outcomes in a cohort of patients with laboratory confirmed norovirus infection. We performed a retrospective chart review of patients with positive norovirus polymerase chain reaction in stool between October 1, 2015, and May 31, 2016. 128 unique patients were identified during the study period, 64 of whom had immune deficiency, of which only 3 patients had a primary immune deficiency (common variable immune deficiency), while 61 patients had a secondary immune deficiency. 50% of patients with immune deficiency were hospitalized as compared to only 30% of the non-immune-deficient cohort (odds ratio: 2.1 (1.1-4.18, P=0.04). One-third (32.8%) of the patients had a polymicrobial stool infection, and 21.1% had concurrent Clostridium difficile infection. Initial mean total leukocyte count was higher in the hospitalized group at 8.40*109/L versus 6.31*109/L in the nonhospitalized group (P=0.049). All 13 patients presenting with fever had symptomatic resolution (P=0.002). The presence of C. difficile infection was correlated with persistent symptoms (OR 2.30 [0.95-5.58], P=0.067). The overall mortality rate among our cohort was 3.13% (4 patients). All deceased patients had secondary immune deficiency, and none had C. difficile coinfection. Presence of an immune deficiency increases the risk of hospitalization with norovirus infection. Absence of fever is associated with lower resolution and possibly may contribute to a persistent infectious state. Presence of concomitant C. difficile infection is correlated with a lower overall mortality rate. PMID- 29398462 TI - Receiver operating characteristic curve analysis of four Aspergillus-specific IgG assays for the diagnosis of chronic pulmonary aspergillosis. AB - Measurement of Aspergillus-specific IgG is central to the diagnosis of chronic pulmonary aspergillosis (CPA), but manufacturers' guidance on test interpretation is based on unpublished data. We performed the first receiver operating characteristic (ROC) area under the curve (AUC) analysis to identify optimal cut offs for this test in relation to European controls. Aspergillus-specific IgG levels were measured in sera from British adults with CPA and European healthy controls by ImmunoCAP, Immulite, Serion and Bio-Rad assays. ROC AUC analysis was performed to identify optimal cut-offs. ROC AUC results were; Bio-Rad 0.955, Immulite 0.948, ImmunoCAP 0.956 and Serion 0.944. Optimal diagnostic cut-offs were 1.5 AU/mL for Bio-Rad (93% sensitive, 98% specific), 25 mg/L for Immulite (93% sensitive, 99% specific), 50 mg/L for ImmunoCAP (84% sensitive, 96% specific) and 50 U/mL for Serion (84% sensitive, 91% specific). These cut-offs differ from manufacturers' guidance and from those previously calculated in relation to Ugandan controls. PMID- 29398463 TI - Coexistence of septic and crystal-induced arthritis: A diagnostic challenge. A report of 25 cases. AB - OBJECTIVE: Septic arthritis is a medical emergency and crystal-induced arthritis is a risk factor for its development. If both occur simultaneously, crystal induced arthritis may mask the diagnosis of infection and delay antibiotic therapy. METHOD: Retrospective analysis of patients with coexistence of septic and crystal-induced arthritis. We included only patients with isolation of crystals in synovial fluid analysis and positive culture of synovial fluid and/or blood culture. RESULTS: A total of 25 patients (17 men and 8 women) with a mean age of 67 years. The most commonly affected joint was the knee. In synovial fluid cytological studies, the most frequently identified crystals were monosodium urate. Risk factors included diabetes and chronic renal failure. The most frequently isolated germs were methicillin-sensitive S. aureus (48%), methicillin resistant S. aureus (12%) and Mycobacterium tuberculosis (12%). In all, 36% of subjects required surgical drainage (excluding those caused by M. tuberculosis). Clinical outcome was favorable in 56%, although intercurrent complications were usual (40%). Mortality was 8%. CONCLUSIONS: Coexistence of septic and crystal induced arthritis represents a diagnostic challenge and requires a high index of suspicion. Gout was the most prevalent crystal-induced arthritis. S. aureus was the most commonly causative pathogen, with a high rate of methicillin-resistant S. aureus infection. If treated early, the outcome is usually favorable, making synovial fluid microbiological study imperative. PMID- 29398464 TI - Syphilis in the Setting of Anti-tumor Necrosis Factor Alpha Therapy. AB - Inhibitors of tumor necrosis factor-alpha (anti-TNF-alpha) are widely used in different medical specialties. The main adverse effect of these agents is the increased risk of infection. We report the case of a 30-year-old man with ankylosing spondylitis who had begun receiving golimumab two weeks earlier. He presented with a 10-day history of salmon-colored lesions on trunk, palms and soles. The clinical suspicion was secondary syphilis. Treponemal and nontreponemal tests confirmed the diagnosis of syphilis. Lumbar puncture was also performed, although there was no neurological involvement, to rule out neurosyphilis. Cases of syphilis in patients in treatment with TNF-alpha inhibitors are uncommon in the literature and there are no established protocols. PMID- 29398465 TI - Noninfectious aortitis: Experience with tocilizumab in a regional hospital. AB - OBJECTIVES: Describe patients with noninfectious aortitis and their response to treatment in a regional hospital. METHODS: Review of patients with noninfectious aortitis, diagnostic technique used and immunosuppressive therapy received. RESULTS: We report 8 patients (7 women and one man) diagnosed with aortitis by positron emission tomography (PET). The mean age was 69years (interquartile range [IQR] 62-72.2). Three months of treatment with tocilizumab improved symptoms, erythrocyte sedimentation rate and C-reactive protein level (P<.001 and P<.012, respectively) in the 6 patients in whom it was used. CONCLUSIONS: Tocilizumab was an effective and safe treatment in those patients diagnosed with aortitis refractory to steroids and conventional immunosuppressive therapy. PMID- 29398466 TI - Relationship between fecal calprotectin, anti-Saccharomyces cerevisiae antibodies and other markers of disease activity in patients with spondyloarthritis. AB - OBJECTIVE: To assess the relationship between the increase of fecal calprotectin, anti-Saccharomyces cerevisiae antibodies (ASCA) and disease markers in a group of patients with spondyloarthritis. METHODS: We evaluated patients who were at least 18-years-old and met the Assessment in Spondyloarthritis International Society (ASAS) criteria for spondyloarthritis or the New York modified criteria. We analyzed activity criteria, physical function, analytical criteria (human leukocyte antigen [HLA] B27, fecal calprotectin, presence of ASCA, among others) and demographic data. RESULTS: We included 33 patients. All but one patient had normal ASCA values. We found statistical significance in the correlation of calprotectin with C-reactive protein (CRP) but not with other parameters. We also found a relationship between calprotectin levels and nonsteroidal anti inflammatory drug (NSAID) intake (P=.001). We found no relationship between CRP levels and NSAID use. After discontinuation of NSAIDs for one month, we found no significant differences in calprotectin levels (P=.9). CONCLUSION: Fecal calprotectin is elevated in patients with spondyloarthritis and correlates positively with CRP. Level of fecal calprotectin is not altered by NSAID use. The amount of ASCA present does not change and does not correlate with any clinical parameters in the study population. PMID- 29398467 TI - Complete Response to Single-agent Palbociclib in Metastatic Breast Cancer: A Case Report. PMID- 29398468 TI - Techniques Used to Localize Occult Breast Lesions: An Update. AB - With breast cancer screening programs becoming more available worldwide and covering larger age ranges, the prevalence of impalpable breast pathology is increasing. Whilst there is a 'tried and tested' technique for localizing occult lesions, the market for alternative methods is increasing and is estimated to pass $1 billion by 2024. In this article, we review the techniques currently available for localization of occult breast lesions and discuss the pros and cons of each. PMID- 29398470 TI - Body Image: Celebrating the past, appreciating the present, and envisioning the future. PMID- 29398469 TI - Proportion of patients with cancer among high-cost Medicare beneficiaries: Who they are and what drives their spending. AB - BACKGROUND: A small proportion of patients account for the majority of health care spending. Of this group, little is known about what proportion have a cancer diagnosis and how their spending pattern compares to those without cancer. METHODS: Using national Medicare data of enrollees 65 or older, we identified patients in the top decile of spending in 2014 and designated them as high-cost. We used ICD-9 codes to identify patients with a cancer diagnosis and examined cancer prevalence among both high-cost and non-high-cost patients. We examined patterns of spending for high-cost patients with and without cancer. RESULTS: While 14.8% of all Medicare beneficiaries have a cancer diagnosis, we found that the prevalence of a cancer diagnosis was much higher among high-cost patients (32.5% versus 12.9% of non-high-cost patients). Thus, having a cancer diagnosis was associated with a 3.1 times greater odds of being high-cost, even after accounting for age (odds ratio 3.09, 95% CI 3.07-3.11; P < 0.001). High-cost patients with cancer had higher total annual spending than high-cost patients without cancer ($66,685 vs. $59,427; p < 0.0001); costs among high-cost cancer patients were driven by greater use of outpatient treatments (19.2% of total spending vs. 13.6% among non-cancer high-cost patients, p < 0.0001) and more prescription drugs (11.9% vs. 9.9%; p < 0.0001). CONCLUSIONS: There is a high prevalence of cancer diagnoses among high-cost Medicare patients. IMPLICATIONS: Programs that target high-cost patients may need to customize interventions based on whether the patient has a cancer diagnosis. PMID- 29398471 TI - Tuberculous Aortitis Associated With Pleuritis and Spondylitis. PMID- 29398472 TI - Long Noncoding RNA AK12348 is Involved in the Regulation of Myocardial Ischaemia Reperfusion Injury by Targeting PARP and Caspase-3. AB - BACKGROUD: Recently long non-coding RNAs (lncRNAs) have attracted attention in several biomedical fields. The purpose of this study is to investigate the profile of myocardial lncRNAs and their potential roles in myocardial ischaemia reperfusion injury (IRI). METHODS: EdgeR bioconductor package was used to screen differentially expressed lncRNAs in myocardial IRI, and lncRNA AK12348 was selected. The mRNA levels of lncRNA AK12348 in normal and anoxia/reoxygenation (A/R) cardiomyocytes were determined by qRT-PCR. After transfection with siRNA lncRNA, AK12348, LDH release and cell apoptotic rates in normal and A/R cardiomyocytes were determined. The protein expression values of PARP and Caspase 3 were also determined by western blotting. RESULTS: The relative level of lncRNA AK12348, LDH release and cell apoptotic rate in A/R cardiomyocytes was significantly higher than that in normal cardiomyocytes. After transfection with siRNA-lncRNA AK12348, LDH release and cell apoptotic rates in A/R cardiomyocytes were reduced, while the values in normal cardiomyocytes had almost no change. The protein expression values of PARP and Caspase-3 in A/R cardiomyocytes were much higher than the Control. After knockdown of lncRNA AK12348, the values decreased. CONCLUSION: Long non-coding RNAs AK12348 could be potential therapeutic targets for the treatment of myocardial IRI. PMID- 29398473 TI - Daily Step Count as a Simple Marker of Disease Severity in Hypertrophic Cardiomyopathy. AB - BACKGROUND: Individuals with hypertrophic cardiomyopathy (HCM) may be asymptomatic or display activity-limiting symptoms. A common cause of symptoms is left ventricular outflow tract obstruction (LVOTO), which may impact the individuals' ability to undertake physical activity. This study sought to examine daily step count as a potential marker of exercise capacity, which may represent a proxy marker of disease severity in HCM. METHODS: A cross-sectional study of 63 HCM patients was conducted from March to November 2015. Participants wore an ActiGraph GT3X+ (Pensacola, Florida, USA) accelerometer for 7 days. Minutes per day of light, moderate and vigorous physical activity and step count were calculated, and those with LVOTO were compared to those without. Similarly, those with good functional capacity (New York Heart Association; NYHA class I) were compared to those with NYHA class II-IV. RESULTS: The majority of HCM patients were male (n=45, 71%) with mean age of 48.8+/-14.9years. Hypertrophic cardiomyopathy patients with history of LVOTO and those NYHA class II-IV took significantly fewer steps per day (LV obstruction: 5527+/-2370 versus 7027+/ 2095, p=0.01 and NYHA: 5346+/-1898 versus 6801+/-2339, p=0.03). No differences were observed across the different intensities of physical activity. CONCLUSIONS: Measurement of daily step count may be a useful and simple tool to determine exercise capacity and provide an indicator of disease severity in individuals with HCM. PMID- 29398474 TI - Measuring tuberculosis transmission in low-incidence countries. PMID- 29398475 TI - 'Tricep tear instead of Tricep Curl': Management in the Emergency Department. PMID- 29398476 TI - Frequent isolation of extended-spectrum beta-lactamase-producing bacteria from fecal samples of individuals with severe motor and intellectual disabilities. AB - Extended-spectrum beta-lactamase (ESBL) producing bacteria spread worldwide and became major concern for antibiotic treatment. Although surveillance reports in general hospitals and long-term care facilities are increasing, their frequencies in individuals with severe motor and intellectual disabilities (SMID) are so far unknown. In this study, we examined the frequency of ESBL in stool samples collected from 146 asymptomatic SMID subjects hospitalized in a single institution. With their clinical information, we evaluated possible risk factors for ESBL colonization. From 146 fecal samples, ESBL-producing bacteria were isolated in 45 cases (31%). Drug sensitivity testing showed that 82% of the isolates were resistant to levofloxacin but were sensitive to tazobactam/piperacillin and cefmetazole. The most frequent genotype was CTX-M-9 detected in 36/45 (80%). A high degree of disability, antibiotic use within three months before sampling and post-tracheostomy were statistically significant risk factors. Tube feeding was also strongly correlated with ESBL colonization (p < 0.001) and associated with lower micro-organismic diversities. Our findings are the first to reveal a high prevalence of ESBL in the fecal samples of SMID individuals and suggest possible relationships between high degree disability, tube feeding and latest histories of antibiotic use. PMID- 29398477 TI - Clinical safety and efficacy of "filgrastim biosimilar 2" in Japanese patients in a post-marketing surveillance study. AB - We conducted a post-marketing surveillance to evaluate the safety and efficacy of TKN732, approved as "filgrastim biosimilar 2", in Japanese patients who developed neutropenia in the course of cancer chemotherapy or hematopoietic stem cell transplantation. A total of 653 patients were registered during the 2-year enrollment period starting from May 2013, and 627 and 614 patients were eligible for safety and efficacy analyses of the G-CSF biosimilar, respectively. Forty three adverse drug reactions were reported in 33 patients (5.26%). Back pain was most frequently observed and reported in 20 patients (3.19%), followed by pyrexia (1.28%) and bone pain (0.96%). Risk factors for adverse reactions identified by logistic regression analyses were younger age, presence of past medical history, and lower total dose at the onset of adverse reactions. Among the 576 cancer patients who developed Grade 2-4 neutropenia after chemotherapy, recovery to Grade 1/0 was reported in 553 patients (96%) following filgrastim biosimilar 2 treatment. The median duration of neutrophil counts below 1500/MUL was 5 days. In addition, all 11 patients who underwent hematopoietic stem cell transplantation had good responses to filgrastim biosimilar 2. In conclusion, this study showed that filgrastim biosimilar 2 has a similar safety profile and comparable effects to the original G-CSF product in the real world clinical setting. PMID- 29398478 TI - Diagnostic predictors of Legionella pneumonia in Japan. PMID- 29398479 TI - Impact of the national routine vaccination program on 23-valent pneumococcal polysaccharide vaccine vaccination rates in elderly persons in Japan. AB - Low vaccination rates with pneumococcal vaccine in elderly persons in Japan are thought to be related to low levels of public subsidy. We previously reported that larger subsidies were significantly associated with elevated vaccination rates with the 23-valent pneumococcal vaccine (PPV23) in elderly persons. Since 2014, the Japanese government has offered subsidies through a 5-year national routine vaccination program for elderly persons at 5-year age intervals. Here, we investigated the effect of the national routine vaccination program on PPV23 vaccination rates. PPV23 vaccination rates were calculated as follows: cumulative amount shipped to each municipality divided by the population aged >=65 years. At the end of 2015, 2 years into the 5-year national immunization program, the estimated vaccination rate was 40.6%, which was significantly increased compared with former periods (p = 0.01). Our findings show that the national routine vaccination program plays an important role in increasing the vaccination rate of PPV23 in Japan. PMID- 29398480 TI - Comparison of Non-human Primate versus Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Treatment of Myocardial Infarction. AB - Non-human primates (NHPs) can serve as a human-like model to study cell therapy using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, whether the efficacy of NHP and human iPSC-CMs is mechanistically similar remains unknown. To examine this, RNU rats received intramyocardial injection of 1 * 107 NHP or human iPSC-CMs or the same number of respective fibroblasts or PBS control (n = 9-14/group) at 4 days after 60-min coronary artery occlusion-reperfusion. Cardiac function and left ventricular remodeling were similarly improved in both iPSC-CM-treated groups. To mimic the ischemic environment in the infarcted heart, both cultured NHP and human iPSC-CMs underwent 24-hr hypoxia in vitro. Both cells and media were collected, and similarities in transcriptomic as well as metabolomic profiles were noted between both groups. In conclusion, both NHP and human iPSC-CMs confer similar cardioprotection in a rodent myocardial infarction model through relatively similar mechanisms via promotion of cell survival, angiogenesis, and inhibition of hypertrophy and fibrosis. PMID- 29398481 TI - In Vitro Modeling of Human Germ Cell Development Using Pluripotent Stem Cells. AB - Due to differences across species, the mechanisms of cell fate decisions determined in mice cannot be readily extrapolated to humans. In this study, we developed a feeder- and xeno-free culture protocol that efficiently induced human pluripotent stem cells (iPSCs) into PLZF+/GPR125+/CD90+ spermatogonium-like cells (SLCs). These SLCs were enriched with key genes in germ cell development such as MVH, DAZL, GFRalpha1, NANOS3, and DMRT1. In addition, a small fraction of SLCs went through meiosis in vitro to develop into haploid cells. We further demonstrated that this chemically defined induction protocol faithfully recapitulated the features of compromised germ cell development of PSCs with NANOS3 deficiency or iPSC lines established from patients with non-obstructive azoospermia. Taken together, we established a powerful experimental platform to investigate human germ cell development and pathology related to male infertility. PMID- 29398482 TI - Testicular Architecture Is Critical for Mediation of Retinoic Acid Responsiveness by Undifferentiated Spermatogonial Subtypes in the Mouse. AB - Spermatogenesis requires retinoic acid (RA) induction of the undifferentiated to differentiating transition in transit amplifying (TA) progenitor spermatogonia, whereas continuity of the spermatogenic lineage relies on the RA response being suppressed in spermatogonial stem cells (SSCs). Here, we discovered that, in mouse testes, both spermatogonial populations possess intrinsic RA-response machinery and exhibit hallmarks of the differentiating transition following direct exposure to RA, including loss of SSC regenerative capacity. We determined that SSCs are only resistant to RA-driven differentiation when situated in the normal topological organization of the testis. Furthermore, we show that the soma is instrumental in "priming" TA progenitors for RA-induced differentiation through elevated RA receptor expression. Collectively, these findings indicate that SSCs and TA progenitor spermatogonia inhabit disparate niche microenvironments within seminiferous tubules that are critical for mediating extrinsic cues that drive fate decisions. PMID- 29398483 TI - Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB. PMID- 29398484 TI - Intraoperative Molecular Imaging in Lung Cancer: The State of the Art and the Future. PMID- 29398485 TI - Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF. AB - Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation. PMID- 29398486 TI - Hepatocyte Growth Factor Improves the Therapeutic Efficacy of Human Bone Marrow Mesenchymal Stem Cells via RAD51. AB - Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease. PMID- 29398488 TI - A guide to interpreting estimated median age of survival in cystic fibrosis patient registry reports. AB - Survival statistics, estimated using data collected by national cystic fibrosis (CF) patient registries, are used to inform the CF community and monitor survival of CF populations. Annual registry reports typically give the median age of survival, though different registries use different estimation approaches and terminology, which has created confusion for the community. In this article we explain how median age of survival is estimated, what its interpretation is, and what assumptions and limitations are involved. Information on survival from birth is less useful for individuals who have already reached a certain age and we propose use of conditional survivor curves to address this. We provide recommendations for CF registries with the aim of facilitating clear and consistent reporting of survival statistics. Our recommendations are illustrated using data from the UK Cystic Fibrosis Registry. PMID- 29398487 TI - Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria. AB - Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 MUM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU. PMID- 29398489 TI - Young patients with cystic fibrosis demonstrate subtle alterations of the cardiovascular system. AB - BACKGROUND: As life expectancy increases in patients with cystic fibrosis, it is important to pay attention to extra-pulmonary comorbidities. Several studies have shown signs of myocardial dysfunction in adult patients, but little is known about onset and development of these changes over time. In this prospective study, cardiac function in children with cystic fibrosis was compared to that of healthy children. METHODS: 33 children, aged 3-12years, with cystic fibrosis were recruited from the Wilhelmina Children's hospital and 33 age-matched healthy children were selected from the WHISTLER study, a population-based cohort study. Measurements of lung function, arterial stiffness, and echocardiography (conventional measures and myocardial deformation imaging) were performed. RESULTS: There were no differences in anthropometrics, lung function and blood pressure between the two groups. The cystic fibrosis children had a higher arterial stiffness compared to the healthy children (pulse wave velocity respectively 5.76+/-0.57m/s versus 5.43+/-0.61m/s, p-value 0.049). Using conventional echocardiographic parameters for right ventricular function, Tricuspid Annular Plane Systolic Excursion) and Tissue Doppler Imaging, cystic fibrosis children had a reduced right ventricular systolic function when compared to the healthy children. After adjustment for lung function, global strains of both right and left ventricles were significantly lower in the cystic fibrosis group than in healthy children (linear regression coefficient 1.45% left ventricle, p-value 0.022 and 4.42% right ventricle, p-value <0.01). Systolic strain rate of basal segment of the left ventricle, the mid segment of the right ventricle and the apical septum were significantly lower in the cystic fibrosis children than in healthy controls. CONCLUSION: Our study suggests that already at a very young age, children with cystic fibrosis show an increased arterial stiffness and some signs of diminished both right and left ventricular function. PMID- 29398490 TI - Reversible Parkinsonism induced by acute exposure glyphosate. PMID- 29398491 TI - Pain sensitivity in Parkinson's disease: Systematic review and meta-analysis. AB - INTRODUCTION: Pain is a common and disabling non-motor symptom of Idiopathic Parkinson's disease (PD) but its underlying pathophysiological mechanisms are not well understood. There is evidence to suggest that altered pain sensitivity may contribute to the experience of pain in PD patients, but clinical studies investigating this have yielded inconsistent results. OBJECTIVES: To examine whether pain thresholds are altered in PD patients compared to normal healthy controls (HC), via the use of systematic review and meta-analysis. DATA SOURCES: A systematic search of the MEDLINE and EMBASE library from 1966 to April 2015. STUDY SELECTION: Studies that compared pain thresholds in PD patients versus HC were included in the systematic review. Additionally, data comparing PD patients off dopaminergic medications (PDMoff) to HC off medications (HCMoff) were pooled for meta-analysis by pain modality. MAIN OUTCOMES: Heat pain threshold, cold pain threshold, electrical pain threshold, nociceptive withdrawal reflex threshold, pressure pain threshold, and pain ratings. RESULTS: 22 studies were reviewed, comprising of 616 PD and 451 HC. In the comparison of PDMoff versus HCMoff, a large majority of trials (15/19) found reduced pain thresholds (increased pain sensitivity) in PD patients. Meta-analysis of these trials revealed significantly reduced pain thresholds, of moderate to large effect size, in PD patients across all pain modalities. Results were much more heterogenous when PD patients on medications were compared with HC off medications, with most trials reporting no significant difference in pain thresholds between groups. No significant differences were found in pain thresholds for trials that compared PD patients on medications and HC on medications. CONCLUSION: PD patients are more sensitive to noxious stimuli compared to HC when tested in the off medication state. This increase in pain sensitivity is observed across all modalities, but is not as apparent when PD patients are administered Levodopa, suggesting that dopamine deficient states may contribute to hyperalgesia. However, it remains to be seen whether or not increased pain sensitivity translates clinically into increased prevalence of pain. Similarly, it is unclear if dopaminergic medications influence pain sensitivity. Performing a meta-analysis on studies comparing pain thresholds in PD patients with and without pain, and on and off dopaminergic medications, may draw more definitive conclusions in this regard. PMID- 29398492 TI - Artificial Intelligence and Radiology: Collaboration Is Key. PMID- 29398493 TI - Impact on Quality When Pediatric Urgent Care Centers Are Staffed With Radiology Technologists. AB - PURPOSE: The proliferation of pediatric urgent care centers has increased the need for diagnostic imaging support, but the impact of employing radiology technologists at these centers is not known. The purpose of this study was to evaluate radiographic impact and quality at urgent care centers with and without radiology technologists. METHODS: A retrospective case-control study was conducted comparing 235 radiographic examinations (study) performed without and 83 examinations (control) performed with a radiology technologist at the authors' pediatric urgent care centers. Studies were evaluated for quality using a five point, Likert-type scale (1 = poor, 5 = best) regarding field of view, presentation, and orthogonal view orientation. Studies were also evaluated for the incidence of positive results, need for repeat imaging, and discrepancies between initial study and follow-up. RESULTS: Imaging quality comparisons between study and control groups were statistically different for field of view (3.98 versus 4.29, P = .014), presentation (4.39 versus 4.51, P = .045), and orthogonal view orientation (4.45 versus 4.69, P = .033). The incidence of repeat imaging was similar (4.7% versus 2.4%, P = 0.526), as well as the discrepancy rates (3.4 versus 2.4%, P = 1.00). The incidence of abnormal radiographic findings for the study and control groups was similar (40.9% versus 34.9%, P = .363). CONCLUSIONS: Radiography is an important triage tool at pediatric urgent care centers. It is imperative to have optimal radiographic imaging for accurate diagnosis, and imaging quality is improved when radiology technologists are available. If not feasible or cost prohibitive, it is important that physicians be given training opportunities to bridge the quality gap when using radiographic equipment and exposing children to radiation. PMID- 29398494 TI - Machine Learning in Medical Imaging. AB - Advances in both imaging and computers have synergistically led to a rapid rise in the potential use of artificial intelligence in various radiological imaging tasks, such as risk assessment, detection, diagnosis, prognosis, and therapy response, as well as in multi-omics disease discovery. A brief overview of the field is given here, allowing the reader to recognize the terminology, the various subfields, and components of machine learning, as well as the clinical potential. Radiomics, an expansion of computer-aided diagnosis, has been defined as the conversion of images to minable data. The ultimate benefit of quantitative radiomics is to (1) yield predictive image-based phenotypes of disease for precision medicine or (2) yield quantitative image-based phenotypes for data mining with other -omics for discovery (ie, imaging genomics). For deep learning in radiology to succeed, note that well-annotated large data sets are needed since deep networks are complex, computer software and hardware are evolving constantly, and subtle differences in disease states are more difficult to perceive than differences in everyday objects. In the future, machine learning in radiology is expected to have a substantial clinical impact with imaging examinations being routinely obtained in clinical practice, providing an opportunity to improve decision support in medical image interpretation. The term of note is decision support, indicating that computers will augment human decision making, making it more effective and efficient. The clinical impact of having computers in the routine clinical practice may allow radiologists to further integrate their knowledge with their clinical colleagues in other medical specialties and allow for precision medicine. PMID- 29398495 TI - Architect Glasses. PMID- 29398496 TI - Author's Reply. PMID- 29398497 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria Routine Chest Radiography. PMID- 29398499 TI - Why CAD Failed in Mammography. PMID- 29398498 TI - Prediction of Occult Invasive Disease in Ductal Carcinoma in Situ Using Deep Learning Features. AB - PURPOSE: The aim of this study was to determine whether deep features extracted from digital mammograms using a pretrained deep convolutional neural network are prognostic of occult invasive disease for patients with ductal carcinoma in situ (DCIS) on core needle biopsy. METHODS: In this retrospective study, digital mammographic magnification views were collected for 99 subjects with DCIS at biopsy, 25 of which were subsequently upstaged to invasive cancer. A deep convolutional neural network model that was pretrained on nonmedical images (eg, animals, plants, instruments) was used as the feature extractor. Through a statistical pooling strategy, deep features were extracted at different levels of convolutional layers from the lesion areas, without sacrificing the original resolution or distorting the underlying topology. A multivariate classifier was then trained to predict which tumors contain occult invasive disease. This was compared with the performance of traditional "handcrafted" computer vision (CV) features previously developed specifically to assess mammographic calcifications. The generalization performance was assessed using Monte Carlo cross-validation and receiver operating characteristic curve analysis. RESULTS: Deep features were able to distinguish DCIS with occult invasion from pure DCIS, with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval, 0.68-0.73). This performance was comparable with the handcrafted CV features (area under the curve = 0.68; 95% confidence interval, 0.66-0.71) that were designed with prior domain knowledge. CONCLUSIONS: Despite being pretrained on only nonmedical images, the deep features extracted from digital mammograms demonstrated comparable performance with handcrafted CV features for the challenging task of predicting DCIS upstaging. PMID- 29398500 TI - The ACR Data Science Institute and AI Advisory Group: Harnessing the Power of Artificial Intelligence to Improve Patient Care. PMID- 29398501 TI - Information and Artificial Intelligence. PMID- 29398502 TI - Comments on "Physician Knowledge of Radiation Exposure and Risk in Medical Imaging". PMID- 29398503 TI - Hypopharyngeal reconstruction using a circular stapler. AB - Distal anastomosis by tubed free flap is one of the main technical difficulties encountered during hypopharyngeal reconstruction. Although high flap survival probability can be achieved by experienced surgical teams, two complications are commonly observed at the flap-oesophagus junction: fistula and stenosis. Use of a circular stapler reduced the frequency of these complications by ensuring a perfectly circular and resistant suture line. Salivary stent placement is therefore unnecessary, allowing earlier resumption of feeding. The stapling procedure is simple, but a few technical skills are required, as the stapler is not specifically designed for this purpose. We describe the indications, surgical procedure and global results based on our series. We consider the forearm flap to be the gold standard for this reconstruction, but thicker flaps, such as pectoralis major flap, can also be used, but with poorer results in terms of healing and swallowing performance. PMID- 29398504 TI - International consensus (ICON) on basic voice assessment for unilateral vocal fold paralysis. AB - There is a growing need for evaluation tools allowing the quantification of the outcome after voice surgeries. Since the end of the 1990s, multiple unfruitful attempts have been made to reach a consensus, including the Dejonckere protocol for the European Laryngological Society in 2001. This suggested to perform objective and quantifiable measures in the following domains: perception, acoustic, aerodynamic, self-evaluation by the patient and videolaryngostroboscopy. But in a PubMed(r) search with the keywords "Voice Assessment" and "Voice Outcome" since 2001 retrieving 452 articles, only 33 of them were using methods taking into account the first four dimensions proposed by Dejonckere. To elaborate a new and simpler protocol, we chose to focus on unilateral vocal fold paralyses (UVFP), which represents a homogeneous disease in terms of physiology. This protocol was elaborated on the basis of a review of the literature and of the database and experience of the IFOS panel members. In summary, our group recommends the use and implementation of the ELS "basic protocol" with some minor modifications. Voice audio recordings are an indispensable prerequisite, and may even have medico-legal implications. We recommend the systematic use of the Voice Handicap Index (VHI). Perceptual analysis must be performed by using Hirano's GRB scale and voice breathiness has to be prioritized. Currently, acoustic analysis remains optional given the lack of data to support clinical usefulness. Aerodynamic studies should include at a minimum an evaluation of the Maximum Phonation Time, calculated in seconds following multiple trials in order to obtain a recording representing the patient's best possible glottis closure. PMID- 29398505 TI - International survey and consensus (ICON) on ambulatory surgery in rhinology. AB - OBJECTIVES: Day-case surgery is the gold standard to several surgical procedures in Rhinology. However, few data and guidelines have been published except in the Anglo-Saxon countries and France. The aim of this survey was to propose a list of issues arising during day-case surgery in order to analyze the different constraints encountered around the world. MATERIAL AND METHOD: It was a prospective multicenter international email survey. The method was based on the formalized expert consensus methodology. A list of 11 issues was based on literature data and was sent by e-mail to 265 key opinion leaders (KOL) who attended the IFOS congress. RESULTS: The response rate was 20% from 27 countries without statistical difference between continents concerning the score on each item. The mean age of KOL was 50+/-10 years. Their mean length of experience was 21+/-10 years. Issues in relation with technical resources and experience showed that the last time at which ambulatory surgery in the day is possible was 4:00 PM but responses varied depending the availability of technical resources. Bleeding or hematoma occurred most frequently between the third and fourth postoperative day whatever the surgical procedure. A strong agreement and consensus was obtained concerning the nasal packing, septal contention and their schedule of removal which were not a contraindication of day-case. Also 75% of participants were agreeing with a therapeutic education program to improve the performance of postoperative care and decrease readmission rates. A relative agreement without consensus were obtained for the distance between the day-case unit and home, the role of surgery duration and the impact of anticoagulant and/or antiplatelet drugs in overnight admission and readmission rates. CONCLUSION: Practice varies widely owing to local organization constraints and the availability of a dedicated day-case unit seems to be the main limiting factor. PMID- 29398506 TI - International consensus (ICON) on management of otitis media with effusion in children. AB - Otitis media with effusion (OME) is a common childhood disease defined as the presence of liquid in the middle ear without signs or symptoms of acute ear infection. Children can be impacted mainly with hearing impairment and/or co occurring recurrent acute otitis media (AOM) thus requiring treatment. Although many meta-analyses and national guidelines have been issued, management remains difficult to standardize, and use of surgical and medical treatments continue to vary. We convened an international consensus conference as part of the 2017 International Federation of Oto-rhino-laryngological Societies Congress, to identify best practices in OME management. Overall, regional differences were minor and consensual management was obtained on several important issues. At initial assessment, although a thorough medical examination is necessary to seek reflux, allergy or nasal obstruction symptoms; an age-appropriate auditory test is the only assessment required in children without abnormal history. Non surgical treatments poorly address the underlying problem of an age-dependent dysfunctional Eustachian tube; auto-inflation seems to be the only beneficial, low-risk and low-cost non-surgical therapy. There was a clear international recommendation against using steroids, antibiotics, decongestants or antihistamines to treat OME, because of side-effects, cost issues and no convincing evidence of long-term effectiveness. Decisions to insert tympanostomy ventilation tubes should be based on an auditory test but also take into account the child's context and overall hearing difficulties. Tubes significantly improve hearing and reduce the number of recurrent AOM with effusion while in place. Adjuvant adenoidectomy should be considered in children over four years of age, and in those with significant nasal obstruction or infection. PMID- 29398507 TI - Anti-H antibody of unusually high titer showing variable reactivities against group A red cells and broad thermal amplitude in a patient with lymphoma. AB - We report a case of a patient with high titer anti-H antibody showing broad thermal amplitude and variable reactivities against group A red cells. A 62-year old Korean female was diagnosed with diffuse large B cell lymphoma involving multiple organs. Her ABO/RhD type was A+ and her genotype was ABO*A.01.01/ABO*O.01.02. Antibody screening test (AST) and antibody identification test (IDT) were strongly positive for all reagent cells. Anti human globulin (AHG) test revealed an antibody titer of 1:256 for 37 degrees C phase and trace positivity for poly- and mono-specific C3d. Reactivity was stronger for O+ red cells than that for A+ red cells across all temperatures tested (4 degrees C, room temperature (RT) and 37 degrees C). This was also found for AHG phase. Anti-IH was ruled out based on agglutination of O+ cord cells (CCs). Antibody was determined as IgM anti-H after DTT treatment. Three batches of 10 A+ red cells from random donors were tested with three consecutive serums for crossmatching using tube method. Interestingly, out of thirty A+ red cells tested, 20 cells at RT, 11 cells at 37 degrees C and 11 cells in the AHG phase showed reactivity of greater than 2+. The patient was transfused with 6 units of packed RBCs subsequently. Chemotherapy (R-CHOP regimen) and Helicobacter pylori eradication were then started. Her antibody titer gradually decreased following such treatment. In conclusion, we identified a case of patient with high titer anti-H with broad thermal amplitude, suggesting that anti-H antibodies might need to be considered for cases with pan-agglutination in AST and IDT. PMID- 29398508 TI - Lipoprotein apheresis affects lipoprotein particle subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study. AB - Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are last therapeutic resorts in patients with familial hypercholesterolemia (FH). We explored changes in lipoprotein subclasses and high density lipoprotein (HDL) function when changing treatment from lipoprotein apheresis to PCSK9 inhibition. We measured the levels of low-density lipoprotein (LDL) and HDL particle subclasses, serum amyloid A1 (SAA1), paraoxonase-1 (PON1) activity and cholesterol efflux capacity (CEC) in three heterozygous FH patients. Concentrations of all LDL particle subclasses were reduced during apheresis (large 68.0 +/- 17.5 to 16.3 +/- 2.1 mg/dL, (p = 0.03), intermediate 38.3 +/- 0.6 to 5.0 +/- 3.5 mg/dL (p = 0.004) and small 5.0 +/- 2.6 to 0.2 +/- 0.1 mg/dL (p = 0.08)). There were non-significant reductions in the LDL subclasses during evolocumab treatment. There were non-significant reductions in subclasses of HDL particles during apheresis, and no changes during evolocumab treatment. CEC was unchanged throughout the study, while the SAA1/PON1 ratio was unchanged during apheresis but decreased during evolocumab treatment. In conclusion, there were significant reductions in large and intermediate size LDL particles during apheresis, and a non-significant reduction in small LDL particles. There were only non-significant reductions in the LDL subclasses during evolocumab treatment. PMID- 29398509 TI - HLA analysis of Mexican candidates for bone marrow transplantation and probability of finding compatible related donors. AB - INTRODUCTION: Oncohematological disorders are the main cause of morbidity in the Mexican population from 1 to 19 years old, where megakaryoblastic and promyelocitic leukemias are more frequent. Considering that the success of a transplant is multifactorial, the criterion of compatibility in the HLA system is crucial and even more so when the source of HSC is bone marrow. OBJECTIVE: To determine the frequency of the HLA genotype in Mexican candidates who require a bone marrow transplant from related donors and the probability to find donors. MATERIALS AND METHODS: One hundred twenty-six candidates for bone marrow transplant and related donors were tested for HLA class I (-A*, -B* alleles) and class II (-DRB1* allele) in intermediate-resolution, as the first phase in the choice of the possible donor. The criteria to identify donors were determined by antigen-matched in each HLA haplotype as follows: 4/6, 5/6 and 6/6 at the HLA-A*, HLA-B*, and HLA-DRB1* alleles. RESULTS: Of all the candidates analyzed, 57.93%, at least one bone marrow donor was identified; in 53 cases, no donor was found. The average size of the families was 4.79 +/- 1.06 members. A higher percentage of compatibility with grade 6/6 (31.6%) was identified with brothers, followed by sisters in 25.3%. The probability to find at least one compatible potential donor was 1.51 +/- 0.92 donors. CONCLUSION: In the first phase to select donors, Mexican patients studied in this work, have a compatible donor, however the grade of resolution test influenced in the probability identified. PMID- 29398510 TI - Minimally Invasive Plate Osteosynthesis for Treatment of Ankle Fractures in High Risk Patients. AB - Wound healing problems are the most common complication after open reduction with internal fixation (ORIF) of unstable ankle fractures. The incidence is especially high among elderly patients with medical comorbidities and patients with compromised soft tissues. Minimally invasive plate osteosynthesis (MIPO) might provide a safer alternative to ORIF by preventing extensive soft tissue dissection and preserving the blood supply. We conducted a retrospective review of 44 consecutive patients who had undergone MIPO of unstable ankle fractures. All patients had a minimum 1-year follow-up (mean 82 weeks); 80% were aged >=60 years, 52% had diabetes, and 45% had a compromised soft tissue envelope. Immediate postoperative radiographs were evaluated for the quality of reduction, and clinical records were analyzed for the complication rate. Good to excellent anatomic reduction was achieved in 89% of the patients. The overall complication rate was 27%, including 25% surgical wound dehiscence, 9% infection, and 11% loss of reduction. No patient experienced nerve injury. Those with a history of ankle fracture dislocation and a compromised soft tissue envelope preoperatively had a significantly greater incidence of surgical wound dehiscence and complications overall compared with those without (p = .016 and p = .035; p = .045 and p = .009, respectively). Peripheral vascular disease was a statistically significant predictor of surgical wound dehiscence (p = .010). The overall complication rate in our study was comparable to that seen in similar populations treated with conventional ORIF. In conclusion, our results suggest that MIPO in high-risk patients is a safe alternative, with predictable outcomes, comparable to those of traditional open techniques. PMID- 29398511 TI - Improved Interobserver Reliability of the Sanders Classification in Calcaneal Fractures Using Segmented Three-Dimensional Prints. AB - We examined the added value of 3-dimensional (3D) prints in improving the interobserver reliability of the Sanders classification of displaced intraarticular calcaneal fractures. Twenty-four observers (radiologists, trainees, and foot surgeons) were asked to rate 2-dimensional (2D) computed tomography images and 3D prints of a series of 11 fractures, selected from cases treatment at our level I trauma center between 2014 and 2016. The interobserver reliability for the Sanders classification was assessed using kappa coefficients. Three versions of the Sanders classification were considered: Sanders classification with subclasses, Sanders classification without subclasses, and the combination of Sanders types III and IV because of the high incidence of comminution in both types. The reference standard for classification was the perioperative findings by a single surgeon. The 3D print always yielded higher values for agreement and chance-corrected agreement. The Brennan-Prediger weighted kappa equaled 0.35 for the 2D views and 0.63 for the 3D prints for the Sanders classification with subclasses (p = .004), 0.55 (2D) and 0.76 (3D) for the classification without subclasses (p = .003), and 0.58 (2D) and 0.78 (3D) for the fusion of Sanders types III and IV (p = .027). Greater agreement was also found between the perioperative evaluation and the 3D prints (88% versus 65% for the 2D views; p < .0001). However, a greater percentage of Sanders type III-IV were classified with 2D than with 3D (56% versus 32%; p < .0001). The interobserver agreement for the evaluation of calcaneal fractures was improved with the use of 3D prints after "digital disarticulation." PMID- 29398512 TI - Atraumatic Spontaneous Achilles Tendon Rupture in Patients Receiving Oral Corticosteroids Treated With the Modified Side-Locking Loop Suture Technique. AB - Atraumatic spontaneous Achilles tendon ruptures sometimes occur in patients receiving oral corticosteroids. In general, these cases are treated surgically; however, delayed postoperative management can lead to impaired activities of daily living. The modified side-locking loop suture (SLLS) technique is a useful suture method for safe and early active mobilization. Three cases of spontaneous Achilles tendon ruptures were treated with the modified SLLS technique with good clinical results. The modified SLLS technique is a useful method with a short rehabilitation period for treating atraumatic spontaneous Achilles tendon rupture in patients undergoing corticosteroid therapy. PMID- 29398513 TI - Determinants of left ventricular diastolic dysfunction in hypertensive patients. AB - INTRODUCTION: The progression of hypertensive heart disease leads to the left ventricular diastolic dysfunction (LVDD), which is associated with increased cardiovascular morbidity and mortality. The purpose of this analysis is to explore the determinants for LVDD in patients with hypertension. METHODS: This is a secondary analysis of data of Impedance Cardiography in the Evaluation of Left Ventricular Diastolic Dysfunction in Patients with Arterial Hypertension (IMPEDDANS) Study. Mann-Whitney and Chi-square tests were used for univariable analysis. Multiple logistic regression was used to model for LVDD occurrence and discriminative capacity of the model assessed by the value of the area under the curve given by the receiver-operating characteristic curve. RESULTS: Older age (65 vs. 58 years, p<0.001), longer duration of hypertension (160 vs. 48 months, p<0.001), uncontrolled hypertension (59.8 vs. 15.9%, p<0.001), tobacco smoking (17.8 vs. 3.8%, p=0.016), higher systolic blood pressure (133 vs. 124mmHg, p=0.001) and slower heart rate (62 vs. 66bpm, p=0.023) were associated with LVDD. Multivariate model identified uncontrolled hypertension (AdjOR 36.90; 95% CI 7.94 171.58; p<0.001), smoking (AdjOR 6.66; 95% CI 1.63-27.26; p=0.008), eccentric hypertrophy (AdjOR 3.59; 95% CI 0.89-14.39; p=0.072), duration of hypertension (AdjOR 1.03; 95% CI 1.02-1.05; p<0.001) and concentric remodeling (AdjOR 0.19; 95% CI 0.04-0.93; p=0.041) as the more determinant for occurrence of LVDD. The discriminative capacity of the model was AUC=0.95 (95% CI 0.91-0.98). CONCLUSION: The occurrence of LVDD in hypertensive patients was strongly associated to long lasting, uncontrolled hypertension, tobacco smoking, concentric remodeling and eccentric hypertrophy. PMID- 29398514 TI - [Klinefelter syndrome and cardiovascular risk]. AB - We present a 45-year-old patient with Klinefelter syndrome, with a history of type 2 diabetes mellitus, obesity, dyslipidemia, obstructive sleep apnoea syndrome and masked arterial hypertension. The purpose of this presentation is to draw attention to the increased cardiovascular risk in these patients and to review the data in the literature on this risk. PMID- 29398515 TI - Informed refusal in oral and maxillofacial radiology: Does it exist? PMID- 29398516 TI - Sclerosing microcystic adenocarcinoma of the tongue: a report of 2 further cases and review of the literature. AB - We present 2 further cases of sclerosing microcystic adenocarcinoma occurring in the tongue in 2 female patients, one age 68 years and the other 49 years. Histopathologically, both tumors were characterized by a diffusely infiltrative lesion consisting of small cuboidal cells arranged in discrete dispersed cords, isolated tubules, and bilayered strands with intervening microcystic lumina set in a sclerotic background. Both lesions showed striking neurotropism with perineural and intraneural infiltration. Extensive invasion of adjacent skeletal muscle was also observed. The tumor cells showed diffuse staining with antibodies to cytokeratin 7 (CK7). A dual population of ductal and myoepithelial cells was identified, with antibodies to CAM5.2 and CK5/6 decorating the inner epithelial layer and antibodies to p63, p40, and S100 staining the outer myoepithelial cell layer. The Ki-67 proliferation index in both cases was less than 5%. An initial diagnosis of adenocarcinoma NOS (not otherwise specified) of salivary gland origin was made on both incisional biopsies and a possible metastatic origin, particularly from the breast, also raised. A local minor salivary gland origin was confirmed after staging investigations and surgical resection. Both patients were t. PMID- 29398517 TI - A practical background correction method for an immediately repeated first-pass radionuclide angiography. AB - BACKGROUND: A satisfactory bolus injection is essential for a successful first pass radionuclide angiography (FPRNA). Rescheduling the FPRNA study is usually needed due to high background interference caused by an unsatisfactory bolus injection. We developed a protocol to correct the pre-existing background activity subsequent to immediately repeating the study. METHODS: Seventy-four consecutive patients who had their bone scan and FPRNA scheduled on the same day were included for analysis. The initial 51 cases constituted the "validation only" group. In the other 23 cases, the "validation plus clearance constants" group, a 5-min dynamic acquisition was performed during the 5-min equilibrium to obtain the background clearance curve and the clearance constants. For all included 74 cases ejection fraction (EF) analysis was proceeded using the images from the first injection, second injection, and second injection with the corrected background to yield EF1, EF2, and EF2', respectively. EF2 and EF2' were then compared to the ejection fraction without background interference, the EF1. RESULTS: For the LV, the mean difference between the EF1 and the uncorrected EF2 (|LVEF1-LVEF2| in mean +/- SD) was 3.1 +/- 2.0% and the difference between the EF1 and the corrected EF2' (|LVEF1-LVEF2'|) was 1.6 +/- 2.1%, while the mean differences for RV are 2.2 +/- 1.9% and 1.8 +/- 1.8%, respectively. A significant difference (p < 0.05) was observed between the uncorrected and the corrected data for both the LV and RV. CONCLUSION: In FPRNA, when a bolus injection is immediately readministered, both LVEF and RVEF can be underestimated. With our correction method, the results are superior to those without correction. PMID- 29398518 TI - Hyperemesis gravidarum is not a negative contributing factor for postpartum bone mineral density. AB - BACKGROUND: Hyperemesis gravidarum (HG), related to protracted vomiting and nausea, is a common cause of hospitalization during the first trimester of pregnancy. It can be accompanied by ketonuria, dehydration, and weight loss. Our aim was to investigate bone loss in patients with HG. METHODS: In our study, we investigated decreased bone mineral density (BMD)in a total of 79 patients (40 HG and 39 control) by means of dual energy X-ray absorptiometry (DEXA) measurements and laboratory parameters related to HG. All patients received DEXA measurement during the early postpartum period (usually two days after delivery, prior to discharge).This study was registered in the database via the Protocol Registration and Results System (PRS) (NCT03127293). RESULTS: There was no significant difference in DEXA results (lumbar spine and total hip) and laboratory parameters between case and control groups, although a significant difference in vitamin intake was identified between cases and controls (65% vs. 92%, respectively, p = 0.003). Except for low serum levels of vitamin D, other laboratory parameters were in normal range in both groups. CONCLUSION: Pregnancies complicated by HG did not have decreased bone mineral density compared to those without HG. There is no evidence to relate HG to future osteoporosis. PMID- 29398519 TI - Compound C enhances tau phosphorylation at Serine396 via PI3K activation in an AMPK and rapamycin independent way in differentiated SH-SY5Y cells. AB - Aggregation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFT) is a main hallmark for Alzheimer's disease (AD). Activation of cellular metabolic axis, made of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) have been implicated in generating tau pathology of AD. Thus, blocking either of these two proteins or both, are suggested as the future therapeutic approaches for AD. How and to what level these approaches could be applied, however are not entirely clear. By using Compound C (CC) in this study, we showed a substantial decrease in mTOR activity in a rapamycin-independent way without blocking AMPK. This decline in mTOR activity was accompanied by an increase in phosphoinositide 3 kinase (PI3K)/Akt activity and a parallel increase in p-tau (Ser396) but not p-tau (Ser262) in differentiated SH-SY5Y neuroblastoma cells. This elevation was blocked when the cells were treated with 15 MUM of LY294002, a specific PI3K inhibitor, suggesting PI3K involvement in CC-mediated tau hyperphosphorylation at Ser396. For all groups the activity levels of glycogen synthase kinase-3beta (GSK-3beta), cyclin dependent kinase-5 (cdk5) and protein phosphatase 2A (PP2A), the other main kinases and phosphatase responsible for tau phosphorylation/dephosphorylation remained unchanged. Collectively, our results demonstrate that rapamycin independent blocking of mTOR enhances p-tau (Ser396) in a PI3K-dependent way, suggesting the careful consideration of future therapeutic approaches for AD, which will be based on mTOR inhibition. PMID- 29398520 TI - Six-month cultured cerebral organoids from human ES cells contain matured neural cells. AB - Recently, researchers have developed protocols for human cerebral organoids using human pluripotent stem cells, which mimic the structure of the developing human brain. Existing research demonstrated that human cerebral organoids which undergo short cultivation periods, contain astrocytes, neurons, and neural stem cells, but lacked mature oligodendrocytes, and mature, fully functional neurons. In this study, we analyzed organoids induced from H9 human embryonic stem (ES) cells that were cultivated for as long as six months. We observed mature oligodendrocytes, positive for MBP (myelin-basic protein), and mature GAD67 (glutamate decarboxylase 67 kDa isoform)-positive inhibitory neurons and VGLUT1 (vesicular glutamate transporter 1)-positive excitatory neurons via immunohistochemical analysis. These observations suggest that long-term cultivation of cerebral organoids can lead to the maturation of human cerebral organoids, which can be used as a tool to study the development of human brains. PMID- 29398521 TI - The effect of celastrol on the ocular hypertension-induced degeneration of retinal ganglion cells. AB - Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii, has been identified as a neuroprotective agent in various models of neurodegenerative disorders. We have reported earlier that systemic and intravitreal administration of celastrol stimulate the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC) and that mechanisms underlying celastrol's RGC protection may be associated with inhibition of TNF alpha-mediated cell death. The present study evaluates the effect of celastrol on the survival of RGCs injured by ocular hypertension. Intraocular pressure (IOP) elevation resulted in approximately 23% of RGCs loss. Reduction in RGC numbers was observed in all four retinal quadrants: 30% in superior, 17% in inferior, 11% in nasal and 35% in temporal regions. Celastrol (1 mg/kg) or vehicle (DMSO) was administered three times per week by intraperitoneal injection, starting on the day of laser photocoagulation of the TM and continued for the entire duration of the experiment (5 weeks). Celastrol treatment stimulated RGC survival by an average of 24% in the entire retina compared to the vehicle-treated group. RGC numbers were increased in all four quadrants: approximately 40%, 17%, 15% and 30% more RGCs were counted in the superior, inferior, nasal and temporal regions, respectively. The average RGC numbers for the entire retinas of the celastrol/IOP group were only ~5% and 10% lower than that in vehicle- or celastrol-injected animals with normal IOP, respectively. Our data indicate a significant celastrol mediated neuroprotection against elevated IOP-induced injury. PMID- 29398522 TI - [Vaginal hysterectomy in outpatient procedure: Feasibility and satisfaction study]. AB - OBJECTIVES: To study the feasibility and patient satisfaction for vaginal hysterectomy in a new outpatient procedure. METHODS: This retrospective study was directed in CHU de Saint-Etienne, Loire, France. All patient who underwent a vaginal hysterectomy in outpatient procedure were included from January 2014 and January 2017. Descriptive data were collected and all patients were called back for satisfaction study. RESULTS: Sixty-five patients were included. Vaginal hysterectomy was performed for 52.3% for pre-menopause bleeding, 24.6% for prolapse, 15.4% for uterine fibroids and 7.6% diverse. Outpatient procedure was performed in 96.9%. Peroperative outcome from Oslo classification were 1.5% for grade 1 and 1.5% for grade 2. Postoperative complications from Clavien-Dindo classification were: 16.9% grade 1 and 6.2% grade 2. Mean postoperative pain scale was 1.02 between H1 and H3 post-operative and 0.84 between H3-H6. Among the patients, 89.2% were very satisfied, 91.9% recommend the same outpatient procedure and 43.2% assumed their daily life since first day postoperative. CONCLUSION: Vaginal hysterectomy in outpatient procedure is today's reality. It is a simple, economic, with few postoperative complications and very high satisfaction scores procedure. Standardized procedure, good patient selection and information are necessary to minimize complications. PMID- 29398523 TI - [C.Lallemand and M-P. Debord in answer to the article by A. Rousseau and al.: "Comparative study about enhanced recovery after cesarean section: what benefits, what risks?" Gynecol Obstet Fertil Senol 2017;45:387-92]. PMID- 29398524 TI - [Use of hydroxychloroquine and prednisone in the presence of serum autoimmunity in female infertility]. AB - OBJECTIVE: Presence of non-specific autoimmunity (antinuclear antibodies without antigenic specificities and/or antiphospholipid antibodies without criteria of antiphospholipid syndrome) seems to be associated with unexplained female infertility. The objective is to study the characteristics of patients who undergone treatment for non-specific antibodies in Medically Assisted Procreation (MAP). METHODS: Ten patients were prospectively followed at MAP center of Grenoble University Hospital. Patient characteristics were collected and evaluated. All patients had a consultation in internal medicine unit as well as an autoimmune assessment (antinuclear antibodies, APL especially) in search of defined autoimmune disease (exclusion criterion). The treatments undertaken were at clinician' discretion. RESULTS: One patient received quadritherapy (heparin, platelet antiaggregant, prednisone and hydroxychloroquine), 5 received triple therapy, 3 had dual therapy, and one patient had prednisone only. The 10 patients had a pregnancy under treatment, 8 of which were completed without complications. The control of autoimmunity under treatment appears to show a decrease in serum antibody levels. Tolerance was good (delayed hypersensitivity to hydrochloroquine resulted in discontinuation of therapy in only one patient). CONCLUSION: The presence of non-specific serum autoimmunity in a context of infertility appears to be pathogenic and immunomodulatory treatments are clinically and/or biologically effective. A prospective and interventional study with a larger number of patients is needed to assess the efficacy of such treatments in patients with unexplained infertility. PMID- 29398525 TI - Remote Coupled Drastic beta-Barrel to beta-Sheet Transition of the Protein Translocation Motor. AB - The membrane protein SecDF, belonging to the RND superfamily, enhances protein translocation at the extracytoplasmic side using a proton gradient. Here, we report the crystal structure of SecDF in a form we named Super-membrane-facing (Super F) form, demonstrating a beta-barrel architecture instead of the previously reported beta-sheet structure. Through this structural insight and supporting results of an in vivo crosslinking experiment, we propose a remote coupling model in which a structural change of the transmembrane region drives a functional, extracytoplasmic conformational transition. PMID- 29398527 TI - Crystal Structures of Fungal Tectonin in Complex with O-Methylated Glycans Suggest Key Role in Innate Immune Defense. AB - Innate immunity is the first line of defense against pathogens and predators. To initiate a response, it relies on the detection of invaders, where lectin carbohydrate interactions play a major role. O-Methylated glycans were previously identified as non-self epitopes and conserved targets for defense effector proteins belonging to the tectonin superfamily. Here, we present two crystal structures of Tectonin 2 from the mushroom Laccaria bicolor in complex with methylated ligands, unraveling the molecular basis for this original specificity. Furthermore, they revealed the formation of a ball-shaped tetramer with 24 binding sites distributed at its surface, resembling a small virus capsid. Based on the crystal structures, a methylation recognition motif was identified and found in the sequence of many tectonins from bacteria to human. Our results support a key role of tectonins in innate defense based on a distinctive and conserved type of lectin-glycan interaction. PMID- 29398526 TI - Structure of the 30 kDa HIV-1 RNA Dimerization Signal by a Hybrid Cryo-EM, NMR, and Molecular Dynamics Approach. AB - Cryoelectron microscopy (cryo-EM) and nuclear magnetic resonance (NMR) spectroscopy are routinely used to determine structures of macromolecules with molecular weights over 65 and under 25 kDa, respectively. We combined these techniques to study a 30 kDa HIV-1 dimer initiation site RNA ([DIS]2; 47 nt/strand). A 9 A cryo-EM map clearly shows major groove features of the double helix and a right-handed superhelical twist. Simulated cryo-EM maps generated from time-averaged molecular dynamics trajectories (10 ns) exhibited levels of detail similar to those in the experimental maps, suggesting internal structural flexibility limits the cryo-EM resolution. Simultaneous inclusion of the cryo-EM map and 2H-edited NMR-derived distance restraints during structure refinement generates a structure consistent with both datasets and supporting a flipped-out base within a conserved purine-rich bulge. Our findings demonstrate the power of combining global and local structural information from these techniques for structure determination of modest-sized RNAs. PMID- 29398528 TI - Completeness of handwritten preanaesthetic records at two veterinary referral institutions. AB - OBJECTIVE: To retrospectively analyse handwritten preanaesthetic records for completeness at two veterinary referral institutions: a university veterinary teaching hospital and a private veterinary referral hospital. To evaluate if emergency records were less complete compared with non-emergency records. Animal or Animal Population Two hundred and fifty preanaesthetic records at each referral institution. MATERIALS AND METHODS: Handwritten preanaesthetic records were analysed for completeness. Data was described as complete or incomplete. In order to be classified as complete information had to be present, legible and correct. Sections of the preanaesthetic record analysed included the date, anaesthetist, clinician, presenting problem, procedure, time food withheld, temperature, pulse rate (PR), respiratory rate (fR), American Society of Anesthesiologists-Physical Status Classification (ASA-PSC), premedication drug name, premedication drug dose, premedication route of administration, premedication time, effect of premedication, induction drug name, induction drug dose, induction time, induction quality, maintenance anaesthetic agent, endotracheal tube (ET) diameter, anaesthetic breathing system and monitoring equipment. RESULTS: At both referral institutions 250 records were analysed. Completeness of data was generally poor, however, several differences did exist. Completion rates were generally higher at the university veterinary teaching hospital. A mix of structured and unstructured (requiring free text) data fields were poorly complete. Emergency records were significantly less complete with respect to: Time food withheld (p = 0.006) and Temperature (p = 0.0275). CONCLUSIONS: Differences observed may be due to anaesthetic record design, anaesthetic caseload, case discussion, education or quality assurance programmes. Clinical relevance Increased emphasis on education and implementation of quality assurance programmes should be considered in order to improve completeness of preanaesthetic records. PMID- 29398529 TI - A sonographic investigation for the development of ultrasound-guided paravertebral brachial plexus block in dogs: cadaveric study. AB - OBJECTIVE: To describe a novel in-plane ultrasound (US)-guided approach to the sixth (C6), seventh (C7), eighth (C8) cervical and to the first thoracic (T1) spinal nerves. STUDY DESIGN: Prospective, descriptive, experimental anatomic study. ANIMALS: A total of seven canine Beagle cadavers. METHODS: Phase 1: One cadaver was used to define bony landmarks for the C6-T1 spinal nerves using computed tomography (CT) and magnetic resonance imaging. An US transducer was positioned lateral to the C6 vertebra. Methylene blue (0.05 mL kg-1) was injected cranial and caudal to the transverse process of C6. The probe was moved caudally to identify the cranial costal fovea of T1 and 0.1 mL kg-1 of methylene blue was injected. Full cadaver dissection was performed to assess the staining of the spinal nerves. Phase 2: The technique was repeated using a 50:50 mixture of iohexol and methylene blue in six dogs. CT verified the proximity of contrast to C6, C7, C8 and T1 nerves. Mediastinal, epidural, intravascular and pleural contamination was recorded. Methylene blue staining of the phrenic nerve was assessed by dissection. RESULTS: Phase1: The identified bony landmarks were the lamina ventralis of C6, the transverse process of C6 and C7, T1 vertebra and the first rib. Phase 2: At all the 12 sites, the C6, C7 and C8 nerves were in contact with contrast material. Contrast was demonstrated in close proximity to the anatomical location of the T1 nerve in 11/12 sites. Mediastinal, epidural and intravascular contamination was observed in six, four and two cadavers, respectively. Pleural contamination was not observed. The phrenic nerve was stained on 2/12 of sides. CONCLUSIONS AND CLINICAL RELEVANCE: In-plane US-guided blockade of the spinal roots is a feasible technique. However, because of the undesirable spreads of contrast, further research is needed to diminish the occurrence of contaminations of noble structures. PMID- 29398530 TI - Sedative effects of intramuscular alfaxalone in pet guinea pigs (Cavia porcellus). AB - OBJECTIVE: To evaluate the efficacy and side effects of alfaxalone administered intramuscularly (IM) as a sedative agent in guinea pigs undergoing survey radiographs. STUDY DESIGN: Prospective clinical trial. ANIMALS: A total of 30 client-owned guinea pigs. METHODS: Following baseline assessments, 5 mg kg-1 alfaxalone was administered IM. Heart rate, arterial haemoglobin oxygen saturation, respiratory rate, rectal body temperature, palpebral reflex, response to toe and ear pinch, righting reflex, posture, jaw tone and reaction to manipulation were assessed before and after sedation at 5-minute intervals. The time elapsed from onset of sedation to return of locomotion and coordinated limb movements, the quality of recovery and the occurrence of undesired effects were observed and recorded. RESULTS: The mean +/- standard deviation onset of sedation was 2.7 +/- 0.6 minutes. The physiological variables remained within normal ranges until completion of the procedure. Palpebral reflex and responsiveness to both ear and toe pinch were maintained during sedation. Neither hypoxaemia nor hypothermia was observed. The duration of sedation was 29.3 +/- 3.2 minutes. Sedation and recovery were uneventful, and adverse effects were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, 5 mg kg-1 of IM alfaxalone represents a valuable sedation protocol for healthy guinea pigs undergoing minor noninvasive procedures. Further trials are required to investigate its cardiovascular effects, clinical usefulness in unhealthy patients and its combined use with analgesics for procedures associated with nociception. PMID- 29398531 TI - Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia. AB - BACKGROUND: Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. METHODS: To address this need, we subjected 7- to 9-week old ovariectomized female mice to filament induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. RESULTS: Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. CONCLUSION: Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke. PMID- 29398532 TI - The Sustained DeyeCOM Sign as a Predictor of Large Vessel Occlusions and Stroke Mimics. AB - INTRODUCTION: Rapid imaging in acute stroke is critical and often occurs before full examination. Early, reliable examination findings clarify diagnosis and improve treatment times. The DeyeCOM sign has been described as a predictor of ischemic stroke. In this study, we evaluate a sustained DeyeCOM sign on serial computed tomography scans in prediction of large vessel occlusion. METHODS: Between April and June 2017, we retrospectively reviewed 46 patients with acute stroke from the University of California, San Diego Stroke Registry, who had both computed tomography and computed tomography angiography as part of their acute work-up. A DeyeCOM(+) sign was defined as a conjugate gaze deviation on imaging of at least 15 degrees . DeyeCOM(++) was defined as sustained gaze deviation on both scans. RESULTS: Three groups of patients were observed: DeyeCOM(++), nonsustained gaze deviation, and no gaze deviation (DeyeCOM(--)). All patients in the DeyeCOM(++) (8 of 8, 100%) had large vessel occlusion. Of those with nonsustained gaze deviation, 2 of 7 (29%) had large vessel occlusion. No patients in the DeyeCOM(--) (0 of 31, 100%) had large vessel occlusion. The specificity and sensitivity of DeyeCOM(++) for large vessel occlusion was 100% (confidence interval [CI] .90-1.0) and 80% (CI .44-.97). The specificity and sensitivity of DeyeCOM(--) for absence of large vessel occlusion was 100% (CI .69-1.0) and 86% (CI .70-.95). CONCLUSIONS: DeyeCOM(++) had 100% specificity for large vessel occlusion, whereas DeyeCOM(--) had a 100% specificity for absence of large vessel occlusion. Sustained DeyeCOM, whether positive or negative, is a strong predictor of ultimate diagnosis that could lead to quicker endovascular treatment times. PMID- 29398533 TI - Cerebral Microbleeds are an Independent Predictor of Hemorrhagic Transformation Following Intravenous Alteplase Administration in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Intravenous alteplase (rt-PA) increases the risk of hemorrhagic transformation of acute ischemic stroke. The objective of our study was to evaluate clinical, laboratory, and imaging predictors on forecasting the risk of hemorrhagic transformation following treatment with rt-PA. We also evaluated the factors associated with cerebral microbleeds that increase the risk of hemorrhagic transformation. METHODS: Consecutive patients with acute ischemic stroke admitted between January 1, 2009 and December 31, 2013 were included in the study if they received IV rt-PA, had magnetic resonance imaging (MRI) of the brain on admission, and computed tomography or MRI of the brain at 24 (18-36) hours later to evaluate for the presence of hemorrhagic transformation. The clinical data, lipid levels, platelet count, MRI, and computed tomography images were retrospectively reviewed. RESULTS: The study included 366 patients, with mean age 67 +/- 15 years; 46% were women and 88% were white. The median National Institutes of Health Stroke Scale (NIHSS) score was 6 (interquartile range 3-15). Hemorrhagic transformation was observed in 87 (23.8%) patients and cerebral microbleeds were noted in 95 (25.9%). Patients with hemorrhagic transformation tended to be older, nonwhite, have atrial fibrillation, higher baseline NIHSS score, lower cholesterol and triglyceride levels, and cerebral microbleeds and nonlacunar infarcts. Patients with cerebral microbleeds were more likely to be older, have hypertension, hyperlipidemia, previous history of stroke, and prior use of antithrombotics. On multivariate analysis race, NIHSS score, nonlacunar infarct, and presence of cerebral microbleeds were independently associated with hemorrhagic transformation following treatment with rt-PA. CONCLUSIONS: Presence of cerebral microbleeds is an independent predictor of hemorrhagic transformation of acute ischemic stroke following treatment with rt-PA. PMID- 29398534 TI - Thrombolysis in Large Diffusion-Weighted Imaging Lesions: Lower Chance but Still a Chance. AB - BACKGROUND: We sought to investigate whether early thrombolytic treatment can result in favorable functional outcome even in patients with large diffusion weighted imaging (DWI) lesions. MATERIALS AND METHODS: We analyzed 566 patients who received intravenous alteplase within 4.5 hours from onset, initially underwent DWI and magnetic resonance angiography, and had acute infarction confined to anterior circulation. DWI lesion volumes were measured semiautomatically. The association between DWI lesion volume and 3-month outcome in patients who achieved early recanalization was assessed. The DWI lesion volume cutoff, which predicts unfavorable outcome despite recanalization, was determined. In patients with large DWI lesions, the distributions of modified Rankin Scale (mRS) score were compared according to the recanalization status. RESULTS: Four hundred thirty-six patients achieved early recanalization. Among these patients, 283 (65%) patients had a favorable functional outcome (mRS score 0-2). DWI lesion volume (odds ratio [OR], 1.38 per 10 mL; 95% confidence interval [CI], 1.22-1.56) was an independent variable associated with poor outcome, along with hypertension (OR, 1.87; 95% CI, 1.12-3.10), National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.13; 95% CI, 1.08-1.19), and onset-to-needle time (OR, 1.08 per 10 minutes; 95% CI, 1.03-1.13). The DWI lesion of 60 mL or higher highly predicted an unfavorable outcome with a positive predictive value of 95.3%. In patients with a DWI lesion of 60 mL or higher, recanalization had no benefit for an mRS score of 0-2 but was significantly associated with an mRS score of 0-3 (OR, 4.64; 95% CI, 1.08-19.97). CONCLUSIONS: Despite early recanalization, the probability of favorable outcome is low in patients with a DWI lesion of 60 mL or higher. Nevertheless, the benefit of recanalization still persists in large DWI lesions. PMID- 29398536 TI - The Dose of Direct Oral Anticoagulants and Stroke Severity in Patients with Acute Ischemic Stroke and Nonvalvular Atrial Fibrillation. AB - BACKGROUND: The severity and the functional outcome of patients with stroke occurring during off-label underdosing of direct-acting oral anticoagulants (DOACs) remain uncertain. METHODS: We studied 53 consecutive patients with acute ischemic stroke and nonvalvular atrial fibrillation who were treated with DOACs before the onset of stroke. Thirty patients were treated for primary prevention of stroke and 23 patients were treated for secondary prevention. DOAC treatments were categorized into 3 groups based on the following doses: (1) standard-dose group (n = 17), (2) low-dose group (n = 23), and (3) off-label underdose group (n = 13). RESULTS: Age was significantly older in the low-dose group than in the standard-dose group (P = .026). The standard-dose group and the low-dose group showed higher CHA2DS2-VASc scores (median, 4) compared with the off-label underdose group (median, 3). More than half of the patients had a National Institutes of Health Stroke Scale score of less than 8, and many patients had a good outcome (modified Rankin Scale score <=1). There were no differences in stroke severity and outcome among the 3 groups. The ratio of being discharged home was the highest in the standard-dose group. CONCLUSIONS: This study shows that patients who have off-label underdosing of DOACs do not develop more severe stroke and a poorer outcome than those with the recommended dose. Careful attention to recommended doses is required for the full benefits from DOACs. PMID- 29398535 TI - The Methylenetetrahydrofolate Reductase C677T (rs1801133) and Apolipoprotein A5 1131T>C (rs662799) Polymorphisms, and Anemia Are Independent Risk Factors for Ischemic Stroke. AB - BACKGROUND: Although there is adequate knowledge as to the role of traditional cardiovascular risk factors on stroke incidence, knowledge of other risk factors, particularly genetic ones, is still incomplete. METHODS: To assess the participation of some polymorphisms, along with other modifiable risk factors, a case-control study was conducted. A total of 253 cases were identified in the emergency room of a general regional hospital, with a clinical trait of stroke confirmed by a skull computerized axial tomography scan. In the surgery ward, 253 controls were identified, gender and age (+/-5 years) matched. Biochemical parameters were measured, and 4 polymorphisms were genotyped by polymerase chain reaction, rs1801133 (methylenetetrahydrofolate reductase [MTHFR]), rs1498373 (dimethylarginine dimethylaminohydrolase type 1 [DDAH1]), rs662799 (apolipoprotein A5 [APOA5]), and rs1799983 (endothelial nitric oxide). Odds ratios were estimated to assess the strength of association, with 95% confidence intervals, both in a matched case-control analysis and in a conditional regression analysis. RESULTS: Cases had higher mean blood pressure and triglycerides and lower hemoglobin levels. Heterozygous and homozygous subjects to the rs1801133 variant of the MTHFR gene had a 3-fold higher risk of stroke. In the dominant model, those with the polymorphism rs662799 of the promoter region for APOA5 had twice the risk of stroke. Anemia increased the risk of stroke 4 fold. CONCLUSIONS: Polymorphisms of the genes MTHFR (rs1801133) and APOA5 (rs662799), as well as anemia, are independent risk factors for stroke in Mexicans, together with traditional cardiovascular risk factors such as high triglycerides and high blood pressure. PMID- 29398537 TI - Left Atrial Appendage Morphology and Embolic Stroke of Undetermined Source: A Cross-Sectional Multicenter Pilot Study. AB - BACKGROUND: The left atrial appendage (LAA) is the main source of thrombus in atrial fibrillation, and there is an association between non-chicken wing (NCW) LAA morphology and stroke. We hypothesized that the prevalence of NCW LAA morphology would be higher among patients with cardioembolic (CE) stroke and embolic stroke of undetermined source (ESUS) than among those with noncardioembolic stroke (NCS). METHODS: This multicenter retrospective pilot study included consecutive patients with ischemic stroke from 3 comprehensive stroke centers who previously underwent a qualifying chest computed tomography (CT) to assess LAA morphology. Patients underwent inpatient diagnostic evaluation for ischemic stroke, and stroke subtype was determined based on ESUS criteria. LAA morphology was determined using clinically performed contrast enhanced thin slice chest CT by investigators blinded to stroke subtype. The primary predictor was NCW LAA morphology and the outcome was stroke subtype (CE, ESUS, NCS). RESULTS: We identified 172 patients with ischemic stroke who had a clinical chest CT performed. Mean age was 70.1 +/- 14.3 years and 51.7% were male. Compared with patients with NCS, the prevalence of NCW LAA morphology was higher in patients with CE stroke (58.7% versus 46.3%, P = .1) and ESUS (58.8% versus 46.3%, P = .2), but this difference did not achieve statistical significance. CONCLUSION: The prevalence of NCW LAA morphology may be similar in patients with ESUS and CE, and may be higher than that in those with NCS. Larger studies are needed to confirm these associations. PMID- 29398538 TI - 2-(2-Benzofuranyl)-2-Imidazoline Mediates Neuroprotection by Regulating the Neurovascular Unit Integrity in a Rat Model of Focal Cerebral Ischemia. AB - BACKGROUND: We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia. METHODS: Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting. RESULTS: 2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 +/- 5.4% vs 56.1 +/- 7.9%, p < 0.05). Significant decreased of brain water content (79.5 +/- 2.6% vs 84.62 +/- 2%, p < 0.05) and Evans Blue extravasation (1.2 +/- 0.5 vs 2.5 +/- 0.41 ug/g, p < 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP 9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups. CONCLUSIONS: These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU. PMID- 29398540 TI - Multiple-step, one-pot synthesis of 2-substituted-3-phosphono-1-thia-4-aza-2 cyclohexene-5-carboxylates and their corresponding ethyl esters. AB - The multiple-step, one-pot procedure for a series of 2-substituted-3-phosphono-1 thia-4-aza-2-cyclohexene-5-carboxylates, analogues of the natural, sulfur amino acid metabolite lanthionine ketimine (LK), its 5-ethyl ester (LKE) and 2 substituted LKEs is described. Initiating the synthesis with the Michaelis Arbuzov preparation of alpha-ketophosphonates allows for a wide range of functional variation at the 2-position of the products. Nine new compounds were synthesized with overall yields range from 40 to 62%. In addition, the newly prepared 2-isopropyl-LK-P, 2-n-hexyl-LKE-P and 2-ethyl-LKE were shown to stimulate autophagy in cultured cells better than that of the parent compound, LKE. PMID- 29398541 TI - Semisynthesis and biological evaluation of a cotylenin A mimic derived from fusicoccin A. AB - In an effort to overcome the unavailability of cotylenin A (CN A), an anticancer agent and a stabilizer of protein-protein interactions (PPIs) mediated by 14-3-3 proteins, ISIR-050 was designed as a CN A mimic. The synthesis was accomplished via a semisynthetic approach starting from fusicoccin A. ISIR-050 showed interferon-alpha (IFNalpha)-dependent growth inhibitory activity and a PPI stabilization effect similar to those of CN A. The biochemical analysis suggested that ISIR-050 and CN A induce the same pharmacological response to IFNalpha treated cancer cells and that 14-3-3 proteins play a role in the mode of action. PMID- 29398539 TI - Synthesis, kinetics and inhibition of Escherichia coli Heptosyltransferase I by monosaccharide analogues of Lipid A. AB - Gram-negative bacteria comprise the majority of microbes that cause infections that are resistant to pre-existing antibiotics. The complex cell wall architecture contributes to their ability to form biofilms, which are often implicated in hospital-acquired infections. Biofilms promote antibiotic resistance by enabling the bacteria to survive hostile environments such as UV radiation, pH shifts, and antibiotics. The outer membrane of Gram-negative bacteria contains lipopolysaccharide (LPS), which plays a role in adhesion to surfaces and formation of biofilms. The main focus of this work was the synthesis of a library of glycolipids designed to be simplified analogues of the Lipid A, the membrane embedded portion component of LPS, to be tested as substrates or inhibitors of Heptosyltransferase I (HepI or WaaC, a glycosyltransferase enzyme involved in the biosynthesis of LPS). Fourteen analogues were synthesized successfully and characterized. While these compounds were designed to function as nucleophilic substrates of HepI, they all demonstrated mild inhibition of HepI. Kinetic characterization of inhibition mechanism identified that the compounds exhibited uncompetitive and mixed inhibition of HepI. Since both uncompetitive and mixed inhibition result in the formation of an Enzyme-Substrate inhibitor complex, molecular docking studies (using AutoDock Vina) were performed, to identify potential allosteric binding site for these compounds. The inhibitors were shown to bind to a pocket formed after undergoing a conformational change from an open to a closed active site state. Inhibition of HepI via an allosteric site suggest that disruption of protein dynamics might be a viable mechanism for the inhibition of HepI and potentially other enzymes of the GT-B structural class. PMID- 29398542 TI - Facile synthesis and evaluation of a dual-functioning furoyl probe for in-cell SHAPE. AB - Recent analysis of transcriptomes has revealed that RNA molecules perform a myriad of functions beyond coding for proteins. RNA molecules can fold into complex secondary and tertiary structures, which are critical for regulating their function. Selective Hydroxyl Acylation analyzed by Primer Extension, or SHAPE is a common method for probing RNA structure in and outside of cells. Recent developments in SHAPE include the design of acyl imidazole acylating electrophiles with alkyl azides to enrich the sites of SHAPE adduct formation. Enrichment is key for next-generation sequencing experiments as it dramatically improves the signal. In a recent comparison of different structures of such reagents, we realized that furoyl acylating reagents form hyper-stable ester adducts with hydroxyls. This prompted us to design, synthesize and test a novel dual-functioning SHAPE probe (FAI-N3), which has the stable furoyl scaffold and the alkyl azide for enrichment. Herein we present the results that show FAI-N3 is a suitable probe for RNA structure analysis by SHAPE and that it can be used for enrichment of SHAPE adducts. These results strongly demonstrate that FAI-N3 is an ideal probe for structure probing in cells and will be very useful for sequencing based analysis of SHAPE. PMID- 29398543 TI - Development of a series of novel o-phenylenediamine-based indoleamine 2,3 dioxygenase 1 (IDO1) inhibitors. AB - A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3 dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. . PMID- 29398544 TI - A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies. AB - Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a alpha acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20 uM, but a low activity in a cell-based assay. Compound 6o, containing a alpha-acylaminoamide moiety, shows an IC50 value of 0.81 uM in the IDO1-based assay, a full biocompatibility at 10 uM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development. PMID- 29398545 TI - Structural development of tetrachlorophthalimides as liver X receptor beta (LXRbeta)-selective agonists with improved aqueous solubility. AB - LXRbeta-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. We have reported a series of tetrachlorophthalimide analogs as an LXRbeta-selective agonist. However, they exhibited poor aqueous solubility probably due to its high hydrophobicity and highly rigid and plane structure. In this report, we present further structural development of tetrachloro(styrylphenyl)phthalimides as the LXRbeta-selective agonists with improved aqueous solubility. PMID- 29398546 TI - Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France. AB - BACKGROUND: Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years. AIMS: To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care. METHODS: We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression. RESULTS: Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32). CONCLUSIONS: Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421). PMID- 29398547 TI - Physicochemical improvement of rabbit derived single-domain antibodies by substitutions with amino acids conserved in camelid antibodies. AB - Recently, we showed that immunized rabbit heavy chain variable regions (rVHs) can have strong antigen binding activity comparable to that of the camelid variable domain of the heavy chain of heavy chain antibody (VHH). These rVHs lack the light chain variable regions (rVLs), which exist in the authentic Fab format; thus, molecular surfaces at the interface region of rVHs are exposed to solvent. This physical feature may change physicochemical properties, such as causing reduced stability. By overcoming potential physicochemical issues through engineering the interface region, rVHs could become more useful as single-domain antibodies. In this study, we substituted amino acid residues conserved at the interface region of rVHs with those of VHHs. These substitutions included V37F, involving substitution of a residue in the hydrophobic core with a bulkier hydrophobic amino acid, and G44E/L45R, involving double substitutions of highly exposed residues with more hydrophilic ones. As expected, biophysical and structural characterizations showed that the V37F substitution markedly enhanced the thermal stability through increased hydrophobic packing, while G44E/L45R substitutions greatly reduced hydrophobicity of the interface. The quadruple substitutions of V37F/G44E/L45R/F91Y resulted in not only enhancements of thermal stability and reduction in hydrophobicity, both in an additive manner, but also synergistic improvement of purification yield. This quadruple mutant exhibited greatly reduced non-specific binding with improved colloidal stability owing to the reduced hydrophobicity. The approach used in this study should further enhance the utility of rVHs and promote research and development of single-domain antibodies. PMID- 29398548 TI - Comparison of growth kinetics between static and dynamic cultures of human induced pluripotent stem cells. AB - Understanding the fundamental mechanisms that govern the growth kinetics of human induced pluripotent stem cells (hiPSCs) contributes to culture design strategies to improve large-scale production. Two hiPSC lines (Tic and 253G1) were cultured under static and dynamic suspension conditions, and growth kinetics were compared during early (24-48 h), middle (48-72 h), and late (72-96 h) stages. In 2D static culture, similar growth profiles were observed for both hiPSC lines. However, there were significant differences in growth profile patterns and aggregate morphologies between hiPSC lines grown in 3D static and dynamic cultures. Based on immunostaining comparing the two hiPSC lines, surface distribution of collagen type I was observed in aggregates of the Tic line, but not in those of the 253G1 line. Compared to that in 3D static culture, the numbers of cells at 96 h were significantly decreased in 3D dynamic culture. The apparent specific growth rate (MUapp) of the Tic line was maintained continuously throughout culture, whereas that of the 253G1 line decreased gradually with culture until the late phase, at which time this parameter was reduced to MUapp = (0.85 +/- 0.71) * 10-2 h-1. This indicates that during the growth of hiPSCs in 3D dynamic culture, cells were damaged by liquid flow, which disrupted the cell-synthesized extracellular matrix (ECM). These results demonstrate that cell-synthesized ECM is an important factor affecting cell growth and morphology, and that changes to the ECM within aggregates lead to reduced growth abilities in dynamic culture. PMID- 29398549 TI - Role of CadC and CadD in the 2,4-dichlorophenoxyacetic acid oxygenase system of Sphingomonas agrestis 58-1. AB - In the present study, we confirm that 2,4-dichlorophenoxyacetic acid (2,4-D) oxygenase from Sphingomonas agrestis 58-1 belongs to the family of Rieske non heme iron aromatic ring-hydroxylating oxygenases, which comprise a core enzyme (oxygenase), ferredoxin, and oxidoreductase. It has previously been shown that cadAB genes are necessary for the conversion of 2,4-D to 2,4-dichlorophenol; however, the respective roles of ferredoxin and oxidoreductase in the 2,4-D oxygenase system from S. agrestis 58-1 remain unknown. Using nucleotide sequence analysis of the plasmid pCADAB1 from Sphingomonas sp. ERG5, which degrades 4 chloro-2-methylphenoxyacetic acid and 2,4-D, Nielsen et al. identified orf95, upstream of cadA, and orf98, downstream of cadB, which were predicted and designated as cadD (oxidoreductase) and cadC (ferredoxin), respectively (Nielsen et al., PLoS One, 8, e83346, 2013). These designations were the result of sequence analysis; therefore, we constructed an expression system of CadABC and CadABCD in Escherichia coli and assayed their enzyme activities. Our findings indicate that CadC is essential for the activity of 2,4-D oxygenase and CadD promotes CadABC activity in recombinant E. coli cells. PMID- 29398550 TI - Evaluation of the impact of dissolved oxygen concentration on biofilm microbial community in sequencing batch biofilm reactor. AB - The effect of dissolved oxygen concentration (DO) during simultaneous nitrification and denitrification (SND) was investigated in a sequencing batch biofilm reactor (SBBR). In addition, the removal rates of nitrogen and bacterial communities were investigated under different concentrations of DO (1.5, 3.5, and 4.5 mg/L). When the SND rate was 95.22%, the chemical oxygen demand and nitrogen removal was 92.22% and 84.15%, respectively, at 2.5 mg/L DO. The denitrification was inhibited by the increase of oxygen concentration. Microelectrode measurements showed that the thickness of oxygen penetration increased from 1.0 mm to 2.7 mm when the DO concentration increased from 1.5 mg/L to 5.5 mg/L. The current location of the aerobic and anaerobic layers in the biofilm was determined for analysis of the microbial community. High-throughput sequencing analysis revealed the communities of the biofilm approached similar structure and composition. Uliginosibacterium species, biofilm-forming bacteria Zoogloea species and Acinetobacter species were dominant. In the aerobic layer, phyla Betaproteobacteria and Saprospirae were predominant, the major phyla were shifted from Proteobacteria followed by Firmicutes and Bacteroidetes, which comprised 82% of the total sequences during the SND period. Anaerolineae was dominated in the anaerobic layer. The high abundance of Nitrospira in the aerobic biofilm provides evidence of the SND system performing better at ammonia oxidization. In addition, real-time PCR indicated that the amount of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) matched the Nitrospirales and Nitrosomonadales abundance well. Collectively, this study demonstrated the dynamics of key bacterial communities in the SND system were highly influenced by the DO concentration. PMID- 29398551 TI - Zipbodyzyme: Development of new antibody-enzyme fusion proteins. AB - A new antibody-enzyme fusion protein, named Zipbodyzyme, composed of a Fab antibody (i.e., an antigen-binding fragment of an antibody) and an enzyme, has been successfully produced in the cytoplasm of Escherichia coli. Zipbodyzymes have a leucine zipper (LZ) pair at the C-termini of the heavy chain (Hc) and the light chain (Lc) of Fab, to promote the association of the Hc and the Lc in E. coli cytoplasm, adjoining a fused enzyme. A Zipbodyzyme containing mouse-derived anti-E. coli O157 Fab and a luciferase or a green fluorescent protein retained both the antigen-binding and an enzymatic activity/fluorescence. The bifunctional proteins were applicable in direct enzyme-linked immunosorbent assay (ELISA) without the need for a secondary antibody, indicating that the utility of the antibody enzyme bifunctional fusion protein will be expanded. PMID- 29398552 TI - Current practice of iron prophylaxis in preterm and low birth weight neonates: A survey among Italian Neonatal Units. AB - BACKGROUND: Preterm babies are at high risk of iron deficiency. METHODS: We investigated current practices regarding iron prophylaxis in preterm and low birth weight newborns among Local Neonatal Units (LNUs, n = 74) and Neonatal Intensive Care Units (NICUs, n = 20) of three Italian Regions (Piemonte, Marche and Lazio). RESULTS: Birth weight is considered an indicative parameter in only 64% of LNUs and 71% of NICUs, with a significant difference between LNUs in the three regions (86%, 20% and 62%, respectively; p < 0.001). Iron is recommended to infants with a birth weight between 2000 and 2500 g in only 25% of LNUs and 21% of NICUs, and to late-preterm (gestational age between 34 and 37 weeks) in a minority of Units (26% of LNUs, 7% of NICUs). CONCLUSIONS: Our pilot survey documents a great variability and the urgent need to standardize practices according to literature recommendations. PMID- 29398553 TI - Identification of the largest homozygous glycine decarboxylase gene deletion in a Turkish infant. PMID- 29398554 TI - Level of maternal triglycerides is a predictor of fetal macrosomia in non-obese pregnant women with gestational diabetes mellitus. AB - BACKGROUND: The role of maternal serum triglycerides (TGs) in the development of fetal macrosomia in different subgroups of body mass index (BMI) has received little attention. The aim of this study was to determine the association between the level of maternal TGs and fetal macrosomia in Iranian pregnant women of different BMI subgroups with gestational diabetes mellitus (GDM). METHODS: This cohort study was conducted on 305 pregnant women with GDM referred for glucose control to Kowsar Hospital in Qazvin, Iran. Level of TGs was measured on the 24th 28th weeks of pregnancy. The ROC curve of the level of TGs was depicted in BMI subgroups to predict fetal macrosomia. Logistic regression analysis was used to determine the risk of macrosomia per 1-SD increase in the level of TGs. RESULTS: The prevalence of hypertriglyceridemia did not significantly differ across BMI subgroups. Macrosomia was more prevalent in obese women (32.2%) than overweight (19.1%) and normal weight (11.1%) women (P < 0.05). A 1-SD increase in the level of TG was associated with 4.2 and 1.9 times increased risk of macrosomia in normal weight (P < 0.01) and overweight (P < 0.01) women, respectively. Serum level of TGs was not associated with macrosomia in any adjustment models in obese women. The area under the curve of the level of TGs for macrosomia was 0.828 (95% CI: 0.712-0.911, P < 0.001) and 0.711 (95% CI: 0.639-0.775, P < 0.001) in normal weight and overweight women, respectively. CONCLUSION: Hypertriglyceridemia was a predictor of macrosomia in non-obese women. More studies on different ethnicities and lifestyles are necessary to determine the association between the level of maternal TG and fetal macrosomia in BMI subgroups. PMID- 29398555 TI - Prevalence of airway hyperresponsiveness and its seasonal variation in children with asthma. AB - BACKGROUND: Airway hyperresponsiveness (AHR) is a key feature of asthma and can be detected using various bronchoprovocation tests. In pediatric populations, the percentage of a positive methacholine challenge test (MCCTs) in children with asthma varies among studies, and some have reported seasonal variability. However, these studies have mostly been conducted in temperate regions. This study evaluated the prevalence of AHR to methacholine and its seasonal variation in asthmatic children in Taiwan, a subtropical country. METHODS: A total of 276 children with asthma and their MCCT results were retrospectively reviewed. All were diagnosed with asthma and received asthma controllers regularly. They were assigned to four season groups depending in which season MCCTs were administered, with seasons categorized by the Central Weather Bureau of Taiwan. Subgroup analyses, including for sex, age, and atopy level, were compared for seasonal difference. RESULTS: The prevalence of methacholine hyperresponsiveness was 70.7% (n = 195), and the children who were younger and had higher total serum IgE were more sensitive to methacholine (p = 0.019 and p < 0.005, respectively). No significant difference in AHR prevalence among seasons was observed (p = 0.480). The percentage of borderline, mild, and moderate severity of MCCT results was almost equally distributed among the seasons. In subgroup analysis, the children with a higher IgE level (>=75th percentile of all data) had a higher proportion of positive MCCTs in summer (88.6%, p = 0.016). CONCLUSION: In total, 70% of the children with asthma in Taiwan had AHR to methacholine, which varied among seasons. Children with a higher total serum IgE level may be more seasonally dependent, particularly in summer. PMID- 29398556 TI - Clinical presentation of PTEN mutations. PMID- 29398557 TI - Loosening the shackles of scientific disciplines with network science: Reply to comments on "Network science of biological systems at different scales: A review". PMID- 29398558 TI - Physics of mind: Experimental confirmations of theoretical predictions. AB - What is common among Newtonian mechanics, statistical physics, thermodynamics, quantum physics, the theory of relativity, astrophysics and the theory of superstrings? All these areas of physics have in common a methodology, which is discussed in the first few lines of the review. Is a physics of the mind possible? Is it possible to describe how a mind adapts in real time to changes in the physical world through a theory based on a few basic laws? From perception and elementary cognition to emotions and abstract ideas allowing high-level cognition and executive functioning, at nearly all levels of study, the mind shows variability and uncertainties. Is it possible to turn psychology and neuroscience into so-called "hard" sciences? This review discusses several established first principles for the description of mind and their mathematical formulations. A mathematical model of mind is derived from these principles. This model includes mechanisms of instincts, emotions, behavior, cognition, concepts, language, intuitions, and imagination. We clarify fundamental notions such as the opposition between the conscious and the unconscious, the knowledge instinct and aesthetic emotions, as well as humans' universal abilities for symbols and meaning. In particular, the review discusses in length evolutionary and cognitive functions of aesthetic emotions and musical emotions. Several theoretical predictions are derived from the model, some of which have been experimentally confirmed. These empirical results are summarized and we introduce new theoretical developments. Several unsolved theoretical problems are proposed, as well as new experimental challenges for future research. PMID- 29398559 TI - Einstein and the physics of the mind: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by Felix Schoeller et al. PMID- 29398560 TI - Rox, a Rifamycin Resistance Enzyme with an Unprecedented Mechanism of Action. AB - Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase that inactivates a broad range of rifamycin antibiotics. Our findings describe a mechanism of rifamycin inactivation initiated by monooxygenation of the 2 position of the naphthyl group, which subsequently results in ring opening and linearization of the antibiotic. The result is an antibiotic that no longer adopts the basket-like structure essential for binding to the RNA exit tunnel of the target RpoB, thereby providing the molecular logic of resistance. This unique mechanism of enzymatic inactivation underpins the broad spectrum of rifamycin resistance mediated by Rox enzymes and presents a new antibiotic resistance mechanism not yet seen in microbial antibiotic detoxification. PMID- 29398563 TI - Public-private partnerships as enablers of progress in the fight against mental disorders: The example of the European Innovative Medicines Initiative. PMID- 29398561 TI - CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis. AB - Mycobacterial cell wall lipids bind the conserved CD1 family of antigen presenting molecules and activate T cells via their T cell receptors (TCRs). Sulfoglycolipids (SGLs) are uniquely synthesized by Mycobacterium tuberculosis, but tools to study SGL-specific T cells in humans are lacking. We designed a novel hybrid synthesis of a naturally occurring SGL, generated CD1b tetramers loaded with natural or synthetic SGL analogs, and studied the molecular requirements for TCR binding and T cell activation. Two T cell lines derived using natural SGLs are activated by synthetic analogs independently of lipid chain length and hydroxylation, but differentially by saturation status. By contrast, two T cell lines derived using an unsaturated SGL synthetic analog were not activated by the natural antigen. Our data provide a bioequivalence hierarchy of synthetic SGL analogs and SGL-loaded CD1b tetramers. These reagents can now be applied to large-scale translational studies investigating the diagnostic potential of SGL-specific T cell responses or SGL-based vaccines. PMID- 29398562 TI - Switch of Mitochondrial Superoxide Dismutase into a Prooxidant Peroxidase in Manganese-Deficient Cells and Mice. AB - Superoxide radical anion (O2?-) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O2?- is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. Here we show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells and in vivo. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells and in vivo. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases. PMID- 29398564 TI - The MINDVIEW project: First results. AB - We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naive, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia. PMID- 29398565 TI - Personalized risk prediction of postoperative cognitive impairment - rationale for the EU-funded BioCog project. AB - Postoperative cognitive impairment is among the most common medical complications associated with surgical interventions - particularly in elderly patients. In our aging society, it is an urgent medical need to determine preoperative individual risk prediction to allow more accurate cost-benefit decisions prior to elective surgeries. So far, risk prediction is mainly based on clinical parameters. However, these parameters only give a rough estimate of the individual risk. At present, there are no molecular or neuroimaging biomarkers available to improve risk prediction and little is known about the etiology and pathophysiology of this clinical condition. In this short review, we summarize the current state of knowledge and briefly present the recently started BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), which is funded by the European Union. It is the goal of this research and development (R&D) project, which involves academic and industry partners throughout Europe, to deliver a multivariate algorithm based on clinical assessments as well as molecular and neuroimaging biomarkers to overcome the currently unsatisfying situation. PMID- 29398566 TI - Adult form of congenital pulmonary venolobar syndrome. PMID- 29398567 TI - Quantification of coronary low-attenuation plaque volume for long-term prediction of cardiac events and reclassification of patients. AB - BACKGROUND: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets. METHODS: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS). RESULTS: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p < .001), clinical risk and CACS (c-index 0.722 vs. 0.771, p < .01) and clinical risk and SIS (c-index 0.735 vs. 0.771, p < .01. A combined approach using quantified LAPV and clinical risk significantly improved the stratification of patients into different risk categories compared to clinical risk alone (categorical net reclassification index 0.69 with 95% CI 0.27 and 0.96, p < .001). The combined approach classified 846 (53.6%) patients as low risk (annual event rate 0.04%), 439 (27.8%) patients as intermediate risk (annual event rate 0.5%) and 292 (18.5%) patients as high risk (annual event rate 0.99%). CONCLUSION: Quantification of LAPV provides incremental prognostic information beyond established CT risk patterns and permits improved stratification of patients into different risk categories. PMID- 29398569 TI - Identifying Malnutrition in Preterm and Neonatal Populations: Recommended Indicators. PMID- 29398568 TI - Association between Diet Quality Scores and Risk of Hip Fracture in Postmenopausal Women and Men Aged 50 Years and Older. AB - BACKGROUND: Although a number of studies showed a lower risk of hip fractures with high-quality diets, few of them were conducted in the United States. OBJECTIVE: This prospective analysis examined the association between several diet quality indexes and risk of hip fractures in US men and women. DESIGN: This is a prospective cohort study. PARTICIPANTS/SETTING: The participants were 74,446 postmenopausal women from the Nurses' Health Study and 36,602 men aged 50 years and older from the Health Professionals Follow-Up Study in the United States. MAIN OUTCOME MEASURE: Hip fractures were self-reported on biennial questionnaires between 1980-2012 in women, and between 1986-2012 in men. STATISTICAL ANALYSIS: Diet was assessed every 4 years with a validated food frequency questionnaire. Relative risks were computed for hip fracture by quintiles of the Alternate Mediterranean Diet score (aMed), the Alternate Healthy Eating Index-2010 (AHEI 2010), and the Dietary Approaches to Stop Hypertension score using Cox proportional hazards models, adjusting for potential confounders. RESULTS: Two thousand one hundred forty-three incident hip fractures in women and 603 in men were reported during follow-up. A significant inverse trend was observed with the cumulative AHEI-2010 score in women (relative risk comparing extreme quintiles 0.87, 95% CI 0.75 to 1.00; P for trend=0.02). There was also a suggestion of an inverse association with the Dietary Approaches to Stop Hypertension score (P for trend=0.03). In addition, significant inverse trends were observed between all three diet quality scores and hip fractures in women younger than age 75 years but not older women. There was no clear association between diet quality indexes and hip fracture in men. CONCLUSIONS: Higher AHEI-2010 scores were associated with a lower risk of hip fractures in US women. The inverse associations with diet quality may be more apparent among those younger than age 75 years. PMID- 29398570 TI - Reliability of Patient-Led Screening with the Malnutrition Screening Tool: Agreement between Patient and Health Care Professional Scores in the Cancer Care Ambulatory Setting. AB - BACKGROUND: The prevalence of malnutrition in patients with cancer is reported as high as 60% to 80%, and malnutrition is associated with lower survival, reduced response to treatment, and poorer functional status. The Malnutrition Screening Tool (MST) is a validated tool when administered by health care professionals; however, it has not been evaluated for patient-led screening. OBJECTIVES: This study aims to assess the reliability of patient-led MST screening through assessment of inter-rater reliability between patient-led and dietitian researcher-led screening and intra-rater reliability between an initial and a repeat patient screening. DESIGN/PARTICIPANTS: This cross-sectional study included 208 adults attending ambulatory cancer care services in a metropolitan teaching hospital in Queensland, Australia, in October 2016 (n=160 inter-rater reliability; n=48 intra-rater reliability measured in a separate sample). MAIN OUTCOME MEASUREMENTS: Primary outcome measures were MST risk categories (MST 0-1: not at risk, MST >=2: at risk) as determined by screening completed by patients and a dietitian-researcher, patient test-retest screening, and patient acceptability. STATISTICAL ANALYSIS: Percent and chance-corrected agreement (Cohen's kappa coefficient, kappa) were used to determine agreement between patient-MST and dietitian-MST (inter-rater reliability) and MST completed by patient on admission to unit (patient-MSTA) and MST completed by patient 1 to 3 hours after completion of initial MST (patient-MSTB) (intra-rater reliability). RESULTS: High inter-rater reliability and intra-rater reliability were observed. Agreement between patient-MST and dietitian-MST was 96%, with "almost perfect" chance-adjusted agreement (kappa=0.92, 95% CI 0.84 to 0.97). Agreement between repeated patient-MSTA and patient-MSTB was 94%, with "almost perfect" chance adjusted agreement (kappa=0.88, 95% CI 0.71 to 1.00). Based on dietitian-MST, 33% (n=53) of patients were identified as being at risk for malnutrition, and 40% of these reported not seeing a dietitian. Of 156 patients who provided feedback, almost all reported that the MST was clear (92%), questions were easy to understand (95%), and completion time was <=5 minutes (99%). CONCLUSION: Patient led screening with the MST is reliable and well accepted by patients. Patient-led screening in the cancer care ambulatory setting has the potential to improve patient autonomy and screening completion rates. PMID- 29398571 TI - Turning the Waiting Room into a Classroom: Weekly Classes Using a Vegan or a Portion-Controlled Eating Plan Improve Diabetes Control in a Randomized Translational Study. AB - BACKGROUND: In research settings, plant-based (vegan) eating plans improve diabetes management, typically reducing weight, glycemia, and low-density lipoprotein (LDL) cholesterol concentrations to a greater extent than has been shown with portion-controlled eating plans. OBJECTIVE: The study aimed to test whether similar benefits could be found using weekly nutrition classes in a typical endocrinology practice, hypothesizing that a vegan eating plan would improve glycemic control, weight, lipid concentrations, blood pressure, and renal function and would do so more effectively than a portion-controlled eating plan. DESIGN: In a 20-week trial, participants were randomly assigned to a low-fat vegan or portion-controlled eating plan. PARTICIPANTS/SETTING: Individuals with type 2 diabetes treated in a single endocrinology practice in Washington, DC, participated (45 starters, 40 completers). INTERVENTION: Participants attended weekly after-hours classes in the office waiting room. The vegan plan excluded animal products and added oils and favored low-glycemic index foods. The portion controlled plan included energy intake limits for weight loss (typically a deficit of 500 calories/day) and provided guidance on portion sizes. MAIN OUTCOME MEASURES: Body weight, hemoglobin A1c (HbA1c), plasma lipids, urinary albumin, and blood pressure were measured. STATISTICAL ANALYSES PERFORMED: For normally distributed data, t tests were used; for skewed outcomes, rank-based approaches were implemented (Wilcoxon signed-rank test for within-group changes, Wilcoxon two-sample test for between-group comparisons, and exact Hodges-Lehmann estimation to estimate effect sizes). RESULTS: Although participants were in generally good metabolic control at baseline, body weight, HbA1c, and LDL cholesterol improved significantly within each group, with no significant differences between the two eating plans (weight: -6.3 kg vegan, -4.4 kg portion controlled, between-group P=0.10; HbA1c, -0.40 percentage point in both groups, P=0.68; LDL cholesterol -11.9 mg/dL vegan, -12.7 mg/dL portion-controlled, P=0.89). Mean urinary albumin was normal at baseline and did not meaningfully change. Blood pressure changes were not significant. CONCLUSIONS: Weekly classes, integrated into a clinical practice and using either a low-fat vegan or portion controlled eating plan, led to clinical improvements in individuals with type 2 diabetes. PMID- 29398572 TI - Enhanced antitumor efficacy through microwave ablation in combination with immune checkpoints blockade in breast cancer: A pre-clinical study in a murine model. AB - PURPOSE: The purpose of this study was to investigate the therapeutic efficacy of the combination of microwave ablation (MWA) in combination with immune checkpoints blockade in the treatment of breast cancer using the 4T1 tumor bearing mice model. MATERIALS AND METHODS: We treated tumor-bearing mice with MWA, programmed cell death protein1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade (P+C), MWA plus PD-1 and CTLA-4 blockade (combination therapy), or no-treatment. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 15 after MWA, five mice from the combination therapy group received tumor rechallenge with 4T1 or CT26 cells and the volumes of rechallenge tumor were calculated every 5 days. Immune cells were identified by immunohistochemistry and flow cytometry, and the concentrations of plasma interferon-gamma (IFN-gamma) were identified by enzyme linked immunosorbent assay (ELISA). RESULTS: The combination therapy significantly prolonged tumor-bearing mice survival compared to no-treatment group, P+C group or MWA group (P<0.001, P<0.001 and P=0.01, respectively) and protected most surviving mice from 4T1 tumor rechallenge (P=0.002) but not CT26 tumor rechallenge (P=0.905). Both local and systemic CD8+ T-cell responses were induced by MWA (all P<0.05) and further augmented by subsequent administration of PD-1 and CTLA-4 blockade (all P<0.05). Plasma IFN-gamma concentrations were significantly elevated in the combination therapy group compared to no-treatment group, P+C group or MWA group (P<0.001, P<0.001 and P=0.01, respectively). CONCLUSION: MWA combined with immune checkpoints blockade could synergistically enhance antitumor efficacy with augmented specific immune responses, and the combination therapy is a promising approach to treat breast cancer. PMID- 29398573 TI - Radiation-related soft tissue sarcoma in a veterinary technician. PMID- 29398574 TI - Comparison of enhancement of the vestibular perilymph between gadoterate meglumine and gadobutrol at 3-Tesla in Meniere's disease. AB - PURPOSE: To compare the degree of enhancement of the perilymph between two macrocyclic gadolinium-based contrast agents (gadobutrol and gadoterate meglumine) in patients with Meniere's disease at 3-T magnetic resonance imaging (MRI). MATERIALS AND METHODS: The MRI examinations of 20 patients with Meniere's disease obtained 4hours after a single intravenous dose of macrocyclic gadolinium based contrast agents were retrospectively compared. Ten patients (median age: 58.5 years; median body mass index [BMI]: 25) have received a single intravenous dose of gadoterate meglumine and 10 patients (median age: 45.5 years; median BMI: 25.4) have received a single-dose of gadobutrol. Two radiologists independently measured the signal intensity ratio (SIR) by using region of interest analysis and performed a visual assessment in order to evaluate the perilymph of each semicircular canal and of the vestibule. RESULTS: No differences in SIR of the symptomatic ear were found between gadobutrol (median SIR: 1.58) and gadoterate meglumine (median SIR: 1.3) (P=0.18). The SIR of the contralateral asymptomatic ear was significantly greater with gadobutrol (median: 1.62) than with gadoterate meglumine (median: 1.21) (P=0.009). No differences in endolymphatic structures visualization were found between gadobutrol and gadoterate meglumine in the symptomatic ears (P=0.27) but gadobutrol allowed a better assessment of endolymphatic structures and semicircular canals in the asymptomatic ear (P<0.001). CONCLUSION: Gadobutrol and gadoterate meglumine provide similar degrees of enhancement of the symptomatic ear in patients with Meniere's disease but gadobutrol provides better anatomical details regarding endolymphatic space and semicircular canals of asymptomatic, contralateral ear. PMID- 29398576 TI - A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder. AB - BACKGROUND: Major depression is the fourth leading cause of disability worldwide and poses a socioeconomic burden worldwide. Transcutaneous vagus nerve stimulation (tVNS) is a promising noninvasive clinical device that may reduce the severity of major depression. However, the neural mechanism underlying continuous tVNS has not yet been elucidated. OBJECTIVE: We aimed to explore the effect of hypothalamic subregion functional connectivity (FC) changes during continuous tVNS treatment on major depressive disorder (MDD) patients and to identify the potential biomarkers for treatment outcomes. METHODS: Forty-one mild to moderate MDD patients were recruited and received either real or sham tVNS treatment for 4 weeks. We used a seed-to-whole brain approach to estimate the FC changes of hypothalamic subregions and their surrounding control areas during continuous tVNS treatment and explored their association with clinical outcome changes after 4 weeks of treatment. RESULTS: Of the thirty-six patients that completed the study, those in the tVNS group had significantly lower scores on the 24-item Hamilton Depression (HAM-D) Rating Scale compared to the sham tVNS group after 4 weeks of treatment. The FC between the bilateral medial hypothalamus (MH) and rostral anterior cingulate cortex (rACC) was significantly decreased during tVNS but not during sham tVNS. The strength of this FC was significantly correlated with HAM-D improvements after 4 weeks of tVNS. CONCLUSION: The FC between the bilateral MH and rACC may serve as a potential biomarker for the tVNS state and predict treatment responses. Our results provide insights into the neural modulation mechanisms of continuous tVNS and reveal a potential therapeutic target for MDD patients. PMID- 29398578 TI - Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung Cancer: A Retrospective Multicenter Analysis. AB - BACKGROUND: Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy. MATERIALS AND METHODS: A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel Haenszel test. RESULTS: The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P < .05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029). Previous radiotherapy also had a positive association with the treatment response (P = .012). CONCLUSION: The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer. PMID- 29398579 TI - The Portuguese version of "The Utrecht Questionnaire for outcome assessment in aesthetic rhinoplasty": validation and clinical application. AB - INTRODUCTION: The evaluation of surgical outcomes measured by patient satisfaction or quality of life is very important, especially in plastic surgery. There is increasing interest in self-reporting outcomes evaluation in plastic surgery. OBJECTIVE: The aim of this study was to perform the translation, cross cultural adaptation and validation of "The Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty" from English to Portuguese. METHODS: Retrospective study involving 50 patients undergoing to rhinoplasty comparing the preoperative period with the current postoperative situation (minimum 6 months and maximum 24 months postoperatively). Statistical analysis was performed to assess internal consistency, test-retest reliability, validity and responsiveness. RESULTS: No patients received a negative score on the visual analogue scale comparing preoperative and postoperative appearance. The postoperative improvement on the visual analogue scale revealed a Gaussian curve of normal distribution with a mean improvement of 4.44 points. The test-retest reliability showed a positive correlation between the postoperative response and the same questionnaire repeated ninety-six hours later. The internal consistency was high (Cronbach's alpha value: Preoperative=0.88; Postoperative=0.86). The authors observed a significant improvement in response for all individual questions in the postoperative phase as compared with preoperative situation (t student test - p<0.05). CONCLUSION: The Portuguese version of "The Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty" is a valid instrument to assess patients' outcomes following rhinoplasty surgery. PMID- 29398580 TI - Septum pyramidal adjustment and repositioning - a conservative and effective rhinoplasty technique. AB - INTRODUCTION: In rhinoplasty, the nasal dorsum has important relevance regarding the esthetic and functional aspects of the surgery. Its reduction should be performed with maximum accuracy and controlled resection to prevent or minimize potential complications. The Septum Pyramidal Adjustment and Repositioning consists of a conservative surgical technique of the nasal dorsum, which does not require the detachment of the upper lateral cartilages of the nasal septum, allowing the remodeling of the nasal dorsum while maintaining esthetic lines and nasal function, potentially reducing frequent complications in more traditional surgeries. OBJECTIVE: To describe the Septum Pyramidal Adjustment technique in detail, presenting its advantages and disadvantages in relation to the other surgical approaches, as well as to disclose results of this surgical procedure in patients submitted to primary rhinoplasty in a specific hospital. METHODS: The medical records of all patients submitted to surgery from 2011 to 2015 through this surgical technique were evaluated by the same team. Of these cases, certain variables were analyzed such as gender, age, indication for reoperation and surgical complications. RESULTS: 153 patients underwent rhinoplasty through Septum Pyramidal Adjustment. Of these, 13 patients experienced an indication for a second surgery and four had some type of postoperative complication. CONCLUSION: The Septum Pyramidal Adjustment surgical technique is a simple procedure, as it does not require the reconstruction of the nasal dorsum. It has a low number of complications and preserves the anatomical structures. PMID- 29398577 TI - Cell Death, Inflammation, Tumor Burden, and Proliferation Blood Biomarkers Predict Lung Cancer Radiotherapy Response and Correlate With Tumor Volume and Proliferation Imaging. AB - INTRODUCTION: There is an unmet need to develop noninvasive biomarkers to stratify patients in drug-radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging. PATIENTS AND METHODS: Blood samples were collected before and during (day 21) radiotherapy. Twenty-six cell-death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor-burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small-cell and non small-cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC. RESULTS: Blood samples from 78 patients were analyzed. Sixty-one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P < .001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02-1.11; P = .017). Baseline IL-1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day-21 cytokeratin-19 antigen modestly improved this model's survival prediction (concordance probability, 0.75-0.78). Chemotherapy (P < .001) and baseline keratinocyte growth factor (P = .019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET). CONCLUSION: Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F-FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates. PMID- 29398575 TI - Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop. AB - BACKGROUND: Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. OBJECTIVE: This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. METHODS: The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. RESULTS: Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. CONCLUSIONS: These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. PMID- 29398581 TI - The ubiquitin proteasome pathway in neuropsychiatric disorders. AB - The ubiquitin proteasome system (UPS) is a highly conserved pathway that tightly regulates protein turnover in cells. This process is integral to neuronal development, differentiation, and function. Several members of the UPS are disrupted in neuropsychiatric disorders, highlighting the importance of this pathway in brain development and function. In this review, we discuss some of these pathway members, the molecular processes they regulate, and the potential for targeting the UPS in an effort to develop therapeutic strategies in neuropsychiatric and neurodevelopmental disorders. PMID- 29398582 TI - Revisiting the alerting effect of light: A systematic review. AB - Light plays an essential role in maintaining alertness levels. Like other non image-forming responses, the alerting effect of light is influenced by its spectral wavelength, duration and intensity. Alertness levels are also dependent on circadian rhythm (process C) and homeostatic sleep pressure (process S), consistent with the classic two-process model of sleep regulation. Over the last decade, there has been increasing recognition of an additional process (referred to as the third process) in sleep regulation. This third process seems to receive sensory inputs from body systems such as digestion, and is usually synchronised with process C and process S. Previous studies on the alerting effect of light have been mostly conducted in laboratories. Although these studies are helpful in delineating the impact of process C and process S, their ability to assist in understanding the third process is limited. This systematic review investigated the factors that influence the alerting effect of light by examining randomised controlled trials and randomised or counterbalanced crossover studies. Factors that influence light's alerting effect were examined with reference to the three process model. The post-illuminance alerting effect was examined separately due to its potential to offer flexible workplace-based light interventions to increase or maintain employees' alertness. PMID- 29398583 TI - Selection of the Best of 2017 in Cardiac Transplant and Ventricular Assist Devices. PMID- 29398584 TI - Endoscopic balloon dilatation in primary obstructive megaureter: Long-term results. AB - BACKGROUND: Open neoureterocystostomy is the traditional surgical treatment for primary obstructive megaureter (POM). Endoscopic balloon dilation is a new minimally invasive alternative. It has been shown to be a safe and effective endoscopic procedure over short-term follow-up; however, few studies have shown its long-term efficacy. OBJECTIVE: The aim of this study was to evaluate the long term results and complications of balloon dilation for the treatment of primary obstructive megaureter in infants. MATERIALS AND METHOD: A retrospective review was performed of patients with primary obstructive megaureter treated with balloon dilation. The diagnosis was made through ultrasonography, diuretic isotopic renogram, and voiding cystourethrogram (VCUG). The indications for surgery were: worsening hydronephrosis, renal function impairment, and recurrent urinary tract infections (UTI). All patients were followed 3 months after the endoscopic procedure with ultrasonography and MAG-3 renogram, and 6 months after surgery with VCUG and ultrasonography. Annual ultrasound and clinical follow-up were performed until present time. RESULTS: Seven boys and six girls were treated (median age 9 months, range 2-24). Ten patients had a prenatal diagnosis of hydronephrosis, and the diagnoses was made after UTI in three patients. No intraoperative complications were observed. One double-J stent was replaced after endoscopic procedure for malpositioning, and four patients developed UTIs after surgery. All patients had non-obstructive MAG-3 diuretic renogram 6 months after surgery. The mean washout on the renogram and the ultrasound pelvic diameter showed pre-operative and postoperative statistical differences (Summary Table). All patients maintained their results without recurrence or any other complications in the long-term follow-up. The median follow-up was 10.3 years (range 4.7-12.2). DISCUSION: In 2014, Aparicio et al. first described balloon dilation being used as a definitive treatment for primary obstructive megaureter in infants. Bujons et al. also presented 20 cases with a mean follow-up of 6.9 years. The current study is the largest to date, with a median follow-up of 10.2 years. It demonstrated the value of balloon dilation as a definitive treatment for POM. Despite these results, it was difficult to establish endoscopic balloon dilation as a definitive treatment for POM, due to the absence of long-term studies like the current one. CONCLUSION: Balloon dilation can be a safe and effective endoscopic procedure for the treatment of primary obstructive megaureter in infants, and has shown good outcomes in long-term follow-up. More studies are needed to demonstrate these results. PMID- 29398585 TI - Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent? AB - INTRODUCTION: Sphincter insufficiency is mostly associated with neurogenic and some structural abnormalities in the pediatric population. As a mini-invasive treatment, urethral bulking agents have been used to treat this problem. OBJECTIVE: The aim was to evaluate if technical success, defined as intraoperative increase in abdominal leak point pressure (ALPP), predicts the outcome of the treatment of sphincter insufficiency with urethral bulking agent. STUDY DESIGN: We reviewed all children treated first time with dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux) for urethral sphincter insufficiency and who intraoperatively had ALPPs measured during 2004-2014. Patient characteristics, change in urinary continence and the duration of the possible response were evaluated in neurogenic and non-neurogenic cases. RESULTS: The median age of the patients was 7.8 years (range 4.1-14.5) at initial treatment and median volume of Dx/HA instilled was 3.5 mL (IQR 2-5). Twelve patients had neurogenic disease and 15 had non-neurogenic disease. Median ALPPs before and after the injections were 19 cmH2O (IQR 14-28) and 70 cmH2O (IQR 48 80), p < 0.001. Increases in ALPPs were similar in both patient groups (p = 0.661) and in 17 patients with any response and 10 patients with no response (p = 0.267). In patients with any response the median duration of the response was only 0.8 years (IQR 0.09-2.0). During a median follow-up of 4.9 years (range 1.7 11.8), 15 patients received one to three repeat injections and eight patients went through sling or bladder neck operation (Summary table). During repeat injections, the preoperative ALPPs had returned to the original levels. Currently, 20% are continent or almost continent with one or more Dx/HA injections. In half of the patients with neurogenic bladder, compliance or volume deteriorated slightly in follow-up. Five out of 15 patients who reached puberty become continent spontaneously after failed bladder neck injection. DISCUSSION: Intraoperative ALPPs increased significantly in most patients during the procedure. However, only 52% of the patients experienced more than 1 month of success after the procedure, and even in those the effect lasted mostly under a year. With one to four injections one-fifth seem to have had a good long-term result. Although the long-term success rate is limited, bulking agent injection allowed the patients with spontaneous voiding to continue it and the injection did not prevent future treatments. CONCLUSION: Intraoperative increased ALPP does not predict a good long-term outcome after Dx/HA injection. At the end, only a fifth of our patients had good result with one or more Dx/HA injections. A change in bladder behavior is possible after treatment. PMID- 29398586 TI - Prospective study of enhanced recovery after surgery protocol in children undergoing reconstructive operations. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocol is a set of peri operative strategies to increase speed of recovery. ERAS is well established in adults but has not been well studied in children. OBJECTIVE: The purpose of the current study was to establish the safety and efficacy of an ERAS protocol in pediatric urology patients undergoing reconstructive operations. It was hypothesized that ERAS would reduce length of stay and decrease complications when compared with historical controls. STUDY DESIGN: Institutional Review Board approval was obtained to prospectively enroll patients aged <18 years if they had undergone urologic reconstruction that included a bowel anastomosis. ERAS included: no bowel preparation, administration of pre-operative oral carbohydrate liquid, avoidance of opioids, regional anesthesia, laparoscopy when feasible, no postoperative nasogastric tube, early feeding, and early removal of intravenous fluids (IVF). Recent (2009-2014) historical controls were propensity matched in a 2:1 ratio on age, sex, ventriculoperitoneal shunt status and whether the patient was undergoing bladder augmentation. Outcomes were protocol adherence, length of stay (LOS), emergency department (ED) visits, re-admission within 30 days, re operations and adverse events occurring within 90 days of surgery. RESULTS: A total of 26 historical and 13 ERAS patients were included. Median ages were 10.4 (IQR 8.0-12.4) and 9.9 years (IQR 9.1-11), respectively (P = 0.94) (see Summary Table). There were no significant between-group differences in prior abdominal surgery (38% vs 62%), rate of augmentation (88% vs 92%) or primary diagnosis of spina bifida (both 62%). ERAS significantly improved use of pre-operative liquid load (P < 0.001), avoidance of opioids (P = 0.046), early discontinuation of IVF (P < 0.001), and early feeding (P < 0.001). Protocol adherence improved from 8/16 (IQR 4-9) historically to 12/16 (IQR 11-12) after implementation of ERAS. LOS decreased from 8 days to 5.7 days (P = 0.520). Complications of any grade per patient decreased from 2.1 to 1.3 (OR 0.71, 95% CI 0.51-0.97). There were fewer complications per patient across all grades with ERAS. No differences were seen in emergency department (ED) visits, re-admissions and re-operations. DISCUSSION: Implementation improved consistency of care delivered. Tenets of ERAS that appeared to drive improvements included maintenance of euvolemia through avoidance of excess fluids, multimodal analgesia, and early feeding. CONCLUSION: ERAS decreased length of stay and 90-day complications after pediatric reconstructive surgery without increased re-admissions, re-operations or ED visits. A multicenter study will be required to confirm the potential benefits of adopting ERAS. PMID- 29398587 TI - Split bolus MR urography in diagnosing obstructing vessels. PMID- 29398589 TI - Efficacy of tiotropium in adults with moderate asthma, by leukotriene receptor antagonist use at baseline. PMID- 29398588 TI - Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia. AB - INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged <=2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management. PMID- 29398590 TI - Surface-enhanced Raman scattering (SERS) of riboflavin on nanostructured Ag surfaces: The role of excitation wavelength, plasmon resonance and molecular resonance. AB - Optimization of surface-enhanced Raman scattering (SERS)-based sensors for (bio)analytical applications has received much attention in recent years. For optimum sensitivity, both the nanostructure fabrication process and the choice of the excitation wavelength used with respect to the specific analyte studied are of crucial importance. In this contribution, detailed SERS intensity profiles were measured using gradient nanostructures with the localized surface-plasmon resonance (LSPR) condition varying across the sample length and using riboflavin as the model biomolecule. Three different excitation wavelengths (633 nm, 515 nm and 488 nm) corresponding to non-resonance, pre-resonance and resonance excitation with respect to the studied molecule, respectively, were tested. Results were interpreted in terms of a superposition of the enhancement provided by the electromagnetic mechanism and intrinsic properties of the SERS probe molecule. The first effect was dictated mainly by the degree of spectral overlap between the LSPR band, the excitation wavelength along with the scattering cross section of the nanostructures, while the latter was influenced by the position of the molecular resonance with respect to the excitation wavelength. Our experimental findings contribute to a better understanding of the SERS enhancement mechanism. PMID- 29398591 TI - Raman imaging of carrier distribution in the channel of an ionic liquid-gated transistor fabricated with regioregular poly(3-hexylthiophene). AB - Raman images of carriers (positive polarons) at the channel of an ionic liquid gated transistor (ILGT) fabricated with regioregular poly(3-hexylthiophene) (P3HT) have been measured with excitation at 785 nm. The observed spectra indicate that carriers generated are positive polarons. The intensities of the 1415 cm-1 band attributed to polarons in the P3HT channel were plotted as Raman images; they showed the carrier density distribution. When the source-drain voltage VD is lower than the source-gate voltage VG (linear region), the carrier density was uniform. When VD is nearly equal to VG (saturation region), a negative carrier density gradient from the source electrode towards the drain electrode was observed. This carrier density distribution is associated with the observed current-voltage characteristics, which is not consistent with the "pinch off" theory of inorganic semiconductor transistors. PMID- 29398592 TI - Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort. AB - OBJECTIVES: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. METHODS: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. RESULTS: Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were >=40 years old. More than 58% had a DLCO <=80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (>=24) groups (p = 0.19 for both). CONCLUSIONS: Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT. PMID- 29398593 TI - Custom mold applicator high-dose-rate brachytherapy for nonmelanoma skin cancer An analysis of 273 lesions. AB - PURPOSE: Nonmelanoma skin cancer is the most commonly diagnosed malignancy in the United States. A modern version of surface brachytherapy, "topographic applicator brachytherapy" (TAB), can be used to treat early-stage nonmelanoma skin cancer (ES-NMSC). The purpose of this study was to evaluate the acute toxicity, chronic toxicity, and recurrence rates of patients with ES-NMSC treated with TAB. METHODS AND MATERIALS: From 2010 to 2013, 172 patients with 273 ES-NMSC tumors were consecutively treated with TAB. A custom applicator was created using a thermoplastic mold with Harrison Anderson Mick applicators. Dose fractionation schemes included 40 Gy in eight fractions delivered twice per week or 48 Gy in 16 fractions delivered four times per week. RESULTS: Of the 273 tumors treated, 23.8% were located on the nose, 54.2% were basal cell carcinoma, 76.2% were Stage I, 89.3% were treated definitively, 98.9% completed treatment, and 75.5% received 40 Gy in eight fractions. Median followup was 25.0 months (0.5-71.0 months). Maximum acute toxicity was G0, 0.4%; G1, 33.3%; G2, 48.7%; G3, 12.1%; and G4, 5.1%. Local recurrence was 4.8% at 25 months, with median time to recurrence being 9 months. There was no regional or distant metastasis documented during the followup. Chronic toxicities included erythema (4.4%), chronic ulceration (4.0%), telangiectasia (2.6%), and pigmentation changes (2.2%). CONCLUSIONS: TAB was able to provide excellent local control (95.2%) with low rates of Grades 3 and 4 toxicities for treatment of ES-NMSC. TAB is a reasonable alternative to surgical resection when there is concern of poor cosmesis/wound healing. PMID- 29398594 TI - A Phase II trial of 8 weeks of degarelix for prostate volume reduction: Efficacy and hormonal recovery. AB - PURPOSE: The purpose of this study was to determine the efficacy of 8 weeks of degarelix for prostate downsizing before interstitial brachytherapy. We also report associated toxicity and the time course of endocrine recovery over the following 12 months. METHODS AND MATERIALS: Fifty patients were accrued to an open-label Phase II clinical trial (www.clinicaltrials.gov ID NCT01446991). Baseline prostate transrectal ultrasound (TRUS) was performed on all patients followed by degarelix administration and a repeat TRUS at Week 8. Brachytherapy was performed within 4 weeks of the 8-week TRUS for all patients who achieved suitable downsizing. RESULTS: The median prostate volume was reduced from 65.0 cc (interquartile range [IQR]: 55.2-80.0 cc) to 48.2 cc at 8 weeks (IQR: 41.2-59.3 cc), representing a median decrease of 26.2% (IQR: 21-31%). Functional recovery of testosterone within an age-adjusted normal range occurred at a median of 34.1 weeks (IQR: 28.2-44.5 weeks) from the date of the final injection. Despite this recovery, follicle-stimulating hormone and luteinizing hormone levels remained abnormally elevated throughout 12 months. Quality-of-life implications are discussed. CONCLUSIONS: Degarelix is effective for prostate downsizing before prostate brachytherapy with a median volume decrease of 26.2% by 8 weeks. Despite the short course of treatment and eventual testosterone recovery, follicle stimulating hormone and luteinizing hormone remain elevated beyond 12 months. Further investigation with randomized comparisons to other hormonal agents is warranted. PMID- 29398595 TI - Ischemia-Reperfusion Injury Reduces Long Term Renal Graft Survival: Mechanism and Beyond. AB - Ischemia-reperfusion injury (IRI) during renal transplantation often initiates non-specific inflammatory responses that can result in the loss of kidney graft viability. However, the long-term consequence of IRI on renal grafts survival is uncertain. Here we review clinical evidence and laboratory studies, and elucidate the association between early IRI and later graft loss. Our critical analysis of previous publications indicates that early IRI does contribute to later graft loss through reduction of renal functional mass, graft vascular injury, and chronic hypoxia, as well as subsequent fibrosis. IRI is also known to induce kidney allograft dysfunction and acute rejection, reducing graft survival. Therefore, attempts have been made to substitute traditional preserving solutions with novel agents, yielding promising results. PMID- 29398596 TI - Allergic Conjunctivitis-induced Retinal Inflammation Promotes Myopia Progression. AB - Myopia is a highly prevalent eye disease. There is limited information suggesting a relationship between myopia and inflammation. We found children with allergic conjunctivitis (AC) had the highest adjusted odds ratio (1.75, 95% confidence interval [CI], 1.72-1.77) for myopia among the four allergic diseases. A cohort study was conducted and confirmed that children with AC had a higher incidence and subsequent risk of myopia (hazard ratio 2.35, 95%CI 2.29-2.40) compared to those without AC. Lower refractive error and longer axial length were observed in an AC animal model. Myopia progression was enhanced by tumor necrosis factor (TNF)-alpha or interleukin (IL)-6 administration, two cytokines secreted by mast cell degranulation. The TNF-alpha or IL-6 weakened the tight junction formed by corneal epithelial (CEP) cells and inflammatory cytokines across the layer of CEP cells, which increased the levels of TNF-alpha, IL-6, and IL-8 secreted by retinal pigment epithelial cells. The expression levels of TNF-alpha, IL-6, IL-8, monocyte chemoattractant protein-1, and nuclear factor kappa B were up-regulated in eyes with AC, whereas IL-10 and the inhibitor of kappa B were down-regulated. In conclusion, the experimental findings in mice corroborate the epidemiological data showing that allergic inflammation influences the development of myopia. PMID- 29398597 TI - Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones. AB - BACKGROUND: Acetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health. METHODS: We first established the metabolome profile that characterizes use of acetaminophen, and we subsequently trained and tested a model that identified metabolomic differences across samples from 455 individuals with and without acetaminophen use. We validated the findings in a European ancestry adult twin cohort of 1880 individuals (TwinsUK), and in a study of 1235 individuals of African American and Hispanic ancestry. We used genomics to elucidate the mechanisms targeted by acetaminophen. FINDINGS: We identified a distinctive pattern of depletion of sulfated sex hormones with use of acetaminophen across all populations. We used a Mendelian randomization approach to characterize the role of Sulfotransferase Family 2A Member 1 (SULT2A1) as the site of the interaction. Although CYP3A7-CYP3A51P variants also modified levels of some sulfated sex hormones, only acetaminophen use phenocopied the effect of genetic variants of SULT2A1. Overall, acetaminophen use, age, gender and SULT2A1 and CYP3A7-CYP3A51P genetic variants are key determinants of variation in levels of sulfated sex hormones in blood. The effect of taking acetaminophen on sulfated sex hormones was roughly equivalent to the effect of 35years of aging. INTERPRETATION: These findings raise concerns of the impact of acetaminophen use on hormonal homeostasis. In addition, it modifies views on the mechanism of action of acetaminophen in pain management as sulfated sex hormones can function as neurosteroids and modify nociceptive thresholds. PMID- 29398598 TI - Protein-Rich or Amino-Acid Only Diets Entrain the Liver Clock: Time to Scrap Insulin? PMID- 29398599 TI - Esophagus-duodenum Gastric Bypass Surgery Improves Glucose and Lipid Metabolism in Mice. AB - BACKGROUND: Despite of its significant therapeutic effects on obesity and metabolic diseases, Roux-en-Y gastric bypass (RYGB) has limited clinical application because of considerable impacts on the gastrointestinal structure and postoperative complications. This study aims to develop a simplified surgical approach with less damage and complication but efficient metabolic benefit. METHODS: The effects of Esophagus-Duodenum gastric bypass (EDGB) on body weight, food intake, glucose and lipid metabolism were compared to RYGB in mice. FINDINGS: EDGB is simple, has higher survival rate and less complication. Relative to RYGB, EDGB demonstrated modest body weight control, identical improvement of glucose and lipid metabolism in obese mice. Blood glucose increased significantly 15 and 30min after oral glucose administration, then markedly decreased in both EDGB and RYGB groups relative to the sham surgery, indicating a quicker absorption of oral glucose and improvement in glucose uptake by insulin targeted tissues. Insulin sensitivity was identically improved. EDGB significantly decreased plasma and hepatic triglyceride levels, while increased browning in visceral and subcutaneous white adipose tissue to the extent identical to RYGB. Levels of ghrelin and nesfatin-1 increased significantly after EDGB and RYGB. INTERPRETATION: EDGB is a valuable model to study the metabolic benefit of bariatric surgery in mice. PMID- 29398600 TI - Markers of Apoptosis Predict Cardiovascular Outcomes and Point to 'Response to Injury' as a Common Pathway Leading to Diabetes and Cardiovascular Events. PMID- 29398602 TI - Anaplasma spp. in North Africa: A review on molecular epidemiology, associated risk factors and genetic characteristics. AB - The genus Anaplasma belonging to the Anaplasmataceae family (order Rickettsiales) comprises obligate intracellular Gram-negative bacteria of veterinary and public health importance. Six species and five types of strains genetically related are currently assigned to the genus Anaplasma including Anaplasma marginale, A. centrale, A. bovis, A. phagocytophilum, A. ovis and A. platys as classified species, and "A. capra", A. odocolei sp. nov., A. phagocytophilum-like 1 (Anaplasma sp.-Japan), A. phagocytophilum-like 2 (Anaplasma sp.-China) and A. platys-like (also named Candidatus Anaplasma camelii) as unclassified strains. Most of these Anaplasma species and strains have been molecularly identified in several animal and/or tick species in the north of Africa. The aim of this review is to summarize the current knowledge about molecular epidemiology, associated risk factors and genetic diversity of Anaplasma species and related strains infecting animals and/or their incriminated tick vectors in North Africa. All these data should be considered when establishing of common management and control programs for anaplasmosis infecting humans and different animal species in North African countries. PMID- 29398601 TI - Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. AB - The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38alpha MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC. PMID- 29398605 TI - Free second dorsal metacarpal artery flap for digital reconstruction: When you cannot go local, you can go free. PMID- 29398604 TI - High prevalence of Rickettsia helvetica in wild small mammal populations in Germany. AB - Since the beginning of the 21st century, spotted fever rickettsioses are known as emerging diseases worldwide. Rickettsiae are obligately intracellular bacteria transmitted by arthropod vectors. The ecology of Rickettsia species has not been investigated in detail, but small mammals are considered to play a role as reservoirs. Aim of this study was to monitor rickettsiae in wild small mammals over a period of five years in four federal states of Germany. Initial screening of ear pinna tissues of 3939 animals by Pan-Rick real-time PCR targeting the citrate synthase (gltA) gene revealed 296 rodents of seven species and 19 shrews of two species positive for rickettsial DNA. Outer membrane protein gene (ompB, ompAIV) PCRs based typing resulted in the identification of three species: Rickettsia helvetica (90.9%) was found as the dominantly occurring species in the four investigated federal states, but Rickettsia felis (7.8%) and Rickettsia raoultii (1.3%) were also detected. The prevalence of Rickettsia spp. in rodents of the genus Apodemus was found to be higher (approximately 14%) than in all other rodent and shrew species at all investigated sites. General linear mixed model analyses indicated that heavier (older) individuals of yellow-necked mice and male common voles seem to contain more often rickettsial DNA than younger ones. Furthermore, rodents generally collected in forests in summer and autumn more often carried rickettsial DNA. In conclusion, this study indicated a high prevalence of R. helvetica in small mammal populations and suggests an age dependent increase of the DNA prevalence in some of the species and in animals originating from forest habitats. The finding of R. helvetica and R. felis DNA in multiple small mammal species may indicate frequent trans-species transmission by feeding of vectors on different species. Further investigations should target the reason for the discrepancy between the high rickettsial DNA prevalence in rodents and the so far almost absence of clinical apparent human infections. PMID- 29398606 TI - An analysis of the breast reduction mammaplasty research pipeline. PMID- 29398603 TI - Pathogen transmission in relation to duration of attachment by Ixodes scapularis ticks. AB - The blacklegged tick, Ixodes scapularis, is the primary vector to humans in the eastern United States of the deer tick virus lineage of Powassan virus (Powassan virus disease); the protozoan parasite Babesia microti (babesiosis); and multiple bacterial disease agents including Anaplasma phagocytophilum (anaplasmosis), Borrelia burgdorferi and Borrelia mayonii (Lyme disease), Borrelia miyamotoi (relapsing fever-like illness, named Borrelia miyamotoi disease), and Ehrlichia muris eauclairensis (a minor causative agent of ehrlichiosis). With the notable exception of Powassan virus, which can be transmitted within minutes after attachment by an infected tick, there is no doubt that the risk of transmission of other I. scapularis-borne pathogens, including Lyme disease spirochetes, increases with the length of time (number of days) infected ticks are allowed to remain attached. This review summarizes data from experimental transmission studies to reinforce the important disease-prevention message that regular (at least daily) tick checks and prompt tick removal has strong potential to reduce the risk of transmission of I. scapularis-borne bacterial and parasitic pathogens from infected attached ticks. The most likely scenario for human exposure to an I. scapularis-borne pathogen is the bite by a single infected tick. However, recent reviews have failed to make a clear distinction between data based on transmission studies where experimental hosts were fed upon by a single versus multiple infected ticks. A summary of data from experimental studies on transmission of Lyme disease spirochetes (Bo. burgdorferi and Bo. mayonii) by I. scapularis nymphs indicates that the probability of transmission resulting in host infection, at time points from 24 to 72 h after nymphal attachment, is higher when multiple infected ticks feed together as compared to feeding by a single infected tick. In the specific context of risk for human infection, the most relevant experimental studies therefore are those where the probability of pathogen transmission at a given point in time after attachment was determined using a single infected tick. The minimum duration of attachment by single infected I. scapularis nymphs required for transmission to result in host infection is poorly defined for most pathogens, but experimental studies have shown that Powassan virus can be transmitted within 15 min of tick attachment and both A. phagocytophilum and Bo. miyamotoi within the first 24 h of attachment. There is no experimental evidence for transmission of Lyme disease spirochetes by single infected I. scapularis nymphs to result in host infection when ticks are attached for only 24 h (despite exposure of nearly 90 experimental rodent hosts across multiple studies) but the probability of transmission resulting in host infection appears to increase to approximately 10% by 48 h and reach 70% by 72 h for Bo. burgdorferi. Caveats to the results from experimental transmission studies, including specific circumstances (such as re-attachment of previously partially fed infected ticks) that may lead to more rapid transmission are discussed. PMID- 29398607 TI - Surgical treatment of axillary bromhidrosis by combining suction-curettage with subdermal undermining through a miniature incision. AB - The suction-curettage technique has been widely applied in the treatment of axillary bromhidrosis. However, it can only moderately eradicate the malodor. From 2011 to 2013, we performed the suction-curettage procedure alone in 91 patients with primary axillary bromhidrosis (group A). From 2014 to 2016, we refined the suction-curettage technique by performing wide subdermal scissors undermining through a miniature incision in 80 patients (group B). Through a miniature incision at the inferior pole of the central axillary crease, the entire subcutaneous tissues containing apocrine glands were initially dissected with scissors within the axillary area and then the undermined apocrine glands were removed by suction-curettage. In group B, 87.5 percent of axillae (140/160) showed significant malodor eradication postoperatively, which was higher than the 33 percent of axillae (60/182) associated with the group A (p < 0.01). Accordingly, patients in group B had a higher satisfaction about the procedure and life quality improvement (p < 0.01). The overall complication rate for the group B was 13.7 percent, which was significantly higher than the 4.4 percent complication rate in the group A (p < 0.01). By combining the suction-curettage with subdermal undermining through a miniature incision, we could achieve a higher curative effect for primary axillary bromhidrosis in comparison to the suction-curettage technique alone. The complication rate was significantly higher than the suction-curettage alone but the final result was acceptable to the patients. PMID- 29398608 TI - Using the internal mammary artery as recipient artery in cervicofacial reconstruction by fibular flap. PMID- 29398609 TI - The use of SERITM Surgical Scaffolds in direct-to-implant reconstruction after skin-sparing mastectomy: A retrospective study on surgical outcomes and a systematic review of current literature. AB - INTRODUCTION: Little is reported on surgical outcomes of SERI Surgical Scaffold, a bioresorbable silk-derived surgical scaffold, developed to provide soft-tissue support and repair, in implant/expander breast reconstruction. METHODS: A retrospective chart study was conducted of all patients who underwent direct-to implant reconstruction with a SERI surgical scaffold after skin-sparing mastectomy, recording surgical characteristics, perioperative complications and reoperations. A systematic literature review was conducted focusing on preclinical and clinical studies reporting on use of SERI in breast surgery. RESULTS: A total of 16 patients (22 breasts) were identified (mean age at surgery was 47 +/- 6.8 years, mean BMI 23.1 +/- 3.1 kg/m2, mean ablation weight 530 +/- 221 g, median clinical follow-up time 27 months (range 25-37)). There were no intraoperative complications. Postoperative bleeding, that required reoperation occurred in one (5%) breast, postoperative seroma in 10 (45%) and surgical site infection in 2 (9%). Scaffold-related complications occurred in 3 (14%) breasts, comprising lack of scaffold integration in all, resulting in skin ulceration in 2 and the scaffold lying free in the breast pocket surrounded with seroma in one. Nine articles were selected and reviewed from the 170 identified. DISCUSSION: The role of silk-derived scaffolds in breast reconstruction is yet to be determined. Though first reports have shown promising results, our and others results suggest that scaffold-related complications, such as lack of scaffold integration, may occur more frequently than previously described. Further research is necessary to determine possible (dis)advantages of the scaffold in specific patient groups. PMID- 29398610 TI - The impact of a career night information session on medical students' perceptions of the scope of practice of plastic surgeons. PMID- 29398611 TI - Invited commentary on "Dutch breast reconstruction guideline". PMID- 29398612 TI - Routine closure of the donor site with a second dorsal metacarpal artery flap to avoid the use of a skin graft after harvest of a first dorsal metacarpal artery flap. AB - AIM: Closure of the donor site on the index finger after raising a first dorsal metacarpal artery (DMA) flap harvest is challenging. The conventional choice is to use a full-thickness skin graft. However, this procedure is associated with several complications and a second donor site to harvest the skin graft is inevitable. The aim of this study was to design a modified incision to allow harvest of a first DMA flap without skin graft. METHODS: From 2015 to 2016, 18 patients with a soft tissue defect of the thumb had reconstruction of the defect using a first DMA flap. A modified incision was used and a relaying perforator flap pedicled on the second DMA was raised through the same incision to cover the donor site. Patient satisfaction, appearance of the injured hand, and the active range of motion (ROM) were assessed. The sensitivity was evaluated by the 2-point discrimination (2-PD) test. RESULTS: All flaps survived completely without complications. Good coverage was obtained with only one linear scar in the dorsum of the hand and no skin grafts. All patients recovered full range of movement in their fingers and regained sensitivity of the flaps. All patients were satisfied with their hand function according to the Michigan Hand Outcomes Questionnaire (MHQ). The mean cosmetic score for the appearance of the injured hand was 8.2 out of 10. CONCLUSIONS: Using our modified incision, it was possible to harvest a second DMA flap at the same time as a first DMA flap allowing simultaneous coverage of the donor defect on the index finger. This prevented the need for a skin graft with all of the associated disadvantages. PMID- 29398613 TI - Intraoperative imaging of lymphatic vessel using ultra high-frequency ultrasound. PMID- 29398614 TI - Anatomical relationship of the right internal jugular vein and the spinal accessory nerve: A word of caution. PMID- 29398616 TI - Hypothalamic miR-219 regulates individual metabolic differences in response to diet-induced weight cycling. AB - : Consumption of a low calorie diet is the most common approach to lose weight. While generally effective at first, it is frequently followed by a relapse where the pre-diet weight is regained, and often exceeded. This pattern of repeated weight loss/regain is referred to as weight cycling and the resulting metabolic response varies greatly between individuals. OBJECTIVE: We attempted to address the issue of individual differences in the response to weight cycling in male mice. METHODS: We first exposed adult wild type mice to repeated cycles of high/low fat food. Next, using a lentiviral approach, we knocked-down or over expressed miR-219 in the ventromedial hypothalamus (VMH) of an additional mouse cohort and performed a full metabolic assessment. RESULTS: Exposure of wild type males to weight cycling resulted in the division of the cohort into subsets of resistant versus metabolic-syndrome-prone (MS) animals, which differed in their metabolic profile and hypothalamic miR-219 levels. Lentiviral knock-down of miR 219 in the VMH led to exacerbation of metabolic syndrome. In contrast, over expression of miR-219 resulted in moderation of the metabolic syndrome phenotype. CONCLUSIONS: Our results suggest a role for miR-219 in the mediation of the metabolic phenotype resulting from repeated weight cycling. PMID- 29398615 TI - Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-beta uptake in astrocytes. AB - OBJECTIVE: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. METHODS: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. RESULTS: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Abeta uptake, both critical functions of astrocytes in the brain. CONCLUSIONS: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies. PMID- 29398617 TI - Exercise increases circulating GDF15 in humans. AB - OBJECTIVE: The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance. Since exercise is a transient physiological stress that has pleiotropic effects on whole-body energy metabolism, we herein explored the effect of exercise on a) circulating GDF15 levels and b) GDF15 release from skeletal muscle in humans. METHODS: Seven healthy males either rested or exercised at 67% of their VO2max for 1 h and blood was sampled from the femoral artery and femoral vein before, during, and after exercise. Plasma GDF15 concentrations were determined in these samples. RESULTS: Plasma GDF15 levels increased 34% with exercise (p < 0.001) and further increased to 64% above resting values at 120 min (p < 0.001) after the cessation of exercise. There was no difference between the arterial and venous GDF15 concentration before, during, and after exercise. During a resting control trial, GDF15 levels measured in the same subjects were unaltered. CONCLUSIONS: Vigorous submaximal exercise increases circulating GDF15 levels in humans, but skeletal muscle tissue does not appear to be the source. PMID- 29398619 TI - Patient Derived Xenografts (PDX) for personalized treatment of pancreatic cancer: emerging allies in the war on a devastating cancer? AB - : The prognosis of pancreatic ductal adenocarcinoma (PDAC), the eighth most lethal cancer for men and ninth for women worldwide, remains dismal. The increasing rates of deaths by PDAC indicate that the overall management of the disease in 21st century is still insufficient. Thus it is obvious that there is an unmet need to improve management of PDAC by finding new biomarkers to screen high risk patients, confirm diagnosis, and predict response to treatment as well more efficacious and safer treatments. Patient Derived Xenografts (PDX) have been developed as a new promising tool in an effort to mirror genetics, tumor heterogeneity and cancer microenvironment of the primary tumor. Herein we aim to give an updated overview of the current status and the perspectives of PDX in the search for the identification of novel biomarkers and improved therapeutic outcomes for PDAC but also their use as a valuable tool towards individualized treatments to improve the outcome of the disease. Furthermore, we critically review the applications, advantages, limitations, and perspectives of PDX in the research towards an improved management of PDAC. SIGNIFICANCE: This review provides a comprehensive overview of the current status and the potential role as well as the challenges of PDX in the road to fight one of the most lethal cancers in the developed countries, pancreatic ductal adenocarcinoma. PMID- 29398618 TI - A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. AB - OBJECTIVE: Regulation of fatty acid (FA) metabolism is central to adipocyte dysfunction during diet-induced obesity (DIO). Long-chain acyl-CoA synthetase-4 (ACSL4) has been hypothesized to modulate the metabolic fates of polyunsaturated FA (PUFA), including arachidonic acid (AA), but the in vivo actions of ACSL4 are unknown. The purpose of our studies was to determine the in vivo role of adipocyte ACSL4 in regulating obesity-associated adipocyte dysfunction. METHODS: We developed a novel mouse model with adipocyte-specific ablation of ACSL4 (Ad KO) using loxP Cre recombinase technology. Metabolic phenotyping of Ad-KO mice relative to their floxed littermates (ACSL4floxed) was performed, including body weight and body composition over time; insulin and glucose tolerance tests; and energy expenditure, activity, and food intake in metabolic cages. Adipocytes were isolated for ex vivo adipocyte oxygen consumption by Clark electrode and lipidomics analysis. In vitro adipocyte analysis including oxygen consumption by Seahorse and real-time PCR analysis were performed to confirm our in vivo findings. RESULTS: Ad-KO mice were protected against DIO, adipocyte death, and metabolic dysfunction. Adipocytes from Ad-KO mice fed high-fat diet (HFD) had reduced incorporation of AA into phospholipids (PL), free AA, and levels of the AA lipid peroxidation product 4-hydroxynonenal (4-HNE). Additionally, adipocytes from Ad-KO mice fed HFD had reduced p53 activation and increased adipocyte oxygen consumption (OCR), which we demonstrated are direct effects of 4-HNE on adipocytes in vitro. CONCLUSION: These studies are the first to elucidate ACSL4's in vivo actions to regulate the incorporation of AA into PL and downstream effects on DIO-associated adipocyte dysfunction. By reducing the incorporation of AA into PL and free fatty acid pools in adipocytes, Ad-KO mice were significantly protected against HFD-induced increases in adipose and liver fat accumulation, adipocyte death, gonadal white adipose tissue (gWAT) inflammation, and insulin resistance (IR). Additionally, deficiency of adipocyte ACSL4 expression in mice fed a HFD resulted in increased gWAT adipocyte OCR and whole body energy expenditure (EE). PMID- 29398620 TI - Corrigendum to "In Reply to the Letter to the Editor Regarding "Endoscopic Endonasal Surgery for Pituitary Apoplexy: Evidence On a 75 Case-Series From a Tertiary Care Center"" [World Neurosurgery 109 (2018) 502]. PMID- 29398623 TI - Platelet lysate enhances synovial fluid multipotential stromal cells functions: Implications for therapeutic use. AB - BACKGROUND AIMS: Although intra-articular injection of platelet products is increasingly used for joint regenerative approaches, there are few data on their biological effects on joint-resident multipotential stromal cells (MSCs), which are directly exposed to the effects of these therapeutic strategies. Therefore, this study investigated the effect of platelet lysate (PL) on synovial fluid derived MSCs (SF-MSCs), which in vivo have direct access to sites of cartilage injury. METHODS: SF-MSCs were obtained during knee arthroscopic procedures (N = 7). Colony forming unit-fibroblast (CFU-F), flow-cytometric phenotyping, carboxyfluorescein succinimidyl ester-based immunomodulation for T-cell and trilineage differentiation assays were performed using PL and compared with standard conditions. RESULTS: PL-enhanced SF-MSC (PL-MSC) proliferation as CFU-F colonies was 1.4-fold larger, and growing cultures had shorter population doubling times. PL-MSCs and fetal calf serum (FCS)-MSCs had the same immunophenotype and similar immunomodulation activities. In chondrogenic and osteogenic differentiation assays, PL-MSCs produced 10% more sulfated glycosaminoglycan (sGAG) and 45% less Ca++ compared with FCS-MSCs, respectively. Replacing chondrogenic medium transforming growth factor-beta3 with 20% or 50% PL further increased sGAG production of PL-MSCs by 69% and 95%, respectively, compared with complete chondrogenic medium. Also, Dulbecco's Modified Eagle's Medium high glucose (HG-DMEM) plus 50% PL induced more chondrogenesis compared with HG-DMEM plus 10% FCS and was comparable to complete chondrogenic medium. CONCLUSIONS: This is the first study to assess SF-MSC responses to PL and provides biological support to the hypothesis that PL may be capable of modulating multiple functional aspects of joint resident MSCs with direct access to injured cartilage. PMID- 29398622 TI - UVR8 Interacts with BES1 and BIM1 to Regulate Transcription and Photomorphogenesis in Arabidopsis. AB - UV-B light (UV-B radiation) is known to inhibit plant growth, but the mechanism is not well understood. UVR8 (UV RESISTANCE LOCUS 8) is a UV-B light photoreceptor that mediates UV-B light responses in plants. We report here that UV-B inhibits plant growth by repressing plant steroid hormone brassinosteroid (BR)-promoted plant growth. UVR8 physically interacts with the functional dephosphorylated BES1 (BRI1-EMS-SUPPRESSOR1) and BIM1 (BES1-INTERACTING MYC-LIKE 1) transcription factors that mediate BR-regulated gene expression and plant growth to inhibit their activities. Genome-wide gene expression analysis defined a BES1-dependent UV-B-regulated transcriptome, which is enriched with genes involved in cell elongation and plant growth. We further showed that UV-B activated and nucleus-localized UVR8 inhibited the DNA-binding activities of BES1/BIM1 to directly regulate transcription of growth-related genes. Our results therefore establish that UVR8-BES1/BIM1 interaction represents an early photoreceptor signaling mechanism in plants and serves as an important module integrating light and BR signaling. PMID- 29398621 TI - Myosin VI-Dependent Actin Cages Encapsulate Parkin-Positive Damaged Mitochondria. AB - Mitochondrial quality control is essential to maintain cellular homeostasis and is achieved by removing damaged, ubiquitinated mitochondria via Parkin-mediated mitophagy. Here, we demonstrate that MYO6 (myosin VI), a unique myosin that moves toward the minus end of actin filaments, forms a complex with Parkin and is selectively recruited to damaged mitochondria via its ubiquitin-binding domain. This myosin motor initiates the assembly of F-actin cages to encapsulate damaged mitochondria by forming a physical barrier that prevents refusion with neighboring populations. Loss of MYO6 results in an accumulation of mitophagosomes and an increase in mitochondrial mass. In addition, we observe downstream mitochondrial dysfunction manifesting as reduced respiratory capacity and decreased ability to rely on oxidative phosphorylation for energy production. Our work uncovers a crucial step in mitochondrial quality control: the formation of MYO6-dependent actin cages that ensure isolation of damaged mitochondria from the network. PMID- 29398624 TI - Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017. AB - A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies. PMID- 29398625 TI - Brain responses to auditory oddball task in children with benign childhood epilepsy with centrotemporal spikes: Quantitative analysis and correlation with neuropsychological assessment scores. AB - OBJECTIVE: Variable degrees of cognitive dysfunction have been reported in children with benign childhood epilepsy with centrotemporal spikes (BCECTS). Our aim was to perform quantitative analyses of the brain responses to cognitive tasks using event-related desynchronization (ERD) and event-related synchronization (ERS) and correlating the results with the scores of neuropsychological tests in patients with BCECTS. METHODS: This case control study included 30 patients with BCECTS and 20 controls. Clinical assessment, neuropsychological tests, the Positive wave at 300 msec (P300) parameters recording, and quantitative electroencephalography (EEG) analysis were carried out for both groups. Alpha power ERD and ERS were measured in six different brain regions during an auditory oddball paradigm. RESULTS: Children with epilepsy showed a statistically significant poorer performance in verbal intelligence quotient (IQ), performance IQ, and total scale IQ and lower number of correct responses. Moreover, both groups showed diffuse alpha power attenuation in response to the target tones. After summation of the alpha power ERD over all brain regions to get the net diffuse ERD, the patients' group showed a statistically significant smaller net alpha ERD compared with that of the control group (P=0.001). No significant correlations between the alpha ERD percentage, recorded P300 parameters, and neuropsychological tests scores were found. CONCLUSIONS: Children with BCECTS have subtle cognitive dysfunction proved by significantly lower scores of verbal IQ and performance IQ subtests. The significantly smaller net diffuse alpha power ERD detected in children with epilepsy may be an electrophysiological indicator of disruptive brain activation in relation to cognitive attentional tasks; however, its correlation with neuropsychological tests was insignificant. PMID- 29398627 TI - Interventional programs to improve therapeutic management of people with epilepsy in low- and middle-income countries. AB - OBJECTIVE: To assess the current status of initiatives carried out in developing countries to improve therapeutic management of people with epilepsy. METHODS: A literature review was performed in 2015 to identify and analyze interventional programs carried out in countries with low- and middle-income economies. Electronic databases were reviewed with no time restriction. Each intervention was categorized according to the level of evidence achieved (A: blind randomized controlled trial, B: randomized controlled trial, C1: randomized trial, C2: controlled trial, D: prospective cohort, E: retrospective evaluation). RESULTS: A total of 46 intervention projects were identified, 13 with no quantitative assessment. The 31 remaining projects were carried out in 18 countries, 52% (16) in Africa, 42% (13) in Asia, and 6% (2) in Latin America. Among those, 13% (4) were level B, 3% (1) C1, 6% (2) C2, 74% (23) D, and 3% (1) were level E. The effectiveness of the intervention, assessed by the efficacy of antiepileptic drugs, was the primary objective in 81% (25). People with epilepsy were on average seizure-free in 44.6%+/-14.4% of cases at one year, ranging from 25.0% to 78.4%. At two years, on average 50.9%+/-29.7% are seizure-free, ranging from 4.6 to 92.7%. The median compliance was 79.3% with a minimum of 21.6% and a maximum of 100.0%. DISCUSSION: No blind randomized controlled trial has been used to assess the efficacy of a program to improve access to antiepileptic drugs (AEDs) in developing countries, and the level of evidence was globally low. Phenobarbital remains the AED predominantly used in programs. Adherence to treatment management has been pointed out to be a key element in the success of a program, sometimes not sufficiently considered. Monthly supply of AEDs, at specific and community level, reducing the costs and time spent traveling, appeared to be the most effective strategies. Homogenization and standardization of evaluation practices of programs to improve the management of epilepsy in resource-limited settings would lead to comparison and meta-analysis which would ultimately improve strategies of support for not only epilepsy but also other noncommunicable diseases in developing countries. PMID- 29398626 TI - Seizure clustering during presurgical electroencephalographic monitoring in children. AB - BACKGROUND: Presurgical evaluation with antiseizure medication tapering in patients with refractory epilepsy places them at risk for seizure clustering or prolonged seizures. We looked at the occurrence of seizure clustering (3 or more seizures within 24h) and prolonged seizures and the factors that influence seizure clustering and affect length of stay (LOS) in pediatric patients during presurgical monitoring. METHODS: We retrospectively reviewed the medical records of all consecutive admissions to the epilepsy monitoring unit (EMU) and included patients undergoing noninvasive presurgical evaluation. Data were extracted regarding demographics, seizure history, details of the EMU admission including occurrence of seizure clusters, prolonged seizures, status epilepticus, treatment, and LOS. RESULTS: Sixty-nine patients met our inclusion criteria. Seizure clustering during monitoring was observed in 33 patients (48%). Prolonged seizures lasting >5min was observed in 14 (20%) patients including 2 with status epilepticus (3%). Seizure clusters necessitated rescue treatment in around 30%. History of seizure clustering at home was the only factor associated with the occurrence of seizure clustering during the EMU stay (p<0.0001). The LOS did not differ significantly between patients who had seizure clustering during monitoring versus those who did not (p=0.369). CONCLUSIONS: Seizure clustering was common in children undergoing presurgical monitoring and seen especially in those with a history of seizure clustering at home. Occurrence of seizure clustering did not prolong the LOS but necessitated the use of rescue medications in about a third of the patients with seizure clusters due to multiple seizures. PMID- 29398628 TI - Association between oxygenation and ventilation indices with the time on invasive mechanical ventilation in infants. AB - BACKGROUND: Invasive mechanical ventilation (IMV) is a common practice in pediatric intensive care unit (PICU). However, the role of oxygenation (OI) and ventilation (VI) indices regarding the time on IMV has not been fully understood. BASIC PROCEDURES: The study was conducted with infants up to 24 months of age, hospitalized in PICU for two consecutive years. The values of ventilatory parameters, OI, VI, and blood gas of infants, collected in the first seven days in IMV, were associated with the time on IMV. IMV was classified into: short (<=seven days) and long time (>seven days). The comparison was made from the first to the seventh day. Alpha=0.05. MAIN FINDINGS: Of 142 infants [mean age=7.51+/-6.33 months], 59 (41.5%) remained on IMV for a short time and 83 (58.5%) for a long time. Differences in PaO2 values were found on the second day, and PaO2/FiO2 ratio on the second, third and fourth days, with higher values in the short-term IMV. For FiO2 from the second to the fifth day; Pinsp from the first to the seventh day; PEEP from the second to the sixth day; mechanical respiratory frequency from the second to the seventh day, PaCO2 on the second day; Paw from the first to the seventh day, OI from the second to the sixth day, and VI from the first to the seventh day, the values were higher in the long-term IMV. CONCLUSIONS: The OI and VI can be considered as potential predictors of long term IMV, along with other markers obtained during the IMV. PMID- 29398629 TI - POST-OP: A Strategy to Improve Clinical Documentation in the Early Postoperative Period. AB - OBJECTIVE: To construct and pilot an educational tool to improve the quality of postoperative documentation at Mayo University Hospital. DESIGN: Retrospective data were collected from 100 consecutive patients treated surgically during October to November 2016. The first written ward based note following surgery was analyzed against RCS quality standards outlined in "Good Surgical Practice." An educational tool was then constructed to improve postoperative documentation. The mnemonic created was POST-OP-physiotherapy/mobilization, operative diagnosis, sepsis, thromboprophylaxis, oral intake/fluid balance, and pain. A second audit cycle involving 103 patients was carried out prospectively in March 2017. SETTING: Mayo University Hospital, a 330 bed teaching hospital affiliated with the National University of Ireland, Galway. PARTICIPANTS: All patients who had undergone either an elective or an emergency general surgery procedure over two 5 week periods. RESULTS: Comparing the 2 study periods, significant improvements in the quality of postoperative surgical documentation was observed. All standards improved including patient identification (17.8% vs 78.1%, p < 0.001) and name of note maker (54.7% vs 86.2%, p < 0.001). There was also improvement in the documentation of antibiotic use (23.8% vs 75.8%, p > 0.001), thromboprophylaxis (7.1% vs 75.8%, p < 0.001), analgesia (36.9% vs 74.7%, p < 0.001), operative diagnosis (66.6% vs 91.9%, p < 0.001), and mobilization (23.6% vs 78.1%, p < 0.001) following the introduction of the POST-OP tool. CONCLUSION: The design and introduction of the POST-OP education tool helped to significantly improve documentation and educate surgical residents on the essential components of postoperative care. The above data suggest that this effective mnemonic can improve the quality of postoperative documentation for surgical patients. PMID- 29398630 TI - A Program for Promoting Clinical Scholarship in General Surgery. AB - OBJECTIVE: The Accreditation Council for Graduate Medical Education mandates resident physician training in the principles and applications of research. To provide a robust early foundation for effective engagement in scholarship, we designed a novel clinical scholarship program (CSP) for PGY1 general surgery residents. SETTING, DESIGN AND OUTCOMES: In a general surgery residency training program, we assessed resident academic productivity (i.e., presentations, publications, and sustained engagement in clinical research) and self-efficacy to conduct clinical research, as well as the overall satisfaction of both residents and faculty mentors. The clinical research appraisal inventory was administered both before and after completion of the CSP rotation. RESULTS: Totally, 44 categorical general surgery trainees and 23 faculty research mentors participated in the CSP from 2011 to 2016; 26 residents (59%) presented at regional or national meetings. Of the 35 residents who were 24 or more months beyond their PGY1 training period, 16 (46%) have published their CSP project, 5 (14%) report continued commitment towards publication, and 22 (63%) have >=1 clinical research publications beyond their CSP participation during residency, excluding publications arising from subsequent formal research fellowships. Clinical research appraisal inventory responses indicate significant improvement (p < 0.005) in clinical research self-efficacy. CONCLUSIONS: A structured CSP increases the confidence of trainees to perform clinical research and leads to significant contributions directed at addressing clinically meaningful problems in surgery. Faculty-guided resident research at a very early stage of clinical training supplements other mentorship experiences and encourages the development of surgeons who will engage in life-long clinical problem solving. PMID- 29398632 TI - Transradial experience with bioresorbable vascular scaffolds: A case-matched study with metallic drug-eluting stents. AB - BACKGROUND: Whether polymeric bioresorbable vascular scaffolds (BVS) implantation with transradial approach is feasible and safe is unknown. We compared the feasibility and safety of the transradial approach for BVS delivery with metallic drug-eluting stents (DES). METHODS: We identified 118 consecutive patients who underwent BVS implantation and we compared 30-days and 1-year results with 118 matched patients with DES. Patients were matched for age, sex, risk factors and clinical indication. RESULTS: Rates of transradial approach were 98% in the BVS group vs 95% in the DES group (P = 0.16) with 5Fr used in 38% and 32% (P = 0.34), respectively. The number of stents was similar in both groups, 2.6 +/- 1.5 vs 2.4 +/- 1.3 (P = 0.23). Although maximal pressure for stent deployment was identical in both groups (16 +/- 3 atm), more lesions were pre-dilated (83% vs 52%, P < 0.001) and post-dilated (71% vs 33%, P < 0.001) in the BVS group. Contrast volume (217 +/- 97 vs 175 +/- 108 ml, P < 0.001), fluoroscopy time (16 [10-23] vs 13 [8 21] min, P = 0.04) and procedure duration (65 +/- 31 vs 56 +/- 47 min, P = 0.045) were significantly higher in the BVS group. Major adverse cardiac events, including death, myocardial infarction and target vessel revascularization remained similar in both groups, 1.7% vs 0.8% (P = 0.56) at 30 days and 10% vs 8.5% (P = 0.66) at 1 year. At 1 year, stent thrombosis occurred in 2 (1.7%) patients in the BVS group and 1 (0.8%) patient in the DES group (P = 0.56). CONCLUSION: The use of transradial approach for BVS compared to DES implantation was feasible and safe in all-comers, although BVS implantation included more technical challenges. Outcomes up to 1-year remained comparable in both groups. PMID- 29398631 TI - Enhancing Confidence in Graduating General Surgery Residents: Establishing a Chief Surgery Resident Service at an Independent Academic Medical Center. AB - OBJECTIVE: Providing opportunities for autonomy to enhance the development of independence and confidence during surgery residency remains among the greatest challenges of the current training paradigm. The objective of this study was to evaluate the implementation and outcomes of a chief resident service (CRS). DESIGN: A CRS was designed with operative, call and office responsibilities. Supervision and evaluation were consistent with institutional guidelines. CRS operative logs from 2011 to 2014 were compared with logs from the participants' first year in practice. Select procedures were compared and evaluations were reviewed. Residency graduates' satisfaction with the CRS was evaluated. SETTING: Independent academic medical center. PARTICIPANTS: Nine general surgery residency graduates with one complete year in practice. RESULTS: Nine residents completed CRS rotations and submitted case logs. Median total case volume was 1101 (994 1311) during the 5-year residency, 92 (20-149) during CRS and 299 (99-784) during the first year in practice. Median case volumes for selected procedures for the entire 5-year residency, CRS, and first year of practice were: 93 (66-97), 7 (3 16), and 9 (1-26) laparoscopic appendectomies; 146 (120-157), 24 (3-32), and 34 (15-112) laparoscopic cholecystectomies; 81 (51-94), 1 (1-4), and 3 (0-8) ileocolectomies; 57 (35-86), 4 (0-9), and 8 (2-34) ventral/incisional hernia repairs; 102 (87-137), 12 (3-16), and 13 (3-86) inguinal hernia repairs. Graduates reported that the CRS experience was very beneficial to their current practice. Annual program reviews emphasized the CRS as a major strength of our residency. CONCLUSIONS: Creation of a CRS to increase resident autonomy and provide continuity of patient care with appropriate faculty supervision was successful. Case mix and volumes provided an opportunity for independent operative and clinical experience during residency which realistically paralleled graduates' first year of practice. PMID- 29398633 TI - Incidence, predictors, and long term clinical outcome of angiographic definite stent thrombosis in real world scenario - A prospective cohort study. AB - BACKGROUND: The occurrence of stent thrombosis (ST) in real world scenario is far different from that mentioned in the literature. Our study identifies the various parameters of ST. METHODS: This is a prospective observational-cohort study where in consecutive patients who received successful percutaneous transluminal angioplasty (PTCA) over the study period of 1-year was included and were followed for 1-year from the primary procedure. RESULTS: The overall incidence of definite ST was 1.4% and 1.7% at 30 days and 1 year respectively. The most common mode of presentation of ST was ST-elevation myocardial infarction (82.6%). The history of prior PTCA, multi-vessel disease, emergent PTCA, acute coronary syndrome and type B2/C lesions were found to be the independent predictors for definite ST. The incidence of late ST was significantly higher with bare metal stent (BMS) than drug-eluting stent (DES) (OR-2.4, 95% CI:1.3-4.5). At mean follow-up of 13.9 months after ST, the overall mortality was 36.9%. The independent predictors of mortality after ST were post-PTCA thrombolysis in myocardial infarction (TIMI) flow grade < 3, and cardiogenic shock at the time of presentation. CONCLUSION: The overall incidence of definite ST is high in the real world scenario and the DES fared better than BMS. ST carries a bad prognosis especially so if the patients present in cardiogenic shock, or unable to achieve TIMI-3 flow after PTCA. PMID- 29398636 TI - Temporal changes in the incidence of treated psychiatric and neurodevelopmental disorders during adolescence: an analysis of two national Finnish birth cohorts. AB - BACKGROUND: Comprehensive overviews of the temporal changes in treated psychiatric and neurodevelopmental disorders during adolescence are scarce. We reviewed data from two national cohorts, 10 years apart, to establish the change in use of specialised services for psychiatric and neurodevelopmental diagnoses in Finland. METHODS: We compared the nationwide register-based incidence of psychiatric and neurodevelopmental diagnoses between the 12th birthday and 18th birthday of adolescents born in Finland in 1987 and 1997. Adolescents who emigrated or died before their 12th birthday and those with missing covariate data were excluded, as were those who, when aged 11 years, had lived in a municipality belonging to a hospital district with obviously incomplete data reports during any follow-up years in our study. Our primary outcomes were time to incident specialised service use for any psychiatric or neurodevelopmental disorder and for 17 specific diagnostic classes. We also investigated whether adolescents who died by suicide had accessed specialised services before their deaths. FINDINGS: The cumulative incidence of psychiatric or neurodevelopmental disorders increased from 9.8 in the 1987 cohort to 14.9 in the 1997 cohort (difference 5.2 percentage points [95% CI 4.8-5.5]) among girls, and from 6.2 in the 1987 cohort to 8.8 in the 1997 (2.6 percentage points [2.4-2.9]) among boys. The hazard ratio for the overall relative increase in neurodevelopment and psychiatric disorders in the 1997 cohort compared with the 1987 cohort was 1.6 (95% CI 1.5-1.8) among girls and 1.5 (1.4-1.6) among boys. Of the studied diagnostic classes, we noted significant (ie, p<0.001) relative increases for ten of 17 diagnoses among girls and 11 among boys. Of the adolescents who died by suicide before age 18, only five of 16 in the 1987 cohort and two of 12 in the 1997 cohort had used specialised services in the 6 months before their death. INTERPRETATION: The large absolute rise in service use for psychiatric or neurodevelopmental disorders points to the need to deliver effective treatment to a rapidly increased patient population, whereas the relative increase in specific diagnoses should inform clinical practice. Despite increasing service use, identification of adolescents at risk of suicide remains a major public health priority. FUNDING: Academy of Finland, Brain and Behavior Research Foundation, Finnish Medical Foundation. PMID- 29398635 TI - Association of vitamin D status with metabolic syndrome and its components: A cross-sectional study in a population of high educated Iranian adults. AB - AIM: We aimed to assess the association of vitamin D status with metabolic syndrome and its components among high educated Iranian adults. METHOD: In this cross-sectional study, 352 faculty members with age of 35 years or more, belong to Tarbiat Modares University, Tehran, Islamic Republic of Iran, were recruited during 2016 and 2017. Fasting blood samples were obtained to quantify serum 25(OH)D concentrations, glycemic indicators and lipid profile. Metabolic syndrome was defined based on the guidelines of the National Cholesterol Education Program Adult Treatment Panel III (ATP III). Multivariate logistic regression adjusted for potential confounders was used to evaluate the association between vitamin D status and metabolic syndrome. RESULT: Metabolic syndrome and vitamin D insufficiency were prevalent among 26% and 60.2% of subjects, respectively. There was no statistically significant difference in the prevalence of metabolic syndrome across quartiles of 25(OH)D levels either before or after adjusting for potential confounders (OR: 0.94, 95% CI: 0.43-1.95). In terms of metabolic syndrome components, subjects in the highest quartile of vitamin D levels had 59% decreased risk of abdominal obesity compared with those in the lowest quartile (OR: 0.41, 95% CI: 0.17-0.99), after adjusting for potential confounders. Such inverse relationship was also seen for elevated blood pressure (OR: 0.37, 95% CI: 0.14-0.99), and abnormal glucose homeostasis (OR: 0.40, 95% CI: 0.19-0.85). CONCLUSION: Serum levels of 25(OH)D was inversely associated with the risk of abdominal obesity, hypertension, and abnormal glucose homeostasis. However, no significant relationship was seen for metabolic syndrome. PMID- 29398634 TI - Existing and potential infection risk zones of yellow fever worldwide: a modelling analysis. AB - BACKGROUND: Yellow fever cases are under-reported and the exact distribution of the disease is unknown. An effective vaccine is available but more information is needed about which populations within risk zones should be targeted to implement interventions. Substantial outbreaks of yellow fever in Angola, Democratic Republic of the Congo, and Brazil, coupled with the global expansion of the range of its main urban vector, Aedes aegypti, suggest that yellow fever has the propensity to spread further internationally. The aim of this study was to estimate the disease's contemporary distribution and potential for spread into new areas to help inform optimal control and prevention strategies. METHODS: We assembled 1155 geographical records of yellow fever virus infection in people from 1970 to 2016. We used a Poisson point process boosted regression tree model that explicitly incorporated environmental and biological explanatory covariates, vaccination coverage, and spatial variability in disease reporting rates to predict the relative risk of apparent yellow fever virus infection at a 5 * 5 km resolution across all risk zones (47 countries across the Americas and Africa). We also used the fitted model to predict the receptivity of areas outside at-risk zones to the introduction or reintroduction of yellow fever transmission. By use of previously published estimates of annual national case numbers, we used the model to map subnational variation in incidence of yellow fever across at-risk countries and to estimate the number of cases averted by vaccination worldwide. FINDINGS: Substantial international and subnational spatial variation exists in relative risk and incidence of yellow fever as well as varied success of vaccination in reducing incidence in several high-risk regions, including Brazil, Cameroon, and Togo. Areas with the highest predicted average annual case numbers include large parts of Nigeria, the Democratic Republic of the Congo, and South Sudan, where vaccination coverage in 2016 was estimated to be substantially less than the recommended threshold to prevent outbreaks. Overall, we estimated that vaccination coverage levels achieved by 2016 avert between 94 336 and 118 500 cases of yellow fever annually within risk zones, on the basis of conservative and optimistic vaccination scenarios. The areas outside at-risk regions with predicted high receptivity to yellow fever transmission (eg, parts of Malaysia, Indonesia, and Thailand) were less extensive than the distribution of the main urban vector, A aegypti, with low receptivity to yellow fever transmission in southern China, where A aegypti is known to occur. INTERPRETATION: Our results provide the evidence base for targeting vaccination campaigns within risk zones, as well as emphasising their high effectiveness. Our study highlights areas where public health authorities should be most vigilant for potential spread or importation events. FUNDING: Bill & Melinda Gates Foundation. PMID- 29398637 TI - Language and psychiatry. PMID- 29398638 TI - Increased psychiatric diagnoses and service use in childhood. PMID- 29398639 TI - Necessity to identify the causative agent for appropriate treatment in fungal corneal ulcer: an in vitro study. AB - OBJECTIVE: Fungal corneal ulcers are a major cause of preventable blindness. Different antifungal agents as natamycin, nystatin, fluconazole, itraconazole, voriconazole are used to treat these ulcers. Among these, natamycin is most widely used as a treatment modality. In natamycin non-responding cases, other drugs especially voriconazole is used. This study was done to assess the use of antifungal drugs in the treatment of fungal corneal ulcer by determining the minimum inhibitory concentration against common fungal pathogens. MATERIAL AND METHODS: Minimum inhibitory concentration of fluconazole, itraconazole, voriconazole, nystatin and natamycin was assessed against the 61 isolated corneal fungal pathogens as per CLSI guidelines. RESULTS: MIC value of different antifungal agents varies as per fungal strains. Voriconazole showed the lowest MIC against the isolated fungi, in comparison to fluconazole and itraconazole. In comparison to other fungi, higher natamycin MIC was observed against Aspergillus species. Itraconazole is poorly effective against Fusarium sp. CONCLUSION: Identification of causative fungi is necessary before antifungal treatment. Lowest voriconazole MIC promotes its use as 1st line drug. Comparative higher natamycin MIC, especially against Aspergillus species, warns clinician to have MIC in each case of a non-responding fungal corneal ulcer. PMID- 29398640 TI - Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma. AB - BACKGROUND: Limited data describe the association between the frequency of asthma exacerbations and the decline in lung function in severe asthma. OBJECTIVE: To determine whether asthma exacerbations are associated with enhanced decline in lung function. METHODS: Changes in lung function were analyzed retrospectively using data from the DREAM and MENSA studies of mepolizumab intervention in patients with severe asthma. Patients were either nonsmokers or former smokers. A linear regression model was used to analyze the relationship between the number of exacerbations and decline in FEV1 across treatment groups. RESULTS: In a combined post hoc analysis, 57% (n = 572) of patients had no exacerbations and experienced an improvement in postbronchodilator FEV1 of 143 mL. In contrast, in patients who experienced 3 or more exacerbations, there was a decrease in postbronchodilator FEV1 of 77 mL in the combined analysis. The linear modeling analysis estimated that for each exacerbation seen during the observational period, there was a decrease of 50 mL in FEV1 (P < .001). CONCLUSIONS: A direct relationship between the number of exacerbations in patients with severe eosinophilic asthma and decline in lung function was observed. Repeated exacerbations may be associated with accelerated loss of lung function. PMID- 29398642 TI - Preoperative position splint versus skin traction in patients with hip fracture: An experimental study. AB - AIM: The aim of the study was to compare the effects of a preoperative position splint and skin traction on pain, comfort, complications, and satisfaction with the treatment and care for patients with hip fracture. METHOD: This randomized trial was conducted with a total of 68 patients with hip fracture in a tertiary care hospital in Turkey. Preoperatively, a position splint was applied to the patients in the intervention group (n = 34) and skin traction was applied to patients (n = 34) in the control group. Outcomes studied were pain, comfort, satisfaction and complications. RESULTS: Mann-Whitney U Test showed a significant difference between the position splint group and skin traction group regarding pain severity after the application (p < .05). A significant difference was demonstrated between the two groups concerning comfort levels after the application (p < .05). The position splint group was significantly more satisfied with the treatment and care than the control group in the later period after the application (p < .05). The number of preoperative complications in the position splint group was significantly fewer than that of the skin traction group in the preoperative period (p < .05). CONCLUSION: Preoperative position splint application in patients with hip fracture relieved pain and complications and increased comfort and satisfaction with treatment and care. PMID- 29398641 TI - Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. AB - Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy. PMID- 29398643 TI - The hypoparathyroidism-deafness-renal dysplasia syndrome: A case report. PMID- 29398644 TI - Microgels produced using microfluidic on-chip polymer blending for controlled released of VEGF encoding lentivectors. AB - : Alginate hydrogels are widely used as delivery vehicles due to their ability to encapsulate and release a wide range of cargos in a gentle and biocompatible manner. The release of encapsulated therapeutic cargos can be promoted or stunted by adjusting the hydrogel physiochemical properties. However, the release from such systems is often skewed towards burst-release or lengthy retention. To address this, we hypothesized that the overall magnitude of burst release could be adjusted by combining microgels with distinct properties and release behavior. Microgel suspensions were generated using a process we have termed on-chip polymer blending to yield composite suspensions of a range of microgel formulations. In this manner, we studied how alginate percentage and degradation relate to the release of lentivectors. Whereas changes in alginate percentage had a minimal impact on lentivector release, microgel degradation led to a 3-fold increase, and near complete release, over 10 days. Furthermore, by controlling the amount of degradable alginate present within microgels the relative rate of release can be adjusted. A degradable formulation of microgels was used to deliver vascular endothelial growth factor (VEGF)-encoding lentivectors in the chick chorioallantoic membrane (CAM) assay and yielded a proangiogenic response in comparison to the same lentivectors delivered in suspension. The utility of blended microgel suspensions may provide an especially appealing platform for the delivery of lentivectors or similarly sized therapeutics. STATEMENT OF SIGNIFICANCE: Genetic therapeutics hold considerable potential for the treatment of diseases and disorders including ischemic cardiovascular diseases. To realize this potential, genetic vectors must be precisely and efficiently delivered to targeted regions of the body. However, conventional methods of delivery do not provide sufficient spatial and temporal control. Here, we demonstrate how alginate microgels provide a basis for developing systems for controlled genetic vector release. We adjust the physiochemical properties of alginate for quicker or slower release, and we demonstrate how combining distinct formulations of microgels can tune the release of the overall composite microgel suspension. These composite suspensions are generated using a straightforward and powerful application of droplet microfluidics which allows for the real-time generation of a composite suspension. PMID- 29398645 TI - The potency of lemon (Citrus limon L.) essential oil to control some fungal diseases of grapevine wood. AB - This study aimed to evaluate the in vitro antifungal activity (AA) of the essential oil (EO) of lemon (Citrus limon L.) against three pathogenic fungi attacking grapevine wood. The composition of the EO was also studied. Ten volatile components were identified by gas chromatography-mass spectrometry. The results showed that the EO consists of volatile components where monoterpene hydrocarbons are the most abundant ones. Four major components were identified, which represent 99.9% of the total EO (limonene, neral, beta-pinene, and gamma terpinene). The AA of the EO was evaluated against three pathogenic fungi attacking grapevine wood (Eutypa sp., Botryosphaeria dothidea, and Fomitiporia mediterranea). The results showed that the EO exerts AA against all tested fungi and significantly inhibits their growth. Eutypa sp. is the most sensitive fungus. These results show, for the first time, a new use for the EO of lemon (C. limon L.) to control fungal diseases of grapevine wood. PMID- 29398646 TI - Responses of rice (Oryza sativa L.) genotypes to different levels of submergence. AB - The study aims at identifying some submergence-tolerant rice genotypes through morphological and molecular characterization and their genetic variability analysis. Ten rice genotypes including two submergence-tolerant checks, two susceptible varieties and six advanced lines were evaluated for submergence tolerance in the laboratory and in the field during January-December 2015. The experiment was conducted in the field following randomized complete block design in a two-factor arrangement using five replications. Ten characters, viz. days to flowering, plant height, tiller number plant-1, effective tiller plant-1, and yield plant-1 etc. were studied for four treatments. A significant genotype*environment interaction was observed for all traits studied in this experiment. The yield was reduced for all genotypes at a different level of submergence stress compared to control. Binadhan-11, Binadhan-12, RC 249 and RC 251 showed tolerance, whereas RC 192, RC 193 and RC 225 showed moderate tolerance in submerged condition. The phenotypic coefficient of variance (PCV) was higher than the genotypic coefficient of variance (GCV) in all the studies traits. High heritability (75-97%) was found for all traits. High heritability along with high genetic advance was found for days to flowering (45.55) and plant height (40.05). Molecular characterization of the used genotypes was done with three SSR markers viz. RM 24, and submergence specific SC3 and SUB1. SC3 was found reliable for detection of submergence tolerant genotypes due to the highest gene diversity (0.840) compared to others. The banding pattern of the submergence specific markers SC3 and SUB1 identified in Binadhan-11, Binadhan-12, RC 192, RC 193, RC 225, RC 227, RC 249, and RC 251, which possess the SUB1 gene. Finally, clustering also separates the tolerant genotypes from the susceptible by dividing them into different clusters. The identified genotypes might be useful for the breeding programme for the development of submergence tolerant as well as resistant rice variety in Bangladesh. PMID- 29398647 TI - Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction. AB - BACKGROUND: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. PATIENTS AND METHODS: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 +/- 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 * 106/kg for pegfilgrastim and 32.50 * 106/kg for filgrastim (95% confidence interval, -4.36 to 0.70 * 106/kg). RESULTS: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 * 106/kg vs. filgrastim, 10.10 * 106/kg; P = .16). CONCLUSION: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy. PMID- 29398648 TI - Cost-Effectiveness of Ibrutinib Compared With Obinutuzumab With Chlorambucil in Untreated Chronic Lymphocytic Leukemia Patients With Comorbidities in the United Kingdom. AB - BACKGROUND: Ibrutinib shows superiority over obinutuzumab with chlorambucil (G Clb) in untreated patients with chronic lymphocytic leukemia with comorbidities who cannot tolerate fludarabine-based therapy. However, ibrutinib is relatively more expensive than G-Clb. In this study we evaluated the cost-effectiveness of ibrutinib compared with G-Clb from the United Kingdom (UK) health care perspective. MATERIALS AND METHODS: A 3-state semi-Markov model was parameterized to estimate the lifetime costs and benefits associated with ibrutinib compared with G-Clb as first-line treatment. Idelalisib with rituximab was considered as second-line treatment. Unit costs were derived from standard sources, (dis)utilities from UK elicitation studies, progression-free survival, progression, and death from clinical trials, and postprogression survival and background mortality from published sources. Additional analyses included threshold analyses with ibrutinib and idelalisib at various discount rates, and scenario analysis with ibrutinib as second-line treatment after G-Clb. RESULTS: An average gain of 1.49 quality-adjusted life-years (QALYs) was estimated for ibrutinib compared with G-Clb at an average additional cost of L112,835 per patient. To be cost-effective as per the UK thresholds, ibrutinib needs to be discounted at 30%, 40%, and 50% if idelalisib is discounted at 0%, 25%, and 50% respectively. The incremental cost-effectiveness ratio was L75,648 and L-143,279 per QALY gained for the base-case and scenario analyses, respectively. Sensitivity analyses showed the robustness of the results. CONCLUSION: As per base-case analyses, an adequate discount on ibrutinib is required to make it cost effective as per the UK thresholds. The scenario analysis substantiates ibrutinib's cost-savings for the UK National Health Services and advocates patient's access to ibrutinib in the UK. PMID- 29398649 TI - Cytosolic and Secreted Peptidoglycan-Degrading Enzymes in Drosophila Respectively Control Local and Systemic Immune Responses to Microbiota. AB - Gut-associated bacteria produce metabolites that both have a local influence on the intestinal tract and act at a distance on remote organs. In Drosophila, bacteria-derived peptidoglycan (PGN) displays such a dual role. PGN triggers local antimicrobial peptide production by enterocytes; it also activates systemic immune responses in fat-body cells and modulates fly behavior by acting on neurons. How these responses to a single microbiota-derived compound are simultaneously coordinated is not understood. We show here that the PGRP-LB locus generates both cytosolic and secreted PGN-cleaving enzymes. Through genetic analysis, we demonstrate that the cytosolic PGRP-LB isoforms cell-autonomously control the intensity of NF-kappaB activation in enterocytes, whereas the secreted isoform prevents massive and detrimental gut-derived PGN dissemination throughout the organism. This study explains how Drosophila are able to uncouple the modulation of local versus systemic responses to a single gut-bacteria derived product by using isoform-specific enzymes. PMID- 29398650 TI - Tracking Vibrio cholerae Cell-Cell Interactions during Infection Reveals Bacterial Population Dynamics within Intestinal Microenvironments. AB - Vibrio cholerae is the causative agent of the diarrheal disease cholera. Although many V. cholerae virulence factors have been studied, the role of interbacterial interactions within the host gut and their influence on colonization are poorly understood. Here, we utilized the conjugative properties of a Vibrio-specific plasmid to serve as a quantifiable genetic marker for direct contact among V. cholerae cells in the infant rabbit model for cholera. In conjunction, we also quantified contact-dependent type 6 secretion system (T6SS)-mediated killing of co-infecting V. cholerae strains. Tracking these interbacterial interactions revealed that most contact-dependent cell-cell interactions among V. cholerae occur in specific intestinal microenvironments, notably the distal small intestine and cecum, and that the T6SS confers a competitive advantage within the middle small intestine. These results support a model for V. cholerae gut colonization, which includes microenvironments where critical microbial-host and bacterial-bacterial interactions occur to facilitate colonization by this pathogen. PMID- 29398651 TI - Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells. AB - Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-kappaB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF kappaB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-kappaB activation in distal colon CECs, which collectively triggers myeloid-cell dependent distal colon tumorigenesis. PMID- 29398652 TI - Prenatal Exposure to Phthalates and the Development of Eczema Phenotypes in Male Children: Results from the EDEN Mother-Child Cohort Study. AB - BACKGROUND: Contradictory results exist regarding the importance of early-life exposure to phthalates for development of childhood eczema. OBJECTIVES: We evaluated the association between maternal urinary concentrations of phthalate metabolites between the 24th and 28th week of gestation and occurrence of eczema in their sons up to 5 y of age, according to allergic sensitization as assessed by total immunoglobulin E (IgE) in a subsample of individuals. METHODS: Data on health outcomes and background factors were collected using five standardized annual questionnaires completed by parents at the children's ages of 1-5 y, and their associations with phthalate metabolite urinary concentrations were assessed in 604 mother-son pairs with adjusted multiple logistic regression and Cox's survival model. Several eczema phenotypes were considered. Atopic status was assessed at 5 y of age in 293 boys through total IgE assessment. RESULTS: At 5 y of age, the prevalence of ever eczema was 30.4%. Metabolites of di-isobutyl phthalate (DiBP) and di-isononyl phthalate (DiNP) were positively associated with early-onset (0-24 mo of age) eczema (15.7%) and late-onset (24-60 mo of age) eczema (14.7%). Applying the Cox's model showed a significant association of occurrence of eczema in the first 5 y of life with DiBP and DiNP metabolites. Among IgE-sensitized boys, metabolites of di-n-butyl phthalate (DBP) and DiBP were significantly associated with ever eczema {hazard ratio (HR)=1.67 [95% confidence interval (CI): 1.10, 2.54], p=0.01 and HR=1.87 (95% CI: 1.01, 3.48), p=0.04, respectively}. CONCLUSIONS: Occurrence of eczema in early childhood may be influenced by prenatal exposure to certain phthalates in boys. Further investigations are needed to confirm this observation. https://doi.org/10.1289/EHP1829. PMID- 29398653 TI - Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved. AB - BACKGROUND: It has been proposed that interactions between selenium and arsenic in the body may affect their kinetics and toxicity. However, it is unknown how the elements influence each other in humans. OBJECTIVES: We aimed to investigate potential interactions in the methylation of selenium and arsenic. METHODS: Urinary selenium (U-Se) and arsenic (U-As) were measured using inductively coupled plasma mass spectrometry (ICPMS) in samples collected from pregnant women (n=226) in rural Bangladesh at gestational weeks (GW) 8, 14, 19, and 30. Urinary concentrations of trimethyl selenonium ion (TMSe) were measured by HPLC-vapor generation-ICPMS, as were inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA). Methylation efficiency was assessed based on relative amounts (%) of arsenic and selenium metabolites in urine. Genotyping for the main arsenite and selenium methyltransferases, AS3MT and INMT, was performed using TaqMan probes or Sequenom. RESULTS: Multivariable-adjusted linear regression analyses indicated that %TMSe (at GW8) was positively associated with %MMA (beta=1.3, 95% CI: 0.56, 2.0) and U-As, and inversely associated with %DMA and U Se in producers of TMSe (INMT rs6970396 AG+AA, n=74), who had a wide range of urinary TMSe (12-42%). Also, %TMSe decreased in parallel to %MMA during pregnancy, especially in the first trimester (-0.58 %TMSe per gestational week). We found a gene-gene interaction for %MMA (p-interaction=0.076 for haplotype 1). In analysis stratified by INMT genotype, the association between %MMA and both AS3MT haplotypes 1 and 3 was stronger in women with the INMT GG (TMSe nonproducers, 5th-95th percentile: 0.2-2%TMSe) vs. AG+AA genotype. CONCLUSIONS: Our findings for Bangladeshi women suggest a positive association between urinary %MMA and %TMSe. Genes involved in the methylation of selenium and arsenic may interact on associations with urinary %MMA. https://doi.org/10.1289/EHP1912. PMID- 29398654 TI - Chips off the Old Block: How a Father's Preconception Exposures Might Affect the Health of His Children. PMID- 29398656 TI - Anthropologia: An (Almost) Forgotten Early Modern History. AB - Approximately thirty almost entirely overlooked books appeared in Europe between 1500 and 1700 that include the word anthropologia in their titles. At first glance, the content of these works bears no resemblance to anthropology as we think of it. They present a combination of medieval traditions, cutting-edge medical practices, and evolving natural philosophical and theological systems found in universities of all confessions across Europe. But these largely overlooked sources reveal that the disciplines we use to study ourselves may have developed from an intertwined natural philosophical and religious system. They suggest that anthropology's typical origin narrative should be reconsidered. PMID- 29398657 TI - The First Orchestrated Attack on Spinoza: Johannes Melchioris and the Cartesian Network in Utrecht. AB - This article examines the immediate Dutch reception of the Tractatus theologico politicus. Using newfound archival sources it demonstrates that the anti-Spinoza activity of the Cartesians in Utrecht extends far beyond the well-known writings of Lambertus van Velthuysen and Regnerus van Mansveld. Their Cartesian network not only produced the very first public refutation to appear, but also formed a center for coordinating much of the Dutch response to Spinoza. This engagement, it is argued in closing, must be accounted for in Spinoza reception history, and forms the background to the mysterious visit Spinoza paid to Utrecht in the summer of 1673. PMID- 29398655 TI - Community-Led Total Sanitation: A Mixed-Methods Systematic Review of Evidence and Its Quality. AB - BACKGROUND: Community-led total sanitation (CLTS) is a widely applied rural behavior change approach for ending open defecation. However, evidence of its impact is unclear. OBJECTIVES: We conducted a systematic review of journal published and gray literature to a) assess evidence quality, b) summarize CLTS impacts, and c) identify factors affecting implementation and effectiveness. METHODS: Eligible studies were systematically screened and selected for analysis from searches of seven databases and 16 websites. We developed a framework to appraise literature quality. We qualitatively analyzed factors enabling or constraining CLTS, and summarized results from quantitative evaluations. DISCUSSION: We included 200 studies (14 quantitative evaluations, 29 qualitative studies, and 157 case studies). Journal-published literature was generally of higher quality than gray literature. Fourteen quantitative evaluations reported decreases in open defecation, but did not corroborate the widespread claims of open defecation-free (ODF) villages found in case studies. Over one-fourth of the literature overstated conclusions, attributing outcomes and impacts to interventions without an appropriate study design. We identified 43 implementation- and community-related factors reportedly affecting CLTS. This analysis revealed the importance of adaptability, structured posttriggering activities, appropriate community selection, and further research on combining and sequencing CLTS with other interventions. CONCLUSIONS: The evidence base on CLTS effectiveness available to practitioners, policy makers, and program managers to inform their actions is weak. Our results highlight the need for more rigorous research on CLTS impacts as well as applied research initiatives that bring researchers and practitioners together to address implementation challenges to improve rural sanitation efforts. https://doi.org/10.1289/EHP1965. PMID- 29398658 TI - The Many Liberalisms of Serge Audier. AB - The French philosopher Serge Audier has perhaps become the leading authority on the history of liberalism in France. However, he is largely unknown in the United States. This article attempts to provide the first critical overview of Audier's work in English. It does so by suggesting that the major aim of Audier's work is to revive a forgotten strand of social liberalism in France. The article illustrates this by looking at Audier's writings on the works of Leon Bourgeois and Raymond Aron and also his critical studies on the history of neoliberalism in France and beyond. PMID- 29398659 TI - Revising History: Introduction to the Symposium on the Bicentennial of the Latin American Revolutions of Independence. AB - Introduction to the symposium on the bicentennial of the Latin American revolutions of independence. PMID- 29398660 TI - Empires, Nations, and Revolutions. AB - This essay examines the ways in which the age of revolutions expanded the repertoire of political ideas and identities available to new and old political subjects. It questions the traditional narrative that replaces a model of old regimes and empires with a new one of imagined unitary nation-states. Instead, it argues that the nature of the political crisis of the Iberian empires gave rise to a reinvention of familiar categories, like monarchy and empire, and sired a wider range of new ones that did not fit the national mold. PMID- 29398661 TI - The Conceptual History of Independence and the Colonial Question in Spanish America. AB - The idea that Spanish American countries experienced colonialism was well accepted for most of the nineteenth and twentieth centuries. The independence movements in the early nineteenth century were viewed as the result of struggles by oppressed nations against the metropole's tyranny. Recent historiography views the collapse of the monarchy as the result of the political and legal crisis brought about by the Napoleonic invasion and the illegal abdications in Bayonne in March 1808. Colonial and post-colonial theories and categories have been brought under scrutiny. The following pages sketch the historiographical and theoretical grounds and consequences of this paradigm shift. PMID- 29398662 TI - Catholic Republicanism: The Creation of the Spanish American Republics during Revolution. AB - The crisis of the Spanish Catholic monarchy paved the way for the creation of more than twenty republics in Latin America between 1810 and 1825. This paper analyzes early nineteenth-century Spanish American republican experiences, which have been generally neglected in the historiography, as constitutive parts of Atlantic republicanism. It focuses on the theologico-political considerations of the res publica from the seventeenth century onwards, the articulation of a patriotic discourse in the American colonies of Spain during the eighteenth century, and how Spanish-American revolutionaries used republican languages based on Roman references, natural rights, and Catholicism to create new political legitimacy. PMID- 29398663 TI - Beyond the "History of Ideas": The Issue of the "Ideological Origins of the Revolutions of Independence" Revisited. AB - This paper analyzes how Latin American historiography has addressed the issue of "the ideological origins of the revolution of independence," and how the formulation of that topic implies assumptions proper to the tradition of the history of ideas and leads to anachronistic conceptual transpositions. Halperin Donghi's work models a different approach, illuminating how a series of meaningful torsions within traditional languages provided the ideological framework for a result incompatible with those languages. This paradox forces a break with the frameworks of the history of ideas and the set of antinomies intrinsic to them, such as that between "tradition" and "modernity." PMID- 29398664 TI - Race, Wars, and Citizenship: Free People of Color in the Spanish American Independence. AB - The role played by free people of color in the Spanish American independence movements is at the center of this essay. Their ambiguous status makes them a privileged group to study when examining the negotiation and formation of racial identity as well as the definition of citizenship requirements in colonial and post-colonial contexts. Through an analysis of the contributions made by recent studies, this article proposes a historiographical survey of the transformation of racial and social hierarchies and of the shaping of new citizenship rights during the crisis of the Spanish Empire and the independence wars. PMID- 29398665 TI - History of Concepts and the Historiography of the Independence of Brazil: A Preliminary Diagnosis. AB - The aim of this article is to discuss the history of the Independence of Brazil by highlighting the historiographical approaches from the so-called "History of Concepts," which in the current Brazilian historiography are related to a German intellectual branch, but often articulated to other approaches that can be referred to as intellectual history, history of languages and of political discourses. It offers a brief overview of the historiography of Independence in the nineteenth and twentieth centuries, through to the diagnosis of their basic lineages, then it discusses current conceptual approaches. The conclusion indicates five points to contribute to a better understanding of the Independence of Brazil. PMID- 29398668 TI - Nardostachys jatamansi Ethanol Extract Ameliorates Abeta42 Cytotoxicity. AB - The Nardostachys jatamansi DC (NJ) root has been used as a sedative or analgesic to treat neurological symptoms and pain in traditional Korean medicine. Here, we investigate the potential effects of NJ on Alzheimer's disease (AD) and reveal the molecular mechanism through which NJ exerts its effects. The neuroprotective effect of the NJ root ethanol extract against beta amyloid (Abeta) toxicity was examined in vitro using a cell culture system and in vivo using a Drosophila AD model. The NJ extract and chlorogenic acid, a major component of NJ, inhibited Abeta-induced cell death in SH-SY5Y cells. Moreover, the NJ extract rescued the neurological phenotypes of the Abeta42-expressing flies (decreased survival and pupariation rate and a locomotor defect) and suppressed Abeta42-induced cell death in the brain. We also found that NJ extract intake reduced glial cell number, reactive oxygen species level, extracellular-signal-regulated kinase (ERK) phosphorylation, and nitric oxide level in Abeta42-expressing flies, without affecting Abeta accumulation. These data suggest that the neuroprotective activity of NJ might be associated with its antioxidant and anti-inflammatory properties, as well as its inhibitory action against ERK signaling; thus, NJ is a promising medicinal plant for the development of AD treatment. PMID- 29398669 TI - Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock induced acute lung injury in rats. AB - It has been demonstrated that tranexamic acid (TXA), a synthetic derivative of lysine, alleviates lung damage in a trauma-hemorrhagic shock (T/HS) model. Nevertheless, the mechanism of TXA against acute lung injury (ALI) has not deeply elaborated. In this study, we generated a T/HS rat model based on previous research, and TXA (50 mg/kg and 100 mg/kg) was intravenously injected into these rats prior to or post T/HS. The results revealed that the decreased survival rate and impaired lung permeability of the rats caused by T/HS were improved by TXA pretreatment or posttreatment. T/HS-triggered over-generation of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar fluid and serum was inhibited by TXA, and the enzymatic activity of myeloperoxidase (MPO) in lung tissues was suppressed by TXA as well. Furthermore, TXA treatment deactivated the poly ADP-ribose polymerase-1 (PARP1)/nuclear factor kappaB (NF kappaB) signaling pathway in the lungs of T/HS rats, as evidenced by increased IkappaBalpha expression, and decreased cleaved PARP1, p-p65 (Ser276), p-p65 (Ser529), p-IkappaBalpha (ser32/ser36), and intercellular adhesion molecule-1. While the expression level of total p65 did not change after T/HS, its DNA binding activity was strengthened. Both TXA pretreatment and posttreatment suppressed this effect on the DNA binding activity of NF-kappaB. Taken together, our results reveal that administration of TXA effectively relieves T/HS-induced ALI, at least in part, by attenuating the abnormal pulmonary inflammation. PMID- 29398671 TI - Microbiological identification and analysis of waterfowl livers collected from backyard farms in southern China. AB - In total, 985 livers were collected from 275 backyard waterfowl farms distributed in seven provinces of southern China. The virus that was most commonly isolated was avian influenza virus, with a 12.1% positivity rate. Of the other positive samples, 10.6% tested positive for avian Tembusu virus, 6.8% for duck hepatitis A virus, 3.8% for duck plague virus, 3.4% for Muscovy duck parvovirus, 3.1% for goose parvovirus, 1.0% for mycoplasma and 0.9% for respiratory enteric orphan virus. The bacterium that was most commonly isolated was Escherichia coli, with a 47.1% positivity rate. This survey suggests that backyard waterfowl in southern China could be an important vector for the storage, variation, and transmission of various pathogens. PMID- 29398672 TI - Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II) - A Randomized Controlled Clinical Trial. AB - BACKGROUND: Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4+/-9.3%, EPO 6,000 IU: 7.3+/-7.7%, Placebo: 8.1+/-8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. CONCLUSIONS: Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721). PMID- 29398670 TI - The effect of sedation with a combination of butorphanol and midazolam on quantitative contrast-enhanced ultrasonography of duodenum in healthy dogs. AB - Quantitative contrast-enhanced ultrasonography (CEUS) enables non-invasive and objective evaluation of intestinal perfusion by quantifying the intensity of enhancement on the intestine after microbubble contrast administration. During CEUS scanning, sedation is sometimes necessary to maintain animal cooperation. Nevertheless, the effect of sedative administration on the canine intestinal CEUS is unknown. This study aimed to investigate the effect of sedation with a combination of butorphanol and midazolam on the duodenal CEUS-derived perfusion parameters of healthy dogs. For this purpose, duodenum was imaged following contrast administration (Sonazoid(r), 0.01 ml/kg) in six healthy beagles before and after intravenous injection of a combination of butorphanol (0.2 mg/kg) and midazolam (0.1 mg/kg). Furthermore, hemodynamic parameters including blood pressure and heart rate were recorded during the procedure. Five CEUS derived perfusion parameters including time-to-peak (TTP), peak intensity (PI), area under the curve (AUC), wash-in and wash-out rates (WiR and WoR, respectively) before and after sedation were statistically compared. The result showed that no significant change was detected in any of perfusion parameters. Systolic and mean arterial pressures significantly reduced after sedative administration, but diastolic arterial pressure and heart rate did not significantly change. Moreover, no significant partial correlation was observed between perfusion parameters and hemodynamic parameters. Thus, we concluded that the combination did not cause significant influence in duodenal CEUS perfusion parameters and could be a good option for sedation prior to duodenal CEUS in debilitated dogs. PMID- 29398673 TI - Atlantooccipital overlapping and its effect on outcomes after ventral fixation in dogs with atlantoaxial instability. AB - We compared clinical outcomes after ventral fixation in dogs with atlantoaxial instability (AAI) on the basis of the presence or absence of atlantooccipital overlapping (AOO). Of 41 dogs diagnosed with AAI and treated ventral fixation, 12 exhibited AOO (AOO group), whereas 29 did not (non-AOO group). The AOO group had significantly higher neurological scores before (P=0.024) and 1 month after (P=0.033) surgery compared with the non-AOO group; however, no significant differences were observed between the groups 2 months after surgery. The presence of complicating AOO affected the clinical signs for dogs with AAI, but did not directly affect the outcome of surgical stabilization of AAI. PMID- 29398674 TI - Canine case of swallowing syncope that improved after pacemaker implantation. AB - A 14-year-old intact male West Highland White Terrier weighing 6.9 kg was admitted to the Tokyo University of Agriculture and Technology Animal Medical Center with the complaint of syncope after showing signs of nausea during feeding. Sinus arrest induced by deglutition was confirmed using a Holter electrocardiography test. However, the clinical symptoms significantly improved after implantation of a permanent pacemaker. Seven months after implantation, the dog died from acute pancreatitis, a cause unrelated to the syncope. Immediately after its death, the heart, lungs, gastrointestinal tract, and other organs were dissected and examined histopathologically. The brain was also examined using magnetic resonance imaging. Examination results led to the diagnosis of swallowing-induced situational syncope. PMID- 29398675 TI - The Novel Apolipoprotein E Mutation ApoE Chengdu (c.518T>C, p.L173P) in a Chinese Patient with Lipoprotein Glomerulopathy. AB - AIMS: Lipoprotein glomerulopathy (LPG) is a rare inherited renal disease. Several apolipoprotein E (apoE) mutations have been reported to be related to LPG. Herein, we report a case of a LPG patient with a novel apoE mutation. METHODS: A 45-year-old Chinese female was diagnosed as LPG by renal biopsy. APOE gene was sequenced. Clinical and genetic studies were conducted. RESULTS: The patient presented with nephrotic syndrome and hypertension. A fasting lipid panel showed mild hyperlipidemia and elevated serum apoE (5.6 mg/dL). Renal biopsy revealed typical LPG lesions with whorled, mesh-like material in dilated glomerular capillary lumens that stained positive for Sudan III and apoE. apoE gene analysis revealed a T-to-C point mutation at amino acid 173 that caused a substitution of a proline residue for a leucine residue, which has not been reported previously. We named this mutation apoE Chengdu (c.518T>C, p.L173P). Two of five of the family members carried this mutation, including the patient's brother who was receiving hemodialysis, and her sister, whose urine protein levels were normal. All mutation carriers were heterozygotes with the apoE genotype epsilon3/epsilon3. This mutation was not found among 200 of the local people. Fenofibrate treatment for one year induced clinical improvement. CONCLUSIONS: ApoE Chengdu (p.L173P) is a novel mutation causing LPG. This case supports the hypothesis that the substitution of proline in or near the LDL receptor-binding area contributes to the development of LPG. The detailed mechanism of action of this variant remains to be elucidated. PMID- 29398677 TI - Trend of HDL increase among Japanese people continues in National Health and Nutrition Survey. PMID- 29398676 TI - Association of the Serum Endostatin Level, Renal Function, and Carotid Atherosclerosis of Healthy Residents of Japan: Results from the Kyushu and Okinawa Population Study (KOPS). AB - AIM: To analyze associations among the serum endostatin level, renal function, and carotid atherosclerosis of healthy residents of Japan. METHODS: Among 1,057 Japanese residents who attended free public physical examinations between 2010 and 2011, we evaluated the data of 648 healthy residents (200 men and 448 women, age 24 to 84 years) for whom the serum endostatin level and common carotid intima media thickness (IMT) were measured. Renal function was assessed by estimated glomerular filtration rate (eGFR). Multiple linear regression analysis was done to determine the association of eGFR and serum endostatin level after adjustment for known covariates. Mediation analysis was done using Baron and Kenny's regression approach. RESULTS: The median endostatin level was 63.7 ng/mL (interquartile range: 49.7-93.2). The mean eGFR was 78.4+/-14.8 mL/min/1.73m2. Univariate analysis showed that age (r=-0.37, P<0.01), non current smoking (85.8+/-13.0 vs. 77.5+/-14.8 mL/min/1.73 m2, P<0.01), hemoglobin A1c (r=-0.08, P=0.05), low-density lipoprotein-cholesterol (r=-0.13, P<0.01), uric acid (r= 0.15, P<0.01), carotid IMT (r=-0.11, P<0.01), and log-transformed endostatin (r= 0.36, P<0.01) were significantly associated with eGFR. In multiple linear regression analysis, log-transformed endostatin was significantly associated with eGFR (beta=-0.24, P<0.01). While, carotid IMT was no longer significant. Mediation analysis showed serum endostatin level to be a mediator in the association between carotid IMT and eGFR. CONCLUSIONS: The association between carotid IMT and eGFR is mediated by the serum endostatin level of healthy individuals. PMID- 29398678 TI - Evaluation of Two Commercial Enzyme-Linked Immunosorbent Assay Kits for the Detection of Human Circulating Metrnl. AB - Metrnl is a newly discovered secreted protein with neurotrophic activity and metabolic effect, while in earlier studies its circulating level in human was not explored. We evaluated two commercial enzyme-linked immunosorbent assay kits (DY7867-05, R&D Systems and SK00478-02, Aviscera Bioscience) for the detection of human circulating Metrnl. The DY7867-05 kit showed superiority over the SK00478 02 kit since it generated better curve fitting degree, smaller variation among tests, higher inter-assay reproducibility and better specificity, and could effectively detect human Metrnl in six types of blood samples. Subsequent analysis was performed using the DY7867-05 kit. Sample storage conditions were investigated. No gender difference in circulating Metrnl levels was found, while people with newly diagnosed type 2 diabetes mellitus (T2DM) had significantly lower Metrnl levels compared to the healthy controls. PMID- 29398679 TI - Azelnidipine Inhibits the Differentiation and Activation of THP-1 Macrophages through the L-Type Calcium Channel. AB - AIM: Recently, calcium channel blockers (CCBs) have been reported to reduce atherosclerosis with anti-inflammatory or antiatherosclerotic effects in vivo. It is well established that monocytes and macrophages play important roles in promoting atherosclerosis. However, the effects of CCBs on macrophage activation remain unclear. The aim of this study was to evaluate the effects of azelnidipine, a dihydropyridine L-type CCB, on the activation of macrophages and to clarify the mechanisms of the effects of CCBs on atherosclerosis. METHODS: THP 1 monocytes, a human leukemic cell line, were stimulated with 50 ng/mL of phorbol 12-myristate-13-acetate (PMA) 1 h after pretreatment with 10 MUM azelnidipine or dimethyl sulfoxide (DMSO), and harvested. RESULTS: Azelnidipine blocked the expression of intercellular adhesion molecule-1 quantified by FACS analysis. The expression levels of Apo E and MMP9, which are markers of macrophage differentiation, were inhibited by azelnidipine as evaluated by quantitative RT PCR. The level of LOX-1 mRNA, a scavenger receptor, was also reduced significantly by pretreatment with 10 MUM azelnidipine. Azelnidipine also lowered the uptake of acetylated LDL. The expression of the L-type calcium channel Cav1.2 was 10-fold higher after 24 h of PMA stimulation. A knockdown of the CACNA1C gene, which encodes Cav1.2 protein in humans, with siRNA blocked the effect of reducing adhesion by azelnidipine, indicating that the effects of azelnidipine on macrophage differentiation were expressed through the CACNA1C gene. CONCLUSION: Our results suggest that azelnidipine has potent antiatherosclerotic properties by inhibition of macrophage activation through Cav1.2. PMID- 29398680 TI - Screening Validity of Arterial Pressure-Volume Index and Arterial Velocity-Pulse Index for Preclinical Atherosclerosis in Japanese Community-Dwelling Adults: the Nagasaki Islands Study. AB - AIM: The arterial pressure-volume index (API) and arterial velocity-pulse index (AVI) are novel measurement indices of arterial stiffness. This study was performed to examine the screening validity of the API and AVI for preclinical atherosclerosis in Japanese community-dwelling adults. METHODS: We conducted a cross-sectional study of 2,809 participants aged >=40 years who underwent Japanese national medical check-ups from 2014 to 2016. Preclinical atherosclerosis was defined as a mean carotid intima-media thickness (CIMT) of >=1.0 mm. Multivariable linear regression analysis was performed to investigate the association of CIMT with API and AVI, adjusting for body mass index, sex, and the Framingham-D'Agostino score. We also examined receiver operating characteristic curves, sensitivity, and specificity to predict preclinical atherosclerosis defined by the CIMT. The cardio-ankle vascular index was also measured for comparison with the API and AVI. RESULTS: Of 2,809 participants, 68 (2.4%) had preclinical atherosclerosis. In the multivariable linear regression analysis, the API and AVI maintained a positive association with the mean CIMT (B=2.6, P=0.009 and B=3.7, P=0.001, respectively). The cut-offs of the API and AVI that demonstrated better sensitivity and specificity for detection of subclinical atherosclerosis were 31 [area under the curve (AUC), 0.64] and 29 (AUC, 0.60). CONCLUSIONS: The API and AVI were positively associated with preclinical carotid atherosclerosis independent of the participants' cardiovascular risk. The ability of these scores to predict carotid atherosclerosis could make them a useful screening tool for atherosclerosis. PMID- 29398681 TI - Double-Face of Vasohibin-1 for the Maintenance of Vascular Homeostasis and Healthy Longevity. AB - The structural and functional integrity of endothelium is essential for the maintenance of vascular health. Vasohibin-1 (VASH1), originally isolated as an endothelium-derived angiogenesis inhibitor, has another function to promote stress tolerance of endothelial cells (ECs), and these functions are critical for the maintenance of vascular homeostasis preventing both pathological angiogenesis and stress-induced vascular diseases. The expression of VASH1 is downregulated during replicative senescence of ECs by the alteration of microRNA expression, and this age-associated downregulation of VASH1 might be a risk of deterioration of vascular homeostasis and age-related vascular diseases. Contrary to this expectation, the lack of Vash1 gene in mice exhibited healthy longevity. Thus, VASH1 has double-face for the maintenance of vascular homeostasis and healthy longevity. This feature of VASH1 and its mechanism will be described in this mini review. PMID- 29398682 TI - Sleep Duration Modifies the Association of Overtime Work With Risk of Developing Type 2 Diabetes: Japan Epidemiology Collaboration on Occupational Health Study. AB - BACKGROUND: Evidence linking working hours and the risk of type 2 diabetes mellitus (T2DM) is limited and inconsistent in Asian populations. No study has addressed the combined association of long working hours and sleep deprivation on T2DM risk. We investigated the association of baseline overtime work with T2DM risk and assessed whether sleep duration modified the effect among Japanese. METHODS: Participants were Japanese employees (28,489 men and 4,561 women) aged 30-64 years who reported overtime hours and had no history of diabetes at baseline (mostly in 2008). They were followed up until March 2014. New-onset T2DM was identified using subsequent checkup data, including measurement of fasting/random plasma glucose, glycated hemoglobin, and self-report of medical treatment. Hazard ratios (HRs) of T2DM were estimated using Cox regression analysis. The combined association of sleep duration and working hours was examined in a subgroup of workers (n = 27,590). RESULTS: During a mean follow-up period of 4.5 years, 1,975 adults developed T2DM. Overtime work was not materially associated with T2DM risk. In subgroup analysis, however, long working hours combined with insufficient sleep were associated with a significantly higher risk of T2DM (HR 1.42; 95% CI, 1.11-1.83), whereas long working hours with sufficient sleep were not (HR 0.99; 95% CI, 0.88-1.11) compared with the reference (<45 hours of overtime with sufficient sleep). CONCLUSIONS: Sleep duration modified the association of overtime work with the risk of developing T2DM. Further investigations to elucidate the long-term effect of long working hours on glucose metabolism are warranted. PMID- 29398683 TI - Living Alone or With Others and Depressive Symptoms, and Effect Modification by Residential Social Cohesion Among Older Adults in Japan: The JAGES Longitudinal Study. AB - BACKGROUND: There is little longitudinal evidence on the impact of specific living arrangements (ie, who individuals live with) on mental health among older adults, and no studies have examined the modifying effect of residential social cohesion level on this association. We aimed to examine the association between living arrangements and depressive symptoms and whether this association varies with residential neighborhood social cohesion level among 19,656 men and 22,513 women aged 65 years and older in Japan. METHODS: We analyzed the association between baseline living arrangements in 2010 and depressive symptoms in 2013. We calculated gender-specific odds ratios (ORs) of living arrangements for depressive symptoms using a logistic regression and conducted subgroup analyses by neighborhood social cohesion level. RESULTS: Among men (but not women), living alone (OR 1.43; 95% confidence intervals [CI], 1.18-1.73) and living with spouse and parent (OR 1.47, 95% CI, 1.09-1.98) were associated with increased odds of depressive symptoms compared with living with a spouse only. Living with spouse and child was a risk for men in the young age group but a protective factor for women. We also identified that the negative impact of living arrangements on depressive symptoms was attenuated in neighborhoods with higher levels of social cohesion. CONCLUSIONS: Living arrangements are associated with risk of depressive symptoms among men and women; these associations differ by gender and neighborhood social cohesion level. Our results suggest the need to pay more attention to whether individuals live alone, as well as who individuals live with, to prevent depressive symptoms among older adults. PMID- 29398685 TI - Prevalence, source and severity of work-related injuries among "foreign" construction workers in a large Malaysian organisation: a cross-sectional study. AB - Malaysian construction sector is regarded as critical in the field of health because of the high rates of accidents and fatalities. This research aimed to determine the prevalence, sources and severity of injuries and its association with commitment to safety among foreign construction workers. A cross-sectional study was conducted among 323 foreign construction workers from six construction projects of a large organization in Malaysia, using a simple random sampling method. Data was collected using a structured questionnaire to assess work related injuries and safety commitment. The collected data was analysed by SPSS 22.0 using descriptive statistics and chi2 test. The prevalence of work-related injuries in a one year period was 22.6%, where most of the injuries were of moderate severity (39.7%) and falls from heights represented the main source (31.5%). The majority of the foreign construction workers had perceived between moderate and high safety commitment, which was significantly associated with work related injuries. The results also showed a significant association of work related injuries with the company's interest in Safety and Health, Safety and Health training, and safety equipment. Thus, the implementation of new procedures and providing relevant trainings and safety equipment; will lead to a decrease in injury rates in construction sites. PMID- 29398684 TI - Relationship between bovine endometrial thickness and plasma progesterone and estradiol concentrations in natural and induced estrus. AB - The objective of this study was to investigate cyclical changes in endometrial thickness in relation to progesterone (P4) and estradiol-17beta (E2) concentrations during natural and induced estrus in 15 cows. In the prostaglandin (PG) F2alpha-induced estrus group, ultrasonography (USG) at 6-h intervals was used to determine endometrial thickness 48-24 h before the PGF2alpha treatment until 24 h after ovulation (ovulation = Day 0). In the natural estrus group, USG was performed every 48 h from Day 3 to Days 15-18 after the first ovulation, and then every 6 h until 24 h after ovulation. Endometrial thickness was standardized using Day 13 as a reference day. Blood was collected during every USG examination and plasma P4 and E2 concentrations were determined. Endometrial thickness of the induced estrus group (n = 11) was greater than that of the natural estrus group (n = 9) between 60 and 12 h before ovulation (P < 0.05). In the natural estrus group, prior to an increase in endometrial thickness, a decrease in P4 and an increase in E2 were detected. In the induced estrus group, based on the time of ovulation, an increase in endometrial thickness was detected at the same time of a decrease in P4 before an increase in E2. These results suggest that decreases in P4 concentrations may be a cue to changes in endometrial thickness, while increases in E2 concentrations appear to sustain and/or enhance these changes. PMID- 29398686 TI - Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation. AB - BACKGROUND: Recent experimental studies have demonstrated that several microRNAs (miRNAs) expressed in atrial tissue promote a substrate of atrial fibrillation (AF). However, because it has not been fully elucidated whether these experimental data contribute to identifying circulating miRNAs as biomarkers for AF, we used a combined analysis of human serum and murine atrial samples with the aim of identifying these biomarkers for predicting AF.Methods and Results:Comprehensive analyses were performed to screen 733 miRNAs in serum from 10 AF patients and 5 controls, and 672 miRNAs in atrial tissue from 6 inducible atrial tachycardia model mice and 3 controls. We selected miRNAs for which expression was detected in both analyses, and their expression levels were changed in the human analyses, the murine analyses, or both. This screening identified 11 candidate miRNAs. Next, we quantified the selected miRNAs using a quantitative RT-PCR in 50 AF and 50 non-AF subjects. The individual assessment revealed that 4 miRNAs (miR-99a-5p, miR-192-5p, miR-214-3p, and miR-342-5p) were significantly upregulated in AF patients. A receiver-operating characteristics curve indicated that miR-214-3p and miR-342-5p had the highest accuracy. The combination of the 4 miRNAs modestly improved the predictive accuracy for AF (76% sensitivity, 80% specificity). CONCLUSIONS: Novel circulating miRNAs were upregulated in the serum of AF patients and might be potential biomarkers of AF. PMID- 29398687 TI - Transcatheter Mitral Valve Prosthesis Dysfunction - Early Valve Degeneration or Thrombosis? PMID- 29398688 TI - Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing. AB - BACKGROUND: Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) revealed a substantial variation in the extent of myocardial scarring, a pathological hallmark of hypertrophic cardiomyopathy (HCM). However, few data exist regarding the relationship between the presence of gene mutations and the extent of LGE. Therefore, we aimed to investigate whether variations in the extent of LGE in HCM patients can be explained by the presence or absence of disease-causing mutations.Methods and Results:We analyzed data from 82 unrelated HCM patients who underwent both LGE-CMR and next-generation sequencing. We identified disease-causing sarcomere gene mutations in 44 cases (54%). The extent of LGE on CMR was an independent factor for predicting mutation-positive HCM (odds ratio 2.12 [95% confidence interval 1.51-3.83], P<0.01). The area under the curve of %LGE was greater than that of the conventional Toronto score for predicting the presence of a mutation (0.96 vs. 0.69, P<0.01). Sensitivity, specificity, positive predictive value, and negative predictive value of %LGE (cutoff >8.1%) were 93.2%, 89.5%, 91.1%, and 91.9%, respectively. CONCLUSIONS: The results demonstrated that %LGE clearly discriminated mutation-positive from mutation-negative HCM in a clinically affected HCM population. HCM with few or no myocardial scars may be genetically different from HCM with a higher incidence of myocardial scars. PMID- 29398689 TI - A Missense Mutation in the NSF Gene Causes Abnormal Golgi Morphology in Arabidopsis thaliana. AB - The Golgi apparatus is a key station of glycosylation and membrane traffic. It consists of stacked cisternae in most eukaryotes. However, the mechanisms how the Golgi stacks are formed and maintained are still obscure. The model plant Arabidopsis thaliana provides a nice system to observe Golgi structures by light microscopy, because the Golgi in A. thaliana is in the form of mini-stacks that are distributed throughout the cytoplasm. To obtain a clue to understand the molecular basis of Golgi morphology, we took a forward-genetic approach to isolate A. thaliana mutants that show abnormal structures of the Golgi under a confocal microscope. In the present report, we describe characterization of one of such mutants, named #46-3. The #46-3 mutant showed pleiotropic Golgi phenotypes. The Golgi size was in majority smaller than the wild type, but varied from very small ones, sometimes without clear association of cis and trans cisternae, to abnormally large ones under a confocal microscope. At the ultrastructual level by electron microscopy, queer-shaped large Golgi stacks were occasionally observed. By positional mapping, genome sequencing, and complementation and allelism tests, we linked the mutant phenotype to the missense mutation D374N in the NSF gene, encoding the N-ethylmaleimide-sensitive factor (NSF), a key component of membrane fusion. This residue is near the ATP binding site of NSF, which is very well conserved in eukaryotes, suggesting that the biochemical function of NSF is important for maintaining the normal morphology of the Golgi.Key words: Golgi morphology, N-ethylmaleimide-sensitive factor (NSF), Arabidopsis thaliana. PMID- 29398690 TI - Prospective Association of Handgrip Strength with Risk of New-Onset Cognitive Dysfunction in Korean Adults: A 6-Year National Cohort Study. AB - Dementia is one of the priority public health problems in the older population, and the number of people with dementia is steadily increasing. The longitudinal association of muscle strength with risk of new-onset cognitive dysfunction in a general population including middle and older adults remains unknown. The purpose of this study was to investigate the effects of low muscle strength on risk for new-onset cognitive dysfunction over 6 years using a large nationwide sample of cognitively healthy adults. Study participants included 6,435 middle and older adults (33,554 person-years of follow-up), using data from the Korean Longitudinal Study of Ageing 2006-2012. Muscular strength was measured using the maximum handgrip strength of each participant as an index of muscle quality. Low muscle strength was defined as one standard deviation below the mean using the handgrip strength index based on the study population. Cognitive function was evaluated using the Mini-Mental Status Evaluation. The hazard ratio (HR) for cognitive dysfunction significantly and linearly increased according to muscle strength status independent of potential confounding factors (HR: 1.36, 95% confidence interval [CI]: 1.18-1.56 for low vs. normal-high group). Using stratified analyses, a significant association between muscle strength status and risk of cognitive impairment was observed in those with low physical activity, but not those with high physical activity. We show that handgrip strength is associated with increased risk of new-onset cognitive dysfunction over 6 years of follow-up in cognitively healthy middle aged and older adults at baseline. PMID- 29398691 TI - Emotional disturbance assessed by the Self-Rating Depression Scale test is associated with mortality among Japanese Hemodialysis patients. AB - Emotional disturbance including depression is associated with increased mortality among dialysis patients. The Self-Rating Depression Scale (SDS) is a simple tool for assessing emotional disturbance. This study investigated the relationship between emotional conditions as assessed with the SDS test and mortality among 491 hemodialysis patients. At baseline, 183 (37.3%), 180 (36.7%), 108 (22.0%), and 20 (4.1%) were classified as normal, borderline depression, depression, and severe depression, respectively. During the two years of observation period, 57 of 491 (11.6%) died. The SDS scores in the non-survivors were significantly higher than those in the survivors (p<0.0001). Logistic analyses showed that the diagnoses made by the SDS test were associated with significantly greater risks for all-cause mortality (99%CI: 1.905-3.698 for that without adjustment, 1.999 4.382 for that with full adjustment). When the SDS score = 50 was selected as the cut off value, the test screened two-year all cause death with sensitivity = 57.9% and the specificity = 78.1%. In conclusion, hemodialysis patients had high prevalence of emotional disturbance assessed by the SDS test, and high SDS score was significantly associated with all-cause mortality. These findings underscore the importance of screening for emotional conditions using the SDS test among hemodialysis patients. PMID- 29398692 TI - lncRNA BG981369 Inhibits Cell Proliferation, Migration, and Invasion, and Promotes Cell Apoptosis by SRY-Related High-Mobility Group Box 4 (SOX4) Signaling Pathway in Human Gastric Cancer. AB - BACKGROUND Human gastric cancer (GC) is a leading primary cause of cancer associated deaths in both males and females worldwide. However, there are few effective diagnostic and therapeutic measures for GC patients due to the complicated underlying mechanisms of GC. Recently, increasing research has indicated that lncRNAs may play a critical role in the progression of GC. MATERIAL AND METHODS AI769947, AK054978, DB077273, BG981369, AK054588, and AF131784 expressions were analyzed by qRT-PCR assay in GC tissues and corresponding normal tissues (n=44). BG981369 expression was detected by qRT-PCR assay in GC cells. BG981369 was overexpressed and silenced in AGS and SNU-5 cells. The proliferation ability was detected by MTT and colony formation assays. Cell cycle distribution and cell apoptosis rate were analyzed by flow cytometry. The migration and invasion abilities were measured by Transwell assay. In addition, SOX4 expression was analyzed by qRT-PCR in GC tissues. The correlation between SOX4 and BG981369 was analyzed by Pearson analysis. RESULTS The results indicated that lncRNA BG981369 was significantly higher in GC tissues than in normal tissues. Overexpression of BG981369 inhibited the proliferation, migration, and invasion and promoted apoptosis of gastric adenocarcinoma (AGS) cells, and silencing of BG981369 promoted proliferation, migration, and invasion, and inhibited cell apoptosis of SNU-5 cells. Furthermore, we found that SOX4 may act as a downstream mediator of BG981369, suggesting that BG981369 inhibits proliferation, migration, and invasion, and promotes apoptosis by targeting SOX4 in the GC cell lines. CONCLUSIONS Our results suggest that BG981369 and SOX4 are potentially effective therapeutic targets for GC. PMID- 29398693 TI - Comparison of Nutrition-Related Adverse Events and Clinical Outcomes Between ICE (Ifosfamide, Carboplatin, and Etoposide) and MCEC (Ranimustine, Carboplatin, Etoposide, and Cyclophosphamide) Therapies as Pretreatment for Autologous Peripheral Blood Stem Cell Transplantation in Patients with Malignant Lymphoma. AB - BACKGROUND The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. MATERIAL AND METHODS We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. RESULTS Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=-0.73, P=0.003; r=-0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). CONCLUSIONS Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation. PMID- 29398694 TI - When Epidemiology Is the Clue to a Positive Outcome: A Case of Malaria During Pregnancy. AB - BACKGROUND Malaria infection during pregnancy is associated with increased perinatal and maternal morbidity and mortality. CASE REPORT A 29-year-old primigravida at 37 weeks of gestation, with no significant medical history, presented complaining of fever, chills, and generalized body aches. She had been living in Malawi for 1 year and was on atovaquone/proguanil prophylaxis until she was found to be pregnant. Prophylaxis was changed to mefloquine and discontinued upon her return to the US. Six weeks prior to presentation, she traveled to Malawi for 1 month when she was off prophylaxis. On admission, vital signs and physical exam results were normal. Given epidemiologic findings, a malaria smear was performed and showed 4% parasitemia. She was treated with mefloquine and discharged. Two days after discharge, she again presented with fever, chills, and body aches. A malaria smear showed <0.01% parasitemia, with 2 ring forms. Serologies for dengue, chikungunya, leptospira, and blood cultures were negative. These symptoms were deemed secondary to early recrudescence. The species was later identified as P. falciparum. The patient was treated with quinine sulfate and clindamycin. She delivered at full term without complication. CONCLUSIONS Pregnant women are more susceptible to severe forms of malaria, such as P. falciparum. A high index of suspicion and early identification of malaria are vital to prevent deleterious outcomes. PMID- 29398695 TI - Author Correction: The inverse-trans-influence in tetravalent lanthanide and actinide bis(carbene) complexes. AB - This corrects the article DOI: 10.1038/ncomms14137. PMID- 29398696 TI - Clinical outcomes of combined pars plana vitrectomy and trans-scleral 4-point suture fixation of a foldable intraocular lens. AB - OBJECTIVE: To describe outcomes of combined pars plana vitrectomy (PPV) and trans scleral 4-point suture fixation of a foldable Akreos AO60 intraocular lens (IOL) in eyes with subluxated or dislocated lens or IOL. METHODS: Retrospective case series of 20 eyes of 18 patients who underwent this procedure with a minimum follow-up of 3 months. Outcome measures included final best-corrected Snellen visual acuity (BCVA), spherical equivalent (SE) and intraoperative and postoperative complications. RESULTS: Mean age at surgery was 43.65 years. The commonest indication for surgery was post-traumatic subluxated or dislocated cataract. Mean BCVA improved from 6/24 preoperatively to 6/9 at final follow-up (p < 0.0001). Mean SE was 5.69 dioptres preoperatively and -1.32 dioptres postoperatively. There were no intraoperative complications. Postoperative complications included transient vitreous haemorrhage in one eye and cystoid macular oedema in one eye. Postoperative Pentacam analysis confirmed the absence of IOL tilt or decentration in six eyes. Mean follow-up was 8.9 months (range 3 30 months). CONCLUSION: Trans-scleral 4-point suture fixation of a foldable Akreos AO60 IOL can be performed safely along with concurrent PPV across varying surgical indications resulting in a substantial improvement in visual acuity with minimal complications. PMID- 29398698 TI - Factors at medical school influencing students' decisions to pursue a career in ophthalmology. PMID- 29398699 TI - A model of clinical practice: a randomised clinical study evaluating patient satisfaction of nurse-led vs consultant-led intravitreal injection. PMID- 29398700 TI - Is there a relationship between surgical success defined by motor and health related quality of life criteria in adult strabismic patients? PMID- 29398697 TI - Clinical pharmacology of intravitreal anti-VEGF drugs. AB - Clinical efficacy of intravitreal anti-VEGF drugs has been widely demonstrated in several angiogenesis-driven eye diseases including diabetic macular edema and the neovascular form of age-related macular degeneration. Pegaptanib, ranibizumab, and aflibercept have been approved for use in the eye, whereas bevacizumab is widely used by ophthalmologists to treat patients "off-label". These drugs are active in the nanomolar to picomolar range; however, caution is required when establishing the rank order of affinity and potency due to in vitro inter experimental variation. Despite the small doses used for eye diseases and the intravitreal route of administration may limit systemic side effects, these drugs can penetrate into blood circulation and alter systemic VEGF with unknown clinical consequences, particularly in vulnerable groups of patients. Clinical pharmacokinetics of ocular anti-VEGF agents should therefore be taken into account when choosing the right drug for the individual patient. The gaps in current understanding that leave open important questions are as follows: (i) uncertainty about which drug should be given first, (ii) how long these drugs can be used safely, and (iii) the choice of the best pharmacological strategy after first-line treatment failure. The current review article, based on the information published in peer-reviewed published papers relevant to anti-VEGF treatments and available on the PubMed database, describes in detail the clinical pharmacology of this class of drugs to provide a sound pharmacological basis for their proper use in ophthalmology clinical practice. PMID- 29398701 TI - Unmeasurable small size of foveal avascular zone without visual impairment in optical coherence tomography angiography. AB - PURPOSE: To report the clinical characteristics of eyes with an unmeasurable small size of foveal avascular zone (FAZ) in the optical coherence tomography angiographic (OCTA) images. METHODS: Two-hundred sixty-seven eyes of 255 patients (mean age 60.4 years) without retinal and choroidal disorders to cause any type of visual impairment were examined by optical coherence tomography angiography (OCTA; RTVue XR Avanti, Optovue, Fremont, CA). Cross-sectional images at the fovea (DRI-OCT, Topcon, Japan) and fundus autofluorescence (CX-1 MYD/NM, Canon, Japan) were also recorded from all eyes. RESULTS: Four eyes (1.5%) of 3 patients (2 men, 1 woman; average age, 63.3 years) were found to have an unmeasurable small size of FAZ in the OCTA images. The best-corrected visual acuity was better than 20/20 in all eyes. Cross-sectional OCT images showed the presence of a foveal depression and the inner retinal layers in the foveal depression. These inner retinal layers were detected as a hyperreflective bands at the fovea. Fundus autofluorescence showed hypo-autofluorescence at the fovea as in normal eyes. CONCLUSIONS: An unmeasurable small size of FAZ without visual impairment was detected in 1.5% of 267 normal eyes. These eyes may be classified as low grade foveal hypoplasia. PMID- 29398702 TI - Paediatric genomics: diagnosing rare disease in children. AB - The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease. Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; and enables provision of better support. PMID- 29398703 TI - Tandem repeats mediating genetic plasticity in health and disease. AB - Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals. TRPs in human genomes may also contribute to the missing heritability of polygenic disorders. A better understanding of tandem repeats and their associated repeatome, as well as their capacity for genetic plasticity via both germline and somatic mutations, is needed to transform our understanding of the role of TRPs in health and disease. PMID- 29398704 TI - The microbial nitrogen-cycling network. AB - Nitrogen is an essential component of all living organisms and the main nutrient limiting life on our planet. By far, the largest inventory of freely accessible nitrogen is atmospheric dinitrogen, but most organisms rely on more bioavailable forms of nitrogen, such as ammonium and nitrate, for growth. The availability of these substrates depends on diverse nitrogen-transforming reactions that are carried out by complex networks of metabolically versatile microorganisms. In this Review, we summarize our current understanding of the microbial nitrogen cycling network, including novel processes, their underlying biochemical pathways, the involved microorganisms, their environmental importance and industrial applications. PMID- 29398706 TI - Altered self: the not-so-neo-antigens. PMID- 29398705 TI - Engineering bacteria for diagnostic and therapeutic applications. AB - Our ability to generate bacterial strains with unique and increasingly complex functions has rapidly expanded in recent times. The capacity for DNA synthesis is increasing and costing less; new tools are being developed for fast, large-scale genetic manipulation; and more tested genetic parts are available for use, as is the knowledge of how to use them effectively. These advances promise to unlock an exciting array of 'smart' bacteria for clinical use but will also challenge scientists to better optimize preclinical testing regimes for early identification and validation of promising strains and strategies. Here, we review recent advances in the development and testing of engineered bacterial diagnostics and therapeutics. We highlight new technologies that will assist the development of more complex, robust and reliable engineered bacteria for future clinical applications, and we discuss approaches to more efficiently evaluate engineered strains throughout their preclinical development. PMID- 29398707 TI - The tumour glyco-code as a novel immune checkpoint for immunotherapy. AB - Tumour growth is accompanied by tumour evasion of the immune system, a process that is facilitated by immune checkpoint molecules such as programmed cell death protein 1 (PD1). However, the role of tumour glycosylation in immune evasion has mostly been overlooked, despite the fact that aberrant tumour glycosylation alters how the immune system perceives the tumour and can also induce immunosuppressive signalling through glycan-binding receptors. As such, specific glycan signatures found on tumour cells can be considered as a novel type of immune checkpoint. In parallel, glycosylation of tumour proteins generates neo antigens that can serve as targets for tumour-specific T cells. In this Opinion article, we highlight how the tumour 'glyco-code' modifies immunity and suggest that targeting glycans could offer new therapeutic opportunities. PMID- 29398708 TI - The role of nephrologists in the management of small renal masses. PMID- 29398709 TI - Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. AB - Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways. PMID- 29398710 TI - Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. AB - Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis. PMID- 29398711 TI - Photocatalytic C-F Reduction and Functionalization. AB - Functionalized polyfluorinated aromatics have become an important group of molecules for pharmaceutical and industrial applications. However, facile access to such valuable molecules remains an unmet challenge. In this review, we present and discuss photocatalytic C-F functionalization, which is emerging as a straightforward and operationally simple path to access partially fluorinated aromatics. PMID- 29398713 TI - Experimental assemblage of novel plant-herbivore interactions: ecological host shifts after 40 million years of isolation. AB - Geographic isolation is the first step in insect herbivore diet specialization. Such specialization is postulated to increase insect fitness, but may simultaneously reduce insect ability to colonize novel hosts. During the Paleocene-Eocene, plants from the order Zingiberales became isolated either in the Paleotropics or in the Neotropics. During the Cretaceous, rolled-leaf beetles diversified in the Neotropics concurrently with Neotropical Zingiberales. Using a community of Costa Rican rolled-leaf beetles and their Zingiberales host plants as study system, we explored if previous geographic isolation precludes insects to expand their diets to exotic hosts. We recorded interactions between rolled leaf beetles and native Zingiberales by combining DNA barcodes and field records for 7450 beetles feeding on 3202 host plants. To determine phylogenetic patterns of diet expansions, we set 20 field plots including five exotic Zingiberales, recording beetles feeding on these exotic hosts. In the laboratory, using both native and exotic host plants, we reared a subset of insect species that had expanded their diets to the exotic plants. The original plant-herbivore community comprised 24 beetle species feeding on 35 native hosts, representing 103 plant herbivore interactions. After exotic host plant introduction, 20% of the beetle species expanded their diets to exotic Zingiberales. Insects only established on exotic hosts that belong to the same plant family as their native hosts. Laboratory experiments show that beetles are able to complete development on these novel hosts. In conclusion, rolled-leaf beetles are pre-adapted to expand their diets to novel host plants even after millions of years of geographic isolation. PMID- 29398712 TI - Correlated evolution of personality, morphology and performance. AB - Evolutionary change in one trait can elicit evolutionary changes in other traits due to genetic correlations. This constrains the independent evolution of traits and can lead to unpredicted ecological and evolutionary outcomes. Animals might frequently exhibit genetic associations among behavioural and morphological physiological traits, because the physiological mechanisms behind animal personality can have broad multitrait effects and because many selective agents influence the evolution of multiple types of traits. However, we currently know little about genetic correlations between animal personalities and nonbehavioural traits. We tested for associations between personality, morphology and locomotor performance by comparing zebrafish (Danio rerio) collected from the wild and then selectively bred for either a proactive or reactive stress coping style ('bold' or 'shy' phenotypes). Based on adaptive hypotheses of correlational selection in the wild, we predicted that artificial selection for boldness would produce correlated evolutionary responses of larger caudal regions and higher fast-start escape performance (and the opposite for shyness). After four to seven generations, morphology and locomotor performance differed between personality lines: bold zebrafish exhibited a larger caudal region and higher fast-start performance than fish in the shy line, matching predictions. Individual-level phenotypic correlations suggested that pleiotropy or physical gene linkage likely explained the correlated response of locomotor performance, while the correlated response of body shape may have reflected linkage disequilibrium, which is breaking down each generation in the laboratory. Our results indicate that evolution of personality can result in concomitant changes in morphology and whole-organism performance, and vice versa. PMID- 29398714 TI - A Proteomic-Based Approach to Study the Mechanism of Cytotoxicity Induced by Interleukin-1alpha and Cycloheximide. AB - Abstract: The exposure of HeLa cells to interleukin-1 alpha (IL-1alpha) in the presence of cycloheximide (CHX) leads to the release of active tumor necrosis factor alpha (TNF-alpha), eliciting cytocidal effect on these cells. A mass spectrometry (MS)-based analysis of the qualitative proteomic profiles of the HeLa cells treated only with IL-1alpha, CHX or simultaneously with IL-1alpha and CHX, in comparison to an untreated control, enabled to distinguish protein candidates possibly involved in this process. Among them protein disulphide isomerase (PDI) seemed to be particularly interesting for further research. Therefore, we focused on quantitative changes of PDI levels in HeLa cells subjected to IL-1alpha and CHX. Enzyme-linked immunosorbent assay (ELISA) was employed for determination of PDI concentrations in the investigated, differently treated HeLa cells. The obtained results confirmed up-regulation of PDI only in the cells stimulated with IL-1alpha alone. In contrary, the PDI levels in HeLa cells exposed to both IL-1alpha and CHX, where apoptotic process was intensive, did not increase significantly. Finally, we discuss how different expression levels of PDI together with other proteins, which were detected in this study, may influence the induction of cytotoxic effect and modulate sensitivity to cytotoxic action of IL1. Graphical Abstract: PMID- 29398715 TI - Preference for ethanol in feeding and oviposition in temperate and tropical populations of Drosophila melanogaster. AB - The natural habitat of Drosophila melanogaster Meigen (Diptera: Drosophilidae) is fermenting fruits, which can be rich in ethanol. For unknown reasons, temperate populations of this cosmopolitan species have higher ethanol resistance than tropical populations. To determine whether this difference is accompanied by a parallel difference in preference for ethanol, we compared two European and two tropical African populations in feeding and oviposition preference for ethanol supplemented medium. Although females of all populations laid significantly more eggs on medium with ethanol than on control medium, preference of European females for ethanol increased as ethanol concentration increased from 2 to 6%, whereas that of African females decreased. In feeding tests, African females preferred control medium over medium with 4% ethanol, whereas European females showed no preference. Males of all populations strongly preferred control medium. The combination of preference for ethanol in oviposition, and avoidance or neutrality in feeding, gives evidence that adults choose breeding sites with ethanol for the benefit of larvae, rather than for their own benefit. The stronger oviposition preference for ethanol of temperate than tropical females suggests that this benefit may be more important in temperate populations. Two possible benefits of ethanol for which there is some experimental evidence are cryoprotection and protection against natural enemies. PMID- 29398716 TI - Characterization of Emissions from Liquid Fuel and Propane Open Burns. AB - The effect of accidental fires are simulated to understand the response of items such as vehicles, fuel tanks, and military ordnance and to remediate the effects through re-design of the items or changes in operational procedures. The comparative combustion emissions of using jet propellant (JP-5) liquid fuel pools or a propane manifold grid to simulate the effects of accidental fires was investigated. A helium-filled tethered aerostat was used to maneuver an instrument package into the open fire plumes to measure CO, CO2, fine particulate matter (PM2.5), polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and elemental/organic/total carbon (EC/OC/TC). The results showed that all emissions except CO2 were significantly higher from JP-5 burns than from propane. The major portion of the PM mass from fires of both fuels was less than 1 MUm in diameter and differed in carbon content. The PM2.5 emission factor from JP-5 burns (129 +/- 23 g/kg Fuelc) was approximately 150 times higher than the PM2.5 emission factor from propane burns (0.89 +/- 0.21 g/kg Fuelc). The PAH emissions as well as some VOCs were more than one hundred times higher for the JP-5 burns than the propane burns. Using the propane test method to study flammability responses, the environmental impact of PM2.5, PAHs, and VOCs would be reduced by 2300, 700, and 100 times per test, respectively. PMID- 29398717 TI - The time to decline: tracing a cohort's descendants in below replacement populations. AB - A number of contemporary populations are exhibiting sustained fertility at levels substantially below long-term replacement. Nonetheless, relatively few populations are actually diminishing in size. Here, we approach that apparent paradox by analyzing the time before the number in a birth cohort, and its descendants, falls below the initial number in the cohort. First, models are examined with constant below replacement fertility, cohort extinction at age 75 or 85, and no mortality below the highest age attained. For a net reproduction rate (NRR) of 0.75, it takes 150 years for the cohort's descendants to be fewer than the cohort's original size if persons live to age 85, and over 130 years if persons live to age 75. If the NRR is at least 0.60, it takes a century before the descendants are fewer in number than the original cohort. Second, projections are done for the USA 2012, Italy 2012, and Hong Kong 2011 assuming that fertility and mortality remain constant. The results resemble the projections. For example, in Italy, with actual mortality and an NRR of 0.70, it takes over 125 years before the descendants of a cohort are fewer in number than the initial cohort. A relatively simple equation for the long term "time to decline" is presented, showing that it depends primarily on the level of fertility, secondarily on longevity, and only modestly on the mean age of fertility. PMID- 29398718 TI - Mortality, morbidity and health in developed societies: a review of data sources. AB - The purpose of this paper is to review the major sources of data on mortality, morbidity and health in Europe and in other developed regions in order to examine their potential for analysing mortality and morbidity levels and trends. The review is primarily focused on routinely collected information covering a whole country. No attempt is made to draw up an inventory of sources by country; the paper deals instead with the pros and cons of each source for mortality and morbidity studies in demography. While each source considered separately can already yield useful, though partial, results, record linkage among data sources can significantly improve the analysis. Record linkage can also lead to the detection of possible causal associations that could eventually be confirmed. More generally, Big Data can reveal changing mortality and morbidity trends and patterns that could lead to preventive measures being taken rather than more costly curative ones. PMID- 29398719 TI - Modeling and experimental studies of enhanced cooling by medical gauze for cell cryopreservation by vitrification. AB - Vitrification is considered as an important alternative approach to traditional slow freezing method for cryopreservation of cells. A typical cell vitrification procedure involves a non-equilibrium cooling process commonly accomplished in liquid nitrogen, while in which film boiling is believed to greatly hinder heat transfer surrounding the sample, resulting in incomplete vitrification or a much higher critical concentration. In this study, we developed a simple while effective approach, wrapping traditional French-type straw with medical gauze, to greatly enhance convective heat transfer during cooling by suppress film boiling. We further established a coupled heat transfer model for cooling and warming of cell suspensions to investigate the inherent thermodynamic mechanism in this approach. The model describes both the macroscale thermal distributions in extracellular solution and the microscale ice crystallization inside the cells. The simulation indicated that straws wrapped with medical gauze would increase cell survival subject to vitrification cryopreservation by significantly increasing the cooling rate to inhibit intracellular ice formation (IIF). Our experiments on human umbilical vein endothelial cells (HUVECs) further confirmed the predictions in that the cell survival rate was significantly increased by wrapping straws with medical gauze. PMID- 29398720 TI - Secure Source Coding with a Public Helper. AB - We consider secure multi-terminal source coding problems in the presence of a public helper. Two main scenarios are studied: 1) source coding with a helper where the coded side information from the helper is eavesdropped by an external eavesdropper, 2) triangular source coding with a helper where the helper is considered as a public terminal. We are interested in how the helper can support the source transmission subject to a constraint on the amount of information leaked due to its public nature. We characterize the tradeoff between transmission rate, incurred distortion, and information leakage rate at the helper/eavesdropper in the form of a rate-distortion-leakage region for various classes of problems. PMID- 29398721 TI - Compression for Quadratic Similarity Queries: Finite Blocklength and Practical Schemes. AB - We study the problem of compression for the purpose of similarity identification, where similarity is measured by the mean square Euclidean distance between vectors. While the asymptotical fundamental limits of the problem - the minimal compression rate and the error exponent - were found in a previous work, in this paper we focus on the nonasymptotic domain and on practical, implementable schemes. We first present a finite blocklength achievability bound based on shape gain quantization: The gain (amplitude) of the vector is compressed via scalar quantization and the shape (the projection on the unit sphere) is quantized using a spherical code. The results are numerically evaluated and they converge to the asymptotic values as predicted by the error exponent. We then give a nonasymptotic lower bound on the performance of any compression scheme, and compare to the upper (achievability) bound. For a practical implementation of such a scheme, we use wrapped spherical codes, studied by Hamkins and Zeger, and use the Leech lattice as an example for an underlying lattice. As a side result, we obtain a bound on the covering angle of any wrapped spherical code, as a function of the covering radius of the underlying lattice. PMID- 29398722 TI - A Hierarchical structure of key performance indicators for operation management and continuous improvement in production systems. AB - Key performance indicators (KPIs) are critical for manufacturing operation management and continuous improvement (CI). In modern manufacturing systems, KPIs are defined as a set of metrics to reflect operation performance, such as efficiency, throughput, availability, from productivity, quality and maintenance perspectives. Through continuous monitoring and measurement of KPIs, meaningful quantification and identification of different aspects of operation activities can be obtained, which enable and direct CI efforts. A set of 34 KPIs has been introduced in ISO 22400. However, the KPIs in a manufacturing system are not independent, and they may have intrinsic mutual relationships. The goal of this paper is to introduce a multi-level structure for identification and analysis of KPIs and their intrinsic relationships in production systems. Specifically, through such a hierarchical structure, we define and layer KPIs into levels of basic KPIs, comprehensive KPIs and their supporting metrics, and use it to investigate the relationships and dependencies between KPIs. Such a study can provide a useful tool for manufacturing engineers and managers to measure and utilize KPIs for CI. PMID- 29398723 TI - Immigration in American Economic History. AB - The United States has long been perceived as a land of opportunity for immigrants. Yet, both in the past and today, US natives have expressed concern that immigrants fail to integrate into US society and lower wages for existing workers. This paper reviews the literatures on historical and contemporary migrant flows, yielding new insights on migrant selection, assimilation of immigrants into US economy and society, and the effect of immigration on the labor market. PMID- 29398724 TI - Morphological, chemical and species delimitation analyses provide new taxonomic insights into two groups of Rinodina. AB - The genus Rinodina (Physciaceae), with approximately 300 species, has been subject to few phylogenetic studies. Consequently taxonomic hypotheses in Rinodina are largely reliant on phenotypic data, while hypotheses incorporating DNA dependent methods remain to be tested. Here we investigate Rinodina degeliana/R. subparieta and the Rinodina mniaraea group, which previously have not been subjected to comprehensive molecular and phenotypic studies. We conducted detailed morphological, anatomical, chemical, molecular phylogenetic and species delimitation studies including 24 newly sequenced specimens. We propose that Rinodina degeliana and R. subparieta are conspecific and that chemical morphs within the R. mniaraea group should be recognized as distinct species. We also propose the placement of the recently described genus Oxnerella in Physciaceae. PMID- 29398725 TI - Lateral flow test for visual detection of silver (I) based on cytosine-Ag(I) cytosine interaction in C-rich oligonucleotides. AB - The authors describe an oligonucleotide-based lateral flow test for visual detection of Ag(I). The assay is based on cytosine-Ag(I)-cytosine [C-Ag(I)-C] coordination chemistry to capture gold nanoparticle (AuNP) tags in the test zone. A thiolated C-rich oligonucleotide probe was immobilized on the AuNPs via gold thiol chemistry, and a biotinylated C-rich oligonucleotide probe was immobilized on the test zone. The AuNPs labelled with C-rich oligonucleotides are captured by Ag(I) ions in the test zone through the C-Ag(I)-C coordination. The resulting accumulation of AuNPs produces a readily visible red band in the test zone. Under optimized conditions, the test is capable of visually detecting 1.0 ppb of Ag(I) which is 50 times lower than the maximum allowable concentration as defined by the US Environmental Protection Agency for drinking water. Hence, the test is inexpensive and highly sensitive. It was applied to the detection of Ag(I) in spiked samples of tap water and river water. In our perception, the test is a particularly valuable tool in limited resource settings. PMID- 29398726 TI - Probabilistic methods surpass parsimony when assessing clade support in phylogenetic analyses of discrete morphological data. AB - Fossil taxa are critical to inferences of historical diversity and the origins of modern biodiversity, but realizing their evolutionary significance is contingent on restoring fossil species to their correct position within the tree of life. For most fossil species, morphology is the only source of data for phylogenetic inference; this has traditionally been analysed using parsimony, the predominance of which is currently challenged by the development of probabilistic models that achieve greater phylogenetic accuracy. Here, based on simulated and empirical datasets, we explore the relative efficacy of competing phylogenetic methods in terms of clade support. We characterize clade support using bootstrapping for parsimony and Maximum Likelihood, and intrinsic Bayesian posterior probabilities, collapsing branches that exhibit less than 50% support. Ignoring node support, Bayesian inference is the most accurate method in estimating the tree used to simulate the data. After assessing clade support, Bayesian and Maximum Likelihood exhibit comparable levels of accuracy, and parsimony remains the least accurate method. However, Maximum Likelihood is less precise than Bayesian phylogeny estimation, and Bayesian inference recaptures more correct nodes with higher support compared to all other methods, including Maximum Likelihood. We assess the effects of these findings on empirical phylogenies. Our results indicate probabilistic methods should be favoured over parsimony. PMID- 29398727 TI - Experiences and practices of evolution instructors at Christian universities that can inform culturally competent evolution education. AB - Students' religious beliefs and religious cultures have been shown to be the main factors predicting whether they will accept evolution, yet college biology instructors teaching evolution at public institutions often have religious beliefs and cultures that are different from their religious students. This difference in religious beliefs and cultures may be a barrier to effective evolution education. To explore when evolution instructors have similar religious cultures and beliefs as their students, we interviewed 32 evolution instructors at Christian universities nationwide about their practices and experiences teaching evolution. Christian university instructors emphasized teaching for acceptance of evolution while holding an inclusive teaching philosophy that they perceived led to a safe environment for students. Additionally, almost all instructors reported using practices that have been shown to increase student acceptance of evolution and reduce student conflict between evolution and religion. Further, we found that these instructors perceived that their own religious backgrounds have guided their decisions to teach evolution to their students in a culturally competent way. We discuss how these data, combined with past research literature on public college instructors, indicate that cultural competence could be a useful new framework for promoting effective evolution education in higher education institutions. PMID- 29398728 TI - Globalization and Contemporary Fertility Convergence. AB - The rise of the global network of nation-states has precipitated social transformations throughout the world. This article examines the role of political and economic globalization in driving fertility convergence across countries between 1965 and 2009. While past research has typically conceptualized fertility change as a country-level process, this study instead employs a theoretical and methodological framework that examines differences in fertility between pairs of countries over time. Convergence in fertility between pairs of countries is hypothesized to result from increased cross-country connectedness and cross national transmission of fertility-related schemas. I investigate the impact of various cross-country ties, including ties through bilateral trade, intergovernmental organizations, and regional trade blocs, on fertility convergence. I find that globalization acts as a form of social interaction to produce fertility convergence. There is significant heterogeneity in the effects of different cross-country ties. In particular, trade with rich model countries, joint participation in the UN and UNESCO, and joining a free trade agreement all contribute to fertility convergence between countries. Whereas the prevailing focus in fertility research has been on factors producing fertility declines, this analysis highlights specific mechanisms-trade and connectedness through organizations-leading to greater similarity in fertility across countries. Globalization is a process that propels the spread of culturally laden goods and schemas impinging on fertility, which in turn produces fertility convergence. PMID- 29398729 TI - Experimental Investigation of Hysteretic Dynamic Capillarity Effect in Unsaturated Flow. AB - The difference between average pressures of two immiscible fluids is commonly assumed to be the same as macroscopic capillary pressure, which is considered to be a function of saturation only. However, under transient conditions, a dependence of this pressure difference on the time rate of saturation change has been observed by many researchers. This is commonly referred to as dynamic capillarity effect. As a first-order approximation, the dynamic term is assumed to be linearly dependent on the time rate of change of saturation, through a material coefficient denoted by tau. In this study, a series of laboratory experiments were carried out to quantify the dynamic capillarity effect in an unsaturated sandy soil. Primary, main, and scanning drainage experiments, under both static and dynamic conditions, were performed on a sandy soil in a small cell. The value of the dynamic capillarity coefficient tau was calculated from the air-water pressure differences and average saturation values during static and dynamic drainage experiments. We found a dependence of tau on saturation, which showed a similar trend for all drainage conditions. However, at any given saturation, the value of tau for primary drainage was larger than the value for main drainage and that was in turn larger than the value for scanning drainage. Each data set was fit a simple log-linear equation, with different values of fitting parameters. This nonuniqueness of the relationship between tau and saturation and possible causes is discussed. PMID- 29398730 TI - Differential Tolerance to Lead and Cadmium of Micropropagated Gypsophila fastigiata Ecotype. AB - In vitro techniques may provide a suitable tool for effective propagation and conservation of plant species representing various ecological niches. The elaboration of such protocols is also prerequisite for selection of heavy-metal tolerant plant material that could be afterwards used for restoration or remediation of polluted sites. In this study, culture protocol for Gypsophila fastigiata propagation was developed. The highest multiplication coefficient, which reached 6.5, and the best growth parameters were obtained on modified MS medium supplemented with 1.0 mg L-1 2iP and 0.2 mg L-1 IAA. The obtained cultures were treated with different concentrations of lead nitrate (0.1, 0.5, and 1.0 mM Pb(NO3)2) or cadmium chloride (0.5, 2.5, and 5.0 MUM CdCl2). The growth parameters, photosynthetic pigments, and phenolic compound content were examined in order to evaluate whether tested metal salts can have an adverse impact on studied culture. It was ascertained that Pb ions induced growth disturbances and contributed to shoot wither. On the contrary, the proliferative shoot cultures were established on media containing Cd ions and the multiplication coefficients and shoot length increased on all media enriched with CdCl2. Chlorophylls and carotenoid contents were negatively affected by application of 5.0 MUM of cadmium; nevertheless, in shoots treated with 2.5 MUM CdCl2, increased accumulation of photosynthetic pigments occurred and their amount was similar to untreated culture. Adaptation to Cd was associated with stimulation of phenolic compound synthesis. Hence, we have reported on unambiguous positive result of in vitro selection procedure to obtain vigorous shoot culture tolerant to cadmium. PMID- 29398731 TI - Quality of life among South African patients receiving antiretroviral therapy in the Western Cape Province. AB - Compared to patients not receiving treatment, antiretroviral therapy (ART) users may experience a lower viral load, an increased CD4 count, slower disease progression, fewer opportunistic infections, and more rapid recovery time from HIV-related illnesses. As such, health related quality of life (HR-QOL) is likely to be considerably greater for ART users than patients not receiving treatment. The dearth of QOL research in sub-Saharan Africa brings into focus the need for and importance of documenting the various dimensions of well-being among persons living with HIV in this region of the world. We thus sought to report on the performance of South African patients enrolled in a public government funded antiretroviral therapy (ART) program. We administered the Functional Assessment of HIV Infection (FAHI) to a convenience sample of patients receiving ART in the Western Cape in South Africa. We used confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) to determine the factor structure of the FAHI amongst South African ART users. The CFA revealed a poor model fit of the data. However the EFA factor structure closely approximated the subscales of the measure, indicating the dimensions of physical, emotional, functional, and social well-being and cognitive functioning. We identified problematic items contributing to the poor model fit and contribute to the knowledge base on QOL amongst ART users in South Africa. PMID- 29398732 TI - The Preparation, Structural Characteristics, and Physical Chemical Properties of Metal-Nitrosyl Complexes. AB - The preparation and characterization of a representative group of novel non-heme metal nitrosyl complexes that have been synthesized over the last decade are discussed here. Their structures are examined and classified based on metal type, the number of metal centers present, and the type of ligand that is coordinated with the metal. The ligands can be phosphorus, nitrogen, or sulfur based (with a few exceptions) and can vary depending on the presence of chelation, intermolecular forces, or the presence of other ligands. Structural and bonding characteristics are summarized and examples of reactivity regarding nitrosyl ligands are given. Some of the relevant physical chemical properties of these complexes, including IR, EPR, NMR, UV-vis, cyclic voltammetry, and X-ray crystallography are examined. PMID- 29398733 TI - TARGETED SEQUENTIAL DESIGN FOR TARGETED LEARNING INFERENCE OF THE OPTIMAL TREATMENT RULE AND ITS MEAN REWARD. AB - This article studies the targeted sequential inference of an optimal treatment rule (TR) and its mean reward in the non-exceptional case, i.e., assuming that there is no stratum of the baseline covariates where treatment is neither beneficial nor harmful, and under a companion margin assumption. Our pivotal estimator, whose definition hinges on the targeted minimum loss estimation (TMLE) principle, actually infers the mean reward under the current estimate of the optimal TR. This data-adaptive statistical parameter is worthy of interest on its own. Our main result is a central limit theorem which enables the construction of confidence intervals on both mean rewards under the current estimate of the optimal TR and under the optimal TR itself. The asymptotic variance of the estimator takes the form of the variance of an efficient influence curve at a limiting distribution, allowing to discuss the efficiency of inference. As a by product, we also derive confidence intervals on two cumulated pseudo-regrets, a key notion in the study of bandits problems. A simulation study illustrates the procedure. One of the corner-stones of the theoretical study is a new maximal inequality for martingales with respect to the uniform entropy integral. PMID- 29398734 TI - Living with a Rare Health Condition: The Influence of a Support Community and Public Stigma on Communication, Stress, and Available Support. AB - People affected by rare diseases often have limited coping resources and sometimes face stigma. They build communities with others who share their conditions, but not all members may benefit from these communities. This study investigated how adults with a rare genetic health condition (Alpha-1 antitrypsin deficiency; AATD) think about both the Alpha-1 community and public stigma about AATD, and how these cognitions were associated with their communication responses and well-being. The results showed that people with AATD encountered stigmatization from various sources, including family, employers, healthcare providers, and insurance companies. Stronger public stigma predicted more secrecy, more stress, and less available support. Stronger group identification with the Alpha-1 community predicted less secrecy; stronger group activism predicted more available support and more communication to challenge stigmatizers. Post-hoc analyses showed significant interactions between public stigma and group cognitions on communication to challenge stigmatizers. Practical implications for bolstering communities to improve the well-being of people with rare diseases were discussed. PMID- 29398735 TI - The Signature of Southern Hemisphere Atmospheric Circulation Patterns in Antarctic Precipitation. AB - We provide the first comprehensive analysis of the relationships between large scale patterns of Southern Hemisphere climate variability and the detailed structure of Antarctic precipitation. We examine linkages between the high spatial resolution precipitation from a regional atmospheric model and four patterns of large-scale Southern Hemisphere climate variability: the southern baroclinic annular mode, the southern annular mode, and the two Pacific-South American teleconnection patterns. Variations in all four patterns influence the spatial configuration of precipitation over Antarctica, consistent with their signatures in high-latitude meridional moisture fluxes. They impact not only the mean but also the incidence of extreme precipitation events. Current coupled climate models are able to reproduce all four patterns of atmospheric variability but struggle to correctly replicate their regional impacts on Antarctic climate. Thus, linking these patterns directly to Antarctic precipitation variability may allow a better estimate of future changes in precipitation than using model output alone. PMID- 29398736 TI - Inflated Uncertainty in Multimodel-Based Regional Climate Projections. AB - Multimodel ensembles are widely analyzed to estimate the range of future regional climate change projections. For an ensemble of climate models, the result is often portrayed by showing maps of the geographical distribution of the multimodel mean results and associated uncertainties represented by model spread at the grid point scale. Here we use a set of CMIP5 models to show that presenting statistics this way results in an overestimation of the projected range leading to physically implausible patterns of change on global but also on regional scales. We point out that similar inconsistencies occur in impact analyses relying on multimodel information extracted using statistics at the regional scale, for example, when a subset of CMIP models is selected to represent regional model spread. Consequently, the risk of unwanted impacts may be overestimated at larger scales as climate change impacts will never be realized as the worst (or best) case everywhere. PMID- 29398737 TI - Trajectories of Ethnoracial Diversity in American Communities, 1980-2010. AB - The ethnoracial makeup of the U.S. population has undergone transformative change during recent decades, with the non-Hispanic white share of the population shrinking while the minority shares expand. Yet this trend toward greater racial diversity is not universal throughout the nation. Here we propose a framework of segmented change, which incorporates both spatial assimilation and ethnic stratification theories, to better understand variation in patterns of diversification across American communities. Our research applies growth mixture models to decennial census data on places for the 1980-2010 period, finding that trajectories of ethnoracial diversity are much more uneven than popularly claimed. Moreover, types of diversity change are stratified by initial racial composition. While places with mostly-white populations in 1980 underwent extensive diversification, places with larger shares of Hispanics and (especially) blacks in 1980 exhibited less uniform movement toward diversity and were more likely to remain racially homogeneous. Analysis of the underlying group specific pathways of change indicates that the diversification of white communities was driven largely by Hispanic growth; when areas with a black presence did diversify, it occurred via contracting white populations. These racially conditioned and locally variable patterns emphasize the segmented nature of diversity change in American society. PMID- 29398738 TI - The Best Predictors of Survival: Do They Vary by Age, Sex, and Race? PMID- 29398739 TI - Rising Educational Participation and the Trend to Later Childbearing. PMID- 29398740 TI - Novice designers' use of prototypes in engineering design. AB - Prototypes are essential tools in product design processes, but are often underutilized by novice designers. To help novice designers use prototypes more effectively, we must first determine how they currently use prototypes. In this paper, we describe how novice designers conceptualized prototypes and reported using them throughout a design project, and compare reported prototyping use to prototyping best practices. We found that some of the reported prototyping practices by novice designers, such as using inexpensive prototypes early and using prototypes to define user requirements, occurred infrequently and lacked intentionality. Participants' initial descriptions of prototypes were less sophisticated than how they later described using them and only upon prompted reflection did participants recognize more specific benefits of using prototypes. PMID- 29398741 TI - Theoretical Insights into Preconception Social Conditions and Perinatal Health: The Role of Place and Social Relationships. AB - : Recent efforts to explain the stark social and racial disparities in adverse birth outcomes that have persisted for decades in the U.S. have looked beyond prenatal factors, to explore preconception social conditions that may influence perinatal health via dysregulation of physiologic processes. The extant evidence supporting this link however remains limited, both due to a lack of data and theory. To address the latter, this manuscript generates a structured set of theoretical insights that further develop the link between two preconception social conditions - place and social relationships - and perinatal health. The insights propose the following. PLACE: necessarily encompasses all social contexts to which females are exposed from infancy through young adulthood; encompasses a variety of related exposures that, when possible, should be jointly considered; and may compound the effect of poverty-in childhood, adolescence, or young adulthood-on perinatal health. Social relationships: span relationships from early life through adulthood, and extend to intergenerational associations; often involve (or induce) major changes in the lives of individuals and should be examined with an emphasis on the developmental stage in which the change occurred; and necessarily encompass a lack of social integration, or, social isolation. We also identify potential biological and social-structural mechanisms linking these preconception social conditions to perinatal health, and conclude by identifying promising directions for future research. PMID- 29398742 TI - Getting Under the Skin: Children's Health Disparities as Embodiment of Social Class. AB - Social class gradients in children's health and development are ubiquitous across time and geography. The authors develop a conceptual framework relating three actions of class-material allocation, salient group identity, and inter-group conflict-to the reproduction of class-based disparities in child health. A core proposition is that the actions of class stratification create variation in children's mesosystems and microsystems in distinct locations in the ecology of everyday life. Variation in mesosystems (e.g., health care, neighborhoods) and microsystems (e.g., family structure, housing) become manifest in a wide variety of specific experiences and environments that produce the behavioral and biological antecedents to health and disease among children. The framework is explored via a review of theoretical and empirical contributions from multiple disciplines and high-priority areas for future research are highlighted. PMID- 29398744 TI - Motherhood in Complex Families. AB - Families formed through multipartner fertility, where children with a common biological mother were conceived by different biological fathers, represent a growing share of all families in the United States. Using data from four waves of the Fragile Families Child and Well-Being Study (N=3,366), I find that women who have engaged in multipartner fertility are more likely to experience parenting stress and depression compared to mothers whose children share the same biological father. Mothers' depression is explained in the short term by poor relationship quality with the father of her prior children and in the longer term by indicators of boundary ambiguity in complex families. Mothers' parenting stress was only weakly explained by variation in perceived kin support, father involvement, or boundary ambiguity. PMID- 29398743 TI - Critical review of the impacts of grazing intensity on soil organic carbon storage and other soil quality indicators in extensively managed grasslands. AB - Livestock grazing intensity (GI) is thought to have a major impact on soil organic carbon (SOC) storage and soil quality indicators in grassland agroecosystems. To critically investigate this, we conducted a global review and meta-analysis of 83 studies of extensive grazing, covering 164 sites across different countries and climatic zones. Unlike previous published reviews we normalized the SOC and total nitrogen (TN) data to a 30 cm depth to be compatible with IPCC guidelines. We also calculated a normalized GI and divided the data into four main groups depending on the regional climate (dry warm, DW; dry cool, DC; moist warm, MW; moist cool, MC). Our results show that taken across all climatic zones and GIs, grazing (below the carrying capacity of the systems) results in a decrease in SOC storage, although its impact on SOC is climate dependent. When assessed for different regional climates, all GI levels increased SOC stocks under the MW climate (+7.6%) whilst there were reductions under the MC climate (-19%). Under the DW and DC climates, only the low (+5.8%) and low to medium (+16.1%) grazing intensities, respectively, were associated with increased SOC stocks. High GI significantly increased SOC for C4-dominated grassland compared to C3-dominated grassland and C3-C4 mixed grasslands. It was also associated with significant increases in TN and bulk density but had no effect on soil pH. To protect grassland soils from degradation, we recommend that GI and management practices should be optimized according to climate region and grassland type (C3, C4 or C3-C4 mixed). PMID- 29398745 TI - Effects of Social Norms Information and Self-Affirmation on Sugar-Sweetened Beverage Consumption Intentions and Behaviors. AB - The separate and combined efficacy of a social norms and a self-affirmation intervention to motivate decreased sugar-sweetened beverage (SSB) consumption was examined in two experiments. College students were randomly assigned to receive information about SSB consumption risks, norms, both, or neither. In addition, participants performed either a self-affirmation or control task. Self affirmation only weakly affected SSB consumption intentions and behaviors. However, participants in Experiment 2 who received risks information, norms information, or both reported greater SSB reduction intentions than did those who received no information. Two-weeks later, those who received both types of information reported more frequent behavior change preparations, and it appears this effect may have been partially mediated by the changes in intentions to reduce SSB consumption. PMID- 29398746 TI - Subtypes of Benign Breast Disease as a Risk Factor for Breast Cancer: A Systematic Review and Meta-Analysis Protocol. AB - Breast cancer is a multifactorial disease. Benign breast disease (BBD) is one of the most important risk factors for breast cancer. The etiology of BBD is unknown. It is divided into nonproliferative and proliferative diseases. The selection of studies will be based on titles, abstract screening, inclusion and exclusion criteria, and quality assessment. Previous studies have shown that all types of BBD increase the risk of breast cancer, but the risk degree is different for each one. Accurate risk estimation of breast cancer in each category can be very important for proper clinical management. This systematic review and meta analysis will be conducted on observational studies (traditional case control, nested case control, case cohort, and cohort) published in the Web of Science (ISI), PubMed (MEDLINE), Scopus, Google Scholar, and the key journals of this field such as Breast Cancer Research and Treatment and Cancer Research from January 2000 to June 2015. Reference lists and gray literature will be reviewed too. All the initial retrievals will be performed by 2 researchers independently. The data extraction form will consist of general information concerning the studies, study eligibility, method, risk of bias assessment, and results including odds ratios, risk ratios, rate ratios, and hazard ratios. The PRISMA and MOOSE guidelines will be used to report our findings. Registration Details: PROSPERO-42016035243. PMID- 29398747 TI - Effects of Folic Acid on Appetite in Children with Attention Deficit Hyperactivity Disorder (ADHD) Treated with Methylphenidate: A Randomized Double Blind Clinical Trial. AB - Background: The highly effective medications in treating attention deficit hyperactivity disorder (ADHD) symptoms are stimulants like methylphenidate. However, they have adverse effects like reduced appetite. We investigated the effects of folic acid on reduced appetite caused by the use of methylphenidate in children with ADHD. Methods: This randomized double-blind clinical trial evaluated 70 outpatients, aged between 6 and 12 years, with a diagnosis of ADHD. The children were recruited from the Outpatient Child and Adolescent Psychiatric Clinic of Golestan Hospital (Ahwaz, Iran) between 2016 and 2017. The study subjects were randomly assigned to 2 groups: Group 1 received an average dose of methylphenidate (1 mg/kg) plus folic acid (5 mg/d) and Group 2 received an average dose of methylphenidate (1 mg/kg) plus a placebo (5 mg of sucrose) for 8 weeks. Assessments, comprising the Conners Parent Questionnaire, anthropometric measurements, and appetite questionnaire, were conducted by a psychiatrist at baseline and then at 2, 4, 6, and 8 weeks after the medication was started using repeated measure analysis. The data were analyzed with the Mann-Whitney U and ANOVA tests using the SPSS statistical software (v. 18.0). Results: Age and gender were not associated with the groups. Weight, height, and the body mass index were not changed during the study in both groups. ADHD symptoms significantly decreased in both groups during the trial; however, no difference was observed between the groups. Moreover, appetite was significantly improved in Group 1. Both medications were well tolerated. Conclusion: It seems that folic acid improved the reduced appetite caused by the use of methylphenidate in our children with ADHD. Trial Registration Number: IRCT2016040927304N1. PMID- 29398748 TI - Inhibition of the CatSper Channel and NOX5 Enzyme Activity Affects the Functions of the Progesterone-Stimulated Human Sperm. AB - Background: Low levels of reactive oxygen species (ROS) and calcium are necessary for sperm function. NADPH oxidase 5 (NOX5) is a membrane enzyme which produces ROS. This enzyme is dependent on calcium for its activity. We investigated the importance of NOX5 and an important calcium channel (CatSper) on sperm function. Methods: This laboratory in-vitro study was done in Shiraz, Iran, 2016. Normal semen samples (n=24) were washed and diluted to 20*106 sperm/mL. The diluted samples were divided into 8 groups, containing Ham's F-10 (control group), 2 uM of NNC (CatSper channel inhibitor), 1 uM DPI (NOX5 inhibitor), and NNC+DPI. The other 4 groups were the same as the 1st ones, except that they contained 1 uM of progesterone. Motility assessment was done by VT-Sperm 3.1. Acrosome status was monitored with acrosome-specific FITC-PSA using fluorescent microscopy. Sperm viability was assessed by Eosin Y. Statistical analysis was performed using SPSS 16 software. The comparison between the groups was done using the one-way ANOVA, followed by Tukey. A P<0.05 was considered significant. Results: The percentage of motile sperm, sperm velocity, and viability decreased significantly in the groups containing NNC. DPI reduced sperm progressive motility only in the progesterone-stimulated condition. Progesterone induced acrosome reaction, but this effect was inhibited by NNC and DPI. Conclusion: CatSper had a prominent role in the motility, acrosome reaction, and viability of the human sperm. The function of NOX5 was important only in the stimulated sperm. We conclude that CatSper has a more prominent role than NOX5 activity. The functional relation between NOX5 and CatSper is not clear but is very probable. PMID- 29398749 TI - Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co supplementation after Disease Progression in Rats. AB - Background: Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD). However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Materials and Methods: Forty male Sprague-Dawley rats (197+/-4 g) were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat), high-fat diet (HFD; receiving 82% of calories as fat), supplementation before disease progression (S+HFD), and supplementation after disease progression (HFD+S). The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. Results: There were significant differences in the average food dietary intake (P<0.001), weight (P<0.001), fasting blood sugar (P=0.005), triglyceride (P<0.001), total cholesterol (P<0.001), low-density lipoprotein cholesterol (P=0.002), high density lipoprotein cholesterol (P=0.001), alanine aminotransferase (P<0.001), and aspartate aminotransferase (P<0.001) between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively). Fat accumulation was significantly reduced in the HFD+S Group (P<0.001). Conclusion: Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD. PMID- 29398750 TI - Effects of the Oral Ingestion of Probiotics on Brain Damage in a Transient Model of Focal Cerebral Ischemia in Mice. AB - Background: Probiotics are microorganisms that may influence brain function via altering brain neurochemistry. New research evidence suggests that probiotic bacteria might protect tissue damage through diminishing the production of free radicals and/or inflammatory cytokines. Therefore, this study was designed to evaluate the effects of probiotic bacteria on the prevention or reduction of brain damage in an experimental model of stroke in mice. Methods: In this study, 30 male BLC57 mice were randomly divided into 6 equal groups. Focal cerebral ischemia was induced via middle cerebral artery occlusion for 45 minutes, followed by 24 hours of reperfusion, in the mice. Probiotics at a concentration of 107 CFU/mL were administered by oral gavage daily for 14 days before ischemia. Infarct size, neurological outcome, and biochemical markers were measured 24 hours after brain ischemia. Statistical analysis were performed using the one-way ANOVA and/or Kruskal-Wallis ANOVA on rank by Sigma Stat (2.0; Jandel Scientific) software. Results: Our results indicated that pretreatment with probiotics significantly reduced infarct size by 52% (P=0.001) but could not improve neurological function (P=0.26). Moreover, the administration of probiotics significantly decreased the malondialdehyde content (P=0.001) and the tumor necrosis factor-alpha level (P=0.004) in the ischemic brain tissue. Conclusion: The findings of the present study showed that probiotic supplements might be useful in the prevention or attenuation of brain ischemic injury in patients at risk of stroke. Probiotics may open new therapeutic alternatives for the prevention of stroke. More preclinical and clinical studies are, however, needed to clarify their efficacy in cerebral stroke. PMID- 29398751 TI - Radioprotective Efficacy of Lutein in Ameliorating Electron Beam Radiation induced Oxidative Injury in Swiss Albino Mice. AB - Background: Lutein, a carotenoid compound, has previously been studied for its antioxidant and medicinal properties as well as the moderate protection it confers against gamma radiation. This study aimed at evaluating the effects of lutein against radiation-induced hematological and biochemical changes in mice. Methods: The optimized dose of the compound was orally administered for 15 days, and the mice were irradiated (6 Gy) on day 15 after the administration of the compound. The groups were divided (6 mice in each group) into normal control, radiation control, gallic acid control, 10% DMSO control, lutein control, and irradiated groups pretreated with gallic acid, 10% DMSO, and lutein. Gallic acid was used to maintain a standard since it is a proven radioprotector. Within 24 hours post irradiation, the animals were anesthetized and sacrificed. The hematological, biochemical, and antioxidant changes were determined using suitable methods. Data were analyzed by the Kaplan-Meier curve (log-rank test) and ANOVA (the Tukey test). The independent t test was used to compare the independent groups. SPSS (ver. 16) was employed. Results: Maximum survival was observed with a dose of 250 mg/kg b.wt lutein. The total leukocyte count and the percentage lymphocyte count exhibited a significant decline in the irradiated groups pretreated with gallic acid and lutein in comparison to their controls, whereas the percentage granulocyte count showed a significant rise. Antioxidant activity had markedly declined in the irradiated groups, indicating oxidative stress. Lutein pretreatment reduced the damage and maintained the antioxidant system. Conclusion: The present study suggests a protective role for lutein in palliating radiation-induced oxidative changes and maintaining the antioxidant system in vivo. PMID- 29398752 TI - Antiproliferative Effects of Pancratium Maritimum Extracts on Normal and Cancerous Cells. AB - Background: Plants are an important natural source of compounds used in cancer therapy. Pancratium maritimum contains potential anti-cancer agents such as alkaloids. In this study, we investigated the anti-proliferative effects of P. maritimum extracts on MDA-MB-231 human epithelial adenocarcinoma cell line and on normal lymphocytes in vitro. Methods: Leaves, flowers, roots, and bulbs of P. maritimum were collected and their contents were extracted and diluted to different concentrations that were applied on MDA-MB-231 cells and normal human lymphocytes cell in vitro for different intervals. Cells viability, proliferation, cell cycle distribution, apoptosis, and growth were evaluated by flow cytometry and microscopy. Parametric unpaired t-test was used to compare effects of plant extracts on treated cell cultures with untreated control cell cultures. IC50 was also calculated. Results: P. maritimum extract had profound effects on MDA-MB-321 cells. It inhibited cell proliferation in a dose- and time dependent manner. The IC50 values were 0.039, 0.035, and 0.026 mg/ml after 48, 72, and 96 hours of treatment with 0.1 mg/ml concentration of bulb extract, respectively. Those values were 0.051 and 0.03 mg/ml after 72 and 96 hours for root extract, respectively, and 0.048 mg/ml after 96 hours for flower extract. There were no significant effects of P. maritimum bulb extracts on normal lymphocytes proliferation. Conclusion: P. maritimum extract has anti proliferative effects on MDA-MB-231 cell line in vitro. The effects imply the involvement of mechanisms that inhibits cell growth and arresting cells at S and G2/M phases. Cyclin B1, Bcl-2, and Ki67 expression was also affected. PMID- 29398753 TI - Evaluation of Psychopathology and Quality of Life in Patients with Anogenital Wart Compared to Control Group. AB - Anogenital warts (AGW) are one of the most common venereal diseases. Psychosocial complications and quality of life (QoL) of AGW patients have been considered only in recent years. Herein, the QoL and psychopathology in patients with AGW are evaluated. In total, 37 AGW patients and 37 healthy controls were recruited in the present cross-sectional study. All participants were provided with the symptom checklist 90-R (SCL-90-R) and short-form (SF-36) questionnaires. All analyses were performed using the SPSS software, version 16.0.1 for Windows. QoL was not significantly different between the study groups (P=0.12). The data showed that mental health, general health, and social functioning were significantly decreased in AGW patients (P<0.05). In addition, AGW patients were significantly more depressed and anxious than the control group (P=0.01 and P=0.04, respectively). AGW has adverse effects on psychological and QoL elements of the infected individuals. Psychological factors should be carefully considered when treating a patient with the HPV virus; hence, referral to a psychiatrist seems mandatory in these cases. PMID- 29398754 TI - The Effect of Prophylactic Infusion of Combined Ephedrin and Phenylephrine on Maternal Hemodynamic after Spinal Anesthesia for Cesarean Section: A Randomized Clinical Trial. AB - : Several techniques have been proposed to prevent hypotension in obstetric patients. Ephedrine and phenylephrine are individually used to prevent maternal hypotension; however, each has its own drawbacks. Some researchers have reported that the infusion of combined ephedrine and phenylephrine immediately after spinal anesthesia for cesarean delivery reduces the incidence of maternal hypotension. Other studies have indicated that the combination is not superior to the infusion of an individual agent. The present study aimed to evaluate the effect of prophylactic infusion of ephedrine and phenylephrine before the induction of spinal anesthesia for cesarean section on maternal hemodynamic. In a randomized, double-blinded clinical trial study, 90 pregnant women that underwent elective cesarean delivery under spinal anesthesia were recruited. Before the spinal anesthesia, the infusion of combined ephedrine and phenylephrine during 15 minutes (study group) or serum NaCl 0.9% (placebo group) was performed. Hemodynamic parameters and fetal blood gas were recorded. The data were analyzed using the SPSS software, version 16.0. The results showed that hypotension and bradycardia after spinal anesthesia were less in the study group. The need for vasopressors and inotropes to treat hypotension, nausea, and vomiting were higher in the placebo group. First- and fifth-minute Apgar scores were higher in the study group. The prophylactic infusion of low-dose ephedrine and phenylephrine before spinal anesthesia for cesarean delivery can be used to decrease the frequency and severity of maternal hypotension and its side effects to the mother and neonate. TRIAL REGISTRATION NUMBER: IRCT201401277013N6. PMID- 29398755 TI - Classic versus Inguinal Approach for Obturator Nerve Block in Transurethral Resection of Bladder Cancer under Spinal Anesthesia: A Randomized Controlled Trial. AB - : Single spinal anesthesia in transurethral resection of bladder tumor (TURBT) has been reported to be unable to prevent obturator nerve stimulation and adductor muscle contraction, which can cause complications like bladder perforation. The present study aimed to compare the effectiveness of the classic and inguinal approaches for obturator nerve block (ONB ). Seventy patients with cancers of the lateral wall of the bladder, scheduled to undergo TURBT at Imam Reza Hospital (Tabriz, Iran) during a 6-month period as of June 2016, were randomly allocated to groups of inguinal and classic methods (n=35). After the infusion of 500 mL of normal saline, spinal anesthesia was commenced using 3 mL (15 mg) of bupivacaine. Then ONB was performed using 10 mL of 1% lidocaine via the inguinal or classic approach in the inguinal group or the classic group, respectively. The success rate, defined as lack of post-block contraction with stimulation or during surgery, number of puncture attempts, time of block onset, and patient and surgeon satisfaction, was compared between the 2 methods using SPSS, version 19. The success rate of ONB was significantly higher in the inguinal group (97.1% vs. 71.4%; P=0.003). The number of puncture attempts in the classic group was more than that in the inguinal group (3.71+/-1.10 vs. 1.66+/ 0.68, respectively; P<0.001). The block onset time was shorter in the inguinal group (1.5+/-0.66 min vs. 2.9+/-1.18 min; P<0.001). Dissatisfaction of the patient (19 cases vs. 2 cases) and the surgeon (10 cases vs. no case) was higher in the classic group (P<0.001). Compared to the classic approach, the inguinal approach for ONB appeared to be an easily performable, effective block with a high success rate, rapid onset, and good patient and surgeon satisfaction. TRIAL REGISTRATION NUMBER: IRCT 201608171772N21. PMID- 29398756 TI - Pachydermoperiostosis in a Patient with Crohn's Disease: Treatment and Literature Review. AB - Pachydermoperiostosis (PDP) is a rare disorder characterized by pachydermia, digital clubbing, periostitis, and an excess of affected males. It is the primary form of hypertrophic osteoarthropathy (HOA) and there are some rare associations of PDP with other disorders. Here we describe a patient with Crohn's disease associated with PDP. A 26-year-old man, who was a known case of Crohn's disease, referred with diffuse swelling in the upper and lower limbs and cutis verticis gyrata since 7 years ago. PDP was suspected and endocrinological and radiological studies were conducted for the evaluation of underlying disease. He was prescribed celecoxib, low-dose prednisolone, and pamidronate to control the swelling, periostitis, azathiopurine, and mesalazine according to gastrointestinal involvement. In conclusion, it is important to identify this condition since a misdiagnosis might subject the patient to unnecessary investigations. PMID- 29398757 TI - Atypical Kawasaki Disease Presenting with Hemiparesis and Aphasia: A Case Report. AB - Kawasaki disease (KD) is an inflammatory vasculitis. KD is classified into two groups based on clinical characteristics criteria, namely classic and incomplete. Cerebral vascular abnormality, especially arterial ischemic stroke (AIS) is very rare and unusual in KD. Here, we report a 4-year-old boy who was referred to our tertiary pediatric center with abrupt right hemiparesis and aphasia. At admission time, he had febrile illness and was toxic. On physical examination, we found unilateral left submandibular lymphadenopathy. On neurologic examination, we obtained right sided hemiparesis with hemiparetic gait and aphasia. His deep tendon reflexes (DTRs) of right extremities were exaggerated and his sensory system was intact. Based on these features, some differential diagnoses were suggested, such as acute encephalitis with focal signs, brain abscess, cerebral vasculitis, hemorrhagic insults, and ischemic stroke, etc. After a complete evaluation, especially brain MRI and MRA, our diagnosis was arterial ischemic stroke (AIS) following atypical KD. Based on these findings, we administered intravenous immunoglobulin (IVIG 2 gm/kg) and oral high dose aspirin (100 mg/kg/d). He responded to these anti-inflammatory treatments dramatically. PMID- 29398758 TI - Papillary Carcinoma of Thyroid with Nasal Cavity Metastases: A Case Report. AB - Papillary thyroid carcinoma (PTC) is one of the most commonly diagnosed types of differentiated carcinoma of the thyroid. It is stated that lung is the most common site of metastasis followed by bone. The incidence of paranasal sinus (PNS) metastasis is fairly uncommon in case of thyroid carcinoma. To the best of our knowledge, no case of metastatic PTC to nasal cavity has been reported. In this case report, we present the first case of papillary carcinoma of the thyroid with nasal cavity metastases in a 55-year-old female. The patient underwent surgical treatment and the mass was completely removed and sent for pathology. The pathology report revealed that it was metastatic papillary cell carcinoma. Surgical approach is usually difficult in view of the cosmetic and functional concerns, but may be considered in selected cases. As described herein, this rare type of metastasis was successfully removed and the patient was symptoms free after 1-year follow-up. PMID- 29398759 TI - Tubercular Mycobacterial Spindle Cell Pseudotumour: A Case Report. AB - Pseudotumour is a benign inflammatory lesion. Mycobacterial spindle cell pseudotumour (MSP) is a rare pseudotumour. It is a benign proliferation of spindle-shaped histiocytes containing acid-fast mycobacterium, commonly reported in immunocompromised patients. MSP is usually associated with mycobacterium avium complex (MAC). Here, we present the case of a 38-year-old gentleman with acquired immune deficiency syndrome (AIDS) who presented with low-grade fever for 1-month duration. Clinically, he had generalised lymphadenopathy. Chest X-ray showed miliary infiltration in bilateral lung fields. Lymph nodal biopsy showed spindle shaped histiocytes filled with acid-fast bacilli on Ziehl-Neelsen (ZN) stain, suggestive of MSP. Immunohistochemical (IHC) stains were positive for CD68, S-100 and negative for CD31, which are consistent with MSP. Polymerase chain reaction (PCR) of the biopsy tissue was positive for MTB. Highly active antiretroviral therapy (HAART) was continued and anti-tubercular therapy (ATT) was started. The fever resolved within two weeks and there was a resolution of lymph nodal swelling by 6 weeks. The diagnosis of MSP associated with mycobacterium tuberculosis (MTB) makes our case interesting. It is of utmost importance to differentiate MSP from Kaposi's sarcoma (KS) and other pseudotumours and to know whether it is of tubercular or non-tubercular origin, as the treatment is entirely different. PMID- 29398760 TI - Primordial Odontogenic Tumor of Mandible; A Case with Proposed Diagnostic Criteria. PMID- 29398761 TI - The Dyadic Construction of Romantic Conflict Recovery Sabotage. AB - This longitudinal study of 100 couples assessed individual and dyadic processes associated with romantic conflict recovery, or how couples behave in the moments following conflict. Couples completed measures of attachment anxiety and avoidance; a conflict discussion during which affect, behavior, and conflict resolution were coded; a cool-down discussion during which post-conflict behavior was coded; and measures of relationship satisfaction and stability one year later. Recovery sabotage (negative behavior and perseveration on conflict in the moments following conflict) was associated with high attachment anxiety and low avoidance. Recovery sabotage was unrelated to affect expressed during conflict and was instead tied to whether partners aired or suppressed grievances. Consistent with the demand-withdraw conflict pattern, recovery sabotage was associated with lower actor conflict avoidance but higher partner conflict avoidance. These effects were independent of conflict resolution, which was not significantly associated with recovery sabotage when other features of conflict were controlled. Recovery sabotage and conflict resolution also differentially predicted satisfaction and stability one year later. Findings suggest recovery sabotage is a distinct, developmentally organized relationship process tied to attachment history and behavioral, rather than affective, transactions between partners during conflict. PMID- 29398762 TI - Intrinsic wheat lipid composition effects the interfacial and foaming properties of dough liquor. AB - Doughs were prepared from a single variety breadmaking flour (cv. Hereward), from three successive harvests (years; 2011, 2012 and 2013). A preparation of the aqueous phase from dough, known as dough liquor (DL), was prepared by ultracentrifugation and its physico-chemical properties were investigated. Surface tension and interfacial rheology, showed that the interface of DL was lipid-dominated and that 2013 DL had a different type of interface to 2011 and 2012 DL. This data was consistent with the improved foam stability observed for 2013 DL and with the types of lipids identified. All foams collapsed quickly, but the most stable foam was from 2013 DL with 89.2% loss in foam, followed by 2011 DL with 91.7% loss and 2012 had the least stable foam with a loss of 92.5% of the foam structure. Glycolipids (DGDG and MGDG) were enriched in 2013 DL, and were also present in DL foam, contributing towards improved stability. Neutral lipids, such as FFAs, were enriched in DL foams contributing towards instability and rapid foam collapse. Baking trials using 2012 and 2013 flour, showed increased loaf volumes and gas bubble diameter in 2013 bread compared to 2012 bread, highlighting the potential impact that surface active polar lipids, enriched in the aqueous phase of dough, could have on improving breadmaking quality. PMID- 29398764 TI - Transatlantic Unity On Display: The "White Legend" and the "Pact of Silence" in Madrid's Museum of the Americas. PMID- 29398763 TI - Early-life immune activation increases song complexity and alters phenotypic associations between sexual ornaments. AB - Early-life adversity can have long-lasting effects on physiological, behavioural, cognitive, and somatic processes. Consequently, these effects may alter an organism's life-history strategy and reproductive tactics.In response to early life immune activation, we quantified levels of the acute phase protein haptoglobin (Hp) during development in male zebra finches (Taeniopygia guttata). Then, we examined the long-term impacts of early-life immune activation on an important static sexual signal, song complexity, as well as effects of early-life immune activation on the relationship between song complexity and a dynamic sexual signal, beak colouration. Finally, we performed mate-choice trials to determine if male early-life experience impacted female preference.Challenge with keyhole limpet hemocyanin (KLH) resulted in increased song complexity compared to lipopolysaccharide (LPS) treatment or the control. Hp levels were inversely correlated with song complexity. Moreover, KLH-treatment resulted in negative associations between the two sexual signals (beak colouration and song complexity). Females demonstrated some preference for KLH-treated males over controls and for control males over LPS-treated males in mate choice trials.Developmental immune activation has variable effects on the expression of secondary sexual traits in adulthood, including enhancing the expression of some traits. Because developmental levels of Hp and adult song complexity were correlated, future studies should explore a potential role for exposure to inflammation during development on song learning.Early-life adversity may differentially impact static versus dynamic signals. The use of phenotypic correlations can be a powerful tool for examining the impact of early-life experience on the associations among different traits, including sexual signals. PMID- 29398765 TI - Increased Educational Attainment among U.S. Mothers and their Children's Academic Expectations. AB - Existing research provides strong evidence that children with more educated parents have higher academic expectations for themselves, but has yet to consider how an increase in the education of lower educated mothers might alter the expectations of their children. In light of the historic increase in U.S. mothers' pursuit of additional education, this study investigates this timely question using data from a nationally representative, intergenerational sample of U.S. children and mothers participating in the National Longitudinal Surveys of Youth (nmothers = 3,265; nchildren = 8,027). Combining random and fixed effects procedures, the findings revealed that that an increase in mothers' educational attainment is linked to an increase in their children's expectations to earn a Bachelor's degree. Increased maternal education did not, however, buffer against the risk that children will downgrade these expectations upon approaching the end of high school. These results have theoretical importance to traditional models of status attainment, which typically view parental education as a stable feature of family background; extend a small but burgeoning literature that explores whether and why increased maternal education improves the mobility prospects of their children; and speak to current two-generation policy approaches that aim to leverage trends in mothers education to reduce inequality for future generations. PMID- 29398766 TI - Missing the Unhealthy? Examining Empirical Validity of Material Deprivation Indices (MDIs) Using a Partial Criterion Variable. AB - This study investigates the empirical validity of the material deprivation indices (MDIs) using a partial criterion variable, namely UHCNIR (unmet health care need due to inadequate resources). This alternative approach helps to assess absolute validity (Type I and II errors) and sources of error in the measurement of poverty for a specific aspect of poverty (in this case inability to receive adequate health care due to affordability problems). A simple mismatch analysis identifies a sizable group, around 1% of the adult EU population, missed by MDIs despite being in UHCNIR. A majority of this 1% experiences not only UHCNIR but also multiple other deprivations, commonly reports having some difficulties making ends meet, and prevalently has a disability or a chronic health problem. The analysis reveals that MDIs miss specifically those "unhealthy poor" since these measures do not include a relevant item, and thus cannot adjust for different needs and costs in health care and account for the distinct poverty experiences of these people. Therefore, the main methodological assumption of MDIs, identifying the people in poverty with only a limited set of key deprivation indicators is not supported by this empirical analysis. PMID- 29398767 TI - Daily Temporal Pathways: A Latent Class Approach to Time Diary Data. AB - Research on daily time and how it is allocated has generally considered the time spent in specific activities. However, social theory suggests that time use is socially patterned whether by social organization, heterogeneity, and/or stratification. Drawing on four broad types of time (contracted, committed, necessary, and free), we use Multinomial Logit Latent Class Analysis to discuss eight daily temporal pathways and associations with individual characteristics. Our analysis highlights the variations and similarities across pathways, the impact of paid work in structuring daily life, the social patterning of sleep and leisure, and socio-demographic profiles of the pathways of working-age Americans. PMID- 29398768 TI - Changes in Social Exclusion Indicators and Psychological Distress Among Homeless People Over a 2.5-Year Period. AB - Although homelessness is inherently associated with social exclusion, homeless individuals are rarely included in conventional studies on social exclusion. Use of longitudinal survey data from a cohort study on homeless people in four major Dutch cities (n = 378) allowed to examine: changes in indicators of social exclusion among homeless people over a 2.5-year period after reporting to the social relief system, and associations between changes in indicators of social exclusion and changes in psychological distress. Multinomial logistic regression analysis was applied to investigate the associations between changes in indicators of social exclusion and changes in psychological distress. Improvements were found in various indicators of social exclusion, whereas financial debts showed no significant improvement. Changes in unmet care needs, health insurance, social support from family and relatedness to others were related to changes in psychological distress. This study demonstrated improvements in various indicators of social exclusion among homeless people over a period of 2.5 years, and sheds light on the concept of social exclusion in relation to homelessness. PMID- 29398769 TI - Setting the Weights: The Women's Capabilities Index for Malawi. AB - Standard indicators of wellbeing such as the QALY for health and GDP per capita for economic development have been increasingly regarded as being too narrow in focus. There is a need to develop multidimensional measures of wellbeing that encompass the full range of factors that make life worth living. This study is part of a project that aims at developing a multidimensional index based on Sen's capability framework to assess women's wellbeing in rural Malawi: the Women's Capabilities Index. The project identifies a set of capabilities relevant to the context; proposes a methodology to measure robustly these capabilities; aggregates the capabilities into a single metric (index); and validates and tests the index. This paper focuses on the weighting and aggregation of the index. Four weighting methods of aggregation are chosen: two normative approaches; a data driven approach; and a hybrid method. The different methods have implications on the results which are critically assessed and compared. This study contributes to the literature on the implications of adopting different methods for setting the weights in composite measures of wellbeing. PMID- 29398770 TI - Measuring Economic Freedom: Better Without Size of Government. AB - The Heritage Foundation and the Fraser Institute measure economic freedom in nations using indices with ten and five indicators respectively. Eight of the Heritage indicators and four of the Fraser-indicators are about specific types of institutional quality, like rule of law, the protection of property, and the provision of sound money. More of these is considered to denote more economic freedom. Both indices also involve indicators of 'big government', or levels of government activities. More of that is seen to denote less economic freedom. Yet, levels of government spending, consumption, and transfers and subsidies appear to correlate positively with the other indicators related to institutional quality, while this correlation is close to zero for the level of taxation as a percentage of GDP. Using government spending, consumption transfers and subsidies as positive indicators is no alternative, because these levels stand for very different government activities, liberal or less liberal. This means that levels of government activities can better be left out as negative or positive indicators. Thus shortened variants of the indices create a better convergent validity in the measurement of economic freedom, and create higher correlations between economic freedom and alternative types of freedom, and between economic freedom and happiness. The higher correlations indicate a better predictive validity, since they are predictable in view of the findings of previous research and theoretical considerations about the relations between types of freedom, and between freedom and happiness. PMID- 29398772 TI - Illicit juvenile weapon possession: The role of serious sanctioning in future behavior. PMID- 29398771 TI - Lessons from in-home air filtration intervention trials to reduce urban ultrafine particle number concentrations. AB - Background: Exposure to airborne ultrafine particle (UFP; <100 nm in aerodynamic diameter) is an emerging public health problem. Nevertheless, the benefit of using high efficiency particulate arrestance (HEPA) filtration to reduce UFP concentrations in homes is not yet clear. Methods: We conducted a randomized crossover study of HEPA filtration without a washout period in 23 homes of low income Puerto Ricans in Boston and Chelsea, MA (USA). Most participants were female, older adults who were overweight or obese. Particle number concentrations (PNC, a proxy for UFP) were measured indoors and outdoors at each home continuously for six weeks. Homes received both HEPA filtration and sham filtration for three weeks each in random order. Results: Median PNC under HEPA filtration was 50-85% lower compared to sham filtration in most homes, but we found no benefit in terms of reduced inflammation; associations between hsCRP, IL 6, or TNFRII in blood samples and indoor PNC were inverse and not statistically significant. Conclusions: Limitations to our study design likely contributed to our findings. Limitations included carry-over effects, a population that may have been relatively unresponsive to UFP, reduction in PNC even during sham filtration that limited differences between HEPA and sham filtration, window opening by participants, and lack of fine-grained (room-specific) participant time-activity information. Our approach was similar to other recent HEPA intervention studies of particulate matter exposure and cardiovascular risk, suggesting that there is a need for better study designs. PMID- 29398774 TI - Pore Functionalized PVDF Membranes with In-Situ Synthesized Metal Nanoparticles: Material Characterization, and Toxic Organic Degradation. AB - Functionalized PVDF membrane platforms were developed for environmentally benign in-situ nanostructured Fe/Pd synthesis and remediation of chlorinated organic compounds. To prevent leaching and aggregation, nanoparticle catalysts were integrated into membrane domains functionalized with poly (acrylic acid). Nanoparticles of 16-19 nm were observed inside the membrane pores by using focused ion beam (FIB). This technique prevents mechanical deformation of the membrane, compared to the normal SEM preparation methods, thus providing a clean, smooth surface for nanoparticles characterization. This allowed quantification of nanoparticle properties (size and distribution) versus depth underneath the membrane surface (0-20 um). The results showed that nanoparticles were uniformly sized and evenly distributed inside the membrane pores. However, the size of nanoparticles inside the membrane pores was 13.9% smaller than those nanoparticles located on the membrane surface. Investigating nanoparticles inside membrane pores increases the accuracy of kinetic analysis and modeling aspects. Furthermore, the Fe/Pd immobilized membranes showed excellent performance in the degradation of chlorinated organics: Over 96% degradation of 3,3',4,4',5 pentachlorobiphenyl (PCB 126) was achieved in less than 15 s residence time in convective flow mode. The regeneration and reuse of this catalytic membrane system were also studied. Particles were examined in XRD upon formation, after deliberate oxidation, and after regeneration. The regenerated sample showed the same crystalline pattern as the original sample. Repeated degradation experiments demonstrated successful PCB 126 dechlorination with nanoparticles regenerated for four cycles with only a small loss in reactivity. It demonstrated that Fe/Pd immobilized membranes have the potential for large-scale remediation applications. PMID- 29398773 TI - The Emergence of Earliest Angiosperms may be Earlier than Fossil Evidence Indicates. AB - Gaps between molecular ages and fossils undermine the validity of time-calibrated molecular phylogenies. An example of the time gap surrounds the age of angiosperm's origin. We calculate molecular ages of the earliest flowering plant lineages using 22 fossil calibrations (101 genera, 40 families). Our results reveal the origin of angiosperms at the late Permian, ~275 million years ago. Different prior probability curves of molecular age calculations on dense calibration point distributions had little effect on overall age estimates compared to the effects of altered calibration points. The same is true for reasonable root age constraints. We conclude that our age estimates based on multiple datasets, priors, and calibration points are robust and the true ages are likely between our extremes. Our results, when integrated with the ecophysiological evolution of early angiosperms, imply that the ecology of the earliest angiosperms is critical to understand the pre-Cretaceous evolution of flowering plants. PMID- 29398775 TI - Influence of platinum group metal-free catalyst synthesis on microbial fuel cell performance. AB - Platinum group metal-free (PGM-free) ORR catalysts from the Fe-N-C family were synthesized using sacrificial support method (SSM) technique. Six experimental steps were used during the synthesis: 1) mixing the precursor, the metal salt, and the silica template; 2) first pyrolysis in hydrogen rich atmosphere; 3) ball milling; 4) etching the silica template using harsh acids environment; 5) the second pyrolysis in ammonia rich atmosphere; 6) final ball milling. Three independent batches were fabricated following the same procedure. The effect of each synthetic parameters on the surface chemistry and the electrocatalytic performance in neutral media was studied. Rotating ring disk electrode (RRDE) experiment showed an increase in half wave potential and limiting current after the pyrolysis steps. The additional improvement was observed after etching and performing the second pyrolysis. A similar trend was seen in microbial fuel cells (MFCs), in which the power output increased from 167 +/- 2 MUW cm-2 to 214 +/- 5 MUW cm-2. X-ray Photoelectron Spectroscopy (XPS) was used to evaluate surface chemistry of catalysts obtained after each synthetic step. The changes in chemical composition were directly correlated with the improvements in performance. We report outstanding reproducibility in both composition and performance among the three different batches. PMID- 29398777 TI - Did Photosymbiont Bleaching Lead to the Demise of Planktic Foraminifer Morozovella at the Early Eocene Climatic Optimum? AB - The symbiont-bearing mixed-layer planktic foraminiferal genera Morozovella and Acarinina were among the most important calcifiers of early Paleogene tropical subtropical oceans. A marked and permanent switch in the abundance of these genera is known to have occurred at low-latitude sites at the beginning of the Early Eocene Climatic Optimum (EECO), such that the relative abundance of Morozovella permanently and significantly decreased along with a progressive reduction in the number of species; concomitantly, the genus Acarinina almost doubled its abundance and diversified. Here we examine planktic foraminiferal assemblages and stable isotope compositions of their tests at Ocean Drilling Program Site 1051 (northwest Atlantic) to detail the timing of this biotic event, to document its details at the species level, and to test a potential cause: the loss of photosymbionts (bleaching). We also provide stable isotope measurements of bulk carbonate to refine the stratigraphy at Site 1051 and to determine when changes in Morozovella species composition and their test size occurred. We demonstrate that the switch in Morozovella and Acarinina abundance occurred rapidly and in coincidence with a negative carbon isotope excursion known as the J event (~53 Ma), which marks the start of the EECO. We provide evidence of photosymbiont loss after the J event from a size-restricted delta13C analysis. However, such inferred bleaching was transitory and also occurred in the acarininids. The geologically rapid switch in planktic foraminiferal genera during the early Eocene was a major evolutionary change within marine biota, but loss of photosymbionts was not the primary causal mechanism. PMID- 29398778 TI - Degradation of poly(beta-amino ester) gels in alcohols through transesterification: A method to conjugate drugs to polymer matrices. AB - Poly(beta amino ester) polymers have received growing attention in the literature, owing to their ease of synthesis, versatile co-monomer selection, and highly tunable degradation kinetics. As such, they have shown extensive potential in many biomedical applications as well. In this work, it is demonstrated for the first time that PbetaAE polymers containing primary and secondary amine groups can undergo degradation by primary alcohols via transesterification mechanism. While this work emphasizes an important aspect of solvent compatibility of these networks, it also represents an interesting, simple mechanism for post synthesis drug incorporation, with riboflavin conjugation being demonstrated as a model compound. PMID- 29398779 TI - Process Intensification of Enzymatic Fatty Acid Butyl Ester Synthesis Using a Continuous Centrifugal Contactor Separator. AB - Fatty acid butyl esters were synthesized from sunflower oil with 1-butanol using a homogeneous Rhizomucor miehei lipase in a biphasic organic (triglyceride, 1 butanol, hexane)- water (with enzyme) system in a continuous setup consisting of a cascade of a stirred tank reactor and a continuous centrifugal contactor separator (CCCS), the latter being used for integrated reaction and liquid-liquid separation. A fatty acid butyl ester yield up to 93% was obtained in the cascade when operated in a once-through mode. The cascade was run for 8 h without operational issues. Enzyme recycling was studied by reintroduction of the water phase from the CCCS outlet to the stirred tank reactor. Product yield decreased over time to an average of 50% of the initial value, likely due to accumulation of 1-butanol in water phase, loss of enzyme due to agglomeration, and the formation of a separate enzyme layer. PMID- 29398780 TI - Collecting wrappers, labels, and packages to enhance accuracy of food records among children 2-8 years in the Pacific region: Children's Healthy Living Program (CHL). AB - The aim was to describe differences in dietary outcomes based on the provision of food wrappers, labels or packages (WLP) to complement data from dietary records (DR) among children from the US Affiliated Pacific. The WLP were intended to aid food coding. Since WLP can be associated with ultra-processed foods, one might expect differences in sodium, sugar, and other added ingredients to emerge. Dietary intakes of children (2-8 y) in Alaska, Hawai'i, Commonwealth of the Northern Mariana Islands, and Guam were collected using parent/caregiver completed 2-day DR. Parents were encouraged to collect WLP associated with the child's intake. Trained staff entered data from the DRs including the WLP when available using PacTrac3, a web application. Of the 1,868 DRs collected and entered at the time of this report, 498 (27%) included WLP. After adjusting for confounders (sex, age, location, education, food assistance), the DRs with WLP had significantly higher amounts of energy (kcal), total fat, saturated fat, added sugar, and sodium. These results suggest the inclusion of WLP enhanced the dietary intake data. The intake of energy, fat, added sugar and sodium derived from processed foods and foods consumed outside the home was better captured in children who had WLP. PMID- 29398776 TI - Bioanalytical applications of surface-enhanced Raman spectroscopy: de novo molecular identification. AB - Surface enhanced Raman scattering (SERS) has become a powerful technique for trace analysis of biomolecules. The use of SERS-tags has evolved into clinical diagnostics, the enhancement of the intrinsic signal of biomolecules on SERS active materials shows tremendous promise for the analysis of biomolecules and potential biomedical assays. The detection of the de novo signal from a wide range of biomolecules has been reported to date. In this review, we examine different classes of biomolecules for the signals observed and experimental details that enable their detection. In particular, we survey nucleic acids, amino acids, peptides, proteins, metabolites, and pathogens. The signals observed show that the interaction of the biomolecule with the enhancing nanostructure has a significant influence on the observed spectrum. Additional experiments demonstrate that internal standards can correct for intensity fluctuations and provide quantitative analysis. Experimental methods that control the interaction at the surface are providing for reproducible SERS signals. Results suggest that combining advances in methodology with the development of libraries for SERS spectra may enable the characterization of biomolecules complementary to other existing methods. PMID- 29398782 TI - A simple plug-in bagging ensemble based on threshold-moving for classifying binary and multiclass imbalanced data. AB - Class imbalance presents a major hurdle in the application of classification methods. A commonly taken approach is to learn ensembles of classifiers using rebalanced data. Examples include bootstrap averaging (bagging) combined with either undersampling or oversampling of the minority class examples. However, rebalancing methods entail asymmetric changes to the examples of different classes, which in turn can introduce their own biases. Furthermore, these methods often require specifying the performance measure of interest a priori, i.e., before learning. An alternative is to employ the threshold moving technique, which applies a threshold to the continuous output of a model, offering the possibility to adapt to a performance measure a posteriori, i.e., a plug-in method. Surprisingly, little attention has been paid to this combination of a bagging ensemble and threshold-moving. In this paper, we study this combination and demonstrate its competitiveness. Contrary to the other resampling methods, we preserve the natural class distribution of the data resulting in well-calibrated posterior probabilities. Additionally, we extend the proposed method to handle multiclass data. We validated our method on binary and multiclass benchmark data sets by using both, decision trees and neural networks as base classifiers. We perform analyses that provide insights into the proposed method. PMID- 29398781 TI - The Effect of a Social-Emotional Intervention on the Development of Preterm Infants in Institutions. AB - This study examined the effect of a social-emotional intervention implemented in one St. Petersburg (Russian Federation) institution (called a Baby Home, BH) on the general behavioral development of preterm children (gestational ages of 30-36 weeks) during their first two years of life. The intervention consisted of training caregivers and implementing structural changes to create a more family like environment. The study included preterm (N = 56) and full-term (N = 93) children from one BH that implemented the intervention and from another BH with no intervention. Children were assessed at 3, 6, 9, 12, 18 and 24 months of age with the Battelle Development Inventory (LINC Associates, 1988). The results showed that the intervention positively influenced the general behavioral development of BH preterm children throughout their first two years of life compared to preterms from the no-intervention BH. Also, results indicated that the intervention effect was developmentally similar for preterm and for full-term children, but preterm children consistently scored lower than full-terms during their first two years living in the BH. In general, our research emphasizes the crucial role of warm, sensitive, and responsive interactions with a constant and emotionally available caregiver for healthy child development for both term and preterm children. PMID- 29398783 TI - Effect of UV-C on the physiology and biochemical profile of fresh Piper nigrum berries. AB - Application of UV-C has been shown to enhance the biochemical profile of various plant materials. This could be used to increase biochemical load, reducing the amount of material required but still impart equivalent flavour. As spices, such as black pepper (Piper nigrum L.), are typically dried to low moisture content to create a stable product for transportation and storage, little work has explored the use of modern postharvest treatments to enhance flavour. In this work, fresh P. nigrum berries were exposed to four UV-C doses (0, 1, 5 and 15 kJ m-2) and subsequently stored at 5 degrees C for ca. 4 weeks. Two separate experiments (early and late season) were conducted across one season. Replicate P. nigrum berry clusters were stored separately within continuously ventilated 13 L boxes. Real-time respiration rate (ex situ), ethylene production, fruit colour and water potential were measured at regular intervals during storage. In addition, piperine and essential oils were assessed using a simple newly developed method which enabled both compound groups to be simultaneously extracted and subsequently quantified. UV-C was found to cause significant changes in colour (from green to brown) whilst also altering the biochemical composition (piperine and essential oils), which was influenced by UV-C dose and berry maturity. Low to medium UV-C doses could potentially enhance flavour compounds in black pepper enabling processors to create products with higher biochemical load. PMID- 29398784 TI - Reconstruction of acquired ischiatic and perineal defects: an anatomical and clinical comparison between gluteal thigh and inferior gluteal perforator flaps. AB - Background: Flap coverage is the gold standard in treating pressure sores, and due to the high recurrence rate, the possibility of multiple surgical procedures should be considered during flap selection. The gluteal thigh (GT) flap has become a workhorse for ischiatic pressure sore treatment at our hospital. Follow up revealed a group of patients presenting recurrence of the pressure sore that needed a second flap. The inferior gluteal artery perforator (IGAP) flap was chosen in this series. The positive experience with both flaps raised the question of which flap should be the first option for the treatment of ischiatic and perineal pressure sores. Methods: IGAP and GT flaps were dissected in 21 fresh human cadavers to allow comparison of anatomical features. In a series of 60 patients, the authors used both the gluteal thigh and the IGAP flap to cover 76 ischiatic and perineal ulcers. Results: The IGAP flap was found to be wider and thicker than the gluteal thigh, but presented a shorter pedicle. All flaps healed uneventfully. Recurrent ulcers were treated successfully with both flaps. Conclusions: Both flaps are suitable for coverage ischiatic and perineal sores. Due to its anatomical features, the IGAP flap should be considered the first choice of treatment for ischiatic ulcers. The gluteal thigh flap should be used in the recurrent sores.Level of Evidence: Level IV, therapeutic study. PMID- 29398785 TI - A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study. AB - Background: Since the management of keloid and hypertrophic scars still remains a difficult clinical problem, there is need for adequate, effective therapy. In this study, we explored for the first time the efficacy and the potential synergetic effect of combined triamcinolone and verapamil for the treatment of hypertrophic and keloid scars. The objective was to assess the efficacy of combined intralesional triamcinolone and verapamil therapy for hypertrophic and keloid scars. Methods: Fifty-eight patients with hypertrophic scars (n = 31) and keloid scars (n = 27) were included. A specific injection therapy scheme was applied. Five follow-up moments were chosen, with a maximum follow-up of nearly 2 years. The effects of combination therapy on scar pliability, thickness, relief, vascularization, surface area, pain, and pruritus were examined by means of the Patient and Observer Scar Assessment Scale (POSAS). Results: Our results reveal a fast and abiding improvement of both keloid and hypertrophic scars after treatment with the combination therapy. All POSAS components showed a reduction in scar score, while scar relief, pain, itchiness, and surface area improved significantly (P < 0.05) in keloids. Significant improvement in hypertrophic scars was found in scar pigmentation, vascularization, pliability, thickness, pain, and surface area. Overall POSAS scores revealed statistically significant decreases between baseline and 3-4 months, 4-6 months, and >12 months after start of therapy in both keloids and hypertrophic scars. Conclusions: This study reveals that combined therapy of triamcinolone and verapamil results in overall significant scar improvement with a long-term stable result.Level of evidence: Level IV, therapeutic study. PMID- 29398786 TI - A Merged Aldol Condensation, Alkene Isomerization, Cycloaddition/Cycloreversion Sequence Employing Oxazinone Intermediates for the Synthesis of Substituted Pyridines. AB - A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels-Alder, and retrograde Diels-Alder with loss of CO2 occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products. PMID- 29398787 TI - All grown up? The fate after 15 years of a quarter of a million UK firms born in 1998. AB - The theory of firm growth is in a rather unsatisfactory state. However, the analysis of large firm-level datasets which have become available in recent years allows us to begin building an evidence base which can, in turn, be used to underpin the development of more satisfactory theory. Here we study the 239 thousand UK private sector firms born in 1998 over their first 15 years of life. A first, and quite striking, finding is the extraordinary force of mortality. By age 15, 90% of the UK firms born in 1998 are dead, and, for those surviving to age 15, the hazard of death is still about 10% a year. The chance of death is related to the size and growth of firms in an interesting way. Whilst the hazard rate after 15 years is largely independent of size at birth, it is strongly affected by the current (age 14) size. In particular, firms with more than five employees are half as likely to die in the next year as firms with less than five employees. A second important finding is that most firms, even those which survive to age 15, do not grow very much. By age 15 more than half the 26,000 survivors still have less than five jobs. In other words, the growth paths - what we call the 'growth trajectories' - of most of the 26,000 survivors are pretty flat. However, of the firms that do grow, firms born smaller grow faster than those born larger. Another striking finding is that growth is heavily concentrated in the first five years. Whilst growth does continue, even up to age 15, each year after age five it involves only a relatively small proportion of firms. Finally, there are two groups of survivors which contribute importantly to job creation. Some are those born relatively large (with more than 20 jobs) although their growth rate is quite modest. More striking though, is a very small group of firms born very small with less than five jobs (about 5% of all survivors) which contribute a substantial proportion (more than one third) of the jobs added to the cohort total by age 15. PMID- 29398788 TI - Examining conscientiousness as a key resource in resisting email interruptions: Implications for volatile resources and goal achievement. AB - : Within the context of the conservation of resources model, when a resource is deployed, it is depleted - albeit temporarily. However, when a 'key', stable resource, such as Conscientiousness, is activated (e.g., using a self-control strategy, such as resisting an email interruption), we predicted that (1) another, more volatile resource (affective well-being) would be impacted and that (2) this strategy would be deployed as a trade-off, allowing one to satisfy task goals, at the expense of well-being goals. We conducted an experience-sampling field study with 52 email-users dealing with their normal email as it interrupted them over the course of a half-day period. This amounted to a total of 376 email reported across the sample. Results were analysed using random coefficient hierarchical linear modelling and included cross-level interactions for Conscientiousness with strategy and well-being. Our first prediction was supported - deploying the stable, key resource of Conscientiousness depletes the volatile, fluctuating resource of affective well-being. However, our second prediction was not fully realized. Although resisting or avoiding an email interruption was perceived to hinder well-being goal achievement by Conscientious people, it had neither a positive nor negative impact on task goal achievement. Implications for theory and practice are discussed. Practitioner points: It may be necessary for highly Conscientious people to turn off their email interruption alerts at work, in order to avoid the strain that results from an activation resistance mechanism afforded by the arrival of a new email.Deploying key resources means that volatile resources may be differentially spent, depending on one's natural tendencies and how these interact with the work task and context. This suggests that the relationship between demands and resources is not always direct and predictable.Practitioners may wish to appraise the strategies they use to deal with demands such as email at work, to identify if these strategies are assisting with task or well-being goal achievement, or whether they have become defunct through automation. PMID- 29398789 TI - The social side of sleep: Elucidating the links between sleep and social processes. AB - Sleep problems have become a public health epidemic with recent data suggesting that over 69% of US adults get less sleep than they need. Despite the important role that sleep plays in our lives, sleep as a variable of interest in interpersonal processes has been historically absent from the psychological literature. Recently, however, researchers have shed some light on the link between sleep and a wide array of social processes. This work illuminates the important role that sleep plays in our social experiences, from basic social perception to complex social interactions. We outline a working model for the bidirectional link between sleep and social processes, including underlying mechanisms, review the recent research that informs this model, and use it to elucidate important next steps to bring together sleep and social psychological research. We also address the pragmatics of measuring sleep for non-sleep researchers. PMID- 29398790 TI - On data processing required to derive mobility patterns from passively-generated mobile phone data. AB - Passively-generated mobile phone data is emerging as a potential data source for transportation research and applications. Despite the large amount of studies based on the mobile phone data, only a few have reported the properties of such data, and documented how they have processed the data. In this paper, we describe two types of common mobile phone data: Call Details Record (CDR) data and sightings data, and propose a data processing framework and the associated algorithms to address two key issues associated with the sightings data: locational uncertainty and oscillation. We show the effectiveness of our proposed methods in addressing these two issues compared to the state of art algorithms in the field. We also demonstrate that without proper processing applied to the data, the statistical regularity of human mobility patterns-a key, significant trait identified for human mobility-is over-estimated. We hope this study will stimulate more studies in examining the properties of such data and developing methods to address them. Though not as glamorous as those directly deriving insights on mobility patterns (such as statistical regularity), understanding properties of such data and developing methods to address them is a fundamental research topic on which important insights are derived on mobility patterns. PMID- 29398791 TI - Plasma Cell Dyscrasias in India-2017 Updates. AB - Rapid advances are being made in the field of plasma cell dyscrasias. Many abstracts pertaining to the laboratory aspects, clinical features, treatment modalities and outcome of plasma cell dyscrasias were presented at Hematocon 2017. All the total of 24 abstracts pertaining to plasma cell dyscrasias presented at the Hematocon 2017 were reviewed. Out of them 10 were original research and 14 were case reports/short case series. The key findings of original research studies conducted in India are being summarized. Exciting research in the field of plasma cell dyscrasias is being carried out by various centers in the country. Data presented on various aspects of research in plasma cell disorders is encouraging. Multicentric research in the field plasma cell dyscrasias should be encouraged to highlight the various aspects of disease biology and challenges in management unique to our country. PMID- 29398792 TI - Hematopoietic Stem Cell Transplantation in India-2017 Annual Update. AB - There has been a steady rise in number of transplant centers in India over last few years. This year many papers related to bone marrow transplants were presented in annual conference of Indian society of Hematology and Transfusion Medicine. All oral and poster presentations which were published were reviewed. There were many publications on autologous transplant, allogeneic transplant and lab aspects of transplant. Centers shared their data on autologous transplants in newly set-up units with resource constraints with good outcomes. Encouraging data from across India is likely to boost more centers to set up transplant centers. PMID- 29398793 TI - Summary and Review of the Abstracts on Disorders of Red Cells and Erythropoiesis Presented at Haematocon 2016-2017. AB - Disorders of red cells and erythropoiesis encompass a vast array of inherited and acquired conditions, several of which are important not just medically but are also concern public health and policy making. Research in India in this area has been plentiful and has, in the past, focused on the laboratory diagnosis and clinical management of these disorders as well as their basic underlying pathogenesis. In the last 2 years too, papers presented at the annual national conferences of the Indian Society of Haematology and Blood Transfusion, ISHBT (Haematocon 2016 and 2017) presented a snapshot of the contemporary research activities that are ongoing in various academic and other centres. This mini review analyzes and summarizes the salient findings of the original research abstracts presented. The papers are divided into broad subsections of alpha- and beta- thalassemias with the hemoglobinopathies, iron deficiency and overload states, red cell membranopathies and enzymopathies, and acquired hemolytic anemias. PMID- 29398794 TI - Fertility Management for the Hemato-Oncologist. AB - For cancer survivors, social parenthood buffers distress and improves quality of life. It is important that physicians dealing with treatment of malignancies are aware of this patient perspective. This review deals with risks of infertility with hematological malignancies and chemotherapy, modes of fertility preservation interventions, time and barriers to referral to specialists offering these interventions. This review aims to guide the hemato-oncologist to make an informed decision with the patient and the partner about fertility preservation at the right time. PMID- 29398795 TI - Comparative Study of Clinico-hematological Features, Molecular Spectrum and Response to Imatinib in Chronic Myelogenous Leukemia Patients: Pediatric and Adolescent Versus Adults. AB - Chronic myelogenous leukemia (CML) is a rare disease in children, accounting for approximately 3% of leukemias in children and adolescents, with an annual incidence of 1 case per million children in western countries. This study was conducted, at PGIMER, Chandigarh. Ninety eight patients, 48 in children and adolescents group, and 50 in adult group were included in the study. Their hematological profiles along with the bone marrow findings were analyzed. The diagnosis of CML was confirmed by cytogenetics and/or molecular analysis. The complete hematological response (CHR) was analyzed at 3 months and cytogentic response (CgR) at 12 months after starting imatinib therapy. Compared to adults, pediatric and adolescent patients were more symptomatic at presentation (93.5 vs. 75%). Among symptomatic patients, massive splenomegaly (>10 cm), higher total leucocyte and platelet counts were seen more frequently in pediatric patients. The most common transcript in both groups was e14a2. The distribution of pediatric and adolescent cases in Sokal, Hasford and EUTOS score, showed only statistically significant difference for low risk Sokal group, which had more patients in pediatric group. Compared to adults, pediatric and adolescent patients had similar CHR rate (91.3 vs. 92%), but showed lesser major CgR rate (90.9 vs. 95.5%) however, this was not statistically significant. PMID- 29398796 TI - Cost of Treatment of Multiple Myeloma in a Public Sector Tertiary Care Hospital of North India. AB - Multiple myeloma (MM) is a neoplastic disorder, which accounts for 13% of all hematological malignancies globally. While, conventional chemotherapy used to be the mainstay treatment for the disease, the landscape of treatment witnessed a paradigm shift with the introduction of high-dose chemotherapy and autologous stem cell transplant (ASCT). In this paper, we present a cost analysis of various services provided to multiple myeloma patients, using either of the two modalities of treatments i.e. conventional chemotherapy or ASCT. Bottom-up costing methodology was used to collect data on all health system resources, i.e. capital or recurrent, which were used to provide various services to MM patients. Capital costs were annualized for their useful life using a discount rate of 5%. Out of pocket expenditure on treatment was also ascertained. Cost was assessed for various services, including outpatient consultation, bed day hospitalization in general ward, high dependency unit intensive care setting and bone marrow transplant unit. Unit costs were calculated from both health system and patient perspective. The overall cost per patient for ASCT (including high dose chemotherapy) and conventional chemotherapy from societal perspective was INR 395,527 (USD 6085) and INR 62,785 (USD 966) respectively. Estimates on cost from our study could be used for planning health services, and evaluating cost effectiveness of different modalities of care for multiple myeloma. PMID- 29398797 TI - Prevalence and Clinical Significance of FLT3 and NPM1 Mutations in Acute Myeloid Leukaemia Patients of Assam, India. AB - Acute Myeloid Leukaemia (AML) is one of the common forms of haematological malignancy in adults. We analysed the prevalence and clinical significance of FMS like tyrosine kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) mutations in AML patients of North East India. Co-prevalence and clinical significance of three recurrent chromosomal translocations namely t(15; 17), t(8; 21), t(16; 16) and expression of epidermal growth factor receptor (EGFR), flow markers were also documented and co-related with disease progress. We analysed bone marrow aspirates or peripheral blood samples from 165 newly diagnosed AML patients. All clinical samples were analysed by Real Time PCR and DNA sequencing based assays. NPM1 was the most frequently detected mutation in the study population (46/165 = 27.90%, 95% CI 20.75-35.05). FLT3 mutations were detected in 27/165 (16.40%, 95% CI 10.45-22.35) patients with internal tandem duplication (FLT3-ITD) in 24/165 (14.60%, 95% CI 8.91-20.29) and FLT3-D835 in 3/165 (1.80%, 95% CI 0-4.13) patients. NPM1 mutations were associated with a higher complete remission rate and longer overall survival (P < 0.01) compared to FLT3-ITD whereas FLT3-ITD showed adverse impact with poor survival rate (P < 0.01), leukocytosis (P < 0.01) and a packed bone marrow. EGFR expression was more in patients with NPM1 mutation compared to FLT3 mutation (P = 0.09). Patients with FLT3 and NPM1 mutations uniformly expressed CD13 and CD33 whereas CD34 was associated with poor prognosis (P <= 0.01) in patients with NPM1 mutation. FLT3-ITD was associated with inferior overall survival. However the clinical significance of FLT3-D835 was not clear due to small number of samples. NPM1 mutation showed better prognosis with increased response to treatment in the absence of FLT3-ITD. PMID- 29398798 TI - Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia and the Role of MRD: A Single Centre Experience from India. AB - Hematopoietic stem cell transplantation (HSCT) is an effective curative option for children with relapsed and high risk acute lymphoblastic leukemia (ALL). The effect of minimal residual disease (MRD) prior to transplantation has a significant impact on the overall outcome. We performed a retrospective analysis of children with ALL who underwent HSCT at our centre from 2002 to 2016. From 2002 to 2008 disease status was determined by morphology and karyotyping and from 2008 onwards by flow cytometry. A total of 46 children were transplanted for ALL at our centre. Of the 19 children who were MRD positive prior to HSCT 5 had a relapse after the transplant. Among the remaining 26 MRD negative children, only one child relapsed post HSCT. The EFS was 66.6% in the MRD negative group and 63.1% in positive group with no significant survival advantage of the first group over the second, (p 0.37). GVHD was the major cause of mortality overall at 56.7% as well as in the MRD negative group at 77.7%(7/9). On the other hand, relapse was the major mortality factor at 71.4%(5/7) in the MRD positive group. Molecular remission prior to HSCT shows a trend towards lesser chance of relapse. We should strive to achieve MRD negative status prior to transplant to improve EFS. However, GVHD is also emerging as a crucial factor and its impact on survival outcome in children undergoing HSCT for ALL needs to be followed up. PMID- 29398799 TI - Evaluating New Markers for Minimal Residual Disease Analysis by Flow Cytometry in Precursor B Lymphoblastic Leukemia. AB - Minimal residual disease is currently the most powerful prognostic indicator in Precursor B lymphoblastic leukemia. Multiparameter flow cytometry is the most commonly used modality. Seventy three B ALL cases and 15 normal marrows were evaluated for expression patterns of leukemia markers (CD38, CD58, CD73) in all 73 cases and CD66c, CD86 and CD123 in 23 cases. CD73 was aberrantly expressed in 90.41% cases and CD86 in 60.87% B ALL cases. Thus addition of these markers in MRD panels can increase the sensitivity of the assay. PMID- 29398800 TI - Role of BAALC Gene in Prognosis of Acute Lymphoblastic Leukemia in Egyptian Children. AB - Acute lymphoblastic leukemia (ALL) is characterized by excess bone marrow lymphoblast cell production. Brain and Acute Leukemia Cytoplasmic gene (BAALC gene) is a recently identified gene on chromosome 8q22.3. The aim of this work was to study the role of BAALC gene in prognosis of ALL in Egyptian children. This study was conducted on 60 children with ALL who were admitted in Oncology Unit in the period from January 2012 to March 2015 including 36 males and 24 females with mean age of 8.74 +/- 2.66 years. For all patients the following were done: Full history taking, thorough clinical examination and laboratory investigations including: complete blood count, LDH, bone marrow aspiration, cytochemistry, immunophenotyping, FISH technique for detection of t(12;21) and t(9;22) and assessment of BAALC gene expression by PCR in bone marrow aspirate mononuclear cells at diagnosis before chemotherapy. Positive BAALC gene expression was found in 36 patients (60%) and negative expression in 24 patients (40%). Positive BAALC gene expression group includes 14 males and 22 females with mean age at presentation of 8.45 +/- 2.77 years while negative BAALC gene expression group includes 18 males and 6 females with mean age at presentation of 8.61 +/- 2.44 years with no significant differences between positive and negative BAALC gene expression groups regarding age, sex, clinical presentations, WBCs and platelets counts, hemoglobin and LDH levels, peripheral blood and BM blast cell counts, immunophenotyping and chromosomal translocations including t(12;21) and t(9;22). There were significant differences in disease outcome between positive and negative BAALC gene expression groups with higher rate of relapse and death and lower rate of complete remission, disease free survival (DFS) and overall survival (OS) in positive BAALC gene expression group compared with negative group (p = 0.028). Multivariate analyses for overall survival and disease free survival shows significant role of BAALC gene expression in OS and DFS. BAALC expression might represent an additional prognostic marker in children with ALL and should be routinely assessed at diagnosis for better prognostic assessment. PMID- 29398801 TI - Neurocognitive Consequences of Childhood Leukemia and Its Treatment. AB - As survival rates have improved in pediatric patients with leukemia, late side effects from chemotherapeutics and radiotherapy have become important considerations. We investigated these side effects and evaluated their impact on neurocognitive functions. The observational study included 68 patients with acute leukemia who were treated at Eskisehir Osmangazi University Medical Faculty. The study also included 62 of the patients' closest age siblings as a control group. Demographic and clinical data, chemotherapy protocol, use of radiotherapy were recorded, neurological and ophthalmological examinations, cranial imaging, electroencephalography, visual evoked potential, and hearing investigations were performed, and neurocognitive functions were evaluated. At least one or more late effects detected by a neurologic abnormality on physical exam, cranial magnetic resonance imaging, neurological tests, or neurocognitive tests was significantly more likely in the patient group (82.4%) compared to the control group (29%, p < 0.001). A higher rate (82.4%) of delayed neurological and cognitive problems occurred in children who received radiotherapy, intrathecal and/or systemic chemotherapy during leukemia treatment compared to age-matched siblings. Patients being treated for leukemia should be periodically evaluated for treatment-related side effects. Prophylactic interventions such cognitive training and maintenance of academic growth may offer the best hope of preventing late effects. PMID- 29398802 TI - Inducing Apoptosis and Decreasing Cell Proliferation in Human Acute Promyelocytic Leukemia Through Regulation Expression of CASP3 by Let-7a-5p Blockage. AB - MicroRNAs (miRNAs) are short and single strand non-coding RNAs that involved in post-transcriptional regulation of gene expression. Dysregulation of miRNA expression is important event in the many of malignant diseases. Up-regulation of Let-7a-5p expression in acute myeloid leukemia in human in previous studies was reported. In this study blockage of Let-7a-5p in human acute promyelocytic leukemia cell line (HL60) was done by using locked nucleic acid (LNA) method and subsequently expression of Let-7a-5p, cell proliferation, apoptosis, necrosis, and CASP3 expression was measured. At three time points 24, 48 and 72 h after LNA anti- Let-7a-5p transfection, assessment of Let-7a-5p expression by qRT real-time PCR was completed. The MTT assay and annexin/PI staining have been performed. Also, CASP3 expression at different time points after LNA anti-Let-7a-5p transfection in HL60 cell line was measured. The results at three-time points after LNA transfection were represented that Let-7a-5p expression was lower in the LNA-anti-Let-7a group compared to the control groups. The cell viability significantly was different between LNA-anti-Let-7a group and control groups. Increasing apoptotic ratio was associated with Let-7a-5p blockage in the LNA-anti Let-7a group compared with control groups. Also, the necrotic ratio was higher in the LNA-anti-Let-7a group rather than the other groups. Western blotting revealed that CASP3 expression associated with Let-7a-5p inhibition. Our results displayed that blockage of Let-7a-5p can reduced cell viability mainly due to the induction of apoptosis and CASP3 up-regulation in HL60 cells. These results can be useful in translational medicine for research of antisense therapy in leukemia. PMID- 29398803 TI - Therapy Related AML/MDS Following Treatment for Childhood Cancer: Experience from a Tertiary Care Centre in North India. AB - Therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) is a devastating late effect of cancer treatment. There is limited data on incidence of t-AML/MDS from India. We retrospectively studied pediatric t AML/MDS at our institute between January 1996 and December 2015. Among 1285 children, 8 patients developed t-AML with a median age of 15.5 years. Overall incidence of t-AML/MDS was 0.62% [0.99% (4/402) in solid tumours and 0.45% (4/883) in leukemia/lymphoma, P = 0.26] with 6390 patient years of follow up. Primary malignancy included sarcoma [bone (2), soft tissue (2)], B-non-Hodgkin lymphoma (2) and acute lymphoblastic leukemia (2). The median cumulative equivalent doses of cyclophosphamide, doxorubicin and etoposide were 6.8, 270 and 2.5 gm/m2 respectively. Two patients received radiotherapy [rhabdomyosarcoma (50 Gy), synovial sarcoma (45 Gy)]. The median latency period to develop t-AML/MDS was 24 months (range 16.5-62 months). Most common FAB morphology was M4/M5 (7/8) and cytogenetic abnormality was MLL rearrangement (4/8). Five patients opted for treatment, 4 achieved remission out of which 2 patients are alive and disease free. Short latency periods, absence of pre-leukemic phase and 11q23 translocations were characteristic in the patients with t-AML/MDS. In view of poor outcome with conventional therapy, novel strategies and prevention need to be considered. PMID- 29398804 TI - Clinical Features and Outcomes of 666 Cases with Therapy-Related Myelodysplastic Syndrome (t-MDS). AB - Therapy-related myelodysplastic syndrome (t-MDS) is a serious complication of chemoradiotherapy for primary diseases. This cohort was aimed to determine the clinical features and outcomes of t-MDS in comparison with de novo MDS. I retrieved data of 666 cases with t-MDS, and 29,703 cases with de novo MDS diagnosed between 2001 and 2012 from the database of U.S. National Cancer Institute. Survival curves were estimated, and Cox proportional hazards model was constructed. Compared with patients with de novo MDS, patients with t-MDS tended to be young (median age; 65 vs. 76 years, p < 0.001), and were more likely to be female-sex (51.4 vs. 44.7%, p = 0.001). Median overall survival (OS) and 5-year OS rate are significantly poorer in t-MDS than de novo MDS (17.2 months and 22% vs. 31 months and 32%, respectively, p < .001). In t-MDS cases, with a median follow-up of 16 months (range 1-143 months), 521 cases (78.2%) had died. Of which, 78 (15%) cases had died from acute myeloid leukemia, and 66 (12.7%) cases had died from solid cancers. Of the total 66 cases died from solid cancers; 19 cases (28.8%) died from cancer of lung/bronchus, 11 cases (16.7%) breast cancers, and 10 cases (15.2%) ovarian cancer. In a multivariate analysis adjusted for clinical features, calendar period and radiotherapy, the hazard of mortality was significantly low in de novo MDS compared with t-MDS (hazard ratio 0.59; p < .001). In conclusions, t-MDS is a distinct entity of MDS in terms of clinical characteristics and prognosis. PMID- 29398805 TI - C-Window Peaks on CE-HPLC are Extremely Rare in Northern India, and Only Infrequently Represent HbC. AB - Hemoglobin C (HbC, HBB:c.19G > A) is a structural variant that has been reported rarely from India. This was a retrospective review of all high performance liquid chromatography (HPLCs) submitted over a 14 year period to a tertiary care center in North India with an aim of finding hemoglobins that elute in the C-window. Of the 32,364 HPLCs screened, 6 cases showed peaks in the C-window. Of these 6 cases, only two cases contained hemoglobin C. These was one case each of HbC/beta thalassemia and compound heterozygosity for HbC and HbD. There were 4 cases which showed very similar red cell indices and chromatograms with multiple peaks eluting in D-window, C-window and an additional peak with a retention time of 4.74 min. These four cases were compound heterozygous for an alpha chain variant HbQ-India and a beta-chain variant HbD. PMID- 29398806 TI - Lower Transcranial Doppler Flow Velocities in Sickle Cell Anemia Patients on Hydroxyurea: Myth or Fact. AB - Transcranial Doppler (TCD) detects stroke risk in patients with sickle cell anemia (SCA). Hydroxyurea therapy has the ability to induce increased levels of fetal hemoglobin in sickle cells thus decreasing tendency for red cell sickling. This study aimed to evaluate TCD findings in SCA patients on hydroxyurea and correlate the time-averaged mean velocity (TAMV) with their hematological parameters. Forty SCA patients of both sexes, aged 16-22 years with no history of stroke were screened with TCD for an elevated TAMV, divided into: Group T (20 patients on blood transfusion); and Group H (20 patients on daily hydroxyurea). For all, full medical history, clinical examination, hemoglobin, hematocrit, leukocytes, platelets, fetal hemoglobin and sickling test, in addition TCD to describe the pattern of cerebral blood flow abnormalities were done. TAMV in all cerebral arteries were significantly higher in Group T than Group H, the highest TAMV (147.5 +/- 57.09 cm/s) was found in the right middle cerebral artery and correlated negatively with hematocrit in Groups H (P < 0.001). There were 2 (10%) abnormal TAMV results and 5 (25%) conditional in Group T, while all results were normal in Group H. Hydroxyurea therapy may lower TCD velocities and prevent the risk of primary stroke in SCA patients. PMID- 29398807 TI - Value of Soluble Transferrin Receptors and sTfR/log Ferritin in the Diagnosis of Iron Deficiency Accompanied by Acute Infection. AB - There are many causes of anemia; the most common of these are acute and chronic infections, iron deficiency, or both. Identifying the cause is a very important step in management of anemia. So, we evaluated the usefulness of soluble transferrin receptor (sTfR) and of the sTfR/log ferritin in the diagnosis of iron deficiency anemia accompanied by acute infection. This study was conducted on 131 children aged 2-11 years old from those who attended the pediatric outpatient clinics in Menoufia university hospital. Hematological indices, iron balance and sTfR were evaluated and the sTfR/log F was calculated for each examined child. From the examined children four groups were distinguished: Group I (control): included 34 healthy children with normal iron status (66.7% males, age 4.2 +/- 1.2). Group II (IDA): included 38 children diagnosed as iron deficiency anemia (47.4% males, age 4.9 +/- 1.6). Group III (IDA + infection): included 26 children with infectious disease (upper respiratory tract infection, otitis media, pneumonia, stomatitis, and urinary tract infection) and anemia meeting criteria of IDA (50% males, age 4.2 +/- 0.7). Group IV (anemia + infection): included 33 children with infectious anemia without iron deficiency (56.2% males, age 5.06 +/ 1.4). It was proved that sTfR and sTfR/log Ferritin were significantly higher in children with anemia due to iron deficiency, and in those with infection + iron deficiency, versus those with infectious anemia or in healthy children. The use of sTfR and sTfR/log ferritin improves the diagnosis of IDA in pediatric patients, especially in the presence of coexisting acute infection. PMID- 29398808 TI - Diagnosis of Compound Heterozygous Hb Tak/beta-Thalassemia and HbD-Punjab/beta Thalassemia by HbA2 Levels on Capillary Electrophoresis. AB - A misdiagnosis of beta-thalassemia carrier in samples with Hb Tak and HbD-Punjab, the beta-variants, can be a cause of inappropriate genetic counseling thus having a new case of beta-thalassemia major. A capillary electrophoresis (CE) is very efficient in separating and quantifying HbA2. In this study, HbA2 levels of samples which were doubted for compound heterozygous Hb Tak/beta-thalassemia or heterozygous HbD-Punjab/beta-thalassemia were measured and compared between CE and high performance liquid chromatography (HPLC). The molecular confirmation for Hb Tak, HbD-Punjab and beta-thalassemia codons 17 (A > T), 41/42 (-TCTT), 71/72 (+A) and IVSI-nt1 (G > T) mutations and 3.4 kb deletion were also performed. Based on DNA analysis, 3 cases were diagnosed as compound heterozygous Hb Tak/beta-thalassemia and one for HbD-Punjab/beta-thalassemia. The elevated HbA2 levels were found in all 4 samples with rages of 4.6-7.3% on CE while those were not found on HPLC. Thus, the elevated HbA2 measured by CE can be used as a screening parameter for differentiating the homozygote of Hb Tak and HbD-Punjab from the compound heterozygote of these hemoglobinopathies and beta-thalassemia. PMID- 29398809 TI - A Study of Platelet Indices in Type 2 Diabetes Mellitus Patients. AB - Altered platelets have been reported in patients with diabetes mellitus and has been considered as a 'prothrombotic state' with enhanced platelet reactivity. They have been associated with increased risk of vascular complications in these patients. Platelet indices correlate with functional status of platelets and is an emerging risk factor of vascular complications in diabetes. The study was undertaken to know the efficacy of platelet analysis in assessing the prognosis of diabetes mellitus. A prospective hospital based study of platelet parameters MPV, PDW and P-LCR was carried out on 280 cases diagnosed with Type 2 diabetes Mellitus and 280 controls with normal blood glucose levels. The blood glucose levels and HbA1c level were also measured. Statistical evaluation was performed by using Student's unpaired t test and Pearson correlation test. The average age of presentation with type 2 diabetes mellitus was 53 +/- 5.7 years. The mean duration of diabetes was 4.7 +/- 2.5 years. MPV, PDW and P-LCR were significantly higher in diabetics compared to non diabetics (11.3 +/- 1.0 vs. 9.0 +/- 0.6, 14.2 +/- 2.5 vs. 10.7 +/- 0.7 fl, 35.0 +/- 8.1 vs. 23.0 +/- 2.4%). Among the diabetics, MPV, PDW and P-LCR were higher in those with complications as compared to those without complications, which was not statistically significant. The higher values of MPV, PDW and P-LCR indicates that they serve as better risk indicator of initial vascular complications in diabetes mellitus patients and can be used as a simple and cost effective tool to assess vascular events. PMID- 29398810 TI - Eosinophil Granulocyte and NK Cell-Mediated Platelet Destruction in Immune Thrombocytopenia. AB - To investigate the contribution and mechanism of eosinophil granulocytes and NK cells-mediated cytotoxicity to the pathogenesis of ITP. Mononuclear cells and platelets were prepared from the bone marrow of 16 ITP patients and 10 healthy controls. Separately, eosinophil granulocytes and NK cells were selected with magnetic microbeads. As the target cells, the autologous platelets were cultured with eosinophil granulocytes and NK cells respectively for 6 h and then stained with annexin V. Ratio of platelets expressing annexin V was determined by flow cytometry. The fraction of NK cells expressing perforin, granzyme B, FasL and TNF were determined by flow cytometry. Human eosinophil cationic protein (ECP) level in the bone marrow was determined by ECP ELISA kit. The annexin V positive platelet ratio of the ITP group was significantly higher than that of the control group; the expression rates of granzyme B, perforin, FasL on NK cells of the ITP group were significantly higher than those of the control group. Expression of human ECP in bone marrow of immune thrombocytopenia patients was higher than that of healthy controls. NK cells and eosinophil granulocytes are activated in ITP and might be involved in the pathogenesis of ITP. PMID- 29398811 TI - Pilot Study on the Performance of a New System for Image Based Analysis of Peripheral Blood Smears on Normal Samples. AB - Image analysis based automated systems aiming to automate the manual microscopic review of peripheral blood smears have gained popularity in recent times. In this paper, we evaluate a new blood smear analysis system based on artificial intelligence, ShonitTM by SigTuple Technologies Private Limited. One hundred normal samples with no flags from an automated haematology analyser were taken. Peripheral blood smear slides were prepared using the autostainer integrated with an automated haematology analyser and stained using May-Grunwald-Giemsa stain. These slides were analysed with ShonitTM. The metrics for evaluation included (1) accuracy of white blood cell classification for the five normal white blood cell types, and (2) comparison of white blood cell differential count with the automated haematology analyser. In addition, we also explored the possibility of estimating the value of red blood cell and platelet indices via image analysis. Overall white blood cell classification specificity was greater than 97.90% and the precision was greater than 93.90% for all the five white blood cell classes. The correlation of the white blood cell differential count between the automated haematology analyser and ShonitTM was found to be within the known inter cell counter variability. ShonitTM was found to show promise in terms of its ability to analyse peripheral blood smear images to derive quantifiable metrics useful for clinicians. Future enhancement should include the ability to analyse abnormal blood samples. PMID- 29398813 TI - A Study of Preoperative Autologous Blood Donation Timing. AB - This study aims to determine the safe and effective autologous blood drawing time for preoperative autologous blood donation (PABDs) by comparing the outcome of two different schedules of PABDs. A total of 144 patients who underwent elective surgery (radical resection of digestive tract tumor, lumbarspinesurgery and Intracranial tumor resection) were retrospectively reviewed. 88 patients had donated autologous blood 2 days before the operation (group 1); 56 patients had donated autologous blood more than 3 days before the operation (group 2). Hb and Hct before the operation and on postoperative days one and three, allogeneic blood transfusions, total bleeding, postoperative length of stay, and length of stay were measured and compared. Hb at postoperative day one was lower in group 2 than in group 1 (P < 0.05). Furthermore, Hb in group 1 was higher at postoperative day one than at postoperative day three (P < 0.05). Differences in postoperative Hct, allogeneic blood transfusions, total bleeding and postoperative length of stay between these two groups were not statistically significant (P > 0.05)., The difference in the average number of postoperative hospitalization days between these two groups was not statistically significant (P > 0.05). The 2 days of PABD did not lead to any adverse recovery effect. It would be helpful to conduct preoperative autologous blood transfusions. PMID- 29398814 TI - Role of Automated Therapeutic Red Cell Exchange in the Setting of Acute Methemoglobinemia: Our Experience. AB - Methemoglobinemia, an altered state of hemoglobin resulting in impaired oxygen delivery to the tissues can be congenital or following exposure/ingestion of various oxidant drugs or toxins. One of the earliest signs of methemoglobinemia is generalized cyanosis not improved on oxygen supplementation and presence of normal PO2 on acid blood-gas analysis. Here, we report two cases of acquired methemoglobinemia following poisoning and our experience of managing them with automated therapeutic red cell exchange. PMID- 29398812 TI - Evaluation of the Role of Novel Aprotic Dimethyl Sulfoxide in Cutaneous Antisepsis Protocols Prior to Blood Donor Phlebotomy with Isopropyl Alcohol, Povidone Iodine or Chlorhexidine. AB - The study was planned to measure the reduction of the load of bacterial flora on the blood donor's arm quantitatively using a three step protocol of donor arm cleansing incorporating either 70% isopropyl alcohol (IPA) or 5% w/v povidone iodine (PVI, 0.5% w/v available iodine) or 4% chlorhexidine gluconate (CHG) with or without the addition of 5% dimethyl sufloxide (DMSO). Single blind randomized study after obtaining ethical clearance, using the Miles and Misra technique for quantification and matrix assisted laser desorption ionization-mass spectrometry for identification of colony morphotypes on blood donor's skin. The mean pre cleansing colony forming units (CFUs) was 89,318 and mean post-cleansing CFUs was 132, with a mean reduction of 99.85% with a mean log reduction of 3.24 (95% CI 2.01-4.47) at a P value of <0.0001. The post-cleansing CFUs was reduced to zero in all 34 samples in the protocol using CHG with DMSO, in 23 of 31 samples in the protocol using PVI with DMSO and 19 of 29 samples in the protocol using IPA with DMSO. The difference in means of the reduction of CFUs in protocols using CHG with DMSO compared with protocols using PVI or IPA with DMSO and PVI or IPA without DMSO was statistically significant with P value of 0.006, 0.0009, 0.015 and 0.05 respectively. The enhanced cutaneous antisepsis effect of CHG when complimented with DMSO in presence of IPA using the three step protocol of donor arm cleansing could stimulate more research and utilization of this as an additional safety towards the prevention of the problem of bacterial contamination of blood and blood components. PMID- 29398815 TI - Chediak-Higashi Syndrome in Accelerated Phase. PMID- 29398816 TI - Stodtmeister Cells (Polymorphs with Pelger-Huet Anomaly) Showing "Faggots" in Mixed Phenotypic Acute Leukemia (T/Myeloid). AB - "Faggot" cells, named for the resemblance of multiple Auer rods to a bundle of sticks, are often considered sine qua non for acute promyelocytic leukemia. However, blasts in other acute myeloid leukemias rarely also show faggot cells. This case demonstrates faggot cells in stodtmeister cells in mixed phenotypic acute leukemia. In addition to being uncommon, this case also highlights the importance of immunophenotyping and genetic analysis in avoiding misdiagnosis and inappropriate therapy. PMID- 29398817 TI - Griscelli Syndrome with Fibronodular Sclerodermatous Chronic Graft Versus Host Disease. PMID- 29398818 TI - An Unusual Cause of Central Nervous System Infection During Acute Myeloid Leukemia Induction Chemotherapy: Acanthamoeba Brain Abscess. PMID- 29398819 TI - Relapsed Myeloma with Hepatic Involvement and Tumour Lysis with Bortezomib. PMID- 29398820 TI - Extensive Megakaryocytic Emperipolesis in an Adult Male with Immune Thrombocytopenia. PMID- 29398821 TI - Hemophagocytic Lymphohistiocytosis: A Confusing Problem of the Diagnosis of Visceral Leishmaniasis. PMID- 29398822 TI - Fractures and Low Bone Mineral Density in Patients with Beta Thalassemia Major. PMID- 29398823 TI - Importance of Indigenous Lectin Panel in Immunohematology. PMID- 29398824 TI - Diagnostic and Prognostic Value of Serum Thymidine Kinase 1 in Cancer Patients. PMID- 29398825 TI - Leukocyte Cell Population Data Provide Clues for Myelodysplastic Syndrome in a 79 Year-old Male. PMID- 29398826 TI - Myeloid Sarcoma Presented as Generalized Lymphadenopathy: Mimicking Malignant Lymphoma. PMID- 29398827 TI - Diagnostic Dilemma in Ambiguous Lineage Acute Leukemia: A Case Report. PMID- 29398828 TI - Ghosal Hemato-diaphyseal Dysplasia: A Rare Variety of Hypoplastic Anemia with Good Response to Steroid Therapy. PMID- 29398829 TI - ABO Hemolytic Disease of Fetus and Newborn; Still a Diagnostic Dilemma: A Case Report. PMID- 29398830 TI - A Compound Heterozygous Asian Indian Inversion Deletion Ggamma(Agammadeltabeta)0 with beta-Thalassemia in Central India: A Case Report. PMID- 29398831 TI - Florid Plasmacytosis in Angioimmunoblastic T Cell Lymphoma: A Diagnostic Conundrum. PMID- 29398832 TI - Pediatric cardiac intervention in a case of congenital factor VII deficiency: a challenge to overcome. PMID- 29398833 TI - Diagnostic Dilemmas in Aggressive Large B Cell Neoplasms with Enigmatic Immunohistochemical Profile: How Far Should We Investigate? PMID- 29398834 TI - Oxidative enzymes activity during abiotic and biotic stresses in Zea mays leaves and roots exposed to Cu, methyl jasmonate and Trigonotylus caelestialium. AB - The activities of antioxidative enzymes, i.e. superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and guaiacol peroxidase (GPX), in the leaves and roots of Zea mays L. plants exposed to abiotic (methyl jasmonate, MJ, or/and copper, Cu) and biotic (Trigonotylus caelestialium) factors were examined. The contribution of MJ as a signal molecule in the defense mechanism against abiotic and biotic stresses was studied. All plants were cultivated hydroponically and divided into three groups: not treated by abiotic factors (control), treated by MJ only (MJ) and by MJ and Cu (MJ + Cu) and in each group half of the plants were exposed to T. caelestialium attack. The enzymatic activities of SOD, CAT, APX, and GPX in the leaves were higher in the insect treated than non-insect-treated control plants, but lower in both MJ + Cu- or MJ- and insect-treated plants. In the roots, the enzyme activities were elevated in all insect-treated plants with the highest rise in MJ + Cu, in comparison with the MJ-treated plants. The results showed that MJ and MJ + Cu were efficient in reducing the activity of the antioxidative enzymes in the leaves under the insect influence by elevating enzyme activity in the roots. PMID- 29398835 TI - Redox metabolic and molecular parameters for screening drought tolerant indigenous aromatic rice cultivars. AB - The present work makes an effort to assess and standardize some redox metabolic and molecular parameters for screening drought tolerant indigenous aromatic rice cultivars of West Bengal, India. PEG-induced dehydration stress during early germination caused disruption of redox-homeostasis and oxidative damage in four IARVs (Jamainadu, Tulaipanji, Sitabhog and Badshabhog) by enhancing the accumulation of pro-oxidants [assessed in terms of oxidation of 2',7' dichlorofluorescindiacetate (DCFDA), accumulation of [Formula: see text] and H2O2 and in situ staining of reactive oxygen species (ROS) in germinating tissue], significant reduction of antioxidative defence (total antioxidant and radical scavenging capacity, total thiol content and activities of antioxidative defence enzymes) and aggravating protein oxidation and lipid peroxidation (assessed in terms of free carbonyl content and accumulation of thiobarbituric acid reactive substances). When compared between the indigenous aromatic rice cultivars, a clear trend in differential redox regulatory properties in which ROS-antioxidant interaction acts at metabolic interface for redox homeostasis was observed in the order Badshabhog > Tulaipanji > Sitabhog > Jamainadu. Moreover, when the efficacy of ascorbate-glutathione cycle for scavenging H2O2 generated during dehydration stress was assessed and compared between the landraces exposed to PEG-induced dehydration stress in germinating tissue, it also exhibited almost the same trend with the landrace Tulaipanji and Badsabhog exhibiting maximum and Jamainadu the minimum efficiencies of the redox cycle. The indigenous aromatic rice cultivars Tulaipanji and Badsabhog resist dehydration stress better than the other two landraces due to its early preparedness to combat oxidative stress by up regulating expression of genes of some enzymes of ascorbate-glutathione cycle along with some other antioxidative enzymes. A model of redox homeostasis in which ROS-antioxidant (ascorbate-glutathione system) acts at metabolic interface for up-regulation of antioxidative gene expression necessary for differential drought stress tolerance among the indigenous aromatic rice varieties is suggested. PMID- 29398836 TI - Grape response to salinity stress and role of iron nanoparticle and potassium silicate to mitigate salt induced damage under in vitro conditions. AB - Grape softwood cuttings of Khoshnaw cultivar were cultured using tissue-culture methods to study the effect of iron nanoparticles and potassium silicate under salinity conditions during the 2015-2016 growing season. The treatments consisted of salinity stress (0, 50, and 100 mM NaCl), nanoparticles of iron (0, 0.08, and 0.8 ppm), and potassium silicate (0, 1, 2 mM). The results also showed that the application of iron nanoparticles and potassium silicate significantly increased the total protein content and reduced proline, enzymatic antioxidant activity and hydrogen peroxide. Salinity stress reduced membrane stability index while increased malondialdehyde content. Increase of membrane stability index and reduction of malondialdehyde content were obtained for 2 mM potassium silicate and 0.8 ppm iron nanoparticle. Iron and potassium silicate were shown to lower the sodium content and increase the potassium content under salinity-stress conditions. The highest ratio of sodium to potassium was observed in plants under salinity conditions (100 mM) treated with neither iron nanoparticles nor potassium silicate; conversely, the lowest ratio was achieved in plants treated with both 0.8 ppm iron nanoparticles with 1 mM and 2 mM potassium silicate under non-stress conditions. These results indicate that the application of micronutrients in stressful conditions is a suitable method to compensate for the negative effects of salinity stress. Tissue culture in this study was shown to be an economically efficient and applicable technique for producing grape softwood cuttings to be used in experiments. PMID- 29398837 TI - Impact of combined stress of high temperature and water deficit on growth and seed yield of soybean. AB - Elevated temperature and water deficit are the major abiotic factors restricting plant growth. While in nature these two stresses often occur at the same time; little is known about their combined effect on plants. Therefore, the main objective of the current study was to observe the effect of these two stresses on phenology, dry matter and seed yield in soybean. Two soybean genotypes JS 97-52 and EC 538828 were grown under green-house conditions which were maintained at different day/night temperatures of 30/22, 34/24, 38/26 and 42/28 degrees C with an average temperature of 26, 29, 32 and 35 degrees C, respectively. At each temperature, pots were divided into three sets, one set was unstressed while second and third set were subjected to water stress at vegetative and reproductive stage, respectively. As compared to 30/22 degrees C increase in temperature to 34/24 degrees C caused a marginal decline in leaf area, seed weight, total biomass, pods/pl, seeds/pl, harvest index, seeds/pod and 100 seed weight. The decline was of higher magnitude at 38/26 and 42/28 degrees C. Water stress imposed at two growth stages also significantly affected dry matter and yield. The highest average seed yield (10.9 g/pl) was observed at 30/22 degrees C, which was significantly reduced by 19, 42 and 64% at 34/24, 38/24 and 42/28 degrees C, respectively. Similarly, compared to unstressed plants (11.3 g/pl) there was 28 and 74% reduction in yield in plants stressed at vegetative and reproductive stage. Thus, both temperature and water stress affected the growth and yield but the effect was more severe when water stress was imposed at higher temperatures. JS 97-52 was more affected by temperature and water stress as compared to EC 538828. Though drought is the only abiotic factor that is known to affect the water status of plants, but the severity of the effect is highly dependent on prevailing temperature. PMID- 29398838 TI - Alternaria brassicae interactions with the model Brassicaceae member Arabidopsis thaliana closely resembles those with Mustard (Brassica juncea). AB - Alternaria leaf blight, a disease of oilseed Brassicas is caused by a necrotrophic phytopathogenic fungus Alternaria brassicae. The details of its pathogenesis and defence responses elicited in the host upon infection have not been thoroughly investigated. Here, Arabidopsis accession Gre-0 was identified to be highly susceptible to A. brassicae. A comparative histopathological analysis for disease progression and plant responses to A. brassicae in Arabidopsis and Brassica juncea revealed significant similarities between the two compatible pathosystems. Interestingly, in both the compatible hosts, ROS accumulation, cell death and callose deposition correlated with the development of the disease. Based on our results we propose that Arabidopsis-Alternaria brassicae can be an apt model pathosystem since it emulates the dynamics of the pathogen interaction with its natural host- Brassicas. The existing genetic diversity in Arabidopsis can be a starting point to screen for variation in responses to Alternaria leaf blight. Furthermore, several tools available for Arabidopsis can facilitate the dissection of genetic and molecular basis of resistance. PMID- 29398839 TI - Expression pattern of salt tolerance-related genes in Aegilops cylindrica. AB - Aegilops cylindrica, a salt-tolerant gene pool of wheat, is a useful plant model for understanding mechanism of salt tolerance. A salt-tolerant USL26 and a salt sensitive K44 genotypes of A. cylindrica, originating from Uremia Salt Lake shores in Northwest Iran and a non-saline Kurdestan province in West Iran, respectively, were identified based on screening evaluation and used for this work. The objective of the current study was to investigate the expression patterns of four genes related to ion homeostasis in this species. Under treatment of 400 mM NaCl, USL26 showed significantly higher root and shoot dry matter levels and K+ concentrations, together with lower Na+ concentrations than K44 genotype. A. cylindrica HKT1;5 (AecHKT1;5), SOS1 (AecSOS1), NHX1 (AecNHX1) and VP1 (AecVP1) were partially sequenced to design each gene specific primer. Quantitative real-time PCR showed a differential expression pattern of these genes between the two genotypes and between the root and shoot tissues. Expressions of AecHKT1;5 and AecSOS1 was greater in the roots than in the shoots of USL26 while AecNHX1 and AecVP1 were equally expressed in both tissues of USL26 and K44. The higher transcripts of AecHKT1;5 in the roots versus the shoots could explain both the lower Na+ in the shoots and the much lower Na+ and higher K+ concentrations in the roots/shoots of USL26 compared to K44. Therefore, the involvement of AecHKT1;5 in shoot-to-root handover of Na+ in possible combination with the exclusion of excessive Na+ from the root in the salt-tolerant genotype are suggested. PMID- 29398840 TI - Desiccation-induced ROS accumulation and lipid catabolism in recalcitrant Madhuca latifolia seeds. AB - Loss of viability in desiccation-sensitive seeds of Madhuca latifolia (Roxb.) J. F. Macbr., an important multipurpose tropical tree, was correlated with seed water content (WC). WC declined from 0.59 to 0.19 g g-1 fresh mass, 35 days after harvest from mother plant, at ambient conditions (temperature 25 +/- 2 degrees C, relative humidity 50 +/- 2%). The desiccation-induced reduction in viability was related with an accumulation of reactive oxygen species (ROS) that promoted lipid peroxidation associated loss of membrane integrity. Conducted study revealed 1.6-19 folds rise in lipid peroxidized products in desiccated M. latifolia seeds, and was found to be linked inversely with WC and germination percentage. Additionally, increased activities (7 and 13 folds) of lipid hydrolyzing enzymes; lipase (EC 3.1.1.3) and lipoxygenase (EC 1.13.11.12) respectively, were discernible in desiccating M. latifolia seeds. In summary, increased ROS, lipid oxidation, lipase and lipoxygenase were strongly correlated with viability loss in desiccating M. latifolia seeds. PMID- 29398841 TI - Plants genotoxicity as pollution bioindicator in Jordan using comet assay. AB - This study aimed to assess genotoxicity in wild plants grown in Jordan as a pollution bioindicator. Comet assay was used to evaluate the level of DNA damage in plants collected from different areas in Jordan. Significant differences in plant DNA damage index and frequency were observed among sites of collection. Results show that plants collected from Aqaba back road and Ghour Assaal had significantly higher damage values. In contrast, plants collected from Wadi Rum, Al Naqab Heights, Swaimeh/Deadsea and Alshoneh Aljanobyeh showed low levels of DNA damage. A similar trend was observed for lipid peroxidation rates. Furthermore, heavy metal analysis showed that plants collected from Aqaba back road and Aqaba airport had the highest Al, Cr, Fe, Cu, Zn, Cd and Pb contents. A significant correlation was observed between DNA Damage Index, DNA Damage Frequency, lipid peroxidation rate, soil Cu, Cd and Pb biomarkers, indicating that heavy metals pollution is a major source for genotoxicity in these plant species. Finally, our results approved the feasibility of using plants and Comet assay system as a diagnostic tool for pollution in any environment adversely affected by different pollution sources. PMID- 29398842 TI - Silicon deposition in roots minimizes the cadmium accumulation and oxidative stress in leaves of cowpea plants. AB - Silicon (Si) frequently accumulates in plants tissues, mainly in roots of dicotyledons, such as cowpea. By contrast, Cadmium (Cd) is a metal that is extremely toxic to plant metabolism. This research aims to investigate if the deposition of Si in root can reduce Cd contents and minimize its negative effects on leaves, measuring gas exchange, chlorophyll fluorescence, antioxidant metabolism, photosynthetic pigments and growth, which may explain the possible role of Si in the attenuation of Cd toxicity in cowpea. This study had a factorial design, with all factors completely randomized and two Cd concentrations (0 and 500 uM Cd, termed as - Cd and + Cd, respectively) and three Si concentrations (0, 1.25 and 2.50 mM Si). Si reduced Cd contents in the roots and in other plant organs, such as stems and leaves. The Si contents were highest in roots, followed by stems and leaves, which was explained by the passive absorption of Si. The application of Si promoted increase in both the macro- and micronutrient contents in all tissues, suggesting that Si mitigates the effect of Cd on nutrient uptake. Si attenuated Cd-mediated effects on light absorption of photosystem II (PSII), increasing the effective quantum yield of PSII photochemistry and the electron transport rate. Additionally, toxic effects induced by Cd on gas exchange were mitigated by the action of Si. Plants treated with Cd + Si showed increase in the activities of antioxidant enzymes and reductions in oxidant compounds; these modifications were promoted by Si via detoxification mechanisms. Increases in the photosynthetic pigments and growth of plants treated with Si and exposed to Cd stress were detected and were due to the reduced deterioration of cell membranes and maintenance of chloroplasts, which had positive repercussions on growth and development. This study validated the hypothesis that the accumulation of Si in roots induces benefits on metabolism and alleviates the toxic effects caused by Cd in leaves of cowpea. PMID- 29398843 TI - Phytotoxicity of pesticides mancozeb and chlorpyrifos: correlation with the antioxidative defence system in Allium cepa. AB - Pesticides are a group of chemical substances which are widely used to improve agricultural production. However, these substances could be persistent in soil and water, accumulative in sediment or bio-accumulative in biota depending on their solubility, leading to different types of environmental pollution. The present study was done to assess the impact of pesticides-mancozeb and chlorpyrifos, via morphological and physiological parameters using Allium cepa test system. Phytotoxic effects of pesticides were examined via germination percentage, survival percentage, root and shoot length, root shoot length ratio, seedling vigor index, percentage of phytotoxicity and tolerance index. Oxidative stress on Allium seedlings caused by pesticides was also assessed by investigating the activity of antioxidative enzymes viz. catalase, peroxidase and superoxide dismutase. Correlation was worked out between morphological parameters and antioxidative enzymes to bring out the alliance between them. Mancozeb and chlorpyrifos concentrations were significantly and positively correlated with the activity of antioxidative enzymes and negatively correlated with morphological parameters. Significant positive correlation between various morphological parameters showed their interdependency. However, negative correlation was obtained between activity of antioxidative enzymes and morphological parameters. The enzymes however, showed positive correlation with each other. Based on our result we can conclude that all morphological parameters were adversely affected by the two pesticides as reflected by phytotoxicity in Allium. Their negative correlation with activity of antioxidative enzymes indicates that upregulation of antioxidative enzymes is not sufficient to overcome the toxic effect, thereby signifying the threat being caused by the regular use of these pesticides. PMID- 29398844 TI - Transcriptome analysis and development of simple sequence repeat (SSR) markers in Zingiber striolatum Diels. AB - Illumina-based paired-end sequencing technology was used for the high-throughput transcriptome sequencing of combined Zingiber striolatum Diels tissues (i.e., root, stem, leaf, flower, and fruit tissues). More than 130 million sequencing reads were generated, and a de novo assembly yielded 287,959 contigs and 112,107 unigenes with an average length of 1029 and 28,891 bp, respectively. Similarity searches with known sequences led to the identification of 51,804 (46.21%) genes. Of the annotated unigenes, 6867 and 51,987 were assigned to Gene Ontology and Clusters of Orthologous Groups categories, respectively. Additionally, 8384 simple sequence repeats (SSRs) were identified as potential molecular markers in the unigenes. Thirty pairs of polymerase chain reaction primers were designed and used to validate the unigenes and assess the associated genomic polymorphism. The PCR amplification products for 25 primer pairs were of the expected size. These primers may represent usable molecular markers. The thousands of SSR markers identified in the present study may be useful for analyses of genetic diversity, genetic linkage mapping, and the identification and improvement of varieties during the breeding of Z. striolatum Diels. The unigene sequences and SSR markers described herein may serve as valuable resources for future investigations of Z. striolatum Diels. PMID- 29398845 TI - Genetic diversity of cucumber estimated by morpho-physiological and EST-SSR markers. AB - In the present study, genetic variation among 40 cucumber genotypes was analyzed by means of morpho-physiological traits and 21 EST-SSR markers. Diversity was observed for morpho-physiological characters like days to 50% female flowering (37-46.9, number of fruits/plant (1.33-5.80), average fruit weight (41-333), vine length (36-364), relative water content (58.5-92.7), electrolyte leakage (15.9 37.1), photosynthetic efficiency (0.40-0.75) and chlorophyll concentration index (11.1-28.6). The pair wise Jaccard similarity coefficient ranged from 0.00 to 0.27 for quantitative traits and 0.24 to 0.96 for EST-SSR markers indicating that the accessions represent genetically diverse populations. With twenty-one EST-SSR markers, polymorphism revealed among 40 cucumber genotypes, number of alleles varied 2-6 with an average 3.05. Polymorphism information content varied from 0.002 to 0.989 (mean = 0.308). The number of effective allele (Ne), expected heterozygosity (He) and unbiased expected heterozygosity (uHe) of these EST-SSRs were 1.079-1.753, 0.074-0.428 and 0.074-0.434, respectively. Same 21 EST-SSR markers transferability checked in four other Cucumis species: snapmelon (Cucumis melo var. momordica), muskmelon (Cucumis melo L.), pickling melon (Cucumis melo var. conomon) and wild muskmelon (Cucumis melo var. agrestis) with frequency of 61.9, 95.2, 76.2, and 76.2%, respectively. Present study provides useful information on variability, which can assist geneticists with desirable traits for cucumber germplasm utilization. Observed physiological parameters may assists in selection of genotype for abiotic stress tolerance also, EST-SSR markers may be useful for genetic studies in related species. PMID- 29398846 TI - Genetic diversity of bread wheat genotypes in Iran for some nutritional value and baking quality traits. AB - Genetic variation among 78 irrigated bread wheat genotypes was studied for their nutritional value and baking quality traits as well as some agronomic traits. The experiment was conducted in a randomized complete block design with three replicates under normal and terminal drought stress conditions in Kermanshah, Iran during 2012-2013 cropping season. The results of combined ANOVA indicated highly significant genotypic differences for all traits. All studied traits except grain yield, hectoliter weight and grain fiber content were significantly affected by genotype * environment interaction. Drought stress reduced grain yield, thousand kernel weight, gluten index, grain starch content and hectoliter weight and slightly promoted grain protein and fiber contents, falling number, total gluten and ratio of wet gluten to grain protein content. Grain yield by 31.66% and falling number by 9.20% attained the highest decrease and increase due to drought stress. There were negative and significant correlations among grain yield with grain protein and fiber contents under both conditions. Results of cluster analysis showed that newer genotypes had more grain yield and gluten index than older ones, but instead, they had the lower grain protein and fiber contents. It is thought that wheat breeders have bred cultivars with high grain yield, low protein content, and improved bread-making attributes during last seven decades. While older genotypes indicated significantly higher protein contents, and some of them had higher gluten index. We concluded from this study that it is imperative for breeders to pay more attention to improve qualitative traits coordinated to grain yield. PMID- 29398847 TI - Characterization of some bread wheat genotypes using molecular markers for drought tolerance. AB - Because of its wide geographical adaptation and importance in human nutrition, wheat is one of the most important crops in the world. However, wheat yield has reduced due to drought stress posing threat to sustainability and world food security in agricultural production. The first stage of drought tolerant variety breeding occurs on the molecular and biochemical characterization and classification of wheat genotypes. The aim of the present study is characterization of widely grown bread wheat cultivars and breeding lines for drought tolerance so as to be adapted to different regions in Turkey. The genotypes were screened with molecular markers for the presence of QTLs mapped to different chromosomes. Results of the molecular studies identified and detected 15 polymorphic SSR markers which gave the clearest PCR bands among the control genotypes. At the end of the research, bread wheat genotypes which were classified for tolerance or sensitivity to drought and the genetic similarity within control varieties were determined by molecular markers. According to SSR based dendrogram, two main groups were obtained for drought tolerance. At end of the molecular screening with SSR primers, genetic similarity coefficients were obtained that ranged from 0.14 to 0.71. The ones numbered 8 and 11 were the closest genotypes to drought tolerant cultivar Gerek 79 and the furthest genotypes from this cultivar were number 16 and to drought sensitive cultivar Sultan 95. The genotypes as drought tolerance due to their SSR markers scores are expected to provide useful information for drought related molecular breeding studies. PMID- 29398848 TI - Aeroponics for adventitious rhizogenesis in evergreen haloxeric tree Tamarix aphylla (L.) Karst.: influence of exogenous auxins and cutting type. AB - Tamarix aphylla (L.) Karst., a drought resistant halophyte tree, is an agroforestry species which can be used for reclamation of waterlogged saline and marginal lands. Due to very low seed viability and unsuitable conditions for seed germination, the tree is becoming rare in Indian Thar desert. Present study concerns the evaluation of aeroponics technique for vegetative propagation of T. aphylla. Effect of various exogenous auxins (indole-3-acetic acid, indole-3 butyric acid, naphthalene acetic acid) at different concentrations (0.0, 1.0, 2.0, 3.0, 5.0, 10.0 mg l-1) was examined for induction of adventitious rooting and other morphological features. Among all three auxins tested individually, maximum rooting response (79%) was observed with IBA 2.0 mg l-1. However, stem cuttings treated with a combination of auxins (2.0 mg l-1 IBA and 1.0 mg l-1 IAA) for 15 min resulted in 87% of rooting response. Among three types of stem cuttings (apical shoot, newly sprouted cuttings, mature stem cuttings), maximum rooting (~ 90%) was observed on mature stem cuttings. Number of roots and root length were significantly higher in aeroponically rooted stem cuttings as compared to stem cuttings rooted in soil conditions. Successfully rooted and sprouted plants were transferred to polybags with 95% survival rate. This is the first report on aeroponic culture of Tamarix aphylla which can be utilized in agroforestry practices, marginal land reclamation and physiological studies. PMID- 29398849 TI - Inhale the future, exhale the past. PMID- 29398850 TI - The much desired educational fillip in periodontology. PMID- 29398851 TI - What makes a tool appropriate to assess patient-reported outcomes of periodontal disease? AB - Context: Patient-reported outcomes (PROs) have become primary or secondary outcome measure in clinical trials and epidemiological studies in Medicine and Dentistry in general and Periodontology in particular. PROs are patients' self perceptions about consequences of a disease or its treatment. They can be used to measure the impact of the disease or the effect of its treatment. There are insufficient data in Periodontology related to scale development methodology although, recently, there is an increase in the number of published studies utilizing such tools in major journals. Aim: This paper is an overview of the development methodology of new PRO tools to study the impact of periodontal disease. Materials and Methods: The iterative process begins with a research question. A well-constructed a priori hypothesis enables validity assessment by hypothesis testing. The qualitative steps in item generation include literature review, focus group discussion, and key informant interviews. Expert paneling, content validity index, and pretesting are done to refine and sequence the items. Test-retest reliability, inter-rater reliability, and internal consistency reliability are assessed. The tool is administered in a representative sample to test construct validity by factor analysis. Conclusion: The steps involved in developing a subjective perception scale are complicated and should be followed to establish the essential psychometric properties. The use of existing tool, if it fulfills the research objective, is recommended after cross-cultural adaptation and psychometric testing. PMID- 29398852 TI - Comparative evaluation of platelet count and antimicrobial efficacy of injectable platelet-rich fibrin with other platelet concentrates: An in vitro study. AB - Background: Platelet concentrates are used in various medical procedures to promote soft- and hard-tissue regeneration. In recent times, their antimicrobial efficacy is also explored. However, various platelet concentrates have evolved which differ in the centrifugation protocols. One such recently introduced platelet concentrate is injectable platelet-rich fibrin (i-PRF) concentrate. Hence, the aim was to evaluate the antimicrobial property, and platelet count of i-PRF in comparison to other platelet concentrates, i.e., PRF, platelet-rich plasma (PRP), and control (whole blood). Materials and Methods: Blood samples were obtained from 10 chronic generalized marginal gingivitis patients. Platelet concentrates were prepared using standardized centrifugation protocol. Platelet count was evaluated by manual counting method using smear preparation of each sample. Subsequently, antimicrobial activity against oral bacteria was examined on blood agar using disc diffusion method to quantify the inhibitory effects. Results: Statistical significance was analyzed by one-way analysis of variance (ANOVA). P <0.05 was considered statistically significant. Mean zone of inhibition around i-PRF (P < 0.01) and PRF (P < 0.05) showed statistical significance. Although a distinct zone of inhibition was seen with PRP, it was not statistically significant (P > 0.05). i-PRF showed statistically significant difference (P < 0.001) in platelet count when compared to control. It was also significant when compared to PRP (P < 0.01), PRF (P < 0.001). Conclusion: i-PRF has maximum antimicrobial efficacy and higher platelet count in comparison to other platelet concentrates, thereby indicating to have a better regenerative potential then others. PMID- 29398853 TI - Comparative scanning electron microscope analysis of diode laser and desensitizing toothpastes for evaluation of efficacy of dentinal tubular occlusion. AB - Background: The present study aims to evaluate the efficacy of diode laser alone and in combination with desensitizing toothpastes in occluding dentinal tubules (both partially occluded and completely occluded tubules) by scanning electron microscope (SEM). Materials and Methods: Fifty human teeth were extracted, cervical cavities were prepared and etched with 17% ethylenediaminetetraacetic acid, and smear layer was removed to expose the tubules. The teeth were divided into five groups: Group I - Application of NovaMin-formulated toothpaste, Group II - Application of Pro-ArginTM-formulated toothpaste, Group III - Application of diode laser in noncontact mode, Group IV - NovaMin-formulated toothpaste followed by laser irradiation, and Group V - Pro-ArginTM-formulated toothpaste followed by laser irradiation. After treatment, quantitative analysis of occluded dentinal tubules was done by SEM analysis. Results: The mean values of percentages of total occlusion of dentinal tubules in Groups I, II, III, IV, and V were 92.73% +/- 1.38, 90.67% +/- 1.86, 96.57% +/- 0.64, 97.3% +/- 0.68, and 96.9% +/- 6.08, respectively. Addition of diode laser (Groups III, IV, and V) yielded a significant occlusion of the dentinal tubules when compared to desensitizing toothpastes alone (Groups I and II). Conclusion: Diode laser (Group III) has shown more efficacy in occluding dentinal tubules when compared with desensitizing toothpastes which was statistically significant (P < 0.05). Among the five groups, NovaMin + diode laser (Group IV) showed the highest percentage of occluded dentinal tubules. PMID- 29398854 TI - Calcitonin receptor gene polymorphisms at codon 447 in patients with osteoporosis and chronic periodontitis in South Indian population - An observational study. AB - Context: Chronic periodontitis and osteoporosis are multifactorial diseases which share common risk factors. Interactions between genetic and other factors determine the likely hood of osteoporotic fractures and chronic periodontitis. Calcitonin receptor (CTR) gene polymorphism is one of the important factors which contribute to the development of osteoporosis and chronic periodontitis. Aims: This study highlights the association of CTR gene polymorphisms at codon 447 in patients with osteoporosis and chronic periodontitis and healthy controls in south Indian population. Settings and Design: The study was designed as a case control retrospective, observational clinical trial which was conducted to assess the role of CTR gene polymorphism in patients with osteoporosis and periodontitis as well as in healthy controls. Materials and Methods: A total of 50 subjects were taken into the study comprising of 20 healthy and 30 osteoporotic subjects with chronic periodontitis between the age group of 30-55 years. Within the limitations of our study, only 50 subjects were taken in the study due to the strict sampling method (Patients who were just diagnosed with osteoporosis and periodontitis and hence not taking any medication). 2 ml of blood sample was collected in ethylenediamine tetra acetic acid containing vials, and polymerase chain reaction was run to identify CTR gene polymorphism. Statistical Analysis Used: Statistical analysis was done by student t-test. Pertaining to C > T allele pattern there was a significant difference between the test and control group. Results: A significant difference was observed between the test and control group in relation to the C > T allele pattern. Patients showing TT genotype distribution had greater periodontal destruction and lower bone-mineral density compared to CT genotype distribution followed by CC genotype distribution indicating TT homozygotes are more prone to the development of osteoporosis with increased risk of fracture and loss of alveolar bone. Males and females showed equal susceptibility to osteoporosis and chronic periodontitis. Conclusions: CTR polymorphism at codon 447 may be associated with osteoporosis and chronic periodontitis. PMID- 29398855 TI - To compare the gingival melanin repigmentation after diode laser application and surgical removal. AB - Aim: The aim of the present study is to compare the gingival melanin repigmentation after diode laser application and surgical removal done by scraping with Kirkland knife. Materials and Methods: This study was a randomized split-mouth study where 10 patients presenting with unattractive, diffuse, dark brown to black gingival discoloration on the facial aspect of the maxillary gingiva were treated by diode laser application and surgical removal and followed up for 3-, 6-, and 9-month intervals. Results: The results showed a statistically significant difference in repigmentation between the groups at the interval of 3 months (P = 0.040), but the difference was statistically not significant at 6 months (P = 0.118) and 9 months (P = 0.146). On surgically treated sites, all cases showed repigmentation of the gingiva, but in laser treated, there were two individuals which did not show repigmentation of the gingiva even at the end of 9 month observation time. Conclusion: The incidence of repigmentation was slightly less in laser-treated sites as compared to surgical depigmentation although the difference was statistically significant only up to 3 months. PMID- 29398856 TI - Comparison of bone mineral density among pre- and post-menopausal women with and without chronic generalized periodontitis. AB - Background: There have been a very limited number of studies regarding the assessment of bone mineral density (BMD) using dual energy X-ray absorptiometry scan. Hence, the purpose of the study was to assess the relationship between BMD and periodontal health in three different study groups. Materials and Methods: The study comprised of thirty female individuals who were categorized into three groups: ten premenopausal women with healthy periodontium (Group A), ten premenopausal women with generalized chronic periodontitis (Group B), and ten postmenopausal women with generalized chronic periodontitis (Group C). Number of teeth, plaque index, probing depth, clinical attachment level, interproximal alveolar bone loss, T-score for dual femur and posteroanterior (PA) spine, and BMD for dual femur and PA spine of each individual were recorded in all the three groups. Results: The BMD and T-score of dual femur and PA spine were found to be low in Group C when compared to Group A and B which was statistically significant. Conclusion: Postmenopausal women with generalized chronic periodontitis (Group C) exhibited severe periodontal destruction with less BMD. Hence, it is suggested that periodontitis may be a risk indicator for osteoporosis in postmenopausal women and vice versa. PMID- 29398857 TI - Comparative evaluation of oral hygiene status and gingival enlargement among epileptic and healthy children as related to various antiepileptic drugs. AB - Background: Epilepsy is a gathering of neurological disorders characterized by epileptic seizures. Epileptic children, who are on active treatment with antiepileptic drugs, have a well-recognized side effect of gingival enlargement. Therefore, all efforts should be made, particularly for the population who are diagnosed or affected by the systemic disease. This study was conducted with an aim to determine oral hygiene status and gingival enlargement among epileptic and healthy children as related to various antiepileptic drugs. Materials and Methods: The cross-sectional observational study was conducted in the department of pedodontics and attached general hospital. A sample size of 120 participants with 60 healthy and 60 epileptic children between age 2 and 14 years were included. Oral health status of participants was examined using oral hygiene simplified index and plaque index. Gingival enlargement was assessed using Miranda-Brunet index. For statistical analysis, one-way ANOVA test, independent t test, and Pearson's Chi-square test were used. Results: From the total participants included in the study, 49% of participants had good oral hygiene from healthy group, and 28% participants had poor oral hygiene from the epileptic group. Sodium valproate was the most common drug used and was associated with increased gingival enlargement. Conclusion: Conclusion can be drawn that epileptic children under medication had poor oral hygiene and an increased risk for gingival enlargement as compared to their healthy counterparts. It must be stressed that the epileptic patients should be given dental care without conditions and provided with best possible care to restore esthetics and functions. PMID- 29398858 TI - A comparative evaluation of the efficacy of curcumin and chlorhexidine mouthrinses on clinical inflammatory parameters of gingivitis: A double-blinded randomized controlled clinical study. AB - Aim: The aim of this study was to assess the efficacy of 0.1% curcumin mouthwash and to compare it with 0.2% chlorhexidine gluconate as an antiplaque agent and its effect on gingival inflammation. Materials and Methods: One hundred and fifty subjects, age between 20 and 30 years were recruited. Study population were randomly divided into three groups. In Group A, 50 subjects were advised the experimental mouthwash. Group B subjects used placebo mouthrinse, and chlorhexidine mouth wash was given to Group C. The subjects were advised to use 10 ml of mouthwash for 1 min twice a day 30 min after brushing. Parameters were recorded for plaque, gingival, and sulcus bleeding indices at day 0, 7, 14, and 28 days along with subjective assessment of taste. Results: On intragroup comparison between curcumin, chlorhexidine, and placebo mouthwash, the mean percentage reduction of the plaque index (PI) between 0 and 28 days were 0.58,0.57 and 1.17, respectively (P < 0.01), percentage reduction of gingival index (GI) between 0 and 28 days were 0.65, 0.66, and 1.09, respectively (P < 0.01) and sulcus bleeding index (SBI) showed a percentage reduction of 0.69, 0.66, and 1.13, respectively The intergroup comparison revealed chlorhexidine and curcumin mouthwash were statistically significant with P < 0.001 as compared to placebo. Conclusion: Curcumin mouthwash has shown an antiplaque and antigingivitis properties comparable to chlorhexidine mouthwash. Thus, curcumin mouthwash and chlorhexidine gluconate can be effectively used as an adjunct to scaling and root planning. PMID- 29398859 TI - "Is powered toothbrush better than manual toothbrush in removing dental plaque?" A crossover randomized double-blind study among differently abled, India. AB - Background: Although mechanical plaque removal is an effective method, powered toothbrushes are specially designed to benefit differently abled. Literature comparing plaque removal efficacy between manual and powered toothbrushes among differently abled is sparse. Study Design and Setting: A cross-over, randomized, double-blind study was conducted in differently abled institution. Materials and Methods: Twenty differently abled participants were randomly assigned to two groups of ten participants. Plaque removal efficacy of battery-operated powered toothbrush was compared with manual toothbrush in a single brushing on the 8th day. After a washout of 1 week, groups were switched. Assessment of plaque scores was done using Turesky's modification of Quigley-Hein plaque index. Statistical Analysis: Difference in plaque score between pre- and post-brushing in each group was compared using paired sample t-test. Results: In the pooled data analysis combining the results of Phase I and II, mean pre- and post-brushing plaque scores with manual toothbrush was 2.26 +/- 0.4 and 1.93 +/- 0.5, respectively, while with powered toothbrush, it was 2.21 +/- 0.4 and 1.96 +/- 0.4, respectively. However, difference in mean plaque reduction between manual and powered toothbrushes was not significant. Conclusion: Manual toothbrushes were equally effective compared to powered toothbrushes. Long-term studies precisely documenting cost-effectiveness and participant perception in the ease of use are recommended to validate our results. PMID- 29398860 TI - Dental health awareness, attitude, and dental health-care seeking practices as risk indicators for the prevalence of periodontal disease among 15-17-year-old school children in Kozhikode district, Kerala, India. AB - Background: Periodontal disease prevalence in children is an indicator of future disease burden in the adult population. Knowledge about the prevalence and risk status of periodontal disease in children can prove instrumental in the initiation of appropriate preventive and therapeutic measures. Aim: This school based cross-sectional survey estimated the prevalence and severity of periodontal disease among 15-17-year-old children in Kozhikode district and assessed the risk factors. Materials and Methods: Multistage stratified random sampling and randomized cluster sampling were used in the selection of schools and study participants, respectively, in three educational districts of Kozhikode. Periodontal disease was assessed among 2000 school children aged 15-17 years, by community periodontal index. A content validated questionnaire was used to evaluate the sociodemographic characteristics and other risk factors. Results: The prevalence of periodontal disease was estimated as 75% (72% gingivitis and 3% mild periodontitis). The prevalence was higher in urban population (P = 0.049) and males had significantly (P = 0.001) higher prevalence. Lower socioeconomic strata experienced slightly more periodontal disease burden. Satisfactory oral hygiene practices (material and frequency) were observed, but oral hygiene techniques were erroneous. Unhealthy dental treatment-seeking practices and unfavorable attitude toward dental treatment (ATDT) significantly influenced periodontal health status. Overall awareness about dental treatment was poor in this study population. Conclusion: The prevalence of periodontal disease among 15 17-year-old school children in Kozhikode district is 75% and is influenced by sociodemographic characteristics. Other risk factors identified were unhealthy dental treatment-seeking practices and unfavorable ATDT. Implementation of well formulated oral health education programs is thus mandatory. PMID- 29398861 TI - Unusual presentation of familial gingival fibromatosis among male siblings. AB - Gingival enlargement refers to any increase in the size of normal gingiva. The gingiva may be enlarged in response to various interactions between the host and the environment. It can be of various types including inflammatory, drug induced, associated with systemic disease, neoplastic, false, and idiopathic. Idiopathic gingival enlargement is a rare condition of undetermined etiology. The enlargement can be localized or generalized to entire dentition and is usually associated with the emergence of the teeth into the oral cavity and may regress after extraction. Treatment aims to solve patient's psychological, esthetic, and masticatory needs. This is a case series of four siblings (3 boys and 1 girl) who reported to the Department of Periodontology with a chief complaint of swollen gums and difficulty in eating. After careful clinical examination and histopathological evaluation, a diagnosis of familial gingival fibromatosis was made. Treatment plan included gingivectomy and gingivoplasty and follow-ups. PMID- 29398862 TI - Tuberculous gingival enlargement: A rare clinical manifestation. AB - Tuberculosis (TB) is an inflammatory granulomatous disease that rarely presents as primary lesion in gingiva. Gingival involvement has been reported in only a very limited number of cases. A 13-year-old boy presented with gingival enlargement in the maxillary and mandibular anterior region associated with enlargement of lower lip with no systemic manifestations. He had a history of tuberculous lymphadenitis before 5 years which was inadequately treated. The patient's erythrocyte sedimentation rate was 70 mm/h. Histopathological report of the gingival lesion revealed noncaseating granulomas with nests of epithelioid cells and multinucleated Langhans giant cells. The patient was then referred to a physician for management, who initiated active antitubercular treatment following which the condition resolved. The aim of this article is to emphasize the importance of early diagnosis of primary TB of the gingiva which may be misdiagnosed when oral lesions are not associated with any apparent systemic infection. PMID- 29398863 TI - Comprehensive rehabilitation using dental implants in generalized aggressive periodontitis. AB - Generalized aggressive periodontitis (GAP) is a debilitating form of the disease and it results in deteriorating effects on the esthetic and functional aspects of the oral cavity. This case report describes the comprehensive rehabilitation of GAP patient using dental implants. The treatment planning involved thorough scaling and root planning (SRP) with oral hygiene instructions. The patient was motivated to adhere to a strict oral hygiene regimen following which periodontal flap surgery employing guided tissue regeneration and bone grafts was performed. Bacterial culture for anaerobic microorganisms was done using a gas pack pre- and postperiodontal treatment to confirm the effectiveness of the periodontal treatment regimen and also to proceed with dental implant placement. The rigorous maintenance program ensured the stability of the periodontium following which immediate placement of dental implants in the maxillary and mandibular anterior region was done. The fixed metal-ceramic prosthesis was fabricated in a step-by step process and the patient was recalled on a periodic basis over a 3-year follow-up duration. This case is a testimonial to the postperiodontal treatment long-term stability with excellent patient cooperation and strict maintenance protocol. PMID- 29398864 TI - Laser-assisted lip repositioning surgery: Novel approach to treat gummy smile. AB - Excessive gingival display (EGD) resulting in a "gummy smile" is a major esthetic concern with ramifications in an individual's personal and social life. Numerous treatment modalities have been used for the correction of EGD. The present case report describes the successful treatment of a young woman with an excess gingival display caused by a hyperactive upper lip and a mild vertical maxillary excess that was treated with a laser-assisted lip repositioning surgical technique accompanied by gingival recontouring. The procedure was accomplished by laser-assisted removal, through scraping a strip of mucosa from the maxillary buccal vestibule and suturing the mucosa of the lip to the mucogingival junction. This technique resulted in shortened vestibule and restricted the muscle pull of the elevator muscles of the lip, thereby reducing gingival display when the patient smiles. Laser-assisted lip repositioning surgery can be a viable, minimally invasive alternative to orthognathic surgery. PMID- 29398865 TI - Tooth for a tooth: Tissue engineering made easy at dental chairside. AB - Background: Stem cells are unspecialized, multipotent cells which can differentiate into different cell types. The human periodontal ligament encloses subpopulation of Periodontal Ligament Stem Cells (PDLSCs) which are able to regenerate the periodontium by differentiating into various cells of PDL. Literature have shown the promising results of periodontal regeneration by exvivo cultured transplantation of PDLSCs into the osseous defects. Methods: Based on current literature on use of ex vivo culture and associated problems, a novel technique is being presented , Stem cell application in periodontal regeneration (SAI-PRT) which uses autologous PDLSCs along with its niche adhering to extracted tooth root for direct application using gelatin sponge as scaffold in regeneration of intrabony periodontal defect bypassing ex-vivo culture. Results: The cases initiated under SAI-PRT protocol, and have shown excellent clinical and radiographic improvement in intrabony defect using direct transplant of autologous PDLSCs . Conclusions: SAI-PRT can be used for the treatment of periodontal osseous defects at chair side. PMID- 29398867 TI - Diet switch and omega-3 hydroxy-fatty acids display differential hepatoprotective effects in an obesity/nonalcoholic fatty liver disease model in mice. AB - AIM: To study the effect of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17 hydroxy-docosahexaenoic acid (17-HDHA) in a murine model of obesity/nonalcoholic fatty liver disease. METHODS: C57BL/6 mice were fed with standard chow diet (CD) or high-fat, fructose-enriched diet (HFD) for 16 wk. Then, three groups were treated for 14 d with either, diet switch (HFD for CD), 18-HEPE, or 17-HDHA. Weight and fasting glucose were recorded on a weekly basis. Insulin tolerance test was performed at the end of treatment. Histological analysis (HE and Masson's trichrome stain) and determination of serum insulin, glucagon, glucagon like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, adiponectin and resistin were carried out as well as liver proteins by western blot. RESULTS: Mice treated with hydroxy-fatty acids 18-HEPE and 17-HDHA displayed no weight loss or improved insulin sensitivity. However, these mice groups showed a significant amelioration on serum GLP-1, adiponectin and resistin levels. Also, a significant reduction on inflammatory infiltrate was observed at both portal and lobular zones. Furthermore, up-regulation of PPARalpha/gamma protein levels was observed in liver tissue and it was associated with decreased levels of NF-kappaB also determined by western blot analysis. On the other hand, diet switch regimen resulted in a marked improvement in most parameters including: weight loss, increased insulin sensitivity, decreased steatosis, restored levels of insulin, glucagon, leptin, adiponectin and resistin. However, no significant changes were observed regarding inflammatory infiltrate in this last group. CONCLUSION: 18 HEPE and 17-HDHA differentially exert hepatoprotective effects through up regulation of nuclear receptors PPARalpha/gamma and amelioration of serum adipokines profile. PMID- 29398868 TI - Overexpression of CREPT confers colorectal cancer sensitivity to fluorouracil. AB - AIM: To investigate expression of cell cycle-related and expression-elevated protein in tumor (CREPT) in colorectal cancer (CRC) and determine its prognostic value in response to 5-fluorouracil (5-FU). METHODS: The relative expression of CREPT in CRC tumor samples was determined using immunohistochemistry. The protein content in cell lines was analyzed by immunoblotting. Cell viability was measured with the CCK-8 assay. Cell cycle and apoptosis analyses were performed with flow cytometry. RESULTS: CREPT was overexpressed in CRC tissues and correlated with histological grade. Clinicopathological analysis indicated that CREPT was positively related to tumor progression. Exogenous expression of CREPT stimulated cell proliferation and accelerated the cell cycle. More importantly, high expression of CREPT sensitized CRC cells to 5-FU treatment. Furthermore, we demonstrated that 5-FU elicited significant apoptosis in CREPT-positive cells. CONCLUSION: Aberrant overexpression of CREPT contributes to tumorigenesis of CRC by promoting cell proliferation and accelerating the cell cycle, and confers sensitivity to 5-FU. CREPT is a potential prognostic biomarker for 5-FU in CRC. PMID- 29398866 TI - Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review. AB - The secosteroid hormone vitamin D has, in addition to its effects in bone metabolism also functions in the modulation of immune responses against infectious agents and in inhibiting tumorigenesis. Thus, deficiency of vitamin D is associated with several malignancies, but also with a plethora of infectious diseases. Among other communicable diseases, vitamin D deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B and C viruses (HBV, HCV) and high prevalence of vitamin D deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infection are found worldwide. Several studies have assessed the effects of vitamin D supplementation on the sustained virological response (SVR) to interferon (IFN) plus ribavirin (RBV) therapy in HBV and HCV infection. In these studies, inconsistent results were reported. This review addresses general aspects of vitamin D deficiency and, in particular, the significance of vitamin D hypovitaminosis in the outcome of HBV- and HCV-related chronic liver diseases. Furthermore, current literature was reviewed in order to understand the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients. PMID- 29398869 TI - Early prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib. AB - AIM: To identify clinical biomarkers that could early predict improved survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with transarterial chemoembolization combined with sorafenib (TACE-S). METHODS: We retrospectively evaluated the medical records of consecutive patients with advanced-stage HCC who underwent TACE-S from January 2012 to December 2015. At the first follow-up 4-6 wk after TACE-S (median, 38 d; range, 33-45 d), patients exhibiting the modified Response Evaluation Criteria in Solid Tumors (mRECIST) evaluated complete response, partial response, and stable disease were categorized as early disease control. At this time point, multiple variables were analyzed to identify the related factors affecting survival. RESULTS: Ninety-five patients were included in this study, and 60 of these patients achieved early disease control, with an overall disease control rate (DCR) of 63.2%. Patients who got sorafenib at the first TACE (no previous TACE) and patients without portal vein tumor thrombus (PVTT) had a higher DCR than those who underwent previous TACE before TACE-S (72.4% vs 48.6%, P = 0.019) and those with PVTT (75.5% vs 50.0%, P = 0.010). Early disease control after TACE-S, no previous TACE, and no PVTT were the independent prognostic factors for survival in the uni and multivariate analyses. CONCLUSION: The first follow-up 4-6 wk after TACE-S can be used as the earliest time point to assess the response to TACE-S, and patients with mRECIST-evaluated early disease control, no previous TACE, and no PVTT had better survival. PMID- 29398870 TI - Low glucose metabolism in hepatocellular carcinoma with GPC3 expression. AB - AIM: To investigate the relationship between glucose metabolism and glypican-3 (GPC3) expression in hepatocellular carcinoma (HCC). METHODS: Immunohistochemical staining of pathological samples for GPC3 and glucose transporter 1 (GLUT1), and whole-body 18F-FDG PET/CT for measuring tumour glucose uptake were performed in 55 newly diagnosed HCC patients. The maximum standard uptake value (SUVmax) and tumour-to-non-tumourous liver uptake (T/NT) ratio were used to quantify 18F-FDG uptake. In vitro18F-FDG uptake assay of GPC3-expressing HepG2 and non-GPC3 expressing RH7777 cells was used to examine the effect of GPC3 in cellular glucose metabolism. The relationships between GPC3 expression and 18F-FDG uptake, GLUT1 expression, tumour differentiation, and other clinical indicators were analysed using Spearman rank correlation, univariate and multiple logistic regression analyses. RESULTS: Positive GPC3 expression was observed in 67.3% of HCC patients, including 75.0% of those with well or moderately differentiated HCC and 36.4% of those with poorly differentiated HCC. There was an inverse relationship between GPC3 expression and SUVmax (Spearman correlation coefficient = -0.281, P = 0.038) and a positive relationship between GLUT1 expression and SUVmax (Spearman correlation coefficient = 0.681, P < 0.001) in patients with HCC. Univariate analysis showed that two glucose metabolic parameters (SUVmax and T/NT ratio), tumour differentiation, lymph node metastasis, and TNM stage were all significantly associated with GPC3 expression (P < 0.05), whereas GLUT1 expression, sex, age, tumour size, intrahepatic lesion number, and distant metastasis showed no statistical association (P > 0.05). Further multivariate analysis revealed that only the T/N ratio was significantly correlated with GPC3 expression in patients with HCC (P < 0.05). In vitro assay revealed that the uptake of 18F-FDG in GPC3-expressing HepG2 cells was significantly lower than that of non-GPC3-expressing RH7777 cells (t = -20.352, P < 0.001). CONCLUSION: The present study demonstrated that GPC3 expression is inversely associated with glucose metabolism, suggesting that GPC3 may play a role in regulating glucose metabolism in HCC. PMID- 29398871 TI - Application value of enhanced recovery after surgery for total laparoscopic uncut Roux-en-Y gastrojejunostomy after distal gastrectomy. AB - AIM: To evaluate the safety and feasibility of enhanced recovery after surgery (ERAS) for total laparoscopic uncut Roux-en-Y gastrojejunostomy after distal gastrectomy. METHODS: The clinical data of 42 patients who were divided into an ERAS group (n = 20) and a control group (n = 22) were collected. The observed indicators included operation conditions, postoperative clinical indexes, and postoperative serum stress indexes. Measurement data following a normal distribution are presented as mean +/- SD and were analyzed by t-test. Count data were analyzed by chi2 test. RESULTS: The operative time, volume of intraoperative blood loss, and number of patients with conversion to open surgery were not significantly different between the two groups. Postoperative clinical indexes, including the time to initial anal exhaust, time to initial liquid diet intake, time to out-of-bed activity, and duration of hospital stay of patients without complications, were significantly different between the two groups (t = 2.045, 8.685, 2.580, and 4.650, respectively, P < 0.05 for all). However, the time to initial defecation, time to abdominal drainage-tube removal, and the early postoperative complications were not significantly different between the two groups. Regarding postoperative complications, on the first and third days after the operation, the white blood cell count (WBC) and C reactive protein (CRP) and interleukin-6 (IL-6) levels in the ERAS group were significantly lower than those in the control group. CONCLUSION: The perioperative ERAS program for total laparoscopic uncut Roux-en-Y gastrojejunostomy after distal gastrectomy is safe and effective and should be popularized. Additionally, this program can also reduce the duration of hospital stay and improve the degree of comfort and satisfaction of patients. PMID- 29398872 TI - Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. AB - AIM: The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines. METHODS: Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes in white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated. RESULTS: Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients (25.0%). C.52G > A and c.36_37insGGAGTC in exon 1 were found in three patients each. All three patients with c.36_37insGGAGTC in exon 1 were heterozygotes of p.Arg139Cys in exon 3. Eighteen patients had p.Arg139Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases (n = 24), and was significantly lower at 6, 8, 10, and 16 wk (P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wild-type and mutated cases. TPMT mutations were not found in any of the patients. CONCLUSION: Mutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed. PMID- 29398873 TI - Impact of mechanical bowel preparation in elective colorectal surgery: A meta analysis. AB - AIM: To analyse the effect of mechanical bowel preparation vs no mechanical bowel preparation on outcome in patients undergoing elective colorectal surgery. METHODS: Meta-analysis of randomised controlled trials and observational studies comparing adult patients receiving mechanical bowel preparation with those receiving no mechanical bowel preparation, subdivided into those receiving a single rectal enema and those who received no preparation at all prior to elective colorectal surgery. RESULTS: A total of 36 studies (23 randomised controlled trials and 13 observational studies) including 21568 patients undergoing elective colorectal surgery were included. When all studies were considered, mechanical bowel preparation was not associated with any significant difference in anastomotic leak rates (OR = 0.90, 95%CI: 0.74 to 1.10, P = 0.32), surgical site infection (OR = 0.99, 95%CI: 0.80 to 1.24, P = 0.96), intra abdominal collection (OR = 0.86, 95%CI: 0.63 to 1.17, P = 0.34), mortality (OR = 0.85, 95%CI: 0.57 to 1.27, P = 0.43), reoperation (OR = 0.91, 95%CI: 0.75 to 1.12, P = 0.38) or hospital length of stay (overall mean difference 0.11 d, 95%CI: -0.51 to 0.73, P = 0.72), when compared with no mechanical bowel preparation, nor when evidence from just randomized controlled trials was analysed. A sub-analysis of mechanical bowel preparation vs absolutely no preparation or a single rectal enema similarly revealed no differences in clinical outcome measures. CONCLUSION: In the most comprehensive meta-analysis of mechanical bowel preparation in elective colorectal surgery to date, this study has suggested that the use of mechanical bowel preparation does not affect the incidence of postoperative complications when compared with no preparation. Hence, mechanical bowel preparation should not be administered routinely prior to elective colorectal surgery. PMID- 29398874 TI - Intraductal papillary bile duct adenocarcinoma and gastrointestinal stromal tumor in a case of neurofibromatosis type 1. AB - We report our experience with a synchronous case of gastrointestinal stromal tumor (GIST) and intraductal papillary neoplasm of the bile duct (IPNB) in an elderly woman with neurofibromatosis type 1 (NF-1). A 72-year-old woman presented with a 2-mo history of right upper abdominal pain unrelated to diet and indigestion. Fourteen years earlier, she had been diagnosed with NF-1, which manifested as cafe au lait spots and multiple nodules on the skin. Computed tomography (CT) revealed a multilocular low-density mass with septation, and mural nodules in the right hepatic lobe, as well as a 1.7-cm-sized well demarcated enhancing mass in the third portion of the duodenum. The patient subsequently underwent right hepatectomy and duodenal wedge resection. We present here the first report of a case involving a synchronous IPNB and GIST in a patient with NF-1. Our findings demonstrate the possibility of various tumors in NF-1 patients and the importance of diagnosis at an early stage. PMID- 29398875 TI - Neuroendocrine carcinoma of the gastric stump: A case report and literature review. AB - We herein report a case of neuroendocrine carcinoma of the gastric stump found 47 years after Billroth II gastric resection for a benign gastric ulcer. A 74-year old man was referred to another hospital with melena. Endoscopic examination revealed a localized ulcerative lesion at the gastrojejunal anastomosis. The diagnosis by endoscopic biopsy was neuroendocrine carcinoma. A total gastrectomy of the remnant stomach with D2 lymphadenectomy was performed at our hospital. The lesion invaded the subserosa, and metastasis was found in two of nine the lymph nodes retrieved. The lesion was positive for synaptophysin and chromogranin A, and the Ki-67 labeling index was 60%. The diagnosis of neuroendocrine carcinoma of the gastric stump was confirmed using World Health Organization 2010 criteria. Subsequently, the patient underwent one course of adjuvant chemotherapy with the etoposide plus cisplatin (EP) regimen; however, treatment was discontinued due to grade 3 myelosuppression. The patient showed lymph node metastasis in the region around the gastrojejunal anastomosis in the abdominal cavity 7 mo post-surgery. He then underwent radiotherapy and platinum-based combination chemotherapy; however, the disease progressed and liver recurrence was observed on follow-up computed tomography at 16 mo post-surgery. The patient then received chemotherapy with regimens used for the treatment of small cell lung cancer in first- and second-line settings. The patient died of disease progression 31 months after surgery. PMID- 29398876 TI - Kernel Methods for Riemannian Analysis of Robust Descriptors of the Cerebral Cortex. AB - Typical cerebral cortical analyses rely on spatial normalization and are sensitive to misregistration arising from partial homologies between subject brains and local optima in nonlinear registration. In contrast, we use a descriptor of the 3D cortical sheet (jointly modeling folding and thickness) that is robust to misregistration. Our histogram-based descriptor lies on a Riemannian manifold. We propose new regularized nonlinear methods for (i) detecting group differences, using a Mercer kernel with an implicit lifting map to a reproducing kernel Hilbert space, and (ii) regression against clinical variables, using kernel density estimation. For both methods, we employ kernels that exploit the Riemannian structure. Results on simulated and clinical data shows the improved accuracy and stability of our approach in cortical-sheet analysis. PMID- 29398877 TI - Fredholmness of multiplication of a weighted composition operator with its adjoint on [Formula: see text] and [Formula: see text]. AB - In this paper, we obtain that [Formula: see text] is bounded below on [Formula: see text] or [Formula: see text] if and only if [Formula: see text] is invertible. Moreover, we investigate the Fredholm operators [Formula: see text] and [Formula: see text] on [Formula: see text] and [Formula: see text]. PMID- 29398878 TI - On a ratio monotonicity conjecture of a new kind of numbers. AB - It is known that the concept of ratio monotonicity is closely related to log convexity and log-concavity. In this paper, by exploring the log-behavior properties of a new combinatorial sequence defined by Z.-W. Sun, we completely solve a conjecture on ratio monotonicity by him. PMID- 29398879 TI - Some complementary inequalities to Jensen's operator inequality. AB - In this paper, we study some complementary inequalities to Jensen's inequality for self-adjoint operators, unital positive linear mappings, and real valued twice differentiable functions. New improved complementary inequalities are presented by using an improvement of the Mond-Pecaric method. These results are applied to obtain some inequalities with quasi-arithmetic means. PMID- 29398880 TI - Peer mentoring for undergraduates in a research-focused diversity initiative. AB - To provide multi-dimensional support for undergraduates from traditionally underrepresented backgrounds who aspire to careers in research, the BUILD EXITO project, part of a major NIH-funded diversity initiative, matches each scholar with three mentors: peer mentor (advanced student), career mentor (faculty adviser), and research mentor (research project supervisor). After describing the aims of the diversity initiative, the institutional context of the BUILD EXITO project, and the training program model, this article devotes special attention to the rationale for and implementation of the peer mentoring component within the context of the multi-faceted mentoring model. PMID- 29398881 TI - The Complexity of the Spanish Subjunctive in Bilingual Children with SLI. AB - This study investigated the use of the Spanish subjunctive in bilingual children with and without specific language impairments (SLI). Using an elicited production task, we examined: (1) the potential of the subjunctive as a grammatical marker of SLI in Spanish-English bilingual children, (2) the extent to which degree of bilingualism affects performance, and (3) the specific patterns of errors across groups. The participants in this study were 16 children with SLI and 16 typically developing children (TD) matched on age, English language proficiency, and mother's education level. Bilingual children were selected based on their English proficiency and were classified either as Spanish dominant children with intermediate English proficiency (asymmetrical bilinguals, AsyBi), or near-balanced bilinguals (BalBi). A completion task elicited the subjunctive in complement, purpose and temporal clauses. Results suggest that (1) level of bilingual proficiency, language clinical status, and age predicted of the accurate production of the subjunctive, (2) temporal clauses might have a better potential to discriminate between TD children and children with SLI in bilingual settings, and (3) tense underspecification errors were common in children with SLI. This study provides general support for grammatically targeted approaches to assessment in bilingual populations, and for theoretical approaches that link SLI to tense deficits. PMID- 29398882 TI - Gaussian Quadrature for Kernel Features. AB - Kernel methods have recently attracted resurgent interest, showing performance competitive with deep neural networks in tasks such as speech recognition. The random Fourier features map is a technique commonly used to scale up kernel machines, but employing the randomized feature map means that O(epsilon-2) samples are required to achieve an approximation error of at most epsilon. We investigate some alternative schemes for constructing feature maps that are deterministic, rather than random, by approximating the kernel in the frequency domain using Gaussian quadrature. We show that deterministic feature maps can be constructed, for any gamma > 0, to achieve error epsilon with O(egamma + epsilon 1/gamma) samples as epsilon goes to 0. Our method works particularly well with sparse ANOVA kernels, which are inspired by the convolutional layer of CNNs. We validate our methods on datasets in different domains, such as MNIST and TIMIT, showing that deterministic features are faster to generate and achieve accuracy comparable to the state-of-the-art kernel methods based on random Fourier features. PMID- 29398883 TI - Adverse Side Effects of Psychotropic Medication and Challenging Behavior: Pilot Work Assessing Impact. AB - Psychotropic medications are often prescribed to reduce challenging behavior in individuals with intellectual and developmental disabilities (IDD). Functional analyses (FAs) have demonstrated utility in assessing medication impact on behavior; however, the impact of adverse side effects (ASE) on challenging behavior is under-assessed. The purpose of this study was to develop a methodology, similar to FAs, to explore potential medication ASE impact on challenging behavior in seven individuals with IDD. Results revealed response rate differences in designed ASE conditions for most participants. Outcomes support further development and use of this methodology to assess the presence and impact of ASEs. PMID- 29398884 TI - Multi-photon vertical cross-sectional imaging with a dynamically-balanced thin film PZT z-axis microactuator. AB - Use of a thin-film piezoelectric microactuator for axial scanning during multi photon vertical cross-sectional imaging is described. The actuator uses thin-film lead-zirconate-titanate (PZT) to generate upward displacement of a central mirror platform, micro-machined from a silicon-on-insulator (SOI) wafer to dimensions compatible with endoscopic imaging instruments. Device modeling in this paper focuses on existence of frequencies near device resonance producing vertical motion with minimal off-axis tilt even in the presence of multiple vibration modes and non-uniformity in fabrication outcomes. Operation near rear resonance permits large stroke lengths at low voltages relative to other vertical microactuators. Highly uniform vertical motion of the mirror platform is a key requirement for vertical cross-sectional imaging in the remote scan architecture being used for multi-photon instrument prototyping. The stage is installed in a benchtop testbed in combination with an electrostatic mirror that performs in plane scanning. Vertical sectional images are acquired from 15 MUm diameter beads and excised mouse colon tissue. PMID- 29398885 TI - Underactuated Potential Energy Shaping with Contact Constraints: Application to a Powered Knee-Ankle Orthosis. AB - Body-weight support (i.e., gravity compensation) is an effective clinical tool for gait rehabilitation after neurological impairment. Body-weight supported training systems have been developed to help patients regain mobility and confidence during walking, but conventional systems constrain the patient's treatment in clinical environments. We propose that this challenge could be addressed by virtually providing patients with bodyweight support through the actuators of a powered orthosis (or exoskeleton) utilizing potential energy shaping control. However, the changing contact conditions and degrees of underactuation encountered during human walking present significant challenges to consistently matching a desired potential energy for the human in closed loop. We therefore derive a generalized matching condition for shaping Lagrangian systems with holonomic contact constraints. By satisfying this matching condition for four phases of gait, we derive passivity-based control laws to achieve virtual body-weight support through a powered knee-ankle orthosis. We demonstrate beneficial effects of virtual body-weight support in simulations of a human-like biped model, indicating the potential clinical value of this proposed control approach. PMID- 29398886 TI - Communicating Tobacco Product Information to the Public. AB - The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) requires tobacco companies to disclose information about the harmful chemicals in their products to the U.S. Food and Drug Administration (FDA). The law requires the FDA, in turn, to communicate this information to the public "in a format that is understandable and not misleading to a lay person." But how should the FDA comply with this requirement? What does it mean for information about complex chemicals to be "understandable and not misleading to a lay person"? These questions are not easy ones to answer. Disclosures about the amount of harmful chemicals (constituents) in different tobacco products may help to inform consumers, but may also conversely prompt consumers to reach incorrect or unsupported conclusions about products' relative health risks. This paper first analyzes the FDA's legal obligation to publish tobacco constituent information so that it is "understandable and not misleading to a layperson." Second, it discusses how that legal analysis has guided scientific research examining how members of the public interpret messages regarding tobacco constituents. Lastly, this paper concludes with policy recommendations for the FDA as it considers how to comply with the law's constituent disclosure requirement while still furthering its overall objective of promoting public health. PMID- 29398887 TI - Home-Based Video Telehealth for Veterans With Dementia. AB - In-home video telehealth supplements office visits and offers comfort and convenience to patients with dementia and their caregivers. PMID- 29398888 TI - The Road Ahead. PMID- 29398889 TI - Characteristics of Individuals with Spinal Cord Injury Who Use Cannabis for Therapeutic Purposes. AB - Background: People with spinal cord injury (SCI) are accessing cannabis for therapeutic purposes (CTP), the use of which has been legalized in more than 20 states. In the past, illicit marijuana use had positive correlations with other health risk behaviors. It is not known whether access to CTP has shifted patterns of use and altered health outcomes. Objective: To describe the self-reported patterns of CTP use among individuals with SCI and correlations with health behaviors and health indicators. Method: Secondary analysis of data from a cross sectional study involving community-dwelling individuals with chronic SCI and neurogenic bladder and bowel, at least 5 years post injury. Data were collected via structured interviews. Results: 92.2% of the current sample (n = 244) lived in states that, at the time of the study, permitted the use of CTP. 22.5% reported using CTP at least monthly to relieve pain (70.4%) and spasticity (46.3%). Of those 54 participants, 52.7% were daily users. Whereas 23.0% of non CTP users endorsed having prescriptions for at least one opioid-based medication, 38.1% of CTP users did so, suggesting that CTP use does not mitigate opioid use. Users were more likely to be single and live alone, report more bladder complications, and perceive their psychosocial functioning as more compromised than non-users. Conclusion: A relatively large percentage of individuals with chronic SCI appear to use CTP on a regular basis. Results suggest that they may be more vulnerable to complications and to risk factors for substance use disorders in SCI, such as social isolation. Although the generalizability of these findings is limited by the sampling strategies and the eligibility criteria of the larger study, CTP use should be assessed and considered when planning health interventions. PMID- 29398890 TI - Health Care Self-Advocacy Strategies for Negotiating Health Care Environments: Analysis of Recommendations by Satisfied Consumers with SCI and SCI Practitioners. PMID- 29398891 TI - Factors Influencing Self-Care Behaviors in Persons with Spinal Cord Injuries and Disorders. AB - Background: Individuals with spinal cord injury/disorder (SCI/D) must learn to adjust to and manage functional challenges after SCI/D onset. For these individuals, resilience (ie, the adaptive response to stressful events) may be related to their willingness and ability to conduct self-care behaviors. Objective: The study objectives were to examine the relationship between patient reported perceptions of independence in performing self-care behaviors and resilience among Veterans with SCI/D and to examine variables (including resilience) associated with high self-care scores (controlling for confounders). Methods: In this cross-sectional survey, we conducted bivariate analyses to examine differences in demographic, injury, and health characteristics and resilience scores for individuals with SCI/D. We conducted a multivariate block design linear regression to examine factors associated with ability to perform self-care. Results: Level of injury (beta = 7.74, P < .0001), resilience (beta = 0.08, P = .0216), marital status (beta = 1.75, P = .0445), and living arrangement (beta = 4.37, P < .0001) were positively related to higher self-care behaviors. Completeness of injury (beta = -2.79, P < .0001), age (beta = -0.09, P = .0052), age at injury (beta = -0.05, P = .0129), and number of comorbid health conditions (beta = -0.72, P < .0001) showed negative relationships with higher self-care. Conclusions: Self-care ability is related to multiple factors, including resilience. The positive relationship between resilience and self-care suggests that greater resilience, independent of injury level/severity, may contribute to improved self-care behaviors in individuals with SCI/D. Other factors that showed a positive relationship with self-care included younger age, living alone, paraplegic level injury, and fewer health conditions. Understanding the profile of persons with SCI/D with regard to self-care behaviors is important to the development of tailored interventions to improve self-care. PMID- 29398892 TI - The Impact of Health Behaviors and Health Management on Employment After SCI: Physical Health and Functioning. AB - Background: Research has shown that employment following spinal cord injury (SCI) is related to health and functioning, with physical health and functioning after SCI frequently identified as a primary barrier to employment. Objective: To examine the relationship between employment and behaviors associated with the management of physical health and functioning as described by individuals with SCI who have been employed post injury. Methods: A qualitative approach using 6 focus groups at 2 sites included 44 participants with SCI who had worked at some time post injury. Heterogeneous and homogeneous groups were created based on specific characteristics, such as education, gender, or race. A semi-structured interview format asked questions about personal, environmental, and policy related factors influencing employment after SCI. Groups were recorded, transcribed, and entered into NVivo before coding by 2 reviewers. Results: Within the area of behaviors and management of physical health and functioning, 4 overlapping themes were identified: (1) relearning your own body and what it can do; (2) general health and wellness behaviors; (3) communication, education, and advocacy; and (4) secondary conditions and aging. Specific themes articulate the many types of behaviors individuals must master and their impact on return to work as well as on finding, maintaining, and deciding to leave employment. Conclusions: Individuals with SCI who are successfully employed after injury must learn how to perform necessary behaviors to manage health and function in a work environment. The decision to leave employment often appears to be associated with secondary complications and other conditions that occur as persons with SCI age. PMID- 29398893 TI - Pilot Study of a Newly Developed Intervention for Families Facing Serious Injury. AB - Background: There is a need to develop interventions that address the entire family after spinal cord injury (SCI), especially in Latin America, where rehabilitation resources are limited and little is known about family adjustment to SCI. Objective: To evaluate the short-term (post-intervention) and longer term (6-month) effectiveness of the newly developed, 8-session manualized family intervention for individuals with SCI and their family members compared to a control group. Methods: In this clinical demonstration project, longitudinal self report data were collected from 8 individuals with SCI and their family members in Colombia, South America. The 8 families were randomly assigned to either the SCI intervention group or the waitlist control group. The intervention group included 10 individuals from 4 different families, with a mean age of 41.40 years (SD = 14.18). The control group was composed of 13 individuals from 4 different families with a mean age of 44.38 years (SD = 14.76). All participants completed Spanish versions of instruments that assessed depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7), burden (Zarit Burden Interview), and perceived problem-solving skills (Problem-Solving Inventory). Results: Results provide preliminary evidence that symptoms of depression, anxiety, and burden as well as problem-solving appraisals improved significantly for individuals who participated in the intervention, whereas no change in symptoms was observed among those in the waitlist control group. Conclusions: Findings suggest that this newly developed intervention for families facing SCI can be beneficial; however, this pilot study represents only the first step in the examination of the efficacy and effectiveness of this intervention. PMID- 29398894 TI - Scapular Stabilization and Muscle Strength in Manual Wheelchair Users with Spinal Cord Injury and Subacromial Impingement. AB - Background: Manual wheelchair users with spinal cord injury (SCI) are frequently diagnosed with subacromial impingement. Objective: To determine whether the pattern of muscle imbalance and impaired scapular stabilization in able-bodied (AB) adults with impingement is different from that in manual wheelchair users with SCI and impingement. Methods: The following measurements were collected from 22 adults with subacromial impingement (11 SCI, 11 AB): ratio of normalized muscle electrical activity of upper and lower trapezius (UT:LT) during arm abduction; force during abduction, adduction, internal rotation, external rotation, and push and pull; ratios of force for abduction to adduction (AB:ADD), internal to external rotation (IR:ER), and push to pull (PUSH:PULL). Results: Shoulders with impingement had significantly higher UT:LT activation (1.46 +/- 0.52) than shoulders without impingement (0.93 +/- 0.45) (P = .006), regardless of wheelchair user status. Significant differences between AB participants and those with SCI were observed for ABD:ADD (P = .005), PUSH:PULL (P = .012), and pull strength (P = .043). Participants with SCI had a significantly greater ABD:ADD (1.37 +/- 0.36) than AB participants (1.04 +/- 0.22) (P = .002) and a significantly greater PUSH:PULL (1.53 +/- 0.36) than AB participants (1.26 +/- 0.18) (P = .005) because of decreased strength in adduction (P = .021) and pull (P = .013). Conclusions: Strategies targeting the posterior shoulder girdle for AB adults are appropriate for manual wheelchair users with SCI and impingement and should focus on scapular retractors and arm adductors with emphasis on scapular depression and posterior tilting. PMID- 29398895 TI - Effects of a Functional Electrical Stimulation-Assisted Cycling Program on Immune and Cardiovascular Health in Persons with Spinal Cord Injury. AB - Background: Spinal cord injury (SCI) is associated with both a state of chronic inflammation and an increased prevalence of cardiovascular disease (CVD). These disorders are closely linked and have been shown to negatively influence one another. Participation in regular exercise has been shown to be an effective intervention strategy in the treatment of each of these disorders. For individuals with SCI who may lack the lower limb motor capabilities to perform certain traditional exercise modalities, functional electrical stimulation (FES) cycling may provide an effective alternative. Objective: The purpose of this study was to examine the effects of 12 weeks of FES training performed 3 times per week on physiological indices of cardiovascular function as well as molecular indices of inflammation and cardiovascular health. Methods: Ten individuals with chronic SCI were included. Measures of central and peripheral cardiovascular function as well as hematological and immunological markers were assessed before and after the 12-week exercise program. Results: Enhancements in exercise performance as well as a corresponding increase in peripheral cardiovascular function were achieved, as shown by a significant 34% increase in pulse volume (P = .04) and trends toward increases in cross-sectional area (P = .09) and arterial inflow volume (P = .11) of the common femoral artery. Despite this, no change in any hematological or immunological markers was evident. Conclusion: Although the efficacy of FES exercise in enhancing exercise performance (time and distance to fatigue) and peripheral cardiovascular function has been reaffirmed, no alterations in any molecular indices of cardiovascular risk were achieved. PMID- 29398896 TI - Gorham's Disease in a Patient with Traumatic Spinal Cord Injury: Case Report and Review of the Literature. AB - Gorham's disease is a rare entity that has been sparsely covered in the medical literature, and its pathophysiology remains poorly understood. We present the case of a 22-year-old man who sustained a traumatic T6 American Spinal Injury Association Impairment Scale B paraplegic injury complicated by a complaint of shoulder pain during his acute rehabilitation stay. He was found to have osteolysis of the distal right clavicle (Gorham's disease). He was treated conservatively with nonsteroidal anti-inflammatory drugs and relative rest and experienced good functional outcome. Although the differential diagnosis for shoulder pain in the paraplegic patient during acute rehabilitation is extensive, it is important to consider less common but still important etiologies such as Gorham's disease. PMID- 29398897 TI - Perceptions of severe storms, climate change, ecological structures and resiliency three years post-hurricane Sandy in New Jersey. AB - Global warming is leading to increased frequency and severity of storms that are associated with flooding, increasing the risk to urban, coastal populations. This study examined perceptions of the relationship between severe storms, sea level rise, climate change and ecological barriers by a vulnerable environmental justice population in New Jersey. Patients using New Jersey's Federally Qualified Health Centers were interviewed after Hurricane [Superstorm] Sandy because it is essential to understand the perceptions of uninsured, underinsured, and economically challenged people to better develop a resiliency strategy for the most vulnerable people. Patients (N = 355) using 6 centers were interviewed using a structured interview form. Patients were interviewed in the order they entered the reception area, in either English or Spanish. Respondents were asked to rate their agreement with environmental statements. Respondents 1) agreed with experts that "severe storms were due to climate change", "storms will come more often", and that "flooding was due to sea level rise", 2) did not agree as strongly that "climate change was due to human activity", 3) were neutral for statements that "Sandy damages were due to loss of dunes or salt marshes". 4) did not differ as a function of ethnic/racial categories, and 5) showed few gender differences. It is imperative that the public understand that climate change and sea level rise are occurring so that they support community programs (and funding) to prepare for increased frequency of storms and coastal flooding. The lack of high ratings for the role of dunes and marshes in preventing flooding indicates a lack of understanding that ecological structures protect coasts, and suggests a lack of support for management actions to restore dunes as part of a coastal preparedness strategy. Perceptions that do not support a public policy of coastal zone management to protect coastlines can lead to increased flooding, extensive property damages, and injuries or loss of life. PMID- 29398898 TI - Stomach Intestinal Pylorus-Sparing Surgery for Morbid Obesity. AB - Background and Objective: The Roux-en-Y duodenal switch (RYDS) is one of the most efficient forms of bariatric surgery. However, diarrhea, malnutrition, ulcers, and internal hernias have hampered its widespread adoption. The stomach intestinal pylorus-sparing (SIPS) procedure was developed to alleviate these sequelae while retaining the same weight loss as the RYDS. In this study, we report our midterm experience with this novel technique. Methods: Retrospective analysis was performed on data from 225 patients who underwent a primary SIPS procedure by 2 surgeons at a single center from October 2013 through December 2016. Results: Two hundred twenty-five patients were identified for analysis. The mean preoperative body mass index (BMI) was 52.4 +/- 9.1 kg/m2. Forty-eight patients were beyond 2 years after surgery, with data available for 30 patients (62.5% follow-up). Three patients were lost to follow-up. At 2 years, the patients had an average change in BMI of 26.6 U (kg/m2) with an average of 88.7% of excess weight loss. Three deaths were related to the surgery. The most common short-term complication was a leak (2.2%), whereas the most common long-term complication was diarrhea (2.2%). Conclusion: In conclusion, SIPS surgery is a safe procedure with favorable weight loss outcomes at 2 years. PMID- 29398899 TI - Clinical Characteristics Differentiating Uterine Sarcoma and Fibroids. AB - Background and Objectives: Uterine fibroids are a common indication for laparoscopy. Unsuspected sarcoma can pose a serious risk if morcellation is used in the procedure. We sought to determine the clinical factors associated with uterine sarcoma compared with uterine fibroids. Methods: We conducted a case control study of 66 women who had hysterectomy for uterine sarcoma from April 1, 2007, to March 31, 2014. Sixty-six patients who had hysterectomy for fibroids were randomly selected as controls. Results: Women with sarcoma vs women with fibroids, tended to be older (mean +/- SD 62.1 +/- 10.1 vs 46.5 +/- 6.6; P < .0001), were more likely to be postmenopausal (81.8% vs 9.2%; P < .0001), and were more likely to have a history of another nonuterine malignancy (16.7% vs 4.6%; P = .02). Women with sarcoma were more likely to have masses that were subserosal (69.4% vs 34.8%; P < .0001), rather than intramural (11.1% vs 37.0%; P = .01), and to have a solitary rather than multiple uterine mass (56.3% vs 18.5%; P < .0001). They were also more likely to have a history of documented rapid growth (16.7% vs 4.6%; P = .02). Conclusion: Despite limitations in sample size related to infrequency of uterine sarcoma, our results suggest some preoperative clinical differences between women who have uterine sarcoma vs uterine fibroids. Further studies on such features may assist us in identifying patients who are at higher risk of having a uterine sarcoma among women with a uterine mass contemplating surgery. PMID- 29398900 TI - Evaluation of New Technologies in Gastrointestinal Endoscopy. AB - Gastrointestinal (GI) tumors are the most commonly diagnosed cancers worldwide and the second leading cause of cancer-related death. Endoscopy is the gold standard for diagnosis of GI cancers. Early diagnosis of GI tumors by endoscopy at the precancerous or early stage may decrease the prevalence and mortality rate of GI cancers. The preventive role of endoscopic interventions and the limitations of conventional white-light endoscopy have given rise to myriad innovations. Chromoendoscopy with dye injection can be used to detect lesions at an early stage. However, the prolonged procedure duration and steep learning curve are disadvantages of chromoendoscopy. Recent technological advances in imaging enhancement have enabled detection of GI lesions without the need for dye injection, using digital chromoendoscopy systems, of which flexible spectral imaging color enhancement, narrow-band imaging, and I-Scan are the most frequently used. The combination of endoscopic image magnification and high definition optical systems using digital endoscopic methods has increased the diagnostic value of endoscopy. The development of confocal laser endomicroscopy has also improved in vivo endoscopic diagnosis. This review focuses on the latest technological innovations in endoscopy. PMID- 29398901 TI - Simultaneous intratunnel cross-linking with intrastromal corneal ring segment implantation versus simultaneous epithelium-off cross-linking with intrastromal corneal ring segment implantation for keratoconus management. AB - Purpose: The purpose of this study is to compare the efficacy of intratunnel cross-linking combined with intrastromal corneal ring segment (ICRS) implantation versus combined epithelium-off (epi-off) cross-linking and ICRS implantation for the management of keratoconus. Methods: Our study included 20 eyes of 12 patients with moderate-to-severe keratoconus. Group A included 10 eyes that underwent simultaneous ICRS implantation with intratunnel cross-linking. Group B included 10 eyes that underwent simultaneous ICRS implantation with epi-off cross-linking. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest sphere and cylinder, mean and maximum keratometric readings, corneal thickness at pachy apex and thinnest location, as well as corneal hysteresis (CH) and corneal resistance factor (CRF) were compared preoperatively and at 6 months postoperatively. Results: The mean UDVA and CDVA improved significantly in both groups with a statistically nonsignificant difference between the groups (P=0.798 and 0.126, respectively). The manifest cylinder decreased significantly in both groups, while the manifest sphere decreased significantly in Group A but nonsignificantly in Group B with a statistically nonsignificant difference between the groups (P=0.773 and 0.111, respectively). Both techniques led to significant flattening of the cornea and a significant decrease of Km and Kmax with a statistically nonsignificant difference between the groups (P=0.312 and 0.857, respectively). There was a statistically significant decrease in CH in both groups postoperatively; however, there was a statistically nonsignificant increase in CRF after both techniques with a statistically nonsignificant difference between the groups in the mean change of CH and CRF (P=0.633 and 0.313, respectively). No intraoperative or postoperative complications were observed in both groups. Conclusion: Both techniques improved the visual and refractive outcomes in cases of moderate and severe keratoconus with no statistically significant difference between the groups; however, simultaneous intratunnel cross-linking and ICRS implantation showed early visual rehabilitation due to the absence of epithelial defect. PMID- 29398902 TI - Elevated levels of plasma tumor necrosis factor alpha in patients with pseudoexfoliation glaucoma. AB - Background: Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine, which plays a role in glaucomatous neurodegeneration. Based on the plausible role of inflammation in the pathogenesis of pseudoexfoliation glaucoma (PEG), we investigated whether there is any relationship between the levels of plasma TNF-alpha and PEG or any of its clinical indices in comparison to normal controls. Methods: The study was designed as a retrospective analysis. Plasma samples from 49 PEG patients and 88 non-glaucomatous controls were evaluated for TNF-alpha levels using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on a biochemical/ELISA analyzer. Results: The two study groups were similar in age, sex and systemic disease distribution. The mean TNF-alpha concentration was significantly higher in the PEG patients (5.54+/-4.58 pg/mL) than in the control subjects (0.93+/-1.49 pg/mL; 95% confidence interval [CI] =3.50-5.72; p=0.000). The overall dose-response trend was significant (chi2=57.07, df=2; p=0.000). A moderate positive and significant correlation was seen between TNF-alpha level and cup/disc ratio, an important clinical index for PEG. Besides, binary logistic regression analysis showed that the risk of PEG was most significantly affected by TNF-alpha level as compared to no association with age and sex. In receiver operating characteristic analysis, the area under the curve was 0.777 (95% CI =0.682-0.872) and statistically significant (p=0.000). Conclusion: Elevated systemic levels of inflammatory marker, TNF-alpha, are associated with PEG and may possibly serve as a biomarker for undiagnosed early glaucoma and/or as a marker for disease progression. PMID- 29398903 TI - Comparison of a single-dose vectored thermal pulsation procedure with a 3-month course of daily oral doxycycline for moderate-to-severe meibomian gland dysfunction. AB - Purpose: The aim of this study was to compare the efficacy of a single bilateral 12-minute vectored thermal pulsation (VTP) procedure versus daily oral doxycycline for 3 months for moderate-to-severe meibomian gland dysfunction (MGD). Methods: This prospective, randomized, parallel-group, single-masked study included 28 subjects who received either a single-dose VTP or 3 months of doxycycline treatment. At baseline and 3 months post treatment, all subjects were evaluated for the following: dry eye symptoms with a standard dry eye questionnaire (the Standard Patient Evaluation for Eye Dryness [SPEED]), meibomian gland (MG) function by counting the number of glands yielding liquid secretion with the MG evaluator (MGE), tear breakup time (TBUT) and corneal and conjunctival staining. Results: In the VTP group, at 3 months, there was a significant improvement in MG function (4.00+/-1.47 to 7.73+/-5.53), SPEED score (11.00+/-3.30 to 5.42+/-2.15), TBUT (6.26+/-2.01 to 8.44+/-1.81), corneal staining (0.38+/-0.50 to 0.12+/-0.33) and conjunctival staining (1.69+/-1.93 to 0.62+/-0.85). In the doxycycline group, there was a significant improvement in MG function (4.63+/-1.41 to 10.63+/-5.91), SPEED score (13.42+/-4.17 to 9.42+/-5.47) and conjunctival staining (2.38+/-1.88 to 1.13+/-1.51), but the improvement in TBUT (6.90+/-2.56 to 7.59+/-2.03) and corneal staining (0.21+/-0.41 to 0.13+/ 0.34) was not statistically significant (p=0.262 and p=0.414, respectively). At 3 months, SPEED score was significantly better in the VTP group (p<0.05); other parameters were comparable between the two groups. Conclusion: A single 12-minute bilateral VTP procedure was significantly more effective than the 3-month daily course of oral doxycycline at improving the dry eye symptoms secondary to MGD. A single 12-minute VTP treatment was at least as effective as a dose of doxycycline for 3 months, in improving MG function and all measured signs of MGD. Given the minimal risk profile of the single VTP procedure over long-term doxycycline use, a single VTP presents a favorable alternative to long-term antibiotic use. PMID- 29398905 TI - Irrigation port hydration in phacoemulsification surgery. AB - Background: In most cases, hydration is performed by water injection into the stromal tissue with a needle. The technique is simple, however it is sometimes troublesome. Purpose: We describe a simple technique for hydrating the corneal stroma in cataract surgery using an irrigation port. Patients and methods: The technique began by pushing the irrigation port against the corneal stroma for a few seconds during phacoemulsification, which generated edema in the corneal incision that subsequently prevented leakage. This procedure is called the hydration using irrigation port (HYUIP) technique. A total of 60 eyes were randomized and placed in two groups, 30 eyes underwent surgeries using the HYUIP technique (HYUIP group) and 30 eyes underwent surgeries without the HYUIP technique (control). The three points evaluated during each surgery included 1) the occurrence of anterior chamber collapse during the pulling out of the I/A tip after inserting the intraocular lens, 2) the need for conventional hydration, and 3) watertight completion at the end stage of surgery. Results: The anterior chamber collapse and the need for conventional hydration were significantly smaller in the HYUIP group compared to the control group. Regarding the self sealing completion, no significant difference was observed between the two groups. Conclusion: The HYUIP technique is an effective method for creating self sealing wound. In addition, this technique helps to prevent anterior chamber collapse. PMID- 29398904 TI - A single vectored thermal pulsation treatment for meibomian gland dysfunction increases mean comfortable contact lens wearing time by approximately 4 hours per day. AB - Purpose: To evaluate the effect of a single vectored thermal pulsation (VTP) treatment in contact lens wearers with meibomian gland dysfunction (MGD) and dry eye symptoms. Methods: The prospective, nonsignificant risk, open-label, randomized, multi-center clinical trial included 55 soft contact lens (SCL) wearers with MGD and evaporative dry eye. Subjects were randomized to the single VTP treatment group or an untreated control. The controls received a crossover VTP treatment at 3 months (crossover treatment group). Primary effectiveness measures were meibomian gland secretion (MGS) score and Standard Patient Evaluation of Eye Dryness (SPEED) that were evaluated at baseline, at 1 and 3 months post-VTP treatment, and at 1 month post-VTP treatment in the crossover treatment group. Exploratory variables included fluorescein tear break-up time (TBUT), lid wiper epitheliopathy (LWE), lid parallel conjunctival folds (LIPCOF), ocular surface staining, frequency of over-the-counter (OTC) drop use, and hours of comfortable contact lens wear. Results: At 3 months, the treatment group showed significantly greater mean change from baseline in MGS (12.4+/-9.1 vs 1.4+/-6.4, p<0.0001), SPEED (-8.4+/-4.7 vs -0.7+/-4.4, p<0.0001) and significantly greater improvement in exploratory variables (TBUT, LWE, and frequency of OTC drop use) relative to the controls. Mean comfortable contact lens wearing time increased by 4.0+/-3.9 hours at 1 month. This was sustained for 3 months with no change in the control group. The crossover treatment group demonstrated similar results to the treatment group at 1 month post-VTP. Conclusion: In SCL wearers with MGD, a single VTP treatment significantly improved mean meibomian gland function and significantly reduced dry eye signs and symptoms compared to an untreated control. The treatment increased mean comfortable lens wearing time by 4 hours (approximately doubling the pretreatment findings). This was sustained for up to 3 months post-treatment on average. PMID- 29398906 TI - Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation. AB - Purpose: Recent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN. Methods: Rats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex ProTM assays. Results: The NCV and expression levels of miR-146a in the DPN group were significantly decreased (P<0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) in the DPN group was significantly increased compared with the control and T2DM groups (P<0.01). Pearson's correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1beta, TNF-alpha and NF-kappaB. Conclusion: miR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries. PMID- 29398907 TI - Patients' perceptions of conservative treatment for a small abdominal aortic aneurysm. AB - Background: An abdominal aortic aneurysm (AAA) is a progressive, generally symptomless disease that could ultimately result in a fatal rupture. Current guidelines advise conservative follow-up, and preventive surgical repair once the risk of rupture outweighs the cost of repair (55 mm in men). In developed countries, the majority of patients are diagnosed with AAAs less than 55 mm, and so enter a period of conservative surveillance. An important question is how patients perceive and cope with risk of rupture, AAA diagnosis and treatment, and presented AAA information. The goal of this study was to gain insight into patients' perceptions of conservative treatment for a small AAA to increase patient satisfaction. Methods: We conducted semistructured in-depth interviews and used questionnaires measuring health-related quality of life (RAND 36-Item Health Survey 1.0), illness-perceptions (Illness Perception Questionnaire - Revised), and anxiety and depression (Hospital Anxiety and Depression Scale). Interviews were audio recorded and transcript contents were analyzed based on grounded theory. Mean scores of the questionnaires were compared to (population) reference groups. Results: This study included ten male patients under surveillance for a small AAA from two hospitals in the Netherlands. Patients expressed no fear for AAA rupture, and also reported low levels of anxiety and depression in both the interviews and the Hospital Anxiety and Depression Scale. The presence of an AAA did not affect their social life or emotional well-being. The reported poorer physical health on RAND 36-Item Health Survey 1.0 presumably reflected common presence of comorbidities. Participants stated to that they were content with the frequency and setup of AAA surveillance. However, they generally lacked knowledge about AAA disease and/or treatment options. Conclusion: Conservative AAA follow-up ensures patients that the risks of AAA disease are limited. The vascular surgeon is the most important source of AAA information to patients, and patients fully rely on their vascular surgeon to take control in AAA treatment. PMID- 29398908 TI - Barriers to treatment: describing them from a different perspective. AB - Background: Poor adherence is the result of many barriers. Most of the adherence research has focused on the patients' hurdles to adherence, instead of the responsibility the physician has for assuring adherence to treatment. Objective: The purpose of this review is to identify barriers to medication adherence and refocus how we describe those barriers in terms of physician behavior hurdles. Methods: PubMed was systematically searched for systematic reviews published between January 01, 2010, and December 06, 2017, that provided barriers to medication adherence. The searches were limited to reviews having adherence to medication prescribed in the outpatient setting as the main topic. Results: Thirty-one reviews were included in this review, covering 13 different disease categories. Fifty-eight different barriers to adherence to medications for chronic conditions were identified. Nineteen barriers were cited 6 or more times, and these were further categorized based on the World Health Organization's 5 dimensions of adherence and the number of times cited. Conclusion: This review provides clear evidence that adherence to medication is affected by multiple barriers. To facilitate this, adherence barriers can be framed as physician/health system hurdles. With that focus in mind, we may put the responsibility where we have the most control. PMID- 29398909 TI - A survey of reasons for continuing warfarin therapy in the era of direct oral anticoagulants in Japanese patients with atrial fibrillation: the SELECT study. AB - Purpose: Although warfarin has historically been the standard of care for preventing ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF), the use of direct oral anticoagulants (DOACs) is rapidly increasing. In this study, we examined the demographic and clinical characteristics of patients continuing warfarin therapy and investigated reasons for warfarin continuation. Patients and methods: Each study site consecutively registered 10 patients with NVAF who had been taking warfarin for at least 12 months. Demographic and clinical characteristics and international normalized ratio (INR) values were collected from medical records. Physicians responded to questionnaires exploring reasons for continuing warfarin therapy. Results: Overall, 313 patients treated with warfarin were registered at 33 sites. Mean +/- SD age was 76.4+/-9.6 years; 62.9% of patients were male. The proportion of patients with INR values in the therapeutic range was 74.6% and 48.8% among patients aged >=70 years and <70 years, respectively. Over half of the patients (51.4%) had been advised to switch from warfarin to DOACs; the primary physician-reported reason for this recommendation was superior safety and effectiveness. However, patients reported continuing warfarin because of the high price of DOACs (47.2%) and long-term positive experiences with warfarin (31.7%). The remaining 48.6% of patients with NVAF had never been counseled by their physicians about DOACs as an alternative to warfarin. For 76% of these patients, physicians favored warfarin for medical reasons, such as impaired renal function and controlled INR, but in the remaining patients, medical reasons for continuing warfarin were lacking. Conclusion: Approximately half of the patients in this study were informed of warfarin alternatives primarily for improved efficacy and safety, but elected not to change regimens because of the high price of DOACs and long-term positive experiences with warfarin. In the remaining half, physician preference or specific patient characteristics prevented a change in therapy. PMID- 29398910 TI - Integrating participatory ergonomic management in non-weight-bearing exercise and progressive resistance exercise on self-care and functional ability in aged farmers with knee osteoarthritis: a clustered randomized controlled trial. AB - Background: Ergonomic hazards are the most important cause of knee osteoarthritis (OA) in aged para rubber farmers. Ergonomic management comprising improvement of working conditions and muscle-strengthening exercise has been well documented in terms of workers' health benefit. However, those interventions were not adequate to sustain the advantage. Few studies have demonstrated the effect of integrating participatory ergonomic management (PEM) in non-weight-bearing exercise (NWE) and progressive resistance exercise (PRE), and none has focused on aged para rubber farmers with knee OA. Purpose: This study investigated the effect of PEM-NWE, PEM PRE, and standard treatment (ST) on self-care and functional ability in the aged population. Materials and methods: A single-blinded, clustered randomized controlled trial was carried out. Participants (n=75) from three different communities in southern Thailand were randomly assigned to PEM-NWE, PEM-PRE, and ST. Self-care and functional ability (pain, stiffness, and physical function) were examined at baseline (B), during the intervention at Week 5 (W5), and after its completion at Week 9 (W9). Mean comparison of those outcomes over time was made using Generalized Linear Mixed Models (GLMMs). Results: Compared to the standard treatment, the means of both groups, PEM-NWE and PEM-PRE, were significantly increased in self-care and functional ability. However, no significant difference between PEM-NWE and PEM-PRE was found. Conclusion: Either or both interventions should be incorporated into nursing practice in order to promote occupational health and enhance quality of work life for Thai aged farmers. Further study on their cost-effectiveness is highly recommended. PMID- 29398911 TI - Influence of cigarette smoking on hormone and lipid metabolism in women in late reproductive stage. AB - Background: The aim of the study was to analyze lipid and hormone metabolism, body mass index (BMI), and age parameters in late reproductive stage women in relation to cigarette smoking. Methods: The study enrolled 345 healthy late reproductive stage women living in Poland; 13.33% were smokers. The first part of the study assessed lipid metabolism (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides) and hormone metabolism (estradiol [E2], follicle-stimulating hormone [FSH], and anti-Mullerian hormone [AMH] levels) in women in the early phase of the follicular menstrual cycle. The second part of study was carried out using the diagnostic survey method, with a standardized questionnaire (Primary Care Evaluation of Mental Disorders [PRIME MD]) and the authors' own research tools. Results: The women were aged 42.3+/-4.5 years (mean +/- SD). The BMI (24.8+/-4.04 kg/m2) did not differ significantly between the groups. The women who smoked cigarettes had a statistically significantly (p<0.05) lower level of HDL as well as higher LDL and triglyceride levels (p<0.05). Differences were also shown in hormone levels: non-smoking participants had statistically significantly higher levels of E2 and FSH (p<0.05). In the group of non-smoking women, age was a predictor exerting a significant positive impact on the levels of total cholesterol, LDL, triglycerides, and AMH (p<0.05). BMI contributed to a decline in HDL and triglyceride levels. In the group of smoking women, age significantly positively influenced the level of E2, and negatively influenced AMH. BMI was associated with a significant decrease in the HDL level. Conclusion: Smoking cigarettes affects the physical health of women in late reproductive stage through negative influences on lipid and hormone metabolism, among other factors. Age is an unmodifiable factor adversely affecting both lipids and hormones. Higher BMI has a negative influence on lipid metabolism in both groups of women in this study. PMID- 29398912 TI - The annual direct costs of stable COPD in Greece. AB - Introduction: Chronic obstructive pulmonary disease (COPD) places a major burden on health care systems and has substantial economic effects; however, the cost of stable disease in Greece has never been thoroughly explored. The objective of the study was to estimate the annual COPD patient cost during the maintenance phase and explore the relationships between the cost and disease severity. Methods: Data were collected from 245 COPD patients (male: 231, mean age: 69.5+/-8.8 years) who visited the outpatient unit of University Hospital of Larissa in 2014 and 2015. Patients were classified according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, and the patients' direct cost during the maintenance phase was calculated. Results: Eleven percent of COPD patients were stage I, 48.2% were stage II, 29% were stage III, and 11.8% were stage IV. According to the GOLD groups, 23.3% of patients were grade A, 15.5% were grade B, 22.9% were grade C, and 38.4% were grade D. The mean annual direct cost for stable disease was estimated at ?1,034.55 per patient, of which ?222.94 corresponded to out-of-pocket payments. The annual cost ranged from ?408.23 to ?2,041.89 depending on GOLD stages (I-IV) and from ?550.01 to ?1,480.00 depending on GOLD groups (A-D). The key cost driver was pharmaceutical treatment, which reflected almost 71% of the total expenses for the management of stable disease. The mean annual per-patient cost was two to three times higher for those with advanced disease (stages III-IV) compared to those with stages I-II disease, and it doubled for "high-risk" patients (groups C-D) compared to "low-risk" patients (groups A-B). Conclusion: The cost of COPD during the maintenance phase is remarkable, with the key cost driver found to be pharmaceutical treatment and social insurance funds the key payer for treating COPD patients in Greece. The cost of stable disease is proportional to the severity of COPD, and it is doubled in patients who belong to high-risk groups. PMID- 29398913 TI - Risk of empyema in patients with COPD. AB - Objective: Pneumonia is one of the most common infectious diseases in patients with COPD. The risk of empyema in COPD is controversial, and its incidence has not been reported. The aim of our study was to determine the risk of empyema in COPD patients and to assess its risk factors. Patients and methods: We used the National Health Insurance Research Database in Taiwan to conduct an observational cohort study. This study analyzed patients who were diagnosed with COPD between January 1, 2003 and December 31, 2009. The earliest date of COPD diagnosis was designated the index date. Patients who were younger than 40 years or had empyema before the index date were excluded. Results: We analyzed 72,085 COPD patients in our study. The incidence of empyema was higher in the COPD group than in the non COPD group (15.80 vs 4.34 per 10,000 person-years). The adjusted hazard ratio for empyema was 3.25 (95% CI =2.73-3.87) in patients with COPD compared with patients without COPD. COPD patients with only comorbidity of stroke, cancer, and chronic renal disease had adjusted hazard ratios of 1.88, 4.84, and 3.90, respectively. Conclusion: The likelihood of developing empyema is higher in patients with COPD than in those without COPD. Some comorbidities, such as stroke, cancer, and chronic renal disease, are associated with an elevated risk for empyema in COPD patients. PMID- 29398914 TI - "Low road" to rehabilitation: a perspective on subliminal sensory neuroprosthetics. AB - Fear can propagate parallelly through both cortical and subcortical pathways. It can instigate memory consolidation habitually and might allow internal simulation of movements independent of the cortical structures. This perspective suggests delivery of subliminal, aversive and kinematic audiovisual stimuli via neuroprosthetics in patients with neocortical dysfunctions. We suggest possible scenarios by which these stimuli might bypass damaged neocortical structures and possibly assisting in motor relearning. Anticipated neurophysiological mechanisms and methodological scenarios have been discussed in this perspective. This approach introduces novel perspectives into neuropsychology as to how subcortical pathways might be used to induce motor relearning. PMID- 29398915 TI - Efficacy of twice-daily vs once-daily sessions of repetitive transcranial magnetic stimulation in the treatment of major depressive disorder: a retrospective study. AB - Purpose: There is no clinical consensus on the optimal protocol for the treatment of major depressive disorder (MDD) using repetitive transcranial magnetic stimulation (rTMS). Accelerated protocols using more than a single session of treatment per day have been suggested as a means to reduce the overall length of time required for rTMS therapy. The objective of this study is to compare the treatment outcomes of patients with MDD who received two sessions of rTMS per day vs those who received one session per day, keeping the overall number of delivered pulses constant. Patients and methods: In a retrospective study, we compared treatment outcomes of 36 patients with MDD who received 30 sessions of high-frequency (10 Hz) rTMS over the left dorsolateral prefrontal cortex. Patients received 3,000 pulses per session (5 s trains, 25 s intertrain interval) at 110% of resting motor threshold using a figure-eight coil. Patients received either two rTMS sessions per day (n=17) or one session per day (n=19). Depression symptoms were assessed by a psychiatrist using the Hamilton Rating Scale for Depression at baseline and after every 10 sessions of rTMS. Results: The majority of patients in both groups responded to treatment, and there was a trend toward greater response rate in the twice-daily (TD) group (82.4%) compared to the once daily (OD) group (52.6%). TD stimulation was tolerable for patients and produced no adverse side effects. Patients in the TD group experienced an improvement in symptoms faster than the OD group due to the accelerated therapy period. Conclusion: Administration of two rTMS treatment sessions per day is tolerable for patients and does not seem to be inferior in efficacy to a OD protocol. TD administration has the benefit of producing symptom improvement over a shorter time span and requires fewer visits to the clinic. PMID- 29398916 TI - Systematic review of catatonia treatment. AB - Objective: To investigate the evidence-based treatment of catatonia in adults. The secondary aim is to develop a treatment protocol. Materials and methods: A systematic review of published treatment articles (case series, cohort or randomized controlled studies) which examined the effects of particular interventions for catatonia and/or catatonic symptoms in adult populations and used valid outcome measures was performed. The articles for this review were selected by searching the electronic databases of the Cochrane Library, MEDLINE, EMBASE and PSYCHINFO. Results: Thirty-one articles met the inclusion criteria. Lorazepam and electroconvulsive therapy (ECT) proved to be the most investigated treatment interventions. The response percentages in Western studies varied between 66% and 100% for studies with lorazepam, while in Asian and Indian studies, they were 0% and 100%. For ECT, the response percentages are 59%-100%. There does not seem to be evidence for the use of antipsychotics in catatonic patients without any underlying psychotic disorder. Conclusion: Lorazepam and ECT are effective treatments for which clinical evidence is found in the literature. It is not possible to develop a treatment protocol because the evidence for catatonia management on the basis of the articles reviewed is limited. Stringent treatment studies on catatonia are warranted. PMID- 29398917 TI - Ticagrelor - toward more efficient platelet inhibition and beyond. AB - Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor's adverse effects, including dyspnea and bradycardia. Large scale clinical trials demonstrated that both standard 12-month therapy and long term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug-drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor. PMID- 29398918 TI - Using Watershed Boundaries to Map Adverse Health Outcomes: Examples From Nebraska, USA. AB - In 2009, a paper was published suggesting that watersheds provide a geospatial platform for establishing linkages between aquatic contaminants, the health of the environment, and human health. This article is a follow-up to that original article. From an environmental perspective, watersheds segregate landscapes into geospatial units that may be relevant to human health outcomes. From an epidemiologic perspective, the watershed concept places anthropogenic health data into a geospatial framework that has environmental relevance. Research discussed in this article includes information gathered from the literature, as well as recent data collected and analyzed by this research group. It is our contention that the use of watersheds to stratify geospatial information may be both environmentally and epidemiologically valuable. PMID- 29398919 TI - Comparison of FOLFOX and DOF regimens as first-line treatment in East Asian patients with advanced gastric cancer. AB - Background: Our study retrospectively assesses the safety and efficacy of the FOLFOX (oxaliplatin, fluorouracil, and leucovorin) versus DOF (docetaxel, oxaliplatin, and fluorouracil) regimens in untreated locally advanced gastric cancer (AGC). Patients and methods: A total of 108 patients underwent DOF (N=58) and FOLFOX (N=50) regimens. The end points were overall response rate (ORR), survival, and toxicity. Kaplan-Meier curve was used to estimate overall survival (OS) and progression-free survival (PFS) and Cox regression for multivariate analysis. Results: The ORRs were 50% for DOF and 30% for FOLFOX groups (P<0.05), and disease control rates were 91.4% and 72%, respectively. The median PFS and OS in DOF group were significantly better than FOLFOX group (8.2 versus 6.4 months, P<0.05; 16.3 versus 11.2 months, P<0.001). Both groups showed acceptable toxicity; all grades and grade 3-4 toxicity had no significant differences (P=0.071; P=0.247). However, the incidence of grade 3-4 peripheral neuropathy was significantly higher in DOF group (10.3% versus 2%, P<0.05). In the subgroup analysis for elderly AGC patients (>=65 years), administration of DOF also resulted in a superior PFS (8.5 versus 5.9 months; P=0.038) and OS (15.3 versus 9.8 months; P=0.004) compared with FOLFOX. However, DOF regimen was associated with more neutropenia (67% versus 30%; P<0.05), thrombocytopenia (61% versus 52%; P<0.05), and peripheral neuropathy (49% versus 22%; P<0.05). Conclusion: DOF regimen was more effective than FOLFOX for AGC, both in younger and older patients. The adverse effects of the two regimens were manageable. The combination of docetaxel/oxaliplatin/fluorouracil was active and well tolerated in AGC patients and deserves further evaluation. However, for elderly patients with AGC, the DOF regimen was associated with worse toxicities; therefore, the FOLFOX regimen might be a more suitable option. PMID- 29398920 TI - Prognostic role of HSF1 overexpression in solid tumors: a pooled analysis of 3,159 patients. AB - Background and objective: HSF1 is reported to be overexpressed in various solid tumors and play a pivotal role in cancer progression. A meta-analysis was conducted to assess the potential prognostic role of HSF1 in patients with solid tumors. Methods: An extensive electronic search of three databases was performed for relevant articles. The pooled hazard ratios (HRs) or odds ratios with their corresponding 95% CI were calculated with a random-effects model. Heterogeneity and publication bias analyses were also conducted. Results: A total of 3,159 patients from 10 eligible studies were included into the analysis. The results showed that positive HSF1 expression was significantly correlated with poor overall survival in all tumors (HR=2.09; 95% CI: 1.62-2.70; P<0.001). Subgroup analysis revealed that there was a significant association between HSF1 overexpression and poor prognosis in esophageal squamous cell carcinoma (ESCC) (HR=1.83; 95% CI: 1.21-2.77; P=0.004), breast cancer (BC) (HR=1.52; 95% CI: 1.24 2.86; P<0.001), hepatocellular carcinoma (HR=3.02; 95% CI: 1.77-5.18; P<0.001), non-small-cell lung cancer (HR=2.19; 95% CI: 1.20-3.99; P=0.01), and pancreatic cancer (HR=2.58; 95% CI: 1.11-6.03; P=0.03) but not in osteosarcoma (HR=1.58; 95% CI: 0.47-5.35; P=0.46). In addition, HSF1 overexpression was significantly associated with some phenotypes of tumor aggressiveness including TNM stage, histological grade, lymph node metastasis, and vascular invasion. Conclusion: HSF1 overexpression may prove to be an unfavorable prognostic biomarker for solid tumor patients. PMID- 29398921 TI - Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study. AB - Background: The prognosis of locally unresectable colon cancer (CC) is poor. This prospective observational study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery in these patients. Patients and methods: We consecutively enrolled patients who were diagnosed with locally unresectable CC from November 2010 to March 2017, and received NACRT followed by surgery. The data of all the patients were collected prospectively. The R0 resection, down-stage and pathologic complete response (pCR) rates were calculated to evaluate the short-term treatment effects. The overall survival (OS) was used to evaluate the long-term outcome. The incidence of NACRT-related acute toxicities and postsurgical complications were used to assess the safety. Results: A total of 60 patients were eligible for analysis, including 57 (95.0%) patients who attained resectability after NACRT. Among patients managed with surgery, 49 cases (86.0%) achieved R0 resection, and 15 cases (26.3%) achieved pCR. Down T stage was seen in 47 cases (82.5%), and down N stage was seen in 53 cases (93.0%). After a median follow-up time of 26 months, the OS appeared as 76.7%. The most common grade 3/4 NACRT-related toxicity was myelosuppression (incidence, 20.0%). The incidence of grade 3/4 surgery-related complication was 7.0%. Conclusion: NACRT might be a safe and effective choice for patients with locally unresectable CC to improve treatment effects, long-term survival and life quality, though further validation is needed. PMID- 29398923 TI - WaLIDD score, a new tool to diagnose dysmenorrhea and predict medical leave in university students. AB - Background: Dysmenorrhea is a frequent and misdiagnosed symptom affecting the quality of life in young women. A working ability, location, intensity, days of pain, dysmenorrhea (WaLIDD) score was designed to diagnose dysmenorrhea and to predict medical leave. Methods: This cross-sectional design included young medical students, who completed a self-administered questionnaire that contained the verbal rating score (VRS; pain and drug subscales) and WaLIDD scales. The correlation between scales was established through Spearman test. The area under the receiver operating characteristic (ROC) curve, sensitivity, specificity, and likelihood ratio (LR +/-) were evaluated to diagnose students availing medical leave due to dysmenorrhea; moreover, to predict medical leave in students with dysmenorrhea, a binary logistic regression was performed. Results: In all, 585 students, with a mean age of 21 years and menarche at 12 years, participated. Most of them had regular cycles, 5 days of menstrual blood flow and 1-2 days of lower abdominal pain. The WaLIDD scale presented an adequate internal consistency and strong correlation with VRS subscales. With a cutoff of >6 for WaLIDD and 2 for VRS subscales (drug subscale and pain subscale) to identify students with dysmenorrhea, these scales presented an area under the curve (AUC) ROC of 0.82, 0.62, and 0.67, respectively. To identify students taking medical leave due to dysmenorrhea, WaLIDD (cutoff >9) and VRS subscales (cutoff >2) presented an AUC ROC of 0.97, 0.68, and 0.81; moreover, the WaLIDD scale showed a good LR +14.2 (95% CI, 13.5-14.9), LR -0.00 (95% CI, undefined), and predictive risk (OR 5.38; 95% CI, 1.78-16.2). Conclusion: This research allowed a comparison between two multidimensional scales regarding their capabilities, one previously validated and a new one, to discriminate among the general population of medical students, among those with dysmenorrhea or those availing medical leave secondary to dysmenorrhea. WaLIDD score showed a larger effect size than the pain and drug score in the students. In addition, this study demonstrated the ability to predict this combination of events. PMID- 29398922 TI - Severe bronchial asthma in children: a review of novel biomarkers used as predictors of the disease. AB - Severe asthma or therapy-resistant asthma in children is a heterogeneous disease that affects all age-groups. Given its heterogeneity, precision in diagnosis and treatment has become imperative, in order to achieve better outcomes. If one is thus able to identify specific patient phenotypes and endotypes using the appropriate biomarkers, it will assist in providing the patient with more personalized and appropriate treatment. However, there appears to be a huge diagnostic gap in severe asthma, as there is no single test yet that accurately determines disease phenotype. In this paper, we review the published literature on some of these biomarkers and their possible role in bridging this diagnostic gap. We also highlight the cellular and molecular mechanisms involved in severe asthma, in order to show the basis for the novel biomarkers. Some markers useful for monitoring therapy and assessing airway remodeling in the disease are also discussed. A review of the literature was conducted with PubMed to gather baseline data on the subject. The literature search extended to articles published within the last 40 years. Although biomarkers specific to different severe asthma phenotypes have been identified, progress in their utility remains slow, because of several disease mechanisms, the variation of biomarkers at different levels of inflammation, changes in relying on one test over time (eg, from sputum eosinophilia to blood eosinophilia), and the degree of invasive tests required to collect biomarkers, which limits their applicability in clinical settings. In conclusion, several biomarkers remain useful in recognizing various asthma phenotypes. However, due to disease heterogeneity, identification and utilization of ideal and defined biomarkers in severe asthma are still inconclusive. The development of novel serum/sputum-based biomarker panels with enhanced sensitivity and specificity may lead to prompt diagnosis of the disease in the future. PMID- 29398924 TI - Implementing a geographical information system to assess endemic fluoride areas in Lamphun, Thailand. AB - Introduction: Many studies have shown that fluoride can cross the placenta and that exposure to high fluoride during pregnancy may result in premature birth and/or a low birth weight. Lamphun is one of six provinces in Thailand where natural water fluoride (WF) concentrations >10.0 mg/L were found, and it was also found that >50% of households used water with high fluoride levels. Nevertheless, geographical information system (GIS) and maps of endemic fluoride areas are lacking. We aimed to measure the fluoride level of village water supplies to assess endemic fluoride areas and present GIS with maps in Google Maps. Methods: A cross-sectional survey was conducted from July 2016 to January 2017. Purpose sampling was used to identify villages of districts with WF >10.0 mg/L in the Mueang Lamphun, Pasang, and Ban Thi districts. Water samples were collected with the geolocation measured by Smart System Info. Fluoride was analyzed with an ion selective electrode instrument using a total ionic strength adjustment buffer. WF >0.70 mg/L was used to identify unsafe drinking water and areas with high endemic fluoride levels. Descriptive statistics were used to describe the findings, and MS Excel was used to create the GIS database. Maps were created in Google Earth and presented in Google Maps. Results: We found that WF concentrations ranged between 0.10-13.60 mg/L. Forty-four percent (n=439) of samples were at unsafe levels (>0.70 mg/L), and. 54% (n=303) of villages and 46% (n=79,807) of households used the unsafe drinking water. Fifty percent (n=26) of subdistricts were classified as being endemic fluoride areas. Five subdistricts were endemic fluoride areas, and in those, there were two subdistricts in which every household used unsafe drinking water. Conclusion: These findings show the distribution of endemic fluoride areas and unsafe drinking water in Lamphun. This is useful for health policy authorities, local governments, and villagers and enables collaboration to resolve these issues. The GIS data are available at https://drive.google.com/open?id=1mi4Pvomf5xHZ1MQjK44pdp2xXFw&usp=sharing. PMID- 29398925 TI - Data quality, floor and ceiling effects, and test-retest reliability of the Mild Cognitive Impairment Questionnaire. AB - Background: The Mild Cognitive Impairment Questionnaire (MCQ) is a 13-item measure that assesses health-related quality of life (HRQoL) in people with mild cognitive impairment (PWMCI); it has two domains assessing the emotional and practical effects. Objective: The aim of this study was to assess the psychometric properties of the MCQ. Design: This is a longitudinal questionnaire based study. Setting: The participants were recruited from the memory clinics and research databases in the South of England. Subjects: A total of 299 people aged 50 years and older with a diagnosis of mild cognitive impairment confirmed within the preceding 12 months. Methods: MCQs were distributed to patients in memory clinics and those listed on research databases. Participants who returned completed questionnaires were sent a second copy of the MCQ to return 2 weeks after receiving the first questionnaire. Results: Five hundred and seven questionnaires were distributed; response rates were 68.2% initially and 89.2% for the second questionnaire. From the returned questionnaires, response rates for each item were high (>98%) and a full range of responses for each item was received with no evidence of significant floor or ceiling effects. Internal consistency reliability for both scale scores at both time points was good, with Cronbach's a>=0.84 in all cases. Test-retest reliability was excellent for both domains with the intraclass correlation coefficients of 0.90 and 0.92 for the practical and emotional domains, respectively. Paired sample t-tests also confirmed the stability of scale score distributions over time. Conclusion: The MCQ has robust psychometric properties, which make it suitable for assessing HRQoL in PWMCI, including comparison of group level data in intervention studies. PMID- 29398926 TI - A Randomized Controlled Trial Comparing the Depth of Maximal Insertion Between Anterograde Single-Balloon Versus Spiral Enteroscopy. AB - Background: Three device-assisted deep endoscopic platforms presently exist and are available for clinical use: double-balloon enteroscopy, single-balloon enteroscopy (SBE), and spiral enteroscopy (SE). In a retrospective study, SE was associated with a greater depth of maximal insertion (DMI) with similar diagnostic yields and procedure time as compared with SBE. Aims: This was a prospective, randomized comparison of SE and SBE with respect to DMI, diagnostic yield, procedure time, and rate of adverse events. Methods: Patients were prospectively randomized to undergo either anterograde SE or SBE. Patient demographics, indication for procedure, DMI, procedure time, therapeutic procedure time, adverse event, diagnostic findings, and therapeutic interventions were prospectively recorded. The primary outcome was DMI. Secondary outcomes included: procedure time; diagnostic yield; therapeutic yield and adverse event rates. Results: During the study period, 30 patients underwent deep enteroscopy (SE 13, SBE 17). The most common indication was gastrointestinal bleeding in both groups. There was no significant difference in the DMI between SE and SBE (330.0 +/- 88.2 cm vs 285.3 +/- 80.8 cm, P = .16). There was no difference between SE and SBE in procedure time (37.0 +/- 10.5 vs 38.3 +/- 12.4, P = .76), diagnostic yield (SE = 9 [69%] vs SBE = 7 [41%], P = .16), or therapeutic yield (SE = 6 [46%] vs SBE = 4 [24%], P = .26). There were no major adverse events in either group. Conclusions: Spiral enteroscopy and SBE are similar with respect to DMI, diagnostic yield, therapeutic yield, procedure time, and rate of adverse events. Small numbers prevent giving a definitive judgment and future adequately powered prospective study is required to confirm these findings. PMID- 29398927 TI - New perspectives in autism spectrum disorders. AB - Autism spectrum disorder, a complex developmental disorder, has been found to be one of the most heritable neuropsychiatric disorders. The next step will be to translate these findings into successful treatments for this disorder. PMID- 29398928 TI - Brain and behavior development in autism from birth through infancy. AB - Autism spectrum disorder (ASD) is a heterogeneous condition that affects 1 in 68 children. Diagnosis is based on the presence of characteristic behavioral impairments that emerge in the second year of life and thus is not typically made until 3 to 4 years of age. Recent studies of early brain and behavior development have provided important new insights into the nature of this condition. Autism specific brain imaging features have been identified as early as 6 months of age, and age-specific brain and behavior changes have been demonstrated across the first 2 years of life, highlighting the developmental nature of ASD. New findings demonstrate that early brain imaging in the first year of life holds great promise for presymptomatic prediction of ASD. There is a general understanding in medicine that earlier treatment has better outcomes than later treatment, and in autism, there is an emerging consensus that earlier intervention results in more successful outcomes for the child. Examining early brain and behavior trajectories also has the potential to parse the etiologic heterogeneity in ASD, a well-recognized impediment to developing targeted, mechanistic treatments. This review highlights the current state of the science in the pursuit of early brain and behavioral markers of autism during infancy and examines the potential implications of these findings for treatment of this condition. PMID- 29398929 TI - Translating genetic and preclinical findings into autism therapies. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations on cellular function leading to disease. Efforts to translate these findings into successful therapies have yet to bear fruit. We discuss how the valuable insight into the disorder provided by these new models can be used to better understand ASD and develop future clinical trials. PMID- 29398930 TI - Autism and talent: the cognitive and neural basis of systemizing. AB - In 2003, we proposed the hypersystemizing theory of autism. The theory proposes that the human mind possesses a systemizing mechanism (SM) that helps identify lawful regularities (often causal) that govern the input-operation-output workings of a system. The SM can be tuned to different levels, from low to high, with a normal distribution of individual differences in how strongly people search for such input-operation-out-put regularities in any data that is systemizable. Evidence suggests that people with autism are on average hypersystemizers, scoring higher than average on the systemizing quotient and on performance tests of systemizing. In this article, we consider the neural basis behind the SM, since there has been little consideration of the brain basis of systemizing. Finally, we discuss directions for future work in this field. PMID- 29398932 TI - Neuropsychological assessment in autism spectrum disorder and related conditions. AB - Neuropsychological assessment provides a profound analysis of cognitive functioning in people with autism spectrum disorder (ASD). Individuals on the autistic spectrum often show a high level of anxiety and are frequently affected by comorbidities that influence their quality of life. Yet, they also have cognitive strengths that should be identified in order to develop effective support strategies. This article presents an overview of five cognitive areas that are essential for neuropsychological evaluation (ie, intelligence, attention, executive function, social cognition, and praxis) and explores the underlying causes of behavioral problems in persons with ASD. Furthermore, it stresses the importance of meticulous neuropsychological testing with regard to cognitive remediation, a method that can help to enhance single cognitive processes in a targeted manner. Objective test results suggest it might be possible to promote an improved sense of coherence. In line with the salutogenic model, this may be fundamental for human health and well-being. PMID- 29398931 TI - Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach. AB - Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the associated spectrum and penetrance of neurobehavioral and somatic manifestations. PMID- 29398933 TI - Sexuality in autism: hypersexual and paraphilic behavior in women and men with high-functioning autism spectrum disorder. AB - Like nonaffected adults, individuals with autism spectrum disorders (ASDs) show the entire range of sexual behaviors. However, due to the core symptoms of the disorder spectrum, including deficits in social skills, sensory hypo- and hypersensitivities, and repetitive behaviors, some ASD individuals might develop quantitatively above-average or nonnormative sexual behaviors and interests. After reviewing the relevant literature on sexuality in high-functioning ASD individuals, we present novel findings on the frequency of normal sexual behaviors and those about the assessment of hypersexual and paraphilic fantasies and behaviors in ASD individuals from our own study. Individuals with ASD seem to have more hypersexual and paraphilic fantasies and behaviors than general population studies suggest. However, this inconsistency is mainly driven by the observations for male participants with ASD. This could be due to the fact that women with ASD are usually more socially adapted and show less ASD symptomatology. The peculiarities in sexual behaviors in ASD patients should be considered both for sexual education and in therapeutic approaches. PMID- 29398935 TI - Vaccination as a cause of autism-myths and controversies. AB - Despite significant progress in the study of the epidemiology and genetics of autism, the etiology and patho-physiology of this condition is far from being elucidated and no curative treatment currently exists. Although solid scientific research continues, in an attempt to find explanations and solutions, a number of nonscientific and pure myths about autism have emerged. Myths that vaccines or mercury are associated with autism have been amplified by misguided scientists; frustrated, but effective parent groups; and politicians. Preventing the protection provided by vaccination or administration of mercury-chelating agents may cause real damage to autistic individuals and to innocent bystanders who as a result may be exposed to resurgent diseases that had already been "extinguished. " That such myths flourish is a consequence of the authority of scientific evidence obtained by scientific methodology losing ground to alternative truths and alternative science. This article presents a narrative of the origin of the myths around autism. PMID- 29398934 TI - Pharmacotherapy of emotional and behavioral symptoms associated with autism spectrum disorder in children and adolescents. AB - Autism spectrum disorder (ASD) is characterized by impairment in social communication and restricted patterns of behavior. Although there is no pharmacological treatment approved by the US Food and Drug Administration (FDA) for the core symptoms of ASD, there is mounting support in the literature for the management of behavioral symptoms associated with this developmental disorder, in particular, irritability and hyperactivity. Aripiprazole and risperidone are currently approved by the FDA for the treatment of irritability in youth with ASD. Though not FDA-approved, methylphenidate and guanfacine are effective for the management of hyperactivity in children with ASD. Selective serotonin reuptake inhibitors are often used in clinical practice to target anxiety and compulsions; however, there is little evidence to support its use in this population. There is a great need for further research on the safety and efficacy of existing psychotropic medications in youth with ASD, as well as the development of new treatment modalities for the core and associated behavioral symptoms. PMID- 29398936 TI - Genetic dissection of agronomically important traits in closely related temperate japonica rice cultivars. AB - Many quantitative trait loci (QTLs) for agronomically important traits such as grain yield, disease resistance, and stress tolerance of rice (Oryza sativa L.) have been detected by using segregating populations derived from crosses between indica and japonica subspecies or with wild relatives. However, the QTLs involved in the control of natural variation in agronomic traits among closely related cultivars are still unclear. Decoding the whole genome sequences of Nipponbare and other temperate japonica rice cultivars has accelerated the collection of a huge number of single nucleotide polymorphisms (SNPs). These SNPs are good resource for developing polymorphic DNA markers and for detecting QTLs distributed across all rice chromosomes. The temperate japonica rice cultivar Koshihikari has remained the top cultivar for about 40 years since 1979 in Japan. Unraveling the genetic factors in Koshihikari will provide important insights into improving agronomic traits in temperate japonica rice cultivars. Here we describe recent progress in our studies as an example of genetic analysis in closely related cultivars. PMID- 29398937 TI - Genome-wide association mapping for flowering and maturity in tropical soybean: implications for breeding strategies. AB - Knowledge of the genetic architecture of flowering and maturity is needed to develop effective breeding strategies in tropical soybean. The aim of this study was to identify haplotypes across multiple environments that contribute to flowering time and maturity, with the purpose of selecting desired alleles, but maintaining a minimal impact on yield-related traits. For this purpose, a genome wide association study (GWAS) was undertaken to identify genomic regions that control days to flowering (DTF) and maturity (DTM) using a soybean association mapping panel genotyped for single nucleotide polymorphism (SNP) markers. Complementarily, yield-related traits were also assessed to discuss the implications for breeding strategies. To detect either stable or specific associations, the soybean cultivars (N = 141) were field-evaluated across eight tropical environments of Brazil. Seventy-two and forty associations were significant at the genome-wide level relating respectively to DTM and DTF, in two or more environments. Haplotype-based GWAS identified three haplotypes (Gm12_Hap12; Gm19_Hap42 and Gm20_Hap32) significantly co-associated with DTF, DTM and yield-related traits in single and multiple environments. These results indicate that these genomic regions may contain genes that have pleiotropic effects on time to flowering, maturity and yield-related traits, which are tightly linked with multiple other genes with high rates of linkage disequilibrium. PMID- 29398938 TI - Effect of indica pedigree on eating and cooking quality in rice backcross inbred lines of indica and japonica crosses. AB - Amylopectin is one of the major determinants of rice (Oryza sativa L.) grain quality, and a large difference in amylopectin is found between two subspecies: japonica and indica. However, the relationship among rice grain quality, indica/japonica genetic background, and amylopectin has not been clearly established. In this study, a series of backcross inbred lines derived from the cross between japonica (cv. Sasanishiki) and indica (cv. Habataki) were used to survey eating and cooking quality (ECQ), rapid visco analyzer (RVA) profiles, and the chain length distribution of amylopectin. The frequency of indica pedigree (Fi) was calculated to analyze the effects of Fi on grain quality and amylopectin. The results showed that the Sasanishiki cultivar was markedly enriched in chain length with DP6-15 and DP34-45 compared to the Habataki. DP34 45 strongly correlated to RVA characteristics, cooking quality, and prolamin content. The Fi also has significant correlations to RVA characteristics and ECQ, but only significantly negative correlation to DP34-45. Seven quantitative trait loci (QTLs) corresponding to amylopectin were mapped, of which three were in agreement with previous findings. The results of this study provide valuable information for amylopectin characteristics in the offspring derived from the subspecies cross, and the novel QTLs may provide new insights to the identification of minor starch synthesis-related genes. PMID- 29398939 TI - Resistance vs. tolerance to Potato virus Y in tobacco-comparing effectiveness using virus isolates from Central Europe. AB - Growing resistant cultivars is the best method of protecting the crops against Potato virus Y (PVY). There are a few sources of PVY resistance/tolerance in tobacco acquired through mass selection, X-ray induced mutagenesis and introgressions from wild Nicotiana species. Here, we compare major sources of PVY resistance/tolerance in inoculation tests using ten PVY isolates collected in Central Europe (Poland and Germany) and differing with their virulence. The diversity of collected isolates was confirmed by DAS-ELISA tests and two PCR assays targeting the most common recombination sites in the PVY genome. We used these isolates in inoculation tests on five resistant cultivars 'V.SCR', 'PBD6', 'TN86', 'VAM', 'Wislica', a tolerant breeding line 'BPA' and four susceptible cultivars 'BP-210', 'K326', 'NC95', 'Samsun H'. None of the tested cultivars/breeding lines showed universal resistance against all ten isolates. However, 'VAM' and 'Wislica' appeared to be the most effective sources, as they showed no symptoms and gave negative DAS-ELISA tests for four out of ten tested PVY isolates. In contrast, tolerance of the breeding line 'BPA' was effective against all tested isolates, because inoculation did not lead to development of full disease symptoms in that breeding line. PMID- 29398940 TI - Improving preharvest sprouting resistance in durum wheat with bread wheat genes. AB - Preharvest sprouting (PHS) of durum wheat (Triticum turgidum ssp. durum (Desf.) Husn.) is an important problem in Japan, where the rainy season overlaps with the harvest season. Since there are few PHS-resistant genetic resources in durum wheat, we introduced an R-gene for red seeds, the MFT gene, and the QPhs-5AL QTL, all of which are associated with PHS resistance, into durum wheat from a PHS resistant bread wheat (T. aestivum L.) cultivar, 'Zenkoujikomugi' (Zen), by backcross breeding. Developed near isogenic lines (NILs) with red seeds had a lower percentage germination (PG) and germination index (GI) than the recurrent parent, and seed color had the greatest effect. A NIL combining all three sequences had the lowest GI and PG, with a similar GI to that of 'Shiroganekomugi' bread wheat. Among NILs with white seeds, a NIL combining MFT and QPhs-5AL had the lowest GI and PG. As the combination of all three sequences from Zen conferred PHS resistance on durum wheat, PHS-resistant genetic resources in bread wheat can be used in breeding durum wheat. PMID- 29398941 TI - Identify QTLs for grain size and weight in common wild rice using chromosome segment substitution lines across six environments. AB - Grain size and weight are important determinants of rice yield. The identification of beneficial genes from wild rice that have been lost or weakened in cultivated rice has become increasingly important for modern breeding strategies. In this study, we constructed a set of chromosome segment substitution lines (CSSLs) of wild rice, Oryza rufipogon with the indica cultivar 9311 genetic background. Four grain-related traits, i.e., grain length (GL), grain width (GW), length-width ratio (LWR), and thousand grain weight (TGW), were screened across six environments. A total of 37 quantitative trait loci (QTLs) were identified in these environments and mapped to 12 chromosomes. Sixteen QTLs were detected in at least two environments, and two QTL clusters were observed on Chr. 4 and Chr. 8. Based on a comparative analysis with QTLs identified in previous studies, the CSSLs between Oryza rufipogon accessions and 9311 had high genetic diversity. Among the sixteen stable QTLs, seven for TGW, LWR, GL, and GW were not previously identified, indicating potentially novel alleles from wild rice. These CSSLs provide powerful tools for functional studies and the cloning of essential genes in rice; furthermore, we identified elite germplasm for rice variety improvement. PMID- 29398942 TI - Genetic variation in heat tolerance-related traits in a population of wheat multiple synthetic derivatives. AB - In wheat (Triticum aestivum L.) high temperature (>=30 degrees C) during grain filling leads to considerable reduction in grain yield. We studied 400 multiple synthetic derivatives (MSD) lines to examine the genetic variability of heat stress-adaptive traits and to identify new sources of heat tolerance to be used in wheat breeding programs. The experiment was arranged in an augmented randomized complete block design in four environments in Sudan. A wide range of genetic variability was found in most of the traits in all environments. For all traits examined, we found MSD lines that showed better performance than their parent 'Norin 61' and two adapted Sudanese cultivars. Using the heat tolerance efficiency, we identified 13 highly heat-tolerant lines and several lines with intermediate heat tolerance and good yield potential. We also identified lines with alleles that can be used to increase wheat yield potential. Our study revealed that the use of the MSD population is an efficient way to explore the genetic variation in Ae. tauschii for wheat breeding and improvement. PMID- 29398943 TI - Genetic variation in resistance to blast (Pyricularia oryzae Cavara) in rice (Oryza sativa L.) germplasms of Bangladesh. AB - Genetic variation in blast resistance was clarified in 334 Bangladesh rice accessions from 4 major ecotypes (Aus, Aman, Boro and Jhum). Cluster analysis of polymorphism data of 74 SSR markers separated these accessions into cluster I (corresponding to the Japonica Group) and cluster II (corresponding to the Indica Group). Cluster II accessions were represented with high frequency in all ecotypes. Cluster II was further subdivided into subclusters IIa and IIb. Subcluster IIa accessions were represented with high frequency in only Aus and Jhum ecotypes. Cluster I accessions were more frequent in the Aman ecotype than in other ecotypes. Distinct variations in resistance were found, and accessions were classified into 4 groups (A1, A2, B1 and B2) based on their reactions to standard differential blast isolates. The most susceptible group was A2 (which included susceptible variety Lijiangxintuanheigu, most of the differential varieties, and a few Bangladesh accessions), followed in order by A1, B2 and B1 (the most resistant). Accessions from 4 ecotypes fell with different frequencies into each of these resistance groups. These results demonstrated that Japonica Group accessions were found mainly in Aman, and Indica Group accessions were distributed across all ecotypes. Susceptible accessions were limited in Aus and Aman. PMID- 29398944 TI - Genetic variation in blast resistance in rice germplasm from West Africa. AB - The genetic variation in resistance to blast (Pyricularia oryzae Cavara) in 195 rice accessions comprising 3 species of the AA genome complex (Asian rice [Oryza sativa L.], African rice [Oryza glaberrima Steud.] and wild rice [Oryza barthii]) was investigated based on their patterns of reaction to standard differential blast isolates (SDBIs) and SSR marker polymorphism data. Cluster analysis of the polymorphism data of 61 SSR markers identified 3 major clusters: cluster A (mainly Japonica Group or upland accessions), cluster B (mainly Indica Group or lowland accessions) and cluster C (O. glaberrima and O. barthii). The accessions were classified again into 3 resistance groups based on reactions to SDBIs: group Ia (susceptible), group Ib (middle resistance) and group II (high resistance). Group Ia included only a few differential varieties, susceptible controls and the Japonica Group cultivar Nipponbare. Accessions in clusters A and B included all 3 resistance groups and showed a wide variation in blast resistance, but cluster C contained only group Ib. These results demonstrated that variations in Asian rice (O. sativa) accessions in West Africa were skewed toward high resistance and that variations in O. glaberrima and O. barthii were limited and lower than the Asian rice accessions. PMID- 29398945 TI - A novel compensating wheat-Thinopyrum elongatum Robertsonian translocation line with a positive effect on flour quality. AB - Wheat flours are used to produce bread, pasta, breakfast cereals, and biscuits; the various properties of these end-products are attributed to the gluten content, produced as seed storage proteins in the wheat endosperm. Thus, genes encoding gluten protein are major targets of wheat breeders aiming to improve the various properties of wheat flour. Here, we describe a novel compensating wheat Thinopyrum elongatum Robertsonian translocation (T1AS.1EL) line involving the short arm of wheat chromosome 1A (1AS) and the long arm of Th. elongatum chromosome 1E (1EL); we developed this line through centric breakage-fusion. Compared to the common wheat cultivars Chinese Spring and Norin 61, we detected two additional 1EL-derived high-molecular-weight glutenin subunits (HMW-GSs) in the T1AS.1EL plants. Based on the results of an SDS-sedimentation volume to estimate the gluten strength of T1AS.1EL-derived flour, we predict that T1AS.1EL derived flour is better suited to bread-making than Chinese Spring- and Norin 61 derived flour and that this is because of its greater gluten diversity. Also, we were able to assign 33 of 121 wheat PCR-based Landmark Unique Gene markers to chromosome 1E of Th. elongatum. These markers can now be used for further chromosome engineering of the Th. elongatum segment of T1AS.1EL. PMID- 29398946 TI - QTL-seq analysis identifies two genomic regions determining the heading date of foxtail millet, Setaria italica (L.) P.Beauv. AB - Heading date is an important event to ensure successful seed production. Although foxtail millet (Setaria italica (L.) P.Beauv.) is an important foodstuff in semiarid regions around the world, the genetic basis determining heading date is unclear. To identify genomic regions regulating days to heading (DTH), we conducted a QTL-seq analysis based on combining whole-genome re-sequencing and bulked-segregant analysis of an F2 population derived from crosses between the middle-heading cultivar Shinanotsubuhime and the early-heading cultivar Yuikogane. Under field conditions, transgressive segregation of DTH toward late heading was observed in the F2 population. We made three types of bulk samples: Y bulk (early-heading), S-bulk (late-heading) and L-bulk (extremely late-heading). By genome-wide comparison of SNPs in the Y-bulk vs. the S-bulk and the Y-bulk vs. the L-bulk, we identified two QTLs associated with DTH. The first QTL, qDTH2, was detected on chromosome 2 from the Y-bulk and S-bulk comparison. The second QTL, qDTH7, was detected on chromosome 7 from the Y-bulk and L-bulk comparison. The Shinanotsubuhime allele for qDTH2 caused late heading in the F2 population, whereas the Yuikogane allele for qDTH7 led to extremely late heading. These results suggest that allelic differences in both qDTH2 and qDTH7 determine regional adaptability in S. italica. PMID- 29398947 TI - Phenotypic changes during 100-year rice breeding programs in Hokkaido. AB - Plant breeding programs in local regions may have genetic and phenotypic variations that are desirable and shape adaptability during the establishment of local populations. Despite the characterization of genetic population structures in various kinds of populations, the effects of variations in phenotype on agro economical traits currently remain unclear. In the present study, we evaluated phenotypic changes in 26 agro-economical traits among the local population during rice breeding programs in Hokkaido. Wide variations were observed in all 26 agro economical traits with continuous distributions. In order to elucidate improvements in these agro-economic traits during rice breeding programs in Hokkaido, values were compared between genetic population structures. Traits were classified into four patterns based on the timing of significant differences. Patterns A and B showed significant differences once and twice, respectively. Pattern C gradually showed significant differences. Pattern D showed no significant differences for the desired directions. Based on the changes in phenotype observed in the present study and the genetic population structure for the local population in Hokkaido, a model of the artificial selection for phenotypes in genetic diversity among the local population during plant breeding programs has been proposed. PMID- 29398948 TI - Development and validation of a functional co-dominant SNP marker for the photoperiod thermo-sensitive genic male sterility pms3 (p/tms12-1) gene in rice. AB - The fertility conversion of photoperiod thermo-sensitive genic male sterility (P/TGMS) lines in rice is mostly regulated by the P/TGMS genes in different environmental conditions. A point mutation with G-C on the pms3 (p/tms12-1) gene regulates the pollen fertility of Nongken58S and a large amount of Nongken58S derived lines. In this study, we developed and designed a functional co-dominant marker according to the SNP loci for the pms3 (p/tms12-1) gene. We can differentiate the SNP loci in pms3 (p/tms12-1) gene from another TGMS lines and inbred cultivars using the dpms3-54 marker. The results showed that 376 bp band was detected in the homozygous genotype for pms3 (p/tms12-1), while 359 bp band was detected in the homozygous genotype for non-pms3 (p/tms12-1), two bands with 376 and 359 bp were detected in the heterozygous genotype. The dpms3-54 marker can be used to test the purity of two-line hybrid rice seeds and to divide each of F1 plant into homozygous and heterozygous genotypes at the seedling stage. Thus, this study provide a useful functional marker to detect pms3 (p/tms12-1) gene in different genetic resources and populations, which can be applied to the development and breeding of P/TGMS lines in two-line hybrid rice system with marker-assisted selection. PMID- 29398949 TI - Identification of QTLs for rice brown spot resistance in backcross inbred lines derived from a cross between Koshihikari and CH45. AB - Rice brown spot (BS), caused by Bipolaris oryzae, is one of the major diseases of rice in Japan. Quantitative resistance has been observed in local cultivars (e.g., CH45), but no economically useful resistant variety has been bred. Using simple sequence repeat (SSR) polymorphic markers, we conducted quantitative trait locus (QTL) analysis of BS resistance in backcross inbred lines (BILs) from a cross between indica CH45 (resistant) and japonica Koshihikari (susceptible). On the basis of field disease evaluations in 2015 and 2016, four QTLs contributing to BS resistance were identified on chromosomes 2 (qBSR2-kc), 7 (qBSR7-kc), 9 (qBSR9-kc), and 11 (qBSR11-kc). The 'CH45' alleles at qBSR2-kc, qBSR7-kc, and qBSR11-kc and the 'Koshihikari' allele at qBSR9-kc increased resistance. The major QTL qBSR11-kc explained 23.0%-25.9% of the total phenotypic variation. Two QTLs (qBSR9-kc and qBSR11-kc) were detected in both years, whereas the other two were detected only in 2016. Genetic markers flanking these four QTLs will be powerful tools for marker-assisted selection to improve BS resistance. PMID- 29398950 TI - A set of tetra-nucleotide core motif SSR markers for efficient identification of potato (Solanum tuberosum) cultivars. AB - Simple sequence repeat (SSR) is a popular tool for individual fingerprinting. The long-core motif (e.g. tetra-, penta-, and hexa-nucleotide) simple sequence repeats (SSRs) are preferred because they make it easier to separate and distinguish neighbor alleles. In the present study, a new set of 8 tetra nucleotide SSRs in potato (Solanum tuberosum) is reported. By using these 8 markers, 72 out of 76 cultivars obtained from Japan and the United States were clearly discriminated, while two pairs, both of which arose from natural variation, showed identical profiles. The combined probability of identity between two random cultivars for the set of 8 SSR markers was estimated to be 1.10 * 10-8, confirming the usefulness of the proposed SSR markers for fingerprinting analyses of potato. PMID- 29398951 TI - The relationship between religious beliefs and behaviors and changes in spiritual health locus of control over time in a national sample of African Americans. AB - Using data from a sample of African Americans, the present study examined the role of religious beliefs and behaviors in predicting changes in spiritual health locus of control (SHLOC), or beliefs about the role that God plays in a person's health. A national sample of African American adults was recruited using a telephone survey and re-contacted 2.5 years later. Overall, results indicated that both higher religious beliefs and behaviors predicted increases in active SHLOC, or the view that one collaboratively works with God to maintain one's health. However, only religious behaviors predicted increases in passive SHLOC, or the view that because God is in complete control of health that one's own behaviors are unnecessary. Among men, religious beliefs predicted strengthening active SHLOC beliefs, while religious behaviors predicted growing passive SHLOC beliefs. Among women, religious behaviors predicted strengthening active and passive SHLOC beliefs. PMID- 29398952 TI - Naphthenic acids removal from high TDS produced water by persulfate mediated iron oxide functionalized catalytic membrane, and by nanofiltration. AB - Oil industries generate large amounts of produced water containing organic contaminants, such as naphthenic acids (NA) and very high concentrations of inorganic salts. Recovery of potable water from produced water can be highly energy intensive is some cases due to its high salt concentration, and safe discharge is more suitable. Here, we explored catalytic properties of iron oxide (FexOy nanoparticles) functionalized membranes in oxidizing NA from water containing high concentrations of total dissolved solids (TDS) using persulfate as an oxidizing agent. Catalytic decomposition of persulfate by FexOy functionalized membranes followed pseudo-first order kinetics with an apparent activation energy of 18 Kcal/mol. FexOy functionalized membranes were capable of lowering the NA concentrations to less than discharge limits of 10 ppm at 40 degrees C. Oxidation state of iron during reaction was quantified. Membrane performance was investigated for extended period of time. A coupled process of advanced oxidation catalyzed by membrane and nanofiltration was also evaluated. Commercially available nanofiltration membranes were found capable of retaining NA from water containing high concentrations of dissolved salts. Commercial NF membranes, Dow NF270 (Dow), and NF8 (Nanostone) had NA rejection of 79% and 82%, respectively. Retentate for the nanofiltration was further treated with advanced oxidation catalyzed by FexOy functionalized membrane for removal of NA. PMID- 29398953 TI - Below the radar innovations and emerging property right approaches in Tibetan medicine. AB - Outside the established legal framework of intellectual property rights, countries have pursued multiple pathways to protect and promote traditional medicine. As Tibetan medicine is a late entrant into commercialization, the proposals to propertize generally fall within the rationale of existing sui generis paradigms of Intellectual property. In this context, the article enquires the state of innovations in this sector viz-a-viz the property right approaches in place especially in India and China. It argues that beyond the usual complex medical science and technology led-innovations, the pathways of cumulative processes and creative additions through informal experiential learning platforms, where the transfers of knowledge become part of livelihood and social benefits (we call them "below the radar innovations") is ubiquitous in Tibetan medicine. The trends and politics in two recent strategies of protection, that is, Tibetan medicine as economic property (emphasizing patents here among many others) and as a cultural property (intangible cultural heritage) are juxtaposed with these informal innovative attempts. The paper underlines that the productivity-based economic rationale of these protection mechanisms should not obscure sustainability alternatives of "below the radar" (BtR) innovations in Tibetan medicine. PMID- 29398954 TI - Oxidation of Vicinal Diols to alpha-Hydroxy Ketones with H2O2 and a Simple Manganese Catalyst. AB - alpha-Hydroxy ketones are valuable synthons in organic chemistry. Here we show that oxidation of vic-diols to alpha-hydroxy ketones with H2O2 can be achieved with an in situ prepared catalyst based on manganese salts and pyridine-2 carboxylic acid. Furthermore the same catalyst is effective in alkene epoxidation, and it is shown that alkene oxidation with the MnII catalyst and H2O2 followed by Lewis acid ring opening of the epoxide and subsequent oxidation of the alkene to alpha-hydroxy ketones can be achieved under mild (ambient) conditions. PMID- 29398955 TI - Black hole solutions in mimetic Born-Infeld gravity. AB - The vacuum, static, and spherically symmetric solutions in the mimetic Born Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite. PMID- 29398956 TI - Rapidity gap survival in enhanced Pomeron scheme. AB - We apply the phenomenological Reggeon field theory framework to investigate rapidity gap survival (RGS) probability for diffractive dijet production in proton-proton collisions. In particular, we study in some detail rapidity gap suppression due to elastic rescatterings of intermediate partons in the underlying parton cascades, described by enhanced (Pomeron-Pomeron interaction) diagrams. We demonstrate that such contributions play a subdominant role, compared to the usual, so-called "eikonal", rapidity gap suppression due to elastic rescatterings of constituent partons of the colliding protons. On the other hand, the overall RGS factor proves to be sensitive to color fluctuations in the proton. Hence, experimental data on diffractive dijet production can be used to constrain the respective model approaches. PMID- 29398957 TI - Awareness of ionizing radiation and its effects among clinicians. PMID- 29398958 TI - Treatment Response Evaluation using Yttrium-90 in Patients with Rheumatoid Arthritis of Knee Joint. AB - For radiosynovectomy, we have measured the retention time of yttrium-90 (90Y) hydroxyapatite (particle size 1-10 MUm) within the knee joint space and evaluated the treatment responses in knees with rheumatoid arthritis. Radioactive measurements in the region of knee after injection of 90Y hydroxyapatite into the joint space were made with a single prove system designed to monitor radioactivity and showed retention of 90Y in the knee ranged 76.6% +/-5.4% after 4 days of injection. The clinical improvements in rheumatoid arthritis of knee joint with steinbroker Stages I and II were increased as time goes by, the improvement ratio is in 72% at 6th months and 76% at 12th months after injection of 90Y 185 MBq (5 mCi) per joint. PMID- 29398959 TI - Synovectomy using Samarium-153 Hydroxyapatite in the Elbows and Ankles of Patients with Hemophilic Arthropathy. AB - This study aimed to evaluate synovectomy with samarium-153 hydroxyapatite (153Sm HA) in synovitis of the elbows and ankles of hemophilic patients. The synovectomy was performed using 185 MBq of 153Sm-HA in 166 joints of 82 hemophilic patients, with a mean age of 24.4 years and follow-up of 12 and 42 months, comprising 63 ankles and 84 elbows. Arthropathy was characterized by recurrent joint bleeding. Episodes of hemarthrosis, use of clotting factors, and pain intensity were evaluated before and after treatment. Scintigraphic controls and adverse effects were also considered. Statistical analyses used P <= 0,005 as significant. The results pointed that (a) reduction in hemarthrosis was 78% and 68% in elbows and 82% and 72% in ankles; (b) use of clotting factors was 80% and 70% in elbows and 85% and 75% in ankles; (c) pain was 37% and 34% in elbows and 61% and 57% in ankles, after 12 and 42 months, respectively. Three cases of mild reactive synovitis were observed in ankles and four in elbows. There was no joint effusion in any of the cases. In conclusion, the use of 153Sm-HA in elbows and ankles was effective, very safe, minimally invasive and showed consistency over time, is another material to utilize in median hemophilic joints. PMID- 29398960 TI - 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in Patients with Borderline Low and Discordant Renal Parameters: Treatment Feasibility Assessment by Sequential Estimation of Triple Parameters and Filtration Fraction. AB - The aim was to assess the effect of standard fixed-dose protocol of 177Lu DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with borderline low renal function of one parameter (glomerular filtration rate [GFR], effective renal plasma flow [ERPF] or serum creatinine), that was discordant with the remaining parameters and determine the feasibility of this procedure in this group of patients. Renal toxicity of PRRT is a routine issue or concern for such cases. We compared different renal parameters used for pretherapy assessment in patients with borderline low single parameter at baseline and their potential significance with regards to deterioration of renal function subsequently. A retrospective analysis was performed in patients of metastatic neuroendocrine tumors who received therapeutic 177Lu-DOTATATE (using standard fixed-dose protocol) and had borderline compromised renal parameter values (either of GFR/ERPF/serum creatinine). Filtration fraction (FF) was also estimated in each case and all renal parameters were correlated using kappa statistics. The characteristics of cases showing progressive worsening of renal function in the follow-ups were also studied. A total of 15 patients (11 males, 4 females; age range: 32-75 years) were selected among a population of 450 patients. The follow up duration ranged from 10 to 48 months and administered cumulative activity ranged 9.9-31.3 GBq (2-5 cycles). Based on the parameter characteristics, the study population was divided into following four groups: (a) patients with reduced GFR and maintained ERPF and normal serum creatinine (n = 3); (b) patients with reduced ERPF with maintained GFR and borderline elevated/normal serum creatinine (n = 3); (c) patients with both reduced GFR and ERPF and maintained serum creatinine (n = 1); (d) patients with compromised single kidney function (n = 5). A total of four patients were found who had normal baseline renal function values but showed progressive worsening in the subsequent period. There was no significant change in renal parameters during the follow-up in both Groups a and c. Two patients of Group b demonstrated well-maintained other renal parameters, whereas in 1 patient, there was the evidence of renal toxicity with gradual fall of GFR and ERPF and progressive increase in serum creatinine level. In patients with compromised single kidney function at baseline (Group d), there was overall maintained normal renal parameters, whereas 3 of 5 (60%) showed the increase of FF of the affected kidney. Interestingly, a compensatory hyperfunction was noted in the contralateral kidney. PRRT with 177Lu-DOTATATE is feasible and can be considered in patients with reduced GFR and with maintained ERPF and normal serum creatinine and also in the presence of single compromised parameter if the other two are normal; however, these patients need critical monitoring. PMID- 29398961 TI - Comparison of Standardized Uptake Value Ratio Calculations in Amyloid Positron Emission Tomography Brain Imaging. AB - Amyloid positron emission tomography (PET) imaging with florbetapir 18F (18F-AV 45) allows in vivo assessment of cerebral amyloid load and can be used in the evaluation of progression of Alzheimer's disease (AD) and other dementias associated with b-amyloid. However, cortical amyloid deposition can occur in healthy cases, as well as in patients with AD and quantification of cortical amyloid burden can improve the 18F-AV-45 PET imaging evaluations. The quantification is mostly performed by cortical-to-cerebellum standardized uptake value ratio (SUVr). The aim of our study was to compare two methods for SUVr calculations in amyloid florbetapir 18F PET brain imaging. In amyloid florbetapir 18F PET brain imaging study, we imaged 42 cases with the mean age of 72.6 +/- 9.9 (mean +/- standard deviation). They were imaged on different PET/computed tomography systems with 369.0 +/- 34.2 kBq of 18F florbetapir. Data were reconstructed using the vendor's reconstruction software. Corresponding magnetic resonance imaging (MRI) data were retrieved, and matched PET and MRI data were transferred to a common platform. Two methods were used for the calculation of the ratio of cortical-to-cerebellar signal (SUVr). One method was based on the MIM Software Inc., Version 6.4 software and only uses PET data. The second approach used the PMOD Neuro tool (version 3.5). This approach utilizes PET and corresponding MRI data (preferably T1-weighted) for better brain segmentation. For all the 42 cases, the average SUVr values for MIM and PMOD applications were 1.24 +/- 0.26 and 1.22 +/- 0.25, respectively, with a mean difference of 0.02 +/- 0.15. The repeatability coefficient was 0.15 (12.3% of the mean). The Spearman's rank correlation coefficient was very high, r = 0.96. For amyloid-negative cases, the average SUVr values were lower than all group SUVr average values, 0.96 +/- 0.07 and 1.00 +/- 0.09, for MIM and PMOD applications, respectively. A mean difference was 0.04 +/- 0.12, the repeatability coefficient was 0.12 (12.9% of the mean) and the Spearman's rank correlation coefficient was modest, r = 0.55. For amyloid-positive patients, the average SUVr values were higher than the same all group values, 1.34 +/- 0.16 and 1.35 +/- 0.20, respectively, with a mean difference of 0.01 +/- 0.16. The repeatability coefficient was 0.16 (11.9% of the mean). The Spearman's rank correlation coefficient was high, r = 0.93. Our results indicated that the SUVr values derived using MIM and PMOD Neuro are effectively interchangeable and well correlated. However, PET template-based quantification (MIM approach) is clinically friendlier and easier to use. MRI template-based quantification (PMOD Neuro) better delineates different regions of the brain, can be used with any tracer, and therefore is more suitable for research. PMID- 29398962 TI - Detection of Lower Limb Deep Vein Thrombosis: Comparison between Radionuclide Venography and Venous Ultrasonography. AB - Deep vein thrombosis (DVT) is a serious medical condition that needs prompt diagnosis and treatment. The invasive gold standard contrast venography has largely been replaced by venous ultrasonography which is currently the imaging modality of choice for DVT diagnosis. Radionuclide venography (RNV) is an alternative test for DVT, but a few studies have directly compared RNV with venous ultrasonography. This study aims to determine the agreement between RNV and venous ultrasonography for diagnosis of DVT and to determine the predictive value of different RNV findings for the prediction of DVT as detected by venous ultrasonography. Imaging results from patients who underwent both RNV and venous ultrasonography for suspected DVT no more than 1 week apart were reviewed. Results from both modalities were compared to determine inter-modality agreement. A total of 121 venous segments from 102 lower limbs of 75 patients could be compared. The prevalence of DVT as detected by venous ultrasonography was 39%. RNV and venous ultrasonography had moderate agreement (73.6% agreement, kappa =0.48, P < 0.0001). The absence of radiotracer activity from a deep venous segment had a positive predictive value (PPV) of 100% for DVT. Other findings such as isolated great saphenous vein activity had a lower PPV. The negative predictive value of RNV is 97.5% with only one patient out of forty with normal RNV found to have DVT by venous ultrasonography, which suggests that DVT can virtually be excluded in patients with normal RNV. PMID- 29398963 TI - Correlation between Standardized Uptake Value of 68Ga-DOTA-NOC Positron Emission Tomography/Computed Tomography and Pathological Classification of Neuroendocrine Tumors. AB - The aim of our study was to correlate tumor uptake of 68Ga-DOTA-NOC positron emission tomography/computed tomography (PET/CT) with the pathological grade of neuroendocrine tumors (NETs). 68Ga-DOTA-NOC PET/CT examinations in 41 patients with histopathologically proven NETs were included in the study. Maximum standardized uptake value (SUVmax) and averaged SUV SUVmean of "main tumor lesions" were calculated for quantitative analyses after background subtraction. Uptake on main tumor lesions was compared and correlated with the tumor histological grade based on Ki-67 index and pathological differentiation. Classification was performed into three grades according to Ki-67 levels; low grade: Ki-67 <2, intermediate grade: Ki-67 3-20, and high grade: Ki-67 >20. Pathological differentiation was graded into well- and poorly differentiated groups. The values were compared and evaluated for correlation and agreement between the two parameters was performed. Our study revealed negatively fair agreement between SUVmax of tumor and Ki-67 index (r = -0.241) and negatively poor agreement between SUVmean of tumor and Ki-67 index (r = -0.094). SUVmax of low-grade, intermediate-grade, and high-grade Ki-67 index is 26.18 +/- 14.56, 30.71 +/- 24.44, and 6.60 +/- 4.59, respectively. Meanwhile, SUVmean of low grade, intermediate-grade, and high-grade Ki-67 is 8.92 +/- 7.15, 9.09 +/- 5.18, and 3.00 +/- 1.38, respectively. As expected, there was statistically significant decreased SUVmax and SUVmean in high-grade tumors (poorly differentiated NETs) as compared with low- and intermediate-grade tumors (well-differentiated NETs). SUV of 68Ga-DOTA-NOC PET/CT is not correlated with histological grade of NETs. However, there was statistically significant decreased tumor uptake of 68Ga-DOTA NOC in poorly differentiated NETs as compared with the well-differentiated group. As a result of this pilot study, we confirm that the lower tumor uptake of 68Ga DOTA-NOC may be associated with aggressive behavior and may, therefore, result in poor prognosis. PMID- 29398964 TI - Stimulated Serum Thyroglobulin Levels versus Unstimulated Serum Thyroglobulin in the Follow-up of Patients with Papillary Thyroid Carcinoma. AB - Serum thyroglobulin (Tg) and thyroid whole-body radioiodine scintigraphy (TWBS) are used in the follow-up of patients with papillary thyroid carcinoma (PTC) after total thyroidectomy. Symptoms of hypothyroidism are frequent as patients discontinue levothyroxine 1 month before visit, favoring the use of unstimulated serum Tg (uSTg) only. This study was done to determine the reliability of stimulated serum Tg levels (sSTg) over uSTg. A total of 650 patients with PTC came for follow-up between June 2011 and 2016. In those who had levels of uSTg and sSTg months measured within an interval of median of 3 months (range from 1 to 8 months), risk stratification was done as per the American Thyroid Association guidelines 2015. Intervention was based on a cutoff value of sSTg >10 ng/ml in our institution and the same was used for data analysis. Out of 650 patients, 106 had paired Tg values. Low-, intermediate-, and high-risk groups comprised 40, 31, and 35 patients, respectively. The sSTg >10 ng/ml with uSTg <10 ng/ml in the same patient was noted in 22.5% (9/40) of the low-risk, 41.9% (13/31) of the intermediate-risk, and 14.2% (5/35) of the high-risk groups. The levels were corroborated with tumor burden as determined by additional clinical, ultrasonography neck, and TWBS findings. Our study highlights the superiority of sSTg over uSTg in the follow-up of PTC patients. Follow-up with uSTg alone may result in underestimating the tumor burden. PMID- 29398965 TI - Unilateral Primary Adrenal Lymphoma: Uncommon Presentation of a Rare Disease Evaluated Using 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Primary adrenal lymphoma (PAL) is a relatively rare disease entity with only fewer than 200 cases reported till date. PAL frequently presents with bilateral adrenal involvement and shows male preponderance. We here present a case of PAL in a 65-year-old female with a relatively uncommon unilateral adrenal involvement. The present case depicts that 18F-fluorodeoxyglucose positron emission tomography/computed tomography had decisive role in the treatment management of this patient suggesting its potential utility in the management of this rare disease. PMID- 29398966 TI - 99m-Technetium Sestamibi Uptake in a Gastric Schwannoma. AB - We report the case of a 74-year-old woman with primary hyperparathyroidism who underwent 99m-technetium-sestamibi single photon emission computed tomography computed tomography for preoperative localization of parathyroid adenoma. Unexpected focal sestamibi uptake was observed at a 5 cm submucosal tumor arising from the greater curve of the stomach. The patient underwent partial gastrectomy and the histological and immunohistochemical findings were consistent with the diagnosis of gastric schwannoma. PMID- 29398967 TI - Active Herpes Zoster Infection Involving Lumbosacral Dermatome, an Unusual Site of Manifestation and Incidental Finding in Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Scan. AB - Herpes zoster virus reactivation in the lumbosacral dermatomal distribution is an unusual site of manifestation and atypical in presentation than its usual sites in thoracolumbar (D3-L2) and facial (V1) dermatomes. Here, we are reporting a patient of marginal zone lymphoma who on fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scan performed for chemotherapy response evaluation showed hypermetabolic cutaneous and subcutaneous lesions in the right vulva and posteromedial aspect of the right thigh along with ipsilateral pelvic lymph nodes involvement as an incidental finding. Subsequently, FDG active lesions were considered to be as herpes zoster virus reactivation rather than the recurrence of lymphoma and treated with antiviral drug. PMID- 29398968 TI - Usefulness of Splenic Scintigraphy in Differentiating Splenosis and Malignancy on Gallium 68 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-NaI3 octreotide. AB - Somatostatin receptor (SSTR) imaging with gallium 68 (Ga-68) 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide positron emission tomography/computed tomography (PET/CT) has been introduced in clinical routine for the diagnosis and staging of neuroendocrine tumors (NETs) with high SSTR expression. Although it has high sensitivity for NETs, there are some known diagnostic pitfalls one should be aware of. We present a case of suspected NET where Ga-68 DOTA-NaI3-octreotide (NOC) PET/CT showed several abdominal lesions with high SSTR expression suggesting malignancy. On magnetic resonance imaging, the differential diagnosis of the lesions also included splenosis. Subsequent splenic scintigraphy with technetium-99m phytate showed uptake in all suspicious lesions, and biopsy confirmed the diagnosis of splenosis. Splenic scintigraphy with single-photon emission computed tomography/CT can be a helpful noninvasive diagnostic tool when splenosis is suspected on Ga-68 DOTA-peptide PET/CT. PMID- 29398969 TI - Bronchopulmonary Sequestration as a Cause of Mismatched Perfusion Defect on Single-photon Emission Computed Tomography Ventilation-perfusion Scan. AB - We present a 46-year-old female with pleuritic chest pain on a background of pulmonary embolism diagnosed on a single-photon emission computed tomography (SPECT) ventilation-perfusion (V/Q) imaging 3 years earlier. A SPECT V/Q scan detected a mismatched perfusion defect in the posterior basal segment of the right lower lobe, essentially unchanged from a defect identified 3 years earlier. Given the atypical finding, the patient went on to have a computed tomographic pulmonary angiogram. It revealed an intralobar bronchopulmonary sequestration as the cause of the right lower lobe mismatched perfusion defect. With growing awareness of radiation safety, the number of V/Q imaging studies being undertaken to investigate suspected pulmonary emboli, especially in young female patients, has increased. This case report serves as a timely reminder of the potential pitfalls associated with V/Q scan image interpretation. PMID- 29398970 TI - Alveolar Soft Part Sarcoma Presenting as Hypervascular Adrenal Metastasis. AB - Hypervascular adrenal masses include pheochromocytoma, metastases caused by clear renal cell carcinoma/hepatocellular carcinoma. Alveolar soft part sarcoma (ASPS) causing hypervascular metastases is not described in the literature. Here, we describe the first case of ASPS presenting as hypervascular metastasis. Our case was a 23-year-old male incidentally detected right adrenal mass during the evaluation of pain in the abdomen. On computed tomography (CT), adrenal mass showed bright enhancement in early arterial phase (unenhanced Hounsfield unit [HU]-45.3; arterial phase HU-158.2). 18- flurodeoxyglucose positron emission tomography/CT showed multiple lesions and was confirmed histologically to be due to ASPS. PMID- 29398971 TI - Incidental Detection of Asymptomatic Brain Metastases on 18F-fluoride Positron Emission Tomography/Computed Tomography and 68Ga DOTANOC Positron Emission Tomography/Computed Tomography in a Patient with Concomitant Breast Carcinoma and a Pancreatic Neuroendocrine Tumor. AB - A 54-year-old female treated for locally advanced ductal breast carcinoma was also diagnosed with a pancreatic neuroendocrine tumour. A staging 68Ga DOTANOC positron emission tomography/computed tomography (PET/CT) demonstrated somatostatin receptor-positive foci within the brain parenchyma. A whole body 18F fluoride PET/CT also demonstrated several foci of low-grade tracer uptake in the brain. Magnetic resonance imaging confirmed several cerebral and cerebellar metastases. This case highlights the need to be aware of each tumor's metastatic profile and the careful attention required for thoroughly evaluating imaging in the presence of multiple pathologies. Furthermore, such incidental findings can have significant treatment and prognostic implications. PMID- 29398972 TI - Patterns, biases and prospects in the distribution and diversity of Neotropical snakes. AB - Motivation: We generated a novel database of Neotropical snakes (one of the world's richest herpetofauna) combining the most comprehensive, manually compiled distribution dataset with publicly available data. We assess, for the first time, the diversity patterns for all Neotropical snakes as well as sampling density and sampling biases. Main types of variables contained: We compiled three databases of species occurrences: a dataset downloaded from the Global Biodiversity Information Facility (GBIF), a verified dataset built through taxonomic work and specialized literature, and a combined dataset comprising a cleaned version of the GBIF dataset merged with the verified dataset. Spatial location and grain: Neotropics, Behrmann projection equivalent to 1 degrees * 1 degrees . Time period: Specimens housed in museums during the last 150 years. Major taxa studied: Squamata: Serpentes. Software format: Geographical information system (GIS). Results: The combined dataset provides the most comprehensive distribution database for Neotropical snakes to date. It contains 147,515 records for 886 species across 12 families, representing 74% of all species of snakes, spanning 27 countries in the Americas. Species richness and phylogenetic diversity show overall similar patterns. Amazonia is the least sampled Neotropical region, whereas most well-sampled sites are located near large universities and scientific collections. We provide a list and updated maps of geographical distribution of all snake species surveyed. Main conclusions: The biodiversity metrics of Neotropical snakes reflect patterns previously documented for other vertebrates, suggesting that similar factors may determine the diversity of both ectothermic and endothermic animals. We suggest conservation strategies for high diversity areas and sampling efforts be directed towards Amazonia and poorly known species. PMID- 29398973 TI - DEEP CLUSTERING AND CONVENTIONAL NETWORKS FOR MUSIC SEPARATION: STRONGER TOGETHER. AB - Deep clustering is the first method to handle general audio separation scenarios with multiple sources of the same type and an arbitrary number of sources, performing impressively in speaker-independent speech separation tasks. However, little is known about its effectiveness in other challenging situations such as music source separation. Contrary to conventional networks that directly estimate the source signals, deep clustering generates an embedding for each time frequency bin, and separates sources by clustering the bins in the embedding space. We show that deep clustering outperforms conventional networks on a singing voice separation task, in both matched and mismatched conditions, even though conventional networks have the advantage of end-to-end training for best signal approximation, presumably because its more flexible objective engenders better regularization. Since the strengths of deep clustering and conventional network architectures appear complementary, we explore combining them in a single hybrid network trained via an approach akin to multi-task learning. Remarkably, the combination significantly outperforms either of its components. PMID- 29398975 TI - The Effects of a Delayed Incentive on Response Rates, Response Mode, Data Quality, and Sample Bias in a Nationally Representative Mixed Mode Study. AB - This article describes the results of an experiment designed to examine the impact of the use and amount of delayed unconditional incentives in a mixed mode (push to web) supplement on response rates, response mode, data quality, and sample bias. The supplement was administered to individuals who participate in the U.S. Panel Study of Income Dynamics, the longest running national household panel in the world. After 10 weeks of data collection, individuals who had not yet completed the interview were sent a final survey request and randomly assigned to one of three treatment conditions: no incentive, US$5, and US$10. The impact of the incentives on response rates and mode, effects on data quality, and sample bias are described. The implications for the use of incentives in mixed mode surveys and directions for future research are discussed. PMID- 29398974 TI - Fatigue Symptom Management in People Living With Human Immunodeficiency Virus. AB - Fatigue is a subjective, unpleasant, potentially disabling symptom rooted in physiological, psychological, and behavioral causes. People living with HIV are a population highly affected by fatigue due to risk factors associated with HIV infection, treatment, and psychosocial disease burden. People with HIV are living longer, and are facing the challenge of a longer disease trajectory. Palliative nurses with expertise in symptom management can play a crucial role in helping people with HIV to engage in health behaviors that prevent or mitigate fatigue. In this paper we present a definition and overview of fatigue, describe the problem of fatigue in people living with HIV, and present a case study that illustrates the role of the palliative nurse in helping a person with HIV to cope with fatigue. PMID- 29398976 TI - Usability and Reliability of Smart Glasses for Secondary Triage During Mass Casualty Incidents. AB - Wearable smart glasses like Google Glass provide real-time video and image transmission to remote viewers. The use of Google Glass and other Augmented Reality (AR) platforms in mass casualty incidents (MCIs) can provide incident commanders and physicians at receiving hospitals real-time data regarding injuries sustained by victims at the scene. This real-time data is critical to allocation of hospital resources prior to receiving victims of a MCI. Remote physician participation in real-time MCI care prior to victims' hospital arrival may improve triage, and direct emergency and critical care services to those most in need. We report the use of Google Glass among first responders to transmit real-time data from a simulated MCI to allow remote physicians to complete augmented secondary triage. PMID- 29398977 TI - mfpa: Extension of mfp using the ACD covariate transformation for enhanced parametric multivariable modeling. AB - In a recent article, Royston (2015, Stata Journal 15: 275-291) introduced the approximate cumulative distribution (acd) transformation of a continuous covariate x as a route toward modeling a sigmoid relationship between x and an outcome variable. In this article, we extend the approach to multivariable modeling by modifying the standard Stata program mfp. The result is a new program, mfpa, that has all the features of mfp plus the ability to fit a new model for user-selected covariates that we call fp1(p1, p2). The fp1(p1, p2) model comprises the best-fitting combination of a dimension-one fractional polynomial (fp1) function of x and an fp1 function of acd (x). We describe a new model-selection algorithm called function-selection procedure with acd transformation, which uses significance testing to attempt to simplify an fp1(p1, p2) model to a submodel, an fp1 or linear model in x or in acd (x). The function selection procedure with acd transformation is related in concept to the fsp (fp function-selection procedure), which is an integral part of mfp and which is used to simplify a dimension-two (fp2) function. We describe the mfpa command and give univariable and multivariable examples with real data to demonstrate its use. PMID- 29398978 TI - Reference-based sensitivity analysis via multiple imputation for longitudinal trials with protocol deviation. AB - Randomized controlled trials provide essential evidence for the evaluation of new and existing medical treatments. Unfortunately, the statistical analysis is often complicated by the occurrence of protocol deviations, which mean we cannot always measure the intended outcomes for individuals who deviate, resulting in a missing data problem. In such settings, however one approaches the analysis, an untestable assumption about the distribution of the unobserved data must be made. To understand how far the results depend on these assumptions, the primary analysis should be supplemented by a range of sensitivity analyses, which explore how the conclusions vary over a range of different credible assumptions for the missing data. In this article, we describe a new command, mimix, that can be used to perform reference-based sensitivity analyses for randomized controlled trials with longitudinal quantitative outcome data, using the approach proposed by Carpenter, Roger, and Kenward (2013, Journal of Biopharmaceutical Statistics 23: 1352-1371). Under this approach, we make qualitative assumptions about how individuals' missing outcomes relate to those observed in relevant groups in the trial, based on plausible clinical scenarios. Statistical analysis then proceeds using the method of multiple imputation. PMID- 29398979 TI - Model selection for univariable fractional polynomials. AB - Since Royston and Altman's 1994 publication (Journal of the Royal Statistical Society, Series C 43: 429-467), fractional polynomials have steadily gained popularity as a tool for flexible parametric modeling of regression relationships. In this article, I present fp_select, a postestimation tool for fp that allows the user to select a parsimonious fractional polynomial model according to a closed test procedure called the fractional polynomial selection procedure or function selection procedure. I also give a brief introduction to fractional polynomial models and provide examples of using fp and fp_select to select such models with real data. PMID- 29398980 TI - Reconstructing time-to-event data from published Kaplan-Meier curves. AB - Hazard ratios can be approximated by data extracted from published Kaplan-Meier curves. Recently, this curve approach has been extended beyond hazard-ratio approximation with the capability of constructing time-to-event data at the individual level. In this article, we introduce a command, ipdfc, to implement the reconstruction method to convert Kaplan-Meier curves to time-to-event data. We give examples to illustrate how to use the command. PMID- 29398981 TI - Comparison between PVI2D and Abreu-Johnson's Model for Petroleum Vapor Intrusion Assessment. AB - Recently, we have developed a two-dimensional analytical petroleum vapor intrusion model, PVI2D (petroleum vapor intrusion, two-dimensional), which can help users to easily visualize soil gas concentration profiles and indoor concentrations as a function of site-specific conditions such as source strength and depth, reaction rate constant, soil characteristics, and building features. In this study, we made a full comparison of the results returned by PVI2D and those obtained using Abreu and Johnson's three-dimensional numerical model (AJM). These comparisons, examined as a function of the source strength, source depth, and reaction rate constant, show that PVI2D can provide similar soil gas concentration profiles and source-to-indoor air attenuation factors (within one order of magnitude difference) as those by the AJM. The differences between the two models can be ascribed to some simplifying assumptions used in PVI2D and to some numerical limitations of the AJM in simulating strictly piecewise aerobic biodegradation and no-flux boundary conditions. Overall, the obtained results show that for cases involving homogenous source and soil, PVI2D can represent a valid alternative to more rigorous three-dimensional numerical models. PMID- 29398982 TI - Probabilistic Solar Wind Forecasting Using Large Ensembles of Near-Sun Conditions With a Simple One-Dimensional "Upwind" Scheme. AB - Long lead-time space-weather forecasting requires accurate prediction of the near Earth solar wind. The current state of the art uses a coronal model to extrapolate the observed photospheric magnetic field to the upper corona, where it is related to solar wind speed through empirical relations. These near-Sun solar wind and magnetic field conditions provide the inner boundary condition to three-dimensional numerical magnetohydrodynamic (MHD) models of the heliosphere out to 1 AU. This physics-based approach can capture dynamic processes within the solar wind, which affect the resulting conditions in near-Earth space. However, this deterministic approach lacks a quantification of forecast uncertainty. Here we describe a complementary method to exploit the near-Sun solar wind information produced by coronal models and provide a quantitative estimate of forecast uncertainty. By sampling the near-Sun solar wind speed at a range of latitudes about the sub-Earth point, we produce a large ensemble (N = 576) of time series at the base of the Sun-Earth line. Propagating these conditions to Earth by a three-dimensional MHD model would be computationally prohibitive; thus, a computationally efficient one-dimensional "upwind" scheme is used. The variance in the resulting near-Earth solar wind speed ensemble is shown to provide an accurate measure of the forecast uncertainty. Applying this technique over 1996 2016, the upwind ensemble is found to provide a more "actionable" forecast than a single deterministic forecast; potential economic value is increased for all operational scenarios, but particularly when false alarms are important (i.e., where the cost of taking mitigating action is relatively large). PMID- 29398983 TI - Data Assimilation in the Solar Wind: Challenges and First Results. AB - Data assimilation (DA) is used extensively in numerical weather prediction (NWP) to improve forecast skill. Indeed, improvements in forecast skill in NWP models over the past 30 years have directly coincided with improvements in DA schemes. At present, due to data availability and technical challenges, DA is underused in space weather applications, particularly for solar wind prediction. This paper investigates the potential of advanced DA methods currently used in operational NWP centers to improve solar wind prediction. To develop the technical capability, as well as quantify the potential benefit, twin experiments are conducted to assess the performance of the Local Ensemble Transform Kalman Filter (LETKF) in the solar wind model ENLIL. Boundary conditions are provided by the Wang-Sheeley-Arge coronal model and synthetic observations of density, temperature, and momentum generated every 4.5 h at 0.6 AU. While in situ spacecraft observations are unlikely to be routinely available at 0.6 AU, these techniques can be applied to remote sensing of the solar wind, such as with Heliospheric Imagers or interplanetary scintillation. The LETKF can be seen to improve the state at the observation location and advect that improvement toward the Earth, leading to an improvement in forecast skill in near-Earth space for both the observed and unobserved variables. However, sharp gradients caused by the analysis of a single observation in space resulted in artificial wavelike structures being advected toward Earth. This paper is the first attempt to apply DA to solar wind prediction and provides the first in-depth analysis of the challenges and potential solutions. PMID- 29398984 TI - Seismic imaging of the Sun's far hemisphere and its applications in space weather forecasting. AB - The interior of the Sun is filled acoustic waves with periods of about 5 min. These waves, called "p modes," are understood to be excited by convection in a thin layer beneath the Sun's surface. The p modes cause seismic ripples, which we call "the solar oscillations." Helioseismic observatories use Doppler observations to map these oscillations, both spatially and temporally. The p modes propagate freely throughout the solar interior, reverberating between the near and far hemispheres. They also interact strongly with active regions at the surfaces of both hemispheres, carrying the signatures of said interactions with them. Computational analysis of the solar oscillations mapped in the Sun's near hemisphere, applying basic principles of wave optics to model the implied p modes propagating through the solar interior, gives us seismic maps of large active regions in the Sun's far hemisphere. These seismic maps are useful for space weather forecasting. For the past decade, NASA's twin STEREO spacecraft have given us full coverage of the Sun's far hemisphere in electromagnetic (EUV) radiation from the far side of Earth's orbit about the Sun. We are now approaching a decade during which the STEREO spacecraft will lose their farside vantage. There will occur significant periods from thence during which electromagnetic coverage of the Sun's far hemisphere will be incomplete or nil. Solar seismology will make it possible to continue our monitor of large active regions in the Sun's far hemisphere for the needs of space weather forecasters during these otherwise blind periods. PMID- 29398985 TI - PET/CT-Guided Interventions in Oncology Patients: A Nursing Perspective. AB - In the past five years, the utilization of PET/CT guidance is more commonly used for cancer patients undergoing biopsy and ablations at this NCI-Designated Cancer Center. The interventional use of PET/CT imaging requires nurses to have a thorough understanding of the mechanisms involved in order to provide the best care in an environment that is safe for patients and staff. Evidence suggests cohesive care and safe practice measures are achieved when patients actively participate and understand their care. This article will discuss how a collaborative, patient-centered approach in caring for oncologic patients undergoing PET/CT interventions is necessary for achieving quality patient outcomes. PMID- 29398986 TI - A Culture of Safety. PMID- 29398987 TI - Shoulder Arthroplasty for Humeral Head Avascular Necrosis Is Associated With Increased Postoperative Complications. AB - Background: Humeral head avascular necrosis (AVN) of differing etiologies may lead to shoulder arthroplasty due to subchondral bone collapse and deformity of the articular surface. There have been no large studies evaluating the complications for these patients after they undergo total shoulder arthroplasty (TSA). Questions/Purposes: The first objective of this study is to evaluate the complication rate after TSA in patients with humeral head AVN. The secondary objective is to compare the complication rates among the different etiologies of the AVN. Methods: Patients who underwent TSA were identified in the PearlDiver database using ICD-9 codes. Patients who underwent shoulder arthroplasty for humeral head AVN were identified using ICD-9 codes and were subclassified according to AVN etiology (posttraumatic, alcohol use, chronic steroid use, and idiopathic). Complications evaluated included postoperative infection within 6 months, dislocation within 1 year, revision shoulder arthroplasty up to 8 years postoperatively, shoulder stiffness within 1 year, and periprosthetic fracture within 1 year and systemic complications within 3 months. Postoperative complication rates were compared to controls. Results: The study cohorts included 4129 TSA patients with AVN with 141,778 control TSA patients. Patients with posttraumatic AVN were significantly more likely to have a postoperative infection (OR 2.47, P < 0.001), dislocation (OR 1.45, P = 0.029), revision surgery (OR 1.53, P = 0.001), stiffness (OR 1.24, P = 0.042), and systemic complication (OR 1.49, P < 0.001). Steroid-associated AVN was associated with a significantly increased risk for a postoperative infection (OR 1.72, P = 0.004), revision surgery (OR 1.33, P = 0.040), fracture (OR 2.76, P = 0.002), and systemic complication (OR 1.59, P < 0.001). Idiopathic and alcohol-associated AVN were not significantly associated with any of the postoperative evaluated complications. Conclusions: TSA in patients with humeral head AVN is associated with significantly increased rates of numerous postoperative complications compared to patients without a diagnosis of AVN, including infection, dislocation, revision arthroplasty, stiffness, periprosthetic fracture, and medical complications. Specifically, AVN due to steroid use or from a posttraumatic cause appears to be associated with the statistically highest rates of postoperative TSA complications. Given these findings, orthopedic surgeons should be increasingly aware of this association, which should influence the shared decision-making process of undergoing TSA in patients with humeral head AVN. PMID- 29398988 TI - Epidemiology and Disease Burden of Lateral Epicondylitis in the USA: Analysis of 85,318 Patients. AB - Background: National rates of lateral epicondylitis and surgical treatment are poorly defined. Disease burden of lateral epicondylitis (LE) continues to increase annually. Further study is necessary to optimize treatment algorithms to reduce associated health-care expenditures. Questions/Purposes: The purpose of this study is to review the annual incidence of LE, surgical rates, and associated health-care costs in a population setting. Methods: A national database was queried for LE from 2007 to 2014. Surgical cases were identified and annual rates were recorded. Demographic and epidemiologic data were reported with descriptive statistics, while trends over time were analyzed using linear regression. Results: Eighty-five thousand three hundred eighteen cases of LE were identified. The annual incidence per 10,000 patients remained constant (p = 0.304). The proportion of diagnoses in patients <65 years decreased (p <= 0.002) and >=65 years increased (p < 0.001) over the study period. One thousand six hundred ninety-four patients (2%) required operative treatment. The annual rate of surgical intervention remained constant (p = 0.623). The proportion of patients <40 years requiring surgery decreased (p < 0.001) as the proportion of patients >=65 years needing surgery increased (p = 0.003). Total reimbursement for LE procedures during the study period was $7,220,912. Average per-patient reimbursement was $4263. Both annual total reimbursement (p = 0.006) and per patient reimbursement rates (p = 0.002) significantly increased. Conclusion: The annual incidence of LE and rate of surgical intervention have remained constant from 2007 to 2014. The proportion of patients over >65 years diagnosed with, and receiving surgical treatment for, LE has significantly increased in recent years. Total reimbursement and average per-patient reimbursement have steadily risen, demonstrating the increasing burden of cost on the health-care system. PMID- 29398989 TI - The Primary Stability of a Bioabsorbable Poly-L-Lactic Acid Suture Anchor for Rotator Cuff Repair Is Not Improved with Polymethylmethacrylate or Bioabsorbable Bone Cement Augmentation. AB - Background: The incidence of osteoporosis and rotator cuff tears increases with age. Cement augmentation of bones is an established method in orthopedic and trauma surgery. Questions/Purposes: This study analyses if polymethylmethacrylate or bioabsorbable cement can improve the primary stability of a bioabsorbable suture anchor in vitro in comparison to a non-augmented suture anchor in osteoporotic human humeri. Methods: The trabecular bone mineral density was measured to ensure osteopenic human specimens. Then the poly-l-lactic acid Bio Corkscrew(r) FT was implanted in the greater tuberosity footprint with polymethylmethacrylate Refobacin(r) cement augmentation (n = 8), with CeramentTM Bone Void Filler augmentation (n = 8) and without augmentation (n = 8). Using a cyclic testing protocol, the failure loads, system displacement, and failure modes were recorded. Results: The CeramentTM augmented Bio-Corkscrew(r) FT yielded the highest failure loads (206.7 N), followed by polymethylmethacrylate Refobacin(r) augmentation (206.1 N) and without augmentation (160.0 N). The system displacement was lowest for CeramentTM augmentation (0.72 mm), followed by polymethylmethacrylate (0.82 mm) and without augmentation (1.50 mm). Statistical analysis showed no significant differences regarding the maximum failure loads (p = 0.1644) or system displacement (p = 0.4199). The main mode of failure for all three groups was suture slippage. Conclusion: The primary stability of the Bio Corkscrew(r) FT is not influenced by bone cement augmentation with polymethylmethacrylate Refobacin(r) or with bioabsorbable CeramentTM in comparison to the non-cemented anchors. The cement augmentation of rotator cuff suture anchors in osteoporotic bones remains questionable since biomechanical tests show no significant advantage. PMID- 29398990 TI - Revision Total Shoulder Arthroplasty is Associated with Increased Thirty-Day Postoperative Complications and Wound Infections Relative to Primary Total Shoulder Arthroplasty. AB - Background: With an increasing volume of primary total shoulder arthroplasties (TSA), the number of revision TSA cases is expected to increase as well. However, the postoperative medical morbidity of revision TSA has not been clearly described. Questions/Purposes: The purpose of this study was to determine the rate of postoperative complications following revision TSA, relative to primary TSA. In addition, we sought to identify independent predictors of complications, as well as to compare operative time and postoperative length of stay between primary and revision TSA. Methods: Patients who underwent primary/revision TSA between 2005 and 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program. Differences in complications, readmission rates, operative time, length of stay, and predictors of complications were evaluated using bivariate and multivariate analyses. Results: A total of 10,371 primary TSA (95.4%) and 496 revision TSA cases (4.6%) were identified. The overall complication rate was 6.5% in primary and 10.7% in revision TSA patients (p < 0.001). Multivariate analysis identified an increased risk of any complication (odds ratio 1.73, p < 0.001), major complication (2.08, p = 0.001), and wound infection (3.45, p = 0.001) in revision TSA patients, relative to primary cases. Operative time was increased in revision cases (mean +/- standard deviation, 125 +/- 62.5), relative to primary (115 +/- 47.7, p < 0.001). Age > 75, female sex, history of diabetes or chronic obstructive pulmonary disease, and American Society of Anesthesiologists classification >= 3 were associated with increased risk of any complication. Smoking history was the only significant predictor of wound infection. Conclusion: Revision TSA, in comparison to primary, poses an increased risk of postoperative complications, particularly wound infections. A history of smoking was an independent predictor of wound infections. PMID- 29398991 TI - Comparative Evaluation of Surgical Procedures with Clinical Equipoise: the Unique Perspective of Our Hand Therapy Colleagues. AB - Background: There are several accepted surgical treatment options available for carpal tunnel syndrome, thumb carpometacarpal joint (CMC), osteoarthritis (OA), and wrist degenerative joint disease. Questions/Purposes: We sought to obtain the views and preferences from a cohort of certified hand therapists (CHT) and hypothesized that this source may identify differences in procedures that are otherwise widely believed to have clinical equipoise. Methods: Five hundred twelve CHTs were surveyed regarding their experience, volume, and referral base along with their subjective assessments and preferences regarding open versus endoscopic carpal tunnel release (CTR), various surgical procedures for CMC OA, and proximal row carpectomy (PRC) versus 4-corner fusion (4-CF). Results: The average CHT surveyed had 15.2 years experience and had a referral base of 7.7 different hand surgeons. Twenty-seven percent of respondents perceived superior pain control and incisional tenderness following open CTR compared to that of endoscopic CTR. However, 68% of CHTs would elect to undergo an open CTR themselves. There was no clear consensus for the optimal reconstructive technique for thumb CMC OA. As compared to that of 4-CF, PRC was thought to result in superior pain control (34 versus 22%), motion (43 versus 18%), and earlier discharge from therapy (32 versus 19%); however, 53% of respondents would prefer a 4-CF for themselves. Conclusions: Hand therapists are intimately involved in the care of surgical patients and provide an educated and unique source for evaluating postoperative outcomes. PMID- 29398992 TI - Long Head of Biceps Tendon Management: a Survey of the American Shoulder and Elbow Surgeons. AB - Background: Management of symptomatic long head of biceps tendon (LHBT) pathology remains a source of debate. Questions/Purposes: The purpose of this study was to identify consensus trends for the treatment of LHBT pathology among specialists. Methods: A survey was distributed to members of the American Shoulder and Elbow Society (ASES), consisting of three sections-demographics, case scenarios, and general LHBT pathology management. Cases presented common clinical scenarios, and surgeons reported their management preferences. Consensus responses were defined as > 50% of participants giving a single response. Results: One hundred and forty two of 417 (34%) surgeons completed surveys. Forty-seven percent of questions reached a consensus answer. Biceps tenodesis was the overwhelmingly preferred technique in cases demonstrating LHBT pathology, as compared to tenotomy. No consensus, however, was reached regarding a specific surgical technique for biceps tenodesis. The two most popular techniques were arthroscopic tenodesis to bone and open subpectoral biceps tenodesis. Fellowship-trained arthroscopic surgeons and surgeons with a largely arthroscopic practice were more likely to perform tenodesis arthroscopically. Conclusion: ASES members favored biceps tenodesis over tenotomy for surgical management of LHBT pathology, without consensus regarding a specific surgical technique. PMID- 29398993 TI - Pregabalin Did Not Improve Pain Management After Spinal Fusions. AB - Background: The treatment of postoperative pain is a challenge after posterior spinal fusions. Pain management using predominantly opioids is often associated with multiple adverse effects, while multimodal postoperative analgesia may provide adequate pain relief with fewer opioid side effects. Questions/Purposes: The purpose of this review is to determine whether addition of 150 mg pregabalin daily would reduce narcotic requirements and improve outcomes after posterior lumbar fusion (PLF). Methods: The method used is a randomized, controlled trial of elective PLF patients who received pregabalin or placebo. With institutional review board (IRB) approval, 86 patients undergoing elective posterior lumbar fusion, ASA I-III, were randomized to receive either a placebo or pregabalin after obtaining written informed consent. Both arms, i.e., placebo and pregabalin, consisted of 43 patients each.The 86 patients for elective PLF were randomly assigned to receive 150 mg of pregabalin 1 h before surgery and then 150 mg daily, or a placebo tablet. All patients received a similar general anesthetic and in the post-anesthesia care unit (PACU), started on intravenous (IV) patient controlled analgesia (PCA) of hydromorphone (0.2 mg/ml). Postoperative pain was assessed daily until discharge using a Numerical Rating Scale (NRS) at rest and with physical therapy (PT). Patients were also assessed twice daily for level of sedation and nausea and/or vomiting and expected PT milestones. All narcotics (IV, oral) were documented. Results: Demographics and operative time between groups were similar. PCA hydromorphone administration and oral narcotic intake were not statistically different between the two groups. However, an increased incidence of nausea and vomiting in the placebo group reached statistical significance (p < 0.05). In addition, there was no statistical difference between groups with respect to achieving PT milestones and hospital discharge day. Conclusion: After PLF, patients receiving pregabalin 150 mg/day did not have reduced IV narcotic usage, improved PT milestones, or reduced length of hospital stay. We were unable to demonstrate an analgesic advantage to prescribing pregabalin to patients undergoing lumbar spinal fusions. PMID- 29398994 TI - Single Local Infiltration Analgesia (LIA) Aids Early Pain Management After Total Knee Replacement (TKR): An Evidence-Based Review and Commentary. AB - Background: There is controversy in the literature regarding the role of single local infiltration analgesia (LIA) after total knee replacement (TKR). Questions/Purposes: Is single LIA really efficient in controlling pain after TKR? Methods: A Cochrane Library and PubMed (MEDLINE) search related to the justification LIA after TKR was analyzed. The main criteria for selection were that the articles were focused in the aforementioned question. Results: Two hundred ninety-nine articles were found until February 9, 2017, but only 27 were selected and reviewed because they were focused on clinical experience with LIA following TKR. Fifteen of them were considered level of evidence (I-II) while 12 had a lower level of evidence (III-IV). LIA reduced the amount of perioperative opioid administration and enabled adequate pain management in conjunction with oral medication without adverse effects. No clinically marked effects on the functional outcome after TKR were detected. Conclusion: Single dose LIA provides effective analgesia in the initial postoperative period after TKR in most randomized clinical trials, systematic reviews, and meta-analyses. PMID- 29398995 TI - Preoperative Valgus Alignment Does Not Predict Inferior Outcome of Total Knee Arthroplasty. AB - Background: Preoperative valgus deformity is present in an estimated 10-20% of patients undergoing total knee replacement (TKR). Questions/Purposes: The objective of this study was to compare the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores after TKR in a matched cohort of patients with preoperative valgus and varus deformities. Methods: This is a matched cohort study of 162 patients with varus native knees and 162 patients with valgus native knees who underwent TKR and were prospectively followed in our institutional registry. Patients matched were based on age, BMI, sex, and severity of preoperative knee deformity, which was classified as mild, moderate, severe varus or valgus, or no deformity. Outcomes were evaluated using the WOMAC preoperatively and at 6 weeks, 3 months, 6 months, and 1 year postoperatively. Results: No significant difference was found between the matched varus and valgus cohorts in all WOMAC subdomain scores except for a marginally worse stiffness at 1 year in patients with valgus deformity (WOMAC stiffness, 75.1 varus vs. 70.1 valgus; P = 0.049). This is below the minimal clinically important difference for WOMAC scores. There was no significant difference in postoperative varus/valgus alignment between the two groups (P = 0.092). Conclusion: We found no clinically significant difference in any of the WOMAC domains in patients with preoperative varus deformity versus valgus deformity within the first year after TKR. These findings may allow surgeons to more appropriately counsel patients with osteoarthritis with valgus deformity that they can expect similar outcomes compared to patients with varus deformity. PMID- 29398996 TI - Scaling Marker Position Determines the Accuracy of Digital Templating for Total Hip Arthroplasty. AB - Background: Digital templating systems foster patient-specific measurements for preoperative planning. Questions/Purposes: We aim (1) to verify the accuracy of a templating system, (2) to describe the effects of scaling marker position on the accuracy of digital templating of the hip, and (3) to provide a practical guide for scaling marker position using patient body mass index (BMI). Methods: A scaling sphere was placed in five positions along the anterior-posterior axis of an acetabular implant and pelvis phantom, and x-rays were obtained. Each radiograph was templated for the acetabular component and recorded. A retrospective review identified CT scans of preoperative hip arthroplasty cases. The center of the greater trochanter was calculated from these CT scans as the percent distance from the anterior thigh and recorded with the patient's BMI. Results: By centering the scaling sphere on the acetabular component, an accurate cup size was achieved. A difference of 3.5 cm in sphere placement resulted in a full cup size magnification error. Positioning the scaling sphere at the level of the pubic symphysis resulted in a difference of four cup sizes. This patient population had an average BMI of 28.72 kg/m2 (standard deviation 6.26 kg/m2) and an average position of the center of the greater trochanter of 51% (standard deviation of 6%) from the anterior surface of thigh. Conclusions: Digital templating relies on scaling marker position to accurately estimate implant size. Based on the findings in this study, scaling markers for hip imaging should be placed laterally, mid-thigh in the anterior-posterior direction for patients with a BMI between 25 and 40 kg/m2. If abnormal hip anatomy or extremes of BMI are discovered, then scaling sphere positioning should be optimized on a case-by-case basis. Digital templating systems for total hip arthroplasty must use precisely placed scaling markers at the level of the hip joint to allow for accurate implant size estimation. PMID- 29398997 TI - No Difference in Conventional Polyethylene Wear Between Yttria-stabilized Zirconia and Cobalt-chromium-molybdenum Femoral Heads at 10 Years. AB - Background: Concerns have arisen regarding deterioration of wear properties of yttria-stabilized zirconia (YSZ) femoral head on conventional polyethylene (PE) bearings due to YSZ phase transformation. Questions/Purposes: The purpose of this study was to determine if there is a difference in long-term PE wear properties between YSZ and cobalt-chromium-molybdenum (Co-Cr-Mo) femoral heads. Methods: Ten year radiographic wear assessment was performed on a cohort of patients enrolled in a prospective randomized clinical trial comparing total hip arthroplasty with YSZ or Co-Cr-Mo femoral heads on conventional, non-cross-linked PE. Results: PE linear wear, annualized wear, and steady-state wear rates remained low and similar between groups. No cases of osteolysis were observed. Conclusions: Measured conventional PE wear was similar between YSZ and Co-Cr-Mo femoral heads with the steady-state wear rates for both remaining below the generally accepted threshold at which osteolysis typically occurs. Whether clinically relevant phase transformation with YSZ femoral heads occurs is uncertain; however, the use of YSZ femoral heads in this study was not associated with increased PE wear, osteolysis, or deterioration of wear properties. PMID- 29398999 TI - The Fascia Iliaca Block as the Primary Intraoperative Anesthesia for Hip Fracture Surgery: A Preliminary Study. AB - Background: Early surgical intervention for hip fractures in the elderly has proven efficacious. However, surgical delays commonly occur in this patient population due to comorbid conditions that put these patients at a high risk for hypotension-related complications of general or neuraxial anesthesia or anticoagulants that delay the safe use of neuraxial anesthesia. Questions/Purposes: The questions/purposes of this study are (1) to investigate if a fascia iliaca block in conjunction with light to moderate sedation could provide adequate analgesia throughout open surgery for intertrochanteric hip fractures (AO/OTA 31-1) without requiring conversion to general anesthesia with airway support and (2) to assess its perioperative complication profile. Methods: A retrospective chart review was conducted to identify patients with intertrochanteric hip fractures who underwent anesthesia with a fascia iliaca block over a 1.5-year period. Results: In the six patients identified, there were no intraoperative conversions to general anesthesia requiring airway support. Additionally, there were no intraoperative complications, no mortalities within 30 days, 2 patients on anticoagulation who required a blood transfusion, and a single patient who developed a postoperative hospital-acquired pneumonia that resolved with an antibiotic course. Conclusions: In this series of patients, we demonstrate that a fascia iliaca block can reliably be utilized as the primary anesthetic for patients undergoing surgical fixation of intertrochanteric hip fractures, with an acceptable perioperative complication profile. Although concomitant sedation was provided with the block, this anesthesia strategy has the potential to reduce preoperative delays and minimize the overall burden of sedative and anesthetic medications in a geriatric population. These initial findings may serve as a basis for future, higher-quality prospective and comparative studies. PMID- 29398998 TI - Postoperative Myocardial Injury and Inflammation Is Not Blunted by a Trial of Atorvastatin in Orthopedic Surgery Patients. AB - Background: Orthopedic patients are at risk for adverse postoperative cardiovascular outcomes. Questions/Purposes: This pilot randomized controlled trial (RCT) of atorvastatin vs. placebo in orthopedic surgery patients was performed in order to assess: (1) the prevalence of perioperative myocardial injury; (2) the effect of atorvastatin on perioperative inflammation; and (3) the feasibility of performing a large RCT of statin therapy in orthopedic patients. Methods: Hip fracture (hip Fx) and total hip and knee replacement (THR and TKR) patients were randomized 1:1 to atorvastatin 40 mg daily vs. placebo, starting preoperatively and continuing until postoperative day (POD) 45. High-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) were measured preoperatively and on POD 2. Patients were monitored for adverse events until POD 90. Results: Five hundred fifty-six patients were screened, 22 were recruited (4 hip Fx, 11 THR, 7 TKR), and 2 withdrew. Most (80%) had detectable hs-cTnI (> 1.1 pg/mL) preoperatively. Twenty percent had a perioperative rise in hs-cTnI (>= 10 pg/mL), which was not blunted by atorvastatin. Hs-CRP rose in 19/20 patients, and IL-6 rose in all patients. However, atorvastatin did not blunt the rise in these inflammatory biomarkers. On POD 2, IL-6 and hs-cTnI levels correlated (rho = 0.59, p = 0.02). Recruitment was limited by the high prevalence of statin use in the screened population and a high prevalence of exclusions among hip fracture patients. Conclusion: Perioperative myocardial injury and inflammation are common in orthopedic patients and do not appear to be reduced in those randomized to atorvastatin. Trial Registration: NCT02197065. PMID- 29399000 TI - Outcomes Following Operative Treatment of Adolescent Mallet Fractures. AB - Background: Many surgeons advocate for surgical intervention of adult mallet fractures that involve either subluxation of the distal interphalangeal (DIP) joint or those that involve more than one-third of the articular surface. However, the efficacy of operative treatment and complication rates are unclear regarding the adolescent population. Questions/Purposes: The goal of this study is to evaluate the clinical outcomes following operative fixation of bony mallet fractures in the adolescent population. Methods: Seventeen patients with bony mallet fractures treated surgically were retrospectively reviewed. Twelve patients were treated by closed reduction with extension block pinning. The other patients underwent an open reduction and pin fixation. The average age was 15.2 years (13-18). Most injuries were sport related. The average time from injury to presentation was 17 days and from injury to surgery was 24.5 days. Nine patients had subluxation at the DIP joint and all involved at least one-third of the articular surface. Results: The average time from surgery to pin removal was 28 days (19-46). All distal phalanx physis were closed or nearly closed. One patient reported pain at the final follow-up. Two patients (11.8%) had major complications. One had an extension contracture postoperatively, did not attend therapy, and re-fractured 5 months later requiring reoperation. The second was treated delayed (32 days) and lost fixation, requiring revision surgery and antibiotics for a superficial infection. Two patients with delayed treatment (32 and 44 days) had an extensor lag (11.8%). Conclusions: Operative treatment of mallet fractures with subluxation or involving more than one-third of the articular surface appears effective. Pin removal 4 weeks postoperatively appears adequate. Complications occurred with delayed presentation and non-compliance. PMID- 29399001 TI - Clavicle Malunions: Surgical Treatment and Outcome-a Literature Review. AB - Background: Successful treatment of clavicle malunion represents a major challenge for orthopedic surgeons. Questions/Purposes: The aim of this study was to provide an overview of surgical options for the treatment of clavicle malunions regarding their technical details and clinical results. Methods: A comprehensive search of the literature was performed to retrieve articles and conference abstracts regarding the surgical treatment of clavicle malunions. A total of 1873 records were identified and 29 studies were included in the present review, with a total of 103 patients. Results: The majority of the patients (77/103) were treated with an osteotomy and subsequent open reduction internal fixation (ORIF). The next most frequent management choice was debridement, excision, or removal of excess callus or bone (n = 19), but other techniques like resection of the clavicle (n = 5) or nerve exploration and decompression (n = 2) were also reported. The preferred method of fixation was plate fixation (n = 53) followed by pin fixation (n = 6). The complication rate was low, reported in less than 6% of patients. Conclusion: All of the currently reported surgical techniques to manage symptomatic clavicle malunion have resulted in good clinical outcomes with a low complication rate. Considering biomechanical aspects, correction osteotomy followed by plate fixation seems to be the preferred method. Further studies are needed to compare the various surgical techniques and their specific outcomes in a prospective manner. Nevertheless, this review article can be used as an overview to help choose an optimal operative treatment for patients presenting with a clavicle malunion. PMID- 29399002 TI - The Infection Rate of Metal-on-Metal Total Hip Replacement Is Higher When Compared to Other Bearing Surfaces as Documented by the Australian Orthopaedic Association National Joint Replacement Registry. AB - Background: Despite the well-documented decline in the use of metal-on-metal (MoM) implants over the last decade, there are still controversies regarding whether all MoM implants are created equally. Complications such as elevated serum metal ion levels, aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) and pseudotumours have all been well documented, but recent studies suggest increased risk of infection with MoM bearing surfaces. Most of these studies however have small patient numbers. Questions/Purposes: The purpose of this study was to examine the cumulative incidence of revision for infection of MoM bearing surfaces in primary hip arthroplasty at a national and single-surgeon level. Methods: Data was collected from the Australian Orthopaedic Association National Joint Replacement Registry, which contains over 98% of all arthroplasties performed in Australia since 2001. The cumulative incidence of revision for infection was extracted at a national level and single-surgeon level. Results: Two hundred seventy-six thousand eight hundred seventy-eight subjects were documented in the Australian registry. The 10-year cumulative percent revision for infection of MoM bearing surfaces in primary total hip replacement (THR) was 2.5% at a national level, compared to 0.8% for other bearing surfaces. The senior author contributed 1755 subjects with 7-year follow up and a cumulative percent revision for infection of MoM bearing surfaces in primary THR of 36.9%, compared to 2.0% for other bearing surfaces. The cumulative percent of revision of MoM bearing surfaces is higher compared to other bearing surfaces; this is especially pronounced in cumulative percent of revision for infection. Conclusion: There was a higher cumulative percent of revision for infection in MoM bearings surfaces (in particular, large-head MoM) compared to other bearing surfaces at both the national and individual-surgeon level. PMID- 29399004 TI - Modeling Active Contraction and Relaxation of Left Ventricle Using Different Zero load Diastole and Systole Geometries for Better Material Parameter Estimation and Stress/Strain Calculations. AB - Modeling ventricle active contraction based on in vivo data is extremely challenging because of complex ventricle geometry, dynamic heart motion and active contraction where the reference geometry (zero-stress geometry) changes constantly. A new modeling approach using different diastole and systole zero load geometries was introduced to handle the changing zero-load geometries for more accurate stress/strain calculations. Echo image data were acquired from 5 patients with infarction (Infarct Group) and 10 without (Non-Infarcted Group). Echo-based computational two-layer left ventricle models using one zero-load geometry (1G) and two zero-load geometries (2G) were constructed. Material parameter values in Mooney-Rivlin models were adjusted to match echo volume data. Effective Young's moduli (YM) were calculated for easy comparison. For diastole phase, begin-filling (BF) mean YM value in the fiber direction (YMf) was 738% higher than its end-diastole (ED) value (645.39 kPa vs. 76.97 kPa, p=3.38E-06). For systole phase, end-systole (ES) YMf was 903% higher than its begin-ejection (BE) value (1025.10 kPa vs. 102.11 kPa, p=6.10E-05). Comparing systolic and diastolic material properties, ES YMf was 59% higher than its BF value (1025.10 kPa vs. 645.39 kPa. p=0.0002). BE mean stress value was 514% higher than its ED value (299.69 kPa vs. 48.81 kPa, p=3.39E-06), while BE mean strain value was 31.5% higher than its ED value (0.9417 vs. 0.7162, p=0.004). Similarly, ES mean stress value was 562% higher than its BF value (19.74 kPa vs. 2.98 kPa, p=6.22E 05), and ES mean strain value was 264% higher than its BF value (0.1985 vs. 0.0546, p=3.42E-06). 2G models improved over 1G model limitations and may provide better material parameter estimation and stress/strain calculations. PMID- 29399003 TI - Dietary Patterns and Colorectal Cancer Risk: A Review of 17 Years of Evidence (2000-2016). AB - Purpose of review: Colorectal cancer (CRC) is a global public health problem, with an estimated 1.4 million cases diagnosed worldwide in 2012. Evidence suggests that diet may be important for primary prevention. Recent findings: The 2017 WCRF/AICR Continuous Update Project on colorectal cancer concluded that there is convincing evidence linking several individual dietary factors with CRC risk but the evidence for dietary patterns was limited and inconclusive. Also, previous reviews and meta-analyses have not critically synthesized various dietary patterns. This review synthesized data from dietary patterns studies over a 17-year period from 2000 to 2016. Summary: We included 49 studies (28 cohort and 21 case-control) that examined the association of index-based and empirically derived dietary patterns and CRC risk. A synthesis of food group components comprising the different index-based and empirically-derived patterns revealed two distinct dietary patterns associated with CRC risk. A "healthy" pattern, generally characterized by high intake of fruits and vegetables, wholegrains, nuts and legumes, fish and other seafood, milk and other dairy products, was associated with lower CRC risk. In contrast, the "unhealthy" pattern, characterized by high intakes of red meat, processed meat, sugar-sweetened beverages, refined grains, desserts and potatoes was associated with higher CRC risk. It is notable that the number of food groups, the intake quantity, the exact types of foods in each food group, differed between populations, yet the two dietary patterns remained consistent across regions, especially in empirically-derived patterns, an indication of the high reproducibility of these patterns. However, findings for CRC risk in both index-based and empirically derived patterns, differed by sex, with stronger associations among men than women; study design, a higher proportion of case-control studies reported significant findings compared to prospective studies. Consuming a dietary pattern high in fruits and vegetables and low in meats and sweets is protective against CRC risk. However, important questions remain about mechanisms underlying differences by sex; life-course timing of exposure to dietary patterns; interaction of dietary patterns with the microbiome or with lifestyle factors including physical activity; and elucidation of subsite differences. PMID- 29399005 TI - Beyond Brainstorming: Exploring Convergence in Teams. AB - Collaborative brainstorming is often followed by a convergence activity where teams extract the most promising ideas on a useful level of detail from the brainstorming results. Contrary to the wealth of research on electronic brainstorming, there is a dearth of research on convergence. We used experimental methods for an in-depth exploration of two facilitation-based interventions in a convergence activity: attention guidance (focusing participants on procedures to execute a convergence task) and discussion encouragement (engaging participants in conversations to combine knowledge on ideas). Our findings show that both attention guidance and discussion encouragement are correlated with higher convergence quality. We argue that attention guidance's contribution is in its support of coordination, information processing, and goal specification. Similar, we argue that discussion encouragement's contribution is in its stimulation of idea clarification and idea combination. Contrary to past research, our findings further show that satisfaction was higher after convergence than after brainstorming. PMID- 29399006 TI - Detecting plague-host abundance from space: Using a spectral vegetation index to identify occupancy of great gerbil burrows. AB - In Kazakhstan, plague outbreaks occur when its main host, the great gerbil, exceeds an abundance threshold. These live in family groups in burrows, which can be mapped using remote sensing. Occupancy (percentage of burrows occupied) is a good proxy for abundance and hence the possibility of an outbreak. Here we use time series of satellite images to estimate occupancy remotely. In April and September 2013, 872 burrows were identified in the field as either occupied or empty. For satellite images acquired between April and August, 'burrow objects' were identified and matched to the field burrows. The burrow objects were represented by 25 different polygon types, then classified (using a majority vote from 10 Random Forests) as occupied or empty, using Normalized Difference Vegetation Indices (NDVI) calculated for all images. Throughout the season NDVI values were higher for empty than for occupied burrows. Occupancy status of individual burrows that were continuously occupied or empty, was classified with producer's and user's accuracy values of 63 and 64% for the optimum polygon. Occupancy level was predicted very well and differed 2% from the observed occupancy. This establishes firmly the principle that occupancy can be estimated using satellite images with the potential to predict plague outbreaks over extensive areas with much greater ease and accuracy than previously. PMID- 29399007 TI - A Short Route to the Ester (+/-) HomoSarkomycin via Johnson-Claisen Rearrangement. AB - Background: alpha-Methylene cycloalkanones are considered of interest because of their biological activity. Herein, in this paper the synthesis of (+/-) HomoSarkomycine Esters was described and characterized. Methods: Using Bylis Hillman adducts, triethlorthoacetate and propanoic acid, (+/-) HomoSarkomycine Esters could be synthesized by smoothly Johnson-Claisen rearrangement. Results: A small library of target compounds was prepared under optimized reaction conditions in moderate yields. The reaction mechanism and the DFT study have been investigated. Conclusion: This methodology provides ready access to 2 hydroxymethyl-2-cyclopentenone 1a which can be served as the raw materials of the synthesis of (+/-) HomoSarkomycine Ester. PMID- 29399008 TI - Low-Cost Reusable Sensor for Cobalt and Nickel Detection in Aerosols Using Adsorptive Cathodic Square-Wave Stripping Voltammetry. AB - A low-cost electrochemical sensor with Nafion/Bi modification using adsorptive stripping voltammetry for Co and Ni determination in airborne particulate matter and welding fume samples is described. Carbon stencil-printed electrodes (CSPEs) manufactured on low-cost PET films were utilized. Dimethylglyoxime (DMG) was used as a Co(II) and Ni(II) chelator with selective chemical precipitation for trace electrochemical analysis. Electrochemical studies of the Nafion/Bi-modified CSPE indicated a diffusion-controlled redox reaction for Co and Ni measurements. The Nafion coating decreased the background current and enhanced the measured peak current. Repeatability tests based on changes in percent relative standard deviation (RSD) of peak current showed the electrode could be used at least 15 times before the RSD exceeded 15% (the reported value of acceptable repeatability from Association of Official Analytical Chemists (AOAC)) due to deterioration of electrode surface. Limits of detection were 1 MUg L-1 and 5 MUg L-1 for Co and Ni, respectively, which were comparable to electrochemical sensors requiring more complicated modification procedures. The sensor produced a working range of 1-250 and 5-175 MUg L-1 for Co and Ni, respectively. Interference studies showed no other metal species interfered with Co and Ni measurements using the optimized conditions. Finally, the developed sensors were applied for Co and Ni determination in aerosol samples generated from Co rods and a certified welding fume reference material, respectively. Validation with ICP-MS showed no statistically different results with 95% confidence between sensor and the ICP methods. PMID- 29399009 TI - Synthesis and Physicochemical Characterization of the One-Carbon Carrier 10 Formyltetrahydrofolate; A Reference Standard for Metabolomics. AB - Introduction: Metabolomics analysis depends on the identification and validation of specific metabolites. This task is significantly hampered by the absence of well-characterized reference standards. The one-carbon carrier 10 formyltetrahydrofolate acts as a donor of formyl groups in anabolism where it is a substrate in formyltransferase reactions in purine biosynthesis. It has been reported as an unstable substance and is currently unavailable as a reference standard for metabolomics analysis. Objectives: The current study was undertaken to provide the metabolomics community thoroughly characterized 10 formyltetrahydrofolate along with analytical methodology and guidelines for its storage and handling. Methods: Anaerobic base treatment of 5,10 methenyltetrahydrofolate chloride in the presence of anti-oxidant was utilized to prepare 10-formyltetrahydrofolate. Results: Pure 10-formyltetrahydrofolate has been prepared and physicochemically characterized. Conditions toward maintaining the stability of a solution of the dipotassium salt of 10-formyltetrahydrofolate in solution have been determined. Conclusion: This study describes the facile preparation of pure (>90%) 10-formyltetrahydrofolate, its qualitative physicochemical characterization, as well as conditions to enable its use as a reference standard in physiologic samples. PMID- 29399011 TI - Mutual Information Correlation with Human Vision in Medical Image Compression. AB - Background: The lossy compression algorithm produces different results in various con-trasts areas. Low contrast area image quality declines greater than that of high contrast regions using equal compression ratio. These results were obtained in a subjective study. The objective image quali-ty metrics are more effective if the calculation method is more closely related to the human vision re-sults. Methods: This study first measured the PSNR and MI for discrimination between different contrast areas responding to lossy image compression in a SMPTE electronic pattern. The MI was consistent with human vision results in SMPTE electronic phantom but PSNR was not. The measurement was also applied to compressed medical images in different contrast cropping regions. Results: The MI was found to be close to human vision in CT and MR but not CRX. Both weighted PSNR and weighted MI were created to respond to the gray value and the contrast areas affected the quality estimation. Conclusion: The W-PSNR and W-MI showed that they can discriminate between different contrast areas using image compression ratios and the series of lines are equal to the contrast values and better than the tranditional approach. The W-MI measures were found to perform better than W-PSNR and can be used as an image quality index. PMID- 29399010 TI - Optic Neuritis: A Model for the Immuno-pathogenesis of Central Nervous System Inflammatory Demyelinating Diseases. AB - Evidence for the tenuous regulation between the immune system and central nervous system (CNS) can be found with examples of interaction between these organ systems gone awry. Multiple sclerosis (MS) is the prototypical inflammatory disease of the CNS and is characterized by widely distributed inflammatory demyelinating plaques that can involve the brain, spinal cord and/or optic nerves. Optic neuritis (ON), inflammatory injury of the optic nerve that frequently occurs in patients with MS, has been the focus of intense study in part given the readily accessible nature of clinical outcome measures. Exploring the clinical and pathological features of ON in relation to other inflammatory demyelinating conditions of the CNS, namely MS and neuromyelitis optica, provides an opportunity to glean common and distinct mechanisms of disease. Emerging data from clinical studies along with various animal models involving ON implicate innate and adaptive immune responses directed at glial targets, including myelin oligodendrocyte glycoprotein and aquaporin 4. Resolution of inflammation in ON is commonly observed both clinically and experimentally, but persistent nerve injury is also one emerging hallmark of ON. One hypothesis seeking evaluation is that, in comparison to other sites targeted in MS, the optic nerve is a highly specialized target within the CNS predisposing to unique immunologic processes that generate ON. Overall, ON serves as a highly relevant entity for understanding the pathogenesis of other CNS demyelinating conditions, most notably MS. PMID- 29399012 TI - Value of Magnetic Resonance Urography Versus Computerized Tomography Urography (CTU) in Evaluation of Obstructive Uropathy: An Observational Study. AB - Background: Obstructive uropathy is a common public health issue that requires imaging research for providing necessary information. The data is important for determining treatment options, and may influence selective management choices. Objective: The aim of the study is to determine whether magnetic resonance urography or computerized tomography urography is the best imaging modality among patients with suspected obstructive uropathy. Methods: Seventy patients; referred from the emergency department for the evaluation of renal colic or hematuria that highly suggested urinary tract abnormalities, were prospectively enrolled. Thirty five women and 35 men were categorized with a mean age of 43.52 years and the mean body weight of 61.31 kg. All participants underwent abdominal ultrasonography and clinical examination to detect the causes of urinary obstruction. Pregnant women were excluded from the study. Both magnetic resonance urography and computerized tomography urography were performed within 30 days of each analysis. Results: Only 54.3% of the participants had urinary stones. Mean size of the renal stone was 11 mm; while mean size of the ureteral stone was 3.8 mm. The approach of magnetic resonance is not only limited to diagnosis, but is also effectively involved in the real time investigations. MRU has more reliability in terms of the diagnosis and anatomic presentation of the kidneys along with the vasculature. All cases of urinary stones were detected by computed tomography (100%); whereas, 78.9% cases were detected by magnetic resonance urography. Conclusion: Computerized tomography urography is more sensitive in detecting kidney stones; whereas, magnetic resonance urography is better in detecting pathology behind the development of kidney stones. PMID- 29399013 TI - The Clinical Value of Prenatal 3D Ultrasonic Diagnosis on Fetus Hemivertebra Deformity- A Preliminary Study. AB - Objective: The present study is planned to discuss the clinical value of prenatal 3D ultra-sonic diagnosis on fetus hemivertebra deformity through the retrospective analysis of clinical data of fetus hemivertebra deformity. Methods: Selected 9 fetus hemivertebra deformity cases, which have been admitted to our hospital during the period from January, 2010 to January, 2016 as study samples, and analyzed their 2D and 3D ultrasonic examination data. Results: 4 cases of the fetus hemivertebra deformity occurred at lumbar vertebra, 3 cases at thoracic vertebra, and 2 cases at thoracolumbar vertebra. There were scoliosis and opened spine bifida (OSB). In 7 cases, there was absence of ribs in fetus. The 2D ultrasonic image showed that: The echo at the center of fetus vertebral arch lesion was blurred or lost. The coronal section showed the deformity of the spine. There was obvious loss of the ossification center. From the cross section, we could see that the vertebral body of the fetus was shrinking and the edges were relatively blurred. The 3D ultrasonic image showed that: the echo at the ossification center of the fetus vertebra was relatively blurred, or even lost. The image also indicated scoliosis deformity of the spine. The vertebral body lesion could be accurately located. Conclusion: 9 cases of fetus hemivertebra deformity have been detected through examination. Labor inductions have been carried out after getting the permission from the family members. The X-ray examination of the fetus after labor induction showed that the diagnosis was correct. Prenatal ultra-sonic examination holds strong potential for the diagnosis of fetus hemivertebra deformity quite early and deserves further clinical evaluation with large sample size. PMID- 29399014 TI - Evaluation of Application Value of Transcranial Doppler (TCD) in the Inspection of Cerebral Vasospasm After the Treatment of Intracranial Aneurysm. AB - : Objective This study aimed to explore the application value of transcranial doppler (TCD) in the inspection of cerebral vasospasm (CVS) after the treatment of intracranial aneurysm. METHODS: 105 cases of patients with confirmed intracranial aneurysm were divided into two groups based on the two different treatments - craniotomy and aneurysmal clipping or interventional emboli-zation therapy. TCD was applied to monitor the conditions of CVS of 105 cases, and case study re-search method was used to analyze and conclude the TCD inspection data of patients with intracrani-al aneurysm detected after operation. RESULTS: The sensitivity of TCD in the detection of CVS was 83% and the specificity was 88%. Fur-ther, the incidence rate of CVS in the group treated with interventional embolization therapy was higher than that of the group treated with aneurysm clipping. CONCLUSIONS: TCD, which can be used to guide the adjustment of treatment and avoid complications, is an effective method in monitoring CVS after the treatment of intracranial aneurysm. PMID- 29399016 TI - The Palladium Acetate-Catalyzed Microwave-Assisted Hirao Reaction without an Added Phosphorus Ligand as a "Green" Protocol: A Quantum Chemical Study on the Mechanism. AB - It was proved by our experiments that on microwave irradiation, the mono- or bidentate phosphorus ligands generally applied in the palladium(II)-catalyzed P-C coupling reaction of aryl bromides and dialkyl phosphites or secondary phosphine oxides may be substituted by the excess of the >P(O)H reagent that exists under a tautomeric equilibrium. Taking into account that the reduction of the palladium(II) salt and the ligation of the palladium(0) so formed requires 3 equivalents of the P-species for the catalyst applied in a quantity of 5-10%, all together, 15-30% of the P-reagent is necessary beyond its stoichiometric quantity. In the coupling reaction of diphenylphosphine oxide, it was possible to apply diethyl phosphite as the reducing agent and as the P-ligand. The reactivities of the diethyl phosphite and diphenylphosphine oxide reagents were compared in a competitive reaction. The mechanism and the energetics of this new variation of the Hirao reaction of bromobenzene with Y2P(O)H reagents (Y=EtO and Ph) was explored by quantum chemical calculations. The first detailed study on simple reaction models justified our assumption that, under the conditions of the reaction, the trivalent form of the >P(O)H reagent may serve as the P-ligand in the palladium(0) catalyst, and shed light on the fine mechanism of the reaction sequence. The existence of the earlier described bis(palladium complex) {[H(OPh2P)2PdOAc]2} was refuted by high level theoretical calculations. This kind of complex may be formed only with chloride anions instead of the acetate anion. The interaction of palladium acetate and Y2P(O)H may result in only the formation of the [(HO)Y2P]2Pd complex that is the active catalyst in the Hirao reaction. The new variation of the Hirao reaction is of a more general value, and represents the greenest protocol, as there is no need for the usual P-ligands. Instead, the >P(O)H reagent should be used in an excess of up to 30%. Hence, the costs and environmental burdens may be decreased. PMID- 29399015 TI - Early Stages of Antibacterial Damage of Metallic Nanoparticles by TEM and STEM HAADF. AB - Background: Propagation of pathogens has considered an important health care problem due to their resistance against conventional antibiotics. The recent challenge involves the design of functional alternatives such as nanomaterials, used as antibacterial agents. Early stages of antibacterial damage caused by metallic nanoparticles (NPs) were studied by Transmission Electron Microscopy (TEM) and combined Scanning Transmission Electron Microscopy with High Angle Annular Dark Field (STEM-HAADF), aiming to contribute to the elucidation of the primary antibacterial mechanism of metallic NPs. Methods: We analyze the NPs morphology by TEM and their antibacterial activity (AA) with different amounts of Ag and Cu NPs. Cultured P. aeruginosa were interacted with both NPs and processed by TEM imaging to determine NPs adhesion into bacteria wall. Samples were analyzed by combined STEM-HAADF to determine the NPs penetration into bacterium and elemental mapping were done. Results: Both NPs displays AA depending on NPs concentration. TEM images show NPs adhesion on bacterial cells, which produces morphological changes in the structure of the bacteria. STEM-HAADF also proves the NPs adhesion and penetration by intracellular localization, detecting Ag/Cu species analyzed by elemental mapping. Moreover, the relative amount of phosphorus (P) and sulfur (S) increases slightly in P. aeruginosa with the presence of NPs. These elements are associated with damaged proteins of the outer cell membrane. Conclusions: Combined microscopy analyses suggest that the early stages of antibacterial damage caused by alteration of bacterial cell wall, and can be considered a powerful tool aiming to understand the primary antibacterial mechanism of NPs. PMID- 29399017 TI - Parametric studies on droplet generation reproducibility for applications with biological relevant fluids. AB - Although the great potential of droplet based microfluidic technologies for routine applications in industry and academia has been successfully demonstrated over the past years, its inherent potential is not fully exploited till now. Especially regarding to the droplet generation reproducibility and stability, two pivotally important parameters for successful applications, there is still a need for improvement. This is even more considerable when droplets are created to investigate tissue fragments or cell cultures (e.g. suspended cells or 3D cell cultures) over days or even weeks. In this study we present microfluidic chips composed of a plasma coated polymer, which allow surfactants-free, highly reproducible and stable droplet generation from fluids like cell culture media. We demonstrate how different microfluidic designs and different flow rates (and flow rate ratios) affect the reproducibility of the droplet generation process and display the applicability for a wide variety of bio(techno)logically relevant media. PMID- 29399018 TI - Separation of Platinum from Palladium and Iridium in Iron Meteorites and Accurate High-Precision Determination of Platinum Isotopes by Multi-Collector ICP-MS. AB - This study presents a new measurement procedure for the isolation of Pt from iron meteorite samples. The method also allows for the separation of Pd from the same sample aliquot. The separation entails a two-stage anion-exchange procedure. In the first stage, Pt and Pd are separated from each other and from major matrix constituents including Fe and Ni. In the second stage, Ir is reduced with ascorbic acid and eluted from the column before Pt collection. Platinum yields for the total procedure were typically 50-70%. After purification, high-precision Pt isotope determinations were performed by multi-collector ICP-MS. The precision of the new method was assessed using the IIAB iron meteorite North Chile. Replicate analyses of multiple digestions of this material yielded an intermediate precision for the measurement results of 0.73 for epsilon192Pt, 0.15 for epsilon194Pt and 0.09 for epsilon196Pt (2 standard deviations). The NIST SRM 3140 Pt solution reference material was passed through the measurement procedure and yielded an isotopic composition that is identical to the unprocessed Pt reference material. This indicates that the new technique is unbiased within the limit of the estimated uncertainties. Data for three iron meteorites support that Pt isotope variations in these samples are due to exposure to galactic cosmic rays in space. PMID- 29399019 TI - Syndromes of collateral-reported psychopathology for ages 18-59 in 18 Societies. AB - The purpose was to advance research and clinical methodology for assessing psychopathology by testing the international generalizability of an 8-syndrome model derived from collateral ratings of adult behavioral, emotional, social, and thought problems. Collateral informants rated 8,582 18-59-year-old residents of 18 societies on the Adult Behavior Checklist (ABCL). Confirmatory factor analyses tested the fit of the 8-syndrome model to ratings from each society. The primary model fit index (Root Mean Square Error of Approximation) showed good model fit for all societies, while secondary indices (Tucker Lewis Index, Comparative Fit Index) showed acceptable to good fit for 17 societies. Factor loadings were robust across societies and items. Of the 5,007 estimated parameters, 4 (0.08%) were outside the admissible parameter space, but 95% confidence intervals included the admissible space, indicating that the 4 deviant parameters could be due to sampling fluctuations. The findings are consistent with previous evidence for the generalizability of the 8-syndrome model in self-ratings from 29 societies, and support the 8-syndrome model for operationalizing phenotypes of adult psychopathology from multi-informant ratings in diverse societies. PMID- 29399020 TI - Comparing Self-Concept Among Youth Currently Receiving Inpatient Versus Outpatient Mental Health Services. AB - Objective: This study compared levels of self-concept among youth who were currently receiving inpatient versus outpatient mental health services. Method: Forty-seven youth were recruited from the Child & Youth Mental Health Program at McMaster Children's Hospital. Self-concept was measured using the Self-Perception Profile for Children and Adolescents. Results: The mean age was 14.5 years and most participants were female (70.2%). ANOVAs comparing self-concept with population norms showed large significant effects (d = 0.77 to 1.93) indicating compromised self-concept among youth receiving mental health services. Regression analyses controlling for patient age, sex, family income, and diagnoses of major depressive disorder, generalized social phobia, and generalized anxiety showed that the inpatient setting was a significant predictor of lower global self-worth (beta=-.26; p=.035). Conclusions: Compared to outpatients, inpatients generally reported lower self-concept, but differences were significant only for global self-worth. Future research replicating this finding and assessing its clinical significance is encouraged. PMID- 29399022 TI - Edematous Hyponatremia Treated with Tolvaptan in a Patient with Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) patients rarely present with either syndrome of inappropriate antidiuretic hormone secretion or generalized edema. Tolvaptan is a selective vasopressin V2 receptor antagonist that produces effective aquaresis, and its use in ALS patients has not been previously reported. A 50 year-old male ALS patient was admitted because of both generalized edema and dilutional hyponatremia. These manifestations were refractory to conventional diuretics and fluid therapy, but a very brisk diuresis was induced by tolvaptan administration. Edema and hyponatremia were also improved, and the patient was able to be discharged without tolvaptan. In this case report, we postulate how edema and dilutional hyponatremia developed in the patient, and discuss the mechanism of tolvaptan in treating hypervolemic hyponatremia. Further experience is necessary to evaluate the usefulness of tolvaptan in patients with neurological disorders. PMID- 29399021 TI - 25-hydroxyvitamin D Levels was not Associated with Blood Pressure and Arterial Stiffness in Patients with Chronic Kidney Disease. AB - Background: We investigated the effect of vitamin D deficiency on cardiovascular risk profiles in an Asian population with chronic kidney disease (CKD). Methods: A total of 210 participants (62 non-dialysis CKD patients and 148 hemodialysis [HD] patients) were enrolled between December 2009 and February 2010. Vitamin D deficiency was determined using the serum 25-hydroxyvitamin D [25(OH)D] concentration. Blood pressure and arterial stiffness were measured. Subjects were divided into groups according to 25(OH)D concentration based on a cut-off of 13.5 ng/mL in non-dialysis CKD patients and 11.3 ng/mL in HD patients. Results: The mean age was 61.7+/-12.3 years in non-dialysis CKD patients and 57.0+/-12.7 years in HD patients. In the non-dialysis CKD group, mean estimated glomerular filtration rate (eGFR) was 29.7+/-15.4 mL/min/1.73 m2. Mean 25(OH)D concentration was 13.6+/-7.8 ng/mL in non-dialysis CKD patients and 11.3+/-6.7 ng/mL in HD patients. More than half of the subjects had vitamin D deficiency (67.6% in non dialysis CKD patients and 80.4% in HD patients). There were no significant differences in systolic blood pressure, pulse pressure, and arterial stiffness between higher and lower 25(OH)D groups among non-dialysis CKD and HD patients. Multivariate analysis revealed that female sex (odds ratio [OR]: 5.890; 95% confidence interval [CI]: 2.597-13.387; p<0.001) and presence of diabetes (OR: 2.434; 95% CI: 1.103-5.370; p=0.028) were significantly associated with lower serum 25(OH)D levels in HD patients. Conclusion: The prevalence of vitamin D deficiency was high in both nondialysis CKD patients and HD patients. Serum 25(OH)D concentration was not a significant factor associated with blood pressure and arterial stiffness among non-dialysis CKD and HD patients. PMID- 29399023 TI - Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Associated with Mediastinal Schwannoma. AB - Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hypo-osmotic hyponatremia. There are several etiologies of SIADH including neuroendocrine tumor, pulmonary disease, infection, trauma, and medications. Here, we report a case of SIADH associated with a schwannoma involving the mediastinum in a 75-year-old woman who presented with nausea, vomiting, and general weakness. Laboratory testing showed hypo-osmolar hyponatremia, with a serum sodium level of 102mmol/L, serum osmolality of 221mOsm/kg, urine osmolality of 382mOsm/kg, urine sodium of 55 mmol/L, and plasma antidiuretic hormone (ADH) of 4.40 pg/mL. Chest computed tomography identified a 1.5-cm-sized solid enhancing nodule in the right lower paratracheal area. A biopsy specimen was obtained by video-assisted thoracoscopic surgery, which was diagnosed on pathology as a schwannoma. The hyponatremia was completely resolved after schwannoma resection and plasma ADH level decreased from 4.40 pg/mL to 0.86 pg/mL. This case highlights the importance of suspecting and identifying the underlying cause of SIADH when faced with refractory or recurrent hyponatremia, and that on possibility is mediastinal schwannoma. PMID- 29399024 TI - A Case of Ethylene Glycol intoxication with Acute Renal Injury: Successful Recovery by Fomepizole and Renal Replacement Therapy. AB - Ethylene glycol is a widely used and readily available substance. Ethylene glycol ingestion does not cause direct toxicity; however, its metabolites are highly toxic and can be fatal even in trace amounts. Poisoning is best diagnosed through inquiry, but as an impaired state of consciousness is observed in most cases, poisoning must be suspected when a significantly elevated osmolar gap or high anion gap metabolic acidosis is found in blood tests. Hemodialysis and alcohol dehydrogenase inhibitors such as ethanol and fomepizole are a part of the basic treatment, and timely diagnosis and treatment are crucial because any delays can lead to death. However, there are few reported cases in Korea, and no report on the use of fomepizole. Herein, we report a case of acute renal failure caused by ethylene glycol poisoning that was treated with fomepizole and hemodialysis and present a literature review. PMID- 29399025 TI - Dendropanax morbifera Leveille extract ameliorates D-galactose-induced memory deficits by decreasing inflammatory responses in the hippocampus. AB - In the present study, we examined the effects of Dendropanax morbifera Leveille leaf extract (DML) on D-galactose-induced morphological changes in microglia and cytokines, including pro-inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) and anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Administration of DML to D-galactose-treated mice significantly improved D-galactose-induced reduction in escape latency, swimming speed, and spatial preference for the target quadrant. In addition, administration of DML to D-galactose-treated mice significantly ameliorated the microglial activation and increases of IL-1beta, IL-6, and TNF-alpha levels in the hippocampus. Administration of D-galactose significantly reduced IL-4 levels in the hippocampus, while administration of DML to D-galactose-treated mice significantly increased IL-4 level. However, we did not observe any significant changes in IL-10 levels in hippocampal homogenates. These results suggest that DML reduces D-galactose-induced mouse senescence by reducing pro-inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha, as well as increasing anti inflammatory cytokine IL-4. PMID- 29399027 TI - Correlation between laxative effects of uridine and suppression of ER stress in loperamide induced constipated SD rats. AB - A correlation between endoplasmic reticulum (ER) stress and laxative effects was first reported in a constipation model treated with an aqueous extract of Liriope platyphylla (AEtLP) roots. To investigate the correlation between the laxative effect of uridine (Urd) and ER stress response, alterations in the key parameters for ER stress were measured in loperamide (Lop) induced constipation Sprague Dawley (SD) rats treated with Urd. The efficacy of the laxative effect of Urd was notable on the symptoms of chronic constipation, including alteration of stool parameters and structure of the transverse colon, in Lop induced constipated SD rats. In the PERK/eIF2-ATF4 pathway of ER stress response, the levels of eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation and DNA damage inducible protein (GADD34) transcripts were significantly enhanced in the Lop+Vehicle treated group. However, the levels were restored in the Lop+Urd treated group, although few differences were detected in the decrease rate. Similar changes were observed for levels of inositol-requiring enzyme 1 beta (IRE1beta) phosphorylation and X-box binding protein 1 (XBP-1) transcript in the IRE1alpha/XBP pathway. Furthermore, the number of ER stress-induced apoptotic cells and Bax and Bcl-2 expression were recovered in the Lop+Urd treated group compared to the Lop+Vehicle treated group. The results of the present study therefore provide first evidence that the laxative effects of Urd may be tightly correlated with the recovery of ER stress response in constipation models. PMID- 29399026 TI - Gold thread implantation promotes hair growth in human and mice. AB - Thread-embedding therapy has been widely applied for cosmetic purposes such as wrinkle reduction and skin tightening. Particularly, gold thread was reported to support connective tissue regeneration, but, its role in hair biology remains largely unknown due to lack of investigation. When we implanted gold thread and Happy LiftTM in human patient for facial lifting, we unexpectedly found an increase of hair regrowth in spite of no use of hair growth medications. When embedded into the depilated dorsal skin of mice, gold thread or polyglycolic acid (PGA) thread, similarly to 5% minoxidil, significantly increased the number of hair follicles on day 14 after implantation. And, hair re-growth promotion in the gold threadimplanted mice were significantly higher than that in PGA thread group on day 11 after depilation. In particular, the skin tissue of gold thread implanted mice showed stronger PCNA staining and higher collagen density compared with control mice. These results indicate that gold thread implantation can be an effective way to promote hair re-growth although further confirmatory study is needed for more information on therapeutic mechanisms and long-term safety. PMID- 29399028 TI - Quercetin attenuates the injury-induced reduction of gamma-enolase expression in a middle cerebral artery occlusion animal model. AB - Quercetin, a natural flavonoid, copiously exists in vegetable, fruits and tea. Quercetin is beneficial to neurodegenerative disorders via its strong anti oxidant and anti-inflammatory activities. gamma-Enolase is one of the enzymes of glycolytic pathway and is predominantly expressed in neuronal cells. The aim of the present study is to verify whether quercetin modulates the expression of gamma-enolase in brain ischemic injury. Adult Sprague-Dawley male rats were subjected to middle cerebral artery occlusion (MCAO) and quercetin (50 mg/kg) or vehicle was administered by intraperitoneal injection at 1 h before MCAO onset. A proteomics study, Western blot analysis, reversetranscription-PCR, and immunofluorescence staining were conducted to investigate the change of gamma enolase expression level. We identified a decline in gamma-enolase expression in MCAO-operated animal model using a proteomic approach. However, quercetin treatment significantly attenuated this decline. These results were confirmed using Western blot analysis, reverse transcription-PCR, and immunofluorescence staining techniques. gamma-Enolase is accepted as a neuron specific energy synthesis enzyme, and quercetin modulates gamma-enolase in a MCAO animal model. Thus, our findings can suggest the possibility that quercetin regulates gamma enolase expression in response to cerebral ischemia, which likely contributes to the neuroprotective effect of quercetin. PMID- 29399029 TI - Erratum: Comparative study of the immunological characteristics of three different C57BL/6N mouse substrains. AB - [This corrects the article on p. 124 in vol. 33, PMID: 28747978.]. PMID- 29399030 TI - Erratum: Comparison of humoral and cell-mediated immunity in three different C57BL/6N mouse substrains. AB - [This corrects the article on p. 132 in vol. 33, PMID: 28747979.]. PMID- 29399031 TI - Erratum: Comparative analysis of basal locomotor activity-related metabolic phenotypes between C57BL/6 mice and ICR mice substrains derived from three different sources. AB - [This corrects the article on p. 140 in vol. 33, PMID: 28747980.]. PMID- 29399032 TI - Erratum: Comparative study of fatty liver induced by methionine and choline deficiency in C57BL/6N mice originating from three different sources. AB - [This corrects the article on p. 157 in vol. 33, PMID: 28747982.]. PMID- 29399033 TI - Erratum: Comparison of doxorubicin-induced cardiotoxicity in the ICR mice of different sources. AB - [This corrects the article on p. 165 in vol. 33, PMID: 28747983.]. PMID- 29399034 TI - Erratum: Annual tendency of research papers used ICR mice as experimental animals in biomedical research fields. AB - [This corrects the article on p. 171 in vol. 33, PMID: 28747984.]. PMID- 29399035 TI - Erratum: Comparative study of fertilization rates of C57BL/6NKorl and C57BL/6N mice obtained from two other sources. AB - [This corrects the article on p. 179 in vol. 33, PMID: 28747985.]. PMID- 29399036 TI - A Pediatric Patient with Idiopathic Short Stature Who Developed Obstructive Sleep Apnea after Starting Growth Hormone Replacement Therapy. AB - Background: Growth hormone (GH) therapy has long been suspected to induce obstructive sleep apnea (OSA) in children and adults. Moreover, reports about GH associated sudden death in children with Prader-Willi syndrome (PWS) have prompted concerns about GH worsening sleep apnea. Previous studies have supported routine polysomnography for children with PWS prior to starting GH treatments, regardless of clinical history. However, there are no established guidelines recommending routine polysomnography (PSG) prior to the commencement of GH therapy in other pediatric patients. Case description: We report a case of a 15 year-old young man with intractable headaches, referred to the sleep clinic to rule out any sleep-related variables. After an initial non-significant (mild snoring) sleep study, the patient returned with worsening snoring about one year after starting GH therapy for concerns of short stature. Results: A second polysomnogram revealed that his obstructive apnea-hypopnea index had risen dramatically from baseline. His symptoms resolved after tonsillectomy and adenoidectomy. Conclusion: This interesting case highlights the need for caution with any patient eligible for GH therapy. We recommend additional research to look in the development of definitive guidelines regarding the indications for polysomnography for patients with idiopathic short stature and non-significant initial sleep history-particularly before and during the administration of GH therapy. PMID- 29399037 TI - Complement activation turnover on surfaces of nanoparticles. AB - The complement system is an important component of the innate immune system, which contributes to non-specific host defence. Particulate matters, such as invading pathogens and nanomedicines, in the blood may activate the complement system through classical, lectin and alternative pathways. Complement activation can aid recognition and clearance of particulate matters by immune cells, but uncontrolled complement activation can inflict damage and be life threatening. Plasma proteins on adsorption to surfaces of nanoparticles also play a significant role in complement activation and particularly through the alternative pathway. This process is continuous and changeable in vivo; protein complement complexes are formed on the nanoparticle surface and then released and the cycle repeats on further plasma protein deposition. This complement activation turnover poses a challenge for design of immune-safe nanomedicines. PMID- 29399038 TI - College students and HIV testing: cognitive, emotional self-efficacy, motivational and communication factors. AB - Most college students have never been tested for HIV, even though they regularly have unprotected sex and multiple sex partners. Theory-based research addressing factors influencing HIV testing among college students is limited. This study explored this topic via a conceptual framework that integrates the health belief model with emotion and communication factors. Data was collected with a sample of four focus group panels, including two male and two female groups (N = 52). Transcripts for the seven discussion questions were produced based on the audio recordings of group sessions. Two research assistants reviewed, summarized and cross-validated the discussion content to address each of the four research questions under study. Students believe HIV to be a severe health threat, but feel 'invincible' about contracting the virus. Their low emotional self-efficacy is a barrier for adopting HIV testing. Gaining social approval and emotional support for making a testing decision can help them overcome the perceived fear, stigma and lack of response efficacy associated with taking the test. Students are open to receiving cues to action via confidential HIV-testing related communication from health professionals or important others as well as media messaging from various sources. Bridging the perceptual-emotional gap between perceived invulnerability and fear can help increase emotional self-efficacy in coping with HIV testing. Normalizing HIV testing as a primary care routine for harm avoidance/reduction will increase perceived benefits of testing. Communicating cues to action will help reinforce HIV testing as a societally approved and socially supported protective behavioral norm. PMID- 29399040 TI - Clinical outcome of patients with obscure gastrointestinal bleeding during antithrombotic drug therapy. AB - Background: The clinical outcome of patients with obscure gastrointestinal bleeding (OGIB) during antithrombotic drug therapy has not been fully investigated. Methods: Patients who underwent video capsule endoscopy (VCE) for the investigation of OGIB at Okayama University Hospital from January 2009 to March 2016 were enrolled. We evaluated the VCE findings, the patterns of OGIB, and the rate of rebleeding within 1 year in antithrombotic drug users and antithrombotic drug nonusers. Results: A total of 181 patients were enrolled. Among the antithrombotic drug users, the rate of VCE positivity in the patients with overt OGIB was significantly higher in comparison with patients with occult OGIB (45% versus 16%, p = 0.014), whereas there was no significant difference among the antithrombotic drug nonusers (27% versus 26%, p = 1.0). Among the antithrombotic drug users, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (50% versus 5.9%, p = 0.011). Moreover, among antithrombotic drug users who did not receive therapeutic intervention, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (75% versus 6.3%, p = 0.001). However, among the antithrombotic drug nonusers who did not receive therapeutic intervention, the rebleeding rate of the VCE-positive patients was not significantly different from that of the VCE-negative patients (20% versus 9.4%, p = 0.43). Conclusion: Therapeutic intervention should be considered for patients with overt OGIB who are VCE positive and who use antithrombotic drugs due to the high risk of rebleeding. PMID- 29399039 TI - Food consumption and dietary intakes in 36,448 adults and their association with irritable bowel syndrome: Nutrinet-Sante study. AB - Introduction: Diet plays an important role for patients with irritable bowel syndrome (IBS). The aim of this study was to compare the diets in terms of food consumption and nutrient intake between subjects with IBS and controls in a large French population. Methods: This study included 36,448 subjects from the Nutrinet Sante cohort study, who completed a questionnaire pertaining to functional bowel disorders based on the Rome III criteria. Dietary data were obtained from at least three self-administered 24 h records via the internet. Association between IBS and diet was evaluated by comparison tests controlled for gender, age and total energy intake (ANCOVA tests). Results: Subjects included were mainly women (76.9%) and the mean age was 50.2 +/- 14.2 years. Among these individuals, 1870 (5.1%) presented with IBS. Compared to healthy controls, they had significantly lower consumption of milk (74.6 versus 88.4 g/day; p < 0.0001), yogurt (108.4 versus 115.5 g/day; p = 0.001), fruits (192.3 versus 203.8 g/day; p < 0.001), and higher soft non-sugared beverages (1167.2 versus 1122.9 ml/day; p < 0.001). They had higher total energy intake (2028.9 versus 1995.7 kcal/day; p < 0.001), with higher intakes of lipids (38.5 versus 38.1% of total energy intake; p = 0.001) and lower intakes of proteins (16.4 versus 16.8% of total energy intake; p < 0.0001), as well as micronutrients (calcium, potassium, zinc and vitamins B2, B5 and B9, all p < 0.0001). Conclusions: In this large sample, these findings suggest that dietary intake of subjects suffering from IBS differs from that of control subjects. They may have adapted their diet according to symptoms following medical or non-medical recommendations. PMID- 29399041 TI - Insights into the management of gastric antral vascular ectasia (watermelon stomach). AB - Gastric antral vascular ectasia (GAVE) is an uncommon but important cause of chronic gastrointestinal bleeding. It is often associated with systemic diseases such as autoimmune diseases, liver cirrhosis, chronic renal insufficiency and cardiovascular disease. The etiology of GAVE has not been fully explored and remains controversial. Diagnosis is mainly based on endoscopic presentation with flat or raised erythematous stripes radiating from the pylorus to the antrum and resembles a watermelon. Clinical presentation may range from iron-deficiency anemia secondary to occult blood loss, melena to hematemesis. In past decades, many therapeutic modalities including medical, endoscopic and surgical intervention have been introduced for GAVE treatment with variable efficacy. Herein, we review the efficacy and safety of these treatment options for GAVE. PMID- 29399042 TI - The Lewis score or the capsule endoscopy Crohn's disease activity index: which one is better for the assessment of small bowel inflammation in established Crohn's disease? AB - Background: Small-bowel capsule endoscopy (CE) is a prime modality for evaluation of the small bowel. The Lewis score (LS) and the Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) are validated endoscopic indices for quantification of small-bowel inflammation on CE. It is unclear whether these indexes are interchangeable for the evaluation of mucosal inflammation in established Crohn's disease (CD). The aim of this study was to compare the quantitative evaluation of small- bowel inflammation by LS and CECDAI. Methods: Patients with known quiescent small-bowel CD for at least 3 months (Crohn's disease activity index < 150) were prospectively recruited and underwent CE. The LS was calculated using RAPID 8 capsule-reading software and the CECDAI was calculated manually. Cumulative LS (C-LS) was calculated by summation of individual tertile LS. Fecal calprotectin (FCP) and C-reactive protein (CRP) levels were measured and correlated with the scores. Results: A total of 50 patients were included in the study. There was a moderate correlation between the worst segment LS and CECDAI (Pearson's r = 0.66, p = 0.001), and a strong correlation between C-LS and CECDAI (r = 0.81, p = 0.0001). CECDAI < 5.4 corresponded to mucosal healing (LS < 135), while CECDAI > 9.2 corresponded to moderate-to-severe inflammation (LS ? 790). There was a moderate correlation between capsule scores and FCP levels (r = 0.39, p = 0.002 for LS, r = 0.48, p = 0.001 for C-LS, and r = 0.53, p = 0.001 for CECDAI, respectively). CRP levels were not significantly correlated with either score. Conclusions: CECDAI and C-LS are strongly correlated and perform similarly for quantitative assessment of mucosal inflammation in established CD. PMID- 29399044 TI - Correlation of hyperglycemia with mortality after acute ischemic stroke. AB - Background: Hyperglycemia has been considered a predictor of stroke outcomes. In this article we study the correlation between blood glucose levels within the first 24 h after stroke onset and patients' outcomes in mortality and hemorrhagic transformations. Methods: Ninety-one non-diabetic patients with acute ischemic stroke admitted to a neurological intensive unit were recruited. Their blood glucose was measured twice within 6 h (baseline) and at every hour after stroke onset. Patients were collected into four groups as follows: those in which normoglycemia and no hyperglycemia were observed at either baseline or 24 h; those with baseline hyperglycemia and hyperglycemia only at baseline; those with 24 h hyperglycemia and hyperglycemia only at 24 h after stroke; and those with persistent hyperglycemia and hyperglycemia at both baseline and at 24 h. Endpoints were designated as the patient's death within 30 days and/or hemorrhagic transformation under computerized tomography within the first 7 days after stroke onset. Results: Persistent hyperglycemia was correlated with an increased risk of mortality within 30 days (OR = 24.0; 95% CI = 2.8-199.3) and it was also correlated with hemorrhagic transformation (OR = 13.3; 95% CI = 2.7 66.1). Baseline or delayed hyperglycemia were not correlated with any outcome. Conclusions: Persistent hyperglycemia was correlated with mortality after acute ischemic stroke. PMID- 29399043 TI - Treatment strategies for autoimmune encephalitis. AB - Autoimmune encephalitis is one of the most rapidly growing research topics in neurology. Along with discoveries of novel antibodies associated with the disease, clinical experience and outcomes with diverse immunotherapeutic agents in the treatment of autoimmune encephalitis are accumulating. Retrospective observations indicate that early aggressive treatment is associated with better functional outcomes and fewer relapses. Immune response to first-line immunotherapeutic agents (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunoadsorption) is fair, but approximately half or more of patients are administered second-line immunotherapy (rituximab and cyclophosphamide). A small but significant proportion of patients are refractory to all first- and second-line therapies and require further treatment. Although several investigations have shown promising alternatives, the low absolute number of patients involved necessitates more evidence to establish further treatment strategies. In this review, the agents used for first- and second-line immunotherapy are discussed and recent attempts at finding new treatment options are introduced. PMID- 29399045 TI - Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis. AB - In this review, we summarize the most important recent developments in the treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying treatment options, several drugs such as dexpramipexole, pioglitazone, lithium, and many others have been tested in large multicenter trials, albeit with disappointing results. Therefore, riluzole remains the only directly disease modifying drug. In addition, we discuss antisense oligonucleotides (ASOs) as a new and potentially causal treatment option. Progress in symptomatic treatments has been more important. Nutrition and ventilation are now an important focus of ALS therapy. Several studies have firmly established that noninvasive ventilation improves patients' quality of life and prolongs survival. On the other hand, there is still no consensus regarding best nutritional management, but big multicenter trials addressing this issue are currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle cramps or sialorrhea remains generally scarce, but some new insights will also be discussed. Growing evidence suggests that multidisciplinary care in specialized clinics improves survival. PMID- 29399046 TI - Extended-release oral capsule of carbidopa-levodopa in Parkinson disease. AB - Motor fluctuations complicate the treatment of patients with Parkinson's disease receiving levodopa. Extended-release carbidopa-levodopa has a pharmacokinetic profile that provides a more continuous levodopa serum concentration. Patients taking this formulation can expect longer duration of action and fewer doses per day, similar clinical improvement when compared to other levodopa formulations, and with a theoretically lower risk of developing motor fluctuations. Several studies, including three randomized control trials provide evidence for the efficacy, safety and tolerability of extended release carbidopa-levodopa in patients with both early and advanced Parkinson's disease are reviewed here. Also provided is guidance for dosing of and conversion to extended release carbidopa levodopa as well as a discussion of its place in the clinical practice. PMID- 29399047 TI - Decreased platelet number in multiple sclerosis during alemtuzumab infusion: a common, transient and clinically silent phenomenon. AB - Background: The cause and clinical significance of the transient decrease in platelet (PLT) count observed in relapsing remitting multiple sclerosis (RRMS) during alemtuzumab administration remain undefined. The aim of this study was to analyse the kinetics and clinical relevance of early onset thrombocytopaenia in alemtuzumab-treated RRMS. Methods: A total of 26 patients with RRMS were included in a longitudinal study. Blood samples were collected immediately before the first alemtuzumab infusion (D0), and after 3 days (D3), 28 days (D28) and 49 days (D49). PLT, red blood cell (RC), leucocyte and lymphocyte counts, haemoglobin (Hb) concentration and haematocrit (Htc) were measured. Patients with MS were clinically evaluated every day of drug infusion and then at D28 and D49 to verify the presence of signs or symptoms suggestive of thrombocytopaenia. Results: PLT number significantly decreased at D3 (p < 0.005) and was associated with a decrease in RC count (r: 0.53, p < 0.01), Hb (r: 0.42, p = 0.05) and Htc (r: 0.53, p < 0.01). A progressive reversion of PLT number to normal values was observed at D28 and D49. A mild thrombocytopaenia was observed in 12 patients (46.2%), 8 of which (66.6%) had PLT nadir values at D3, and 4 (33.3%) at D28. No sign or symptom suggestive of thrombocytopaenia was observed. A strong correlation between pretreatment and nadir PTL counts (r: 0.59, p < 0.005) was observed; indeed, mild thrombocytopaenia was observed more frequently in these patients with a baseline PTL count lower than 230 * 109/L (83.3% versus 42.9%, p < 0.05). Conclusions: The early PLT decrease in alemtuzumab-treated patients is transient, mild, not associated with clinically relevant events and is probably related to the cytokine-released syndrome. Notwithstanding this, our findings suggest the opportunity for PLT monitoring during infusion and in the following 2 months, since a decrease in PLT count may occur. PMID- 29399049 TI - Brivaracetam: a novel antiepileptic drug for focal-onset seizures. AB - Brivaracetam (BRV), the n-propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7-8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50-200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life. PMID- 29399050 TI - Vascular medicine and thrombectomy in stroke. AB - The treatment of stroke caused by intracranial vessel occlusion with intravenous recombinant tissue plasminogen activator (rt-PA) was the only evidence-based treatment option for a long time. Nevertheless the response rate was disappointing in large vessel occlusions. Five studies that evaluated the efficacy of mechanical thrombectomy published in 2015 proved a significant clinical benefit for selected patients suffering from acute ischemic stroke. These results are the basis for extensive technical, institutional, and personal structural changes in the neurovascular field of stroke treatment. This review gives an overview of the current status of mechanical thrombectomy and future expectations and challenges are discussed. PMID- 29399048 TI - The prospects of CRISPR-based genome engineering in the treatment of neurodegenerative disorders. AB - Over the past few decades, as gene discovery methods and sequencing technologies have evolved, many genetic variations that significantly increase the risk of or cause neurodegenerative diseases have been identified. However, knowledge of those pathogenic mutations and subsequent mechanism-focused studies has rarely yielded effective treatments, warranting alternative strategies for refining rational therapeutic targets. Nevertheless, with the evolution of gene targeting methods, it has been increasingly recognized that the disease-causing gene itself is the best therapeutic target even when we do not have a full understanding of its biological functions. Considering this, CRISPR/Cas gene editing technology offers the promise of permanently silencing or correcting the disease-causing mutations, potentially overcoming key limitations of RNA-targeting approaches. The versatile CRISPR/Cas-based strategies have the potential to become treatment options for challenging disorders such as neurodegenerative diseases. Here, we summarize recent reports of preclinical applications of CRISPR/Cas in models of neurodegenerative disorders to provide perspectives on therapeutic gene editing for diseases of the nervous system. PMID- 29399051 TI - Sleep disturbances in tension-type headache and migraine. AB - Current research into the pathogenesis of tension-type headache (TTH) and migraine is focused on altered nociceptive pain processing. Among the potential factors that influence sensitization mechanisms, emotional stress, depression, or sleep disorders all have an essential role: they increase the excitability of nociceptive firing and trigger hyperalgesic responses. Sleep disturbances and headache disorders share common brain structures and pathogenic mechanisms and TTH, migraine, and sleep disturbances often occur together; for example, 50% of individuals who have either TTH or migraine have insomnia. Moreover, insomnia and poor sleep quality have been associated with a higher frequency and intensity of headache attacks, supporting the notion that severity and prevalence of sleep problems correlate with headache burden. It should be noted that the association between headaches and sleep problems is bidirectional: headache can promote sleep disturbances, and sleep disturbances can also precede or trigger a headache attack. Therefore, a better understanding of the factors that affect sleep quality in TTH and migraine can assist clinicians in determining better and adequate therapeutic programs. In this review, the role of sleep disturbances in headaches, and the association with depression, emotional stress, and pain sensitivity in individuals with TTH or migraine are discussed. PMID- 29399052 TI - Patient satisfaction and healthcare services in specialized multiple sclerosis centres in Germany. AB - Background: As patients with multiple sclerosis (MS) require lifelong treatment, optimization of therapy with respect to efficacy and safety is needed to limit long-term disease progression. Patients with MS also need a range of health related services. Satisfaction with these as well as treatment is clinically relevant because satisfied patients are more likely to adhere to therapy. The aim of this study was to determine the status of patient satisfaction and of healthcare services in 70 specialized MS centres in Germany. Methods: In 2011, patients with MS responded to a questionnaire, which solicited clinical and demographic information, as well as patients' perceptions of their overall situation and their satisfaction with treatment. Results: Of 2791 patients surveyed, 81.9% had relapsing-remitting MS with mild disability [mean (standard deviation) Expanded Disability Status Scale score: 2.6 (1.8)]. Disease activity data were collected from 2205 patients, of whom 57.6% had remained relapse-free during the preceding 12 months. However, 38.9% had experienced one or more relapses, most of whom (67.3%) while receiving immunomodulatory treatment. About one-third of the patients indicated that they were more dissatisfied with their overall situation compared with the time before diagnosis. However, many patients (58.3%) were satisfied with their existing medication. Overall, 72.8% of patients would prefer oral to injectable treatments, assuming there was no difference in their efficacy. Conclusions: A substantial proportion of patients experienced breakthrough disease on treatment and may potentially benefit from a change of therapy. Although largely satisfied with treatment, most patients with MS would choose oral over injectable treatments. PMID- 29399053 TI - An epidemiological study on the course of disease and therapeutic considerations in relapsing-remitting multiple sclerosis patients receiving injectable first line disease-modifying therapies in Germany (EPIDEM). AB - Background: In relapsing-remitting multiple sclerosis (RRMS), 'no evidence of disease activity' (NEDA) is regarded as a key treatment goal. The increasing number of treatments allows for individualized treatment optimization in patients with suboptimal response to first-line disease-modifying therapies (DMTs). Therefore, monitoring of clinical and subclinical disease activity on DMTs has been recognized as an important component of long-term patient management. Methods: EPIDEM was a multicenter non-interventional retrospective study in a large cohort of RRMS patients receiving injectable DMTs for at least 2 years in outpatient centers throughout Germany. It documented measures and ratings of disease activity on DMTs to characterize the factors that made the treating neurologists consider to switch therapy towards potentially more effective or better-tolerated drugs. Results: The cohort included predominantly female patients with a mean age of 45 years and a mean disease duration of 9.6 years, who had been continuously treated with an injectable DMT for a median duration of 54 months. Overall, 34.0% of the patients had experienced ?1 relapse on any DMT in the previous 2 years; 21.0% exhibited magnetic resonance imaging (MRI) activity, and the Kurtzke Expanded Disability Status Scale (EDSS) score increased by at least 0.5 points in 20.1%. Overall, 50.3% of the patients with EDSS progression and 70.6% of the patients with relapses were assessed as clinically stable by the neurologists. A change of treatment was considered in a fraction of patients with disease activity: in 22.8% of those with relapse activity, in 37.8% of those with MRI activity and in 20.1% of those with EDSS progression. Conclusion: The results of EPIDEM underline the importance of standardized evaluation and documentation of ongoing disease activity and disability deterioration. Judged from the present data, the current paradigm of low tolerance for disease activity and recommendations for early treatment optimization have not been turned fully into action as yet. More widespread implementation of current guideline recommendations may allow patients to more benefit from the growing panel of effective treatment options. PMID- 29399054 TI - Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. AB - Background: The CLARITY and CLARITY Extension studies demonstrated that treatment of relapsing-remitting multiple sclerosis (RRMS) with cladribine tablets (CT) results in significant clinical improvements, compared with placebo. This paper presents the key magnetic resonance imaging (MRI) findings from the CLARITY Extension study. Methods: Patients who received a cumulative dose of either CT 3.5 or 5.25 mg/kg in CLARITY were rerandomized to either placebo or CT 3.5 mg/kg in CLARITY Extension. Patients from the arm that received placebo in CLARITY were assigned to CT 3.5 mg/kg. MRI assessments were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96, and in a supplemental follow up period. Results: At CLARITY Extension baseline, patients who received placebo during CLARITY had more T1 gadolinium-enhanced (Gd+) lesions than patients who received CT during CLARITY. These patients, who were then exposed to cladribine 3.5 mg/kg during the extension, experienced a 90.4% relative reduction (median difference -0.33, 97.5% confidence interval -0.33-0.00; p < 0.001) in T1 Gd+ lesions at the end of the extension compared with the end of CLARITY. Overall, the majority of patients in each treatment group remained free from T1 Gd+ lesions throughout CLARITY Extension. However, a small proportion of patients who were treated with cladribine in CLARITY and received placebo in CLARITY Extension showed evidence of increased MRI activity, and this was associated with a prolonged treatment gap between CLARITY and CLARITY Extension. Conclusion: A 2 year treatment with CT 3.5 mg/kg has a durable effect on MRI outcomes in the majority of patients, an effect that was sustained in patients who were not retreated in the subsequent 2 years after initial treatment. ClinicalTrials.gov identifier: NCT00641537. PMID- 29399056 TI - Cryptogenic organizing pneumonia masquerading as lung carcinoma: A case report and review of the literature. AB - Cryptogenic organizing pneumonia (COP) is a rare pulmonary disorder of unknown etiology. COP with hemoptysis as the primary presenting symptom has rarely been reported. The present study reported a case of COP that resembled lung carcinoma with hemoptysis as the only clinical symptom. The patient recovered well following thoracoscope surgery. A literature review of 119 COP cases between 1995 and 2015 was presented. Cough, fever and dyspnea were the most common clinical manifestations. The most common imaging manifestations were multiple or single consolidation, lung nodules, migratory sign, reversed halo sign, and multiple ground-glass opacity. A total of 3 cases exhibited COP accompanied by lung cancer. Glucocorticoids were effective for the majority of cases and invasive surgeries were implemented in most cases. The majority of cases recovered or relieved, and the prognosis of COP was relatively good. COP was easily confused with lung tumor and it is necessary to make differential diagnosis between COP and lung cancer. Invasive surgery should be avoided when possible to avoid or reduce patient trauma. PMID- 29399055 TI - Refractory thyroid carcinoma: which systemic treatment to use? AB - The incidence of thyroid cancer has increased markedly in recent decades, but has been stable in terms of mortality rates. For the most part, these cancers are treated with surgery, which may or may not be followed by radioactive iodine depending on the tumor subtype. Still, many of these cancers will recur and may be treated with radioactive iodine or another surgery. It is unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. Chemotherapy has a very low response rate. However, in the past few years, several systemic therapies, primarily targeted, have emerged to improve the overall survival of these patients. Alternative treatments are also of interest, namely peptide receptor radionuclide therapy or immunotherapy. PMID- 29399057 TI - MicroRNA-29b alleviates oxygen and glucose deprivation/reperfusion-induced injury via inhibition of the p53-dependent apoptosis pathway in N2a neuroblastoma cells. AB - Cerebral ischemic injury causes severe brain damage and remains one of the leading causes of morbidity and mortality worldwide. Members of the microRNA-29 (miR-29) family are involved in regulating the process of ischemia and may be developed as biomarkers to diagnose and treat cerebral ischemia. The role of miR 29b in cerebral ischemia injury remains poorly understood. The purpose of the present study was to investigate whether miR-29b overexpression suppressed cerebral ischemic injury and to explore its underlying mechanism of action. The results demonstrated that levels of miR-29b in N2a neuroblastoma cells decreased following oxygen and glucose deprivation/reperfusion (OGD/R) treatment. Transfection with miR-29b mimics significantly increased cell viability, decreased lactate dehydrogenase (LDH) leakage, inhibited apoptosis by decreasing morphological changes occurring in the nuclei and reduced caspase-3 activity in OGD/R-treated N2a cells. Conversely, miR-29b inhibitors enhanced OGD/R-induced cytotoxicity and apoptosis. In addition, the miR-29b mimics blocked the increase in Bax and p53 expression and decreased Bcl-2 expression in OGD/R-treated N2a cells, whereas miR-29b inhibitors exacerbated the changes in the expression of these apoptosis-associated proteins caused by OGD/R. p53 knockdown using p53 small interfering RNA decreased cell viability and increased LDH leakage, reversing the improvements that the miR-29b mimics induced in damaged cells. Taken together, the results of the present study demonstrated that miR-29b attenuates ischemic injury by negatively regulating the p53-dependent apoptosis pathway and may therefore be a novel potential therapeutic target for treating ischemic stroke. PMID- 29399058 TI - MicroRNA-296 mediated corneal neovascularization in an animal model of corneal burns after alkali exposures. AB - Alkali burns of the cornea may lead to permanent visual impairment or complete blindness. In the current study, the role of microRNA 296 (miR-296) was explored in mouse corneal neovascularization induced by alkali burns. An alkali burn model in Balb/c mice was developed to study chemical corneal injuries. The expression of the miR-296 gene was measured by reverse-transcription-quantitative polymerase chain reaction. Fibroblast growth factor 23 (FGF23) protein expression was measured by western blot analysis. Possible impacted pathways were analyzed by Kyoto Encyclopedia of Genes and Genomes pathway analysis. miR-296 gene expression was examined following chemical corneal injury and it was demonstrated that different topical eye medications decreased miR-296 gene expression. miR-296 may participate in cytokine-cytokine receptor interaction pathways to influence corneal inflammatory responses. It was also revealed that FGF23 was expressed following chemical corneal injury and that different treatments with topical eye drops decreased its expression. miR-296 is a novel molecular modulator for alkali burns in the mouse cornea. PMID- 29399059 TI - microRNA-612 is downregulated by platelet-derived growth factor-BB treatment and has inhibitory effects on vascular smooth muscle cell proliferation and migration via directly targeting AKT2. AB - Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) has been implicated in neointimal formation, and therefore is suggested to contribute to arteriosclerosis and restenosis. Previous studies have suggested that some microRNAs (miRs) serve crucial roles in VSMC proliferation and invasion; however, the underlying mechanism remains largely unknown. In the present study, it was demonstrated that treatment with platelet-derived growth factor (PDGF)-BB significantly promoted the proliferation and migration of VSMCs, and decreased miR-612 levels in VSMCs. Overexpression of miR-612 significantly inhibited PDGF BB-induced migration and invasion of VSMCs, through inducing cell cycle arrest at G1 stage. AKT2 was further identified as a direct target gene of miR-612, and its expression was negatively regulated by miR-612 in VSMCs. Further investigation confirmed that overexpression of miR-612 suppressed the PDGF-BB-induced upregulation of AKT2 protein expression. In conclusion, the present study demonstrated that miR-612 is downregulated by PDGF-BB treatment and has inhibitory effects on VSMC proliferation and migration via targeting AKT2. These findings suggest that miR-612 may be used as a potential therapeutic candidate for neointimal formation in patients with atherosclerosis. PMID- 29399060 TI - Acai (Euterpe oleracea Mart.) attenuates alcohol-induced liver injury in rats by alleviating oxidative stress and inflammatory response. AB - The present study aimed to investigate the therapeutic effects of Euterpe oleracea Mart. (EO) on alcoholic liver diseases (ALD). A total of 30 Wistar rats were randomly divided into three groups (10 rats per group), including alcohol group (alcohol intake), EO group (alcohol + EO puree intake) and control group (distilled water intake). The activity of superoxide dismutase (SOD) and alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of cholesterol (CHO), triglyceride (TG), malondialdehyde (MDA) and glutathione (GSH) in the serum as well as the liver tissue levels of interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were measured. Histopathological changes in liver tissues were observed by hematoxylin and eosin staining. Reverse-transcription quantitative PCR analysis was performed for detecting the expression of nuclear factor (NF)-kappaB and CD68. The results indicated that EO intake significantly decreased ALT, AST, ALP, TG and CHO as well as the hepatic index in alcohol treated rats. In addition, EO treatment relieved alcohol-induced oxidative stress by decreasing the levels of MDA and TG, and increasing the activity of SOD and GSH levels. In addition, the expression of TNF-alpha, TGF-beta, IL-8, NF-kappaB and CD-68 in the liver were decreased by EO treatment. Furthermore, EO intake alleviated the histopathological liver damage, including severe steatosis and abundant infiltrated inflammatory cells. In conclusion, EO alleviated alcohol induced liver injury in rats by alleviating oxidative stress and inflammatory response. PMID- 29399061 TI - Neuroprotective effect of local hypothermia in a computer-controlled compression model in minipig: Correlation of tissue sparing along the rostro-caudal axis with neurological outcome. AB - This study investigated the neuroprotective efficacy of local hypothermia in a minipig model of spinal cord injury (SCI) induced by a computer-controlled impactor device. The tissue integrity observed at the injury epicenter, and up to 3 cm cranially and caudally from the lesion site correlated with motor function. A computer-controlled device produced contusion lesions at L3 level with two different degrees of tissue sparing, depending upon pre-set impact parameters (8N and 15N-force impact). Hypothermia with cold (4 degrees C) saline or Dulbecco's modified Eagle's medium (DMEM)/F12 culture medium was applied 30 min after SCI (for 5 h) via a perfusion chamber (flow 2 ml/min). After saline hypothermia, the 8N-SCI group achieved faster recovery of hind limb function and the ability to walk from one to three steps at nine weeks in comparison with non-treated animals. Such improvements were not observed in saline-treated animals subjected to more severe 15N-SCI or in the group treated with DMEM/F12 medium. It was demonstrated that the tissue preservation in the cranial and caudal segments immediately adjacent to the lesion, and neurofilament protection in the lateral columns may be essential for modulation of the key spinal microcircuits leading to a functional outcome. Tissue sparing observed only in the caudal sections, even though significant, was not sufficient for functional improvement in the 15N SCI model. PMID- 29399062 TI - The effect of hydroxy safflower yellow A on coronary heart disease through Bcl 2/Bax and PPAR-gamma. AB - The aim of the present study was to investigate the effect of hydroxy safflower yellow A (HSYA) on coronary heart disease through assessing the expression of B cell lymphoma 2 (Bcl-2)/Bcl-2-like protein 4 (Bax) and peroxisome proliferator activated receptor (PPAR)-gamma. Coronary heart disease was induced in male Bama miniature swines via thoracoscope to serve as an animal model. Coronary heart disease swine were lavaged with 20 or 40 mg/kg HSYA. The mRNA levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected using reverse transcription-quantitative polymerase chain reaction. The protein expression of Bcl-2, Bax, PPAR-gamma, phosphorylation of Janus kinase (JAK)2 and phosphorylation of signal transducer and activator of transcription (STAT)3 were detected using western blot analysis. Treatment with HSYA significantly suppressed the mRNA levels of IL-1beta (P<0.01), IL-6 (P<0.01), TNF-alpha (P<0.01), COX-2 (P<0.01) and iNOS (P<0.01), and significantly increased IL-10 mRNA level in the coronary heart disease model (P<0.01). Furthermore, HSYA treatment significantly decreased the Bcl-2/Bax ratio (P<0.01) in the coronary heart disease model group, and enhanced the phosphorylation of JAK2/STAT3 pathway (P<0.01). However, HSYA had no significant effect on the expression of PPAR-gamma protein. The results of the present study suggest that HSYA is able to weaken coronary heart disease via inflammation, Bcl-2/Bax and the PPAR-gamma signaling pathway. PMID- 29399063 TI - Expression profile and promoter analysis of HEPIS. AB - Human embryo lung cellular protein interacting with severe acute respiratory syndrome-coronavirus nonstructural protein-10 (HEPIS) is a novel transcriptional repressor, the expression profile and promoter activity of which have not been well studied. In the present study, in situ hybridization of RNA was used to study differential HEPIS expression levels in different types of cancer and normal tissues. A total of six truncated lengths of the HEPIS promoter regulatory sequences were cloned into the pGL3-basic vector, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) and dual luciferase reporter assays were performed. The results of RT-qPCR demonstrated that HEPIS expression levels differed across four breast cancer cell lines. The results of the dual luciferase reporter assays revealed that the activities of the reporter gene fragments spanning -1334/+373, -1203/+373, -1060/+373 and -899/+373 bp were higher compared with the reporter gene fragments spanning -759/+373 and -279/+373 bp. A search of the transcription factor database TRANSFAC identified numerous octamer transcription factor-1 (OCT-1), nuclear factor (NF)-kappaB and C-JUN transcription factor binding sites located on the HEPIS promoter (pHEPIS). Furthermore, the results revealed that mutations of the OCT-1 (-1236/-1223 bp), NF-kappaB (-1186/-1176 bp) and C-JUN (-856/-846 bp) sites on the human pHEPIS resulted in a decrease in luciferase activity. A chromatin immunoprecipitation assay revealed that OCT-1, NF-kappaB and C-JUN bound to pHEPIS in a site dependent manner at the basal state. The TRANSFAC database was used to analyze the pHEPIS of multiple species and several activator protein-1, NF-kappaB and OCT 1 transcription factor binding sites were predicted. In conclusion, the results of the present study suggest that HEPIS is expressed at different levels in multiple organs and breast cancer cell lines. Furthermore, these findings indicate that OCT-1, NF-kappaB and C-JUN transcription factors are associated with transcriptional regulation of the HEPIS gene. PMID- 29399064 TI - Venom based neural modulators. AB - Different types of neuronal nicotinic acetylcholine receptors (nAChRs) are expected to occur in vivo, most structure-activity relationship studies have been carried out for just a few neuronal subtypes. The present review enlightens current aspects of venom modulators of nAChRs. Important electronic databases such as PubMed or Google scholar were explored for the collection of latest studies in the field. Clinical and basic research has shown that cholinergic receptors play a role in several disorders of the nervous system such as chronic pain, Alzheimers disease and addiction to nicotine, alcohol and drugs. Unfortunately, the lack of selective modulators for each subtype of nAChR makes their pharmacological characterization difficult, which has slowed the development of therapeutic nAChR modulators with high selectivity and absence of off-target side-effects. Animal venoms have proven to be an excellent natural source of bioactive molecules with activity against ion channels. The present review concludes that the presence of small-molecule nAChR modulators in spider venoms support the use of venoms as a potential source of novel modulators. PMID- 29399065 TI - Inhibition of miR-186-5p contributes to high glucose-induced injury in AC16 cardiomyocytes. AB - A growing body of evidence has demonstrated that microRNAs (miRs) have pivotal roles in the pathophysiological development mechanisms of diabetic cardiomyopathy (DCM). Previous studies have demonstrated that miR-186-5p was significantly decreased in DCM. In addition, it has recently been reported that an imbalance of miR-186 is associated with a variety of physiological and pathological processes. Therefore, the present study was designed to investigate the role of miR-186-5p in high glucose (HG)-induced cytotoxicity and apoptosis in AC16 cardiomyocytes. Reverse transcription-polymerase chain reaction was used to demonstrate the significant decrease in the level of miR-186-5p in HG-treated AC16 cells (P<0.05). Subsequently, it was clarified that pre-transfection with miR-186-5p mimic significantly ameliorated the effects of high glucose, which induced a significant decrease in the viability of AC16 cells (P<0.05) and increases in apoptosis, as evidenced by the appearance of apoptotic nucleus and the significant upregulation of apoptosis rate in AC16 cells (P<0.05). In addition, the significantly increased expression of caspase-3 induced by HG (P<0.01) was also reversed by miR-186-5p mimic (P<0.01). Conversely, transfection with miR-186 5p inhibitor significantly reduced the viability of AC16 cells (P<0.05) and promoted apoptosis (P<0.05) as well as the expression of caspase-3 in AC16 cells (P<0.01), indicating the beneficial role of miR-186-5p in the physiological process of HG-induced damage. In conclusion, these results suggest that the distribution of miR-186-5p contributes to HG-induced cytotoxicity and apoptosis in AC16 cardiomyocytes. PMID- 29399066 TI - Combination therapy of hTERTR and FAM96A for hepatocellular carcinoma through enhancing apoptosis sensitivity. AB - Avoidance of apoptosis induced by anticancer drugs is an essential factor of carcinogenesis and a hallmark of resistance to cancer therapy. Human telomerase reverse transcriptase receptor (hTERTR) is a potential anti-cancer agent for inhibiting tumor growth. Family with sequence similarity 96 member A (FAM96A) is a ubiquitous, conserved protein and possesses apoptosome-activating and pro apoptotic tumor suppressor potential in hepatocellular carcinoma (HCC). In the present study, hTERTR and FAM96A were identified as efficient anti-cancer agents for activating apoptosomes and reducing tumor growth. The potential tumor suppressor function of combination treatment with hTERTR and FAM96A in HCC was also investigated. hTERTR and FAM96A proteins were expressed by genetic engineering and their anti-cancer function was explored in vitro and in vivo. Effects of hTERTR and FAM96A on improvement of apoptotic sensitivity and inhibition of migration and invasion were examined in cancer cells and in a mouse model. The present results demonstrated that the therapeutic effects of hTERTR and FAM96A were effective for inhibiting tumor growth and inducing apoptosis of HCC cells in H22-bearing nude mice compared with single agent treatment. hTERTR and FAM96A were found to bind with apoptotic protease activating factor 1 and human telomerase reverse transcriptase, which enhanced the apoptosis of tumor cells and apoptosis sensitivity. In addition, hTERTR and FAM96A therapy enhanced cytotoxic effects by cytotoxic T lymphocyte responses, interferon-gamma release, T lymphocytes infiltration and apoptosis on tumor cells. Furthermore, hTERTR and FAM96A protein inhibited tumor growth in HCC mice. In conclusion, the present findings suggested that combination therapy with hTERTR and FAM96A may serve as novel tumor suppressor agents. PMID- 29399067 TI - Assessment of tumor growth factor-beta1 neutralizing antibody in the treatment of allergic rhinitis and asthma. AB - To identify a novel and effective therapy for allergic rhinitis and asthma (ARA), the present study focused on treatment with tumor growth factor (TGF)-beta1 neutralizing antibody. In the present study, four medications were administered to mice with ovalbumin-induced allergic inflammation. Allergic symptoms in the lungs and nasal mucosa were evaluated by detecting the secretion of cytokines from helper T cells (Th) in the peripheral blood, nasal lavage fluid and bronchoalveolar lavage fluid using ELISA. Defects in regulatory T (Treg) cells in peripheral blood mononuclear cells were also detected using flow cytometry. Furthermore, the expression of TGF-beta1 and activation of Smad2/3 pathways were assessed using immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction, and western blotting. It was observed that TGF-beta1 neutralizing antibody inhibited symptoms of inflammation in the upper and lower airways. TGF-beta1 neutralizing antibody also restored the Th1/Th2 balance and ameliorated Treg cell defects induced by ARA. Furthermore, the therapeutic effects of TGF-beta1 neutralizing antibody were related to its inhibitory effects on TGF-beta1 expression and Smad2/3 signaling in nasal and lung tissues. Therefore, TGF-beta1 neutralizing antibody may be an effective medicine for the treatment of ARA. PMID- 29399068 TI - MicroRNA-185 suppresses pancreatic cell proliferation by targeting transcriptional coactivator with PDZ-binding motif in pancreatic cancer. AB - The aim of the present study was to compare the expression of transcriptional coactivator with the PDZ-binding motif (TAZ) in pancreatic cancer (PC) patients, and to investigate the regulation mechanisms of TAZ in the proliferation of PC. PC tissues and matched peritumoral tissues, pancreatic juice and serum were collected from PC patients who underwent pancreatectomy between June 2012 and December 2015 at the Affiliated Hospital of Qingdao University (Qingdao, China). Pancreatic juice and serum were collected from patients with chronic pancreatitis as a control. The levels of taz mRNA expression in the samples were examined by reverse-transcription quantitative polymerase chain reaction, and the protein expression of TAZ was assessed by western blot analysis and ELISA. MicroRNAs (miRNAs) that regulate TAZ expression were also predicted by bioinformatics analysis and validated by dual luciferase reporter and rescue assays. In addition, the proliferation of PC cells was evaluated after transfection with TAZ small interfering RNA (siRNA) or its upstream miRNA agomir. Expression of TAZ was significantly increased in the PC tissues, pancreatic juice and serum of PC patients at the mRNA and protein levels compared with controls (P<0.05). Furthermore, TAZ was predicted and verified to be a target of miRNA (miR)-185, and miR-185 and TAZ were inversely expressed in samples from PC patients (P<0.05). In addition, TAZ siRNA or agomiR-185 transfection significantly inhibited human pancreatic adenocarcinoma cell proliferation (P<0.05). However, overexpression of TAZ in the agomiR-185 group rescued the inhibition (P<0.05). Finally, the expression of TAZ effector proteins, namely ankyrin repeat domain containing protein and cysteine-rich 61, were upregulated in PC tissues (P<0.05), but repressed following transfection of PC cells with agomiR-185 (P<0.05). Thus, miR-185 may regulate the proliferation of PC by targeting TAZ, making it a promising diagnostic marker for PC. PMID- 29399069 TI - Effectiveness of dynamic fixation Coflex treatment for degenerative lumbar spinal stenosis. AB - The aim of the present study was to examine the curative effect of dynamic fixation Coflex treatment for patients with degenerative lumbar spinal stenosis. In the present study, 78 patients with degenerative lumbar spinal stenosis were recruited and divided equally into the control and observation groups. The control group was treated with traditional decompression fusion and the observation group received dynamic fixation Coflex system. Surgery and hospitalization were shorter in the observation group than in the control group. Intraoperative blood loss and drainage volume after surgery were significantly lower in the observation group compared to the control group. The treatment effective rate for the observation group was significantly higher. Visual analogue scale, Oswestry disability index and Japanese Orthopaedic Association pain and functional scores as well as postoperative vertebral canal area and adjacent segment quantitative scores improved after surgery in the two groups, but the observation group showed greater improvement. The curative effect of dynamic fixation Coflex treatment for degenerative lumbar spinal stenosis demonstrates advantages over traditional surgery, including less trauma and bleeding, pain reduction, improved postoperative rehabilitation, and lower incidence of adjacent segment degeneration. PMID- 29399070 TI - Analysis of the clinical value of fractional flow reserve for prognosis evaluation of patients of percutaneous coronary intervention. AB - We investigated the clinical value of fractional flow reserve (FFR) for the prognostic evaluation of patients with percutaneous coronary intervention. We enrolled 120 patients who were admitted to the hospital to undergo percutaneous coronary intervention for acute coronary syndromes between May 2014 and June 2015. The 120 patients were divided into two groups, the observation group and the control group, according to the post-surgery level of FFR. Each cohort contained 60 patients. These patients were divided into the occurrence group (n=45) and the non-occurrence group (n=75), classified according to the occurrence of major adverse cardiovascular events (MACE). There were no statistically significant differences in the comparison of the occurrence rate of MACE within 30 days after surgery, such as lethal or non-lethal myocardial infarction or non-lethal cerebrovascular events, between the observational group and the control group (P>0.05). For the observation group, the 1-year survival cases were 56 with a survival rate of 93.3%, and 2-year survival cases were 50 with a survival rate of 83.3%. In the control group, the 1-year and 2-year survival cases were respectively 55 and 49 (survival rate of 91.7 and 81.7%). The occurrence rates of hyperlipidemia and ratio of patients with a history of smoking and drinking in the occurrence group were significantly higher than those in the non-occurrence group (P<0.05). The mean arterial pressure in the occurrence group was significantly higher than that in the non-occurrence group (P<0.05). Heart rate in the occurrence group is significantly faster than that in the non-occurrence group (P<0.05) and the stenosis degree in the occurrence group was significantly higher than that in the non-occurrence group (P<0.05). The left ventricular ejection fraction (LVEF) before surgery in the occurrence group was significantly lower than that in the non-occurrence group (P<0.05). There were no remarkable differences in comparison of the pre-treatment FFR between the occurrence group and the non-occurrence group (P>0.05), but the post-treatment FFR in the occurrence group was significantly lower than that in the non occurrence group (P<0.05). Increased blood fat, a history of smoking and drinking, augmented mean arterial pressure, accelerated heart rate, severe coronary artery stenosis and the remarkably decreased LVEF were all identified as independent risk factors leading to major adverse myocardial events. The sum of specificity and sensitivity of treatment reached the peak when the post-surgery FFR was 0.875, the calculated sensitivity was 82.4%, and the specificity was 50.8%. In conclusion, measurement of FFR after percutaneous coronary intervention could not only effectively evaluate the target vessel revascularization, but also predict the occurrence of major adverse myocardial events 1 year after surgery, which could serve as the guidance for clinical treatment. PMID- 29399071 TI - Protective effect of histatin 1 against ultraviolet-induced damage to human corneal epithelial cells. AB - The aim of the present study was to investigate the role of histatin 1 (Hst1) in human corneal epithelial cells (HCECs) exposed to ultraviolet (UV) radiation. Prior to UV irradiation for various durations, HCECs were pre-treated with different concentrations of Hst1 and the effect on cell apoptosis and cell viability were examined by flow cytometry, alamarBlue(r) and MTT assays to determine the optimal concentration of Hst1 and UV dose. Cells were then subjected to quantitative PCR, ELISA and western blot analysis to determine the expression of cell damage-associated genes. HCECs exposed to UV light for 1 h displayed decreased viability when compared to that of control cells, and a 3 h UV exposure markedly increased the apoptotic rate of HECEs, while apoptosis was inhibited by pre-treatment with Hst1. UV radiation downregulated expression of insulin-like growth factor (IGF)-1 and B-cell lymphoma 2 (Bcl-2), while it upregulated Bcl-2-associated X protein (Bax) expression. Hst1 protected HCECs against UV-induced damage by upregulating the expression of IGF-1 protein and increasing the Bcl-2/Bax ratio. In conclusion, Hst1 may prevent UV-induced damage to corneal epithelial tissue injury and promote its healing. PMID- 29399072 TI - Radiosensitivity of human ovarian cancer cells is enhanced by pseudolaric acid B due to the inhibition of the Ras/Raf/ERK signaling pathway. AB - Ovarian cancer has the highest mortality rate among gynecological cancers; the most effective therapy for this cancer is a combination of radiation treatment and chemotherapy. However, radiation resistance is the leading factor associated with treatment failure. The present study aimed to investigate pseudolaric acid B (PAB) as a potential radiosensitizer for the treatment of ovarian cancer. The present study performed MTT and clonogenic assays, and demonstrated that PAB could induce a radiosensitizing effect on SKOV-3 cells. An Annexin V/propidium iodide staining assay revealed that PAB exerted a radiosensitizing effect by inducing SKOV-3 cell apoptosis. In addition, western blot analysis demonstrated that the activity of the Ras/RAF proto-oncogene serine/threonine-protein kinase/extracellular signal-regulated kinase signaling pathway was reduced by combination therapy with PAB and irradiation. In conclusion, the present study establishes PAB as a radiosensitizer, and provides a rational basis for the use of PAB and irradiation as a combination therapy to treat ovarian cancer. PMID- 29399073 TI - Relaxin ameliorates high glucose-induced cardiomyocyte hypertrophy and apoptosis via the Notch1 pathway. AB - The present study aimed to investigate the role of relaxin (RLX) on high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis, as well as the possible molecular mechanism. H9c2 cells were exposed to 33 mmol/l HG with or without RLX (100 nmol/ml). Cell viability, apoptosis, oxidative stress, cell hypertrophy and the levels of Notch1, hairy and enhancer of split 1 (hes1), atrial natriuretic polypeptide (ANP), brain natriuretic peptide (BNP), manganese superoxide dismutase (MnSOD), cytochrome C and caspase-3 were assessed in cardiomyocytes. Compared with the HG group, the viability of H9c2 cells was increased by RLX in a time- and dose-dependent manner, and was accompanied with a significant reduction in apoptosis. Furthermore, RLX significantly suppressed the formation of reactive oxygen species and malondialdehyde, and enhanced the activity of SOD. In addition, the levels of ANP, BNP, cytochrome C and caspase-3 were increased and Notch1, hes1 and MnSOD were inhibited in the HG group compared with those in the normal group. However, the Notch inhibitor DAPT almost abolished the protective effects of RLX. These results suggested that RLX protected cardiomyocytes from HG induced hypertrophy and apoptosis partly through a Notch1-dependent pathway, which may be associated with reducing oxidative stress. PMID- 29399074 TI - Protective effects of D-Limonene against transient cerebral ischemia in stroke prone spontaneously hypertensive rats. AB - Stroke is a leading cause of disability and death world-wide and there is currently a lack of effective treatments for acute stroke. D-Limonene is a common natural monocyclic monoterpene possessing various activities. The present study aimed to evaluate the therapeutic efficacy of D-limonene against ischemia associated cerebral injury in hypertensive SHRsp rats. Although systolic blood pressure was not altered by ischemia, D-Limonene decreased the systolic blood pressure of SHRsp rats following stroke. Induction of stroke resulted in increased escape latency time, decreased time spent in the target quadrant in the probe trial, decreased capacity to distinguish between familiar objects and novel objects, and increased sensory neglect in the SHRsp rat, however these symptoms were significantly inhibited by D-limonene. D-limonene also decreased the cerebral infarct size in the SHRsp rats following stroke. D-Limonene markedly decreased the mRNA expression of interleukin-1beta, monocyte chemoattractant protein-1 and cyclooxygenase-2 in SHRsp rats following stroke. The mRNA expression of vascular endothelial growth factor in the brain of SHRsp rats following stroke was significantly increased by D-Limonene. D-Limonene increased the activities of superoxide dismutase and catalase, decreased the malondialdehyde level, increased glutathione content and reduced the DHE-staining in SHRsp rats following stroke. Overall, inhibition of cerebral inflammation, vascular remodeling and antioxidant activities of D-Limonene may be involved in the protective effects against ischemia-induced damage in SHRsp rats. The present study identified D-Limonene as a potential therapeutic candidate for treatment of stroke-associated cerebral and vascular damage under conditions of hypertension. PMID- 29399076 TI - Effects of calcium dobesilate on Nrf2, Keap1 and HO-1 in the lenses of D galactose-induced cataracts in rats. AB - This study investigated the effects of calcium dobesilate on Nrf2, Keap1 and HO-1 in the lenses of D-galactose-induced cataracts in rats. Thirty Sprague-Dawley rats were randomly divided into three groups: a blank control group, a model control group and a model administration group. A normal diet was given to the rats in the blank control group and the rats with D-galactose-induced cataracts of the model control group. Calcium dobesilate was also given to the rats with D galactose-induced cataracts of the model administration group. A slit lamp microscope was used to check the degree of lens opacity. RT-PCR and western blot analysis were used to detect the mRNA and protein expression of Nrf2, Keap1 and HO-1 in the lenses of the three groups. There was a significant difference in the degree of lens opacity among the three groups (P<0.05). The model control group was the most turbid of the three groups, followed by the model administration group. Moreover, the mRNA and protein expression of Nrf2, Keap1 and HO-1 in the lenses of the three groups were also significantly different (P<0.05). The mRNA levels of Nrf2 and HO-1 were the highest in the model control group, followed by the model administration group, and were the lowest in the blank control group. However, the mRNA expression level of Keap1 among the three groups had an opposite trend. In conclusion, calcium dobesilate can effectively increase the levels of Nrf2 and HO-1 in the lenses of diabetic cataract rats and inhibit the level of Keap1. Therefore, the therapeutic effect of calcium dobesilate against cataracts is related to the improvement of the Nrf2-Keap1 signaling pathway. PMID- 29399077 TI - Relationship between intestinal flora and inflammatory factors in patients with nonalcoholic steatohepatitis. AB - This study was conducted to analyze the change in intestinal flora of patients with nonalcoholic steatohepatitis and its correlation to the levels of the inflammatory cytokines interleukin-10 (IL-10) and IL-17. We selected 90 patients that were diagnosed with and treated for nonalcoholic steatohepatitis as the patient group and 80 healthy cases as the control group. We then compared the intestinal flora in the subject feces and the intestinal colonization resistance (B/E, Bifidobacterium to Enterobacter) of both groups. Using RT-PCR, we also detected IL-10 and IL-17 mRNA levels in the peripheral blood mononuclear cells of both groups. Furthermore, we used the ELISA method to determine serum IL-10 and IL-17 levels in order to explore the correlation between IL-10, IL-17 and B/E. The number of Bifidobacterium and Lactobacillus were significantly lower in the patient group than the control group (P<0.05), while Enterobacter and Enterococcus pathogenic bacteria were significantly higher in the patient group than the control group (P<0.05). The B/E value was lower in the patient group than the control group (P<0.05). The relative expression of IL-10 and IL-17 mRNA in the patient group was significantly higher than in the control group (P<0.05). In the patient group, the serum IL-10 levels were 1.17+/-0.15 pg/ml, which is significantly higher than the control group serum IL-10 levels which were 0.32+/ 0.04 pg/ml (P<0.05). The serum IL-17 levels in the patient groups were 0.96+/ 0.11 pg/ml, which was significantly higher than the control group, which had an average of 0.28+/-0.01 pg/ml serum IL-17 levels (P<0.05). Pearson's correlation analysis showed that the change of B/E value of intestinal flora in the patients group were negatively correlated with serum IL-10 (r=-0.546, P<0.05), and negatively correlated with serum IL-17 (r=-0.535, P<0.05). Therefore, compared to healthy people, the expression of IL-10 and IL-17 in the peripheral blood of patients with non-alcoholic fatty liver is high. The changes in intestinal flora in patients with nonalcoholic steatohepatitis are closely related to the changes of serum IL-10 and IL-17 levels, and they are involved in the development of nonalcoholic steatohepatitis. PMID- 29399075 TI - Impact of collateral circulation status on favorable outcomes in thrombolysis treatment: A systematic review and meta-analysis. AB - Collateral circulation affects the prognosis of patients with acute ischemic stroke (AIS) treated by thrombolysis. The present study performed a systematic assessment of the impact of the collateral circulation status on the outcomes of patients receiving thrombolysis treatment. Relevant full-text articles from the Cochrane Library, Ovid, Medline, Embase and PubMed databases published from January 1, 2000 to November 1, 2016 were retrieved. The quality of the studies was assessed and data were extracted by 2 independent investigators. The random effects model was used to estimate the impact of good vs. poor collateral circulation, as well as baseline characteristics, on the outcome within the series presented as risk ratios. Subgroup analyses explored the potential factors that may interfere with the effects of the collateral circulation status on the outcome. A total of 29 studies comprising 4,053 patients were included in the present meta-analysis. A good collateral circulation status was revealed to have a beneficial effect on favorable functional outcome (modified Rankin scale, 0-3 at 3-6 months; P<0.001) and a higher rate of recanalization (P<0.001) compared with poor collateral circulation. Good collateral circulation was also associated with a lower rate of symptomatic intracranial hemorrhage (P<0.01), a lower rate of mortality (P<0.01) and a smaller infarct size (P<0.01). In conclusion, good collateral circulation was demonstrated to have a favorable prognostic value regarding the outcome for patients with AIS receiving thrombolysis treatment. Assessment of collateral circulation and penumbra area during pre-treatment imaging within an appropriate time-window prior to thrombolytic therapy will therefore improve the identification of AIS patients who may benefit from thrombolysis treatment. PMID- 29399078 TI - Correlation between the vitamin D levels and asthma attacks in children: Evaluation of the effects of combination therapy of atomization inhalation of budesonide, albuterol and vitamin D supplementation on asthmatic patients. AB - The aim of the present study was to analyze the correlation between the vitamin D (VitD) levels and asthma attack in children, and to evaluate the effects of combination therapy of atomization inhalation of budesonide, albuterol and VitD supplementation on asthmatic children. The total sample size comprised of 96 children with asthma from the time period between May 2015 to April 2016. At the same time, 96 healthy children were also selected from the physical examination center for comparison study. The levels of serum VitD in both groups were detected by the enzyme-linked immunosorbent assay (ELISA). Pulmonary function index that includes the measurement of FEV1, FVC, FEV1/FVC, MEF25 and MEF50 were performed to analyze the results. The patients in the control group were treated with only the budesonide therapy and the patients in the observation group were treated with atomization inhalation of budesonide combined with salbutamol and VitD supplementation. After the treatment, the levels of inflammatory cell indicators (IL-2, IL-4, IL-6 and IFN-gamma) and pulmonary function in the two groups were compared. The levels of serum VitD in the children with asthma were significantly lower than those in the normal children. The serum IgE level in children with asthma was significantly higher than that in the normal children (P<0.05). Pearson correlation coefficient analyses showed that VitD levels were not correlated with FEV1, FVC and FEV1/FVC levels (P>0.05), but was positively correlated with MEF25 and MEF50 (P<0.05). After the treatment, the levels of IL-2 and IFN-gamma in the observation group were significantly higher and levels of IL 4 and IL-6 were significantly lower than those in the control group (P<0.05). The pulmonary function (FEV1, FVC, FEV1/FVC, MEF25 and MEF50) of the observation group was better than that of the control group (P<0.05). The serum VitD levels of children with asthma were closely related to the acute asthmatic attacks. The lower the levels of serum VitD further leads to higher possibility of asthmatic attacks. Atomization inhalation of budesonide combined with albuterol and VitD supplementation can significantly improve the inflammatory response of the children with asthma. PMID- 29399079 TI - Rivaroxaban for the treatment of venous thromboembolism in patients with nephrotic syndrome and low AT-III: A pilot study. AB - The anticoagulation effect of heparin requires adequate serum antithrombin (AT) III levels. Rivaroxaban, however, exhibits its anticoagulation effects independent of AT-III. The aim of the present study was to evaluate the efficacy and safety of rivaroxaban as a treatment for venous thromboembolism in patients with AT-III deficiency due to nephrotic syndrome. Patients with nephrotic syndrome and low serum concentration and functional activity of AT-III and venous thromboembolism were randomly assigned to the rivaroxaban group (n=8) and low weight molecular heparin group (n=8). The patients were treated for 4 weeks and evaluated at weeks 2 and 4. The primary endpoint was thrombus dissolution or a >90% decrease in thrombus volume in 4 weeks. Secondary endpoints included an increase in the volume of the pre-existing thrombosis and safety assessments. In each of the two groups, 7/8 patients achieved a primary endpoint. At week 2, 5 patients in the rivaroxaban group and 4 in the low weight molecular heparin group had achieved the primary endpoint. Notably, at week 2 the patients whose AT-III levels and functional activity remained low in the low weight molecular heparin group did not achieve the primary endpoint. The adverse effects were similar in both groups, with no severe hemorrhage observed. In conclusion, the results of this pilot study demonstrate that rivaroxaban may be an effective, safe, single agent approach for treating vein thromboembolism in patients with nephrotic syndrome and low AT-III levels. The potential benefits of rivaroxaban over low weight molecular heparin treatment require further investigation with a larger sample size in order to validate the findings of the present study. PMID- 29399080 TI - Aripiprazole exerts a neuroprotective effect in mouse focal cerebral ischemia. AB - Previous studies have demonstrated that aripiprazole (APZ), a third-generation atypical antipsychotic drug, exhibits anti-depressant and neuroprotective effects by promoting dopaminergic neuronal cell recovery in stroke. To investigate the neuroprotective effects of APZ, behavioral and histopathological experiments were performed in the current study a mouse model of middle cerebral artery occlusion (MCAO)-induced ischemia following administration of APZ. The subacute phase of ischemic assaults was divided into 3 periods, each with a duration of 5 days, according to the start of APZ (3 mg/kg) administration (1-5, 5-9 or 10-14 days following MCAO). The beneficial effects of APZ on motor behavior demonstrated in the cylinder, rotarod and wire suspension tests were greatest when APZ was administered 1-5 days following MCAO, with clear improvements in motor function compared with vehicle-treated mice. Histopathological analysis revealed that prominent atrophic changes occurred in the striatum of MCAO mice and that these changes were reduced following APZ treatment. APZ also attenuated dopaminergic neuronal injury in the striatum. Cell death and microglial activation were decreased and the expression of Ca2+/calmodulin-dependent protein kinase II delta was enhanced following APZ treatment. These results indicate that the atypical antipsychotic drug, APZ, exhibits a neuroprotective effect in dopaminergic neuronal cells that may improve behavioral function following ischemic stroke. PMID- 29399081 TI - Evaluation of the inactivation effect of riboflavin photochemical method on duck hepatitis B virus. AB - Hepatitis B virus (HBV) is a common and widespread infection that poses a serious threat among carriers for the development of life-threatening liver diseases. The aim of the present study was to evaluate the effectiveness of the riboflavin photochemical method in inactivating duck hepatitis B virus (DHBV) in plasma via an animal model. Forty ducks were selected and randomly divided into the experimental (n=10), the virus control (n=10), the visible light control (n=10) and the plasma control group (n=10). Ducks in the experimental group were injected with plasma inactivated by the riboflavin photochemical method; in the virus control group were injected with plasma without inactivation treatment; in the visible light control group were injected with plasma irradiated by visible light; and in the plasma control group were injected with normal plasma. The serum of the ducks in each group was taken at different time points to detect DHBV-DNA levels via FQ-PCR and duck hepatitis B surface antigen (DHBsAg) via ELISA. DHBV-DNA in the experimental group was decreased gradually over time until it disappeared and there was a significant difference in DHBsAg between the experimental and control groups (P<0.05). In conclusion, the results showed that the riboflavin photochemical method is effective in the inactivation of viruses in plasma, which has relevance for preventive strategies against transfusion derived infections. PMID- 29399082 TI - Identifying pathway modules of tuberculosis in children by analyzing multiple different networks. AB - Tuberculosis (TB), which is caused by the mycobacterium TB, is the major cause of human death worldwide. The aim of this study was to identify the biomarkers involved in child TB. Gene expression data were obtained from the Array Express Archive of Functional Genomics Data. Gene expression data and protein-protein interaction (PPI) data were downloaded to construct differential gene co expression networks (DCNs). The Benjamini-Hochberg algorithm was used to correct the P-value. In total, 3,820 edges (PPIs) and 1,359 nodes (genes) were obtained from the human-related PPIs data and gene expression data at the criteria of absolute value of Pearson's correlation coefficient >0.8. The DCNs were formed by these edges and nodes. Thirteen seed genes were obtained by ranging z-scores. Eight significant multiple different modules were identified from DCNs using the statistical significant test. In conclusion, the seed genes and significant modules constitute potential biomarkers that reveal the underlying mechanisms in child TB. The new identified biomarkers may contribute to an understanding of TB and provide a new therapeutic method for the treatment of TB. PMID- 29399083 TI - Investigation of the molecular mechanisms underlying postoperative recurrence in prostate cancer by gene expression profiling. AB - The present study aimed to identify potential genes associated with prostate cancer (PCa) recurrence following radical prostatectomy (RP) in order to improve the prediction of the prognosis of patients with PCa. The GSE25136 microarray dataset, including 39 recurrent and 40 non-recurrent PCa samples, was downloaded from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) were identified using limma packages, and the pheatmap package was used to present the DEGs screened using a hierarchical cluster analysis. Furthermore, gene ontology functional enrichment analysis was used to predict the potential functions of the DEGs. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to analyze pathway enrichment of DEGs in the regulatory network. Lastly, a protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software to understand the interactions between these DEGs. A total of 708 DEGs were identified in the recurrent and non recurrent PCa samples. Functional annotation revealed that these DEGs were primarily involved in cell adhesion, negative regulation of growth, and the cyclic adenosine monophosphate and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, five key genes, including cluster of differentiation 22, insulin-like growth factor-1, inhibin beta A subunit, MAPK kinase 5 and receptor tyrosine kinase like orphan receptor 1, were identified through PPI network analysis. The results of the present study have provided novel ideas for predicting the prognosis of patients with PCa following RP. PMID- 29399084 TI - Blood rheology of angina pectoris patients with myocardial injury after ischemia reperfusion and its effect on thromboxane B2 levels. AB - This study investigated the changes in the blood rheology of patients with angina pectoris and ischemia reperfusion injury and their effect on thromboxane B2 (TXB2) levels to examine their relationship. Forty patients with unstable angina pectoris who underwent elective percutaneous coronary intervention (PCI) were selected for the unstable angina group (UA group) and forty patients deemed free of coronary heart disease by coronary angiography were selected for the control group. Venous blood samples were drawn from all participants; patients in the UA group had blood drawn 1 day before and 1 day after the PCI procedure. Blood samples were used to analyze blood rheology and examine hemodynamic parameters, at the same time radioimmunoassay was applied to measure the concentrations of serum endothelin-1 (ET-1) and TXB2, and an automatic biochemical analyzer was used to detect the content of superoxide dismutase (SOD) and malondialdehyde (MDA). Our results showed the patients in the UA group all presented hyperviscosity; however the levels were higher for the patients in the UA group (after surgery) than for those in the UA group (before surgery). Patients in the control group exhibited normal levels, and the differences among groups were significant in pairwise comparisons (P<0.05). The levels of ET-1 and TXB2 in the UA group were increased compared with those in control group and they were highest after surgery (P<0.05). For the patients in the UA group, the serum TXB2 concentration increased gradually along with the increase in risk stratification. There were significant differences in comparisons between different strata and between UA patients and those in the control group (P<0.05). The serum SOD activity levels were lowest in the UA group (after surgery), higher in the UA group (before surgery) and highest in the control group. Conversely, the MDA content was highest in the UA group (after surgery), lower in the UA group (before surgery) and smallest in the control group; there were significant differences in pairwise comparisons. Based on our findings, a hyperviscosity syndrome was manifested in the blood rheology of patients with angina pectoris and ischemia reperfusion injury. The higher than normal TXB2 levels can be used as a marker of platelet activation and a reference for clinical risk stratification, thus having great significance for the prevention and treatment of ischemia reperfusion injury and assessment of disease progression. PMID- 29399085 TI - Correlations of chemokine CXCL16 and TNF-alpha with coronary atherosclerotic heart disease. AB - This study determined the correlations of CXC ligand 16 (CXCL16) and tumor necrosis factor-alpha (TNF-alpha) levels with coronary atherosclerotic heart disease (CAHD) and screened for new clinical markers for the prognosis and treatment of the disease. Eighty patients with coronary heart disease and 50 healthy subjects were enrolled into a CAHD or healthy control group, respectively. Computed tomography (CT) coronary angiography and Gensini integral were used to classify plaques and evaluate patients with coronary heart disease. The serum levels of CXCL16 and TNF-alpha of subjects in each group were detected by enzyme-linked immunosorbent assays (ELISA), and the correlation between levels and clinical markers (such as blood pressure, glucose, lipid and heart rate) and the severity of disease were analyzed. Our results showed the serum levels of CXCL16 and TNF-alpha were significantly higher in the CAHD group than those in the CK group. The serum CXCL16 levels of the CAHD group patients with plaques were distinctly higher than those of the CADH group patients without plaques, but there were no significant difference in serum TNF-alpha levels between these two groups of patients. The level of CXCL16 had a significantly positive correlation with the severity of disease, but there was no significant correlation between TNF-alpha level and the severity of disease. Also, there was no significant correlation between the CXCL16 levels and blood pressure, blood glucose, heart rate, total cholesterol, triglyceride or high-density lipoprotein cholesterol, but there was a clear correlation with the low-density lipoprotein cholesterol. Finally no significant correlations were found between TNF-alpha levels and each of the clinical markers studied. Based on our findings, the levels of CXCL16 and TNF-alpha in the patients with coronary heart disease were abnormally increased and the level of CXCL16 correlated closely with the severity of disease. These markers seem to be reliable biological markers for prognosis and disease evaluation in coronary heart disease patients. PMID- 29399086 TI - COPB2 suppresses cell proliferation and induces cell cycle arrest in human colon cancer by regulating cell cycle-related proteins. AB - Coat proteins (COPs), including the major types clathrin, COPI and COPII, play a considerable role in intracellular transport by initiating the formation of transport vesicles. Coatomer protein complex subunit beta2 (COPB2) is one of the seven subunits that make up a COPI complex. In the present study, we found that COPB2 was highly expressed in human colon cancer specimens. However, to date, there have been no reports describing the functions of COPB2 in human colon cancer cells. In this study, we analyzed the functions of COPB2 in the proliferation and cell cycle arrest of human RKO and HCT116 colon cancer cells by using lentivirus-mediated RNAi infection. Our results demonstrated that the silencing of COPB2 in vitro could inhibit the proliferation and colony formation abilities of RKO and HCT116 cells. Furthermore, measurement of cell cycle distribution indicated that the downregulation of COPB2 could induce G0/G1 or S phase cell cycle arrest by regulating cell cycle-related proteins. In conclusion, our results suggest that COPB2 plays a key role in the proliferation and cell cycle progression of human RKO and HCT116 colon cancer cells, thus indicating that COPB2 might be a potential therapeutic target for the treatment of human colon cancer. PMID- 29399087 TI - Simultaneous harvesting of endothelial progenitor cells and mesenchymal stem cells from the human umbilical cord. AB - The human umbilical cord (UC) is usually discarded as biological waste. However, it has attracted interest as a source of cells including endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs), which have demonstrated enormous potential in regenerative medicine. The present study describes a convenient protocol that has been developed to sequentially extract these two cell types from a single UC. EPCs which had properties of progenitor cells were successfully isolated from the UC vein. These cells had cobble-shaped morphology and expressed Flt-1, KDR, VE-cadherin, von Willebrand factor and CD31 mRNA, in addition to CD73, CD105 and vascular endothelial growth factor receptor-2. In addition to absorbing fluorescent-labeled acetylated low density protein and binding to fluorescein isothiocyanate-UEA-l, they were able to form vascular tube-like structures on Matrigel. Typical fibroblast-like cells, which were isolated from the Wharton's jelly, were confirmed to be MSCs by their expression of CD73, CD90 and CD105, and their ability to differentiate into adipocytes and osteoblasts. Thus, the human UC-derived cells may be suitable for use in tissue engineering and cell therapy. PMID- 29399088 TI - Protective effects of new Wenshen Shengjing Decoction on cyclosporine-induced impairment of testosterone synthesis and spermatogenic apoptosis. AB - The aim of the present study was to investigate the potential protective effects of new Wenshen Shengjing Decoction (new WSSJD; including Cornu Cervi Nippon Parvum, Panax ginseng, Cynomorium songaricum, Cistanche deserticola, Radix Astragali, Epimedium brevicornum and Angelica sinensis) on cyclosporine-induced impairment of testosterone synthesis and spermatogenic apoptosis in mice. A total of 90 adult male Kunming mice were divided into the following 6 groups: Control (no intervention), dimethylsulfoxide (DMSO; received only DMSO), cyclosporine A (CsA), clomifene citrate (CC; CsA + CC, 15 mg/kg/day), WSSJD (CsA + WSSJD, crude drug 12 g/kg/day) and new WSSJD (CsA + new WSSJD, crude drug 12 g/kg/day). All mice were treated for 30 days via oral gavage. The testes were subsequently fixed and stained with hematoxylin & eosin to assess the development of seminiferous epithelia. Immunohistochemical techniques were used to detect the expression of luteinizing hormone receptor (LHR) and P450 side chain cleavage (P450scc) in testicular Leydig cells. In addition, the apoptosis of spermatogenic cells in the testes was detected using a terminal dexynucleotidyl transferase-mediated dUTP nick-end labeling assay, and flow cytometry was used to analyze the survival rate and early apoptosis of sperm in the epididymis. Compared with the CsA and CC groups, new WSSJD administration significantly increased levels of serum testosterone and the expressions of LHR and P450scc in testicular Leydig cells (P<0.05), while the apoptosis of spermatogenic cells in the seminiferous tubules and early apoptosis of mature sperm were significantly decreased (P<0.05). These results suggest that new WSSJD may ameliorate CsA-induced spermatogenic damage in male mice by enhancing testosterone synthesis and the secretion of testicular Leydig cells, and by reducing the apoptosis of spermatogenic cells. PMID- 29399090 TI - Report and literature review on two cases with different kinds of Creutzfeldt Jakob disease. AB - Creutzfeldt-Jakob disease (CJD), also known as corticostriate spinal degeneration, subacute spongiform encephalopathy or infectious spongiform encephalopathy, is a type of degenerative disease of the central nervous system caused by prion protein (PrP) infection, which is the most common type of human PrP disease. CJD is genetic and infectious, and is one of the most common causes of rapid progressive dementia with rare clinical occurrence. Herein, we report the clinical conditions of 2 cases of patients with different type of CJD we treated and followed up recently, and a review of relevant literature. The patient in case 1 was admitted due to 'dizziness with hypomnesis, and mental and behavior disorder'. He was considered to suffer from a central nervous system infection - a viral encephalitis, but one month later, a repeated cranial MRI showed lace sign of bilateral frontotemporal parietal lobe in DWI sequence, an AEEG indicated periodic synchronous discharge, and the detection of cerebrospinal fluid 14-3-3 protein was positive. It was suggested to be diagnosed as the sporadic CJD. The patient in case 2 was admitted because of 'progressive hypomnesis'. Cerebrospinal fluid 14-3-3 protein detection was negative, but the V203I-related mutation was found in the PRNP gene detection. The patient was suggested to be diagnosed as genetic CJD. Both patients died in a short time. An earlier diagnosis can provide a time window for treatment, and avoid unnecessary transmission in hospital, as well as doctor-patient dispute. PMID- 29399089 TI - Effects of ganoderic acid A on lipopolysaccharide-induced proinflammatory cytokine release from primary mouse microglia cultures. AB - For several thousand years, Ganoderma lucidum (Ling-Zhi in Chinese and Reishi in Japanese) has been widely used as a traditional medication for the prevention and treatment of various diseases in Asia. Its major biologically active components, ganoderic acids (GAs), exhibit significant medicinal value due to their anti inflammatory effects. Dysregulation of microglial function may cause seizures or promote epileptogenesis through release of proinflammatory cytokines, including interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. At present, only little information is available on the effects of GAs on microglia-mediated inflammation in vitro and/or in vivo. The present study aimed to investigate the role of GA-A on microglia-mediated inflammation in vitro. In addition, the effect of GA-A on lipopolysaccharide (LPS)-evoked alterations in mitochondrial metabolic activity of microglia was evaluated. The results of the present study demonstrated that GA-A significantly decreased LPS-induced IL-1beta, IL-6 and TNF alpha release from mouse-derived primary cortical microglial cells in a concentration-dependent manner. GA-A treatment reduced LPS-induced expression of nuclear factor (NF)-kappaB (p65) and its inhibitor, demonstrating that non-toxic suppression of IL-1beta, IL-6 and TNF-alpha production by GA-A is, at least in part, due to suppression of the NF-kappaB signaling pathway. In addition, the LPS induced stimulation of mitochondrial activity of microglial cells was abolished by co-treatment with GA-A. Thus, GA-A treatment may be a potential therapeutic strategy for epilepsy prevention by suppressing microglia-derived proinflammatory mediators. PMID- 29399091 TI - SDHB downregulation facilitates the proliferation and invasion of colorectal cancer through AMPK functions excluding those involved in the modulation of aerobic glycolysis. AB - Loss-of-function of succinate dehydrogenase-B (SDHB) is a predisposing factor of aerobic glycolysis and cancer progression. Adenosine monophosphate activated protein kinase (AMPK) is involved in the regulation of aerobic glycolysis and the diverse hallmarks of cancer. The present study investigated whether AMPK mediated the regulatory effects of SDHB in aerobic glycolysis and cancer growth. The expression of SDHB and AMPK in colorectal cancer (CRC) and normal tissues was assessed by western blotting. HT-29 CRC cells were used to establish in vitro models of ectopic overexpression and knockdown of SDHB. SDHB was downregulated, while AMPK and phosphorylated-AMPK (Thr172) were upregulated in CRC tissues. Experiments involving the loss- or gain-of-function of SDHB, revealed that this protein negatively regulated AMPK by influencing its expression and activity. However, SDHB and AMPK were identified to suppress lactic acid production in CRC cells, indicating that each had an inhibitory effect on aerobic glycolysis. Therefore, the regulation of aerobic glycolysis by SDHB is unlikely to be mediated via AMPK. SDHB knockdown promoted the viability, migration and invasion of HT-29 cells, whereas inhibition of AMPK demonstrated the opposite effect. SDHB overexpression impaired cell migration and invasion, and this effect was reversed following AMPK activation. These results indicate that AMPK may mediate the effects of SDHB in CRC cell proliferation and migration. In conclusion, SDHB downregulation in CRC cells may increase AMPK activity, which may subsequently facilitate the proliferation and invasion of these cancer cells. However, the regulation of aerobic glycolysis by SDHB may be independent of AMPK. Further studies are warranted to elucidate the mechanism by which SDHB regulates aerobic glycolysis. PMID- 29399092 TI - Expression of caspase-3, Bax and Bcl-2 in hippocampus of rats with diabetes and subarachnoid hemorrhage. AB - The expression of caspase-3, Bax and Bcl-2 in hippocampus of rats with diabetes and subarachnoid hemorrhage (SAH) were investigated. Diabetes mellitus model was established by intraperitoneal injection of STZ. On the basis of diabetes mellitus model, SAH animal model was established by injecting fresh autologous femoral artery blood into cerebellomedullary cisten. Rats were divided into blank control group, diabetes control group and diabetes + SAH group. TUNEL method was used to detect cell apoptosis of hippocampus. Expression levels of caspase-3, Bax and Bcl-2 were detected by real-time quantitative reverse transcription PCR and western blot analysis at mRNA and protein levels, respectively. Apoptotic cells were not detected in blank control group and diabetes group, and number of apoptotic cells was the highest in the diabetic SAH group. Expression levels of caspase-3, Bax and Bcl-2 mRNA and protein were significantly higher in diabetes + SAH group than in blank control group and diabetes group. In conclusion, Hippocampal neuron apoptosis was induced by diabetes + SAH and expression levels of caspase-3, Bax and Bcl-2 were also increased. Our study provided experimental basis for further studies of the relationship between SAH and cell apoptosis. PMID- 29399093 TI - Ratio of beta-amyloid protein (Abeta) and Tau predicts the postoperative cognitive dysfunction on patients undergoing total hip/knee replacement surgery. AB - beta-amyloid (Abeta) and Tau proteins are biomarkers of Alzheimer's disease neuropathogenesis. We hypothesized that they are also potential biomarkers for postoperative cognitive dysfunction (POCD). The present study was designed to evaluate the use of the Abeta-42/Tau ratio for the diagnosis of POCD in patients undergoing hip/knee replacement surgery. A total of 80 patients who underwent total hip/knee replacement surgery were grouped into POCD or non-POCD patients at 7 days, 1 and 3 months after surgery, according to a z-score recommended by the international study of POCD. Cerebrospinal fluid samples were collected prior to surgery and the concentration of Abeta-42 and Tau protein were detected. The ratio of Abeta-42/Tau was compared between the two groups at different time points. The patients completed the whole battery of neuropsychological tests following surgery. The POCD occurrence rates at 7 days, 1 and 3 months were 40, 25 and 15%, respectively. The Abeta-42/Tau ratios were much lower in the POCD group than those in the non-POCD group at 7 days (1.7+/-0.4 vs. 2.6+/-0.3), 1 month (1.6+/-0.5 vs. 2.4+/-0.4), and 3 months (1.6+/-0.4 vs. 2.5+/-0.4). The sensitivity and specificity for diagnosis of POCD as indicated by the ratios, at the three time points, were 91.7 vs. 81.2%, 86.7 vs. 70%, and 88 vs. 75.5%, respectively. The results show the incidence of POCD of patients aged at least 65 years who have undergone hip or knee fracture surgery gradually decrease as more patients recover. However, the Abeta-42/Tau ratio can be used in forecasting the occurrence of POCD elderly patients. PMID- 29399094 TI - Expression of tissue inhibitor of metalloproteinases-1 and B-cell lymphoma-2 in the synovial membrane in patients with knee osteoarthritis. AB - The purpose of this study was to determine the expression and impact of tissue inhibitor of metalloproteinases-1 (TIMP-1) and B-cell lymphoma-2 (Bcl-2) in knee osteoarthritis (KOA). We collected synovial fluids from the knee joint of 70 KOA patients and 30 controls. The expression levels of TIMP-1 and Bcl-2 were significantly higher in KOA patients than those in the control group (P<0.01). We also found positive correlation between the severity of KOA and the expression level of TIMP-1 (r=0.8027, P<0.05) and and Bcl-2 (r=0.5336, P<0.05). However, we found no correlation between the expression levels of TIMP-1 and Bcl-2 in the synovial membranes of KOA patients (P>0.05). Both TIMP-1 and Bcl-2 are expressed at high levels in the synovial membrane with KOA, and are closely related to the occurrence and development of KOA. Thus, detection of TIMP-1 and Bcl-2 in KOA patients can be helpful in diagnosing the state of KOA. PMID- 29399095 TI - Predicting the visual acuity for retinal vein occlusion after ranibizumab therapy with an original ranking for macular microstructure. AB - The study investigated predictive factors for best-corrected visual acuity (BCVA) after ranibizumab treatment in patients with macular edema (ME) associated with retinal vein occlusion (RVO) with an original ranking for the impairment of macular microstructure. In this retrospective study, 31 eyes of 31 patients with RVO received 3 monthly consecutive ranibizumab injections and another 3 months of follow-up. An original method was applied to rank the impairment of the external limiting membrane (ELM) and the ellipsoid zone (previously called the photoreceptor inner and outer segment junction, IS/OS) integrity on the baseline optical coherence tomography (OCT) images. Univariate and multivariate linear regression analyses were performed to assess the association between the baseline factors and post-treatment BCVA. ELM integrity and baseline BCVA were shown to be independent factors in the prediction of post-treatment BCVA. Comparison of post treatment BCVA between original ELM ranks after adjusting for the baseline BCVA revealed the ELM integrity beneath the center of the fovea was important to post treatment BCVA. ELM integrity in particular beneath the center of the fovea and baseline BCVA may be more useful than other factors in the prediction of visual function in patients with ME secondary to RVO after ranibizumab injections. PMID- 29399096 TI - The effect of focal cerebral ischemia-reperfusion injury on TLR4 and NF-kappaB signaling pathway. AB - The present study analyzed the change of Toll-like receptor 4 (TLR4) and nuclear factor-kappaB (NF-kappaB) expression in focal cerebral ischemia-reperfusion injury model. A sample of 36 Sprague-Dawley rats were randomly selected and divided into sham operation group (group S), control group (group C) and Chrysanthemum ester group (NF-kappaB inhibitor, group CE), each group consisted of 12 rats. The rat model of focal cerebral ischemia-reperfusion was established. The physiological indexes and neurological severity score of rats was recorded by a double-blind method. The cerebral infarction area was evaluated by triphenyltetrazole oxide (TTC) staining on brain slices. Apoptosis was evaluated by TUNEL staining. Semi-quantitative PCR and western blot analysis was used to measure the expression of TLR4 and NF-kappaB. The neurological severity score of rats in group C and CE were found to be significantly lower than group S (P<0.01). The TTC staining results showed that group C and CE had different levels of cerebral infarction but the area of infarction in group CE was significantly lower than group C (P<0.01). In addition, the number of TUNEL positive cells in group CE was significantly lower than group C (P<0.01). Semi quantitative PCR and westernblot analysis results showed that the expression of NF-kappaB and TLR4 of group S was significantly lower than that of group C and group CE (P<0.01), the relative expression of NF-kappaB and TLR4 of group CE was significantly lower than that of group C (P<0.01). Moreover, the expression of NF kappaB p65/p50 of group CE and group C was significantly higher than that of group S (P<0.01). This study concludes that the focal cerebral ischemia reperfusion injury in rats can cause brain damage and cell apoptosis. This effect might be associated to the increased expression of NF-kappaB and TLR4, and the activation of TLR4/NF-kappaB signaling pathway. PMID- 29399097 TI - Atorvastatin improves coronary flow and endothelial function in patients with coronary slow flow. AB - The underlying mechanisms behind the effect of atorvastatin on patients with coronary slow flow (CSF) remain largely unknown. To investigate the possible underlying molecular mechanisms 108 patients were divided into atorvastatin group and control group. Coronary flow was quantified according to corrected TIMI frame count (CTFC). Serum high sensitivity C-reactive protein (hs-CRP), lipids, ET-1, interleukin (IL)-6, NO, circulating endothelial progenitor cell (cEPC) count, adhesion, migration and proliferation were measured in pretreatment and post treatment. After respective treatment, the atorvastatin group had significantly decreased levels of TC, TG, LDL-C, hs-CRP, ET-1 and IL-6 and increased NO compared to the control group. The atorvastatin group had a more significant improvement of CTFC, effective rate, cEPC number, EPC adhesion, migration and proliferation compared to the control group. In conclusion, atorvastatin can be used in treatment of CSF by suppressing inflammation and improving endothelial function. PMID- 29399098 TI - Effects of telmisartan on vascular endothelial function, inflammation and insulin resistance in patients with coronary heart disease and diabetes mellitus. AB - The aim of the present study was to investigate the effects of telmisartan on vascular endothelial functions, inflammatory factors and insulin resistance of coronary heart disease patients complicated with diabetes mellitus. In total, 80 coronary heart disease patients complicated with type 2 diabetes mellitus, admitted and treated in the Zhangqiu Hospital from January 2016 to March 2017 were enrolled in the study. Each patient was randomly assigned to an observation (n=40) or a control group (n=40) using a random number table. Conventional symptomatic and supporting therapies were administered to all the patients in the two groups for 12 consecutive weeks, while additional telmisartan was given only to patients in the observation group. Markers of glucose metabolism, vascular endothelial function and inflammation were determined before and after intervention, to compare averages between groups. Results showed the levels of fasting blood glucose and blood glucose in the observation group were significantly lower than those in the control group (p<0.05) after 4 weeks of treatment. The levels of HOMA-IR in the observation group were clearly improved compared to those in the control group during the same period (p<0.05). After the intervention, the levels of FINS and HOMA-IR in the observation group improved significantly more compared with those in the control group (p<0.05), while the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C reactive protein (CRP) were much lower than those in the control group (p<0.05). Furthermore, at the 4th, 8th and 12th week after starting the treatment, the vascular endothelin (ET) levels in the observation group were significantly lower than those in the control group (p<0.05). In addition, the brachial artery diameters in the basal state were significantly larger than those in the control group (p<0.05) for the same time-points. Coronary heart disease patients complicated with diabetes mellitus whose treatment includes telmisartan can better regulate their blood glucose, reduce the insulin resistance and body inflammatory responses and improve their vascular endothelial functions. PMID- 29399099 TI - Expression of intercellular adhesion molecule-1 in umbilical vascular of pregnant women with gestational diabetes mellitus and the clinical significance. AB - The purpose of this study was to investigate the expression of intercellular adhesion molecule-1 (ICAM-1) in umbilical vascular of pregnant women with gestational diabetes mellitus (GDM) and the clinical significance. A total of 103 pregnant women with GDM were selected in the First Hospital of Lanzhou University and the Second Affiliated Hospital of Xi'an Jiaotong University from January 2016 to December 2016 as GDM group. At the same time, 106 normal pregnant women were selected as control group. i) General information of the two groups of pregnant women including age, gestational age, gravida, parity, BMI, systolic blood pressure and diastolic blood pressure were compared; ii) the laboratory indicators of the two groups of pregnant women including fasting blood glucose, glycosylated hemoglobin (HbA1c), umbilical cord arterial pH, partial pressure of oxygen (pO2) and carbon dioxide (pCO2) in umbilical artery were compared; iii) expression of ICAM-1 in umbilical vascular was detected by immunohistochemistry; iv) expression levels of ICAM-1 in umbilical vascular of the two groups of patients were compared. i) There was no significant difference in the age, smoking, gestational age, gravida, parity, BMI, systolic blood pressure and diastolic blood pressure between the two groups (p>0.05); ii) no significant differences in HbA1c, umbilical cord arterial pH, pO2 and pCO2 were found between the groups (p>0.05); iii) ICAM-1 was expressed in umbilical vessels of both groups of pregant women; iv) no significant differences in expression levels of ICAM-1 in umbilical artery and umbilical vein endothelial cells were found between the groups (p>0.05). Therefore, GDM patients with good blood glucose control have no umbilical cord endothelial cell damage. PMID- 29399100 TI - Effect of HBIG combined with hepatitis B vaccine on blocking HBV transmission between mother and infant and its effect on immune cells. AB - The effect of hepatitis B immune globulin (HBIG) combined with hepatitis B vaccine on blocking hepatitis B virus (HBV) transmission between mother and infant and its effect on immune cells were studied. Ninety newborn infants confirmed to be HBV surface antigen (HBsAg)-positive were divided equally into three groups. Group A newborns received the hepatitis B vaccine at 0, 1 and 6 months after birth (10 ug/time). Group B newborns received an intramuscular injection of 100 IU HBIG 2 h after birth before the same treatment as group A. Mothers of group C newborns received three gluteus maxinus injections of 200 IU HBIG. The newborns in group C got the same treatment as group B. The blocking effect of HBV transmission between mother and infant was evaluated, and cell immune function was assessed. There were significant differences in comparison of blocking success rates between group A and B, and between group A and C as well (p<0.05). At the end of 12 months follow-up, the CD4+ level and CD4+/CD8+ ratio in group C were higher thanthose in group A and B (p<0.05). In addition, the level of CD8+ T lymphocyte in group C was lower than those in group A and B (p<0.05). In comparison of levels of CD4+T lymphocyte at the end of 12 months follow-up and 24 h after birth, the differences were significant (p<0.05) in bothgroup B and C. The differences of IFN-gamma levels betweengroups B/C and group A were significant (p<0.05). Forthose newborn infants born to mothers who were positivefor both HBsAg and HBeAg, HBIG intervention formothers during late pregnancy, together with combinedtreatment of HBIG and hepatitis B vaccine for infants, gavebetter blocking result of HBV transmission. PMID- 29399101 TI - Vaccarin alleviates hypertension and nephropathy in renovascular hypertensive rats. AB - The kidney is an important organ in the regulation of blood pressure, and it is also one of the primary target organs of hypertension. Kidney damage in response to hypertension eventually leads to renal insufficiency. The authors previously demonstrated that vaccarin exhibits a protective role in endothelial injury. However, the effects of vaccarin on the two-kidney, one clip (2K1C) renovascular hypertension model and subsequent kidney injury have yet to be fully elucidated. The present study was designed to investigate the roles and mechanisms of vaccarin in attenuating hypertension and whether vaccarin had beneficial effects on kidney injury. The 2K1C rats had greater fibrosis, apoptosis, reactive oxygen species production, inflammation, angiotensin II (Ang II) and angiotensin type 1 (AT1) receptors in the right kidney compared with normotensive rats, which were alleviated by a high dose of vaccarin and captopril. Vaccarin treatment attenuated hypertension, reduced fibrosis markers, NADPH oxidase (NOX)-2, NOX-4, 3-nitrotyrosine, tumor necrosis factor-alpha, interleukin 1beta (IL-1beta), and IL-6 protein levels and altered pro-apoptotic protein levels including caspase-3, anti-apoptosis protein B cell lymphoma (Bcl)-2 and Bcl-2 associated X, apoptosis regulator in the right kidney of 2K1C rats. These findings suggest that the protective effects of vaccarin on the right kidney in renovascular hypertension are possibly due to downregulation of fibrosis, inflammatory molecules, oxidative stress, Ang II, and AT1 receptor levels. PMID- 29399102 TI - Modified closed-loop double-endobutton technique for repair of rockwood type III acromioclavicular dislocation. AB - Acromioclavicular dislocation (ACD) is a common injury. According to the Rockwood classification, ACD is classified into six types (type I-VI); however, for type III injuries, it remains controversial whether or not operative treatment should be applied. Numerous studies have advocated early surgical treatment to ensure early rehabilitation activities. Thus, the present study aimed to investigate a modified closed-loop double-endobutton technique (MCDT), that may be used to repair Rockwood type III ACD. In the current study, 61 patients with Rockwood type III ACD were enrolled during a period of 5 years at the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University. Patients were divided into three groups according to the surgical method used, the MCDT group (n=20), the common closed-loop double-endobutton technique (CCDT) group (n=21), and the clavicular hook plate fixation (CHPF) group (n=20). Preoperative and intraoperative information were recorded. Furthermore, the functional scores of injured shoulder were evaluated prior to surgery and following surgery with a 1-year follow-up. Among the three groups, postoperative functional scores were significantly more improved compared with those prior to surgery (P<0.05), and no significant difference was observed regarding the coracoclavicular interval with the 1-year follow-up (P>0.05). Postoperative functional scores in the MCDT and CCDT groups were significantly more improved compared those in the CHPF group (P<0.05). In addition, the duration of surgery in the MCDT group was significantly shorter compared with that in the CCDT group (P<0.05). Furthermore, compared with the CHPF group, the incision length was significantly shorter with reduced hemorrhage in the MCDT group (P<0.05). In conclusion, the results of the current study suggest that MCDT is more simple, convenient and efficient compared with CCDT, and is worth popularizing. PMID- 29399103 TI - Bone mesenchymal stem cells co-expressing VEGF and BMP-6 genes to combat avascular necrosis of the femoral head. AB - The aim of the present study was to investigate the potential of bone mesenchymal stem cells (BMSCs) treated with a combination of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-6 (BMP-6) genes for the treatment of avascular necrosis of the femoral head (ANFH). Rat BMSCs were isolated and purified using a density gradient centrifugation method. The purity and characteristics of the BMSCs were detected by cell surface antigens identification using flow cytometry. The experimental groups were administered with one of the following adeno-associated virus (AAV) vector constructs: AAV green fluorescent protein (AAV-GFP), AAV-BMP-6, AAV-VEGF or AAV-VEGF-BMP-6. The expression of VEGF and BMP-6 was detected by reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA assays. The effects of VEGF and BMP-6 on BMSCs were evaluated by angiogenic and osteogenic assays. The transfected BMSCs were combined with a biomimetic synthetic scaffold poly lactide co-glycolide (PLAGA) and they were then subcutaneously implanted into nude mice. After four weeks, the implants were analyzed with histology and subsequent immunostaining to evaluate the effects of BMSCs on blood vessel and bone formation in vivo. In the AAV-VEGF-BMP-6 group, the expression levels of VEGF and BMP-6 were significantly increased and human umbilical vein endothelial cells tube formation was significantly enhanced compared with other groups. Capillaries and bone formation in the AAV-VEGF-BMP-6 group was significantly higher compared with the other groups. The results of the present study suggest that BMSCs expressing both VEGF and BMP-6 induce an increase in blood vessels and bone formation, which provides theoretical support for ANFH gene therapy. PMID- 29399104 TI - Protective effect of vascular endothelial growth factor against cardiopulmonary bypass-associated acute kidney injury in beagles. AB - The present study aimed to examine the hypothesis that vascular endothelial growth factor (VEGF) has a protective effect against cardiopulmonary bypass (CPB) associated acute kidney injury (AKI). Eighteen male beagles were randomly allocated to three groups (n=6 per group): Sham group, animals received sternotomy without going through CPB; CPB group, animals received CPB only; VEGF group, animals received CPB and VEGF. VEGF infusion was completed 1 h prior to the initiation of CPB. Renal microcirculation perfusion, serum creatinine (SCr) and blood urea nitrogen (BUN), histopathological injury score and apoptotic index were determined. Hypoxia inducible factor-1alpha, VEGF, phosphorylated (p)-Akt serine/threonine kinase (Akt), p-endothelial nitric oxide synthase (eNOS), cleaved caspase-3, B-cell lymphoma 2 (Bcl-2) and cluster of differentiation (CD)95 expression levels were assessed by western blot analysis, Enzyme-linked immunosorbent assay quantitative assays were used to evaluate tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, superoxide dismutase and malondialdehyde levels. Renal microcirculation perfusion of the VEGF group was higher than that of the CPB group (P<0.05) and lower than that of the sham surgery group (P<0.05). SCr and BUN were significantly elevated after CPB in the CPB and VEGF groups, with significantly lower levels in group VEGF than group CPB. Renal pathology scores and apoptotic indices were significantly lower in the VEGF group than the CPB group. Levels of TNF-alpha, IL-6 in the VEGF group were significantly lower than in the CPB group. Levels of VEGF, p-Akt, p-eNOS and Bcl-2 expression in the VEGF group increased significantly in comparison with group CPB. Cleaved caspase 3 in the VEGF group was significantly lower than in the group CPB. CPB-associated reduction of renal microcirculation perfusion may predispose to AKI. VEGF appears to provide a protective effect on the kidneys through improvement in renal microperfusion. PMID- 29399105 TI - Health-related quality of life on the clinical course of patients with chronic hepatitis C receiving daclatasvir/asunaprevir therapy: A prospective observational study comparing younger (<70) and elderly (>=70) patients. AB - Interferon-free direct acting antiviral agent regimens for chronic hepatitis C (CHC) have been developed. These regimens have shown a high rate of sustained virologic response (SVR), and a reduction in side effects during treatment is also anticipated. However, the impact of the regimens on health-related quality of life (HRQOL) and side effects during treatment is not fully understood. The purpose of the present study was to evaluate HRQOL in the clinical course of patients with CHC receiving daclatasvir/asunaprevir (DCV/ASV) therapy using the Short Form-36 (SF-36) method. Twenty-eight patients with CHC receiving DCV/ASV therapy were analyzed in the present study, and HRQOL was measured by SF-36. Patients were asked to fill out the SF-36 prior to therapy (baseline), following 12 weeks of therapy, at the end of treatment and at SVR week 24 (SVR24) to evaluate HRQOL. Laboratory data were also investigated during the same period, and associations between these results and SF-36 were investigated. Aspartate aminotransferase, alanine aminotransferase, serum albumin, alpha-fetoprotein, platelet counts and Fibrosis (Fib)-4 index were all significantly improved at each time point when compared with baseline. With regard to alterations in HRQOL during therapy, the >=70-year-old group displayed a significantly greater improvement in physical functioning during the period between baseline and 12 weeks when compared with the <70-year-old group. In the analysis of the SF-36 differences within each group, general health improved significantly in the >=70 year-old group, as well as albumin levels. In addition, Fib-4-index significantly improved at all time points (12 and 24 weeks, and SVR24) when compared with baseline in the >=70-year-old group. Therefore, DCV/ASV therapy may improve HRQOL and hepatic functional reserve, particularly in elderly patients. PMID- 29399106 TI - TGF-beta1 stimulates epithelial-mesenchymal transition mediated by ADAM33. AB - The present study aimed to determine the effects of transforming growth factor (TGF)-beta1 on disintegrin and metalloproteinase domain-containing protein 33 (ADAM33) expression in airway epithelial cells in order to investigate the association between ADAM33 expression and TGF-beta1-induced epithelial to mesenchymal transition (EMT), and to further explore the mechanisms underlying the role of ADAM33 in airway remodeling in asthma. The human bronchial epithelial cell line HBE was transfected with small interfering RNA targeting ADAM33 (siADAM33) and treated with different concentrations of TGF-beta1 (10, 20 or 30 ng/ml), while untransfected cells were used as controls. At 72 h after treatment, cellular morphology and immunohistochemical staining were observed under a microscope. The protein and mRNA expression levels of ADAM33 and the EMT markers E-cadherin and vimentin were detected by western blot analysis and reverse transcription quantitative polymerase chain reaction, respectively. In addition, a correlation analysis of ADAM33 expression and E-cadherin/vimentin expression was performed. A wound healing migration assay and a cell invasion assay were also performed. The results of the cellular morphology, migration and invasion studies suggested that TGF-beta1 treatment induced typical EMT changes in HBE cells. In addition, treatment with various concentrations of TGF-beta1 significantly increased the protein and mRNA expression levels of ADAM33 and vimentin compared with those in untreated cells. TGF-beta1 treatment also decreased the protein and mRNA expression levels of E-cadherin in a dose dependent manner. By contrast, transfection with siADAM33 promoted the protein expression of E-cadherin and decreased the protein expression of vimentin. Furthermore, ADAM33 and E-cadherin expression levels exhibited a significant negative correlation, whereas ADAM33 and vimentin were positively correlated. In conclusion, the results suggested that TGF-beta1 enhances ADAM33 expression in airway epithelial cells, and that ADAM33 induces the EMT of airway epithelial cells, thus participating in airway remodeling in asthma. PMID- 29399107 TI - Effect of PrP105-132 on the secretion of interleukin-6 and interleukin-8 from microglial cells in vitro. AB - In the present study, the effect of prion protein (PrP) on the secretion of interleukin-6 (IL-6) and IL-8 from microglial cells in vitro and its possible underlying pathway were investigating by establishing a cell model for prion disease. Rat neuroglial cells were cultured in vitro, and were treated with 80 uM PrP peptides 105-132 (PrP105-132) only, PrP+MG132 or PrP+cyclosporin A (CsA). After 48 h, the IL-6 and IL-8 levels in the supernatant fluid of the treated cells were detected using enzyme-linked immunosorbent assay. In addition, the expression levels of nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT) were evaluated using reverse transcription-polymerase chain reaction. The results indicated that the microglial cells were activated by treatment with PrP peptides. Cell bodies were augmented and appeared to have round, rod and amoeba-like shapes. In addition, the protuberances were shortened and eventually disappeared. Furthermore, the mRNA expression levels of NF-kappaB and NFAT in microglial cells increased, as well as the IL-6 and IL-8 levels in the supernatant fluid after treatment with PrP. However, the mRNA expression levels of NF-kappaB, and the IL-6 and IL-8 levels decreased after these cells were treated with MG132, a specific inhibitor of NF-kappaB. The mRNA expression of NFAT decreased after these cells were treated with CsA, a specific inhibitor of NFAT; however, the IL-6 level decreased, while no significant difference was observed in the IL-8 level. In conclusion, PrP-treated microglial cells secreted IL-6 and IL-8, and the secretion of IL-6 was associated with the activation of NF kappaB and NFAT pathways. In addition, the secretion of IL-8 was mainly dependent on the NF-kappaB pathway. PMID- 29399108 TI - Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via anti-oxidant and anti-apoptotic mechanisms in mice. AB - The present study investigated the effects and potential mechanisms of action of magnesium isoglycyrrhizinate (MgIG) in doxorubicin (DOX)-treated mice. Histopathological analysis and western blot analysis were conducted in the liver and heart tissues and biochemical analysis of the serum was performed. The results revealed that MgIG (10, 20 and 40 mg/kg/day) could protect the structure and functions of the liver and heart by inhibiting the activities of the myocardial enzymes creatine kinase (CK), CK-MB and lactate dehydrogenase and the hepatic-specific enzymes aspirate aminotransferase and alanine aminotransferase, increasing the activities of the antioxidants superoxide dismutase and glutathione peroxidase, and inhibiting cellular apoptosis induced by DOX (30 mg/kg). These results demonstrate that inhibiting lipid peroxidation and reducing myocardial and hepatocyte apoptosis may be one of the mechanisms by which MgIG exhibits hepatoprotective and cardioprotective effects in DOX-treated mice. PMID- 29399109 TI - Biological functions of lung cancer cells are suppressed in co-culture with mesenchymal stem cells isolated from umbilical cord. AB - Stem cell-based therapy serves a key role in clinical treatments, and mesenchymal stem cells (MSCs) have been widely used in clinical tumor therapy trials. In the present study, MSCs were isolated from umbilical cord (UC) and co-cultured with the lung cancer cell line H1299. The effects of UC-derived MSCs (UCMSCs) on H1299 cell invasion and proliferation were evaluated using a Matrigel-based Transwell assay and CCK8 assay, respectively. Apoptosis and cell cycle progression among H1299 cells were detected by flow cytometry, and kinase expression in H1299 cells was detected by western blotting. The results indicated that UCMSCs significantly inhibited H1299 cell invasion and significantly induced apoptosis of H1299 cells, but exhibited no effect on H1299 cell proliferation and cell cycle progression. It was also identified that H1299 cell expression of key kinases (AKT, phosphoinositide 3-kinase, signal transducer and activator of transcription 3 and mechanistic target of rapamycin) was significantly suppressed in the presence of UCMSCs. To the best of our knowledge, the present study demonstrates for the first time that UCMSCs have an anti-tumor effect against lung cancer cells, which may indicate that AKT/phosphoinositide 3-kinase/signal transducer and activator of transcription 3 signaling is important in the UCMSC-mediated regulation of H1299 cell functions. PMID- 29399110 TI - MicroRNA-370 suppresses the progression and proliferation of human astrocytoma and glioblastoma by negatively regulating beta-catenin and causing activation of FOXO3a. AB - Certain microRNAs (miRs) regulate the progression and metastasis of various cancer types. In the present study, the role of miR-370 in the progression and proliferation of human astrocytoma and glioblastoma cells was assessed and the underlying molecular mechanism was investigated. miR-370 levels in clinical specimens of human glioma and peritumoral tissues were determined by reverse transcription quantitative PCR. Oligonucleotide mimics and inhibitors were transfected into the U-251MG human astrocytoma cell line and the and U-87MG glioblastoma cell line and the cell viability of was determined by an MTT assay. The expression of beta-catenin and forkhead box protein (FOX)O3a was determined by western blot analysis. The results revealed that the expression of miR-370 in human glioma tissues was significantly decreased compared with that in peritumoral tissues. The miR-370 levels in patients with grade III/IV gliomas were significantly decreased compared with those in grade I/II. Transfection with miR-370 mimics inhibited the proliferation of U-251MG and U-87MG cells. Furthermore, the miR-370 levels were negatively correlated with beta-catenin and positively correlated with nuclear FOXO3a. In conclusion, miR-370 inhibited the proliferation of human glioma cells by regulating the levels of beta-catenin and the activation of FOXO3a, suggesting that miR-370 was a tumor suppressor in the progression of human astrocytoma and glioblastoma cells. PMID- 29399111 TI - (-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1. AB - The Epstein-Barr virus (EBV) lytic cycle contributes to the development of EBV associated diseases. EBV-encoded latent membrane protein 1 (LMP1) is key to EBV lytic replication, and our previous work indicated that epigallocatechin-3 gallate (EGCG) inhibited constitutive EBV lytic infection through the suppression of LMP1-activated phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-related protein kinase 1/2 signaling. The present study demonstrated that LMP1 in CNE-LMP1 constructed cells significantly induced the expression of the EBV lytic proteins BZLF1 (P<0.001) and BMRF1 (P<0.05) compared with CNE1 cells. Following treatment with a specific DNAzyme that targets LMP1, significantly reduced protein expression levels of BZLF1 and BMRF1 in EBV-associated epithelial carcinoma CNE1-LMP1 cells (P<0.001 and P<0.01, respectively) and lymphoma B95.8 cells (both P<0.01) were observed. Furthermore, EGCG significantly inhibited the mRNA and protein expression levels of LMP1 (P<0.05) in an apparent dose-dependent manner in CNE1-LMP1 and B95.8 cells. Thus, the present findings indicated that the molecular mechanism underlying EGCG inhibition of EBV lytic infection involves downregulation of LMP1. PMID- 29399112 TI - Neuroprotective effect of berberine against learning and memory deficits in diffuse axonal injury. AB - The aim of the present study was to assess the neuroprotective effect of berberine against learning and memory deficits in diffuse axonal injury (DAI). DAI rats were orally gavaged with berberine at a dose of 200 mg/kg of body weight for 4 weeks. Behavioral tests were used to analyze the neuroprotective effect of berberine against DAI-induced learning and memory deficits. In the present study, treatment with berberine significantly protected against DAI-induced inhibition of learning and memory in rats. Notably, berberine significantly suppressed the levels of tumor necrosis factor, interleukin-1beta and monocyte chemoattractant protein-1, as well as reduced the protein expression levels of nuclear factor kappaB, Bcl-2-associated X protein and cytochrome c in DAI rats. In addition, berberine significantly suppressed the protein expression of p38 mitogen activated protein kinase, activating transcription factor 2 and vascular endothelial growth factor in DAI rats. These results suggested that berberine exhibited a neuroprotective effect against learning and memory deficits in severe DAI through the suppression of inflammation, angiogenesis and apoptosis in a rat model. PMID- 29399113 TI - Geniposide attenuates epilepsy symptoms in a mouse model through the PI3K/Akt/GSK 3beta signaling pathway. AB - Previous reports on the pharmacological actions of geniposide have indicated that it has anti-asthmatic, anti-inflammatory and analgesic effects in the liver and gallbladder, and therapeutic effects in neurological, cardiovascular and cerebrovascular diseases. The results of the current study demonstrate that geniposide attenuates epilepsy in a mouse model through the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. A mouse model of epilepsy was induced by maximal electric shock (50 mA, 50 Hz, 1 sec). Epilepsy mice were intragastrically administered with 0, 5, 10 or 20 mg/kg geniposide. Geniposide significantly reduced the incidence and significantly increased the latency of clonic seizures in epileptic mice compared with non-treated epileptic mice (both P<0.01). Geniposide treatment significantly inhibited cyclooxygenase-2 mRNA expression in epilepsy mice (P<0.01). Furthermore, geniposide significantly suppressed the protein expression of activator protein 1, increased the activation of Akt and increased the protein expression of GSK-3beta and PI3K in epilepsy mice (all P<0.01). These results suggest that geniposide attenuates epilepsy in mice through the PI3K/Akt/GSK 3beta signaling pathway. PMID- 29399114 TI - Mechanism for carbapenem resistance of clinical Enterobacteriaceae isolates. AB - Carbapenemase-producing 'super bacteria', particularly NDM-1 and its variants, have become a major public health concern worldwide. The present study aimed to explore the molecular mechanism for carbapenem resistance of clinical Enterobacteriaceae isolates. Seventy-eight non-repeated Enterobacteriaceae strains resistant to any carbapenem were screened at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between December 2011 and December 2015. Outer membrane porin (OMP) proteins were detected using SDS-PAGE. Carbapenemases, extended-spectrum beta-lactamases (ESBLs) and plasmid AmpC enzyme genes were detected using polymerase chain reaction (PCR). PCR and SDS-PAGE demonstrated that 60.3% (47/78) of the strains produced carbapenemases, of which 33.3% (26/78) produced KPC-2 carbapenemase, suggesting that the strains resisted carbapenems primarily through carbapenemases. SDS-PAGE showed that the OMP proteins in the majority of carbapenem-resistant Enterobacteriaceae (CRE) strains were deleted or decreased compared with those in the sensitive strains. Of the 44 Klebsiella strains, 59.1% (26/44) did not express or expressed less OmpK35 or OmpK36. Among the 34 strains of other enterobacteria, 97.1% (33/34) did not express or expressed less OmpC or OmpF. Of all CRE strains, 35.9% (28/78) lost at least one OMP protein, indicating that the strains resisted carbapenems also by producing ESBLs and/or plasmid AmpC enzyme, as well as by losing OMP proteins. The resistance of clinically isolated CRE strains may primarily be attributed to the production of carbapenemases, and may also involve the deletion of OMP proteins or mutation of OMP genes. PMID- 29399115 TI - Analysis of stress application at the thoracolumbar junction and influence of vertebral body collapse on the spinal cord and cauda equina. AB - The thoracolumbar junction comprises the spinal cord, nerve roots and the cauda equina, exhibiting unique anatomical features that may give rise to a diverse array of symptoms under conditions of injury, thus complicating the diagnosis of compressive disorders. The present study aimed to examine varying degrees and forms of compression at this level of the spinal cord using a two-dimensional model to calculate the relationship of these variables to injury. The degree of compression was expressed as a percentage of the spinal canal that was occupied. Results were compared with findings from clinical observations to assess the validity of the model. Analysis revealed that higher levels of compression/spinal canal occupation are associated with the presence of neurological symptoms. This finding was consistent with clinical data. Results of the present analysis warrant further research involving evaluation of compression with respect to other parameters, such as blood flow, as well as more anatomically accurate three dimensional analysis. PMID- 29399116 TI - Extraction of flavonoids from Chrysanthemum morifolium and antitumor activity in vitro. AB - The aim of the present study was to optimize flavonoid extraction from Chrysanthemum morifolium and to study the antitumor effects of flavonoids on human gastric cancer MKN45 cells in vitro. A single factor experiment was designed and the extraction process was optimized using an orthogonal test. MKN45 cells were treated with different concentrations of flavonoid from Chrysanthemum morifolium for 24 and 48 h and the inhibitory effect on the MKN45 cells was evaluated using an MTT assay. Following staining with Annexin V-fluorescein isothiocyanate/propidium iodide, flow cytometry was performed. The optimized flavonoid extraction conditions were as follows: Duration of ultrasonic treatment: 35 min; ethanol concentration: 75%; extraction temperature: 80 degrees Cand liquid-to-solid ratio 25: 1. Under the above conditions, the extraction rate of flavonoids was 5.24%. When compared with a blank control group, flavonoids extracted from Chrysanthemum morifolium inhibited the proliferation of MKN45 cells in a dose- and time-dependent manner. Furthermore, in cell groups treated with low, moderate and high concentrations of flavonoid, it was observed that the proportion of apoptotic cells increased in a dose-dependent manner. The extraction process optimized by the orthogonal test achieved a high yield and satisfactory extraction efficiency. Additionally, the experiment demonstrated that flavonoids from Chrysanthemum morifolium inhibited the growth of MKN45 cells and induced their apoptosis. Thus, flavonoids from Chrysanthemum morifolium exerted antitumor effects on MKN45 cells, which may be exploited as a potential antitumor therapeutic for gastric cancer. PMID- 29399117 TI - Observation of the effect of physical rehabilitation therapy combined with the medication on pelvic floor dysfunction. AB - We observed the effects of physical rehabilitation therapy combined with medication on pelvic floor dysfunction (PFD). We collected the medical records of 84 maternal patients with PFD who received treatment at the Affiliated Hospital of Hebei University between May 2015 and October 2016. These patients were randomly divided into two groups, the control group (n=42) and observation group (n=42). In the control group, patients received conventional physical rehabilitation therapy while in observation group, patients received the shixiao powder combined with siwu decoction in addition to the physical rehabilitation. The therapeutic effects were compared between the two groups. The total effective rate of the observation group was 97.6%, which was significantly higher than 78.6% in the control group (P<0.05). In observation group, the index scores of pelvic floor function under rest state, such as electromyo-graphy amplitude, contraction force, coordinate strength and urine flow rate, were significantly higher than those in control group (P<0.05). The rate of Grade II perineal muscle strength in the observation group was 7.32%, which was significantly lower than 47.62% in control group (P<0.05). In observation group, the rates of Grade III and Grade IV muscle strength were respectively 43.91 and 29.26%, which were significantly higher than those in control group (P<0.05). Before the administration of treatment, there were no significant differences in the comparison of the urinary incontinence and sexual life quality of patients between the two groups (P>0.05). In observation group, after treatment, the rehabilitation effects of urinary incontinence and sexual life quality at 3 months post-delivery were significantly better than those in control group (P<0.05). Before treatment, there were no significant differences in the comparison of levels of C-reactive protein (CRP) and interleukin-10 (IL-10) between the two groups (P>0.05), however, after treatment, the levels of CRP and IL-10 of patients in observation group were significantly lower than those in control group (P<0.05). In the observation group, the incidence rate of complications (7.14%) were significantly lower than that in control group (23.81%; P<0.05). Therefore, physical rehabilitation therapy combined with the shixiao powder and siwu decoction exhibits significant efficacy in the treatment of PFD by effectively improving the pelvic floor functions, increasing perineal muscle strength, and decreasing expression levels of inflammatory factors, which can significantly ameliorate life quality and reduce the incidence rate of complications. Thus, this treatment method shows great application value in clinical practice. PMID- 29399118 TI - Epidermal growth factor receptor aptamer-conjugated polymer-lipid hybrid nanoparticles enhance salinomycin delivery to osteosarcoma and cancer stem cells. AB - Osteosarcoma is a common childhood bone cancer with a poor survival rate. Osteosarcoma cancer stem cells (CSCs) contribute to the recurrence, drug resistance and metastasis of this disease. Previous evidence suggested that cancer cells are able to spontaneously turn into CSCs, thus it is crucial to simultaneously target osteosarcoma cells and CSCs. Our previous studies have demonstrated that salinomycin preferably eliminated osteosarcoma CSCs. In addition, amplification of the epidermal growth factor receptor (EGFR) is a common genetic aberration in osteosarcoma, and thus EGFR is a promising target in osteosarcoma. The present study aimed to develop EGFR aptamer-conjugated salinomycin-loaded polymer-lipid hybrid nanoparticles (EGFR-SNPs) to target both osteosarcoma cells and CSCs. The results revealed that EGFR was overexpressed in these cells, and that EGFR-SNPs possessed a small size of 95 nm, suitable drug encapsulation efficiency (63%) and sustained drug release over 120 h. EGFR-SNPs targeted EGFR-overexpressing osteosarcoma cells and CSCs, resulting in an enhanced cytotoxic effect compared with non-targeted SNPs and salinomycin. Notably, EGFR-SNPs was able to reduce the osteosarcoma tumorsphere formation rate and proportion of CD133+ osteosarcoma CSCs in the osteosarcoma cell lines more effectively compared with SNPs and salinomycin, suggesting that EGFR-SNPs effectively reduced the proportion of osteosarcoma CSCs. In conclusion, the interaction of EGFR aptamers and EGFR is a potential approach to promote the effective delivery of salinomycin to osteosarcoma. The study results suggested that EGFR-SNPs represents a promising approach to target osteosarcoma cells and CSCs. PMID- 29399119 TI - Expression of MMP-2 and TIMP-1 in cerebrospinal fluid and the correlation with dynamic changes of serum PCT in neonatal purulent meningitis. AB - Matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in cerebrospinal fluid of pediatric patients with neonatal purulent meningitis were observed to analyze changes in serum procalcitonin (PCT) and the correlation among the three factors (MMP-2, TIMP-1 and PCT). Sixty pediatric patients with neonatal purulent meningitis from April 2015 to December 2016 were enrolled as the purulent meningitis group and 60 pediatric patients with viral encephalitis treated during the same period were enrolled as the viral encephalitis group. Additionally, 60 healthy newborns who underwent physical examinations in our hospital during the same period were enrolled as the control group. The levels of MMP-2 were 136.73+/-25.42 ng/ml in the purulent meningitis group, 45.32+/-6.57 ng/ml in the viral encephalitis group and 1.32+/-0.51 ng/ml in the control group and the differences between the three groups were statistically significant (F=15.052, p<0.05). The levels of TIMP-1 in cerebrospinal fluid were 374.55+/-36.04 ng/ml in the purulent meningitis group, 176.61+/-21.06 ng/ml in the viral encephalitis group and 7.72+/-2.44 ng/ml in the control group. The serum levels of PCT were 14.56+/-2.21 ng/ml in the purulent meningitis group, 9.04+/-1.17 ng/ml in the viral encephalitis group and 0.38+/ 0.14 ng/ml in the control group. The level of MMP-2 in cerebrospinal fluid of pediatric patients in the purulent meningitis group was positively correlated with the level of serum PCT (r=0.582, p<0.05); the level of TIMP-1 in cerebrospinal fluid of pediatric patients in the viral encephalitis group was positively correlated with the level of serum PCT (r=0.635, p<0.05). In conclusion, MMP-2 and TIMP-1 were positively correlated with the levels of serum PCT, suggesting that MMP-2, TIMP-1 and PCT were involved in the occurrence and development of neonatal purulent meningitis. PMID- 29399120 TI - Significance of dynamic evolution of TNF-alpha, IL-6 and intestinal fatty acid binding protein levels in neonatal necrotizing enterocolitis. AB - To study the significance of dynamic evolution of serum tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and intestinal fatty acid-binding protein (I-FABP) levels in neonatal necrotizing enterocolitis (NEC). A total of 45 NEC child patients, 45 non-NEC child patients and 45 healthy newborns were enrolled. After the day age, weight, gestational week and delivery mode were matched, the serum TNF-alpha, IL-6 and I-FABP levels at 6, 24 and 72 h after admission were measured via ELISA method, and their correlations with prognosis were analyzed. The levels of serum TNF-alpha and IL-6 in NEC and non-NEC group reached the peak at 24 h and fell at 72 h; there were no differences in each time point between the two groups (P>0.05), but the levels of serum TNF-alpha and IL-6 were higher than those in the control group (P<0.05). The level of serum I-FABP in NEC and non-NEC group reached the peak at 6 h, and it fell at 72 h in NEC group and 24 h in non-NEC group; the level of I-FABP in each time point in NEC was significantly higher than that in non-NEC group, and the level was the lowest in healthy group; the differences were statistically significant (P<0.05). There were 40 cases of survival and 5 cases of death (11.1%) in NEC group, while there were 43 cases of survival and 2 cases of death (4.4%) in non-NEC group. There were no differences in serum TNF-alpha and IL-6 levels at different times between surviving child patients and dead child patients in NEC group (P>0.05), but the levels of serum I FABP in surviving child patients at 6 h and 24 h were significantly lower than those in dead child patients (P<0.05), and there was no difference at 72 h (P>0.05). There were no differences in serum TNF-alpha, IL-6 and I-FABP levels at different times between surviving and dead child patients in non-NEC group (P>0.05). Serum I-FABP level and its dynamic evolution may be important indexes of early diagnosis and prognosis evaluation of NEC. PMID- 29399121 TI - Protective effects of beef decoction rich in carnosine on cerebral ischemia injury by permanent middle cerebral artery occlusion in rats. AB - Inflammation has a role in the cerebral injury induced by ischemia and the present study aimed to determine the mechanism of the protective effect of beef decoction (BD) with carnosine against it. A rat model of permanent middle cerebral artery occlusion was established using a suture method in the vehicle and each of the BD groups. In experiment 1, 72 Sprague Dawley (SD) rats were randomly divided into three groups: Sham, vehicle and BD-treated group. Rats in the BD group were given 600 mg/kg BD by oral gavage for 1, 3 and 7 days. The sham and vehicle group rats received an equivalent amount of normal saline. In experiment 2, 60 SD rats were randomly divided into six groups: Sham-operated I, sham-operated II, vehicle, low-dose BD, medium-dose BD and high-dose BD group. Rats in the low-, medium- and high-dose BD groups were given BD at the dose of 200, 400 and 600 mg/kg, respectively, by oral gavage for 7 days. Rats in the sham operated II group were given 600 mg/kg BD. Rats in the sham-operated I group and vehicle group were given the same volume of normal saline by oral gavage. The body weight, neurological deficits and infarct volume were recorded at 1, 3 and 7 days after the operation. Furthermore, the effect of different doses of BD on interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in peripheral blood was measured at 7 days. BD-treated rats showed less neurological deficits and a smaller infarct volume at 7 days. BD at 400 and 600 mg/kg significantly decreased the infarct volume in rats. At 600 mg/kg BD, a decline in IL-6, TNF-alpha, IFN-gamma and an increase in IL-4 expression was observed in the BD groups, while no difference in body weight and neurological dysfunction was detected. In conclusion, BD is a neuroprotective agent that may be used as a supplement treatment of ischemic stroke. PMID- 29399122 TI - Investigation of inflammatory bowel disease risk factors in 4 families in central China. AB - The prevalence of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is increasing markedly in China. The present study performed pedigree analysis of 4 families with a history of IBD and investigated the association of genetic and environmental factors with susceptibility to IBD. A total of 10 IBD patients (8 CD patients and 2 UC patients) and 90 family members were included in the present study. The clinical characteristics of familial subjects were compared with those of patients with sporadic IBD. Previously reported mutations, namely interleukin-10 receptor (IL10R)-A Thr84Ile, IL10RA Gly141Arg, IL10RB Trp159X, X-linked inhibitor of apoptosis (XIAP) Cys203Tyr, nucleotide-binding oligomerization domain-containing protein 2 (NOD2) Arg702Trp, NOD2 Gly908Arg and NOD2 Leu1007fsinsC, were screened in the patients with IBD, and selected demographic factors were compared between the patients and their unaffected family members. It was observed that single gene and multi-gene inheritance patterns contributed to IBD in Chinese families. Based on data from the registry system, the ratio of patients with a family history of IBD was 1.25%, which was lower than that in the Western population. First-degree relatives were found to be more susceptible to IBD, and siblings were affected more frequently. Furthermore, the median age of diagnosis was younger in familial patients than in sporadic patients (29.0 vs. 36.0 for CD; 35.5 vs. 41.0 for UC). However, none of the 7 susceptibility loci were present in any of the familial patients. Immigration was a significant risk factor of IBD (odds ratio: 4.667; 95% confidence interval: 1.165-18.690; P=0.021). In conclusion, genetic heterogeneity exits between Chinese families with IBD and the Western population. The present findings suggest that genetic background and environmental factors serve a role in the pathogenesis of IBD. PMID- 29399123 TI - MicroRNA-124-3p inhibits cell growth and metastasis in cervical cancer by targeting IGF2BP1. AB - MicroRNAs (miRs) serve a role in promoting and suppressing tumors in various types of malignant cancer, such as cervical cancer. However, the regulatory mechanism of miR-124-3p in cervical cancer remains unclear. In the present study, miR-124-3p was significantly downregulated in cervical cancer tissues and cell lines compared with matching adjacent non-tumor tissues and the normal cervical epithelial cell line End1/E6E7, respectively. Decreased expression of miR-124-3p was associated with advanced cervical cancer and the results of an in vitro study demonstrated that the ectopic expression of miR-124-3p significantly decreased the proliferation, migration and invasion of cervical cancer Caski cells. Furthermore, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) was identified as a novel target of miR-124-3p. Overexpression of miR-124-3p decreased the expression of IGF2BP1, whereas miR-124-3p knockdown promoted IGF2BP1 expression at the post-transcriptional level in Caski cells. Additionally, overexpression of IGF2BP1 attenuated the suppressive effects of miR 124-3p on the proliferation, migration and invasion of Caski cells. IGF2BP1 was upregulated in cervical cancer tissues and cell lines compared with matching adjacent non-tumor tissues and the End1/E6E7 cell line, respectively. Therefore, the present study suggests that miR-124-3p suppresses the growth and metastasis of cervical cancer by directly targeting IGF2BP. Thus, miR-124-3p may be developed as a novel method of treating cervical cancer. PMID- 29399124 TI - Effects of luteolin on regulatory proteins and enzymes for myocyte calcium circulation in hypothermic preserved rat heart. AB - Heart transplantation has been applied in the clinic as an optimal solution for patients with end stage cardiac failure for a number of years. However, hypothermic preservation of the heart remains limited to 4-6 h and calcium accumulation over time is an important factor resulting in cell death. To provide longer and safer storage for donor hearts, it was demonstrated in our previous study that luteolin, a traditional Chinese medicine used to treat cardiovascular diseases, inhibits cell death and L-type calcium currents during hypothermic preservation. In the current study, the protective role of luteolin in modulating cardiomyocyte calcium cycling was further investigated. Intracellular calcium overload has already been implicated in hypothermia-induced dysfunction of cardiomyocytes. University of Wisconsin (UW) solution supplemented with 7.5, 15 or 30 umol/l luteolin was used to preserve fresh isolated cardiomyocytes at 4 degrees C. The results demonstrated that all three doses of luteolin supplementation attenuated calcium overload over a 6 h preservation period. Luteolin also suppressed the accumulation of important regulatory proteins and enzymes for cardiomyocyte calcium circulation, mitochondria Ca2+ uniporter and calmodulin, which are normally induced by cold storage in UW solution. Protein Kinase A activity was also suppressed in cardiomyocytes preserved in luteolin supplemented UW solution, while Ca2+-Mg2+-ATPase activity was increased. The results demonstrated that luteolin confers a cardioprotective effect through inhibiting the changes of calcium regulators during cold storage and therefore ameliorates Ca2+ overload in rat cardiomyocytes. PMID- 29399125 TI - Identification of potentially relevant genes for myocardial infarction using RNA sequencing data analysis. AB - Myocardial infarction (MI) is a heart disease with high morbidity and mortality rates, thus it is critical to identify genes that serve roles during its pathogenesis. The objective of the present study was to identify potentially relevant genes during the progression of the disease. Blood samples from patients with MI and normal controls (n=3/group) were obtained, the RNA was extracted and cDNA libraries were established. RNA sequencing (RNA-seq) was performed on a HiSeq 2500 platform and fragments per kilobase of exon per million fragments mapped was utilized to calculate the gene expression value following preprocessing of the RNA-seq data. Electronic validation of several identified differentially expressed genes (DEGs) was performed on a Gene Expression Omnibus (GEO) dataset GSE59867 (390 cases and 46 healthy controls). Functional enrichment and protein-protein interaction network analysis was conducted for DEGs. A total of 977 DEGs, including 817 upregulated and 160 downregulated genes were identified in patients with MI. These DEGs were significantly enriched for 'positive regulation of the immune system process,' 'inflammatory response,' 'regulation of I-kappaB-kinase/NF-kappaB signaling' and 'TNF signaling pathway'. A protein-protein interaction network of the top 40 DEGs was used to identify high degree genes, including interferon induced protein with tetratricopeptide repeats 3 (IFIT3), MX dynamin like GTPase 1 (MX1), major histocompatibility complex, class II, DQ alpha1 (HLA-DQA1), RAR related orphan receptor A (RORA), prostaglandin D2 synthase (PTGDS), cysteine rich protein 2 (CRIP2), collagen type VI alpha 2 chain (COL6A2) and S100 calcium binding protein P (S100P). The results of validation in the GEO dataset were consistent with the sequencing analysis. A total of eight genes, including IFIT3, MX1, HLA-DQA1, RORA, PTGDS, CRIP2, COL6A2 and S100P may therefore be considered as potentially relevant genes in the pathology of MI. PMID- 29399126 TI - Improvement of bone defect healing in rats via mesenchymal stem cell supernatant. AB - The effects of mesenchymal stem cells (MSCs) from three different sources in the treatment of bone defect with stem cells, and the differences of curative effects were studied. The umbilical cord, adipose and bone marrow mesen-chymal stem cells (BMSCs) of Sprague-Dawley (SD) rats were isolated and extracted, and the phenotype was identified for the 4th generation. The SD rat model of bone defect was established. The rats were randomly divided into: Normal saline group, umbilical cord mesenchymal stem cell (UMSC) group, adipose mesenchymal stem cell (AMSC) group and BMSC group. Rats were treated with tail intravenous injection, followed by radiological examination. The relative expression levels of factors bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), alkaline phosphatase (ALP), sclerostin (SOST), collagen carboxy-terminal telopeptide (CTX) and tartrated resistant acid phosphatase (TRACP) were measured via fluorescence quantitative PCR and western blotting. Among the three different kinds of stem cell supernatant, the detection using bicinchoninic acid (BCA) method showed that the content of P4-generation new cytokines was the highest. Wound healing in the three stem cell supernatant groups was significant at 3 weeks after operation, which was faster than that in DF12 control group; the expression levels of BMP-2, OCN and ALP in the bone samples treated with three kinds of MSC supernatants after 5 weeks were significantly increased compared with those in control group. The expression levels of SOST, CTX and TRACP were significantly decreased compared with those in control group. Three kinds of MSC supernatants can promote the bone regeneration through promoting the secretion of relatively more osteoblast factors, and inhibit the bone loss. The concentration of cytokines in UMSC supernatant was the highest under the same culture condition, and BMSC supernatant has a better effect in improving the bone defect repair of rats under the same concentration of cytokines. PMID- 29399127 TI - Astragaloside protects myocardial cells from apoptosis through suppression of the TLR4/NF-kappaB signaling pathway. AB - Astragaloside is a monomer isolated from Astragalus membranaceus, a flowering plant in the family Fabaceae. The aim of the present study was to investigate the anti-apoptotic affect of astragaloside on myocardial cells through the TLR4/NF kappaB signaling pathway. Astragaloside, NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and Toll-like receptor 4 (TLR4) blocking antibody solution were prepared in vitro, and myocardial cells were incubated and cultured in serum free medium overnight. Cells were divided into five groups: the normal control group, serum-free group, astragaloside group, TLR4 blocking antibody group and NF kappaB inhibitor PDTC group. The myocardial cell apoptosis in each group was detected using flow cytometry, and the expression levels of TLR4 and NF-kappaB were detected via western blotting. The apoptosis rate in the serum-free group was significantly higher than that in the normal control group. The apoptosis rate of myocardial cells in the TLR4 blocking antibody group and NF-kappaB inhibitor PDTC group was lower than that in the serum-free group. In addition, the myocardial cell apoptosis was more obviously decreased in the astragaloside group, and the protein expression levels of TLR4 and NF-kappaB in the serum-free group were significantly higher than those in normal control group. The protein expression levels of TLR4 and NF-kappaB in the astragaloside group were obviously lower than those in the serum-free group, and the protein expression levels of TLR4 and NF-kappaB in the TLR4 blocking antibody group and NF-kappaB inhibitor PDTC group were decreased. In conclusion, astragaloside reduced myocardial cell apoptosis and protected myocardial cells, which may be one of the mechanisms of a traditional Chinese medicine monomer in treating heart failure. PMID- 29399128 TI - Cooperation of CD4+ T cells and CD8+ T cells and release of IFN-gamma are critical for antileukemia responses of recipient mice treated by microtransplantation. AB - Previous studies have demonstrated that infusion of allogeneic matched and haploidentical peripheral blood stem cells with minimal conditioning (microtransplantation) achieved durable responses in patients with refractory leukemia/lymphoma in the absence of engraftment. The mechanisms underlying this response have not been thoroughly elucidated, while host-versus-graft reactions are likely to have an important role. The present study established a mismatched microtransplantation mouse model of leukemia to study the roles of CD4+ T cells and CD8+ T cells in changes of interferon (IFN)-gamma and interleukin (IL)-4 release to explore the mechanisms of the effects of microtransplantation. It was demonstrated that IFN-gamma is critical to the antileukemia response in a mouse model of microtransplantation. The therapeutic efficacy was associated with the number of CD4+ T cells (Pearson's r=0.722). In addition, CD8+ T cells increased the release of IFN-gamma with assistance from CD4+ T cells. IL-2 augmented IFN gamma release, partly by increasing CD4+ T cells (42.8 vs. 35.6%; P<0.05). The present study suggested that the release of IFN-gamma via cooperation of CD4+ T cells and CD8+ T cells represents a crucial mechanism in the antileukemia responses of recipient leukemic mice treated by microtransplantation. During this process, the cooperation of CD4+ T cells and CD8+ T cells was demonstrated to have a major role in the antileukemia effect. IL-2 may be developed into an agent used for improving the efficacy of microtransplantation by increasing CD4+ T cells. PMID- 29399129 TI - Efficacy of salmeterol and formoterol combination treatment in mice with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a severe lung disease characterized by progressive airflow limitation. Salmeterol and formoterol are two commonly used drugs in COPD therapy, which act as beta2-receptor agonists. In the current study, a mouse model of COPD induced by airway lipopolysaccharide inhalation was established. The therapeutic efficacy of salmeterol and formoterol co-treatment was investigated in this model over a 56-day-long observation period. It was also identified that functional residual capacity and inspiratory resistance were significantly improved after salmeterol and/or formoterol treatment compared with the control group (all P<0.01). Furthermore, histological staining of lung tissue samples indicated that inflammation, thickening of the smooth muscle, goblet cell hyperplasia and pulmonary small vessel obstruction were reduced in the mice treated with salmeterol and/or formoterol, suggesting that salmeterol and formoterol were beneficial for ongoing airway and blood vessel remodeling in mice with COPD. The most common treatment-associated adverse events were hypertension and proteinuria. In conclusion, combined salmeterol and formoterol treatment was more effective compared with either single agent, suggesting that salmeterol and formoterol combined treatment has therapeutic value for the clinical treatment of patients with COPD. PMID- 29399130 TI - Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy. AB - The present study investigated the aptness of assessing the levels of progastrin releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3+, CD4+, CD8+ and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21 1. The results revealed that in NSCLC patients, CD8+ T lymphocytes and Treg populations were decreased, and that CD3+ and CD4+ T lymphocytes as well as the CD4+/CD8+ ratio were increased after therapy; in SCLC patients, CD3+, CD4+ and CD8+ T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination of tumor cells and improve the immune surveillance function in cancer patients, and also restrained the immune evasion of the tumor, leading to decreased Pro-GRP levels. PMID- 29399131 TI - Efficacy of caspofungin combined with trimethoprim/sulfamethoxazole as first-line therapy to treat non-HIV patients with severe pneumocystis pneumonia. AB - Combined treatment with caspofungin and trimethoprim/sulfamethoxazole (TMP/SMZ) as salvage therapy in non-HIV positive patients with severe pneumocystis pneumonia (PCP) yields poor outcomes. It remains unknown whether the use of this combination strategy as a first-line therapy would improve patient outcomes. The present study aimed to assess the efficacy of caspofungin combined with TMP/SMZ as a first-line therapy in non-HIV positive patients with severe PCP. A retrospective cohort study was conducted between March 2016 and February 2017. Patient clinical characteristics and outcomes were compared between two groups receiving first-line and second-line therapy respectively. In addition, similar cases from previous studies were assessed. A total of 14 patients were included in the present study (mean age, 58.79+/-14.41 years); including 9 patients receiving caspofungin and TMP/SMZ as a first-line therapy and 5 that received it as a second-line therapy. The overall positive response rate was 71.43% (10/14), with 88.89 (8/9) and 40.00% (2/5) in the first-line and second-line therapy groups, respectively (P=0.095). The positive response rates of patients requiring invasive mechanical ventilation differed significantly between the first-line (5/6, 83.33%) and the second-line (0/3, 0%) therapy groups (P=0.048). All-cause hospital mortality was 42.86% (6/14), with mortality rates of 33.33 (3/9) and 60.00% (3/5) in the first-line and second-line therapy groups, respectively (P=0.580). Combined with previously reported cases (n=27), the positive response rate was significantly greater in the first-line therapy group (11/12, 91.67%) than in the second-line therapy group (8/15, 53.33%, P=0.043). No significant differences were in all-cause mortality rates between the two groups (25.00 vs. 46.67%, P=0.424) were identified, despite the fact that all-course mortality in the first-line therapy group was ~50% that of the second-line therapy group. Therefore, the results of the present study indicate that combined caspofungin and TMP/SMZ as first-line therapy may be a promising and effective strategy to treat non-HIV positive patients with severe PCP, particularly for those requiring invasive mechanical ventilation. PMID- 29399132 TI - Water-extracted plum (Prunus salicina L. cv. Soldam) attenuates adipogenesis in murine 3T3-L1 adipocyte cells through the PI3K/Akt signaling pathway. AB - The objective of the present study was to evaluate the effects of water-extracted plum (WEP) on adipocyte differentiation, adipogenesis and inflammation in differentiated 3T3-L1 adipocyte cells. WEP was assessed for basic analyses, including high-performance liquid chromatography, total phenolic and flavonoid content and antioxidant activity [1,1-diphenyl-2-picrylhydrazyl (DPPH) assays] in vitro. Moreover, the cell viability was measured using an MTT assay. Adipogenesis and lipid accumulation in 3T3-L1 adipocytes was investigated using Oil Red O staining, and the expression of genes and proteins associated with adipogenesis and lipolysis were examined by reverse transcription polymerase chain reaction and western blotting. In addition, sulforaphane using a positive control was performed simultaneously. The WEP significantly suppressed adipocyte differentiation and lipid accumulation in differentiated adipocytes without cytotoxicity. WEP resulted in direct anti-obesity effects through the modulation of adenosine monophosphate-activated protein kinase, sterol regulatory element binding protein 1c, cytidine-cytidine-adenosine-adenosine-thymidine/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma. These regulations of molecular expressions were significantly activated via the phosphoinositide 3-kinase/Akt pathway. Moreover, these results provide potential anti-adipogenic effects of WEP and may have potential as a natural agent for the prevention and improvement of obesity. PMID- 29399133 TI - Investigation into the optimal prosthetic material for wound healing of abdominal wall defects. AB - The purpose of this experimental study is to investigate and compare the effects of prosthetic materials used for wound healing of abdominal wall hernias. A total of 60 rats were divided into five equal groups: Group I, control subjected to laparotomy; group II, abdominal wall defect 3*2 cm+polypropylene (PP) mesh; group III, abdominal wall defect 3*2 cm+PP mesh+hyaluronate and carboxymethylcellulose (H-CMC; Seprafilm(r)); group IV, abdominal wall defect 3*2 cm+polytetrafluoroethylene (PTFE; ComposixTM); and group V, abdominal wall defect 3*2 cm+polyethylene terephthalate (PET; Dacron(r)). A total of 14 days after the surgery, rats were sacrificed and the meshes with the surrounding tissue were extracted in block. The breaking strength of the mesh from the fascia was recorded. The healing tissue was examined with the index of histopathology and the hydroxyproline value was analyzed using the Switzer method. Both the breaking strength and histopathological index of the wound healing were significantly improved in groups II and III compared with that in groups IV and V (P<0.001). Hydroxyproline values were the highest in group I (P<0.001). There was also a statistically significant difference between groups II and IV, and group V and the other groups (P<0.001). The present findings demonstrated that PP mesh and PP mesh+H-CMC had a superior breaking strength and improved histopathologic indices compared with PTFE and PET. Furthermore, hydroxyproline values were the lowest in the PET group. In conclusion, wound healing was improved in the PP mesh group and the PP mesh+H-CMC group compared with the PTFE and PET groups according to the present study parameters. PMID- 29399134 TI - Increased expression of tight junction protein occludin is associated with the protective effect of mosapride against aspirin-induced gastric injury. AB - Mosapride is known to affect gastric motility, however whether mosapride has anti ulcergenic effects in gastric mucosal injury is unclear. The aim of the present study was to investigate the effects of mosapride on aspirin-induced gastric injuries. GES-1 cells were cultured and divided into 5 groups: Control group, aspirin injury group (treated with 18.2 mmol/l aspirin) and mosapride pretreatment groups (treated with 0.4, 0.5, or 0.6 umol/l mosapride). Cell proliferation was evaluated via MTT assay and cell apoptosis was investigated via flow cytometry. The expression of occludin was determined by western blot analysis. A total of 40 male Sprague-Dawley rats were randomized into five groups: Control group, aspirin injury group (150 mg/kg) and mosapride pretreatment groups (0.25, 0.50 or 0.75 mg/kg). Gastric mucosal lesions were induced by administering 200 mg/kg aspirin daily for 4 days. Rats in the mosapride groups were pretreated with mosapride 1 h prior to aspirin administration. Histological changes were evaluated under a light microscope and gastric epithelial TJs were observed via transmission electron microscopy. The results revealed that cell apoptosis was significantly increased in the aspirin injury group compared with the control (P<0.05), whereas apoptosis was significantly decreased in the mosapride pretreatment groups compared with the aspirin group (P<0.05). Cell viability was significantly increased in the mosapride pretreatment groups compared with the aspirin injury group (P<0.05), and that of the aspirin injury group was significantly decreased compared with the control group (P<0.05). Compared with the aspirin injury group, occludin expression was significantly increased in the three mosapride pre-treatment groups (all P<0.05). It was also demonstrated that gastric damage was significantly attenuated in the mosapride pretreatment groups compared with the aspirin injury group (P<0.05). Impaired TJ integrity was observed in aspirin injury group, whereas TJs in the mosapride groups were almost intact. In conclusion, the results of the present study suggest that mosapride exerts a gastroprotective action on aspirin-induced gastric mucosal injury at least in part via attenuating cell apoptosis and increasing occludin expression. PMID- 29399135 TI - Efficacy of arthroscopic loose body removal for knee osteoarthritis. AB - The purpose of the present study was to explore the efficacy of arthroscopic loose body removal for knee osteoarthritis (KOA). A total of 23 patients with KOA were enrolled and randomly received conservative treatment (conservative group; n=10) or loose body removal surgery (surgery group; n=13). The serum levels of disease activity indices, including hypersensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR) and synovial inflammatory factors [interleukin (IL)-1 and IL-6] were detected prior to surgery, and at 4 days, 2 or 4 weeks after surgery. All patients were followed up for 2 years and the cure rate was estimated. No significant difference was identified in pre-operative plasma levels of hs-CRP and ESR as well as the synovial concentration of IL-1 and IL-6 between the two groups (all P>0.05). At 2 and 4 weeks after treatment, the levels of these parameters in the surgery group were significantly lower than those in the conservative group (all P<0.05), although the maximum value of these parameters was higher in the surgery group than in the conservative group at 4 days after surgery. The cure rate for KOA in the surgery group was significantly higher than that in the conservative group. In conclusion, the results demonstrated that arthroscopic loose body removal is a more effective treatment than conservative therapy for KOA. PMID- 29399137 TI - Diagnostic value of T-Spot TB combined with INF-gamma and IL-27 in tuberculous pleurisy. AB - The purpose of the present study was to investigate the diagnostic value of T cells spot test (T-Spot TB) combined with interferon-gamma (INF-gamma) and interleukin-27 (IL-27) in tuberculous pleurisy. Sixty patients with tuberculous pleurisy (observation group) and 60 patients with non-tuberculous pleurisy (control group) were enrolled in this study. T-Spot TB was performed to detect the pleural effusion of two groups of patients. Levels of IFN-gamma and IL-27 in serum and pleural effusion were detected by enzyme-linked immunosorbent assay (ELISA). Relative expression of IFN-gamma mRNA and IL-27 mRNA in peripheral blood mononuclear cells were detected by RT-PCR. Positive rate of T-Spot TB in observation group was 96.7% (58 cases), which was significantly higher than that in control group (p<0.05). Concentration of INF-gamma in pleural effusion of observation group was 468.6+/-24.8 ng/l, which was significantly higher than that in control group (131.3+/-18.7 ng/l, p<0.05). Concentration of IL-27 in pleural effusion of observation group was 423.4+/-37.2 ng/l, which was significantly higher than that in control group (116.2+/-15.5 ng/l, p<0.05). Concentrations of INF-gamma and IL-27 in serum of observation group were 48.2+/-13.4 and 41.7+/ 10.6 ng/l, respectively, which were significantly higher than those in control group (38.6+/-11.2 and 35.3+/-8.4 ng/l, p<0.05). Relative expression levels of INF-gamma mRNA and IL-27 mRNA in observation group were significantly higher than those in control group (p<0.05). Therefore, combination of T-Spot TB with INF gamma and IL-27 has significant application value in the clinical diagnosis of tuberculous pleurisy, and should be popularized. PMID- 29399136 TI - Sijunzi decoction-treated rat serum induces apoptosis of side population cells in gastric carcinoma. AB - Sijunzi decoction (SJZD) is a traditional Chinese herbal medicine. Previous studies have indicated that SJZD exhibits antitumor activity. However, the underlying molecular mechanism has not been fully elucidated. To explore the antitumor mechanism of SJZD, the effects of serum from rats treated with SJZD on the proliferation of MKN-28 and HGC-27 gastric carcinoma cell lines were systematically investigated. It was found that SJZD-treated rat serum significantly inhibited the growth of MKN-28 and HGC-27 cells in vitro. The results obtained from a colony formation assay showed that SJZD-treated rat serum decreased the colony formation ability of MKN-28 and HGC-27 cells. The apoptosis rate in MKN-28 and HGC-27 cells was also increased following treatment with SJZD treated rat serum. Flow cytometry with cell sorting revealed the presence of side population (SP) cells in MKN-28 and HGC-27 cells though Hoechst 33342 staining, and verapamil reduced the SP percentage. Further analysis showed that SJZD treated rat serum promoted the apoptosis of SP cells in MKN-28 and HGC-27 cell lines by upregulating Bax, caspase-3 and PARP and downregulating bcl-2. These data revealed the therapeutic effect of SJZD-treated rat serum on gastric carcinoma. Following the preliminary identification of the inhibitory effect on the growth of gastric cancer cells in vitro, the growth inhibitory effect of SJZD treated rat serum on SP cells was confirmed, and this inhibition particularly involved the induction of cell apoptosis. PMID- 29399138 TI - Lymphadenitis associated with cat-scratch disease simulating a neoplasm: Imaging findings with histopathological associations. AB - The lymphadenitis associated with cat-scratch disease (CSD) is often confused with neoplasms by a number of radiologists and clinicians, and consequently, unnecessary invasive procedures or surgeries are performed. In the present study, the contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) findings of 10 patients (6 men and 4 women) with clinically and pathologically confirmed lymphadenitis associated with CSD were retrospectively analyzed (CT in 3 patients, MRI in 6 patients, and CT and MRI in 1 patient) at The Second Affiliated Hospital of Zhejiang University School of Medicine (Hangzhou, China) between January 2007 and November 2014. As a result, 17 enlarged lymph nodes were identified in 10 cases. The 5 nodes identified by CT scan exhibited relatively inhomogeneous isodensity to muscle, with patchy low density in the center. All 14 nodes identified by MRI scan exhibited homogeneous or heterogeneous isointensity to muscle or slightly increased intensity compared with that of muscle on T1-weighted images (T1WI), and homogeneous or heterogeneous hyperintensity on fat-suppressed T2WI. Following enhancement, all 17 enlarged lymph nodes associated with CSD demonstrated the following 3 different enhancement patterns: Moderate homogeneous enhancement (n=8), which was associated with histologically identified early disease stage; marked heterogeneous enhancement with no enhancement of the necrotic areas (n=4), and heterogeneous enhancement with progressively 'spoke-wheel-like' (defined as radiating enhancement from the center) enhancement of the patchy low-density area (n=1), which was associated with histologically identified intermediate disease stage; and astral low-density/hypointensity with marked enhancement (n=2) or a 'rose flower' sign (n=2), which was associated with histologically identified late disease stage. We hypothesized that the CT and MRI results of lymphadenitis in CSD may be associated with the pathological features. It may be suggested that the diagnosis of CSD may be formed when considering the characteristic CT and MRI features of astral low-density/hypointensity with marked enhancement or a 'rose flower' sign (defined as marginal petaloid enhancement) in the late disease stage, or the MRI results of homogeneous, moderate enhancement in the early disease stage, or the CT/MRI data of heterogeneous enhancement with non-enhancing area in the center in the intermediate disease stage, in solitary or multiple enlarged lymph nodes associated with general subcutaneous edema in the vicinity of the nodes on CT/MRI and with a history of cat exposure. PMID- 29399139 TI - SERPINA3 induced by astroglia/microglia co-culture facilitates glioblastoma stem like cell invasion. AB - Glioblastoma (GBM) is a highly invasive and malignant brain tumor. Currently, it remains unclear whether Glioblastoma stem-like cells (GSCs) contribute to the invasive phenotype of GBM. Invasion is a complex process involving interactions between tumor cells with the extracellular matrix (ECM), in addition to normal cells. The present study aimed to identify the regulators of GSCs invasion in the GBM tumor microenvironment. An integrative analysis was conducted to identify genes that are important for GSC invasion and are specifically upregulated in astroglia/microglia co-cultured GSCs. Of the identified genes, serpin peptidase inhibitor clade A member 3 (SERPINA3) was observed to be abnormally overexpressed in astroglia/microglia co-cultured GSCs. To further investigate the role of SERPINA3 in glioma pathogenesis and prognosis, a tissue microarray analysis was conducted to evaluate the expression of SERPINA3 and its association to clinicopathological factors and patient survival. The data indicated that upregulation of SERPINA3 was significantly associated with glioma progression and poor patient survival. Furthermore, it was demonstrated that the upregulation of SERPINA3 in glioma may contribute to the invasive behavior of GBM cells by remodeling of the ECM. Overall, the findings of the present study may be useful in future prognosis of GBM patients, suggesting that SERPINA is a potential therapeutic target, and may lead to further understanding of GBM and cancer progression as a whole. PMID- 29399140 TI - Cancer-testis antigens are predominantly expressed in uterine leiomyosarcoma compared with non-uterine leiomyosarcoma. AB - Leiomyosarcomas account for ~24% of all adult sarcomas, and develop predominantly either in the uterus [uterine leiomyosarcoma (ULMS)] or in deep soft tissue or the retroperitoneum [non-uterine leiomyosarcoma (NULMS)]. Leiomyosarcomas are relatively chemoresistant tumors, and the prognosis of patients with leiomyosarcomas is poor. Cancer-testis (CT) antigens are considered promising immunotherapeutic targets because of their restricted expression in normal tissue, except in the testis. Little is known about the expression of CT antigens in leiomyosarcomas. In the present study, the protein expression of the CT antigens MAGE family member A (MAGEA)1, MAGEA3, MAGEA4, G antigen 7 (GAGE7) and cancer/testis antigen 1 (NY-ESO-1) in ULMS and NULMS were investigated using immunohistochemistry (IHC), and their expression profiles compared. In ULMS and NULMS, positive expression was observed in 11/32 (31%) and 1/31 (3%; MAGEA1), 15/32 (47%) and 5/31 (16%; MAGEA3), 11/32 (34%) and 3/31 (10%; MAGEA4), 23/32 (72%) and 11/31 (35%; GAGE7) and 3/32 (9%) and 0/31 (0%; NY-ESO-1), respectively. The ULMSs demonstrated significantly higher positive expression of MAGEA1 (P=0.0034), MAGEA3 (P=0.0141), MAGEA4 (P=0.0319) and GAGE7 (P=0.0054) compared with the NULMSs. The ULMSs also had significantly higher IHC scores for MAGEA1 (P=0.0023), MAGEA3 (P=0.0474), MAGEA4 (P=0.011), GAGE7 (P=0.0319) and NY-ESO-1 (P=0.0437). The results of the present study support the potential utility of MAGEA1, MAGEA3, MAGEA4 and GAGE7 in ULMS and GAGE7 in NULMS as immunotherapeutic targets. PMID- 29399141 TI - Cancer-associated fibroblasts regulate the biological behavior of cancer cells and stroma in gastric cancer. AB - Gastric cancer (GC) is a frequently diagnosed type of cancer in China, and is associated with a high mortality rate. The biological behavior of GC requires investigation in order to provide an evidence base for the development of strategies to prevent and treat GC. For this purpose, the present review outlines the process of tumor microenvironment (TME) evolution, including the dynamic biological behavior of different types of cancer cell and stroma. Cancer associated fibroblasts (CAFs) serve as prominent stromal cellular components in the GC TME, and exhibit an essential function in GC progression. In the present study, the function of CAFs in cancer cell proliferation, cell migration, invasion, extracellular matrix remodeling, pathological angiogenesis and immune cell infiltration were investigated. The studies discussed in the present review demonstrate that the cross-talk between CAF, cancer cells and tumor stroma promotes GC progression. PMID- 29399143 TI - Microscopic peritoneal carcinomatosis in gastric cancer: Prevalence, prognosis and predictive factors. AB - Peritoneal carcinomatosis (PC) is typically identified in advanced stage gastric cancer and is frequently considered to be an incurable disease. Along with macroscopic PC, microscopic PC may be diagnosed through pathological examination of tissue specimens and is not detectable during surgical intervention. The present study aimed to analyse the prevalence, prognostic value and predictive factors for microscopic PC. In the present retrospective study, data from patients with epithelial gastric cancer that were treated with curative intent surgery were examined. Patients with macroscopic PC were excluded. Additionally, the study population was divided into two groups based on the presence or absence of microscopic PC. The prevalence of microscopic PC was 5.5%. Microscopic PC exhibited a significant negative effect on overall survival. In addition, multivariate analyses revealed that the significant predictive factors for the presence of microscopic PC were adenocarcinoma of a diffuse type, lymphatic and vascular invasion, cancer location at the site of previous gastric surgery and a tumour extent >T2. In particular, the presence of lymphatic and vascular invasion was the most significant predictive factor. These results indicate that >=5.5% of patients with gastric cancer who undergo surgery with a curative intent may benefit from more aggressive loco-regional treatment against microscopic PC at the time of surgery. PMID- 29399142 TI - Human leukocyte antigen-G expression and polymorphisms promote cancer development and guide cancer diagnosis/treatment. AB - Human leukocyte antigen-G (HLA-G) is a non-classical HLA molecule, predominantly expressed in cytotrophoblast cells to protect the fetus during pregnancy. Notably, a high frequency of HLA-G expression has been observed in a wide variety of cancer types in previous studies. Furthermore, HLA-G expression in cancer has been considered to be detrimental, since it can protect cancer cells from natural killer cell cytotoxic T lymphocyte-mediated destruction, promote tumor spreading and shorten the survival time of patients by facilitating tumor immune evasion. In addition, HLA-G polymorphisms have been investigated in numerous types of cancer and are considered as risk factors and predictive markers of cancer. This review focuses on HLA-G expression and its polymorphisms in cancer, analyzing the mechanisms of HLA-G in promoting cancer development, and evaluating the potential and value of its clinical application as a diagnostic and prognostic biomarker, or even as a prospective therapeutic target in certain types of tumors. PMID- 29399144 TI - Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is a rare hereditary disease caused by mutations in serine threonine kinase 11 (STK11) and characterized by an increased risk of developing cancer. Inactivation of STK11 has been associated with the mammalian target of rapamycin (mTOR) pathway. Hyperactivation and phosphorylation of the key downstream target genes ribosomal protein S6 kinase 1 (S6K1) and S6 promote protein synthesis and cell proliferation. To better understand the effects of STK11 dysfunction in the pathogenesis of PJS, genomic DNA samples from 21 patients with PJS from 11 unrelated families were investigated for STK11 mutations in the present study. The results revealed 6 point mutations and 2 large deletions in 8 (72.7%, 8/11) of the unrelated families. Notably, 3 novel mutations were identified, which included 2 missense mutations [c.88G>A (p.Asp30Asn) and c.869T>C (p.Leu290Pro)]. Subsequent immunohistochemical analysis revealed staining for phosphorylated-S6 protein in colonic hamartoma and breast benign tumor tissues from patients with PJS carrying the two respective missense mutations. Additionally, the novel missense STK11 mutants induced phosphorylation of S6K1 and S6, determined using western blot analysis, and promoted the proliferation of HeLa and SW1116 cells, determined using Cell Counting Kit-8 and colony formation assays. Collectively, these findings extend the STK11 mutation spectrum and confirm the pathogenicity of two novel missense mutations. This study represents a valuable insight into the molecular mechanisms implicated in the pathogenesis of PJS. PMID- 29399145 TI - Lentiviral delivery of CTLA-4 shRNA improves the expansion of cytokine-induced killer cells and enhances cytotoxic activity in vitro. AB - Cytokine-induced killer (CIK) cells are in vitro-expanded cells harboring potent toxicity against tumor cells. Recently, it was identified that the cytotoxicity and proliferation of CIK cells are restricted by a prolonged CIK cell culture period. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves a negative role in T cell activation and proliferation. This study aims to determine whether CTLA-4 expression is associated with the inhibition of CIK cells. CIK cells were generated from peripheral blood mononuclear cells (PBMCs), and CTLA-4 shRNA (shCTLA-4) lentivirus was applied to knockdown CTLA-4 expression in CIK cells. The proliferation of CIK cells was evaluated following shCTLA-4 lentiviral transduction, and the cytotoxicity of CIK cells was investigated using the CytoTox 96 Non-Radioactive Cytotoxicity assay. The expression of CTLA-4 in CIK cells was significantly increased, compared with that in PBMCs. The shCTLA-4 lentivirus efficiently knocked down the expression of CTLA-4 in CIK cells. The shCTLA-4 lentivirus transduction of CIK cells promoted the proliferation of CIK cells in vitro (3.18+/-0.19-fold vs. 2.42+/-0.29-fold). Furthermore, the cytotoxicity of shCTLA-4 lentivirus-transduced CIK cells was significantly improved when compared with that of control shRNA lentivirus-transduced CIK cells (54.5+/-2.13% vs. 30.5+/-1.67%). Thus, the suppression of CTLA-4 expression increases cytotoxicity and ex vivo expansion of CIK cells, which indicates a clinical significance for CTLA-4 blockade in CIK cell therapy. PMID- 29399146 TI - Loperamide, an antidiarrheal agent, induces apoptosis and DNA damage in leukemia cells. AB - Loperamide, an antidiarrheal agent, is frequently used to treat patients with leukemia with symptoms of diarrhea during treatment. However, the effect of loperamide on leukemia cells is unknown. The MTT assay was used to explore the cytotoxic effect of loperamide on leukemia cells. Morphological analysis and flow cytometry were performed to determine the level of apoptosis in leukemia cells following loperamide treatment. Western blotting was conducted to test the activation of the apoptotic pathway. The comet assay was used to determine the DNA damage induced by loperamide. Loperamide potently inhibited the proliferation of leukemia cell lines and primary leukemia cells from 9 patients with acute myeloid leukemia (AML) and 6 patients with acute lymphocytic leukemia (ALL) in a dose-dependent manner. Loperamide increased the expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, decreased the expression of myeloid cell lekeumia-1 and induced the apoptosis of leukemia cells. In addition, treatment with 20 uM loperamide increased the expression level of the protein rH2ax and promoted the formation of long DNA comet tails, thus triggering DNA damage in leukemia cells. Finally, DNA damage was confirmed by the activation of the ataxia telangiectasia mutated serine/threonine kinase (ATM)-checkpoint kinase 2 (Chk2) signaling pathway. The phosphorylation level of ATM (Ser1981) and Chk2 (Thr68) was activated and upregulated following DNA damage triggered by loperamide. Loperamide was demonstrated to perform an inhibitory role in the growth of leukemia cell lines and primary leukemia cells. Of note, apoptosis and DNA damage were induced following loperamide treatment in leukemia cell lines and primary leukemia cells. PMID- 29399147 TI - MicroRNA-378 regulates cell proliferation and migration by repressing RNF31 in pituitary adenoma. AB - MicroRNA-378 (miR-378) is dysregulated in multiple malignancies and is associated with tumor progression. However, the expression and mechanism of miR-378 in pituitary adenoma (PA) remains to be elucidated. In the present study, the role and mechanism of miR-378 in PA tumorigenesis and development was investigated. It was revealed that the levels of miR-378 expression were markedly downregulated in PA tissues. CCK-8 and wound healing assays revealed that transfection with miR 378 mimics was able to markedly inhibit the proliferation and migration of GH3 cells. Furthermore, quantitative polymerase chain reaction analysis demonstrated that ring finger protein 31 (RNF31) was upregulated in PA specimens and the levels of RNF31 expression was negatively regulated by miR-378. In addition, knockdown of RNF31 markedly suppressed cell proliferation and migration in GH3 cells. In conclusion, the present study provides a molecular basis for the function of miR-378/RNF31 in the progression of human PA, indicating a potential novel target for the treatment of PA. PMID- 29399148 TI - Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival. AB - Genetic intratumor heterogeneity is associated with tumor occurrence, development and overall outcome. The present study aims to explore the association between mutant-allele fraction (MAF) heterogeneity and patient overall survival in lung cancer. Somatic mutation data of 939 non-small cell lung cancer (NSCLC) cases were obtained from The Cancer Genome Atlas. Entropy-based mutation allele fraction (EMAF) score was used to describe the uncertainty of individual somatic mutation patterns and to further analyze the association with patient overall survival. Results indicated that association between EMAF and overall survival was significant in the discovery set [hazard ratio (H)R=1.62; 95% confidence interval (CI): 1.08-2.41; P=0.018] and replication set (HR=1.63; 95% CI: 1.11 2.37; P=0.011). In addition, EMAF was also significantly different in lung adenocarcinoma and squamous cell carcinoma. Furthermore, a significant difference was indicated in early-stage patients. Results from c-index analysis indicated that EMAF improved the model predictive performance on the 3-year survival beyond that of traditional clinical staging, particularly in early-stage patients. In conclusion, EMAF successfully reflected MAF heterogeneity among patients with NSCLC. Additionally, EMAF improved the predictive performance in early-stage patient prognosis beyond that of traditional clinical staging. In clinical application, EMAF appears to identify a subset of early-stage patients with a poor prognosis and therefore may help inform clinical decisions regarding the application of chemotherapy after surgery. PMID- 29399149 TI - MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2. AB - Hepatocellular carcinoma (HCC) is one of the most widespread malignant human tumors worldwide. Treatment options include radiotherapy, surgical intervention and chemotherapy; however, drug resistance is an ongoing treatment concern. In the present study, the effects of a microRNA (miR/miRNA), miR-9, on the sensitivity of HCC cell lines to the epidermal growth factor receptor inhibitor, cetuximab, were examined. miR-9 has been proposed to serve a role in tumorigenesis and tumor progression. In the present study, bioinformatics analyses identified the eukaryotic translation initiation factor 5A2 (eIF-5A-2) as a target of miR-9. The expression levels of miR-9 and eIF-5A-2 were examined by reverse transcription-quantitative polymerase chain reaction and HCC cell lines were transfected with miR-9 mimics and inhibitors to determine the effects of the miRNA on cell proliferation and viability. The miR-9 mimic was revealed to significantly increase the sensitivity of epithelial phenotype HCC cells (Hep3B and Huh7) to cetuximab, while the miR-9 inhibitor triggered the opposite effect. There were no significant differences in sensitivity to cetuximab observed in mesenchymal phenotype HCC cells (SNU387 and SNU449). Cells lines displaying high expression levels of eIF-5A-2 were more resistant to cetuximab. Transfection of cells with a miR-9 mimic resulted in downregulation of the expression of eIF-5A-2 mRNA, while an miR-9 inhibitor increased expression. When expression of eIF-5A-2 was knocked down with siRNA, the effects of miR-9 on cetuximab sensitivity were no longer observed. Taken together, these data support a role for miR-9 in enhancing the sensitivity of epithelial phenotype HCC cells to cetuximab through regulation of eIF-5A-2. PMID- 29399150 TI - Virosecurinine induces apoptosis in human leukemia THP-1 cells and other underlying molecular mechanisms. AB - Virosecurinine, a primary alkaloid from Securinega suffruticosa plant is known as a potent differentiation-inducing agent in acute leukemia cells. The present study aimed to investigate the effects and underlying mechanisms of virosecurinine on human leukemia THP-1 cells in vitro. The effects of virosecurinine on cell proliferation were assessed by CCK-8. The effects on apoptosis and cell cycle were assessed by staining with annexin V-fluorescein isothiocyanate and propidium iodide, respectively followed by flow cytometric analysis. The apoptotic cell bodies were observed using a transmission electron microscope, while the mRNA expression of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), mechanistic target of rapamycin (mTOR) and phosphatase and tensin homolog (PTEN) in THP-1 was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Treatment with virosecurinine was able to decrease the viability of THP-1 cells in a dose- and time-dependent manner. The IC50 values of virosecurinine at 24, 48, and 72 h post-treatment were 68.128, 23.615, and 13.423 umol/l, respectively. Cell cycle was arrested at the G1/S phase in virosecurinine-treated cells; however, not in untreated control cells. Numerous apoptotic bodies were observed in the THP-1 cells, which were treated with 12.5 umol/l virosecurinine for 48 h. RT-qPCR indicated that treatment with virosecurinine resulted in upregulated PTEN expression and downregulated expression of PI3K, AKT and mTOR in THP-1 cells. The present study demonstrated that treatment with virosecurinine was able to inhibit proliferation and induce apoptosis in THP-1cells by exerting an inhibitory effect on the activation of PI3K/AKT/mTOR signaling pathways. Therefore, our data suggested that virosecurinine is a promising anti-tumor agent for the treatment of acute monocytic leukemia. PMID- 29399151 TI - Pseudolaric acid B induced autophagy, but not apoptosis, in MRC5 human fibroblast cells. AB - Autophagy and apoptosis are closely associated. In previous studies, pseudolaric acid B (PAB), a diterpene acid isolated from the root and trunk bark of Pseudolarix kaempferi Gordon (Pinaceae), was demonstrated to induce apoptosis in various cell lines. However, in L929 murine fibrosarcoma and SW579 human thyroid squamous cell carcinoma cells, only autophagy was induced. In the present study, another cell line, MRC5 human lung fibroblast cells, was identified in which PAB only induced autophagy. The relationship between apoptosis and autophagy subsequent to PAB treatment in MRC5 cells was explored. When autophagy was inhibited by 3-methyladenine (3MA), apoptosis was induced in the PAB-treated MRC5 cells. To study the mechanism for the promotion of apoptosis by 3MA in the PAB treated cells, the expression of members from the apoptotic signal pathways was assessed. As Bcl-2, Bcl-2 associated X and pro-caspase-9 expression following PAB treatment was not affected by 3MA treatment, it was determined that apoptosis was induced independent of the mitochondrial pathway of apoptosis. As Fas and pro caspase-8 expression following PAB treatment were not altered by 3MA, it was further determined that the death receptor pathway was not induced. However, the phosphorylation of c-Jun-N-terminal kinase and the expression of pro-caspase-3 were upregulated, and the phosphorylation of extracellular signal-regulated kinase downregulated, by the combination of PAB and 3MA treatment compared with PAB alone. It was also observed that 3MA did not affect the microtubule aggregation ability of PAB. Therefore, inhibiting autophagy in MRC5 cells did not affect the role of PAB in microtubule aggregation, while apoptosis was induced. This may present a strategy to enhance the anti-tumor effects of PAB. PMID- 29399152 TI - CITED2 attenuates macrophage recruitment concordant with the downregulation of CCL20 in breast cancer cells. AB - The transcriptional co-regulator Cbp/p300-interacting transactivator with Glu/Asp rich carboxy-terminal domain-2 (CITED2) may promote breast tumor growth; however, the mechanisms by which its effects are mediated remain to be fully elucidated. Tumor-associated macrophages serve an important function in tumor development and progression and are recruited by chemotactic factors produced by cells within the tumor microenvironment. The present study assessed the effects of CITED2 silencing on macrophage recruitment in two xenograft mouse models of human breast cancer, one in which tumor growth was sensitive to CITED2 silencing (MDA-MB-231) and one in which it was insensitive (MDA-MB-468). The present study identified that silencing CITED2 significantly attenuated macrophage infiltration in MDA-MB 231 but not MDA-MB-468 orthotopic tumors, concordant with its effect on tumor growth. Correspondingly, conditioned media obtained from CITED2-silenced MDA-MB 231 cells exhibited a significantly decreased ability to induce macrophage recruitment by Transwell migration assay, whereas the chemotactic effect of MDA MB-468 conditioned media was unaffected. Examining the expression of macrophage chemoattractants within orthotopic tumors and tumor cell-conditioned media revealed a significant decrease in C-C motif chemokine ligand (CCL)20 mRNA and protein expression following CITED2-silencing in MDA-MB-231 cells, compared with that in cells transfected with scramble shRNA. However, mRNA and protein expression was unaffected by CITED2-silencing in MDA-MB-468 cells. Furthermore, chromatin immunoprecipitation analysis revealed that CITED2 was localized to the CCL20 promoter in MDA-MB-231 cells, suggesting that it serves a direct function in its regulation, which is consistent with the effect of CITED2 silencing on CCL20 expression. Lastly, neutralizing CCL20 in the conditioned media of MDA-MB 231 cells significantly inhibited macrophage recruitment. Collectively, these results suggest that CITED2 is involved in modulating macrophage recruitment, representing a novel mechanism through which it may influence tumor growth. This may be partly mediated by regulating tumor cell production of the chemokine CCL20. PMID- 29399153 TI - Silymarin-mediated regulation of the cell cycle and DNA damage response exerts antitumor activity in human hepatocellular carcinoma. AB - A novel module-search algorithm method was used to screen for potential signatures and investigate the molecular mechanisms of inhibiting hepatocellular carcinoma (HCC) growth following treatment with silymarin (SM). The modules algorithm was used to identify the modules via three major steps: i) Seed gene selection; ii) module search by seed expansion and entropy minimization; and iii) module refinement. The statistical significance of modules was computed to select the differential modules (DMs), followed by the identification of core modules using the attract method. Pathway analysis for core modules was implemented to identify the biological functions associated with the disease. Subsequently, results were verified in an independent sample set using reverse transcription polymerase chain reaction (RT-PCR). In total, 18 seed genes and 12 DMs (modules 1 12) were identified. The core modules were isolated using gene expression data. Overall, there were 4 core modules (modules 11, 5, 6 and 12). Additionally, DNA topoisomerase 2-binding protein 1 (TOPBP1), non-structural maintenance of chromosomes condensing I complex subunit H, nucleolar and spindle associated protein 1 (NUSAP1) and cell division cycle associated 3 (CDCA3) were the initial seed genes of module 11, 5, 6 and 12, respectively. Pathway results revealed that cell cycle signaling pathway was enriched by all core modules simultaneously. RT PCR results indicated that the level of CDCA3, TOPBP1 and NUSAP1 in SM-treated HCC samples was markedly decreased compared with that in non-SM-treated HCC. No statistically significant difference between the transcriptional levels of CDCA3 in SM-treated and non-treated HCC groups was identified, although CDCA3 expression was increased in the treated group compared with the untreated group. Furthermore, although the expression level of TOPBP1 and NUSAP1 in the SM-treated group was decreased compared with that in the normal group, no significant difference was observed. From the results of the present study it can be inferred that TOPBP1, NUSAP1 and CDCA3 of the core modules may serve notable functions in SM-associated growth suppression of HCC. PMID- 29399154 TI - Lysosome-associated membrane protein 2 (LAMP-2) expression induced by miR-194-5p downregulation contributes to sunitinib resistance in human renal cell carcinoma cells. AB - Sunitinib is a tyrosine kinase inhibitor that is used as the primary treatment in metastatic renal cell carcinoma (RCC). The main difficulty associated with its use is the development of drug resistance. In the present study, ACHN cells, a human renal cell carcinoma cell line, were used to establish sunitinib-resistant (SR) cells. Microarray analysis and reverse transcription-quantitative polymerase chain reaction revealed that miR-194-5p expression was significantly decreased in SR-ACHN cells when compared with that observed in ACHN cells (P<0.05). Transfection of miR-194-5p, though not with negative control miR, in SR-ACHN cells could significantly inhibit cell proliferation following sunitinib treatment (2.5-40 uM; P<0.05). Western blotting demonstrated that the expression of lysosome-associated membrane protein-2 (LAMP-2), which attenuates the anti proliferative effect of sunitinib, was significantly higher in SR-ACHN than in ACHN cells (P<0.01). In addition, LAMP-2 expression was suppressed by miR-194-5p transfection in SR-ACHN cells. These data suggested that miR-194-5p downregulation may be associated with sunitinib resistance via the induction of LAMP-2 expression in human RCC. PMID- 29399155 TI - Amyloid precursor protein has clinical and prognostic significance in AML1-ETO positive acute myeloid leukemia. AB - Amyloid precursor protein (APP) has been reported to be highly expressed in acute myeloid leukemia (AML)1-eight-twenty one (ETO)-positive AML. In the present study, the clinical and prognostic significance of APP expression was assessed in 65 patients with AML1-ETO-positive AML using reverse transcription-quantitative polymerase chain reaction. The patients were divided into an APP-high expression (APP-H) group (n=32) and an APP-low expression (APP-L) group (n=33) according to the cut-off value of APP relative expression, which was calculated by receiver operating characteristic curve analysis. It was observed that C-KIT mutations (14/32 vs. 3/33, P=0.009), white blood cell count (median, 23.2*109 vs. 12.4*109 cells/l; P=0.011) and bone marrow cellularity (median, 91.0 vs. 84.0%; P=0.039) and incidence of extramedullary leukemia (11/32 vs. 3/33, P=0.013) were all significantly increased in the APP-H group compared with the APP-L group. Furthermore, significantly lower rate of cumulative two-cycle complete remission (83.9 vs. 100%, P=0.016), major molecular remission following two courses of consolidation (34.5 vs. 71.4%, P=0.005), and poorer relapse-free survival (RFS) (33.5+/-5.2% vs. 76.3+/-6.9%, P<0.001) and overall survival (OS) (44.5+/-7.0% vs. 81.9+/-5.8%, P=0.002) were associated with APP overexpression. Multivariate analysis revealed that APP overexpression was a significant adverse factor affecting both RFS and OS. Taken together, these data suggest that APP may be correlated with C-KIT mutations and involved in leukemia cell proliferation, and its overexpression has an adverse effect on the prognosis in AML1-ETO-positive AML. PMID- 29399157 TI - The serum metabolic profiles of different Barcelona stages hepatocellular carcinoma associated with hepatitis B virus. AB - The present study aimed to explore the characteristic ions distinguishing different Barcelona stages in patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) using the ultra-performance liquid chromatography mass spectrometry (UPLC-MS) platform, and to evaluate their value in diagnosing and monitoring the progress of HCC. The serum was sampled from 20 healthy volunteers, 20 patients with HBV-induced cirrhosis and 75 patients with HBV associated HCC of different BCLC stages. Samples were all examined using UPLC-MS. Principal components analysis (PCA) and the orthogonal partial least squares discriminant analysis (OPLS-DA) model were constructed to determine potential biomarkers. Then, the independent sample-nonparametric test was used to perform the final screening for ion identification. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of these ions. Serum metabolomic PCA and OPLS-DA models were established to diagnose different BCLC stages of HCC associated with HBV, with OPLS-DA model parameters (R2X=67.2%, R2Y=82%, Q2Y=61.1%). A total of 20 metabolites with statistically significant differences among groups were identified, primarily including amino acids, bile acid, fatty acid and phosphatidate. The area under the curve (AUC) of LysoPC [18:2 (9Z,12Z)], LysoPC (P-16:0), asparaginyl-proline and vaccenic acid in the comparison between HCC and cirrhosis were all increased compared with that of AFP, indicating a more improved diagnosis ability. Furthermore, the AUC of L aspartyl-4-phosphate and LysoPC [20:5 (5Z,8Z,11Z,14Z,17Z)] in the stage A vs. B comparison were increased compared with that of AFP, but were decreased in the comparison between stage B and C. The present study succeeded in screening metabolic ions that reflect the progress of HCC with high diagnostic value. Thus, the identified ions may serve a role in clinically diagnosing HBV-associated HCC and monitoring the development of the disease. PMID- 29399156 TI - Role of piwi-interacting RNA-651 in the carcinogenesis of non-small cell lung cancer. AB - Piwi-interacting RNAs (piRNAs/piRs) are small non-coding RNAs that can serve important roles in genome stability by silencing transposable genetic elements. piR651, one of these novel piRNAs, regulates a number of biological functions, as well as carcinogenesis. Previous studies have reported that piR651 is overexpressed in human gastric cancer tissues and in several cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines. However, the role of piRNAs in carcinogenesis has not been clearly defined. In the present study, a small interfering RNA inhibitor of piR651 was transfected into the NSCLC A549 and HCC827 cell lines to evaluate the effect of piR651 on cell growth. The association between piR651 expression and apoptosis was evaluated by flow cytometry and western blot analysis. Wound-healing and Transwell migration and invasion assays were used to determine the effect of piR651 on the migration and invasion of NSCLC cell lines. The results revealed that inhibition of piR651 inhibited cell proliferation and significantly increased the apoptotic rate compared with the negative control (NC), as well as altering the expression of apoptosis-associated proteins. There were fewer migrating and invading cells in the piR651-inhibited group than in the NC group in the Transwell assays. Furthermore, in the wound-healing assay, the wound remained wider in the piR651 inhibitor group, suggesting decreased cell migration compared with that in the NC group. The results of the present study demonstrate that piR651 potentially regulates NSCLC tumorigenic behavior by inhibiting cell proliferation, migration and invasion and by inducing apoptosis. Therefore, piR651 is a potential cancer diagnosis marker. PMID- 29399158 TI - MicroRNA-1 inhibits tumorigenicity of esophageal squamous cell carcinoma and enhances sensitivity to gefitinib. AB - Dysregulation of microRNAs in various types of human cancer promote or suppress oncogenesis. MicroRNA (miR)-1 was previously revealed to function as a tumor suppressor in prostate cancer cells, and its expression was associated with reduced metastatic potential in lung cancer. The present study investigated the role of miR-1 and its association with phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit alpha (PIK3CA) in the pathophysiology of esophageal squamous cell carcinoma (ESCC), and analyzed the effects of miR-1 inhibitor or mimics on sensitivity to epidermal growth factor receptor-tyrosine kinase inhibitors, the alterations of cell cycle distribution and apoptosis in ESCC cells. Compared with normal tissues, the level of miR-1 expression was significantly lower and PIK3CA expression was higher in ESCC tissues. The level of miR-1 expression was also inversely associated with the level of PIK3CA mRNA expression. Low miR-1 and high PIK3CA expression levels were strongly associated with lymph node metastasis, and the level of miR-1 expression was negatively associated with clinical Tumor-Node-Metastasis stage. Furthermore, exogenous expression of miR-1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIK3CA protein expression levels. Furthermore, overexpression of miR-1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib. A possible mechanism for this increased sensitivity to gefitinib may be inactivation of the PIK3CA signaling pathway. To the best of our knowledge, this is the first time that the results of the present study demonstrated that miR-1 upregulation may be a potential strategy for the treatment of human ESCC. PMID- 29399159 TI - Triple negative breast cancer and immunoglobulin A nephropathy: A case report and literature review. AB - The association between malignant tumors and the occurrence of glomerular disease has been well documented in previous studies. The most common types of malignant tumor include Hodgkin's lymphoma with minimal change glomerular nephritis, solid tumor with membranous nephropathy and renal cell carcinoma with immunoglobulin (Ig)A nephropathy. The present case study describes a case of a 31-year-old Chinese female patient who was hospitalized with chronic glomerulonephritis. The patient self-administered unknown traditional Chinese medicine; however, protein excretion/24-h remained increased compared with normal levels. After 34 months, a tumor was identified in the patient. Subsequently, the patient was administered breast-conserving surgery and sentinel lymph node biopsy, which validated the diagnosis of triple negative breast cancer at stage IA (T1cN0M0). The patient received chemotherapy and radiotherapy. Following the review of the relevant studies within the last 30 years, it was demonstrated that the present report was the second documented case of breast cancer associated with IgA nephropathy. Thus, the present study hypothesized that IgA nephropathy may be a tumor manifestation in breast cancer. PMID- 29399160 TI - Microglia immunophenotyping in gliomas. AB - Microglia, once assimilated to peripheral macrophages, in gliomas has long been discussed and currently it is hypothesized to play a pro-tumor role in tumor progression. Uncertain between M1 and M2 polarization, it exchanges signals with glioma cells to create an immunosuppressive microenvironment and stimulates cell proliferation and migration. Four antibodies are currently used for microglia/macrophage identification in tissues that exhibit different cell forms and cell localization. The aim of the present work was to describe the distribution of the different cell forms and to deduce their significance on the basis of what is known on their function from the literature. Normal resting microglia, reactive microglia, intermediate and bumpy forms and macrophage-like cells can be distinguished by Iba1, CD68, CD16 and CD163 and further categorized by CD11b, CD45, c-MAF and CD98. The number of microglia/macrophages strongly increased from normal cortex and white matter to infiltrating and solid tumors. The ramified microglia accumulated in infiltration areas of both high- and low grade gliomas, when hypertrophy and hyperplasia occur. In solid tumors, intermediate and bumpy forms prevailed and there is a large increase of macrophage-like cells in glioblastoma. The total number of microglia cells did not vary among the three grades of malignancy, but macrophage-like cells definitely prevailed in high-grade gliomas and frequently expressed CD45 and c MAF. CD98+ cells were present. Microglia favors tumor progression, but many aspects suggest that the phagocytosing function is maintained. CD98+ cells can be the product of fusion, but also of phagocytosis. Microglia correlated with poorer survival in glioblastoma, when considering CD163+ cells, whereas it did not change prognosis in isocitrate dehydrogenase-mutant low grade gliomas. PMID- 29399161 TI - MicroRNA-144 inhibits proliferation by targeting WW domain-containing transcription regulator protein 1 in papillary thyroid cancer. AB - Papillary thyroid carcinoma (PTC), the most common histological subtype of thyroid cancer, accounts for between 80 and 90% of all thyroid cancer cases. Previous studies have suggested that microRNAs (miRNAs/miRs) are involved in the development of PTC. The aim of the present study was to investigate whether miR 144 inhibits cellular proliferation in PTC. The expression of miR-144 was detected in PTC and corresponding adjacent non-cancerous tissues, and in the PTC cell line IHH4, using reverse transcription-quantitative polymerase chain reaction. Associations between miR-144 expression levels and the clinicopathological characteristics were analyzed. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of miR-144 expression, and the potential function of miR-144 was investigated in IHH4 cells using a Cell Counting Kit-8 and colony formation assays. Western blotting was applied to analyze the expression level of WW domain-containing transcription regulator 1 (WWTR1) in PTC tissues. miR-144 was significantly downregulated in PTC tissues and the PTC cell line. Low expression of miR-144 was associated with larger tumor sizes (P<0.001). The ROC curves demonstrated that miR-144 may be a potential biomarker for identifying PTC and non-cancerous diseases (sensitivity, 58.7%; specificity, 87.3%) as well as to differentiate PTC with tumor sizes >=2 cm (sensitivity, 79.2%; specificity, 69.2%). Upregulation of miR-144 significantly suppressed proliferation in IHH4 cells. WWTR1 was overexpressed in PTC tissues compared with in adjacent non-cancerous tissues, and the ectopic expression of miR-144 downregulated WWTR1 in IHH4 cells. Co-transfection with pcDNA-WWTR1 and miR-144 'rescued' the proliferation inhibition. The results of the present study collectively demonstrated that miR-144 is downregulated in PTC, that low expression levels of miR-144 are associated with larger tumor sizes and that miR-144 inhibits cellular proliferation in PTC by targeting WWTR1. PMID- 29399162 TI - Effects of ginkgol C17:1 on cisplatin-induced autophagy and apoptosis in HepG2 cells. AB - Previous studies have demonstrated that ginkgol C17:1 significantly inhibits human liver cancer cells and enhances the anticancer activity of cisplatin in vivo and in vitro. However, the mechanism and biological function of ginkgol C17:1 on cells undergoing chemotherapy remain unclear. The aim of the present study was to determine the antitumor activity and mechanism of ginkgol C17:1 in combination with cisplatin in human hepatoblastoma HepG2 cells. The green fluorescent protein (GFP)-light chain 3 (LC3) adenovirus was transfected into HepG2 cells and autophagic flux was determined using fluorescence microscopy. Western blot analysis was also conducted to measure the expression of proteins associated with apoptosis, autophagy and their associated signaling pathways. Compared with the control group, autophagic flux and nucleus aberration rates were significantly increased (P<0.05), and the expression of proteins associated with autophagy and apoptosis were increased in the groups treated with cisplatin or ginkgol C17:1, respectively. However, following co-treatment with ginkgol C17:1 and cisplatin, the autophagic flux and the expression of autophagy proteins decreased; however, the nucleus aberration rate and apoptosis protein expression significantly increased (P<0.05) compared with the group treated with cisplatin alone. Additionally, the signaling pathways of autophagy and apoptosis were also activated following treatment with cisplatin, alone and in combination with ginkgol C17:1. Taken together, these results indicate that ginkgol C17:1 inhibits cisplatin-induced autophagy via AMP-activated protein kinase/ULK1signaling and increases cisplatin-induced apoptosis in HepG2 cells via the phosphoinositide 3 kinase/Akt/mechanistic target of rapamycin pathway. PMID- 29399163 TI - Increased expression of the high-mannose M6N2 and NeuAc3H3N3M3N2F tri-antennary N glycans in cholangiocarcinoma. AB - Changes in protein glycosylation have been reported in various types of cancer, including cholangiocarcinoma (CCA). Nanospray ionization-linear ion trap mass spectrometry (NSI-MS n ) was used in the present study to determine the comparative structural glycomics of the N-linked glycans in the serum of patients with CCA compared with healthy controls. A total of 5 high-mannose and 4 complex N-linked glycans were detected. Mannose7-N-acetyl-glucosamine2 was the most abundant structure among the high-mannose types (control 12.12+/-2.54 vs. CCA 9.27+/-2.66%), whereas NeuAc2H2N2M3N2 predominated the complex types (control 61.17+/-2.55 vs. CCA 64.68+/-4.23%). The expression of 3 different N-glycans differed significantly between the CCA cases and controls. These included mannose6-N-acetyl-glucosamine2 (P=0.044), mannose9-N-acetyl-glucosamine2 (Rho=0.030) and NeuAc3H3N3M3N2F (Rho=0.002). These three glycan structures may therefore be associated with tumor progression in CCA and may be useful for its diagnosis. PMID- 29399164 TI - Prognostic significance of expression of epithelial-mesenchymal transition driver brachyury in breast cancer and its association with subtype and characteristics. AB - Brachyury is a T-box transcription factor characterized as a driver of the epithelial-to-mesenchymal process, which is associated with poor prognosis of patients with breast cancer. The present study investigated expression of brachyury in breast cancer including primary tumor, metastatic and recurred tumor tissues, and the clinical significance and value of brachyury as a prognostic biomarker. This retrospective study included a series of 102 consecutive patients surgically resected between January 2005 and December 2011. Brachyury expression in tumor cell was evaluated using immunohistochemistry and scored as the immunoactivity. Of 102 patients, 62 primary tumors were positive for brachyury expression and 40 were negative. Multivariate analysis of disease-free survival (DFS) revealed brachyury expression, HER2 and lymphovascular invasion as independent prognostic factors [brachyury negative vs. positive hazard ratio (HR), 3.0; P=0.024; HER2 negative vs. positive HR, 4.9; P=0.003; lymphovascular invasion absent vs. present HR, 3.5; P=0.020]. These results were particularly observed in triple-negative breast cancer (TNBC), no recurrence or mortality occurred in brachyury negative group during the follow-up period, and therefore a significantly improved prognosis was demonstrated in these patients compared with the brachyury positive group [overall survival (OS), P=0.022; DFS, P=0.002]. Brachyury expression in metastatic lymph node/recurred tumors was not significantly associated with prognosis (OS, P=0.745; DFS, P=0.189). Therefore, Brachyury expression in primary tumor independently is a potential predictor of poor prognosis, particularly in TNBC, where it appears to serve a crucial function in recurrence and mortality. Brachyury vaccines under clinical trials are likely to be useful in patients with breast cancer. PMID- 29399165 TI - Phosphorylation of phosphatase and tensin homolog induced by Helicobacter pylori promotes cell invasion by activation of focal adhesion kinase. AB - Phosphorylation of the phosphatase and tensin homolog (PTEN) tumor suppressor at Ser380/Thr382/Thr383 residues is a novel mechanism underlying PTEN inactivation in gastric carcinogenesis, which may be triggered by Helicobacter pylori infection. To investigate this further, the effect of H. pylori infection on PTEN phosphorylation and the subsequent activation of focal adhesion kinase (FAK), were evaluated in gastric tissue samples from Mongolian gerbils and in the human gastric epithelial mucosa cell line GES-1 using immunohistochemistry, western blotting and Transwell assays. The in vivo and in vitro results of the present study demonstrated that H. pylori infection induced the phosphorylation and inactivation of PTEN at Ser380/Thr382/383, and the subsequent phosphorylation and activation of FAK at Tyr397. Gastric epithelial cell invasion was also increased. Furthermore, stable expression of a dominant-negative PTEN mutant inhibited the enhanced FAK activation and cell invasion induced by H. pylori infection. These results suggest that the mechanism underlying H. pylori-induced carcinogenesis may involve promoting cell invasion through the phosphorylation of PTEN and the activation of FAK. PMID- 29399166 TI - Association between Twist and multidrug resistance gene-associated proteins in Taxol(r)-resistant MCF-7 cells and a 293 cell model of Twist overexpression. AB - Multidrug resistance (MDR) severely limits the effectiveness of chemotherapy. Previous studies have identified Twist as a key factor of acquired MDR in breast, gastric and prostate cancer. However, the underlying mechanisms of action of Twist in MDR remain unclear. In the present study, the expression levels of MDR associated proteins, including lung resistance-related protein (LRP), topoisomerase IIalpha (TOPO IIalpha), MDR-associated protein (MRP) and P glycoprotein (P-gp), and the expression of Twist in cancerous tissues and pericancerous tissues of human breast cancer, were examined. In order to simulate Taxol(r) resistance in cells, a Taxol(r)-resistant human mammary adenocarcinoma cell subline (MCF-7/Taxol(r)) was established by repeatedly exposing MCF-7 cells to high concentrations of Taxol(r) (up to 15 ug/ml). Twist was also overexpressed in 293 cells by transfecting this cell line with pcDNA5/FRT/TO vector containing full-length hTwist cDNA to explore the dynamic association between Twist and MDR gene-associated proteins. It was identified that the expression levels of Twist, TOPO IIalpha, MRP and P-gp were upregulated and LRP was downregulated in human breast cancer tissues, which was consistent with the expression of these proteins in the Taxol(r)-resistant MCF-7 cell model. Notably, the overexpression of Twist in 293 cells increased the resistance to Taxol(r), Trichostatin A and 5 fluorouracil, and also upregulated the expression of MRP and P-gp. Taken together, these data demonstrated that Twist may promote drug resistance in cells and cancer tissues through regulating the expression of MDR gene-associated proteins, which may assist in understanding the mechanisms of action of Twist in drug resistance. PMID- 29399167 TI - MicroRNA-27a functions as an oncogene in human osteosarcoma by targeting CCNG1. AB - Osteosarcoma is the most common type of malignant tumor arising from bone in children and adolescents. Accumulating evidences have shown the aberrant expression of numerous miRNAs is associated with the development and metastasis of osteosarcoma. The present study was conducted to investigate miR-27a expression in osteosarcoma tissues and cells. In the present study, quantitative RT-qPCR was used to measure the expression levels of miRNA and mRNA in osteosarcoma tissues and cells. Transwell assays were used to detect the effects of miR-27a on the invasive and migratory potential of cells. Luciferase reporter and western blot analysis were conducted to confirm cyclin G1 (CCNG1) as the target gene of miR-27a. The results showed that miR-27a was significantly upregulated in human osteosarcoma tissues and cell lines. The western blot analysis revealed that the overexpression of miR-27a suppressed CCNG1 protein expression. Luciferase reporter assays confirmed that CCNG1 is a direct target of miR-27a in osteosarcoma cells. The results suggest that miR-27a downregulates CCNG1 expression in osteosarcoma and acts as an oncogene directly targeting CCNG1. Thus, the miR-27a/CCNGI axis is a potential therapeutic target for human osteosarcoma. PMID- 29399168 TI - Effect of FOLFOX4 combined with Brucea javanica emulsion on VEGF in patients with gastric cancer. AB - The aim of the study was to investigate the effect of FOLFOX4 regimen combined with Brucea javanica emulsion on the content of serum vascular endothelial growth factor (VEGF) in patients with gastric cancer, and to evaluate the efficacy of FOLFOX4 regimen combined with Brucea javanica emulsion on gastric cancer. A total of 60 patients with gastric ulcer were selected as the normal group, and another 150 patients with gastric cancer were randomly divided into two groups, of which 75 patients with gastric cancer treated with FOLFOX4 regimen after operation were selected as the control group and another 75 patients with gastric cancer treated with FOLFOX4 regimen combined with Brucea javanica emulsion after operation were selected as the experimental group. The serum VEGF levels of patients in the different groups before operation, after chemotherapy for 3 times and at 1 and 3 months after chemotherapy were compared via enzyme-linked immunosorbent assay. The content of serum VEGF in patients with gastric cancer before operation was significantly higher than that in the normal group (P<0.05). After administration of chemotherapy 3 times, the content of serum VEGF in the control group had no significant difference from that in the experimental group (P>0.05). Additionally, at 1 and 3 months after chemotherapy, the content of serum VEGF of patients in the experimental group were significantly lower than those in the control group (P<0.05). The results showed that FOLFOX4 regimen combined with Brucea javanica emulsion can significantly reduce the level of serum VEGF in patients with gastric cancer, and has a certain effect in reducing the postoperative recurrence rate of gastric cancer and improving the effect of chemotherapy. PMID- 29399170 TI - miR-133b induces chemoresistance of osteosarcoma cells to cisplatin treatment by promoting cell death, migration and invasion. AB - As an important chemotherapeutic agent for the treatment of osteosarcoma, the effectiveness of cisplatin is considered to be due to its unique properties, which allow it to penetrate the cell membrane and form various DNA-platinum adducts, resulting in genetic alterations or DNA damage. However, chemoresistance to cisplatin remains a major challenge for its use and chemotherapeutic effects. In the present study, an isogenic model of a cisplatin resistant osteosarcoma cell line, MG63-DDP, was generated from the original MG63 cell line. The expression level of microRNA (miR)-133b in the MG63-DDP cisplatin-resistant osteosarcoma cell line was analyzed by reverse transcription-quantitative polymerase chain reaction (PCR). Cisplatin-DNA adduct formation, cell death (carboxyfluorescein succinimidyl ester/propidium iodide staining) and clonogenic survival assays (crystal violet staining) were performed, comparing various cell types. The effect of miR-133b on migration (scratch wound assay) and invasion (Transwell assay) was also evaluated. Characterization studies have previously revealed an increased level of miR-133b in MG63-DDP cells compared with normal MG63 cells. Upregulation of miR-133b was associated with the accumulation of cisplatin-DNA adducts and an increase in cisplatin-induced cell death. Furthermore, increased miR-133b expression levels enhanced the migration and invasion of MG63 cells under cisplatin stress. Concordantly, in MG63-DDP cells the neutralization of miR-133b demonstrated opposite effects, as compared with the upregulation of miR-133b. To the best of our knowledge, the present study demonstrated for the first time that cisplatin-resistant MG63 cells exhibit an increased level of miR-133b expression. The endogenous expression level of miR 133b is sufficient for inducing cisplatin resistance, which suggests that miR 133b may be a biomarker for cisplatin resistance in osteosarcoma. PMID- 29399169 TI - Histone deacetylation, as opposed to promoter methylation, results in epigenetic BIM silencing and resistance to EGFR TKI in NSCLC. AB - Drug resistance remains a major challenge in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Bcl-2-like protein 11 (BIM), a B cell lymphoma 2 family pro-apoptotic protein, is a prime target for specific anti cancer therapeutics. However, the epigenetic regulation of BIM in non-small cell lung cancer (NSCLC) cell lines and patients with NSCLC in association with EGFR TKI resistance requires investigation. Methylation-specific PCR (MSP), pyrosequencing, and nested quantitative (q)-MSP were conducted to explore the methylation status of BIM in NSCLC cell lines. In addition, the methylation profile of BIM in patients with NSCLC was assessed by nested q-MSP using circulating free DNA. Cell lines, treated with methylation inhibitor 5-Aza-2' deoxycytidine (AZA) or histone deacetylation inhibitor trichostatin A (TSA) prior to gefitinib treatment, were examined for BIM gene expression and resistance to gefitinib. All cell lines used in the present study presented with hypo methylated BIM. Treatment with AZA had no effect on BIM RNA expression in PC9 cells or the gefitinib-resistant cell lines PC9/R and PC9/G2, nor did it reverse their resistance to gefitinib. In contrast, TSA treatment produced the opposite result. In the present study, 25 (78.1%) patients with hypo-methylated BIM and 7 patients (21.9%) with partial or hyper-methylated BIM were identified. The clinicopathological data revealed a random hypo-methylated BIM distribution amongst patients with NSCLC. In the overall study group and EGFR mutant group, hypo-methylated BIM carriers presented with no significant differences in progression free survival compared with patients with partial or hyper-methylated BIM. All cell lines in the present study and the majority of patients with NSCLC carried hypo-methylated BIM. Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing of BIM and lead to EGFR TKI resistance in NSCLC. PMID- 29399171 TI - Expression of PIM-1 in salivary gland adenoid cystic carcinoma: Association with tumor progression and patients' prognosis. AB - Pim-1 proto-oncogene, serine/threonine kinase (PIM-1) phosphorylates a series of substrates to exert its oncogenic function in numerous malignancies. The present study investigated the clinical significance of the PIM-1 protein, apoptosis status and apoptosis-associated proteins, including forkhead box O3a (FOXO3a), B cell lymphoma-2 (BCL-2) and BCL-2-associted agonist of cell death (BAD), were investigated in salivary gland adenoid cystic carcinoma (ACC) tissues. PIM-1 expression levels in 4 pairs of ACC tissues and corresponding normal salivary gland tissues were determined by western blot analysis. PIM-1, FOXO3a, BAD and BCL-2 expression levels in 60 ACC tissues were evaluated by immunohistochemistry (IHC). A terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay was performed to detect the apoptosis status of ACC tissues. PIM-1 was revealed to be highly expressed in ACC tissues compared with adjacent normal tissues. IHC staining results demonstrated high expression ratios of PIM-1, FOXO3a, BCL-2 and BAD [33.33% (20/60), 51.67% (31/60), 51.67% (31/60) and 55% (33/60)], respectively, and significant correlations between the expression of PIM-1 and FOXO3a and BCL-2 (P<0.05). Apoptotic rates were significantly associated with PIM-1, FOXO3a, BCL-2 and BAD expression levels (P<0.05). PIM-1 expression levels were significantly associated with tumor size, lymph node involvement, nerve invasion, distant metastasis and weakly associated with tumor node metastasis stage. Kaplan-Meier survival curves revealed that PIM-1 expression level was significantly associated with disease-free survival of patients with ACC (P=0.009). Cox regression multivariate analysis results revealed that histotype, distant metastasis and apoptotic rate were independent prognosis factors for ACC. Assessment of PIM-1 may be useful in investigating the malignant behaviors of ACC and predicting the outcome of patients with ACC. PMID- 29399172 TI - Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes. AB - The clinicopathological significance and prognostic value of the expression of proteins associated with autophagy, beclin 1 (BECN1), 1A/1B-light chain 3 (LC3) and high mobility group box-1 protein (HMGB-1), were investigated in patients with ovarian carcinoma, receiving combination chemotherapy with a platinum agent and a taxane. Immunohistochemical staining was performed for autophagy-associated proteins in tumor tissues from 141 patients with ovarian carcinoma. Clinical data were collected retrospectively by reviewing medical charts, and the association between protein expression, clinicopathological features and survival was investigated. Amongst 141 ovarian carcinoma samples, the loss of BECN1, LC3, and HMGB-1 expression was identified in 59 (41.8%), 35 (24.8%), and 66 (46.8%) samples, respectively. Clinicopathological factors were not significantly associated with the loss of BECN1 expression. However, significant associations were demonstrated between the expression of BECN1, LC3, and HMGB-1. In addition, loss of BECN1 expression demonstrated a significant association with poor progression-free and poor overall survival. Multivariate analysis demonstrated that loss of BECN1 expression and postoperative residual tumor were significant independent predictors of poor progression-free survival and poor overall survival. These results indicated that loss of BECN1 expression in ovarian carcinoma is a negative prognosticator in patients receiving platinum-based chemotherapy. Assessment of BECN1 expression may be useful for predicting an unfavorable response to platinum-based chemotherapy in ovarian carcinoma. PMID- 29399173 TI - Upregulation of microRNA-383 inhibits the proliferation, migration and invasion of colon cancer cells. AB - Increasing evidence demonstrates that microRNAs (miRNAs/miRs), a type of non coding small RNA, can regulate tumor cell migration, invasion and metastasis, and may therefore serve a major function in the occurrence and development of tumors. The present study investigated the effect of miR-383 on the proliferation, migration and invasion of colon cancer HT-29 and LoVo cell lines. The expression of miR-383 in colon cancer and adjacent non-tumor tissues was examined by reverse transcription-quantitative polymerase chain reaction. MiR-383 upregulation was stimulated by transfection with a miR-383 mimic. Cell proliferation was measured with MTT and colony formation assays, and cell migration and invasion potential were examined by Transwell chamber assays. A proliferating-inducing ligand (APRIL), myeloid cell leukemia-1 and cyclooxygenase-2 protein expression was analyzed by western blotting. The expression of miR-383 was decreased in colon cancer tissues compared with adjacent non-tumor tissues (P<0.05). Transfection with a miR-383 mimic suppressed proliferation and inhibited cell migration and invasion in HT-29 and LoVo colon cancer cell lines. Overexpression of miR-383 in HT-29 and LoVo cells resulted in the suppression of APRIL protein expression. In conclusion, miR-383 was downregulated in colon cancer. The upregulation of miR 383 inhibited proliferation, migration and invasion of colon cancer cells, potentially through the regulation of target gene APRIL. PMID- 29399174 TI - Prognoses of advanced esophago-gastric junction cancer may be modified by thoracotomy and splenectomy. AB - Globally, the incidence of esophago-gastric junction (EGJ) cancer is rapidly increasing. However, the proposed strategies for the treatment of these types of cancer are so diverse that there is no established consensus on the optimal treatment. The aim of the present study was to identify independent prognostic factors to delineate the optimal strategies for the treatment of EGJ cancer. The medical records of 150 patients with EGJ cancer who underwent curative surgery at the Kitasato University were retrospectively reviewed. The median follow-up period was 48 months. The patients with tumors that were classified as post treatment primary tumor stage 3 [(y)pT3] or higher had a 5-year disease-specific survival (DSS) rate of 53%, whereas those with tumors that were classified as (y)pT0-2 had a 5-year DSS rate of 90%. Therefore, prognostic analysis was restricted to those tumors that were designated (y)pT3 or higher. A multivariate Cox's proportional hazards model identified the following independent prognostic factors that negatively influenced the DSS: i) Presence of tumors classified as post-treatment regional lymph node stage 1-3 [(y)pN1-3] [hazard ratio (HR), 3.62; 95% confidence interval (CI), 1.39-12.36]; ii) not undergoing treatment with splenectomy (HR, 2.40; 95% CI, 1.15-5.15); and iii) undergoing treatment with thoracotomy (HR, 2.07; 95% CI, 1.02-4.23). In patients with (y)pN0 tumors, the DSS rate was significantly improved for those who underwent splenectomy than for those who did not (P=0.024). In patients with (y)pN1-3 tumors, the DSS rate was significantly worse for those who underwent thoracotomy compared with those who did not (P=0.004). Splenectomy and thoracotomy may critically affect prognosis in locally advanced EGJ cancer that are classified as (y)pN0 and (y)pN1-3, respectively. Surgical treatments require optimization in order to improve prognoses in advanced EGJ cancer. PMID- 29399175 TI - Effects of Wnt-1 blockade in DEN-induced hepatocellular adenomas of mice. AB - Recent evidence has suggested that downregulation of the Wnt/beta-catenin signaling pathway may contribute to the development and growth of HCC. Consequently, elements of this pathway have begun to emerge as potential targets for improving outcomes of anti-HCC. Thus, the present study sought to examine the effects of Wnt-1 blockade using the classical diethylnitrosamine (DEN)-induced chemical carcinogenesis mouse model of HCC. The depletion of Wnt-1 using neutralizing antisera was done for ten consecutive days at the age of 9 months and mice were examined for the following 20 days. At that time, DEN-treated mice had multiple variably-sized hepatic cell adenomas. Anti-Wnt-1 was particularly potent in suppressing the expression of critical elements of the Wnt/beta-catenin signaling pathway, such as beta-catenin and Frizzled-1 receptor, however, not Dickkopf-related protein 1. This effect co-existed with the suppression of Cyclin D1, FOXM1, NF-kappaBeta and c-Jun commensurate with proliferation and apoptosis blockade in hepatocellular adenomas, and reduced Bcl-2 and c-Met in the serum of mice. Nonetheless, tumor size and multiplicity were found to be unaffected, suggesting that apoptosis may be equally important to proliferation in the context of counteracting DEN induced hepatocellular adenomas of mice. PMID- 29399176 TI - Identification of candidate genes that may contribute to the metastasis of prostate cancer by bioinformatics analysis. AB - To screen for marker genes associated with to the metastasis of prostate cancer (PCa), in silico analysis of the Gene Expression Omnibus dataset GSE27616, which included 4 metastatic and 5 localized PCa tissue samples, was performed. Differentially expressed genes (DEGs) were identified. Their potential functions were identified by Gene Ontology and Kyoto Encyclopedia of Gene Genomes pathway enrichment analyses. Furthermore, protein-protein interaction (PPI) networks for DEGs were constructed using Cytoscape. Module analysis of the PPI networks was performed with Cluster ONE. A total of 561 DEGs were screened, including 208 upregulated and 353 downregulated genes. Proliferating cell nuclear antigen (PCNA) and cluster of differentiation 4 (CD4) exhibited the highest degrees of connectivity in the PPI networks for up- and down-regulated DEGs, respectively. The DEGs in module A, including CD58, 2, 4 and major histocompatibility complex, class II DP-beta1 were enriched in 'cell adhesion molecules'. Anaphase promoting complex subunit 4, cell division cycle 20 and cell division cycle 16 in module B were primarily enriched in 'cell cycle'. The DEGs, including CD4, PCNA and baculoviral IAP repeat containing 5, may have critical roles in PCa metastasis and could thus be used as novel biomarker candidates for metastatic PCa. However, further studies are required to verify these results. PMID- 29399177 TI - Overexpression of asparaginyl endopeptidase is significant for esophageal carcinoma metastasis and predicts poor patient prognosis. AB - Esophageal cancer is one of the most common types of cancer with poor prognosis. The molecular mechanisms of esophageal cancer progression remain unknown. In the present study, the aim was to investigate the clinical significance and biological function of protease asparaginyl endopeptidase (AEP) in esophageal cancer. The expression of AEP in esophageal cancer was examined, and its association with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanistic assays were performed to further investigate the underlying molecular mechanisms, and functions in esophageal cancer. The expression of AEP was elevated in esophageal cancer tissues, and patients with high AEP expression displayed a significantly shorter survival time compared with those with low AEP expression. In addition, loss of function experiments demonstrated that knockdown of AEP significantly reduced the migration and invasion ability of esophageal cancer cells. Furthermore, the pro oncogenic effects of AEP in esophageal cancer were mediated by the upregulation of matrix-metalloproteinase 2 and 3. Taken together, the data from the present study indicates that high AEP expression is associated with esophageal cancer progression and AEP is an indicator of poor prognosis in patients with esophageal cancer. AEP therefore, may be considered as a novel prognostic biomarker or potential therapeutic target in esophageal cancer. PMID- 29399178 TI - G-CSF producing oral carcinoma with diffuse uptake of FDG in the bone marrow: A case report. AB - A 78-year-old male patient was referred to the Department of Oral Surgery, Hokuto Hospital (Obihiro, Japan) for painless swelling on the left neck and tongue. Histopathological examination of a biopsy specimen resulted in a diagnosis of squamous cell carcinoma of the tongue. Imaging examinations revealed cervical lymph node metastases on both sides, along with diffuse uptake of 18F fluorodeoxyglucose (FDG) in the bone marrow of the spine and pelvis. Hematologic tests revealed an increased white blood cell (WBC) count and serum concentrations of granulocyte colony stimulating factor (G-CSF). These findings suggested a G CSF producing tumor, with fluctuations of WBC count, serum G-CSF concentration, and FDG uptake in the bone marrow, associated with tumor shrinkage and enlargement, an indicator of tumor status. PMID- 29399179 TI - Antitumor and immunostimulatory activities of a genotype V recombinant attenuated veterinary Newcastle disease virus vaccine. AB - Antitumor conventional treatments including chemo/radiotherapy result in several side effects and non-specificity. Therapies including the use of oncolytic viruses, particularly the Newcastle disease virus (NDV), have emerged as an attractive alternative due to their capacity to kill cancer cells directly or through stimulation of the immune system. In the present study, a commercial vaccine composed of a recombinant attenuated NDV strain P05 (rNDV-P05) was assessed for antitumor and immunostimulatory activity. Firstly, hemagglutination activity was evaluated at different pH and temperature conditions. Then, cancer cell lines and peripheral blood mononuclear cells (PBMC) were co-cultured with or without rNDV-P05 and cytoplasmic nucleosomes were measured by enzyme-linked immunosorbent assay (ELISA) as an apoptosis indicator. Antitumor cytokines produced by PBMC in response to the virus were analyzed by ELISA and reverse transcription quantitative polymerase chain reaction. Characterization of rNDV P05 indicates that the virus is slightly sensible to acid and basic pH, and stable at temperatures no greater than 42 degrees C. The majority of cell lines developed apoptosis in co-culture with rNDV-P05 in a dose-time dependent manner. The highest level of HeLa, HCC1954 and HepG2 cell apoptosis was at 48 h/50 hemagglutination units (HU), and HL-60 was 24 h/50 HU. A549 cell line and PBMC did not show sensitivity to apoptosis by the virus. PBMC from healthy donors stimulated with the rNDV-P05 increased significantly the levels of interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and soluble TNF-related apoptosis-inducing ligand in culture supernatants, as well as their mRNA expression. These results demonstrate that the pro-apoptotic effect of rNDV-P05 and its magnitude is specific to particular tumor cell lines and is not induced on PBMC; and the virus stimulates the expression of several key antitumor cytokines. This study promotes the use of rNDV-P05 in an alternate application of different viral strains during virotherapy with NDV. PMID- 29399180 TI - Characteristics of doxorubicin-selected multidrug-resistant human leukemia HL-60 cells with tolerance to arsenic trioxide and contribution of leukemia stem cells. AB - The present study selected and characterized a multidrug-resistant HL-60 human acute promyelocytic leukemia cell line, HL-60/RS, by exposure to stepwise incremental doses of doxorubicin. The drug-resistant HL-60/RS cells exhibited 85.68-fold resistance to doxorubicin and were cross-resistant to other chemotherapeutics, including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. The cells over-expressed the transporters P-glycoprotein, multidrug resistance-related protein 1 and breast-cancer-resistance protein, encoded by the adenosine triphosphate-binding cassette (ABC)B1, ABCC1 and ABCG2 genes, respectively. Unlike other recognized chemoresistant leukemia cell lines, HL 60/RS cells were also strongly cross-resistant to arsenic trioxide. The proportion of leukemia stem cells (LSCs) increased synchronously with increased of drug resistance in the doxorubicin-induced HL-60 cell population. The present study confirmed that doxorubicin-induced HL-60 cells exhibited multidrug resistance and high arsenic-trioxide resistance. Drug-resistance in these cells may be due to surviving chemoresistant LSCs in the HL-60 population, which have been subjected to long and consecutive selection by doxorubicin. PMID- 29399181 TI - Downregulation of miRNA-15a and miRNA-16 promote tumor proliferation in multiple myeloma by increasing CABIN1 expression. AB - Multiple myeloma (MM) is a malignant disorder characterized by the neoplastic growth of plasma cells in the bone marrow. MicroRNAs (miRNAs/miRs) modulate key regulatory cell pathways via their influence on target genes, and may serve a crucial function in tumorigenesis. Previous studies have indicated that the downregulation of miR-15a and miR-16 contributes to MM pathogenesis. However, the functional mechanisms of miR-15a and miR-16 in MM remain unclear. In the present study, potential target sites for miR-15a and miR-16 were identified on the calcineurin-binding protein 1 (CABIN1) mRNA sequence from analyses of previously published crosslinking, ligation and sequencing of hybrids data. Again-of function study was also performed, which determined that miR-15a/16 directly targeted CABIN1 mRNA and negatively regulated the expression of CABIN1 at the mRNA and protein level in MM cells. A cell proliferation assay demonstrated that the upregulation of miR-15a and miR-16 inhibited the proliferation of MM cells via targeting CABIN1. miR-15a and miR-16 were significantly decreased in MM specimens, compared with in normal specimens, whereas CABIN1 mRNA levels were significantly higher in MM samples compared with in normal samples. CABIN1 mRNA levels were negatively correlated with miR-15a and miR-16 expression levels in MM tissues, as determined using Pearson's correlation coefficient analysis. The results of the present study indicate that the downregulation of miR-15a and miR 16 promotes tumor proliferation in MM by increasing CABIN1 expression. The present study may aid elucidation of the functions of miR-15a and miR-16 and their function in MM carcinogenesis. PMID- 29399182 TI - Use of antigen-primed dendritic cells for inducing antitumor immune responses in vitro in patients with non-small cell lung cancer. AB - Cancer is associated with a reduction in immature and mature circulating dendritic cells (DCs), and with an impaired migratory capacity, compared with healthy donors. Therefore, modern approaches to the in vitro generation of DCs loaded with tumor antigens and their use for inducing antitumor immune responses in vivo are being investigated. The purpose of the present study was to investigate the phenotypic and functional characteristics of peripheral blood DC subsets in patients with non-small cell lung cancer (NSCLC), and the development of an antitumor cytotoxic response by mononuclear cells (MNCs) from patients using in vitro generated antigen-primed DCs. Heparinized peripheral venous blood samples were obtained from 10 healthy donors and 20 patients with a histologically verified diagnosis of NSCLC. The ability of antigen-activated DCs to stimulate the activity of MNCs against autologous tumor cells was evaluated using a cytotoxic test. Peripheral blood DC subsets from patients with NSCLC were identified to be decreased and to exhibit an impaired ability to mature, compared with healthy donors. Furthermore, DCs generated from MNCs from patients with NSCLC were able to stimulate a specific cytotoxic response when loaded with autologous tumor lysates or RNA and matured, in vitro. A perforin and granzyme B dependent mode of cytotoxicity was primarily induced. The ability of DCs loaded with tumor antigens to increase the cytotoxic activity of MNCs against NSCLC cells in vitro indicates the effective induction and co-stimulation of T lymphocytes by the generated DCs. PMID- 29399183 TI - MicroRNA-509-3p inhibits cell proliferation and invasion via downregulation of X linked inhibitor of apoptosis in glioma. AB - Malignant glioma is an aggressive type of cancer. Increasing evidence has suggested that microRNAs (miRs) regulate gene expression post-transcriptionally to affect cancer development and progression. Aberrant expression of miR-509-3p has been reported in cancer studies. However, the expression and mechanism of its function in glioma remains unclear. The present study demonstrated that miR-509 3p was downregulated in glioma tissue samples relative to non-tumor tissues, and that low miR-509-3p expression was associated with a reduced overall survival time. Functional studies revealed that the overexpression of miR-509-3p inhibited cell proliferation, induced apoptosis and suppressed cell migration and invasion via negatively regulating the expression of X-linked inhibitor of apoptosis. The data therefore suggested that miR-509-3p serves an important role in the development and progression of glioma, implicating its possible application in clinical practice as a biomarker and a potential novel therapeutic target. PMID- 29399184 TI - Influence of hypoxia-related genetic polymorphisms on the prognosis of patients with metastatic gastric cancer treated with EOF. AB - Tumor hypoxia is common in a number of solid tumor types including gastric cancer, and is associated with treatment resistance and poor prognosis. The present study aimed to investigate the function of hypoxia-associated genetic polymorphisms in predicting treatment response and survival in patients with metastatic gastric cancer (MGC) treated with EOF (oxaliplatin and 5-fluorouracil combined with epirubicin) as first-line chemotherapy. The present retrospective study enrolled 108 Chinese patients with MGC receiving EOF as first-line chemotherapy, and genotyped six single nucleotide polymorphisms (SNPs) in four hypoxia-associated genes [myoglobin (MB) rs7292 and rs7293, ATP Binding Cassette Subfamily G Member 2 rs2231142, MutL homolog 1 (MLH1) rs1800734 and rs9852810, and Poly(ADP-Ribose) Polymerase 1 rs1136410]. The results of the present study indicated that the CT/TT genotype of MB rs7292, as well as the GG genotype of MLH1 rs9852810, were independent favorable predictive factors of progression-free survival [PFS; MB rs7292: hazard ratio (HR)=0.135, 95% confidence interval (CI)=0.057-0.321, P<0.001; MLH1 rs9852810: HR=0.494, 95% CI=0.267-0.913, P=0.024). Using a prognostic index based on the favorable SNPs for PFS (MB rs7292 CT/TT genotype, and MLH1 rs9852810 GG genotype), patients were classified into a low-risk group (involving one or two of the two SNPs) and a high-risk group (involving neither of the two SNPs), with a PFS of 180.0 and 117.0 days, respectively (P=0.002). The results of the present study demonstrated that the CT/TT genotype of MB rs7292 and the GG genotype of MLH1 rs9852810 were independent favorable predictive factors of PFS in patients with MGC treated with EOF. Identification of those SNPs in blood samples may allow for the prediction of the short-term efficacy of first-line EOF treatment in patients with MGC. PMID- 29399185 TI - IL-8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells. AB - Interleukin-8 (IL-8) serves an important function in chronic inflammation and cancer development; however, the underlying molecular mechanism(s) of IL-8 in uterine cervical cancer remains unclear. The present study investigated whether IL-8 and its receptors [IL-8 receptor (IL-8R)A and IL-8RB] contributed to the proliferative and migratory abilities of HeLa cervical cancer cells, and also investigated the potential underlying molecular mechanisms. Results demonstrated that IL-8 and its receptors were detected in HeLa cells, and levels of IL-8RA were significantly increased compared with those of IL-8RB. Furthermore, the level of IL-8 in cervical cancer tissues was significantly increased compared with that in normal uterine cervical tissues, and migratory and proliferative efficiencies of HeLa cells treated with exogenous IL-8 were increased, compared with untreated HeLa cells. In addition, exogenous IL-8 was able to downregulate endocytic adaptor protein (NUMB), and upregulate IL-8RA, IL-8RB and extracellular signal-regulated protein kinases (ERKs) expression levels in HeLa cells. Results suggest that IL-8 and its receptors were associated with the tumorigenesis of uterine cervical cancer, and exogenous IL-8 promotes the carcinogenic potential of HeLa cells by increasing the expression levels of IL-8RA, IL-8RB and ERK, and decreasing the expression level of NUMB. PMID- 29399186 TI - Detachment from the primary site and suspension in ascites as the initial step in metabolic reprogramming and metastasis to the omentum in ovarian cancer. AB - Cancer cell metabolism is currently considered to be context dependent, and metabolic reprogramming is being widely investigated. It is known that ovarian cancer often metastasizes to the omentum. Given that the omentum itself contains a high concentration of adipocytes, ovarian cancer is thought to be a good model for research into metabolic reprogramming (particularly the shift to lipid metabolism). The present study investigated the switch to lipid metabolism in the metabolic reprogramming of ovarian cancer cells. The present study first considered the possibility of epigenetic involvement. Using an open database (GSE 85293 and GSE2109), the methylation status and gene expression patterns of the primary tumor site (ovary) and the metastatic tumor site (omentum) were compared. However, no evidence was obtained regarding the involvement of epigenetics (at least in terms of DNA methylation). The influence of suspension in ascites on metabolism was then considered, and a suspension culture was used as an in vitro model. It was demonstrated that ovarian cancer cells that are detached from the primary site and suspended in ascites have enhanced lipid metabolism. Additionally, it was demonstrated that these cells express high levels of the cancer stem cell (CSC) marker cluster of differentiation 44 and c-kit in a balanced manner as they approach the omentum. Accordingly, these cells activate the mammalian target of rapamycin pathway, which is thought to be advantageous for cancer cell metastasis. In conclusion, the present study proposed one explanation for why ovarian cancer cells are likely to disseminate to the peritoneal cavity, and in particular to the omentum. PMID- 29399187 TI - Oridonin inhibits migration, invasion, adhesion and TGF-beta1-induced epithelial mesenchymal transition of melanoma cells by inhibiting the activity of PI3K/Akt/GSK-3beta signaling pathway. AB - Epithelial-mesenchymal transition (EMT) has been reported to play pivotal roles in tumor invasion and metastasis. Inhibition of EMT may exert beneficial effects in regulating metastasis. Oridonin (ORI), an active diterpenoid compound isolated from Rabdosia rubescens, was found to be a potent anti-metastatic agent. However, the possible involvement of ORI in the EMT in malignant melanoma is unclear. The present study found that ORI inhibited cell migration, invasion, and adhesion in A375 and B16-F10 melanoma cells. The transforming growth factor-beta1 (TGF-beta1) induced EMT was also inhibited in ORI-treated cells, as reflected in the upregulation of E-cadherin, and downregulation of vimentin and Snail. Similar results were observed in A375 and B16-F10 melanoma cells treated with ORI. Furthermore, pre-treatment with ORI blocked the TGF-beta1-induced phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (Akt)/glycogen synthase kinase (GSK)-3beta signaling pathway activation. These effects mimicked PI3 kinase inhibitor LY294002 treatment. ORI interfered with the PI3K/Akt/GSK 3beta pathway, and reversed TGF-beta1-induced EMT, which suppressed the invasion and metastasis of melanoma cells. Taken together, the present study demonstrated that ORI inhibits melanoma cells migration, invasion, and adhesion and TGF-beta1 induced EMT through the PI3K/Akt/GSK-3beta signaling pathway. These findings suggest that ORI is a promising anti-metastasis agent for melanoma. PMID- 29399188 TI - The role of cadherin-11 in microcystin-LR-induced migration and invasion in colorectal carcinoma cells. AB - The present study aimed to explore whether microcystin-LR (MC-LR; a well-known cyanobacterial toxin produced in eutrophic lakes or reservoirs) induced tumor progression by activating cadherin-11(CDH11). A previous tumor metastasis PCR array demonstrated that MC-LR exposure resulted in a significant increase in the expression of CDH11. In the present study, to confirm the effect of the MC-LR treatment on CDH11 expression, HT-29 cell migration and invasion following MC-LR treatment were tested by Transwell assays, and protein levels of CDH11 were tested by immunofluorescence and western blot analysis. The results demonstrated that MC-LR activated CDH11 expression in addition to cell migration and invasion in HT-29 cells. To further investigate the association between MC-LR-induced CDH11 upregulation, and higher motility and invasiveness in HT-29 cells, knockdown of CDH11 using small interfering RNA (siRNA) in HT-29 cells was performed. Subsequent Transwell assays confirmed that MC-LR-induced enhancement of migration and invasion was significantly decreased following CDH11 knockdown by CDH11-siRNA in HT-29 cells. The results from the present study indicate that MC-LR may act as a CDH11 activator to promote HT-29 cell migration and invasion. PMID- 29399189 TI - MicroRNA-26b suppresses autophagy in breast cancer cells by targeting DRAM1 mRNA, and is downregulated by irradiation. AB - MicroRNAs (miRs) are small RNAs that do not code for proteins, but instead decrease the stability and suppress the translation of target mRNAs by binding with complementary sequences in their 3'-untranslated regions (3'-UTRs). In the present study, it is reported that breast cancer tumor tissue, as well as irradiated MCF7 breast cancer cells, exhibit decreased levels of miR-26b expression compared with normal breast tissue and MCF7 cells without exposure to radiation. Additionally, a luciferase reporter assay was used to demonstrate that miR-26b directly targetsDNA damage-regulated autophagy modulator 1 (DRAM1). MCF7 cells that were transfected with an miR-26b mimicexhibited the downregulated expression of DRAM1 protein and a reduced level of irradiation-induced autophagy. Inhibiting miR-26b resulted in the upregulation of DRAM1 and increased levels of irradiation-induced autophagy in MCF7 cells. These results suggest that therapeutic strategies to target miR-26b may increase the efficacy of certain types of cancer therapy. PMID- 29399191 TI - Effects of flurbiprofen on serum level of interleukin-6, prostacyclin and corticosteroid A2 in patients with bone metastases of cancer. AB - The present study aimed to investigate the effects of flurbiprofen on serum level of interleukin-6 (IL-6), prostacyclin (PGI2) and corticosteroid A2 (TXA2) in patients with bone metastases of cancer. A total of 210 patients with bone metastasis of cancer were randomly divided into two groups: Flurbiprofen axetil analgesia group (group A) and dezocine analgesia group (group B), 105 cases in each group. The analgesic effect was evaluated using visual analogue scale (VAS) scoring system at 1, 12, 24 and 48 h after treatment. Serum levels of IL-6, PGI2 and TXA2 at 12 and 24 h after treatment were detected using double-antibody sandwich enzyme-linked immunosorbent assay. No significant differences in VAS scores were found between the two groups at 1, 12, 24 and 48 h after treatment, and no gastrointestinal adverse events and abnormal bleeding were observed. No significant differences in the serum levels of IL-6 were found between the two groups at 12 and 24 h after treatment. Significantly lower serum levels of TXA2 and PGI2 were found in group A compared to group B at 12 and 24 h after treatment (P<0.05). Serum level of PGI2 was positively correlated with serum level of TXA2 (r=0.7212, P<0.05) and VAS score (r=0.7159, P<0.05). Serum level of IL-6 was positively correlated with VAS score (r=0.7997, P<0.05). The results show that flurbiprofen axetil can effectively relieve pain in patients with bone metastases of cancer, can inhibit platelet activation, adhesion and aggregation, and reduce the formation of deep vein thrombosis, and can inhibit stress response and inflammatory response in the body. PMID- 29399190 TI - Utility of bronchial lavage fluids for epithelial growth factor receptor mutation assay in lung cancer patients: Comparison between cell pellets, cell blocks and matching tissue specimens. AB - The detection of epidermal growth factor receptor (EGFR) mutations is necessary for the selection of suitable patients with non-small cell lung cancer (NSCLC) for treatment with EGFR tyrosine kinase inhibitors. Cytology specimens are known to be suitable for EGFR mutation detection, although tissue specimens should be prioritized; however, there are limited studies that examine the utility of bronchial lavage fluid (BLF) in mutation detection. The purpose of the present study was to investigate the utility of BLF specimens for the detection of EGFR mutations using a conventional quantitative EGFR polymerase chain reaction (PCR) assay. Initially, quantification cycle (Cq) values of cell pellets, cell-free supernatants and cell blocks obtained from three series of 1% EGFR mutation positive lung cancer cell line samples were compared for mutation detection. In addition, PCR analysis of BLF specimens obtained from 77 consecutive NSCLC patients, detecting EGFR mutations was validated, and these results were compared with those for the corresponding formalin-fixed paraffin-embedded (FFPE) tissue specimens obtained by surgical resection or biopsy of 49 of these patients. The Cq values for mutation detection were significantly lower in the cell pellet group (average, 29.58) compared with the other groups, followed by those in cell free supernatants (average, 34.15) and in cell blocks (average, 37.12) for all three series (P<0.05). Mutational status was successfully analyzed in 77 BLF specimens, and the results obtained were concordant with those of the 49 matching FFPE tissue specimens. Notably, EGFR mutations were even detected in 10 cytological specimens that contained insufficient tumor cells. EGFR mutation testing with BLF specimens is therefore a useful and reliable method, particularly when sufficient cancer cells are not obtained. PMID- 29399192 TI - Comparison of the expression of TGF-beta1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1alpha in oral squamous cell carcinoma and lymph node metastases of humans and mice. AB - The aim of the present study was to prove that a mouse model closely simulates human oral cancer progression by comparing the expression levels of transforming growth factor (TGF)-beta1, E-cadherin, N-cadherin, tumor protein (TP)53, RB1 inducible coiled-coil (RB1CC)1 and hypoxia inducible factor (HIF)-1alpha at different stages of oral squamous cell carcinoma (OSCC) in humans and mice. The expression levels of TGF-beta1, E-cadherin, N-cadherin, TP53, RB1CC1, and HIF 1alpha were detected by immunohistochemical staining in normal oral mucosa, oral mucosa dysplasia, OSCC primary tumor and carcinoma tissues from lymph node metastases. Tissue samples were obtained from human specimens and the Balb/c mouse model of lymphatic metastases oral carcinoma, induced by 4-nitroquinoline-1 oxide in drinking water. The results indicated no significant differences in the expression levels of TGF-beta1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF 1alpha between humans and mice, at any stage of OSCC examined (P>0.05). The expression of TGF-beta1, N-cadherin, TP53 and RB1CC1 increased in different stages of OSCC in both humans and mice. The expression of E-cadherin decreased from normal oral mucosa to OSCC, and increased in lymph node metastases in both human and mouse samples. The expression of HIF-1alpha increased from normal oral mucosa to OSCC, and decreased in lymph node metastases in both human and mouse samples. Additionally, the expression of p53 was positively correlated with that of RB1CC1 in human and mouse samples (r=0.971, P=0.029; r=0.97, P=0.03). Overall, the similar expression of multiple molecules in both human and mouse carcinoma prove that the mouse model of lymphatic metastases from oral carcinoma established in the present study may closely mimic human oral cancer. PMID- 29399193 TI - Pre-treatment neutrophil-to-lymphocyte ratio predicts survival in patients with laryngeal cancer. AB - An increased neutrophil-to-lymphocyte ratio (NLR) is associated with poorer prognostic outcomes in numerous types of cancer. However, a small number of studies have demonstrated the prognostic role of NLR in patients with laryngeal cancer. The present study evaluated the association between NLR and survival outcomes in patients with laryngeal squamous cancer. All patients were scheduled for follow-up visits. The levels of cytokines from tumor tissues were analyzed by ELISA. A classification and regression tree (CART) was used to determine the optimal cutoff values of NLR. The clinical features and NLR were determined using Kaplan-Meier analysis and Cox regression to analyze the survival outcomes and associated risks. Of the total 654 patients, 70 patients (70/654; 10.7%) failed to receive follow-up. Blood and biochemical parameters, including NLR, platelet to-lymphocyte ratio and albumin-to-globulin ratio were associated with clinical characteristics of the patients, with the exception of histologic grade. Only one node with NLR at 3.18 divided patients into different categories, according to CART analysis. Survival analysis demonstrated that NLR at cutoff values subdivided patients into different survival outcomes (P<0.001). Subsequent to adjustments for age and other clinical features, NLR was identified to be an independent prognostic factor for overall survival and progression-free survival (P<0.05). Increased levels of cytokines, including IL-6 and IL-8, in tumor tissues were associated with NLR values. In summary, pre-treatment NLR was associated with the prognostic outcomes for patients with laryngeal cancer, and may assist to establish prognostic factors for these patients. PMID- 29399194 TI - Characterization of the T-cell receptor repertoire by deep T cell receptor sequencing in tissues from patients with prostate cancer. AB - Prostate cancer (PC) is the most prevalent urological cancer in men. T cells serve a central role in the cancer's immunological microenvironment. In the present study, we applied multiplex PCR and Illumina next-generation sequencing to study the clonal diversity of the T-cell receptor (TCR) repertoire in cancer tissues and paracancer tissues from patients with PC. It was found that the TCR repertoire in the PC samples had a notably more skewed clonotype composition, with a greater number of highly expanded clones (HECs) compared with the prostate paracancer samples. The amino acid sequences ATSRVAGETQY (1.008 vs. 0.002%), ATSRTGRWETQY (3.985 vs. 0.007%), ATSDSSDYEQY (12.464 vs. 0.027%), ATSDFRGQPQETQY (2.205 vs. 0.06%), ASSQQDEAF (1.109 vs. 0.002%) and ARPTRTEETQY (1.263 vs. 0.002%) were found to vary markedly between cancer and paracancer tissues, respectively. In conclusion, the present study identified PC-specific HECs, which are critical to improving understanding of the TCR repertoire in PC. This may accelerate the screening process for potential new autoantigens and provide information for generating more effective T cell-targeted diagnostic and therapeutic strategies. PMID- 29399195 TI - Piperlongumine inhibits cancer stem cell properties and regulates multiple malignant phenotypes in oral cancer. AB - Piperlongumine (PL), a natural product of Piper longum, inhibits multiple malignant phenotypes. Therefore, the present study examined whether PL suppresses cancer stemness in oral cancer. The cellular effects of PL were determined by examining alterations in tumor sphere formation, cell migration, invasion, proliferation ability, chemosensitivity and radiosensitivity. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting were performed in order to determine molecular expression levels. The present study revealed that PL inhibited cancer stem cell-forming ability and suppressed the expression of the stemness-related transcription factors SRY-Box 2, POU class 5 homeobox 1, and Nanog homeobox. However, it increased the expression of the differentiation marker cytokeratin 18. PL also suppressed cell migration and invasion, resulting in the elimination of the epithelial mesenchymal transition. Furthermore, PL increased chemo- and radiosensitivity and suppressed tumor growth in vitro and in vivo. The results of the present study suggested that PL inhibits malignant phenotypes via the suppression of cancer stemness in oral cancer. Thus, PL may serve as an effective therapeutic agent for oral cancer. PMID- 29399196 TI - Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT-rich interactive domain 1A in endometrial cancer. AB - Mutations in the gene encoding AT-rich interactive domain 1A (ARID1A) are frequently observed in endometrial cancer (EC) but the molecular mechanisms linking the genetic changes remain to be fully understood. The present study aimed to elucidate the influence of ARID1A mutations on signaling pathways. Missense, synonymous and nonsense heterozygous ARID1A mutations in the EC HEC-1-A cell line were verified by Sanger sequencing. Mutated ARID1A small interfering RNA was transfected into HEC-1-A cells. Biochemical microarray analysis revealed 13 upregulated pathways, 17 downregulated pathways, 14 significantly affected disease states and functions, 662 upstream and 512 downstream genes in mutated ARID1A-depleted HEC-1-A cells, among which the mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin-like growth factor-1 (IGF1) signaling pathways were the 2 most downregulated pathways. Furthermore, the forkhead box protein O1 pathway was upregulated, while the IGF1 receptor, insulin receptor substrate 1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit b pathways were downregulated. Carcinoma tumorigenesis, tumor cell mitosis and tumor cell death were significantly upregulated disease states and functions, while cell proliferation and tumor growth were significantly downregulated. The results of the present study suggested that ARID1A may be a potential prognostic and therapeutic molecular drug target for the prevention of EC progression. PMID- 29399197 TI - Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells. AB - Previous studies have demonstrated that Licochalcone A possesses anti inflammatory, anticancer, anti-bacterial, anti-malarial and anti-parasitic activities. In the present study the potential anticancer effects of Licochalcone A on MCF-7 cells were investigated. Licochalcone A significantly decreased cell viability and promoted autophagy and apoptosis, as demonstrated by an MTT assay, acridine orange staining and Annexin V-fluorescein isothiocyanate staining, respectively. Western blot analyses demonstrated that Licochalcone A treatment activated the LC3-II signaling pathway while suppressing the phosphoinositide 3 kinase (PI3K)/RAC-alpha serine-threonine-protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. In addition, Licochalcone A significantly increased caspase-3 activity and significantly decreased B-cell lymphoma-2 expression. The results from the present study indicate that Licochalcone A inhibits PI3K/Akt/mTOR activation, and promotes autophagy and apoptosis in MCF-7 cells. PMID- 29399198 TI - Combined small cell carcinoma with giant cell carcinoma component of the lung: A case successfully diagnosed by computed tomography-guided fine-needle aspiration cytology. AB - Combined small cell lung carcinoma (SCLC) is a rare variant of SCLC and is defined as a mixture of SCLC and non-SCLC components. Although any histopathological subtype may be present as a non-SCLC component, the presence of pleomorphic carcinoma components are extremely rare. The present report describes the first documented cytological features of combined SCLC with a giant cell carcinoma component. A 50-year-old Japanese female with a history of smoking presented with a mass lesion in the left lung. Computed tomography-guided fine needle aspiration cytology and needle biopsy were performed, followed by a lobectomy. A Papanicolaou smear revealed the presence of two distinct neoplastic components in a necrotic background. One component was SCLC, which comprised small-sized neoplastic cells containing scant cytoplasm and round to oval nuclei with dispersed granular chromatin without nucleoli. The other component was giant cell carcinoma, which was composed of large-sized neoplastic cells containing irregular large hyperchromatic nuclei (approximately 7 to 10 times larger than those of SCLC). SCLC was demonstrated in the biopsy specimen, however no giant cell carcinoma component was present. Histopathological study of the lobectomy specimen verified a diagnosis of combined SCLC with giant cell carcinoma component. Both SCLC and giant cell carcinoma exhibit characteristic cytological features, therefore, albeit extremely rare, careful observation may lead to a correct diagnosis of combined SCLC in the cytological specimen. PMID- 29399199 TI - Cytotoxic action of methylquercetins in human lung adenocarcinoma cells. AB - Lung cancer is the malignant disorder associated with a high number of fatalities in women and men worldwide. Despite continuous improvements in diagnostic strategies and therapeutic modalities over the past decades, the prognosis and survival rate of patients suffering from lung cancer are still unsatisfactory and suggest the requirement for further molecular studies with different lung cancer models. In the present study, the anticancer action of two methylated metabolites of quercetin, isorhamnetin and tamarixetin, was assessed by studying their antiproliferative and apoptosis-inducing potential in human lung adenocarcinoma cell lines, A549 and HCC-44. Both methylquercetins decreased the viability of lung cancer cells at doses significantly lower than those effective for parent quercetin. The IC50 values measured for isorhamnetin were 26.6 and 15.9 uM in A549 and HCC-44 cells, respectively. For tamarixetin, the IC50 values were 19.6 and 20.3 uM in A549 and HCC-44 cells, respectively. These results were many-fold lower than the respective values for quercetin (72.2 and 107.6 uM for A549 and HCC-44 cells, respectively). Based on the activation of caspase family members, both metabolites induced apoptotic cell death in the tested cell lines, predominantly via the extrinsic pathway in A549 cells and in both intrinsic and extrinsic pathways in HCC-44 cells. As A549 and HCC-44 lines were originally established from a male and female patient, current data may suggst some gender differences in the action of quercetin derivatives. Addition of a methyl group in the 3'- or 4'-position of the B-ring of quercetin significantly increased the anticancer activity of this flavonol towards lung adenocarcinoma cells, which demonstrated that these compounds may be considered as potential novel candidates for the development of future chemotherapeutics in the fight against lung cancer. PMID- 29399200 TI - Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin. AB - Atorvastatin (ATST), a drug commonly used to reduce the levels of cholesterol and low-density lipoproteins, is a prospective agent for the prevention of colorectal cancer in patients with hyperlipidemia. ATST in combination with functional components is a promising strategy for cancer chemoprevention. In the present study, the growth inhibitory effect of ATST combined with phloretin (PT) on SW620 and HCT116 colon cancer cells was investigated. The results of MTT assays indicated that the combination of PT and ATST markedly reduced cell survival in both cell lines compared with PT or ATST treatment administered individually. The interaction indexes between PT and ATST, which were used to analyze their interaction pattern, were computed by the median-effect equation. The interaction indexes of each PT and ATST concentration pair were <1.0, which indicated a strong synergistic effect between the two compounds. The data obtained by flow cytometry and western blot analysis of cleaved-poly (ADP-ribose) polymerase indicated a synergistic effect resulted in apoptosis and cell cycle arrest at the G2/M checkpoint. Furthermore, combined treatment with PT and ATST markedly downregulated the expression of cyclin B and upregulated the expression of phospho-cdc2 and Myt1, which suggested that the activation of cdc2 was downregulated. This combined treatment strategy enhanced the anti-cancer activity of ATST at a relatively low dosage and suggested a possible method of preventing colorectal cancer in patients with hyperlipidemia. PMID- 29399201 TI - Role of prolactin/adenoma maximum diameter and prolactin/adenoma volume in the differential diagnosis of prolactinomas and other types of pituitary adenomas. AB - The present study aimed to investigate the function of the prolactin/adenoma maximum diameter (PRL/MD) and the prolactin/adenoma volume (PRL/V) in the differential diagnosis of prolactinomas and other types of pituitary adenomas. A total of 118 patients with pituitary adenoma, hyperprolactinemia and a plasma PRL <250 ug/l were enrolled. Clinical data from these patients were retrospectively analyzed. A receiver operating characteristic curve was plotted. The function of PRL, PRL/MD and PRL/V in the differential diagnosis of prolactinomas and other types of pituitary adenomas was compared. The results revealed that a PRL of 55.65 ug/l was the most accurate [sensitivity (SE), 0.800; specificity (SP), 0.716; positive predictive value (PPV), 0.857; negative predictive value (NPV), 0.933; and Youden index (YI), 0.516]. The PRL/MD with the highest diagnostic value was 4.03 ug/(l * mm) (SE, 0.800; SP, 0.898; PPV, 0.727; NVP, 0.929; and YI, 0.698). The PRL/V with the highest diagnostic value was 54.00 ug/(l * cm3) (SE, 0.900; SP, 0.966; PPV, 0.900; NVP, 0.966; and YI, 0.866). The PRL/MD tended to be of higher diagnostic accuracy than PRL, but this difference was not statistically significant (P=0.097). The differentiation ability of PRL/V was significantly stronger than that of PRL (P=0.028). Thus, serum PRL, PRL/MD and PRL/V levels may be able to differentiate prolactinomas from other types of hyperprolactinemia causing pituitary adenomas prior to treatment. PRL/V may be better than the PRL level in achieving a differential diagnosis, and the optimal PRL/V ratio for differentiating prolactinomas from other types of hyperprolactinemia-causing pituitary adenomas was 54.00 ug/(l * cm3). PMID- 29399203 TI - 3D Characterization of corneal deformation using ultrasound speckle tracking. AB - The three-dimensional (3D) mechanical response of the cornea to intraocular pressure (IOP) elevation has not been previously reported. In this study, we use an ultrasound speckle tracking technique to measure the 3D displacements and strains within the central 5.5 mm of porcine corneas during the whole globe inflation. Inflation tests were performed on dextran-treated corneas (treated with a 10% dextran solution) and untreated corneas. The dextran-treated corneas showed an inflation response expected of a thin spherical shell, with through thickness thinning and in-plane stretch, although the strain magnitudes exhibited a heterogeneous spatial distribution from the central to more peripheral cornea. The untreated eyes demonstrated a response consistent with swelling during experimentation, with through-thickness expansion overriding the inflation response. The average volume ratios obtained in both groups was near 1 confirming general incompressibility, but local regions of volume loss or expansion were observed. These results suggest that biomechanical measurements in 3D provide important new insight to understand the mechanical response of ocular tissues such as the cornea. PMID- 29399202 TI - Characterization of cluster of differentiation 47 expression and its potential as a therapeutic target in esophageal squamous cell cancer. AB - The increased expression of cluster of differentiation (CD)47 has been identified in a number of different tumor types and is recognized as an adverse prognostic factor that indicates an increased risk of mortality in patients. The binding of CD47 to signal regulatory protein alpha (SIRPalpha) inhibits the macrophage phagocytosis of tumor cells by triggering an inhibitory 'do not eat me' signal. This is one of the mechanisms used by tumor cells to evade immune surveillance. In the present study, CD47 levels and macrophage infiltration were assessed in patients with esophageal squamous cell cancer (ESCC). CD47-overexpressing ESCC cell lines were selected and human M2 macrophage phagocytic activity was measured. The results revealed that CD47 is highly expressed and macrophages are markedly infiltrated in cancerous tissue compared with non-cancerous tissue. High CD47 expression was detected in ESCC cell lines and the results of a phagocytosis assay indicated that human M2 macrophages phagocytized tumor cells in a dose dependent manner following the blocking of CD47-SIRPalpha signaling by anti-CD47 antibodies. The results of the present study therefore support the use of anti CD47 immunotherapy to treat patients with ESCC. PMID- 29399204 TI - Thrombi produced in stagnation point flows have a core-shell structure. AB - Introduction: In regions of flow separation/reattachment within diseased arteries, the local hemodynamics can result in stagnation point flow that provides an atypical environment in atherosclerosis. Impinging flows occur with recirculation eddies distal of coronary stenosis or diseased carotid bifurcations. Methods: By perfusing whole blood directly perpendicular to a fibrillar collagen thrombotic surface, a microfluidic device produced a stagnation point flow. Side view visualization of thrombosis in this assay allowed for observation of clot structure and composition at various flow rates and blood biochemistry conditions. Results: For clotting over collagen/tissue factor surfaces, platelet thrombi formed in this device displayed a core-shell architecture with a fibrin-rich, platelet P-selectin-positive core and an outer platelet P-selectin-negative shell. VWF was detected in clots at low and high shear, but when N-acetylcysteine was added to the whole blood, both platelet and VWF deposition were markedly decreased at either low or high flow. To further examine the source of clot stability, 1 mM GPRP was added to prevent fibrin formation while allowing the PAR1/4-cleaving activity of thrombin to progress. The inhibition of fibrin polymerization did not change the overall structure of the clots, demonstrating the stability of these clots without fibrin. Conclusion: Impinging flow microfluidics generate thrombi with a core-shell structure. PMID- 29399205 TI - A LASSO Method to Identify Protein Signature Predicting Post-transplant Renal Graft Survival. AB - Identifying novel biomarkers to predict renal graft survival is important in post transplant clinical practice. Serum creatinine, currently the most popular surrogate biomarker, offers limited information of the underlying allograft profiles. It is known to perform unsatisfactorily to predict renal function. In this paper, we apply a LASSO machine-learning algorithm in the Cox proportional hazards model to identify promising proteins that are associated with the hazard of allograft loss after renal transplantation, motivated by a clinical pilot study that collected 47 patients receiving renal transplants at the University of Michigan Hospital. We assess the association of 17 proteins previously identified by Cibrik et al. [5] with allograft rejection in our regularized Cox regression analysis, where the LASSO variable selection method is applied to select important proteins that predict the hazard of allograft loss. We also develop a post-selection inference to further investigate the statistical significance of the proteins on the hazard of allograft loss, and conclude that two proteins KIM 1 and VEGF-R2 are important protein markers for risk prediction. PMID- 29399206 TI - Joint Modeling of Repeated Measures and Competing Failure Events In a Study of Chronic Kidney Disease. AB - We are motivated by the Chronic Renal Insufficiency Cohort (CRIC) study to identify risk factors for renal progression in patients with chronic kidney diseases. The CRIC study collects two types of renal outcomes: glomerular filtration rate (GFR) estimated annually and end stage renal disease (ESRD). A related outcome of interest is death which is a competing event for ESRD. A joint modeling approach is proposed to model a longitudinal outcome and two competing survival outcomes. We assume multivariate normality on the joint distribution of the longitudinal and survival outcomes. Specifically, a mixed effects model is fit on the longitudinal outcome and a linear model is fit on each survival outcome. The three models are linked together by having the random terms of the mixed effects model as covariates in the survival models. EM algorithm is used to estimate the model parameters and the non-parametric bootstrap is used for variance estimation. A simulation study is designed to compare the proposed method with an approach that models the outcomes sequentially in two steps. We fit the proposed model to the CRIC data and show that the protein-to-creatinine ratio is strongly predictive of both estimated GFR and ESRD but not death. PMID- 29399208 TI - Facile Synthesis of a Novel Hierarchical ZSM-5 Zeolite: A Stable Acid Catalyst for Dehydrating Glycerol to Acrolein. AB - Catalytic biomass conversion is often hindered by coking. Carbon compounds cover active surface and plug pores, causing catalyst deactivation. Material design at the nanoscale allows tailoring of the catalytic activity and stability. Here, we report a simple synthesis of nanosized ZSM-5 materials by using a silicalite-1 seeding suspension. ZSM-5 crystals were grown from a deionized silica source in the presence of ammonia. By using silicalite-1 seeds, crystalline ZSM-5 is synthesized without any structure-directing agent. This method allows parallel preparation of a range of ZSM-5 samples, eliminating time-consuming ion-exchange steps. Mesoporosity is introduced by formation of intercrystallite voids, owing to nanocrystal agglomeration. The effects of crystal sizes and morphologies are then evaluated in the catalytic dehydration of glycerol to acrolein, with results compared against commercial ZSM-5. The most active nanosized ZSM-5 catalysts were five times more stable compared with commercial ZSM-5, giving quantitative conversion and twice the acrolein yield compared with the commercial catalyst. The influence of the catalyst structure on the chemical diffusion and the resistance to coking are discussed. PMID- 29399207 TI - Mechanism of Carbon Monoxide Dissociation on a Cobalt Fischer-Tropsch Catalyst. AB - The way in which the triple bond in CO dissociates, a key reaction step in the Fischer-Tropsch (FT) reaction, is a subject of intense debate. Direct CO dissociation on a Co catalyst was probed by 12C16O/13C18O scrambling in the absence and presence of H2. The initial scrambling rate without H2 was significantly higher than the rate of CO consumption under CO hydrogenation conditions, which indicated that the surface contained sites sufficiently reactive to dissociate CO without the assistance of H atoms. Only a small fraction of the surface was involved in CO scrambling. The minor influence of CO scrambling and CO residence time on the partial pressure of H2 showed that CO dissociation was not affected by the presence of H2. The positive H2 reaction order was correlated to the fact that the hydrogenation of adsorbed C and O atoms was slower than CO dissociation. Temperature-programmed in situ IR spectroscopy underpinned the conclusion that CO dissociation does not require H atoms. PMID- 29399209 TI - Automated Determination of Oxygen-Dependent Enzyme Kinetics in a Tube-in-Tube Flow Reactor. AB - Enzyme-mediated oxidation is of particular interest to synthetic organic chemists. However, the implementation of such systems demands knowledge of enzyme kinetics. Conventionally collecting kinetic data for biocatalytic oxidations is fraught with difficulties such as low oxygen solubility in water and limited oxygen supply. Here, we present a novel method for the collection of such kinetic data using a pressurized tube-in-tube reactor, operated in the low-dispersed flow regime to generate time-series data, with minimal material consumption. Experimental development and validation of the instrument revealed not only the high degree of accuracy of the kinetic data obtained, but also the necessity of making measurements in this way to enable the accurate evaluation of high KMO enzyme systems. For the first time, this paves the way to integrate kinetic data into the protein engineering cycle. PMID- 29399210 TI - The Impact of Mindfulness and Perspective-Taking on Implicit Associations Toward the Elderly: a Relational Frame Theory Account. AB - Perspective-taking interventions have been shown to improve attitudes toward social outgroups. In contrast, similar interventions have produced opposite effects (i.e., enhanced negativity) in the context of attitudes toward elderly groups. The current study investigated whether a brief perspective-taking intervention enhanced with mindfulness would be associated with less negativity than perspective-taking alone. One hundred five participants were randomly assigned to 1 of 4 conditions which comprised of an active or control perspective taking component and an active or control mindfulness component. Participants were then administered an Implicit Associated Test to assess implicit biases toward the elderly. Results supported previous findings in that the condition in which perspective-taking was active but mindfulness was inactive was associated with greater negative implicit bias toward the elderly; however, some of this negativity decreased in the active perspective-taking and active mindfulness condition. The current findings and other mixed effects that have emerged from perspective-taking interventions are discussed from a Relational Frame Theory perspective. PMID- 29399211 TI - Intra Nasal In situ Gelling System of Lamotrigine Using Ion Activated Mucoadhesive Polymer. AB - Background: A novel drug delivery system for treating acute epileptic condition. Objective: To develop an intranasal mucoadhesive formulation of Lamotrigine (LTG) loaded insitu gel, for the treatment of epilepsy to avoid possible side effects and first pass metabolism associated with conventional treatment. Methods: Lamotrigine was loaded into different polymeric solutions of gellan and xanthan gum. Results: All formulations subjected to various evaluation studies were within their acceptable limits. The pH of formulation ranges between 5.8 +/-.001 to 6.8 +/-.005 indicating that no mucosal irritation is expected as pH was in acceptable range. Invitro drug release from the mucoadhesive insitu gel formulations showed immediate drug release pattern with a maximum drug release of 97.02 +/-0.54% for optimized G5 formulation within 20min. Exvivo permeation studies of optimized formulation G5 and control formulation was estimated. Exvivo permeation studies of G5 insitu formulation done for a period of 12 h resulted in slow, sustained release and greater permeability significance(P <0.05) through nasal mucosa when compared to control. Histopathological studies showed that G5 formulation was safer for nasal administration without any irritation. The stability studies indicated that gels were stable over 45 days in refrigerated condition (4+/-2oC). Conclusion: The intranasal insitu gelling system is a promising novel drug delivery system for an antiepileptic drug lamotrigine which could enhance nasal residence time with increased viscosity and mucoadhesive character and provided better release profile of drug for treating acute epileptic conditions. PMID- 29399212 TI - Insulin Sensitivity and Insulin Resistance in Non-Diabetic Middle-Aged Patients with Obstructive Sleep Apnoea Syndrome. AB - Background: Obstructive sleep apnoea syndrome (OSAS) has been linked with abnormal glucose metabolism, insulin resistance (IR) and development of diabetes mellitus. Methods: Non-diabetic patients (n=69) with OSAS, diagnosed by polysomnography, were prospectively recruited. To evaluate IR among OSAS patients, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Insulin sensitivity by Quantitative Insulin sensitivity Check Index (QUICKI) were used. Results: HOMA-IR was positively associated with body-mass index (BMI) (rho=0.364, p=0.002), time with oxyhaemoglobin saturation <90% (rho=0.291, p=0.015), arousal index (rho=0.268, p=0.027), Epworth sleepiness scale (ESS) score (rho=0.293, p=0.019) and negatively with average oxyhaemoglobin saturation (rho=-0.398, p=0.001) and minimum oxyhaemoglobin saturation (rho=-0.327, p=0.006). QUICKI was positively associated with forced vital capacity (r=0.301, p=0.014), average oxyhaemoglobin saturation (r=0.443, p<0.001), minimum oxyhaemoglobin saturation (rho=0.318, p=0.008), and negatively associated with sleep stage transitions (r=-0.266, p=0.032), oxygen desaturation index (r=-0.404, p=0.005), time with oxyhaemoglobin saturation <90% (r=-0.311, p=0.019), arousal index (r=-0.344, p=0.004) and ESS score (r=-0.299, p=0.016). After adjustment for age and BMI, HOMA-IR was associated with sleep stage transitions, time with oxyhaemoglobin saturation <90%, average oxyhaemoglobin saturation, minimum oxyhaemoglobin saturation and arousal index. QUICKI was associated with oxygen desaturation index, sleep stage transitions, ESS score, minimum oxyhaemoglobin saturation and arousal index. Conclusions: An independent association between OSAS and IR in patients without pre-existing diabetes mellitus was observed. Recurrent hypoxia and sleep fragmentation in OSAS are associated with IR in these patients. PMID- 29399213 TI - Successful Nonoperative Treatment of a Lumbar Spine Extension Injury with Disruption of all Three Bony Columns in a Patient with Ankylosing Spondylitis - A Case Report. AB - Study Design: A case report. Background: Patients with ankylosing spondylitis have altered spinal biomechanics putting them at increased risk of spinal fractures that are unstable. As a result there is an increasing trend to treat these fractures with surgical stabilization. We hypothesize that the fracture pattern is also an important factor in patients with this disease and that those with an extension injury in the lumbar spine can be treated with brace immobilization. Objective: Report on the non-operative management of an elderly patient, with ankylosing spondylitis, who sustained an extension injury of all three bony columns of the lumbar spine. Methods: A case report of a 70-year-old man who fell from a standing height, sustaining a three-column fracture at L1-2, who did not want surgical stabilization. Results: External brace immobilization was used and the patient was closely monitored. At his final 13 month follow-up, the patient had no clinical evidence of spinal instability or neurologic compromise and radiologically we could see callous formation anteriorly and laterally between the L1 and L2 vertebral bodies.These bridged the trebeculae across the middle and posterior columns at L1 and L2 on the lateral view, and there was no change in the sagittal or coronal alignment" to "There was mature bridging bone across the middle and posterior columns at L1 and L2 on the lateral view, and there was no change in the sagittal or coronal alignment. Conclusion: This case supports our hypothesis that the fracture pattern is an important factor in patients with ankylosing spondylitis and adds to the body of knowledge in the scientific literature concerning non-operative treatment of fractures in patients with ankylosed spines. Further study is required to determine whether ours is an isolated case or whether this applies to a wider population of ankylosing spondylitis patients. PMID- 29399214 TI - Relationship Between Periodontal Disease and Serum Factors in Patients Undergoing Hemodialysis. AB - Background: Chronic renal disease is a common condition with several recognized risk factors. Periodontal disease is a recently suggested risk factor for renal disease. We aimed to assess the relationship between periodontal disease and several serum factors in patients undergoing hemodialysis. Methods: This descriptive cross-sectional study was conducted on 57 patients undergoing hemodialysis. Periodontal examination was done by measuring the mean Pocket Depth (PD), Silness-Loe Plaque Index (PI), Ainamo and Bay Bleeding On Probing (BOP), Loe and Silness Gingival Index (GI) and Clinical Attachment Loss (CAL). Serum levels of albumin, calcium, phosphorus, hemoglobin, ferritin and creatinine were measured via a routine blood test. Cystatin C was separately measured. Data were analyzed using independent t-test, Pearson's correlation coefficient, chi square test and Mann Whitney test (alpha=0.05). Results: 37 men and 20 women were evaluated. Of these, 26.3% had periodontitis and 73.7% had gingivitis. Serum level of albumin (P=0.02) and ferritin (P=0.043) in patients with periodontitis was significantly higher than that in patients with gingivitis. The serum level of creatinine (P=0.02), cystatin C (P=0.013), calcium (P=0.046) and phosphorus (P=0.037) had a significant correlation with severity of periodontitis and increase in CAL. Conclusion: Increase in the serum levels of albumin and ferritin was related to the progression of gingivitis to periodontitis. Also, the serum levels of creatinine, cystatin C, calcium and phosphorus increased with an increase in CAL. PMID- 29399215 TI - Risk Factors of Orofacial Pain: A Population-Based Study in West Java Province, Indonesia. AB - Background: The management of orofacial pain in Indonesia has not been well performed, which consequently led to an increase in the orofacial pain occurrences and a decreased quality of life. One of the possible reasons for this particular matter is the lack of evaluation on the risk factors that might induce orofacial pain in some individuals. Objective: The objective of the current study was to evaluate the risk factors of orofacial pain on productive age population in West Java province, Indonesia. Methods: One thousand and fifty-six participants (522 males; 534 females) were recruited for the study. A questionnaire that consists of demographic questions and questions evaluating several assumed risk factors for orofacial pain was used in a single interview. All data was analyzed by using Chi Square test to test the significance, Odds Ratio (OR), as well as Relative Risk (RR) by using SPSS version 23 (IBM Statistic, USA). Results: The result of the current study revealed that bruxism (p<0.01), daytime clenching (p<0.01), and unilateral chewing (p<0.01) were significantly related to the occurrence of orofacial pain. It was also found that participants who performed multitude of heavy liftings at work have an increased risk (RR=1.19: 95% CI: 1.04 - 1.35) of having orofacial pain compared to those who do not. Conclusion: Risk factors for the occurrence of orofacial pain on productive age population in Indonesian sample consisted of oral parafunctional habits and non-parafunctional habits, such as heavy lifting. Further study in this particular topic is of importance. PMID- 29399216 TI - In vitro Antibacterial Activity and Phytochemical Analysis of Nicotiana tabacum L. Extracted in Different Organic Solvents. AB - Background: Controlling infectious disease using medicinal plants is the oldest healthcare known to mankind. Regardless of the enormous advances observed in modern medicine, medicinal plants are still playing vital roles. However, only a small proportion of medicinal plants are examined for bioactive compounds which may vary in different factors. This study aimed to evaluate phytochemical constituent and antimicrobial activities of Nicotiana tabacum L. extracted by different solvents against three set of bacteria. Methods: Nicotiana tabacum L. was collected from the Western Ethiopia and extracted in seven organic solvents. An in-vitro anti-bacterial activity of plant extracts was carried out by agar well diffusion assay against microbial type culture collection of human pathogens, clinical bacterial isolates, and biofilm forming bacteria. Gas Chromatographic and Mass Spectroscopic (GC-MS) analysis was used to determine the phytochemical constituents. Results: Antimicrobial activities of plant extract vary by extraction solvents; and ethyl acetate based extracts showed better antimicrobial activities. Of the experimental organisms, biofilm forming uropathogens were the most sensitive while clinical isolates were quite resistant. Analysis of the active ethyl acetate extract by GC-MS evinced a mixture of five volatile compounds; and Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S) was the major compound detected. The overall results of the present study revealed that N. tabacum L extract has high antimicrobial activities against biofilm forming uropathogens. Conclusion: High antimicrobial activity was observed in ethyl acetate extract of N. tabacum against the biofilm forming bacteria whereas the clinically isolated bacteria were the most resistant group. The antibacterial property demonstrated could be due to Pyridine, 3-(1-methyl-2 pyrrolidinyl)-(S) with a broad spectrum of activity. PMID- 29399217 TI - Epidemiology of Clostridium Difficile Infection in a Large Hospital in Northern Italy: Questioning the Ward-Based Transmission. AB - Background: Clostridium Difficile infection (CDI) is considered a ward-based nosocomial infection, due to contagion among patients. Molecular studies recently questioned ward-based contact for disease spread. Objective: To investigate whether it is plausible that CDI spread in San Martino Hospital of Genoa was due to a ward-based contact and patient-to-patient diffusion. Methods: We conducted a retrospective cohort study of CDI cases from April 2010 to March 2015. We referred to Hospital data set and Admission Service. Multilevel modelling approach and ecological analysis were used to assess C. difficile infection risk according to wards and time of occurrence. Six representative CD strains were ribotyped to assess a possible equivalence. Results: The assessment of 514 CDI cases showed that the risk of disease and rate of incidence in wards were independent, while frequency of cases and number of wards involved exhibited a positive relationship, excluding the typical epidemic pattern of contagious diffusion, i.e., many cases in few wards. The extra-binomial variability due to ward clustering was not significant, indicating homogeneity in the probability of CDI occurrence across all wards. Three hundred sixty-eight patients changed ward, without showing connection between the frequency of cases in new wards and incidence among new subjects. Trigonometric components described a significant contribution of seasonality, with excess of CDI cases during the winter months. Molecular analysis showed different ribotypes of CD strains from the same ward. Conclusion: From our results it seems unlikely that in our institution CDI occurrence is due to ward-based contact and inter-human contagion of the organism. PMID- 29399218 TI - Antimicrobial Activity of Bacillus Persicus 24-DSM Isolated from Dead Sea Mud. AB - Intorduction: Dead Sea is a hypersaline lake with 34% salinity, gains its name due to the absence of any living macroscopic creatures. Despite the extreme hypersaline environment, it is a unique ecosystem for various halophilic microorganisms adapted to this environment. Aims & Objectives: Halophilic microorganisms are known for various potential biotechnological applications, the purpose of the current research is isolation and screening of halophilic bacteria from Dead Sea mud for potential antimicrobial applications. Methods & Materials: Screening for antagonistic bacteria was conducted by bacterial isolation from Dead Sea mud samples and agar plate antagonistic assay. The potential antagonistic isolates were subjected to biochemical characterization and identification by 16S-rRNA sequencing. Among the collected isolates, four isolates showed potential antagonistic activity against Bacillus subtilis 6633 and Escherichia coli 8739. The most active isolate (24-DSM) was subjected for antagonistic activity and minimal inhibitory concentration against different gram positive and negative bacterial strains after cultivation in different salt concentration media. Results: The results of 16S-rRNA analysis revealed that 24 DSM is very closely related to Bacillus persicus strain B48, which was isolated from hypersaline lake in Iran. Conclusion: Therefore, the isolate 24-DSM is assigned as a new strain of B. persicusi isolated from the Dead Sea mud. B. persicusi 24-DSM showed higher antimicrobial activity, when it was cultivated with saline medium, against all tested bacterial strains, where the most sensitive bacterial strain was Corynebacterium diphtheria 51696. PMID- 29399219 TI - Identification of Bacteria in the Sputum of a Cystic Fibrosis patient; A Comparison of Phenotypic and Molecular Methods. AB - Background: Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator gene, is a common autosomal recessive disease. Accurate isolation and identification of the bacteria underlying these infections are is critical to the therapeutic management of CF. Objective: To compare phenotypic bacterial identification with a molecular method in a CF patient sputum. Methods: Bacterial identification done by standard microbiological method from a CF patient. Same sample underwent a molecular method involving 16S rDNA amplification, cloning, and sequencing. Results: All isolated bacteria from culture were also found after cloning PCR Product. Conversely, 9 pathogenic bacterial species were only detected after PCR and cloning. Conclusion: This study supports prior suggestions that a sequence-based molecular approach to clinical microbiology can significantly enhance the standard clinical culture based view. PMID- 29399221 TI - Cadaveric Study of the Junction Point Where the Gastrocnemius Aponeurosis Joins the Soleus Aponeurosis. AB - Purpose: To study the location of the junction point where the gastrocnemius aponeurosis joins the soleus aponeurosis to form the Achilles tendon. Methods: Twelve lower limb specimens were used. The distance between the medial tibial plateau and the superior border of the posterior calcaneal tubercle (A) was measured and the distances of the junction point to the superior border of the posterior calcaneal tubercle (B) were measured. Result: The ratio B/A averaged 0.45. The gastrocnemius muscle reached or extended beyond the junction point in eight specimens (67%). The average distance from the lowest border of the muscle to the junction point was 0+/-12mm (-25-25). Conclusion: There are great anatomical variations of the gastrocnemius insertion. Resection of muscle bound portion of the gastrocnemius aponeurosis is a more appropriate approach of endoscopic gastrocnemius aponeurosis recession. Clinical Relevance: This report suggests that resection of muscle bound portion rather than the muscle void portion of the gastrocnemius aponeurosis is a more appropriate approach of endoscopic gastrocnemius aponeurosis recession. PMID- 29399222 TI - The Changing Paradigm in the Management of Spinal Deformities. PMID- 29399220 TI - Psychophysical and Patient Factors as Determinants of Pain, Function and Health Status in Shoulder Disorders. AB - Objective: To estimate the extent to which psychophysical quantitative sensory test (QST) and patient factors (gender, age and comorbidity) predict pain, function and health status in people with shoulder disorders. To determine if there are gender differences for QST measures in current perception threshold (CPT), vibration threshold (VT) and pressure pain (PP) threshold and tolerance. Design: A cross-sectional study design. Setting: MacHAND Clinical Research Lab at McMaster University. Subjects: 34 surgical and 10 nonsurgical participants with shoulder pain were recruited. Method: Participants completed the following patient reported outcomes: pain (Numeric Pain Rating, Pain Catastrophizing Scale, Shoulder Pain and Disability Index) and health status (Short Form-12). Participants completed QST at 4 standardized locations and then an upper extremity performance-based endurance test (FIT-HaNSA). Pearson r's were computed to determine the relationships between QST variables and patient factors with either pain, function or health status. Eight regression models were built to analysis QST's and patient factors separately as predictors of either pain, function or health status. An independent sample t-test was done to evaluate the gender effect on QST. Results: Greater PP threshold and PP tolerance was significantly correlated with higher shoulder functional performance on the FIT HANSA (r =0.31-0.44) and lower self-reported shoulder disability (r = -0.32 to 0.36). Higher comorbidity was consistently correlated (r =0.31-0.46) with more pain, and less function and health status. Older age was correlated to more pain intensity and less function (r =0.31-0.57). In multivariate models, patient factors contributed significantly to pain, function or health status models (r2 =0.19-0.36); whereas QST did not. QST was significantly different between males and females [in PP threshold (3.9 vs. 6.2, p < .001) and PP tolerance (7.6 vs. 2.6, p < .001) and CPT (1.6 vs. 2.3, p =.02)]. Conclusion: Psychophysical dimensions and patient factors (gender, age and comorbidity) affect self-reported and performance-based outcome measures in people with shoulder disorders. PMID- 29399223 TI - A Modern Historical Perspective of Schroth Scoliosis Rehabilitation and Corrective Bracing Techniques for Idiopathic Scoliosis. AB - The treatment of scoliosis has a long history dating back to Hippocrates and his luxation table. In recent history, conservative rehabilitation treatment methods have come and gone. Some have had more longevity than others and currently there are only a handful of these "schools" for rehabilitation in existence. What is important to note in this twenty-first century world is that any approach to bracing or scoliosis rehabilitation must strive for a correction effect and be as user-friendly as possible. Patients look to achieve some measure of success, whether it be halted Cobb angle, improved breathing function, decreased rotation, or postural improvement via trunk symmetry. Katharina Schroth created her method in 1921 as a result of self-analysis of her own imperfect scoliotic torso and the effect on it as she altered her breathing patterns. It was from these observations and self-experimentation that she devised her rotational angular breathing method. Subsequently, the Schroth method evolved under the leadership of her daughter, Christa Lehnert-Schroth P.T., and grandson, Dr. Hans-Rudolf Weiss. Collaboration with Dr. Jacques Cheneau led to a new Schroth method compatible scoliosis bracing approach. The most recent advancement of Cheneau bracing is the Gensingen Brace(r) (GBW). Gensingen braces have an asymmetric design and rely on Schroth principles of correction in a smaller, lighter, more wearer-friendly brace. Each brace is designed to be a complementary supportive orthosis. It may be used independently, or in conjunction with Schroth exercise protocols. PMID- 29399225 TI - Cobb Angle Reduction in a Nearly Skeletally Mature Adolescent (Risser 4) After Pattern-Specific Scoliosis Rehabilitation (PSSR). AB - Introduction: It has long been said that exercise-based rehabilitation for scoliosis is ineffective, however, these reports studied general exercises. This case report is a prospective one-year follow-up of a nearly skeletally mature adolescent female (Risser 4) with idiopathic scoliosis treated with Pattern Specific-Scoliosis Rehabilitation (PSSR). Methods: The 15-year old patient recommended for surgery (initial Cobb angle of 45 degrees ) completed a 16-hour scoliosis-specific back school (according to Schroth Best Practice(r)), over the course of five weeks. She continued with her program at home, and followed up with the lead author after 6 months and 1 year. Results: The patient achieved a 13 degrees reduction in her primary thoracic Cobb angle. Postural improvement and reduction in trunk rotation (ATR) was also achieved (-4 degrees in the thoracic spine, and -5 degrees in the lumbar spine). Conclusion: Pattern specific scoliosis rehabilitation (PSSR) works to reduce the asymmetrical load caused by scoliosis. PSSR is effective in stabilizing Cobb angle, and can, in some cases, reduce Cobb angle in adolescents. Patients recommended for surgery may be candidates for conservative treatment. This case suggests that the practice of discontinuing conservative treatment at Risser stage 4 should be re evaluated. PMID- 29399224 TI - Etiological Theories of Adolescent Idiopathic Scoliosis: Past and Present. AB - Adolescent idiopathic scoliosis is one of the most common spinal deformities, yet its cause is unknown. Various theories look to biomechanical, neuromuscular, genetic, and environmental origins, yet our understanding of scoliosis etiology is still limited. Determining the cause of a disease is crucial to developing the most effective treatment. Associations made with scoliosis do not necessarily point to causality, and it is difficult to determine whether said associations are primary (playing a role in development) or secondary (develop as a result of scoliosis). Scoliosis is a complex condition with highly variable expression, even among family members, and likely has many causes. These causes could be similar among homogenous groups of AIS patients, or they could be individual. Here, we review the most prevalent theories of scoliosis etiology and recent trends in research. PMID- 29399226 TI - Imaging in the Diagnosis and Monitoring of Children with Idiopathic Scoliosis. AB - The paper reviews the current imaging methods in the diagnosis and monitoring of patients with adolescent idiopathic scoliosis. Radiography is generally used in the initial diagnosis of the condition. Postero-anterior erect full spine radiograph is generally prescribed, and is supplemented by lateral full spine radiograph when indicated. To reduce the radiation hazard, only the area of interest should be exposed, and follow-up radiographs should be taken with as few projections as possible. When available, EOS(r) stereoradiography should be used. The radiation of the microdose protocol is 45 times less than that of the conventional radiography. Surface topography offers another approach to monitoring changes of curvatures in AIS patients. Recently, 3D ultrasound has been found to be able to measure the Cobb angle accurately. Yet, it is still in the early developmental stages. The inherent intrinsic and external limitations of the imaging system need to be resolved before it can be widely used clinically. For AIS patients with atypical presentation, computed tomography (CT) and/or magnetic resonance imaging (MRI) may be required to assess for any underlying pathology. As CT is associated with a high radiation dose, it is playing a diminishing role in the management of scoliosis, and is replaced by MRI, which is also used for pre-operative planning of scoliosis. The different imaging methods have their limitations. The EOS(r) stereoradiography is expensive and is not commonly available. The surface topography does not enable measurement of Cobb angle, particularly when the patient is in-brace. The 3D ultrasound scanning has inherent intrinsic technical limitation and cannot be used in all subjects. Radiography, however, enables diagnosis and monitoring of the adolescent idiopathic scoliosis (AIS). It is thus the gold standard in the evaluation and management of scoliosis curves. PMID- 29399228 TI - The Role of Correction in the Conservative Treatment of Adolescent Idiopathic Scoliosis. AB - Introduction: Physiotherapeutic Scoliosis-Specific Exercises (PSSE) and bracing have been found to be effective in the stabilization of curves in patients with Adolescent Idiopathic Scoliosis (AIS). Yet, the difference among the many PSSEs and braces has not been studied. The present review attempts to investigate the role of curve correction in the outcome of treatment for PSSEs and braces. Material and Methods: A PubMed manual search has been conducted for studies on the role of correction in the effectiveness of PSSE and bracing. For the PSSEs, the key words used were "adolescent idiopathic scoliosis, correction, physiotherapy, physical therapy, exercise, and rehabilitation." For bracing, the key words used were "adolescent idiopathic scoliosis, correction and brace". Only papers that were published from 2001-2017 were included and reviewed, as there were very few relevant papers dating earlier than 2001. Results: The search found no studies on the role of correction on the effectiveness of different PSSEs. The effectiveness of different PSSEs might or might not be related to the magnitude of curve correction during the exercises. However, many studies showed a relationship between the magnitude of in-brace correction and the outcome of the brace treatment. Discussion: The role of correction on the effectiveness of PSSE has not been studied. In-brace correction, however, has been found to be associated with the outcome of brace treatment. An in-brace correction of < 10% was associated with an increased rate of failure of brace treatment, whereas an in-brace correction of >40-50% was associated with an increased rate of brace treatment success (i.e. stabilization or improvement of curves). Thus, in the treatment of AIS, patients should be advised to use highly corrective braces, in conjunction with PSSE since exercises have been found to help stabilize the curves during weaning of the brace. Presently, no specific PSSE can be recommended. Conclusion: Braces of high in-brace correction should be used in conjunction with PSSEs in the treatment of AIS. No specific PSSE can be recommended as comparison studies of the effectiveness of different PSSEs are not found at the time of this study. PMID- 29399227 TI - Management of Spinal Deformities and Evidence of Treatment Effectiveness. AB - Introduction: The review evaluates the up-to-date evidence for the treatment of spinal deformities, including scoliosis and hyperkyphosis in adolescents and adults. Material and Methods: The PubMed database was searched for review articles, prospective controlled trials and randomized controlled trials related to the treatment of spinal deformities. Articles on syndromic scoliosis were excluded and so were the articles on hyperkyphosis of the spine with causes other than Scheuermann's disease and osteoporosis. Articles on conservative and surgical treatments of idiopathic scoliosis, adult scoliosis and hyperkyphosis were also included. For retrospective papers, only studies with a follow up period exceeding 10 years were included. Results: The review showed that early onset idiopathic scoliosis has a worse outcome than late-onset idiopathic scoliosis, which is rather benign. Patients with AIS function well as adults; they have no more health problems when compared to patients without scoliosis, other than a slight increase in back pain and aesthetic concern. Conservative treatment of adolescent idiopathic scoliosis (AIS) using physiotherapeutic scoliosis-specific exercises (PSSE), specifically PSSR and rigid bracing was supported by level I evidence. Yet to date, there is no high quality evidence (RCT's) demonstrating that surgical treatment is superior to conservative treatment for the management of AIS. For adult scoliosis, there are only a few studies on the effectiveness of PSSEs and a conclusion cannot as yet be drawn.For hyperkyphosis, there is no high-quality evidence for physiotherapy, bracing or surgery for the treatment of adolescents and adults. However, bracing has been found to reduce thoracic hyperkyphosis, ranging from 55 to 80 degrees in adolescents. In patients over the age of 60, bracing improves the balance score, and reduces spinal deformity and pain. Surgery is indicated in adolescents and adults in the presence of progression of kyphosis, refractory pain and loss of balance. Discussion: The available evidence reviewed has suggested that different approaches are needed towards the management of different spinal deformities. Specific exercises should be prescribed in children and adolescents with a Cobb angle in excess of 15 degrees . In progressive curves, they should be used in conjunction with bracing. Clarity regarding differences and similarities is given as to what makes PSSE and PSSR specific exercises. As AIS is relatively benign in nature, conservative treatment should be tried when the curve is at a surgical threshold, before surgery is considered. Similarly, bracing and exercises should be prescribed for patients with hyperkyphosis, particularly when the lumbar spine is afflicted. Surgery should be considered only when the symptoms cannot be managed conservatively. Conclusion: There is at present high quality evidence in support of the conservative treatment of AIS. The current evidence supports the use of PSSE, especially those using PSSR, together with bracing in the treatment of AIS. In view of the lack of medical consequences in adults with AIS, conservative treatment should be considered for curves exceeding the formerly assumed range of conservative indications.There is, however a lack of evidence in support of any treatment of choice for hyperkyphosis in adolescents and spinal deformities in adults. Yet, conservative treatment should be considered first. Yet to date, there is no high quality evidence (RCT's) demonstrating that surgical treatment is superior to conservative treatment for the management of AIS and hyperkyphosis. Additionally, surgery needs to be considered with caution, as it is associated with a number of long-term complications. PMID- 29399229 TI - A Prospective Cohort Study of AIS Patients with 40 degrees and More Treated with a Gensingen Brace (GBW): Preliminary Results. AB - Introduction: There is a growing resistance from patients and their families to spinal fusion surgery for scoliosis. Due to inconclusive evidence that surgery has a long-term effect on scoliosis and/or improves the quality of life for patients with scoliosis, there is a need to extend the conservative perspective of treatment to patients with curvatures greater than 40 degrees. For that reason, a prospective cohort study was initiated to determine the effectiveness of the Gensingen brace (a Cheneau-style TLSO) in preventing progression in skeletally immature patients. Materials and Methods: Since 2011, fifty-five patients have been enrolled in this prospective cohort study. This report includes the mid-term results of twenty-five of these patients, who have a minimum follow-up of 18 months and an average follow-up of 30.4 months (SD 9.2). The twenty-five patients had the following characteristics at the start of treatment: Cobb angle: 49 degrees (SD 8.4; 40o-71o); 12.4 years old (SD 0.82); Risser: 0.84 (SD 0.94; 0-2). A z-test was used to compare the success rate in this cohort to the success rate in the prospective braced cohort from BrAIST. Results: After follow-up, the average Cobb angle was 44.2 degrees (SD 12.9). Two patients progressed, 12 patients were able to achieve halted progression, and eleven patients improved. Angle of trunk rotation (ATR) decreased from 12.2 to 10.1 degrees in the thoracic spine (p = 0.11) while the ATR decreased from 4.7 to 3.6 degrees in the lumbar spine (p = 0.0074). When comparing the success rate of the BrAIST cohort with the success rate of patients in this cohort, the difference was statistically significant (z = -3.041; p = 0.01). Conclusion: Conservative brace treatment using the Gensingen brace was successful in 92% of cases of patients with AIS of 40 degrees and higher. This is a significant improvement compared to the results attained in the BrAIST study (72%). Reduction of the ATR shows that postural improvement is also possible. PMID- 29399230 TI - New Treatment Strategy for a Delayed Skin Necrosis Related to a Calcaneal Fracture. AB - In calcaneal avulsion fractures, skin necrosis as a result of pressure from the underlying fragment is a fairly common and serious complication. In spite of proper treatment, skin healing complication may occur. We report a calcaneal fracture case complicated by skin necrosis and managed with a novel treatment strategy including application of Platelet Rich Plasma (PRP) and Vacuum Assisted Closure (VAC). This is the first application of combined PRP and VAC treatment in a calcaneal fracture complicated by skin necrosis and was accompanied with very favorable outcomes while avoiding other more complex treatment modalities. PMID- 29399231 TI - Biceps Tenotomy Does not Affect the Functional Outcomes of Patients Treated with Spacer Implantation Due to Massive Irreparable Rotator Cuff Tears. AB - Background: Lesions of the long head of the biceps (LHB) tendon are frequently associated with massive rotator cuff tears (RCT) and may be responsible for shoulder pain and disability. Objective: This study aimed to evaluate functional outcomes of arthroscopic biodegradable spacer implantation with or without biceps tenotomy as treatment for persistent shoulder dysfunction and pain due to a massive irreparable RCT. Methods: A total of 48 patients were implanted with the subacromial spacer using arthroscopic approach with or without biceps tenotomy. All patients were assessed for up to 12 months post-implantation and 18 patients were assessed for at least 24 months (and a maximum of 40 months). Improvement in shoulder function was assessed using Constant score. Results: Subacromial spacer implantation was performed arthroscopically in 48 patients. The mean total Constant score increased from 36 at baseline to 67 points at 12 months post implantation. Patients who underwent LHB tenotomy in addition to the subacromial spacer presented similar improvement of their shoulder function and score compared to the group that was treated with the spacer alone. Conclusion: Current study demonstrates that spacer implantation in this patient population provides significant improvement in function and decreases the pain. Additional LHB tenotomy did not influence the postoperative results during the follow-up. PMID- 29399232 TI - A Diagnostic Laboratory-Based Study on Frequency and Distribution of Viral Hepatitis B and C Among Sudanese. AB - Background: Hepatitis B infection is an alarming public health problem. Almost two billion people of the population alive today, would have been infected at some time in their lives by hepatitis B. Hepatitis C virus is another life threatening condition, and about 425,000 deaths occur each year due to its complications.The current study was carried out to provide care givers and health planners basic epidemiological data regarding the frequency and distribution of HBV and HCV based on age and sex during a time period of more than 5 years. Result: A total of 2109 different patients were found to be infected by HBV during the study period; 1641 (77.81%) were males and 468 (22.19%) were females with the age group of 20-39 years predominating (64%). In addition,16% of patients tested for HBeAg were found reactive. Conclusion: There were significant correlations observed between the levels of HBV DNA and ALT, AST and AFP. Regarding HCV, 70 males (54.9%) and 63 females (45.1%) were found to be infected, with preponderance of the age group 41 - 60 years and the genotype 4. Designing knowledge raising campaigns is appreciated as well as repetition of similar studies among larger populations in the following few years will help track a way to improvement. PMID- 29399233 TI - The Effect of Ranibizumab on Normal Neurosensory Retina in the Eyes of Patients with Exudative Age Related Macular Degeneration. AB - Background: Anti-vascular endothelial growth factors have become the mainstay treatment for neovascular age related macular degeneration. Prolonged suppression of vascular endothelial growth factor raises concerns as it may result in harmful effects on retina. Objective: The purpose of this retrospective chart review is to evaluate the 1-year effect of treatment with intravitreal injections of ranibizumab on normal neurosensory retinal tissue of patients with exudative age related macular degeneration using the Optical Coherence Tomography (OCT). Method: The study included sixty five eyes of 62 patients (32 male and 30 female; mean age 74.97+/-8.5 years) with exudative age related macular degeneration treated with intravitreal injections of ranibizumab with a pro re nata treatment regimen over a period of 1 year. The MM5 thickness maps acquired with the Optovue RTVue-100 Fourier-domain OCT at baseline, at 3 months, after the 3 loading doses of ranibizumab, and at the 1 year follow-up visit were used for analysis. Changes of inner and outer retinal thickness in four selected points of normal retina on the MM5 scan were evaluated. Results: The patients received a mean of 6.4 +/- 1.8 (median 6, range 3-11) intravitreal injections of ranibizumab over a period of 12 months. No significant change was observed in inner and outer retinal thickness at pre-selected spots of normal retina during the first year of intravitreal administration of ranibizumab. Conclusion: One year treatment with ranibizumab on an individualized, according to need dosing regimen does not seem to induce any detectable structural damage in the unaffected, normal retina. PMID- 29399234 TI - How to Help the Suicidal Person to Choose Life: The Ethic of Care and Empathy as an Indispensable Tool for Intervention by K. Stephany. PMID- 29399235 TI - Challenges of Obtaining Informed Consent in Emergency Ward: A Qualitative Study in One Iranian Hospital. AB - Background and Objective: Regarding the fact that emergency ward has unique characteristics, whose uniqueness affects informed consent processes by creating specific challenges. Hence, it seems necessary to identify the process and challenges of informed consent in the emergency ward through a qualitative study to understand actual patients' and health care providers' experiences, beliefs, values, and feelings about the informed consent in the emergency ward. Through such studies, new insight can be gained on the process of informed consent and its challenges with the hope that the resulting knowledge will enable the promotion of ethical, legal as well as effective health services to the patients in the emergency ward. Method: In this qualitative study, research field was one of the emergency wards of educational and public hospitals in Iran. Field work and participant observation were carried out for 515 hours from June 2014 to March 2016. Also, conversations and semi-structured interviews based on the observations were conducted. The participants of the study were nurses and physicians working in the emergency ward, as well as patients and their attendants who were involved in the process of obtaining informed consent. Results: Three main categories were extracted from the data: a sense of frustration; reverse protection; and culture of paternalism in consent process. Conclusion: Findings of this study can be utilized in correcting the structures and processes of obtaining informed consent together with promotion of patients' ethical and legal care in emergency ward. In this way, the approaches in consent process will be changed from paternalistic approach to patient-centered care which concomitantly protects patient's autonomy. PMID- 29399236 TI - Changing to Concept-Based Curricula: The Process for Nurse Educators. AB - Background: The complexity of health care today requires nursing graduates to use effective thinking skills. Many nursing programs are revising curricula to include concept-based learning that encourages problem-solving, effective thinking, and the ability to transfer knowledge to a variety of situations requiring nurse educators to modify their teaching styles and methods to promote student-centered learning. Changing from teacher-centered learning to student centered learning requires a major shift in thinking and application. Objective: The focus of this qualitative study was to understand the process of changing to concept-based curricula for nurse educators who previously taught in traditional curriculum designs. Methods: The sample included eight educators from two institutions in one Western state using a grounded theory design. Results: The themes that emerged from participants' experiences consisted of the overarching concept, support for change, and central concept, finding meaning in the change. Finding meaning is supported by three main themes: preparing for the change, teaching in a concept-based curriculum, and understanding the teaching-learning process. Conclusion: Changing to a concept-based curriculum required a major shift in thinking and application. Through support, educators discovered meaning to make the change by constructing authentic learning opportunities that mirrored practice, refining the change process, and reinforcing benefits of teaching. PMID- 29399237 TI - Workflow as a Service in the Cloud: Architecture and Scheduling Algorithms. AB - With more and more workflow systems adopting cloud as their execution environment, it becomes increasingly challenging on how to efficiently manage various workflows, virtual machines (VMs) and workflow execution on VM instances. To make the system scalable and easy-to-extend, we design a Workflow as a Service (WFaaS) architecture with independent services. A core part of the architecture is how to efficiently respond continuous workflow requests from users and schedule their executions in the cloud. Based on different targets, we propose four heuristic workflow scheduling algorithms for the WFaaS architecture, and analyze the differences and best usages of the algorithms in terms of performance, cost and the price/performance ratio via experimental studies. PMID- 29399238 TI - Progress towards automated Kepler scientific workflows for computer-aided drug discovery and molecular simulations. AB - We describe the development of automated workflows that support computed-aided drug discovery (CADD) and molecular dynamics (MD) simulations and are included as part of the National Biomedical Computational Resource (NBCR). The main workflow components include: file-management tasks, ligand force field parameterization, receptor-ligand molecular dynamics (MD) simulations, job submission and monitoring on relevant high-performance computing (HPC) resources, receptor structural clustering, virtual screening (VS), and statistical analyses of the VS results. The workflows aim to standardize simulation and analysis and promote best practices within the molecular simulation and CADD communities. Each component is developed as a stand-alone workflow, which allows easy integration into larger frameworks built to suit user needs, while remaining intuitive and easy to extend. PMID- 29399239 TI - Additive Effects of Cointoxicants in Single-Opioid Induced Deaths. AB - A forensic drug database (FDD) was used to capture comprehensive data from all drug-related deaths in West Virginia, with deaths also included from the northern New England states of Maine, Vermont, and New Hampshire. All four states serve predominantly rural populations under two million and all have similar state medical examiner systems that employ statewide uniform death certification policies and practices. This study focused on 1482 single opioid deaths (fentanyl, hydrocodone, methadone, and oxycodone) in the FDD from 2007-2011. We modeled relationships between the opioid concentrations and the presence or absence of the following commonly occurring non-opioid cointoxicants: benzodiazepines (alprazolam and diazepam), alcohol, tricyclic antidepressants, selective serotonin reuptake inhibitors, and diphenhydramine. Additional covariates of state, age, body mass index, and sex were included. Results showed that the presence of alcohol, benzodiazepines, and antidepressants were each associated with statistically significant lower concentrations of some but not all of the opioids studied, which may obscure the interpretation of postmortem toxicology results alone. Fentanyl concentrations appeared to be the least associated with the presence or absence of the variables studied, and cointoxicant alcohol appeared to be associated with lower concentrations in opioid concentrations than were most of the other factors in the model studied. These findings underscore the importance of documenting all potential cointoxicants in opioid-related deaths. PMID- 29399240 TI - ROBUST MIXED EFFECTS MODEL FOR CLUSTERED FAILURE TIME DATA: APPLICATION TO HUNTINGTON'S DISEASE EVENT MEASURES. AB - An important goal in clinical and statistical research is properly modeling the distribution for clustered failure times which have a natural intraclass dependency and are subject to censoring. We handle these challenges with a novel approach that does not impose restrictive modeling or distributional assumptions. Using a logit transformation, we relate the distribution for clustered failure times to covariates and a random, subject-specific effect. The covariates are modeled with unknown functional forms, and the random effect may depend on the covariates and have an unknown and unspecified distribution. We introduce pseudovalues to handle censoring and splines for functional covariate effects, and frame the problem into fitting an additive logistic mixed effects model. Unlike existing approaches for fitting such models, we develop semiparametric techniques that estimate the functional model parameters without specifying or estimating the random effect distribution. We show both theoretically and empirically that the resulting estimators are consistent for any choice of random effect distribution and any dependency structure between the random effect and covariates. Last, we illustrate the method's utility in an application to a Huntington's disease study where our method provides new insights into differences between motor and cognitive impairment event times in at-risk subjects. PMID- 29399241 TI - BAYESIAN LARGE-SCALE MULTIPLE REGRESSION WITH SUMMARY STATISTICS FROM GENOME-WIDE ASSOCIATION STUDIES. AB - Bayesian methods for large-scale multiple regression provide attractive approaches to the analysis of genome-wide association studies (GWAS). For example, they can estimate heritability of complex traits, allowing for both polygenic and sparse models; and by incorporating external genomic data into the priors, they can increase power and yield new biological insights. However, these methods require access to individual genotypes and phenotypes, which are often not easily available. Here we provide a framework for performing these analyses without individual-level data. Specifically, we introduce a "Regression with Summary Statistics" (RSS) likelihood, which relates the multiple regression coefficients to univariate regression results that are often easily available. The RSS likelihood requires estimates of correlations among covariates (SNPs), which also can be obtained from public databases. We perform Bayesian multiple regression analysis by combining the RSS likelihood with previously proposed prior distributions, sampling posteriors by Markov chain Monte Carlo. In a wide range of simulations RSS performs similarly to analyses using the individual data, both for estimating heritability and detecting associations. We apply RSS to a GWAS of human height that contains 253,288 individuals typed at 1.06 million SNPs, for which analyses of individual-level data are practically impossible. Estimates of heritability (52%) are consistent with, but more precise, than previous results using subsets of these data. We also identify many previously unreported loci that show evidence for association with height in our analyses. Software is available at https://github.com/stephenslab/rss. PMID- 29399242 TI - WAVELET-BASED GENETIC ASSOCIATION ANALYSIS OF FUNCTIONAL PHENOTYPES ARISING FROM HIGH-THROUGHPUT SEQUENCING ASSAYS. AB - Understanding how genetic variants influence cellular-level processes is an important step toward understanding how they influence important organismal-level traits, or "phenotypes," including human disease susceptibility. To this end, scientists are undertaking large-scale genetic association studies that aim to identify genetic variants associated with molecular and cellular phenotypes, such as gene expression, transcription factor binding, or chromatin accessibility. These studies use high-throughput sequencing assays (e.g., RNA-seq, ChIP-seq, DNase-seq) to obtain high-resolution data on how the traits vary along the genome in each sample. However, typical association analyses fail to exploit these high resolution measurements, instead aggregating the data at coarser resolutions, such as genes, or windows of fixed length. Here we develop and apply statistical methods that better exploit the high-resolution data. The key idea is to treat the sequence data as measuring an underlying "function" that varies along the genome, and then, building on wavelet-based methods for functional data analysis, test for association between genetic variants and the underlying function. Applying these methods to identify genetic variants associated with chromatin accessibility (dsQTLs), we find that they identify substantially more associations than a simpler window-based analysis, and in total we identify 772 novel dsQTLs not identified by the original analysis. PMID- 29399243 TI - Does Early Mathematics Intervention Change the Processes Underlying Children's Learning? AB - Early educational intervention effects typically fade in the years following treatment, and few studies have investigated why achievement impacts diminish over time. The current study tested the effects of a preschool mathematics intervention on two aspects of children's mathematical development. We tested for separate effects of the intervention on "state" (occasion-specific) and "trait" (relatively stable) variability in mathematics achievement. Results indicated that, although the treatment had a large impact on state mathematics, the treatment had no effect on trait mathematics, or the aspect of mathematics achievement that influences stable individual differences in mathematics achievement over time. Results did suggest, however, that the intervention could affect the underlying processes in children's mathematical development by inducing more transfer of knowledge immediately following the intervention for students in the treated group. PMID- 29399244 TI - Exertional Observation in Adults Performing Intermittent Treadmill Walking and Running. AB - The present investigation examined the Adult OMNI Walk-Run Scale for use by an independent observer to rate an individual's perception of exertion during intermittent treadmill walking and running. Forty (22.4 +/- 2.9 yrs) recreationally active males (n = 18) and females (n = 22) completed three 5-min intermittent bouts of treadmill exercise. The exercise bouts were a level walk (LW; 4.0 km.hr-1, 0% grade), hill walk (HW; 5.6 km.hr-1, 5% grade), and run (R; 8 km.hr-1, 2.5% grade). Each bout was separated by a 5-min recovery period. RPE responses were simultaneously estimated by an observer and self-estimated by the participant during each bout using the Adult OMNI Walk-Run Scale. Session RPE responses were simultaneously estimated by the same observer and self-estimated by the participant 5-min post-exercise session. Analysis of variance indicated no significant mean differences between observer RPE and participant RPE (p > 0.05) except for males during the running bout (p < 0.05). Additionally, there were no significant mean differences between the observer RPE and the participant RPE for the session ratings (p > 0.05). Finally, strong positive correlations were found between observer and participant RPE ranging from 0.79-0.84 for exercise bouts and moderate-strong positive correlations ranging from 0.58-0.64 for the exercise session. Results support the use of the OMNI RPE Scale in a direct observation procedure to estimate exertion in female and male young adults performing intermittent treadmill walking and running. This observation-based procedure provides the practitioner with an opportunity to independently evaluate the perceptual intensity of individuals involved in aerobic exercise. PMID- 29399245 TI - Effect of Seat Tube Angle and Exercise Intensity on Muscle Activity Patterns in Cyclists. AB - Previous studies have reported improved efficiency at steeper seat tube angle (STA) during ergometer cycling; however, neuromuscular mechanisms have yet to be fully determined. The current study investigated effects of STA on lower limb EMG activity at varying exercise intensities. Cyclists (n=11) were tested at 2 workloads; 160W and an individualised workload (IWL) equivalent to lactate threshold (TLac) minus 10%delta (derived from maximal incremental data), using 3 STA (70, 75 and 80 degrees ). Electromyographic data from Vastus Medialis (VM), Rectus Femoris (RF), Vastus Lateralis (VL) and Biceps Femoris (BF) were assessed. The timing and magnitude of activation were quantified and analysed using a two way ANOVA. STA had significant (P < 0.05) effects on timing of onset and offset of VM, timing of offset of VL, and angle at peak for RF, all occurring later at 80 vs. 70 degrees STA at IWL. In RF, increased activity occurred during the first 108 degrees of the crank cycle at 80 vs. 70 degrees at IWL (P < 0.01). As most of the power in the pedal stroke is generated during the mid-section of the down-stroke, movement of the activation range of knee extensors into the predominantly power phase of the pedal stroke would potentially account for increased efficiency and decreased cardio-respiratory costs. Greater activity of bi-articular RF, in the first 108o of the crank cycle at IWL (80 vs. 70o) may more closely resemble the pelvic stabilising activity of RF in running biomechanics; and potentially explain the more effective transition from cycling to running reported in triathletes using steeper STA. PMID- 29399246 TI - Extreme Conditioning Program Induced Acute Hypotensive Effects are Independent of the Exercise Session Intensity. AB - The aim of the study was to determine the acute systolic (SBP) and diastolic (DBP) blood pressure, rating of perceived exertion (RPE) and heart rate (HR) responses following two intense training sessions (24 hours apart). Nine male extreme conditioning program (ECP) practitioners with more than 6 months of experience (age 26.7 +/- 6.6 years; body mass 78.8 +/- 13.2 kg; body fat 13.5 +/- 6.2 %) completed two experimental ECP sessions. Cardiovascular variables were measured before, immediately after and every 15 min during a 45 min recovery following each experimental session. Compared with pre-exercise data, our results showed a SBP decrease at 30 min post exercise session 1 (P<=0.05) and at 45 min following exercise session 2. DBP decreased (P<=0.05) at 15 min and 30 min following exercise session 1 and at 30 min after the exercise session 2, respectively. HR remained significantly higher (P<=0.05) 45 min following the first and second exercise session compared with pre-exercise values. Exercise session 1 induced a higher increase in HR (86 +/- 11% of HRmax versus 82 +/- 12% of HRmax, p = 0.01) and RPE (8.8 +/- 1.2 versus 8.0 +/- 1.2, p = 0.02) when compared to exercise session 2. In conclusion, post-exercise hypotension occurs following strenuous exercise sessions, regardless of the session design, which may have an important role in the prevention of cardiovascular diseases. PMID- 29399247 TI - Resistance Exercise Training on Disease Impact, Pain Catastrophizing and Autonomic Modulation in Women with Fibromyalgia. AB - Women with fibromyalgia (FM) often complain of whole-body pain, and muscle fatigue, which may be related to autonomic dysfunction. Therefore, the purpose of the present study was to investigate the effects of resistance exercise training (RET) on disease impact, pain catastrophizing, and autonomic modulation in women with FM. Women with FM (n=26) and healthy control women (HC: n=9), aged 19-65 yrs, were compared at rest. Women with FM were randomly assigned to a resistance training group (FM-RT: n=14) or a non-exercising control group (FM-CON: n=12). Women in the FM-RT group underwent 8-weeks of RET on 4 different exercises, 2 times per week, 3 sets of 8-12 repetitions at 50%-60% of the pre-determined 1 repetition max (1RM). Autonomic modulation was assessed using heart rate variability and heart rate complexity. Healthy control women had a lower resting heart rate, decreased normalized low-frequency power, and increased normalized high-frequency power compared to the FM groups at rest. After the 8-week intervention, significant increases (p <= 0.05) in 1RM were observed for both chest press and leg extension for women in the RT group. Disease impact was significantly reduced (p <= 0.05) for participants in the FM-RT group (FM-RT: 59+/-12 to 41+/-24 units; FM-CON: 72+/-7 to71+/-8 units), but pain catastrophizing was unaltered. There were no significant changes in autonomic modulation after the RET intervention. These data demonstrate that while women with FM may still have autonomic dysfunction after undergoing a RET program, disease impact was significantly reduced. PMID- 29399248 TI - The Efficacy of Handheld Resistive Exercise Device (HRED) Training on Wellness Outcome in Older Adults. AB - The primary purpose of this study was to examine the efficacy of Handheld Resistive Exercise Device (HRED) training on wellness outcomes in older adults. A secondary purpose was to assess the utilization of an HRED in older adult fitness program. A group of healthy, active older adults (N=28, 76.6 +/- 6.7 years old) volunteered to complete a 10-week HRED training program. Pre- and post intervention changes were evaluated for muscular strength, static balance, mobility, fall-efficacy, and self-efficacy for activities of daily living. Significant improvement was seen in muscular strength (grip strength, p < 0.01), mobility (TUG time, p <0.01), and self-efficacy for jogging (p = 0.036) and push ups (p = 0.045). Most of participants (92.9%) indicated that they would like to continue exercising with the HRED. A 10-week HRED exercise program produced some improvement on wellness outcomes in older adults and the HRED is an acceptable fitness device for this population. PMID- 29399249 TI - Achilles Tendon Cross Sectional Area Changes Over a Division I NCAA Cross Country Season. AB - : Tracking Achilles tendon cross sectional area (CSA) changes may help clinicians understand exercise adaptations and Achilles tendon injury mechanisms. To track adaptations in the Achilles tendon in response to a cross country season. Design: Longitudinal study. Musculoskeletal (MSK) ultrasound images were obtained in a research laboratory. Cross country athletes ran with no restrictions outdoors and indoors. Participants were Division I NCAA cross country athletes (N = 24, age = 19.9 +/- 2.1 years, mass = 61.32 +/- 20.16 kg, height = 168.92 +/- 17.16 cm, sex = 8 males and 16 females). Achilles tendon CSA was obtained through MSK ultrasound imaging at a pre-season baseline measurement, every 3 weeks throughout the season, and at post-season for a total of 4 measurements. Participants followed their normal running regimen outlined by their cross country coach. The dependent variable was Achilles tendon CSA measured by ultrasound imaging. We used a repeated measures ANCOVA to determine differences in CSA over the cross country season. CSA increased from baseline (0.439 +/- .081 cm), to 0.466 +/- 0.096 cm at 3-weeks, to 0.471 +/- 0.092 cm 6-weeks, and decreased to 0.451 +/- 0.104 cm at the post-season measurement. The 3-week and 6-week measures significantly increased from baseline (F3,72 = 8.575, p < .001). Achilles tendon CSA increased during the cross country season, but returned to baseline values at the end of a cross country season. Clinicians should be aware of the changing nature of the Achilles tendon CSA when treating cross country runners. PMID- 29399250 TI - A Comparison of Body Composition Across Two Phases of the Menstrual Cycle Utilizing Dual-Energy X-Ray Absorptiometry, Air Displacement Plethysmography, and Bioelectrical Impedance Analysis. AB - The purpose of this investigation was to utilize several different technologies to compare body composition results across two phases of the menstrual cycle, and to investigate whether being on hormonal birth control or not has any effect on results. The secondary purpose was to determine if body satisfaction or perception of fluid retention differed across phases or between groups. A total of 39 females with a mean age of 26 +/- 7 yrs were included in the study, 15 were on hormonal birth control (BC) and 24 were not (non-BC). Participants came into the lab for two trials: once while menstruating and another during the estimated pre-ovulation phase of the menstrual cycle. Demographic and body satisfaction questionnaires were completed prior to body composition testing. This testing included dual-energy x-ray absorptiometry, BOD POD(r), and three separate bioelectrical impedance analyses. Participants completed the body satisfaction questionnaire and all body composition tests on each trial. No significant differences (P > 0.05) were found between body fat percentage or total body water estimates taken during menses and pre-ovulation for the BC or non-BC group. There was no significant difference (P > 0.05) in overall body satisfaction across the two phases for the non-BC group, though the BC group had significantly lower body satisfaction during menses (P < 0.01). Participants in both groups identified feeling more bloated during menses (P < 0.001). Results suggest that menses should not affect the reliability of body composition estimates regardless of whether or not females are on hormonal BC. PMID- 29399251 TI - The Body Mass Index of San Francisco Cold-water Swimmers: Comparisons to U.S. National and Local Populations, and Pool Swimmers. AB - To determine if cold-water swimmers have substantial differences in BMI, which might have a protective effect against heat loss during swims in cold water without wetsuits, and to determine if obesity is more or less prevalent in cold water swimmers, we compared the body mass index (BMI) values of 103 recreational open-water swimmers (mean age 54.3 +/-10.8 years) to data from various population groups. Swimmers swam consistently throughout the winter months, in the San Francisco Bay (water temperature range: 9.6 degrees C [49.3 degrees F] to 12.6 degrees C [54.7 degrees F]), without wetsuits. After matching for age and sex, the average BMI of cold-water swimmers (25.9 kg/m2) was lower than the corresponding predicted U.S. average BMI (29.2 kg/m2; p<.001), the predicted California state average BMI (28.0 kg/m2; p<.001), and the predicted San Francisco city average BMI (26.6 kg/m2; p=.047). The average BMI value for cold water swimmers (25.9 kg/m2) was not significantly different from values of North American masters pool swimmers (25.1 kg/m2; p=.15) or international masters pool swimmers (25.3 kg/m2; p=.16). 10.7% of cold-water swimmers were classified as obese (BMI > 30 kg/m2) vs. 35.7%, 25.8%, and 11.8% of the U.S., California, and San Francisco populations, respectively. The lower or similar BMI values of our swimmers suggest that successful recreational swimming in cold water is influenced by factors other than body habitus, such as acclimatization, heat production while swimming, and most importantly, limiting immersion time. The relatively low prevalence of obesity in our swimmers suggests that cold-water swimming could contribute to a healthy lifestyle. PMID- 29399252 TI - Effects of Environmental Context on Physiological Response During Team Handball Small Sided Games. AB - This study examined the distance covered and physiological effects of altering the number of players during small-sided games (SSG) in team handball. Twelve professional female handball players [24.6+/-3.7 years, 172+/-6.2 cm, 68.2 +/- 9.9kg, 22.7 +/- 2 kg/m2] participated in this study. The SSG were played, first with five on each side (SSG 5), then four (SSG 4), then three (SSG 3). Each game was four minutes long, followed by three minutes of rest. The distance covered and time spent in four speed zones (based on player movement speed) were selected for analysis: Zone 1 (0-1.4 m/s), Zone 2 (1.5-3.4 m/s), Zone 3 (3.5-5.2 m/s), and Zone 4 (>5.2 m/s). Statistically significant differences were found in Zone 2, between conditions SSG 3 and SSG 4 (p=.049,omega2= .32). The highest average heart rate (HR) occurred during SSG 3. Average HR between SSG 3 (89.7 % HRmax) and SSG 5 (87.8 % HRmax) (p= .04, omega2= .26) were also significantly different. Participant HR response between the speed zones was not statistically significant. HR response was negatively correlated with the number of players within the SSG condition. Statistically significant results were found for RPE between SSG 3 and the other two SSG conditions (SSG 4, p = .01, and SSG 5, p = .00). These results indicate that changing the number of SSG players can be used to manipulate the physiological response during handball training. PMID- 29399253 TI - The Effects of Overfeeding on Body Composition: The Role of Macronutrient Composition - A Narrative Review. AB - Compared to investigations on hypocaloric diets, the effects of chronic overfeeding have been less studied. It has been posited that consuming calories in excess of daily caloric requirements will result in a gain in body weight and in particular fat mass regardless of which macronutrient(s) are consumed. However, recent evidence suggests that there is a quantitative difference in protein versus carbohydrate and/or fat overfeeding as it relates to body composition. Protein overfeeding or the consumption of a high protein diet may not result in a gain in body weight or fat mass despite consuming calories that exceed one's normal or habitual intake. Therefore, this review will provide an up to-date narrative on the current scientific literature on various combinations of macronutrient overfeeding and its effects on body composition. PMID- 29399255 TI - Treatment Satisfaction, Product Perception, and Quality of Life in Plaque Psoriasis Patients Using Betamethasone Dipropionate Spray 0.05. AB - Objective: To assess patient-reported satisfaction, efficacy, and tolerability associated with the use of betamethasone dipropionate spray 0.05% when applied twice daily in subjects with moderate plaque psoriasis. Design: This was an open label, multicenter study involving 45 patients with moderate plaque psoriasis, with the aim of evaluating patient-reported outcomes with betamethasone dipropionate spray 0.05%. Patients treated all affected areas twice daily with betamethasone dipropionate (BD) spray 0.05% for 28 days per label instructions. Measurements: Outcome measures included the Treatment Satisfaction Questionnaire for Medication (TSQM), Dermatology Life Quality Index (DLQI), Investigators Global Assessment (IGA), and Total Sign Score (TSS). In addition, the lesions were photographed at baseline (Day 1) and on Day 8, Day 14, and Day 29. Results: The results indicated that BD spray 0.05% treatment is associated with improved quality of life. BD spray 0.05% also led to improved IGA and TSS values and a reduction in the percentage of body surface area affected. Conclusion: In subjects with moderate plaque psoriasis, BD spray 0.05% demonstrated good levels of patient satisfaction and quality of life measures, in combination with improvements in the global assessment of disease and the level of itching experienced by subjects. PMID- 29399254 TI - Effects of a Supportive Audience on a Handgrip Squeezing Task in Adults. AB - The role of social facilitation by way of audience effect in select exercise related variables during an isometric handgrip task was assessed using a mixed design. Fifty three moderately active participants (Mage= 21.76 +/- 5.27) were recruited from the Midwestern United States. Participants were randomly assigned to one of two groups: supportive audience or control. Audience members provided positive verbal encouragement to participants in the experimental condition throughout the task performance. Participants in the control group performed the task in the absence of an audience and did not receive any verbal encouragement. Participants provided anxiety ratings pre- and post-task using the State-trait anxiety inventory for adults (STAI). Participants' ratings of perceived exertion (RPE) and heart rate (HR) were monitored and assessed at 30-second intervals. Upon task completion, sustained effort in the form of time on task was recorded in seconds. A repeated measures analysis of variance (RM ANOVA) revealed that there was a time effect within groups of HR = ( F(2.64, 131.85) = 189.3, p <0.001) and within groups of RPE = (F(2.97, 139.42) = 2189.43 p <0.001). An independent sample T-test revealed significant differences in HR at 0, 30 and 60 seconds between the groups. An independent sample T-test revealed no significant differences in anxiety and RPE between the groups. These results partially support the notion of social facilitation and may have implications for research and practice. PMID- 29399256 TI - Lip Measurements and Preferences in Asians and Hispanics: A Brief Review. AB - Objective: Most literature regarding lip augmentation refers to Caucasian anthropometric measurements, but ethnic differences affect facial dimensions and the evaluation of beauty. Specifically with regard to Asians and Hispanics, dermatology does not have much literature on the subject. This review investigates the differences in lip measurements and preferences of Asians and Hispanics compared with those of Caucasians. Design: A literature search of other fields, including plastic surgery, maxillofacial surgery, orthodontics, and forensic anthropology, was conducted, and relevant articles were selected that applied to the discussion of lip measurements and preferences in Asians and Hispanics. Results: Lip measurements do appear to differ between Asians, Hispanics, and Caucasians, and ethnic background appears to influence lip preferences. Conclusions: It is inappropriate to use Caucasian measurements and generalizations in lip preferences when determining what is "ideal" when aesthetically augmenting lips among Asians and Hispanics. Ultimately, it is important to take into account the goals, anatomy, and ethnic background of each individual patient before performing lip augmentation. PMID- 29399257 TI - Oxygeneo(r)-A Unique Three-in-one Treatment of Exfoliation, Infusion, and Oxygenation via the Bohr Effect and TriPollarTM Radiofrequency for Skin Rejuvenation. AB - Background: Oxygenation of the skin has been shown to improve cell growth and cell biosynthesis, which can subsequently improve the skin's appearance.1,2 However, the majority of skin oxygenation techniques are invasive.3,4 A noninvasive skin oxygenation treatment, also known as a carboxytherapy facial, with TriPollar(r) radiofrequency device has emerged called OxyGeneoTM, which is provided by the geneO+TM skin care platform (Pollogen Ltd., Tel Aviv, Israel). Objective: This study addresses the clinical effectiveness of the aforementioned noninvasive skin oxygenation treatment on skin texture, fine lines/wrinkles, and skin pigmentation over an eight-week time period. Methods and materials: Ten patients with fine lines, wrinkles, hyperpigmentation, and rough skin texture received six weekly treatments over a two-month period. Five patients received NeoReviveTM and five received NeoBrightTM topical infusions, with the selection made according to each individual's skin conditions and type. These patients were evaluated using the VISIA complexion analysis system (Canfield Scientific, Inc., Parsippany, New Jersey) and patient and evaluator assessments and satisfaction surveys. Results: Each individual measurement varied by patient, but the change in value of each category that was assessed prior to treatment and post-treatment indicated an improvement. All patients in the study stated an improvement in overall skin appearance, skin texture, brightness, and shininess. Nine out of the 10 patients reported that their skin was softer and had a more youthful appearance after the treatments, and seven out of the 10 patients saw a minor improvement in fine lines and wrinkles. Lastly, five out of the 10 patients noticed an improvement in skin pigmentation. Conclusion: The results indicated the combination of the three-in-one OxyGeneo treatment of exfoliation, infusion and oxygenation using TriPolar radiofrequency prompted an improvement in skin texture and tone. This is an optimal procedure that can be implemented in patients looking for noninvasive, safe, and effective rejuvenation treatments with no associated downtime post-procedure. PMID- 29399258 TI - Three-Day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: Cosmetic Outcomes and Patient Satisfaction from a Phase II Trial. AB - Objective: To report cosmetic outcomes and patient satisfaction with ingenol disoxate (LEO 43204) used in a once-daily, three-day field treatment regimen in patients with actinic keratosis. Design: This was a phase II, multicenter, open label trial (ClinicalTrials.gov: NCT02305888) involving 20 trial sites in the United States. Participants: Patients with between five and 20 clinically typical actinic keratoses lesions on the full face/250cm2 on the chest, 25cm2 to 250cm2 on the scalp, or 250cm2 on the trunk/extremities were included. Measurements: The assessment methods in this study included the examination of global photo-damage at Week 8; a cosmetic outcome questionnaire to evaluate the overall appearance and feel of the skin following treatment at Week 8; and a treatment satisfaction questionnaire for medication (TSQM) to evaluate patient satisfaction with treatment at Week 8. Results: Treatment adherence was high, with 97 percent of patients overall applying the full three-day regimen. Global photo-damage improvement was seen in 66, 69, and 72 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Improved overall appearance of the treatment area was reported by 95, 97, and 80 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. In addition, overall feel of the treatment area was reported as improved by 92, 95, and 70 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Overall, the mean scores for all four treatment satisfaction questionnaires for medication domains were high in each treatment group, ranging from 66.7/100 to 91.3/100. In particular, mean scores for global satisfaction were 73.9/100, 79.7/100, 66.7/100 for the face/chest, scalp, and trunk/extremities groups, respectively. Conclusion: Actinic keratosis field treatment with ingenol disoxate provided favorable cosmetic benefits and high treatment satisfaction. PMID- 29399259 TI - Doppler versus Histopathology in the Assessment of Egyptian Patients with Psoriasis Treated with Acitretin. AB - Psoriasis is one of the most common chronic inflammatory skin diseases, characterized by erythema and the formation of plaques. The diagnosis of psoriasis is based on clinical examination, and its severity is assessed by the Psoriasis Area and Severity Index. Histologic examination is still the standard method for the final diagnosis. Sonography has proved to be a suitable noninvasive imaging method for studying soft tissue in dermatologic diseases such as psoriasis. This study evaluated the effect of Doppler sonography in the assessment of psoriasis in comparison with histopathology. Clinical, multifrequency sonography, and histological examinations were completed in 30 patients with chronic plaque psoriasis before and after acitertin treatment. After a 12-week treatment period, there was a notable decrease of psoriatic plaques in 28 patients with Psoriasis Area and Severity Index-1 severity and in two patients with Psoriasis Area and Severity Index-2 severity. Multifrequency sonography results after treatment of the same plaques showed normal finding in five patients, mild sonographic changes in 24 patients, and moderate sonographic changes in one patient. Histopathology findings after treatment were normal epidermis and dermis in six patients, mild histopathological changes in 22 patients, and moderate changes in two patients. In conclusion, there were significant correlations between sonography and histopathology in the diagnosis and evaluation of a psoriatic skin treatment regimen. PMID- 29399260 TI - Effect of Miracle Fruit (Synsepalum dulcificum) Seed Oil (MFSO(r)) on the Measurable Improvement of Hair Breakage in Women with Damaged Hair: A Randomized, Double-blind, Placebo-controlled, Eight-month Trial. AB - Background: Hair breakage is a common unrecognized form of hair loss in women most often the result of hair weathering and traumatic grooming practices. Lipids are major determinants of the physical properties of the hair. Synsepalum dulcificum seed oil (MFSO(r); Miracle Fruit Oil Co., Miami Beach, Florida), is an exotic fruit oil with physicochemical properties suited to providing a superior ability to reduce hair breakage. Objective: To assess the safety and efficacy of a hair oil containing MFSO and its effects on hair breakage rates. Methods: Healthy, long-haired women (age range: 19-63 years, mean age: 36.7 years, standard deviation: 10.77 years) with excessive hair breakage were randomized in this double-blind, placebo-controlled study to receive MFSO (n=24), vehicle (n=17), or argan oil (n=16). Measurements of hair length, hair diameter, and Hair Mass Index were performed at baseline, Month 4, and Month 8. Hair Breakage Index and the Healthy Hair Index values were calculated from the trichometer measurements, and subject self-assessment questionnaires were conducted. The primary efficacy endpoints were the percent change in Healthy Hair Index 75 and Healthy Hair Index 50 measurements from baseline to the eighth month. Results: The Healthy Hair Index calculations, expressed as percent change from baseline to Month 4 and from baseline to Month 8, revealed that the MFSO(r) treatment group improved by 103.6 percent and 215.7 percent for the Healthy Hair Index 75 and 133.7 and 188.3 percent for the Healthy Hair Index 50 values, respectively. When compared with the vehicle and the argan oil brand groups, the Healthy Hair Index levels were significantly higher (p < 0.001) for the MFSO(r) treatment group, indicating a much greater ability to increase the levels of unbroken hairs by reducing hair breakage. With respect to the mean percent improvements from baseline to Month 4 and Month 8, the MFSO(r) hair oil treatment group was better than each of the other two treatment groups by at least 117.6 percent and 234.9 percent for the Healthy Hair Index 75 and 316.5 percent and 312 percent for the Healthy Hair Index 50 values, respectively, thereby achieving the primary efficacy objective. Subjects favored the MFSO(r) hair oil treatment, rating it as safe, effective, and aesthetically pleasing. Conclusions: The MFSO hair oil product is a safe and effective option for the treatment of women suffering from hair breakage and damaged hair. PMID- 29399261 TI - Hyaluronic Acid Sodium Salt 0.2% Gel in the Treatment of a Recalcitrant Distal Leg Ulcer: A Case Report. AB - Venous leg ulcers can lead to debilitation and a decrease in quality of life and can require costly treatments. Compression therapy remains the foundation of conservative treatment. However, some ulcers become indolent, chronic, and unresolved for years, even with adherence to standard of care. Here, the authors describe the case of a 56-year-old male patient with a recalcitrant recurrent distal leg ulcer. The ulcer was treated initially with debridement and compression therapy, respectively, and then subsequently with hyaluronic acid sodium salt 0.2% gel, which prompted complete wound closure. Hyaluronic acid is known to stimulate angiogenesis and exert fibrogenic action within inflamed and impaired healing tissues. Only a limited number of studies have been conducted to evaluate the clinical use of hyaluronic acid for treating venous leg ulcers. Success obtained with this patient should spur future clinical studies to fully evaluate this modality as a safe, efficacious, expeditious, and cost-effective option for the management of recalcitrant chronic ulcers. PMID- 29399262 TI - Optimizing Facial Rejuvenation with a Combination of a Novel Topical Serum and Injectable Procedure to Increase Patient Outcomes and Satisfaction. AB - BACKGROUND: Neuromodulator injection procedures are an effective treatment for moderate-to-severe facial wrinkles, but do not address the superficial fine lines and wrinkles caused by age-related loss of intrinsic hyaluronic acid levels in the epidermis. OBJECTIVE: In this study, the authors assess overall facial skin quality and patient satisfaction when combining topical treatment with the a topical cosmetic serum (HA5) and applying to the entire face following a pre elected neuromodulator injection treatment to the lateral canthal areas. METHODS AND MATERIALS: Twenty female subjects aged 36 to 63 years with moderate-to-severe under-the-eye fine lines and/or wrinkles enrolled in the study. HA5 was applied the entire face at baseline immediately post-injection and twice daily for eight weeks. Clinical assessments were conducted at baseline; 15 minutes post procedure; and at Weeks 2, 4, and 8. RESULTS: Statistically significant improvements were observed immediately post-procedure and after eight weeks, along with high patient satisfaction. CONCLUSION: The combination of topical serum and injectable procedure provided a rapid onset of improvements in fine lines/wrinkles appearance and skin texture and long-term overall improvements in areas not treated by the injection. These results support how this novel combination can provide physicians with a comprehensive approach to optimize patient outcomes. PMID- 29399263 TI - Three-day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: A Phase II Trial. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of ingenol disoxate gel using a once-daily, three-day field treatment regimen in patients with actinic keratosis. DESIGN: This was a Phase II, multicenter, open label trial (clinicaltrials.gov: NCT02305888). SETTING: The study was conducted in 20 trial sites in the United States. PARTICIPANTS: Participants included patients with 5 to 20 clinically typical actinic keratosis lesions on the full face/chest (250cm2), scalp (25-250cm2), or the trunk/extremities (250cm2). MEASUREMENTS: We measured incidence of dose-limiting events based on local skin responses. Percentage reduction in actinic keratosis lesion count from baseline, complete clearance, and partial clearance (>=75%) of actinic keratosis lesions were assessed at Week 8. RESULTS: Nine of 63 (14.3%) patients in the face/chest group reported dose-limiting events; zero of 63 patients in the scalp group reported dose-limiting events; and 11 of 62 (17.7%) patients in the trunk/extremities group reported dose-limiting events. Mean composite local skin response scores peaked at Day 4, then rapidly declined, reaching or approaching baseline levels by Week 4. Less than five percent of patients reported severe adverse events; the most common treatment-related adverse events were application site pain and pruritus. The reduction in actinic keratosis lesion count was 78.9, 76.3, and 69.1 percent for the face/chest, scalp, and trunk/extremities groups, respectively. Complete clearance was achieved in 36.5, 39.7, and 22.6 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Partial clearance was achieved in 71.4, 65.1, and 50.0 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. CONCLUSION: Ingenol disoxate demonstrated adverse events and local skin reaction profiles similar to results seen in trials evaluating shorter two-day regimens and was effective in patients with actinic keratosis. These data support the use of ingenol disoxate gel for actinic keratosis field treatment. PMID- 29399264 TI - Efficacy and Safety of an Anti-aging Technology for the Treatment of Facial Wrinkles and Skin Moisturization. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of five topical test products intended to reduce the appearance of lines and wrinkles, increase skin moisturization, and reduce transepidermal water loss. DESIGN: Two studies-a controlled clinical trial for each individual test product and an experience trial involving more than 200 patients using a strategic combination of products were done. Test products included a day facial cream, a night facial cream, an eye cream, a day lip cream, and a night lip cream. SETTING: The setting for the first study was AMA Laboratories (New York, New York)and 19 physician practices for the second. PARTICIPANTS: For the first study, participants were recruited via advertisements, phone solicitation, or electronic media. Patients of the second study (N=222) were from 19 physician practices. MEASUREMENTS: For the first study, efficacies of the facial and eye creams were determined by measuring the surface evaluation of living skin, transepidermal water loss, and electroconductivity. Efficacy of the lip creams was evaluated by measuring surface evaluation of living skin and electroconductivity. These evaluation parameters were measured at the test sites prior to initial application of test product,15 minutes after the initial application, and at seven, 14, 28, and 56 days of test product use. For the second study, each subject completed an assessment of the topical product(s) effects after four weeks of use. RESULTS: With each of the five topical test products, an improvement in surface evaluation of living skin became apparent within 15 minutes of initial application of test products and continued for at least 56 days of regular use. Electroconductivity data showed that each product dramatically increased the moisture content in the skin almost immediately after application and for at least 56 days. Improvement in transepidermal water loss was nearly immediate and continued over time with the day and night facial creams and eye cream. For the experience trial, a significant majority of subjects achieved one or more endpoints within 30 days or less. CONCLUSION: The facial, eye, and lip creams are effective anti-aging products that reduce the appearance of both fine and coarse lines and wrinkles, dramatically increase the moisturization of the skin, and, in the case of the face and eye products, reduces transepidermal water loss. These changes last for at least 56 days without significant adverse effects. PMID- 29399265 TI - Efficacy of Fractional Carbon Dioxide Laser in the Treatment of Mature Burn Scars: A Clinical, Histopathological, and Histochemical Study. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of fractional carbon dioxide laser use in the treatment of mature burn scars. DESIGN: This was an uncontrolled, open-label clinical trial. SETTING: The setting for this study was Dermatology Department at Cairo University in Cairo, Egypt. PARTICIPANTS: Twenty patients with mature burn scars were included in the study. MEASUREMENTS: Three fractional carbon dioxide laser sessions were given, 4 to 8 weeks apart. Primary outcome was measured using two scar scales, the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale. Secondary outcomes included evaluation of collagen and elastic fibers using routine hematoxylin and eosin, Masson's trichrome, and orcein stains. Outcomes were measured two months after the last laser session. RESULTS: Both Vancouver Scar Scale and Patient and Observer Scar Assessment Scale showed significant reduction following treatment (p<0.001). Scar relief and pliability improved most followed by vascularity. Pigmentation improved the least. Percent improvement in Patient and Observer Scar Assessment Scale patients' overall assessment was 44.44 percent. The pattern and arrangement of collagen and elastic fibers showed significant improvement (p<0.001, p=0.001, respectively), together with significant improvement in their amounts (p=0.020, p<0.001, respectively). No significant correlation existed between clinical and histopathological/histochemical scores. Side effects and complications were mild and tolerable. CONCLUSION: Fractional carbon dioxide laser use is an effective and safe method for treating burn scars with a significant change in the opinion of the patients about their scar appearance. PMID- 29399266 TI - A Retrospective Analysis of Surveillance Adherence of Patients after Treatment of Primary Cutaneous Melanoma. AB - BACKGROUND: Melanoma surveillance serves to identify new primary melanomas and curable locoregional or early distant recurrences. Although an optimal melanoma surveillance strategy has not been determined, several clinical guidelines exist. OBJECTIVE: The aim of this study was to identify demographic and clinico pathologic variables associated with poor adherence to National Comprehensive Cancer Network (NCCN) melanoma surveillance guidelines. DESIGN: We retrospectively reviewed the initial five-year dermatology follow-up visit frequencies of melanoma patients and extracted basic demographic and clinical data from their medical records. PARTICIPANTS: Of 186 patients included, the mean age was 55 (standard deviation=15); 47.5 percent (n=85) were female, 93.0 percent (n=173) were white, and 76.2 percent (n=141) were married. Sixty percent of patients lived at locations more than 10 miles from the clinic, and 58.6 percent had private insurance. MEASUREMENTS: "Aggressive" and "conservative" surveillance schedules were adapted from National Comprehensive Cancer Network visit frequency guidelines. RESULTS: Between 58.4 and 74.5 percent of patients adhered to "aggressive" surveillance, with decreasing rates over the five-year period. Annual rates of poor surveillance adherence (7.3-23.6%) increased over time. Based on adjusted odds ratios, patients younger than 50 years of age (odds ratios 2.11 [95% CI 1.13-3.93], p<0.05), those lacking health insurance (odds ratios 3.08 [95% CI 1.09-8.68], p<0.05), and those with at least Stage IIB disease (odds ratios 3.21 [95% CI 1.36-7.58], p<0.01) are more likely to be poorly adherent to melanoma surveillance. CONCLUSION: This study's findings highlight some variables associated with poor surveillance adherence among melanoma survivors that could help to guide efforts in counseling this at-risk population. PMID- 29399267 TI - Pseudocellulitis Need Not be Benign: Three Cases of Superficial Migratory Thrombophlebitis with "Negative" Venous Duplex Ultrasonography. AB - Trousseau syndrome is a rare phenomenon in cancer patients characterized by superficial migratory thrombophlebitis. In this brief report, the authors describe three recent case presentations of patients without a prior history of cancer who were treated for cellulitis prior to be admitted to the hospital. All three patients were found to have "negative" testing on venous duplex scanning. Communication with the technicians and additional clinical and laboratory evaluations confirmed Trousseau syndrome as well as an underlying hematologic cancer in each patient. Dermatologists should be aware of the diagnostic limitations in the venous duplex scanning, especially when evaluating superficial veins or areas overlying pain, and should recognize the importance of communicating with the technician performing the procedure. PMID- 29399268 TI - A Multialgorithm Approach to Land Surface Modeling of Suspended Sediment in the Colorado Front Range. AB - A new paradigm of simulating suspended sediment load (SSL) with a Land Surface Model (LSM) is presented here. Five erosion and SSL algorithms were applied within a common LSM framework to quantify uncertainties and evaluate predictability in two steep, forested catchments (>1,000 km2). The algorithms were chosen from among widely used sediment models, including empirically based: monovariate rating curve (MRC) and the Modified Universal Soil Loss Equation (MUSLE); stochastically based: the Load Estimator (LOADEST); conceptually based: the Hydrologic Simulation Program-Fortran (HSPF); and physically based: the Distributed Hydrology Soil Vegetation Model (DHSVM). The algorithms were driven by the hydrologic fluxes and meteorological inputs generated from the Variable Infiltration Capacity (VIC) LSM. A multiobjective calibration was applied to each algorithm and optimized parameter sets were validated over an excluded period, as well as in a transfer experiment to a nearby catchment to explore parameter robustness. Algorithm performance showed consistent decreases when parameter sets were applied to periods with greatly differing SSL variability relative to the calibration period. Of interest was a joint calibration of all sediment algorithm and streamflow parameters simultaneously, from which trade-offs between streamflow performance and partitioning of runoff and base flow to optimize SSL timing were noted, decreasing the flexibility and robustness of the streamflow to adapt to different time periods. Parameter transferability to another catchment was most successful in more process-oriented algorithms, the HSPF and the DHSVM. This first-of-its-kind multialgorithm sediment scheme offers a unique capability to portray acute episodic loading while quantifying trade-offs and uncertainties across a range of algorithm structures. PMID- 29399269 TI - Hindcasting the Madden-Julian Oscillation With a New Parameterization of Surface Heat Fluxes. AB - The recently developed maximum entropy production (MEP) model, an alternative parameterization of surface heat fluxes, is incorporated into the Weather Research and Forecasting (WRF) model. A pair of WRF cloud-resolving experiments (5 km grids) using the bulk transfer model (WRF default) and the MEP model of surface heat fluxes are performed to hindcast the October Madden-Julian oscillation (MJO) event observed during the 2011 Dynamics of the MJO (DYNAMO) field campaign. The simulated surface latent and sensible heat fluxes in the MEP and bulk transfer model runs are in general consistent with in situ observations from two research vessels. Compared to the bulk transfer model, the convection envelope is strengthened in the MEP run and shows a more coherent propagation over the Maritime Continent. The simulated precipitable water in the MEP run is in closer agreement with the observations. Precipitation in the MEP run is enhanced during the active phase of the MJO with significantly reduced regional dry and wet biases. Large-scale ocean evaporation is stronger in the MEP run leading to stronger boundary layer moistening to the east of the convection center, which facilitates the eastward propagation of the MJO. PMID- 29399270 TI - The Weighted-Average Lagged Ensemble. AB - A lagged ensemble is an ensemble of forecasts from the same model initialized at different times but verifying at the same time. The skill of a lagged ensemble mean can be improved by assigning weights to different forecasts in such a way as to maximize skill. If the forecasts are bias corrected, then an unbiased weighted lagged ensemble requires the weights to sum to one. Such a scheme is called a weighted-average lagged ensemble. In the limit of uncorrelated errors, the optimal weights are positive and decay monotonically with lead time, so that the least skillful forecasts have the least weight. In more realistic applications, the optimal weights do not always behave this way. This paper presents a series of analytic examples designed to illuminate conditions under which the weights of an optimal weighted-average lagged ensemble become negative or depend nonmonotonically on lead time. It is shown that negative weights are most likely to occur when the errors grow rapidly and are highly correlated across lead time. The weights are most likely to behave nonmonotonically when the mean square error is approximately constant over the range forecasts included in the lagged ensemble. An extreme example of the latter behavior is presented in which the optimal weights vanish everywhere except at the shortest and longest lead times. PMID- 29399271 TI - Extended Adjuvant Aromatase Inhibitor Therapy in Post-Menopausal Women. AB - Purpose of the review: To understand the evidence for extending adjuvant aromatase inhibitor (AI) therapy from 5 to 10 years in post-menopausal women with hormone receptor positive (HR+) breast cancer. Recent findings: Multiple large trials have investigated this question. The two trials most representative of the dilemma faced in clinical practice are the MA.17R and NSABP-B42 trials, which both investigated the benefit of continuing versus stopping AI therapy beyond 5 years. Both trials showed that extended AI therapy led to a reduction in new or recurrent breast cancers, but had no effect on survival outcomes when death from any cause was included. Summary: The decision to extend AI therapy beyond 5 years remains a personalized one based on a discussion of the projected risk of recurrence, the expected benefits of prolonged AI treatment, and the patient's ability to tolerate side effects so that quality of life is preserved. PMID- 29399272 TI - Parent-Adolescent Relationships among Chinese Immigrant Families: An Indigenous Concept of Qin. AB - This study investigated cultural meanings of positive Chinese parent-child relationships through exploration of an indigenous concept, qin, as experienced by Chinese American adolescents of immigrant parents. Semi-structured interviews were conducted with 15, first- and second-generation Chinese American high school students of immigrant parents, focusing on adolescents' descriptions of the meaning of qin and parental behaviors that foster this quality. According to the Chinese American adolescents who were interviewed, being qin with parents was characterized as closeness to parents and a general sense of togetherness and harmony; showing parents their love through respect, obedience, academic effort, and appreciation; and open communication with the parents particularly about school. This relationship is primarily fostered by parental devotion and sacrifice, particularly for the child's education, future opportunities, success, and needs. The results highlight the role of child reciprocation of love and devotion for the parents in a qin relationship. PMID- 29399273 TI - Role of inflammatory response in liver diseases: Therapeutic strategies. AB - Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus (HCV) infection, and sterile stressors (oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1beta and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro- or anti-apoptotic. Acute and chronic liver diseases are cytokine-driven diseases as several proinflammatory cytokines (IL-1alpha, IL-1beta, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1beta production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases. PMID- 29399274 TI - Preserved liver regeneration capacity after partial hepatectomy in rats with non alcoholic steatohepatitis. AB - AIM: To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH). METHODS: Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration. RESULTS: The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05). CONCLUSION: NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC. PMID- 29399276 TI - Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease. AB - AIM: To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis (CF) patients with hepatic steatosis as compared to normal CF controls. METHODS: We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging (ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls. RESULTS: Data was collected on 114 patients meeting inclusion criteria. Seventeen patients (14.9%) were found to have hepatic steatosis on imaging. Being overweight (BMI > 25) (P = 0.019) and having a higher ppFEV1 (75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level (27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes. CONCLUSION: Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher ppFEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis. PMID- 29399275 TI - Bioengineered humanized livers as better three-dimensional drug testing model system. AB - AIM: To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. METHODS: Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses. RESULTS: The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs. CONCLUSION: The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems. PMID- 29399277 TI - Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina. AB - AIM: To investigate any changing trends in the etiologies of hepatocellular carcinoma (HCC) in Argentina during the last years. METHODS: A longitudinal cohort study was conducted by 14 regional hospitals starting in 2009 through 2016. All adult patients with newly diagnosed HCC either with pathology or imaging criteria were included. Patients were classified as presenting non alcoholic fatty liver disease (NAFLD) either by histology or clinically, provided that all other etiologies of liver disease were ruled out, fatty liver was present on abdominal ultrasound and alcohol consumption was excluded. Complete follow-up was assessed in all included subjects since the date of HCC diagnosis until death or last medical visit. RESULTS: A total of 708 consecutive adults with HCC were included. Six out of 14 hospitals were liver transplant centers (n = 484). The prevalence of diabetes mellitus was 27.7%. Overall, HCV was the main cause of liver disease related with HCC (37%) including cirrhotic and non cirrhotic patients, followed by alcoholic liver disease 20.8%, NAFLD 11.4%, cryptogenic 9.6%, HBV 5.4% infection, cholestatic disease and autoimmune hepatitis 2.2%, and other causes 9.9%. A 6-fold increase in the percentage corresponding to NAFLD-HCC was detected when the starting year, i.e., 2009 was compared to the last one, i.e., 2015 (4.3% vs 25.6%; P < 0.0001). Accordingly, a higher prevalence of diabetes mellitus was present in NAFLD-HCC group 61.7% when compared to other than NAFLD-HCC 23.3% (P < 0.0001). Lower median AFP values at HCC diagnosis were observed between NAFLD-HCC and non-NAFLD groups (6.6 ng/mL vs 26 ng/mL; P = 0.02). Neither NAFLD nor other HCC etiologies were associated with higher mortality. CONCLUSION: The growing incidence of NAFLD-HCC documented in the United States and Europe is also observed in Argentina, a confirmation with important Public Health implications. PMID- 29399278 TI - Current state and clinical outcome in Turkish patients with hepatocellular carcinoma. AB - AIM: To investigate clinical, etiological, and prognostic features in patients with hepatocellular carcinoma. METHODS: Patients with hepatocellular carcinoma who were followed-up from 2001 to 2011 were included in the study. The diagnosis was established by histopathological and/or radiological criteria. We retrospectively reviewed clinical and laboratory data, etiology of primary liver disease, imaging characteristics and treatments. Child-Pugh and Barcelona Clinic Liver Cancer stage was determined at initial diagnosis. Kaplan-Meier survival analysis was done to find out treatment effect on survival. Risk factors for vascular invasion and overall survival were investigated by multivariate Cox regression analyses. RESULTS: Five hundred and forty-five patients with hepatocellular carcinoma were included in the study. Viral hepatitis was prevalent and 68 patients either had normal liver or were non-cirrhotic. Overall median survival was 16 (13-19) mo. Presence of extrahepatic metastasis was associated with larger tumor size (OR = 3.19, 95%CI: 1.14-10.6). Independent predictor variables of vascular invasion were AFP (OR = 2.95, 95%CI: 1.38-6.31), total tumor diameter (OR = 3.14, 95%CI: 1.01-9.77), and hepatitis B infection (OR = 5.37, 95%CI: 1.23-23.39). Liver functional reserve, tumor size/extension, AFP level and primary treatment modality were independent predictors of overall survival. Transarterial chemoembolization (HR = 0.38, 95%CI: 0.28-0.51) and radioembolization (HR = 0.36, 95%CI: 0.18-0.74) provided a comparable survival benefit in the real life setting. Surgical treatments as resection and transplantation were found to be associated with the best survival compared with loco-regional treatments (log-rank, P < 0.001). CONCLUSION: Baseline liver function, oncologic features including AFP level and primary treatment modality determines overall survival in patients with hepatocellular carcinoma. PMID- 29399279 TI - Predicting early outcomes of liver transplantation in young children: The EARLY study. AB - AIM: To determine potentially modifiable predictors of early outcomes after liver transplantation in children of age < 3 years. METHODS: This study was a retrospective chart review including all consecutive children of age less than 3 years-old having had a liver transplant done at the Western Canadian referral center from June 2005 to June 2015. Pre-specified potential predictor variables and primary and secondary outcomes were recorded using standard definitions and a case report form. Associations between potential predictor variables and outcomes were determined using univariate and multiple logistic [odds ratio (OR); 95%CI] or linear (effect size, ES; 95%CI) regressions. RESULTS: There were 65 children, of mean age 11.9 (SD 7.1) mo and weight 8.5 (2.1) kg, with biliary-atresia in 40 (62%), who had a living related donor [LRD; 29 (45%)], split/reduced [21 (32%)] or whole liver graft [15 (23%)]. Outcomes after liver transplant included: ventilator-days of 12.5 (14.1); pediatric intensive care unit mortality of 5 (8%); re-operation in 33 (51%), hepatic artery thrombosis (HAT) in 12 (19%), portal vein thrombosis (PVT) in 11 (17%), and any severe complication (HAT, PVT, bile leak, bowel perforation, intraabdominal infection, retransplant, or death) in 32 (49%) patients. Predictors of the prespecified primary outcomes on multiple regression were: (1) HAT: split/reduced (OR 0.06; 0.01, 0.76; P = 0.030) or LRD (OR 0.16; 0.03, 0.95; P = 0.044) vs whole liver graft; and (2) ventilator-days: surgeon (P < 0.05), lowest antithrombin (AT) postoperative day 2-5 (ES -0.24; 0.47, -0.02; P = 0.034), and split/reduced (ES -12.5; -21.8, -3.2; P = 0.009) vs whole-liver graft. Predictors of the pre-specified secondary outcomes on multiple regression were: (1) any thrombosis: LRD (OR 0.10; 0.01, 0.71; P = 0.021) or split/reduced (OR 0.10; 0.01, 0.85; P = 0.034) vs whole liver graft, and lowest AT postoperative day 2-5 (OR 0.93; 0.87, 0.99; P = 0.038); and (2) any severe complication: surgeon (P < 0.05), lowest AT postoperative day 2-5 (OR 0.92; 0.86 0.98; P = 0.016), and split/reduced (OR 0.06; 0.01, 0.78; P = 0.032) vs whole liver graft. CONCLUSION: In young children, whole liver graft and surgeon was associated with more complications, and higher AT postoperative day 2-5 was associated with fewer complications early after liver transplantation. PMID- 29399280 TI - Collagen proportionate area correlates to hepatic venous pressure gradient in non abstinent cirrhotic patients with alcoholic liver disease. AB - AIM: To explore the relationship between collagen proportionate area (CPA) and portal hypertension-related clinical manifestations in alcoholic liver disease (ALD). METHODS: Retrospective study with chart review of patients with ALD adressed to our center between January 2012 and December 2013 for a transjugular liver biopsy (TJLB) and hepatic hemodynamic study. Patients were included if they met the following criteria: (1) Medical indication for a liver biopsy in the setting of ALD; (2) recent (< 15 d) clinical, radiological, endoscopic and biological data available; and (3) estimated follow-up of at least 6 mo. Liver tissue from cirrhotic subjects obtained from transjugular liver biopsies was stained with PicroSirius red and computer-assisted digital image analysis to determine fibrosis density using CPA was performed. RESULTS: We included 61 patients with alcoholic ALD, subdivided in 41 active alcohol drinkers and 20 durably abstinent patients. Nine healthy liver donors served as controls. Mean CPA in patients with ALD was 7.1%, with no difference between active drinkers and abstinent patients (P = 0.17). Using a fibrosis density cutoff of 5%, we observed a positive correlation between high fibrosis density and the hepatic venous pressure gradient (HVPG) only in active drinkers (P = 0.02). At 12-mo of follow up, in the group of active alcohol drinkers, patients reaching a composite outcome showed a higher HVPG value as compared to those who did not (18.5 mmHg vs 14.5 mmHg P < 0.04) whereas CPA values were similar (6.9% vs 11%, P = 0.23). CONCLUSION: In active alcoholic ALD, CPA correlates to portal pressure but only HVPG predicts clinical events, pointing to the role of alcohol as a modulator of portal hypertension. PMID- 29399281 TI - Ratio of mean platelet volume to platelet count is a potential surrogate marker predicting liver cirrhosis. AB - AIM: To provide a simple surrogate marker predictive of liver cirrhosis (LC). METHODS: Specimens from 302 patients who underwent resection for hepatocellular carcinoma between January 2006 and December 2012 were retrospectively analyzed. Based on pathologic findings, patients were divided into groups based on whether or not they had LC. Parameters associated with hepatic functional reserve were compared in these two groups using Mann-Whitney U-test for univariate analysis. Factors differing significantly in univariate analyses were entered into multivariate logistic regression analysis. RESULTS: There were significant differences between the LC group (n = 100) and non-LC group (n = 202) in prothrombin activity, concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, cholinesterase, type IV collagen, hyaluronic acid, indocyanine green retention rate at 15 min, maximal removal rate of technitium-99m diethylene triamine penta-acetic acid-galactosyl human serum albumin and ratio of mean platelet volume to platelet count (MPV/PLT). Multivariate analysis showed that prothrombin activity, concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin and hyaluronic acid, and MPV/PLT ratio were factors independently predictive of LC. The area under the curve value for MPV/PLT was 0.78, with a 0.8 cutoff value having a sensitivity of 65% and a specificity of 78%. CONCLUSION: The MPV/PLT ratio, which can be determined simply from the complete blood count, may be a simple surrogate marker predicting LC. PMID- 29399282 TI - Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience. AB - AIM: To evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital. METHODS: All patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12). RESULTS: A total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR. CONCLUSION: The SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs. PMID- 29399283 TI - Efficacy of intra-arterial contrast-enhanced ultrasonography during transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. AB - AIM: To assess the usefulness of intra-arterial contrast-enhanced ultrasonography (IAUS) during transarterial chemoembolization (TACE) with drug-eluting beads (DEB) for hepatocellular carcinoma (HCC). METHODS: Thirty two patients with 39 HCC underwent DEB-TACE guided with IAUS, and examined by contrast-enhanced ultrasonography (CEUS) or dynamic CT after DEB-TACE were enrolled in this study. CEUS findings before DEB-TACE and IAUS findings were compared. Treatments judged to be complete and incomplete for lesions were appropriate and insufficient, respectively. Findings on CEUS and/or dynamic CT performed 1, 3 and 6 mo after DEB-TACE were evaluated using mRECIST (CR/PR/SD/PD). RESULTS: The treatments were complete and incomplete in 26 and 13 lesions, respectively. On imaging evaluation using CEUS and/or dynamic CT one month after treatment, 25 and 1 lesions were judged to be CR and PR, respectively, and at 6 mo after treatment, the results were CR, PR, SD and PD for 24, 1, 0 and 1 of these lesions, respectively, in the 26 completely treated lesions. Of the 13 lesions in which treatment was incomplete, the results on imaging at one month after treatment were CR, PR, SD and PD for 0, 6, 4 and 3 lesions, respectively. The overall CR rate at 6 mo after treatment was 61.5% (24/39). CONCLUSION: A combination of DEB-TACE with IAUS can improve the therapeutic effects in patients with HCC. PMID- 29399284 TI - Proton nuclear magnetic resonance-based metabonomic models for non-invasive diagnosis of liver fibrosis in chronic hepatitis C: Optimizing the classification of intermediate fibrosis. AB - AIM: To develop metabonomic models (MMs), using 1H nuclear magnetic resonance (NMR) spectra of serum, to predict significant liver fibrosis (SF: Metavir >= F2), advanced liver fibrosis (AF: METAVIR >= F3) and cirrhosis (C: METAVIR = F4 or clinical cirrhosis) in chronic hepatitis C (CHC) patients. Additionally, to compare the accuracy of the MMs with the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4). METHODS: Sixty-nine patients who had undergone biopsy in the previous 12 mo or had clinical cirrhosis were included. The presence of any other liver disease was a criterion for exclusion. The MMs, constructed using partial least squares discriminant analysis and linear discriminant analysis formalisms, were tested by cross-validation, considering SF, AF and C. RESULTS: Results showed that forty two patients (61%) presented SF, 28 (40%) AF and 18 (26%) C. The MMs showed sensitivity and specificity of 97.6% and 92.6% to predict SF; 96.4% and 95.1% to predict AF; and 100% and 98.0% to predict C. Besides that, the MMs correctly classified all 27 (39.7%) and 25 (38.8%) patients with intermediate values of APRI and FIB-4, respectively. CONCLUSION: The metabonomic strategy performed excellently in predicting significant and advanced liver fibrosis in CHC patients, including those in the gray zone of APRI and FIB-4, which may contribute to reducing the need for these patients to undergo liver biopsy. PMID- 29399285 TI - High burden of hepatocellular carcinoma and viral hepatitis in Southern and Central Vietnam: Experience of a large tertiary referral center, 2010 to 2016. AB - AIM: To examine the largest tertiary referral center in southern and central Vietnam from 2010 to 2016, evaluating epidemiological trends of hepatocellular carcinoma (HCC) and viral hepatitis B-C in this resource-limited setting. METHODS: We extracted data of patients receiving care from Cho Ray Hospital (Ho Chi Minh City), the largest oncology referral center in southern and central Vietnam, from 2010 to 2016. We collected information on patient age, gender, geographic distribution, and disease characteristics including disease stage, tumor biomarker levels [serum alpha-fetoprotein (AFP), AFP-L3 isoform percentage, and prothrombin induced by induced by vitamin K absence-II], and serological testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. RESULTS: Data from 24091 HCC patients were extracted, with sample demographics comprising mostly male (81.8%) and older age (however with 8.5% younger than 40 years old). This patient sample included a geographic catchment population of 56 million people (60% of the country's total population of 92.7 million), derived from 38 provinces and municipalities in Vietnam. Chronic HBV infection was found in 62.3% of cases, and chronic HCV infection in 26.0%. HBV and HCV co-infection was seen in 2.7%. Cirrhosis was found in an estimated 30% to 40% of cases. Nine percent of patients were not found to have chronic viral hepatitis. Twenty three point two percent of the patients had a normal AFP level. A total of 2199 patients were tested with AFP-L3 and PIVKA II over two years, with 57.7% having elevated AFP-L3%, and 88.5% with elevated PIVKA II levels. Over this 7-year period, the incidence of HCC increased, with a large proportion of cases (overall 40.8%) presenting initially an advanced stage, not amendable to surgical or locoregional therapy. CONCLUSION: HCC contributes significant health care burden in southern and central Vietnam, with increasing case volume over this seven-year period. Viral hepatitis likely explains this high HCC prevalence. PMID- 29399286 TI - Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites. AB - AIM: To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS: We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS: We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION: Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections. PMID- 29399287 TI - Effect of transplant center volume on post-transplant survival in patients listed for simultaneous liver and kidney transplantation. AB - AIM: To examine the effect of center size on survival differences between simultaneous liver kidney transplantation (SLKT) and liver transplantation alone (LTA) in SLKT-listed patients. METHODS: The United Network of Organ Sharing database was queried for patients >= 18 years of age listed for SLKT between February 2002 and December 2015. Post-transplant survival was evaluated using stratified Cox regression with interaction between transplant type (LTA vs SLKT) and center volume. RESULTS: During the study period, 393 of 4580 patients (9%) listed for SLKT underwent a LTA. Overall mortality was higher among LTA recipients (180/393, 46%) than SLKT recipients (1107/4187, 26%). The Cox model predicted a significant survival disadvantage for patients receiving LTA vs SLKT [hazard ratio, hazard ratio (HR) = 2.85; 95%CI: 2.21, 3.66; P < 0.001] in centers performing 30 SLKT over the study period. This disadvantage was modestly attenuated as center SLKT volume increased, with a 3% reduction (HR = 0.97; 95%CI: 0.95, 0.99; P = 0.010) for every 10 SLKs performed. CONCLUSION: In conclusion, LTA is associated with increased mortality among patients listed for SLKT. This difference is modestly attenuated at more experienced centers and may explain inconsistencies between smaller-center and larger registry-wide studies comparing SLKT and LTA outcomes. PMID- 29399288 TI - Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta analysis of pooled data. AB - AIM: To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Two individual reviewers identified relevant studies using the PubMed, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows: (1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and (2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P < 0.05 was considered statistically significant. RESULTS: A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference = -0.86, P = 0.08 (-4.17, 2.46)]. A meta-regression evaluation of serum vitamin 25 (OH)D levels across the individual stages (F0-F4) of fibrosis did not show an association for the six included studies. CONCLUSION: Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD. PMID- 29399289 TI - Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta analysis. AB - AIM: To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis. METHODS: PubMed and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationally-predicted annotations for significant association of genes to curated molecular pathways. RESULTS: From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and cAMP-mediated signalling. CONCLUSION: Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome. PMID- 29399290 TI - Contrast uptake in primary hepatic angiosarcoma on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in the hepatobiliary phase. AB - Primary hepatic angiosarcoma is the most common malignant mesenchymal tumor of the liver. It has a poor prognosis and various appearances on magnetic resonance (MR) images. We report a case of hepatic angiosarcoma with a characteristic appearance on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB DTPA)-enhanced MR imaging in the hepatobiliary phase. A 72-year-old man was admitted with a complaint of abdominal pain. Gd-EOB-DTPA-enhanced MR imaging revealed a liver tumor that showed slight hyperintensity in the hepatobiliary phase. These findings suggested Gd-EOB-DTPA uptake in the tumor. An autopsy revealed the solid proliferation and sinusoidal spreading of hepatic angiosarcoma cells. Immunohistochemistry indicated that the tumor was negative for OATP1B3. Gd EOB-DTPA uptake in the liver tumor in the hepatobiliary phase suggested sinusoidal tumor invasion with residual normal hepatocytes. PMID- 29399291 TI - Sageretia thea fruit extracts rich in methyl linoleate and methyl linolenate downregulate melanogenesis via the Akt/GSK3beta signaling pathway. AB - BACKGROUND/OBJECTIVES: Sageretia thea is traditionally used as a medicinal herb to treat various diseases, including skin disorders, in China and Korea. This study evaluated the inhibitory effect of Sageretia thea fruit on melanogenesis and its underlying mechanisms in B16F10 mouse melanoma cells. The active chemical compounds in anti-melanogenesis were determined in Sageretia thea. MATERIALS/METHODS: Solvent fractions from the crude extract were investigated for anti-melanogenic activities. These activities and the mechanism of anti melanogenesis in B16F10 cells were examined by determining melanin content and tyrosinase activity, and by performing western blotting. RESULTS: The n-hexane fraction of Sageretia thea fruit (HFSF) exhibited significant anti-melanogenic activity among the various solvent fractions without reducing viability of B16F10 cells. The HFSF suppressed the expression of tyrosinase and tyrosinase-related protein 1 (TRP1). The reduction of microphthalmia-associated transcription factor (MITF) expression by the HFSF was mediated by the Akt/glycogen synthase kinase 3 beta (GSK3beta) signaling pathway, which promotes the reduction of beta-catenin. Treatment with the GSK3beta inhibitor 6-bromoindirubin-3'-oxime (BIO) restored HFSF-induced inhibition of MITF expression. The HFSF bioactive constituents responsible for anti-melanogenic activity were identified by bioassay-guided fractionation and gas chromatography-mass spectrometry analysis as methyl linoleate and methyl linolenate. CONCLUSIONS: These results indicate that HFSF and its constituents, methyl linoleate and methyl linolenate, could be used as whitening agents in cosmetics and have potential for treating hyperpigmentation disorders in the clinic. PMID- 29399292 TI - Anti-neuroinflammatory effects of ethanolic extract of black chokeberry (Aronia melanocapa L.) in lipopolysaccharide-stimulated BV2 cells and ICR mice. AB - BACKGROUND/OBJECTIVES: One of the mechanisms considered to be prevalent in the development of Alzheimer's disease (AD) is hyper-stimulation of microglia. Black chokeberry (Aronia melanocapa L.) is widely used to treat diabetes and atherosclerosis, and is known to exert anti-oxidant and anti-inflammatory effects; however, its neuroprotective effects have not been elucidated thus far. MATERIALS/METHODS: We undertook to assess the anti-inflammatory effect of the ethanolic extract of black chokeberry friut (BCE) in BV2 cells, and evaluate its neuroprotective effect in the lipopolysaccharide (LPS)-induced mouse model of AD. RESULTS: Following stimulation of BV2 cells by LPS, exposure to BCE significantly reduced the generation of nitric oxide as well as mRNA levels of numerous inflammatory factors such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha). In addition, AD was induced in a mouse model by intraperitoneal injection of LPS (250 ug/kg), subsequent to which we investigated the neuroprotective effects of BCE (50 mg/kg) on brain damage. We observed that BCE significantly reduced tissue damage in the hippocampus by downregulating iNOS, COX-2, and TNF-alpha levels. We further identified the quinic acids in BCE using liquid chromatography-mass spectrometry (LCMS). Furthermore, we confirmed the neuroprotective effect of BCE and quinic acid on amyloid beta-induced cell death in rat hippocampal primary neurons. CONCLUSIONS: Our findings suggest that black chokeberry has protective effects against the development of AD. PMID- 29399293 TI - Anti-hyperglycemic effects and signaling mechanism of Perilla frutescens sprout extract. AB - BACKGROUND/OBJECTIVES: Perilla frutescens (L.) Britton var. (PF) sprout is a plant of the labiate family. We have previously reported the protective effects of PF sprout extract on cytokine-induced beta-cell damage. However, the mechanism of action of the PF sprout extract in type 2 diabetes (T2DM) has not been investigated. The present study was designed to study the effects of PF sprout extract and signaling mechanisms in the T2DM mice model using C57BL/KsJ-db/db (db/db) mice. MATERIALS/METHODS: Male db/db mice were orally administered PF sprout extract (100, 300, and 1,000 mg/kg of body weight) or rosiglitazone (RGZ, positive drug, 1 mg/kg of body weight) for 4 weeks. Signaling mechanisms were analyzed using liver tissues and HepG2 cells. RESULTS: The PF sprout extract (300 and 1,000 mg/kg) significantly reduced the fasting blood glucose, serum insulin, triglyceride and total cholesterol levels in db/db mice. PF sprout extract also significantly improved glucose intolerance and insulin sensitivity, decreased hepatic gluconeogenic protein expression, and ameliorated histological alterations of the pancreas and liver. Levels of phosphorylated AMP-activated protein kinase (AMPK) protein expression also increased in the liver after treatment with the extract. In addition, an increase in the phosphorylation of AMPK and decrease in the phosphoenolpyruvate carboxykinase and glucose 6 phosphatase proteins in HepG2 cells were also observed. CONCLUSIONS: Our results sugges that PF sprout displays beneficial effects in the prevention and treatment of type 2 diabetes via modulation of the AMPK pathway and inhibition of gluconeogenesis in the liver. PMID- 29399294 TI - Topical or oral treatment of peach flower extract attenuates UV-induced epidermal thickening, matrix metalloproteinase-13 expression and pro-inflammatory cytokine production in hairless mice skin. AB - BACKGROUND/OBJECTIVES: Ultraviolet radiation (UV) is a major cause of skin photoaging. Previous studies reported that ethanol extract (PET) of Prunus persica (L.) Batsch flowers (PPF, peach flowers) and its subfractions, particularly the ethylacetate (PEA) and n-butanol extracts (PBT), have potent antioxidant activity and attenuate the UV-induced matrix metalloproteinase (MMP) expression in human skin cells. In this study, we investigated the protective activity of PPF extract against UV-induced photoaging in a mouse model. MATERIALS/METHODS: Hairless mice were treated with PET or a mixture of PEA and PBT either topically or orally along with UV irradiation. Histological changes and biochemical alterations of mouse skin were examined. Major phenolic compounds in PPF extract were analyzed using an ACQUITY UPLC system. RESULTS: The overall effects of topical and oral treatments with PPF extract on the UV-induced skin responses exhibited similar patterns. In both experiments, the mixture of PEA and PBT significantly inhibited the UV-induced skin and epidermal thickening, while PET inhibited only the UV-induced epidermal thickening. Treatment of PET or the mixture of PEA and PBT significantly inhibited the UV-induced MMP-13 expression, but not typeI collagen expression. Topical treatment of the mixture of PEA and PBT with UV irradiation significantly elevated catalase, superoxide dismutase (SOD) and glutathione-peroxidase (GPx) activities in the skin compared to those in the UV irradiated control group, while oral treatment of the mixture of PEA and PBT or PET elevated only catalase and SOD activities, but not GPx. Thirteen phytochemical compounds including 4-O-caffeoylquinic acid, cimicifugic acid E and B, quercetin-3-O-rhamnoside and kaempferol glycoside derivatives were identified in the PPF extract. CONCLUSIONS: These results demonstrate that treatment with PET or the mixture of PEA and PBT, both topically or orally, attenuates UV induced photoaging via the cooperative interactions of phenolic components having anti-oxidative and collagen-protective activities. PMID- 29399295 TI - Radioprotective effects of delphinidin on normal human lung cells against proton beam exposure. AB - BACKGROUND/OBJECTIVES: Exposure of the normal lung tissue around the cancerous tumor during radiotherapy causes serious side effects such as pneumonitis and pulmonary fibrosis. Radioprotectors used during cancer radiotherapy could protect the patient from side effects induced by radiation injury of the normal tissue. Delphinidin has strong antioxidant properties, and it works as the driving force of a radioprotective effect by scavenging radiation-induced reactive oxygen species (ROS). However, no studies have been conducted on the radioprotective effect of delphinidin against high linear energy transfer radiation. Therefore, this study was undertaken to evaluate the radioprotective effects of delphinidin on human lung cells against a proton beam. MATERIALS/METHODS: Normal human lung cells (HEL 299 cells) were used for in vitro experiments. The 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay assessed the cytotoxicity of delphinidin and cell viability. The expression of radiation induced cellular ROS was measured by the 2'-7'-dicholordihydrofluorescein diacetate assay. Superoxide dismutase activity assay and catalase activity assay were used for evaluating the activity of corresponding enzymes. In addition, radioprotective effects on DNA damage-induced cellular apoptosis were evaluated by Western blot assay. RESULTS: Experimental analysis, including cell survival assay, MTT assay, and Western blot assay, revealed the radioprotective effects of delphinidin. These include restoring the activities of antioxidant enzymes of damaged cells, increase in the levels of pro-survival protein, and decrease of pro-apoptosis proteins. The results from different experiments were compatible with each to provide a substantial conclusion. CONCLUSION: Low concentration (2.5 uM/mL) of delphinidin administration prior to radiation exposure was radioprotective against a low dose of proton beam exposure. Hence, delphinidin is a promising shielding agent against radiation, protecting the normal tissues around a cancerous tumor, which are unintentionally exposed to low doses of radiation during proton therapy. PMID- 29399296 TI - Folate food source, usual intake, and folate status in Korean adults. AB - BACKGROUND/OBJECTIVES: The purposes of the study were to investigate folate intakes and plasma folate concentrations as well as estimate folate status in Korean healthy adults. SUBJECTS/METHODS: A total of 254 healthy 19- to 64-year old adults (68 men and 186 women) living in Seoul metropolitan area, Gumi, and Kwangju, Korea participated. Three consecutive 24-hour dietary recalls, information on folate supplementation, and fasting blood samples were collected from the subjects. RESULTS: The mean dietary folate intakes were 587.4 and 499.2 ug dietary folate equivalent (DFE)/day for men and women, respectively. The median dietary intakes of men and women were 566.6 and 474.6 ug DFE/day, respectively. Forty subjects (16.7% of total) less total folate than the estimated average requirement (EAR). Folate intakes of 23.3% of men and 34.8% of women aged 19-29 years did not meet the EAR for folate. Major food sources consumed for dietary folate were baechukimchi (Chinese cabbage kimchi), rice, spinach, eggs, and laver, which provided 44% of dietary folate intake for the subjects. Plasma folate concentrations were 23.4 nmol/L for men and 28.3 nmol/L for women, and this level was significantly lower in men than in women. Approximately 13% of men and 3% of women were folate-deficient, and the percentages of subjects showing folate concentrations lower than 10 nmol/L were 27.9% of men and 6.4% of women. CONCLUSIONS: Folate intakes of Korean adults in this study were generally adequate. However, one-third of young adults had inadequate folate intakes. PMID- 29399297 TI - Development of quantitative index evaluating anticancer or carcinogenic potential of diet: the anti-cancer food scoring system 1.0. AB - BACKGROUND/OBJECTIVE: Cancer is closely related to diet. One of the most reliable reports of the subject is the expert report from the World Cancer Research Fund & American Institute of Cancer Research (WCRF&AICR). However, majority of the studies including above were written with academic terms and in English. The aim of this study is to create a model, named Anti-Cancer Food Scoring System (ACFS), to provide a simple index of the anticancer potential of food. SUBJECTS/METHODS: We created ACFS codes of various food groups. The evidence of the ACFS codes was provided by the literature at a level comparable to that suggested in the WCRF&AICR report or from the WCRF&AICR report. The ACFS grade was calculated considering food group, cooking, and normalization. Application was performed for Koreans' 20 common meals, which encompass multinational recipes. RESULT: We calculated the ACFS grades of Koreans' 20 common meals. The results were not significantly different from the WCRF&AICR guidelines or information from the National Cancer Information Center of Korea. The grades were briefly interpreted as follows: grade S. ideal for cancer prevention; grade A. good for cancer prevention; grade B, might have anticancer potential; grade C, difficult to be regarded as preventive or carcinogenic; grade D, might against cancer prevention; grade E, probably against cancer prevention. CONCLUSIONS: The ACFS provides a simple index of anticancer potential of diets. This indicator can be useful for the people without expertise, and is effective in evaluating the diets including Asian foods. The ACFS can help design of future clinical or nutritional studies of cancer prevention. PMID- 29399298 TI - Apolipoprotein A5 3'-UTR variants and cardiometabolic traits in Koreans: results from the Korean genome and epidemiology study and the Korea National Health and Nutrition Examination Survey. AB - BACKGROUND/OBJECTIVES: This study aimed to test the association between APOA5 3' UTR variants (rs662799) and cardiometabolic traits in Koreans. SUBJECTS/METHODS: For this study, epidemiological data, Apolipoprotein A5 (APOA5) genotype information, and lymphoblastoid cell line (LCL) biospecimens from a subset of the Ansung-Ansan cohort within the Korean Genome and Epidemiology study (KoGES-ASAS; n = 7,704) as well as epidemiological data along with genomic DNA biospecimens of participants from a subset of the Korea National Health and Nutrition Examination Survey (KNHANES 2011-12; n = 2,235) were obtained. APOA5 mRNA expression was also measured. RESULTS: APOA5 rs662799 genotype distributions in both the KoGES-ASAS and KNHANES groups were 50.6% for TT, 41.3% for TC, and 8.1% for CC, which are similar to those in previous reports. In both groups, minor C allele carriers, particularly subjects with CC homozygosity, had lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels than TT homozygotes. Linear regression analysis showed that the minor C allele significantly contributed to reduction of circulating HDL cholesterol levels [beta = -2.048, P < 0.001; beta = -2.199, P < 0.001] as well as elevation of circulating triglyceride levels [beta = 0.053, P < 0.001; beta = 0.066, P < 0.001] in both the KoGES-ASAS and KNHANES groups. In addition, higher expression levels of APOA5 in LCLs of 64 healthy individuals were negatively associated with body mass index (r = -0.277, P = 0.027) and circulating triglyceride level (r = -0.340, P = 0.006) but not significantly correlated with circulating HDL cholesterol level. On the other hand, we observed no significant difference in the mRNA level of APOA5 according to APOA5 rs662799 polymorphisms. CONCLUSIONS: The C allele of APOA5 rs662799 was found to be significantly associated with cardiometabolic traits in a large Korean population from the KoGES-ASAS and KNHANES. The effect of this genotype may be associated with post-transcriptional regulation, which deserves further experimental confirmation. PMID- 29399299 TI - Self-management levels of diet and metabolic risk factors according to disease duration in patients with type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Metabolic risk factors should be managed effectively in patients with type 2 diabetes mellitus (T2DM) to prevent or delay diabetic complications. This study aimed to compare the self-management levels of diet and metabolic risk factors in patients with T2DM, according to the duration of illness, and to examine the trends in self-management levels during the recent decades. SUBJECTS/METHODS: Data were collected from the Korea National Health and Nutrition Examination Surveys (KNHANES, 1998-2014). In our analysis, 4,148 patients with T2DM, aged >= 30 years, were categorized according to the duration of their illness (< 5 years, 5-9 years, and >= 10 years). Demographic and lifestyle information was assessed through self-administered questionnaires, and biomarker levels (e.g., fasting glucose level, blood pressure, or lipid level) were obtained from a health examination. Dietary intake was assessed by a 24 recall, and adherence level to dietary guidelines (meal patterns and intake levels of calories, carbohydrates, vegetable/seaweed, sodium, and alcohol) were assessed. Multivariable generalized linear regression and unconditional logistic regression models were used to compare the prevalence rates of hyperglycemia, dyslipidemia, and hypertension according to the duration of patients' illness, accounting for the complex survey design of the KNHANES. RESULTS: In the multivariable adjusted models, patients with a longer duration (>= 10 years) of T2DM had a higher prevalence of hyperglycemia than those with a shorter duration of T2DM (< 5 years) (odds ratio 2.20, 95% confidence interval 1.61-3.01, P for trend < 0.001). We did not observe any associations of disease duration with the prevalence of hypertension and dyslipidemia. In addition, the adherence levels to dietary recommendations did not significantly differ according to disease duration, except adherence to moderate alcohol consumption. There were significant decreasing trends in the prevalence of hyperglycemia in patients with a duration of illness >= 10 years (P for trend = 0.004). CONCLUSION: Although the proportion of patients with adequate control of glucose levels has improved in recent decades, poorer self-management has been found in those with a longer disease duration. These findings suggest the need for well-planned and individualized patient education programs to improve self-management levels and quality of life by preventing or delaying diabetic complications. PMID- 29399301 TI - A Mixed Application of Geographically Weighted Regression and Unsupervised Classification for Analyzing Latex Yield Variability in Yunnan, China. AB - This paper introduces a mixed method approach for analyzing the determinants of natural latex yields and the associated spatial variations and identifying the most suitable regions for producing latex. Geographically Weighted Regressions (GWR) and Iterative Self-Organizing Data Analysis Technique (ISODATA) are jointly applied to the georeferenced data points collected from the rubber plantations in Xishuangbanna (in Yunnan province, south China) and other remotely-sensed spatial data. According to the GWR models, Age of rubber tree, Percent of clay in soil, Elevation, Solar radiation, Population, Distance from road, Distance from stream, Precipitation, and Mean temperature turn out statistically significant, indicating that these are the major determinants shaping latex yields at the prefecture level. However, the signs and magnitudes of the parameter estimates at the aggregate level are different from those at the lower spatial level, and the differences are due to diverse reasons. The ISODATA classifies the landscape into three categories: high, medium, and low potential yields. The map reveals that Mengla County has the majority of land with high potential yield, while Jinghong City and Menghai County show lower potential yield. In short, the mixed method can offer a means of providing greater insights in the prediction of agricultural production. PMID- 29399300 TI - Awareness, knowledge, and use of folic acid among non-pregnant Korean women of childbearing age. AB - BACKGROUND/OBJECTIVES: Folic acid supplementation before pregnancy is known to reduce the risk of neural tube defects. The purposes of this study were to investigate the awareness, knowledge, and use of folic acid supplements along with their associated factors among non-pregnant Korean women of childbearing age. SUBJECTS/METHODS: From August 2012 to March 2013, 704 women aged 19-45 years completed a self-administered questionnaire regarding their awareness, knowledge, and use of folic acid as well as questions to identify risk of inadequate folate intake. RESULTS: Approximately 67% of women reported that they had heard of folic acid, and 23.7% had knowledge of both the role of folic acid in preventing birth defects and appropriate time for taking folic acid supplements to prevent birth defects. However, only 9.4% of women took folic acid supplements at the time of the survey. Women aged 19-24 years, unmarried women, and women who had never been pregnant were less likely to be aware and knowledgeable of folic acid or take folic acid supplements. In addition, women at high risk of inadequate folate intake were less likely to take folic acid supplements. In a multivariate analysis, women aged 19-24 years, women with a high school diploma or lower education level, and unmarried women were less likely to be aware and have knowledge of folic acid. The percentage of women taking folic acid supplements was significantly higher among knowledgeable women than among unknowledgeable women. CONCLUSIONS: These results support our hypothesis that women with knowledge of folic acid are more likely to take folic acid supplements. Therefore, educational programs or campaigns to improve knowledge regarding the importance of folic acid and to promote consumption of folic acid supplements as well as folate-rich foods are needed to target young, less educated, and unmarried women. PMID- 29399302 TI - Laser Application in Iran Urology: A Narrative Review. AB - The usage of laser in medicine is not recent, and its history in urology goes back to 40 years ago. For the last 2 decades, common uses of laser have been treatments of subjects with urolithiasis, bladder tumors, benign prostatic enlargement, lesions of the genitalia and urinary tract strictures. To evaluate laser application in urology in Iran, we reviewed all of the Iranian literature on the topic. This study was designed to retrieve all studies on laser application in urology in Iran, regardless of publication status or language, covering years 1990-2017. Twenty-six articles were identified: 12 about urolithiasis, 8 about benign prostatic hyperplasia (BPH), 2 case reports, 1 paper about prostate cancer, 1 on female urethral stricture, 1 review and 1 basic sciences study. We conclude that the use of this technology has not yet found its position in Iran, especially in the field of urology. The main causes for it are the difficult accessibility and disturb of laser devices and its accessories, as well as the lack of adequate knowledge of the medical community about this modality. PMID- 29399303 TI - The Combined Effects of Levothyroxine and Low Level Laser Therapy on Wound Healing in Hypothyroidism Male Rat Model. AB - Introduction: Hypothyroidism is caused by inadequate production and storage of thyroid hormones. Hypothyroidism is associated with delayed wound healing. Laser therapy may stimulate wound regeneration. The aim of this study was to determine the combined effects of levothyroxine and low level laser therapy during the wound healing process on skin of hypothyroidism male rat model. Methods: Thirty male Wistar rats were randomly divided into 5 groups: control group, hypothyroidism group, hypothyroidism group treated by laser, hypothyroidism group treated by levothyroxine, and hypothyroidism group treated by laser and levothyroxine. To induce hypothyroidism, methimazole was given at a dose of 4 mg/100 mL in their drinking water. After hypothyroidism was proven through immunoassay commercial kit, rats were generally anesthetized with ketamine and xylazine, then, an incisional skin wound was created in a length of 1.2 cm on the back of the ribcage. The surgical day is considered as the zero day. The third and fifth groups were treated with a pulse laser, 810 nm wavelength 80 Hz frequency and 0.2 J/cm2 energy densities for 200 seconds. Levothyroxine was injected to the fourth and fifth groups intraperitoneally. On the 14th day, a normal sample of each healing skin wound was harvested for biomechanical examination. The obtained data were analyzed by the SPSS software 21 and reported as a mean +/- standard error of mean (SEM). P < 0.05 was considered statistically significant. Results: The results showed that the mean maximum force and the accomplished work (energy) made a significant difference in the group receiving both laser and levothyroxine synchronously rather than the other groups (P <= 0.05). The elasticity of the wound healing in the groups that received laser and levothyroxine synchronously was significantly higher in comparison with the control and hypothyroidism groups but the difference was not significant in comparison with the laser or levothyroxine groups. Conclusion: The results of our study showed that the application of laser and levothyroxine synchronously improves the biomechanical parameters of wound during healing in comparison to the use of laser and levothyroxine solely. PMID- 29399304 TI - The Effect of Photobiomodulation on the Depth of Anesthesia During Endodontic Treatment of Teeth With Symptomatic Irreversible Pulpitis (Double Blind Randomized Clinical Trial). AB - : Introduction: Achieving appropriate anesthesia in patients with symptomatic irreversible pulpitis in mandibular molars during endodontic treatment is always one of the most challenging aspects. Photobiomodulation (PBM) has been used in dentistry due to its anti-inflammatory properties and regenerative effects. This study evaluates the effects of PBM in the depth of anesthesia in inferior alveolar nerve block. Methods: In this randomized clinical trial, 44 patients requiring endodontic treatment in lower molar, left or right were selected, half of them were randomly treated with PBM therapy. Laser irradiation by 980 nm diode laser with a single dose (15 J/cm2, for 20 seconds) before anesthesia was performed at the buccal aspect. Inferior alveolar nerve block was performed once. Success was defined as no or mild pain (no need for any supplemental injection), based on the visual analogue scale during access cavity preparation. Results were evaluated using SPSS software. RESULTS: The results of this study showed that the necessity for supplemental injection was lower in the group receiving laser than in the group without laser (P = 0.033). The mean pain intensity during dentin cutting was lower in the group receiving laser than in the group without laser (P = 0.031). Also, the mean pain intensity during pulp dropping was lower in the group receiving laser, than the group without laser (P = 0.021). Conclusion: Based on the results of this study, it seems that the application of PBM before anesthesia is effective on increasing depth of anesthesia. PMID- 29399305 TI - Fractionated CO2 Laser in the Treatment of Striae Alba in Darker Skinned Patients - A Prospective Study. AB - Introduction: In recent years, the positive effect of fractional CO2 laser on increasing collagen fibers, and consequently its effect on treating striae has been suggested. The present study aims to assess the effectiveness of CO2 fractional laser 10600-nm in the treatment of striae alba. Methods: In this prospective clinical trial, 2 treatment sessions of fractional CO2 laser with 4 week interval was given to 30 patients with striae alba. Cutaneous resonance running time (CRRT) was measured at baseline and at week 4 and 3 months after the last session of laser therapy. The level of improvement was assessed by 2 independent dermatologists and patients after 3 months of follow up. Results: 16.7% of patients had moderate improvement, 63.3% had minimal improvement, and 20% had no improvement. A statistical significant difference was found in median CRRT during the study (P < 0.0001). The median CRRT levels were significantly higher in week 4 and 3 months after the last treatment compared to the baseline (both P < 0.001). Likewise, a significant increase was observed in median CRRT level from week 4 till the end of study (P < 0.001). Evaluation of participant satisfaction revealed that 10% were very satisfied, 10% satisfied, 3.3% slightly satisfied, and 76.7% unsatisfied. Conclusion: Striae alba remain a challenging condition to treat. The treatment of striae alba with CO2 fractional laser results in minimal improvement with mild side effects. PMID- 29399306 TI - Topical Halometasone Reduces Acute Adverse Effects Induced by Pulsed Dye Laser for Treatment of Port Wine Stain Birthmarks. AB - Introduction: Pulsed dye laser (PDL) for treatment of port wine stain (PWS) usually causes some acute adverse effects, including pain, erythema, scabbing and swelling. This study aimed to determine whether topical halometasone can be used to reduce these acute adverse effects for post-PDL care of patients. Methods: A total of 40 PWS subjects were enrolled in this study and randomly assigned into two regimens: PDL alone and PDL + halometasone. All subjects were given a single treatment of PDL with wavelength of 595 nm, fluence of 8.0~13.5 J/cm2, pulse duration of 0.45~20 ms (We mainly used purpuric pulse duration for PWS) and spot size of 7 mm. Subjects in the PDL + halometasone group received topical application of halometasone daily for 3 days. Subjects were followed-up on days 3, 7 and one month post-PDL to evaluate the reduction of adverse effects. Results: Subjects in the PDL + halometasone group had significantly improved erythema and scab scores and had less erythema duration days as compared to those in the PDL alone group. Topical halometasone also showed a decrease in pain index among subjects, but was statistically insignificant. Topical halometasone did not affect the ultimate efficacy of PDL treatment for PWS. Conclusion: Topical halometasone can significantly reduce acute adverse effects induced by PDL for treatment of PWS birthmarks, thus providing a safe and efficacious solution for post-PDL care of PWS patients. PMID- 29399307 TI - The Clinical Efficacy of Infrared Photocoagulation Versus Closed Hemorrhoidectomy in Treatment of Hemorrhoid. AB - Introduction: Infrared photocoagulation (IRC) was introduced as a mainstay procedure for treatment of hemorrhoids. The present study aimed to compare the clinical efficacy of IRC compared to closed hemorrhoidectomy. Methods: Forty patients suffering grade-3 hemorrhoid that referred to the surgery clinic at Imam Hossein hospital in Tehran in 2013 were randomly assigned to groups treated with the IRC modality or Ferguson's closed hemorrhoidectomy method. The patients in the 2 groups were followed-up for the first 24 hours after surgery and 8 weeks later. Postoperative pain was assessed using visual analogue scale (VAS) at three time points of 24 hours, 2 weeks and 8 weeks after operation. Results: Regarding bleeding, its overall prevalence was 5.0% in the IRC group and 30.0% in the hemorrhoidectomy group, which was significantly less prevalent in the IRC group. Notably, the IRC group had a lower mean postoperative pain score compared to the hemorrhoidectomy group. Time of return to work was significantly shorter in the IRC group; no difference was found in the mean duration of hospital stay, and recurrence rate across 2 groups. Conclusion: IRC procedure is safer than closed hemorrhoidectomy with lower postoperative pain severity, less secondary bleeding, and leads to earlier return to work in patients with hemorrhoid. PMID- 29399308 TI - Comparison of Tooth Color Change After Bleaching With Conventional and Different Light-Activated Methods. AB - Introduction: The demand for esthetic dental treatments is increasing in recent years mainly due to improved oral hygiene and better maintenance of oral health and teeth in older individuals. Bleaching of discolored anterior teeth is the most popular among esthetic dental treatments. Even individuals with sound teeth and adequate esthetics seek to have whiter teeth in the anterior region. The aim of this study was to evaluate tooth color changes following conventional in office bleaching techniques compared to light-activated methods using different light sources. Methods: Seventy sound anterior teeth (devoided of caries and/or fracture), extracted for periodontal and orthodontic reasons were selected and allocated to 7 groups: (A) control, (B) conventional bleaching (C) LED-activated bleaching, (D) KTP laser-activated bleaching, (E) diode laser-activated bleaching, (F) Nd:YAG laser-activated bleaching and (G) CO2 laser-activated bleaching. Colorimetric evaluation was carried out before and after treatment using a spectrophotoradiometer. Data were analyzed by one- and two-way analysis of variance (ANOVA) as well as multiple comparison methods. Results: The results showed that all bleaching procedures were effective in reducing the yellowness index. However, the KTP laser-activated bleaching was significantly more effective than the other techniques in 95% confidence level. It was also seen that CO2 laser activated method has outperformed groups E, F and G and the conventional bleaching without light activation was not effective at all and represented similar results with the control group. Furthermore, the groups E and G had almost the same results in decreasing the yellowness index. Conclusion: The results showed that all bleaching techniques were effective however, the KTP laser-activated bleaching was significantly more efficient, closely followed by the CO2 laser-activated bleaching technique. PMID- 29399309 TI - Ablative Fractional 10 600 nm Carbon Dioxide Laser Versus Non-ablative Fractional 1540 nm Erbium-Glass Laser in Egyptian Post-acne Scar patients. AB - Introduction: Non-ablative fractional erbium-doped glass 1540 nm and fractional ablative 10600 nm carbon dioxide lasers are regarded as effective modalities for treating acne atrophic scars. In this study, we aimed to compare the effectiveness of fractional CO2 laser and fractional nonablative 1540 nm erbium doped glass laser in treating post acne atrophic scars in Egyptian patients. Methods: Fifty-eight patients complaining of moderate and severe acne atrophic scars were randomly divided into 2 groups of 29 patients each. Both groups were subjected to 4 treatment sessions with 3 weeks interval and were followed up for 3 months. In group A, enrolled patient sreceived C2 laser, while in group B, patients were treated with 1540 nm erbium glass fractional laser. Results: Clinical assessment revealed that the mean grades of progress and improvement were higher with fractional 10600 nm CO2 laser but with non-significant difference between both treatments (P = 0.1). The overall patients' satisfaction with both lasers were not significantly different (P = 0.44). Conclusion: Both fractional ablative CO2 and fractional non-ablative erbium glass lasers are good modalities for treating acne scars with a high efficacy and safety profile and good patient satisfaction. The fractional ablative laser showed higher efficacy while non-ablative laser offered less pain and shorter downtime. PMID- 29399310 TI - Bond Strength of Fiber Posts to Composite Core: Effect of Surface Treatment With Er,Cr:YSGG Laser and Thermocycling. AB - Introduction: This study aimed to determine the bond strength of fiber post to composite core following surface treatment with Er,Cr:YSGG laser at different powers and sandblasting with and without thermocycling. Methods: In this experimental study, 30 fiber posts (Glassix, Nordin, Switzerland) were randomly divided into 5 groups of sandblasting, no treatment and laser irradiation at 1, 1.5 and 2 W powers. Following composite filling and mounting, 1-mm thick sections were made for pushout bond strength testing. Half of the samples in each group were subjected to thermocycling (n=15). Two-way analysis of variance (ANOVA) was used to analyze the bond strength values. Pairwise comparisons were made using Tukey test (P<0.05). Results: Effect of treatment method on push-out bond strength of fiber post to composite core was significant (P=0.017), while thermocycling had no significant effect on bond strength (P=0.964). Pairwise comparison of surface treatment methods revealed no significant difference in groups with and without thermocycling (P>0.05), but Er,Cr:YSGG laser irradiation with 1 W power yielded significantly higher bond strength than the control group (P=0.01). Conclusion: Irradiation of Er,Cr:YSGG laser at 1 W power increased the bond strength of fiber post to composite core. Thermocycling slightly decreased the bond strength at the fiber postcore interface. PMID- 29399311 TI - Effect of CO2 Laser and Fluoride Varnish Application on Microhardness of Enamel Surface Around Orthodontic Brackets. AB - Introduction: Orthodontic treatment has many advantages such as esthetic improvement and self-esteem enhancement; yet it has some disadvantages such as increasing the risk of formation of white spot lesions, because it makes oral hygiene more difficult. It is rational to implement procedures to prevent these lesions. The present study was aimed to assess the effect of CO2 laser and fluoride varnish on the surface of the enamel surface microhardness around the orthodontic braces. Methods: Eighty extracted premolar teeth were selected, scaled, polished with nonfluoridated pumic and metal brackets were bonded to them. Then, they were randomly allocated to 5 groups: control (neither fluoride nor laser is used on enamel surfaces), fluoride (4 minutes fluoride varnish treatment of the enamel surfaces), CO2 laser (10.6 um CO2 laser irradiation of the teeth), laserfluoride (fluoride application after laser irradiation) and fluoride-laser (fluoride was applied and then teeth were irradiated with laser). After surface treatment around brackets on enamel, the samples were stored in 0.1% thymol for less than 5 days and then they were exposed to a 10-day microbiological caries model. Microhardness values of enamel were evaluated with Vickers test. One sample of each group (5 teeth from 80 samples) was prepared for SEM (scanning electron microscopy) and the data from 75 remaining teeth were analyzed with analysis of variance (ANOVA) and chi-square tests (alpha =0.05). Results: Microhardness mean values from high to low were as follow: fluoride laser, laser-fluoride, laser, fluoride and control. Microhardness in fluoride laser group was significantly higher compared with that of the control group. Distribution adhesive remnant index (ARI) scores were significantly different between groups and most of bond failures occurred at the enamel-adhesive interface in groups 2 to 5 and at the adhesive-bracket interface in the control group. Conclusion: Combination of fluoride varnish and CO2 laser irradiation can reduce enamel demineralization around orthodontic brackets. PMID- 29399312 TI - Near-Infrared Visual Differentiation in Normal and Abnormal Breast Using Hemoglobin Concentrations. AB - Introduction: Near-infrared (NIR) optical imaging is a non-ionizing modality that is emerging as a diagnostic/prognostic tool for breast cancer according to NIR differentiation of hemoglobin (Hb) concentration. Methods: The transmission values of LED-sourced light at 625 nm were measured by power meter to evaluate the optical properties of Hb in breast phantom containing major and minor vessels. For the simulation of blood variations in cancerous breast condition, we prepared 2 concentrations of pre-menopausal Hb and 4 concentrations of post menopausal Hb and, for comparison with normal tissue, one concentration of Hb injected inside the phantom's vessels. Imaging procedure on the phantom was also conducted by LED source and CCD camera. The images from the experiments were compared with the results obtained from the images analyzed by MATLAB software. Finally, mammography of phantom including various concentration of Hb was prepared. Results: The transmitting intensities of NIR in blood containing 1, 2 and 4 concentrations of Hb in the major vessels were 52.83+/-2.85, 43.00+/-3.11 and 31.17+/-2.27 uW, respectively, and in minor vessels containing similar Hb concentrations were 73.50+/-2.43, 60.08+/-5.09 and 42.42+/-4.86 uW, respectively. The gray-scale levels on the major vessel were about 96, 124, 162 and on the minor vessel about 72, 100, 130 measured for 1, 2 and 4 Hb concentrations, respectively. The sensitivity and specificity of NIR imaging differentiation were 97.4% and 91.3%, respectively. Conclusion: Significant differences in transmitting intensity, optical imaging as well as software analysis of images were observed for 1, 2 and 4 concentrations of Hb in major and minor breast phantom vessels. Differentiation capability of minor vessels was higher than major vessels for Hb concentrations. Despite a good detection for location of vessels by mammography, it could not show differences between vessels with various concentrations. However, NIR optical imaging demonstrated a good image contrast for showing vessels in terms of concentration. This study recommends NIR optical imaging for prescreening breast cancer due to its potential for early diagnosis. PMID- 29399314 TI - Therapeutic and Analgesic Efficacy of Laser in Conjunction With Pharmaceutical Therapy for Trigeminal Neuralgia. AB - Introduction: Trigeminal neuralgia (TN) is the most common neuralgia in the head and neck region and a common cause of orofacial pain. It is routinely treated with carbamazepine. Laser, acupuncture and radiofrequency are among other treatment modalities for this condition. This study sought to assess the efficacy of laser therapy in conjunction with carbamazepine for treatment of TN. Methods: A total of 30 patients who met the inclusion criteria were divided into 2 groups of cases and controls (n=15) by double blind randomized controlled clinical trial. All patients received 100 mg carbamazepine at baseline and another 100 mg after 2 days for pain control. In the case group, low level laser therapy (LLLT) was also performed in addition to pharmaceutical therapy. Sham laser was used in the control group instead of LLLT. Treatment was continued for 9 sessions (3 days a week). The intensity of pain was measured and compared in the 2 groups using visual analog scale (VAS) in 3 period. The qualitative variables among the groups were compared using the repeated measures analysis of variance (ANOVA). Results: The severity of pain was lower at the end of treatment in the case compared to the control group so this difference was statistically significant (P=0.003). The severity of pain decreased in both groups over time. Significant difference was noted in this regard between the 2 groups either (P=0.003). At the end of treatment pain intensity dropped in the intervention group from 6/8 to 1/2 and control group from 6/6 to 2/7. Conclusion: Laser therapy did add to the value of pharmaceutical therapy for treatment of TN. Both groups experienced significant improvement over time. So it is better to used laser complementary therapy to reduce side effects and the medicine dosage. PMID- 29399313 TI - Effects of Erbium Family Laser on Shear Bond Strength of Composite to Dentin After Internal Bleaching. AB - Introduction: The aim of this study was to assess the effect of surface treatment with erbium: yttrium-aluminum-garnet (Er:YAG) and erbium, chromium: yttrium scandium-gallium-garnet (Er,Cr:YSGG) lasers on shear bond strength of composite resin to recently bleached dentin. Methods: In this study, 40 extracted human premolars were selected. The teeth were cut 4 mm apical to the cusp tip and were randomly divided into four groups (n=10 in each group) for shear bond strength testing. For bleaching, 35% hydrogen peroxide (H2 o2 ) gel (Opalescence Endo, Ultradent, South Jordan, UT, USA) was applied to dentin surfaces of all specimens for 10 days. Before etching and bonding, in Er,Cr:YSGG and Er:YAG laser groups, dentin surfaces were irradiated with Er,Cr:YSGG and Er:YAG lasers, respectively. In Er,Cr:YSGG group, Er:YAG group and control group, composite restoration was performed immediately after bleaching while in common procedure group, composite restoration was performed after seven days. The teeth were then subjected to shear bond strength testing machine. The data were statistically analyzed using analysis of variance (ANOVA) and Tukey test. Results: The mean and standard deviation (SD) of shear bond strength was 4.3 +/- 1.4 MPa for control group, 6.7 +/- 2.0 Mpa for Er,Cr:YSGG group, 14.4 +/- 3.7 Mpa for Er:YAG group and 19.4 +/- 2.6 Mpa for common procedure group. Conclusion: The shear strength of composite to Er:YAG laser-treated bleached dentin was significantly higher than control group while significantly lower than common procedure. PMID- 29399315 TI - Evaluation of 200 Mm, 365 Mm and 500 Mm Fibers of Ho:YAG Laser in Transurethral Lithotripsy of Ureteral: A Randomize Control Trial. AB - Introduction: Presently, different holmium: yttrium aluminum garnet (Ho:YAG) laser calibers are used for endoscopic stone treatment, which include 200, 365, 500 and 1000 Mm fibers. Currently, there are not enough studies to compare the performance of these fibers. In this retrospective investigation, we compared the outcome of 200, 365 and 500 Mm fibers of Ho:YAG laser in transurethral lithotripsy of ureteral stone. Methods: From January 2016 to June 2017, 74 subjects with mean age of 35.3 +/- 5.6 were randomly allocated to 3 groups according to the caliber of laser, 200, 365 and 500 Mm for transurethral lithotripsy. The main purpose of this investigation was to evaluate mean operation time (MOT), stone free rate (SFR) and complications. Results: MOT and SFR were significantly different in 500 Mm laser caliber (P=0.046, P=0.029, respectively). There was no remarkable difference between the 3 groups in this regard. Conclusion: Based upon our data, the clinical potency of the Ho: YAG laser was great in all 3 fiber calibers. The most important results of this comparison were the significantly higher SFR with increased laser caliber. PMID- 29399316 TI - Adjunct Use of Low-Level Laser Therapy on the Treatment of Necrotizing Ulcerative Gingivitis: A Case Report. AB - Necrotizing ulcerative gingivitis (NUG) is a microbial disease of the gingiva in the context of an impaired host response. This form of gingivitis is relatively rare. NUG is an infection characterized by gingival necrosis presenting as "punched-out" papillae, spontaneous bleeding, pain, oral malodor, and pseudomembrane formation. The primary predisposing factors are bacterial plaque and an inadequate diet, but smoking and psychological stress may also affect the disease severity. NUG is associated with a characteristic bacterial flora, which includes fusiform bacteria, spirochetes, and Prevotella intermedia. Conventional treatment includes control of both the bacterial plaque and the secondary factors, as well as topical or systemic treatment biostimulative effect on wound healing, pain control, and inflammatory processes. Patients with NUG were treated using adjunct use of a diode laser (980 nm) for the control of pain and to accelerate the wound healing at day 2. 3. 5. 9, energy density was 9 J/cm2 . After treatment, the patients' quality of life improved faster than with conventional treatment. These results suggest that low-level laser therapy (LLLT) is an effective treatment for the reduction of pain levels and healing times. As a result, our case report shows that LLTT has a positive effect in relieving the symptoms of NUG. PMID- 29399317 TI - Metal-dependent allosteric activation and inhibition on the same molecular scaffold: the copper sensor CopY from Streptococcus pneumoniae. AB - Resistance to copper (Cu) toxicity in the respiratory pathogen Streptococcus pneumoniae is regulated by the Cu-specific metallosensor CopY. CopY is structurally related to the antibiotic-resistance regulatory proteins MecI and BlaI from Staphylococcus aureus, but is otherwise poorly characterized. Here we employ a multi-pronged experimental strategy to define the Spn CopY coordination chemistry and the unique mechanism of allosteric activation by Zn(ii) and allosteric inhibition by Cu(i) of cop promoter DNA binding. We show that Zn(ii) is coordinated by a subunit-bridging 3S 1H2O complex formed by the same residues that coordinate Cu(i), as determined by X-ray absorption spectroscopy and ratiometric pulsed alkylation-mass spectrometry (rPA-MS). Apo- and Zn-bound CopY are homodimers by small angle X-ray scattering (SAXS); however, Zn stabilizes the dimer, narrows the conformational ensemble of the apo-state as revealed by ion mobility-mass spectroscopy (IM-MS), and activates DNA binding in vitro and in cells. In contrast, Cu(i) employs the same Cys pair to form a subunit-bridging, kinetically stable, multi-metallic Cu.S cluster (KCu ~ 1016 M-1) that induces oligomerization beyond the dimer as revealed by SAXS, rPA-MS and NMR spectroscopy, leading to inhibition of DNA binding. These studies suggest that CopY employs conformational selection to drive Zn-activation of DNA binding, and a novel Cu(i)-mediated assembly mechanism that dissociates CopY from the DNA via ligand exchange-catalyzed metal substitution, leading to expression of Cu resistance genes. Mechanistic parallels to antibiotic resistance repressors MecI and BlaI are discussed. PMID- 29399318 TI - Is There a Common Summary Statistical Process for Representing the Mean and Variance? A Study Using Illustrations of Familiar Items. AB - A number of studies revealed that our visual system can extract different types of summary statistics, such as the mean and variance, from sets of items. Although the extraction of such summary statistics has been studied well in isolation, the relationship between these statistics remains unclear. In this study, we explored this issue using an individual differences approach. Observers viewed illustrations of strawberries and lollypops varying in size or orientation and performed four tasks in a within-subject design, namely mean and variance discrimination tasks with size and orientation domains. We found that the performances in the mean and variance discrimination tasks were not correlated with each other and demonstrated that extractions of the mean and variance are mediated by different representation mechanisms. In addition, we tested the relationship between performances in size and orientation domains for each summary statistic (i.e. mean and variance) and examined whether each summary statistic has distinct processes across perceptual domains. The results illustrated that statistical summary representations of size and orientation may share a common mechanism for representing the mean and possibly for representing variance. Introspections for each observer performing the tasks were also examined and discussed. PMID- 29399319 TI - Engineering large cartilage tissues using dynamic bioreactor culture at defined oxygen conditions. AB - Mesenchymal stem cells maintained in appropriate culture conditions are capable of producing robust cartilage tissue. However, gradients in nutrient availability that arise during three-dimensional culture can result in the development of spatially inhomogeneous cartilage tissues with core regions devoid of matrix. Previous attempts at developing dynamic culture systems to overcome these limitations have reported suppression of mesenchymal stem cell chondrogenesis compared to static conditions. We hypothesize that by modulating oxygen availability during bioreactor culture, it is possible to engineer cartilage tissues of scale. The objective of this study was to determine whether dynamic bioreactor culture, at defined oxygen conditions, could facilitate the development of large, spatially homogeneous cartilage tissues using mesenchymal stem cell laden hydrogels. A dynamic culture regime was directly compared to static conditions for its capacity to support chondrogenesis of mesenchymal stem cells in both small and large alginate hydrogels. The influence of external oxygen tension on the response to the dynamic culture conditions was explored by performing the experiment at 20% O2 and 3% O2. At 20% O2, dynamic culture significantly suppressed chondrogenesis in engineered tissues of all sizes. In contrast, at 3% O2 dynamic culture significantly enhanced the distribution and amount of cartilage matrix components (sulphated glycosaminoglycan and collagen II) in larger constructs compared to static conditions. Taken together, these results demonstrate that dynamic culture regimes that provide adequate nutrient availability and a low oxygen environment can be employed to engineer large homogeneous cartilage tissues. Such culture systems could facilitate the scaling up of cartilage tissue engineering strategies towards clinically relevant dimensions. PMID- 29399321 TI - Fragger: a protein fragment picker for structural queries. AB - Protein modeling and design activities often require querying the Protein Data Bank (PDB) with a structural fragment, possibly containing gaps. For some applications, it is preferable to work on a specific subset of the PDB or with unpublished structures. These requirements, along with specific user needs, motivated the creation of a new software to manage and query 3D protein fragments. Fragger is a protein fragment picker that allows protein fragment databases to be created and queried. All fragment lengths are supported and any set of PDB files can be used to create a database. Fragger can efficiently search a fragment database with a query fragment and a distance threshold. Matching fragments are ranked by distance to the query. The query fragment can have structural gaps and the allowed amino acid sequences matching a query can be constrained via a regular expression of one-letter amino acid codes. Fragger also incorporates a tool to compute the backbone RMSD of one versus many fragments in high throughput. Fragger should be useful for protein design, loop grafting and related structural bioinformatics tasks. PMID- 29399322 TI - Evaluation of predicted Medfly ( Ceratitis capitata) quarantine length in the United States utilizing degree-day and agent-based models. AB - Invasions by pest insects pose a significant threat to agriculture worldwide. In the case of Ceratitis capitata incursions on the US mainland, where it is not officially established, repeated detections are followed by quarantines and treatments to eliminate the invading population. However, it is difficult to accurately set quarantine duration because non-detection may not mean the pest is eliminated. Most programs extend quarantine lengths past the last fly detection by calculating the amount of time required for 3 generations to elapse under a thermal unit accumulation development model ("degree day"). A newer approach is to use an Agent-Based Simulation (ABS) to explicitly simulate population demographics and elimination. Here, predicted quarantine lengths for 11 sites in the continental United States are evaluated using both approaches. Results indicate a strong seasonality in quarantine length, with longer predictions in the second half of the year compared with the first; this pattern is more extreme in degree day predictions compared with ABS. Geographically, quarantine lengths increased with latitude, though this was less pronounced under the ABS. Variation in quarantine lengths for particular times and places was dramatically larger for degree day than ABS, generally spiking in the middle of the year for degree day and peaking in second half of the year for ABS. Analysis of 34 C. capitata quarantines from 1975 to 2017 in California shows that, for all but two, quarantines were started in the second half of the year, when degree day quarantine lengths are longest and have the highest uncertainty. For a set of hypothetical outbreaks based on these historical quarantines, the ABS produced significantly shorter quarantines than degree day calculations. Overall, ABS quarantine lengths were more consistent than degree day predictions, avoided unrealistically long values, and captured effects of rare events such as cold snaps. PMID- 29399320 TI - Neuromodulation for the treatment of eating disorders and obesity. AB - Eating disorders and obesity adversely affect individuals both medically and psychologically, leading to reduced life expectancy and poor quality of life. While there exist a number of treatments for anorexia, morbid obesity and bulimia, many patients do not respond favorably to current behavioral, medical or bariatric surgical management. Neuromodulation has been postulated as a potential treatment for eating disorders and obesity. In particular, deep brain stimulation and transcranial non-invasive brain stimulation have been studied for these indications across a variety of brain targets. Here, we review the neurobiology behind eating and eating disorders as well as the current status of preclinical and clinical neuromodulation trials for eating disorders and obesity. PMID- 29399323 TI - Advances in the understanding of IgM monoclonal gammopathy of undetermined significance. AB - Among monoclonal gammopathies of undetermined significance (MGUSs), the immunoglobulin M (IgM) MGUS subtype stands as a unique entity and plays a pivotal role as a pre-malignant condition for multiple B-cell non-Hodgkin lymphomas, most notably Waldenstrom macroglobulinemia (WM). A relationship between IgM MGUS and WM has been proposed for decades. However, insight regarding the pathobiology of these two conditions improved significantly in recent years, strengthening the hypothesis that WM and IgM MGUS are different stages of the same disease. Therefore, the understanding of IgM MGUS and that of WM are interconnected and advances in one will likely impact the other. Furthermore, IgM MGUS has been more commonly recognized as the underlying etiology of IgM-related disorders. In this review, we explore recent advances in the understanding of the pathobiology of IgM MGUS and WM and the treatment of common IgM-related disorders. PMID- 29399325 TI - A proposal to change the name of the NBPF/DUF1220 domain to the Olduvai domain. AB - We are jointly proposing a new name for a protein domain of approximately 65 amino acids that has been previously termed NBPF or DUF1220. Our two labs independently reported the initial studies of this domain, which is encoded almost entirely within a single gene family. The name Neuroblastoma Breakpoint Family ( NBPF) was applied to this gene family when the first identified member of the family was found to be interrupted in an individual with neuroblastoma. Prior to this discovery, the PFAM database had termed the domain DUF1220, denoting it as one of many protein domains of unknown function. It has been PFAM's intention to use "DUF" nomenclature to serve only as a temporary placeholder until more appropriate names are proposed based on research findings. We believe that additional studies of this domain, primarily from our laboratories over the past 10 years, have resulted in furthering our understanding of these sequences to the point where proposing a new name for this domain is warranted. Because of considerable data linking the domain to human specific evolution, brain expansion and cognition, we believe a name reflecting these findings would be appropriate. With this in mind, we have chosen to name the domain (and the repeat that encodes it) Olduvai. The gene family will remain as NBPF for now. The primary domain subtypes will retain their previously assigned names (e.g. CON1-3; HLS1-3), and the three-domain block that expanded dramatically in the human lineage will be termed the Olduvai triplet. The new name refers to Olduvai Gorge, which is a site in East Africa that has been the source of major anthropological discoveries in the early-mid 1900's. We also chose the name as a tribute to the scientists who made important contributions to the early studies of human origins and our African genesis. PMID- 29399326 TI - Analysis of removal of cadmium by action of immobilized Chlorella sp. micro-algae in alginate beads. AB - Cadmium (Cd) is a metal that can negatively interfere with the metabolic systems of living beings. The objective of this work was to evaluate the capacity for cadmium removal in aqueous solutions by immobilized Chlorella sp. in calcium alginate beads. Beads without Chlorella sp. were used as a control. All the treatments were established in triplicate for 80 min, at four concentrations of cadmium (0, 20, 100 and 200 ppm), taking samples of aqueous solution every 10 min, to be read using atomic absorption equipment. The study determined that the treatment of alginate beads with immobilized Chlorella sp. removed 59.67% of cadmium at an initial concentration of 20 ppm, this being the best removal result. PMID- 29399324 TI - Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps. AB - Disseminated intravascular coagulation (DIC) is an acquired condition that develops as a complication of systemic and sustained cell injury in conditions such as sepsis and trauma. It represents major dysregulation and increased thrombin generation in vivo. A poor understanding and recognition of the complex interactions in the coagulation, fibrinolytic, inflammatory, and innate immune pathways have resulted in continued poor management and high mortality rates in DIC. This review focuses attention on significant recent advances in our understanding of DIC pathophysiology. In particular, circulating histones and neutrophil extracellular traps fulfil established criteria in DIC pathogenesis. Both are damaging to the vasculature and highly relevant to the cross talk between coagulation and inflammation processes, which can culminate in adverse clinical outcomes. These molecules have a strong potential to be novel biomarkers and therapeutic targets in DIC, which is still considered synonymous with 'death is coming'. PMID- 29399327 TI - Recent advances in understanding and management of acquired thrombocytopenia. AB - There are numerous congenital and acquired causes of thrombocytopenia. Thrombocytopenia could be a result of decreased bone marrow production, increased consumption, increased destruction, splenic sequestration or a combination of these causes. In this review, we have focused on some of the serious acquired causes of thrombocytopenia. There have been some significant advances in our understanding of the pathophysiology, diagnostic testing, and treatment of immune thrombocytopenia, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome over the past five years. These advances have resulted in a significant decrease in mortality and morbidity of patients with these disorders. Despite these advances, we are still faced with numerous unanswered questions in the pathophysiology and management of these complex thrombocytopenic disorders. PMID- 29399329 TI - Intestinal failure: a review. AB - Intestinal failure (IF) is the inability of the gut to absorb necessary water, macronutrients (carbohydrate, protein, and fat), micronutrients, and electrolytes sufficient to sustain life and requiring intravenous supplementation or replacement. Acute IF (types 1 and 2) is the initial phase of the illness and may last for weeks to a few months, and chronic IF (type 3) from months to years. The challenge of caring for patients with IF is not merely the management of the underlying condition leading to IF or the correct provision of appropriate nutrition or both but also the prevention of complications, whether thromboembolic phenomenon (for example, venous occlusion), central venous catheter-related bloodstream infection, IF-associated liver disease, or metabolic bone disease. This review looks at recent questions regarding chronic IF (type 3), its diagnosis and management, the role of the multidisciplinary team, and novel therapies, including hormonal treatment for short bowel syndrome but also surgical options for intestinal lengthening and intestinal transplant. PMID- 29399328 TI - JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. AB - JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib) in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and one JAK1/JAK3 inhibitor (tofacitinib) in methotrexate-resistant rheumatoid arthritis. The non approved compounds exhibited many off-target effects leading to neurological and gastrointestinal toxicities, as seen in clinical trials for MPNs. Ruxolitinib is a well-tolerated drug with mostly anti-inflammatory properties. Despite a weak effect on the cause of the disease itself in MPNs, it improves the clinical state of patients and increases survival in myelofibrosis. This limited effect is related to the fact that ruxolitinib, like the other type I JAK2 inhibitors, inhibits equally mutated and wild-type JAK2 (JAK2WT) and also the JAK2 oncogenic activation. Thus, other approaches need to be developed and could be based on either (1) the development of new inhibitors specifically targeting JAK2V617F or (2) the combination of the actual JAK2 inhibitors with other therapies, in particular with molecules targeting pathways downstream of JAK2 activation or the stability of JAK2 molecule. In contrast, the strong anti-inflammatory effects of the JAK inhibitors appear as a very promising therapeutic approach for many inflammatory and auto-immune diseases. PMID- 29399330 TI - Recent advances in managing differentiated thyroid cancer. AB - The main clinical challenge in the management of thyroid cancer is to avoid over treatment and over-diagnosis in patients with lower-risk disease while promptly identifying those patients with more advanced or high-risk disease requiring aggressive treatment. In recent years, novel clinical and molecular data have emerged, allowing the development of new staging systems, predictive and prognostic tools, and treatment approaches. There has been a notable shift toward more conservative management of low- and intermediate-risk patients, characterized by less extensive surgery, more selective use of radioisotopes (for both diagnostic and therapeutic purposes), and less intensive follow-up. Furthermore, the histologic classification; tumor, node, and metastasis (TNM) staging; and American Thyroid Association risk stratification systems have been refined, and this has increased the number of patients in the low- and intermediate-risk categories. There is now a need for new, prospective data to clarify how these changing practices will impact long-term outcomes of patients with thyroid cancer, and new follow-up strategies and biomarkers are still under investigation. On the other hand, patients with more advanced or high-risk disease have a broader portfolio of options in terms of treatments and therapeutic agents, including multitarget tyrosine kinase inhibitors, more selective BRAF or MEK inhibitors, combination therapies, and immunotherapy. PMID- 29399331 TI - Eating disorders in children: is avoidant-restrictive food intake disorder a feeding disorder or an eating disorder and what are the implications for treatment? AB - Avoidant-restrictive food intake disorder (ARFID) is a current diagnosis in the "Feeding and Eating Disorders" section of the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) and captures a heterogeneous presentation of eating disturbances. In recent years, ARFID has been studied primarily within the context of eating disorders despite having historical roots as a feeding disorder. The following review examines ARFID's similarities with and differences from feeding disorders and eating disorders, focusing on research published within the last three years. Implications of this differentiation for treatment are discussed. PMID- 29399333 TI - Cardio-Oncology: mechanisms of cardiovascular toxicity. AB - The therapeutic options available to treat a wide range of malignancies are rapidly increasing. At the same time, the population being treated is aging with more cardiovascular risk factors, comorbid conditions, and associated poor cardiac reserve. Both traditional chemotherapeutic agents (for example, anthracyclines) and newer therapies (for example, targeted tyrosine kinase inhibitors and immune checkpoint inhibitors) have demonstrated profound cardiovascular toxicities. It is important to understand the mechanisms of these toxicities to establish strategies for the prevention and management of complications-arrhythmias, heart failure, and even death. In the first of this two-part review series, we focus on what is known and hypothesized about the mechanisms of cardiovascular toxicity from anthracyclines, HER2/ErbB2 inhibitors, immune checkpoint inhibitors, and vascular endothelial growth factor inhibitors. PMID- 29399332 TI - Recent advances in understanding hematopoiesis in Fanconi Anemia. AB - Fanconi anemia is an inherited disease characterized by genomic instability, hypersensitivity to DNA cross-linking agents, bone marrow failure, short stature, skeletal abnormalities, and a high relative risk of myeloid leukemia and epithelial malignancies. The 21 Fanconi anemia genes encode proteins involved in multiple nuclear biochemical pathways that effect DNA interstrand crosslink repair. In the past, bone marrow failure was attributed solely to the failure of stem cells to repair DNA. Recently, non-canonical functions of many of the Fanconi anemia proteins have been described, including modulating responses to oxidative stress, viral infection, and inflammation as well as facilitating mitophagic responses and enhancing signals that promote stem cell function and survival. Some of these functions take place in non-nuclear sites and do not depend on the DNA damage response functions of the proteins. Dysfunctions of the canonical and non-canonical pathways that drive stem cell exhaustion and neoplastic clonal selection are reviewed, and the potential therapeutic importance of fully investigating the scope and interdependences of the canonical and non-canonical pathways is emphasized. PMID- 29399334 TI - Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells. AB - Tumor cells carry various genetic and metabolic alterations, which directly contribute to their growth and malignancy. Links between metabolism and cancer are multifaceted. Metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Understanding these metabolic alterations is crucial for development of novel anti-cancer therapeutic strategies. In the present review, the broad importance of metabolism in tumor biology is discussed, and the current knowledge on dysregulated metabolic enzymes involved in the vital regulatory steps of glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid, amino acid, and mitochondrial metabolism pathways are reviewed. PMID- 29399335 TI - Progress in research on intracranial multiple dural arteriovenous fistulas. AB - Intracranial multiple dural arteriovenous fistulas (MDAVFs) are rare lesions that are difficult to treat. The key factors involved in the development of MDAVFs remain unknown. At present, the majority of reports on intracranial MDAVFs are confined to case reports and small case series, and thus understanding of MDAVFs is limited. The current review assesses the available literature to date with the aim of reviewing the progress in research on intracranial MDAVFs. Intracranial MDAVFs may be divided into two types: Synchronous and metachronous. While the exact pathogenesis of MDAVFs is unknown, a number of possible mechanisms are considered relevant. The first is that MDAVFs develop following recanalization of a large sinus thrombosis that involves several sinuses. The second possibility is that a pre-existing DAVF may induce sinus thrombosis or venous hypertension, resulting in a new MDAVF. The third is that MDAVFs are caused by increased angiogenic activity, which may induce the development of MDAVFs. Intracranial MDAVFs have a malignant clinical course, and their symptoms generally rapidly progress following onset. It is therefore important to identify intracranial MDAVFs at an early stage. A number of imaging technologies, including computed tomography (CT), magnetic resonance imaging (MRI), digital subtraction angiography (DSA) and single-photon emission computed tomography (SPECT), may be used to detect MDAVFs. Of these, CT and MRI provide information on brain morphology, SPECT provides brain blood flow information, and DSA is the gold standard that may be used to identify angioarchitecture and hemodynamics. MDAVFs require timely and aggressive treatment, which may include endovascular embolization, surgical resection, radiosurgery and conservative treatment, and in some cases, combined treatments are required. Appropriate and aggressive treatment regimens can markedly improve neurological deficits and cognitive function in patients with MDAVFs. PMID- 29399336 TI - Cardiovascular characteristics of chronic fatigue syndrome. AB - Patients with chronic fatigue syndrome (CFS) commonly exhibit orthostatic intolerance. Abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli was previously described in numerous studies. The aim of the current study was to describe cardiological and clinical characteristics of Italian patients with CFS. All of the patients were of Caucasian ethnicity and had been referred to our center, the Cardiology Department of the University Hospital of Pavia (Pavia, Italy) with suspected CFS. A total of 44 patients with suspected CFS were included in the present study and the diagnosis was confirmed in 19 patients according to recent clinical guidelines. The characteristics at baseline of the population confirm findings from various previous reports regarding the prevalence in females with a female to male ratio of 4:1, the age of onset of the pathology and the presence of previous infection by the Epstein-Barr virus, cytomegalovirus and other human herpesviruses. Despite the current data indicating that the majority of the cardiological parameters investigated are not significantly different in patients with and without CFS, a significant association between the disease and low levels of blood pressure was identified. Other pilot studies revealed a higher prevalence of hypotension and orthostatic intolerance in patients with CFS. Furthermore, many of the CFS symptoms, including fatigue, vertigo, decreased concentration, tremors and nausea, may be explained by hypotension. PMID- 29399337 TI - Neuroprotective effects of selegiline on rat neural stem cells treated with hydrogen peroxide. AB - Oxidative stress and reactive oxygen species generation have been implicated in the pathogenesis of several neurological disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. In the present study, the neuroprotective effects of selegiline against hydrogen peroxide-induced oxidative stress in hippocampus-derived neural stem cells (NSCs) were evaluated. NSCs isolated from neonatal Wistar rats were pretreated with different doses of selegiline for 48 h and then exposed to 125 uM H2O2 for 30 min. Using MTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, acridine orange/ethidium bromide staining and reverse transcription-quantitative polymerase chain reaction, the effects of selegiline on cell survival, apoptosis and the expression of B-cell lymphoma 2 (Bcl-2) and heat shock protein 4 (Hspa4) in pretreated stem cells were assessed compared with a control group lacking pretreatment. The results indicated that the viability of cells pretreated with 20 uM selegiline was significantly increased compared with the control group (P<0.05). Additionally, 20 uM selegiline increased the mRNA expression of Bcl-2 and Hspa4 (P<0.05 vs. control) and suppressed oxidative stress-induced cell death (apoptosis and necrosis; P<0.05 vs. control and 10 uM groups). From these findings, it was concluded that selegiline may be a therapeutic candidate for the treatment of neurological diseases mediated by oxidative stress. PMID- 29399338 TI - Expression of doublecortin and CaM kinase-like-1 protein in serrated neoplasia of the colorectum. AB - The adenoma-carcinoma sequence (ACS) and the serrated pathway are two distinct developmental routes leading to the formation of colorectal carcinoma. Recently, the doublecortin and CaM kinase-like-1 protein (DCLK1) has been reported to serve as an intestinal cancer stem cell marker and has been demonstrated to be overexpressed through the ACS; however, there is a lack of reports on the role of DCLK1 in the serrated pathway. To clarify the correlation between DCLK1 protein expression and clinicopathological characteristics of the serrated tumorigenic pathway, the present study used immunohistochemistry to examine the expression of DCLK1 in endoscopically resected samples of 62 serrated polyps [20 hyperplastic polyps (HPs), 16 traditional serrated adenomas (TSAs) and 26 sessile serrated adenoma-polyps (SSA/Ps)], as well as 20 non-serrated adenomas, 20 carcinoma in adenomas (CIAs) and 18 early pure colorectal carcinomas without any adenoma component (EPCs). Based on immunostaining score, high DCLK1 expression was detected in 20.0% of HPs (23.1% of microvesicular HPs and 14.3% of goblet cell HPs), 37.5% of TSAs, 7.7% of SSA/Ps, 80.0% of non-serrated adenomas, 75.0% of CIAs and 50.0% of EPCs. Negative or low DCLK1 expression was frequently observed in TSAs (P<0.005), SSA/Ps (P<0.00001) and EPCs (P<0.04) compared with non serrated adenomas and CIAs. In addition, negative or low DCLK1 expression was significantly more frequent in SSA/Ps (92.3%) compared with TSAs (62.5%; P<0.05). Thus, the expression pattern of DCLK1 between the serrated pathway and ACS differed, indicating that DCLK1 expression may perform a secondary role in serrated tumorigenesis. In addition, the data indicates that EPCs may contain tumors derived from the serrated pathway as well as the ACS. PMID- 29399339 TI - High HPV16 E6 viral load in the oral cavity is associated with an increased number of bacteria: A preliminary study. AB - In a previous study, the present research group reported that males had a significantly higher prevalence of human papillomavirus (HPV)16 than females in oral rinse samples. The objective of the present study was to examine the relationship between HPV16 viral load and clinical factors, including remaining teeth, denture use and numbers of oral bacteria. A total of 124 patients (48 males and 76 females; mean age, 61.6 years; age range, 20-97 years) who visited the Department of Oral and Maxillofacial Reconstructive Surgery of Hiroshima University Hospital (Hiroshima, Japan) between November 2016 and August 2017 were analyzed. None of the patients had evidence of oral cancer or pre-malignant lesions, including epithelial dysplasia and leukoplakia. Quantitative polymerase chain reaction (qPCR) analysis was employed to examine the number of HPV16 viral copies. Furthermore, the number of oral bacteria was determined using the dielectrophoretic impedance measurement method. HPV16 was below the limit of detection in qPCR findings for samples obtained from 30 of the 124 subjects, thus the association of HPV16 viral copy number with clinical parameters was examined in the remaining 94 patients. The average number of HPV16 E6 DNA copies was 1.65+/-3.47 copies/cell (range, 0.07-25.3 copies/cell) and was significantly higher in subjects with a high oral bacteria count [>=106.5 colony forming unit (CFU)/ml] than in those with a low count (<106.5 CFU/ml) (0.79+/-0.98 vs. 2.06+/ 4.11 copies/cell; P=0.030). The present results indicated that HPV16 viral load may be related to an increased bacterial number in the oral cavity. Further investigations are required to clarify the correlation between oral HPV load and oral hygiene status. PMID- 29399340 TI - Gene polymorphisms of fibronectin rs2289202 and fibrillin 2 rs331069 associate with vascular disease, the TAMRISK study. AB - Cell surface heparan sulfate (HS) proteoglycans interact with other extracellular matrix (ECM) components, and HS-binding regions are present in ECM proteins such as fibronectin and fibrillin. Because of their previously established role in susceptibility to intracranial aneurysms, the authors sought to determine whether polymorphisms of fibronectin (FN1, rs2289202) and fibrillin 2 (FBN2, rs331069) associate with selected cardiovascular risk factors and events in the TAMRISK study. A 50-year-old Finnish cohort of 810 subjects of whom 340 had diagnosed hypertension was analyzed. Samples were genotyped for FN1 rs2289202 and FBN2 rs331069 polymorphisms. Incidence of myocardial infarction (I21-I22), transient cerebral ischemic attacks (TIA, G45) and cerebrovascular diseases (I60-I69) were followed up until the subjects were on the average 60 years old. Subjects with FN1 rs2289202 (G>A) minor genotype AA had significantly more cerebrovascular disease than those with the G allele [P<0.001, odds ratio (OR), 8.73; confidence index (CI), 2.79-27.31], although those with the A allele had lower body mass index (P=0.008). Subjects with fibrillin rs331069 (T>C) minor genotype CC had more atherothrombotic disease (P=0.012, OR, 3.16; CI, 1.29-7.71), as measured by combined myocardial infarction and TIA, than those with the T allele. The gene polymorphisms for fibronectin and fibrillin 2 appear to associate with vascular disease. PMID- 29399341 TI - Effect of branched-chain amino acid supplementation on insulin resistance and quality of life in chronic hepatitis C patients. AB - The incidence rate of insulin resistance (IR) in patients with chronic hepatitis C (CHC) is high. Recently, branched-chain amino acids (BCAA) have been shown to attenuate IR in CHC patients; however, their effect on patient quality of life remains unclear. Therefore, the aim of the current prospective study was to determine the effects of BCAA supplement on IR and health-related quality of life (HR-QoL) in patients with CHC. In the study, 20 non-diabetic patients with CHC, who were non-responders to peginterferon-alpha and ribavirin, were recruited. Patients took a BCAA supplement once a day (30 g, after a minimum 10-h overnight fast) for 3 months. Serum levels of glucose, insulin, albumin, triglycerides and cholesterol were measured at 0 and 3 months. Additionally, IR was measured using the Homeostasis Model Assessment-IR, HR-QoL was assessed using the 36-item Short Form Health Survey and viral load was measured by reverse transcription polymerase chain reaction using Taqman probes. The Wilcoxon signed-rank test was used to determine statistical significance. The results indicated that 70% of the subjects were positive for IR, which decreased to 50% by the end of the study; furthermore, 85% of the subjects demonstrated some level of improvement. Overall, the BCAA treatment significantly decreased IR (P=0.006) and augmented serum albumin concentration (P=0.008) compared with basal values. Additionally, by the end of the treatment, viral load and triglycerides levels had decreased, though these results were not significant (P=0.084 and P=0.080, respectively). BCAA treatment also improved HR-QoL regarding role limitations due to physical health problems (P=0.017), role limitations due to emotional problems (P=0.026) and social function (P=0.008). In conclusion, BCAA supplementation reduced IR and improved HR-QoL in patients with CHC. These findings support the application of IR therapy as a possible therapeutic strategy for hepatitis C infection. PMID- 29399342 TI - Analysis of IL6-protein complexes in chondrosarcoma. AB - Cytokines produced in the tumour microenvironment serve important roles in cancer pathogenesis or in the supression of disease progression. Metastatic chondrosarcoma is a cancer of the cartilage, and our group previously reported from a human ELISA assay that interleukin 6 (IL6) expression in JJ012 chondrosarcoma cells was 86-fold lower than that in C28 chondrocytes, indicating its role as an anti-inflammatory and anti-tumorigenic factor. Additionally, to the best of our knowledge, the study was the first to demonstrate downregulation of IL6 in a human chondrosarcoma cell line. To fully elucidate the effect of this IL6 downregulation, it is important to identify protein complexes and components that bind IL6 and potentially affect its gene expression directly or indirectly. To investigate IL6-protein interactions leading to these differences in IL6 expression, the current study performed a gel retardation electrophoretic mobility shift assay (EMSA), followed by 2D gel phoresis, in-gel trypsin digestion and proteomic mass spectral analysis. The results indicated a presence of ubiquitination enzymes in C28 chondrocytes, while none were identified in JJ012 chondrosarcoma cells. While it seems counterintuitive, it may be that the absence of ubiquitination of certain factors leads to the downregulation of IL6 expression in human chondrosarcoma. Therefore, dysregulated ubiquitination may be among the possible mechanisms for the markedly reduced IL6 expression in chondrosarcoma. PMID- 29399343 TI - Abnormally expressed microRNA as auxiliary biomarkers for nasopharyngeal carcinoma: A meta-analysis. AB - Aberrant expression of microRNA (miRNA) has been highlighted as a helpful indicator to aid in nasopharyngeal carcinoma (NPC) diagnosis. The present meta analysis aimed to validate the efficacy of miRNA as potential biomarkers for NPC detection. Publication searches were conducted on the online PubMed and EMBASE databases from inception to June 2016. A bivariate meta-analysis was performed to generate the diagnostic parameters based on Meta-Disc 1.4 and Stata 12.0 programs. Sensitivity analysis and meta-regression tests were applied to trace heterogeneity sources among eligible studies. A total of six studies comprising 528 patients with NPC and 252 matched controls were enrolled. Results from the present meta-analysis demonstrated that miRNA testing achieved a pooled sensitivity of 0.78 [95% confidence interval (CI), 0.70-0.84] and specificity of 0.79 (95% CI, 0.73-0.84) in confirming NPC, corresponding to an area under the curve (AUC) value of 0.85. Additionally, the pooled diagnostic odds ratio was estimated to be 9.01 (95% CI, 5.62-14.44), along with a positive likelihood ratio of 2.81 (95% CI, 2.19-3.61) and negative likelihood ratio of 0.35 (95% CI, 0.28 0.44). Additionally, the stratified analyses revealed that paralleled testing of miRNA sustained a pooled accuracy superior compared with that of single miRNA testing (sensitivity, 0.88 vs. 0.70; specificity, 0.85 vs. 0.69; AUC, 0.95 vs. 0.75). Testing of miRNA harbors a moderate diagnostic efficacy and is acceptable as an auxiliary biomarker for NPC diagnosis. PMID- 29399344 TI - Erratum: Recent advances in the molecular mechanisms of Mayer-Rokitansky-Kuster Hauser syndrome. AB - [This corrects the article DOI: 10.3892/br.2017.929.]. PMID- 29399345 TI - ATP-binding cassette transporter A1: A promising therapy target for prostate cancer. AB - ATP-binding cassette transporter A1 (ABCA1) has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), and is essential for the synthesis of high-density lipoprotein. Mutations of the ABCA1 gene may induce Tangier disease and familial hypoalphalipoproteinemia; they may also lead to loss of cellular cholesterol homeostasis in prostate cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The aim of the present review was to focus on the current views on prostate cancer progression and the various functions of ABCA1, in order to provide new therapeutic targets for prostate cancer. PMID- 29399347 TI - Lateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva: A case report. AB - Lateral retropharyngeal lymph node (LRPLN) is located between the internal carotid artery and the prevertebral muscles. Metastasis to the LRPLN is frequent in nasopharyngeal cancer, but is rare in oral cancer. The prognosis of patients with oral cancer with LRPLN metastasis is usually poor. The present study reported a patient with LRPLN metastasis from squamous cell carcinoma of the upper gingiva, who survived for >7 years. Docetaxel, cisplatin and fluorouracil (TPF) therapy was performed as induction chemotherapy and it was planned to subsequently conduct chemoradiotherapy or surgery. As the tumor only exhibited a transient response to TPF, surgery was selected. Postoperatively, only radiotherapy was performed and a favorable outcome was achieved. PMID- 29399346 TI - The evolution of proton beam therapy: Current and future status. AB - Proton beam therapy (PBT) has been increasingly used in a variety of cancers due to its excellent physical properties and superior dosimetric parameters. PBT may improve patient survival by improving the local tumor treatment rate while reducing injury to normal organs, which may result in fewer radiation-induced adverse effects. However, the significant cost of establishing and maintaining proton facilities cannot be overlooked. In addition, there has been significant controversy regarding routine application of this treatment in certain types of cancer. The challenges of PBT in the future mainly include the lack of basic clinical trials, unclear biological effects, immature imaging technology and miniaturization of imaging guidance. Overcoming these limitations may promote the rapid development of PBT. We herein provide an overview of the existing literature on the efficacy and toxicity of common oncological applications of proton beam therapy. PMID- 29399348 TI - Xp11.2 translocation renal cell carcinoma with TFE3 gene fusion: A case report. AB - Xp11.2 translocation renal cell carcinoma (RCC) with transcription factor E3 (TFE3) gene fusion is a rare tumor, and the prognosis of this tumor is poorer compared with that of other subtypes of RCC. The patient presented herein was a 70-year-old man who presented with a solid mass sized ~8.2*6.1 cm in the right kidney and underwent radical right nephrectomy. Following pathological and immunohistochemical (IHC) examination and fluorescent in situ hybridization (FISH), the patient was diagnosed with Xp11.2 translocation RCC with TFE3 gene fusion. These tumors are more commonly encountered in children rather than in adults, and adult Xp11.2 translocation RCC is associated with a poorer prognosis compared with its pediatric counterpart. IHC assay and FISH are important diagnostic methods. However, there is currently no established effective treatment for Xp11.2 RCC. PMID- 29399349 TI - Atypical spleen tuberculosis in a melanoma patient accidentally detected during a 18F-FDG PET/CT study: Case report. AB - The present study, discussed a rare case of a 50-year-old woman who was treated for malignant melanoma and underwent 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) examination for evaluation of disease. 18F-FDG-PET/CT examination was performed from the top of the head down to the knee using a Gemini TF PET/CT scanner 60 min following intravenous injection of radiotracer with mean activity of 364+/-75 MBq. Previous performed laboratory test and clinical examination was irrelevant. By abdominal ultrasound no abnormalities in abdominal organs beside the liver cyst were found. The 18F FDG PET/CT exam showed an increased glucose metabolism in the anterior pole of the spleen, which was considered as melanoma metastasis. Splenectomy was performed and histopathology examination tuberculous lesion in the spleen was revealed. Histopathology examination showed epithelioid granuloma and in correlation with the patient's history allowed to establish tuberculous-like lesions in the spleen. In the present study, authors used 18F-FDG PET/CT examination to detect the melanoma metastasis of a 50-year-old woman, and found that abnormal focal accumulation of radiotracer with limited cancer specificity in PET/CT examination in cancer patients should not be unambiguously taken as a metastatic lesion. PMID- 29399350 TI - Extraskeletal osteosarcoma of the lung following treatment of primary small-cell lung carcinoma with chemoradiotherapy: A case report. AB - Primary pulmonary osteosarcoma is a rare entity, with only a few cases reported in the literature to date. Moreover, secondary extraskeletal osteosarcoma of the lung following chemoradiotherapy is extremely rare and, to the best of our knowledge, this is the first reported case. We herein present the case of an 80 year-old male patient with small-cell lung cancer (SCLC), who developed what it was initially considered as recurrence of the tumor after chemoradiotherapy. The patient eventually succumbed to the disease, and on autopsy it was discovered that the lung tumor was not in fact SCLC, but rather a secondary osteosarcoma. Osteosarcoma metastasis to the lung is very rare, but must be considered in the differential diagnosis when there is relapse following treatment for primary SCLC. PMID- 29399351 TI - Extremely large epithelial ovarian cancer associated with pregnancy: A case report. AB - Ovarian malignancies are rare in pregnancy; however, the incidence of abnormal adnexal masses diagnosed during pregnancy is increasing. The most common masses are ovarian cysts, and only 3-6% of those are malignant. The majority of ovarian masses are diagnosed at an early stage by routine ultrasound examinations. Malignant germ cell tumors are the most common ovarian malignancies associated with pregnancy, while the incidence of epithelial ovarian cancer is only 1:12,000 1:50,000 of pregnancies. The diagnosis and management of ovarian cancer during pregnancy remain unclear due to the rare occurrence and scant data on this condition. We herein report the case of 23-year-old woman with an extremely large ovarian papillary mucinous cystadenocarcinoma diagnosed during pregnancy, identified on ultrasound and magnetic resonance imaging, and treated by surgical resection followed by adjuvant chemotherapy with carboplatin and paclitaxel. PMID- 29399352 TI - Surgical management of metastatic lesions of the proximal femur with pathological fractures using intramedullary nailing or endoprosthetic replacement. AB - Endoprosthetic replacement (EPR) and intramedullary nailing (IMN) are the two most commonly applied surgical methods used to treat proximal metastatic lesions; however, indication of the above procedures remains controversial. The aim of the present study was to evaluate the clinical, functional and oncological outcomes of patients who underwent EPR compared to IMN for the treatment of proximal femur metastases to investigate the surgical indication for patients. The records of patients (n=88) with pathological fractures secondary to metastatic tumors of the proximal femur admitted between January 2005 and December 2014 to West China Hospital, Sichuan University (Chengdu, China) were retrospectively studied. A total of 57 patients were treated with EPR (34 males and 23 females; mean age, 62.5 years) and 31 patients were stabilized with IMN (19 males and 12 females; mean age, 60.2 years). Patients were analyzed regarding surgery time, blood loss, hospital stay, Musculoskeletal Tumor Society (MSTS) score, survival, recurrence and complications. The median follow-up period was 12.9 (range, 3-98) months. The median survival time in EPR was 10.0 months and 7.5 months in IMN. The surgery time was 142.6+/-22.7 min in the EPR group and 98.7+/-19.5 min in the IMN group (P=0.001). Significantly less blood loss was observed in the IMN group (345.2+/ 66.4 ml) than in the EPR group (631.5+/-103.6 ml; P=0.001). The median hospital stay in the EPR group was 8 (quartile range, 7-9) days and 5 (quartile range, 5 6) days in the IMN group (P=0.001). Local recurrence rate was 10.5% (6/57) in the EPR group and 25.8% (8/31) in the IMN group (P=0.074). The complication rates were 10.5% (6/57) in the EPR group and 29.0% (9/31) in the IMN group (P=0.038). MSTS-93 score was higher in IMN compared with EPR at 6 weeks postoperatively (P=0.001), while the EPR group demonstrated a higher score at 6 months postoperatively (P=0.001). EPR has the advantage of better functional outcomes and higher life quality in the long term, with lower complication rates in treating metastatic lesions of the proximal femur with pathological fractures. EPR is recommended for patients with relatively good general condition and prognosis. IMN is best indicated when the patient's life expectancy is extremely limited. PMID- 29399353 TI - Osseous choristoma of the tongue: A case report with dermoscopic study. AB - Osseous choristomas are rare benign lesions characterized by ectopic bone formation in the soft tissue of the head and neck region. Dermoscopy visualizes the morphological characteristics that are not observable by the naked eye, and may be used for the evaluation of calcification under the skin. The present study reports a case of an osseous choristoma arising in the tongue, and reveals the dermoscopic features of osseous choristoma from a surgical specimen. A 7-year-old boy was referred to the Department of Dentistry and Oral Surgery, with an asymptomatic pedunculated mass in the tongue. The lesion was removed completely with the adjacent normal tissue under general anesthesia. Dermoscopy of the surgical specimen revealed the hypovascular and homogeneous pattern of the lesion with round extruded whitish material. Based on dermoscopic findings, the presence of calcified hard tissue in the submucosa was verified by the dermatologist. Radiographic examination of the surgical specimen revealed the lesion contained a radiopaque trabeculated mass. Histologically, the lesion contained an osseous tissue, and the pathological diagnosis of osseous choristoma was made following consideration of the ectopic bony tissues that were localized away from the maxillo-mandibular bone. The postoperative course was uneventful with no signs of recurrence during the 36 months following surgery. To the best of the author's knowledge, this is the first report of evaluation of osseous choristoma using dermoscopy. The observation indicates the usefulness of dermoscopy for the diagnosis of oral ossified lesion in oral soft tissue. PMID- 29399354 TI - Efficacy of osimertinib in a patient with non-small cell lung cancer harboring epithelial growth factor receptor exon 19 deletion/T790M mutation, with poor performance status. AB - Osimertinib, a third-generation epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated to be effective for treating patients with T790M-positive advanced non-small cell lung cancer (NSCLC) with a relatively good performance status (grade 0-1). Reports of therapeutic response to osimertinib in advanced NSCLC patients with poor performance status are infrequent. The present case report discusses a patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion and T790M mutation with central nervous system involvement and poor performance status. The patient had a past history of partial lung resection due to lung adenocarcinoma, positive genetic test for EGFR exon 19 deletion in post-surgical tumor specimens, and therapy with erlotinib and onartuzumab for the appearance of a lung metastatic tumor during the post-surgical follow-up. The combined therapy was continued until the discovery of metastatic tumors in bones and the central nervous system. The Cobas test performed using tissue from bone metastatic tumor was positive for exon 19 deletion and for T790M mutation. The patient was treated with osimertinib and adverse effects or hematological toxicity were not observed. Performance status of the patient improved from grade 4 to 2. Subsequent studies revealed remission of bone metastasis and reduced central nervous system lesions. This report provides evidence on the safety and efficacy of osimertinib for treating NSCLC patients with progressive disease, central nervous system lesion and poor performance status. PMID- 29399355 TI - Radiation-induced angiosarcoma of the omentum diagnosed by laparoscopy: A case report. AB - Angiosarcoma is a rare malignant tumor with an aggressive clinical course and a poor prognosis. Intraperitoneal angiosarcoma, especially originating from the omentum, is extremely rare. We report a case of radiation-induced angiosarcoma of the omentum that arose in a 38-year-old female seven years after concurrent chemoradiotherapy for cervical cancer. The primary tumor was unknown until diagnostic laparoscopy revealed an unresectable omental mass. Pathological examination revealed high-grade malignant cells positive for endothelial markers. Although the small number of cases limits the consensus on optimal therapy for advanced angiosarcoma, the patient was managed successfully by taxane-based chemotherapy, leading to complete response and consequent complete cytoreductive surgery. Our report is the fifth case of radiation-induced angiosarcoma of the omentum, and all have developed after treatment for gynecologic cancer. Although very rare, this complication should be considered after radiation therapy in cancer treatment, particularly given the increasing importance of this therapy. PMID- 29399356 TI - Endoscopic removal of laser-cut covered self-expandable metallic biliary stents: A report of six cases. AB - Covered self-expandable metallic stents (CSEMS) may provide palliative drainage for unresectable distal malignant biliary strictures. Laser-cut CSEMS allows easy positioning due to its characteristic of minimal stent shortening. Endoscopic stent removal is sometimes recommended for recurrent biliary obstruction (RBO). However, there are no previous reports of endoscopic removal of laser-cut CSEMS. The current study presents data from 6 patients who were placed a laser-cut CSEMS for unresectable distal malignant biliary strictures, and later endoscopic stent removal was attempted for RBO at the present institute. The duration of stent placement, the procedural success rate, the procedural duration, and accidental complications were evaluated. The mean duration of stent placement was 156+/-37.9 days (range, 117-205). The procedural success rate was 100%. The mean procedural duration was 11.8+/-7.5 min (range, 5-24). No complications were reported. Laser cut CSEMS were safely removed from all patients. The present case report is the first to demonstrate that Endoscopic stent removal of laser-cut CSEMS was safely performed. PMID- 29399357 TI - Anticancer effects of Bilberry anthocyanins compared with NutraNanoSphere encapsulated Bilberry anthocyanins. AB - Rapidly accumulating laboratory and clinical research evidence indicates that anthocyanins exhibit anticancer activity and the evaluation of bilberry anthocyanins as chemo-preventive agents is progressing. It has previously been demonstrated that anthocyanins upregulate tumor suppressor genes, induce apoptosis in cancer cells, repair and protect genomic DNA integrity, which is important in reducing age-associated oxidative stress, and improve neuronal and cognitive brain function. Bilberry anthocyanins have pronounced health effects, even though they have a low bioavailability. To increase the bioavailability, Bilberry was encapsulated in 5.5 nm diameter liposomal micelles, called NutraNanoSpheres (NNS), at a concentration of 2.5 mg/50 ul [25% (w/w) anthocyanins]. These Bilberry NNS were used to study the apoptotic/cytotoxic effects on K562 Human Erythroleukemic cancer cells. Flow cytometric fluorescent quantification of the uptake of propidium iodide in a special cell viability formulation into dead K562 cells was used to determine the effects of Bilberry on the viability of K562 cells. The concentrations of Bilberry that demonstrated the greatest levels of percentage inhibition, relative to the control populations, were biphasic, revealing a 60-70% inhibition between 0.018-1.14 mg/ml (n=6) and 60% inhibition at 4 mg/ml. The lowest percentage inhibition (30%) occurred at 2 mg/ml. The lethal dose 50 was determined to be 0.01-0.04 mg/ml of Bilberry per 105 K562 cells at 72 h of cell culture exposure. At 48 h incubation, the highest percentage of inhibition was only 27%, suggesting involvement of a long-term apoptotic event. These levels, which demonstrated direct cytotoxic effects, were 8-40 times lower than levels required for Bilberry that is not encapsulated. The increase in bioavailability with the Bilberry NNS and its water solubility demonstrated the feasibility of using Bilberry NNS in cancer patient clinical trials. PMID- 29399358 TI - Predictive biomarkers for combined chemotherapy with 5-fluorouracil and cisplatin in oro- and hypopharyngeal cancers. AB - The present study aimed to identify significant correlations between gene expression and chemotherapy response to 5-fluorouracil (5-FU)/cisplatin in head and neck squamous cell carcinoma (HNSCC), and to identify patients who would benefit from induction chemotherapy for both organ preservation and survival. A total of 64 patients who underwent radical treatment for HNSCC were enrolled. All patients received induction chemotherapy with 5-FU/cisplatin and tumor responses were evaluated. Pretreatment biopsy specimens from all patients were assayed for mRNA expression of thymidylate synthase, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, tymidine phosphorylase, glutathione S transferase-pi, p53, RB Transcriptional Corepressor 1, B-cell lymphoma 2 (Bcl-2), Bcl-xL, E2F Transcription Factor 1, epidermal growth factor receptor, human epidermal growth factor receptor 2, phosphoinositide 3-kinase, phosphatase and tensin homolog, vascular endothelial growth factor (VEGF), cyclooxygenase-2, XPA, DNA Damage Recognition And Repair Factor, excision repair cross-complementing 1 (ERCC1), multidrug resistance gene 1 (MDR1), multidrug resistance-associated protein 1, equilibrative nucleoside transporter 1 and beta-tubulin by reverse transcription-quantitative polymerase chain reaction, and the association between the expression levels of these genes and patient response to chemotherapy was determined. The complete response (CR) group and non-CR group for induction chemotherapy comprised 32.8 and 67.2% of patients, respectively. The 5-year overall survival rate was significantly higher for the CR group (95%) compared with the non-CR group (57%). According to univariate analysis, chemotherapy response was associated with T-class and mRNA expressions of DPD, ERCC1, XPA, p53, Bcl-2, VEGF and MDR1. Multivariate analysis identified ERCC1 expression and T-class as significant predictors of response to chemotherapy, indicating that a DNA-repair pathway and apoptosis pathway are pivotal mechanisms governing response to chemotherapy. The findings suggest that ERCC1 expression could be a predictive biomarker for chemotherapy response to 5-FU/cisplatin in HNSCC. Assessing mRNA expression is a standard method for these studies, however further investigations examining polymorphisms and mutations in addition to apoptotic responses are required to determine target gene activation in HNSCC. PMID- 29399359 TI - Association between smoking and non-alcoholic fatty liver disease: A systematic review and meta-analysis. AB - Background/aims: Non-alcoholic fatty liver disease is one of the most common chronic liver diseases. Some risk factors are known to influence the development of non-alcoholic fatty liver disease, but the effect of tobacco smoking on the progression of non-alcoholic fatty liver disease is controversial. The main goal of this systematic review and meta-analysis is to investigate the association between smoking and non-alcoholic fatty liver disease. Method: Electronic databases (PubMed, Scopus, and ISI Web of Science) were searched to find published articles on non-alcoholic fatty liver disease and smoking until December 2016. All relevant studies were screened by inclusion and exclusion criteria and compatible studies were chosen. The Newcastle-Ottawa Scale was used to assess the methodological quality of eligible articles. Subsequently, information was gathered based on the following: author, publication year, keywords, country, inclusion and exclusion criteria, main results, study design, conclusion, and confounder variables (age, body mass index, gender, ethnicity, and diabetes). Finally, analyses were performed using Comprehensive Meta-Analysis Software. Results: Data were extracted from 20 observational studies (9 cross sectional, 6 case-control, 4 cohort studies, and 1 retrospective cohort study). A significant association was observed between smoking and non-alcoholic fatty liver disease with a pooled odds ratio of 1.110 (95% confidence interval, 1.028 1.199), p-value = 0.008. The statistical heterogeneity was medium with an I2 of 40.012%, p-heterogeneity = 0.074. Also there was a significant relation between non-alcoholic fatty liver disease and passive smoking with a pooled odds ratio of 1.380 (95% confidence interval, 1.199-1.588; p-value = 0.001; I2 = 59.41; p heterogeneity = 0.117). Conclusion: Our meta-analysis demonstrated that smoking is significantly associated with non-alcoholic fatty liver disease. Further prospective studies exploring the underlying mechanisms of this association should be pursued. Also passive smoking increases the risk of non-alcoholic fatty liver disease about 1.38-fold. The effects of smoking cigarettes on active smokers (current smoker, former smoker, and total smoker) are less than passive smokers. Further studies are needed to compare the of effects of passive and active smoking on non-alcoholic fatty liver disease. PMID- 29399360 TI - Physiological plasticity in a successful invader: rapid acclimation to cold occurs only in cool-climate populations of cane toads (Rhinella marina). AB - Physiological plasticity may facilitate invasion of novel habitats; but is such plasticity present in all populations of the invader or is it elicited only by specific climatic challenges? In cold-climate areas of Australia, invasive cane toads (Rhinella marina) can rapidly acclimate to cool conditions. To investigate whether this physiological plasticity is found in all invasive cane toads or is only seen in cool climates, we measured the acclimation ability of toads from across Australia and the island of Hawai'i. We collected toads from the field and placed them at either 12 or 24 degrees C for 12 h before measuring their righting response as a proxy for critical thermal minimum (CTmin). Toads from the coolest Australian region (New South Wales) demonstrated plasticity (as previously reported), with exposure to 12 degrees C (vs. 24 degrees C) decreasing CTmin by 2 degrees C. In toads from other Australian populations, CTmins were unaffected by our thermal treatments. Hawai'ian toads from a cool, wet site also rapidly acclimated to cool conditions, whereas those from warmer and drier Hawai'ian sites did not. Thermal plasticity has diverged among populations of invasive cane toads, with rapid acclimation manifested only in two cool-climate populations from widely separated sites. Predictions about the potential range of invasive species thus must consider the possibility of geographic (intraspecific) heterogeneity in thermal plasticity; data from other parts of the species' range may fail to predict levels of plasticity elicited by thermal challenges. PMID- 29399361 TI - Dietary changes during weaning shape the gut microbiota of red pandas (Ailurus fulgens). AB - Mammalian herbivores have developed numerous adaptations to utilize their plant based diets including a modified gastrointestinal tract (GIT) and symbiosis with a GIT microbiota that plays a major role in digestion and the maintenance of host health. The red panda (Ailurus fulgens) is a herbivorous carnivore that lacks the specialized GIT common to other herbivores but still relies on microorganisms for survival on its almost entirely bamboo diet. The GIT microbiota is of further importance in young red pandas, as high cub mortality is problematic and has been attributed to failure to meet nutritional requirements. To gain insight into the establishment of the GIT microbiota of red pandas, we examined microbial communities in two individuals following dietary changes associated with weaning using next-generation 16S rRNA Illumina MiSeq paired-end sequencing of faecal samples. Across all four stages (pre-weaning, during weaning, post-weaning and adult), the GIT microbial community displayed low diversity and was dominated by bacteria in the phylum Firmicutes with lesser contributions from the Proteobacteria. A core community was found consistently across all weaning stages and included species within the taxa Escherichia-Shigella, Streptococcus, Clostridium and an unclassified Clostridiaceae. Analysis of the overall community composition and structure showed that although the GIT microbiota is established early in red pandas, dietary changes during weaning further shape the community and are correlated with the presence of new bacterial species. This work is the first analysis of the GIT microbiota for red panda cubs during weaning and provides a framework for understanding how diet and host microbiota impact the development of these threatened animals. PMID- 29399362 TI - Can concentrations of steroid hormones in brown bear hair reveal age class? AB - Although combining genetic and endocrine data from non-invasively collected hair samples has potential to improve the conservation of threatened mammals, few studies have evaluated this opportunity. In this study, we determined if steroid hormone (testosterone, progesterone, estradiol and cortisol) concentration profiles in 169 hair samples collected from free-ranging brown bears (Ursus arctos) could be used to accurately discriminate between immature and adult bears within each sex. Because hair samples were acquired opportunistically, we also needed to establish if interactions between hormones and several non-hormone factors (ordinal day, year, contact method, study area) were associated with age class. For each sex, we first compared a suite of candidate models by Akaike Information Criteria model selection, using different adult-age thresholds (3, 4 and 5 years), to determine the most supported adult age. Because hair hormone levels better reflect the endocrine state at an earlier time, possibly during the previous year, then at the time of sampling, we re-analysed the data, excluding the records for bears at the adult-age threshold, to establish if classification accuracy improved. For both sexes, candidate models were most supported based on a 3-year-old adult-age threshold. Classification accuracy did not improve with the 3-year-old bear data excluded. Male age class was predicted with a high degree of accuracy (88.4%) based on the concomitant concentrations of all four hormones. Female age class was predicted with less accuracy (77.1%) based only on testosterone and cortisol. Accuracy was reduced for females, primarily because we had poor success in correctly classifying immature bears (60%) whereas classification success for adult females was similar to that for males (84.5%). Given the small and unbalanced sample used in this study, our findings should be viewed as preliminary, but they should also provide a basis for more comprehensive future studies. PMID- 29399364 TI - Hypercalcemia of malignancy treated with cinacalcet. AB - : Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range. Learning points: Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.Breast cancer has the highest prevalence of hypercalcemia.The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option. PMID- 29399363 TI - Conservation choice on the rare endangered plants Glehnia littoralis. AB - The coastal herbs Glehnia littoralis have been domesticated as traditional medicines for many centuries. The domestication may have caused changes or declines of cultivated G. littoralis (CGL) relative to wild G. littoralis (WGL). By comparing fruit properties of CGL and WGL, we tested the hypothesis that domesticated G. littoralis have suffered major declines, and human cultivation cannot be sufficient to conserve this species. We collected fruits of CGL and WGL in the Shandong peninsula, China, and compared their buoyancy in seawater, germination potential after seawater immersion, and thousand-grain weights. Float rates of the WGL and CGL fruits were 95.6 (mean) +/- 2.6% (standard deviation) and 30.0 +/- 7.1%, respectively. The germination potential of CGL was significantly reduced, although the thousand-grain weights of CGL (21.85 +/- 0.17 g) were higher than those of the WGL fruits (14.73 +/- 0.21 g). These results suggest that the CGL have experienced significant declines relative to the WGL, presumably due to the loss of seawater inundation, selection and dispersal. These declines disfavour the persistence of CGL, and human domestication and cultivation are believed to be insufficient for conserving G. littoralis. Sand coasts where WGL still persists should be designated timely as nature reserves to conserve this species. PMID- 29399365 TI - Urinary Hepcidin-25 Is Elevated in Patients That Avoid Acute Kidney Injury Following Cardiac Surgery. AB - Background: Acute kidney injury (AKI) following cardiac surgery leads to increased morbidity and mortality. Characterization and validation of early biomarkers of AKI may ultimately facilitate early therapeutic intervention. We have previously identified that elevated urinary hepcidin-25 is inversely and independently associated with the development of AKI in adult cardiac surgery patients. Hepcidin-25 is an antimicrobial peptide that sequesters iron intracellularly, and its elevation following human ischemia reperfusion injury may represent a renoprotective response to minimize renal injury. Objective: Our goal was to validate urinary hepcidin-25 as a non-invasive biomarker in an independent cardiac surgery cohort, within the context of clinical AKI predictors. Design: Prospective observational cohort study. Setting: Adult cardiac surgery program at St. Boniface Hospital, Winnipeg, Manitoba, Canada. Patients: Adult cardiac surgery patients undergoing cardiopulmonary bypass (CPB), n = 306. Measurements: Urine hepcidin-25, measured on post-operative day (POD) 1. Methods: A prospective, observational cohort of adult CPB patients (n = 306) was collected with serial perioperative urine samples. Urine hepcidin-25 at POD 1 was measured by competitive ELISA. Its diagnostic performance was evaluated in conjunction with clinical parameters and the Thakar clinical prediction score, using multivariate logistic regression. Results: Urinary hepcidin-25 is elevated following cardiac surgery in AKI and non-AKI patients. Elevated urinary hepcidin 25 concentration was inversely associated with AKI on both univariate (odds ratio [OR]: 0.61, 95% confidence interval [CI]: 0.45-0.83, P = .002) and multivariate analysis (OR: 0.67, 95% CI: 0.50-0.95, P = .02). A combined model with clinical risk factors demonstrated that baseline estimated glomerular filtration rate (eGFR), diabetes mellitus, and urinary hepcidin-25 concentration had an overall area under the curve (AUC) of 0.82 (0.75-0.88) for predicting subsequent AKI development, which was superior to clinical prediction alone as determined by the Thakar score. Limitations: (1) A single-center observational study. (2) Polyclonal antibody-based competitive ELISA. Conclusion: Hepcidin-25 is inversely associated with AKI in a multivariate model when combined with eGFR and diabetes mellitus, with an overall AUC of 0.82. Notably, urinary hepcidin-25 improves on clinical AKI prediction compared to the Thakar score alone. PMID- 29399366 TI - Nephrology eConsults for Primary Care Providers: Original Investigation. AB - Background: The Champlain BASETM (Building Access to Specialists through eConsultation) eConsult service allows primary care providers (PCPs) to submit patient-specific clinical questions to specialists via a secure web service. Objective: Our objective was to describe the types of nephrology questions asked through an eConsult service based in eastern Ontario and assess the service's impact on the need for face-to-face consultations. Design: Cross-sectional study using descriptive statistics was conducted using nephrology cases submitted between May 2011 and January 2015. Specialist response times and referral avoidance were collected. Validated taxonomies were used to categorize cases based on question type and content. Setting: Patient cases were collected from PCPs in Ottawa, Ontario, and its surrounding communities and submitted to nephrologists at the Ottawa Hospital. Patients: During the study period, 155 eConsults were submitted to nephrology. Measurement: Utilization and survey data were collected for all eConsults. Questions were categorized by subject matter and question type. Results: A traditional consult visit was avoided in 45% of cases based on the specialist's advice; 21% cases required referral. Thirty-two percent of eConsults took specialists less than 10 minutes to complete, 55% took 10 to 15 minutes, 11% took 15 to 20 minutes, and only 2% took more than 20 minutes. Twenty-five percent of cases were related to proteinuria, 18% to chronic kidney disease (CKD), 17% to imaging, and 12% to drug use in CKD. Common question types included general management (37%), interpretation of laboratory test (17%), interpretation of an image report (13%), and need for nephrology referral (11%). Limitations: Some consults contained multiple categories and question types. Our analyses required a single classification, which may underestimate the number of questions in each category. Our study had a small sample size using cases completed in a single health jurisdiction, limiting generalizability. Conclusions: The Champlain BASETM eConsult service provided guidance to PCPs and reduced the number of face-to-face nephrology consultations. PMID- 29399367 TI - A novel approach to studying co-evolution of understanding and research: Family bereavement and the potential for organ donation as a case study. AB - A novel approach to data extraction and synthesis was used to explore the connections between research priorities, understanding and practice improvement associated with family bereavement in the context of the potential for organ donation. Conducting the review as a qualitative longitudinal study highlighted changes over time, and extraction of citation-related data facilitated an analysis of the interaction in this field. It was found that lack of 'communication' between researchers contributes to information being 'lost' and then later 'rediscovered'. It is recommended that researchers should plan early for dissemination and practice improvement to ensure that research contributes to change. PMID- 29399368 TI - Successful treatment of Providencia rettgeri cholecystitis and neutrophilic cholangitis in a cat. AB - Case summary: A 15-year-old male neutered domestic shorthair cat was presented with a recent history of seizures, diarrhoea, lethargy, fever and jaundice. Marked elevation of liver enzyme activity was present and ultrasound examination was suggestive of cholecystitis and hepatitis. Neutrophilic cholangitis was confirmed on histopathology of liver biopsies. Bile culture identified a monomicrobial infection with Providencia rettgeri, which was resistant to multiple antimicrobial agents. The cat was treated with oral pradofloxacin for 4 weeks and remained well 4 months later. Relevance and novel information: Providencia species are rarely reported in the veterinary literature and are an uncommon cause of disease in humans. The significance of this species in humans relates to the high prevalence of antimicrobial resistance. This is the first report of P rettgeri causing clinical illness in a cat and highlights the importance of bile cultures in hepatic disease. PMID- 29399369 TI - Prevalence of Anaplasma phagocytophilum infection in feral cats in Massachusetts. AB - Objectives: The primary objective of this study was to determine the prevalence of Anaplasma phagocytophilum infection and exposure in adult feral cats in Massachusetts, an endemic area for A phagocytophilum and its tick vector Ixodes scapularis. The secondary objective was to determine if there were correlations between A phagocytophilum infection and the presence of anemia and thrombocytopenia. Methods: Blood samples were collected between June and December 2015 from 175 apparently healthy adult feral cats that were presented to trap and release spay/neuter centers in Massachusetts. Complete blood count, blood smear evaluation, SNAP 4Dx Plus test (IDEXX) and A phagocytophilum PCR were performed on all samples to document acute infection (PCR-positive and/or inclusions observed on blood smear) and exposure to A phagocytophilum (SNAP 4Dx Plus positive for A phagocytophilum antibodies). Results: The prevalence of exposure to A phagocytophilum in feral cats in Massachusetts was 9.7%, whereas the prevalence of acute infection was 6.9%. All blood smears were negative for Anaplasma species inclusions; therefore, acute infection was defined as testing positive on PCR analysis. No statistically significant correlations were identified for cats that were positive for A phagocytophilum on PCR analysis or SNAP 4Dx Plus test and the presence of anemia or thrombocytopenia. Conclusions and relevance: The prevalence of A phagocytophilum exposure in feral cats approaches 10% and is higher than the previously reported national average prevalence of 4.3% in the USA. A phagocytophilum infection may be an emerging infectious disease in cats. Further research is needed to determine the prevalence of clinical illness associated with A phagocytophilum infection in cats living in endemic areas. PMID- 29399370 TI - An open source, 3D printed preclinical MRI phantom for repeated measures of contrast agents and reference standards. AB - In medical imaging, clinicians, researchers and technicians have begun to use 3D printing to create specialized phantoms to replace commercial ones due to their customizable and iterative nature. Presented here is the design of a 3D printed open source, reusable magnetic resonance imaging (MRI) phantom, capable of flood filling, with removable samples for measurements of contrast agent solutions and reference standards, and for use in evaluating acquisition techniques and image reconstruction performance. The phantom was designed using SolidWorks, a computer aided design software package. The phantom consists of custom and off-the-shelf parts and incorporates an air hole and Luer Lock system to aid in flood filling, a marker for orientation of samples in the filled mode and bolt and tube holes for assembly. The cost of construction for all materials is under $90. All design files are open-source and available for download. To demonstrate utility, B0 field mapping was performed using a series of gadolinium concentrations in both the unfilled and flood-filled mode. An excellent linear agreement (R2>0.998) was observed between measured relaxation rates (R1/R2) and gadolinium concentration. The phantom provides a reliable setup to test data acquisition and reconstruction methods and verify physical alignment in alternative nuclei MRI techniques (e.g. carbon-13 and fluorine-19 MRI). A cost-effective, open-source MRI phantom design for repeated quantitative measurement of contrast agents and reference standards in preclinical research is presented. Specifically, the work is an example of how the emerging technology of 3D printing improves flexibility and access for custom phantom design. PMID- 29399371 TI - Influence of hypophysectomy, ovariectomy and gonadectomy on postoperative hypersensitivity in rats. AB - Surgical procedures lead to profound and sustained (up to 1-2 weeks) activation of the pituitary gland, resulting in changes in endocrine function. Questions remain on whether activation of the pituitary influences the threshold and development time-course of postoperative pain. To address these questions, we evaluated postoperative hypersensitivity in female and male rats with ablated pituitary and gonadal hormone productions via hypophysectomy, ovariectomy and gonadectomy, respectively. Plantar incision, a model of acute postoperative pain, or sham operation was performed on rat hind paws. Hypophysectomy, ovariectomy and gonadectomy were achieved by surgical disconnection of pituitary, ovaries and testicles, respectively. Postoperative thermal and mechanical hypersensitivity were monitored for 7 days post incision. Hypophysectomy on female and male rats produced statistically similar thermal and mechanical postoperative hypersensitivity thresholds and time-courses as compared to intact estrous female and male rats. Moreover, ovariectomy and gonadectomy did not significantly change postoperative hypersensitivity observed in control female and male animals. Our experiments demonstrate that hypophysectomy, ovariectomy and gonadectomy do not significantly impact postoperative hypersensitivity observed in normal female and male animals. These data suggest that surgery-induced changes in the endocrine system via activation of pituitary and subsequently gonadal tissues have little impact on the threshold and development of postoperative pain in female and male rats. PMID- 29399372 TI - Proximal Humerus Fractures: Evaluation and Management in the Elderly Patient. AB - Introduction: Proximal humerus fractures are common in the elderly. The evaluation and management of these injuries is often controversial. The purpose of this study is to review recent evidence and provide updated recommendations for treating proximal humerus fractures in the elderly. Methods: A literature review of peer-reviewed publications related to the evaluation and management of proximal humerus fractures in the elderly was performed. There was a focus on randomized controlled trials and systematic reviews published within the last 5 years. Results: The incidence of proximal humerus fractures is increasing. It is a common osteoporotic fracture. Bone density is a predictor of reduction quality and can be readily assessed with anteroposterior views of the shoulder. Social independence is a predictor of outcome, whereas age is not. Many fractures are minimally displaced and respond acceptably to nonoperative management. Displaced and severe fractures are most frequently treated operatively with intramedullary nails, locking plates, percutaneous techniques, or arthroplasty. Discussion: Evidence from randomized controlled trials and systematic reviews is insufficient to recommend a treatment; however, most techniques have acceptable or good outcomes. Evaluation should include an assessment of the patient's bone quality, social independence, and surgical risk factors. With internal fixation, special attention should be paid to medial comminution, varus angulation, and restoration of the calcar. With arthroplasty, attention should be paid to anatomic restoration of the tuberosities and proper placement of the prosthesis. Conclusion: A majority of minimally displaced fractures can be treated conservatively with early physical therapy. Treatment for displaced fractures should consider the patient's level of independence, bone quality, and surgical risk factors. Fixation with percutaneous techniques, intramedullary nails, locking plates, and arthroplasty are all acceptable treatment options. There is no clear evidence-based treatment of choice, and the surgeon should consider their comfort level with various procedures during the decision-making process. PMID- 29399374 TI - Sporadic hemangioblastoma of the film terminale with peritumoral cyst. AB - Background: Spinal hemangioblastoma originating from the film terminale are rare tumors. Here, we present a film terminale hemangioblastoma and review the appropriate literature. Case Description: A 37-year-old female presented with bilateral lower extremity pain without a focal neurological deficit. The magnetic resonance (MR) image demonstrated an intradural spinal tumor at the L1 level, which was accompanied by peritumoral cysts. In addition, there were multiple surpentine flow voids (e.g., consistent with torturous and convoluted vessels), which is typical for hemangioblastoma. At surgery, a spinal hemangioblastoma originating from the film terminale with peritumoral cysts at the L1 level was fully excised without producing a focal postoperative neurological deficit. Histological examination revealed stromal cells with vacuolated cytoplasm and small nuclei in a rich capillary network accompanied by several enlarged vessels. These finding were compatible with a hemangioblastoma. Conclusions: We reported a rare case of a hemangioblastoma originating from the conus presenting at the L1 level. Complete surgical resection was accomplished without any motor deficit. PMID- 29399373 TI - Difference in aneurysm characteristics between ruptured and unruptured aneurysms in patients with multiple intracranial aneurysms. AB - Background: The risk of aneurysmal rupture is dependent upon numerous factors, however, there are inconsistencies in the results between studies, which may be due to confounding factors. This can be avoided by comparing the characteristics of ruptured and unruptured aneurysms within the same patient. We sought to analyze the aneurysm characteristics of patients with acute aneurysmal subarachnoid hemorrhage (SAH) and multiple intracranial aneurysms. Methods: We reviewed our prospectively maintained institutional database, between 01/10/2007 and 01/01/2017, for all patients with confirmed SAH and >1 aneurysm. We recorded the size, location, and morphology and calculated secondary geometric indices such as bottleneck factor and aspect ratio. Results: During the study period, a total of 694 patients with aneurysmal SAH were admitted to our institution. We identified 113 patients (74.3% female, average age 51.7 +/- 12.3). The majority of patients had only one associate unruptured aneurysm (79.6%). The average unruptured aneurysm was 3.1 +/- 1.5 mm and the average ruptured aneurysm was 5.7 +/- 2.7 mm (P < 0.001). In the multivariate analysis, aneurysm location, aneurysm morphology, and size were independently associated with rupture. A complex aneurysm morphology was the strongest risk factor for rupture (OR, 29.27; 95% CI 14.33-59.78; P < 0.001) with size >7 mm (OR, 17.74; 95% CI 4.07-77.35; P < 0.001), and AcomA location also showing a strong independent association. Conclusion: Size plays an important part in determining rupture risk, however, other factors such as location and in particular morphology must also be considered. We believe that the introduction of vessel wall imaging will help to risk stratify aneurysms. PMID- 29399375 TI - Treatment of colloid cyst of the third ventricle by stereotactic aspiration followed by radiosurgery: Report of four cases. AB - Background: Colloid cysts are rare benign lesions with potentially devastating results. Complications intra and posttreatment can result in high rates of recurrence. Stereotactic radiosurgery may present an attractive option for decreasing the rate of recurrence in conjunction with stereotactic aspiration. Case Description: Here, we report four cases of colloid cyst of the third ventricle managed by stereotactic aspiration with the use of the Leksell frame followed by stereotactic radiosurgery with the BrainLab/Novalis linear accelerator. Follow-up ranged from 7 to 10 years. There were no complications related to the treatment and no recurrence of the cysts, to date. All four patients remain asymptomatic. Conclusions: The combination of stereotactic aspiration and radiosurgery may have a role in the management of colloid cysts of the third ventricle. PMID- 29399376 TI - Isolated ligamentum flavum ossification in primary hypoparathyroidism. AB - Background: The ligamenta flava can undergo ossification and calcification resulting in myelopathy. Only seven cases of ligamentum flavum ossification in association with hypoparathyroidism have been reported, most of which had concurrent osseous changes in other spinal ligaments. Here, we report a patient with hypoparathyroidism who presented with ligamentum flavum ossification causing both cervical and thoracic myelopathy. Case Description: A 43-year-old male presented with backache, urinary retention, and lower limb weakness for the last few days. Magnetic resonance imaging scan showed ossification of the ligamentum flavum in the cervical and thoracic regions, with severe spinal stenosis. Following spinal decompressive surgery, the patient made a complete recovery. Primary hypoparathyroidism was found to be the underlying cause for ligamentum flavum ossification. Conclusion: Ossification of ligamentum flavum secondary to hypoparathyroidism should be considered as a possible cause of myelopathy in all patients presenting with symptoms of spinal cord compression. PMID- 29399377 TI - Using the "ligamentum flavum gap" to identify originally missed type B vertebral fractures. AB - Background: Spine fractures may involve the ligamentum flavum (LF). Here, we utilized the "ligamentum flavum gap," defined by the discontinuity of the LF at the level of a vertebral fracture, to document a vertebral fracture. Methods: Utilizing X-rays, computed tomography (CT), and magnetic resonance (MR) studies, 10 patients with type B vertebral fractures were diagnosed with the ligamentum flavum gap (LFG: discontinuity of the LF) at the fracture levels. The fractures were located in 2 patients in the cervical and 8 in the thoracolumbar spine. Results: All 10 patients with vertebral fractures had complained of axial pain. Four also showed progressive thoracic kyphosis. Notably, all demonstrated a loss of continuity in the LF at the level of fracture "ligamentum flavum gap." T2 weighted and short tau inversion recovery (STIR) MR sagittal studies were best at locating LFG at the level of a fracture. Conclusion: Here, we identified best on sagittal T2 and STIR-weighted MR studies 10 patients for whom discontinuity of the ligamentum flavum (LFG) correlated with the location of type B vertebral fractures. PMID- 29399378 TI - Reliability of a Feedback-Controlled Treadmill Algorithm Dependent on the User's Behavior. AB - The reliability of the treadmill belt speed using a feedback-controlled treadmill algorithm was analyzed in this study. Using biomechanical factors of the participant's walking behavior, an estimated walking speed was calculated and used to adjust the speed of the treadmill. Our proposed algorithm expands on the current hypotheses of feedback-controlled treadmill algorithms and is presented below. Nine healthy, young adults walked on a treadmill controlled by the algorithm for three trials over two days. Each participant walked on the feedback controlled treadmill for one 16-minute and one five-minute trial during day one and one 16-minute trial during day two. Mean, standard deviation, interclass correlation coefficient (ICC), and standard error of measurement (SEM) were analyzed on the treadmill belt speed mean, standard deviation, and coefficient of variation. There were significantly high ICC for mean treadmill speed within- and between-days. Treadmill speed standard deviation and coefficient of variation were significantly reliable within-day. These results suggest the algorithm will reliably produce the same treadmill belt speed mean, but may only produce a similar treadmill belt speed standard deviation and coefficient of variation if the trials are performed in the same day. A feedback-controlled treadmill algorithm that accounts for the user's behavior provides a greater level of control and minimizes any possible constraints of walking on a conventional treadmill. PMID- 29399379 TI - Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase. AB - Terpene cyclases catalyze the highly stereospecific molding of polyisoprenes into terpenes, which are precursors to most known natural compounds. The isoprenoids are formed via intricate chemical cascades employing rich, yet highly erratic, carbocation chemistry. It is currently not well understood how these biocatalysts achieve chemical control. Here, we illustrate the catalytic control exerted by trichodiene synthase, and in particular, we discover two features that could be general catalytic tools adopted by other terpenoid cyclases. First, to avoid formation of byproducts, the enzyme raises the energy of bisabolyl carbocation, which is a general mechanistic branching point in many sesquiterpene cyclases, resulting in an essentially concerted cyclization cascade. Second, we identify a sulfur-carbocation dative bonding interaction that anchors the bisabolyl cation in a reactive conformation, avoiding tumbling and premature deprotonation. Specifically, Met73 acts as a chameleon, shifting from an initial sulfur-pi interaction in the Michaelis complex to a sulfur-carbocation complex during catalysis. PMID- 29399380 TI - Effects of Different Communication Tools on the Efficiency of Anesthesiologists in the Perioperative Setting. AB - Objective: To assess if Real Time Locating Systems (RTLS) technology has an effect on the perioperative efficiency of anesthesiologists at our institution. Methods: A retrospective chart review was performed for all outpatient and short stay patients who received general anesthesia and monitored anesthesia care between January and June of 2016. Patients over 18 years with an ASA classification of 1, 2, and 3 were included. Time was used as a measure of efficiency between two groups of anesthesiologists.These two comparison groups were as follows: Group 1: Anesthesiologists at the academic center's main campus who do not have access to RTLSGroup 2: Anesthesiologists at Josie Robertson Ambulatory Surgical Center where RTLS is available and use of RTLS is compulsoryTwo outcome measures were collected from patient electronic records: DUR1: Duration between when patient is admitted to a presurgical bed and preoperative evaluation by the attending anesthesiologistDUR2: Duration between when patient is admitted to the operating room and initiation of induction by the attending anesthesiologist. Results: Anesthesiologists who had access to RTLS technology were found to be more efficient in completing their preoperative anesthesia evaluation and initiating intraoperative induction. They took less time to complete these tasks and the difference was statistically significant to p<0.0001. Conclusion: Anesthesiologists at our institution, who have access to RTLS as an additional communication tool, were found to be consistently more efficient in their perioperative workflow. There are confounding factors that can account for the shorter times and more efficient perioperative workflow of anesthesiologists. With continued application and investigation over time, the utility of RTLS on workflow efficiency of healthcare providers will become more apparent. PMID- 29399381 TI - Anticancer Activity of Ganoderic Acid DM: Current Status and Future Perspective. AB - Ganoderma lucidum is a mushroom that has a long history of medicinal use in the Far East countries as this mushroom is revered for its supposed miracle cures and life improving properties. Recently, this mushroom has come under scientific scrutiny to examine the possibility of finding biologically active compounds that may have an impact on human physiology. The main category of biologically active compounds produced in the G. lucidum, are the triterpenoids, which are known as Ganoderic Acids. In this review, we discuss one Ganoderic Acid in particular known as Ganoderic Acid-DM (GA-DM) that is extracted from the Ganoderma lucidum mushroom. We will discuss GA-DM as a potential therapeutic candidate for treating a number of diseases yet will focus on the potential to be used as an alternative or supplemental therapeutic agent in regards to various cancer types. The urge for this promising therapeutic agent is that GA-DM is capable of inducing cell death in cancer cells while exhibiting minimal toxicity to normal bystander cells. Furthermore, this review will look at GA-DM's ability to stimulate an immune response in the tumor environment to potentially provide long-term protection from the malignant tumors. We will also discuss the known routes of administration of GA-DM and pose the advantages and disadvantages of each route in a comparative manner. Finally, we will cover current status of the roles GA-DM may have as a therapeutic agent in respect to different cancer types as wells as discuss about its future perspective as a therapeutic candidate in other diseases as well. PMID- 29399382 TI - Epidemiological Review of Francisella Tularensis: A Case Study in the Complications of Dual Diagnoses. AB - Introduction: Tularemia is a rare but potentially fatal disease that develops in numerous wild and domestic animals, including lagomorphs, rodents, cats, and humans. Francisella tularensis bacterium, the causative agent of tularemia, was identified by veterinary personnel at Fort Riley, Kansas during a routine post mortum evaluation of a domestic feline. However, before formal diagnosis was confirmed, the sample was sent and prepared for rabies testing at the Department of Defense (DoD) U.S. Army Public Health Command Central (PHC-C), Food Analysis and Diagnostic Laboratory (FADL). This case report provides insight on how veterinarian staff and laboratory personnel can clinically manage esoteric, unexplained, or post-mortum examinations. The epidemiologic characteristics of tularemia, F. tularensis as an organism of military interest, potential laboratory management of F. tularensis, and clinical findings on a case of feline tularemia are discussed. It further raises questions as to whether or not dead animals should be treated as sentinels and be pre-screened for select agents, especially in instances of dual diagnoses. Methods: A necropsy was performed on the cat by the Fort Riley veterinarian, DNA extraction and PCR analyses were conducted by FADL microbiologists, histology and immunohistology analyses were conducted by the Kansas State Veterinary Diagnostic Laboratory, and feline tissue and blood were sent to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) for confirmatory testing and strain identification of tularemia. Results: Tularemia was identified in the spleen of the cat by the Fort Riley veterinarian and during the histological sampling of the spleen by the Kansas State Veterinary Diagnostic Laboratory. A specific subsequent real-time polymerase chain reaction (RT-PCR) in vitro diagnostic detection of target DNA sequences of F. tularensis was conducted by the FADL microbiologists using a Joint Biological Agent Identification and Diagnostic System (JBAIDS) Tularemia Detection Kit to detect a presumptive qualitative result to detect tularemia in feline and blood samples. USAMRIID also performed RT-PCR and identified genomic DNA from F. tularensis Type A, (SPL15.013.02), thus confirming the FADL's initial presumptive result of F. tularensis. USAMRIID attempted to culture F. tularensis from three samples (swab, feline tissue, and transfer pipette tip), but no growth consistent with F. tularensis was observed on the cysteine heart agar with sheep blood and antibiotics (CHAB) and chocolate (CHOC) plates. Discussions: Our case study of a dual diagnosis of presumptive F. tularensis and possible rabies exposure transmission from a pet cat to its owner provides insight on how veterinarian staff and laboratory personnel can clinically manage esoteric, unexplained, or post-mortum examinations. Our case study also demonstrates the obligation for cooperation between animal health, human health, and public health professionals in the management of zoonotic diseases. PMID- 29399383 TI - Epigenetic Regulators Modulate Muscle Damage in Duchenne Muscular Dystrophy Model. AB - Histone acetyl transferases (HATs) and histone deacetylases (HDAC) control transcription during myogenesis. HDACs promote chromatin condensation, inhibiting gene transcription in muscle progenitor cells until myoblast differentiation is triggered and HDACs are released. HATs, namely CBP/p300, activate myogenic regulatory and elongation factors promoting myogenesis. HDAC inhibitors are known to improve regeneration in dystrophic muscles through follistatin upregulation. However, the potential of directly modulating HATs remains unexplored. We tested this possibility in a well-known zebrafish model of Duchenne muscular dystrophy. Interestingly, CBP/p300 transcripts were found downregulated in the absence of Dystrophin. While investigating CBP rescuing potential we observed that dystrophin-null embryos overexpressing CBP actually never show significant muscle damage, even before a first regeneration cycle could occur. We found that the pan HDAC inhibitor trichostatin A (TSA) also prevents early muscle damage, however the single HAT CBP is as efficient even in low doses. The HAT domain of CBP is required for its full rescuing ability. Importantly, both CBP and TSA prevent early muscle damage without restoring endogenous CBP/p300 neither increasing follistatin transcripts. This suggests a new mechanism of action of epigenetic regulators protecting dystrophin-null muscle fibres from detaching, independent from the known improvement of regeneration upon damage of HDACs inhibitors. This study builds supporting evidence that epigenetic modulators may play a role in determining the severity of muscle dystrophy, controlling the ability to resist muscle damage. Determining the mode of action leading to muscle protection can potentially lead to new treatment options for muscular dystrophies in the future. PMID- 29399384 TI - Engineering Microvascularized 3D Tissue Using Alginate-Chitosan Microcapsules. AB - Construction of vascularized tissues is one of the major challenges of tissue engineering. The goal of this study was to engineer 3D microvascular tissues by incorporating the HUVEC-CS cells with a collagen/alginate-chitosan (AC) microcapsule scaffold. In the presence of AC microcapsules, a 3D vascular-like network was clearly observable. The results indicated the importance of AC microcapsules in engineering microvascular tissues -- providing support and guiding alignment of HUVEC-CS cells. This approach provides an alternative and promising method for constructing vascularized tissues. PMID- 29399385 TI - Understanding the Clustering Patterns in Physician Distribution Through Affinity Propagation. AB - The spatial distribution of physicians has a significant impact in public health research. It is critical to clarify whether the addresses provided by the physicians are the home addresses or the practice addresses, since the practice address is the key to understand relevant issues of maldistribution, accessibility and disparity. Through a pilot study as partial effort of the research project "Reducing Physician Distribution Uncertainty in Spatial Accessibility Research" sponsored by the National Institutes of Health (NIH award number 1R21CA182874-01), appropriate solutions were developed to differentiate the home addresses from practice addresses. This paper introduces how to understand the clustering patterns in physician distribution through Affinity Propagation, a relatively new clustering algorithm, to derive the potential extent of the practice locations for those physicians who provided home addresses. The physician data is derived from the 2014 American Medical Association (AMA) Physician Masterfile, while two counties (Fulton and DeKalb) in the metropolitan area of Atlanta, Georgia were selected as the study area. Both Euclidian distance and driving distance were applied in the AP algorithm, while gravity models based AP calculation were applied in comparison to the clustering of individual physicians. By justifying preference and similarity parameters in the AP calculation, hierarchical clustering patterns can be derived and perceived. Future research challenges in AP clustering are identified, while this pilot study can be extended with broader impact in public health research. PMID- 29399386 TI - Synthesis of Degradable Poly(vinyl alcohol) by Radical Ring-Opening Copolymerization and Ice Recrystallization Inhibition Activity. AB - Poly(vinyl alcohol) (PVA) is the most active synthetic mimic of antifreeze proteins and has extremely high ice recrystallization inhibition (IRI) activity. Addition of PVA to cellular cryopreservation solutions increases the number of recovered viable cells due to its potent IRI, but it is intrinsically nondegradable in vivo. Here we report the synthesis, characterization, and IRI activity of PVA containing degradable ester linkages. Vinyl chloroacetate (VClAc) was copolymerized with 2-methylene-1,3-dioxepane (MDO) which undergoes radical ring-opening polymerization to install main-chain ester units. The use of the chloroacetate monomer enabled selective deacetylation with retention of esters within the polymer backbone. Quantitative IRI assays revealed that the MDO content had to be finely tuned to retain IRI activity, with higher loadings (24 mol %) resulting in complete loss of IRI activity. These degradable materials will help translate PVA, which is nontoxic and biocompatible, into a range of biomedical applications. PMID- 29399387 TI - Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. AB - Although immune checkpoint blockade have demonstrated promising results, their effects on gastric cancer (GC) are under investigation. Understanding the clinical significance of PD1 and its ligands' expression, together with T cell infiltration might provide clues for biomarkers screening in GC immunotherapy. Immunohistochemistry were performed on a tissue microarray including 1,014 GC specimens using PD1, PDL1 and PDL2 antibodies. T cell markers CD3 and CD8 were also stained and quantified by automated image analysis. Correlation with clinical features and outcome were analyzed after controlling for potential confounders including EBV infection, HER2, C-met and PCNA expression. 37.8% of the cases showed membranous PD-L1 expression in tumor cells and 74.9% in infiltrating immune cells. PDL1 expression rate was rather higher in patients without metastasis, in EBV positive group and those with C-met and PCNA expression. GC patients with high level PDL1 expression exhibited better survival. GC Patients with higher T cell infiltration also showed elevated PDL1, PDL2 and PD1 expression and predict favorable outcome, indicating an adaptive immune resistance mechanism may exist. The group of patients infiltrated with lower density CD3+ T cells also without PDL1 expression in tumor cells predict the worst outcome in the subgroup of different PTNM stage, which may suggest an inactive immune status. These results highlights the need to assess both PDL1 expression in all tumor context and the characterization of the GC immune microenvironment. PMID- 29399388 TI - T cells specific for a TAP-independent self-peptide remain naive in tumor-bearing mice and are fully exploitable for therapy. AB - Cancers frequently evade immune-recognition by lowering peptide:MHC-I complexes on their cell surface. Limited peptide supply due to TAP-deficiency results in such MHC-Ilow immune-escape variants. Previously, we reported on a category of TAP-independent self-peptides, called TEIPP, with selective presentation by these tumors. Here we demonstrate that in contrast to T cells specific for conventional tumor antigens, TEIPP-directed T cells remain naive in mice bearing immune escaped tumors. This unaffected state was caused by low levels of MHC-I on the tumors and the failure to cross-present low levels of antigenic protein by host APCs. Importantly, increased levels of MHC-I, antigen or co-stimulation resulted in potent activation of TEIPP-specific T cells via direct presentation. Genetic knockdown by CRISPR/Cas9 technology of the relevant MHC-I allele in tumor cells indeed abrogated T cell activation. Vaccine-mediated priming of TEIPP-specific T cells induced efficient homing to MHC-Ilow tumors and subsequently protected mice against outgrowth of their MHC-Ilow tumor. Thus, our data open up the search of TEIPP-specific T cells in cancer patients to explore their application against MHC-Ilow tumor cells. PMID- 29399389 TI - PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue - prognostic implications and rationale for immunotherapy. AB - Therapies targeting programmed death 1-(PD-1) or its ligand (PD-L1), promoting antitumor T-cell activity have been successfully introduced into clinical practice. Clinical response correlates with PD-L1 expression by tumor cells or immune cells within the tumor microenvironment. The PD-L1/PD-1 axis and tumor microenvironment has been rarely studied in high-grade sarcomas of soft tissue (hSTS), a group of rare, genetically heterogenous and clinically aggressive tumors. We examined PD-L1 protein and CD274/PD-L1 gene copy number variations in 128 primary resected, therapy-naive hSTS using immunohistochemistry and fluorescence-in-situ hybridization. Frequency of tumoral PD-L1 expression varied widely in different disease subentities, with highest rates of positivity (40%) seen in undifferentiated pleomorphic sarcomas (UPS) and rare positivity detected in synovial sarcomas (6%). Amplification of the CD274/PD-L1 gene occurred in 14% of UPS and was rare in other subtypes. PD-L1 protein expression was significantly more frequent in CD274/PD-L1 amplified cases (p = 0.015). The subgroup of UPS was further characterized regarding the interaction between PD-L1 and the immunologic tumor microenvironment. High density of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) was significantly correlated with the presence of PD-L1 expression and seen more frequently in tumors with lower TNM stage (p = 0.024). Both, PD-L1 expression and high density lymphocytic infiltration were independent prognostic factors for a favorable overall (p = 0.001, HR 6.105 (2.041-8.258)), disease-specific (p = 0.003, HR 10.536 (2.186-50.774)) and disease-free survival (p = 0.020, HR 3.317 (1.209-9.106); values for CD8) in this particular subgroup of hSTS, whereas PD-L1 expression in TILs or CD274/PD-L1 gene amplification were not associated with outcome. These findings represent novel insights into the immune landscape of soft tissue sarcomas, in particular UPS and strengthen the rationale for immunotherapy, including targeting the PD-1/PD-L1 axis in these tumors. PMID- 29399390 TI - CCL3 augments tumor rejection and enhances CD8+ T cell infiltration through NK and CD103+ dendritic cell recruitment via IFNgamma. AB - Inflammatory chemokines are critical contributors in attracting relevant immune cells to the tumor microenvironment and driving cellular interactions and molecular signaling cascades that dictate the ultimate outcome of host anti-tumor immune response. Therefore, rational application of chemokines in a spatial temporal dependent manner may constitute an attractive adjuvant in immunotherapeutic approaches against cancer. Existing data suggest that the macrophage inflammatory protein (MIP)-1 family and related proteins, consisting of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), and CCL5 (RANTES), can be major determinant of immune cellular infiltration in certain tumors through their direct recruitment of antigen presenting cells, including dendritic cells (DCs) to the tumor site. In this study, we examined how CCL3 in a murine colon tumor microenvironment, CT26, enhances antitumor immunity. We identified natural killer (NK) cells as a major lymphocyte subtype that is preferentially recruited to the CCL3-rich tumor site. NK cells contribute to the overall IFNgamma content, CD103+ DC accumulation, and augment the production of chemokines CXCL9 and CXCL10 for enhanced T cell recruitment. We further demonstrate that both soluble CCL3 and CCL3-secreting irradiated tumor vaccine can effectively halt the progression of established tumors in a spatial-dependent manner. Our finding implies an important contribution of NK in the CCL3 - CD103+ DC - CXCL9/10 signaling axis in determining tumor immune landscape within the tumor microenvironment. PMID- 29399391 TI - Dendritic cell vaccine induces antigen-specific CD8+ T cells that are metabolically distinct from those of peptide vaccine and is well-combined with PD 1 checkpoint blockade. AB - The success of immune checkpoint blockade has unequivocally demonstrated that anti-tumor immunity plays a pivotal role in cancer therapy. Because endogenous tumor-specific T-cell responsiveness is essential for the success of checkpoint blockade, combination therapy with cancer vaccination may facilitate tumor rejection. To select the best vaccine strategy to combine with checkpoint blockade, we compared dendritic cell-based vaccines (DC-V) with peptide vaccines for induction of anti-tumor immunity that could overcome tumor-induced immunosuppression. Using B16 melanoma and B16-specific TCR-transgenic T-cells (pmel-1), we found that DC-V efficiently primed and expanded pmel-1 cells with an active effector and central memory phenotype that were not exhausted. Vaccine primed cells were metabolically distinct from naive cells. DC-V-primed pmel-1 cells contained the population that shifted metabolic pathways away from glycolysis to mitochondrial oxidative phosphorylation. They displayed better effector function and proliferated more than those induced by peptide vaccination. DC-V inhibited tumor growth in prophylactic and therapeutic settings. Only DC-V but not peptide vaccine showed augmented anti-tumor activity when combined with anti-PD-1 therapy. Thus, DC-V combined with PD-1 checkpoint blockade mediates optimal anti-cancer activity in this model. PMID- 29399392 TI - Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses. AB - Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-gamma (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients. PMID- 29399393 TI - PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. AB - Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8+ T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8+ T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB. PMID- 29399394 TI - Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. AB - T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy. PMID- 29399395 TI - Tumor lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer: The LYMPHOREC study. AB - Introduction: Some studies have suggested that baseline tumor-infiltrating lymphocytes (TILs), such as CD8+ and FoxP3+ T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods: We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3+) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline. The primary endpoint was to assess the impact of infiltration of the tumor or tumor site after preopRT on progression-free survival (PFS) and overall survival (OS). Secondary endpoints were the impact of dose fractionation scheme on TILs. Results: In univariate analysis, several factors significantly correlated (p<0.05) with PFS and/or OS (T-stage, M-stage, the delay between RT and surgery). A high level of post-treatment FoxP3+ TIL density correlated significantly with a better PFS (p = 0.007). In multivariate analysis, a decrease in the CD8+/FoxP3+ iTILs ratio after preopRT correlated with better PFS and OS (p = 0.049 and p = 0.024, respectively). More particularly, patients with a delta CD8+/FoxP3+ <-3.8 had better PFS and OS. Interestingly, the dose fractionation scheme significantly influenced the CD8+/FoxP3+ ratio after treatment (p = 0.027) with a lower ratio with hypofractionated RT (>=2 Gy). Conclusion: Patients with LARC who had a significant decrease in the CD8+/FoxP3+ ratio after preopRT were more likely to live longer. This ratio needs to be validated prospectively to guide physicians in adjuvant treatment decision-making. PMID- 29399397 TI - IL-25 dampens the growth of human germinal center-derived B-cell non Hodgkin Lymphoma by curtailing neoangiogenesis. AB - Interleukin (IL)-25, a member of the IL-17 cytokine superfamily, is produced by immune and non-immune cells and exerts type 2 pro-inflammatory effects in vitro and in vivo. The IL-25 receptor(R) is composed of the IL-17RA/IL-17RB subunits. Previous work showed that germinal centre (GC)-derived B-cell non Hodgkin lymphomas (B-NHL) expressed IL-17AR, formed by IL-17RA and IL-17RC subunits, and IL-17A/IL-17AR axis promoted B-NHL growth by stimulating neoangiogenesis. Here, we have investigated expression and function of IL-25/IL-25R axis in lymph nodes from human GC-derived B-NHL, i.e. Follicular Lymphoma (FL,10 cases), Diffuse Large B Cell Lymphoma (6 cases) and Burkitt Lymphoma (3 cases). Tumor cells expressed IL-25R and IL-25 that was detected also in non-malignant cells by flow cytometry. Immunohistochemical studies confirmed expression of IL-25R and IL-25 in FL cells, and highlighted IL-25 expression in bystander elements of the FL microenvironment. IL-25 i) up-regulated phosphorylation of NFkBp65, STAT-1 and JNK in B-NHL cells; ii) inhibited in vitro proliferation of the latter cells; iii) exerted anti-tumor activity in two in vivo B-NHL models by dampening expression of pro-angiogenic molecules as VEGF-C, CXCL6 and ANGPT3. In conclusion, IL-25, that is intrinsically pro-angiogenic, inhibits B-NHL growth by reprogramming the angiogenic phenotype of B-NHL cells. PMID- 29399396 TI - Serine protease inhibitor 6 protects alloreactive T cells from Granzyme B mediated mitochondrial damage without affecting graft-versus-tumor effect. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for hematologic malignancies. Donor T cells are able to eliminate residual tumor cells after allo-HCT, producing the beneficial graft versus-tumor (GVT) effect, but can also cause graft-versus-host disease (GVHD) when attacking host normal tissues. We previously reported that granzyme B (GzmB) is involved in activation-induced cell death (AICD) of donor T cells and exerts differential impacts on GVHD and GVT effect. Serine protease inhibitor 6 (Spi6) is the sole endogenous inhibitor of GzmB that can protect immune and tissue cells against GzmB-mediated damage. This study is aimed to delineate the mechanism by which the GzmB-Spi6 axis regulates allogeneic T cell response. Using multiple clinically relevant murine allo-HCT models, we have found that Spi6 is concentrated in mitochondria during allogeneic T cell activation, while Spi6-/- T cells exhibit abnormal mitochondrial membrane potential, mass, reactive oxygen species (ROS) production and increased GzmB-dependent AICD mainly in the form of fratricide. Compared with WT T cells, Spi6-/- T cells exhibit decreased expansion in the host and cause significantly reduced GVHD. Notably, however, Spi6-/- T cells demonstrate the same level of GVT activity as WT T cells, which were confirmed by two independent tumor models. In summary, our findings demonstrate that Spi6 plays a novel and critical role in maintaining the integrity of T cell mitochondrial function during allogeneic response, and suggest that disabling Spi6 in donor T cells may represent a novel strategy that can alleviate GVHD without sacrificing the beneficial GVT effect. PMID- 29399398 TI - Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models. AB - Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naive T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100) alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an "off-the-shelf" cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time consuming preparation step of autologous DCs. PMID- 29399399 TI - Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune environment. AB - Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8+ T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8+ and CD4+ T-lymphocytes co cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8+ T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune environment. PMID- 29399400 TI - Harnessing innate lung anti-cancer effector functions with a novel bacterial derived immunotherapy. AB - Acute infection is known to induce strong anti-tumor immune responses, but clinical translation has been hindered by the lack of an effective strategy to safely and consistently provoke a therapeutic response. These limitations are overcome with a novel treatment approach involving repeated subcutaneous delivery of a Klebsiella-derived investigational immunotherapeutic, QBKPN. In preclinical models of lung cancer, QBKPN administration consistently showed anti-cancer efficacy, which was dependent on Klebsiella pre-exposure, but was independent of adaptive immunity. Rather, QBKPN induced anti-tumor innate immunity that required NK cells and NKG2D engagement. QBKPN increased NK cells and macrophages in the lungs, altered macrophage polarization, and augmented the production of cytotoxic molecules. An exploratory trial in patients with non-small cell lung cancer demonstrated QBKPN was well tolerated, safe, and induced peripheral immune changes suggestive of macrophage polarization and reduction of PD-1 and PD-L1 expression on leukocytes. These data demonstrate preclinical efficacy, and clinical safety and tolerability, for this cancer immunotherapy strategy that exploits innate anti-tumor immune mechanisms. PMID- 29399401 TI - A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. AB - Despite approval for the treatment of various malignancies, clinical application of cytokines such as type I interferon (IFN) is severely impeded by their systemic toxicity. AcTakines (Activity-on-Target cytokines) are optimized immunocytokines that, when injected in mice, only reveal their activity upon cell specific impact. We here show that type I IFN-derived AcTaferon targeted to the tumor displays strong antitumor activity without any associated toxicity, in contrast with wild type IFN. Treatment with CD20-targeted AcTaferon of CD20+ lymphoma tumors or melanoma tumors engineered to be CD20+, drastically reduced tumor growth. This antitumor effect was completely lost in IFNAR- or Batf3 deficient mice, and depended on IFN signaling in conventional dendritic cells. Also the presence of, but not the IFN signaling in, CD8+ T lymphocytes was critical for proficient antitumor effects. When combined with immunogenic chemotherapy, low-dose TNF, or immune checkpoint blockade strategies such as anti PDL1, anti-CTLA4 or anti-LAG3, complete tumor regressions and subsequent immunity (memory) were observed, still without any concomitant morbidity, again in sharp contrast with wild type IFN. Interestingly, the combination therapy of tumor targeted AcTaferon with checkpoint inhibiting antibodies indicated its ability to convert nonresponding tumors into responders. Collectively, our findings demonstrate that AcTaferon targeted to tumor-specific surface markers may provide a safe and generic addition to cancer (immuno)therapies. PMID- 29399402 TI - Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma. AB - Pediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+ T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers. PMID- 29399403 TI - Lack of MHC class II molecules favors CD8+ T-cell infiltration into tumors associated with an increased control of tumor growth. AB - Regulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as for preventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. In the TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstrated that the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declines with tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, we demonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression of immunosuppressive molecules. Both intratumoral effector CD4+ T cells (Teffs) and Tregs expressed high levels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restore the therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited to the tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4+ effector T-cells. We demonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which were recruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with a strong increase in the intratumoral recruitment of CD8+ T-cells. In addition, in mice that spontaneously rejected their tumors, the infiltration of E7-specific CD8+ T-cells was significantly higher than in MHC-II KO mice with a growing tumor. These results demonstrate that tumor-specific CD8+ T-cells can be efficiently activated and recruited in the absence of MHC class II molecules and of CD4+ T-cell help. PMID- 29399404 TI - Frequent adaptive immune responses against arginase-1. AB - The enzyme arginase-1 reduces the availability of arginine to tumor-infiltrating immune cells, thus reducing T-cell functionality in the tumor milieu. Arginase-1 is expressed by some cancer cells and by immune inhibitory cells, such as myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and its expression is associated with poor prognosis. In the present study, we divided the arginase-1 protein sequence into overlapping 20-amino-acid-long peptides, generating a library of 31 peptides covering the whole arginase-1 sequence. Reactivity towards this peptide library was examined in PBMCs from cancer patients and healthy individuals. IFNgamma ELISPOT revealed frequent immune responses against multiple arginase-1-derived peptides. We further identified a hot-spot region within the arginase-1 protein sequence containing multiple epitopes recognized by T cells. Next, we examined in vitro-expanded tumor infiltrating lymphocytes (TILs) isolated from melanoma patients, and detected arginase-1-specific T cells that reacted against epitopes from the hot-spot region. Arginase-1-specific CD4+T cells could be isolated and expanded from peripheral T cell pool of a patient with melanoma, and further demonstrated the specificity and reactivity of these T cells. Overall, we showed that arginase-1 specific T cells were capable of recognizing arginase-1-expressing cells. The activation of arginase-1-specific T cells by vaccination is an attractive approach to target arginase-1-expressing malignant cells and inhibitory immune cells. In the clinical setting, the induction of arginase-1-specific immune responses could induce or increase Th1 inflammation at the sites of tumors that are otherwise excluded due to infiltration with MDSCs and TAMs. PMID- 29399405 TI - Genomic landscape of advanced basal cell carcinoma: Implications for precision treatment with targeted and immune therapies. AB - Metastatic basal cell cancer (BCC) is an ultra-rare malignancy with no approved therapies beyond Hedgehog inhibitors. We characterized the genomics, tumor mutational burden (TMB), and anti-PD-1 therapy responses in patients with locally advanced or metastatic BCC. Overall, 2,039 diverse cancer samples that had undergone comprehensive genomic profiling (CGP) were reviewed. Eight patients with locally advanced/metastatic BCC were identified (two had two CGP analyses; total, 10 biopsies). Two tumors demonstrated PD-L1 amplification. Seven patients had >1 actionable alteration. The TMB (mutations/mb) (median (range)) was 90 (3 103) for the BCCs versus 4 (1-860) for 1637 cancers other than BCC (P < 0.0001). Median progression-free survival (PFS) for all four patients treated with PD-1 blockade was 10.7 months (range, 3.8 to 17.6+ months); three patients had an objective response. In conclusion, advanced/metastatic BCC often has biological features (high TMB; PD-L1 amplification) predictive of immunotherapy benefit, and patients frequently respond to PD-1 blockade. PMID- 29399406 TI - Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia. AB - Although the anti-CCR4 antibody mogamulizumab (moga) shows striking antitumor activity against adult T cell leukemia (ATL), it can also cause fatal immunological pathology such as severe skin rash and graft-versus-host disease, which might be attributed to depletion of CCR4+ regulatory T cells. We previously showed that next generation sequencing enables precise analysis of the T cell receptor (TCR) repertoire, and we here used the technique to reveal the immunological dynamics in moga-treated ATL patients. Treatment with moga resulted in remarkable reduction or elimination of clonal cells, and enhanced reconstitution of non-tumor polyclonal CD4+ T cells and oligoclonal CD8+ T cells. Interestingly, cutaneous T cells infiltrating moga-related skin rashes did not share the same major clones in peripheral blood, which minimizes the possibility of cross-reaction. Thus, deep sequencing of the TCR can reveal the immune reconstitution of moga-treated ATL and provides powerful insights into its mode of action. PMID- 29399407 TI - Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice. AB - Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of beta-adrenergic receptor (betaAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (beta-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan beta-blockers. This retrospective analysis is reinforced by results showing that betaAR blockade enhances the control of murine melanoma growth by anti-(alpha)PD-1 checkpoint blockade. However, this effect was most significant when beta-blocker was combined with dual alphaPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of beta2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies. PMID- 29399408 TI - Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells. AB - Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1. We show that the co-culture of NY ESO-1neg/HLA-DP4pos melanoma cells with NY-ESO-1pos/HLA-DP4neg melanoma cells infected and killed by different OV induces an intercellular transfer of NY-ESO-1 that allows the recognition of NY-ESO-1neg/HLA-DP4pos tumor cells by an HLA DP4/NY-ESO-1(157-170)-specific CD4+ cytotoxic T cell clone, NY67. We then confirmed this result in a second model with an HLA-DP4+ melanoma cell line that expresses a low amount of NY-ESO-1. Recognition of this cell line by the NY67 clone is largely increased in the presence of OV productive infection. Altogether, our results show for the first time another mechanism of stimulation of the anti-tumor immune response by OV, via the loading of tumor cells with TAA that sensitizes them for direct recognition by specific effector CD4+ T cells, supporting the use of OV for cancer immunotherapy. PMID- 29399409 TI - Development of chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK and CRISPR-edited T cell lines. AB - Relapsed T-cell malignancies have poor outcomes when treated with chemotherapy, but survival after allogeneic bone marrow transplantation (BMT) approaches 50%. A limitation to BMT is the difficulty of achieving remission prior to transplant. Chimeric antigen receptor (CAR) T-cell therapy has shown successes in B-cell malignancies. This approach is difficult to adapt for the treatment of T-cell disease due to lack of a T-lymphoblast specific antigen and the fratricide of CAR T cells that occurs with T-cell antigen targeting. To circumvent this problem two approaches were investigated. First, a natural killer (NK) cell line, which does not express CD5, was used for CAR expression. Second, CRISPR-Cas9 genome editing technology was used to knockout CD5 expression in CD5-positive Jurkat T cells and in primary T cells, allowing for the use of CD5-negative T cells for CAR expression. Two structurally distinct anti-CD5 sequences were also tested, i) a traditional immunoglobulin-based single chain variable fragment (scFv) and ii) a lamprey-derived variable lymphocyte receptor (VLR), which we previously showed can be used for CAR-based recognition. Our results show i) both CARs yield comparable T-cell activation and NK cell-based cytotoxicity when targeting CD5 positive cells, ii) CD5-edited CAR-modified Jurkat T cells have reduced self activation compared to that of CD5-positive CAR-modified T cells, iii) CD5-edited CAR-modified Jurkat T cells have increased activation in the presence of CD5 positive target cells compared to that of CD5-positive CAR-modified T cells, and iv) although modest effects were seen, a mouse model using the CAR-expressing NK cell line showed the scFv-CAR was superior to the VLR-CAR in delaying disease progression. PMID- 29399411 TI - Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma. AB - We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4+ endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/Mphi) to be selectively enriched in the perivascular areas of CXCR4+ vessels in HCC samples. The depletion of Mo/Mphi with gadolinium chloride (GdCl3) or zoledronic acid (ZA) treatment significantly reduced vascular CXCR4 expression in HCC tumors. This phenomenon was also confirmed in CCR2-KO mice, which exhibited reduced infiltration of inflammatory Mo/Mphi in tumor tissues. Mechanistic studies revealed that inflammatory cytokines derived from tumor conditioned Mo/Mphi, especially TNF-alpha, could up-regulate CXCR4 expression on ECs. TNF-alpha-induced activation of the Raf-ERK pathway, but not Notch signaling, was responsible for the expression of CXCR4. Moreover, the combination treatment of sorafenib with ZA was associated with improved anti tumor efficacy by significantly reducing vascular CXCR4 expression. These findings revealed that Mo/Mphi could regulate CXCR4 expression in the tumor vasculature. Thus, the inhibition of Mo/Mphi inflammation might enhance the treatment efficacy of sorafenib in HCC. PMID- 29399410 TI - Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade. AB - Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5. IFN-beta was partially responsible for the elevated PD-1 ligand expression on these cells. Moreover, real-time PCR and chloroquine-mediated blocking experiments indicated that poly(I:C) triggered Toll-like receptor 3 to elicit its effect. Cocultures of poly(I:C)-treated glioblastoma cells with peripheral blood mononuclear cells enhanced lymphocytic activation (CD69, IFN-gamma) and cytotoxic capacity (CD107a, granzyme B). Additional PD-L1 blockade further propagated immune activation. Besides activating immunity, poly(I:C)-treated glioblastoma cells also doubled the attraction of CD8+ T cells, and to a lesser extent CD4+ T cells, via a mechanism which included CXCR3 and CCR5 ligands. Our results indicate that by triggering glioblastoma cells, poly(I:C) primes the tumor microenvironment for an immune response. Secreted cytokines allow for immune activation while chemokines attract CD8+ T cells to the front, which are postulated as a prerequisite for effective PD-1/PD-L1 blockade. Accordingly, additional blockade of the concurrently elevated tumoral PD-L1 further reinforces the immune activation. In conclusion, our data proposes poly(I:C) treatment combined with PD-L1 blockade to invigorate the immune checkpoint inhibition response in glioblastoma. PMID- 29399412 TI - A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo. AB - Aggressive forms of breast cancer, such as Her2+ and triple negative breast cancer (TNBC), are enriched in breast cancer stem cells (BCSC) and have limited therapeutic options. BCSC represent a key cellular reservoir for relapse, metastatic progression and therapeutic resistance. Their ability to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cystine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults. Our previous work showed that xCT is highly expressed in tumorspheres derived from breast cancer cell lines and downregulation of xCT altered BCSC function in vitro and inhibited pulmonary metastases in vivo. We further strengthened these observations by developing a virus-like-particle (VLP; AX09-0M6) immunotherapy targeting the xCT protein. AX09-0M6 elicited a strong antibody response against xCT including high levels of IgG2a antibody. IgG isolated from AX09-0M6 treated mice bound to tumorspheres, inhibited xCT function as assessed by reactive oxygen species generation and decreased BCSC growth and self-renewal. To assess if AX09-0M6 impacts BCSC in vivo seeding, Her2+ TUBO-derived tumorspheres were injected into the tail vein of AX09-0M6 or control treated female BALB/c mice. AX09-0M6 significantly inhibited formation of pulmonary nodules. To evaluate its ability to impact metastases, AX09-0M6 was administered to mice with established subcutaneous 4T1 tumors. AX09-0M6 administration significantly hampered tumor growth and development of pulmonary metastases. These data show that a VLP-based immunization approach inhibits xCT activity, impacts BCSC biology and significantly reduces metastatic progression in preclinical models. PMID- 29399413 TI - Cellular vaccination of MLH1-/- mice - an immunotherapeutic proof of concept study. AB - Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1-/- knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers. Therapeutic application of the vaccine prolonged overall survival (median time: 11.5 (lysate) and 12 weeks (lysate + CpG ODN) vs. 3 weeks (control group), respectively) along with reduced tumor burden, as confirmed by PET/CT imaging and immune stimulation (increased CD3+CD8+ T - and NK cell numbers, reduced levels of TIM-3+ cells in both treatment groups). Coding microsatellite analysis of MMR-D related target genes revealed increased mutational load upon vaccination (total mutation frequency within 28 genes: 28.6% vaccine groups vs. 14.9% control group, respectively). Reactive immune cells recognized autologous tumor cells, but also NK cells target YAC-1 in IFNgamma ELISpot and, even more importantly, in functional kill assays. Assessment of tumor microenvironment revealed infiltration of CD8+ T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1). The present study is the first reporting in vivo results on a therapeutic cellular MMR-D vaccine. Vaccination-induced prolonged survival was achieved in a clinically-relevant mouse model for MMR-D related diseases by long-term impairment of tumor growth and this could be attributed to re-activated immune responses. PMID- 29399414 TI - Virus-like particle display of HER2 induces potent anti-cancer responses. AB - Overexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20 30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccination may represent a safer, more effective and cheaper alternative, although the induction of strong and durable autoantibody responses is hampered by immune-tolerogenic mechanisms. Using a novel virus-like particle (VLP) based vaccine platform we show that directional, high-density display of human HER2 on the surface of VLPs, allows induction of therapeutically potent anti-HER2 autoantibody responses. Prophylactic vaccination reduced spontaneous development of mammary carcinomas by 50%-100% in human HER2 transgenic mice and inhibited the growth of HER2-positive tumors implanted in wild-type mice. The HER2-VLP vaccine shows promise as a new cost-effective modality for prevention and treatment of HER2-positive cancer. The VLP platform may represent an effective tool for development of vaccines against other non-communicable diseases. PMID- 29399415 TI - Melanoma induced immunosuppression is mediated by hematopoietic dysregulation. AB - Tumors are associated with expansion of immunosuppressive cells such as tumor associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). These cells promote tumor growth, angiogenesis, metastasis and immune escape. Cancer patients frequently present symptoms such as anemia, leukocytosis and/or cytopenia; associated with poor prognosis. To uncover tumor-mediated hematopoietic abnormalities and identify novel targets that can be harnessed to improve tumor-specific immune responses, we investigated the hematopoietic stem and progenitor cell compartment in melanoma bearing mice. We show that melanoma growth results in expansion of myeloid lineages such as MDSCs, macrophages and DCs along with a reduction in mature RBCs and platelets. Mature B lymphocytes in the blood and BM of melanoma mice were also reduced. Mice bearing melanoma showed extramedullary hematopoiesis in the spleen. Increased expansion of myeloid lineages occurred directly at the level of stem and progenitor cells. The reduction in mature B lymphocytes resulted from a block at the Pro-B cell stage in the bone marrow. Addition of recombinant IL-3 to bone marrow cells resulted in the expansion of committed myeloid progenitors including common myeloid precursors, granulocyte-monocyte precursors and megakaryocyte-erythrocyte precursors. In vivo, IL-3 receptor stimulation in melanoma bearing mice using an IL-3 antibody also resulted in a robust expansion of committed myeloid progenitors and hematopoietic stem cells. Collectively our findings demonstrate that tumor growth plays a pivotal role in reprogramming the host immune system by impacting hematopoiesis directly at the level of stem cell compartment. PMID- 29399416 TI - Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment. AB - While the importance of iron for tumor development is widely appreciated, the exact sources of tumor-supporting iron largely remain elusive. The possibility that iron might be provided by stromal cells in the tumor microenvironment was not taken into account so far. In the present study, we show that tumor associated macrophages (TAM) acquire an iron-release phenotype upon their interaction with tumor cells, thereby increasing the availability of iron in the tumor microenvironment. Mechanistically, TAM expressed elevated levels of the high-affinity iron-binding protein lipocalin-2 (LCN-2), which appeared to be critical for the export of iron from TAM, and in turn enhanced tumor cell proliferation. Moreover, in PyMT-mouse tumors as well as in primary human breast tumors LCN-2 was predominantly expressed in the tumor stroma as compared to tumor cells. LCN-2 expression in the stroma further correlated with enhanced tumor proliferation in vivo. Our data suggest a dominant role of TAM in the tumor iron management and identify LCN-2 as a critical iron transporter in this context. Targeting the LCN-2 iron export mechanism selectively in stromal cells might open for future iron-targeted tumor therapeutic approaches. PMID- 29399417 TI - A calendar method of collecting remittance use data in a remittance dependent setting of Nepal1. AB - This methodological paper describes the design and refinement of a calendar method of collecting data on remittance receipt and remittance use and its piloting in a rural remittance dependent setting of Nepal. Much of the previous national surveys collected remittance receipt and remittance use cross-sectional data that used a time frame ranging from 12 - 24 months. These surveys collected remittance receipt data by asking, 'How much money has he/she sent in the past 12 months or 2 years?' We believe that the long time frame of one to two years adds burden to respondents for unnecessary calculations and is prone to re-call bias. Moreover, these surveys used vague words such as 'capital formation' or 'daily consumption' to measure the uses of remittances. Thus, the instrument per se is unreliable posing threats to collecting valid responses. Considering these flaws, in 2013, we designed a calendar with shorter timing cues and simple words for collecting longitudinal data on remittance receipt and remittance use. First, we describe the calendar design process. Next, we provide descriptive results of household responses on the amount of remittance received and the remittance used on various socio-economic and cultural dimensions of household activities. The implications of the insights gained from this study are discussed. PMID- 29399418 TI - Sacred Space. AB - A space can be sacred, providing those who inhabit a particular space with sense of transcendence-being connected to something greater than oneself. The sacredness may be inherent in the space, as for a religious institution or a serene place outdoors. Alternatively, a space may be made sacred by the people within it and events that occur there. As medical providers, we have the opportunity to create sacred space in our examination rooms and with our patient interactions. This sacred space can be healing to our patients and can bring us providers opportunities for increased connection, joy, and gratitude in our daily work. PMID- 29399419 TI - BI-RADS 3: Current and Future Use of Probably Benign. AB - Purpose of Review: Probably benign (BI-RADS 3) causes confusion for interpreting physicians and referring physicians and can induce significant patient anxiety. The best uses and evidence for using this assessment category in mammography, breast ultrasound, and breast MRI will be reviewed; the reader will have a better understanding of how and when to use BI-RADS 3. Recent Findings: Interobserver variability in the use of BI-RADS 3 has been documented. The 5th edition of the BI-RADS atlas details the appropriate use of BI-RADS 3 for diagnostic mammography, ultrasound, and MRI, and discourages its use in screening mammography. Data mining, elastography, and diffusion weighted MRI have been evaluated to maximize the accuracy of BI-RADS 3. Summary: BI-RADS 3 is an evolving assessment category. When used properly, it reduces the number of benign biopsies while allowing the breast imager to maintain a high sensitivity for the detection of early stage breast cancer. PMID- 29399421 TI - Extracellular Vesicles: Biomarkers, Therapeutics, and Vehicles in the Visual System. AB - Purpose: We discuss recent advances in extracellular vesicle (EV) technology as biomarkers, therapeutics, and drug delivery vehicles in the visual system with an emphasis on the retina. Recent Findings: Retinal cell-type specific EVs can be detected in the blood and in the aqueous humor and EV miRNA cargoes can be used diagnostically to predict retinal disease progression. Studies have now shown EVs can deliver bioactive miRNA and AAV cargoes to the inner retinal cell layers and, in some models, improve retinal ganglion cell (RGC) survival and axon regeneration. Summary: EV molecular profiles and cargoes are attractive biomarkers for retinal and optic nerve disease and trauma and EVs offer a safe and tunable platform for delivering therapies to ocular tissues. However, EVs are heterogeneous by nature with variable lipid membranes, cargoes, and biologic effects, warranting stringent characterization to understand how heterogeneous EV populations modulate positive tissue remodeling. PMID- 29399420 TI - Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions. AB - Purpose of Review: The aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments. Recent Findings: Therapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule aggregation. Summary: A1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity. PMID- 29399422 TI - Lessons learnt from the introduction of the contraceptive implant in South Africa AB - In 2014, South Africa (SA) introduced the subdermal contraceptive implant with the aim of expanding the contraceptive method mix and availability of long-acting reversible methods in the public sector. Three years on, concerns have been raised about the decline in uptake, early implant removals and challenges in service delivery. This article explores the lessons learnt from the introduction of contraceptive technologies elsewhere and applies these to the SA context. Drawing on the World Health Organization's conceptual framework for the introduction of new contraceptive methods, and subsequent literature on the topic, lessons are classified into six cross-cutting themes. Recommendations highlight the need for SA to review and explore strategies to strengthen current implant services, including the provision of improved provider training aimed at sensitive, client-centred approaches; increased community engagement; and improved systems for programmatic monitoring and evaluation. With implementation of these recommendations, worrying trends in the provision of implants could be reversed. PMID- 29399423 TI - Distinct patterns of reduced prefrontal and limbic grey matter volume in childhood general and internalizing psychopathology. AB - Reduced grey matter volume (GMV) is widely implicated in psychopathology, but studies have found mostly overlapping areas of GMV reduction across disorders rather than unique neural signatures, potentially due to pervasive comorbidity. GMV reductions may be associated with broader psychopathology dimensions rather than specific disorders. We used an empirically supported bifactor model consisting of common psychopathology and internalizing- and externalizing specific factors to evaluate whether latent psychopathology dimensions yield a clearer, more parsimonious pattern of GMV reduction in prefrontal and limbic/paralimbic areas implicated in individual disorders. A community sample of children (n=254, ages 6-10) was used to to evaluate whether GMV reductions could constitute early neural risk factors. The common psychopathology factor was associated with reduced GMV in prefrontal areas (dorsal, orbitofrontal, ventrolateral). The internalizing-specific factor was related to reduced GMV in limbic/paralimbic areas (hippocampus, amygdala, insula). No significant associations were found between GMV and the externalizing-specific factor after accounting for common psychopathology. PMID- 29399424 TI - Diagnostic Dilemma: Cerebellopontine Angle Lipoma Versus Dermoid Cyst. AB - Both lipomas and dermoid cysts of the cerebellopontine angle are rare tumors. These tumors differ in their embryological origin but share similar features on imaging. Both of these congenital lesions can be found in the cerebellopontine angle (CPA), and symptomatic clinical presentation is dictated by the location of the lesion. This paper demonstrates a unique case in which a CPA lipoma was misidentified as a dermoid cyst, leading to surgical intervention. Further, the paper provides a literature review of CPA lipomas and dermoid cysts to aid readers in further differentiating between these two unique tumors. PMID- 29399425 TI - Cervico-thoracic Interspinous Bursitis Associated with Bilateral Upper-extremity Numbness: A Case Report. AB - The authors describe a 48-year-old woman suffering from bilateral upper-extremity numbness and axial radiating pain. Magnetic resonance imaging revealed soft tissue edema and enhancement surrounding the dorsal tip of the C7 spinous process. Excisional biopsy of the lesion revealed a mildly inflamed bursa, with no evidence of an active infection. Removal of the inflamed bursa resulted in complete resolution of the upper-extremity numbness and improvement in her neck pain. Although similar cases have been reported to be associated with rheumatologic conditions, most notably polymyalgia rheumatica (PMR), the current report underlines the presentation of radicular-like complaints associated with interspinous bursitis in the absence of other conditions affecting the musculoskeleton. PMID- 29399426 TI - Intercostal Nerve to Long Thoracic Nerve Transfer for the Treatment of Winged Scapula: A Cadaveric Feasibility Study. AB - There are very few surgical options available for treating a patient with winged scapula caused by a long thoracic nerve (LTN) injury. Therefore, we devised a novel technique based on a cadaveric dissection whereby regional intercostal nerves (ICN) were harvested and transposed to the adjacent LTN in 10 embalmed cadavers (20 sides). The LTN was identified along the lateral border of the serratus anterior and ICNs were identified at the mid-axillary line inferior to the lower edge of the pectoralis major muscle. Along the mid-clavicular line, each ICN was transected and transposed to the adjacent LTN. The length and diameter of each ICN available for mobilization to the LTN were measured. All measurements were made with microcalipers. Within the operative site, the mean proximal and distal diameters of the LTN were 1.6 and 1.1 mm, respectively. The adjacent ICN had a mean diameter of 1.3 mm. On all sides, the ICN branches were easily transposed to the adjacent LTN without any tension. Anastomosis to the LTN was performed to the third through sixth ICN provided each intercostal was preserved and mobilized anteriorly at least as far as the midclavicular line. The end to end size match between donor and LTN was appropriate on all sides. We found that it is feasible to harvest adjacent ICNs and move these to the adjacent LTN. Such a procedure, after being confirmed in patients, might offer a new technique for restoring protraction following an LTN injury. PMID- 29399427 TI - Myocardial Ischemia with Cannabinoid Use in an Adolescent. AB - A 16-year-old male presented to the emergency department with chest pain after smoking a synthetic cannabinoid from a vape pen. He had rising troponin I levels, and his exercise stress echocardiogram showed distal apical and septal hypokinesis that resolved at six-month follow-up. This case report raises concern about cardiac ischemia related to synthetic cannabinoid abuse in the pediatric population in the current era of cannabis legalization. PMID- 29399428 TI - Comparison of Live Versus Online Instruction of a Novel Soft Skills Course in Mongolia. AB - Background Soft skills are essential for employee success in the global marketplace; however, many developing countries lack content experts to provide the requisite instruction to an emerging workforce. One possible solution is to use an online, open-access curriculum. To date, no studies on soft skills curricula using an online learning platform have been undertaken in Mongolia. Objective To evaluate the efficacy of an online versus classroom platform to deliver a novel soft skills course in Mongolia. Methods A series of eight lectures along with corresponding surveys and multiple choice question tests were developed and translated into the Mongolian language. Two different delivery modalities, online and traditional classroom lectures, were then compared for knowledge gain, comfort level, and satisfaction. Knowledge gain and comfort level were assessed pre- and post-course, while satisfaction was assessed only post course. Results Enrollment in the online and classroom courses was 89 students and 291 students, respectively. Sixty-two online students (68% female) and 114 classroom students (77% female) completed the entire course and took the post test. The online cohort had higher pre-test scores than the classroom cohort (46.4% and 37.3%, respectively, p < 0.01). The online cohort's overall knowledge gain was not significant (0.4%, p=0.87), but the classroom cohort's knowledge gain was significant (13.9%, p < 0.01). Both the online and classroom cohorts demonstrated significant improvement in overall comfort level for all soft skills topics (p < 0.01). Both cohorts were also highly satisfied with the course, as assessed on a Likert scale (4.59 for online, 4.40 for classroom). Conclusion The study compared two cohorts of Mongolian college students who took either an online or classroom-based soft skills course, and it was found that knowledge gain was significantly higher for the classroom group, while comfort and satisfaction with individual course topics was comparable. PMID- 29399430 TI - Radio Frequency Electromagnetic Radiation From Streamer Collisions. AB - We present a full electromagnetic model of streamer propagation where the Maxwell equations are solved self-consistently together with electron transport and reactions including photoionization. We apply this model to the collision of counter-propagating streamers in gaps tens of centimeters wide and with large potential differences of hundreds of kilovolts. Our results show that streamer collisions emit electromagnetic pulses that, at atmospheric pressure, dominate the radio frequency spectrum of an extended corona in the range from about 100 MHz to a few gigahertz. We also investigate the fast penetration, after a collision, of electromagnetic fields into the streamer heads and show that these fields are capable of accelerating electrons up to about 100 keV. By substantiating the link between X-rays and high-frequency radio emissions and by describing a mechanism for the early acceleration of runaway electrons, our results support the hypothesis that streamer collisions are essential precursors of high-energy processes in electric discharges. PMID- 29399429 TI - Leptin Contributes to the Development of the Corpus Luteum. AB - The mechanistic events of female infertility have been investigated for over 50 years and despite progress many causes of infertility remain elusive. However, over half of idiopathic infertility issues have been attributed to a defective ovarian tissue responsible for the maintenance of a conceptus, the corpus luteum (CL). Many CL defects are attributed, in part, to abnormal vascularization (angiogenesis), which occurs primarily during the developmental stage of the luteal lifespan. A few well-established angiogenic growth promotants have been implicated in luteal angiogenic processes but the mechanisms of the process are still under investigation. Recent evidence supports a role for the adipokine hormone leptin as a probable component in the angiogenic and developmental processes of a CL. Leptin expression is present during the developmental and maturation stages of the luteal lifespan and stimulates the expression of angiogenic hormones in the CL. Induced leptin deficient CL have a higher occurrence of abnormal, underdeveloped gross morphology and an increase in the number of large diameter vessels and large luteal cells. Leptin replacement therapy in leptin deficient CL accelerates tissue development, increasing overall tissue mass and forming a structure that resembled a mature CL during the early stages of development. Collectively, the evidence supports the supposition that leptin is involved in the angiogenic and developmental processes of luteal tissue. PMID- 29399431 TI - Simultaneous Remote Observations of Intense Reconnection Effects by DMSP and MMS Spacecraft During a Storm Time Substorm. AB - During a magnetic storm on 23 June 2015, several very intense substorms took place, with signatures observed by multiple spacecraft including DMSP and Magnetospheric Multiscale (MMS). At the time of interest, DMSP F18 crossed inbound through a poleward expanding auroral bulge boundary at 23.5 h magnetic local time (MLT), while MMS was located duskward of 22 h MLT during an inward crossing of the expanding plasma sheet boundary. The two spacecraft observed a consistent set of signatures as they simultaneously crossed the reconnection separatrix layer during this very intense reconnection event. These include (1) energy dispersion of the energetic ions and electrons traveling earthward, accompanied with high electron energies in the vicinity of the separatrix; (2) energy dispersion of polar rain electrons, with a high-energy cutoff; and (3) intense inward convection of the magnetic field lines at the MMS location. The high temporal resolution measurements by MMS provide unprecedented observations of the outermost electron boundary layer. We discuss the relevance of the energy dispersion of the electrons, and their pitch angle distribution, to the spatial and temporal evolution of the boundary layer. The results indicate that the underlying magnetotail magnetic reconnection process was an intrinsically impulsive and the active X-line was located relatively close to the Earth, approximately at 16-18 RE. PMID- 29399432 TI - Mistrustful and Misunderstood: A Review of Paranoid Personality Disorder. AB - Purpose of review: Paranoid Personality Disorder (PPD) has historically been neglected by science out of proportion to its prevalence or its association with negative clinical outcomes. This review provides an update on what is known about PPD regarding its prevalence, demographics, comorbidity, biological mechanism, risk factors, and relationship to psychotic disorders. Recent Findings: PPD has long been the subject of a rich and prescient theoretical literature which has provided a surprisingly coherent account of the psychological mechanism of non delusional paranoia. Available data indicate that PPD has a close relationship with childhood trauma and social stress. Descriptive data on a sample of 115 individuals with Paranoid Personality Disorder is examined in comparison with a group of individuals with Borderline Personality Disorder. The descriptive data largely confirm previously identified relationships between Paranoid Personality Disorder and childhood trauma, violence, and race. We identify important similarities to and differences from Borderline Personality Disorder. Summary: PPD continues to be an important construct in the clinic and the laboratory. Available data lead to a reconsideration of the disorder as more closely related to trauma than to schizophrenia. PMID- 29399433 TI - Administrative Claims Data Versus Augmented Pregnancy Data for the Study of Pharmaceutical Treatments in Pregnancy. AB - Purpose of Review: Administrative claims databases, which collect reimbursement related information generated from healthcare encounters, are increasingly used to evaluate medication safety in pregnancy. We reviewed the strengths and limitations of claims-only databases and how other data sources may be used to improve the accuracy and completeness of information critical for studying medication safety in pregnancy. Recent Findings: Research on medication safety in pregnancy requires information on pregnancy episodes, mother-infant linkage, medication exposure, gestational age, maternal and birth outcomes, confounding factors, and (in some studies) long-term follow-up data. Claims data reliably identifies live births and possibly other pregnancies. It allows mother-infant linkage and has prospectively collected prescription medication information. Its diagnosis and procedure information allows estimation of gestational age. It captures maternal medical conditions but generally has incomplete data on reproductive and lifestyle factors. It has information on certain, typically short-term maternal and infant outcomes that may require chart review confirmation. Other data sources including electronic health records and birth registries can augment claims data or be analyzed alone. Interviews, surveys, or biological samples provide additional information. Nationwide and regional birth and pregnancy registries, such as those in several European and North American countries, generally contain more complete information essential for pregnancy research compared to claims-only databases. Summary: Claims data offers several advantages in medication safety in pregnancy research. Its limitations can be partially addressed by linking it with other data sources or supplementing with primary data collection. Rigorous assessment of data quality and completeness is recommended regardless of data sources. PMID- 29399434 TI - Steep switching devices for low power applications: negative differential capacitance/resistance field effect transistors. AB - Simply including either single ferroelectric oxide layer or threshold selector, we can make conventional field effect transistor to have super steep switching characteristic, i.e., sub-60-mV/decade of subthreshold slope. One of the representative is negative capacitance FET (NCFET), in which a ferroelectric layer is added within its gate stack. The other is phase FET (i.e., negative resistance FET), in which a threshold selector is added to an electrode (e.g., source or drain) of conventional field effect transistor. Although the concept of the aforementioned two devices was presented more or less recently, numerous studies have been published. In this review paper, by reviewing the published studies over the last decade, we shall de-brief and discuss the history and the future perspectives of NCFET/phase FET, respectively. The background, experimental investigation, and future direction for developing the aforementioned two representative steep switching devices (i.e., NCFET and phase FET/negative resistance FET) are to be discussed in detail. PMID- 29399435 TI - Stimuli-disassembling gold nanoclusters for diagnosis of early stage oral cancer by optical coherence tomography. AB - A key design consideration in developing contrast agents is obtaining distinct, multiple signal changes in diseased tissue. Plasmonic gold nanoparticles (Au NPs) have been developed as contrast agents due to their strong surface plasmon resonance (SPR). This study aims to demonstrate that stimuli-responsive plasmonic Au nanoclusters (Au NCs) can be used as a contrast agent for optical coherence tomography (OCT) in detecting early-stage cancer. Au NPs were clustered via acid cleavable linkers to synthesize Au NCs that disassemble under mildly acidic conditions into individual Au NPs, simultaneously diminishing SPR effect (quantified by scattering intensity) and increasing Brownian motion (quantified by Doppler variance). The acid-triggered morphological and accompanying optico physical property changes of the acid-disassembling Au NCs were confirmed by TEM, DLS, UV/Vis, and OCT. Stimuli-responsive Au NCs were applied in a hamster check pouch model carrying early-stage squamous carcinoma tissue. The tissue was visualized by OCT imaging, which showed reduced scattering intensity and increased Doppler variance in the dysplastic tissue. This study demonstrates the promise of diagnosing early-stage cancer using molecularly programmable, inorganic nanomaterial-based contrast agents that are capable of generating multiple, stimuli-triggered diagnostic signals in early-stage cancer. PMID- 29399436 TI - Current state of follow-up care for patients with Hymenoptera venom anaphylaxis in southwest Germany: Major impact of early information. AB - Background: Up to 3.5% of the population experience anaphylactic reactions in response to Hymenoptera stings. Current guidelines are in place for the diagnostic workup and follow-up care of patients with Hymenoptera venom anaphylaxis (HVA). However, little is known about the degree of implementation of the recommendations and patient attitudes toward the recommendations in the general patient population. Methods: For the analysis of the follow-up care in real life, a retrospective questionnaire-based study was conducted in unselected patients who had received treatment from an emergency medical response team for HVA, as documented in records of three regional Medical Emergency Response Centers. Results: From over 125,000 cases, a filtered list of 1895 patients that coded for anaphylaxis was generated and examination of paper records identified 548 patients with a documented insect sting anaphylaxis. Patients were sent a standardized questionnaire addressing different aspects of diagnostics and follow up care. Almost 40% of the patients did not receive a referral to an allergist at the emergency center, over 50% did not consult an allergy specialist at any time after the index sting, 25% did not receive any form of diagnostic workup, over 30% did not receive any information about venom immunotherapy (VIT) as treatment option, and only 50% were eventually started on VIT. Emergency medication was prescribed in 90% of the cases, 77% including an adrenalin auto injector, of which 47% were expired at the time of the survey. Patients who were informed about diagnostic and treatment options early during the index event, i. e., during the stay in the emergency department, displayed a higher rate of referral to an allergist (70% vs. 17%), higher rate of diagnostic workup (88% vs. 59%), and a higher rate of initiation of VIT (89% vs. 64%), as compared to patients who did not. Conclusion: Our results demonstrate that there are missed opportunities for secondary and tertiary prevention of anaphylaxis due to insect venom allergy and that early information on required diagnostics and treatment options has a major impact on the degree of proper follow-up care in line with current guideline recommendations. PMID- 29399437 TI - A non-rigid registration method for the analysis of local deformations in the wood cell wall. AB - This paper concerns the problem of wood cellular structure image registration. Given the large variability of wood geometry and the important changes in the cellular organization due to moisture sorption, an affine-based image registration technique is not exhaustive to describe the overall hygro-mechanical behaviour of wood at micrometre scales. Additionally, free tools currently available for non-rigid image registration are not suitable for quantifying the structural deformations of complex hierarchical materials such as wood, leading to errors due to misalignment. In this paper, we adapt an existing non-rigid registration model based on B-spline functions to our case study. The so-modified algorithm combines the concept of feature recognition within specific regions locally distributed in the material with an optimization problem. Results show that the method is able to quantify local deformations induced by moisture changes in tomographic images of wood cell wall with high accuracy. The local deformations provide new important insights in characterizing the swelling behaviour of wood at the cell wall level. PMID- 29399438 TI - Type 2 cytokine responses: regulating immunity to helminth parasites and allergic inflammation. AB - Purpose of Review: It is well established that T helper type 2 (TH2) immune responses are necessary to provide protection against helminth parasites but also to promote the detrimental inflammation associated with allergies and asthma. Given the importance of type 2 immunity and inflammation, many studies have focused on better understanding the factors that regulate TH2 cell development and activation. As a result, significant progress has been made in understanding the signaling pathways and molecular events necessary to promote TH2 cell polarization. In addition to the adaptive compartment, emerging studies are better defining the innate immune pathways needed to promote TH2 cell responses. Given the recent and substantial growth of this field, the purpose of this review is to highlight recent studies defining the innate immune events that promote immunity to helminth parasites and allergic inflammation. Recent Findings: Emerging studies have begun to elucidate the importance of cytokine alarmins such as thymic stromal lymphopoietin (TSLP), IL-25 (IL-17E) and IL-33 in promoting type 2 immunity and inflammation following helminth challenge or exposure to allergens. Specifically, recent reports have begun to define the complex cellular networks these alarmins activate and their contribution to type 2 immunity and inflammation. Summary: Our increased understanding of the pathways that regulate type 2 cytokine-mediated immunity and inflammation have revealed novel therapeutic targets to treat both helminth infections and allergic disease states. PMID- 29399440 TI - Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes. AB - : This review highlights the recent advances in our understanding of adipocyte contributions to carcinogenesis or cancer disease progression for cancers in the bone. Purpose: In this review, we aim to describe bone marrow adipose tissue and discuss the soluble adipocyte-derived cytokines (adipokines) or endocrine factors, adipocyte-derived lipids, and the actual or putative juxtacrine signaling between bone marrow adipocytes and tumor cells in the bone marrow. This relationship likely affects tumor cell initiation, proliferation, metastasis, and/or drug resistance. Recent Findings: Bone marrow adipose may affect tumor proliferation, drug resistance, or cancer-induced bone disease and hence may be a new target in the fight against cancer. Summary: Overall, evidence is mixed regarding the role of bone marrow adipose and adipocytes in cancer progression, and more research in this arena is necessary to determine how these bone marrow microenvironmental cells contribute to malignancies in the marrow to identify novel, potentially targetable pathways. PMID- 29399442 TI - Sulfonamides as Inhibitors of Leishmania - Potential New Treatments for Leishmaniasis. AB - Introduction: Leishmaniasis is an endemic disease caused by the protozoan parasite Leishmania. Current treatments for the parasite are limited by cost, availability and drug resistance as the occurrence of leishmaniasis continues to be more prevalent. Sulfonamides are a class of compounds with medicinal properties which have been used to treat bacterial and parasitic disease via various pathways especially as antimetabolites for folic acid. Methods: New derivatives of sulfonamide compounds were assessed for their impact on Leishmania cell viability and potential pathways for inhibition were evaluated. Leishmania tarentolae (ATCC Strain 30143) axenic promastigote cells were grown in brain heart infusion (BHI) medium and treated with varying concentrations of the new sulfonamide compounds. Light microscopy and viability tests were used to assess the cells with and without treatment. Discussion: A non-water soluble sulfonamide was determined to have 90-96% viability inhibition 24 hours after treatment with 100 uM final concentration. Because Leishmania are also autotrophs for folate precursors, the folic acid pathway was identified as a target for sulfonamide inhibition. When folic acid was added to untreated Leishmania, cell proliferation increased. A water soluble derivative of the inhibitory sulfonamide was synthesized and evaluated, resulting in less viability inhibition with a single dose (approximately 70% viability inhibition after 24 hours with 100 uM final concentration), but additive inhibition with multiple doses of the compound. Results: However, the potential mechanism of inhibition was different between the water-soluble and non-water soluble sulfonamides. The inhibitory effects and potential pathways of inhibition indicate that these compounds may be new treatments for this disease. PMID- 29399443 TI - The "Floating Labrum": Bankart Lesion Repair With Anterior Capsular Extension Using 2 Anterior Working Portals. AB - Surgical repair of a Bankart lesion requires thorough recognition of the capsulolabral attachment and adequate visualization for suture anchor repair. The glenoid labrum usually detaches from its capsule and bony attachment anteriorly and inferiorly; however, the labral and capsule detachment can sometimes extend beyond this zone of injury. Identification and repair may require additional viewing and working portals to allow for ease of suture passage and anchor placement. This technique guide describes a case scenario of a Bankart lesion with anterior extension of the capsular tear, repaired with use of 2 anterior working portals. PMID- 29399441 TI - NK Cells and gammadeltaT Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT). AB - Purpose of review: The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and gammadeltaT cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or alphabeta-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and gammadeltaT cells and minimal usage of GVHD prophylaxis. In this review we will discuss strategies to retain and expand the quantity, diversity and functionality of these reconstituting innate cell types. Recent findings: Bisphosphonates, IL 15 cytokine administration, specific antibodies, checkpoint inhibitors and (CMV based) vaccination are currently being evaluated to enhance IR. All these approaches have shown to potentially enhance both NK and gammadeltaT cell immuno repertoires. Summary: Rapidly accumulating data linking innate biology to proposed clinical immune interventions, will give unique opportunities to unravel shared pathways which determine the Graft-versus-Tumor effects of NK and gammadeltaT cells. PMID- 29399439 TI - Plant flavone apigenin: An emerging anticancer agent. AB - Research in cancer chemoprevention provides convincing evidence that increased intake of vegetables and fruits may reduce the risk of several human malignancies. Phytochemicals present therein provide beneficial anti-inflammatory and antioxidant properties that serve to improve the cellular microenvironment. Compounds known as flavonoids categorized anthocyanidins, flavonols, flavanones, flavonols, flavones, and isoflavones have shown considerable promise as chemopreventive agents. Apigenin (4', 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties affecting several molecular and cellular targets used to treat various human diseases. Epidemiologic and case-control studies have suggested apigenin reduces the risk of certain cancers. Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers. Apigenin's anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies. Here we discuss the anticancer role of apigenin highlighting its potential activity as a chemopreventive and therapeutic agent. We also highlight the current caveats that preclude apigenin for its use in the human trials. PMID- 29399444 TI - Arthroscopic Management of Isolated Tibial Plateau Defect With Microfracture and Micronized Allogeneic Cartilage-Platelet-Rich Plasma Adjunct. AB - Articular cartilage lesions of the tibial plateau are an uncommonly encountered clinical entity, and they have been comparatively less well studied than femoral condyle or patellofemoral defects. The management of these lesions is complicated by the challenging geometry, difficult surgical approach, and proximity to important anatomic structures, and thus, treating these lesions by previously established methods, such as osteochondral allograft transplantation or osteochondral autograft transfer, can be a technically challenging endeavor. These lesions remain readily available to undergo microfracture, and this is the preferred method of management in the senior author's practice. Although less technically difficult and less invasive than other techniques, microfracture is currently limited by concerns over the long-term durability of the method. Current research seeks to improve the quality of cartilage fill stimulated by microfracture, and adjunct techniques have become increasingly popular. In this technical report, we present a technique for arthroscopic treatment of an isolated tibial plateau defect with microfracture using a micronized allogeneic cartilage (BioCartilage; Arthrex, Naples, FL) and platelet-rich plasma adjunct. PMID- 29399446 TI - Mini-open Subpectoral Biceps Tenodesis Using a Suture Anchor. AB - The long head of the biceps (LHB) tendon is a potential source of shoulder pain encountered by orthopaedic surgeons. A multitude of approaches to addressing LHB tendinopathy have been described. These include various surgical techniques such as tenodesis versus tenotomy, an arthroscopic versus an open approach, and differing methods of tenodesis fixation. Our preferred approach to addressing LHB tendinopathy is through a mini-open approach using a double-loaded 4.5-mm suture anchor. This Technical Note with accompanying video describes our technique for performing this procedure, as well as supporting clinical evidence and technical pearls. PMID- 29399445 TI - Arthroscopic Lateral Border Resection in Medialized Scapula Neck Fractures. AB - Scapula neck fractures are rare injuries, leaving several treatment options. Standardized markers for operative treatment are a decreased glenopolar angle <=22 degrees , lateral border offset (LBO) of the glenoid >=20 mm, angular deformity >=45 degrees , or LBO >=15 mm plus angular deformity >=35 degrees . If operative treatment is not performed before union, the fracture heals malaligned with possible mechanical complications due to a medialized glenoid and the protruding lateral border. Common operative treatment comprises a corrective osteotomy for the anatomic correction of the malunited fracture, leaving intra articular pathologies like adhesive capsular stiffness unaddressed. Our presented arthroscopic technique for the treatment of sequelae of scapula neck fractures combines a 270 degrees capsulotomy with arthroscopic resection of a protruding lateral border. With use of this technique, excellent shoulder function can be restored with a minimally invasive procedure. Therefore, arthroscopic treatment could be favorable in selected cases of malunited scapula neck fractures. PMID- 29399447 TI - Prevention of Medial Femoral Condyle Injury by Using a Slotted Cannula in Anterior Cruciate Ligament Reconstruction. AB - Anterior cruciate ligament injury is one of the most common ligament injuries of the knee in sports medicine. The treatment of choice is anterior cruciate ligament reconstruction, which requires an experienced surgeon. Complications may occur at every step of the procedure. The surgeon should be especially careful when performing the step of femoral tunnel creation. Damage to the medial femoral condyle (MFC) could occur; thus, the full functional outcome of the knee might be affected. There are many surgical techniques to avoid MFC injury. We propose a surgical technique that could reduce the risk of MFC injury. This technique uses a Fast-Fix slotted cannula (Smith & Nephew) as a protector. Because such equipment is available in all meniscus instrument sets, this surgical technique is a feasible and easy method to use during the femoral tunnel creation step. PMID- 29399449 TI - Viable Osteochondral Allograft for the Treatment of a Full-Thickness Cartilage Defect of the Patella. AB - Isolated cartilage defects can lead to significant pain and disability, prompting the development of a number of options for restorative treatment. Each method has advantages and limitations, and no single technique has gained widespread use. We present a technique for implantation of a cryopreserved osteochondral allograft (Cartiform) for the treatment of full-thickness cartilage defects. Cartiform is a cryopreserved osteochondral allograft composed of chondrocytes, chondrogenic growth factors, and extracellular matrix proteins. This implant allows for regenerative treatment of full-thickness cartilage lesions in a single surgical procedure. PMID- 29399448 TI - Arthroscopic Bone Grafting of the Humeral Head for Treatment of a Deep Hill-Sachs Lesion. AB - Recurrent anterior shoulder dislocation often leads to the presence of a Hill Sachs lesion. A large Hill-Sachs lesion compromises shoulder stability and should be addressed with bone augmentation when it is too deep. Here, we introduce a method of arthroscopic bone grafting of the humeral head for the treatment of a deep Hill-Sachs lesion in patients with anterior shoulder instability. Our indication for this procedure is a deep off-track Hill-Sachs lesion measuring at least 8 mm in depth and 10 mm in width. The main steps of this procedure include graft placement via special shoulder bone grafting instruments, graft suspension fixation using suture anchors, and bone fragment compression using the infraspinatus tendon. We routinely use this technique in combined treatment procedures for complicated anterior shoulder instability. PMID- 29399450 TI - The Tripod-Pulley Technique for Arthroscopic Remplissage in Engaging Hill-Sachs Lesions. AB - Arthroscopic Bankart repair is now a well-established technique for the treatment of shoulder instability. However, failure rates are considerable when significant bony defects are not addressed. Hill-Sachs lesions, present in the vast majority of those with recurrent anterior instability, when of significant dimension and location, may account for some of these failures. The remplissage procedure involves capsulotenodesis of the posterior capsule and the infraspinatus tendon to fill the Hill-Sachs lesion. "Double-pulley" remplissage is a transtendinous technique that has been described elsewhere and that may simplify the procedure. We present a modification of this technique, the "tripod-pulley" technique, which we feel may potentiate healing of the Hills-Sachs lesions of the capsule and infraspinatus by increasing the surface contact area. At the same time, this technique minimizes the risk of potential damage to the infraspinatus as it uses 2.3-mm "all-suture" anchors. PMID- 29399451 TI - Arthroscopic Primary Posterior Cruciate Ligament Repair With Suture Augmentation. AB - Isolated posterior cruciate ligament (PCL) injuries are relatively rare and PCL injuries most commonly occur in the setting of multiligamentous knee injuries. PCL injuries can be treated with primary repair, which has the advantages of preserving the native tissue, maintaining proprioception, and minimal invasive surgery when compared with reconstruction surgery. Historically, primary repair of PCL injuries was performed in all tear types using an open approach, and, although the subjective outcomes were relatively good, patients often had residual laxity. Modern advances and increasing knowledge could improve the outcomes of PCL repair. With magnetic resonance imaging patients with proximal tears and sufficient tissue quality can be selected, and with arthroscopy and suture anchors minimal invasive surgery with direct fixation can be performed. Furthermore, with suture augmentation the healing of the repaired PCL can be protected and the residual laxity can be prevented. In this Technical Note, we describe the surgical technique of arthroscopic primary repair of proximal PCL tears with suture anchors and suture augmentation. The goal of arthroscopic primary repair is the preservation of the native PCL using a minimally invasive method and subsequent protection of this repair using suture augmentation. PMID- 29399452 TI - Reverse Total Shoulder Arthroplasty With Humeral Head Autograft Fixed Onto Glenoid for Treatment of Severe Glenoid Retroversion. AB - Advanced glenohumeral osteoarthritis can transform glenoid morphology and, in some cases, is found in association with severe glenoid retroversion. The associated glenoid retroversion leads to difficulty in fixation of the glenoid component in reverse total shoulder arthroplasty. In the context of extreme glenoid wear, structural grafts can be used to restore glenoid volume and version in order for the glenoid component of the reverse total shoulder arthroplasty to be more easily implanted. Nevertheless, literature regarding structural grafts remains limited, with optimal graft choice and technique still controversial at best. This article details our technique for humeral head autograft transplantation before reverse total shoulder arthroplasty in the context of extreme glenoid retroversion with advanced osteoarthritis. PMID- 29399453 TI - Arthroscopic Excision of the Sternoclavicular Joint. AB - Osteoarthritis changes at the sternoclavicular joint (SCJ) have been shown to be present on computed tomography in more than 90% of people over the age of 60 years. Although usually asymptomatic, when symptoms do occur, they can be very debilitating. Most patients respond favorably to conservative treatment, but there is a small cohort of patients who continue to be symptomatic despite adequate conservative treatment. Surgical management with an open SCJ excision has been shown to give satisfactory results. However, probably due to concerns with regard to damage to the mediastinal structures, instability, and scarring, there is a high threshold for surgery. Arthroscopic SCJ excision has been shown to achieve similar results to an open procedure while avoiding some of the risks. In this Technical Note, we describe the indications, imaging, and the technique of an arthroscopic excision of the SCJ. PMID- 29399454 TI - Osteochondral Allograft Transplants for Large Trochlear Defects. AB - Focal articular cartilage injuries in the knee are common and can cause severe morbidity and reduced function. The articular cartilage is avascular and has limited ability to heal, and hence, patients with cartilage injuries have increased risk of progressing to osteoarthritis. Most of the cartilage injuries are located on the femoral condyles. Engaging focal cartilage injuries involving the trochlea are challenging because of the morbidity caused by these injuries and the limited treatment options. Osteochondral allograft transplantation is emerging as a promising treatment for full-thickness articular cartilage defects. Recent studies have reported high success rates with the use of osteochondral allografts. This article reports our technique of osteochondral allograft transplantation for the treatment of a focal full-thickness defect of the trochlea. PMID- 29399455 TI - A Shortcut to Arthroscopic Suprascapular Nerve Decompression at the Suprascapular Notch: Arthroscopic Landmarks and Surgical Technique. AB - Arthroscopic suprascapular nerve decompression at the suprascapular notch is a technically demanding surgical procedure with a steep learning curve. The aim of this Technical Note is to describe important pearls for an arthroscopic decompression of the suprascapular nerve relying on the palpation of the coracoclavicular ligaments before starting the arthroscopic visualization. This reduces the time and minimizes the resection of the surrounding fat. PMID- 29399456 TI - Repair of an Isolated Coracoid Fracture With Suture Anchor Fixation. AB - Coracoid fractures are rare injuries, which may occur in isolation or in association with other shoulder pathology. The mechanism of trauma consists of a strong contraction of the conjoint tendon as a result of direct trauma. The diagnosis is usually difficult and many times overlooked, thereby requiring a high level of suspicion. In many cases, standard trauma series shoulder radiographs are unable to provide a definitive and reliable diagnosis. Therefore, other imaging modalities may be necessary to confirm the diagnosis. Although uncommon, if left untreated, a coracoid fracture will result in chronic pain and shoulder disability. Both conservative and surgical techniques have been previously reported and shown positive outcomes. In regard to the surgical technique, most reports describe the use of screw fixation, which has been associated with full recovery and high patient satisfaction. Nevertheless, the purpose of this Technical Note is to describe our preferred method to treat an isolated type II displaced coracoid process fracture through suture anchor fixation. PMID- 29399457 TI - Anatomic Acromioclavicular Joint Reconstruction With Semitendinosus Allograft: Surgical Technique. AB - Acromioclavicular joint separations are common shoulder injuries in the active patient population. Nonoperative management is recommended for Rockwood type I and II injuries, whereas surgical reconstruction is recommended for type IV and VI separations. The management for type III and V injuries is more controversial and is determined on a case-by-case basis. A multitude of surgical reconstruction techniques exist, and there is little evidence to support one technique over another. The anatomic technique aims at reconstructing the coracoclavicular ligaments and bringing the clavicle back into its anatomic position. When the anatomic technique is augmented with a graft, biomechanical studies have shown superior reconstruction strength and stability compared with standard nonanatomic techniques. Additionally, anatomic reconstruction allows for better cosmesis and functional outcome measures at midterm follow-up compared with nonanatomic techniques. In this Technical Note, we describe our preferred technique for anatomic repair of acromioclavicular joint separation using a semitendinosus allograft. PMID- 29399458 TI - Treatment of Osteochondral Lesions of the Talus With Cell-free Polymer-based Scaffold in Single-Step Arthroscopic Surgery. AB - Arthroscopic techniques have recently gained popularity for the treatment of osteochondral defects of the talus. The microfracture procedure is the most commonly applied arthroscopic technique. However, it is not effective for the treatment of larger lesions. Tissue-engineered scaffolds have been used for cartilage regeneration arthroscopically, and promising results have been reported. We treated larger osteochondral lesions of the talus with polyglycolic acid-hyaluronan scaffold biomaterial (Chondrotissue, BioTissue AG, Zurich, Switzerland) in a single-step arthroscopic surgery. Traction methods and fibrin glue were avoided. PMID- 29399459 TI - Opening Wedge High Tibial Osteotomy and Anterior Cruciate Ligament Reconstruction or Revision. AB - High tibial osteotomy (HTO) is a valid treatment option for young active patients with medial tibiofemoral osteoarthrosis (OA) and varus deformity. Sometimes medial OA is combined with symptomatic anterior cruciate ligament (ACL) deficiency. Although isolated HTO (with possible delayed ACL reconstruction) might be indicated in the older population, young active patients may require combined HTO and ACL reconstruction. In addition, an abnormally increased tibial slope may predispose to ACL reconstruction failure and should be addressed for a successful ACL revision. The combination of HTO and ACL reconstruction produces good results, with resumption of normal daily activities, as well as recreational sports, and does not seem to increase the risk of complications compared with isolated HTO. The purpose of this Technical Note is to describe our indications, planning, and technique for opening wedge HTO fixed with a spacer plate and anatomic soft-tissue (autograft or allograft) ACL reconstruction, with proximal extracortical suspension and distal interference screw fixation. PMID- 29399460 TI - Arthroscopic Intramuscular Side-to-Side Repair of an Isolated Infraspinatus Tear. AB - Intramuscular, full-thickness rotator cuff tears are uncommon and present a challenging clinical scenario for repair because traditional suture anchor or transosseous repair techniques are less feasible. The goal of repair is to achieve a tension-free reduction of both ends of the muscle to allow for adequate healing over time. Intramuscular tears of the infraspinatus specifically have rarely been reported. The clinical presentation of these patients can be challenging to interpret, and other causes of rotator cuff dysfunction, including compression to the suprascapular nerve, must be ruled out. In this Technical Note, we describe our technique for arthroscopic side-to-side suture repair of an isolated intramuscular infraspinatus tear. PMID- 29399461 TI - Figure-of-8 Reconstruction Technique for Chronic Posterior Sternoclavicular Joint Dislocation. AB - Dislocation of the sternoclavicular joint is a rare injury and typically requires high-energy forces applied through the joint. Initial treatment is dependent on the direction of dislocation, with acute reduction indicated for posterior dislocations presenting with signs of tracheal, esophageal, or neurovascular compression. Although most patients do well with conservative treatment after the initial trauma, some can have persistent pain and scapular dyskinesia due to instability or locked dislocation of the sternoclavicular joint. Stabilization of the sternoclavicular joint with reconstruction may be indicated for those with persistent symptoms despite a trial of steroid injections and physical therapy. In this report and video, we present a figure-of-8 reconstruction technique to reduce and stabilize a posterior dislocation of the sternoclavicular joint using a gracilis autograft. Ultimately, this reconstruction technique can be performed in a safe, efficient, and reliable manner when appropriate surgical steps are followed. PMID- 29399462 TI - Lesser Trochanter Osteoplasty for Ischiofemoral Impingement. AB - Ischiofemoral impingement is a newly recognized cause of extra-articular hip pain, and is caused by contact between the lesser trochanter and ischium. Surgical intervention has been proven successful for patients with persistent pain and disability after failure of nonoperative management. This technique article provides a reliable method for endoscopic lesser trochanter osteoplasty using an anterior approach. PMID- 29399463 TI - Adipose-Derived Stem Cell Transplant Technique for Degenerative Joint Disease. AB - The treatment of mild to moderate osteoarthritis can be a challenging problem for orthopaedic surgeons. As new research and treatment strategies have emerged, stem cell therapy has risen in popularity for the management of degenerative joint conditions. In this article, we describe a stepwise technical approach with tips and pearls to performing adipose-derived stem cell transplantation for degenerative joint disease of the knee. PMID- 29399464 TI - Split Pectoralis Major Transfer for Chronic Medial Scapular Winging. AB - Scapular winging can be a significant source of chronic pain, weakness, and disability of the shoulder. Isolated serratus anterior palsy from long thoracic nerve injury, which is the most common cause of this condition, produces prominent winging and medial malpositioning of the inferior angle of the scapula. In the case of persistent symptoms despite conservative care, treatment options primarily include scapulothoracic fusion and pectoralis major transfer. Outcomes of scapulothoracic fusion are notable for a high complication rate and limited functional improvements. We describe our technique of indirect, split pectoralis major transfer to the inferolateral scapula with allograft tissue augmentation for the surgical treatment of chronic medial winging. This procedure provides dynamic stabilization of the scapula with secure and tension-free tendon transfer. Advantages over alternative treatments include a relatively low complication rate, acceptable cosmesis, and better range of motion. The rationale and technical aspects of this procedure are discussed. Additional clinical studies are warranted to compare outcomes for the direct and indirect split transfer methods. PMID- 29399465 TI - Endoscopic All-inside Repair of the Flexor Hallucis Longus Tendon in Posterior Ankle Impingement Patients. AB - Longitudinal flexor hallucis longus (FHL) tendon tears are sometimes complicated by posterior ankle impingement syndrome (PAIS), especially in ballet dancers. In recent years, PAIS has been treated endoscopically, but it is difficult to suture FHL tendon tears endoscopically. In this report, we describe how to suture the FHL tendon endoscopically with the Meniscal Viper Repair system (Arthrex, Naples, FL). Without our endoscopic technique, when a patient is found to have a longitudinal tear of the FHL under endoscopy, we must choose to either neglect the tear or convert to an open repair. Open tendon suture techniques have reportedly had relatively good results but require a longer skin incision than endoscopic surgery for PAIS. Compared with the open repair, the advantages of our technique include earlier recovery, less pain, a lower rate of soft tissue complications, and improved healing through better preservation of the blood supply. This technique is an attractive and useful option because it is an easy and safe method for longitudinal FHL tendon tears. PMID- 29399466 TI - Right Versus Left Hip Arthroscopy for Surgeons on the Learning Curve. AB - Hip arthroscopy is a technically demanding procedure that is currently characterized by a "steep" learning curve. Therefore, achieving an advanced technical level is often challenging, especially for the amateur hip arthroscopist. Hand laterality when training in hip arthroscopy is an aspect that has been omitted. In addition, the technical differences regarding the handling of the surgical instruments when performing hip arthroscopy on the left versus right hip can influence the technical excellence. This Technical Note summarizes our preferred hip arthroscopy technique by comparing the surgeon's hand position when operating on the left versus right hip. We also emphasize how the surgeon's hand laterality affects the instrument manipulation during the procedure and potentially the clinical outcomes. PMID- 29399467 TI - Comprehensive Clinical Evaluation of Femoroacetabular Impingement: Part 1, Physical Examination. AB - A thorough evaluation of the hip must include a comprehensive medical and surgical history focused on the hip joint, surrounding soft tissues, and the associated structures of the spine, pelvis, and lower extremities. These details can guide the physical examination and provide insight into the cause of the patient's chief complaints. A proper examination includes physical examination while the patient is in the upright, supine, prone, and lateral position, as well as an evaluation of gait. Guided by a thorough history, the physical examination enables the surgeon to distinguish between intra-articular and extra-articular contributors to hip pain, selection of appropriate imaging modalities, and ultimately supports medical decision making. PMID- 29399468 TI - Comprehensive Clinical Evaluation of Femoroacetabular Impingement: Part 2, Plain Radiography. AB - The use of hip arthroscopy to treat various forms of hip pathology continues to grow. As part of a standard evaluation for eligibility for hip arthroscopy, we routinely obtain standard radiographs to assess the hip joint. These include orthogonal projections of the acetabulum and proximal femur, which can be obtained with a standing false profile, supine anteroposterior pelvis, and a lateral view of the proximal femur (either Dunn 45 degrees or 90 degrees , frog leg lateral, or cross-table lateral). A comprehensive analysis of the radiographs is of utmost importance in order to indicate a patient for hip arthroscopy, for preoperative planning, and to determine prognosis. The purpose of this Technical Note is to provide a comprehensive guide of how our group performs qualitative and quantitative analysis of hip radiographs in a potential candidate for hip arthroscopy. PMID- 29399469 TI - Comprehensive Clinical Evaluation of Femoroacetabular Impingement: Part 3, Magnetic Resonance Imaging. AB - Radiologic imaging is an essential supplement to the physical examination in the evaluation of a patient with femoroacetabular impingement. Plain radiographs are the initial modality of choice for the evaluation of bony anatomy and pathology. Magnetic resonance imaging supplements the physical examination and standard radiographs by enabling qualitative and quantitative evaluation of both articular cartilage and soft tissues about the hip. Magnetic resonance imaging also provides improved 3-dimensional characterization of the bony anatomy owing to the multiplanar nature of this technique. This article describes a comprehensive approach to interpretation of magnetic resonance examination of the hip. PMID- 29399471 TI - Platelet-Rich Fibrin Clot-Augmented Repair of Horizontal Cleavage Meniscal Tear. AB - Although horizontal tears of the meniscus have historically been treated with partial meniscectomy due to poor vascularity within the tear, evidence suggests that repair of horizontal meniscal tears may be advantageous to partial meniscectomy. Furthermore, the addition of platelet-rich plasma has shown promise in improving meniscal healing. We present our technique of platelet-rich fibrin clot-augmented repair of horizontal cleavage meniscal tear. PMID- 29399470 TI - Combined All-arthroscopic Hill-Sachs Remplissage, Latarjet, and Bankart Repair in Patients With Bipolar Glenohumeral Bone Loss. AB - Patients presenting with recurrent shoulder instability and bipolar glenohumeral bone loss are at risk of failed standard soft-tissue repair techniques. Even isolated bony-stabilization procedures such as the Latarjet or remplissage technique may not provide sufficient stability in the face of combined bone loss. We use a combined all-arthroscopic remplissage, Latarjet, and Bankart repair for patients with significant combined glenohumeral bone loss and/or in the revision setting. This allows reconstruction of both the Hill-Sachs and glenoid bone defects and repair of the capsulolabral complex in a minimally invasive manner. Furthermore, the use of cortical-button fixation of the coracoid bone graft may reduce the risk of hardware-related complications while still achieving excellent bone union. PMID- 29399472 TI - Arthroscopic Transfer of the Subscapularis Tendon for Treatment of a Reverse Hill Sachs Lesion. AB - Posterior shoulder instability occurs less often than anterior shoulder instability but is increasingly recognized as a relatively common condition. The reverse Hill-Sachs lesion is present in some patients with posterior instability and is best described as an impaction fracture of the anterior humeral head. These reverse Hill-Sachs lesions can predispose the patient to recurrent instability events and may need to be addressed directly at the time of surgery. Multiple open and arthroscopic procedures have been described to transfer bone or soft tissue structures into this reverse Hill-Sachs defect. An arthroscopic technique for the transfer of the subscapularis tendon into the defect using a standard 30 degrees arthroscope, standard portals, and suture anchors is described. PMID- 29399473 TI - Pre- and post-operative visualization of neonatal esophageal atresia/tracheoesophageal fistula via magnetic resonance imaging. AB - Esophageal atresia (EA) is a relatively uncommon congenital anomaly, often observed in conjunction with tracheoesophageal fistula (TEF). Surgical repair in neonates typically takes place with little information about the pre-existing EA/TEF structure because there are currently no acceptable tools for evaluating EA/TEF anatomy prior to repair; chest x-ray radiograph does not identify malformation sub-type or gap length, while x-ray computed tomography (CT) demonstrate an unacceptably high exposure to ionizing radiation. There is a need for safe imaging methods to evaluate pre-operative EA/TEF anatomy, which would add value in surgical planning; this need may be met with high-resolution structural MRI. We report three cases of Type-C EA/TEF in neonates. Patients were imaged prior to surgical repair using high-resolution ultrashort echo time (UTE) magnetic resonance imaging (MRI) to visualize tracheoesophageal anatomy and allow for informed surgical planning and risk management. One of the three patients was imaged post-repair to evaluate surgical efficacy and evolution of the tracheoesophageal anatomy. PMID- 29399474 TI - Management of bleeding from an abnormally located S6 arterial branch in a common origin with S2 branch during live surgery. AB - In 24th/03/2016 we organized the first uniportal video-assisted thoracic surgery (VATS) live surgery workshop in Jerusalem at our institution with our special guest Dr. Diego Gonzalez-Rivas, more than 30 participants attended this workshop from Israeli and the Palestinian territories (cardiothoracic and vascular surgeons, general surgeons, anesthesiologists and nurses). During the workshop Dr. Gonzalez operated two complex cases while the first case was an anatomical S1 segmentectomy, the second case (the one which we are reporting in this paper) was bilobectomy of right middle and lower lobes, during this case a profuse bleeding appeared while introducing the stapler in the interlobar fissure, the source of this bleeding was an abnormally located arterial branch, however the bleeding managed perfectly by Dr. Gonzalez-Rivas, although this surgery kept all of us in a state, all the attendees were happy to see the way how this bleeding managed and everybody was satisfied with the final result. PMID- 29399475 TI - The highlights in the 3rd International Uniportal VATS Course. PMID- 29399476 TI - Right pneumonectomy for carcinoid tumor extending through the intermediate bronchus and the interlobar artery. AB - Uniportal video-assisted thoracic surgery (VATS) is the emerging technique in the modern thoracic surgery practice in Assiut University Hospitals in Egypt we try to keep up with the cutting edge of knowledge to deliver the best available service to our patient. So we invite Dr. Diego Gonzalez-Rivas the world pioneer surgeon in uniportal VATS approach to initiate a uniportal VATS program starting with a workshop with live surgery. The workshop was attended by 84 thoracic surgeons from all across Egypt with a high motivation for adopting the technique in the everyday practice. We believe that uniportal will be the first choice approach for thoracic surgeon in Egypt in the upcoming year. PMID- 29399477 TI - Subxiphoid uniportal video-assisted thoracoscopic trisegmentectomy. PMID- 29399478 TI - The evolution of uniportal video assisted thoracic surgery in Costa Rica. AB - Video-assisted thoracic surgery (VATS) has become one of the most important advances in thoracic surgery in this generation. It has evolved continuously into a less invasive approach, being uniportal VATS the last step in this evolution. Since the first uniportal VATS lobectomy was performed in La Coruna in 2010, the procedure has suffered and exponential growth that has allowed it to widespread around the world, expanding the indications from initially early stage lung cancer cases to complex advance cases nowadays. In Costa Rica, uniportal VATS started to be used for major pulmonary resection in June 2014, thanks to the tutoring from Dr. Gonzalez-Rivas. In our center, uniportal VATS is the standard approach for minimally invasive procedures, and major pulmonary resections had only been done through the single port approach. In order to evolve and progress in the experience of the procedure, and to expand the indications in which it was being performed, a "uniportal VATS master class" was held in Rafael Angel Calderon Guardia Hospital in San Jose, Costa Rica, from September 16 to September 18 2015. The master class was led by Dr. Diego Gonzalez-Rivas and it counted with the contribution of Dr. Li Wentao and Dr. Yang Yang, from Shanghai Pulmonary Hospital. The course attracted almost every thoracic surgeon in our country and participants also included anesthesiologists, pulmonologists, nurses and medical students. Three uniportal VATS were performed during the course, a left lower and a right upper lobectomy and a wedge resection that was the first non-intubated VATS procedure ever performed in our country. PMID- 29399479 TI - Video-assisted thoracic surgery? Yes, but the best interest of the patient always first. PMID- 29399480 TI - Uniportal lobectomy in Jordan-the journey continues. AB - Report of the first uniportal video-assisted thoracic surgery (VATS) lobectomy live surgeries course in Jordan. Live surgeries were performed in collaboration between Dr. Diego Gonzalez-Rivas and our Thoracic/Pulmonary Team at Istishari Hospital in Jordan. Such experience will pave the way for more thoracic surgeons to embrace the newest of the less-invasive thoracic surgical techniques in Jordan. PMID- 29399481 TI - Video-assisted thoracic surgery micro pneumonectomy, a new approach. AB - Background: Video-assisted thoracic surgery (VATS) pneumonectomy is normally limited due to the difficulty to remove the whole lung via the utility incision. We present our technique of VATS pneumonectomy, this we call micropneumonectomy. Methods: A 75-year-old male current smoker with a right hilar mass, invading both upper and lower lobe bronchi to segmental level on CT scan and PET scan, pathology from CT guided biopsy showed squamous cell carcinoma. The patient had a mediastinoscopy just prior to pneumonectomy, primarily to remove station 7 lymph nodes and to mobilize the carina to facilitate the VATS pneumonectomy. Results: Smooth postoperative course, and patient was fit for discharge two and half days post operatively. Conclusions: Our technique showed an effective way of doing pneumonectomy via VATS technique, which expands the use of VATS technique into pneumonectomies, with three intercostals incisions smaller than 5 mm, in addition to a single sub-xiphoid incision which can take 12 mm instruments. PMID- 29399482 TI - Four years' experience in uniportal video-assisted thoracoscopic surgery for major lung resections: influence of silicosis in clinical outcomes. AB - Background: Crystalline silica (CS) is one of the most common minerals and a common particulate air pollutant in both working and living environments. Lung cancer is considered one of the serious consequences of silica exposure. This paper gives an overview of the role of silicosis in results of perioperative and postoperative of lung resection surgery performed by the most up to date video assisted thoracoscopic surgery (VATS) approach: the uniportal VATS. Methods: In January 2012 a program of video-assisted thoracoscopic anatomic pulmonary resections through a uniportal approach (no rib spreading) was started in our institution by a single surgeon experienced in postero-lateral open major resections and in other VATS procedures except lobectomies. We have retrospectively reviewed our first 4 years of experience in which 128 consecutive patients had undergone this approach, setting as a variable comparison of the results the presence of silicosis. Results: Between January 2012 to December 2015, 128 anatomical resections where attempted. Of these attempted major resections, 115 (90%) were successfully completed. Out of 128 patients 21 (16%) had a diagnosis of complex silicosis. The most frequent resection was left upper lobectomy. The mean surgical time was 178+/-65 min. The median postoperative chest drain time was 3 days and the median postoperative hospital stay time was 3 days. There were 25 (19%) minor complications 17 (68%) of them in the first year of experience, and 3 (2.3%) had major complications. Preoperative forced expiratory volume in one second (FEV1) less than 60%, diagnosis of chronic obstructive pulmonary disease (COPD) and silicosis have been predictive of postoperative minor complications. Conclusions: The uniportal VATS for major anatomic lung resections is reproducible and safe with good results when performed by surgeons experienced in both open major resections (anterior or postero-lateral thoracotomy), and multiport VATS minor procedures, even in highly complex cases such as patients with silicosis. Presence of silicosis should be taken into account as a predictive factor for postoperative complications. Therefore, overestimation of the benefits of the procedure in the patient selection process especially in the initial part of the experience must be avoided. PMID- 29399483 TI - A tale of surviving three consecutive cardiorespiratory arrests on table during a right sided pneumonectomy. AB - Background: Intraoperative cardiorespiratory arrest secondary to lower airway obstruction is often difficult to manage. We describe the management of one such technically challenging case of three consecutive cardiorespiratory arrests during a right pneumonectomy in a young boy. Methods: A 10 years boy with a large fleshy vascular endobronchial tumor (biopsy proven squamous papilloma), completely occluding the right main-stem bronchus with collapse-consolidation of underlying right lung, was posted for a right pneumonectomy. There were dense adhesions of lung to the parieties and the lung was completely damaged. Twenty five minutes into the surgery, patient started desaturating and the anesthetist was having difficulty in ventilating him. Check bronchoscopy showed endobronchial bleeding and the double lumen tube abutting the tumor. He was turned supine and CPR performed along with suctioning of blood and repositioning of tube. Patient revived and surgery continued. One and a half hour into the surgery the boy had a second cardiorespiratory arrest due to similar airway obstruction and managed in similar fashion. Lower lobectomy was speedily done to gain access to the hilum followed by quick completion pneumonectomy. Immediately following specimen removal, the patient had the third cardiorespiratory arrest and anesthetist was unable to ventilate the patient even after suctioning and repositioning of tube. With patient in lateral position, through the thoracotomy, right bronchial stump was opened and a quick bronchial intubation performed by the surgeon in chief. On opening the bronchus a tumor ball was seen occluding the left main bronchus, which probably got detached from the main tumor during pneumonectomy. Residual tumor was delivered out and the bronchial stump closed. Patient was transferred to ICU on ventilatory support. Results: Postoperatively he was extubated after 48 hours and was found to have no neurological deficit. Chest drain came out on POD2 and he was discharged on POD5. Conclusions: Promptly and methodically addressing this technical challenge helped us to prevent mortality. We also managed to avoid neurological sequelae of cardiorespiratory arrest. Learning point in this case is that when faced with a similar situation, it's important to stay calm and focused and to handle the challenge in a scientific and logical manner. PMID- 29399484 TI - Dr. Naruke, as a Father. PMID- 29399485 TI - How to step over the learning curve of laparoscopic spleen-preserving splenic hilar lymphadenectomy. PMID- 29399486 TI - Incorporating vacuum bell therapy into pectus excavatum treatment. AB - Vacuum bell therapy (VBT) was initially described over 100 years ago by Lange in 1910 but this treatment option has been substantially refined in the last decade largely due to the efforts, work, and collaboration of Dr. Frank-Martin Haecker with Eckart Klobe, the engineer who designed and produces the most commonly used vacuum bell today. PMID- 29399487 TI - Delta-shaped Billroth-I anastomosis in totally laparoscopic distal gastrectomy with D2 lymph node dissection for gastric cancer. AB - Background: It is attractive to complete laparoscopic reconstruction of digestive tract as a part of totally laparoscopic distal gastrectomy for patients of distal gastric cancer with its obvious advantage of minimal invasiveness. Delta-shaped Billroth-I anastomosis provides a feasible option for these patients, as we herein describe. Methods: A 61-year-old woman who was diagnosed with early gastric cancer (type III) of 1.0 cm in diameter at the gastric angle by gastroscopy underwent totally laparoscopic distal gastrectomy with D2 lymph node dissection and delta-shaped Billroth-I anastomosis. Results: The operation lasted for about 120 min with blood loss of about 50 mL. The patient recovered well and was discharged from hospital on postoperative day 11. Conclusions: Delta-shaped Billroth-I anastomosis by laparoscopic linear staplers is a safe procedure of alimentary reconstruction for totally laparoscopic distal gastrectomy and preferred for patients with early gastric cancer at gastric angle. PMID- 29399488 TI - Simultaneous laparoscopic distal gastrectomy (uncut Roux-en-Y anastomosis), right hemi-colectomy and radical rectectomy (Dixon) in a synchronous triple primary stomach, colon and rectal cancers patient. AB - Background: Gastric and colorectal cancers are both one of the most common tumors worldwide, while the morbidity of multiple synchronous primary tumors are really rare, and triple synchronous primary cancers are considered has a lower incidence. In this report, we demonstrate a rare case of synchronous triple primary cancers involving gastric, colon and rectal, and the laparoscopic operation procedure of the patient. Methods: A 49-year-old male diagnosed with synchronous triple primary gastric, colon and rectal cancer, underwent simultaneous laparoscopic distal gastrectomy (uncut Roux-en-Y anastomosis, D2), right hemi-colectomy and radical rectectomy (Dixon). Results: The operation lasts 305 min with about 300 mL blood lost. The patient discharged from hospital on the 12th day without any complication. Conclusions: Laparoscopic surgery is a safe and feasible way in synchronous gastrointestinal triple primary cancers. Nevertheless, because of the rare incidence, many details and specific condition should be considered during the peri-operative period of this multiple synchronous cancers patient. PMID- 29399490 TI - Diagnosis in chest wall deformities. PMID- 29399489 TI - Video-assisted thoracoscopy the total mesoesophageal excision and systematic en bloc mediastinal lymph node dissection. AB - A 59-year-old female presented with upper esophageal squamous cell carcinoma had swallowing disorders. We performed the total mesoesophageal excision (TME) and systematic en bloc mediastinal lymph node dissection via VATS. The surgery process was successful and the postoperative course was uneventful. A squamous cell carcinoma of stage T1aN0M0 was identified on pathological examination, and the postoperative examination of esophageal swallow diatrizoate meglumine and computed tomography (CT) scan confirmed no anastomosis fistula and no signs of recurrence. PMID- 29399491 TI - Prof. Thoralf Sundt: not just the error prevention, but also error management. PMID- 29399492 TI - Subxiphoid mediastinal lymphadenectomy. AB - Video-assisted thoracoscopic surgery (VATS) has experience an exponential growth in lung anatomic resections. Since its beginnings in early 90s with the conventional multiport VATS to the more recent uniportal approach, a continuous search for a less invasive procedure has fueled the development of minimally invasive thoracic surgery. In this sense, subxiphoid uniportal VATS has surge as a uniportal option that avoids damage to the intercostal nerve created in a transthoracic approach. In order for this technique to become as an acceptable choice for lung cancer, oncologic principles must be respected, including a feasible and safe mediastinal lymphadenectomy. Although technically more difficult than other VATS approaches, a complete lymphadenectomy is possible in the hands of expert VATS surgeons through a subxiphoid approach. PMID- 29399493 TI - Prof. Hiroyuki Oizumi: 3D CT simulation is very promising. PMID- 29399494 TI - Subxiphoid approach, a new prospective to see the minimally invasive thoracic surgery. PMID- 29399495 TI - Why perform uniportal video-assisted thoracic surgery?-multiple considerations. PMID- 29399496 TI - Positive video-assisted thoracoscopic pericardial window management of a right ventricle stab wound with minimally invasive technique. AB - This is a case report of a successful right ventricle stab wound suture through a video-assisted pericardial thoracoscopic window, avoiding the need of a thoracotomy diminishing its associated risks, morbidity and costs. A 22-year-old patient was admitted to the emergency room with a stab wound on the left side of his chest, the patient showed symptoms of dyspnea and signs of pulmonary hypoventilation on his left lung, a chest tube were placed on the affected side with an improvement on his symptoms. A video-assisted thoracoscopic pericardial window (VATPW) was performed within the next 24 hours to rule out underlying heart wound. A VATPW shows a 1 cm right ventricle wound which was treated through the same portals avoiding a thoracotomy. The left chest tube was removed 48 hours after de procedure and the patient underwent a control echocardiogram, with no abnormalities reported and no symptoms of dyspnea, respiratory distress or palpitation the patient was subsequently discharged. The VATPW is a feasible and safe procedure to rule out underlying heart injury in individualized cases and it provides a minimally invasive treatment option in selected patients avoiding major surgery like thoracotomy or sternotomy and the added morbidity that carry with them. PMID- 29399497 TI - Transition from thoracotomy to uniportal video-assisted thoracic surgery in non small cell lung cancer-the Oslo experience. AB - Thoracoscopic surgery has been applied in medicine for more than 100 years. Still it is only within the last decade that it has gained momentum as a method in non small cell lung cancer (NSCLC) surgery. Several approaches have been published, one of the more resent being uniportal video-assisted thoracic surgery (VATS). In this article we describe the transition from thoracotomy to uniportal VATS in our institution, the last step to uniportal VATS exemplified with two cases performed during our masterclass held in May 2016. PMID- 29399499 TI - Dr. Diego Gonzalez-Rivas: uniportal video-assisted thoracic surgery has become increasingly important. PMID- 29399498 TI - Subxiphoid single-port video-assisted thoracoscopic surgery. AB - Background: We report the feasibility and safety of chest surgery through the subxiphoid single port approach based on our preliminary experience. Methods: From December 2013 till January 2016, 39 patients underwent 40 thoracoscopic surgeries via a 3- to 4-cm subxiphoid single incision. A sternal lifter was applied for better entrance and working angle. A zero-degree deflectable scope was preferred. The technique for anatomic resection was similar to that in the traditional single-port approach. Patient characteristics and demographic data were analyzed. Results: There were 29 females and 10 males, with a median age of 56 years. Indication for surgery included 24 patients with primary lung cancer, eight with lung metastases, two with benign lung lesions, one with bilateral pneumothorax, and five with mediastinal tumors. Surgeries included lobectomy in 21, segmentectomy in five, wedge resection in nine, and mediastinal surgery in five patients. There was no surgical mortality. Complications (10%, 4 in 40) included postoperative bleeding in one patient, chylothorax in one patient, and transient arrhythmia in the early learning curve in two patients. Conclusions: Our results indicated that subxiphoid single-incision thoracoscopic pulmonary resection could be performed safely but under careful patient selection with modification of instruments. Moreover, having a previous single-port incision experience was crucial. Major limitations of this approach included more frequently encountered instrument fighting; interference of left-side procedure related to heartbeat and radical mediastinal lymph node (LN) dissection; and the ability to handle complex conditions, such as anthracotic LNs, diffuse adhesion, and major bleeding. PMID- 29399500 TI - A combination of transanal minimally invasive surgery and transanal technique to facilitate suturing during transanal minimally invasive surgery. AB - Transanal minimally invasive surgery (TAMIS) is an effective option for the local excision of benign, non-invasive rectal lesions, or selected early stage rectal cancers. However, the suturing encountered in TAMIS remains technically challenging. A combination of TAMIS and transanal approach to suturing is demonstrated to address this challenge. A 64-year-old female with a T1N0 adenocarcinoma located in the anterior mid-rectum underwent TAMIS for resection of the lesion. Total operative time was 91 minutes. Free peritoneal defect was closed in two layers. The patient was discharged on postoperative day 1. Final pathology revealed a 0.7 cm T1 well-differentiated adenocarcinoma 0.8 cm from the closest resection margin. The patient remains free of systemic or local recurrence at 24 months. TAMIS is a safe and effective option for removal of benign rectal lesions or selected low grade T1 adenocarcinomas of the rectum. A hybrid TAMIS and transanal approach to suturing may often easily address the technical challenge of pure laparoscopic suturing in TAMIS. PMID- 29399501 TI - Video-assisted thoracoscopic right upper sleeve lobectomy for fixated interlobar lymph node. AB - We report a 59-year-old male who underwent video-assisted thoracoscopic right upper lobe sleeve lobectomy because of a fixated interlobar lymph node. A squamous cell carcinoma of stage T3N1M0 was disclosed on pathological examination. The bronchial anastomosis was performed using a running suture with 3-0 prolene. The postoperative course was uneventful. The patient has been doing well for 18 months. PMID- 29399502 TI - Laparoscopic resection of gastric wall tumor. AB - Laparoscopic resection of gastric wall tumor is commonly performed nowadays. The exact surgical procedure was decided according to the location, size and morphology of the tumor. In this video, we performed a laparoscopic resection of a 5cm tumor located at distal posterior gastric wall near the greater curvature. Technical consideration was discussed. PMID- 29399503 TI - Learning curve and subxiphoid lung resections most common technical issues. AB - Background: Subxiphoid uniportal video-assisted thoracic surgery (SVATS) for major lung resections is a new approach. Clinical evidence is lacking. The aim of this article is to describe the learning curve of the 200 selected patients who underwent uniportal subxiphoid lobectomy or segmentectomy by subxiphoid midline incision, and with the lessons learned from this early experience in SVATS and from the experience with transthoracic uniportal VATS we sought to compile "tips and tricks" for managing the multiple intraoperative technical difficulties that can arise during the SVATS and help to set the recommendations for a SVATS program. Methods: We describe the learning curve of the first 200 selected patients who underwent uniportal subxiphoid lobectomy or segmentectomy by subxiphoid midline incision From September 2014 with early-stage non-small cell lung carcinoma (NSCLC) and benign disease. We examine the rate of conversion and the operating time comparing group one (first 100 cases) with group two (subsequent 100 cases). Results: Of the 200 consecutive selected cases (72 males, 128 females) with a mean age of 57.4+/-9 years, underwent either uniportal subxiphoid lobectomy or segmentectomy 136 were lobectomies and 64 were segmental resections The mean operating time was 170+/-45 mins; the average and after the case 86 the rate of the operating time appears to be similar. The conversion rate decrease from 13% in group one to 8% in group two. Conclusions: There is a gradual reduction in the operating time and rate conversion with increasing experience. Lessons from our initial experience in the learning curve period in SVATS helps to create this trouble shooting guide that offers "tips and tricks" to both avoid and manage numerous intra-operative technical difficulties that commonly arise during the SVATS initial experience. PMID- 29399504 TI - Robotic subxiphoid thymectomy. AB - When endoscopic surgery is indicated for myasthenia gravis and thymomas, most institutions use a lateral thoracic approach that includes robot-assisted surgery. However, with the unilateral thoracic approach, it can be difficult to ensure the operative field in the neck and difficult to identify the location of the contralateral phrenic nerve. In 2015, we reported on a robotic subxiphoid thymectomy (RST) in which the camera is inserted from the subxiphoid incision and robotic forceps are inserted from the bilateral intercostal spaces. With this approach, a camera is inserted into a subxiphoid incision which is the midline of the body and a surgical field comparable to that in a median sternotomy can be achieved. This makes it easier to identify the location of the bilateral phrenic nerves and offer the good visualization in the neck area. Here we report on our RST techniques. For a thymectomy without suturing, a subxiphoid, single-port thymectomy is performed because it is minimally invasive. In patients who require suturing, such as with a pericardial patch closure, RST is selected. The RST has excellent operability when performed with a robot, making it suitable for more difficult procedures. In the future, we believe that a robot-assisted thymectomy might become the standard method. PMID- 29399505 TI - Endoscopic ultrasound of pancreatic lesions. AB - Endoscopic ultrasound (EUS) is a well-established tool for the evaluation of pancreatic lesions. Due to the closer proximity of EUS to the pancreas, EUS offers a high sensitivity for detection of small pancreatic mass and is the preferred modality for obtaining tissue for diagnosis of pancreatic mass. Contrast-enhanced EUS and/or elastography provide additional information to the fundamental B-mode ultrasound images, leading to more accurate diagnosis. The aim of this video-article is to show the different steps in performing EUS on pancreatic lesions and to provide some tips and tricks to improve and facilitate the execution of EUS on pancreatic lesions. PMID- 29399506 TI - Beyond cardiac surgery: the expanded education of a false god. PMID- 29399507 TI - Laparoscopic radical antegrade modular pancreatosplenectomy. AB - Although laparoscopic distal pancreatectomy is widely accepted for benign or borderline malignant pancreatic diseases, its application for pancreatic ductal adenocarcinoma (PDAC) remains controversial. Several recent reports have shown that laparoscopic surgery, for the treatment of PDAC, is associated with similar postoperative complications and survival outcomes compared with open surgery, and offers several advantages, particularly shorter hospital stay and less blood loss. However, potential risk of bias cannot be excluded because these results were obtained in retrospective studies. More importantly, it is unclear whether the extent of surgical resection is comparable between laparoscopic and open distal pancreatectomy. The aim of this video article is to show the technical feasibility of laparoscopic surgery to reproduce open radical antegrade modular pancreatosplenectomy (RAMPS) in terms of the extent of surgical resection. PMID- 29399509 TI - Prof. Diego Gonzalez-Rivas & Prof. Alan Sihoe: what do we need to think about uniportal video-assisted thoracoscopic surgery? PMID- 29399508 TI - Uniportal subxiphoid video-assisted thoracoscopic thymectomy. AB - With a uniportal subxiphoid video-assisted thoracoscopic surgery (VATS) thymectomy, the thymus is not accessed through the ribs, which avoids intercostal nerve damage. Furthermore, compared to a VATS thymectomy via the lateral chest, decreased use of postoperative analgesics (lower doses and shorter duration), decreased blood loss, and shorter surgical duration and hospital stay have been reported. Here we report our surgical method and solutions for a uniportal subxiphoid VATS thymectomy. A uniportal subxiphoid VATS thymectomy is indicated for patients with myasthenia gravis and anterior mediastinal tumors who do not require surgical suturing. The operator stands between the patient's legs and the scopist stands to the right of the patient to operate the camera scope. To begin with, a 3-cm transverse incision was made along Langer's lines 1 cm caudal below the xiphoid process. The CO2 insufflation is performed in the mediastinum at 8 mmHg. The pericardial adipose tissue and thymus are detached from the pericardium in an anterior manner from the bilateral phrenic nerves. The resected thymus is placed in a pouch in the mediastinum and removed from the body through the subxiphoid incision. The subxiphoid approach is highly beneficial for the patient in that it results in superior esthetic outcomes considering that there is no sternotomy and no intercostal nerve damage; thus, it is a surgical procedure that surgeons should learn. PMID- 29399510 TI - Subxiphoid uniportal video-assisted bilateral surgery: right upper lobectomy and left upper wedge resection S3. AB - Traditional approach of bilateral lesions usually involves bilateral approaches instead of classical thoracotomy or video-assisted thoracoscopic surgery (VATS) surgery, and often at two different times. During visit of Dr. Gonzalez Rivas at Master Class to Malaga, we performed right upper lobectomy and S3 wedge resection left upper lobe of a two synchronous bilateral lung lesions case with subxiphoid single incision approach. We are reporting the first case of a lobectomy combined with a wedge resection performed through an uniportal subxiphoid bilateral VATS in Spain. PMID- 29399511 TI - Video-assisted thoracoscopic surgery lobectomy using "the caudal approach": results and evolution. AB - Background: Video-assisted thoracoscopic surgery (VATS) has become a common surgical approach in the diagnosis and treatment of lung and mediastinal diseases. In this study, we reported our current experience of thoracoscopic surgery using a new caudal position technique for anatomical lung resections and compared it with the standard anterior VATS technique. Methods: From January 2016 to October 2017, 92 consecutive patients with lung cancer underwent VATS lobectomy. Among these, 34 patients were treated by conventional anterior three portal VATS lobectomy, and 58 patients were treated using the caudal three port VATS lobectomy. The mean operative time, conversion rate, hospital stay, post operative drainage, reoperation, post operative pain were compared between each group. Results: No differences between the two groups are showed in terms of surgical time, post-operative drainage, incidence of prolonged air leaks and post operative pain. Conclusions: The caudal approach to major pulmonary resection of thoracoscopic lobectomy results in a reliable and comfortable procedure for the surgeon. Once demonstrated the reliability of the VATS lobectomy with three accesses using the caudal position, we are starting to standardize biportal and uniportal VATS with the surgeon in the caudal position. PMID- 29399512 TI - Thoracoscopic anatomic lung resections for cancer in patients with previous cardiac surgery. AB - We reported the feasibility of thoracoscopic anatomical resections for lung cancer in four consecutive patients undergoing previous cardiac surgeries as coronary artery by-pass graft (CABG) using left internal mammary artery (LIMA) graft (n=1), cardiac transplantation (n=2), and mitral valve replacement (n=1). A three-port approach was used in all patients but one where an uniportal approach was adopted. Lobectomy was carried out in two patients; left upper three segmentectomy and upper bilobectomy in the other two. All procedures were successfully performed without needing conversion. No intra-operative, post operative morbidity and mortality were recorded. At last follow-up, all patients were alive without recurrence but one who had cerebral metastasis. Thoracoscopic lung resection after cardiac surgery is a feasible but complex procedure that should be performed in centres having a cardiac surgery team ready to operate in case of cardiac complications. PMID- 29399513 TI - Thoracoscopic lobectomy after induction therapy-a paradigm shift? AB - Video-assisted thoracoscopic approaches (or VATS) have gained significant momentum in the management of locally advanced NSCLC in the current era. Accrual of experiences and concurrent improvements in instrumentation and video technology have further enhanced its role in patients with stage IIIA (N2) non small cell lung cancer (NSCLC). However, substantial controversy exists around the notion of mediastinal staging and restaging after induction therapy, the utility of induction chemotherapy versus chemoradiation for N2 disease, and subsequent role of video-assisted thoracoscopic surgery (VATS) lobectomy following induction therapy. This perspective will closely examine these issues in the context of existing guidelines and contemporary studies. PMID- 29399515 TI - Thrombosis. PMID- 29399514 TI - Contributions of Noncanonical Smoothened Signaling During Embryonic Development. AB - The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein-independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease. PMID- 29399516 TI - Below-knee deep vein thrombosis (DVT): diagnostic and treatment patterns. AB - Background: Guidelines are lacking for isolated below-knee deep vein thrombosis (BKDVT). The American College of Chest Physicians (ACCP) suggests anticoagulation only if symptoms are severe, otherwise surveillance with follow-up ultrasound in 2 weeks is recommended. Yet clinical practice remains highly variable. Little is known about the natural history of BKDVT and how to best manage these patients. Methods: A retrospective analysis was conducted of medical records from 2014 2016. Risk factors were assessed such as age, gender, malignancy, recent surgery, and history of DVT. Treatment decisions and outcomes were identified. Radiology reports were graded for clarity. Chi-square and logistic regression were used to correlate risk factors with outcomes and determine odds of treatment. Results: New isolated BKDVT was identified in 102 patients. Patients were symptomatic or had previous pulmonary embolism (PE) or DVT in all cases. Eighteen were positive for PE at diagnosis (17.6% of all patients or 62.1% with chest CT). Malignancy was independently associated with PE (P=0.015); no other risk factors were significant. Treatment was not associated with clinical risk factors. The language used for radiology reports was highly variable and was associated with the decision to treat with anticoagulation. One hundred percent were treated (n=24) when the report stated "positive DVT" and 89.2% (n=58) were treated after an objective description without the word "DVT" (P=0.01). Treatment was much less likely if the report described BKDVT anatomically but was said to be "negative for DVT" (P<0.001). A total of 86.3% (n=88) of all patients were treated, compared to 46.2% (n=6) of patients in this group (n=13). IVC filters were placed in 3 patients. Of the 14 untreated patients, 5 received surveillance, 3 developed new proximal DVT, and none developed PE. Conclusions: About 90% of patients diagnosed with BKDVT received anticoagulation after the initial diagnosis. Surveillance was not commonly recommended and is likely underutilized. Radiology reporting was highly variable and correlated with clinical treatment decisions, whereas other clinical risk factors did not. Describing BKDVT findings only in terms of being "positive" or "negative" for DVT may be inadequate. PMID- 29399517 TI - Neutrophil extracellular traps are increased in cancer patients but does not associate with venous thrombosis. AB - Background: A single center, prospective tissue-based study was conducted to investigate an association between neutrophil extracellular traps (NETs) and venous thromboembolic disease in patients with malignancy. Methods: Plasma was collected from 65 patients in which 27 were cancer patients and 38 were age matched non-cancer patients. Plasma NETs, circulating free DNA (cfDNA), DNase-1, endonuclease-G, endonuclease activity and thrombin-antithrombin III (TAT) complex levels was quantified. Laboratory values were also compared. Additionally, NETs detection and quantification was performed with fluorescent immunohistochemistry (IHC) in tissue-banked tumor sections and fresh human venous thrombus derived from cancer patients. Results: Plasma samples from cancer patients contained higher levels of nucleosomes (P=0.0009) and cfDNA (P=0.0008) compared to the non cancer group. Western blot analysis revealed significantly lower DNase-1 protein levels (P=0.016) that paralleled lower nuclease activity (P=0.03) in plasma samples from cancer patients compared to non-cancer patients. Thrombus tissue from cancer patients and tumor tissue from liver and lung cancer also showed marked levels of NETs. However, increased levels of NETs in cancer patients did not correlate with TAT complex activation or prevalence of venous thrombosis in cancer patients. Conclusions: Further studies are warranted to determine the role of NETs as a procoagulant in human thrombosis. PMID- 29399518 TI - Risk factors for stent graft thrombosis after transjugular intrahepatic portosystemic shunt creation. AB - Background: To identify risk factors of stent graft thrombosis after transjugular intrahepatic portosystemic shunt (TIPS) creation. Methods: Patients who underwent TIPS creation between June 2003 and January 2016 and with follow-up assessing stent graft patency were included (n=174). Baseline comorbidities, liver function, procedural details and follow-up liver function tests were analyzed in association with hazards of thrombosis on follow-up. Competing risk cox regression models were used considering liver transplant after TIPS creation as the competing risk variable. Results: One-, 2- and 5-year primary patency rates were 94.1%, 91.7% and 78.2%, respectively. Patient age [sub-hazard ratio (sHR): 1.13; P=0.001], body mass index (BMI) <30 (sHR: 33.08; P=0.008) and a higher post TIPS portosystemic pressure gradient (sHR: 1.14; P=0.023) were significantly associated with TIPS thrombosis in multivariate analysis. A higher rate of TIPS thrombosis was observed in those for whom the procedure was clinically unsuccessful (P=0.014). A significant increase in incidence of thrombosis was noted with increasing tertiles of post-TIPS portosystemic gradients (P value for trend=0.017). Conclusions: Older age, lower BMI and higher post-TIPS portosystemic gradients were associated with higher hazards of shunt thrombosis after TIPS creation using stent grafts. Higher rates of shunt thrombosis were seen in patients for whom TIPS creation was clinically unsuccessful. The association between TIPS thrombosis and higher post-TIPS portosystemic gradients may indicate impaired flow through the shunt, a finding which may be technical or anatomic in nature and should be assessed before procedure completion. PMID- 29399519 TI - May-Thurner: diagnosis and endovascular management. AB - Common left iliac vein compression, otherwise known as May-Thurner (MT), is an anatomical risk factor for lower extremity deep vein thrombosis (DVT). MT refers to chronic compression of the left iliac vein against the lumbar spine by the overlying right common iliac artery. The compression may be asymptomatic. The syndrome is a clinical spectrum of physical findings and history plus the lesion. It is characterized by the varying degrees of venous hypertension. This can be non-thrombotic, combined with acute DVT or post-thrombotic. Traditionally, acute DVT was treated with standard anticoagulation and sometimes, thrombectomy. However these measures do not address the underlying culprit lesion of mechanical compression. Furthermore, if managed only with anticoagulation, patients with residual thrombus are at risk for developing recurrent DVT or post-thrombotic syndrome (PTS). Both retrospective and prospective studies have shown that endovascular management should be the preferred approach to dissolve proximal thrombus and to also treat the underlying compression with endovascular stent placement. PMID- 29399521 TI - Thrombosis in cancer patients: etiology, incidence, and management. AB - Venous thromboembolism (VTE) is the second most common cause of mortality in cancer patients. The mechanisms of cancer-associated thrombosis (CAT), much like cancer itself, are multi-factorial and incompletely understood. Cancer type, stage, tumor-derived factors and genetics all affect CAT risk. Furthermore, cancer therapies as well as the indwelling vascular devices through which these therapies are delivered can increase the risk for CAT. In this review, we summarize mechanisms of hypercoagulability in cancer patients, patterns of thrombosis associated with cancer, current guidelines for the diagnosis and management of CAT, and important considerations regarding the placement of implantable vascular devices in the care of cancer patients with VTE. PMID- 29399520 TI - Tumor thrombus: incidence, imaging, prognosis and treatment. AB - Intravascular tumor extension, also known as tumor thrombus, can occur in many different types of cancer. Those with the highest proclivity include Wilm's tumor, renal cell carcinoma (RCC), adrenal cortical carcinoma (ACC) and hepatocellular carcinoma (HCC). The presence of tumor thrombus markedly worsens prognosis and impacts treatment approach. Imaging plays a key role in its diagnosis. Endovascular methods also play a large role in treatment. PMID- 29399522 TI - Can thrombus age guide thrombolytic therapy? AB - Venous thrombosis (VT) is a common yet complex clinical condition that has shown minimal alteration in clinical management for decades. It is well known that thrombus evolves structurally over time, with complex changes resulting from the interplay between coagulation factors, cytokines, leukocytes and a myriad of other factors. Our current treatment options are most effective in the acute thrombus, which is composed predominantly of a loose mesh of fibrin and red blood cells (RBCs), making current anticoagulation therapies and thrombolytics quite effective in treatment. Later stages of thrombus are more cellular containing leukocytes, and develop a fibrotic collagenous framework that is more resistant to our current treatments. Understanding the biology of an evolving thrombus will allow us to tailor our treatment and optimize outcomes, as well as focus on novel therapies for the treatment of chronic thrombus. Given the morbidity and mortality of both post thrombotic syndrome (PTS) in patients with deep VT, as well as chronic thromboembolic pulmonary hypertension (CTEPH) in patients with pulmonary embolism (PE), new and innovative therapies must continue to be explored to help prevent these potentially devastating conditions. PMID- 29399523 TI - Animal models of venous thrombosis. AB - Venous thrombosis (VT) is a prevalent clinical condition with significant adverse sequela or mortality. Anticoagulation and pharmacologic or pharmacomechanical thrombolytic therapies are the mainstays of VT treatment. An understanding of thrombosis biology will allow for more effective VT-tailored diagnosis and therapy. In vivo models of thrombosis provide indispensable tools to study the pathogenesis of thrombus formation and to evaluate novel therapeutic or preventive adjuncts for VT management or prevention. In this article, we review the most prominent in vivo models of VT created in rodents and swine species and outline how each model can serve as a useful tool to promote our understanding of VT pathogenesis and to examine novel therapies. PMID- 29399524 TI - Statins as a preventative therapy for venous thromboembolism. AB - The anti-inflammatory effects of statins have likely not been used to their fullest extent, particularly in reducing venous thromboembolic events. Current therapy for thrombotic events hinges on anticoagulation via heparin, warfarin or new oral anticoagulants. Interventional procedures with thrombectomy may also play a critical role. Unfortunately, thrombotic events can occur and recur despite meticulous anticoagulation therapy. Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE), two complicated and prevalent diseases that can cause chronic disease states such as post-thrombotic syndrome (PTS). In 2009 the JUPITER trial demonstrated that rosuvastatin may be effective when dealing with vascular inflammation by providing an anti inflammatory effect. Multiple subsequent studies have looked at this association with some promising findings. The mechanism of action for statins is not entirely understood but there has been a variety of proposals and subsequent testing of inflammatory biomarkers. Additional prospective trials are needed to confirm the possible benefit of VTE reduction through an anti-inflammatory effect, but if this can be shown then statins may become a safe adjunctive therapy for VTE prevention. PMID- 29399525 TI - Transplant artery thrombosis and outcomes. AB - Post-transplantation allograft arterial thrombosis is a well-recognized complication associated with solid organ transplantation. Much of the literature is centered on liver and kidney transplantation, which will therefore serve as the principle basis for this review, with a brief discussion on pancreas transplantation and associated arterial complications. The number of solid organ transplants has been steadily increasing over the past decade in parallel with growing demand for organs and expansion of the transplantation criteria for both donors and recipients. This increase has been accompanied by a number of innovative medical advances and surgical techniques, as well as improved imaging that has allowed for thoughtful exploration of vascular anatomic variants and the possibilities for transplant with which they are associated. It has also been accompanied by a growing field of behavioral research, as potential recipients must weigh the risk of accepting certain organs based on perceived outcomes that may differ according to the quality of the underlying organ. Improvements in imaging technology have brought greater sensitivity to detecting arterial complications in post-operative surveillance examinations and have allowed for further development of tailored endovascular and surgical interventions for transplant-associated vascular complications. This review will focus on post transplantation solid organ allograft artery thrombosis, including discussion of risk factors, diagnostic imaging, natural history, and therapeutic options. PMID- 29399526 TI - Catheter-directed thrombolysis of deep vein thrombosis: literature review and practice considerations. AB - Deep vein thrombosis (DVT) is a major health problem worldwide. The risk of pulmonary embolism following DVT is well established, but the long-term vascular sequelae of DVT are often underappreciated, costly to manage, and can have extremely detrimental effects on quality of life. Treatment of DVT classically involves oral anticoagulation, which reduces the risk of pulmonary embolism but does not remove the clot. Anticoagulation therefore does little to prevent the venous damage and scarring that occurs following DVT, leaving the patient at risk for permanent venous insufficiency and development of post-thrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) is a minimally invasive endovascular treatment that is used as an adjunct to anticoagulation. CDT lowers the risk of PTS by reducing clot burden and protecting against valvular damage. A catheter is advanced directly to the site of thrombosis under fluoroscopy followed by a slow, prolonged infusion of a relatively low dose of thrombolytic agent. CDT restores venous patency faster than anticoagulation, which hastens the relief of acute symptoms. Adjunctive CDT modalities have become increasingly popular among interventional radiologists, allowing for additional mechanical thrombectomy or ultrasound-enhanced thrombolysis at the time of catheter placement. These pharmacomechanical CDT (PCDT) techniques have the potential to reduce treatment time and associated healthcare costs. Numerous observational and retrospective studies have consistently shown a benefit of CDT plus anticoagulation over anticoagulation alone for prevention of PTS. Patients with long life expectancy and acute thrombosis involving the iliac and proximal femoral veins (iliofemoral DVT) have the greatest benefit from CDT, which may decrease the risk of PTS and/or decrease the severity of PTS symptoms if they do occur. Randomized controlled trials remain limited but generally support the observational data. CDT also plays an important role in those with acute limb-threatening venous occlusion or severe symptoms from DVT. Although adverse outcomes are rare, a potential devastating outcome is intracranial bleeding. While the available literature suggests the risk of serious morbidity from bleeding is quite rare, the absolute risk of bleeding is not clear and will require outcomes data from randomized trials. Future studies should also examine the cost-effectiveness of CDT for PTS prevention, particularly with respect to quality-adjusted life years, and compare the effectiveness of available PCDT devices. PMID- 29399527 TI - Elastography techniques in the evaluation of deep vein thrombosis. AB - Deep venous thrombosis (DVT) is a significant medical problem with an incidence of 1 in 1,000 adults and greatly reduces quality of life through post-thrombotic syndrome. Treatment choice for DVT can be influenced by the age of the clot. While new endovascular catheter techniques treat venous clots to potentially prevent post-thrombotic syndrome, they require improved imaging techniques to accurately determine clot age. This review investigates experimental and clinical evidence of elastography techniques for aging DVT. Strain elastography and shear wave elastography are the most common techniques to age thrombus. These elastography techniques can distinguish between acute and chronic clots by characterizing tissue stiffness. When clot age cannot be determined with ultrasound duplex analysis, elastography may offer a helpful adjunct. However, further investigation is required to validate accuracy and reproducibility for clinical implementation of this novel technique. PMID- 29399529 TI - Re-intervention for occluded iliac vein stents. AB - Iliac vein stenting has become more frequent with improved diagnostic capabilities of intra-vascular ultrasound (IVUS) for recognizing May-Thurner syndrome, chronic venous insufficiency (CVI) and thrombus. In this manuscript, we discuss the reasons for initial stenting, with long-term outcomes and some of the associated pitfalls. The best techniques for re-intervention when iliac stents become occluded will also be discussed. PMID- 29399528 TI - Anti-fouling strategies for central venous catheters. AB - Central venous catheters (CVCs) are ubiquitous in the healthcare industry and carry two common complications, catheter related infections and occlusion, particularly by thrombus. Catheter-related bloodstream infections (CRBSI) are an important cause of nosocomial infections that increase patient morbidity, mortality, and hospital cost. Innovative design strategies for intravenous catheters can help reduce these preventable infections. Antimicrobial coatings can play a major role in preventing disease. These coatings can be divided into two major categories: drug eluting and non-drug eluting. Much of these catheter designs are targeted at preventing the formation of microbial biofilms that make treatment of CRBSI nearly impossible without removal of the intravenous device. Exciting developments in catheter impregnation with antibiotics as well as nanoscale surface design promise innovative changes in the way that physicians manage intravenous catheters. Occlusion of a catheter renders the catheter unusable and is often treated by tissue plasminogen activator administration or replacement of the line. Prevention of this complication requires a thorough understanding of the mechanisms of platelet aggregation, signaling and cross linking. This article will look at the advances in biomaterial design specifically drug eluting, non-drug eluting, lubricious coatings and micropatterning as well as some of the characteristics of each as they relate to CVCs. PMID- 29399530 TI - Hemostasis and nanotechnology. AB - Hemorrhage accounts for significant morbidity and mortality. Various techniques have been employed to augment hemostasis from simple tourniquets to self assembling nanoparticles. A growing understanding of the natural clotting cascade has allowed agents to become more targeted for potential use in different clinical scenarios. This review discusses current and developing hemostatic techniques, including matrix agents, external agents, biologically inspired agents, and synthetic and cell-derived nanoparticles. PMID- 29399531 TI - Deep vein thrombosis: pathogenesis, diagnosis, and medical management. AB - Deep vein thrombosis (DVT) is a major preventable cause of morbidity and mortality worldwide. Venous thromboembolism (VTE), which includes DVT and pulmonary embolism (PE), affects an estimated 1 per 1,000 people and contributes to 60,000-100,000 deaths annually. Normal blood physiology hinges on a delicate balance between pro- and anti-coagulant factors. Virchow's Triad distills the multitude of risk factors for DVT into three basic elements favoring thrombus formation: venous stasis, vascular injury, and hypercoagulability. Clinical, biochemical, and radiological tests are used to increase the sensitivity and specificity for diagnosing DVT. Anticoagulation therapy is essential for the treatment of DVT. With few exceptions, the standard therapy for DVT has been vitamin K-antagonists (VKAs) such as warfarin with heparin or fractionated heparin bridging. More recently, a number of large-scale clinical trials have validated the use of direct oral anticoagulants (DOACs) in place of warfarin in select cases. In this review, we summarize the pathogenesis, diagnosis, and medical management of DVT, with particular emphasis on anticoagulation therapy and the role of DOACs in the current treatment algorithm. PMID- 29399532 TI - Paget-Schroetter syndrome: treatment of venous thrombosis and outcomes. AB - Thoracic outlet syndrome (TOS) is a rare clinical entity with many etiologies. Venous thoracic outlet syndrome (VTOS), also called Paget-Schroetter syndrome (PSS), is a primary "effort" thrombosis. Here we will focus on the pathophysiology, anatomy, clinical presentation, treatments, and outcomes of VTOS. Treatment involves anticoagulation, catheter-directed thrombolysis, and surgical decompression. Early diagnosis and treatment can improve symptoms and quality of life. PMID- 29399533 TI - Pathogenesis of thrombosis: cellular and pharmacogenetic contributions. AB - Our understanding of thrombosis formation has evolved significantly ever since physician Rudolf Virchow proposed his "triad" theory in 1856. Modern science has elucidated the mechanisms of stasis, hypercoagulability, and endothelial dysfunction. Today, we have a firm understanding of the key molecular factors involved in the coagulation cascade and fibrinolytic system, as well as the underlying genetic influences. This knowledge of cellular and genetic contributors has been translated into diverse pharmaceutical interventions. Here, we examine the molecular and cellular mechanisms of thrombosis and its associated pathologies. We also review the current state of pharmacologic interventions, including pro- and anti-thrombotics, direct oral anticoagulants, and anti platelet therapies. The pharmacogenetic factors that guide clinical decision making and prognosis are described in detail. Finally, we explore new approaches to thrombosis drug discovery, repurposing, and diagnostics. We argue that network biology tools will enable a systems pharmacology revolution in the next generation of interventions, facilitating precision medicine applications and ultimately leading to improved patient outcomes. PMID- 29399534 TI - Hemodialysis access thrombosis. AB - For the over 400,000 patients in the United States dependent on hemodialysis, arteriovenous (AV) access thrombosis may lead to missed dialysis sessions, inpatient admissions and the need for placement of temporary dialysis catheters. It is also the leading cause of permanent access loss. Percutaneous declotting is generally preferred over surgical thrombectomy. Various percutaneous approaches can be employed including the lyse-and-wait technique, thromboaspiration, pulse spray aided pharmacomechanical thrombolysis, and use of mechanical thrombectomy device. PMID- 29399535 TI - Deep venous thrombosis in pregnancy: incidence, pathogenesis and endovascular management. AB - Deep venous thrombosis (DVT) during pregnancy is associated with high mortality, morbidity, and costs. Pulmonary embolism (PE), its most feared complication, is the leading cause of maternal death in the developed world. DVT can also result in long-term complications that include postthrombotic syndrome (PTS) adding to its morbidity. Women are up to 5 times more likely to develop DVT when pregnant. The current standard of care for this condition is anticoagulation. This review discusses the epidemiology, pathogenesis, prophylaxis and diagnosis of DVT during pregnancy, and then focuses on endovascular treatment modalities. Inferior vena cava (IVC) filter placement and pharmacomechanical catheter directed thrombolysis (PCDT) in the pregnant patient are discussed, as well as patient selection criteria, and complications. PMID- 29399536 TI - Rationale for catheter directed therapy in pulmonary embolism. AB - Pulmonary embolism (PE) is a widespread health concern associated with major morbidity and mortality. Catheter directed therapy (CDT) has emerged as a treatment option for acute PE adding to the current potential options of systemic thrombolysis or anticoagulation. The purpose of this review is to understand the rationale and indications for CDT in patients with PE. While numerous studies have shown the benefits of systemic thrombolysis compared to standard anticoagulation, these are balanced by the increased risk of major bleeding. With this in mind, CDT has the potential to offer the benefits of systemic thrombolysis and in theory, a reduced risk of bleeding. This article will review current treatment guidelines in both massive and submassive PE evaluating both short and long term benefits. The role of CDT will be highlighted, with an emphasis on efficacy and safety. PMID- 29399537 TI - Bioengineered in vitro models of thrombosis: methods and techniques. AB - Thrombosis is a prevailing vascular disorder that has been historically studied in vivo with conventional animal models. Here we review recent advances in methods and techniques that allow for engineering of biomimetic in vitro models of thrombosis, usually combined with microfluidic devices, termed thrombosis-on-a chip systems, to reproduce such vascular pathology outside living organisms. These human cell-based thrombosis-on-a-chip platforms recapitulate the important characteristics of native thrombosis in terms of vascular structures, extracellular matrix properties, cellular composition, and pathophysiology, making them enabling in vitro models to study this important class of vascular disorders as well as to develop personalized treatment regimens. PMID- 29399538 TI - Impact of RAD51C-mediated Homologous Recombination on Genomic Integrity in Barrett's Adenocarcinoma Cells. AB - BACKGROUND: In normal cells, RAD51-mediated homologous recombination (HR) is a precise DNA repair mechanism which plays a key role in the maintenance of genomic integrity and stability. However, elevated (dysregulated) RAD51 is implicated in genomic instability and is a potential target for treatment of certain cancers, including Barrett's adenocarcinoma (BAC). In this study, we investigated genomic impact and translational significance of moderate vs. strong suppression of RAD51 in BAC cells. METHODS: BAC cells (FLO-1 and OE33) were transduced with non targeting control (CS) or RAD51-specific shRNAs, mediating a moderate (40-50%) suppression or strong (80-near 100%) suppression of the gene. DNA breaks, spontaneous or following exposure to DNA damaging agent, were examined by comet assay and 53BP1 staining. Gene expression was monitored by microarrays (Affymetrix). Homologous recombination (HR) and single strand annealing (SSA) activities were measured using plasmid based assays. RESULTS: We show that although moderate suppression consistenly inhibits/reduces HR activity, the strong suppression is associated with increase in HR activity (by ~15 - >= 50% in various experiments), suggesting activation of RAD51-independent pathway. Contrary to moderate suppression, a strong suppression of RAD51 is associated with a significant induced DNA breaks as well as altered expression of genes involved in detection/processing of DNA breaks and apoptosis. Stronger RAD51 suppression was also associated with mutagenic single strand annealing mediated HR. Suppression of RAD51C inhibited RAD51-independent (SSA-mediated) HR in BAC cells. CONCLUSION: Elevated (dysregulated) RAD51 in BAC is implicated in both the repair of DNA breaks as well as ongoing genomic rearrangements. Moderate suppression of this gene reduces HR activity, whereas strong or near complete suppression of this gene activates RAD51C-dependent HR involving a mechanism known as single strand annealing (SSA). SSA-mediated HR, which is a mutagenic HR pathway, further disrupts genomic integrity by increasing DNA breaks in BAC cells. PMID- 29399539 TI - Chirality of Modern Antidepressants: An Overview. AB - The majority of modern antidepressants (selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors) have one or two centers of asymmetry in their structure; resulting in the formation of enantiomers which may exhibit different pharmacodynamic and pharmacokinetic properties. Recent developments in drug stereochemistry has led to understanding the role of chirality in modern therapy correlated with increased knowledge regarding the molecular structure of specific drug targets and towards the possible advantages of using pure enantiomers instead of racemic mixtures. The current review deals with chiral antidepressant drugs; presenting examples of stereoselectivity in the pharmacological actions of certain antidepressants and their metabolites and emphasizing the differences between pharmacological actions of the racemates and pure enantiomers. PMID- 29399540 TI - Drug Interactions of Metformin Involving Drug Transporter Proteins. AB - Metformin is a most widely used medication all around the world to treat Type 2 diabetes mellitus. It is also found to be effective against various conditions including, Prediabetes, Gestational diabetes mellitus (GDM), Polycystic Ovarian Syndrome (PCOS), Obesity, Cancer, etc. It is a cationic drug and it depends Organic Cation Transporters (OCTs) and Multidrug and Toxin Extruders (MATEs) mostly for its pharmacokinetics movement. The probability of drug interaction increases with the number of concomitant medications. This article focuses the drug interactions of metformin and most of them are linked to the inhibition of OCTs and MATEs leading to increased plasma metformin concentrations and subsequent elevation of risk of Metformin Associated Lactic Acidosis (MALA). By identifying the drugs inhibiting OCTs and MATEs, the healthcare professionals can predict the drug interactions of metformin. PMID- 29399541 TI - Cholinergic Anti-Inflammatory Pathway and the Liver. AB - The hepatic vagus branches innervate the liver and serve an important role in liver-brain connection. It appears that brain modulates inflammatory responses by activation of vagal efferent fibers. This activation and subsequent acetylcholine releases from vagus nerve terminals leads to inhibition of inflammatory cytokines through alpha7 nicotinic acetylcholine receptors (alpha7nAChRs) which located on the surface of different cell types such as liver Kupffer cells. This protective role of vagus-alpha7nAChR axis in liver diseases has been shown in several experimental studies. On the other hand, accumulated evidence clearly demonstrate that, autonomic dysfunction which is reduced functioning of both vagal and sympathetic nervous system, occurs during chronic liver disease and is well-known complication of patients suffering from cirrhosis. This review describes the impact and significance of cholinergic anti-inflammatory pathway in the liver and discusses about its disease-related dysfunction on the progression of cirrhosis. Considering the fact that sepsis is major cause of death in cirrhotic patients, convergence of these findings, may lead to designing novel therapeutic strategies in the field of chronic liver diseases management involving selective drug targeting and electrical nerve stimulation. PMID- 29399542 TI - Cross-Linked Hydrogel for Pharmaceutical Applications: A Review. AB - Hydrogels are promising biomaterials because of their important qualities such as biocompatibility, biodegradability, hydrophilicity and non-toxicity. These qualities make hydrogels suitable for application in medical and pharmaceutical field. Recently, a tremendous growth of hydrogel application is seen, especially as gel and patch form, in transdermal drug delivery. This review mainly focuses on the types of hydrogels based on cross-linking and; secondly to describe the possible synthesis methods to design hydrogels for different pharmaceutical applications. The synthesis and chemistry of these hydrogels are discussed using specific pharmaceutical examples. The structure and water content in a typical hydrogel have also been discussed. PMID- 29399544 TI - Micromanaging Glucose Tolerance and Diabetes. AB - MicroRNAs (miRNAs) are endogenous non-coding RNAs that have significant roles in biological processes such as glucose homoeostasis. MiRNAs fine-tune target genes expression via sequence-specific binding of their seed sequence to the untranslated region of mRNAs and degrade target mRNAs. MicroRNAs in islet beta cells regulate beta-cell differentiation, proliferation, insulin transcription and glucose-stimulated insulin secretion. Furthermore, miRNAs play key roles in the regulation of glucose and lipid metabolisms and modify insulin sensitivity by controlling metabolic functions in main target organs of insulin such as skeletal muscle, liver and adipose tissue. Moreover, since circulating miRNAs are detectable and stable in serum, levels of certain miRNAs seem to be novel biomarkers for prediction of diabetes mellitus. In this article, due to the prominent impact of miRNAs on diabetes, we overviewed the microRNAs regulatory functions in organs related to insulin resistance and diabetes and shed light on their potential as diagnostic and therapeutic markers for diabetes. PMID- 29399545 TI - The Impact of Amorphisation and Spheronization Techniques on the Improved in Vitro & in Vivo Performance of Glimepiride Tablets. AB - Purpose: Triple solid dispersion adsorbates (TSDads) and spherical agglomerates (SA) present new techniques that extensively enhance dissolution of poorly soluble drugs. The aim of the present study is to hasten the onset of hypoglycemic effect of glimepiride through enhancing its rate of release from tablet formulation prepared from either technique. Methods: Drug release from TSDads or SA tablets with different added excipients was explored. Scanning electron microscopy (SEM) and effect of compression on dissolution were illustrated. Pharmacodynamic evaluation was performed on optimized tablets. Results: TSDads & SA tablets with Cross Povidone showed least disintegration times of 1.48 and 0.5 min. respectively. Kinetics of drug release recorded least half-lives (54.13 and 59.83min for both techniques respectively). Cross section in tablets displayed an organized interconnected matrix under SEM, accounting for the rapid access of dissolution media to the tablet core. Components of tablets filled into capsules showed a similar release profile to that of tablets after compression as indicated by similarity factor. The onset time of maximum reduction in blood glucose in male albino rabbits was hastened to 2h instead of 3h for commercial tablets. Conclusion: After optimization of tablet excipients that interacted differently with respect to their effect on drug release, we could conclude that both amorphisation and spheronization were equally successful in promoting in vitro dissolution enhancement as well as providing a more rapid onset time for drug action in vivo. PMID- 29399546 TI - Surface Solid Dispersion and Solid Dispersion of Meloxicam: Comparison and Product Development. AB - Purpose: A comparative study was carried out between surface solid dispersion (SSD) and solid dispersion (SD) of meloxicam (MLX) to assess the solubility and dissolution enhancement approach and thereafter develop as patient friendly orodispersible tablet. Methods: Crospovidone (CPV), a hydrophilic carrier was selected for SSD preparation on the basis of 89% in- vitro MLX adsorption, 19% hydration capacity and high swelling index. SD on the other hand was made with PEG4000. Both were prepared by co-grinding and solvent evaporation method using drug: carrier ratios of 1:1, 1:4, and 1:8. Formulation SSDS3 (MLX: CPV in 1:8 ratio) made by solvent evaporation method showed t50% of 28 min and 80.9% DE50min which was higher in comparison to the corresponding solid dispersion, SDS3 (t50% of 35min and 76.4% DE50min). Both SSDS3 and SDS3 were developed as orodispersible tablets and evaluated. Results: Tablet formulation F3 made with SSD3 with a disintegration time of 11 secs, by wetting time= 6 sec, high water absorption of 78%by wt and cumulative drug release of 97% proved to be superior than the tablet made with SD3. Conclusion: Conclusively, the SSD of meloxicam has the potential to be developed as fast acing formulation that can ensure almost complete release of drug. PMID- 29399543 TI - The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate. AB - Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs. PMID- 29399547 TI - Caffeine Neuroprotective Mechanism Against beta-Amyloid Neurotoxicity in SHSY5Y Cell Line: Involvement of Adenosine, Ryanodine, and N-Methyl-D-Aspartate Receptors. AB - Purpose: Some reports have shown neuroprotective effects of caffeine in several neurodegenerative disorders. However, its mechanism of action is not completely clear. Therefore, the aim of this study was to explore the interference of ryanodine, N-methyl-D-aspartate (NMDA) and adenosine modulators with the neuroprotective effects of caffeine against beta-amyloid (Abeta) neurotoxicity in the SHSY5Y cells. Methods: The SHSY5Y cells were treated with Abeta23-35 (20uM) and/or caffeine (0.6 and 1mM), or both for 24 hours. Adenosine (20, 40, 60, 80, 100uM), NMDA (20, 50, 70, 90uM), dantrolene (2, 4, 6, 8, 10uM) were also added to the medium and incubated for 24 hours. The cell viability was measured via the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) method. The data were analyzed using one-way ANOVA followed by Bonferroni test. Results: Caffeine at all the used concentrations (0.6, 0.8, 0.9, 1, and 3mM) significantly protected neuronal cells against Abeta neurotoxicity. Adenosine at the concentrations of 20, 40, 80 and 100MUM diminished the neuroprotective effects of caffeine (0.6 and 1mM) against Abeta neurotoxicity. NMDA at the concentrations of 20, 50, 70 and 90MUM blocked caffeine (0.6 and 1mM) neuroprotective effects. Dantrolene at the concentration of 2, 4, 6, 8 and 10MUM diminished the neuroprotective effects of caffeine (0.6mM) and at the concentrations of 2 and 10MUM impede caffeine (1mM) neuroprotection against Abeta neurotoxicity. Conclusion: Caffeine produced neuroprotective effect against Abeta neurotoxicity. Blockade of adenosine and NMDA receptors, as well as the activation of ryanodine receptors, may contribute to the neuroprotective effects of caffeine. PMID- 29399548 TI - Anti-Inflammatory and Anti-Angiogenesis Effects of Verapamil on Rat Air Pouch Inflammation Model. AB - Purpose: In the present study, the effects of verapamil on inflammation and angiogenesis in air pouch model were studied. Methods: To create a model of inflammation in the rats, on days 1 and 3 sterile air, and on the sixth day, carrageenan was injected into the pouch subcutaneously. Normal saline as control, diclofenac sodium and dexamethasone as standards and verapamil (0.05, 0.1 and 0.2mg/rat) was injected into the pouch simultaneously with carrageenan and as well as 24 and 48 hours later. After 72 hours, volume of exudate, the leukocytes count, concentration of VEGF and IL-1beta, granulomatous tissue weight, histopathological changes and angiogenesis were considered. Results: Verapamil significantly reduced leukocyte accumulation in all doses, but effect of 0.1mg/rat was more significant (P<0.001). The exudate volume and granulomatous tissue weight was reduced with all doses, especially 0.1mg/rat (P<0.01). Doses 0.05, 0.1 and 0.2mg/rat of verapamil compared with the control group (carrageenan) led to a reduction in the amount of hemoglobin in the tissue as the angiogenesis indicator (P<0.001, P<0.01 and P<0.05, respectively). VEGF level of exudate was reduced by doses of 0.05 and 0.1mg/rat (P<0.05). In addition, IL 1beta concentration was lowered by 0.1mg/rat of verapamil (P<0.05). Histopathological changes, severity of granulomatous inflammation, granulomatous tissue cell density and angiogenesis in verapamil group were markedly lower compared to carrageenan group. Conclusion: Verapamil has significant anti inflammatory and anti-angiogenesis effects in the air pouch model probably due to attenuation effects of verapamil on IL-1beta and VEGF. PMID- 29399549 TI - Novel Doxorubicin Derivatives: Synthesis and Cytotoxicity Study in 2D and 3D in Vitro Models. AB - Purpose: Multidrug resistance (MDR) of tumors to chemotherapeutics often leads to failure of cancer treatment. The aim of the study was to prepare novel MDR overcoming chemotherapeutics based on doxorubicin (DOX) derivatives and to evaluate their efficacy in 2D and 3D in vitro models. Methods: To overcome MDR, we synthesized five DOX derivatives, and then obtained non-covalent complexes with human serum albumin (HSA). Drug efficacy was evaluated for two tumor cell lines, namely human breast adenocarcinoma MCF-7 cells and DOX resistant MCF-7/ADR cells. Additionally, MCF-7 cells were entrapped in alginate-oligochitosan microcapsules, and generated tumor spheroids were used as a 3D in vitro model to study cytotoxicity of the DOX derivatives. Results: Due to 3D structure, the tumor spheroids were more resistant to chemotherapy compared to monolayer culture. DOX covalently attached to palmitic acid through hydrazone linkage (DOX N2H-Palm conjugate) was found to be the most promising derivative. Its accumulation levels within MCF-7/ADR cells was 4- and 10-fold higher than those of native DOX when the conjugate was added to cultivation medium without serum and to medium supplemented with 10% fetal bovine serum, respectively. Non covalent complex of the conjugate with HSA was found to reduce the IC50 value from 32.9 uM (for free DOX-N2H-Palm) to 16.8 uM (for HSA-DOX-N2H-Palm) after 72 h incubation with MCF-7/ADR cells. Conclusion: Palm-N2H-DOX conjugate was found to be the most promising DOX derivative in this research. The formation of non covalent complex of Palm-N2H-DOX conjugate with HSA allowed improving its anti proliferative activity against both MCF-7 and MCF-7/ADR cells. PMID- 29399550 TI - Strategies for Improving siRNA-Induced Gene Silencing Efficiency. AB - Purpose: Human telomerase reverse transcriptase (hTERT) plays a crucial role in tumorigenesis and progression of cancers. Gene silencing of hTERT by short interfering RNA (siRNA) is considered as a promising strategy for cancer gene therapy. Various algorithms have been devised for designing a high efficient siRNA which is a significant issue in the clinical usage. Thereby, in the present study, the relation of siRNA designing criteria and the gene silencing efficiency was evaluated. Methods: The siRNA sequences were designed and characterized by using on line soft wares. Cationic co-polymer (polyethylene glycol-g-polyethylene imine (PEG-g-PEI)) was used for the construction of polyelectrolyte complexes (PECs) containing siRNAs. The cellular uptake of the PECs was evaluated. The gene silencing efficiency of different siRNA sequences was investigated and the effect of observing the rational designing on the functionality of siRNAs was assessed. Results: The size of PEG-g-PEI siRNA with N/P (Nitrogen/Phosphate) ratio of 2.5 was 114 +/- 0.645 nm. The transfection efficiency of PECs was desirable (95.5% +/ 2.4%.). The results of Real-Time PCR showed that main sequence (MS) reduced the hTERT expression up to 90% and control positive sequence (CPS) up to 63%. These findings demonstrated that the accessibility to the target site has priority than the other criteria such as sequence preferences and thermodynamic features. Conclusion: siRNA opens a hopeful window in cancer therapy which provides a convenient and tolerable therapeutic approach. Thereby, using the set of criteria and rational algorithms in the designing of siRNA remarkably affect the gene silencing efficiency. PMID- 29399551 TI - Development of Nanoemulsion Based Gel Loaded with Phytoconstituents for the Treatment of Urinary Tract Infection and in Vivo Biodistribution Studies. AB - Purpose: A nanoemulsion based gel containing Polyphenon 60 (P60) and cranberry (CRB) has been developed to deliver via intravaginal route for the treatment of urinary tract infection. Methods: Polyphenon 60 and cranberry were loaded in a single nanoemulsion gel (NBG) by ultra-sonication method and characterized for particle size, rheological properties, in vitro release and growth curve analysis. P60+CRB NBG were radiolabelled using technetium pertechnetate (99mTc) to perform in vivo pharmacokinetic studies in animals. Results: The finalized NE had a droplet size of 58+/-1 nm. In vitro release of 90.92 +/- 0.6% in 8 hr for P60 and 99.39 +/- 0.5% in 6 hr for CRB was observed in simulated vaginal fluid. Growth curve of E. coli indicated the inhibitory action of nanoemulsion based gel at the fifth hour of inoculation. Gamma scintigraphy studies on female Sprague Dawley rats showed transport of nanoemulsion based gel from the vaginal cavity into the systemic circulation. Further, biodistribution studies with radiolabelled P60+CRB NBG showed significant higher uptake of radiolabelled actives by kidney (3.20+/-0.16) and urinary bladder (3.64+/-0.29), when administered intravaginally. Conclusion: The findings suggested 99mTc-P60+CRB NBG can potentially be transported through vaginal cavity and reach the target organs and showed effective distribution in organs affected in urinary tract infection. PMID- 29399552 TI - Combined Activity of Colloid Nanosilver and Zataria Multiflora Boiss Essential Oil-Mechanism of Action and Biofilm Removal Activity. AB - Purpose: The aim of this study was to investigate antimicrobial and biofilm removal potential of Zataria multiflora essential oil (ZEO) and silver nanoparticle (SNP) alone and in combination on Staphylococcus aureus and Salmonella Typhimurium and evaluate the mechanism of action. Methods: The minimum inhibitory concentration (MIC), and optimal inhibitory combination (OIC) of ZEO and SNP were determined according to fractional inhibitory concentration (FIC) method. Biofilm removal potential and leakage pattern of 260-nm absorbing material from the bacterial cell during exposure to the compounds were also investigated. Results: MICs of SNP for both bacteria were the same as 25 MUg/ mL. The MICs and MBCs values of ZEO were 2500 and 1250 MUg/mL, respectively. The most effective OIC value for SNP and ZEO against Salm. Typhimurium and Staph. aureus were 12.5, 625 and 0.78, 1250 MUg/ mL, respectively. ZEO and SNP at MIC and OIC concentrations represented a strong removal ability (>70%) on biofilm. Moreover, ZEO at MIC and OIC concentrations did a 6-log reduction of primary inoculated bacteria during 15 min contact time. The effect of ZEO on the loss of 260-nm material from the cell was faster than SNP during 15 and 60 min. Conclusion: Combination of ZEO and SNP had significant sanitizing activity on examined bacteria which may be suitable for disinfecting the surfaces. PMID- 29399553 TI - Effects of Ectoine on Behavior and Candidate Genes Expression in ICV-STZ Rat Model of Sporadic Alzheimer's Disease. AB - Purpose: Alzheimer's disease (AD) is pathologically defined by the presence of amyloid plaques and tangles in the brain, therefore, any drug or compound with potential effect on lowering amyloid plaques, could be noticed for AD management especially in the primary phases of the disease. Ectoine constitutes a group of small molecule chaperones (SMCs). SMCs inhibit proteins and other changeable macromolecular structures misfolding from environmental stresses. Ectoine has been reported successfully prohibit insulin amyloid formation in vitro. Methods: We selected eight genes, DAXX, NFkappabeta, VEGF, PSEN1, MTAP2, SYP, MAPK3 and TNFalpha genes which had previously showed significant differential expression in Alzheimer human brain and STZ- rat model. We considered the neuroprotective efficacy by comparing the expression of candidate genes levels in the hippocampus of rat model of Sopradic Alzheimer's disease (SAD), using qPCR in compound treated and control groups as well as therapeutic effects at learning and memory levels by using Morris Water Maze (MWM) test. Results: Our results showed significant down-regulation of Syp, Mapk3 and Tnfalpha and up-regulation of Vegf in rat's hippocampus after treatment with ectoine comparing to the STZ-induced group. In MWM, there was no significant change in swimming distance and time for finding the hidden platform in treated comparing to STZ-induced group. In addition, it wasn't seen significant change in compound-treated comparing to STZ induced and control groups in memory level. Conclusion: It seems this compound may have significant effect on expression level of some AD- related genes but not on clinical levels. PMID- 29399554 TI - siRNA-Mediated Silencing of CIP2A Enhances Docetaxel Activity Against PC-3 Prostate Cancer Cells. AB - Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an identified human oncoprotein which modulates malignant cell growth. It is overexpressed in human prostate cancer and in most of the human malignancies. The aim of this study was to investigate the effects of CIP2A silencing on the sensitivity of PC 3 prostate cancer cells to docetaxel chemotherapy. Methods: PC-3 cells were transfected using CIP2A siRNA. CIP2A mRNA and protein expression were assessed after CIP2A gene silencing using q-RT PCR and Western blotting. Proliferation and apoptosis were analyzed after treatment with docetaxol using MTT assay, DAPI staining, and flow cytometry, respectively. Results: Silencing of CIP2A enhanced the sensitivity of PC-3 cells to docetaxel by strengthening docetaxel induced cell growth inhibition and apoptosis against PC-3 cells. Conclusion: Silencing of CIP2A may potentiate the cytotoxic effects of docetaxel and this might be a promising therapeutic approach in prostate cancer treatment. PMID- 29399555 TI - Effect of Daily Caper Fruit Pickle Consumption on Disease Regression in Patients with Non-Alcoholic Fatty Liver Disease: a Double-Blinded Randomized Clinical Trial. AB - Purpose: Despite numerous studies on the effects of complementary medicine, to our knowledge, there is no study on the effects of Capparis spinosa on disease regression in non-alcoholic fatty liver disease (NAFLD) patients. We compared the effects of caper fruit pickle consumption, as an Iranian traditional medicine product, on the anthropometric measures and biochemical parameters in different NAFLD patients. Methods: A 12-weeks randomized, controlled, double-blind trial was designed in 44 NAFLD patients randomly categorized for the control (n=22) or caper (n=22). The caper group received 40-50 gr of caper fruit pickles with meals daily. Before and after treatment, we assessed anthropometric measures, grade of fatty liver, serum lipoproteins and liver enzymes. Results: Weight and BMI were significantly decreased in the caper (p<0.001 and p<0.001) and control group (p=0.001 and p=0.001), respectively. Serum TG, TC and LDL.C just were significantly decreased in the control group (p=0.01, p<0.001 and p<0.001, respectively). Adjusted to the baseline measures, serum ALT and AST reduction were significantly higher in the caper than control group from baseline up to the end of the study (p<0.001 and p=0.02, respectively). After weeks 12, disease severity was significantly decreased in the caper group (p <0.001). Conclusion: Our results suggest that daily caper fruit pickle consumption for 12 weeks may be potentially effective on improving the biochemical parameters in NAFLD patients. Further, additional larger controlled trials are needed for the verification of these results. PMID- 29399556 TI - Role of Essential Oil of Mentha Spicata (Spearmint) in Addressing Reverse Hormonal and Folliculogenesis Disturbances in a Polycystic Ovarian Syndrome in a Rat Model. AB - Purpose: Given the antiandrogenic effects of spearmint, in this study we evaluated the effects of its essential oil on polycystic ovarian syndrome in a rat model. Methods: Female rats were treated as follows: Control, normal rats which received 150 mg/kg spearmint oil or 300 mg/kg spearmint oil, or sesame oil; and PCOS-induced rats which received 150 mg/kg spearmint oil or 300 mg/kg spearmint oil, or sesame oil. Then the animals were killed and the levels of LH, FSH, testosterone and ovarian folliculogenesis were evaluated. Results: Spearmint oil reduced body weight, testosterone level, ovarian cysts and atretic follicles and increased Graafian follicles in PCOS rats. Conclusion: Spearmint has treatment potential on PCOS through inhibition of testosterone and restoration of follicular development in ovarian tissue. PMID- 29399557 TI - Chemical Profile and Biological Activity of Casimiroa Edulis Non-Edible Fruit's Parts. AB - Purpose: the non-edible fruit parts of Casimiroa edulis Llave et were evaluated for their active constituents and their potential as antioxidants, anti inflammatory and antitumor activity. Methods: Fruits peel (FP) and seeds kernel (SK) of Casimiroa edulis Llave et Lex. were extracted successively with hexane and then methanol. Fatty acids were prepared from hexane extracts and identified by GC. Total flavonoid, phenolic acids and tannins contents in methanol extracts were determined by UV spectrophotometer and identified by HPLC. Antioxidant, in vitro anti-inflammatory activity and antitumor effect against Caco-2 cell line were determined. Results: GC analysis of hexane extracts showed that oleic acid (47.00%) was the major unsaturated fatty acids in both extracts while lignoceric acid (15.49%) is the most abundant saturated fatty acid in (FP). Total phenolic, flavonoid and tannin contents in (FP) & (SK) methanol extracts were; 37.5+/-1.5, 10.79+/-0.66 and 22.28+/-0.23 for (FP); 53.5+/-1.5mg/g, 14.44+/-0.32 mg/g; and 53.73+/-3.58 mg/g for (SK) respectively. HPLC analysis of methanol extract revealed that; the major phenolic compound was pyrogallol in (FP) and p hydroxybenzoic acid in (SK), the major flavonoid was luteolin 6-arabinose-8 glucose in (FP) and acacetin in (SK). Conclusion: This study showed that non edible parts of C. edulis fruit is a rich source of different phenolic compounds and fatty acids which has great antioxidant, anti-inflammatory and antitumor activities; that could be used as a natural source in pharmaceutical industry. PMID- 29399558 TI - Effects of NDRG2 Overexpression on Metastatic Behaviors of HCT116 Colorectal Cancer Cell Line. AB - Purpose: N-myc downstream-regulated gene 2 (NDRG2) is frequently down-regulated in cancer, and plays an important role in the control of tumor growth and metastasis. Its manipulation has been suggested as a therapy in cancer. Here, we examined the outcome of NDRG2 overexpression on proliferation, invasion, migration and MMP activity of HCT116 colorectal cancer cell line. Methods: The HCT116 cell line (human colorectal cancer) was transfected with pCMV6-AC-GFP NDRG2. 2,5diphenyltetrazolium bromide (MTT) assay was used to detect cell proliferation. The invasion and migration of the transfected cells were examined through transwell chambers while the MMP-9 activity was detected by the ability of the cells to digest gelatin. Results: Overexpression of NDRG2 by stable NDRG2 transfection decreased cell proliferation, migration and invasion ability, along with decreasing MMP-9 activity. Conclusion: Our data indicate that NDRG2 overexpression can suppress several aspect of tumorigenesis. Further investigations are necessitated to verify if NDRG2 molecule can be a therapeutic target in colorectal cancer. PMID- 29399559 TI - Molecular Diagnosis of Tuberculosis. AB - Tuberculosis (TB) is one of the leading causes of adult death in the Asia-Pacific Region, including Indonesia. As an infectious disease caused by Mycobacterium tuberculosis (MTB), TB remains a major public health issue especially in developing nations due to the lack of adequate diagnostic testing facilities. Diagnosis of TB has entered an era of molecular detection that provides faster and more cost-effective methods to diagnose and confirm drug resistance in TB cases, meanwhile, diagnosis by conventional culture systems requires several weeks. New advances in the molecular detection of TB, including the faster and simpler nucleic acid amplification test (NAAT) and whole-genome sequencing (WGS), have resulted in a shorter time for diagnosis and, therefore, faster TB treatments. In this review, we explored the current findings on molecular diagnosis of TB and drug-resistant TB to see how this advancement could be integrated into public health systems in order to control TB. PMID- 29399560 TI - Functional Relevance of Macrophage-mediated Inflammation to Cardiac Regeneration. AB - Cardiovascular disease remains the leading cause of death worldwide and regenerative medicine is a promising therapeutic option for this disease. We have developed various techniques to attenuate the cardiac remodeling and to regenerate cardiovascular systems via stem cell application. Besides cell therapy, we are interested in the modulation of pathological inflammation mediated by macrophages in the damaged heart tissue to arouse endogenous reparative responses with biocompatible small molecules. Certainly, current understanding of mechanisms of tissue regeneration will lead to the development of innovative regenerative medicine for cardiovascular disease. PMID- 29399561 TI - Salicylic Acid Reduces OmpF Expression, Rendering Salmonella enterica Serovar Typhimurium More Resistant to Cephalosporin Antibiotics. AB - Salmonella enterica serovar Typhimurium is one of the most important bacterial pathogens causing diarrhea. The resistance of S. typhimurium to antimicrobial agents, which has recently been isolated from patients, is causing serious problems. We investigated the effects of salicylic acid (Sal) and acetyl salicylate (AcSal) on the susceptibility of S. typhimurium to cephalosporin antibiotics, which are known to increase resistance to cephalosporin and quinolone antibiotics. The MIC of cephalosporin antibiotics was higher than that of the media without Sal. The rate of accumulation of ethidium bromide (EtBr) in the bacteria by the outer membrane protein (Omp) was not different from that of the bacteria cultured in the medium containing Sal. However, Carbonyl cyanide-m chlorophenylhydrazone (CCCP), an inhibitor of bacterial efflux pumps, significantly reduced the rate of accumulation of EtBr in bacteria cultured on Sal containing medium. In the medium containing CCCP, the MIC of the antimicrobial agent tended to decrease as compared with the control. In addition, the MIC of the bacteria treated with CCCP and Sal was higher than that of the antimicrobial agent against the CCCP treated experimental bacteria. These results suggest that Sal decreases the expression of OmpF in the Omp of S. typhimurium and reduces the permeability of cephalosporin antibiotics to bacteria, which may induce tolerance to cephalosporin antibiotics. PMID- 29399562 TI - Antidiabetic Drug Metformin Protects Neuronal Cells against Quinolinic Acid Induced Excitotoxicity by Decreasing Intracellular Calcium. AB - The antidiabetic drug metformin has been found to have beneficial effects in various neurological disorders; however, the molecular mechanisms underlying these effects remain unclear. Here we report that metformin protects neuronal cells from quinolinic acid (QUIN)-induced excitotoxicity. For this, we pretreated N18D3 neuronal cells with metformin prior to QUIN for 24 h. We found that pretreating the cells with metformin significantly improved cell survival rate in a concentration-dependent manner and reduced apoptotic cell death, as revealed by a MTT assay and DAPI staining, respectively. Calcium imaging using fluo-4 showed that metformin (100 uM) inhibited the intracellular calcium increase that was induced by QUIN. In addition, mRNA expression of pro-apoptotic genes, p21 and Bax, was decreased and of anti-apoptotic genes, Bcl-2 and Bcl-xl, was increased with metformin treatment compared to QUIN-induced cells. The immunoreactivity of phosphorylated ERK1/2 was elevated in cells treated with metformin, indicating the ERK1/2 signaling pathway in the neuroprotective effects of metformin in QUIN induced cell death. Collectively, our data demonstrates that metformin exerts its neuroprotective effects by inhibiting intracellular calcium increases, allowing it to regulate ERK1/2 signaling and modulate cell survival and death genes. PMID- 29399563 TI - Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts. AB - We aimed to evaluate the prevalence of familial hypercholesterolaemia (FH) in a subject with hypercholesterolaemia from two population-based cohorts in South Korea. A total of 283 subjects with total cholesterol levels of 290 mg/dL (7.5 mmol/L) or higher were selected from the Namwon and Dong-gu Studies. We used next generation sequencing (NGS) to detect mutations in low-density lipoprotein receptors (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. We have confirmed 17 different mutations of the LDLR, APOB and PCSK9 in 23 subjects (8.1%). Eleven LDLR variants and one APOB variant have been previously reported. One LDLR and two PCSK9 rare variants were identified in the variants database, but not in the FH mutation database. Two novel LDLR variants were found, p.Leu680Val, and p.Thr734Phe. No LDLR, APOB or PCSK9 deletions nor insertions were found. When the subjects were restricted to 110 subjects with a total cholesterol >=310 mg/dL, only 10 variants were found in the 10 subjects (9.1%). These results suggest that given the low prevalence of FH mutations in subjects with high total cholesterol levels, NGS-based testing for a population-based approach to FH detection may not be cost-effective. PMID- 29399564 TI - The Benefits of Resection for Gastric Carcinoma Patients with Non-curative Factors. AB - The benefits of resection for gastric carcinoma patients with non-curative factors remain controversial. Thus, we evaluated the survival benefits of resection in these gastric carcinoma patients. We reviewed the hospital records of 467 gastric carcinoma patients with non-curative factors who had resection (n=305) and compared their clinicopathological findings with individuals (n=162) who underwent bypass or exploration from 1996 to 2010. The 3-year survival rate of patients who had resection was higher than was that of patients who did not (13.2 vs. 7.2%, respectively p<0.001). Cox's proportional hazard regression analysis revealed that only one factor was an independent, statistically significant prognostic parameter: the presence of peritoneal dissemination (risk ratio, 1.37; 95% confidence interval, 1.04-1.79; p<0.05). The 3-year survival rate of patients with peritoneal dissemination was higher in individuals who underwent resection compared with those who did not (9.5 vs. 4.7%, respectively; p<0.001). The current results highlight the improved survival rates of gastric carcinoma patients with non-curative factors who underwent surgery compared with those who did not. Although resection is not curative in this group of patients, we still recommend performing the procedure. PMID- 29399565 TI - Clinical Outcomes of Elderly Patients with Non ST-Segment Elevation Myocardial Infarction Undergoing Coronary Artery Bypass Surgery. AB - The aim of this study is to investigate the clinical outcomes of the elderly patients with Non ST-segment elevation myocardial infarction (NSTEMI) undergoing coronary artery bypass surgery (CABG) compared to non-elderly patients. Patients with NSTEMI and undergoing CABG (n=451) who were registered in the Korea Acute Myocardial Infarction Registry between December 2003 and August 2012 were divided into two groups.; the non-elderly group (<75 years, n=327) and the elderly group (>=75 years, n=124). In-hospital mortality was higher in the elderly group (4.9% vs. 11.3%, p=0.015), but cardiac death, myocardial infarction, and major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, percutaneous revascularization, and redo-CABG after a one-year follow up were not different between the two groups. Predictors of in-hospital mortality in patients with NSTEMI undergoing CABG were left ventricular (LV) dysfunction (ejection fraction <=40%) [hazard ratio (HR): 2.76, 95% confidence interval (CI): 1.16 6.57, p=0.022] and age (HR: 1.05, 95% CI: 1.01-1.10, p=0.047). So elderly NSTEMI patients should be considered for CABG if appropriate, but careful consideration for surgery is required, especially if the patients have severe LV systolic dysfunction. PMID- 29399566 TI - Predictive Value of Procalcitonin for Infection and Survival in Adult Cardiogenic Shock Patients Treated with Extracorporeal Membrane Oxygenation. AB - Procalcitonin (PCT) is a predictive marker for the occurrence of bacterial infection and the decision to terminate antibiotic treatment in critically ill patients. An unusual increase in PCT, regardless of infection, has been observed during extracorporeal membrane oxygenation (ECMO) support. We evaluated trends and the predictive value of PCT levels in adult cardiogenic shock during treatment with ECMO. We reviewed the clinical records of 38 adult cardiogenic shock patients undergoing veno-arterial ECMO support between January 2014 and December 2016. The exclusion criteria were age <18 years, pre-ECMO infection, and less than 48 hours of support. The mean patient age was 56.7+/-14.7 years and 12 (31.6%) patients were female. The mean duration of ECMO support was 9.0+/-7.6 days. The rates of successful ECMO weaning and survival to discharge were 55.3% (n=21) and 52.6% (n=20), respectively. There were 17 nosocomial infections in 16 (42.1%) patients. Peak PCT levels (mean 25.6+/-9.4 ng/mL) were reached within 48 hours after initiation of ECMO support and decreased to <=5 ng/mL within one week. The change in PCT levels was not useful in predicting the occurrence of new nosocomial infections during the ECMO run. However, a PCT level >10 ng/mL during the first week of ECMO support was significantly associated with mortality (p<0.01). The change in PCT level was not useful in predicting new infection during ECMO support. However, higher PCT levels within the first week of the ECMO run are associated with significantly higher mortality. PMID- 29399567 TI - Safety and Efficacy of the Endeavor Resolute(r) Stent in Patients with Multivessel Disease: The HEART (Honam EndeAvor ResoluTe) Prospective, Multicenter Trial. AB - The Endeavor Resolute(r) (ER) is a zotarolimus-eluting stent (ZES) with a biocompatible BioLinx polymer. This study prospectively compared the clinical outcomes of 2 versions of ZES, ER and Endeavor Sprint(r) (ES), in patients with multivessel disease. A total of 488 patients who underwent multivessel percutaneous coronary intervention (PCI) were divided into 2 groups the ER group (n=288) and the ES group (n=200). The primary endpoint was a composite of major adverse cardiac events (MACE) consisting of death, myocardial infarction, and target vessel revascularization after 12 months. In all patients, the prevalence of diabetes was higher in the ER group (42.7% vs. 31.0%, p=0.009). The rate of post-PCI Thrombolysis in Myocardial Infarction flow grade 3 was higher in the ER group (100.0% vs. 98.0%, p=0.028). There were no between-group differences in the in-hospital, 1-month and 12-month clinical outcomes. In the propensity score matched cohort (n=200 in each group), no differences were observed in the baseline and procedural characteristics. There were no statistical differences in the rates of in-hospital, 1-month and 12-month events (12-month MACE in the ER and ES groups: 6.0% vs. 3.5%, p=0.240, respectively). The safety and efficacy of both versions of ZES were comparable in patients with multivessel disease during a 12-month clinical follow-up. PMID- 29399569 TI - Vocal Cord Palsy after Left Pulmonary Artery Stent Insertion. PMID- 29399568 TI - Effects of ATP on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Small Intestine. AB - Purinergic receptors play an important role in regulating gastrointestinal (GI) motility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate GI smooth muscle activity. We studied the functional roles of external adenosine 5' triphosphate (ATP) on pacemaker activity in cultured ICCs from mouse small intestines by using the whole-cell patch clamp technique and intracellular Ca2+ ([Ca2+]i) imaging. External ATP dose-dependently depolarized the resting membrane and produced tonic inward pacemaker currents, and these effects were antagonized by suramin, a purinergic P2 receptor antagonist. ATP-induced effects on pacemaker currents were suppressed by an external Na+-free solution and inhibited by the nonselective cation channel blockers, flufenamic acid and niflumic acid. The removal of external Ca2+ or treatment with thapsigargin (inhibitor of Ca2+ uptake into endoplasmic reticulum) inhibited the ATP-induced effects on pacemaker currents. Spontaneous [Ca2+]i oscillations were enhanced by external ATP. These results suggest that external ATP modulates pacemaker activity by activating nonselective cation channels via external Ca2+ influx and [Ca2+]i release from the endoplasmic reticulum. Thus, it seems that activating the purinergic P2 receptor may modulate GI motility by acting on ICCs in the small intestine. PMID- 29399570 TI - Recovery of High Degree Atrioventricular Block in a Patient with Cardiac Sarcoidosis by Corticosteroid Therapy. PMID- 29399571 TI - Imaging Findings of Venous Malformation in Neck. PMID- 29399572 TI - Hypophosphatemic Osteomalacia with Multiple Bone Fractures: ADV-Induced Fanconi's Syndrome. PMID- 29399573 TI - De Novo CD5-Positive Primary Gastric Diffuse Large B-Cell Lymphoma Coexpressing MYC and BCL6: Towards a Proper Subset of Double-Hit, Triple-Hit and, Maybe, Quadruple-Hit B-Cell Lymphomas? PMID- 29399574 TI - Positive affect, depressive symptoms, and arthritis pain of elderly people over time. AB - Background: Older adults frequently experience physical symptoms of arthritis pain. We examined the dynamic change of arthritis pain and depressive symptoms over time. We also addressed the influence of time varying arthritis pain on depressive symptoms and positive affect among community dwelling older individuals. Methods: Analyses were based on data from 4 annual follow-ups in a sample of 299 elderly residents (M=83.78) of Florida retirement communities. We estimated a hierarchical growth curve model that related the effects of time varying pain and characteristics of participants such as age, gender, cognitive functioning, emotional support and health. Growth curve modeling was used to assess changes in emotional well-being as a function of arthritis pain over time. Results: We found that depressive symptoms increased over 4 years whereas positive affect declined over 4 years with significant between-person differences in levels and slopes. As predicted, changes in arthritis pain co-varied with both depressive symptoms and positive affect over time. Gender, cognitive functioning, health conditions and emotional support from others were associated with between person differences in level of emotional well-being. Conclusions: Our findings suggest that conceptualization of emotional well-being of older adults as a dynamic, changing construct applies both depressive symptoms and positive affect. Findings also suggest that arthritis pain as well as emotional support contribute to depressive symptoms and to positive affect among older adults with arthritis. PMID- 29399575 TI - Challenges of influenza A viruses in humans and animals and current animal vaccines as an effective control measure. AB - Influenza A viruses (IAVs) are genetically diverse and variable pathogens that share various hosts including human, swine, and domestic poultry. Interspecies and intercontinental viral spreads make the ecology of IAV more complex. Beside endemic IAV infections, human has been exposed to pandemic and zoonotic threats from avian and swine influenza viruses. Animal health also has been threatened by high pathogenic avian influenza viruses (in domestic poultry) and reverse zoonosis (in swine). Considering its dynamic interplay between species, prevention and control against IAV should be conducted effectively in both humans and animal sectors. Vaccination is one of the most efficient tools against IAV. Numerous vaccines against animal IAVs have been developed by a variety of vaccine technologies and some of them are currently commercially available. We summarize several challenges in control of IAVs faced by human and animals and discuss IAV vaccines for animal use with those application in susceptible populations. PMID- 29399576 TI - Distinct features of dendritic cell-based immunotherapy as cancer vaccines. AB - Dendritic cells (DCs) are the most professional antigen presenting cells that play important roles in connection between innate and adaptive immune responses. Numerous studies revealed that the functions of DCs are related with the capture and processing of antigen as well as the migration to lymphoid tissues for the presenting antigens to T cells. These unique features of DCs allow them to be considered as therapeutic vaccines that can induce immune responses and anti tumor activity. Here, we discuss and understand the immunological basis of DCs and presume the possibilities of DC-based vaccines for the promising cancer therapy. PMID- 29399577 TI - Calcium-dependent protein kinases are potential targets for Toxoplasma gondii vaccine. AB - Toxoplasma gondii belongs to the Apicomplexa phylum that caused a widespread zoonotic infection in wide range of intermediate hosts. Over one-third of the world's population are latently infected with T. gondii and carry it. The complex life cycle of T. gondii indicates the presence of a plurality of antigenic epitopes. During the recent years, continuous efforts of scientists have made precious advances to elucidate the different aspects of the cell and molecular biology of T. gondii. Despite of great progresses, the development of vaccine candidates for preventing of T. gondii infection in men and animals is still remains a challenge. The calcium-dependent protein kinases (CDPKs) belongs to the superfamily of kinases, which restricted to the apicomplexans, ciliates, and plants. It has been documented that they contribute several functions in the life cycle of T. gondii such as gliding motility, cell invasion, and egress as well as some other critical developmental processes. In current paper, we reviewed the recent progress concerning the development of CDPK-based vaccines against acute and chronic T. gondii. PMID- 29399578 TI - Anti-infective potential of catechins and their derivatives against viral hepatitis. AB - Polyphenols including catechins from green tea (Camellia sinensis) have been reported to have anti-infective activities against a broad spectrum of viruses and other pathogens. During the last two decades, antiviral activities of catechins with different modes of action have been demonstrated on diverse families of viruses, such as human immunodeficiency virus, Herpes simplex virus, influenza virus, hepatitis B and C virus. In this study, we focused on the antiviral properties of catechins and their derivatives against viral hepatitis which have become a key public health issue due to their serious impact on human health with liver diseases. PMID- 29399579 TI - Epidemiology of severe fever and thrombocytopenia syndrome virus infection and the need for therapeutics for the prevention. AB - Over the past ten years there has been a marked increase in cases of severe fever and thrombocytopenia syndrome in East Asia. This tick-borne hemorrhagic fever presents along with clinical signs including high fever and leukopenia. In addition to humans, the virus has also been detected with shared genetic homology in farm animals including goats, cattle, horses, and pigs. Furthermore, several genotypes of severe fever and thrombocytopenia syndrome virus (SFTSV) are currently co-circulating between humans and animals. In China, where the virus was first detected in rural areas in 2009, the SFTSV mortality rate has been reported to be as 6% and higher than 30%, especially in immuno-compromised patients. Moreover, this virus has been isolated in neighbor countries including Japan and South Korea where the fatality rates in 2015 were more than 30% in both countries. In this review, we comprehensively summarize the virology, genotypes, pathogenesis, and epidemiology of SFTSV infection in humans and animals. Currently, a collaborative global approach against SFTSV infection is being undertaken; however, the need for continuous disease surveillance and production of an effective vaccine is imperative as this virus may lead to an epidemic of irreversible status in both humans and animals. PMID- 29399580 TI - Immunogenicity of the nanovaccine containing intimin recombinant protein in the BALB/c mice. AB - Purpose: Escherichia coli O157:H7 is one of the most important pathogens which create hemorrhagic colitis and hemolytic uremic syndrome in human. It is one of the most prevalent causes of diarrhea leading to death of many people every year. The first diagnosed gene in the locus of enterocyte effacement pathogenicity island is eae gene. The product of this gene is a binding protein called intimin belonging to the group of external membrane proteins regarded as a good stimulants of the immune system. Chitosan with its lipophilic property is an environmentally friendly agent able to return to the environment. Materials and Methods: Intimin recombinant protein was expressed in pET28a vector with eae gene and purification was performed using Ni-NTA and finally the recombinant protein was approved through western blotting. This protein was encapsulated using chitosan nanoparticles and the size of nanoparticles was measured by Zetasizer. Intimin encapsulated was prescribed for three sessions among three groups of oral, injection, and oral-injection using Chitosan nanoparticles. Challenge was performed for all three groups with 108E. coli O157:H7 bacteria. Results: Intimin produced by chitosan nanoparticles improves immunological responses through the adjuvant nature of chitosan nanoparticles. Chitosan may be used as a carrier for transportation of the prescribed vaccine. Among the mice, encapsulated intimin could be able to provide suitable titers of IgG and IgA by the aid of chitosan nanoparticles. Results of mice challenge showed that decreased the bacterial shedding significantly. Conclusion: Results showed that the chitosan nanovaccine with intimin protein may be used as a suitable candidate vaccine against E. coli O157:H7. PMID- 29399581 TI - Efficacy of inactivated variant porcine epidemic diarrhea virus vaccines in growing pigs. AB - Purpose: The first aim of this study was to develop a novel inactivated porcine epidemic diarrhea virus (PEDV) vaccine using the recently isolated Korean PEDV QIAP1401 strain and to evaluate its protective efficacy in growing pigs. The second was to determine the optimum adjuvant formulation of the inactivated PEDV vaccine that induces protection against viral challenge. Materials and Methods: To generate high titers of infectious PEDV, the QIAP1401 isolate was passaged in Vero cells. The experimental vaccines were prepared from a binary ethyleneimine inactivated QIAP1401 strain passaged sequentially 70 times (QIAP1401-p70), formulated with four commercial adjuvants, and administered twice intramuscularly to growing pigs. Challenge studies using a virulent homologous strain of PEDV QIAP1401-p11, which was passaged 11 times after isolation, were performed to assess protection against disease progression and viral shedding during the 15 day observation period. The vaccine-induced antibody responses were measured in serum samples collected at predetermined time points by indirect enzyme-linked immunosorbent assay and virus neutralization test. Results: The QIAP1401-p70 strain had 42 amino acid (aa) mutations, including a 25 aa deletion, and was selected as the inactivated PEDV vaccine candidate. Although none of the pigs that received the experimental vaccines were completely protected against subsequent viral challenge, they exhibited a significantly higher immune response than did non-vaccinated control pigs. Among the vaccine groups, the highest antibody responses were observed in the pigs that received an oil-based multiphasic water/oil/water (W/O/W) emulsion adjuvanted vaccine, which delayed the onset of clinical symptoms and viral shedding. Conclusion: A novel inactivated PEDV vaccine formulated with a W/O/W emulsion adjuvant was both immunogenic and protective against viral challenge. PMID- 29399582 TI - Outbreak investigation of pertussis in an elementary school: a case-control study among vaccinated students. AB - Purpose: A pertussis patient from an elementary school, in Gyeonggi Province, Korea, was notified to public health authority on July 25, 2017. Epidemiologic investigation was conducted to identify the magnitude, possible source of infection and risk factors for this outbreak on August 17, 2017. Materials and Methods: A case was defined as the school student experiencing cough for more than two weeks with or without paroxysmal, whoop, or post-tussive vomiting. Control was defined as the student polymerase chain reaction-negative at the school. School based surveillance was implemented to identify additional cases. Results: From June 29 to August 27, 2017, nine patients of pertussis were identified from an elementary school. Among nine cases, eight were confirmed by polymerase chain reaction positive. All cases had cough, one (11%) had post tussive vomiting, and one (11%) had fever. Eight cases had macrolide for 7 days in outpatient clinic, and one case admitted in a hospital. There was no significant difference of demographic factors including gender (p=0.49), age group (p=0.97), number of series of vaccination of pertussis (p=0.52), the number of participation of after school activity (p=0.28), and the time elapsed since last vaccination (p=0.42). However, we found the history of contact within the classroom or after-school activity was only the independent risk factor among all the demographic factors collected (odds ratio, 63.61; 95% confidence interval, 4.35 to 930.79). Conclusion: The contributing factor for transmission is associated with the case-contact. Immediate identification of pertussis with use of appropriate diagnostic test may help to avoid a large number of cases. PMID- 29399583 TI - Status of group B streptococcal vaccine development. AB - Streptococcus agalactiae (group B streptococcus, GBS) is a leading causal organism of neonatal invasive diseases and severe infections in the elderly. Despite significant advances in the diagnosis and treatment of GBS infections and improvement in personal hygiene standards, this pathogen is still a global health concern. Thus, an effective vaccine against GBS would augment existing strategies to substantially decrease GBS infection. In 2014, World Health Organization convened the first meeting for consultation on GBS vaccine development, focusing on the GBS maternal immunization program, which was aimed at reducing infections in neonates and young infants worldwide. Here, we review the history of GBS infections, the current vaccine candidates, and the current status of immunogenicity assays used to evaluate the clinical efficacy of GBS vaccines. PMID- 29399584 TI - Evaluation of two different enzyme-linked immunosorbent assay for severe fever with thrombocytopenia syndrome virus diagnosis. AB - To develop the large scale serological assay for severe fever with thrombocytopenia syndrome virus (SFTSV) infection, we evaluated two different enzyme-linked immunosorbent assay (ELISA) methods using nucleocapsid protein (NP) and Gn proteins of CB1 (genotype B) SFTSV strains. The NP-based ELISA tests showed more sensitive with broad cross-reactivity between two different genotype A and B strains compared with those of Gn-based ELISA tests. However, Gn-based ELISA showed more genotype specificity and specificity. These result suggested that NP-based ELISA test could be applicable for general sero-prevalence studies of SFTSV infections, while Gn-based ELISA could be applicable for a certain specific genotype sero-prevalence study. PMID- 29399585 TI - The Effect of Educational Program on Self-efficacy of Women with Rheumatoid Arthritis: A Randomized Controlled Clinical Trial. AB - Background: Rheumatoid Arthritis (RA) is a chronic and inflammatory disorder which is the major cause of disability in adults. Patient training is a vital aspect of nursing care for people with arthritis aiming to enable them to live as independently as possible. In the present study, we aimed to evaluate the effect of the educational program on self-efficacy on women with rheumatoid arthritis. Methods: This study was an open randomized controlled clinical trial during May to July 2013. Women (64 participants) with confirmed RA and a mean+/-SD age of 48.6+/-9.83 years were enrolled; they were randomly assigned into intervention and control groups (32 in each group). The patients in the intervention group participated in a training programs consisting of two 30-minute sessions per week for 8 consecutive weeks. Data were collected by using Arthritis Self-Efficacy Scale (ASES) and demographic questionnaire. ASES questionnaire was filled in three times by the participants: before, immediately after, and three months after the intervention. Data were analyzed using SPSS software, version 20, and statistical tests including Chi-square and t-test. Results: The results showed that the mean of self-efficacy scores of the intervention group, immediately and three months after the intervention, significantly enhanced in all dimensions compared with the control group (P<0.001, P<0.001). Conclusion: It can be concluded that training programs is effective for improving self-efficacy in the patients suffering from RA by raising their awareness towards their disease and methods of adaptation with it. But as to the sustainability of the impact of educational courses on self-efficacy, it seems that more research is required. Trial Registration Number: IRCT201308187531N3. PMID- 29399586 TI - A Case of Myocarditis and Near-Lethal Arrhythmia Associated With Interleukin-2 Therapy. AB - We present a case of a 48-year-old female who developed myocarditis and near fatal arrhythmias during high dose Il-2 therapy for metastatic renal cancer. On day 5 of therapy, the patient developed sudden onset chest pain, elevated cardiac enzymes and ST segment changes on EKG. Coronary angiogram was normal, however echocardiogram showed reduced ejection fraction and hemodynamic measurements showed elevated bilateral elevated filling pressures. The patient then developed episodes of recurrent ventricular arrhythmia, precipitated by bradycardia and PVC, requiring defibrillation and temporary pacemaker placement. Endomycardial biopsy was nonspecific showing fibrosis with subsequent cardiac MRI showed evidence of myocardial edema, consistent with Il-2 induced myocarditis in the setting of no prior cardiac history. After the discontinuation of Il-2 therapy, the patient displayed clinical improvement as well as improved ejection fraction. This case brings attention to the cardiac toxicities associated with high dose Il 2 therapy including potentially lethal arrhythmias and highlights the importance of careful cardiac screening prior to initiation of treatment. PMID- 29399587 TI - Oligosecretory Myeloma With Amyloidosis and Alopecia. AB - Amyloidosis is a systemic illness characterized by the extracellular deposition of abnormal proteins in body tissues and organs. In addition to renal involvement, amyloidosis can also present with a variety of skin manifestations, though rarely with alopecia. Sixteen cases of alopecia secondary to systemic amyloidosis are reported. There is one reported case that presented with alopecia universalis. We report a case of a 68-year-old woman presenting with alopecia universalis, rapid decline in kidney function, and nephrotic syndrome who was found to have multiple myeloma-associated AL amyloidosis (immunoglobulin light chain). Her serological workup including serum electrophoresis was negative and she underwent renal biopsy. Pathology revealed eosinophilic material within the mesangium that was Congo-red positive, had apple-green birefringence under polarized light, and ultramicroscopically appeared as fibrillary material. Subsequent bone marrow examination showed a diffuse increase in plasma cells with atypia indicating plasma cell neoplasm. This case underlines several interesting aspects of multiple myeloma and the way it may present with amyloidosis. The lack of monoclonal spike on electrophoresis yet positive light chain analysis deserves special attention by clinicians to avoid a missed diagnosis. The extensive skin involvement also raises several questions regarding the pathologic mechanisms of alopecia in a patient with amyloidosis. PMID- 29399588 TI - Career Length and Injury Incidence After Anterior Cruciate Ligament Reconstruction in Major League Soccer Players. AB - Background: Little is known about career length after anterior cruciate ligament (ACL) reconstruction in Major League Soccer (MLS), the top men's professional soccer league in the United States. Further, it is unspecified whether athletes returning to soccer after ACL reconstruction are at a higher risk for injuries, beyond new knee injuries. Purpose: To examine career length and the incidence of lower extremity injuries in MLS athletes after ACL reconstruction in comparison with age-matched controls. Study Design: Cohort study; Level of evidence, 3. Methods: Injuries and athletic exposures (AEs; games and training sessions) were recorded in the HealtheAthlete database, the injury surveillance system of MLS. All athletes who had undergone ACL reconstruction and returned to MLS were identified and age-matched with controls. Multivariate analyses of variance were used to compare career length and percentage of regular/postseason games that athletes started, substituted, or did not play. Generalized linear model regressions were used to examine the injury risk. Results: Athletes in the ACL group had shorter careers (1.3 +/- 1.3 years) than those in the control group (2.5 +/- 1.3 years) (P < .01), but while they were playing, athletes in the ACL group participated in a similar number of AEs as those in the control group (169.9 +/- 129.0 vs 171.6 +/- 124.9 AEs, respectively; P = .95). Athletes in the ACL group started fewer regular/postseason games (36.7% +/- 34.3% vs 60.1% +/- 33.8%, respectively; P < .01) and did not play in more regular/postseason games (47.4% +/- 35.5% vs 31.0% +/- 34.4%, respectively; P = .03) compared with those in the control group. The ACL group was not at a significantly greater risk for lower extremity injuries compared with the control group (relative risk, 0.87; 95% CI, 0.55-1.37). Conclusion: Although MLS athletes after ACL reconstruction are not at a greater risk for lower extremity injuries, this study suggests that they are not utilized in regular/postseason games as frequently and that their careers in MLS are shorter than age-matched controls. Further research is necessary to elucidate reasons for these athletes' shortened MLS careers. This study supports the view of return to sport not as a single time point but as a continuum from return to participation to return to play and return to performance. PMID- 29399589 TI - Web-Based Education Prior to Outpatient Orthopaedic Surgery Enhances Early Patient Satisfaction Scores: A Prospective Randomized Controlled Study. AB - Background: A good patient-surgeon relationship relies on adequate preoperative education and counseling. Several multimedia resources, such as web-based education tools, have become available to enhance aspects of perioperative care. Purpose/Hypothesis: The purpose of this study was to evaluate the effect of an interactive web-based education tool on perioperative patient satisfaction scores after outpatient orthopaedic surgery. It was hypothesized that web-based education prior to outpatient orthopaedic surgery enhances patient satisfaction scores. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: All patients undergoing knee arthroscopy with meniscectomy, chondroplasty, or anterior cruciate ligament reconstruction or shoulder arthroscopy with rotator cuff repair were eligible for inclusion and were randomized to the study or control group. The control group received routine education by the surgeon, whereas the study group received additional web-based education. At the first postoperative visit, all patients completed the OAS CAHPS (Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems) survey. Differences in patient satisfaction scores between the study and control groups were determined with an independent t test. Results: A total of 177 patients were included (104 [59%] males; mean age, 42 +/- 14 years); 87 (49%) patients were randomized to receive additional web-based education. Total patient satisfaction score was significantly higher in the study group (97 +/- 5) as compared with the control group (94 +/- 8; P = .019), specifically for the OAS CAHPS core measure "recovery" (92 +/- 13 vs 82 +/- 23; P = .001). Age, sex, race, workers' compensation status, education level, overall health, emotional health, procedure type and complexity, and addition of a video did not influence patient satisfaction scores. Conclusion: Supplemental web-based patient education prior to outpatient orthopaedic surgery enhances patient satisfaction scores. PMID- 29399590 TI - Medial Patellofemoral Ligament Reconstruction Reduces Radiographic Measures of Patella Alta in Adults. AB - Background: Patellar height has long been considered a risk factor for patellofemoral instability. However, recent pediatric literature demonstrated a reduction in patellar height measurements following medial patellofemoral ligament (MPFL) reconstruction. Purpose: To assess the mean change in patellar height and the percentage of skeletally mature patients with patellar height ratios reduced to within-normal limits following MPFL reconstruction. Study Design: Case series; Level of evidence, 4. Methods: Adult patients undergoing primary MPFL reconstruction for recurrent lateral patellar instability between 2005 and 2013 were identified. Pre- and postoperative (within 1 year of surgery) lateral knee radiographs were assessed for patellar height indices, including Caton-Deschamps, Blackburne-Peel, and Insall-Salvati ratios. The change in patellar height and the number of patients reduced from abnormal to normal patellar height ratios following MPFL reconstruction were assessed. Results: Overall, 32 adult patients were included in the study, with a mean age of 25.7 years (range, 18-55 years). There were 21 women (66%) and 11 men (34%). Insall Salvati, Blackburne-Peel, and Caton-Deschamps ratios all demonstrated significant reductions in patellar height between pre- and postoperative lateral knee radiographs (P < .001). All 3 indices showed a reduction in the number of patients meeting the criteria for patella alta following MPFL reconstruction. A total of 64% of patients had an abnormal preoperative Caton-Deschamps ratio reduced to within normal limits postoperatively. Conclusion: MPFL reconstruction provides a consistent reduction in patellar height measurements. The Caton Deschamps ratio was reduced to the reference range following MPFL reconstruction in 64% of patients with preoperative patella alta. Surgeons treating patellofemoral instability should expect a reduction in patellar height after ligament reconstruction, which may affect the need for more invasive distalization procedures. PMID- 29399592 TI - Rule-based and Word-level Statistics-based Processing of Language: Insights from Neuroscience. AB - To flexibly convey meaning, the human language faculty iteratively combines smaller units such as words into larger structures such as phrases based on grammatical principles. During comprehension, however, it remains unclear how the brain encodes the relationship between words and combines them into phrases. One hypothesis is that internal grammatical principles governing language generation are also used to parse the hierarchical syntactic structure of spoken language during comprehension. An alternative hypothesis suggests, in contrast, that decoding language during comprehension solely relies on statistical relationships between words or strings of words, i.e., the N-gram statistics, while grammatical rules are not used and no hierarchical linguistic structures are constructed. Here, we briefly review distinctions between rule-based hierarchical models and statistics-based linear string models for comprehension, and how the neurolinguistic approach can shed light on this debate. Recent neurolinguistic studies show that tracking of probabilistic relationships between words is not sufficient to explain cortical encoding of linguistic constituent structure and support the involvement of rule-based processing during language comprehension. PMID- 29399591 TI - Underappreciated Factors to Consider in Revision Anterior Cruciate Ligament Reconstruction: A Current Concepts Review. AB - Primary anterior cruciate ligament (ACL) reconstructions (ACLRs) are being performed with increasing frequency. While many of these will have successful outcomes, failures will occur in a subset of patients who will require revision ACLRs. As such, the number of revision procedures will continue to rise as well. While many reviews have focused on factors that commonly contribute to failure of primary ACLR, including graft choice, patient factors, early return to sport, and technical errors, this review focused on several factors that have received less attention in the literature. These include posterior tibial slope, varus malalignment, injury to the anterolateral ligament, and meniscal injury or deficiency. This review also appraised several emerging techniques that may be useful in the context of revision ACL surgery. While outcomes of revision ACLR are generally inferior to those of primary procedures, identifying these potentially underappreciated contributing factors preoperatively will allow the surgeon to address them at the time of revision, ideally improving patient outcomes and preventing recurrent ACL failure. PMID- 29399593 TI - Learning new meanings for known words: Biphasic effects of prior knowledge. AB - In acquiring word meanings, learners are often confronted by a single word form that is mapped to two or more meanings. For example, long after how to roller "skate", one may learn that "skate" is also a kind of fish. Such learning of new meanings for familiar words involves two potentially contrasting processes, relative to new form-new meaning learning: 1) Form-based familiarity may facilitate learning a new meaning, and 2) meaning-based interference may inhibit learning a new meaning. We examined these two processes by having native English speakers learn new, unrelated meanings for familiar (high frequency) and less familiar (low frequency) English words, as well as for unfamiliar (novel or pseudo-) words. Tracking learning with cued-recall tasks at several points during learning revealed a biphasic pattern: higher learning rates and greater learning efficiency for familiar words relative to novel words early in learning and a reversal of this pattern later in learning. Following learning, interference from original meanings for familiar words was detected in a semantic relatedness judgment task. Additionally, lexical access to familiar words with new meanings became faster compared to their exposure controls, but no such effect occurred for less familiar words. Overall, the results suggest a biphasic pattern of facilitating and interfering processes: Familiar word forms facilitate learning earlier, while interference from original meanings becomes more influential later. This biphasic pattern reflects the co-activation of new and old meanings during learning, a process that may play a role in lexicalization of new meanings. PMID- 29399594 TI - Interactions between Lexical Access and Articulation. AB - This study investigates the interaction of lexical access and articulation in spoken word production, examining two dimensions along which theories vary. First, does articulatory variation reflect a fixed plan, or do lexical access articulatory interactions continue after response initiation? Second, to what extent are interactive mechanisms hard-wired properties of the production system, as opposed to flexible? In two picture-naming experiments, we used semantic neighbor manipulations to induce lexical and conceptual co-activation. Our results provide evidence for multiple sources of interaction, both before and after response initiation. While interactive effects can vary across participants, we do not find strong evidence of variation of effects within individuals, suggesting that these interactions are relatively fixed features of each individual's production system. PMID- 29399595 TI - The role of linguistic experience in the processing of probabilistic information in production. AB - Speakers track the probability that a word will occur in a particular context and utilize this information during phonetic processing. For example, content words that have high probability within a discourse tend to be realized with reduced acoustic/articulatory properties. Such probabilistic information may influence L1 and L2 speech processing in distinct ways (reflecting differences in linguistic experience across groups and the overall difficulty of L2 speech processing). To examine this issue, L1 and L2 speakers performed a referential communication task, describing sequences of simple actions. The two groups of speakers showed similar effects of discourse-dependent probabilistic information on production, suggesting that L2 speakers can successfully track discourse-dependent probabilities and use such information to modulate phonetic processing. PMID- 29399596 TI - Cost-effectiveness of WHO-Recommended Algorithms for TB Case Finding at Ethiopian HIV Clinics. AB - Background: The World Health Organization (WHO) recommends active tuberculosis (TB) case finding and a rapid molecular diagnostic test (Xpert MTB/RIF) to detect TB among people living with HIV (PLHIV) in high-burden settings. Information on the cost-effectiveness of these recommended strategies is crucial for their implementation. Methods: We conducted a model-based cost-effectiveness analysis comparing 2 algorithms for TB screening and diagnosis at Ethiopian HIV clinics: (1) WHO-recommended symptom screen combined with Xpert for PLHIV with a positive symptom screen and (2) current recommended practice algorithm (CRPA; based on symptom screening, smear microscopy, and clinical TB diagnosis). Our primary outcome was US$ per disability-adjusted life-year (DALY) averted. Secondary outcomes were additional true-positive diagnoses, and false-negative and false positive diagnoses averted. Results: Compared with CRPA, combining a WHO recommended symptom screen with Xpert was highly cost-effective (incremental cost of $5 per DALY averted). Among a cohort of 15 000 PLHIV with a TB prevalence of 6% (900 TB cases), this algorithm detected 8 more true-positive cases than CRPA, and averted 2045 false-positive and 8 false-negative diagnoses compared with CRPA. The WHO-recommended algorithm was marginally costlier ($240 000) than CRPA ($239 000). In sensitivity analysis, the symptom screen/Xpert algorithm was dominated at low Xpert sensitivity (66%). Conclusions: In this model-based analysis, combining a WHO-recommended symptom screen with Xpert for TB diagnosis among PLHIV was highly cost-effective ($5 per DALY averted) and more sensitive than CRPA in a high-burden, resource-limited setting. PMID- 29399597 TI - Getting to the Heart of the Matter: A 20-Year-Old Man With Fever, Rash, and Chest Pain. AB - Infection with Helicobacter cinaedi can encompass a wide spectrum of clinical manifestations, including fever, rash, endocarditis, osteomyelitis, and meningitis. The present case demonstrates the ability of H cinaedi to masquerade as acute rheumatic fever and represents the first reported case of cardiac tamponade caused by H cinaedi. PMID- 29399598 TI - Long-Acting Lipoglycopeptides for Gram-Positive Bacteremia at the End of Life to Facilitate Hospice Care: A Report of 3 Cases. AB - Administering and monitoring intravenous antimicrobials may cause discomfort in patients at the end of life and delay transition to hospice. We describe 3 patients with terminal cancer with methicillin-resistant Staphylococcus aureus, Streptococcus gallolyticus, and Granulicatella adiacens bacteremia who were managed with the long-acting lipoglycopeptide oritavancin to facilitate discharge to hospice. PMID- 29399599 TI - Temporal Causality Analysis of Sentiment Change in a Cancer Survivor Network. AB - Online health communities constitute a useful source of information and social support for patients. American Cancer Society's Cancer Survivor Network (CSN), a 173,000-member community, is the largest online network for cancer patients, survivors, and caregivers. A discussion thread in CSN is often initiated by a cancer survivor seeking support from other members of CSN. Discussion threads are multi-party conversations that often provide a source of social support e.g., by bringing about a change of sentiment from negative to positive on the part of the thread originator. While previous studies regarding cancer survivors have shown that members of an online health community derive benefits from their participation in such communities, causal accounts of the factors that contribute to the observed benefits have been lacking. We introduce a novel framework to examine the temporal causality of sentiment dynamics in the CSN. We construct a Probabilistic Computation Tree Logic representation and a corresponding probabilistic Kripke structure to represent and reason about the changes in sentiments of posts in a thread over time. We use a sentiment classifier trained using machine learning on a set of posts manually tagged with sentiment labels to classify posts as expressing either positive or negative sentiment. We analyze the probabilistic Kripke structure to identify the prima facie causes of sentiment change on the part of the thread originators in the CSN forum and their significance. We find that the sentiment of replies appears to causally influence the sentiment of the thread originator. Our experiments also show that the conclusions are robust with respect to the choice of the (i) classification threshold of the sentiment classifier; (ii) and the choice of the specific sentiment classifier used. We also extend the basic framework for temporal causality analysis to incorporate the uncertainty in the states of the probabilistic Kripke structure resulting from the use of an imperfect state transducer (in our case, the sentiment classifier). Our analysis of temporal causality of CSN sentiment dynamics offers new insights that the designers, managers and moderators of an online community such as CSN can utilize to facilitate and enhance the interactions so as to better meet the social support needs of the CSN participants. The proposed methodology for analysis of temporal causality has broad applicability in a variety of settings where the dynamics of the underlying system can be modeled in terms of state variables that change in response to internal or external inputs. PMID- 29399600 TI - Infectious Subviral Particle to Membrane Penetration Active Particle (ISVP-to ISVP*) Conversion Assay for Mammalian Orthoreovirus. AB - The mammalian orthoreovirus (reovirus) outer capsid undergoes a series of conformational changes prior to or during viral entry. These transitions are necessary for delivering the genome-containing core across host cell membranes. This protocol describes an in vitro assay for monitoring the transition into a membrane penetration-active form (i.e., ISVP*). PMID- 29399601 TI - Exploring the Experiences of Deportation and Reintegration of Aging Deported Men in Trinidad and Tobago. AB - Older deported men in Trinidad and Tobago face unique challenges in reintegrating into life after deportation. This qualitative study examined the intersection of aging and deportation to identify factors that affect the reintegration experiences of aging deported men. Qualitative interviews were conducted with 16 deported men over the age of 50 and were analyzed using the constant comparison method. Findings show that reintegration was influenced by complex intrapersonal, subsistence, and social challenges. The findings in this study point to the need to expand social support networks available to aging deported men and provide greater opportunities for them to meet their economic and subsistence needs, and the need to strengthen strategies to reduce the stigma and discrimination associated with aging deported populations. PMID- 29399602 TI - Hyperkalemia Was an Independent Risk Factor for Death While Under Mechanical Ventilation Among Children Hospitalized With Diarrhea in Bangladesh. AB - Objectives. We sought to evaluate the admission and hospital risk factors for death in children with diarrhea requiring mechanical ventilation (MV). Methods. This was a retrospective study. We enrolled children aged 0 to 59 months admitted with diarrhea to the intensive care unit of the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) between August 2009 and July 2013 and required MV. To evaluate the risk factors for death in MV, we compared the clinical and laboratory characteristics of the children requiring MV. We matched up to the clinical characteristics presented on admission and subsequently developed before MV during hospital stay with the survivors and deaths of children having MV. Results. Among 73 enrolled children, 58 (80%) died. Incidence of death in MV was higher among children having hyperkalemia (P <= .001), hypoglycemia (P <= .001), and metabolic acidosis (P = .06) on admission and lower in children having tracheal isolates (P <= .001) during hospitalization. After adjusting for covariates by using multivariate robust Poisson regression, children with hyperkalemia (incidence ratio = 1.34; P = .03; confidence interval = 1.02-1.76) on admission was the only independent risk factor for death of children with MV. Conclusion. Children with hyperkalemia on admission and subsequently requiring MV were more likely to die compared with those without hyperkalemia. PMID- 29399603 TI - Preliminary Impacts of an HIV-Prevention Program Targeting Out-of-School Youth in Postconflict Liberia. AB - Adolescents in Sub-Saharan Africa account for greater HIV/STI (human immuno defiency virus/sexually transmitted infection) burdens and difficult-to-reach populations. This study implemented a community-based HIV/STI program to reach at risk youth aged 15 to 17 years in postconflict Liberia. Using a randomized controlled trial, community youths were assigned to an adapted version of an effective HIV/STI program, Making Proud Choices, or attention-matched comparison curriculum, General Health Program. Both programs were of similar doses, reach and coverage, and administered in classroom settings by trained health educators. The findings suggest that the adapted HIV/STI program had positive effects on knowledge, sexual refusal and condom use self-efficacy, condom negotiation self efficacy, positive condom attitudes, parental communication about sex, and negative condom attitudes over time. Culturally adapted community-based, behavioral-driven programs can positively affect mediators of sexual behaviors in at-risk adolescents in postconflict settings. This is the first published report of an evidence-based HIV/STI program on sexual risk-taking behaviors of community youths in Liberia. PMID- 29399604 TI - Cognitive-motivational interactions: beyond boxes-and-arrows models of the mind brain. AB - How do motivation and cognitive control interact in brain and behavior? The past decade has witnessed a steady growth in studies investigating both the behavioral and the brain basis of these interactions. In this paper, I describe such interactions in the context of the dual completion model, which proposes that motivational significance influences both perceptual and executive competition. Embracing a research agenda that attempts to understand cognition-motivation interactions highlights considerable challenges faced by investigators. For example, even the standard language utilized, with terms such as "perception," "attention," "cognition," and "motivation," encourages a modular-like conceptualization of the underlying processes and mechanisms. I propose that large-scale interactions involving both task-related and valuation-related networks help understand how motivation shapes executive function. I argue that, ultimately, the mind and brain sciences need to move beyond "boxes and arrows" and fully embrace the richness and complexity of the interactions between motivation and cognition. In the last 10 years, the study in humans of the interactions of motivation with perception and cognition has grown at a fast pace. The growth has included behavioral studies characterizing the processes involved, and neuroimaging studies investigating the regions and circuits underlying the behaviors in question. This literature acknowledges the fact that perception and cognition do not happen in a vacuum but are, instead, situated in contexts that feature value. Although this assertion is uncontroversial, the mind and brain sciences have studied perception and cognition for many decades by largely extricating value from them. Fortunately, this state of affairs has now changed and the field has a newfound vigor in attempting to understand the impact of motivation on these mental functions. PMID- 29399605 TI - Improved Thermal and Electrical Properties of Nanocomposites Based on Poly(vinyl pyrrolidone)/Poly(acrylonitrile)/Multiwalled Carbon Nanotubes. AB - Poly(vinyl pyrrolidone)/Poly(acrylonitrile)/multi-walled carbon nanotubes composites (PVP/PAN/MWNTs) were fabricated by a simple solution cast technique with a wide composition range from 0 to 3.12 wt% of MWNTs. The nanocomposites were characterized by fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). A percolated MWNTs network structure and relatively good dispersion of MWNTs are evident in PVP/PAN/MWNTs nanocomposites with 3.12 wt% of MWNTs. The thermal properties of the polymer blend with MWNTs were carried out by means of different scanning calorimetry (DSC). It indicated that the incorporation of MWNTs had a significant influence on crystallization and melting behaviors for the polymer nanocomposites. The four point probe method was used to measure the electrical conductivity, and the result showed ionic conductivity of the order of 2.87 * 10-4 S/cm to 1.91 * 10-2 S/cm. The effect of the concentration of the filler on the conductivity of the polymer nanocomposite was discussed. Nanocomposites based on PVP/PAN and MWNTs as filler show a significant enhancement in the electrical conductivity as a function of temperature. The low percolation threshold in PVP/PAN/MWNTs nanocomposites was explained by high aspect ratio of the nanotubes and their distribution inside the polymer blend. PMID- 29399606 TI - A BRIEF INTRODUCTION TO THE NEUROGENETICS OF COGNITION-EMOTION INTERACTIONS. AB - Neuroscience research has demonstrated that cognition, emotion, and their dynamic interactions emerge from complex and flexible patterns of activity across distributed neural circuits. A parallel branch of research in genetics has begun to identify common variation in the human DNA sequence (i.e., genome) that may shape individual differences in cognition-emotion interactions by altering molecular and cellular pathways that modulate the activity of these neural circuits. Here we provide a brief introduction to such neurogenetics research and how it may usefully inform our understanding of the biological mechanisms through which dynamic cognition-emotion interactions emerge and, subsequently, help shape normal and abnormal behavior. PMID- 29399607 TI - Synthesis, characterization, and electrospinning of novel polyaniline-peptide polymers. AB - Aniline-peptide (FLDQV, FLDQVC, Dansyl-FLDQV, Dansyl-FLDQVC, and FLDQV-AMC) mixtures underwent oxidative chemical and electrochemical polymerization in excess of aniline. The products of the chemical polymerization were low molecular weight polymers containing more than 70% peptide. Electrochemically polymerized species polyaniline-FLDQV (PANI-FLDQV) consisted mainly of polyaniline units containing about 10% peptide. The solubility of the latter in 1,1,1,3,3,3 hexafluoro-2-propanol (HFP) was similar to the camphorsulfonic acid (CSA) doped emeraldine base (PANI-CSA) solubility, however the weight composition of the electrospun fibers produced from the two polymers was significantly different. 2D 1H-13C HSQC analyses were employed to analyze the binding between the aniline and peptide moieties. Binding of peptide to polyaniline is reflected by the appearance of extra cross-peaks which display line broadening between the free polyaniline and the free pentapeptide. Peptides may be chemically bonded to the polymer molecules, but they may also act as doping agents to the nitrogen atoms via hydrogen bonding. PMID- 29399608 TI - Endoscopic ultrasound-guided hepaticogastrostomy and antegrade clearance of biliary lithiasis in patients with surgically-altered anatomy. AB - Background and study aims: Endoscopic retrograde cholangiography (ERC) in patients with complex surgically-altered anatomy (SAA) is technically demanding and has limitations. Developments in EUS-guided procedures allow alternative approaches for patients with altered gastrointestinal anatomy and biliary lithiasis. Patients and methods: Single-center, retrospective review of prospectively entered patients with SAA who underwent EUS-guided hepaticogastrostomy (HGS) followed by an interval antegrade endoscopic clearance of biliary lithiasis. Results: 9 patients with Roux-en-Y anatomy underwent HGS to allow clearance of biliary lithiasis after a mean of 2.5 procedures. Technical success was achieved in 100 % of patients utilizing subsequent antegrade endoscopic techniques after HGS including: balloon sweep (9), transpapillary balloon dilation (8), cholangioscopy with electrohydraulic lithotripsy (4), and mechanical lithotripsy (1). HGS stents were removed in all patients. 1 adverse event (cholangitis) occurred after cholangioscopy and prolonged intraductal electrohydraulic lithotripsy. Conclusion: EUS-guided antegrade therapy for the management of biliary lithiasis in patients with altered gastrointestinal anatomy appears efficacious with a low risk of adverse events. These preliminary results suggest this approach should be considered at centers with available expertise. PMID- 29399609 TI - Complex biliary stones management: cholangioscopy versus papillary large balloon dilation - a randomized controlled trial. AB - Background and study aims: Endoscopic removal of biliary stones has high success rates, ranging between 85 % to 95 %. Nevertheless, some stones may be challenging and different endoscopic methods have evolved. Papillary large balloon dilation after sphincterotomy is a widely used technique with success rates ranging from 68 to 90 % for stones larger than 15 mm. Cholangioscopy allows performing lithotripsy under direct biliary visualization, either by laser or electrohydraulic waves, which have similar success rate (80 % - 90 %). However, there is no study comparing these 2 techniques. Patients and methods: From April 2014 to June 2016, 100 patients were enrolled and randomized in 2 groups, using a non-inferiority hypothesis: cholangioscopy + electrohydraulic lithotripsy (group 1) and endoscopic papillary large balloon dilation (group 2). The main outcome was complete stone removal. Adverse events were documented. Mechanical lithotripsy was not performed. Failure cases had a second session with crossover of the methods. Results: The mean age was 56 years. 74 (75.5 %) patients were female. The initial overall complete stone removal rate was 74.5 % (77.1 % in group 1 and 72 % in group 2, P > 0.05). After second session the overall success rate achieved 90.1 %. Procedure time was significantly lower in group 2, - 25.2 min (CI95 % - 12.48 to - 37.91). There were no significant differences regarding technical success rate, radiologic exposure and adverse events. Conclusion: Single-operator cholangioscopy-guided lithotripsy and papillary large balloon dilation are effective and safe approaches for removing complex biliary stones. PMID- 29399610 TI - Deep learning analyzes Helicobacter pylori infection by upper gastrointestinal endoscopy images. AB - Background and study aims : Helicobacter pylori (HP)-associated chronic gastritis can cause mucosal atrophy and intestinal metaplasia, both of which increase the risk of gastric cancer. The accurate diagnosis of HP infection during routine medical checks is important. We aimed to develop a convolutional neural network (CNN), which is a machine-learning algorithm similar to deep learning, capable of recognizing specific features of gastric endoscopy images. The goal behind developing such a system was to detect HP infection early, thus preventing gastric cancer. Patients and methods: For the development of the CNN, we used 179 upper gastrointestinal endoscopy images obtained from 139 patients (65 were HP-positive: >= 10 U/mL and 74 were HP-negative: < 3 U/mL on HP IgG antibody assessment). Of the 179 images, 149 were used as training images, and the remaining 30 (15 from HP-negative patients and 15 from HP-positive patients) were set aside to be used as test images. The 149 training images were subjected to data augmentation, which yielded 596 images. We used the CNN to create a learning tool that would recognize HP infection and assessed the decision accuracy of the CNN with the 30 test images by calculating the sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (AUC). Results: The sensitivity and specificity of the CNN for the detection of HP infection were 86.7 % and 86.7 %, respectively, and the AUC was 0.956. Conclusions: CNN-aided diagnosis of HP infection seems feasible and is expected to facilitate and improve diagnosis during health check-ups. PMID- 29399611 TI - Multiple convex demarcation line for prediction of benign depressed gastric lesions in magnifying narrow-band imaging. AB - Background and study aims: With magnifying narrow-band imaging (M-NBI) of the gastric mucosa, a characteristic demarcation line (DL) is occasionally found in non-cancerous depressed lesions. This DL forms multiple convex shapes along the edge of the epithelia of surrounding mucosa. We have termed this novel finding a multiple convex DL (MCDL). In this study, we clarified the prevalence of an MCDL in depressed gastric lesions detected in patients at high risk for gastric cancer and determined the diagnostic yield necessary to distinguish between cancer and non-cancer. Patients and methods: This was a post hoc analysis of a multicenter prospective trial. In total, 362 small (<= 10 mm) depressed lesions were detected in 1353 patients. Presence or absence of a DL in target lesions was evaluated on M-NBI images. The proportion of MCDLs among lesions with a DL was evaluated. Results : Images of 347 lesions (39 cancerous and 308 non-cancerous) were evaluable. A DL was present in 252/347 lesions (73 %). When the cutoff value for the proportion of MCDLs needed to distinguish non-cancer from cancer was set at two-thirds, an MCDL was observed in 86/252 lesions (34 %). In 86 lesions with an MCDL, 83 (97 %) were non-cancerous. The sensitivity, specificity, positive predictive value, and negative predictive value of an MCDL for non-cancerous lesions were 38 %, 91 %, 97 %, and 19 %, respectively. Conclusions: Presence of an MCDL had high specificity and positive predictive value for non-cancerous lesions. Evaluating the shape of the DL is useful for differentiation between cancer and non-cancerous lesions. PMID- 29399612 TI - Validity of conventional endoscopy using "non-extension sign" for optical diagnosis of colorectal deep submucosal invasive cancer. AB - Background and study aims: The non-extension sign relates to a localized increase in thickness and rigidity due to deep submucosal invasive (SM-d: depth of 1000 MUm or more) cancer. The present study aimed to evaluate the efficacy of the non-extension sign in assessing the optical diagnosis of colorectal SM-d cancer. Patients and methods: We retrospectively analyzed 309 patients with 315 early colorectal cancers that had been endoscopically or surgically resected. The non-extension sign was judged from chromoendoscopy (CE) using conventional white light imaging with indigo carmine, and is taken to be positive when any one of the findings of rigidity of a circular arc, trapezoid elevation, or converging mucosal folds are seen. We assessed comparing the accuracy of CE, magnifying chromoendoscopy (M-CE), and magnifying narrow-band imaging (M-NBI) for the optical diagnosis of colorectal SM-d cancer. Results : Sensitivity, specificity, and accuracy for the diagnosis of SM-d cancer were 66.0 %, 95.8 %, and 86.3 % for CE; 80 %, 90.7 %, and 87.3 % for M-CE; and 65.0 %, 94.4 %, and 85.1 % for M-NBI, respectively. The specificity of CE was significantly higher than that of M-CE ( P = 0.034). The sensitivity of M-CE was significantly higher than that of CE ( P = 0.026). In a comparison of positive and negative groups for the non-extension sign in SM-d cancer, SM invasion was significantly deeper in the positive group than in the negative group (3012.5 MUm vs 2002.4 MUm, respectively; P < 0.0001) and the rate of lymphovascular invasion was significantly higher in the positive group than in the negative group (63.6 % vs 41.2 %, respectively; P = 0.032). Conclusions: The non-extension sign offers high diagnostic specificity for SM-d cancer, and surgery should be considered in patients with a positive non extension sign. PMID- 29399613 TI - Ankylosaurus back sign: novel endoscopic finding in esophageal eosinophilia patients indicating proton pump inhibitor response. AB - Background and study aims : Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods : Fifty-five patients diagnosed with EE (>= 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results: Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (kappa 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions: Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further. PMID- 29399614 TI - High complete resection rate for pre-lift and cold biopsy of diminutive colorectal polyps. AB - Background and study aims: The majority of polyps removed at colonoscopy are diminutive (<= 5 mm) to small (< 10 mm) and there are few guidelines for the best way for these polyps to be removed. We aimed to assess the feasibility and effectiveness of cold biopsy forceps polypectomy with pre-lift (CBPP) for polyps <= 7 mm. Our aims were to assess completeness of histological resection of this technique, to identify factors contributing to this and assess secondary considerations such as timing, retrieval and complication rates. Patients and methods : We conducted a prospective cohort study on consecutive patients receiving a colonoscopy at Cheltenham General Hospital, as part of the National Bowel Cancer Screening Program (BCSP) in England. The study included only polyps that were judged as <= 7 mm by the colonoscopist. A small sub-mucosal pre-lift injection was administered prior to removal of the polyp using cold biopsy forceps. One or more biopsies were taken until the polyp was confidently assessed visually as being completely removed by the colonoscopist. The entire polypectomy site was then removed en bloc by endomucosal resection (EMR) with a margin of at least 1 to 2 mm around defect. This was sent for histopathological analysis to assess completeness of resection. Polypectomy timing, tissue retrieval, number of bites required for visual resection and complications were recorded at the time of the procedure. Results : Sixty-four patients were recruited and consented. Of them, 42 patients had a total of 60 polyps resected. Three patients had inflammatory polyps and were excluded from the study, leaving 57/60 polyps for final analysis. Seventeen were hyperplastic and 40 adenomatous polyps. Retrieval was complete for all 57 polyps and there were no complications both during or post- polypectomy. The complete resection rate (CRR) was 86 %. The technique was more effective in smaller polyps with 91.7 % of diminutive polyps (<= 5 mm) completely excised. Conclusions : CBPP is a safe and highly effective technique for polyps < 5 mm with a high complete resection and retrieval rate. The time taken for the procedure is significantly greater than cold forceps alone, or cold snare as seen in other studies. PMID- 29399615 TI - Initial experience with percutaneous endoscopic gastrostomy with T-fastener fixation in pediatric patients. AB - Background and study aims: Insertion of a percutaneous endoscopic gastrostomy (PEG) with push-through technique and T-fastener fixation (PEG-T) has recently been introduced in pediatric patients. The T-fasteners allow a primary insertion of a balloon gastrostomy. Due to limited data on the results of this technique in children, we have investigated peri- and postoperative outcomes after implementation of PEG-T in our department. Patients and methods: This retrospective chart review included all patients below 18 years who underwent PEG T placement from 2010 to 2014. Main outcomes were 30-day postoperative complications and late gastrostomy-related complications. Results: In total, 87 patients were included, and median follow-up time was 2.4 years (1 month - 4.9 years). Median age and weight at PEG-T insertion were 1.9 years (9.4 months - 16.4 years) and 10.4 kg (5.4 - 33.0 kg), respectively. Median operation time was 28 minutes (10 - 65 minutes), and 6 surgeons and 3 endoscopists performed the procedures. During the first 30 days, 54 complications occurred in 41 patients (47 %). Most common were peristomal infections treated with either local antibiotics in 11 patients (13 %) or systemic antibiotics in 11 other patients (13 %). 9 patients (10 %) experienced tube dislodgment. Late gastrostomy-related complications occurred in 33 patients (38 %). The T-fasteners caused early and late complications in 9 (10 %) and 11 patients (13 %), respectively. Of these, 4 patients (5 %) had subcutaneously migrated T-fasteners which were removed under general anesthesia. Conclusion: We found a high rate of complications after PEG T. In particular, problems with the T-fasteners and tube dislodgment occurred frequently after PEG-T insertion. PMID- 29399616 TI - A case of a rectal stricture related to ischemic proctitis following rupture of an aortic aneurysm. AB - Background and study aims Ischemic proctitis is a rare disease and comprises 2 % to 5 % of cases of ischemic colitis, because the rectum has abundant blood supply and rich collaterals. Herein, we report a case of a 73-year-old male patient with a pronounced rectal stricture caused by ischemic proctitis resulting from an abdominal aortic rupture and treated by endoscopic balloon dilation therapy. To date, only 3 cases of rectal stricture related to ischemic proctitis including our case have been reported, and this is the first case of rectal stricture related to ischemic proctitis, which was successfully treated by endoscopic balloon dilation. PMID- 29399617 TI - Outcomes of anterior myotomy versus posterior myotomy during POEM: a randomized pilot study. AB - Background and study aims: Peroral endoscopic myotomy (POEM) can be performed via an anterior or posterior approach, depending on the operator's preference. Data are lacking on comparative outcomes of both approaches. Patients and methods: This is a pilot randomized study comparing endoscopic anterior and posterior myotomy during POEM in patients with Achalasia cardia (AC). Patients were randomized into 2 groups (n = 30 in each group); anterior myotomy group (AG) and posterior myotomy group (PG) and were followed at 1, 3 and 6 months after POEM. Results: Technical success was achieved in 100 % of cases in both groups and total operative time was comparable (AG - 65 +/- 17.65 minutes versus PG - 61.2 +/- 16.67; P = 0.38); Mucosotomies were more frequent in AG (20 % vs 3.3 %; P = 0.02). Difference in other perioperative adverse events (AE) including insufflation-related AE and bleeding in both groups were statistically insignificant. At 1-month follow-up Eckardt score AG 0.57 +/- 0.56 vs PG 0.53 +/- 0.71; ( P = 0.81), mean LES pressure AG 11.93 +/- 6.36 vs PG 11.77 +/- 6.61; ( P = 0.59) and esophageal emptying on timed barium swallow at 5 minutes AG 1.32 +/- 1.08 cm vs PG 1.29 +/- 0.79 cm; ( P = 0.09) were comparable in both groups. At 3 months, Eckardt score (0.52 +/- 0.59 vs 0.63 +/- 0.62; P = 0.51) was similar in both groups. Incidence of esophagitis on EGD was comparable in both groups (24 % vs 33.3 %; P = 0.45), however, pH metry at 3 months showed significantly more esophageal acid exposure in posterior group (2.98 % +/- 4.24 vs 13.99 % +/- 14.48; P < 0.01). At 6 months clinical efficacy and LES pressures were comparable in both groups. Conclusion: Anterior and posterior approaches to POEM seem to have equal efficacy. However, the occurrence of mucosotomies was higher in the anterior myotomy group and acid exposure was higher with the posterior myotomy approach during POEM. PMID- 29399618 TI - Usefulness of cholangioscopic-guided mapping biopsy using SpyGlass DS for preoperative evaluation of extrahepatic cholangiocarcinoma: a pilot study. AB - Background and study aims: Evaluation of longitudinal tumor extent is indispensable for curative surgical treatment of extrahepatic cholangiocarcinoma. The aim of this study was to evaluate the usefulness and feasibility of cholangioscopic-guided mapping biopsy using a newly developed peroral digital cholangioscope, SpyGlass DS (SpyDS), for preoperative evaluation of extrahepatic cholangiocarcinoma. Patients and methods: Thirteen patients (mean age, 75 years; male 10, female 3) with extrahepatic cholangiocarcinoma who underwent cholangioscopic-guided mapping biopsy using SpyDS for preoperative evaluation were included in this study. Successful cholangioscopic-guided mapping biopsy was defined as the acquisition of specimens sufficient for histopathological diagnosis. Results: The mean number of biopsies was 5 per patient. The overall success rate for cholangioscopic-guided mapping biopsy was 88 % (59/67). The success rate for cholangioscopic-guided mapping biopsy from the confluence of the right and left hepatic ducts was 89 %, that from the B4 confluence was 93 %, that from the confluence of the right anterior and right posterior segmental ducts was 86 %, that from the intrapancreatic common bile duct was 67 %, and that from the main lesion was 100 %. The overall diagnostic accuracy of longitudinal tumor extent at the hepatic side, the duodenal side and overall by cholangioscopic findings and mapping biopsy, was 88 % (7/8), 88 % (7/8) and 88 % (7/8), respectively. Assessment according to location of the main lesion revealed that diagnostic accuracy in the patients with distal bile duct carcinoma was 100 % (5/5) and that in patients with perihilar bile duct carcinoma was 66 % (2/3). Complications after the procedure did not occur in any patients. Conclusions: Cholangioscopic-guided mapping biopsy using SpyDS is thought to be feasible for preoperative evaluation of extrahepatic cholangiocarcinoma. PMID- 29399619 TI - Novel experimental and software methods for image reconstruction and localization in capsule endoscopy. AB - Background and study aims : Capsule endoscopy (CE) is invaluable for minimally invasive endoscopy of the gastrointestinal tract; however, several technological limitations remain including lack of reliable lesion localization. We present an approach to 3D reconstruction and localization using visual information from 2D CE images. Patients and methods : Colored thumbtacks were secured in rows to the internal wall of a LifeLike bowel model. A PillCam SB3 was calibrated and navigated linearly through the lumen by a high-precision robotic arm. The motion estimation algorithm used data (light falling on the object, fraction of reflected light and surface geometry) from 2D CE images in the video sequence to achieve 3D reconstruction of the bowel model at various frames. The ORB-SLAM technique was used for 3D reconstruction and CE localization within the reconstructed model. This algorithm compared pairs of points between images for reconstruction and localization. Results: As the capsule moved through the model bowel 42 to 66 video frames were obtained per pass. Mean absolute error in the estimated distance travelled by the CE was 4.1 +/- 3.9 cm. Our algorithm was able to reconstruct the cylindrical shape of the model bowel with details of the attached thumbtacks. ORB-SLAM successfully reconstructed the bowel wall from simultaneous frames of the CE video. The "track" in the reconstruction corresponded well with the linear forwards-backwards movement of the capsule through the model lumen. Conclusion: The reconstruction methods, detailed above, were able to achieve good quality reconstruction of the bowel model and localization of the capsule trajectory using information from the CE video and images alone. PMID- 29399620 TI - Exploring the practicing-connections hypothesis: using gesture to support coordination of ideas in understanding a complex statistical concept. AB - In this article, we begin to lay out a framework and approach for studying how students come to understand complex concepts in rich domains. Grounded in theories of embodied cognition, we advance the view that understanding of complex concepts requires students to practice, over time, the coordination of multiple concepts, and the connection of this system of concepts to situations in the world. Specifically, we explore the role that a teacher's gesture might play in supporting students' coordination of two concepts central to understanding in the domain of statistics: mean and standard deviation. In Study 1 we show that university students who have just taken a statistics course nevertheless have difficulty taking both mean and standard deviation into account when thinking about a statistical scenario. In Study 2 we show that presenting the same scenario with an accompanying gesture to represent variation significantly impacts students' interpretation of the scenario. Finally, in Study 3 we present evidence that instructional videos on the internet fail to leverage gesture as a means of facilitating understanding of complex concepts. Taken together, these studies illustrate an approach to translating current theories of cognition into principles that can guide instructional design. PMID- 29399621 TI - Teaching the science of learning. AB - The science of learning has made a considerable contribution to our understanding of effective teaching and learning strategies. However, few instructors outside of the field are privy to this research. In this tutorial review, we focus on six specific cognitive strategies that have received robust support from decades of research: spaced practice, interleaving, retrieval practice, elaboration, concrete examples, and dual coding. We describe the basic research behind each strategy and relevant applied research, present examples of existing and suggested implementation, and make recommendations for further research that would broaden the reach of these strategies. PMID- 29399622 TI - Visual adaptation and the amplitude spectra of radiological images. AB - We examined how visual sensitivity and perception are affected by adaptation to the characteristic amplitude spectra of X-ray mammography images. Because of the transmissive nature of X-ray photons, these images have relatively more low frequency variability than natural images, a difference that is captured by a steeper slope of the amplitude spectrum (~ - 1.5) compared to the ~ 1/f (slope of - 1) spectra common to natural scenes. Radiologists inspecting these images are therefore exposed to a different balance of spectral components, and we measured how this exposure might alter spatial vision. Observers (who were not radiologists) were adapted to images of normal mammograms or the same images sharpened by filtering the amplitude spectra to shallower slopes. Prior adaptation to the original mammograms significantly biased judgments of image focus relative to the sharpened images, demonstrating that the images are sufficient to induce substantial after-effects. The adaptation also induced strong losses in threshold contrast sensitivity that were selective for lower spatial frequencies, though these losses were very similar to the threshold changes induced by the sharpened images. Visual search for targets (Gaussian blobs) added to the images was also not differentially affected by adaptation to the original or sharper images. These results complement our previous studies examining how observers adapt to the textural properties or phase spectra of mammograms. Like the phase spectrum, adaptation to the amplitude spectrum of mammograms alters spatial sensitivity and visual judgments about the images. However, unlike the phase spectrum, adaptation to the amplitude spectra did not confer a selective performance advantage relative to more natural spectra. PMID- 29399623 TI - Chronic Pancreatitis Associated Acute Respiratory Failure. AB - Pancreatitis is a condition characterized by parenchymal inflammation of the pancreas, which is often associated with lung injury due to low level of oxygen and the condition is termed as acute pancreatitis-associated lung injury (APALI). Clinical reports indicated that ~ 20% to 50% of patients from low oxygen levels in blood with acute respiratory distress syndrome (ARDS). ARDS is a severe form of acute lung injury (ALI), a pulmonary disease with impaired airflow making patients difficult to breathe. ALI is frequently observed in patients with severe acute pancreatitis. Approximately one third of severe pancreatitis patients develop acute lung injury and acute respiratory distress syndrome that account for 60% of all deaths within the first week. The major causes of ALI and ARDS are sepsis, trauma, aspiration, multiple blood transfusion, and most importantly acute pancreatitis. The molecular mechanisms of ALI and ARDS are still not well explored, but available reports indicate the involvement of several pro inflammatory mediators including cytokines (TNF-alpha, IL-1beta, IL-6) and chemokines [like interleukin-8 (IL-8) and macrophage inhibitory factor (MIF)], as well as macrophage polarization regulating the migration and pulmonary infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the pulmonary parenchyma. Acute lung injury and acute respiratory distress syndrome in acute pancreatitis remains an unsolved issue and needs more research and resources to develop effective treatments and therapies. However, recent efforts have tested several molecules in an experimental model and showed promising results as a treatment option. The current review summarized the mechanism that is operational in pancreatitis-associated acute respiratory failure and respiratory distress syndrome in patients and current treatment options. PMID- 29399624 TI - Fluctuations of Estimated Glomerular Filtration Rate Outside Kidney Disease Improving Global Outcomes Diagnostic Criteria for Acute Kidney Injury in End Stage Liver Disease Outpatients and Outcome Postliver Transplantation. AB - Background: Renal dysfunction in end-stage liver disease (ESLD) results from systemic conditions that affect both liver and kidney with activation of vasoconstrictor systems. In this setting, estimated glomerular filtration rate (eGFR) may undergo variations often outside Kidney Disease Improving Global Outcomes criteria for acute kidney injury (AKI) diagnosis, whose meaning is not clear. The aim of this study was to evaluate eGFR variations in ESLD outpatients listed for liver transplant (liver Tx) and the association with post-Tx outcome. Methods: Fifty-one patients with ESLD were retrospectively evaluated from listing to transplant (L-Tx time), intraoperatively (Tx time), and up to 5 years post-Tx time. Variations between the highest and the lowest eGFR occurring in more than 48 hours, not satisfying Kidney Disease Improving Global Outcomes guideline, were considered as fluctuations (eGFR-F). Fluctuations of eGFR greater than 50% were defined as eGFR drops (DeGFR). Early graft dysfunction, AKI within 7 days, chronic kidney disease, and short- and long-term patient survivals were considered as outcomes. Results: All patients presented eGFR-F, whereas DeGFR were observed in 18 (35.3%) of 51 (DeGFR+ group). These patients presented higher levels of Model for End-stage Liver Disease score, pre-Tx bilirubin and significantly greater incidence of post-Tx AKI stages 2 to 3 compared with patients without drops (DeGFR-). DeGFR was the only independent predictive factor of the occurrence of post-Tx AKI. The occurrence of AKI post-Tx was associated with the development of chronic kidney disease at 3 months and 5 years post-Tx. Conclusions: Drops of eGFR are more frequently observed in patients with a worse degree of ESLD and are associated with a worse post-Tx kidney outcome. PMID- 29399625 TI - Successful Desensitization of T cell Flow Cytometry Crossmatch Positive Renal Transplant Recipients Using Plasmapheresis and Super High-Dose Intravenous Immunoglobulin. AB - Background: High-dose IVIG (2 g/kg) alone or low-dose IVIG (100 mg/kg) in conjunction with plasma exchange is typically administered as a renal transplantation desensitization therapy. Herein, we monitored changes in T cell and B cell flow cytometry crossmatch (FCXM) to assess the effects of short-term super high-dose IVIG (4 g/kg) administration with plasmapheresis before living donor renal transplantation. Methods: Seventeen patients, each showing positive T cell FCXM (median ratio, >= 1.4) after 2 rounds of double-filtration plasmapheresis, received 4-day regimens of IVIG (1 g/kg per day) over 1-week periods. T cell and B cell FCXM determinations were obtained after every IVIG dose and again up to 4 weeks after initiating IVIG to ascertain negative conversion of T cell FCXM (median ratio < 1.4). The primary study endpoint was the percentage of patients achieving T cell FCXM-negative status after the 4-dose IVIG regimen. Results: Upon completion (4 g/kg total) or discontinuation of IVIG administration, 8 (47.1%) of 17 patients displayed negative T cell FCXM. Based on Kaplan-Meier estimates, the cumulative T cell FCXM-negative conversion rate 4 weeks after IVIG administration initiation was 60.3%. The T cell FCXM-negative conversion rates after cumulative doses of 1, 2, 3, and 4 g/kg IVIG were 29.4%, 35.3%, 56.3%, and 46.7%, respectively. Conclusions: Desensitization of donor specific antibody-positive renal transplant recipients seems achievable in only a subset of recipients through IVIG dosing (1 g/kg * 4) within 1 week after double filtration plasmapheresis. The T cell FCXM-negative conversion rate resulting from a cumulative IVIG dose of 3 g/kg or greater surpassed that attained via conventional single-dose IVIG (2 g/kg) protocol. This short-term high-dose IVIG desensitization protocol may be an alternative to conventional protocols for recipients with donor-specific antibody. PMID- 29399626 TI - Development of a Formula to Correct Particle-Enhanced Turbidimetric Inhibition Immunoassay Values so That it More Precisely Reflects High-Performance Liquid Chromatography Values for Mycophenolic Acid. AB - Background: Mycophenolic acid (MPA) concentration measured by homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINA) may be overestimated due to its cross-reactivity with pharmacologically inactive MPA glucuronide (MPAG), as well as other minor metabolites, accumulated with renal function impairment or co-administered cyclosporine A. In contrast, high performance liquid chromatography (HPLC) is precise because it can exclude the cross-reactivity. In this study, we assumed HPLC values for MPA (HPLC-MPA) as a reference and aimed to develop a formula correcting PETINA values for MPA (PETINA MPA) to more precisely reflect HPLC-MPA. Methods: MPA trough concentrations were measured both by HPLC-UV and PETINA in 39 samples issued from 39 solid-organ transplant recipients. MPAG concentrations were also measured using HPLC UV assay. We determined the impacts of renal function and coadministered calcineurin inhibitor on concentrations of MPA and MPAG measured by HPLC. Then, we evaluated the difference between PETINA-MPA and HPLC-MPA. Finally, we develop a formula to reflect HPLC-MPA by using multilinear regression analysis. Results: MPAG concentration was negatively correlated with estimated glomerular filtration rate (eGFR) (R2 = 0.376, P < 0.001), although MPA was not correlated with eGFR. There were no significant differences in MPA or MPAG concentrations per dose between the patients who were co-administered tacrolimus versus cyclosporine A. Finally, we developed the formulas to reflect HPLC-MPA:Formula 1: Estimated MPA concentration = 0.048 + 0.798 * PETINA-MPAFormula 2: Estimated MPA concentration = - 0.059 + 0.800 * PETINA-MPA + 0.002 * eGFRHowever, there was no significant improvement in the coefficient of determination with addition of eGFR in the formula, suggesting that HPLC-MPA can be well predicted by only 1 variable, PETINA-MPA. Conclusions: This study developed a formula so that PETINA-MPA can be corrected to more precisely reflect HPLC-MPA. PMID- 29399627 TI - Simulation and Experimental Assembly of DNA-Graft Copolymer Micelles with Controlled Morphology. AB - Nanoparticles formed through complexation of plasmid DNA and copolymers are promising gene-delivery vectors, offering a wide range of advantages over alternative delivery strategies. Notably, recent research has shown that the shape of these particles can be tuned, which makes it possible to gain understanding of their shape-dependent transfection properties. Whereas earlier methods achieved shape tuning through the use of block copolymers and variation of solvent polarity, here we demonstrate through a combined experimental and computational approach that the same degree of shape control can be achieved through the use of graft copolymers that are easier to synthesize and provide a wider range of parameters for shape control. Moreover, the approach presented here does not require the use of organic solvents. The simulation work provides insight into the mechanism governing the shape variation as well as an effective model to guide further design of non-viral gene-delivery vectors. Our experimental findings offer important opportunities for the facile and large scale synthesis of biocompatible gene-delivery vectors with well-controlled shape and tunable transfection properties. The in vitro study shows that both micelle shape and transfection efficiency are strongly correlated with the key structural parameters of the graft copolymer carriers. PMID- 29399628 TI - In-air microfluidics enables rapid fabrication of emulsions, suspensions, and 3D modular (bio)materials. AB - Microfluidic chips provide unparalleled control over droplets and jets, which have advanced all natural sciences. However, microfluidic applications could be vastly expanded by increasing the per-channel throughput and directly exploiting the output of chips for rapid additive manufacturing. We unlock these features with in-air microfluidics, a new chip-free platform to manipulate microscale liquid streams in the air. By controlling the composition and in-air impact of liquid microjets by surface tension-driven encapsulation, we fabricate monodisperse emulsions, particles, and fibers with diameters of 20 to 300 MUm at rates that are 10 to 100 times higher than chip-based droplet microfluidics. Furthermore, in-air microfluidics uniquely enables module-based production of three-dimensional (3D) multiscale (bio)materials in one step because droplets are partially solidified in-flight and can immediately be printed onto a substrate. In-air microfluidics is cytocompatible, as demonstrated by additive manufacturing of 3D modular constructs with tailored microenvironments for multiple cell types. Its in-line control, high throughput and resolution, and cytocompatibility make in-air microfluidics a versatile platform technology for science, industry, and health care. PMID- 29399629 TI - Fragmentation of Andes-to-Amazon connectivity by hydropower dams. AB - Andes-to-Amazon river connectivity controls numerous natural and human systems in the greater Amazon. However, it is being rapidly altered by a wave of new hydropower development, the impacts of which have been previously underestimated. We document 142 dams existing or under construction and 160 proposed dams for rivers draining the Andean headwaters of the Amazon. Existing dams have fragmented the tributary networks of six of eight major Andean Amazon river basins. Proposed dams could result in significant losses in river connectivity in river mainstems of five of eight major systems-the Napo, Maranon, Ucayali, Beni, and Mamore. With a newly reported 671 freshwater fish species inhabiting the Andean headwaters of the Amazon (>500 m), dams threaten previously unrecognized biodiversity, particularly among endemic and migratory species. Because Andean rivers contribute most of the sediment in the mainstem Amazon, losses in river connectivity translate to drastic alteration of river channel and floodplain geomorphology and associated ecosystem services. PMID- 29399630 TI - Agriculture is a major source of NO x pollution in California. AB - Nitrogen oxides (NO x = NO + NO2) are a primary component of air pollution-a leading cause of premature death in humans and biodiversity declines worldwide. Although regulatory policies in California have successfully limited transportation sources of NO x pollution, several of the United States' worst-air quality districts remain in rural regions of the state. Site-based findings suggest that NO x emissions from California's agricultural soils could contribute to air quality issues; however, a statewide estimate is hitherto lacking. We show that agricultural soils are a dominant source of NO x pollution in California, with especially high soil NO x emissions from the state's Central Valley region. We base our conclusion on two independent approaches: (i) a bottom-up spatial model of soil NO x emissions and (ii) top-down airborne observations of atmospheric NO x concentrations over the San Joaquin Valley. These approaches point to a large, overlooked NO x source from cropland soil, which is estimated to increase the NO x budget by 20 to 51%. These estimates are consistent with previous studies of point-scale measurements of NO x emissions from the soil. Our results highlight opportunities to limit NO x emissions from agriculture by investing in management practices that will bring co-benefits to the economy, ecosystems, and human health in rural areas of California. PMID- 29399632 TI - The generational scalability of single-cell replicative aging. AB - Despite the identification of numerous genes able to modulate lifespan, it remains unknown whether these genes interact to form a regulatory network that governs aging. Here we show that genetic interventions that extend or shorten replicative lifespan in Saccharomyces cerevisiae elicit proportional scaling of survival curve dynamics. The scalable nature of replicative lifespan distributions indicates that replicative aging is governed by a global state variable that determines cell survival by integrating effects from different risk factors. We also show that the Weibull survival function, a scale-invariant mathematical form, is capable of accurately predicting experimental survival distributions. We demonstrate that a drift-diffusion model of aging state with random challenge arrival effectively captures mortality risk. Measuring single cell generation durations during aging, we uncover power-law dynamics with strain specific speeds of increase in generation durations. Our application of quantitative modeling approaches to high-precision replicative aging data offers novel insights into aging dynamics and lifespan determinants in single cells. PMID- 29399631 TI - DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. AB - Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing beta cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation. PMID- 29399634 TI - Post-Traumatic Stress Disorder (PTSD) in Sexually Abused Children and Educational Status in Kenya: A Longitudinal Study. AB - Children who experience sexual abuse often meet the criteria of Post-Traumatic Stress Disorder and other psychiatric disorders. This article examines Post Traumatic Stress Disorder and their educational status among children who have been sexually abused and its effects on the children's educational status. The study was carried out between June 2015 and July 2016. The study adopted a longitudinal study design. The study was conducted at Kenyatta National Teaching and Referral Hospital and Nairobi Women's Hospitals in Kenya. The children who had experienced sexual abuse and their parents/legal guardians were followed up for a period of one year after every four months interval. One hundred and ninety one children who had experienced sexual abuse and their parents/legal guardians were invited to participate in the study. Findings indicate that the children continued to experience PTSD one year after the sexual abuse incidence. PTSD was associated with the length of time taken to receive medical attention (p<0.005). Children with partial PTSD who had experienced sexual abuse were 2 times more likely to perform above average than children with full PTSD, OR=2.1 [95% CI of OR 1.2-3.8], p=0.01. Children who experience sexual abuse have negative mental health outcomes. These outcomes have detrimental effects to the normal development of children and educational status. There is need to screen for PTSD and offer psychosocial support and follow up to children who have been sexual abuse. PMID- 29399635 TI - ADAPTING A STIGMA SCALE FOR ASSESSMENT OF TUBERCULOSIS-RELATED STIGMA AMONG ENGLISH/SWAHILI-SPEAKING PATIENTS IN AN AFRICAN SETTING. AB - Objective: To adapt a validated instrument that quantitatively measures stigma among English/Swahili speaking TB (tuberculosis) patients in Kenya, a high burden TB country. Methods: Following ethical approval, we elicited feedback on the English and Swahili translated Stigma Scale for Chronic Illness (SSCI) tools through cognitive interviews. We assessed difficulties in translation, differences in meaning, TB contextual relevance, patients' acceptability to the questions, and issues in tool structure. The interviews were audio recorded, transcribed and translated. Open coding and thematic analysis of the data was conducted by two independent researchers. Results: Between May and September 2015 we conducted a qualitative study among 20 adult TB patients attending 11 health facilities in Nairobi County, Kenya. Most questions were understood in both English and Swahili, deemed relevant in the context of TB and acceptable to TB patients. Key areas of adaptation of the SSCI included adding questions addressing fear of infecting others and death, HIV stigma, and intimate, family and workplace relationship contexts. Questions were revised for non-redundancy, specificity and optimized sequence. Conclusion: The adapted 8-item SSCI appears to be a useful tool that may be administered by health workers in English or Swahili to quantify TB stigma among TB patients in Kenya. PMID- 29399636 TI - Overcoming Barriers to Lung Cancer Screening by Implementing a Single-Visit Patient Experience. PMID- 29399633 TI - Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. AB - Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)-dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7-mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5 independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K mTOR signaling. Together, our integrative analyses establish IL-7R-mTORC1-Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R-Stat5 signaling. PMID- 29399637 TI - Direct and Second Hand Cigarette Smoke Exposure and Development of Childhood Asthma. AB - This is a comprehensive review about the role of direct and second hand cigarette smoke exposure in the development of childhood asthma. Smoking, both during pregnancy and postnatal have an adverse impact on the infant's chances of developing respiratory illness. Second hand smoke exposure has also known to cause worsening of childhood asthma with an impact on hospital admissions. Correlation between maternal second hand smoke exposure during pregnancy and development of childhood asthma has also been investigated. It is, thus essential to address this prenatally as well as post-natal by reducing smoking as well as smoke exposure. PMID- 29399638 TI - A Randomized Controlled Study on the Effects of a Documentary on Students' Empathy and Attitudes towards Older Adults. AB - Background: Despite the rapid increase in the size of the geriatric population, no current published literature is available based on the effects of viewing a documentary covering medical and psychosocial issues concerning older adults influencing young people's empathy and ageism. The aim of the current study was to test whether participants who viewed an original documentary about older adults experiencing physical pain would report lower ageism and higher empathy scores when compared to participants who watched a neutral documentary. Method: Seventy-seven students (ages 18-29 years) were randomized to either the experimental (pain documentary) or the control (neutral documentary) conditions and given pre- and post-test measures of empathy and ageism. Results: The results of a series of Profile Analyses (Multivariate Mixed ANOVAs) showed a significant interaction (Wilk's lambda=0.933, F(1,75)=5.389, p=0.023, partial eta2=0.067) between treatment and time (pre- vs. post-viewing the film) for the empathy measure that was confirmed by follow-up t-tests. The latter showed a significant increase in empathy scores for only the experimental group, t(37)=-2.999, p=0.005. However, contrary to the original prediction, this same treatment by time effect was not observed for ageism (Wilk's lambda=0.994, F(1,75)=0.482, p=0.490, partial eta2=0.006), as the experimental participants did not significantly reduce their ageism scores, t(38)=0.725, p=0.473. The results of these analyses, as well as those obtained by using the subscales of each questionnaire, have been discussed. Conclusions: The findings of this preliminary study indicate that showing a pain-based, anti-bias documentary feature film has the potential to significantly improve empathy towards older adults in university students. PMID- 29399639 TI - Increasing verbal knowledge mediates development of multidimensional emotion representations. AB - How do people represent their own and others' emotional experiences? Contemporary emotion theories and growing evidence suggest that the conceptual representation of emotion plays a central role in how people understand the emotions both they and other people feel.1-6 Although decades of research indicate that adults typically represent emotion concepts as multidimensional, with valence (positive negative) and arousal (activating-deactivating) as two primary dimensions,7-10 little is known about how this bidimensional (or circumplex) representation arises.11 Here we show that emotion representations develop from a monodimensional focus on valence to a bidimensional focus on both valence and arousal from age 6 to age 25. We investigated potential mechanisms underlying this effect and found that increasing verbal knowledge mediated emotion representation development over and above three other potential mediators: (i) fluid reasoning, (ii) the general ability to represent non-emotional stimuli bidimensionally, and (iii) task-related behaviors (e.g., using extreme ends of rating scales). These results suggest that verbal development facilitates the expansion of emotion concept representations (and potentially emotional experiences) from a "positive or negative" dichotomy in childhood to a multidimensional organization in adulthood. PMID- 29399640 TI - Detection and Mapping of DNA Methylation with 2D Material Nanopores. AB - DNA methylation is an epigenetic modification involving the addition of a methyl group to DNA, which is heavily involved in gene expression and regulation, thereby critical to the progression of diseases such as cancer. In this work we show that detection and localization of DNA methylation can be achieved with nanopore sensors made of two-dimensional (2D) materials such as graphene and molybdenum di-sulphide (MoS2). We label each DNA methylation site with a methyl CpG binding domain protein (MBD1), and combine molecular dynamics simulations with electronic transport calculations to investigate the translocation of the methylated DNA-MBD1 complex through 2D material nanopores under external voltage biases. The passage of the MBD1-labeled methylation site through the pore is identified by dips in the current blockade induced by the DNA strand, as well as by peaks in the transverse electronic sheet current across the 2D layer. The position of the methylation sites can be clearly recognized by the relative positions of the dips in the recorded ionic current blockade with an estimated error ranging from 0% to 16%. Finally, we define the spatial resolution of the 2D material nanopore device as the minimal distance between two methylation sites identified within a single measurement, which is 15 base pairs by ionic current recognition, but as low as 10 base pairs by transverse electronic conductance detection, indicating better resolution with this latter technique. The present approach opens a new route for precise and efficient profiling of DNA methylation. PMID- 29399641 TI - Novel approaches for quantitative electrogram analysis for intraprocedural guidance for catheter ablation: A case of a patient with persistent atrial fibrillation. AB - Purpose: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that causes stroke affecting more than 2.3 million people in the US and is increasing in prevalence due to ageing population causing a new global epidemic. Catheter ablation with pulmonary vein isolation (PVI) to terminate AF is successful for paroxysmal AF but suffers limitations with persistent AF patients as current mapping methods cannot identify AF active substrates outside of PVI region. Recent evidences in the mechanistic understating of AF pathophysiology suggest that ectopic activity, localized re-entrant circuit with fibrillatory propagation and multiple circuit re-entries may all be involved in human AF. The authors developed novel electrogram analysis methods and validated using optical mapping data from isolated rabbit hearts to accurately identify rotor pivot points. The purpose of this study was to assess the feasibility of generating patient-specific 3D maps for intraprocedural guidance for catheter ablation using intracardiac electrograms from a persistent AF patient using novel electrogram analysis methods. Methods: A persistent AF patient with clinical appointment for AF ablation was recruited for this study with IRB approval. 1055 electrograms throughout the left and right atrium were obtained for offline analysis with the novel approaches such as multiscale entropy, multiscale frequency, recurrence period density entropy, kurtosis and empirical mode decomposition to generate patient specific 3D maps. 3D Shannon Entropy, Renyi Entropy and Dominant frequency maps were also generated for comparison purposes along with local activation time and complex fractionated electrogram analysis maps. Results: Patient specific 3D maps were obtained for each of the different approach. The 3D maps indicate potential active sites outside the PVI region. However, presence of rotors cannot be confirmed and validation of these approaches is required on a larger dataset. Conclusions: Conventional catheter mapping system can be used for generating patient specific 3D maps with short time series analysis using the novel approaches. PMID- 29399642 TI - Incorporating spatial dose metrics in machine learning-based normal tissue complication probability (NTCP) models of severe acute dysphagia resulting from head and neck radiotherapy. AB - Severe acute dysphagia commonly results from head and neck radiotherapy (RT). A model enabling prediction of severity of acute dysphagia for individual patients could guide clinical decision-making. Statistical associations between RT dose distributions and dysphagia could inform RT planning protocols aiming to reduce the incidence of severe dysphagia. We aimed to establish such a model and associations incorporating spatial dose metrics. Models of severe acute dysphagia were developed using pharyngeal mucosa (PM) RT dose (dose-volume and spatial dose metrics) and clinical data. Penalized logistic regression (PLR), support vector classification and random forest classification (RFC) models were generated and internally (173 patients) and externally (90 patients) validated. These were compared using area under the receiver operating characteristic curve (AUC) to assess performance. Associations between treatment features and dysphagia were explored using RFC models. The PLR model using dose-volume metrics (PLRstandard) performed as well as the more complex models and had very good discrimination (AUC = 0.82) on external validation. The features with the highest RFC importance values were the volume, length and circumference of PM receiving 1 Gy/fraction and higher. The volumes of PM receiving 1 Gy/fraction or higher should be minimized to reduce the incidence of severe acute dysphagia. PMID- 29399643 TI - Recruitment and baseline characteristics of the Community of Voices choir study to promote the health and well-being of diverse older adults. AB - Objective: To describe the recruitment and baseline results of the Community of Voices study that aims to examine the effect of a community choir intervention on the health and well-being of older adults from diverse racial/ethnic and socioeconomic backgrounds. Method: Using community-based participatory research methods, we recruited adults age 60 and over from 12 Administration on Aging supported senior centers in San Francisco into a 2-arm cluster-randomized controlled trial of the community choir intervention. Multiple outreach methods were used. We tracked outreach, screening, and recruitment metrics and collected demographics and baseline outcomes via community-based, interviewer-administered surveys and performance measures of cognition, physical function, and psychosocial variables. Results: The study contacted 819 individuals, screened 636, and enrolled 390 diverse older adults over a 42-month, phased recruitment period. The mean age was 71.2 (SD = 7.3), and the majority were women. Two-thirds of the sample are non-white, and 20% of participants reported having financial hardship. Discussion: Outreach and recruitment methods used in the Community of Voices trial facilitated enrollment of a large proportion of minority and lower SES older adults in the final sample. Similar recruitment approaches could serve as a model for recruiting diverse racial/ethnic and socioeconomic older adults into research. PMID- 29399644 TI - Cognitive Functioning, Health Screening Behaviors and Desire to Improve One's Health in Diabetic versus Healthy Older Women. AB - Aims: To attempt to fill a gap in the literature on diabetic versus healthy older women on desire to improve one's health, health screening behaviors, and cognitive health. Study Design: Between-subjects design. Place and Duration of Study: Department of Psychology, California State University Northridge, between July 2013 and June 2015. Methodology: In this preliminary study, we compared 30 diabetic older women to 42 healthy older women (i.e., respondents who reported having no physical illnesses and not taking any medications) on: desire to improve their health (hypothesized as being higher in the diabetes group), receiving mammograms and regular health screenings (analyzed without any hypotheses, due to the lack of evidence on this topic), as well as cognitive functioning (hypothesized as lower in the diabetes group, based on prior research findings). Participants (N=72, mean age=69.29, SD=6.579, age range=50-90) were multiethnic, non-institutionalized women over the age of 50 residing in Los Angeles County who completed our research packet. The latter contained the first author's demographics list and her original structured interview protocol on older women's health, as well as the well-known Mini-Cog. Results: The results of an Analysis of Variance (ANOVA) showed that, as hypothesized, diabetic women desired to improve their health more than the women in the control group [F (1,70)=11.87, p<.05, eta2 =.15]. Additionally, upon implementing Chi-square analyses, we discovered that diabetic respondents were significantly more likely to receive mammograms [X2 (1)=5.87, p<.05] and general health screenings [X2 (1)=4.51, p<.05] than healthy women. Moreover, in contrast with prior literature's findings, cognitive health in the diabetic group obtained marginal significance in an ANOVA as being better than the cognitive health of the control group [F(1,68)=3.30, p=.06, eta2 =.05]. Conclusion: We have established a significant relationship between diabetes and a) desire to improve one's health and b) health screening behaviors, as well as c) cognitive impairment (at a marginally significant level) among diabetic versus healthy women. This has important clinical and public health implications. Although the findings of prior research suggest that diabetic older women often experience impaired cognitive performance compared to healthy older women, our marginally significant results showed that the opposite is true, at least in our ethnically diverse sample of modest size. Moreover, we found that diabetic older women desired to improve their health significantly more than healthy women and pursued cancer screenings and general health screenings more than their healthy counterpart. The limited size of our sample does not allow for generalizations of our findings. Additional research with larger samples is definitely needed to investigate these topics further. PMID- 29399645 TI - Oxidative Stress and Acute Hepatic Injury. AB - Reactive oxygen species have long been implicated in the pathophysiology of acute liver injury. However, the translation of these findings to the clinic and the development of therapeutic agents have been slow mainly due to the poor mechanistic understanding of the pathophysiology and the many indirect approaches used to characterize the role of oxidant stress in liver injury. The current review discusses in depth the sources of reactive oxygen, the oxidants involved and the impact of this oxidant stress in the mechanism of cell death in 3 different clinically relevant acute liver injury models. PMID- 29399646 TI - Novel biomaterials to study neural stem cell mechanobiology and improve cell replacement therapies. AB - Neural stem cells (NSCs) are a valuable cell source for tissue engineering, regenerative medicine, disease modeling, and drug screening applications. Analogous to other stem cells, NSCs are tightly regulated by their microenvironmental niche, and prior work utilizing NSCs as a model system with engineered biomaterials has offered valuable insights into how biophysical inputs can regulate stem cell proliferation, differentiation, and maturation. In this review, we highlight recent exciting studies with innovative material platforms that enable narrow stiffness gradients, mechanical stretching, temporal stiffness switching, and three-dimensional culture to study NSCs. These studies have significantly advanced our knowledge of how stem cells respond to an array of different biophysical inputs and the underlying mechanosensitive mechanisms. In addition, we discuss efforts to utilize engineered material scaffolds to improve NSC-based translational efforts and the importance of mechanobiology in tissue engineering applications. PMID- 29399647 TI - E-Cigarette Airflow Rate Modulates Toxicant Profiles and Can Lead to Concerning Levels of Solvent Consumption. AB - Electronic cigarettes enabling enhanced airflow have grown in popularity in recent years. The objective of this study is to show that flow rates modulate the levels of specific aerosol toxicants produced in electronic cigarettes. Flow rates used in various laboratory investigations involving e-cigarettes have varied widely to date, and can thus promote interlaboratory variability in aerosol product profiles. The thermal decomposition of hydroxyacetone and glycolaldehyde is less favorable at lower temperatures, supporting the observations of these products at higher flow rates/lower heating coil temperatures. Higher temperatures promote the formation of acetaldehyde from hydroxyacetone and formaldehyde from both hydroxyacetone and glycolaldehyde. A separate finding is that greater airflow can also expose users to concerning levels of e-liquid solvents. Under the modest conditions studied, propylene glycol aerosol levels are found at above the acceptable inhalation levels defined by NASA, and in range of the generally recognized as safe levels for daily ingestion. PMID- 29399648 TI - Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures. AB - Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG). The highly cross linked heptapeptide aglycon structure of vancomycin is the d-Ala-d-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus modified vancomycin derivatives: desleucyl-vancomycin, vancomycinNtoC, and vancomycinSar, binding to a PG unit of the sequence l-Ala-d-iso-Gln-l-Lys-d-Ala-d Ala with an intact pentaglycine bridge structure attached to the bridge link of l Lys were carried out. Glycopeptide-PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide-PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the d-Ala-d-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide-PG binding interactions. PMID- 29399650 TI - LC-MS/MS-Based Method for the Multiplex Detection of 24 Fentanyl Analogues and Metabolites in Whole Blood at Sub ng mL-1 Concentrations. AB - The United States and numerous other countries worldwide are currently experiencing a public health crisis due to the abuse of illicitly manufactured fentanyl (IMF) and its analogues. This manuscript describes the development of a liquid chromatography-tandem mass spectrometry-based method for the multiplex detection of N = 24 IMF analogues and metabolites in whole blood at concentrations as low as 0.1-0.5 ng mL-1. These available IMFs were fentanyl, norfentanyl, furanyl norfentanyl, remifentanil acid, butyryl norfentanyl, remifentanil, acetyl fentanyl, alfentanil, AH-7921, U-47700, acetyl fentanyl 4 methylphenethyl, acrylfentanyl, para-methoxyfentanyl, despropionyl fentanyl (4 ANPP), furanyl fentanyl, despropionyl para-fluorofentanyl, carfentanil, (+/-)-cis 3-methyl fentanyl, butyryl fentanyl, isobutyryl fentanyl, sufentanil, valeryl fentanyl, para-fluorobutyryl fentanyl, and para-fluoroisobutyryl fentanyl. Most IMF analogues (N = 22) could be easily distinguished from one another; the isomeric forms butyryl/isobutyryl fentanyl and para-fluorobutyryl/para fluoroisobutyryl fentanyl could not be differentiated. N = 13 of these IMF analogues were quantified for illustrative purposes, and their forensic quality control standards were also validated for limit of detection (0.017-0.056 ng mL 1), limit of quantitation (0.100-0.500 ng mL-1), selectivity/sensitivity, ionization suppression/enhancement (87-118%), process efficiency (60-95%), recovery (64-97%), bias (<20%), and precision (>80%). This flexible, time- and cost-efficient method was successfully implemented at the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory in Dayton, Ohio, where it aided in the analysis of N = 725 postmortem blood samples collected from February 2015 to November 2016. PMID- 29399649 TI - Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes. AB - Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt and lipid membranes. SM composition is altered in HD, and GM1 has been shown to have protective effects in animal models of HD. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy (AFM) were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added SM or GM1. The addition of either SM or GM1 decreased htt insertion into the lipid monolayers. However, TBLE vesicles with an increased SM content were more susceptible to htt-induced permeabilization, whereas GM1 had no effect on permeablization. Pure TBLE bilayers and TBLE bilayers enriched with GM1 developed regions of roughened, granular morphologies upon exposure to htt-exon1, but plateau-like domains with a smoother appearance formed in bilayers enriched with SM. Oligomeric aggregates were observed on all bilayer systems regardless of induced morphology. Collectively, these observations suggest that the lipid composition and its subsequent effects on membrane material properties strongly influence htt binding and aggregation on lipid membranes. PMID- 29399651 TI - Ionotactile Stimulation: Nonvolatile Ionic Gels for Human-Machine Interfaces. AB - We report the application of a nonvolatile ionic gel as a soft, conductive interface for electrotactile stimulation. Materials characterization reveals that, compared to a conventional ionic hydrogel, a glycerol-containing ionic gel does not dry out in air, has better adhesion to skin, and exhibits a similar impedance spectrum in the range of physiological frequencies. Moreover, psychophysical experiments reveal that the nonvolatile gel also exhibits a wider window of comfortable electrotactile stimulation. Finally, a simple pixelated device is fabricated to demonstrate spatial resolution of the haptic signal. PMID- 29399652 TI - Impact of an N-terminal Polyhistidine Tag on Protein Thermal Stability. AB - For years, the use of polyhistidine tags (His-tags) has been a staple in the isolation of recombinant proteins in immobilized metal affinity chromatography experiments. Their usage has been widely beneficial in increasing protein purity from crude cell lysates. For some recombinant proteins, a consequence of His-tag addition is that it can affect protein function and stability. Functional proteins are essential in the elucidation of their biological, kinetic, structural, and thermodynamic properties. In this study, we determine the effect of N-terminal His-tags on the thermal stability of select proteins using differential scanning fluorimetry and identify that the removal of the His-tag can have both beneficial and deleterious effects on their stability. PMID- 29399653 TI - Formation of 2-Imino Benzo[e]-1,3-oxazin-4-ones from Reactions of Salicylic Acids and Anilines with HATU: Mechanistic and Synthetic Studies. AB - We describe a new 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 b]pyridinium 3-oxide hexafluorophosphate (HATU)-mediated coupling reaction to produce 2-imino benzo[e]-1,3-oxazin-4-ones from salicylic acids and anilines. Mechanistic studies support a reaction pathway in which HATU mediates carbon transfer to the initially formed salicylanilides to form in succession reactive tetramethylisouronium and N-acyl(dimethyl)isouronium intermediates, which then undergo imine-iminium exchange to generate the desired oxazinones. PMID- 29399654 TI - Size-Dependent Inhibitory Effects of Antibiotic Drug Nanocarriers against Pseudomonas aeruginosa. AB - Multidrug membrane transporters (efflux pumps) are responsible for multidrug resistance (MDR) and the low efficacy of therapeutic drugs. Noble metal nanoparticles (NPs) possess a high surface-area-to-volume ratio and size dependent plasmonic optical properties, enabling them to serve both as imaging probes to study sized-dependent MDR and as potential drug carriers to circumvent MDR and enhance therapeutic efficacy. To this end, in this study, we synthesized three different sizes of silver nanoparticles (Ag NPs), 2.4 +/- 0.7, 13.0 +/- 3.1, and 92.6 +/- 4.4 nm, functionalized their surface with a monolayer of 11 amino-1-undecanethiol (AUT), and covalently conjugated them with antibiotics (ofloxacin, Oflx) to prepare antibiotic drug nanocarriers with conjugation ratios of 8.6 * 102, 9.4 * 103, and 6.5 * 105 Oflx molecules per NP, respectively. We purified and characterized the nanocarriers and developed cell culture medium in which the cells grew normally and the nanocarriers were stable (non-aggregated), to quantitatively study the size, dose, and efflux pump (MexAB-OprM) dependent inhibitory effect of the nanocarriers against two strains of Pseudomonas aeruginosa, WT (normal expression of MexAB-OprM) and DeltaABM (deletion of MexAB OprM). We found that the inhibitory effect of these nanocarriers highly depended on the sizes of NPs, the doses of antibiotic, and the expression of MexAB-OprM. The same amount of Oflx on the largest nanocarriers (92.6 +/- 4.4 nm) showed the highest inhibitory effect (the lowest minimal inhibitory concentration) against P. aeruginosa. Surprisingly, the smallest nanocarriers (2.4 +/- 0.7 nm) exhibited a lower inhibitory effect than free Oflx. The results suggest that size-dependent multivalent effects, the distribution and localization of Oflx (pharmacodynamics), and the efflux of Oflx all play a role in the inhibitory effects. Control experiments using three sizes of AgMUNH2 NPs (absence of Oflx) showed that these NPs do not exhibit any significant inhibitory activity toward both strains. These new findings demonstrate the need for and possibility of designing optimal sized antibiotic nanocarriers to achieve the highest efficacy against P. aeruginosa. PMID- 29399655 TI - Asymmetric Choreography in Pairs of Orthogonal Rotors. AB - An asymmetric mechanism for correlated motion occurring in noninteracting pairs of adjacent orthogonal 1,4-bis(carboxyethynyl)bicyclo[1.1.1]pentane (BCP) rotators 1 in the solid state is unraveled and shown to play an important role in understanding the dynamics in the crystalline rotor, Bu4N+[1-].H2O. Single crystal X-ray diffraction and calculation of rotor-rotor interaction energies combined with variable-temperature, variable-field 1H spin-lattice relaxation experiments led to the identification and microscopic rationalization of two distinct relaxation processes. PMID- 29399656 TI - Severe Neonatal Hyperbilirubinemia in Crigler-Najjar Syndrome Model Mice Can Be Reversed With Zinc Protoporphyrin. AB - Neurotoxic bilirubin is solely conjugated by UDP-glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase-I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1-/- mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin-induced neonatal lethality. Zinc protoporphyrin-treated Ugt1-/- mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down-regulated in a serum bilirubin level dependent manner. Conclusion: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin-induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin. PMID- 29399657 TI - Lay Consultations in Heart Failure Symptom Evaluation. AB - Purpose: Lay consultations can facilitate or impede healthcare. However, little is known about how lay consultations for symptom evaluation affect treatment decision-making. The purpose of this study was to explore the role of lay consultations in symptom evaluation prior to hospitalization among patients with heart failure. Methods: Semi-structured interviews were conducted with 60 patients hospitalized for acute decompensated heart failure. Chi-square and Fisher's exact tests, along with logistic regression were used to characterize lay consultations in this sample. Results: A large proportion of patients engaged in lay consultations for symptom evaluation and decision-making before hospitalization. Lay consultants provided attributions and advice and helped make the decision to seek medical care. Men consulted more often with their spouse than women, while women more often consulted with adult children. Conclusions: Findings have implications for optimizing heart failure self-management interventions, improving outcomes, and reducing hospital readmissions. PMID- 29399658 TI - Dissecting the Role of Disturbed ER-Golgi Trafficking in Antivirals and Alcohol Abuse-Induced Pathogenesis of Liver Disorders. AB - Antiviral drugs and alcohol abuse-induced organelle stresses have been linked to many disorders and the underlying molecular mechanisms are under intense investigations. This brief review communicates emerging evidence and research trends on how certain antivirals and alcohol affect ER-Golgi trafficking, which potentially impacts the function and integrity of the Golgi apparatus contributing to endoplasmic reticulum stress and cellular injury. PMID- 29399659 TI - A Retrospective Review to Determine If Children with Sickle Cell Disease Receive Hydroxyurea Monitoring. AB - Introduction: Sickle Cell Disease (SCD) guidelines recommend that patients on hydroxyurea receive monitoring at least every 2-3 months, but it is unknown if this occurs in clinical practice. This study aimed to determine if patients with SCD at Nationwide Children's Hospital (NCH) had at least four, in-person monitoring visits during a 12-month period and if frequent monitoring was associated with hydroxyurea adherence and clinical outcomes. Methods: We performed a retrospective analysis of children on hydroxyurea for at least 12 months during 2010-2015. Patients' demographics, laboratory studies, prescriptions, and number of hydroxyurea and acute visits were recorded from their 12-month period that met eligibility criteria. Patients were considered frequently monitored if they had >=4 hydroxyurea visits and adherent if they had prescriptions for hydroxyurea for >=80% of the days in their 12-month period. Results: Seventy-four children met the eligibility criteria and 57 (77%) had frequent monitoring. The most common reason for not obtaining frequent monitoring was missing a scheduled appointment. A greater proportion of frequently monitored patients were adherent to hydroxyurea (66.7% vs. 17.7%, p<0.001) and they had significantly fewer acute visits (median 1 vs. 2 visits, p=0.032) compared to infrequently monitored patients. Conclusions: Our study shows that most children on hydroxyurea at NCH received frequent monitoring and that it was associated with improved adherence and outcomes. Our results suggest that frequent in-person monitoring could be an opportunity to identify poorly adherent patients. These data inform our next quality improvement initiative that will maximize adherence to these monitoring guidelines. PMID- 29399661 TI - What you don't know can kill you. PMID- 29399662 TI - miRNA-15a, miRNA-15b, and miRNA-499 are Reduced in Erythrocytes of Pre-Diabetic African-American Adults. AB - Aims: The use of circulatory miRNAs as biomarkers and therapeutic targets for T2DM is an explosive area of study. However, no study has investigated circulatory miRNA expression exclusively in African-American adults. The aim of this study was to identify the expression of nine selected miRNAs in erythrocytes of pre-diabetic and type 2 diabetic African-American adults. Main Methods: Patients were recruited from the Howard University Hospital Diabetes Treatment Center following an 8 to 10 hour overnight fast. Expression of the nine selected miRNAs (miRNA-499, miRNA-146, miRNA-126, miRNA-223, miRNA-15a, miRNA-15b, miRNA 224, miRNA-326, and miRNA-375) was evaluated using quantitative real time PCR. Key Findings: miRNA-15a, miRNA-15b, and miRNA-499 were significantly reduced in erythrocytes of pre-diabetic African-American adults. In the T2DM group, we found significant correlations between miRNA-15a and BMI (r=0.59, p=0.04), miRNA-15a and weight (r=0.52, p=0.01), and miRNA-15b and diastolic blood pressure (r=-0.52, p=0.02). In the pre-diabetic group, we found significant correlations between miRNA-15b and weight (r=0.90, p=0.02) and miRNA-499 and HbA1c (r=-0.89, p=0.01). Significance: To our knowledge, this is the first study investigating miRNA expression in erythrocytes of non-diabetic high-risk obese--pre-diabetic and type 2 diabetic African-American adults. The findings of this study are consistent with previous reports of reduced expression of miRNA-15a, miRNA-15b, and miRNA 499 in human plasma or serum and in animal models. The current findings support the use of circulating miRNA-15a, miRNA-15b, and miRNA-499 as potential biomarkers for T2DM in African-American adults. PMID- 29399660 TI - Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance. AB - Genomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments-that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance. PMID- 29399663 TI - Can Diabetes Be Controlled by Lifestyle Activities? AB - Diabetes is a complex disease that affects millions of people worldwide. Diabetes is a metabolic disease, in which increased blood glucose levels ultimately lead to heart disease, stroke, kidney failure, foot ulcers, and damage to the eyes. Current prevalence rates of diabetes are extremely high in countries throughout the world. Multiple forms of diabetes have been identified, including type 1, type 2, type 3, neonatal and gestational. The purpose of this article is to discuss recent developments in diabetes research, including prevalence, morbidity and mortality rates, and lifestyle factors that are associated with diabetes onset and progression. This article also discusses how lifestyle factors delay and/or prevent diabetes. PMID- 29399664 TI - Anyone Can Become a Troll: Causes of Trolling Behavior in Online Discussions. AB - In online communities, antisocial behavior such as trolling disrupts constructive discussion. While prior work suggests that trolling behavior is confined to a vocal and antisocial minority, we demonstrate that ordinary people can engage in such behavior as well. We propose two primary trigger mechanisms: the individual's mood, and the surrounding context of a discussion (e.g., exposure to prior trolling behavior). Through an experiment simulating an online discussion, we find that both negative mood and seeing troll posts by others significantly increases the probability of a user trolling, and together double this probability. To support and extend these results, we study how these same mechanisms play out in the wild via a data-driven, longitudinal analysis of a large online news discussion community. This analysis reveals temporal mood effects, and explores long range patterns of repeated exposure to trolling. A predictive model of trolling behavior shows that mood and discussion context together can explain trolling behavior better than an individual's history of trolling. These results combine to suggest that ordinary people can, under the right circumstances, behave like trolls. PMID- 29399665 TI - Modeling Semantic Fluency Data as Search on a Semantic Network. AB - Psychologists have used the semantic fluency task for decades to gain insight into the processes and representations underlying memory retrieval. Recent work has suggested that a censored random walk on a semantic network resembles semantic fluency data because it produces optimal foraging. However, fluency data have rich structure beyond being consistent with optimal foraging. Under the assumption that memory can be represented as a semantic network, we test a variety of memory search processes and examine how well these processes capture the richness of fluency data. The search processes we explore vary in the extent they explore the network globally or exploit local clusters, and whether they are strategic. We found that a censored random walk with a priming component best captures the frequency and clustering effects seen in human fluency data. PMID- 29399666 TI - Resistive-Pulse Analysis of Single Phospholipid Vesicles Using Quartz Nanochannels. AB - We report the use of resistive-pulse method and quartz nanochannels for the detection and size analysis of single vesicles. Cylindrical shape quartz nanochannels have been used to detect single phospholipid vesicles ranging from 100 to 300 nm and polystyrene nanoparticles ranging from 170 to 400 nm in diameter. Translocations of single vesicles and nanoparticle were detected as individual square current pulses, which could be used to determine particle size. Our results show excellent agreement between the particle/vesicle sizes obtained from nanochannels and those from dynamic light scattering (DLS) and scanning electron microscopy (SEM). This electronic-based method was found to be fast, simple, and used cheap and robust microsensors made in house. The application of a quartz channel might be combined with other analytical methods, such as amperometry and fluorescence microscopy, to yield more complete information about biological and artificial vesicles. PMID- 29399667 TI - Fast Simulation of Mitral Annuloplasty for Surgical Planning. AB - Mitral valve repair is a complex procedure that requires the ability to predict closed valve shape through the examination of an unpressurized, accid valve. These procedures typically include the remodeling of the mitral annulus through the insertion of an annuloplasty ring. While simulations could facilitate the planning of the procedure, traditional finite-element models of mitral annuloplasty are too slow to be clinically feasible and have never been validated in tissue. This work presents a fast method for simulating valve closure post annuloplasty using a mass-spring tissue model and subject-specific valve geometry. Closed valve shape is predicted in less than one second. The results are validated by implanting an annuloplasty ring in an excised porcine heart and comparing simulated to imaged results. Results indicate that not only can mitral annuloplasty be simulated quickly, but also with submillimeter accuracy. PMID- 29399668 TI - Coupling Genetic Addiction Risk Score (GARS) and Pro Dopamine Regulation (KB220) to Combat Substance Use Disorder (SUD). PMID- 29399669 TI - A Quality Improvement Initiative to Increase Colorectal Cancer (CRC) Screening: Collaboration between a Primary Care Clinic and Research Team. AB - Background: Multiple randomized controlled trials have demonstrated that mailed fecal testing programs are effective in increasing colorectal cancer screening participation. However, few healthcare organization in the US have Implemented such programs. Methods: Stakeholders from one clinic in an integrated healthcare system in Washington State initiated collaboration with researchers with expertise in CRC screening, aiming to increase screening rates at their clinic. Age-eligible individuals who were overdue for CRC screening and had previously completed a fecal test were randomized to receive mailed fecal immunochemical test kits (FIT) at the start of the project (Early) or 6 months later (Late). Outcomes included comparing FIT completion at 6 months by randomization group, and overall CRC screening rates at 12 months. We also assessed implementation facilitators and challenges. Results: Overall 2,421 FIT tests were mailed at a cost of $10,739. At 6 months, FIT completion was significantly higher among the Early compared to the Late group (62% vs.47%, p <0.001). By 12 months, after both groups had received mailings, 71% in each group had completed a FIT. The clinic's overall CRC screening rate was 75.1% at baseline and 78.0% 12 months later. Key constructs associated with successful program implementation included strong stakeholder involvement, use of evidence-based strategies, simplicity, and low cost. Challenges included lack of a plan for maintaining the program. Discussion: Collaboration between clinic stakeholders and researchers led to a successful project that rapidly increased CRC screening rates. However, institutional normalization of the program would be required to maintain it. PMID- 29399670 TI - 4D Multi-atlas Label Fusion using Longitudinal Images. AB - Longitudinal reproducibility is an essential concern in automated medical image segmentation, yet has proven to be an elusive objective as manual brain structure tracings have shown more than 10% variability. To improve reproducibility, longitudinal segmentation (4D) approaches have been investigated to reconcile temporal variations with traditional 3D approaches. In the past decade, multi atlas label fusion has become a state-of-the-art segmentation technique for 3D image and many efforts have been made to adapt it to a 4D longitudinal fashion. However, the previous methods were either limited by using application specified energy function (e.g., surface fusion and multi model fusion) or only considered temporal smoothness on two consecutive time points (t and t+1) under sparsity assumption. Therefore, a 4D multi-atlas label fusion theory for general label fusion purpose and simultaneously considering temporal consistency on all time points is appealing. Herein, we propose a novel longitudinal label fusion algorithm, called 4D joint label fusion (4DJLF), to incorporate the temporal consistency modeling via non-local patch-intensity covariance models. The advantages of 4DJLF include: (1) 4DJLF is under the general label fusion framework by simultaneously incorporating the spatial and temporal covariance on all longitudinal time points. (2) The proposed algorithm is a longitudinal generalization of a leading joint label fusion method (JLF) that has proven adaptable to a wide variety of applications. (3) The spatial temporal consistency of atlases is modeled in a probabilistic model inspired from both voting based and statistical fusion. The proposed approach improves the consistency of the longitudinal segmentation while retaining sensitivity compared with original JLF approach using the same set of atlases. The method is available online in open source. PMID- 29399671 TI - Big Data Provenance: Challenges, State of the Art and Opportunities. AB - Ability to track provenance is a key feature of scientific workflows to support data lineage and reproducibility. The challenges that are introduced by the volume, variety and velocity of Big Data, also pose related challenges for provenance and quality of Big Data, defined as veracity. The increasing size and variety of distributed Big Data provenance information bring new technical challenges and opportunities throughout the provenance lifecycle including recording, querying, sharing and utilization. This paper discusses the challenges and opportunities of Big Data provenance related to the veracity of the datasets themselves and the provenance of the analytical processes that analyze these datasets. It also explains our current efforts towards tracking and utilizing Big Data provenance using workflows as a programming model to analyze Big Data. PMID- 29399672 TI - Knowledge-Based Biomedical Word Sense Disambiguation with Neural Concept Embeddings AB - Biomedical word sense disambiguation (WSD) is an important intermediate task in many natural language processing applications such as named entity recognition, syntactic parsing, and relation extraction. In this paper, we employ knowledge based approaches that also exploit recent advances in neural word/concept embeddings to improve over the state-of-the-art in biomedical WSD using the public MSH WSD dataset [1] as the test set. Our methods involve weak supervision we do not use any hand-labeled examples for WSD to build our prediction models; however, we employ an existing concept mapping program, MetaMap, to obtain our concept vectors. Over the MSH WSD dataset, our linear time (in terms of numbers of senses and words in the test instance) method achieves an accuracy of 92.24% which is a 3% improvement over the best known results [2] obtained via unsupervised means. A more expensive approach that we developed relies on a nearest neighbor framework and achieves accuracy of 94.34%, essentially cutting the error rate in half. Employing dense vector representations learned from unlabeled free text has been shown to benefit many language processing tasks recently and our efforts show that biomedical WSD is no exception to this trend. For a complex and rapidly evolving domain such as biomedicine, building labeled datasets for larger sets of ambiguous terms may be impractical. Here, we show that weak supervision that leverages recent advances in representation learning can rival supervised approaches in biomedical WSD. However, external knowledge bases (here sense inventories) play a key role in the improvements achieved. PMID- 29399673 TI - DRIVING PERFORMANCE AND DRIVER STATE IN OBSTRUCTIVE SLEEP APNEA: WHAT CHANGES WITH POSITIVE AIRWAY PRESSURE? AB - We evaluated naturalistic driving in 65 drivers with obstructive sleep apnea (OSA) before and after positive airway pressure (PAP) therapy and in 43 comparison drivers. Driving performance metrics included speed (mean, variability), and lateral, and longitudinal acceleration (g's). Driver state measures included sleepiness and attention to the driving task based on sampled trigger and baseline video clips. OSA drivers showed less variability in speed and lateral g's compared to control drivers before and after PAP treatment when vehicle speed was <45mph. There were no driving performance differences when vehicle speed exceeded 45 mph. OSA drivers remained less alert than comparison drivers before and after PAP. Average hours of nightly PAP-use predicted improved alertness and lower levels of sleepiness among OSA drivers. The findings suggest increased crash risk among OSA drivers may result from lower levels of attention to the driving task that result in performance lapses that may lead to crashes, rather than to clear and specific patterns of performance deficits in vehicle control. PMID- 29399674 TI - THE EFFECTS OF GUIDANCE METHOD ON DETECTION AND SCANNING AT INTERSECTIONS - A PILOT STUDY. AB - Older drivers are frequently involved in collisions at intersections. One reason may be inadequate head and eye scanning when approaching the intersection. Prior driving simulator research on scanning at intersections has employed two main methods to guide subjects through the simulated world: auditory instructions similar to GPS navigation and following a lead vehicle. However, these two methods may have differing effects on head and eye scanning behaviors. We therefore conducted a pilot study to assess the effects of guidance method on participants' head and eye movements as well as their detection of motorcycle hazards at intersections. Detection rates were significantly higher when following a lead vehicle than when following GPS instructions, but participants were closer to the intersection when they responded. Preliminary examination of the head and eye movement data suggests participants scanned less frequently when following the lead vehicle. PMID- 29399675 TI - Augmented Personalized Health: How Smart Data with IoTs and AI is about to Change Healthcare. AB - Healthcare as we know it is in the process of going through a massive change - from episodic to continuous, from disease focused to wellness and quality of life focused, from clinic centric to anywhere a patient is, from clinician controlled to patient empowered, and from being driven by limited data to 360-degree, multimodal personal-public-population physical-cyber-social big data driven. While ability to create and capture data is already here, the upcoming innovations will be in converting this big data into smart data through contextual and personalized processing such that patients and clinicians can make better decisions and take timely actions for augmented personalized health. This paper outlines current opportunities and challenges, with a focus on key AI approaches to make this a reality. The broader vision is exemplified using three ongoing applications (asthma in children, bariatric surgery, and pain management) as part of the Kno.e.sis kHealth personalized digital health initiative. PMID- 29399676 TI - Factor VIII Level is Not Modifiable by Improved Glycemic Control in Patients with Ischemic Stroke. AB - Aims: To determine whether the degree of glycemic control was related to change in Factor VIII (FVIII) level in patients with acute ischemic stroke (AIS). Methods: From our stroke registry, all AIS patients admitted between 07/2008 05/2014 with baseline HbA1c and FVIII levels were eligible. Of these, patients with follow-up HbA1c and FVIII levels post-discharge were included. Elevation in FVIII was defined as level >150%. Diabetic control was categorized according to HbA1c levels:uncontrolled (>7.1%), controlled (5.7-7.0%), and normal (<5.7%) HbA1c and FVIII levels were further analyzed for evidence of a correlation as continuous variables. Results: Among 1,631 AIS cases, 63 patients met inclusion criteria. Of these, 21 patients (33.3%) had uncontrolled diabetes, 27 patients (42.8%) had controlled diabetes, and 15 patients (23.4%) had normoglycemia. Baseline demographic characteristics differed only for history of hyperlipidemia (57.1% uncontrolled, 25.9% controlled, 26.7% normal, p=0.0443). Time between baseline and follow-up measures of both FVIII and HbA1c did not differ between groups (p=0.0812 and p=0.6969, respectively). There was no association between HbA1C group and FVIII level at baseline (p=0.2197) nor between change in HbA1c and change in FVIII from baseline to follow-up (r=0.0147, p=0.9092). Additionally, no statistically significant level at baseline or follow-up. Conclusions: While hyperglycemia and FVIII level are associated in the acute phase of AIS, long-term glycemic control before or subsequent to AIS was unrelated to FVIII level. Our results suggest that these stroke risk factors are independent of each other and that FVIII level cannot be modified by controlling diabetes. PMID- 29399677 TI - Guest editorial: Effective use of radiation in dentistry: Evolving concepts that promote efficacy. PMID- 29399678 TI - Chronic non-suppurative mandibular osteomyelitis with proliferative periostitis: A review. AB - Chronic non-suppurative osteomyelitis (CNSO) is a chronic bone disease and may be associated with a reparative periosteum entity called proliferative periostitis (PP). This condition rarely affects the maxillofacial region. Mandibular cases were already described for an infectious dental cause, often with an "onion skin" radiographic aspect, but some rare reported cases showed no obvious etiology. They represent a challenge for diagnosis because of possible misdiagnosis leading to unsuccessful or inappropriate treatment attempts. An uncommon case of mandibular CNSO associated with PP in a 9-year-old boy with no obvious infectious or inflammatory causes is reported. Clinical and radiographic examinations revealed a swelling in the left hemimandible, associated with multiple osteolytic areas inside both medullary and newly formed periosteal bone and cortical bone perforations. Recovery signs were seen after a 22-month follow-up period, and radiographic signs of bone healing were observed. From this new case report, a review of the literature was performed on reported cases of mandibular CNSO with PP, and discussed the etiological, clinical, radiologic, and therapeutic aspects of this pathology. This work highlights the importance of considering CNSO with PP in the differential diagnosis of one-sided painless mandibular swellings, even in the absence of an obvious cause. PMID- 29399679 TI - Bonding to Sound and Caries-Affected Dentin: A Systematic Review and Meta Analysis. AB - PURPOSE: This study systematically reviewed the literature to compare the bonding ability of dental adhesives applied to sound dentin (SoD) vs caries-affected dentin (CAD). MATERIALS AND METHODS: Three international databases (Medline/PubMed, Scopus, and Web of Science) were searched. Eligible studies which evaluated the bond strength to both SoD and CAD were included. Random effects meta-analyses were conducted to calculate pooled mean difference between substrates, separately for etch-and-rinse and self-etch adhesives. Subgroup analyses were carried out to explore heterogeneity considering the methods used for removal of infected carious dentin. A comparison between etch-and-rinse and self-etch adhesives restricted to CAD was also performed. Statistical heterogeneity was considered using the I2 test. The risk of bias of all included studies was assessed. RESULTS: In total, 2260 articles were found, 65 were selected for full-text reading, and 40 studies were included. The meta-analyses favored SoD over CAD for both etch-and-rinse (effect size: -10.04; 95% confidence interval [CI]: -11.94, -8.14; I2 = 95%) and self-etch adhesives (effect size: 6.76; 95% CI: -8.23, -5.30; I2 = 89%). In the subgroup analyses, SoD was favored irrespective of the method used for caries removal (effect size <= -4.86; I2 >= 28%): excavation (manual or with burs), grinding with abrasive papers, combination of more than one method, and when the method was not mentioned. The meta-analysis restricted to CAD favored etch-and-rinse over self-etch adhesives (effect size: 3.13; 95% CI: 1.82, 4.44; I2 = 72%). Most included studies were judged as having an unclear risk of bias. CONCLUSION: Bonding to SoD yields better results compared to CAD. Etch-and-rinse adhesives performed better than self-etch adhesives when applied to CAD. PMID- 29399680 TI - Design and synthesis of multifunctional metal-organic zeolites. AB - Metal-organic zeolites (MOZs) are an important branch of metal-organic frameworks (MOFs) and combine the advantages of zeolites and MOFs, such as high surface area and porosity as well as the exceptional stability of zeolites, which would have a significant impact on catalysis chemistry, inorganic chemistry, coordination chemistry, materials science and other areas. In this review, we focus on the recent advances in MOZs with a brief outline of the most prominent examples. In particular, we highlight the basic principles of the design and synthesis approaches toward the construction of MOZs. Obeying the principle of charge matching, tuning tetrahedral metal centers, using enlarged tetrahedral building units as clusters, introducing functional groups into ligands, and combining traditional inorganic TO4 sites in MOZs enable the final materials with diverse topological structures to exhibit superior performance for various applications, such as gas sorption/separation, catalysis, enantio-selectivity, luminescence, etc. PMID- 29399681 TI - Direct detection of the photoinduced charge-separated state in a Ru(ii) bis(terpyridine)-polyoxometalate molecular dyad. AB - Observation of photoinduced intramolecular charge-separation is difficult for photosensitizer-POM dyads because of rapid backward electron transfer. We report here for the first time on a long-lived charge-separated state (tau = 470 ns) observed in a Ru(ii) bis(terpyridine)-based dyad. Charge-separation occurs despite virtually no driving force and the short intrinsic excited-state lifetime of the photosensitizer. PMID- 29399682 TI - The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue. AB - Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh3SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh3Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC50 0.57 +/- 0.15 MUM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg-1 daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti inflammatory drug candidates with balanced pro/anti-oxidative properties. PMID- 29399683 TI - Sodium hypophosphite induced a simultaneous P doping and hollowing process of TiO2 spherical nanostructures with enhanced photocatalytic activity. AB - Sodium hypophosphite induced a simultaneous P doping and hollowing process of TiO2 spherical nanostructures and produced P-doped hollow spherical nanostructures via a simple one-step hydrothermal method. The as-synthesized P doped hollow spherical nanostructures demonstrated significantly enhanced photocatalytic activity for MB degradation compared to the undoped TiO2 and P25 under sunlight irradiation. PMID- 29399684 TI - Polyoxometalate-encapsulated twenty-nuclear silver-tetrazole nanocage frameworks as highly active electrocatalysts for the hydrogen evolution reaction. AB - Two unprecedented polyoxometalate-encapsulated twenty-nuclear silver-tetrazole nanocage frameworks have been synthesized, which exhibit high activity in hydrogen evolution reaction. HUST-100 shows an onset overpotential of 148 mV and a Tafel slope of 82 mV dec-1, and the catalytic current density approaches 10 mA cm-2 at an overpotential of 234 mV. PMID- 29399686 TI - Near-infrared electrochemiluminescence from orange fluorescent Au nanoclusters in water. AB - We report the unusual generation of near-infrared (near-IR) electrochemiluminescence (ECL) from water-soluble Au nanoclusters (NCs), of which the photoluminescence is primarily within the visible wavelength region. The near IR ECL is ascribed to the Au(0)-glutathione motif in the Au NCs stabilized by glutathione in water. PMID- 29399685 TI - Molecular dynamics investigations of cello-oligosaccharide recognition by Cel9G CBM3c from Clostridium cellulovorans. AB - The processive mechanism of cellulases against cellulose represents one of the key mechanisms in the conversion of biomass. A reliable model of substrate binding in a multidomain cellulase is a prerequisite for fully understanding this mechanism. In this study, the specificity of the recognition of the polysaccharide by the multidomain endoglucanase Cel9G from Clostridium cellulovorans was investigated by molecular dynamics simulations. Aromatic ring containing residues were found to be critical for stabilizing the substrate. The calculated subtotal contributions of polar residues close to the active site, e.g., D58, E244, R315 and D420, also have some critical functions in substrate binding. Unlike other members of the carbohydrate-binding module family, CBM3c alone is shown not to bind cellulose very well, which is also consistent with experimental conclusions. PMID- 29399687 TI - Intermolecular and very strong intramolecular C-SeO/N chalcogen bonds in nitrophenyl selenocyanate crystals. AB - Single-crystal X-ray diffraction reveals that polymorphic ortho-nitrophenyl selenocyanate (o-NSC, crystals 1a and 1b) and monomorphic para-nitrophenyl selenocyanate (p-NSC, crystal 2) crystals are all stabilized mainly by intermolecular and very strong intramolecular C-SeO/N chalcogen bonds, as well as by other different interactions. Thermogravimetric (TG) and differential scanning calorimetry thermogram (DSC) analyses show that the starting decomposition temperatures and melting points of the three crystals are different, following the order 1b > 1a > 2, which is consistent with the structural characteristics of the crystals. In addition, atoms in molecules (AIM) and natural bond orbital (NBO) analyses indicate that the total strengths of the C-SeO and C-SeN chalcogen bonds decrease in the order 1b > 1a > 2. This study could be significant for engineering functional crystals based on robust C-SeO and C-SeN chalcogen bonds, and for designing drugs containing selenium as well as understanding their interaction in biosystems. PMID- 29399688 TI - Reduction of the thermal conductivity of a graphene/hBN heterobilayer via interlayer sp3 bonds. AB - Thermal conductivities (TCs) of graphene (g)/hexagonal boron nitride (hBN) heterobilayers with interlayer sp3 bonds are computed using nonequilibrium molecular dynamics (NEMD) simulations. It is revealed that the TC of a g/hBN heterobilayer drastically decreases if there is even a few interlayer sp3 bonds, and continues to gradually decrease upon increasing their fraction up to 0.25, where the fraction of the interlayer sp3 bonds is defined by the atomic fraction of interlayer-sp3-bonded carbon atoms within graphene constituting a g/hBN heterobilayer. If their fraction exceeds 0.25, the TC of a g/hBN heterobilayer gradually increases, namely, the TC of a g/hBN heterobilayer takes a minimum at the fraction of 0.25 of the interlayer sp3 bonds. In order to understand such a behavior of the TC of the heterobilayer, the local phonon density of states (DOSs) in each of the two layers is calculated. By examining the local phonon DOSs, it was found that the existence of the minimum TC of the heterobilayer can be understood by considering both the phonon scattering and the characteristic change of the heterobilayer structure. In the range of the low fractions of interlayer sp3 bonds, the van der Waals (vdW) interactions are predominantly effective for binding the two layers, and the interlayer sp3 bonds act as phonon scatterers like defects to make the TC of the heterobilayer decrease. Upon increasing the fraction of interlayer sp3 bonds, the contribution of the interlayer sp3 bonds to the unification of the two layers becomes stronger, and hence the rigidity of the heterobilayer structure gradually increases. If their fraction exceeds 0.25, the heterobilayer structure approaches a quasi-three dimensional one, so that the TC of the heterobilayer increases. These findings will be useful for tuning the TCs of g/hBN heterobilayers via interlayer sp3 bonds. PMID- 29399689 TI - Towards flexible solid-state supercapacitors for smart and wearable electronics. AB - Flexible solid-state supercapacitors (FSSCs) are frontrunners in energy storage device technology and have attracted extensive attention owing to recent significant breakthroughs in modern wearable electronics. In this study, we review the state-of-the-art advancements in FSSCs to provide new insights on mechanisms, emerging electrode materials, flexible gel electrolytes and novel cell designs. The review begins with a brief introduction on the fundamental understanding of charge storage mechanisms based on the structural properties of electrode materials. The next sections briefly summarise the latest progress in flexible electrodes (i.e., freestanding and substrate-supported, including textile, paper, metal foil/wire and polymer-based substrates) and flexible gel electrolytes (i.e., aqueous, organic, ionic liquids and redox-active gels). Subsequently, a comprehensive summary of FSSC cell designs introduces some emerging electrode materials, including MXenes, metal nitrides, metal-organic frameworks (MOFs), polyoxometalates (POMs) and black phosphorus. Some potential practical applications, such as the development of piezoelectric, photo-, shape memory, self-healing, electrochromic and integrated sensor-supercapacitors are also discussed. The final section highlights current challenges and future perspectives on research in this thriving field. PMID- 29399690 TI - Cooperative 5- and 10-membered ring interactions in the 10-helix folding of oxetin homo-oligomers. AB - Homo-oligomers of the natural product oxetin (cis-3-amino-2-oxetanecarboxylic acid) were prepared and their conformational behaviour studied in solution and solid state and by molecular modelling. The predominant secondary structure was a 10-helix, propiciously stabilized by a network of 5-membered ring H-bonds implicating ring oxygens and neighboring amide hydrogen atoms. PMID- 29399691 TI - Effect of counterion excluded volume on the conformational behavior of polyelectrolyte chains. AB - Conformational behavior of a single strongly charged polyelectrolyte chain in a dilute solution is studied by molecular dynamics simulations. The novel feature of the model is variation of the excluded volume of counterions for investigating its effect on the chain conformation, especially in low-polar media. It has been confirmed that the chain with conventional counterions collapses into a dense globule with increasing electrostatic interactions. However, if the counterions are bulky enough, they prevent the chain collapse even in media with strong electrostatic interactions. They stay bound in the vicinity of the backbone of the chain that adopts a swollen conformation. In this conformation, the scaling relation for the polymer dimensions with the chain length is the same as for neutral macromolecules in a good solvent, however the polyelectrolyte chain complexed with bulky counterions has a larger gyration radius than its uncharged analogue due to the excluded volume of the counterions contributing to the chain rigidity. Study of the counterion mobility has shown that, similar to the conventional counterions, the bulky counterions do not form stable ion pairs with ions on the polymer chain even in media with strong electrostatic interactions, but rather freely move along the chain backbone. In solutions containing mixtures of counterions with a bimodal size distribution, the conformations of linear polyelectrolytes depend considerably on the fraction of bulky counterions. Furthermore, a kind of intramolecular microphase separation can take place within a polyelectrolyte globule with the formation of a core-shell particle: the smaller counterions concentrate within the globular core while the bulkier counterions form a shell on the globule surface. The stability of the core-shell globule depends on the relative size of the counterions as well as their fractions in the solution. Thus, fine tuning of the balance between the counterion excluded volume and the electrostatic interactions opens new ways for controlling the conformational behavior of polyelectrolytes. PMID- 29399692 TI - Competing failure modes in finite adhesive pads. AB - Thin adhesive pads used to attach objects to each other often fail catastrophically. Here we consider the nature of failure of such a pad under loading parallel to the adhesive substrate. To determine the modes of failure of the pad and to understand what limits its load bearing capacity, we conduct experiments with finite pads composed of a soft adhesive layer with a stiff backing and load them parallel to the surface of adhesion. We find that two different peeling mechanisms emerge as a function of the slenderness of the adhesive pad: an interfacial peeling mechanism that starts close to the pulling end for very long pads, and an unstable curling mechanism that starts at the opposite end for relatively short pads. A minimal theoretical framework allows us to explain our observations and reveals the adhesive bond stiffness as a dominant parameter in defining the peeling mode. A phase diagram that delineates the different regimes of peeling modes brings our experiments and theory together. Our results suggest that unstable peeling by curling may be more common than previously thought, and could perhaps occur naturally in such examples as the gecko foot. PMID- 29399693 TI - Visible light-driven photocatalytic generation of sulfonamidyl radicals for alkene hydroamination of unsaturated sulfonamides. AB - A visible light-driven photocatalytic generation of sulfonamidyl radicals, and application to intramolecular alkene hydroamination, has been accomplished, providing a mild and efficient approach to various functionalized isoxazolidines. The success of this protocol is based on the strategy of oxidative deprotonation electron transfer by merging the base and the photocatalyst under visible light irradiation, obviating installation of a photolabile handle or stoichiometric external oxidants. PMID- 29399694 TI - Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). AB - An uncontrolled cell cycle is an obvious marker of tumor cells. The G1-S phase is an important restriction point in the normal cell cycle, but in cancer cells the restriction function is reduced, leading to uncontrolled cell proliferation. Two cyclin-dependent kinases (CDKs), CDK4 and CDK6, play a crucial role in the G1-S phase transition. Inhibitors of CDK4/6 are presently the subjects of numerous studies, and PD 0332991, an inhibitor of CDK4/6, has been used to treat hormone receptor (HR)-positive, advanced-stage breast cancer. This inhibitor has also been studied in other cancers, such as lung cancer. In this review, we will discuss the regulation of the normal cell cycle transition from G1 to S phase, the most promising inhibitor of CDK4/6, PD 0332991, as applied in different cancers, and finally we propose a mechanism of acquired resistance as well as the incredible potential for CDK4/6 inhibitors in the treatment of cancer. Briefly, we assert that, going forward, a new treatment pattern for cancer may be a combination therapy with a cell cycle inhibitor and a molecular targeted drug. PMID- 29399695 TI - MicroRNA-16/VEGFR2/p38/NF-kappaB signaling pathway regulates cell growth of human pituitary neoplasms. AB - The association of microRNA (miRNA) with tumor has gradually become an active medical research field, since its discovery in 1993. The aim of the present study was to clarify how microRNA-16 expression affects the proliferation and survival of pituitary tumor, revealing its potential mechanism. MicroRNA-16 expression of pituitary tumor patients was observably declined, compared with the normal group. A high expression of microRNA-16 showed longer survival in pituitary tumor patients, compared to a low expression of microRNA-16 in pituitary tumor patients. MicroRNA-16 upregulation effectively decreased cell proliferation and induced apoptosis in HP75 cells. MicroRNA-16 overexpression effectively induced p27, Bax protein expression and caspase-3/8 activities, and suppressed phosphorylation-(p)-p38, NF-kappaB, MMP-9 and VEGFR2 protein expression in HP75 cells. After VEGFR2 suppression, the effects of microRNA-16 overexpression on cell proliferation and apoptosis were significantly inhibited in HP75 cells. Moreover, the effects of microRNA-16 overexpression on p27, Bax protein expression and caspase-3/8 activities were significantly decreased in HP75 cells after p38 suppression. VEGFR2 or NF-kappaB suppression reduced the effects of microRNA-16 overexpression on p-p38, NF-kappaB, MMP-9 and VEGFR2 protein expression inhibition in HP75 cells. Our results suggest that microRNA-16 expression affects the proliferation and angiogenesis of pituitary cancer through the VEGFR2/p38/NF-kappaB signaling pathway. PMID- 29399696 TI - Fra-1 enhances the radioresistance of colon cancer cells to X-ray or C-ion radiation. AB - Fos-related antigen 1 (Fra-1) has roles in a variety of cell functions, including cell proliferation, differentiation, transformation, and invasiveness, and it is upregulated in various cancers. We investigated the role of Fra-1 in cellular radioresistance using cells of two human colorectal cancer cell lines, SW620 and SW480. We found that SW620 cells are more sensitive than SW480 cells at doses greater than 6 Gy for X-ray or 3 Gy for carbon-ion (C-ion) radiation. Fra-1 expression tended to be decreased by the radiation in a dose-dependent manner in both cell lines; of note, a greater reduction of Fra-1 expression was observed in SW620 cells, especially at 6 Gy of X-ray or 3 Gy of C-ion irradiation, than in SW480 cells, indicating a possible association between Fra-1 downregulation and cellular radiosensitivity. Knockdown of Fra-1 in SW480 cells significantly increased the radiosensitivity to X-ray or C-ion radiation. On the other hand, overexpression of Fra-1 in SW620 cells significantly enhanced the radioresistance to C-ion radiation, suggesting a role of Fra-1 in radioresistance. Furthermore, we found that downregulation of Fra-1 protein in irradiated SW620 cells was regulated via protein degradation through a proteasome-dependent pathway. Overall, our results indicate a role of Fra-1 in radioresistance to both X-ray and C-ion radiation for colorectal cancer cell lines. PMID- 29399697 TI - A 60 kDa prolactin variant secreted by cervical cancer cells modulates apoptosis and cytokine production. AB - Prolactin (PRL) is associated with different types of cancer, such as cervical cancer. Recombinant PRL has antiapoptotic effect on cervical cancer cells, and it can also induce cytokine production on macrophages. A 60 kDa variant of PRL is produced by cervical cancer cells. The aim of the present study was to evaluate this variant's bioactivity, to test its effect on cervical cancer cell apoptosis, and to assess its ability to induce cytokine production on THP-1 macrophages. First, 60 kDa PRL was isolated and used to stimulate Nb2 cells. Later, apoptosis was measured after exposure to 60 kDa PRL. Finally, cytokines were measured on THP-1 stimulated supernatants. Our results show that 60 kDa PRL increased Nb2 cell proliferation. Apoptosis was decreased after stimuli with 60 kDa PRL in cervical cancer cells. IL-1beta and TNF-alpha are produced by THP-1 macrophages after stimuli. These results suggest that 60 kDa PRL produced by cervical cancer cells is able to reduce apoptosis in HeLa, SiHa and C-33A cells and induce IL 1beta and TNF-alpha production by THP-1 macrophages. PMID- 29399698 TI - MicroRNA-125 modulates radioresistance through targeting p21 in cervical cancer. AB - Cervical cancer (CC) is one of the most common cancers diagnosed in women worldwide, and it is estimated that ~500,000 new patients are diagnosed with cervical cancer annually and that ~270,000 deaths occur each year. Patients with cervical cancer are treated with different radiotherapy schedules, either alone or with adjuvant chemotherapy. Unfortunately, nearly 50% of all patients with cervical cancer do not respond to standard treatment due to tumor radioresistance. In this scenario, several microRNAs (miRNAs) have been associated with the acquisition of the radioresistance phenotype. The aim of the present study was to evaluate the possible role of miR-125a in the acquisition of radioresistance in cervical cancer. The expression of miR-125a was assessed by means of RT-qPCR in 30 cervical cancer samples from patients receiving standard treatment and 3 induced radioresistant cervical cancer cell lines. In addition, we employed miR-125a mimics and inhibitors to evaluate its function in the induction of radioresistance. We showed that miR-125a was downregulated in patients with cervical cancer who did not respond to standard treatment. Concordantly, radioresistant SiHa, CaSki and HeLa cell lines had low levels of miR-125a with respect to the sensitive cell lines. Finally, we demonstrated that overexpression of miR-125a sensitized cervical cancer cells to radiation therapy through the downregulation of CDKN1A. Our data corroborate previously published studies in which it was demonstrated that miRNAs could play a role in the regulation of the process of radioresistance. Additionally, we showed that overexpression of miR-125a could be used as a radioresistance biomarker in patients with cervical cancer. PMID- 29399699 TI - The role of aldehyde dehydrogenase 1A1 in B-cell non-Hodgkin's lymphoma. AB - Previously we showed that aldehyde dehydrogenase 1A1 (ALDH1A1) is a new mediator for resistance of DLBCL to CHOP and a facility predictor of clinical prognosis. In the present study, knockdown and inhibitor of ALDH1A1 were applied to identify the role of ALDH1A1 in Raji cells. CCK-8 and clone formation assay were applied to determine the CHOP sensitivity and clone formation ability. Caspase colorimetric assay and Annexin V/FITC staining was performed to determine the degree of apoptosis. Western blot analysis was used to detect the NF-kappaB/STAT3 signaling proteins and apoptotic-associated proteins. Real-time quantitative PCR (RT-PCR) was used to identify the differential expression of ALDH1A1 between NHL patients and healthy donors. We demonstrated that inhibition of ALDH1A1 increased the sensitivity of Raji cells to CHOP, as indicated by increased cytotoxicity, reduced clonogenicity, activated caspase-3/-9, decreased NF-kappaB/STAT3 signaling and increased pro-apoptosis signaling, ad increased apoptosis rate. Moreover, we found high ALDH1A1 expression was associated with poor prognosis in NHL patients. Our data revealed the critical role of ALDH1A1 in NHL and provides a theoretical basis for the use of ALDH1A1 inhibitors in NHL patients. PMID- 29399700 TI - NEK2 promotes hepatocellular carcinoma migration and invasion through modulation of the epithelial-mesenchymal transition. AB - Never in mitosis gene-A (NIMA)-related expressed kinase 2 (NEK2) has been recently reported to play a role in tumor progression, drug resistance and tumorigenesis. However, little is known about the effects of NEK2 in hepatocellular carcinoma (HCC) metastasis and the underlying mechanism. NEK2 expression levels were examined by immunochemistry, qRT-PCR and western blot analyses in HCC cell lines and HCC tissues. A Transwell assay was used to determine the migration and invasion capacity of NEK2-silenced or NEK2 overexpressing HCC cells. Cell proliferation was investigated by MTT [(3-(4,5) dimethylthiazol(-z-y1)-3,5-di-phenytetrazolium bromide] assay. The expression levels of epithelial-mesenchymal transition (EMT) markers in NEK2-silenced or NEK2-overexpressing HCC cells were examined by western blot analyses and qRT-PCR. The correlations between NEK2 expression and clinicopathological characteristics were further analyzed. Gene microarray was further used to analyze the effect of NEK2 expression on downstream cell signals. Our study showed that NEK2 was overexpressed in human HCC (37.84%; 98/259). NEK2 overexpression was significantly associated with liver non-capsulation and predicted poor survival outcomes in HCC patients after hepatectomy. In addition, NEK2 significantly enhanced HCC cell invasive ability. Mechanistically, we found that the epithelial mesenchymal transition (EMT) plays a pivotal role in the NEK2-mediated promotion of HCC cell invasion. Furthermore, we provided evidence that signaling through the Wnt, NF-kappaB, focal adhesion, VEGF, Hippo and p53 pathways may be downstream of NEK2. Our findings highlight the importance of NEK2 in HCC metastasis and suggest that NEK2 is a reliable prognostic marker for HCC patients after hepatectomy. PMID- 29399701 TI - Sigma-1 receptor (sigma1R) is downregulated in hepatic malignant tumors and regulates HepG2 cell proliferation, migration and apoptosis. AB - Sigma-1 receptor (sigma1R), an important transmembrane structural protein, has been demonstrated to be overexpressed in various types of human cancer, and has been confirmed to be involved in many biological behaviors during tumorigenesis and tumor progression. The aim of the present study was to explore the essential role of sigma1R in hepatic malignant tumors (HMTs), which, to the best of our knowledge, has not been reported to date. We assessed sigma1R expression in hepatocellular carcinoma (HCC) tissues and found that sigma1R was significantly decreased in HCC when compared with that in benign liver tissues (P<0.01). Additionally, the expression of sigma1R was shown to be inversely correlated with HCC grade (r=-0.424, P=0.021, Kendall's tau-b-test). We further used a FLAG-SV40 neomycin-plasmid strategy to increase sigma1R expression in the HepG2 hepatoblastoma cell line. Overexpression of sigma1R impaired cell proliferation, inhibited cell migration, induced cell cycle arrest at G1 phase, and increased cell apoptosis in vitro. Furthermore, overexpression of sigma1R decreased the expression levels of STAT-3 and NF-kappaB, which provided insight into the underlying mechanisms of sigma1R-associated HMT development and progression. These findings suggest that the decreased expression of sigma1R plays an essential role in hepatic tumorigenesis, and that it may serve as a potential predictive factor and therapeutic target for the treatment of HMTs. PMID- 29399702 TI - Actin-capping protein CapG is associated with prognosis, proliferation and metastasis in human glioma. AB - Glioma is the most aggressive and malignant primary brain tumor in adults. In the present study, we identified a vital oncoprotein, capping actin protein, gelsolin like (CapG), and investigated its roles in the prognosis, proliferation and metastasis in glioma. The mRNA and protein levels of CapG were significantly increased in human glioma, and higher CapG expression was an independent prognostic factor for predicting unfavorable prognosis. The expression level of CapG was found to be associated with several common molecular features of glioblastoma (GBM; WHO grade IV glioma) in The Cancer Genome Atlas (TCGA) cohort. When analyzing the prognosis of GBM patients according to these molecular features, we observed that the prognostic value of CapG was affected by amplification of CDK6 or EGFR. However, overexpression of CapG markedly promoted cell growth in vitro, while depletion of CapG significantly inhibited cell proliferation by blocking the cell cycle in G1/S transition. Moreover, CapG manipulation in glioma cell lines U87 and U251 showed CapG-dependent cellular migration and invasiveness. These data suggest that CapG may serve as a prognostic biomarker with potentially important therapeutic implications for glioma. PMID- 29399703 TI - Release of nickel and chromium ions from orthodontic wires following the use of teeth whitening mouthwashes. AB - BACKGROUND: Corrosion resistance is an important requirement for orthodontic appliances. Nickel and chromium may be released from orthodontic wires and can cause allergic reactions and cytotoxicity when patients use various mouthwashes to whiten their teeth. Our study aimed to assess the release of nickel and chromium ions from nickel titanium (NiTi) and stainless steel (SS) orthodontic wires following the use of four common mouthwashes available on the market. METHODS: This in vitro, experimental study was conducted on 120 orthodontic appliances for one maxillary quadrant including five brackets, one band and half of the required length of SS, and NiTi wires. The samples were immersed in Oral B, Oral B 3D White Luxe, Listerine, and Listerine Advance White for 1, 6, 24, and 168 h. The samples immersed in distilled water served as the control group. Atomic absorption spectroscopy served to quantify the amount of released ions. RESULTS: Nickel ions were released from both wires at all time-points; the highest amount was in Listerine and the lowest in Oral B mouthwashes. The remaining two solutions were in-between this range. The process of release of chromium from the SS wire was the same as that of nickel. However, the release trend in NiTi wires was not uniform. CONCLUSIONS: Listerine caused the highest release of ions. Listerine Advance White, Oral B 3D White Luxe, and distilled water were the same in terms of ion release. Oral B showed the lowest amount of ion release. PMID- 29399705 TI - Coreferential Relations in Basque: The Annotation Process. AB - In this paper we present the coreferential tagging of part of the EPEC Corpus of Basque. Although coreference is a pragmatic linguistic phenomenon highly dependent on the situational context, it shows some language-specific patterns that vary according to the features of each language. Due to the fact that Basque is not an Indo-European language, it differs considerably in grammar from the languages spoken in surrounding areas. We will explain these features and the decisions made in each case. After describing the criteria defined for coreferential tagging in Basque, the annotation process will be explained. Our annotation is based on a morphologically and syntactically annotated corpus that provides us with a manageable environment, in which the specific structures that are part of a reference chain can be more easily identified. A part of the corpus was tagged by two annotators who marked up the same text independently, and by another annotator that acted as judge, solving problems in case of disagreement. All this process has been automatized as a result of previous studies carried out in this field. The automatic detection of mentions (Soraluze et al., in: Proceedings of Konvens, 2012) has provided us with a better working environment, and given us the possibility to build a first significant corpus for a later computational treatment of automatic coreferential resolution. PMID- 29399704 TI - How removing visual information affects grasping movements. AB - Our interaction with objects is facilitated by the availability of visual feedback. Here, we investigate how and when visual feedback affects the way we grasp an object. Based on the main views on grasping (reach-and-grasp and double pointing views), we designed four experiments to test: (1) whether the availability of visual feedback influences the digits independently, and (2) whether the absence of visual feedback affects the initial part of the movement. Our results show that occluding (part of) the hand's movement path influences the movement trajectory from the beginning. Thus, people consider the available feedback when planning their movements. The influence of the visual feedback depends on which digit is occluded, but its effect is not restricted to the occluded digit. Our findings indicate that the control mechanisms are more complex than those suggested by current views on grasping. PMID- 29399706 TI - Differential diagnostic perspectives provided by en face microscopic examination of articular surface defects. AB - Surface defects have a central position in diagnosis of articular pathology. Recognizing the limitations of standard radiologic techniques and those imposed by positioning and averaging artifacts on CT evaluation, direct visualization of surface defects was pursued to identify disease characteristics that would facilitate interpretation of radiologic findings. Epi-illumination surface microscopy was utilized to examine macroscopically recognized articular surface defects in individuals in the Hamann-Todd, Terry, and Huntington human skeletal collections with previously verified diagnoses of rheumatoid arthritis, spondyloarthropathy, juvenile inflammatory arthritis (JIA), calcium pyrophosphate deposition disease (CPPD), gout, metastatic cancer, multiple myeloma, septic arthritis, tuberculosis, fungal arthritis, histiocytosis and sickle cell anemia (Rothschild and Rothschild Clin Infect Dis 20(5):1402-1408, 1995; Rothschild et al. Amer J Phys Anthropol 82(4):441-449, 1990; Rothschild and Rothschild Amer J Phys Anthropol 96(4):357-563, 1995; Rothschild and Woods Clin Exp Rheumatol 10(2):117-122, 1992; Barrett and Keat Radiographics 24(6):1679-1691, 2004; Rothschild and Heathcote Amer J Phys Anthropol 98(4):519-525, 1995; Rothschild and Woods Am J Phys Anthropol 85:25-34, 1991; Hershkovitz et al. Amer J Phys Anthropol 106(1):47-60, 1998; Winland et al. Amer J Phys Anthropol 24:S243, 1997; Rothschild et al. Clin Exp Rheumatol 10(6):557-564, 1992; Rothschild and Martin , 2006; Rothschild et al. Amer J Phys Anthropol 102(2):249-264, 1997). Observed alterations were compared with standard radiographs. Fronts of resorption distinguished inflammatory arthritis from those caused by the other disorders studied. Multiple myeloma, fungal disease, and gout are expansile character; the latter accompanied by reactive new bone formation more prominent than that noted with spondyloarthropathy and JIA. Those were clearly distinguished from the crumbling alterations found with CPPD. Histiocytosis had a unique crenulated appearance, while nodules were prominent with syphilis. Defects in sickle cell anemia had ivory fragments at their base. These findings provided explanation for radiologic observations. Direct surface microscopy revealed characteristics apparently pathognomonic for specific disorders and facilitated distinguishing among them. The technique provides visualization an order of magnitude greater than that available with clinical radiologic techniques and identifies new characteristics which should facilitate clinical diagnoses. This demonstrates that there would be value to the development of higher resolution, clinically applicable imaging techniques. PMID- 29399707 TI - Impact of surgical management in cases of intraoperative membrane perforation during a sinus lift procedure: a follow-up on bone graft stability and implant success. AB - BACKGROUND: Until now, sinus floor elevation represents the gold standard procedure in the atrophic maxilla in order to facilitate dental implant insertion. Although the procedure remains highly predictive, the perforation of the Schneiderian membrane might compromise the stability of the augmented bone and implant success due to chronic sinus infection. The aim of this retrospective cohort study was to show that a membrane tear, if detected and surgically properly addressed, has no influence on the survival of dental implants and bone resorption in the augmented area. METHODS: Thirty-one patients with 39 perforations could be included in this evaluation, and a control group of 32 patients with 40 sinus lift procedures without complications were compared regarding the radiographically determined development of bone level, peri-implant infection, and implant loss. RESULTS: Implant survival was 98.9% in the perforation group over an observation period of 2.7 (+/- 2.03) years compared to 100% in the control group after 1.8 (+/- 1.57) years. The residual bone level was significantly lower in the perforation group (p = 0.05) but showed no difference direct postoperatively (p = 0.7851) or in the follow-up assessment (p = 0.2338). Bone resorption remained not different between both groups (p = 0.945). A two stage procedure was more frequent in the perforation group (p = 0.0003) as well as peri-implantitis (p = 0.0004). CONCLUSIONS: Within the limits of our study, the perforation of the Schneiderian membrane did not have a negative impact on long-term graft stability or the overall implant survival. PMID- 29399708 TI - Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study. PMID- 29399709 TI - QUIET PLEASE! Effect of distraction on simulated posterior segment surgical performance. AB - PURPOSE: To determine the effect of distraction on posterior segment surgical performance using a virtual reality simulator in expert and novice ophthalmic surgeons. METHODS: Twenty subjects were given 6 min to read an unpublished research paper and then were randomized into two groups. Group 1 subjects were allowed 3 min to complete a standardized vitreoretinal simulated task undistracted. Group 2 subjects were asked six questions on the research paper whilst completing the same task. Each subject then performed the alternate scenario. Finally, all participants were asked six questions on the research paper whilst not operating. RESULTS: There was no evidence of a difference in the odometer values (p = 0.127), cognitive task score (p = 0.390) or overall surgical task scores (p = 0.113) between the two groups. The time taken by the distracted group was significantly greater (95% CI -26.03 to -1.67, t-test p = 0.028). CONCLUSION: Distraction significantly increases the time taken to perform a simulated vitreoretinal surgical task for all grades of surgeon. More studies are required to understand the impact on different types of distraction on surgical performance. PMID- 29399710 TI - Kernel Reconstruction for Delayed Neural Field Equations. AB - Understanding the neural field activity for realistic living systems is a challenging task in contemporary neuroscience. Neural fields have been studied and developed theoretically and numerically with considerable success over the past four decades. However, to make effective use of such models, we need to identify their constituents in practical systems. This includes the determination of model parameters and in particular the reconstruction of the underlying effective connectivity in biological tissues.In this work, we provide an integral equation approach to the reconstruction of the neural connectivity in the case where the neural activity is governed by a delay neural field equation. As preparation, we study the solution of the direct problem based on the Banach fixed-point theorem. Then we reformulate the inverse problem into a family of integral equations of the first kind. This equation will be vector valued when several neural activity trajectories are taken as input for the inverse problem. We employ spectral regularization techniques for its stable solution. A sensitivity analysis of the regularized kernel reconstruction with respect to the input signal u is carried out, investigating the Frechet differentiability of the kernel with respect to the signal. Finally, we use numerical examples to show the feasibility of the approach for kernel reconstruction, including numerical sensitivity tests, which show that the integral equation approach is a very stable and promising approach for practical computational neuroscience. PMID- 29399711 TI - Formation of Se(0), Te(0), and Se(0)-Te(0) nanostructures during simultaneous bioreduction of selenite and tellurite in a UASB reactor. AB - Simultaneous removal of selenite and tellurite from synthetic wastewater was achieved through microbial reduction in a lab-scale upflow anaerobic sludge blanket reactor operated with 12 h hydraulic retention time at 30 degrees C and pH 7 for 120 days. Lactate was supplied as electron donor at an organic loading rate of 528 or 880 mg COD L-1 day-1. The reactor was initially fed with a synthetic influent containing 0.05 mM selenite and tellurite each (phase I, day 1 60) and subsequently with 0.1 mM selenite and tellurite each (phase II, day 61 120). At the end of phase I, selenite and tellurite removal efficiencies were 93 and 96%, respectively. The removal percentage dropped to 87 and 81% for selenite and tellurite, respectively, at the beginning of phase II because of the increased influent concentrations. The removal efficiencies of both selenite and tellurite were gradually restored within 20 days and stabilized at >= 97% towards the end of the experiment. Powder X-ray diffraction and Raman spectroscopy confirmed the formation of biogenic Se(0), Te(0), and Se(0)-Te(0) nanostructures. Scanning transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy showed aggregates comprising of Se(0), Te(0), and Se-Te nanostructures embedded in a layer of extracellular polymeric substances (EPS). Infrared spectroscopy confirmed the presence of chemical signatures of the EPS which capped the nanoparticle aggregates that had been formed and immobilized in the granular sludge. This study suggests a model for technologies for remediation of effluents containing Se and Te oxyanions coupled with biorecovery of bimetal(loid) nanostructures. PMID- 29399712 TI - A novel riboregulator switch system of gene expression for enhanced microbial production of succinic acid. AB - In this paper, a novel riboregulator Switch System of Gene Expression including an OFF-TO-ON switch and an ON-TO-OFF switch was designed to regulate the expression state of target genes between "ON" and "OFF" by switching the identifiability of ribosome recognition site (RBS) based on the thermodynamic stability of different RNA-RNA hybridizations between RBS and small noncoding RNAs. The proposed riboregulator switch system was employed for the fermentative production of succinic acid using an engineered strain of E. coli JW1021, during which the expression of mgtC gene was controlled at "ON" state and that of pepc and ecaA genes were controlled at the "OFF" state in the lag phase and switched to the "OFF" and "ON" state once the strain enters the logarithmic phase. The results showed that using the strain of JW1021, the yield and productivity of succinic acid can reach 0.91 g g-1 and 3.25 g L-1 h-1, respectively, much higher than those using the strains without harboring the riboregulator switch system. PMID- 29399713 TI - Bipedal robotic walking control derived from analysis of human locomotion. AB - This paper proposes the design of a bipedal robotic controller where the function between the sensory input and motor output is treated as a black box derived from human data. In order to achieve this, we investigated the causal relationship between ground contact information from the feet and leg muscle activity n human walking and calculated filter functions which transform sensory signals to motor actions. A minimal, nonlinear, and robust control system was created and subsequently analysed by applying it to our bipedal robot RunBot III without any central pattern generators or precise trajectory control. The results demonstrate that our controller can generate stable robotic walking. This indicates that complex locomotion patterns can result from a simple model based on reflexes and supports the premise that human-derived control strategies have potential applications in robotics or assistive devices. PMID- 29399714 TI - Kidney Autotransplantation: Between the Past and the Future. AB - PURPOSE OF REVIEW: The practice of kidney autotransplantation (KAT) has become an increasingly favorable approach in the treatment of certain renovascular, ureteral, and malignant pathologies. Current KAT literature describes conventional open procedures, which are associated with substantial risks. We sought to compare previously reported outcomes, evaluate common surgical indications, and assess associated risks and benefits of current KAT methods. A thorough evaluation and review of the literature was performed with the keywords "autologous transplantation" and "kidney." RECENT FINDINGS: Early outcomes of robotic KAT are encouraging and have been associated with fewer complications and shorter hospital stay, but require robotic technique proficiency. KAT is an important method to manage selected complex urological pathologies. Robotic KAT is promising. Nevertheless, future studies should utilize larger patient cohorts to better assess the risks and benefits of KAT and to further validate this approach. PMID- 29399715 TI - Introductory Overview of the Natural Experiments for Translation in Diabetes 2.0 (NEXT-D2) Network: Examining the Impact of US Health Policies and Practices to Prevent Diabetes and Its Complications. AB - PURPOSE OF REVIEW: Diabetes incidence is rising among vulnerable population subgroups including minorities and individuals with limited education. Many diabetes-related programs and public policies are unevaluated while others are analyzed with research designs highly susceptible to bias which can result in flawed conclusions. The Natural Experiments for Translation in Diabetes 2.0 (NEXT D2) Network includes eight research centers and three funding agencies using rigorous methods to evaluate natural experiments in health policy and program delivery. RECENT FINDINGS: NEXT-D2 research studies use quasi-experimental methods to assess three major areas as they relate to diabetes: health insurance expansion; healthcare financing and payment models; and innovations in care coordination. The studies will report on preventive processes, achievement of diabetes care goals, and incidence of complications. Some studies assess healthcare utilization while others focus on patient-reported outcomes. NEXT-D2 examines the effect of public and private policies on diabetes care and prevention at a critical time, given ongoing and rapid shifts in the US health policy landscape. PMID- 29399716 TI - Pharmacogenetics of post-transplant diabetes mellitus in children with renal transplantation treated with tacrolimus. AB - BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a major complication of immunosuppressive therapy, with many risk factors reported in adults with renal transplantation. The objective of this study was to investigate potential non genetic and genetic risk factors of PTDM in children with renal transplantation treated with tacrolimus. METHODS: A national database was screened for patients developing PTDM within 4 years following tacrolimus introduction. PTDM was defined as glucose disorder requiring anti-diabetic treatment. PTDM patients were matched to "non-PTDM" control transplanted children according to age, gender, and duration of post-transplant follow-up. Patients were genotyped for six selected genetic variants in POR*28 (rs1057868), PPARa (rs4253728), CYP3A5 (rs776746), VDR (rs2228570 and rs731236), and ABCB1 (rs1045642) genes, implicated in glucose homeostasis and tacrolimus disposition. RESULTS: Among the 98 children with renal transplantation enrolled in this multicentre study, 18 developed PTDM. None of the clinical and biological parameters was significant between PTDM and control patients. Homozygous carriers of POR*28 or wild-type ABCB1 (rs1045642) gene variants were more frequent in PTDM than in control patients with differences close to significance (p = 0.114 and p = 0.066 respectively). A genetic score based on these variants demonstrated that POR*28/*28 and ABCB1 CC or CT genotype carriers were at a significantly higher risk of developing PTDM after renal transplantation. CONCLUSION: Identification of PTDM risk factors should allow clinicians to allocate the best immunosuppressant for each patient with renal transplantation, and improve care for patients who are at a higher risk. PMID- 29399718 TI - Electronic and optical properties of functionalized zigzag ZnO nanotubes. AB - The present paper reports the analysis of surface decoration on the structural, electronic, and optical properties of (n,0) ZnO nanotubes, performed by means of a density function theory based ab-initio approach. Fe functionalization induced buckling in ZnO nanotubes affects its electronic and optical properties. Increase in Fe functionalization leads to better stability of ZnO nanotube and shows enhanced metallic character. The possibility of its use in optoelectronics has been analyzed in terms of dielectric constant, absorption coefficient, and refractive index. In another observation, the high sensitivity of the HCN molecule for the Fe-incorporated ZnO nanotube suggests it as a potential gas sensor. Graphical abstract HCN-adsorbed Fe-ZnO nanotube, electron difference density, and PDOS analysis of different orbitals. PMID- 29399717 TI - New insights into the metabolism of aspartate-family amino acids in plant seeds. AB - KEY MESSAGE: Aspartate-family amino acids. Aspartate (Asp)-family pathway, via several metabolic branches, leads to four key essential amino acids: Lys, Met, Thr, and Ile. Among these, Lys and Met have received the most attention, as they are the most limiting amino acid in cereals and legumes crops, respectively. The metabolic pathways of these four essential amino acids and their interactions with regulatory networks have been well characterized. Using this knowledge, extensive efforts have been devoted to augmenting the levels of these amino acids in various plant organs, especially seeds, which serve as the main source of human food and livestock feed. Seeds store a number of storage proteins, which are utilized as nutrient and energy resources. Storage proteins are composed of amino acids, to guarantee the continuation of plant progeny. Thus, understanding the seed metabolism, especially with respect to the accumulation of aspartate derived amino acids Lys and Met, is a crucial factor for sustainable agriculture. In this review, we summarized the Asp-family pathway, with some new examples of accumulated Asp-family amino acids, particularly Lys and Met, in plant seeds. We also discuss the recent advances in understanding the roles of Asp-family amino acids during seed development. PMID- 29399719 TI - Sleep in Type 1 Diabetes: Implications for Glycemic Control and Diabetes Management. AB - PURPOSE OF REVIEW: To highlight recent findings from studies of sleep in type 1 diabetes (T1D), with a focus on the role of sleep in self-management, the cognitive and psychosocial outcomes related to sleep disturbances, and factors associated with sleep disturbances specific to T1D. RECENT FINDINGS: People with T1D experience higher rates of sleep disturbances than people without diabetes, and these disturbances have negative implications for glycemic control and diabetes management, as well as psychosocial and cognitive outcomes. Inconsistent sleep timing (bedtime and wake time) has emerged as a potential target for interventions, as variability in sleep timing has been linked with poorer glycemic control and adherence to treatment. Sleep-promoting interventions and new diabetes technology have the potential to improve sleep in people with T1D. Sleep is increasingly considered a critical factor in diabetes management, but more multi-method and longitudinal research is needed. We emphasize the importance of sufficient and consistent sleep for people with T1D, and the need for providers to routinely assess sleep among patients with T1D. PMID- 29399720 TI - The effects of early age thermal conditioning and vinegar supplementation of drinking water on physiological responses of female and male broiler chickens reared under summer Mediterranean temperatures. AB - The effects of early age thermal conditioning (ETC), vinegar supplementation (VS) of drinking water, broilers' gender, and their interactions on respiratory rate, body temperature, and blood parameters (biochemical, hematological, and thyroid hormones) of broiler chickens reared under high ambient temperatures were determined. A total of 1100 1-day-old chicks were divided into four treatments: the "control" which were non-conditioned and non-supplemented; "heat-conditioned" which were exposed to 38 +/- 1 degrees C for 24 h at 5 days of age; "vinegar supplemented" which were given drinking water supplemented with 0.2% of commercial vinegar from 28 to 49 days of age; and "combined" which were both heat conditioned and vinegar supplemented. All groups were exposed to the natural fluctuations of summer ambient temperature (average diurnal ambient temperature of about 30 +/- 1 degrees C and average relative humidity of 58 +/- 5%). ETC and broiler gender did not affect the respiratory rate or body temperature of chronic heat-exposed chickens. VS changed the body temperature across time (d35, d42, d49) (linear and quadratic effects, P < 0.05) without changing respiratory rate. Heat-conditioned chickens exhibited lower levels of glycemia (P < 0.0001) and higher hematocrit and red blood cell counts (P < 0.05). Furthermore, the greatest effects of VS, alone or associated with ETC, were the lowering of cholesterol and triglyceride blood concentrations. A significant (P < 0.05) effect of ETC, gender, and ETC*gender on T3:T4 ratio was observed. Finally, some beneficial physiological responses induced by ETC and VS, separately or in association, on chronically heat-stressed chickens were observed. However, the expected cumulative positive responses when the two treatments were combined were not evident. PMID- 29399721 TI - Cannabinoid Receptors in Diabetic Kidney Disease. AB - PURPOSE OF REVIEW: The purpose of this review is to examine and summarize studies assessing the relevance of the endocannabinoid system (ECS) in diabetic kidney disease (DKD). RECENT FINDINGS: Endocannabinoids and endocannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R) are present in the normal kidney. Expression of CB1R and CB2R is altered in experimental DKD. Studies in experimental animals and cultured kidney cells show a beneficial effect of peripheral CB1R blockade and CB2R activation in DKD and an even greater efficacy of a combined treatment. Preclinical studies confirm that both CB1R and CB2R are implicated in the pathogenesis of DKD and may represent novel targets for treatment. However, we need to gain a better understanding of the ECS prior to move to human clinical trial. PMID- 29399722 TI - Rural versus urban differences in end-of-life care for lung cancer patients in Germany. AB - PURPOSE: To assess rural-urban differences in healthcare utilization and supportive care at the end-of-life in German lung cancer patients. METHODS: We identified 12,929 patients with incident lung cancer in 2009 from claims data and categorized them to four district types (major city, urban, rural, remote rural). We compared site of death, unplanned hospitalizations, hospital days, outpatient doctor, general practitioner (GP) and home visits, structured palliative care, therapy with antidepressants, pain relief medication and chemotherapy, and therapeutic puncturing in the last 30 and 14 days of life using mixed models with logistic link function for binary outcomes and log link function for count data. We adjusted all models by age, sex, comorbidities, metastases location and presence of multiple tumors at diagnosis, survival in months, and type of tumor directed treatment. RESULTS: We found significant differences in two of the outcomes measured. The likelihood of > 14 hospital days in the last 30 days was significantly higher in rural districts than in remote rural districts (1.27 [1.05, 1.52], p = 0.0003). The number of visits to the GP in the last 30 days of life was significantly lower in urban districts than in remote rural districts (beta = - 0.19 [- 0.32, - 0.06], p = <0.0001). No other endpoints were associated with regional differences. Triggering factors for high and low utilization of healthcare were mostly age, comorbidities, and prior anticancer treatment. CONCLUSION: Healthcare utilization and supportive care did not differ significantly between different district types. Results reject the hypothesis of regional inequity in end-of-life care of lung cancer patients in Germany. PMID- 29399723 TI - Evolution of the Application of Techniques Derived from Abdominal Transplant Surgery in Urologic Oncology. AB - PURPOSE OF REVIEW: The techniques derived from abdominal transplant surgery have become a major actor in recent surgical evolution by providing a more optimal solution for urologic malignancies hosted in the upper abdomen. To describe in detail the objectives, rationale, relevant milestones, and surgical maneuvers of the so-called transplant techniques as applied to complex urologic oncology cases. RECENT FINDINGS: The transplant-based surgical approach aims to decrease perioperative complications by improving tumor accessibility and field visibility through an enhanced exposure (via the use of a transverse incision, a specific retractor, and specific surgical maneuvers). A sequence of milestones inspired these advances, which finally brought the technique into maturation. The transplant-based approach has demonstrated its safety and usefulness even in the low-volume practice of more complicated urologic oncology, offering protection against the occurrence of perioperative adverse events and placing us at the gates of a new stage of surgical innovation. PMID- 29399724 TI - Type 2 Diabetes and Thiazide Diuretics. AB - PURPOSE OF REVIEW: In patients with prediabetes or type 2 diabetes, the use of thiazides as antihypertensive agents has been challenged because associated metabolic adverse events, including new-onset diabetes. RECENT FINDINGS: These metabolic disturbances are less marked with low-dose thiazides and, in most but not all studies, with thiazide-like diuretics (chlorthalidone, indapamide) than with thiazide-type diuretics (hydrochlorothiazide). In post hoc analyses of subgroups of patients with hypertension and type 2 diabetes, thiazides resulted in a significant reduction in cardiovascular events, all-cause mortality, and hospitalization for heart failure compared to placebo and generally were shown to be non-inferior to other antihypertensive agents. Benefits attributed to thiazide diuretics in terms of cardiovascular event reduction outweigh the risk of worsening glucose control in type 2 diabetes and of new-onset diabetes in non diabetic patients. Thiazides still play a key role in the management of patients with type 2 diabetes and hypertension. PMID- 29399725 TI - POTENCI: prediction of temperature, neighbor and pH-corrected chemical shifts for intrinsically disordered proteins. AB - Chemical shifts contain important site-specific information on the structure and dynamics of proteins. Deviations from statistical average values, known as random coil chemical shifts (RCCSs), are extensively used to infer these relationships. Unfortunately, the use of imprecise reference RCCSs leads to biased inference and obstructs the detection of subtle structural features. Here we present a new method, POTENCI, for the prediction of RCCSs that outperforms the currently most authoritative methods. POTENCI is parametrized using a large curated database of chemical shifts for protein segments with validated disorder; It takes pH and temperature explicitly into account, and includes sequence-dependent nearest and next-nearest neighbor corrections as well as second-order corrections. RCCS predictions with POTENCI show root-mean-square values that are lower by 25-78%, with the largest improvements observed for 1Halpha and 13C'. It is demonstrated how POTENCI can be applied to analyze subtle deviations from RCCSs to detect small populations of residual structure in intrinsically disorder proteins that were not discernible before. POTENCI source code is available for download, or can be deployed from the URL http://www.protein-nmr.org . PMID- 29399726 TI - Renal Embolization: Current Recommendations and Rationale for Clinical Practice. AB - PURPOSE OF REVIEW: Renal embolization (RE) is a minimally invasive endovascular procedure performed primarily by interventional radiology that can be used to treat a variety of urologic conditions including malignant renal tumors, angiomyolipomas, renal trauma, and complications following biopsy. The following review examines renal embolization indications, technique, and potential complications. RECENT FINDINGS: Renal embolization is a versatile therapeutic and adjunctive tool for many acute and chronic urologic conditions. RE has become a first-line therapy for renal trauma in lower grade injuries and increasing in prevalence for higher grade injuries. Additionally, the safety and efficacy of chemoembolization for primary treatment of renal cell carcinoma is under evaluation. A multidisciplinary approach between urology and interventional radiology should be pursued for all patients undergoing renal embolization regardless of indication. Preprocedural planning and careful monitoring of complications should be performed to optimize clinical outcomes. PMID- 29399728 TI - Vessel segmentation and catheter detection in X-ray angiograms using superpixels. AB - Coronary artery disease (CAD) is the leading cause of death around the world. One of the most common imaging methods for diagnosing CAD is the X-ray angiography (XRA). Diagnosing using XRA images is usually challenging due to some reasons such as, non-uniform illumination, low contrast, presence of other body tissues, and presence of catheter. These challenges make the diagnosis task hard and more prone to misdiagnosis. In this paper, we propose a new method for coronary artery segmentation, catheter detection, and centerline extraction in X-ray angiography images. For the segmentation, initially, three different superpixel scales are exploited, and a measure for vesselness probability of each superpixel is determined. A voting mechanism is used for obtaining an initial segmentation map from the three superpixel scales. The initial segmentation is refined by finding the orthogonal line on each ridge pixel of vessel region. The catheter is detected in the first frame of the angiography sequence and is tracked in other frames by fitting a second order polynomial on it. Also, we use the image ridges for extracting the coronary artery centerlines. We evaluated and compared our method with one of the previous well-known coronary artery segmentation methods on two challenging datasets. The results show that our method can segment the vessels and also detect and track the catheter in the XRA sequences. In general, the results assessed by a cardiologist show that 83% of the images processed by our proposed segmentation method were labeled as good or excellent, while this score for the compared method is 48%. Also, the evaluation results show that our method performs 67% faster than the compared method. Graphical abstract Proposed framework for coronary artery detection. PMID- 29399729 TI - The autopsy and diagnosis of pulmonary thrombo-embolism. AB - Pulmonary thrombo-embolism (PTE) is a common cause of death but is frequently undetected by clinicians in spite of advanced diagnostic techniques. The autopsy has traditionally been used to identify the rate of PTE in hospital patients, but the decline in autopsy rates - especially in hospitals - has led to insufficient recent data from which to comment with confidence on the true rate of death from latent PTE. Widespread prophylactic anticoagulation regimens against venous thrombosis may induce complacency amongst clinicians. PTE continues to occur and to kill, and autopsies should be performed more frequently to better estimate the true prevalence of this condition. PMID- 29399727 TI - Implications of Lipids in Neonatal Body Weight and Fat Mass in Gestational Diabetic Mothers and Non-Diabetic Controls. AB - PURPOSE OF REVIEW: Maternal lipid metabolism greatly changes during pregnancy and we review in this article how they influence fetal adiposity and growth under non diabetic and gestational diabetic conditions. RECENT FINDINGS: In pregnant women without diabetes (control), maternal glycemia correlates with neonatal glycemia, neonatal body weight and fat mass. In pregnant women with gestational diabetes mellitus (GDM), maternal glucose correlates with neither neonatal glycemia, neonatal birth weight nor fat mass, but maternal triacylglycerols (TAG), non esterified fatty acids (NEFA) and glycerol do correlate with birth weight and neonatal adiposity. The proportions of maternal plasma arachidonic (AA) and docosahexaenoic (DHA) acids decrease from the first to the third trimester of pregnancy, and at term these long-chain polyunsaturated fatty acids are higher in cord blood plasma than in mothers, indicating efficient placental transfer. In control or pregnant women with GDM at term, the maternal concentration of individual fatty acids does not correlate with neonatal body weight or fat mass, but cord blood fatty acid levels correlate with birth weight and neonatal adiposity-positively in controls, but negatively in GDM. The proportion of AA and DHA in umbilical artery plasma in GDM is lower than in controls but not in umbilical vein plasma. Therefore, an increased utilization of those two fatty acids by fetal tissues, rather than impaired placental transfer, is responsible for their smaller proportion in plasma of GDM newborns. In control pregnant women, maternal glycemia controls neonatal body weight and fat mass, whereas in mothers with GDM-even with good glycemic control-maternal lipids and their greater utilization by the fetus play a critical role in neonatal body weight and fat mass. We propose that altered lipid metabolism rather than hyperglycemia constitutes a risk for macrosomia in GDM. PMID- 29399730 TI - Postmortem radiological case series of acetabular fractures after fatal aviation accidents. AB - The purpose of this study was to describe radiological fracture patterns of the acetabulum sustained after fatal small aircraft aviation accidents, aiming at facilitating a better understanding of trauma mechanisms in a forensic setting. Postmortem conventional radiographs or CT scans of 29 victims of 20 small aircraft aviation accidents were analyzed for skeletal acetabular trauma. Among the 29 fatalities (27 males and 2 females, median age 55 years (range: 21-76 years)), 20 victims had pelvic fractures (69%), of which 19 victims (66%) had one or more acetabular fractures. Bilateral acetabular fractures occurred in 11 victims. When considering left and right acetabula in each victim as separate entities, 38 of the 58 acetabula included in this case series exhibited one or more fractures. Both the anterior and posterior acetabular columns were fractured in 28 acetabula. Acetabular fractures were frequently encountered in this series of 29 victims of small fatal aircraft accidents. Fractures of the acetabulum occur from ventrally directed impact (i.e. to the knee) or laterally directed impact (i.e. to the greater trochanter of the femur). Radiological descriptions of the fracture patterns can therefore aid in the forensic analysis of the mechanism of trauma in aviation accidents. Postmortem multi-slice CT scan images are preferrable in the assessment of acetabular fractures. PMID- 29399732 TI - Rupture of Hepatocellular Carcinoma: a Tale of 20 Cases from a Tertiary Care Center in Northern India. PMID- 29399731 TI - Complications following immediate compared to delayed deep inferior epigastric artery perforator flap breast reconstructions. AB - PURPOSE: As more breast cancer patients opt for immediate breast reconstruction, the incidence of complications should be evaluated. The aim of this study was to analyze the recipient-site complications and flap re-explorations of immediate compared to delayed deep inferior epigastric artery perforator (DIEP) flap breast reconstructions. METHODS: For this multicenter retrospective cohort study, the medical records of all patients who underwent DIEP flap breast reconstruction in three hospitals in the Netherlands between January 2010 and June 2017 were reviewed. Patient demographics, risk factors, timing of reconstruction, recipient site complications, and flap re-explorations were recorded. RESULTS: A total of 910 DIEP flap breast reconstructions (n = 397 immediate and n = 513 delayed reconstructions) in 737 patients were included. There were no significant differences in major complications or flap re-explorations between immediate and delayed reconstructions. The total flap failure rate was 1.5 and 2.5% in the immediate and delayed group, respectively. Significantly more hematomas (OR 2.91; 95% CI 1.59-5.30; p = 0.001) and seromas (OR 3.60; 95% CI 1.14-11.4; p = 0.029) occurred in immediate reconstructions, whereas wound problems were more frequently observed in delayed reconstructions (OR 1.99; 95% CI 1.27-3.11; p = 0.003). Correction for potential confounders still showed significant differences for hematoma and seroma, but no longer for wound problems (p = 0.052). CONCLUSIONS: This study demonstrated similar incidences of major recipient-site complications and flap re-explorations between immediate and delayed DIEP flap breast reconstructions. However, hematoma and seroma occurred significantly more often in immediate reconstructions, while wound problems were more frequently observed in delayed reconstructions. PMID- 29399734 TI - Oncologists and Breaking Bad News-From the Informed Patients' Point of View. The Evaluation of the SPIKES Protocol Implementation. AB - The way that bad news is disclosed to a cancer patient has a crucial impact on physician-patient cooperation and trust. Consensus-based guidelines provide widely accepted tools for disclosing unfavorable information. In oncology, the most popular one is called the SPIKES protocol. A 17-question survey was administered to a group of 226 patients with cancer (mean age 59.6 years) in order to determine a level of SPIKES implementation during first cancer disclosure. In our assessment, the patients felt that the highest compliance with the SPIKES protocol was with Setting up (70.6%), Knowledge (72.8%), and Emotions (75.3%). The lowest was with the Perception (27.7%), Invitation (30.4%), and Strategy & Summary (56.9%) parts. There could be improvement with each aspect of the protocol, but especially in Perception, Invitation, and Strategy & Summary. The latter is really important and must be done better. Older patients felt the doctors' language was more comprehensible (r = 0.17; p = 0.011). Patients' satisfaction of their knowledge about the disease and follow-up, regarded as an endpoint, was insufficient. Privacy was important in improving results (p < 0.01). In practice, the SPIKES protocol is implemented in a satisfactory standard, but it can be improved in each area, especially in Perception, Invitation, and Summary. It is suggested that more training should be done in undergraduate and graduate medical education and the effectiveness of the disclosure continue to be evaluated and improved. PMID- 29399733 TI - Genome-wide identification of barley MCs (metacaspases) and their possible roles in boron-induced programmed cell death. AB - Developmental processes and stress-induction activate many key proteins in plants such as metacaspase which regulate programmed cell death (PCD). In this study, identification of barley metacaspases and their possible roles upon boron (B) induction was investigated by using in silico and wet-lab methods. Genome-wide analysis revealed that barley genome harbor ten metacaspases which divided into three groups: Type-I, -I* and -II. Segmental and tandem duplication contributed their expansion. Metacaspase-specific catalytic residues (His and Cys) were found to be altered in HvMC1, 2, and 4, in which His exchanged to Meth or Ala, critical for their activity and substrate selectivity. Cis-acting elements were found to be associated with three main processes: stress response, growth/development, and light response. Digital expression analysis from eight tissues revealed tissue specific metacaspase expressions. In addition, RT-qPCR analysis conducted in appropriate (50 uM) and excess-B (1 and-3 mM) conditions in different time points (3 and 10 days). Toxic level of B caused growth inhibition and chlorosis which appeared at the leaf tips. Also, PCD initiation was detected after 3 days of excess-B exposure. Digital expression and qPCR analysis agreed with each other that HvMC4 expression was significantly increased upon excess-B supplementation. In opposite, HvMC5 was down-regulated in the leaf zones which was another critical B-responsive gene in barley. Hence, HvMC4 and HvMC5 seem to have antagonistic effect during PCD regulation. These results can provide insights for metacaspase functionality in barley, not only limited for B-induction but also various kinds of PCD-causing conditions. PMID- 29399735 TI - Rotator cuff repair: post-operative rehabilitation concepts. AB - PURPOSE OF REVIEW: With improvements in surgical techniques and increased knowledge of rotator cuff healing, there was a need to identify a safe progression after rotator cuff repair. The rehabilitation specialist plays an integral role in the care of these patients, and by implementing an evidence and criteria-based model, patients may be able to return to their prior levels of function sooner with fewer complications. RECENT FINDINGS: Timing of progression for rotator cuff patients should align not only with healing but also potential strain on the involved tissue. Recent electromyography studies have identified exercises which elicit highest level of muscle activation for individual dynamic stabilizers. The physical therapist should also be aware of potential complications and be prepared to manage appropriately if they should arise. During rehabilitation after rotator cuff repair, there should be constant communication with the surgical team. Awareness of complication management, healing potential of the repaired tendon, and anatomy of the shoulder complex are critical. During the early stages, reducing pain and inflammation should be prioritized followed by progressive restoration of range of motion. When advancing range of motion, progression from passive, active assisted, and active movements allow for gradual introduction of stress to the healing construct. Even though time frames are not used for progression, it is important not to place excessive stress on the shoulder for up to 12 weeks to allow for proper tendon-to bone healing. As exercises are progressed, scapular muscle activation is initiated, followed by isometric and lastly isotonic rotator cuff exercises. When treating overhead athletes, advanced strengthening in the overhead position is performed, followed by plyometric training. Advanced strengthening is initiated when all preceding criteria have been met. It is important that patients are educated early in the rehabilitation process so that they can manage their expectations to realistic time frames. PMID- 29399737 TI - Drought neutralises plant-soil feedback of two mesic grassland forbs. AB - Plant-soil feedbacks (PSFs) describe the effect of a plant species on soil properties, which affect the performance of future generations. Here we test the hypothesis that drought alters PSFs by reducing plant-microbe associations and nutrient uptake. We chose two grassland forb species, previously shown to respond differently to soil conditioning and drought, to test our hypothesis. We conditioned unsterilised grassland soil with one generation of each species, and left a third soil unconditioned. We grew a second generation consisting of each combination of plant species, soil, and drought in a full factorial design, and measured soil microbial community and nutrient availability. Scabiosa columbaria displayed negative PSF (smaller plants) under non-droughted conditions, but neutral under drought, suggesting that drought disrupts plant-soil interactions and can advantage the plant. Photosynthetic efficiency of S. columbaria was reduced under drought, but recovered on rewetting regardless of soil conditioning, indicating that PSFs do not impede resilience of this species. Sanguisorba minor showed positive PSFs (larger plants), probably due to an increase in soil N in conspecific soil, but neutral PSF under drought. PSF neutralisation appeared to occur through drought-induced change in the soil microbial community for this species. When S. minor was planted in conspecific soil, photosynthetic efficiency declined to almost zero, with no recovery following rewetting. We attributed this to increased demand for water through higher demand for nutrients with positive PSF. Here we show that drought neutralises PSFs of two grassland forbs, which could have implications for plant communities under climate change. PMID- 29399736 TI - Oxygen drives hepatocyte differentiation and phenotype stability in liver cell lines. AB - The in vitro generation of terminally differentiated hepatocytes is an unmet need. We investigated the contribution of oxygen concentration to differentiation in human liver cell lines HepaRG and C3A. HepaRG cells were cultured under hypoxia (5%O2), normoxia (21%O2) or hyperoxia (40%O2). Cultures were analysed for hepatic functions, gene transcript levels, and protein expression of albumin, hepatic transcription factor CEBPalpha, hepatic progenitor marker SOX9, and hypoxia inducible factor (HIF)1alpha. C3A cells were analysed after exposure to normoxia or hyperoxia. In hyperoxic HepaRG cultures, urea cycle activity, bile acid synthesis, CytochromeP450 3A4 (CYP3A4) activity and ammonia elimination were 165-266% increased. These effects were reproduced in C3A cells. Whole transcriptome analysis of HepaRG cells revealed that 240 (of 23.223) probes were differentially expressed under hyperoxia, with an overrepresentation of genes involved in hepatic differentiation, metabolism and extracellular signalling. Under hypoxia, CYP3A4 activity and ammonia elimination were inhibited almost completely and 5/5 tested hepatic genes and 2/3 tested hepatic transcription factor genes were downregulated. Protein expression of SOX9 and HIF1alpha was strongly positive in hypoxic cultures, variable in normoxic cultures and predominantly negative in hyperoxic cultures. Conversely, albumin and CEBPalpha expression were highest in hyperoxic cultures. HepaRG cells that were serially passaged under hypoxia maintained their capacity to differentiate under normoxia, in contrast to cells passaged under normoxia. Hyperoxia increases hepatocyte differentiation in HepaRG and C3A cells. In contrast, hypoxia maintains stem cell characteristics and inhibits hepatic differentiation of HepaRG cells, possibly through the activity of HIF1alpha. PMID- 29399738 TI - Biogeographic differences in soil biota promote invasive grass response to nutrient addition relative to co-occurring species despite lack of belowground enemy release. AB - Multiple plant species invasions and increases in nutrient availability are pervasive drivers of global environmental change that often co-occur. Many plant invasion studies, however, focus on single-species or single-mechanism invasions, risking an oversimplification of a multifaceted process. Here, we test how biogeographic differences in soil biota, such as belowground enemy release, interact with increases in nutrient availability to influence invasive plant growth. We conducted a greenhouse experiment using three co-occurring invasive grasses and one native grass. We grew species in live and sterilized soil from the invader's native (United Kingdom) and introduced (New Zealand) ranges with a nutrient addition treatment. We found no evidence for belowground enemy release. However, species' responses to nutrients varied, and this depended on soil origin and sterilization. In live soil from the introduced range, the invasive species Lolium perenne L. responded more positively to nutrient addition than co occurring invasive and native species. In contrast, in live soil from the native range and in sterilized soils, there were no differences in species' responses to nutrients. This suggests that the presence of soil biota from the introduced range allowed L. perenne to capture additional nutrients better than co-occurring species. Considering the globally widespread nature of anthropogenic nutrient additions to ecosystems, this effect could be contributing to a global homogenization of flora and the associated losses in native species diversity. PMID- 29399740 TI - Comparing the Effects of Chitosan Scaffolds Containing Various Divalent Metal Phosphates on Osteogenic Differentiation of Stem Cells from Human Exfoliated Deciduous Teeth. AB - Inducing the differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) proceeds with low efficiency, which greatly limits clinical applications. Divalent metal elements play an important role in osteoinductivity for bone remodeling because they can simulate bone formation and decrease bone resorption. The purpose of this study was to investigate the effect of some divalent metal phosphates on osteogenic differentiation from human exfoliated deciduous teeth. These divalent metal ions can be gradually released from the scaffold into the culture medium and continually induce osteoblastic differentiation. Experimental results revealed that SHEDs cultured in chitosan scaffolds containing divalent metal phosphates had notably increased osteoblastic differentiation compared with cells cultured without divalent metal phosphates. This effect was due to the high activity of alkaline phosphatase, as well as the bone-related gene expression of collagen type I, Runx2, osteopontin, osteocalcin, VEGF, and Ang-1, shown through RT-PCR and bone-related protein immunocytochemistry stains. A calcium-content assay further revealed significant enhancement of deposited minerals on the scaffolds after 21 days of culture, particularly for magnesium phosphate and zinc phosphate. Thus, divalent metals, except for barium phosphate, effectively promoted SHED cell differentiation and osteoblastic cell maturation. This study demonstrated that the divalent metal elements magnesium, strontium, and zinc could effectively induce SHED osteoblastic differentiation for use in tissue engineering and bone repair. PMID- 29399739 TI - ICAM-1null C57BL/6 Mice Are Not Protected from Experimental Ischemic Stroke. AB - Accumulation of neutrophils in the brain is a hallmark of cerebral ischemia and considered central in exacerbating tissue injury. Intercellular adhesion molecule (ICAM)-1 is upregulated on brain endothelial cells after ischemic stroke and considered pivotal in neutrophil recruitment as ICAM-1-deficient mouse lines were found protected from experimental stroke. Translation of therapeutic inhibition of ICAM-1 into the clinic however failed. This prompted us to investigate stroke pathogenesis in Icam1tm1Alb C57BL/6 mutants, a true ICAM-1null mouse line. Performing transient middle cerebral artery occlusion, we found that absence of ICAM-1 did not ameliorate stroke pathology at acute time points after reperfusion. Near-infrared imaging showed comparable accumulation of neutrophils in the ischemic hemispheres of ICAM-1null and wild type C57BL/6 mice. We also isolated equal numbers of neutrophils from the ischemic brains of ICAM-1null and wild type C57BL/6 mice. Immunostaining of the brains showed neutrophils to equally accumulate in the leptomeninges and brain parenchymal vessels of ICAM 1null and wild type C57BL/6 mice. In addition, the lesion size was comparable in ICAM-1null and wild type mice. Our study demonstrates that absence of ICAM-1 neither inhibits cerebral ischemia-induced accumulation of neutrophils in the brain nor provides protection from ischemic stroke. PMID- 29399741 TI - Organisms in wall ecosystems as biomonitors of metal deposition and bioavailability in urban environments. AB - Vegetated walls are common structures in urban environments, and aiming to test the hypothesis that the biogenic crusts and plant and animal communities inhabiting these vertical surfaces can be more reliable indicators of atmospheric metal deposition than plants or animals inhabiting urban soils, we analyzed the chemical composition of the wall crusts, moss cushions (Tortula muralis) and the shells, soft tissues and feces of the stonework snail Papillifera papillaris collected in three small towns in Tuscany (Central Italy). Crusts and mosses from the same stones or bricks indicated that Cd, Pb, and Zn are the main pollutants released by vehicular traffic, while Hg and Cu probably originate from other sources. The soft tissues of P. papillaris (purged of the gut contents) showed as well higher Cd, Pb, and Zn and lower Hg concentrations at more traffic-affected sites, while data from shells and feces suggested that this species probably ingests large amounts of Al, Cr, Fe, Mn, and Pb, and avoids eating mosses. Most lithophilic elements and Pb are scarcely absorbed in the snail digestive tract and soft tissues mainly accumulate Cd and essential elements such as Cu and Mn. This study definitively confirms the extraordinary Mn bioaccumulation in P. papillaris soft tissues and reports extraordinary Mn levels also in the shell. The shells also contain unusually high Cu, Fe, and Zn concentrations and this bioaccumulation likely remains after death, potentially providing a historical record of the snail exposure to metals over lifetime. PMID- 29399742 TI - Aqueous aggregation and stability of graphene nanoplatelets, graphene oxide, and reduced graphene oxide in simulated natural environmental conditions: complex roles of surface and solution chemistry. AB - Graphene-family nanomaterials (GFNs) exhibit universal applications and consequently will inevitably enter aquatic systems. However, both the fate and behavior of GFNs in aquatic environments have not been completely explored at field relevant conditions. Herein, we have systematically investigated the aqueous aggregation and stability of graphene nanoplatelets (GNPs), graphene oxide (GO), and reduced graphene oxide (RGO) under varied solution chemistry parameters (pH, divalent cations, and dissolved organic carbon (DOC)) during 21 days of incubation in simulated natural environmental conditions. Results indicate that pH values from 6 to 9 had a notable impact on the aqueous behaviors of the three GFNs. Divalent cations (Ca2+ and Mg2+) at the concentrations of 2.5 and 10 mM remarkably increased the extent of aggregation of the three GFNs and resulted in severe sedimentation, independently of surface chemical functionalization. The presence of only DOC ranging from 0.5 to 2 mg C/L significantly elevated the dispersion stability of GNPs and RGO in a dose dependent manner, whereas no effects were observed on GO. Furthermore, DOC at the studied concentrations and surface functionality were insufficient to counterbalance the impact of the divalent cations. Direct visual and in situ observations further supported the conclusions on the effects of divalent cations or/and DOC. These findings further underline that the environmental behaviors of GFNs are controlled by the complex interplay between water chemistry parameters and GFN surface properties. PMID- 29399743 TI - Predicted environmental concentration and fate of the top 10 most dispensed Australian prescription pharmaceuticals. AB - A basic environmental risk assessment was carried out for the top 10 dispensed pharmaceuticals in Melbourne, Australia, in contrast to the more commonly assessed measure of the most used drugs by physical mass. This allowed for the evaluation of compounds that had not previously been the subject of risk assessment. Estimations of the possible fate and behaviour of the target pharmaceuticals in sewage treatment plants were also made. The predicted removal rates of most drugs within standard sewage treatment were expected to be low, with the exception of the statins, which had high removal rates. Each pharmaceutical was predicted to be present in Melbourne wastewater at the nanogram per litre range or lower. All compounds were predicted to be of low toxicity risk, although it was not possible to model mixture effects. Atorvastatin and Irbesartan were also found to possess the potential to possibly bioaccumulate in the aquatic food chain but not to the extent that would require regulation or labelling. PMID- 29399744 TI - Electrophysiological properties of anion exchangers in the luminal membrane of guinea pig pancreatic duct cells. AB - The pancreatic duct epithelium secretes the HCO3--rich pancreatic juice. The HCO3 transport across the luminal membrane has been proposed to be mediated by SLC26A Cl--HCO3- exchangers. To examine the electrophysiological properties of Cl--HCO3- exchangers, we directly measured HCO3- conductance in the luminal membrane of the interlobular pancreatic duct cells from guinea pigs using an inside-out patch clamp technique. Intracellular HCO3- increased the HCO3- conductance with a half maximal effective concentration value of approximately 30 mM. The selectivity sequence based on permeability ratios was SCN- (1.4) > Cl- (1.2) = gluconate (1.1) = I- (1.1) = HCO3- (1.0) > methanesulfonate (0.6). The sequence of the relative conductance was HCO3- (1.0) > SCN- (0.7) = I- (0.7) > Cl- (0.5) = gluconate (0.4) > methanesulfonate (0.2). The current dependent on intracellular HCO3- was reduced by replacement of extracellular Cl- with gluconate or by H2DIDS, an inhibitor of Cl--HCO3- exchangers. RT-PCR analysis revealed that the interlobular and main ducts expressed all SLC26A family members except Slc26a5 and Slc26a8. SLC26A1, SLC26A4, SLC26A6, and SLC26A10 were found to be localized to the luminal membrane of the guinea pig pancreatic duct by immunohistochemistry. These results demonstrate that these SLC26A Cl--HCO3- exchangers may mediate the electrogenic HCO3- transport through the luminal membrane and may be involved in pancreatic secretion in guinea pig ducts. PMID- 29399745 TI - Effect of beta-cyclodextrins Derivatives on Steroids Biotransformation by Arthrobacter simplex. AB - beta-cyclodextrins derivatives (CDs) have applied in steroids biotransformation industry because of their unique properties. However, the effect of beta-CDs on the growth rate, activity, conversion, and characters of whole cells has not been concerned. In this study, the growth rate and cellular morphology of Arthrobacter simplex (ASP) pretreated by six kinds of beta-CDs were measured. The results showed that most beta-CDs inhibited the growth of ASP, among which randomly methylated-beta-CDs has the most serve inhibition; however, sulfonic acid-beta-CD promoted the growth of cells. The morphology size and the surface of all beta-CDs pretreated cells were changed compared with the control group. Besides, the conversion of cortisone acetate (CA) increased in beta-CDs-pretreatment system and beta-CDs-containing system, which reached 97.98% in hydroxypropyl-beta cyclodextrin (HP-beta-CD) containing-system and 78.69% in HP-beta-CD-pretreatment system, but the dehydrogenase activity of all beta-CDs-pretreated cells decreased. beta-CDs with higher K value have stronger inclusion ability with CA, and along with the membrane permeability of beta-CDs-pretreated cells increased more, but they also have more serve damage on the ASP cells, which is negative to increase the conversion of CA. This study improved our understanding of the effect of beta-CDs when they were used in the steroids biotransformation by ASP whole cells, and provided data basis for the selection of suitable CDs for application. PMID- 29399746 TI - Correction to: Complete genome sequence of a phage hyperparasite of Candidatus Xenohaliotis californiensis (Rickettsiales) - a pathogen of Haliotis spp (Gasteropoda). AB - Unfortunately, the family name of the co-author Roberto Cruz-Flores was incorrectly published in the original publication and corrected here by this correction. The original article has been corrected. PMID- 29399749 TI - Should the Macular Lesions Around Spinal Dysraphism Be Excised? Analysis of Macular Lesions Accompanying Spinal Dysraphism. AB - AIM: Whether the macular lesions associated with spinal dysraphism should be preserved is controversial. This area is usually excised during reconstruction. This study aims to characterize the macular lesions associated with spinal dysraphism and to determine the outcomes of cases in which macular lesions are not excised. MATERIAL AND METHODS: The patient cohort comprised 17 patients with spinal dysraphism who were treated at Mersin University Hospital from 2005 through 2007. Blood and tissue samples were obtained from these patients. RESULTS: Electron microscopy results of tissue samples obtained from macular lesions are not consistent with those of hemangiomas. Increased numbers of vessels and significant dilatation was noted upon examination by light microscopy. The number of mast cell numbers, blood estradiol levels, expression of tissue inhibitor matrix metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF), and dermal collagen fiber diameter were within normal range. Estrogen receptor-beta was not expressed. The number of endothelial cells expressing von-Willebrand factor was higher in the macular lesions. CONCLUSION: The characteristics of macular lesions associated with spinal dysraphism are consistent with those of capillary malformations. We believe that the preservation of these macular lesions during soft tissue reconstruction of spinal dysraphism defects, either by mobilization on a flap or primary closure, does not compromise the viability of the macular region. By preserving these macular lesions, the creation of larger defects during excision is avoided. PMID- 29399748 TI - Acute hepatitis E in India appears to be caused exclusively by genotype 1 hepatitis E virus. AB - BACKGROUND: Hepatitis E is caused by infection with hepatitis E virus (HEV), which has four well-known genotypes. Genotypes 1 and 2 HEV have been reported from human cases in areas where the disease is highly endemic. By contrast, genotypes 3 and 4 HEV, which primarily infect several animal species worldwide, have been reported mainly from sporadic human cases in non-endemic areas such as Japan and high-income countries of Europe and North America. To determine whether genotype 3/4 HEV cause sporadic disease in India, a disease-endemic area, we determined HEV genotype in a group of patients with such disease. METHODS: A part of the HEV open reading frame (ORF) 1 was amplified and sequenced from sera of 74 patients with sporadic acute viral hepatitis E from four cities in India. The sequences were compared with prototype sequences for various HEV genotypes and subgenotypes and analyzed using phylogenetic tools to determine the genotype of the isolates. For 12 specimens, a part of HEV ORF2 was also similarly analyzed. RESULTS: Partial ORF1 sequences of all the 74 isolates belonged to genotype 1 HEV, with 88.2% to 100% nucleotide identity with the prototype genotype 1 isolates. Partial ORF2 sequences for all the 12 isolates also belonged to genotype 1 HEV. On phylogenetic analysis, 71 isolates clustered with prototype genotype 1a HEV; the remaining three isolates were located between subgenotypes 1a and 1c but were closer to the former. CONCLUSION: Human sporadic acute hepatitis E in India is caused almost exclusively by genotype 1 HEV. PMID- 29399747 TI - Association of IL-28B, TBX21 gene polymorphisms and predictors of virological response for chronic hepatitis C. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. The outcomes of both spontaneous HCV clearance and response to therapy depend on both viral and host factors. To investigate the influence of polymorphisms of IL-28B rs12979860 and TBX21 rs17250932, rs4794067 as well as viral factors (HCV genotype, F protein) on the outcome of HCV infection, we genotyped 565 patients with chronic HCV infection, 191 patients spontaneously resolved from HCV infection, 359 healthy controls and 383 treatment-naive CHC patients with pegylated interferon-alpha and ribavirin (PEG IFN-alpha/RBV). Results showed that TBX21 rs4794067 variant genotypes significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735). We also found that the rs12979860, rs2227982 and rs36084323 polymorphisms showed no significant associations with susceptibility or spontaneous clearance of HCV in the anti-F antibody subgroup; however, the anti-F antibody positive subgroup might show an increased risk of N-SVR (all P < 0.001). Our results demonstrate that variant factors in both the host and pathogen are commonly important for HCV clearance. In addition rs4794067 and F protein status may be strong predictive markers in the Chinese population. PMID- 29399750 TI - Implantable loop recorders in patients with unexplained syncope:Clinical predictors of pacemaker implantation. AB - BACKGROUND: Implantable loop recorders (ILR) are a valuable tool for the investigation of unexplained syncopal episodes. The aim of this retrospective single center study was to identify predictive factors for pacemaker implantation in patients with unexplained syncope who underwent ILR insertion. METHODS: 106 patients were retrospectively analyzed (mean age 59.1 years; 47.2% male) with unexplained syncope and negative conventional testing who underwent ILR implantation. The primary study endpoint was detection of symptomatic or asymptomatic bradycardia requiring pacemaker implantation. RESULTS: The average follow-up period after ILR implantation was 20 +/- 15 months. Pacemaker implantation according to current guidelines was necessary in 22 patients (20.8%), mean duration until index bradycardia was 81 +/- 88 (2-350) days. Ten patients (45.5%) received a pacemaker due to sinus arrest, 7 patients (31.8%) due to third-degree atrioventricular block, 2 patients (9.1%) due to second-degree atrioventricular block and 1 patient (4.5%) due to atrial fibrillation with a slow ventricular rate. Three factors remained significant in multivariate analysis: obesity, which defined by a body mass index above 30 kg/m2 (OR: 7.39, p = 0.014), a right bundle branch block (OR: 9.40, p = 0.023) and chronic renal failure as defined by a glomerular filtration rate of less than 60 ml/min (OR: 6.42, p = 0.035). CONCLUSIONS: Bradycardia is a frequent finding in patients undergoing ILR implantation due to unexplained syncope. Obesity, right bundle branch block and chronic renal failure are independent clinical predictors of pacemaker implantation. PMID- 29399751 TI - Revisiting the relationship between the submandibular duct, lingual nerve and hypoglossal nerve. AB - BACKGROUND: The aim of the study was to evaluate the relations between submandibular duct, lingual nerve and hypoglossal nerve for making a reassessment of this area in fresh frozen specimens. Also, the distance between the angle of the mandible and the vertical line drawn from the point where submandibular duct crossed lingual nerve to the base of the mandible was measured to determine a new landmark for neck surgeons. MATERIALS AND METHODS: Fourteen fresh frozen head and neck specimens were dissected and evaluated. A marginal mandibular incision was made from the mastoid process to the chin. RESULTS: In 8 cases, lingual nerve was crossing the submandibular duct superiorly; in 5 cases, lingual nerve was crossing the duct infero-medially and in 1 case it was parallel to the duct. In 1 case, lingual nerve subdivided into anterior and posterior branches. In 2 cases, 2 parallel submandibular ducts were found and the lingual nerve was crossing the upper duct from superior. In 1 case, lingual nerve was crossing the duct infero medially and then it was subdividing into branches superior to mylohyoid. In 12 cases, the course of hypoglossal nerve was classical. In 1 case, hypoglossal nerve crossed the submandibular duct medially and coursed parallel to the tendon of posterior belly of digastric. And in another case, hypoglossal nerve crossed the inferior branch of submandibular duct medially. The other structures in this area were as usual. CONCLUSIONS: The main factor for reducing nerve damage during surgery is the understanding of the anatomy of this area. PMID- 29399752 TI - Assessment of dimensions of pneumatisation of the anterior clinoid process in middle Anatolian population by computed tomography. AB - BACKGROUND: The anterior clinoid process (ACP) is usually removed during surgical procedures of the cellar region. The ACP may be different length and width in people; it may be also pneumatic. Therefore, we aimed to determine dimensions and rates of pneumatisation of the ACP in the large study group with clinically importance. MATERIALS AND METHODS: One thousand and thirty-one (592 female, 439 male) cranial computed tomography (CT) of the middle Anatolian population was used in this study. The length and basal width of the ACP were measured on the cranial CT. Also; incidence and degree of ACP pneumatisation were identified. RESULTS: The width of the right and left ACPs in females were 10.80 +/- 2.27 mm and 10.53 +/- 2.07 mm, respectively. The width of the right and left ACPs in males were 11.08 +/- 2.39 mm and 10.98 +/- 2.35 mm, respectively. The length of the right and left ACPs in females were 8.32 +/- 2.40 mm and 8.34 +/- 2.35 mm, respectively. The length of the right and left ACPs in males were 8.87 +/- 2.62 mm and 8.93 +/- 2.64 mm, respectively. There was statistically significant difference between males and females in ACP dimensions, except for the width of the right ACP. Pneumatisation of the ACP was observed on the right side in 46 (9.3%) cases, on the left side in 53 (10.6%) cases, and bilaterally in 32 (6.5%) cases. Incidence of pneumatisation of the ACP was decreased in the age group of 1 month to 20 years. While the incidence of bilateral pneumatisation of the ACP was higher in individuals aged 21-40. CONCLUSIONS: Radiologically recognising pneumatisation and anatomical variations of the ACP may be helpful in decreasing the incidence of surgical complications during anterior clinoidectomy. PMID- 29399753 TI - Sonography in the instability of the long head of the biceps tendon confronted with histopathologic and arthroscopic findings. AB - BACKGROUND: Disorders of the long head of the biceps (LHB) tendon are a common source of shoulder pain and disability. This tendon can be well visualised using ultrasonography; however, little is known if such examination allows clinicians to predict pathological changes of the tendon structure. In the study described below, we compare preoperative sonographic findings with the data from shoulder arthroscopy and microscopic examination of the excised tendon fragments in 19 consecutive patients with LHB tendinopathy and clinical suspicion of its instability. MATERIALS AND METHODS: Preoperative ultrasonographic (US) inspection assessed several features of the tendon, whereas its stability was verified arthroscopically. In all cases, tenodesis or tenotomy procedures were performed and excised tendon fragments were harvested for microscopic examination based on the semiquantitative Bonar score. RESULTS: The most common US findings were hypoechoic areas, tendon thickening, an increased power Doppler signal and mechanical instability. Just as shoulder arthroscopy confirmed all mechanical instability cases detected in US, microscopic assessment revealed advanced degeneration in all samples. CONCLUSIONS: Our study indicates that US is a useful tool in identifying cases of advanced instability and LHB tendinopathy, whereas biceps tendon instability is a biomechanically complex, gradually progressing phenomenon, frequently associated with additional shoulder lesions. PMID- 29399754 TI - Evaluation of anatomical and morphological characteristics of the nasopalatine canal in a Turkish population by cone beam computed tomography. AB - BACKGROUND: The aim of this study was to analyse as three dimensions the anatomical and morphometric dimensions of nasopalatine canal (NPC) in the coronal, axial and sagittal directions using cone beam computed tomography (CBCT) and to evaluate the effect of age, gender and maxillary dental status on NPC and buccal bone thickness (BBT). MATERIALS AND METHODS: In this study, CBCT data of the 619 individuals aged between 17 and 86 years were examined retrospectively with respect to dimensions and anatomic variations of the NPC and BBTs. The correlation of age, gender, and status of edentulism of anterior maxilla with all the variables were evaluated. RESULTS: The NPC and BBT showed important variability in terms of morphology and dimensions. Morphological assessment of NPC revealed that 26.17% of NPCs were conical shape, 24.71% of canals were hourglass-shaped, 16.80% of canals were cylindrical shaped, 15.83% of canals were funnel-like shaped, 11.14% of canals were banana-like shaped, and 5.33% of canals were tree branch-like shaped. Males and females showed significant differences in the length of the NPC and BBTs in the sagittal sections. There were significant differences between age and BBTs. In addition, the length of NPC and BBTs were statistically different according to dental status. CONCLUSIONS: These anatomical changes in terms of dimensional and morphological parameters revealed the importance of three-dimensional imaging. Dentists should know and consider the variations in this canal in order to avoid possible complications during anaesthesia and surgical procedures which were applied to the maxillary anterior region. More precautions should be taken during surgical procedures in females, elderly and edentulous patients. PMID- 29399755 TI - Using three-dimensional digital models to establish alveolar morphotype. AB - BACKGROUND: The aim of the study was to propose a classification of alveolar morphotype and assess a relationship between extraction/non-extraction orthodontic treatment and changes to the alveolar process. MATERIALS AND METHODS: Seventy-five subjects (mean age = 23.2, SD = 5.1) were selected. Areas of the sections of the alveolar process (ASAP) at three different levels (0, 2, and 4 mm) were measured on pre- and post-treatment three-dimensional digital models. Method reliability was analysed using Dahlberg's formula, intraclass correlation coefficient, and paired t-tests. RESULTS: The mean ASAP was smallest at level 0 and largest at level 4. Pre-treatment ASAP < 773 mm2, < 863.9 mm2, and < 881.1 mm2 at levels 0, 2, and 4 mm, respectively, should be described as a "thin" alveolar morphotype. Regression models showed that pre-treatment ASAP was a predictor of the change of the alveolus during treatment only at level 2. CONCLUSIONS: Patients for whom pre-treatment ASAP is < 773 mm2, < 863.9 mm2, and < 881.1 mm2 at levels 0, 2, and 4 mm, respectively, should be described as having a "thin" alveolar morphotype. In these patients, extraction treatment, associated with a decrease in the alveolus area, should be exercised with caution. PMID- 29399757 TI - Clinical usefulness of epicardial adipose tissue in patients with high intermediate pre-test probability for coronary artery disease. AB - BACKGROUND: Epicardial adipose tissue (EAT) is thought to be associated with the extension and severity of coronary artery disease (CAD), and echocardiographic measurement of EAT thickness is considered to be a possible cardiovascular risk indica-tor. The European Society of Cardiology Task Force recommends further non invasive testing in patients with an intermediate pre-test probability (PTP) for the diagnosis of CAD. AIM: We sought to evaluate the clinical usefulness of performing EAT measurements in patients with a high-intermediate PTP. METHODS: Patients referred to an outpatient clinic with stable chest pain symptoms, with PTP for CAD between 66% and 85%, were included in the study. Echocardiographic measurement of the EAT was identified as the echo-free space between the outer wall of the myocardium and the visceral layer of the pericardium. Single-photon emission computed tomography (SPECT) was performed in all patients. The diagnosis of CAD was based on the presence of reversible perfusion defects on SPECT. RESULTS: A total of 126 patients (76 men, 60.3%) with a mean age of 65.3 +/- 9.1 years were recruited. The EAT thickness was 7.3 +/- 0.7 mm in patients with positive SPECT and 6.2 +/- 0.6 mm in patients with negative SPECT (p < 0.001). Multivariable analysis revealed higher rates of positive SPECT in patients with higher EAT (odds ratio [OR] 9.80; 95% confidence interval [CI] 3.72-25.79; p < 0.001), and receiver operating characteristic curve analysis showed that the greatest specificity was obtained when the cut-off value of EAT thickness was 6.75 mm (sensitivity 76%; specificity 74%). CONCLUSIONS: In patients with high intermediate PTP, EAT is a useful measurement that may assist in risk stratification. PMID- 29399756 TI - Cardiovascular risk assessment, cardiovascular disease risk factors, and lung function parameters. AB - BACKGROUND: Decreased lung function is related to higher cardiovascular disease (CVD) incidence and mortality. However, little is known about the relationship between the risk factors of CVD and pulmonary function. AIM: The aim of the study was to assess the relationship between the prevalence of cardiovascular risk factors, the total CVD risk, and pulmonary function. METHODS: The analysis included 4104 men and women aged 45 to 69 years, participants of the Polish part of the Health, Alcohol, and Psychosocial factors In Eastern Europe (HAPIEE) Project, who provided valid measurements of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) using a Micro-Medical Microplus spirometer. The prevalence of CVD risk factors was defined as follows: hypertension (systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg or taking hypertension medication), diabetes (glucose >= 7.1 mmol/L or self-reported diabetes), and hypercholesterolaemia (total cholesterol >= 5 mmol/L or low-density lipoprotein-cholesterol >= 3 mmol/L or taking lipid lowering medication). Categories of total CVD risk were defined according to the 2016 European Guidelines on CVD prevention in clinical practice. The analysis of covariance was used to compare the lung function in the CVD risk factors and the total CVD risk categories. RESULTS: Mean values of FEV1 and FVC, adjusted for age and height, were significantly higher in men than in women (3.02 L; 95% confidence interval [CI] 2.96-3.08 L vs. 2.52 L; 95% CI 2.45-2.63 L for FEV1 and 3.62 L; 95% CI 3.56-3.69 L vs. 3.05 L; 95% CI 2.98-3.12 L for FVC). Obesity was significantly associated with FVC in men and women; it was associated with FEV1 only in men. Compared with participants with normal body mass index, obese men and women had 280 mL and 112 mL lower mean FVC, respectively. Men without hypertension had almost 100 mL higher mean FVC than those with hypertension. The difference in FVC in women was approximately 80 mL. Diabetes was associated with lower values of FVC in both sexes and with FEV1 in women. A significant negative trend was observed in the mean FVC and FEV1 by the considered CVD risk categories. CONCLUSIONS: Impaired lung function was associated with higher CVD risk, which could be explained partly by an adverse association between lung function and prevalence of obesity, hypertension, and diabetes. PMID- 29399758 TI - Prevalence, diagnosis, and treatment of familial hypercholesterolaemia in outpatient practices in Poland. AB - BACKGROUND: Familial hypercholesterolaemia (FH) is the most common genetic disease leading to premature atherosclerosis. AIM: The aim of the study was to evaluate the prevalence, diagnosis, and treatment of FH in outpatient practices in Poland. METHODS: The study included a representative sample of 147 primary care physicians, cardiologists, and diabetologists caring for 2812 adult patients with hypercholesterolaemia and low-density lipoprotein cholesterol (LDL-C) level > 1.8 mmol/L, who were treated with statins or did not receive statins due to intolerance or contraindications. The physicians declared whether they diagnosed FH in the study group. In addition, we evaluated the Dutch Lipid Clinic Network (DLCN) diagnostic criteria for FH in all patients. The results were weighted and extrapolated to the general outpatient population in Poland. Treatment and its effectiveness were also evaluated. RESULTS: FH6+ score by the DLCN criteria was found in 3.6% of the study group, which translates by extrapolation to 136,300 adult patients with FH in Poland. Among patients with FH6+, this diagnosis was correctly made by physicians in 25% of cases and was not established in 75% of cases. Only 32.8% of patients received high statin doses. High LDL-C levels were found in a large proportion of patients, including levels >= 5.0 mmol/L in 42.7% of patients and >= 4.1 mmol/L in 59.7% of patients. CONCLUSIONS: Familial hypercholesterolaemia is inadequately diagnosed and treated in Poland, which calls for a radical im-provement of pre- and postgraduate education in this regard. PMID- 29399759 TI - MiR-130a inhibition protects rat cardiac myocytes from hypoxia-triggered apoptosis by targeting Smad4. AB - BACKGROUND: Cardiomyocyte death facilitates the pathological process underlying ischaemic heart diseases, such as myocardial infarction. Emerging evidence suggests that microRNAs play a critical role in the pathological process underlying myocardial infarction by regulating cardiomyocyte apoptosis. However, the relevance of miR-130a in regulating cardiomyocyte apoptosis and the underlying mechanism are still uncertain. AIM: We sought to explore the regulatory effect of miR-130a on hypoxic cardiomyocyte apoptosis. METHODS: The expression of miR-130a was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell survival was determined by the MTT assay. The lactate dehydrogenase (LDH) assay was performed to deter-mine the severity of hypoxia-induced cell injury. Apoptosis was assessed via caspase-3 analysis. Protein expression level was determined by Western blotting. The genes targeted by miR-130a were predicted using bioinformatics and were validated via the dual-luciferase reporter assay system. RESULTS: We found that miR-130a expression was greatly increased in hypoxic cardiac myocytes, and that the downregulation of miR-130a effectively shielded cardiac myocytes from hypoxia triggered apoptosis. In bioinformatic analysis the Smad4 gene was predicted to be the target of miR-130a. This finding was validated through the Western blot assay, dual-luciferase reporter gene assay, and qRT-PCR. MiR-130a inhibition significantly promoted the activation of Smad4 in hypoxic cardiomyocytes. Inter estingly, knockdown of Smad4 markedly reversed the protective effects induced by miR-130a inhibition. Moreover, we found that the inhibition of miR-130a promoted the activation of transforming growth factor-b1 signalling. Blocking of Smad4 signal-ling significantly abrogated the protective effects of miR-130a inhibition. CONCLUSIONS: The findings indicate that inhibition of miR-130a, which targets the Smad4 gene, shields cardiac myocytes from hypoxic apoptosis. This study offers a novel perspective on the molecular basis of hypoxia-induced cardiomyocyte apoptosis and suggests a possible drug target for the treatment of myocardial infarction. PMID- 29399760 TI - Impact of previous percutaneous coronary interventions on the course and clinical outcomes of coronary artery bypass grafting. AB - BACKGROUND: Despite the increasing number of patients after percutaneous coronary intervention (PCI) requiring coronary artery bypass grafting (CABG), studies on the impact of these procedures on surgical revascularisation outcomes are sparse. Furthermore, advances in cardiology require reassessment of their potential prognostic significance. AIM: We sought to assess the influence of previous PCI on CABG outcomes. METHODS: A total of 211 consecutive patients scheduled for CABG were enrolled into this prospective study. Patients after PCI (group 1, n = 99) were compared with subjects with no history of PCI (group 2, n = 112) in terms of preoperative, operative, and postoperative data. All the patients were followed up for the incidence of in-hospital (cardiogenic shock, myocardial infarction, stroke, acute renal failure, reoperation, death) and long-term (overall mortality, occlusion of at least one graft in 64-row computed tomography) clinical endpoints. RESULTS: Group 1 had more advanced heart failure and coronary artery disease as reflected by New York Heart Association (2.43 +/- 0.57 vs. 2.17 +/- 0.68; p < 0.001) and Canadian Cardiovascular Society (2.44 +/- 0.59 vs. 2.03 +/- 0.65; p < 0.001) scales, respectively. Compared with group 2, longer aortic cross-clamp (33.5 +/- 9.9 vs. 29.5 +/- 8.4; p < 0.05) and cardiopul-monary bypass (67.5 +/- 28.2 vs. 56.5 +/- 17.9; p < 0.001) times were observed as well as a higher number of implanted grafts (3.0 +/- 0.7 vs. 2.8 +/- 0.70; p < 0.05). No significant differences were observed in terms of in-hospital clinical endpoints. During 12 +/- 3.41 months of follow-up group 1 had higher mortality (5.05% vs. 0%; p < 0.05) but similar graft patency. CONCLUSIONS: "Stent-loaded" patients undergo more time-consuming CABG with a higher number of grafts. Furthermore, they have higher long-term mortality but similar graft patency and in-hospital mortality/morbidity. PMID- 29399761 TI - Postoperative kinetics of common inflammatory biomarkers after congenital heart defect procedures with extracorporeal circulation in children. AB - BACKGROUND: Extracorporeal circulation is associated with systemic inflammatory response syndrome. Therefore, the diagnosis of infection should be differentiated from a typical postoperative course. AIM: The aim of the study was to evaluate the kinetics of inflammatory biomarkers in children in the first days after cardiac surgery with extracorporeal circulation. METHODS: Prospective data were collected from 51 consecutive children referred for surgical treatment in Department of Paediatric Cardiac Surgery, St. Adalbertus Hospital in Gdansk, between February and August 2015. Blood samples were collected on the first, second, and third postoperative days and sent to the institutional laboratory for routine investigations: white blood cell count, serum C-reactive protein (CRP) and procalcitonin concentrations. RESULTS: The highest levels of procalcitonin were on the first postoperative day (median 3.53 ng/mL), although the peak values of CRP concentration and white blood cell count were on the second postoperative day (96 mg/L and 17.3 G/L). In the group of patients with foreign material implantation (Contegra(r) or Gore-Tex(r)), the higher values of procalcitonin concentration and white blood cell count were measured in the subsequent postoperative days. CONCLUSIONS: The kinetics of analysed inflammatory biomarkers on the first days after cardiac surgery for congenital heart disease in children have different characteristics. The knowledge about the kinetics of inflammatory biomarkers could be useful in determining the possibility of evolving infections in the early postoperative period. PMID- 29399762 TI - The effects of supraphysiological oestrogen levels on ventricular repolarisation parameters. AB - BACKGROUND: The frequency of arrhythmic death developing without a structural cardiac disease is higher in women. Also, female sex is an independent risk factor regarding development of torsades de pointes. Several studies have been conducted on the physiological and therapeutic effects of sex hormones on the cardiac conduction system. AIM: In this study we aim to examine the effect of hormonal changes, especially supraphysiological E2 level changes occurring during in vitro fertilisation treatment, on ventricular repolarisation parameters. METHODS: The study included female patients aged between 23 and 39 years, who were administered controlled ovarian hyperstimulation treatment. Patients' electrocardiograms and blood samples were obtained and analysed before and after the ovarian hyperstimulation treatment. RESULTS: Mean QTc intervals before ovarian hyperstimulation were 411.9 +/- 23.7 ms. Measurements during oestradiol peak were calculated as 420.7 +/- 23.3 ms, and the QTc interval increase was significant (p = 0.007). Corrected QT dispersion averages were not significant before or after hyperstimulation (53 +/- 17 ms vs. 54.5 +/- 18.2 ms, respectively, p > 0.05). Tp-e, J-T peak, and PR dispersion changes were not significant after the ovarian hyperstimulation therapy. CONCLUSIONS: Supraphysiological oestradiol levels that occur during controlled ovarian hyperstimulation cause prolongation of QTc intervals, but not to a pathological level. Although this prolongation is not significant in healthy individuals, it might increase ventricular arrhythmia risk in patients with congenital long QT syndrome and in patients taking medication that prolongs QT. PMID- 29399763 TI - Significant mitral regurgitation as a predictor of long-term prognosis in patients receiving cardiac resynchronisation therapy. AB - BACKGROUND: Cardiac resynchronisation therapy (CRT) has been shown to reduce functional mitral regurgitation, although the relationship between significant mitral regurgitation (SMR) and the clinical prognosis of CRT remains uncertain. AIM: We sought to investigate the association of baseline SMR with long-term outcomes in patients undergoing CRT. METHODS: A total of 296 consecutive patients undergoing CRT were enrolled. SMR was quantified by colour Doppler in all patients at baseline and defined as level >= 3 on the severity scale. The primary endpoints included all-cause death, heart failure hospitalisation (HFH), and heart transplantation, and the secondary endpoints were response to CRT and New York Heart Association (NYHA) class III or IV six months after CRT implantation. RESULTS: The mean age was 59 +/- 11 years, and 202 (68.2%) patients were male. Among all patients, 124 (41.9%) presented with baseline SMR. Over a mean follow up of 4.17 +/- 3.16 years, there were 53 (17.9%) cases of all-cause death, 41 (13.8%) cases of HFH, and four (1.4%) cases of heart transplantation. SMR was positively associated with primary endpoint events (hazard ratio [HR] 1.602, 95% confidence interval [CI] 1.083-2.371, p = 0.019), HFH (HR 3.567, 95% CI 1.763 7.219, p < 0.001) and NYHA class III or IV (HR 2.101, 95% CI 1.313-3.363, p = 0.002). After adjusting for multiple factors, we found that SMR (HR 1.785, 95% CI 1.091-2.920, p = 0.021), ischaemic heart disease (HR 1.628, 95% CI 1.062-2.494, p = 0.025), and the lack of use of spironolactone (HR 2.044, 95% CI 1.040-4.017, p = 0.038) were independent predictors of primary endpoints, and SMR remained an independent predictor of HFH (HR 4.622, 95% CI 1.955-10.923, p < 0.001). CONCLUSIONS: Significant mitral regurgitation before CRT implantation was strongly associated with long-term poor progno-sis. SMR was positively associated with HFH rather than all-cause death and CRT response. PMID- 29399764 TI - Editorial. PMID- 29399765 TI - [2017 ESC/EACTS Guidelines for the management of valvular heart disease]. PMID- 29399766 TI - The first successful bridging with an Impella CP(r) to minimally invasive HeartMate 3 LVAD implantation in Poland. PMID- 29399767 TI - Angiographic appearance of the HeartMate 3TM. AB - The use of Left Ventricular Assist Devices (LVADs) has substantially increased in recent years, being a valid therapeutic option for a growing population of patients with advanced heart failure. A 54 year old male had had the HeartMate 3TM implanted in a prepericardiac location due to end-stage congestive heart failure. We present the angiographic data of our patient. PMID- 29399768 TI - Percutaneous transmitral commissurotomy in calcified, restenosed mitral valve: a technical challenge. PMID- 29399769 TI - Augmented reality in left atrial appendage occlusion. PMID- 29399770 TI - Device-associated thrombus after left atrial appendage occlusion. PMID- 29399771 TI - Cardiac malignant peripheral nerve sheath tumours arising from atrial neurofibroma as an unusual complication of neurofibromatosis. PMID- 29399772 TI - [Expert consensus on the usefulness of natriuretic peptides in heart failure.] AB - Heart failure (HF) has becoming an increasing clinical and social problem worldwide and despite modern therapy the syndrome still imposes high burden on healthcare systems. In contrast to western countries, the diagnosis of HF in Poland is established later, at more advanced stage of the disease, thus leaving less time for modern therapy and more frequently requiring hospitalisation. As a result, the alarmingly high proportion of patients with HF is treated in hospitals in Poland. According to current guidelines clinical suspicion of HF should be verified based on early assessment of plasma levels of natriuretic peptides. Unfortunately, the key test for early diagnosis, especially in emergency departments and in general practice is not reimbursed and therefore hardly available. The paper provides a short review on the physiology and pathophysiology of natriuretic peptides. Important laboratory issues as well as limitations of their use in specific clinical situations are briefly discussed. Further, we focus on clinical use of natriuretic peptides as an important tool for HF diagnosis, guiding therapy and prognosis. Finally, we put spotlight on the use of natriuretic peptides in prevention of HF and also in ambulatory general practice. PMID- 29399773 TI - Deciphering bioresorbable stent thrombosis: investigating the mechanisms. PMID- 29399774 TI - Parameters of platelet indices in young patients with ST elevation myocardial infarction. Commentary to the article: "Platelet distribution width and plateletcrit: novel biomarkers of ST elevation myocardial infarction in young patients". PMID- 29399775 TI - Response to the letter concerning the article: "Platelet distribution width and plateletcrit: novel biomarkers of ST elevation myocardial infarction in young patients". PMID- 29399776 TI - Lichen sclerosus on the face. PMID- 29399777 TI - Investigation of the effect of Equivac(r) HeV Hendra virus vaccination on Thoroughbred racing performance. AB - OBJECTIVE: To evaluate the effect of Equivac(r) HeV Hendra virus vaccine on Thoroughbred racing performance. DESIGN: Retrospective pre-post intervention study. METHODS: Thoroughbreds with at least one start at one of six major south eastern Queensland race tracks between 1 July 2012 and 31 December 2016 and with starts in the 3-month periods before and after Hendra virus vaccinations were identified. Piecewise linear mixed models compared the trends in 'Timeform rating' and 'margin to winner' before and after initial Hendra virus vaccination. Generalised linear mixed models similarly compared the odds of 'winning', 'placing' (1st-3rd) and 'winning any prize money'. Timeform rating trends were also compared before and after the second and subsequent vaccinations. RESULTS: Analysis of data from 4208 race starts by 755 horses revealed no significant difference in performance in the 3 months before versus 3 months after initial Hendra vaccination for Timeform rating (P = 0.32), 'Margin to winner' (P = 0.45), prize money won (P = 0.25), wins (P = 0.64) or placings (P = 0.77). Further analysis for Timeform rating for 7844 race starts by 928 horses failed to identify any significant change in Timeform rating trends before versus after the second and subsequent vaccinations (P = 0.16) or any evidence of a cumulative effect for the number of vaccines received (P = 0.22). CONCLUSION: No evidence of an effect of Hendra virus vaccination on racing performance was found. The findings allow owners, trainers, industry regulators and animal health authorities to make informed decisions about vaccination. PMID- 29399778 TI - A repeatable geometric morphometric approach to the analysis of hand entheseal three-dimensional form. AB - OBJECTIVES: The purpose of this study was to put forth a precise landmark-based technique for reconstructing the three-dimensional shape of human entheseal surfaces, to investigate whether the shape of human entheses is related to their size. The effects of age-at-death and bone length on entheseal shapes were also assessed. MATERIALS AND METHODS: The sample comprised high-definition three dimensional models of three right hand entheseal surfaces, which correspond to 45 male adult individuals of known age. For each enthesis, a particular landmark configuration was introduced, whose precision was tested both within and between observers. The effect of three-dimensional size, age-at-death, and bone length on shape was investigated through shape regression. RESULTS: The method presented high intra-observer and inter-observer repeatability. All entheses showed significant allometry, with the area of opponens pollicis demonstrating the most substantial relationship. This was particularly due to variation related to its proximal elongated ridge. The effect of age-at-death and bone length on entheses was limited. DISCUSSION: The introduced methodology can set a reliable basis for further research on the factors affecting entheseal shape. Using both size and shape, variables can provide further information on entheseal variation and its biomechanical implications. The low entheseal variation by age verifies that specimens under 50 years of age are not substantially affected by age-related changes. The lack of correlation between entheseal shape and bone length or age implies that other factors may regulate entheseal surfaces. Future research should focus on multivariate shape patterns among entheses and their association with occupation. PMID- 29399779 TI - Archaeogenetics of Late Iron Age Cemialo Sirti, Batman: Investigating maternal genetic continuity in north Mesopotamia since the Neolithic. AB - OBJECTIVES: North Mesopotamia has witnessed dramatic social change during the Holocene, but the impact of these events on its demographic history is poorly understood. Here, we study this question by analysing genetic data from the recently excavated Late Iron Age settlement of Cemialo Sirti in Batman, southeast Turkey. Archaeological and radiocarbon evidence indicate that the site was inhabited during the second and first millennia BCE. Cemialo Sirti reveals nomadic items of the Early Iron Age, as well as items associated with the Late Achaemenid and subsequent Hellenistic Periods. We compare Cemialo Sirti mitochondrial DNA profiles with earlier and later populations from west Eurasia to describe genetic continuity patterns in the region. MATERIALS AND METHODS: A total of 16 Cemialo Sirti individuals' remains were studied. PCR and Sanger sequencing were used to obtain mitochondrial DNA HVRI-HVRII sequences. We studied haplotype diversity and pairwise genetic distances using FST , comparing the Cemialo Sirti population with ancient and modern-day populations from west Eurasia. Coalescent simulations were carried out to test continuity for specific population comparisons. RESULTS: Mitochondrial DNA (mtDNA) haplotypes from 12 Cemialo Sirti individuals reveal high haplotype diversity in this population, conspicuously higher than early Holocene west Eurasian populations, which supports the notion of increasing population admixture in west Eurasia through the Holocene. In its mtDNA composition, Cemialo Sirti shows highest affinity to Neolithic north Syria and Neolithic Anatolia among ancient populations studied, and to modern-day southwest Asian populations. Based on population genetic simulations we cannot reject continuity between Neolithic and Iron Age, or between Iron Age and present-day populations of the region. DISCUSSION: Despite the region's complex sociopolitical history and indication for increased genetic diversity over time, we find no evidence for sharp shifts in north Mesopotamian maternal genetic composition within the last 10,000 years. PMID- 29399780 TI - Generalized Procrustes analysis of an ontogenetic series of modified crania: Evaluating the technique of modification in the Migration Period of Europe (4th 7th century AD). AB - OBJECTIVES: The arrival of the Huns into Europe in the fourth century AD increased the occurrence of intentional cranial modification among European nomads. It has been postulated that the Huns used a two-bandage cranial binding technique to differentiate themselves from surrounding nomadic groups, including those from Georgia. This study examines this hypothesis by comparing Migration Period (4th to 7th century AD) juvenile crania, which retain strong impressions of bindings, with adult modified crania from Hungary and Georgia. MATERIALS AND METHODS: Twelve surface landmarks and 251 semi-landmarks were used to study ontogenetic trajectories in 9 juvenile and 16 adult modified skulls from 8 Hungarian sites and 21 adult skulls from two Georgian sites. Generalized Procrustes analysis, linear regression of Procrutes distance on dental age and log centroid size, and warping the principal components (PCs) in shape space helped to identify cranial shape changes. RESULTS: The PCs provide significant separation of the juvenile and adult groups from Georgia and Hungary. Variation in modified cranial shape was limited in Hungary compared to Georgia. There was stronger correlation between juvenile and adult modified cranial shape in Hungary than in Georgia. Warping along the first axis reveals the trajectory from marked flattening of the frontal and occipital regions in juveniles to diminished flattening in the same regions in adult crania, corresponding with one binding. Another depression extending from the post-bregmatic region to the temporal region, similarly strong in juveniles but diminishing in adults, marks the second binding. DISCUSSION: Hungarian crania were modified with two bindings with limited shape variation, whereas the Georgian crania had greater variation in shape being also modified with antero-posterior bindings. The findings from this study alongside contemporary historical sources help to understand the role of intentional cranial modification as a mark of social identity among nomads in the Migration Period of Europe. PMID- 29399781 TI - Epidural extension failure in obese women is comparable to that of non-obese women. AB - BACKGROUND: Management of labor epidurals in obese women is difficult and extension to surgical anesthesia is not always successful. Our previous retrospective pilot study found epidural extension was more likely to fail in obese women. This study used a prospective cohort to compare the failure rate of epidural extension in obese and non-obese women and to identify risk factors for extension failure. METHODS: One hundred obese participants (Group O, body mass index >= 40 kg/m2 ) were prospectively identified and allocated two sequential controls (Group C, body mass index <= 30 kg/m2 ). All subjects utilized epidural labor analgesia and subsequently required anesthesia for cesarean section. The primary outcome measure was failure of the labor epidural to be used as the primary anesthetic technique. Risk factors for extension failure were identified using Chi-squared and logistic regression. RESULTS: The odds ratio (OR) of extension failure was 1.69 in Group O (20% vs. 13%; 95% CI: 0.88-3.21, P = 0.11). Risk factors for failure in obese women included ineffective labor analgesia requiring anesthesiologist intervention, (OR 3.94, 95% CI: 1.16-13.45, P = 0.028) and BMI > 50 kg/m2 (OR 3.42, 95% CI: 1.07-10.96, P = 0.038). CONCLUSION: The failure rate of epidural extension did not differ significantly between the groups. Further research is needed to determine the influence of body mass index > 50 kg/m2 on epidural extension for cesarean section. PMID- 29399782 TI - Prenatal detection of uniparental disomy of chromosome 2 carrying a CHRND pathogenic variant that causes lethal multiple pterygium syndrome. PMID- 29399783 TI - Oral retinoids and depression. PMID- 29399784 TI - Subcutaneous methotrexate in patients with moderate-to-severe psoriasis: a critical appraisal. AB - AIM: Warren et al. set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate-to-severe chronic plaque psoriasis. SETTING AND DESIGN: This was a prospective, double-blind, randomized (3 : 1), placebo-controlled study, conducted across 16 centres in Germany, France, the Netherlands and the U.K. STUDY EXPOSURE: Methotrexate-naive adults with a diagnosis of moderate-to-severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17.5 mg, or placebo for 16 weeks (first phase). Dose escalation to 22.5 mg per week was implemented after 8 weeks if patients did not achieve >= 50% improvement in Psoriasis Area and Severity Index (PASI 50). Treatment was combined with folic acid 5 mg per week. The first phase of the study was followed by an open-label period from 16 to 52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22.5 mg per week was possible in patients not achieving PASI 50. OUTCOMES: Psoriasis severity was measured using PASI. The authors also used two other psoriasis severity measures and two quality of-life measures, looked at safety indices and performed a substudy analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin-17A, interferon-gamma and tumour necrosis factor-alpha). PRIMARY OUTCOME MEASURES: The primary outcome was the proportion of patients reaching PASI 75 at week 16. RESULTS: In total 120 patients were included in this trial, most of whom were middle-aged white men with long-standing psoriasis, and the mean body mass index was 30.1 kg m-2 . PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (relative risk 3.93, 95% confidence interval 1.31-11.81; P = 0.0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52-week study. CONCLUSION: Warren et al. conclude that the 52-week risk-benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis. PMID- 29399785 TI - A new mobile learning module using smartphone wallpapers in identification of medical fungi for medical students and residents. AB - INTRODUCTION: Medical students and residents will encounter many cutaneous fungal infections in medical practice. However, the training for identification of medical fungi has been insufficient due to limited lecture-based courses. The objective of this study was to evaluate the impact of using smartphone-based wallpapers in learning the microscopic morphology and colony characteristics of medical fungi for medical students and residents. METHODS: A smartphone-based wallpaper learning module using a wallpaper-changing software application (app) was introduced in this 3-week training course. Twenty-six participants were enrolled and divided into two groups: nondermatology trainees, including medical students and postgraduate year one (PGY-1) doctors who have not yet specialized, and dermatology trainees (dermatology residents). All of the participants completed a 3-week training course, and the effectiveness of the module was evaluated by pre- and post-course multiple-choice examinations. RESULTS: Both nondermatology and dermatology trainees scored significantly higher in post course examinations than pre-course examinations (P < 0.001). The dermatology trainees performed better than nondermatology trainees in the pre-course examinations (P < 0.001). In the post-course examinations, no significant difference in scores was noted between dermatology and nondermatology trainees (P = 0.573). DISCUSSION: The smartphone-based wallpaper learning module was effective in helping medical students and residents learn and memorize morphologic characteristics of fungi. In comparison to conventional lecture-based learning, this new mobile module was more readily accessible and convenient for learners to engage in learning. PMID- 29399786 TI - Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome. AB - Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1. This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN. PMID- 29399787 TI - Disseminated actinomycetoma due to Nocardia wallacei. AB - BACKGROUND: Actinomycetoma caused by Nocardia usually responds well to antibiotics. Emerging species of Nocardia, such as N. wallacei, can be a therapeutic challenge. AIMS: Confirm the therapeutic effectivity of linezolid in multidrug resistant Nocardia Wallacei actinomycetoma. MATERIALS AND METHODS: We evaluated the medical management of an 18-year-old man with multidrug resistant actinomycetoma of the left leg caused by N. transvalensis complex treated 17 years ago with linezolid 1200 mg a day. This bacteria was recently reclassified as Nocardia Wallacei by specific molecular biology technique. RESULTS: The infection was cured after 3 months of treatment; the patient remained asymptomatic for the past 17 years. No adverse effects were found. DISCUSSION: Frequently, strains of N. transvalensis complex have aminoglycoside resistance; in this case, we highlight the effectiveness of linezolid for the successful medical management of multidrug resistant actinomycetoma. CONCLUSION: Linezolid can be an alternative for the treatment of multidrug resistant Nocardia Wallacei. PMID- 29399788 TI - Brief communication: Dental microwear and diet of Homo naledi. AB - OBJECTIVES: A recent study of dental chipping suggested that Homo naledi teeth were exposed to "acute trauma" on a regular basis during life, presumably from the consumption of grit-laden foods. This follows debate concerning the etiology of dental chips in South African hominin teeth that dates back more than half a century. Some have argued that antemortem chips result from consumption of hard foods, such as nuts and seeds or bone, whereas others have claimed that exogenous grit on roots and tubers are responsible. Here we examine the dental microwear textures of H. naledi, both to reconstruct aspects of diet of these hominins and to assess the possibility that hard foods (gritty or otherwise) are the culprits for the unusually high antemortem chip incidence reported. METHODS: We made high resolution replicas of original molars and found that ten individuals preserve antemortem wear. These were scanned by white-light scanning confocal profilometry and analyzed using scale-sensitive fractal analysis. Resulting data were compared with those published for other fossil hominins and extant non-human primates. RESULTS: Our results indicate that H. naledi had complex microwear textures dominated by large, deep pits. The only known fossil hominin with higher average texture complexity is Paranthropus robustus, and the closest extant primates in a comparative baseline series appear to be the hard-object feeder, Cercocebus atys, and the eurytopic generalist, Papio ursinus. CONCLUSIONS: This study suggests that H. naledi likely consumed hard and abrasive foods, such as nuts or tubers, at least on occasion, and that these might well be responsible for the pattern of chipping observed on their teeth. PMID- 29399789 TI - Treatment response to omalizumab in patients with refractory chronic spontaneous urticaria. AB - BACKGROUND: Previous clinical trials have demonstrated the efficacy and safety of the anti-IgE monoclonal antibody omalizumab in chronic spontaneous urticaria (CSU) not responding to antihistamine treatment. The primary aim of our study was to describe the response patterns of patients with refractory CSU treated with omalizumab in a real-world clinical setting. METHODS: A retrospective analysis of medical records of 20 patients with refractory CSU was performed. Demographic, clinical, and laboratory features were retrieved and analyzed in correlation with treatment data. RESULTS: Mean age of our patient population was 54.5 years, while the majority were females (15/20 cases, 75%). Mean disease duration prior to omalizumab administration was 21.8 months. All patients had a history of chronic urticaria, refractory to high antihistamine and corticosteroid treatment, and responded favorably to omalizumab after administration of 1-5 doses of omalizumab; complete response was observed in 17/20 patients (85%) and well controlled disease in the remaining 3/20 patients (15%). In a subset of cases (6/20, 30%), best response to omalizumab was achieved after interval administration of a 9-day course of methylprednisolone (total dose of 188 mg). Late response to omalizumab (after three-month treatment) was significantly correlated (P = 0.026) with shorter disease duration before initiation of omalizumab. CONCLUSION: In the present series, omalizumab, either alone or in combination with a short-term course of corticosteroids, was highly effective in resolution of refractory CSU. Furthermore, disease duration prior to omalizumab had a significant effect on timing of response. PMID- 29399790 TI - Pollen competition between morphs in a pollen-color dimorphic herb and the loss of phenotypic polymorphism within populations. AB - Flower color polymorphism is relatively uncommon in natural flowering plants, suggesting that maintenance of different color morphs within populations is difficult. To address the selective mechanisms shaping pollen-color dimorphism, pollinator preferences and reproductive performance were studied over three years in Epimedium pubescens in which some populations had plants with either green or yellow pollen (and anthers). Visitation rate and pollen removal and receipt by the bee pollinator (Andrena emeishanica) did not differ between the two color morphs. Compared to the green morph, siring success of the yellow morph's pollen was lower, but that of mixtures of pollen from green and yellow morphs was lowest. This difference, corresponding to in vivo and ex vivo experiments on pollen performance, indicated that pollen germination, rather than tube growth, of the green morph was higher than that of the yellow morph and was seriously constrained in both morphs if a pollen competitor was present. A rare green morph may invade a yellow-morph population, but the coexistence of pollen color variants is complicated by the reduced siring success of mixed pollinations. Potential pollen competition between morphs may have discouraged the maintenance of multiple phenotypes within populations, a cryptic mechanism of competitive exclusion. PMID- 29399792 TI - Papilledema in Idiopathic Intracranial Hypertension. PMID- 29399791 TI - Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. AB - We convened an international group of experts to standardize definitions of New Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in-person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions. PMID- 29399793 TI - MRI Findings in Varicella Zoster Trigeminal Neuritis Without Rash. PMID- 29399794 TI - Vitamin D supplementation for bone health in adults with epilepsy: A systematic review. AB - OBJECTIVE: Several antiepileptic drugs (AEDs) have been associated with a detrimental effect on bone health through a reduction in serum vitamin D. Subsequently, several studies have investigated the effect of vitamin D supplementation in persons with epilepsy being treated with AEDs. The present systematic review of published literature was conducted to determine the effect of vitamin D intervention on bone health in adults with epilepsy. METHODS: The following databases were searched using keywords including but not limited to epilepsy, bone, and vitamin D: PubMed, Medline, Embase, Scopus, Cochrane Clinical Trials, International Pharmaceutical Abstracts, Health Canada Clinical Trials Database, ClinicalTrials.gov, EU Clinical Trials, and Google. Studies were eligible if there was an epilepsy diagnosis, participants were adults (18+ years old), and vitamin D treatment and bone outcome were provided. Articles were screened independently by 2 reviewers. Methodological quality was assessed using the Cochrane Collaboration's tool and a modified Newcastle Ottawa Scale for nonrandomized studies. RESULTS: Nine studies were found to be eligible for this review. After vitamin D treatment, there appeared to be positive changes in bone turnover markers; 3 of 8 studies found the increase in serum calcium to be significant, 6 of 8 studies found the decrease in alkaline phosphatase to be significant, and 2 of 4 studies found the decrease in parathyroid hormone to be significant. All 6 studies that investigated bone mineralization had significant findings; however, due to varying methodologies, the impact of vitamin D on bone mineralization was inconclusive. SIGNIFICANCE: Vitamin D does appear to have some benefit to bone health in adults with epilepsy, and therefore supplementation could potentially be a requisite to using some AEDs. To clarify the role of vitamin D supplementation to manage the adverse effect of AEDs on bone health in adults with epilepsy, long-term trials that use higher doses (>1800 IU) and measure bone mineral density are necessary. PMID- 29399795 TI - Circadian anosmia: A rare clinical presentation. AB - We report the case of a 27-year-old female who presented with a peculiar story of anosmia fluctuating in a circadian manner. Olfactory function appeared an hour after breakfast, was normal during daytime, and disappeared in the early evening. Imaging confirmed chronic rhinosinusitis (CRS). Initial systemic, followed by topical steroid treatment, rapidly and sustainably reversed this condition. The olfactory fluctuation paralleled the endogenous steroid production. This suggests that slight congestion changes in a chronically inflamed nasal mucosa may have been sufficient to induce this circadian anosmia. The importance of identifying fluctuation of olfactory function as a sign of CRS is emphasized and discussed. Laryngoscope, 128:1537-1539, 2018. PMID- 29399796 TI - Zygomaticofacial Neuralgia: A New Cause of Facial Pain. PMID- 29399797 TI - The survival impact of surgical therapy in squamous cell carcinoma of the hard palate. AB - OBJECTIVE: To describe the incidence and determinants of survival of patients with squamous cell carcinoma of the hard palate (SCCHP) between the years of 1973 to 2014 using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Retrospective, population-based cohort study of patients in the SEER tumor registry who were diagnosed with SCCHP from 1973 to 2014. Outcomes and measures included overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 1,489 cases of primary SCCHP were identified. Of those, 53.2% were females and 47.8% presented with stage IV disease. The mean age at diagnosis was 69.8 years. Overall survival at 2, 5, and 10 years was 44%, 33%, and 21%, respectively. A total of 66.2% of patients underwent surgery (with or without radiation therapy [RT]); 20.1% received RT; and 22.4% had both surgical and RT. On multivariate analysis, RT, advanced age, stage, and grade were associated with worse OS and DSS (P < 0.05). Surgical therapy (with or without radiation) was an independent favorable predictor of OS and DSS (P < 0.05). CONCLUSION: SCCHP is relatively infrequent tumor that portends an overall poor prognosis when advanced stage and a greater prognosis when early stage. Surgical therapy was found to be an independent predictor for improved OS and DSS, whereas RT was associated with reduced OS and DSS. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2050-2055, 2018. PMID- 29399798 TI - In Response to Should Infants Who Fail Their Newborn Hearing Screen Undergo Cytomegalovirus Testing? PMID- 29399799 TI - Synergistic effects of intravenous and intra-articular tranexamic acid on reducing hemoglobin loss in revision total knee arthroplasty: a prospective, randomized, controlled study. AB - BACKGROUND: Tranexamic acid decreases blood loss in primary total knee arthroplasty, and no related prospective randomized clinical trials have been conducted to evaluate the effectiveness and safety of tranexamic acid in revision total knee arthroplasty. Thus, we conducted this work to evaluate the synergistic effects of intravenous plus intra-articular tranexamic acid on reducing hemoglobin loss compared with intra-articular tranexamic acid alone in revision total knee arthroplasty. STUDY DESIGN AND METHODS: This prospective, controlled study randomized 96 patients undergoing revision total knee arthroplasty into two groups: an intravenous plus intra-articular tranexamic acid group (48 patients who received 20 mg/kg intravenous tranexamic acid and 3.0 g intra-articular tranexamic acid); and an intra-articular tranexamic acid alone group (48 patients who received the same intravenous volume of normal saline and 3.0 g intra articular tranexamic acid). The primary outcome was hemoglobin loss. Secondary outcomes included the volume of drain output, the percentage of patients who received transfusions, the number of units transfused, and thromboembolic events. RESULTS: The baseline data, preoperative hemoglobin, and tourniquet time were similar in both groups. There was significantly less hemoglobin loss in the intravenous plus intra-articular tranexamic acid group compared with the intra articular tranexamic acid alone group (2.7 +/- 0.6 g/dL and 3.7 +/- 0.7 g/dL; p < 0.001). Compared with the intra-articular tranexamic acid alone group, the intravenous plus intra-articular tranexamic acid group also had significantly less drain output, fewer patients who received transfusions, and fewer units transfused (all p < 0.05). There were no significant differences in thromboembolic events in the two groups during the 3-month follow-up. CONCLUSION: Compared with intra-articular tranexamic acid alone, combined intravenous plus intra-articular tranexamic acid significantly reduced hemoglobin loss and the need for transfusion without an apparent increase in thromboembolic events in patients who underwent revision total knee arthroplasty. PMID- 29399800 TI - Double-blind, placebo-controlled study with alginate suspension for laryngopharyngeal reflux disease. AB - OBJECTIVE: Treatment for laryngopharyngeal reflux disease (LPRD) is challenging because of delays in recognition and poor responsiveness to proton-pump inhibitor therapy. The aim of this study was to determine the efficacy and safety of liquid alginate suspension for treating LPRD. METHODS: A double-blind, placebo controlled, prospective study comparing 8 weeks of treatment with Alginos Oral Suspension (TTY Biopharm Co. Ltd., Taipei, Taiwan) (sodium alginate 1,000 mg three times daily) with a placebo was conducted on patients who fulfilled the criteria of at least one symptom consistent with LPRD, a total reflux symptom index (RSI) score of > 10, and a total reflux finding score (RFS) of > 5. Those with erosive gastroesophageal reflux disease, as evidenced through screened transnasal upper gastrointestinal endoscopy, were excluded. Efficacy was assessed by RSI, RFS, and ambulatory multichannel intraluminal impedance and pH (MII-pH) monitoring. RESULTS: A total of 80 patients aged 22 to 72 years were enrolled. Compared with baseline, both Alginos (TTY Biopharm Co. Ltd.) and the placebo significantly reduced the total RSI (P < 0.001) and the total number of reflux episodes shown by MII-pH monitoring (P < 0.05) after 8 weeks of treatment. However, liquid alginate suspension was unable to show superiority over the placebo. The incidence of various adverse events from Alginos (TTY Biopharm Co. Ltd.) was relatively low (7.7%) and mild. CONCLUSION: This study showed that liquid alginate suspension was well tolerated by LPRD patients. It effectively improved symptoms and reflux numbers but was unable to show superiority over placebo. As observed in previous studies, a great placebo effect was present. The importance of lifestyle modification could not be overlooked. LEVEL OF EVIDENCE: 2. Laryngoscope, 128:2252-2260, 2018. PMID- 29399801 TI - The Potential Role of Bile Acids in Acquired Laryngotracheal Stenosis. AB - OBJECTIVE: Gastroesophageal reflux is thought to be a risk factor for laryngotracheal stenosis. Bile acids are a component of gastric refluxate and have previously been implicated in the development of fibrosis in other airway subsites. There is clear evidence that bile acids reflux into the upper airway. We therefore investigated the potential role of bile acids in the pathophysiology of laryngotracheal fibrosis and stenosis, specifically investigating the highly conserved process of epithelial-mesenchymal transition (EMT). STUDY DESIGN: Translational research study. METHODS: Human primary tracheal epithelial cells (PTECs) were challenged with the four most common digestive bile acids (cholic, chenodeoxycholic, deoxycholic, and lithocholic). EMT markers transforming growth factor (TGF)-beta1, Matrix metalloproteinase (MMP)-9, and procollagen proteins were measured in the supernatant at 48 hours via enzyme-linked immunosorbent assay. Real-time polymerase chain reaction was also used to measure E-cadherin and fibronectin expression. RESULTS: Significantly greater concentrations of TGF beta1 and MMP-9 were measured in the culture supernatants of cells treated with each bile acid at 10 umol/L. Lithocholic acid and deoxycholic acid induced significantly increased expression of procollagen protein. Upregulation of fibronectin and downregulation of E-cadherin were observed with all bile acids, except for deoxycholic acid. CONCLUSION: This is the first proof of principle demonstration that physiologically relevant bile acid challenge induces EMT mechanisms in PTECs. This implies a potential role for bile acids in laryngotracheal scarring and airway remodeling of potential translational significance in laryngotracheal stenosis. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:2029-2033, 2018. PMID- 29399802 TI - Stem cells enhance reperfusion following ischemia: Validation using laser speckle imaging in predicting tissue repair. AB - OBJECTIVES: The lack of real-time assessment of vascular perfusion changes remains a major weakness in assessing the efficacy of bone marrow stromal cells (BMSC) therapeutic ischemia reperfusion (I/R) injury. This study provides for the first time the real-time in vivo perfusion monitoring in I/R mice with BMSC therapy. STUDY DESIGN: Animal model. METHODS: Surgically created cutaneous flaps perfused by the inferior epigastric vessels were subjected to 3.5 hours of ischemia/reperfusion. Wound healing and vascular perfusion were assessed by Image J and laser speckle contrast analysis (LSCA) in three groups (sham, I/R, and I/R + BMSC). BMSC tracking was quantified in an additional two groups (with/without I/R) using intravital fluorescent microscopy. The histopathology of skin flaps was examined by hematoxylin and eosin stain. Infiltrated macrophages were analyzed by confocal immunofluorescent microscopy. RESULTS: Postischemic tissues treated with BMSC demonstrated significantly greater survival than I/R control. On days 3 to 7 postreperfusion, both proximal and distal areas in BMSC-treated flaps demonstrated greater levels of perfusion than untreated I/R flaps (P < 0.05). Intravital fluorescent microscopy revealed that numbers of labeled BMSC were significantly increased in the distal area compared to the proximal area in both with and without ischemic mice. Histological examination showed lower necrosis and infiltrated inflammatory cells in I/R + BMSC-treated mice versus I/R controls. CONCLUSION: BMSC accumulated in I/R flaps and exerted beneficial effects including: 1) improving vascular perfusion and 2) attenuating inflammatory cell infiltration. LSCA facilitates monitoring of the real-time restitution of perfusion during flap wound healing in experimental animals and could also similarly applied in clinical investigations. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E198-E205, 2018. PMID- 29399803 TI - HaNDL Syndrome with Fever in a 12-Year-Old Boy - A Case Report. PMID- 29399804 TI - Constraining uncertainty in the timescale of angiosperm evolution and the veracity of a Cretaceous Terrestrial Revolution. AB - Through the lens of the fossil record, angiosperm diversification precipitated a Cretaceous Terrestrial Revolution (KTR) in which pollinators, herbivores and predators underwent explosive co-diversification. Molecular dating studies imply that early angiosperm evolution is not documented in the fossil record. This mismatch remains controversial. We used a Bayesian molecular dating method to analyse a dataset of 83 genes from 644 taxa and 52 fossil calibrations to explore the effect of different interpretations of the fossil record, molecular clock models, data partitioning, among other factors, on angiosperm divergence time estimation. Controlling for different sources of uncertainty indicates that the timescale of angiosperm diversification is much less certain than previous molecular dating studies have suggested. Discord between molecular clock and purely fossil-based interpretations of angiosperm diversification may be a consequence of false precision on both sides. We reject a post-Jurassic origin of angiosperms, supporting the notion of a cryptic early history of angiosperms, but this history may be as much as 121 Myr, or as little as 23 Myr. These conclusions remain compatible with palaeobotanical evidence and a more general KTR in which major groups of angiosperms diverged later within the Cretaceous, alongside the diversification of pollinators, herbivores and their predators. PMID- 29399806 TI - Occupational allergic contact dermatitis caused by antibiotics in healthcare workers - relationship with non-immediate drug eruptions. AB - BACKGROUND: Occupational allergic contact dermatitis (ACD) in healthcare workers (HCWs) is common, but systemic antibiotics are rarely reported as the cause. OBJECTIVES: Characterize occupational ACD by handling systemic antibiotics. METHOD: A retrospective analysis was performed of ACD caused by systemic antibiotics among HCWs patch tested between 2010 and 2016 with a series of systemic antibiotics. RESULTS: We studied 4 female nurses aged 28-47 years who developed ACD while working in surgical departments. They had eczema of the hands, and forearms or face, and 1 patient, who previously had exanthema caused by flucloxacillin, also developed a generalized rash following airborne exposure to systemic antibiotics. Patch tests showed positive reactions to ampicillin and cefazolin in 1 patient, to cefotaxime and ceftriaxone in 2 patients, and to several penicillins in another patient. Three patients also reacted to rubber allergens, fragrances, and/or preservatives. All patients admitted having direct and sporadic exposure to systemic antibiotic solutions. Avoidance resulted in a significant improvement of ACD, but 1 patient had to change job. CONCLUSIONS: Occupational ACD caused by beta-lactam antibiotics, particularly cephalosporins, is significant in HCWs. Cross-reactions between beta-lactams are similar to those described in non-immediate drug eruptions. A relationship between systemic delayed drug hypersensitivity and ACD, as observed in one case, suggests that patients should avoid future use of the antibiotic to which they are sensitized. PMID- 29399805 TI - Risks of red blood cell alloimmunization in transfusion-dependent beta thalassemia in Oman: a 25-year experience of a university tertiary care reference center and a literature review. AB - BACKGROUND: beta-Thalassemia is a common hemoglobinopathy in the Arabian Peninsula. Red blood cell (RBC) transfusion is a cornerstone for its management, but can create significant challenges including RBC alloimmunization. Herein, we examine alloimmunization risk factors in Omani patients with transfusion dependent beta-thalassemia. Existing literature is summarized. STUDY DESIGN AND METHODS: A retrospective review of all patients attending our center over 25 years was performed. Clinical and transfusion records were examined. Chi-square test was used to assess the association between the categorical variables. Nonparametric Mann-Whitney test was used to assess the association between transfusion and risk of alloimmunization. RESULTS: A total of 268 patients were identified (168 adults and 100 pediatrics), of whom 226 are alive (84.3%). Males accounted for 53.4%. The cohort had a median age of 22 years (range, 2-43 years). The most common blood group was O+ (39%). The prevalence of alloimmunization was 9.3% with anti-E (24%) and anti-K (24%) being the commonest antibodies identified. There was a significant association between age and alloimmunization, with 68% of alloimmunized patients in the age group of 19 to 30 years (p < 0.01). Among adults, there was a significant association between alloimmunization and number of units transfused (p = 0.001). There was no association between alloimmunization and sex or history of splenectomy. CONCLUSION: Our study shows an association between alloimmunization and the age of the patients and number of units transfused. Transfusion support of this group of patients necessitates the availability of needed expertise and blood bank facilities. PMID- 29399807 TI - Ethylene-vinyl acetate foam as a new lung substitute in radiotherapy. AB - PURPOSE: The purpose of this study was to evaluate ethylene-vinyl acetate (EVA) foam as a new lung substitute in radiotherapy and to study its physical and dosimetric characteristics. METHODS: We calculated the ideal vinyl acetate (VA) content of EVA foam sheets to mimic the physical and dosimetric characteristics of the ICRU lung tissue. We also computed the water-to-medium mass collision stopping power ratios, mass attenuation coefficients, CT numbers, effective atomic numbers and electron densities for: ICRU lung tissue, the RANDO commercial phantom, scaled WATER and EVA foam sheets with varying VA contents in a range between the minimum and maximum values supplied by the manufacturer. For all these substitutes, we simulated percent depth-dose curves with EGSnrc Monte Carlo (MC PDDs) in a water-lung substitute-water slab phantom expressed as dose-to medium and dose-to-water for 3 * 3- and 10 * 10-cm2 field sizes. PDD for the 10 * 10-cm2 field size was also calculated with the MultiGrid Superposition algorithm (MGS PDD) for a relative electron density to water ratio of 0.26. The latter was compared with the MC PDDs in dose-to-water for scaled WATER and EVA foam sheets with the VA content that was most similar to the calculated ideal content that is physically achievable in practice. RESULTS: We calculated an ideal VA content of 55%; however, the maximum physically achievable content with current manufacturing techniques is 40%. The physical characteristics of the EVA foam sheets with a VA content of 40% (EVA40) are very close to those of the ICRU lung reference. The physical densities of the EVA40 foam sheets ranged from 0.030 to 0.965 g/cm3 , almost covering the entire physical density range of the inflated/deflated lung (0.260-1.050 g/cm3 ). Its mass attenuation coefficient at the effective energy of a 6-MV photon beam agrees within 0.8% of the ICRU reference value, and its CT number agrees within 6 HU. The effective atomic number for EVA40 varies by less than 0.42 of the ICRU value, and its effective electron density is within 0.9%. PDDs expressed in dose-to-medium and dose-to water agree with the ICRU curve within 2% in all regions. PDDs calculated with both MC and MGS were within 1.5%. CONCLUSIONS: The EVA40 is an excellent cork like lung substitute for radiotherapy applications. From a sole material used in footwear, it is possible to obtain a lung substitute that mimics the physical and dosimetric characteristics of ICRU lung tissue even better than the RANDO commercial phantom. PMID- 29399808 TI - Disease prevention and delayed aging by dietary sulfur amino acid restriction: translational implications. AB - Sulfur amino acids (SAAs) play numerous critical roles in metabolism and overall health maintenance. Preclinical studies have demonstrated that SAA-restricted diets have many beneficial effects, including extending life span and preventing the development of a variety of diseases. Dietary sulfur amino acid restriction (SAAR) is characterized by chronic restrictions of methionine and cysteine but not calories and is associated with reductions in body weight, adiposity and oxidative stress, and metabolic changes in adipose tissue and liver resulting in enhanced insulin sensitivity and energy expenditure. SAAR-induced changes in blood biomarkers include reductions in insulin, insulin-like growth factor-1, glucose, and leptin and increases in adiponectin and fibroblast growth factor 21. On the basis of these preclinical data, SAAR may also have similar benefits in humans. While little is known of the translational significance of SAAR, its potential feasibility in humans is supported by findings of its effectiveness in rodents, even when initiated in adult animals. To date, there have been no controlled feeding studies of SAAR in humans; however, there have been numerous relevant epidemiologic and disease-based clinical investigations reported. Here, we summarize observations from these clinical investigations to provide insight into the potential effectiveness of SAAR for humans. PMID- 29399809 TI - The differential expression of the blood group P1 -A4GALT and P2 -A4GALT alleles is stimulated by the transcription factor early growth response 1. AB - BACKGROUND: The P1 /P2 phenotypic polymorphism is one of the earliest blood groups discovered in humans. These blood groups have been connected to different levels of expression of the A4GALT gene in P1 and P2 red blood cells; however, the detailed molecular genetic mechanism that leads to these two phenotypes has not been established. STUDY DESIGN AND METHODS: After our previous identification of an association between the single-nucleotide polymorphisms (SNPs) rs2143918 and rs5751348 in A4GALT gene and the P1 /P2 phenotype, we conduct a survey of transcription factors that might connect these SNPs with the differential expression of the P1 -A4GALT and P2 -A4GALT alleles. An in silico analysis of potential transcription factor binding motifs within the polymorphic SNPs rs2143918 and rs5751348 genomic regions was performed, and this was followed by reporter assays examining the candidate transcription factors, gene expression profiling, electrophoretic mobility shift assays, and P1 -A4GALT and P2 -A4GALT allelic expression analysis. RESULTS: The results revealed that the differential binding of transcription factor early growth response 1 to the SNP rs5751348 genomic region with the different genotypes in the A4GALT gene leads to differential activation of P1 -A4GALT and P2 -A4GALT expression. CONCLUSION: The present investigation, together with our previous study (Lai et al., Transfusion 2014;54:3222-31), have elucidated the molecular genetic details associated with the P1 /P2 blood groups. PMID- 29399810 TI - Absorbed dose distributions from ophthalmic 106 Ru/106 Rh plaques measured in water with radiochromic film. AB - PURPOSE: Brachytherapy with 106 Ru/106 Rh plaques offers good outcomes for small to-medium choroidal melanomas and retinoblastomas. The dose measurement of the plaques is challenging, due to the small range of the emitted beta particles and steep dose gradients involved. The scarce publications on film dosimetry of 106 Ru/106 Rh plaques used solid phantoms. This work aims to develop a practical method for measuring the absorbed dose distribution in water produced by 106 Ru/106 Rh plaques using EBT3 radiochromic film. METHODS: Experimental setups were developed to determine the dose distribution at a plane perpendicular to the symmetry axis of the plaque and at a plane containing the symmetry axis. One CCA and two CCX plaques were studied. The dose maps were obtained with the FilmQA Pro 2015 software, using the triple-channel dosimetry method. The measured dose distributions were compared to published Monte Carlo simulation and experimental data. RESULTS: A good agreement was found between measurements and simulations, improving upon published data. Measured reference dose rates agreed within the experimental uncertainty with data obtained by the manufacturer using a scintillation detector, with typical differences below 5%. The attained experimental uncertainty was 4.1% (k = 1) for the perpendicular setup, and 7.9% (k = 1) for the parallel setup. These values are similar or smaller than those obtained by the manufacturer and other authors, without the need of solid phantoms that are not available to most users. CONCLUSIONS: The proposed method may be useful to the users to perform quality assurance preclinical tests of 106 Ru/106 Rh plaques. PMID- 29399811 TI - Novel JK allele background associated with production of anti-JK3 during pregnancy. PMID- 29399812 TI - Technical Note: On EM reconstruction of a multi channel shielded applicator for cervical cancer brachytherapy: A feasibility study. AB - PURPOSE: Electromagnetic tracking (EMT) is a promising technology for automated catheter and applicator reconstructions in brachytherapy. In this work, a proof of-concept is presented for reconstruction of the individual channels of a new shielded tandem (140 mm long shield) dedicated to intensity-modulated brachytherapy. METHODS: All six channels of a straight prototype were reconstructed using an electromagnetic (EM) system from Aurora (NDI, Waterloo, ON, Canada). The influence of the shield on the EMT system was characterized by taking measurements at nine different positions with and without the shielded part of the applicator next to the probe. A Student t-test was used to analyze the data. RESULTS: For registration purposes, the center-to-center distance (4 mm) was taken from the computed-assisted design (CAD) structure. The computed interchannel distances from the three opposite pairs were 4.33 +/- 0.40 mm, 4.14 +/- 0.35 mm, and 3.88 +/- 0.26 mm. All interchannel distances were within the geometrical tolerance in the shielded portion of the applicator (+/-0.6 mm) and account for the fact that the sensor (0.8 mm diameter) was smaller than the channel diameter. According to the paired Student t-test, the data given by the EM system with and without the shielded applicator tip are not significantly different. CONCLUSION: This study shows that the reconstruction of channel path is possible within the mechanical accuracy of the applicator. PMID- 29399813 TI - Textile contact dermatitis caused by octylisothiazolinone in compression stockings. PMID- 29399814 TI - FALDI-based decomposition of an atomic interaction line leads to 3D representation of the multicenter nature of interactions. AB - Atomic interaction lines (AILs) and the QTAIM's molecular graphs provide a predominantly two-center viewpoint of interatomic interactions. While such a bicentric interpretation is sufficient for most covalent bonds, it fails to adequately describe both formal multicenter bonds as well as many non-covalent interactions with some multicenter character. We present an extension to our Fragment, Atomic, Localized, Delocalized and Interatomic (FALDI) electron density (ED) decomposition scheme, with which we can measure how any atom-pair's delocalized density concentrates, depletes or reduces the electron density in the vicinity of a bond critical point. We apply our method on five classical bonds/interactions, ranging from formal either two- or three-center bonds, a non covalent interaction (an intramolecular hydrogen bond) to organometallic bonds with partial multicenter character. By use of 3D representation of specific atom pairs contributions to the delocalized density we (i) fully recover previous notion of multicenter bonding in diborane and predominant bicentric character of a single covalent C?C bond, (ii) reveal a multicenter character of an intramolecular H-bond and (iii) illustrate, relative to a Schrock carbene, a larger degree of multicenter M?C interaction in a Fischer carbene (due to a presence of a heteroatom), whilst revealing the holistic nature of AILs from multicenter ED decomposition. (c) 2018 Wiley Periodicals, Inc. PMID- 29399815 TI - Web-4D-QSAR: A web-based application to generate 4D-QSAR descriptors. AB - A web-based application is developed to generate 4D-QSAR descriptors using the LQTA-QSAR methodology, based on molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package. The LQTAGrid module calculates the intermolecular interaction energies at each grid point, considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. A friendly front end web interface, built using the Django framework and Python programming language, integrates all steps of the LQTA-QSAR methodology in a way that is transparent to the user, and in the backend, GROMACS and LQTAGrid are executed to generate 4D-QSAR descriptors to be used later in the process of QSAR model building. (c) 2018 Wiley Periodicals, Inc. PMID- 29399816 TI - Characterization and virus susceptibility of a continuous cell line derived from the brain of Aequidens rivulatus (Gunther). AB - Cell cultures derived from the brain tissues of Aequidens rivulatus (Gunther) have been characterized previously. In this study, a continuous cell line ARB8 was further established, and its growth characteristics, transcription and susceptibility to fish viruses-including chum salmon reovirus (CSV), marbled eel infectious pancreative necrosis virus (MEIPNV), grouper nervous necrosis virus (GNNV), giant seaperch iridovirus (GSIV), red seabream iridovirus (RSIV), koi herpesvirus (KHV), herpesvirus anguilla (HVA) and marbled eel polyoma-like virus (MEPyV)-were examined. ARB8 cells that showed epithelioid morphology and were passaged >80 times grew well at temperatures ranging from 25 degrees C to 30 degrees C in L-15 medium containing 5%-15% foetal bovine serum. The cells constitutively transcribed connexion 43, glutamine synthetase, nestin and nkx6-2, which are markers for neural progenitor cells. The cells were highly susceptible to CSV, MEIPNV, GSIV and RSIV and showed the typical cytopathic effect (CPE). However, the cells were resistant to GNNV, KHV, HVA and MEPyV because no significant CPE was noted after infection. Optimal temperatures for virus production ranged from 25 degrees C to 30 degrees C. The results revealed that the neural progenitor cell line ARB8 can potentially serve as a useful tool for investigating fish viruses and isolating new viruses in ornamental cichlid fishes. PMID- 29399817 TI - President's message: Maintaining the right vision. PMID- 29399818 TI - Laws and regulations of laser operation in the United States. AB - The laws and regulations governing laser operation in the United States are vague, complex, and vary state-to-state. The objective of this study is to present an overview of the laws and regulations of laser operation in each of the 50 states. We performed an extensive online search of the law in each of the 50 states by examining multiple state cosmetology boards, state legislative boards, state nursing boards, and state medical boards. Laser regulations are best divided into three categories: delegation, supervision, and operation. Our findings demonstrate the complicated nature of the regulations covering this issue and identify a lack of regulation in numerous states. Lasers Surg. Med. 50:272-279, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29399819 TI - Spirituality, infertility-related stress, and quality of life in Brazilian infertile couples: Analysis using the actor-partner interdependence mediation model. AB - Infertility has a stressful impact on both partners, with adverse effects on the quality of life of infertile couples. Spirituality is a meaning-based strategy that can protect couples against infertility's negative impact on quality of life, but analysis of this mediator relationship in infertile couples has not been reported. We adopted a dyadic approach and used the actor-partner interdependence mediation model to examine whether and how women's and men's spirituality was associated with their own and their partners' infertility related stress and quality of life. In 2014, 152 infertile couples starting their first fertility treatment at a private clinic in Brazil were recruited and completed self-reports of spirituality, infertility-related stress, and quality of life. Results indicated that women's and men's level of spirituality was positively associated with their own quality of life directly and indirectly, by reducing their own infertility-related stress. Their spirituality was associated with an increase in their partners' quality of life only indirectly, by reducing their partners' infertility-related stress. Findings highlight the importance of assessing and promoting spirituality as a coping resource that infertile women and men might use to deal with the stress of infertility and reduce its adverse effects on quality of life. PMID- 29399820 TI - Comparison of the periodic slab approach with the finite cluster description of metal-organic interfaces at the example of PTCDA on Ag(110). AB - We present a comparative study of metal-organic interface properties obtained from dispersion corrected density functional theory calculations based on two different approaches: the periodic slab-supercell technique and cluster models with 32-290 Ag atoms. Fermi smearing and fixing of cluster borders are required to make the cluster calculation feasible and realistic. The considered adsorption structure and energy of a PTCDA molecule on the Ag(110) surface is not well reproduced with clusters containing only two metallic layers. However, all clusters with four layers of silver atoms and sufficient lateral extension reproduce the adsorbate structure within 0.04 A with respect to the slab supercell structure and provide adsorption energies of ( -4.45+/- 0.08 eV) consistent with the slab result of -4.47 eV. Thus, metal-organic adsorbate systems can be realistically represented by properly defined cluster models. (c) 2018 Wiley Periodicals, Inc. PMID- 29399821 TI - Study of the affinity between the protein kinase PKA and homoarginine-containing peptides derived from kemptide: Free energy perturbation (FEP) calculations. AB - Protein kinases (PKs) discriminate between closely related sequences that contain serine, threonine, and/or tyrosine residues. Such specificity is defined by the amino acid sequence surrounding the phosphorylatable residue, so that it is possible to identify an optimal recognition motif (ORM) for each PK. The ORM for the protein kinase A (PKA), a well-known member of the PK family, is the sequence RRX(S/T)X, where arginines at the -3 and -2 positions play a key role with respect to the primed phosphorylation site. In this work, differential affinities of PKA for the peptide substrate Kemptide (LRRASLG) and mutants that substitute the arginine residues by the unnatural peptide homoarginine were evaluated through molecular dynamics (MD) and free energy perturbation (FEP) calculations. The FEP study for the homoarginine mutants required previous elaboration of a CHARMM "arginine to homoarginine" (R2B) hybrid topology file which is available in this manuscript as Supporting Information. Mutants substituting the arginine residues by alanine, lysine, and histidine were also considered in the comparison by using the same protocol. FEP calculations allowed estimating the free energy changes from the free PKA to PKA-substrate complex (DeltaDeltaGE->ES ) when Kemptide structure was mutated. Both DeltaDeltaGS->ES values for homoarginine mutants were predicted with a difference below 1 kcal/mol. In addition, FEP correctly predicted that all the studied mutations decrease the catalytic efficiency of Kemptide for PKA. (c) 2018 Wiley Periodicals, Inc. PMID- 29399823 TI - Recent Publications of Interest. PMID- 29399822 TI - Automated error control in divide-and-conquer self-consistent field calculations. AB - In linear-scaling divide-and-conquer (DC) electronic structure calculations, a buffer region is used to control the error introduced by the DC approximation. In this study, an energy-based error estimation scheme is proposed for the DC self consistent field method with a two-layer buffer region scheme. Based on this scheme, a procedure to automatically determine the appropriate buffer region in the DC method is proposed. It was confirmed that the present method works satisfactorily in calculations of water clusters and proteins, although its performance was insufficient for the calculation of a delocalized graphene system. (c) 2018 Wiley Periodicals, Inc. PMID- 29399826 TI - Photodynamic therapy via navigational bronchoscopy for peripheral lung cancer in dogs. AB - OBJECTIVE: In the setting of lung cancer, photodynamic therapy (PDT) is typically used to treat centrally located endobronchial tumors. The development of navigational bronchoscopy has opened the potential for using PDT to treat peripheral lung tumors. However, there is limited information about the feasibility of this approach for treating peripheral lung cancers, and about its effects on surrounding healthy lung tissue. We studied the use of PDT delivered by electromagnetic navigational bronchoscopy to treat peripheral lung cancer in dogs. MATERIALS AND METHODS: Three dogs with peripheral lung adenocarcinomas were given intravenous porfimer sodium (Photofrin(r) [Pinnacle Biologics, Inc., Chicago, IL]) to photosensitize the tumors, then navigational bronchoscopy was used to deliver photoradiation. One week after PDT, the tumors and involved lung lobe were surgically excised and evaluated histologically. RESULTS: PDT was successful in all three dogs and was associated with tolerable and manageable adverse effects. Tissue sections from within PDT-treated tumors showed regions of coagulative central necrosis admixed with small numbers of inflammatory cells, and arterial thrombosis. Viable adenocarcinoma was seen in the surrounding areas. CONCLUSION: These results suggest that PDT can be successfully deployed to treat peripheral lung cancers using navigational bronchoscopy. Furthermore, damage to surrounding noncancerous tissues can be minimized with accurate placement of the optical fiber. Studies of this modality to treat peripheral lung cancers in humans may be warranted. Lasers Surg. Med. 50:483-490, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29399827 TI - Disinfection of an EMS/AHPND strain of Vibrio parahaemolyticus using ozone nanobubbles. PMID- 29399825 TI - Testing Tele-Savvy: Protocol for a randomized controlled trial. AB - Many informal caregivers of persons with dementia suffer adverse health consequences. Although established psychoeducation programs are known to benefit caregivers, attending in-person programs is challenging for them. To address this challenge, the Savvy Caregiver Program, an evidence-based psychoeducation program with demonstrated effectiveness for caregiving and disease-related outcomes, was transformed into an on-line program, Tele-Savvy. This article describes the rationale for and design of a prospective longitudinal randomized controlled trial (targeted N = 215), currently underway. The trial aims to establish Tele Savvy's efficacy in (i) reducing the negative effects of caregiving on caregivers; (ii) promoting care recipients' quality of life; (iii) improving caregiver mastery; and to explore (iv) Tele-Savvy's efficacy among caregivers of different races/ethnicities. The mediating role of mastery will be assessed. Participants are randomized to the active condition (immediate Tele-Savvy participation), attention control, or usual care. Participants in the two latter conditions will complete Tele-Savvy 6 months post-baseline. Multilevel mixed effects models will be used to examine changes in outcomes and to model group by time (months since baseline) interactions. The exploratory aim will be addressed using analysis of covariance and qualitative analysis. This trial's results may be used by healthcare and community organizations to implement Tele-Savvy in dementia care, increasing caregivers' access to this evidence-based intervention. PMID- 29399828 TI - A case report of spontaneous staphylococcal meningitis in a cynomolgus monkey. AB - This report describes a suppurative meningitis in a young cynomolgus. The animal had neutrophil aggregation in the subarachnoid space and hemorrhage in bilateral adrenal glands. Staphylococcus was identified by FISH in brain. To our knowledge, this is the first case of staphylococcal meningitis with Waterhouse-Friderichsen syndrome in a cynomolgus monkey. PMID- 29399824 TI - ATLANTIC MAMMAL TRAITS: a data set of morphological traits of mammals in the Atlantic Forest of South America. AB - Measures of traits are the basis of functional biological diversity. Numerous works consider mean species-level measures of traits while ignoring individual variance within species. However, there is a large amount of variation within species and it is increasingly apparent that it is important to consider trait variation not only between species, but also within species. Mammals are an interesting group for investigating trait-based approaches because they play diverse and important ecological functions (e.g., pollination, seed dispersal, predation, grazing) that are correlated with functional traits. Here we compile a data set comprising morphological and life history information of 279 mammal species from 39,850 individuals of 388 populations ranging from -5.83 to -29.75 decimal degrees of latitude and -34.82 to -56.73 decimal degrees of longitude in the Atlantic forest of South America. We present trait information from 16,840 individuals of 181 species of non-volant mammals (Rodentia, Didelphimorphia, Carnivora, Primates, Cingulata, Artiodactyla, Pilosa, Lagomorpha, Perissodactyla) and from 23,010 individuals of 98 species of volant mammals (Chiroptera). The traits reported include body mass, age, sex, reproductive stage, as well as the geographic coordinates of sampling for all taxa. Moreover, we gathered information on forearm length for bats and body length and tail length for rodents and marsupials. No copyright restrictions are associated with the use of this data set. Please cite this data paper when the data are used in publications. We also request that researchers and teachers inform us of how they are using the data. PMID- 29399829 TI - Hydride-Triel Bonds. AB - In this article, we present the results of our comprehensive studies of 72 dimers of the R3XXH?YR3Y type (X = Si, Ge; Y = B, Al, Ga; RX = H, Cl, Me; RY = H, F, Cl, Me) and featuring hydride-triel bonds (i.e., charge-inverted hydrogen bonds). Influence of X and Y atoms as well as RX and RY substituents on various properties of these dimers is investigated in detail. In particular the strength of the H?Y hydride-triel bonds is paid a close attention and it is shown that hydride-triel bonds can be strong enough to considerably determine structure and properties of molecular systems. In addition, properties of the investigated dimers are largely governed by the charge transfer from the Lewis base to the Lewis acid, which is particularly important if more bulky and polarizable RY and Y atoms are present in the YR3Y molecule. Several excellent linear (R2 close to 1) and exponential correlations between pairs of diverse parameters are presented. Few instances are discussed where somewhat unexpected bond paths exist between two atoms featuring partial negative charges (e.g., between hydride hydrogen and halogen and between lateral sides of two halogens) showing that in some cases a bond path prefers to link two closely spaced electron-rich atoms instead of two atoms that are expected to form a bond. (c) 2018 Wiley Periodicals, Inc. PMID- 29399830 TI - Electronic device generated light increases reactive oxygen species in human fibroblasts. AB - OBJECTIVES: Our skin is constantly exposed to light from solar radiation and electronic devices, which impact skin physiology and aging. The biological altering properties of ultraviolet (UV) solar radiation on skin have been well established. There is significant scientific and public interest on the effects of electronic device generated light (EDGL) on skin. Currently, the effects of EDGL on skin are largely unknown. EDGL includes UV, visible, and infrared light from consumer electronics such as smartphones, computers, and televisions. In this study, we measured the wavelength specific irradiance from electronic devices, and irradiated fibroblasts with white EDGL to determine changes in reactive oxygen species generation, apoptosis, and necrosis. METHODS: To determine the EDGL output of commonly used consumer electronic devices, we measured the irradiance from electronic devices at the manufacturers' recommended reading distances and at 1 cm. To determine the effect of EDGL on human skin cells, we irradiated AG13145 fibroblasts with EDGL for 1 hour at a distance of 1 cm and measured changes in reactive oxygen species generation, apoptosis, and necrosis. RESULTS: ROS increased significantly by 81.71%, 85.79%, and 92.98% relative to control following 1 hour of white EDGL from iPhone 8+, iPhone 6, and iPad (first generation), respectively. There was a non-significant change in apoptosis following irradiation with an iPhone 8+, iPhone 6, and iPad. Total necrosis was less than 2% for all treatment and control groups. CONCLUSIONS: Our results suggest that short exposures of EDGL increase ROS generation, but the long-term effects associated with repeated exposures of EDGL are unknown. As electronic devices become more widely used and integrated into society globally, we anticipate greater scientific research and general public interest on the effects of visible EDGL on skin. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29399831 TI - Interpretation of ANN-based QSAR models for prediction of antioxidant activity of flavonoids. AB - Quantitative structure-activity relationships (QSARs) built using machine learning methods, such as artificial neural networks (ANNs) are powerful in prediction of (antioxidant) activity from quantum mechanical (QM) parameters describing the molecular structure, but are usually not interpretable. This obvious difficulty is one of the most common obstacles in application of ANN based QSAR models for design of potent antioxidants or elucidating the underlying mechanism. Interpreting the resulting models is often omitted or performed erroneously altogether. In this work, a comprehensive comparative study of six methods (PaD, PaD2 , weights, stepwise, perturbation and profile) for exploration and interpretation of ANN models built for prediction of Trolox-equivalent antioxidant capacity (TEAC) QM descriptors, is presented. Sum of ranking differences (SRD) was used for ranking of the six methods with respect to the contributions of the calculated QM molecular descriptors toward TEAC. The results show that the PaD, PaD2 and profile methods are the most stable and give rise to realistic interpretation of the observed correlations. Therefore, they are safely applicable for future interpretations without the opinion of an experienced chemist or bio-analyst. (c) 2018 Wiley Periodicals, Inc. PMID- 29399832 TI - Autophagy is essential for the maintenance of amino acids and ATP levels during acute amino acid starvation in MDAMB231 cells. AB - : Autophagy plays a major role in the adaptive metabolic response of cancer cells during adverse conditions such as nutrient deprivation. However, specific data that assess metabolite profiles in context with adenosine triphosphate (ATP) availability and cell death susceptibility remain limited. Human breast cancer cells, MDAMB231, and normal breast epithelial cells, MCF12A, were subjected to short-term amino acid starvation and the cellular apoptotic and autophagic responses assessed. The role of autophagy in the control of cellular amino acid, ATP, free fatty acid, and glucose levels during amino acid starvation were compared. We demonstrate that breast cancer cells have an increased metabolic demand contributing to significant amino acid and ATP depletion in a nutrient poor environment. Upregulation of autophagy was important for the generation of amino acids and free fatty acids and maintenance of cellular ATP levels. In contrast to normal cells, breast cancer cells were unable to maintain the response after 12 hours of amino acid starvation. Regulation of autophagic activity in these environments had indirect consequences on cell death susceptibility. Overall, our data provide support for autophagy as an important survival mechanism capable of providing metabolic substrates when cancer cells are faced with nutrient-deprived environments. SIGNIFICANCE OF STUDY: The results obtained in this study helps to expand our current knowledge on how cells respond to environmental changes; the biochemical and metabolic consequences and the physiological processes activated in response. The environmental stress applied in this study is relevant to tumour physiology, and results can be translated to cancer therapeutic and clinical research areas, ultimately assisting in the specific targeting of cancer cells while avoiding harm to normal cells. PMID- 29399833 TI - Testing causal effects in observational survival data using propensity score matching design. AB - Time-to-event data are very common in observational studies. Unlike randomized experiments, observational studies suffer from both observed and unobserved confounding biases. To adjust for observed confounding in survival analysis, the commonly used methods are the Cox proportional hazards (PH) model, the weighted logrank test, and the inverse probability of treatment weighted Cox PH model. These methods do not rely on fully parametric models, but their practical performances are highly influenced by the validity of the PH assumption. Also, there are few methods addressing the hidden bias in causal survival analysis. We propose a strategy to test for survival function differences based on the matching design and explore sensitivity of the P-values to assumptions about unmeasured confounding. Specifically, we apply the paired Prentice-Wilcoxon (PPW) test or the modified PPW test to the propensity score matched data. Simulation studies show that the PPW-type test has higher power in situations when the PH assumption fails. For potential hidden bias, we develop a sensitivity analysis based on the matched pairs to assess the robustness of our finding, following Rosenbaum's idea for nonsurvival data. For a real data illustration, we apply our method to an observational cohort of chronic liver disease patients from a Mayo Clinic study. The PPW test based on observed data initially shows evidence of a significant treatment effect. But this finding is not robust, as the sensitivity analysis reveals that the P-value becomes nonsignificant if there exists an unmeasured confounder with a small impact. PMID- 29399834 TI - MOBILE-izing Adolescent Sexual and Reproductive Health Care: A Pilot Study Using a Mobile Health Unit in Chicago. AB - BACKGROUND: Adolescents experience numerous barriers to obtaining sexual and reproductive health care (SRHC). Mobile Health Units (MHUs) can remove some barriers by traveling to the community. This pilot study developed Mobile SRHC through an iterative process on an existing MHU and evaluated it among adolescents and providers. METHODS: Mobile SRHC was developed through a mixed method, multiphase study. Three key informant interviews with MHU providers, an adolescent needs assessment survey, and a Youth Model Development Session informed model development. Emergency contraception (EC), oral contraceptive pills (OCPs), and depot-medroxyprogesterone acetate (DMPA) were sequentially incorporated into MHU services. Administrative data assessed method distribution and surveys assessed patient satisfaction. RESULTS: Key informants held positive attitudes toward implementing Mobile SRHC into their practice. Needs assessment surveys (N = 103) indicated a majority was interested in learning about sexual health (66.0%) and obtaining birth control (54.4%) on an MHU. Over 3 months, 123 adolescents participated in Mobile SRHC. Seven packs and 9 prescriptions of EC, 8 3-month packs and 10 prescriptions of OCPs, and 5 injections and 5 prescriptions of DMPA were distributed. Ninety-two percent of adolescent participants reported they would recommend Mobile SRHC to friends. CONCLUSIONS: Mobile SRHC is a feasible approach for reproductive health care among adolescents. PMID- 29399836 TI - Corrigendum. PMID- 29399835 TI - Physical Activity and Energy Expenditure During an After-School Running Club: Laps Versus Game Play. AB - BACKGROUND: After-school programs (ASPs) have the potential to contribute to student physical activity (PA), but there is limited empirical evidence to guide program development and implementation. METHODS: We used pedometry to assess the overall effectiveness of an elementary school ASP running program relative to national and state PA recommendations and to compare 2 different formats (laps vs games) on PA and energy expenditure. RESULTS: Both running laps and running games contributed substantially to PA accrual and energy expenditure (overall 24.2 minutes of PA and 52.6 kcal during sessions averaging 37 minutes), but the formats provided different outcomes relative to PA intensity and energy expenditure. Overall PA% was higher on lap days, but MVPA% (moderate-to-vigorous PA) was higher on game days. Only game days met the stipulation that ASPs provide activities at an intensity in which MVPA% of PA >= 50%. CONCLUSIONS: Both running laps and running games in an ASP can contribute to PA accrual. ASP providers should weigh the demands and outcomes of program activities, and especially consider the quality of activities, students' feelings about them, and the implementation demands on instructors. PMID- 29399837 TI - Perceived Weight and Bullying Victimization in Boys and Girls. AB - BACKGROUND: Research suggests that perceived weight poses separate risks from objective weight on adolescents' risks of being bullied. We examined if the prevalence of bullying victimization differed by perceived and objective weight status, and how these associations varied by sex. METHODS: Data were analyzed for 6716 8th and 11th graders from the School Physical Activity and Nutrition project, a Texas statewide survey of public school students. Participants reported demographics, bullying victimization, and weight perceptions. Height and weight were measured. RESULTS: In the last 6 months, 10.8% of students reported being bullied. Nearly 70% of normal weight and overweight and 50% of obese adolescents perceived themselves as weighing the right amount. Perceiving oneself as weighing too little or too much was significantly associated with increased bullying victimization (p < .05 for both), whereas objective weight was not. Statistical interactions between perceived weight and sex were significantly associated with victimization (p < .05) among boys only; boys who perceived themselves as weighing too little had higher predicted probabilities of victimization. CONCLUSIONS: Perceived weight may play a greater role in bullying victimization than objective weight, especially among boys. Interventions to prevent bullying should consider adolescents' self-perceptions of weight to effectively identify those at greater risk for victimization. PMID- 29399838 TI - The School Contextual Effect of Sexual Debut on Sexual Risk-Taking: A Joint Parameter Approach. AB - BACKGROUND: Previous research has identified individual and school-level characteristics that are associated with sexual risk-taking, but the impact of school-level mechanisms on sexual risk-taking is not well understood. We examine the aggregated effects that early sex at the school level have on risky sexual behaviors. METHODS: We use 3 waves of data from the National Longitudinal Study of Adolescent Health. An individual's first sexual intercourse before age 15 was recorded along with various risky sexual behaviors at debut. Two variables at respondent's later stage of life were also included: having sex in exchange for drugs or money, and contraction of sexually transmitted disease (STD). Longitudinal analysis was conducted using a joint parameter model that tested unobserved school effects on individual behaviors simultaneously. RESULTS: An increase in early sexual initiation at the school level was associated with higher probability of sexual debut, along with increased involvement in sexual risk-taking controlling for student family background. CONCLUSIONS: School behavioral mechanisms are directly related to sexual health behaviors among youth. Our findings have implications for school-based interventions, education programs, and the role of parents. PMID- 29399839 TI - Sexting, Risk Behavior, and Mental Health in Adolescents: An Examination of 2015 Pennsylvania Youth Risk Behavior Survey Data. AB - BACKGROUND: Sexting, the sharing of sexually suggestive photos, may be a gateway behavior to early sexual activity and increase the likelihood of social ostracism. METHODS: Youth Risk Behavior Survey (N = 6021) data from 2015 among Pennsylvania 9th-12th grade students were used to examine associations between consensual and nonconsensual sexting and substance use, mental health, neighborhood safety, and demographic variables. RESULTS: Almost one-third (29%) of students reported consensual sexting, while 3% reported nonconsensual sexting. Female students were 49% less likely to report consensual sexting (OR = .69, 95% confidence interval [CI]: [0.54, 0.87]); consensual sexting was significantly more likely in students who reported depressive symptoms (OR = 1.39, 95% CI: [1.10, 1.75]), electronic bullying (OR = 1.46, 95% CI: [1.05, 2.04]), suicide attempts (OR = 1.96, 95% CI: [1.22, 3.17]), current tobacco use (OR = 1.99, 95% CI: [1.30, 3.03]), current alcohol use (OR = 4.23, 95% CI: [3.04, 5.89]), ever having sex (OR = 5.21, 95% CI: [3.87, 7.02]), and reported both ever having sex, and current alcohol use (OR = 7.74, 95% CI: [5.37, 11.14]). CONCLUSIONS: High school students, particularly men, that report sexting may be more likely to participate in other risk behaviors and experience negative mental health outcomes. Further research should clarify the temporality of links between sexting, cyberbullying, depression, and suicide to inform mental health screening and treatment availability in high schools. PMID- 29399840 TI - Drinker Identity: Key Risk Factor for Adolescent Alcohol Use. AB - BACKGROUND: Adolescent alcohol use continues to be a critical public health problem with both short- and long-term negative health consequences. Defining oneself in terms of alcohol, a drinking-related identity, has been shown to predict high levels of alcohol use. Because adolescence is the developmental period during which identity development is most salient, preventing the development of the drinker identity and early identification of youth who have a developing drinker identity may be important for prevention and early intervention. METHODS: We review the theory- and evidence-based literature about identity development and the effects of a drinker identity on alcohol use behaviors in adolescents, discuss potential determinants of the drinker identity, and discuss future implications for practice and research. RESULTS: There is some evidence that the drinker identity forms in early adolescence and becomes more well-developed during adolescence. The drinker identity predicts alcohol use behaviors both concurrently and over time in adolescence and young adulthood. There is also some evidence that early exposure to alcohol may contribute to formation of the drinker identity. CONCLUSIONS: Identity-based approaches may be promising strategies to identify adolescents who are at risk for alcohol use and to intervene with early prevention or treatment within the school setting. PMID- 29399841 TI - School Connectedness and Protection From Symptoms of Depression in Sexual Minority Adolescents Attending School in Atlantic Canada. AB - BACKGROUND: In examining associations of sexual orientation, school connectedness (SC), and depression, no studies have used a continuum of sexual orientation. Additionally, no study has examined whether individuals with higher SC within subgroups of the continuum of sexual orientation are protected from symptoms of depression when compared to others within their own group. Our study aimed to address these deficiencies. METHODS: Data were from a cross-sectional survey of 6643 public high school students. Logistic regression was used to determine if higher SC was associated with protection from symptoms of depression comparing students with minority sexual orientations to heterosexual students, and whether SC was protective within subgroups of orientation. RESULTS: Mean SC scores were higher in heterosexuals than in all other orientation subgroups. Except for bisexual boys, compared with being heterosexual, being in other subgroups of orientation was associated with symptoms of depression, independent of SC. In both sexes SC was protective against depression risk within all categories of orientation except mostly/100% homosexual girls. CONCLUSIONS: Within all subgroups of sexual orientation except mostly/completely homosexual girls, SC was protective for symptoms of depression, indicating its potential importance for prevention of depression in all students, including perhaps particularly those with minority orientation. PMID- 29399842 TI - Suicide Risk and Resiliency Factors Among Hispanic Teens in New Mexico: Schools Can Make a Difference. AB - BACKGROUND: Youth suicide is a serious public health problem in the United States. School environments, and the attention of school adults, are promising but minimally studied avenues for promoting mental health among students. METHODS: The 2013 New Mexico Youth Risk and Resiliency Survey data were analyzed to identify ways in which the school environment influences suicide attempts in a sample of Hispanic students. Factors examined were: relationships with school adults, speaking a language other than English at home, being born outside the United States and not having enough to eat. Odds ratios were used to measure relationships. RESULTS: Factors influencing suicide attempt were similar for boys and girls. The odds of suicide attempt declined by approximately one third as measures of positive relationships with school adults increased. Post-high school education plans also were protective. Being born outside the United States and not having enough to eat increased the odds of past-year suicide attempt. Speaking a language other than English at home was a weak risk factor for suicide attempt only among Hispanic girls. CONCLUSIONS: Teachers and other school adults can decrease suicide risk for Hispanic teens by forming supportive relationships with students. Special consideration should be given to providing free breakfast in schools. PMID- 29399843 TI - Longitudinal Examination of Aggression and Study Skills From Middle to High School: Implications for Dropout Prevention. AB - BACKGROUND: High school completion provides health and economic benefits. The purpose of this study is to describe dropout rates based on longitudinal trajectories of aggression and study skills using teacher ratings. METHODS: The sample consisted of 620 randomly selected sixth graders. Every year from Grade 6 to 12, a teacher completed a nationally normed behavioral rating scale. We used latent class mixture modeling to identify the trajectories. RESULTS: Participants followed 3 trajectories of aggression (Low, Medium Desisting, and High Desisting) and 5 trajectories of study skills (Low, Average-Low, Decreasing, Increasing, and High). Over three-quarters of the sample were in stable trajectories of study skills over time. Most students in the High Desisting Aggression group were in the Low Study Skills group, and all students in the High Study Skills group were in the Low Aggression group. The overall dropout rate was 17%, but varied dramatically across combined aggression and study skills groups, ranging from 2% to 50%. CONCLUSIONS: The results highlight the importance of early prevention that combines academic enhancement and behavioral management for reducing school dropout. PMID- 29399844 TI - Best Practices in Preparing School Health Education Teachers: The Need for Future Research-A Commentary. PMID- 29399845 TI - The blood flow characteristics of polypoidal choroidal vasculopathy and the choroidal remodelling process after photodynamic therapy. AB - OBJECTIVES: To investigate the blood flow characteristics of polypoidal choroidal vasculopathy (PCV) using optical coherence tomography angiography (OCTA) and to analyse photodynamic therapy (PDT) effects on choroidal remodelling in PCV. MATERIALS AND METHODS: Diagnostic indocyanine green angiography and OCTA were performed. All patients underwent PDT with full-dose verteporfin and were followed up with enhanced-depth imaging optical coherence tomography. RESULTS: At baseline, a branching vascular network (BVN) was clearly demonstrated in all patients with PCV who underwent OCTA examinations as opposed to polyps. Additionally, the choroidal thickness (266 [range: 74-456] um) showed a positive relationship with polyp size (0.59 [range: 0.33-0.94] mm2 , r = 0.679, P = 0.0022). The subfoveal choroidal thickness and choroidal thickness at polyp sites increased within 1 day after PDT and atrophied 1-3 months after PDT. CONCLUSIONS: The differences in imaging characteristics between BVNs and polyps on OCTA were presumably due to both blood turbulence (different flow orientations) within polyps and the velocities detectable on OCTA. Moreover, the choroidal remodelling effects of PDT in PCV suggested the occurrence of transitional reactive inflammatory choroidal vascular hyperpermeability and choroidal exudation. PCV involved the entire choroids rather than only focal lesions. Lasers Surg. Med. 50:427-432, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29399846 TI - Plasma phospholipid profiling of a mouse model of anxiety disorder by hydrophilic interaction liquid chromatography coupled to high-resolution mass spectrometry. AB - Glycerophospholipids (PLs), as amphipathic small molecules and the main constituents of biological membranes, play an important role in several cellular processes, even though their accurate identification from complex biological samples remains a challenge. In this paper, we report a fast and comprehensive HILIC-ESI-MS method for the analysis of glycerophospholipid classes using high resolution mass spectrometry in negative mode. The final method enabled the quantitative analysis of 130 endogenous PL species in mouse plasma. The application of the method developed was to find differences of plasma PL composition in a mouse model of anxiety disorder. In the case of four PL classes and 35 PL species, significant differences were observed comparing low anxiety related behavior with high anxiety-related behavior groups. The most characteristic trend was up-regulation in both the PL classes and PL species, and decreases were only detected in two phosphatidylcholines among 35 species in mice having elevated anxiety. PMID- 29399847 TI - Effects of myogenic precursor cells (C2C12) transplantation and low-level laser therapy on muscle repair. AB - OBJECTIVE: The aim of the present study was to evaluate the effects of myoblast inoculation in combination with photobiomodulation therapy (PBMT) on skeletal muscle tissue following injury. MATERIALS AND METHODS: Sixty-five Wistar rats were divided into five groups: Control-animals not submitted to any procedure; Injury-cryoinjury of the tibialis anterior muscle; HBSS-animals submitted to cryoinjury and intramuscular Hank's Balanced Salt Solution; Injury + Cells animals submitted to cryoinjury, followed by myogenic precursor cells (C2C12) transplantation; Injury + Cells + LLLT-animals submitted to cryoinjury, followed by myogenic precursor cells (C2C12) transplantation and PBMT (780 nm, 40 mW, 3.2 J in 8 points). The periods analyzed were 1, 3, and 7 days. The tibialis anterior muscle was harvest for histological analysis, collagen analysis, and immunolabeling of macrophages. RESULTS: No differences were found between the HBSS group and injury group. The Injury + Cells group exhibited an increase of inflammatory cells and immature fibers as well as a decrease in the number of macrophages on Day 1. The Injury + Cells + LLLT group exhibited a decrease in myonecrosis and inflammatory infiltrate at 7 days, but an increase in inflammatory infiltrate at 1 and 3 days as well as an increase in blood vessels at 3 and 7 days, an increase in macrophages at 3 days and better collagen organization at 7 days. CONCLUSION: Cell transplantation combined with PBMT led to an increase in the number of blood vessels, a reduction in myonecrosis and total inflammatory cells as well as better organization of collagen fibers during the skeletal muscle repair process. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29399848 TI - Evaluation of the Brachial Plexus With Shear Wave Elastography After Radiotherapy for Breast Cancer. AB - OBJECTIVES: The aim of this study was to analyze the elasticity characteristics of the brachial plexus by shear wave elastography (SWE) in patients receiving radiation therapy (RT) for breast cancer and to compare them with their contralateral brachial plexus to evaluate whether elasticity properties can be used as supporting findings for the early diagnosis of brachial plexus involvement in patients receiving RT. METHODS: A prospective analysis with electromyography and SWE was performed on 23 brachial plexuses of patients receiving RT for breast cancer and their contralateral brachial plexuses. An electromyographic device was used for nerve conduction studies. Evaluations were done by the same investigator, and superficial electrodes were used in the recordings. A quantitative analysis of the brachial plexus with SWE was performed, with values in kilopascals on a color scale ranging from 0 (red, soft) to 150 (dark blue, hard) kPa. RESULTS: Mean SWE values +/- SD were 51.0 +/- 14.0 kPa for the ipsilateral brachial plexuses of patients receiving RT and 18.0 +/- 4.2 kPa for the contralateral brachial plexuses. Statistically significant differences were observed between the groups in the analysis of SWE values (P < .001). No significant correlation was found between the nerve conduction parameters and elastographic values (P > .05). CONCLUSIONS: Shear wave elastography showed that the brachial plexuses of patients receiving RT were stiffer than the unaffected brachial plexuses. Brachial plexus stiffening may be associated with fibrotic processes. PMID- 29399849 TI - Comparison of the chromatographic fingerprint, multicomponent quantitation and antioxidant activity of Salvia miltiorrhiza Bge. between sweating and nonsweating. AB - Salvia miltiorrhiza Bge. is a traditional Chinese medicine applied in the treatment of various diseases in clinical practice. In the course of its processing, S. miltiorrhiza Bge. is usually processed by sweating. This study employed 10-component contents determination coupled with high-performance liquid chromatography (HPLC) fingerprint and antioxidant activity to investigate the effect of sweating on S. miltiorrhiza Bge. so as to evaluate the quality of S. miltiorrhiza Bge. The HPLC method was performed using C18 and 0.05% phosphoric acid aqueous solution-acetonitrile with a gradient elution system. It was validated for linearity, precision, repeatability, stability and recovery. Similarity analysis, principal components analysis and antioxidant activity assays were used to compare sweated S. miltiorrhiza Bge. (SSM) and nonsweated S. miltiorrhiza Bge. (NSSM). SSM and NSSM showed good similarities in HPLC fingerprint (>0.9), but principal components analysis could classify the HPLC fingerprint and 10-component quantitation analysis. Meanwhile, the antioxidant activity of SSM was significantly higher than that of NSSM (p < 0.01). The results of this study indicated that sweating could alter the content of chemical constituents in S. miltiorrhiza Bge., and could also improve its antioxidant activity. In addition, the method not only affords a viable strategy for comparing SSM and NSSM and assessing the quality of S. miltiorrhiza Bge., but also provides a reference for other herbal medicine that suffers from sweating. PMID- 29399850 TI - Three-Dimensional Shear Wave Elastography of Skeletal Muscle: Preliminary Study. AB - OBJECTIVES: Two-dimensional (2D) shear wave elastography (SWE) can measure the elasticity of skeletal muscle, tendons, and ligaments. Three-dimensional (3D) SWE has been used to detect breast cancer but has not been applied to the musculoskeletal system. This study aimed to investigate whether 3D SWE could be used in skeletal muscles in vivo. METHODS: The study enrolled 20 healthy volunteers at Beijing Chaoyang Hospital from August to October 2016. Two dimensional and 3D SWE scans were used to measure the Young modulus of the flexor carpi radialis in the relaxed state. Longitudinal and transverse scanning was performed. Data were analyzed by a 1-way analysis of variance/least significant difference post hoc test, a paired t test, and Bland-Altman plots. RESULTS: The participants included 10 male and 10 female volunteers with a mean age +/- SD of 25 +/- 5 years. The Young modulus did not differ between 3D and 2D SWE for the sagittal plane (longitudinal scanning, 34.9 +/- 5.7 versus 32.7 +/- 5.2 kPa; P = .096) or transverse plane (transverse scanning, 9.1 +/- 2.1 versus 9.2 +/- 1.6 kPa; P = .877). The Young modulus did not differ between sagittal, transverse, and coronal planes for 3D SWE longitudinal scanning (34.9 +/- 5.7, 34.3 +/- 5.8, and 34.8 +/- 5.9 kPa, respectively; P = .936) or 3D SWE transverse scanning (9.1 +/- 2.0, 9.1 +/- 2.1, and 8.8 +/- 2.1 kPa; P = .838). However, the Young modulus for each individual plane (sagittal, transverse, or coronal) differed significantly between longitudinal and transverse scanning (P < .001). CONCLUSIONS: Both 2D SWE and 3D SWE are suitable techniques for clinical use, depending on the examiner's experience/preference. However, 3D SWE provides a multiplanar/multislice view that better illustrates the spatial characteristics of muscle tissue. Three-dimensional SWE may be a new method for fully visualizing the musculoskeletal system. PMID- 29399851 TI - Ultrasound Strain Imaging to Assess the Biceps Brachii Muscle in Chronic Poststroke Spasticity. AB - OBJECTIVES: The aim of the study was to assess the feasibility of ultrasound strain imaging in characterizing the biceps brachii muscle in chronic poststroke spasticity. METHODS: We prospectively analyzed strain imaging data from bilateral biceps brachii muscles in 8 healthy volunteers and 7 patients with poststroke chronic spasticity. Axial deformations of the biceps brachii muscle and overlying subcutaneous tissue were produced by external compression using a sandbag (1.0 kg) attached to a transducer. The lengthening and shortening of the biceps brachii muscle and subcutaneous tissue were produced by manual passive elbow extension (from 90 degrees to 0 degrees ) and flexion (from 0 degrees to 90 degrees ), respectively. We used offline 2-dimensional speckle tracking to estimate axial and longitudinal strain ratios (biceps brachii strain/subcutaneous tissue strain), and the longitudinal tissue velocity of the biceps brachii muscle. Statistical analyses included analysis of variance for testing differences in strain imaging parameters among healthy, nonspastic, and spastic biceps brachii muscles, the Bonferroni correction for further testing differences in US strain imaging among paired groups (healthy versus spastic, nonspastic versus spastic, and healthy versus nonspastic), and the Pearson correlation coefficient for assessing the intraobserver reliability of performing strain imaging in stroke survivors. RESULTS: The differences in strain imaging parameters between healthy and spastic and between nonspastic and spastic biceps brachii muscles were significant at both 90 degrees elbow flexion and maximal elbow extension (P < .01). There was no significant difference in axial strain ratios at 90 degrees of elbow flexion or longitudinal tissue velocities between healthy and nonspastic muscles (P > .05). The intraobserver reliability of performing strain imaging in stroke survivors was good (r = 0.85; P < .01). CONCLUSIONS: Ultrasound strain imaging seems to be feasible for characterizing the biceps brachii muscle in chronic poststroke spasticity. PMID- 29399852 TI - Effects of training physicians in electronic prescribing in the outpatient setting on clinical, learning and behavioural outcomes: a cluster randomized trial. AB - AIMS: Electronic prescribing systems may improve medication safety, but only when used appropriately. The effects of task analysis-based training on clinical, learning and behavioural outcomes were evaluated in the outpatient setting, compared with the usual educational approach. METHODS: This was a multicentre, cluster randomized trial [EDUCATional intervention for IT-mediated MEDication management (MEDUCATE trial)], with physicians as the unit of analysis. It took place in the outpatient clinics of two academic hospitals. Participants comprised specialists and residents (specialty trainees, in the UK) and their patients. Training took the form of a small-group session and an e-learning. The primary outcome was the proportion of medication discrepancies per physician, measured as discrepancies between medications registered by physicians in the electronic prescribing system and those reported by patients. Clinical consequences were estimated by the proportion of patients per physician with at least one missed drug-drug interaction with the potential for causing adverse drug events. A questionnaire assessed physicians' knowledge and skills. RESULTS: Among 124 participating physicians, primary outcome data for 115 (93%) were available. A total of 1094 patients were included. A mean of 48% of registered medications per physician were discrepant with the medications that their patients reported in both groups (P = 0.14). Due to registration omissions, a mean of 4% of patients per physician had one or more missed drug-drug interactions with the potential to cause a clinically relevant adverse drug event in the intervention group, and 7% in controls (P = 0.11). The percentages of correct answers on the knowledge and skills test were higher in the intervention group (57%) compared with controls (51%; P = 0.01). CONCLUSION: The training equipped outpatient physicians with the knowledge and skills for appropriate use of electronic prescribing systems, but had no effect on medication discrepancies. PMID- 29399853 TI - Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. AB - The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (>=50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies. PMID- 29399854 TI - Antenatal Prediction of Neonatal Survival in Sacrococcygeal Teratoma. AB - OBJECTIVES: In sacrococcygeal teratoma, the presence of high-output cardiac failure resulting from arteriovenous shunting through the large tumor has been associated with an adverse outcome. The objective of this study was to determine whether the tumor size and cardiac biomarkers in cord blood can predict neonatal survival in sacrococcygeal teratoma. METHODS: The study population consisted of 25 neonates with sacrococcygeal teratoma. Tumor size was calculated by the ellipsoid formula using dimensions measured by antenatal ultrasound ([length * width * depth in cm] * 0.52= volume in cm3 ). To adjust the gestational age, the tumor volume index (tumor volume/biparietal diameter) was adopted in the analysis. Cardiac biomarkers for heart failure (N-terminal pro-B-type natriuretic peptide [NT-pro-BNP] and cardiac troponin T [cTnT]) were measured in cord blood taken at the time of delivery. RESULTS: The rate of neonatal death was 24% (6 of 25). The cases that resulted in neonatal death had a higher tumor volume index and higher concentrations of NT-pro-BNP and cTnT than those with survival. A tumor volume index of greater than 60 cm3 /cm, elevated NT-pro-BNP (>2000 pg/mL), and elevated cTnT (>0.08 ng/mL) had sensitivity of 100% for prediction of neonatal death. CONCLUSIONS: The tumor volume index and cord blood biomarkers for heart failure can be promising prognostic markers for neonatal survival in sacrococcygeal teratoma. PMID- 29399855 TI - The frequency spectrum of bladder non-voiding activity as a trigger-event for conditional stimulation: Closed-loop inhibition of bladder contractions in rats. AB - AIMS: To test the hypothesis that the frequency of bladder non-voiding contractions (NVCs) can be used as a trigger event for closed-loop conditional inhibition of detrusor contractions via tibial nerve (TN) or dorsal penile nerve (DPN) stimulation. METHODS: In urethane anaesthetized male Wistar rats, the bladder was filled continuously with saline to evoke contractions. To test the plausibility of conditional inhibition via the TN, electrical stimulation was switched on manually when the pressure increased above a threshold of 10 cmH2 0 above the baseline. For testing conditional stimulation via the DPN, the pressure signal was continuously stored and a baseline threshold, the area under the curve (AUC) of the amplitude spectrum in the 0.2-20 Hz range of a 5 s window at the beginning of filling was calculated. When the AUC of subsequent pressure windows superseded the baseline threshold, the DPN was automatically stimulated. RESULTS: TN stimulation failed to inhibit evoked voiding contractions. The NVC frequency spectrum based DPN stimulation successfully inhibited 70% of the evoked contractions and resulted in a 45% increase in bladder capacity (BC). CONCLUSIONS: While, conditional TN stimulation failed to suppress bladder contractions, DPN stimulation, automatically triggered by an increased frequency of bladder non-voiding activity, resulted in bladder inhibition, and a consequential increase in BC. This study demonstrates the plausibility of using the frequency of NVCs as a trigger event for conditional inhibition of detrusor contractions. PMID- 29399856 TI - Case of atopic dermatitis concurrent with idiopathic thrombocytopenic purpura, whose serum thymus and activation-regulated chemokine level remained undetectable. AB - We report a 9-year-old Japanese female patient with atopic dermatitis associated with idiopathic thrombocytopenic purpura. She demonstrated high serum immunoglobulin (Ig)E and IgE specific to several environmental allergens, but extremely low serum thymus and activation-regulated chemokine (TARC) levels regardless of the disease progression. This case suggests platelets as the main source of serum TARC. PMID- 29399857 TI - Heterochrony in fringeheads (Neoclinus) and amplification of an extraordinary aggressive display in the Sarcastic Fringehead (Teleostei: Blenniiformes). AB - The Sarcastic Fringehead (Neoclinus blanchardi, Teleostei) exhibits an extreme version of a common aggressive display, the "gaping display," in which an open mouth is presented toward an opponent. Males of this species have extremely long jaws that extend posteriorly well past the posterior margin of the head and are flared laterally during the gaping display. In this study, we explored morphological traits related to this extraordinary display in this and related species of blennies. Morphological modifications include enlargement of the buccopalatal membrane, elongation of the maxilla via an uncalcified posterior extension, and evolution of a novel hinge between the anterior maxilla and lacrimal bones permitting lateral movement of the upper jaw. Geometric morphometry using the truss network system, thin-plate spline, and PCA of three closely related species of Neoclinus indicate that the elongate maxilla of N. blanchardi most likely evolved via acceleration (faster growth compared to outgroups) and hypermorphosis (continued growth to a larger body size), both forms of peramorphic heterochrony. Coloration and fluorescence of the buccopalatal membrane may also serve to amplify the extraordinary gaping display of the Sarcastic Fringehead. PMID- 29399858 TI - Pharmacological behaviour support for adults with intellectual disabilities: Frequency and predictors in a national cross-sectional survey. AB - OBJECTIVE: To report frequency and predictors of reported pharmacological behaviour support use among older adults with intellectual disabilities (ID) accessing dental care in Ireland. METHODS: Data from a nationally representative cross-sectional survey of adults with ID over 40 years of age allowed identification of the reported frequency of pharmacological behaviour support use. Predictors of pharmacological support were identified using multiple logistic regression. RESULTS: Most older adults with ID did not report the use of any pharmacological support to receive dental care: only 0.9% reported use of inhalation sedation; 2.4% intravenous (IV) sedation; 8.6% general anaesthesia (GA); and 16.0% oral sedation. Participants reporting challenging behaviour (OR = 1.9, 95% CI = 1.3-2.9), significant difficulty speaking (OR = 3.0, 95% CI = 1.8 4.8) and obvious oral problems (OR = 2.5, 95% CI = 1.6-4.1) had greater odds of reporting pharmacological, that is, GA or conscious sedation (CS), rather than nonpharmacological supports for dental care, compared to those who were not. CONCLUSIONS: People with ID report a diverse range of support use, with many using GA or CS, particularly oral sedation, for dental treatment. This highlights a need for training and governance for dentists who provide this care. Patients who present with challenging behaviour, oral problems and, interestingly, difficulty with expressive communication are more likely to report use of pharmacological supports. The above has implications for dental service design and delivery for this population. PMID- 29399859 TI - Hyperleukocytosis in infant acute leukemia: a role for manual exchange transfusion for leukoreduction. AB - BACKGROUND: Hyperleukocytosis is a serious, life-threatening complication of pediatric acute leukemia that can cause neurologic injury, pulmonary leukostasis, metabolic derangements, and coagulopathy. Acute leukemia has the highest risk of mortality and morbidity at presentation when associated with hyperleukocytosis. Infant leukemia presents unique challenges and treatment considerations due to the disease itself and size and overall health of the patient. While medical management of hyperleukocytosis in older patients with acute leukemia has been described, including cytoreductive procedures with automated leukapheresis (AL) or manual whole blood (WB) exchange transfusion, very little data exist for standardized management of hyperleukocytosis in infant leukemia patients. CASE REPORTS: We describe four cases of infant acute leukemia presenting with hyperleukocytosis and leukostasis who each received manual WB exchange transfusions in conjunction with induction chemotherapy and review the existing literature on the use of procedural leukoreduction in infants with hyperleukocytosis. Special attention is given to challenges and technical aspects of leukapheresis in infants: when to perform manual WB exchange versus AL, optimal vascular access, blood product selection, exchange rates, and the monitoring for complications. Using published cases, we outline benefits versus risks of manual WB exchange and AL in infants less than 10 kg. CONCLUSION: If providers perform procedural leukoreduction, the literature and our experience demonstrate manual WB exchange transfusion is favored over AL in infants less than 10 kg because of technical and complication risks associated with AL. Additional studies are needed to understand the impact of cytoreduction on long term outcomes. PMID- 29399860 TI - Reproducibility of Lung-to-Head Ratio Ultrasound Measurements in Congenital Diaphragmatic Hernia. AB - OBJECTIVES: This study investigated the reproducibility of standardization of lung-to-head ratio measurements in congenital diaphragmatic hernia (CDH) at our center among sonographers after we standardized the method. METHODS: We reviewed ultrasound images of 12 fetuses with CDH at Mayo Clinic from 2010 to 2016. Nine operators (1 maternal-fetal medicine specialist with experience in measuring the lung-to-head ratio and 8 sonographers), who were blinded to previous findings, reviewed 33 selected images from 12 fetuses with left CDH. The method for lung-to head ratio measurement was standardized before starting the measurements. The lung-to-head ratio was assessed by different methods to obtain the lung areas: anteroposterior, longest, and area tracing. We evaluated the correlation between operators using the intraclass correlation coefficient (ICC). We also compared agreement between the sonographers and a physician with experience in measuring the lung-to-head ratio using a Bland-Altman analysis. RESULTS: The methods with the best interoperator reproducibility were the standardized anteroposterior lung to-head ratio (ICC, 0.69) and the standardized lung-to-head ratio tracing (ICC, 0.65) compared to the longest lung-to-head ratio (ICC, 0.56). The standardized lung-to-head ratio tracing had the best agreement among sonographers and the physician (bias, 0.11; limits of agreement, -0.27 to +0.49) than the anteroposterior lung-to-head ratio (bias, 0.35; limits of agreement, -0.13 to + 0.83) and the longest lung-to-head ratio (bias, 0.27; limits of agreement, -0.35 to +0.89). CONCLUSIONS: We demonstrated that the lung-to-head ratio tracing method has high interoperator reproducibility and the best agreement among the operators at our center. Further multicenter studies are necessary to confirm our results. PMID- 29399861 TI - Resolution of a Low-Lying Placenta and Placenta Previa Diagnosed at the Midtrimester Anatomy Scan. AB - OBJECTIVES: To identify the incidence and resolution rates of a low-lying placenta or placenta previa and to assess the optimal time to perform follow-up ultrasonography (US) to assess for resolution. METHODS: We conducted a retrospective cohort study of women with a diagnosis of a low-lying placenta or placenta previa at routine anatomic screening. Follow-up US examinations were reviewed to estimate the proportion of women who had resolution. A Kaplan-Meier survival curve was generated to estimate the median time to resolution. The distance of the placental edge from the internal cervical os was used to categorize the placenta as previa or low-lying (0.1-10 or >= 10-20 mm). A time-to event analysis was used to estimate predictive factors and the time to resolution by distance from the os. RESULTS: A total of 1663 (8.7%) women had a diagnosis of a low-lying placenta or placenta previa. The cumulative resolution for women who completed 1 or more additional US examinations was 91.9% (95% confidence interval, 90.2%-93.3%). The median time to resolution was 10 (interquartile range [IQR], 7-13) weeks. The distance from the internal cervical os was known for 658 (51.0%) women. The probability of resolution was inversely proportional to the distance from the internal os: 99.5% (>=10-20 mm), 95.4% (0.1-10 mm), and 72.3% (placenta previa; P < .001). The median times to resolution were 9 (IQR, 7-12) weeks for 10 to 20 mm, 10 (IQR, 7-13) weeks for 0.1 to 10 mm, and 12 (IQR, 9-15) weeks for placenta previa (P = .0003, log rank test). CONCLUSIONS: A low-lying placenta or placenta previa diagnosed at the midtrimester anatomy survey resolves in most patients. Resolution is near universal in patients with an initial distance from the internal os of 10 mm or greater. PMID- 29399862 TI - Comparing Percutaneous Dilatational Tracheostomy With Bronchoscopic and Ultrasound Guidance. PMID- 29399863 TI - Photodynamic therapy in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Photodynamic therapy (PDT) is a minimally invasive treatment for malignant tumors. The aim of this study was to determine the efficacy of PDT in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty three patients with HNSCC were treated with porfimer sodium-mediated PDT followed by intraoperative light activation at 630 nm via fiber optic microlens delivered after 48 hours of injection. RESULTS: The complete response (CR) rate was 72.7%, while the efficacy (CR + partial response) rate was 97.0%. The rate of good local control (i.e., CR without recurrence after PDT) achieved after the initial PDT (82.6%) was significantly higher than that achieved after the second or third PDT (10%); this rate remained at 62.1% without functional disturbance and disfigurement even after excluding four previously untreated patients. The final local control rate following PDT plus additional therapies was 73.8%. CONCLUSIONS: PDT is an effective therapy to treat HNSCC, and leads to an improved quality of life in patients with residual or recurrent disease. Lasers Surg. Med. 50:420-426, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29399864 TI - In-house monitoring of steroid hormone metabolites in urine informs breeding management of a giant anteater (Myrmechophaga tridactyla). AB - Although numbers of giant anteaters within North American facilities have been steadily increasing for the last 15 years, the population now exhibits an unstable age distribution with genetically valuable individuals nearing reproductive senescence. Contributing to this issue is the Association of Zoos and Aquariums (AZA) described lack of standardization of breeding introduction practices and high risk of female injury occurring during such pairings. This report describes the development of a successful breeding protocol at Cleveland Metroparks Zoo based on hormone monitoring and efficient communication between science and animal management teams that minimizes risk of female injury. By training a female giant anteater for urine sample and body weight data collection, staff members accurately predicted estrus, and timed breeding introductions to facilitate positive interactions between the male and female. Such training also allowed for careful monitoring of two pregnancies through parturition (169-184 days from breeding) and post-partum return to estrus (114 129 days from parturition). Urinary hormone monitoring revealed a sharp progestogen increase averaging >five-fold over basal levels (0.52 +/- 0.05 ng/mg creatinine) which was sustained throughout the second half of pregnancy. Mean regular estrous cycle length (n = 14 cycles), was calculated as 46.17 +/- 1.39 days, measured as days between estrogen peaks of mean concentration 2.27 +/- 0.19 ng/mg creatinine. This report summarizes impressive collaborative efforts among multiple zoological departments to achieve extensive hormonal and body weight monitoring from a female giant anteater, adding valuable information on reproductive parameters, and specifics for novel hormone assay techniques. PMID- 29399866 TI - Tooth germ initiation patterns in a developing dentition: An in vivo study of Xenopus laevis tadpoles. AB - The transparency of soft tissue in Xenopus laevis tadpoles and the anterior posterior orientation of their developing tooth germs in the upper jaw offer a unique opportunity for the in vivo charting of the first 15-20 days of the developing dentition. Twenty-two X. laevis tadpoles were anesthetized daily and their mouths opened to record the first appearance, position, and development of tooth germs in the upper jaw. The initiation patterns revealed considerable variability between animals, and even between the jaw quadrants in the same animal. This variability appears within a structural boundary and the results are consistent with the presence of an odontogenic band. The final length of dental rows far exceeded the jaw growth for each quadrant during the recording period. This in vivo investigation underlines the limits of cross-sectional studies, and in particular the assumption that tooth germs initiate at the same position in the dental row. The tooth germ initiation patterns in this study did not align with the predictions of standard models for the development of the dentition Zahnreihen, Clone, and New Progress Zone theories. PMID- 29399865 TI - Efficacy of oral cholecalciferol on rhododendrol-induced vitiligo: A blinded randomized clinical trial. AB - Rhododendrol (RD), 4-(4-hydroxyphenyl)-2-butanol, inhibits melanin synthesis and has been used for skin-whitening cosmetic products. RD has been very effective in lightening skin pigmentation, but some persons have developed so-called RD vitiligo, in which vitiligo starts on the face, neck and hands where topical RD has been applied and even extended over skin areas where RD has not been applied. RD vitiligo lesions in some patients have lasted for years and have been resistant to conventional vitiligo treatments. We examined the effects of cholecalciferol on RD vitiligo in a blinded randomized clinical trial. Forty eight female RD vitiligo patients were recruited for the trial and were randomized into two groups: the vitamin D (VD)-intervention group that received daily 5000 IU cholecalciferol for 5 months and the control group. Three blinded investigators scored vitiligo improvement by comparing photographic images of baseline and at 5-month observation. Serum 25(OH)D3 of RD vitiligo patients was not significantly different from age-matched healthy volunteers. Twenty-two in the VD-intervention group and 23 in the control group completed the 5-month observation. Serum 25(OH)D3 levels were significantly increased after the 5-month VD intervention, while the control group did not change. The improvement scores were significantly higher in the VD-intervention group than the control group. The improvement scores were positively correlated with the serum 25(OH)D3 levels after the 5-month intervention period but not before the treatment. This blinded randomized clinical trial showed favor in administrating 5000 IU cholecalciferol daily to RD vitiligo patients. PMID- 29399867 TI - Evaluation of fetal heart geometry during pregnancy by three-dimensional ultrasound using the STIC rendering mode. AB - OBJECTIVE: To determine fetal heart geometry during pregnancy using three dimensional (3D) ultrasound and the spatiotemporal image correlation (STIC) rendering mode. METHODS: This prospective, cross-sectional study evaluated 250 normal singleton pregnancies from 20 to 33 weeks and 6 days of gestation. STIC rendering was used to calculate the eight angles of the fetal heart: apex, base, mitral valve, tricuspid valve, left ventricle, right ventricle, left atrium, and right atrium angles. The concordance correlation coefficient (CCC) was used for intra- and inter-observer tests. RESULTS: The average +/- SD maternal age was 31.7 +/- 4.9 years, and the average gestational age was 26.3 +/- 4.2 weeks. There was little variation in fetal heart angles using STIC rendering according to the gestational age, with determination coefficient (R2 ) values of 0.01 for the apex and mitral valve angles and <0.01 for the base, tricuspid valve, left ventricle, right ventricle, left atrium, and right atrium angles. Moderate/good intra- and inter-observer concordance was observed for the measurement of fetal heart angles using STIC rendering, and the obtained CCC varied from 0.74 to 0.93. CONCLUSION: The fetal heart geometry did not present significant variations during pregnancy using 3D ultrasound and the STIC rendering mode. PMID- 29399868 TI - Transesophageal echocardiography for the assessment of left atrial appendage thrombus: Study of the additional value of systematic real time 3D imaging after regular 2D evaluation. AB - BACKGROUND: Two-dimensional transesophageal echocardiography (2DTEE) is currently validated for left atrial appendage (LAA) thrombus assessment but has some limitations. AIMS: To evaluate the performance and interest of systematic real time three-dimensional transesophageal echocardiography (3DTEE) for LAA thrombus assessment, when performed after 2DTEE. METHODS AND RESULTS: Consecutive patients undergoing TEE were prospectively included. LAA was first evaluated using 2DTEE, and patients were classified as "2D-NT" if no thrombus was found, "2D-T" in case of clear thrombus, or "2D-EQ" if equivocal. Then, 3DTEE of the LAA was performed and patients were similarly classified as "3D-NT," "3D-T," or "3D-EQ." Additional LAA CT scan was only performed if LAA thrombus was not clearly ruled out or confirmed by TEE. Additional value of 3DTEE after 2DTEE LAA evaluation was then assessed. We included 104 patients undergoing TEE. Agreement between 2DTEE and 3DTEE was very good for thrombus diagnosis (k = 0.936), but moderate for vacant LAA (k = 0.562) due to more frequent 2D-EQ than 3D-EQ (11.5% vs 2.9%; P = .016). 3DTEE allowed to refine the LAA status in 11 of 12 (91.7%) 2D-EQ patients: 10 3D NT, 1 3D-T, and 1 3D-EQ. Coupling 3DTEE to 2DTEE permitted a definite LAA diagnosis in 103 of 104 (99%) vs 92 of 104 (88.5%) patients when 2DTEE was used alone (P = .002). Nine (8.7%) LAA thrombi were diagnosed, and 3 CT scan were performed. CONCLUSION: 3DTEE of the LAA is more effective for thrombus assessment than 2DTEE. 3DTEE should be particularly considered in case of equivocal 2DTEE, as it allows to reach a definite LAA diagnosis in almost all of the patients. PMID- 29399869 TI - Deep learning with domain adaptation for accelerated projection-reconstruction MR. AB - PURPOSE: The radial k-space trajectory is a well-established sampling trajectory used in conjunction with magnetic resonance imaging. However, the radial k-space trajectory requires a large number of radial lines for high-resolution reconstruction. Increasing the number of radial lines causes longer acquisition time, making it more difficult for routine clinical use. On the other hand, if we reduce the number of radial lines, streaking artifact patterns are unavoidable. To solve this problem, we propose a novel deep learning approach with domain adaptation to restore high-resolution MR images from under-sampled k-space data. METHODS: The proposed deep network removes the streaking artifacts from the artifact corrupted images. To address the situation given the limited available data, we propose a domain adaptation scheme that employs a pre-trained network using a large number of X-ray computed tomography (CT) or synthesized radial MR datasets, which is then fine-tuned with only a few radial MR datasets. RESULTS: The proposed method outperforms existing compressed sensing algorithms, such as the total variation and PR-FOCUSS methods. In addition, the calculation time is several orders of magnitude faster than the total variation and PR-FOCUSS methods. Moreover, we found that pre-training using CT or MR data from similar organ data is more important than pre-training using data from the same modality for different organ. CONCLUSION: We demonstrate the possibility of a domain adaptation when only a limited amount of MR data is available. The proposed method surpasses the existing compressed sensing algorithms in terms of the image quality and computation time. PMID- 29399870 TI - Assessment of myocardial strain in children with risk factors for atherosclerosis with use of 3D speckle tracking echocardiography. AB - BACKGROUND: The known risk factors for atherosclerosis such as dyslipidemia, hypertension, obesity, and fasting hyperglycemia are associated with subclinical myocardial dysfunction. We assessed myocardial strain in children who had risk factors for atherosclerosis with use of 3D speckle tracking echocardiography (3DSTE). METHODS: A total of 340 eligible children (mean age [+/-SD]: 9.5 [+/ 1.9] years; range, 7.1-12.2; 189 males, 151 females). Levels of serum cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) were investigated. The parameters of left ventricular (LV) myocardial strain including global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were measured with use of real time 3DSTE. RESULTS: Left ventricular (LV) global longitudinal strain and global circumferential strain in the groups with isolated dyslipidemia, isolated hypertension, isolated obese/overweight, and combination groups were lower than those in healthy controls (P < .01 for all). Global longitudinal strain (GLS) and GCS showed a negative correlation with the respective risk factors (TG, TC, and LDL-C; SBP and DBP; weight and BMI) (P < .05 for all). Multiple stepwise regression analysis showed a significant negative correlation of GLS and GCS with BMI, TC, TG, and SBP. The degree of myocardial strain aggravated significantly with increase in the number of risk factors in an individual subject. PMID- 29399871 TI - The correlation between cardiac magnetic resonance T2* and left ventricular global longitudinal strain in people with beta-thalassemia. AB - BACKGROUND: Heart failure is the biggest cause of mortality and morbidity in people with thalassemia, and iron deposition in cardiac tissue impairs cardiovascular function. Therefore, early detection of cardiac involvement is important to improve the prognosis in these individuals. METHOD: Two- and three dimensional echocardiography was performed to evaluate left ventricular ejection fraction (LVEF), left ventricular volumes and diameters, and global longitudinal strain (GLS) in 130 individuals with beta-thalassemia using the speckle tracking method. Magnetic resonance imaging (MRI) was carried out on both the heart and liver. The participants were divided into 2 groups based on cardiac T2* values (normal and abnormal cardiac iron load), and the correlation between cardiac T2* MRI and GLS was evaluated. RESULTS: The statistical analysis showed a significant correlation between cardiac T2* MRI and left ventricular global longitudinal strain. There was a significant difference in global longitudinal strain (P < .0001), liver MRI T2*( P < .0001), and left ventricular ejection fraction (P < .001) between the 2 groups. The optimal cutoff value for GLS was -18.5% with sensitivity and specificity 73.0% and 63.0%, respectively (postitive predictive value = 50%, negative predictive value = 82.3%, AUC = 0.742, std. error = 0.046) which predicts T2* value of <20 ms, according to cardiac MRI. CONCLUSIONS: The participants with cardiac iron overload had a lower GLS than those without one. This suggests that GLS may be a useful method to predict myocardial iron overload particularly in beta-thalassemia patients with subclinical cardiac involvement. PMID- 29399872 TI - Left ventricular myocardial performance index in prediabetic patients without coronary artery disease. AB - INTRODUCTION: Prediabetes is a high-risk condition for diabetes mellitus type 2, which is an important public health issue. The myocardial performance index (MPI) is a noninvasive Doppler measurement of global ventricular function. We evaluated the MPI and left ventricular (LV) function in prediabetic patients who did not have coronary artery disease. METHODS: In total, 80 prediabetics (34 females and 46 males) and an equal number of sex-matched healthy volunteers (35 females and 45 males) were enrolled prospectively. All subjects underwent laboratory analyses and echocardiographic examinations, including MPI measurements. RESULTS: There was a moderate increase in MPI between healthy controls and prediabetics (P < .001). Prediabetes was strongly associated with MPI (r = .553, P < .001). We found that MPI was associated with prediabetes on multivariate logistic regression analysis (Odds Ratio (OR) = 1.967, 95% confidence interval [CI] = 1.574-2.459, P < .001). CONCLUSIONS: The results of this study show that systolic functions and LV diastolic parameters were adversely affected in prediabetic patients. Prediabetes is closely associated with subclinical LV systolic and diastolic dysfunction as assessed by MPI. PMID- 29399873 TI - Bicuspid aortic valve morphology and its impact on aortic diameters-A systematic review with meta-analysis and meta-regression. AB - AIM: To evaluate the impact of the 2 most common bicuspid aortic valve (BAV) morphology patterns [right-left (RL) vs right-noncoronary (RN) cusp fusion] on the aortic diameters and the impact of gender, aortic stenosis (AS), aortic regurgitation (AR), and age on the observed effects. METHODS: The PubMed databases was searched up to December 31, 2016 to identify studies investigating the morphology of BAV and aortic diameters. Inclusion criteria were as follows: the data on diameter of sinuses of Valsalva (SVD) and/or ascending aorta (AAD) and BAV morphology. The additional characteristics [gender, AS and AR (% of patients with moderate or severe AS/AR) and mean age] were collected to perform a meta-regression analysis. RESULTS: A total of 12 studies with 2192 patients with indexed AAD, 15 studies with 3104 patients with nonindexed AAD and 8 studies with 1271 patients with indexed SVD, and 16 studies with 3454 patients with nonindexed SVD were included. There was no difference between RL and RN group in indexed/nonindexed AAD-mean difference (MD): 0.06 mm/m2 (95% CI: -0.65 to 0.77 mm/m2 , P = .87) and -0.06 mm (95% CI: 1.10-0.97 mm, P = .91). Differently, the RL BAV was associated with larger indexed/nonindexed SVD than RN phenotype-MD: 1.66 mm/m2 (95% CI: 0.83-2.49 mm/m2 , P < .001) and 2.03 mm (95% CI: 0.97-3.09 mm, P < .001). Age, gender, AS, and AR had no influence on observed differences. CONCLUSIONS: RL BAV phenotype is associated with larger SVD than RN BAV, and the observed differences are independent from aortic valve dysfunction degree, age, and gender. PMID- 29399874 TI - T1 -based sensing of mammographic density using single-sided portable NMR. AB - PURPOSE: A single-sided NMR instrument was used to investigate the ability of the T1 relaxation constant to distinguish between regions of low and high mammographic density in human breast tissue. METHODS: Measurements were performed on 5 breast slices obtained from 3 women undergoing breast reduction surgery or prophylactic mastectomy. RESULTS: T1 values measured in regions of high mammographic density in both the full breast slices (T1 = 170 +/- 30 ms) and excised regions (T1 = 160 +/- 30 ms) were found to be significantly different (P < .001) from those measured in regions of low mammographic density, in which T1 = 120 +/- 10 ms was observed both in full slices and excised regions. There was no statistically significant difference between the T1 values measured in the full breast slices and those measured in the excised regions. CONCLUSION: The findings suggest that portable NMR may provide a low-cost means of assessing mammographic density in vivo. PMID- 29399876 TI - Extracellular proteases of Staphylococcus epidermidis: roles as virulence factors and their participation in biofilm. AB - Staphylococci produce a large number of extracellular proteases, some of which are considered as potential virulence factors. Staphylococcus epidermidis is a causative agent of nosocomial infections in medical devices by the formation of biofilms. It has been proposed that proteases contribute to the different stages of biofilm formation. S. epidermidis secretes a small number of extracellular proteases, such as serine protease Esp, cysteine protease EcpA, and metalloprotease SepA that have a relatively low substrate specificity. Recent findings indicate a significant contribution of extracellular proteases in biofilm formation through the proteolytic inactivation of adhesion molecules. The objective of this work is to provide an overview of the current knowledge of S. epidermidis' extracellular proteases during pathogenicity, especially in the different stages of biofilm formation. PMID- 29399875 TI - Perioperative management of a redo aortic root replacement in a patient with severe factor XI deficiency. AB - Factor XI deficiency is associated with significant bleeding in the setting of trauma and surgery. We present a patient with FXI deficiency and multiple red blood cell allo-antibodies requiring repeat aortic root replacement and discuss the perioperative management of patients with FXI deficiency undergoing cardiac surgery. PMID- 29399877 TI - Acute humoral rejection in an infant without risk factors after heart transplantation. AB - Graft rejection is the most common factor that limits graft survival after transplantation. During infancy, the humoral immune system is partially suppressed and humoral rejection of a cardiac allograft has not been reported in the absence of risk factors such as prior transplantation, blood transfusions, ventricular assist devices, and elevation of panel reactive antibodies. We present a case of an infant with dilated cardiomyopathy who developed multiple episodes of acute humoral rejection after heart transplantation in the absence of risk factors. PMID- 29399878 TI - Incremental prognostic value of multichamber deformation imaging and renal function status to predict adverse outcome in heart failure with reduced ejection fraction. AB - AIMS: Deformation imaging, particularly of left-sided heart, is fast becoming an essential tool in clinical cardiology. However, data are scant regarding the value of biventricular and bi-atrial deformation in association with comorbidities in heart failure with reduced left ventricular ejection fraction (HFREF). METHODS AND RESULTS: Forty-nine subjects (72 +/- 13 years; 28 male) with HFREF and 14 age-matched controls underwent deformation imaging including LV global longitudinal strain (LVGLS%), right ventricular strain (RVS%), and left atrial reservoir strain (LARS%). Standard echo parameters included LVEF%, E/E' ratio, and pulmonary artery systolic pressure (PASP). Mean +/- SD of LVEF, LVGLS%, and RVS% were 31% +/- 8%, 7% +/- 3%, and 17% +/- 7%, respectively, and were significantly lower compared with controls (all P < .0001). Over a follow-up period of 4.2 years, 24% of patients died and 48% had a composite outcome of death and heart failure hospitalization. In the logistic regression model, taking the composite of death and heart failure hospitalization as a dichotomous variable, RVS%, E/E' ratio, and PASP were the only significant univariate predictors of adverse outcome (R2 = .68, all P < .05). In the multivariate model, however, only PASP predicted adverse outcome. PASP also had the largest AUC (0.8) in the ROC analysis. A creatinine level of >88 MUmol/L (SCREAT) and a cutoff value of LA reservoir strain (LARS %) at <16.7% provided the best sensitivity (86%) and specificity (40%) with an odds ratio of 3.8. In the Kaplan Meier survival estimate, LARS%-SCREAT predicted all-cause mortality and HF hospitalization. CONCLUSION: Multichamber deformation imaging along with renal function and PASP could best predict adverse outcome in HFREF. PMID- 29399879 TI - Coexisting bicuspid aortic and pulmonary valves diagnosed by 3D transthoracic echocardiography. AB - Coexisting bicuspid aortic and pulmonary valves is an extremely rare condition, and there have been few published cases. Diagnosis of bicuspid aortic valve is straightforward with 2D echocardiography; however, analysis of the morphology of the pulmonary valve is challenging. In this study, we report on a case of a 32 year-old man with bicuspid aortic and pulmonary valves diagnosed by 2D and 3D transthoracic echocardiography. The enlarged pulmonary artery without any obvious etiology led us to suspect a pulmonary valve anomaly; thus, we comprehensively evaluated it with 2D and 3D echocardiography, which confirmed the diagnosis of bicuspid pulmonary valve. PMID- 29399880 TI - The microglial reaction signature revealed by RNAseq from individual mice. AB - Microglial cells have a double life as the immune cells of the brain in times of stress but have also specific physiological functions in homeostatic conditions. In pathological contexts, microglia undergo a phenotypic switch called "reaction" that promotes the initiation and the propagation of neuro-inflammation. Reaction is complex, molecularly heterogeneous and still poorly characterized, leading to the concept that microglial reactivity might be too diverse to be molecularly defined. However, it remains unknown whether reactive microglia from different pathological contexts share a common molecular signature. Using improved flow cytometry and RNAseq approaches we studied, with higher statistical power, the remodeling of microglia transcriptome in a mouse model of sepsis. Through bioinformatic comparison of our results with published datasets, we defined the microglial reactome as a set of genes discriminating reactive from homeostatic microglia. Ultimately, we identified a subset of 86 genes deregulated in both acute and neurodegenerative conditions. Our data provide a new comprehensive resource that includes functional analysis and specific molecular markers of microglial reaction which represent new tools for its unambiguous characterization. PMID- 29399881 TI - A novel image processing workflow for the in vivo quantification of skin microvasculature using dynamic optical coherence tomography. AB - BACKGROUND: Currently, imaging technologies that can accurately assess or provide surrogate markers of the human cutaneous microvessel network are limited. Dynamic optical coherence tomography (D-OCT) allows the detection of blood flow in vivo and visualization of the skin microvasculature. However, image processing is necessary to correct images, filter artifacts, and exclude irrelevant signals. The objective of this study was to develop a novel image processing workflow to enhance the technical capabilities of D-OCT. MATERIALS AND METHODS: Single center, vehicle-controlled study including healthy volunteers aged 18-50 years. A capsaicin solution was applied topically on the subject's forearm to induce local inflammation. Measurements of capsaicin-induced increase in dermal blood flow, within the region of interest, were performed by laser Doppler imaging (LDI) (reference method) and D-OCT. RESULTS: Sixteen subjects were enrolled. A good correlation was shown between D-OCT and LDI, using the image processing workflow. Therefore, D-OCT offers an easy-to-use alternative to LDI, with good repeatability, new robust morphological features (dermal-epidermal junction localization), and quantification of the distribution of vessel size and changes in this distribution induced by capsaicin. The visualization of the vessel network was improved through bloc filtering and artifact removal. Moreover, the assessment of vessel size distribution allows a fine analysis of the vascular patterns. CONCLUSION: The newly developed image processing workflow enhances the technical capabilities of D-OCT for the accurate detection and characterization of microcirculation in the skin. A direct clinical application of this image processing workflow is the quantification of the effect of topical treatment on skin vascularization. PMID- 29399882 TI - Urothelial tumors with villous morphology: Histomorphology and role of immunohistochemistry in diagnosis. AB - Villous adenoma and urothelial carcinoma with villoglandular differentiation (UCVGD) are rare urothelial tumours showing villous morphology, the former being a preneoplastic entity and the latter being a malignant one. The detailed immunohistochemistry of these entities is previously not described in the literature. Moreover, a limited biopsy sample of UCVGD or a villous adenoma with or without adenocarcinoma may be difficult to distinguish on the basis of the histomorphology alone. An immunohistochemical panel comprising of GATA3, p63, beta-catenin, CK7 and CK20 was performed on five cases of UCVGD and three cases of villous adenoma with the aim of studying the expression of the proteins thereby aiding in the diagnosis of these entities in a limited surgical pathology specimen. The mean age of UCVGD was 66.8 years and all the patients were male. All the cases of UCVGD were associated with high grade papillary urothelial carcinoma with lamina propria invasion. The immunohistochemical panel showed strong nuclear GATA3 expression in the urothelial component of UCVGD. Interestingly, the high grade and the low grade villoglandular components of UCVGD also expressed GATA3 (nuclear) with a progressive loss of expression from the high grade to the low grade component. The villous adenomas showed negativity or aberrant cytoplasmic positivity for GATA3. The beta-catenin showed a gradual loss of membranous expression from villous adenoma to low grade and high grade villoglandular components of UCVGD with a patchy membranous expression in the urothelial component of the UCVGD. p63 showed strong nuclear positivity in the urothelial component and uniform negativity in the villous adenoma and villoglandular component of UCVGD irrespective of its grade, thereby distinguishing the villoglandular component from the urothelial component. The urothelial component of UCVGD showed strong membranous CK7 expression and was higher than the CK20 expression in the urothelial component. In contrast, CK20 expression was higher in villous adenoma as compared to CK7. There was no difference in the expression of CK7 and CK20 in the villoglandular components and low grade and high grade villoglandular areas. The above-mentioned immunohistochemical pattern may help to distinguish the UCVGD from the villous adenoma. PMID- 29399883 TI - DNA damage-induced apoptosis and mitogen-activated protein kinase pathway contribute to the toxicity of dronedarone in hepatic cells. AB - Dronedarone, an antiarrhythmic drug, has been marketed as an alternative to amiodarone. The use of dronedarone has been associated with severe liver injury; however, the mechanisms remain unclear. In this study, the possible mechanisms of dronedarone induced liver toxicity were characterized in HepG2 cells. Dronedarone decreased cells viability and induced apoptosis and DNA damage in a concentration and time-dependent manner. Pretreatment of the HepG2 cells with apoptosis inhibitors (caspase-3, -8, and -9) or the necrosis inhibitor (Necrox-5), partially, but significantly, reduced the release of lactate dehydrogenase. Dronedarone caused the release of cytochrome c from mitochondria to cytosol, a prominent feature of apoptosis. In addition, the activation of caspase-2 was involved in dronedarone induced DNA damage and the activation of JNK and p38 signaling pathways. Inhibition of JNK and p38 by specific inhibitors attenuated dronedarone-induced cell death, apoptosis, and DNA damage. Additionally, suppression of caspase-2 decreased the activities of JNK and p38. Dronedarone triggered DNA damage was regulated by downregulation of topoisomerase IIalpha at both transcriptional and post-transcriptional levels. Taken together, our data show that DNA damage, apoptosis, and the activation of JNK and p38 contribute to dronedarone-induced cytotoxicity. Environ. Mol. Mutagen. 59:278-289, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29399884 TI - Effect of high-frequency near-infrared diode laser irradiation on periodontal tissues during experimental tooth movement in rats. AB - BACKGROUND AND OBJECTIVES: Tooth movement during orthodontic treatment is associated with bone neoplasticity and bone resorption on the tension and pressure sides. Previous clinical studies have suggested that low-power laser irradiation can accelerate tooth movement during orthodontic treatment, although the underlying mechanism remains unclear. In this study, we used a high-frequency near-infrared diode laser that generates less heat and examined the histologic changes in periodontal tissue during experimental tooth movement with laser irradiation. METHODS: A nickel-titanium closed coil was mounted between the maxillary left side first molar and incisor of rats to model experimental tooth movement. The laser-irradiation and the control groups were set, and the amount of movement of the first molar on 7th and 14th days after the start of pulling of the first molar tooth on the maxillary left was measured by three-dimensional analysis of uCT. After tooth movement, tissue samples from the mesial and tension sides were collected, and successive horizontal sections were prepared and examined using hematoxylin-eosin and TRAP staining and immunohistochemical staining for RANKL, OPG, ALP, and proliferating cell nuclear antigen (PCNA). Changes in tissue temperature following laser irradiation were also examined. RESULTS: Laser irradiation significantly increased tooth movement compared with non-irradiated controls. Histologic staining of the pressure-side mesial root in laser-irradiated rats revealed enhanced RANKL expression and increased numbers of TRAP-positive cells compared with controls. By contrast, on the tension side, laser irradiation led to increased expression of ALP and PCNA. These data indicate that high-frequency near-infrared diode laser irradiation on the pressure side upregulates RANKL expression and accelerates osteoclast differentiation, facilitating bone resorption, whereas bone formation is induced on the tension side. CONCLUSION: This study demonstrates that high-frequency near infrared diode laser irradiation of periodontal tissue leads to metabolic activation, which ultimately increases the rate of tooth movement. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29399885 TI - Comparison of late adverse events after endoscopic sphincterotomy versus endoscopic papillary large balloon dilation for common bile duct stones: A propensity score-based cohort analysis. AB - BACKGROUND AND AIM: Endoscopic sphincterotomy (ES) is a standard procedure for the treatment of common bile duct stones (CBDS). Endoscopic papillary large balloon dilation (EPLBD) is emerging as an effective method to treat difficult CBDS, providing several advantages over ES without increasing early adverse events (AE). However, the late AE of EPLBD have not yet been well studied. The aim of the present study was to compare late AE after EPLBD versus ES for the treatment of CBDS using a propensity score-based cohort analysis. METHODS: Propensity score matching was introduced to reduce the possible bias in baseline characteristics between two treatment groups and formed the matched cohort including 240 patients. Primary endpoint was cumulative as well as estimated 1 year and 3-year late AE rates. Secondary outcome was the incidence of early AE. RESULTS: Cumulative late AE rates were 12.5% and 16.7% in the ELPBD and ES groups (P = 0.936) with a median follow-up period of 915.5 and 1544.5 days, respectively. Estimated 1-year and 3-year late AE rates were 8.4% and 13.1% in the EPLBD group and 5.0% and 15.0% in the ES group, respectively. In multivariate analysis, >=two procedures were identified as independent risk factors for late AE. Overall early AE rate did not differ between the groups. CONCLUSION: In the present study, late AE rate after EPLBD showed no significant difference compared with that after ES, which had a relatively long follow-up period. Therefore, EPLBD could be used for the treatment of CBDS, if CBDS are considered difficult to treat. Clinical Trial Registry: UMIN000027798. PMID- 29399886 TI - Relation between Mitral Annular Plane Systolic Excursion and Global longitudinal strain in normal subjects: The HUNT study. AB - BACKGROUND: Left ventricular (LV) systolic long-axis shortening can be measured as Mitral Annular Plane Systolic Excursion (MAPSE). Global longitudinal strain (GLS) is relative LV shortening, equivalent to normalizing MAPSE for LV length (MAPSEn). The objective of this study was to test whether normalizing LV shortening reduced biological variability of MAPSE due to normalizing for heart size and, possibly BSA. Secondly to provide normal reference values for MAPSE. METHODS AND RESULTS: A total of 1266 subjects from the Nord-Trondelag Health Study (HUNT), without evidence of heart disease were examined. MAPSE and wall lengths were measured in all three standard apical views, while GLS has been published previously. Mean MAPSE was 1.58 (0.25) cm, MAPSEn 16.3 (2.4)%, and GLS 16.7 (2.4)%. All measures declined with age, correlations between -0.50 and 0.41. MAPSE was gender independent, and less BSA dependent than MAPSEn and GLS, while relative standard deviations (SDs) were similar for all three measures. CONCLUSIONS: MAPSE, MAPSEn, and GLS have similar biological variability, which is mainly due to age variation, indicating they are equivalent in normal, and normalizing for BSA will not reduce the variability. Normalizing MAPSE for LV length (MAPSEn and GLS) normalizes for one dimension only, inducing a systematic error, which increases BSA and gender dependence. Normal age-related, gender independent values for MAPSE are provided. PMID- 29399887 TI - Spontaneous rupture of the ascending aorta-size may not matter. PMID- 29399889 TI - Local contrast-enhanced MR images via high dynamic range processing. AB - PURPOSE: To develop a local contrast-enhancing and feature-preserving high dynamic range (HDR) image processing algorithm for multichannel and multisequence MR images of multiple body regions and tissues, and to evaluate its performance for structure visualization, bias field (correction) mitigation, and automated tissue segmentation. METHODS: A multiscale-shape and detail-enhancement HDR-MRI algorithm is applied to data sets of multichannel and multisequence MR images of the brain, knee, breast, and hip. In multisequence 3T hip images, agreement between automatic cartilage segmentations and corresponding synthesized HDR-MRI series were computed for mean voxel overlap established from manual segmentations for a series of cases. Qualitative comparisons between the developed HDR-MRI and standard synthesis methods were performed on multichannel 7T brain and knee data, and multisequence 3T breast and knee data. RESULTS: The synthesized HDR-MRI series provided excellent enhancement of fine-scale structure from multiple scales and contrasts, while substantially reducing bias field effects in 7T brain gradient echo, T1 and T2 breast images and 7T knee multichannel images. Evaluation of the HDR-MRI approach on 3T hip multisequence images showed superior outcomes for automatic cartilage segmentations with respect to manual segmentation, particularly around regions with hyperintense synovial fluid, across a set of 3D sequences. CONCLUSION: The successful combination of multichannel/sequence MR images into a single-fused HDR-MR image format provided consolidated visualization of tissues within 1 omnibus image, enhanced definition of thin, complex anatomical structures in the presence of variable or hyperintense signals, and improved tissue (cartilage) segmentation outcomes. PMID- 29399890 TI - Conjugated Polymers for Flexible Energy Harvesting and Storage. AB - Since the discovery of conjugated polymers in the 1970s, they have attracted considerable interest in light of their advantages of having a tunable bandgap, high electroactivity, high flexibility, and good processability compared to inorganic conducting materials. The above combined advantages make them promising for effective energy harvesting and storage, which have been widely studied in recent decades. Herein, the key advancements in the use of conjugated polymers for flexible energy harvesting and storage are reviewed. The synthesis, structure, and properties of conjugated polymers are first summarized. Then, their applications in flexible polymer solar cells, thermoelectric generators, supercapacitors, and lithium-ion batteries are described. The remaining challenges are then discussed to highlight the future direction in the development of conjugated polymers. PMID- 29399891 TI - Hybrid procedure combining endoscopic gallbladder lavage and internal drainage with elective cholecystectomy for acute cholecystitis: A prospective pilot study (The BLADE study). AB - BACKGROUND AND AIM: Percutaneous transhepatic drainage is the most common method for non-operative gallbladder drainage, but the technique does have several disadvantages because of its invasive nature and requirement for continuous drainage. To overcome these disadvantages, we developed a novel procedure, endoscopic gallbladder lavage followed by stent placement, carried out in a single endoscopic session. Our aim was to prospectively evaluate the efficacy and safety of this procedure in patients with acute cholecystitis. METHODS: Patients diagnosed with moderate cholecystitis at four tertiary care centers were enrolled in this study. We initially placed a 5-Fr tube to carry out gallbladder lavage. The tube was then cut to the optimal length and placed as a stent. Main outcomes were procedural and clinical success rates. RESULTS: The procedure was attempted in 40 patients and was successful in 30 (75.0%). Minor adverse events occurred in two (5.0%) patients: perforation of the cystic duct by the guidewire in one patient and pancreatitis in the other. Among the 30 patients in whom the procedure was successfully done, clinical resolution was obtained in 29 (96.6%). Elective cholecystectomy was carried out in 37 patients (92.5%), with a median delay after drainage of 42 days (range, 12-138 days). There were no adverse events during the waiting period. CONCLUSIONS: Gallbladder rinsing followed by internal drainage using a 5-Fr nasobiliary tube is considered an effective and safe alternative to other techniques, providing an acceptable success rate in patients with acute cholecystitis prior to elective surgery. CLINICAL TRIAL INFORMATION: http://www.umin.ac.jp/ctr/index.htm (ID: UMIN-000009680). PMID- 29399892 TI - Specific fetometric formulas of ICC and BP for calculating the parturition date in the miniature breeds of canine. AB - The aim of this study was to derive the growth curves of the inner chorionic cavity and the biparietal distance in miniature dog breeds by ultrasonographic fetometry and present new specific formulas for prediction of parturition date. In this study, foetal biometry parameters were obtained using serial ultrasonographic examinations in 24 pregnant bitches of six different miniature breeds (<=5 kg). The mating time was unknown. Overall, 25 inner chorionic cavity diameter (ICC) and 22 biparietal diameter (BP) measurements were taken. The relationship between ICC or BP growth and days to parturition was analysed by linear regression. The results showed a significant relationship between days before delivery and ICC or BP. The equations derived from the growth curves can be used in practical prediction of parturition date in miniature dog breeds. PMID- 29399893 TI - Mimicking Synaptic Plasticity and Neural Network Using Memtranstors. AB - Artificial synaptic devices that mimic the functions of biological synapses have drawn enormous interest because of their potential in developing brain-inspired computing. Current studies are focusing on memristive devices in which the change of the conductance state is used to emulate synaptic behaviors. Here, a new type of artificial synaptic devices based on the memtranstor is demonstrated, which is a fundamental circuit memelement in addition to the memristor, memcapacitor, and meminductor. The state of transtance (presented by the magnetoelectric voltage) in memtranstors acting as the synaptic weight can be tuned continuously with a large number of nonvolatile levels by engineering the applied voltage pulses. Synaptic behaviors including the long-term potentiation, long-term depression, and spiking-time-dependent plasticity are implemented in memtranstors made of Ni/0.7Pb(Mg1/3 Nb2/3 )O3 -0.3PbTiO3 /Ni multiferroic heterostructures. Simulations reveal the capability of pattern learning in a memtranstor network. The work elucidates the promise of memtranstors as artificial synaptic devices with low energy consumption. PMID- 29399894 TI - Soft Ultrathin Electronics Innervated Adaptive Fully Soft Robots. AB - Soft robots outperform the conventional hard robots on significantly enhanced safety, adaptability, and complex motions. The development of fully soft robots, especially fully from smart soft materials to mimic soft animals, is still nascent. In addition, to date, existing soft robots cannot adapt themselves to the surrounding environment, i.e., sensing and adaptive motion or response, like animals. Here, compliant ultrathin sensing and actuating electronics innervated fully soft robots that can sense the environment and perform soft bodied crawling adaptively, mimicking an inchworm, are reported. The soft robots are constructed with actuators of open-mesh shaped ultrathin deformable heaters, sensors of single-crystal Si optoelectronic photodetectors, and thermally responsive artificial muscle of carbon-black-doped liquid-crystal elastomer (LCE-CB) nanocomposite. The results demonstrate that adaptive crawling locomotion can be realized through the conjugation of sensing and actuation, where the sensors sense the environment and actuators respond correspondingly to control the locomotion autonomously through regulating the deformation of LCE-CB bimorphs and the locomotion of the robots. The strategy of innervating soft sensing and actuating electronics with artificial muscles paves the way for the development of smart autonomous soft robots. PMID- 29399896 TI - Parasitism and venom of ectoparasitoid Scleroderma guani impairs host cellular immunity. AB - Venom is a prominently maternal virulent factor utilized by parasitoids to overcome hosts immune defense. With respect to roles of this toxic mixture involved in manipulating hosts immunity, great interest has been mostly restricted to Ichneumonoidea parasitoids associated with polydnavirus (PDV), of which venom is usually considered as a helper component to enhance the role of PDV, and limited Chalcidoidea species. In contrast, little information is available in other parasitoids, especially ectoparasitic species not carrying PDV. The ectoparasitoid Scleroderma guani injects venom into its host, Tenebrio molitor, implying its venom was involved in suppression of hosts immune response for successful parasitism. Thus, we investigated the effects of parasitism and venom of this parasitoid on counteracting the cellular immunity of its host by examining changes of hemocyte counts, and hemocyte spreading and encapsulation ability. Total hemocyte counts were elevated in parasitized and venom-injected pupae. The spreading behavior of both granulocytes and plasmatocytes was impaired by parasitization and venom. High concentration of venom led to more severely increased hemocyte counts and suppression of hemocyte spreading. The ability of hemocyte encapsulation was inhibited by venom in vitro. In addition to immediate effects observed, venom showed persistent interference in hosts cellular immunity. These results indicate that venom alone from S. guani plays a pivotal role in blocking hosts cellular immune response, serving as a regulator that guarantees the successful development of its progenies. The findings provide a foundation for further investigation of the underlying mechanisms in immune inhibitory action of S. guani venom. PMID- 29399895 TI - Leucine supplementation attenuates macrophage foam-cell formation: Studies in humans, mice, and cultured macrophages. AB - Whereas atherogenicity of dietary lipids has been largely studied, relatively little is known about the possible contribution of dietary amino acids to macrophage foam-cell formation, a hallmark of early atherogenesis. Recently, we showed that leucine has antiatherogenic properties in the macrophage model system. In this study, an in-depth investigation of the role of leucine in macrophage lipid metabolism was conducted by supplementing humans, mice, or cultured macrophages with leucine. Macrophage incubation with serum obtained from healthy adults supplemented with leucine (5 g/d, 3 weeks) significantly decreased cellular cholesterol mass by inhibiting the rate of cholesterol biosynthesis and increasing cholesterol efflux from macrophages. Similarly, leucine supplementation to C57BL/6 mice (8 weeks) resulted in decreased cholesterol content in their harvested peritoneal macrophages (MPM) in relation with reduced cholesterol biosynthesis rate. Studies in J774A.1 murine macrophages revealed that leucine dose-dependently decreased cellular cholesterol and triglyceride mass. Macrophages treated with leucine (0.2 mM) showed attenuated uptake of very low-density lipoproteins and triglyceride biosynthesis rate, with a concurrent down-regulation of diacylglycerol acyltransferase-1, a key enzyme catalyzing triglyceride biosynthesis in macrophages. Similar effects were observed when macrophages were treated with alpha-ketoisocaproate, a key leucine metabolite. Finally, both in vivo and in vitro leucine supplementation significantly improved macrophage mitochondrial respiration and ATP production. The above studies, conducted in human, mice, and cultured macrophages, highlight a protective role for leucine attenuating macrophage foam-cell formation by mechanisms related to the metabolism of cholesterol, triglycerides, and energy production. (c) 2018 BioFactors, 44(3):245-262, 2018. PMID- 29399898 TI - Short-term tolerance of equine spermatozoa to various abiotic factors. AB - The aim of this study was to determine the effects of various abiotic factors, such as light, physical stress (pipetting) and thermal shock, on the quality of fresh and cooled equine sperm. In experiment I, four sperm aliquots were subjected to different light exposures: (i) protected control samples (CTRL), (ii) exposed to UV light at 10 cm (UV10), (iii) exposed to UV light at 20 cm (UV20) and (iv) exposed to laboratory lighting (LAB). In experiment II, four semen aliquots were subjected to repeated pipetting for 0, 10, 20 and 30 times (CTRL, P10, P20 and P30, respectively). In experiment III, four semen aliquots at 15 degrees C were subjected to thermal oscillations: (i) cooled control sperm at 15 degrees C (CTRL), (ii) oscillations of 1.9 degrees C/min to a temperature of 30 degrees C (T30), (iii) oscillations of 1.4 degrees C/min, with the temperature rapidly falling until reaching 1.3 degrees C (T0R) and (iv) oscillations of 1.1 degrees C/min, with the temperature slowly falling until reaching 4.2 degrees C (T0S). The results revealed that after 30 min, UV10 and UV20 sperm samples showed significantly (p < .05) lower total and progressive motility values, sperm kinematic parameters and mitochondrial potential. After 45 min of exposure, differences were highly significant (p < .001). No significant differences (p > .05) were found for pipetting or thermal oscillations. The results suggest that, even if equine sperm samples are not handled in the laboratory under optimal conditions, fresh and cooled equine spermatozoa are able to resist the impact of various abiotic stimuli without any reduction in their quality. This study analyses the effect on normospermic samples, but future research could look at the tolerance that asthenozoospermic equine samples have to these abiotic influences. PMID- 29399897 TI - alpha-Tocopherol promotes HaCaT keratinocyte wound repair through the regulation of polarity proteins leading to the polarized cell migration. AB - In many developed countries including Japan, how to care the bedridden elderly people with chronic wounds such as decubitus becomes one of the most concerned issues. Although antioxidant micronutrients including vitamin E, especially alpha tocopherol (alpha-Toc), are reported to shorten a period of wound closure, the promoting effect of alpha-Toc on wound healing independent of its antioxidant activity remains to be fully elucidated. The aim of this study was to examine whether alpha-Toc affects wound-mediated HaCaT keratinocyte polarization process including the recruitment of polarity regulating proteins, leading to wound repair independently of its antioxidant activity. We investigated the effects of alpha-Toc and other antioxidants such as Trolox, a cell-permeable alpha-Toc analog on the migration, proliferation, and cell polarization of HaCaT keratinocytes after wounding. We analyzed the localization and complex formation of polarity proteins, partitioning defective 3 (Par3), and atypical protein kinase C (aPKC), and aPKC activity by immunohistochemistry, immunoprecipitation analyses, and in vitro kinase assays, respectively. alpha-Toc but not other antioxidants enhanced the wound closure and cell polarization in HaCaT keratinocytes after wounding. alpha-Toc regulated the localization and complex formation of Par3 and aPKC during wound healing. Knockdown of aPKC or Par3 abrogated alpha-Toc-mediated promotion of the wound closure and cell polarization in HaCaT keratinocytes. Furthermore, aPKC kinase activity was significantly increased in alpha-Toc-treated cells through activation of phosphatidylinositol 3 kinase/Akt signaling pathway. These results suggest that alpha-Toc promotes HaCaT keratinocyte wound repair by regulating the aPKC kinase activity and the formation of aPKC-Par3 complex. (c) 2017 BioFactors, 44(2):180-191, 2018. PMID- 29399899 TI - Short- and long-term outcomes following redo valvular surgery. AB - AIM: We reviewed our experience in redo valvular surgery to evaluate trends in short- and long-term outcomes. METHODS: We reviewed 414 patients (mean age, 62.8 +/- 13.6 years) who underwent redo valvular surgery in the past 25 years. A total of 301 patients (54.2%) underwent first-time redo valvular surgeries; 178 (32.1%) were second redos, 60 (10.8%) were third redos, and 16 were fourth redos (2.9%). The mean follow-up period was 6.8 +/- 6.3 years. RESULTS: Hospital mortality was 5.8%. New York Heart Association (NYHA) class III/IV (P = 0.0007, odds ratio = 4.403) and hemodialysis (P = 0.0383, odds ratio = 7.196) were risk factors for hospital death. Long-term survival rates at 15 and 20 years were 64.7% +/- 4.3% and 59.1% +/- 5.0%, respectively. Predictors of late death were first time redo (P = 0.0076, hazard ratio = 0.422) and age younger than 61 years (P = 0.0005, hazard ratio = 0.229). There were significant differences in long-term survival between NYHA classes I/II and III/IV (log-rank test, P = 0.0419) and between the time from redo surgery (log-rank test, P = 0.0189) and age (log-rank test, P = 0.0001). CONCLUSIONS: The hospital mortality rate for redo valve surgery has improved. Early referral for redo surgery can contribute to improving early and late outcomes. PMID- 29399900 TI - Organisational silence among nurses and physicians in public hospitals. AB - AIMS AND OBJECTIVES: To define the underlying reasons that lead physicians and nurses who provide patient care and treatment, to maintain silence in their work and how they perceive the consequences of such silence in public hospitals. BACKGROUND: The concept of organisational silence is described as employees' avoidance of stating his/her opinions, thoughts and suggestions, which would improve the organisation and enable it to provide better processes or services. This concept has been examined more frequently in the international literature in the past decade, and it has drawn attention as one of the most important barriers to employees' contributions to their organisation. DESIGN: Descriptive and cross sectional study. METHODS: The study sample consisted of 601 physicians and nurses who work in five hospitals with bed capacities of 100 or more. The data were collected using a two-part form: an introductory information form and an organisational silence scale. RESULTS: Administrative and organisational topics were prominent among the reasons for employees of healthcare organisations to remain silent for both physicians and nurses. CONCLUSIONS: The results of this study should be considered by physicians and nurses to realise and improve themselves. Also, decision makers and managers of public hospitals might evaluate and remove organisational and communicative barriers to employees' contributions to their organisations based on these results. RELEVANCE TO CLINICAL PRACTICE: Physicians and nurses are responsible for the fulfilment of highly important tasks for their organisations. Their contributions help their organisations remain competitive, improve the health services, ensure and sustain patient safety. Hence, these results will provide information to facilitate an understanding of the topics, causes and consequences of organisational silence among physicians and nurses, two key healthcare professions, and will be helpful in the development of medical and nursing human resources in clinical settings. PMID- 29399901 TI - Re-embodying eating after surgery for oesophageal cancer: Patients' lived experiences of participating in an education and counselling nutritional intervention. AB - AIMS AND OBJECTIVES: To provide in-depth insight into patients' lived experiences of participating in an education and counselling nutritional intervention after curative surgery for oesophageal cancer. BACKGROUND: Surgery for oesophageal cancer carries a risk of malnutrition. The consequences of nutritional problems may lead to increased morbidity and mortality postoperatively and have consequences for convalescence, rehabilitation and quality of life. DESIGN: Qualitative study based on a phenomenological approach. The theoretical framework was grounded in the philosophy of Merleau-Ponty. METHODS: Qualitative interviews were conducted with 10 patients who participated in an education and counselling nutritional intervention after surgery for oesophageal squamous-cell carcinoma. Data were analysed according to the principles of Kvale and Brinkmann, and their three levels of interpretation were applied. FINDINGS: The essence of experiencing the education and counselling nutritional intervention can be divided into three themes: embodied disorientation, living with increased attention to bodily functions and re-embodying eating. CONCLUSIONS: Patients were living with increased attention to bodily functions and tried to find a balance between the task of eating and nutritional needs. Despite the embodied perceptions of alterations after oesophageal cancer surgery, the patients developed high levels of bodily awareness and skills in self-management. This process was characterised by reconnecting to the body and re-embodying eating. The intervention empowered the patients to regain some control of their own bodies in an effort to regain agency in their own lives. RELEVANCE TO CLINICAL PRACTICE: There is a need for systematic long-term follow-up after surgery for oesophageal cancer regarding nutrition. The findings of this study can inform future supportive nutrition care service development aimed at supporting patients to learn to eat sufficiently after oesophageal resection. PMID- 29399902 TI - Left-side pericardial agenesis: Putting the pieces together. AB - A 56-year-old woman complained of atypical chest pain. At initial diagnostic workup, chest radiograph and transthoracic echocardiogram depict specific findings that raised the suspicion of pericardial agenesis. Cardiac computed tomography showed extreme levoposition of the heart and interposition of lung parenchyma between the aorta and the pulmonary artery. Those findings were consistent with the diagnosis of left-side pericardial agenesis, which was subsequently confirmed in cardiac magnetic resonance study. Left-side pericardial agenesis is rare and can result in nonspecific symptoms. An integrated multimodality imaging approach may provide incremental value on diagnosis approach. Its benign prognosis allows a conservative approach. PMID- 29399903 TI - Identifying the nontechnical skills required of nurses in general surgical wards. AB - AIMS AND OBJECTIVES: To identify the nontechnical skills (NTS) required of nurses in general surgical wards for safe and effective care. BACKGROUND: As the largest occupational group, nurses are in an ideal position to block the vulnerabilities of patient adverse events in a surgical ward. Previous studies in the surgical environment have identified the NTS required of nurses for safe care in operating rooms; however, these skills have not been identified for nurses in general surgical wards. DESIGN: A nonparticipant observational descriptive design was used. METHOD: A purposive sample of 15 registered nurses was recruited from four surgical wards and observed for a full shift on a morning, afternoon or night shift. Nonparticipant observations were conducted using field notes to collect data. A coding frame was developed, and an inductive process was used to analyse the data. RESULTS: A taxonomy comprising seven NTS required of nurses in their roles in surgical ward teams emerged from the data analysis. They are communication, leadership and management, planning, decision-making, situation awareness, teamwork and patient advocacy. CONCLUSION: Patient care provided by general surgical nurses involved the seven identified key NTS. These particular NTS are an important component of safe nursing practice as they underpin the provision of safe and effective care for general surgical patients. Nurses block the trajectory of error by using NTS to address the vulnerabilities in the system that can lead to adverse patient events. RELEVANCE TO CLINICAL PRACTICE: Identifying general surgical nurses' NTS enables the development of teaching strategies that target the learning of those skills to achieve successful work outcomes and improve patient safety. PMID- 29399904 TI - Privacy at end of life in ICU: A review of the literature. AB - AIMS AND OBJECTIVES: To explore the issues surrounding privacy during death in ICU. BACKGROUND: While the provision of ICU care is vital, the nature and effect of the potential lack of privacy during death and dying in ICUs have not been extensively explored. DESIGN: A literature search using CINAHL and Pubmed revealed articles related to privacy, death and dying in ICU. METHOD: Keywords used in the search were "ICU," "Privacy," "Death" and "Dying." A combination of these terms using Boolean operators "or" or "and" revealed a total of 23 citations. Six papers were ultimately deemed suitable for inclusion in the review and were subjected to code analysis with Atlas.ti v8 QDA software. FINDINGS: The analysis of the studies revealed eight themes, and this study presents the three key themes that were found to be recurring and strongly interconnected to the experience of privacy and death in ICU: "Privacy in ICU," "ICU environment" and "End-of-Life Care". CONCLUSIONS: Research has shown that patient and family privacy during the ICU hospitalisation and the provision of the circumstances that lead to an environment of privacy during and after death remains a significant challenge for ICU nurses. Family members have little or no privacy in shared room and cramped waiting rooms, while they wish to be better informed and involved in end-of-life decisions. Hence, death and dying for many patients takes place in open and/or shared spaces which is problematic in terms of both the level of privacy and respect that death ought to afford. RELEVANCE TO CLINICAL PRACTICE: It is best if end-of-life care in the ICU is planned and coordinated, where possible. Nurses need to become more self-reflective and aware in relation to end-of-life situations in ICU in order to develop privacy practices that are responsive to family and patient needs. PMID- 29399905 TI - A rating instrument for fear of hospitalisation. AB - AIMS AND OBJECTIVES: To develop and validate a reliable instrument that can measure fear of hospitalisation experienced by outpatients. BACKGROUND: After having a diagnosis established, some patients experience sense of fear, unpleasantness and embarrassment due to the possibility to be admitted to a hospital. Currently, there is no available instrument for measuring fear of hospitalisation. DESIGN: Cross-sectional study for assessing reliability and validity of a questionnaire. METHOD: The questionnaire with 17 items and answers according to the Likert scale was developed during two brainstorming sessions of the research team. Its reliability, validity and temporal stability were tested on the sample of 330 outpatients. The study was multicentric, involving patients from seven cities and three countries. RESULTS: Fear of hospitalisation scale showed satisfactory reliability, when rated both by the investigators (Cronbach's alpha .799) and by the patients themselves (Cronbach's alpha .760). It is temporally stable, and both divergent and convergent validity tests had good results. Factorial analysis revealed three domains: fear of being injured, trust to medical staff and fear of losing privacy or autonomy. CONCLUSIONS: This study developed new reliable and valid instrument for measuring fear of hospitalisation. RELEVANCE TO CLINICAL PRACTICE: Identification of patients with high level of fear of hospitalisation by this instrument should help clinicians to administer measures which may decrease fear and prevent avoidance of healthcare utilisation. PMID- 29399906 TI - Medium Resolution 1 H-NMR at 62 MHz as a New Chemically Sensitive Online Detector for Size-Exclusion Chromatography (SEC-NMR). AB - A state-of-the-art, medium-resolution 1 H-NMR spectrometer (62 MHz) is used as a chemically sensitive online detector for size-exclusion chromatography of polymers such as polymethylmethacrylate (PMMA) and polystyrene (PS). The method uses protonated eluents and works at typical chromatographic conditions with trace amounts of analytes (<0.5 g L-1 after separation). Strong solvent suppression, e.g., by a factor of 500, is achieved by means of T1 -filtering and mathematical subtraction methods. Substantial improvements are made with respect to previous work in terms of the sensitivity (signal-to-noise ratio up to 130:1, PMMA O?CH3 ) and selectivity (peak width, full width half maximum (FWHM) 4 Hz on flow). Typical homopolymers and a blend are investigated to deformulate their composition along the dimensions of molecular weight and NMR chemical shift. These results validate this new hyphenated chromatography method, which can greatly facilitate analysis and is much more effective than previously published results. PMID- 29399907 TI - Students' perspectives on basic nursing care education. AB - AIMS AND OBJECTIVES: To explore the perspectives of nursing students on their education concerning basic nursing care, learned either during theoretical education or clinical placement, with a specific focus on nutrition and communication. BACKGROUND: Basic care activities lie at the core of nursing, but are ill-informed by evidence and often poorly delivered. Nursing students' education on basic care might be lacking, and the question remains how they learn to deliver basic care in clinical practice. DESIGN: Descriptive study, using an online questionnaire. METHODS: Nursing students at the vocational and bachelor level of six nursing schools in the Netherlands were invited to complete an online questionnaire regarding their perception of basic nursing care education in general (both theoretical education and clinical placement) and specifically in relation to nutrition and communication. RESULTS: Nursing students (n = 226 bachelor students, n = 30 vocational students) completed the questionnaire. Most students reported that they learned more about basic nursing care during clinical placement than during theoretical education. Vocational students also reported learning more about basic nursing care in both theoretical education and clinical practice than bachelor students. In terms of nutrition, low numbers of students from both education levels reported learning about nutrition protocols and guidelines during theoretical education. In terms of communication, vocational students indicated that they learned more about different aspects of communication during clinical practice than theoretical education and were also more likely to learn about communication (in both theoretical education and clinical practice) than were bachelor students. CONCLUSION: Basic nursing care seems to be largely invisible in nursing education, especially at the bachelor level and during theoretical education. RELEVANCE TO CLINICAL PRACTICE: Improved basic nursing care will enhance nurse-sensitive outcomes and patient satisfaction and will contribute to lower healthcare costs. This study shows that there is scope within current nurse education in the Netherlands to focus more systematically and explicitly on basic nursing care. PMID- 29399908 TI - Nurses' concerns about caring for patients with acute and chronic traumatic brain injury. AB - AIMS AND OBJECTIVES: As a first step in developing traumatic brain injury specific nursing education, the purpose of this study was to investigate nurses' concerns about caring for patients with moderate-to-severe traumatic brain injury. BACKGROUND: Patients with moderate-to-severe traumatic brain injury typically have significant immediate and chronic cognitive impairments. These cognitive impairments can negatively affect their inpatient stay after an acute traumatic brain injury and affect their health care later in life when seeking care for other acute health conditions during the chronic phase of traumatic brain injury. Nurses must be knowledgeable about modifying care to accommodate the cognitive impairments of these patients throughout the continuum of care. Yet, current guidelines focus exclusively on acute care and do not address nurses' central role in dealing with residual cognitive impairments of these patients. Thus, educational and training interventions are needed to ensure nurses have adequate knowledge to care for these patients. DESIGN: We conducted a cross-sectional, exploratory survey of 692 nurses across hospital departments at three hospitals between October 2014-August 2015. Nurses answered the following qualitative open-ended question: "What are your primary concerns about providing care to patients with moderate-to-severe traumatic brain injury?" METHODS: Conventional qualitative content analysis was used to analyse nurses' responses. RESULTS: Findings showed nurses reported multiple concerns about caring for patients in the acute phase after traumatic brain injury, but few concerns about caring for patients in the chronic phase. Some of the concerns nurses reported included: (i) preventing physical injury; (ii) missing changes in condition; (iii) providing adequate education; (iv) providing support; and (v) promoting recovery. Barriers to providing adequate care were as follows: (i) lack of knowledge; (ii) limited staffing; and (iii) inadequate resources. CONCLUSIONS: Findings have implications for education of nurses and development of nursing guidelines for management of patients with traumatic brain injury, including providing direction for nurses on development of care plans for patients in the chronic phase after a moderate-to-severe traumatic brain injury. PMID- 29399909 TI - Effects of patient participation in the management of daily nursing goals on function recovery and resilience in surgical patients. AB - AIMS AND OBJECTIVE: To examine the effects of active patient participation in the management of daily nursing goal on surgical patient recovery. BACKGROUND: Nursing processes involving patient participation enable nursing interventions solely based on individual needs and expectations. This permits the establishment of nurse-patient treatment goals and supports permanent and effective nursing interventions through evaluation activities. DESIGN: A quasi-experiment that relies on a nonequivalent pretest-post-test design for the control group. METHODS: A nursing intervention involving patient participation was applied to patients who underwent digestive cancer surgery in a surgical ward in the Republic of Korea. A daily goals sheet for patient participation was developed. Twenty-nine patients in the experimental group received the intervention every day from postoperative days 1-7 through the daily goals sheet. Data were collected on recovery in mobility, recovery of bowel movements, peak expiratory flow rate and pain and resilience after the experimental intervention. The control group contained 27 patients who were provided with routine nursing care alone. RESULTS: The daily nursing goal management group showed more rapid recovery in bowel movement, higher peak expiratory flow rate and lower pain scores than the control group. The daily nursing goal management group also had significantly higher resilience than the control group. CONCLUSIONS: Daily nursing goal management is an effective nursing intervention for improving function recovery and resilience in surgical patients. RELEVANCE TO CLINICAL PRACTICE: Patient participation in daily nursing goal management is an effective nursing intervention applicable to nurse-patient treatment goals and supports permanent and effective nursing interventions through evaluation activities. PMID- 29399910 TI - Mothers' experience of caring for a child with early onset scoliosis: A qualitative descriptive study. AB - AIMS AND OBJECTIVES: This study aimed to identify and describe the experience of parents of children diagnosed with early onset scoliosis living in Australia. BACKGROUND: Chronic childhood disease has a major impact on health-related quality of life. Caring for a child with a chronic illness is well documented but the specific experiences of parents who care for children with early onset scoliosis, a rare but devastating illness, has not been explored. Numerous studies have described the interrelated psychological, financial, social, physical and logistical factors that impact the experience of the caregiver role with various diseases, but in the case of early onset scoliosis, limited studies have been conducted about the parental experience. METHODS: A qualitative descriptive design was used. A snowball sampling technique assisted in the recruitment. Parents invited to the study included mothers, fathers and guardians. Data were collected through semistructured interviews and transcribed verbatim. Transcripts were analysed thematically. Data collection complied with the Consolidated criteria for reporting qualitative research guidelines. FINDINGS: Twelve mothers of children with early onset scoliosis were interviewed, as only mothers consented to participate. Four major themes emerged: emotional rollercoaster ride, a lack of resources, money talks and pervasive burden. Factors that impacted on the participants' ability to confront, manage and endure caring for a child with early onset scoliosis emerged from the data. CONCLUSION: The findings suggest there are multiple factors that influence the experience of mothers' caring for a child with early onset scoliosis. The recognition and appropriate management of these factors by healthcare professionals have the potential to improve the quality of life of parents who care for a child with early onset scoliosis. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals have first-line contact with parents of children with early onset scoliosis and are well placed to provide parents with evidence-based education and increased support. PMID- 29399911 TI - A Highly Stretchable Self-Healing Poly(dimethylsiloxane) Elastomer with Reprocessability and Degradability. AB - It is a challenge to synthesize materials that possess the properties of high stretchability and self-healability. Herein a new poly(dimethylsiloxane) elastomer with high stretchability, room-temperature self-healability, repeatable reprocessability, and controlled degradability is reported by incorporating an aromatic disulfide bond and imine bond. The as-prepared elastomer can be stretched to over 2200% of its original length. Without external stimuli, a damaged sheet can completely heal in 4 h. In addition, the elastomer can be reprocessed multiple times without obvious performance degradation and degraded controllably by three ways. All these properties of the elastomer can be ascribed to the unique dual-dynamic-covalent sacrificial system. PMID- 29399913 TI - Thermally Switchable Fluorescence Resonance Energy Transfer via Reversible Diels Alder Reaction of pi-Conjugated Oligo-(Phenylene Ethynylene)s. AB - The combination of reversible, dynamic covalent bonds and pi-conjugated oligo (phenylene ethynylene)s is utilized for exchange reactions between two acceptors and one donor containing copolymer in the solid state upon thermal treatment. The specific molecular design of the polymers allows upon thermally triggering the reshuffling of the pi-conjugated donor and acceptor moieties. Depending on the nature of the acceptor, an increased and a decreased fluorescence resonance energy transfer (FRET), respectively, can be observed for the mixing of the copolymers or the demixing of a donor-acceptor copolymer. PMID- 29399912 TI - Dental enamel defects predict adolescent health indicators: A cohort study among the Tsimane' of Bolivia. AB - OBJECTIVES: Bioarchaeological findings have linked defective enamel formation in preadulthood with adult mortality. We investigated how defective enamel formation in infancy and childhood is associated with risk factors for adult morbidity and mortality in adolescents. METHODS: This cohort study of 349 Amerindian adolescents (10-17 years of age) related extent of enamel defects on the central maxillary incisors (none, less than 1/3, 1/3 to 2/3, more than 2/3) to adolescent anthropometrics (height, weight) and biomarkers (hemoglobin, glycated hemoglobin, white blood cell count, and blood pressure). Risk differences and 95% confidence intervals were estimated using multiple linear regression. Enamel defects and stunted growth were compared in their ability to predict adolescent health indicators using log-binomial regression and receiver operating characteristics (ROCs). RESULTS: Greater extent of defective enamel formation on the tooth surface was associated with shorter height (-1.35 cm, 95% CI: -2.17, -0.53), lower weight (-0.98 kg, 95% CI: -1.70, -0.26), lower hemoglobin (-0.36 g/dL, 95% CI: -0.59, -0.13), lower glycated hemoglobin (-0.04 %A1c , 95% CI: -0.08, 0.00008), and higher white blood cell count (0.74 109 /L, 95% CI: 0.35, 1.14) in adolescence. Extent of enamel defects and stunted growth independently performed similarly as risk factors for adverse adolescent outcomes, including anemia, prediabetes/type II diabetes, elevated WBC count, prehypertension/hypertension, and metabolic health. CONCLUSIONS: Defective enamel formation in infancy and childhood predicted adolescent health outcomes and may be primarily associated with infection. Extent of enamel defects and stunted growth may be equally predictive of adverse adolescent health outcomes. PMID- 29399914 TI - Semi-Fluorinated Methacrylates: A Class of Versatile Monomers for Polymerization Induced Self-Assembly. AB - A series of polymerization-induced self-assembly (PISA) formulations are developed based on reversible addition-fragmentation chain-transfer (RAFT) dispersion polymerization of semi-fluorinated methacrylates. Alcoholic RAFT dispersion polymerization of 2-(perfluorobutyl)ethyl methacrylate (FBEMA), 2 (perfluorohexyl)ethyl methacrylate (FHEMA), and 2-(perfluorooctyl)ethyl methacrylate (FOEMA) is systematically evaluated to extend the general usability of semi-fluorinated methacrylates to PISA. The nanostructure of the assemblies is correlated to the side-chain length of the monomer: RAFT dispersion polymerization of FBEMA produces spherical micelles, wormlike micelles, and vesicles depending on its degree of polymerization (DP), while only spheres are generated for the PISA of FHEMA. PISA of FOEMA generates liquid crystalline cylindrical micelles, whose diameter increases with the DP of FOEMA. These results demonstrate the general feasibility of semi-fluorinated methacrylates to PISA. Besides, PISA of FHEMA is also realized in a variety of solvents, including iso-propanol, toluene, dioxane, and dimethyl formamide, exhibiting the superior solvent serviceability of the PISA formulations based on semi-fluorinated methacrylates. PMID- 29399915 TI - Manipulation of Phonon Transport in Thermoelectrics. AB - For several decades, thermoelectric advancements have largely relied on the reduction of lattice thermal conductivity (kappaL ). According to the Boltzmann transport theory of phonons, kappaL mainly depends on the specific heat, the velocity, and the scattering of phonons. Intensifying the scattering rate of phonons is the focus for reducing the lattice thermal conductivity. Effective scattering sources include 0D point defects, 1D dislocations, and 2D interfaces, each of which has a particular range of frequencies where phonon scattering is most effective. Because acoustic phonons are generally the main contributors to kappaL due to their much higher velocities compared to optical phonons, many low kappaL thermoelectrics rely on crystal structure complexity leading to a small fraction of acoustic phonons and/or weak chemical bonds enabling an overall low phonon propagation velocity. While these thermal strategies are successful for advancing thermoelectrics, the principles used can be integrated with approaches such as band engineering to improve the electronic properties, which can promote this energy technology from niche applications into the mainstream. PMID- 29399916 TI - Fundamental care guided by the Careful Nursing Philosophy and Professional Practice Model(c). AB - AIMS AND OBJECTIVES: To propose the Careful Nursing Philosophy and Professional Practice Model(c) as a conceptual and practice solution to current fundamental nursing care erosion and deficits. BACKGROUND: There is growing awareness of the crucial importance of fundamental care. Efforts are underway to heighten nurses' awareness of values that motivate fundamental care and thereby increase their attention to effective provision of fundamental care. However, there remains a need for nursing frameworks which motivate nurses to bring fundamental care values to life in their practice and strengthen their commitment to provide fundamental care. DESIGN: This descriptive position paper builds on the Careful Nursing Philosophy and Professional Practice Model(c) (Careful Nursing). Careful Nursing elaborates explicit nursing values and addresses both relational and pragmatic aspects of nursing practice, offering an ideal guide to provision of fundamental nursing care. METHOD: A comparative alignment approach is used to review the capacity of Careful Nursing to address fundamentals of nursing care. CONCLUSIONS: Careful Nursing provides a value-based comprehensive and practical framework which can strengthen clinical nurses' ability to articulate and control their practice and, thereby, more effectively fulfil their responsibility to provide fundamental care and measure its effectiveness. RELEVANCE TO CLINICAL PRACTICE: This explicitly value-based nursing philosophy and professional practice model offers nurses a comprehensive, pragmatic and engaging framework designed to strengthen their control over their practice and ability to provide high-quality fundamental nursing care. PMID- 29399917 TI - The function of fatigue and illness perceptions as mediators between self efficacy and health-related quality of life during the first year after surgery in persons treated for colorectal cancer. AB - AIMS AND OBJECTIVES: To measure changes in health-related quality of life, two dimensions of illness perceptions (i.e., consequences and emotional representations), fatigue and self-efficacy in persons treated for colorectal cancer during the first year after surgical treatment, and to study how fatigue, illness perceptions and self-efficacy measured at 3 months affect health-related quality of life at 12 months postsurgery. BACKGROUND: There are fluctuations in health-related quality of life during the first year after treatment for colorectal cancer, and fatigue may negatively influence health-related quality of life. Illness perceptions (consequences and emotional representations) and self efficacy have been shown to be associated with health-related quality of life in other cancer diagnoses. Concerning colorectal cancer, there is a lack of knowledge concerning how illness perceptions and self-efficacy change during recovery, and how these variables and fatigue at 3 months relate to health related quality of life at 12 months. DESIGN: A prospective longitudinal design. METHODS: Thirty-nine persons surgically treated for colorectal cancer, of whom 17 had a colostomy, participated. Health-related quality of life, fatigue, illness perceptions and self-efficacy were assessed using QLQ-C30, the Revised Illness Perception Questionnaire and the Maintain Function Scale. Descriptive and analytical statistics were used. RESULTS: No changes were reported in levels of health-related quality of life, fatigue or illness perceptions. Self-efficacy was lower at 12 months compared to 3 months. Fatigue and one dimension of illness perceptions mediated the effect of self-efficacy at 3 months on health-related quality of life at 12 months. CONCLUSION: Persons treated for colorectal cancer who have lower self-efficacy 3 months postsurgery are inclined to have more negative illness perceptions concerning emotions and to experience more fatigue. RELEVANCE TO CLINICAL PRACTICE: Nurses need to support persons with fatigue and negative illness perceptions concerning emotions and to bolster their self efficacy, that is carry out follow-up consultations focusing on illness management, symptoms, emotions and information on ways to increase self-efficacy. PMID- 29399918 TI - ECG electrode reversals: An opportunity to learn from mistakes. AB - An ECG with an "odd" appearance may raise the suspicion that ECG recording electrodes may have been reversed. Odd appearances include unexpected Q-waves or R-waves, markedly isoelectric leads, and abrupt changes from previous ECGs. A few examples of ECG electrode reversal provide the opportunity to review some fundamental principles of ECG recording. Some ECG electrode reversals will invert the QRS complex recorded in a lead. Other ECG leads may be affected in a manner that initially may seem unexpected. These patterns may be understood upon reviewing the genesis of the "unipolar" leads, particularly the "augmented" leads. Recording an ECG between electrodes placed on the two legs will produce a nearly isoelectric tracing. Elucidation of electrode reversals is often less difficult than it seems, may present an enjoyable intellectual challenge, and provides insight into the process of ECG recording. PMID- 29399919 TI - The transformative power of understanding and trust in AF care: How doctors can provide better treatment by understanding the hearts - and minds - of AF patients. PMID- 29399920 TI - Leadership behaviours play a significant role in implementing evidence-based practice. PMID- 29399921 TI - Status of knowledge on student-learning environments in nursing homes: A mixed method systematic review. AB - AIM AND OBJECTIVE: To give an overview of empirical studies investigating nursing homes as a learning environment during nursing students' clinical practice. BACKGROUND: A supportive clinical learning environment is crucial to students' learning and for their development into reflective and capable practitioners. Nursing students' experience with clinical practice can be decisive in future workplace choices. A competent workforce is needed for the future care of older people. Opportunities for maximum learning among nursing students during clinical practice studies in nursing homes should therefore be explored. DESIGN: Mixed method systematic review using PRISMA guidelines, on learning environments in nursing homes, published in English between 2005-2015. METHODS: Search of CINAHL with Full Text, Academic Search Premier, MEDLINE and SocINDEX with Full Text, in combination with journal hand searches. Three hundred and thirty-six titles were identified. Twenty studies met the review inclusion criteria. Assessment of methodological quality was based on the Mixed Methods Appraisal Tool. Data were extracted and synthesised using a data analysis method for integrative reviews. RESULTS: Twenty articles were included. The majority of the studies showed moderately high methodological quality. Four main themes emerged from data synthesis: "Student characteristic and earlier experience"; "Nursing home ward environment"; "Quality of mentoring relationship and learning methods"; and "Students' achieved nursing competencies." CONCLUSION: Nursing home learning environments may be optimised by a well-prepared academic-clinical partnership, supervision by encouraging mentors and high-quality nursing care of older people. Positive learning experiences may increase students' professional development through achievement of basic nursing skills and competencies and motivate them to choose the nursing home as their future workplace. RELEVANCE TO CLINICAL PRACTICE: An optimal learning environment can be ensured by thorough preplacement preparations in academia and in nursing home wards, continuous supervision and facilitation of team learning. PMID- 29399922 TI - LDL dinitrosyl iron complex: A new transferrin-independent route for iron delivery in hepatocytes. AB - In view of the interrelations between NO, Fe, and LDL in the cardiovascular system it appears interesting to find out, if the lipoprotein particles undergo the process of iron-nitrosylation, commonly observed for other proteins and what is the biological fate of iron-nitrosylated LDL particles. Iron-nitrosylated LDL preparation containing Fe(NO)2 motif (DNICLDL) was obtained and characterized for the first time. In order to test its interactions with potential target cells, DNICLDL was administered to the hepatoma HepG2 cells. The effects were referred to those induced by native LDL (nLDL) and oxidized LDL (oxLDL) particles. DNICLDL administration considerably increased total iron content in the studied cell line, but did not influence the level of calcein-chelatable ions. DNICLDL was found to be low toxic to cells. The study suggests that DNICLDL might be a potential transducer of iron. (c) 2017 BioFactors, 44(2):192-201, 2018. PMID- 29399923 TI - Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: A propensity score-matched analysis of in-hospital outcomes in the United States. AB - INTRODUCTION: Monomorphic ventricular tachycardia (VT) is an important cause of morbidity and mortality. Use and outcome data of catheter ablation for VT in nonischemic cardiomyopathy (NICM) are limited. METHODS AND RESULTS: We obtained data from the 2003-2014 National Inpatient Sample databases. We used propensity score matching to compare patients undergoing catheter ablation versus medical therapy of VT related to NICM, and described the temporal trends in utilization and in-hospital outcomes of catheter ablation of VT in patients with NICM in the United States. From 2003 to 2014, of 133,529 patients hospitalized with the principal diagnosis of VT in NICM, 14,651 (11.0%) underwent catheter ablation. In this period, there was an increasing trend in utilization of catheter ablation (9.3% in 2003-2004 to 12.1% in 2003-2014, adjusted OR [per year], 1.12; 95% CI, 1.08-1.16; Ptrend < 0.001). After propensity score matching, in-hospital mortality occurred in 172 of 14,318 (1.2%) patients in the catheter ablation group, compared with 297 of 14,156 (2.1%) of patients undergoing medical therapy (47% lower; 43% relative difference [adjusted OR, 0.53; 95% CI, 0.43-0.66]). CONCLUSIONS: In patients with NICM, catheter ablation of VT is associated with lower in-hospital mortality compared with those managed medically. The utilization rates of CA for VT related to NICM have increased in the past decade. Adequately powered randomized trials will be necessary to confirm these findings. PMID- 29399924 TI - Oesophageal atresia: Are "long gap" patients at greater anesthetic risk? AB - BACKGROUND: Long gap oesophageal atresia occurs in approximately 10% of all oesophageal atresia infants and surgical repair is often difficult with significant postoperative complications. Our aim was to describe the perioperative course, morbidity, and early results following repair of long gap oesophageal atresia and to identify factors which may be associated with complications. METHODS: This is a single center retrospective cohort study of consecutive patients with oesophageal atresia undergoing surgical repair at The Royal Children's Hospital Melbourne from January 2006 to June 2017. RESULTS: Two hundred and thirty-nine consecutive oesophageal atresia infants included 44 long gap oesophageal atresia infants and 195 non-long gap infants. A high rate of prematurity (24.7%), major cardiac (17%), and other surgically relevant malformations (12.6%) was found in both groups. The median age at oesophageal anastomosis surgery was 65.5 days for the long gap group vs 1 day for the oesophageal atresia group (mean difference 56.8 days, 95% CI 48.1-65.5 days, P < .01). Surgery for long gap oesophageal atresia included immediate primary anastomosis (n = 10), delayed primary anastomosis (n = 11), oesophageal lengthening techniques (n = 12) and primary oesophageal replacement (n = 6). Long gap oesophageal atresia was not associated with an increased incidence of difficult intubation (OR 2.8, 95% CI 0.6-22.1, P = .17), intraoperative hypoxemia (OR 1.6, 95% CI 0.6-4.5, P = .32), or hypotension (OR 0.9, 95% CI 0.5-1.8, P = .81). The surgical duration (177.7 vs 202.1 minute, mean difference [95% CI], 28 [5.5-50.4 minutes], P = .04) and mean duration of postoperative mechanical ventilation (107 vs 199.8 hours, mean difference [95% CI], 91.8 [34.5-149.1 hours], P < .01) were shorter for the non-long gap group. Overall in-hospital mortality was 7.5% (15.9% long gap vs 5.6% non-long gap oesophageal atresia OR 1.1, 95% CI 0.4-3.4, P = .85). CONCLUSION: Long gap oesophageal atresia infants have a similar incidence of perioperative complications to other infants with oesophageal atresia. Current surgical approaches to long gap repair, however, are associated with longer anesthetic exposures and require multiple procedures in infancy to achieve oesophageal continuity. PMID- 29399925 TI - Molecular Phylogenetic Positions and Ultrastructure of Marine Gregarines (Apicomplexa) Cuspisella ishikariensis n. gen., n. sp. and Loxomorpha cf. harmothoe from Western Pacific scaleworms (Polynoidae). AB - Marine gregarines are unicellular parasites of invertebrates commonly found infecting the intestine and coelomic spaces of their hosts. Situated at the base of the apicomplexan tree, marine gregarines offer an opportunity to explore the earliest stages of apicomplexan evolution. Classification of marine gregarines is often based on the morphological traits of the conspicuous feeding stages (trophozoites) in combination with host affiliation and molecular phylogenetic data. Morphological characters of other life stages such as the spore are also used to inform taxonomy when such stages can be found. The reconstruction of gregarine evolutionary history is challenging, due to high levels of intraspecific variation of morphological characters combined with relatively few traits that are taxonomically unambiguous. The current study combined morphological data with a phylogenetic analysis of small subunit rDNA sequences to describe and establish a new genus and species (Cuspisella ishikariensis n. gen., n. sp.) of marine gregarine isolated from the intestine of a polynoid host (Lepidonotus helotypus) collected from Hokkaido, Japan. This new species possesses a set of unusual morphological traits including a spiked attachment apparatus and sits on a long branch on the molecular phylogeny. Furthermore, this study establishes a molecular phylogenetic position for Loxomorpha cf. harmothoe, a previously described marine gregarine, and reveals a new group of gregarines that infect polynoid hosts. PMID- 29399926 TI - The choice between deceased- vs living-donor renal transplantation in children: Analysis of data from a Belgian tertiary center. AB - Pediatric renal transplantation with a living donor (LD) has superior outcome, but there is a paucity of studies analyzing the reasons for not undertaking living donation in West-European countries. The aim of this study was to retrospectively review the choice of donor source in our center. We also aimed to identify factors which prevented transplantation with a LD. This retrospective study was performed including children aged 2-19 years who underwent kidney transplantation (KT) at the Ghent University Hospital between 1996 and 2016. Relevant data were collected from medical files to identify the main medical, psychological, and socio-economic factors influencing the choice of the donor source. There were 48 patients (boys n = 33) who underwent KT. Thirty-nine patients received a deceased donor (DD) kidney and nine patients received a LD kidney. Sixteen of 48 transplantations were preemptive. The reasons for DD KT included socio-economic factors such as single caregiver families, one or both parents with a criminal record or convictions and religious or cultural constraints (n = 15), medical considerations (n = 13), refusal of the close relatives/parents to donate (n = 7), and acceptance of an organ from a DD while prospective donor was undergoing medical screening (n = 4). The low incidence of living kidney donation can be explained by socio-economic and medical factors. Refusal to donate is a potentially modifiable factor and strategies aimed at education and guidance of the families might contribute to a higher incidence of living donation in our setting. PMID- 29399927 TI - Irreversible electroporation ablation for atrial fibrillation. AB - Atrial fibrillation (AF) is one of the most important problems in modern cardiology. Thermal ablation therapies, especially radiofrequency ablation (RF), are currently "gold standard" to treat symptomatic AF by localized tissue necrosis. Despite the improvements in reestablishing sinus rhythm using available methods, both success rate and safety are limited by the thermal nature of procedures. Thus, while keeping the technique in clinical practice, safer and more versatile methods of removing abnormal tissue are being investigated. This review focuses on irreversible electroporation (IRE), a nonthermal ablation method, which is based on the unrecoverable permeabilization of cell membranes caused by short pulses of high voltage/current. While still in its preclinical steps for what concerns interventional cardiac electrophysiology, multiple studies have shown the efficacy of this method on animal models. The observed remodeling process shows this technique as tissue specific, triggering apoptosis rather than necrosis, and safer for the structures adjacent the myocardium. So far, proposed IRE methodologies are heterogeneous. The number of devices (both generators and applicators), techniques, and therapeutic goals impair the comparability of performed studies. More questions regarding systemic safety and optimal processes for AF treatment remain to be answered. This work provides an overview of the electroporation process, and presents different results obtained by cardiology-oriented research groups that employ IRE ablation, with focus of AF related targets. This contribution on the topic aspires to be a practical guide to approach IRE ablation for cardiac arrhythmias, and to highlight controversial features and existing knowledge, to provide background for future improved experimentation with IRE in arrhythmology. PMID- 29399928 TI - The Un(f)told Story of General Anesthesia. AB - Inhalational anesthetics are routinely employed in clinical practice to accomplish general anesthesia. Concerns have recently emerged regarding the deleterious impact of these volatile agents on cognitive performance, immune functions, and tumor recurrence and metastasis. These agents have been shown to modify the gene-expression pattern as well as cell signaling in tumor cells, but the underlying molecular mechanisms remain a matter of conjecture. Regulatory/signaling proteins either of cytosolic or membrane origin abundantly contain intrinsically disordered sequences, the conformational pliability of which is pivotal in their biological functions. It is well known that chloroform (an anesthetic itself), trifluoroethanol, hexafluoroisopropanol, and related haloalcohols markedly affect the structure of disordered proteins and protein regions by inducing folding, misfolding, or even aggregation. Taking into consideration the physicochemical similarities and protein interaction modes of these volatile solvents and inhaled anesthetics, it is postulated that administration of these drugs can also modify the secondary structure of disordered protein segments. Accordingly, pharmacological effects of anesthetics may, at least in part, be mediated by conformational perturbations of intrinsic disorder-based regulatory protein networks of cells. PMID- 29399929 TI - Electrocardiographic parameters effectively predict ventricular tachycardia/fibrillation in acute phase and abnormal cardiac function in chronic phase of ST-segment elevation myocardial infarction. AB - BACKGROUND: Abnormal cardiac repolarization is closely associated with ventricular tachycardia/ventricular fibrillation (VT/VF). Myocardial ischemia and infarction aggravate cardiac repolarization dispersion, and VT/VF could be lethal in the early stage of ST-segment elevation myocardial infarction (STEMI). Unfortunately, VT/VF cannot be effectively predicted in current clinical practice. The present study aimed to assess electrocardiographic parameters of the sinus rhythmic complex in relation to cardiac repolarization, e.g., QT interval and T-peak to T-end interval (TpTe), to independently predict VT/VF in acute STEMI. Additionally, we hypothesized that QT and TpTe of PVC would be also valuable to predict VT/VF in STEMI. METHODS AND RESULTS: A total of 198 cases diagnosed as STEMI with PVC on admission by electrography were included. During hospitalization, VT/VF values were recorded. Logistic analysis was performed between patients with and without VT/VF to validate independent electrocardiographic predictors. QTcPVC interval > 520 ms (OR = 3.2; P = 0.027), TpTe interval > 100 ms (OR = 3.1; P = 0.04), TpTePVC > 101 ms (OR = 3.6; P = 0.029), TpTe/QT > 0.258 (OR = 5.7; P = 0.003), and TpTe/QTPVC > 0.253 (OR = 3; P = 0.048). However, QRS duration, QTc interval, coupling interval, and QRSPVC duration did not predict VT/VF. Besides, QRSPVC duration >140 ms (OR = 2.6; P = 0.001) independently predicted LVEF decrease after 1 year or more. CONCLUSIONS: QTcPVC interval, TpTe interval, TpTePVC interval, TpTe/QT ratio, and TpTe/QTPVC ratio are risk factors for ECG independent from other confounding factors in predicting VT/VF in the acute phase of STEMI. In addition, PVC characteristics as risk factors for VT/VF in acute phase and LVEF decrease in chronic phase were firstly reported. PMID- 29399930 TI - Multi-level mixed models for evaluating factors affecting the mortality and weaning weight of piglets in large-scale commercial farms in central China. AB - This study investigated the factors affecting piglet mortality (square root of mortality, SQRM) and average weaning weight (AWW) in commercial farms in central China. Information on sow diets, management and climate from 2478 weaning batches completed in 16 pig farms was collected from 2009 to 2013. Multi-level mixed models, which included batch level (level 1) and farm level (level 2), were used to analyze the factors associated with SQRM and AWW. The mean values of SQRM and AWW were 2.52% (SD = 0.96) and 7.31 (SD = 0.77), respectively. Lactation sow diets supplemented with oregano essential oils (OEOs) decreased the SQRM (P < 0.05) and increased the AWW of piglets (P < 0.01). The SQRM was lower in period 2 (June to September, hot) than in period 1 (February to May, warm) and period 3 (October to January, cold; P < 0.05 and 0.001, respectively). The AWW was lower in periods 2 and 3 than in period 1 (P < 0.01). In conclusion, supplying OEOs to lactation diets can increase the weaning weight and reduce the mortality of piglets. The sources of variations in SQRM and AWW are of greater concern in the warm season than in the hot season. PMID- 29399931 TI - Correlation of adipokines and markers of oxidative stress in women with gestational diabetes mellitus and their newborns. AB - AIM: We have shown that some markers of oxidative stress were higher in women with gestational diabetes mellitus (GDM). This study examines the relationship between adipokines and oxidative stress and their potential effects in pregnant women. METHODS: Three markers of oxidative stress (malondialdehyde, 8-isoprostane and xanthine oxidase) and three adipokines (leptin, adiponectin and resistin) were measured in maternal plasma, cord plasma and placenta of 208 pregnant women. RESULTS: Among all these women, 105 were diagnosed with GDM while the other 103 were controls. Leptin, resistin, malondialdehyde, xanthine oxidase and 8 isoprostane in maternal plasma, cord plasma and placenta were significantly higher while maternal adiponectin significantly lower in women with GDM (P < 0.05). Adipokines in maternal plasma, cord plasma and placenta were positively correlated with markers of oxidative stress. Both markers of oxidative stress and adipokines were correlated inversely with homeostasis model assessment of insulin resistance whereas positively with quantitative insulin sensitivity check index (P < 0.01). Adiponectin is negatively correlated with leptin and resistin. Placental/cord leptin and cord resistin levels were higher in the macrosomia while maternal adiponectin level was lower (P < 0.05) than normal birthweight newborns. Both markers of oxidative stress and adipokines in maternal and cord plasma are negatively correlated with newborn birthweight (P < 0.05). CONCLUSION: Adipokines interact with markers of oxidative stress, both of which lead to insulin resistance, GDM and macrosomia. It has long been known that placenta involves in the development of GDM. Adipokines might participate in this process and need to be confirmed by further studies. PMID- 29399932 TI - Size-Dependent Phase Separation in Emulsion Droplets. AB - Phase separation occurs in emulsion droplets containing poly (ethylene glycol) diacrylate (PEGDA), glycerol, and ethanol to form a glycerol-in-PEGDA structure, and the phase separation process is found to depend on the droplet size. The mechanism of this size-dependent phase separation is dependent on the droplet sizes changing the phase separation time by changing the evaporation speed of mutual solvent ethanol, and the relationship between the separation time T and the droplet diameter D is derived as T~D2 , which has been validated by experiment results. According to this finding, the structures of the droplets can be designed by applying UV curing at different stages of the phase separation, and the monodispersity of droplets is necessary to achieve polymerized particles with the same structure. PMID- 29399933 TI - Loganic Acid Methyltransferase: Insights into the Specificity of Methylation on an Iridoid Glycoside. AB - Loganin is an iridoid glycoside of interest as both an intermediate in the biosynthesis of indole alkaloids in plants and as a bioactive compound itself. Loganic acid methyltransferase catalyzes the methylation of a monoterpenoid glycoside precursor to produce loganin and demonstrates stereospecificity for the (6S,7R) substrate. We have biochemically characterized this biocatalyst and elucidated the basis for its strict substrate specificity. These studies could help facilitate the design of new classes of monoterpenoid indole alkaloids of pharmaceutical interest. PMID- 29399934 TI - Predictors of health-promoting behaviors in children from low-income families: An ecological approach. AB - In this study, we investigated the ecological factors that influence health promoting behaviors in children from low-income families in South Korea using a descriptive correlational design. The participants included 297 elementary school students who used community childcare centers, 297 caregivers, and 68 teachers at the centers. Data were collected using a structured self-report survey, and were subjected to a multi-level regression analysis. The factors influencing the health-promoting behaviors of children were as follows: self-efficacy and self regulation as intrapersonal factors; caregivers' parenting behavior and peer relationships as interpersonal factors; and the number of months since the centers' establishment, teachers workloads, and centers' perceived environments as institutional factors. The findings emphasize the need to create a healthy environment to promote the health of children from vulnerable groups, and that community-based participatory research might be an effective strategy to address these environmental problems, and ultimately help reduce health disparities between children. PMID- 29399935 TI - Spin-Noise-Detected Two-Dimensional Nuclear Magnetic Resonance at Triple Sensitivity. AB - A major breakthrough in speed and sensitivity of 2 D spin-noise-detected NMR is achieved owing to a new acquisition and processing scheme called "double block usage" (DBU) that utilizes each recorded noise block in two independent cross correlations. The mixing, evolution, and acquisition periods are repeated head-to tail without any recovery delays and well-known building blocks of multidimensional NMR (constant-time evolution and quadrature detection in the indirect dimension as well as pulsed field gradients) provide further enhancement and artifact suppression. Modified timing of the receiver electronics eliminates spurious random excitation. We achieve a threefold sensitivity increase over the original snHMQC (spin-noise-detected heteronuclear multiple quantum correlation) experiment (K. Chandra et al., J. Phys. Chem. Lett. 2013, 4, 3853) and demonstrate the feasibility of spin-noise-detected long-range correlation. PMID- 29399936 TI - Train-of-four recovery precedes twitch recovery during reversal with sugammadex in pediatric patients: A retrospective analysis. AB - BACKGROUND: After reversal of a rocuronium-induced neuromuscular blockade with sugammadex, the recovery of train-of-four ratio to 0.9 is faster than recovery of first twitch of the train-of-four to 90% in adults. These findings after reversal of neuromuscular blockade with sugammadex have not yet been investigated in pediatric patients. AIMS: The aim of this retrospective analysis was to investigate the relationship of the recovery of first twitch of the train-of-four height and train-of-four ratio after reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric patients. METHODS: Patients ASA I-III, aged 2-11 years, and who underwent abdominal and/or perineal surgery were included in the analysis. After extracting the necessary data from the hospital database, the patients were divided into 2 groups based on the dose of sugammadex received: group A: 2 mg.kg-1 for reversal of moderate neuromuscular blockade and group B: 4 mg.kg-1 for reversal of deep neuromuscular blockade. The relationship of the recovery of first twitch of the train-of-four height and train-of-four ratio in these 2 groups were analyzed. RESULTS: Data from 43 pediatric patients aged 2-11 years could be analyzed. The first twitch of the train-of-four height at the recovery of train-of-four ratio to 0.9 in group B was statistically significantly lower compared with group A. This height 3 and 5 minutes after the train-of-four ratio reached 0.9 showed no statistically significant differences between groups. CONCLUSION: The results were in line with the results found in adults and showed that the train-of-four ratio recovered to 0.9 was faster than first twitch of the train-of-four height recovered to the same level. PMID- 29399937 TI - First case of the migrating MiniMizer ring. PMID- 29399938 TI - Neoadjuvant radiotherapy provided survival benefit compared to adjuvant radiotherapy for hepatocellular carcinoma. AB - BACKGROUND: This study compared the impact of neoadjuvant radiotherapy (RT) and adjuvant RT on survival for patients with hepatocellular carcinoma (HCC). METHODS: Patients with HCC were identified from the Surveillance, Epidemiology and End Results (SEER) database. The Kaplan-Meier method and multivariate Cox regression analysis were used to compare the impact of neoadjuvant RT on survival with adjuvant RT. Subsequently, a propensity score-matched analysis was performed to confirm the result. RESULTS: A total of 244 patients with HCC identified from the SEER database (2004-2014) received preoperative or post-operative radiation. A total of 151 patients received post-operative RT and 93 patients received preoperative RT. Preoperative RT had a clear superiority in terms of unadjusted overall survival and cancer-specific survival (P < 0.001 for log-rank test). After adjusting for confounding variables, hazard ratios (HRs) for all-cause (HR: 0.33; 95% CI: 0.19-0.53, P < 0.001) and cancer-specific (HR: 0.32; 95% CI: 0.19 0.53, P < 0.001) mortality risks in preoperative RT group were significantly lower than that of post-operative RT group. Subsequently, a propensity score matched analysis was performed to confirm this result. Further univariate and multivariate survival analyses revealed that there was a persistent superiority of overall survival and cancer-specific survival in patients who received preoperative radiation than patients without RT. CONCLUSION: We found that neoadjuvant RT was associated with improved long-term survival for patients with HCC versus adjuvant RT. PMID- 29399939 TI - Online Social Interactions Predict Academic and Emotional Adjustment in the Transition to University. AB - We investigated the developmental implications of online social interactions among 590 youth transitioning to university. We observed friends' posts on participants' Facebook pages, and considered attributes of friends' posts used to indicate positive and negative relationship quality in face-to-face interactions. After statistical control of beginning-of-year functioning and participants' Facebook content, Facebook friends' deviant content posts (swearing; illegal/sexualized activities) predicted participants' lower grade point average, Facebook friends' posts indicating connection to participants predicted participants' lower psychopathology, and Facebook friends' verbal aggression posts predicted participants' lower institutional attachment, by the end of the year. Negative effects of friends' posts were strongest for participants who were disliked by peers face to face. The online context may uniquely influence youth adjustment in conjunction with face-to-face relationships. PMID- 29399940 TI - General hospital health professionals' attitudes and perceived dangerousness towards patients with comorbid mental and physical health conditions: Systematic review and meta-analysis. AB - The stigmatization of mental health is present in general hospital settings impacting quality of care. We hypothesized that health professionals in these areas would elicit negative attitudes and a perceived level of dangerousness across a range of mental health disorders. We aimed to conduct a systematic review and meta-analysis to examine these attitudes and perceptions. We searched the bibliographic databases of CINAHL Complete, MEDLINE Complete, PsycINFO, and Psychology and Behavioral Sciences Collection in May 2017 (no date parameters were set). Quantitative studies investigating generalist health professionals' attitudes towards mental health conditions were selected. Initially, prevalence meta-analyses were conducted to assess the extent of perceived danger, followed by a series of comparative meta-analyses in which the perceived dangerousness of mental health conditions was compared. Of the 653 citations retrieved, eight studies met the inclusion criteria. The overall sample included 2548 health professionals. A majority of health professionals perceived patients with substance use disorder as dangerous 0.60 (95% CI: 0.32-0.88) when compared with patients who had an alcohol-related disorder, schizophrenia, and depression. The results also indicated that a large proportion of staff perceived patients with a diagnosis of schizophrenia as dangerous 0.42 (95% CI: 0.33-0.52). Negative attitudes towards people experiencing mental illness in general hospital settings may be attributed to poor mental health literacy, skills and limited exposure, and social and cultural beliefs about mental illness. Ongoing professional development targeting mental health knowledge is recommended for health professionals working in general hospital settings. PMID- 29399941 TI - Esthetic and functional management of an ankylosed central incisor with a conservative restorative approach. AB - In this case report, we share a conservative and simple restorative management approach for a relatively complex esthetic situation on an adult patient with an ankylosed maxillary central incisor in infra-occlusion. A 37-year-old healthy female patient presented for a consultation with a chief complaint of an unappealing smile. The intraoral exam revealed tooth #8 (FDI 11) was in obvious and significant infra-occlusion due to altered eruption. Periapical radiographs of this area were non-contributory and all teeth responded within normal limits to pulp vitality tests. After review of several treatment options, the patient opted for a conservative restorative approach in which a partial ceramic veneer was planned for the ankylosed tooth, while composite resin was used on the contralateral central incisor to achieve a symmetric and pleasant result. CLINICAL SIGNIFICANCE: A relatively complex clinical problem was satisfactorily resolved with a very conservative option in which composite resin and a ceramic veneer were used to restore an asymmetric smile. PMID- 29399942 TI - Basic nursing care: The most provided, the least evidence based - A discussion paper. AB - AIMS AND OBJECTIVES: To describe and discuss the "Basic Care Revisited" (BCR) research programme, a collaborative initiative that contributes to evidence-based basic nursing care and raises awareness about the importance of basic nursing care activities. BACKGROUND: While basic nursing care serves nearly all people at some point in their lifetime, it is poorly informed by evidence. There is a need to prioritise and evaluate basic nursing care activities to improve patient outcomes and improve the quality of care. DESIGN: Discussion paper METHOD: The discussion presented in this paper is based on nursing literature and theory and supported by the authors' clinical and research experiences. We present the developmental process and content of a research programme called "Basic Care Revisited" (BCR) as a solution to move forward and improve basic nursing care. DISCUSSION: To prioritise basic nursing care, we propose a research programme entitled "Basic Care Revisited" that aims to create awareness and expand knowledge on evidence-based basic nursing care by addressing four basic nursing care themes (bathing and dressing, communication, mobility, and nutrition) in different settings. The paper discusses a pathway to create a sustainable and productive research collaborative on basic nursing care and addresses issues to build research capacity. RELEVANCE TO CLINICAL PRACTICE: Revaluation of these important nursing activities will not only positively influence patient outcomes, but also have an impact on staff outcomes and organisational outcomes. PMID- 29399944 TI - The fluorescence quenching of Ru(bipy)32+ : an application for the determination of bilirubin in biological samples. AB - A simple, sensitive and efficient fluorescence method has been established for the quantitative analysis of bilirubin. The fluorometric determination method was based on the kinetic quenching of ruthenium(II) fluorescence. The quenching effect may be due to the complexation reaction of bilirubin with ruthenium(II). Therefore, the effects of ruthenium concentrations and different surfactants have been studied. Under the optimized experimental parameters, the fluorescence intensity decreased proportionally with the bilirubin concentration and linearity was established in the range of 3.3 * 10-7 to 3.0 * 10-4 M bilirubin. The detection limit calculated from the calibration graph was found to be 5.2 * 10-8 M. The relative standard deviation (RSD) of 10 consecutive measurements of 8.0 * 10-6 M bilirubin was 3.0%, while the recoveries of bilirubin in both human serum and urine samples were obtained in the range 94.0-99.5%. The interference study shows that the developed fluorescence based technique is fast, easy to carry out and shows negligible interference. The developed technique was successfully applied for the analysis of bilirubin in human urine and serum samples. All the experimental results and quality parameters confirmed the sensitivity and reproducibility of the proposed technique for bilirubin determination in human urine and serum samples. PMID- 29399943 TI - High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men. AB - The biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high-throughput proteomics approach to identify serum peptides and proteins associated with 5-year mortality in community-dwelling men age >=65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography-ion mobility-mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri-annual questionnaire. Rigorous statistical methods were utilized to identify 56 peptides (31 proteins) that were associated with 5-year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality-associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g., C-reactive protein, alpha 1-antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy-associated plasma protein, VE-cadherin, leucine-rich alpha-2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptor, and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5-year mortality risk. This work may serve to identify novel biomarkers for near term mortality. PMID- 29399945 TI - Attachment style among outpatients with substance use disorders in psychological treatment. AB - OBJECTIVES: To explore the associations between self-rated attachment style, psychological distress and substance use among substance use disorder (SUD) outpatients in psychological treatment. DESIGN AND METHODS: In this practice based study, 108 outpatients were asked to fill in the Experiences in Close Relationships - Short form, the Clinical Outcomes in Routine Evaluation - Outcome Measure (CORE-OM), the Alcohol Use Disorders Identification Test (AUDIT), and the Drug Use Disorders Identification Test (DUDIT) at treatment start and end. Patients were given psychological treatments with a directive, reflective or supportive orientation. RESULTS: An insecure attachment style was more common among the SUD outpatients, compared to non-clinical groups. Patients with a fearful attachment style scored higher on psychological distress than patients with a secure attachment style. The associations between the attachment dimensions and psychological distress were stronger than those between attachment and SUD. Significantly more patients had a secure attachment style at treatment end. CONCLUSIONS: This study shows significant relations between patients' attachment style and their initial psychological distress. The causal relationship between attachment style and psychological distress is, however, not clear and can likely go in both directions. The psychological treatment of patients with SUD contributed significantly to changes from insecure to secure attachment style. PRACTITIONER POINTS: We found among patients with SUD a strong relation between patients' attachment style and their psychological distress. Knowledge of the patient's attachment style may help the therapist to tailor the treatment to the patient's needs. A change from insecure to secure attachment style can be an important goal for a SUD treatment, as it may prevent the patient from using defence strategies involving substance use for regulating emotions and interpersonal relationships. PMID- 29399946 TI - Techniques for trans-catheter retrieval of embolized Nit-Occlud(r) PDA-R and ASD R devices. AB - BACKGROUND: Nit-Occlud(r) (atrial septal defect) ASD-R and (patent ductus arteriosus) PDA-R devices are used outside the United States for percutaneous closure of the patent ductus arteriosus and atrial septal defects. When embolization occurs, these devices have been difficult to retrieve. METHODS: Bench simulations of retrieval of PDA-R and ASD-R devices were performed in a vascular model. Retrieval of each device was attempted using snare techniques or with bioptome forceps with a range of devices. The same devices were then intentionally embolized in an animal model. Retrieval methods were systematically tested in a range of sheath sizes, and graded in terms of difficulty and retrieval time. RESULTS: Devices that were grasped by the bioptome in the center of the proximal part of the devices were easily retrieved in both models. Bench studies determined the minimum sheath sizes needed for retrieval of each device with this method. In general sheathes two french sizes greater than the delivery sheath were successful with this technique. Three out of the four PDA-R devices were successfully retrieved in vivo. Two were retrieved by grasping the middle of the PA end of the PDA-R device with a Maslanka bioptome and one small PDA-R device was retrieved using a 10 mm Snare. Four of the five ASD-R devices were retrieved successfully grasping the right atrial ASD-R disc or by passing a wire through the device and snaring this loop. For ASD-R 28 and 30 mm devices, a double bioptome technique was needed to retrieve the device. CONCLUSION: ASD-R and PDA-R devices can be successfully retrieved in the catheterization lab. It is critical to grab the center portion of the right atrial disc of the ASD-R device or pulmonary portion of the PDA-R device and to use adequately sized sheathes. PMID- 29399947 TI - Supra-annular structure assessment for self-expanding transcatheter heart valve size selection in patients with bicuspid aortic valve. AB - OBJECTIVES: To explore assessment of supra-annular structure for self-expanding transcatheter heart valve (THV) size selection in patients with bicuspid aortic stenosis (AS). BACKGROUND: Annulus-based device selection from CT measurement is the standard sizing strategy for tricuspid aortic valve before transcatheter aortic valve replacement (TAVR). Because of supra-annular deformity, device selection for bicuspid AS has not been systemically studied. METHODS: Twelve patients with bicuspid AS who underwent TAVR with self-expanding THVs were included in this study. To assess supra-annular structure, sequential balloon aortic valvuloplasty was performed in every 2 mm increments until waist sign occurred with less than mild regurgitation. Procedural results and 30 day follow up outcomes were analyzed. RESULTS: Seven patients (58.3%) with 18 mm; three patients (25%) with sequential 18 mm, 20 mm; and only two patients (16.7%) with sequential 18 mm, 20 mm, and 22 mm balloon sizing were performed, respectively. According to the results of supra-annular assessment, a smaller device size (91.7%) was selected in all but one patient compared with annulus based sizing strategy, and the outcomes were satisfactory with 100% procedural success. No mortality and 1 minor stroke were observed at 30 d follow-up. The percentage of NYHA III/IV decreased from 83.3% (9/12) to 16.7% (2/12). No new permanent pacemaker implantation and no moderate or severe paravalvular leakage were found. CONCLUSIONS: A supra-annular structure based sizing strategy is feasible for TAVR in patients with bicuspid AS. PMID- 29399949 TI - Adaptive behavior in infants and toddlers with Down syndrome and fragile X syndrome. AB - Individuals with Down syndrome (DS) experience deficits across all domains of adaptive functioning, however little is known about the emergence and age-related changes of these impairments compared to other neurogenetic disorders with similar intellectual disability impairments, such as fragile X syndrome (FXS). Adaptive behavior is key for optimal functioning in these populations. Participants aged 5-45 months comprised three age-matched groups, DS (n = 64), FXS (n = 69), and typically developing controls (TD; n = 69). Adaptive behavior was measured on the Vineland Adaptive Behavior Scales-II. Regressions were used to examine adaptive behavior in a cross-sectional design across age. DS infants and toddlers evidenced deficits across all areas of adaptive behaviors compared to the age-matched TD group, with clear impairments present in the first year of life. Motor skills were the area of greatest weakness in children with DS with significant impairment evident at 12 months of age that remained low through 3 years. Compared to age-matched children with FXS, children with DS showed initially lower standard scores at 12 months of age, but slower declines in standard scores across age, resulting in less impaired functioning at 36 months. This is the first study to compare adaptive behavior in infants and toddlers with DS to FXS, and demonstrate the phenotypic specificity of adaptive profiles in this diagnostic group. These findings provide evidence that adaptive behavior should be a major target of intervention in children with FXS and DS, and that these differences are potentially driven by unique etiologies attributable to each disorder. PMID- 29399950 TI - A literature review on the new polymer-infiltrated ceramic-network material (PICN). AB - OBJECTIVES: Ceramics and composites are the most used materials for dental application. Recently, the characteristics of both were combined on the called "polymer-infiltrated ceramic-network" (PICN). The aim of this review is to report the behavior of PICN, comparing the findings that may support the correct clinical application. OVERVIEW: The PICN material is a structure with a sintered ceramic matrix infiltrated with a polymer matrix. Studies evaluated this material microstructure and composition, mechanical properties and adhesive behavior. The most cited mechanical properties are flexural strength, compressive strength, elastic modulus, Weibull modulus, hardness, fracture toughness and fatigue resistance. Most studies compared PICN with feldspathic porcelain, lithium disilicate glass-ceramic, lithium silicate, zirconia-reinforced glass-ceramic, leucite reinforced glass-ceramic, polycrystalline alumina and zirconia. Other studies evaluated a similar material (a nanoceramic resin). CLINICAL SIGNIFICANCE: The mechanical properties of the PICN are equivalent to the properties of nanoceramic resins, lower to lithium disilicate glass ceramic and superior to feldspathic porcelain. Yet, the findings suggest a highly resistant material to degradation at low loads (close to physiological situation) when cemented on a substrate. PMID- 29399948 TI - A parent-of-origin analysis of paternal genetic variants and increased risk of conotruncal heart defects. AB - The association between conotruncal heart defects (CTHDs) and maternal genetic and environmental exposures is well studied. However, little is known about paternal genetic or environmental exposures and risk of CTHDs. We assessed the effect of paternal genetic variants in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs in offspring. We utilized National Birth Defects Prevention Study data to conduct a family-based case only study using 616 live-born infants with CTHDs, born October 1997-August 2008. Maternal, paternal and infant DNA was genotyped using an Illumina(r) Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR) and 95% confidence intervals (CI) from log-linear models determined parent of origin effects for 921 SNPs in 60 candidate genes involved in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs. The risk of CTHD among children who inherited a paternally derived copy of the A allele on GLRX (rs17085159) or the T allele of GLRX (rs12109442) was 0.23 (95%CI: 0.12, 0.42; p = 1.09 * 10-6 ) and 0.27 (95%CI: 0.14, 0.50; p = 2.06 * 10-5 ) times the risk among children who inherited a maternal copy of the same allele. The paternally inherited copy of the GSR (rs7818511) A allele had a 0.31 (95%CI: 0.18, 0.53; p = 9.94 * 10-6 ] risk of CTHD compared to children with the maternal copy of the same allele. The risk of CTHD is less influenced by variants in paternal genes involved in the folate, homocysteine, or transsulfuration pathways than variants in maternal genes in those pathways. PMID- 29399951 TI - A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells. AB - Bone metastasis occurs at ~70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 um thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis. PMID- 29399952 TI - The last taboo: The experience of violence in first-episode psychosis caregiving relationships. AB - OBJECTIVES: Informal caregiving relationships play an important role in facilitating recovery outcomes in psychosis. The relationship can serve as a source of positive experiences that co-exist alongside common challenges typically associated with mental health problems. People with psychosis, when compared to the general population, are more likely to perpetrate acts of violence, a relationship that is particularly evident during the first psychosis episode. Although victims of service user violence are typically people already known to them, such as informal carers, there remains a lack of understanding about their caring experiences and needs. This study sought to address gaps in the literature by exploring the subjective accounts of informal carers supporting a relative experiencing their first episode of psychosis who has also behaved violently towards them. DESIGN: A cross-sectional design was employed. METHODS: Individual semi-structured interviews, which were audio recorded and later transcribed for analyses, were undertaken with a convenience sample of eight carers drawn from a specialist early psychosis service. Interview questions focused on their experiences of patient violence, the subjective impact, and coping strategies. An interpretative phenomenological approach was used to analyse the data. RESULTS: Participants were mostly living with their relative with psychosis and were typically female, parents, and from a black and minority ethnic background. Data analyses identified seven key themes from participant interviews including the lack of predictability over when the violence occurred, being scared and fearful, keeping quiet about what happens at home and in the caregiving relationship, and staying safe. CONCLUSIONS: Reports by informal carers about experiencing violence and victimization from their relatives with psychosis are an important issue in some caregiving relationships during the first episode. Developing a more informed understanding of the specific needs of these carers and the caregiving relationship is indicated. The implications for service providers are discussed. PRACTITIONER POINTS: Carers were exposed to a broad range of patient violence, which included being kicked and having weapons used against them. The violence typically occurred within carers' homes, when no other people were around. Patient violence impacted negatively on carer emotional and physical functioning, which included leaving carers living in fear of their own safety and what might become of their relative. The results highlight the importance of routinely asking first-episode carers about their experience of patient violence. The development of interventions (e.g., identification of early triggers, de-escalation) that are able to take account of the ongoing nature and complexity of the caregiving relationship but are purposefully aimed at supporting carers to remain safe in their relationship should be explored for their impact. PMID- 29399953 TI - History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands. AB - The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands. PMID- 29399954 TI - Proton-Gated Rectification Regimes in Nanofluidic Diodes Switched by Chemical Effectors. AB - During the last decade, nanofluidic devices based on solid-state nanopores and nanochannels have come into scene in materials science and will not leave anytime soon. One of the main reasons for this is the excellent control over ionic transport exerted by such devices that promises further important advances when integrated into more complex molecular devices. As a result, pH, temperature, and voltage-regulated devices have been obtained. However, nowadays, there is still a necessity for molecule-driven nanofluidic devices. Here, a sugar-regulated pH responsive nanofluidic diode is presented obtained by surface modification of conical polycarbonate nanochannels with electropolymerized 3-aminophenylboronic acid. Control over the ionic transport has been achieved by a successful decoration of asymmetric nanochannels with integrated molecular systems. The as synthesized boronate-appended zwitterionic polymer exhibits an acid-base equilibrium that depends on the concentration of sugar, which ultimately acts as a chemical effector setting different pH-dependent rectification regimes. As a result, the same nanodevice can perform completely different proton-regulated nanofluidic operations, i.e., anion-driven rectification, cation-driven rectification, and no rectification, by simply varying the concentration of fructose in the electrolyte solution. PMID- 29399956 TI - Mentalizing countertransference? A model for research on the elaboration of countertransference experience in psychotherapy. AB - As a construct, the elaboration of countertransference experience (ECE) is intended to depict the implicit and explicit psychological work to which therapists submit their experiences with clients. Through ECE, defined as a mentalizing process of a particular kind, therapists' experiences are presumed to acquire and increase in mental quality and become available for meaning-making and judicious clinical use. In this paper, we claim that such an ongoing process facilitates engagement with common therapeutic factors, such as the therapeutic alliance and countertransference management, enhancing therapist responsiveness in psychotherapy. We synthesize relevant literature on countertransference, mentalization, and, in particular, therapists' mentalization, informed by a systematic literature review. As a result, we propose a model for assessing ECE in psychotherapy, comprising 6 diversely mentalized countertransference positions (factual-concrete, abstract-rational, projective-impulsive, argumentative, contemplative-mindful, and mentalizing), 2 underlying primary dimensions (experiencing, reflective elaboration), and 5 complementary dimensions of elaboration. Strengths and limitations of the model are discussed. PMID- 29399955 TI - Hydrogen Bond Induces Hierarchical Self-Assembly in Liquid-Crystalline Block Copolymers. AB - Microphase-separated structures of block copolymers (BCs) with a size of sub-10 nm are usually obtained by hydrogen-bond-induced self-assembly of BCs through doping with small molecules as functional additives. Here, fabrication of hierarchically self-assembled sub-10 nm structures upon microphase separation of amphiphilic liquid-crystalline BCs (LCBCs) at the existence of hydrogen bonds but without any dopants is reported. The newly introduced urethane groups in the side chain of the hydrophobic block of LCBCs interact with the ether groups of the hydrophilic poly(ethylene oxide) (PEO) block, leading to imperfect crystallization of the PEO blocks. Both crystalline and amorphous domains coexist in the separated PEO phase, enabling a lamellar structure to appear inside the PEO nanocylinders. This provides an elegant method to fabricate controllable sub 10 nm microstructures in well-defined polymer systems without the introduction of any dopants. PMID- 29399957 TI - Amorphous Red Phosphorus Embedded in Sandwiched Porous Carbon Enabling Superior Sodium Storage Performances. AB - The red P anode for sodium ion batteries has attracted great attention recently due to the high theoretical capacity, but the poor intrinsic electronic conductivity and large volume expansion restrain its widespread applications. Herein, the red P is successfully encapsulated into the cube shaped sandwich-like interconnected porous carbon building (denoted as P@C-GO/MOF-5) via the vaporization-condensation method. Superior cycling stability (high capacity retention of about 93% at 2 A g-1 after 100 cycles) and excellent rate performance (502 mAh g-1 at 10 A g-1 ) can be obtained for the P@C-GO/MOF-5 electrode. The superior electrochemical performance can be ascribed to the successful incorporation of red P into the unique carbon matrix with large surface area and pore volume, interconnected porous structure, excellent electronic conductivity and superior structural stability. PMID- 29399958 TI - Green Synthesis of Hierarchically Porous Carbon Nanotubes as Advanced Materials for High-Efficient Energy Storage. AB - Hierarchically porous carbon nanomaterials with well-defined architecture can afford a promising platform for effectively addressing energy and environmental concerns. Herein, a totally green and straightforward synthesis strategy for the fabrication of hierarchically porous carbon nanotubes (HPCNTs) by a simple carbonization treatment without any assistance of soft/hard templates and activation procedures is demonstrated. A high specific surface area of 1419 m2 g 1 and hierarchical micro-/meso-/macroporosity can be achieved for the HPCNTs. The unique porous architecture enables the HPCNTs serving as excellent electrode/host materials for high-performance supercapacitors and Li-sulfur batteries. The design strategy may pave a new avenue for the rational synthesis of hierarchically porous carbon nanostructures for high-efficient energy storage applications. PMID- 29399959 TI - Re: Quality of warfarin therapy and risk of stroke, bleeding, and mortality among patients with atrial fibrillation. PMID- 29399960 TI - Flexible Lithium-Ion Batteries with High Areal Capacity Enabled by Smart Conductive Textiles. AB - Increasing demand for flexible devices in various applications, such as smart watches, healthcare, and military applications, requires the development of flexible energy-storage devices, such as lithium-ion batteries (LIBs) with high flexibility and capacity. However, it is difficult to ensure high capacity and high flexibility simultaneously through conventional electrode preparation processes. Herein, smart conductive textiles are employed as current collectors for flexible LIBs owing to their inherent flexibility, fibrous network, rough surface for better adhesion, and electrical conductivity. Conductivity and flexibility are further enhanced by nanosizing lithium titanate oxide (LTO) and lithium iron phosphate (LFP) active materials, and hybridizing them with a flexible 2D graphene template. The resulting LTO/LFP full cells demonstrate high areal capacity and flexibility with tolerance to mechanical fatigue. The battery achieves a capacity of 1.2 mA h cm-2 while showing excellent flexibility. The cells demonstrate stable open circuit voltage retention under repeated flexing for 1000 times at a bending radius of 10 mm. The discharge capacity of the unflexed battery is retained in cells subjected to bending for 100 times at bending radii of 30, 20, and 10 mm, respectively, confirming that the suggested electrode configuration successfully prevents structural damage (delamination or cracking) upon repeated deformation. PMID- 29399961 TI - Dispersion Polymerization of Substituted Acetylenes in the Presence of Chiral Source for Preparing Monodispersed Chiral Nanoparticles. AB - Chiral helical polymer nanoparticles have constituted a significant category of advanced functional particles by creatively combining chirality with nanoscale size into one unity. However, their further progress has been confronted with intractable difficulties, especially due to the limited kinds and number of chiral monomers and the lack of effective and universal preparation methods. In this study, the first protocol, that is, dispersion polymerization, for preparing monodispersed, chiral helical polymer nanoparticles derived from substituted acetylenic monomers, is reported. The possible formation mechanism of polymer nanoparticles is proposed. More excitingly, achiral monomers subsequently undergo helix-sense-selective dispersion polymerization with d(l)-lactide as chiral additive, directly leading to optically active helical polymer nanoparticles. The present study not only provides a novel approach for preparing chiral helical polymer nanoparticles but also significantly expands the type and number of monomers for constructing chiral nanoparticles. PMID- 29399962 TI - Tailoring Highly N-Doped Carbon Materials from Hexamine-Based MOFs: Superior Performance and New Insight into the Roles of N Configurations in Na-Ion Storage. AB - To prepare highly N-doped carbon materials (HNCs) as well as to determine the influence of N dopants on Na-ion storage performance, hexamine-based metal organic frameworks are employed as new and efficient precursors in the preparation of HNCs. The HNCs possess reversible capacities as high as 160 and 142 mA h g-1 at 2 A g-1 (~8 C) and 5 A g-1 (~20 C), respectively, and maintain values of 145 and 123 mA h g-1 after 500 cycles, thus exhibiting excellent rate and long-term cyclic performance. Based on systematic analysis, a new insight into the roles of the different N configurations in Na-ion storage is proposed. The adsorption of Na ions on pyridinic-N (N-6) and pyrrolic-N (N-5) is fully irreversible, whereas the adsorption on graphitic-N (N-Q) is partially reversible and the adsorption on N-oxide (N-O) is fully reversible. More importantly, the N 6/N-Q ratio is an intrinsic parameter that reflects the relationship between the N configurations and carbon textures for N-doped carbons prepared from in situ pyrolysis of organic precursors. The cyclic stability and rate-performance improve with decreasing N-6/N-Q ratio. Therefore, this work is of great significance for the design of N-doped carbon electrodes with high performance for sodium ion batteries. PMID- 29399963 TI - Scalable 2D Mesoporous Silicon Nanosheets for High-Performance Lithium-Ion Battery Anode. AB - Constructing unique mesoporous 2D Si nanostructures to shorten the lithium-ion diffusion pathway, facilitate interfacial charge transfer, and enlarge the electrode-electrolyte interface offers exciting opportunities in future high performance lithium-ion batteries. However, simultaneous realization of 2D and mesoporous structures for Si material is quite difficult due to its non-van der Waals structure. Here, the coexistence of both mesoporous and 2D ultrathin nanosheets in the Si anodes and considerably high surface area (381.6 m2 g-1 ) are successfully achieved by a scalable and cost-efficient method. After being encapsulated with the homogeneous carbon layer, the Si/C nanocomposite anodes achieve outstanding reversible capacity, high cycle stability, and excellent rate capability. In particular, the reversible capacity reaches 1072.2 mA h g-1 at 4 A g-1 even after 500 cycles. The obvious enhancements can be attributed to the synergistic effect between the unique 2D mesoporous nanostructure and carbon capsulation. Furthermore, full-cell evaluations indicate that the unique Si/C nanostructures have a great potential in the next-generation lithium-ion battery. These findings not only greatly improve the electrochemical performances of Si anode, but also shine some light on designing the unique nanomaterials for various energy devices. PMID- 29399964 TI - Penne-Like MoS2 /Carbon Nanocomposite as Anode for Sodium-Ion-Based Dual-Ion Battery. AB - The dual-ion battery (DIB) system has attracted great attention owing to its merits of low cost, high energy, and environmental friendliness. However, the DIBs based on sodium-ion electrolytes are seldom reported due to the lack of appropriate anode materials for reversible Na+ insertion/extraction. Herein, a new sodium-ion based DIB named as MoS2 /C-G DIB using penne-like MoS2 /C nanotube as anode and expanded graphite as cathode is constructed and optimized for the first time. The hierarchical MoS2 /C nanotube provides expanded (002) interlayer spacing of 2H-MoS2 , which facilitates fast Na+ insertion/extraction reaction kinetics, thus contributing to improved DIB performance. The MoS2 /C-G DIB delivers a reversible capacity of 65 mA h g-1 at 2 C in the voltage window of 1.0 4.0 V, with good cycling performance for 200 cycles and 85% capacity retention, indicating the feasibility of potential applications for sodium-ion based DIBs. PMID- 29399965 TI - Magnetic Gated Biomimetic Artificial Nanochannels for Controllable Ion Transportation Inspired by Homing Pigeon. AB - The homing pigeon-inspired artificial nanochannel can be modulated by moderate magnetic field in a fast and noncontacting way. The ionic current, as well as rectifying ability and conductance is controlled by the magnetic field reversibly through elastic deformation of the nanochannel. Different gating effects are obtained at the two sides of the asymmetrically conical nanochannel due to the different response models. The magnetic gated nanochannel system also exhibits an excellent stability and a quick response in a noncontacting way, which may be promising in electronic devices related to biological or healthcare applications. PMID- 29399966 TI - Morphologically 'invisible' proinsulin - secreting adenoma detected by Ga-68 Exendin-4 (GLP-1 Receptor) positron emission tomography/CT. AB - This case report of a young man suffering from recurring hypoglycaemia illustrates a rare condition of a neuroendocrine tumour, predominantly secreting proinsulin and invisible to conventional imaging approaches. Only a GLP-1 receptor PET/CT using Exendin-4 visualized the pancreatic lesion and enabled curative therapy, confirming the diagnostic value of this tracer for detection of neuroendocrine tumours. As only few publications on this topic are available, an overview of the available data is also given. The known cut-off value of 60% for proinsulin level indicating malignancy is critically discussed. PMID- 29399967 TI - Exosomes derived from B16F0 melanoma cells alter the transcriptome of cytotoxic T cells that impacts mitochondrial respiration. AB - : While recent clinical studies demonstrate the promise of cancer immunotherapy, a barrier for broadening the clinical benefit is identifying how tumors locally suppress cytotoxic immunity. As an emerging mode of intercellular communication, exosomes secreted by malignant cells can deliver a complex payload of coding and noncoding RNA to cells within the tumor microenvironment. Here, we quantified the RNA payload within tumor-derived exosomes and the resulting dynamic transcriptomic response to cytotoxic T cells upon exosome delivery to better understand how tumor-derived exosomes can alter immune cell function. Exosomes derived from B16F0 melanoma cells were enriched for a subset of coding and noncoding RNAs that did not reflect the abundance in the parental cell. Upon exosome delivery, RNAseq revealed the dynamic changes in the transcriptome of CTLL2 cytotoxic T cells. In analyzing transiently coexpressed gene clusters, pathway enrichment suggested that the B16F0 exosomal payload altered mitochondrial respiration, which was confirmed independently, and upregulated genes associated with the Notch signaling pathway. Interestingly, exosomal miRNA appeared to have no systematic effect on downregulating target mRNA levels. DATABASES: Gene expression data are available in the GEO database under the accession SuperSeries number GSE102951. PMID- 29399968 TI - Utility of 18F-fluorodeoxyglucose-positron emission tomography in the differential diagnosis of benign and malignant gynaecological tumours. AB - INTRODUCTION: Positron emission tomography/computed tomography (PET/CT) involving 18F-fluorodeoxyglucose (FDG) is widely used for systemic cancer and recurrence diagnosis. However, the differential diagnosis of benign and malignant gynaecological tumours according to FDG accumulation is unclear. This study aimed to investigate the intensity of FDG uptake/metabolic activity for the differential diagnosis of benign and malignant gynaecological tumours. METHODS: This study included seven patients with physiological phenomena, 34 with benign tumours, 13 with borderline malignant tumours and 119 with malignant tumours who underwent 18F-FDG PET/CT. We assessed the maximum standardized uptake value (SUVmax) and determined its utility in the diagnosis of benign and malignant tumours using a receiver operating characteristic (ROC) curve analysis. RESULTS: Among the 63 patients with ovarian tumours, the mean SUVmax of 22 patients with benign ovarian tumours was 2.48 and the mean SUVmax of 41 patients with malignant ovarian tumours was 10.98 (P < 0.001). In the ROC curve analysis, the area under the curve (AUC) was 0.977, with a 95% confidence interval of 0.947-1.000. With a cut-off value of 3.97 for the optimal SUVmax, the sensitivity and specificity were 95.1% and 86.4%, respectively. In addition, the AUC was 0.911 (95% CI: 0.768 1.000) for the assessment of uterine myomas and sarcomas. With a cut-off value of 10.62 for the optimal SUVmax, the sensitivity and specificity were 91.7% and 86.7% respectively. CONCLUSIONS: The SUVmax value helps differentiate benign and malignant ovarian tumours, as well as uterine myomas and uterine sarcomas. PMID- 29399969 TI - Role of virtual reality in congenital heart disease. AB - OBJECTIVE: New platforms for patient imaging present opportunities for improved surgical planning in complex congenital heart disease (CHD). Virtual reality (VR) allows for interactive manipulation of high-resolution representations of patient specific imaging data, as a supplement to traditional 2D visualizations and 3D printed heart models. DESIGN: We present the novel use of VR for the presurgical planning of cardiac surgery in two infants with complex CHD to demonstrate interactive real-time views of complex intra and extracardiac anatomy. RESULTS: The use of VR for cardiac presurgical planning is feasible using existing imaging data. The software was evaluated by both pediatric cardiac surgeons and pediatric cardiologists, and felt to be reliable and operated with a very short learning curve. CONCLUSIONS: VR with controller-based interactive capability allows for interactive viewing of 3D models with complex intra and extracardiac anatomy. This serves as a useful complement to traditional preoperative planning methods in terms of its potential for group based collaborative discussion, user defined illustrative views, cost-effectiveness, and facility of use. PMID- 29399970 TI - Analysis of DICER1 in familial and sporadic cases of transposition of the great arteries. AB - OBJECTIVE: We previously identified a pathogenic germline DICER1 variant in a child with transposition of the great arteries who was a member of a family with DICER1 syndrome. In view of a report linking Dicer1 knockout in murine cardiomyocytes to cardiac outflow defects, we investigated the involvement of DICER1 in transposition of the great arteries. DESIGN: We used Fluidigm access array followed by next generation sequencing to screen for variants in the coding exons, their exon/intron boundaries and the 3' untranslated region of DICER1 in patient DNA. CASES: Germline DNA was collected from 129 patients with either sporadic or familial forms of transposition of the great arteries from two sites in Australia and Italy. RESULTS: Most cases (85%) did not have any germline DICER1 variants. In the remaining 15% of cases, we identified 16 previously reported variants (5 synonymous, 6 intronic, and 5 missense) and 2 novel variants (1 intronic and 1 missense). None of the identified variants were predicted to be pathogenic. CONCLUSIONS: Here, we report that neither likely pathogenic nor pathogenic variants in DICER1 appear to play a major role in transposition of the great arteries. PMID- 29399971 TI - Benefits and Harms in Pivotal Trials of Oral Centrally Acting Antiobesity Medicines: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the benefits and harms of oral centrally acting antiobesity medicinal products in pivotal trials. METHODS: The European Medicines Agency and Federal Drug Administration websites, PubMed, and ClinicalTrials.gov were searched to identify pivotal trials used to gain marketing authorizations. Pivotal phase III trials on which marketing authorizations were based were included. The data were analyzed by using Cochrane Review Manager (RevMan), and quality assessments for each outcome were performed by using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE). RESULTS: Five products (16 trials with 24,555 participants) were included. Significantly more participants who took the antiobesity products achieved >= 5% reduction in body weight (risk ratio [RR] 2.39; 95% CI: 2.09-2.74; GRADE = low). However, the products significantly increased the risk of adverse events (RR 1.12; 95% CI: 1.07-1.17; GRADE = very low) and the risk of discontinuation because of adverse events (RR 1.52; 95% CI: 1.33-1.74; GRADE = low). There were no significant differences for most outcomes between currently approved and withdrawn products. CONCLUSIONS: Although oral centrally acting antiobesity products generate modest weight losses, they also increase the risks of adverse events and discontinuations because of adverse events. The premarketing benefit-to-harm profiles of currently available products and products that were later withdrawn because of harms are similar. Targeted study designs, better outcomes reporting, and improved postmarketing monitoring of harms are needed. PMID- 29399972 TI - Dosimetric differences between local failure and local controlled non-small cell lung cancer patients treated with stereotactic body radiotherapy: A matched-pair study. AB - INTRODUCTION: Concerns were raised about the accuracy of pencil beam (PB) calculation and potential underdosing of medically inoperable non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). From our institutional series, we designed a matched-pair study where each local failure and controlled patient was matched based upon several clinical factors, to investigate the dose difference between the matched-pair. METHODS: Eighteen pairs of NSCLC patients, treated with 50 Gy in five fractions, were selected. These patients were matched based on treatment intent, tumour size, histology and clinical follow-up. All PB calculated clinical plans were retrospectively recalculated with a MC algorithm. The D99 and DMean of the gross tumour volume (GTV) and D95 and DMean of the planning tumour volume (PTV) from PB and Monte Carlo (MC) calculation were compared between local failures and controls using the Mann-Whitney test. RESULTS: The mean PB calculated D95 of PTV was 50.4 Gy for both failures and controls (P = 0.85), indicating no planning differences between the groups. From MC calculations, the mean (+/-SD) of GTV D99 , GTV DMean , PTV D95 , PTV DMean were 47.6 +/- 2.6/46.3 +/- 2.4, 50.4 +/- 2.1/49.8 +/- 1.6, 44.4 +/- 2.7/43.6 +/- 3.1, 48.7 +/- 2.4/48.2 +/- 2.4 Gy for failure/controlled groups, respectively, and there was no significant difference between two groups (all P > 0.1). The dose differences between MC and PB calculations were in agreement with other literatures and there was no significant difference between two groups. CONCLUSIONS: While PB algorithms may overestimate tumour doses relative to MC algorithms, our matched-pair study did not find dose differences between local failure and local controlled cases. PMID- 29399973 TI - Remote limb ischemic postconditioning promotes motor function recovery in a rat model of ischemic stroke via the up-regulation of endogenous tissue kallikrein. AB - AIMS: Remote ischemic conditionings, such as pre- and per-conditioning, are known to provide cardioprotection in animal models of ischemia. However, little is known about the neuroprotection effect of postconditioning after cerebral ischemia. In this study, we aim to evaluate the motor function rescuing effect of remote limb ischemic postconditioning (RIPostC) in a rat model of acute cerebral stroke. METHODS: Left middle cerebral artery occlusion (MCAO) was performed to generate the rat model of ischemic stroke, followed by daily RIPostC treatment for maximum 21 days. The motor function after RIPostC was assessed with foot fault test and balance beam test. Local infarct volume was measured through MRI scanning. Neuronal status was evaluated with Nissl's, HE, and MAP2 immunostaining. Lectin immunostaining was performed to evaluate the microvessel density and area. RESULTS: Daily RIPostC for more than 21 days promoted motor function recovery and provided long-lasting neuroprotection after MCAO. Reduced infarct volume, rescued neuronal loss, and enhanced microvessel density and size in the injured areas were observed. In addition, the RIPostC effect was associated with the up-regulation of endogenous tissue kallikrein (TK) level in circulating blood and local ischemic brain regions. A TK receptor antagonist HOE 140 partially reversed RIPostC-induced improvements, indicating the specificity of endogenous TK mediating the neuroprotection effect of RIPostC. CONCLUSION: Our study demonstrates RIPostC treatment as an effective rehabilitation therapy to provide motor function recovery and alleviate brain impairment in a rat model of acute cerebral ischemia. We also for the first time provide evidence showing that the up-regulation of endogenous TK from remote conditioning regions underlies the observed effects of RIPostC. PMID- 29399974 TI - Early repeat computed tomographic imaging in transferred trauma and neurosurgical patients: Incidence, indications and impact. AB - INTRODUCTION: Computed tomographic (CT) imaging is widely available in Australian rural and remote hospitals and is often performed prior to patient transfer to definitive tertiary hospital care. We hypothesised that critically ill trauma and neurosurgical patients might have CT scans repeated after interhospital transfer and that the utility of this practice might be low in relation to the additional financial cost and radiation exposure. METHODS: We conducted a retrospective review of clinical records to determine the proportion of trauma and neurosurgical patients transferred to our tertiary ICU from other hospitals between 1 June 2013 and 30 June 2014 who underwent a repeat CT scan. The additional effective radiation dose was estimated using the dose length product method and the Australian Medicare Benefits Schedule was used to estimate the associated cost. RESULTS: Of the 247 patients transferred for trauma and neurosurgical indications, many (144; 58%) had undergone CT imaging at the referring hospital. Repeat scans were performed in 60 (42%) already imaged patients (24% of all transferred patients), most frequently for changed clinical indications. While in 11 (18%) of those 60 already imaged patients the repeat scan led to an identifiable change in management, for another 13 (22%) patients the repeat scans appeared to be potentially avoidable. The median cost of a repeat scan was AU$250 and the median additional effective radiation dose was 2.74 mSv per patient. CONCLUSION: Repeat CT scans for patients already imaged prior to transfer were relatively common, occurring mostly for apparently valid clinical reasons. However, the additional radiation risk and financial cost of these repeat scans appeared on retrospective audit to be potentially avoidable in approximately one in five cases. PMID- 29399975 TI - Diagnostic imaging of ankle syndesmosis injuries: A general review. AB - Literature on the various techniques for imaging injuries to the ankle syndesmosis to determine the most appropriate imaging modality for diagnosing syndesmosis ligament disruption and instability was reviewed using the following data sources: Pubmed, Google scholar, SportsDiscus, E-journals and PLOSone. Search terms used were: syndesmosis paired with injury, imaging, radiology, X ray, stress X-ray, arthrography, ultrasound, nuclear medicine scan, CT scan, MRI and arthroscopy. Articles were selected by reading abstracts and the full article if indicated. Further articles were derived from the references of the primary articles. Plain x-rays of the ankle will detect approximately half on AP view to two-thirds on mortise view of syndesmosis injuries. Syndesmosis injuries frequently occur in association with tibial or fibular fractures. Intra-operative stress radiography failed to detect approximately half of instabilities confirmed at arthroscopy. The current benchmark imaging techniques to diagnose syndesmosis injury and diastasis are arthroscopy and high-power (3T) MRI. Ultrasound is a promising, developing, cost-effective imaging technique which is yet to reach its full diagnostic potential. CT and nuclear medicine scans have limited roles. MRI (3T) scanning in the plane of the syndesmotic ligaments is the investigation of choice to detect ankle syndesmosis injuries. In the presence of associated injuries requiring surgery, arthroscopic viewing with stress examination is the diagnostic benchmark when available. PMID- 29399976 TI - Combined Analysis of Stress- and ECM-Related Genes in Their Effect on Weight Regain. AB - OBJECTIVE: During weight loss, the volume of adipocytes decreases, leading to stress because of the misfit between the cell contents and the surrounding extracellular matrix (ECM). This stress can be resolved by remodeling the ECM or the restorage of triglycerides within the adipocytes. The objective of this study was to investigate the existence of a connection between stress-related and ECM related genes that is associated with weight regain. METHODS: Thirty-one participants with overweight or obesity followed a 5-week very-low-calorie diet (500 kcal/d) with a subsequent 4-week weight-stable diet (WS), and then an uncontrolled 9-month follow-up. Adipose tissue biopsies were collected for microarray analysis. A correlation and interaction analysis was performed with the weight regain percentage (WR%) ([weight after follow-up - weight after WS] / weight after WS * 100%) by using two gene sets that were previously defined as "stress-related" (n = 107) and "ECM-related" genes (n = 277). RESULTS: During WS, a coexpression network of 8 stress-related genes and 15 ECM-related genes correlating with WR% could be constructed, with links to multiple biological processes. Interaction analysis between stress- and ECM-related genes revealed that several gene combinations were highly related to weight regain. CONCLUSIONS: Our findings underscore the importance of the connection between stress- and ECM related genes in the risk for weight regain. PMID- 29399977 TI - Construction of T-Motif-Based DNA Nanostructures through Enzymatic Reactions. AB - The most common way to fabricate DNA nanostructures is to mix individually synthesized DNA oligomers in one pot. However, if DNA nanostructures could be produced through enzymatic reactions, they could be applied in various environments, including in vivo. Herein, an enzymatic method developed to construct a DNA nanostructure from a simple motif called a T-motif is reported. A long, repeated structure was replicated from a circular template by rolling circle amplification and then cleaved into T-motif segments by restriction enzymes. These motifs have been successfully assembled into a ladder-like nanostructure without purification or controlled annealing. This approach is widely applicable to constructing a variety of DNA nanostructures through enzymatic reactions. PMID- 29399978 TI - Randomized control trial to test the effect of a feed additive on Campylobacter contamination in commercial broiler flocks up to slaughter. AB - A randomized controlled trial (RCT) was carried to evaluate the effect of a feed additive on Campylobacter contamination of broilers reared in commercial conditions. Twenty-four broiler flocks naturally contaminated with Campylobacter were enrolled in the RCT: 12 were assigned to a control group (C) fed with a conventional finishing feed from 4 weeks of age to slaughter (around 35 days), and the other group of 12 flocks (S) was fed with a finishing feed supplemented with 250 ppm of a patented feed additive (an ion-exchanged clay compound) previously proven to reduce Campylobacter contamination in broiler caeca under experimental conditions. Enumeration of Campylobacter colonies in caeca (8 per flock) was carried out following ISO standards before feed distribution and at slaughter. Before treatment, the caecal Campylobacter load tended to be lower in C flocks (7.1 +/- 1.9 log CFU/g, CI95% [6.6-7.5]) than in S flocks (7.7 +/- 1.0 log UFC/g, CI95% [7.5-7.9]) (p = .05). At slaughter, the bacterial load was similar in the S (7.7 +/- 1.0 log CFU/g, CI95% [7.5-7.9]) and C groups (7.5 +/- 1.2 log CFU/g, CI95% [7.2-7.8]) (p = .73). Therefore, the feed additive had no significant effect on the caecal Campylobacter load at slaughter under the tested conditions. The logistical constraints inherent in field trials and the natural variability of Campylobacter contamination in naturally infected broiler flocks make it difficult to reproduce experimental results in in situ farm conditions. RCT testing of an intervention strategy in commercial situation is therefore a key step in evaluating pre-harvest interventions against food-borne pathogens. PMID- 29399979 TI - Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments. AB - For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month. PMID- 29399980 TI - Tunable excitation properties of ZnCdS:Mn/ZnS quantum dots for cancer imaging. AB - Water-soluble ZnS:Mn quantum dots (QDs) were synthesized using a hydrothermal method with 3-mercaptopropionic acid as stabilizer. The optical properties of ZnS:Mn QDs were thoroughly investigated by tuning the doping concentration of Mn2+ and the Zn/S precursor ratio, to obtain an optimal parameter for QDs with excellent fluorescence characteristics. ZnS:Mn QDs excited at only one wavelength, however, which seriously limited their further application. Here, a trace Cd ion was doped into a ZnS host, resulting in QD excitation covering a wide adjustable waveband. Furthermore, when a ZnS shell was coated onto the surface of the ZnCdS:Mn QDs, photoluminescence intensity and stability were further enhanced. After coupling with an anti-CK 19 antibody, the ZnCdS:Mn/ZnS core/shell QDs were able to function by labeling cancer cells, indicating that they could be considered as a suitable bio-probe for cells and tissue imaging. PMID- 29399981 TI - Maternal Metabolic Health Parameters During Pregnancy in Relation to Early Childhood BMI Trajectories. AB - OBJECTIVE: The objective of this study was to evaluate the associations between maternal metabolic parameters and early childhood BMI trajectories. METHODS: Two thousand two hundred fifty-one children born in Spain between 2004 and 2008 were analyzed. Five BMI z score trajectories from birth to age 4 years were identified by using latent class growth analysis. Multinomial regression assessed the associations between maternal metabolic parameters and offspring's BMI trajectories. RESULTS: Children in the reference BMI trajectory had average size at birth followed by a slower BMI gain. Maternal prepregnancy obesity was associated with trajectories of accelerated BMI gain departing from either higher (relative risk ratio [RRR] = 1.77; 95% CI: 1.07-2.91) or lower size at birth (RRR = 1.91; 95% CI: 1.17-3.12). Gestational weight gain (GWG) above clinical guidelines was associated with a trajectory of higher birth size followed by accelerated BMI gain (RRR = 2.14; 95% CI: 1.53-2.97). Maternal serum triglycerides were negatively associated with BMI trajectories departing from lower birth sizes. Gestational diabetes, maternal serum cholesterol, and C reactive protein were unrelated to children's BMI trajectories. CONCLUSIONS: Maternal prepregnancy obesity, GWG, and serum triglycerides are associated with longitudinal BMI trajectories in early childhood that may increase disease risk in later life. Health initiatives should promote healthy weight status before and during pregnancy to improve maternal and child health. PMID- 29399982 TI - Warthins tumor: Cyto histological spectrum with emphasis on diagnostic difficulties. AB - Warthins tumour is characterized by the presence of epithelial proliferation in a lymphoid stroma. It has been categorized as Sieferts types: 1-4, depending on the proportions of the 2 components. Although FNA is fairly accurate in establishing the diagnosis, the cytologic diagnosis of this tumor has potential sources of error. This retrospective study was conducted in the Department of Pathology and Lab Medicine, of a tertiary care hospital. Cytology and surgical pathology records of past 15 years were screened. A total of 1200 FNAC cases of salivary gland lesions in the past 15 years were retrieved. 36 cases with presumptive cytodiagnosis of WT were identified and histopathological correlation was done. Histopathological correlation could be done in 24 cases. 19 out of 24 cases, were confirmed as WT. The 5 cases with discordance were analyzed for potential diagnostic pitfalls. The most common discordance was in the category of papillary proliferation with minimal lymphoid infiltrate. One case proved as oncocytoma and the other was papillary oncocyticcystadenoma. The other major pitfalls, were the interpretation of atypical squamoid cells. Their presence in a lymphoid background needs consideration of cytologic diagnosis of WT, mucoepidermoid carcinoma and metastatic squamous carcinoma. FNA showed an accuracy of 79% for WT. Cytological misinterpretation can thus occur in presence of morphology other than classical Siefert type1. An awareness of these potential pitfalls should push the need for avoiding single cytologic interpretation. PMID- 29399983 TI - Inferior alveolar nerve injury: Correlation between indicators of risk on panoramic radiographs and the incidence of tooth and mandibular canal contact on cone-beam computed tomography scans in a Western Australian population. AB - AIM: The aim of the present study was to assess risks prior to third molar removal. A 2-D panoramic radiograph or a 3-D cone-beam computed tomography (CBCT) scan can be used to visualize the proximity of the third molar to the mandibular canal. We aimed to correlate panoramic indicators of risk with the incidence of contact between these two structures on CBCT scans. METHODS: Patients were selected from a Western Australian population if they had a panoramic radiograph that illustrated signs of risk of inferior alveolar nerve injury and had a CBCT scan on file. Statistically-significant relationships between the relative position and distance between the mandibular canal and third molar were investigated using chi2 -test and Fisher's exact test in Stata version 13. RESULTS: Within the Western Australian sample (N = 100), of six possible panoramic indicators of risk, two were significantly associated with contact between the tooth and mandibular canal on CBCT: (a) interruption of the radiographic white line of the canal; and (b) darkening of the root(s). CONCLUSIONS: Two panoramic radiograph risk signs are significantly more likely to indicate contact on the CBCT scans: interruption of the white line and darkening of the root(s). Further research is required to develop CBCT prescription guidelines for surgical planning. PMID- 29399985 TI - Retraction. AB - : 'EphB3-targeted regulation of miR-149 in the migration and invasion of human colonic carcinoma HCT116 and SW620 cells' by Guodong Zhang, Xiaozhu Liu, Yinfeng Li, Yan Wang, Huankun Liang, Kangyan Li, Laiqing Li, Cuicui Chen, Wenqiao Sun, Shoulei Ren, Pengfei Zhu and Licheng Zhang1 . The above article from Cancer Science, first published on 3 April 2017 in Wiley Online Library (wileyonlinelibrary.com) and in Volume 108, pp. 408-418, has been retracted by the journal Editor in Chief, Yusuke Nakamura, and John Wiley & Sons Australia, Ltd. This article has been retracted as the Journal has been notified that one of the authors, Dr Guodong Zhang, misappropriated material without permission as part of this article and was subsequently found guilty of academic misconduct by The Academic Committee of Cancer Center of Guangzhou Medical University. REFERENCE: 1. Zhang G, Liu X, Li Y, Wang Y, Liang H, Li K, Li L, Chen C, Sun W, Ren S, Zhu P, Zhang L. EphB3-targeted regulation of miR-149 in the migration and invasion of human colonic carcinoma HCT116 and SW620 cells. Cancer Sci. 2017; 108: 408-418. https://doi.org/10.1111/cas.13161. PMID- 29399986 TI - 2015 American College of Rheumatology Workforce Study: The Role of Graduate Medical Education in Adult Rheumatology. AB - OBJECTIVE: Graduate medical education (GME), through fellowship training, plays a critical role in preparing new rheumatologists for our workforce and is an essential component when addressing the gap of excess demand for adult rheumatology care. This study was undertaken to assess the demographic characteristics and employment trends of new entrants entering the rheumatology workforce and the impact this will have on the supply of rheumatologits over the next 15 years. METHODS: Primary and secondary data sources were used to develop an integrated workforce model. Factors specific to new graduates entering the workforce included available and filled fellowship positions, gender shifts, planned work schedules (part-time or full-time), practice settings (academic or non-academic, private practice), and number of international medical graduates (IMGs) anticipating US practice. RESULTS: In 2015, there were 113 adult rheumatology programs, with 431 of 468 available positions filled. Using the 215 actual positions available annually in fellowship programs as a starting point, after all factors were applied, the projected clinical full-time equivalent number entering the workforce each year was 107; this number was affected significantly by gender and generational trends. In addition, 17% of IMGs self identified their plan to practice outside the US. Confounding predictions included a large proportion of current rheumatologists planning retirement with substantially reduced patient loads by 2030. CONCLUSION: The current US adult rheumatology workforce is in jeopardy of accelerated decline at a time when demands on the workforce face tremendous growth. The current GME training structure cannot support the increased demand. Potential strategies to address this gap include innovative mechanisms for GME funding to increase fellowship training positions, incentives for pursuing rheumatology training (e.g., loan repayment programs), and novel means for recruitment of care to underserved areas of the US. PMID- 29399987 TI - Nickel(0)-Catalyzed Hydroalkenylation of Imines with Styrene and Its Derivatives. AB - A nickel(0)-catalyzed hydroalkenylation of imines with styrene and its derivatives is described. A wide range of aromatic and aliphatic imines directly coupled with styrene and its derivatives, thus providing various synthetically useful allylic amines with up to 95 % yield. The reaction offers a new atom- and step-economical approach to allylic amines by using alkenes instead of alkenyl metallic reagents. Experiments and DFT calculations showed that TsNH2 promotes the proton transfer from the coordinated olefin to the imine, accompanied by a new C-C bond formation. PMID- 29399989 TI - Pharmacokinetics, tissue distribution, and excretion of FGF-21 following subcutaneous administration in rats. AB - As one of the fibroblast growth factor (FGF) superfamily, FGF-21 has been extensively investigated for its functions and roles since its discovery. It has been demonstrated to be one of the key regulators for glucose and lipid metabolism, and exhibits beneficial effects on cardiovascular disease. However, studies focusing on its pharmacokinetic behavior in vivo as a novel therapeutic agent have not been reported. In the present study, rapid and sensitive analytical approaches including radioactivity assay and assay after precipitation/separation by high performance liquid chromatography (HPLC) were established to determine the content of FGF-21 tagged with 125 I in plasma, tissue, and excrement. The results indicated that FGF-21 were quickly absorbed into systematic circulation and slowly eliminated; Cmax and exposure increased in a dose-dependent manner, exhibiting a typical linear pharmacokinetic pattern. Tissue distribution also confirmed that the kidney is the primary organ for FGF 21 to be distributed, even though radioactivity of FGF-21 was recovered in all tissues examined. In addition, the results also supported that urinary excretion was the critical route for FGF-21 to be eliminated. The study fully clarifies the pharmacokinetic behavior of FGF-21 and can provide valuable information and support further safety and toxicology development. PMID- 29399988 TI - Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control. AB - BACKGROUND: Intramuscular fatty infiltration is generally associated with the accumulation of white adipocytes in skeletal muscle and unfavourable metabolic outcomes. It is, however, still unclear whether intramuscular adipocytes could also acquire a brown-like phenotype. Here, we detected intramuscular expression of brown adipocyte markers during fatty infiltration in an obesity-resistant mouse strain and extensively compared the potential of two different stem cell populations residing in skeletal muscle to differentiate into brown-like adipocytes. METHODS: Fatty infiltration was induced using intramuscular glycerol or cardiotoxin injection in the tibialis anterior muscles of young or aged 129S6/SvEvTac (Sv/129) mice or interleukin-6 (IL-6) knockout mice, and the expression of general and brown adipocyte markers was assessed after 4 weeks. Fibro/adipogenic progenitors (FAPs) and myogenic progenitors were prospectively isolated using fluorescence-activated cell sorting from skeletal muscle of male and female C57Bl6/6J and Sv/129 mice, and monoclonal and polyclonal cultures were treated with brown adipogenic medium. Additionally, FAPs were differentiated with medium supplemented or not with triiodothyronine. RESULTS: Although skeletal muscle expression of uncoupling protein 1 (Ucp1) was barely detectable in uninjected tibialis anterior muscle, it was drastically induced following intramuscular adipogenesis in Sv/129 mice and further increased in response to beta 3-adrenergic stimulation. Intramuscular Ucp1 expression did not depend on IL 6 and was preserved in aged skeletal muscle. Myogenic progenitors did not form adipocytes neither in polyclonal nor monoclonal cultures. Fibro/adipogenic progenitors, on the other hand, readily differentiated into brown-like, UCP1+ adipocytes. Uncoupling protein 1 expression in differentiated FAPs was regulated by genetic background, sex, and triiodothyronine treatment independently of adipogenic differentiation levels. CONCLUSIONS: Intramuscular adipogenesis is associated with increased Ucp1 expression in skeletal muscle from obesity resistant mice. Fibro/adipogenic progenitors provide a likely source for intramuscular adipocytes expressing UCP1 under control of both genetic and hormonal factors. Therefore, FAPs constitute a possible target for therapies aiming at the browning of intramuscular adipose tissue and the metabolic improvement of skeletal muscle affected by fatty infiltration. PMID- 29399990 TI - Preoperative sarcopenia and post-operative accelerated muscle loss negatively impact survival after resection of pancreatic cancer. AB - BACKGROUND: Sarcopenia and post-operative accelerated muscle loss leading to cachexia are commonly observed in patients with pancreatic cancer. This study aimed to assess the influence of body compositions and post-operative muscle change on survival of patients with surgically treated pancreatic cancer. METHODS: We analysed data of patients diagnosed with pancreatic adenocarcinoma who underwent surgery from 2008 to 2015. Skeletal muscle areas, muscle attenuation, and visceral and subcutaneous adipose tissue areas were measured from two sets of computed tomography images at L3 vertebral levels. In addition, muscle change was calculated from images obtained before and after cancer resection. We set our own cut-off values of various body compositions based on sex-specific tertiles. RESULTS: A total of 180 patients were analysed. Patients with perioperative sarcopenia (n = 60) showed poorer overall survival than those without perioperative sarcopenia (P = 0.031). Fifty (28.6%) patients with accelerated muscle loss after surgery (>10%/60 days) had poorer survival compared with the others (P = 0.029). Sarcopenia (hazard ratio, 1.79: 95% confidence interval, 1.20-2.65] and post-operative muscle change (%/60 days) (hazard ratio, 0.94: 95% confidence interval, 0.92-0.96) were identified as significant predictors of survival on multivariable analyses. CONCLUSIONS: Preoperative sarcopenia identified on CT scan was associated with poor overall survival in patients with pancreatic cancer following surgery. Accelerated muscle loss after surgery also negatively impacted survival in pancreatic cancer patients. PMID- 29399991 TI - Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA. AB - Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization. PMID- 29399992 TI - Edge-Riched MoSe2 /MoO2 Hybrid Electrocatalyst for Efficient Hydrogen Evolution Reaction. AB - Molybdenum diselenide (MoSe2 ) is widely considered as one of the most promising catalysts for the hydrogen evolution reaction (HER). However, the absence of active sites and poor conductivity of MoSe2 severely restrict its HER performance. By introducing a layer of MoO2 on Mo foil, MoSe2 /MoO2 hybrid nanosheets with an abundant edge and high electrical conductivity can be synthesized on the surface of Mo foil. Metallic MoO2 can improve the charge transport efficiency of MoSe2 /MoO2 , thereby enhancing the overall HER performance. MoSe2 /MoO2 exhibits fast hydrogen evolution kinetics with a small overpotential of 142 mV versus RHE at a current density of 10 mA cm-2 and Tafel slope of 48.9 mV dec-1 . PMID- 29399993 TI - Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement. AB - : Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found. SUMMARY: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance. PMID- 29399996 TI - Corrigendum. PMID- 29399994 TI - Recent Advances in Layered Ti3 C2 Tx MXene for Electrochemical Energy Storage. AB - Ti3 C2 Tx , a typical representative among the emerging family of 2D layered transition metal carbides and/or nitrides referred to as MXenes, has exhibited multiple advantages including metallic conductivity, a plastic layer structure, small band gaps, and the hydrophilic nature of its functionalized surface. As a result, this 2D material is intensively investigated for application in the energy storage field. The composition, morphology and texture, surface chemistry, and structural configuration of Ti3 C2 Tx directly influence its electrochemical performance, e.g., the use of a well-designed 2D Ti3 C2 Tx as a rechargeable battery anode has significantly enhanced battery performance by providing more chemically active interfaces, shortened ion-diffusion lengths, and improved in plane carrier/charge-transport kinetics. Some recent progresses of Ti3 C2 Tx MXene are achieved in energy storage. This Review summarizes recent advances in the synthesis and electrochemical energy storage applications of Ti3 C2 Tx MXene including supercapacitors, lithium-ion batteries, sodium-ion batteries, and lithium-sulfur batteries. The current opportunities and future challenges of Ti3 C2 Tx MXene are addressed for energy-storage devices. This Review seeks to provide a rational and in-depth understanding of the relation between the electrochemical performance and the nanostructural/chemical composition of Ti3 C2 Tx , which will promote the further development of 2D MXenes in energy-storage applications. PMID- 29399998 TI - Association of stent-induced changes in coronary geometry with late stent failure: Insights from three-dimensional quantitative coronary angiographic analysis. AB - BACKGROUND: The relationship between vessel angulation and large changes in vessel geometry after stent implantation and the occurrence of stent failure still remains unclear. We sought to investigate the association of the change in the coronary bending angle after stenting and the risk for late stent failure by three-dimensional quantitative coronary angiography (3D QCA). METHODS: The bending angle in coronary lesions that presented with late stent failure and those without stent failure was computed during the cardiac cycle, before and after stenting using a recently developed 3D QCA software. RESULTS: A total of 40 lesions with stent failure (cases) were successfully matched to 47 lesions without stent failure (controls).The mean duration to follow-up coronary angiography was 1,011 days in cases and 1,109 days in the control group (P = 0.14). In stent failure, the systolic bending angle after stenting was smaller (14.45 degrees [12.18, 17.68] versus 18.20 degrees [14.00, 20.30], P = 0.01), while the stent-induced change in systolic bending angle was significantly larger (4.15 degrees [1.13, 7.20] versus 1.80 degrees [-1.90, 4.40], P = 0.004). Multivariable logistic regression analysis suggested that systolic bending angle after stenting (odds ratio: 0.88; 95% CI: 0.79-0.99; P = 0.03), and decrease in systolic bending angle after stenting (odds ratio: 1.13; 95% CI: 1.02-1.26; P = 0.03) were predictors of stent failure. CONCLUSIONS: Our study suggests that a change in the natural tortuous course of the coronaries by stent implantation with the decrease in coronary bending angle is a potentially major contributor in stent failure. PMID- 29399997 TI - Clinical outcomes of percutaneous or surgical closure of ruptured sinus of Valsalva aneurysm. AB - OBJECTIVE: To evaluate the clinical efficacy, safety, and long-term outcomes of percutaneous closure (PC) and surgical repair of ruptured sinus of Valsalva aneurysm (RSVA). METHODS: Eighty-five consecutive patients with RSVA were included in this study. Patients were considered candidates for PC if they met the criterion, surgical repair was performed on patients who were unsuitable or failed PC. Of them, 30 patients underwent PC, while the other 55 patients had surgical repair. RESULTS: RSVA was successfully occluded in 29 of 30 patients who were treated by PC. The mean narrowest diameter at the ruptured site was 6.45 +/- 1.60 mm measured by aortography. One patient developed serious occluder-related aortic regurgitation and underwent surgery. The success rate of the interventional approach was 96.7%. In the surgical group, 23 patients underwent repair of combined RSVA and ventricular septal defect. The hospital mortality rate of the surgical approach was 3.57%. During a median follow-up of 83 months (8-152 months), the improvement in NYHA functional class in the PC group was significantly greater than those in the surgical group (P < .01). One patient died of infective endocarditis in the surgical group. There were no further serious complications. CONCLUSIONS: PC is a safe alternative to surgical repair for patients with isolated RSVA. Surgical repair is more suitable for those who have multiple cardiac lesions requiring surgical treatment or failed PC. PMID- 29399999 TI - Effect of length and location of edentulous area on the accuracy of prosthetic treatment plan incorporation into cone-beam computed tomography scans. AB - BACKGROUND: Effects of length and location of the edentulous area on the accuracy of prosthetic treatment plan incorporation into cone-beam computed tomography (CBCT) scans has not been investigated. PURPOSE: To evaluate the effect of length and location of the edentulous area on the accuracy of prosthetic treatment plan incorporation into CBCT scans using different methods. MATERIAL AND METHODS: Direct digital scans of a completely dentate master model with removable radiopaque teeth were made using an intraoral scanner, and digital scans of stone duplicates of the master model were made using a laboratory scanner. Specific teeth were removed to simulate different clinical situations and their CBCT scans were made. Surface scans were registered onto the CBCT scans. Radiographic templates for each clinical situation were also fabricated and used during CBCT scans of the master models. Using metrology software, three-dimensional (3D) deviation was measured on standard tesselation language (STL) files created from the CBCT scans against an STL file of the master model created from a CBCT scan. Statistical analysis was done using the MIXED procedure in a statistical software and Tukey HSD test (alpha =.05). RESULTS: The interaction between location and method was significant (P = .009). Location had no significant effect on registration methods (P > .05), but on the radiographic templates (P = .011). Length of the edentulous area did not have any significant effect (P > .05). CONCLUSIONS: Accuracy of digital image registration methods was similar and higher than that of radiographic templates in all clinical situations. Tooth bound radiographic templates were significantly more accurate than the free-end templates. The results of this study suggest using image registration instead of radiographic templates when planning dental implants, particularly in free-end situations. PMID- 29400000 TI - Correlation analysis of mesenchymal-epithelial transition factor protein and human epidermal growth receptor 2 protein expression in 1479 cases of lung adenocarcinoma in China. AB - BACKGROUND: To investigate the correlation between mesenchymal-epithelial transition factor (C-Met) and human epidermal growth receptor 2 (HER2) protein expression in primary lung adenocarcinoma tissues. METHOD: A total of 1479 resected primary lung adenocarcinoma patients were enrolled in the present study for detecting of C-Met and HER2 protein by immunohistochemistry, and correlation analysis was made between the above two biomarkers and related clinicopathological features. RESULT: Both C-Met and HER2 proteins were found to stain highly positive in lung adenocarcinomas, and a positive correlation was found between them (chi2 = 118.5, P = 2.707 * 10-21 ). In addition, HER2 protein expression was correlated with sex, pathological stage, lymph node metastasis, and major subtypes; and C-Met was correlated with sex (P < 0.05). CONCLUSION: The expression of C-Met and HER2 protein in lung adenocarcinoma is highly correlated, and whether it is synergistic in the targeted therapy of lung adenocarcinoma deserves further study. PMID- 29400001 TI - WS2 /Graphitic Carbon Nitride Heterojunction Nanosheets Decorated with CdS Quantum Dots for Photocatalytic Hydrogen Production. AB - Two-dimensional/two-dimensional (2D/2D) stacking heterostructures are highly desirable in fabricating efficient photocatalysts because face-to-face contact can provide a maximized interfacial region between the two semiconductors; this largely facilitates the migration of charge carriers. Herein, a WS2 /graphitic carbon nitride (CN) 2D/2D nanosheet heterostructure decorated with CdS quantum dots (QDs) has been designed, for the first time. Optimized CdS/WS2 /CN without another cocatalyst exhibits a significantly enhanced photocatalytic H2 evolution rate of 1174.5 MUmol h-1 g-1 under visible-light irradiation (lambda>420 nm), which is nearly 67 times higher than that of the pure CN nanosheets. The improved photocatalytic activity can be primarily attributed to the highly efficient charge-transfer pathways built among the three components, which effectively accelerate the separation and transfer of photogenerated electrons and holes, and thus, inhibit their recombination. Moreover, the extended light-absorption range also contributes to excellent photocatalytic efficiency. In addition, the CdS/WS2 /CN photocatalyst shows excellent stability and reusability without apparent decay in the photocatalytic H2 evolution within 4 cycles in 20 h. It is believed that this work may shed light on specifically designed 2D/2D nanosheet heterostructures for more efficient visible-light-driven photocatalysts. PMID- 29400002 TI - Interleukin-2, -16, and -17 gene polymorphisms in Iranian patients with chronic periodontitis. AB - AIM: Chronic periodontitis (CP) is a multifactorial disease and the most common type of periodontitis mainly caused by microbial plaque. CP can be brought on by, and progresses with, insufficient oral hygiene, and environmental and genetic susceptibilities. The aim of the present study was to investigate the association between interleukin (IL)-2 (T-330G), IL-16 (T-295C), and IL-17 (A-7383G) gene polymorphisms and the susceptibility to CP in an Iranian population. METHODS: Ninety-nine cases diagnosed with CP and 75 matched healthy controls engaged in the present study. 3 cc peripheral blood samples were obtained for DNA isolation. Genotype analysis was performed using restriction fragment length polymorphism polymerase chain reaction. Genotype distribution and allele frequencies within groups were compared using chi2 -test, and logistic regression analysis was used to recognize the independent relation between the disease and the absence or presence of alleles. RESULTS: There was no polymorphism in IL-2 (T-330G) among our patients, and the TT genotype was present in both study groups. Moreover, none of the studied genotypes and alleles of IL-16 (T-295C) and IL-17 (A-7383G) was significantly associated with CP. CONCLUSION: The present study demonstrated no association between IL-2 (T-330G), IL-16 (T-295C), and IL-17 (A-7383G) genotypes and CP in an Iranian population. PMID- 29400003 TI - Incidence and outcome of subarachnoid haemorrhage in the general and emergency department populations in Queensland from 2010 to 2014. AB - OBJECTIVES: To determine: (i) incidence and outcome of subarachnoid haemorrhage (SAH) in the general population; and (ii) proportions of SAH in both the general ED population and in ED patients presenting with headache. METHODS: A population based study in Queensland from January 2010 to December 2014 was conducted. Data were sourced from the Australian Bureau of Statistics, Queensland Hospital Admitted Patient Data Collection linked to the Queensland death registry and ED Information System. Admitted patients with SAH were identified from ICD-10-AM codes. Inter-hospital transfers and repeat admissions for previously diagnosed SAH were excluded. Pre-hospital deaths from SAH were included. ED patients with headache were identified from ICD-10-AM codes and finding 'headache' in the triage free-text entry. The incidence of SAH, in-hospital mortality, proportions of SAH in the general ED population and ED patients with headache were calculated. RESULTS: There were 1975 incident cases of SAH in admitted patients and 294 pre-hospital deaths from SAH. The incidence of SAH was 9.9 (95% confidence interval [CI] 9.5-10.4) per 100 000 person-years. The incidence standardised to the 'World Standard Population' was 7.0 per 100 000 person-years. The in-hospital mortality was 23.8% (95% CI 22.0-25.8%). SAH was found in 1407 (1.9%, 95% CI 1.8-2.0) of ED patients with headache. Overall, there were 2.4 (95% CI 2.3-2.5) SAH per 10 000 of all ED attendances. CONCLUSIONS: The incidence of SAH was similar to that previously reported for Australia. One in 50 ED patients with headache had SAH. Ten in 50 000 ED attendances had a SAH. These estimates can assist in the risk assessment for SAH. PMID- 29400004 TI - Trends in Obesity, Overweight, and Thinness in Children in the Seychelles Between 1998 and 2016. AB - OBJECTIVE: This study assessed trends in the prevalence of children and adolescents with obesity, overweight, and thinness in the Seychelles, a rapidly developing nation in the Indian Ocean, and changes in the distribution of BMI over time. METHODS: Between 1998 and 2016, examination surveys were conducted every year in all students of four selected school grades (kindergarten, primary 4, secondary 1, and secondary 4) in all schools. We categorized BMI by using the International Obesity Task Force criteria. RESULTS: Based on 70,187 observations, the prevalence of combined overweight or obesity increased largely and monotonically between 1998 and 2016, from 8.9% to 20.0% in boys and from 12.3% to 23.6% in girls, but the prevalence of underweight did not decrease. BMI increased mostly in the upper range of the BMI population distribution: percentile 5 (P5), 1.7%; P10, -0.8%; P25, 0.3%; P50, 2.5%; P75, 7.4%; P90, 12.7%; and P95, 13.3%. CONCLUSIONS: The distribution of BMI was increasingly skewed, with a rising prevalence of obesity, a modest or null increase in BMI in a substantial proportion of the population, and a continued burden of underweight. Further studies should assess child growth trajectories and their underlying determinants, which may bear significance for weight control strategies. PMID- 29400005 TI - Optimizing patient care and outcomes through the congenital heart center of the 21st century. AB - Pediatric cardiovascular services are responding to the dynamic changes in the medical environment, including the business of medicine. The opportunity to advance our pediatric cardiology field through collaboration is now realized, permitting us to define meaningful quality metrics and establish national benchmarks through multicenter efforts. In March 2016, the American College of Cardiology hosted the first Adult Congenital/Pediatric Cardiology Section Congenital Heart Community Day. This was an open participation meeting for clinicians, administrators, patients/parents to propose metrics that optimize patient care and outcomes for a state-of-the-art congenital heart center of the 21st century. Care center collaboration helps overcome the barrier of relative small volumes at any given program. Patients and families have become active collaborative partners with care centers in the definition of acute and longitudinal outcomes and our quality metrics. Understanding programmatic metrics that create an environment to provide outstanding congenital heart care will allow centers to improve their structure, processes and ultimately outcomes, leading to an increasing number of centers that provide excellent care. This manuscript provides background, as well listing of proposed specialty domain quality metrics for centers, and thus serves as an updated baseline for the ongoing dynamic process of optimizing care and realizing patient value. PMID- 29400007 TI - Editorial: Ensuring the Future of Rheumatology: A Multi-Dimensional Challenge and Call to Action. PMID- 29400006 TI - Cytology and clinical features of myelomatous pleural effusion: Three case reports and a review of the literature. AB - The purpose of this study was to report the clinical features, laboratory findings, and cytomorphology, and prognosis of three patients with myelomatous pleural effusion (MPE). The literature pertaining to MPE was reviewed. The three cases and literature review suggest that MPE is rare and often associated with a poor prognosis. The correct diagnosis depends on the aggressive clinical characteristics, laboratory findings, and chromosomal abnormalities, but routine pathological examination of the pleural effusion has low sensitivity. Cell blocks stained with hematoxylin & eosin and by immunohistochemistry revealed that abnormal proliferation of plasma cells and light chain restrictive expression in MPE may be helpful for improving the detection rate of MPE. PMID- 29400008 TI - Improving the Performance of Layered Oxide Cathode Materials with Football-Like Hierarchical Structure for Na-Ion Batteries by Incorporating Mg2+ into Vacancies in Na-Ion Layers. AB - The development of advanced cathode materials is still a great interest for sodium-ion batteries. The feasible commercialization of sodium-ion batteries relies on the design and exploitation of suitable electrode materials. This study offers a new insight into material design to exploit high-performance P2-type cathode materials for sodium-ion batteries. The incorporation of Mg2+ into intrinsic Na+ vacancies in Na-ion layers can lead to a high-performance P2-type cathode material for sodium-ion batteries. The materials prepared by the coprecipitation approach show a well-defined morphology of secondary football like hierarchical structures. Neutron power diffraction and refinement results demonstrate that the incorporation of Mg2+ into intrinsic vacancies can enlarge the space for Na-ion diffusion, which can increase the d-spacing of the (0 0 2) peak and the size of slabs but reduce the chemical bond length to result in an enhanced rate capability and cycling stability. The incorporation of Mg2+ into available vacancies and a unique morphology make Na0.7 Mg0.05 Mn0.8 Ni0.1 Co0.1 O2 a promising cathode, which can be charged and discharged at an ultra-high current density of 2000 mA g-1 with an excellent specific capacity of 60 mAh g-1 . This work provides a new insight into the design of electrode materials for sodium-ion batteries. PMID- 29400009 TI - 2015 American College of Rheumatology Workforce Study: Supply and Demand Projections of Adult Rheumatology Workforce, 2015-2030. AB - OBJECTIVE: To describe the character and composition of the 2015 US adult rheumatology workforce, evaluate workforce trends, and project supply and demand for clinical rheumatology care for 2015-2030. METHODS: The 2015 Workforce Study of Rheumatology Specialists in the US used primary and secondary data sources to estimate the baseline adult rheumatology workforce and determine demographic and geographic factors relevant to workforce modeling. Supply and demand was projected through 2030, utilizing data-driven estimations regarding the proportion and clinical full-time equivalent (FTE) of academic versus nonacademic practitioners. RESULTS: The 2015 adult workforce (physicians, nurse practitioners, and physician assistants) was estimated to be 6,013 providers (5,415 clinical FTE). At baseline, the estimated demand exceeded the supply of clinical FTE by 700 (12.9%). By 2030, the supply of rheumatology clinical providers is projected to fall to 4,882 providers, or 4,051 clinical FTE (a 25.2% decrease in supply from 2015 baseline levels). Demand in 2030 is projected to exceed supply by 4,133 clinical FTE (102%). CONCLUSION: The adult rheumatology workforce projections reflect a major demographic and geographic shift that will significantly impact the supply of the future workforce by 2030. These shifts include baby-boomer retirements, a millennial predominance, and an increase of female and part-time providers, in parallel with an increased demand for adult rheumatology care due to the growing and aging US population. Regional and innovative strategies will be necessary to manage access to care and reduce barriers to care for rheumatology patients. PMID- 29400010 TI - Systematic review and meta-analysis of cannabinoids in palliative medicine. AB - We provide a systematic review and meta-analysis on the efficacy, tolerability, and safety of cannabinoids in palliative medicine. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus, and http://clinicaltrials.gov, and a selection of cancer journals were searched up until 15th of March 2017. Of the 108 screened studies, nine studies with a total of 1561 participants were included. Overall, the nine studies were at moderate risk of bias. The quality of evidence comparing cannabinoids with placebo was rated according to Grading of Recommendations Assessment, Development, and Evaluation as low or very low because of indirectness, imprecision, and potential reporting bias. In cancer patients, there were no significant differences between cannabinoids and placebo for improving caloric intake (standardized mean differences [SMD]: 0.2 95% confidence interval [CI]: [-0.66, 1.06] P = 0.65), appetite (SMD: 0.81 95% CI: [-1.14, 2.75]; P = 0.42), nausea/vomiting (SMD: 0.21 [-0.10, 0.52] P = 0.19), >30% decrease in pain (risk differences [RD]: 0.07 95% CI: [-0.01, 0.16]; P = 0.07), or sleep problems (SMD: -0.09 95% CI: [-0.62, 0.43] P = 0.72). In human immunodeficiency virus (HIV) patients, cannabinoids were superior to placebo for weight gain (SMD: 0.57 [0.22; 0.92]; P = 0.001) and appetite (SMD: 0.57 [0.11; 1.03]; P = 0.02) but not for nausea/vomiting (SMD: 0.20 [-0.15, 0.54]; P = 0.26). Regarding side effects in cancer patients, there were no differences between cannabinoids and placebo in symptoms of dizziness (RD: 0.03 [-0.02; 0.08]; P = 0.23) or poor mental health (RD: -0.01 [-0.04; 0.03]; P = 0.69), whereas in HIV patients, there was a significant increase in mental health symptoms (RD: 0.05 [0.00; 0.11]; P = 0.05). Tolerability (measured by the number of withdrawals because of adverse events) did not differ significantly in cancer (RD: 1.15 [0.80; 1.66]; P = 0.46) and HIV patients (RD: 1.87 [0.60; 5.84]; P = 0.28). Safety did not differ in cancer (RD: 1.12 [0.86; 1.46]; P = 0.39) or HIV patients (4.51 [0.54; 37.45]; P = 0.32) although there was large uncertainty about the latter reflected in the width of the CI. In one moderate quality study of 469 cancer patients with cancer-associated anorexia, megestrol was superior to cannabinoids in improving appetite, producing >10% weight gain and tolerability. In another study comparing megestrol to dronabinol in HIV patients, megestrol treatment led to higher weight gain without any differences in tolerability and safety. We found no convincing, unbiased, high quality evidence suggesting that cannabinoids are of value for anorexia or cachexia in cancer or HIV patients. PMID- 29400011 TI - Clinical outcomes of patients with clear cell and endometrioid ovarian cancer arising from endometriosis. AB - OBJECTIVE: The aim of this investigation is to compare outcomes of patients according to the presence of cancer arising from endometriosis in ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC). METHODS: This study retrospectively investigated 224 CCC and EC patients treated in Samsung Medical Center from 2001 to 2015 to identify cancer arising from endometriosis according to Sampson and Scott criteria. Propensity score matching was performed to compare patients arising from endometriosis to patients without endometriosis (ratio 1:1) according to stage, age, lymph node metastasis (LNM), cancer antigen (CA)-125 level, and residual status after debulking surgery. RESULTS: Forty-five cases arising from endometriosis were compared with 179 cases without endometriosis. CCC and EC arising from endometriosis tended to present with early age (mean, 45.2 vs. 49.2 years; p=0.003), early-stage (stages I and II, 92.7% vs. 62.3%; p<0.001), lower CA-125 level (mean, 307.1 vs. 556.7; p=0.041), higher percentages of no gross residual disease after surgery (87.8% vs.56.8%; p=0.001), and higher percentages of negative LNM (82.9% vs. 59.0%; p=0.008) compared to cases without endometriosis. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) showed better outcomes for groups with cancer arising from endometriosis (p=0.014 for PFS; and p=0.010 for OS). However, the association with endometriosis was not significant in multivariate analysis. Also, after propensity score matching, survival differences between the 2 groups were not significant. CONCLUSION: CCC and EC arising from endometriosis are diagnosed at an earlier age and stage. However, cancer arising from endometriosis was not a significant prognostic factor. PMID- 29400012 TI - Therapeutic significance of full lymphadenectomy in early-stage ovarian clear cell carcinoma. AB - OBJECTIVES: This study evaluated the therapeutic significance of full lymphadenectomy in early-stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively reviewed records of 127 consecutive patients with pT1/pT2 and M0 OCCC who were treated between January 1995 and December 2015. We compared survival outcomes between those who did and did not undergo para-aortic lymph node dissection (PAND), and analyzed independent prognostic factors (Cox proportional hazards model with backward stepwise elimination). RESULTS: Of the 127 patients, 36 (28%) did not undergo lymphadenectomy; 12 (10%) patients underwent pelvic lymph node dissection (PLND) only; and 79 (62%) patients underwent both PLND and PAND. Of the 91 patients with lymphadenectomy, 11 (12%) had lymph node metastasis (LNM). The PAND- and PAND+ groups did not significantly differ in age, distribution of pT status, radiologically enlarged lymph nodes, positive peritoneal cytology, capsule rupture, peritoneal involvement, and combined chemotherapy. Cox regression multivariate analysis confirmed that older age (hazard ratio [HR]=2.1; 95% confidence interval [CI]=1.0-4.3), LNM (HR=4.4; 95% CI=1.7-11.6), and positive peritoneal cytology (HR=4.2; 95% CI=2.1-8.4) were significantly and independently related to poor disease-specific survival (DSS), but implementation of both PLND and PAND (HR=0.4; 95% CI=0.2-0.8) were significantly and independently related to longer DSS. CONCLUSION: Although few in number, there are some patients with early-stage OCCC who can benefit from full lymphadenectomy. Its therapeutic role should be continuously investigated in OCCC patients at potential risk of LNM. PMID- 29400013 TI - Seromucinous component in endometrioid endometrial carcinoma as a histological predictor of prognosis. AB - OBJECTIVE: In 2014 World Health Organization criteria, seromucinous carcinoma was defined as a new histological subtype in ovarian carcinomas, but "seromucinous carcinoma" was not defined in endometrial carcinomas. The aim of this study was to identify seromucinous carcinoma resembling ovarian seromucinous carcinoma in endometrial carcinomas, and to evaluate the clinical significance for prognoses of the patients. METHODS: Central pathological review was conducted for patients with endometrioid carcinoma of the endometrium treated by primary surgery at our hospital between 1990 and 2013. RESULTS: Among 340 cases included in the study, no case had all tumor cells resembling ovarian seromucinous carcinoma in all specimens, and 31 cases (9.1%) had seromucinous component in combination with endometrioid carcinomas. Immunohistochemical analysis revealed seromucinous component had positive reactivity for cytokeratin (CK) 7, and negative reactivity for CK20 and caudal type homeobox 2 (CDX2) in all cases. Seromucinous component showed lower immunoreactivity of estrogen receptor and progesterone receptor, compared with endometrioid carcinoma component. Progression-free survival of the cases with seromucinous component was better than those without seromucinous component (p=0.049). CONCLUSION: Seromucinous component was identified in approximately 10% of endometrioid carcinoma, and could be a histological predictor for prognosis. PMID- 29400014 TI - Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility? AB - OBJECTIVE: Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1. METHODS: Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400-600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed. RESULTS: Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%). CONCLUSION: Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1. PMID- 29400015 TI - Trends of uterine carcinosarcoma in the United States. AB - OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare type of high-grade endometrial cancer (EC) that has been understudied with population-based statistics due to its rarity. This study examined temporal trends in the proportion of UCS among women with EC. METHODS: This is a retrospective observational study examining The Surveillance, Epidemiology, and End Results program between 1973-2013. Primary EC cases were eligible for analysis, and a time-specific proportion of UCS was examined during the study period. RESULTS: UCS was seen in 11,000 (4.7%) women among 235,849 primary EC cases. Mean age at UCS diagnosis increased from 65.9 to 71.7 years between 1973-1989 and then decreased from 71.7 to 67.0 years between 1989-2013 (both, p<0.001). Proportion of Black women significantly increased during the study period (11.9%-20.0%, p<0.001), whereas the proportion of White women decreased from 86.0% to 60.5% between 1987-2013 (p<0.001). There was a significant increase in the proportion of UCS among primary EC from 1.7% to 5.6% between 1973-2013 (p<0.001). Among type II ECs (n=76,118), the proportion of UCS also increased significantly from 6.0% to 17.5% between 1973-2013 (p<0.001). An increasing proportion of UCS was seen in both young and older women but the magnitude of interval increase was larger in the older age group between 1973 2013 (<60 years, from 1.3% to 3.3%. p<0.001; and >=60 years, from 2.6% to 7.0%, p<0.001). CONCLUSION: Our study demonstrated that the proportion of UCS has significantly increased among EC, accounting for more than 5% in recent years. PMID- 29400016 TI - Impact of institutional accreditation by the Japan Society of Gynecologic Oncology on the treatment and survival of women with cervical cancer. AB - OBJECTIVE: The Japan Society of Gynecologic Oncology (JSGO) initiated a nation wide training system for the education and certification for gynecologic oncologists in 2005. To assess the impact of the quality of the JSGO-accredited institutions, JSGO undertook an analysis of the Uterine Cervical Cancer Registry of the Japan Society of Obstetrics and Gynecology (JSOG) to determine the effectiveness of the JSGO-accredited institutions on the treatment and survival of women with cervical cancer. METHODS: The effectiveness of 119 JSGO-accredited institutions and 125 non-JSGO-accredited institutions on the treatment and survival of women with cervical cancer were compared by analyzing the tumor characteristics, treatment patterns, and survival outcomes of women with stage T1B-T4 cervical cancer utilizing the data in the JSOG nation-wide registry for cervical cancer (2006-2009). RESULTS: A total of 14,185 eligible women were identified: 10,920 (77.0%) cases for 119 JSGO-accredited institutions and 3,265 (23.0%) cases for 125 non-accredited institutions. A multivariate analysis showed that age, stage, histology type, and treatment pattern were independently associated with mortality. Moreover, women who received treatment at the JSGO accredited institutions had a significantly decreased mortality risk compared to non-accredited institutions (adjusted hazard ratio [aHR]=0.843; 95% confidence interval [CI]=0.784-0.905). Similar findings on multivariate analysis were seen among subset of women who received surgery alone (aHR=0.552; 95% CI=0.393-0.775) and among women who received radiotherapy (aHR=0.845; 95% CI=0.766-0.931). CONCLUSION: Successful implementation of gynecologic oncology accrediting institution was associated with improved survival outcome of women with cervical cancer in Japan. PMID- 29400017 TI - Trends in single women with malignancy of the uterine cervix in United States. AB - OBJECTIVE: To examine trends and characteristics of single women with malignancy of the uterine cervix. METHODS: This is a retrospective observational study examining the United States population-based tumor registry (the Surveillance, Epidemiology, and End Results program). Time-specific trends in single marital status were examined in 3,294,208 women among 12 common female malignancies including 87,151 women with uterine cervical malignancy between 1973 and 2013. RESULTS: While the proportion of single women in the majority of malignancies increased during the study time, the proportion of single women with cervical malignancy significantly increased more than in other malignancies (29.3% in 2013 from 6.3% in 1973). There was a surge in the proportion of single women with cervical malignancy starting in the early 1990s, exhibiting the largest annual percentage rate change (APC) among all examined malignancies (1.8%; 95% confidence interval [CI]=1.6, 2.0; p<0.001). There was a significant decrease in the proportion of women aged <40 years with cervical malignancy between 1989 and 2013 (APC, -1.2%; 95% CI=-1.4, -1.0; p<0.001). However, when stratified by age, the proportion of single women aged >=40 years increased significantly during the time (APC, 2.7%; 95% CI=2.3, 3.2; p<0.001) but did not in those who were <40 years (APC, 0.1%; 95% CI=-0.7, 0.6; p=0.850). CONCLUSION: The proportion of single women with malignancy of the uterine cervix has significantly increased in the past 4 decades. This increase was most dramatic in single women aged >=40 years. Improving screening strategies in single women aged >=40 years may help reduce the incidence of this malignancy. PMID- 29400018 TI - Impact of adjuvant hysterectomy on prognosis in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy: a meta-analysis. AB - OBJECTIVE: Few data exist regarding adjuvant hysterectomy (AH) in locally advanced cervical cancer (LACC) patients treated with chemoradiotherapy. We investigated the effect of AH on prognosis in LACC patients, through meta analysis. METHODS: EMBASE and MEDLINE databases and the Cochrane Library were searched for published studies comparing LACC patients who received AH after chemoradiotherapy with those who did not, through April 2016. Endpoints were mortality and recurrence rates. For pooled estimates of the effect of AH on mortality/recurrence, random- or fixed-effects meta-analytical models were used. RESULTS: Two randomized trials and six observational studies (AH following chemoradiotherapy, 630 patients; chemoradiotherapy, 585 patients) met our search criteria. Fixed-effects model-based meta-analysis indicated no significant difference in mortality between the groups (odds ratio [OR]=1.01; 95% confidence interval [CI]=0.58-1.78; p=0.968) with low cross-study heterogeneity (p=0.73 and I2=0.0). This pattern was observed in subgroup analysis for study design, radiation type, response after chemoradiotherapy, and hysterectomy type. The pooled OR for AH and recurrence was 0.59 (95% CI=0.44-0.79; p<0.05) with low cross-study heterogeneity (p=0.29 and I2=17.8), favoring the AH group. However, this pattern was not observed in the subgroup analysis for the randomized trials. There was no evidence of publication bias. CONCLUSION: In this meta-analysis, AH following chemoradiotherapy did not improve survival in patients with LACC, although it seemed to reduce the risk of recurrence. Concerning the significant morbidity of AH after chemoradiotherapy, routine use of AH should be avoided. PMID- 29400019 TI - What MRI features suspect malignant pure mesenchymal uterine tumors rather than uterine leiomyoma with cystic degeneration? AB - OBJECTIVE: To retrospectively assess conventional magnetic resonance imaging (MRI) features that differentiate malignant pure mesenchymal uterine tumors (MPMUT); endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) from uterine leiomyoma with cystic degeneration (ULCD). METHODS: We retrospectively reviewed magnetic resonance (MR) images of 30 patients with ULCD, 18 with ESS, and 15 with LMS, to assess tumor location, margin, T2 signal intensity (SI), speckled appearance, and peripheral band using univariate and multivariate analyses. RESULTS: ULCD more frequently showed subserosal location (53.3%), well-defined margin (96.7%), and speckled appearance (90.0%) compared with ESS (0%, 33.3%, and 33.3%, respectively) or LMS (20.0%, 33.3%, and 60.0%, respectively). In quantitative T2 SI comparisons, the T2 SI ratio of the main solid tumor portion to gluteus maximus muscle differed significantly among the three groups, with ULCD showing a lower SI ratio (0.62) compared with ESS (2.44) and LMS (1.13). On multivariate analysis, an ill-defined margin (odds ratio [OR]=44.885; p=0.003) and high T2 SI (OR=4.396; p=0.046) were the significant MR differentiators. CONCLUSION: An ill-defined tumor margin and high T2 SI ratio of the main solid tumor-to-gluteus maximus muscle were useful MRI features in the differentiation of MPMUT from ULCD. PMID- 29400020 TI - Programmed death-1 (PD-1) expression in cervical intraepithelial neoplasia and its relationship with recurrence after conization. AB - OBJECTIVE: Impaired local cellular immunity contributes to persistent human papillomavirus (HPV) infection and development of cervical intraepithelial neoplasia (CIN). Programmed death-1 (PD-1) and its ligands PD-ligand-1 (L1) and PD-L2 are negative regulators of T cell activity in various cancers, but few studies exist. The aim of this study was to determine the clinicopathologic and immunologic parameters (PD-1, PD-L1, and PD-L2) related to the persistence/recurrence of CIN after conization. METHODS: Medical records of 652 patients diagnosed with CIN and underwent conization were reviewed. The associations between clinicopathologic parameters (e.g., age, parity, initial HPV load, etc.) and persistence/recurrence of CIN were analyzed. Expression of PD-1, PD-L1, and PD-L2 was assessed on 100 conization specimens by immunohistochemistry (IHC) in women matched for propensity-score (50 with persistence/recurrence and 50 without). RESULTS: Initial HPV load (>1,000 relative light unit) and positive margin were shown to be significantly associated with CIN persistence/recurrence (p=0.012 and p<0.001, respectively). Multivariate analysis showed that margin status was an independent predictor of persistence/recurrence (hazard ratio=8.86; 95% confidence interval=1.67-16.81; p<0.001). On IHC analysis, none of the patients expressed PD-L1. PD-1+ T cells were observed in 25 of 100 patients. Also, PD-1+ T cells were significantly correlated with increasing grade of CIN (p=0.031). In addition, patients with persistence/recurrence had increased expression of PD-1 compared with those without (36% vs. 14%, respectively; p=0.020). Although PD-L2 expression did not differ between 2 groups, it was significantly higher in patients with high-grade CIN compared to low-grade (34.7% vs. 12%, respectively; p=0.041). CONCLUSION: Positive surgical margin and expression of PD-1+ T cells were associated with CIN persistence/recurrence after conization. PMID- 29400021 TI - Risk factors in progression from endometriosis to ovarian cancer: a cohort study based on medical insurance data. AB - OBJECTIVE: The objective was to identify risk factors that were associated with the progression from endometriosis to ovarian cancer based on medical insurance data. METHODS: The study was performed on a dataset obtained from the National Health Insurance Research Database, which covered all the inpatient claim data from 2000 to 2013 in Taiwan. The International Classification of Diseases (ICD) code 617 was used to screen the dataset for the patients who were admitted to hospital due to endometriosis. They were then tracked for subsequent diagnosis of ovarian cancer, and available biological, socioeconomic and clinical information was also collected. Univariate and multivariate analyses were then performed based on the Cox regression model to identify risk factors. C-index was calculated and cross validated. RESULTS: A total of 229,617 patients who were admitted to hospital due to endometriosis from 2000 to 2013 were included in the study, out of whom 1,473 developed ovarian cancer by the end of 2013. A variety of factors, including age, residence, hospital stratification, premium range, and various comorbidities had significant impact on the progression (p<0.05). Among them, age, urbanization of residence, hospital stratification, premium range, post-endometriosis childbearing, pelvic inflammation, and depression all had independent, significant impact (p<0.05). The validated C-index was 0.69. CONCLUSION: For a woman diagnosed with endometriosis, increased age, residing in a highly urbanized area, low or high income, depression, pelvic inflammation, and absence of childbearing post-endometriosis all put her at high-risk to develop ovarian cancer. The findings may be of help to gynecologists to identify high risk patients. PMID- 29400022 TI - Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer. AB - OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients. PMID- 29400023 TI - Diagnostic value of integrated 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography in recurrent epithelial ovarian cancer: accuracy of patient selection for secondary cytoreduction in 134 patients. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic value of integrated 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) for suspected recurrence of epithelial ovarian cancer (EOC) with non-disseminated lesions. METHODS: We retrospectively reviewed the medical records of recurrent EOC patients who underwent secondary cytoreduction from January 2000 to December 2013. A total of 134 patients underwent secondary cytoreduction after imaging with either 18F-FDG-PET/CT or contrast-enhanced computed tomography (CECT). RESULTS: In a patient-based analysis of 134 patients, 124 (92.5%) were confirmed to be positive for malignancy. Among 72 patients with suspected non-disseminated recurrence on 18F-FDG-PET/CT, 65 (89.0%) were confirmed to have recurrence, giving 98.5% sensitivity, 87.7% accuracy, and 88.9% positive predictive value (PPV). In the 65 patients with recurrence, residual tumor remained in 14 patients, giving an accuracy of patient selection for secondary cytoreduction of 69.4% (50/72) and it is higher than that of CECT (64.0%). In 169 lesions removed from patients who underwent preoperative 18F-FDG PET/CT, 135 (79.9%) were confirmed to be positive for malignancy and 124 were accurately detected by 18F-FDG-PET/CT, giving 91.9% sensitivity, 81.1% accuracy, and 85.5% PPV. Foreign body granuloma was found in 33.3% of 21 lesions with false positive 18F-FDG-PET/CT findings (7/21). The mean preoperative cancer antigen 125 (CA-125) level in false-positive patients was 28.8 U/mL. CONCLUSION: Compared with CECT, 18F-FDG-PET/CT shows higher sensitivity in lesion-based analysis and better accuracy of patient selection for secondary cytoreduction. However, there is still a need for integration of the results of 18F-FDG-PET/CT, CECT, and CA 125 levels to aid treatment planning. PMID- 29400025 TI - Strengthening implant provision and acceptance in South Africa with the 'Any woman, any place, any time' approach: An essential step towards reducing unintended pregnancies AB - Progress in reducing unintended pregnancies in South Africa is slow. The implant, introduced in 2014, expanded the range of available longacting reversible contraceptives (LARCs) and held much promise. Uptake, however, has declined precipitously, in spite of its 'unmatched effectiveness' and high levels of satisfaction for most users. We propose policy and provider interventions to raise implant use, underscored by a 'LARC-first' approach. Contraceptive counselling should focus on the particular benefits of LARCs and methods be presented in order of effectiveness. Moreover, implants hold particular advantages for certain groups, especially adolescents and young women, in whom it is considered first-line contraception. Provision of immediate postpartum and post-abortion implants is safe and highly acceptable, yet remains under-utilised. Implant services at HIV and tuberculosis clinics are a key priority, as is inclusion of LARC provision within school health services. Implants could also be delivered by existing mobile outreach services, for example in sex worker programmes. Services could be built around nurses dedicated solely to providing implants, with other health workers receiving brief refresher training. Women who experience side-effects, especially abnormal bleeding, require timely interventions, following a standardised protocol, including use of medications. Encouraging return for side-effects, follow-up phone calls and home visits would raise continuation rates. Removal services require doctor support or designated nurses at specific centres. Limited access to removal services, health workers' resistance or botched procedures will further undermine implant provision. Rapid implant demonstration projects in postpartum wards, schools, outreach services and by dedicated providers may rapidly advance the field. Together, the actions outlined here will ensure that the implant fulfils its potential and reinvigorates family planning services. PMID- 29400024 TI - E2/E6 ratio and L1 immunoreactivity as biomarkers to determine HPV16-positive high-grade squamous intraepithelial lesions (CIN2 and 3) and cervical squamous cell carcinoma. AB - OBJECTIVE: Human papillomavirus (HPV) 16 is the most carcinogenic HPV genotype. We investigated if HPV16 L1 capsid protein and E2/E6 ratio, evaluated by cervical cytology, may be used as biomarkers of >=cervical intraepithelial neoplasia (CIN) 2 lesions. METHODS: Cervical specimens were obtained from 226 patients with HPV16 single infection. Using cytology specimen, L1 capsid protein and E2/E6 ratio were detected and the results were compared with those of the conventional histologic analysis of cervical tissues (CIN1-3 and squamous cell carcinoma [SCC]) to evaluate the association. RESULTS: The L1 positivity of CIN2/3 was significantly lower than that of normal cervical tissue (p<0.001) and SCC demonstrated significantly lower L1 positivity than CIN1 (p<0.001). The mean E2/E6 ratios of specimens graded as SCC (0.356) and CIN2/3 (0.483) were significantly lower than those of specimens graded as CIN1 (0.786) and normal (0.793) (p<0.05). We observed that area under the receiver operating characteristic curve (AUC) for E2/E6 ratio (0.844; 95% confidence interval [CI]=0.793-0.895) was higher than that for L1 immunochemistry (0.636; 95% CI=0.562-0.711). A combination of E2/E6 ratio and L1 immunocytochemistry analyses showed the highest AUC (0.871; 95% CI=0.826-0.917) for the prediction of >=CIN2 lesions. CONCLUSION: To our knowledge, this is the first study to validate HPV L1 capsid protein expression and decreased HPV E2/E6 ratio as valuable predictive markers of >=CIN2 cervical lesions. Cervical cytology may be analyzed longitudinally on an outpatient basis with noninvasive procedures as against invasive conventional histologic analysis. PMID- 29400026 TI - [Innovations in interventional radiology applied to the field of otolaryngology: A pictorial essay]. AB - The management of hypervascular ENT tumors is usually complex and requires a multidisciplinary approach because of the risk of serious intra-operative bleeding and of potential injuries to cranial nerves and/or large cervical vessels. Over the last four decades, advances in neuro-interventional radio logical procedures have produced a range of adjunctive endo-vascular techniques in addition to conventional surgery. A pictorial essay in ENT specialty is presented in this article highlighting the most relevant innovations in interventional radiology. PMID- 29400027 TI - [Comparison of stapes protheses: A prospective analysis of audiometric results obtained after stapedotomy by implantation of a teflon piston and a Soft-CliP(r) piston]. AB - A wide variety of pistons are available for stapes surgery in otosclerosis. The objective of this work was to analyze the short-term and medium-term results of Soft-CliP(r) piston in prima-ry stapes surgery and to compare it with a conventional prosthesis. The study was prospective, monocentric, rando-mi-zed, based on efficiency of Soft-CliP(r) prosthesis (11 patients) versus Causse(r) Teflon prosthesis (9 patients) in otosclerosis surgery. Epidemiological data, treatment modalities, pure-tone audiometric results and outcome of patients were studied. Mean follow-up was 10 months. Soft-CliP(r) placement was statisti-cally longer. The mean postoperative air-bone gap was within 10 dB in 73% and 67% of cases at 2 months and in 82% and 89% of cases at medium-term in Soft-CliP(r) and Teflon groups respectively. A statistically significant decrease in mean air-bone gap and for all frequencies was observed at 2 months and at medium term, with no difference between the 2 groups. The main result was the demonstration of the reliability and safety of Soft-CliP(r) prosthesis. With a new design, Soft CliP(r) place-ment was easy. The biomechanics of ossicular chain should be better preserved, and the risk of incus erosion and necrosis decreased. A study on a larger population in the long-term would validate these results. PMID- 29400028 TI - [ENT localisation of amyloidosis: 20 patients report]. AB - Background: Amyloidosis is a rare pathology, due to a toxic accumulation of amyloid proteins infiltrating tissues. Published studies have low statistical power. However it seems that ENT localization have favorable prognosis. Management and check up are not well codified. Methods: Bicentric retros-pec-tive study conducted between 1987 and 2015, from patient diagnosed with ENT amyloidosis. The study was performed to the database of the pathology department. People concerned, history, symptoms and diagnostic features were analysed. The immunologic and clinical status, locations, extension check, treatment and prognosis have been evaluated. Results: Twenty patients were evaluated, ten men and ten women, average age was 55.5 year of age. Three patients were afflicted with familial amyloidosis. Main localisation was larynx (80%), main type was immunoglobulinic (AL) (80%). Amyloidosis was mostly localised (90%) and primary form (80%). Dysphonia was the most frequently encountered symptom. Most performed exami-na-tion were local biopsy and creatinine clearance (100%), serum protein electrophoresis (SEP) (89%), myelogram and/or bone marrow aspiration (75%), and trans thoracic echography (TTE) (75%). Surgical removal was performed for 75% of the patients. Global rate of recurrence was 70%, about 4.6 years after diagnosis. In familial forms, overall survival was 66% at ten years. In non-familial forms, overall survival was 100%. Conclusion: ENT amyloidosis are mostly AL, laryngeal, prima-ry and localised. Distant extension check should be managed by internal medicine specialist and associate creati-ni-ne clea-ran-ce, local biopsy, TTE, SEP and myelogram. Head and neck forms treatment is based on surgical removal, familial forms are of poor prognosis. PMID- 29400029 TI - [Hearing disorders at the candidates of the National Gendarmerie's competition, Ivory Coast]. AB - Objective: Detect the hearing deficiencies of the candi-da-tes of the gendarmerie's competition. Material and method: Pros-pec-tive study realized over 3 years (2008-2010), in the ENT service of the Gendarmerie to Agban (Abidjan). Examination included an otoscopy and a pure tone audiometry. Results: On 23121 candidates, 1245 had a plug of earwax (5.4%). They were aged from 18 to 25 years old (average age: 22.85 years). Eardrum was pathological in 0.5 % of the cases. Prevalence of hearing loss was 1.5%. Hearing loss included sensorineural hearing loss (56.7%), deafness of transmission (29.4%) and mixed deafness (13.9%). Deafness was unilateral in 79.8% and bilateral in 20.2%. Conclusion: Result of audio-gram will be useful for tracking or assessing cases of noise-induced hearing loss attributable to military service. PMID- 29400030 TI - [Dermatofibrosarcoma protuberans of the face: Long term patient of a follow up]. AB - We report the case of a patient 40 years old affected by a facial tumour diagnosed as a dermatofibrosarcoma protu-berans. He has been followed in our clinic for the last 22 years. He got a recurrency after 11 years and after an other surgery he his actually free of disease. The purpose of this article is to evaluate the tumoral recurrency and the long term follow up. PMID- 29400031 TI - [Ectopic thyroid basi-lingual: A case report]. AB - Introduction: The thyroid ectopic gland is a rare anomaly, especially when it's a lingual thyroid. It is characterized by aspecific clinical presentation, causing a diagnostic problem. The diagnosis is based on a combination of imaging techniques as well as histological examination. Case presentation: We are presenting a case of a patient with thyroid basi-lingual treated surgically. Discussion: The low incidence of ectopic lingual thyroid , and their clinical variability requires radiological and isotopic investigations. Conclusion: The diagnosis of this disease is primarily histological. The management of these ectopic thyroid is surgical. PMID- 29400032 TI - [Eagle's syndrome: A case report ]. AB - Introduction: Eagle syndrome, also termed stylohyoid syndrome is a radioclinical entity characterized by an elongated styloid process. Although frequent, it remains largely underdiagnosed by clinicians [1]. We report one case of Eagle syndrome studied at the ENT and radiology departments of the Heinrich Lubke hospital in Dioubrel. Radiologic, therapeutic and clinical data have been documented. The aim of our work is to report a case of Eagle syndrome in a 32 year old patient and to present the diversity of the presenting symptoms, the diagnostic challenges and the therapeutic options. Conclusion: Eagle syndrome represents an unusual and underappreciated entity and must be sought after in every underlying pharyngeal symptomatology with a normal clinical examination. PMID- 29400033 TI - [Kikuchi Fujimoto, one case report and review of the literature]. AB - Histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto disease is characterized by chronic cervical lymphadenopathy associated with fever. The pathogenesis is unknown and she can make many and different clinical aspect. Para clinical evalua tion not contribuate to the diagnosis and it requires patho-logical exam after adenectomy (para cortical necrosis and nuclear histiocytic caryorrhexie ). Evolution is often favorable with the possibility of occurrence in time of systemic lupus erythematosus. PMID- 29400034 TI - [Benign tumors of the nasal cavity, new classification and review of the literature. Report of 54 cases]. AB - Benign tumors of the nasal cavity is an uncommon disease and very diverse about histological variety. Theses tumors are seen at any age without specificity in semiological aspect. The diagnostic approach is based on nasal endoscopy, imaging (CT-MRI) and biopsy. In some anatomo clinical varieties the result of biopsy is so difficult and we must analyze all the tumor specimen after surgery with modern biological procedure (immunohistochemistry, molecular biology). The treatment is surgery especially with endonasal endoscopic procedure. Our series included 54 benign endonasal tumors between January 1998 and December 2008. The mean age of our population is 28 years with a female sex ratio of 1.16. Endoscopic examina tion and a CT scan of facial bones were systematic. The tumors of nasal septum were predominant. The histological variety are dominated by vascular tumors (hemangioma) in 36 cases (66.6%) and papilloma (papilloma and inverted papilloma) in 15 cases (27.7%), two cases of fibroma (37%) and one case of leiomyoma. The treatment was surgical with an endonasal approach in 37 cases (68.5%), endonasal and endoscopic in 11 cases (20.3%) and external 6 cases (11.1%). A review of the literature on tumors of the nasal cavity is made during this study. PMID- 29400035 TI - [Face and neck lift using a superficial musculo-aponeuro-t-ic system (SMAS) plication: Radiological analysis of tissu displacement, a case report]. AB - Objectives: Face and neck lift (FNL) using SMAS plication is a simple and well known surgical technique. The principle of smas plication from two fixed points allows an important tissue ascension. Our purpose was to objectively evaluate the SMAS plication results, although a common critic may be due to its early deep tissular displacement. Materials and methods: We present the case of a 65 y.o. female patient who received a FNL. Miniature metal pins were placed on the external surface of the SMAS in order to ensure radiological monitoring. A cephalo-metric and photographic monitoring were performed pre-operatively and on day 1, months 2, 6 and 16 postoperatively . We performed a computed numerised analysis of the movement of the markers in an orthogonal axis. Results: All our bearings kept a constant position in the radiographic follow-up , demons-tra-ting the fixity of SMAS kinked 16 months postoperatively. Clinically the correction remained a good appearance with a very slight relaxation of the superficial tissues (skin and subcutaneous fat). Conclusion: In the case of our patient, the tensioning of the deep facial plan (the SMAS) objectively appeared to be efficient over time, with an overall delay of 16 months. Our protocole appeared to be coherent without any specific complication. It permits to objectively differentiate the relaxation of the deep or superfial tissues after a facial lift procedure. PMID- 29400036 TI - [Predictive factors for recurrence after surgery of nasal polyposis]. AB - Introduction: Endoscopic sinus surgery has become the treatment of choice in the surgical management of patients with nasal polyposis. The aim of our study is to identify the role of some epidemiological, clinical and therapeutic factors in recurrence after surgery of nasal polyposis. Materials and methods: We conducted a retrospective study over a period of 11 years (between 2000 and 2010) including 184 patients operated for nasal polyposis after failure of prolonged medical treatment. We evaluated the impact of epidemiological and clinical factors (age, sex, asthma, Widal disease, allergy and stage of nasal polyposis at the time of surgery) and treatment (surgical technique, observance of postoperative topical steroids ) on postoperative recurrence. Results: Nasal poly-posis recurred in 26.6% of patients after an average period of 23 months. Widal disease, asthma and bad observance of the intranasal steroid therapy were significantly associated with postoperative recurrence in the univariate analysis. In multi-variate analysis the bad observance of the intranasal steroid therapy was the only factor significantly associated with recurren-ce. Conclusion: Postoperative steroids prescribed routi-nely in our practice can effectively prevent recurrence after endonasal surgery and this result was found in both uni-variate and multivariate analysis. PMID- 29400037 TI - Peptide receptor radionuclide therapy in head and neck paragangliomas - Report of 14 cases. AB - Background: Peptide receptor radionuclide therapy (PRRT) is a very promising treatment option in neuroendocrine tumours, with good results, but there are only few reports regar-ding its use in paragangliomas. Methods: The authors conduc-ted a retrospective study during the period of May 2011 to February 2014 in an Oncological Centre. Ten patients with jugular-tympanic paragangliomas and four with carotid body paragangliomas were treated with three cycles of Lutetium labelled peptide (177 Lu-DOTATATE). Treatment response was assessed with a PET-CT with 68 Ga-DOTANOC and clinical crite-ria. Results: Ten of the fourteen patients showed a decrea-se in the tumor standard uptake value (SUV) after treat-ment. 90% of patients with Jugulotympanic paraganglio-mas had symptomatic improvement or stabilization. Patients with carotid body paragangliomas and patients with a low uptake of 68 Ga-DOTANOC had a worse response to the treatment. The tumor SUV value was a predictor of treatment response [R= 0,64; F= 8,212; p= 0,014]. Conclusion: Peptide receptor radio-nuclide therapy can be a therapeutic option in selected cases of head and neck paragangliomas. PMID- 29400038 TI - [Multiple intracranial epidermoid cysts: Case report]. AB - Epidermoid cyst is a benign and rare tumor, that evolves slowly. We describe the case of a 55 years-old woman, who came to our consultation for atypical trigeminal neuralgia of left V1 and V2 nerves. Brain MRI found two tumors: T1W hypointense with no appreciable enhancement after gadolinium injection and T2W and diffusion hyperintense. This last feature was in favour of an epidermoid cyst, but the multiplicity of cerebral lesions was definitely not in favor of such a diagnos-tic. They were located behind the right eye and in the left Meckel's cave (trigeminal cave). The surgical strategy consis-ted in removal the retro orbital tumor witch was the most acces-si-ble of both the diagnostic of epidermoid cyst was retaned thanks to the anatomopathology report. As these lesions had the exact same characteristics, we concluded that they were simi-lar. The second epidermoid cyst was not removed because of surgical risk, its benign nature and low evolutionary potential. PMID- 29400039 TI - Cholesteatoma and osteoradionecrosis after radio-therapy of the temporal bone: Surgical aspects. AB - Introduction: The treatment for head and neck cancer with radiotherapy can cause different alterations of the auditory system. We report two cases of chronic otitis of the external and middle ear secondary to osteoradionecrosis of the temporal bone. This article aims to report the experience of the surgical approach in such condition. Cases report: The first patient was treated with radiotherapy in his childhood for a cerebellar tumor. He developed years later a cholesteatoma which invaded the mastoid cavities through a destruction of the external auditory canal. The second was treated for a malignant parotid tumour 15 years before by surgery and radiotherapy. She developed a chronic otorrhea with a partial destruction of the bony external auditory canal. Both patients were treated by surgery with reconstruction including bone, cartilage, fascia and skin grafts. The outcome was good in both cases. Osteo-radio-necrosis of the temporal bone is a rare but serious complication of radiotherapy for head and neck cancer. This complication can occur even many years after the treatment. Our two cases demonstrate a way to solve this pathology. A long term supervision with regular cares is essential in order to get a good healing. Due to the improvement of the radiation therapy we could expect less complications of this type in the future. PMID- 29400040 TI - Giant metastasis invading pharyngeal wall, pterygo-maxillary space, submaxillary and parotid glands. PMID- 29400041 TI - [Therapeutic education of total laryngectomy patients: Influence of social factors]. AB - Current health policies promote patient education, parti-cu-lar-ly in oncology. Therapeutic education program must be tailo-red to the characteristics, needs and expectations of the population. In the ENT Department of Head and Neck Surgery, Larrey Hospital in Toulouse, a therapeutic education program for patient with total laryngectomy has been experienced since 2011. But its propagation remains difficult. The aim of this study is to determine if social factors are nfluencing the parti-cipation of the laryngectomized population in the program. The brochure explaining this program and a registration form coupled with a survey questionnaire were distributed to the regio-nal population of patient with total laryngectomy. After two months of investigation we collected 42 responses. It is clear from their analysis that social factors underlie partici-pa-tion, particularly educational level, available financial resources level and the socio professional group. PMID- 29400042 TI - [Dynamic palatography: Diagnostic tool for dysfunc-tional swallowing? Feasibility study]. AB - Objective: Dysfunctional swallowing may cause transverse occlusal disorders. The speech re-education of dysfunctional swallowing aims to correct or prevent the recurrence of occlu-sal disorders. The main objective was to test the dynamic palato-graphy as a diagnosis and quantification tool of the dysfunctional swallowing. Material and methods: The study was prospective and descriptive. Twelve average 23.5 years old women with a clinical dysfunctional swallowing have been included between January and May 2014. None was aware of presenting an atypical swallowing or dento-facial dysmorphism of class II. The dynamic palatography device measured the pressure force of the language on the palate during the lingual rest, swallowing saliva and water. Parameters measured were the duration and magnitude of support of the tongue on the palate. Results: Dynamic palatography showed a trend to predominant anterior contact during rest position (25%), and lower position of the language with little contact during swallo-wing of saliva and water. Discussion: Palatography results are consistent with the clinical diagnostic criteria of atypical swallo-wing. Our palatography tool has the advantage of being unobtrusive in the mouth compared to other pre existing systems. This device should be tested on larger patient popu-la-tions and could enable monitore atypical swallowing rehabili-ta-tion efficiency. The palatography could complete the swallo-wing assessment and be a monitoring and rehabilitation tool in real time. PMID- 29400043 TI - [Dysphonia in children: Retrospective and comparative study between the late 1980s and today]. AB - Child dysphonia is a frequent pathological situation which concerns 6 to 38 percent of a school attending population. Thus it demands a specific and adapted treatment. Because of its direct consequences on social, family and school lives, parents often seek advice from a speech specialist. This study focuses on the specificities of those individuals having diagnosed child dysphonia, as well as the treatment which can be given to them. Our work covers a period of twenty years of comparative studies. We have read through dr Coulombeau's files, from 2005 to 2011, and we have made up a series of questions addressed to the speech therapists having speech impaired children in their practice. We have cross examined these data with those of Dr Cornut's, covering a period of seven years (1985-1991). The qualitative and quantitative studies which have been carried out enabled us to highlight the fact there has been a constant background of child dysphonia and an evolution in the offered treatments. Indeed, we have realised that the number of individuals having diagnosed child dysphonia are less and less operated on. In the same time people tend to ignore the offered treatments. Though the follow-ups to a prior visit at a speech therapist have decreased for twenty years, it still remains the most common treatment. Our analysis does not focus on the effects of the given treatments on a long term basis. It thus appears that a study consisting in analysing the development of these children through adulthood would be greatly accurate. PMID- 29400044 TI - [The Bell Labs contributions to (singing) voice enginee-ring]. AB - While in "art" and "traditional" music, the nimbleness of the voice and the mastering of the vocal tone are put into pers-pective, in "popular" music, sound engineering takes the lead, and relegates the vocal virtuosity of the interpreter to second place. We propose to study here three technologies with contri-butions to music. All are developed and patented by the Bell Labs: The artificial larynx (and its derivatives, Sonovox and TalkBox), the vocoder and the speech synthesis. After a presen-tation of the source-filter theory, vital to these innovations, the principle of these three technologies is explained. A brief historical is outlined and is complemented by examples of films and musical selections depicting these processes. In light of these elements, we conclude: Sound engineering, and in parti-cular the modification of voice sonority, has become an indis-pensable component in the process of "pop" artistic musical creation. PMID- 29400045 TI - [Hearing aids at the International Center of Auditory rehabilitation in Abidjan: Prosthetics gains and satisfaction in patients]. AB - Subject: To evaluate patients wearing hearing aid at the International Center of Auditory Correction in Abidjan. Method and material: It is a descriptif and transversal study from 07/01/99 to 06/30/10. We have included the files of patients completely filled. We have stu-died the indications, prosthetics gains and the satisfaction after hearing aid. Results: We have achieved 536 files. The ave-rage was 36 years. The indications have been in 76.1% cases of sensorineural hearing loss. The hearing loss has been associa-ted in 13.2% cases to language disorder. For all patient we have noticed bilateral hearing loss in 496 cases (92.5%). The behind the ear aids have been chosen in 69% cases. The type was analogical or digital respectively in 65% and 35% des cas. The prosthetic pure tonal gain was more than 30 dB in 66.8% cases and the prosthetic speech reception threshold gain more than 30 dB in 55.3% cases. The patients have been respectively satisfied less satisfacted, no satisfacted in 68.47%, 22.76% and 8.7% cases. Conclusion: The hearing aids have improved the audition in most of the indications. The proportion of patients satisfied was proportionally equivalent to the audiometric results. PMID- 29400046 TI - [Implications of multilingualism in the manifestations of stuttering]. AB - Stuttering is a communication disorder affecting speech which is then considered disfluent. What happens when a person who stutters speaks several languages? There will be constant interactions between multilinguism and stuttering. The disorder will generally appear differently according to the spoken language. Linguistic factors have an impact on stutte-ring, with disfluencies appearing differently according to the speaker's proficiency in using each language. Emotional factors related to the choice of the spoken language can exag-ge-rate the disorder, hence influencing the speaker's choice of a language, even choices in life. These factors are to be taken into consideration when assessing stuttering, with a particular attention to cultural aspects. Finally, stuttering variability according to the spoken language will also have an impact on therapeutic decisions. PMID- 29400047 TI - [Put sound, but the sense, the multilinguisms]. AB - Exchanges, travel, intercountry adoption which has become an increasingly common practice, uprooting, etc. have disrupted the compositions of increasingly multilingual socie-ties and families. The development of research in cognitive sciences and the birth of bilingualism as a field of study since the 1970s, together with recent advances in linguistics, psycho-logy, neuroimaging and speech therapy have made it possible to better describe the neuropsychological function and develop-ment of the bilingual person, particularly in the development of the normo and hearing-impaired child, in both language and behavior. It also involves other pathological situations such as stuttering and autism seen in Alzheimer's disease. Bilingualism is now a recognized cultural, social, educational and professio-nal substantial asset. Children who are able to express them-selves in more than one language see their metalinguistic skills increase and show a stronger attachment to their parent's culture of origin. PMID- 29400048 TI - [Monolingualism, an overlooked multilingual?] AB - There has been some emphasis on the practice of multi-lingualism. It is seen as encouraging children creativity, lin-guis--tic sensitivity and openness. In this article, we seek to find out if the different qualities demonstrated in multilingualism can also be developed in a monolingualism context. Despite the fact that it is a single language system - where grammar, accents, the rhythm of the sentence remain unchanged - it will be interesting to draw some parallels with multilingualism. This will lead us to study the processes of oral and written language acquisition in children. The associations with stuttering will also be mentioned. PMID- 29400049 TI - Ratiometric Near-Infrared Fluorescent Probe for Synergistic Detection of Monoamine Oxidase B and Its Contribution to Oxidative Stress in Cell and Mice Aging Models. AB - As new biomarkers, monoamine oxidases (MAOs) play important roles in maintaining the homeostasis of biogenic amines via catalyzing the oxidation of biogenic amines to corresponding aldehydes with the generation of reactive oxygen species (ROS). MAOs have two isoforms, MAO-A and MAO-B. MAO-A is considered to be a major factor of neuropsychiatric and depressive disorders. However, MAO-B is thought to be involved in several neurodegenerative diseases. Therefore, to explore their distinct roles in different diseases, the selective detection of MAOs is essential. Herein, two new types of near-infrared (NIR) fluorescent probes, MitoCy-NH2 and MitoHCy-NH2, are provided for synergistic imaging of MAO-B and its contribution to oxidative stress in cells and in mice aging models. These probes are composed of three moieties: heptamethine cyanine as fluorophore, propanamide as recognition group, and triphenylphosphonium cation as mitochondrial targeting group. The amine oxidation and beta-elimination reaction can lead to obvious fluorescence increase and color changes from green to blue. The probe MitoHCy-NH2 can be used to synergistically detect MAO-B and its contribution to oxidative stress in the replicative senescence model. And the probe MitoCy-NH2 can offer ratiometric near-infrared fluorescence for the selective detection of MAO-B in the H2O2-induced cell aging model and in mice aging models. The results reveal that there are different MAO-B levels in different ages of mice models. MitoCy NH2 also can evaluate therapeutic effects of pargyline and selegiline in mice models. The desirable analytical behaviors of our probes make them useful chemical tools for the selective detection of MAO-B and its contribution to oxidative stress in biosystems. PMID- 29400050 TI - Highly Specific near-Infrared Fluorescent Probe for the Real-Time Detection of beta-Glucuronidase in Various Living Cells and Animals. AB - beta-Glucuronidase (GLU) is an important biomarker for primary cancers and intestinal metabolism of drugs or endogenous substances; however, an effective optical probe for near-infrared (NIR) monitoring in vivo is still lacking. Herein, we design an enzyme-activated off-on NIR fluorescent probe, HC-glu, based on a hemicyanine keleton, which is conjugated with a d-glucuronic acid residue via a glycosidic bond, for the fluorescent quantification and trapping of endogenous GLU activity in vitro and in vivo. The newly developed NIR probe exhibited prominent features including prominent selectivity, high sensitivity, and ultrahigh imaging resolution. It has been successfully used to detect and image endogenous GLU in various hepatoma carcinoma cells, tumor tissues, and tumor-bearing mouse models, for cancer diagnosis and therapy. Moreover, it could detect the in vivo activity of GLU in the intestinal tracts of animals including mice and zebrafish, where GLU performs a vital biological function and is mainly distributed. It could also evaluate real intestinal distribution and real-time variations of GLU in development and growth, all of which are very helpful to guide rational drug use in the clinic. Our results fully demonstrated that HC-glu may serve as a promising tool for evaluating the biological function and process of GLU in living systems. PMID- 29400051 TI - Highly Stable Conjugated Polymer Dots as Multifunctional Agents for Photoacoustic Imaging-Guided Photothermal Therapy. AB - Theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, most photothermal agents are limited by their instability and low photothermal conversion efficiency. In this study, we report new conjugated polymer dots (Pdots) as multifunctional agents for photoacoustic (PA) imaging guided PTT. The novel 4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]-2,6 bis(trimethylstannyl)benzo[1,2-b:4,5-b']dithiophene-6,6'-dibromo-N,N'-(2 ethylhexyl)isoindigo (BDT-IID) Pdots are readily fabricated though nanoreprecipitation and can absorb strongly in the 650-700 nm region. Furthermore, the BDT-IID Pdots possess a stable nanostructure and an extremely low biotoxicity. In particular, its photothermal conversion efficiency can be up to 45%. More importantly, our in vivo results exhibit that the BDT-IID Pdots are able to offer concurrently enhanced PA contrast and sufficient photothermal effect. Consequently, the BDT-IID Pdots can be exploited as a unique theranostic nanoplatform for PA imaging-guided PTT of tumors, holding great promise for their clinical translational development. PMID- 29400052 TI - Quantification of Au Nanoparticle Biouptake and Distribution to Freshwater Algae Using Single Cell - ICP-MS. AB - Quantifying metal and nanoparticle (NP) biouptake and distribution on an individual cellular basis has previously been impossible, given available techniques which provide qualitative data that are laborious to acquire and prone to artifacts. Quantifying metal and metal NP uptake and loss processes in environmental organisms will lead to mechanistic understanding of biouptake and improved understanding of potential hazards and risks of metals and NPs. In this work, we present a new technique, single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), which allows quantification of metal concentrations on an individual cell basis down to the attogram (ag) per cell level. We present data validating the novel method, along with the mass of metal per cell. Finally, we use SC-ICP-MS, with ancillary cell counting methods, to quantify the biouptake and strong sorption and distribution of both dissolved Au and Au NPs in a freshwater alga (Cyptomonas ovate). The data suggests differences between dissolved and NP uptake and loss. In the case of NPs, there was a dose and time dependent uptake, but individual cellular variations; at the highest realistic exposure conditions used in this study up to 40-50% of cells contained NPs, while 50-60% of cells did not. PMID- 29400053 TI - Two-In-One Method for Graphene Transfer: Simplified Fabrication Process for Organic Light-Emitting Diodes. AB - Graphene as one of the most promising transparent electrode materials has been successfully applied in organic light-emitting diodes (OLEDs). However, traditional poly(methyl methacrylate) (PMMA) transfer method usually results in hardly removed polymeric residues on the graphene surface, which induces unwanted leakage current, poor diode behavior, and even device failure. In this work, we proposed a facile and efficient two-in-one method to obtain clean graphene and fabricate OLEDs, in which the poly(9,9-di-n-octylfluorene-alt-(1,4-phenylene-(4 sec-butylphenyl)imino)-1,4-phenylene) (TFB) layer was inserted between the graphene and PMMA film both as a protector during the graphene transfer and a hole-injection layer in OLEDs. Finally, green OLED devices were successfully fabricated on the PMMA-free graphene/TFB film, and the device luminous efficiency was increased from 64.8 to 74.5 cd/A by using the two-in-one method. Therefore, the proposed two-in-one graphene transfer method realizes a high-efficient graphene transfer and device fabrication process, which is also compatible with the roll-to-roll manufacturing. It is expected that this work can enlighten the design and fabrication of the graphene-based optoelectronic devices. PMID- 29400054 TI - Targeted Analysis of the Concentration Changes of Phenolic Compounds in Persian Lime (Citrus latifolia) during Fruit Growth. AB - Citrus fruits possess a high content of phenolic compounds; however, few studies have focused on the changes occurring during fruit growth. In this study, the changes in the concentration of 20 flavonoids, 4 phenolic acids, and their biosynthetic precursors phenylalanine and tyrosine have been evaluated during fruit maturation (14 weeks). Extracts from all samples, obtained by ultrasound assistance, were analyzed by liquid chromatography coupled to tandem mass spectrometry with a triple quad system (LC-QqQ MS/MS). In general, the concentration of flavanones, which represented over 70% of the studied phenols, and flavones increased during fruit growth, reaching their maximum concentration around week 12. In general, flavanols and phenolic acids exhibited their maximum concentration at week 5 and then decreasing significantly during the rest of maturation. Phenylalanine and tyrosine showed a sinuous behavior during fruit growth. Partial least-squares showed a clear differentiation among fruits belonging to different maturation stages, coumaric acid derivatives being the most influential variables on the projection. PMID- 29400055 TI - Biotransformation of Benzo[ a]pyrene by Three Rainbow Trout ( Onchorhynchus mykiss) Cell Lines and Extrapolation To Derive a Fish Bioconcentration Factor. AB - Permanent fish cell lines constitute a promising complement or substitute for fish in the environmental risk assessment of chemicals. We demonstrate the potential of a set of cell lines originating from rainbow trout ( Oncorhynchus mykiss) to aid in the prediction of chemical bioaccumulation in fish, using benzo[ a]pyrene (BaP) as a model chemical. We selected three cell lines from different tissues to more fully account for whole-body biotransformation in vivo: the RTL-W1 cell line, representing the liver as major site of biotransformation, and the RTgill-W1 (gill) and RTgutGC (intestine) cell lines, as important environment-organism interfaces, which likely influence chemical uptake. All three cell lines were found to effectively biotransform BaP. However, rates of in vitro clearance differed, with the RTL-W1 cell line being most efficient, followed by RTgutGC. Co-exposures with alpha-naphthoflavone as potent inhibitor of biotransformation, assessment of CYP1A catalytic activity, and the progression of cellular toxicity upon prolonged BaP exposure revealed that BaP is handled differently in the RTgill-W1 compared to the other two cell lines. Application of the cell-line-derived in vitro clearance rates into a physiology-based toxicokinetic model predicted a BaP bioconcentration factor (BCF) of 909-1057 compared to 920 reported for rainbow trout in vivo. PMID- 29400056 TI - 2D Intrinsic Ferromagnets from van der Waals Antiferromagnets. AB - Intrinsically ferromagnetic 2D semiconductors are essential and highly sought for nanoscale spintronics, but they can only be obtained from ferromagnetic bulk crystals, while the possibility to create 2D intrinsic ferromagnets from bulk antiferromagnets remains unknown. Herein on the basis of ab initio calculations, we demonstrate this feasibility with the discovery of intrinsic ferromagnetism in an emerging class of single-layer 2D semiconductors CrOX (CrOCl and CrOBr monolayers), which show robust ferromagnetic ordering, large spin polarization, and high Curie temperature. These 2D crystals promise great dynamical and thermal stabilities as well as easy experimental fabrication from their bulk antiferromagnets. The Curie temperature of 2D CrOCl is 160 K, which exceeds the record (155 K) of the most-studied dilute magnetic GaMnAs materials, and could be further enhanced by appropriate strains. Our study offers an alternative promising way to create 2D intrinsic ferromagnets from their antiferromagnetic bulk counterparts and also renders 2D CrOX monolayers great platform for future spintronics. PMID- 29400057 TI - Dual-Functional Starfish-like P-Doped Co-Ni-S Nanosheets Supported on Nickel Foams with Enhanced Electrochemical Performance and Excellent Stability for Overall Water Splitting. AB - Dual-functional electrocatalysts have recently been reported to improve the conversion and storage of energy generated from overall water splitting in alkaline electrolytes. Herein, for the first time, a shape-controlled synthesis of starfish-like Co-Ni-S nanosheets on three-dimensional (3D) hierarchically porous nickel foams (Co-Ni-S/NF) via a one-step hydrothermal method was developed. The influence of reaction time on the nanosheet structure and properties was intensively studied. After 11 h reaction, the Co-Ni-S/NF-11 sample displays the most regular structure of nanosheets and the most outstanding electrochemical properties. As to water splitting, hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) required overpotentials of 284.3 and 296 mV, respectively, to provide a current density of 100 mA cm-2. The marvelous electrochemical performance can be attributed to the conductive networks of 3D layered porous nickel skeletons that are highly interconnected, which provided a large specific area and highly active sites. To further enhance the electrochemical performances of the electrocatalyst, the influence of the doping of the P element was also studied. The results proved that the P-doped Co-Ni-S/NF maintains the starfish structure and demonstrates outstanding properties, providing a current density of 100 mA cm-2 with only 187.4 and 292.2 mV overpotentials for HER and OER, respectively. It exhibited far more excellent properties than reported dual-functional electrocatalysts. Additionally, when used as an overall water-splitting catalyst, P-Co-Ni-S/NF can provide a 10 mA cm 2 current density at a given cell voltage of 1.60 V in 1 M KOH, which is competitive to the best-known electrocatalysts, with high long-term stability. PMID- 29400058 TI - Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive Heteroaromatic Enones. AB - Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophene-yl, and 2-benzothiophene-yl) have traditionally proven difficult or impossible to cyclize with typical Bronsted and Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with typical UV exposure times of 3.4-6.8 min. In all cases, 2-furyl and 2-thiophene-yl enones cyclized, whereas 2-benzofuryl and 2-benzothiophene-yl enones exhibited divergent properties with reactivity patterns tied to the identity of the vinyl group. This report discloses the first photo-Nazarov reactions of tetrahydropyridine-substituted 2-furyl ketones, providing a direct approach to the corresponding fused heterocyclic motifs built around a central cyclopentanone. These motifs constitute the core structures of biologically active natural products, including the marine alkaloid nakadomarin A. PMID- 29400059 TI - Control of Electronic Structure and Conductivity in Two-Dimensional Metal Semiquinoid Frameworks of Titanium, Vanadium, and Chromium. AB - The isostructural, two-dimensional metal-organic frameworks (H2NMe2)2M2(Cl2dhbq)3 (M = Ti, V; Cl2dhbqn- = deprotonated 2,5-dichloro-3,6-dihydroxybenzoquinone) and (H2NMe2)1.5Cr2(dhbq)3 (dhbqn- = deprotonated 2,5-dihydroxybenzoquinone) are synthesized and investigated by spectroscopic, magnetic, and electrochemical methods. The three frameworks exhibit substantial differences in their electronic structures, and the bulk electronic conductivities of these phases correlate with the extent of delocalization observed via UV-vis-NIR and IR spectroscopies. Notably, substantial metal-ligand covalency in the vanadium phase results in the quenching of ligand-based spins, the observation of simultaneous metal- and ligand-based redox processes, and a high electronic conductivity of 0.45 S/cm. A molecular orbital analysis of these materials and a previously reported iron congener suggests that the differences in conductivity can be explained by correlating the metal-ligand energy alignment with the energy of intervalence charge-transfer transitions, which should determine the barrier to charge hopping in the mixed-valence frameworks. PMID- 29400060 TI - Programmable Modulation of Copper Nanoclusters Electrochemiluminescence via DNA Nanocranes for Ultrasensitive Detection of microRNA. AB - The DNA nanocrane with functionalized manipulator and fixed-size base offered a programmable approach to modulate the luminous efficiency of copper nanoclusters (Cu NCs) for achieving remarkable electrochemiluminescence (ECL) enhancement, further the Cu NCs as signal label was constructed in biosensor for ultrasensitive detection of microRNA-155. Herein, the DNA nanocrane was first constructed by combining binding-induced DNA assembly as manipulator and tetrahedral DNA nanostructure (TDN) as base, which harnessed a small quantity of specific target (microRNA (miRNA)-155) binding to trigger assembly of separate DNA components for producing numerous AT-rich double-stranded DNA (dsDNA) on the vertex of TDN. Upon the incubation of Cu2+ on the AT-rich dsDNA, each DNA stabilized Cu NCs probe could be in situ electrochemically generated on an individual TDN owing to the A-Cu2+-T bond. Thus, the generation of Cu NCs was highly regulated with AT-rich dsDNA as the template, and its lateral distance was tuned by the TDN size, which were two key factors to influence the luminous efficiency of Cu NCs. By coordinate modulation, the detection limit of the ultrasensitive biosensor for miRNA-155 down to 36 aM and the programmable modulation strategy paved the way for comprehensive applications of DNA nanomachines and metal nanoclusters in biosensing and clinical diagnosis. PMID- 29400061 TI - Implications of Thermal Annealing on the Benzene Vapor Sensing Behavior of PEVA Graphene Nanocomposite Threads. AB - The effect of thermal treatments, on the benzene vapor sensitivity of polyethylene (co-)vinylacetate (PEVA)/graphene nanocomposite threads, used as chemiresistive sensors, was investigated using DC resistance measurements, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). These flexible threads are being developed as low-cost, easy-to-measure chemical sensors that can be incorporated into smart clothing or disposable sensing patches. Chemiresistive threads were solution-cast or extruded from PEVA and <10% graphene nanoplatelets (by mass) in toluene. Threads were annealed at various temperatures and showed up to 2 orders of magnitude decrease in resistance with successive anneals. Threads heated to >=80 degrees C showed improved limits of detection, resulting from improved signal-noise, when exposed to benzene vapor in dry air. In addition, annealing increased the speed of response and recovery upon exposure to and removal of benzene vapor. DSC results showed that the presence of graphene raises the freezing point, and may allow greater crystallinity, in the nanocomposite after annealing. SEM images confirm increased surface roughness/area, which may account for the increase response speed after annealing. Benzene vapor detection at 5 ppm is demonstrated with limits of detection estimated to be as low as 1.5 ppm, reflecting an order of magnitude improvement over unannealed threads. PMID- 29400062 TI - Transition-Metal-Free Oxidative Aminooxyarylation of Alkenes: Annulations toward Aminooxylated Oxindoles. AB - An efficient oxidative aminooxyarylation of alkenes under a transition-metal-free condition was described. Under the reaction conditions, N-hydroxyphthalimide (NHPI) reacted readily with N-arylacrylamides to produce cyclic products via a radical C-H functionalization process, achieving both C-O and C-C bonds formation in one pot. This reaction provided a facile access to the valuable aminooxylated oxindoles. The benzylic and alpha-methylene C(sp3)-H bonds were also aminooxylated under the reaction conditions. PMID- 29400063 TI - Energy Renormalization for Coarse-Graining the Dynamics of a Model Glass-Forming Liquid. AB - Coarse-grained modeling achieves the enhanced computational efficiency required to model glass-forming materials by integrating out "unessential" molecular degrees of freedom, but no effective temperature transferable coarse-graining method currently exists to capture dynamics. We address this fundamental problem through an energy-renormalization scheme, in conjunction with the localization model of relaxation relating the Debye-Waller factor ?u2? to the structural relaxation time tau. Taking ortho-terphenyl as a model small-molecule glass forming liquid, we show that preserving ?u2? (at picosecond time scale) under coarse-graining by renormalizing the cohesive interaction strength allows for quantitative prediction of both short- and long-time dynamics covering the entire temperature range of glass formation. Our findings provide physical insights into the dynamics of cooled liquids and make progress for building temperature transferable coarse-grained models that predict key properties of glass-forming materials. PMID- 29400064 TI - Dispersed Uniform Nanoparticles from a Macroscopic Organosilica Powder. AB - A colloidal dispersion of uniform organosilica nanoparticles could be produced via the disassembly of the non-surfactant-templated organosilica powder nanostructured folate material (NFM-1). This unusual reaction pathway was available because the folate and silica-containing moieties in NFM-1 are held together by noncovalent interactions. No precipitation was observed from the colloidal dispersion after a week, though particle growth occurred at a solvent dependent rate that could be described by the Lifshitz-Slyozov-Wagner equation. An organosilica film that was prepared from the colloidal dispersion adsorbed folate-binding protein from solution but adsorbed ions from a phosphate-buffered saline solution to a larger degree. To our knowledge, this is the first instance of a colloidal dispersion of organosilica nanoparticles being derived from a macroscopic material rather than from molecular precursors. PMID- 29400065 TI - The Role of Ultrasound-Guided Therapeutic Paracentesis in an Outpatient Transitional Care Program: A Case Series. AB - BACKGROUND: Patients with ascites suffer from distressing symptoms and are at high risk for readmission after hospitalization. Timely paracentesis is an important palliative tool in managing this vulnerable population. At our institution, we have developed a multidisciplinary transitional care program for patients discharged from the hospital with a wide range of complex conditions including refractory ascites. METHODS: We present a case series of 10 patients with symptomatic ascites who were enrolled in our transitional care program and treated with ultrasound-guided therapeutic paracentesis in our clinic. Patient medical records were retrospectively reviewed to collect procedure details, outcomes, and follow-up data on emergency department (ED) visits and readmissions. Cost data were obtained from the hospital financial system. RESULTS: Over the span of 9 months (September 2016 to July 2017), 22 total therapeutic paracenteses were performed on 10 unique patients in the transitional care clinic. Median age of the patient cohort was 52.5 years (range: 27-71 years). All patients reported immediate relief of ascites-related discomfort following the procedure. We did not observe any major adverse effects due to the in-clinic procedure. Nine of the 10 patients did not have any ED visits or readmissions within 30 days of discharge. The cost of performing ultrasound guided paracentesis in the transitional care clinic was US$546.77 compared to US$978.32 when performed in the hospital. CONCLUSION: Our experience suggests that outpatient paracentesis may be a safe, feasible, and cost-effective means of providing symptom management for patients with ascites during their transition from hospital to home. PMID- 29400066 TI - Increasing the use of mobile technology-derived endpoints in clinical trials. PMID- 29400070 TI - Effect of accelerometer-based feedback on physical activity in hospitalized patients with ischemic stroke: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of accelerometer-based feedback on physical activity in hospitalized patients with ischemic stroke. DESIGN: Randomized controlled trial. SETTING: Acute care hospital. SUBJECTS: A total of 55 patients with ischemic stroke who could walk without assistance were randomly assigned to the intervention group ( n = 27) or the control group ( n = 28). INTERVENTIONS: At the baseline measurement, patients did not receive accelerometer-based feedback. At follow-up, a physical therapist provided instruction on accelerometer-based feedback, discussed physical activity targets and encouraged the patients to walk more until discharge. MAIN MEASURES: The average daily number of steps taken was used as the index of daily hospitalized physical activity. RESULTS: The study sample consisted of 48 patients, of whom 23 patients comprised the intervention group and 25 patients comprised the control group. Although there were no significant differences in physical activity values between the two groups at the baseline measurement, the values in the intervention group at follow-up were significantly higher than those in the control group (5180.5 +/- 2314.9 vs. 3113.6 +/- 1150.9 steps/day, P = 0.0003). The effect size of physical activity values (Cohen's d = 1.15) at follow-up was large between the two groups. CONCLUSION: Exercise training combined with accelerometer-based feedback effectively increased physical activity in hospitalized patients with ischemic stroke. PMID- 29400071 TI - The impact of wrist fracture, surgical repair and immobilization on patients: a qualitative study. AB - OBJECTIVE: To investigate patients' experience following wrist fracture, surgical repair and immobilization. DESIGN: A qualitative investigation involving individual participant interviews. SETTING: A metropolitan trauma service. SUBJECTS: In all, 31 participants were consecutively recruited from three groups within a randomized controlled trial comparing immobilization for one ( n = 11), three ( n = 10) or six weeks ( n = 10) following surgical treatment for wrist fracture. INTERVENTION: Individual interviews were conducted within three months of cast removal. Questions prompted discussion of the experience of fracture, surgery and immobilization. Interviews were audio-recorded, transcribed verbatim. At least two independent researchers performed coding and theming following principles of thematic analysis. RESULTS: Two themes were identified: (1) impact of the injury varies widely and (2) health care consumers want trustworthy dialogue. Participant reports indicated that recovery from wrist fracture, surgery and immobilization is challenging with significant changes to social role and increased dependence. For many, lack of empathy from health professionals and limited acknowledgement of the personal impact of injury led to dissatisfaction. Health professionals did not consistently tailor communication or adopt strategies to address specific needs for pain management, education and support requirements. There was no evidence that processes were implemented to enhance participant recall and comprehension. Most participants experienced their cast as a barrier to function. However, within the group of participants immobilized for one week, a number felt the cast was removed too soon. CONCLUSION: Participant reports indicate that recovery from surgically repaired wrist fracture is challenging. Opportunities exist to refine care in pain management, education and active engagement of patients in their care. PMID- 29400072 TI - Role of Integrin Signaling Activation on the Development of Human T Cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis: Its Relationship to HTLV-1-Infected CD4+ T Cell Transmigrating Activity into the Tissues. AB - The main clinical feature of human T cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is slowly progressive spastic paraparesis with bladder dysfunction. HAM/TSP is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by the interaction between infiltrated Th1-like, HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells (CTL), is probably critical for the induction of chronic inflammation. Although the HTLV-1-infected CD4+ T cells in HAM/TSP appear to play a crucial role in the initial pathogenesis of HAM/TSP, the exact mechanisms of how these cells acquire their function as the first responders in the pathogenesis of HAM/TSP still remain unresolved. Herein, we propose the importance of the activation of both outside-in signals from integrin signaling and inside-out signals for integrin signaling in the HTLV-1-infected CD4+ T cells of HAM/TSP patients. PMID- 29400074 TI - Scientific authorship, pluralism, and practice. AB - In this article, I argue that understanding authorship requires that we grapple with the plurality of distinct accounts of scientific authorship. As a result, we should be careful in how we identify and quantify unethical practices such as ghostwriting. Judgements about who should be able to decide who is an author raise interesting questions about the autonomy of scientific practices. PMID- 29400073 TI - Oral hormonal therapy with ethinylestradiol-levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats. AB - Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol-levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 MUg ethinylestradiol and 5.0 MUg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-beta, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic beta-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen deficient rats. PMID- 29400076 TI - Exposure to the Chinese famine in early life and depression in adulthood. AB - We aimed to investigate whether exposure to the Chinese famine (1959-1961) in early life was associated with depression in adulthood. We included 17,505 participants from the China health and retirement longitudinal study (CHARLS). Participants were classified into indirect and direct exposure groups. And the directly exposure groups including prenatal, childhood, adolescence/adult exposure groups. Depression was diagnosed by Center for Epidemiological Studies Depression Scale-10 (CES-D) score. Multivariate logistic regression model was used to calculate the odd ratios (ORs) and 95% confidence intervals (CIs) of depression. In women, prenatal, childhood, adolescence/adult exposure groups had higher depression risk than indirect exposure group (OR = 1.46, 1.40, and 1.67, respectively). However, there was no significant association between famine exposure and depression among men. Exposure to famine during prenatal (OR: 1.48; 95% CI: 1.07-2.06), childhood (OR: 1.47; 95% CI: 1.13-1.91), and adolescence/adult (OR: 1.63; 95% CI: 1.24-2.15) period were associated with depression among subjects living in rural, but not those living in urban. Exposure to the Chinese famine in early life had sex and area-specific associations with depression. PMID- 29400077 TI - Severe Unintentional Injuries to Ohio Children: What We Should Be Addressing at Well-Child Visits. AB - This was a retrospective study examining severe injuries to Ohio children in order to provide pediatricians with targeted injury talking points at well visits. We included children <=14 years old from the Ohio Trauma Acute Care Registry with severe unintentional injuries from January 1, 2003, to December 31, 2012. There were 45 347 patients; 611 died, and the mean age was 6.8 years. Fractures/dislocations were common (46.6%), and many injuries occurred at home (49.1%). In children <=2 years old, the leading causes of injury were falls and burns/fire; falls and motor vehicle collisions (MVCs) predominated above this age. Leading causes of death were MVCs, drowning, and suffocation. We concluded that national data may not always reflect state-specific injury patterns. In Ohio, though falls and MVCs were the most common mechanisms, fire and drowning also caused significant injury. Given limited time to discuss injury prevention, pediatricians should concentrate on statewide injuries. PMID- 29400078 TI - Socio-emotional adjustment of adolescents with cochlear implants: Loneliness, emotional autonomy, self-concept, and emotional experience at the hospital. AB - Recent studies have reported contrasting results in the socio-emotional adjustment of Italian adolescents with cochlear implants (CIs). The aim of the present study is to explore the relationship between the socio-emotional adjustment of adolescents with CIs, the quality of their hospital stay, and their age at CI activation. The participants were 29 adolescents with CIs (CI group) and 29 typically developing adolescents (TD group). The Emotional Autonomy Scale, the Loneliness and Aloneness Scale for Children and Adolescents, and the Multidimensional Self-Concept Scale were administered to each participant. The emotional experience reported during the hospital stay was considered for each participant in the CI group. The adolescents with CIs displayed significantly higher levels of loneliness and lower levels of aversion toward aloneness than the TD group participants. Adolescents who had received the CI in preschool displayed a higher level of physical self-concept than adolescents who had received it later. The adolescents' emotional experiences at the hospital were reported to be quite complex and related to their relationships with parents. In summary, the findings point to a specific type of fragility in socio-emotional adjustment-focused on loneliness/aloneness-rather than a general one. PMID- 29400079 TI - Drug Eruption to Rosuvastatin With Recurrence on Simvastatin: A Case Report. PMID- 29400081 TI - Association of Statin Therapy With Risk of Epilepsy in 2 Propensity Score-Matched Cohorts. AB - BACKGROUND: Studies have suggested that statins may have a neuroprotective effect against epilepsy. However, evidence from rat models and case reports have suggested an opposite effect. Overall data are limited. OBJECTIVE: To examine the association between statin use and epilepsy risk in a general population and in a healthy population (individuals with no severe comorbidities). METHODS: Patients were Tricare beneficiaries from October 2003 to March 2012. Based on patients' characteristics during baseline phase (fiscal year [FY] 2004-2005), 2 propensity score (PS)-matched cohorts of statin users and nonusers were formed: (1) a PS matched general cohort and (2) a PS-matched healthy cohort. Our outcome was defined using inpatient or outpatient ICD-9 codes for epilepsy during the follow up phase (FY 2006 to March 2012) in the cohorts of statin users and nonusers. RESULTS: The study included a total of 43 438 patients (13 626 statin users and 29 812 nonusers). The PS-matched general cohort matched 6342 statin users to 6342 nonusers; the odds ratio (OR) of epilepsy in this cohort during follow-up was 0.91; 95% CI = 0.67-1.23. The PS-matched healthy cohort matched 3351 statin users to 3351 nonusers; OR in the PS-matched healthy cohort during follow-up was 1.08; 95% CI = 0.64-1.83. CONCLUSIONS: This study did not demonstrate a significant beneficial or deleterious effect of statin use on risk of being diagnosed with epilepsy. Clinicians should not withhold statins, whenever indicated, in patients with epilepsy. PMID- 29400080 TI - Chronic intermittent hypobaric hypoxia provides vascular protection in the aorta of the 2-kidney, 1-clip rat model of hypertension. AB - Many studies have demonstrated that chronic intermittent hypobaric hypoxia (CIHH) can reduce blood pressure in spontaneously hypertensive rats and renovascular hypertensive (RVH) rats in which endothelial dysfunction is determined as a critical factor. However, whether CIHH can regulate vasodilation of the aorta in RVH rats remains unknown. The purpose of this study was to investigate the effect of CIHH on impaired relaxation of the aorta in the 2-kidney, 1-clip (2K1C) RVH rat model. The results showed CIHH improved the impaired endothelium-dependent relaxation in the 2K1C rat aorta. The endothelial dysfunction was prevented by the p38 antagonist SB203580, but not by the ERK1/2 antagonist PD98059 or JNK antagonist SP600125. Furthermore, the expression of p-eNOS, HIF-1alpha, and HIF 2alpha increased while that of p-p38 and BMP-4 decreased in CIHH-treated aortas from 2K1C rats. Finally, the p-eNOS expression was upregulated and the p-p38 expression was downregulated by pre-incubation of SB203580 or the BMP-4 antagonist Noggin with the aorta. CIHH ameliorated the impairment of endothelium dependent relaxation through upregulating the expression of p-eNOS, which may be mediated by the inhibition of BMP-4/p-p38 MAPK, and upregulating the expression of HIFs in the 2K1C rat aorta. PMID- 29400082 TI - Administration Rates of the Tdap Vaccine in Obstetric Patients. AB - BACKGROUND: Infants younger than 6 months of age are at high risk for contracting pertussis because of not being fully vaccinated. The Advisory Committee on Immunization Practices (ACIP) recommends vaccinating all pregnant women with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) between 27 and 36 weeks to offer passive immunity to the infant to help protect them until they are able to receive the full pertussis series. OBJECTIVE: To assess and compare compliance with the 2013 ACIP recommendation of vaccinating pregnant women with Tdap at 27 to 36 weeks' gestation in 2 obstetric clinics. METHODS: This cross-sectional, retrospective chart review evaluated Tdap vaccine compliance in a random sample of obstetric patients from October 2013 to September 2014. The primary outcome evaluated the proportion of patients who received Tdap between 27 and 36 weeks' gestation. Secondary outcomes included the proportion of patients who received Tdap at any point in pregnancy and within 30 days postpartum. RESULTS: The charts of 573 patients were reviewed, and 237 met inclusion criteria. For the primary outcome, 142 patients (59.9%) received the Tdap vaccine. Overall, 156 patients (65.8%) received Tdap at some point during the pregnancy. Factors associated with receiving the Tdap vaccination were insurance status, prenatal care risk level and site of prenatal care, receipt of the influenza vaccine, and preterm labor in the current pregnancy. CONCLUSION: The Tdap vaccine rate was 65.8%, with 59.9% of patients receiving the vaccine within the recommended ACIP timeframe. Further education, improvements in documentation, and chart reminders are needed to enhance administration. PMID- 29400083 TI - Community Readiness to Prevent Opioid Overdose. AB - Effective community-based actions are urgently needed to combat the ongoing epidemic of opioid overdose. Community readiness (CR) has been linked to communities' support for collective action, which in turn has been associated with the success of community-wide prevention strategies and resulting behavior change. Our study, conducted in North Carolina, assessed the relationship between CR and two indices of opioid overdose. County-level data included a survey of health directors that assessed CR to address drug overdose prevention programs, surveillance measures of opioid overdose collected from death records and emergency departments, and two indicators of general health-related status. We found that counties' rates of CR were positively associated with their opioid related mortality (but not morbidity) and that this relationship persisted when we controlled for health status. North Carolina counties with the highest opioid misuse problems appear to be the most prepared to respond to them. PMID- 29400084 TI - The CHAMPIONS NETWork: Training Chicago High School Students as Health Advocates to Improve Health Equity. AB - In Chicago, major disparities exist across ethnic groups, income levels, and education levels for common chronic conditions and access to care. Concurrently, many of Chicago's youth are unemployed, and the number of minorities pursuing health professions is low. In an effort to eliminate this health equity gap, the University of Illinois at Chicago convened a community-university-hospital partnership to implement the CHAMPIONS NETWork (Community Health And eMPowerment through Integration Of Neighborhood-specific Strategies using a Novel Education & Technology-leveraged Workforce). This innovative workforce training program is a "High School to Career Training Academy" to empower underserved youth to improve population health in their communities, expose them to careers in the health sciences, and provide resources for them to become community and school advocates for healthy lifestyles. This program differs from other traditional pipeline programs because it gives its students a paid experience, extends beyond the summer, and broadens the focus to population health with patient contact. The CHAMPIONS NETWork creates a new type of health workforce that is both sustainable and replicable throughout the United States. PMID- 29400085 TI - Oligochitosan-pluronic 127 conjugate for delivery of honokiol. AB - Honokiol-loaded micelles were prepared by emulsion-solvent evaporation procedure when oligochitosan-pluronic conjugate (CS-F127) as carrier. Differential scanning calorimetry (DSC) indicated that honokiol existed in amorphous form when it was encapsulated into the micelles with 87.54 +/- 1.52% of encapsulation efficiency (EE) and 12.51 +/- 0.22% of drug loading (DL) capacity. The water-solubility was increased to 1.46 mg/mL, being >27-folds higher than pure honokiol. The in vitro release study demonstrated a slow and sustained +/- release of honokiol from the drug-loaded micelles with pure honokiol as control. The in vitro antifungal and cellular uptake tests indicated that the drug-loaded micelles showed the same activity as pure honokiol against Candida albicans due to its good cellular uptake although it slowly released honokiol. The pharmacokinetic test results showed that the honokiol-loaded micelles increased area under curves and mean retention time of honokiol with low clearance rate and apparent distribution volume when compared with pure honokiol, showing its ability to improve honokiol's pharmacokinetic properties. The honokiol-loaded micelles also showed good bio-security to normal cells and main organs of mice. In conclusion, the CS F127 conjugate should be a potential carrier for honokiol or other antifungal agents in the treatment of fungal infections. PMID- 29400086 TI - Integration of aerobic granular sludge and membrane bioreactors for wastewater treatment. AB - Environmental deterioration together with the need for water reuse and the increasingly restrictive legislation of water quality standards have led to a demand for compact, efficient and less energy consuming technologies for wastewater treatment. Aerobic granular sludge and membrane bioreactors (MBRs) are two technologies with several advantages, such as small footprint, high-microbial density and activity, ability to operate at high organic- and nitrogen-loading rates, and tolerance to toxicity. However, they also have some disadvantages. The aerobic granular sludge process generally requires post-treatment in order to fulfill effluent standards and MBRs suffer from fouling of the membranes. Integrating the two technologies could be a way of combining the advantages and addressing the main problems associated with both processes. The use of membranes to separate the aerobic granules from the treated water would ensure high-quality effluents suitable for reuse. Moreover, the use of granular sludge in MBRs has been shown to reduce fouling. Several recent studies have shown that the aerobic granular membrane bioreactor (AGMBR) is a promising hybrid process with many attractive features. However, major challenges that have to be addressed include how to achieve granulation and maintain granular stability during continuous operation of reactors. This paper aims to review the current state of research on AGMBR technology while drawing attention to relevant findings and highlight current limitations. PMID- 29400087 TI - Chalcogen-containing phenolics as antiproliferative agents. AB - AIM: The increasing number of cancer cases has stimulated researchers to seek for novel approaches. We have combined two bioactive moieties: a polyphenolic scaffold and an organoselenium motif. Four different families (isothiocyanates/thioureas, and their selenium isosters) derived from dopamine, (+/-)-norepinephrine and R-epinephrine were accessed. RESULTS: Heterocumulenes derived from dopamine and beta-O-methylnoradrenaline were strong antiproliferative agents (GI50<10 MUM). Selenoureas derived from beta-O methylnoradrenaline bearing electron-withdrawing groups (halogen, -NO2, -Ph) on the phenyl ring, were also strong antiproliferative agents, besides exhibiting good antiradical and glutathione peroxidase-like activities. Up to a 14-fold increased activity was achieved compared with classical chemotherapeutic agents, exhibiting also different mechanisms of action (cell cycle assays). Redox analysis on HeLa cells suggested an increase of ROS levels after the incubation period. CONCLUSION: the combination of organoselenium and phenolic moieties might provide valuable lead compounds with relevant antiproliferative properties. PMID- 29400088 TI - Effects of continuous and pulsatile flows generated by ventricular assist devices on renal function and pathology. AB - INTRODUCTION: Continuous-flow (CF) left ventricular assist devices (LVADs) are widely used to treat end-stage heart failure. Despite substantial improvement in clinical results, numerous complications remain associated with this technology. Worsening renal function is one, associated with morbidity and mortality in patients supported by CF LVADs. The effects of CF LVAD support on renal function have been investigated since the mid-1990s by many research groups. Area covered: We review the current status of LVAD therapy, experimental results regarding the effects of types of flow generated by LVADs on renal function and pathology, changes in renal function after LVAD implant, the influence of renal function on outcomes, and risk factors for renal dysfunction post implant. This information was obtained through online databases and direct extraction of single studies. Expert commentary: Immediately after CF LVAD implantation, renal function improves temporarily as patients recover from the kidneys' previously low perfusion and congestive state. However, many studies have shown that this initially recovered renal function gradually declines during long-term CF LVAD support. Although it is known that CF LVAD support adversely affects renal function over the long term, just how it does has not yet been clearly defined in terms of clinical symptoms or signs. PMID- 29400090 TI - Symbicort(r) Maintenance and Reliever Therapy (SMART) and the evolution of asthma management within the GINA guidelines. AB - INTRODUCTION: The Global Initiative for Asthma (GINA) annual report summarizes the latest evidence for asthma management. GINA recommends stepwise pharmacological treatment, advocating inhaled corticosteroids (ICS) plus rapid, long-acting beta2-agonists (LABA) delivered in a single inhaler for maintenance and relief at Steps 3 (moderate persistent asthma requiring 1-2 controllers plus as-needed reliever), 4 (severe persistent asthma requiring >=2 controllers plus as-needed reliever), and 5 (higher level care and/or add-on treatment). Areas covered: Randomized controlled trials and real-world evidence demonstrate that flexibly dosed budesonide/formoterol for maintenance and relief (Symbicort(r) Maintenance And Reliever Therapy [SMART]) is associated with reductions in severe exacerbations, prolongs time to first exacerbation, and provides fast symptom relief. Expert commentary: SMART provides greater or equal levels of sustained asthma control than similar or higher fixed doses of ICS/LABA plus short-acting beta2-agonist (SABA) as needed or higher ICS plus SABA as needed, with lower overall ICS doses and cost. The simplified dosing strategy may improve adherence and overall asthma control but relies on patient education. Budesonide/formoterol as needed in mild asthma (patients qualifying for regular low-dose ICS) is currently under investigation in two double-blind randomized studies, SYGMA1/2 (NCT02149199/NCT02224157), comparing budesonide/formoterol as needed with budesonide plus SABA and SABA alone. PMID- 29400089 TI - What are the images used to diagnose and assess suspected strokes?: A systematic literature review of care in four European countries. AB - INTRODUCTION: The cost-effectiveness of clinical interventions is often assessed using current care as comparator. However, evidence suggests practice variation in stroke imaging across countries. For the purpose of feeding into cost effectiveness analysis, this research aims to describe the patterns of stroke imaging, examine practice variations across countries and, as such, obtain results reflecting current care. Areas covered: A systematic literature review was conducted to identify original studies reporting the imaging workup used in acute stroke care in clinical practice in Hungary, Germany, Sweden and the UK. Information regarding the type and frequency of stroke imaging was analysed. Computed Tomography (CT) was reported as the main diagnostic imaging modality used in stroke care (78-98% across patient profiles and time periods). This review revealed patterns that were not observed in individual studies. Comparisons of UK studies revealed considerable variations in the proportion of scanned patients and timing of imaging. Expert commentary: While the evidence about thrombectomy is difficult to translate in clinical practice, the evidence regarding the optimal imaging approach to diagnose stroke patients is lacking. The heterogeneity in stroke imaging reinforces the need to compare the quality of stroke care within and between countries. PMID- 29400091 TI - Fellowship Program in Health System Improvement: A novel approach integrating leadership development and patient-centred health system transformation. AB - This article highlights a novel approach to professional development, integrating leadership, development and patient-centred health system transformation in the new Fellowship Program in Health System Improvement offered by the School of Public Health at the University of Alberta. Early assessment of the program is also provided. PMID- 29400092 TI - Partnering with parents to advance child health research. AB - Although patient engagement in research is widely touted as an important foundation for improving the relevance and sustainability of research findings, there is little consensus on how to do it in practice. This article describes our research team's experiences working with and engaging parents throughout the entire research process to reach full partnership in the identification, management, and dissemination of research. Our report of these experiences includes lessons learned along the way regarding how healthcare and research organizations can better support researchers and patients to achieve successful partnerships. PMID- 29400093 TI - Lead exposure induces oxidative stress, apoptosis, and attenuates protection of cardiac myocytes against ischemia-reperfusion injury. AB - Disrupting role of lead toxicity in heart functions and prognosis of cardiovascular diseases is not well known. This study investigated the interference of lead in heart functions and pacing postconditioning-mediated protection to the heart from ischemia-reperfusion injury. Lead exposure decreased the body weight and increased the heart weight in male rats (p < 0.001). Long term lead exposure (45 days exposure to lead) increased total oxidant levels (p < 0.001) in the heart. Furthermore, lead exposure abrogated the pacing postconditioning-mediated protection from ischemia-reperfusion injury. The latter effect showed an association with reduced total antioxidants levels (p < 0.001). In the short-term study (5 days exposure to lead), pacing postconditioning protected the heart from ischemia-reperfusion injury despite the reduced total antioxidant levels (p < 0.001). Lead toxicity caused a drastic increase in the heart weight in male rats and apoptosis. The induced oxidative stress showed association with the lack of pacing postconditioning-mediated protection of the heart. However, long-term lead exposure eliminated pacing postconditioning mediated protection of the heart from ischemia-reperfusion injury. PMID- 29400096 TI - Editorial: Innovative practice. PMID- 29400097 TI - [Tibor Donath (1926-2018)]. PMID- 29400094 TI - GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy. AB - INTRODUCTION: GATA1, the founding member of a family of transcription factors, plays important roles in the development of hematopoietic cells of several lineages. Although loss of GATA1 has been known to impair hematopoiesis in animal models for nearly 25 years, the link between GATA1 defects and human blood diseases has only recently been realized. Areas covered: Here the current understanding of the functions of GATA1 in normal hematopoiesis and how it is altered in disease is reviewed. GATA1 is indispensable mainly for erythroid and megakaryocyte differentiation. In erythroid cells, GATA1 regulates early stages of differentiation, and its deficiency results in apoptosis. In megakaryocytes, GATA1 controls terminal maturation and its deficiency induces proliferation. GATA1 alterations are often found in diseases involving these two lineages, such as congenital erythroid and/or megakaryocyte deficiencies, including Diamond Blackfan Anemia (DBA), and acquired neoplasms, such as acute megakaryocytic leukemia (AMKL) and the myeloproliferative neoplasms (MPNs). Expert commentary: Since the first discovery of GATA1 mutations in AMKL, the number of diseases that are associated with impaired GATA1 function has increased to include DBA and MPNs. With respect to the latter, we are only just now appreciating the link between enhanced JAK/STAT signaling, GATA1 deficiency and disease pathogenesis. PMID- 29400098 TI - [Taking patients' views into consideration at planning and evaluating care. Patient Reported Outcomes]. AB - Provision of patient-centred health care is impossible without the knowledge of the patient's perceptions, feelings and expectations. In contrast, participants feel the available time limited for satisfactory communication. This shortage may partially be compensated by measurements belonging to the concept of Patient Reported Outcomes. Concept definition, invention circle and use of the methods are largely diverse, eventually leading to misinterpretation of outcomes. For this reason, some organizations developed instructions, guidelines supporting uniform interpretation and application. Measures so far have rather served research goals yet may be applied in the clinical practice as well. They are not only appropriate for the evaluation of outcomes, judgement of adequacy and safety of care on systemic or institutional level, but also for the planning of individual patient care and supporting communication and co-operation. The present paper aims to provide general information and references for introducing the details. Orv Hetil. 2018; 159(6): 215-222. PMID- 29400100 TI - [Colorectal cancer heterogeneity: the clinical impact of sporadic lesions arising via the serrated pathway]. AB - Today, colorectal cancer is regarded as a heterogeneous disease. Its heterogeneity is caused by genetic alterations, molecular aberrations, different developing pathways as well as by micro- and macroenviromental agents. In the last decade, beside the classic genetic model for colorectal tumuorgenesis that follows the adenoma-carcinoma sequence, an alternative pathway has been identified. This pathway is called the serrated pathway and it is responsible for approximately one third of all colorectal lesions. Beyond their dissimilar molecular characteristics, these tumours also show different macroscopic and histologic appearance. Moreover, their malignant potency and progressive ability distinguish them from tumours of the classic genetic model. The aim of this review is to summarize the molecular and pathologic features of serrated lesions and the serrated pathway to colorectal cancer and to highlight their clinical impact. Orv Hetil. 2018; 159(6): 206-2014. PMID- 29400101 TI - [Nobel Prize for the discoveries of genetic mechanisms controlling the circadian rythm]. PMID- 29400102 TI - [In vivo analysis of circulating cell-free DNA release and degradation]. AB - INTRODUCTION: Cell-free DNA (cfDNA) was first detected in human plasma in the 1940s, but the knowledge on its regulation and rate of release is incomplete. CfDNA can originate from both normal and tumour cells. AIM: Our aims were to investigate the rate of cfDNA's release in SHO mice/HT-29 colorectal adenocarcinoma cell line xenograft model and to define the decay of methylated and non-methylated DNA fragments in C57BL/6 bloodstream. METHOD: SHO mice were xenografted with human HT-29 cells, than blood samples were collected over 2 months. CfDNA was isolated, then quantified by real-time PCR with highly specific genomic and mitochondrial human and mouse primer sets. This method permitted to define the ratio of human/mouse DNA. To assess the degradation rate of cfDNA, 3000 bp sized methylated and non-methylated DNA fragments were injected into healthy and C38 tumour-cell vaccinated C57BL/6 mice's bloodstream. The decay of amplicons was measured with 19 PCR assays. RESULTS: The amount of human DNA until the 2nd week was below the limit of detection. From the third week, a continuous growth was experienced, which reached 18.26% by the 8th week. Moreover, it was found that in healthy animals the non-methylated DNA disappears from the plasma after 6 hours, while the methylated fragment was detectable even after 24 hours. In animals with tumour, both amplicons were detectable after 24 hours. CONCLUSION: The examination of the role and mechanism of cfDNA shows an increasing level of interest. This work can contribute to a better understanding of the release and degradation of cfDNA. Orv Hetil. 2018; 159(6): 223-233. PMID- 29400103 TI - [Four-year follow-up of a neurosyphilis case presenting psychiatric symptoms]. AB - The authors present a case of neurosyphilis associated with predominant psychiatric symptoms. The elderly man was admitted because of confused behavior, maniform state, lack of critical judgement and grandiose delusions. On admission, right central facial nerve paresis, hand tremor and parkinsonism were also found. Acute brain imaging and routine laboratory tests failed to identify a firm etiology of the confusional state. The psychiatric treatment resulted in complete recovery from delirium. Afterwards, maniform psychosis dominated the clinical picture for which antipsychotics were administered. Later, rapid cognitive deterioration and progression of motor symptoms were observed. MRI revealed cortical and hippocampal atrophy and white matter hyperintensities. Lumbar puncture found pleocytosis and elevated cerebrospinal fluid protein levels. Neurosyphilis had been confirmed by serologic tests. The cognitive symptoms improved and the psychiatric symptoms remitted under penicillin treatment. Four years after diagnosis, there is a gradual progression in the cognitive decline. Two additional hospitalizations were necessary due to the relapses of psychiatric symptoms. Orv Hetil. 2018; 159(6): 234-238. PMID- 29400105 TI - Identification of a MYO7A mutation in a large Chinese DFNA11 family and genotype phenotype review for DFNA11. AB - BACKGROUND: The molecular and genetic research showed the association between DFNA11 and mutations in MYO7A. This research aimed to identify a MYO7A mutation in a family with nonsyndromic autosomal dominant hearing loss. METHODS: We have ascertained one large multigenerational Chinese family (Z029) with autosomal dominant late-onset progressive non-syndromic sensorineural hearing loss. Genome wide linkage analysis of the family mapped the disease locus to the DFNA11 interval, where the MYO7A was considered as a candidate gene. Sequencing of the PCR products was carried out for each sample. One hundred and fifty one control subjects with normal hearing functions were also evaluated. RESULTS: The pathogenic mutation (c.2011G>A) was identified in the family. This mutation co segregated with hearing loss in this family. No mutation of MYO7A gene was found in the 151 controls. CONCLUSIONS: The missense mutation of MYO7A is identified in the family displaying the pedigree consistent with DFNA11. We not only examined the clinical and genetic characteristics of the family, but also provided a basis for genetic counseling. We also summarized and analyzed the phenotypes and genotypes of all DFNA11 families, four of nine are Chinese families, suggesting that MYO7A mutations are not rare. Therefore, we should pay more attention to Chinese patients. PMID- 29400106 TI - Do dual-mobility cups cemented into porous tantalum shells reduce the risk of dislocation after revision surgery? AB - Background and purpose - Dual-mobility cups (DMCs) reduce the risk of dislocation and porous tantalum (TM) shells show favorable osseointegration after acetabular revision surgery, yet the combination of these implants has not been studied. We hypothesized that (1) cementing a DMC into a TM shell decreases the risk of dislocation; (2) DMCs cemented into TM shells are not at greater risk of re revision; (3) liberation of tantalum ions is marginal after use of this combined technique. Patients and methods - We investigated the outcome in 184 hips (184 patients) after acetabular revision surgery with TM shells, fitted either with DMCs (n = 69), or with standard poly-ethylene (PE) liners (n = 115). Chart follow up was complete for all patients, and the occurrence of dislocations and re revisions was recorded. 20 were deceased, 50 were unable to attend follow-up, leaving 114 for assessment of hip function after 4.9 (0.5-8.9) years, radiographs were obtained in 99, and tantalum concentrations in 84 patients. Results - 1 patient with a DMC had a dislocation, whereas 14 patients with PE liners experienced at least 1 dislocation. 11 of 15 re-revisions in the PE group were necessitated by dislocations, whereas none of the 2 re-revisions in the DMC group was performed for this reason. Hence, dislocation-free survival after 4 years was 99% (95% CI 96-100) in the DMC group, whereas it was 88% (CI 82-94, p = 0.01) in the PE group. We found no radiographic signs of implant failure in any patient. Mean tantalum concentrations were 0.1 ul/L (CI 0.05-0.2) in the DMC group and 0.1 ug/L (CI 0.05-0.2) in the PE group. Interpretation - Cementing DMCs into TM shells reduces the risk of dislocation after acetabular revision surgery without jeopardizing overall cup survival, and without enhancing tantalum release. PMID- 29400107 TI - Twelve tips for expanding undergraduate clinical teaching capacity. AB - Undergraduate medical education has expanded substantially in recent years, through both establishing new programs and increasing student numbers in existing programs. This expansion has placed pressure on the capacity for training students in clinical placements, raising concerns about the risk of dilution of experience, and reducing work readiness. The concerns have been greatest in more traditional environments, where clinical placements in large academic medical centers are often the "gold standard". However, there are ways of exposing medical students to patient interactions and clinical supervisors in many other contexts. In this paper, we share our experiences and observations of expanding clinical placements for both existing and new medical programs in several international locations. While this is not necessarily an easy task, a wide range of opportunities can be accessed by asking the right questions of the right people, often with only relatively modest changes in resource allocation. PMID- 29400108 TI - Nontuberculous mycobacterium infection in renal transplant recipients: a systematic review. AB - BACKGROUND: Nontuberculous mycobacterium (NTM) infections are important complications in renal transplant recipients. METHODS: Cases of NTM diseases post renal transplantation published in English were identified in the PubMed database. The clinical and laboratory characteristics of these cases were reviewed. RESULTS: One-hundred and fifteen cases of NTM infection in renal transplant recipients in 100 articles were identified. The median time of NTM infection from renal transplantation was 37 months (range, 3 d to 252 months). Disseminated disease (40.0%) was the most common manifestation of NTM infection in renal transplant recipients. The main diagnostic procedure was culture combined with histopathological examination (38.3%). Thirteen NTM species were identified; the most common pathogen was Mycobacterium chelonae (19.1%). The anti Mycobacterium treatment lasted more than 12 months in 43.3% of the recorded patients. During the treatment, 30.2% of the recipients lost kidney graft function and 20.9% died from NTM infection and/or other complications, including cardiac death and respiratory failure. CONCLUSIONS: NTM infection is easily neglected. Physicians must keep a high suspicion for NTM infections in renal transplant recipients. PMID- 29400109 TI - Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. AB - In vivo 1H magnetic resonance spectroscopy (1H-MRS) investigations of amyotrophic lateral sclerosis (ALS) mouse brain may provide neurochemical profiles and alterations in association with ALS disease progression. We aimed to longitudinally follow neurochemical evolutions of striatum, brainstem and motor cortex of mice transgenic for G93A mutant human superoxide dismutase type-1 (G93A SOD1), an ALS model. Region-specific neurochemical alterations were detected in asymptomatic G93A-SOD1 mice, particularly in lactate (-19%) and glutamate (+8%) of brainstem, along with gamma-amino-butyric acid (-30%), N-acetyl-aspartate ( 5%) and ascorbate (+51%) of motor cortex. With disease progression towards the end-stage, increased numbers of metabolic changes of G93A-SOD1 mice were observed (e.g. glutamine levels increased in the brainstem (>+66%) and motor cortex (>+54%)). Through ALS disease progression, an overall increase of glutamine/glutamate in G93A-SOD1 mice was observed in the striatum ( p < 0.01) and even more so in two motor neuron enriched regions, the brainstem and motor cortex ( p < 0.0001). These 1H-MRS data underscore a pattern of neurochemical alterations that are specific to brain regions and to disease stages of the G93A SOD1 mouse model. These neurochemical changes may contribute to early diagnosis and disease monitoring in ALS patients. PMID- 29400110 TI - Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARgamma/PGC-1alpha-Nrf2 pathway. AB - Nonalcoholic fatty liver disease (NAFLD) is characterised by excessive accumulation of hepatic lipids and oxidative injury of hepatocytes. Scutellarin is a flavonoid glycoside having antioxidative stress activity. Our current study aims to investigate the molecular mechanism of scutellarin ameliorating NAFLD. Scutellarin treatment was applied to male C57BL/6 mice maintained on a high-fat diet (HFD) and HepG2 cells challenged with oleic acid. The antioxidation biochemical indicators and lipid levels in the liver and cells were detected by kits. Liver pathology was observed by light microscope, Oil Red O staining, and transmission electron microscope (TEM). In addition, quantitative real-time polymerase chain reactions (qRT-PCR) and western blot assays were employed to detect the mRNA and protein levels of various antioxidative-related genes in the presence or absence of peroxisome proliferator-activated receptor gamma (PPARgamma); inhibitor GW9662. Our results showed that scutellarin could significantly reduce blood lipid levels and enhance antioxidative capacities in both the models. In addition, scutellarin treatment conspicuously activated PPARgamma, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), nuclear factor erythroid-2-related factor (Nrf2), haem oxygenase-1 (HO-1), glutathione S-transferase (GST), and NAD(P)H quinone dehydrogenase one (NQO1), while it significantly inhibited nuclear factor kappa B (NF-kappaB), Kelch-like ECH-associated protein 1 (Keap1) at both the mRNA and protein levels. However, after interfered by GW9662, scutellarin effect was significantly decreased. The experimental data demonstrated that scutellarin showed strong hypolipidaemic, antioxidative, and liver protective activity which could be attributed to its regulating activity in the PPARgamma/PGC-1alpha-Nrf2 signaling pathway. PMID- 29400111 TI - Hearing loss prevalence and risk factors among older adults in China. AB - OBJECTIVE: This study aims to investigate the prevalence of hearing loss, and to analyse the major demographics and risk factors that influence the prevalence in older adults of China. DESIGN: Cross-sectional investigation. STUDY SAMPLE: Probability proportionate to size sampling (PPS) was adopted for this survey. Among 45,052 individuals, 6984 older adults (>=60 years) were selected as subjects for this study. RESULTS: The prevalence of hearing loss defined as a speech frequency pure tone average of more than 25 dB HL in the better ear was 58.85%. Age and gender were the factors most strongly associated with hearing loss after multivariate adjustment. Ear disease, diabetes, hypertension, atherosclerosis, noise exposure, and ototoxic drugs were significantly correlated with hearing loss. The largest effects were found for ear disease and noise exposure (OR = 2.83 [95% CI: 2.43-3.29]; OR = 2.59 [95% CI: 1.80-3.72]). CONCLUSIONS: Hearing loss is prevalent in nearly two thirds of adults aged 60 years and older in China population. Chronic diseases, ear disease, and noise are important factors in adults aged 60 years and older. PMID- 29400112 TI - Risk of neonatal care unit admission in small for gestational age fetuses at term: a prediction model and internal validation. AB - OBJECTIVE: Small for gestational age (SGA) fetuses are at increased risk of admission to the neonatal unit, even at term. We aimed to develop and validate a predictive model for the risk of prolonged neonatal unit admission in suspected SGA fetuses at term. METHODS: A single-center cohort study of singleton pregnancies with SGA fetus, defined as estimated fetal weight (EFW) less than the 10th centile, at term. The variables included known risk factors for neonatal unit admissions: maternal characteristics, EFW, abdominal circumference (AC), fetal Dopplers, gestational age (GA) at delivery, and intrapartum risk factors (meconium, pyrexia). Logistic regression analysis was used for model building and the prediction models were validated internally using bootstrapping. RESULTS: Seven hundred and one SGA pregnancies at term were included; 5.9% had prolonged neonatal unit admission (>48 h). The multivariable model (AUC 0.71; 95% CI: 0.63 0.79) included GA at delivery <39 weeks (OR 2.76; 95% CI 1.23-6.04, p = .011), cerebroplacental ratio (CPR) multiples of median (MoM) (OR 0.21; 95% CI 0.05 0.79, p = .023), and EFW below the third centile (OR 2.43; 95% CI 1.26-4.68, p < .007). The combined model showed a sensitivity 30.9% (95% CI: 16.6-45.2%) for a fixed 10% false positive rate. CONCLUSION: The prediction model shows good accuracy and good calibration for assessing the risk of neonatal unit admission in suspected SGA fetuses. It has the potential to be used for patient counseling, determining the timing of delivery and the individual risk. Brief rationale Objective: The objective of this study is to determine the factors associated with prolonged neonatal unit admissions in small for gestational age fetuses at term. What is already known: Fetal weight and Doppler parameters are associated with adverse outcome in small for gestational age fetuses. However, most studies use composite outcome criteria by combining neonatal unit admission with adverse delivery outcomes. A comprehensive model combining antenatal and intrapartum variables is also lacking. WHAT THIS STUDY ADDS: Our model describes the association of antenatal and intrapartum variables with prolonged neonatal unit admission without using a composite adverse outcome measure. Estimated fetal weight, gestational age at delivery, and the cerebroplacental ratio can be used to estimate the risk of prolonged neonatal unit admission. The risk estimation can be useful for patient counseling and to determine the time of delivery. PMID- 29400113 TI - Focal myositis diffusely involving multiple masticatory muscles. PMID- 29400114 TI - Outcomes in subsequent pregnancies after wedge resection for interstitial ectopic pregnancy: a retrospective cohort study. AB - OBJECTIVE: The objective of this study is to evaluate pregnancy outcomes in patients with a history of wedge resection for interstitial ectopic pregnancy (WRIEP). METHODS: Retrospective cohort study of pregnancies with a history of WRIEP from 2000 to 2013 at two inner city hospitals in Detroit, MI. Pregnant matched controls (1:3) were selected and included patients with history of surgically treated tubal ectopic pregnancy and delivered patients without history of ectopic pregnancy. Pregnancy outcomes, including a composite, were compared among the groups. RESULTS: Eighty-three cases of interstitial pregnancy were identified. Sixty-three (75.9%) underwent WRIEP from which 19 (30.2%) had a subsequent pregnancy and 11 (57.9%) carried it >=20 weeks. No difference in subsequent pregnancy outcomes including the composite was found among patients with prior WRIEP and patients with history of surgically treated tubal ectopic pregnancy except for a longer interpregnancy interval. Compared with delivered patients without a history of ectopic pregnancy, no difference in late obstetric outcomes was found including the composite, gestational age at delivery in weeks (38.2 versus 38.1, p = .955), preterm delivery rate (30% versus 21%, p = .674), and proportion of term vaginal (40% versus 52%, p = .721) or cesarean deliveries (60% versus 30%, p = .137). The most common indication for cesarean among patients with a history of WRIEP was a history of such (5/6, 83.3%) and there were no cases of abnormal placentation. CONCLUSION: Findings suggest that a history of WRIEP is not associated with increased risk of adverse pregnancy outcomes. PMID- 29400115 TI - Correction to: Koide et al., Substrate-dependent effects of molecular-targeted anticancer agents on activity of organic anion transporting polypeptide 1B1. PMID- 29400116 TI - Subacute inhalation toxicity study of synthetic amorphous silica nanoparticles in Sprague-Dawley rats. AB - Synthetic amorphous silica nanoparticles (SiNPs) are one of the most applied nanomaterials and are widely used in a broad variety of industrial and biomedical fields. However, no recent long-term inhalation studies evaluating the toxicity of SiNPs are available and results of acute studies are limited. Thus, we conducted a subacute inhalation toxicity study of SiNPs in Sprague-Dawley rats using a nose-only inhalation system. Rats were separated into four groups and target concentrations selected in this study were as follows: control (fresh air), low- (0.407 +/- 0.066 mg/m3), middle- (1.439 +/- 0.177 mg/m3) and high concentration group (5.386 +/- 0.729 mg/m3), respectively. The rats were exposed to SiNPs for four consecutive weeks (6 hr/day, 5 days/week) except for control group of rats which received filtered fresh air. After 28-days of inhalation exposure to SiNPs, rats were sacrificed after recovery periods of one, seven and 28 days. Although there were minimal toxic changes such as temporary decrease of body weight after exposure, increased levels of red blood cells (RBCs) and hemoglobin (Hb) concentration, the lung histopathological findings and inflammatory markers in bronchoalveolar lavage (BAL) fluid including polymorphonuclear (PMN) leukocyte, lactate dehydrogenase (LDH), albumin and protein did not show significant changes at any recovery period. The results of this study suggest that the subacute inhalation of SiNPs had no toxic effects on the lung of rats at the concentrations and selected time points used in this study. PMID- 29400117 TI - Social Cognitive Theory and Physical Activity Among Korean Male High-School Students. AB - The most critical step in developing and implementing effective physical activity interventions is to understand the determinants and correlates of physical activity, and it is strongly suggested that such effort should be based on theories. The purpose of this study is to test the direct, indirect, and total effect of social cognitive theory constructs on physical activity among Korean male high-school students. Three-hundred and forty-one 10th-grade male students were recruited from a private single-sex high school located in Seoul, South Korea. Structural equation modeling was used to test the expected relationships among the latent variables. The proposed model accounted for 42% of the variance in physical activity. Self-efficacy had the strongest total effect on physical activity. Self-efficacy for being physically active was positively associated with physical activity ( p < .01). Self-efficacy also had positive indirect effects on physical activity through perceived benefits ( p < .05) and goal setting ( p < .01). The results of this study indicated that the social cognitive theory is a useful framework to understand physical activity among Korean male adolescents. Physical activity interventions targeting Korean male high-school students should focus on the major sources of efficacy. PMID- 29400118 TI - Trabecular metal acetabular components in primary total hip arthroplasty. AB - Background and purpose - Trabecular metal (TM) cups have demonstrated favorable results in acetabular revision and their use in primary total hip arthroplasty (THA) is increasing. Some evidence show that TM cups might decrease periprosthetic infection (PPI) incidence. We compared the survivorship of TM cups with that of other uncemented cups in primary THA, and evaluated whether the use of TM cups is associated with a lower risk of PPI. Patients and methods - 10,113 primary THAs with TM cup and 85,596 THAs with other uncemented cups from 2 high quality national arthroplasty registries were included. The mean follow-up times were 3.0 years for the TM cups and 3.8 years for the other uncemented cups. Results - The overall survivorship up to 8 years for TM cups and other uncemented cups was 94.4% and 96.2%, respectively (p = < 0.001). Adjusting for relevant covariates in a Cox regression model the TM cups had a persistently higher revision risk than other uncemented cups (HR =1.5, 95% CI 1.4-1.7, p = < 0.001). There was a slightly higher, though not statistically significant, revision rate for PPI in the TM group (1.2, 95% CI 1.0-1.6, p = 0.09). Interpretation - Risk of revision for any reason was higher for the TM cup than for other uncemented cups in primary THA. In contrast to our hypothesis, there was no evidence that the revision rate for PPI was lower in the TM cup patients. Regardless of the promising early and mid-term results for TM cups in hip revision arthroplasty, we would like to sound a note of caution on the increasing use of the TM design, especially in uncomplicated primary THAs, where uncemented titanium cups are considered to provide a reliable outcome. PMID- 29400119 TI - Morbidity, mortality, and management of methicillin-resistant S. aureus bacteremia in the USA: update on antibacterial choices and understanding. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with significant healthcare costs, morbidity, and mortality in the United States. Complications of MRSA bacteremia include infective endocarditis, osteomyelitis, and sepsis, all of which are difficult to treat. Time to effective therapy and antibacterial choice greatly affect patient outcomes. Vancomycin and daptomycin remain first-line therapies; however, reports of vancomycin-associated treatment failure and reduced daptomycin susceptibility highlight the need to define alternative strategies for MRSA bacteremia treatment. In addition, several patient- and pathogen-specific factors influence the outcomes of MRSA bacteremia. It is, therefore, critical to explore the interaction between host- and pathogen specific factors and its effect on MRSA bacteremia pathogenesis and mortality. This review discusses the factors that drive the development of MRSA bacteremia and examines alternative treatment strategies. PMID- 29400120 TI - Clinical correlates of longitudinal MRI changes in CADASIL. AB - Previous studies showed that various types of cerebral lesions, as assessed on MRI, largely contribute to the clinical severity of CADASIL. However, the clinical impact of longitudinal changes of classical markers of small vessel disease on conventional MRI has been only poorly investigated. One hundred sixty NOTCH3 mutation carriers (mean age +/- SD, 49.8 +/- 10.9 years) were followed over three years. Validated methods were used to determine the percent brain volume change (PBVC), number of incident lacunes, change of volume of white matter hyperintensities and change of number of cerebral microbleeds. Multivariable logistic regression analyses were performed to assess the independent association between changes of these MRI markers and incident clinical events. Mixed-effect multiple linear regression analyses were used to assess their association with changes of clinical scales. Over a mean period of 3.1 +/- 0.2 years, incident lacunes are found independently associated with incident stroke and change of Trail Making Test Part B. PBVC is independently associated with all incident events and clinical scale changes except the modified Rankin Scale at three years. Our results suggest that, on conventional MRI, PBVC and the number of incident lacunes are the most sensitive and independent correlates of clinical worsening over three years in CADASIL. PMID- 29400122 TI - Factors associated with urban non-fatal road-accident severity. AB - This paper reports on the factors associated with non-fatal urban-road accident severity. Data on accidents were gathered from the local traffic police in the City of Palermo, one of the six most populated cities in Italy. Findings from a mixed-effects logistic-regression model suggest that accident severity increases when two young drivers are involved, road traffic conditions are light/normal and when vehicles crash on a two-way road or carriageway. Speeding is more likely to cause slight or serious injury even when compared to a vehicle moving towards the opposite direction of traffic. An accident during the summer is more likely to result in a slight or serious injury than an accident during the winter, which is in line with evidence from Southern Europe and the Middle East. Finally, the severity of non-fatal accident injuries in an urban area of Southern Europe was significantly associated with speeding, the age of the driver and seasonality. PMID- 29400121 TI - "Guys Don't Have Breasts": The Lived Experience of Men Who Have BRCA Gene Mutations and Are at Risk for Male Breast Cancer. AB - Men with BRCA1 or BRCA2 gene mutations are at increased risk of developing breast cancer and may have an indication for breast cancer screening using mammography. Since breast cancer is often viewed as a woman's disease, visibilizing and understanding men's experience of having a BRCA mutation and specifically, of screening for breast cancer through mammography, were the objectives of this research study. The theoretical framework of interpretive phenomenology guided the process of data collection, coding, and analysis. Phenomenology is both a philosophy and research method which focuses on understanding the nature of experience from the perspectives of people experiencing a phenomenon, the essence of and commonalities among people's experiences, and the ways in which people experience the world through their bodies. Data were collected via in-depth interviews with a purposive sample of 15 male participants recruited from the Male Oncology Research and Education (MORE) Program. This article reports findings about participants' use of gender-specific language to describe their breasts, awareness of the ways in which their bodies changed overtime, and experiences of undergoing mammograms. This study is the first to describe men with BRCA's perceptions of their breasts and experiences of mammography in a high risk cancer screening clinic. This study sheds light on an under-researched area breasts and masculinities-and could potentially lead to improved clinical understanding of men's embodied experiences of BRCA, as well as suggestions for improving the delivery of male breast cancer screening services. PMID- 29400123 TI - Increased adhesion molecule levels in systemic lupus erythematosus: relationships with severity of illness, autoimmunity, metabolic syndrome and cortisol levels. AB - Background This study was performed to assess adhesion molecules in systemic lupus erythematosus (SLE). Methods This case-control study examined 126 SLE patients and 48 healthy individuals. Blood levels of six adhesion molecules, cortisol, nuclear autoantibody (ANA) and anti-double stranded DNA (anti-dsDNA) titers were measured, while disease activity was assessed using the SLE Disease Activity Index (SLEDAI) score. Results Platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, P selectin, and plasminogen activator inhibitor type-1 (PAI-1) were significantly higher in SLE patients than in controls. Binary logistic regression analysis showed that PECAM-1 and PAI-1 predicted SLE with a sensitivity of 86.5% and a specificity of 81.3%. ANA titers were significantly and positively associated with PECAM-1, VCAM-1, E-selectin, and PAI-1, whereas there were no associations between anti-dsDNA titers and adhesion molecules. Cortisol was negatively associated with PCAM-1 and ICAM-1. There were significant associations between metabolic syndrome (MetS) and E-selectin and PAI-1. 14.8% of the variance in the SLEDAI score was explained by the regression on PECAM-1 and MetS. Conclusions Our data show that adhesion molecules, especially PECAM-1, are significantly associated with SLE and disease activity, suggesting that they play a role in SLE pathophysiology. While MetS, ANA titers and cortisol levels modulate adhesion molecule levels, these associations do not explain the increased levels of adhesion molecules in SLE. Increased levels of adhesion molecules are new drug targets in SLE. PMID- 29400124 TI - Organ donation. AB - Department of Health is consulting on opt-in or opt-out for organ donation for transplantation. Merits and demerits. Cooperation between doctors and the family is essential. PMID- 29400125 TI - Regression: simple linear. PMID- 29400126 TI - Emergency department visits coded for swimming pool diving injuries. AB - Despite legislative efforts to enhance safety in public swimming pools, diving injuries are still common. This study investigated the characteristics of emergency departments (EDs) visits for diving accidents. This study utilized 2006 2014 data from the Nationwide Emergency Department Sample and examined visits for accidents due to diving or jumping into water (swimming pool). Data were stratified by age categories. Over 83,000 ED visits were found and the majority of visits were by males. Significantly more patients were in the 15-24 age category. The majority of patients were discharged and were covered by private insurance. Total charges for the six-year period approached $620 million. Spinal cord injuries were more common in those over age 25, whereas intracranial injuries occurred more frequently in younger patients. This study provides a profile of patients presenting to US EDs for diving-related injuries. PMID- 29400127 TI - Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications. AB - Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset. The molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are multiple and not yet fully elucidated, they include alpha-synuclein aggregation, lysosomal-autophagy dysfunction and endoplasmic reticulum stress. Moreover, dysfunction of glucocerebrosidase has also been demonstrated in non-GBA PD, suggesting its interaction with other pathogenic mechanisms. Therefore, GBA enzyme function represents an interesting pharmacological target for PD. Cell and animal models suggest that increasing GBA enzyme activity can reduce alpha synuclein levels. Clinical trials of ambroxol, a glucocerebrosidase chaperone, are currently ongoing in PD and PD dementia, as is a trial of substrate reduction therapy. The aim of this review is to summarise the main features of GBA-PD and discuss the implications of glucocerebrosidase modulation on PD pathogenesis. PMID- 29400128 TI - Resistance to change: Role of relationship and communal coping for coronary heart disease patients and their partners in making lifestyle changes. AB - BACKGROUND: Lifestyle behaviours are important risk factors for coronary heart disease (CHD) and, hence, motivation for lifestyle changes is suggested to be a key factor in the success of cardiac rehabilitation and secondary prevention programmes. The motivation for changing lifestyle among people with CHD may be influenced by those with whom they have long-term, intimate relationships. AIMS: This study explores the role of the relationship between people with CHD and those closest to them in making lifestyle changes. This includes investigating if patients and partners experience autonomy, competence, and relatedness, and what role communal, i.e. relationship-centred coping serves in relation to patients' health behaviour. METHODS: The study is based on semi-structured, in-depth interviews with 10 couples; people who have experienced acute coronary syndrome, and their partners. Participants had diverse histories of disease and social backgrounds. A three-stage interview process was undertaken including focus group interviews, couple interviews and individual interviews. A thematic analysis, inspired by the self-determination theory and the interdependence theory, was conducted. RESULTS: Communal coping is evident in various forms, and at different levels, among people with CHD and their partners. Satisfaction with new lifestyle, ownership of change, confidence in ability to change, and emotional distress are all factors that affect how couples deal with lifestyle changes in the aftermath of CHD. CONCLUSIONS: Rehabilitation efforts, aimed at lifestyle changes, need to address each individual, as well as the dyadic interaction within couples. Incorporating a dyadic perspective in the rehabilitation process may lead to a reduction in motivational barriers to lifestyle changes. PMID- 29400129 TI - Development and characterization of a synthetic PVC/DEHP myocardial tissue analogue material for CT imaging applications. AB - A simple myocardial analogue material has great potential to help researchers in the creation of medical CT Imaging phantoms. This work aims to outline a Bis(2 ethylhexyl) phthalate (DEHP) plasticizer/PVC material to achieve this. DEHP-PVC was manufactured in three ratios, 75, 80, and 85% DEHP by heating at 110 degrees C for 10 min to promote DEHP-PVC binding followed by heating at 150 degrees C to melt the blend. The material was then tested utilizing FTIR, tensile testing, dynamic mechanical analysis and imaged with computed tomography. The FTIR testing finds the presence of C-CL and carbonyl bonds that demonstrate the binding required in this plasticized material. The tensile testing finds a modulus of 180 20 kPa that increases with the proportion of plasticizer. The dynamic mechanical analysis finds a linear increase in viscoelastic properties with a storage/loss modulus of 6/.5-120/18 kPa. Finally, the CT number of the material increases with higher PVC content from 55 to 144HU. The 80% DEHP-PVC ratio meets the mechanical and CT properties necessary to function as a myocardial tissue analogue. PMID- 29400130 TI - Biologically functional molecules from mushroom-forming fungi. AB - Fungi including mushrooms have been proved to be an important biosource of numerous metabolites having a huge variety of chemical structures and diverse bioactivities. Metabolites of mushrooms are of remarkable importance as new lead compounds for medicine and agrochemicals. This review presents some of our studies on biologically functional molecules purified from mushroom-forming fungi; (1) endoplasmic reticulum stress suppressor, (2) osteoclast-forming suppressing compounds, (3) plant growth regulators. PMID- 29400131 TI - Use of Moringa oleifera seed extracts to polish effluents from natural systems treating faecal sludge. AB - The removal of pathogens in irrigation water is of great importance in developing countries. Indeed, wastewater generally reused for agriculture in countries such as Cameroon is associated with health and environmental concerns. Recent studies have shown a strong disinfectant action of the natural coagulant from the seeds of Moringa oleifera. These findings have raised the question whether or not they can be used to polish effluents from natural systems treating faecal sludge. This paper deals with trials carried out to investigate the effect of these extracts in reducing faecal indicators from initially treated faecal sludge leachate. Bacteriological and physico-chemical parameters were used to determine the optimum conditions and assess treatment efficacy. Settling time of 3 h at a concentration of extracts between 267 and 333 mg/L permitted to reduce Escherichia coli and faecal coliforms from 4.85 to 3.92 ulog (86.74%) and from 5.75 to 4.87 ulog (86.39%) respectively with 1 ulog equal to 90%. For the same settling time and at a concentration of 333 mg/L, faecal streptococci were removed from 6.40 to 5.67 ulog (81.33%). This level of removal suggests that this natural coagulant cannot be used alone for disinfection of heavily loaded effluent. Further investigations are therefore still needed to fulfil the Cameroon and WHO guidelines for safe reuse in agriculture. PMID- 29400132 TI - How does buoyancy affect performance during a 200m maximum front crawl swim? AB - We investigated the rotational effect of buoyant force around the body's transverse axis, termed buoyant torque, during a 200m front crawl maximal swim. Eleven male swimmers of national or international level participated. One stroke cycle (SC) for each 50m was recorded with two above and four below water cameras. The following variables were analysed: swimming velocity; absolute and normalised buoyant force; minimum, average and maximum buoyant torque; SC and arm recovery times. The average value of buoyant torque was higher in the first 50m (14.2 +/- 4.5Nm) than in the following 150m (9.3 +/- 4.1Nm~10.9 +/- 4.5Nm) and was directed to raise the legs and lower the head throughout the race. The change in its magnitude seemed to be linked to the shorter time spent proportionally in arm recovery (first 50m: 27.6% of SC time; next 150m: 23.3-24.4% of SC time). Most swimmers had periods of the SC where buoyant torque was directed to sink the legs, which accounted to 10% of SC time in the first 50m and about twice this duration in the next 150m. These periods were observed exclusively at some instances when the recovering arm had entered the water while the opposite arm was still underwater. PMID- 29400133 TI - Joint assessment of handedness and footedness through latent class factor analysis. AB - Recently, some studies have demonstrated the effectiveness of two latent variable approaches in which hand preferences are analysed using either latent class methods or latent class factor (LCF) methods. The main aims of this study are: (i) to establish whether these approaches are adequate for assessing footedness, (ii) to evaluate their appropriateness when hand and foot preferences are jointly analysed, and (iii) to measure the association between handedness and footedness based on the examined latent variable models. To this end, a dataset providing information about the limb used to perform ten hand actions and three foot movements by 2236 young Italian sportspeople is analysed. The first aim is pursued through an exploratory analysis of the observed foot preferences; according to this analysis, footedness patterns are adequately described by two latent levels of footedness. As far as the second aim is concerned, a confirmatory analysis of foot and hand preferences is carried out; the best fit to the dataset is obtained using a two-dimensional LCF model with four latent levels of handedness and two latent levels of footedness. Finally, the association between handedness and footedness resulting from the employed methods is remarkably lower than that registered in other studies. PMID- 29400134 TI - Visual brokerage: Communicating data and research through visualisation. AB - Researchers increasingly use visualisation to make sense of their data and communicate findings more widely. But these are not necessarily straightforward processes. Theories of knowledge brokerage show how sociopolitical contexts and intermediary organisations that translate research for public audiences shape how users engage with evidence. Applying these ideas to data visualisation, I argue that several kinds of brokers (such as data collectors, designers and intermediaries) link researchers and audiences, contributing to the ways that people engage with visualisations. To do this, I draw on qualitative focus groups that elicited non-academic viewers' reactions to visualisations of data about UK migration. The results reveal two important features of engagement: perceptions of brokers' credibility and feelings of surprise arising from visualisations' content and design. I conclude by arguing that researchers, knowledge brokers and the public produce - as well as operate within - a complex visualisation space characterised by mutual, bi-directional connections. PMID- 29400135 TI - The Temporal Impact of Economic Insecurity on Child Maltreatment: A Systematic Review. AB - Economically insecure children experience 3-9 times more maltreatment than economically secure children. Although economic insecurity is associated with child physical abuse, neglect, and psychological maltreatment, there have been no systematic reviews dedicated to the relation between familial economic insecurity and child maltreatment. This is problematic because multiple forms of familial economic insecurity-including debt, material hardship, income, unemployment, and income transfers-are related to child maltreatment. These findings, however, are not causal or reliably replicated across studies. Until we identify the state of the evidence concerning the temporal association between economic insecurity and child maltreatment, our ability to reduce child maltreatment may be limited. In this systematic review (PROSPERO registration # CRD42017081445), we searched PsycINFO, PubMed, Scopus, ProQuest Dissertations, and the gray literature for English-language, peer-reviewed articles and dissertations published between 1970 and 2016. We synthesized evidence from 26 longitudinal studies on the temporal relation between economic insecurity and child maltreatment. Income losses, cumulative material hardship, and housing hardship were the most reliable predictors of child maltreatment. Implications for research, policy, and practice are discussed. PMID- 29400136 TI - Cultural concepts of the person and mental health in Africa. AB - People in different cultures have different concepts of the person that underlie self-understanding and self-representation. These concepts influence many aspects of individuals' life experience, including illness and expectations toward recovery. Psychotherapies aim to promote adaptive change in experience and behavior. This goal is embedded in a social and cultural context that promotes or sanctions a particular notion of personhood. If every system of psychotherapy depends on implicit models of personhood, which varies cross-culturally, then the goals and methods of therapeutic change must consider the cultural concept of the person. This paper reviews cultural concepts of the person in relation to communal values, practices, and systems of thought observed across many African cultural contexts. It presents a practical framework that can inform therapists working with African clients. Many African cultures promote a relational-oriented personhood, in which an individual manifests his or her personhood through connections to three distinct forms of agency: (a) spiritual agency, including God, ancestors, and spirits that influence the person; (b) social agency, including the family, the clan, and the community, with extension to humanity; and (c) self-agency, which is responsible for the person's inner experience. This distinctive form of personhood underlies concepts of the "normal" person, understandings of mental illness, help-seeking behavior, and clients' needs and expectations. Implications of this cultural concept of the person for psychotherapy with African clients are discussed. PMID- 29400138 TI - Functional comparision between truncated MTT1 and truncated MTT2 from Tetrahyemna thermophila. AB - Metallothioneins (MTs) are low-molecular-weight proteins with high Cys content and high metal-chelating ability. CdMT and CuMT subfamilies present different characteristics in Tetrahymena. To explore the effect of the cysteine arrangement and sequence length of MTs for binding different metal ions, MTT1, truncated MTT1 (TM1), MTT2, and truncated MTT2 (TM2) were expressed in E. coli. The half-maximal inhibiting concentrations (IC50) of Cd2+ and Cu+ for the recombinant strains were different. Furthermore, E. coli cells expressing MTT1 and TM1 exhibited higher accumulating ability for Cd2+ than cells expressing MTT2 and TM2. However, the opposite is true for Cu+. The binding ability of the different recombinant proteins to Cd2+ and Cu+ were also different. MTT1 and truncated mutant TM1 were the preference for Cd2+, whereas MTT2 and truncated mutant TM2 were the preference for Cu+ coordination. These results showed that metal ion tolerance and accumulation ability not only depended on cysteine arrangement pattern but also on sequence length of MT in Tetrahymena. PMID- 29400139 TI - Medical student evaluation of measuring engagement in clinical learning. PMID- 29400140 TI - Scaffold-Based Temporomandibular Joint Tissue Regeneration in Experimental Animal Models: A Systematic Review. AB - Reconstruction of degenerated temporomandibular joint (TMJ) structures remains a clinical challenge. Tissue engineering (TE) is a promising alternative to current treatment options, where the TMJ is either left without functional components, or replaced with autogenous, allogeneic, or synthetic grafts. The objective of this systematic review was to answer the focused question: in experimental animal models, does the implantation of biomaterial scaffolds loaded with cells and/or growth factors (GFs) enhance regeneration of the discal or osteochondral TMJ tissues, compared with scaffolds alone, without cells, or GFs? Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines, electronic databases were searched for relevant controlled preclinical in vivo studies. Thirty studies reporting TMJ TE strategies in both small (rodents, rabbits; n = 25) and large animals (dogs, sheep, goats; n = 5) reporting histological and/or radiographic outcomes were included. Twelve studies reported ectopic (subcutaneous) implantation models in rodents, whereas 18 studies reported orthotopic, surgically induced defect models in large animals. On average, studies presented with an unclear-to-high risk of bias. In most studies, mesenchymal stem cells or chondrocytes were used in combination with either natural or synthetic polymer scaffolds, aiming for either TMJ disc or condyle regeneration. In summary, the overall preclinical evidence (ectopic [n = 6] and orthotopic TMJ models [n = 6]) indicate that addition of chondrogenic and/or osteogenic cells to biomaterial scaffolds enhances the potential for TMJ tissue regeneration. Standardization of animal models and quantitative outcome evaluations (biomechanical, biochemical, histomorphometric, and radiographic) in future studies, would allow more reliable comparisons and increase the validity of the results. PMID- 29400143 TI - Overcoming challenges in primary care in Brazil: successful experiences in family medicine education. AB - Since 1988, Brazil has built a national health system procuring a response that meets universal health care. The government created the Family Health Strategy (FHS) to help improve access to health services through primary health care teams developing interdisciplinary actions. Scarcity of doctors with family medicine (FM) competencies in Brazil limits the FHS effectiveness. The lack of family physicians can be traced primarily to the medical schools where training supports other specialties besides FM. Innovation is required to bring students to the specialty and medical marketplace. The authors relate their experience and advances in designing alternatives to seize solutions to address challenges related to strategic aspects of FM that can improve medical education practices. Challenges presented exemplify means to expose students to key principles of FM practice such as continuity, commitment and longitudinal care, together with other attributes of FM practice such as team work and interprofessional action. A key asset in overcoming the challenges for primary health care through improved FM practice is the exposure of students to FM practitioners that mentor student practices as role models in different settings where health care is provided. PMID- 29400142 TI - Markers of vitamin D metabolism and incidence of clinically diagnosed abdominal aortic aneurysm: The Atherosclerosis Risk in Communities Study. AB - Little is known about whether markers of vitamin D metabolism are associated with the development of abdominal aortic aneurysm (AAA), though these markers have been linked to other cardiovascular diseases. We tested the hypotheses that risk of AAA is higher among individuals with low serum concentrations of 25-hydroxy vitamin D [25(OH)D], and among those with elevated concentrations of calcium, fibroblast growth factor 23 (FGF23), phosphorus, and parathyroid hormone (PTH) using data from a cohort of black and white individuals with long-term follow-up. Markers of vitamin D metabolism were measured using serum collected in 1990-1992 from ARIC study participants (mean +/- SD age 56.9 +/- 5.7 years, 43.2% male, 23.9% black). A total of 12,770 participants were followed until 2011 for incident AAA. Multivariable-adjusted Cox regression models were used. A total of 449 incident AAA events occurred over a median follow-up of 19.7 years. For the association between serum calcium and risk of incident AAA there was evidence of interaction by sex ( p-interaction 0.02). Among women, in the fully adjusted model, the hazard ratio (95% confidence interval) comparing the highest to lowest quartile was 2.43 (1.25-4.73), whereas in men it was 1.01 (0.72-1.43). Not associated with risk of incident AAA were 25(OH)D, FGF23, phosphorus, and PTH. In this large prospective cohort, there was little evidence that markers of vitamin D metabolism are associated with risk of incident AAA. The positive association of calcium with AAA among women may warrant further investigation and replication in other populations. PMID- 29400144 TI - Palliative care triggers in progressive neurodegenerative conditions: An evaluation using a multi-centre retrospective case record review and principal component analysis. AB - BACKGROUND: The use of specific triggers has been suggested to help identify patients with progressive neurological disease who would benefit from palliative care. AIM: This study aimed to improve the evidence base for the use of triggers for patients with progressive neurological disease. DESIGN: An evaluation of palliative care services was undertaken using a retrospective case note review of the timing and presence of triggers in the last 2 years of life. SETTING/PARTICIPANTS: A total of 12 specialist palliative care units across the United Kingdom provided data from 300 patients: mean patient age 70 years, 50% male, diagnoses included motor neurone disease 58%, Parkinson's disease 17% and Parkinson's Plus syndromes 12%. RESULTS: There was a high burden of triggers - 17 in the last 2 years of life and 10 in the last 6 months of life. The most frequent triggers were deteriorating physical function, complex symptoms and dysphagia. Four factors were found to explain 64% of the total variance: Factor 1 - Deterioration in physical function, dysphagia, significant complex symptoms and pain; Factor 2 - Weight loss and respiratory symptoms; Factor 3 - Recurrent infections and cognitive decline; Factor 4 - Aspiration pneumonia. Cox regression analyses found different triggers were associated with survival from diagnosis versus survival from referral to palliative care. Different triggers were also associated with survival for different neurological conditions. CONCLUSION: This study demonstrates that there is a high burden of triggers in the last months and years of life and that these could potentially be reduced to fewer components. Prospective studies assessing which triggers are useful for different conditions are now required. PMID- 29400145 TI - Treatment of mining waste leachate by the adsorption process using spent coffee grounds. AB - The removal of heavy metals from mining waste leachate by spent coffee grounds has been investigated. In synthetic solutions, metal uptake was studied in batch adsorption experiments as a function of pH, contact time, initial metal concentration, adsorbent concentration, particle size, and the effect of co-ions (Na, K, Ca, Mg, Cu, Cd, Ni, Zn). Results showed that adsorption was significantly affected by pH, showing the highest affinity within a pH range of 5-7. Sorption of heavy metals reached equilibrium in 3 h. Removal percentages of metals ions increased with increasing dosage. Particle size did not have a significant influence on metal uptake. The adsorption of heavy metals was found to fit Langmuir and Freundlich isotherms. Maximum Zn, Cd and Ni uptake values were calculated as 10.22, 5.96 and 7.51 mg/g, respectively, using unwashed coffee grounds (UCG) as the adsorbent and 5.36, 4.28 and 4.37 mg/g when employing washed coffee grounds as the adsorbent. The presence of co-ions inhibited the uptake of heavy metals, divalent ions having a more negative effect than monovalent ions. The results obtained in the experiments with mining waste leachate showed that UCG is effective in removing heavy metals. PMID- 29400146 TI - Effects of emulsifying conditions on creaming effect, mechanical properties and microstructure of processed cheese using a rapid visco-analyzer. AB - The creaming effects, mechanical properties and microstructures of processed cheeses were investigated under different emulsifying conditions using a rapid visco-analyzer, and the changes in protein network related to the creaming effect and the occurrence of yielding points were discussed. The higher stirring speed affected the fat globules to be smaller, and gave the processed cheese more firmness at fixed stirring time. The longer stirring time caused the protein network to become fine-stranded. A fine-stranded structure promoted the creaming effect, and hence the formation of yielding point in the mechanical properties. The emulsifying salts had active effects on the creaming effect and mechanical properties at longer stirring time. The fine-stranded structures were shown in the cases of a binary mixture of polyphosphate and disodium phosphate (PDSP), polyphosphate (PP), and trisodium citrate (TSC). Monophosphate (MP) showed the lowest ability to alter the protein network, but was assisted at the higher stirring speed. PMID- 29400147 TI - Molecular evaluation of microalgal communities in full-scale waste stabilisation ponds. AB - Waste stabilisation ponds (WSPs) are widely used across the world as a passive wastewater treatment for domestic wastewaters, but little is known about their ecology, especially their phototrophic communities. This study uses molecular methods and flow cytometry to assess the cyanobacterial and eukaryotic communities longitudinally throughout two systems, one treating domestic wastewater and the other mixed industrial/domestic wastewaters. More variation was seen between the systems than between different stages in the treatment processes for both eukaryotic and cyanobacterial communities. Chlorella species and Planktophrix cyanobacteria dominated both treatment systems. Arthrospira cyanobacteria were detected only in the industrial/domestic system. The balance between non-photosynthetic and photosynthetic organisms is rarely considered, though both play vital roles in WSP functioning. Flow cytometry showed that the facultative and first maturation pond in the industrial system contained a lower proportion of photosynthetic organisms compared to the domestic system. This is reflected in the species richness data and low dissolved oxygen levels detected. All data indicated that both systems are significantly different from one another and that variation longitudinally throughout the systems is lower. A more systematic study is needed to determine if it is the wastewater source rather than the initial inoculum that drives community composition. PMID- 29400148 TI - Minority and Immigrant Youth Exposure to Community Violence: The Differential Effects of Family Management and Peers. AB - Experiences with neighborhood violence can produce negative consequences in youth, including stress, anxiety, and deviant behavior. Studies report that immigrant and minority youth are more likely to be exposed to violence but less likely to perpetrate it. Similarly, research shows parenting practices are differentially adopted by Blacks, Whites, and Hispanics. Although family management strategies can often act as a barrier to the detrimental effects of exposure to community violence (ETV-C), there is a paucity of investigation on how Hispanic subgroups (e.g., Puerto Rican, Mexican) and immigrant families employ such practices in protecting their children against victimization and violence in the community. Applying an ecological framework, we use data from the Project on Human Development in Chicago Neighborhoods to examine the role of parenting and peer relationships on youth ETV-C, across race/ethnicity and immigrant generational status. Our sample is drawn from Cohorts 9, 12, and 15, and is over 40% Hispanic-Latino. We investigate the differences in within and outside the home family management strategies in terms of both race/ethnicity and immigrant generational status. Our work also seeks to determine the effects of race/ethnicity and immigrant status on youth ETV-C, while examining the influence of family management and peer relations. Results indicate that the adoption of family management practices is not homogeneous across Hispanic subgroups or immigrant generational status, and parenting practices seem to mediate the relationship between these characteristics and exposure to violence. Variations in parenting practices underscore the need to disentangle the cultural plurality of racial/ethnic grouping and how immigrant generational status influences parenting choices that protect children from exposure to violence in the community. PMID- 29400149 TI - 10-Year Study of Christian Church Support for Domestic Violence Victims: 2005 2015. AB - : Religious beliefs play a significant role in the lives of victims of domestic violence. Victims find strength in their faith and would rather endure the violence at all costs to keep a family or a marriage together, than to compromise their faith by leaving. PURPOSE: This 10 -year study explored the climate of support for victims of domestic violence among Christian clergy and church members between 2005 and 2015. METHOD: Using a convenience sample, surveys were sent out to congregations in the Upper Midwest in 2005 and 2015. The survey included demographics; two items measuring perception of domestic violence in the congregation andcommunity; six Likert Scale items regarding agreement with statements concerning leaving an abusive marriage; four 'Yes-No' items regarding the impact of faith in leaving, support of the congregation, community resources,and clergy as counselors. The clergy's survey had the same questions, plus open-ended questions about their skills in counseling victims, their congregation's support for victims, community resources, and beliefs that could impact a victim's choice in leaving. ANALYSIS: Data were analyzed using descriptive statistics, simple frequencies, and bivariate correlations. Narrative data were analyzed using content analysis. RESULTS: The results of this study indicated that change is slow. Members want their clergy to become more educated in counseling and in speaking about domestic violence from the pulpit. Clergy felt comfortable in making referrals for professional counseling, while the majority of members would prefer counseling with their pastor if they were in a violent relationship. Both clergy and members want to create a safe and supportive environment for victims/survivors of violent relationships. Findings from this study exemplify the need for pastors to remove the silence about domestic violence in their congregations and address the misunderstood social religious beliefs that may bind a victim to the violence. PMID- 29400150 TI - Does Educational Success Mitigate the Effect of Child Maltreatment on Later Offending Patterns? AB - Analyses examined offending patterns during adolescence and adulthood and their relation to child maltreatment subtypes and education factors measured during adolescence and adulthood. A total of 356 participants were followed from preschool to adulthood in a prospective longitudinal study. Child maltreatment subtypes include physical-emotional abuse, sexual abuse, and neglect. Offending patterns were analyzed as latent classes of (a) chronic offending, (b) desistence, and (c) stable low-level or non-offending. Physical-emotional and sexual abuse were associated with a higher likelihood of chronic offending relative to stable low-level offending. Education variables, including high educational engagement and good academic performance, predicted a higher likelihood of low-level offending relative to desistence, but not desistence relative to chronic offending. Only educational attainment predicted desistence relative to chronic offending. There was no moderating effect of education variables on the association between child maltreatment subtypes and later offending patterns. Implications for research, practice, and policy are discussed. PMID- 29400250 TI - "The Journey I Have Been Through": The Role of Religion and Spirituality in Aging Well Among HIV-Positive Older Adults. AB - The National Institutes of Health human immunodeficiency virus (HIV) and Aging Working Group identified spirituality as a research emphasis. This qualitative study examines the importance of religion and spirituality among 30 HIV-positive older adults. Using modified grounded theory, adults 50+ were recruited in Ontario, Canada, through AIDS service organizations, clinics, and community agencies. Descriptions of religion and spirituality encapsulated the idea of a journey, which had two components: the long-term HIV survivor profile combined with the experience of aging itself. A final category of HIV as a spiritual journey was finalized through consensus and included the properties of (1) being rejected by as well as rejection of formalized religion, (2) differentiating spirituality from religion, (3) having a connection, (4) feeling grateful, and (5) mindfulness and learning new skills. Interventions fostering resilience and strengths in HIV-positive older adults using spirituality should be considered, including the promotion of person-centered spirituality and interventions that include mindfulness and skill building. PMID- 29400251 TI - Safety of 'the vulnerable road users': current challenges and need for a new approach. PMID- 29400252 TI - First results concerning the safety, walking, and satisfaction with an innovative, microprocessor-controlled four-axes prosthetic foot. AB - BACKGROUND: The microprocessor-controlled foot Meridium is a prosthetic component with adjustable stance-phase characteristics. OBJECTIVES: To investigate subjects' and prosthetists' perception of safety, walking, and satisfaction during first routine fittings. STUDY DESIGN: Multicenter, prospective, observational cohort study. METHODS: Data regarding demographics, fitting process, safety, daily life activities, and satisfaction were obtained through questionnaires. The follow-up period was 7 months. RESULTS: In all, 89% of 70 users were satisfactorily fitted within the first two visits. Compared to previous feet, users reported improvements in walking on level ground (54% of subjects), uneven ground (82%), ascending (97%), and descending ramps (91%). More than 45% of the users perceived an improvement in safety and stability while standing and walking. No difference was observed in concentration, exertion, and pain. Overall user satisfaction with Meridium was 50% and the foot was preferred by 40% of users. Amputation level, age and mobility grade did not influence subjects' preference. Prosthetists recommended Meridium for 59% of subjects. A correlation analysis revealed that transfemoral amputees fitted with Genium and/or having a long residual limb strongly preferred Meridium ( p < 0.05). CONCLUSION: Meridium was appreciated by amputees with a preference for natural walking and requirement to safely and comfortably negotiate uneven terrain and slopes. Clinical relevance Amputees preferring Meridium perceive benefits with safe, comfortable, and natural walking. While the perception of benefits regarding the negotiation of uneven terrain and slopes is very high, the correlation to product preference is moderate. Individual assessment and trial fitting might be essential to identify patients who benefit greatly. PMID- 29400254 TI - Histomorphologic Analysis of the Late-term Rat Fetus and Placenta. AB - Histological examination of the rat placenta and fetus is uncommon. Toxicological studies mainly rely on gross examination of the fetus and on fetal and placental weights. These are often insufficient to assess the fetal and placental toxicity of xenobiotics. The small size of the fetus makes its dissection labor-intensive. Thus, our objective was to develop a simple and accurate technique to evaluate the rat fetus and placenta. Sprague-Dawley rat fetuses at gestational day 19.5 ( n = 18) and their placentas ( n = 32) were fixed in formalin. Placentas were cut transversally in the center. Fetuses were cut following a freehand whole-body serial sectioning diagram adapted from Wilson's method. Sections were stained with hematoxylin-eosin-phloxine-saffron, and histomorphometry was used to measure the area of the fetal placental region (27.2 +/- 1.7 mm2), including the labyrinth (22.2 +/- 1.0 mm2) and the basal zone (4.8 +/- 0.8 mm2). Our whole fetus serial sectioning technique resulted in 12 precise cutting planes that fit on 3 histological slides, enabling the examination of most organs without labor intensive dissection. Quantitative analysis of placental areas improves the understanding of the pathogenesis of treatment-related changes. This technique provides a standardized method for future research in pertinent fields such as developmental biology and toxicology. PMID- 29400255 TI - Navigating the Perioperative Landscape of Patient-Oriented Outcome Studies of Cardiothoracic and Abdominal Transplant Surgical Patients in 2017. PMID- 29400256 TI - Noteworthy Cardiac Surgery Literature 2017: Technology Pushing Care Forward. AB - In review of the current cardiac surgical literature, the care for complex pathology continues to make big strides forward. Much of this "progress" is driven by new technology or new applications for technology. In both mitral disease and type A dissection management, technology is changing the way the pathologies are approached. This article addresses some of the advances demonstrated in the literature and gives a perspective on how they affect current practice. PMID- 29400257 TI - Noteworthy Literature published in 2017 for Congenital Cardiac Anesthesiologists. AB - This review focuses on the literature published during the 13 months from December 2016 to December 2017 that is of interest to anesthesiologists taking care of children and adults with congenital heart disease. Five themes are addressed during this time period and 100 peer-reviewed articles are discussed. PMID- 29400258 TI - Noteworthy Literature published in 2017 for Abdominal Organ Transplantation. AB - In 2017, we identified more than 400 peer reviewed publications on the topic of pancreas transplantation, more than 500 on intestinal transplantation, more than 4000 on renal transplantation, and more than 4700 on liver transplantation. This annual review highlights the most pertinent literature for anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We explore a wide range of topics, including risk for and prediction of perioperative complications, recommendations on perioperative management, economic analyses, and education of the trainees in abdominal transplantation anesthesia and critical care. PMID- 29400259 TI - Noteworthy Literature published in 2017 for Perioperative Echocardiography. AB - In this inaugural review, we present noteworthy advances in perioperative echocardiography relevant to the cardiac anesthesiologist. These studies come from different clinical realms including advances in mitral valve imaging, perioperative echocardiographic evaluation, and critical care echocardiography. The importance of perioperative echocardiography continues to grow with cardiac anesthesiologists positioned in a critical role throughout the perioperative care continuum. PMID- 29400260 TI - Noteworthy Literature published in 2017 for Cardiothoracic Anesthesiologists. AB - The year 2017 was a year dominated by large-scale clinical studies reporting the outcome of various interventions in cardiac surgery and heart failure (HF) patients, relevant to all cardiothoracic anesthesiologists. Among them were studies investigating the addition of levosimendan, an alternative inotropic agent, to standard management of patients with HF undergoing cardiac surgery. Also, corticosteroids have been used for various purposes in cardiac patients. Here, a new study reports the effect of high-dose methylprednisolone on recovery and delirium. Furthermore, with increasing evidence that transfusions increase morbidity and mortality, a publication reports the use of rotational thromboelastometry to reduce transfusion requirements. In addition, several randomized controlled multicenter studies report the outcomes of patients undergoing cardiac procedures: surgical versus transcatheter aortic valve replacement in intermediate-risk patients and the use of centrifugal-flow versus axial-flow left-ventricular devices in patients with HF. These studies demonstrate the dynamic and ever-evolving state of perioperative cardiovascular medicine and show us the direction of future developments. PMID- 29400261 TI - Psychosocial outcomes in a cohort of perinatally HIV-infected adolescents in Western Jamaica. AB - BACKGROUND: Psychosocial factors interact with adolescent development and affect the ability of HIV-infected adolescents to cope with and adhere to treatment. AIM: To evaluate psychosocial outcomes in perinatally HIV-infected adolescents (PHIVAs) in Western Jamaica after psychosocial intervention. METHODS: The Bright Futures Paediatric Symptom Checklist (BF-PSC) was used for psychological screening of PHIVAs in Western Jamaica. Referred patients were evaluated using the Youth version of the Columbia Impairment Scale (CIS). Demographic, laboratory and clinical data obtained between July 2014 and June 2016 were evaluated retrospectively and outcomes were reviewed before and after psychosocial intervention. RESULTS: Sixty PHIVAs were enrolled and 36 (60%) had a positive BF PSC score that necessitated referral. The BF-PSC correctly identified 89% of patients with impaired psychosocial assessment by CIS scores. Referred patients were less likely to adhere to treatment, to be virologically suppressed or to have a CD4+ count of >500 cells/MUl, and were more likely to be in the late teenage group or to be of orphan status. After intervention, the prevalence of viral suppression increased and median viral load decreased. A difference in mean CD4+ cell count was detected before but not after intervention in teenage and orphan groups. CONCLUSIONS: The BF-PSC identified at-risk PHIVAs with impaired psychosocial functioning. Increased vulnerability was noted in orphans and older teenagers. Psychosocial interventions (including family therapy) reduced psychosocial impairment and improved virological suppression. Mental health intervention should be instituted to facilitate improved clinical outcomes, autonomy of care and transition to adult care. PMID- 29400263 TI - Geometric Deformations of the Thoracic Aorta and Supra-Aortic Arch Branch Vessels Following Thoracic Endovascular Aortic Repair. AB - OBJECTIVE: To utilize 3-D modeling techniques to better characterize geometric deformations of the supra-aortic arch branch vessels and descending thoracic aorta after thoracic endovascular aortic repair. METHODS: Eighteen patients underwent endovascular repair of either type B aortic dissection (n = 10) or thoracic aortic aneurysm (n = 8). Computed tomography angiography was obtained pre- and postprocedure, and 3-D geometric models of the aorta and supra-aortic branch vessels were constructed. Branch angle of the supra-aortic branch vessels and curvature metrics of the ascending aorta, aortic arch, and stented thoracic aortic lumen were calculated both at pre- and postintervention. RESULTS: The left common carotid artery branch angle was lower than the left subclavian artery angles preintervention ( P < .005) and lower than both the left subclavian and brachiocephalic branch angles postintervention ( P < .05). From pre- to postoperative, no significant change in branch angle was found in any of the great vessels. Maximum curvature change of the stented lumen from pre- to postprocedure was greater than those of the ascending aorta and aortic arch ( P < .05). CONCLUSION: Thoracic endovascular aortic repair results in relative straightening of the stented aortic region and also accentuates the native curvature of the ascending aorta when the endograft has a more proximal landing zone. Supra-aortic branch vessel angulation remains relatively static when proximal landing zones are distal to the left common carotid artery. PMID- 29400264 TI - Mood and Personality Characteristics are Associated with Metamemory Knowledge Accuracy in a Community-Based Cohort of Older Adults. AB - OBJECTIVES: Emerging work reveals the neuroanatomic changes that compromise metacognition; however, little is known about the impact of premorbid factors. Research suggests that psychological variables influence the perception of cognition, but whether they influence the accuracy of those perceptions (i.e., metacognition) has not been directly examined. PARTICIPANTS AND METHODS: Using Latent Class Analysis (LCA), we tested for discrete personality (NEOFFI) and mood (STAI, BDI-II, and GDS) classes among a community-based cohort of 151 older adults, enrolled in the NKI-Rockland study. Metamemory was calculated by comparing subjective memory ratings (modified Cognitive Failures Questionnaire) to objective memory (Rey Auditory Verbal Learning Test) to determine the degree to which individuals were overconfident, underconfident, or accurate in their self-assessment. A generalized linear model was used to examine whether metamemory differed across the emergent classes. A one sample t test was used to determine whether the metamemory scores of the emergent classes were statistically significantly different from zero, that is, over or under confident. RESULTS: Two discrete classes emerged in the LCA: Class 1 was characterized predominantly by high extraversion and conscientiousness and low neuroticism and anxiety; Class 2 was characterized predominantly by low extraversion and conscientiousness and high neuroticism and anxiety. Metamemory differed significantly as a function of Class Membership (F(4,151)=5.42; p<.001), with Class 1 demonstrating accurate metamemory (M=0.21; SD=1.31) and Class 2 demonstrating under-confidence (M=-0.59; SD=1.39) in their memory. CONCLUSIONS: The significant association between psychological factors and metamemory knowledge accuracy suggests that such characteristics may be important to consider in the conceptualization, assessment, and treatment of metacognitive disturbances. (JINS, 2018, 24, 498-510). PMID- 29400262 TI - Air pollution as a risk factor in health impact assessments of a travel mode shift towards cycling. AB - BACKGROUND: Promotion of active commuting provides substantial health and environmental benefits by influencing air pollution, physical activity, accidents, and noise. However, studies evaluating intervention and policies on a mode shift from motorized transport to cycling have estimated health impacts with varying validity and precision. OBJECTIVE: To review and discuss the estimation of air pollution exposure and its impacts in health impact assessment studies of a shift in transport from cars to bicycles in order to guide future assessments. METHODS: A systematic database search of PubMed was done primarily for articles published from January 2000 to May 2016 according to PRISMA guidelines. RESULTS: We identified 18 studies of health impact assessment of change in transport mode. Most studies investigated future hypothetical scenarios of increased cycling. The impact on the general population was estimated using a comparative risk assessment approach in the majority of these studies, whereas some used previously published cost estimates. Air pollution exposure during cycling was estimated based on the ventilation rate, the pollutant concentration, and the trip duration. Most studies employed exposure-response functions from studies comparing background levels of fine particles between cities to estimate the health impacts of local traffic emissions. The effect of air pollution associated with increased cycling contributed small health benefits for the general population, and also only slightly increased risks associated with fine particle exposure among those who shifted to cycling. However, studies calculating health impacts based on exposure-response functions for ozone, black carbon or nitrogen oxides found larger effects attributed to changes in air pollution exposure. CONCLUSION: A large discrepancy between studies was observed due to different health impact assessment approaches, different assumptions for calculation of inhaled dose and different selection of dose-response functions. This kind of assessments would improve from more holistic approaches using more specific exposure-response functions. PMID- 29400265 TI - Socio-economic, environmental and nutritional characteristics of urban and rural South Indian women in early pregnancy: findings from the South Asian Birth Cohort (START). AB - OBJECTIVE: High frequency of low birth weight (LBW) is observed in rural compared with urban Indian women. Since maternal BMI is known to be associated with pregnancy outcomes, the present study aimed to investigate factors associated with BMI in early pregnancy of urban and rural South Indian women. DESIGN: Prospective observational cohort. SETTING: A hospital-based study conducted at an urban and a rural health centre in Karnataka State. SUBJECTS: Pregnant women (n 843) aged 18-40 years recruited in early pregnancy from whom detailed sociodemographic, environmental, anthropometric and dietary intake information was collected. RESULTS: A high proportion of low BMI (32 v. 26 %, P<0.000) and anaemia (48 v. 23 %, P<0.000) was observed in the rural v. the urban cohort. Rural women were younger, had lower body weight, tended to be shorter and less educated. They lived in poor housing conditions, had less access to piped water and good sanitation, used unrefined fuel for cooking and had lower standard of living score. The age (beta=0.21, 95 % CI 0.14, 0.29), education level of their spouse (beta=1.36, 95 % CI 0.71, 2.71) and fat intake (beta=1.24, 95 % CI 0.20, 2.28) were positively associated with BMI in urban women. CONCLUSIONS: Our findings indicate that risk factors associated with BMI in early pregnancy are different in rural and urban settings. It is important to study population specific risk factors in relation to perinatal health. PMID- 29400266 TI - Molecular differentiation of three canine and feline hookworms in South China through HRM analysis. AB - To investigate the prevalence of canine and feline hookworms in South China, and to assess the risk of zoonotic hookworms to humans, one pair of primers (HRM F/HRM-R) was designed to establish a high-resolution melting (HRM) method based on internal transcribed spacer 1 (ITS-1) rDNA for the detection of Ancylostoma ceylanicum, A. caninum and A. tubaeforme infection. The results showed that the HRM for the three hookworms produced different melting-curve profiles, where melting temperature (T m) values were 84.50 degrees C for A. ceylanicum, 82.25 degrees C for A. caninum and 81.73 degrees C for A. tubaeforme, respectively. The reproducibility of intra- and inter-assay melting curves was almost perfect. The lowest concentration detected was about 5.69 *10-4 g/MUl. The HRM detection results from 18 canine and feline hookworm samples were in complete accordance with their sequencing results. The HRM method was more sensitive than the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in the detection of 98 clinical samples. It is concluded that the HRM method can differentiate between A. ceylanicum, A. caninum, A. tubaeforme and their mixed infections, which may provide important technical support for the zoonotic risk assessment and molecular epidemiological survey of canine and feline hookworms. PMID- 29400267 TI - Trypanosoma cruzi: death phenotypes induced by ortho-naphthoquinone substrates of the aldo-keto reductase (TcAKR). Role of this enzyme in the mechanism of action of beta-lapachone. AB - Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldo-keto reductase from this parasite (TcAKR) reduces o NQs, such as beta-lapachone (beta-Lap) and 9,10-phenanthrenequinone (9,10-PQ), with concomitant reactive oxygen species (ROS) production. Recent characterization of TcAKR activity and expression in two T. cruzi strains, CL Brener and Nicaragua, showed that TcAKR expression is 2.2-fold higher in CL Brener than in Nicaragua. Here, we studied the trypanocidal effect and induction of several death phenotypes by beta-Lap and 9,10-PQ in epimastigotes of these two strains. The CL Brener strain was more resistant to both o-NQs than Nicaragua, indicating that greater TcAKR activity is unlikely to be a major influence on o NQ toxicity. Evaluation of changes in ROS production, mitochondrial membrane potential, phosphatidylserine exposure and monodansylcadaverine labelling evidenced that beta-Lap and 9,10-PQ induce different death phenotypes depending on the combination of drug and T. cruzi strain analysed. To study whether TcAKR participates in o-NQ activation in intact parasites, beta-Lap and 9,10-PQ trypanocidal effect was next evaluated in TcAKR-overexpressing parasites. Only beta-Lap was more effective and induced greater ROS production in TcAKR overexpressing epimastigotes than in controls, suggesting that TcAKR may participate in beta-Lap activation. PMID- 29400268 TI - Could diet composition modulate pathological outcomes in schistosomiasis mansoni? A systematic review of in vivo preclinical evidence. AB - Schistosomiasis and malnutrition are often overlapped in poor communities, resulting in disproportionately high mortality rates. Currently, fragmented data make it difficult to define the relationship between diet and schistosomiasis. Thus, we systematically review the preclinical evidence on the impact of diet in Schistosoma mansoni infection. From a structured search, we recovered 27 original articles. All studies used mice and most of them investigated hypoproteic (70.37%), hyperlipidic (22.22%) or vitamin-deficient (7.41%) diets. Diets based on carbohydrate, zinc or milk supplementation were investigated at a reduced frequency (3.70% each). Hypoproteic diets attenuated parasitic load and granulomatous inflammation, but also reduced host resistance to S. mansoni infection, determining higher mortality rates. By stimulating steatohepatitis, parasitic load and granulomatous inflammation, hyperlipidic diets increase organ damage and mortality in infected animals. Although a high-sugar diet and vitamin restriction potentiate and zinc supplementation attenuates S. mansoni infection, the current evidence for these diets remains inconclusive. Analysis of methodological quality indicated that the current evidence is at high risk of bias due to incomplete characterization of the experimental design, diet composition and treatment protocols. From the bias analysis, we report methodological limitations that should be considered to avoid systematic reproduction of inconsistent and poorly reproducible experimental designs. PMID- 29400269 TI - Facing a Paradigm Shift in the Sustainable Development Goal Era. AB - The Sustainable Development Goals challenge us to step beyond traditional development approaches and to consider strategies that are evidence informed and innovative. The concepts are familiar; themes aligned with Harmonization, Primary Healthcare, Leadership, Public Private Partnerships, Community Engagement, and Integrated Technologies. However, to optimize resources and overcome today's challenge with sustainable solutions, we must capture lessons learned and apply evidence developed to inform and expand the thinking to shape and inform new paradigms. The tools, the experience, and the evidence are at our finger-tips. We must hold ourselves accountable to turn that rudder and hold the line so that the ship can advance toward universal health coverage that ensures healthy lives and promotes wellbeing for all at all ages. Health is where economic well-being, labour opportunities, educational advancement, gender equity and access to food, water, clean air come together to advance the wellbeing of all. This juncture is most significant at community level, where health systems intertwine with the social and cultural fabric and health workers stand at the interface between the health system and the people it serves. In these manuscripts, thought leaders in the health sector share evidence and experience to help us consider how we will use this intersection to push all nations to achieve all the SDGs. PMID- 29400270 TI - The UN High-Level Commission on Health Employment and Economic Growth: The Opportunity for Communities and their Primary Health Systems. AB - Focusing on the UN High-Level Commission on Health Employment and Economic Growth, this paper examines its potential impact on primary health-care to communities. It contains a set of curated interviews with key decision-makers who are determining how health workers are trained and employed all over the world. The commentaries come from individuals who have either been or have not been directly involved in the work of the Commission, exploring the necessary actions needed in support of implementing these recommendations, highlighting the ultimate potential impact at the local level - health systems and health workers working in communities and their primary health systems. Please note that the full submissions for these individuals are contained in Appendix 1 (available at: www.longwoods.com/content/25309). PMID- 29400271 TI - Enhancing Harmonization to Ensure Alignment of Partners, Implementation and Priorities for Provision of Quality Primary Healthcare to Communities in Rural Zambia. AB - This paper discusses the processes of harmonization of various approaches by partners that have been implemented in Zambia, in an attempt to overcome the fragmented implementation of Community based primary healthcare (CBPHC) systems strengthening, facilitated by multiple non-governmental organizations (NGOs) and donors, impeding country ownership and nationalization. To achieve equitable and sustained improvements in health, social and economic development outcomes for all, there is evidence that governments should consider building CBPHC systems based on three legs namely: 1. Front-line health workers trained, supervised and able to deliver services; 2. Community engagement through interactions to enhance community participation and Social Accountability for delivery of healthcare services; 3. Enabling environments through strengthening of community health systems. To realize a harmonized approach and alignments, the government and key stakeholders must uphold a common vision ensuring that all the three legs of CBPHC systems are implemented to scale. In evaluating the health system in Zambia and the related healthcare provision at community level, gaps were identified in the available mechanisms for the provision of quality CBPHC thus necessitating processes of harmonization, that include capacity building and orientations at all levels on importance of taking to scale the three legs of CBPHC systems, revision of the Community Health Strategy, and elaboration of Operational Guide for Neighbourhood Health Committees, clarifying the role of NHC as platform for community engagement and Community-Based Volunteers (CBVs). There is need for harmonization of health systems at national, provincial, district, zonal and communal levels to ensure the delivery of quality, cost-effective healthcare as close to the family as possible. PMID- 29400272 TI - There Is Much to Learn When You Listen: Exploring Citizen Engagement in High- and Low-Income Countries. AB - The need for engaging citizens in healthcare policy making is critical, and different approaches are gaining traction internationally. However, citizen engagement seems more difficult to implement in low- and middle-income countries because of political, practical and cultural reasons. Despite this, countries such as India, Malawi, Tanzania, Ethiopia, Rwanda, Mozambique, Egypt have initiated community engagement initiatives, which are contextually unique, and can be used as examples to learn from for the future. Overall, community voices need to play a bigger role in forming policy; they hold the key to improve health and forward growth. Evidence needs to move out of communities and districts through broader communication and knowledge translation avenues to influence and shape national and global level policies and strategies. PMID- 29400273 TI - Accelerating Harmonization in Digital Health. AB - : Digital tools play an important role in supporting front-line health workers who deliver primary care. This paper explores the current state of efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. Through examples from health information systems, data and health worker training, this paper demonstrates how governments and stakeholders are working to integrate digital health services. We emphasize three factors as crucial for this integration: development and implementation of national digital health strategies; technical interoperability and collaborative approaches to ensure that digital health has an impact on the primary care level. Consolidation of technologies will enable an integrated, scaleable approach to the use of digital health to support health workers. PURPOSE: As this edition explores a paradigm shift towards harmonization in primary healthcare systems, this paper explores complementary efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. It describes a paradigm shift towards integrated and interoperable systems that respond to health workers' needs in training, data and health information; and calls for the consolidation and integration of digital health tools and approaches across health areas, functions and levels of the health system. It then considers the critical factors that must be in place to support this paradigm shift. This paper aims not only to describe steps taken to move from fractured pilots to effective systems, but to propose a new perspective focused on consolidation and collaboration guided by national digital health strategies. PMID- 29400274 TI - A Formative Assessment of Nurses' Leadership Role in Zambia's Community Health System. AB - BACKGROUND: Despite its achievements in decreasing HIV prevalence and under-five mortality, Zambia still faces high maternal and neonatal mortality, particularly in the rural and remote areas where almost 60% of the population resides. After significant investments in developing its community health system, the Zambian Ministry of Health was interested to understand how to leverage the role of nurses to sustain achievements made and further improve the quality of care in rural communities. The Ministry joined research partners in an assessment into the role and leadership capacity of nurses heading rural health facilities. METHODS: A seven-member research team conducted 30 in-depth interviews and 10 focus group discussions in four provinces with four categories of respondents: national decision-makers, provincial and district managers, rural facility staff and community respondents (neighborhood health committee members and volunteers). An initial scoping visit and literature review informed the development of specific interview guides for each category of respondent. After audio-recording and transcription, research team members identified and reached consensus on key themes, and presented and validated the findings at a national stakeholder workshop. RESULTS: Zambia's front-line health teams are a complex mixture of professional facility staff, community providers, community-based volunteers and neighborhood health committees. Nurses and nurse-midwives head over half the rural facilities in Zambia, where they are expected to lead the delivery of safe, high-quality care with staff and volunteers who often operate beyond their level of training. Nurses and midwives who are assigned to head rural facilities are not adequately prepared or recognized for the leadership responsibilities they are expected to fulfill. CONCLUSIONS: This paper highlights opportunities to support rural facility heads in effectively leading front-line health teams to deliver primary healthcare to rural communities. Front-line teams require a leader to coordinate and motivate seamless and sustainable quality services that are accessible to all. Zambia has the potential to support integrated, responsive quality care and advance toward universal health coverage if nurses are adequately prepared and recognized with job descriptions that reflect their responsibilities and opportunities for career advancement. PMID- 29400275 TI - Transforming Health Workers' Education for Universal Health Coverage: Global Challenges and Recommendations. AB - Health workforce challenges remain a critical bottleneck in achieving universal health coverage (UHC) goals in most countries. As it stands, health professional training is primarily clinical, curricular and delinked from the needs of the health system. To achieve global health goals and maximize opportunities for employment and economic growth, all in the context of limited fiscal realities, a paradigm shift is needed with respect to the health workforce and corresponding education systems. There is a need to shift towards fair, gender friendly employment at a rate that matches the overall growth of the health economy, which acknowledges the role of the private sector in education and training. This paper emphasizes the importance and implications of such a paradigm shift. It argues the need for a 21st century framework for health professional education. This framework should represent a more satisfactory interface between supply and demand for health professional labor, in line with the need for UHC, job creation and economic growth. PMID- 29400276 TI - The Collaboration Challenge: Global Partnerships to Achieve Global Goals. AB - As capitalism is being re-invented and the voices of multiple stakeholders are becoming more prevalent and demanding, it is the perfect time for the private sector to embrace large-scale collaboration and a shared sense of purpose. Since the explosive growth of Corporate Social Responsibility (CSR) in the 1990s, a new era of responsibility, purpose and a re-envisioned capitalism are dramatically apparent. Beyond financial support, business leaders have the opportunity to galvanize networks, advocate for regulation and policy change, and form supporting consortia to support global development. The role of the private sector in development has changed significantly from a model of benevolent contributor to a model of collaborator, investor, business partner and exponential value creator. The new era of collaboration should move beyond a shared value mindset to new models of partnership where each contributor plays an equal role in defining challenges and designing solutions with the greater goal of sustainable value creation. Non-Governmental Organizations (NGOs) have the unprecedented opportunity to take leadership roles in engaging the private sector in more game-changing collaborations. PMID- 29400277 TI - Who you gonna call? PMID- 29400278 TI - Subclinical leaflet thrombosis - a concern, but also an issue? PMID- 29400279 TI - Keep bifurcation stenting simple and cheap or controlled and optimised? PMID- 29400280 TI - Standardising definitions for bioprosthetic structural valve deterioration and failure: the European avant-garde. PMID- 29400281 TI - Necrotizing fasciitis following minor skin surgery in a patient receiving treatment with infliximab and prednisolone. PMID- 29400282 TI - Ustekinumab in patients previously treated with TNFalpha inhibitors: a real-life study. PMID- 29400284 TI - Third-line pembrolizumab-induced immune-related interstitial pneumonitis after ipilimumab and nivolumab failure. PMID- 29400283 TI - Extranodal natural killer/T-cell lymphoma, nasal type: a Spanish multicentric retrospective survey. AB - BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is an aggressive lymphoma with a very low incidence in western populations. OBJECTIVE: To review the clinicopathological features and outcome of a multicentre series of ENKTL in Spain. MATERIALS & METHODS: A multicentre retrospective study was performed based on cases of ENKTL, collected from 1995 to 2004, from 12 dermatology departments included in the Spanish Lymphoma Study Group. The clinical, histopathological, and evolutive features of all these cases were reviewed. RESULTS: Eighteen patients (three male, 15 female) with median age of 67 years were included in the study. The onset of lesions occurred in the nasal region in 11 patients and on the skin outside this region in the remaining cases. The observed lesions were clinically heterogeneous, corresponding to papules, plaques, and nodules, with or without ulceration. All patients except four received different polychemotherapy regimens, either alone (n = 11) or in combination with radiotherapy (n = 4). After a variable follow-up period (1-36 months), only two patients remained alive. One patient was recently diagnosed (four months ago) with ENKTL in the nasal region and the other presented with skin-limited disease. The median overall survival was 9.5 months. CONCLUSIONS: The results of this retrospective survey confirm that ENKTL is a rare subtype of lymphoma in the Spanish population. All patients showed an aggressive clinical course and poor prognosis, regardless of the initial clinical presentation. Prospective data on larger series of patients treated homogenously are needed to establish the best treatment modality. PMID- 29400285 TI - Dynamic changes of sarcoidosis presenting as acquired ichthyosiform erythroderma. PMID- 29400286 TI - Cutaneous Rosai-Dorfman disease of the face with a leonine appearance: successful response to dapsone. PMID- 29400287 TI - Improvement of erosive pustular dermatosis of the scalp following discontinuation of chemotherapy with afatinib. PMID- 29400288 TI - A case of severe pityriasis rubra pilaris with a dramatic response to apremilast. PMID- 29400289 TI - Wells' syndrome-like reaction following Argas reflexus bites. PMID- 29400290 TI - Sunlight is merely a temporary modifier of dyschromatosis symmetrica hereditaria. PMID- 29400291 TI - Erythema nodosum-like eruption after uterine artery embolization: a case report and literature review. PMID- 29400292 TI - No recurrence of nivolumab-induced idiopathic thrombocytopenic purpura in a metastatic melanoma patient switched to ipilimumab. PMID- 29400293 TI - Localized bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitor treatment. PMID- 29400294 TI - Mycobacterium iranicum infection in a patient with fish tank granuloma: a first case report. PMID- 29400295 TI - DITRA syndrome in a Vietnamese patient: efficacy of etanercept. PMID- 29400296 TI - A case of dermatomyositis presenting with inverse Gottron's papules as the first manifestation. PMID- 29400297 TI - Perianal Paget disease secondary to pagetoid spread of mucinous adenocarcinoma of the anal canal. PMID- 29400298 TI - Neuroprotective effects of lithium: what are the implications in humans with neurodegenerative disorders? AB - Lithium is used as a first line treatment in bipolar disorder. The neuroprotective effects of lithium in this indication tend to be well known and are mediated by its action on two enzymes: glycogen synthase kinase-3 and inositol monophosphatase-1. Preclinical and clinical studies seek to evaluate the neuroprotective effect of lithium in neurodegenerative disorders. The aims of this literature review is to gather clinical studies that investigated the efficacy of lithium in neurodegenerative diseases, using a systematic method based on PubMed data. Results were found concerning Alzheimer's disease and related dementias, Huntington's disease, amyotrophic lateral sclerosis and spino cerebellar ataxia. Lithium exposure showed a potential neuroprotective effect in studies on psychiatric populations with a lower prevalence of Alzheimer's disease in exposed patients. In patients with mild cognitive impairment, lithium would be associated with clinical improvement and a lower level of cerebrospinal phosphorylated tau protein. Lithium would allow at least a partial improvement in symptoms, including suicidal thoughts, in Huntington's disease. Despite several positive case reports and short studies, further controlled researches have failed to substantiate any positive effects of lithium exposure in amyotrophic lateral sclerosis. In spinocerebellar ataxia, introduction of lithium may be of benefits in terms of improvement of cerebellar symptoms. Large randomized controlled trials are required to asses the effect of early exposure lithium in these indications, based on reliable biological markers of disease. PMID- 29400299 TI - An interesting case of Piebaldism with cafe-au-lait macules and freckling: the use of targeted next-generation sequencing for molecular diagnosis. PMID- 29400300 TI - Preoperative assessment of tumour thickness and vascularity using high-frequency ultrasonography in ten cases of cutaneous melanoma. PMID- 29400301 TI - A Chinese family with autosomal recessive congenital ichthyosis and Leber congenital amaurosis due to mutations in PNPLA1 and LCA5. PMID- 29400302 TI - A novel missense mutation in exon 3 of the TRPS1 gene in a patient with a mild phenotype of tricho-rhino-phalangeal syndrome type 1. PMID- 29400304 TI - Acroangiodermatitis with pincer nail of the finger due to venous hypertension from hemodialysis arteriovenous shunt. PMID- 29400303 TI - Acute generalized exanthematous pustulosis associated with Helicobacter pylori eradication therapy with elevated serum procalcitonin. PMID- 29400305 TI - History of Balkan Medical Journal: Road to High-Impact Journal. PMID- 29400306 TI - General Concepts in Adult Congenital Heart Disease. AB - Congenital heart disease in adults (adult congenital heart disease) is a growing burden for healthcare systems. While infant mortality due to congenital heart disease in the last four decades decreased by almost 3-fold, adult congenital heart disease prevalence increased by more than 2-fold in United States. Adult congenital heart disease prevalence is expected to increase steadily until 2050 in projections. Adult congenital heart disease is a multifaceted problem with many dimensions. This manuscript aims to provide an overview of the common adult congenital heart diseases and summarize important points in management of these diseases with possible problems and complications that the patients and the physicians face. PMID- 29400307 TI - Serrated Polyposis Syndrome in a Single-Center 10-Year Experience. AB - AIMS: Serrated polyposis syndrome is a disease that is often missed in the clinical setting and is associated with colorectal cancer. We investigated the prevalence of SPS and the association between colorectal or other cancers in a 10 year, retrospective data analysis. METHODS: We reviewed complete colonoscopy data obtained from January 2005 through January 2015 at a health-screening centre. Serrated polyposis syndrome was defined on the basis of the criteria established by the 2010 World Health Organization. RESULTS: Of a total of 53.842 consecutive subjects who underwent complete colonoscopy, 12 (0.022%) patients had serrated polyposis syndrome. All of these cases were under-recognized by the endoscopist or referring physician. The mean patient age was 58.6 years; 67% of the patients were men and 33% were women. No serrated polyposis syndrome patients had a first degree relative with serrated polyposis syndrome, and no serrated polyposis syndrome patients had colorectal cancer. Two cases (17%) had extra-colonic cancers (prostate cancer and thyroid cancer). Eight cases (67%) had a family history of cancer (stomach, breast, lung, pancreas, prostate and colorectal cancer). CONCLUSION: Serrated polyposis syndrome was a rare condition in a 10 year database, and it was diagnosed late in all cases. Serrated polyposis syndrome may be associated with an increased risk of extra-colonic cancer. PMID- 29400308 TI - A Misclassification of Pulmonary Stenosis Using Conventional Echocardiographic Methods. AB - BACKGROUND: The classification of pulmonary stenosis (PS) severity based on the transpulmonary pressure gradient, which is affected by flow rate. CASE REPORT: We report the first case of a pregnant patient with atrial septal defect (ASD) and pulmonary stenosis that was misclassified by conventional echocardiographic methods. Most importantly, three-dimensional transoesophageal echocardiographic assessment of pulmonary stenosis changed the entire treatment strategy. CONCLUSION: The planimetric calculation of the pulmonary valve (PV) opening area using three-dimensional transoesophageal echocardiographic may be helpful, especially in encounters with specialized conditions such as ASD and/or pregnancy, which can cause inaccurate recordings of the transvalvular peak gradient. PMID- 29400309 TI - Novel Founder Mutation in FANCA Gene (c.3446_3449dupCCCT) Among Romani Patients from the Balkan Region. AB - BACKGROUND: Fanconi anemia is a rare autosomal recessive or X-linked disorder characterised by clinical and genetic heterogeneity. Most fanconi anemia patients harbour homozygous or double heterozygous mutations in the FANCA (60-65%), FANCC (10-15%), FANCG (~10%) or FANCD2 (3-6%) genes. We have already reported the FANCA variant c.190-256_283+1680del2040dupC as a founder mutation among Macedonian fanconi anemia patients of Gypsy-like ethnic origin. Here, we present a novel FANCA mutation in two patients from Macedonia and Kosovo. CASE REPORT: The novel FANCA mutation c.3446_3449dupCCCT was identified in two fanconi anemia patients with Romany ethnicity; a 2-year-old girl from Macedonia who is a compound heterozygote for a previously reported FANCA c.190-256_283+1680del2040dupC and the novel mutation and a 10-year-old girl from Kosovo who is a homozygote for the novel FANCA c.3446_3449dupCCCT mutation. The novel mutation is located in exon 35 in the FAAP20-binding domain which plays a crucial role in the FANCA-FAAP20 interaction and is required for integrity of the fanconi anemia pathway. CONCLUSION: The finding of the FANCA c.3446_3449dupCCCT mutation in two unrelated FA patients with Romani ethnicity from Macedonia and Kosovo suggests it is a founder mutation in the Romani population living in the Balkan region. PMID- 29400310 TI - Maxillo Ostio Choanal Polyp. PMID- 29400311 TI - Patent Omphalomesenteric Duct with Protruding Bowels through a Ruptured Omphalocele. PMID- 29400312 TI - Charging effect at grain boundaries of MoS2. AB - Grain boundaries (GBs) are inherent extended defects in chemical vapor deposited (CVD) transition metal dichalcogenide (TMD) films. Characterization of the atomic structure and electronic properties of these GBs is crucial for understanding and controlling the properties of TMDs via defect engineering. Here, we report the atomic and electronic structure of GBs in CVD grown MoS2 on epitaxial graphene/SiC(0001). Using scanning tunneling microscopy/spectroscopy, we find that GBs mostly consist of arrays of dislocation cores, where the presence of mid gap states shifts both conduction and valence band edges by up to 1 eV. Our findings demonstrate the first charging effect near GBs in CVD grown MoS2, providing insights into the significant impact GBs can have on materials properties. PMID- 29400313 TI - Chirality and grain boundary effects on indentation mechanical properties of graphene coated on nickel foil. AB - We investigate chirality and grain boundary (GB) effects on indentation mechanical properties of graphene coated on nickel foil using molecular dynamics simulations. The models of graphene with different chirality angles, different numbers of layers and tilt GBs were established. It was found that the chirality angle of few-layer graphene had a significant effect on the load bearing capacity of graphene/nickel systems, and this turns out to be more significant when the number of layers is greater than one. The enhancement to the contact stiffness, elastic capacity and the load bearing capacity of graphene with tilt GBs was lower than that of pristine graphene. PMID- 29400314 TI - A-TEEMTM, a new molecular fingerprinting technique: simultaneous absorbance transmission and fluorescence excitation-emission matrix method. AB - We investigate the new simultaneous absorbance-transmission and fluorescence excitation-emission matrix method for rapid and effective characterization of the varying components from a mixture. The absorbance-transmission and fluorescence excitation-emission matrix method uniquely facilitates correction of fluorescence inner-filter effects to yield quantitative fluorescence spectral information that is largely independent of component concentration. This is significant because it allows one to effectively monitor quantitative component changes using multivariate methods and to generate and evaluate spectral libraries. We present the use of this novel instrument in different fields: i.e. tracking changes in complex mixtures including natural water, wine as well as monitoring stability and aggregation of hormones for biotherapeutics. PMID- 29400315 TI - The Pex4p-Pex22p complex from Hansenula polymorpha: biophysical analysis, crystallization and X-ray diffraction characterization. AB - Peroxisomes are a major cellular compartment of eukaryotic cells, and are involved in a variety of metabolic functions and pathways according to species, cell type and environmental conditions. Their biogenesis relies on conserved genes known as PEX genes that encode peroxin proteins. Peroxisomal membrane proteins and peroxisomal matrix proteins are generated in the cytosol and are subsequently imported into the peroxisome post-translationally. Matrix proteins containing a peroxisomal targeting signal type 1 (PTS1) are recognized by the cycling receptor Pex5p and transported to the peroxisomal lumen. Pex5p docking, release of the cargo into the lumen and recycling involve a number of peroxins, but a key player is the Pex4p-Pex22p complex described in this manuscript. Pex4p from the yeast Saccharomyces cerevisiae is a ubiquitin-conjugating enzyme that is anchored on the cytosolic side of the peroxisomal membrane through its binding partner Pex22p, which acts as both a docking site and a co-activator of Pex4p. As Pex5p undergoes recycling and release, the Pex4p-Pex22p complex is essential for monoubiquitination at the conserved cysteine residue of Pex5p. The absence of Pex4p-Pex22p inhibits Pex5p recycling and hence PTS1 protein import. This article reports the crystallization of Pex4p and of the Pex4p-Pex22p complex from the yeast Hansenula polymorpha, and data collection from their crystals to 2.0 and 2.85 A resolution, respectively. The resulting structures are likely to provide important insights to understand the molecular mechanism of the Pex4p-Pex22p complex and its role in peroxisome biogenesis. PMID- 29400316 TI - Human CCL5 trimer: expression, purification and initial crystallographic studies. AB - The chemokine CCL5 is considered to be a potential therapeutic target because of its ability to recruit immune cells to inflammatory sites. CCL5 aggregates under physiological conditions, and high-order oligomer formation is considered to be significant for cell migration, immune-cell activation and HIV cell entry. The structure of the high-order oligomer is unknown and the mechanism by which the oligomer is derived has yet to be established. Here, a CCL5 mutant (CCL5-E66S) which is deficient in oligomer formation was mixed with native CCL5 to prepare a protein trimer. At an optimized ratio the trimeric CCL5 crystallized, and the crystal belonged to the tetragonal space group P41212, with unit-cell parameters a = 56.6, b = 56.6, c = 154.1 A. The Matthews coefficient (VM) of the crystal is 2.58 A3 Da-1 (three molecules in the asymmetric unit), with a solvent content of 52.32%. Diffraction data were collected to a resolution of 1.87 A and the statistics indicated satisfactory data quality. The new structure will reveal the interfaces in the CCL5 oligomer, therefore assisting in understanding the mechanism of CCL5 oligomerization. PMID- 29400317 TI - X-ray crystallographic and high-speed AFM studies of peroxiredoxin 1 from Chlamydomonas reinhardtii. AB - Peroxiredoxins (PRXs) are a group of antioxidant enzymes that are found in all organisms, including plants and green algae. The 2-Cys PRX from Chlamydomonas reinhardtii (CrPRX1) is a chloroplast-localized protein that is critical for clearing reactive oxygen species in chloroplasts. CrPRX1 is reduced by thioredoxins or calredoxin (CrCRX), a recently identified calcium-dependent redox protein. The molecular interaction between PRXs and thioredoxin/CrCRX is functionally important, but discussion has been limited owing to a lack of structural information on CrPRX1, especially regarding its oligomeric state. In this study, high-speed atomic force microscopy (HS-AFM) images of CrPRX1 and an X ray crystallographic analysis have enabled examination of the oligomeric state of CrPRX1. Diffraction data from a crystal of the Cys174Ser mutant of CrPRX1 indicate the existence of noncrystallographic fivefold symmetry. HS-AFM images of CrPRX1 further show that CrPRX1 particles form rings with pentagonal rotational symmetry. On the basis of these findings, the oligomeric state of CrPRX1 is discussed and it is concluded that this PRX exists in a ring-shaped decameric form comprising a pentamer of dimers. PMID- 29400318 TI - Structure of bovine cytochrome c oxidase in the ligand-free reduced state at neutral pH. AB - Cytochrome c oxidase (CcO), the terminal oxidase in cellular respiration, couples proton pumping to O2 reduction. Mammalian CcO resides in the inner mitochondrial membrane. Previously, a model of H-pathway proton pumping was proposed based on various CcO crystal structures. However, all previously determined structures were solved using crystals obtained at pH 5.7, which differs from the environmental pH of CcO in the inner membrane. The structures of fully oxidized and ligand-free reduced CcO at pH 7.3 have now been determined. Structural comparison between the oxidized and reduced states revealed that the structural alterations that occurred upon redox change at pH 5.7 in Asp51, the magnesium containing cluster, haem groups and helix X, which provide important structural evidence for the H-pathway proton-pumping proposal, also occur at pH 7.3. These structural alterations were restricted to a local region of CcO; no domain movement was detected, nor were significant structural alterations detected in peripheral regions at either pH value. These observations indicate that the small and precise structural alterations that occur over the course of the reaction cycle are not affected by pH change, and that isolated CcO precisely performs proton pumping via the H-pathway over a wide pH range. Because the pH is not uniform across the molecular surface of CcO, the fact that the overall structure of CcO is not affected by pH changes ensures the high enzymatic efficiency of this protein in the mitochondria. PMID- 29400319 TI - Ribokinase from Leishmania donovani: purification, characterization and X-ray crystallographic analysis. AB - Leishmania is an auxotrophic protozoan parasite which acquires D-ribose by transporting it from the host cell and also by the hydrolysis of nucleosides. The enzyme ribokinase (RK) catalyzes the first step of ribose metabolism by phosphorylating D-ribose using ATP to produce D-ribose-5-phosphate. To understand its structure and function, the gene encoding RK from L. donovani was cloned, expressed and purified using affinity and size-exclusion chromatography. Circular dichroism spectroscopy of the purified protein showed comparatively more alpha helix in the secondary-structure content, and thermal unfolding revealed the Tm to be 317.2 K. Kinetic parameters were obtained by functional characterization of L. donovani RK, and the Km values for ribose and ATP were found to be 296 +/- 36 and 116 +/- 9.0 uM, respectively. Crystals obtained by the hanging-drop vapour diffusion method diffracted to 1.95 A resolution and belonged to the hexagonal space group P61, with unit-cell parameters a = b = 100.25, c = 126.77 A. Analysis of the crystal content indicated the presence of two protomers in the asymmetric unit, with a Matthews coefficient (VM) of 2.45 A3 Da-1 and 49.8% solvent content. Further study revealed that human counterpart of this protein could be used as a template to determine the first three-dimensional structure of the RK from trypanosomatid parasites. PMID- 29400320 TI - Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK). AB - Enoyl-acyl carrier protein (ACP) reductase II (FabK) is a critical rate-limiting enzyme in the bacterial type II fatty-acid synthesis (FAS II) pathway. FAS II pathway enzymes are markedly disparate from their mammalian analogs in the FAS I pathway in both structure and mechanism. Enzymes involved in bacterial fatty-acid synthesis represent viable drug targets for Gram-negative pathogens, and historical precedent exists for targeting them in the treatment of diseases of the oral cavity. The Gram-negative organism Porphyromonas gingivalis represents a key causative agent of the costly and highly prevalent disease known as chronic periodontitis, and exclusively expresses FabK as its enoyl reductase enzyme in the FAS-II pathway. Together, these characteristics distinguish P. gingivalis FabK (PgFabK) as an attractive and novel narrow-spectrum antibacterial target candidate. PgFabK is a flavoenzyme that is dependent on FMN and NADPH as cofactors for the enzymatic reaction, which reduces the enoyl substrate via a ping-pong mechanism. Here, the structure of the PgFabK enzyme as determined using X-ray crystallography is reported to 1.9 A resolution with endogenous FMN fully resolved and the NADPH cofactor partially resolved. PgFabK possesses a TIM-barrel motif, and all flexible loops are visible. The determined structure has allowed insight into the structural basis for the NADPH dependence observed in PgFabK and the role of a monovalent cation that has been observed in previous studies to be stringently required for FabK activity. The PgFabK structure and the insights gleaned from its analysis will facilitate structure-based drug-discovery efforts towards the prevention and treatment of P. gingivalis infection. PMID- 29400321 TI - Xylanase B from Clostridium cellulovorans 743B: overexpression, purification, crystallization and X-ray diffraction analysis. AB - Clostridium cellulovorans produces multi-enzyme complexes called cellulosomes capable of efficiently degrading cellulosic biomass. There are three xylanase genes containing a sequence corresponding to a dockerin domain that are necessary for constructing cellulosomes in the genome. Among the xylanases encoded by these genes, xylanase B (XynB) contains a catalytic domain belonging to glycoside hydrolase family 10 and a carbohydrate-binding module (CBM) at the N-terminus, making it a member of CBM family 22. In this study, XynB was cloned, overexpressed, purified and crystallized. XynB was crystallized using the hanging drop vapour-diffusion method in the presence of 0.2 M sodium acetate trihydrate, 0.1 M Tris-HCl pH 8.5, 32%(w/v) PEG 4000 at 293 K. X-ray diffraction analysis revealed that the crystal diffracted to 1.95 A resolution and belonged to space group P212121, with unit-cell parameters a = 74.28, b = 77.55, c = 88.20 A, alpha = beta = gamma = 90 degrees . The data-evaluation statistics revealed high quality of the collected data, thereby establishing a solid basis for determination of the structure of cellulosomal xylanase from C. cellulovorans. PMID- 29400322 TI - A thermostable and alkaline GDSL-motif esterase from Bacillus sp. K91: crystallization and X-ray crystallographic analysis. AB - The esterase Est8 from the thermophilic bacterium Bacillus sp. K91 belongs to the GDSL family and is active on a variety of acetylated compounds, including 7 aminocephalosporanic acid. In contrast to other esterases of the GDSL family, the catalytic residues Asp182 and His185 were more pivotal for the catalytic activity of Est8 than the Ser11 residue. To better understand the biochemical and enzymatic properties of Est8, recombinant Est8 protein was purified and crystallized. Crystals of Est8 were obtained by the hanging-drop vapour-diffusion method using 2.0 M ammonium sulfate, 5%(v/v) 2-propanol as the crystallization solution. X-ray diffraction data were collected to a resolution of 2.30 A with an Rmerge of 16.4% from a crystal belonging to space group P41212 or P43212, with unit-cell parameters a = b = 68.50, c = 79.57 A. PMID- 29400323 TI - N-Oxide-N-oxide interactions and Cl...Cl halogen bonds in pentachloropyridine N oxide: the many-body approach to interactions in the crystal state. AB - Pentachloropyridine N-oxide, C5Cl5NO, crystallizes in the monoclinic space group P21/c. In the crystal structure, molecules are linked by C-Cl...Cl halogen bonds into infinite ribbons extending along the crystallographic [100] direction. These molecular aggregates are further stabilized by very short intermolecular N-oxide N-oxide interactions into herringbone motifs. Computations based on quantum chemistry methods allowed for a more detailed description of the N-oxide-N-oxide interactions and Cl...Cl halogen bonds. For this purpose, Hirshfeld surface analysis and the many-body approach to interaction energy were applied. PMID- 29400324 TI - High-pressure synthesis and crystal structure of the strontium tungstate Sr3W2O9. AB - The strontium tungstate compound Sr3W2O9 was prepared by a high-pressure synthesis technique. The crystal structure was determined by single-crystal X-ray diffraction and transmission electron microscopy. The structure was found to be a hettotype structure of the high-pressure phase of Ba3W2O9, which has corner sharing octahedra with a trigonal symmetry. Sr3W2O9 has a monoclinic unit cell of C2/c symmetry. One characteristic of the structure is the breaking of the threefold rotation symmetry existing in the high-pressure phase of Ba3W2O9. The substitution of Sr at the Ba site results in a significant shortening of the interlayer distances of the [AO3] layers (A = Ba, Sr) and causes a distortion in the crystal structure. In Sr3W2O9, there is an off-centre displacement of W6+ ions in the WO6 octahedra. Such a displacement is also observed in the high pressure phase of Ba3W2O9. PMID- 29400325 TI - Triethanolaminate iron perchlorate revisited: change of space group, chemical composition and oxidation states in [Fe7(tea)3(tea-H)3](ClO4)2 (tea-H3 is triethanolamine). AB - The X-ray crystal structure of tris[N-(2-hydroxyethyl)-2,2' iminodiethanolato]tris(2,2',2''-nitrilotriethanolato)tetrairon(II)triiron(III) bis(perchlorate), [Fe7(C6H12NO3)3(C6H13NO3)3](ClO4)2 or [Fe7(tea)3(tea H)3](ClO4)2 (tea-H3 is triethanolamine), is known from the literature [Liu et al. (2008). Z. Anorg. Allg. Chem. 634, 778-783] as a heptanuclear coordination cluster. The space group was given as I213 and is reinvestigated in the present study. We find a new space-group symmetry of Pa-3 and could detect O-H hydrogens, which were missing in the original publication. Consequences on the Fe oxidation states are investigated with the bond-valence method, resulting in a mixed valence core of four FeII and three FeIII centres. Symmetry relationships between the two space groups and the average supergroup Ia-3 are discussed in detail. PMID- 29400326 TI - Mixed Ca/Sr salt forms of salicylic acid: tuning structure and aqueous solubility. AB - Ten isostructural single-crystal diffraction studies of mixed cation Ca/Sr salt forms of the salicylate anion are presented, namely catena poly[[diaquacalcium(II)/strontium(II)]-bis(MU2-2-hydroxybenzoato)], [Ca1 xSrx(C7H5O3)2(H2O)2]n, where x = 0, 0.041, 0.083, 0.165, 0.306, 0.529, 0.632, 0.789, 0.835 and 1. The structure of an isostructural Sr/Ba species, namely catena-poly[[diaquastrontium(II)/barium(II)]-bis(MU2-2-hydroxybenzoato)], [Sr0.729Ba0.271(C7H5O3)2(H2O)2], is also described. The Ca/Sr structures form a series where, with increasing Sr content, the unit cell expands in both the crystallographic a and c directions (by 1.80 and 3.18%, respectively), but contracts slightly in the b direction (-0.31%). The largest percentage structural expansion lies parallel to the direction of propagation of the one-dimensional coordination polymer that is the primary structural feature. This structural expansion is thus associated with increased M-O distances. Aqueous solubility measurements show that solubility generally increases with increasing Sr content. Thus, tuning the composition of these mixed counter-ion salt forms leads to systematic structural changes and allows solubility to be tuned to values between those for the pure Ca and Sr species. PMID- 29400327 TI - Manganese(II), lead(II) and cadmium(II) coordination complexes containing a tetrazole-based acylamide ligand: synthesis and the influence of the metal ions on the structures. AB - Three new manganese(II), lead(II) and cadmium(II) coordination complexes have been prepared by reaction of N-(1H-tetrazol-5-yl)cinnamamide (HNTCA) with divalent metal salts (MnCl2, PbCl2 and CdCl2) in a mixed-solvent system, affording mononuclear to trinuclear structures namely, bis(methanol-kappaO)bis[5 (3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido-kappa2N1,O]manganese(II), [Mn(C10H8N5O)2(CH3OH)2], (1), bis[MU-5-(3-phenylprop-2-enamido)-1H-1,2,3,4 tetrazol-1-ido]-kappa3N1,O:N2;kappa3N2:N1,O-bis{aqua[5-(3-phenylprop-2-enamido) 1H-1,2,3,4-tetrazol-1-ido-kappa2N1,O]lead(II)}, [Pb2(C10H8N5O)4(H2O)2], (2), and hexakis[MU2-5-(3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido kappa3N1,O:N2]tricadmium(II), [Cd3(C10H8N5O)6], (3). The structures of these three compounds reveal that the nature of the metal ions and the side groups of the organic building blocks have a significant effect on the structures of the coordination compounds formed. Intermolecular hydrogen bonds link the molecules into two-dimensional [complex (1)] and three-dimensional hydrogen-bonded networks. Complexes (2) and (3) show significant fluorescence, while complex (1) displays no fluorescence. PMID- 29400328 TI - Synthesis, crystal structure and biological properties of a cis dichloridobis(diimine)copper(II) complex. AB - The mechanisms of interaction of inorganic complexes with DNA are important in the design and development of new metal-based drug molecules. The limitations of cis-platin have encouraged the design and development of new metal-based target specific anticancer drugs having reduced side effects. The complex cis dichloridobis(1,2,5-thiadiazolo[3,4-f][1,10]phenanthroline kappa2N1,N10)copper(II), [CuCl2(C12H6N4S)2], has been synthesized and characterized. The complex crystallizes in the monoclinic space group C2/c. The covalent binding of the complex with DNA was studied by absorption spectroscopy. The anticancer activity of the complex on the Human Lung Carcinoma (A549) cell line was investigated by MTT assay. The complex exhibits higher toxicity than cis platin and induces an apoptotic mode of cell death. PMID- 29400329 TI - Formaldehyde-aminoguanidine condensation and aminoguanidine self-condensation products: syntheses, crystal structures and characterization. AB - Guanidine is the functional group on the side chain of arginine, one of the fundamental building blocks of life. In recent years, a number of compounds based on the aminoguanidine (AG) moiety have been described as presenting high anticancer activities. The product of condensation between two molecules of AG and one molecule of formaldehyde was isolated in the protonated form as the dinitrate salt (systematic name: 2,8-diamino-1,3,4,6,7,9-hexaazanona-1,8-diene 1,9-diium dinitrate), C3H14N82+.2NO3-, (I). The cation lacks crystallographically imposed symmetry and comprises two terminal planar guanidinium groups, which share an N-C-N unit. Each cation in (I) builds 14 N-H...O hydrogen bonds and is separated from adjacent cations by seven nitrate anions. The AG self-condensation reaction in the presence of copper(II) chloride and chloride anions led to the formation of the organic-inorganic hybrid 1,2-bis(diaminomethylidene)hydrazine 1,2-diium tetrachloridocuprate(II), (C2H10N6)[CuCl4], (II). Its asymmetric unit is composed of half a diprotonated 1,2-bis(diaminomethylidene)hydrazine-1,2-diium dication and half a tetrachloridocuprate(II) dianion, with the CuII atom situated on a twofold rotation axis. The planar guanidinium fragments in (II) have their planes twisted by approximately 77.64 (5) degrees with respect to each other. The tetrahedral [CuCl4]2- anion is severely distorted and its pronounced 'planarity' must originate from its involvement in multiple N-H...Cl hydrogen bonds. It was reported that [CuCl4]2- anions, with a trans-Cl-Cu-Cl angle (Theta) of ~140 degrees , are yellow-green at room temperature, with the colour shifting to a deeper green as Theta increases and toward orange as Theta decreases. Brown salt (II), with a Theta value of 142.059 (8) degrees , does not fit the trend, which emphasizes the need to take other structural factors into consideration. In the crystal of salt (II), layers of cations and anions alternate along the b axis, with the minimum Cu...Cu distance being 7.5408 (3) A inside a layer. The structures of salts (I) and (II) were substantiated via spectroscopic data. The endothermic reaction involved in the thermal decomposition of (I) requires additional oxygen. The title salts may be useful for the screening of new substances with biological activity. PMID- 29400330 TI - A versatile synthesis of cyclic dipeptides using the stepwise construction of the piperazine-2,5-dione ring from simple precursors: synthetic sequence and the structure of a representative product, (3RS)-4-(2-allyl-3,5-dimethylphenyl)-1 benzyl-3-phenylpiperazine-2,5-dione. AB - A versatile synthesis of multiply substituted cyclic dipeptides has been designed, based on the stepwise construction of the piperazine-2,5-dione ring using molecular fragments from four different precursor molecules. Starting from substituted 2-allylanilines, reaction with methyl 2-bromo-2-phenylacetate yields the corresponding methyl 2-(2-allylanilino)-2-phenylacetates, which react with haloacetyl chlorides to give methyl 2-[N-(2-allylphenyl)-2-haloacetamido]-2 phenylacetates, which then undergo ring closure with benzylamine to yield the corresponding cyclic dipeptides of type 4-(2-allylphenyl)-1-benzyl-3 phenylpiperazine-2,5-dione. (3RS)-4-(2-Allyl-3,5-dimethylphenyl)-1-benzyl-3 phenylpiperazine-2,5-dione, C28H28N2O2, (IIId), crystallizes with Z' = 2 in the space group P21/c; the allyl groups in the two independent molecules adopt different conformations and, in one of them, the allyl group is disordered over two sets of atomic sites having occupancies of 0.534 (4) and 0.466 (4). In both molecules, the piperazine-2,5-dione ring adopts a boat conformation, with the 3 phenyl ring in a quasi-axial site. The molecules of (IIId) are linked into a three-dimensional framework structure by a combination of three C-H...O hydrogen bonds and three C-H...pi(arene) hydrogen bonds. Comparisons are made with some related structures. PMID- 29400331 TI - Synthesis, crystal structure and characterization of a three-dimensional CdII coordination polymer constructed from 2,5-bis(1H-1,2,4-triazol-1 yl)terephthalate. AB - Bifunctional organic ligands are very popular for the design of coordination polymers because they allow the formation of a great diversity of structures. In the title coordination polymer, the new bifunctional inversion-symmetric ligand 2,5-bis(1H-1,2,4-triazol-1-yl)terephthalic acid (abbreviated as H2bttpa) links CdII cations, giving rise to the three-dimensional CdII coordination polymer catena-poly[diaqua[MU4-2,5-bis(1H-1,2,4-triazol-1-yl)terephthalato kappa4O1:O4:N4:N4']cadmium(II)], [Cd(C12H6N6O4)(H2O)2]n or [Cd(bttpa)(H2O)2]n. The asymmetric unit consists of half a CdII cation, half a bttpa2- ligand and one coordinated water molecule. The CdII cation is located on a twofold axis and is hexacoordinated in a distorted octahedral environment of four O and two N atoms. Four different bttpa2- ligands contribute to this coordination, with two carboxylate O atoms in trans positions and two triazole N atoms in cis positions. Two aqua ligands in cis positions complete the coordination sphere. The fully deprotonated bttpa2- ligand sits about a crystallographic centre of inversion and links two CdII cations to form a chain in a MU2-terephthalato-kappa2O1:O4 bridge. This chain extends in the other two directions via the triazole heterocycles, producing a three-dimensional framework. O-H...O hydrogen bonds and weak C-H...N interactions stabilize the three-dimensional crystal structure. The FT-IR spectrum, X-ray powder pattern, thermogravimetric behaviour and solid-state photoluminescence of the title polymer have been investigated. The photoluminescence is enhanced and red-shifted with respect to the uncoordinated ligand. PMID- 29400332 TI - Synthesis, crystal structure and photophysical properties of 1,4-bis(1,3 diazaazulen-2-yl)benzene: a new pi building block. AB - A dimerized 1,3-diazaazulene derivative, namely 1,4-bis(1,3-diazaazulen-2 yl)benzene [or 2,2'-(1,4-phenylene)bis(1,3-diazaazulene)], C22H14N4, (I), has been synthesized successfully through the condensation reaction between 2 methoxytropone and benzene-1,4-dicarboximidamide hydrochloride, and was characterized by 1H NMR and 13C NMR spectroscopies, and ESI-MS. X-ray diffraction analysis reveals that (I) has a nearly planar structure with good pi-electron delocalization, indicating that it might serve as a pi building block. The crystal belongs to the monoclinic system. One-dimensional chains were formed along the a axis through pi-pi interactions and adjacent chains are stabilized by C-H...N interactions, forming a three-dimensional architecture. The solid emission of (I) in the crystalline form exhibited a 170 nm red shift compared with that in the solution state. The observed optical bandgap for (I) is 3.22 eV and a cyclic voltammetry experiment confirmed the energy levels of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The calculated bandgap for (I) is 3.37 eV, which is very close to the experimental result. In addition, the polarizability and hyperpolarizability of (I) were appraised for its further application in second-order nonlinear optical materials. PMID- 29400333 TI - The effect of amino acid backbone length on molecular packing: crystalline tartrates of glycine, beta-alanine, gamma-aminobutyric acid (GABA) and DL-alpha aminobutyric acid (AABA). AB - We report a novel 1:1 cocrystal of beta-alanine with DL-tartaric acid, C3H7NO2.C4H6O6, (II), and three new molecular salts of DL-tartaric acid with beta alanine {3-azaniumylpropanoic acid-3-azaniumylpropanoate DL-tartaric acid-DL tartrate, [H(C3H7NO2)2]+.[H(C4H5O6)2]-, (III)}, gamma-aminobutyric acid [3 carboxypropanaminium DL-tartrate, C4H10NO2+.C4H5O6-, (IV)] and DL-alpha aminobutyric acid {DL-2-azaniumylbutanoic acid-DL-2-azaniumylbutanoate DL tartaric acid-DL-tartrate, [H(C4H9NO2)2]+.[H(C4H5O6)2]-, (V)}. The crystal structures of binary crystals of DL-tartaric acid with glycine, (I), beta alanine, (II) and (III), GABA, (IV), and DL-AABA, (V), have similar molecular packing and crystallographic motifs. The shortest amino acid (i.e. glycine) forms a cocrystal, (I), with DL-tartaric acid, whereas the larger amino acids form molecular salts, viz. (IV) and (V). beta-Alanine is the only amino acid capable of forming both a cocrystal [i.e. (II)] and a molecular salt [i.e. (III)] with DL tartaric acid. The cocrystals of glycine and beta-alanine with DL-tartaric acid, i.e. (I) and (II), respectively, contain chains of amino acid zwitterions, similar to the structure of pure glycine. In the structures of the molecular salts of amino acids, the amino acid cations form isolated dimers [of beta alanine in (III), GABA in (IV) and DL-AABA in (V)], which are linked by strong O H...O hydrogen bonds. Moreover, the three crystal structures comprise different types of dimeric cations, i.e. (A...A)+ in (III) and (V), and A+...A+ in (IV). Molecular salts (IV) and (V) are the first examples of molecular salts of GABA and DL-AABA that contain dimers of amino acid cations. The geometry of each investigated amino acid (except DL-AABA) correlates with the melting point of its mixed crystal. PMID- 29400334 TI - Structure and electrical properties of a one-dimensional polymeric silver thiosaccharinate complex with argentophilic interactions. AB - Among the potential applications of coordination polymers, electrical conductivity ranks high in technological interest. We report the synthesis, crystal structure and spectroscopic analysis of an AgI-thiosaccharinate one dimensional coordination polymer {systematic name: catena-poly[[[aquatetrakis(MU3 1,1-dioxo-1,2-benzisothiazole-3-thiolato-kappa3N:S3:S3)tetrasilver(I)]-MU2-4,4' (propane-1,3-diyl)dipyridine-kappa2N:N'] dimethyl sulfoxide hemisolvate]}, {[Ag4(C7H4NO2S2)4(C13H14N2)(H2O)].0.5C2H6OS}n, with the 4,4'-(propane-1,3 diyl)dipyridine ligand acting as a spacer. A relevant feature of the structure is the presence of an unusually short Ag...Ag distance of 2.8306 (9) A, well within the range of argentophilic interactions, confirmed experimentally as such by a Raman study on the low-frequency spectrum, and corroborated theoretically by an Atoms in Molecules (AIM) analysis of the calculated electron density. Electrical conductivity measurements show that this complex can act as a semiconductor with moderate conductivity. PMID- 29400335 TI - Higher hydrates of lithium chloride, lithium bromide and lithium iodide. AB - For lithium halides, LiX (X = Cl, Br and I), hydrates with a water content of 1, 2, 3 and 5 moles of water per formula unit are known as phases in aqueous solid liquid equilibria. The crystal structures of the monohydrates of LiCl and LiBr are known, but no crystal structures have been reported so far for the higher hydrates, apart from LiI.3H2O. In this study, the crystal structures of the di- and trihydrates of lithium chloride, lithium bromide and lithium iodide, and the pentahydrates of lithium chloride and lithium bromide have been determined. In each hydrate, the lithium cation is coordinated octahedrally. The dihydrates crystallize in the NaCl.2H2O or NaI.2H2O type structure. Surprisingly, in the tri and pentahydrates of LiCl and LiBr, one water molecule per Li+ ion remains uncoordinated. For LiI.3H2O, the LiClO4.3H2O structure type was confirmed and the H-atom positions have been fixed. The hydrogen-bond networks in the various structures are discussed in detail. Contrary to the monohydrates, the structures of the higher hydrates show no disorder. PMID- 29400336 TI - Synthesis and structures of six closely related N-[3-(2-chlorobenzoyl)-5 ethylthiophen-2-yl]arylamides, together with an isolated reaction intermediate: order versus disorder, molecular conformations and hydrogen bonding in zero, one and two dimensions. AB - Six closely related N-[3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl]arylamides have been synthesized and structurally characterized, together with a representative reaction intermediate. In each of N-[3-(2-chlorobenzoyl)-5-ethylthiophen-2 yl]benzamide, C20H16ClNO2S, (I), N-[3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl]-4 phenylbenzamide, C26H20ClNO2S, (II), and 2-bromo-N-[3-(2-chlorobenzoyl)-5 ethylthiophen-2-yl]benzamide, C20H15BrClNO2S, (III), the molecules are disordered over two sets of atomic sites, with occupancies of 0.894 (8) and 0.106 (8) in (I), 0.832 (5) and 0.168 (5) in (II), and 0.7006 (12) and 0.2994 (12) in (III). In each of N-[3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl]-2-iodobenzamide, C20H15ClINO2S, (IV), and N-[3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl]-2 methoxybenzamide, C21H18ClNO3S, (V), the molecules are fully ordered, but in N-[3 (2-chlorobenzoyl)-5-ethylthiophen-2-yl]-2,6-difluorobenzamide, C20H14ClF2NO2S, (VI), which crystallizes with Z' = 2 in the space group C2/c, one of the two independent molecules is fully ordered, while the other is disordered over two sets of atomic sites having occupancies of 0.916 (3) and 0.084 (3). All of the molecules in compounds (I)-(VI) exhibit an intramolecular N-H...O hydrogen bond. The molecules of (I) and (VI) are linked by C-H...O hydrogen bonds to form finite zero-dimensional dimers, which are cyclic in (I) and acyclic in (VI), those of (III) are linked by C-H...pi(arene) hydrogen bonds to form simple chains, and those of (IV) and (V) are linked into different types of chains of rings, built in each case from a combination of C-H...O and C-H...pi(arene) hydrogen bonds. Two C-H...O hydrogen bonds link the molecules of (II) into sheets containing three types of ring. In benzotriazol-1-yl 3,4-dimethoxybenzoate, C15H13N3O4, (VII), the benzoate component is planar and makes a dihedral angle of 84.51 (6) degrees with the benzotriazole unit. Comparisons are made with related compounds. PMID- 29400337 TI - Characterization and gas adsorption of a novel three-dimensional metal-organic framework (MOF) generated from a new polydentate fluorene-bridged ligand. AB - A polydentate ligand bridged by a fluorene group, namely 9,9-bis(2-hydroxyethyl) 2,7-bis(pyridin-4-yl)fluorene (L), has been prepared under solvothermal conditions in acetonitrile. Crystals of the three-dimensional metal-organic framework (MOF) poly[[[MU3-9,9-bis(2-hydroxyethyl)-2,7-bis(pyridin-4-yl)fluorene kappa3N:N':O]bis(methanol-kappaO)(MU-sulfato-kappa2O:O')nickel(II)] methanol disolvate], {[Ni(SO4)(C27H24N2O2)(CH3OH)].2CH3OH}n, (I), were obtained by the solvothermal reaction of L and NiSO4 in methanol. The ligand L forms a two dimensional network in the crystallographic bc plane via two groups of O-H...N hydrogen bonds and neighbouring two-dimensional planes are completely parallel and stack to form a three-dimensional structure. In (I), the NiII ions are linked by sulfate ions through Ni-O bonds to form inorganic chains and these Ni containing chains are linked into a three-dimensional framework via Ni-O and Ni-N bonds involving the polydentate ligand L. With one of the hydroxy groups of L coordinating to the NiII atom, the torsion angle of the hydroxyethyl group changes from that of the uncoordinated molecule. In addition, the adsorption properties of (I) with carbon dioxide were investigated. PMID- 29400338 TI - A new CdII coordination polymer with a self-penetrating architecture induced by the molecular conformation of a rigid bithiophene ligand. AB - The design and synthesis of coordination polymers with a self-penetrating architecture has attracted much interest not only due to their interesting structures but also due to their potential applications. 5,5'-Bis(pyridin-4-yl) 2,2'-bithiophene (bpbp), as a conjugated bithiophene ligand, can exhibit trans and cis conformations and this can lead to the construction of a self-penetrating architecture. In addition, the semi-rigid ancillary ligand 4,4'-oxybis(benzoic acid) (H2oba) can adopt different coordination modes, resulting in coordination polymers with high-dimensional skeletons. A new CdII coordination polymer based on mixed ligands, namely poly[diaquapentakis[MU-5,5'-bis(pyridin-4-yl)-2,2' bithiophene-kappa2N:N']bis(nitrato-kappa2O,O')tetrakis(MU3-4,4'-oxydibenzoato) kappa10O:O,O':O'',O''';kappa6O:O':O''-pentacadmium(II)], [Cd5(C14H14O5)4(NO3)2(C18H12N2S2)5(H2O)2]n, (I), has been synthesized under solvothermal conditions and characterized by single-crystal X-ray diffraction, IR spectroscopy and elemental analysis. Single-crystal X-ray diffraction indicates that there are three crystallographically independent CdII cations, three bpbp ligands, two deprotonated oba2- ligands, one nitrate ligand and one coordinated water molecule in the asymmetric unit. One CdII centre is seven-coordinated, exhibiting a distorted {CdN2O5} pentagonal bipyramidal geometry, while the other two Cd centres are both six-coordinated, showing slightly distorted {CdN2O4} octahedral geometries. The most interesting feature is the co-existence of trans and cis conformations in a single net, allowing structural interpenetration via self-threading and yet the expected self-penetrating structure was obtained. Topological analysis shows that the whole three-dimensional framework can be classified as a 3-nodal (4,6,6)-c net with Schlafli symbol {613.82}2{66}, which is a new topology. Furthermore, the luminescence properties of (I) were examined in the solid state at room temperature. PMID- 29400339 TI - Crystal and electronic structure of a hexacarbonyldiiron cluster tethered to naphthalene-2-thiolate ligands. AB - The structure of the previously reported complex bis(MU-naphthalene-2-thiolato kappa2S:S)bis(tricarbonyliron)(Fe-Fe), [Fe2(C10H7S)2(CO)6], has been characterized by X-ray diffraction. In the solid state, the dinuclear complex adopts a butterfly-like shape, with an equatorial-axial spatial orientation of the naphthalene groups covalently coupled to the [S2Fe2(CO)6] unit. The asymmetric unit contains three independent [(MU-naphthalene-2-thiolato)2Fe2(CO)6] molecules. These molecules show intermolecular pi-pi stacking interactions between the naphthalene rings, which was confirmed by Hirshfield surface analysis. The electronic spectrum of the complex recorded in acetonitrile shows a band centered at 350 nm (E = 4.6 * 103 M-1 cm-1) and tailing into the visible region. This absorption can be attributed to a pi->pi* electronic transition within the naphthalene moiety and a metal-based d->d transition. PMID- 29400340 TI - High-temperature monoclinic alpha-SrHfF6, and isostructural alpha-SrZrF6: associating Hf2F12 bipolyhedra and SrF8 snub disphenoids. AB - The structure of the high-temperature monoclinic variety alpha-SrHfF6 (strontium hafnium hexafluoride) [and of isostructural alpha-SrZrF6 (strontium zirconium hexafluoride)] associates Hf2F12 bipolyhedra and SrF8 snub disphenoids, forming zigzag twisted [SrF6]n layers. The distribution of the Hf and Sr polyhedra forms a three-dimensional framework which can be related to the family of anion-excess ReO3-related superstructures. alpha-SrHfF6 corresponds to a new ABX6 type and is compared to the other main families already described. A partial amorphization of this structure is observed in samples quenched from the melt. PMID- 29400341 TI - Promising solid electrolyte material for an IT-SOFC: crystal structure of the cerium gadolinium holmium oxide Ce0.8Gd0.1Ho0.1O1.9 between 295 and 1023 K. AB - The crystal structure of Ce0.8Gd0.1Ho0.1O1.9 (cerium gadolinium holmium oxide) has been determined from powder X-ray diffraction data. This is a promising material for application as a solid electrolyte for intermediate-temperature solid oxide fuel cells (IT-SOFCs). Nanoparticles were prepared using a novel sodium alginate sol-gel method, where the sodium ion was exchanged with ions of interest and, after washing, the gel was calcined at 723 K in air. The crystallographic features of Gd and Ho co-doped cerium oxide were investigated around the desired operating temperatures of IT-SOFCs, i.e. 573 <= T <= 1023 K. We find that the crystal structure is a stable fluorite structure with the space group Fm-3m in the entire temperature range. In addition, the trend in lattice parameters shows that there is a monotonic increase with increasing temperature. PMID- 29400342 TI - Two novel alkaline earth coordination polymers constructed from cinnamic acid and 1,10-phenanthroline: synthesis and structural and thermal properties. AB - In coordination chemistry and crystal engineering, many factors influence the construction of coordination polymers and the final frameworks depend greatly on the organic ligands used. The diverse coordination modes of N-donor ligands have been employed to assemble metal-organic frameworks. Carboxylic acid ligands can deprotonate completely or partially when bonding to metal ions and can also act as donors or acceptors of hydrogen bonds; they are thus good candidates for the construction of supramolecular architectures. We synthesized under reflux or hydrothermal conditions two new alkaline earth(II) complexes, namely poly[(1,10 phenanthroline-kappa2N,N')bis(MU-3-phenylprop-2-enoato-kappa3O,O':O)calcium(II)], [Ca(C10H7O2)2(C10H8N2)]n, (1), and poly[(1,10-phenanthroline-kappa2N,N')(MU3-3 phenylprop-2-enoato-kappa4O:O,O':O')(MU-3-phenylprop-2-enoato kappa3O,O':O)barium(II)], [Ba(C10H7O2)2(C10H8N2)]n, (2), and characterized them by FT-IR and UV-Vis spectroscopies, thermogravimetric analysis (TGA) and single crystal X-ray diffraction analysis, as well as by powder X-ray diffraction (PXRD) analysis. Complex (1) features a chain topology of type 2,4 C4, where the Ca atoms are connected by O and N atoms, forming a distorted bicapped trigonal prismatic geometry. Complex (2) displays chains of topology type 2,3,5 C4, where the Ba atom is nine-coordinated by seven O atoms of bridging/chelating carboxylate groups from two cinnamate ligands and by two N atoms from one phenanthroline ligand, forming a distorted tricapped prismatic arrangement. Weak C-H...O hydrogen bonds and pi-pi stacking interactions between phenanthroline ligands are responsible to the formation of a supramolecular three-dimensional network. The thermal decompositions of (1) and (2) in the temperature range 297 1173 K revealed that they both decompose in three steps and transform to the corresponding metal oxide. PMID- 29400345 TI - Proper use of history. PMID- 29400343 TI - Inhibition of Siah2 Ubiquitin Ligase by Vitamin K3 Attenuates Chronic Myeloid Leukemia Chemo-Resistance in Hypoxic Microenvironment. AB - BACKGROUND A hypoxic microenvironment is associated with resistance to tyrosine kinase inhibitors (TKIs) and a poor prognosis in chronic myeloid leukemia (CML). The E3 ubiquitin ligase Siah2 plays a vital role in the regulation of hypoxia response, as well as in leukemogenesis. However, the role of Siah2 in CML resistance is unclear, and it is unknown whether vitaminK3 (a Siah2 inhibitor) can improve the chemo-sensitivity of CML cells in a hypoxic microenvironment. MATERIAL AND METHODS The expression of Siah2 was detected in CML patients (CML-CP and CML-BC), K562 cells, and K562-imatinib-resistant cells (K562-R cells). We measured the expression of PHD3, HIF-1alpha, and VEGF in both cell lines under normoxia and hypoxic conditions, and the degree of leukemic sensitivity to imatinib and VitaminK3 were evaluated. RESULTS Siah2 was overexpressed in CML-BC patients (n=9) as compared to CML-CP patients (n=13). Similarly, K562-imatinib resistant cells (K562-R cells) showed a significantly higher expression of Siah2 as compared to K562 cells in a hypoxic microenvironment. Compared to normoxia, under hypoxic conditions, both cell lines had lower PHD3, higher HIF-1alpha, and higher VEGF expression. Additionally, Vitamin K3 (an inhibitor of Siah2) reversed these changes and promoted a higher degree of leukemic sensitivity to imatinib. CONCLUSIONS Our findings indicate that the Siah2-PHD3- HIF-1alpha-VEGF axis is an important hypoxic signaling pathway in a leukemic microenvironment. An inhibitor of Siah2, combined with TKIs, might be a promising therapy for relapsing and refractory CML patients. PMID- 29400344 TI - Modular approach for single docking robotic colorectal surgery. PMID- 29400346 TI - Unusual Stability of Anabaena Sensory Rhodopsin Transducer from Anabaena PCC7120. AB - Advances in biotechnology generated wide range of microbial genome and their related protein database. Freshwater cyanobacterium Anabaena PCC7120 sensory rhodopsin, ASR in contrast to classical haloarchaeal sensory rhodopsins interacts with putative soluble transducer, ASRT. The 125 amino acid transducer exists as a soluble protein and is involved in photoreceptor binding. Recombinant DNA tools in biotechnology conventionally support the use of affinity tags for ease of protein purification and subsequent studies. The ASRT exists as a stable tetramer. Both X-ray crystal structure and solution NMR results with ASRT utilizing hexa-histidine affinity tag reveal it as a primarily beta-stranded protein We have observed that the affinity tagged ASRT exhibits altered oligomeric stability. In this communication we outlined the effect of commonly used denaturant, Sodium Dodecyl Sulfate (SDS) on the tetrameric packing of ASRT. Our results support that N-terminus hexa-histidine tagged ASRT displayed unusual SDS-resistant structure. The unusual stability of ASRT and its homologues present in other microbial population could provide further insight towards their role in receptor, other ligand binding and signaling. PMID- 29400348 TI - Creative construction: crafting, negotiating and performing urban food sharing landscapes. AB - Activities utilising online tools are an increasingly visible part of our everyday lives, providing new subjects, objects and relationships - essentially new landscapes - for research, as well as new conceptual and methodological challenges for researchers. In parallel, calls for collaborative interdisciplinary, even transdisciplinary, research are increasing. Yet practical guidance and critical reflection on the challenges and opportunities of conducting collaborative research online, particularly in emergent areas, is limited. In response, this paper details what we term the 'creative construction' involved in a collaborative project building an exploratory database of more than 4000 food sharing activities in 100 cities that utilise internet and digital technologies in some way (ICT mediated for brevity) to pursue their goals. The research was undertaken by an international team of researchers, including geographers, which utilised a combination of reflexive coding and online collaboration to develop a system for exploring the practice and performance of ICT-mediated food sharing in cities. This paper will unpack the black box of using the internet as a source of data about emergent practices and provide critical reflection on that highly negotiated and essentially handcrafted process. While the substance of the paper focuses on the under-determined realm of food sharing, a site where it is claimed that ICT is transforming practices, the issues raised have resonance far beyond the specificities of this particular endeavour. While challenging, we argue that handcrafting systems for navigating emergent online data is vital, not least to render visible the complexities and contestations around definition, categorisation and translation. PMID- 29400349 TI - The emotional challenges of conducting in-depth research into significant health issues in health geography: reflections on emotional labour, fieldwork and life course. AB - Emotions are increasingly being recognised and integrated into human geography and it has been highlighted that focusing on the 'interrelatedness' of the research process is crucial. By contextualising fieldwork within the life course of the researcher, greater acknowledgement of the 'emotional labour' involved in fieldwork can be highlighted. The author reflects on the 'emotional geographies' of conducting PhD research into significant health issues with participants who had recently suffered a heart attack in Fife, Scotland. This paper reveals emotions involved in this kind of research, drawing on perspectives from participants as well as the researcher. The author also draws attention to, and reflects on, the lack of engagement with researcher's emotional labour within formal academic structures, such as research training and ethics application processes. Reflecting on fieldwork experiences from a distance, the author discusses the influence and impact of her emotional experiences of fieldwork. This paper contributes to work concerned with emotions and fieldwork in geography and asserts that greater importance and value needs to be given to this type of emotion work as embedded and situated within researchers' life courses. PMID- 29400347 TI - Effects of early trauma on psychosis development in clinical high-risk individuals and stability of trauma assessment across studies: a review. AB - Early trauma (ET), though broadly and inconsistently defined, has been repeatedly linked to numerous psychological disturbances, including various developmental stages of psychotic disorders. The prodromal phase of psychosis highlights a unique and relevant population that provides insight into the critical periods of psychosis development. As such, a relatively recent research focus on individuals at clinical high risk (CHR) for psychosis reveals robust associations of early life trauma exposures with prodromal symptoms and function in these cohorts. While prevalence rates of ET in CHR cohorts remain consistently high, methodological measures of traumatic experiences vary across studies, presenting potential problems for reliability and validity of results. This review aims to 1) highlight the existing evidence identifying associations of ET, of multiple forms, with both symptom severity and transition rates to psychosis in CHR individuals, 2) present data on the variability among trauma assessments and its implications for conclusions about its relationship with clinical variables, 3) describe cognitive deficits common in CHR cohorts, including perceptual and neurocognitive impairments, and their neural correlates, that may modify the relationship of ET to symptoms, and 4) propose future directions for standardization of trauma assessment in CHR cohorts to better understand its clinical and cognitive correlates. PMID- 29400350 TI - Institutional pioneers in world politics: Regional institution building and the influence of the European Union. AB - What drives processes of institution building within regional international organizations? We challenge those established theories of regionalism, and of institutionalized cooperation more broadly, that treat different organizations as independent phenomena whose evolution is conditioned primarily by internal causal factors. Developing the basic premise of 'diffusion theory' - meaning that decision-making is interdependent across organizations - we argue that institutional pioneers, and specifically the European Union, shape regional institution-building processes in a number of discernible ways. We then hypothesize two pathways - active and passive - of European Union influence, and stipulate an endogenous capacity for institutional change as a key scope condition for their operation. Drawing on a new and original data set on the institutional design of 34 regional international organizations in the period from 1950 to 2010, the article finds that: (1) both the intensity of a regional international organization's structured interaction with the European Union (active influence) and the European Union's own level of delegation (passive influence) are associated with higher levels of delegation within other regional international organizations; (2) passive European Union influence exerts a larger overall substantive effect than active European Union influence does; and (3) these effects are strongest among those regional international organizations that are based on founding contracts containing open-ended commitments. These findings indicate that the creation and subsequent institutional evolution of the European Union has made a difference to the evolution of institutions in regional international organizations elsewhere, thereby suggesting that existing theories of regionalism are insufficiently able to account for processes of institution building in such contexts. PMID- 29400351 TI - 3-D Imaging of Mars' Polar Ice Caps Using Orbital Radar Data. AB - Since its arrival in early 2006, various instruments aboard NASA's Mars Reconnaissance Orbiter (MRO) have been collecting a variety of scientific and engineering data from orbit around Mars. Among these is the SHAllow RADar (SHARAD) instrument, supplied by Agenzia Spaziale Italiana (ASI) and designed for subsurface sounding in the 15-25 MHz frequency band. As of this writing, MRO has completed over 46,000 nearly polar orbits of Mars, 30% of which have included active SHARAD data collection. By 2009, a sufficient density of SHARAD coverage had been obtained over the polar regions to support 3-D processing and analysis of the data. Using tools and techniques commonly employed in terrestrial seismic data processing, we have processed subsets of the resulting collection of SHARAD observations covering the north and south polar regions as SHARAD 3-D volumes, imaging the interiors of the north and south polar ice caps known, respectively, as Planum Boreum and Planum Australe. After overcoming a series of challenges revealed during the 3-D processing and analysis, a completed Planum Boreum 3-D volume is currently being used for scientific research. Lessons learned in the northern work fed forward into our 3-D processing and analysis of the Planum Australe 3-D volume, currently under way. We discuss our experiences with these projects and present results and scientific insights stemming from these efforts. PMID- 29400352 TI - On absence and abundance: biography as method in archival research. AB - Geographical scholarship has rightly problematised the act of archival research, showing how the practice of archiving is not only concerned with how a society collectively remembers, but also forgets. As such, the dominant motif for discussing historical methods in geography has been through the lens of absence: the archive is a space of 'traces', 'fragments' and 'ghosts'. In this paper I suggest that the focus on incompleteness and partiality, while true, may also belie what many geographers working in archives find their greatest difficulty: an overwhelming volume of source materials. I reflect on my own research experiences in the pacifist archive to suggest that the growing scale and scope of many collections, along with the taxing research demands of transnational perspectives, pose immediate practical challenges for geographers characterised as much by abundance as by absence. In the second half of the paper, drawing on recent scholarship in history and geography, I argue that the method of biography offers one possible strategy for navigating archival abundance, allowing geographers to tell stories that are wider, deeper and more revealingly complex within the existing time and financial constraints of humanities research. PMID- 29400353 TI - Heritage of the late Professor Tsuguo Naruke. PMID- 29400354 TI - Computational Nosology and Precision Psychiatry. AB - This article provides an illustrative treatment of psychiatric morbidity that offers an alternative to the standard nosological model in psychiatry. It considers what would happen if we treated diagnostic categories not as causes of signs and symptoms, but as diagnostic consequences of psychopathology and pathophysiology. This reformulation (of the standard nosological model) opens the door to a more natural description of how patients present-and of their likely responses to therapeutic interventions. In brief, we describe a model that generates symptoms, signs, and diagnostic outcomes from latent psychopathological states. In turn, psychopathology is caused by pathophysiological processes that are perturbed by (etiological) causes such as predisposing factors, life events, and therapeutic interventions. The key advantages of this nosological formulation include (i) the formal integration of diagnostic (e.g., DSM) categories and latent psychopathological constructs (e.g., the dimensions of the Research Domain Criteria); (ii) the provision of a hypothesis or model space that accommodates formal, evidence-based hypothesis testing (using Bayesian model comparison); and (iii) the ability to predict therapeutic responses (using a posterior predictive density), as in precision medicine. These and other advantages are largely promissory at present: The purpose of this article is to show what might be possible, through the use of idealized simulations. PMID- 29400355 TI - EPA Leadership on Science, Innovation, and Decision Support Tools for Addressing Current and Future Challenges. AB - When the U.S. Environmental Protection Agency (EPA) was established nearly 50 years ago, the nation faced serious threats to its air, land, and water, which in turn impacted human health. These threats were effectively addressed by the creation of EPA (in 1970) and many subsequent landmark environmental legislations which in turn significantly reduced threats to the Nation's environment and public health. A key element of historic legislation is research aimed at dealing with current and future problems. Today we face national and global challenges that go beyond classic media-specific (air, land, water) environmental legislation and require an integrated paradigm of action and engagement based on (1) innovation based on science and technology, (2) stakeholder engagement and collaboration, and (3) public education and support. This three-pronged approach recognizes that current environmental problems, include social as well as physical and environmental factors, are best addressed through collaborative problem solving, the application of innovation in science and technology, and multiple stakeholder engagement. To achieve that goal, EPA's Office of Research and Development (ORD) is working directly with states and local communities to develop and apply a suite of accessible decision support tools (DST) that aim to improve environmental conditions, protect human health, enhance economic opportunity, and advance a resilient and sustainability society. This paper showcases joint EPA and state actions to develop tools and approaches that not only meet current environmental and public health challenges, but do so in a way that advances sustainable, healthy, and resilient communities well into the future. EPA's future plans should build on current work but aim to effectively respond to growing external pressures. Growing pressures from megatrends are a major challenge for the new Administration and for cities and states across the country. The recent hurricanes hitting Texas and the Gulf Coast, part of the increase in extreme weather events, make it clear that building resilient infrastructure is a crucial step to sustainability. PMID- 29400356 TI - Coherent optical adaptive technique improves the spatial resolution of STED microscopy in thick samples. AB - Stimulated emission depletion microscopy (STED) is one of far-field optical microscopy techniques that can provide sub-diffraction spatial resolution. The spatial resolution of the STED microscopy is determined by the specially engineered beam profile of the depletion beam and its power. However, the beam profile of the depletion beam may be distorted due to aberrations of optical systems and inhomogeneity of specimens' optical properties, resulting in a compromised spatial resolution. The situation gets deteriorated when thick samples are imaged. In the worst case, the sever distortion of the depletion beam profile may cause complete loss of the super resolution effect no matter how much depletion power is applied to specimens. Previously several adaptive optics approaches have been explored to compensate aberrations of systems and specimens. However, it is hard to correct the complicated high-order optical aberrations of specimens. In this report, we demonstrate that the complicated distorted wavefront from a thick phantom sample can be measured by using the coherent optical adaptive technique (COAT). The full correction can effectively maintain and improve the spatial resolution in imaging thick samples. PMID- 29400357 TI - Large-scale DCMs for resting-state fMRI. AB - This paper considers the identification of large directed graphs for resting state brain networks based on biophysical models of distributed neuronal activity, that is, effective connectivity. This identification can be contrasted with functional connectivity methods based on symmetric correlations that are ubiquitous in resting-state functional MRI (fMRI). We use spectral dynamic causal modeling (DCM) to invert large graphs comprising dozens of nodes or regions. The ensuing graphs are directed and weighted, hence providing a neurobiologically plausible characterization of connectivity in terms of excitatory and inhibitory coupling. Furthermore, we show that the use of to discover the most likely sparse graph (or model) from a parent (e.g., fully connected) graph eschews the arbitrary thresholding often applied to large symmetric (functional connectivity) graphs. Using empirical fMRI data, we show that spectral DCM furnishes connectivity estimates on large graphs that correlate strongly with the estimates provided by stochastic DCM. Furthermore, we increase the efficiency of model inversion using functional connectivity modes to place prior constraints on effective connectivity. In other words, we use a small number of modes to finesse the potentially redundant parameterization of large DCMs. We show that spectral DCM-with functional connectivity priors-is ideally suited for directed graph theoretic analyses of resting-state fMRI. We envision that directed graphs will prove useful in understanding the psychopathology and pathophysiology of neurodegenerative and neurodevelopmental disorders. We will demonstrate the utility of large directed graphs in clinical populations in subsequent reports, using the procedures described in this paper. PMID- 29400359 TI - Ecological restoration should be redefined for the twenty-first century. AB - Forty years ago, ecological restoration was conceptualized through a natural science lens. Today, ecological restoration has evolved into a social and scientific concept. The duality of ecological restoration is acknowledged in guidance documents on the subject but is not apparent in its definition. Current definitions reflect our views about what ecological restoration does but not why we do it. This viewpoint does not give appropriate credit to contributions from social sciences, nor does it provide compelling goals for people with different motivating rationales to engage in or support restoration. In this study, I give a concise history of the conceptualization and definition of ecological restoration, and I propose an alternative definition and corresponding viewpoint on restoration goal-setting to meet twenty-first century scientific and public inquiry. PMID- 29400360 TI - Ultrasound applications for regional anaesthetists - thinking outside the box. AB - . PMID- 29400358 TI - Learning and Choice in Mood Disorders: Searching for the Computational Parameters of Anhedonia. AB - Computational approaches are increasingly being used to model behavioral and neural processes in mood and anxiety disorders. Here we explore the extent to which the parameters of popular learning and decision-making models are implicated in anhedonic symptoms of major depression. We first highlight the parameters of reinforcement learning that have been implicated in anhedonia, focusing, in particular, on the role that choice variability (i.e., "temperature") may play in explaining heterogeneity across previous findings. We then turn to neuroimaging findings implicating attenuated ventral striatum response in anhedonic responses and discuss possible causes of the heterogeneity in the literature. Taken together, the reviewed findings highlight the potential of the computational approach in teasing apart the observed heterogeneity in both behavioral and functional imaging results. Nevertheless, considerable challenges remain, and we conclude with five unresolved questions that seek to address issues highlighted by the reviewed data. PMID- 29400361 TI - Greyscale and contrast enhanced ultrasonography for characterization of gastric malignant tumors. AB - AIMS: To evaluate the utility of grey scale ultrasonography (US) and contrast enhanced ultrasonography (CEUS) for characterization of malignant gastric tumors. MATERIAL AND METHODS: The study was conducted prospectively and it included a number of 30 patients with malignant gastric tumors diagnosed through upper tract endoscopy and biopsy: 25 adenocarcinomas, 3 lymphomas, and 2 stromal tumors. All the patients were examined by US, followed immediately by CEUS, using both oral and intravenous contrast agents. CEUS assessed the dynamics of the contrast agent during the arterial phase and the venous phase. The distribution characteristics of the contrast agent inside the region of interest (ROI) were also evaluated. Twenty four patients underwent surgery. RESULTS: Adenocarcinomas presented heterogeneous enhancement with variable pattern, followed by a delayed wash-out in almost all of the situations. Lymphomas presented a variable pattern, intensity and homogeneity of the enhancement, followed by delayed wash-out. Stromal tumors showed early arterial intense and homogenous enhancement followed by moderate wash-out in venous phase. CONCLUSIONS: Grey scale US and CEUS are useful methods in characterizing gastric tumors and contribute to a more adequate evaluation of the lesions. The dynamics of the contrast agent may be suggestive for the anatomopathological nature of the tumor. Larger studies will be necessary in order to determine thepractical value of the method. PMID- 29400362 TI - Motion effects on the measurement of stiffness on ultrasound shear wave elastography: a moving liver fibrosis phantom study. AB - AIMS: To evaluate the differences between shear wave velocities (SWVs) measured with ultrasound elastography during the continuous motion using liver fibrosis phantoms. MATERIALS AND METHODS: Elasticities were measured with convex and linear transducers of supersonic shear wave imaging (SSI) and acoustic radiation force impulse imaging (ARFI) using liver elasticity phantoms (3.0 and 16.9 kPa) at depths of 2, 3, 4, and 5 cm. Motion velocities were 30 and 60 rpm with the phantoms in an upright position on the Orbital shaker. To simulate different directional motion, the phantoms were laid on their side on the shaker. The values between moving and static status were compared, and the number of measurement failure was counted. Results: In SSI, the convex transducer was less affected by motion at 30 rpm with the 3 kPa phantom. In the higher velocity motion and in the higher stiffness phantom, most values from SSI were different comparing with static status, and there was a tendency for elasticity values to increase during movement. In ARFI, there were frequent measurement failures without stable results during the motion. CONCLUSIONS: Motion affected the measurement of elasticity differently in SSI and ARFI, according to the velocity, direction of the motion, and phantom stiffness. The convex transducer of SSI was less affected by motion in lower velocity motion and when using normal liver stiffness phantom. PMID- 29400363 TI - Value of Shear Wave Elastography for differentiating benign and malignant renal lesions. AB - AIMS: To investigate the diagnostic accuracy of shear-wave elastography (SWE) for assessing malignant and benign kidneymasses. MATERIALS AND METHODS: Forty patients with solid renal masses underwent US elastographic evaluation. SWE values of the lesions and adjacent cortical renal parenchyma and SWER were detected prospectively. Malignant tumors were recorded as group 1 and benign tumors were recorded as group 2. RESULTS: The highest elasticity values were 27.27+/-25.66 kPa for group 1 and 16.13+/-8.89 kPa for group 2. The mean+/-SD elasticity values for adjacent renal cortex for groups 1 and 2 were 2.7+/-2.08 and 2.75+/-1.35, respectively. For group 1, a negative correlation was observed between the age of the patients and SWER value (p=0.047, rs=-0.401). There was also a negative correlation between the SWER value and the SWE value of adjacent renal cortex (p=0.004, rs=-0.555). CONCLUSION: SWE is a noninvasive method that provides quantitative elasticity informationon tissues. Overlaps among different types of renal lesions may be due to heterogeneity of the lesions. Larger studygroups may clarify the other factors affecting SWE values under both normal and pathological conditions. PMID- 29400364 TI - Is there a correlation between kidney shear wave velocity measured with VTQ and histological parameters in patients with chronic glomerulonephritis? A pilot study. AB - AIM: To analyze the relationship between shear wave velocity in the kidney measured by point shear wave elastography using Virtual Touch Quantification (VTQ) (Siemens Acuson S2000) and histological parameters obtained from renal biopsies, in patients with chronic glomerulonephritis (CGN). MATERIAL AND METHODS: The study group included 20 patients (mean age 47.95+/-13.59 years) with different types of CGN, that had underwent renal biopsy and 57 normal controls (mean age 38.07+/-17.32 years). In all patients, five valid stiffness measurements were obtained in each kidney, with the patient in lateral decubitus. Regarding the histological results, we assessed the presence or absence of glomerulosclerosis, interstitial fibrosis, and arteriolo-hyalinosis. RESULTS: In patients with CGN we obtained the following mean values of VTQ values: right kidney: 2.12+/-0.81 m/s, left kidney 1.65+/-0.54 m/s, while in the normal controls significantly higher VTQ values were obtained: right kidney 2.69+/-0.72 m/s (p=0.004), left kidney 2.48+/-0.73 m/s (p<0.0001). In patients with CGN no statistically significant correlations between VTQ values and eGFR (r=0.37, p=0.12) or proteinuria (r=0.2, p=0.37) were found. We found significantly lower VTQ values in patients with interstitial fibrosis (1.46 vs. 1.99 m/s, p<0.05) and also in patients with arteriolo-hyalinosis (1.55 vs. 2.47 m/s, p<0.05). CONCLUSION: Our pilot study shows that shear wave velocity values in patients with CGN are significantly lower compared to normal controls, and there is a tendency to decrease with the decrease of eGFR, with the presence of interstitial fibrosis and of arteriolo-hyalinosis. PMID- 29400366 TI - Correlation between Contrast-Enhanced Ultrasound and Microvessel Density via CD31 and CD34 in a rabbit VX2 lung peripheral tumor model. AB - AIM: To evaluate the tumor angiogenesis in lung peripheral VX2 tumor model by contrast-enhanced ultrasound (CEUS) and to determine the correlation between CEUS parameters and microvessel density (MVD) calculated via CD31 and CD34 expression. MATERIAL AND METHODS: VX2 pulmonary tumors were created in eight Japanese white rabbits by implanting a VX2 sarcoma into the lower portion of the right lung through ultrasound guidance. Tumors were allowed to grow for 14-21 days to achieve a diameter of 7-15 mm, and were examined by CEUS using a SonoVue contrast agent. The results were recorded as digital video images, and the time-intensity curves and hemodynamic parameters were analyzed. Pathological tumor specimens were immediately obtained after the ultrasound examinations. Tumor specimens were stained with hematoxylin and eosin (H&E) and expressed as CD31 and CD34. The different endothelial cell markers were determined by immunohistochemical staining. MVD was calculated via CD 31 and CD34, and the relationship between CEUS parameters and MVD was analyzed. RESULTS: Two distinct types of microvessels were identified in lung peripheral VX2 tumors: differentiated (CD34+) and undifferentiated (CD31+) vessels. A significant correlation was found between CEUS parameters and undifferentiated MVD (CD31+ vessels) in lung peripheral VX2 tumors (p<0.05). A reverse correlation was observed between different MVDs. CONCLUSIONS: Two different degrees of differentiation of vascular endothelial cells (CD31 and CD34) exist in the rabbit lung peripheral VX2 tumor model. CD31 MVD can more effectively evaluate tumor angiogenesis compared with CD34 MVD. CEUS, as a non-invasive imaging method, can effectively evaluate tumor angiogenesis in rabbit peripheral lung cancer. PMID- 29400365 TI - Sensitivity and specificity of ultrasound for the diagnosis of acute pulmonary edema: a systematic review and meta-analysis. AB - AIMS: This study aimed to determine the sensitivity and specificity of ultrasound for the diagnosis of acute pulmonary edema by meta-analysis. MATERIALS AND METHODS: A systematic search was conducted through the following databases: Cochrane, PubMed, EMBASE and Ovid MEDLINE. Prospective cohort and prospective case-control studies that reported sensitivity and specificity of lung ultrasound in diagnosis of acute pulmonary edema were selected. An independent review of citations was carried out for inclusion and data extraction. Quality assessment was conducted using the QUADAS-2 tool. Sensitivity and specificity were taken from the studied articles and then calculated with the contingency tables. A total of 984 articles were identified but only eight studies (1301 patients) were included in this meta-analysis. One study was a case-control study and seven studies were prospective cohort study. RESULTS: The overall sensitivity of ultrasound for the diagnosis of acute pulmonary edema is 97% (95% CI: 96%-98%) and the overall specificity was 98% (95% CI: 97%-99%). CONCLUSION: The diagnostic test accuracy suggests that lung ultrasound using B-lines is a useful and reliable diagnostic tool for critically illpatients with acute pulmonary edema. PMID- 29400367 TI - Benefit of Shear-wave Elastography in the differential diagnosis of breast lesion: a diagnostic meta-analysis. AB - AIMS: The purpose of this diagnostic meta-analysis was to explore the benefit of shear wave elastography (SWE) combinedly used with conventional ultrasound (US) in the diagnosis of the benign and malignant breast lesion. MATERIAL AND METHODS: After a literature search on MEDLINE, Cochrane library, and Embase we included 14 studies with a total 1951 patients and 2060 breast lesions for further analyses. Summary descriptive statistics such as pooled sensitivity, specificity, and summary receiver operating characteristics curve were generated via a bivariate random effect model. Summary indicators such as area under curve (AUC) and confident region were used to compare the performance of conventional US and combination of conventional US and shear wave imaging (SWI) or two-dimensional and three-dimensional SWI. RESULTS: As indicated by the results, the pooled sensitivity, specificity, and diagnostic odds ratio for combined usage of SWE and the conventional US were 0.877 (95%CI: 0.855-0.896) and 0.849 (95%CI: 0.826 0.869) and 40.164 (95%CI:31.135- 51.811). The AUC for combined use and the conventional US only were 0.928 and 0.899, suggesting a promise of integrating SWE in the routine of breast lesion examination. Also, the summary AUC for 2D and 3D SWE were 0.917 and 0.952 respectively. No significant difference was found between 2D and 3D SWE. No obvious publication bias was identified after employing Deeks' regression test for asymmetry. CONCLUSION: Our analysis concluded that SWE improved the differential diagnosis of the breast lesion. PMID- 29400368 TI - Ultrasound-guided biopsy of osteolytic metastasis - could be less than three cores enough? AB - AIMS: The purpose of this study was to analyze the diagnostic yield and accuracy of the ultrasound (US) guided core biopsy in a population of patients with osteolytic metastasis. MATERIALS AND METHODS: We performed a retrospective analysis of 16 consecutive cases of US-guided core biopsies of osteolytic lesions performed in our Ultrasound Unit, from January 2006 to May 2017. We used 18G or 16G Tru-cut needles coupled with automated biopsy guns. We procured a maximum number of two tissue specimens per patient. RESULTS: We obtained a diagnostic yield and accuracy of 93.75% (15 of 16 patients) for US-guided core biopsy of osteolytic metastasis. Most of our cases were metastasis of adenocarcinomas (8 patients), squamous cell carcinomas (3 patients) followed by multiple myelomas (2 patients). Other pathologic lesions recorded were undifferentiated carcinoma (1 patient) and mesenchimal undifferentiated tumor (1 patient). The pathologic result was inconclusive in one patient. CONCLUSIONS: Our study supports the important diagnostic role of US-guided core biopsy for osteolytic bone metastasis. Two US-guided passages may be sufficient to procure a diagnostic tissue samples from osteolytic bone metastasis, if theirlength is at least 10 mm. PMID- 29400369 TI - Correlation between protein YKL-40 and ultrasonographic findings in active knee osteoarthritis. AB - : The aim of our study was to analyze the level of the glycoprotein YKL-40 in patients with active knee osteoarthritis (OA) and to search possible correlations with local inflammation and ultrasound (US) findings. MATERIAL AND METHODS: A prospective study with fifty consecutive patients with active knee OA (diagnosed based on the American College of Rheumatology criteria for OA with radiographic confirmation) was performed. Concentrations of YKL-40 in serum and synovial fluid were measured by ELISA. US examinations - Gray scale (GS) US and Power Doppler (PD) US - of the knee was performed according to international guidelines. The suprapatellar, medial and lateral parapatellar recesses were scanned in each knee to evaluate synovial hypertrophy and vascularization. RESULTS: Forty women (mean age 61.50+/-11.33 years old) and 10 men (aged 68.50+/-6.60 years old) were enrolled. We found that the synovial level of the glycoprotein (237.80+/-104.08 ng/ml) was significantly higher compared to the serum concentration (112.83+/ 60.61 ng/ml, p<0.001). The serum concentration in OA patients was higher comparing with age-matched healthy controls (84.19+/-11.39 ng/ml) (p<0.05). A statistically significant association between YKL- 40 in synovial fluid and serum levels was shown. We determined a moderately positive linear relationship between the synovial level of the glycoprotein and the serum concentration. No association between the levels of inflammatory markers - erythrocyte sedimentation rate and C-reactive protein - and YKL-40 concentrations was detected. Our study revealed a strong relationship between YKL-40 in synovial fluid and GS US and feeble with PD US. YKL-40 correlated with inflammatory activity in knee joints and neovascularization detected by US. CONCLUSIONS: YKL 40 is involved in the pathogenesis of OA synovitis. Evaluation of YKL-40 levels in parallel with US might provide more sensitive and reliable information for the diagnosis and understanding of OA. PMID- 29400370 TI - High-resolution ultrasonography in assessing temporomandibular joint disc position. AB - AIMS: The purpose of this study was to determine the diagnostic value of high resolution ultrasonography (US) in temporomandibular joint (TMJ) disc displacements. MATERIALS AND METHODS: A number of 74 patients (148 TMJs) with signs and symptoms of TMJ disorders, according to the Research Diagnostic Criteria for Temporomandibular Disorders, were included in this study. All patients received US and magnetic resonance imaging (MRI) of both TMJs 1 to 5 days after the clinical examination. MRI examinations were performed using 1.5 T MRI equipment (Siemens Avanto, Siemens, Erlangen). Ultrasonographic examination was performed on a Hitachi EUB 8500 (Hitachi Medical Corp., Tokyo, Japan) scanner with L 54 M6.5-13 MHz linear transducer. RESULTS: MRI depicted 68 (45.95%) normal joints, 47 (31.76%) with disc displacement with reduction, 33 (22.3%) with disc displacement without reduction and 34 (22.97%) with degenerative changes. US detected 78 (52.7%) normal joints, 37 (25%) with disc displacement with reduction, 33 (22.3%) with disc displacement without reduction and 21 (14.19%) with degenerative changes. Compared to MRI, US showed a sensitivity of 93.1%, specificity of 87.88%, accuracy of 90.32%, a positive predictive value of 87.1% and a negative predictive value of 93.55% for overall diagnosis of disc displacement. The Youden index was 0.81. CONCLUSIONS: Based on our results, high resolution ultrasonography showed high sensitivity, specificity and accuracy in the diagnosis of TMJ disc displacement. It could be a valuable imaging technique in assessing TMJ disc position. The diagnostic value of high-resolution ultrasonography depends strictly on the examiner's skills and on the equipment used. PMID- 29400371 TI - Effects of chronic flexed wrist posture on the elasticity and crosssectional area of the median nerve at the carpal tunnel among chronic stroke patients. AB - AIM: To investigate the effects of chronic flexed wrist posture following spasticity on the elasticity and cross-sectional area (CSA) of the median nerve at the carpal tunnel among chronic stroke patients. MATERIAL AND METHOD: This prospective study included 24 consecutive patients (mean age, 56.5+/-11.56 years) with unilateral wrist spasticity following a stroke in a chronic phase. The CSA of the median nerve was measured by ultrasound (US). The elasticity was measured by Virtual Touch tissue imaging quantification (VTIQ; Siemens, Erlangen, Germany). SWV and CSA of the median nerves of the affected and unaffected sides for each patient were compared. The correlations between duration of time since the stroke, SWV and CSA of the median nerve were assessed. The interobserver agreement was assessed. RESULTS: The CSA of the median nerve at the affected side was significantly lower than that of the unaffected side (p = 0.03). The SWV of the median nerve at the affected side was significantly higher than that on the unaffected side (p < 0.001). The interobserver agreement was excellent for both CSA and SWV measurements. There was a negatively fair correlation between CSA at the affected side and duration of time since stroke (r = -0.58, p < 0.05). The SWV of the median nerve at the affected side was not correlated with the duration of time since stroke (r <= 0.3, p >= 0.05). CONCLUSIONS: These results suggest that chronic flexed wrist posture may cause atrophy of the median nerve due to chronic compression after stroke and increase in the stiffness of the median nerve. PMID- 29400372 TI - Evaluation of the optic nerve and scleral-choroidal-retinal layer with ultrasound elastography in glaucoma and physiological optic nerve head cupping. AB - AIM: To evaluate the strain ratio of the optic nerve and retina-choroid-sclera (RCS) layers in individuals with physiological optic disc cupping (PC) and glaucoma patients using strain elastography. MATERIAL AND METHODS: We evaluated 56 eyes of 56 subjects (20 eyes with glaucoma, 19 eyes with PC, and 17 normal eyes). The strain ratio of orbital fat to optic nerve (SROFON) was calculated as the ratio of the optic nerve to intraconal fat tissue and the strain ratio of orbital fat to retina-choroid-sclera (SROFRCS) was calculated as the ratio of RCS layers to intraconal fat tissue. RESULTS: SROFON was 0.92 in the control group, 1.07 in the PC group and 1.6 in the glaucoma group and a statistically significant difference was present between the three groups (p<0.05). SROFRCS had no statistically significant difference between the three groups. CONCLUSIONS: SROFON values could contribute to the differentiation of the patients with glaucoma and PC. PMID- 29400373 TI - Diagnostic value of musculoskeletal ultrasound in patients with low back pain - a review of the literature. AB - Patients with low back pain (LBP) frequently undergo various imaging studies in the pursuit of a more precise diagnosis. Ultrasound (US) has the advantage of being a widely available, multiplanar, fast and radiation-free diagnostic tool. Moreover, compared to most of the other imaging modalities, it is particularly efficient in the visualization and assessment of soft tissues. Consequently, the question about the possible diagnostic application of US in such a common pathology as LBP is very relevant to the clinical practice. For this reason, we performed a review of the literature on the diagnostic value of US in differentconditions that could cause LBP. We hereby discuss available studies on the diagnostic application of US in spinal canal stenosis and disc herniation (probably of historical significance only), as well as in the pathology of soft tissue structures like the lumbar and pelvic ligaments, muscles and entheses, the thoracolumbar fascia and the sacroiliac joints (maybe of greater importance nowadays). The evidence for the diagnostic value of US is not equivocal, though promising for some of the causative conditions, and clearly this area remains open to further research. PMID- 29400374 TI - The role of 4D US in evaluation of fetal movements and facial expressions and their relationship with fetal neurobehaviour. AB - The introduction of four-dimensional (4D) ultrasonography (US) allows the study of fetal movements and facial expressions in real time. The possibility of evaluating fetal movements has led to the study of fetal neurobehaviour, which has been for a long period of time a mystery for physicians. The study of fetal activity in utero could differentiate between normal and abnormal behavioural patterns, thus making possible the early recognition of fetal brain impairment. Facial expressions observed with 4D US represent a marker for neurobehaviour and at the same time could enhance fetal-maternal bonding. The present review represents an update of the literature on fetal movements, facial expressions, and their relationship with fetal neurobehaviour. PMID- 29400375 TI - Breast cystic lesions: Not so simple after all? An ultrasonographic tactical approach. AB - A wide spectrum of breast diseases breast diseases have or exhibit at some point in their natural history a complex cystic aspect. Through the lens of B-mode and Doppler ultrasound with sonoelastographic augmentation, conditions ranging from the utterly benign fibrocystic change to the most intricate encysted or cystically degenerated cancerous lesions, are covered in detail in this review. The aim of this paper is to familiarize the practitioner with the ultrasonographic aspects of complex breast cystic masses and to implement a gradual, strategic approach in the diagnostic algorithm. PMID- 29400376 TI - Prenatal diagnosis of the fetal common arterial trunk. A case series. AB - Fetal common arterial trunk is an anomaly represented by a unique arterial trunk that arouses from the base of the heart, and gives birth to systemic branches, both pulmonary and coronary, frequently associated with a ventricular septal defect (VSD) and has a poor prognosis. We present a series of 17 cases diagnosed in our tertiary center with different types of fetal common arterial trunk, its associated disorders, the evolution of the pregnancies, and of the neonates. We concluded that our cases support the fact that a complete intrauterine evaluation of each case of the common arterial trunk is impossible. The postnatal prognosis of the cases from our center was fatal, similar to most reports of the literature. PMID- 29400377 TI - The added value of contemporary ultrasound technologies in the diagnosis of malignant tumours of the gastrointestinal system - a case report. AB - Ultrasound of the gastrointestinal system has become more popular among clinicians and is an important tool for evaluation and follow-up. Ultrasound has a special value in patients with Crohn's disease for the evaluation of disease activity but also for the evaluation of abdominal complications and shows comparable results to other imaging modalities. With the introduction of elastography and contrast-enhanced ultrasound into clinical routine, THE sonographic evaluation of the small bowel is even more sophisticated and even more precise. This case report summarizes all available modern ultrasound imaging technologies and highlights the possibilities in daily clinical use. PMID- 29400378 TI - The value of ultrasound diagnosis in the multidisciplinary approach of cutaneous tumours. Case report. AB - We report the case of a senior patient, presenting with two cutaneous tumours in which the clinical and dermoscopic examination pointed towards a basal cell carcinoma. Ultrasound revealed highly vascularised tumours and elastography showed increased rigidity. Histological examination of both lesions following complete resection was consistent with squamous cell carcinomas. The distinctive feature of this case consists of the complex non-invasive diagnostic imaging of the tumour morphology, performed in real time, revealing aspects compatible with highly proliferative malignant tumours. This case emphasises the importance of ultrasound diagnosis in a multi-disciplinary approach for better and more predictable results. PMID- 29400379 TI - Case report of a rare glomus jugulare tumor extended within the extracranial internal jugular vein: emphasis on initial ultrasound findings and literature review. AB - Glomus jugulare tumor (GJT) is a rare benign neoplasm that is located in the skull base; it is impossible for ultrasonography to detect it in most cases. In this article, we present the case of a rare giant GJT, which extended into the internal jugular vein in the neck, initially detected by ultrasonography and confirmed by MRI and pathology. We highlight the initial ultrasonography findings and review the literature to summarize the ultrasonographic features of GJT. PMID- 29400380 TI - Extensor pollicis longus (EPL) tendon rupture as a complication of distal radius fracture: the role of ultrasound examination. AB - . PMID- 29400381 TI - Ultrasound Guided Injection for Medial and Lateral Pterygoid Muscles: A Novel Treatment for Orofacial Pain. AB - . PMID- 29400382 TI - Ultrasound to depict anatomical abnormality: an example of potential alliance of rehabilitation professionals. AB - . PMID- 29400383 TI - Solvation dynamics in polar solvents and imidazolium ionic liquids: failure of linear response approximations. AB - This study presents the large scale computer simulations of two common fluorophores, N-methyl-6-oxyquinolinium betaine and coumarin 153, in five polar or ionic solvents. The validity of linear response approximations to calculate the time-dependent Stokes shift is evaluated in each system. In most studied systems linear response theory fails. In ionic liquids the magnitude of the overall response is largely overestimated, and linear response theory is not able to capture the individual contributions of cations and anions. In polar liquids, the timescales of solvation dynamics are often not correctly reproduced. These observations are complemented by a detailed analysis of Gaussian statistics including higher order correlation functions, variance of the energy gap distribution and its time evolution. The analysis of higher order correlation functions was found to be not suitable to predict a failure of linear response theory. Further analysis of radial distribution functions and hydrogen bonds in the ground and excited state, as well as the time evolution of the number of hydrogen bonds after solute excitation reveal an influence of solvent structure in some of the studied systems. PMID- 29400384 TI - Visible-light-induced oxidative difunctionalization of styrenes: synthesis of alpha-trifluoromethylthio-substituted ketones. AB - A novel and practical synthesis of alpha-trifluoromethylthio-substituted ketones has been accomplished through the visible-light-induced aerobic oxidation of styrenes. The protocol employs the combination of CF3SO2Na and CS2 as a new source of SCF3 radicals in the presence of eosin Y as a photoredox catalyst. PMID- 29400385 TI - New insights into the plasmonic enhancement for photocatalytic H2 production by Cu-TiO2 upon visible light illumination. AB - Cu nanoparticles were deposited on the surface of commercial TiO2 nanoparticles (Cu-TiO2) using different methods aiming at the production of highly efficient visible light photocatalysts. Photocatalytic H2 evolution rates obtained from methanol/water mixtures revealed no significant influence of the presence of copper oxides on the photoreaction upon visible light illumination. The photocatalytic H2 production rates were evaluated upon illumination with different spectral ranges (>=420 nm or >=500 nm) and the results evidenced that the visible light induced charge carrier formation on the Cu-TiO2 photocatalysts consists of two distinct pathways: the direct excitation of TiO2 and the induced excitation by the so-called surface plasmon resonance (SPR) effect of the Cu nanoparticles on the TiO2 surface. Both pathways are present when the full visible range of the spectrum is used (>=420 nm), while for illumination at longer wavelengths (>=500 nm), the photocatalytic activity is solely promoted by the Cu-SPR effect. Electron paramagnetic resonance (EPR) and laser flash photolysis measurements were performed to clarify the underlying mechanism of Cu TiO2 photocatalysts upon visible light illumination. PMID- 29400386 TI - Insight into the local near-infrared photothermal dynamics of graphene oxide functionalized polymers through optical microfibers. AB - Recently, although great attention has been paid to the design and exploitation of new classes of near-infrared (NIR) light-induced materials, the photothermal dynamics of these materials have not been fully explored. However, understanding the photothermal dynamics of NIR-light-responsive composites is of fundamental importance from the viewpoint of smart material design and processing at the nanoscale, and for the understanding of a number of related phenomena. Herein, an alternative approach to observe the dynamics of the photothermal process is developed, which relies on probing the local refractive index change in the nanocomposite matrix with a silica microfiber interferometer. In this approach, the light-induced morphological change of the polymer is captured by the microfiber because of the strong evanescent-field interaction, and is translated into a significant wavelength shift in the interferometric fringe. Therefore, probing the matrix to study the local photothermal dynamics is possible. The optical microfiber records various phase-transformation stages of the photothermal nanocomposites induced by different optothermal mechanisms, especially revealing the reconstruction process of Ag@reduced graphene oxide (Ag@G) nanosheets during the initial stage of the photothermal process. The feasibility of using optical fibers for studying the inner mechanism of material phase change is presented herein and it provides a new approach for fundamental investigations into smart material development at the nanoscales. PMID- 29400389 TI - Coiled coil protein origami: from modular design principles towards biotechnological applications. AB - The design of new protein folds represents a grand challenge for synthetic, chemical and structural biology. Due to the good understanding of the principles governing its pairing specificity, coiled coil (CC) peptide secondary structure elements can be exploited for the construction of modular protein assemblies acting as a proxy for the straightforward complementarity of DNA modules. The prerequisite for the successful translation of the modular assembly strategy pioneered by DNA nanotechnology to protein design is the availability of orthogonal building modules: a collection of peptides that assemble into CCs only with their predetermined partners. Modular CC-based protein structures can self assemble from multiple polypeptide chains whose pairing is determined by the interaction pattern of the constituent building blocks. Orthogonal CC sets can however also be used for the design of more complex coiled coil protein origami (CCPO) structures. CCPOs are based on multiple CC modules concatenated into a single polypeptide chain that folds into a polyhedral protein cage as the peptide segments assemble into CC dimers. The CCPO strategy has hitherto led to successful de novo design of protein cages in the shape of a tetrahedron, square pyramid and triangular prism. Recent advances in the design of CC modules and design principles have enabled the construction of CCPOs that self-assemble in vivo without any apparent toxicity to human cells or animals, opening the path towards therapeutic applications. The CCPO platform therefore has potential for diverse applications in biomedicine and biotechnology, from drug delivery to molecular cages. PMID- 29400390 TI - Correction: C-H and H-H activation at a di-titanium centre. AB - Correction for 'C-H and H-H activation at a di-titanium centre' by Nikolaos Tsoureas et al., Chem. Commun., 2017, 53, 13117-13120. PMID- 29400392 TI - Temperature-dependent structure and dynamics of highly-branched poly(N isopropylacrylamide) in aqueous solution. AB - Small-angle neutron scattering (SANS) and neutron spin-echo (NSE) have been used to investigate the temperature-dependent solution behaviour of highly-branched poly(N-isopropylacrylamide) (HB-PNIPAM). SANS experiments have shown that water is a good solvent for both HB-PNIPAM and a linear PNIPAM control at low temperatures where the small angle scattering is described by a single correlation length model. Increasing the temperature leads to a gradual collapse of HB-PNIPAM until above the lower critical solution temperature (LCST), at which point aggregation occurs, forming disperse spherical particles of up to 60 nm in diameter, independent of the degree of branching. However, SANS from linear PNIPAM above the LCST is described by a model that combines particulate structure and a contribution from solvated chains. NSE was used to study the internal and translational solution dynamics of HB-PNIPAM chains below the LCST. Internal HB PNIPAM dynamics is described well by the Rouse model for non-entangled chains. PMID- 29400396 TI - Gestational diabetes: Is early testing appropriate and does it identify women at increased pregnancy risk? PMID- 29400397 TI - Welcome to ANZJOG 2018. PMID- 29400395 TI - Interventions to prevent injuries in construction workers. AB - BACKGROUND: Construction workers are frequently exposed to various types of injury-inducing hazards. There are a number of injury prevention interventions, yet their effectiveness is uncertain. OBJECTIVES: To assess the effects of interventions for preventing injuries in construction workers. SEARCH METHODS: We searched the Cochrane Injuries Group's specialised register, CENTRAL (issue 3), MEDLINE, Embase and PsycINFO up to April 2017. The searches were not restricted by language or publication status. We also handsearched the reference lists of relevant papers and reviews. SELECTION CRITERIA: Randomised controlled trials, controlled before-after (CBA) studies and interrupted time-series (ITS) of all types of interventions for preventing fatal and non-fatal injuries among workers at construction sites. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed their risk of bias. For ITS studies, we re-analysed the studies and used an initial effect, measured as the change in injury rate in the year after the intervention, as well as a sustained effect, measured as the change in time trend before and after the intervention. MAIN RESULTS: Seventeen studies (14 ITS and 3 CBA studies) met the inclusion criteria in this updated version of the review. The ITS studies evaluated the effects of: introducing or changing regulations that laid down safety and health requirements for the construction sites (nine studies), a safety campaign (two studies), a drug-free workplace programme (one study), a training programme (one study), and safety inspections (one study) on fatal and non-fatal occupational injuries. One CBA study evaluated the introduction of occupational health services such as risk assessment and health surveillance, one evaluated a training programme and one evaluated the effect of a subsidy for upgrading to safer scaffoldings. The overall risk of bias of most of the included studies was high, as it was uncertain for the ITS studies whether the intervention was independent from other changes and thus could be regarded as the main reason of change in the outcome. Therefore, we rated the quality of the evidence as very low for all comparisons.Compulsory interventionsRegulatory interventions at national or branch level may or may not have an initial effect (effect size (ES) of -0.33; 95% confidence interval (CI) -2.08 to 1.41) and may or may not have a sustained effect (ES -0.03; 95% CI -0.30 to 0.24) on fatal and non-fatal injuries (9 ITS studies) due to highly inconsistent results (I2 = 98%). Inspections may or may not have an effect on non-fatal injuries (ES 0.07; 95% CI 2.83 to 2.97; 1 ITS study).Educational interventionsSafety training interventions may result in no significant reduction of non-fatal injuries (1 ITS study and 1 CBA study).Informational interventionsWe found no studies that had evaluated informational interventions alone such as campaigns for risk communication.Persuasive interventionsWe found no studies that had evaluated persuasive interventions alone such as peer feedback on workplace actions to increase acceptance of safe working methods.Facilitative interventionsMonetary subsidies to companies may lead to a greater decrease in non-fatal injuries from falls to a lower level than no subsidies (risk ratio (RR) at follow-up: 0.93; 95% CI 0.30 to 2.91 from RR 3.89 at baseline; 1 CBA study).Multifaceted interventionsA safety campaign intervention may result in an initial (ES -1.82; 95% CI -2.90 to -0.74) and sustained (ES -1.30; 95% CI -1.79 to -0.81) decrease in injuries at the company level (1 ITS study), but not at the regional level (1 ITS study). A multifaceted drug-free workplace programme at the company level may reduce non-fatal injuries in the year following implementation by -7.6 per 100 person-years (95% CI -11.2 to -4.0) and in the years thereafter by -2.0 per 100 person-years (95% CI -3.5 to -0.5) (1 ITS study). Introducing occupational health services may result in no decrease in fatal or non-fatal injuries (one CBA study). AUTHORS' CONCLUSIONS: The vast majority of interventions to adopt safety measures recommended by standard texts on safety, consultants and safety courses have not been adequately evaluated. There is very low-quality evidence that introducing regulations as such may or may not result in a decrease in fatal and non-fatal injuries. There is also very low-quality evidence that regionally oriented safety campaigns, training, inspections or the introduction of occupational health services may not reduce non-fatal injuries in construction companies. There is very low-quality evidence that company-oriented safety interventions such as a multifaceted safety campaign, a multifaceted drug workplace programme and subsidies for replacement of scaffoldings may reduce non fatal injuries among construction workers. More studies, preferably cluster randomised controlled trials, are needed to evaluate different strategies to increase the employers' and workers' adherence to the safety measures prescribed by regulation. PMID- 29400399 TI - Evidence-based medicine - the promise, the reality. PMID- 29400398 TI - Harmonisation of research outcomes for meaningful translation to practice: The role of Core Outcome Sets and the CROWN Initiative. PMID- 29400400 TI - Interaction Effects of Neighborhood Disadvantage and Individual Social Support on Frequency of Alcohol Use in Youth Living with HIV. AB - Youth living with HIV (YLH) experience multiple disease-related stresses along with the same structural and developmental challenges faced by their uninfected peers; alcohol use among YLH represents a risk behavior by virtue of potential effects on youth health and increased likelihood of engaging in unprotected sex while drinking alcohol. Research aimed at better understanding the interplay of individual- and neighborhood-level influences on alcohol use for YLH is needed to inform interventions. This study examined whether socioeconomic disadvantage (SED) and social support influence, independently and through interaction, alcohol use in YLH. Data from the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) consisted of YLH across 538 neighborhoods in the United States who acquired HIV behaviorally. Neighborhood-specific data were compiled from the 2010 U.S. Census Bureau and matched with individual-level data from the ATN (N = 1,357) to examine effects that contribute to variation in frequency of alcohol use. Other drug use, being male, being non-Black, and older age were associated with greater alcohol use. Higher social support was negatively associated with alcohol use frequency. A cross-level interaction indicated that the association found between decreasing social support and increasing alcohol use frequency was weakened in areas with lower SED. Implications are discussed. PMID- 29400401 TI - Emotional preferences and goals and emotion dysregulation in children with Asperger's syndrome and typically developing children. AB - OBJECTIVES: Emotion goals lie at the heart of emotion regulation, as people have to first decide what emotions they want to feel before engaging in emotion regulation. Given that children with Asperger's syndrome (AS) are characterized by exhibiting difficulties in emotion regulation, studying whether they display similar or different emotion goals compared to typically developing (TD) children may provide insightful information. METHODS: Thirty AS and 30 TD children (10-12 years) reported about their general (i.e., how they want to feel in general) and contextualized (i.e., how they want to feel when confronting vs. collaborating with someone) emotion goals, and about their difficulties in emotion regulation through questionnaires. RESULTS: Results showed that both groups did not differ in their general emotional goals and in their contextualized emotion goals for happiness for collaboration and anger for confrontation. AS children only differed from TD children in a higher preference for sadness for collaboration and happiness for confrontation. These emotion goals predicted their difficulties to engage in goal-directed behaviour. CONCLUSIONS: The obtained results support the need to further study emotion goals as an aspect of emotion dysregulation, namely the difficulties to engage in goal-directed behaviour when experiencing different emotions. PRACTITIONER POINTS: AS and TD children did not differ in their general emotion goals. AS and TD children did not vary in their preferences for happiness for collaboration and anger for confrontation. AS children only differed in a higher preference for sadness for collaboration and happiness for confrontation. Understanding emotion goals might help practitioners to develop better interventions. PMID- 29400402 TI - The Importance of Parents' Community Connections for Adolescent Well-being: An Examination of Military Families. AB - Drawing from the Social Organization Theory of Action and Change (SOAC), this analysis of 223 military families, including active duty (AD) military and civilian partners, examines how parents' sense of community and community engagement (two elements of community connections) are associated with their own resilient coping, and ultimately with important outcomes capturing their adolescent offspring's individual well-being (depression, anxiety, and self efficacy) and family well-being (family functioning and parenting quality). The roles of child gender and military context were also examined. Parents with stronger community connections, including greater sense of community and community engagement, reported more resilient coping when faced with adversity. The resilient coping of mothers, in turn, was particularly significant for more positive youth outcomes, when compared to that of fathers. While gender and military context were associated with individual and family well-being, analyses of model invariance indicated that the model fit similarly for male and female adolescents and those experiencing high and low levels of military transitions. Indirect effects were also examined. These findings illuminate malleable dimensions of both community life and family life, primarily showing that community contexts matter for multiple family members. PMID- 29400404 TI - Total prostatectomy as a treatment for prostatic carcinoma in 25 dogs. AB - OBJECTIVE: To describe the complications and outcome after total prostatectomy in dogs with histologically confirmed prostatic carcinoma. STUDY DESIGN: Multi institutional retrospective case series. ANIMALS: 25 client-owned dogs. METHODS: Medical records of dogs undergoing total prostatectomy were reviewed from 2004 to 2016. Data retrieved included signalment, presenting signs, preoperative clinical findings, laboratory data, diagnostic imaging, surgical technique, histologic diagnosis, postoperative complications, occurrence of postoperative metastasis, and survival. RESULTS: Twenty-five dogs underwent total prostatectomy for prostatic carcinoma. Urinary anastomotic techniques included urethrourethral anastomosis in 14 dogs, cystourethral anastomosis in 9 dogs, ureterocolonic anastomosis in 1 dog, and anastomosis between the bladder neck and penile urethra in 1 dog. All dogs survived to discharge. Fifteen dogs were diagnosed with transitional cell carcinoma, 8 dogs with prostatic adenocarcinoma, 1 with prostatic cystadenocarcinoma, and 1 with an undifferentiated carcinoma. Permanent postoperative urinary incontinence was present in 8 of 23 dogs. The median survival time was shorter in dogs with extracapsular tumor extension compared with those with intracapsular tumors. The overall median survival time was 231 days (range, 24-1255), with 1- and 2-year survival rates equal to 32% and 12%, respectively. CONCLUSION AND CLINICAL SIGNIFICANCE: Total prostatectomy, combined with adjunct therapies, prolongs survival and lowers complication rates compared to previous reports of dogs with prostatic carcinoma. It should be noted, however, that case selection likely played a significant role in postoperative outcome. PMID- 29400403 TI - Evaluation of pet owner preferences for operative sterilization techniques in female dogs within the veterinary community. AB - OBJECTIVE: To describe pet owner preferences within the veterinary community when choosing operative techniques for canine spay. STUDY DESIGN: Prospective survey. SAMPLE POPULATION: 1234 respondents from 5 veterinary university teaching hospitals in North America. METHODS: An electronic survey was distributed to faculty, students, and staff that currently are or previously were dog owners. Responses were analyzed to determine what spay technique respondents would choose for their own dogs. Surgical options offered included open celiotomy, 2-port (TP) laparoscopy, single-port (SP) laparoscopy, and natural orifice transluminal endoscopic surgery (NOTES). RESULTS: TP laparoscopic ovariectomy (OVE) was the most popular choice, followed by SP laparoscopic OVE; NOTES was the least popular technique when all surgical options were available. If only minimally invasive surgeries were offered, 0.3% of respondents would refuse surgery. Nearly half (48%) of respondents were willing to spend between $100 and $200 more for a minimally invasive OVE than for an open celiotomy. CONCLUSION: Minimally invasive OVE is an acceptable operative approach to those in the veterinary community. Additional study is required to correlate these findings with the general veterinary client population. PMID- 29400405 TI - Expression and characterization of the processive exo-beta-1,4-cellobiohydrolase SCO6546 from Streptomyces coelicolor A(3). AB - The sco6546 gene of Streptomyces coelicolor A3(2) was annotated as a putative glycosyl hydrolase belonging to family 48. It is predicted to encode a 973-amino acid polypeptide (103.4 kDa) with a 39-amino acid secretion signal. Here, the SCO6546 protein was overexpressed in Streptomyces lividans TK24, and the purified protein showed the expected molecular weight of the mature secreted form (934 aa, 99.4 kDa) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. SCO6546 showed high activity toward Avicel and carboxymethyl cellulose, but low activity toward filter paper and beta-glucan. SCO6546 showed maximum cellulase activity toward Avicel at pH 5.0 and 50 degrees C, which is similar to the conditions for maximum activity toward cellotetraose and cellopentaose substrates. The kinetic parameters kcat and KM , for cellotetraose at pH 5.0 and 50 degrees C were 13.3 s-1 and 2.7 mM, respectively. Thin layer chromatography (TLC) of the Avicel hydrolyzed products generated by SCO6546 showed cellobiose only, which was confirmed by mass spectral analysis. TLC analysis of the cello-oligosaccharide and chromogenic substrate hydrolysates generated by SCO6546 revealed that it can hydrolyze cellodextrins mainly from the non-reducing end into cellobiose. These data clearly demonstrated that SCO6546 is an exo-beta-1,4-cellobiohydrolase (EC 3.2.1.91), acting on nonreducing end of cellulose. PMID- 29400406 TI - Early labor force exit subsequent to permanently impairing occupational injury or illness among workers 50-64 years of age. AB - BACKGROUND: Severity of workplace injury tends to increase with age. Whether older workers who experience a workplace injury or illness exit the labor force sooner than comparable peers is not established. METHODS: A case-cohort study design and complementary log-log model were used to identify factors associated with average time to early substantial labor force exit among workers' compensation claimants 50-64 years of age with permanent impairment from an occupational injury or illness. Analysis was based on Ontario's workers' compensation claimant data from 1998 to 2006 linked with Canadian tax files. RESULTS: Workers with permanent impairment left the labor force earlier, on average, than peers without claims. Early retirement was associated with older age in the injury/illness year, greater impairment, lower pre-claim income, physically demanding jobs, and soft-tissue injuries. CONCLUSIONS: Policies aiming to extend older adults' working lives should account for the potentially disparate impacts on older workers of occupational injury and illness. PMID- 29400407 TI - Prosthetic mesh repair of abdominal wall hernias in horses. AB - Repair of hernias of the abdominal wall of horses is often augmented by inserting a prosthetic mesh. In this review, we describe the various characteristics of prosthetic meshes used for hernia repair and present 2 systems that are used by surgeons in the human medical field to classify techniques of prosthetic mesh herniorrhaphy. Both of these classification systems distinguish between onlay, inlay, sublay, and underlay placements of mesh, based on the location within the abdominal wall in which the prosthetic mesh is inserted. We separate the published techniques of prosthetic mesh herniorrhaphy of horses using this classification system, ascribing names to the techniques of herniorrhaphy where none existed, and report the success rates and complications associated with each technique. By introducing a classification system widely used in the human medical field and illustrating each technique in a figure, we hope to clarify inconsistent nomenclature associated with prosthetic mesh herniorrhaphy performed by veterinary surgeons. PMID- 29400408 TI - Analysis of ruthenium anticancer agents by MEEKC-UV and MEEKC-ICP-MS: Impact of structural motifs on lipophilicity and biological activity. AB - We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral RuIII (azole) through to RuII (arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC-ICP-MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono- or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano-stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties. PMID- 29400409 TI - Axl and MerTK receptor tyrosine kinases maintain human macrophage efferocytic capacity in the presence of viral triggers. AB - The requirement to remove apoptotic cells is equally important in homeostasis and inflammatory disease. In particular, during viral infections large quantities of infected cells undergo apoptosis and need to be efficiently cleared by phagocytes to prevent secondary necrosis. Although specific roles of several apoptotic cell sensors, such as the TAM (Tyro3, Axl, MerTK) receptor family, have been characterized in mouse models, little is known about their regulation and involvement in apoptotic cell uptake (efferocytosis) by human macrophages under inflammatory conditions. We show that whereas pro-inflammatory stimuli consistently downregulated MerTK expression in human monocyte-derived macrophages (MDMs), stimuli indicative of a viral infection, interferon-alpha (IFN-alpha) and the TLR3 ligand poly(I:C), specifically induced Axl expression and promoted binding of the bridging molecule Gas6. Axl induction by IFN-alpha and poly(I:C) was associated with higher MDM efferocytic capacity compared to cells treated with other pro-inflammatory stimuli, such as LPS and IFN-gamma. While MerTK blocking antibody uniformly suppressed apoptotic cell uptake by MDMs, Axl blocking antibody significantly reduced efferocytosis by poly(I:C)-stimulated MDMs, but not by resting MDMs. Our observations demonstrate that Axl induction during viral infections contributes to maintaining macrophage capacity to engulf apoptotic cells, which may have important consequences for resolution of anti viral immune responses. PMID- 29400410 TI - Discussion group networks in occupational medicine: A tool for continuing education to promote the integration of workers with disabilities. AB - BACKGROUND: Despite their legal rights, individuals with disabilities face numerous obstacles to integration in the workplace which can result in their discharge from the labor force. Currently occupational physicians have few resources to help decide whether to integrate disabled workers in pre-placement, or in cases of return-to-work. METHODS: A network of 13 discussion groups comprised of the occupational physicians of each regional clinic of a large Health Maintenance Organization (HMO) in Israel was created to deal with disability management dilemmas. A moderator compiles and shares the physicians' opinions and experiences with all network members thus assisting the consulting physician in decision-making. RESULTS: Successful management of three representative cases is described to illustrate real-life implementations of this network. CONCLUSION: The network enables both the consulting and other physicians to tap a large knowledge base and decision-making experience concerning cases of occupational disability management, contributing to professional development and improved service delivery. PMID- 29400411 TI - Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors. AB - A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX 2 rather than COX-1, and the IC50 values (0.25-1.7 uM) were lower than that of indomethacin (IC50 = 9.47 uM) and somewhat higher than that of celecoxib (IC50 = 0.071 uM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02-74.03 uM, while the IC50 of the reference zileuton was 0.83 uM. The most active compound 4c (4 chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site. PMID- 29400412 TI - Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole-based 2,4-thiazolidinedione derivatives as PPAR-gamma modulators. AB - The design, synthesis, structure-activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-gamma (PPAR-gamma) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-gamma by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > -8 as compared to the standard drug, rosiglitazone (Glide XP score = 9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR-gamma transactivation and in vivo blood glucose lowering activity in the streptozotocin-induced diabetic rat model. Compounds 5o, 5n, 5a, 5i, and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR-gamma transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o, 5n, and 5a (140.1 +/- 4.36, 141.4 +/- 6.15, and 150.7 +/- 4.15, respectively), along with reference drugs pioglitazone (135.2 +/- 4.91) and rosiglitazone (141.1 +/- 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR-gamma gene expression by 2.35-fold as compared to rosiglitazone (1.27-fold) and pioglitazone (1.6-fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver. PMID- 29400413 TI - Pregnancy and delivery outcomes from patients with repaired anomalous origin of the left coronary artery from the pulmonary artery. AB - AIM: We investigated the clinical courses before and during pregnancy and after delivery in patients with repaired anomalous origin of the left coronary artery from the pulmonary artery to determine the impact of the hemodynamic changes and cardiac function on the selection of the appropriate mode of delivery. METHODS: Six patients who underwent coronary artery reimplantation delivered 10 infants. We scrutinized the patients' hemodynamic changes on echocardiographs and the plasma brain natriuretic peptide levels before and during pregnancy and after delivery, the perinatal outcomes and maternal and fetal events. RESULTS: All patients were asymptomatic and categorized as having New York Heart Association functional class I before pregnancy. In 8 of 10 pregnancies, vaginal deliveries were performed; two elective cesarean sections were performed because of symptomatic heart failure. The hemodynamic parameters were stable throughout pregnancy and postdelivery, and no maternal or fetal events occurred in the patients who underwent vaginal deliveries. One cesarean section patient developed significant heart failure during the late second and third trimesters, which was accompanied by hemodynamic changes, including increased brain natriuretic peptide levels, left ventricular diastolic dysfunction and worsening arrhythmias, and thrombosis and post-partum hemorrhage occurred postdelivery. The baby had intrauterine growth retardation and small for gestational age. None of the babies had congenital anomalies. CONCLUSION: Pregnancy was safe in most of the asymptomatic patients long after anomalous origin of the left coronary artery from the pulmonary artery was repaired. Symptomatic heart failure might occur during pregnancy in patients with persisting myocardial damage. Pregnancy and delivery should be carefully managed. PMID- 29400414 TI - Culturally-grounded mother-daughter communication-focused intervention for Thai female adolescents. AB - Teenage pregnancy-prevention interventions have fallen short in significantly decreasing risk of pregnancy for Thai populations. The "breaking the voice" ("rak luk khun tong pood") culture-appropriate teenage pregnancy-prevention program was developed using community-based research. Qualitative analyses of focus group data identified salient factors related to sexual communication and behavior. The integration of focus group results with theoretical constructs guided the development of an intervention to reduce risky sexual behavior by increasing communication between mothers and their adolescent daughters. A total of 157 mother-daughter dyads from congested areas in Bangkok participated in pilot testing of the intervention by the use of a survey. The findings indicated a significant increase in the frequency of and number of sexual risk communication (P < .05). There was a significant increase in perceived power in relationship control, ability to prevent sexual risk, assertiveness, and ability to decrease sexual risk among daughters (P < .05). "Breaking the voice" represents a female focused and culturally-relevant intervention to combat teenage pregnancy. PMID- 29400415 TI - Apoptosis of posterior silk gland of Bombyx mori during spinning period and the role of PI3K/Akt pathway. AB - Bombyx mori is an economic insect of the Lepidoptera. Its posterior silk gland (PSG) is an important organ for fibroin synthesis. In order to study the occurrence of apoptosis in PSG and the role of PI3K/Akt signaling pathway during spinning period, changes in morphology of silk gland, expressions of fibroin components Fib-H, Fib-L and P25 and Akt, TOR2, P70S6K and S6 in PI3K/Akt pathway, expressions of apoptosis related genes caspase-3, caspase-9 and activity of caspase-3 were explored. The results showed that the morphology of silk gland dramatically degenerated; transcription of Fib-H, Fib-L, and P25 gradually declined with time; and Fib-L protein level reduced by 0.6-fold at 72 h. Moreover, the transcription levels of Akt, TOR2, P70S6K, and S6 also decreased by 0.3-, 0.8-, 0.7-, and 0.1-fold, respectively, indicating that the downregulation of PI3K/Akt signaling pathway could lead to reduction in fibroin synthesis. In addition, the transcription levels of caspase-3 and caspase-9 increased by 1.3- and 3.6-fold, respectively, and the enzyme activity of caspase-3 grew at a maximum of 1.6-fold. The results showed the occurrence of apoptosis in PSG during spinning period. In conclusion, the present study indicated that both the decline in fibroin components and the increase in apoptosis-related genes were regulated by PI3K/Akt signaling pathway during spinning period, which shed new light on the functions of PI3K/Akt signaling pathway. PMID- 29400416 TI - Placental mesenchymal dysplasia with severe fetal growth restriction in one placenta of a dichorionic diamniotic twin pregnancy. AB - We report a rare case of placental mesenchymal dysplasia (PMD) with fetal growth restriction (FGR) in one placenta of a dichorionic diamniotic (DD) twin pregnancy. A 24-year-old woman was referred to our hospital at 24 weeks' gestation due to FGR and ipsilateral placental abnormality in DD twins. Ultrasound and magnetic resonance imaging showed one placenta of the FGR fetus was bulky and had multiple cysts, while the other fetus placenta appeared normal. Cesarean section was performed at 32 weeks' gestation; the first and second neonates weighted 1799 and 1215 g, respectively. Macroscopically, chorionic vessels on the placental surface of the second neonate were prominently enlarged. Pathological findings demonstrated swelling stem villi with enlarged vessels and increased interstitial cells without trophoblast proliferation. Immunostaining for p57kip2 was negative in interstitial cells and cytotrophoblasts of the swelling stem villi. This suggested that PMD occurred in one placenta of the DD twin, leading to early-onset FGR. PMID- 29400417 TI - Brain structure differences between Chinese and Caucasian cohorts: A comprehensive morphometry study. AB - Numerous behavioral observations and brain function studies have demonstrated that neurological differences exist between East Asians and Westerners. However, the extent to which these factors relate to differences in brain structure is still not clear. As the basis of brain functions, the anatomical differences in brain structure play a primary and critical role in the origination of functional and behavior differences. To investigate the underlying differences in brain structure between the two cultural/ethnic groups, we conducted a comparative study on education-matched right-handed young male adults (age = 22-29 years) from two cohorts, Han Chinese (n = 45) and Caucasians (n = 45), using high dimensional structural magnetic resonance imaging (MRI) data. Using two well validated imaging analysis techniques, surface-based morphometry (SBM) and voxel based morphometry (VBM), we performed a comprehensive vertex-wise morphometric analysis of the brain structures between Chinese and Caucasian cohorts. We identified consistent significant between-group differences in cortical thickness, volume, and surface area in the frontal, temporal, parietal, occipital, and insular lobes as well as the cingulate cortices. The SBM analyses revealed that compared with Caucasians, the Chinese population showed larger cortical structures in the temporal and cingulate regions, and smaller structural measures in the frontal and parietal cortices. The VBM data of the same sample was well-aligned with the SBM findings. Our findings systematically revealed comprehensive brain structural differences between young male Chinese and Caucasians, and provided new neuroanatomical insights to the behavioral and functional distinctions in the two cultural/ethnic populations. PMID- 29400418 TI - Esophageal reconstruction after oncological total laryngopharyngoesophagectomy: Algorithmic approach. AB - BACKGROUND: Reconstruction for total laryngopharyngoesophagectomy is accomplished mainly by gastrointestinal transposition but can be complicated by anastomotic tension or associated neck-skin defect. Here, we present the results of total esophageal reconstruction by gastrointestinal transposition alone or with additional free tissue transfer and propose an algorithm accordingly. METHODS: We reviewed patients who had oncologic total laryngopharyngoesophagectomy between January 2012 and January 2016. Twenty-four men and one woman were included with a mean age of 54 (range, 41-72) years. Patients were grouped by reconstruction into the gastric pull-up (GP, n = 15), colon interposition (CI, n = 2), GP combined with free jejunal flap (GPFJ, n = 6), or GP combined with anterolateral thigh flap (GPALT, n = 2) group to compare clinical outcomes. RESULTS: The mean operation time was 1037.3 minutes and was significantly longer in the GPALT group than in the GP group (1235.0 +/- 50.0 minutes vs. 929.7 +/- 137.7 minutes, p =.009). All flaps survived. After a mean follow-up of 18 months, the overall leakage, stricture, and successful swallowing rates were 44%, 4%, and 76%, respectively. There was no significant difference in the leakage (53.3%, 50.0%, 16.7%, and 50.0%, p =.581), stricture (6.7%, 0%, 0%, and 0%, p = 1.000), or successful swallowing (73.3%, 50.0%, 83.3%, and 100%, p =.783) rates between GP, CI, GPFJ, and GPALT groups, respectively. CONCLUSIONS: The proposed algorithm that ranks gastric pull-up as a priority and uses additional free tissue transfer to overcome the anastomotic tension or associated neck-skin defect is feasible. PMID- 29400419 TI - Endometrioid carcinoma arising from diaphragmatic endometriosis treated with laparoscopy: A case report. AB - Malignant transformation of diaphragmatic endometriosis is rare. We present a case of endometrioid carcinoma arising from diaphragmatic endometriosis treated with laparoscopy. A 59-year-old primigravida woman who had undergone abdominal hysterectomy for adenomyosis at the age of 47 years was referred to our hospital for investigation of a tumor on the surface of the liver. An integrated positron emission tomography-computed tomography scan revealed a 3-cm nodule on the surface of the liver with abnormal fluorine-18-deoxyglucose accumulation. Partial resection of the diaphragm and liver was performed. Histopathological examination revealed an endometrioid carcinoma arising from diaphragmatic endometriosis. We additionally performed laparoscopic bilateral salpingo-oophorectomy and partial omentectomy. The resected tissues revealed no malignancy. Adjuvant chemotherapy with paclitaxel and carboplatin was administered. In cases of diaphragmatic tumors, endometriosis and its associated malignancies should be considered. Laparoscopic surgery is effective in patients with such conditions. PMID- 29400420 TI - Musical training induces functional and structural auditory-motor network plasticity in young adults. AB - Playing music requires a strong coupling of perception and action mediated by multimodal integration of brain regions, which can be described as network connections measured by anatomical and functional correlations between regions. However, the structural and functional connectivities within and between the auditory and sensorimotor networks after long-term musical training remain largely uninvestigated. Here, we compared the structural connectivity (SC) and resting-state functional connectivity (rs-FC) within and between the two networks in 29 novice healthy young adults before and after musical training (piano) with those of another 27 novice participants who were evaluated longitudinally but with no intervention. In addition, a correlation analysis was performed between the changes in FC or SC with practice time in the training group. As expected, participants in the training group showed increased FC within the sensorimotor network and increased FC and SC of the auditory-motor network after musical training. Interestingly, we further found that the changes in FC within the sensorimotor network and SC of the auditory-motor network were positively correlated with practice time. Our results indicate that musical training could induce enhanced local interaction and global integration between musical performance-related regions, which provides insights into the mechanism of brain plasticity in young adults. PMID- 29400421 TI - Effects of adverse events in health care on acute care nurses in an Australian context: A qualitative study. AB - Adverse events in health care significantly impact health professionals who become the second victims of medical error. The aim of the present study was to understand the effects of adverse events in health care on nurses in acute health care settings in an Australian context. In this qualitative, descriptive study, we used purposeful sampling and recruited 10 acute care nurses. Interviews were conducted from 2011 to 2012 and were recorded, transcribed, and returned to participants to verify their accuracy. Data were categorized and analyzed to determine four emergent themes and subthemes. The four themes were: rescuing patients, effects on nurses, professional responsibility, and needs of nurses. Our analysis indicated that nurses need organizational responses to adverse events, including the provision of information and collegial support after adverse events occur. This will minimize the psychological trauma associated with these events for second victims and support effective communication and collegial working relationships. PMID- 29400422 TI - Don't Leave MONEY on the Table. Mastering MACRA, PQRS, and Value-Based Purchasing: How Quality Coding Impacts Quality Reporting. PMID- 29400423 TI - Pain at the PRINTER. PMID- 29400424 TI - RELEASE OF INFORMATION: When to Call a Healthcare Compliance Attorney. PMID- 29400425 TI - Winning the Coding Trifecta: CAC, CDI, and ICD-10. How CAC can strengthen your CDI Program and Increase Collaboration with Coding and Quality Improvement. PMID- 29400426 TI - OCR Continues to Define Patient Access Guidelines. PMID- 29400427 TI - Study Analyzes Causes and Consequences of Patient Overlay Errors. PMID- 29400428 TI - Understanding Information in EHR Systems: Paving the Road for Semantic Interoperability through Standards. PMID- 29400429 TI - The Information Governance Road Map: Mile Marker 3--Travel to America's Most Prized Treasures. PMID- 29400430 TI - Managing the Present on Admission Reporting Process. PMID- 29400431 TI - Converting the Conducting Behavior of Graphene Oxides from n-Type to p-Type via Electron-Beam Irradiation. AB - We studied the effects of electron-beam irradiation (EBI) on the structural and gas-sensing properties of graphene oxide (GO). To understand the effects of EBI on the structure and gas-sensing behavior of irradiated GO, the treated GO was compared with nonirradiated GO. Characterization results indicated an enhancement in the number of oxygen functional groups that occurs with EBI exposure at 100 kGy and then decreases with doses in the range of 100-500 kGy. Data from Raman spectra indicated that EBI could generate defects, and NO2-sensing results at room temperature showed a decreased NO2 response after exposure to EBI at 100 kGy; further increasing the dose to 500 kGy resulted in p-type semiconducting conductivity. The conversion of GO from n-type to p-type via EBI is explained not only through the generation of holes but also the variation in the amount of residual functional groups, including carboxyl (COOH) and hydroxyl groups (C-OH). The obtained results suggest that EBI can be a useful tool to convert GO into a diverse range of sensing devices. PMID- 29400432 TI - All-Inorganic Perovskite Nanowires-InGaZnO Heterojunction for High-Performance Ultraviolet-Visible Photodetectors. AB - Inorganic cesium lead halide perovskites have attracted intense interest in optoelectronic applications due to the relatively stable performance in air. However, most reported inorganic perovskite-based optoelectronic devices exhibit low photosensitivity, which greatly hinders their further applications. Here, we first demonstrate a hybrid optical structure, which combines the n-type thin-film InGaZnO and the all-inorganic perovskite nanowires of CsPbBr3 together. By this way, excellent optical and electrical properties such as a low dark current of 10 10 A (at -5 V), a high Iph/Idark of 1.2 * 104, a response time of 2 ms and photoresponsivity of 3.794 A/W have been obtained. It is also found that the photodetector shows good stability in air ambient for 2 months with little reduction in performance. Moreover, such hybrid photodetectors exhibit enhanced photocurrent and Iph/Idark in high-temperature environment. This work paves a new way for high-performance photodetectors and points out the possible application of the inorganic cesium lead halide perovskites in harsh environment. PMID- 29400433 TI - Intermolecular G-Quadruplex Induces Hyaluronic Acid-DNA Superpolymers Causing Cancer Cell Swelling, Blebbing, and Death. AB - Over the past decade, nanomedicine has gained considerable attraction through its relevance, for example, in "smart" delivery, thus creating platforms for novel treatments. Here, we report a natural polymer-DNA conjugate that undergoes self assembly in a K+-dependent fashion to form a G-quadruplex (GQ) and generate superpolymeric structures. We derivatized a thiolated conjugate of the naturally occurring glycosaminoglycan polymer hyaluronic acid (HASH) with short G-rich DNA (HASH-DNA) that can form an intermolecular noncanonical GQ structure. Gel mobility shift assay and circular dichroism measurements confirmed HASH conjugation to DNA and K+-dependent GQ formation, respectively. Transmission electron microscopy and scanning electron microscopy results indicated that the addition of K+ to the HASH-DNA conjugate led to the formation of micron-range structures, whereas control samples remained unordered and as a nebulous globular form. Confocal microscopy of a fluorescently labeled form of the superpolymer verified increased cellular uptake. The HASH-DNA conjugates showed toxicity in HeLa cells, whereas a scrambled DNA (Mut) conjugate HASH-Mut showed no cytotoxicity, presumably because of nonformation of the superpolymeric structure. To understand the mechanism of cell death and if the superpolymeric structure is responsible for it, we monitored the cell size and observed an average of 23% increase in size compared to 4.5% in control cells at 4.5 h. We believe that cellular stress is generated presumably by the intracellular assembly of this large superpolymeric nanostructure causing cell blebbing with no exit option. This approach provides a new strategy of cellular delivery of a targeted naturally occurring polymer and a novel way to induce superpolymeric structure formation that acts as a therapeutic. PMID- 29400434 TI - Fabrication of High-Sensitivity Skin-Attachable Temperature Sensors with Bioinspired Microstructured Adhesive. AB - In this study, we demonstrate the fabrication of a highly sensitive flexible temperature sensor with a bioinspired octopus-mimicking adhesive. A resistor-type temperature sensor consisting of a composite of poly(N-isopropylacrylamide) (pNIPAM)-temperature sensitive hydrogel, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, and carbon nanotubes exhibits a very high thermal sensitivity of 2.6%. degrees C-1 between 25 and 40 degrees C so that the change in skin temperature of 0.5 degrees C can be accurately detected. At the same time, the polydimethylsiloxane adhesive layer of octopus-mimicking rim structure coated with pNIPAM is fabricated through the formation of a single mold by utilizing undercut phenomenon in photolithography. The fabricated sensor shows stable and reproducible detection of skin temperature under repeated attachment/detachment cycles onto skin without any skin irritation for a long time. This work suggests a high potential application of our skin-attachable temperature sensor to wearable devices for medical and health-care monitoring. PMID- 29400435 TI - Bottom-up, Robust Graphene Ribbon Electronics in All-Carbon Molecular Junctions. AB - Large-area molecular electronic junctions consisting of 5-carbon wide graphene ribbons (GR) with lengths of 2-12 nm between carbon electrodes were fabricated by electrochemical reduction of diazotized 1,8-diaminonaphthalene. Their conductance greatly exceeds that observed for other molecular junctions of similar thicknesses, by a factor of >1 * 104 compared to polyphenylenes and >1 * 107 compared to alkane chains. The remarkable increase of conductance of the GR nanolayer results from (i) uninterrupted planarity of fused-arene structure affording extensive pi-electron delocalization and (ii) enhanced electronic coupling of molecular layer with the carbon bottom contact by two-point covalent bonding, in agreement with DFT-based simulations. PMID- 29400436 TI - Copper-Phenylacetylide Nanobelt/Single-Walled Carbon Nanotube Composites: Mechanochromic Luminescence Phenomenon and Thermoelectric Performance. AB - We report flexible films of organic-inorganic thermoelectric (TE) composites based on organometallic coordination compound [copper-phenylacetylide (PhC2Cu)] nanobelts and single-walled carbon nanotubes (SWCNTs). Interestingly, an unusual mechanochromic luminescence phenomenon from bright green to dark red is clearly observed after grinding the PhC2Cu crystalline nanobelts. The PhC2Cu/SWCNT composites display high mechanical flexibility and excellent TE performance. The maximum power factor at room temperature can reach as high as 200.2 +/- 10.9 MUW m-1 K-2. The present study opens an avenue to fabricate novel organic-inorganic TE composite materials using organometallic coordination compounds such as PhC2Cu. PMID- 29400437 TI - Different Bioactive Neuropeptides are Expressed in Two Sub-Classes of GABAergic RME Nerve Ring Motorneurons in Ascaris suum. AB - Neuropeptides can have significant effects on neurons and synapses, but among the ~250 predicted peptides in nematodes, few have been characterized functionally. Here, we report new neuropeptides in the 4 RME nerve ring motorneurons of the nematode Ascaris suum. These GABAergic neurons are involved in three-dimensional head movement. Mass spectrometry (MS) of single dissected RMEs detected a total of 12 neuropeptides (encoded by five genes), nine of which are novel. None of these are expressed in the DI/VI inhibitory GABAergic motorneurons that synapse onto body wall muscle. Using peptide sequences obtained by tandem MS, we cloned the peptide-encoding transcripts and synthesized riboprobes for in situ hybridization (ISH). This complementary technique corroborated the results from single-cell MS, showing that the dissections were not contaminated with adhering tissue from other cells. We also synthesized a multiple antigenic peptide to raise a highly specific antibody against one of the endogenous peptides, which labeled the same cells detected by MS and ISH. Our results show that the RMEs can be divided into two subsets: RMED/V (expressing afp-2, afp-15, Asu-nlp-58, and high levels of afp-16) and RMEL/R (expressing afp-15 and low levels of afp-4 and afp-16). Almost all of these peptides are bioactive in A. suum. PMID- 29400438 TI - Atomic-Level Co3O4 Layer Stabilized by Metallic Cobalt Nanoparticles: A Highly Active and Stable Electrocatalyst for Oxygen Reduction. AB - Developing atomic-level transition oxides may be one of the most promising ways for providing ultrahigh electrocatalytic performance for oxygen reduction reaction (ORR), compared with their bulk counterparts. In this article, we developed a set of atomically thick Co3O4 layers covered on Co nanoparticles through partial reduction of Co3O4 nanoparticles using melamine as a reductive additive at an elevated temperature. Compared with the original Co3O4 nanoparticles, the synthesized Co3O4 with a thickness of 1.1 nm exhibits remarkably enhanced ORR activity and durability, which are even higher than those obtained by a commercial Pt/C in an alkaline environment. The superior activity can be attributed to the unique physical and chemical structures of the atomic level oxide featuring the narrowed band gap and decreased work function, caused by the escaped lattice oxygen and the enriched coordination-unsaturated Co2+ in this atomic layer. Besides, the outstanding durability of the catalyst can result from the chemically epitaxial deposition of the Co3O4 on the cobalt surface. Therefore, the proposed synthetic strategy may offer a smart way to develop other atomic-level transition metals with high electrocatalytic activity and stability for energy conversion and storage devices. PMID- 29400439 TI - Functional Relevance of Endocannabinoid-Dependent Synaptic Plasticity in the Central Nervous System. AB - The endocannabinoid (eCB) signaling system plays a key role in short-term and long-term synaptic plasticity in brain regions involved in various neural functions ranging from action selection to appetite control. This review will explore the role of eCBs in shaping neural circuit function to regulate behaviors. In particular, we will discuss the behavioral consequences of eCB mediated long-term synaptic plasticity in different brain regions. This review brings together evidence from in vitro and ex vivo studies and points out the need for more in vivo studies. PMID- 29400440 TI - Fabrication of a Combustion-Reacted High-Performance ZnO Electron Transport Layer with Silver Nanowire Electrodes for Organic Solar Cells. AB - Herein, a new methodology for solution-processed ZnO fabrication on Ag nanowire network electrode via combustion reaction is reported, where the amount of heat emitted during combustion was minimized by controlling the reaction temperature to avoid damaging the underlying Ag nanowires. The degree of participation of acetylacetones, which are volatile fuels in the combustion reaction, was found to vary with the reaction temperature, as revealed by thermogravimetric and compositional analyses. An optimized processing temperature of 180 degrees C was chosen to successfully fabricate a combustion-reacted ZnO and Ag nanowire hybrid electrode with a sheet resistance of 30 Omega/sq and transmittance of 87%. A combustion-reacted ZnO on Ag nanowire hybrid structure was demonstrated as an efficient transparent electrode and electron transport layer for the PTB7-Th based polymer solar cells. The superior electrical conductivity of combustion reacted ZnO, compared to that of conventional sol-gel ZnO, increased the external quantum efficiency over the entire absorption range, whereas a unique light scattering effect due to the presence of nanopores in the combustion-derived ZnO further enhanced the external quantum efficiency in the 450-550 nm wavelength range. A power conversion efficiency of 8.48% was demonstrated for the PTB7-Th based polymer solar cell with the use of a combustion-reacted ZnO/Ag NW hybrid transparent electrode. PMID- 29400441 TI - A New Concentration Jump Strategy Reveals the Lifetime of i-Motif at Physiological pH without Force. AB - Concentration jumps for kinetics measurement remain a challenge for single molecule techniques, which have demonstrated superior signal-to-noise levels compared to ensemble average approaches. Currently, all concentration jumps use mixing strategies. Here, we report a simple and drastically different jump strategy by rapid transportation of molecules between two side-by-side laminar streams in 80 ms. This allowed us to measure the lifetime of bioactive DNA i motif structures at physiological pH without force. We placed a human telomeric i motif inside a DNA hairpin-based mechanical reporter. Since the folded or unfolded state of the hairpin correlates with that of the i-motif, by recording hairpin transitions, a half-life of ~3 s was found for the DNA i-motif at neutral pH without force. Such a lifetime is sufficient for i-motif to interact with proteins to modulate cellular processes. We anticipate this concentration jump offers a generic platform to investigate single-molecule kinetics. PMID- 29400442 TI - High-Capacity and Long-Cycle Life Aqueous Rechargeable Lithium-Ion Battery with the FePO4 Anode. AB - Aqueous lithium-ion batteries are emerging as strong candidates for a great variety of energy storage applications because of their low cost, high-rate capability, and high safety. Exciting progress has been made in the search for anode materials with high capacity, low toxicity, and high conductivity; yet, most of the anode materials, because of their low equilibrium voltages, facilitate hydrogen evolution. Here, we show the application of olivine FePO4 and amorphous FePO4.2H2O as anode materials for aqueous lithium-ion batteries. Their capacities reached 163 and 82 mA h/g at a current rate of 0.2 C, respectively. The full cell with an amorphous FePO4.2H2O anode maintained 92% capacity after 500 cycles at a current rate of 0.2 C. The acidic aqueous electrolyte in the full cells prevented cathodic oxygen evolution, while the higher equilibrium voltage of FePO4 avoided hydrogen evolution as well, making them highly stable. A combination of in situ X-ray diffraction analyses and computational studies revealed that olivine FePO4 still has the biphase reaction in the aqueous electrolyte and that the intercalation pathways in FePO4.2H2O form a 2-D mesh. The low cost, high safety, and outstanding electrochemical performance make the full cells with olivine or amorphous hydrated FePO4 anodes commercially viable configurations for aqueous lithium-ion batteries. PMID- 29400444 TI - Anisotropic, Mesoporous Microfluidic Frameworks with Scalable, Aligned Cellulose Nanofibers. AB - Cellulose paper has been extensively used in microfluidic analytical devices because of its hydrophilic nature. However, cellulose is randomly packed in paper without any particular orientation or channels within the bulk of the material, necessitating a complicated design of hydrophilic microchannels to guide the liquid flow. Herein, we develop an anisotropic mesoporous microfluidic framework (named as white wood) with aligned cellulose nanofibers and inherent microchannels via a facile one-step delignification process from natural wood. The hydrophilic nature of the innate microchannels in white wood makes it ideal for application as a pump-free microfluidic chip, exhibiting a fast and anisotropic liquid and large solid particle (as demonstrated with carbon nanotubes) mass transport, with a high transport speed along the channel direction approximately five times faster than that perpendicular to the channel direction. The anisotropic mass transport is further exemplified in the fabrication of chitosan films with aligned microstructures and birefringence, formed by virtue of unidirectional capillary forces exerted by the microchannels. We envision that our anisotropic mesoporous framework can have great applications to pump-free microfluidics, and the simple preparation process will pave a new way for the development of microfluidic devices based on chemically modified wood. PMID- 29400445 TI - 3D Printing of Highly Stretchable, Shape-Memory, and Self-Healing Elastomer toward Novel 4D Printing. AB - The three-dimensional (3D) printing of flexible and stretchable materials with smart functions such as shape memory (SM) and self-healing (SH) is highly desirable for the development of future 4D printing technology for myriad applications, such as soft actuators, deployable smart medical devices, and flexible electronics. Here, we report a novel ink that can be used for the 3D printing of highly stretchable, SM, and SH elastomer via UV-light-assisted direct ink-write printing. An ink containing urethane diacrylate and a linear semicrystalline polymer is developed for the 3D printing of a semi interpenetrating polymer network elastomer that can be stretched by up to 600%. The 3D-printed complex structures show interesting functional properties, such as high strain SM and SM -assisted SH capability. We demonstrate that such a 3D printed SM elastomer has the potential application for biomedical devices, such as vascular repair devices. This research paves a new way for the further development of novel 4D printing, soft robotics, and biomedical devices. PMID- 29400443 TI - In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains. AB - Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent 18F-labeled PDE10A radioligands (18F-TZ19106B and 18F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of 18F-TZ19106B and 18F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). 18F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than 18F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BPND) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of 18F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 18F TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of 18F TZ19106B. Our results indicate that 18F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies. PMID- 29400446 TI - Promising and Reversible Electrolyte with Thermal Switching Behavior for Safer Electrochemical Storage Devices. AB - A major stumbling block in large-scale adoption of high-energy-density electrochemical devices has been safety issues. Methods to control thermal runaway are limited by providing a one-time thermal protection. Herein, we developed a simple and reversible thermoresponsive electrolyte system that is efficient to shutdown the current flow according to temperature changes. The thermal management is ascribed to the thermally activated sol-gel transition of methyl cellulose solution, associated with the concentration of ions that can move between isolated chains freely or be restricted by entangled molecular chains. We studied the effect of cellulose concentration, substituent types, and operating temperature on the electrochemical performance, demonstrating an obvious capacity loss up to 90% approximately of its initial value. Moreover, this is a cost-effective approach that has the potential for use in practical electrochemical storage devices. PMID- 29400447 TI - Correction to "Total Synthesis of Longeracinphyllin A". PMID- 29400448 TI - High Catalytic Activity of Vanadium Complexes in Alkane Oxidations with Hydrogen Peroxide: An Effect of 8-Hydroxyquinoline Derivatives as Noninnocent Ligands. AB - Five monomeric oxovanadium(V) complexes [VO(OMe)(N?O)2] with the nitro or halogen substituted quinolin-8-olate ligands were synthesized and characterized using Fourier transform infrared, 1H and 13C NMR, high-resolution mass spectrometry electrospray ionization as well as X-ray diffraction and UV-vis spectroscopy. These complexes exhibit high catalytic activity toward oxidation of inert alkanes to alkyl hydroperoxides by H2O2 in aqueous acetonitrile with the yield of oxygenate products up to 39% and turnover number 1780 for 1 h. The experimental kinetic study, the C6D12 and 18O2 labeled experiments, and density functional theory (DFT) calculations allowed to propose the reaction mechanism, which includes the formation of HO. radicals as active oxidizing species. The mechanism of the HO. formation appears to be different from those usually accepted for the Fenton or Fenton-like systems. The activation of H2O2 toward homolysis occurs upon simple coordination of hydrogen peroxide to the metal center of the catalyst molecule and does not require the change of the metal oxidation state and formation of the HOO. radical. Such an activation is associated with the redox active nature of the quinolin-8-olate ligands. The experimentally determined activation energy for the oxidation of cyclohexane with complex [VO(OCH3)(5-Cl quin)2] (quin = quinolin-8-olate) is 23 +/- 3 kcal/mol correlating well with the estimate obtained from the DFT calculations. PMID- 29400449 TI - Preparation, Characterization and Reactivity of a Bis-hypochlorite Adduct of a Chiral Manganese(IV) Salen Complex. AB - A bis-hypochlorite adduct of a manganese(IV) salen complex having a chiral (R,R) cyclohexane-1,2-diamine linkage (2-tBu) is successfully prepared and characterized by various spectroscopic methods. The reactions of 2-tBu with various organic substrates show that 2-tBu is capable of sulfoxidation, epoxidation, chlorination, and hydrogen abstraction reactions. However, the enantioselectivity of the epoxidation reactions by 2-tBu is much lower than that reported for the catalytic reactions by Jacobsen's catalyst. The low enantioselectivity is consistent with a planar conformation of the salen ligand, which is suggested by circular dichroism spectroscopy. This study suggests that 2 tBu is not a reactive intermediate of Jacobsen's enantioselective epoxidation catalysis. PMID- 29400450 TI - Multifunctional Metal-Organic Frameworks Based on Redox-Active Rhenium Octahedral Clusters. AB - The redox-active rhenium octahedral cluster unit [Re6Se8(CN)6]4- was combined with Gd3+ ions and dicarboxylate linkers in novel types of metal-organic frameworks (MOFs) that display a set of functional properties. The hydrolytically stable complexes [{Gd(H2O)3}2(L)Re6Se8(CN)6].nH2O (1, L = furan-2,5 dicarboxylate, fdc; 2, L = thiophene-2,5-dicarboxylate, tdc) exhibit a 3D framework of trigonal symmetry where 1D chains of [{Gd(H2O)3}2(L)]4+ are connected by [Re6Se8(CN)6]4- clusters. Frameworks contain spacious channels filled with H2O. Solvent molecules can be easily removed under vacuum to produce permanently porous solids with high volumetric CO2 uptake and remarkable CO2/N2 selectivity at room temperature. The frameworks demonstrate an ability for reversible redox transformations of the cluster fragment. The orange powders of compounds 1 and 2 react with Br2, yielding dark-green powders of [{Gd(H2O)3}2(L)Re6Se8(CN)6]Br.nH2O (3, L = fdc; 4, L = tdc). Compounds 3 and 4 are isostructural with 1 and 2 and also have permanently porous frameworks but display different optical, magnetic, and sorption properties. In particular, oxidation of the cluster fragment "switches off" its luminescence in the red region, and the incorporation of Br- leads to a decrease of the solvent accessible volume in the channels of 3 and 4. Finally, the green powders of 3 and 4 can be reduced back to the orange powders of 1 and 2 by reaction with hydrazine, thus displaying a rare ability for fully reversible chemical redox transitions. Compounds 1-4 are mentioned as a new class of redox-active cluster based MOFs with potential usage as multifunctional materials for gas separation and chemical contamination sensors. PMID- 29400451 TI - Synthesis and Photophysical Properties of lambda5-Phosphinines as a Tunable Fluorophore. AB - A practical synthesis of a variety of lambda5-phosphinines, which show distinct fluorescence both in solution and solid state, is described. Both C4-selective electrophilic substitutions and the following conversions realized an easy preparation of a wide range of derivatives having several substituents for electronic modification, which provides the potential for fine-tuning of the photophysical properties. PMID- 29400452 TI - Stable and Inert Yttrium(III) Complexes with Pyclen-Based Ligands Bearing Pendant Picolinate Arms: Toward New Pharmaceuticals for beta-Radiotherapy. AB - We report the synthesis of two azaligands based on the pyclen macrocyclic platform containing two picolinate and one acetate pendant arms. The two ligands differ in the relative positions of the pendant functions, which are arranged either in a symmetrical (L3) or nonsymmetrical (L4) fashion. The complexation properties of the ligands toward natY3+ and 90Y3+ were investigated to assess their potential as chelating units for radiopharmaceutical applications. The X ray structures of the YL3 and YL4 complexes show nonadentate binding of the ligand to the metal ions. A multinuclear 1H, 13C, and 89Y NMR study shows that the complexes present a structure in solution similar to that observed in the solid state. The two complexes present very high thermodynamic stability constants (log KYL = 23.36(2) and 23.07(2) for YL3 and YL4, respectively). The complexes also show a remarkable inertness with respect to their proton-assisted dissociation, especially YL4. 90Y radiolabeling was proved to be efficient under mild conditions. The 90YL3 and 90YL4 radiochelates were found to be more stable than 90Y(DOTA). PMID- 29400453 TI - Competitive Self-Assembly Kinetics as a Route To Control the Morphology of Core Crystalline Cylindrical Micelles. AB - Nucleated self-assembly in selective solvents of core-crystalline block copolymers (BCPs) is a special case of living supramolecular polymerization, leading to rodlike micelles of controlled and uniform length. For the crystallization-driven self-assembly of PFS-containing BCPs (PFS = polyferrocenyldimethylsilane), the formation of block comicelles by sequential addition of different BCPs is well-established. But there are only a few examples of living copolymerization, the simultaneous addition of pairs of BCPs with different corona-forming chains. At present, relatively little is known about the competitive kinetics of different BCPs crystallizing on a common seed. Here we report a systematic study of the competitive seeded growth kinetics of pairs of linear PFS-containing BCPs and show that one can manipulate the kinetics to control the morphology of the comicelles. We found that the seeded-growth kinetics of the individual BCP unimer dominates the coassembly behavior and thus the morphology of the corona. Patchy comicelles with microphase-segregated corona chains are formed when the epitaxial growth rates of the two different BCPs on the common seed are similar. In contrast, factors that lead to dissimilar growth rates (long corona-forming blocks or introduction of charges on corona-forming chains) promote large-scale separation of the corona blocks, leading to block comicelles. Because the termini of the comicelles remain living, they can further direct the growth of unimers, resulting in hierarchical block comicelles with patchy blocks and single-component (homo) blocks. Furthermore, the patchy comicelles can be loaded with either gold or platinum nanoparticles, generating organic-inorganic hybrid materials with potential application in catalysis. PMID- 29400454 TI - Biochemistry of Peroxynitrite and Protein Tyrosine Nitration. AB - Peroxynitrite is a short-lived and reactive biological oxidant formed from the diffusion-controlled reaction of the free radicals superoxide (O2*-) and nitric oxide (*NO). In this review, we first analyze the biochemical evidence for the formation of peroxynitrite in vivo and the reactions that lead to it. Then, we describe the principal reactions that peroxynitrite undergoes with biological targets and provide kinetic and mechanistic details. In these reactions, peroxynitrite has roles as (1) peroxide, (2) Lewis base, and (3) free radical generator. Physiological levels of CO2 can change the outcome of peroxynitrite reactions. The second part of the review assesses the formation of protein 3 nitrotyrosine (NO2Tyr) by peroxynitrite-dependent and -independent mechanisms, as one of the hallmarks of the actions of *NO-derived oxidants in biological systems. Moreover, tyrosine nitration impacts protein structure and function, tyrosine kinase signal transduction cascades and protein turnover. Overall, the review is aimed to provide an integrated biochemical view on the formation and reactions of peroxynitrite under biologically relevant conditions and the impact of this stealthy oxidant and one of its major footprints, protein NO2Tyr, in the disruption of cellular homeostasis. PMID- 29400456 TI - Analysis of Urinary Eicosanoids by LC-MS/MS Reveals Alterations in the Metabolic Profile after Smoking Cessation. AB - A preceding untargeted metabolic fingerprinting approach in our lab followed by targeted fatty acid analysis revealed alterations in arachidonic acid metabolism in samples derived from a diet-controlled smoking cessation study in which compliant subjects ( N = 39) quit smoking at baseline and were followed over the course of 3 months. Consequently, urinary eicosanoids were evaluated by means of a validated LC-MS/MS method. A significant decrease was obtained for the prostaglandins PGF2alpha, 8-iso-PGF2alpha, thromboxane 2,3-d-TXB2, and leukotriene E4 upon quitting smoking. These findings indicate a partial recovery of smoking-induced alterations in the eicosanoid profile due to a reduction in oxidative stress and the inflammatory response. PMID- 29400455 TI - Biomimetic Desymmetrization of a Carboxylic Acid. AB - The enantioselective desymmetrization of carboxylic acids by chiral Bronsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Bronsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes. PMID- 29400457 TI - Zintl Ions within Framework Channels: The Complex Structure and Low-Temperature Transport Properties of Na4Ge13. AB - Single crystals of a complex Zintl compound with the composition Na4Ge13 were synthesized for the first time using a high-pressure/high-temperature approach. Single-crystal diffraction of synchrotron radiation revealed a hexagonal crystal structure with P6/m space group symmetry that is composed of a three-dimensional sp3 Ge framework punctuated by small and large channels along the crystallographic c axis. Na atoms are inside hexagonal prism-based Ge cages along the small channels, while the larger channels are occupied by layers of disordered sixfold Na rings, which are in turn filled by disordered [Ge4]4- tetrahedra. This compound is the same as "Na1-xGe3+z" reported previously, but the availability of single crystals allowed for more complete structural determination with a formula unit best described as Na4Ge12(Ge4)0.25. The compound is the first known example of a guest-host structure where discrete Zintl polyanions are confined inside the channels of a three-dimensional covalent framework. These features give rise to temperature-dependent disorder, as confirmed by first-principles calculations and physical properties measurements. The availability of single-crystal specimens allowed for measurement of the intrinsic low-temperature transport properties of this material and revealed its semiconductor behavior, which was corroborated by theoretical calculations. PMID- 29400458 TI - Role of Immobile Kaolinite Colloids in the Transport of Heavy Metals. AB - Predicting the transport of contaminants in porous media is crucial to protecting public health and remediating contaminated soil and groundwater. However, the prediction of contaminant transport is challenging due to the presence of mobile and immobile colloids. The work performed in this experimental investigation quantified the role of immobile clay colloids on metal transport through sets of column breakthrough experiments under varying solution chemistry, clay content, and flow rate. Georgia kaolinite was chosen as the colloidal material, and Pb(II) was chosen as the dissolved contaminant. The silica sand used as the bed material was sized to ensure that the kaolinite colloids remained stationary during the column experiments. Results indicated that retardation of the Pb(II) breakthrough curve was observed as ionic strength decreased and kaolinite content and pH increased, while no significant variation of Pb(II) breakthrough was observed at any kaolinite content as flow rate decreased. This work demonstrated that, in the presence of immobile kaolinite colloids, Pb(II) breakthrough curves strongly depended on the pH and ionic strength, which controlled the charge on the surface functional groups and the surface availability of metal adsorption sites on immobile kaolinite colloids. In addition, the evaluation of unknown first-order coefficients in the continuum governing equation, bed efficiency, and Pb(II) saturation provided a quantitative description of Pb(II) breakthrough curves. PMID- 29400459 TI - Excited State Magnetic Exchange Interactions Enable Large Spin Polarization Effects. AB - Excited state processes involving multiple electron spin centers are crucial elements for both spintronics and quantum information processing. Herein, we describe an addressable excited state mechanism for precise control of electron spin polarization. This mechanism derives from excited state magnetic exchange couplings that occur between the electron spins of a photogenerated electron-hole pair and that of an organic radical. The process is initiated by absorption of a photon followed by ultrafast relaxation within the excited state spin manifold. This leads to dramatic changes in spin polarization between excited states of the same multiplicity. Moreover, this photoinitiated spin polarization process can be "read" spectroscopically using a magnetooptical technique that is sensitive to the excited state electron spin polarizations and allows for the evaluation of wave functions that give rise to these polarizations. This system is unique in that it requires neither intersystem crossing nor magnetic resonance techniques to create dynamic spin-polarization effects in molecules. PMID- 29400460 TI - Engineering a Zirconium MOF through Tandem "Click" Reactions: A General Strategy for Quantitative Loading of Bifunctional Groups on the Pore Surface. AB - Metal-organic frameworks (MOFs) assembled from linkers of identical length but with different functional groups have gained increasing interests recently. However, it is very challenging for precise control of the ratios of different functionalities. Herein, we reported a stable azide- and alkyne-appended Zr-MOF that can undergo quantitative tandem click reactions on the different functional sites, thus providing a unique platform for quantitative loading of bifunctional moieties. As an added advantage, the same MOF product can be obtained via two independent routes. The method is versatile and can tolerate a wide variety of functional groups, and furthermore, a heterogeneous acid-base MOF organocatalyst was synthesized by tandemly introducing both acidic and basic groups onto the predesigned pore surface. The presented strategy provides a general way toward the construction of bifunctional MOFs with a precise control of ratio of different functionalities for desirable applications in future. PMID- 29400462 TI - Copper(II) Triflate As a Reusable Catalyst for the Synthesis of trans-4,5-Diamino cyclopent-2-enones in Water. AB - trans-4,5-Diamino-cyclopent-2-enones (CP) are usually prepared by Lewis acid catalyzed condensation of furfural and a secondary amine in an organic solvent. The reaction proceeds through the formation of a Stenhouse salt (SS) intermediate followed by an electrocyclization reaction to afford the desired CP. Herein, we described the use of Cu(OTf)2 as a very efficient catalyst for the synthesis of CP in water at room temperature. Furthermore, the mild reaction conditions, catalyst reusability, and outstanding functional group tolerance suggest that this CP platform can be further used in chemical biology. PMID- 29400463 TI - Peloruside A-Induced Cell Death in Hypoxia Is p53 Dependent in HCT116 Colorectal Cancer Cells. AB - HCT116 colorectal cancer cell sensitivity to peloruside A (PLA) in normoxia is not altered by hypoxia preconditioning of the cells. We examined whether the PLA effects were altered in hypoxia and whether the activity was dependent on p53. The cytotoxicity of PLA in wild-type HCT116 cells was largely unaffected by hypoxia; however, cells in which p53 was knocked out showed resistance. Knockout of the p21 gene had little effect on the activity of PLA in hypoxia. It was concluded that the response of cells to the microtubule-stabilizing agent PLA under hypoxic conditions is a p53-dependent process. PMID- 29400461 TI - Conformational Ensembles of Calmodulin Revealed by Nonperturbing Site-Specific Vibrational Probe Groups. AB - Seven native residues on the regulatory protein calmodulin, including three key methionine residues, were replaced (one by one) by the vibrational probe amino acid cyanylated cysteine, which has a unique CN stretching vibration that reports on its local environment. Almost no perturbation was caused by this probe at any of the seven sites, as reported by CD spectra of calcium-bound and apo calmodulin and binding thermodynamics for the formation of a complex between calmodulin and a canonical target peptide from skeletal muscle myosin light chain kinase measured by isothermal titration. The surprising lack of perturbation suggests that this probe group could be applied directly in many protein-protein binding interfaces. The infrared absorption bands for the probe groups reported many dramatic changes in the probes' local environments as CaM went from apo- to calcium-saturated to target peptide-bound conditions, including large frequency shifts and a variety of line shapes from narrow (interpreted as a rigid and invariant local environment) to symmetric to broad and asymmetric (likely from multiple coexisting and dynamically exchanging structures). The fast intrinsic time scale of infrared spectroscopy means that the line shapes report directly on site-specific details of calmodulin's variable structural distribution. Though quantitative interpretation of the probe line shapes depends on a direct connection between simulated ensembles and experimental data that does not yet exist, formation of such a connection to data such as that reported here would provide a new way to evaluate conformational ensembles from data that directly contains the structural distribution. The calmodulin probe sites developed here will also be useful in evaluating the binding mode of calmodulin with many uncharacterized regulatory targets. PMID- 29400464 TI - Conformational Flexibility Is a Determinant of Permeability for Cyclosporin. AB - Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known example, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability; however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery. PMID- 29400465 TI - Correction to Connecting Metallic Nanoparticles by Optical Printing. PMID- 29400466 TI - Influence of Transketolase-Catalyzed Reactions on the Formation of Glycolaldehyde and Glyoxal Specific Posttranslational Modifications under Physiological Conditions. AB - In the present study, we investigated the role of transketolase (TK) in the modulation of glycolaldehyde driven Maillard reactions. In vitro experiments with recombinant human TK reduced glycolaldehyde and glyoxal induced carbonyl stress and thereby suppressed the formation of advanced glycation endproducts up to 70% due to the enzyme-catalyzed conversion of glycolaldehyde to erythrulose. This was further substantiated by the use of 13C-labeled compounds. For the first time, glycolaldehyde and other sugars involved in the TK reaction were quantified in vivo and compared to nondiabetic uremic patients undergoing hemodialysis. Quantitation revealed amounts of glycolaldehyde up to 2 MUM and highlighted its crucial role in the formation of AGEs in vivo. In this context, a LC-MS2 method for the comprehensive detection of sedoheptulose-7-phosphate, fructose-6 phosphate, ribose-5-phosphate, erythrose-4-phosphate, erythrulose, and glycolaldehyde in whole blood, plasma, and red blood cells was established and validated based on derivatization with 1-naphthylamine and sodium cyanoborohydride. PMID- 29400467 TI - Determination of Taichunamide H and Structural Revision of Taichunamide A. AB - A new indole alkaloid, named taichunamide H (1), was obtained from cultures of the fungus Aspergillus versicolor. With observation of a carbon resonance with a chemical shift of 190.4 ppm, generally thought to be a carbonyl, the structure of 1 was initially proposed to be a diastereomer of taichunamide A that contains a unique spiro-azetidine moiety. Further analysis of compound 1 using X-ray diffraction showed that the spiro-azetidine moiety should be revised as a fused imine-containing pyrrole ring, with the resonance at 190.4 ppm assigned as an imine carbon. Accordingly, the structure of taichunamide A was also revised. PMID- 29400468 TI - Structurally Diverse Cytotoxic Dimeric Chalcones from Oxytropis chiliophylla. AB - Ten isomeric cyclobutane- and cyclohexene-containing chalcone dimers, oxyfadichalcones A-G, were isolated from the aerial parts of Oxytropis chiliophylla. These included six new compounds and three pairs of enantiomers that are being reported from natural sources for the first time. The relative configurations were elucidated by spectroscopic data analysis, while the absolute configurations were determined by comparing the experimental and calculated electronic circular dichroism spectra. Quantitative LC-MS analysis of the main dimers from different parts of the plant revealed their characteristic accumulation in the viscous secretion and provided supporting evidence for the hypothesized photochemical biosynthesis. In addition, the cytotoxic activities of all isolates against the PC-3 human prostate cancer cell line are reported. PMID- 29400469 TI - Deposition Dynamics of Rod-Shaped Colloids during Transport in Porous Media under Favorable Conditions. AB - A three-dimensional computational modeling study of the deposition dynamics of rod-shaped colloids during transport in porous media under favorable conditions (no energy barrier to deposition) is presented. The objective was to explore the influences of the particle shape on colloid transport and retention. During simulation, both translation and rotation of ellipsoidal particles were tracked and evaluated based on an analysis of all forces and torques acting on the particle. We observed that the shape was a key factor affecting colloid transport and attachment. Rod particles exhibited enhanced retention compared with spheres of equivalent volume in the size range greater than ~200 nm. The shape effect was the most pronounced for particles around 200 nm to 1 MUm under simulated conditions. The shape effect was also strongly dependent upon the fluid velocity; it was most significant at high velocity, but not so at very low velocity. The above-described shape effect on retention was directly related to particle rotation dynamics due to the coupled effects from rotational diffusion and flow hydrodynamics. Rotational diffusion changed the particle orientation randomly, which caused the rod particles to drift considerably across flow streamlines for attachment in the size range from 200 nm to 1 MUm. The hydrodynamic effect induced periodic particle rotation and oscillation, which rendered large-sized rod particles to behave like "spinning bodies," prescribed by their long axes so as to easily intercept with the collector surface for retention. Our findings demonstrated that the practice of using equivalent spheres to approximate rods is inadequate in predicting the transport fate and adhesion dynamics of rod-shaped colloids in porous media. PMID- 29400471 TI - Highly Oxidized Guaianolide Sesquiterpenoids with Potential Anti-inflammatory Activity from Chrysanthemum indicum. AB - Ten new highly oxidized monomeric (1-8) and dimeric guaianolides (9 and 10), along with two known guaianolide derivatives (11 and 12), were isolated from the aerial parts of Chrysanthemum indicum using a bioassay-guided fractionation procedure. The new compounds were characterized by the basic analysis of the spectroscopic data obtained, and the absolute configurations were determined by both empirical approaches and ECD calculations. Inhibitory effects of 1-12 on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and most of them (1-8 and 11) displayed IC50 values in the range 1.4 9.7 MUM. Moreover, a mechanistic study revealed that the potential anti inflammatory activity of compound 1 appears to be mediated via suppression of an LPS-induced NF-kappaB pathway and down-regulation of MAPK activation. PMID- 29400470 TI - The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration. AB - A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile. PMID- 29400472 TI - Frustrated Lewis Pair Catalyzed C-H Activation of Heteroarenes: A Stepwise Carbene Mechanism Due to Distance Effect. AB - This study presents new mechanistic insights into the frustrated Lewis pairs (FLPs) catalyzed C-H activation of heteroarenes. Besides the generally accepted concerted C-H activation, a novel stepwise carbene type pathway is proposed as an alternative mechanism. The reaction mechanisms can be varied by tuning the distance between Lewis acid and Lewis base due to catalyst-substrate match. These results should expand the understanding of the structure and function of FLPs for catalyzed C-H activation. PMID- 29400473 TI - phpMs: A PHP-Based Mass Spectrometry Utilities Library. AB - The recent establishment of cloud computing, high-throughput networking, and more versatile web standards and browsers has led to a renewed interest in web-based applications. While traditionally big data has been the domain of optimized desktop and server applications, it is now possible to store vast amounts of data and perform the necessary calculations offsite in cloud storage and computing providers, with the results visualized in a high-quality cross-platform interface via a web browser. There are number of emerging platforms for cloud-based mass spectrometry data analysis; however, there is limited pre-existing code accessible to web developers, especially for those that are constrained to a shared hosting environment where Java and C applications are often forbidden from use by the hosting provider. To remedy this, we provide an open-source mass spectrometry library for one of the most commonly used web development languages, PHP. Our new library, phpMs, provides objects for storing and manipulating spectra and identification data as well as utilities for file reading, file writing, calculations, peptide fragmentation, and protein digestion as well as a software interface for controlling search engines. We provide a working demonstration of some of the capabilities at http://pgb.liv.ac.uk/phpMs . PMID- 29400474 TI - Access to 3-Prenylated Oxindoles by alpha-Regioselective Prenylation: Application to the Synthesis of (+/-)-Debromoflustramine E. AB - The development of a rapid, highly efficient, and one-pot synthesis of C3-alpha prenylated oxindoles with simple reagents is described. The process is based on zinc-mediated alpha-regioselective prenylation of 3-acylidene-oxindole with commercially available prenyl bromide using inexpensive CeCl3 as the catalyst. The new transformation tolerates a wide range of 3-acylidene-oxindoles, providing easy access to a variety of functionalized 3-prenylated oxindoles. The synthetic utility of the approach is verified by formal synthesis of the flustramine family alkaloid (+/-)-debromoflustramine E. PMID- 29400475 TI - Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile. AB - The prostate-specific membrane antigen (PSMA) has emerged as an attractive prostate cancer associated target for radiotheragnostic application using PSMA specific radioligands. The aim of this study was to design new PSMA ligands modified with an albumin-binding moiety in order to optimize their tissue distribution profile. The compounds were prepared by conjugation of a urea-based PSMA-binding entity, a DOTA chelator, and 4-( p-iodophenyl)butyric acid using multistep solid phase synthesis. The three ligands (PSMA-ALB-02, PSMA-ALB-05, and PSMA-ALB-07) were designed with varying linker entities. Radiolabeling with 177Lu was performed at a specific activity of up to 50 MBq/nmol resulting in radioligands of >98% radiochemical purity and high stability. In vitro investigations revealed high binding of all three PSMA radioligands to mouse (>64%) and human plasma proteins (>94%). Uptake and internalization into PSMA positive PC-3 PIP tumor cells was equally high for all radioligands. Negligible accumulation was found in PSMA-negative PC-3 flu cells, indicating PSMA-specific binding of all radioligands. Biodistribution and imaging studies performed in PC 3 PIP/flu tumor-bearing mice showed enhanced blood circulation of the new radioligands when compared to the clinically employed 177Lu-PSMA-617. The PC-3 PIP tumor uptake of all three radioligands was very high (76.4 +/- 2.5% IA/g, 79.4 +/- 11.1% IA/g, and 84.6 +/- 14.2% IA/g, respectively) at 24 h post injection (p.i.) resulting in tumor-to-blood ratios of ~176, ~48, and ~107, respectively, whereas uptake into PC-3 flu tumors was negligible. Kidney uptake at 24 h p.i. was lowest for 177Lu-PSMA-ALB-02 (10.7 +/- 0.92% IA/g), while 177Lu PSMA-ALB-05 and 177Lu-PSMA-ALB-07 showed higher renal retention (23.9 +/- 4.02% IA/g and 51.9 +/- 6.34% IA/g, respectively). Tumor-to-background ratios calculated from values of the area under the curve (AUC) of time-dependent biodistribution data were in favor of 177Lu-PSMA-ALB-02 (tumor-to-blood, 46; tumor-to-kidney, 5.9) when compared to 177Lu-PSMA-ALB-05 (17 and 3.7, respectively) and 177Lu-PSMA-ALB-07 (39 and 2.1, respectively). The high accumulation of the radioligands in PC-3 PIP tumors was visualized on SPECT/CT images demonstrating increasing tumor-to-kidney ratios over time. Taking all of the characteristics into account, 177Lu-PSMA-ALB-02 emerged as the most promising candidate. The applied concept may be attractive for future clinical translation potentially enabling more potent and convenient prostate cancer radionuclide therapy. PMID- 29400476 TI - StPeter: Seamless Label-Free Quantification with the Trans-Proteomic Pipeline. AB - Label-free quantification has grown in popularity as a means of obtaining relative abundance measures for proteomics experiments. However, easily accessible and integrated tools to perform label-free quantification have been lacking. We describe StPeter, an implementation of Normalized Spectral Index quantification for wide availability through integration into the widely used Trans-Proteomic Pipeline. This implementation has been specifically designed for reproducibility and ease of use. We demonstrate that StPeter outperforms other state-of-the art packages using a recently reported benchmark data set over the range of false discovery rates relevant to shotgun proteomics results. We also demonstrate that the software is computationally efficient and supports data from a variety of instrument platforms and experimental designs. Results can be viewed within the Trans-Proteomic Pipeline graphical user interfaces and exported in standard formats for downstream statistical analysis. By integrating StPeter into the freely available Trans-Proteomic Pipeline, users can now obtain high-quality label-free quantification of any data set in seconds by adding a single command to the workflow. PMID- 29400477 TI - Asymmetric Formal Synthesis of (-)-Cephalotaxine via Palladium-Catalyzed Enantioselective Tsuji Allylation. AB - Asymmetric synthesis of the pentacyclic alkaloid (-)-cephalotaxine was accomplished via palladium-catalyzed enantioselective Tsuji allylation for construction of the aza-containing tetrasubstituted stereogenic center (95% yield, 93% ee). The allyl enol carbonate precursor was prepared from Hanaoka's ketone intermediate, which was formed by a novel formic acid promoted ring expansion reaction. PMID- 29400478 TI - Rhodium-Catalyzed Enantioselective Decarboxylative Alkynylation of Allenes with Arylpropiolic Acids. AB - A rhodium-catalyzed chemo-, regio-, and enantioselective intermolecular decarboxylative alkynylation of terminal allenes with arylpropiolic acids is reported. Employing a Rh(I)/(R)-Tol-BINAP catalytic system, branched allylic 1,4 enynes were obtained under mild conditions. The overall utility of this protocol is exemplified by a broad functional group compatibility. PMID- 29400479 TI - Temperamental workers: Psychology, business, and the Humm-Wadsworth Temperament Scale in interwar America. AB - This article traces the history of a popular interwar psychological test, the Humm-Wadsworth Temperament Scale (HWTS), from its development in the early 1930s to its adoption by corporate personnel departments. In popular articles, trade magazines, and academic journals, industrial psychologist Doncaster Humm and personnel manager Guy Wadsworth trumpeted their scale as a scientific measure of temperament that could ensure efficient hiring practices and harmonious labor relations by screening out "problem employees" and screening for temperamentally "normal" workers. This article demonstrates how concerns about the epistemological and scientific credibility of the HWTS were intimately entangled with concerns about its value to business at every step in the test's development. The HWTS sought to measure the emotional and social dimensions of an individual's personality so as to assess their suitability for work. The practice of temperament testing conjured a vision of the subject whose emotional and social disposition was foundational to their own capacity to find employment, and whose capacity to appropriately express, but regulate, their emotions was foundational to corporate order. The history of the HWTS offers an instructive case of how psychological tests embed social hierarchies, political claims, and economic ideals within their very theoretical and methodological foundations. Although the HWTS itself may have faded from use, the test directly inspired creators of subsequent popular personality tests, such as the Minnesota Multiphasic Personality Inventory and the Myers-Briggs Type Indicator. (PsycINFO Database Record PMID- 29400480 TI - Through the looking-glass: PsycINFO as an historical archive of trends in psychology. AB - Those interested in tracking trends in the history of psychology cannot simply trust the numbers produced by inputting terms into search engines like PsycINFO and then constraining by date. This essay is therefore a critical engagement with that longstanding interest to show what it is possible to do, over what period, and why. It concludes that certain projects simply cannot be undertaken without further investment by the American Psychological Association. This is because forgotten changes in the assumptions informing the database make its index terms untrustworthy for use in trend-tracking before 1967. But they can indeed be used, with care, to track more recent trends. The result is then a Distant Reading of psychology, with Digital History presented as enabling a kind of Science Studies that psychologists will find appealing. The present state of the discipline can thus be caricatured as the contemporary scientific study of depressed rats and the drugs used to treat them (as well as of human brains, mice, and myriad other topics). To extend the investigation back further in time, however, the 1967 boundary is also investigated. The author then delves more deeply into the prehistory of the database's creation, and shows in a precis of a further project that the origins of PsycINFO can be traced to interests related to American national security during the Cold War. In short: PsycINFO cannot be treated as a simple bibliographic description of the discipline. It is embedded in its history, and reflects it. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29400481 TI - Is action execution part of the decision-making process? An investigation of the embodied choice hypothesis. AB - In this study, we aimed to explore whether action execution is an inherent part of the decision-making process. According to the hypothesis of embodied choice, the decision-making process is bidirectional as action dynamics exert their backward influence on decision processes through changing the cost and value of the potential options. This influence takes place as moving toward one option increases the commitment to and, therefore, the likelihood of choosing that option. This commitment effect can be the result of either (a) the continuous act of getting closer to this option or (b) the increased movement cost associated with changing the movement direction to select a different option. To disentangle the potential influence of these two factors, we developed the Guided Movement Task, a choice task designed to bias participant's computer-mouse movements by constraining the allowed movement space by a corridor. Using this task, we created different conditions in which the participants' mouse cursor, after being guided toward one of the options, either had equal or unequal distances to the choice options. By this manipulation, we could test whether the continuous act of getting closer to an option in itself is sufficient to influence people's decisions-a claim of "strong embodiment." In two experiments, we found that the likelihood of choosing an option only increased when the distances between the two options were unequal after the initial movement but not when they were equal. These results disagree with the hypothesis that action execution is an inherent part of the decision-making process. (PsycINFO Database Record PMID- 29400483 TI - William James and the Heidelberg fiasco. AB - Urged on by his father to become a physician instead of a painter, William James pursued 3 evasion stratagems. First, to avoid becoming a practitioner, he declared that he wanted to specialize in physiology. Based upon this premise, he left for Germany in the spring of 1867. The second step was giving up general physiology and announcing that he would specialize in the nervous system and psychology. Based upon this premise, he declared that he would go to Heidelberg and study with Helmholtz and Wundt. However, he then deferred going there. When, at last, he was urged by an influential friend of his father's to accompany him to Heidelberg, he employed his default stratagem: He simply fled. He returned home after 3 terms in Europe without enrolling at a single university. There is no evidence that he had learned anything there about psychology or experimental psychology, except, possibly, by reading books. James's "Heidelberg fiasco" was the apogee of his evasion of his father's directive. A dense fog of misinformation surrounds his stay in Heidelberg to this day. By analyzing circumstances and context, this article examines the fiasco and places it in the pattern of his behavior during his stay in Europe. Nevertheless, experiencing this fiasco potentially shaped James's ambivalent attitude toward experimental psychology on a long-term basis. (PsycINFO Database Record PMID- 29400484 TI - Poetry corner. AB - This issue's poem is of historical interest due to its biographical features and celebratory tone, if not for its craft or lyricism per se. It was written by Joyce M. Hoffman for E. G. Boring on the occasion of his eightieth birthday. Division 26 was also founded that year (1966), with Boring named as its honorary first president. (PsycINFO Database Record PMID- 29400485 TI - The 100th anniversary of the death of Julian Ochorowicz (1850-1917). AB - This article talks about the life of Julian Ochorowicz. It encompasses his life as a scientist, psychologist, his works, reputation and other events. In conclusion, this article denotes the relevancy of Ochorowicz's life. (PsycINFO Database Record PMID- 29400486 TI - Nonperturbative Treatment of non-Markovian Dynamics of Open Quantum Systems. AB - We identify the conditions that guarantee equivalence of the reduced dynamics of an open quantum system (OQS) for two different types of environments-one a continuous bosonic environment leading to a unitary system-environment evolution and the other a discrete-mode bosonic environment resulting in a system-mode (nonunitary) Lindbladian evolution. Assuming initial Gaussian states for the environments, we prove that the two OQS dynamics are equivalent if both the expectation values and two-time correlation functions of the environmental interaction operators are the same at all times for the two configurations. Since the numerical and analytical description of a discrete-mode environment undergoing a Lindbladian evolution is significantly more efficient than that of a continuous bosonic environment in a unitary evolution, our result represents a powerful, nonperturbative tool to describe complex and possibly highly non Markovian dynamics. As a special application, we recover and generalize the well known pseudomodes approach to open-system dynamics. PMID- 29400487 TI - Creation of Spin-Triplet Cooper Pairs in the Absence of Magnetic Ordering. AB - In superconducting spintronics, it is essential to generate spin-triplet Cooper pairs on demand. Up to now, proposals to do so concentrate on hybrid structures in which a superconductor (SC) is combined with a magnetically ordered material (or an external magnetic field). We, instead, identify a novel way to create and isolate spin-triplet Cooper pairs in the absence of any magnetic ordering. This achievement is only possible because we drive a system with strong spin-orbit interaction-the Dirac surface states of a strong topological insulator (TI)-out of equilibrium. In particular, we consider a bipolar TI-SC-TI junction, where the electrochemical potentials in the outer leads differ in their overall sign. As a result, we find that nonlocal singlet pairing across the junction is completely suppressed for any excitation energy. Hence, this junction acts as a perfect spin triplet filter across the SC, generating equal-spin Cooper pairs via crossed Andreev reflection. PMID- 29400488 TI - Microwave Properties of Superconductors Close to the Superconductor-Insulator Transition. AB - Strongly disordered pseudogapped superconductors are expected to display arbitrarily high values of kinetic inductance close to the superconductor insulator transition (SIT), which make them attractive for the implementation of large dissipationless inductance. We develop the theory of the collective modes in these superconductors and discuss associated dissipation at microwave frequencies. We obtain the collective mode spectra dependence on the disorder level and conclude that collective modes become a relevant source of dissipation and noise in the outer proximity of the SIT. PMID- 29400489 TI - Structuring of Fluid Adlayers upon Ongoing Unimolecular Adsorption. AB - Fluids with spatial density variations of single or mixed molecules play a key role in biophysics, soft matter, and materials science. The fluid structures usually form via spinodal decomposition or nucleation following an instantaneous destabilization of the initially disordered fluid. However, in practice, an instantaneous quench is often not viable, and the rate of destabilization may be gradual rather than instantaneous. In this work we show that the commonly used phenomenological descriptions of fluid structuring are inadequate under these conditions. We come to that conclusion in the context of surface catalysis, where we employ kinetic Monte Carlo simulations to describe the unimolecular adsorption of gaseous molecules onto a metal surface. The adsorbates diffuse at the surface and, as a consequence of lateral interactions and due to an ongoing increase of the surface coverage, phase separate into coexisting low- and high-density regions. The typical size of these regions turns out to depend much more strongly on the rate of adsorption than predicted from recently reported phenomenological models. We discuss how this finding contributes to the fundamental understanding of the crossover from liquid-liquid to liquid-solid demixing of solution-cast polymer blends. PMID- 29400490 TI - Pion Condensation by Rotation in a Magnetic Field. AB - We show that the combined effects of a rotation plus a magnetic field can cause charged pion condensation. We suggest that this phenomenon may yield to observable effects in current heavy ion collisions at collider energies, where large magnetism and rotations are expected in off-central collisions. PMID- 29400491 TI - Ion Transport and Precipitation Kinetics as Key Aspects of Stress Generation on Pore Walls Induced by Salt Crystallization. AB - The stress generation on pore walls due to the growth of a sodium chloride crystal in a confined aqueous solution is studied from evaporation experiments in microfluidic channels in conjunction with numerical computations of crystal growth. The study indicates that the stress buildup on the pore walls is a highly transient process taking place over a very short period of time (in less than 1 s in our experiments). The analysis makes clear that what matters for the stress generation is not the maximum supersaturation at the onset of the crystal growth but the supersaturation at the interface between the solution and the crystal when the latter is about to be confined between the pore walls. The stress generation is summarized in a simple stress diagram involving the pore aspect ratio and the Damkholer number characterizing the competition between the precipitation reaction kinetics and the ion transport towards the growing crystal. This opens up the route for a better understanding of the damage of porous materials induced by salt crystallization, an important issue in Earth sciences, reservoir engineering, and civil engineering. PMID- 29400492 TI - Chirality in Magnetic Multilayers Probed by the Symmetry and the Amplitude of Dichroism in X-Ray Resonant Magnetic Scattering. AB - Chirality in condensed matter has recently become a topic of the utmost importance because of its significant role in the understanding and mastering of a large variety of new fundamental physical mechanisms. Versatile experimental approaches, capable to reveal easily the exact winding of order parameters, are therefore essential. Here we report x-ray resonant magnetic scattering as a straightforward tool to reveal directly the properties of chiral magnetic systems. We show that it can straightforwardly and unambiguously determine the main characteristics of chiral magnetic distributions: i.e., its chiral nature, the quantitative winding sense (clockwise or counterclockwise), and its type, i.e., Neel [cycloidal] or Bloch [helical]. This method is model independent, does not require a priori knowledge of the magnetic parameters, and can be applied to any system with magnetic domains ranging from a few nanometers (wavelength limited) to several microns. By using prototypical multilayers with tailored magnetic chiralities driven by spin-orbit-related effects at Co|Pt interfaces, we illustrate the strength of this method. PMID- 29400493 TI - Einstein Equations from Varying Complexity. AB - A recent proposal equates the circuit complexity of a quantum gravity state with the gravitational action of a certain patch of spacetime. Since Einstein's equations follow from varying the action, it should be possible to derive them by varying complexity. I present such a derivation for vacuum solutions of pure Einstein gravity in three-dimensional asymptotically anti-de Sitter space. The argument relies on known facts about holography and on properties of tensor network renormalization, an algorithm for coarse-graining (and optimizing) tensor networks. PMID- 29400494 TI - Vortex Thermometry for Turbulent Two-Dimensional Fluids. AB - We introduce a new method of statistical analysis to characterize the dynamics of turbulent fluids in two dimensions. We establish that, in equilibrium, the vortex distributions can be uniquely connected to the temperature of the vortex gas, and we apply this vortex thermometry to characterize simulations of decaying superfluid turbulence. We confirm the hypothesis of vortex evaporative heating leading to Onsager vortices proposed in Phys. Rev. Lett. 113, 165302 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.165302, and we find previously unidentified vortex power-law distributions that emerge from the dynamics. PMID- 29400495 TI - Distinct Nature of Static and Dynamic Magnetic Stripes in Cuprate Superconductors. AB - We present detailed neutron scattering studies of the static and dynamic stripes in an optimally doped high-temperature superconductor, La_{2}CuO_{4+y}. We observe that the dynamic stripes do not disperse towards the static stripes in the limit of vanishing energy transfer. Therefore, the dynamic stripes observed in neutron scattering experiments are not the Goldstone modes associated with the broken symmetry of the simultaneously observed static stripes, and the signals originate from different domains in the sample. These observations support real space electronic phase separation in the crystal, where the static stripes in one phase are pinned versions of the dynamic stripes in the other, having slightly different periods. Our results explain earlier observations of unusual dispersions in underdoped La_{2-x}Sr_{x}CuO_{4} (x=0.07) and La_{2 x}Ba_{x}CuO_{4} (x=0.095). PMID- 29400496 TI - Spin Current Noise of the Spin Seebeck Effect and Spin Pumping. AB - We theoretically investigate the fluctuation of a pure spin current induced by the spin Seebeck effect and spin pumping in a normal-metal-(NM-)ferromagnet(FM) bilayer system. Starting with a simple ferromagnet-insulator-(FI-)NM interface model with both spin-conserving and non-spin-conserving processes, we derive general expressions of the spin current and the spin-current noise at the interface within second-order perturbation of the FI-NM coupling strength, and estimate them for a yttrium-iron-garnet-platinum interface. We show that the spin current noise can be used to determine the effective spin carried by a magnon modified by the non-spin-conserving process at the interface. In addition, we show that it provides information on the effective spin of a magnon, heating at the interface under spin pumping, and spin Hall angle of the NM. PMID- 29400497 TI - Superconductivity in Pristine 2H_{a}-MoS_{2} at Ultrahigh Pressure. AB - As a follow-up of our previous work on pressure-induced metallization of the 2H_{c}-MoS_{2} [Chi et al., Phys. Rev. Lett. 113, 036802 (2014)PRLTAO0031 900710.1103/PhysRevLett.113.036802], here we extend pressure beyond the megabar range to seek after superconductivity via electrical transport measurements. We found that superconductivity emerges in the 2H_{a}-MoS_{2} with an onset critical temperature T_{c} of ca. 3 K at ca. 90 GPa. Upon further increasing the pressure, T_{c} is rapidly enhanced beyond 10 K and stabilized at ca. 12 K over a wide pressure range up to 220 GPa. Synchrotron x-ray diffraction measurements evidenced no further structural phase transition, decomposition, and amorphization up to 155 GPa, implying an intrinsic superconductivity in the 2H_{a}-MoS_{2}. DFT calculations suggest that the emergence of pressure-induced superconductivity is intimately linked to the emergence of a new flat Fermi pocket in the electronic structure. Our finding represents an alternative strategy for achieving superconductivity in 2H-MoS_{2} in addition to chemical intercalation and electrostatic gating. PMID- 29400498 TI - Experimental High-Dimensional Einstein-Podolsky-Rosen Steering. AB - Steering nonlocality is the fundamental property of quantum mechanics, which has been widely demonstrated in some systems with qubits. Recently, theoretical works have shown that the high-dimensional (HD) steering effect exhibits novel and important features, such as noise suppression, which appear promising for potential application in quantum information processing (QIP). However, experimental observation of these HD properties remains a great challenge to date. In this work, we demonstrate the HD steering effect by encoding with orbital angular momentum photons for the first time. More importantly, we have quantitatively certified the noise-suppression phenomenon in the HD steering effect by introducing a tunable isotropic noise. We believe our results represent a significant advance of the nonlocal steering study and have direct benefits for QIP applications with superior capacity and reliability. PMID- 29400500 TI - Gravitational Waves from Oscillons with Cuspy Potentials. AB - We study the production of gravitational waves during oscillations of the inflaton around the minimum of a cuspy potential after inflation. We find that a cusp in the potential can trigger copious oscillon formation, which sources a characteristic energy spectrum of gravitational waves with double peaks. The discovery of such a double-peak spectrum could test the underlying inflationary physics. PMID- 29400501 TI - Comment on "Fundamental Resolution of Difficulties in the Theory of Charged Point Defects in Semiconductors". PMID- 29400502 TI - Quasinormal Modes and Strong Cosmic Censorship. AB - The fate of Cauchy horizons, such as those found inside charged black holes, is intrinsically connected to the decay of small perturbations exterior to the event horizon. As such, the validity of the strong cosmic censorship (SCC) conjecture is tied to how effectively the exterior damps fluctuations. Here, we study massless scalar fields in the exterior of Reissner-Nordstrom-de Sitter black holes. Their decay rates are governed by quasinormal modes of the black hole. We identify three families of modes in these spacetimes: one directly linked to the photon sphere, well described by standard WKB-type tools; another family whose existence and time scale is closely related to the de Sitter horizon; finally, a third family which dominates for near-extremally charged black holes and which is also present in asymptotically flat spacetimes. The last two families of modes seem to have gone unnoticed in the literature. We give a detailed description of linear scalar perturbations of such black holes, and conjecture that SCC is violated in the near extremal regime. PMID- 29400499 TI - Evaluation of the Interplanetary Magnetic Field Strength Using the Cosmic-Ray Shadow of the Sun. AB - We analyze the Sun's shadow observed with the Tibet-III air shower array and find that the shadow's center deviates northward (southward) from the optical solar disk center in the "away" ("toward") interplanetary magnetic field (IMF) sector. By comparing with numerical simulations based on the solar magnetic field model, we find that the average IMF strength in the away (toward) sector is 1.54+/ 0.21_{stat}+/-0.20_{syst} (1.62+/-0.15_{stat}+/-0.22_{syst}) times larger than the model prediction. These demonstrate that the observed Sun's shadow is a useful tool for the quantitative evaluation of the average solar magnetic field. PMID- 29400503 TI - Suppression of the Nonlinear Zeeman Effect and Heading Error in Earth-Field-Range Alkali-Vapor Magnetometers. AB - The nonlinear Zeeman effect can induce splitting and asymmetries of magnetic resonance lines in the geophysical magnetic-field range. This is a major source of "heading error" for scalar atomic magnetometers. We demonstrate a method to suppress the nonlinear Zeeman effect and heading error based on spin locking. In an all-optical synchronously pumped magnetometer with separate pump and probe beams, we apply a radio-frequency field which is in phase with the precessing magnetization. This results in the collapse of the multicomponent asymmetric magnetic-resonance line with ~100 Hz width in the Earth-field range into a single peak with a width of 22 Hz, whose position is largely independent of the orientation of the sensor within a range of orientation angles. The technique is expected to be broadly applicable in practical magnetometry, potentially boosting the sensitivity and accuracy of Earth-surveying magnetometers by increasing the magnetic-resonance amplitude, decreasing its width, and removing the important and limiting heading-error systematic. PMID- 29400504 TI - Wu, Zhang, and Pantelides Reply. PMID- 29400505 TI - Erratum: Wald Entropy for Ghost-Free, Infinite Derivative Theories of Gravity [Phys. Rev. Lett. 114, 201101 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.201101. PMID- 29400506 TI - Machine Learning Based Localization and Classification with Atomic Magnetometers. AB - We demonstrate identification of position, material, orientation, and shape of objects imaged by a ^{85}Rb atomic magnetometer performing electromagnetic induction imaging supported by machine learning. Machine learning maximizes the information extracted from the images created by the magnetometer, demonstrating the use of hidden data. Localization 2.6 times better than the spatial resolution of the imaging system and successful classification up to 97% are obtained. This circumvents the need of solving the inverse problem and demonstrates the extension of machine learning to diffusive systems, such as low-frequency electrodynamics in media. Automated collection of task-relevant information from quantum-based electromagnetic imaging will have a relevant impact from biomedicine to security. PMID- 29400507 TI - Electron Dynamics Driven by Light-Pulse Derivatives. AB - We demonstrate that ultrashort pulses carry the possibility for a new regime of light-matter interaction with nonadiabatic electron processes sensitive to the envelope derivative of the light pulse. A standard single pulse with its two peaks in the derivative separated by the width of the pulse acts in this regime like a traditional double pulse. The two ensuing nonadiabatic ionization bursts have slightly different ionization amplitudes. This difference is due to the redistribution of continuum electron energy during the bursts, negligible in standard photoionization. A time-dependent close-coupling approach based on cycle averaged potentials in the Kramers-Henneberger reference frame permits a detailed understanding of light-pulse derivative-driven electron dynamics. PMID- 29400508 TI - Covariant Structure of Models of Geophysical Fluid Motion. AB - Geophysical models approximate classical fluid motion in rotating frames. Even accurate approximations can have profound consequences, such as the loss of inertial frames. If geophysical fluid dynamics are not strictly equivalent to Newtonian hydrodynamics observed in a rotating frame, what kind of dynamics are they? We aim to clarify fundamental similarities and differences between relativistic, Newtonian, and geophysical hydrodynamics, using variational and covariant formulations as tools to shed the necessary light. A space-time variational principle for the motion of a perfect fluid is introduced. The geophysical action is interpreted as a synchronous limit of the relativistic action. The relativistic Levi-Civita connection also has a finite synchronous limit, which provides a connection with which to endow geophysical space-time, generalizing Cartan (1923). A covariant mass-momentum budget is obtained using covariance of the action and metric-preserving properties of the connection. Ultimately, geophysical models are found to differ from the standard compressible Euler model only by a specific choice of a metric-Coriolis-geopotential tensor akin to the relativistic space-time metric. Once this choice is made, the same covariant mass-momentum budget applies to Newtonian and all geophysical hydrodynamics, including those models lacking an inertial frame. Hence, it is argued that this mass-momentum budget provides an appropriate, common fundamental principle of dynamics. The postulate that Euclidean, inertial frames exist can then be regarded as part of the Newtonian theory of gravitation, which some models of geophysical hydrodynamics slightly violate. PMID- 29400509 TI - Realization of an Electrically Tunable Narrow-Bandwidth Atomically Thin Mirror Using Monolayer MoSe_{2}. AB - The advent of two-dimensional semiconductors, such as van der Waals heterostructures, propels new research directions in condensed matter physics and enables development of novel devices with unique functionalities. Here, we show experimentally that a monolayer of MoSe_{2} embedded in a charge controlled heterostructure can be used to realize an electrically tunable atomically thin mirror, which effects 87% extinction of an incident field that is resonant with its exciton transition. The corresponding maximum reflection coefficient of 41% is only limited by the ratio of the radiative decay rate to the nonradiative linewidth of exciton transition and is independent of incident light intensity up to 400 W/cm^{2}. We demonstrate that the reflectivity of the mirror can be drastically modified by applying a gate voltage that modifies the monolayer charge density. Our findings could find applications ranging from fast programable spatial light modulators to suspended ultralight mirrors for optomechanical devices. PMID- 29400510 TI - Magnetopolaritons in Weyl Semimetals in a Strong Magnetic Field. AB - Exotic topological and transport properties of Weyl semimetals have generated a lot of excitement in the condensed matter community. Here we show that Weyl semimetals in a strong magnetic field are highly unusual optical materials. The propagation of electromagnetic waves is affected by an interplay between the plasmonic response of chiral Weyl fermions and extreme anisotropy induced by a magnetic field. The resulting magnetopolaritons possess a number of peculiar properties, such as hyperbolic dispersion, photonic stop bands, coupling-induced transparency, and broadband polarization conversion. These effects can be used for optical spectroscopy of these materials including detection of the chiral anomaly or for broadband terahertz or infrared applications. PMID- 29400512 TI - ^{3}He-^{129}Xe Comagnetometery using ^{87}Rb Detection and Decoupling. AB - We describe a ^{3}He-^{129}Xe comagnetometer using ^{87}Rb atoms for noble-gas spin polarization and detection. We use a train of ^{87}Rb pi pulses and sigma^{+}/sigma^{-} optical pumping to realize a finite-field Rb magnetometer with suppression of spin-exchange relaxation. We suppress frequency shifts from polarized Rb by measuring the ^{3}He and ^{129}Xe spin precession frequencies in the dark, while applying pi pulses along two directions to depolarize Rb atoms. The plane of the pi pulses is rotated to suppress the Bloch-Siegert shifts for the nuclear spins. We measure the ratio of ^{3}He to ^{129}Xe spin precession frequencies with sufficient absolute accuracy to resolve Earth's rotation without changing the orientation of the comagnetometer. A frequency resolution of 7 nHz is achieved after integration for 8 h without evidence of significant drift. PMID- 29400513 TI - Microscopic Theory of Surface Topological Order for Topological Crystalline Superconductors. AB - We construct microscopic Hamiltonians for symmetry-preserving topologically ordered states on the surface of topological crystalline superconductors, protected by a Z_{2} reflection symmetry. Starting from nu Majorana cones on the surface, we show that the semion-fermion topological order emerges for nu=2, and more generally, SO(nu)_{nu} topological order for all nu>=2 and Sp(n)_{n} for nu=2n when n>=2. PMID- 29400514 TI - High-Temperature Terahertz Optical Diode Effect without Magnetic Order in Polar FeZnMo_{3}O_{8}. AB - We present a terahertz spectroscopic study of polar ferrimagnet FeZnMo_{3}O_{8}. Our main finding is a giant high-temperature optical diode effect, or nonreciprocal directional dichroism, where the transmitted light intensity in one direction is over 100 times lower than intensity transmitted in the opposite direction. The effect takes place in the paramagnetic phase with no long-range magnetic order in the crystal, which contrasts sharply with all existing reports of the terahertz optical diode effect in other magnetoelectric materials, where the long-range magnetic ordering is a necessary prerequisite. In FeZnMo_{3}O_{8}, the effect occurs resonantly with a strong magnetic dipole active transition centered at 1.27 THz and assigned as electron spin resonance between the eigenstates of the single-ion anisotropy Hamiltonian. We propose that the optical diode effect in paramagnetic FeZnMo_{3}O_{8} is driven by single-ion terms in magnetoelectric free energy. PMID- 29400515 TI - Control of Ultracold Photodissociation with Magnetic Fields. AB - Photodissociation of a molecule produces a spatial distribution of photofragments determined by the molecular structure and the characteristics of the dissociating light. Performing this basic reaction at ultracold temperatures allows its quantum mechanical features to dominate. In this regime, weak applied fields can be used to control the reaction. Here, we photodissociate ultracold diatomic strontium in magnetic fields below 10 G and observe striking changes in photofragment angular distributions. The observations are in excellent agreement with a multichannel quantum chemistry model that includes nonadiabatic effects and predicts strong mixing of partial waves in the photofragment energy continuum. The experiment is enabled by precise quantum-state control of the molecules. PMID- 29400516 TI - Squeezing on Momentum States for Atom Interferometry. AB - We propose and analyze a method that allows for the production of squeezed states of the atomic center-of-mass motion that can be injected into an atom interferometer. Our scheme employs dispersive probing in a ring resonator on a narrow transition in order to provide a collective measurement of the relative population of two momentum states. We show that this method is applicable to a Bragg diffraction-based strontium atom interferometer with large diffraction orders. This technique can be extended also to small diffraction orders and large atom numbers N by inducing atomic transparency at the frequency of the probe field, reaching an interferometer phase resolution scaling Deltaphi~N^{-3/4}. We show that for realistic parameters it is possible to obtain a 20 dB gain in interferometer phase estimation compared to the standard quantum limit. Our method is applicable to other atomic species where a narrow transition is available or can be synthesized. PMID- 29400517 TI - Dimensionality Driven Enhancement of Ferromagnetic Superconductivity in URhGe. AB - In most unconventional superconductors, like the high-T_{c} cuprates, iron pnictides, or heavy-fermion systems, superconductivity emerges in the proximity of an electronic instability. Identifying unambiguously the pairing mechanism remains nevertheless an enormous challenge. Among these systems, the orthorhombic uranium ferromagnetic superconductors have a unique position, notably because magnetic fields couple directly to ferromagnetic order, leading to the fascinating discovery of the reemergence of superconductivity in URhGe at a high field. Here we show that uniaxial stress is a remarkable tool allowing the fine tuning of the pairing strength. With a relatively small stress, the superconducting phase diagram is spectacularly modified, with a merging of the low- and high-field superconducting states and a significant enhancement of the superconductivity. The superconducting critical temperature increases both at zero field and under a field, reaching 1 K, more than twice higher than at ambient pressure. This enhancement of superconductivity is shown to be directly related to a change of the magnetic dimensionality detected from an increase of the transverse magnetic susceptibility: In addition to the Ising-type longitudinal ferromagnetic fluctuations, transverse magnetic fluctuations also play an important role in the superconducting pairing. PMID- 29400518 TI - Ultimate Absorption in Light Scattering by a Finite Obstacle. AB - Based on fundamental properties of the light scattering by a particle under a plane, linearly polarized wave illumination, we rigorously prove the existence of the ultimate upper limit for the light absorption by any partial mode and calculate this limit explicitly. The limit is a certain simple universal function of the incident light wave number, and the multipolarity of the corresponding partial mode solely. It does not depend on the optical constants of the scatterer, its size, or even its shape. First, we obtain this result for the scattering by a spherical particle. Then, we generalize it to an arbitrary finite obstacle. The results are valid for any polarization of the incident wave, any angle of its incidence, and any type of the scatterer (homogeneous, stratified, or with smoothly variable refractive index). We also prove that the maximal partial absorption cross section for any finite scatterer cannot exceed the corresponding value for a homogeneous sphere in 3D and circular cylinder in 2D. As an example, the results are applied to maximize the absorption cross section of a spherical core-shell structure. PMID- 29400520 TI - Electro-Optic Frequency Beam Splitters and Tritters for High-Fidelity Photonic Quantum Information Processing. AB - We report the experimental realization of high-fidelity photonic quantum gates for frequency-encoded qubits and qutrits based on electro-optic modulation and Fourier-transform pulse shaping. Our frequency version of the Hadamard gate offers near-unity fidelity (0.99998+/-0.00003), requires only a single microwave drive tone for near-ideal performance, functions across the entire C band (1530 1570 nm), and can operate concurrently on multiple qubits spaced as tightly as four frequency modes apart, with no observable degradation in the fidelity. For qutrits, we implement a 3*3 extension of the Hadamard gate: the balanced tritter. This tritter-the first ever demonstrated for frequency modes-attains fidelity 0.9989+/-0.0004. These gates represent important building blocks toward scalable, high-fidelity quantum information processing based on frequency encoding. PMID- 29400519 TI - Large Excitonic Reflectivity of Monolayer MoSe_{2} Encapsulated in Hexagonal Boron Nitride. AB - We demonstrate that a single layer of MoSe_{2} encapsulated by hexagonal boron nitride can act as an electrically switchable mirror at cryogenic temperatures, reflecting up to 85% of incident light at the excitonic resonance. This high reflectance is a direct consequence of the excellent coherence properties of excitons in this atomically thin semiconductor. We show that the MoSe_{2} monolayer exhibits power-and wavelength-dependent nonlinearities that stem from exciton-based lattice heating in the case of continuous-wave excitation and exciton-exciton interactions when fast, pulsed laser excitation is used. PMID- 29400521 TI - Many-Body Localization Dynamics from Gauge Invariance. AB - We show how lattice gauge theories can display many-body localization dynamics in the absence of disorder. Our starting point is the observation that, for some generic translationally invariant states, the Gauss law effectively induces a dynamics which can be described as a disorder average over gauge superselection sectors. We carry out extensive exact simulations on the real-time dynamics of a lattice Schwinger model, describing the coupling between U(1) gauge fields and staggered fermions. Our results show how memory effects and slow, double logarithmic entanglement growth are present in a broad regime of parameters-in particular, for sufficiently large interactions. These findings are immediately relevant to cold atoms and trapped ion experiments realizing dynamical gauge fields and suggest a new and universal link between confinement and entanglement dynamics in the many-body localized phase of lattice models. PMID- 29400522 TI - Low-Field Bi-Skyrmion Formation in a Noncentrosymmetric Chimney Ladder Ferromagnet. AB - The real-space spin texture and the relevant magnetic parameters were investigated for an easy-axis noncentrosymmetric ferromagnet Cr_{11}Ge_{19} with Nowotny chimney ladder structure. Using Lorentz transmission electron microscopy, we report the formation of bi-Skyrmions, i.e., pairs of spin vortices with opposite magnetic helicities. The quantitative evaluation of the magnetocrystalline anisotropy and Dzyaloshinskii-Moriya interaction (DMI) proves that the magnetic dipolar interaction plays a more important role than the DMI on the observed bi-Skyrmion formation. Notably, the critical magnetic field value required for the formation of bi-Skyrmions turned out to be extremely small in this system, which is ascribed to strong easy-axis anisotropy associated with the characteristic helix crystal structure. The family of Nowotny chimney ladder compounds may offer a unique material platform where two distinctive Skyrmion formation mechanisms favoring different topological spin textures can become simultaneously active. PMID- 29400523 TI - Domain Wall Orientations in Ferroelectric Superlattices Probed with Synchrotron X Ray Diffraction. AB - Ferroelectric domains in PbTiO_{3}/SrTiO_{3} superlattices are studied using synchrotron x-ray diffraction. Macroscopic measurements reveal a change in the preferential domain wall orientation from {100} to {110} crystallographic planes with increasing temperature. The temperature range of this reorientation depends on the ferroelectric layer thickness and domain period. Using a nanofocused beam, local changes in the domain wall orientation within the buried ferroelectric layers are imaged, both in structurally uniform regions of the sample and near defect sites and argon ion-etched patterns. Domain walls are found to exhibit a preferential alignment with the straight edges of the etched patterns as well as with structural features associated with defect sites. The distribution of out-of plane lattice parameters is mapped around one such feature, showing that it is accompanied by inhomogeneous strain and large strain gradients. PMID- 29400524 TI - Comment on "Fundamental Resolution of Difficulties in the Theory of Charged Point Defects in Semiconductors". PMID- 29400525 TI - Discrete Self-Similarity in Interfacial Hydrodynamics and the Formation of Iterated Structures. AB - The formation of iterated structures, such as satellite and subsatellite drops, filaments, and bubbles, is a common feature in interfacial hydrodynamics. Here we undertake a computational and theoretical study of their origin in the case of thin films of viscous fluids that are destabilized by long-range molecular or other forces. We demonstrate that iterated structures appear as a consequence of discrete self-similarity, where certain patterns repeat themselves, subject to rescaling, periodically in a logarithmic time scale. The result is an infinite sequence of ridges and filaments with similarity properties. The character of these discretely self-similar solutions as the result of a Hopf bifurcation from ordinarily self-similar solutions is also described. PMID- 29400526 TI - Surface-Induced Near-Field Scaling in the Knudsen Layer of a Rarefied Gas. AB - We report on experiments performed within the Knudsen boundary layer of a low pressure gas. The noninvasive probe we use is a suspended nanoelectromechanical string, which interacts with ^{4}He gas at cryogenic temperatures. When the pressure P is decreased, a reduction of the damping force below molecular friction ?P had been first reported in Phys. Rev. Lett. 113, 136101 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.136101 and never reproduced since. We demonstrate that this effect is independent of geometry, but dependent on temperature. Within the framework of kinetic theory, this reduction is interpreted as a rarefaction phenomenon, carried through the boundary layer by a deviation from the usual Maxwell-Boltzmann equilibrium distribution induced by surface scattering. Adsorbed atoms are shown to play a key role in the process, which explains why room temperature data fail to reproduce it. PMID- 29400527 TI - Polariton Chimeras: Bose-Einstein Condensates with Intrinsic Chaoticity and Spontaneous Long-Range Ordering. AB - The system of cavity polaritons driven by a plane electromagnetic wave is found to undergo the spontaneous breaking of spatial symmetry, which results in a lifted phase locking with respect to the driving field and, consequently, in the possibility of internal ordering. In particular, periodic spin and intensity patterns arise in polariton wires; they exhibit strong long-range order and can serve as media for signal transmission. Such patterns have the properties of dynamical chimeras: they are formed spontaneously in perfectly homogeneous media and can be partially chaotic. The reported new mechanism of chimera formation requires neither time-delayed feedback loops nor nonlocal interactions. PMID- 29400528 TI - Symmetry-Adapted Machine Learning for Tensorial Properties of Atomistic Systems. AB - Statistical learning methods show great promise in providing an accurate prediction of materials and molecular properties, while minimizing the need for computationally demanding electronic structure calculations. The accuracy and transferability of these models are increased significantly by encoding into the learning procedure the fundamental symmetries of rotational and permutational invariance of scalar properties. However, the prediction of tensorial properties requires that the model respects the appropriate geometric transformations, rather than invariance, when the reference frame is rotated. We introduce a formalism that extends existing schemes and makes it possible to perform machine learning of tensorial properties of arbitrary rank, and for general molecular geometries. To demonstrate it, we derive a tensor kernel adapted to rotational symmetry, which is the natural generalization of the smooth overlap of atomic positions kernel commonly used for the prediction of scalar properties at the atomic scale. The performance and generality of the approach is demonstrated by learning the instantaneous response to an external electric field of water oligomers of increasing complexity, from the isolated molecule to the condensed phase. PMID- 29400529 TI - Long-Range Big Quantum-Data Transmission. AB - We introduce an alternative type of quantum repeater for long-range quantum communication with improved scaling with the distance. We show that by employing hashing, a deterministic entanglement distillation protocol with one-way communication, one obtains a scalable scheme that allows one to reach arbitrary distances, with constant overhead in resources per repeater station, and ultrahigh rates. In practical terms, we show that, also with moderate resources of a few hundred qubits at each repeater station, one can reach intercontinental distances. At the same time, a measurement-based implementation allows one to tolerate high loss but also operational and memory errors of the order of several percent per qubit. This opens the way for long-distance communication of big quantum data. PMID- 29400530 TI - Wu, Zhang, and Pantelides Reply. PMID- 29400531 TI - Thermal Decoherence of a Nonequilibrium Polariton Fluid. AB - Exciton polaritons constitute a unique realization of a quantum fluid interacting with its environment. Using selenide-based microcavities, we exploit this feature to warm up a polariton condensate in a controlled way and monitor its spatial coherence. We determine directly the amount of heat picked up by the condensate by measuring the phonon-polariton scattering rate and comparing it with the loss rate. We find that, upon increasing the heating rate, the spatial coherence length decreases markedly, while localized phase structures vanish, in good agreement with a stochastic mean-field theory. From the thermodynamical point of view, this regime is unique, as it involves a nonequilibrium quantum fluid with no well-defined temperature but which is nevertheless able to pick up heat with dramatic effects on the order parameter. PMID- 29400532 TI - Cooperative Effects in Closely Packed Quantum Emitters with Collective Dephasing. AB - In a closely packed ensemble of quantum emitters, cooperative effects are typically suppressed due to the dephasing induced by the dipole-dipole interactions. Here, we show that by adding sufficiently strong collective dephasing, cooperative effects can be restored. Specifically, we show that the dipole force on a closely packed ensemble of strongly driven two-level quantum emitters, which collectively dephase, is enhanced in comparison to the dipole force on an independent noninteracting ensemble. Our results are relevant to solid-state systems with embedded quantum emitters such as color centers in diamond and superconducting qubits in microwave cavities and waveguides. PMID- 29400533 TI - Anomalous Features in the Potential Energy Landscape of a Waterlike Monatomic Model with Liquid and Glass Polymorphism. AB - We study the potential energy landscape (PEL) of a waterlike monatomic liquid that exhibits a liquid-liquid phase transition (LLPT) and glass-glass transformation (GGT). We identify two anomalous features of the PEL that give origin to both phenomena. Specifically, during the pressure-induced LLPT and GGT, (i) the inherent structures (IS) energy becomes a concave function of volume, and (ii) the IS pressure exhibits a van der Waals-like loop. We argue that features (i) and (ii) imply that the GGT is a (nonequilibrium) first-order phase transition, analogous to the LLPT. Interestingly, contrary to the case of the classical ST2 model for water, (a) we do not find two separate PEL megabasins (one for the low-density glass and liquid, and another for the high-density glass and liquid), and (b) features (i)-(ii) persist at temperatures well above the LLPT. PMID- 29400534 TI - Spinon Magnetic Resonance of Quantum Spin Liquids. AB - We describe electron spin resonance in a quantum spin liquid with significant spin-orbit coupling. We find that the resonance directly probes spinon continuum, which makes it an efficient and informative probe of exotic excitations of the spin liquid. Specifically, we consider spinon resonance of three different spinon mean-field Hamiltonians, obtained with the help of projective symmetry group analysis, which model a putative quantum spin liquid state of the triangular rare earth antiferromagnet YbMgGaO_{4}. The band of absorption is found to be very broad and exhibit strong van Hove singularities of single spinon spectrum as well as pronounced polarization dependence. PMID- 29400535 TI - High-Precision Mass Measurement of ^{56}Cu and the Redirection of the rp-Process Flow. AB - We report the mass measurement of ^{56}Cu, using the LEBIT 9.4 T Penning trap mass spectrometer at the National Superconducting Cyclotron Laboratory at Michigan State University. The mass of ^{56}Cu is critical for constraining the reaction rates of the ^{55}Ni(p,gamma) ^{56}Cu(p,gamma) ^{57}Zn(beta^{+}) ^{57}Cu bypass around the ^{56}Ni waiting point. Previous recommended mass excess values have disagreed by several hundred keV. Our new value, ME=-38626.7(7.1) keV, is a factor of 30 more precise than the extrapolated value suggested in the 2012 atomic mass evaluation [Chin. Phys. C 36, 1603 (2012)CPCHCQ1674-113710.1088/1674 1137/36/12/003], and more than a factor of 12 more precise than values calculated using local mass extrapolations, while agreeing with the newest 2016 atomic mass evaluation value [Chin. Phys. C 41, 030003 (2017)CPCHCQ1674-113710.1088/1674 1137/41/3/030003]. The new experimental average, using our new mass and the value from AME2016, is used to calculate the astrophysical ^{55}Ni(p,gamma) and ^{56}Cu(p,gamma) forward and reverse rates and perform reaction network calculations of the rp process. These show that the rp-process flow redirects around the ^{56}Ni waiting point through the ^{55}Ni(p,gamma) route, allowing it to proceed to higher masses more quickly and resulting in a reduction in ashes around this waiting point and an enhancement to higher-mass ashes. PMID- 29400536 TI - Universally Fisher-Symmetric Informationally Complete Measurements. AB - A quantum measurement is Fisher symmetric if it provides uniform and maximal information on all parameters that characterize the quantum state of interest. Using (complex projective) 2-designs, we construct measurements on a pair of identically prepared quantum states that are Fisher symmetric for all pure states. Such measurements are optimal in achieving the minimal statistical error without adaptive measurements. We then determine all collective measurements on a pair that are Fisher symmetric for the completely mixed state and for all pure states simultaneously. For a qubit, these measurements are Fisher symmetric for all states. The minimal optimal measurements are tied to the elusive symmetric informationally complete measurements, which reflects a deep connection between local symmetry and global symmetry. In the study, we derive a fundamental constraint on the Fisher information matrix of any collective measurement on a pair, which offers a useful tool for characterizing the tomographic efficiency of collective measurements. PMID- 29400537 TI - Superresolution Microscopy of Single Rare-Earth Emitters in YAG and H3 Centers in Diamond. AB - We demonstrate superresolution imaging of single rare-earth emitting centers, namely, trivalent cerium, in yttrium aluminum garnet crystals by means of stimulated emission depletion (STED) microscopy. The achieved all-optical resolution is ~50 nm. Similar results were obtained on H3 color centers in diamond. In both cases, STED resolution is improving slower than the conventional inverse square-root dependence on the depletion beam intensity. In the proposed model of this effect, the anomalous behavior is caused by excited state absorption and the interaction of the emitter with nonfluorescing crystal defects in its local surrounding. PMID- 29400538 TI - Simulating Open Quantum Systems with Hamiltonian Ensembles and the Nonclassicality of the Dynamics. AB - The incoherent dynamical properties of open quantum systems are generically attributed to an ongoing correlation between the system and its environment. Here, we propose a novel way to assess the nature of these system-environment correlations by examining the system dynamics alone. Our approach is based on the possibility or impossibility to simulate open-system dynamics with Hamiltonian ensembles. As we show, such (im)possibility to simulate is closely linked to the system-environment correlations. We thus define the nonclassicality of open system dynamics in terms of the nonexistence of a Hamiltonian-ensemble simulation. This classifies any nonunital open-system dynamics as nonclassical. We give examples for open-system dynamics that are unital and classical, as well as unital and nonclassical. PMID- 29400539 TI - Critical Bursts in Filtration. AB - Particle detachment bursts during the flow of suspensions through porous media are a phenomenon that can severely affect the efficiency of deep bed filters. Despite the relevance in several industrial fields, little is known about the statistical properties and the temporal organization of these events. We present experiments of suspensions of deionized water carrying quartz particles pushed with a peristaltic pump through a filter of glass beads measuring simultaneously the pressure drop, flux, and suspension solid fraction. We find that the burst size distribution scales consistently with a power law, suggesting that we are in the presence of a novel experimental realization of a self-organized critical system. Temporal correlations are present in the time series, like in other phenomena such as earthquakes or neuronal activity bursts, and also an analog to Omori's law can be shown. The understanding of burst statistics could provide novel insights in different fields, e.g., in the filter and petroleum industries. PMID- 29400540 TI - Suppression of Electron Thermal Conduction by Whistler Turbulence in a Sustained Thermal Gradient. AB - The dynamics of weakly magnetized collisionless plasmas in the presence of an imposed temperature gradient along an ambient magnetic field is explored with particle-in-cell simulations and modeling. Two thermal reservoirs at different temperatures drive an electron heat flux that destabilizes off-angle whistler type modes. The whistlers grow to large amplitude, deltaB/B_{0}?1, and resonantly scatter the electrons, significantly reducing the heat flux. Surprisingly, the resulting steady-state heat flux is largely independent of the thermal gradient. The rate of thermal conduction is instead controlled by the finite propagation speed of the whistlers, which act as mobile scattering centers that convect the thermal energy of the hot reservoir. The results are relevant to thermal transport in high-beta astrophysical plasmas such as hot accretion flows and the intracluster medium of galaxy clusters. PMID- 29400541 TI - Neutron-Star Radius from a Population of Binary Neutron Star Mergers. AB - We show how gravitational-wave observations with advanced detectors of tens to several tens of neutron-star binaries can measure the neutron-star radius with an accuracy of several to a few percent, for mass and spatial distributions that are realistic, and with none of the sources located within 100 Mpc. We achieve such an accuracy by combining measurements of the total mass from the inspiral phase with those of the compactness from the postmerger oscillation frequencies. For estimating the measurement errors of these frequencies, we utilize analytical fits to postmerger numerical relativity waveforms in the time domain, obtained here for the first time, for four nuclear-physics equations of state and a couple of values for the mass. We further exploit quasiuniversal relations to derive errors in compactness from those frequencies. Measuring the average radius to well within 10% is possible for a sample of 100 binaries distributed uniformly in volume between 100 and 300 Mpc, so long as the equation of state is not too soft or the binaries are not too heavy. We also give error estimates for the Einstein Telescope. PMID- 29400542 TI - Cold Collisions in a Molecular Synchrotron. AB - We study collisions between neutral, deuterated ammonia molecules (ND_{3}) stored in a 50 cm diameter synchrotron and argon atoms in copropagating supersonic beams. The advantages of using a synchrotron in collision studies are twofold: (i) By storing ammonia molecules many round-trips, the sensitivity to collisions is greatly enhanced; (ii) the collision partners move in the same direction as the stored molecules, resulting in low collision energies. We tune the collision energy in three different ways: by varying the velocity of the stored ammonia packets, by varying the temperature of the pulsed valve that releases the argon atoms, and by varying the timing between the supersonic argon beam and the stored ammonia packets. These give consistent results. We determine the relative, total, integrated cross section for ND_{3}+Ar collisions in the energy range of 40-140 cm^{-1}, with a resolution of 5-10 cm^{-1} and an uncertainty of 7%-15%. Our measurements are in good agreement with theoretical scattering calculations. PMID- 29400543 TI - First Observation of Bright Solitons in Bulk Superfluid ^{4}He. AB - The existence of bright solitons in bulk superfluid ^{4}He is demonstrated by time-resolved shadowgraph imaging experiments and density functional theory (DFT) calculations. The initial liquid compression that leads to the creation of nonlinear waves is produced by rapidly expanding plasma from laser ablation. After the leading dissipative period, these waves transform into bright solitons, which exhibit three characteristic features: dispersionless propagation, negligible interaction in a two-wave collision, and direct dependence between soliton amplitude and the propagation velocity. The experimental observations are supported by DFT calculations, which show rapid evolution of the initially compressed liquid into bright solitons. At high amplitudes, solitons become unstable and break down into dispersive shock waves. PMID- 29400545 TI - Ultrasound elastography as an imaging biomarker for detection of early tumor response to chemotherapy in a murine breast cancer model: a feasibility study. AB - OBJECTIVE: This study investigated the feasibility of using strain elastography (SE) and real time shear wave elastography (RT-SWE) to evaluate early tumor response to cytotoxic chemotherapy in a murine xenograft breast cancer tumor model. METHODS: MCF-7 breast cancer-bearing nude mice were treated with either cisplatin 2 mg kg-1 plus paclitaxel 10 mg kg-1 (treatment group) or sterile saline (control group) once daily for 5 days. The tumor elasticity was measured by SE or RT-SWE before and after therapy. Tumor cell density was assessed by hematoxylin and eosin staining, and the ratio of collagen fibers in the tumor was evaluated by Van Gieson staining. The correlation between tumor elasticity, as determined by SE and SWE, as well as the pathological tumor responses were analyzed. RESULTS: Chemotherapy significantly attenuated tumor growth compared to the control treatment (p < 0.05). Chemotherapy also significantly increased tumor stiffness (p < 0.05) and significantly decreased (p < 0.05) tumor cell density compared with the control. Moreover, chemotherapy significantly increased the ratio of collagen fibers (p < 0.05). Tumor stiffness was positively correlated with the ratio of collagen fibers but negatively correlated with tumor cell density. CONCLUSION: The study suggests that ultrasound elastography by SE and SWE is a feasible tool for assessing early responses of breast cancer to chemotherapy in our murine xenograft model. Advances in knowledge: This study showed that the tumor elasticity determined by ultrasound elastography could be a feasible imaging biomarker for assessing very early therapeutic responses to chemotherapy. PMID- 29400547 TI - The Official Journal of ATTD Advanced Technologies & Treatments for Diabetes Conference Austria, Vienna-February 14-17, 2018. PMID- 29400546 TI - Reflections of a CEQ Examiner. AB - The Critical Essay Question (CEQ) tests some of the key skills necessary for the practice of psychiatry. Many candidates find the CEQ a challenge but there are some basic rules of writing which can help. PMID- 29400544 TI - Satellite-Relayed Intercontinental Quantum Network. AB - We perform decoy-state quantum key distribution between a low-Earth-orbit satellite and multiple ground stations located in Xinglong, Nanshan, and Graz, which establish satellite-to-ground secure keys with ~kHz rate per passage of the satellite Micius over a ground station. The satellite thus establishes a secure key between itself and, say, Xinglong, and another key between itself and, say, Graz. Then, upon request from the ground command, Micius acts as a trusted relay. It performs bitwise exclusive or operations between the two keys and relays the result to one of the ground stations. That way, a secret key is created between China and Europe at locations separated by 7600 km on Earth. These keys are then used for intercontinental quantum-secured communication. This was, on the one hand, the transmission of images in a one-time pad configuration from China to Austria as well as from Austria to China. Also, a video conference was performed between the Austrian Academy of Sciences and the Chinese Academy of Sciences, which also included a 280 km optical ground connection between Xinglong and Beijing. Our work clearly confirms the Micius satellite as a robust platform for quantum key distribution with different ground stations on Earth, and points towards an efficient solution for an ultralong-distance global quantum network. PMID- 29400548 TI - Civil forensic psychiatry - Part 1: an overview. AB - Objectives This paper provides an overview for general and forensic psychiatrists of the complexity and challenge of working in the civil medico-legal arena. It covers expert evidence, ethics, core concepts in civil forensic psychiatry and report writing. Conclusions Civil forensic psychiatry is an important sub speciality component of forensic psychiatry that requires specific skills, knowledge and the ability to assist legal bodies in determining the significance of psychiatric issues. PMID- 29400549 TI - Case formulation using pattern-based formulation methodology: clinical case 3. AB - OBJECTIVE: The objective of this study is to determine if pattern-based formulation (PBF) can accurately contribute to case formulation. CONCLUSIONS: The application of three PBFs accurately contributed to the development of this patient's case formulation. The case formulation demonstrated here, and the patterns introduced in this paper, will serve as educational materials for teaching psychiatric case formulation. PMID- 29400550 TI - Who let the dogs out? Therapy dogs in clinical practice. AB - OBJECTIVES: Animal-assisted therapy (AAT) is a growing field in Australia, and therapy dogs are becoming increasingly common in clinical settings. This paper aims to highlight the current issues facing AAT in Australia and to make recommendations on how to progress the field. We acknowledge that there are several ways that therapy dogs may enhance treatment outcomes for clients, such as reductions in stress and acute anxious arousal, and improvements in engagement and rapport. These psychological and physiological advantages, however, may not be sustained once interaction with the dog ceases. Clinicians require adequate training and support to develop and implement interventions that are based on sound theoretical foundations, and take advantage of the adjunctive benefits of animal presence. CONCLUSIONS: A series of recommendations are made for the professionalisation of AAT, including the development of consensus definitions, clinical governance, accreditation, research and evaluation. PMID- 29400551 TI - Amyloid beta-targeted metal complexes for potential applications in Alzheimer's disease. AB - Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder that affects millions of people around the world. The aggregation of amyloid-beta peptides (Abeta), one of the primary pathological hallmarks of AD, plays a key role in the AD pathogenesis. In this regard, Abeta aggregates have been considered as both biomarkers and drug targets for the diagnosis and therapy of AD. Various Abeta-targeted metal complexes have exhibited promising potential as anti-AD agents due to their fascinating physicochemical properties over the past two decades. This review classifies the complexes into three groups based on their potential applications in AD including therapy, diagnosis and theranosis. The recent representative examples are highlighted in terms of design rationale, working mechanism and potential applications. PMID- 29400552 TI - Integrating mammographic breast density in glandular dose calculation. AB - OBJECTIVE: This work proposes the use of mammographic breast density (MBD) to estimate actual glandular dose (AGD), and assesses how AGD compares to mean glandular dose (MGD) estimated using Dance et al method. METHODS: A retrospective sample of anonymised mammograms (52,405) was retrieved from a central database. Technical parameters and patient characteristics were exported from the Digital Imaging and Communication in Medicine (DICOM) header using third party software. LIBRA (Laboratory for Individualized Breast Radiodensity Assessment) software package (University of Pennsylvania, Philadelphia, USA) was used to estimate MBDs for each mammogram included in the data set. MGD was estimated using Dance et al method, while AGD was calculated by replacing Dance et al standard glandularities with LIBRA estimated MBDs. A linear regression analysis was used to assess the association between MGD and AGD, and a Bland-Altman analysis was performed to assess their mean difference. RESULTS: The final data set included 31,097 mammograms from 7728 females. MGD, AGD, and MBD medians were 1.53 , 1.62 mGy and 8% respectively. When stratified per breast thickness ranges, median MBDs were lower than Dance's standard glandularities. There was a strong positive correlation (R2 = 0.987, p < 0.0001) between MGD and AGD although the Bland Altman analysis revealed a small statistically significant bias of 0.087 mGy between MGD and AGD (p < 0.001). CONCLUSION: AGD estimated from MBD is highly correlated to MGD from Dance method, albeit the Dance method underestimates dose at smaller CBTs. Advances in knowledge: Our work should provide a stepping-stone towards an individualised dose estimation using automated clinical measures of MBD. PMID- 29400555 TI - Emotional Self-Disclosure in Online Breast Cancer Support Groups: Examining Theme, Reciprocity, and Linguistic Style Matching. AB - The present study investigated emotional self-disclosure (ESD) patterns and their effects in online support groups specific to different stages of breast cancer. Linguistic features of messages posted to an online breast cancer support group were analyzed. ESD was common, and was consistent across four stage forums. Emotional talk was linked to a variety of themes, but most prominently in the context of discussions about social connections rather than health or death. Linguistic style matching mediated the relationship between ESD in posts and reciprocal ESD in comments, suggesting a key role for mutual understanding and engagement between posters and commenters. Implications for health communication theory and practice were discussed. PMID- 29400553 TI - Single-institution experience of intensity-modulated radiotherapy for malignant pleural mesothelioma at University of Catania. AB - AIM: The multimodal approach to malignant pleural mesothelioma is gradually becoming the standard of care for this disease in patients with good performance status. Materials & methods: We report our experience concerning eight cases treated with the use of static step-and-shoot intensity-modulated radiotherapy to the whole pleural cavity, in patients already undergoing surgical and/or antiblastic therapy. Results & conclusion: Results at a median follow-up of 16 months showed a median survival from the initial treatment of 29 months, with lung toxicity of grade II reported only in two patients. PMID- 29400556 TI - Is it appropriate to perform video-assisted thoracoscopic surgery for advanced lung cancer? AB - Video-assisted thoracoscopic surgery (VATS) has showed benefits in terms of pain, hospital stay and accomplishment of adjuvancy therapy versus open surgery in early stage of non-small-cell lung cancer. Over the last years, the indication of VATS technique has been expanded to advanced lung cancer. In this article, we discuss the definition of VATS and advanced lung cancer, and the safety and feasibility of VATS technique for the resection of advanced tumors. PMID- 29400557 TI - A Qualitative Assessment of the Acceptability of Smartphone Applications for Improving Sleep Behaviors in Low-Income and Minority Adolescents. AB - BACKGROUND: Daily behaviors such as sleep can be targeted by smartphone app-based interventions, with potential utility among young people of minority ethnic backgrounds who commonly access smartphone devices and are short sleepers. There is a need to understand the acceptability and youth's readiness to use apps to improve sleep, and to identify desired app components that would motivate engagement. PARTICIPANTS AND METHODS: We conducted three focus group discussions (N = 27 total, age 14-18 years) within low- and middle-income ethnically diverse Boston neighborhoods. We also interviewed 10 participants who provided specific feedback on two commercially available sleep-promoting apps, one of which they had used on their smartphone preceding the interviews. All focus group discussions and interviews were audio-recorded, transcribed, and thematically analyzed. RESULTS: We identified several barriers to adoption of sleep hygiene interventions, namely reluctance to follow scheduled sleep routines on weekends and concern about "parting" with electronics at bedtime. Participants were intrigued by the idea of adopting an app-based sleep intervention, but were skeptical that they could successfully adopt sleep hygiene practices, and were more interested in making changes on school days than on weekends. Nonetheless, the overall feedback on two commercial sleep apps, neither targeted at youth, was positive, with a good adherence and engagement rate, and perceived health benefits. CONCLUSIONS: Our findings highlight the need to adapt sleep hygiene recommendations to targeted populations, considering preferences and social and cultural contextual factors. Our research also underscores the importance of the platform, setting, and messenger when delivering health information to adolescents. PMID- 29400558 TI - Response to "Medication for addiction treatment (MAT)". PMID- 29400559 TI - Enhanced Recovery After Surgery (ERAS(r)) in thoracic surgical oncology. AB - Enhanced recovery after surgery (ERAS(r)) is a strategy that seeks to reduce patients' perioperative stress response, thereby reducing potential complications, decreasing hospital length of stay and enabling patients to return more quickly to their baseline functional status. The concept was introduced in the late 1990s and was first adopted for use with patients undergoing open colorectal surgery. Since that time, the concept of ERAS has spread to multiple surgical specialties. This article explores the key elements for patient care using an ERAS protocol applied to minimally invasive thoracic surgery. PMID- 29400560 TI - Movies in Mind: 'The Wizard of Lies' - Psychopathy or callous ingenuity? PMID- 29400562 TI - The Psychiatry Ashes Test February update. PMID- 29400561 TI - Health risks, needs and service delivery. PMID- 29400564 TI - Rejoinder. PMID- 29400566 TI - Advantages of Anticipated Emotions over Anticipatory Emotions and Cognitions in Health Decisions: A Meta-Analysis. AB - Recent persuasion theories and some empirical studies indicate that emotional responses can be more persuasive than cognitive evaluations under certain circumstances. The aim of this meta-analysis was to compare the effects of emotions and perceived risk on health-related intentions and behavior. Ten studies which examined anticipated emotions (AdE) and 19 studies which examined anticipatory emotions (AyE) were included. AdE was moderately associated with health intention (r = 0.38, 95% CI 0.24-0.51) and behavior (r = 0.48, 95% CI 0.43 0.53). The average correlations with AyE were small (with intention r = 0.25, 95% CI 0.18-0.31; with behavior r = 0.18, 95% CI 0.11-0.23). AdE was significantly more likely to lead to ideal intentions and behavior than perceived risk, and was more likely to promote desired behaviors than AyE. AdE had a stronger effect on intentions to prevent disease compared to detect disease. Other moderators were discussed. Theoretical and practical implications are provided. PMID- 29400565 TI - Endophyte fungi, Cladosporium species-mediated synthesis of silver nanoparticles possessing in vitro antioxidant, anti-diabetic and anti-Alzheimer activity. AB - This research study is to develop an easy and eco-friendly method for the synthesis of AgNPs using aqueous extract of endophytic fungi, Cladosporium species (CsAgNPs) and investigated the effects of antioxidant, anti-diabetic and anti-acetylcholinesterase (AChE), anti-butyrylcholinesterase (BChE) activity. Cladosporium species-mediated silver nanoparticles were characterized by UV-Vis spectrophotometer, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDX). The aqueous extract of Cladosporium species has shown the presence of carbohydrates, tannin, phenolic glycosides, terpenoids, alkaloids, phenol and anthraquinones. At 438 nm conformed the absorbance of AgNPs. The SEM result confirms that size, morphology and high density of the synthesized nanoparticles with huge disparity in the particle size distribution. The FTIR analysis confirmed the important biological compounds responsible for reduction of silver. Strong absorption property of AgNPs was studied by EDX. In antioxidant activity, CsAgNPs showed the involvement of NADPH-dependent reductase in the formation of AgNPs. The AgNPs has reduced the activity of alpha-amylase, alpha-glucosidase and dipeptidyl peptidase IV in vitro antidiabetic activity. The CsAgNPs showed significant glucose uptake in 3T3L1 cell line. The AgNPs have shown excellent inhibitory activity against AChE and BChE. To our best knowledge, this is the first on the synthesis of silver nanoparticles using endophytic fungi, Cladosporium species isolated from healthy leaf of Loranthus micranthus. Hence, to validate our results the in vivo animal studies at molecular level are needed to develop an antioxidant, anti-diabetic and anti-cholinesterase agent. PMID- 29400568 TI - Analyzing the association between aortic regurgitation and atherosclerosis: is pulse pressure a cause of atherosclerosis? AB - If pulse pressure, one of the mechanical stresses, is a risk factor for atherosclerotic cardiovascular disease, then atherosclerosis should be progressive in aortic regurgitation which is a representative disease with increased pulse pressure. This cross-sectional study included 1,149 patients. We examined the influence of aortic regurgitation on maximum intima-media thickness or brachial-ankle pulse wave velocity. The degree of aortic regurgitation was classified into 4 grades by color Doppler examination. There were 177 patients with aortic regurgitation. Pulse pressure was significantly higher in patients with aortic regurgitation than in those without it. On multiple regression analysis, aortic regurgitation was not found to be a significant independent variable for maximum intima-media thickness [standard partial regression coefficient: aortic regurgitation = grade 1, 0.011, P = 0.7635; aortic regurgitation >= grade 2, -0.034, P = 0.3289] and brachial-ankle pulse wave velocity [standard partial regression coefficient: aortic regurgitation = grade1, -0.043, P = 0.1197; aortic regurgitation >= grade2, 0.002, P = 0.9358] after adjusting for age, sex, body mass index, presence or absence of cardiovascular disease, antihypertensive treatment, diabetes, dyslipidemia, and smoking. These results found no causal association between aortic regurgitation and atherosclerosis, and were a contradiction to the opinion that pulse pressure was a risk factor of atherosclerosis. PMID- 29400567 TI - Regulatory network analysis of hypertension and hypotension microarray data from mouse model. AB - We aimed to identify the potential genes related to blood pressure regulation and screen target genes for high blood pressure (BPH) and low blood pressure (BPL) treatment. The GSE19817 microarray dataset, which included the aorta, liver, heart, and kidney samples from BPH, BPL, and normotensive mice, was downloaded from the Gene Expression Omnibus. Principal component analysis (PCA) was performed based on the entire expression profile. Differentially expressed genes (DEGs) were screened, followed by pathway enrichment analysis. Finally, gene regulatory networks were constructed based on BPH-related and BPL-related DEGs in the aorta, liver, heart, and kidney samples. As a result, DEGs were screened within their respective tissues due to high heterogeneity of different tissues. Totally, 2,726 BPH-related DEGs and 2,472 BPL-related DEGs were screened, which were mainly enriched in pathways such as immune response. The topology data of gene regulatory networks constructed by DEGs in the heart, kidney, and liver were similar than that in aorta. Finally, among BPH-related DEGs, Sept6 and Pigx were found in the top 10 differentially regulated DEGs by comparing the BPH-related DEGs of the aorta with the DEGs of the other 3 tissues in the regulatory network. Although among the top 10 differentially regulated BPL-related DEGs, no common differentially regulated DEGs were found, Wif1, Urb2, and Gtf2ird1 were found among the top ten DEGs in the three tissues other than the kidney tissue. Sept6 and Pigx might participate in the pathogenesis of BPH, whereas Gtf2ird1, Urb2, and Wif1 might be critical target genes for BPL treatment. PMID- 29400569 TI - The value of the identification of predisposing factors for post-traumatic amnesia in management of mild traumatic brain injury. AB - OBJECT: To identify the risk factors for post-traumatic amnesia (PTA) and to document the incidence of PTA after mild traumatic brain injuries. METHODS: This was a prospective study, affecting mild TBI (mTBI) (Glasgow Coma Scale 14-15) cases attending to the Emergency Department between January 2009 and April 2012 (40 months duration). Patients were divided into two groups (Group A: without PTA, and Group B: with PTA, and they were assessed according to the risk factors. RESULTS: A total of 1762 patients (males: 1002, 56.8%) were meeting study inclusion criteria [Group A: n = 1678 (83.8%), Group B: n = 84 (4.2%)]. Age, CT findings: (traumatic focal HCs in the frontal and temporal lobes or more diffuse punctate HCs, and skull base fractures), anticoagulation therapy and seizures were independent factors of PTA. There was no statistically significant correlation between PTA and sex, convexity fractures, stroke event, mechanism of mTBI (fall +/or beating), hypertension, coronary heart disease, chronic smokers and diabetes (p > 0.005). CONCLUSION: CT findings: (traumatic focal HCs in the frontal and temporal lobes or more diffuse punctate HCs and skull base fractures), age, seizures and anticoagulation/antiplatelet therapy, were independent factors of PTA and could be used as predictive factors after mTBI. PMID- 29400511 TI - First Search for Nontensorial Gravitational Waves from Known Pulsars. AB - We present results from the first directed search for nontensorial gravitational waves. While general relativity allows for tensorial (plus and cross) modes only, a generic metric theory may, in principle, predict waves with up to six different polarizations. This analysis is sensitive to continuous signals of scalar, vector, or tensor polarizations, and does not rely on any specific theory of gravity. After searching data from the first observation run of the advanced LIGO detectors for signals at twice the rotational frequency of 200 known pulsars, we find no evidence of gravitational waves of any polarization. We report the first upper limits for scalar and vector strains, finding values comparable in magnitude to previously published limits for tensor strain. Our results may be translated into constraints on specific alternative theories of gravity. PMID- 29400570 TI - Analysis of serum cortisol to predict recovery in paediatric sport-related concussion. AB - OBJECTIVE: To study the relationship between acute serum cortisol following pediatric sport-related concussion (SRC) and clinical outcome measures of symptom burden and length to return to sport (RTS) Methods: Prospective observational study of ice hockey players ages 11-12 recruited prior to the hockey season. Players sustaining a SRC were assessed by a sports medicine physician completed a child Sport Concussion Assessment Tool-3 (childSCAT-3) and serum cortisol samples. RESULTS: Of 636 ice hockey players enrolled, 41 sustained a SRC. In total, 22 serum cortisol samples were collected, with 14 (63.6%) meeting inclusion criteria. Four players presented with abnormally low cortisol and were more likely to experienced more symptoms (17.8 +/- 1.9 vs. 7.5 +/- 6.0) more severe symptoms (28.5 +/- 5.8 vs. 10.2. +/-8.8) and took longer RTS (23 +/- 13.6 vs. 14.0.7 +/- 7.9.). CONCLUSION: Paediatric ice hockey players following SRC with abnormally low cortisol may be more susceptible to experiencing increase symptom burden and take longer to return to sport than players with population based normal cortisol. PMID- 29400571 TI - The human right to communicate: A survey of available services in Saudi Arabia. AB - Article 19 of the Universal Declaration of Human Rights states: "Everyone has the right to freedom of opinion and expression." However, people with communication disabilities may be more likely to lose the right to express their opinions as a consequence of their atypical communication methods; hence they may be denied a basic human right. The purpose of the current study was to investigate the availability of speech-language pathology services in Saudi Arabia's public health sector. The data were collected using a telephone survey. The results found a shortage of and an uneven distribution of health-based speech-language pathology services. Of the 196 major governmental hospitals surveyed, 29 were identified as having speech-language pathology services, which were distributed over 7 of Saudi Arabia's 13 Administrative Regions. Obtaining accurate information regarding the availability of these services is an important first step in informing policy development and aiding health-service planners to train more professional staff, expand services methodically and use existing resources effectively to meet the rights of people with communication disabilities. PMID- 29400575 TI - Correction to: Valgaeren, Koppen and Van Camp, A New Perspective on the Genetics of Keratoconus: Why Have We Not Been More Successful? PMID- 29400572 TI - Characterizing bacterial glycoproteins with LC-MS. AB - INTRODUCTION: Though eukaryotic glycoproteins have been studied since their discovery in the 1930s, the first bacterial glycoprotein was not identified until the 1970s. As a result, their role in bacterial pathogenesis is still not well understood and they remain an understudied component of bacterial virulence. In recent years, mass spectrometry has emerged as a leading technology for the study of bacterial glycoproteins, largely due to its sensitivity and versatility. Areas covered: Identification and comprehensive characterization of bacterial glycoproteins usually requires multiple complementary mass spectrometry approaches, including intact protein analysis, top-down analysis, and bottom-up methods used in combination with specialized liquid chromatography. This review provides an overview of liquid chromatography separation technologies, as well as current and emerging mass spectrometry approaches used specifically for bacterial glycoprotein identification and characterization. Expert commentary: Bacterial glycoproteins may have significant clinical utility as a result of their unique structures and exposure on the surface of the cells. Better understanding of these glycoconjugates is an essential first step towards that goal. These often unique structures, and by extension the key enzymes involved in their synthesis, represent promising targets for novel antimicrobials, while unique carbohydrate structures may be used as antigens in vaccines or as biomarkers. PMID- 29400574 TI - Comparison of Posterolateral Fusion and Posterior Lumbar Interbody Fusion in the Treatment of Lumbar Spondylolithesis: A Meta-Analysis. AB - AIM: Both posterior lumbar interbody fusion (PLIF) and posterolateral fusion (PLF) are the frequently-used techniques to treat lumbar spondylolithesis. The aim of this meta-analysis is to compare the safety and effectiveness between these two methods. MATERIALS AND METHODS: The multiple databases were used to search for the relevant studies, and full-text articles involved in the comparison between PLIF and PLF were reviewed. Review Manager 5.0 was adopted to estimate the effects of the results among selected articles. Forest plots, sensitivity analysis and bias analysis for the articles included were also conducted. RESULTS: Finally, 11 relevant studies were eventually satisfied the included criteria. The meta-analysis suggested that there was no significant difference of the clinical outcome, fusion rate, complication rate and blood loss (RR = 1.07, 95%CI [0.97, 1.17], P = 0.16; RR = 0.84, 95%CI [0.49, 1.45], P = 0.54; RR = 1.07, 95%CI [0.95, 1.21], P = 0.25; SMD = 0.24, 95%CI [-0.50, 0.98], P = 0.52; respectively). No publication bias was observed in this study (P > 0.05). CONCLUSIONS: Both these two procedures provide excellent outcomes for patients with spondylolisthesis. There was no significant difference of clinical outcome, complication rate, fusion rate and blood loss between PLIF and PLF techniques. PMID- 29400573 TI - Longitudinal change in end-digit preference in blood pressure recordings in the hypertension patients followed up in primary care clinics. AB - SUBJECT: This study was to evaluate whether a special lecture on the Chinese Guideline for Blood Pressure Measurement (CGBPM) improves end-digit preference (EDP) of blood pressure (BP) recordings in primary care clinics. METHODS: In 2012, the doctors working in a clinic received a lecture, which emphasizes that when mercurial sphygmomanometer was used, only 0, and even numbers could be recorded as BP end-digit. In 2016, we collected the BP recordings (2011-2015) of 462 hypertensive patients followed in the educated clinic or in another no educated clinic. The percentages of 0, 2, 4, 6, 8 in BP end-digit were calculated for evaluating zero EDP, and the percent decline in each year was calculated on the formula: (baseline percentage - actual percentage in a year)/baseline percentage. RESULTS: In 2011, the percentage of zero end-digit was over 75% for SBP or DBP in both clinics. Against the no-educated clinic, the educated clinic had significant higher percent decline of zero EDP on SBP (31.5% vs -2.6%) and DBP (36.9% vs -14.3%) in 2013, and in 2014 (SBP 38.0% vs 11.6%; DBP 42.8% vs 4.0%). In 2015, the educated clinic still had higher percent decline of zero EDP on DBP (43.3% vs 29.3%). Furthermore, the percentages of zero end-digit for SBP (43.6% vs 49.2%) or for DBP (43.5% vs 59.0%) were lower in the educated clinic in 2015. CONCLUSION: Education on BP measurement and recording could improve the quality of BP recordings, and this effect may last for three years. PMID- 29400576 TI - Effects of salt substitute on home blood pressure differs according to age and degree of blood pressure in hypertensive patients and their families. AB - BACKGROUND: It is known that home blood pressure (HBP) is a more reliable assessment of hypertension treatments than clinical blood pressure (BP). Despite this, HBP response to a salt substitute has only been evaluated by one study which, did not look at the salt substitute's effect on family members and did not analyze by age, gender, or BP degree. The aim of this current study was to assess the effects of a low-sodium and high-potassium salt substitute on HBP among hypertensive patients and their family members. METHODS: A total of 220 households (including 220 hypertensive patients and 380 their families) were randomly assigned to the regular salt or salt substitute groups. HBP was measured at the beginning, 3rd, 6th, and 12th months. Among the patients (n = 220), only home systolic blood pressure (HSBP) was significantly reduced, by an adjusted baseline BP of 4.2 mm Hg (95% CI: 1.3-7.0 mm Hg), in the salt substitute group compared with those in the regular salt group at each visit (all P < 0.05). There were no detectable differences between groups for home diastolic blood pressure (HDBP) at any visit. Among the family members, HSBP and HDBP were not significantly different between the groups. Furthermore, Individuals >=60 years old, hypertensive patients with stage-2 hypertension, family members with hypertension, and women experienced greater HSBP reduction. CONCLUSIONS: Older subjects, those with higher blood pressure, and women experienced greater home blood pressure reduction from the salt substitute compared to regular salt. PMID- 29400577 TI - Paracrine Interactions between the Conjunctival and Corneal Epithelial Cells Regulate Microenvironmental Homeostasis during Artificially Induced Inflammation. AB - : Purpose/Aim of the study: The corneal and conjunctival epithelium interact with each other and reciprocally modulate the levels of soluble mediators to maintain balance in the ocular surface. The aim of the present study was to analyze paracrine interactions between the corneal and conjunctival epithelium in an inflamed microenvironment (LPS or PMA induction) to test the levels of pro- and anti-inflammatory cytokines and nitric oxide released by the epithelia. MATERIALS AND METHODS: The corneal (pRSV-T) and conjunctival (HC0597) epithelial cell cultures and their indirect co-cultures were treated for 2 h with LPS (E. coli) or for 30 min with phorbol 12-myristate-13-acetate (PMA) to induce inflammation. Cytokine expression (IL-1beta, IL-6, IL-10) and the level of apoptosis were analyzed by ELISA, and the nitric oxide (NO) level by Griess reaction. Cells were incubated for 24 h. RESULTS: The apoptosis of the corneal and conjunctival epithelia decreased (by 43% and 53%, respectively) in co-cultures compared to corresponding monocultures. The conjunctival epithelium produced lower amounts (23%) of NO than the corneal epithelium. PMA and LPS had comparable effects on the levels of NO in mono- and co-cultures. The levels of the tested cytokines changed depending on the type of cell culture and culture conditions (mono- vs. co-cultures and inflammation). The most striking changes were observed for IL-6 expression. CONCLUSIONS: Paracrine interactions between the corneal and conjunctival epithelia may regulate microenvironmental homeostasis during artificially induced inflammation among others by balancing the levels of NO, cytokines, and the viability of cells. PMID- 29400578 TI - The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus. AB - The circadian timing system controls many biological functions in mammals including xenobiotic metabolism, detoxification, cell proliferation, apoptosis and immune functions. Everolimus is a mammalian target of rapamycin inhibitor, whose immunosuppressant properties are both desired in transplant patients and unwanted in cancer patients, where it is indicated for its antiproliferative efficacy. Here we sought whether everolimus circadian timing would predictably modify its immunosuppressive effects so as to optimize this drug through timing. C57BL/6J mice were synchronized with light-dark 12h:12h, with L onset at Zeitgeber Time (ZT) 0. Everolimus was administered orally to male (5 mg/kg/day) and female mice (15 mg/kg/day) at ZT1, during early rest span or at ZT13, during early activity span for 4 weeks. Body weight loss, as well as hematological, immunological and biochemical toxicities, were determined. Spleen and thymus were examined histologically. Everolimus toxicity was less severe following dosing at ZT13, as compared to ZT1, as shown with least body weight inhibition in both genders; least reductions in thymus weight both in males (p < 0.01) and females (p < 0.001), least reduction in female spleen weight (p < 0.05), and less severe thymic medullar atrophy both in males (p < 0.001) and females (p < 0.001). The mean circulating counts in total leukocytes, total lymphocytes, T-helper and B lymphocytes displayed minor and non-significant changes following dosing at ZT13, while they were decreased by 56.9% (p < 0.01), 45.5% (p < 0.01), 43.1% (p < 0.05) and 48.7% (p < 0.01) after everolimus at ZT1, respectively, in only male mice. Chronotherapy of everolimus is an effective way to increase the general tolerability and decrease toxicity on the immune system. PMID- 29400580 TI - Picosecond alexandrite laser is superior to Q-switched Nd:YAG laser in treatment of minocycline-induced hyperpigmentation: A case study and review of the literature. AB - BACKGROUND: Minocycline is a commonly prescribed tetracycline antibiotic used for the treatment of a number of dermatological conditions including acne and rosacea. Long-term adverse effects of minocycline include cutaneous hyperpigmentation. Various treatment options have been suggested for the treatment of minocycline pigmentation. We report a case of a patient on long-term low-dose minocycline for the treatment of rosacea with type III minocycline hyperpigmentation. A comparison was made between Q-Switch Nd:YAG and picosecond laser over a nine 9-period with treatments spaced 1 month apart, with a clearance in the patient pigmentation after four treatments with picosecond laser. PMID- 29400579 TI - Occult urolithiasis in asymptomatic primary hyperparathyroidism. AB - OBJECTIVE: Recent international guidelines suggest renal imaging to detect occult urolithiasis in all patients with asymptomatic primary hyperparathyroidism (PHPT), but data regarding their prevalence and associated risk factors are limited. We evaluated the prevalence and risk factors for occult urolithiasis. METHODS: Cross-sectional analysis of 96 asymptomatic PHPT patients from a university hospital in the United States with and without occult nephrolithiasis. RESULTS: Occult urolithiasis was identified in 21% of patients. Stone formers had 47% higher 24-hour urinary calcium excretion (p = 0.002). Although available in only a subset of patients (n = 28), activated vitamin D [1,25(OH)2D] was 29% higher (p = 0.02) in stone formers. There was no difference in demographics, BMI, calcium or vitamin D intake, other biochemistries, renal function, BMD, or fractures. Receiver operating characteristic curves indicated that urinary calcium excretion and 1,25(OH)2D had an area under the curve of 0.724 (p = 0.003) and 0.750 (p = 0.04), respectively. A urinary calcium threshold of >211mg/day provided a sensitivity of 84.2% and a specificity of 55.3% while a 1,25(OH)2D threshold of >91pg/mL provided a sensitivity and specificity of 62.5% and 90.0% respectively for the presence of stones. CONCLUSION: Occult urolithiasis is present in about one-fifth of patients with asymptomatic PHPT and is associated with higher urinary calcium and 1,25(OH)2D. Given that most patients will not have occult urolithiasis, targeted imaging in those most likely to have occult stones rather than screening all asymptomatic PHPT patients may be useful. The higher sensitivity of urinary calcium versus 1,25(OH)2D suggests screening those with higher urinary calcium may be an appropriate approach. PMID- 29400581 TI - Infrared thermography as control of handheld IPL device for home-use. AB - Infrared thermography as contactless method for determining the temperature distribution on the surface is used for analyzing the impact of intense pulsed light hair removal device (IPL) on the skin. Depth of light penetration depending of wavelength is described as well as absorption curves and IPL impulse shapes. Energy balance and IPL impulse influence on the skin is analyzed. Melanin temperature rise by different fluence operation and temperature distribution in the modeled hair is used in order to determine overall skin temperature rise. Estimated energy balance provided by mathematical model has been confirmed with experimental results. Performed measurements, beside determination of the right emissivity, required the identification of most significant parameter in the process which proved to be the skin reference temperature and real temperature rise. Practical IPL application with detailed body temperature analysis is comprehensively described and thermal imaging interpretation problem and determination of the temperature rise is observed. PMID- 29400582 TI - Prognostic value of tissue Doppler E/e' ratio in hypertension patients with preserved left ventricular ejection fraction. AB - OBJECTIVES: This study aims to investigate the association of tissue Doppler E/e' with cardiac events in hypertension patients, independent of and incremental to clinical and left ventricular geometric patterns. METHODS: We retrospectively enrolled 222 asymptomatic nonischemic patients with hypertension who had echocardiogram in 2012 to evaluate tissue Doppler E/e'. Patients were followed up for cardiac events (cardiac events were defined as myocardial infarction, coronary revascularization procedures, new-onset angina (stable or unstable), heart failure). A cox regression was used to assess the association of the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') with cardiac events. RESULTS: A total of 222 patients were included in analysis. There were 10 primary cardiac events during 3.2 +/- 0.4 years follow-up. The E/e' ratio was the strongest predictor of cardiac events in Cox-proportional hazards models. Following adjustment for covariates, a unit rise in the E/e' ratio was associated with a 26% increment in risk of a cardiac event (HR 1.26, CI 1.06-1.50, p = 0.008). When E/e' >14 the hazard ratio of cardiac event was significantly increased compared with E/e' <= 14 in Kaplan-Meier analysis (log-rank ratio, 16.26; p < 0.001). CONCLUSIONS: E/e', a non-invasive estimate of left ventricular filling pressure, predicts cardiac events in hypertensive population with preserved left ventricular ejection fraction, independent of and incremental to clinical and left ventricular geometric patterns. E/e' represents an early, effective tool for cardiovascular risk stratification in hypertension population. PMID- 29400583 TI - Glycol chitosan/oxidized hyaluronic acid hydrogels functionalized with cartilage extracellular matrix particles and incorporating BMSCs for cartilage repair. AB - In this article, we fabricated a bioactive hydrogel composed of glycol chitosan (G-CS) and oxidized hyaluronic acid (OHA) via Schiff base reaction. Cartilage extracellular matrix (ECM) particles with different concentrations were used to functionalize G-CS/OHA (S1) hydrogel. The results demonstrated that S3 (G CS/OHA/ECM 2% w/v) hydrogel exhibited the most suitable compression strength and provided the optimal environment for proliferation of bone marrow mesenchymal stem cells (BMSCs). To assess the chondroinductivity of ECM in vitro, we compared the chondrogenesis of BMSCs in S1 (G-CS/OHA) and S3 (G-CS/OHA/ECM 2% w/v) hydrogels. The results confirmed that the higher levels of glycosaminoglycans (GAGs) and collagen type II (COL II) were accumulated in S3 hydrogel. In vivo, cartilage defects of rats generated most mature tissue within BMSCs-laden S3 hydrogel (S3/BMSCs group). The tissues were more integrative and contained higher levels of COL II and GAGs compared to the other groups. All these results suggested that the G-CS/OHA hydrogel functionalized with ECM particles is a good candidate biomaterial to be applied in cartilage tissue engineering. PMID- 29400584 TI - Biosynthesis of pure hematite phase magnetic iron oxide nanoparticles using floral extracts of Callistemon viminalis (bottlebrush): their physical properties and novel biological applications. AB - Aqueous floral extracts of Callistemon viminalis were used to synthesize Fe2O3 nanoparticles (IONPs) which were intensively characterized through UV-vis, X-ray diffraction, HR-SEM/HR-TEM, Fourier- transform infrared spectroscopy (FTIR) and energy dispersive X-ray spectroscopy (EDS). Their physical properties were studied in response to different annealing temperatures. It was observed that the increase in the annealing temperature produced small-sized nanoparticles. The nanoparticle size was calculated as 32, 26 and 22 nm for annealing at 300, 400 and 500 degrees C, respectively. The magnetic nature of the bioinspired IONPs was revealed by superconducting quantum interference device (SQUID). Their antibacterial potential was investigated against nine pathogenic bacterial strains (gram positive and gram negative) using disc diffusion method while their MIC was calculated using broth dilution assay. Bioinspired IONPs were found to be highly effective against HepG2 cells (IC50=20 ug/mL). Moderate antileishmanial activities against the promastigotes and amastigotes cultures are reported. Moderate acetylcholine esterase (AchE), butylcholine esterase (BchE) and alpha Glycosidase inhibition are reported. Additional assessment of the biocompatibility was performed using haemolytic activity on the freshly isolated human red blood cells and macrophages. Furthermore, the antioxidant activities, including TAC, DPPH and TRP were also performed. Our results indicate that the biogenic and magnetic Fe2O3 can be used for diverse biomedical applications. PMID- 29400585 TI - Fatal collision? Are wireless headsets a risk in treating patients? AB - Wireless-enabled headsets that connect to the internet can provide remote transcribing of patient examination notes. Audio and video can be captured and transmitted by wireless signals sent from the computer screen in the frame of the glasses. But using wireless glass-type devices can expose the user to a specific absorption rates (SAR) of 1.11-1.46 W/kg of radiofrequency radiation. That RF intensity is as high as or higher than RF emissions of some cell phones. Prolonged use of cell phones used ipsilaterally at the head has been associated with statistically significant increased risk of glioma and acoustic neuroma. Using wireless glasses for extended periods to teach, to perform surgery, or conduct patient exams will expose the medical professional to similar RF exposures which may impair brain performance, cognition and judgment, concentration and attention and increase the risk for brain tumors. The quality of medical care may be compromised by extended use of wireless-embedded devices in health care settings. Both medical professionals and their patients should know the risks of such devices and have a choice about allowing their use during patient exams. Transmission of sensitive patient data over wireless networks may increase the risk of hacking and security breaches leading to losses of private patient medical and financial data that are strictly protected under HIPPA health information privacy laws. PMID- 29400586 TI - Prevalence of buried probe in complex congenital nasolacrimal duct obstruction and evaluation of its success rate post 'probing and irrigation': a single-centre retrospective study. AB - INTRODUCTION: The aim of this study was to determine the prevalence of buried probe variant of complex congenital nasolacrimal duct obstruction (CNLDO) and to evaluate the outcome of probing and irrigation in such cases. Institutional review board approval was taken. MATERIAL & METHODS: A total of 309 eyes (258 patients) were diagnosed with CNLDO during the study period of January 2014-March 2017. A retrospective file review of 25 lacrimal systems of 20 patients diagnosed as buried probe variant of complex CNLDO was carried out during the study period. RESULT: Buried probe variant of complex CNLDO was found to be 8% of the total CNLDO cases during the study period. Mean age at presentation was 1.7 years (range 8-48 months). Discharge and matting of eyelashes were the presenting symptoms in 22 out of 25 (88%) cases, whereas the only epiphora was the presenting symptom in three (12%) cases. Regurgitation of mucopurulent discharge on pressure over lacrimal sac area was positive in 16 out of 25 (64%) eyes. Associated lacrimal and nasal pathologies were seen in six out of 25 cases (24%). Success rate in buried probe variant cases of CNLDO in our study at 3-month follow-up was 88% (22 of 25 cases). CONCLUSION: A high period prevalence of 8% out of all CNLDO cases in our study suggests that the buried probe should be considered in selective cases of CNLDO and earlier unsuccessful probing. PMID- 29400587 TI - Combined use of microfocused ultrasound and a calcium hydroxylapatite dermal filler for treating atrophic acne scars: A pilot study. AB - BACKGROUND: An unfortunate consequence of severe acne is scarring, which can have serious psychosocial consequences. Available methods for treating acne scars have varying degrees of effectiveness. OBJECTIVE: This nonrandomized, retrospective pilot study assessed the safety and effectiveness of combining microfocused ultrasound with visualization (MFU-V; Ultherapy(r)) and a calcium hydroxylapatite dermal filler (CaHA; Radiesse(r)) for treating atrophic acne scars. METHODS: Healthy subjects 35-55 years old with moderate-to-severe facial acne scars were enrolled. MFU-V was applied bilaterally using two transducers with focal depths of 3.0 and 1.5 mm. Using a cross-hatch pattern, 75 treatment lines were applied 2 3 mm apart. Immediately afterward, the same areas were injected with 1.5 mL of CaHA diluted with 1.5 mL of lidocaine 2% without epinephrine. Scar severity changes were assessed by two independent physicians using the Goodman Acne Scar Scale at post-treatment Day 90. Subject satisfaction was assessed with a questionnaire. RESULTS: Treated subjects (N = 10) achieved significant overall improvement in baseline acne scar severity (P = 0.002). When stratified by severity, a clear trend was apparent with the greatest improvement observed among subjects with severe scars. Subjects were very satisfied (n = 9) or satisfied (n = 1) with their aesthetic results. No adverse events were observed. CONCLUSIONS: Combining MFU-V and diluted CaHA is effective for treating atrophic acne scars. PMID- 29400589 TI - Putting an End to Emergency Room Injection/Infusion Coding Confusion. PMID- 29400588 TI - Polymorphism of the DNA methyltransferase 1 gene is associated with the susceptibility to essential hypertension in male. AB - Essential hypertension is a leading global public health issue, billions of people suffered from it every year. Recently, multiple evidence suggests that DNA methylation play an important role in regulating blood pressure. Here, we tested the risk for essential hypertension conferred by single nucleotide polymorphisms (SNPs) within DNA methyltransferase 1 (DNMT1). Three loci (rs2228611, rs2228612, and rs16999593) were selected to be analyzed in 3410 cases and 1307 normal controls in southern Chinese aged 60 or above. No significant association with essential hypertension was observed for rs2228612 and rs16999593. A higher risk of essential hypertension was found in the minor A allele of rs2228611 in the codominant and recessive model (P < 0.05). After stratified by sex, this association was found in male but not female. Furthermore, this difference was abolished after BMI adjustment in the whole population and reduced in male. In addition, the mutation rate of rs2228611 was higher in the obesity group compared with the normal weight group of male. Intriguingly, rs2228611 was also a risk factor of essential hypertension in normal weight male. These findings indicated that rs2228611 might contribute to male hypertension via BMI-dependent mechanisms in obesity male and BMI-independent mechanisms in normal weight male. PMID- 29400590 TI - Lichen amyloidosis successfully treated with fractional ablative laser CO2: A new alternative therapeutic. AB - Lichen amyloidosis is a primary localized cutaneous amyloidosis. Different types of treatment have been used without complete resolution. Herein, we report a case of patient suffering from lichen amyloidosis successfully treated with fractional ablative laser CO2. He was a 59-year-old man diagnosed lichen amyloidosis localized on the legs 10 years ago. He was treated with topical corticosteroids without any improvement. Then, we started treating the affected area with CO2 laser (limmer*) at a setting of 5-8 J/cm2 and 8 mm laser spot size. A considerable improvement was noticed after the first session. A total healing was reported after four sessions. To the best of our knowledge, only 11 reported cases of lichen amyloidosis have been successfully treated with laser CO2. However, our clinical finding seems to be one of the best reported results. PMID- 29400591 TI - Psychometric Evaluation of the 'Evidence Based Practice Competencies Questionnaire - Cerebral Palsy'. AB - AIM: To understand whether knowledge translation activities are effective, good measurement of practice is required. This study investigated the psychometric properties of a self-report measure of allied health practitioner (AHP) evidence based behaviors when working with children with cerebral palsy. METHODS: Construct validity and reliability studies were undertaken for the 12-item Evidence Based Practice Competency Questionnaire - Cerebral Palsy (EBP-CQ-CP) using the Consensus-based Standards of Measurement Instruments methods. Factor analysis tested construct validity. Weighted Kappa tested chance-corrected agreement for each item and intra-class correlation coefficients (ICC) the reliability of factors derived in the validity study. RESULTS: In the validity study 259 AHP completed the EBP-CQ-CP on occasion 1, and 228 on occasion 2. In the reliability study 46 AHP completed the questionnaire twice. Exploratory factor analysis determined the EBP-CQ-CP contained two scales: 'communicating evidence based expectations' and 'evidence based assessment practices'. Confirmatory factor analysis using data from the second occasion of assessment supported the findings. Excellent consistency in ratings across factor scores were obtained from 46 pairs of raters: Factor 1, ICC = 0.93 (95% Confidence Interval 0.88-0.96); Factor 2, ICC = 0.94 (95% Confidence Interval 0.88-0.97). CONCLUSIONS: This study supports the interpretation of the EBP-CQ-CP in a clinically meaningful and psychometrically robust manner. PMID- 29400592 TI - Movement goals encoded within the cortex and muscle synergies to reduce redundancy pre and post-stroke. The relevance for gait rehabilitation and the prescription of walking-aids. A literature review and scholarly discussion. AB - Current knowledge of neural and neuromuscular processes controlling gait and movement as well as an understanding of how these mechanisms change following stroke is an important basis for the development of effective rehabilitation interventions. To support the translation of findings from basic research into useful treatments in clinical practice, up-to-date neuroscience should be presented in forms accessible to all members of the multidisciplinary team. In this review we discuss aspects of cortical control of gait and movement, muscle synergies as a way of translating cortical commands into specific muscle activity and as an efficient means of reducing neural and musculoskeletal redundancy. We discuss how these mechanisms change following stroke, potential consequences for gait rehabilitation, and the prescription and use of walking-aids as well as areas requiring further research. PMID- 29400593 TI - The role of the therapeutic alliance on pain relief in musculoskeletal rehabilitation: A systematic review. AB - The aim of this systematic review was to investigate the role of therapeutic alliance in pain relief in patients with musculoskeletal disorders treated by physiotherapy. Manual and database searches (Medline, Embase, ISI Web of Knowledge, CINAHL, PEDro, Lilacs, Cochrane Library, and PsycINFO) were performed with no restrictions of language and publication date. We included prospective studies with samples of patients undergoing physiotherapy for musculoskeletal conditions, with one measure of therapeutic alliance and the outcome pain. Methodological quality was assessed by the Methodological Index for Nonrandomized Studies and the Cochrane tool for risk of bias. Six articles from four studies were included out of the 936 manuscripts identified. All studies used samples composed of patients with chronic low back pain. Two studies applied therapeutic alliance incentive measures during treatment and reported significant improvement in pain. The remaining studies, without alliance incentives, showed divergence regarding the relationship between the therapeutic alliance and pain. Methodological quality analysis determined low risk of bias of the studies. A lack of studies on the therapeutic alliance regarding musculoskeletal physiotherapy was verified. Existing studies fail to provide evidence of a strong relationship between the therapeutic alliance and pain relief. PMID- 29400594 TI - Prospective Associations of Actual and Perceived Descriptive Norms with Drinking Among Emerging Adults. AB - BACKGROUND: Descriptive norms are commonly associated with participant drinking. However, study participants may incorrectly perceive that their peers drink about the same amount as they do, which would bias estimates of drinking homogeneity. OBJECTIVES: This research examined the magnitude of associations between emerging adults' reports of their own drinking and peer drinking measured the previous year by measures of (1) participants' perceptions of friends' drinking; and (2) actual drinking reported by nominated peers. METHODS: The data are from annual surveys conducted in 2014 and 2015, Waves 4 and 5 (the first 2 years after high school) of 7 annual assessments as part of the NEXT Generation Health Study (n = 323). Associations of participant alcohol use with perceived friend use (five closest, closest male, and closest female friends), and with actual peer use. Logistic regression analyses estimated the magnitudes of prospective associations between each measure of peer drinking at W4 and participant drinking at W5. PMID- 29400596 TI - Conflict-driven adaptive control is enhanced by integral negative emotion on a short time scale. AB - Negative emotion influences cognitive control, and more specifically conflict adaptation. However, discrepant results have often been reported in the literature. In this study, we broke down negative emotion into integral and incidental components using a modern motivation-based framework, and assessed whether the former could change conflict adaptation. In the first experiment, we manipulated the duration of the inter-trial-interval (ITI) to assess the actual time-scale of this effect. Integral negative emotion was induced by using loss related feedback contingent on task performance, and measured at the subjective and physiological levels. Results showed that conflict-driven adaptive control was enhanced when integral negative emotion was elicited, compared to a control condition without changes in defensive motivation. Importantly, this effect was only found when a short, as opposed to long ITI was used, suggesting that it had a short time scale. In the second experiment, we controlled for effects of feature repetition and contingency learning, and replicated an enhanced conflict adaptation effect when integral negative emotion was elicited and a short ITI was used. We interpret these new results against a standard cognitive control framework assuming that integral negative emotion amplifies specific control signals transiently, and in turn enhances conflict adaptation. PMID- 29400595 TI - Remembering the past and imagining the future: attachment effects on production of episodic details in close relationships. AB - Attachment theories and studies have shown that Internal Working Models (IWMs) can impact autobiographical memory and future-oriented information processing relevant to close relationships. According to the constructive episodic simulation hypothesis (CESH), both remembering the past and imagining the future rely on episodic memory. We hypothesised that one way IWMs may bridge past experiences and future adaptations is via episodic memory. The present study investigated the association between attachment and episodic specificity in attachment-relevant and attachment-irrelevant memory and imagination among young and older adults. We measured the attachment style of 37 young adults and 40 older adults, and then asked them to remember or imagine attachment-relevant and attachment-irrelevant events. Participants' narratives were coded for internal details (i.e., episodic) and external details (e.g., semantic, repetitions). The results showed that across age group, secure individuals generated more internal details and fewer external details in attachment-relevant tasks compared to attachment-irrelevant tasks; these differences were not observed in insecure individuals. These findings support the CESH and provide a new perspective to understand the function of IWMs. PMID- 29400597 TI - Parental perceptions of child placement within vehicles: a focus group study. AB - Although rear-seating children in motor vehicles results in fewer injuries and fatalities in motor vehicle crashes, many children continue to be front-seated. This study seeks to identify parental barriers to rear-seating children in motor vehicles and strategies to increase child rear seat placement. Focus groups were conducted with parents of children 12 or younger to determine barriers to rear seating and strategies to increase child rear seat placement. Barriers to rear seat placement identified include the logistics of transporting multiple children with limited rear seat availability, the potential of children to harm themselves if rear-seated, and peer pressure. Parents felt there should be no option to sit elsewhere within the vehicle to help normalize rear-seating. Successful interventions to increase child rear seat placement should focus on parental barriers to rear-seat their children in vehicles, including normalizing rear seat placement, and determining approaches to make rear-seat placement with multiple children uncomplicated. PMID- 29400598 TI - Circumstances of hospital admissions in palliative care: A cross-sectional survey of patients admitted to hospital with palliative care needs. AB - BACKGROUND: On average, people will experience 2.28 hospital admissions in the last year of life with the likelihood of a hospital admission increasing in the last 2 weeks of life. Reducing hospital admissions has become a focus for high income countries as they work to manage the financial implications of an ageing population. However, the circumstances by which patients with palliative care needs are admitted to hospital remain poorly understood. AIM: To explore the circumstances of hospital admissions for patients with palliative care needs. DESIGN: Cross-sectional survey design using face-to-face questionnaires. SETTING/PARTICIPANTS: In total, 116 patients aged >18 years admitted to a tertiary hospital with palliative care needs. RESULTS: Those with a non-cancer diagnosis and those aged over 75 years were less likely to have hospice involved prior to the admission ( x2 (1, n = 116) = 10.19, p = 0.00). Few patients recognised community services as having a role in enabling them to remain at home. Those with cancer placed a significantly higher priority on receiving information about their illness ( t(114) = 2.03, p = 0.04) and receiving tests and investigations ( t(114) = 2.37, p = 0.02) in hospital. CONCLUSION: This study has demonstrated the complexity of hospital admissions in palliative care. Further research is needed to explore patient perceptions of care at home and the role of community services to enable them to remain at home. Understanding the motivation to come to hospital in the context of an incurable illness and limited treatment options may help to inform the development of services that can enable better care at home. PMID- 29400599 TI - A prognosis and impact factor analysis of DC-CIK cell therapy for patients with hepatocellular carcinoma undergoing postoperative TACE. AB - Dendritic cell-cytokine-induced killer (DC-CIK) cell therapy has been experimentally implemented for enhancing anti-tumoral immunity in patients with hepatocellular carcinoma (HCC) undergoing postoperative transcatheter arterial chemoembolization (POTACE). We performed a retrospective study to evaluate the clinical efficacies of DC-CIK cell therapy and its correlations with several immune factors of the primary tumors. The overall survival time of HCC patients with HBV infection in the study group (POTACE plus DC-CIK cell therapy) was significantly longer than that of the control group (POTACE alone). The expression level of PD-L1 but not the tumor-infiltrated CD8 and CD4 T cells in the tumor tissues showed significant negative correlations with relapse-free survival (RFS) and overall survival (OS), which was also an independent prognostic factor for the five-years' suvival of patients with HCC receiving POTACE treatment. Furthermore, our study validated that PD-L1 expression was significantly inversely correlated with the survival time of HCC patients receiving POTACE plus DC-CIK cell therapy treatment. More importantly, DC-CIK cell therapy provided the best clinical benefits to HCC patients with the low PD L1 expression receiving POTACE, which indicate that PD-L1 expression level can serve as a pivotal predictor for the therapeutic efficacy of DC-CIK cell therapy for HCC patients receiving POTACE treatment. PMID- 29400600 TI - Cocaine abuse: Longitudinal MR imaging of lasting diffused leukoencephalopathy. AB - Cocaine use has been known to cause a number of adverse neurological conditions, such as cerebral ischemia and posterior reversible leukoencephalopathy. The radiologic appearance of cocaine-induced leukoencephalopathy is confounded by a common contaminant, levamisole, which is also known to cause multifocal leukoencephalopathy. However, we encountered a case of diffuse leukoencephalopathy in a patient with cocaine use that had extensive involvement of the cerebral white matter, globus pallidi as well as the cerebellum. Our case also presented with a severe clinical presentation, with the patient demonstrating minimal neurologic response after a prolonged period of critical care management. The severe clinical course and diffuse radiologic involvement of our case differs from previously reported cases of cocaine- or levamisole-induced leukoencephalopathy. PMID- 29400601 TI - Intentional and automatic processing of numerical information in mathematical anxiety: testing the influence of emotional priming. AB - Current theoretical approaches suggest that mathematical anxiety (MA) manifests itself as a weakness in quantity manipulations. This study is the first to examine automatic versus intentional processing of numerical information using the numerical Stroop paradigm in participants with high MA. To manipulate anxiety levels, we combined the numerical Stroop task with an affective priming paradigm. We took a group of college students with high MA and compared their performance to a group of participants with low MA. Under low anxiety conditions (neutral priming), participants with high MA showed relatively intact number processing abilities. However, under high anxiety conditions (mathematical priming), participants with high MA showed (1) higher processing of the non-numerical irrelevant information, which aligns with the theoretical view regarding deficits in selective attention in anxiety and (2) an abnormal numerical distance effect. These results demonstrate that abnormal, basic numerical processing in MA is context related. PMID- 29400602 TI - Identification of SP1683 as a pneumococcal protein that is protective against nasopharyngeal colonization. AB - Serotype-independent protein-based pneumococcal vaccines represent attractive alternatives to capsular polysaccharide-based vaccines. The aim of this study was to identify novel immunogenic proteins from Streptococcus pneumoniae that may be used in protein-based pneumococcal vaccine. An immunoproteomics approach and a humanized severe combined immunodeficient mouse model were used to identify S. pneumoniae proteins that are immunogenic for the human immune system. Among the several proteins identified, SP1683 was selected, recombinantly produced, and infection and colonization murine models were used to evaluate the capacity of SP1683 to elicit protective responses, in comparison to known pneumococcal immunogenic proteins (PhtD and detoxified pneumolysin, dPly). Immunisation with SP1683 elicited a weaker antibody response than immunisation with PhtD and did not provide protection in the model of invasive disease. However, similar to PhtD, it was able to significantly reduce colonization in the mouse model of nasopharyngeal carriage. Treatment with anti-IL17A and anti-IL17F antibodies abolished the protection against colonization elicited by SP1683 or PhtD + dPly, which indicated that the protection afforded in this model was Th17-dependent. In conclusion, intranasal immunization with the pneumococcal protein SP1683 conferred IL17-dependent protection against nasopharyngeal carriage in mice, but systemic immunization did not protect against invasive disease. These results do not support the use of SP1683 as an isolated pneumococcal vaccine antigen. Nevertheless, SP1683 could be used as a first line of defence in formulations combining several proteins. PMID- 29400603 TI - A novel bicistronic gene design couples stable cell line selection with a fucose switch in a designer CHO host to produce native and afucosylated glycoform antibodies. AB - The conserved glycosylation site Asn297 of a monoclonal antibody (mAb) can be decorated with a variety of sugars that can alter mAb pharmacokinetics and recruitment of effector proteins. Antibodies lacking the core fucose at Asn297 (afucosylated mAbs) show enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and increased efficacy. Here, we describe the development of a robust platform for the manufacture of afucosylated therapeutic mAbs by engineering a Chinese hamster ovary (CHO) host cell line to co-express a mAb with GDP-6-deoxy-D lyxo-4-hexulose reductase (RMD), a prokaryotic enzyme that deflects an intermediate in the de novo synthesis of fucose to a dead-end product, resulting in the production of afucosylated mAb (GlymaxXTM Technology, ProBioGen). Expression of the mAb and RMD genes was coordinated by co-transfection of separate mAb and RMD vectors or use of an internal ribosome entry site (IRES) element to link the translation of RMD with either the glutamine synthase selection marker or the mAb light chain. The GS-IRES-RMD vector format was more suitable for the rapid generation of high yielding cell lines, secreting afucosylated mAb with titers exceeding 6.0 g/L. These cell lines maintained production of afucosylated mAb over 60 generations, ensuring their suitability for use in large-scale manufacturing. The afucosylated mAbs purified from these RMD-engineered cell lines showed increased binding in a CD16 cellular assay, demonstrating enhancement of ADCC compared to fucosylated control mAb. Furthermore, the afucosylation in these mAbs could be controlled by simple addition of L-fucose in the culture medium, thereby allowing the use of a single cell line for production of the same mAb in fucosylated and afucosylated formats for multiple therapeutic indications. PMID- 29400604 TI - Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance. METHODS: We monitored the plasma circulating tumor DNA (ctDNA) using captured based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance. RESULTS: ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib. CONCLUSIONS: Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC. PMID- 29400605 TI - Comparing the effectiveness of virtual reality and video modelling as an intervention strategy for individuals with Autism Spectrum Disorder: Brief report. AB - : The increasing numbers of individuals diagnosed with Autism Spectrum Disorder (ASD) has foreshadowed a greater need for effective intervention procedures to aid learning. PURPOSE: This study compared the effectiveness of video modelling (VM) and virtual reality (VR) for teaching adults with ASD. METHODS: Using an alternating treatments design without baseline two participants completed paper folding projects of varying difficulty following exposure to either VM or VR task modelling. The rate of learning (ROL) determined treatment effectiveness. RESULTS: One participant reached mastery criterion for the intermediate project on the 5th trial with both VR and VM (i.e. equal ROL). The other achieved mastery by the 6th trial of VM, but did not attain mastery in VR. Both participants reported enjoying both procedures. CONCLUSIONS: The results suggest that VM was more effective than VR in facilitating learning. Implications for future research are discussed. PMID- 29400606 TI - A problem of the safety of vulnerable road users in Montenegro. AB - Research on the safety of vulnerable road users in Montenegro and in the European Union found that pedestrian fatality rates are the highest, followed by motorcyclists, and then cyclists. In the European Union, fatality rates are decreasing for all groups of vulnerable road users, while in Montenegro the fatality rate of pedestrians and cyclists is decreasing. The safety improvement for vulnerable road users is less successful than that for people in vehicles. Pedestrians in Montenegro are at the highest risk in the European Union. In Montenegro, pedestrians and cyclists are most vulnerable on the streets in the most developed settlements, while moped riders and motorcyclists are most vulnerable on the main roads. The implementation of control measures led to a turning point, and further improvement was obtained after implementing safety campaigns; for greater improvements, it will be necessary to establish local institutions for traffic safety management. PMID- 29400607 TI - Experienced and Anticipated Pride and Shame as Predictors of Goal-Directed Behavior. AB - This study examined how experienced and anticipated pride and shame were related to time spent training and effort expended toward training the following week. Participants (N = 158, 76% women; Mage = 35.51, SD = 10.29 years) training for a marathon/half-marathon completed a weekly online questionnaire for 5 weeks leading up to a race. In the multilevel models, time spent training was positively predicted by race proximity, age, and effort expended that week. Effort expended toward training was predicted by the current week's effort, the amount of time spent training that week, and was greater for participants who usually reported experiencing more pride than others. Neither anticipated pride or shame predicted time or effort, nor did experienced shame. The findings indicate that it is functional to foster high levels of pride when training for a long-distance race. Further work is needed to ascertain the relationship between anticipated emotions on goal-directed behavior. PMID- 29400608 TI - Subgrouping children with cerebral palsy from a broader perspective using two methods. AB - The purpose was to develop two versions of a body function index in cerebral palsy (BFI-CP I and BFI-CP II) using two methods to explore the relationship and differences among them and the Gross Motor Function Classification System (GMFCS) and to explore the differences among subsets of the classifications that do not correspond to the ordinal levels of the GMFCS. Data on various measures from 405 children with CP between 18 months and 5 years of age were extracted from the Move & PLAY Study. The BFI-CP I was developed using a summing technique and the BFI-CP II was developed using cluster analysis. There was a strong correlation between the BFI-CP I and the GMFCS (r = 0.92), between the BFI-CP II and the GMFCS (r = 0.93), and between the BFI-CP I and II (r = 0.92) all (p < 0.001). There was also a significant difference between the BFI-CP I and the GMFCS (chi2 = 670.49, df = 16, p < 0.001) and between the BFI-CP II and the GMFCS (chi2 = 685.57, df = 16, p < 0.001). The findings of this study indicate that the two versions of the BFI-CP could be used as complementary methods in describing children with CP. PMID- 29400610 TI - Psychosocial functioning in adolescents: results according to Amiel-Tison neurological assessment in a group of preterm infants. AB - OBJECTIVE: This prospective study investigated the relationship between Amiel Tison neurological assessment (ATNA) in preterm children and their psychosocial functioning in adolescence. METHODS: From the initial group of 45 children regularly assessed by the ATNA from term until the age of 2 years, 27 participated in the follow-up at 13 years. RESULTS: Of the three groups categorized by neurological signs as normal, intermediate or abnormal, parents of adolescents with normal ATNA reported the lowest number of executive function problems (p = 0.019) and behavioral symptoms (p = 0.011), while the adolescents themselves reported the lowest number of behavioral symptoms (p = 0.005) and the highest quality of life (p = 0.012). The number of problems reported increased with the number of abnormal neurological signs. CONCLUSION: Standardized neurological assessment may be a helpful clinical tool for the identification of children at risk for later psychosocial problems who could benefit from prevention and early intervention programs. PMID- 29400609 TI - Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity. AB - Adipose tissue autophagy (AT) is associated with human obesity and increased metabolic risk. Recent findings establish a role for autophagy in lipid metabolism. Here, we compared the expression of autophagy-related and lipolysis genes in human abdominal subcutaneous AT (SCAT) in overweight/obese subjects (n = 17) with or without impaired glucose tolerance in comparison with lean normal glucose tolerant individuals (n = 9), and investigated the association between AT autophagy and lipolysis. Human multipotent adipose-derived stem cells (hMADS) were used to investigate the effect of pharmacological HSL inhibition on changes in the autophagic flux. The expression of autophagy-related genes (ATG) 5, 7 and 12 in SCAT was significantly higher (p = 0.043, p = 0.015, p = 0.004, respectively) in overweight/obese compared to lean men, while expression of the classical lipases HSL (p = 0.092) and ATGL (p = 0.084) tended to be lower. ATG12 mRNA was positively correlated with BMI (r = 0.407, p = 0.039). ATG7 mRNA correlated positively with waist/hip ratio (WHR) (r = 0.420, p = 0.041), 2 h glucose concentration (r = 0.488, p = 0.011) and insulin (r = 0.419, p = 0.033). Multiple linear regressions revealed that ATG7 gene expression was positively related to 2 h glucose, independent of BMI, WHR and insulin. Gene expression interaction analysis showed that ATG7 mRNA negatively correlated with HSL (p<0.01) and ATGL mRNA expression (p<0.01). In line, treatment of differentiated hMADS with an HSL inhibitor increased LC3 accumulation, a marker of increased autophagic flux. Collectively, the present study demonstrated that a low expression of classical lipases in abdominal SCAT is accompanied by an increased expression of ATGs in overweight/obese subjects, which seems to be mainly related to glucose tolerance. PMID- 29400611 TI - Does attitude acquisition in evaluative conditioning without explicit CS-US memory reflect implicit misattribution of affect? AB - Research that dissociates different types of processes within a given task using a processing tree approach suggests that attitudes may be acquired through evaluative conditioning in the absence of explicit encoding of CS-US pairings in memory. This research distinguishes explicit memory for the CS-US pairings from CS-liking acquired without encoding of CS-US pairs in explicit memory. It has been suggested that the latter effect may be due to an implicit misattribution process that is assumed to operate when US evocativeness is low. In the present research, the latter assumption was supported neither by two high-powered experiments nor by complementary meta-analytic evidence, whereas evocativeness exerted an influence on explicit memory. This pattern of findings is inconsistent with the view that CS-liking acquired without encoding of CS-US pairs in explicit memory reflects an implicit misattribution process at learning. Hence, the underlying learning process is awaiting further empirical scrutiny. PMID- 29400613 TI - Automated Artifact-Detection Procedure for Vaginal Photoplethysmography. AB - Vaginal photoplethysmography is the most commonly used method of assessing women's genital sexual arousal. Raw photoplethysmograph data consist of a series of peaks and troughs, and movement by the participant results in artifacts indicated by unusually high or low peak-to-trough amplitudes. The gold-standard approach to artifact detection involves visual inspection by a trained experimenter and manual removal of artifacts from the data set, however, this process is time-consuming and subject to human error. We present an automated data-processing procedure that uses a series of smoothing regression splines to model the data and identify outliers. The automated procedure was applied to a set of neutral data and sexual-arousal response data, and artifacts identified were compared to artifacts identified by the standard approach of visual inspection. The automated method showed acceptable accuracy in terms of sensitivity and specificity comparable to the manual-processing method. The automated procedure could reduce human error and data-processing time for studies using vaginal photoplethysmography. PMID- 29400612 TI - The pharmacoepigenomics informatics pipeline defines a pathway of novel and known warfarin pharmacogenomics variants. AB - AIM: 'Pharmacoepigenomics' methods informed by omics datasets and pre-existing knowledge have yielded discoveries in neuropsychiatric pharmacogenomics. Now we evaluate the generality of these methods by discovering an extended warfarin pharmacogenomics pathway. MATERIALS & METHODS: We developed the pharmacoepigenomics informatics pipeline, a scalable multi-omics variant screening pipeline for pharmacogenomics, and conducted an experiment in the genomics of warfarin. RESULTS: We discovered known and novel pharmacogenomics variants and genes, both coding and regulatory, for warfarin response, including adverse events. Such genes and variants cluster in a warfarin response pathway consolidating known and novel warfarin response variants and genes. CONCLUSION: These results can inform a new warfarin test. The pharmacoepigenomics informatics pipeline may be able to discover new pharmacogenomics markers in other drug disease systems. PMID- 29400614 TI - Coach ratings of skills and their relations to practice, play and successful transitions from youth-elite to adult-professional status in soccer. AB - Elite soccer players (~15 yr) from professional academies in the UK were rated on technical, tactical, physical and creative skills by coaches at time 1 (T1). Players estimated accumulated hours in soccer practice (coach-led activities) and play (self-led activities) during childhood. Coach-ratings were again collected 2.5 yr later (T2) for players that received a professional contract (~17 yr). Adult-professional status was determined at T3 (~ 20 yr). Skill ratings distinguished across the three "future" groups (academy-only, youth-professional only and adult-professional), for all but creative skill. For players that transitioned to youth-professional, medium sized correlations were noted between childhood practice amounts and technical and creative skill ratings at T1, although practice amounts correlated more strongly with skill ratings at T2. Play amounts were not related to any skills. Within groups of youth elite athletes, domain-specific play in childhood, and to a lesser degree practice, were generally not good discriminators of specific-skills. The effects of sport specific practice on the development (and discriminability) of skills takes time to emerge. We consider the implications for talent development models and purported links between play and creativity. PMID- 29400615 TI - Gender differences in driving under the influence (DUI) program client characteristics: Implications for treatment delivery. AB - The purpose of this descriptive study was to examine gender differences in the characteristics of clients in a large Driving Under the Influence (DUI) program in Southern California. We analyzed secondary de-identified data from a large DUI program for the years 2009-2014 (n = 19,619). Sociodemographic characteristics, measures of physical and mental comorbidity, and alcohol use severity measures were compared for male and female clients. Women averaged 32.85 years of age (SD = 10.70), while men were slightly older at 34.2 years (SD = 11.19). Females comprised an increasingly greater percentage of the client population over the time period studied (27.6%-30.7%). In a multivariable model, compared to male clients, females were more likely to be White non-Hispanic, not currently married, and younger. Women were more likely than men to report anxiety, depression, and a history of domestic violence. Blood alcohol content at arrest and measures of hazardous drinking did not differ significantly by gender. Results suggested that gender-specific DUI programs might be useful. PMID- 29400616 TI - Repeated-sprint training in hypoxia induced by voluntary hypoventilation improves running repeated-sprint ability in rugby players. AB - PURPOSE: The goal of this study was to determine the effects of repeated-sprint training in hypoxia induced by voluntary hypoventilation at low lung volume (VHL) on running repeated-sprint ability (RSA) in team-sport players. METHODS: Twenty one highly trained rugby players performed, over a 4-week period, seven sessions of repeated 40-m sprints either with VHL (RSH-VHL, n = 11) or with normal breathing (RSN, n = 10). Before (Pre-) and after training (Post-), performance was assessed with an RSA test (40-m all-out sprints with a departure every 30 s) until task failure (85% of the reference velocity assessed in an isolated sprint). RESULTS: The number of sprints completed during the RSA test was significantly increased after the training period in RSH-VHL (9.1 +/- 2.8 vs. 14.9 +/- 5.3; +64%; p < .01) but not in RSN (9.8 +/- 2.8 vs. 10.4 +/- 4.7; +6%; p = .74). Maximal velocity was not different between Pre- and Post- in both groups whereas the mean velocity decreased in RSN and remained unchanged in RSH-VHL. The mean SpO2 recorded over an entire training session was lower in RSH-VHL than in RSN (90.1 +/- 1.4 vs. 95.5 +/- 0.5%, p < .01). CONCLUSION: RSH-VHL appears to be an effective strategy to produce a hypoxic stress and to improve running RSA in team-sport players. PMID- 29400617 TI - Utilizing Bloom's taxonomy to design a substance use disorders course for health professions students. AB - BACKGROUND: Substance use disorders (SUDs) are a public health problem affecting millions of Americans. Despite their prevalence, there are few health care resources allocated for SUDs treatment. Relatively few health care professionals are exposed to SUDs education in their respective programs, which may be one reason for this resource insufficiency. In hopes of rectifying this gap, the authors developed a SUDs course for health professions students combining classroom learning with practical application to patient care. METHODS: The authors used Bloom's taxonomy of cognitive, affective, and psychomotor learning domains as an educational framework to create numerous opportunities for students to deepen their knowledge, assess their attitudes, and develop their motivational interviewing skills. The primary outcome of the study was a comparison of students' scores on the Substance Abuse Attitude Scale (SAAS) pre- and post course completion. Secondary outcome was to compare students' self-assessment scores of their patient counseling with residents' assessments of them on the Liverpool Communication Skills Assessment Scale (LCSAS). RESULTS: One hundred twelve students participated in the authors' SUDs course over a 9-month period. Ninety-five students completed both the pre- and post-course SAAS surveys. The total SAAS survey score and individual domain scores for nonmoralizing, treatment optimism, and treatment intervention demonstrated significant improvement post course. Eighty-nine students completed a motivational interview with a patient. Eighty students had a LCSAS self-assessment paired with a residents' assessment. Mean scores for individual items on the LCSAS for both groups' assessment were approximately 3.5, indicating that students' communication was assessed as "acceptable" to "good." CONCLUSIONS: This study demonstrates that Bloom's taxonomy was a useful educational framework to ensure a systematic development of the authors' SUDs course. Through participation in our course, students touched each of the 3 domains in Bloom's taxonomy. The authors believe their course design may serve as a framework for future SUDs courses. PMID- 29400618 TI - The longitudinal relationship between generalized self-efficacy and physical activity in school-aged children. AB - Our understanding of the longitudinal relationship between generalized self efficacy (GSE) and physical activity in children and youth is limited. The purpose of this study was to investigate the effect of GSE towards physical activity on sedentary behaviours and physical activity in school-aged children over time. A total of 2278 nine-year-old children (1120 girls and 1158 boys) were recruited at baseline and followed for seven waves of data collection from 2005 to 2008. All children completed questionnaires at each wave assessing their GSE (adequacy, predilection, and enjoyment), sedentary behaviours, free play, and organized activity. Mixed-effects models were used to estimate changes in physical activity and GSE within individuals over time, controlling for gender and motor ability. The results showed that participation in free play significantly increased over time, whereas organized activity significantly decreased over the same period. Children with high perceived adequacy and predilection had higher free play and organized activity participation relative to other children over time. However, the effect of perceived adequacy diminished over time, while the gaps between groups with different levels of predilection widened over time. While sedentary behaviours were lower over time in children with high predilection, these behaviours were consistently higher in children with high enjoyment. The differences in sedentary behaviours between groups increased over time for both predilection and enjoyment. This study highlights the importance of different components of GSE on physical activity participation. In addition, interventions targeting the enhancement of predilection may facilitate physical activity and reduce sedentary behaviours. PMID- 29400619 TI - Family carers' experiences of coping with the deaths of adults in home settings: A narrative analysis of carers' relevant background worries. AB - BACKGROUND: Internationally, evidence on the support needs of family carers who look after a terminally ill adult in home settings is incomplete. AIM: To illustrate the relevance of 'relevant background worries' in family carers' accounts of caring at home for a dying adult. DESIGN: A qualitative cross sectional observational study was conducted in England, United Kingdom, in 2011 2013 on the experiences of adult family carers ( n = 59) of older dying adults (aged 50+ years) with malignant and/or non-malignant conditions. Interviews occurred post-bereavement. This article reports on a subset of participants' interview transcripts ( n = 30) where narrative analysis was undertaken. SETTING/PARTICIPANTS: Carers were interviewed in their home setting, having been purposively recruited via general practitioner practices in two study sites in England. The subset of participants ( n = 30) was purposively selected from the parent sample with reference to carers' age, relationship to the patient, family circumstances and study sites. RESULTS: Evidence is provided on the importance of what we conceptualise as carers' 'relevant background worries'; these varied in nature, significance and impact. Four case studies are presented where these worries constituted psychosocial factors that impacted on caregivers' actions and emotional well-being. Two themes are discussed: (1) whether relevant background worries are important enough to be identified and responded to and (2) how such worries could be picked up and managed by professionals. CONCLUSION: It is argued that the quality of clinical practice could be improved if specialist palliative care teams in community contexts both identified and responded to significant support needs associated with family carers' relevant background worries. PMID- 29400620 TI - Integrated palliative care networks from the perspectives of patients: A cross sectional explorative study in five European countries. AB - BACKGROUND: Although examining perspectives of patients on integrated palliative care organisation is essential, available literature is largely based on administrative data or healthcare professionals' perspectives. AIM: (1) Providing insight into the composition and quality of care networks of patients receiving palliative care and (2) describing perceived integration between healthcare professionals within these networks and its association with overall satisfaction. DESIGN: Cross-sectional explorative design. SETTING/PARTICIPANTS: We recruited 157 patients (62% cancer, 25% chronic obstructive pulmonary disease, 13% chronic heart failure, mean age 68 years, 55% female) from 23 integrated palliative care initiatives in Belgium, Germany, the United Kingdom, Hungary and the Netherlands. RESULTS: About 33% reported contact with a palliative care specialist and 48% with a palliative care nurse. Relationships with palliative care specialists were rated significantly higher than other physicians ( p < 0.001). Compared to patients with cancer, patients with chronic obstructive pulmonary disease (odds ratio = 0.16, confidence interval (0.04; 0.57)) and chronic heart failure (odds ratio = 0.11, confidence interval (0.01; 0.93)) had significantly lower odds of reporting contact with palliative care specialists and patients with chronic obstructive pulmonary disease (odds ratio = 0.23, confidence interval (0.08; 0.71)) had significantly lower odds of reporting contact with palliative care nurses. Perceptions of main responsible healthcare professionals or caregivers in patient's care networks varied across countries. Perceived integration was significantly associated with overall satisfaction. CONCLUSION: Palliative care professionals are not always present or recognised as such in patients' care networks. Expert palliative care involvement needs to be explicated especially for non-cancer patients. One healthcare professional should support patients in understanding and navigating their palliative care network. Patients seem satisfied with care provision as long as continuity of care is provided. PMID- 29400621 TI - Study protocol of a randomized controlled trial comparing integrative body-mind spirit intervention and cognitive behavioral therapy in fostering quality of life of patients with lung cancer and their family caregivers. AB - Compared to cancers at other sites, lung cancer often results in greater psychosocial distress to both the patients and their caregivers, due to the poor prognosis and survival rate, as well as the heavy symptom burden. In recent years, making protocols of proposed or on-going studies publicly available via clinical trial registries and/or peer-reviewed journals has benefited health sciences with timely communication of the latest research trends and improved transparency in reporting. However, such practice is yet to be a common sight in evidence-informed social work. Hence, this paper discusses the value of publishing protocols in social work research and presents the protocol of a randomized controlled trial that compares the effectiveness of integrative body mind-spirit intervention with cognitive behavioral therapy for enhancing quality of life of patients with lung cancer and their family caregivers. The data collection process was still on-going at the time of manuscript submission. PMID- 29400622 TI - A retrospective analysis of boarding times for adolescents in psychiatric crisis. AB - The boarding of children and adolescents with identified psychiatric conditions at medical facilities has numerous negative effects on the patients and the systems that treat them. Efforts to minimize boarding times serves to increase patients' access to appropriate levels of care, redirect medical resources to patients who need them most, and reduce safety risks to people and property. This study explores the role Clinical Social Workers can play in facilitation of care and highlights the advantages of a coordinated data collection process facilitated by the effective use of the Electronic Medical Record. A retrospective chart analysis of 100 patients admitted to the Emergency department at a pediatric hospital in Central Florida was conducted for patients seen between 1 January 2015 and 30 June 2016. The data suggest key correlates that may impact the boarding times of pediatric patients presenting in a psychiatric crisis and the average duration of boarding time in hours (M = 5.11, SD = 2.07) was found to be significantly lower than prior published studies in the adult and pediatric literature. Discussion of these data implications on behavioral health practice is discussed. PMID- 29400624 TI - Performance and activated sludge characteristics at short solid retention time in a submerged MBR: effects of C/N ratio of wastewater. AB - This study investigated the effect of carbon to nitrogen (C/N) ratio of influent wastewater on performance and activated sludge properties at a sludge retention time of 5 d in a submerged membrane bioreactor. The chemical oxygen demand and ammonia-Nitrogen (NH3-N) removal efficiencies were found to be over 96.3% and 86.9% in the sMBRs having different C/N ratios. It was found that total extracellular polymeric substances and total soluble microbial products increased with an increase in C/N ratio. It was also observed that critical flux, relative hydrophobicity and zeta potential values decreased, and capillary suction time, particle size and viscosity of sludge increased as the C/N ratio increased. PMID- 29400623 TI - Energy expenditure and EPOC between water-based high-intensity interval training and moderate-intensity continuous training sessions in healthy women. AB - The present study compared the energy expenditure (EE) during and after two water aerobics protocols, high-intensity interval training (HIIT) and moderate continuous training (CONT). A crossover randomized design was employed comprising 11 healthy young women. HIIT consisted of eight 20s bouts at 130% of the cadence associated with the maximal oxygen consumption (measured in the aquatic environment) with 10s passive rest. CONT corresponded to 30 min at a heart rate equivalent to 90-95% of the second ventilatory threshold. EE was measured during and 30 min before and after the protocols and excess post-exercise oxygen consumption (EPOC) was calculated. Total EE during session was higher in CONT (227.62 +/- 31.69 kcal) compared to HIIT (39.91 +/- 4.24 kcal), while EE per minute was greater in HIIT (9.98 +/- 1.06 kcal) than in CONT (7.58 +/- 1.07 kcal). Post-exercise EE (64.48 +/- 3.50 vs. 63.65 +/- 10.39 kcal) and EPOC (22.53 +/- 4.98 vs.22.10 +/- 8.00 kcal) were not different between HIIT and CONT, respectively. Additionally, oxygen uptake had already returned to baseline fifteen minutes post-exercise. These suggest that a water aerobics CONT session results in post-exercise EE and EPOC comparable to HIIT despite the latter supramaximal nature. Still, CONT results in higher total EE. PMID- 29400625 TI - Undisclosed conflicts of interest among biomedical textbook authors. AB - BACKGROUND: Textbooks are a formative resource for health care providers during their education and are also an enduring reference for pathophysiology and treatment. Unlike the primary literature and clinical guidelines, biomedical textbook authors do not typically disclose potential financial conflicts of interest (pCoIs). The objective of this study was to evaluate whether the authors of textbooks used in the training of physicians, pharmacists, and dentists had appreciable undisclosed pCoIs in the form of patents or compensation received from pharmaceutical or biotechnology companies. METHODS: The most recent editions of six medical textbooks, Harrison's Principles of Internal Medicine (HarPIM), Katzung and Trevor's Basic and Clinical Pharmacology (KatBCP), the American Osteopathic Association's Foundations of Osteopathic Medicine (AOAFOM), Remington: The Science and Practice of Pharmacy (RemSPP), Koda-Kimble and Young's Applied Therapeutics (KKYAT), and Yagiela's Pharmacology and Therapeutics for Dentistry (YagPTD), were selected after consulting biomedical educators for evaluation. Author names (N = 1,152, 29.2% female) were submitted to databases to examine patents (Google Scholar) and compensation (ProPublica's Dollars for Docs [PDD]). RESULTS: Authors were listed as inventors on 677 patents (maximum/author = 23), with three-quarters (74.9%) to HarPIM authors. Females were significantly underrepresented among patent holders. The PDD 2009-2013 database revealed receipt of US$13.2 million, the majority to (83.9%) to HarPIM. The maximum compensation per author was $869,413. The PDD 2014 database identified receipt of $6.8 million, with 50.4% of eligible authors receiving compensation. The maximum compensation received by a single author was $560,021. Cardiovascular authors were most likely to have a PDD entry and neurologic disorders authors were least likely. CONCLUSION: An appreciable subset of biomedical authors have patents and have received remuneration from medical product companies and this information is not disclosed to readers. These findings indicate that full transparency of financial pCoI should become a standard practice among the authors of biomedical educational materials. PMID- 29400627 TI - Relationship of perceived job strain and workplace support to antenatal depressive symptoms among pregnant employees in Taiwan. AB - Most Taiwanese women continue to work throughout pregnancy. Few studies have investigated the prevalence of antenatal depressive symptoms in employed women and their relationship with work-related factors. We explored the relations of work-related factors, including perceived job strain and workplace support, to depressive symptoms among pregnant Taiwanese employees. During 2015-2016, we interviewed 153 employees in their third trimester of pregnancy using questionnaires to collect data on demographics, pregnancy status, physical conditions, work-related factors, family function, the Edinburgh Postnatal Depression Scale (EPDS), and health-related quality of life (HRQoL). The prevalence of antenatal depressive symptoms, based on EPDS scores>=13, was 13.7%. Pregnant employees with depressive symptoms had lower Family APGAR scores (p < 0.0001) and lower scores on all scales of the HRQoL (p < 0.05). Controlling for covariates, work-related feelings of stress and distress were associated with increased odds of antenatal depressive symptoms (Odds Ratio [OR] = 4.7, 95% confidence Interval [95% CI] = 1.3-19.9). Feeling tired at work (OR = 9.1, 95% CI = 2.3-47.0) and lack of support from colleagues (OR = 16.7, 95% CI = 2.9-53.1) were significantly associated with antenatal depressive symptoms. Such information will facilitate implementation of supportive workplace climates for pregnant employees by employers, supervisors, and occupational and environmental health nurses, which may help improve the health of pregnant employees. PMID- 29400626 TI - Short-term folinic acid supplementation and aerobic exercise improve vascular reactivity in HIV-infected individuals. AB - The aim of this study was to determine the effect of supervised exercise and folinic acid supplementation on endothelial function in HIV-infected individuals. A randomized clinical trial, double blinded, was conducted with 16 HIV-infected individuals, antiretroviral therapy (at least 6 months) with undetectable viral load (<50 copies/mL), and CD4 count > 200 cells/mm3. The subjects were randomized to aerobic exercise (n = 5) and daily intake for 4 weeks of 5 mg of folinic acid (n = 6) or placebo (n = 5) groups. To assess endothelial function, venous occlusion plethysmography in the brachial artery by the protocol of reactive hyperemia was performed. The aerobic protocol consisted in cycling exercise, 3 times/week at 60-80% VO2max, for 4 weeks. Exercise group (Delta6.5 mL/min/100 mL) and folinic acid group (Delta7.3 mL/min/100 mL) improved reactive hyperemia, but no difference was found in placebo group (from Delta -0.3 ml/min/100 ml, time p < 0.001, interaction p = 0.02). Results demonstrate that supervised exercise and folinic acid supplementation in very short term improve endothelial function in HIV-infected individuals. As exercise and folate supplementation are safe and relatively inexpensive, this finding deserves more attention in large randomized clinical trials in an attempt to reduce cardiovascular risk in HIV-infected population. PMID- 29400628 TI - Reproductive factors influencing bone mineral density in postmenopausal women. AB - This study examined the relationship between reproductive characteristics and bone mineral density (BMD) in postmenopausal women who had been referred to the menopause clinics of the National Population and Family Development Board and of the Hospital Kuala Lumpur from July 2011 to January 2012. The participants of this study were 201 postmenopausal Malaysian women aged 45-71 years. Some socio demographic, lifestyle, and reproductive factors were recorded. Calcaneal BMD was measured by quantitative ultra-sonography. Correlations of reproductive factors with BMD were assessed by Pearson's correlation test and multiple regression analysis. Age at menopause was not significantly correlated with BMD, while the years after menopause, age at the first menstrual period, number of pregnancies, and total lactation periods were inversely correlated with it. Among reproductive factors, only the association between lactation duration and BMD remained significant after adjusting for age, body mass index, activity, and calcium intake. The results indicated that except for prolonged total time of lactation, other reproductive factors were not significantly associated with BMD in postmenopausal women. PMID- 29400629 TI - Introducing volume 8 of Neurodegenerative Disease Management. AB - Welcome to the eighth volume of Neurodegenerative Disease Management. At the start of a new volume, it is interesting to look back at which content proved most popular in 2017, and also to take a look forward to the content of this issue and beyond. PMID- 29400630 TI - Does having a buddy help women with young children increase physical activity? Lessons learned from a pilot study. AB - A 12-week pilot controlled trial of a physical activity (PA) buddy program was designed for women with young children. Conducted in January 2015 through March 2016, 49 women (mean age = 36.4 +/- 4.8 years) were randomized to one of two groups. Both conditions received an in-person session, weekly step goals based on their baseline number of steps, an accelerometer, and its mobile app. Only women assigned to the intervention group brought their buddies and exercised together at least once per week. Buddies also received an accelerometer and its mobile app. Among 47 women who completed the study, we found no significant difference between groups in changes in the mean number of daily steps for the prior week (p = 0.56). When women were categorized into three groups based on change in buddies' PA, those with inactive buddies had significantly less change in number of steps than those with an active buddy and those in the control group (p < 0.018). Those with an active buddy also had higher friend social support scores for PA than the other two groups (p = 0.05). Thus, to improve PA, creating a social environment in which women associate with active individuals may be necessary. PMID- 29400631 TI - Open communication strategies between a triad of 'experts' facilitates death in usual place of residence: A realist evaluation. AB - BACKGROUND: In order to meet policy drivers on death in usual place of residence, it is key to understand how shared decision-making can be facilitated in practice. An integrated care pathway was implemented in primary care in the North East of England to facilitate death in usual place of residence. AIM: To understand how, for whom and in which circumstances death in usual place of residence is facilitated. DESIGN: A mixed method realist evaluation was employed. Local primary care practice death audit data were analysed to identify outcomes using a mixed effects logistic regression model. Focus groups and interviews with staff of the integrated care pathway and bereaved relatives were analysed to identify the related contexts and mechanisms. SETTING/PARTICIPANTS: Death audit data of 4182 patients were readily available from 14 general practitioner practices. Three focus groups were conducted with primary and secondary care staff, voluntary sector organisations and care home representatives. Interviews with bereaved relatives were carried out in participants' homes ( n = 5). RESULTS: A mixed effects logistic regression model indicated a significant effect of year on death in usual place of residence when compared to a model without year using an analysis of deviance ( p = 0.016). Qualitative analysis suggested that this outcome was achieved when a triad of 'experts' (comprising patient, family members/family carers/formal carers and healthcare professionals) used open communication strategies. CONCLUSION: An empirically supported theory of how, for whom and in which circumstances death in usual place of residence happens is provided, which has important implications for both policy and practice. PMID- 29400632 TI - Ulinastatin Supplementation During Human Amniotic Membrane Preservation to Improve its Viability. AB - PURPOSE: The amniotic membrane (AM) is the transparent innermost layer of the placenta and it facilitates rapid wound healing in a diversity of ocular surface disorders. However, extended periods of cryopreservation before use induce significant impairment of cell viability due to oxidative stresses and inflammatory responses. We investigated the effect of supplementing ulinastatin (ULI), a known serine protease inhibitor, and relevant mechanisms of action in AM preservation solution through the hypothermic continuum on inflammatory and apoptotic signals and viability of AM tissue. MATERIALS AND METHODS: The expression of inflammatory signal factors, including high mobility group box 1 (HMGB1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and anti TNF-inducible gene 6 (TSG-6) which is a TNF-alpha-inducible anti-inflammatory protein, and the expression of apoptotic signal factors, including caspase (Cas) 9 and Cas-8, the initiators, and Cas-3, the executioner caspase and Bax were analyzed with or without ULI during hypothermic preservation of human AM. Subsequently, the actual viability of human AM tissue was verified with or without ULI supplementation throughout hypothermic continuum (both hypothermic- and cryopreservation). RESULTS: Hypothermic AM preservation with ULI for 48 h resulted in downregulated expression of cold-inducible inflammatory factors, including HMGB1 and NF-kappaB, as well as RIPK3. In addition, ULI suppressed apoptotic signals related with Cas-9, Cas-8, and Cas-3 under hypothermic conditions. Furthermore, ULI supplementation during hypothermic- and cryopreservation of AM significantly enhanced viability of AM tissue and amniotic epithelial cells. CONCLUSIONS: Supplementation of ULI during human AM preservation through the hypothermic continuum may be a feasible dual anti inflammatory and anti-apoptotic strategy that enhances the viability of AM tissue. PMID- 29400633 TI - The Challenge of "Fixing the Debt": Recommendations from the Summit. AB - With education debt repayment taking up a significant amount of veterinarians' salaries, for a significant time into the working years, concern has been building that the current debt to starting salary ratio in the veterinary profession is not sustainable. The current ratio is 1.99:1, but it can be significantly higher for students who attend schools as an out-of-state resident. In April, 180 people concerned about this issue gathered at Michigan State University's College of Veterinary Medicine for a Fix the Debt Summit, which focused on actions that would reduce this ratio to a more sustainable level. Attendees were students; new graduates; those working in veterinary academia; employers of veterinarians; and those affiliated with the profession, such as professional associations. As solutions were proposed, participants also committed to taking action within their field of influence. PMID- 29400634 TI - Teaching Tip: The Development of an Interactive Computer-Based Training Program for Timely and Humane On-Farm Pig Euthanasia. AB - With extensive knowledge and training in the prevention, management, and treatment of disease conditions in animals, veterinarians play a critical role in ensuring good welfare on swine farms by training caretakers on the importance of timely euthanasia. To assist veterinarians and other industry professionals in training new and seasoned caretakers, an interactive computer-based training program was created. It consists of three modules, each containing five case studies, which cover three distinct production stages (breeding stock, piglets, and wean to grower-finisher pigs). Case study development was derived from five specific euthanasia criteria defined in the 2015 Common Swine Industry Audit, a nationally recognized auditing program used in the US. Case studies provide information regarding treatment history, clinical signs, and condition severity of the pig and prompt learners to make management decisions regarding pig treatment and care. Once a decision is made, feedback is provided so learners understand the appropriateness of their decision compared to current industry guidelines. In addition to training farm personnel, this program may also be a valuable resource if incorporated into veterinary, graduate, and continuing education curricula. This innovative tool represents the first interactive euthanasia-specific training program in the US swine industry and offers the potential to improve timely and humane on-farm pig euthanasia. PMID- 29400635 TI - Nuclear epidemiologic studies and the estimation of DREF. AB - PURPOSE: Estimating cancer risks for continuous radiation exposures based upon data from acute exposures has been an important public health problem. A dose and dose rate effectiveness factor (DDREF) is typically used to estimate cancer risks for chronic exposures based upon risk estimates from acute exposures. A value of 2 for a DDREF has most often been used as proposed by the ICRP in ICRP60; however, an influential analysis of several cohorts concluded that there is no risk difference between acute and chronic exposures. It is the purpose of this article to analyze the recent nuclear worker studies and estimate the dose rate effectiveness factor, DREF, for solid cancers. MATERIALS AND METHODS: Twelve mortality studies were identified each with at least 100 cancer deaths and a meta analysis was then carried out using their individual ratio of low dose rate cancer effect (LDR) to the corresponding high dose rate effect from the A-bomb cohort (LSS). The ratio is denoted by Q and its reciprocal is then an estimate of the DREF. RESULTS: The result was Q= 0.36 (95% CI = 0.11, 0.60) and DREF = 2.63 (95% confidence interval [CI] = 1.61, 7.14). Clearly, this estimate is more consistent with a DREF of 2 than with a DREF of 1. The difficulty with the estimate Q = 0.36 is that it is driven by only two large and dissimilar worker studies, the INWORKS study (q1 = 1.14) and the Mayak worker cohort (q3 = 0.30). The higher exposures for these nuclear workers were often in the early years (e.g. before 1960) with exposures from neutrons and internal emitters that are not included in the risk analyses resulting in likely overestimation of cancer effects per dose which would increase the estimate of the DREF. The Mayak study did, however, adjust for plutonium exposures. Finally, consideration is given to other cohort studies where DREF values may possibly be determined, such as the environmental exposures to the Techa River area residents and the Chernobyl cleanup workers as well as medical X-ray workers. Although dissimilar an overall meta-analysis yielded a Q = 0.45 (95% CI = 0.24, 0.66). CONCLUSIONS: It is concluded that the best estimate of a DREF is still about 2. However, because of the various problems with the epidemiology studies, especially their dosimetry, it is concluded that a DREF of about 2 should be accepted with considerable caution since it is driven solely by the Mayak study. PMID- 29400636 TI - Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel. AB - Buformin is an old anti-diabetic agent and manifests potent anti-tumor activities in several malignancies. In the present study, we aimed to explore the functions of buformin in human cervical cancer. As our data shown, buformin exhibited significant anti-proliferative effects in a dose-dependent manner in 4 cervical cancer cell lines. Compared to the control, buformin notably suppressed colony formation and increased ROS production in C33A, Hcc94 and SiHa cells. Flow cytometric analysis showed that buformin induced marked cell cycle arrest but only resulted in mild apoptosis. The invasion of C33A and SiHa cells sharply declined with buformin treatment. Consistently, western blotting showed that buformin activated AMPK and suppressed S6, cyclin D1, CDK4, and MMP9. Moreover, we found that buformin enhanced glucose uptake and LDH activity, increased lactate level, while decreased ATP production in cervical cancer cells. In addition, low doses of buformin synergized with routine chemotherapeutic drugs (such as paclitaxel, cisplatin, and 5-FU) to achieve more significant anti-tumor effects. In vivo, a single use of buformin exerted moderate anti-tumor effects, and the combination with buformin and paclitaxel exhibited even greater suppressive effects. Buformin also consistently showed synergistic effects with paclitaxel in treating primary cultures of cervical cancer cells. Take together, we are the first to demonstrate that buformin suppresses cellular proliferation and invasion through the AMPK/S6 signaling pathway, which arrests cell cycle and inhibits cellular invasion. Buformin also could synergize with routine chemotherapies, producing much more powerful anti-tumor effects. With these findings, we strongly support buformin as a potent choice for treating cervical cancer, especially in combination with routine chemotherapy. PMID- 29400637 TI - Development and initial validation of the urban adolescent hope scale. AB - OBJECTIVE: Hope is an important component to adolescents' mental health and well being. While much study and theory have explored hope, few examine the idea within contextualized factors such as locale. Even fewer have sought to measure hope for urban adolescents. The Urban Adolescent Hope Scale (UAHS) was developed to measure hope in a contextualized manner as guided by previous qualitative inquiry. This study aims to establish initial validation for the UAHS. METHOD: Using findings from qualitative inquiry, a 24-item proposed measure of hope for urban adolescents was developed. Experts in various fields were consulted to provide face and content validity. The instrument was then given at school-wide needs assessment at an urban Midwestern high school. RESULTS: Using a confirmatory factor analysis, fit indices (RMSEA, TLI, CFI, and SRMR) and measures of internal consistency indicated a reliable five-factor structure of hope consisted of Spirituality (alpha = .936), Personal Agency (alpha = .930), The Basics (alpha = .936), Education (alpha = .921), and Caring Connections (alpha = .875). CONCLUSION: The findings from this study indicate the UAHS has initial validity and reliability to be used as a measure of hope for urban adolescents. Future implications for research and practice are provided. PMID- 29400638 TI - The relationship between general health and coping style with perceived stress in primigravida healthy pregnant women: Using the PATH model. AB - The aim of this study was to analyze relationships among general health, coping style, and perceived stress in healthy primigravida pregnant women. A cross sectional study was conducted at public health clinics in Hamadan city, Iran between July and December 2015. In total, 380 pregnant women were selected through stratified random sampling. Data were collected using the Revised Prenatal Coping Inventory and General Health Questionnaire. Perceived stress was assessed through an interview comprised of open-ended questions. The final PATH model fit well; general health (beta = 0.02) as well as anxiety and sleep disorders (beta = 0.03) were slightly directly associated with perceived stress, and only planning-preparation was related to perceived stress through general health (beta = 0.09). The findings enhance the knowledge gained from previous perinatal stress research. General health status was directly related to stress, and coping style was indirectly related to stress. Coping styles may mediate the relationship between general health status and perceived stress, suggesting that midwives should attempt to improve the general health of women to reduce stress and its consequences during pregnancy by teaching patients appropriate coping styles. Further studies on the effect of coping style interventions on stress are warranted. PMID- 29400639 TI - Singing it for "us": Team passion displayed during national anthems is associated with subsequent success. AB - The present research examined the link between passion displayed by team members during the singing of national anthems at UEFA Euro 2016 and team performance in the tournaments' 51 games. Drawing on social identity theorising, we hypothesised a positive relationship between passion and performance. Consistent with this hypothesis, results showed that teams that sang national anthems with greater passion went on to concede fewer goals. Moreover, results provided evidence that the impact of passion on the likelihood of winning a game depended on the stage of the competition: in the knockout stage (but not the group stage) greater passion was associated with a greater likelihood of victory. Extending recent reviews that highlight the importance of social identity processes in sporting contexts, these results suggest that team members' identity-based expression of passion for the collective can be an important predictor of subsequent performance. PMID- 29400640 TI - Mothers' perceptions and experiences of using maternal health-care services in Rwanda. AB - Reducing barriers to use maternal health care is one of the critical components to improving maternal health. Rwanda is among the countries that have made tremendous efforts to reduce maternal mortality. However, the current maternal mortality ratio is still high which calls for further efforts to be considered. This study used a qualitative approach to understand mothers' perceptions and experiences of using maternal health care in Rwanda. Using in-depth interviews and focus group discussions, data were collected in the Western and Eastern provinces of the country where forty-five women participated in the study from June to August 2014. This paper highlights perceptions of these participants regarding issues that contribute to suboptimal use of maternal health-care services. The geographical, financial, and social-cultural barriers that emerged in this study highlight the need to understand mothers' experiences and perceptions when using maternal health care as Rwanda and other countries strive to reduce negative maternal health outcomes. PMID- 29400641 TI - Diagnosis makes a difference: Perceptions of older persons with dementia symptoms. AB - : Background/Study Context: Employing the stereotype content model and terror management theory, we examined whether stereotypes and feelings about persons with dementia vary depending on the type of dementia diagnosis and purported causes of the dementia. METHODS: Participants were randomly assigned to read one of four vignettes that depicted a man who consulted his doctor because of memory problems. All vignettes described the same symptoms and diagnostic tests, but each of four groups read a different result: all tests normal (Normal); Alzheimer's disease (AD); Wernicke-Korsakoff Syndrome (WKS) associated with alcohol abuse; and chronic traumatic encephalopathy (CTE) associated with head injuries from playing football in high school and college. Measures included a word fragment completion task, a stereotype content scale, and an emotions scale. RESULTS: Results showed no differences in the number of death-related words generated in the word fragment completion task and no differences in assessment of competence across the four groups. Those in the Normal, AD, and CTE groups evaluated the man as warmer than those in the WKS group. Participants in the AD condition showed more empathy than those in the WKS group. There were no differences in pity or fear but the CTE condition produced more envy and admiration and the WKS condition produced more contempt. CONCLUSION: These results suggest that different forms of dementia elicit varying emotional and cognitive responses. PMID- 29400642 TI - Production of biostimulants from okara through enzymatic hydrolysis and fermentation with Bacillus licheniformis: comparative effect on soil biological properties. AB - In this work okara (OK), a by-product of soy milk manufacturing, is submitted to an enzymatic hydrolysis and a fermentative process to produce different soil biostimulants (BS): EH, hydrolysate obtained by the enzymatic process; FHEB, fermentation broth with Bacillus licheniformis and the enzymes secreted during the fermentation; FHE, fermentation broth without bacteria and FH, the FHE hydrolysate in which enzymes were denatured. Enzymatic hydrolysates showed a different chemical composition compared with fermented hydrolysates and OK. It had a higher protein concentration as well as C, P and K. The proteins of OK were converted into peptides with a lower molecular weight, the fermented hydrolysates being those with the lowest molecular weight profile. The influences of hydrolysates and OK were tested in soil, finding that beta-glucosidase, phosphatase and dehydrogenase activities were stimulated by every treatment. However, it was observed that EH produced a greater stimulation of dehydrogenase and phosphatase than both OK and fermented BS. The bacterial and fungal phospholipid fatty acids were also higher in soils amended with BS than those of the control and soils with OK. It has also been found that beta-glucosidase, phosphatase and microbial biomass were dose-dependent in every treatment, but dehydrogenase only was dose-dependent in EH and OK treatments. PMID- 29400643 TI - We do not receive wisdom. We must discover it for ourselves. PMID- 29400644 TI - Why do we persist with teaching students in antagonistic unrepresentative learning environments? PMID- 29400645 TI - Expanding Canadian Medicare to include a national pharmaceutical benefit while controlling expenditures: possible lessons from Israel. AB - In Canada, there is an ongoing debate about whether to expand Medicare to include a national pharmaceutical benefit on a universal basis. The potential health benefits are understood to be significant, but there are ongoing concerns about affordability. In Israel, the National Health Insurance benefits package includes a comprehensive pharmaceutical benefit. Nonetheless, per capita pharmaceutical spending is well below that of Canada and the Organization for Economic Co operation and Development average. This paper highlights seven strategies that Israel has employed to constrain pharmaceutical spending: (1) prioritizing new technologies, subject to a global budget constraint; (2) using regulations and market power to secure fair and reasonable prices; (3) establishing an efficient pharmaceutical distribution system; (4) promoting effective prescribing behavior; (5) avoiding artificial inflation of consumer demand; (6) striking an appropriate balance between respect for IP rights, access and cost containment; and (7) developing a shared societal understanding about the value and limits of pharmaceutical spending. Some of these strategies are already in place in some parts of Canada. Others could be introduced into Canada, and might contribute to the affordability of a national pharmaceutical benefit, but substantial adaptation would be needed. For example, in Israel the health maintenance organizations (HMOs) play a central role in promoting effective prescribing behavior, whereas in HMO-free Canada other mechanisms are needed to advance this important goal. PMID- 29400646 TI - Zika Virus MB16-23 in Mosquitoes, Miami-Dade County, Florida, USA, 2016. AB - We isolated a strain of Zika virus, MB16-23, from Aedes aegypti mosquitoes collected in Miami Beach, Florida, USA, on September 2, 2016. Phylogenetic analysis suggests that MB16-23 most likely originated from the Caribbean region. PMID- 29400647 TI - Isoenzymatic characterization of Phlebotomus ariasi and P. perniciosus of canine leishmaniasis foci from Eastern Pyrenean regions and comparison with other populations from Europe. AB - An entomological survey was carried out in 2007 in two Pyrenean counties of Lleida province (north-eastern Spain), where cases of autochthonous canine leishmaniasis have been recently reported. Phlebotomus ariasi and P. perniciosus, vectors of Leishmania infantum in the Mediterranean area, were captured. The aim of the present study was to compare these phlebotomine populations with others captured in known leishmaniasis foci in Europe. Populations of these species were studied by analysing the polymorphism of seven enzymatic systems (HK, PGI, PGM, MDH, 6PGD, FUM and ACO) and compared with other specimens from endemic regions of France, Italy, Malta, Portugal and Spain captured in other campaigns, and also with previously published results. Phlebotomus ariasi was more polymorphic than P. perniciosus. Only the ACO locus had diagnostic alleles, but some other alleles show high characteristic frequencies for each species. The neighbour-joining trees separated two population groups in both species. On the basis of the isoenzyme study results, sand fly populations of the Pyrenean region in Lleida province are closely related to those of other nearby leishmaniasis endemic regions in France and Spain. PMID- 29400648 TI - YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development. AB - Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels. PMID- 29400649 TI - TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells. AB - Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin. PMID- 29400651 TI - Hybrid percutaneous treatment of iatrogenic coronary artery dissection complicating a spontaneous coronary artery dissection. PMID- 29400652 TI - Comparison between two biodegradable polymer-based sirolimus-eluting stents with differing drug elution and polymer absorption kinetics: two-year clinical outcomes of the PANDA III trial. AB - AIMS: In the PANDA III trial, the novel poly-lactide-co-glycolide polymer-based BuMA sirolimus-eluting stent (SES) was non-inferior to the polylactide polymer based Excel SES for the primary endpoint of one-year target lesion failure (TLF), with a lower incidence of stent thrombosis. We sought to investigate whether the effectiveness profile of BuMA SES, with more rapid drug elution and polymer absorption kinetics, would persist at two years. METHODS AND RESULTS: A total of 2,348 patients (mean age, 61.2+/-10.6 years; 24.3% diabetics; 31.2% with acute myocardial infarction within one month) were randomly assigned to receive either BuMA SES (n=1,174) or Excel SES (n=1,174) in the "all-comer" PANDA III trial. Two year clinical follow-up was available for 2,262 (96.3%) patients. The incidence of TLF and the patient-oriented composite endpoint (PoCE) was low and similar between the BuMA and Excel groups (7.4% vs. 6.9%, p=0.67, and 13.1% vs. 10.9%, p=0.11, respectively). The rate of any revascularisation was significantly higher with the BuMA SES (6.8% vs. 4.6%, p=0.03). Definite and probable thrombosis occurred in 0.7% and 1.4% of patients in the BuMA and Excel groups, respectively (p=0.10). CONCLUSIONS: Two-year rates of TLF and PoCE events were low and similar between the two biodegradable polymer-based SES. PMID- 29400650 TI - Spatially resolved RNA-sequencing of the embryonic heart identifies a role for Wnt/beta-catenin signaling in autonomic control of heart rate. AB - Development of specialized cells and structures in the heart is regulated by spatially -restricted molecular pathways. Disruptions in these pathways can cause severe congenital cardiac malformations or functional defects. To better understand these pathways and how they regulate cardiac development we used tomo seq, combining high-throughput RNA-sequencing with tissue-sectioning, to establish a genome-wide expression dataset with high spatial resolution for the developing zebrafish heart. Analysis of the dataset revealed over 1100 genes differentially expressed in sub-compartments. Pacemaker cells in the sinoatrial region induce heart contractions, but little is known about the mechanisms underlying their development. Using our transcriptome map, we identified spatially restricted Wnt/beta-catenin signaling activity in pacemaker cells, which was controlled by Islet-1 activity. Moreover, Wnt/beta-catenin signaling controls heart rate by regulating pacemaker cellular response to parasympathetic stimuli. Thus, this high-resolution transcriptome map incorporating all cell types in the embryonic heart can expose spatially restricted molecular pathways critical for specific cardiac functions. PMID- 29400653 TI - Short-term dual antiplatelet therapy after interventional left atrial appendage closure with different devices. AB - AIMS: We aimed to assess the feasibility, efficacy and safety of short-term dual antiplatelet therapy (DAPT) for six weeks after left atrial appendage closure (LAAC). METHODS AND RESULTS: Data of the Cardioangiologisches Centrum Bethanien LAAC registry were analysed. DAPT (aspirin 100 mg plus clopidogrel 75 mg) was administered until transoesophageal echocardiography (TEE) evaluation six weeks after LAAC. In the absence of significant peri-device flow or device-related thrombus (DRT), the medication was decreased to single antiplatelet therapy (SAPT). Outpatient visits were timed at six-month intervals. The incidences of major bleeding (BARC >=3) and of thromboembolic events were investigated. A total of 298 patients (76+/-8 years; 62% male; CHA2DS2-VASc 4.3+/-1.5; HAS-BLED 3.5+/ 1.0; 61% with history of bleeding) with successful LAAC were included. TEE revealed DRT in 7/298 (2.3%) patients (five at six-week follow-up [FU] 45+/-10 days after implant, two during a median long-term FU of 731 days). Non-procedure related bleeding events occurred in 25/298 (8.4%) patients and non-procedure related thromboembolic events in 11/298 (3.7%) patients. This translated into 3.9 bleeding events/100 patient-years and 1.7 thromboembolic events/100 patient years, respectively. Procedure-related events consisted of major bleeding in 7/298 (2.3%) patients and stroke in 2/298 (0.7%) patients. Age >=75 years (OR 3.2; CI: 1.2-8.0; p=0.015) and renal impairment (OR 2.5; CI: 1.1-5.7; p=0.027) were identified as independent predictors for major bleeding after LAAC. CONCLUSIONS: Short-term DAPT for six weeks appears to be a viable alternative for patients after LAAC. Age >=75 years and renal impairment increase major bleeding events threefold. PMID- 29400654 TI - Thrombogenicity at the jailed side branch ostia in the provisional stenting technique: insights from an in vitro model. PMID- 29400655 TI - A new optical coherence tomography-based calcium scoring system to predict stent underexpansion. AB - AIMS: This was a retrospective study to develop and validate an optical coherence tomography (OCT)-based calcium scoring system to predict stent underexpansion. METHODS AND RESULTS: A calcium score was developed using 128 patients with pre- and post-stent OCT (test cohort) and then validated in an external cohort of 133 patients. In the test cohort, a multivariable model showed that the independent predictors of stent expansion were maximum calcium angle per 180 degrees (regression coefficient: -7.43; p<0.01), maximum calcium thickness per 0.5 mm ( 3.40; p=0.02), and calcium length per 5 mm (-2.32; p=0.01). A calcium score was then defined as 2 points for maximum angle >180 degrees , 1 point for maximum thickness >0.5 mm, and 1 point for length >5 mm. In the validation cohort, the lesions with calcium score of 0 to 3 had excellent stent expansion, whereas the lesions with a score of 4 had poor stent expansion (96% versus 78%, p<0.01). On multivariate analysis the calcium score was an independent predictor of stent underexpansion. CONCLUSIONS: An OCT-based calcium scoring system can help to identify lesions that would benefit from plaque modification prior to stent implantation. Lesions with calcium deposit with maximum angle >180 degrees , maximum thickness >0.5 mm, and length >5 mm may be at risk of stent underexpansion. PMID- 29400656 TI - Outcome after revascularisation of acute myocardial infarction with cardiogenic shock on extracorporeal life support. AB - AIMS: The aim of the study was to identify independent correlates of survival in patients undergoing PCI for refractory cardiogenic shock due to myocardial infarction (RCS-MI) with the need for extracorporeal life support (ECLS). METHODS AND RESULTS: This observational single tertiary centre study enrolled 106 consecutive patients (52.7+/-10.4 years) with ECLS placed before or after the PCI. Half of the patients had triple vessel disease and PCI was attempted whenever possible (74.5%). The 30-day mortality rate was 63.2%. Left main culprit vessel disease (19% of patients) (adj. HR [95% CI]: 2.31 [1.27-4.18], p=0.006) and sepsis-related organ failure assessment >=13 (adj. HR 2.17 [1.25-3.75], p=0.005) were independently associated with 30-day mortality. The use of intra aortic balloon pump (IABP) combined with ECLS was an independent protective factor (adj. HR 0.48 [0.28-0.80], p=0.006). Neither complete (p=0.66) nor successful (p=0.69) myocardial revascularisation was associated with 30-day survival. CONCLUSIONS: RCS in MI patients often reveals a severe multivessel coronary artery disease with no impact of early percutaneous coronary revascularisation on clinical outcome. The survival advantage of IABP when combined with ECLS further suggests that achieving an early effective haemodynamic support should be the major goal in this young patient population. PMID- 29400657 TI - National trends, predictors of use, and in-hospital outcomes in mechanical circulatory support for cardiogenic shock. AB - AIMS: Despite rising rates of cardiogenic shock (CS), data on trends and in hospital outcomes of short-term non-durable mechanical circulatory support (MCS) are limited. Thus, we aimed to identify recent national trends in MCS utilisation in the USA, patient-level predictors of MCS use, and in-hospital outcomes in CS inclusive of extracorporeal membrane oxygenation (ECMO). METHODS AND RESULTS: Hospitalisations of US adults with a discharge diagnosis of CS, from January 2004 to December 2014, in the National Inpatient Sample were included. Rates of MCS were stratified by device type and clinical presentation. Outcomes included in hospital mortality, hospitalisation costs, and number of procedures. A total of 183,516 hospitalisations with CS (47,636 [25.9%] involving MCS) were included. MCS recipients were younger, less frequently female, received more procedures, had higher costs, and more frequently presented with MI (MCS vs. non-MCS: 71.6% vs. 42.9%; p<0.0001). Growth in CS hospitalisations (214.4%) outpaced annual MCS use (160.0%), with relative declines in intra-aortic balloon pump use starting in 2008. Right heart catheterisation rates for both groups remained low (MCS vs. non MCS: 5.9% vs. 3.3%; p<0.0001). In-hospital mortality declined but remained high in both groups (MCS vs. non-MCS [2014]: 32.7% vs. 41.5%; p<0.0001). CONCLUSIONS: In-hospital mortality for CS has declined but remains high. Rates of CS have outpaced MCS utilisation which remains uncommon in non-MI hospitalisations with shock. MCS is associated with utilisation of other procedures during hospitalisation. PMID- 29400658 TI - Human erythrocyte lifespan measured by Levitt's CO breath test with newly developed automatic instrument. AB - Existing standard techniques for erythrocyte (RBC) lifespan measurement, such as quantitation of labeling with isotopes or biotin, are cumbersome and time consuming. Given that endogenous CO originates mainly from degraded RBCs, a team lead by Levitt developed a CO breath test to enable more efficient RBC lifespan estimation. The purpose of this study was to evaluate the reliability of Levitt's CO breath test method with our newly developed automatic instrument. RBC lifespan measurements conducted by Levitt's CO breath test method were conducted in 109 healthy subjects and 91 patients with chronic hemolytic anemia. In healthy subjects, the RBC lifespan was 126 +/- 26 days, similar to values obtained with classical standard labeling methods. RBC lifespan did not differ significantly between males and females or between juveniles and adults, and did not correlate with age. To our knowledge, this datum represents an RBC lifespan average for the largest sample to date. In subjects with hemolytic anemia, RBC lifespan was 29 +/ 14 days, which is significantly shorter than that of the healthy subjects (p = 0.001). Using 75 days as a cut-off, diagnostic accuracy for hemolytic anemia in the present study sample was 100%. In conclusion, the present results indicate that Levitt's CO breath test is an ideal method for human RBC lifespan measurement, and the newly developed automatic instrument is reliable and convenient for clinical practice. PMID- 29400659 TI - Asymmetric transmission of a planar metamaterial induced by symmetry breaking. AB - Asymmetric transmission (AT) is widely used in polarization transformers and polarization-controlled devices. In this paper, a planar metamaterial nanostructure with connected gammadion-shaped nanostructure (CGN) is proposed to achieve AT effect for forward and backward propagations of circular polarized light. The CGN arrays can produce magnetic moment oscillation that is normal to the metamaterial plane, which is weakly coupled to free space and generates transmission valleys. The introduction of symmetry breaking exerts a strong influence on the AT effects, and these effects can be tuned by the structural parameters. Our planar metamaterials may have potential for application in the future design of polarization-controlling devices. PMID- 29400660 TI - Plasma exosomes as novel biomarker for the early diagnosis of gastric cancer. AB - Exosomes are lipid bilayer vesicles of endocytic origin ranging from 30 to 100 nm in size, and contain various nucleic acid molecules such as DNA, mRNA, miRNA, lncRNA and multiple proteins, which could be transferred into target cells. Recent study indicated that exosomes as information carriers between cells has introduced us to a new previously unknown biological communication system. Increasing evidences show that exosomes play a crucial role in gastric cancer because they are potential to influence normal cellular physiology and promote various states of the cancer. In this review, we focus on the latest findings on exosomes in the plasma of gastric cancer patients, mainly summarizing the functions of miRNAs, lncRNAs and multiple proteins in diagnosis, prognosis, and in establishing treatment regimens against gastric cancer. Furtherly, potential functions of exosomes as novel diagnostic biomarkers for gastric cancer are discussed extensively. Exosomes are believed to be a non-invasive disease biomarker with a dual capability to provide insights into the early diagnosis for gastric cancer. PMID- 29400661 TI - The Mediator complex subunit MED15, a promoter of tumour progression and metastatic spread in renal cell carcinoma. AB - BACKGROUND/OBJECTIVE: MED15 is a part of the multiprotein Mediator complex which is involved in the transcription of polymerase (Pol) II-dependent genes. Several studies in this field have reported altered expressions of distinct subunits in human malignancy. However, the role of MED15 in renal cell carcinoma (RCC) has not be investigated yet. METHODS: First, we performed an RNA expression and survival analysis of MED15 in RCC by using the database cBioPortal. To confirm these data on the protein level, we executed immunohistochemical (IHC) staining against MED15 on a tissue microarray containing 184 samples of the most common subtypes of the tumour at the various stages. Further, we performed functional analysis including proliferation, migration, and invasion assays on the RCC cell lines A-498 and ACHN following the siRNA-mediated MED15 knockdown. RESULTS: On the mRNA level, higher expression of MED15 was associated with worse patient survival rates. IHC staining validated this tendency, unfortunately the results were not significant. However, supporting this tendency, in vitro-assays showed a significant decrease in proliferation, migration, and invasion after knockdown of MED15. CONCLUSION: The research concludes that MED15 does seem to play a tumour promoting role in the progression and metastatic spread of renal cell carcinoma. PMID- 29400662 TI - Growth/differentiation factor 15 (GDF-15) as new potential serum marker in patients with metastatic colorectal cancer. AB - BACKGROUND: GDF-15 is a protein belonging to the transforming growth factor beta superfamily that has a role in regulating inflammatory and apoptotic pathways. High level GDF-15 in tumor tissues and plasma correlate with an increased risk of recurrence and reduced overall survival. OBJECTIVE: The aim of this study was to screen GDF-15 capacity to detecting metastatic CRC and compare it with standard tumor markers CEA and CA19-9. METHODS: We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of GDF-15, CEA and CA19-9 were measured by immunochemically. A Kaplan-Meier curve was applied for analysis of survival rates, and a log-rank was used for univariate analysis. RESULTS: Serum levels of GDF-15 were significantly higher in patients with colorectal cancer compared to healthy controls (p< 0.001). In addition, serum levels of GDF-15 correlated with extent of liver involvement and patients with higher GDF-15 levels had significantly worse outcome (p< 0.0001). CONCLUSIONS: Our results show GDF-15 as an effective biomarker in patients with metastatic colorectal cancer with the same sensitivity as CEA. In addition, GDF-15 levels strongly correlate with extension of liver involvement in contrast with CEA. PMID- 29400663 TI - Clusterin promotes growth and invasion of clear cell renal carcinoma cell by upregulation of S100A4 expression. AB - BACKGROUND AND OBJECTIVE: Clusterin promotes cell proliferation, motility and invasiveness in human renal cell carcinoma (RCC) cells but the underlying molecular mechanisms of this action are largely unknown. The aim of this study was to investigate the effects of clusterin on cancer cell growth, invasion and S100A4 expression and to determine the effects of clusterin on in vitro cell proliferation and migration and in vivo tumour growth in RCC cells. METHODS: We have established stable transfectants of highly invasive Caki-1 human RCC cells with expression of clusterin shRNA targeting clusterin (Caki-1/clusterin shRNA). We also established stable transfectants of 786-O human RCC cells with expression of clusterin cDNA plaismid (786-O/clusterin cDNA). Clusterin and S100A4 expression was detected by reverse transcription (RT) PCR and western blot assay; Caki-1/clusterin shRNA and 786-O/clusterin cDNA clones were subjected to in vitro invasion assays. Cell viability and cell growth was assessed in MTT and clonogenic assay. Specific small interfering RNA was employed to down-regulate S100A4. The expression plasmid for S100A4 (pCMV-S100A4) was used to upregulate S100A4. Caki-1/clusterin shRNA clones were injected subcutaneously in nude mice to determine tumour growth and cancer cell invasiveness in vivo. Xenograft tumour tissues were assessed by immunohistochemistry and frozen tissues were used for the detection of S100A4 and clusterin. RESULTS: Overexpression of clusterin increased cell invasiveness; and targeting clusterin reduced cell invasiveness in vitro. This increase in cell invasiveness was mediated by S100A4. Targeting clusterin decreased cell proliferation and down-regulated cellular S100A4 levels in Caki-1 cells; Overexpression of clusterin increased cell proliferation and up regulated cellular S100A4 levels in 786-O cells; Stable Caki-1/clusterin shRNA transfectants produced smaller xenograft tumours containing reduced S100A4 protein levels in vivo. Stable 786-O/clusterin cDNA transfectants produced larger xenograft tumours containing increased S100A4 protein levels in vivo. CONCLUSION: Our results indicate that clusterin promotes growth and invasion in RCC cells in vitro and in vivo through upregulation of S100A4; And targeting clusterin confers growth inhibitory and anti-invasive properties in RCC cells in vitro and in vivo through a down-regulation of S100A4. These findings provide the rationale for future oncostatic strategies aimed at suppressing clusterin-mediated signal transduction pathways as a novel therapeutic approach in human RCC. PMID- 29400664 TI - Chances and limitations of isolated mouse heart models for investigating the endothelial glycocalyx1. AB - BACKGROUND: The endothelial glycocalyx plays a decisive role in maintaining vascular homeostasis. Previous animal models have mainly focused on in-vitro experiments or the isolated beating guinea pig heart. To further evaluate underlying mechanisms of up- and down regulation, knock-out animals seem to be a promising option. OBJECTIVE: Aim of the present study was to evaluate if an isolated mouse-heart model is suitable for glycocalyx research. METHODS: Isolated beating mouse hearts (C57/Bl6J) underwent warm, no-flow ischemia and successive reperfusion. Coronary effluent was analyzed by ELISA and Western blot for the glycocalyx core protein: syndecan-1. Hearts were prepared for either immunofluorescence or electron microscopy and lysed for Western blot analysis. RESULTS: An endothelial glycocalyx covering the total capillary circumference and syndecan-1 were detected by electron and immunofluorescence microscopy. Ischemia/reperfusion seriously deteriorated both findings. Confoundingly, syndecan-1 was not detectable either in the coronary effluent or in the lysates of blood-free hearts by ELISA or Western blot technique. CONCLUSIONS: Blood vessels of mouse hearts contain an endothelial glycocalyx comparable to that of other animals also with respect to its core protein syndecan-1. But, for studies including quantification of intravascular soluble glycocalyx constituents, the amount of syndecan-1 in mouse hearts seems to be too low. PMID- 29400665 TI - Noninvasive quantitative assessment of microcirculatory disorders of the upper extremities with 2D fluorescence optical imaging. AB - BACKGROUND: Quantitative Imaging of microcirculatory disorders is challenging. OBJECTIVE: To investigate the feasibility of 2D Fluorescence Optical Imaging (FOI) for characterization and quantification of microcirculatory disorders in peripheral arterial occlusive disease (PAOD) of the upper extremity. METHODS: 9 patients with various clinical presentations of PAOD of the upper extremity were included. Quantitative analysis of both hands was performed by assessing the fluorescence intensity of Indocyanine Green (ICG) dynamically over a time period of 360 seconds. Analysis of the signal intensity within multiple regions of both hands was calculated and time-dependent perfusion curves for each region of interest were plotted over time. RESULTS: Compared to the healthy, vascular non impaired segments, pathological segments with an impaired tissue perfusion were identified through a decreased rate of early tissue enhancement (p = 0.02) and increased signal intensity of the optical perfusion agent per second (p < 0.001). The affected segments showed a decreased maximum signal intensity and a prolonged interval to reach the maximum signal intensity (time to peak). CONCLUSION: 2D FOI allows quantitative assessment of the peripheral microcirculation in various vascular pathophysiologies and is able to detect the impaired tissue perfusion in patients with vascular disorders of the upper extremity. PMID- 29400666 TI - Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer's Disease. AB - The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer's disease (AD) patients. This is a non randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD. PMID- 29400667 TI - Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease. AB - The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AbetaPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-beta (Abeta) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Abeta40 and Abeta42 in mutant AbetaPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Abeta42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AbetaPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AbetaPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons. PMID- 29400669 TI - Development of an item list to assess bilateral upper extremity function of stroke patients with hemiplegia. AB - BACKGROUND: Although there is a myriad of unilateral assessments for stroke survivors, few address bilateral function, which is critical for many daily living tasks. OBJECTIVE: To develop an activities of daily living list of tasks requiring bilateral upper extremity function for use when assessing patients with stroke. METHOD: A list of 938 items was generated based on a literature review, opinions of occupational therapists and patients with stroke. A panel of professional experts then validated that the items were bilateral and functional. Similar items were then combined and duplicates eliminated. RESULTS: The list was reduced to 69 items and 40 items were selected based on the content validity index. Based on the bilateral function, importance, expansion, and deletion criteria, the expert panel selected 27 items that best represented bilateral activities of daily living. CONCLUSIONS: A final list of 27 activities of daily living requiring bilateral function was generated and validated. Future work will focus on development of a tool to assess bilateral upper extremity function of patients with stroke. PMID- 29400668 TI - Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson's Disease in Rodents. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting approximately one-percent of the population over the age of sixty. Although many animal models have been developed to study this disease, each model presents its own advantages and caveats. A unique model has arisen to study the role of alpha-synuclein (aSyn) in the pathogenesis of PD. This model involves the conversion of recombinant monomeric aSyn protein to a fibrillar form-the aSyn pre formed fibril (aSyn PFF)-which is then injected into the brain or introduced to the media in culture. Although many groups have successfully adopted and replicated the aSyn PFF model, issues with generating consistent pathology have been reported by investigators. To improve the replicability of this model and diminish these issues, The Michael J. Fox Foundation for Parkinson's Research (MJFF) has enlisted the help of field leaders who performed key experiments to establish the aSyn PFF model to provide the research community with guidelines and practical tips for improving the robustness and success of this model. Specifically, we identify key pitfalls and suggestions for avoiding these mistakes as they relate to generating the aSyn PFFs from monomeric protein, validating the formation of pathogenic aSyn PFFs, and using the aSyn PFFs in vivo or in vitro to model PD. With this additional information, adoption and use of the aSyn PFF model should present fewer challenges, resulting in a robust and widely available model of PD. PMID- 29400670 TI - Upper limb robot-assisted therapy in subacute and chronic stroke patients using an innovative end-effector haptic device: A pilot study. AB - BACKGROUND: Significant results have been shown when an upper limb robot-assisted rehabilitation is delivered to stroke patients. OBJECTIVE: To evaluate the effects of upper limb robot-assisted rehabilitation on motor recovery in stroke patients who underwent a treatment based on a haptic device. METHODS: Thirty-nine stroke patients (twenty-three subacute and sixteen chronic) underwent rehabilitation training by using MOTORE/Armotion haptic system. Thirteen healthy subjects were recruited for comparison purpose.The following clinical outcome measures were used: Chedoke-McMaster Stroke Assessment, Modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FM), Medical Research Council, Motricity Index (MI), Box and Block Test (B&B) and Modified Barthel Index (mBI).The following parameters were computed: mean speed, maximum speed, mean time, path length, normalized jerk, mean force, mean error, mean energy expenditure and active patient-robot interaction percentage.The assessments were carried-out before and after treatment. RESULTS: Significant changes were observed in both groups in the FM, MI, B&B and mean speed. Significant changes were observed in mBI, mean time, mean force, mean energy expenditure and active patient-robot interaction percentage in subacute stroke patients. In chronic stroke patients significant changes were found on the MAS-elbow. CONCLUSIONS: The haptic device used is at least as effective as an existing device used in similar studies. PMID- 29400671 TI - Effects of modified constraint-induced movement therapy with trunk restraint in early stroke patients: A single-blinded, randomized, controlled, pilot trial. AB - BACKGROUND: Reducing compensatory strategies during repetitive upper-limb training may be helpful in relearning motor skills. OBJECTIVE: To explore the effects of modified constraint-induced movement therapy (mCIMT), additionally modified by adding trunk restraint (TR), on upper-limb function and activities of daily living (ADLs) in early post-stroke patients. METHODS: Twenty-four participants with early stroke were randomly assigned to mCIMT combined with TR (mCIMT + TR) or mCIMT alone. Each group underwent twenty sessions (1 h/d, 5 d/wk for 4 weeks). Patients were assessed with the action research arm test (ARAT), the Fugl-Meyer Assessment-Upper extremity (FMA-UE), the Modified Barthel index (MBI), the Maximal elbow extension angle during reaching (MEEAR), and Motor Activity Logs (MAL-AOU and MAL-QOM). RESULTS: The mCIMT + TR group exhibited greater improvement in the ARAT, FMA-UE, MBI, MEEAR, and MAL-AOU, and MAL-QOM than the mCIMT group. Statistical analyses showed significant differences in ARAT (P = 0.003), FMA-UE (P = 0.042), MBI (P = 0.001), MEEAR (P = 0.002), and MAL-AOU (P = 0.005) between the groups. CONCLUSION: Modified CIMT combined with TR may be more effective than mCIMT alone in improving upper-limb function and ADLs in patients with early stroke. PMID- 29400672 TI - French validation of the Stroke Specific Quality of Life Scale (SS-QoL). AB - OBJECTIVE: To adapt the SS-QoL into French and test its psychometric properties. METHODS: Seventy-seven patients from a population-based registry were enrolled 3 months after their stroke. SS-QoL, NIHSS score, Barthel index, HAD, FSS, SF-36 scales, and MMSE were administered at enrolment. SS-QoL was re-administered at 15 days and 2 months. Internal consistency was assessed by Cronbach's alpha coefficients, factorial validity by an exploratory factor analysis and external validity by Mann-Whitney test and Spearman's correlations (rho), comparing SS-QoL scores with those obtained from established scales. Reliability was assessed by intra-class correlation coefficients (ICC) and responsiveness by standardized effect sizes (ES). RESULTS: Test-retest and inter-observer reliabilities were excellent (ICC> 0.88). Internal consistency was acceptable (alpha= 0.65-0.91), except for the Personality domain (alpha= 0.58). Factor analysis individualized eight homogenous axes. SS-QoL scores were different between groups opposed by their modified Rankin score at enrolment or their overall quality of life compared with pre-stroke status (p < 0.001). Ten of the twelve domains correlated moderately (rho> 0.35) to strongly (rho> 0.5) with established measures. Nine domains were mildly to moderately responsive to change (ES> 0.3). CONCLUSION: The French version of the SS-QoL is a valid, reliable and moderately responsive instrument. PMID- 29400673 TI - Validation of Manual Muscle Testing (MMT) in children and adolescents with cerebral palsy. AB - BACKGROUND: Weakness is a major impairment in many movement disorders, including cerebral palsy (CP), which presents as a decrease in muscle strength. Manual muscle testing (MMT) is very popular in clinical practice, however it has many limitations. OBJECTIVE: (1) Whether maximum voluntary contraction (MVC) measures differ across clinical MMT groups; (2) Whether an association exists between clinical MMT score groups and instrumental MVC measures. METHODS: Twenty-one participants with spastic CP were recruited (11 females and 10 males; age = 13.46+/-3.62 years). To achieve the aims of the study, we investigated the relationship between qualitative (MMT) and instrumental (MVC) measures of knee flexor muscles' strength in patients with CP. RESULTS: MVC values increased somewhat proportionally with increasing MMT score group (p = 0.032, MS = 207.54, F = 3.75). The differences in MVC values was only statistically significant between score groups 3 and 5. A weak correlation (R = 0.4, MVC = -2.54 + 4.50 MMT, p < 0.01) was found between measured MVCs and the MMT score groups. CONCLUSIONS: In pediatric research studies, instrumental MVC should be preferred over MMT scoring. Also, MMT score groups higher than 3 should be modified in clinical testing of children and adolescents with cerebral palsy. PMID- 29400674 TI - Reproducibility of gait kinematics and kinetics in chronic stroke patients. AB - BACKGROUND: The search for reliable techniques to assess gait in stroke patients is crucial for the design and follow-up of rehabilitation programs. OBJECTIVE: To assess the reproducibility of kinematic and kinetic gait parameters in chronic stroke patients using a three-dimensional gait analysis system. METHODS: Ten chronic stroke patients were assessed while walking along a 20 m walkway at their natural speed, using a gait analysis system of six infrared cameras and two force plates. Each patient performed 10 gait trials on 2 separate days. Inter measurement agreement was assessed with the Coefficient of Multiple Correlation, while Root Mean Square Differences were used to quantify the variability of the trials. RESULTS: The majority of kinetics and kinematics showed excellent reproducibility in all patients. Joints' power seemed to be more reliable compared with joints' angle and moment. Most parameters presented greater variability in non-paretic than the paretic leg, while they were less variable in the sagittal compared with the non-sagittal planes. Less than 10 trials were sufficient to obtain excellent reproducibility for most kinematic and kinetic parameters. CONCLUSIONS: The reproducibility of movement assessment through three dimensional gait analysis appears excellent in chronic stroke patients. PMID- 29400675 TI - Sense of Coherence in persons with late effects of polio. AB - BACKGROUND: Sense of Coherence (SOC) is important for successful adaptation and mental well-being in people with life-long medical conditions. Late effects of polio (LEoP) often lead to a life-long disability, but no study has assessed SOC in this population. OBJECTIVE: To assess SOC in persons with LEoP and to explore the association between SOC, demographics (age, gender, marital status and level of education) and variables related to LEoP (age at polio onset, number of years from polio until onset of LEoP and self-rated disability). METHOD: Ninety-three community-dwelling persons with clinically verified LEoP responded to a postal survey with the Sense of Coherence Scale (SOC-13). A hierarchical multiple regression analysis was performed to explore the associations with SOC. RESULTS: SOC varied considerably among the participants. The mean and median SOC-13 total sum score was 71.8 and 76 points, which is similar to age-matched non-disabled people. The number of years before onset of LEoP and self-rated disability together with the participants' marital status and level of education explained 37% (p < 0.001) of the variance in SOC. CONCLUSION: Persons with LEoP have a level of SOC indicating that they generally have the ability to understand, handle and being motivated when dealing with stressful events and problems arising in their lives as a result of their disability. Being married and having a higher education, living many years before onset of LEoP and perceiving a mild to moderate disability contributed to a strong SOC. PMID- 29400676 TI - Bilateral anodal transcranial direct current stimulation effect on balance and fearing of fall in patient with Parkinson's disease. AB - BACKGROUND: A number of studies have examined the therapeutic effects of transcranial direct current stimulation (tDCS) stimulation in patients with Parkinson's disease (PD) using unilateral anodal stimulation applied either on the left or right brain hemisphere. However, PD involves the dysfunctions of both brain hemispheres. OBJECTIVES: This study investigates the therapeutic effects of bilateral anodal tDCS stimulation on balance and fear of fall outcomes in patient with PD. METHODS: Eighteen patients with idiopathic PD completed the study. Ten sessions of bilateral anodal tDCS stimulation were applied over the FC1 and FC2 targeting both pre-frontal and motor areas for each patient, 5 sessions per week for 2 weeks. Berg Balance Scale (BBS), Falls Efficacy Scale-International (FES I), and 10 meters walk test (10mwt) were applied before and after the stimulation therapy. RESULTS: Paired t-test showed a significant increase in the BBS scores and decrease in the FES-I scores after the bilateral tDCS compared with those scores before tDCS therapy (P < 0.05), as well improvement in the 10mwt scores. CONCLUSION: Our data showed that bilateral anodal tDCS serves as an effective, safe and feasible approach for rehabilitation of patients with PD with the issues related to balance and fear of fall. PMID- 29400677 TI - Male and female opinions about orthotic devices of the lower limb: A multicentre, observational study in patients with central neurological movement disorders. AB - BACKGROUND AND OBJECTIVE: Because user-satisfaction and acceptance may partly determine the grade of compliance to an orthotic device (OD), the aim of this multicentre observational study was to inquire the reasons for acceptance and the user-satisfaction of an OD of the lower limb in male and female central neurological movement disorders (CNMD) patients. METHODS: Persons with CNMD having at least one prescribed OD of the lower limb were included. Two questionnaires were used: the MIRAD-ACCORT-II (reasons for acceptance) and a modified version of the D-QUEST 2.0 (user-satisfaction). Descriptive analyses were performed and to analyse the differences between the males' and females' answers Chi2- and Mann-Whitney U tests were used. RESULTS: Twenty-six stroke and 23 multiple sclerosis patients participated (53% males). "Comfort", "safety", "effectiveness" and "ease of use" were reported as most important aspects. 86% of the patients were (very) satisfied about their OD. Only for the aspect safety, compared to males, significant more females reported that if the OD is not safe enough they will not use it. CONCLUSION: For both, males and females, aspects related to comfort and functionality were reported as much more important than the esthetical aspects, and in general they are quite satisfied with the OD and the process of providing the OD. Orthopaedic technicians and health care providers can take these aspects into account when developing, constructing and providing OD's. PMID- 29400678 TI - A comparative study of rehabilitation therapy in traumatic upper limb peripheral nerve injuries. AB - INTRODUCTION: Lower motor neurons are the only neurons of the central nervous system (CNS) with the ability to regenerate without any intervention after an axotomy. AIM: This present study was conducted to analyze clinical and electrophysiological parameters in four groups of upper limb peripheral neuropathies, before and after treatment, comparing the results obtained after three cures of complex rehabilitation therapy. MATERIALS AND METHODS: We selected a number of 107 patients (66 women and 41 men) aged between 29 and 77 years (mean age = 49.6). Clinical (muscular strength, sensitivity) and electrophysiological parameters (accommodation coefficient alpha, nerve conduction velocity) were analyzed. All patients received 3 comprehensive treatment cures, each cure of 14 days and a rest period of 3 months between the cures. RESULTS: From the total of 107 patients included in the study, 52 were diagnosed with brachial plexus palsy, 27 with radial nerve palsy, 18 with median nerve palsy and 10 with ulnar nerve palsy. We did not observe a statistically significant difference between the mean age of males (47.2) and females (51.2) (p = 0.07), but peripheral neuropathies were more common in young males. At the end of the rehabilitation treatment all patients achieved better outcomes in muscle strength, sensitivity, adjustment coefficient alpha and nerve conduction velocity (p < 0.001).CONCLUSIONThe intervention of a physical therapy program in patients with peripheral neuropathies provided significantly better outcomes in clinical and electrophysiological parameters. Our rehabilitation protocol can be considered an alternative in order to stimulate and accelerate the nerve regeneration process. PMID- 29400679 TI - What is the opinion of patients with multiple sclerosis and their healthcare professionals about lower limb orthoses? A qualitative study using focus group discussions. AB - OBJECTIVE: The aim of this study was to collect patients' and healthcare professionals' opinions about lower limb orthoses (LL-orthoses): 1) the positive and negative aspects; 2) the differences in wearing them according to location; and 3) their recommendations for future modifications. METHODS: Four focus group discussions were performed, with in total twenty patients with MS with a prescribed LL-orthosis and seven healthcare professionals. Audiotaped discussions were transcribed and qualitatively processed (NVivo11). RESULTS: Healthcare professionals and patients state that a LL-orthosis improves gait and reduces the risk of falling. Some negative aspects were indicated like stigmatization, difficulties to put on and off the LL-orthosis and the aesthetic aspects. Several patients mentioned that they did not get enough or no correct information about the adaptability and use of the orthoses. Opinions regarding differences in wearing according to location (e.g. in and outside the rehabilitation center) were diverse. Recommendations for future changes were e.g. more refined and firmer orthoses. CONCLUSIONS: The opinions collected are interesting for taking into account in the process of construction and delivering of LL-orthoses. Future research should focus on the opinions concerning different types of LL-orthosis in relation with the severity of the limitations of the patients. PMID- 29400680 TI - Mildly disabled persons with multiple sclerosis use similar net joint power strategies as healthy controls when walking speed increases. AB - BACKGROUND: To improve walking in persons with multiple sclerosis (MS), it is essential to understand the underlying mechanisms of walking. This study examined strategies in net joint power generated or absorbed by hip flexors, hip extensors, hip abductors, knee extensors, and plantar flexors in mildly disabled persons with MS and healthy controls at different walking speeds. METHODS: Thirteen persons with MS and thirteen healthy controls participated and peak net joint power was calculated using 3D motion analysis. RESULTS: In general, no differences were found between speed-matched healthy controls and persons with MS, but the fastest walking speed was significantly higher in healthy controls (2.42 m/s vs. 1.70 m/s). The net joint power increased in hip flexors, hip extensors, hip abductors, knee extensors and plantar flexors in both groups, when walking speed increased. Significant correlations between changes in walking speed and changes in net joint power of plantar flexors, hip extensors and hip flexors existed in healthy controls and persons with MS, and in net knee extensor absorption power of persons with MS only. CONCLUSION: In contrast to previous studies, these findings suggest that mildly disabled persons with MS used similar kinetic strategies as healthy controls to increase walking speed. PMID- 29400681 TI - Using association rules to measure Subjective Organization after Acquired Brain Injury. AB - BACKGROUND: Subjective Organization (SO) refers to the human tendency to impose organization on our environment. Persons with Acquired Brain Injury (ABI) often lose the ability to organize however, there are no performance based measures of organization that can be used to document this disability. OBJECTIVE: The authors propose a method of association rule analysis (AR) that can be used as a clinical tool for assessing a patient's ability to organize. METHOD: Twenty three patients with ABI recalled a list of twelve unrelated nouns over twelve study and test trials. Several measures of AR computed on these data were correlated with various measures of short-term, long-term, and delayed recall of the words. RESULTS: All of the AR measures correlated significantly with the short-term and long-term memory measures. The confidence measure was the best predictor of memory and the number of association rules generated was the best predictor of learning. CONCLUSIONS: The confidence measure can be used as a clinical tool to assess SO with individual ABI survivors. PMID- 29400682 TI - Swallowing impairments in Amyotrophic Lateral Sclerosis and Myotonic Dystrophy type 1: Looking for the portrait of dysphagic patient in neuromuscular diseases. AB - BACKGROUND: Dysphagia is a critical symptom of Neuromuscular Diseases and is often associated with considerable morbidity and mortality. OBJECTIVE: This study is designed to investigate the prevalence of dysphagia and to identify different clinical profiles of swallowing disorders in Myotonic Dystrophy type 1 (DM1) and Amyotrophic Lateral Sclerosis (ALS), the most common Neuromuscular Diseases in the adult age. METHODS: Consecutive DM1 and ALS patients from 2013 to 2015 referred to a Centre for Neuromuscular Disease were enrolled. A comprehensive assessment of swallowing function with a Clinical Swallowing Examination and Fluid and Food Trials was performed. RESULTS: 157 patients were included: 86 ALS, 71 DM1. The dysphagic patients affected by ALS and DM1 (79% and 86% of the respective samples) showed two different profiles. ALS patients with dysphagia were older and underweight. They experienced a global dysfunction of the oral and pharyngeal phases with more difficulty in swallowing thin liquids. Conversely, DM1 patients with dysphagia were younger and tended to obesity. Most of them showed impairment of oral phase and had more frequently difficulty in swallowing solid bolus. CONCLUSION: The recognition of specific clinical profiles supports and guides the detection of swallowing disorders in patients with neuromuscular diseases. PMID- 29400683 TI - Preliminary research of a novel center-driven robot for upper extremity rehabilitation. AB - BACKGROUND: Loss of upper limb function often appears after stroke. Robot assisted systems are becoming increasingly common in upper extremity rehabilitation. Rehabilitation robot provides intensive motor therapy, which can be performed in a repetitive, accurate and controllable manner. OBJECTIVE: This study aims to propose a novel center-driven robot for upper extremity rehabilitation. METHODS: A new power transmission mechanism is designed to transfer the power to elbow and shoulder joints from three motors located on the base. The forward and inverse kinematics equations of the center-driven robot (CENTROBOT) are deduced separately. The theoretical values of the scope of joint movements are obtained with the Denavit-Hartenberg parameters method. A prototype of the CENTROBOT is developed and tested. RESULTS: The elbow flexion/extension, shoulder flexion/extension and shoulder adduction/abduction can be realized of the center-driven robot. The angles value of joints are in conformity with the theoretical value. CONCLUSIONS: The CENTROBOT reduces the overall size of the robot arm, the influence of motor noise, radiation and other adverse factors by setting all motors on the base. It can satisfy the requirements of power and movement transmission of the robot arm. PMID- 29400685 TI - Bone mineral density and serum 25-hydroxyvitamin D in patients with idiopathic benign paroxysmal positional vertigo. AB - The aim of this study was to evaluate the relationship between bone mineral density (BMD) and 25-hydroxyvitamin D with the occurrence and recurrence of BPPV. The records of 130 idiopathic BPPV patients (55+/-12 years old, 30 men and 100 women) and 130 age- and sex-matched controls who underwent bone mineral densitometry between April 2012 and September 2015 were reviewed retrospectively. We compared the BMD and serum 25-hydroxyvitamin D between the patients and controls, and also compared the BMD between recurrent and non-recurrent BPPV groups. Among the female subjects, the BPPV group showed a significantly decreased BMD compared to the controls (p < 0.05). The men in the control group had significantly higher 25-hydroxyvitamin D levels than the men with BPPV (p < 0.05). Sixty-three patients (48%) reported recurrent attacks of BPPV. The women with recurrent BPPV were significantly older and showed a significantly lower BMD than non-recurrent women (p < 0.001). However, multiple regression analysis revealed that age alone was significantly associated with the recurrence of BPPV in women. BMD in women and serum 25-hydroxyvitamin D levels in men are associated with the occurrence of BPPV. Only age is an independent predictor of recurrence, though a low BMD and age correlate with the recurrence of BPPV. PMID- 29400684 TI - Visual dependence and spatial orientation in benign paroxysmal positional vertigo. AB - People with benign paroxysmal positional vertigo (BPPV) probably have otoconial particles displaced from the utricle into the posterior semicircular canal. This unilateral change in the inertial load distributions of the labyrinth may result in visual dependence and may affect balance control. The goal of this study was to explore the interaction between visual dependence and balance control. We compared 23 healthy controls to 17 people with unilateral BPPV on the Clinical Test of Sensory Interaction and Balance on compliant foam with feet together, the Rod-and-Frame Test and a Mental Rotation Test. In controls, but not BPPV subjects, subjects with poor balance scores had significantly greater visual dependence, indicating that reliance on visual cues can affect balance control. BPPV and control subjects did not differ on the mental rotation task overall but BPPV reaction time was greater at greater orietantions, suggesting that this cognitive function was affected by BPPV. The side of impairment was strongly related to the side of perceived bias in the Earth vertical determined by BPPV subjects, indicating the relationship between the effect of asymmetric otolith unloading with simultaneous canal loading on spatial orientation perception. PMID- 29400687 TI - Vergence increases the gain of the human angular vestibulo-ocular reflex during peripheral hyposensitivity elicited by cold thermal irrigation. AB - BACKGROUND: When viewing a far target, the gain of the horizontal vestibulo ocular reflex (VOR) is around 1.0, but when viewing a near target there is an increased response. It has been shown that while this convergence-mediated modulation is unaffected by canal plugging and clinically practical transmastoid galvanic stimulation, it is eliminated by a partial peripheral gentamicin lesion. OBJECTIVE: The aim of this study was to determine if convergence increases the gain during peripheral hyposensitivity elicited by cold thermal irrigation. METHODS: The high frequency VOR gain was measured using video head impulse testing immediately after the cold caloric stimulus in 9 healthy human subjects with the lateral semicircular canals oriented approximately earth-vertical. RESULTS: Before caloric irrigation, near viewing (15 cm) increased the average VOR gain by 28% (from 1 to 1.28). Cold (24 degrees C) water irrigation of the right ear decreased the gain to 0.66 (far viewing) and 0.82 (near viewing) (22% difference). Although vergence also increased the gain for impulses to the left to the same degree before caloric stimulus, the caloric irrigation itself (applied to the right ear) did not influence the gain for contralateral impulses. CONCLUSION: In our experiments vergence increased the gain of the human angular VOR during peripheral hyposensitivity elicited by cold thermal irrigation. These results suggest that cold irrigation does not abolish the function of the nonlinear/phasic vestibular afferent pathway. PMID- 29400686 TI - PREHAB vs. REHAB - presurgical treatment in vestibular schwannoma surgery enhances recovery of postural control better than postoperative rehabilitation: Retrospective case series. AB - OBJECT: To evaluate post-surgical postural stability when treating patients with remaining vestibular function with intratympanic gentamicin (PREHAB) prior to schwannoma surgery. METHOD: 44 consecutive patients with some form remaining vestibular function scheduled for vestibular schwannoma surgery. 20 were medically deafferented with intratympanic gentamicin before surgery and 24 were not. Both groups were of the same age, had the same tumor size, same type of surgery, and same perioperative sensory rehabilitation (training exercises), and no surgical complications. Postural stability measured as energy expenditure while standing on a force platform during vibratory stimulation of the calf muscles, performed prior to surgery (or gentamicin treatment) and 6 months after surgery. RESULTS: Patients pretreated with gentamicin had significantly better postural stability at the time for follow-up (p < 0.05) and displayed a better adaptive capacity when faced with a postural challenge (p < 0.01). They were also able to use vision more efficiently to control their stability (p < 0.05). CONCLUSIONS: By separating the sensory loss (through intratympanic gentamicin, that ablates the remaining vestibular function) from the intracranial surgical trauma, the postural control system benefited from a better short-term (adaptation) and long-term (habituation) recovery, when experiencing a postural challenge or resolving a sensory conflict. The benefits could be attributed to; active and continuous motor learning as the vestibular function slowly attenuates; no concomitant central nervous dysfunction due to effects from neurosurgery, thus allowing time for a separate unimpeded recovery process with more limited challenges and objectives; and the initiation and certain progression of sensory reweighting processes allowed prior to surgery. In contrast, worse compensation could be due to; immobilization from nausea after surgery, harmful amount of stress and cognitive dysfunction from the combination of surgical and sensory trauma and an abrupt vestibular deafferentation and its consequences on sensory reweighting. PMID- 29400688 TI - Treatment of vestibular disorders with weak asymmetric base-in prisms: An hypothesis with a focus on Meniere's disease. AB - BACKGROUND: Regular treatments of Meniere's disease (MD) vary largely, and no single satisfactory treatment exists. A complementary treatment popular among Dutch and Belgian patients involves eyeglasses with weak asymmetric base-in prisms, with a perceived high success rate. An explanatory mechanism is, however, lacking. OBJECTIVE: To speculate on a working mechanism explaining an effectiveness of weak asymmetric base-in prims in MD, based on available knowledge. METHODS: After describing the way these prisms are prescribed using a walking test and its effect reported on, we give an explanation of its underlying mechanism, based on the literature. RESULTS: The presumed effect can be explained by considering the typical star-like walking pattern in MD, induced by a drifting after-image comparable to the oculogyral illusion. Weak asymmetric base-in prisms can furthermore eliminate the conflict between a net vestibular angular velocity bias in the efferent signal controlling the VOR, and a net re-afferent ocular signal. CONCLUSIONS: The positive findings with these glasses reported on, the fact that the treatment itself is simple, low-cost, and socially acceptable, and the fact that an explanation is at hand, speak in favour of elaborating further on this treatment. PMID- 29400689 TI - Effect of spaceflight on the spatial orientation of the vestibulo-ocular reflex during eccentric roll rotation: A case report. AB - BACKGROUND: Ground-based studies have reported shifts of the vestibulo-ocular reflex (VOR) slow phase velocity (SPV) axis toward the resultant gravito-inertial force vector. The VOR was examined during eccentric roll rotation before, during and after an 8-day orbital mission. On orbit this vector is aligned with the head z-axis. Our hypothesis was that eccentric roll rotation on orbit would generate horizontal eye movements. METHODS: Two subjects were rotated in a semi-supine position with the head nasal-occipital axis parallel to the axis of rotation and 0.5 m off-center. The chair accelerated at 120 deg/s2 to 120 deg/s, rotated at constant velocity for one minute, and then decelerated to a stop in similar fashion. RESULTS: On Earth, the stimulation primarily generated torsional VOR. During spaceflight, in one subject torsional VOR became horizontal VOR, and then decayed very slowly. In the other subject, torsional VOR was reduced on orbit relative to pre- and post-flight, but the SPV axis did not rotate. CONCLUSION: We attribute the shift from torsional to horizontal VOR on orbit to a spatial orientation of velocity storage toward alignment with the gravito-inertial force vector, and the inter-individual difference to cognitive factors related to the subjective straight-ahead. PMID- 29400690 TI - The impact of visible and invisible symptoms on employment status, work and social functioning in Multiple Sclerosis. AB - BACKGROUND: Frequently diagnosed in young adulthood, multiple sclerosis (MS) and several MS-related factors can influence patients' unemployment status and negatively affect work productivity and daily functioning. OBJECTIVE: We examined MS patients' employment status and evaluated clinical features influencing it. Furthermore, we investigated patients' burdens due to visible and invisible MS symptoms through their worsening daily functioning. METHODS: The study included outpatients affected by MS according to the 2010 McDonald criteria. The co occurrence of invisible symptoms (fatigue, depression and apathy) was stated using validated, self-administered tools: Fatigue Severity Scale (FSS); Beck Depression Inventory-Second Edition (BDI-II); Apathy Evaluation Scale (AES). Impairment in daily functioning due to MS was assessed using the Work and Social Adjustment Scale (WSAS). Descriptive statistics, hierarchical regression analyses, Pearson's correlation, and the t-test were conducted. RESULTS: Of the 123 participants, 52 (42.3%) were unemployed. Results showed employment to be positively associated with higher education levels (p 0.01); female gender (p 0.03) and higher disability (p 0.02) showed negative associations with employment. No associations were found between employment and fatigue or clinically relevant depressive and apathetic symptoms. High correlations were found between WSAS score and Expanded Disability Status Scale score (r = 565, p < 0.001), BDI-II score (r = 588, p < 0.001), and FSS score (r = 545, p < 0.001). CONCLUSION: Our study revealed physical disability's significance in determining MS patients' unemployment. Alternatively, invisible MS symptoms negatively affected principally patients' social lives. Therefore, programs should be designed to improve MS patients' work integration and daily activities. PMID- 29400691 TI - Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation. AB - Claudin 18 (CLDN18) is a tight junction protein that is highly expressed in the lung. While mice lacking CLDN18 exhibit the expected loss of epithelial integrity in the lung, these animals also have unexpectedly large lungs. In this issue of the JCI, Zhou, Flodby, and colleagues reveal that the increased lung size of Cldn18-/- mice is the result of increased type 2 alveolar epithelial (AT2) cell proliferation. This increase in proliferation was shown to be driven by translocation of the transcriptional regulator Yes-associated protein (YAP) to the nucleus and subsequent induction of proliferative pathways. CLDN18-deficent mice also had increased frequency of lung adenocarcinomas. Together, the results of this study advance our understanding of the mechanisms that likely regulate homeostasis of the normal lung as well as promote the proliferative state of malignant cells found in lung adenocarcinomas thought to originate from AT2 cells. PMID- 29400692 TI - Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. AB - Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten-/- Sav1-/- mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV Cas9 successfully repressed liver tumorigenesis in Pten-/- Sav1-/- mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer. PMID- 29400694 TI - All plugged up - noninvasive mucus score to assess airway dysfunction in asthma. AB - Asthma is remarkably heterogeneous, and there are multiple underlying inflammatory pathways and structural airway abnormalities that lead to symptomatic disease. Consequently, a current challenge in the field is to precisely characterize different types of asthma, with the goal of developing personalized approaches to therapy. In the current issue of the JCI, Dunican et al. developed a noninvasive way to assess airway dysfunction in asthma by measuring mucus accumulation using multidetector computed tomography (MDCT) and found that mucus plugging of small airways was remarkably common in subjects with severe asthma. This work highlights the importance of noninvasive imaging approaches in defining specific asthma subsets and guiding targeted therapies. PMID- 29400693 TI - Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. AB - BACKGROUND: The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS: In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS: Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in >= 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION: Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION: Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING: NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428. PMID- 29400696 TI - A tribute to Terry Strom. PMID- 29400695 TI - Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. AB - Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury. PMID- 29400697 TI - Randomized, controlled trial of TNF-alpha antagonist in CTL-mediated severe cutaneous adverse reactions. AB - BACKGROUND: Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-alpha and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-alpha antagonist in CTL-mediated SCARs. METHODS: We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-alpha antagonist etanercept versus traditional corticosteroids. RESULTS: Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-alpha and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS: The anti-TNF-alpha biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01276314. FUNDING: Ministry of Science and Technology of Taiwan. PMID- 29400698 TI - Clonally expanded gammadelta T cells protect against Staphylococcus aureus skin reinfection. AB - The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1beta-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The gammadelta T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-gamma, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus-induced gammadelta T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant Vgamma5+ dendritic epidermal T cells. However, this T cell receptor gamma (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-gamma-producing gammadelta T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded gammadelta T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections. PMID- 29400699 TI - Characterization of a group I Nme protein of Capsaspora owczarzaki-a close unicellular relative of animals. AB - Nucleoside diphosphate kinases are enzymes present in all domains of life. In animals, they are called Nme or Nm23 proteins, and are divided into group I and II. Human Nme1 was the first protein identified as a metastasis suppressor. Because of its medical importance, it has been extensively studied. In spite of the large research effort, the exact mechanism of metastasis suppression remains unclear. It is unknown which of the biochemical properties or biological functions are responsible for the antimetastatic role of the mammalian Nme1. Furthermore, it is not clear at which point in the evolution of life group I Nme proteins acquired the potential to suppress metastasis, a process that is usually associated with complex animals. In this study we performed a series of tests and assays on a group I Nme protein from filasterean Capsaspora owczarzaki, a close unicellular relative of animals. The aim was to compare the protein to the well known human Nme1 and Nme2 homologs, as well as with the homolog from a simple animal-sponge (Porifera), in order to see how the proteins changed with the transition to multicellularity, and subsequently in the evolution of complex animals. We found that premetazoan-type protein is highly similar to the homologs from sponge and human, in terms of biochemical characteristics and potential biological functions. Like the human Nme1 and Nme2, it is able to diminish the migratory potential of human cancer cells in culture. PMID- 29400700 TI - Southern Hemisphere climate variability forced by Northern Hemisphere ice-sheet topography. AB - The presence of large Northern Hemisphere ice sheets and reduced greenhouse gas concentrations during the Last Glacial Maximum fundamentally altered global ocean atmosphere climate dynamics. Model simulations and palaeoclimate records suggest that glacial boundary conditions affected the El Nino-Southern Oscillation, a dominant source of short-term global climate variability. Yet little is known about changes in short-term climate variability at mid- to high latitudes. Here we use a high-resolution water isotope record from West Antarctica to demonstrate that interannual to decadal climate variability at high southern latitudes was almost twice as large at the Last Glacial Maximum as during the ensuing Holocene epoch (the past 11,700 years). Climate model simulations indicate that this increased variability reflects an increase in the teleconnection strength between the tropical Pacific and West Antarctica, owing to a shift in the mean location of tropical convection. This shift, in turn, can be attributed to the influence of topography and albedo of the North American ice sheets on atmospheric circulation. As the planet deglaciated, the largest and most abrupt decline in teleconnection strength occurred between approximately 16,000 years and 15,000 years ago, followed by a slower decline into the early Holocene. PMID- 29400701 TI - Global patterns of declining temperature variability from the Last Glacial Maximum to the Holocene. AB - Changes in climate variability are as important for society to address as are changes in mean climate. Contrasting temperature variability during the Last Glacial Maximum and the Holocene can provide insights into the relationship between the mean state of the climate and its variability. However, although glacial-interglacial changes in variability have been quantified for Greenland, a global view remains elusive. Here we use a network of marine and terrestrial temperature proxies to show that temperature variability decreased globally by a factor of four as the climate warmed by 3-8 degrees Celsius from the Last Glacial Maximum (around 21,000 years ago) to the Holocene epoch (the past 11,500 years). This decrease had a clear zonal pattern, with little change in the tropics (by a factor of only 1.6-2.8) and greater change in the mid-latitudes of both hemispheres (by a factor of 3.3-14). By contrast, Greenland ice-core records show a reduction in temperature variability by a factor of 73, suggesting influences beyond local temperature or a decoupling of atmospheric and global surface temperature variability for Greenland. The overall pattern of reduced variability can be explained by changes in the meridional temperature gradient, a mechanism that points to further decreases in temperature variability in a warmer future. PMID- 29400702 TI - Integrin CD11b negatively regulates Mincle-induced signaling via the Lyn SIRPalpha-SHP1 complex. AB - During mycobacteria infection, anti-inflammatory responses allow the host to avoid tissue damage caused by overactivation of the immune system; however, little is known about the negative modulators that specifically control mycobacteria-induced immune responses. Here we demonstrate that integrin CD11b is a critical negative regulator of mycobacteria cord factor-induced macrophage inducible C-type lectin (Mincle) signaling. CD11b deficiency resulted in hyperinflammation following mycobacterial infection. Activation of Mincle by mycobacterial components turns on not only the Syk signaling pathway but also CD11b signaling and induces formation of a Mincle-CD11b signaling complex. The activated CD11b recruits Lyn, SIRPalpha and SHP1, which dephosphorylate Syk to inhibit Mincle-mediated inflammation. Furthermore, the Lyn activator MLR1023 effectively suppressed Mincle signaling, indicating the possibility of Lyn mediated control of inflammatory responses. These results describe a new role for CD11b in fine-tuning the immune response against mycobacterium infection. PMID- 29400703 TI - Comprehensive review of autoantibodies in patients with hyper-IgM syndrome. AB - Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene. The CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary cholangitis. In the present study, we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M syndrome. Serum, liver-related and liver-not-related autoantibodies IgG, IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients (8 males and 5 females, aged 1-12 years) with hyper immunoglobulin M syndrome during 1995-2012 and, as controls, 21 age- and gender matched blood donors. The level of IgM antibody against MIT3 was significantly higher in patients than in controls (35.8 vs 10.7, P=0.002). Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls (P<0.0001). Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05% of controls. By immunofluorescence, 92.3% of patients were MIT3 IgM positive vs none of the controls. In conclusion, the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper immunoglobulin M syndrome. The presence of the hallmark of primary biliary cholangitis, a disease where the CD40 ligand is a key player, in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis. PMID- 29400704 TI - Functions of NKG2D in CD8+ T cells: an opportunity for immunotherapy. AB - Natural killer group 2 member D (NKG2D) is a type II transmembrane receptor. NKG2D is present on NK cells in both mice and humans, whereas it is constitutively expressed on CD8+ T cells in humans but only expressed upon T-cell activation in mice. NKG2D is a promiscuous receptor that recognizes stress induced surface ligands. In NK cells, NKG2D signaling is sufficient to unleash the killing response; in CD8+ T cells, this requires concurrent activation of the T-cell receptor (TCR). In this case, the function of NKG2D is to authenticate the recognition of a stressed target and enhance TCR signaling. CD28 has been established as an archetype provider of costimulation during T-cell priming. It has become apparent, however, that signals from other costimulatory receptors, such as NKG2D, are required for optimal T-cell function outside the priming phase. This review will focus on the similarities and differences between NKG2D and CD28; less well-described characteristics of NKG2D, such as the potential role of NKG2D in CD8+ T-cell memory formation, cancer immunity and autoimmunity; and the opportunities for targeting NKG2D in immunotherapy. PMID- 29400705 TI - TAOK1 negatively regulates IL-17-mediated signaling and inflammation. AB - Interleukin 17 (IL-17) is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases. However, the regulation of its signaling transduction has not been well described. In this study, we report that thousand and one kinase 1 (TAOK1) functions as a negative regulator of IL-17-mediated signal transduction and inflammation. TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-kappaB. We further demonstrate that TAOK1 interacts with IL-17 receptor A (IL-17RA) independent of its kinase activity, and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1 (nuclear factor activator 1, also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2) complex. Consistent with this, TAOK1 deficiency exacerbates colitis in the 2,4,6 trinitrobenzenesulfonic acid)-induced experimental model of inflammatory bowel disease, likely by its promotion of the IL-17-mediated signaling pathway. TAOK1 expression is decreased in the colons of ulcerative colitis patients. In conclusion, these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders. PMID- 29400706 TI - Profiling the pattern of the human T-cell receptor gammadelta complementary determinant region 3 repertoire in patients with lung carcinoma via high throughput sequencing analysis. AB - gammadelta T cells function as sentinels in early host responses to infections and malignancies. Specifically, gammadelta T cells recognize tumor-associated stress antigens via T-cell receptor (TCR) gammadelta and play important roles in the antitumor immune response. In this study, we characterized the pattern of the human TCR gammadelta complementary determinant region 3 (CDR3) repertoire in patients with lung carcinoma (LC) via high-throughput sequencing. The results showed that the diversity of CDR3delta was significantly reduced, and that of CDR3gamma was unchanged in LC patients compared with healthy individuals; in addition, LC patients shared significantly more CDR3delta sequences with each other than healthy individuals. The CDR3 length distribution and N-addition length distribution did not significantly differ between LC patients and healthy individuals. In addition, the CDR3 repertoire tended to use more Vdelta2 and fewer Vdelta1 germline gene fragments among LC patients. Moreover, we found a combination of four TCR gammadelta repertoire features that focus on CDR3delta and can be used as a biomarker for LC diagnosis. Our research suggests that the TCR gammadelta CDR3 repertoire changed in LC patients due to the antitumor immune response by gammadelta T cells in vivo, and these changes primarily focus on the amplification of certain tumor-specific CDR3delta clones among patients. This study demonstrates the role of gammadelta T cells from the TCR gammadelta CDR3 repertoire in tumor immunity and lays the foundation for elucidating the mechanism underlying the function of gammadeltaT cells in antitumor immunity.Cellular and Molecular Immunology advance online publication, 5 February 2018; doi:10.1038/cmi.2017.157. PMID- 29400707 TI - IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL 13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis. AB - Viral hepatitis is still a public health problem affecting several million people around the world. Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection. However, the role of neutrophils in viral infection is not fully understood. By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis, we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+ T-cell responses. Liver neutrophils expressed high levels of immunomodulatory cytokines, such as C-X-C chemokine ligand 2, arginase-1, inducible nitric oxide synthase and interleukin (IL)-10, demonstrating immunosuppressive properties. Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage. IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation. Mechanistically, we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell (ILC2)-derived IL-13. Additionally, IL-13 increased the inhibitory effect of neutrophils on CD8+ T-cell proliferation in vitro, partially through arginase-1. Finally, we found that IL 13 induced arginase-1 expression, depending on signal transducer and activator of transcription factor 6 (STAT6) signaling. Therefore, IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis. Collectively, our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.Cellular and Molecular Immunology advance online publication, 5 February 2018; doi:10.1038/cmi.2017.147. PMID- 29400708 TI - Predictive immune biomarkers: an unattainable chimera? PMID- 29400710 TI - A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. AB - The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor beta-chain (IL 2Rbeta) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-DeltaIL2RB-z(YXXQ)). The 28-DeltaIL2RB-z(YXXQ) CAR-T cells showed antigen dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-DeltaIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken together, these results suggest that our new generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted. PMID- 29400709 TI - Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. AB - Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth. PMID- 29400711 TI - Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. AB - Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease. PMID- 29400712 TI - Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. AB - Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies. PMID- 29400713 TI - Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. AB - Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28alpha in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity. PMID- 29400716 TI - Eighth Hypertension Research Award for authors of outstanding papers in Hypertension Research. PMID- 29400715 TI - RNA-protein interaction detection in living cells. AB - RNA-protein interactions play numerous roles in cellular function and disease. Here we describe RNA-protein interaction detection (RaPID), which uses proximity dependent protein labeling, based on the BirA* biotin ligase, to rapidly identify the proteins that bind RNA sequences of interest in living cells. RaPID displays utility in multiple applications, including in evaluating protein binding to mutant RNA motifs in human genetic disorders, in uncovering potential post transcriptional networks in breast cancer, and in discovering essential host proteins that interact with Zika virus RNA. To improve the BirA*-labeling component of RaPID, moreover, a new mutant BirA* was engineered from Bacillus subtilis, termed BASU, that enables >1,000-fold faster kinetics and >30-fold increased signal-to-noise ratio over the prior standard Escherichia coli BirA*, thereby enabling direct study of RNA-protein interactions in living cells on a timescale as short as 1 min. PMID- 29400718 TI - Evaluation of the communication quality of free-space laser communication based on the power-in-the-bucket method. AB - Atmospheric turbulence seriously affects the quality of free-space laser communication. The Strehl ratio (SR) is used to evaluate the effect of atmospheric turbulence on the receiving energy of free-space laser communication systems. However, the SR method does not consider the area of the laser-receiving end face. In this study, the power-in-the-bucket (PIB) method is demonstrated to accurately evaluate the effect of turbulence on the receiving energy. A theoretical equation is first obtained to calculate PIB. Simulated and experimental validations are then performed to verify the effectiveness of the theoretical equation. This work may provide effective guidance for the design and evaluation of free-space laser communication systems. PMID- 29400719 TI - Fiber-based simultaneous mode and wavelength demultiplexer. AB - We theoretically design and analyze the performance of a fiber-based linearly polarized (LP) mode demultiplexer using a Fabry-Perot interferometer. The all fiber geometry of the reported demultiplexer is obtained by writing fiber Bragg gratings (FBGs) in a few-mode fiber (FMF), such that the FBGs act as partial reflecting mirrors for the LP modes. We also demonstrate the ability to decompose a received optical signal into its individual LP components in wavelength division multiplexing networks. PMID- 29400714 TI - Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. AB - An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD. PMID- 29400720 TI - Kinematic model for material removal distribution and surface figure in full aperture polishing. AB - Full-aperture polishing is a significant process for fabricating large ultra precision optic flats. The surface figure is one of the key specifications required of the optic flats, which is determined by the material removal distribution during polishing. To date, the most frequently referred to equation, the Preston equation, only provides a solution for qualitative calculation of material removal of a single point on the optic surface. In this study, we present a kinematic model for deterministic calculation of the removal amount at every local optic position. The model is based on the sliding track of each local optic position on the lap, and it incorporates local pressure and most key kinematic parameters and considers the effect of the lap grooves. With this model, we analyzed the impacts of various kinematic parameters and groove features on the distribution of the removal amount in terms of sliding distance, assuming a uniform pressure distribution at the lap/optic interface. Several polishing experiments have been carried out in which the model is validated. PMID- 29400721 TI - Orthogonal vector algorithm to obtain the solar vector using the single scattering Rayleigh model. AB - Information obtained from a polarization pattern in the sky provides many animals like insects and birds with vital long-distance navigation cues. The solar vector can be derived from the polarization pattern using the single-scattering Rayleigh model. In this paper, an orthogonal vector algorithm, which utilizes the redundancy of the single-scattering Rayleigh model, is proposed. We use the intersection angles between the polarization vectors as the main criteria in our algorithm. The assumption that all polarization vectors can be considered coplanar is used to simplify the three-dimensional (3D) problem with respect to the polarization vectors in our simulation. The surface-normal vector of the plane, which is determined by the polarization vectors after translation, represents the solar vector. Unfortunately, the two-directionality of the polarization vectors makes the resulting solar vector ambiguous. One important result of this study is, however, that this apparent disadvantage has no effect on the complexity of the algorithm. Furthermore, two other universal least squares algorithms were investigated and compared. A device was then constructed, which consists of five polarized-light sensors as well as a 3D attitude sensor. Both the simulation and experimental data indicate that the orthogonal vector algorithms, if used with a suitable threshold, perform equally well or better than the other two algorithms. Our experimental data reveal that if the intersection angles between the polarization vectors are close to 90 degrees , the solar-vector angle deviations are small. The data also support the assumption of coplanarity. During the 51 min experiment, the mean of the measured solar vector angle deviations was about 0.242 degrees , as predicted by our theoretical model. PMID- 29400722 TI - Light propagation in ordered and disordered optical waveguide arrays with a transverse loss gradient. AB - We first investigate the propagation of an initially localized optical beam through an ordered waveguide array in which the real part of the refractive index of all waveguides is the same, while there is a linear gradient loss along the transverse direction x. When the optical loss is an increasing function of x, the beam injected into every point of the array propagates to the left edge of the array. But for the case at which optical loss is a decreasing function of x, the optical beam propagates to the right edge of the array. In both cases, as the beam reaches the array edge, it is first reflected by the edge due to the presence of a repulsive potential near the array boundary, and then its width remains constant. We next study the wave propagation through a disordered array of waveguides in which the real parts of the refractive indices of waveguides are random numbers, and there exists a transverse loss gradient. For different random realizations with the same disorder level, when the beam is injected into the central waveguide, the beam becomes localized near the array edge with the lower loss. PMID- 29400723 TI - Influence of absorption on the refractive index determination accuracy by the minimum deviation method. AB - By means of computer simulation, the influence of absorption index, kappa, on the accuracy of determining the refractive index, n, of optical materials by the minimum deviation method (prism method) is studied at different measuring angular accuracies from 5'' to 0.1''. The n values within 1.0-4.0 and kappa values within 0-0.1 are considered. It is shown that (1) except for the far-infrared region, the error in determining n by formula (1) commonly used in the minimum deviation method, i.e., neglecting absorption, is less than the error due to the accuracy of measuring the prism and minimum deviation angles; (2) the difference between n values calculated with and without absorption taken into consideration is, in most cases, negligible throughout the optical range; (3) however, the total error in determination of n is higher when absorption is taken into account than that in the case when absorption is neglected. The further the increase in accuracy of measuring the angles and sensitivity of radiation detectors, the more the proposed calculation technique will allow one to optimize the prism angle value and to calculate more correctly the values of n and error in its determination. PMID- 29400724 TI - Research on the compensation of laser launch optics to improve the performance of the LGS spot. AB - To improve the beam quality of the uplink laser, a 37 channel piezo-ceramic deformable mirror was inserted into the laser launch optics to compensate the static aberrations. An interferometer was used as the calibration light source as well as the wavefront sensor to perform closed-loop correction for the moment. About 0.38lambda root mean square (rms) aberrations, including the deformable mirror's initial figure error, were compensated, and the residual error was less than 0.07lambda rms. Field observations with a 2 m optical telescope demonstrated that the peak intensity value of the laser guide star (LGS) spot increased from 5650 to 7658, and the full width at half-maximum (FWHM) size reduced from 4.07 arcseconds to 3.52 arcseconds. With the compensation, an improved guide star spot can be obtained, which is crucial for the adaptive optics systems of ground-based large telescopes. PMID- 29400725 TI - Room temperature slow light in an optical fiber with dual-frequency laser pumping. AB - We demonstrate room temperature optically controllable group delay using population oscillation in an Er3+-doped fiber under a dual-frequency pumping laser. Using the numerical calculations, we study the effect of the pump power ratio (M) on the time delay and the group velocity of slow light propagation. The maximum time delay of 0.70 ms under a dual-frequency pump laser with two directions is obtained. Compared with a single pump method, the time delay can be increased with dual-frequency laser pumping. Moreover, we demonstrate clearly the influence of M on the maximum fractional delay and the optimal modulation frequency with an input signal power of 4.0 mW. PMID- 29400726 TI - Analytical approach of Brillouin amplification over threshold. AB - We report on an accurate closed-form analytical model for the gain of a Brillouin fiber amplifier that accounts for material loss in the depleted pump regime. We determined the operational model limits with respect to its relevant parameters and pump regimes through both numerical and experimental validation. As such, our results enable accurate performance prediction of Brillouin fiber amplifiers operating in the weak-pump, high-gain, and saturation regimes alike. PMID- 29400727 TI - Ultra-widely tunable mid-infrared (6-18 MUm) optical vortex source. AB - We demonstrate the generation of an ultra-widely tunable mid-infrared (6-18 MUm) optical vortex output with a moderate pulse energy from a AgGaSe2 difference frequency generator pumped by an optical vortex parametric oscillator. The handedness of the vortex output can be controlled/selected by swapping the lasing frequencies of the signal and idler outputs and rotating the AgGaSe2 crystal by 90 deg. PMID- 29400728 TI - High-accuracy vibration sensor based on a Fabry-Perot interferometer with active phase-tracking technology. AB - A novel position-sensitive Fabry-Perot interferometer was constructed with direct phase modulation by a built-in electro-optic modulator. Pure sinusoidal phase modulation of the light was produced, and the first harmonic of the interference signal was extracted to dynamically maintain the interferometer phase to the most sensitive point of the interferogram. Therefore, the minute vibration of the object was coded on the variation of the interference signal and could be directly retrieved by the output voltage of a photodetector. The operating principle and the signal processing method for active feedback control of the interference phase have been demonstrated in detail. The developed vibration sensor was calibrated through a high-precision piezo-electric transducer and tested by a nano-positioning stage under a vibration magnitude of 60 nm and a frequency of 300 Hz. The active phase-tracking method of the system provides high immunity against environmental disturbances. Experimental results show that the proposed interferometer can effectively reconstruct tiny vibration waveforms with subnanometer resolution, paving the way for high-accuracy vibration sensing, especially for micro-electro-mechanical systems/nano-electro-mechanical systems and ultrasonic devices. PMID- 29400729 TI - Backscatter signals in underwater lidars: temporal and frequency features. AB - Backscatter signal formation in underwater lidar systems is studied and temporal and frequency characteristics are analyzed using the Monte Carlo technique. Both frequency and phase responses of the backscattered signal demonstrate similar dependencies, showing stronger frequency dependence in the high-frequency range. The beats of the frequency response due to dephasing of corresponding spectral harmonics are shown in the high-frequency range. Results of Monte Carlo simulations of the backscattered signal are in good agreement with the approximate analytical expression derived in the small-angle approximation; however, frequency responses calculated by the Monte Carlo technique and by small angle approximation demonstrate a difference in the high-frequency range due to interference effects, while the phase response demonstrated good agreement in the entire frequency range. PMID- 29400730 TI - Polarization-independent directional coupler and polarization beam splitter based on asymmetric cross-slot waveguides. AB - The polarization dependence of a directional coupler (DC) based on asymmetric cross-slot waveguides is investigated. Due to structural birefringence, the coupling behaviors of the quasi-TE and quasi-TM modes in the DC vary with the waveguide geometry. A polarization-independent directional coupler (PIDC) and polarization beam splitter (PBS) are proposed by tailoring the ratio of the coupling length for quasi-TE and quasi-TM modes. The simulated results show that the coupling lengths of the designed PIDC and PBS are 8 and 28.25 MUm, respectively. Both the PIDC and PBS show an insertion loss (IL) <0.7 dB on a bandwidth over 100 nm. The extinction ratios are ~20 dB for PIDC and ~14 dB for PBS. The fabrication-error tolerance of the practical devices is also discussed. In this study, we employ a commercial software tool for finite difference eigenmode and three-dimensional finite difference time domain methods to perform the numerical simulations. PMID- 29400731 TI - Investigation of a pressure-dependent refractive index of germanium film with an optical fiber film sensor. AB - The refractive index of Ge is found in decline with applied pressure at a specific wavelength in the absorption region below 1900 nm, where the absorption coefficient rises dramatically with decreased wavelength. In this paper, we use a Ge-coated fiber optic probe to demonstrate quantitatively that the downward trend in the refractive index to increasing pressure matches the theoretically simulated optical properties of Ge with a measurement error of 1.03*10-3 in the refractive index, which is further calculated within the framework of density functional theory with local density approximation. For the first time, to the best of our knowledge, both theoretical and experimental results prove that the refractive index reduces linearly with a gradient of -3.30*10-4/MPa as the pressure increases from 0 to 20 MPa. PMID- 29400732 TI - Tunable mechanisms of quantum efficiencies in CdSe and TiO2 quantum dot solar cells. AB - The absorption spectra of CdSe/ZnO and TiO2/MgZnO quantum dot (QD) solar cells were calculated, then their quantum efficiencies (QEs) were studied at different QD sizes and junction depths. Many mechanisms for tuning QE are examined. The first mechanism is doping the QD layer only, which is the case of CdSe, and it gives high QE. The second one is doping the bulk layer in addition to QDs, and it gives low QE but at a wide bandwidth, as in TiO2/MgZnO QD solar cells. Changing QD size is also another mechanism that can tune QE and its spectrum. The structures studied cover the range of 120-370 nm, which is important in photodetecting applications. PMID- 29400733 TI - Coherent anti-Stokes Raman scattering under frequency comb excitation. AB - We study the efficiency of coherent anti-Stokes Raman scattering (CARS) under frequency comb excitation. We calculate the power density of the anti-Stokes signal for two major cases: (1) molecular excitation by frequency comb and cw probe and, (2) both excitation and probing by frequency combs. In the first case, average CARS power varies as an inverse third degree of frequency combs free spectral range (FSR-3); in the second case, it varies as FSR-5. These results were applied to the CARS on blood glucose under frequency comb excitation. It was found that the resulting glucose CARS signal could approach nanowatt (nW) level at FSR=10 GHz. PMID- 29400734 TI - Finding trap stiffness of optical tweezers using digital filters. AB - Obtaining trap stiffness and calibration of the position detection system is the basis of a force measurement using optical tweezers. Both calibration quantities can be calculated using several experimental methods available in the literature. In most cases, stiffness determination and detection system calibration are performed separately, often requiring procedures in very different conditions, and thus confidence of calibration methods is not assured due to possible changes in the environment. In this work, a new method to simultaneously obtain both the detection system calibration and trap stiffness is presented. The method is based on the calculation of the power spectral density of positions through digital filters to obtain the harmonic contributions of the position signal. This method has the advantage of calculating both trap stiffness and photodetector calibration factor from the same dataset in situ. It also provides a direct method to avoid unwanted frequencies that could greatly affect calibration procedure, such as electric noise, for example. PMID- 29400735 TI - Zeonex-based asymmetrical terahertz photonic crystal fiber for multichannel communication and polarization maintaining applications. AB - We report on the design, in-depth analysis, and characterization of a novel elliptical array shaped core rectangular shaped cladded photonic crystal fiber (PCF) for multichannel communication and polarization maintaining applications of terahertz waves. The asymmetrical structure of air holes in both core and cladding results in increased birefringence, while a compact geometry and different cladding air hole size makes the dispersion characteristic flat. The modal characteristics of the PCF are calculated using a finite element method. The simulated results show a near-zero dispersion flattened property of +/-0.02 ps/THz/cm, high birefringence of 0.063, low effective material loss of 0.06 cm 1, and negligible confinement loss of 5.45*10-13 cm-1 in the terahertz frequency range. Additionally, the core power fraction, effective area, physical attributes, and potential fabrication possibilities of the fiber are discussed. PMID- 29400736 TI - Python-based dynamic scheduling assistant for atmospheric measurements by Bruker instruments using OPUS. AB - Atmospheric remote sensing by instruments such as spectrometers and interferometers often requires scheduling that is dependent on external factors, for example; time and solar (or lunar) zenith angle. Such instruments manufactured by Bruker often use the software package OPUS, which, while useful, is not flexible enough for automatic, repeated, atmospheric measurements of this nature. In this brief paper, we describe ASAP, a Python tool developed to run our network of Fourier transform interferometers in New Zealand and Antarctica. It allows the automated scheduling of measurements by time, lunar, or solar zenith angle while accounting for weather or other external parameters. There is a wide range of useful functions, all packaged in a simple graphical user interface; it is available on request. PMID- 29400737 TI - Multiple scattering of polarized light in birefringent slab media: experimental verifications and simulations. AB - The effective scattering Mueller matrices were measured for backward and forward scattering by applying a narrow polarized light on a polyacrylamide slab gel, which was strained vertically to generate birefringence inside. Monte Carlo simulations were performed in conditions that were the same as possible. The measured and simulated matrices were simplified to the reduced ones. They agreed well in both original and reduced forms. While they approximately take reciprocal forms for backward scattering, they approximately satisfy matrix forms that correspond to a reciprocal position of the mirror image for forward scattering. The reduced matrices were factorized by the Lu-Chipman polar decomposition to obtain the polarization parameters. The polarization parameters were in good agreement between the measurement and simulation and showed characteristic features of anisotropic slab media with a birefringence axis parallel to the slab surface. PMID- 29400738 TI - Phase unwrapping algorithm using polynomial phase approximation and linear Kalman filter. AB - A noise-robust phase unwrapping algorithm is proposed based on state space analysis and polynomial phase approximation using wrapped phase measurement. The true phase is approximated as a two-dimensional first order polynomial function within a small sized window around each pixel. The estimates of polynomial coefficients provide the measurement of phase and local fringe frequencies. A state space representation of spatial phase evolution and the wrapped phase measurement is considered with the state vector consisting of polynomial coefficients as its elements. Instead of using the traditional nonlinear Kalman filter for the purpose of state estimation, we propose to use the linear Kalman filter operating directly with the wrapped phase measurement. The adaptive window width is selected at each pixel based on the local fringe density to strike a balance between the computation time and the noise robustness. In order to retrieve the unwrapped phase, either a line-scanning approach or a quality guided strategy of pixel selection is used depending on the underlying continuous or discontinuous phase distribution, respectively. Simulation and experimental results are provided to demonstrate the applicability of the proposed method. PMID- 29400739 TI - Slowing down light using terahertz semiconductor metamaterial for dual-band thermally tunable modulator applications. AB - Compared to the neighboring infrared and microwave regions, the terahertz regime is still in need of fundamental technological advances. We have designed a terahertz (THz) semiconductor metamaterial (MM) waveguide system, which exhibits a significant slow-light effect, based on a classical electromagnetically induced transparency phenomenon. The potential of MMs for THz radiation originates from a resonant electromagnetic response that can be tailored for specific applications. By appropriately adjusting the distance between the two radiative and nonradiative modes, a flat band corresponding to a nearly constant group index (of the order of 4924) in the THz regime can be achieved. Finite-difference time domain simulations show that the incident pulse can be slowed down. The proposed device from a paucity of naturally occurring materials has useful applications in electronic or photonic properties at terahertz frequencies. This proposed compact configuration may find potential applications in plasmonic slow-light systems, optical buffers, and thermal and electromagnetic modulating applications and temperature sensors. PMID- 29400740 TI - Theoretical and experimental evaluation of piezo-optic parameters and photoelastic constant in tetragonal PWO. AB - The tetragonal PbWO4 (PWO) is one of the most important scintillating crystals, being used both in the Compact Muon Solenoid (CMS) experiment at the European Organization for Nuclear Research (CERN) and in the PANDA project at the Facility for Antiproton and Ion Research (FAIR). Light yield and other relevant scintillation properties depend, among many factors, also on the crystal mechanical quality. Accordingly, a detailed knowledge of crystal piezo-optic properties is a mandatory step toward understanding elasto-optic behavior and performing crystal quality control. In this paper, we evaluate for the first time, to the best of our knowledge, by means of both photoelastic and x-ray measurements, some components of the piezo-optic tensor; moreover, when the crystal is acted upon by a uniaxial stress, we obtain an evaluation for the rotation angle of the optic plane under stress as well as the photoelastic constant. These parameters are necessary to detect the residual stresses within the crystal, if any, and to give an overall quality measure. Such a methodology is in general suitable for any tetragonal crystals. PMID- 29400741 TI - Spatial characterization of light beams analyzed by cylindrical-grating slit-less spectrometers. AB - In this work, we theoretically analyze the spatial information provided by cylindrical-grating slit-less spectrometers. We raise attention on the often not considered property that the spatial features acquired using these spectrometers are different from what can be obtained using a spectrometer with an entrance slit. In relation to this, we also highlight that they do not provide information directly on the real spatial beam profile. It is important to consider this fact in spatio-spectral analysis of extreme ultraviolet radiation, often carried out using cylindrical-grating slit-less spectrometers. Since the models used are based on the Fresnel diffraction integral and ideal optical systems, the results are valid also for other spectral regions. PMID- 29400742 TI - Statistical and temporal irradiance fluctuations modeling for a ground-to geostationary satellite optical link. AB - An optical communication link performance between the ground and a geostationary satellite can be impaired by scintillation, beam wandering, and beam spreading due to its propagation through atmospheric turbulence. These effects on the link performance can be mitigated by tracking and error correction codes coupled with interleaving. Precise numerical tools capable of describing the irradiance fluctuations statistically and of creating an irradiance time series are needed to characterize the benefits of these techniques and optimize them. The wave optics propagation methods have proven their capability of modeling the effects of atmospheric turbulence on a beam, but these are known to be computationally intensive. We present an analytical-numerical model which provides good results on the probability density functions of irradiance fluctuations as well as a time series with an important saving of time and computational resources. PMID- 29400743 TI - Decomposition of group-velocity-locked-vector-dissipative solitons and formation of the high-order soliton structure by the product of their recombination. AB - By using a polarization manipulation and projection system, we numerically decomposed the group-velocity-locked-vector-dissipative solitons (GVLVDSs) from a normal dispersion fiber laser and studied the combination of the projections of the phase-modulated components of the GVLVDS through a polarization beam splitter. Pulses with a structure similar to a high-order vector soliton could be obtained, which could be considered as a pseudo-high-order GVLVDS. It is found that, although GVLVDSs are intrinsically different from group-velocity-locked vector solitons generated in fiber lasers operated in the anomalous dispersion regime, similar characteristics for the generation of pseudo-high-order GVLVDS are obtained. However, pulse chirp plays a significant role on the generation of pseudo-high-order GVLVDS. PMID- 29400744 TI - Time-domain fluorescence lifetime imaging by nonlinear fluorescence microscopy constructed of a pump-probe setup with two-wavelength laser pulses. AB - We propose a time-domain approach for fluorescence lifetime measurements using nonlinear fluorescence microscopy constructed of a pump-probe setup with two wavelength laser pulses. Nonlinear fluorescence signals generated by fluorescence reduction due to stimulated emission were detectable through a lock-in technique. Changing the time delay between the two-wavelength pulses enables acquisition of a time-resolved nonlinear fluorescence signal, which directly reflects the fluorescence lifetime of the sample and is thus applicable to fluorescence lifetime imaging. We also quantitatively demonstrate that nonlinear fluorescence microscopy possesses better optical resolution than conventional laser-scanning fluorescence microscopy. Experimental trials indicate that straightforward fluorescence lifetime imaging with high optical resolution is readily available. PMID- 29400745 TI - Investigation of focusing and correcting aberrations with binary amplitude and polarization modulation. AB - We investigate the focusing and correcting wavefront aberration of an optical wave using binary amplitude and polarization modulation. Focusing is performed by selectively modulating the field in different zones of the pupil to obtain on axis constructive interference at a given distance. The conventional Soret zone plate (binary amplitude profile) is expanded to a polarization Soret zone plate with twice the focusing efficiency. Binary pixelated devices that approximate the sinusoidal transmission profile of a Gabor zone plate by spatial dithering are also investigated with amplitude and polarization modulation. Wavefront aberrations are corrected by modulation of the field in the pupil plane to prevent destructive interference in the focal plane of an ideal focusing element. Polarization modulation improves the efficiency obtained by amplitude-only modulation, with a gain that depends on the aberration. Experimental results obtained with Cr-on-glass devices for amplitude modulation and liquid crystal devices operating in the Mauguin condition for polarization modulation are in very good agreement with simulations. PMID- 29400746 TI - Dynamic analysis and rotation experiment of an optical-trapped microsphere in air. AB - A dual-fiber optical trap system to trap and rotate a borosilicate microsphere has been proposed and experimentally demonstrated. The trapping system can be used as a probe to measure environmental parameters, such as torque, force, and viscosity of the surrounding medium. Under various conditions with different fiber misalignments, optical power, and fiber separation, the trapped sphere will exhibit three motion profiles including random oscillation, round rotation, and abnormal rotation. The power spectrum analysis method is used to measure rotation rates up to 385 Hz, which can be further increased by increasing laser power. In addition, simulation and experiment show consistent results in rotation rates and motion trajectory, which verifies the validity and accuracy of dynamic analysis. PMID- 29400747 TI - Broadband self-collimating phenomenon in a low-loss hybrid plasmonic photonic crystal. AB - A 2D planar self-collimating photonic crystal, based on a dielectric square lattice and a hexagonal lattice, is proposed. We demonstrate that the proposed structure can support the propagation of a hybrid surface plasmon polarition (SPP) mode with a loss of -0.017 dB/MUm, and the mode size is only 0.33 MUm. The defined figure of merit is one order of magnitude higher than that of the dielectric-metal structure. In addition, the self-collimating angle of more than 10 degrees can be tuned with a silica index change of 0.08. The proposed structure possesses broad operation bandwidth of 88 nm and 58 nm for a dielectric square lattice and a hexagonal lattice, respectively. These two kinds of photonic crystals promise potential applications in photonic modulators and SPP photonic devices. PMID- 29400748 TI - No-reference high-dynamic-range image quality assessment based on tensor decomposition and manifold learning. AB - The practical applications of the full-reference image quality assessment (IQA) method are limited. Here, we propose a new no-reference quality assessment method for high-dynamic-range (HDR) images. First, tensor decomposition is used to generate three feature maps of an HDR image, considering color and structure information of the HDR image. Second, for a given HDR image, because its first feature map contains its main energy and important structural feature information, manifold learning is used in the first feature map to find the inherent geometric structure of high-dimensional data in a low-dimensional manifold. In addition, the corresponding multi-scale manifold structure features are extracted from the first feature map. For the second and third feature maps of the HDR image, multi-scale contrast features are extracted, as they reflect the perceived detail contrast information of the HDR image. Finally, the extracted features are aggregated by support vector regression to obtain the objective quality prediction score of the HDR image. Experimental results show that the proposed method is superior to some representative full- and no reference methods, and even superior to the full-reference HDR IQA method, HDR VDP-2.2, on the Nantes database. The proposed method has a higher consistency with human visual perception. PMID- 29400749 TI - Lumen degradation analysis of LED lamps based on the subsystem isolation method. AB - The lumen degradation of LED lamps undergoing an accelerated aging test is investigated. The entire LED lamp is divided into three subsystems, namely, driver, lampshade, and LED light source. The parameters of output power [Watts (W)], transmittance (%), and lumen flux (lm) are adopted in the analysis of the degradation of the driver, lampshade, and LED light source, respectively. Two groups of LED lamps are aged under the ambient temperatures of 25 degrees C and 85 degrees C, respectively, with the aging time of 2000 h. The lumen degradation of the lamps is from 3.8% to 4.9% for the group under a temperature of 25 degrees C and from 10.6% to 12.7% for the group under a temperature of 85 degrees C. The LED light source is the most aggressive part of the three subsystems, which accounts for 70.5% of the lumen degradation of the LED lamp on average. The lampshade is the second degradation source, which causes 21.5% of the total amount on average. The driver is the third degradation source, which causes 6.5% under 25 degrees C and 2.8% under 85 degrees C of the total amount on average. PMID- 29400750 TI - Sensitivity of diffraction efficiency to period width errors for multilayer diffractive optical elements. AB - Multilayer diffractive optical elements (MLDOEs) can achieve broadband high efficiency in the hybrid refractive-diffractive optical systems. The reliable performance of MLDOEs requires high precision during manufacture. The microstructure period width errors should be well defined. In this work, the relationship between diffraction efficiency and different period width errors was analyzed with the rigorous electromagnetic method. Compared to results predicted by the most used scalar diffraction method, the effect of period width errors on diffraction efficiency is underrated. The simulation results showed that diffraction efficiency is sensitive to the period width errors. This research provides a reliable method to control the fabrication errors for fabricating MLDOEs. PMID- 29400751 TI - Image decomposition model Shearlet-Hilbert-L2 with better performance for denoising in ESPI fringe patterns. AB - In this paper, we propose an image decomposition model Shearlet-Hilbert-L2 with better performance for denoising in electronic speckle pattern interferometry (ESPI) fringe patterns. In our model, the low-density fringes, high-density fringes, and noise are, respectively, described by shearlet smoothness spaces, adaptive Hilbert space, and L2 space and processed individually. Because the shearlet transform has superior directional sensitivity, our proposed Shearlet Hilbert-L2 model achieves commendable filtering results for various types of ESPI fringe patterns, including uniform density fringe patterns, moderately variable density fringe patterns, and greatly variable density fringe patterns. We evaluate the performance of our proposed Shearlet-Hilbert-L2 model via application to two computer-simulated and nine experimentally obtained ESPI fringe patterns with various densities and poor quality. Furthermore, we compare our proposed model with windowed Fourier filtering and coherence-enhancing diffusion, both of which are the state-of-the-art methods for ESPI fringe patterns denoising in transform domain and spatial domain, respectively. We also compare our proposed model with the previous image decomposition model BL-Hilbert L2. PMID- 29400752 TI - High-sensitivity optical fiber relative humidity probe with temperature calibration ability. AB - A high-sensitivity optical fiber relative humidity (RH) sensing probe with the ability of temperature calibration is proposed and experimentally demonstrated. It consists of a simple Fabry-Perot interferometer constructed by coating a layer of thin polyimide (PI) film on the end face of single-mode fiber and an upstream fiber Bragg grating (FBG). PI is one of the organic polymer humidity-sensitive materials with good comprehensive properties. The cascaded FBG is used for temperature calibration and elimination of the temperature cross-sensitivity in the process of measuring RH. Experimental results show that this sensing probe can realize simultaneous measurement of temperature and RH. The RH response sensitivity reaches up to 986.25 pm/%RH. This sensing probe with the advantages of simple structure, compact size, high sensitivity, easy packaging, and dual parameter measurement has an extensive application prospect. PMID- 29400753 TI - Tunable plasmon-induced transparency in H-shaped Dirac semimetal metamaterial. AB - We present a numerical and theoretical study on the realization of tunable plasmon-induced transparency (PIT) effect at terahertz frequencies in Dirac semimetal (known as "three-dimensional graphene") metamaterials. Simulations reveal that the PIT effect is generated by an electric field transferred from the central strip to side strips due to the structural symmetry breaking. The most prominent feature is that the plasmonic resonance in Dirac semimetals can be actively tuned by changing the Fermi energy and an ultrahigh group delay of about 6.81 ps is obtained in our proposed design. Our study can provide guidance for various terahertz devices in practical applications. PMID- 29400754 TI - Characterization of the pinhole diffraction based on the waveguide effect in a point diffraction interferometer. AB - The nearly ideal spherical wavefront generated by pinhole diffraction is the key factor determining the achievable accuracy in point diffraction interferometers (PDIs), as it is employed as the reference wavefront. A comprehensive characterization of the diffraction of a pinhole at the operating-wavelength scale that is normally adopted in PDI is given. The incident light is coupled into the pinhole, which functions as a cylindrical waveguide, and is diffracted in the end. The field in the pinhole is analyzed based on mode theory and the diffraction wave in the far field is derived from the field equivalence principle. The diffraction wave is characterized by the light transmittance, the polarization, and the wavefront aberration, which are all determined by the properties of the mode in the pinhole. The diameter of the pinhole should not be smaller than 0.6lambda to make the transmittance sufficient. With a linearly polarized incident light, the diffraction wave is elliptically polarized, and the wavefront aberration is dominated by the astigmatic component. The method explicitly reveals the physical mechanism of pinhole diffraction. The analytic solutions are fast to compute, easy to analyze, and intuitively show the diffractive properties of the pinhole. The conclusions are significant for insight into the nature of pinhole diffraction and provide theoretical reference for analysis of numerical results and the design of PDI systems. PMID- 29400755 TI - Acceleration of diffraction calculations in cylindrically symmetrical optics. AB - We have significantly accelerated diffraction calculations using three independent acceleration devices. These innovations are restricted to cylindrically symmetrical systems. In the first case, we consider Wolf's formula for integrated flux in a circular region following diffraction of light from a point source by a circular aperture or a circular lens. Although the formula involves a double sum, we evaluate it with the effort of a single sum by use of fast Fourier transforms (FFTs) to perform convolutions. In the second case, we exploit properties of the Fresnel-Kirchhoff propagator in the Gaussian, paraxial optics approximation to achieve the propagation of a partial wave from one optical element to the next. Ordinarily, this would involve a double loop over the radial variables on each element, but we have reduced the computational cost by a factor approximately equal to the smaller number of radius values. In the third case, we reduce the number of partial waves, for which the propagation needs to be calculated, to determine the throughput of an optical system of interest in radiometry when at least one element is very small, such as a pinhole aperture. As a demonstration of the benefits of the second case, we analyze intricate diffraction effects that occur in a satellite-based solar radiometry instrument. PMID- 29400756 TI - Conventional soliton or stretched pulse delivered by nanotube-mode-locked fiber laser. AB - We propose a nanotube-mode-locked erbium-doped fiber laser that can deliver conventional solitons (CSs) or stretched pulses (SPs) based on a D-shaped fiber saturable absorber where evanescent-field interaction works. The net cavity dispersion of the laser is slightly negative. In our experiment, by optimizing the polarization controller in the cavity, CS and SP can be obtained at the central wavelengths of 1530.6 nm and 1530.3 nm due to carbon nanotubes and the spectral filtering effect induced by nonlinear polarization rotation. Although the acquired CS and SP nearly have the same central wavelengths, they show distinct optical spectra, 3-dB bandwidths. The proposed fiber laser is attractive for practical applications. PMID- 29400757 TI - Practical splicing of poly-methyl-methacrylate plastic optical fibers. AB - This Engineering and Laboratory Note describes a simple, fast, cost-effective, and practical splicing technique for poly-methyl-methacrylate (PMMA) plastic optical fibers. We believe this technique can be useful for home networks, laboratory research, and educational uses. It employs a widely available, low cost transparent adhesive combined with a suitable alignment sleeve. The fiber tips did not need to be cleaned or polished, and the polyethylene jacket did not need to be removed. The alignment between the cleaved fibers was performed by means of the jacket. Low insertion losses were measured for the main PMMA-based fiber types. PMID- 29400758 TI - Hybrid quantum receiver for quadrature amplitude modulation coherent-state discrimination beating the classical limit. AB - We present a quantum receiver for quadrature amplitude modulation (QAM) coherent state discrimination with the homodyne-displacement hybrid structure. Our strategy is to carry out two successive measurements on parts of the quantum states. The homodyne result of the first measurement reveals partial information about the state and is forwarded to a displacement receiver, which finally identifies the input state by using feedback to adjust a reference field. Theoretical analysis and numerical simulation results show that for 16-QAM, the hybrid receiver could outperform the standard quantum limit using only on-off single-photon detectors with a reduced number of signal-state partitions, showing great potential toward implementing the receiver practically. PMID- 29400759 TI - Use of a broadband monitoring system for the determination of the optical constants of a dielectric bilayer. AB - This paper extends a method previously applied to the determination of the optical constants of a high-index thin film to a dielectric bilayer. This method is based on the time recording of the spectral transmittance of the stack during its deposition with the help of an in situ broadband monitoring system. PMID- 29400760 TI - Alignment of sensor arrays in optical instruments using a geometric approach. AB - Alignment of sensor arrays in optical instruments is critical to maximize the instrument's performance. While many commercial systems use standardized mounting threads for alignment, custom systems require specialized equipment and alignment procedures. These alignment procedures can be time-consuming, dependent on operator experience, and have low repeatability. Furthermore, each alignment solution must be considered on a case-by-case basis, leading to additional time and resource cost. Here I present a method to align a sensor array using geometric analysis. By imaging a grid pattern of dots, I show that it is possible to calculate the misalignment for a sensor in five degrees of freedom simultaneously. I first test the approach by simulating different cases of misalignment using Zemax before applying the method to experimentally acquired data of sensor misalignment for an echelle spectrograph. The results show that the algorithm effectively quantifies misalignment in five degrees of freedom for an F/5 imaging system, accurate to within +/-0.87 deg in rotation and +/-0.86 MUm in translation. Furthermore, the results suggest that the method can also be applied to non-imaging systems with a small penalty to precision. This general approach can potentially improve the alignment of sensor arrays in custom instruments by offering an accurate, quantitative approach to calculating misalignment in five degrees of freedom simultaneously. PMID- 29400762 TI - Closed-loop laser polishing using in-process surface finish metrology. AB - This paper lays out the trail onto a closed-loop polishing process of optical elements enabling the application of the optimum polishing time needed. To that aim, an in-process testing method for monitoring an inclusive microsurface quality (e.g., comprising surface roughness and scratch-and-dig) within the polishing spot is analyzed, and its applicability to closed-loop polishing for classical loose-abrasive full-aperture polishing as well as for computer controlled laser polishing is experimentally tested and verified. This enables the determination of the optimum local dwell time resulting in stable and cost optimized polishing. PMID- 29400761 TI - Design and experimental verification of a photoacoustic flow sensor using computational fluid dynamics. AB - A photoacoustic (PA) sensor for fast and real-time gas sensing is demonstrated. The PA sensor is a stand-alone system controlled by a field-programmable gate array. The PA cell has been designed for flow noise immunity using computational fluid dynamics (CFD) analysis. The aim of the CFD analysis was to investigate and minimize the influence of the gas distribution and flow noise on the PA signal. PA measurements were conducted at different flow rates by exciting molecular C-H stretch vibrational bands of hexane (C6H14) and decane (C10H22) molecules in clean air at 2950 cm-1 (3.38 MUm) with a custom-made mid-infrared interband cascade laser. We observe a (1sigma, standard deviation) sensitivity of 0.4+/-0.1 ppb (nmol/mol) for hexane in clean air at flow rates up to 1.7 L/min, corresponding to a normalized noise equivalent absorption coefficient of 2.5*10-9 W cm-1 Hz-1/2, demonstrating high sensitivity and fast real-time gas analysis. An Allan deviation analysis for decane shows that the detection limit at optimum integration time is 0.25 ppbV (nmol/mol). PMID- 29400763 TI - Optimized digital speckle patterns for digital image correlation by consideration of both accuracy and efficiency. AB - The technique of digital image correlation (DIC), which has been widely used for noncontact deformation measurements in both the scientific and engineering fields, is greatly affected by the quality of speckle patterns in terms of its performance. This study was concerned with the optimization of the digital speckle pattern (DSP) for DIC in consideration of both the accuracy and efficiency. The root-mean-square error of the inverse compositional Gauss-Newton algorithm and the average number of iterations were used as quality metrics. Moreover, the influence of subset sizes and the noise level of images, which are the basic parameters in the quality assessment formulations, were also considered. The simulated binary speckle patterns were first compared with the Gaussian speckle patterns and captured DSPs. Both the single-radius and multi radius DSPs were optimized. Experimental tests and analyses were conducted to obtain the optimized and recommended DSP. The vector diagram of the optimized speckle pattern was also uploaded as reference. PMID- 29400764 TI - Exact surface profile measurement without subtracting dispersion phase through Fourier transform in a white-light scanning interferometer. AB - A new signal processing is proposed in which the dispersion phase is not subtracted from the detected spectral phase distribution. The linear and bias components in the spectral phase distribution are used to calculate the complex valued interference signal (CVIS). The simulations verify that the dispersion phase generates an inclination in the measured surface profile along one direction in which the magnitude of the dispersion phase changes linearly. The simulations also show that the position of zero phase nearest the position of amplitude maximum in the CVIS almost does not change due to the bias component, although the random phase noise contained in the interference signal changes the slope of the linear component. Measured surface profiles show that the new signal processing achieves highly accurate measurement by the CVIS. PMID- 29400765 TI - High-efficiency polarization-independent wideband multilayer dielectric reflective bullet-alike cross-section fused-silica beam combining grating. AB - A high-efficiency polarization-independent wideband multilayer dielectric reflective bullet-alike cross-section (combination of trapezoidal-rectangular grating profile) fused-silica beam combining grating (BCG) used in the -1st order for spectral beam combining (SBC) is designed and fabricated. Exact grating profile parameters are optimized by using the rigorous coupled-wave analysis and simulated annealing algorithm. As a comparison, traditional pure trapezoidal and pure rectangular gratings are also designed. Numerical results show that such a bullet-alike cross-section BCG exhibits wide bandwidth with the lowest maximum electric field enhancement in the grating material, which is greatly beneficial for the promotion of the power scaling level of the grating-based SBC system. A two-step dry-etching procedure is developed to fabricate such a grating. The averaged diffraction efficiency of greater than 91% was experimentally demonstrated. PMID- 29400766 TI - Tracking moving targets behind a scattering medium via speckle correlation. AB - Tracking moving targets behind a scattering medium is a challenge, and it has many important applications in various fields. Owing to the multiple scattering, instead of the object image, only a random speckle pattern can be received on the camera when light is passing through highly scattering layers. Significantly, an important feature of a speckle pattern has been found, and it showed the target information can be derived from the speckle correlation. In this work, inspired by the notions used in computer vision and deformation detection, by specific simulations and experiments, we demonstrate a simple object tracking method, in which by using the speckle correlation, the movement of a hidden object can be tracked in the lateral direction and axial direction. In addition, the rotation state of the moving target can also be recognized by utilizing the autocorrelation of a speckle. This work will be beneficial for biomedical applications in the fields of quantitative analysis of the working mechanisms of a micro-object and the acquisition of dynamical information of the micro-object motion. PMID- 29400767 TI - Volumetric calibration of a plenoptic camera. AB - The volumetric calibration of a plenoptic camera is explored to correct for inaccuracies due to real-world lens distortions and thin-lens assumptions in current processing methods. Two methods of volumetric calibration based on a polynomial mapping function that does not require knowledge of specific lens parameters are presented and compared to a calibration based on thin-lens assumptions. The first method, volumetric dewarping, is executed by creation of a volumetric representation of a scene using the thin-lens assumptions, which is then corrected in post-processing using a polynomial mapping function. The second method, direct light-field calibration, uses the polynomial mapping in creation of the initial volumetric representation to relate locations in object space directly to image sensor locations. The accuracy and feasibility of these methods is examined experimentally by capturing images of a known dot card at a variety of depths. Results suggest that use of a 3D polynomial mapping function provides a significant increase in reconstruction accuracy and that the achievable accuracy is similar using either polynomial-mapping-based method. Additionally, direct light-field calibration provides significant computational benefits by eliminating some intermediate processing steps found in other methods. Finally, the flexibility of this method is shown for a nonplanar calibration. PMID- 29400768 TI - Full-field fabric stress mapping by micro Raman spectroscopy in a yarn push-out test. AB - The full-field stress distribution of a two-dimensional plain fabric was mapped using micro Raman spectroscopy (MRS) through a novel yarn push-out test, simulating a quasi-static projectile impact on the fabric. The stress-strain relationship for a single yarn was established using a digital image correlation method in a single-yarn tensile test. The relationship between Raman peak shift and aramid Kevlar 49 yarn stress was established using MRS in a single-yarn tensile test. An out-of-plane loading test was conducted on an aramid Kevlar 49 plain fabric, and the yarn stress was measured using MRS. From the full-field fabric stress distribution, it can be observed that there is a cross-shaped distribution of high yarn stress; this result would be helpful in further studies on load transfer on a fabric during a projectile impact. PMID- 29400769 TI - Spectral optimization of phosphor-coated white LED for road lighting based on the mesopic limited luminous efficacy and IES color fidelity index. AB - The spectral optimization of phosphor-coated white LED (pc-WLED) with green and orange phosphors excited by blue chip for road lighting was investigated based on the mesopic limited luminous efficacy (LLEm) and IES (the Illuminating Engineering Society of North America) color fidelity index (Rf). The average LLEm of four road lighting standards of the USA and the UK decreases as Rf increases, but the optimal scotopic/photopic ratio increases slightly with Rf increases for a given correlated color temperature (CCT). The average LLEm could reach the highest of 339 lm/W for Rf=70, 326 lm/W for Rf=80, and 309 lm/W for Rf=90 at CCT=5000 K. Six real pc-WLEDs with different Rf at CCT~5000 K and with Rf~70 at different CCT were demonstrated. Compared with current pc-WLEDs with yttrium aluminum garnet doped with Ce3+ (YAG:Ce3+) phosphors, the average LLEm of six demonstrated pc-WLEDs will be over 5.0% and above. So, it is suggested that the road lighting should choose pc-WLEDs with high efficiency green phosphors (520 530 nm) instead of YAG:Ce3+ phosphors. PMID- 29400770 TI - Measuring optical activity with the internal reflection in a glass prism. AB - A novel internal reflection-based polarimeter and measurement method to characterize optically active substances is presented. The working principle relies on the phase difference acquired by s- and p-polarized light undergoing internal reflection: they interfere after passing through an analyzer and produce a minimum near the critical angle, whose position depends on the rotation angle imposed by the optically active sample. Since the location of the minimum does not depend on the laser power, the measurement is nearly insensitive to any power fluctuation. Furthermore, this low-cost device is rugged, very compact and stable, and practically immune to mechanical vibrations. It was used to measure concentrations of sucrose and fructose dissolved in distilled water and presented a resolution better than 0.04 degrees . PMID- 29400771 TI - Nanofinishing of BK7 glass using a magnetorheological solid rotating core tool. AB - Surface finishing is a promising method to improve the optical characteristics of crown glass. BK7 finds its applications in transmissive optics, i.e., lenses of binoculars, lenses of microscopes, lenses of telescopes, and light-emitting diodes. The magnetorheological (MR) nanofinishing of optical glasses using a solid rotating core tool is found more advantageous than the other advanced finishing processes in aspects such as precision and accuracy. In the present research, the MR nanofinishing with a solid rotating core tool is carried out on the BK7 glass of size 10*10*3 mm. Response surface methodology is conducted in order to find the optimum process parameters. The effects of process parameters on the percentage change in surface roughness are analyzed. The best surface roughness Ra and Rq values are achieved at 22 nm and 32 nm from the initial of 41 nm and 57 nm in 30 min of the finishing time cycle. To study the surface morphology of nanofinished BK7 glass, scanning electron microscopy is performed with sputter coating of gold on a glass specimen. PMID- 29400772 TI - Dynamic microscopic 3D shape measurement based on marker-embedded Fourier transform profilometry. AB - In recent years, the fringe projection profilometry (FPP) technique has shown great prospects in the field of dynamic 3D measurement of microscopic surface shape. However, under dynamic conditions, it is desirable to use fewer projected patterns to minimize the sensitivity to motion. The commonly used phase-shifting method needs at least three fringe patterns to retrieve the wrapped phase, which depends heavily on the high-speed hardware to alleviate the effect of motion. Besides, to achieve an unambiguous measurement, at least two wrapped phase maps are required to obtain the absolute phase map, resulting in six pattern projections. In this paper, we propose the marker-embedded Fourier transform profilometry (MEFTP), which extends the modified Fourier transform profilometry with two embedded markers suited to assist the phase-unwrapping process. Combining the embedded markers with temporal phase difference information, the absolute phase can be reliably reconstructed with only two projected patterns. Furthermore, since the phase information is only encoded within a single high frequency fringe, MEFTP is more suitable for measuring fast-moving or surface changing objects compared with the phase-shifting method. Experiments on both static and dynamic scenes are performed, verifying that our method can achieve an accurate and robust measurement of a vibrating diaphragm at the speed of 200 frames per second. PMID- 29400773 TI - Dual-view-zone tabletop 3D display system based on integral imaging. AB - In this paper, we propose a dual-view-zone tabletop 3D display system based on integral imaging by using a multiplexed holographic optical element (MHOE) that has the optical properties of two sets of microlens arrays. The MHOE is recorded by a reference beam using the single-exposure method. The reference beam records the wavefronts of a microlens array from two different directions. Thus, when the display beam is projected on the MHOE, two wavefronts with the different directions will be rebuilt and the 3D virtual images can be reconstructed in two viewing zones. The MHOE has angle and wavelength selectivity. Under the conditions of the matched wavelength and the angle of the display beam, the diffraction efficiency of the MHOE is greatest. Because the unmatched light just passes through the MHOE, the MHOE has the advantage of a see-through display. The experimental results confirm the feasibility of the dual-view-zone tabletop 3D display system. PMID- 29400774 TI - Multilayer graphene-based metasurfaces: robust design method for extremely broadband, wide-angle, and polarization-insensitive terahertz absorbers. AB - In this study, by using an equivalent circuit method, a polarization-insensitive terahertz (THz) absorber based on multilayer graphene-based metasurfaces (MGBMs) is systematically designed, providing an extremely broad absorption bandwidth (BW). The proposed absorber is a compact, three-layer structure, comprising square-, cross-, and circular-shaped graphene metasurfaces embedded between three separator dielectrics. The equivalent-conductivity method serves as a parameter retrieval technique to characterize the graphene metasurfaces as the components of the proposed circuit model. Good agreement is observed between the full-wave simulations and the equivalent-circuit predictions. The optimum MGBM absorber exhibits >90% absorbance in an extremely broad frequency band of 0.55-3.12 THz (BW=140%). The results indicate a significant BW enhancement compared with both the previous metal- and graphene-based THz absorbers, highlighting the capability of the designed MGBM absorber. To clarify the physical mechanism of absorption, the surface current and the electric-field distributions, as well as the power loss density of each graphene metasurface, are monitored and discussed. The MGBM functionality is evaluated under a wide range of incident wave angles to prove that the proposed absorber is omnidirectional and polarization-insensitive. These superior performances guarantee the applicability of the MGBM structure as an ultra-broadband absorber for various THz applications. PMID- 29400775 TI - Scattering phase function depolarization parameter model and its application to water droplets sizing using off-axis lidar measurements at multiple angles. AB - The backscattering lidar depolarization parameter D of water droplets contains information on their size that can be directly modeled as a function of the forward-scattering diffraction peak. Using a polarimetric Monte Carlo simulator, water clouds having different extinctions and droplet size distributions are analyzed to estimate their depolarization parameter at various backscattering off axis angles. It is shown that the depolarization parameter of the polarimetric phase function can be found using off-axis lidar measurements at multiple angles, and that it could be used to estimate the water-cloud droplet size. PMID- 29400776 TI - Multilevel data writing in nanoporous glass by a few femtosecond laser pulses. AB - Multidimensional data recording inside nanoporous high-silica glass by a femtosecond laser beam has been investigated. It is shown that three femtosecond laser pulses at pulse repetition rates up to 1 MHz are sufficient for recording 3 bits of information inside nanoporous glass, which is an order of magnitude lower than the number of pulses required for data writing in silica glass and provides a corresponding gain in the data writing speed. Multilayer data recording and reading were demonstrated providing the storage density corresponding to the capacity of 25 GB in the optical compact disc form factor. An outstanding thermal stability of the proposed optical data storage is confirmed by the 24 h long heat treatment at 700 degrees C, which could not damage the recorded data. PMID- 29400777 TI - Holographic scattering in an angular-multiplexed hologram on a photopolymer. AB - Holographic scattering (HS) is a phenomenon that occurs when a scattered light wave is recorded on a holographic recording medium and is important for applications using volume holograms, such as holographic data storage, three dimensional displays, and waveguides for head-mounted displays. We investigated the occurrence mechanism and characteristics of HS occurring in angular-multiplex recording of plane-wave holograms on a photopolymer. First, the reconstruction condition of the hologram formed by scattered light waves during multiplex recording is formulated. Then the diffracted light waves are visualized as the intensity distribution on a virtual screen. Using these results, we proposed a model of the HS-generation mechanism by the superposition of diffracted light waves and self-amplification of hologram reconstruction. The validity of the model is confirmed through experiments, and the diffraction efficiency of HS is measured and discussed. PMID- 29400778 TI - Fabrication of cerium-doped beta-Ga2O3 epitaxial thin films and deep ultraviolet photodetectors. AB - High-quality cerium-doped beta-Ga2O3 (Ga2O3:Ce) thin films could be achieved on (0001)alpha-Al2O3 substrates using a pulsed-laser deposition method. The impact of dopant contents concentration on crystal structure, optical absorption, photoluminescence, and photoelectric properties has been intensively studied. X ray diffraction analysis results have shown that Ga2O3:Ce films are highly (2-01) oriented, and the lattice spacing of the (4-02) planes is sensitive to the Ce doping level. The prepared Ga2O3:Ce films show a sharp absorption edge at about 250 nm, meaning a high transparency to deep ultraviolet (DUV) light. The photoluminescence results revealed that the emissions were in the violet-blue green region, which are associated with the donor-acceptor transitions with the Ce3+ and oxygen vacancies related defects. A simple DUV photodetector device with a metal-semiconductor-metal structure has also been fabricated based on Ga2O3:Ce thin film. A distinct DUV photoresponse was obtained, suggesting a potential application in DUV photodetector devices. PMID- 29400779 TI - Analysis of fluoroquinolones antibiotic residue in feed matrices using terahertz spectroscopy. AB - As antibiotic residue becomes more and more serious all over the world, a rapid and effective detection method is needed to evaluate the antibiotic residue in feed matrices to ensure food safety for consumers. In this study, three different kinds of fluoroquinolones (norfloxacin, enrofloxacin, and ofloxacin) in feed matrices were analyzed using terahertz (THz) spectroscopy, respectively. Meanwhile, pure fluoroquinolones and pure feed matrices were also measured in the same way. Then, the absorption spectra of all of the samples were extracted in the transmission mode. Pure norfloxacin has two absorption peaks at 0.825 and 1.187 THz, and they could still be observed when mixing norfloxacin with feed matrices. Also, there was an obvious and strong absorption peak for ofloxacin at 1.044 THz. However, no obvious absorption peak for enrofloxacin was observed, and only a weak absorption peak was located at 0.8 THz. Then, the different models were established with different chemometrics to identify the fluoroquinolones in feed matrices and determined the fluoroquinolones content in the feed matrices. The least squares support vector machines, Naive Bayes, Mahalanobis distance, and back propagation neural network (BPNN) were used to build the identification model with a Savitzky-Golay filter and standardized normal variate pretreatments. The results show that the excellent classification model was acquired with the BPNN combined with no pretreatment. The optimal classification accuracy was 80.56% in the testing set. After that, multiple linear regression and stepwise regression were used to establish the quantitative detection model for different kinds of fluoroquinolones in feed matrices. The optimal correlation coefficients for norfloxacin, enrofloxacin, and ofloxacin in the prediction set were obtained with multiple linear regression that combined absorption peaks with wavelengths selected by stepwise regression, which were 0.867, 0.828, and 0.964, respectively. Overall, this research explored the potential of identifying the fluoroquinolones in feed matrices using THz spectroscopy without a complex pretreatment process and then quantitatively detecting the fluoroquinolones content in feed matrices. The results demonstrate that THz spectra could be used to identify fluoroquinolones in feed matrices and also detect their content quantitatively, which has great significance for the food safety industry. PMID- 29400780 TI - Multi-aperture laser transmissometer system for long-path aerosol extinction rate measurement. AB - We present the theory, design, simulation, and experimental evaluations of a new laser transmissometer system for aerosol extinction rate measurement over long paths. The transmitter emits an ON/OFF modulated Gaussian beam that does not require strict collimation. The receiver uses multiple point detectors to sample the sub-aperture irradiance of the arriving beam. The sparse detector arrangement makes our transmissometer system immune to turbulence-induced beam distortion and beam wander caused by the atmospheric channel. Turbulence effects often cause spatial discrepancies in beam propagation and lead to miscalculation of true power loss when using the conventional approach of measuring the total beam power directly with a large-aperture optical concentrator. Our transmissometer system, on the other hand, combines the readouts from distributed detectors to rule out turbulence-induced temporal power fluctuations. As a result, we show through both simulation and field experiments that our transmissometer system works accurately with turbulence strength Cn2 up to 10-12 m-2/3 over a typical 1-km atmospheric channel. In application, our turbulence- and weather-resistant laser transmissometer system has significant advantages for the measurement and study of aerosol concentration, absorption, and scattering properties, which are crucial for directed energy systems, ground-level free-space optical communication systems, environmental monitoring, and weather forecasting. PMID- 29400781 TI - Fiber-coupled ultrashort-pulse-laser-based electronic-excitation tagging velocimetry. AB - Transmission of intense ultrashort laser pulses through hollow-core fibers (HCFs) is investigated for molecular-tagging velocimetry. A low-vacuumed HCF beam delivery system is developed to transmit high-peak-power pulses. Vacuum pressure effects on transmission efficiency and nonlinear effects at the fiber output are studied for 100 ps and 100 fs laser beams. With a 0.1 bar vacuum in the fiber, transmission efficiency increases by ~30%, while spectral broadening is reduced. A 1 m long, 1 mm core metal-dielectric-coated HCF can transmit ~45 mJ/pulse and ~2.9 mJ/pulse for 100 ps laser pulses (at 532 nm) and 100 fs laser pulses (at 810 nm), respectively. Proof-of-principle, single-laser-shot, fiber-coupled, ps and fs laser-based, nitrogen electronic-excitation tagging velocimetry is demonstrated in a free jet. Flow velocities are measured at 200 kHz to capture high-frequency flow events. PMID- 29400782 TI - Phase control of highly efficient four-wave mixing in a six-level tripod atomic system. AB - We investigate theoretically an enhancement of four-wave mixing (FWM) process in phase-dependent double electromagnetically induced transparency (EIT) six-level atomic media. It is shown, owing to the multiphoton destructive interference, that the conversion efficiency of FWM can be enhanced by manipulating the relative phase of the applied fields in this ultraslow propagation regime. Moreover, we also find that the conversion efficiency is amplified with the presence of the microwave field in comparison with the previous six-level scheme [Phys. Rev. A76, 043809 (2007)PLRAAN1050-294710.1103/PhysRevA.76.043809]. PMID- 29400783 TI - Continuous-wave and chemical vapor deposition graphene-based passively Q-switched Er:Y2O3 ceramic lasers at 2.7 MUm. AB - We report on 976-nm diode-pumped Er:Y2O3 ceramic lasers in continuous-wave and passively Q-switched regimes. The maximum output power of continuous-wave laser operation is about 0.78 W with slope efficiency of about 11.8% at 2.7 MUm. Passively Q-switched Er:Y2O3 ceramic laser operation with chemical vapor deposition (CVD) graphene as the saturable absorber is also demonstrated for the first time, to our knowledge. Using a monolayer CVD graphene, the achieved shortest pulse width is about 408 ns, while the shortest pulse width reduces to about 296 ns with pulse energy of 2.59 MUJ and peak power of 8.77 W by using a three-layer CVD graphene. The results reveal that graphene is a very promising saturable absorber operating in the middle infrared spectral region. PMID- 29400784 TI - Tapering of femtosecond laser-written waveguides. AB - The vast development of integrated quantum photonic technology enables the implementation of compact and stable interferometric networks. In particular, laser-written waveguide structures allow for complex 3D circuits and polarization encoded qubit manipulation. However, the main limitation in the scaling up of integrated quantum devices is the single-photon loss due to mode-profile mismatch when coupling to standard fibers or other optical platforms. Here we demonstrate tapered waveguide structures realized by an adapted femtosecond laser writing technique. We show that coupling to standard single-mode fibers can be enhanced up to 77% while keeping the fabrication effort negligible. This improvement provides an important step for processing multiphoton states on chip. PMID- 29400785 TI - Numerical study on supercontinuum generation by different optical modes in AsSe2 As2S5 chalcogenide microstructured fiber. AB - We investigate supercontinuum generation (SCG) in AsSe2-As2S5 chalcogenide microstructured optical fibers (MOFs) pumped by different optical modes. The influence on SCG by different optical modes including the fundamental and high order modes is analyzed numerically. The evolution of the supercontinuum (SC) is investigated by changing the pump wavelength (2120, 2580, and 3280 nm) and peak power (from 200 to 1000 W) of each optical mode (LP01,LP11,LP31) in the MOFs with different fiber lengths. SCG in MOFs with different core diameters is also simulated. The different optical modes cause the variation of the chromatic dispersion profile and the effective nonlinearity, which induces different mechanisms of the SCG and changes the spectral range. The maximum SC spectral range covers 12.931 MUm from 1.389 to 14.320 MUm when pumped by the LP11 mode with the peak power of 1000 W at 3280 nm. The simulated results will be instructive for the experimental SCG up to the midinfrared waveband longer than 10 MUm. PMID- 29400786 TI - Pixel-sized infrared filters for a multispectral focal plane array. AB - We present a theoretical study of guided-mode-resonance filters made of two sub wavelength metallic gratings and a dielectric waveguide, with lateral geometries compatible with the size of infrared focal plane array pixels. Contrary to most of the studies described in the literature, we consider here a focused beam on finite-sized filters, and we investigate the optical properties of a mosaic of 30 MUm-long filters. We demonstrate the spectral filtering ability and low crosstalk of such components. We also study the impact of an oblique beam onto a filtering mosaic. We finally discuss the opportunities offered by these results for a new generation of multispectral infrared cameras, and we give an example of a simple architecture. PMID- 29400787 TI - Panoramic stereo imaging system for efficient mosaicking: parallax analyses and system design. AB - Panoramic stereo images, captured by distributed devices then mosaicking, are competent contents for virtual reality applications. Mosaicking raw images with different perspectives into satisfying final results is still not efficient enough, even if state-of-the-art algorithms are employed. For improving this efficiency in optical methods, we delve into the potential of the capturing system. Two parallax factors, peak parallax and deviation of parallaxes, are proposed to assess the mosaicking capability. By controlling variables and numerical computation, rules between parallax factors and design parameters have been revealed. Validation by simulations, large capturing distance, more cameras, compact arrangement, and moderate overlaps are suggested as the general design strategy. Benefiting from efficient mosaicking, systems based on our design strategy would have potential for real-time applications. PMID- 29400788 TI - Qualitative and quantitative analysis of an additive element in metal oxide nanometer film using laser induced breakdown spectroscopy. AB - The photoelectric performance of metal ion-doped TiO2 film will be improved with the changing of the compositions and concentrations of additive elements. In this work, the TiO2 films doped with different Sn concentrations were obtained with the hydrothermal method. Qualitative and quantitative analysis of the Sn element in TiO2 film was achieved with laser induced breakdown spectroscopy (LIBS) with the calibration curves plotted accordingly. The photoelectric characteristics of TiO2 films doped with different Sn content were observed with UV visible absorption spectra and J-V curves. All results showed that Sn doping could improve the optical absorption to be red-shifted and advance the photoelectric properties of the TiO2 films. We had obtained that when the concentration of Sn doping in TiO2 films was 11.89 mmol/L, which was calculated by the LIBS calibration curves, the current density of the film was the largest, which indicated the best photoelectric performance. It indicated that LIBS was a potential and feasible measured method, which was applied to qualitative and quantitative analysis of the additive element in metal oxide nanometer film. PMID- 29400789 TI - Photodiode array for characterizing optical fibers. AB - An innovative approach is proposed and demonstrated for measuring the attenuation of light in optical fibers. The technique utilizes a silicon device containing a v-groove that positions the fiber and detector array along the v-groove. The detectors within the v-groove are designed to partially surround the fiber in order to maximize the coupling of scattered light from the fiber into each detector. PMID- 29400790 TI - Spatial phase-shift dual-beam speckle interferometry. AB - The spatial phase-shift technique has been successfully applied to an out-of plane speckle interferometry system. Its application to a pure in-plane sensitive system has not been reported yet. This paper presents a novel optical configuration that enables the application of the spatial phase-shift technique to pure in-plane sensitive dual-beam speckle interferometry. The new spatial phase-shift dual-beam speckle interferometry (SPS-DBSP) uses a dual-beam in-plane electronic speckle pattern interferometry configuration with individual aperture shears, avoiding the interference in the object plane by the use of a low coherence source, and different optical paths. The measured object is illuminated by two incoherent beams that are generated by a delay line, which is larger than the coherence length of the laser. The two beams reflected from the object surface interfere with each other at the CCD plane because of different optical paths. A spatial phase shift is introduced by the angle between the two apertures when they are mapped to the same optical axis. The phase of the in-plane deformation can directly be extracted from the speckle patterns by the Fourier transform method. The capability of SPS-DBSI is demonstrated by theoretical discussion as well as experiments. PMID- 29400791 TI - Quantification of tomographic PIV uncertainty using controlled experimental measurements. AB - The goal of this work was to experimentally quantify the uncertainty of three dimensional (3D) and three-component (3C) velocity measurements using tomographic particle image velocimetry (tomo-PIV). Controlled measurements were designed using tracer particles embedded in a solid sample, and tomo-PIV measurements were performed on the sample while it was moved both translationally and rotationally to simulate various known displacement fields, so the 3D3C displacements measured by tomo-PIV can be directly compared to the known displacements created by the sample. The results illustrated that (1) the tomo-PIV technique was able to reconstruct the 3D3C velocity with an averaged error of 0.8-1.4 voxels in terms of magnitude and 1.7 degrees -1.9 degrees in terms of orientation for the velocity fields tested; (2) view registration (VR) plays a significant role in tomo-PIV, and by reducing VR error from 0.6 degrees to 0.1 degrees , the 3D3C measurement accuracy can be improved by at least 2.5 times in terms of both magnitude and orientation; and (3) the use of additional cameras in tomo-PIV can extend the 3D3C velocity measurement to a larger volume, while maintaining acceptable accuracy. These results obtained from controlled tests are expected to aid the error analysis and the design of tomo-PIV measurements. PMID- 29400792 TI - Fabrication of blue light-blocking optical interference coatings by the solgel method. AB - We report on the solgel method of fabrication of thin films of high optical quality and with tunable index of refraction. The resulting coatings are hard, durable and robust against humidity and common organic solvents. Bragg mirrors and edge filters have been made by stacking these films. A blue light-blocking edge filter made by 2*21 stacked layers shows a transmittance of less than 1% in the stop band region while maintaining a high transmittance of over 80% in the rest of the visible spectral region with an integrated photopic transmittance of 89.7%. PMID- 29400794 TI - Non-contact temperature-independent random-displacement sensor using two fiber Bragg gratings. AB - We present a full-range displacement sensor system using two fiber Bragg gratings (FBGs). The magnetic-scale-combined FBGs allow the exploration of random position. The sinusoidal function variations are displayed by two detectors with a phase difference of 90 deg, and the optimal magnetic gap is explored through numerical simulations. The feasibility of the method is demonstrated in experiments that show the sinusoidal relation between center wavelength shifts with the linear displacement. Results showed that the amplitudes of the tensile compressive load were 446.1 MUepsilon and 434.7 MUepsilon, respectively, with linearity of 0.998 and 0.999 at 1.5 mm between the detector and the magnetic scale. These results demonstrate that the sensors can realize non-contact, temperature-independent and full-range measurement. PMID- 29400793 TI - Methods for quantitative infrared directional-hemispherical and diffuse reflectance measurements using an FTIR and a commercial integrating sphere. AB - We have developed methods to measure the directional-hemispherical (rho) and diffuse (rhod) reflectances of powders, liquids, and disks of powders and solid materials using a commercially available, matte gold-coated integrating sphere and Fourier transform infrared spectrometer. To determine how well the sphere and protocols produce quantitative reflectance data, measurements were made of three diffuse and two specular standards prepared by the National Institute of Standards and Technology (NIST), LabSphere Infragold and Spectralon standards, hand-loaded sulfur and talc powder samples, and water. Relative to the NIST measurements of the NIST standards, our directional hemispherical reflectance values are within +/-4% for four of the standards and within +/-7% for a low reflectance diffuse standard. For the three diffuse reflectance NIST standards, our diffuse reflectance values are within +/-5% of the NIST values. For the two specular NIST standards, our diffuse reflectance values are an order of magnitude larger than those of NIST, pointing to a systematic error in the manner in which diffuse reflectance measurements are made for specular samples using our methods and sphere. Sources of uncertainty are discussed in the paper. PMID- 29400795 TI - X-ray verification of an optically aligned off-plane grating module. AB - Off-plane x-ray reflection gratings are theoretically capable of achieving high resolution and high diffraction efficiencies over the soft x-ray bandpass, making them an ideal technology to implement on upcoming x-ray spectroscopy missions. To achieve high effective area, these gratings must be aligned into grating modules. X-ray testing was performed on an aligned grating module to assess the current optical alignment methods. Results indicate that the grating module achieved the desired alignment for an upcoming x-ray spectroscopy suborbital rocket payload with modest effective area and resolving power. These tests have also outlined a pathway towards achieving the stricter alignment tolerances of future x-ray spectrometer payloads, which require improvements in alignment metrology, grating fabrication, and testing techniques. PMID- 29400796 TI - Digital-holographic detection in the off-axis pupil plane recording geometry for deep-turbulence wavefront sensing. AB - This paper uses wave-optics and signal-to-noise models to explore the estimation accuracy of digital-holographic detection in the off-axis pupil plane recording geometry for deep-turbulence wavefront sensing. In turn, the analysis examines three important parameters: the number of pixels across the width of the focal plane array, the window radius in the Fourier plane, and the signal-to-noise ratio. By varying these parameters, the wave-optics and signal-to-noise models quantify performance via a metric referred to as the field-estimated Strehl ratio, and the analysis leads to a method for optimal windowing of the turbulence limited point spread function. Altogether, the results will allow future research efforts to assess the number of pixels, pixel size, pixel-well depth, and read noise standard deviation needed from a focal-plane array when using digital holographic detection in the off-axis pupil plane recording geometry for estimating the complex-optical field when in the presence of deep turbulence and detection noise. PMID- 29400797 TI - Bidirectional mode-division multiplexers with antireflection gratings. AB - A bidirectional mode-division multiplexer (BMDM) with antireflection gratings is designed, and its performance in terms of S-parameters is presented. A BMDM can (de)multiplex three modes with only two waveguides and a Bragg grating. The impact of return losses on the performance of BMDMs is studied and antireflection gratings are designed to reduce their effects. A theoretical analysis of the proposed (de)multiplexer is developed based on the perturbative coupled-mode theory. Analytical expressions for the coupled-mode equations of the proposed device are obtained, taking into account the effects of return losses. Both duty cycle and teeth depths of the antireflection gratings are determined based on optimizing a cost function. In addition, FDTD simulation of the proposed device is performed, and its S-parameters are obtained and studied. PMID- 29400798 TI - Heat suppression of the fiber coating on a cladding light stripper in high-power fiber laser. AB - We present a theoretical model for the thermal effect of the fiber coating on a high-power cladding light stripper, which is fabricated by chemical etching. For the input and output of the fiber coating, a novel segmented corrosion method and increasing attenuation method are proposed for heat suppression, respectively. The relationship between the attenuation and temperature rise of the fiber coating at the output is experimentally demonstrated. The temperature distribution of the fiber coating at the input as well as the return light power caused by scattering are measured for the etched fiber with different surface roughness values. The results suggest that the rise in temperature is primarily caused by the scattering light propagating into the coating. Finally, an attenuation of 27 dB is achieved. At a room temperature of 23 degrees C and input pump power of 438 W, the highest temperature of the input fiber coating decreases from 39.5 degrees C to 27.9 degrees C by segmented corrosion, and the temperature rise of the output fiber coating is close to 0. PMID- 29400799 TI - Polymer-coated FBG sensor for simultaneous temperature and strain monitoring in composite materials under cryogenic conditions. AB - A polymer-coated fiber Bragg grating (PCFBG) is examined for real-time temperature and strain monitoring in composite materials at cryogenic temperatures. The proposed sensor enables the simultaneous measurement of temperature and strain at extremely low temperatures by tracking the changes in the reflected center wavelengths from a pair of PCFBGs embedded in a composite material. The cryogenic temperature sensing was realized by introducing polymer coatings onto bare FBGs, which resulted in high temperature sensitivity under cryogenic conditions. A comparison of wavelength responses of the Bragg grating with and without a polymer coating toward temperatures ranging from 25 degrees C to -180 degrees C was performed. The polymer-coated FBG exhibited a sensitivity of 48 pm/ degrees C, which is 10 times greater than that of the bare FBGs. In addition, the encapsulation of the FBG in a capillary tube made it possible to evaluate the strain accumulated within the composite during operation under cryogenic conditions. PMID- 29400800 TI - Measurement of surface position by focusing an interference pattern of multiple apertures with a confocal system. AB - We propose a method to measure the position of a flat mirror based on the identification of the best focused interferogram on the mirror. The interferogram is generated using a wavefront-splitting interferometer in a confocal configuration. The wavefront is sampled with an array of identical circular apertures. We analyze experimentally and theoretically the diffraction pattern for one, two, and three apertures when they are focused on the mirror. For the theoretical analysis we solve numerically the Rayleigh-Sommerfeld integral, and for the experimental analysis we measure the axial irradiance and the square power of the interferogram as a function of the axial displacement of the mirror. The maximum of these measurements corresponds to the best focused interferogram. The experimental and theoretical results are in good agreement. We found that the uncertainty associated with the axial position of the mirror is reduced significantly (about 161 times) when we use the interferogram generated by three apertures in comparison with the diffraction pattern for one aperture. PMID- 29400801 TI - Dynamic changes in higher-order aberrations after correction of lower-order aberrations with adaptive optics in myopic and emmetropic eyes. AB - This study investigated the instantaneous changes of higher-order aberrations (HOAs) following lower-order aberrations (LOAs) correction with a closed-loop adaptive optics (AO) system in myopic and emmetropic eyes. Data were analyzed using generalized additive mixed models. Time-related changes in HOAs were modeled with two-piecewise linear regressions and were compared between myopic and emmetropic eyes. Both vertical coma and spherical aberrations shifted to the positive direction immediately after LOA correction. The fluctuations of the above values were significantly faster in myopic than in emmetropic eyes. Understanding these changes in HOAs following LOA correction may help in achieving better visual outcomes. PMID- 29400802 TI - All-optical switch based on doped graphene quantum dots in a defect layer of a one-dimensional photonic crystal. AB - We discuss the light pulse propagation in a one-dimensional photonic crystal doped by graphene quantum dots in a defect layer. The graphene quantum dots behave as a three-level quantum system and are driven by three coherent laser fields. It is shown that the group velocity of the transmitted and reflected pulses can be switched from subluminal to superluminal light propagation by adjusting the relative phase of the applied fields. Furthermore, it is found that by proper choice of the phase difference between applied fields, the weak probe field amplification is achieved through a one-dimensional photonic crystal. In this way, the result is simultaneous subluminal transmission and reflection. PMID- 29400803 TI - Surface relief and refractive index gratings patterned in chalcogenide glasses and studied by off-axis digital holography. AB - Surface relief gratings and refractive index gratings are formed by direct holographic recording in amorphous chalcogenide nanomultilayer structures As2S3 Se and thin films As2S3. The evolution of the grating parameters, such as the modulation of refractive index and relief depth in dependence of the holographic exposure, is investigated. Off-axis digital holographic microscopy is applied for the measurement of the photoinduced phase gratings. For the high-accuracy reconstruction of the wavefront (amplitude and phase) transmitted by the fabricated gratings, we used a computational technique based on the sparse modeling of phase and amplitude. Both topography and refractive index maps of recorded gratings are revealed. Their separated contribution in diffraction efficiency is estimated. PMID- 29400804 TI - Mode control in a multimode fiber through acquiring its transmission matrix from a reference-less optical system. AB - A simple imaging system, together with complex semidefinite programming, is used to generate the transmission matrix (TM) of a multimode fiber. Once the TM is acquired, we can modulate the phase of the input signal to induce strong mode interference at the fiber output. The optical design does not contain a reference arm, no internal reference signal is used, and no interferometric measurements are required. We use a phase-only spatial light modulator to shape the profile of the propagating modes, and the output intensity patterns are collected. The semidefinite program uses a convex optimization algorithm to generate the TM of the optical system using intensity only measurements. This simple, yet powerful, method can be used to compensate for modal dispersion in multimode fiber communication systems. It also yields great promise for the next generation biomedical imaging, quantum communication, and cryptography. PMID- 29400805 TI - Single-frequency blue laser fiber amplifier. AB - An all-fiber amplifier for a single-frequency blue laser was demonstrated for the first time, to the best of our knowledge. Over 150 mW continuous-wave single transverse-mode blue laser output was obtained with a 10 m 1000 ppm thulium-doped fluoride fiber pumped by a 1125 nm fiber laser at a power of 2 W. The output power was limited due to the onset of the competitive lasing at 783 nm. Photodarkening and photo-curing of the thulium-doped fiber amplifier were also studied and analyzed. PMID- 29400806 TI - Dual-polarization interference microscopy for advanced quantification of phase associated with the image field. AB - A new concept of dual-polarization spatial light interference microscopy (DPSLIM) is proposed and demonstrated experimentally. The method works with two orthogonally polarized modes in which signal and reference waves are combined to realize the polarization-sensitive phase-shifting, thus allowing advanced reconstruction of the phase associated with the image field. The image phase is reconstructed directly from four polarization encoded interference records by a single step processing. This is a progress compared with common methods, in which the phase of the image field is reconstructed using the optical path difference and the amplitudes of interfering waves, which are calculated in multiple-step processing of the records. The DPSLIM is implemented in a common-path configuration using a spatial light modulator, which is connected to a commercial microscope Nikon E200. The optical performance of the method is demonstrated in experiments using both polystyrene microspheres and live LW13K2 cells. PMID- 29400807 TI - Linear spectral response of a Fano-resonant graded-stub filter based on pillar photonic-crystal waveguides. AB - To achieve high spectral linearity, we developed a Fano-resonant graded-stub filter on the basis of a pillar-photonic-crystal (PhC) waveguide. In a numerical simulation, the availability of a linear region within a peak-to-bottom wavelength span was nearly doubled compared to that of a sinusoidal spectrum, which was experimentally demonstrated with a fabricated silicon-pillar PhC stub filter. The high linearity of this filter is suitable for optical modulators used in multilevel amplitude modulation. PMID- 29400808 TI - Optical orbital angular momentum: twisted light and chirality. AB - The question of how the orbital angular momentum of structured light might engage with chiral matter is a topic of resurgent interest. By taking account of electric quadrupole transition moments, it is shown that the handedness of the beam can indeed be exhibited in local chiral effects, being dependent on the sign of the topological charge. In the specific case of absorption, a significant interplay of wavefront structure and polarization is resolved, and clear differences in behavior are identified for systems possessing a degree of orientational order and for those that are randomly oriented. PMID- 29400809 TI - Fiber optics frequency comb enabled linear optical sampling with operation wavelength range extension. AB - Although the linear optical sampling (LOS) technique is powerful enough to characterize various advanced modulation formats with high symbol rates, the central wavelength of a pulsed local oscillator (LO) needs to be carefully set according to that of the signal under test, due to the coherent mixing operation. Here, we experimentally demonstrate wideband LOS enabled by a fiber optics frequency comb (FOFC). Meanwhile, when the broadband FOFC acts as the pulsed LO, we propose a scheme to mitigate the enhanced sampling error arising in the non ideal response of a balanced photodetector. Finally, precise characterizations of arbitrary 128 Gbps PDM-QPSK wavelength channels from 1550 to 1570 nm are successfully achieved, when a 101.3 MHz frequency spaced comb with a 3 dB spectral power ripple of 20 nm is used. PMID- 29400810 TI - Innovative scheme for high-repetition-rate imaging of CN radical. AB - We have employed, to the best of our knowledge, a novel excitation scheme to perform the first high-repetition-rate planar laser-induced fluorescence (PLIF) measurements of a CN radical in combustion. The third harmonic of a Nd:YVO4 laser at 355 nm due to its relatively large linewidth overlaps with several R branch transitions in a CN ground electronic state. Therefore, the 355 nm beam was employed to directly excite the CN transitions with good efficiency. The CN measurements were performed in premixed CH4-N2O flames with varying equivalence ratios. A detailed characterization of the high-speed CN PLIF imaging system is presented via its ability to capture statistical and dynamical information in these premixed flames. Single-shot CN PLIF images obtained over a HMX pellet undergoing self-supported deflagration are presented as an example of the imaging system being applied towards characterizing the flame structure of energetic materials. PMID- 29400811 TI - Accurate terahertz spectroscopy of supported thin films by precise substrate thickness correction. AB - We present a new approach for accurate terahertz time-domain spectroscopy of thin films deposited on dielectric substrates. Our approach relies on the simultaneous measurement of film and substrate, allowing for 15 nm-precise determination of the thickness variation between the sample and reference. Our approach allows for unprecedentedly accurate determination of the terahertz conductivity of the thin film. We demonstrate our approach on a 10 nm thin iron film deposited on a 500 MUm MgO substrate. We determine the Drude momentum relaxation time in iron to within 0.15 fs uncertainty. PMID- 29400812 TI - Inversion of water cloud lidar returns using the azimuthal dependence of the cross-polarization signal. AB - The contrast in the azimuthal pattern of cross-polarized lidar data is used directly to retrieve the extinction coefficient profile of water droplet clouds. Using a Monte Carlo simulation, we demonstrate that there is a simple mathematical relationship between the optical depth and the contrast of the cross polarization azimuthal pattern. This relationship is independent of the water cloud droplet size, cloud position, and extinction profile. The derivation of the extinction profile of a water droplet cloud is obtained directly using the simple mathematical relationship without performing lidar equation inversion. The technique is limited to spherical particles. PMID- 29400813 TI - Ultra-efficient nanoparticle trapping by integrated plasmonic dimers. AB - We numerically demonstrate that gold dimers coupled with a silicon-on-insulator waveguide enable an efficient plasmonic tweezing of dielectric nanobeads, having radii down to 50 nm. By means of a rigorous 3D finite difference time domain and simplified gradient force-based calculations, we investigate the effect of the gap size involved on the tweezing action. We also demonstrate that the scattering force helps the trapping in the proximity of the dimer, thanks to the establishment of light vortices. PMID- 29400814 TI - 12 mJ Yb:YAG/Cr:YAG microchip laser. AB - We have developed a quasi-continuous wave diode end-pumped cryogenically cooled Yb:YAG/Cr:YAG passively Q-switched microchip laser. A maximum energy of 12.1 mJ with 3.7 MW of peak power was obtained. To the best of our knowledge, this is the highest energy and peak power obtained by an Yb:YAG/Cr:YAG microchip laser so far. PMID- 29400815 TI - Magnetic and electric hotspots via fractal clusters of hollow silicon nanoparticles. AB - We show that fractal clusters of hollow Si nanoparticles provide both magnetic hotspots (MHs) and electric hotspots (EHs). The hollow size tailors the wavelength dependence of the field enhancement. In the wavelength window 400-750 nm, magnetic field intensity enhancements of 10-3790 and electric field intensity enhancements of 10-400 are achievable. Wavelength-tuned MHs and EHs allow better enhancement of Raman optical activity, fluorescence and circular dichroism of molecules, and so on. Si nanoparticles overcome the limitations of metallic ones, which provide only EHs at the price of heat perturbations on a nearby quantum emitter due to metallic ohmic losses. PMID- 29400816 TI - Tunable coupling of spin ensembles. AB - Spin ensembles are promising candidates for quantum memory units because they have long coherence time. Controlling the coupling between spin ensembles is necessary and important in quantum information processing. In this Letter, we propose a method to realize tunable coupling between spin ensembles by a superconducting flux qubit acting as a coupler. The resulting coupling can be used to high-fidelity speed up the adiabatic transfer of quantum information. PMID- 29400817 TI - Impulsive Raman spectroscopy via precision measurement of frequency shift with low energy excitation. AB - Stimulated Raman scattering (SRS) has recently become useful for chemically selective bioimaging. It is usually measured via modulation transfer from the pump beam to the Stokes beam. Impulsive stimulated Raman spectroscopy, on the other hand, relies on the spectral shift of ultrashort pulses as they propagate in a Raman active sample. This method was considered impractical with low energy pulses since the observed shifts are very small compared to the excitation pulse bandwidth, spanning many terahertz. Here we present a new apparatus, using tools borrowed from the field of precision measurement, for the detection of low frequency Raman lines via stimulated-Raman-scattering-induced spectral shifts. This method does not require any spectral filtration and is therefore an excellent candidate to resolve low-lying Raman lines (<200 cm-1), which are commonly masked by the strong Rayleigh scattering peak. Having the advantage of the high repetition rate of the ultrafast oscillator, we reduce the noise level by implementing a lock-in detection scheme with a wavelength shift sensitivity well below 100 fm. This is demonstrated by the measurement of low-frequency Raman lines of various liquid samples. PMID- 29400818 TI - Low-loss two-dimensional silicon photonic grating coupler with a backside metal mirror. AB - We design and fabricate a low-loss silicon photonic two-dimensional grating coupler that serves to couple light between standard single-mode fibers and single-mode waveguides in the silicon-on-insulator platform and to split both orthogonal polarization states. The efficiency of the fabricated device is enhanced by a backside metal mirror and reaches a record value of -1.8 dB with a 1 dB bandwidth of 32 nm around 1550 nm. The demonstrated coupling efficiency is 2.2 dB better than the conventional two-dimensional grating coupler without a metal mirror. PMID- 29400819 TI - Self-organized compound pattern and pulsation of dissipative solitons in a passively mode-locked fiber laser. AB - We experimentally observe soliton self-organization and pulsation in a passively mode-locked fiber laser. The optomechanical interaction in the optical fiber is key to the formation of equidistant soliton bunches. These solitons simultaneously undergo a pulsation process with a period corresponding to tens of the cavity round trip time. Using the dispersive Fourier transformation technique, we find that the Kelly sidebands in the shot-to-shot spectra appear periodically, synchronizing with the pulsation. PMID- 29400820 TI - Longitudinal pixel averaging for improved compensation in backscattering interferometry. AB - Longitudinal averaging of the interference pattern in a compensated backscattering interferometer provides improved compensation for temperature induced refractive index perturbations. Fringe pattern likeness between two discrete detection regions of an off-the-shelf microfluidic chip illuminated by an inexpensive diode laser scales with interrogation length. Averaging the intensity distribution along a 2.75 mm length of the channel results in a 750 fold reduction in sensitivity to temperature and a baseline noise level of 3*10-8 refractive index units (RIU). These observations enable nanoliter-volume interferometric measurements at a level of 10-7 RIU in the presence of a 2 degrees C temperature variation without the need for temperature control. PMID- 29400821 TI - Asterisk-shaped microstructured fiber for an octave coherent supercontinuum in a sub-picosecond region. AB - We selected two thermally matched silicate glasses with fair refractive index contrast and developed an asterisk-shaped all-solid microstructured optical fiber. The fiber presents a low, ultra-flat, and all-normal dispersion in a wide wavelength range, allowing for the generation of an octave-spanning coherent supercontinuum (SC) in a 20 dB dynamic range with 0.5 ps pump pulses at 1.55 MUm. This result improves pump pulse duration that is only ~100 fs, related to the broadband and highly coherent SC generation in fibers with all-normal dispersion. This enables broadband SC sources with all-fiber, high-power, and highly coherent properties. PMID- 29400822 TI - Ultraslow long-living plasmons with electromagnetically induced transparency. AB - We analytically examine propagation of surface plasmon polaritons (SPPs) at a thin metallic film between a glass substrate and an electromagnetically induced transparency (EIT) medium. High precision and high resolution in the frequency domain provided by EIT paves the way toward plasmonic group velocities' reduction, even by up to four orders of magnitude, and corresponding lifetime enhancement of SPPs up to microseconds. PMID- 29400823 TI - Spectrotemporal dynamics of a picosecond OPO based on chirped quasi-phase matching: erratum. AB - This erratum is to correct an error made in our paper [Opt. Lett.40, 280 (2015)OPLEDP0146-959210.1364/OL.40.000280] regarding the sign of the quasi-phase matching chirp rate. PMID- 29400824 TI - Dependence of quality factor on surface roughness in crystalline whispering gallery mode resonators. AB - We present an experimental study of the variation of quality factor (Q-factor) of WGM resonators as a function of surface roughness. We consider mm-size whispering gallery mode resonators manufactured with fluoride crystals, featuring Q-factors of the order of 1 billion at 1550 nm. The experimental procedure consists of repeated polishing steps, after which the surface roughness is evaluated using profilometry by white-light phase-shifting interferometry, while the Q-factors are determined using the cavity-ring-down method. This protocol permits us to establish an explicit curve linking the Q-factor of the disk-resonator to the surface roughness of the rim. We have performed measurements with four different crystals, namely, magnesium, calcium, strontium, and lithium fluoride. We have thereby found that the variations of Q-factor as a function of surface roughness is universal, in the sense that it is globally independent of the bulk material under consideration. We also discuss our experimental results in the light of theoretical estimates of surface scattering Q-factors already published in the literature. PMID- 29400825 TI - Splitting an optical vortex beam to study photonic orbit-orbit interactions. AB - We numerically and experimentally evidence photonic orbit-orbit interactions in freely propagating asymmetrical beams carrying orbital angular momentum. A Fresnel biprism is used to carry out the wavefront division of an optical vortex beam, generating two complementary asymmetrical beams. The optical orbital Hall effect is presented in the form of angular deviations from the beam's geometrical expectation. We also observe the rotation of the field transverse profile near the nominal propagation axis upon propagation, which direction depends on orbital momentum currents. PMID- 29400826 TI - Metamaterial engineered transparency due to the nullifying of multipole moments. AB - Here we propose, to the best of our knowledge, a novel transparency effect in cylindrical all-dielectric metamaterials. We show that the cancellation of multipole moments of the same kind leads to almost zero radiation losses in all dielectric metamaterials due to the counter-directed multipolar moments in metamolecule. The nullifying of multipoles, mainly dipoles, and suppression of higher multipoles, results in the ideal transmission of an incident wave through the designed metamaterial. The observed effect could pave the road to the new generation of light-manipulating transparent metadevices such as filters, waveguides, and cloaks. PMID- 29400827 TI - InP femtosecond mode-locked laser in a compound feedback cavity with a switchable repetition rate. AB - A monolithically integrated mode-locked semiconductor laser is proposed. The compound ring cavity is composed of a colliding pulse mode-locking (ML) subcavity and a passive Fabry-Perot feedback subcavity. These two 1.6 mm long subcavities are coupled by using on-chip reflectors at both ends, enabling harmonic mode locking. By changing DC-bias conditions, optical mode spacing from 50 to 450 GHz is experimentally demonstrated. Ultrafast pulses shorter than 0.3 ps emitted from this laser diode are shown in autocorrelation traces. PMID- 29400828 TI - Active frequency matching in stimulated Brillouin amplification for production of a 2.4 J, 200 ps laser pulse. AB - A frequency matching Brillouin amplification in high-power solid-state laser systems is proposed. The energy extraction efficiency could be maintained at a high level in a non-collinear Brillouin amplification structure using an exact Stokes frequency shift. Laser pulses having a width of 200 ps and energy of 2.4 J were produced. This method can be used to transfer energy from a long pulse to a short pulse through a high-power solid-state laser system. PMID- 29400829 TI - Performance enhancement of AlGaN-based 365 nm ultraviolet light-emitting diodes with a band-engineering last quantum barrier. AB - In this Letter, the characteristics of the AlGaN-based near-ultraviolet light emitting diodes with a band-engineering last quantum barrier (LQB) were analyzed experimentally and numerically. The experimental results show that the peak wavelengths of UV-LEDs are around 368 nm with a full width at half-maximum of 12 14 nm, and the optical and electrical properties are improved by using an AlxGa1 xN LQB with a gradually decreasing Al content. The designed LQB can reduce the forward voltage from 4.35 to 4.29 V and markedly enhance LOP by 47.4% at an injection current of 200 mA, compared with the original structure. These improvements are mainly attributed to less electron leakage and higher hole injection efficiency, resulting from the weakened polarization field in the electron-blocking layer (EBL) and LQB, as well as the alleviation of the band bending at the EBL/LQB interface. PMID- 29400830 TI - Terahertz Dyakonov surface waves in plasma metamaterials. AB - Metamaterials in which plasmas are included have significant properties that may not be found in ordinary metamaterials. The permittivity function of these engineered materials can be rapidly manipulated by applying external electric and magnetic field or changing the gas pressure, temperature, and collisional frequency. We investigate the conditions necessary for the existence of Dyakonov surface waves (DSWs) propagating along the interface of a plasma metamaterial (PMM) and an isotropic dielectric material in the terahertz region. We assume the PMM to be a multilayer structure that consists of plasma and background isotropic material alternately. The influence of considering the plasma collisional loss in the DSW dispersion curve is studied. We demonstrate that the angular regions in which the DSW propagation is allowed can be tuned and significantly expanded. We also show that the large birefringence represented by the PMM allows DSWs to exist within large angular existence domains and levels of localization similar to plasmons, thus making these surface waves available for practical applications. PMID- 29400831 TI - Abnormal nonlinear optical properties of hybrid graphene-TiO2 nanostructures. AB - The nonlinear optical (NLO) properties of graphene-TiO2 nanoparticle (GNP) composite and graphene-TiO2 nanowire composite (GNW) are investigated by spatial self-phase modulation (SSPM) and Z-scan. The SSPM results of the GNP and GNW show that they possess strong self-diffraction effects at 1100 nm and no signal at 700 nm, which is different from all previous reports of other two-dimensional materials. A possible mechanism is that NLO behaviors are dominated by TiO2 at the visible wavelength, while by graphene at a near-infrared wavelength. The Z scan results of the GNP and GNW show reverse saturable absorption (RSA) at 700 nm, but saturable absorption (SA) at 1100 nm. Our results demonstrate that, by choosing appropriate coupling, we could design two-dimensional materials that have specific NLO properties at particular wavelengths. PMID- 29400832 TI - Cloaking of metal grid electrodes on Lambertian emitters by free-form refractive surfaces. AB - We discuss invisibility cloaking of metal grid electrodes on Lambertian light emitters by using dielectric free-form surfaces. We show that cloaking can be ideal in geometrical optics for all viewing directions if reflections at the dielectric-air interface are negligible. We also present corresponding white light proof-of-principle experiments that demonstrate close-to-ideal cloaking for a wide range of viewing angles. Remaining imperfections are analyzed by ray tracing calculations. The concept can potentially be used to enhance the luminance homogeneity of large-area organic light-emitting diodes. PMID- 29400833 TI - Compact assembly-free vector bend sensor based on all-in-fiber-core Mach-Zehnder interferometer. AB - A novel low-cost, compact, assembly-free and sensitive optical fiber curvature sensor is presented. This device consists of an off-axis positive refractive index modified zone (PRIMZ), induced by a direct femtosecond laser, written in a single-mode fiber (SMF) core. The PRIMZ transforms the original SMF section into a few-mode fiber (FMF). As a result, the whole fiber forms an assembly-free "SMF FMF-SMF" sandwich Mach-Zehnder interferometer. When the device is bent, a direction-dependent spectral shift of the interference pattern is produced. The sensitivity of the sensor is up to 2.53 and 2.24 nm/m-1 for the 0 degrees and 180 degrees orientations in a wide bend range (from 0 to 4 m-1). In addition, the device is immune to the surrounding refractive index and has a low temperature crosstalk, which makes it very attractive for practical structural monitoring applications. PMID- 29400834 TI - High-power Yb-based all-fiber laser delivering 300 fs pulses for high-speed ablation-cooled material removal. AB - We report on a 72 W Yb all-fiber ultrafast laser system with 1.6 GHz intra-burst and 200 kHz burst repetition rate developed to demonstrate ablation-cooled material removal at high speeds. Up to 24 W is applied on Cu and Si samples with pulses of ~300 fs, and record-high ablation efficiencies are obtained, compared to published results to date, despite using only ~100 nJ pulses. Ablation speeds approaching 1 mm3/s are reported with 24 W of average power, limited by available laser power and beam scanning speed. More significantly, these results experimentally confirm the theoretically expected linear scaling of the ablation cooled regime to higher average powers without sacrificing efficiency, which implies that further scaling is possible with further increases in laser power and scanning speeds. PMID- 29400835 TI - 30.5-MUJ, 10-kHz, picosecond optical parametric oscillator pumped synchronously and intracavity by a regenerative amplifier. AB - We have proposed a novel approach to realize a high-energy ultrafast optical parametric oscillator (OPO) by intracavity pumping in a regenerative amplifier. In this way, we have experimentally demonstrated an unprecedented pulse energy of 30.5 MUJ from a 1.5-MUm singly resonant synchronously pumped OPO at a pulse repetition rate of 10 kHz with a pulse width of 7.0 ps. To the best of our knowledge, this is the highest pulse energy from an ultrafast laser OPO. PMID- 29400836 TI - Terahertz ptychography. AB - We realized a phase retrieval technique using terahertz (THz) radiation as an alternative to THz digital holography, named THz ptychography. Ptychography has been used in x-ray imaging as a groundbreaking improvement of conventional coherent diffraction imaging. Here we show that ptychography can be performed at THz frequencies too. We reconstructed an amplitude and a phase object with both simulated and real data. Lateral resolution accounts to <2lambda, while depth variations as low as lambda/30 can be assessed. PMID- 29400837 TI - Counter-rotating cavity solitons in a silicon nitride microresonator. AB - We demonstrate the generation of counter-rotating cavity solitons in a silicon nitride microresonator using a fixed, single-frequency laser. We demonstrate a dual three-soliton state with a difference in the repetition rates of the soliton trains that can be tuned by varying the ratio of pump powers in the two directions. Such a system enables a highly compact, tunable dual comb source that can be used for applications such as spectroscopy and distance ranging. PMID- 29400838 TI - Femtosecond laser tagging for velocimetry in argon and nitrogen gas mixtures. AB - Tagging is demonstrated in argon and nitrogen gases using a femtosecond laser with pulse energies of approximately 70 MUJ through a nonresonant ionization process at 267 nm. The signal fluorescence lifetime in pure argon and nitrogen argon mixtures are measured and found to be long enough to make mean velocity and turbulence measurements in a subsonic flow. In pure argon, the dominating processes involve atomic transitions between 700 and 900 nm. In argon-nitrogen mixtures, nitrogen quenches atomic argon species and the dominant radiating processes are transitions in the nitrogen second positive system. In pure nitrogen, emission on the microsecond time scale comes from the nitrogen first positive system. Lower energy density is needed for tagging and narrower tagged lines are produced using 267 nm as compared to femtosecond laser tagging in argon and nitrogen using 400 nm or 800 nm. Velocimetry using the 267 nm line is demonstrated in a turbulent argon pipe flow and the Taylor microscale of the flow is determined. PMID- 29400839 TI - Reconfigurable photonic microwave convolver for pulse compression of a phase coded microwave waveform. AB - A reconfigurable photonic microwave convolver is proposed. The scheme simply consists of the evenly spaced optical carriers (ESOCs), an optical dispersion module (ODM), a wavelength selector (WS), and a balanced photodetector. By adjusting the ESOCs, the dispersion value of the ODM, and the setup of the WS, the proposed convolver is reconfigurable. With the convolver, pulse compressions of the phase-coded microwave waveforms (PCMWs) are realized. Compressions of two PCMWs with different code patterns and respective coding rates of 1.8 and 3.6 Gbit/s are experimentally demonstrated. Full widths at half-maximum (FWHMs) of the main lobe are 0.56 and 0.28 ns, and the peak-to-side lobe ratios are 11.1 and 10.8 dB, respectively. The results are in agreement with the theoretical values. Besides, due to the flexible reconfigurability, it can adapt to various PCMWs by simple operation. PMID- 29400840 TI - Diameter measurement of optical nanofiber based on high-order Bragg reflections using a ruled grating. AB - A convenient method using a commercially available ruled grating for precise and overall diameter measurement of optical nanofibers (ONFs) is presented. We form a composite Bragg reflector with a micronscale period by dissolving aluminum coating, slicing the grating along ruling lines, and mounting it on an ONF. The resonant wavelengths of high-order Bragg reflections possess fiber diameter dependence, enabling nondestructive measurement of the ONF diameter profile. This method provides an easy and economic diagnostic tool for wide varieties of ONF based applications. PMID- 29400841 TI - Large brightness enhancement for quasi-continuous beams by diamond Raman laser conversion. AB - High average power lasers with high beam quality are critical for emerging applications in industry and research for defense, materials processing, and space applications. However, overcoming thermal effects in the gain medium remains the key challenge for increasing laser brightness at high powers. Here we report a means for increasing the beam brightness of high-power continuous-wave (CW) beams based on external cavity Raman lasers using diamond, a material with thermal properties far superior to any other laser material. With pump beam quality in the range M2=2.3-7.3, efficient pump-limited conversion to an M2=1.1 Stokes beam is achieved in all cases, with increases in brightness from the pump by factors as high as 12.7. The influence of pump beam quality on laser threshold and slope efficiency is analyzed. This Letter foreshadows an alternative approach for scaling the brightness of CW lasers using high-power, moderate beam quality pumps up to M2=20 or more, such as thin-disk and slab lasers and fiber lasers operating in a mode instability regime. PMID- 29400842 TI - Raman fiber laser with random distributed feedback based on a twin-core fiber. AB - An operation of a linearly polarized Raman fiber laser with random distributed feedback based on a polarization-maintaining twin-core fiber (TCF) is demonstrated for the first time, to the best of our knowledge. The results indicate that the TCF allows one to obtain laser generation with a linewidth that is about five times smaller than that for the random laser based on a conventional fiber with similar parameters. The reasons for narrowing include both the weakening of nonlinear effects due to the power density reduction and the spectrally selective properties of the TCF. PMID- 29400843 TI - Performance enhancement using a stable low-pretilt molecular configuration and a novel driving method for optically compensated bend liquid crystal devices. AB - A stable low-pretilt molecular configuration (SLPMC) is successfully developed in optically compensated bend (OCB) liquid crystal (LC) devices by simultaneously employing the curing voltage and surface-anchored crosslinking monomer during the polymerization process. For the SLPMC OCB cell with the low-bend state, the warm up voltage making the LC molecules reorient from the splay to the bend state is annihilated, and the transient twist state occurring as the driven LC molecules recover from the bend to the splay state is also eliminated. In addition, with the novel driving method selecting the specific driving point, the proposed SLPMC OCB cell not only exhibits a good response performance, but also outputs a higher light transmittance, which is superior to the conventional OCB and no-bias-bend cells. This Letter demonstrates an effective SLPMC fabrication method, and points out the significant contributions of SLPMC on the electro-optical properties, which will benefit and enhance the performance design in OCB-based applications. PMID- 29400844 TI - Bound states in the continuum in a two-dimensional PT-symmetric system. AB - We address a 2D parity-time (PT)-symmetric structure built as a chain of waveguides, where all waveguides except for the central one are conservative, while the central one is divided into two halves with gain and losses. We show that such a system admits bound states in the continuum (BICs) whose properties vary drastically with the orientation of the line separating amplifying and absorbing domains, which sets the direction of internal energy flow. When the flow is perpendicular to the chain of the waveguides, narrow BICs emerge when the standard defect mode, which is initially located in the finite gap, collides with another mode in a standard symmetry breaking scenario, and its propagation constant enters the continuous spectrum upon increase of the strength of gain/losses. In contrast, when the energy flow is parallel to the chain of the waveguides, the symmetry gets broken even for a small strength of the gain/losses. In that case, the most rapidly growing mode emerges inside the continuous spectrum and realizes a weakly localized BIC. All BICs found here are the most rapidly growing modes; therefore, they can be excited from noisy inputs and, importantly, should dominate the beam dynamics in experiments. PMID- 29400845 TI - High-speed waveguide photodetector for 64 Gbaud coherent receiver. AB - A high-speed waveguide photodetector has been successfully fabricated for an integrated coherent receiver. Dual laterally tapered structures are introduced for a spot-size converter. We optimize the responsivity and the polarization dependent loss of the spot-size converter-integrated waveguide photodetector through the beam propagation method simulation. The waveguide photodetector is designed with electrical as well as optical optimizations. The photodetector provides sufficient alignment tolerance, high responsivity of 0.73 A/W, and low polarization-dependent loss of 0.27 dB, which is in good agreement with the simulation results. By increasing the thickness of the matching layer and the n doped upper taper, the electrical properties of the photodetector are enhanced. The photodetector has a 3 dB bandwidth of 45 GHz, providing high-speed operation. Through the electrical and optical optimizations, we successfully obtain the high speed waveguide photodetector for a 64 Gbaud integrated coherent receiver. PMID- 29400846 TI - Simultaneous frequency upconversion and phase coding of a radio-frequency signal for photonic radars. AB - We report a photonic approach to simultaneously realize frequency upconversion and phase coding of a radio-frequency (RF) signal based on polarization manipulation of optical signals. An intermediate frequency (IF) signal is upconverted to the local frequency (LO) band using a dual-polarization dual parallel Mach-Zehnder modulator, while a high-speed polarization modulator is used to realize high-speed phase coding of the upconverted signal. The key advantage of the proposed method is that no optical or electrical filters are required to remove the residual IF, LO, and undesired downconverted signals, which ensures a broad operation bandwidth, excellent isolation, and wide tunability. The proposed scheme is theoretically analyzed and experimentally verified. PMID- 29400847 TI - Interplay of Kerr and Raman beam cleaning with a multimode microstructure fiber. AB - We experimentally study the competition between Kerr beam self-cleaning and Raman beam cleanup in a multimode air-silica microstructure optical fiber. Kerr beam self-cleaning of the pump is observed for a certain range of input powers only. Stokes Raman beam generation and cleanup lead to both depletion and degradation of beam quality for the pump. The interplay of modal four-wave mixing and Raman scattering in the infrared domain leads to the generation of a multimode supercontinuum ranging from 500 nm up to 1800 nm. PMID- 29400849 TI - Devising genuine twisted cross-spectral densities. AB - Sticking a twist to a partially coherent source cannot be done at will, since the result can violate the definiteness property of the corresponding cross-spectral density. As a matter of fact, the study of twisted sources has been mainly concentrated on the original case proposed by Simon and Mukunda [J. Opt. Soc. Am. A10, 95 (1993)JOAOD60740-323210.1364/JOSAA.10.000095] of circularly symmetric Gaussian Schell-model sources. Here, we discuss a modeling procedure that can be used to generate numberless genuine twisted sources without symmetry constraints. As geometrically simple examples, two cases of non-Gaussian twisted sources endowed with circular or rectangular symmetry are explicitly worked out. PMID- 29400848 TI - nBn extended short-wavelength infrared focal plane array. AB - An extended short-wavelength nBn InAs/GaSb/AlSb type-II superlattice-based infrared focal plane array imager was demonstrated. A newly developed InAs0.10Sb0.90/GaSb superlattice design was used as the large-bandgap electron barrier in this photodetector. The large band gap electron-barrier design in this nBn photodetector architecture leads to the device having lower dark current densities. A new bi-layer etch-stop scheme using a combination of InAs0.91Sb0.09 bulk and AlAs0.1Sb0.9/GaSb superlattice layers was introduced to allow complete substrate removal and a shorter wavelength cut-on. Test pixels exhibit 100% cutoff wavelengths of ~2.30 and ~2.48 MUm at 150 and 300 K, respectively. The devices achieve saturated quantum efficiency values of 59.7% and 63.8% at 150 and 300 K, respectively, under backside illumination and without any antireflection coating. At 150 K, photodetectors exhibit dark current density of 8.75*10-8 A/cm2 under -400 mV applied bias, providing specific detectivity of 2.82*1012 cm.Hz1/2/W at 1.78 MUm. At 300 K, the dark current density reaches 4.75*10-2 A/cm2 under -200 mV bias, providing a specific detectivity of 8.55*109 cm.Hz1/2/W 1.78 MUm. PMID- 29400850 TI - Time-multiplexed light field synthesis via factored Wigner distribution function. AB - An optimization algorithm for preparing display-ready holographic elements (hogels) to synthesize a light field is outlined, and proof of concept is experimentally demonstrated. This method allows for higher-rank factorization, which can be used for time-multiplexing multiple frames for improved image quality, using phase-only and fully complex modulation with a single spatial light modulator. PMID- 29400851 TI - Broadband femtosecond nonlinear optical properties of CsPbBr3 perovskite nanocrystals. AB - We report the broadband nonlinear optical (NLO) properties of CsPbBr3 perovskite films achieved from colloidal nanocrystals prepared following a room temperature and open atmosphere anti-solvent precipitation method. The NLO studies were performed on the films of nanocubes (NCs) and nanorods (NRs) using the Z-scan technique with 1 kHz femtosecond pulses at 600, 700, and 800 nm. Large two-photon absorption cross sections (~105 GM) were retrieved by fitting the open-aperture Z-scan data. Strong third-order NLO susceptibility (~10-10 esu) was observed in these films. At higher peak intensities a switching of sign (in both NCs and NRs) in the real and imaginary parts of the NLO susceptibility was observed from the studies on these CsPbBr3 nanocrystals. The obtained NLO coefficients clearly suggest that these materials are promising for ultrafast photonic applications. PMID- 29400852 TI - Coherent-perfect-absorber and laser for bound states in a continuum. AB - It is shown that two fundamentally different phenomena, the bound states in continuum and the spectral singularity (or time-reversed spectral singularity), can occur simultaneously. This can be achieved in a rectangular core dielectric waveguide with an embedded active (or absorbing) layer. In such a system a two dimensional bound state in a continuum is created in the plane of a waveguide cross section, and it is emitted or absorbed along the waveguide core. The idea can be used for experimental implementation of a laser or a coherent-perfect absorber for a photonic bound state that resides in a continuous spectrum. PMID- 29400853 TI - Continuous-wave operation in directly patterned perovskite distributed feedback light source at room temperature. AB - We report a directly patterned perovskite distributed feedback (DFB) resonator and show narrow amplified spontaneous emission (ASE) at pump powers as low as 0.1 W/cm2 under continuous-wave (CW) optical pumping conditions at room temperature. Compared to the pristine thin film photoluminescence spectrum, a 16-fold reduction in emission linewidth in the MAPbI3 DFB cavity was observed. The direct nanostructuring of perovskites was achieved by thermal nanoimprint lithography. Our findings pave the way toward realizing CW pumped perovskite lasers at room temperature and energy-efficient perovskite light sources. PMID- 29400854 TI - Third-harmonic generation and scattering in combustion flames using a femtosecond laser filament. AB - Coherent radiation in the ultraviolent (UV) range has high potential applicability to the diagnosis of the formation processes of soot in combustion because of the high scattering efficiency in the UV wavelength region, even though the UV light is lost largely by the absorption within the combustion flames. We show that the third harmonic (TH) of a Ti:sapphire 800 nm femtosecond laser is generated in a laser-induced filament in a combustion flame and that the conversion efficiency of the TH varies sensitively by the ellipticity of the driver laser pulse but does not vary so much by the choice of alkanol species introduced as fuel for the combustion flames. We also find that the TH recorded from the side direction of the filament is the Rayleigh scattering of the TH by soot nanoparticles within the flame and that the intensity of the TH varies depending on the fuel species as well as on the position of the laser filament within the flame. Our results show that a remote and in situ measurement of distributions of soot nanoparticles in a combustion flame can be achieved by Rayleigh scattering spectroscopy of the TH generated by a femtosecond-laser induced filament in the combustion flame. PMID- 29400855 TI - In vivo broadband visible light optical coherence tomography probe enables inverse spectroscopic analysis. AB - We report the design and characterization of a 6 mm outer diameter pull-back circumferential scanning visible optical coherence tomography probe. The probe's large visible bandwidth (500-695 nm) allowed for inverse spectroscopic analysis and an axial resolution of ~1.1 MUm in tissue. We verify spectral imaging capabilities by measuring microsphere backscattering spectra and demonstrate in vivo spatial nanoscale characterization of tissue. PMID- 29400856 TI - High-energy thermoelectrically cooled Fe:ZnSe laser tunable over 3.75-4.82 MUm. AB - The characteristics of an Fe:ZnSe laser thermoelectrically cooled to 220 K are described. Output energy of 7.5 J and optical-to-optical efficiency of 30% have been demonstrated in single-shot operation at 4.3 MUm with a 2.94 MUm Er:YAG pump laser. By using an intracavity prism, continuous tuning from 3.75 to 4.82 MUm has been obtained at output energy up to 3.1 J. PMID- 29400857 TI - Angle-insensitive amorphous silicon optical filter for fluorescence contact imaging. AB - We introduce a novel amorphous silicon absorption filter that has high rejection for all angles of incident light for wavelengths below approximately 700 nm. This filter is used for microscopic cancer tissue detection in a small intraoperative contact fluorescence imaging system that requires excitation light at oblique angles. Our 15 MUm thick filter presents over five orders of magnitude rejection at 633 nm, making it compatible with several clinically tested fluorophores, including IR700DX. We have demonstrated imaging of fluorescently labeled human epidermal growth factor receptor 2+ breast cancer tissue using the filter, and we can reliably detect microscopic clusters of breast cancer cells with only a 75 ms integration time. PMID- 29400858 TI - Fiber-facet-integrated guided-mode resonance filters and sensors: experimental realization. AB - Guided-mode resonant (GMR) thin films integrated on fiber tips are known to realize compact filters and sensors. However, limited progress in experimental realization has been reported to date. Here we provide a considerable advance in this technology, as we experimentally demonstrate efficient fiber-facet mounted device prototypes. To retain a large aperture for convenient coupling, we design and fabricate silicon nitride-based resonators on the tip of a multimode fiber. We account for light propagation along the multimode fiber with exact numerical methods. This establishes the correct amplitude and phase distribution of the beam incident on the tip-mounted GMR element, thus enabling us to properly predict the resonance response. To fabricate the integrated GMR structures on the tips of fibers, we employ standard microfabrication processes, including holographic interference lithography and reactive-ion etching. The experimental results agree with simulation with an example device achieving high efficiency of ~77% in transmission. To investigate fiber sensor operation, an etched silicon nitride fiber tip filter is surrounded with solutions of various refractive indices, yielding an approximate sensitivity of 200 nm/RIU. PMID- 29400859 TI - Tamm-plasmon polaritons in one-dimensional photonic quasi-crystals. AB - We present an investigation to ascertain the existence of Tamm-plasmon-polariton like modes in one-dimensional (1D) quasi-periodic photonic systems. Photonic bandgap formation in quasi-crystals is essentially a consequence of long-range periodicity exhibited by multilayers and, thus, it can be explained using the dispersion relation in the Brillouin zone. Defining a "Zak"-like topological phase in 1D quasi-crystals, we propose a recipe to ascertain the existence of Tamm-like photonic surface modes in a metal-terminated quasi-crystal lattice. Additionally, we also explore the conditions of efficient excitation of such surface modes along with their dispersion characteristics. PMID- 29400860 TI - Energy deposition of single femtosecond filaments in the atmosphere: erratum. AB - In this erratum the funding section of Opt. Lett.41, 3908 (2016)OPLEDP0146 959210.1364/OL.41.003908 has been updated. PMID- 29400861 TI - Interpreting angular momentum transfer between electromagnetic multipoles using vector spherical harmonics. AB - The transfer of angular momentum between a quadrupole emitter and a dipole acceptor is investigated theoretically. Vector spherical harmonics are used to describe the angular part of the field of the mediating photon. Analytical results are presented for predicting angular momentum transfer between the emitter and absorber within a quantum electrodynamical framework. We interpret the allowability of such a process, which appears to violate conservation of angular momentum, in terms of the breakdown of the isotropy of space at the point of photon absorption (detection). That is, collapse of the wavefunction results in loss of all angular momentum information. This is consistent with Noether's Theorem and demystifies some common misconceptions about the nature of the photon. The results have implications for interpreting the detection of photons from multipole sources and offers insight into limits on information that can be extracted from quantum measurements in photonic systems. PMID- 29400862 TI - Single-shot transient absorption spectroscopy with a 45 ps pump-probe time delay range. AB - We report a single-shot transient absorption apparatus that successfully uses a tilted pump pulse to spatially encode a 45 ps pump-probe time delay. The time delay range is significantly improved over other reported instruments by using a spatial light modulator to flatten the intensity of the excitation field at the sample position. The full time delay range of the instrument is demonstrated by measuring a long-lived dye. A signal-to-noise ratio of >35 is attained in 8 s. This advance will enable the measurement of excited state dynamics of systems that are not at structural equilibrium. PMID- 29400863 TI - Broadband bright twin beams and their upconversion. AB - We report on the observation of broadband (40 THz) bright twin beams through high gain parametric downconversion in an aperiodically poled lithium niobate crystal. The output photon number is shown to scale exponentially with the pump power and not with the pump amplitude, as in homogeneous crystals. Photon number correlations and the number of frequency/temporal modes are assessed by spectral covariance measurements. By using sum-frequency generation on the surface of a non-phase-matched crystal, we measure a cross-correlation peak with the temporal width of 90 fs. PMID- 29400864 TI - Poincare sphere representation for spatially varying birefringence. AB - The Poincare sphere is a graphical representation in a three-dimensional space for the polarization of light. Similarly, an optical element with spatially varying birefringence can be represented by a surface on a four-dimensional "Poincare hypersphere." A projection of this surface onto the traditional Poincare sphere provides an intuitive geometric description of the polarization transformation performed by the element, as well as the induced geometric phase. We apply this formalism to quantify the effects of birefringence on the image quality of an optical system. PMID- 29400865 TI - High-charge and multiple-star vortex coronagraphy from stacked vector vortex phase masks. AB - Optical vortex phase masks are now installed at many ground-based large telescopes for high-contrast astronomical imaging. To date, such instrumental advances have been restricted to the use of helical phase masks of the lowest even order, while future giant telescopes will require high-order masks. Here we propose a single-stage on-axis scheme to create high-order vortex coronagraphs based on second-order vortex phase masks. By extending our approach to an off axis design, we also explore the implementation of multiple-star vortex coronagraphy. An experimental laboratory demonstration is reported and supported by numerical simulations. These results offer a practical roadmap to the development of future coronagraphic tools with enhanced performances. PMID- 29400866 TI - Giant visible and infrared light attenuation effect in nanostructured narrow bandgap glasses. AB - A unique effect of Bi on the optical and electrical properties of mixed Ga containing Ge-Se and Ge-Te glasses is discovered. It is shown that glass with a low Bi content is completely transparent in a 3-16 MUm spectral range, while the glass with a slightly higher Bi content possesses a large (>10 db/mm) attenuation coefficient, making a ~millimeter thick glass sample fully opaque to VIS-IR radiation. Despite this contrast, both types of glass are found to retain their semiconducting properties, the DC conductivity at room temperature, sigmaDC~10-3 S/m, being comparable to that of silicon. PMID- 29400867 TI - Spectral responses of linear grating filters under full-conical incidence. AB - To completely clarify the spectral responses of linear grating filters (LGFs) under full-conical incidence (where the incident plane is parallel to the linear grating bars), a bandstop LGF is implemented on an HfO2-on-silicon platform, and its spectral responses are comprehensively investigated. The measured spectra agree well with the simulated outcomes. For the TM- (or TE-) polarized wave under full-conical incidence, there exists a pair of resonance bands, whose spectral features differ significantly from each other. One resonance band has a high angular tolerance and is capable of accommodating divergent waves, whereas the other band presents a tunable spectral linewidth and can be used to achieve an ultra-high Q-factor. In particular, it is demonstrated that all of the resonance bands under full-conical incidence are degenerate regardless of what the value of the incident angle is. Our investigations reveal interesting spectral attributes of LGFs under full-conical incidence, which are highly beneficial for developing new filtering devices. PMID- 29400868 TI - Role of symmetry in mode coupling in twisted microstructured optical fibers. AB - We have studied the effect of symmetry on coupling between core and cladding modes in helical microstructured fibers, which gives rise to resonant loss peaks observed in the fiber transmission spectra. We demonstrate that the selection rules for orbital and spin angular momenta of coupled modes, proposed first for twisted conventional fibers, are universal characteristics and correctly identify the coupled cladding modes in helical microstructured optical fibers (MOFs). Moreover, we show for the first time (to our knowledge) the effect of coupling between modes of opposite polarization handedness in twisted MOFs. PMID- 29400869 TI - Two-color interpolation of the absorption response for quantitative acousto-optic imaging. AB - Diffuse optical tomography (DOT) is a reliable and widespread technique for monitoring qualitative changes in absorption inside highly scattering media. It has been shown, however, that acousto-optic (AO) imaging can provide significantly more qualitative information without the need for inversion algorithms due to the spatial resolution afforded by ultrasound probing. In this Letter, we show how, by using multiple-wavelength AO imaging, it is also possible to perform quantitative measurements of absorber concentration inside scattering media. PMID- 29400870 TI - Silicon traveling-wave Mach-Zehnder modulator under distributed-bias driving. AB - The silicon traveling-wave (TW) Mach-Zehnder modulator (MZM) is one of the most important devices in silicon photonic transceivers for high-speed optical interconnects. Its phase shifter utilizes carrier depletion of pn diodes for high speed, but suffers low modulation efficiency. Extensive efforts have been made on pre-fabrication optimizations, including waveguides, doping, and electrodes to enhance high-frequency modulation efficiency. Instead, we here propose an adaptive post-fabrication distributed-bias driving method that enables 20%~30% high-frequency efficiency enhancement at both 10 and 25 Gbps without doing any optimizations for a silicon TW-MZM. This method explores the bias nonlinearity of index modulation which, to the best of our knowledge, is utilized for the first time in driving silicon modulators to improve the efficiency. We demonstrated the viability of this adaptive driving concept to achieve better performance, and this Letter could open new avenues for silicon traveling-wave modulator design and performance trade-off. PMID- 29400871 TI - Reliable profile reconstruction of GRIN lenses produced by ion-exchange processes. AB - We propose a method that allows for a fast and accurate reconstruction of the refractive index profile of radially symmetric gradient index lenses fabricated by ion-exchange processes. The presented method enables the reconstruction of the profile up to the 10th polynomial order without direct spatially resolved refractive index measurements. It requires as input a working distance measurement at the paraxial limit and an accurate wavefront aberration measurement at full aperture. In addition, the approach combines the information about the optical behavior with the knowledge about the overall mass density changes of the glass rods during the ion exchange production processes to refine the reconstruction. Finally, the reconstruction of multiple profiles produced with different boundary conditions is demonstrated and confirms the functionality of the method. PMID- 29400872 TI - 4.24 MUm mid-infrared laser based on a single Fe2+-doped ZnSe microcrystal. AB - In this Letter, we report for the first time, to the best of our knowledge, a micron-sized mid-infrared Fe2+:ZnSe laser based on a single microcrystal. Typical laser emissions centering at 4.24 MUm are observed from a selected Fe2+-doped ZnSe microcrystal under 2.94 MUm excitation of Er:YAG laser at room temperature. The laser linewidth is ~10 nm, the pulse width is ~50 ns, and the lasing threshold is ~7.4 mJ/pulse. The lasing wavelength is stable as the pump energy increases and is consistent with the strong absorption position of carbon dioxide in the atmosphere. PMID- 29400873 TI - Chip-based arbitrary radio-frequency photonic filter with algorithm-driven reconfigurable resolution. AB - All programmable microwave photonic filters to date have been limited by the trade-off between the resolution and the operation bandwidth to construct arbitrary filter shapes. Here, we propose a new approach to synthesize a radio frequency photonic filter with an arbitrary response and reconfigurable resolution through phase-only tailoring, which is implemented in a low-loss photonic chip. Based on an algorithm, incorporating the target transfer function of the filter optimum resolution can be intelligently chosen by tuning the coupling coefficients and the round-trip phase of cascaded ring resonators. We achieved filtering with tunable resolution from 300 MHz to 25 GHz along with various filtering shapes and multiple passbands. PMID- 29400874 TI - Structure from motion with efficient homography-based line matching. AB - A novel structure from motion (SfM) pipeline that combines point features and line features together is presented in this paper. Line segments usually are more difficult to handle than points in SfM due to the instability of their end points and the property of being unconstrained by epipolar geometry. Our proposed method first implements a very robust and efficient line segment matching by applying homography and optical flow tracking. Global homography and multiple homography schemes are combined to get a better effect. By virtue of sampling lines, line matching is converted to point matching. A unified global SfM pipeline is then available for both lines and points. In the end, the proposed method is evaluated through various datasets. The result shows that our line-based SfM can generate accurate 3D models with lines and give meaningful representation for a man-made environment. PMID- 29400875 TI - Simple and practical approach for computing the ray Hessian matrix in geometrical optics. AB - A method is proposed for simplifying the computation of the ray Hessian matrix in geometrical optics by replacing the angular variables in the system variable vector with their equivalent cosine and sine functions. The variable vector of a boundary surface is similarly defined in such a way as to exclude any angular variables. It is shown that the proposed formulations reduce the computation time of the Hessian matrix by around 10 times compared to the previous method reported by the current group in Advanced Geometrical Optics (2016). Notably, the method proposed in this study involves only polynomial differentiation, i.e., trigonometric function calls are not required. As a consequence, the computation complexity is significantly reduced. Five illustrative examples are given. The first three examples show that the proposed method is applicable to the determination of the Hessian matrix for any pose matrix, irrespective of the order in which the rotation and translation motions are specified. The last two examples demonstrate the use of the proposed Hessian matrix in determining the axial and lateral chromatic aberrations of a typical optical system. PMID- 29400876 TI - Advances in edge diffraction algorithms. AB - Starshade external occulters are a leading technology that provide the starlight suppression needed to directly image and spectroscopically characterize Earth sized exoplanets in the habitable zone of nearby stars. A high-priority technology area identified in need of development for a future starshade mission is the development and validation of high-fidelity optical models to predict the performance of a full-scale starshade. We present the generalization of an algorithm to formulate the Fresnel diffraction equation as a one-dimensional integral around the edge of an arbitrary binary diffraction screen. Our edge integral provides an efficient method for capturing diffraction over a large range of size scales and is computationally superior to standard two-dimensional codes. We also present a novel method to implement wavefront errors with the edge integral. This paper provides the derivation of the algorithms and their validation with comparisons to known solutions and results from standard Fresnel propagation codes. PMID- 29400877 TI - Goos-Hanchen and Imbert-Fedorov shifts: relation with the irradiance moments of a beam. AB - We present closed and simple expressions of the spatial and angular Goos-Hanchen and Imbert-Fedorov shifts in terms of the second-order irradiance moments of a beam. Our results are applicable to a general totally polarized partially coherent beam. One of the main advantages of this formalism is that it can be applied directly from the knowledge of the cross-spectral density function and the polarization state without using any modal beam expansion. The obtained expressions allow understanding of the relationship between the global spatial characteristics of the incident beam and the experimented shifts in the reflected beam. Cosine-Gaussian Schell-model beams with rectangular symmetry are used to exemplify results. PMID- 29400878 TI - Amplitude and phase retrieval with simultaneous diversity estimation using expectation maximization. AB - Iterative amplitude and phase retrieval algorithms have been proven to accurately reconstruct arbitrary wavefronts from multiple intensity measurements when system parameters are known exactly, given the ability to induce phase diversity between images. Such sets of intensity images with phase diversity can be generated by moving a lens in the optical system, but any position error on the lens will degenerate the reconstruction result. We demonstrate the use of an expectation maximization algorithm with Kalman smoothing for recovering both the complex field and the lens position from a stack of intensity images. Our method successfully reduces the mean-squared-error of the estimated wavefront in comparison to an approach without position error estimation. We present and discuss the results of using a Kalman smoother and nonlinear least-squares optimization for the estimation of the moving lens position. PMID- 29400879 TI - On the depolarization in granular thin films: a Mueller-matrix approach. AB - We describe a general method to disclose the information hidden in Mueller matrices experimentally obtained from depolarizing samples. Although spectroscopic Mueller-matrix ellipsometry allows for a model-free characterization of inhomogeneous samples, i.e., independently from any assumption on the sample structure, the interpretation of the obtained results is often challenging. The proposed method combines three different decomposition techniques applied to the measured Mueller matrices in transmission and reflection of granular thin films with different thicknesses and densities. We demonstrate that the comparative analysis of the respective differential-, product-, and sum-decomposition of the Mueller matrices, together with correlation effects and the visualization as a Poincare sphere, reveals the particular underlying physical processes of depolarization. As an example, we apply this method on granular BaSO4 thin films. This method is general and can be applied to a wide variety of intrinsically inhomogeneous materials with applications in physics, industry, biology, or medicine. PMID- 29400880 TI - Stroboscopic effect: contrast threshold function and dependence on illumination level. AB - The stroboscopic visibility measure (SVM) is a method used to quantify the stroboscopic effect visibility in general illumination application. SVM has been defined previously based on a limited number of frequencies and participants. To validate and extend SVM, five perception experiments are presented, measuring the visibility threshold of light waveforms modulated at several frequencies, conducted in two different labs. A power function is fitted through the aggregated results to develop a stroboscopic effect contrast threshold function for a "standard observer," which can be used to normalize SVM. An additional experiment shows the dependency on illumination level, extending the validity of SVM to other applications. PMID- 29400881 TI - Security analysis of a double-image encryption technique based on an asymmetric algorithm. AB - In this paper, we evaluate the security of a double-image encryption technique based on an asymmetric algorithm. Compared with traditional cryptosystems based on a phase-truncated Fourier transform, the technique is able to improve the security of the encryption by combining a joint transform correlator; consequently, the encryption scheme is immune to some common attacks. We propose a special attack based on a phase retrieval algorithm with median filtering and normalization operation to break the cryptosystem. Low key sensitivity of a position parameter set has been found and an additional constraint is utilized to improve the attack to simplify the process and further decrease the computational time. Numerical simulation results show that the cryptosystem is vulnerable to the proposed special attack. PMID- 29400882 TI - Optical properties of spatially dispersive dielectric spheres: erratum. AB - Corrections are given for typographical errors in J. Opt. Soc. Am.71, 755 (1981)JOSAAH0030-394110.1364/JOSA.71.000755. PMID- 29400883 TI - Synchronization-based clustering algorithm for reconstruction of multiple reconstructed targets in fluorescence molecular tomography. AB - Fluorescence molecular tomography (FMT) is an important in vivo molecular imaging technique and has been widely studied in preclinical research. Many methods perform well in the reconstruction of a single fluorescent target but may fail in reconstructing multiple targets because of the severe ill-posedness of the FMT inverse problem. In this paper the original synchronization-inspired clustering algorithm (OSC) is introduced into FMT for resolving multiple targets from the reconstruction result. Based on OSC, a synchronization-based clustering algorithm for FMT (SC-FMT) is developed to further improve location accuracy. Both algorithms utilize the minimum spanning tree to automatically identify the number of the reconstructed targets without prior information and human intervention. A serial of numerical simulation results demonstrates that SC-FMT and OSC can resolve multiple targets robustly and automatically, which also shows the potential of the proposed postprocessing algorithms in FMT reconstruction. PMID- 29400884 TI - Analysis of lateral binding force exerted on a bi-sphere induced by an elliptic Gaussian beam. AB - Based on the generalized Lorentz-Mie theory (GLMT) and the localized approximation of the beam shape coefficients, we derived the expansions of incident elliptic Gaussian (EG) beams in terms of spherical vector wave functions (SVWFs). Utilizing multiple scattering (MS) equations and electromagnetic momentum (EM) theory, the lateral binding force (BF) exerted on a bi-sphere induced by an EG beam is calculated. Numerical effects of various parameters such as beam waist widths, beam polarization states, incident wavelengths, particle sizes, and material losses are analyzed and compared with the results of a circular Gaussian (CG) beam in detail. The observed dependence of the separation of optically bound particles on the incidence of an EG beam is in agreement with earlier theoretical predictions. Accurate investigation of BF induced by an EG beam could provide an effective test for further research on BF between more complex particles, which plays an important role in using optical manipulation on particle self-assembly. PMID- 29400885 TI - One-stop measurement model for fast and accurate tensor display characterization. AB - Many light field displays are fundamentally different from other displays in that they do not have quantized pixels, quantized angular outputs, or a physical screen position, which can make definitions and characterization problematic. We have determined that it is more appropriate to express the spatial resolution in terms of spatial cutoff frequency rather than a physical distance as in the case of a display with actual quantized pixels. This concept is then extended to also encompass angular resolution. The technique exploits the fact that when spatial resolution of a sinusoidal grating pattern is halved, its contrast ratio is reduced by a known proportion. An improved model, based on an earlier design concept, has been developed. It not only can be used to measure spatial and angular cutoff frequencies, but also can enable comprehensive characterization of the display. This model provides fast, simple measurement with good accuracy. It does not use special equipment or require time-consuming subjective evaluations. Using the model to characterize images in a rapid, accurate manner validates the effectiveness of this technique. PMID- 29400887 TI - Getting it right at JOSA A: editorial. AB - Editor-in-Chief P. Scott Carney discusses the importance of corrections to the published literature. PMID- 29400886 TI - Optimized diffusion approximation. AB - We show that the diffusion approximation (DA) to the radiative transport equation, which is commonly used in biomedical optics to describe propagation of light in tissues, contains a previously unexplored adjustable parameter. This parameter is related to the rate of exponential decay of the reduced intensity. In conventional theories, there are two distinct choices for this parameter. However, neither of these choices is optimal. When the optimal value for the parameter is used, the resulting DA becomes much more accurate near the medium boundaries, e.g., at the depth of up to a few l*, where l* is the transport mean free path (typically, about 1 mm in tissues). We refer to the new adjustable parameter as the reduced extinction coefficient. The proposed technique can reduce the relative error of the predicted diffuse density of the optical energy from about 30% to less than 1%. The optimized DA can still be inaccurate very close to an interface or in some other physical situations. Still, the proposed development extends the applicability range of the DA significantly. This result can be useful, for instance, in tomographic imaging of relatively shallow (up to a few l* deep) layers of tissues in the reflection geometry. PMID- 29400888 TI - Bi-tangent line based approach for multi-camera calibration using spheres. AB - This paper presents a novel approach for multi-camera calibration using spheres. We determine the projection of sphere centers first through bi-tangent lines of projection conics, which provides another solution for camera parameters on the basis of the relationship between the images of spheres and the image of the absolute conic in dual space. All parameters are refined by an optimization with the purpose of minimizing the reprojection error, which is divided into two independent parts associated with the corresponding shape parameters of the conics. Experimental results from the synthetic and real data show the feasibility and the accuracy achieved by our approach. PMID- 29400889 TI - Propagation of on-axis and off-axis Bessel beams in a gradient-index medium. AB - Bessel beams have been increasingly used for their advantages of non-diffraction and long focal depth. In this paper, we studied the propagation of on-axis and off-axis Bessel beams in a gradient-index medium. By expressing a Bessel beam in integral form, the analytical expression of an on-axis, decentered, and tilted Bessel beam through a paraxial optical system is derived with the ABCD matrix method and Collins diffraction integral formula. Main lobe size and trajectory of the zeroth- and second-order Bessel beam are obtained, demonstrating that the Bessel beam is focused by the gradient-index medium and its main lobe trajectory is exactly the same as the corresponding geometrical ray for both the decentered and tilted Bessel beam. Effects of beam apodization are finally studied by the Fourier beam propagation method, showing that the side lobes of the Bessel beam vanish when the beam is focused inside the medium as only part of the beam enters the lens. PMID- 29400890 TI - Double freeform illumination design for prescribed wavefronts and irradiances. AB - A mathematical model in terms of partial differential equations (PDE) for the calculation of double freeform surfaces for irradiance and phase control with predefined input and output wavefronts is presented. It extends the results of Bosel and Gross [J. Opt. Soc. Am. A34, 1490 (2017)JOAOD60740 323210.1364/JOSAA.34.001490] for the illumination design of single freeform surfaces for zero-etendue light sources to double freeform lenses and mirrors. The PDE model thereby overcomes the restriction to paraxiality or the requirement of at least one planar wavefront of the current design models in the literature. In contrast with the single freeform illumination design, the PDE system does not reduce to a Monge-Ampere type equation for the unknown freeform surfaces, if nonplanar input and output wavefronts are assumed. Additionally, a numerical solving strategy for the PDE model is presented. To show its efficiency, the algorithm is applied to the design of a double freeform mirror system and double freeform lens system. PMID- 29400891 TI - Revisited Yule-Nielsen model without fitting of the n parameter. AB - We introduce a so-called "mean-path-defined Yule-Nielsen" (MPD-YN) model for predicting the color of halftone prints in reflectance or transmittance modes, inspired by the Yule-Nielsen modified spectral Neugebauer model, where the empirical n value is replaced with a spectral parameter different for each halftone, directly calculated thanks to a closed-form formula, a function of the measured spectral reflectances (or accordingly transmittances) of full-tone calibration patches and the surface coverages of the Neugebauer primaries in the halftone. This parameter is based on the average number of internal reflections undergone by light between two half layers of the print, whose expression derives from a flux transfer model between the two half layers. According to the tests carried out in this study with paper printed in inkjet, the predictive performances of the MPD-YN model are rather good and very close to those obtained with the Yule-Nielsen model. PMID- 29400892 TI - Adaptive threshold method for recovered images of FMT. AB - This paper proposes a post-processing strategy for recovered images of fluorescence molecular tomography. A threshold value is adaptively obtained from the recovered images without external interference, which is objective because it is extracted from the reconstructed result. The recovered images from simulation experiments and physical phantom experiments are processed by this threshold method. And by visualization, the processed images are clearer than those with no post-processing. The full width at half-maximum and contrast-to-noise ratio are then utilized to further verify the effectiveness of the post-processing method, being capable of removing spurious information from the original images, thus bringing convenience to users. PMID- 29400893 TI - Hyperbolic accelerating beams and their relation with Hermite-Gaussian beams. AB - We derive the initial distributions of phase and complex amplitude of accelerating beams with arbitrary predesigned hyperbolic trajectories using the caustic-design method and explore the relation between these beams and Hermite Gaussian beams. The results show the hyperbolic accelerating beams are a larger class of beams than Hermite-Gaussian beams. When the bending parameter is an integer, the hyperbolic accelerating beams have a similar initial complex amplitude distribution and almost the same propagating characteristics as Hermite Gaussian beams. Through the analysis of the ray-based method, we also derive an approximate expression for the initial complex amplitude of Hermite-Gaussian beams after introducing an amplitude distribution function. Although the proposed approximate expressions of complex amplitude are more complex than the usually used Hermite-Gaussian function, they explicitly indicate the information on local amplitude, wave vector, and internal ray structure (including caustics) of these beams and thus provide us clearer geometrical insights into these beams. PMID- 29400894 TI - Wavefronts and caustics associated with Mathieu beams. AB - In this work we compute the wavefronts and the caustics associated with the solutions to the scalar wave equation introduced by Durnin in elliptical cylindrical coordinates generated by the function A(phi)=cenu(phi,q)+isenu(phi,q), with nu being an integral or nonintegral number. We show that the wavefronts and the caustic are invariant under translations along the direction of evolution of the beam. We remark that the wavefronts of the separable Mathieu beams generated by A(phi)=cenu(phi,q) and A(phi)=senu(phi,q) are cones and their caustic is the z axis; thus, they are not structurally stable. However, in general, the Mathieu beam generated by A(phi)=cenu(phi,q)+isenu(phi,q) is stable because locally its caustic has singularities of the fold and cusp types. To show this property, we present the wavefronts and the caustics for the Mathieu beams with characteristic value anu=0 and q=0,0.2,0.3,0.5. For q=0, we obtain the Bessel beam of order zero; in this case, the wavefronts are cones and the caustic coincides with the z axis. For q?0, the wavefronts are deformations of conical ones, and the caustic surface, for some values of q, has singularities of the cusp ridge type. Furthermore, we remark that the set of Mathieu beams with characteristic value anu=0 and 0<=q<1 has associated a caustic with singularities of the swallowtail type, which is structurally stable. Therefore, we conclude that this type of Mathieu beam is more stable than plane waves, Bessel beams, parabolic beams, and those generated by A(phi)=cenu(phi,q) and A(phi)=senu(phi,q). To support this conclusion, we present experimental results showing the pattern obtained after obstructing a plane wave, the Bessel beam of order m=5, and the Mathieu beam of order m=5 and q=50 with complex transversal amplitude given by Ce5(xi,50)ce5(eta,50)+iSe5(xi,50)se5(eta,50), where (xi, eta) are the elliptical coordinates on the plane. PMID- 29400895 TI - Point-of-care ultrasound: Deploying in primary care. PMID- 29400896 TI - Point-of-care ultrasound: Coming soon to primary care? AB - Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAA), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient. In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam, the lung exam, the screening exam for AAAs, and the evaluation for DVT. For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non radiology specialists, including family physicians. PMID- 29400897 TI - Osteoporosis: A quick update. AB - Researchers estimate that approximately 10.2 million Americans have osteoporosis, and an additional 43 million have low bone density. Equally stark are the ramifications of these numbers. About one out of every 2 Caucasian women will experience an osteoporosis-related fracture at some point in their lifetime, as will approximately one in 5 men. Family physicians can have a meaningful impact on the extent to which this condition affects the population. To that end, we have put together a brief summary of the screening recommendations to keep in mind and a comparison of the different agents used to treat and prevent osteoporosis. PMID- 29400898 TI - Inpatient antibiotic resistance: Everyone's problem. AB - Greater efforts aimed at using antimicrobials sparingly and appropriately, as well as developing new antimicrobials with activity against multidrug-resistant pathogens, are ultimately needed to address the threat of antimicrobial resistance. This article describes the evidence-based management of inpatient infections caused by resistant bacteria and the role family physicians can play in reducing further development of resistance through antimicrobial stewardship practices. PMID- 29400899 TI - Mild cough . wheezing . loud heart sounds . Dx? AB - A 25-year-old man, who was an active duty US Navy sailor, went to his ship's medical department complaining of a mild cough that he'd had for 2 days. He denied having any fevers, chills, night sweats, angina, or dyspnea. He said he hadn't experienced any exertional fatigue or difficulty completing the rigorous physical tasks of his occupation as an engineman on the ship. The patient had no medical or surgical history of significance, and he wasn't taking any medications or supplements. On exam, he was not in acute distress and his vital signs were within normal limits. Auscultation revealed mild wheezing throughout the upper lung fields and loud heart sounds throughout his chest that were audible even with gentle contact of the stethoscope diaphragm. He had no discernible murmurs, rubs, or gallops. In light of the unusually loud heart sounds heard on exam, we performed an electrocardiogram. The EKG revealed a normal sinus rhythm, slight right axis deviation indicated by tall R-waves in V1 (also suggestive of right ventricular hypertrophy), an incomplete right bundle branch block, and a crochetage sign (a notch in the R-waves of the inferior leads). A chest x-ray revealed a normal-sized heart and dilated pulmonary vasculature suggestive of pulmonary hypertension. PMID- 29400901 TI - Behavioral Health Consult: Schizophrenia: Ensuring an accurate Dx, optimizing treatment. AB - Steven R, a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs. How would you proceed with this patient? PMID- 29400900 TI - PURLs: Does fish oil during pregnancy help prevent asthma in kids? AB - A 24-year-old G2P1 at 24 weeks' gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend? PMID- 29400902 TI - Persistent rash on feet. AB - A 49-year-old Hispanic woman presented with a 4-month history of scaling and a macerated rash localized between her toes. The rash was malodorous, mildly erythematous, and sometimes associated with pruritus. The patient had no relevant medical history. Potassium hydroxide testing was performed and found to be negative. So a Wood's lamp was used to examine the patient's toes--and it revealed the diagnosis. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT? PMID- 29400903 TI - Clinical Inquiry: How do oral NSAIDs compare to other oral analgesics right after an acute musculoskeletal injury? AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are at least as effective as other oral analgesics (opioids, acetaminophen) in relieving pain in the first few days after an acute musculoskeletal injury. Evidence also indicates that using NSAIDs results in fewer adverse events than using narcotics (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCTs], as well as individual RCTs). PMID- 29400904 TI - Clinical Inquiry: Is megestrol acetate safe and effective for malnourished nursing home residents? AB - No. Megestrol acetate (MA) is neither safe nor effective for stimulating appetite in malnourished nursing home residents. It increases the risk of deep vein thrombosis (strength of recommendation [SOR]: C, 2 retrospective chart reviews), but isn't associated with other new or worsening events or disorders (SOR: B, single randomized controlled trial [RCT]). Over a 25-week period, MA wasn't associated with increased mortality (SOR: B, single RCT). After 44 months, however, MA-treated patients showed decreased median survival (SOR: B, single case-control study). Consistent, meaningful weight gain was not observed with MA treatment (SOR: B, single case-control study, single RCT, 2 retrospective chart reviews, single prospective case-series). PMID- 29400905 TI - Elevated serum alkaline phosphatase . generalized pruritus . Dx? AB - A 34-year-old woman was referred to the hepatology clinic for evaluation of an increased serum alkaline phosphatase (ALP) level. She was gravida 5 and in her 38th week of gestation. Her obstetric history was significant for 2 uncomplicated spontaneous term vaginal deliveries resulting in live births and 2 spontaneous abortions. The patient reported generalized pruritus for 2 months prior to the visit. She had no comorbidities and denied any other symptoms. She reported no family history of liver disease or complications during pregnancy in relatives. The patient did not smoke or drink, and had come to our hospital for her prenatal care visits. The physical exam revealed normal vital signs, no jaundice, a gravid uterus, and acanthosis nigricans on the neck and axilla with scattered excoriations on the arms, legs, and abdomen. Her serum ALP level was 1093 U/L (normal: 50-136 U/L). Immediately before this pregnancy, her serum ALP had been normal at 95 U/L, but it had since been increasing with a peak value of 1134 U/L by 37 weeks' gestation. Serum transaminase activities and albumin and bilirubin concentrations were normal, as was her prothrombin time. The rest of her lab tests were also normal, including her fasting serum bile acid concentration, which was 9 mcmol/L (normal: 4.5-19.2 mcmol/L). PMID- 29400906 TI - Maxwell-Hall access resistance in graphene nanopores. AB - The resistance due to the convergence from bulk to a constriction, for example, a nanopore, is a mainstay of transport phenomena. In classical electrical conduction, Maxwell, and later Hall for ionic conduction, predicted this access or convergence resistance to be independent of the bulk dimensions and inversely dependent on the pore radius, a, for a perfectly circular pore. More generally, though, this resistance is contextual, it depends on the presence of functional groups/charges and fluctuations, as well as the (effective) constriction geometry/dimensions. Addressing the context generically requires all-atom simulations, but this demands enormous resources due to the algebraically decaying nature of convergence. We develop a finite-size scaling analysis, reminiscent of the treatment of critical phenomena, that makes the convergence resistance accessible in such simulations. This analysis suggests that there is a "golden aspect ratio" for the simulation cell that yields the infinite system result with a finite system. We employ this approach to resolve the experimental and theoretical discrepancies in the radius-dependence of graphene nanopore resistance. PMID- 29400907 TI - How Economic Disadvantage Affects the Availability and Nature of Mentoring Relationships During the Transition to Adulthood. AB - Supportive nonparental adults, particularly nonfamilial adults, provide critical support during the transition to adulthood, opening doors to educational and career paths. This study examined whether economic disadvantage shapes access to these relationships. Results showed that low-income adolescents had reduced access to naturally occurring mentors, and the relationships they did form tended to be close bonds with family and friends, rather than nonfamilial adults. Their mentors were more likely to focus on practical support, and less likely to serve as role models or provide career advice. These effects of socioeconomic status on natural mentoring relationships remained evident, even when accounting for youth race/ethnicity. Findings suggest that networks of support differ depending on a youth's socioeconomic context in ways that could perpetuate social and economic inequalities. PMID- 29400908 TI - Monilethrix: A case report imaged by trichoscopy, reflectance confocal microscopy and histopathology. PMID- 29400909 TI - Somatic and germline FOXP3 mosaicism in the mother of a boy with IPEX syndrome. AB - Confirmatory Sanger sequencing of whole exome sequencing first identified a somatic and germline FOXP3 mosaicism with two different mutational events of c.210 + 1G > T and c.210 + 1G > A in the mother of a boy with IPEX syndrome. PMID- 29400910 TI - Environmental dredging residual generation and management. AB - The presence and magnitude of sediment contamination remaining in a completed dredge area can often dictate the success of an environmental dredging project. The need to better understand and manage this remaining contamination, referred to as "postdredging residuals," has increasingly been recognized by practitioners and investigators. Based on recent dredging projects with robust characterization programs, it is now understood that the residual contamination layer in the postdredging sediment comprises a mixture of contaminated sediments that originate from throughout the dredge cut. This mixture of contaminated sediments initially exhibits fluid mud properties that can contribute to sediment transport and contamination risk outside of the dredge area. This article reviews robust dredging residual evaluations recently performed in the United States and Canada, including the Hudson River, Lower Fox River, Ashtabula River, and Esquimalt Harbour, along with other projects. These data better inform the understanding of residuals generation, leading to improved models of dredging residual formation to inform remedy evaluation, selection, design, and implementation. Data from these projects confirm that the magnitude of dredging residuals is largely determined by site conditions, primarily in situ sediment fluidity or liquidity as measured by dry bulk density. While the generation of dredging residuals cannot be avoided, residuals can be successfully and efficiently managed through careful development and implementation of site-specific management plans. Integr Environ Assess Manag 2018;14:335-343. (c) 2018 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 29400911 TI - Elevations of metabolic risk factors 20 years or more before diagnosis of type 2 diabetes: Experience from the AMORIS study. AB - AIMS: To describe trajectories for metabolic risk factors for type 2 diabetes (T2D) up to 25 years prior to diagnosis and to estimate the absolute 20-year risk for T2D based on a simple set of commonly measured key risk factors. METHODS: From the Swedish AMORIS cohort we included 296 428 individuals with data on fasting glucose obtained in health examinations during 1985-1996 (baseline period). All participants were followed until 2012 for development of incident T2D. The 20-year T2D risk based on age, sex, body mass index (BMI), fasting glucose and triglycerides was estimated. Trajectories for biomedical risk factors of T2D starting from >20 years before diagnosis and including fasting glucose, triglycerides and BMI were evaluated according to yearly means for cases and controls. RESULTS: We identified 28 244 new T2D cases during the study period, with an average 20-year risk of 8.1%. This risk was substantially increased in overweight and obese participants and those with elevated fasting glucose and triglyceride levels, in both men and women. T2D cases had higher mean BMI and fasting glucose and triglyceride levels compared with controls >20 years before diagnosis and the difference in fasting glucose levels increased over time. CONCLUSIONS: Development of T2D is associated with subtle elevations in glucose and lipid levels >20 years before diagnosis. This suggests that diabetogenic processes tied to chronic insulin resistance operate for decades prior to the development of T2D. A simple risk classification can help in early identification of individuals who are at increased risk. PMID- 29400912 TI - Classic Block Design "Pseudo"-Resting-State fMRI Changes After a Neurorehabilitation Program in Patients with Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: The goal of this study was to assess changes in the resting-state networks (RSNs) of patients with multiple sclerosis (MS) after a cognitive rehabilitation program (CRP), by retrospectively analyzing functional magnetic resonance imaging (fMRI) studies using the classical block design. METHODS: Fifteen patients with MS (2 primary progressive, 3 relapsing-remitting, 10 secondary progressive) were scanned before and after the CRP on a 1.5T MRI scanner. In addition, patients underwent pre- and post-CRP neuropsychological assessment using a battery of standardized tests. Five healthy individuals were scanned at the same time points to confirm the test-retest reliability of the imaging technique. For each study, the individual fMRI blocks of rest were merged to produce a "pseudo"-resting-state (pseudo-RS) of 3 minutes duration. RS studies were analyzed with the MELODIC toolbox. A dual regression analysis was applied to estimate the longitudinal changes in RSNs of patients and test controls relative to a set of predefined RSNs used as templates. RESULTS: In healthy individuals, there were no significant differences in RSN results between the two time points studied. In the group of patients with MS, significant differences were found post-CRP in the visual medial, cerebellar, auditory, and frontal-executive RSNs. Furthermore, synchronization increases in the frontal-executive RSN were associated with cognitive improvement on neuropsychological testing. CONCLUSIONS: Results obtained using a pseudo-RS approach to analyze data from block-design fMRI studies suggest that a CRP of 5 weeks' duration induces measurable changes in specific RSNs of patients with MS. PMID- 29400914 TI - Do You Want Fries With That? Decoding All the 'Extras' in Physician Visits. PMID- 29400915 TI - Copy and Paste Run Amok--EHRs and Malpractice. PMID- 29400913 TI - Separation and Recovery of a Hemicellulose-Derived Sugar Produced from the Hydrolysis of Biomass by an Acidic Ionic Liquid. AB - Biomass processing with ionic liquids (ILs) has been one of the most topical research areas in recent years. However, separation and recovery of biomass products and ILs are currently a challenge. Recovery of produced monosaccharides from an IL postreaction solution and the possibility to reuse the IL are strongly required to guarantee the sustainability of biomass processing. The present study demonstrates a novel approach that aims at separating a biomass hemicellulose derived product, namely, xylose, and 1-ethyl-3-methylimidazolium hydrogensulfate ([emim][HSO4 ]). High polarity of a postreaction system composed of xylose, IL, and water is one of the major hindrances in the separation performance. A proposed solution is fine-tuning of the system polarity by the addition of moderately polar acetonitrile. To scrutinize the potential of xylose and IL separation, phase equilibria of a system constituted by [emim][HSO4 ], water, and acetonitrile were studied. Additionally, preparative chromatography experiments with alumina as a stationary phase were performed to determine the conditions required for efficient separation of the sugar and the IL by selective adsorption of xylose on alumina in detriment of IL. The amount and treatment of the stationary phase, eluent polarity, and amount of loaded sample were also scrutinized in this study. Treatment of alumina was considered as a necessary step to achieve recovery yields of 90.8 and 98.1 wt % for the IL and xylose, respectively, as separate fractions. PMID- 29400931 TI - AHIMA World Congress. Empowering Members Around the Globe. PMID- 29400932 TI - Health Information Plays BIG ROLE in Competitive Strategies of Population Health Analytics. PMID- 29400933 TI - Uniting HIM and IT. PMID- 29400934 TI - Navigating the Waters of HIPAA Regulations and Resources: The Basics. PMID- 29400935 TI - Automating HIM through Health Information Exchange: An Information Exchange: An Informatics Approach. PMID- 29400936 TI - Population Health Management: Proven Model Drives New Solutions. PMID- 29400937 TI - Strategic Alignment: The Driving Force for Information Governance. PMID- 29400938 TI - A Provider's Condensed Resource for Revenue Cycle, Coding Tools, and More. PMID- 29400939 TI - The Heart of the Matter: ICD-10-PCS Cardiac Coding. PMID- 29400940 TI - Fundamental Limits of Optical Tweezer Nanoparticle Manipulation Speeds. AB - Optical tweezers are a noncontact method of 3D positioning applicable to the fields of micro- and nanomanipulation and assembly, among others. In these applications, the ability to manipulate particles over relatively long distances at high speed is essential in determining overall process efficiency and throughput. In order to maximize manipulation speeds, it is necessary to increase the trapping laser power, which is often accompanied by undesirable heating effects due to material absorption. As such, the majority of previous studies focus primarily on trapping large dielectric microspheres using slow movement speeds at low laser powers, over relatively short translation distances. In contrast, we push nanoparticle manipulation beyond the region in which maximum lateral movement speed is linearly proportional to laser power, and investigate the fundamental limits imposed by material absorption, thus quantifying maximum possible speeds attainable with optical tweezers. We find that gold and silver nanospheres of diameter 100 nm are limited to manipulation speeds of ~0.15 mm/s, while polystyrene spheres of diameter 160 nm can reach speeds up to ~0.17 mm/s, over distances ranging from 0.1 to 1 mm. When the laser power is increased beyond the values used for these maximum manipulation speeds, the nanoparticles are no longer stably trapped in 3D due to weak confinement as a result of material absorption, heating, microbubble formation, and enhanced Brownian motion. We compared this result to our theoretical model, incorporating optical forces in the Rayleigh regime, Stokes' drag, and absorption effects, and found good agreement. These results show that optical tweezers can be fast enough to compete with other common, serial rapid prototyping and nanofabrication approaches. PMID- 29400941 TI - MOFwich: Sandwiched Metal-Organic Framework-Containing Mixed Matrix Composites for Chemical Warfare Agent Removal. AB - This work describes a new strategy for fabricating mixed matrix composites containing layered metal-organic framework (MOF)/polymer films as functional barriers for chemical warfare agent protection. Through the use of mechanically robust polymers as the top and bottom encasing layers, a high-MOF-loading, high performance-core layer can be sandwiched within. We term this multifunctional composite "MOFwich". We found that the use of elastomeric encasing layers enabled core layer reformation after breakage, an important feature for composites and membranes alike. The incorporation of MOFs into the core layer led to enhanced removal of chemical warfare agents while simultaneously promoting moisture vapor transport through the composite, showcasing the promise of these composites for protection applications. PMID- 29400942 TI - Ligand-Dependent Nanoparticle Assembly and Its Impact on the Printing of Transparent Electrodes. AB - Metal grids with submicron line diameters are optically transparent, mechanically flexible, and suitable materials for transparent and flexible electronics. Printing such narrow lines with dilute metal nanoparticle inks is challenging because it requires percolation throughout the particle packing. Here, we print fully connected submicron lines of 3.2 nm diameter gold nanoparticles and vary the organic ligand shell to study the relation between colloidal interactions, ligand binding to the metal core, and conductivity of the printed lines. We find that particles with repulsive potentials aid the formation of continuous lines, but the required long ligand molecules impede conductivity and need to be removed after printing. Weakly bound alkylamines provided sufficient interparticle repulsion and were easy to remove with a soft plasma treatment after printing, so that grids with a transparencies above 90% and a conductivity of 150 Omega sq-1 could be printed. PMID- 29400943 TI - Facile Access to Y2C2n (2n = 92-130) and Crystallographic Characterization of Y2C2@C1(1660)-C108: A Giant Nanocapsule with a Linear Carbide Cluster. AB - A series of giant metallofullerenes Y2C2n (2n = 92-130) have been successfully obtained through the treatment of the fraction enriched by 1,2-dichlorobenzene with SnCl4. Subsequent chromatographic separation gives a pure sample with a composition of Y2C110. Crystallographic results reveal that this endohedral takes the carbide form, namely Y2C2@C1(1660)-C108, representing as the largest metallofullerene that has been characterized by crystallography to date. Despite the disorder of the metal cluster, the major Y2C2 adopts a previously predicted linear configuration, indicating that the compression of the internal cluster by the cage is almost negligible in this giant cage. Electrochemical studies suggest that Y2C2@C1(1660)-C108 is a good electron donor instead of an electron acceptor. PMID- 29400944 TI - Gene Drive: Evolved and Synthetic. AB - Drive is a process of accelerated inheritance from one generation to the next that allows some genes to spread rapidly through populations even if they do not contribute to-or indeed even if they detract from-organismal survival and reproduction. Genetic elements that can spread by drive include gametic and zygotic killers, meiotic drivers, homing endonuclease genes, B chromosomes, and transposable elements. The fact that gene drive can lead to the spread of fitness reducing traits (including lethality and sterility) makes it an attractive process to consider exploiting to control disease vectors and other pests. There are a number of efforts to develop synthetic gene drive systems, particularly focused on the mosquito-borne diseases that continue to plague us. PMID- 29400945 TI - The Effects of Ultraviolet Radiation on Nucleoside Modifications in RNA. AB - Ultraviolet radiation (UVR) is a known genotoxic agent. Although its effects on DNA have been well-documented, its impact on RNA and RNA modifications is less studied. By using Escherichia coli tRNA (tRNA) as a model system, we identify the UVA (370 nm) susceptible chemical groups and bonds in a large variety of modified nucleosides. We use liquid chromatography tandem mass spectrometry to identify specific nucleoside photoproducts under in vitro and in vivo conditions, which were then verified by employing stable-isotope labeled tRNAs. These studies suggest that the -amino or -oxy groups of modified nucleosides, in addition to sulfur, are labile in the oxidative environment generated by UVA exposure. Further, these studies document a range of RNA photoproducts and post transcriptional modifications that arise because of UVR-induced cellular stress. PMID- 29400946 TI - Stable, Heat-Conducting Phosphor Composites for High-Power Laser Lighting. AB - Solid-state lighting using laser diodes is an exciting new development that requires new phosphor geometries to handle the greater light fluxes involved. The greater flux from the source results in more conversion and therefore more conversion loss in the phosphor, which generates self-heating, surpassing the stability of current encapsulation strategies used for light-emitting diodes, usually based on silicones. Here, we present a rapid method using spark plasma sintering (SPS) for preparing ceramic phosphor composites of the canonical yellow emitting phosphor Ce-doped yttrium aluminum garnet (Ce:YAG) combined with a chemically compatible and thermally stable oxide, alpha-Al2O3. SPS allows for compositional modulation, and phase fraction, microstructure, and luminescent properties of ceramic composites with varying compositions are studied here in detail. The relationship between density, thermal conductivity, and temperature rise during laser-driven phosphor conversion is elucidated, showing that only modest densities are required to mitigate thermal quenching in phosphor composites. Additionally, the scattering nature of the ceramic composites makes them ideal candidates for laser-driven white lighting in reflection mode, where Lambertian scattering of blue light offers great color uniformity, and a luminous flux >1000 lm is generated using a single commercial laser diode coupled to a single phosphor element. PMID- 29400947 TI - Toward the Development of an Artificial Brain on a Micropatterned and Material Regulated Biochip by Guiding and Promoting the Differentiation and Neurite Outgrowth of Neural Stem/Progenitor Cells. AB - An in vitro model mimicking the in vivo environment of the brain must be developed to study neural communication and regeneration and to obtain an understanding of cellular and molecular responses. In this work, a multilayered neural network was successfully constructed on a biochip by guiding and promoting neural stem/progenitor cell differentiation and network formation. The biochip consisted of 3 * 3 arrays of cultured wells connected with channels. Neurospheroids were cultured on polyelectrolyte multilayer (PEM) films in the culture wells. Neurite outgrowth and neural differentiation were guided and promoted by the micropatterns and the PEM films. After 5 days in culture, a 3 * 3 neural network was constructed on the biochip. The function and the connections of the network were evaluated by immunocytochemistry and impedance measurements. Neurons were generated and produced functional and recyclable synaptic vesicles. Moreover, the electrical connections of the neural network were confirmed by measuring the impedance across the neurospheroids. The current work facilitates the development of an artificial brain on a chip for investigations of electrical stimulations and recordings of multilayered neural communication and regeneration. PMID- 29400948 TI - "Triple-Punch" Anticancer Strategy Mediated by Near-Infrared Photosensitizer/CpG Oligonucleotides Dual-Dressed and Mitochondria-Targeted Nanographene. AB - Nanomedicine-based combination therapy has sparked a growing interest in clinical disease treatment and pharmaceutical industry. In this study, a mitochondria targeted and near-infrared (NIR) light-activable multitasking nanographene (i.e., GT/IR820/DP-CpG) was engineered to in situ trigger highly efficient "triple punch" strategy of cancer photodynamic therapy, photothermal therapy, and immunotherapy. Modification of triphenylphosphonium on graphene made the vehicle specifically guide the NIR dye IR820 home to mitochondria, followed by lysosomes escape in a time-dependent manner. The photoactive nanocomplex generated an abundant reactive oxygen species as well as photothermal heat to ultimately kill cancer cells by inducing mitochondrial collapse and irreversible cell apoptosis upon the NIR laser irradiation. Further introduction of an immunostimulatory conjugate DP-CpG significantly promoted the secretion of proinflammatory cytokines (i.e., interleukin-6, tumor necrosis factor-alpha, and interferon gamma) and thus improved the immunogenicity of tumors. In vivo studies demonstrated that GT/IR820/DP-CpG remarkably inhibited tumor growth (tumor inhibition rate, ~88%) resulting from the combinational phototherapeutic effect of IR820 and immunostimulatory activity of DP-CpG, thereby causing negligible toxic effects on mice. Our work provides a new paradigm of architecting organelle targeted and stimulative nanocomplex for highly efficient cancer photoimmunotherapy. PMID- 29400949 TI - Isolating Degradation Mechanisms in Mixed Emissive Layer Organic Light-Emitting Devices. AB - Degradation in organic light-emitting devices (OLEDs) is generally driven by reactions involving excitons and polarons. Accordingly, a common design strategy to improve OLED lifetime is to reduce the density of these species by engineering an emissive layer architecture to achieve a broad exciton recombination zone. Here, the effect of exciton density on device degradation is analyzed in a mixed host emissive layer (M-EML) architecture which exhibits a broad recombination zone. To gain further insight into the dominant degradation mechanism, losses in the exciton formation efficiency and photoluminescence (PL) efficiency are decoupled by tracking the emissive layer PL during device degradation. By varying the starting luminance and M-EML thickness, the rate of PL degradation is found to depend strongly on recombination zone width and hence exciton density. In contrast, losses in the exciton formation depend only weakly on the recombination zone, and thus may originate outside of the emissive layer. These results suggest that the lifetime enhancement observed in the M-EML architectures reflects a reduction in the rate of PL degradation. Moreover, the varying roles of excitons and polarons in degrading the PL and exciton formation efficiencies suggest that kinetically distinct pathways drive OLED degradation and that a single degradation mechanism cannot be assumed when attempting to model the device lifetime. This work highlights the potential to extract fundamental insight into OLED degradation by tracking the emissive layer PL during lifetime testing, while also enabling diagnostic tests on the root causes of device instability. PMID- 29400950 TI - Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry. AB - The prediction and interpretation of structural properties are the starting points for a deep understanding of thermochemistry, kinetics, and spectroscopic signatures of molecular systems. To give an example, detailed knowledge of the conformational behavior of the main building blocks of biomolecules in the gas phase (i.e., without the perturbing effect of the environment) is a mandatory prerequisite toward the understanding of the role played by different interactions in determining the biological activity in terms of structure activity relationships. The first step to take is an unambiguous definition of molecular structure. We address the so-called Born-Oppenheimer equilibrium structure, which is defined in a rigorous manner and isotopically independent, and the target accuracy. For the latter, we aim at so-called "spectroscopic" accuracy, which implies uncertainties of a few milliangstroms for bond lengths and smaller than a tenth of degree for angles. If on one side the continuous enhancements of the experimental techniques give access to new and unprecedented spectroscopic determinations, on the other side they require increasing efforts for an unbiased interpretation and analysis. Among the pieces of information, accurate molecular structures play a particularly important role. Indeed, there is a strong relationship between the experimental outcome and the electronic structure of the system. Spectroscopic techniques, in particular those exploited in the gas phase, are therefore accurate and reliable sources for structural information. However, it is seldom straightforward to derive molecular structures directly from the experimental information. Indeed, even in the favorable case of investigations in the gas phase, vibrational effects are always present, and disentangling their contributions requires collection of information for all vibrational modes, a nearly impossible task. To overcome these limitations, joint theory-spectroscopy strategies can be identified, which are referred to as "top down" and "bottom-up". The first approach, denoted as the semiexperimental approach, relies on extracting from experimental outcomes the equilibrium structure by using quantum-chemical computations to recover vibrational effects. The bottom-up approach consists in verifying the computed equilibrium geometry by means of a comparison between calculated and experimental spectroscopic parameters that probe structural characteristics. In this contribution, we try to review the most important challenges in accurate molecular structure determinations, with particular emphasis on the "solution" provided by a joint theoretical-experimental approach and on the current state of the art. Starting from the illustration of different strategies, we proceed by addressing the increasing complexity in the derivation of equilibrium geometries: we start from the construction of a database of accurate structures, we then face the problem of extending the dimension of the systems amenable to accurate structural determinations, and finally we move to the challenge of understanding the nature of intermolecular interactions. PMID- 29400951 TI - Dehydration of the Uranyl Peroxide Studtite, [UO2(eta2-O2)(H2O)2].2H2O, Affords a Drastic Change in the Electronic Structure: A Combined X-ray Spectroscopic and Theoretical Analysis. AB - The minerals studtite, [UO2(eta2-O2)(H2O)2].2H2O, and metastudtite, [UO2(eta2 O2)(H2O)2], are uranyl peroxide minerals that are major oxidative alteration phases of UO2 under conditions of geological storage. The dehydration of studtite has been studied using X-ray photoelectron spectroscopy (XPS) and X-ray absorption spectroscopy. XPS of the U 4f region shows small but significant differences between studtite and metastudtite, with the 4f binding energy of studtite being the highest reported for a uranyl mineral studied by this technique. Further information about the changes in the electronic structure was elucidated using U M4-edge high-energy resolution X-ray absorption near-edge structure (HR-XANES) spectroscopy, which directly probes f orbital states. The transition from the 3d to 5fsigma* orbital is sensitive to variations in the U?Oaxial bond length and to changes in the bond covalency. We report evidence that the covalence in the uranyl fragment decreases upon dehydration. Photoluminescence spectroscopy at near-liquid helium temperatures reveals significant spectral differences between the two materials, correlating with the X-ray spectroscopy results. A theoretical investigation has been conducted on the structures of both studtite and metastudtite and benchmarked to the HR-XANES spectra. These illustrate the sensitivity of the 3d to 5f sigma* transition toward U?Oaxial bond variation. Small structural changes upon dehydration have been shown to have an important electronic effect on the uranyl fragment. PMID- 29400952 TI - Combining Anisotropic Etching and PDMS Casting for Three-Dimensional Analysis of Laser Ablation Processes. AB - State-of-the-art laser ablation (LA) depth-profiling techniques (e.g. LA-ICP-MS, LIBS, and LIMS) allow for chemical composition analysis of solid materials with high spatial resolution at micro- and nanometer levels. Accurate determination of LA-volume is essential to correlate the recorded chemical information to the specific location inside the sample. In this contribution, we demonstrate two novel approaches towards a better quantitative analysis of LA craters with dimensions at micrometer level formed by femtosecond-LA processes on single crystalline Si(100) and polycrystalline Cu model substrates. For our parametric crater evolution studies, both the number of applied laser shots and the pulse energy were systematically varied, thus yielding 2D matrices of LA craters which vary in depth, diameter, and crater volume. To access the 3D structure of LA craters formed on Si(100), we applied a combination of standard lithographic and deep reactive-ion etching (DRIE) techniques followed by a HR-SEM inspection of the previously formed crater cross sections. As DRIE is not applicable for other material classes such as metals, an alternative and more versatile preparation technique was developed and applied to the LA craters formed on the Cu substrate. After the initial LA treatment, the Cu surface was subjected to a polydimethylsiloxane (PDMS) casting process yielding a mold being a full 3D replica of the LA craters, which was then analyzed by HR-SEM. Both approaches revealed cone-like shaped craters with depths ranging between 1 and 70 MUm and showed a larger ablation depth of Cu that exceed the one of Si by a factor of about 3. PMID- 29400953 TI - Glucose-Appended Platinum(II)-BODIPY Conjugates for Targeted Photodynamic Therapy in Red Light. AB - Platinum(II) complexes [Pt(L1)(R-BODIPY)]Cl (1) and [Pt(L2)(R-BODIPY)]Cl (2), where R-BODIPY is 8-(4-ethynylphenyl)-distyryl-4,4-difluoro-5,7-dimethyl-4-bora 3a,4a-diaza-s-indacene-3, L1 is 4'-phenyl-2,2':6',2"-terpyridine, and L2 is (2,2':6',2"-terpyridin-4'-oxy)ethyl-beta-d-glucopyranoside, were synthesized and characterized, and their photocytotoxicity was studied. The phenylacetylide complex [Pt(L1)(C=CPh)]Cl (3) was prepared and used as a control. Complexes 1 and 2 showed near-IR absorption bands at 713 nm (epsilon = 3.47 * 104 M-1 cm-1) and 715 nm (3.2 * 104 M-1 cm-1) in 10% dimethyl sulfoxide (DMSO)-Dulbecco's Modified Eagle's Medium (DMEM) (pH 7.2). The BODIPY complexes are emissive in 10% DMSO DMEM at pH 7.2 with lambdaem (lambdaex, Phif) = 822 nm (710 nm, 0.022) for complex 1 and lambdaem (lambdaex, Phif) = 825 nm (710 nm, 0.026) for complex 2. They generated singlet oxygen (1O2) in red light as evidenced from 1,3 diphenylisobenzofuran (DPBF) titration experiments. The singlet oxygen quantum yield (PhiDelta) values for 1 and 2 were ~0.6 signifying their photosensitizing ability. They were remarkably photodynamic therapy (PDT) active in red light showing significant red light-induced cytotoxicity in cervical HeLa, lung cancer A549, and breast cancer MCF-7 cells (IC50: 2.3-24.7 MUM in light) with negligible dark toxicity (IC50 > 100 MUM). A significant enhancement in cellular uptake was observed for 2 having glucose-appended terpyridine ligand compared to 1. The confocal microscopy showed significant mitochondrial localization of the complexes as evidenced from the JC-1 assay. The complexes released the photoactive R-BODIPY ligand upon red light-irradiation as evidenced from the mass and 1H NMR spectral studies. Complex 2 is remarkable in satisfying the essential requirements of targeted PDT in red light. PMID- 29400954 TI - Characterization of a Transcriptional Regulator, BrWRKY6, Associated with Gibberellin-Suppressed Leaf Senescence of Chinese Flowering Cabbage. AB - Phytohormone gibberellin (GA) and plant-specific WRKY transcription factors (TFs) are reported to play important roles in leaf senescence. The association of WRKY TFs with GA-mediated leaf senescence of economically important leafy vegetables like Chinese flowering cabbage, however, remains largely unknown. In this study, we showed that exogenous application of GA3 suppressed Chinese flowering cabbage leaf senescence, with GA3-treated cabbages maintaining a higher level of maximum quantum yield (Fv/Fm) and total chlorophyll content. GA3 treatment also led to lower electrolyte leakage and expression level of a series of senescence associated genes (SAGs) including BrSAG12 and BrSAG19, and chlorophyll catabolic genes (CCGs) BrPPH1, BrNYC1, and BrSGRs. In addition, higher transcription levels of GA biosynthetic genes BrKAO2 and BrGA20ox2 were found after GA3 treatment. More importantly, a GA-repressible, nuclear-localized WRKY TF, BrWRKY6, a homologue of the Arabidopsis AtWRKY6, was identified and characterized. BrWRKY6 was GA-repressible and localized in the nucleus. Further experiments revealed that BrWRKY6 repressed the expression of BrKAO2 and BrGA20ox2, while it activated BrSAG12, BrNYC1, and BrSGR1, through binding to their promoters via the W-box cis element. Together, the novel GA-WRKY link reported in our study provides new insight into the transcriptional regulation of GA-suppressed leaf senescence in Chinese flowering cabbage. PMID- 29400955 TI - Localized Surface Plasmon Resonance in Semiconductor Nanocrystals. AB - Localized surface plasmon resonance (LSPR) in semiconductor nanocrystals (NCs) that results in resonant absorption, scattering, and near field enhancement around the NC can be tuned across a wide optical spectral range from visible to far-infrared by synthetically varying doping level, and post synthetically via chemical oxidation and reduction, photochemical control, and electrochemical control. In this review, we will discuss the fundamental electromagnetic dynamics governing light matter interaction in plasmonic semiconductor NCs and the realization of various distinctive physical properties made possible by the advancement of colloidal synthesis routes to such NCs. Here, we will illustrate how free carrier dielectric properties are induced in various semiconductor materials including metal oxides, metal chalcogenides, metal nitrides, silicon, and other materials. We will highlight the applicability and limitations of the Drude model as applied to semiconductors considering the complex band structures and crystal structures that predominate and quantum effects that emerge at nonclassical sizes. We will also emphasize the impact of dopant hybridization with bands of the host lattice as well as the interplay of shape and crystal structure in determining the LSPR characteristics of semiconductor NCs. To illustrate the discussion regarding both physical and synthetic aspects of LSPR active NCs, we will focus on metal oxides with substantial consideration also of copper chalcogenide NCs, with select examples drawn from the literature on other doped semiconductor materials. Furthermore, we will discuss the promise that LSPR in doped semiconductor NCs holds for a wide range of applications such as infrared spectroscopy, energy-saving technologies like smart windows and waste heat management, biomedical applications including therapy and imaging, and optical applications like two photon upconversion, enhanced luminesence, and infrared metasurfaces. PMID- 29400956 TI - Long-Lived Charge-Transfer States of Nickel(II) Aryl Halide Complexes Facilitate Bimolecular Photoinduced Electron Transfer. AB - Here we investigate the photophysics and photochemistry of Ni(II) aryl halide complexes common to cross-coupling and Ni/photoredox reactions. Computational and ultrafast spectroscopic studies reveal that these complexes feature long-lived 3MLCT excited states, implicating Ni as an underexplored alternative to precious metal photocatalysts. Moreover, we show that 3MLCT Ni(II) engages in bimolecular electron transfer with ground-state Ni(II), which enables access to Ni(III) in the absence of external oxidants or photoredox catalysts. As such, it is possible to facilitate Ni-catalyzed C-O bond formation solely by visible light irradiation, thus representing an alternative strategy for catalyst activation in Ni cross-coupling reactions. PMID- 29400957 TI - New alpha-Pyridones with Quorum-Sensing Inhibitory Activity from Diversity Enhanced Extracts of a Streptomyces sp. Derived from Marine Algae. AB - Four new alpha-pyrones (1-4) and eight known analogues (5-12) were identified from the secondary metabolites of Streptomyces sp. OUCMDZ-3436 derived from the marine green algae Enteromorpha prolifera. Seven new alpha-pyridones (14-20) were constructed by diversity-oriented synthesis, which has been an effective approach to expanding the chemical space of natural-product-like compounds. Compounds 16, 17, 19, and 20 were found to have inhibitory effect on the gene expression controlled by quorum sensing in Pseudomonas aeruginosa QSIS-lasI. PMID- 29400958 TI - Spin-Center Shift-Enabled Direct Enantioselective alpha-Benzylation of Aldehydes with Alcohols. AB - Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated "spin-center shift" (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two electron pathways. We report herein an enantioselective alpha-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design. PMID- 29400959 TI - General, Mild, and Selective Method for Desaturation of Aliphatic Amines. AB - A novel method for desaturation of aliphatic amines into enamines as well as allylic and homoallylic amines has been developed. This general protocol operates via putative aryl hybrid Pd-radical intermediates, which combine the signature features of radical chemistry, a hydrogen atom transfer (HAT) process, and transition metal chemistry, a selective beta-hydride elimination step, to achieve efficient and selective desaturation of amines. These hybrid Pd-radical intermediates are efficiently generated under mild photoinduced conditions and are capable of a 1,n-HAT (n = 5-7) event at C(sp3)-H sites. The selectivity of HAT is tunable by varying different auxiliaries, which highlight the generality of this method. Remarkably, this desaturation method, which operates under mild conditions and does not require employment of exogenous photosensitizers or oxidants, can be performed in a practical scalable fashion from simple amines. PMID- 29400960 TI - Comparison of the Magnetic Anisotropy and Spin Relaxation Phenomenon of Dinuclear Terbium(III) Phthalocyaninato Single-Molecule Magnets Using the Geometric Spin Arrangement. AB - Herein we report the synthesis and characterization of a dinuclear TbIII single molecule magnet (SMM) with two [TbPc2]0 units connected via a fused phthalocyaninato ligand. The stable and robust complex [(obPc)Tb(Fused Pc)Tb(obPc)] (1) was characterized by using synchrotron radiation measurements and other spectroscopic techniques (ESI-MS, FT-IR, UV). The magnetic couplings between the TbIII ions and the two pi radicals present in 1 were explored by means of density functional theory (DFT). Direct and alternating current magnetic susceptibility measurements were conducted on magnetically diluted and nondiluted samples of 1, indicating this compound to be an SMM with improved properties compared to those of the well-known [TbPc2]-/0/+ and the axially symmetric dinuclear TbIII phthalocyaninato triple-decker complex (Tb2(obPc)3). Assuming that the probability of quantum tunneling of the magnetization (QTM) occurring in one TbPc2 unit is PQTM, the probability of QTM simultaneously occurring in 1 is PQTM2, meaning that QTM is effectively suppressed. Furthermore, nondiluted samples of 1 underwent slow magnetic relaxation times (tau ~ 1000 s at 0.1 K), and the blocking temperature (TB) was determined to be ca. 16 K with an energy barrier for spin reversal (Ueff) of 588 cm-1 (847 K) due to D4d geometry and weak inter- and intramolecular magnetic interactions as an exchange bias (Hbias), reducing QTM. Four hyperfine steps were observed by micro-SQUID measurement. Furthermore, solution NMR measurements (one-dimensional, two-dimensional, and dynamic) were done on 1, which led to the determination of the high rotation barrier (83 +/- 10 kJ/mol) of the obPc ligand. A comparison with previously reported TbIII triple-decker compounds shows that ambient temperature NMR measurements can indicate improvements in the design of coordination environments for SMMs. A large Ueff causes strong uniaxial magnetic anisotropy in 1, leading to a chiax value (1.39 * 10-30 m3) that is larger than that for Tb2(obPc)3 (0.86 * 10-30 m3). Controlling the coordination environment and spin arrangement is an effective technique for suppressing QTM in TbPc2-based SMMs. PMID- 29400962 TI - Correction to Multimodal Probes: Superresolution and Transmission Electron Microscopy Imaging of Mitochondria, and Oxygen Mapping of Cells, Using Small Molecule Ir(III) Luminescent Complexes. PMID- 29400963 TI - Half-Sandwich Iridium(III) and Ruthenium(II) Complexes Containing P^P-Chelating Ligands: A New Class of Potent Anticancer Agents with Unusual Redox Features. AB - A series of half-sandwich IrIII pentamethylcyclopentadienyl and RuII arene complexes containing P^P-chelating ligands of the type [(Cpx/arene)M(P^P)Cl]PF6, where M = Ir, Cpx is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5 tetramethyl cyclopentadienyl (CpxbiPh); M = Ru, arene is 3-phenylpropan-1-ol (bz PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20 bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(eta6-p-cym)Ru(P^P)Cl]PF6 (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(eta5 Cp*)Ir(P^P)Cl]PF6 (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD+/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G1 phase and G1 phase, respectively, and cause cell apoptosis toward A549 cells. PMID- 29400961 TI - Dioxygen Activation by Nonheme Diiron Enzymes: Diverse Dioxygen Adducts, High Valent Intermediates, and Related Model Complexes. AB - A growing subset of metalloenzymes activates dioxygen with nonheme diiron active sites to effect substrate oxidations that range from the hydroxylation of methane and the desaturation of fatty acids to the deformylation of fatty aldehydes to produce alkanes and the six-electron oxidation of aminoarenes to nitroarenes in the biosynthesis of antibiotics. A common feature of their reaction mechanisms is the formation of O2 adducts that evolve into more reactive derivatives such as diiron(II,III)-superoxo, diiron(III)-peroxo, diiron(III,IV)-oxo, and diiron(IV) oxo species, which carry out particular substrate oxidation tasks. In this review, we survey the various enzymes belonging to this unique subset and the mechanisms by which substrate oxidation is carried out. We examine the nature of the reactive intermediates, as revealed by X-ray crystallography and the application of various spectroscopic methods and their associated reactivity. We also discuss the structural and electronic properties of the model complexes that have been found to mimic salient aspects of these enzyme active sites. Much has been learned in the past 25 years, but key questions remain to be answered. PMID- 29400964 TI - Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin. AB - The human 20S proteasome inhibitor scytonemide A (1), a macrocyclic imine originally isolated from the cyanobacterium Scytonema hofmanni, was synthesized via a biomimetic solid-phase peptide synthesis (SPPS) approach employing the Weinreb AM resin. Utilizing this approach, cyclization of the protected heptapeptide via formation of the imine bond occurred spontaneously upon cleavage from the resin in the presence of a reducing agent and subsequent aqueous workup. The final deprotection step necessary to produce the natural product was accomplished under slightly basic conditions, facilitating cleavage of the silyl ether group while leaving the macrocycle intact. Purification of the synthetic scytonemide A was accomplished via normal-phase flash column chromatography, potentially facilitating larger scale preparation of the compound necessary for future mechanistic and SAR studies. The structure of the target compound was confirmed by NMR spectroscopy, which also shed light on differences in the spectroscopic data obtained for the synthetic and natural scytonemide A samples for some of the amide and alcohol signals in the 1H NMR spectrum. PMID- 29400965 TI - Structure-Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles. AB - The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted MU-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands. PMID- 29400966 TI - Mucroniferanines A-G, Isoquinoline Alkaloids from Corydalis mucronifera. AB - Five pairs of isoquinoline alkaloid enantiomers, mucroniferanines A-E (1-5), two inseparable epimeric pairs, mucroniferanines F and G (6, 7), and 10 known isoquinoline alkaloids (8-17) were obtained from Corydalis mucronifera. The structures were characterized using spectroscopic data analysis, and the absolute configurations were established by ECD and X-ray data analysis. The new compounds except for 3 possess a rare 9-methyl group in the isoquinoline alkaloids, and compounds 2 and 3 possess rare benzo[1,2-d:3,4-d]bis[1,3]dioxole moieties. It is the first report of stereoisomerism involving the 9-methyl phthalideisoquinoline alkaloids. Compounds (-)-4, 6, and 7 exhibited acetylcholinesterase inhibitory activities with IC50 values of 28.3, 12.2, and 11.3 MUM, respectively. PMID- 29400967 TI - Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. AB - The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized. PMID- 29400968 TI - Synthesis of 4-Aryl Isoquinolinedione Derivatives by a Palladium-Catalyzed Coupling Reaction of Aryl Halides with Isoquinoline-1,3(2 H,4 H)-diones. AB - The palladium-catalyzed cross-coupling reaction of aryl halides with isoquinoline 1,3(2 H,4 H)-diones for the synthesis of 4-aryl isoquinoline-1,3(2 H,4 H)-diones was developed. The reaction conditions exhibit remarkable compatibility with various aryl halides and isoquinoline-1,3(2 H,4 H)-diones, and the product could be conveniently transformed to 4-aryl tetrahydroisoquinolines. (+/-) Dichlorofensine was synthesized using this protocol in two steps with an overall yield of 71%. PMID- 29400969 TI - DFT Investigation of the Diastereoselectivity of the MX2 and MX3 Lewis-Acid Catalyzed Mukaiyama Aldol Reaction between C,O,O-Tris(trimethylsilyl)ketene Acetal and Aldehydes. AB - The kinetics and diastereoselectivity of the Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and aromatic substituents is influenced by the nature of Lewis acid catalysts. A density functional theory investigation using the M06-2X exchange-correlation functional and the PCM scheme to account for solvent effects has been carried out to characterize the structure and energetics of the transition state when the Lewis acid is ZnBr2 (MX2) or GaCl3 (MX3) in comparison to the uncatalyzed reaction. The main observations are that (i) the pro-syn transition states are always more stable than the pro-anti ones; (ii) for MX2, the transition state presents a cyclic structure, whereas it is open for MX3, owing to steric interactions; (iii) the difference of activation free enthalpy between the pro anti and pro-syn transition states decreases when the reaction is catalyzed, by either MX2 or MX3, demonstrating a reduction of the diastereoselectivity with respect to the uncatalyzed reaction; (iv) this decrease of diastereoselectivity is larger for MX3- than for MX2-catalyzed reactions; and (v) the MX3-catalyzed reactions are kinetically favored by 1-2 kcal mol-1 with respect to the MX2 ones. PMID- 29400970 TI - Nickel-Catalyzed Desymmetrizing Cross-Electrophile Coupling of Cyclic Meso Anhydrides. AB - A Ni-catalyzed desymmetrizing cross-electrophile coupling of cyclic meso anhydrides with aryl triflates has been successfully demonstrated. This is the only example using cyclic meso-anhydrides in cross-electrophile coupling reactions. A diverse array of valuable gamma-keto acid building blocks can be generated under these conditions with excellent functional group tolerance and stereochemical fidelity. PMID- 29400971 TI - Iridium-Catalyzed Dehydrogenative alpha-Functionalization of (Hetero)aryl-Fused Cyclic Secondary Amines with Indoles. AB - Herein, by employing dehydrogenation as a substrate-activating strategy, a new iridium-catalyzed direct alpha-functionalization of (hetero)aryl-fused cyclic secondary amines with indoles has been demonstrated, which proceeds with merits that include high step- and atom-efficiency, readily available feedstocks, a simple catalyst system, good functional group tolerance, and operational simplicity. PMID- 29400972 TI - Multifunctional Microelectro-Opto-mechanical Platform Based on Phase-Transition Materials. AB - Along with the rapid development of hybrid electronic-photonic systems, multifunctional devices with dynamic responses have been widely investigated for improving many optoelectronic applications. For years, microelectro-opto mechanical systems (MEOMS), one of the major approaches to realizing multifunctionality, have demonstrated profound reconfigurability and great reliability. However, modern MEOMS still suffer from limitations in modulation depth, actuation voltage, or miniaturization. Here, we demonstrate a new MEOMS multifunctional platform with greater than 50% optical modulation depth over a broad wavelength range. This platform is realized by a specially designed cantilever array, with each cantilever consisting of vanadium dioxide, chromium, and gold nanolayers. The abrupt structural phase transition of the embedded vanadium dioxide enables the reconfigurability of the platform. Diverse stimuli, such as temperature variation or electric current, can be utilized to control the platform, promising CMOS-compatible operating voltage. Multiple functionalities, including an active enhanced absorber and a reprogrammable electro-optic logic gate, are experimentally demonstrated to address the versatile applications of the MEOMS platform in fields such as communication, energy harvesting, and optical computing. PMID- 29400973 TI - Metal-Free Synthesis of (E)-Monofluoroenamine from 1-Sulfonyl-1,2,3-triazole and Et2O.BF3 via Stereospecific Fluorination of alpha-Diazoimine. AB - A general, stereospecific, and straightforward method for the rapid preparation of functionalized (E)-monofluoroenamines is reported. Rather than transition metals (Rh, Ni, Pd, Cu, Ag, etc.), Et2O.BF3 was employed to promote the formation of alpha-diazoimine through the Dimroth equilibrium of common 1-sulfonyl-1,2,3 triazole for the first time. An overall migration of fluoride from boron to the diazo-linked carbon of alpha-diazoimine was achieved. Derivations and late-stage modification of bioactive molecule were conducted. A plausible mechanism was also proposed. PMID- 29400974 TI - Bimetallic Au@M (M = Ag, Pd, Fe, and Cu) Nanoarchitectures Mediated by 1,4 Phenylene Diisocyanide Functionalization. AB - Hybridization with gold has attracted a lot of attention in many application areas such as energy, nanomedicine, and catalysts. Here, we demonstrate electrochemical hybridization of two different metals by using bare and 1,4 phenylene diisocyanide (PDI) functionalized gold nanoislands (GNIs) supported on a Si substrate. As pristine GNIs are not tightly locked on the Si surface, bimetallic Au@M (M = Ag, Pd, Fe, and Cu) core-shell type nanostructures are produced by an electric-field-induced clustering of GNIs and metal deposition. On the other hand, upon functionalization of GNIs by PDI, 3D island growth on the functionalized GNI template is observed as PDI acts as a protector against the electric-field-induced clustering. Depth-profiling X-ray photoelectron spectroscopy reveals no discernible difference in the interfacial electronic structures of hybrid metals prepared by using pristine and PDI-functionalized GNI templates. This work demonstrates a new approach to produce a secured template and to manipulate growth of hybrid nanoparticles on this template supported on a Si substrate by using electrodeposition and organic functionalization. PMID- 29400975 TI - Functionalized Magnetic Silica Nanoparticles for Highly Efficient Adsorption of Sm3+ from a Dilute Aqueous Solution. AB - Separation of Sm3+ from a dilute solution via conventional solvent extraction is often plagued by emulsion and third phase formation. These problems can be overcome with functionalized magnetic nanoparticles that can capture the target species and be separated from the raffinae phase rapidly and efficiently on application of a magnetic field. Magentic silica nanoparticles (Fe2O3/SiO2) were synthesized by a modified Stober method and functionalized with carboxylate (Fe2O3/SiO2/RCOONa) and phosphonate (Fe2O3/SiO2/R1R2PO3Na) groups to achieve high adsorption capacity and fast adsorption kinetics. The adsorbents were characterized by X-ray diffraction analysis, transmission electron microscopy, BET measurements, magnetization property evaluation, Fourier infrared spectroscopy, and thermogravimetric analysis. Equilibrium adsorption of Sm3+ on Fe2O3/SiO2/RCOONa particles was attained within 10 min and within 20 min on Fe2O3/SiO2/R1R2PO3Na nanoparticles. The kinetic data were correlated well with a pseudo-second-order model. Adsorption capacities of Fe2O3/SiO2/RCOONa and Fe2O3/SiO2/R1R2PO3Na were 228 and 180 mg/g, respectively. The recovery of the adsorbed Sm3+ using 2 mol/L HCl as desorption agent was evaluated. The adsorption mechanism is discussed based on FTIR analysis, carboxylate group/Sm3+ molar ratio, phosphonate group/Sm3+ molar ratio, and pH. The adsorbents show significant potential for Sm3+ recovery in industrial applications. PMID- 29400976 TI - Acid-Mediated Oxychalcogenation of o-Vinylanilides with N (Arylthio/arylseleno)succinimides. AB - An efficient acid-mediated oxythiolation of o-vinylanilides has been accomplished, employing N-(arylthio)succinimide as an electrophilic arylthiolating reagent for the synthesis of various arylthio tethered benzoxazine derivatives in good to excellent yield. The important features of this method include wide functional group tolerance, quick reaction time, absence of metal or additive, and excellent substrates scope. The developed method was also successfully extended to the oxyselenation of o-vinylanilides in the absence of acid promoter. PMID- 29400977 TI - Highly Active PdNi/RGO/Polyoxometalate Nanocomposite Electrocatalyst for Alcohol Oxidation. AB - A PdNi/RGO/polyoxometalate nanocomposite has been successfully synthesized by a simple wet-chemical method. Characterizations such as transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction analysis, and X-ray photoelectron spectroscopy are employed to verify the morphology, structure, and elemental composition of the as-prepared nanocomposite. Inspired by the fast-developing fuel cells, the electrochemical catalytic performance of the nanocomposite toward methanol and ethanol oxidation in alkaline media is further tested. Notably, the nanocomposite exhibits excellent catalytic activity and long-term stability toward alcohol electrooxidation compared with the PdNi/RGO and commercial Pd/C catalyst. Furthermore, the electrochemical results reveal that the prepared nanocomposite is attractive as a promising electrocatalyst for direct alcohol fuel cells, in which the phosphotungstic acid plays a crucial role in enhancing the electrocatalytic activities of the catalyst. PMID- 29400978 TI - In Situ Resonant Raman Spectroscopy to Monitor the Surface Functionalization of MoS2 and WSe2 for High-k Integration: A First-Principles Study. AB - Surface functionalization of the dangling-bond-free MoS2, WSe2, and other TMDs (transition metal dichalcogenides) is of large practical importance, for example, in providing nucleation sites for the subsequent high-k dielectric integration. Of the surface functionalization methods, the reversible O or N atom adsorption on top of the chalcogen atoms is most promising. However, hazards such as severe oxidation or nitridation persist when the adsorption coverage is high. An in situ characterization technique, which can be integrated with the surface functionalization and dielectric deposition chamber, becomes valuable to enable the real-time monitoring of surface adsorption conditions. Raman spectroscopy, as a nondestructive characterization method without vacuum requirement, is a strong candidate. By utilizing first-principles calculations, Raman spectra of single layer MoS2 and WSe2 with various O/N adsorption coverages are studied. The calculations suggest that the low-coverage O/N adsorbates will act as perturbations to the periodic lattice and activate the acoustic-phonon Raman scatterings. While high-coverage adsorptions will further activate and intensify the optical-phonon Raman scatterings of previously silent A2u and E1g modes, due to the breaking of reflection symmetry in the z direction, new phonon modes associated with the adatom oscillations are also introduced. All these pieces of evidence, together with the peak shifts of previously active A1g and E2g1 modes, suggest that in situ resonant Raman spectroscopy is capable of providing important information to quantify the O/N adsorption coverage and can be used as a valuable real-time characterization technique to monitor and control the surface functionalization conditions of MoS2 and WSe2. PMID- 29400979 TI - Vertical and In-Plane Current Devices Using NbS2/n-MoS2 van der Waals Schottky Junction and Graphene Contact. AB - A van der Waals (vdW) Schottky junction between two-dimensional (2D) transition metal dichalcogenides (TMDs) is introduced here for both vertical and in-plane current devices: Schottky diodes and metal semiconductor field-effect transistors (MESFETs). The Schottky barrier between conducting NbS2 and semiconducting n-MoS2 appeared to be as large as ~0.5 eV due to their work-function difference. While the Schottky diode shows an ideality factor of 1.8-4.0 with an on-to-off current ratio of 103-105, Schottky-effect MESFET displays little gate hysteresis and an ideal subthreshold swing of 60-80 mV/dec due to low-density traps at the vdW interface. All MESFETs operate with a low threshold gate voltage of -0.5 ~ -1 V, exhibiting easy saturation. It was also found that the device mobility is significantly dependent on the condition of source/drain (S/D) contact for n channel MoS2. The highest room temperature mobility in MESFET reaches to approximately more than 800 cm2/V s with graphene S/D contact. The NbS2/n-MoS2 MESFET with graphene was successfully integrated into an organic piezoelectric touch sensor circuit with green OLED indicator, exploiting its predictable small threshold voltage, while NbS2/n-MoS2 Schottky diodes with graphene were applied to extract doping concentrations in MoS2 channel. PMID- 29400980 TI - Collision and Coalescence of Single Attoliter Oil Droplets on a Pipet Nanopore. AB - We describe the use of a quartz pipet nanopore to study the collision and coalescence of individual emulsion oil droplets and their subsequent nanopore translocation. Collision and coalescence of single toluene droplets at a nanopore orifice are driven primarily by electroosmosis and electrophoresis and lead to the fast growth of a trapped oil droplet. This results in a stepwise current response due to the coalesced oil droplet increasing its volume and its ability to partially block the nanopore's ionic current, allowing us to use the resistive pulse method to resolve single droplet collisions. Further growth of the trapped oil droplet leads to a complete blockage of the nanopore and a nearly 100% current decay. The trapped oil droplet shows enormous mechanical stability at lower voltages and stays in its trapped status for hundreds of seconds. An increased voltage can be used to drive the trapped droplet into the pipet pore within several milliseconds. Simultaneous fluorescence imaging and amperometry were performed to examine droplet collision, coalescence, and translocation, further confirming the proposed mechanism of droplet-nanopore interaction. Moreover, we demonstrate the unique ability to perform fast voltammetric measurements on a nanopore-supported attoliter oil droplet and study its voltage driven ion transfer processes. PMID- 29400981 TI - Buffer Layer Assisted Chemistry over Amorphous Solid Water: Oxide Thin Film or Metallic Nanoparticles Formation. AB - Novel procedures to grow pure thin metal oxide films are always welcome in view of their wide range of applications including photocatalysis, solar cells, sensors, and more. In this paper we present a unique way to grow pure nanofilms of metal oxides in vacuo at the temperature range 110-170 K. The reactive layer assisted deposition (RLAD) procedure for thin oxide films growth is based on the evaporation of a reactive metal element on top of a condensed layer of amorphous solid water (D2O-ASW). When applied to metals that do not react with the water layer, the process yields metal nanoclusters on the substrate. We observed that metal oxide films are formed if the redox potential is of -1.0 V or less, leading to deuterium molecules ejection to the gas phase (e.g., Ti and Al) while metals such as Zn, Fe, and Ag, with redox potentials more than -1.0 V, transform into nanoclusters, as revealed by SEM studies. We conclude that the redox potential ia a parameter that enables one to predict the nature and outcome of the ASW buffer layer assisted chemistry. PMID- 29400982 TI - First-Principles Study on Layered C2N-Metal Interfaces. AB - Using first-principles calculations, we perform a comprehensive study of representative metal (Al, Sc, Pd, Ag, Pt, and Au) contacts with monolayer (ML) and bilayer (BL) C2N, which is a low-cost and easily synthesized two-dimensional metal-free semiconductor. Through analyzing the geometries, electronic structures, and Fermi level pinning effects of C2N-metal interfaces, we find metals Al and Sc top contact with ML C2N are Ohmic, which can be ascribed to the strong interactions and large orbital overlaps. Besides, owing to weak van der Waals interactions at interfaces and low work functions of metallic materials, Ohmic contacts can also be realized in ML/BL C2N-Ag and BL C2N-Sc systems. Furthermore, it was also predicted that C2N-Sc and C2N-Ag systems still maintain Ohmic features along the edge contacts. Given the lower resistance of the Ag electrode, the C2N-Ag electrode should be a more attractive electrode in practical applications. These predictions not only provide insights into the fundamental properties of the layered C2N-metal interfaces but also pave way to design high-performance devices using low-cost layered C2N. PMID- 29400983 TI - Palladium-Catalyzed Asymmetric Nitrogen-Selective Addition Reaction of Indoles to Alkoxyallenes. AB - A new palladium-catalyzed asymmetric addition reaction of indoles to alkoxyallenes is reported. Remarkably, the reaction showed complete regioselectivity toward the nitrogen. A new mechanism distinct from that of conventional pi-allyl chemistry is proposed to explain this unique selectivity. The utility of the reaction is demonstrated by highly efficient and flexible synthesis of N-glycosylindoles. PMID- 29400984 TI - Antigen Presentation by Extracellular Vesicles from Professional Antigen Presenting Cells. AB - The initiation and maintenance of adaptive immunity require multifaceted modes of communication between different types of immune cells, including direct intercellular contact, secreted soluble signaling molecules, and extracellular vesicles (EVs). EVs can be formed as microvesicles directly pinched off from the plasma membrane or as exosomes secreted by multivesicular endosomes. Membrane receptors guide EVs to specific target cells, allowing directional transfer of specific and complex signaling cues. EVs are released by most, if not all, immune cells. Depending on the type and status of their originating cell, EVs may facilitate the initiation, expansion, maintenance, or silencing of adaptive immune responses. This review focusses on EVs from professional antigen presenting cells, their demonstrated and speculated roles, and their potential for cancer immunotherapy. PMID- 29400985 TI - IgA Function in Relation to the Intestinal Microbiota. AB - IgA is the dominant immunoglobulin isotype produced in mammals, largely secreted across the intestinal mucosal surface. Although induction of IgA has been a hallmark feature of microbiota colonization following colonization in germ-free animals, until recently appreciation of the function of IgA in host-microbial mutualism has depended mainly on indirect evidence of alterations in microbiota composition or penetration of microbes in the absence of somatic mutations in IgA (or compensatory IgM). Highly parallel sequencing techniques that enable high resolution analysis of either microbial consortia or IgA sequence diversity are now giving us new perspectives on selective targeting of microbial taxa and the trajectory of IgA diversification according to induction mechanisms, between different individuals and over time. The prospects are to link the range of diversified IgA clonotypes to specific antigenic functions in modulating the microbiota composition, position and metabolism to ensure host mutualism. PMID- 29400986 TI - The Genomic Commons. AB - Over its 30 or so years of existence, the genomic commons-the worldwide collection of publicly accessible repositories of human and nonhuman genomic data has enjoyed remarkable, perhaps unprecedented, success. Thanks to the rapid public data release policies initiated by the Human Genome Project, free access to a vast array of scientific data is now the norm, not only in genomics, but in scientific disciplines of all descriptions. And far from being a monolithic creation of bureaucratic fiat, the genomic commons is an exemplar of polycentric, multistakeholder governance. But like all dynamic and rapidly evolving systems, the genomic commons is not without its challenges. Issues involving scientific priority, intellectual property, individual privacy, and informed consent, in an environment of data sets of exponentially expanding size and complexity, must be addressed in the near term. In this review, we describe the characteristics and unique history of the genomic commons, then address some of the trends, challenges, and opportunities that we envision for this valuable public resource in the years to come. PMID- 29400987 TI - Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. AB - PURPOSE: To present a position statement from the Hematology/Oncology Pharmacy Association (HOPA) that pertains to dose rounding of biologic and cytotoxic anticancer agents. METHODS: The HOPA Standards Committee organized a work group of oncology pharmacist specialists to examine the safety and value of dose rounding of biologic and cytotoxic anticancer agents. Primary literature that describes methods for dose rounding, with clinical or economic data, were analyzed. Relevant pharmacokinetic characteristics and aspects of product formulation were considered. Issues for institutional application were addressed. RESULTS: Rounding of biologic and cytotoxic agents within 10% of the ordered dose is designated as acceptable for routine clinical care. Dose changes <= 10% are not expected to reduce the safety or effectiveness of therapy. The rounding amount-10%-is rational in the context of standard dose adjustments for patient tolerance and tumor response (>= 20%), clinical trial deficiency criteria (> 10%), and the influence of interpatient pharmacokinetic variability. HOPA supports the use of the same threshold for dose rounding of anticancer drugs as that used for palliative and curative therapy. Potential exceptions to dose rounding are discussed. CONCLUSION: Dose rounding reduces waste and health care costs. HOPA recommends that each institution develop its own dose-rounding policy that addresses biologic and cytotoxic agents. Institutional guidelines for dose rounding of anticancer agents, including criteria for automatic dose rounding, the allowable percentage, and institutional processes for operationalizing and documenting dose rounding, should be determined by collaborative stakeholder consensus. Exceptions to dose rounding should be determined a priori. Additional studies that evaluate the impact of dose rounding on patient outcome are warranted. PMID- 29400988 TI - The effects of robot assisted gait training on temporal-spatial characteristics of people with spinal cord injuries: A systematic review. AB - CONTEXT: Robotic assisted gait training (RAGT) technology can be used as a rehabilitation tool or as an assistive device for spinal cord injured (SCI) individuals. Its impact on upright stepping characteristics of SCI individuals using treadmill or overground robotic exoskeleton systems has yet to be established. OBJECTIVE: To systematically review the literature and identify if overground or treadmill based RAGT use in SCI individuals elicited differences in temporal-spatial characteristics and functional outcome measures. METHODS: A systematic search of the literature investigating overground and treadmill RAGT in SCIs was undertaken excluding case-studies and case-series. Studies were included if the primary outcomes were temporal-spatial gait parameters. Study inclusion and methodological quality were assessed and determined independently by two reviewers. Methodological quality was assessed using a validated scoring system for randomized and non-randomized trials. RESULTS: Twelve studies met all inclusion criteria. Participant numbers ranged from 5-130 with injury levels from C2 to T12, American Spinal Injuries Association A-D. Three studies used overground RAGT systems and the remaining nine focused on treadmill based RAGT systems. Primary outcome measures were walking speed and walking distance. The use of treadmill or overground based RAGT did not result in an increase in walking speed beyond that of conventional gait training and no studies reviewed enabled a large enough improvement to facilitate community ambulation. CONCLUSION: The use of RAGT in SCI individuals has the potential to benefit upright locomotion of SCI individuals. Its use should not replace other therapies but be incorporated into a multi-modality rehabilitation approach. PMID- 29400989 TI - Barium isotope fractionation during the experimental transformation of aragonite to witherite and of gypsum to barite, and the effect of ion (de)solvation. AB - In this study, we present the experimental results for stable barium (Ba) isotope fractionation (137Ba/134Ba) during the transformation of aragonite (CaCO3) and gypsum (CaSO4.2H2O) in Ba-bearing aqueous solution to witherite (BaCO3) and barite (BaSO4), respectively. The process was studied at three temperatures between 4 and 60 degrees C. In all cases, the transformation leads to a relative enrichment of the lighter 134Ba isotope in the solid compared to the aqueous solution, with 137/134Ba enrichment factors between -0.11 and -0.17 0/00 for BaCO3, and -0.21 and -0.26 0/00 for BaSO4. The corresponding mass-dependent 138/134Ba enrichment factors are -0.15 to -0.23 0/00 for BaCO3, and -0.28 to 0.35 0/00 for BaSO4. The magnitude of isotope fractionation is within the range of recent reports for witherite and barite formation, as well as trace Ba incorporation into orthorhombic aragonite, and no substantial impact of temperature can be found between 4 and 80 degrees C. In previous studies, ion (de)solvation has been suggested to impact both the crystallization process of Ba bearing solids and associated Ba isotope fractionation. Precipitation experiments of BaSO4 and BaCO3 using an methanol-containing aqueous solution indicate only a minor effect of ion and crystal surface (de)solvation on the overall Ba isotope fractionation process. PMID- 29400990 TI - Inspiratory muscle training is feasible and safe for patients with acute spinal cord injury. AB - Objective To investigate the feasibility and safety and, to a lesser extent efficacy, of inspiratory muscle training (IMT) for patients with acute complete cervical or thoracic spinal cord injury (SCI). Design Prospective, observational pilot study comprising a series of case reports. Setting Tertiary care, public hospital. Participants Seven adult subjects with an acute complete cervical or thoracic SCI. Interventions Participants received IMT as soon as their respiratory condition was stable. A high-resistance, low-repetition program of IMT using a POWERbreathe KH1 device was instituted. Training comprised 3-6 sets of 6 breaths, commenced at 50% maximum inspiratory pressure with the training load progressively increased. Outcome measures Feasibility (number of sessions when the criteria to participate in IMT were met/not met), safety (symptoms and physiological stability) before, during and after IMT sessions and efficacy (lung function) were measured. Results There were 50 sessions in total where participants met the criteria to receive IMT, with a mean (range) of 7.1 (3-11) IMT sessions per participant delivered over 10.7 (4-17) days. IMT was feasible, with all 50 planned sessions of IMT able to be delivered, and safe, with stable physiological parameters and no adverse symptoms or events recorded before, during or after IMT. Maximal inspiratory pressure increased for four participants and forced vital capacity increased for three participants over the duration of their IMT sessions. Conclusion A high-resistance, low-repetition program of IMT was feasible and safe in adults with an acute complete cervical or thoracic SCI whose respiratory status was stable. Trial registration Australian New Zealand Clinical Trials Registry (ACTRN 12614000975695). PMID- 29400991 TI - Lifestyle genomics and the metabolic syndrome: A review of genetic variants that influence response to diet and exercise interventions. AB - Metabolic syndrome (MetS) comprises a cluster of risk factors that includes central obesity, dyslipidemia, impaired glucose homeostasis and hypertension. Individuals with MetS have elevated risk of type 2 diabetes and cardiovascular disease; thus placing significant burdens on social and healthcare systems. Lifestyle interventions (comprised of diet, exercise or a combination of both) are routinely recommended as the first line of treatment for MetS. Only a proportion of people respond, and it has been assumed that psychological and social aspects primarily account for these differences. However, the etiology of MetS is multifactorial and stems, in part, on a person's genetic make-up. Numerous single nucleotide polymorphisms (SNPs) are associated with the various components of MetS, and several of these SNPs have been shown to modify a person's response to lifestyle interventions. Consequently, genetic variants can influence the extent to which a person responds to changes in diet and/or exercise. The goal of this review is to highlight SNPs reported to influence the magnitude of change in body weight, dyslipidemia, glucose homeostasis and blood pressure during lifestyle interventions aimed at improving MetS components. Knowledge regarding these genetic variants and their ability to modulate a person's response will provide additional context for improving the effectiveness of personalized lifestyle interventions that aim to reduce the risks associated with MetS. PMID- 29400992 TI - Promoting Prevention Under the Affordable Care Act. AB - The Affordable Care Act (ACA) of 2010 placed a substantial emphasis on public health and prevention. Subsequent research on its effects reveals some notable successes and some missteps and offers important lessons for future legislators. The ACA's Prevention and Public Health Fund, intended to give public health budgetary flexibility, provided crucial funding for public health services during the Great Recession but proved highly vulnerable to subsequent budget cuts. Several programs that aimed to increase strategic thinking and planning around public health at the state level have proven to be more enduring, suggesting that the convening authority of the federal government can be a powerful tool for progress, especially when buttressed by some funding. Most important, by expanding insurance and mandating a minimum level of coverage, the ACA both increased access to clinical preventive services and freed up local public health budgets to engage in population health activities. PMID- 29400993 TI - Migrant Workers and Their Occupational Health and Safety. AB - In 2015, approximately 244 million people were transnational migrants, approximately half of whom were workers, often engaged in jobs that are hazardous to their health. They work for less pay, for longer hours, and in worse conditions than do nonmigrants and are often subject to human rights violations, abuse, human trafficking, and violence. Worldwide, immigrant workers have higher rates of adverse occupational exposures and working conditions, which lead to poor health outcomes, workplace injuries, and occupational fatalities. Health disparities of immigrant workers are related to environmental and occupational exposures and are a result of language/cultural barriers, access to health care, documentation status, and the political climate of the host country. Recommendations on global and local scales are offered as potential solutions to improving the health of immigrant workers. PMID- 29400994 TI - Advances in Understanding the Molecular Basis of the Mediterranean Diet Effect. AB - Increasingly, studies showing the protective effects of the Mediterranean diet (MedDiet) on different diseases (cardiovascular, diabetes, some cancers, and even total mortality and aging indicators) are being published. The scientific evidence level for each outcome is variable, and new studies are needed to better understand the molecular mechanisms whereby the MedDiet may exercise its effects. Here, we present recent advances in understanding the molecular basis of MedDiet effects, mainly focusing on cardiovascular diseases but also discussing other related diseases. There is heterogeneity in defining the MedDiet, and it can, owing to its complexity, be considered as an exposome with thousands of nutrients and phytochemicals. We review MedDiet composition and assessment as well as the latest advances in the genomic, epigenomic (DNA methylation, histone modifications, microRNAs, and other emerging regulators), transcriptomic (selected genes and whole transcriptome), and metabolomic and metagenomic aspects of the MedDiet effects (as a whole and for its most typical food components). We also present a critical review of the limitations of the studies undertaken and propose new analyses and greater bioinformatic integration to better understand the most important molecular mechanisms whereby the MedDiet as a whole, or its main food components, may exercise their protective effects. PMID- 29400995 TI - Use of Electrohydrodynamic Processing for Encapsulation of Sensitive Bioactive Compounds and Applications in Food. AB - The use of vitamins, polyphenolic antioxidants, omega-3 polyunsaturated fatty acids (PUFAs), and probiotics for the fortification of foods is increasing. However, these bioactive compounds have low stability and need to be protected to avoid deterioration in the food system itself or in the gastrointestinal tract. For that purpose, efficient encapsulation of the compounds may be required. Spray drying is one of the most commonly used encapsulation techniques in the food industry, but it uses high temperature, which can lead to decomposition of the bioactive compounds. Recently, alternative technologies such as electrospraying and electrospinning have received increasing attention. This review presents the principles of electrohydrodynamic processes for the production of nano microstructures (NMSs) containing bioactive compounds. It provides an overview of the current use of this technology for encapsulation of bioactive compounds and discusses the future potential of the technology. Finally, the review discusses advanced microscopy techniques to study the morphology of NMSs. PMID- 29400996 TI - Morphological and Molecular Characterization of Post-Larval Pre-Tetrathyridia of Mesocestoides sp. (Cestoda: Cyclophyllidea) from Ground Skink, Scincella lateralis (SAURIA: SCINCIDAE), FROM SOUTHEASTERN OKLAHOMA. AB - Free pre-tetrathyridia of Mesocestoides sp. are described, for the first time, from samples obtained from the coelomic cavity of a ground skink, Scincella lateralis, from Oklahoma. Closer examination of these early-stage tapeworms revealed they were transitional metamorphosis stages between a post-hexacanth procercoid form to the full metacestode of Mesocestoides. A series of transitional stages was found that span the full period of sucker and apical organ development. However, we did not see any fully developed tetrathyridia, i.e., having classic Mesocestoides morphology but with the apical sucker absent following developmental atrophy. This is the first time that metamorphic pre tetrathyridial stages of a Mesocestoides sp. have been reported in vivo from a natural infection. These observations corroborate earlier reports of such stages of Mesocestoides vogae developed in vitro, though the previously reported isolate of M. vogae is asexually proliferative, and the species from the present study showed no sign of asexual proliferation. The fact that these immediately post hexacanth stages can occur in a single lizard intermediate host may suggest that Mesocestoides spp. might develop through a simple 2-host life cycle rather than an obligate 3-host cycle that has been speculated to occur by most previous authors. DNA sequence comparisons and phylogenetic analyses based on mitochondrial 12S, cox1, and nad1 genes have demonstrated that our specimens from S. lateralis represent a species clearly distinct from all previously sequenced Mesocestoides and closely related to 2 forms from domestic dogs and Channel Island fox in California previously published as Mesocestoides sp. C. PMID- 29400998 TI - Apoptosis and Clearance of Apoptotic Cells. AB - The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an "eat me" signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease. PMID- 29400997 TI - Intradermal delivery of a fractional dose of influenza H7N9 split vaccine elicits protective immunity in mice and rats. AB - Vaccination is the most effective method of preventing the spread of the influenza virus. However, the traditional intramuscular (IM) immunization causes fear, pain, and cross infection. In contrast, needle-free (NF) immunization is quick and easy for medical personnel and painless and safe for patients. In this study, we assessed the safety and protective efficacy of NF intradermal (ID) immunization with the influenza H7N9 split vaccine (Anhui H7N9/PR8). A preliminary safety evaluation showed that ID immunization with 15 MUg of the H7N9 influenza vaccine was not toxic in rats. Moreover, the antigen was metabolized more rapidly after ID than after IM immunization, as determined by in vivo imaging, and ID immunization accelerated the generation of a specific immune response. Additionally, ID immunization with a 20% dose of the H7N9 split vaccine Anhui H7N9/PR8 offered complete protection against lethal challenge by the live H7N9 virus. Taken together, our findings suggest that NF ID immunization with the H7N9 influenza vaccine induces effective protection, has a good safety profile, requires little antigen, and elicits an immune response more rapidly than does IM immunization. This approach may be used to improve the control of influenza H7N9 outbreaks. PMID- 29400999 TI - The Formation and Function of Granulomas. AB - Granulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells. These evolutionarily ancient structures form in response to persistent particulate stimuli-infectious or noninfectious-that individual macrophages cannot eradicate. Granulomas evolved as protective responses to destroy or sequester particles but are frequently pathological in the context of foreign bodies, infections, and inflammatory diseases. We summarize recent findings that suggest that the granulomatous response unfolds in a stepwise program characterized by a series of macrophage activations and transformations that in turn recruit additional cells and produce structural changes. We explore why different granulomas vary and the reasons that granulomas are protective and pathogenic. Understanding the mechanisms and role of granuloma formation may uncover new therapies for the multitude of granulomatous diseases that constitute serious medical problems while enhancing the protective function of granulomas in infections. PMID- 29401000 TI - Principles of Protein Stability and Their Application in Computational Design. AB - Proteins are increasingly used in basic and applied biomedical research. Many proteins, however, are only marginally stable and can be expressed in limited amounts, thus hampering research and applications. Research has revealed the thermodynamic, cellular, and evolutionary principles and mechanisms that underlie marginal stability. With this growing understanding, computational stability design methods have advanced over the past two decades starting from methods that selectively addressed only some aspects of marginal stability. Current methods are more general and, by combining phylogenetic analysis with atomistic design, have shown drastic improvements in solubility, thermal stability, and aggregation resistance while maintaining the protein's primary molecular activity. Stability design is opening the way to rational engineering of improved enzymes, therapeutics, and vaccines and to the application of protein design methodology to large proteins and molecular activities that have proven challenging in the past. PMID- 29401001 TI - When Action-Inaction Framing Leads to Higher Escalation of Commitment: A New Inaction-Effect Perspective on the Sunk-Cost Fallacy. AB - Escalation of commitment to a failing course of action occurs in the presence of (a) sunk costs, (b) negative feedback that things are deviating from expectations, and (c) a decision between escalation and de-escalation. Most of the literature to date has focused on sunk costs, yet we offer a new perspective on the classic escalation-of-commitment phenomenon by focusing on the impact of negative feedback. On the basis of the inaction-effect bias, we theorized that negative feedback results in the tendency to take action, regardless of what that action may be. In four experiments, we demonstrated that people facing escalation decision situations were indeed action oriented and that framing escalation as action and de-escalation as inaction resulted in a stronger tendency to escalate than framing de-escalation as action and escalation as inaction (mini-meta analysis effect d = 0.37, 95% confidence interval = [0.21, 0.53]). PMID- 29401003 TI - Prostate Cancer Screening and the Goldilocks Principle: How Much Is Just Right? PMID- 29401002 TI - Phosphatidylinositol 3-Kinase alpha-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. AB - Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase alpha (PI3Kalpha)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses >= 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (>= 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA altered solid tumors, supporting the rationale for selective PI3Kalpha inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors. PMID- 29401004 TI - Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. AB - Purpose In response to advances in the field, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recently updated their recommendations for molecular testing for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The molecular testing guideline was reviewed for developmental rigor by methodologists. Then an ASCO Expert Panel reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline with minor modifications. Recommendations This update clarifies that any sample with adequate cellularity and preservation may be tested and that analytical methods must be able to detect mutation in a sample with as little as 20% cancer cells. It strongly recommends against evaluating epidermal growth factor receptor (EGFR) expression by immunohistochemistry for selection of patients for EGFR-targeted therapy. New for 2018 are recommendations for stand-alone ROS1 testing with additional confirmation testing in all patients with advanced lung adenocarcinoma, and RET, ERBB2 (HER2), KRAS, and MET testing as part of larger panels. ASCO also recommends stand-alone BRAF testing in patients with advanced lung adenocarcinoma. Recommendations are also provided for testing methods for lung cancers that have a nonadenocarcinoma non-small-cell component, for patients with targetable mutations who have relapsed on targeted therapy, and for testing the presence of circulating cell-free DNA. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki . PMID- 29401005 TI - Association Of A Regional Health Improvement Collaborative With Ambulatory Care Sensitive Hospitalizations. AB - Although regional health improvement collaboratives have been adopted nationwide to improve primary care quality, their effects on avoidable hospitalizations and costs remain unclear. We quantified the association of the Better Health Partnership, a primary care-led regional health improvement collaborative operating in Cuyahoga County, Ohio (Cleveland and surrounding suburbs), with hospitalization rates for ambulatory care-sensitive conditions. The partnership uses a positive deviance approach to identify, disseminate publicly, and accelerate adoption of best practices for care of patients with diabetes, heart failure, and hypertension. Using a difference-in-differences approach, we compared rates of hospitalizations for ambulatory care-sensitive conditions in six Ohio counties before (2003-08) and after (2009-14) the establishment of the partnership. Age- and sex-adjusted hospitalization rates for targeted ambulatory care-sensitive conditions in Cuyahoga County declined significantly more than the rates in the comparator counties in 2009-11 (106 fewer hospitalizations per 100,000 adult residents) and 2012-14 (91 fewer hospitalizations). We estimated that 5,746 hospitalizations for ambulatory care-sensitive conditions were averted in 2009-14, leading to cost savings of nearly $40 million. PMID- 29401006 TI - Government As Innovation Catalyst: Lessons From The Early Center For Medicare And Medicaid Innovation Models. AB - Congress established the Center for Medicare and Medicaid Innovation (CMMI) to design, test, and spread innovative payment and service delivery models that either reduce spending without reducing the quality of care or improve the quality of care without increasing spending. CMMI sought to leverage these models to foster market innovation and accelerate the transformation of payment and care delivery to achieve the Triple Aim of better health, better care, and lower cost. This article provides a perspective on the design and execution of CMMI's five initial models, the resulting outcomes and lessons, and how their core concepts evolved within and spread beyond CMMI. This experience yields three key insights that could inform future efforts by CMMI and public and private payers, including model designs and policy decisions. These insights center on the need for iterative testing and learning guided by market feedback, more realistic time frames to demonstrate impact on cost and quality, and greater integration of models. PMID- 29401008 TI - Emergency Psychiatric Care: The Authors Reply. PMID- 29401009 TI - Emergency Care For The Mentally Ill. PMID- 29401010 TI - Errata. PMID- 29401011 TI - Diffusion Of Innovations Theory, Principles, And Practice. AB - Aspects of the research and practice paradigm known as the diffusion of innovations are applicable to the complex context of health care, for both explanatory and interventionist purposes. This article answers the question, "What is diffusion?" by identifying the parameters of diffusion processes: what they are, how they operate, and why worthy innovations in health care do not spread more rapidly. We clarify how the diffusion of innovations is related to processes of dissemination and implementation, sustainability, improvement activity, and scale-up, and we suggest the diffusion principles that can be readily used in the design of interventions. PMID- 29401012 TI - The Hidden Roles That Management Partners Play In Accountable Care Organizations. AB - Accountable care organizations (ACOs) are often discussed and promoted as driven by physicians, hospitals, and other health care providers. However, because of the flexible nature of ACO contracts, management organizations may also become partners in ACOs. We used data from 2013-15 on 276 ACOs from the National Survey of Accountable Care Organizations to understand the prevalence of nonprovider management partners' involvement in ACOs, the services these partners provide, and the structure of ACOs that have such partners. We found that 37 percent of ACOs reported having a management partner, and two-thirds of these ACOs reported that the partner shared in the financial risks or rewards. Among ACOs with partners, 94 percent had data services provided by the partner, 87 percent received administrative services, 68 percent received educational services, and 66 percent received care coordination services. Half received all four of these services from their partner. ACOs with partners were more heavily primary care than other ACOs. ACOs with and without partners had similar performance on costs and quality in Medicare ACO programs. Our findings suggest that management partners play a central role in many ACOs, perhaps supplying smaller and physician-run ACOs with services or expertise perceived as necessary for ACO success. PMID- 29401013 TI - New Risk-Adjustment Policies Reduce But Do Not Eliminate Special Enrollment Period Underpayment. AB - Millions of uninsured Americans do not sign up for available coverage despite job loss or other factors that would make them eligible for special enrollment periods (SEPs). Such periods let people enroll in nongroup insurance outside the usual open enrollment period for Marketplace coverage. Concerned that risk adjustment results in underpayment for the health risks associated with SEP enrollees, carriers rarely market their products to consumers eligible for SEPs, and many do not pay agents and brokers to enroll such consumers. To address the apparent underpayments, federal officials added enrollment duration factors that, starting in 2017, increased risk scores for SEP enrollees and other part-year members. Using individual-market claims data for 2015 from two large carriers, we found that risk adjustment did, in fact, undercompensate plans for part-year members. However, underpayment was much larger for SEP enrollees than for part year members who joined during open enrollment periods. Short-term, urgent health problems appeared to drive enrollment more for SEP enrollees than for part-year members who signed up during open enrollment. We also found that the federal government's enrollment duration factors will remedy underpayment for part-year members whose coverage begins during open enrollment but leave carriers significantly underpaid for SEP enrollees. For carriers to recruit rather than avoid SEP enrollees, further increases to risk adjustment for such enrollees are likely needed. PMID- 29401014 TI - Learning Collaboratives: Insights And A New Taxonomy From AHRQ's Two Decades Of Experience. AB - Learning collaboratives are increasingly used as mechanisms to support and hasten the diffusion and implementation of innovation, clinical evidence, and effective models of care. Factors contributing to the collaboratives' success or failure are poorly understood. The Agency for Healthcare Research and Quality (AHRQ) has sponsored collaboratives for nearly two decades to support improvements in health care quality and value by accelerating the diffusion and implementation of innovation. We examined AHRQ's experience with these collaboratives to characterize their attributes, identify factors that might contribute to their success or failure, and assess the challenges they encountered. Building on the literature and insights from AHRQ's experience, we propose a taxonomy that can offer guidance to decision makers and funders about the factors they should consider in developing collaboratives and planning their evaluation, as well as to researchers who seek to conduct research that will ultimately help decision makers make better investments in diffusing innovation and evidence. PMID- 29401015 TI - Palliative Care Leadership Centers Are Key To The Diffusion Of Palliative Care Innovation. AB - Between 2000 and 2015 the proportion of US hospitals with more than fifty beds that had palliative care programs tripled, from 25 percent to 75 percent. The rapid adoption of this high-value program, which is voluntary and runs counter to the dominant culture in US hospitals, was catalyzed by tens of millions of dollars in philanthropic support for innovation, dissemination, and professionalization in the palliative care field. We describe the dissemination strategies of the Center to Advance Palliative Care in the context of the principles of social entrepreneurship, and we provide an in-depth look at its hallmark training initiative, Palliative Care Leadership Centers. Over 1,240 hospital palliative care teams have trained at the Leadership Centers to date, with 80 percent of them instituting palliative care services within two years. We conclude with lessons learned about the role of purposeful technical assistance in promoting the rapid diffusion of high-value health care innovation. PMID- 29401016 TI - Taking Innovation To Scale In Primary Care Practices: The Functions Of Health Care Extension. AB - Health care extension is an approach to providing external support to primary care practices with the aim of diffusing innovation. EvidenceNOW was launched to rapidly disseminate and implement evidence-based guidelines for cardiovascular preventive care in the primary care setting. Seven regional grantee cooperatives provided the foundational elements of health care extension-technological and quality improvement support, practice capacity building, and linking with community resources-to more than two hundred primary care practices in each region. This article describes how the cooperatives varied in their approaches to extension and provides early empirical evidence that health care extension is a feasible and potentially useful approach for providing quality improvement support to primary care practices. With investment, health care extension may be an effective platform for federal and state quality improvement efforts to create economies of scale and provide practices with more robust and coordinated support services. PMID- 29401017 TI - Rethinking The Traditional Doctor's Visit. AB - A physician and a patient find the missing element for healing in an alternative model of care: shared medical appointments. PMID- 29401019 TI - Diffusion Of Innovation. AB - Health care providers are in the midst of a massive effort to diffuse innovative approaches to patient care. While most innovations fail, a few diffuse successfully and are sustained. This month's DataGraphic describes the spread or outcomes of four important health care delivery innovations adopted by hospitals or primary care clinicians: hospital palliative care, electronic consults for preoperative anesthesiology assessment, Medicare's free annual wellness visit, and a primary care improvement network. PMID- 29401018 TI - Innovative Use Of Electronic Consultations In Preoperative Anesthesiology Evaluation At VA Medical Centers In New England. AB - Electronic consultations (e-consults) improve access to specialty care without requiring face-to-face patient visits. We conducted a mixed-methods descriptive study to understand the variability in e-consult use across anesthesiology departments in the Veterans Affairs New England Healthcare System (VANEHS). In the period 2012-15, the system experienced a rapid increase in the use of anesthesiology e-consults: 5,023 were sent in 2015, compared with 103 in 2012. Uptake across sites varied from near-universal use of e-consults for preoperative assessment to use for only selected low-risk patients or no use. Interviews with stakeholders revealed considerable differences in the perceived impact of e consults on workflow and patient-centeredness. Clinicians at sites with high use of e-consults noted that they improved workflow efficiency. In comparison, clinicians at sites with low use preferentially valued face-to-face visits for some or all patients. The adoption of a health information technology innovation can alter the process of care delivery, depending on perceptions of its value by key stakeholders. PMID- 29401020 TI - Overcoming Challenges In Codifying And Replicating Complex Health Care Interventions. AB - The complex nature of many health care interventions poses challenges for successful replication. This article presents insights on tackling these challenges primarily drawn from recent research and programs in the UK. These insights include the need to codify complex interventions in ways that reflect their social, context-sensitive, and dynamic nature; to capture learning as the intervention is implemented in new contexts; and to design programs in ways that respect adopters' role in the spread process. We argue that program leaders should have familiarity with theoretical approaches for conceptualizing complex interventions, that a discrete testing-and-revision phase should be recognized as part of the spread process, and that programs should be designed in ways that build and sustain adopter commitment. These perspectives complement the traditional focus on the innovator in models of spread by highlighting the role adopters play in adapting interventions and generating learning, and they have implications for the design of programs to spread innovation. PMID- 29401021 TI - The Equity Impact Vaccines May Have On Averting Deaths And Medical Impoverishment In Developing Countries. AB - With social policies increasingly directed toward enhancing equity through health programs, it is important that methods for estimating the health and economic benefits of these programs by subpopulation be developed, to assess both equity concerns and the programs' total impact. We estimated the differential health impact (measured as the number of deaths averted) and household economic impact (measured as the number of cases of medical impoverishment averted) of ten antigens and their corresponding vaccines across income quintiles for forty-one low- and middle-income countries. Our analysis indicated that benefits across these vaccines would accrue predominantly in the lowest income quintiles. Policy makers should be informed about the large health and economic distributional impact that vaccines could have, and they should view vaccination policies as potentially important channels for improving health equity. Our results provide insight into the distribution of vaccine-preventable diseases and the health benefits associated with their prevention. PMID- 29401022 TI - A Payer-Guided Approach To Widespread Diffusion Of Behavioral Health Homes In Real-World Settings. AB - People with serious mental illness experience decreased life expectancy related to co-occurring medical conditions. A nonprofit behavioral health managed care organization implemented an innovative behavioral health home, in partnership with community mental health providers, to build a culture of wellness among all staff members, with a focus on prevention and holistic (that is, behavioral, social, and physical) health. The behavioral health home added one of two distinct care approaches, one patient driven and the other provider driven. The innovative approaches were implemented at eleven community mental health providers: Six delivered patient-driven care, and five delivered provider-driven care. We studied outcomes in the period October 2013-January 2016. Multiple diffusion strategies were utilized to encourage uptake. Our results revealed that both approaches significantly increased patient activation in care (more quickly in provider-supported care), engagement in primary and specialty care, and perceived mental health status. The success of this behavioral health home in improving important outcomes and the use of novel diffusion strategies led to its dissemination to forty-three additional providers across Pennsylvania. PMID- 29401023 TI - Errata. PMID- 29401025 TI - Errata. PMID- 29401024 TI - The Choosing Wisely Campaign. PMID- 29401026 TI - Funders' Efforts To Prevent Substance Use Disorders. PMID- 29401027 TI - Integrating Social Needs Into Health Care: A Twenty-Year Case Study Of Adaptation And Diffusion. AB - The US health care system has recently begun to account for patients' unmet social needs in care delivery and payment reform. This article presents a twenty year qualitative case study of five stages of diffusion-testing and learning, standardization, replication, shifting from doing to enabling, and catalyzing broad adoption-of a practical approach for integrating social needs into clinical care. This case study of Health Leads and its funders confirms the importance of focusing on a clear aim, investing in model testing and standardization to enable subsequent responsiveness to the market, and the willingness of innovators and their investors to cede control of a model to allow local adaption and accelerate broad adoption. PMID- 29401028 TI - Medicaid Expansion And Payday Loans. PMID- 29401030 TI - Road Map For Diffusion Of Innovation In Health Care. AB - New scientific knowledge and innovation are often slow to disseminate. In other cases, providers rush into adopting what appears to be a clinically relevant innovation, based on a single clinical trial. In reality, adopting innovations without appropriate translation and repeated testing of practical application is problematic. In this article we provide examples of clinical innovations (for example, tight glucose control in critically ill patients) that were adopted inappropriately and that caused what we term a malfunction. To address the issue of malfunctions, we review various examples and suggest frameworks for the diffusion of knowledge leading to the adoption of useful innovations. The resulting model is termed an integrated road map for coordinating knowledge transformation and innovation adoption. We make recommendations for the targeted development of practice change procedures, practice change assessment, structured descriptions of tested interventions, intelligent knowledge management technologies, and policy support for knowledge transformation, including further standardization to facilitate sharing among institutions. PMID- 29401031 TI - Data-Driven Diffusion Of Innovations: Successes And Challenges In 3 Large-Scale Innovative Delivery Models. AB - Failed diffusion of innovations may be linked to an inability to use and apply data, information, and knowledge to change perceptions of current practice and motivate change. Using qualitative and quantitative data from three large-scale health care delivery innovations-accountable care organizations, advanced primary care practice, and EvidenceNOW-we assessed where data-driven innovation is occurring and where challenges lie. We found that implementation of some technological components of innovation (for example, electronic health records) has occurred among health care organizations, but core functions needed to use data to drive innovation are lacking. Deficits include the inability to extract and aggregate data from the records; gaps in sharing data; and challenges in adopting advanced data functions, particularly those related to timely reporting of performance data. The unexpectedly high costs and burden incurred during implementation of the innovations have limited organizations' ability to address these and other deficits. Solutions that could help speed progress in data-driven innovation include facilitating peer-to-peer technical assistance, providing tailored feedback reports to providers from data aggregators, and using practice facilitators skilled in using data technology for quality improvement to help practices transform. Policy efforts that promote these solutions may enable more rapid uptake of and successful participation in innovative delivery system reforms. PMID- 29401032 TI - HIV Prevention Drug's Slow Uptake Undercuts Its Early Promise. AB - Initially billed as a game changer, Truvada has faced multiple obstacles to widespread adoption. PMID- 29401033 TI - Diffusion Of Innovation. PMID- 29401035 TI - Practices Caring For The Underserved Are Less Likely To Adopt Medicare's Annual Wellness Visit. AB - In 2011 Medicare introduced the annual wellness visit to help address the health risks of aging adults. The visit also offers primary care practices an opportunity to generate revenue, and may allow practices in accountable care organizations to attract healthier patients while stabilizing patient practitioner assignments. However, uptake of the visit has been uneven. Using national Medicare data for the period 2008-15, we assessed practices' ability and motivation to adopt the visit. In 2015, 51.2 percent of practices provided no annual wellness visits (nonadopters), while 23.1 percent provided visits to at least a quarter of their eligible beneficiaries (adopters). Adopters replaced problem-based visits with annual wellness visits and saw increases in primary care revenue. Compared to nonadopters, adopters had more stable patient assignment and a slightly healthier patient mix. At the same time, visit rates were lower among practices caring for underserved populations (for example, racial minorities and those dually enrolled in Medicaid), potentially worsening disparities. Policy makers should consider ways to encourage uptake of the visit or other mechanisms to promote preventive care in underserved populations and the practices that serve them. PMID- 29401036 TI - Slow Photoelectron Velocity-Map Imaging of Cryogenically Cooled Anions. AB - Slow photoelectron velocity-map imaging spectroscopy of cryogenically cooled anions (cryo-SEVI) is a powerful technique for elucidating the vibrational and electronic structure of neutral radicals, clusters, and reaction transition states. SEVI is a high-resolution variant of anion photoelectron spectroscopy based on photoelectron imaging that yields spectra with energy resolution as high as 1-2 cm-1. The preparation of cryogenically cold anions largely eliminates hot bands and dramatically narrows the rotational envelopes of spectral features, enabling the acquisition of well-resolved photoelectron spectra for complex and spectroscopically challenging species. We review the basis and history of the SEVI method, including recent experimental developments that have improved its resolution and versatility. We then survey recent SEVI studies to demonstrate the utility of this technique in the spectroscopy of aromatic radicals, metal and metal oxide clusters, nonadiabatic interactions between excited states of small molecules, and transition states of benchmark bimolecular reactions. PMID- 29401037 TI - Excitons in Single-Walled Carbon Nanotubes and Their Dynamics. AB - Understanding exciton dynamics in single-walled carbon nanotubes (SWCNTs) is essential to unlocking the many potential applications of these materials. This review summarizes recent progress in understanding exciton photophysics and, in particular, exciton dynamics in SWCNTs. We outline the basic physical and electronic properties of SWCNTs, as well as bright and dark transitions within the framework of a strongly bound one-dimensional excitonic model. We discuss the many facets of ultrafast carrier dynamics in SWCNTs, including both single exciton states (bright and dark) and multiple-exciton states. Photophysical properties that directly relate to excitons and their dynamics, including exciton diffusion lengths, chemical and structural defects, environmental effects, and photoluminescence photon statistics as observed through photon antibunching measurements, are also discussed. Finally, we identify a few key areas for advancing further research in the field of SWCNT excitons and photonics. PMID- 29401038 TI - Permutationally Invariant Potential Energy Surfaces. AB - Over the past decade, about 50 potential energy surfaces (PESs) for polyatomics with 4-11 atoms and for clusters have been calculated using the permutationally invariant polynomial method. This is a general, mainly linear least-squares method for precise mathematical fitting of tens of thousands of electronic energies for reactive and nonreactive systems. A brief tutorial of the methodology is given, including several recent improvements. Recent applications to the formic acid dimer (the current record holder in size for a reactive system), the H2-H2O complex, and four protonated water clusters [H+(H2O)n=2,3,4,6] are given. The last application also illustrates extension to large clusters using the many-body representation. PMID- 29401039 TI - Graph Theory and Ion and Molecular Aggregation in Aqueous Solutions. AB - In molecular and cellular biology, dissolved ions and molecules have decisive effects on chemical and biological reactions, conformational stabilities, and functions of small to large biomolecules. Despite major efforts, the current state of understanding of the effects of specific ions, osmolytes, and bioprotecting sugars on the structure and dynamics of water H-bonding networks and proteins is not yet satisfactory. Recently, to gain deeper insight into this subject, we studied various aggregation processes of ions and molecules in high concentration salt, osmolyte, and sugar solutions with time-resolved vibrational spectroscopy and molecular dynamics simulation methods. It turns out that ions (or solute molecules) have a strong propensity to self-assemble into large and polydisperse aggregates that affect both local and long-range water H-bonding structures. In particular, we have shown that graph-theoretical approaches can be used to elucidate morphological characteristics of large aggregates in various aqueous salt, osmolyte, and sugar solutions. When ion and molecular aggregates in such aqueous solutions are treated as graphs, a variety of graph-theoretical properties, such as graph spectrum, degree distribution, clustering coefficient, minimum path length, and graph entropy, can be directly calculated by considering an ensemble of configurations taken from molecular dynamics trajectories. Here we show percolating behavior exhibited by ion and molecular aggregates upon increase in solute concentration in high solute concentrations and discuss compelling evidence of the isomorphic relation between percolation transitions of ion and molecular aggregates and water H-bonding networks. We anticipate that the combination of graph theory and molecular dynamics simulation methods will be of exceptional use in achieving a deeper understanding of the fundamental physical chemistry of dissolution and in describing the interplay between the self aggregation of solute molecules and the structure and dynamics of water. PMID- 29401040 TI - Imaging Follow-up of Low-Risk Incidental Pancreas and Kidney Findings: Effects of Patient Age and Comorbidity on Projected Life Expectancy. AB - Purpose To determine the effects of patient age and comorbidity level on life expectancy (LE) benefits associated with imaging follow-up of Bosniak IIF renal cysts and pancreatic side-branch (SB) intraductal papillary mucinous neoplasms (IPMNs). Materials and Methods A decision-analytic Markov model to evaluate LE benefits was developed. Hypothetical cohorts with varied age (60-80 years) and comorbidities (none, mild, moderate, or severe) were evaluated. For each finding, LE projections from two strategies were compared: imaging follow-up and no imaging follow-up. Under follow-up, it was assumed that cancers associated with the incidental finding were successfully treated before they spread. For patients without follow-up, mortality risks from Bosniak IIF cysts (renal cell carcinoma) and SBIPMNs (pancreatic ductal adenocarcinoma) were incorporated. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. Results In the youngest, healthiest cohorts (age, 60 years; no comorbidities), projected LE benefits from follow-up were as follows: Bosniak IIF cyst, 6.5 months (women) and 5.8 months (men); SBIPMN, 6.4 months (women) and 5.3 months (men). Follow-up of Bosniak IIF cysts in 60-year-old women with severe comorbidities yielded a LE benefit of 3.9 months; in 80-year-old women with no comorbidities, the benefit was 2.8 months, and with severe comorbidities the benefit was 1.5 months. Similar trends were observed in men and for SBIPMN. Results were sensitive to the performance of follow-up for cancer detection; malignancy risks; and stage at presentation of malignant, unfollowed Bosniak IIF cysts. Conclusion With progression of age and comorbidity level, follow-up of low risk incidental findings yields increasingly limited benefits for patients. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29401042 TI - Effect of In Vitro Human Digestion on Biogenic Amine (Tyramine) Formation in Various Fermented Sausages. AB - Biogenic amines are formed in various fermented foods by microbial amino acid decarboxylation activities, and ingestion of these amines may cause human illness. However, the effect of digestion on the biogenic amines in fermented sausages has not been studied. This study was conducted to determine the effect of in vitro human digestion with the enterobacteria Escherichia coli and Lactobacillus casei on concentrations of the biogenic amine tyramine in six types of fermented sausages. Tyramine concentration was not significantly changed until simulated digestion in the small intestine. However, tyramine concentration for all sausage samples was increased after simulated digestion in the large intestine. Addition of E. coli and L. casei dramatically increased the tyramine concentrations ( P < 0.05). This result indicates that enterobacteria increase biogenic amine concentrations during human digestion. PMID- 29401041 TI - Perivascular Epicardial Fat Stranding at Coronary CT Angiography: A Marker of Acute Plaque Rupture and Spontaneous Coronary Artery Dissection. AB - Purpose To evaluate the frequency and implications of perivascular fat stranding on coronary computed tomography (CT) angiograms obtained for suspected acute coronary syndrome (ACS). Materials and Methods This retrospective registry study was approved by the institutional review board. The authors reviewed the medical records and images of 1403 consecutive patients (796 men, 607 women; mean age, 52.8 years) who underwent coronary CT angiography at the emergency department from February 2012 to March 2016. Fat attenuation, length and number of circumferential quadrants of the affected segment, and attenuation values in the unaffected epicardial and subcutaneous fat were measured. "Cases" were defined as patients with perivascular fat stranding. Patients with significant stenosis but without fat stranding were considered control subjects. Baseline imaging characteristics, ACS frequency, and results of subsequent downstream testing were compared between cases and control subjects by using two-sample t, Mann-Whitney U, and Fisher tests. Results Perivascular fat stranding was seen in 11 subjects, nine with atherosclerotic lesions and two with spontaneous coronary artery dissections, with a mean fat stranding length of 19.2 mm and circumferential extent averaging 2.9 quadrants. The mean attenuation of perivascular fat stranding, normal epicardial fat, and normal subcutaneous fat was 17, -93.2, and 109.3 HU, respectively (P < .001). Significant differences (P < .05) between cases and control subjects included lower Agatston score, presence of wall motion abnormality, and initial elevation of serum troponin level. ACS frequency was 45.4% in cases and 3.8% in control subjects (P = .001). Conclusion Recognition of perivascular fat stranding may be a helpful additional predictor of culprit lesion and marker of risk for ACS in patients with significant stenosis or spontaneous coronary artery dissection. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29401044 TI - Machine Learning Approaches for Clinical Psychology and Psychiatry. AB - Machine learning approaches for clinical psychology and psychiatry explicitly focus on learning statistical functions from multidimensional data sets to make generalizable predictions about individuals. The goal of this review is to provide an accessible understanding of why this approach is important for future practice given its potential to augment decisions associated with the diagnosis, prognosis, and treatment of people suffering from mental illness using clinical and biological data. To this end, the limitations of current statistical paradigms in mental health research are critiqued, and an introduction is provided to critical machine learning methods used in clinical studies. A selective literature review is then presented aiming to reinforce the usefulness of machine learning methods and provide evidence of their potential. In the context of promising initial results, the current limitations of machine learning approaches are addressed, and considerations for future clinical translation are outlined. PMID- 29401045 TI - Antisocial Personality as a Neurodevelopmental Disorder. AB - Although antisocial personality disorder (APD) is one of the most researched personality disorders, it is still surprisingly resistant to treatment. This lack of clinical progress may be partly due to the failure to view APD as a neurodevelopmental disorder and to consider early interventions. After first defining what constitutes a neurodevelopmental disorder, this review evaluates the extent to which APD meets neurodevelopmental criteria, covering structural and functional brain imaging, neurocognition, genetics and epigenetics, neurochemistry, and early health risk factors. Prevention and intervention strategies for APD are then outlined, focusing on addressing early biological and health systems, followed by forensic and clinical implications. It is argued both that APD meets criteria for consideration as a neurodevelopmental disorder and that consideration should be given both to the possibility that early onset conduct disorder is neurodevelopmental in nature, and also to the inclusion of psychopathy as a specifier in future Diagnostic and Statistical Manual revisions of APD. PMID- 29401043 TI - Lay Health Worker Involvement in Evidence-Based Treatment Delivery: A Conceptual Model to Address Disparities in Care. AB - Mobilizing lay health workers (LHWs) to deliver evidence-based treatments (EBTs) is a workforce strategy to address mental health disparities in underserved communities. LHWs can be leveraged to support access to EBTs in a variety of ways, from conducting outreach for EBTs delivered by professional providers to serving as the primary treatment providers. This critical review provides an overview of how LHW-supported or -delivered EBTs have been leveraged in low-, middle-, and high-income countries (HICs). We propose a conceptual model for LHWs to address drivers of service disparities, which relate to the overall supply of the EBTs provided and the demand for these treatments. The review provides illustrative case examples that demonstrate how LHWs have been leveraged globally and domestically to increase access to mental health services. It also discusses challenges and recommendations regarding implementing LHW-supported or -delivered EBTs. PMID- 29401046 TI - Culture's Influence on Stressors, Parental Socialization, and Developmental Processes in the Mental Health of Children of Immigrants. AB - Children of immigrants represent one in four children in the United States and will represent one in three children by 2050. Children of Asian and Latino immigrants together represent the majority of children of immigrants in the United States. Children of immigrants may be immigrants themselves, or they may have been born in the United States to foreign-born parents; their status may be legal or undocumented. We review transcultural and culture-specific factors that influence the various ways in which stressors are experienced; we also discuss the ways in which parental socialization and developmental processes function as risk factors or protective factors in their influence on the mental health of children of immigrants. Children of immigrants with elevated risk for mental health problems are more likely to be undocumented immigrants, refugees, or unaccompanied minors. We describe interventions and policies that show promise for reducing mental health problems among children of immigrants in the United States. PMID- 29401047 TI - Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders. AB - Evolutionary medicine uses evolutionary theory to help elucidate why humans are vulnerable to disease and disorders. I discuss two different types of evolutionary explanations that have been used to help understand human psychiatric disorders. First, a consistent finding is that psychiatric disorders are moderately to highly heritable, and many, such as schizophrenia, are also highly disabling and appear to decrease Darwinian fitness. Models used in evolutionary genetics to understand why genetic variation exists in fitness related traits can be used to understand why risk alleles for psychiatric disorders persist in the population. The usual explanation for species-typical adaptations-natural selection-is less useful for understanding individual differences in genetic risk to disorders. Rather, two other types of models, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data. Second, species-typical capacities to mount reactions to negative events are likely to have been crafted by natural selection to minimize fitness loss. The pain reaction to tissue damage is almost certainly such an example, but it has been argued that the capacity to experience depressive symptoms such as sadness, anhedonia, crying, and fatigue in the face of adverse life situations may have been crafted by natural selection as well. I review the rationale and strength of evidence for this hypothesis. Evolutionary hypotheses of psychiatric disorders are important not only for offering explanations for why psychiatric disorders exist, but also for generating new, testable hypotheses and understanding how best to design studies and analyze data. PMID- 29401048 TI - To Die at Home. PMID- 29401049 TI - A Randomized Controlled Trial of Financial Incentives for Medicaid Beneficiaries with Diabetes. AB - BACKGROUND: The Medicaid Incentives for Prevention of Chronic Diseases program was authorized by the Affordable Care Act to determine the effectiveness of providing financial incentives. OBJECTIVE: To examine the impact of incentives on adult Medicaid beneficiaries' diabetes self-management using the Hawaii Patient Reward And Incentives to Support Empowerment project. METHODS: A randomized controlled trial study was conducted at Kaiser Permanente Hawaii with 320 participants (159 intervention group/161 control group). Participants could earn up to $320/y of financial incentives, distributed in the form of a debit card. Evaluation measures included 1) clinical outcomes of change in hemoglobin A1C, blood pressure, and cholesterol; 2) compliance with American Diabetes Association standards; 3) cost effectiveness; 4) quality of life; 5) self-management activities; and 6) satisfaction with incentives. RESULTS: No significant differences in clinical outcomes were found between groups. There were no differences in observance of American Diabetes Association standards of medical care between the intervention and control group. The project also did not show reduction in health cost. However, participants in the intervention group reported significantly higher adherence with the recommended general diet than those in the control group during the course of the study. They also reported statistically better physical health than their control counterparts at the midpoint of the study; however, the perception of increased physical health didn't sustain to the end of the study. Participants' satisfaction with incentives was high. CONCLUSION: Overall, this study found no conclusive evidence that financial incentives alone had beneficial effects on improving standards of medical care in diabetes. PMID- 29401051 TI - Letting Me Off the Hook. PMID- 29401050 TI - Real-World Effectiveness of a Medically Supervised Weight Management Program in a Large Integrated Health Care Delivery System: Five-Year Outcomes. AB - CONTEXT: There are insufficient data on the long-term, nonsurgical, nonpharmacologic treatment of obesity. OBJECTIVE: To determine changes in weight over 5 years in participants enrolled between April 1, 2007, and December 31, 2014, in a medically supervised weight management program at Kaiser Permanente Northern California Medical Centers. The program consisted of 3 phases: Complete meal replacement for 16 weeks; transition phase, 17 to 29 weeks; and lifestyle maintenance phase, 30 to 82 weeks. DESIGN: Retrospective observational study of 10,693 participants (2777 available for analysis at 5 years); no comparator group. MAIN OUTCOME MEASURES: Average change in weight from baseline to follow up. RESULTS: Average age was 51.1 (standard deviation = 12.4) years, and 72.8% were women. Average baseline weight in the entire cohort was 112.9 kg (standard error [SE] = 0.23). Weight (kg) significantly changed over time: 4 months, -17.3 (SE = 0.12); 1 year, -14.2 (SE = 0.12); 2 years, -8.6 (SE = 0.14); 3 years, -6.9 (SE = 0.17); 4 years, -6.5 (SE = 0.16), and 5 years, -6.4 (SE = 0.29); p < 0.0001). In those with 5-year follow-up, weight loss between 5.0 and 9.9% below baseline occurred in 16.3% (SE = 0.004, 95% CI = 15.3% - 17.2%) and weight loss of 10.0% or more of baseline occurred in 35.2% (SE = 0.01, 95% CI = 33.6% - 36.7%). CONCLUSION: The average weight change of obese adults who participated in a medically supervised weight management program, with available 5-year data, was a statistically and clinically significant 5.8% weight loss from baseline. PMID- 29401052 TI - Psychiatric Aspects of Extreme Sports: Three Case Studies. AB - Extreme sports, defined as sporting or adventure activities involving a high degree of risk, have boomed since the 1990s. These types of sports attract men and women who can experience a life-affirming transcendence or "flow" as they participate in dangerous activities. Extreme sports also may attract people with a genetic predisposition for risk, risk-seeking personality traits, or underlying psychiatric disorders in which impulsivity and risk taking are integral to the underlying problem. In this report, we attempt to illustrate through case histories the motivations that lead people to repeatedly risk their lives and explore psychiatry's role in extreme sports. A sports psychiatrist can help with therapeutic management, neuromodulation of any comorbid psychiatric diagnosis, and performance enhancement (eg, risk minimization) to cultivate improved judgment which could include identifying alternative safer recreational options. Because flirting with death is critical to the extreme sports ethos, practitioners must gain further understanding of this field and its at-risk participants. PMID- 29401053 TI - Medical Students' Perspectives on Trauma-Informed Care Training. AB - INTRODUCTION: Adults exposed to traumatic events during childhood commonly seek medical services, but health care practitioners hesitate to address and assess early trauma despite its known negative health effects. This study examines medical students' perspectives on a brief course that addressed the health care needs of patients exposed to adverse childhood experiences. METHODS: A convenience sample of 20 University of California, Davis medical students from the Summer Institute on Race and Health received 6 hours of trauma-informed care training. The course was delivered in 2-hour modules during the course of 3 days, and included lectures, discussions, and practice. A questionnaire assessing students' perspectives on training benefits, current practice challenges, and necessary resources to provide trauma-informed medical care was distributed posttraining. RESULTS: From the students' perspectives, this course increased their ability to recognize various clinical manifestations of adverse childhood experience exposure in adult patients. Students said they learned how to ask about and respond to adverse childhood experience disclosures and identify necessary resources to responsibly implement trauma-informed care in medical settings. Students identified provision of adequate resources and links to appropriate treatment identified as common challenges in providing health care to trauma-affected patients. CONCLUSION: Study findings illustrate that trauma training can fill a knowledge gap and provide associated benefits for medical students. Initial training may pique students' interest by demonstrating the relevance of trauma knowledge in clinical practice; additional training likely is needed to support skills and confidence. PMID- 29401054 TI - Impact of Standardizing Management of Atrial Fibrillation with Rapid Heart Rate in the Emergency Department. AB - CONTEXT: There is substantial variation in the emergency treatment of atrial fibrillation with tachycardia. A standardized treatment approach at an academic center decreased admissions without adverse outcomes, but this approach has not been evaluated in a community Emergency Department (ED). OBJECTIVE: To evaluate the implementation of a standardized treatment guideline for patients with atrial fibrillation and a rapid heart rate in a community ED. DESIGN: An observational pre-/postimplementation (August 2013 to July 2014 and August 2014 to July 2015, respectively) study at a community ED. The standardized treatment guideline encouraged early oral treatment with rate control medication, outpatient echocardiogram, and early follow-up. A multiple logistic regression model adjusting for patient characteristics was generated to investigate the association between the intervention and ED discharge rate. MAIN OUTCOME MEASURES: The primary measure was ED discharge. Secondary measures included stroke or death, ED return visit, hospital readmission, length of stay, and use of oral rate control medications. RESULTS: A total of 199 (104 pre/95 post) ED encounters were evaluated. The ED discharge rate increased 14% after intervention (57.7% to 71.6%, p = 0.04), and use of rate control medications increased by 19.4% (p < 0.01). Adjusted multivariate results showed a nearly 2-fold likelihood of ED discharge after guideline implementation (odds ratio = 1.97, 95%confidence interval = 1.07-3.63). Length of stay, return visits, and hospital readmissionswere similar. CONCLUSION: A standardized approach to ED patients with atrial fibrillation and tachycardia is associated with a decrease in hospital admissions without adversely affecting patient safety. PMID- 29401056 TI - Cervical Vestibular Evoked Myogenic Potentials and Hypoglossal Nerve Schwannoma. PMID- 29401055 TI - On Becoming Trauma-Informed: Role of the Adverse Childhood Experiences Survey in Tertiary Child and Adolescent Mental Health Services and the Association with Standard Measures of Impairment and Severity. AB - CONTEXT: There is a movement toward trauma-informed, trauma-focused psychiatric treatment. OBJECTIVE: To examine Adverse Childhood Experiences (ACE) survey items by sex and by total scores by sex vs clinical measures of impairment to examine the clinical utility of the ACE survey as an index of trauma in a child and adolescent mental health care setting. DESIGN: Descriptive, polychoric factor analysis and regression analyses were employed to analyze cross-sectional ACE surveys (N = 2833) and registration-linked data using past admissions (N = 10,400) collected from November 2016 to March 2017 related to clinical data (28 independent variables), taking into account multicollinearity. RESULTS: Distinct ACE items emerged for males, females, and those with self-identified sex and for ACE total scores in regression analysis. In hierarchical regression analysis, the final models consisting of standard clinical measures and demographic and system variables (eg, repeated admissions) were associated with substantial ACE total score variance for females (44%) and males (38%). Inadequate sample size foreclosed on developing a reduced multivariable model for the self-identified sex group. CONCLUSION: The ACE scores relate to independent clinical measures and system and demographic variables. There are implications for clinical practice. For example, a child presenting with anxiety and a high ACE score likely requires treatment that is different from a child presenting with anxiety and an ACE score of zero. The ACE survey score is an important index of presenting clinical status that guides patient care planning and intervention in the progress toward a trauma-focused system of care. PMID- 29401057 TI - Effects of Early- and Late-Arriving Room Reflections on the Speech-Evoked Auditory Brainstem Response. AB - BACKGROUND: Room reverberation alters the acoustical properties of the speech signals reaching our ears, affecting speech understanding. Therefore, it is important to understand the consequences of reverberation on auditory processing. In perceptual studies, the direct sound and early reflections of reverberated speech have been found to constitute useful energy, whereas the late reflections constitute detrimental energy. PURPOSE: This study investigated how various components (direct sound versus early reflections versus late reflections) of the reverberated speech are encoded in the auditory system using the speech-evoked auditory brainstem response (ABR). RESEARCH DESIGN: Speech-evoked ABRs were recorded using reverberant stimuli created as a result of the convolution between an ongoing synthetic vowel /a/ and each of the following room impulse response (RIR) components: direct sound, early reflections, late reflections, and full reverberation. Four stimuli were produced: direct component, early component, late component, and full component. STUDY SAMPLE: Twelve participants with normal hearing participated in this study. DATA COLLECTION AND ANALYSIS: Waves V and A amplitudes and latencies as well as envelope-following response (EFR) and fine structure frequency-following response (FFR) amplitudes of the speech-evoked ABR were evaluated separately with one-way repeated measures analysis of variances to determine the effect of stimulus. Post hoc comparisons using Tukey's honestly significant difference test were performed to assess significant differences between pairs of stimulus conditions. RESULTS: For waves V and A amplitudes, a significant difference or trend toward significance was found between direct and late components, between direct and full components, and between early and late components. For waves V and A latencies, significant differences were found between direct and late components, between direct and full components, between early and late components, and between early and full components. For the EFR and FFR amplitudes, a significant difference or trend toward significance was found between direct and late components, and between early and late components. Moreover, eight, three, and one participant reported the early, full, and late stimuli, respectively, to be the most perceptually similar to the direct stimulus. CONCLUSIONS: The stimuli that are acoustically most similar (direct and early) result in electrophysiological responses that are not significantly different, whereas the stimuli that are acoustically most different (direct and late, early and late) result in responses that are significantly different across all response measures. These findings provide insights toward the understanding of the effects of the different components of the RIRs on auditory processing of speech. PMID- 29401058 TI - Predictive Accuracy of Sweep Frequency Impedance Technology in Identifying Conductive Conditions in Newborns. AB - BACKGROUND: Diagnosing conductive conditions in newborns is challenging for both audiologists and otolaryngologists. Although high-frequency tympanometry (HFT), acoustic stapedial reflex tests, and wideband absorbance measures are useful diagnostic tools, there is performance measure variability in their detection of middle ear conditions. Additional diagnostic sensitivity and specificity measures gained through new technology such as sweep frequency impedance (SFI) measures may assist in the diagnosis of middle ear dysfunction in newborns. PURPOSE: The purpose of this study was to determine the test performance of SFI to predict the status of the outer and middle ear in newborns against commonly used reference standards. RESEARCH DESIGN: Automated auditory brainstem response (AABR), HFT (1000 Hz), transient evoked otoacoustic emission (TEOAE), distortion product otoacoustic emission (DPOAE), and SFI tests were administered to the study sample. STUDY SAMPLE: A total of 188 neonates (98 males and 90 females) with a mean gestational age of 39.4 weeks were included in the sample. Mean age at the time of testing was 44.4 hr. DATA COLLECTION AND ANALYSIS: Diagnostic accuracy of SFI was assessed in terms of its ability to identify conductive conditions in neonates when compared with nine different reference standards (including four single tests [AABR, HFT, TEOAE, and DPOAE] and five test batteries [HFT + DPOAE, HFT + TEOAE, DPOAE + TEOAE, DPOAE + AABR, and TEOAE + AABR]), using receiver operating characteristic (ROC) analysis and traditional test performance measures such as sensitivity and specificity. RESULTS: The test performance of SFI against the test battery reference standard of HFT + DPOAE and single reference standard of HFT was high with an area under the ROC curve (AROC) of 0.87 and 0.82, respectively. Although the HFT + DPOAE test battery reference standard performed better than the HFT reference standard in predicting middle ear conductive conditions in neonates, the difference in AROC was not significant. Further analysis revealed that the highest sensitivity and specificity for SFI (86% and 88%, respectively) was obtained when compared with the reference standard of HFT + DPOAE. Among the four single reference standards, SFI had the highest sensitivity and specificity (76% and 88%, respectively) when compared against the HFT reference standard. CONCLUSIONS: The high test performance of SFI against the HFT and HFT + DPOAE reference standards indicates that the SFI measure has appropriate diagnostic accuracy in detection of conductive conditions in newborns. Hence, the SFI test could be used as adjunct tool to identify conductive conditions in universal newborn hearing screening programs, and can also be used in diagnostic follow-up assessments. PMID- 29401059 TI - Survey of Current Practice in the Fitting and Fine-Tuning of Common Signal Processing Features in Hearing Aids for Adults. AB - BACKGROUND: Current guidelines for adult hearing aid fittings recommend the use of a prescriptive fitting rationale with real-ear verification that considers the audiogram for the determination of frequency-specific gain and ratios for wide dynamic range compression. However, the guidelines lack recommendations for how other common signal-processing features (e.g., noise reduction, frequency lowering, directional microphones) should be considered during the provision of hearing aid fittings and fine-tunings for adult patients. PURPOSE: The purpose of this survey was to identify how audiologists make clinical decisions regarding common signal-processing features for hearing aid provision in adults. RESEARCH DESIGN: An online survey was sent to audiologists across the United States. The 22 survey questions addressed four primary topics including demographics of the responding audiologists, factors affecting selection of hearing aid devices, the approaches used in the fitting of signal-processing features, and the strategies used in the fine-tuning of these features. STUDY SAMPLE: A total of 251 audiologists who provide hearing aid fittings to adults completed the electronically distributed survey. The respondents worked in a variety of settings including private practice, physician offices, university clinics, and hospitals/medical centers. DATA COLLECTION AND ANALYSIS: Data analysis was based on a qualitative analysis of the question responses. The survey results for each of the four topic areas (demographics, device selection, hearing aid fitting, and hearing aid fine-tuning) are summarized descriptively. RESULTS: Survey responses indicate that audiologists vary in the procedures they use in fitting and fine tuning based on the specific feature, such that the approaches used for the fitting of frequency-specific gain differ from other types of features (i.e., compression time constants, frequency lowering parameters, noise reduction strength, directional microphones, feedback management). Audiologists commonly rely on prescriptive fitting formulas and probe microphone measures for the fitting of frequency-specific gain and rely on manufacturers' default settings and recommendations for both the initial fitting and the fine-tuning of signal processing features other than frequency-specific gain. CONCLUSIONS: The survey results are consistent with a lack of published protocols and guidelines for fitting and adjusting signal-processing features beyond frequency-specific gain. To streamline current practice, a transparent evidence-based tool that enables clinicians to prescribe the setting of other features from individual patient characteristics would be desirable. PMID- 29401060 TI - Exponential Modeling of Frequency-Following Responses in American Neonates and Adults. AB - BACKGROUND: The scalp-recorded frequency-following response (FFR) has been widely accepted in assessing the brain's processing of speech stimuli for people who speak tonal and nontonal languages. Characteristics of scalp-recorded FFRs with increasing number of sweeps have been delineated through the use of an exponential curve-fitting model in Chinese adults; however, characteristics of speech processing for people who speak a nontonal language remain unclear. PURPOSE: This study had two specific aims. The first was to examine the characteristics of speech processing in neonates and adults who speak a nontonal language, to evaluate the goodness of fit of an exponential model on neonatal and adult FFRs, and to determine the differences, if any, between the two groups of participants. The second aim was to assess effective recording parameters for American neonates and adults. RESEARCH DESIGN: This investigation employed a prospective between-subject study design. STUDY SAMPLE: A total of 12 American neonates (1-3 days old) and 12 American adults (24.1 +/- 2.5 yr old) were recruited. Each neonate passed an automated hearing screening at birth and all adult participants had normal hearing and were native English speakers. DATA COLLECTION AND ANALYSIS: The English vowel /i/ with a rising pitch contour (117 166 Hz) was used to elicit the FFR. A total of 8,000 accepted sweeps were recorded from each participant. Three objective indices (Frequency Error, Tracking Accuracy, and Pitch Strength) were computed to estimate the frequency tracking acuity and neural phase-locking magnitude when progressively more sweeps were included in the averaged waveform. For each objective index, the FFR trends were fit to an exponential curve-fitting model that included estimates of asymptotic amplitude, noise amplitude, and a time constant. RESULTS: Significant differences were observed between groups for Frequency Error, Tracking Accuracy, and Pitch Strength of the FFR trends. The adult participants had significantly smaller Frequency Error (p < 0.001), better Tracking Accuracy (p = 0.001), and larger Pitch Strength (p = 0.003) values than the neonate participants. The adult participants also demonstrated a faster rate of improvement (i.e., a smaller time constant) in all three objective indices compared to the neonate participants. The smaller time constants observed in adults indicate that a larger number of sweeps will be needed to adequately assess the FFR for neonates. Furthermore, the exponential curve-fitting model provided a good fit to the FFR trends with increasing number of sweeps for American neonates (mean r2 = 0.89) and adults (mean r2 = 0.96). CONCLUSIONS: Significant differences were noted between the neonatal and adult participants for Frequency Error, Tracking Accuracy, and Pitch Strength. These differences have important clinical implications in determining when to stop a recording and the number of sweeps needed to adequately assess the frequency-encoding acuity and neural phase-locking magnitude in neonates and adults. These findings lay an important foundation for establishing a normative database for American neonates and adults, and may prove to be useful in the development of diagnostic and therapeutic paradigms for neonates and adults who speak a nontonal language. PMID- 29401061 TI - The Phoneme Identification Test for Assessment of Spectral and Temporal Discrimination Skills in Children: Development, Normative Data, and Test-Retest Reliability Studies. AB - BACKGROUND: Previous research suggests that a proportion of children experiencing reading and listening difficulties may have an underlying primary deficit in the way that the central auditory nervous system analyses the perceptually important, rapidly varying, formant frequency components of speech. PURPOSE: The Phoneme Identification Test (PIT) was developed to investigate the ability of children to use spectro-temporal cues to perceptually categorize speech sounds based on their rapidly changing formant frequencies. The PIT uses an adaptive two-alternative forced-choice procedure whereby the participant identifies a synthesized consonant-vowel (CV) (/ba/ or /da/) syllable. CV syllables differed only in the second formant (F2) frequency along an 11-step continuum (between 0% and 100% representing an ideal /ba/ and /da/, respectively). The CV syllables were presented in either quiet (PIT Q) or noise at a 0 dB signal-to-noise ratio (PIT N). RESEARCH DESIGN: Development of the PIT stimuli and test protocols, and collection of normative and test-retest reliability data. STUDY SAMPLE: Twelve adults (aged 23 yr 10 mo to 50 yr 9 mo, mean 32 yr 5 mo) and 137 typically developing, primary-school children (aged 6 yr 0 mo to 12 yr 4 mo, mean 9 yr 3 mo). There were 73 males and 76 females. DATA COLLECTION AND ANALYSIS: Data were collected using a touchscreen computer. Psychometric functions were automatically fit to individual data by the PIT software. Performance was determined by the width of the continuum for which responses were neither clearly /ba/ nor /da/ (referred to as the uncertainty region [UR]). A shallower psychometric function slope reflected greater uncertainty. Age effects were determined based on raw scores. Z scores were calculated to account for the effect of age on performance. Outliers, and individual data for which the confidence interval of the UR exceeded a maximum allowable value, were removed. Nonparametric tests were used as the data were skewed toward negative performance. RESULTS: Across participants, the median value of the F2 range that resulted in uncertain responses was 33% in quiet and 40% in noise. There was a significant effect of age on the width of this UR (p < 0.00001) in both quiet and noise, with performance becoming adult like by age 9 on the PIT Q and age 10 on the PIT N. A skewed distribution toward negative performance occurred in both quiet (p = 0.01) and noise (p = 0.006). Median UR scores were significantly wider in noise than in quiet (T = 2041, p < 0.0000001). Performance (z scores) across the two tests was significantly correlated (r = 0.36, p = 0.000009). Test-retest z scores were significantly correlated in both quiet and noise (r = 0.4 and 0.37, respectively, p < 0.0001). CONCLUSIONS: The PIT normative data show that the ability to identify phonemes based on changes in formant transitions improves with age, and that some children in the general population have performance much worse than their age peers. In children, uncertainty increases when the stimuli are presented in noise. The test is suitable for use in planned studies in a clinical population. PMID- 29401062 TI - The Parsing Syllable Envelopes Test for Assessment of Amplitude Modulation Discrimination Skills in Children: Development, Normative Data, and Test-Retest Reliability Studies. AB - BACKGROUND: Intensity peaks and valleys in the acoustic signal are salient cues to syllable structure, which is accepted to be a crucial early step in phonological processing. As such, the ability to detect low-rate (envelope) modulations in signal amplitude is essential to parse an incoming speech signal into smaller phonological units. PURPOSE: The Parsing Syllable Envelopes (ParSE) test was developed to quantify the ability of children to recognize syllable boundaries using an amplitude modulation detection paradigm. The envelope of a 750-msec steady-state /a/ vowel is modulated into two or three pseudo-syllables using notches with modulation depths varying between 0% and 100% along an 11-step continuum. In an adaptive three-alternative forced-choice procedure, the participant identified whether one, two, or three pseudo-syllables were heard. RESEARCH DESIGN: Development of the ParSE stimuli and test protocols, and collection of normative and test-retest reliability data. STUDY SAMPLE: Eleven adults (aged 23 yr 10 mo to 50 yr 9 mo, mean 32 yr 10 mo) and 134 typically developing, primary-school children (aged 6 yr 0 mo to 12 yr 4 mo, mean 9 yr 3 mo). There were 73 males and 72 females. DATA COLLECTION AND ANALYSIS: Data were collected using a touchscreen computer. Psychometric functions (PFs) were automatically fit to individual data by the ParSE software. Performance was related to the modulation depth at which syllables can be detected with 88% accuracy (referred to as the upper boundary of the uncertainty region [UBUR]). A shallower PF slope reflected a greater level of uncertainty. Age effects were determined based on raw scores. z Scores were calculated to account for the effect of age on performance. Outliers, and individual data for which the confidence interval of the UBUR exceeded a maximum allowable value, were removed. Nonparametric tests were used as the data were skewed toward negative performance. RESULTS: Across participants, the performance criterion (UBUR) was met with a median modulation depth of 42%. The effect of age on the UBUR was significant (p < 0.00001). The UBUR ranged from 50% modulation depth for 6-yr olds to 25% for adults. Children aged 6-10 had significantly higher uncertainty region boundaries than adults. A skewed distribution toward negative performance occurred (p = 0.00007). There was no significant difference in performance on the ParSE between males and females (p = 0.60). Test-retest z scores were strongly correlated (r = 0.68, p < 0.0000001). CONCLUSIONS: The ParSE normative data show that the ability to identify syllable boundaries based on changes in amplitude modulation improves with age, and that some children in the general population have performance much worse than their age peers. The test is suitable for use in planned studies in a clinical population. PMID- 29401063 TI - Test-Retest Reliability of Dual-Recorded Brainstem versus Cortical Auditory Evoked Potentials to Speech. AB - BACKGROUND: Auditory-evoked potentials have proven useful in the objective evaluation of sound encoding at different stages of the auditory pathway (brainstem and cortex). Yet, their utility for use in clinical assessment and empirical research relies critically on the precision and test-retest repeatability of the measure. PURPOSE: To determine how subcortical/cortical classes of auditory neural responses directly compare in terms of their internal consistency and test-retest reliability within and between listeners. RESEARCH DESIGN: A descriptive cohort study describing the dispersion of electrophysiological measures. STUDY SAMPLE: Eight young, normal-hearing female listeners. DATA COLLECTION AND ANALYSIS: We recorded auditory brainstem responses (ABRs), brainstem frequency-following responses (FFRs), and cortical (P1-N1-P2) auditory-evoked potentials elicited by speech sounds in the same set of listeners. We reassessed responses within each of four different test sessions over a period of 1 mo, allowing us to detect possible changes in latency/amplitude characteristics with finer detail than in previous studies. RESULTS: Our findings show that brainstem and cortical amplitude/latency measures are remarkably stable; with the exception of slight prolongation of the P1 wave, we found no significant variation in any response measure. Intraclass correlation analysis revealed that the speech-evoked FFR amplitude and latency measures achieved superior repeatability (intraclass correlation coefficient >0.85) among the more widely used obligatory brainstem (ABR) and cortical (P1-N1-P2) auditory evoked potentials. Contrasting these intersubject effects, intrasubject variability (i.e., within-subject coefficient of variation) revealed that while latencies were more stable than amplitudes, brainstem and cortical responses did not differ in their variability at the single subject level. CONCLUSIONS: We conclude that (1) the variability of auditory neural responses increases with ascending level along the auditory neuroaxis (cortex > brainstem) between subjects but remains highly stable within subjects and (2) speech-FFRs might provide a more stable measure of auditory function than other conventional responses (e.g., click-ABR), given their lower inter- and intrasubject variability. PMID- 29401064 TI - Higher Asymmetry Ratio and Refixation Saccades in Individuals with Motion Sickness. AB - BACKGROUND: Motion sickness is a complex autonomic phenomenon caused by the intersensory conflict among the balancing systems, resulting in a mismatch of signals between static physical conditions of the susceptible individual exposed to dynamic environment. PURPOSE: The present study was done to assess the sacculocollic reflex pathway and six semicircular canals in individuals susceptible to motion sickness. RESEARCH DESIGN: Standard group comparison was used. STUDY SAMPLE: A total of 60 participants with an age range of 17-25 yr were included, where group I comprised 30 participants with motion sickness and group II comprised 30 participants without motion sickness. The Motion Sickness Susceptibility Questionnaire-Short was administered to classify the participants into groups with or without motion sickness. DATA COLLECTION AND ANALYSIS: The cervical vestibular-evoked myogenic potential (cVEMP) test and video head impulse test (vHIT) were administered to all participants. The Shapiro-Wilk test revealed normal distribution of the data (p > 0.05). Hence a parametric independent sample t test was done to check significant difference in cVEMP and vHIT parameters between the two groups. RESULTS: The present study revealed no significant difference for cVEMP latencies and amplitude in individuals with motion sickness. However, significantly higher cVEMP asymmetry ratio was observed in individuals with motion sickness. Though the vestibulo-ocular reflex (VOR) gain values showed no significant difference between the two groups except for the right anterior left posterior plane, the asymmetry in VOR gain values revealed significant difference between the groups, suggesting asymmetry as a better parameter than absolute VOR gain values. Also, the presence of refixation saccades in 100% of the individuals with motion sickness accorded with various studies reported earlier with vestibular-related pathologies. CONCLUSIONS: Presence of higher asymmetry ratio in cVEMP and vHIT test results plus refixation saccades to stabilize the gaze in vHIT can suggest some amount of vestibular anomalies in individuals with motion sickness. PMID- 29401065 TI - Cervical Vestibular Evoked Myogenic Potential in Hypoglossal Nerve Schwannoma: A Case Report. AB - BACKGROUND: Schwannoma of the hypoglossal nerve is rare. This case report documents an atypical abnormality of the cervical vestibular evoked myogenic potential (cVEMP) in a patient with schwannoma of the hypoglossal nerve. The observed abnormality was attributed to the proximity of the hypoglossal nerve to the spinal accessory nerve in the medullary cistern and base of the skull. PURPOSE: To report cVEMP abnormality in a patient with hypoglossal nerve schwannoma and provide an anatomical correlation for this abnormality. RESEARCH DESIGN: Case report. STUDY SAMPLE: A 44-yr-old woman. DATA COLLECTION: Pure-tone and speech audiometry, tympanometry, acoustic stapedial reflex, auditory brainstem response, and cVEMP testing were performed. RESULTS: The audiological test results were normal except for the absence of cVEMP on the lesion side (right). CONCLUSIONS: A cVEMP abnormality indicating a compromised spinal accessory nerve was observed in a patient with hypoglossal nerve schwannoma. This case report highlights the importance of recording cVEMP in relevant neurological conditions and provides clinical proof for the involvement of the spinal accessory nerve in the vestibulocollic reflex pathway. PMID- 29401066 TI - Lattice response to the relaxation of electronic pressure of ultrafast laser irradiated copper and nickel nanofilms. AB - The impact of electronic pressure and electronic pressure gradient induced by laser excitation on the dynamic response of metals (Cu and Ni) has been numerically investigated using two complementary approaches. In the framework of DFPT, for electronic temperatures up to 6 eV, we demonstrate that electronic pressure results in a higher lattice stability. In other words, the electronic pressure has a negative influence on the phonon entropy and induces an increase in the shear modulus, which improves the melting temperature and lattice vibration frequency. Given the relaxation of electronic pressure during an extreme non-equilibrium state, we adopt a modified 2T-MD model to identify the contribution of the electronic pressure gradient to the atomic dynamics during fs laser excitation. Our results indicate the presence of rapid destabilization of the structure of Cu and Ni nano-films along the electronic pressure gradients. Specifically, the nucleation of the voids and heterogeneous nucleation occur at the surface layer, at a depth of several nanometers, for Cu and Ni, respectively. With the coexistence of a-thermal and thermal effects on scales, two different ultrafast destructuring processes of Cu and Ni both interrelate a hot electronic blast force and classical electron-ion dynamics. PMID- 29401067 TI - Dwell time, Hartman effect and transport properties in a ferromagnetic phosphorene monolayer. AB - In this paper, spin-dependent dwell time, spin Hartman effect and spin-dependent conductance were theoretically investigated through a rectangular barrier in the presence of an exchange field by depositing a ferromagnetic insulator on the phosphorene layer in the barrier region. The existence of the spin Hartman effect was shown for all energies (energies lower than barrier height) and all incident angles in phosphorene. We also compared our results of the dwell time in the phosphorene structure with similar research performed on graphene. We reported a significant difference between the tunneling time values of incident quasiparticles with spin-up and spin-down. We found that the barrier was almost transparent for incident quasiparticles with a wide range of incident angles and energies higher than the barrier height in phosphorene. We also found that the maximum spin-dependent transmission probability for energies higher than barrier height does not necessarily occur in the zero incident angle. In addition, we showed that the spin conductance for energies higher (lower) than barrier height fluctuates (decays) in terms of barrier thickness. We discovered that, in contrast to graphene, the Klein paradox does not occur in the normal incident in the phosphorene structure. Furthermore, the results demonstrated the achievement of good total conductance at certain thicknesses of the barrier for energies higher than the barrier height. This study could serve as a basis for investigations of the basic physics of tunneling mechanisms and also for using phosphorene as a spin polarizer in designing nanoelectronic devices. PMID- 29401068 TI - Camptocormia Induced by a Dopaminergic Agonist. AB - Camptocormia, a condition that involves the abnormal flexion of the trunk and results in a forward-bending posture, is relatively common during the course of Parkinson disease (PD). Despite this, there is ongoing controversy concerning its mechanisms and no consensus regarding the underlying etiology. This report demonstrates a case in which a dopaminergic agonist (DA) was implicated in the onset of camptocormia episodes in a non-PD patient who developed camptocormia after the start of DA treatment. Over a course of 8 years, the patient experienced intermittent camptocormia, which resulted in multiple falls. After cessation of the DA, the patient showed decreased camptocormia symptoms. This case report suggests that clinicians should consider the possibility of DA induced camptocormia in patients with PD and non-PD patients receiving DA treatments, and serves to caution clinicians regarding the administration of DAs. PMID- 29401069 TI - Validity and Reproducibility of Various Measurement Methods for Craniocervical Sagittal Balance. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To identify the best indicator for reproducible representation of craniocervical sagittal balance (CCSB). SUMMARY OF BACKGROUND DATA: Spinal sagittal balance is considered one of the most critical factors affecting the health-related quality of life. Although standard indicators of spinopelvic balance have been established, these do not include the craniocervical balance and there is no standard parameter for evaluating the CCSB. MATERIALS AND METHODS: Six kinds of sagittal vertical axis (SVA) were drawn by a total of 9 spine or orthopedic surgeons, from the anterior margin of the external auditory canal: cranial center of gravity (CCG), C1 (center of the anterior arch), C2 (C2vb: center of the vertebral body, C2e: center of the lower endplate), and C7 (C7vb: center of the vertebral body, C7p: posterosuperior corner). Eight SVA distances were measured by using 30 radiographs; CCG-C7vb, C1 C7vb, C2e-C7vb, C2vb-C7vb, CCG-C7p, C1-C7p, C2e-C7p, and C2bv-C7p.The interobserver and intraobserver reliabilities, and the correlations between CCG and C1, C2e, or C2bv were calculated among the main groups or subgroups. RESULTS: In the overall analysis, although the intraclass correlation coefficients (ICC) (1, 1) of all parameters were >0.900, the ICC (2, 1) of CCG-C7p and CCG-C7vb were <0.900. The same trends were noted in the subgroups based on observer's experience. Comparing C7p-related and C7vb-related parameters, ICC (2, 1) showed 0.901 in C7p-related and 0.849 in C7bv-related parameters. In the analysis of the correlation between cranial SVAs, C1-C7p and C2vb-C7p SVAs correlated highly with CCG-C7p SVA (0.905, 0.805, respectively). CONCLUSIONS: Although the CCG SVA represents the center of the head, the current results revealed its low reproducibility. The low values were notable in those unfamiliar with craniocervical anatomy. The correlation analysis indicated that C1-C7p and C2vb C7p SVA parameters are suitable for CCG-C7p SVA. Therefore, these 2 are considered as possible standard parameters in evaluating CCSB. LEVEL OF EVIDENCE: Level III. PMID- 29401070 TI - Digital Audio Feedback Technology: Nursing Students' Perspectives. PMID- 29401072 TI - Using eHealth to Increase Autonomy Supportive Care: A Multicenter Intervention Study in Antenatal Care. PMID- 29401071 TI - Alliance for Nursing Informatics Involvement With Consumer-Directed Exchange and the CARIN Alliance. PMID- 29401073 TI - Growth Friendly Surgery and Serial Cast Correction in the Treatment of Early onset Scoliosis for Patients With Prader-Willi Syndrome. AB - BACKGROUND: Prader-Willi syndrome (PWS) patients can present with scoliosis which can be treated with serial cast correction (SCC) or with growth friendly surgery (GFS). This study's purpose was to describe the results of SCC as well as GFS for PWS patients with early-onset scoliosis (EOS). METHODS: PWS patients were identified from 2 international multicenter EOS databases. Scoliosis, kyphosis, spine height (T1-S1), right/left hemithoracic heights/widths (RHTH, LHTH, RHTW, LHTW) were measured pretreatment, postoperation, and at 2-year follow-up. Complications were recorded. RESULTS: Overall, 23 patients with 2-year follow-up were identified. Pretreatment; patients treated with SCC (n=10) had mean age of 1.8+/-0.6 years; body mass index (BMI), 16+/-1.5 kg/m; scoliosis, 45+/-18 degrees; kyphosis, 56+/-9 degrees; T1-S1, 22.4+/-2.4 cm; RHTH, 8.0+/-2.0 cm; LHTH, 8.5+/-1.7 cm; RHTW, 6.6+/-1.3 cm; and LHTW, 8.0+/-1.0 cm. Patients treated with GFS (n=13) had mean age of 5.8+/-2.6 years; BMI, 21+/-5.4 kg/m; scoliosis, 76+/-14 degrees; kyphosis, 59+/-25 degrees; T1-S1, 24.1+/-3.6 cm; RHTH, 10.0+/ 1.6 cm; LHTH, 10.6+/-1.6 cm; RHTW, 9.4+/-2.5 cm; and LHTW, 8.1+/-2.8 cm. At 2 year follow-up, patients treated with SCC had mean scoliosis 37+/-11 degrees (18% correction, P=0.06); kyphosis, 42+/-6 degrees (NS); T1-S1, 26.4+/-2.1 cm (P<0.01); RHTH, 9.0+/-1.1 cm (13%; P=0.30); LHTH, 10.0+/-1.5 cm (18%, P<0.01); RHTW, 7.4+/-1.1 cm (12%, P<0.01); and LHTW, 8.0+/-1.0 cm (0%, P=0.34). At 2-year follow-up, patients treated with GFS had mean scoliosis 42+/-13 degrees (45% correction, P<0.000001); kyphosis, 53+/-13 degrees (10%, P=0.19); T1-S1, 31.5+/ 5.4 cm (P<0.00001); RHTH, 12.0+/-2.4 cm (20%; P<0.01); LHTH, 12.0+/-1.7 cm (13%; P<0.01); RHTW, 9.8+/-1.3 cm (4%; P=0.27); and LHTW, 7.9+/-2.3 cm (3%;P=0.11). As an entire group, patients with a BMI>17 kg/m2 had more device-related than disease-related complications (P=0.09). Patients treated with SCC had 0.9 complications per patient. Patients treated with GFS had 2.2 complications per patient [<=5 y more often had >=2 complications (P=0.05)]. CONCLUSIONS: At 2-year follow-up, SCC and GFS were both effective in treating EOS in PWS patients. Patients treated with SCC had significant improvements in spine height and LHTH. Patients treated with GFS had significant improvements in scoliosis magnitude, spine height, RHTH, and LHTH. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 29401074 TI - The Economic Burden of Musculoskeletal Disease in Children and Adolescents in the United States. AB - BACKGROUND: Musculoskeletal conditions are among the most common and costly conditions suffered by Americans. In 2011, there was an estimated $213 billion in annual cost of direct treatment for and lost wages due to musculoskeletal disease in the United States. Data on economic burden, however, comes mostly from the adult population, with significantly less information regarding the burden of these conditions in young patients available. The purpose of this report is to provide data on the economic burden of musculoskeletal diseases in children and adolescents in the United States. METHODS: Eleven diagnosis categories were identified, with health care visits and hospitalization data derived from ICD-9 CM codes for each of the conditions searched. The largest database utilized was the Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID). Total visits came from the KID, HCUP NEDS (emergency department), NCHS NHAMCS OP (outpatient), and NCHS NAMCS (physician office) databases. The National Health Interview Survey (NHIS) child sample was additionally searched to obtain patient/parent-reported data. RESULTS: In 2012, more than 19 million children and adolescents received treatment in medical centers, physicians' offices, and hospitals for a musculoskeletal-related condition. The most common reason for treatment (68%) was traumatic injury, followed by a pain syndrome (13%) and deformity (9%). Total hospital charges in 2012 for children and adolescents with a primary musculoskeletal-related diagnosis totaled $7.6 billion. Trauma (43%) and deformity (38%) were the major contributors to total hospital charges. CONCLUSIONS: Although we found that hospital-related charges for musculoskeletal diseases for children and adolescents in 2012 totaled $7.6 billion, this number underestimates the total cost for all pediatric musculoskeletal conditions. Musculoskeletal conditions accounted for 5.4% of hospital charges in the pediatric population. However, only 1.4% of pediatric research funding is designated to musculoskeletal research. Going forward, the data in this report may be used to further research and to stimulate development of better methods with which to measure the direct and indirect costs of musculoskeletal conditions in children. LEVEL OF EVIDENCE: Level IV-economic and decision analysis. PMID- 29401075 TI - Comparison of Nasal Intubations by GlideScope With and Without a Bougie Guide in Patients Who Underwent Maxillofacial Surgeries: Randomized Clinical Trial. AB - BACKGROUND: Nasotracheal intubation is commonly performed to provide a secure airway for the maintenance of general anesthesia in maxillofacial surgeries. Routine nasotracheal intubation is performed under general anesthesia by direct laryngoscopy, frequently with the aid of Magill forceps. This method can be time consuming and may cause bleeding in the field of view. A gum elastic bougie (GEB) is a cheap, slender, and flexible device that could expedite nasotracheal intubation. The aim of this study was to evaluate the use of a GEB during nasotracheal intubation to facilitate the procedure and reduce the rate of complications. METHODS: In this randomized clinical trial study, 110 patients with American Society of Anesthesiologists (ASA) physical status I-II from 15 to 65 years of age were randomized into 2 equal groups. In both groups, a GlideScope and armored tube were used. In the GEB group, GEB was used to facilitate nasal intubation while the nasal intubation was performed without the aid of GEB in the routine group. The difficult intubation (defined as >1 attempt for intubation) was the primary outcome, and the duration of the intubation, the presence of traces of bleeding, the need for a tube replacement, and the usage of Magill forceps were the secondary outcomes. RESULTS: The incidence of bleeding in the GEB group was 1.81% vs 43.63% in the routine group (P < .001). In 5.5% of the GEB group, Magill forceps were used to advance the tube versus 67.3% in the routine group (P < .001). The mean time for intubation in GEB group was 48.63 +/- 8.53 vs 55.9 +/- 10.76 seconds in the routine group (P < .001). CONCLUSIONS: The GEB is a useful aid to nasotracheal intubation, reducing bleeding, the requirement for Magill forceps and, to a small degree, intubation time. A case exists for its routine use for this purpose. PMID- 29401076 TI - SmartTots Update Regarding Anesthetic Neurotoxicity in the Developing Brain. AB - SmartTots (http://smarttots.org/) represents a public-private partnership between the International Anesthesia Research Society and the US Food and Drug Administration. Over the past 7 years, SmartTots has worked in collaboration with various stakeholders to determine whether anesthetic drugs have detrimental effects on the developing brain. SmartTots has funded clinical and preclinical studies, organized meetings, served as a repository of peer-reviewed information, and facilitated the development of consensus-based statements. Here, we report advances in the field of anesthetic neurotoxicity and provide an update on SmartTots' activities. Clinical studies have provided some reassurance that a brief exposure to anesthetic drugs does not cause overt, persistent cognitive deficits. New recommendations aim to increase the reproducibility and "clinical relevance" of data from studies of laboratory animals. Overall, the field has advanced substantially; however, it remains paramount to definitively resolve whether anesthetic drugs are neurotoxic to the immature brain. The results of SmartTots efforts will either ally unwarranted fears or substantially change pediatric anesthetic practice and prompt studies to identify neuroprotective strategies. PMID- 29401077 TI - Chronic Pain and the Opioid Epidemic: Are We Ignoring the Potential Benefits of Nitrous Oxide? PMID- 29401078 TI - Teaching Medical Students Clinical Anesthesia. AB - There are many reasons for evaluating our approach and improving our teaching of America's future doctors, whether they become anesthesiologists (recruitment) or participate in patient management in the perioperative period (general patient care). Teaching medical students the seminal aspects of any medical specialty is a continual challenge. Although no definitive curricula or single clinical approach has been defined, certain key features can be ascertained from clinical experience and the literature. A survey was conducted among US anesthesiology teaching programs regarding the teaching content and approaches currently used to teach US medical students clinical anesthesia. Using the Accreditation Council for Graduate Medical Education website that lists 133 accredited anesthesiology programs, residency directors were contacted via e-mail. Based on those responses and follow-up phone calls, teaching representatives from 125 anesthesiology departments were identified and asked via e-mail to complete a survey. The survey was returned by 85 programs, yielding a response rate of 68% of individuals contacted and 63% of all departments. Ninety-one percent of the responding departments teach medical students, most in the final 2 years of medical school. Medical student exposure to clinical anesthesia occurred as elective only at 42% of the institutions, was requirement only at 16% of responding institutions, and the remainder had both elective and required courses. Anesthesiology faculty at 43% of the responding institutions reported teaching in the preclinical years of medical school, primarily in the departments of pharmacology and physiology. Forty-five percent of programs reported interdisciplinary teaching with other departments teaching classes such as gross anatomy. There is little exposure of anesthesiology faculty to medical students in other general courses. Teaching in the operating room is the primary teaching method in the clinical years. Students are allowed full access to patient care, including performing history and physical examinations, participating in the insertion of IVs and airway management. Simulation-based teaching was used by 82% of programs during medical student anesthesia clerkships. Sixty-eight percent of respondents reported that they have no formal training for their anesthesiology faculty teachers, 51% stated that they do not receive nonclinical time to teach, and 38% of respondents stated that they received some form of remuneration for teaching medical students, primarily nonclinical time. This article presents a summary of these survey results, provides a historical review of previous evaluations of teaching medical students clinical anesthesia, and discusses the contributions of anesthesiologists to medical student education. PMID- 29401079 TI - Effect-Site Target-Controlled Infusion in the Obese: Model Derivation and Performance Assessment. AB - BACKGROUND: The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. METHODS: In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data. Population modeling analysis was performed by nonlinear mixed effects regression in NONMEM (ICON, Dublin, Ireland). PK data from 3 previous studies in obese adult patients (n = 47), including PD (BIS) data from 1 of these studies (n = 20), were pooled and simultaneously analyzed. A decrease in NONMEM objective function (DeltaOBJ) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. In the second step of the study, we analyzed the predictive performance (median predictive errors [MDPE] and median absolute predictive errors [MDAPE]) of the current model and of other available models using an independent data set (n = 14). RESULTS: Step 1: The selected PKPD model produced an adequate fit of the data. Total body weight resulted in the best size scalar for volumes and clearances (DeltaOBJ, -18.173). Empirical allometric total body weight relationships did not improve model fit (DeltaOBJ, 0.309). A lag time parameter for BIS response improved the fit (DeltaOBJ, 89.593). No effect of age or gender was observed. Step 2: Current model MDPE and MDAPE were 11.5% (3.7 25.0) and 26.8% (20.7-32.6) in the PK part and 0.4% (-10.39 to 3.85) and 11.9% (20.7-32.6) in the PD part. The PK model developed by Eleveld et al resulted in the lowest PK predictive errors (MDPE = <10% and MDAPE = <25%). CONCLUSIONS: We derived and validated a propofol PKPD model to perform effect-site TCI in obese patients. This model, derived exclusively from obese patient's data, is not recommended for TCI in lean patients because it carries the risk of underdosing. PMID- 29401080 TI - The Effect of Intermittent Oxytocin Pretreatment on Oxytocin-Induced Contractility of Human Myometrium In Vitro. AB - BACKGROUND: Prolonged continuous oxytocin administration during labor may induce oxytocin receptor desensitization, which attenuates the response of the myometrium to further oxytocin, increasing the risk of postpartum hemorrhage. The literature comparing pulsatile (intermittent) versus continuous oxytocin administration for induction and augmentation of labor is inconsistent with regard to maternal outcomes. We aimed to determine the effect of intermittent versus continuous oxytocin preexposure on myometrial responsiveness to subsequent oxytocin. We hypothesized that intermittent oxytocin pretreatment would result in superior subsequent oxytocin-induced contractility than continuous oxytocin pretreatment. METHODS: This in vitro study was undertaken using myometrium obtained from women undergoing elective cesarean deliveries. Each myometrial strip was mounted in an individual organ bath with physiological salt solution under homeostatic conditions and allocated to one of 3 groups: (1) control (no pretreatment); (2) continuous (pretreatment with oxytocin 10 M for 2 hours); or (3) intermittent (pretreatment with alternating oxytocin 10 M and physiological salt solution every 15 minutes, for 2 hours). After pretreatment, dose-response testing to oxytocin 10 to 10 M was performed and contractile parameters were measured. The primary outcome was motility index (MI, amplitude * frequency) of contractions. RESULTS: Eighteen women were recruited, and 86 successful experiments were performed (control n = 29, continuous n = 28, intermittent n = 29). The means (standard errors) of MI (?g.contractions/10 min) in the control, continuous, and intermittent groups were 2.34 (0.09), 1.78 (0.09), and 2.13 (0.11), respectively. The MI was significantly reduced in the continuous group when compared to the control (estimated difference [95% confidence interval {CI}], -0.56 [-0.81 to -0.31]; P < .01) and intermittent group (estimated difference [95% CI], -0.35 [-0.62 to -0.08]; P = .01). There was no significant difference in MI between the intermittent and control group (estimated difference [95% CI], -0.21 [-0.51 to 0.09]; P = .17). CONCLUSIONS: Human myometrium remains more responsive to subsequent oxytocin after intermittent compared to continuous exposure to oxytocin, most likely due of reduction in oxytocin receptor desensitization, or facilitation of receptor resensitization in the intermittent group. Hence, intermittent oxytocin administration during labor warrants further investigation as a technique to improve uterine oxytocin responsiveness. PMID- 29401081 TI - In Response. PMID- 29401082 TI - Effect of a Delayed Start to Oral Feeding on Feeding Performance and Physiological Responses in Preterm Infants: A Randomized Clinical Trial. AB - BACKGROUND: The efficient and safe oral feeding of preterm infants, an essential criterion for hospital discharge, is affected by neurodevelopmental maturation. However, the timing of initiating oral feeding and its relation to maturation, feeding performance, and physiological responses are unclear. PURPOSE: The aim of this study was to determine the effect of a 1-week delay in the initiation of oral feeding on feeding performance, transition time, weight gain, and cardiorespiratory responses in preterm infants. METHODS: In this randomized controlled trial, 40 infants with a gestational age at birth of less than 32 weeks were recruited. The control group (n = 18) began oral feeding when the infants were physiologically stable, whereas the experimental group (n = 22) began oral feeding 1 week later. Infant feeding performance, heart rate, and oxygen saturation were measured before, during, and after feeding on the first day of oral feeding and 3 days later. Daily weight gain was calculated by measuring body weight every morning, and transition time was calculated by counting the number of days from the initiation of oral feeding to the termination of tube feeding. RESULTS: There were no significant differences between the two groups in terms of feeding performance, weight gain, or postmenstrual age at the completion of full oral feeding. The transition time was significantly shorter in the experimental group than in the control group. More infants in the control group experienced episodes of oxygen desaturation during feeding than in the experimental group. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: For infants with a postmenstrual age of greater than 32 weeks who are ready to initiate oral feeding, postponing oral bottle feeding for 1 week may be considered as an intervention to reduce physiological distress. PMID- 29401083 TI - Molecular Comparison of Adult and Pediatric Ulcerative Colitis Indicates Broad Similarity of Molecular Pathways in Disease Tissue. AB - BACKGROUND: Efficacy data from adult ulcerative colitis (UC) clinical trials are often extrapolated for pediatric prescribing. Consequently, it is important to understand similarities/differences in pediatric and adult UC. Pediatric UC tends to have more extensive disease at presentation, yet genetic studies have not detected pathways that distinguish the populations, and differences in mucosal gene expression between adult and pediatric UC are not well characterized. METHODS: Using colonic microarray data from a phase 3 trial of golimumab in adult UC (87 UC; 21 healthy), the GSE10616 pediatric dataset (10 UC; 11 healthy), and a phase 1B trial of golimumab in pediatric UC (n = 19), UC expression profiles were compared and unique genes were defined as those with significant changes (|FC|>2*, adjusted P < 0.05) in one population, but not the other (|FC| < 1.2*, adjusted P > 0.05). Pathway and upstream regulator analyses were performed. Profiles by disease extent (extensive [pancolitis] vs limited [left-sided] involvement) were compared within each population. RESULTS: Pediatric and adult disease profiles overlapped substantially, with ~50% to 75% overlap, depending on the fold-change cutoff used. Conversely, <10% of the disease profiles were unique to each population. Similar canonical pathways were enriched in both datasets. Predicted upstream regulators were also concordant, including lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha. Expression profiles of extensive UC were indistinguishable from those of patients with limited involvement in each population. CONCLUSIONS: The UC gene expression landscape is shared by adults and children, independent of disease extent. This supports extrapolation of efficacy from adults to children in developing new therapies for UC. PMID- 29401084 TI - Safety and Efficacy of Bedside Percutaneous Endoscopic Gastrostomy Placement in the Neonatal Intensive Care Unit. AB - OBJECTIVE: The aim of the study is to describe the safety and efficacy of bedside percutaneous endoscopic gastrostomy (PEG) placement in a level 3 neonatal intensive care unit (NICU). METHODS: A retrospective chart review was performed on 106 infants with a birthweight <=6 kg receiving bedside PEG placement at Johns Hopkins All Children's Hospital between 2007 and 2013. Preprocedure, postprocedure, and demographic data were collected. The main safety outcome was postprocedure complication rate and the main efficacy outcome was time to initiate feeds and time on respiratory support. RESULTS: The mean birth weight and mean gestational age of our population at the time of procedure were 2.2 kg and 33 weeks, respectively. There were 9 total complications (8.5%) with major complications being only 2 (1.8%). There were no instances of blood stream infections. The mean length of time to initiate feeds was 1.2 days (standard deviation [SD] = 1.2). Ninety-three percent of patients were extubated within 24 hours. CONCLUSIONS: Bedside PEG placement is safe with minimal complications. It is associated with little need for ventilator support and allows for early re initiation of feeds and early success at reaching goal feedings. PMID- 29401085 TI - Creation of Experience-based Celiac Benchmarks: The First Step in Pretransition Self-management Assessment. AB - OBJECTIVES: Transition planning for children with chronic disease includes the development of independence in many self-management tasks. Conditions that depend on diet have distinct skill sets not well assessed by the traditional transition readiness tools. There has been literature that describes age-appropriate skill acquisition for diabetes and food allergy patients. There are, however, no age appropriate benchmarks established for celiac disease (CD). METHODS: CD experts (including physician, nurse, dietician, social worker, patient, and parent) created a list of celiac-related tasks, which formed the basis of the survey. Patients with CD, and their parents, were recruited from outpatient celiac clinic and support groups, and invited to report the age each task was mastered. RESULTS: Respondents included 204 patients and 155 parents. Mean age was 12 years (standard deviation 4.6) with average of 4 years since diagnosis. The earliest tasks were mastered by a median age of 8 years, such as recognizing GF as gluten free, eating safely in a shared space and recognizing basic unsafe foods. Describing the effects of eating gluten or explaining CD to a friend or stranger occurred around age 10. Asking about gluten-free preparation in a restaurant, and identifying gluten-free medications or vitamins was mastered around age 12, whereas tasks involved with safe domestic travel or assessing risk in a job environment occurred between 14 and 16. The interquartile range was about 4 years for each question. No significant difference seen between patient and parent reports. CONCLUSIONS: This novel patient-centered celiac skill list may improve anticipatory guidance and accelerate self-management skills. PMID- 29401086 TI - Comparing Functional Outcomes After Injury-Specific Fixation of Posterior Malleolar Fractures and Equivalent Ligamentous Injuries in Rotational Ankle Fractures. AB - OBJECTIVES: To evaluate the effect of posterior bony versus ligamentous injury pattern on functional outcomes in operatively treated rotational ankle fractures. DESIGN: Retrospective cohort analysis of prospective registry. SETTING: Academic Level I trauma center. PATIENTS/PARTICIPANTS: Operatively treated supination external rotation IV and pronation external rotation IV ankle fractures. INTERVENTION: Lateral malleolus plate fixation with either posterior malleolus (PM) plate fixation or posterior inferior tibiofibular ligament (PITFL) repair. MAIN OUTCOME MEASUREMENTS: Foot and ankle outcome scores at minimum 12 months postoperatively. RESULTS: One hundred seventy-eight fractures were treated with injury-specific anatomic fixation of a PM fracture (n = 122) or torn PITFL (n = 56). The PM group was significantly older, contained more women, and had lower mean body mass index versus the PITFL group. There was a higher rate of medial malleolar fracture in the PM group; other fracture and baseline characteristics were similar between groups. Univariate and multivariable analysis revealed no difference in foot and ankle outcome scores for any of the 5 summary domains (symptoms, pain, activities of daily living, sports, or quality of life) at the time of most recent follow-up. The median length of follow-up was 16.3 and 12.8 months in the PM and PITFL groups, respectively. CONCLUSIONS: In our cohort of ankle fractures, we have demonstrated comparable outcomes in stage IV rotational ankle fractures with and without PM fractures, indicating that the presence of a PM fracture may not result in inferior outcomes compared with ligamentous equivalent injuries if these fractures are addressed in an injury-specific manner. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401087 TI - Nail Fit: Does Nail Diameter to Canal Ratio Predict the Need for Exchange Nailing in the Setting of Aseptic, Hypertrophic Femoral Nonunions? AB - OBJECTIVES: To evaluate patient-independent risk factors for aseptic femoral hypertrophic nonunion requiring exchange nailing, with particular reference to the fit of the nail at the isthmus within the canal. DESIGN: Retrospective case control study. SETTING: Level 1 trauma center. MAIN OUTCOME MEASUREMENTS: Between 2008 and 2012, 211 patients without any patient-dependent risk factors for nonunion were treated with a locked reamed intramedullary nail for a femoral shaft fracture. Twenty-three cases went on to hypertrophic nonunion requiring exchange nailing (treatment group) and 188 cases went on to union (control group). Patient-independent risk factors for exchange nailing were documented. RESULTS: Patient-independent risk factors for exchange nailing were poor fracture reduction [Odds ratio (OR): 11.5, 95% confidence interval (CI), 4.0-33.4, P < 0.001], open fracture (OR: 7.6, 95% CI, 3.0-19.6, P = 0.004), Winquist classification of 4 (OR: 4.4, 95% CI, 1.9-6.7, P = 0.016), and poor nail fit (OR: 10.3, 95% CI, 5.1-28.4, P < 0.001). Multivariate analysis revealed nail fit as an independent predictor of femoral nonunion requiring exchange nailing (OR: 11.4, 95% CI, 6.9-15.2, P < 0.001). Moreover, we found a direct relationship between increasingly poor nail fit and increased risk of exchange nailing, with the criterion occurring at a nail fit ratio <70%. CONCLUSION: When proceeding to femoral fracture reamed intramedullary nailing, we recommend a minimum nail fit of 70% at the isthmus and ideally 90% or more, to avoid surgical reintervention. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401088 TI - Safe Zone Quantification of the Third Sacral Segment in Normal and Dysmorphic Sacra. AB - OBJECTIVE: To quantify the osseous anatomy of the dysmorphic third sacral segment and assess its ability to accommodate internal fixation. DESIGN: Retrospective chart review of a trauma database. SETTING: University Level 1 Trauma Center. PATIENTS: Fifty-nine patients over the age of 18 with computed tomography scans of the pelvis separated into 2 groups: a group with normal pelvic anatomy and a group with sacral dysmorphism. MAIN OUTCOME MEASUREMENTS: The sacral osseous area was measured on computed tomography scans in the axial, coronal, and sagittal planes in normal and dysmorphic pelves. These measurements were used to determine the possibility of accommodating a transiliac transsacral screw in the third sacral segment. RESULTS: In the normal group, the S3 coronal transverse width averaged 7.71 mm and the S3 axial transverse width averaged 7.12 mm. The mean S3 cross-sectional area of the normal group was 55.8 mm. The dysmorphic group was found to have a mean S3 coronal transverse width of 9.49 mm, an average S3 axial transverse width of 9.14 mm, and an S3 cross-sectional area of 77.9 mm. CONCLUSIONS: The third sacral segment of dysmorphic sacra has a larger osseous pathway available to safely accommodate a transiliac transsacral screw when compared with normal sacra. The S3 segment of dysmorphic sacra can serve as an additional site for screw placement when treating unstable posterior pelvic ring fractures. PMID- 29401089 TI - Biomechanical Comparison of 3 Inferiorly Directed Versus 3 Superiorly Directed Locking Screws on Stability in a 3-Part Proximal Humerus Fracture Model. AB - OBJECTIVE: To quantify the stability of 3 points of inferiorly directed versus 3 points of superiorly directed locking screw fixation compared with the full contingent of 6 points of locked screw fixation in the treatment of a 3-part proximal humerus fracture. METHODS: A standardized 3-part fracture was created in 10 matched pairs (experimental groups) and 10 nonmatched humeri (control group). Osteosynthesis was performed using 3 locking screws in the superior hemisphere of the humeral head (suspension), 3 locking screws in the inferior hemisphere (buttress), or the full complement of 6 locking screws (control). Specimens were tested in varus cantilever bending (7.5 Nm) to 10,000 cycles or failure. Construct survival (%) and the cycles to failure were compared. RESULTS: Seven of 10 controls survived the 10,000-cycle runout (70%: 8193 average cycles to failure). No experimental constructs survived the 10,000-cycle runout. Suspension and buttress screw groups failed an average of 331 and 516 cycles, respectively (P = 1.00). The average number of cycles to failure and the number of humeri surviving the 10,000-cycle runout were greater in the control group than in the experimental groups (P <= 0.006). CONCLUSION: Data support the use of a full contingent of 6 points of locking screw fixation over 3 superior or 3 inferior points of fixation in the treatment of a 3-part proximal humerus fracture with a locking construct. No biomechanical advantage to the 3 buttress or 3 suspension screws used in isolation was observed. PMID- 29401090 TI - Orthopaedic Trauma Association Annual Meeting Program Committee: Analysis of Impact of Committee Size and Review Process on Abstract Acceptance. AB - OBJECTIVE: To evaluate whether scientific abstracts selected for podium presentation at the Orthopaedic Trauma Association (OTA) Annual Meeting differ based on the program committee size and/or the proportion of abstracts each committee member evaluates. METHODS: Abstract scores from the Orthopaedic Trauma Association program committee from 2010 through 2016 were obtained. All members (range, 8-9) reviewed each clinical abstract (range, 506-778) each year in a blinded fashion. The 90 top-scoring abstracts were considered "accepted" for this study. To determine the effect of reducing the committee size, all possible combinations of reviewers for each possible committee size were modeled. To determine the effect of reducing the number of abstracts each member reviewed, we used Monte Carlo simulation with 100 cycles to generate possible combinations of 1-9 reviewers for each abstract. Mean percent agreement with the actual selection was the primary outcome. RESULTS: The mean percent agreement progressively declined from 90.2% with 1 less committee member to 56.7% with only a single reviewer. For each reduction in the number of committee members, 4.4% agreement was lost. If all committee members were retained but the number of reviewers per abstract was reduced from 8 to 1, the mean percent agreement declined from 88.8% to 43.0%. Each reduction in reviewers per abstract reduced the mean percent agreement 6.3%. CONCLUSION: The findings inform program committees striving to balance the trade-off between an acceptable reduction in agreement, given a reduction in the program committee size or the proportion of abstracts each committee member evaluates. PMID- 29401091 TI - Pathoanatomy of the Tongue-Type Calcaneus Fracture: Assessment Using 2- and 3 Dimensional Computed Tomography. AB - OBJECTIVE: To define the pathoanatomy of the tongue-type calcaneus fracture and assess the appropriateness of percutaneous techniques in addressing all planes of deformity in this injury. DESIGN: Retrospective cohort. SETTING: ACS Level I trauma center. PATIENTS/PARTICIPANTS: Fifty-six displaced Sanders 2B and 2C tongue-type calcaneus fractures identified from an initial cohort of 1118 calcaneus fractures treated over a 16-year period. MAIN OUTCOME MEASUREMENTS: We reviewed cross-sectional imaging and documented the presence of a varus/valgus (coronal plane) or adduction/abduction (axial plane) position of the tongue fragment in relation to the intact posterior facet, with greater than 10 degrees of angulation being diagnostic of displacement. RESULTS: When assessing for displacement and angulation in the coronal plane, 98% of tongue fragments were either in a position of valgus (77%) or neutral (21%), with a mean valgus angulation of 17.3 degrees. In the axial plane, 98% of tongue pieces were in a position of adduction (64%) or neutral (34%), with an average angulation into adduction of 15.0 degrees. Sanders 2B fractures were more likely to be in a position of valgus and adduction than those of 2C fractures. DISCUSSION: The tongue-type calcaneus fracture most often displaces into a position of plantarflexion, valgus, and adduction. Knowledge of this deformity may aid in achieving successful closed reduction when using the Essex-Lopresti maneuver or other less invasive techniques. PMID- 29401092 TI - Minimizing Leg Length Discrepancy After Intramedullary Nailing of Comminuted Femoral Shaft Fractures: A Quality Improvement Initiative Using the Scout Computed Tomography Scanogram. AB - OBJECTIVES: To prevent leg length discrepancy (LLD) after locked femoral nailing in patients with comminuted femoral shaft fractures. DESIGN: Prospective consecutive case series aimed at quality improvement. SETTING: Level 1 Trauma Center PATIENTS:: Ninety-eight consecutive patients with a comminuted femoral shaft fracture underwent statically locked intramedullary nailing, with a focused attempt at minimizing LLD during surgery. INTERVENTION: A computed tomography scanogram of both legs was performed on postoperative day 1 to assess for residual LLD. Patients were offered the option to have LLD >1.5 cm corrected before discharge. MAIN OUTCOME MEASURE: LLD >1.5 cm. RESULTS: Twenty-one patients (21.4%) were found to have an LLD >1.5 cm. An LLD >1.5 cm occurred in 10/55 (18%) antegrade nail patients and 11/43 (26%) retrograde nail patients (P = 0.27). No difference was noted based on the mechanism of injury, surgeon training and OTA/AO type B versus C injury. Ninety of 98 patients left with <1.5 cm LLD, 13/21 had a correction all to <=0.6 cm, and 8 decided to accept the LLD and declined early correction. CONCLUSIONS: No patient left the hospital with an LLD >1.5 cm after locked intramedullary nailing for a comminuted femoral shaft fracture without being informed and the option of early correction. We recommend using a full-length computed tomography scanogram after IM nailing of comminuted femur fractures to prevent iatrogenic LLD. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401093 TI - Intraoperative Vancomycin Powder Reduces Staphylococcus aureus Surgical Site Infections and Biofilm Formation on Fixation Implants in a Rabbit Model. AB - OBJECTIVES: To evaluate the effectiveness of intraoperative vancomycin powder in prevention of surgical site infection and biofilm formation on implants in a contaminated animal fixation model. METHODS: We created a rabbit surgical model including fixation implants at a tibial surgical site seeded with methicillin resistant Staphylococcus aureus. Our study cohort included 18 rabbits. Nine received vancomycin powder at the surgical site, and the other 9 did not. Serum vancomycin levels were measured at scheduled time points over 24 hours. Bone infection and implant biofilm formation were determined based on the number of colony-forming units present 2 weeks after surgery. Radiography, histology, and electron microscopy aided in evaluation. RESULTS: No bone infection or implant colonization occurred in the vancomycin powder group. Six bone infections and 6 implant biofilm formations (67%; 95% confidence interval, 45%-88%) occurred in the group that did not receive vancomycin powder (P = 0.009). Serum vancomycin levels were detectable at minimal levels at 1 and 6 hours only. Pathological changes occurred in the specimens that were positive for infection. CONCLUSIONS: Intraoperative vancomycin powder application at the time of fixation decreases risk for bone infection and biofilm formation on implants in a rabbit model, with minimal increase in serum vancomycin levels. The results are encouraging and support the rationale for a clinical trial investigating the use of local vancomycin powder to reduce the rate of surgical site infections. CLINICAL RELEVANCE: Infection is a common complication of surgery, especially with implants. Simple methods to prevent or decrease the occurrence of infection would benefit the patient and the health care system. PMID- 29401094 TI - Ultralow-Dose CT (REDUCTION Protocol) for Extremity Fracture Evaluation Is as Safe and Effective as Conventional CT: An Evaluation of Quality Outcomes. AB - OBJECTIVES: To assess clinical and hospital quality outcomes of patients receiving the previously reported Reduced Effective Dose Using Computed Tomography In Orthopaedic Injury (REDUCTION) imaging protocol. DESIGN: Retrospective Chart review. SETTING: Level I Trauma Center and affiliated Tertiary Care Hospital Center. PATIENTS/PARTICIPANTS: Fifty patients who received this protocol for acute traumatic fracture evaluation and met the inclusion criteria were compared with a cohort of 50 patients matched for age and fracture type who previously received conventional CT scanning for acute traumatic fracture evaluation. INTERVENTION: Reduced Effective Dose Using Computed Tomography In Orthopaedic Injury (REDUCTION) protocol for diagnostic fracture evaluation. MAIN OUTCOME MEASURES: Estimated effective radiation doses were calculated and compared using Digital Imaging and Communications in Medicine (DICOM) information from all included studies. Patient outcomes between groups were compared with time to fracture union as the primary outcome. Secondary outcome measures included the presence of complication defined as infection, malunion, nonunion, failure of nonoperative treatment, painful implants, and implant failure. Other secondary quality outcomes that were recorded included readmission within 30 days and hospital length of stay. Functional quality measures included joint range of motion. Statistical analyses were conducted to identify significant differences between cohorts (significance designated as P < 0.05). RESULTS: Patient characteristics between cohorts were not significantly different with respect to age, sex, body mass index, comorbidities, injury mechanism, or injury location. Fractures of the elbow, hip, knee, and foot/ankle were evaluated. Mean clinical follow-up was 9.5 +/- 4.9 months for the REDUCTION cohort and 12.4 +/- 5.3 months for the conventional CT cohort. Mean estimated effective dose for all REDUCTION scans was 0.15 milliSieverts (mSv) as compared to 1.50 mSv for the conventional CT cohort (P = 0.037). Preoperative diagnosis was confirmed intraoperatively in 49/50 cases in the REDUCTION cohort compared with 48/50 cases in the conventional CT cohort (P = 0.79). Outcomes including time to union, range of motion, complications, readmission, treatment failure, reoperation, and length of stay were not significantly different between groups. CONCLUSIONS: The REDUCTION protocol represents ultralow-dose CT developed for minimizing radiation exposure to patients presenting with traumatic fractures. This protocol resulted in a 10-fold reduction in radiation exposure. No difference in clinical or hospital quality outcomes was detected between patients who received this protocol as compared to those receiving automated dose CT. The REDUCTION protocol is a safe and effective method of performing CT for extremity fractures with significantly reduced radiation risk. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401095 TI - High Rate of Union for Aseptic Distal Tibial Nonunions in Adults Treated With Slow Gradual Compression via Circular External Fixation. AB - OBJECTIVE: To evaluate the healing rate of aseptic nonunions of the distal third of the tibia treated with Ilizarov slow gradual compression and deformity correction. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS/PARTICIPANTS: Ninety-four consecutive adult patients with 94 distal third tibial aseptic nonunions. INTERVENTION: Ilizarov external fixation and slow gradual compression; most patients also underwent bone grafting, deformity correction, or both before the initiation of compression. MAIN OUTCOME MEASUREMENTS: Rate of bony union. RESULTS: Eighty-seven of 94 cases (92.6%) healed after slow gradual compression across the nonunion site with a circular external fixator. Four of the 7 patients who failed treatment healed after additional operative treatment, and the remaining 3 refused further care. CONCLUSIONS: Circular external fixation with slow gradual compression was successful in treating aseptic nonunions of the distal third of the tibia in 92.6% of cases. Careful selection of patients for this treatment method can lead to a high success rate with a relatively low rate of major complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401096 TI - Impact of Psychiatric Illness on Outcomes After Operatively Managed Tibial Plateau Fractures (OTA-41). AB - OBJECTIVES: To assess the role self-reported treatment for a psychiatric diagnosis may play in long-term functional outcomes after operatively managed tibial plateau fractures. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: Over an 11-year period, patients were screened and identified on presentation to the emergency department or in the clinical office for inclusion in an IRB-approved registry. A total of 245 patients were included in the study. Twenty-one patients reported treatment for a psychiatric diagnosis. INTERVENTION: Surgical repair of tibial plateau fractures. MAIN OUTCOME MEASURE: Patients were divided into 2 cohorts; 1 cohort being those who self-reported receiving treatment of a psychiatric diagnosis (PI); the other group being those who did not self-report receiving treatment of a psychiatric diagnosis (NPI). Three-month, 6-month, and long-term outcomes (mean = 18 months) were evaluated using the Short Musculoskeletal Function Assessment (SMFA), pain scores, and postoperative complications (infection, VTE, nonunion, and necessity for secondary operations). RESULTS: Pain scores were higher in patients who self reported receiving treatment for a psychiatric diagnosis (P = 0.012). Long-term functional outcomes as measured by the SFMA were demonstrated to be worse in patients who self-reported treatment for a psychiatric diagnosis (P = 0.034). No differences existed between groups in regards to postoperative complications. Multiple linear regression analysis revealed that being treated for diagnosis of a mental health illness was an independent predictor of worse functional outcomes at long-term follow-up [B = 8.874, 95% confidence interval (CI) = 0.354-17.394, P = 0.041]. CONCLUSIONS: Mental health plays a crucial role in long-term outcomes after operative fixation of tibial plateau fractures. Patients who have been diagnosed with a mental health illness have significantly worse outcomes at long term follow-up. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401097 TI - What Is the Ideal Starting Point for an Olecranon Screw? An Anatomic Cadaveric Study. AB - OBJECTIVE: To assess whether "center-center" position is ideal starting point for minimum fracture displacement when placing an intramedullary (IM) screw in the ulna. METHODS: Thirty-six arms (average age, 82 years) underwent a posterior approach to the olecranon and were randomized into 3 groups: center-center (center in sagittal plane, center in coronal plane), posterior-lateral (posterior in sagittal plane, lateral in coronal plane), and posterior-medial (posterior in sagittal plane, medial in coronal plane). Groups were matched into 18 pairs, and fixation was performed with an IM screw. Primary outcome measure was articular surface displacement on the olecranon. Measurements were compared across each combination of locations using the Kruskal-Wallis rank sums test, and a sign test determined whether each location differed from anatomic reduction. RESULTS: Articular step-off measurements were significantly different between center center (0.6 mm) and posterior-medial (2.1 mm) groups (P = 0.01) and approached significance with posterior-lateral versus posterior-medial (0.9 mm) locations (P = 0.07). No significant difference was found comparing center-center with posterior-lateral locations (P = 0.7). The articular surface (P = 0.04), posterior cortex (P = 0.02), and medial cortex (P = 0.001) measurements for the posterior-medial starting point were all worse compared with anatomic reduction. CONCLUSIONS: Malreduction of a simulated olecranon fracture was most significant when the starting point for the IM screw was malpositioned medially. A central or laterally based starting point was more forgiving. Avoiding a medially based starting point is crucial for achieving benefits of fixation with an IM screw and reduces the chance of malreduction after fixation. PMID- 29401098 TI - Discriminative Ability for Adverse Outcomes After Surgical Management of Hip Fractures: A Comparison of the Charlson Comorbidity Index, Elixhauser Comorbidity Measure, and Modified Frailty Index. AB - OBJECTIVES: The Charlson comorbidity index (CCI), Elixhauser comorbidity measure (ECM), and modified frailty index (mFI) have been associated with mortality after hip fracture. The present study compares the clinically informative discriminative ability of CCI, ECM, and mFI, as well as demographic characteristics for predicting in-hospital adverse outcomes after surgical management of hip fractures. METHODS: Patients undergoing hip fracture surgery were selected from the 2013 National Inpatient Sample. The discriminative ability of CCI, ECM, and mFI, as well as demographic factors for adverse outcomes were assessed using the area under the curve analysis from receiver operating characteristic curves. Outcomes included the occurrence of any adverse event, death, severe adverse events, minor adverse events, and extended hospital stay. RESULTS: In total, 49,738 patients were included (mean age: 82 years). In comparison with CCI and mFI, ECM had the significantly largest discriminative ability for the occurrence of all outcomes. Among demographic factors, age had the sole or shared the significantly largest discriminative ability for all adverse outcomes except extended hospital stay. The best performing comorbidity index (ECM) outperformed the best performing demographic factor (age) for all outcomes. CONCLUSION: Among both comorbidity indices and demographic factors, the ECM had the best overall discriminative ability for adverse outcomes after surgical management of hip fractures. The use of this index in correctly identifying patients at risk for postoperative complications may help set appropriate patient expectations, assist in optimizing prophylaxis regimens for medical management, and adjust reimbursements. More widespread use of this measure for hip fracture studies may be appropriately considered. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29401099 TI - Surgeon Concordance in the Assessment of Resectability for Stage IA Nodular Lymphocyte Predominant Hodgkin Lymphoma. PMID- 29401100 TI - Primary Central Nervous System Malignant Melanoma in Children: A Case Series and Review of the Literature. AB - We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established. PMID- 29401101 TI - Risk Factors and the Prevention of Weight Gain During Induction Chemotherapy in Children With Acute Lymphoblastic Leukemia. AB - Weight gain is often observed in children with acute lymphoblastic leukemia (ALL) who undergo chemotherapy including steroids. An increase in body mass index (BMI) standard deviation score (SDS) during induction therapy is reported as a risk factor for obesity after treatment. However, risk factors of an increase in BMI SDS during induction therapy are not known. Ninety-six patients with ALL who were treated at our hospital between 1996 January and September 2013 were analyzed retrospectively. Daily body weight measurement was initiated in July 2005 in an attempt to control weight. Fifty-four patients were boys and 42 were girls. The median age at onset was 5.1 years (0.5-16.6 y), and 7.3% of patients were overweight/obese at onset. BMI-SDS increased +0.1% (-3.3% to +3.2%) during induction therapy. BMI-SDS increased by 1 and 2 or more SDs in 20% and 3% of patients, respectively. In multivariate analysis, non-high-risk treatment and earlier treatment start date (before daily body weight measurement) were independent risk factors. Ten percent of patients were overweight/obese at 3 years after completion therapy, and high BMI-SDS after induction therapy was a risk factor. Daily body weight measurement might prevent excess weight gain during induction therapy, resulting in patients maintaining a healthy weight after ALL treatment. PMID- 29401102 TI - Acquired Hypofibrinogenemia Before Asparaginase Exposure During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia: A Report of 2 Cases and Review of the Literature. AB - Coagulopathy in pediatric leukemia patients is typically associated with acute promyelocytic leukemia or after asparaginase use in acute lymphoblastic leukemia. Rarely seen in acute lymphoblastic leukemia, we report 2 patients who presented with normal coagulation markers, but subsequently developed severe hypofibrinogenemia and bleeding in induction before administration of asparaginase. In both cases, cryoprecipitate was administered as initial treatment for bleeding associated with the hypofibrinogenemia. One patient was refractory to cryoprecipitate replacement and required treatment with human fibrinogen concentrate due to the persistence of hypofibrinogenemia with significant bleeding. The hypofibrinogenemia was transient in both cases and resolved within a few weeks. PMID- 29401103 TI - Megakaryocytic Emperipolesis in an Adolescent With Hodgkin Lymphoma. PMID- 29401104 TI - A Case of Small Cell Lung Carcinoma in a 15-Year-Old Boy and Literature Review. AB - Small cell lung carcinoma (SCLC), also known as high-grade neuroendocrine tumor of the lung, is exceedingly rare in the pediatric population. SCLC is usually fast growing and often has metastasized at diagnosis. It frequently responds well to therapy initially, however, has a high relapse and mortality rate. There are limited published data on SCLC in children and no existing pediatric treatment protocols. In this report, we present a case of extensive stage SCLC in a 15-year old boy who responded to single-agent gemcitabine therapy and review similar cases reported in the medical literature. PMID- 29401105 TI - Deep Vein Thrombosis in a Young, Healthy Baseball Catcher: A Case Report and Review of the Literature. AB - Venous thromboembolism is becoming increasingly recognized as a significant cause of morbidity and mortality in the hospitalized pediatric population. However, young healthy athletes can present with unique risk factors for deep vein thrombosis (DVT) that can be overlooked. Here we report a case of an adolescent male with no inherited risk factors or prior history of DVTs who developed a right femoral vein DVT in the context of playing catcher in baseball after recovering from a bout of streptococcal pharyngitis. We review the evidence that suggests that repetitive squatting-induced compression of the femoral vein can cause the venous stasis and endothelial microtrauma that contributed to the formation of this thrombus. PMID- 29401106 TI - CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study. AB - OBJECTIVE: To test the hypothesis that APOE epsilon4 status and cerebrospinal fluid (CSF) Abeta42, T-tau and P-tau would independently predict the risk of postoperative delirium. BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium. METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium. RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Abeta42 (P < 0.01) were independent predictors of postoperative delirium. CONCLUSIONS: This study is the first to show an independent association between CSF Abeta42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease. PMID- 29401107 TI - Ulysses Syndrome: The Modern-day Odyssey of Pediatric Patients With Uncomplicated Acute Appendicitis. PMID- 29401108 TI - Commentary on Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery. PMID- 29401109 TI - Response: "Conversion During Laparoscopic Liver Resections: a Step Forward". PMID- 29401110 TI - Autopsy Case of a Penetrating Wound to the Left Cerebral Hemisphere Caused by an Accidental Shooting With a Crossbow. AB - A crossbow is a bow that shoots an arrow when a gun-like trigger is pulled. Deaths caused by accidental crossbow shootings are extremely rare. Here we describe an autopsy case of a penetrating wound to the left cerebral hemisphere caused by an accidental shooting with a crossbow. A man in his early 60s who lived with his wife and had used crossbows for 20 years as his hobby was found one early morning in the shed of his house, collapsed and bleeding from the head and neck. He was taken to a hospital and died after approximately 3 days of conservative treatment. At autopsy, a penetrating wound between the upper part of the left anterior neck and the left frontoparietal region was evident. Traumatic intracerebral hematoma was observed in the left frontal lobe, and severe traumatic subarachnoid hemorrhage was present throughout the brain. Cerebral contusion and hematoma without any organization were noted around the penetration. The cause of death was determined to be cerebral contusion and intracerebral hematoma due to the penetrating wound by the crossbow arrow. He was probably trying to load an arrow into the crossbow by placing it on the floor, pointing upward, and made a mistake in its operation that resulted in the shooting of the arrow. This case is unique because it was a rare accidental death caused by a crossbow arrow, and a detailed histopathological examination was performed. PMID- 29401112 TI - Ogbunabali[COMBINING DOT BELOW] and Hypnos, 1949. PMID- 29401111 TI - Basal Subnuclear Vacuolization, Armanni-Ebstein Lesions, Wischnewsky Lesions, and Elevated Vitreous Glucose and beta-Hydroxybuyrate: Is It Hypothermia, Diabetic Ketoacidosis, or Both? AB - Hypothermia and diabetic ketoacidosis are both potentially fatal conditions, which have historically been considered to have associated pathognomonic pathologies. Hypothermia and diabetic ketoacidosis share similar pathological mechanisms, which result in metabolic derangement, with increased post mortem vitreous glucose and beta-hydroxybuyrate, and are able to exacerbate and precipitate one another. Although Wischnewsky lesions are associated with hypothermia, and Armanni-Ebstein lesions and basal subnuclear vacuolization are associated with diabetic ketoacidosis, recent studies have demonstrated that there is a significant overlap between the pathological findings of these 2 conditions. We report a case of a 50-year-old woman with type 1 diabetes who was found deceased in the middle of winter. Autopsy showed Wischnewsky lesions, Armanni-Ebstein lesions, and basal subnuclear vacuolization, together with elevated vitreous glucose and beta-hydroxybuyrate. The cause of death was the combined effects of hypothermia and diabetic ketoacidosis. This case highlights the overlapping clinical presentation, pathophysiology, and pathology of these 2 conditions. PMID- 29401114 TI - Efficacy of a Structured Exercise Program for Improving Functional Capacity and Quality of Life in Patients With Stage 3 and 4 Sarcoidosis: A RANDOMIZED CONTROLLED TRIAL. AB - PURPOSE: This study investigated the effects of an exercise program on functional capacity and quality of life in patients with stage 3 and stage 4 sarcoidosis. METHODS: Eighteen patients with stage 3 and 4 sarcoidosis were recruited; 9 received 12 wk of supervised exercise training and 9 received usual care. Patients underwent the following evaluations at baseline and follow-up: 6-min walk test, maximal inspiratory and expiratory pressure tests, back and leg dynamometer test, modified Medical Research Council Dyspnea Scale, Fatigue Severity Scale, St George Respiratory Questionnaire, Short Form-36 Quality of Life Questionnaire, Hospital Anxiety and Depression Questionnaire, body plethysmography, carbon monoxide diffusing capacity test, and blood gas analysis. RESULTS: The median (interquartile range) increase in 6-min walk distance in the intervention group was 40 (31-62) m. Improvement in functional capacity; perception of dyspnea; fatigue; anxiety; peripheral and inspiratory muscle strength; partial arterial oxygen pressure; arterial oxygen saturation; and the symptom, activity, and total scores of the St George Respiratory Questionnaire were significantly greater in the intervention group than in the usual care group at follow-up (P < .05). CONCLUSIONS: Exercise training improves functional capacity, muscle strength, dyspnea, quality of life, anxiety, fatigue, and oxygenation in patients with stage 3 and stage 4 sarcoidosis. Standard treatment of patients with late-stage sarcoidosis should integrate exercise training and pulmonary rehabilitation. PMID- 29401113 TI - Clozapine for Treatment-Refractory Behavioral Disturbance in Dementia. AB - BACKGROUND: Behavioral and psychological symptoms in dementia significantly contribute to caregiver burden and impose patient hospitalization. The goal of treatment of admitted patients is the rapid remission of symptoms to allow their return to home as soon as possible. Intervention requires an intrusive approach with parenteral treatment and physical restraints, with a negative emotional impact on patients and their families. Despite the large utilization of antipsychotics for behavioral and psychological symptoms, there is no antipsychotic approved by the Food and Drug Administration for agitation in dementia. STUDY QUESTION: To evaluate efficacy and tolerability of clozapine in patients with treatment-resistant agitation associated with dementia. STUDY DESIGN: Cohort study with 337 patients, admitted between January 1, 2012 and December 31, 2016, with dementia according to The Diagnostic and Statistical Manual of Mental Disorders 4th ed. criteria. Clozapine was given in standard titration, starting with 6.25 or 12.5 mg. MEASURES AND OUTCOMES: Efficacy was measured by the need for physical restraints and time to discharge and tolerability by recording all side effects. Data collected included demographics, psychotropics used, physical restraints, length of stay, destination after discharge, and comorbidities. RESULTS: Of 337 cases, 315 (93.5%) patients received antipsychotics. There were 27 cases treated with clozapine. Before clozapine initiation, haloperidol was given in 16 cases (55.17%, mean = 7.43 mg/d, SD = +/-4.01), and the treatment was stopped mainly because of extrapyramidal side effects. Other antipsychotics used were quetiapine (mean dose = 260 mg/d, SD = +/-54.77), risperidone (mean dose = 3.3 mg/d, SD = +/-0.57), and olanzapine (mean dose = 8.33 mg/d, SD = +/-2.88). Mean dose of clozapine was 59.16 mg/d, (SD = +/-40.48), ranging from 12.5 to 200 mg/d. There were a lower number of physical restraints after clozapine initiation than before (12 vs. 34, P < 0.05). CONCLUSIONS: Clozapine therapy seemed beneficial in treatment resistant agitation in patients with dementia. The risk-benefit balance must be well weighed when clozapine is chosen. More studies are needed. PMID- 29401115 TI - Artificial intelligence and the dreaded 's. PMID- 29401116 TI - Postpartum depression in older women. AB - Postpartum depression, which affects 10% to 20% of women in the United States, can significantly harm the health and quality of life for mother, child, and family. This article reviews the risk factors, pathophysiology, clinical manifestations, diagnosis, and treatment of postpartum depression with specific focus on women of advanced maternal age. PMID- 29401117 TI - Provider-performed microscopy empowers PAs at the point of care. AB - Provider-performed microscopy (PPM) is a diagnostic tool recommended when patients present with several types of gynecologic infections or fungal infections of skin or nails. PPM allows for immediate and accurate treatment, and can strengthen the relationship between clinician and patient. This article reviews two microscopy techniques, the saline wet mount and the potassium hydroxide (KOH) preparation, and discusses their indications for use. PMID- 29401118 TI - How does abatacept really work in rheumatoid arthritis? AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the current knowledge concerning the mechanisms of action of Abatacept in patients with rheumatoid arthritis. RECENT FINDINGS: Abatacept (CTLA-4Ig) represents a soluble, recombinant, fully humanized fusion protein, comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1. Abatacept binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells (APC), thereby blocking interaction with CD28 on T cells. In humans, Abatacept treatment was shown to be effective in patients with various autoinflammatory diseases including rheumatoid arthritis. Although the prevention of T-cell activation by interfering with signaling via CD28 still represents the main mechanism of action Abatacept acts on additional cell populations including regulatory T cells (Treg), monocytes/macrophages, osteoclasts, and B cells. SUMMARY: Effects of Abatacept on other cell populations besides T cells have to be taken into account and might represent a valuable contribution to the therapeutic success. PMID- 29401119 TI - Anti-DFS70 autoantibodies in HIV-1-positive individuals. AB - PURPOSE OF REVIEW: The aim of this review is to summarize the recent studies regarding the relationship between anti-DFS70 antibodies and HIV-1 infection. Examining the interaction between HIV-1 integrate (HIV-IN) and DFS70 and its role in the integration into the host's chromatin. Then, summarizing the importance of anti-DFS70 autoantibodies binding the DFS70 in the same region as the HIV-IN. RECENT FINDINGS: The interaction between HIV-IN and DFS70 protein could be a proficient target in the treatment against HIV-1 infection. The blockade of DFS70 is more effective than the blockade of HIV-IN as anti-HIV-1 drug. The anti-DFS70 autoantibodies could be an interesting therapeutic target for anti-HIV-1 treatment. Currently, there are no studies that measured the levels of anti-DFS70 autoantibodies in HIV-1-infected individuals. SUMMARY: The anti-DFS70 antibodies bind to the DFS70 autoantigen in the same region as the HIV-IN. This fact makes the autoantibodies a potential treatment for HIV-1-infected individuals. Blood levels of anti-DFS70 antibodies have not been measured in HIV-1-infected individuals. This issue opens new lines of research about the protective role of antibodies against HIV-1 infection. PMID- 29401120 TI - Mental health and substance use in HIV-infected adolescents. AB - PURPOSE OF REVIEW: Adolescents with HIV include both those infected perinatally and behaviourally. This population is confronted by normative challenges and HIV stressors as they move towards becoming increasingly independent adults. This review focuses on mental health and substance use in adolescents with HIV. These are important issues in their own right as well as having implications for antiretroviral therapy (ART) adherence and HIV management. RECENT FINDINGS: Sixteen articles, published from 1 January 2016 to 1 September 2017, were included from 13 distinct studies, mostly from the United States and Africa. Cross-sectional designs predominated. There was only one intervention study. There was evidence of mental health and substance use difficulties, although not at a higher level than comparison groups. Consistent associations were found between ART nonadherence and both mental health difficulties and substance use; environmental stressors and mental health difficulties. SUMMARY: Adolescents with HIV display considerable resilience. There is a need, however, for interventions for mental health difficulties and substance use, and for ART adherence interventions to consider these issues. Studies on mental health and substance use should cover a wider range of regions. Mitigating the impact and reducing exposure to environmental stressors is a priority. PMID- 29401121 TI - Barriers to, and emerging strategies for, HIV testing among adolescents in sub Saharan Africa. AB - PURPOSE OF REVIEW: HIV/AIDS is one of the leading causes of death among adolescents in sub-Saharan Africa and 40% of new HIV infections worldwide occur in this group. HIV testing and counselling (HTC) is the critical first step to accessing HIV treatment. The prevalence of undiagnosed HIV infection is substantially higher in adolescents compared with adults. We review barriers to HTC for adolescents and emerging HTC strategies appropriate to adolescents in sub Saharan Africa. RECENT FINDINGS: There are substantial individual, health system and legal barriers to HTC among adolescents, and stigma by providers and communities remains an important obstacle. There has been progress made in recent years in developing strategies that address some of these barriers, increase uptake of HTC and yield of HIV. These include targeted approaches focused on provision of HTC among those higher risk of being infected, for example, index linked HTC and use of screening tools to identify those at risk of HIV. Community based HIV-testing approaches including HIV self-testing and incentives have also been shown to increase uptake of HTC. SUMMARY: In implementing HTC strategies, consideration must be given to scalability and cost-effectiveness. HTC approaches must be coupled with linkage to appropriate care and prevention services. PMID- 29401122 TI - Corneal Endothelial Tolerance After Iris-Fixated Phakic Intraocular Lens Implantation: A Model to Predict Endothelial Cell Survival. AB - PURPOSE: To evaluate the long-term endothelial tolerance of iris-fixated phakic intraocular lenses (pIOLs) over a 10-year period, to identify predictive factors for endothelial decompensation, and to develop a model to predict endothelial cell survival after pIOL implantation. METHODS: This retrospective study included 130 eyes in 60 patients who underwent pIOL implantation for correction of high myopia from January 2003 to October 2012 at Edouard Herriot Hospital in Lyon, France. Endothelial cell densities (ECDs) were measured using specular microscopy before and biannually after pIOL implantation. Best-corrected visual acuity was measured before and 6 months after pIOL implantation. The annual postoperative decrease in ECD was estimated using a mixed linear regression model with a random intercept. Patient and eye characteristics were introduced into the model to quantify their effect on ECD change. The main outcome measures were annual postoperative reduction of ECD and best-corrected visual acuity. RESULTS: The preoperative ECD was 2770 +/- 265 cells/mm (2134-3200 cells/mm). The ECD decreased by 1.83%, on average (95% confidence interval, 1.54-2.10), during the first postoperative year. Thereafter, the mean decrease in annual ECD was estimated to be 0.87% (95% confidence interval, 0.78-0.95). For a cell number of 3500, 3000, 2500, and 2000, the number of years required to reach the threshold of 1500 cells/mm was estimated to be approximately 96, 78, 57, and 32 years, respectively. No predictive factors for endothelial decompensation were identified. CONCLUSIONS: pIOL implantation is a safe surgical means to correct high myopia in phakic patients without compromising corneal endothelium survival. PMID- 29401123 TI - Outcome of Portopulmonary Hypertension After Liver Transplantation: Perhaps Not So Optimistic. PMID- 29401124 TI - Skin Burn Associated With Photochemotherapy. AB - OBJECTIVE: psoralen and ultraviolet A (PUVA) phototherapy (PT) has become a standard treatment for several severe skin diseases. Photosensitization is done by oral psoralen intake. In minor cases, PUVA can lead to skin changes like erythema and hyperpigmentation. However, it can also lead to severe burn injuries when exposed to extensive UV light. This makes the treatment in a burn center inevitable. METHODS: We report the clinical observation of a 38-year-old man presenting with an extensive burn injury caused by sun tanning after PUVA PT. CONCLUSIONS: There are just few cases of extensive burns induced by PUVA PT. Prevention becomes manifest in patient information, correct calculation of dosage, evaluation of photosensitivity, and close observation. In cases of severe burn injuries, patients should be referred to a burn center for optimal conservative treatment. Surgical intervention is usually not necessary. PMID- 29401125 TI - Masculinizing Top Surgery: A Systematic Review of Techniques and Outcomes. AB - BACKGROUND: Chest wall masculinization by means of mastectomy is an important gender affirming surgery for transmasculine and non-binary patients. Limited data exist comparing commonly used techniques in masculinizing top surgery, and most are single institution studies. METHODS: A systematic review was performed on primary literature dedicated specifically to the technical aspects and outcomes of mastectomy for masculinizing top surgery. For each study, patient demographics and surgical outcomes were compared. RESULTS: Eight studies met inclusion criteria. There were 2138 breasts with an average patient age of 28.6 years and the average breast weight was 353 g. The most commonly reported techniques are those without skin resection (8.0%), those with periareolar skin resection (34.1%), inferior pedicle mammoplasty (15.7%), and inframammary fold skin excision with free nipple grafting (FNG, 42.2%). In total, 6.0% of all breasts required acute reoperation for hematoma and 26.5% required secondary operations. Acute reoperation occurred significantly less often in the FNG cohort (4.8%) compared with both the inferior pedicle mammaplasty cohort (8.9%, P < 0.05) and techniques without skin resection cohort (10.3%, P < 0.05). Secondary operations occurred significantly more often in the periareolar skin resection cohort (37.5%) than techniques without skin resection cohort (19.0%, P < 0.01), inferior pedicle mammaplasty cohort (27.9%, P < 0.01), and FNG cohort (20.3%, P < 0.05). In addition, secondary operations occurred significantly more often in inferior pedicle mammaplasty cohort (27.9%) compared with FNG cohort (20.3%, P < 0.01). CONCLUSIONS: This analysis notes several significant differences with regard to percentage requiring acute reoperation and percentage requiring secondary revision based on technique. Candidates for masculinizing top surgery should be educated on these differences. PMID- 29401126 TI - Successful Separation of Conjoined Twins: The Contemporary Experience and Historic Review in Memphis. AB - Conjoined twins are a rare phenomenon with historically poor outcomes after separation. We present a review of 8 sets of conjoined twins operated on in Memphis, Tenn, from 1953-2016. Except for 1 set of twins, before 2010, all experienced at least 1 fatality either before, during, or as a result of separation. Since 2010, we have separated an additional 2 sets of conjoined twins with no mortality related to the separation, although 1 of the first twins had significant cardiac and respiratory abnormalities and died several years after the separation. Each set of twins presented many challenges in reconstruction; however, the use of tissue expansions in the 2 most recent sets of twins proved to be beneficial. Although improvements in imaging, surgical technology, and postoperative monitoring likely have contributed to the increased survival, previous experience and meticulous planning with a multidisciplinary approach may have been the most influential. PMID- 29401127 TI - Gender Affirmation Surgery: A Synopsis Using American College of Surgeons National Surgery Quality Improvement Program and National Inpatient Sample Databases. AB - BACKGROUND: Gender affirmation surgery (GAS) is a heterogeneous group of body transformational procedures to match one's gender identity. There is a paucity of literature on the outcomes and safety profile of GAS. This study aims to examine trends and outcomes of GAS from 2010 to 2015 using the American College of Surgeons National Surgery Quality Improvement Program and National Inpatient Sample databases. METHODS: Patients with a primary diagnosis of gender dysphoria at the time of surgery were identified in both databases. Thirty-day complication rates were determined using the National Surgery Quality Improvement Program database. Patient socioeconomic status and hospital characteristics were examined using the National Inpatient Sample database. RESULTS: The number of cases per year increased from 5 in 2010 to 231 in 2015. The overall 30-day complication rate was 5.5%. Younger age was an independent risk factor for overall complications and reoperation. Total operating time was an independent risk factor for overall complications and infection. Black/African American race was associated with an increased risk of reoperation and readmission. Most patients (80%) had income at or above the national median income level; most were self-pay or had private insurance (90%). The typical hospitals providing GAS were large, urban, nonteaching, private nonprofit institutions in the US West Coast and Northeast. CONCLUSIONS: Gender affirmation surgery has an acceptable safety profile. The marked increase in case numbers likely reflects recent improvements in social climate and access to care. However, there are socioeconomic disparities in utilization and surgical outcomes among this already vulnerable patient population. PMID- 29401128 TI - Autologous Fat Grafting in the Treatment of Cleft Lip Volume Asymmetry. AB - BACKGROUND: The goal of cleft lip repair is a symmetrical balanced lip with minimal scar. Fat grafting is an established procedure in cosmetic and reconstructive surgery for restoration or correction of contour deformity, volume loss, and improved tissue characteristics. In this study, we evaluated the use of fat grafting in correction of cleft lip volume asymmetry. METHODS: We performed a retrospective analysis of our series of patients who underwent fat grafting using the Coleman technique for cleft lip volume asymmetry. Sex, age at primary repair, age at fat grafting, perioperative data, and preoperative and postoperative photographs were reviewed. RESULTS: A total of 52 children underwent fat grafting as secondary revision for both unilateral and bilateral cleft lip repair. Fat was hand suctioned from the abdominal or buttock region with a mean yield of 3.0 mL (range, 2.0-5.0 mL). An average total volume of 3.0 mL (range, 2.0-4.5 mL) of fat was injected via an intraoral incision into the philtrum, vermillion, and volume deficiencies in the vertical component of the lip for volume restoration. No complications were noted with fat harvest or with fat grafting. Mean follow-up was 48 months. Postoperative assessment revealed improved volume symmetry in all patients, and all patients or families were pleased with the results. CONCLUSIONS: Fat grafting via an intraoral incision is a minimally invasive, safe, and reliable secondary procedure to improve volume asymmetries after cleft lip repairs. PMID- 29401129 TI - Early Ambulation After Microsurgical Reconstruction of the Lower Extremity. AB - Successful outcomes after microsurgical reconstruction of the lower extremity include timely return to ambulation. Some combination of physical examination, ViOptix tissue oxygen saturation monitoring, and the implantable venous Doppler have shown promise in increasing sensitivity of current flap monitoring. We have incorporated this system into our postoperative monitoring protocol in an effort to initiate earlier dependency protocols. A prospective analysis of 36 anterolateral thigh free flap and radial forearm flaps for lower extremity reconstruction was performed. Indications for reconstruction were acute and chronic wounds, as well as oncologic resection. Twenty-three patients were able to ambulate and 3 were able to dangle their leg on the first postoperative day. One flap showed early mottling that improved immediately after elevation. After reelevation and return to baseline, the dependency protocol was successfully implemented on postoperative day 3. All flaps went on to successful healing. Physical examination, implantable venous Doppler, and ViOptix can be used reliably as an adjunct to increase the sensitivity of detecting poorly performing flaps during the postoperative progression of dependency. PMID- 29401130 TI - The Impact of Residents on Patient Satisfaction. AB - BACKGROUND: High-quality physician communication is the foundation for achieving high patient satisfaction. Increasing importance is placed on eliciting feedback from patients. However, there have been few studies looking at the impact of resident involvement on patient satisfaction. Our hospital system values the patient's likelihood to recommend the practice as the top marker for patient satisfaction. METHODS: Between May 2016 and December 2016 at University of California, San Diego, all outpatient appointments were randomly mailed Press Ganey surveys or an eSurvey regarding their experience. The surveys were filtered based on resident participation, and an chi test was performed to assess the impact of residents. An additional aim was to determine the degree to which the impact of resident involvement differed between surgical specialties. Binomial probability was calculated for each specialty using the 'no resident' group as the reference percentage. RESULTS: A total of 73,834 surveys were mailed or sent electronically, and 17,653 surveys were returned (23.9% response rate). Overall, patients expressed high levels of satisfaction with the quality of physician communication. Patients who had residents involved in their care reported a decrease in satisfaction with physician communication and a decrease in the likelihood to recommend the practice (88.7% vs 90.4%, P < 0.001). In the analysis of resident impact by surgical specialty, 9 specialties qualified for analysis. Resident involvement was associated with lower physician communication scores in orthopedic surgery (P = 0.032), otolaryngology (P = 0.015), and vascular surgery (P = 0.01). In all other surgical subspecialties, there was no statistically significant difference between groups. CONCLUSIONS: Overall, patients expressed high levels of satisfaction with the quality of physician communication with and without resident involvement. Resident physician involvement in surgical clinic visits was associated with lower overall patient satisfaction and decreased likelihood of recommending the practice. In addition, we observed that resident involvement was not associated with lower communication scores in most surgical specialties, including Plastic Surgery. PMID- 29401131 TI - Secondary Mastopexy After Nipple-Sparing Mastectomy and Staged Subcutaneous Expander/Implant Reconstruction. AB - BACKGROUND: The acceptance of nipple-sparing mastectomy for the treatment of breast cancer in selected patients has introduced ancillary procedures to improve breast shape, correct ptosis, and enhance breast symmetry. Mastopexy before or at the time of nipple-sparing mastectomy has been performed to correct ptosis, but there have been no reports on secondary Wise pattern mastopexy after completion of staged subcutaneous expander/implant reconstruction. METHODS: Between 2005 and 2015, 155 patients (255 breasts) underwent staged subcutaneous implant/expander based reconstruction after inframammary nipple-sparing mastectomy. Of the 155 patients, 10 (6.5%) patients required a secondary Wise pattern mastopexy (n = 14, 5.5%). The nipple was raised 2.5 to 6 cm (range, 3.8 cm), and the implant location was adjusted accordingly for optimal positioning with respect to the nipple-areola. The secondary mastopexy was performed to correct ptosis, improve breast symmetry and/or contour deformities of the breast, and relieve pain associated with large implants. RESULTS: All mastopexies healed without complications, and the goals of the revisions were achieved. There were no capsular contractures after an average of 50 months (range, 19-92 months). The patients were satisfied with the aesthetic and functional improvement. CONCLUSIONS: Secondary mastopexy after 2-stage subcutaneous expander/implant breast reconstruction is uncommon, but if needed, it may be safely performed to correct ptosis and improve breast shape, symmetry, and function. PMID- 29401132 TI - Defining Infection in Breast Reconstruction: A Literature Review. AB - PURPOSE: Postoperative infection is the most common complications after implant based immediate breast reconstruction (IBR), with reported rates ranging from less than 1% to 43%. This heterogeneity among the literature may be explained by a lack of consensus on the definition of postoperative infection. The purpose of this study was to review the prevalence of infection and how it is defined in studies involving prosthetic-based IBR. It is necessary to establish a clear definition of infection to standardize the reporting of complications. METHODS: A comprehensive literature review was performed to identify infection rates among implant/tissue expander-based IBR performed between 1996 and 2017. A PubMed search using the keywords "immediate breast reconstruction" matched with "infection" and "tissue expanders" or "implant" was performed. Reconstructive modality, infection rates, and definitions were recorded and reviewed. RESULTS: An initial search provided 196 articles; 138 articles met inclusion criteria and were reviewed. Eighty-five (61%) articles failed to define infection and reported an infection rate ranging from 0% to 22%. The studies that characterized infection had highly variable definitions. Whereas some authors chose to define infection based on Centers for Disease Control guidelines, others used more subjective findings such as clinical signs of infection. CONCLUSIONS: Currently, there is no consensus on the definition of infection after implant-based IBR. We propose that the definition should include the administration of antibiotics beyond the surgeon's standard perioperative period with or without the presence of localized clinical signs of infection (erythema, pain, increased temperature, etc). A universal definition of postoperative infection after implant-based IBR that accurately captures the incidence of infection will allow better comparisons between future studies. PMID- 29401133 TI - Randomized Controlled Trial of Liberal Versus Restricted Fluid Management in Patients Undergoing Pancreatectomy: Erratum. PMID- 29401134 TI - The Impact of Preoperative Serum Anti-TNFalpha Therapy Levels on Early Postoperative Outcomes In Inflammatory Bowel Disease Surgery: Erratum. PMID- 29401135 TI - Readiness of US General Surgery Residents for Independent Practice: Erratum. PMID- 29401136 TI - Results of the First Prospective Multi-institutional Treatment Study in Children With Bilateral Wilms Tumor (AREN0534) A Report From the Children's Oncology Group: Erratum. PMID- 29401137 TI - Differential Effects of Selective and Nonselective Potassium Channel Inhibitors in Ovine Endotoxemic Shock (Macrocirculation) and in a Rat Model of Septic Shock (Microcirculation). AB - BACKGROUND: Potassium-(K)-channel inhibitors may increase systemic vascular resistance in vasodilatory shock states. OBJECTIVE: The purpose of the present study was to compare the macro- and microvascular effects of the adenosine triphosphate-sensitive K-channel-(KATP)-inhibitor glipizide and the nonselective K-channel inhibitor tetraethylammonium (TEA) in ovine endotoxemic shock and septic shock in rats. DESIGN: Two randomized, controlled laboratory studies. ANIMALS: Thirty female sheep and 40 male Sprague Dawley rats. SETTING: Animal research facility INTERVENTION:: Systemic hemodynamics were analyzed in ovine endotoxemic shock with guideline-oriented supportive therapy. Sheep were allocated to three treatment groups for 12 h: glipizide 10 mg kg.h, TEA 8 mg kg.h, or 0.9% saline. The microvascular effects of each drug were evaluated in septic rats (cecal ligation and puncture model) receiving a 2-h infusion of each study drug: glipizide 20 mg kg.h; TEA 50 mg kg.h, or 0.9% saline, respectively, followed by intravital microscopy of villi microcirculation. RESULTS: Compared with the control group, glipizide infusion increased systemic vascular resistance index and decreased cardiac index and heart rate (HR) in sheep (P < 0.05), whereas TEA infusion decreased HR and resulted in a decreased survival time (P = 0.001). In rats, glipizide infusion resulted in an increase in mean arterial pressure and a decrease in HR compared with baseline measurement (P < 0.05) without relevant effects on the villi microcirculation. TEA decreased HR and decreased capillary perfusion of the villi microcirculation compared with the sham group (P = 0.002). CONCLUSIONS: Selective inhibition of KATP-channels in ovine endotoxemic shock with glipizide partially restored vasomotor tone without exerting harmful effects on intestinal microcirculation in septic shock in rats. On the contrary, nonselective K-channel inhibition with TEA showed deleterious effects in both models, including impaired microcirculation and decreased survival time. Future research on glipizide in vasodilatory shock may be warranted. PMID- 29401138 TI - Introduction to the Special Edition of Annals of Surgery: The Johns Hopkins Festschrift. PMID- 29401139 TI - Therapeutic Plasma Exchange in Critically Ill Children Requiring Intensive Care. AB - OBJECTIVE: To characterize the clinical indications, procedural safety, and outcome of critically ill children requiring therapeutic plasma exchange. DESIGN: Retrospective observational study based on a prospective registry. SETTING: Tertiary and quaternary referral 30-bed PICU. PATIENTS: Forty-eight critically ill children who received therapeutic plasma exchange during an 8-year period (2007-2014) were included in the study. INTERVENTIONS: Therapeutic plasma exchange. MEASUREMENTS AND MAIN RESULTS: A total of 48 patients underwent 244 therapeutic plasma exchange sessions. Of those, therapeutic plasma exchange was performed as sole procedure in 193 (79%), in combination with continuous renal replacement therapy in 40 (16.4%) and additional extracorporeal membrane oxygenation in 11 (4.6%) sessions. The most common admission diagnoses were hematologic disorders (30%), solid organ transplantation (20%), neurologic disorders (20%), and rheumatologic disorders (15%). Complications associated with the procedure occurred in 50 (21.2%) therapeutic plasma exchange sessions. Overall, patient survival from ICU was 82%. Although patients requiring therapeutic plasma exchange alone (n = 31; 64%) had a survival rate of 97%, those with additional continuous renal replacement therapy (n = 13; 27%) and extracorporeal membrane oxygenation (n = 4; 8%) had survival rates of 69% and 50%, respectively. Factors associated with increased mortality were lower Pediatric Index of Mortality 2 score, need for mechanical ventilation, higher number of failed organs, and longer ICU stay. CONCLUSION: Our results indicate that, in specialized centers, therapeutic plasma exchange can be performed relatively safely in critically ill children, alone or in combination with continuous renal replacement therapy and extracorporeal membrane oxygenation. Outcome in children requiring therapeutic plasma exchange alone is excellent. However, survival decreases with the number of failed organs and the need for continuous renal replacement therapy and extracorporeal membrane oxygenation. PMID- 29401140 TI - CORR Insights(r): Severe Hemorrhagic Shock Leads to a Delayed Fracture Healing and Decreased Bone Callus Strength in a Mouse Model. PMID- 29401141 TI - Abdominal Muscle Density Is Inversely Related to Adiposity Inflammatory Mediators. AB - PURPOSE: Skeletal muscle is the largest regulator of glucose metabolism, but few population-based studies have examined the associations between muscle and inflammation. We studied the relationships between abdominal muscle area and density with selected adiposity-associated inflammatory mediators. METHODS: Nearly 2000 subjects underwent computed tomography of the abdomen and had venous fasting blood drawn concomitantly. The computed tomography scans were interrogated for visceral and subcutaneous fat, as well as abdominal lean muscle areas and densities. We then categorized the muscle into locomotion (psoas) and stabilization (rectus, obliques, and paraspinal) groups. Blood samples were assayed for interleukin-6 (IL-6), resistin, C-reactive protein, and TNF-alpha. RESULTS: The mean age was 64.7 yr, and 49% were female. Forty percent were white, 26% Hispanic/Latino American, 21% African American, and 13% Chinese American. The mean body mass index was 28.0 kg.m, and 30% were obese (body mass index, >30 kg.m). Using multivariable linear regression models that included adjustment for abdominal muscle area, a 1-SD increment in the mean densities for total, stabilization, and locomotive abdominal muscle were each significantly associated with lower levels of IL-6 (beta = -15%, -15%, and -9%, P < 0.01 for all) and resistin (beta = -0.11, -0.11, and -0.07 ng.mL, P < 0.02 for all), but not C reactive protein or TNF-alpha. Conversely, muscle area was not independently associated with any of the inflammatory mediators studied. CONCLUSIONS: Higher densities of several muscle groups in the abdomen are significantly associated with lower IL-6 and resistin levels, independent of the muscle area in these groups. Techniques that enhance muscle density may reduce levels of adiposity associated inflammatory mediators. PMID- 29401142 TI - Pancreatic Malignancy or Not?: Role of 18F-FDG PET/CT in Solving the Diagnostic Dilemma and Evaluating Treatment Response. AB - Immunoglobulin G4-related disease is an autoimmune entity with multisystem involvement. F-FDG PET/CT can provide important information about disease extent and severity and also aid in treatment response evaluation. We report a case of a 57-year-old woman presenting with abdominal discomfort, belching, and loss of weight in whom F-FDG PET/CT provided valuable information in diagnosis and monitoring treatment response. PMID- 29401143 TI - False-Positive 18F-FDG PET/CT Due to Filgrastim That Induced Extramedullary Liver Hematopoiesis in a Burkitt Lymphoma. AB - We report a case of Burkitt lymphoma with largely extranodal disease localizations at staging. Chemotherapy was given, thus obtaining a complete metabolic response in all previous disease sites as shown at a control PET, however associated to the appearance of new focal uptake areas in the liver; these findings were confirmed at US and MRI. Chemotherapy determined also neutropenia that was treated by filgrastim, followed by a prompt and important medullary response. Liver biopsy revealed extramedullary hematopoiesis, probably filgrastim induced. Filgrastim administration may cause false-positive findings in the liver at FDG PET. PMID- 29401144 TI - Incidental Detection of Synchronous Lung Melanoma on 18F-FDG PET/CT in a Patient With Parotid Gland Myoepithelial Carcinoma. AB - The detection of synchronous or metachronous malignancies is on the rise with the advent of whole-body F-FDG PET/CT. It has shown its utility in detecting second primary carcinoma in patients undergoing imaging for evaluation of primary carcinoma, influencing the management and overall survival. Primary malignant melanoma of the lung is an extremely rare entity, accounting for 0.01% of all lung tumors. It is an even rare occurrence as a synchronous malignancy. We present the case of a 33-year-old woman with primary parotid myoepithelial carcinoma and incidental detection of second primary malignant melanoma of lung during F-FDG PET/CT imaging. PMID- 29401145 TI - Clear Cell Sarcoma of the Tongue on MRI and PET/CT. AB - F-FDG PET/CT and MRI were performed in a 44-year-old woman to characterize a mass of the anterior tongue. MR images showed a voluminous mass, well circumscribed and enhanced heterogeneously after gadolinium chelates injection. There was an intense uptake on PET/CT. Pathological examination and molecular analysis revealed the diagnosis of clear cell sarcoma of the tongue. We present a case of clear cell sarcoma of the tongue, which includes imaging features. It is an extremely rare tumor, with only 3 cases previously reported in the literature. PMID- 29401146 TI - 177Lu-Prostate-Specific Membrane Antigen Super Scan and Good Response Even After 1 Cycle of Radioligand Therapy. AB - A 76-year-old man with castration-resistant prostate cancer and widespread skeletal metastases underwent 2 cycles of Lu-prostate-specific membrane antigen (PSMA) 617 therapy in our department. Whole-body Lu-PSMA scan after the first cycle showed diffuse skeletal PSMA-avid lesions, whereas no PSMA uptake was evident in the kidneys with minimal PSMA uptake by salivary glands (super scan). After 6 weeks, he received the second dose of Lu-PSMA and whole-body scan after the treatment showed remarkable resolution of skeletal metastases and normal PSMA uptake by the kidneys and salivary glands. To our best knowledge, this is the first case report of Lu-PSMA super scan. PMID- 29401147 TI - SPECT/CT MIBG Imaging Is Crucial in the Follow-up of the Patients With High-Risk Neuroblastoma. AB - BACKGROUND: Planar whole-body imaging with I-radiolabeled metaiodobenzylguanidine (I-MIBG) is routinely used in the follow-up evaluation of neuroblastoma. In recent years, SPECT with integrated low-dose CT (SPECT/CT) has become more accessible. We investigated how much SPECT/CT can have additional diagnostic value over planar imaging in detection of residual and recurrent neuroblastoma. METHODS: A total of 170 planar I-MIBG imaging scans with SPECT/CT follow-up scans performed in 147 patients with known high-risk neuroblastoma were retrospectively analyzed. Regions of increased I-MIBG uptake on planar images and the findings on SPECT/CT were compared. RESULTS: In 61% of the studies, the whole-body planar images and SPECT/CT images yielded the same result. In 39% of the time, however, SPECT/CT images provided additional information. CONCLUSIONS: In the follow-up of patients with high-risk neuroblastoma, SPECT/CT can significantly improve planar imaging interpretation and impact patient management. PMID- 29401148 TI - Detecting Intestinal Malrotation on Hepatobiliary Scintigraphy: Making a Case for a Better Standardized Reporting Template. AB - Intestinal malrotation displays classic pattern of the small bowel activity on hepatobiliary scintigraphy that could lead to the diagnosis, but only if an interpreting physician looks for it. Presented are 2 cases, one demonstrates diagnostic findings during the first 60-minute phase, whereas the other reveals the diagnosis only on the later sincalide stimulation phase. The currently recommended structured reporting for hepatobiliary scintigraphy does not include examination of bowel activity pattern, which could result in a missed diagnosis. Including interrogation of the small bowel pattern into the structured reporting checklist would ensure consistent detection of this rare but most consequential diagnosis. PMID- 29401149 TI - Superior Pituitary Border Analysis in Immunotherapy-Induced Hypophysitis. AB - Immunotherapy-induced hypophysitis presents with headache, fatigue, and visual disturbances. The diagnosis is supported by imaging findings of pituitary swelling, enhancement, and hypermetabolism and established by low levels of pituitary hormones. A 64-year-old man with metastatic melanoma on nivolumab presented with a severe headache, initially attributed to sinus disease. Contrast CT was interpreted as minor sinus disease and no pituitary abnormality. Hypophysitis was eventually diagnosed and successfully treated based on PET and laboratory findings. Our retrospective analysis demonstrated abnormal convex superior pituitary border visible on contrast and noncontrast CT and PET. This feature may aid diagnosis in the challenging cases. PMID- 29401150 TI - 68Ga-Prostate-Specific Membrane Antigen Expression in Neurocysticercosis Lesions in a Patient With Prostate Carcinoma. AB - Ga-prostate-specific membrane antigen (PSMA) ligand is a well-known tracer used in prostate cancer. Nevertheless, there are reports of unusual Ga-PSMA uptake in variety of benign lesions. We report a case of prostate cancer in which Ga-PSMA PET/CT revealed tracer avidity in the enhancing walls of cystic lesions in the brain consistent with the features of neurocysticercosis. The uptake of Ga-PSMA in neurocysticercosis is not known and may be attributed to angiogenesis occurring at the periphery of these lesions. PMID- 29401151 TI - SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer. AB - BACKGROUND: Tc-MIP-1404 (Progenics Pharmaceuticals, Inc, New York, NY) is a novel ligand binding to prostate-specific membrane antigen suitable for SPECT. There are, as yet, no data concerning its use in whole-body primary staging and its interobserver variability in patients with prostate cancer (PC) prior to therapy. METHODS: A search of our clinical database from April 2013 to May 2017 yielded 93 patients with histologically confirmed cancer in whom Tc-MIP-1404 SPECT/CT had been performed for primary whole-body staging before therapy. Whole-body planar and SPECT/CT images of the lower abdomen and thorax had been obtained 3 to 4 hours postinjection of 706 +/- 72 MBq Tc-MIP-1404. Images were visually analyzed for extent and location of abnormal uptake by 2 experienced nuclear physicians. Interobserver agreement for detection of primary tumor and metastatic lesions was assessed. In addition, SUVs of prostate-specific membrane antigen-positive regions of the prostate were determined in all patients, and from these, a variable reflecting total tumor load in the prostate gland was calculated (TUprostate). Follow-up reports of subsequent therapeutic interventions were available in 52 (56%) of all patients with a median follow-up of 18 months. RESULTS: In 90 (97%) of 93 patients, prostate uptake above background was detected as correlate of the histologically diagnosed PC. Forty-eight lymph node and 29 bone metastases were detected in 16 and 9 patients, respectively. In addition, 3 patients had disseminated bone metastases. No distant organ metastases were found. Interobserver agreement was high for the overall scan result (97%), as well as for the detection of the primary tumor (97%), of lymph node metastases (97%), and of bone metastases (99%). Recurrence of PC occurred in 5 patients in whom follow-up was available (10%). TUprostate was significantly higher in patients with Gleason scores of 8 or greater compared with patients with Gleason scores of 7 or less and at prostate-specific antigen (PSA) serum levels of 10 ng/mL or greater compared with PSA serum levels of 10 ng/mL or less. TUprostate of greater than 26 in the primary tumor predicted the occurrence of lymph node or bone metastases with a sensitivity of 82% and specificity of 76%. CONCLUSIONS: MIP-1404 SPECT/CT has a high accuracy and low interobserver variability in the diagnosis of PC and allows detection of lymph node and bone metastases in a significant proportion of as yet untreated PC patients. TUprostate is correlated with Gleason score and PSA serum concentration and allows prediction of the occurrence of lymph node and bone metastases with moderate accuracy at primary staging. PMID- 29401152 TI - Prostate-Specific Membrane Antigen PET/CT Incidental Finding of a Schwannoma. AB - We describe a case of a 73-year-old man with newly diagnosed prostate cancer referred to Ga-PSMA PET/CT for staging. A focal uptake of PSMA was visualized in the prostate compatible with primary prostate cancer. Outside the prostate, a PSMA-avid paravertebral soft tissue mass was observed. Further investigation with MRI of the same region showed signs compatible with schwannoma. This case shows the importance of including schwannoma in the differential diagnostic evaluation of patients with Ga-PSMA-positive foci in paravertebral locations, as schwannomas may show avid PSMA uptake and may potentially lead to an incorrect diagnosis of metastasis. PMID- 29401153 TI - 68Ga-DOTATATE PET/CT Reveals Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma in a Case of Suspected Sphenoid Wing Meningioma. AB - In this case of suspected sphenoid wing meningioma, Ga-DOTATATE PET/CT showed a somatostatin receptor (SSR)-expressing tumor with extension to the nasopharynx and SSR-expressing cervical lymph nodes. Subsequent biopsy from the nasopharynx revealed an Epstein-Barr virus (EBV)-associated, undifferentiated World Health Organization type 3 nasopharyngeal carcinoma (NPC), a potential clinical pitfall due to the reported high SSR expression of this tumor subtype. In consideration of the high target-to-background contrast, SSR ligands might be superior to F-FDG for EBV-associated NPC PET imaging, particularly at the skull base. Somatostatin receptor ligands might furthermore offer interesting theranostic possibilities for patients with advanced/extensive EBV-associated NPC. PMID- 29401154 TI - Bereaved Caregivers to Patients With High-Grade Glioma: A Qualitative Explorative Study. AB - PURPOSE: The disease and treatment trajectory of patients with high-grade glioma is a burdensome period for the patients' closest relatives who become informal caregivers. Caregivers experiencing this demanding shift in role are at risk of developing symptoms such as depression. Few studies have explored the needs and experiences of bereaved caregivers, and there is lack of evidence-based practice. This study explores the perspectives of newly bereaved caregivers to patients with high-grade glioma on end-of-life caregiving and bereavement. METHODS: This qualitative exploratory study was composed of individual semistructured telephone interviews with bereaved caregivers (n = 8) to patients with high-grade glioma who deceased during participation in the mixed-methods Neuro-oncological Rehabilitation study. A thematic analysis was conducted following Braun and Clarke's guidelines. RESULTS: Four main themes were identified concerning the bereavement experience: (1) late-stage caregiving is comprehensive and taxing, (2) releasing the responsibility of the primary caregiving role, (3) feelings of grief and relief, and (4) suggestions for clinical practice. CONCLUSION: Late stage caregiving is a difficult and challenging experience at the end of an already burdening treatment trajectory. Caregivers prefer to actively share responsibility and practical tasks with professionals, family, and friends. The bereaved caregivers' key areas of concern indicate the need for additional research in advance care planning within neuro-oncology caregiving to establish evidence-based practice guidelines and recommendations. PMID- 29401155 TI - Combined NMDA Inhibitor Use in a Patient With Multisubstance-induced Psychotic Disorder. AB - : : Novel psychoactive substance use is a major social concern. Their use may elicit or uncover unpredictably as yet undescribed clinical pictures. We aimed to illustrate a multisubstance use case indistinguishable from paranoid schizophrenia, so to alert clinicians on possibly misdiagnosing substance-induced psychotic disorders. CASE REPORT: We describe a case of a 32-year-old man who started at 18 years with cannabinoids and ketamine, and is currently using N methyl-D-aspartate (NMDA) antagonists. At age 23, he developed social withdrawal after being assaulted by a stranger, but did not consult psychiatrists until age 26; during this period, he was using internet-purchased methoxetamine and ketamine, and was persecutory, irritable, suspicious, and insomniac and discontinued all received medical prescriptions. He added dextromethorphan to his list of used substances. At age 31, while using phencyclidine, and, for the first time, methoxphenidine, he developed a religious delusion, involving God calling him to reach Him, and the near-death experiences ensured by NMDA antagonists backed his purpose. He received Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnosis of multisubstance-induced psychotic disorder and was hospitalized 8 times, 6 of which after visiting the emergency room due to the development of extreme anguish, verbal and physical aggression, and paranoia. He reportedly used methoxphenidine, methoxyphencyclidine, ethylnorketamine, norketamine, and deschlorketamine, to achieve near-death experiences, and eventually to reach God in heavens. CONCLUSIONS: This case points to the need for better control of drugs sold on the internet. It also illustrates that people using NMDA antagonists may present clinical pictures indistinguishable from those of major psychoses and are likely to be misdiagnosed. PMID- 29401157 TI - Supraciliary Implant Placement and Postoperative Suprachoroidal Hemorrhage After Nonpenetrating Deep Sclerectomy. AB - PURPOSE: The purpose if this study was to evaluate the clinical characteristics and risk factors of 3 eyes (3 patients), with primary open-angle glaucoma (POAG), in whom a postoperative suprachoroidal hemorrhage (SCH) occurred after a previous nonpenetrating deep sclerectomy (NPDS) augmented with a supraciliary nonabsorbable implant placement. METHODS AND SURGICAL TECHNIQUE: This is a report of 3 eyes of the 3 patients who underwent NPDS in 3 different centers, by 3 experienced surgeons, and were the only ones to develop postoperative SCH in the last 18 years. All were operated with a one-third thickness outer scleral flap measuring 5*5 mm dissected until it reached 1 to 2 mm into the clear cornea. Mitomycin C (MMC, 0.02%) was applied for 1 minute and an inner scleral flap measuring 4*4 mm was dissected leaving only 10% of scleral thickness below. Then, the inner wall of Schlemm canal was removed. A supraciliary implant, T-flux (Carl Zeiss Meditec, Zeiss, Spain) in case 2 and Esnoper (AJL Ophthalmics SA, Minano, Spain) in cases 1 and 3, was placed through a full-thickness escleral incission 2 mm behind the scleral spur. RESULTS: Three eyes with uncontrolled primary open angle glaucoma had a delayed SCH after an uneventful NPDS. Time lapse from filtering surgery to the SCH ranged from 12 hours in case number 1, to 3 weeks in case 3. Several risk factors for DSH were present, but the only common clinical feature for all of them, was the nonabsorbable implant that was placed in the supraciliary space. A Hema implant (Esnoper) was used in 2 eyes (cases 1 and 3), and T-flux, was implanted in the case 2. Case 1 required vitreoretinal surgery and had poor visual outcome, but cases 2 and 3 recovered with conservative treatment. CONCLUSIONS: Although taking the potential bias arising from the nature of the current cases report into consideration, supraciliary placement of the implant in NPDS could be a risk factor for SCH. Consequently, it seems reasonable to avoid it, especially in the presence of other best recognized factors. PMID- 29401156 TI - Growth Factors, Oxidative Damage, and Inflammation in Exfoliation Syndrome. AB - Exfoliation syndrome (XFS) produces deleterious ocular aging and has protean systemic manifestations. Local ocular production of TGFbeta1 is of central importance in XFS. TGFbeta1 appears to induce the expression of LOXL1 and the production of other extracellular matrix components which are known to be present in exfoliation material. Furthermore, results from several studies find that the aqueous humor of exfoliation glaucoma patients exhibits a decreased antioxidant defense and increased oxidative stress systems. Finally, studies show that the levels of interleukin-6 and interleukin-8 in the aqueous humor of XFS patients were 3-fold higher than in controls. Overall TGFbeta1, as well as a prooxidative and proinflammatory environment seems to play an important role in XFS. PMID- 29401158 TI - Neurovascular Changes Associated With the Water Drinking Test. AB - PURPOSE: The water drinking test (WDT) is currently used to temporarily elevate intraocular pressure (IOP) and predict peak IOP in glaucoma. This study investigates neurovascular changes associated with WDT in normal subjects. METHODS: The effect of WDT (1 L in 5 min) on IOP, mean brachial blood pressure, heart rate, and pattern electroretinogram was assessed within the next hour in 16 healthy subjects (mean age: 33.5+/-7.9 y). As a control, testing was repeated in the same subjects without WDT 1 week later. RESULTS: Compared with control, WDT resulted in significant peak changes of the following parameters compared with baseline: IOP: +1.7+/-1.8 mm Hg after 30', mean brachial blood pressure: +3.9+/ 6.3 mm Hg after 15'; heart rate: -9.2+/-9.8 bpm after 15', pattern electroretinogram latency: +2.1+/-0.9 ms after 15'. CONCLUSIONS: In addition to IOP elevation, WDT was associated with significant changes of hemodynamic parameters and retinal ganglion cell function in young healthy subjects. As these represent risk factors for glaucoma, their assessment upon WDT might increase its predictive power for glaucoma development. PMID- 29401159 TI - Late Spontaneous Dislocation of an Ab Interno Gelatin Microstent. AB - PURPOSE: To report a case of spontaneous dislocation of a gelatin microstent 6 months after the initial uncomplicated surgery. PATIENTS AND METHODS: We describe a 73-year-old man with a history of advanced primary open-angle glaucoma who had previously undergone an unsuccessful micropulse transcleral cyclophotocoagulation of the left eye. He underwent an uncomplicated combined phacoemulsification with an ab interno gelatin microstent, but was noted to have a spontaneous dislocation of the microstent 6 months postoperatively. RESULTS: His postoperative course was largely unremarkable. He underwent a total of 5 bleb needlings, 1 immediately postoperatively because of intra-Tenon's positioning of the microstent. At his 6 month follow-up, he had a needling with both 5-flurouracil and subconjunctival bevacizumab. Despite postprocedural gonioscopy confirmation of the microstent positioning, the patient returned 1 week later with a fully dislocated microstent. The dislocation was asymptomatic, and his intraocular pressure remained in the single digits. CONCLUSIONS: The ab interno gelatin microstent is a promising new procedure, but presents unique challenges. As the procedure is still new, more complications are expected to come to light. Although gelatin microstent migration and dislocation appears to be rare, it is important to recognize this postoperative complication. To our knowledge, this is the first report of a spontaneous dislocation of the gelatin microstent without a clear inciting event. This case reiterates the importance of continued follow-up of these cases, and will hopefully help begin to shed light on preoperative considerations and patient selection. PMID- 29401160 TI - Meibomian Gland Features and Conjunctival Goblet Cell Density in Glaucomatous Patients Controlled With Prostaglandin/Timolol Fixed Combinations: A Case Control, Cross-sectional Study. AB - PURPOSE: To investigate, using in vivo confocal microscopy (IVCM), the Meibomian gland (MG) features and conjunctival goblet cell density (GCD) in glaucomatous patients controlled with prostaglandin/timolol fixed combinations (PTFCs). MATERIALS AND METHODS: In this cross-sectional study, 60 white patients were treated with PTFCs, 15 with latanoprost+timolol (L+T) unfixed combination, and 15 controls were enrolled. Patients underwent the Ocular Surface Disease Index questionnaire, tear film breakup time, corneal staining, Schirmer test I, and IVCM of MGs and goblet cells. The main outcome measures were: mean Meibomian acinar density (MMAD) and area (MMAA), inhomogeneity of glandular interstice (InI) and acinar wall (InAW), and GCD. RESULTS: PTFCs were: latanoprost/timolol (LTFC, 15 eyes), travoprost/timolol (TTFC, 15), bimatoprost/timolol (BTFC, 15), and preservative-free bimatoprost/timolol (PF-BTFC, 15) fixed combinations. Mean time on therapy did not differ among treatments. IVCM documented lower GCD, MMAD, and MMAA (P<0.001), and greater InI and InAW (P<0.05) in glaucoma patients compared with controls. L+T showed worse values compared with PTFCs and PF-BTFC (P<0.05). Preserved PTFCs showed lower MMAD, MMAA, GCD, and greater InI and InAW compared with PF-BTFC (P<0.05) and controls (P<0.001). Differences were not found among PTFCs. InI and InAW significantly correlated with Ocular Surface Disease Index and breakup time (P<0.001), corneal staining (P<0.05), and GCD (P<0.001); GCD correlated with MMAD (P<0.05). CONCLUSIONS: PTFCs were less toxic towards MGs and goblet cells compared with the L+T unfixed combination, with PF-BTFC presenting the most tolerated profile. These findings should be carefully considered given the role of these structures in the induction of the glaucoma related ocular surface disease. PMID- 29401161 TI - The Cellular Response of Keloids and Hypertrophic Scars to Botulinum Toxin A: A Comprehensive Literature Review. AB - BACKGROUND: Keloids and hypertrophic scars are conditions of pathologic scarring characterized by fibroblast hyperproliferation and excess collagen deposition. These conditions significantly impact patients by causing psychosocial, functional, and aesthetic distress. Current treatment modalities have limitations. Clinical evidence indicates that botulinum toxin A (BoNT-A) may prevent and treat keloids and hypertrophic scars. OBJECTIVE: To examine investigated cellular pathways involved in BoNT-A therapeutic modulation of keloids and hypertrophic scars. METHODS: The authors searched PubMed, Embase, and Web of Science for basic science articles related to botulinum toxin therapy, scarring, fibroblasts, keloids, and hypertrophic scars. RESULTS: Eleven basic science articles involving keloids and hypertrophic scars were reviewed. DISCUSSION: BoNT-A may reduce skin fibrosis by decreasing fibroblast proliferation, modulating the activity of transforming growth factor-beta, and reducing transcription and expression of profibrotic cytokines in keloid-derived and hypertrophic scar-derived dermal fibroblasts. BoNT-A may modulate collagen deposition, but there is a paucity of evidence regarding specific mechanisms of action. CONCLUSION: Overall, BoNT-A has the potential to prevent or treat pathologic scars in patients with a known personal or family history of keloids and hypertrophic scars, which may improve patient psychosocial distress and reduce clinic visits and health care costs. Variability in keloid and hypertrophic scar response to BoNT-A may be due to interexperiment differences in dosing, tissue donors, and assay sensitivity. PMID- 29401162 TI - Commentary on Atypical Melanocytic Proliferations. PMID- 29401163 TI - Reconstruction of a Lateral Upper Lip Defect. PMID- 29401164 TI - Regional Dermabrasion of Nasal Surgical Scars and Rhinophyma Using Electrocautery Scratch Pads. PMID- 29401165 TI - HMGN2: An Antitumor Effector Molecule of gammadeltaT Cells. AB - gammadeltaT cells function in the regulation of T-cell activation in cancer and have been identified as a novel target for cancer immunotherapy. Activated gammadeltaT cells release a series of cytotoxic molecules-including granulysin, perforin, Fas/Fas ligand (Fas-L), and granzymes A and B-to kill target cells. Our previous research has shown that high mobility group nucleosomal-binding domain 2 (HMGN2), which is expressed at a high level in activated CD8T cells, is an antitumor effector molecule of CD8T cells. In the present study, we examined the expression and antitumor effects of HMGN2 in gammadeltaT cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors with a PBMC separation column. PMBCs were stimulated with isopentenyl pyrophosphate (IPP) and interleukin-2 (IL-2) for 10 days for activation and expansion. Activated gammadeltaT cells were isolated from IPP-pretreated PBMCs with a Moflo XDP flow cytometry sorter. The expression of HMGN2 in gammadeltaT cells was detected by flow cytometry and enzyme-linked immunosorbent assay. The cytotoxic effects of gammadeltaT cells and HMGN2 were analyzed by carboxyfluorescein succinimidyl ester labeling. IPP combined with IL-2 induced significant activation and expansion of gammadeltaT cells in vitro. HMGN2 was constitutively expressed in gammadeltaT cells. IPP-activated gammadeltaT cells expressed a high level of HMGN2 that could be detected intracellularly and in the supernatant. Moreover, supernatants of purified gammadeltaT cells were sufficient to kill tumor cells and could be blocked with anti-human HMGN2 antibody. This study suggests that HMGN2 is an antitumor effector molecule of gammadeltaT cells. PMID- 29401166 TI - The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. AB - Checkpoint inhibitors are a first-line therapy for advanced melanoma, though their use is limited by diarrhea and colitis. The aim of our study was to determine the risk of these toxicities associated with immunotherapy in advanced melanoma. Electronic databases were searched through June 2017 for prospective studies reporting the risk of diarrhea and colitis in advanced melanoma treated with anti-programmed death-1 (PD-1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Standardized definitions assessed the grade of diarrhea and colitis. Pooled incidence and weighted relative risk estimates with 95% confidence intervals (CI) were estimated using random effects model. Eighteen studies were included: 6 studies (1537 patients) with PD-1 inhibitors and 15 studies (3116 patients) with CTLA-4 inhibitors. The incidence of all-grade diarrhea was 13.7% (95% CI, 10.1%-17.2%) for anti-PD-1 and 35.4% (95% CI, 30.4% 40.5%) for anti-CTLA-4. The incidence of all-grade colitis was 1.6% (95% CI, 0.7% 2.4%) for anti-PD-1, and 8.8% (95% CI, 6.1%-11.5%) for anti-CTLA-4. When PD-1 inhibitors were compared directly with CTLA-4 inhibitors, the relative risk of all-grade diarrhea was 0.58 (95% CI, 0.43-0.77), and the relative risk of all grade colitis was 0.16 (95% CI, 0.05-0.51). The rate of therapy discontinuation was numerically higher for anti-CTLA-4 therapy compared with anti-PD-1 therapy. Finally, 2 studies compared combination immunotherapy with anti-CTLA-4 therapy alone. The relative risk of developing all-grade diarrhea and colitis with combination therapy was 1.31 (95% CI, 1.09-1.57) and 1.21 (95% CI, 0.73-1.99), respectively. Diarrhea and colitis are frequent toxicities associated with checkpoint inhibitors, and seem to be most common with CTLA-4 inhibitors. PMID- 29401168 TI - Long-term Outcomes of Gastroenteropancreatic Neuroendocrine Tumors. AB - OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare but have been increasing in incidence. Limited data on the long-term outcomes of patients with these tumors are available. METHODS: In this study, we used population-based data from the National Cancer Institute to assess long-term disease-specific survival (DSS) of patients who have undergone surgery for nonmetastatic disease. All patients with NETs of the stomach, small intestine, colon, rectum, appendix, and pancreas diagnosed between 1988 and 2009 were identified from the Surveillance, Epidemiology and End Results registry. Staging was derived from Surveillance, Epidemiology and End Results data using the European Neuroendocrine Tumor Society guidelines. Cases with incomplete staging data were excluded, along with those with stage IV disease, or those who did not undergo surgical resection. RESULTS: Kaplan-Meier analyses were constructed to determine DSS. Analyses were further stratified according to tumor site, stage at diagnosis, and tumor grade. Overall, 13,348 patients with GEP-NETs meeting the inclusion criteria were identified. CONCLUSIONS: There were excellent outcomes for most GEP-NET patients, with a 20-year DSS of greater than 75% across all sites and stages. Pancreatic tumors had the worst outcomes, but DSS remains greater than 50% at 20 years. PMID- 29401167 TI - The Association of Recently Diagnosed Diabetes and Long-term Diabetes With Survival in Pancreatic Cancer Patients: A Pooled Analysis. AB - OBJECTIVES: It is unclear whether long-standing diabetes or new-onset pancreatogenic diabetes contributes to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We investigated the influence of diabetes diagnosed shortly before PDAC and long-term diabetes on overall survival in 2792 PDAC patients who had participated in 3 PDAC case-control studies in the Pancreatic Cancer Case-Control Consortium. There were 300 patients with long-term diabetes of more than 3 years' duration (11%) and 418 patients with recently diagnosed diabetes of 3-year duration or less (15%). We performed Cox regression to determine the association of long-term diabetes and recently diagnosed diabetes with overall survival, adjusting for study site, age, sex, race, stage of disease, surgery, chemotherapy, smoking history, and body mass index at diagnosis. RESULTS: In the overall population, neither long-term diabetes (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.97-1.26) nor recently diagnosed diabetes (HR, 1.06; 95% CI, 0.94-1.18) was associated with shorter survival. When stratified by stage of disease, long-term diabetes was associated with 42% increase in rate of death in persons with resectable PDAC (HR, 1.42; 95% CI, 1.13 1.78), whereas it was not associated with survival in PDAC patients with more advanced disease. CONCLUSION: Long-term diabetes was associated with increased rate of death in patients with resectable PDAC. PMID- 29401169 TI - Per-Pass Performance Characteristics of Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Malignant Solid Pancreatic Masses in a Large Multicenter Cohort. AB - OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is widely performed for the evaluation of pancreatic masses. We evaluated the performance characteristics of EUS-FNA in obtaining a diagnosis of pancreatic malignancy. METHODS: We performed a multicenter study of patients who underwent EUS-FNA for a solid pancreatic mass. Endoscopic ultrasound-guided FNA was standardized using a 25-gauge needle, slow-pull stylet technique for specimen acquisition, and on-site cytopathology. For the primary analysis, only malignant cytology was regarded as positive. A secondary analysis was performed in which malignant and/or suspicious cytology was regarded as positive. RESULTS: A total of 138 patients underwent EUS-FNA. In the primary analysis, the sensitivity of EUS-FNA for malignancy was 56.7% on first pass, 73.3% on second pass, 83.3% on third pass, 89.2% on fourth pass, and 90.8% on fifth pass, with no increase beyond the fifth pass. In the secondary analysis, the sensitivity was 75.0% on first pass, 89.2% on second pass, 93.3% on third pass, and 95.8% on fourth pass, with no increase beyond the fourth pass. No significant relationship was seen between lesion size and diagnostic yield. CONCLUSIONS: Using a 25-gauge needle, the maximal diagnostic yield of EUS-FNA for a solid pancreatic mass is reached after 4 needle passes. PMID- 29401170 TI - Effect of Reprimo Down-regulation on Malignant Transformation of Intraductal Papillary Mucinous Neoplasm. AB - OBJECTIVES: Reprimo gene is a cytoplasmic protein belonging to a family of molecules controlled by p53 that inhibits cell cycle progression. Ectopic expression of Reprimo results in cell cycle arrest at the G2 phase. The aim of this study was to investigate the impact of Reprimo expression on tumorigenesis of intraductal papillary mucinous neoplasm (IPMN). METHODS: Thirty-seven surgical cases of IPMN were collected retrospectively. Twenty-eight patients had benign IPMNs (low-grade dysplasia, n = 18; intermediate-grade dysplasia, n = 10), and the remaining 9 had malignant IPMNs (high-grade dysplasia, n = 4; invasive carcinoma, n = 5). DNA from tumor samples was extracted. DNA methylation patterns of Reprimo were determined by the methods of methylation-specific polymerase chain reaction and immunohistochemistry. The methylation status of Reprimo was compared between benign IPMNs and malignant IPMNs. RESULTS: The incidence of aberrant DNA methylation of Reprimo was significantly higher in malignant IPMNs than in benign IPMNs (78% vs 32%, P = 0.016). Furthermore, the incidence of immunohistochemical Reprimo expression was significantly lower in malignant IPMNs than in benign IPMNs (22% vs 82%, P = 0.002). CONCLUSIONS: Reprimo methylation was found more frequently in malignant IPMNs. Reprimo methylation is involved in malignant transformation of IPMNs. PMID- 29401171 TI - Primary and Secondary Organ Failures Cause Mortality Differentially in Acute Pancreatitis and Should be Distinguished. AB - OBJECTIVE: The aim of this study was to study the development of early and late organ failure (OF) and their differential impact on mortality in patients with acute pancreatitis (AP). METHODS: Consecutive patients (N = 805) with acute pancreatitis were included in an observational study. Organ failure was categorized as primary if it occurred early due to pancreatitis per se and secondary if it occurred late due to infected pancreatic necrosis (IPN). Primary outcome was a relative contribution of primary OF, secondary OF, and IPN to mortality. RESULTS: Of the 614 patients (mean age, 38.8; standard deviation, 14.6 years; 430 males) in a derivation cohort, 274 (44.6%) developed OF, with 177 having primary OF and 97 secondary OF due to sepsis. Primary OF caused early mortality in 15.8% and was a risk factor for IPN in 76% of patients. Mortality in patients with primary OF and IPN was 49.5% versus 36% in those with IPN and secondary OF (P = 0.06) and 4% in those with IPN but without OF (P < 0.001). The results of the 191 patients in the validation cohort confirmed the relative contribution of primary and secondary OF to mortality. CONCLUSION: Primary and secondary OF contributed to mortality independently and are distinct in their timing, window of opportunity for intervention, and prognosis. PMID- 29401172 TI - The 2012 International Consensus Guidelines of Intraductal Papillary Mucinous Neoplasms of the Pancreas (Fukuoka Criteria) Predict the Malignant Potential, Even in Actual Clinical Situations. AB - OBJECTIVES: The aim of the present study was to validate the use of the 2012 International Consensus Guidelines for intraductal papillary mucinous neoplasm (IPMN) (Fukuoka criteria) in patients without findings of obstructive jaundice and/or an enhanced solid component. METHODS: This retrospective study included patients who underwent pancreatectomy for IPMN between October 2002 and September 2016. The sensitivity, specificity, and positive and negative predictive values for malignancy were calculated for each feature of high-risk stigmata. RESULTS: Of the 135 patients who underwent surgery for IPMN, 50 (37.0%) had low/intermediate-grade dysplasia, 25 (18.5%) had high-grade dysplasia, and the remaining 60 (44.5%) had invasive carcinoma. A malignant potential was, thus, present in 63% of all resected cases. Considering an actual clinical situation, the predictors for malignant potential were assessed in 62 patients without findings of obstructive jaundice and/or an enhanced solid component. A multivariate analysis revealed that the Fukuoka criteria were the only independent factor for predicting the malignant potential (odds ratio, 5.69; P = 0.036). CONCLUSIONS: The present study suggested that malignant potential can be accurately detected by faithfully keeping to the Fukuoka criteria. Using these criteria enables us to identify patients with malignant potential, even in the actual clinical situations. PMID- 29401173 TI - Clinical presentation of autoimmune and viral encephalitides. AB - PURPOSE OF REVIEW: We describe clinical and diagnostic features of various autoimmune and viral encephalitis subtypes. RECENT FINDINGS: Population-based studies have demonstrated both autoimmune and viral causes have similar prevalence and incident rates. Repertoire of autoimmune biomarkers has considerably increased with discovery of many novel neural antibodies including glial fibrillary acidic proteinalpha-immunoglobulin G. Similarly, with use of next generation sequencing and DNA libraries, many viral causes are being detected which would have been categorized as encephalitis of unknown cause a decade ago. SUMMARY: Autoimmune and viral encephalitides can resemble one another and sometimes autoimmune encephalitis may be triggered by viral infections. Early diagnosis and treatment is the key to both causes, which emphasizes the importance of clinical diagnosis before laboratory confirmation. PMID- 29401174 TI - Autophagy: should it play a role in ICU management? AB - PURPOSE OF REVIEW: This review is to discuss the role of autophagy in the critically ill patient population. As the understanding of autophagy continues to expand and evolve, there are certain controversies surrounding whether intensivist should allow the benefit of autophagy to supersede gold standard of insulin therapy or early nutritional support. RECENT FINDINGS: The review is relevant as the current literature seems to support under-feeding patients, and perhaps the reason these studies were positive could be prescribed to the mechanisms of autophagy. It is well understood that autophagy is a physiologic response to stress and starvation, and that the inducible form could help patients with end-organ dysfunction return to homeostasis. SUMMARY: The jury is still out as to how autophagy will play into clinical practice as we review several gold standard therapies for the critically ill. PMID- 29401175 TI - Is hemoglobin good for cerebral oxygenation and clinical outcome in acute brain injury? AB - PURPOSE OF REVIEW: The purpose of this review is to highlight the role of hemoglobin in cerebral physiology and pathophysiology. We review the existing as well as recent evidence detailing the effects of red blood cell transfusion on cerebral oxygenation and clinical outcome. RECENT FINDINGS: Hemoglobin is a key component in oxygen delivery, and thus cerebral oxygenation. Higher hemoglobin levels and red blood cell transfusion are associated with higher cerebral oxygen delivery and decreased cerebral ischemic burden. Recent studies suggest that this may be associated with improved clinical outcomes. However, these results are limited to only a few, small studies and the results have not been consistent. Further studies are required. SUMMARY: Hemoglobin is important for cerebral oxygenation and strategies to minimize anemia should be undertaken. Although higher hemoglobin levels are associated with less cerebral ischemia and better clinical outcome, whether this remains true whenever red blood cell transfusion is used to achieve this result remains unclear. PMID- 29401176 TI - CORRELATIONS BETWEEN CHANGES IN PHOTORECEPTOR LAYER AND OTHER CLINICAL CHARACTERISTICS IN CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To clarify the correlations between changes in the photoreceptor layer (PRL) and other clinical characteristics during central serous chorioretinopathy. METHODS: Patients with central serous chorioretinopathy with one eye affected were enrolled. Photoreceptor layer appearance within the detached area was evaluated, and its correlations with symptom duration, best-corrected visual acuity, and the difference in the foveal outer nuclear layer thickness between the affected and contralateral eyes were analyzed. RESULTS: A total of 222 patients were included. The PRL outer border appeared either smooth, granulated, or as scattered dots attached to external limiting membrane. These different appearances were associated with elongation in symptom duration (18, 180, and 1,855 days), decreases in best-corrected visual acuity (6/10, 6/15, and 6/120), and increases in the difference of foveal outer nuclear layer thickness (-16, 32, and -60 MUm). Among eyes with smooth PRL outer border, which had similar symptom duration, eyes with foveal PRL defect had poorer best-corrected visual acuity and greater reduction in outer nuclear layer thickness than the other eyes (all P = 0.00). CONCLUSION: Morphologic changes in PRL, best-corrected visual acuity, the reduction in foveal outer nuclear layer thickness, and symptom duration correlate closely but may behave asynchronously. These objective parameters, besides symptom duration, could be helpful when considering the timing of central serous chorioretinopathy treatment.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29401177 TI - ACUTE EFFECT OF CAFFEINE ON MACULAR MICROCIRCULATION IN HEALTHY SUBJECTS: An Optical Coherence Tomography Angiography Study. AB - PURPOSE: To evaluate the acute effects of caffeine on macular microvasculature using quantitative optical coherence tomography angiography analysis. METHODS: Fifty-two healthy subjects aged 24 to 48 years were randomly divided into 2 groups: a control group, which received placebo, and a study group, which was subjected to caffeine. All participants underwent optical coherence tomography angiography at baseline and 1 hour after 200-mg oral caffeine intake in the study group and after oral placebo in the control group. Macular flow area, macular vessel density, and foveal avascular zone (FAZ) area were analyzed in both the groups. RESULTS: The study group consisted of 14 men and 12 women with a mean age of 40.6 +/- 8.9 years. The mean age of control group was 39.5 +/- 9.4 years, which consisted of 13 men and 13 women. Baseline macular flow area, vessel density, and FAZ area measurements of the study and control groups showed no significant difference (P > 0.05). Oral caffeine intake caused a significant reduction in macular flow area (superficial, deep, and choriocapillaris) and vessel density (P < 0.05). However, there was no statistically significant difference in FAZ area after caffeine intake when compared with baseline measurements (P = 0.063). CONCLUSION: We found a significant decrease in macular flow area (superficial, deep, and choriocapillaris) and vessel density after caffeine intake. Our findings are consistent with previous studies using other techniques. We believe that the results of this preliminary study will be useful in future studies about this topic. PMID- 29401178 TI - Decision-Making Data: Expectations for Reproducibility of Lifting on Separate Days. AB - PURPOSE: The purpose of this study was to explore the difference in maximal lifting capability between 2 modes of lifting (traditional crate and XRTS Lever Arm) over multiple days. The differences in absolute strength values were compared with existing criteria for sincere effort during distraction-based lifting. In addition, rate of perceived exertion (RPE) is presented for the 2 modes of lifting on each day. PRIMARY PRACTICE SETTING: Workers' compensation. METHODOLOGY AND SAMPLE: Forty-four subjects between the ages of 20 and 44 years participated in this study. Investigators established 1 repetition maximum (RM) for each subject performing the crate lift. Subjects were randomly assigned 5 weights ranging from 10% to 100% of their determined 1RM and asked to give their rating of perceived exertion after each lift. The same procedure was repeated 2-5 days later using the XRTS Lever Arm. Paired t tests and Spearman's correlation coefficient were used for data analysis. Alpha was set at less than .05. RESULTS: There was a statistically significant difference (p < .04) between maximal lift values for the 2 lifting modes. The percent difference between the modes of lifting was 10.5% +/- 6.4%. In addition, there was a positive correlation between the RPE on the 2 modes of lifting (p = .87). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: A functional capacity evaluation (FCE) is typically ordered after the completion of physical rehabilitation and before releasing a patient to full or modified duty. In addition to assessing the ability to function within normal job demands, an assessment of effort by the participant typically takes place during an FCE. Case managers and physicians are presented with information, allowing them to make comparisons between functional lifting abilities displayed during treatment sessions and the FCE. These comparisons may often take place with the subpoena of medical records and may be discussed during the deposition or trial process. If an FCE takes place at a different facility than the physical therapy or work conditioning treatment, 2 different modes of lifting may take place based on the equipment within each facility. The results of this study indicate that the 2 modes of lifting on separate days meet established criteria for lift comparison testing during FCEs. PMID- 29401179 TI - OPHTHALMIC ARTERY OCCLUSION AFTER FOREHEAD AUTOLOGOUS FAT INJECTION. AB - PURPOSE: To present clinical findings of ophthalmic artery occlusion, a devastating ocular complication because of forehead autologous fat injection. METHODS: Retrospective study of three eyes of three patients whereby ophthalmic artery occlusion and/or hemiplegia occurred after forehead autologous fat injection in China. RESULTS: All patients suffered severe ocular pain, vomiting, and vision loss immediately after the injections and had unilateral permanent blindness. CONCLUSION: Physicians performing cosmetic facial surgery involving autologous fat injection need to be aware of this potential risk and should inform the patient before the surgery.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29401180 TI - Blur Detection, Depth of Field, and Accommodation in Emmetropic and Hyperopic Children. AB - SIGNIFICANCE: Our results demonstrate that blur detection thresholds are elevated in young children compared with adults, and poorer blur detection thresholds are significantly correlated with the magnitude of accommodative microfluctuations. Given that accommodative microfluctuations are greater with greater accommodative responses, these findings may have implications for young uncorrected hyperopes. PURPOSE: This study investigated the association between subjective blur detection thresholds and accommodative microfluctuations in children 3 years to younger than 10 years old and adults. METHODS: Blur detection thresholds were determined in 49 children with habitually uncorrected refractive error (+0.06 to +4.91 diopters [D] spherical equivalent) and 10 habitually uncorrected adults (+0.08 to +1.51 D spherical equivalent) using a custom blur chart with 1 degrees sized optotypes at 33 cm. Letters were blurred by convolution using a Gaussian kernel (SDs of 0.71 to 11.31 arc minutes in ?2 steps). Subjective depth of field was determined in subjects 6 years or older and adults. Accommodative microfluctuations, pupils, and lag were measured using infrared photorefraction (25 Hz). RESULTS: Children had greater blur detection thresholds (P < .001), accommodative microfluctuations (P = .001), and depth of field (P < .001) than adults. In children, increased blur detection thresholds were associated with increased accommodative microfluctuations (P < .001), increased uncorrected hyperopia (P = .01), decreased age (P < .001), and decreased pupil size (P = .01). In a multiple linear regression analysis, blur detection thresholds were associated with accommodative microfluctuations (P < .001) and age (P < .001). Increased accommodative microfluctuations were associated with increased uncorrected hyperopia (P = .004) and decreased pupil size (P = .003) and independently associated with uncorrected hyperopia (P = .001) and pupil size (P = .003) when controlling for age and lag. CONCLUSIONS: Children did not have adult-like blur detection thresholds or depth of field. Increased accommodative microfluctuations and decreased age were independently associated with greater blur detection thresholds in children 3 years to younger than 10 years. Larger amounts of uncorrected hyperopia in children appear to increase blur detection thresholds because the greater accommodative demand and resulting response increase accommodative microfluctuations. PMID- 29401181 TI - Retinal Nerve Fiber Layer Protrusion Associated with Tilted Optic Discs. AB - SIGNIFICANCE: This study resulted in the identification of an optic nerve head (ONH) feature associated with tilted optic discs, which might potentially contribute to ONH pathologies. Knowledge of such findings will enhance clinical insights and drive future opportunities to understand disease processes related to tilted optic discs. PURPOSE: The aim of this study was to identify novel retinal nerve fiber layer (RNFL) anomalies by evaluating tilted optic discs using optical coherence tomography. An observed retinal nerve fiber protrusion was further investigated for association with other morphological or functional parameters. METHODS: A retrospective review of 400 randomly selected adult patients with ONH examinations was conducted in a referral-only, diagnostic imaging center. After excluding other ONH pathologies, 215 patients were enrolled and evaluated for optic disc tilt and/or torsion. Gross anatomical ONH features, including size and rim or parapapillary region elevation, were assessed with stereoscopic fundus photography. Optical coherence tomography provided detailed morphological information of individual retinal layers. Statistical analysis was applied to identify significant changes between individual patient cohorts. RESULTS: A dome-shaped hyperreflective RNFL bulge, protruding into the neurosensory retina at the optic disc margins, was identified in 17 eyes with tilted optic discs. Available follow-up data were inconclusive regarding natural changes with this ONH feature. This RNFL herniation was significantly correlated with smaller than average optic disc size (P = .005), congenital disc tilt (P < .0001), and areas of rim or parapapillary elevation (P < .0001). CONCLUSIONS: This study reports an RNFL protrusion associated with tilted optic discs, which has not previously been assessed as an independent ONH structure. The feature is predominantly related to congenital crowded, small optic discs and variable between patients. This study is an important first step to elucidate diagnostic capabilities of tilted disc morphological changes and understanding associated functional deficits. PMID- 29401182 TI - Association between Contrast Sensitivity and Reading with Macular Pathology. AB - SIGNIFICANCE: Comparison between the role of spatial and temporal contrast sensitivities in the association with reading may provide insight into how visual tasks (such as reading) are related to primary optical or neural (or both) effects. More insight into primary visual factors influencing reading is important for understanding reading problems. PURPOSE: The aim of this study was to gain insight into the association between optical and neural components of contrast sensitivity (CS), operationalized as spatial CS (optical and neural) or temporal CS (solely neural), and reading speed in a clinical sample of participants with macular pathologies. The precision and agreement were also investigated. METHODS: The Mars test and temporal CS implementation of the C Quant device were used to measure spatial CS and temporal CS, respectively. Tests were performed with 47 participants: mean age, 77 years (range, 52 to 92 years). Associations were investigated with correlations and linear regression models. Precision was defined by coefficients of repeatability. The 95% limits of agreement between spatial CS and temporal CS values were assessed. RESULTS: Reading speed correlated with both spatial CS (r = 0.35, P = .015) and temporal CS (r = 0.66, P < .001). After correction for visual acuity, central loss, and education level, the association between temporal CS and reading speed was not significant anymore. The coefficients of repeatability and reproducibility were 0.20 and 0.28 log unit (spatial CS) and 0.33 and 0.35 log unit (temporal CS), respectively. The values for temporal CS were 0.08 and 0.13 log unit higher than those for spatial CS. CONCLUSIONS: For spatial CS and temporal CS, moderate to strong correlations were found, respectively, with reading speed in patients with maculopathies. The stronger association between temporal CS and reading speed is suggested to reflect a high sensitivity for neural integrity of temporal CS. The differences in coefficients of repeatability and reproducibility could be explained by the psychometrical differences between methods. PMID- 29401185 TI - Serious About the Opioid Epidemic? Expand Medicaid. PMID- 29401183 TI - Cognitive Aids Do Not Prompt Initiation of Cardiopulmonary Resuscitation in Simulated Pediatric Cardiopulmonary Arrests. AB - INTRODUCTION: Although American Heart Association guidelines exist for proper management of cardiopulmonary arrest (CPA), in-hospital cardiopulmonary resuscitation (CPR) may be of poor quality and is not performed in all indicated situations. Cognitive aids have been created to assist in rapid, accurate recall of guidelines for pediatric CPA management. METHODS: Pediatric residents participated in individual mock codes for two years. Using a high-fidelity simulator, each resident participated in a standardized scenario that required management of both pulseless ventricular tachycardia and pulseless electrical activity. The primary study objective was to calculate the proportion of residents (a) who were not performing CPR on a simulated "pulseless" patient when cognitive aid use was first initiated and (b) who subsequently initiated CPR after cognitive aid use. RESULTS: One hundred thirty-two (83.5%) of 158 pediatric residents participated, and of 125 videos available for review, 107 residents (85.6%) used a cognitive aid. Mean (SD) time to cognitive aid use was 106 (100) seconds after the mannequin became pulseless. Most common immediate actions prompted by cognitive aid use were the following: defibrillation, 43 (40%) of 107; and adrenaline (epinephrine) administration, 28 (26%) of 107. Most alarmingly, 58 (54%) of 107 were not performing CPR on the pulseless patient when cognitive aid use was initiated and only two (3.4%) of 58 were subsequently prompted to initiate chest compressions. DISCUSSION: Cognitive aids in use during this study did not prompt timely initiation of CPR, potentially contributing to delays and errors in CPA management. Failure of these aids to prompt CPR initiation represents a "missed opportunity" to enhance performance of this vital skill. PMID- 29401186 TI - Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 30 , 90-, and 180-Day Hospital Readmission Rates. AB - INTRODUCTION: Smoking is a risk factor for hospitalization and interferes with patient care due to its effects on pulmonary function, wound healing, and interference with treatments and medications. Although benefits of stopping smoking are well-established, few hospitals provide tobacco dependence treatment services (TDTS) due to cost, lack of mandatory tobacco cessation standards and lack of evidence demonstrating clinical and financial benefits to hospitals and insurers for providing services. METHODS: This study explored the effect of an inpatient TDTS on 30-, 90-, and 180-day hospital readmissions. To carry out this work, 3 secondary datasets were linked, which included clinical electronic health record data, tobacco cessation program data, and statewide health care utilization data. Odds ratios (ORs) were calculated using inverse propensity score-weighted logistic regression models, with program exposure as the primary independent variable and 30 (90 and 180)-day readmission rates as the dependent variable, and adjustment for putative covariates. RESULTS: Odds of readmission were compared for patients who did and did not receive TDTS. At 30 days postdischarge, smokers exposed to the TDTS had a lower odds of readmission (OR=0.77, P=0.031). At 90 and 180 days, odds of readmission remained lower in the TDTS group (ORs=0.87 and 0.86, respectively), but were not statistically significant. DISCUSSION: Findings from the current study, which are supported by prior studies, provide evidence that delivery of TDTS is a strategy that may help to reduce hospital readmissions. PMID- 29401187 TI - New Opportunities for Cancer Health Services Research: Linking the SEER-Medicare Data to the Nursing Home Minimum Data Set. AB - BACKGROUND: The Surveillance, Epidemiology and End Results (SEER)-Medicare data combine clinical information from population-based cancer registries with Medicare claims. These data have been used in many studies to understand cancer screening, treatment, outcomes, and costs. However, until recently, these data included limited information related to the characteristics and outcomes of cancer patients residing in or admitted to nursing homes. OBJECTIVES: To provide an overview of the new linkage between SEER-Medicare data and the Minimum Data Set (MDS), a nursing home resident assessment instrument detailing residents' physical, psychological, and psychosocial functioning as well as any therapies or treatments received. RESEARCH DESIGN: This is a descriptive, retrospective cohort study. SUBJECTS: Persons in SEER-Medicare diagnosed with cancer from 2004 to 2013 were linked to the 2011-2014 MDS, with 17% of SEER-Medicare patients linked to the MDS data. During 2011-2014, we identified 318,617 cancer patients receiving care in a nursing home and 256,947 cancer patients newly admitted to a total of 10,953 nursing homes. Of these patients, approximately two thirds were Medicare fee-for-service beneficiaries. RESULTS: The timing from cancer diagnoses to nursing home admission varied by cancer. In total, 93% of all patients were admitted directly to a nursing home from an acute care hospital. The majority of patients were cognitively intact, 21% reported some level of depression, and 9% had severe functional limitations. CONCLUSIONS: The new SEER-Medicare-MDS dataset provides a valuable resource for understanding the postacute and long-term care experiences of cancer patients receiving care in United States' nursing homes. PMID- 29401188 TI - Hospital variation in mortality after emergent bowel resections: The role of failure-to-rescue. AB - BACKGROUND: Hospital variation in failure-to-rescue (FTR) rates has partially explained nationwide differences in mortality after elective surgeries. To examine the role of FTR among emergency general surgery, we compared nationwide risk-adjusted mortality, complications, and FTR rates after emergent bowel resections. METHODS: We identified patients who underwent emergent small or large bowel resections in the 2010 to 2011 Nationwide Inpatient Sample using the American Association for the Surgery of Trauma criteria. We then calculated risk adjusted mortality rates for each hospital using multivariable logistic regressions and postestimation, which adjusted for patient age, sex, race and ethnicity, payer status, comorbidities, and hospital clustering. After excluding hospitals with fewer than 10 resections per year, we ranked the remaining hospitals by their risk-adjusted mortality rates and divided them into five quintiles. We compared both risk-adjusted complication rates and FTR rates between the top (lowest mortality) and bottom (highest mortality) quintiles. RESULTS: We identified 21,564 emergent bowel resections, weighted to 105,925 procedures nationwide. The bottom quintile of hospitals had an overall risk adjusted mortality rate that was 10.9 times higher than that of the top quintile of hospitals (15.3% vs. 1.4%). While risk-adjusted complication rates were similarly high for both the bottom and the top quintiles of hospitals (22.5% vs. 15.7%), the risk-adjusted FTR rates were 10.8 times higher in the bottom quintile of hospitals relative to the top quintile of hospitals (33.4% vs. 3.1%). Using larger hospital volume thresholds yielded similar findings. Furthermore, large variations existed in complication-specific FTR rates (surgical site infection [6.6%] to myocardial infarction [29.4%]). CONCLUSION: Nationwide hospital variation in risk-adjusted mortality rates exist after emergent bowel resections. As complication rates were similar across hospitals, the significantly higher FTR rates at higher-mortality hospitals may drive this variation in mortality. System level initiatives addressing the management of postoperative complications may improve patient care and reduce variation in outcomes. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level IV. PMID- 29401189 TI - Prophylactic use of resuscitative endovascular balloon occlusion of the aorta in women with abnormal placentation: A systematic review, meta-analysis, and case series. AB - BACKGROUND: We describe intraoperative and postdischarge outcomes of a case series after the prophylactic use of resuscitative endovascular balloon occlusion of the aorta (REBOA) during elective cesarean delivery in pregnant women with morbidly adherent placenta (MAP). We furthermore performed a systematic review and meta-analysis to investigate the safety and effectiveness of the use of REBOA during elective cesarean delivery in pregnant women with MAP. METHODS: Descriptive case series of REBOA (December 2015 to June 2017) used during elective cesarean delivery in pregnant women with MAP. The systematic review was conducted following PRISMA guidelines. We included studies involving pregnant women with a diagnosis of MAP who underwent an elective cesarean delivery with prophylactic REBOA placement. A meta-analysis was performed to assess the overall amount of transfusions and intraoperative hemorrhage of REBOA compared to NO REBOA cases. RESULTS: A total of 12 patients with MAP underwent elective cesarean delivery with REBOA deployment. The median (interquartile range) of packed red blood cells transfused during the first 24 hours following surgery was two units (0-3.5). The median (interquartile range) of intraoperative blood loss was 1,500 mL (900-2,750). At 28 days, all patients were alive, and no adverse outcomes were observed. Four articles were included in the systematic review and meta-analysis. These articles included a total of 441 patients. Quantitative synthesis (meta analysis) found that the use of REBOA as prophylaxis for the prevention of major hemorrhage was associated with a lower amount of intraoperative hemorrhage (in milliliters) (weighted mean difference, -1,384.66; 95% confidence interval, 2,141.74 to -627.58) and lower requirements of blood products transfusions (in units) (weighted mean difference, -2.42; 95% confidence interval, -3.90 to 0.94). CONCLUSION: We provide clinical data supporting the use of REBOA in the management of pregnant women with MAP undergoing elective cesarean delivery. Our findings demonstrate the feasibility of REBOA as a prophylactic intervention to improve outcomes in women at risk of catastrophic postpartum hemorrhage. LEVEL OF EVIDENCE: Therapeutic study, level V; Systematic Review, level IV. PMID- 29401190 TI - Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model. AB - BACKGROUND: Hemorrhage is a leading preventable cause of death. Nonselective histone deacetylase inhibitors (HDACIs), such as valproic acid (VPA), have been shown to improve outcomes in hemorrhagic shock (HS). The HDACs can be divided into four functional classes (I, IIa/IIb, III, and IV). Classes I, IIa/IIb, and III have previously been implicated in the pathophysiology of HS. This study aimed to determine which HDAC class, or classes, are responsible for the survival benefit observed with nonselective HDACIs. METHODS: Survival study: Sprague Dawley rats were subjected to lethal HS (50% hemorrhage) and randomized to the following groups (n = 8): (1) no treatment, (2) normal saline vehicle, (3) cyclodextrin vehicle, (4) MS275 (class I HDACI), (5) VPA (class I/IIa HDACI), (6) MC1568 (class IIa HDACI), (7) ACY1083 (class IIb HDACI), and (8) EX527 (class III HDACI). Survival was monitored for 24 hours. Mechanistic study: Sprague-Dawley rats were subjected to sublethal HS (40% hemorrhage) and randomized to the same groups (n = 3), excluding EX527, based on results of the survival study. Tissues were harvested at 3 hours posttreatment, and expression of phosphorylated-AKT, beta-catenin, acetylated histones H3 and H4, and acetylated alpha-tubulin were analyzed in myocardial tissue. RESULTS: Survival rate was 12.5% in the untreated group, and did not improve with vehicle or MS275 treatment. EX527 improved survival to 50%, although this did not achieve statistical significance (p = 0.082). However, treatment with VPA, MC1568, and ACY1083 improved survival rates to 87.5%, 75%, and 75%, respectively (p < 0.05). The VPA-induced acetylation of both histones H3 and H4, while MC1568 and ACY1083 increased acetylation of histone H4. ACY1083 also induced acetylation of alpha-tubulin. All treatment groups, except MS275, increased phosphorylated-AKT, and beta-catenin. CONCLUSION: Inhibition of HDAC classes IIa or IIb, but not class I, activates prosurvival pathways, which may be responsible for the improved outcomes in rodent models of HS. PMID- 29401191 TI - Immunomodulatory effects of plasma products on monocyte function in vitro. AB - BACKGROUND: Restoration of a balanced innate immune response is paramount to recovery from critical injury. Plasma transfusion may modulate innate immune responses; however, little is known about the immunomodulatory potential of various plasma products. We conducted in vitro experiments to determine the effects of fresh frozen plasma, thawed plasma, solvent/detergent plasma, and an investigational spray-dried solvent/detergent plasma product on monocyte function. METHODS: Monocytes were isolated from healthy adult volunteers and cocultured with aliquots of autologous plasma (control), fresh frozen plasma, thawed plasma, solvent/detergent treated plasma, or spray-dried solvent/detergent plasma. Monocyte function was assessed by cytokine production with and without lipopolysaccharide (LPS) stimulation, and flow cytometric assessment of HLA-DR cell surface expression. RESULTS: Monocyte cytokine production was not significantly altered after exposure to fresh frozen plasma or thawed plasma. In the absence of LPS, spray-dried solvent/detergent plasma exposure resulted in markedly increased IL-8 production compared to other plasma groups and controls (p = 0.01, analysis of variance [ANOVA]). Likewise, spray-dried SD plasma exposure resulted in higher LPS-induced IL-8, TNFalpha, and IL-1beta production compared with autologous plasma controls (p < 0.0001; p < 0.0001, p = 0.002, respectively; ANOVA). LPS-induced IL-8 and TNFalpha production was lowest after exposure to solvent/detergent plasma (p < 0.0001, ANOVA). CONCLUSION: Exposure to spray-dried solvent/detergent plasma resulted in marked augmentation of monocyte inflammatory cytokine production. Solvent/detergent plasma exposure resulted in the lowest cytokine production, suggesting lower immunomodulatory potential. Further work is needed to determine how these in vitro findings may translate to the bedside. PMID- 29401192 TI - Examination of a Multi-ingredient Preworkout Supplement on Total Volume of Resistance Exercise and Subsequent Strength and Power Performance. AB - Bergstrom, HC, Byrd, MT, Wallace, BJ, and Clasey, JL. Examination of a multi ingredient preworkout supplement on total volume of resistance exercise and subsequent strength and power performance. J Strength Cond Res 32(6): 1479-1490, 2018-This study examined the acute effects of a multi-ingredient preworkout supplement on (a) total-, lower-, and upper-body volume of resistance exercise and (b) the subsequent lower-body strength (isokinetic leg extension and flexion), lower-body power (vertical jump [VJ] height), upper-body power (bench throw velocity [BTv]), and cycle ergometry performance (critical power and anaerobic work capacity). Twelve men completed baseline strength and power measures before 2 experimental visits, supplement (SUP) and placebo (PL). The experimental visits involved a fatiguing cycling protocol 30 minutes after ingestion of the SUP or PL and 15 minutes before the beginning of the resistance exercise protocol, which consisted of 4 upper-body and 4 lower-body resistance exercises performed for 4 sets to failure at 75% 1 repetition maximum. The exercise volume for the total, lower, and upper body was assessed. The VJ height and BTv were measured immediately after the resistance exercise. Postexercise isokinetic leg extension and flexion strength was measured 15 minutes after the completion of a second cycling protocol. There was a 9% increase in the total body volume of exercise and a 14% increase in lower-body volume of exercise for the SUP compared with the PL, with no effect on exercise volume for the upper body between the SUP and PL. The increased lower-body volume for the SUP did not result in greater lower-body strength and power performance decrements after exhaustive exercise, compared with the PL. These findings suggested the potential for the SUP to increase resistance exercise volume, primarily related to an increased lower-body volume of exercise. PMID- 29401193 TI - The Physical Activity and Physiological Profiles of Elite International Female Field Hockey Players Across the Quarters of Competitive Match-Play. AB - The aim of the current investigation was to quantify the physical and physiological demands of elite international female field hockey across the quarters of match-play. Twenty-seven elite International female field hockey outfield players (23 +/- 3 years; 162.6 +/- 13.0 cm; 66.0 +/- 6.0 kg) participated in the current observational study during the 2016-2017 season. Participants were monitored with GPS technology and HR monitors. Players were categorised based on three different playing positions. Activity was categorized into total distance (m), relative total distance (RTD), low, moderate and high intensity distance (m), max velocity (km?h), and percentage maximal velocity (%). Physiological demands were quantified via players HRPeak which was classified based on the player's individual HRmax determined via a Yo-Yo intermittent recovery level 1 test. Players spent on average 38 +/- 8 min in match play. The total distance covered was 4847 +/- 583 m (127.6 +/- 15.6 m.min). Defenders covered a greater total distance across all three positions (p = <= 0.05). The midfielders covered a greater moderate intensity distance (p <=0.001) while the forwards covered more high-intensity distance (p <=0.001). The HRpeak of the players was 198 +/- 4 b.min with a mean exercise intensity of 95 +/- 1 % HRmax. The time spent > 70 % HRmax decreased significantly across the quarters (p = 0.01, eta2 = 0.03). Defenders were found to spend more time >85 % HRmax when compared to other positions (p <=0.001, eta = 0.28). The current study provides normative data that coaches should consider when developing training drills to better optimize the positional physical and physiological activity profiles that best replicate match-play. PMID- 29401194 TI - Anthropometric and Physiological Characteristics of Brazilian Jiu-Jitsu Athletes. AB - Ovretveit, K. Anthropometric and physiological characteristics of Brazilian jiu jitsu athletes. J Strength Cond Res 32(4): 997-1004, 2018-The aim of this study was to describe anthropometric and physiological characteristics of Brazilian jiu jitsu (BJJ) athletes. For this purpose, 42 male athletes were recruited from one of the largest BJJ academies in central Norway. The subjects were 32 +/- 6 (SD) years old, 181.9 +/- 7.2 cm tall, had a body mass (mb) of 85.7 +/- 10.6 kg, and 5.5 +/- 3.7 years of BJJ training experience. The subjects underwent segmental multifrequency bioelectrical impedance analysis of body composition (BIA), direct measurements of pulmonary function and maximal oxygen uptake (V[Combining Dot Above]O2max), assessments of 1-repetition maximum (1RM) in the parallel squat and paused bench press, and one set of pronated-grip pull-ups to muscular failure. The average body fat percentage (BF) was 12.9 +/- 5.3%. The subjects achieved a V[Combining Dot Above]O2max of 50.6 +/- 4.6 mL.kg.min. Absolute squat 1RM (113.2 +/- 20.4 kg) was significantly higher than bench press 1RM (87.6 +/- 16.5 kg) (p < 0.001). The mean number of pull-ups achieved was 9 +/- 4. These characteristics were generally independent of rank, training experience, weekly training volume, competition volume, and style preference. Additional strength training was associated with improved bench press performance (p < 0.05). Beyond that, additional strength and/or conditioning training had no apparent relationship with any variable (p > 0.05). This study provides novel insight into the fitness levels of BJJ athletes. These findings indicate the degree of exercise response to BJJ training and are applicable in athlete assessment and exercise prescription in this population. PMID- 29401195 TI - Effects of Foam Rolling on Range of Motion, Peak Torque, Muscle Activation, and the Hamstrings-to-Quadriceps Strength Ratios. AB - Madoni, SN, Costa, PB, Coburn, JW, and Galpin, AJ. Effects of foam rolling on range of motion, peak torque, muscle activation, and the hamstrings-to-quadriceps strength ratios. J Strength Cond Res 32(7): 1821-1830, 2018-To examine the effects of foam rolling (FR) on range of motion (ROM), peak torque (PT), hamstrings-to-quadriceps (H:Q) ratios, and muscle activation. Twenty-two recreationally active women (mean age +/- SD = 21.55 +/- 1.82 years, 161.91 +/- 6.58 cm, 61.47 +/- 10.54 kg) volunteered for this study. Participants performed pre- and posttests analyzing PT and surface electromyography (EMG) of their dominant limb, completing maximal knee extension and flexion at 3 different velocities. Participants foam rolled the hamstrings muscles or sat for the control condition between the pre- and posttests. Hamstrings ROM increased in the FR condition from (mean +/- SE) 123.23 +/- 3.49 to 126.41 +/- 3.62 degrees (p < 0.001) and decreased in the control condition from 118.82 +/- 4.25 to 117.95 +/- 4.29 degrees (p = 0.013). Concentric hamstrings PT and conventional H:Q ratios decreased after both conditions, with smaller decreases after FR (p <= 0.05). No significant changes were found for eccentric hamstrings PT, eccentric hamstrings EMG, or functional H:Q ratios (p > 0.05). Foam rolling resulted in greater changes in hamstrings ROM without creating a deficit in PT or muscle activation when compared with the control group. When compared with other methods of stretching, FR may be beneficial in increasing ROM without decreasing functional H:Q ratios. PMID- 29401196 TI - An Acceleration Profile of Elite Gaelic Football with Special Reference to Position of Play. AB - The current study aimed to characterize the positional match-play demands of elite Gaelic football players with special reference to acceleration utilizing predetermined 5- min periods (epochs). Thirty-five male Gaelic players (Mean +/- SD, age: 24 +/- 6 years; height: 180 +/- 7 cm; mass: 81 +/- 7 kg) across five playing positions (full-back, half-back, midfield, half-forward, full-forward) were monitored during the investigation. Player movement was recorded during nineteen matches using 4-Hz global positioning system technology (GPS; VXSport, New Zealand) resulting in 154 player observations. GPS was used to record total distance (m), high-speed running (HSR; m; >=17 kmh), very high-speed running distance, (VHSR; m; >=22 kmh), the number of accelerations (n), duration of accelerations (s), peak acceleration (m), and distance of accelerations (m). Acceleration profiles were position dependent with midfielders found to have a high accumulation of acceleration movements when compared to all other positions (p < 0.05). Declines of -2% to -32% for acceleration distance (m) depending on positional line of play were observed during match-play. Less HSR and VHSR, was performed by the full-back line (HSR; -39%, VHSR; -36%) and full-forward line ( 35%; -29%) when compared to half-back, midfielders and half-forwards (p=0.01, d = 1.35 to 1.77). Similar trends were reported for peak acceleration distance (p=0.01, d = 1.15 to 1.93). The current investigation provides a greater understanding of temporal differences in acceleration profiles of playing position. We show that half-back, midfield and half-forwards have the highest acceleration movements these data can assist coaches in appropriately preparing players for the required acceleration distances required during match-play. PMID- 29401197 TI - Effects of an 8-Week Body-Weight Neuromuscular Training on Dynamic Balance and Vertical Jump Performances in Elite Junior Skiing Athletes: A Randomized Controlled Trial. AB - Vitale, JA, La Torre, A, Banfi, G, and Bonato, M. Effects of an 8-week body weight neuromuscular training on dynamic balance and vertical jump performances in elite junior skiing athletes: a randomized controlled trial. J Strength Cond Res 32(4): 911-920, 2018-The aim of the present randomized controlled trial was to evaluate the effects of an 8-week neuromuscular training program focused on core stability, plyometric, and body-weight strengthening exercises on dynamic postural control and vertical jump performance in elite junior skiers. Twenty four Italian elite junior male skiers were recruited and randomized to either an experimental group (EG), performing neuromuscular warm-up exercises, (EG; n = 12; age 18 +/- 1 years; body mass 66 +/- 21 kg; height 1.70 +/- 0.1 m) or a control group (CG) involved in a standard warm-up (CG; n = 12; age 18 +/- 1 years; body mass 62 +/- 14 kg; height 1.73 +/- 0.1 m). lower quarter Y-Balance Test (YBT), countermovement jump (CMJ), and drop jump (DJ) at baseline (PRE) and at the end (POST) of the experimental procedures were performed. No significant differences between EG and CG were observed at baseline. Results showed that EG achieved positive effects from PRE to POST measures in the anterior, posteromedial, posterolateral directions, and composite score of YBT for both lower limbs, whereas no significant differences were detected for CG. Furthermore, 2-way analysis of variance with Bonferroni's multiple comparisons test did not reveal any significant differences in CMJ and DJ for both EG and CG. The inclusion of an 8-week neuromuscular warm-up program led to positive effects in dynamic balance ability but not in vertical jump performance in elite junior skiers. Neuromuscular training may be an effective intervention to specifically increase lower limb joint awareness and postural control. PMID- 29401198 TI - Analysis of the Effects of Sex and Age on Upper- and Lower-Body Power for Law Enforcement Agency Recruits Before Academy Training. AB - Lockie, RG, Dawes, JJ, Orr, RM, Stierli, M, Dulla, JM, and Orjalo, AJ. Analysis of the effects of sex and age on upper- and lower-body power for law enforcement agency recruits before academy training. J Strength Cond Res 32(7): 1968-1974, 2018-Power is an important characteristic for law enforcement officers. Tasks such as carrying or dragging a civilian to safety, jumping or vaulting, and suspect restraint and pursuit require power to be effective. Certain recruits may be lacking in these qualities even if they have been accepted to a law enforcement agency (LEA). This study investigated upper- and lower-body power in male and female LEA recruits, and recruits of different ages, before academy training. Retrospective analysis of recruit data from one LEA was conducted. The measurements were: vertical jump (VJ) height; peak anaerobic power calculated by the Sayers equation; power-to-body mass ratio (P:BM); seated medicine ball throw (MBT) distance; and MBT distance relative to body mass. Independent-sample t tests were used to compare the sexes, whereas a 1-way analysis of variance with Bonferroni post hoc compared the pooled data for recruits across different age groups (20-24; 25-29; 30-34; and 35+ years). The male recruits demonstrated superior performance across all power tests compared with the female recruits (p < 0.001). Regarding age, the 35+ year group performed less than optimally in the VJ and P:BM compared with the 20-24 and 24-29 years groups, and in the relative MBT compared with the 20-24 and 30-34 years groups (p = 0.003-0.037). Despite being accepted to a LEA, female recruits and recruits aged 35+ years of age may be lacking in upper- and lower-body power. Female and older recruits should participate in strength and power training before academy attendance to maintain or enhance these qualities. PMID- 29401199 TI - Effect of A 16 Week Combined Strength and Plyometric Training Program Followed by A Detraining Period on Athletic Performance in Pubertal Volleyball Players. AB - The purpose of this study was to determine the effects of 16 weeks of combined strength and plyometric training or plyometric training alone, and how a detraining program can modify adaptations in response to the training stimulus. Sixty male volleyball players (circa PHV:-1 to +1 years from PHV) were assigned to a Combined Training group (CTG) (n=20), a Plyometric Training group (PTG) (n=20) or a control group (CG) (n=20). The experimental groups (CTG and PTG) participated in training twice weekly for 16 weeks. Thigh muscle volume, body fat, flexibility, sprint, jump height and medicine ball throw were measured at pre-training, post-training and detraining. Respectively, the CTG and PTG showed increases in thigh muscle volume (Effect size: 0.71 and 0.42), and decreases in body fat (-0.42 and -0.34) as well as improvements in 5 m sprint (-0.69 and 0.46) 10 m sprint (-0.31 and -0.3), lower body muscle power (0.44 and 0.36) and upper body muscle power (1.32 and 0.7). After the detraining period, all groups maintained previously attained muscle power (6.79% to 9.87%; p<0.001). In conclusion, combined strength and plyometric training provided better improvements than plyometric training only. The combination of strength and plyometric training is a time-effective training modality that confers improvements in physical performance measures, muscle size and body fat. A temporary period of detraining may not undermine performance gains in pubertal volleyball players. PMID- 29401201 TI - Relationship Between Reactive Strength Index Variants in Rugby League Players. AB - Two reactive strength index (RSI) variants exist, the RSI and RSI modified (RSImod) which are typically calculated during the drop jump (DJ) and countermovement jump (CMJ), respectively. Both RSI variants have been used to monitor athletes' ability to complete stretch-shortening cycle actions quickly, but they have never been compared. The purpose of this study was to determine if they yield relatable information about reactive strength characteristics. Male professional rugby league players (n = 21, age = 20.8+/-2.3 years, height = 1.82+/-0.06 m and body mass = 94.3+/-8.4 kg) performed three DJs (30 cm) and CMJs on a force plate. RSI and RSImod were subsequently calculated by dividing jump height by ground contact time (GCT) and time to take-off (TTT), respectively. All variables were highly reliable (intraclass correlation coefficient >=0.78) with acceptable levels of variability (coefficient of variation <=8.2%), albeit larger variability was noted for DJ variables. Moreover, there was a large relationship between RSI and RSImod (r=0.524, P=0.007), whereas very large relationships were noted between jump heights (r=0.762, P<0.001) and between GCT and TTT (rho=0.705, P<0.001). Additionally, RSI (0.90+/-0.22) was largely and significantly (d=2.57, P<0.001) greater than RSImod (0.47+/-0.08). The DJ-derived RSI yields much larger values than the CMJ-derived RSImod and although a large relationship was noted between them, it equated to just 22% shared variance. These results suggest that the two RSI variants do not explain each other well, indicating that they do not assess entirely the same reactive strength qualities and should not be used interchangeably. PMID- 29401200 TI - ACTN3 Genotype in Professional Sport Climbers. AB - Ginszt, M, Michalak-Wojnowska, M, Gawda, P, Wojcierowska-Litwin, M, Korszen Pilecka, I, Kusztelak, M, Muda, R, Filip, AA, and Majcher, P. ACTN3 genotype in professional sport climbers. J Strength Cond Res 32(5): 1311-1315, 2018-The functional RR genotype of the alpha-actinin-3 (ACTN3) gene has been reported to be associated with elite sprint/power athlete status. Although large and rapidly increasing number of studies have investigated the associations between the ACTN3 genotypes and athletic performance in various sport disciplines, there is a lack of studies on the genetic predisposition in sport climbing, which was selected to be part of the next Summer Olympic Games in Tokyo 2020 with three subdisciplines ("lead climbing," "speed climbing," and "bouldering"). The aim of the study is to determine the frequency distribution of ACTN3 genotypes and alleles in professional lead climbers and boulderers. 100 professional sport climbers from Poland, Russia, and Austria were divided into 2 equal groups: professional boulderers and professional lead climbers were involved in the study. ACTN3 allele frequencies and genotypes were compared with 100 sedentary controls. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism method. The percent distribution of RR genotype in the boulderers was significantly higher than in lead climbers and controls (62 vs. 26%; 33%, respectively; chi = 17.230, p = 0.0017). The frequencies of ACTN3 R allele in boulderers differed significantly from lead climbers and controls (77 vs. 51%; 58%, respectively; chi = 15.721, p = 0.0004). The proportion of the ACTN3 RR genotype is significantly higher in boulderers than in lead climbers and may be related to the specific type of predisposition to this subdiscipline. PMID- 29401202 TI - Effects of Different Plyometric Training Frequency on Measures of Athletic Performance in Prepuberal Male Soccer Players. AB - This study aimed to compare the effects of one vs. two sessions of equal-weekly volume plyometric training (PT) across 8 weeks on measures of athletic performance (i.e., sprint-time, change of direction [CoD], jumping ability, and muscle strength) in prepuberal male soccer players. Thirty participants were randomly assigned either to one session PT group (1SPT [n=15]) or two sessions PT group (2SPT [n=15]). Plyometric training was integrated into their regular soccer training routine. Pre- and post-training tests for the assessment of sprint-time (e.g., 5-m, 10-m, 20-m, and 30-m), CoD (e.g., T-test and modified Illinois change of direction test [MICODT]), jumping ability (e.g., standing long jump [SLJ], counter-movement jump [CMJ], and squat jump [SJ]), muscle strength (reactive strength index [RSI]), and kicking distance were conducted. Results showed a main effect of time for 5-m sprint-time performance (F(1,56)=4.00, ES=0.53 [medium], p=0.05), T-test (F(1,56)=23.19, ES=1.28 [large], p<0.001), MICODT (F(1,56)= 5.72, ES=0.94 [large], p=0.02), SLJ (F(1,56)=16.63, ES=1.09 [large], p<0.001), CMJ (F(1,56) =15.43, ES= 1.04 [large], p<0.001), SJ (F(1,56) =20.27, ES=1.20 [large], p<0.001), RSI (F(1,56)=26.26, ES=1.36 [large], p<0.001), and kicking distance (F(1,56)=47.19, ES=1.83 [large], p<0.001). There were no training group * time interactions in all the measured outcomes. In conclusion, when an equated moderate volume of jumps is performed, higher PT frequency across 8 weeks has no extra-effects on prepuberal male soccer players' measures of athletic performance. The present findings may help optimizing PT interventions dedicated to prepuberal male soccer players. PMID- 29401203 TI - Effect of Accommodating Resistance on the Postactivation Potentiation Response in Rugby League Players. AB - Scott, DJ, Ditroilo, M, and Marshall, P. Effect of accommodating resistance on the post-activation potentiation response in rugby league players. J Strength Cond Res 32(9): 2510-2520, 2018-This study examined the postactivation potentiation (PAP) response of 2 conditioning activities (CA), the hex bar deadlift and back squat, combined with accommodating resistance; this adds a percentage of the total resistance during the exercise. Twenty amateur rugby league players performed 2 experimental trials and a control trial without a CA. Participants performed a countermovement jump (CMJ) before and 30, 90, and 180 seconds after 1 set of 3 repetitions of each CA at 70% 1 repetition maximum (RM), with up to an additional 23% 1RM from accommodating resistance. Peak power output (PPO), force at PPO, velocity at PPO, and jump height were calculated for each CMJ. Surface electromyography (EMG) of the vastus lateralis (VL), rectus femoris (BF), tibialis anterior (TA), and gastrocnemius medialis (GM) was also measured. Repeated-measures analysis of variance revealed no significant (p > 0.05) PAP response for either exercise condition when comparing CMJ variables with baseline values nor were there any significant (p > 0.05) differences between exercise conditions. However, individualized recovery intervals (baseline vs. maximum potentiation response) demonstrated significant (p <= 0.05) improvements in PPO (3.99 +/- 4.99%), force at PPO (4.87 +/- 6.41%), velocity at PPO (4.30 +/- 5.86%), jump height (8.45 +/- 10.08%), VL EMG (20.37 +/- 34.48%), BF EMG (22.67 +/- 27.98%), TA EMG (21.96 +/- 37.76%), and GM EMG (21.89 +/- 19.65%). Results from this study must be interpreted with caution; however, it is conceivable that athletic performance can be acutely enhanced when complex training variables are individualized. PMID- 29401204 TI - Power Testing in Basketball: Current Practice and Future Recommendations. AB - Wen, N, Dalbo, VJ, Burgos, B, Pyne, DB, and Scanlan, AT. Power testing in basketball: Current practice and future recommendations. J Strength Cond Res 32(9): 2686-2700, 2018-Numerous foundational movements performed during basketball are predicated on underlying power-related attributes, including speed, change-of-direction (COD), and jumping. Accordingly, fitness testing batteries for basketball have incorporated an assortment of linear speed tests, COD tests, and jump tests. However, because of the wide variety of testing options, it is difficult for basketball practitioners to select appropriate testing protocols for the assessment of power-related attributes. As a result, there is a need to review the relevant literature to identify game-specific, power-related attributes important in basketball and the most appropriate tests available to assess power-related attributes for basketball practitioners. Therefore, the aims of this review were to: (a) identify essential power-related attributes important in basketball; (b) discuss the suitability of common and novel power-related tests; and (c) provide recommendations for future research and best practice approaches for basketball coaching staff. In this review, we propose a series of novel tests that are more targeted and specific to basketball movements including: (a) 5- and 10-m linear sprints, (b) modified agility T-test, (c) change-of-direction deficit (CODD), (d) lateral bound, (e) Sargent jump, (f) one-step jump, and (g) isometric midthigh pull test. Improved testing of power related attributes should enable basketball practitioners to develop targeted training plans for enhancing player performance. PMID- 29401205 TI - Protein Kinases Type II (PKG II) Combined with L-Arginine Significantly Ameliorated Xenograft Tumor Development: Is L-Arginine a Potential Alternative in PKG II Activation? AB - BACKGROUND The mammalian cyclic guanosine monophosphate (cGMP)-dependent protein kinases type II (PKG II) plays critical physiological or pathological functions in different tissues. However, the biological effects of PKG II are dependent on cGMP. Published data indicated that L-arginine (L-Arg) promoted NO production, NO can activate soluble guanylate cyclase (sGC), and catalyzes guanosine triphosphate (GTP) into cGMP, which suggested L-Arg could activate PKG II. Therefore, the present work was performed to address: (i) whether L-Arg could be a potential alternative in PKG II activation, and (ii) whether L-Arg also contributes to PKG II against cancer. MATERIAL AND METHODS Nude BALB/c mice were inoculated with human MCF-7, HepG2, and SW480 cell lines via subcutaneous (s.c.) injecting. After 7 days of inoculation, Ad-PKG II was injected into the cancer tissues every 4 days, and the next day 10 MUmol/mouse L-Arg was administered. Western blotting and immunohistochemistry were used to assess protein expression. RESULTS Our results demonstrated that L-Arg significantly activated PKG II and effectively ameliorated xenograft tumor development through inhibiting cancer growth, angiogenesis, and metastasis, which was partially dependent on blocking of epidermal growth factor receptor (EGFR) activity, as well as downstream signaling pathways such as Erk1/2. CONCLUSIONS Our results provide an exciting new insight: L-Arg is a potential alternative to PKG II activation. PMID- 29401207 TI - Making America great again requires acting on scientific knowledge. PMID- 29401208 TI - Conservation stories from the front lines. PMID- 29401209 TI - The Burden of Guardianship: A Matched Cohort Study. AB - BACKGROUND: In cases where patients are unable to provide informed consent and have no surrogate decisionmaker, a hospital must seek guardian appointment as a legally recognized surrogate decision-maker. OBJECTIVE: The aim of this study was to examine the magnitudes of length of stay (LOS) beyond medical clearance and healthcare costs among patients referred for guardianship. DESIGN, SETTING, PATIENTS: This was a retrospective cohort study of all 61 adult inpatients in a single tertiary care hospital requiring guardianship between October 1, 2014, and September 30, 2015, matched with up to 3 controls from the same discharging services and hospitalized for at least as long as the date of clearance for referred patients. MEASUREMENTS: The following parameters were measured using generalized estimating equations: total LOS, LOS beyond medical clearance (excess LOS), medical complications, and total charges among referred patients, and the LOS and costs were compared with those of matched controls. RESULTS: Mean LOS for patients requiring guardianship was 31 +/- 2 days, and the total charges averaged $179,243 +/- 22,950. We documented 12 hospital-acquired complications in 10 (16%; 95% confidence interval [CI], 8%-28%) unique patients. Accounting for potential confounders, the process of obtaining guardianship was associated with a 37% longer total LOS (95% CI [12%- 67%]; P = .002), 58% higher excess LOS (95% CI [2% 145%]; P = .04), and 23% higher total charges (95% CI [4%-46%]; P = .02). CONCLUSIONS: In this single-center cohort study, the guardianship process was associated with prolonged hospital stay and higher total hospital charges even when compared with matched controls. Furthermore, one in six patients suffered from a hospital-associated complication after medical clearance. PMID- 29401206 TI - Parallel trends in cortical gray and white matter architecture and connections in primates allow fine study of pathways in humans and reveal network disruptions in autism. AB - Noninvasive imaging and tractography methods have yielded information on broad communication networks but lack resolution to delineate intralaminar cortical and subcortical pathways in humans. An important unanswered question is whether we can use the wealth of precise information on pathways from monkeys to understand connections in humans. We addressed this question within a theoretical framework of systematic cortical variation and used identical high-resolution methods to compare the architecture of cortical gray matter and the white matter beneath, which gives rise to short- and long-distance pathways in humans and rhesus monkeys. We used the prefrontal cortex as a model system because of its key role in attention, emotions, and executive function, which are processes often affected in brain diseases. We found striking parallels and consistent trends in the gray and white matter architecture in humans and monkeys and between the architecture and actual connections mapped with neural tracers in rhesus monkeys and, by extension, in humans. Using the novel architectonic portrait as a base, we found significant changes in pathways between nearby prefrontal and distant areas in autism. Our findings reveal that a theoretical framework allows study of normal neural communication in humans at high resolution and specific disruptions in diverse psychiatric and neurodegenerative diseases. PMID- 29401210 TI - Evaluating the Benefits of Hospital Room Artwork for Patients Receiving Cancer Treatment: A Randomized Controlled Trial. AB - We examined whether placing a painting in the line of vision of a hospitalized patient improves patient outcomes and satisfaction and whether having patients choose their paintings offers greater benefit. From 2014 to 2016, we enrolled 186 inpatients with cancer diagnoses from Pennsylvania State University Cancer Institute and randomly assigned them to 3 groups: those who chose paintings displayed in rooms, those whose paintings were randomly selected, and those with no paintings. We assessed anxiety, mood, depression, quality of life, perceptions of hospital environment, sense of control and/or influence, self-reported pain, and length of stay and compared patients with paintings versus those without paintings, as well as those with an artwork choice versus those with no choice. There were no differences in psychological and/or clinical outcomes across the groups, but patients in the 2 groups with paintings reported significantly improved perceptions of the hospital environment. Integrating artwork into inpatient rooms may represent one means of improving perceptions of the institution. PMID- 29401211 TI - Shared Decision-Making During Inpatient Rounds: Opportunities for Improvement in Patient Engagement and Communication. AB - BACKGROUND: Shared decision-making (SDM) improves patient engagement and may improve outpatient health outcomes. Little is known about inpatient SDM. OBJECTIVE: To assess overall quality, provider behaviors, and contextual predictors of SDM during inpatient rounds on medicine and pediatrics hospitalist services. DESIGN: A 12-week, cross-sectional, single-blinded observational study of team SDM behaviors during rounds, followed by semistructured patient interviews. SETTING: Two large quaternary care academic medical centers. PARTICIPANTS: Thirty-five inpatient teams (18 medicine, 17 pediatrics) and 254 unique patient encounters (117 medicine, 137 pediatrics). INTERVENTION: Observational study. MEASUREMENTS: We used a 9-item Rochester Participatory Decision-Making Scale (RPAD) measured team-level SDM behaviors. Same-day interviews using a modified RPAD assessed patient perceptions of SDM. RESULTS: Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient's hospital stay, and amount of time rounding per patient (P < .05). The most frequently observed behaviors across all services included explaining the clinical issue and matching medical language to the patient's level of understanding. The least frequently observed behaviors included checking understanding of the patient's point of view, examining barriers to follow through, and asking if the patient has any questions. Patients and guardians had substantially higher ratings for SDM quality compared to peer observers (7.2 vs 4.4 out of 9). CONCLUSIONS: Important opportunities exist to improve inpatient SDM. Team size, number of learners, patient census, and type of decision being made did not affect SDM, suggesting that even large, busy services can perform SDM if properly trained. PMID- 29401212 TI - GEMMER: GEnome-wide tool for Multi-scale Modeling data Extraction and Representation for Saccharomyces cerevisiae. AB - Motivation: Multi-scale modeling of biological systems requires integration of various information about genes and proteins that are connected together in networks. Spatial, temporal and functional information is available; however, it is still a challenge to retrieve and explore this knowledge in an integrated, quick and user-friendly manner. Results: We present GEMMER (GEnome-wide tool for Multi-scale Modeling data Extraction and Representation), a web-based data integration tool that facilitates high quality visualization of physical, regulatory and genetic interactions between proteins/genes in Saccharomyces cerevisiae. GEMMER creates network visualizations that integrate information on function, temporal expression, localization and abundance from various existing databases. GEMMER supports modeling efforts by effortlessly gathering this information and providing convenient export options for images and their underlying data. Availability and implementation: GEMMER is freely available at http://gemmer.barberislab.com. Source code, written in Python, JavaScript library D3js, PHP and JSON, is freely available at https://github.com/barberislab/GEMMER. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29401213 TI - Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials. AB - Background: ATX-101 (deoxycholic acid injection) is the only injectable drug approved for submental fat (SMF) reduction. In the phase 3 REFINE trials, adults with moderate or severe SMF who were dissatisfied with the appearance of their face/chin were eligible to receive up to 6 treatment sessions with ATX-101 (2 mg/cm2) or placebo. Primary and secondary endpoints, evaluated at 12 weeks after last treatment, significantly favored ATX-101 supporting its efficacy for reducing SMF and the psychological impact of SMF, and increasing satisfaction with the appearance of the face/chin. Objectives: To evaluate the efficacy and safety of ATX-101 by treatment session. Methods: This post hoc analysis used pooled data from the REFINE trials to evaluate efficacy endpoints and adverse events following each treatment session to further characterize the ATX-101 treatment response and safety profile. Results: In both treatment groups, mean injection volume declined over subsequent treatment sessions, though more markedly in the ATX-101 group. The majority of ATX-101-treated patients achieved a >=1-grade improvement in SMF within 2 to 4 treatment sessions based on either clinician or patient assessment. Furthermore, 19.1% of ATX-101-treated patients (vs 3.9% of placebo-treated patients) received fewer than 6 treatment sessions owing to patient satisfaction with treatment or lack of sufficient SMF for further treatment. In both treatment groups, the incidence/severity of common injection-site adverse events declined over subsequent treatment sessions. Conclusions: Although up to 6 treatment sessions were permitted in the REFINE trials, most ATX-101-treated patients achieved an improvement in SMF within 2 to 4 treatment sessions. Level of Evidence: 3. PMID- 29401214 TI - The Influence of Paranasal Augmentation on the Measurement of the Nose for the Treatment of Midfacial Concavity. AB - Background: A concave midface with its associated deep nasolabial folds is more aesthetically displeasing than a convex midface. Midfacial concavity may be addressed with autologous tissue and implants. Objectives: The aim of this study was to determine the effect of paranasal augmentation on photogrammetric parameters. Methods: Between July 2013 and August 2016, 12 patients underwent paranasal augmentation to address midface concavity. Augmentation was performed with autologous rib cartilage, autologous mandibular bone, or preshaped porous polyethylene (PPE). All operations were performed through the upper gingivobuccal approach. Twelve patients who underwent malar reduction using the same approach acted as a control group to account for the influence of the approach on soft tissue change. Preoperative and postoperative measurements were made photogrammetrically. Results: The average follow-up period was 12.8 months (range, 5-30 months) for both groups. The mean thickness of augmentation grafts was 5.18 mm (range, 3-7 mm). Alar width and alar base width increased 4.84% (P = 0.01) and 7.66% (P = 0.01), respectively. The nasolabial angle increased from 97.2 degrees to 103.6 degrees and the columellar inclination increased from 116.0 degrees to 119.1 degrees but neither were statistically significant. Photogrammetric parameters did not change significantly in the control group. Partial wound dehiscence occurred in one case. There was greater postoperative increase in alar width (P = 0.020), alar base width (P = 0.024), and nasolabial angle (P = 0.033) in the experimental group compared to the control group. Conclusions: Paranasal augmentation using PPE or autologous material generates measurable soft tissue changes designed to enhance paranasal aesthetics. Level of Evidence 3: PMID- 29401215 TI - The Use of Poly-4-Hydroxybutyrate (P4HB) Scaffold in the Ptotic Breast: A Multicenter Clinical Study. AB - Background: Mastopexy and reduction mammaplasty are often limited by the patient's poor native soft tissue quality, resulting in ptosis recurrence and loss of rejuvenated surgical results. Surgical scaffolds and acellular dermal matrices are used in these procedures to provide physical and mechanical stabilization of weakened or compromised tissue. GalaFLEX scaffold, made from poly-4-hydroxybutyrate (P4HB), is a next-generation product for soft tissue reinforcement that resorbs gradually while aiding tissue regeneration to achieve excellent outcomes. Objectives: To assess the clinical performance of GalaFLEX scaffold in soft tissue reinforcement during elective mastopexy and reduction mammaplasty. Methods: This multicenter, single-arm, observational study assessed product performance and outcomes of GalaFLEX scaffold when used in breast surgery. Outcomes included ptosis correction and maintenance, associated adverse events, patient and surgeon satisfaction, and mammographic and ultrasound imaging evaluation. Results: At 6 centers in the US, 62 of 69 enrolled patients were treated. Of this population, 89.7% had successful ptosis correction and maintenance at 1 year, with high patient and surgeon satisfaction for breast shape, droop/sag of the breast, and maintenance of results at 1 year. There were 5 adverse events deemed related to the device (8.0%), including nerve pain, breast swelling, ptosis, and 2 instances of asymmetry. Conclusions: GalaFLEX scaffold safely and successfully supports and elevates breast tissue in mastopexy and reduction mammaplasty, with maintained support at 1 year. Surgeon and patient satisfaction were high. No mammogram or ultrasound interference was detected. Level of Evidence 4: PMID- 29401216 TI - Commentary on: The Influence of Paranasal Augmentation on the Measurement of the Nose for the Treatment of Midfacial Concavity. PMID- 29401217 TI - Inferring and analyzing module-specific lncRNA-mRNA causal regulatory networks in human cancer. AB - It is known that noncoding RNAs (ncRNAs) cover ~98% of the transcriptome, but do not encode proteins. Among ncRNAs, long noncoding RNAs (lncRNAs) are a large and diverse class of RNA molecules, and are thought to be a gold mine of potential oncogenes, anti-oncogenes and new biomarkers. Although only a minority of lncRNAs is functionally characterized, it is clear that they are important regulators to modulate gene expression and involve in many biological functions. To reveal the functions and regulatory mechanisms of lncRNAs, it is vital to understand how lncRNAs regulate their target genes for implementing specific biological functions. In this article, we review the computational methods for inferring lncRNA-mRNA interactions and the third-party databases of storing lncRNA-mRNA regulatory relationships. We have found that the existing methods are based on statistical correlations between the gene expression levels of lncRNAs and mRNAs, and may not reveal gene regulatory relationships which are causal relationships. Moreover, these methods do not consider the modularity of lncRNA-mRNA regulatory networks, and thus, the networks identified are not module-specific. To address the above two issues, we propose a novel method, MSLCRN, to infer and analyze module-specific lncRNA-mRNA causal regulatory networks. We have applied it into glioblastoma multiforme, lung squamous cell carcinoma, ovarian cancer and prostate cancer, respectively. The experimental results show that MSLCRN, as an expression-based method, could be a useful complementary method to study lncRNA regulations. PMID- 29401218 TI - MutHTP: mutations in human transmembrane proteins. AB - Motivation: Existing sources of experimental mutation data do not consider the structural environment of amino acid substitutions and distinguish between soluble and membrane proteins. They also suffer from a number of further limitations, including data redundancy, lack of disease classification, incompatible information content, and ambiguous annotations (e.g. the same mutation being annotated as disease and benign). Results: We have developed a novel database, MutHTP, which contains information on 183 395 disease-associated and 17 827 neutral mutations in human transmembrane proteins. For each mutation site MutHTP provides a description of its location with respect to the membrane protein topology, structural environment (if available) and functional features. Comprehensive visualization, search, display and download options are available. Availability and implementation: The database is publicly available at http://www.iitm.ac.in/bioinfo/MutHTP/. The website is implemented using HTML, PHP and javascript and supports recent versions of all major browsers, such as Firefox, Chrome and Opera. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29401219 TI - Older Adults' Utilization of Community Resources Targeting Fall Prevention and Physical Activity. AB - Background and Objectives: Despite the availability of community resources, fall and inactivity rates remain high among older adults. Thus, in this article, we describe older adults' self-reported awareness and use of community resources targeting fall prevention and physical activity. Research Design and Methods: In depth, semistructured interviews were conducted in Phase 1 with community center leaders (n = 5) and adults (n = 16) >=70 years old whose experience with community programs varied. In Phase 2, surveys were administered to intervention study participants (n = 102) who were >=70 years old, did not have a diagnosis of dementia, and reported low levels of physical activity. Results: Four themes emerged from Phase 1 data: (a) identifying a broad range of local community resources; (b) learning from trusted sources; (c) the dynamic gap between awareness and use of community resources; and (d) using internal resources to avoid falls. Phase 2 data confirmed these themes; enabled the categorization of similar participant-identified resources (10); and showed that participants who received encouragement to increase community resource use, compared to those who did not, had significantly greater odds of using >=1 resource immediately postintervention, but not 6 months' postintervention. Discussion and Implications: Although participants in this study were aware of a broad range of local community resources for physical activity, they used resources that support walking most frequently. Additionally, receiving encouragement to use community resources had short-term effects only. Findings improve our understanding of resources that need bolstering or better dissemination and suggest researchers identify best promotion, dissemination, implementation strategies. PMID- 29401220 TI - Differences in Mental, Cognitive, and Functional Health by Sexual Orientation Among Older Women: Analysis of the 2015 Behavioral Risk Factor Surveillance System. AB - Background and Objectives: This study addresses a gap in the knowledge base regarding whether there are differences in mental, cognitive, and functional health between sexual minority women aged 65 and older and their heterosexual counterparts, as well as whether disparities are moderated by age, socioeconomic status, and race/ethnicity. Research Design and Methods: This study analyzes 2015 Behavioral Risk Factor Surveillance System data from 21 states. Multivariate logistic regression is used to test the hypotheses. Results: Compared to heterosexual women, lesbian/gay women aged 65 and older report worse functional health and bisexual women report worse cognitive health and more difficulties with instrumental activities of daily living. Disparities are particularly present for women in their late 60s and those in their 70s. While the likelihood of a depression diagnosis tends to be lower for heterosexual women with higher income, the inverse is true of sexual minority women. Additionally, sexual minority women with less education have lower odds of frequent mental distress and activity limitations than those with some college education. Sexual minority women of color have significantly lower odds of frequent mental distress, activity limitations, and use of special equipment compared to white sexual minority women. Discussion and Implications: Findings indicate a need for gerontological services that provide support to older sexual minority women, particularly in relation to cognitive and functional health. Future research is needed to understand risk and protective factors contributing to these disparities, including forms of resilience that occur among older sexual minority women of color. PMID- 29401221 TI - Measuring Awareness of Age-Related Change: Development of a 10-Item Short Form for Use in Large-Scale Surveys. AB - Background and Objectives: Existing measures of subjective aging have been useful in predicting developmental outcomes. Unlike other constructs of subjective aging, Awareness of Age-Related Change (AARC) focuses on how adults' self perceptions of aging result in an awareness of age-related gains and losses. We developed a 10-item short form (SF) of the existing 50-item AARC questionnaire as a reliable, valid, and parsimonious solution for use primarily in large-scale surveys but also in applied contexts. Research Design and Methods: AARC was assessed in a German and North American sample of 819 individuals. Item selection for the suggested AARC-10 SF was based on multidimensional item response theory (MIRT). Multi-group confirmatory factor analysis (CFA) was used to test for measurement invariance (MI) across groups of participants in middle age (40-69 years), early old age (70-79 years), and advanced age (80+ years). Concurrent and discriminant validity in old age was assessed with regard to established measures of subjective aging, well-being, and health. Results: The AARC-10 SF showed adequate fit to the data and reliability for the perceived gains and losses composites. Valid comparison of latent means was confirmed for early old and advanced age respondents and with some reservation also for middle-aged individuals due to partial MI. Concurrent and discriminant validity were confirmed. Discussion and Implications: The proposed AARC-10 SF offers an economic device to measure AARC and use the construct as an antecedent or outcome in the context of substantive model testing in large-scale survey data. PMID- 29401222 TI - Older Coresearchers Exploring Age-Friendly Communities: An "Insider" Perspective on the Benefits and Challenges of Peer-Research. AB - Background and Objectives: A growing body of work suggests that co- or peer research may contribute to understanding the complex health and social problems experienced in later life. Yet, only a limited number of studies have involved older persons as partners in the research process. Moreover, in conflict with the philosophy of participatory research, the views of those acting as coresearchers tend to be ignored. This paper gives an "insider" account of the process of coresearch, drawing upon the experiences of older people trained to undertake a community-based research project. Research Design and Methods: Eighteen older adults were recruited and trained as coresearchers to take a leading role in a study aimed at developing "age-friendly" communities in Manchester, UK. The coresearchers completed 68 interviews with residents aged 60 years and over who were experiencing isolation within their neighborhood. The findings are based upon four reflection meetings held with the coresearchers, all of which were transcribed with thematic analysis conducted using Atlas.ti. Results: Coresearchers identified a range of advantages associated with the coresearch approach, these linked to the recruitment of participants, quality of data, potential for social change as well as personal benefits. They also identified ethical, methodological, and practical issues encountered during the research. Discussion and Implications: The study demonstrates the contribution of coresearch for expanding methodological diversity, accessing seldom heard populations, and utilizing the skills and resources of older people. The research also highlights the opportunities for partnerships between older people and local stakeholders to facilitate community change and social action. PMID- 29401223 TI - Global tobacco control and economic norms: an analysis of normative commitments in Kenya, Malawi and Zambia. AB - Tobacco control norms have gained momentum over the past decade. To date 43 of 47 Sub-Saharan African countries are party to the Framework Convention on Tobacco Control (FCTC). The near universal adoption of the FCTC illustrates the increasing strength of these norms, although the level of commitment to implement the provisions varies widely. However, tobacco control is enmeshed in a web of international norms that has bearing on how governments implement and strengthen tobacco control measures. Given that economic arguments in favor of tobacco production remain a prominent barrier to tobacco control efforts, there is a continued need to examine how economic sectors frame and mobilize their policy commitments to tobacco production. This study explores the proposition that divergence of international norms fosters policy divergence within governments. This study was conducted in three African countries: Kenya, Malawi, and Zambia. These countries represent a continuum of tobacco control policy, whereby Kenya is one of the most advanced countries in Africa in this respect, whereas Malawi is one of the few countries that is not a party to the FCTC and has implemented few measures. We conducted 55 key informant interviews (Zambia = 23; Kenya = 17; Malawi = 15). Data analysis involved deductive coding of interview transcripts and notes to identify reference to international norms (i.e. commitments, agreements, institutions), coupled with an inductive analysis that sought to interpret the meaning participants ascribe to these norms. Our analysis suggests that commitments to tobacco control have yet to penetrate non-health sectors, who perceive tobacco control as largely in conflict with international economic norms. The reasons for this perceived conflict seems to include: (1) an entrenched and narrow conceptualization of economic development norms, (2) the power of economic interests to shape policy discourses, and (3) a structural divide between sectors in the form of bureaucratic silos. PMID- 29401224 TI - Pumpkin as an Alternate Host Plant for Laboratory Colonies of Grape Mealybug. AB - The grape mealybug, Pseudococcus maritimus (Ehrhorn; Hemiptera: Pseudococcidae), is the primary vector of Grapevine Leafroll associated Viruses (GLRaVs) in Washington State vineyards. Rearing laboratory colonies of grape mealybug has proven difficult. Several host plants were tested to determine their suitability for use as an alternate host plants for laboratory colonies of grape mealybug. Of the plants tested, colonies of grape mealybug were successful on pumpkin (Cucurbita pepo cv 'Connecticut field') leaves and vines. Mealybugs were able to develop from the crawler stage, through developmental instars, and adults were able to reproduce viable offspring. To date this is the only successful study to raise grape mealybugs on a cucurbit. Pumpkin appears to be a viable alternate host plant for laboratory colonies of the grape mealybug. PMID- 29401225 TI - Reducing the period of data collection for intake and gain to improve response to selection for feed efficiency in beef cattle. AB - Shortening the period of recording individual feed intake may improve selection response for feed efficiency by increasing the number of cattle that can be recorded given facilities of fixed capacity. Individual DMI and ADG records of 3,462 steers and 2,869 heifers over the entire intake recording period (range 62 to 154 d; mean 83 d; DMI83 and ADG83, respectively), DMI and ADG for the first 42 d of the recording period (DMI42 and ADG42, respectively), and postweaning ADG based on the difference between weaning and yearling weights (PADG) were analyzed. Genetic correlations among DMI42 and DMI83, ADG42 and ADG83, ADG42 and PADG, and ADG83 and PADG were 0.995, 0.962, 0.852, and 0.822, respectively. Four objective functions [feed:gain ratio in steers (FGS) and heifers (FGH); residual gain (RG); and residual feed intake (RFI)] based on DMI83 and ADG83 were considered. Indices using DMI42 and ADG42 (I42); DMI42 and PADG (IPW); and DMI42, ADG42, and PADG (IALL) were developed. Accuracy of the 5 EBV, 4 objectives, and 12 objective * index combinations were computed for all 12,033 animals in the pedigree. Accuracies of indices (IA) were summarized for animals with accuracies for objectives (OA) of 0.25, 0.5, 0.75, and 1. For the RG objective and animals with OA of 0.75, indices I42, IPW, and IALL had IA of 0.63, 0.55, and 0.67, respectively. Differences in IA increased with increased emphasis on ADG83 in the objective. Differences in IA between I42 and IPW usually increased with OA. Relative efficiency (RE) of selection on 42-d tests compared with 83 d was computed based on differences in IA and selection intensities of 5%, 25%, 50%, and 75% under the 83-d scenario, assuming 65% more animals could be tested for 42 d. For 25% selected for the RG objective, and animals with OA of 0.75, indices I42, IPW, and IALL had RE of 1.02, 0.90, and 1.10, respectively. As % selected, OA, and emphasis on DMI increased, RE increased. Relative efficiency varied considerably according to assumptions. One-half of the scenarios considered had RE > 1.15 with a maximum of 2.02 and 77% RE > 1.0. A shorter period of recording DMI can improve selection response for feed efficiency. Selection for the efficiency objectives would not affect PADG. It will be most effective if ADG over the period coinciding with intake recording and ADG over a much longer period of time are simultaneously included in a multiple-trait genetic evaluation with DMI and used in a selection index for efficiency. PMID- 29401226 TI - Electron Beam-Induced Sterility and Inhibition of Ovarian Development in the Sakhalin Pine Longicorn, Monochamus saltuarius (Coleoptera: Cerambycidae). AB - The Sakhalin pine longicorn, Monochamus saltuarius (Gebler; Coleoptera: Cerambycidae), is an insect vector of the pine wilt nematode (PWN), Bursaphelenchus xylophilus (Steiner et Buhrer) Nickle, and is widely distributed in central Korea. M. saltuarius is a forest pest that seriously damages Pinus densiflora (Siebold et Zucc, Pinales: Pinaceae) and Pinus koraiensis (Siebold & Zucc, Pinales: Pinaceae) forests. We examined the effect of electron beam irradiation on the mating, DNA damage and ovarian development of M. saltuarius adults and sought to identify the optimal dose for sterilizing insects. When the adults were irradiated with electron beams, both females and males were completely sterile at 200 Gy. In a reciprocal crossing experiment between unirradiated and irradiated adults, the reproductive ability of wild adults was recovered by crossing with wild adults even after crossing previously with sterile adults. When a pair of unirradiated adults (?- * ?-) and 10 or 20 irradiated adults (?+ or ?+) were kept together, the control effect was as high as 80~90%. After electron beam irradiation at 200 Gy, the DNA of M. saltuarius adults was damaged, the ovarian development of female adults was inhibited, and the level of vitellogenin was significantly decreased compared with that in unirradiated female adults. These results suggest that pine wilt disease can be effectively controlled if a large number of sterilized M. saltuarius male adults are released into the field. PMID- 29401227 TI - Longevity of Fly Baits Exposed to Field Conditions. AB - Insecticidal fly baits are important tools for adult house fly, Musca domestica L. (Diptera: Muscidae), control, especially on animal operations. Two house fly baits, containing either cyantraniliprole or dinotefuran, were tested on a dairy farm for attractiveness over time compared to a sugar control. Sticky trap and bucket trap house fly catches were recorded for each bait type at 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, 72 h, and 168 h. After 1 wk of exposure to flies and field conditions, these 'aged' baits were tested against fresh baits for fly visitation in the field over 1 h. House flies from each bait type (aged and fresh) were collected and kept under laboratory conditions to assess mortality over 3 d. Average visitation of individual flies to each bait type (fresh) in the field was also evaluated. Sticky traps did not show significant fly catch differences among bait types over time, however bucket trap catches did show significant differences for cyantraniliprole bait and dinotefuran bait compared to sugar at 72 h and 168 h. No significant differences among fly visitation to aged or fresh baits were found. Fresh cyantraniliprole bait and dinotefuran bait resulted in greater fly mortality compared to controls, but not compared to aged toxic baits. Average house fly visitation time was greatest for sugar and cyantraniliprole bait. PMID- 29401228 TI - Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemoradiotherapy before surgery in patients with locally advanced rectal cancer: is it ready for primetime? PMID- 29401229 TI - TFL1-Like Proteins in Rice Antagonize Rice FT-Like Protein in Inflorescence Development by Competition for Complex Formation with 14-3-3 and FD. AB - Hd3a, a rice homolog of FLOWERING LOCUS T (FT), is a florigen that induces flowering. Hd3a forms a ternary 'florigen activation complex' (FAC) with 14-3-3 protein and OsFD1 transcription factor, a rice homolog of FD that induces transcription of OsMADS15, a rice homolog of APETALA1 (AP1), which leads to flowering. TERMINAL FLOWER 1 (TFL1) represses flowering and controls inflorescence architecture. However, the molecular basis for floral repression by TFL1 remains poorly understood. Here we show that RICE CENTRORADIALIS (RCN), rice TFL1-like proteins, compete with Hd3a for 14-3-3 binding. All four RCN genes are predominantly expressed in the vasculature, and RCN proteins are transported to the shoot apex to antagonize florigen activity and regulate inflorescence development. The antagonistic function of RCN to Hd3a is dependent on its 14-3-3 binding activity. Our results suggest a molecular basis for regulation of the balance between florigen FT and anti-florigen TFL1. PMID- 29401230 TI - Differential Age Effects of Transcranial Direct Current Stimulation on Associative Memory. AB - Objectives: Older adults experience associative memory deficits relative to younger adults (Old & Naveh-Benjamin, 2008). The aim of this study was to test the effect of transcranial direct current stimulation (tDCS) on face-name associative memory in older and younger adults. Method: Experimenters applied active (1.5 mA) or sham (0.1 mA) stimulation with the anode placed over the left dorsolateral prefrontal cortex (dlPFC) during a face-name encoding task, and measured both cued recall and recognition performance. Participants completed memory tests immediately after stimulation and after a 24-h delay to examine both immediate and delayed stimulation effects on memory. Results: Results showed improved face-name associative memory performance for both recall and recognition measures, but only for younger adults, whereas there was no difference between active and sham stimulation for older adults. For younger adults, stimulation induced memory improvements persisted after a 24-h delay, suggesting delayed effects of tDCS after a consolidation period. Discussion: Although effective in younger adults, these results suggest that older adults may be resistant to this intervention, at least under the stimulation parameters used in the current study. This finding is inconsistent with a commonly seen trend, where tDCS effects on cognition are larger in older than younger adults. PMID- 29401231 TI - Could We Harness Human Immunodeficiency Virus Antibodies to Monitor the Brain? PMID- 29401232 TI - The Relation Between Age and Three-Dimensional Wisdom: Variations by Wisdom Dimensions and Education. AB - Objectives: Curvilinear relations between age and wisdom have been found in prior research with its peak either in young adulthood or in midlife. This study tested whether the association between age and three-dimensional wisdom differed for the cognitive, reflective, and compassionate (affective) wisdom dimensions and whether the results varied by education. Method: OLS regression was used to analyze an online sample of 14,248 adults between the ages of 18 and 98 years (mean [M] = 36.46, standard deviation [SD] = 12.68) from four educational groups. Results: The relation between age and three-dimensional wisdom was curvilinear and varied in shape by wisdom dimensions and education. The association between age and wisdom followed an inverse U-curve with the peak at midlife and almost opposing shapes for the cognitive and compassionate dimensions and an intermediate shape for the reflective dimension. Education was positively related to wisdom and affected the shape of the relationships. Discussion: Because the association between age and wisdom appears to be curvilinear and varies by education, studies that test a linear association without separating the sample by education might arrive at the wrong conclusions. In general, education seems to promote the attainment of wisdom and also inoculate individuals against a decline in wisdom later in life. PMID- 29401233 TI - Recognition Memory Dysfunction Relates to Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly Impaired Older Adults. AB - Objectives: The current study examined recognition memory dysfunction and its neuroanatomical substrates in cognitively normal older adults and those diagnosed with mild cognitive impairment (MCI). Methods: Participants completed the Mnemonic Similarity Task, which provides simultaneous measures of recognition memory and mnemonic discrimination. They also underwent structural neuroimaging to assess volume of medial temporal cortex and hippocampal subfields. Results: As expected, individuals diagnosed with MCI had significantly worse recognition memory performance and reduced volume across medial temporal cortex and hippocampal subfields relative to cognitively normal older adults. After controlling for diagnostic group differences, however, recognition memory was significantly related to whole hippocampus volume, and to volume of the dentate gyrus/CA3 subfield in particular. Recognition memory was also related to mnemonic discrimination, a fundamental component of episodic memory that has previously been linked to dentate gyrus/CA3 structure and function. Discussion: Results reveal that hippocampal subfield volume is sensitive to individual differences in recognition memory in older adults independent of clinical diagnosis. This supports the notion that episodic memory declines along a continuum within this age group, not just between diagnostic groups. PMID- 29401234 TI - Expression of glucose transporters SLC2A1, SLC2A8, and SLC2A12 in different chicken muscles during ontogenesis. AB - Glucose transport into cells is the first limiting step for the regulation of glucose homeostasis. In mammals, it is mediated by a family of facilitative glucose transporters (GLUTs) (encoded by SLC2A* genes), with a constitutive role (GLUT1), or insulin-sensitive transporters (GLUT4, GLUT8, and GLUT12). Compared to mammals, the chicken shows high levels of glycemia and relative insensitivity to exogenous insulin. To date, only GLUT1, GLUT8, and GLUT12 have been described in chicken skeletal muscles but not fully characterized, whereas GLUT4 was reported as lacking. The aim of the present study was to determine the changes in the expression of the SLC2A1, SLC2A8, and SLC2A12 genes, encoding GLUT1, GLUT8, and GLUT12 proteins respectively, during ontogenesis and how the respective expression of these three genes is affected by the muscle type and the nutritional or insulin status of the bird (fed, fasted, or insulin immunoneutralized). SLC2A1 was mostly expressed in the glycolytic pectoralis major (PM) muscle during embryogenesis and 5 d posthatching while SLC2A8 was mainly expressed at hatching. SLC2A12 expression increased regularly from 12 d in ovo up to 5 d posthatching. In the mixed-type sartorius muscle, the expression of SLC2A1 and SLC2A8 remained unchanged, whereas that of SLC2A12 was gradually increased during early muscle development. The expression of SLC2A1 and SLC2A8 was greater in oxidative and oxidoglycolytic muscles than in glycolytic muscles. The expression of SLC2A12 differed considerably between muscles but not necessarily in relation to muscle contractile or metabolic type. The expression of SLC2A1, SLC2A8, and SLC2A12 was reduced by fasting and insulin immunoneutralization in the PM muscle, while in the leg muscles only SLC2A12 was impaired by insulin immunoneutralization. Our findings clearly indicate differential regulation of the expression of three major GLUTs in skeletal muscles, with some type-related features. They provide new insights to improve the understanding of the fine regulation of glucose utilization in chicken muscles. PMID- 29401235 TI - Arrhythmogenic response to isoproterenol testing vs. exercise testing in arrhythmogenic right ventricular cardiomyopathy patients. AB - Aims: To compare the arrhythmic response to isoproterenol and exercise testing in newly diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. Methods and results: We studied isoproterenol [continuous infusion (45 ug/min) for 3 min] and exercise testing (workload increased by 30 W every 3 min) performed in consecutive newly diagnosed ARVC patients. Both tests were evaluated with regard to the incidence of (i) polymorphic premature ventricular contractions (PVCs) and couplet(s) or (ii) sustained or non-sustained ventricular tachycardia (VT) with left bundle branch block [excluding right ventricular outflow tract VT]; and compared to a control group referred for the evaluation of PVCs without structural heart disease. Thirty-seven ARVC patients (63.5% male, age 38 +/- 16 years) were included. The maximal sinus rhythm heart rate achieved during isoproterenol testing was significantly lower compared to exercise testing (149 +/- 17 bpm vs. 166 +/- 19 bpm, P < 0.0001). However, the incidence of polymorphic ventricular arrhythmias was much higher during isoproterenol testing compared to exercise testing [33/37 (89.2%) vs. 16/37 (43.2%), P < 0.0001]. Interestingly, isoproterenol testing was arrhythmogenic in all 15 patients in whom baseline PVCs were reduced or suppressed during exercise testing. During both isoproterenol and exercise testing, control group presented a low incidence of ventricular arrhythmias compared to ARVC patients (8.1% vs. 89.2%, P < 0.0001 and 2.7% vs. 43.2%, P < 0.0001, respectively). Conclusions: The incidence of polymorphic ventricular arrhythmias is significantly higher during isoproterenol compared to exercise testing in newly diagnosed ARVC patients, suggesting its potential utility for the diagnosis. PMID- 29401236 TI - Conservation Below the Species Level: Suitable Evolutionarily Significant Units among Mountain Vipers (the Montivipera raddei complex) in Iran. AB - Northern and western mountains of Iran are among the most important biodiversity and endemism hot spots for reptiles in the Middle East. Among herpetofauna, the montivipers represent an emblematic and fragmented endemic group for which estimating their level of genetic differentiation and defining conservation priorities is urgently needed. Here, we present the most comprehensive phylogenetic study on the Montivipera raddei species group comprising all 5 known taxa, among which 3 are endemic to Iran. Based on 2 mitochondrial genes, phylogenetic and phylogeographic analyses revealed 3 major lineages each presenting very contrasting distribution areas. The Iranian montivipers are highly structured in clades showing low genetic diversity and corresponding to high altitude summits. Molecular dating revealed the role of Quaternary paleo climatic oscillations and altitudinal movements of montivipers in shaping genetic diversity and differentiation of these sky-island taxa. In addition, the best scenario of historical biogeography allowed identifying 3 possible refugial areas in Iran most likely arising by vicariance. Based on our mitochondrial results and pending additional data, we recognize 3 candidate species among the M. raddei complex: M. raddei, Montivipera latifii, and Montivipera kuhrangica that are coherent with their geographical distribution. We propose that the most appropriate evolutionary significant units for conservation of the montivipers are represented by 13 units among which 6 are recognized as high priority. Finally, we suggest some recommendations to the IUCN as well as to the Iranian conservation policies with respect to conservation prioritization. PMID- 29401237 TI - Pre-emptive glottic enlargement before laryngotracheal surgery in patients at high risk for postoperative bilateral vocal fold paralysis. AB - OBJECTIVES: Bilateral vocal fold paralysis (VFP) is a severe complication after laryngotracheal (LT) surgery. The reduced glottic opening leads to significant respiratory distress immediately after the operation and requires the placement of a tracheostomy in most cases. Patients with a pre-existing unilateral VFP or expected recurrent nerve resection are at the highest risk for glottic failure. These patients might benefit from a pre-emptive glottic enlargement before LT surgery. METHODS: We performed a retrospective review of patients who received a pre-emptive glottis enlargement before LT surgery at the Medical University of Vienna from October 2011 to December 2016. Peri- and postoperative outcomes of this strategy were analysed. RESULTS: Six patients underwent preparatory glottic enlargement prior to LT resection. Four patients had recurrent thyroid cancer, and 1 patient had thymic cancer invading the cervical airway. The remaining patient had a complex benign glotto/subglottic stricture complicated by a pre existing bilateral VFP. All patients received oblique cricotracheal resections extending into the larynx [resection length 39 +/- 7 mm (mean +/- SD)]. Extubation within 24 h after surgery was achieved in 5 of 6 cases, although all patients had postoperative unilateral (n = 5) or bilateral (n = 1) VFP as anticipated. In 5 of the 6 patients, oral intake could be started immediately after the operation. The remaining patient regained full swallowing function after intensive swallowing rehabilitation. Postoperative voice quality was subjectively perceived as satisfactory by all patients. CONCLUSIONS: Pre-emptive glottic enlargement is a valuable treatment strategy in patients at highest risk for postoperative bilateral VFP. It facilitates immediate postoperative extubation, despite at least unilateral VFP and extensive LT surgical procedures. PMID- 29401238 TI - Maneuvering Together, Apart, and at Odds: Residents' Care Convoys in Assisted Living. AB - Objectives: Frail and disabled individuals such as assisted living residents are embedded in "care convoys" comprised of paid and unpaid caregivers. We sought to learn how care convoys are configured and function in assisted living and understand how and why they vary and with what resident and caregiver outcomes. Method: We analyzed data from a qualitative study involving formal in-depth interviews, participant observation and informal interviewing, and record review. We prospectively studied 28 residents and 114 care convoy members drawn from four diverse assisted living communities over 2 years. Results: Care convoys involved family and friends who operated individually or shared responsibility, assisted living staff, and multiple external care workers. Residents and convoy members engaged in processes of "maneuvering together, apart, and at odds" as they negotiated the care landscape routinely and during health crises. Based on consensus levels, and the quality of collaboration and communication, we identified three main convoy types: cohesive, fragmented, and discordant. Discussion: Care convoys clearly shape care experiences and outcomes. Identifying strategies for establishing effective communication and collaboration practices and promoting convoy member consensus, particularly over time, is essential to the creation and maintenance of successful and supportive care partnerships. PMID- 29401240 TI - Long-term Associations Between Physical Frailty and Performance in Specific Cognitive Domains. AB - Objectives: No longitudinal epidemiological research has reported associations between physical frailty and performance in specific cognitive domains. Our aim was to investigate whether such associations existed in the absence of accompanying neurodegenerative disorders such as mild cognitive impairment (MCI) and dementia. Method: We addressed this issue in a population-based sample of 896 adults aged 70 years and older over 4 waves of data covering a 12-year period. Physical frailty was assessed and a cognitive battery included measures of processing speed, verbal fluency, face and word recognition, episodic memory and simple and choice reaction time (RT). Results: Latent growth models showed frailty was associated with poorer baseline performance in processing speed, verbal fluency, simple and choice RT, and choice intraindividual RT variability. However, no significant effects of frailty on slopes of cognition were observed, suggesting that frailty was not associated with cognitive decline. Importantly, when the models took possible dementia into account, significant effects were retained suggesting that differences were not associated with dementia-related neurodegenerative disorders. Discussion: The findings suggest that frailty related cognitive deficits may exist independently of mechanisms underpinning neurodegenerative disorders such as MCI and dementia. If confirmed, this finding suggests a new avenue for preventative and therapeutic interventions in clinical and public health contexts for older adults. PMID- 29401239 TI - Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. AB - Aims: Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Methods and results: We randomized patients with early persistent AF and mild-to moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P < 0.001) and statin use (111 [93%] vs. 61 [48%], P < 0.001). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers were not different. Cardiac rehabilitation was completed in 109 (92%) patients. Underlying conditions were more successfully treated in the intervention group. At 1 year, sinus rhythm was present in 89 (75%) patients in the intervention vs. 79 (63%) in the conventional group (odds ratio 1.765, lower limit of 95% confidence interval 1.021, P = 0.042). Conclusions: RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Trial Registration number: Clinicaltrials.gov NCT00877643. PMID- 29401241 TI - Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701). AB - Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4 87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819. PMID- 29401242 TI - Intergenerational Contact Predicts Attitudes Toward Older Adults Through Inclusion of the Outgroup in the Self. AB - Objectives: With our rapidly aging population, it is critical to understand biases toward older people and what can be done to reduce ageism. Intergenerational contact can improve attitudes towards older people, but the effect of inclusion of outgroups in the self (IOS) in the context of intergenerational contact remains unexplored. In addition, stereotypes of warmth and incompetence may be affected differently by contact experiences and have different roles in effecting change in ageist attitudes. Method: In this study, we modeled the relationships between intergenerational contact, IOS, and stereotypes of warmth and incompetence in predicting attitudes towards older adults in a young community sample (n = 302; 18-30-year olds). Results: We found that positive contact with one older adult reduced incompetence stereotypes both directly and through an increase in IOS, and both the increase in IOS and the decrease in incompetence stereotypes predicted better attitudes towards older adults. Incompetence stereotypes were a stronger predictor of age-related attitudes than warmth stereotypes. Discussion: This suggests that interventions aimed at improving ageist attitudes through intergenerational contact should focus primarily on disconfirming incompetence stereotypes instead of merely increasing warmth perceptions, which could be done in part by increasing cognitive overlap with older adults. PMID- 29401243 TI - Population structure of Streptococcus pneumoniae colonizing children before and after universal use of pneumococcal conjugate vaccines in Brazil: emergence and expansion of the MDR serotype 6C-CC386 lineage. AB - Objectives: To determine the population structure and change in drug resistance of pneumococci colonizing children before and after the introduction of the 10 valent and 13-valent pneumococcal conjugate vaccines (PCV10/13) in Brazil. Methods: We used MLST to analyse 256 pneumococcal isolates obtained from children aged <6 years before (2009-10; n = 125) and after (2014; n = 131) the introduction of the PCV10 and PCV13. Antimicrobial susceptibility and capsular types were previously determined. Results: We identified 97 different STs. Ninety (35.2%) isolates were related to international clones. The most frequent lineages were serogroup 6-CC724 (where CC stands for clonal complex) and the MDR serotype 6C-CC386 in the pre- and post-PCV10/13 periods, respectively. Penicillin-non susceptible pneumococci (PNSP) formed 24% and 38.9% of the pre- and post-PCV10/13 isolates, respectively (P = 0.01). In the pre-PCV10/13 period, serotype 14-ST156 was the predominant penicillin-non-susceptible lineage, but it was not detected in the post-PCV10/13 period. Serotype 14-ST156 and serotype 19A-ST320 complex isolates had the highest penicillin and ceftriaxone MICs in the pre- and post PCV10/13 periods, respectively. In turn, serotype 6C-CC386 comprised almost 30% of the PNSP and over 40% of the erythromycin-resistant isolates (MIC >256 mg/L) in the post-PCV10/13 period. Conclusions: Although PNSP strains were polyclonal, most resistant isolates belonged to a single genotype from each period. Higher erythromycin resistance prevalence (42%) in the post-PCV10/13 period was mainly attributed to MDR serotype 6C-CC386. Ongoing surveillance of pneumococcal clonal composition is important to evaluate PCV use outcomes and to identify factors other than PCVs that drive pneumococcal drug resistance evolution. PMID- 29401244 TI - Pneumonia in Ghana-a need to raise the profile. AB - Despite the high mortality, pneumonia retains a relatively low profile among researchers, funders and policymakers. Here we reflect on the problems and priorities of pneumonia in Ghana, briefly review the evidence base and reflect upon in-person discussions between Southampton-based authors MGH and JB and academic, clinical and policy colleagues in Ghana. The discussions took place in Accra in August 2017. PMID- 29401245 TI - A subarachnoid haemorrhage-specific outcome tool. AB - Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these scales in subarachnoid haemorrhage is hampered by well recognized limitations. We set out to develop and validate a new condition-specific subarachnoid haemorrhage outcome tool (SAHOT). Items addressing diverse aspects of the impact of subarachnoid haemorrhage were collected during focus groups involving patients, next-of-kin and multidisciplinary professionals involved in subarachnoid haemorrhage management. After a series of iterative revisions, the resultant questionnaire was applied to patients and their next-of-kin at 1, 3 and 6 months post-subarachnoid haemorrhage. Rasch methodology was used to finalize the structure of the questionnaire and explore the extent to which SAHOT scores met Rasch-based criteria of successful measurement. The SAHOT was further assessed using traditional scale evaluation techniques, and validated in a second separate subarachnoid haemorrhage patient cohort. The final SAHOT included 56 items dealing with cognitive, physical, and behavioural/psychological consequences of subarachnoid haemorrhage. Rasch analysis indicated the scale successfully measured functional outcome post-subarachnoid haemorrhage. Three item scoring categories produced the best scale performance. There was no evidence of differential item functioning between patients and next-of-kin. The SAHOT was found to be acceptable, have good convergent and divergent validity, good discrimination and excellent responsiveness. It was successfully validated in a second subarachnoid haemorrhage patient cohort. The SAHOT offers the first subarachnoid haemorrhage-specific scientifically robust outcome measure with potential utility in neurovascular clinical services and research studies. PMID- 29401246 TI - Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study. AB - Background: Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent antimitotic agent, monomethyl auristatin E, which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and methods: Platinum-resistant OC patients were randomized to receive LIFA [2.4 mg/kg, intravenously, every 3 weeks (Q3W)] or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary end point was progression-free survival (PFS) in intent-to-treat (ITT) and NaPi2b high patients. Results: Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 [95% confidence interval (95% CI), 0.46 1.31; P = 0.34] with a median PFS of 5.3 versus 3.1 months (LIFA versus PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40-1.26; P = 0.24) with a median PFS of 5.3 months versus 3.4 months (LIFA versus PLD arm, respectively) in NaPi2b-high patients. The objective response rate was 34% (95% CI, 22% to 49%, LIFA) versus 15% (95% CI, 7% to 28%, PLD) in the ITT population (P = 0.03), and 36% (95% CI, 22% to 52%, LIFA) versus 14% (95% CI, 6% to 27%, PLD) in NaPi2b-high patients (P = 0.02). Toxicities included grade >=3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA versus 2 (4%) PLD patients had grade >=2 neuropathy. Conclusion: LIFA Q3W was well tolerated and improved objective response rate with a modest, nonstatistically significant improvement of PFS compared with PLD in platinum-resistant OC. While the response rate for the monomethyl auristatin E-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADCs in OC. Clinical trials.gov: NCT01991210. PMID- 29401248 TI - Donation programme of returned medicines: role of donors and point of view of beneficiaries. AB - Background: Donation of returned medicines is a debated health policy issue as it is discouraged by WHO, but accepted in some countries. Methods: Lessons learned from a donation programme of returned medicines carried out in Europe were documented. Results: The donation programme we reviewed followed a strict protocol for collection, sorting and distribution of returned drugs, in order to avoid the major limitations associated with unused medicine donations. Over a period of 3 years, 23 145 boxes of medicines were donated to 14 organizations operating in Europe, Africa and Latin America. Conclusions: The donations covered about one-third of the volume of medicines used by beneficiary organizations. The programme helped to decrease expenditure by both patients and health facilities. PMID- 29401247 TI - Estimating optimal observational sampling frequency of behaviors for cattle fed high- and low-forage diets. AB - Video recordings of behavioral activities including eating, ruminating, drinking, standing, and lying were monitored to determine the minimum number of sampling days and sampling frequency required to obtain reliable estimates of these behaviors. Eight continental crossbred heifers, individually housed in a tie stall barn with total mixed ration provided once per day, were divided by BW into two blocks and assigned to each of the two dietary treatments in a crossover design: high-forage diet (HF, forage:concentrate ratio 70:30) and low-forage diet (LF, forage:concentrate ratio 30:70). The cows were monitored continuously using a digital video recording system for 6 d in each of the two periods and a trained observer manually recorded the behavioral activities by minute. Mean time spent performing each behavior for 6 d with instantaneous samples of 1 min was compared with those obtained using fewer sampling days (1, 2, 3, 4, and 5 d) and less frequent scanning (2, 3, 4, 5, 10, 15, 30, and 60 min) using linear regression analysis, and the minimum number of sampling days or frequency was determined. Diet did not affect the accuracy and precision of predicting behavior from video recordings of the cows. When sampling days and scanning intervals were combined, the minimum recommended sampling frequency for accurately estimating a specific set of behaviors of beef heifers in tie stalls was: eating, 2 d with 4-min intervals; ruminating, 3 d with 4-min intervals; drinking, 2 d with 3-min intervals; and standing and lying, 2 d with 15-min intervals. Increasing sampling frequency beyond these minimums further enhanced the accuracy and precision of predictions. The total time of each behavioral activity was different between cows fed HF and LF diets with eating, ruminating, total chewing, and standing of heifers fed the HF diet greater (P < 0.01), but the lying (P < 0.01) and drinking time (P = 0.028) of heifers fed the LF diet greater. Meal patterns were different (P < 0.05) between the treatments except when meal size (kg) was expressed as DM or OM intake. For rumination patterns, the mean or maximum bout length (min/bout) was greater, but the maximum or minimum length of time heifers took to ruminate after eating was lower for the HF diet. From a practical standpoint, it is recommended to use 3 days of observations scanned at an interval of 4 min to reliably estimate the behavior of cows. If the focus is only lying and standing time, then 2 days with 15 min intervals can be used. PMID- 29401250 TI - How a bite on the cheek of a 29-year-old female patient with Crohn's disease turned out to be tuberculosis. PMID- 29401249 TI - Cross-Generalization Profile to Orosensory Stimuli of Rats Conditioned to Avoid a High Fat/High Sugar Diet. AB - The orosensory characteristics of a diet play a role in its acceptance and rejection. The current study was designed to investigate the gustatory components that contribute to the intake of a palatable, high-energy diet (HE; 45% calories from fat, 17% calories from sucrose). Here, rats were conditioned to avoid HE diet by pairings with i.p. injections of LiCl to induce visceral malaise. Subsequently, the degree of generalization was tested to an array of taste compounds using a brief-access lick procedure (10-s trials, 30-min sessions). Compared to NaCl-injected controls, LiCl-injected rats suppressed licking response to 100% linoleic acid and 20% intralipid, and to a lesser extent 17% sucrose. There was more variability in the lick responses to sucrose among the LiCl-injected rats. Rats that tended to suppress licking responses to sucrose generalized this response to glucose, fructose and Na-saccharin but not to Polycose. In contrast, LiCl-injected rats did not significantly suppress lick responses to water, NaCl, citric acid, or quinine compared to controls rats. The brief access feature of this procedure, allows for behavioral measures when postingestive factors are minimized. These findings support a role for gustatory cues in the detection of high fat/high sugar diets. Furthermore, it appears that the fat component is a more salient orosensory feature of the HE diet. PMID- 29401251 TI - James T Willerson MD. PMID- 29401252 TI - Why do the Media report negative news about statins? PMID- 29401253 TI - Cardiac screening in Nepal. PMID- 29401254 TI - Ride to Barcelona. PMID- 29401255 TI - Beyond nitrogen metabolism: nitric oxide, cyclic-di-GMP and bacterial biofilms. AB - The nitrogen cycle pathways are responsible for the circulation of inorganic and organic N-containing molecules in nature. Among these pathways, those involving amino acids, N-oxides and in particular nitric oxide (NO) play strategic roles in the metabolism of microorganisms in natural environments and in host-pathogen interactions. Beyond their role in the N-cycle, amino acids and NO are also signalling molecules able to influence group behaviour in microorganisms and cell cell communication in multicellular organisms, including humans. In this minireview, we summarise the role of these compounds in the homeostasis of the bacterial communities called biofilms, commonly found in environmental, industrial and medical settings. Biofilms are difficult to eradicate since they are highly resistant to antimicrobials and to the host immune system. We highlight the effect of amino acids such as glutamate, glutamine and arginine and of NO on the signalling pathways involved in the metabolism of 3',5'-cyclic diguanylic acid (c-di-GMP), a master regulator of motility, attachment and group behaviour in bacteria. The study of the metabolic routes involving these N containing compounds represents an attractive topic to identify targets for biofilm control in both natural and medical settings. PMID- 29401257 TI - The key is in the air: transthoracic echocardiogram leading to diagnose emphysematous gastritis. PMID- 29401256 TI - SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment. AB - Background: Glioblastoma (GBM) is one of the most aggressive human brain tumors, with a median survival of 15-18 months. There is a desperate need to find novel therapeutic targets. Various receptor protein kinases have been identified as potential targets; however, response rates in clinical studies have been somewhat disappointing. Targeting the spleen tyrosine kinase (SYK), which acts downstream of a range of oncogenic receptors, may therefore show more promising results. Methods: Kinase expression of brain tumor samples including GBM and low-grade tumors were compared with normal brain and normal human astrocytes by microarray analysis. Furthermore, SYK, LYN, SLP76, and PLCG2 protein expressions were analyzed by immunohistochemistry, western blot, and immunofluorescence of additional GBM patient samples, murine glioma samples, and cell lines. SYK was then blocked chemically and genetically in vitro and in vivo in 2 different mouse models. Multiphoton intravital imaging and multicolor flow cytometry were performed in a syngeneic immunocompetent C57BL/6J mouse GL261 glioma model to study the effect of these inhibitors on the tumor microenvironment. Results: SYK, LYN, SLP76, and PLCG2 were found expressed in human and murine glioma samples and cell lines. SYK inhibition blocked proliferation, migration, and colony formation. Flow cytometric and multiphoton imaging imply that targeting SYK in vivo attenuated GBM tumor growth and invasiveness and reduced B and CD11b+ cell mobility and infiltration. Conclusions: Our data suggest that gliomas express a SYK signaling network important in glioma progression, inhibition of which results in reduced invasion with slower tumor progression. PMID- 29401258 TI - Olfactory Adaptation is Dependent on Route of Delivery. AB - Odorants are perceived orthonasally (nostrils) or retronasally (oral cavity). Prior research indicates route of delivery impacts odorant perception, pleasantness, and directed behaviors thus suggesting differential processing of olfactory information. Adaptation is a form of neural processing resulting in decreased perceived intensity of a stimulus following prolonged and continuous exposure. The present study objective was to determine whether route of delivery differentially impacts olfactory adaptation and whether cross-adaptation occurs between orthonasal and retronasal pathways. Linalool (12%) or vanillin (25%) were delivered orthonasally [6 L/min (LPM)] and retronasally (8 LPM) in air phase through a custom-built olfactometer. Perceived odorant intensity was collected every 5 min over 10-min exposure. Immediately following the exposure period, cross-adaptation was assessed by shunting the delivery of the odorant from the nostrils to the oral cavity, or vice versa. A control study was also completed in which subjects underwent the orthonasal adaptation protocol using stimulus concentrations matched to the intensity of restronasal stimuli (e.g., 1.5% linalool and 6.25% vanillin). Following orthonasal delivery of both high and low vanillin concentrations, results showed perceived intensity decreased significantly at 5 and 10 min. High concentrations of orthonasal linalool similarly decreased significantly whereas lower concentrations decreased but did not reach statistical significance. Linalool and vanillin delivered retronasally did not adapt as perceived intensity actually increased significantly following a 10-min exposure. In addition, evidence of cross-adaptation was not obvious following extended odorant exposure from either delivery pathway. This study suggests that olfactory processing may be affected by the route of odorant delivery. PMID- 29401260 TI - Intraspecies polymorphisms of Kluyveromyces marxianus strains from Yaghnob valley. AB - In this study, 29 strains of Kluyveromyces marxianus with peculiar genetic and phenotypic traits previously isolated from a fermented goat milk of Yaghnob valley were investigated for chromosome length polymorphism (CLP) by PFGE, adhesion properties and carbon usage by Biolog analysis. Obtained data showed that strains differed in terms of number and size of chromosome bands. The number of bands ranged from 5 to 7, suggesting a probable genome size from 1.4 to 2.6 Mb. Strains showed a certain level of cell surface hydrophobicity ranging from 32% to 77.7%. Strains were also tested for their ability to form a biofilm on polystyrene plates: planktonic cells ranged from 6.3 cfu/mL to 7.95 cfu/mL, while sessile from 7.11 cfu/mL to 8.6 cfu/mL. The strains able to adhere to polystyrene plates were also able to form a mature MAT. Biolog analysis revealed that almost all strains were able to use putrescine, malic acid, alpha-D lactose, phenylethylamine, beta-methyl D-gucoside and xylose; 5 strains were able to grow on cellobiose and 3 were able to catabolise alpha-ketobutyric. The obtained data highlighted a number of interesting features underlying the peculiar capacities of these strains for industrial applications. PMID- 29401259 TI - Structure of a human cap-dependent 48S translation pre-initiation complex. AB - Eukaryotic translation initiation is tightly regulated, requiring a set of conserved initiation factors (eIFs). Translation of a capped mRNA depends on the trimeric eIF4F complex and eIF4B to load the mRNA onto the 43S pre-initiation complex comprising 40S and initiation factors 1, 1A, 2, 3 and 5 as well as initiator-tRNA. Binding of the mRNA is followed by mRNA scanning in the 48S pre initiation complex, until a start codon is recognised. Here, we use a reconstituted system to prepare human 48S complexes assembled on capped mRNA in the presence of eIF4B and eIF4F. The highly purified h-48S complexes are used for cross-linking/mass spectrometry, revealing the protein interaction network in this complex. We report the electron cryo-microscopy structure of the h-48S complex at 6.3 A resolution. While the majority of eIF4B and eIF4F appear to be flexible with respect to the ribosome, additional density is detected at the entrance of the 40S mRNA channel which we attribute to the RNA-recognition motif of eIF4B. The eight core subunits of eIF3 are bound at the 40S solvent-exposed side, as well as the subunits eIF3d, eIF3b and eIF3i. elF2 and initiator-tRNA bound to the start codon are present at the 40S intersubunit side. This cryo-EM structure represents a molecular snap-shot revealing the h-48S complex following start codon recognition. PMID- 29401261 TI - The beta-Ketoacyl-CoA Synthase HvKCS1, Encoded by Cer-zh, Plays a Key Role in Synthesis of Barley Leaf Wax and Germination of Barley Powdery Mildew. AB - The cuticle coats the primary aerial surfaces of land plants. It consists of cutin and waxes, which provide protection against desiccation, pathogens and herbivores. Acyl cuticular waxes are synthesized via elongase complexes that extend fatty acyl precursors up to 38 carbons for downstream modification pathways. The leaves of 21 barley eceriferum (cer) mutants appear to have less or no epicuticular wax crystals, making these mutants excellent tools for identifying elongase and modification pathway biosynthetic genes. Positional cloning of the gene mutated in cer-zh identified an elongase component, beta ketoacyl-CoA synthase (CER-ZH/HvKCS1) that is one of 34 homologous KCSs encoded by the barley genome. The biochemical function of CER-ZH was deduced from wax and cutin analyses and by heterologous expression in yeast. Combined, these experiments revealed that CER-ZH/HvKCS1 has a substrate specificity for C16-C20, especially unsaturated, acyl chains, thus playing a major role in total acyl chain elongation for wax biosynthesis. The contribution of CER-ZH to water barrier properties of the cuticle and its influence on the germination of barley powdery mildew fungus were also assessed. PMID- 29401262 TI - Novel insights by 4D Flow imaging on aortic flow physiology after valve-sparing root replacement with or without neosinuses. AB - OBJECTIVES: This study was undertaken to evaluate the flow dynamics in the aortic root after valve-sparing root replacement with and without neosinuses of Valsalva reconstruction, by exploiting the capability of 4D Flow imaging to measure in vivo blood velocity fields and 3D geometric flow patterns. METHODS: Ten patients who underwent valve-sparing root replacement utilizing grafts with neosinuses or straight tube grafts (5 cases each) were evaluated by 4D Flow imaging at a mean of 46.5 months after surgery. We used in-house processing tools to quantify relevant bulk flow variables (flow rate, stroke volume, peak velocity and mean velocity), wall shear stresses and the amount of flow rotation characterizing the region enclosed by the graft and the aortic valve leaflets. RESULTS: Despite bulk flows with similar peak velocities, flow rates and stroke volumes (P = 0.31 1.00), the neosinuses graft was associated with a lower mean velocity (P < 0.03) and magnitude of wall shear stress along the axial direction of the vessel wall (P < 0.05) at the proximal root level but remained comparable along the circumferential direction (P = 0.22-1.0) to the straight tube graft. Flow rotation was evidently and systematically higher in the neosinuses grafts, characterized by streamline rotations higher than 270 degrees , nearly triple that of tubular grafts (10.3 / 14.0% of all aortic streamline vs 2.2 / 5.7%, P = 0.008). CONCLUSIONS: Recreation of the sinuses of Valsalva during valve-sparing root replacement is associated with significantly lower wall shear stress and organized vortical flows at the level of the sinus that are not evident using the straight tube graft. These findings need confirmation in larger studies and could have important implications in terms of aortic valve durability. PMID- 29401263 TI - Contractual health services performance agreements for responsive health systems: from conception to implementation in the case of Qatar. AB - Objective: Despite their use worldwide, strategy-based performance management is limited in the Eastern Mediterranean Region. This article explores Qatar's experience, the first from the Region, in implementing contractual agreements between healthcare providers and the regulator-Ministry of Public Health-to align strategy, performance and accountabilities. Design: mixed-methods including tools development and pilot-testing, guided by performance management cycle with a focus on knowledge translation and key principles: feasibility; mandatory participation; participatory approach through Steering Committee. Setting: All public, private and semi-governmental hospitals and primary healthcare centers. Intervention(s): (i) semi-structured interviews; (ii) review of 4982 indicators; (iii) Delphi technique for selecting indicators with > 80% agreement on importance and > 60% agreement on feasibility; (iv) capacity-building of providers and Ministry staff and 2-month pilot assessed by questionnaire with indicators scoring > 3 considered valid, reliable and feasible; and (v) 1-year grace period assessed by questionnaire. Main Outcome Measure(s): Approach strengths and challenges; Data collection and healthcare quality improvements. Results: Contracts mandate reporting 25 hospital and 15 primary healthcare indicators to the regulator, which delivers confidential benchmarking reports to providers. Scorecards were discussed with the regulator for evidence-informed policymaking. The approach uncovered system-related challenges and learning for public and private sectors: providers commended the participatory approach (82%) and indicated that contracts enabled collecting valid and timely data (64%) and improved healthcare quality (55%). Conclusion: This experience provides insights for countries implementing performance management, responsive regulation and public-private partnerships. It suggests that contractual agreements can be useful, despite their mandatory nature, if clear principles are applied early on. PMID- 29401264 TI - Stretch-induced compliance: a novel adaptive biological mechanism following acute cardiac load. AB - Aims: The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms. Methods and results: Left ventricles (LVs) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 min in all species and experimental preparations. Stretching by volume loading in volunteers and cardiac surgery patients resulted in E/E' and EDP decreases, respectively, after sustained stretching. Stretched samples had increased myocardial cGMP levels, increased phosphorylated vasodilator-stimulated phosphoprotein phosphorylation, as well as, increased titin phosphorylation, which was reduced by prior protein kinase G (PKG) inhibition (PKGi). Skinned cardiomyocytes from stretched and non-stretched myocardia were studied. Skinned cardiomyocytes from stretched hearts showed decreased PT, which was abrogated by protein phosphatase incubation; whereas those from non-stretched hearts decreased PT after PKG incubation. Pharmacological studies assessed the role of nitric oxide (NO) and natriuretic peptides (NPs). PT decay after stretching was significantly reduced by combined NP antagonism, NO synthase inhibition and NO scavenging, or by PKGi. Response to stretching was remarkably reduced in a rat model of LV hypertrophy, which also failed to increase titin phosphorylation. Conclusions: We describe and translate to human physiology a novel adaptive mechanism, partly mediated by titin phosphorylation through cGMP-PKG signalling, whereby myocardial compliance increases in response to acute stretching. This mechanism may not function in the hypertrophic heart. PMID- 29401265 TI - Preslaughter handling practices and their effects on animal welfare and pork quality. AB - At all times, prior to slaughter, pigs may experience stress from a range of handling practices, such as fasting, loading and transport, mixing, and interaction with humans. These factors can affect the welfare of pigs and carcass and meat quality, both individually and collectively. Preslaughter stress is both an animal welfare and a meat quality issue. Behavioral and physiological studies have revealed that poor handling practices at the farm, during transport and at the slaughter plant, have an adverse effect on pigs and may result in the loss of profits due to animal losses during transport and in lairage. Also, poor preslaughter handling can also lead to losses in carcass value as a result of reduced yield, the presence of lesions and bacterial contamination, and meat quality defects (e.g., pale, soft, exudative and dark, firm, dry pork). These economic losses can be limited by improving the design of facilities, controlling the environmental conditions, and implementing training programs for the correct animal handling at any stage preslaughter. The objective of this review was to review research findings on the effects of preslaughter practices on ante-mortem behavioral and physiological response in pigs, including muscle metabolism, and to provide recommendations aimed at limiting the impact of preslaughter handling on animal losses and pork quality. PMID- 29401266 TI - Randomized trial of the Carpentier-Edwards supra-annular prosthesis versus the Medtronic Mosaic aortic prosthesis: 10-year results. AB - OBJECTIVES: We performed a prospective randomized study comparing the clinical performance of the Carpentier-Edwards supra-annular valve (CE-SAV) (Edwards Lifesciences, Irvine, CA, USA) and the newer Mosaic (Medtronic Corporation, Minneapolis, MN, USA) porcine bioprostheses in the aortic position over a 10-year period. METHODS: Between January 2001 and March 2005, 394 patients undergoing bioprosthetic aortic valve replacement were randomized to receive either the CE SAV (n = 191) or the Mosaic (n = 203) prosthesis. The preoperative demographics, EuroSCORE and intraoperative characteristics concerning cardiopulmonary bypass of the 2 groups were comparable. All patients were followed annually for 10 years. RESULTS: There were 77 (40.3%) deaths in the CE-SAV group and 93 (45.8%) deaths in the Mosaic group. The 10-year survival rate in the 2 groups was 59.7% and 54.2%, respectively (P = 0.27). There were no statistically significant differences between the 2 groups in terms of structural valve deterioration (P = 0.08), endocarditis (P = 0.95), thromboembolism (P = 0.06) and major bleeds (P = 0.09). However, the incidence of paravalvular leaks and valve-related reoperations were higher in the Mosaic group, with 5 leaks and 6 reoperations when compared to none in the CE-SAV group, (P = 0.02) and (P = 0.01) respectively. CONCLUSIONS: At 10 years after implantation, freedom from reoperation was greater in the CE-SAV group with no incidences of paravalvular leaks. There were no other statistically significant differences between CE-SAV and Mosaic aortic prostheses. Clinical trial registration: clinicaltrial.gov ID 1301 (NCT03346044). PMID- 29401267 TI - Genomic insights into metabolic potentials of two simultaneous aerobic denitrification and phosphorus removal bacteria, Achromobacter sp. GAD3 and Agrobacterium sp. LAD9. AB - Bacteria capable of simultaneous aerobic denitrification and phosphorus removal (SADPR) are promising for the establishment of novel one-stage wastewater treatment systems. Nevertheless, insights into the metabolic potential of SADPR related bacteria are limited. Here, comprehensive metabolic models of two efficient SADPR bacteria, Achromobacter sp. GAD3 and Agrobacterium sp. LAD9, were obtained for the first time by high-throughput genome sequencing. With succinate as the preferred carbon source, both strains employed a complete TCA cycle as the major carbon metabolism for potentials of various organic acids and complex carbon oxidation. Complete and truncated aerobic denitrification routes were confirmed in GAD3 and LAD9, respectively, facilitated by all the major components of the electron transfer chain via oxidative phosphorylation. Comparative genome analysis revealed distinctive ecological niches involved in denitrification among different phylogenetic clades within Achromobacter and Agrobacterium. Excellent phosphorus removal capacities were contributed by inorganic phosphate uptake, polyphosphate synthesis and phosphonate metabolism. Additionally, the physiology of GAD3/LAD9 is different from that displayed by most available polyphosphate accumulating organisms, and reveals both strains to be more versatile, carrying out potentials for diverse organics degradation and outstanding SADPR capacity within a single organism. The functional exploration of SADPR bacteria broadens their significant prospects for application in concurrent aerobic carbon and nutrient removal. PMID- 29401268 TI - Voluntary intake and digestibility by sheep of alfalfa ensiled at different moisture concentrations following fertilization with dairy slurry. AB - Dairy slurry is used commonly as an animal-sourced fertilizer in agronomic production. However, residual effects of slurry application on intake and digestibility of alfalfa (Medicago sativa L.) silage from subsequent harvests are not well known. The objective of this study was to determine if moisture concentration of alfalfa silage and timing of dairy slurry application relative to subsequent harvest affected intake and digestibility by sheep. Katahdin crossbred ewes (n = 18; 48 +/- 5.3 kg) in mid-gestation were stratified by BW and allocated randomly in each of two periods to one of six treatments arranged in a two * three factorial arrangement. Treatments consisted of recommended (RM; 46.8%) or low (LM; 39.7%) moisture at baling after either no slurry application (NS), slurry application to stubble immediately after removal of the previous cutting (S0), or slurry application 14 d after removal of the previous cutting (S14). Silages were chopped through a commercial straw chopper, packed into plastic trash cans, and then offered to ewes within 4 d of chopping. Period 1 of the intake and digestion study consisted of a 14-d adaptation followed by a 7-d fecal collection period. Period 2 followed period 1 after a 4-d rest and consisted of an 11-d adaptation followed by 7 d of fecal collection. Ewes were housed individually in 1.4 * 4.3-m pens equipped with rubber mat flooring. Feces were swept from the floor twice daily, weighed, and dried at 50 degrees C. Ewes had ad libitum access to water and were offered chopped silage for a minimum of 10% refusal (DM). Blood samples were collected immediately prior to feeding, and 4 and 8 h after feeding on the day prior to the end of each period. Organic matter intake (g/kg BW) and OM digestibility tended (P < 0.10) to be, and digestible OM intake (g/kg BW) was reduced by slurry application. Lymphocytes (% of total white blood cells) were greater (P < 0.05) from LM vs. RM and from NS vs. S0 and S14. Red blood cell concentrations were greater (P < 0.05) from S14 vs. S0 and from S0 and S14 vs. NS. Serum urea N concentrations did not differ (P > 0.17) across treatments. Therefore, moisture concentration of alfalfa silage within the range used in this study may not affect voluntary intake or digestibility, but slurry application may have an effect on digestible OM intake. Also, moisture concentration of alfalfa silage and time of dairy slurry application may affect specific blood hemograms. PMID- 29401269 TI - Chronic hyperandrogenemia and western-style diet beginning at puberty reduces fertility and increases metabolic dysfunction during pregnancy in young adult, female macaques. AB - STUDY QUESTION: What are the impacts of elevated testosterone (T) and an obesogenic western-style diet (WSD), either independently or together, on fertility and metabolic adaptations of pregnancy in primates? SUMMARY ANSWER: Testosterone increases the time to achieve pregnancy, while a WSD reduces overall fertility, and the combination of testosterone and WSD additionally impairs glucose tolerance and causes pregnancy loss. WHAT IS KNOWN ALREADY: Both hyperandrogenemia and obesity are hallmarks of polycystic ovary syndrome, which is a leading cause of infertility among women worldwide. Female macaques receiving T and WSD beginning at puberty show increased metabolic, ovarian and uterine dysfunction in the non-pregnant state by 3 years of treatment. STUDY DESIGN, SIZE, DURATION: The same cohort of female rhesus macaques continued treatments from the time of puberty (2.5 years) to 4 years, including this fertility trial. There were four groups (n = 9-10/group): controls (C), T-treated (T; average total serum level 1.35 ng/ml), WSD-treated, and combined T and WSD treated (T + WSD) females. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females, which were typically having menstrual cycles, were paired for 4 days with a proven male breeder following the late follicular rise in circulating estradiol (>=100 pg/ml). The presence of sperm in the reproductive tract was used to confirm mating. Animals went through up to three successive rounds of mating until they became pregnant, as confirmed by a rise in circulating mCG during the late luteal phase and ultrasound evidence of a gestational sac at Day 30 post mating (GD30). Placental vascular parameters were also measured at GD30. Metabolic measurements consisted of fasting levels of blood glucose and insulin at approximately GD30, 60, 90 and 115, as well as an intravenous (iv) glucose tolerance test (GTT) at GD115. MAIN RESULTS AND THE ROLE OF CHANCE: While all animals in the C and T groups eventually became pregnant, T-treated females on average had a greater interval to achieve pregnancy (P < 0.05). However, only ~70% of animals in the WSD and T + WSD groups became pregnant (P < 0.004). One pregnancy in T + WSD group resulted in an anembryonic pregnancy which miscarried around GD60, while another T + WSD female conceived with a rare identical twin pregnancy which required cessation due to impending fetal loss at GD106. Thus, the number of viable fetuses was less in the T + WSD group, compared to C, T or WSD. Placental blood volume at GD30 was reduced in all treatments compared to the C group (P < 0.05). Maternal P4 levels were elevated in the WSD (P < 0.03) group and E2 levels were elevated in T + WSD animals (P < 0.05). An increase in serum A4 levels throughout gestation was observed in all groups (P < 0.03) except WSD (P = 0.3). All groups displayed increased insulin resistance with pregnancy, as measured from the ivGTT during pregnancy. However, only the T + WSD group had a significant increase in fasting glucose levels and glucose clearance during the GTT indicating a worsened glucose tolerance. WSD treatment decreased female fetuses third trimester weights, but there was an interaction between WSD and T to increase female fetal weight when normalized to maternal weight. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The small number of pregnancies in the WSD and T + WSD groups hampers the ability to make definitive conclusions on effects during gestation. Also, the high fertility rate in the controls indicates the cohort was at their breeding prime age, which may impair the ability to observe subtle fertility defects. The low number of fetuses used for male and female analysis requires additional studies. WIDER IMPLICATIONS OF THE FINDINGS: The current findings strongly suggest that both hyperandrogenemia and obesity have detrimental effects on fertility and gestation in primates, which may be directly relevant to women with polycystic ovary syndrome. STUDY FUNDING/COMPETING INTEREST(S): All ONPRC Cores and Units were supported by NIH Grant P51 OD011092 awarded to ONPRC. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to R.L.S.). The authors have no competing conflict of interests to disclose. PMID- 29401270 TI - Impact of Timing of Antiretroviral Treatment and Birth Weight on Mother-to-Child Human Immunodeficiency Virus Transmission: Findings From an 18-Month Prospective Cohort of a Nationally Representative Sample of Mother-Infant Pairs During the Transition From Option A to Option B+ in Zimbabwe. AB - Background: Preventing mother-to-child transmission of human immunodeficiency virus transmission (MTCT) depends on early initiation of antiretroviral therapy (ART). We report the 18-month MTCT risk during the transition from Option A to Option B+ in Zimbabwe, and assess whether ART preconception could eliminate MTCT in breastfeeding populations. Methods: In 2013, we consecutively recruited a nationally representative sample of 6051 infants aged 4-12 weeks and their mothers from 151 immunization clinics using a multistage stratified cluster sampling method. We identified 1172 human immunodeficiency virus (HIV)-exposed infants and evaluated them at baseline and every 3 months until the child became HIV-infected, died, or reached age 18 months. Results: The cumulative MTCT risk through 18 months postdelivery was 7.0%. Of the HIV-infected mothers, 35.3% started ART preconception, 28.9% during pregnancy, and 9.7% after delivery, and 16.0% received zidovudine during pregnancy. Compared to mothers without antiretroviral drug use, MTCT among those starting ART preconception and during pregnancy was lower by 88% (adjusted hazard ratio [aHR], 0.12; 95% confidence interval [CI], .06-.24) and 75% (aHR, 0.25; 95% CI, .14-.45), respectively. HIV exposed infants with birth weight <2.5 kg (low birth weight) were 2.6-fold more likely to acquire HIV infection compared to those with birth weight >=2.5 kg (aHR, 2.57; 95% CI, 1.44-4.59). Controlling for other factors, breastfeeding was not significantly associated with MTCT. Conclusions: ART preconception has the highest impact on reducing MTCT, indicating that HIV-infected, reproductive-age women should be prioritized in "treat-all" strategies. HIV-infected mothers without ART use should be identified at the first immunization visit and treatment initiated to reduce postdelivery MTCT. MTCT risk is higher in mothers with low-birth-weight deliveries. PMID- 29401271 TI - Evidence for Cross-species Influenza A Virus Transmission Within Swine Farms, China: A One Health, Prospective Cohort Study. AB - Background: Our understanding of influenza A virus transmission between humans and pigs is limited. Methods: Beginning in 2015, we used a One Health approach and serial sampling to prospectively study 299 swine workers and 100 controls, their 9000 pigs, and 6 pig farm environments in China for influenza A viruses (IAVs) using molecular, culture, and immunological techniques. Study participants were closely monitored for influenza-like illness (ILI) events. Results: Upon enrollment, swine workers had higher serum neutralizing antibody titers against swine H1N1 and higher nasal wash total immunoglobulin A (IgA) and specific IgA titers against swine H1N1 and H3N2 viruses. Over a period of 12 months, IAVs were detected by quantitative reverse-transcription polymerase chain reaction in 46 of 396 (11.6%) environmental swabs, 235 of 3300 (7.1%) pig oral secretion, 23 of 396 (5.8%) water, 20 of 396 (5.1%) aerosol, and 19 of 396 (4.8%) fecal-slurry specimens. Five of 32 (15.6%) participants with ILI events had nasopharyngeal swab specimens that were positive for IAV, and 17 (53.1%) demonstrated 4-fold rises in neutralization titers against a swine virus. Reassorted Eurasian avian lineage H1N1, A(H1N1)pdm09-like, and swine-lineage H3N2 viruses were identified in pig farms. The A(H1N1)pdm09-like H1N1 viruses identified in swine were nearly genetically identical to the human H1N1 viruses isolated from the participants with ILI. Conclusions: There was considerable evidence of A(H1N1)pdm09-like, swine-lineage H1N1, and swine-lineage H3N2 viruses circulating, likely reassorting, and likely crossing species within the pig farms. These data suggest that stronger surveillance for novel influenza virus emergence within swine farms is imperative. PMID- 29401273 TI - Low Risk of Primary Clostridium difficile Infection With Tetracyclines: A Systematic Review and Metaanalysis. AB - Background: The choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and metaanalysis of studies that assessed the risk of CDI with tetracyclines compared to other antibiotics. Methods: We conducted a systematic search of Medline, Embase, and Web of Science from January 1978 through December 2016 to include studies that assessed the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale. Results: Six studies (4 case control, 2 cohort) with patient recruitment between 1993 and 2012 were included. Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47-0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40-0.75; P < .001). Conclusions: Metaanalyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease CDI associated with antibiotic use. PMID- 29401272 TI - Identifying Immune Correlates of Protection Against Plasmodium falciparum Through a Novel Approach to Account for Heterogeneity in Malaria Exposure. AB - Background: A main criterion to identify malaria vaccine candidates is the proof that acquired immunity against them is associated with protection from disease. The age of the studied individuals, heterogeneous malaria exposure, and assumption of the maintenance of a baseline immune response can confound these associations. Methods: Immunoglobulin G/immunoglobulin M (IgG/ IgM) levels were measured by Luminex(r) in Mozambican children monitored for clinical malaria from birth until 3 years of age, together with functional antibodies. Studied candidates were pre-erythrocytic and erythrocytic antigens, including EBAs/PfRhs, MSPs, DBLs, and novel antigens merely or not previously studied in malaria exposed populations. Cox regression models were estimated at 9 and 24 months of age, accounting for heterogeneous malaria exposure or limiting follow-up according to the antibody's decay. Results: Associations of antibody responses with higher clinical malaria risk were avoided when accounting for heterogeneous malaria exposure or when limiting the follow-up time in the analyses. Associations with reduced risk of clinical malaria were found only at 24 months old, but not younger children, for IgG breadth and levels of IgG targeting EBA140III-V, CyRPA, DBL5epsilon and DBL3x, together with C1q-fixation activity by antibodies targeting MSP119. Conclusions: Malaria protection correlates were identified, only in children aged 24 months old when accounting for heterogeneous malaria exposure. These results highlight the relevance of considering age and malaria exposure, as well as the importance of not assuming the maintenance of a baseline immune response throughout the follow-up. Results may be misleading if these factors are not considered. PMID- 29401274 TI - Prevalence of Hypogammaglobulinemia in Adult Invasive Pneumococcal Disease. AB - Background: Patients with humoral immune deficiency are susceptible to invasive pneumococcal disease (IPD). This study estimates the prevalence of underlying hypogammaglobulinemia in admitted IPD cases and examines whether IPD cases had received preventative treatment. Methods: All adult IPD cases (Streptococcus pneumoniae in blood or cerebrospinal fluid) admitted to The Ottawa Hospital (TOH) from January 2013 to December 2015 were identified through the Eastern Ontario Regional Laboratory. Documented clinical demographics, S. pneumoniae serotype, serum immunoglobulins measured previously or in convalescence, and vaccination status of the cases were collected retrospectively for descriptive analyses. Results: There were 134 IPD in 133 patients (47.4% male; mean age 63, standard deviation [SD] = 15.6 years) during a 3-year observation period. All-cause mortality rate was 22.6% over a mean follow-up time of 362, SD = 345 days. Fifty seven patients (42.9%) had serum immunoglobulin levels measured. Eighteen were either found to have hypogammaglobulinemia in convalescence (8/18) or previously known to have hypogammaglobulinemia (10/18). None of the known hypogammaglobulinemic patients had received antibiotic prophylaxis and/or immunoglobulin replacement therapy within 4 months prior to IPD. The high and low estimates of prevalence of hypogammaglobulinemia were 31.6% (of all measured) and 13.5% (of all cases). Among 18 patients with hematological malignancies in our cohort, 13 had hypogammaglobulinemia. Many isolates were vaccine serotypes; however, only 8 had documented previous pneumococcal vaccination. Conclusions: IPD has high mortality, and hypogammaglobulinemia was present in at least 13.5% of IPD cases. Secondary hypogammaglobulinemia is especially common in cases with hematological malignancy and IPD. PMID- 29401275 TI - Primary Amebic Meningoencephalitis Associated With Rafting on an Artificial Whitewater River: Case Report and Environmental Investigation. AB - Background: Naegleria fowleri is a thermophilic ameba found in freshwater that causes primary amebic meningoencephalitis (PAM) when it enters the nose and migrates to the brain. Patient exposure to water containing the ameba typically occurs in warm freshwater lakes and ponds during recreational water activities. In June 2016, an 18-year-old woman died of PAM after traveling to North Carolina, where she participated in rafting on an artificial whitewater river. Methods: We conducted an epidemiologic and environmental investigation to determine the water exposure that led to the death of this patient. Results: The case patient's most probable water exposure occurred while rafting on an artificial whitewater river during which she was thrown out of the raft and submerged underwater. The approximately 11.5 million gallons of water in the whitewater facility were partially filtered, subjected to ultraviolet light treatment, and occasionally chlorinated. Heavy algal growth was noted. Eleven water-related samples were collected from the facility; all were positive for N. fowleri. Of 5 samples collected from the nearby natural river, 1 sediment sample was positive for N. fowleri. Conclusions: This investigation documents a novel exposure to an artificial whitewater river as the likely exposure causing PAM in this case. Conditions in the whitewater facility (warm, turbid water with little chlorine and heavy algal growth) rendered the water treatment ineffective and provided an ideal environment for N. fowleri to thrive. The combination of natural and engineered elements at the whitewater facility created a challenging environment to control the growth of N. fowleri. PMID- 29401277 TI - Polysaccharide Antibody Deficiency: Specific or General? PMID- 29401276 TI - Adult-Onset Recurrent Bacterial Meningitis: Immunological Red Herrings. PMID- 29401278 TI - Reply to Gilchrist et al. and to Musher. PMID- 29401282 TI - Effect of comprehensive smoke-free legislation on asthma and coronary disease trends in Spanish primary care patients. AB - Background: To examine the impact of comprehensive smoke-free legislation (SFL) (Law 42/2010) on the incidence and prevalence of adult asthma and coronary disease in primary health care (PHC) patients from three Spanish regions, overall and stratified by sex. Methods: Longitudinal observational study conducted between 2007 and 2013 in the population over 15 years of age assigned to 66 PHC teams in Catalonia, Navarre and the Balearic Islands. Crude rates and age standardized (truncated: asthma >= 16 years and coronary disease >= 35 years) incidence and prevalence rates using the direct method based on the European Standard Population were estimated based on data from PHC electronic health records. Joinpoint analysis was used to analyse the trends of age-standardized incidence and prevalence rates. Trends were expressed as annual percentage change and average annual percent change (AAPC). Results: The standardized asthma incidence rate showed a non-significant downward trend and the standardized prevalence rates rose significantly in the three regions. Standardized coronary disease incidence and prevalence rates were considerably higher for men than for women in all regions. The standardized coronary disease incidence rates in Catalonia (AAPC: -8.00%, 95% CI: -10.46; -5.47) and Navarre (AAPC: -3.66%, 95% CI: -4.95;-2.35) showed a significant downward trend from 2007 to 2013, overall and by sex. The standardized coronary disease prevalence trend rate increased significantly in the whole period in Catalonia and the Balearic Islands, although a non-significant downward trend was observed from 2010 in Catalonia. Conclusion: No changes in the trends of adult asthma and coronary disease in PHC Spanish patients were detected after the introduction of comprehensive SFL. PMID- 29401283 TI - Expansion of the 'Antibiotic Guardian' one health behavioural campaign across Europe to tackle antibiotic resistance: pilot phase and analysis of AMR knowledge. AB - Antimicrobial resistance (AMR) is a major public health threat. The UK Antibiotic Guardian (AG) behavioural change campaign developed to tackle AMR was expanded across Europe through translation into Russian, Dutch and French. Demographics and knowledge of AGs were analyzed between 01 November 2016 and 31 December 2016. A total of 367 pledges were received with the majority from the public and health care professionals. The pilot has significantly increased the proportion of pledges from Europe (excluding UK) (chi2 = 108.7, P < 0.001). AMR knowledge was greater in AGs (including the public) compared to the EU Eurobarometer survey. Further promotion across Europe is required to measure an impact on tackling AMR. PMID- 29401281 TI - Exogenous strigolactone interacts with abscisic acid-mediated accumulation of anthocyanins in grapevine berries. AB - Besides signalling to soil organisms, strigolactones (SLs) control above- and below-ground morphology, in particular shoot branching. Furthermore, SLs interact with stress responses, possibly thanks to a crosstalk with the abscisic acid (ABA) signal. In grapevine (Vitis vinifera L.), ABA drives the accumulation of anthocyanins over the ripening season. In this study, we investigated the effects of treatment with a synthetic strigolactone analogue, GR24, on anthocyanin accumulation in grape berries, in the presence or absence of exogenous ABA treatment. Experiments were performed both on severed, incubated berries, and on berries attached to the vine. Furthermore, we analysed the corresponding transcript concentrations of genes involved in anthocyanin biosynthesis, and in ABA biosynthesis, metabolism, and membrane transport. During the experiment time courses, berries showed the expected increase in soluble sugars and anthocyanins. GR24 treatment had no or little effect on anthocyanin accumulation, or on gene expression levels. Exogenous ABA treatment activated soluble sugar and anthocyanin accumulation, and enhanced expression of anthocyanin and ABA biosynthetic genes, and that of genes involved in ABA hydroxylation and membrane transport. Co-treatment of GR24 with ABA delayed anthocyanin accumulation, decreased expression of anthocyanin biosynthetic genes, and negatively affected ABA concentration. GR24 also enhanced the ABA-induced activation of ABA hydroxylase genes, while it down-regulated the ABA-induced activation of ABA transport genes. Our results show that GR24 affects the ABA-induced activation of anthocyanin biosynthesis in this non-climacteric fruit. We discuss possible mechanisms underlying this effect, and the potential role of SLs in ripening of non-ABA-treated berries. PMID- 29401284 TI - Urine mitochondrial DNA and diabetic nephropathy-a new frontier. PMID- 29401285 TI - Community structure explains antibiotic resistance gene dynamics over a temperature gradient in soil. AB - Soils are reservoirs of antibiotic resistance genes (ARGs), but environmental dynamics of ARGs are largely unknown. Long-term disturbances offer opportunities to examine microbiome responses at scales relevant for both ecological and evolutionary processes and can be insightful for studying ARGs. We examined ARGs in soils overlying the underground coal seam fire in Centralia, PA, which has been burning since 1962. As the fire progresses, previously hot soils can recover to ambient temperatures, which creates a gradient of fire impact. We examined metagenomes from surface soils along this gradient to examine ARGs using a gene targeted assembler. We targeted 35 clinically relevant ARGs and two horizontal gene transfer-related genes (intI and repA). We detected 17 ARGs in Centralia: AAC6-Ia, adeB, bla_A, bla_B, bla_C, cmlA, dfra12, intI, sul2, tetA, tetW, tetX, tolC, vanA, vanH, vanX and vanZ. The diversity and abundance of bla_A, bla_B, dfra12 and tolC decreased with soil temperature, and changes in ARGs were largely explained by changes in community structure. We observed sequence-specific biogeography along the temperature gradient and observed compositional shifts in bla_A, dfra12 and intI. These results suggest that increased temperatures can reduce soil ARGs but that this is largely due to a concomitant reduction in community-level diversity. PMID- 29401286 TI - Is single ovary a detrimental factor for live-birth rate in IVF? PMID- 29401287 TI - Opiate use in the Cath Lab. PMID- 29401288 TI - Describing the retention in care of human immunodeficiency virus-positive young adults who transition from adolescent to adult care. AB - Background: There is a high rate of lost to programme (LTP) in human immunodeficiency virus (HIV)-positive young adults transitioning from paediatric/adolescent to adult care. Methods: We describe and identify risk factors for LTP in all patients 18-23 y of age at the Infectious Diseases Institute (Kampala, Uganda) from 2010 to 2014. Results: A total of 260 of 907 young adults (28.6%) became LTP. Among those on antiretroviral treatment, 39.3% became LTP. We found that the only risk factor associated with LTP was being in World Health Organization stage 3 or 4. Conclusion: There is a need for tracing studies to evaluate the true vital status of LTP in this group. PMID- 29401289 TI - Isolation and Characterization of the Soybean Sg-3 Gene that is Involved in Genetic Variation in Sugar Chain Composition at the C-3 Position in Soyasaponins. AB - Soyasaponins are specialized metabolites present in soybean seeds that affect the taste and quality of soy-based foods. The composition of the sugar chains attached to the aglycone moiety of soyasaponins is regulated by genetic loci such as sg-1, sg-3 and sg-4. Here, we report the cloning and characterization of the Sg-3 gene, which is responsible for conjugating the terminal (third) glucose (Glc) at the C-3 sugar chain of soyasaponins. The gene Glyma.10G104700 is disabled in the sg-3 cultivar, 'Mikuriya-ao', due to the deletion of genomic DNA that results in the absence of a terminal Glc residue on the C-3 sugar chain. Sg 3 encodes a putative glycosyltransferase (UGT91H9), and its predicted protein sequence has a high homology with that of the product of GmSGT3 (Glyma.08G181000; UGT91H4), which conjugates rhamnose (Rha) to the third position of the C-3 sugar chain in vitro. A recombinant Glyma.10G104700 protein could utilize UDP-Glc as a substrate to conjugate the third Glc to the C-3 sugar chain, and introducing a functional Glyma.10G104700 transgene into the mutant complemented the sg-3 phenotype. Conversely, induction of a premature stop codon mutation in Glyma.10G104700 (W270*) resulted in the sg-3 phenotype, suggesting that Glyma.10G104700 was Sg-3. The gmsgt3 (R339H) mutant failed to accumulate soyasaponins with the third Rha at the C-3 sugar chain, and the third Glc and Rha conjugations were both disabled in the sg-3 gmsgt3 double mutant. These results demonstrated that Sg-3 and GmSGT3 are non-redundantly involved in conjugation of the third Glc and Rha at the C-3 sugar chain of soyasaponins, respectively. PMID- 29401290 TI - Standardized ileal digestible valine:lysine dose response effects in 25- to 45-kg pigs under commercial conditions. AB - Two experiments were conducted to estimate the standardized ileal digestible valine:lysine (SID Val:Lys) dose response effects in 25- to 45-kg pigs under commercial conditions. In experiment 1, a total of 1,134 gilts (PIC 337 * 1050), initially 31.2 kg +/- 2.0 kg body weight (BW; mean +/- SD) were used in a 19-d growth trial with 27 pigs per pen and seven pens per treatment. In experiment 2, a total of 2,100 gilts (PIC 327 * 1050), initially 25.4 +/- 1.9 kg BW were used in a 22-d growth trial with 25 pigs per pen and 12 pens per treatment. Treatments were blocked by initial BW in a randomized complete block design. In experiment 1, there were a total of six dietary treatments with SID Val at 59.0, 62.5, 65.9, 69.6, 73.0, and 75.5% of Lys and for experiment 2 there were a total of seven dietary treatments with SID Val at 57.0, 60.6, 63.9, 67.5, 71.1, 74.4, and 78.0% of Lys. Experimental diets were formulated to ensure that Lys was the second limiting amino acid throughout the experiments. Initially, linear mixed models were fitted to data from each experiment. Then, data from the two experiments were combined to estimate dose-responses using a broken-line linear ascending (BLL) model, broken-line quadratic ascending (BLQ) model, or quadratic polynomial (QP). Model fit was compared using Bayesian information criterion (BIC). In experiment 1, ADG increased linearly (P = 0.009) with increasing SID Val:Lys with no apparent significant impact on G:F. In experiment 2, ADG and ADFI increased in a quadratic manner (P < 0.002) with increasing SID Val:Lys whereas G:F increased linearly (P < 0.001). Overall, the best-fitting model for ADG was a QP, whereby the maximum mean ADG was estimated at a 73.0% (95% CI: [69.5, >78.0%]) SID Val:Lys. For G:F, the overall best-fitting model was a QP with maximum estimated mean G:F at 69.0% (95% CI: [64.0, >78.0]) SID Val:Lys ratio. However, 99% of the maximum mean performance for ADG and G:F were achieved at, 68% and 63% SID Val:Lys ratio, respectively. Therefore, the SID Val:Lys requirement ranged from73.0% for maximum ADG to 63.2% SID Val:Lys to achieve 99% of maximum G:F in 25- to 45-kg BW pigs. PMID- 29401291 TI - The influence of surfaces and interfaces on high spatial resolution vibrational EELS from SiO2. AB - High-resolution monochromated electron energy-loss spectroscopy has the potential to map vibrational modes at nanometer resolution. Using the SiO2/Si interface as a test case, we observe an initial drop in the SiO2 vibrational signal when the electron probe is 200 nm from the Si due to long-range nature of the Coulomb interaction. However, the distance from the interface at which the SiO2 integrated signal intensity drops to half its maximum value is 5 nm. We show that nanometer resolution is possible when selecting the SiO2/Si interface signal which is at a different energy position than the bulk signal. Calculations also show that, at 60 kV, the signal in the SiO2 can be treated non-relativistically (no retardation) while the signal in the Si, not surprisingly, is dominated by relativistic effects. For typical transmission electron microscope specimen thicknesses, surface coupling effects must also be considered. PMID- 29401292 TI - Asymmetric Auxin Distribution is Not Required to Establish Root Phototropism in Arabidopsis. AB - An asymmetric auxin distribution pattern is assumed to underlie the tropic responses of seed plants. It is unclear, however, whether this pattern is required for root negative phototropism. We here demonstrate that asymmetric auxin distribution is not required to establish root phototropism in Arabidopsis. Our detailed analyses of auxin reporter genes indicate that auxin accumulates on the irradiated side of roots in response to an incidental gravitropic stimulus caused by phototropic bending. Further, an agravitropic mutant showed a suppression of this accumulation with an enhancement of the phototropic response. In this context, our pharmacological and genetic analyses revealed that both polar auxin transport and auxin biosynthesis are critical for the establishment of root gravitropism, but not for root phototropism, and that defects in these processes actually enhance phototropic responses in roots. The auxin response factor double mutant arf7 arf19 and the auxin receptor mutant tir1 showed a slight reduction in phototropic curvatures in roots, suggesting that the transcriptional regulation by some specific ARF proteins and their regulators is at least partly involved in root phototropism. However, the auxin antagonist PEO IAA [alpha-(phenylethyl-2-one)-indole-3-acetic acid] suppressed root gravitropism and enhanced root phototropism, suggesting that the TIR1/AFB auxin receptors and ARF transcriptional factors play minor roles in root phototropism. Taken together, we conclude from our current data that the phototropic response in Arabidopsis roots is induced by an unknown mechanism that does not require asymmetric auxin distribution and that the Cholodny-Went hypothesis probably does not apply to root phototropism. PMID- 29401293 TI - Fruit and vegetable consumption and risk of endometriosis. AB - STUDY QUESTION: Is there an association between intake of fruits and vegetables and risk of laparoscopically confirmed endometriosis? SUMMARY ANSWER: Higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis. WHAT IS KNOWN ALREADY: Two case-control studies have examined the associations between fruit and vegetable intake and endometriosis risk with contrasting results. Diets rich in fruits and vegetables include higher levels of pro-vitamin A nutrients (alpha-carotene, beta-carotene, beta-cryptoxanthin) and women with endometriosis have been reported to have lower intake of vitamin A than women without endometriosis. STUDY DESIGN SIZE, DURATION: A prospective cohort study using data collected from 70 835 premenopausal women from 1991 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed with a validated food frequency questionnaire (FFQ) every 4 years. Cases were restricted to laparoscopically confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: During 840 012 person-years of follow-up, 2609 incident cases of laparoscopically confirmed endometriosis were reported (incidence rate = 311 per 100 000 person-years). We observed a non linear inverse association between higher fruit consumption and risk of laparoscopically confirmed endometriosis (Psignificance of the curve = 0.005). This inverse association was particularly evident for citrus fruits. Women consuming >=1 servings of citrus fruits/day had a 22% lower endometriosis risk (95% CI = 0.69-0.89; Ptrend = 0.004) compared to those consuming <1 serving/week. No association was observed between total vegetable intake and endometriosis risk. However, women consuming >=1 servings/day cruciferous vegetables had a 13% higher risk of endometriosis (95% CI = 0.95-1.34; Ptrend = 0.03) compared to those consuming <1 serving/week. Of the nutrients examined, only beta cryptoxanthin intake was significantly associated with lower endometriosis risk (RR fifth quintile = 0.88; 95% CI = 0.78-1.00; Ptrend = 0.02). LIMITATIONS REASONS FOR CAUTION: Some error in the self-reporting of dietary intake is expected, however, use of a validated FFQ and examining diet prospectively across multiple time points, make it unlikely that this non-differential misclassification strongly influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that a higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis, and beta cryptoxanthin in these foods may partially explain this association. In contrast to what we hypothesized, consumption of some vegetables increased endometriosis risk which may indicate a role of gastrointestinal symptoms in both the presentation and exacerbation of endometriosis-related pain; however, it is not clear what components of these foods might underlie the observed associations. Future studies examining dietary patterns that consider different combinations of food intake may help clarify these associations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants HD4854, HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and grant P30 DK046200 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Nurses' Health Study II is supported by the Public Health Service grant UM1 CA176726 from the National Cancer Institute, National Institutes of Health. HRH is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). No competing interests. TRIAL REGISTRATION NUMBER: n/a. PMID- 29401294 TI - The first 365 days on haemodialysis: variation in the haemodialysis access journey and its associated burden. AB - Background: The modality by which haemodialysis (HD) is delivered [arteriovenous fistula (AVF), arteriovenous graft (AVG) or central venous catheter (CVC)] varies widely and is influenced by clinical evidence, patient factors and the prevailing service configuration. The aim of this study was to determine the outcome and impact of access strategy on patient outcome by mapping out the HD journey in a cohort of incident patients. Methods: A 2-year cohort of consecutive incident HD patients from the point of referral for first dialysis access to completion of the first 365 days of HD was prospectively reviewed. Data were sought on access type; radiological, surgical and other access-related activity; bacteraemic events; admission rates and cumulative financial cost. Results: A total of 144 patients started RRT for the first time with HD over the 2-year period. All were followed up to 1 year after starting HD, generating a total of 47 753 observed HD days. Activity prior to starting HD for the full cohort was found to average 0.92 arteriovenous (AV) access creation procedures, 0.40 CVC insertions, 0.14 interventional radiology procedures and 0.41 ultrasound examinations per patient. The small number of patients who started on an AVG had a tendency towards higher pre-HD surgical and imaging activity than those who started on an AVF or CVC. Activity after starting HD varied greatly with the access type used at the start of HD, with AVF patients experiencing less hospitalization, procedure and imaging activity and financial costs compared with those who start HD with a CVC. Patients who started on an AVG had a tendency towards lower surgical activity rates and financial costs than those who started on a CVC. Conclusions: Providing, maintaining and dealing with the complications of HD vascular access places a significant burden of activity that is shared across nephrology, surgery and imaging services. A well-functioning AVF is associated with the lowest burden, whereas a failed AVF or CVC access is associated with the highest burden. Patient journeys are shaped by the vascular access that they use and we suggest that the contemporary pursuit of HD access should focus on delivering personalized access solutions. PMID- 29401295 TI - Aligning dynamic networks with DynaWAVE. PMID- 29401296 TI - Changes in keratin 8/18 expression in human granulosa cell lineage are associated to cell death/survival events: potential implications for the maintenance of the ovarian reserve. AB - STUDY QUESTION: Is keratin 8/18 (K8/K18) expression linked to cell death/survival events in the human granulosa cell lineage? SUMMARY ANSWER: A close association exists between changes in K8/K18 expression and cell death/survival events along the human granulosa cell lineage lifespan. WHAT IS KNOWN ALREADY: In addition to their structural and mechanical functions, K8/K18 play essential roles regulating cell death, survival and differentiation in several non-gonadal epithelial tissues. Transfection of the granulosa-like tumor KGN cells with siRNA to interfere KRT8 and KRT18 expression increases FAS-mediated apoptosis, while an inverse association between K8/K18 expression and cell death has been found in the bovine antral follicles and corpus luteum. Yet, only fragmentary and inconclusive information exists regarding K8/K18 expression in the human ovary. STUDY DESIGN, SIZE, DURATION: Expression of K8/K18 was assessed by immunohistochemistry at different stages of the granulosa cell lineage, from flattened granulosa cells in primordial follicles to fully luteinized granulosa lutein cells in the corpus luteum (including corpus luteum of pregnancy). PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemical detection of K8/K18 was conducted in 40 archival ovarian samples from women aged 17-39 years. K8/K18 expression was analyzed at the different stages of follicle development and corpus luteum lifespan. The proportions of primordial follicles showing all K8/K18-positive, all K8/K18 negative, or a mixture of K8/K18 negative and positive granulosa cells were quantified in 18 ovaries, divided into three age groups: <= 25 years (N = 6), 26-30 (N = 6) and 31-36 (N = 6) years. A total number of 1793 primordial, 750 transitional and 140 primary follicles were scored. MAIN RESULTS AND THE ROLE OF CHANCE: A close association was found between changes in K8/K18 expression and cell death/cell survival events in the human granulosa cell lineage. Large secondary and early antral follicles (most of them undergoing atresia) and regressing corpora lutea displayed low/absent K8/K18 expression. Conversely, early growing and some large antral follicles, functional menstrual corpora lutea, as well as life-extended corpus luteum of pregnancy, in which cell death was scarce, showed high K8/K18 expression. Three sub-populations of primordial follicles were observed with respect to the presence of K8/K18 in their flattened granulosa cells, ranging from primordial follicles showing only positive granulosa cells [P0(+)], to others with a mixture of positive and negative cells [P0(+/-)] or follicles with only negative cells [P0(-)]. Significant age-related changes were found in the proportions of the different primordial follicle types. In relation to age, a positive correlation was found for P0(+) primordial follicles (R2= 0.7883, N = 18; P < 0.001), while negative correlations were found for P0(+/-) (R2 = 0.6853, N = 18; P < 0.001) and P0(-) (R2 = 0.6725, N = 18; P < 0.001) follicles. Furthermore, an age-related shift towards greater keratin expression was found in P0(+/-) follicles (chi2 = 19.07, P < 0.05). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: This is a descriptive study. Hence, a cause-and-effect relationship between K8/K18 expression and cell death/survival cannot be directly established. WIDER IMPLICATIONS OF THE FINDINGS: This study describes, for the first time, the existence of sub-populations of primordial follicles on the basis of K8/K18 expression in granulosa cells, and that their proportions change with age. While a progressive increase in K8/K18 expression cannot be ruled out, our data are consistent with the hypothesis that primordial follicles expressing low levels of K8/K18 are preferentially ablated by follicle attrition, while primordial follicles showing high K8/K18 levels are those predominantly recruited into the growing pool. This suggests that K8/K18 expression could constitute a novel factor regulating primordial follicle death/survival, and raises the possibility that alterations of K8/K18 expression could be involved in the accelerated depletion of the ovarian reserve leading to premature ovarian insufficiency. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grants BFU2011 025021 and BFU2014-57581-P (Ministerio de Economia y Competitividad, Spain; co funded with EU funds from FEDER Program); project PIE14-00005 (Flexi-Met, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain); Projects P08-CVI 03788 and P12-FQM-01943 (Junta de Andalucia, Spain); and EU research contract DEER FP7-ENV-2007-1. CIBER Fisiopatologia de la Obesidad y Nutricion is an initiative of Instituto de Salud Carlos III. The authors have nothing to disclose in relation to the contents of this study. PMID- 29401297 TI - Long-term Outcome of Early Combined Immunosuppression Versus Conventional Management in Newly Diagnosed Crohn's Disease. AB - Background and Aims: Long-term outcomes of early combined immunosuppression [top down] compared to conventional management [step-up] in recently diagnosed Crohn's disease [CD] are unknown. We aimed to investigate long-term outcomes of participants of the Step-up/Top-down-trial. Methods: Trial participants' medical records were reviewed retrospectively. For 16 semesters following the 2-year trial, we recorded: clinical activity, medication use, flares, hospitalization, surgery and fistulas. Colonoscopy reports were scored as: endoscopic remission, aphthous/small ulcers or large ulcers. The primary endpoint was the proportion of semesters in remission. Results: Data were available from 119/133 patients [step up n = 60]. During a median follow-up of 8 years, clinical remission rates were similar (70% vs 73% [p = 0.85] in step-up and top-down patients, respectively). A shorter time to flare was observed in step-up patients [median five vs nine semesters, p = 0.01]. Cumulatively, 62% of step-up patients used corticosteroids compared to 41% of top-down patients [p = 0.02]. Anti-tumour necrosis factor [anti-TNF] use was higher in the step-up group [73% vs 54%, p = 0.04]. No differences were found in to time to CD hospitalization [respectively 13 vs 14 semesters, p = 0.30], new fistula [14 vs 15 semesters, p = 0.20] or CD surgery [14 vs 15 semesters, p = 0.25]. Mucosal healing 2 years after treatment was associated with a reduced anti-TNF use, but not with differences in other long term outcomes. Endoscopic remission occurred at similar rates between groups. Conclusions: Top-down treatment did not result in increased clinical remission during long-term follow-up, compared to step-up treatment. However, lower relapse rates and a reduced use of anti-TNF agents and corticosteroids were observed. No difference was found in rates of endoscopic remission, hospitalization, surgery or new fistulas. PMID- 29401299 TI - Cornelis (Kees) Franciscus Maria de Lange (1961-2016): a brief biography. PMID- 29401298 TI - The effects of nutrient restriction on mRNA expression of endogenous retroviruses, interferon-tau, and pregnancy-specific protein-B during the establishment of pregnancy in beef heifers. AB - We hypothesize that syncytin-Rum1, bovine endogenous retrovirus-K1 (BERV-K1), pregnancy-specific protein-B (PSP-B), and interferon-tau (IFN-tau) will be influenced by maternal nutrient restriction and be differentially expressed during key stages (day 16, 34, and 50) of the establishment of gestation when fed to meet industry standards. Commercial crossbred heifers (n = 49) were maintained on a total mixed ration and supplemented with dried distillers grains with solubles. All heifers were subjected to 5-d CO-Synch + CIDR estrus synchronization protocol. Non-pregnant, non-bred control (NP-NB) heifers (n = 6) were ovariohysterectomized on day 16, and the remaining heifers were AI to a single Angus sire (day of breeding = day 0). On the day of breeding, heifers were randomly assigned to dietary treatments. One half were assigned to control treatment (CON) targeted to gain 0.45 kg/d, and the remaining half were assigned to restricted treatment (RES), which received 60% of control diets. Heifers were subjected to ovariohysterectomy on day 16, 34, or 50 of gestation. Utero placental tissues were obtained from the uterine horn ipsilateral (P) and contralateral (NP) to the corpus luteum and separated into maternal caruncle (CAR), maternal endometrium, inter-caruncle, (ICAR), and fetal membrane (FM). There were no interactions between stage of gestation and nutritional treatment for syncytin-Rum1 or PSP-B (P > 0.22). Expression of BERV-K1 was influenced by a treatment * stage of gestation interaction (P = 0.03) in NP-CAR. On day 50, heifers fed the CON diet had greater BERV-K1 expression compared with CON heifers on day 16 and 34 and RES heifers at all sampling time points. There was a treatment * stage of gestation interaction (P < 0.01) for IFN-tau in FM tissue. On 16 d, mRNA expression of IFN-tau was greater (P < 0.01) compared with day 34 and 50 for both CON and RES heifers, but RES FM had greater (P < 0.01) IFN-tau expression compared with CON FM. In P-CAR, PSP-B expression increased (P < 0.01) by 18 000-fold on day 50 compared with NP-NB heifers. In P-ICAR, expression of syncytin-Rum1 in P-ICAR was greater (P = 0.01) on day 16 with a 14.14-fold increase compared with relative expression on day 34 and 50; whereas, PSP-B was increased (P < 0.01) on day 34 and 50 compared with day 16. In conclusion, 40% nutrient restriction had limited influence on mRNA of ERVs, PSP-B, and IFN-tau but stage of gestation differences reinforced the importance of these genes during the establishment of pregnancy. PMID- 29401300 TI - Short- and long-term effects of clinical pathway on the quality of surgical non small cell lung cancer care in China: an interrupted time series study. AB - Objective: To examine the short- and long-term effect of clinical pathway for non small cell lung cancer surgery on the length of stay, the compliance of quality indicators and risk-adjusted post-operative complication rate. Design: A retrospective quasi-experimental study from June 2011 to October 2015. Setting: A tertiary cancer hospital in China. Participants: Patients diagnosed as non-small cell lung cancer who underwent curative resection. Intervention(s): Clinical pathway was implemented at January 2013. Hence, the study period was divided into three periods: pre-pathway, from June 2011 to December 2012; short-term period, from January 2013 to December 2013; long-term period, from January 2014 to October 2015. Main Outcome Measure(s): Three length of hospital stay indicators, four process performance indicators and one outcome indicator. Results: ITS showed there was a significant decline of 2 days (P = 0.0421) for total length of stay and 2.23 days (P = 0.0199) for post-operative length of stay right after the implementation of clinical pathway. Short-term level changes were found in the compliance rate of required number of lymph node sampling (-8.08%, P = 0.0392), and risk-adjusted complication rate (9.02%, P = 0.0001). There were no statistically significant changes in other quality of care indicators. Conclusions: The clinical pathway had a positive impact on the length of stay but showed a transient negative effect on complication rate and the quality of lymph node sampling. PMID- 29401302 TI - A Gatekeeper Residue of ClpS1 from Arabidopsis thaliana Chloroplasts Determines its Affinity Towards Substrates of the Bacterial N-End Rule. AB - Proteins that are to be eliminated must be proficiently recognized by proteolytic systems so that inadvertent elimination of useful proteins is avoided. One mechanism to ensure proper recognition is the presence of N-terminal degradation signals (N-degrons) that are targeted by adaptor proteins (N-recognins). The members of the caseinolytic protease S (ClpS) family of N-recognins identify targets bearing an N-terminal phenylalanine, tyrosine, tryptophan or leucine residue, and then present them to a protease system. This process is known as the 'bacterial N-end rule'. The presence of a ClpS protein in Arabidopsis thaliana chloroplasts (AtClpS1) prompted the hypothesis that the bacterial N-end rule exists in this organelle. However, the specificity of AtClpS1 is unknown. Here we show that AtClpS1 has the ability to recognize bacterial N-degrons, albeit with low affinity. Recognition was assessed by the effect of purified AtClpS1 on the degradation of fluorescent variants bearing bacterial N-degrons. In many bacterial ClpS proteins, a methionine residue acts as a 'gatekeeper' residue, fine-tuning the specificity of the N-recognin. In plants, the amino acid at that position is an arginine. Replacement of this arginine for methionine in recombinant AtClpS1 allows for high-affinity binding to classical N-degrons of the bacterial N-end rule, suggesting that the arginine residue in the substrate binding site may also act as a gatekeeper for plant substrates. PMID- 29401301 TI - Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics. AB - Short read massive parallel sequencing has emerged as a standard diagnostic tool in the medical setting. However, short read technologies have inherent limitations such as GC bias, difficulties mapping to repetitive elements, trouble discriminating paralogous sequences, and difficulties in phasing alleles. Long read single molecule sequencers resolve these obstacles. Moreover, they offer higher consensus accuracies and can detect epigenetic modifications from native DNA. The first commercially available long read single molecule platform was the RS system based on PacBio's single molecule real-time (SMRT) sequencing technology, which has since evolved into their RSII and Sequel systems. Here we capsulize how SMRT sequencing is revolutionizing constitutional, reproductive, cancer, microbial and viral genetic testing. PMID- 29401303 TI - Contribution of Breastfeeding to False-Positive Saliva Polymerase Chain Reaction for Newborn Congenital Cytomegalovirus Screening. AB - Real-time polymerase chain reaction (PCR) of saliva is highly sensitive for newborn congenital cytomegalovirus (CMV) screening. This study uses nationally published CMV seroprevalence and breastfeeding rates to estimate the contribution of CMV DNA in breast milk to false-positive saliva PCR results. The false positive rates adjusted for breastfeeding ranged from 0.03% in white Hispanic persons to 0.14% in white non-Hispanic persons. Saliva CMV PCR for newborn screening is highly sensitive, and the low false-positive rates in this study suggest that saliva PCR results are unlikely to be significantly influenced by breastfeeding or other perinatal exposures. PMID- 29401304 TI - Coordinated responses of plant hydraulic architecture with the reduction of stomatal conductance under elevated CO2 concentration. AB - Stomatal conductance (gs) generally decreases under elevated CO2 concentration (eCO2) and its sensitivity varies widely among species, yet the underlying mechanisms for these observed patterns are not totally clear. Understanding these underlying mechanisms, however, is critical for addressing problems regarding plant-environment interactions in a changing climate. We examined gs, water transport efficiency of different components along the whole-plant hydraulic system and allometric scaling in seedlings of six tree species grown under ambient and eCO2 treatments (400 and 600 ppm, respectively). Growth under eCO2 caused gs to decrease in all species but to highly variable extents, ranging from 13% (Populus tremuloides Michx.) to 46% (Gymnocladus dioicus (L.)). Accompanying this significant decrease in gs, substantial changes in plant hydraulic architecture occurred, with root hydraulic conductance expressed both on leaf area and root mass bases overall exhibiting significant decreases, while stem and leaf hydraulic efficiency either increased or showed no consistent pattern of change. Moreover, significant changes in allometry in response to eCO2 affected the whole-plant water supply and demand relations. The interspecific variation in gs response among species was not correlated with relative changes in stem and leaf hydraulic conductance but was most strongly correlated with the relative change in the allometric scaling between roots and leaves, and to a lesser extent with the intrinsic root hydraulic conductance of the species. The results underscore that allometric adjustments between root and leaf play a key role in determining the interspecific sensitivity of gs responses to eCO2. Plant hydraulics and their associated allometric scaling are important changes accompanying gs responses to eCO2 and may play important roles in mediating the interspecific variations of leaf gas exchange responses, which suggests that mechanistic investigations regarding plant responses to eCO2 need to integrate characteristics of hydraulics and allometric scaling in the future. PMID- 29401305 TI - Population Testing for High Penetrance Genes: Are We There Yet? PMID- 29401306 TI - Subaxillary approach to cardiac electronic device implantation using a single surgical incision: a single-centre experience. AB - OBJECTIVES: Pacemakers and implantable cardioverter defibrillators have become more common in younger individuals, owing to broader indications and technological advances. Our goal was to report our long-term experience of implanting cardiac devices in young adults via a subaxillary approach with a hidden single incision, to minimize the aesthetic impact of the device. METHODS: From 2003 to 2012, 23 patients underwent cardiac device implantation via a subaxillary approach while they were under general anaesthesia. The axillary vein was punctured under contrast-medium radiological guidance. The devices were positioned into the pocket under the pectoralis major muscle and over the fascia that envelopes the pectoralis minor muscle, through a lateral surgical access along the midaxillary line. RESULTS: Twenty-two single- and dual-chamber implantable cardioverter defibrillator and 1 dual-chamber pacemaker were implanted (mean age 32.2 +/- 13.4 years). All procedures were successfully performed without complications; overall hospitalization after implantation was 3.3 days. During mean a follow-up of 65 +/- 18 months, no deaths, infections or device migrations occurred. Two ventricular lead dislodgements requiring repositioning occurred within 1 month, and 1 defibrillation lead fracture occurred 5 years after implantation. All patients were extremely satisfied with the aesthetic result. A mild increase in the pacing threshold (0.88 +/- 0.6 V at 0.4/0.5 ms at implantation vs 1.00 +/- 0.3 V at 0.4/0.5 ms at 2-year follow-up, P = 0.063) and a statistically significant decrease in the pacing impedance (637 +/ 161 ohm at implantation vs 499 +/- 81 ohm at 2-year follow-up, P = 0.001) were observed, without any consequences. CONCLUSIONS: The subaxillary approach is a safe, feasible technique that requires a simple surgical procedure. The implantable cardioverter defibrillator functions properly at implantation and at long-term follow-up. PMID- 29401307 TI - "Do No Harm. Do Some Good." A Call for Members to Attend the Upcoming Annual AAPM Meeting in Vancouver, BC. PMID- 29401309 TI - Potential Mandated Lowering of Nicotine Levels in Cigarettes: A Plant Perspective. AB - Introduction: The FDA has announced the potential for mandated lowering of nicotine levels in combustible cigarettes. The World Health Organization has recommended a lowering of cigarette filler nicotine levels to below 0.4 mg/g. To devise appropriate nicotine control strategies, regulators must consider technical feasibility, timelines for compliance, and potential impediments to implementation. Outlined here is previously unsummarized information on genetic approaches that might be used to reduce nicotine levels in cured tobacco leaves. For the benefit of regulators, altered alkaloid or toxicant profiles that might result by implementation of some of these methodologies are discussed. Also mentioned are potential licensing or regulatory impediments to use of some of the technologies per se. Implications: An understanding of technical feasibility of plant-based nicotine reduction technologies, along with the potential for corresponding alterations in alkaloid or toxicant profiles, is needed by regulators in order to develop effective nicotine control strategies with minimal impediments or undesirable consequences. PMID- 29401308 TI - Anti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir? AB - Background: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Methods: Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Results: Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite >10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold (P > .0001) and blood antibodies by 7-fold (P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. Conclusions: To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection. PMID- 29401310 TI - Human cis-acting elements regulating escape from X-chromosome inactivation function in mouse. AB - A long-standing question concerning X-chromosome inactivation (XCI) has been how some genes avoid the otherwise stable chromosome-wide heterochromatinization of the inactive X chromosome. As 20% or more of human X-linked genes escape from inactivation, such genes are an important contributor to sex differences in gene expression. Although both human and mouse have genes that escape from XCI, more genes escape in humans than mice, with human escape genes often clustering in larger domains than the single escape genes of mouse. Mouse models offer a well characterized and readily manipulated system in which to study XCI, but given the differences in genes that escape it is unclear whether the mechanism of escape gene regulation is conserved. To address conservation of the process and the potential to identify elements by modelling human escape gene regulation using mouse, we integrated a human and a mouse BAC each containing an escape gene and flanking subject genes at the mouse X-linked Hprt gene. Escape-level expression and corresponding low promoter DNA methylation of human genes RPS4X and CITED1 demonstrated that the mouse system is capable of recognizing human elements and therefore can be used as a model for further refinement of critical elements necessary for escape from XCI in humans. PMID- 29401311 TI - Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study. AB - Background: The number of kidney transplant recipients (KTRs) being waitlisted for a subsequent transplantation has disproportionately increased to almost 25%. Evidence for the optimal management of the failed allograft, however, remains inconsistent. Methods: We studied 111 KTRs who underwent their second kidney transplantation from 1998 to 2015. In 51/111 KTRs (46%) the failed allograft was removed and in 60/111 (54%) the failed allograft was retained. KTRs with primary non-function and allograft loss <12 months of the first failed allograft were excluded from analysis. Samples were collected before transplantation and at 1 month posttransplantation and donor-reactive T cells were measured using an interferon-gamma enzyme-linked immunosorbent spot assay. Results: KTRs with the previous allograft removed showed significantly higher rates of acute cellular rejection compared with KTRs with the previous allograft retained [27/51 KTRs (53%) versus 18/60 KTRs (30%); P = 0.019]. KTRs with the previous allograft removed showed significantly inferior death-censored allograft survival compared with KTRs with the previous allograft retained (P = 0.022). Here, KTRs with the previous allograft removed showed significantly higher donor-reactive T cells pretransplantation compared with KTRs with the previous allograft retained (P = 0.012). Interestingly, no differences were observed for the presence of panel reactive antibodies and for the development of de novo donor-specific antibodies. Conclusions: Our data suggest higher cellular presensitization among KTRs with the previous allograft removed, which is associated with higher rates of acute cellular rejection and inferior allograft survival. Immunological mechanisms that may account for these differences may include prolonged maintenance immunosuppression to save urine output in KTRs with the first kidney allograft retained and cellular presensitization after withdrawal of maintenance immunosuppression, which lead to allograft rejection and ultimately to allograft nephrectomy. PMID- 29401313 TI - Can an increase in autoantibody levels predict arthritis in arthralgia patients? PMID- 29401314 TI - Sleep duration and incidence of obesity in infants, children, and adolescents: a systematic review and meta-analysis of prospective studies. AB - Study Objectives: To assess the prospective relationship between sleep and obesity in a paediatric population. Methods: We performed a systematic search using PubMed, Embase, Web of Science, and Cochrane (up to September 25, 2017). Included studies were prospective, had follow-up of >=1 year, had duration of sleep at baseline, and measures of incidence of overweight or obesity and/or changes in body mass index (BMI) z-score and BMI during follow-up. We extracted relative risks or changes in BMI z-score or BMI and 95% confidence intervals (CI) and pooled them using a random effect model. Results: Forty-two studies were included but, as there was significant heterogeneity, results are presented by age strata. Short sleep was associated with a greater risk of developing overweight or obesity in infancy (seven studies, 14738 participants, risk ratio [RR]: 1.40; 95% CI 1.19 to 1.65; p < .001), early childhood (eight studies, 31104 participants, RR: 1.57; 1.40 to 1.76; p < .001), middle childhood (three studies, 3005 participants, RR: 2.23; 2.18 to 2.27; p < .001), and adolescence (three studies, 26652 participants, RR: 1.30; 1.11 to 1.53; p < .002). Sleep duration was also associated with a significant change in BMI z-score (14 studies, 18 cohorts, 31665 participants; mean difference -0.03; -0.04 to -0.01 per hour sleep; p = .001) and in BMI (16 studies, 24 cohorts, 24894 participants; mean difference -0.03 kg/m2; -0.04 to -0.01 for every hour of increase in sleep; p = .001). Conclusions: Short sleep duration is a risk factor or marker of the development of obesity in infants, children, and adolescents. PMID- 29401312 TI - Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma. AB - Both exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) have been linked to decreased conventional outflow of aqueous humor (AH). To better understand the molecular changes in the AH content under such conditions, we analyzed the miRNA profiles of AH samples from patients with POAG and XFG compared to non-glaucoma controls. Individual AH samples (n = 76) were collected from POAG and XFG patients and age-matched controls during surgical procedure. After RNA extraction, the miRNA profiles were individually determined in 12 POAG, 12 XFG and 11 control samples. We identified 205, 295 and 195 miRNAs in the POAG, XFG and control samples, respectively. Our differential expression analysis identified three miRNAs (miR-125b-5p, miR-302d-3p and miR-451a) significantly different between POAG and controls, five miRNAs (miR-122-5p, miR-3144-3p, miR 320a, miR-320e and miR-630) between XFG and controls and one miRNA (miR-302d-3p) between POAG and XFG. While none of these miRNAs have been previously linked to glaucoma, miR-122-5p may target three glaucoma-associated genes: OPTN, TMCO1 and TGF-beta1. Pathway analysis revealed that these miRNAs are involved in potential glaucoma pathways, including focal adhesion, tight junctions, and TGF-beta signaling. Comparison of the miRNA profile in AH to unrelated human serum (n = 12) exposed potential relationships between these two fluids, although they were not significantly correlated. In summary, we have successfully profiled the miRNA expression without amplification in individual human AH samples and identified several POAG or XFG-associated miRNAs. These miRNAs may play a role in pathways previously implicated in glaucoma and act as biomarkers for disease pathogenesis. PMID- 29401315 TI - Vaccine-Associated Maintenance of Epithelial Integrity Correlated With Protection Against Virus Entry. AB - To identify the mechanisms by which human immunodeficiency virus type 1 (HIV-1) might penetrate the epithelial barrier during sexual transmission to women and the mechanisms of vaccine-associated protection against entry, we characterized early epithelial responses to vaginal inoculation of simian immunodeficiency virus strain mac251 (SIVmac251) in naive or SIVmac239Deltanef-vaccinated rhesus macaques. Vaginal inoculation induced an early stress response in the cervicovaginal epithelium, which was associated with impaired epithelial integrity, damaged barrier function, and virus and bacterial translocation. In vaccinated animals, early stress responses were suppressed, and the maintenance of epithelial barrier integrity correlated with prevention of virus entry. These vaccine-protective effects were associated with a previously described mucosal system for locally producing and concentrating trimeric gp41 antibodies at the mucosal interface and with formation of SIV-specific immune complexes that block the stress responses via binding to the epithelial receptor FCGR2B and subsequent inhibitory signaling. Thus, blocking virus entry may be one protective mechanism by which locally concentrated non-neutralizing Ab might prevent HIV sexual transmission to women. PMID- 29401316 TI - Cambial phenology in Juniperus przewalskii along different altitudinal gradients in a cold and arid region. AB - Knowing more precisely the cambial phenology and wood formation dynamics of trees can lead to a better understanding on how trees react to short-term changes in environmental conditions. Such an understanding could also shed light on the physiological foundation of climate-growth interactions at a regional scale. Although it has been documented that temperature is an important factor determining the cambial phenology in cold and humid climates, there is less agreement on the driver(s) that trigger the onset and end of wood formation in cold and arid climates. Here, the phenological traits of cambial activity and xylem formation were analyzed biweekly along an altitudinal transect ranging from 3580 to 3980 m above sea level, a transect that covers the distribution of Qilian juniper (Juniperus przewalskii Kom.) along a slope of the Tibetan Plateau. Cambial phenology and the duration and rate of wood formation were assessed from anatomical observations during the growing season of the developing xylem obtained from microcores collected from the stem of 10 trees total in 2012 (five at two altitudes each) and 25 trees (five at five altitudes each) in 2013. We found that the onset of wood formation was significantly correlated with altitude in 2013, with onset beginning 8.2 days earlier with every 100 m decrease in elevation. The change in onset with elevation corresponds to a change of 14.1 days degrees C-1 when adjusted for the monitored altitudinal lapse rate of -0.58 degrees C per 100 m. The duration of wood formation lasted from mid-May to mid August, with the length of the 2013 growing season decreasing from 97 to 65 days from low to high elevation. Although the end of growing season appeared minimally related to altitude during both growing seasons, differences in end of wood production and wood formation between the two growing seasons were significant. It appears that summer drought conditions constricted the end of growing season across all elevations along our transect in 2013. Sensitivity analysis found xylem growth was positively correlated with rate and duration of wood production, with the former explaining most variability in growth. Our findings provide new data on the timing and duration of wood formation and help quantify the potential impacts of global warming on tree growth and productivity in cold and arid regions. PMID- 29401317 TI - HIV-TRACE (TRAnsmission Cluster Engine): a Tool for Large Scale Molecular Epidemiology of HIV-1 and Other Rapidly Evolving Pathogens. AB - In modern applications of molecular epidemiology, genetic sequence data are routinely used to identify clusters of transmission in rapidly evolving pathogens, most notably HIV-1. Traditional 'shoe-leather' epidemiology infers transmission clusters by tracing chains of partners sharing epidemiological connections (e.g., sexual contact). Here, we present a computational tool for identifying a molecular transmission analog of such clusters: HIV-TRACE (TRAnsmission Cluster Engine). HIV-TRACE implements an approach inspired by traditional epidemiology, by identifying chains of partners whose viral genetic relatedness imply direct or indirect epidemiological connections. Molecular transmission clusters are constructed using codon-aware pairwise alignment to a reference sequence followed by pairwise genetic distance estimation among all sequences. This approach is computationally tractable and is capable of identifying HIV-1 transmission clusters in large surveillance databases comprising tens or hundreds of thousands of sequences in near real time, that is, on the order of minutes to hours. HIV-TRACE is available at www.hivtrace.org and from www.github.com/veg/hivtrace, along with the accompanying result visualization module from www.github.com/veg/hivtrace-viz. Importantly, the approach underlying HIV-TRACE is not limited to the study of HIV-1 and can be applied to study outbreaks and epidemics of other rapidly evolving pathogens. PMID- 29401319 TI - Rotavirus Vaccines: A Social Injustice Story. PMID- 29401320 TI - Abdominal submuscular implant of subcutaneous implantable cardioverter defibrillator in a young child. PMID- 29401318 TI - Telmisartan Therapy Does Not Improve Lymph Node or Adipose Tissue Fibrosis More Than Continued Antiretroviral Therapy Alone. AB - Background: Fibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor gamma agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection. Methods: In this 48-week, randomized, controlled trial, adults continued HIV-suppressive ART and received telmisartan or no drug. Collagen I, fibronectin, and phosphorylated SMAD3 (pSMAD3) deposition in lymph nodes, as well as collagen I, collagen VI, and fibronectin deposition in adipose tissue, were quantified by immunohistochemical analysis at weeks 0 and 48. Two-sided rank sum and signed rank tests compared changes over 48 weeks. Results: Forty-four participants enrolled; 35 had paired adipose tissue specimens, and 29 had paired lymph node specimens. The median change overall in the percentage of the area throughout which collagen I was deposited was -2.6 percentage points (P = 0.08) in lymph node specimens and -1.3 percentage points (P = .001) in adipose tissue specimens, with no between-arm differences. In lymph node specimens, pSMAD3 deposition changed by -0.5 percentage points overall (P = .04), with no between-arm differences. Telmisartan attenuated increases in fibronectin deposition (P = .06). In adipose tissue, changes in collagen VI deposition (-1.0 percentage point; P = .001) and fibronectin deposition (-2.4 percentage points; P < .001) were observed, with no between-arm differences. Conclusions: In adults with treated HIV infection, lymph node and adipose tissue fibrosis decreased with continued ART alone, with no additional fibrosis reduction with telmisartan therapy. PMID- 29401321 TI - Plasma cell leukemia masquerading as a relapse of the Nephrotic syndrome. PMID- 29401322 TI - Prevalence of Paget's disease of bone in Lancaster: time for an update. PMID- 29401323 TI - De-freezing frozen patient management. PMID- 29401324 TI - Effects and interactions of myostatin and callipyge mutations: I. Growth and carcass traits. AB - Objectives were to document effects of the Texel myostatin mutation (MSTN) on growth and carcass traits and also test whether or not interactions with the callipyge mutation (CLPG) could be detected. Twelve rams heterozygous at both loci on the two different chromosomes were mated to 215 terminal-sire type composite crossbred ewes genotyped as non-carriers for both loci. A total of 365 lambs were born, 362 of those were genotyped and 236 lambs contributed carcass data to estimate effects and interactions among the four genotype combinations produced. The four genotype combinations were defined as follows: ++/++ for wild type at both loci; ++/C+ for wild-type at MSTN and heterozygous at CLPG; M+/++ for heterozygous at MSTN and wild-type at CLPG; and M+/C+ for heterozygous at both loci. The two independently segregating sire-derived alleles represent different breed-of-origin contrasts at each locus (Texel vs. composite origin for MSTN and Dorset vs. Texel origin for CLPG). Birth weight was recorded on all lambs, and subsequent body weights were adjusted to 56 (weaning), 70, and 140 d of age. Within sire-sex-genotype subgroups, naturally reared lambs were assigned to one of eight slaughter groups accounting for variation in birth date. Lambs were serially slaughtered at weekly intervals, 30 lambs per group, from roughly 26 to 33 wk of age. In addition to standard carcass traits, subjective leg scores were assigned and widths of carcasses were measured at the widest points of the shoulder and rump. Differences in birth weight were detected (P < 0.01) for the combination of the two loci and birth type, with single-born differences among genotypes exceeding differences among twin born progeny. Those interaction differences among genotypes were not as important at weaning (P = 0.36). Impact on growth rate differences among the genotypes during the post-weaning period were variable and dependent on sex of the lamb (P < 0.01). A synergistic interaction between MSTN and CLPG was observed for leg muscling scores (P < 0.05) but no other measures of carcass shape were affected. One copy of MSTN had a more modest impact on fat deposition and muscle conformation than did CLPG and did not interact (all values P > 0.20). Although some non-additive interactions that vary by trait and sex were detected, in general the data are consistent with the two mutations acting on muscle growth through independent pathways. PMID- 29401325 TI - Safety and Immunogenicity of 3 Formulations of an Investigational Respiratory Syncytial Virus Vaccine in Nonpregnant Women: Results From 2 Phase 2 Trials. AB - Background: Respiratory syncytial virus (RSV) causes bronchiolitis and pneumonia in neonates and infants. RSV vaccination during pregnancy could boost preexisting neutralizing antibody titers, providing passive protection to newborns. Methods: Two observer-blinded, controlled studies (RSV F-020 [clinical trials registration NCT02360475] and RSV F-024 [NCT02753413]) evaluated immunogenicity and safety of an investigational RSV vaccine in healthy, nonpregnant 18-45-year-old women. Both studies used a licensed adult formulation of combined tetanus toxoid-diphtheria toxoid-acellular pertussis (Tdap) vaccine as a control. RSV F-020 evaluated immunogenicity and safety: participants were randomized (1:1:1:1) to receive 1 dose of RSV-prefusion F protein (PreF) vaccine containing 30 ug or 60 ug of nonadjuvanted RSV-PreF, 60 ug of aluminum-adjuvanted RSV-PreF, or Tdap. RSV F-024 evaluated safety: participants were randomized 1:1 to receive 1 dose of 60 ug of nonadjuvanted RSV-PreF or Tdap. Results: Both studies showed similar reactogenicity profiles for RSV-PreF and Tdap. No serious adverse events were considered vaccine related. In RSV F-020, geometric mean ratios of RSV-A neutralizing antibody levels at day 30 versus prevaccination were 3.1-3.9 in RSV PreF recipients and 0.9 in controls. Palivizumab-competing antibody concentrations increased >14-fold in RSV-PreF recipients on day 30. RSV antibody titers waned after day 30 but remained well above baseline through day 90. Conclusions: All formulations of RSV-PreF boosted preexisting immune responses in 18-45-year old women with comparable immunogenicity. The RSV-PreF safety profile was similar to that of Tdap vaccine. PMID- 29401326 TI - Post-deployment Mental Health in Reserve and National Guard Service Members: Deploying With or Without One's Unit and Deployment Preparedness. AB - Background: Given the greater prevalence of post-deployment mental health concerns among reservists, the higher likelihood of deploying without their regular unit, and potentially lower rates of deployment preparedness, we examined associations between deploying with or without one's regular unit (individual augmentee status, IAS), deployment preparedness, and mental health problems including post-traumatic stress disorder (PTSD), depression (MDD), and binge drinking in a nationally representative sample of Reserve Component (RC) Army and Marine-enlisted males (n = 705). Methods: A series of multivariate regressions examined the association of mental health with IAS and deployment preparedness, adjusting for demographics. To examine whether deployment preparedness varied by IAS, an IAS * deployment preparedness interaction was included. Findings: In an adjusted model, being an individual augmentee and low deployment preparedness were associated with any mental health problem (screening positive for PTSD, MDD, binge drinking, or any combination of the three). There was a significant IAS * deployment preparedness interaction. Mental health problems did not vary by preparedness among individual augmentees. Participants deploying with regular units with low-medium preparedness had greater risk for mental health problems (odds ratio [OR] = 3.69, 95% confidence interval [CI] = 1.78-7.62 and OR = 2.29, 95% CI = 1.12-4.71), than those with high preparedness. RC-enlisted male personnel who deployed without their regular unit were five times more likely to have a mental health problem, and were 61% more likely to report binge drinking. Additionally, those with lower levels of deployment preparedness were up to three times more likely to have a mental health problem and up to six times more likely to report PTSD. Discussion: The current investigation found that both IAS and deployment preparedness were associated with negative mental health outcomes in a large representative sample of previously deployed RC-enlisted male personnel. In particular, low deployment preparedness was associated with an increased likelihood of PTSD, and deploying without one's regular unit was associated with increased rates of binge drinking. There were also significant main and interaction effects of IAS and deployment preparedness on having a mental health problem. It is possible that limiting the number of RC personnel deploying without their regular unit may help to decrease alcohol misuse among U.S. Armed Services reservists during and after future conflicts. Also, to the extent that deployment preparedness is a modifiable risk factor, future studies should examine whether increasing deployment preparedness could mitigate some of the correlates of deployment-related trauma exposure. Finally, future investigation is needed to explain why those who deploy without their regular unit, but who report high deployment preparedness, remain at elevated risk for mental health problems. It is possible that individual augmentees can benefit from a specific preparation for deployment. Those deploying without their regular unit had higher rates of mental health problems regardless of preparedness. These findings have implications for deployment preparedness training for those deploying without their regular unit. PMID- 29401327 TI - Beyond the Dirty Dozen: A Proposed Methodology for Assessing Future Bioweapon Threats. AB - Background: Defense policy planners and countermeasure developers are often faced with vexing problems involving the prioritization of resources and efforts. This is especially true in the area of Biodefense, where each new emerging infectious disease outbreak brings with it questions regarding the causative agent's potential for weaponization. Recent experience with West Nile Virus, Severe Acute Respiratory Syndrome, Monkeypox, and H1N1 Influenza highlights this problem. Appropriately, in each of these cases, the possibility of bioterrorism was raised, although each outbreak ultimately proved to have a natural origin. In fact, determining whether an outbreak has an unnatural origin can be quite difficult. Thus, the questions remain: could the causative agents of these and other emerging infectious disease outbreaks pose a future weaponization threat? And how great is that threat? Should precious resources be diverted from other defense efforts in order to prepare for possible hostile employment of novel diseases by belligerents? Answering such critical questions requires some form of systematic threat assessment. Methods: Through extensive collaborative work conducted within NATO's Biomedical Advisory Council, we developed a scoring matrix for evaluating the weaponization potential of the causative agents of such diseases and attempted to validate our matrix by examining the reproducibility of data using known threat agents. Our matrix included 12 attributes of a potential weapon and was provided, along with detailed scoring instructions, to 12 groups of biodefense experts in 6 NATO nations. Study participants were asked to score each of these 12 attributes on a scale of 0-3: Infectivity, Infection-to-Disease Ratio (Reliability), Predictability (& Incubation Period), Morbidity & Mortality (Virulence), Ease of Large-Scale Production & Storage, Aerosol Stability, Atmospheric Stability, Ease of Dispersal, Communicability, Prophylactic Countermeasure Availability, Therapeutic Countermeasure Availability, and Ease of Detection. Reproducibility of scoring data was assessed by examining the standard deviations (SD) of mean scores. Results: Our results were unexpected. Several familiar biothreat diseases such as anthrax and tularemia were judged, by our experts, to be less threatening than many others owing to a number of factors including ease of detection, lack of communicability, and the ready availability of countermeasures. Conversely, several toxins were judged by experts to have very high potential as threat agents owing, in part, to their reliability, virulence, and a lack of available countermeasures. Agreement among experts, as determined by lower SD about a mean score, was greater for more familiar threats. Discussion: Our study was designed to provide a concise and east-to-apply set of criteria that could be used by NATO nations to evaluate emerging infectious disease threats with respect to their weaponization potential. Our results were unexpected. We believe that a lack of appropriate weighting factors may explain these results and suggest that future studies weigh each of the 12 proposed criteria based on the intended use of the assessment data and other situational factors. We believe that the greatest value of our study lies in a codification of the attributes of a biological weapon. PMID- 29401328 TI - Implications of New Cholesterol Treatment Guidelines on Statin Utilization, Intensity, and Costs in Active Duty Service Members. AB - Background: The recommendations in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) blood cholesterol guidelines expanded the indications and level of intensity of statin therapy for the primary prevention of cardiovascular disease. We assessed the treatment and cost implications of theseguidelines within a cohort of active duty service members. Methods: Using the military electronic medical record system, the Armed Forces Health Longitudinal Technology Application, we randomly selected 1,000 active duty persons aged 40 yr or older and reviewed their lipid profiles and medical records to identify risk factors for atherosclerotic cardiovascular disease. We compared the recommended cholesterol treatment under the new ACC/AHA guidelines versus the Third Adult Treatment Panel of the National Cholesterol Education Program. Findings: The mean age was 49 +/- 7 yr, 36% were female, 22% were on baseline statin therapy (4% high intensity), and 13% were not at Third Adult Treatment Panel cholesterol goal. There was no difference in the proportion eligible for statin therapy between ACC/AHA and Third Adult Treatment Panel guidelines. Statin treatment under the ACC/AHA guideline resulted in a mean statin dose increase from 25 +/- 20 mg to 36 +/- 25 mg (p < 0.001) with an increase in those eligible for high-intensity statin therapy, 6% to 11% (p < 0.001). These changes translated to higher estimated yearly statin acquisition costs, $40,197 versus $52,527 per 1,000 patient-years of treatment (p < 0.001). Discussion: Within a low-risk active duty population over 40 yr, application of the 2013 ACC/AHA cholesterol treatment guidelines may not significantly increase those eligible for statins, but may increase statin treatment intensity and costs. PMID- 29401329 TI - Building Relationships and Trust One Needle at a Time: A Recipe for Success for the International Health Specialist (IHS). PMID- 29401330 TI - Return to Military Duty After Anterior Cruciate Ligament Reconstruction. AB - Background: Return to play and risk factors for functional limitations have been widely reported among athletes following anterior cruciate ligament reconstruction (ACLR) but has not been well studied in the military population. Methods: We conducted a retrospective review of all active duty service members who underwent primary ACLR at our institution between 2005 and 2010. The primary endpoints evaluated included Medical Evaluation Board (MEB) and activity limitations as noted by permanent profile (PP) following surgery. Demographic and surgical information was collected including age, gender, Military Occupational Specialty, tobacco use, rank, associated meniscal/chondral injuries, graft type, graft size, graft failure, and subsequent surgeries. All patients were greater than 2 yr postoperatively from index ACLR. Findings: A total of 470 patients met inclusion criteria for the study. There were 428 men and 42 women with a mean age of 28.5 yr. Of the 470 patients, 247 (52.6%) required either MEB, PP, or both following surgery; 129 (27.4%) required a PP only; 53 (11.3%) required a MEB only; and 65 (13.8%) required both PP and MEB following surgery. Only 223 patients (47.4%) returned to full duty without restrictions following ACLR. Both anterior cruciate ligament graft failure and subsequent surgeries were found to be statistically significant predictors for PP and/or MEB (p < 0.0001). Age, tobacco use, rank, associated meniscal/chondral injury, graft type, and graft size were not found to be significant predictors for subsequent PP and/or MEB. Female gender trended toward significance as a risk factor with 27 of 41 females (65.9%) requiring PP and/or MEB (p = 0.07). Service members in a noncombat arms role were more likely to require PP and/or MEB than those in a combat arms role (p = 0.03). Discussion: Return to full duty following ACLR in active duty soldiers is lower than may be expected. More than 50% of service members have activity limitations or are unable to return to duty following surgery. These findings allow for preoperative discussion of expected outcome and the possibility that an anterior cruciate ligament tear even when reconstructed can lead to permanent military activity limitations and MEB. PMID- 29401331 TI - Supraclavicular Thoracic Outlet Decompression in the High-Performance Military Population. AB - Background: Neurogenic thoracic outlet syndrome (nTOS) is a relatively common disorder and often affects younger, physically active populations. The modern American military is a population at risk for the development of nTOS given the intense physical training requirements. The purpose of this study is to determine functional recovery in the active duty military population resulting in full, unrestricted return-to-duty status following supraclavicular thoracic outlet decompression with partial first rib resection, partial anterior scalenectomy, and brachial plexus neurolysis. Methods: This retrospective study was approved by the Institutional Review Board at Walter Reed National Military Medical Center, Bethesda, Maryland to evaluate functional recovery following the surgery management of nTOS. In accordance with the Walter Reed National Military Medical Center Institutional Review Board, patient informed consent was obtained for this study. An institutional procedural database (Walter Reed National Military Medical Center Surgery Scheduling System) was queried for consecutive patients who underwent supraclavicular thoracic outlet decompression from January 2011 to May 2015. This study involved the completion of two survey instruments: the Disabilities of the Arm, Shoulder, and Hand survey and the Cervical Brachial Symptoms Questionnaire. Patients were asked to complete the preoperative surveys and the postoperative surveys. Results: Twenty responses were obtained with a 57% (20/35) overall response rate. Due to the low sample size, results were reported as a median rather than a mean to reduce the bias of outliers. Of the 20 patients who underwent supraclavicular thoracic outlet decompression, 85% reported improved functional recovery, 10% demonstrated no improvement but maintained stable functional and symptomatic deficits, and 5% demonstrated worsening of their functional and symptomatic status. The median total preoperative Disabilities of the Arm, Shoulder, and Hand score was calculated at 112 (interquartile range [IQR] 94-122) with an overall score reduction demonstrated by the median total postoperative Disabilities of the Arm, Shoulder, and Hand score of 50 (IQR 40-71). The median total score reduction of 57 (IQR 28.5-72) represented improved clinical and functional recovery (p < 0.001). The median total preoperative Cervical Brachial Symptoms Questionnaire score was 96 (IQR 74 111) with an overall score reduction revealed by the median total postoperative Cervical Brachial Symptoms Questionnaire score of 28 (IQR 19-45). The median total score reduction of 60 (IQR 23-77) reflected significant functional recovery consistent with clinical improvement (p < 0.001). Around 89% of patients had a predecompression temporary profile secondary to physical debilitation directly related to nTOS. Following surgery, temporary profile status was reduced to 39%. Around 61% of patients were able to complete and pass their service-specific physical fitness testing. Around 56% of patients demonstrated a full return-to duty status without limitations. Conclusion: Supraclavicular partial first rib resection, partial anterior scalenectomy, and brachial plexus neurolysis results in significant improvement in functional recovery in the military active duty patient population. Prospective studies are warranted to further characterize and define nTOS functional recovery after surgery in this population. PMID- 29401332 TI - Augmenting Fellow Education Through Spaced Multiple-Choice Questions. AB - Background: The San Antonio Uniformed Services Health Education Consortium Infectious Disease Fellowship program historically included a monthly short answer and multiple-choice quiz. The intent was to ensure medical knowledge in relevant content areas that may not be addressed through clinical rotations, such as operationally relevant infectious disease. After completion, it was discussed in a small group with faculty. Over time, faculty noted increasing dissatisfaction with the activity. Spaced interval education is useful in retention of medical knowledge and skills by medical students and residents. Its use in infectious disease fellow education has not been described. To improve the quiz experience, we assessed the introduction of spaced education curriculum in our program. Materials and Methods: A pre-intervention survey was distributed to assess the monthly quiz with Likert scale and open-ended questions. A multiple choice question spaced education curriculum was created using the Qstream(R) platform in 2011. Faculty development on question writing was conducted. Two questions were delivered every 2 d. Incorrectly and correctly answered questions were repeated after 7 and 13 d, respectively. Questions needed to be answered correctly twice to be retired. Fellow satisfaction was assessed at semi-annual fellowship reviews over 5 yr and by a one-time repeat survey. Results: Pre intervention survey of six fellows indicated dissatisfaction with the time commitment of the monthly quiz (median Likert score of 2, mean 6.5 h to complete), neutral in perceived utility, but satisfaction with knowledge retention (Likert score 4). Eighteen fellows over 5 yr participated in the spaced education curriculum. Three quizzes with 20, 39, and 48 questions were designed. Seventeen percentage of questions addressed operationally relevant topics. Fifty nine percentage of questions were answered correctly on first attempt, improving to 93% correct answer rate at the end of the analysis. Questions were attempted 2,999 times. Fellows consistently indicated that the platform was "highly enjoyed," "beneficial," a "fun format," and "completely satisfied." Fellows additionally commented that they desired more questions and considered the platform helpful in board preparation. Formal survey data post-intervention found that the fellows were satisfied with the new approach, found it to be useful in board preparation, overall educational value, and in-line with their personal learning style (median Likert score of 4 for all queries). Fellows were satisfied with time commitment, spending a mean of 47 min on the spaced education curriculum questions per month. Conclusions: Introduction of a spaced education curriculum resulted in a sustained positive learner experience for >5 yr with demonstrated mastery of material. Spaced education learning is a viable addition to augment training experience, especially in areas of curricular gaps such as operational medicine. Correct answer data may also be useful to perform Accreditation Council for Graduate Medical Education-required objective assessment of knowledge. PMID- 29401333 TI - Recognizing the Importance of Leadership: A Recent Graduate Develops a Corpsman. AB - There is a growing interest in leadership development within the field of medicine both within the military and the larger medical community. Recognition of the importance of leadership training during graduate medical education has grown, but many residents and faculty still argue that residency training should focus on clinical skills and medical knowledge. Most graduates of training programs in the military quickly find themselves in formal leadership positions or they must informally lead in their clinical practice. As these new graduates enter practice, they quickly realize the need to be able to effectively lead. In order to highlight some of the leadership challenges that junior military physicians face, Military Medicine is starting a new column called "Leadership Lessons from the Field." This article is the first in the series and discusses a recent graduate's experience in dealing with an underperforming corpsman. The article reviews the importance of emotional intelligence, feedback, and goal setting. PMID- 29401334 TI - Financial and Temporal Advantages of Virtual Consultation in Veterans Requiring Specialty Care. AB - Background: Access to specialty health care in the Veterans Affairs (VA) system continues to be problematic. Given the potential temporal and fiscal benefits of telehealth, the Madison VA developed a virtual consultation (VC) mechanism to expedite diagnostic and therapeutic interventions for Veterans with incidentally discovered pulmonary nodules. Materials and. Methods: VC, a remote encounter between referring provider and thoracic surgeon for incidentally discovered pulmonary nodules, was implemented at the Madison VA between 2009 and 2011. Time from request to completion of consultation, hospital cost, and travel costs were determined for 157 veterans. These endpoints were then compared with in-person consultations over a concurrent 6-mo period. Results: For the entire study cohort, the mean time to completion of VC was 3.2 d (SD +/- 4.4 d). For the 6-mo period of first VC availability, the mean time to VC completion versus in-person consultation was 2.8 d (SD +/- 2.8 d) and 20.5 d (SD +/- 15.6 d), respectively (p < 0.05). Following initial VC, 84 (53%) veterans were scheduled for virtual follow-up alone; no veteran required an additional office visit before further diagnostic or therapeutic intervention. VA hospital cost was $228 per in-person consultation versus $120 per episode for VC - a 47.4% decrease. The average distance form veteran home to center was 86 miles, with an average travel reimbursement of $112 per in-person consultation, versus no travel cost associated with VC. Conclusions: VC for incidentally discovered pulmonary nodules significantly decreases time to consultation completion, hospital cost, and veteran travel cost. These data suggest that a significant opportunity exists for expansion of telehealth into additional practice settings within the VA system. PMID- 29401335 TI - Influence of Personality Traits on the Effective Performance of Lifesaving Interventions: Example of the Tourniquet Application in Forward Combat Casualty Care. AB - Introduction: Health care delivery in military conflicts implies high-stress environments. Hemorrhage is the first cause of survivable death among combat casualties, and tourniquet application is one of the most critical lifesaving interventions on the battlefield. However, previous studies have shown high failure rates in tourniquet application. Our study aimed to assess the correlation between personality traits that may interfere with effective tourniquet application in a simulated extremity hemorrhage. Materials: Seventy two French soldiers, previously trained to forward combat casualty care, were evaluated by self-administered questionnaires and submitted to the simulation in group of six. We focused on measuring the empathic personality of the subjects, their peer-to-peer relationships (altruism), as well as their relationship to themselves (mindfulness and self-esteem). The effectiveness of the tourniquet was evidenced by the interruption of the popliteal artery flow Doppler signal. A composite variable called "efficiency" was defined by elimination of popliteal pulse Doppler signal in less than 60 s. Results: Tourniquet application interrupted arterial flow in 37 participants (51.39%). Efficiency was obtained by 19 participants (26.39%). We observed that soldiers with high active altruism applied less-efficient tourniquet (odds ratio = 0.15; 95% confidence interval = 0.04-0.59). On the contrary, soldiers with high self-esteem scores applied more efficient tourniquet (odds ratio = 3.95; 95% confidence interval = 1.24-12.56). There was no significant difference concerning empathy and mindfulness scores. Conclusion: Tourniquet application is technically simple but painful and may involve personal sensitivity. These initial findings highlight the necessity to further explore the psychological processes involved in lifesaving interventions. Self-esteem stands out as a real asset in terms of military competence and resilience, a major prerequisite in stressful situations. Changing altruistic motivations of soldiers is likely not desirable, but being aware of its potential effects may help to develop personal adaptive strategies and to optimize collective training. PMID- 29401336 TI - CAVH in the Combat Environment: A Case Report and Lessons Learned in Southern Afghanistan. AB - Background: Acute kidney injury is a common complication of both civilian and military trauma. The lack of dedicated resources restrict dialysis in the forward setting. We report a case of a combat polytrauma and renal failure, using continuous arteriovenous hemofiltration to clear uremia and remove volume, allowing for ventilator liberation and safe disposition. Materials and Methods: The patient presented with traumatic lower extremity injuries and abdominal wounds and developed acute post-traumatic renal failure. Using available supplies, the patient was cannulated for continuous arteriovenous hemofiltration. Aggressive fluid and electrolyte management accomplished specific goals of ventilator liberation and clearance of uremia. Results: Over 48 h, blood urea nitrogen was reduced from 101 mg/dL to 63 mg/dL. Creatinine was reduced from 8.2 mg/dL to 4.7 mg/dL. Acute respiratory distress syndrome was improved reducing P:F (PaO2:FiO2) ratio from 142 to 210. The patient was extubated and transferred safely. Conclusions: The ability to perform acute dialysis can be lifesaving. Although resource constrained, we created a dialysis system in the forward environment with a filter and universally available equipment. This represents the first described use of continuous arteriovenous hemofiltration at the NATO Role 3 hospital in Afghanistan. This technique represents another potential tool for deployed trauma teams to improve care. PMID- 29401337 TI - Skills Decay in Military Medical Training: A Meta-synthesis of Research Outcomes. AB - Background: In fiscal year 2012, the Medical Simulation and Information Sciences Research Program released two Skills Decay (SD) research program announcements (PAs) under the Medical Readiness Initiative entitled "Medical Practice Initiative Breadth of Medical Practice & Disease Frequency Exposure (MPI-BMP)" and the "Medical Practice Initiative Procedural Skill Decay and Maintenance (MPI PSD)." The Office of Naval Research also released a PA entitled "Medical Modeling and Simulation (MM&S) for Military Training and Education." A total investment of $12 M was made. This article provides a meta-synthesis of the Skills Decay research conducted under these efforts. Methods: The MSIRRP Medical Simulation Portfolio collected, reviewed, and analyzed the final reports of the Skills Decay research efforts from the three PAs. This paper provides a meta-synthesis of the outcomes of those studies. Focus of this study was to determine if the anticipated goals of the Skills Decay PAs were met as well as to provide a summary of lessons learned to the research community. Discussion: Fourteen research questions posed by the PAs were structured into four main goals: (1) Skills Decay identification, (2) creation/validity of Skills Decay tools and feasibility and viability of data extraction project, (3) refreshment training to prevent or alleviate Skills Decay project, and (4) Skills Decay education content. Conclusion: Using a combination of training styles, choosing variables known to have Skills Decay predication value, and developing better ways of mining available data that can, in turn, provide feedback to training needs, it is possible for accurate Skills Decay models to be developed. These technologies have the ability not only capture the learner's reaction during the simulation, but to capture the simulation outcomes to predict a medical professional's level of experience and background. Lessons learned from the investments made by the government are extremely important in order to ensure that the outcomes of the research touch the lives of the warfighter. PMID- 29401338 TI - A Tertiary Care Center's Experience with Novel Molecular Meningitis/Encephalitis Diagnostics and Implementation with Antimicrobial Stewardship. AB - Background: Novel molecular techniques, such as the Biofire FilmArray Meningitis/Encephalitis (ME) panel, are increasingly used to improve pathogen detection and time to detection (TtD). The Brooke Army Medical Center antibiotic stewardship program evaluated the impact of the ME panel on empiric antimicrobial usage. Methods: Negative ME panels were analyzed for days of therapy (DOT). The ME panel became available at Brooke Army Medical Center on January 1, 2016 and a retrospective chart review was performed on all hospitalized patients tested by ME panel through April 30, 2016. Demographic data, cerebral spinal fluid (CSF) leukocyte count, immunocompromised status, and intensive care unit admission status were collected. TtD by ME panel and CSF culture were compared and DOT for common antimicrobials were quantified. Positive ME panels were analyzed for same demographic data, diagnoses, and microbiologic workup including CSF cultures and send out polymerase chain reactions. Results: Of the 77 ME panels performed during the study period, 54 (70%) were conducted on inpatients and included in the analysis. The majority of patients were males (n = 29, 54%) and the median age was 24 yr (interquartile range [IQR] 45; range 1 d to 83 yr). A total of eight (15%) patients were immunocompromised and 17 (31%) required intensive care unit level of care. The median TtD with the ME panel and CSF culture was 2.75 (IQR 2.16, 3.64) and 68.5 (IQR 63.87, 78.37) h, respectively. For negative ME panels, the overall median DOT for antimicrobials was 3 (IQR 1.5, 4.0) d, whereas the median DOT for individual agents was 2 (IQR 1.0, 4.0) d for vancomycin (n = 15), 1.5 (IQR 1.0, 2.25) d for ceftriaxone (n = 16), 3 (IQR 3.0, 4.0) d for ampicillin (n = 15), 3.5 (IQR 2.75, 4.0) d for gentamicin (n = 8), 3.5 (IQR 2.25, 4.0) d for cefotaxime (n = 6), and 5 (IQR 3.0, 5.5) d for acyclovir (n = 7); the median CSF leukocyte is of 2 cells/mm3 (IQR 1.0, 7.5). DOT excluded cases of positive ME panels: human herpes virus-6 (n = 2), herpes simplex virus-2 (n = 3), enterovirus (n = 1), and Streptococcus pneumoniae (n = 1). Of these, there were two discordance diagnoses between ME panel and convention microbiologic methods. S. pneumonia was detected on the ME panel and not on the CSF culture. One bone marrow transplant recipient had symptoms of encephalitis caused by human herpes virus-6 detected only by the ME panel, the send out human herpes virus-6 polymerase chain reaction was negative. Conclusion: The ME panel appears to improve diagnostic yield in our facility, and there is potential for improvement in decreasing empiric antimicrobial usage, particularly in patients with a negative ME panel and absence of CSF pleocytosis. This demonstrates the need for antibiotic stewardship program involvement to assist in implementation of rapid diagnostic tests through methods such as education, clinical guidelines, and prospective audit and feedback to improve meningitis and encephalitis management. PMID- 29401339 TI - Gender Disparities Within US Army Orthopedic Surgery: A Preliminary Report. AB - INTRODUCTION: Women account for approximately 15% of the active duty US Army, and studies show that women may be at an increased risk of musculoskeletal injury during sport and military training. Nationally, the field of orthopedic surgery comprises 14% women, lagging behind other surgical fields. Demographics for US Military orthopedic surgeons are not readily available. Similarly, demographic data of graduating medical students entering Military Medicine are not reported. We hypothesize that a gender disparity within military orthopedics will be apparent. We will compare the demographic profile of providers to our patients and hypothesize that the two groups are dissimilar. Secondarily, we examine the demographics of military medical students potentially entering orthopedics from the Uniformed Services University of the Health Sciences (USUHS) or the Health Professions Scholarship Program. METHODS: A census was formed of all US Army active duty orthopedic surgeons to include staff surgeons and residents, as well as US Army medical student graduates and orthopedic patients. RESULTS: There are 252 Army orthopedic surgeons and trainees; 26 (10.3%) are women and 226 (89.7%) are men. There were no significant demographic differences between residents and staff. Between 2014 and 2017, the 672 members of the USUHS graduating classes included 246 Army graduates. Of those, 62 (25%) were female. Army Health Professions Scholarship Program graduated 1,072 medical students, with women comprising 300 (28%) of the group. No statistical trends were seen over the 4 yr at USUHS or in Health Professions Scholarship Program. In total, 2,993 orthopedic clinic visits during the study period were by Army service members, 23.6% were women. CONCLUSION: There exists a gender disparity among US Army orthopedic surgeons, similar to that seen in civilian orthopedics. Gender equity is also lacking among medical students who feed into Army graduate medical education programs. The gender profile of our patient population is not reflected by that of providers. Because patients prefer providers of the same gender, this is a limitation to patient satisfaction and access to care for musculoskeletal injuries. Further study is underway to identify perceptions and potential causes of these disparities, including the critical perspective of our patients. In addition to the inherent benefits offered by diversity (e.g., expanding the talent pool and more perspectives for decision-making), ultimately it affords a greater ability to maintain a fit and ready force. PMID- 29401340 TI - Prevalence of Use and Perceptions of Electronic Smoking Devices in a US Army Infantry Division. AB - Introduction: The increasing interest in electronic smoking devices (ESDs) among consumers shows promise for ESDs as a less harmful alternative for smoking and possibly for smoking cessation. Limited data on prevalence of ESD use in the military are available and data on perceptions of ESD use have not yet been published within an active duty, military-specific population. The primary outcome of this study was to define the prevalence of ESD use in a US Army division. Methods: We surveyed 1,288 military service members (response rate 95%, n = 1,225) from the 25th Infantry Division, Schofield Barracks, HI, in late 2015, on smoking habits, ESD usage, and perceptions surrounding ESDs. Chi-squared and Fisher's exact tests were used to assess categorical associations between smoking status, ESD usage, socio-demographic factors, cessation strategies, and perceptions regarding ESDs. Results: The prevalence of current ESD use was 20%, whereas the prevalence of having ever used an ESD was 61%. The daily smoking rate of participants was 23%. Those with lower education, current smokers, and ex smokers were the most likely to be using an ESD. Current smokers and ESD users had a more favorable perception of ESDs with regard to their utility and health effectiveness. Conclusions: There is a high prevalence of current and ever use ESD among active duty service members assigned to a US Army Infantry Division. Data from similar studies suggest that this rate is growing. The rates of ESD use in military populations should continue to be monitored as the clinical utility of these devices continues to be investigated. PMID- 29401341 TI - Long-Term Results of a Monocentric Series of Soldiers After Latarjet Procedure for Anterior Shoulder Instability. Implications for the Assessment of Soldiers' Medical Ability. AB - Introduction: Stabilizing surgery of the shoulder with a coracoid graft according to Latarjet is a recognized surgical treatment for anterior instability of the shoulder. This pathology frequently affects soldiers. Postoperatively, the potential risk of recurrence or of secondary shoulder arthritis can limit the practitioner in their ability assessment. The aim of this study is to analyze the long-term outcomes of this surgery in a military population, in order to assess the possible implications for French soldiers' medical ability. Material and Methods: Twenty soldiers operated on the shoulder by Latarjet procedure by the same surgeon were retrospectively reviewed after more than 15 yr. All of them did regular physical activity for leisure or competitions. None had preoperative osteoarthritis injuries. The number of dislocation recurrences, the functional score, and the rate of radiographic osteoarthritis were assessed. Results: After more than 16.3 yr (extremes: 15-24 yr), none displayed a dislocation recurrence. The average Rowe's score was 91.8 +/- 9.9. The average subjective shoulder value was 89.2 +/- 9.7. All patients had resumed sport. Three of them developed level 1 or 2 radiological signs of osteoarthritis according to Samilson. No level 3 or 4 osteoarthritis was found. Among all the patients, 14 still did regular physical activity. Discussion: In view of our results and of those from the literature, the results of treatment for anterior shoulder instability with the Latarjet procedure are good, even very good in the long term. These data must be considered to favor this procedure for soldiers with shoulder instability and from a medico-administrative viewpoint for military patients in order to pursue their careers without any job restrictions. PMID- 29401342 TI - Absent Inferior Vena Cava Leading to Recurrent Lower Extremity Deep Vein Thrombosis in a United States Marine. AB - Introduction: Anomalies of the inferior vena cava (AIVC) are rare but well recognized anatomic abnormalities that can lead to clinically significant deep vein thrombosis (DVT) in a subset of otherwise healthy patients. This report illustrates an uncommon congenital anomaly that military clinicians should consider when evaluating unprovoked DVT in young patients. Materials and Methods: Single case report and literature review. Results: We describe a case of a 24-yr old United States Marine who presented with abdominal pain for 2 wk. After conservative therapy failed, a contrast-enhanced abdominal computed tomography (CT) scan was performed. The CT scan revealed an absent inferior vena cava with evidence of right venous thrombophlebitis. We include four contrast-enhanced helical CT scans that illustrate this phenomenon. Conclusion: Due to the lack of available studies and data, we do not know the relative risk of DVT in patients with AIVC. However, the literature review suggests that there is a pro thrombogenic effect of this congenital anomaly. Clinicians should include AIVC in their differential when treating young, otherwise healthy patients with unprovoked DVT. This population is much more likely to have an AIVC than the general population. In addition to thrombophilia markers, a contrast-enhanced CT scan should be considered as part of the initial workup. PMID- 29401343 TI - Health- and Performance-Related Outcomes in Air Force Medical Service Personnel with a Post-Deployment Mental Health Condition. AB - Background: This study examined associations between incident post-deployment mental health (PDMH) conditions and health- and performance-related outcomes in the population of Air Force Medical Service personnel on active duty between 2003 and 2013 who had at least one deployment. Methods: Using a posttest-only with nonequivalent groups design, the study cohort was divided into two groups based on the occurrence of an incident PDMH condition, and the groups were then compared in terms of the following health- and performance-related outcomes: health care and pharmaceutical utilization, duty and mobility restrictions, and physical fitness assessment exemptions and composite fitness score. Archival data were extracted from existing databases and associations were assessed using both parametric and nonparametric approaches. Results: The cohort comprised 12,216 participants, from which subcohorts were drawn to assess specific outcome measures. Participants with an incident PDMH used health care at 1.8 times the rate and were 6.2 times more likely to be classified as a high utilizer of health care as compared with those without a PDMH condition (controls). They were 2.1 103.0 times more likely to be prescribed one of 22 therapeutic classes of medication and were 2.4 times more likely to have polypharmacy than controls. They were 2.5 times more likely to have a duty or mobility restriction, and the ratio of days spent with a restriction to days without a restriction was 1.8 times that of controls. Lastly, they were 2.4 times more likely to have a physical fitness assessment exemption, but there was no significant difference in the likelihood of a composite fitness score of <90 points. Conclusions: The presence of an incident PDMH condition was associated with increased health care and pharmaceutical utilization and decreased occupational performance as assessed in terms of restricted duty status and participation in physical fitness assessments. PMID- 29401344 TI - Considerations for Retrograding Deployed Army Pharmacy Operations: What about Department of Defense Civilian Contractors? Lessons from Kosovo. AB - Background: Over the past two decades, changes in mission and expectations of deployed medical assets are requiring adaptations of pharmacy services. Specifically, the Department of Defense (DOD)-deployed contractors in theater are now eligible for varying levels of care from DOD-deployed assets. Pharmacy must now stock and maintain a complex medication footprint. This new requirement makes the attempt to retrograde a long established deployed pharmacy difficult and presents new challenges. Methods: We review the issues surrounding this quandary from the perspective of the deployed pharmacy in Kosovo, one of the longest standing theaters of deployed medical assets. Findings: Data from the 20th and 21st medical rotations in this theater demonstrate that DOD contractors consume a significant portion of pharmacy operational support. However, not only do contractors increase the volume but also pharmacy must address the use and monitoring of complex medications such as anticoagulants, antidiabetics, sleep, and psychiatric medications, as well as chronic obstructive pulmonary disease and asthma drugs, which are not typical in the deployed environment. Discussion/Impact/Recommendations: Contractors are now serving in the Balkan theater at a greater than 1:1 ratio of contractors to soldiers. Contractors are typically older than deployed soldiers and thus their pharmaceutical needs are more complex. This complicates the pharmacy operation, which on the one hand is trying to retrograde as the mission winds down, yet, on the other hand, must expand to more complex operations to support the DOD contractors in theater. PMID- 29401345 TI - Psychiatric History, Deployments, and Potential Impacts of Mental Health Care in a Combat Theater. AB - Introduction: Increasing numbers of U.S. service members access mental health care while deployed and at home station. Multiple deployments carry with them a higher risk of exposure to combat as well as the impact of cumulative stressors associated with separation from family, hostile environments, and high operations tempo. However, mental health care resources continue to be underutilized, potentially because of higher levels of stigma regarding mental health care and concerns about career impact among service members. Some studies indicate that service members who have previously sought mental health care are likely to continue to do so proactively as needed. This study examined the associations between prior deployments, prior mental health treatment, and subsequent career impacting recommendations (e.g., duty limitations and medical evacuation) among deployed service members seeking mental health care. Materials and. Methods: This study is a retrospective review of clinical records from three U.S. military Combat and Operational Stress Control units in Afghanistan. Data were drawn from the mental health records of 1,639 Army service members presenting for outpatient mental health services while deployed in Afghanistan from years 2006 to 2008. Results: In an unadjusted logistic regression model, service members with at least one prior deployment had a 38% greater odds (odds ratio [OR] = 1.38, 95% confidence interval [95% CI] 1.06, 1.80; p < 0.05) of receiving career-impacting recommendations than those without a prior deployment. However, after adjusting for demographics (age, gender, marital status, rank, and military status), there was no association between prior deployments and career-impacting recommendations (OR = 1.06, 95% CI 0.78, 1.43; p = 0.716). In the second unadjusted model, service members with prior mental health treatment had a 57% lower odds (OR = 0.43, 95% CI 0.34, 0.56; p < 0.001) of receiving career-impacting recommendations than those without prior mental health treatment. After adjusting for demographics and number of prior deployments, service members with prior mental health treatment had a 58% lower odds (OR = 0.42, 95% CI 0.33, 0.56; p < 0.001) of receiving career-impacting recommendations than those without prior mental health treatment. Conclusion: Among service members who had a clinical mental health encounter, prior deployment was not associated with career-impacting recommendations and prior mental health treatment appeared to be protective against career-impacting recommendations. These results are in line with research indicating that service members who have previous experience with mental health care tend to seek help sooner than those without prior treatment. Those service members who had previously sought care were more likely to express decreased stigma and seek mental health care while deployed. Consequently, service members who have prior mental health treatment may seek care before their concerns become marked enough to warrant duty-limiting recommendations to command. These findings have important implications for campaigns to reduce stigma and promote early help seeking among service members. Efforts should continue to study and respectively make known the rates of career impact with the goal of increased early service utilization and increased ability to sustain service members' military readiness and personal functioning. PMID- 29401346 TI - Future Health and Economic Impact of Comprehensive Tobacco Control in DoD: A Microsimulation Approach. AB - Background: Tobacco use is a major concern to the Military Health System of the Department of Defense (DoD). The 2011 DoD Health Related Behavior Survey reported that 24.5% of active duty personnel are current smokers, which is higher than the national estimate of 20.6% for the civilian population. Overall, it is estimated that tobacco use costs the DoD $1.6 billion a year through related medical care, increased hospitalization, and lost days of work, among others. Methods: This study evaluated future health outcomes of Tricare Prime beneficiaries aged 18-64 yr (N = 3.2 million, including active duty and retired military members and their dependents) and the potential economic impact of initiatives that DoD may take to further its effort to transform the military into a tobacco-free environment. Our analysis simulated the future smoking status, risk of developing 25 smoking related diseases, and associated medical costs for each individual using a Markov Chain Monte Carlo microsimulation model. Data sources included Tricare administrative data, national data such as Centers for Disease Control and Prevention mortality data and National Cancer Institute's cancer registry data, as well as relative risks of diseases obtained from a literature review. Findings: We found that the prevalence of active smoking among the Tricare Prime population will decrease from about 24% in 2015 to 18% in 2020 under a status quo scenario. However, if a comprehensive tobacco control initiative that includes a 5% price increase, a tighter clean air policy, and an intensified media campaign were to be implemented between 2016 and 2020, the prevalence of smoking could further decrease to 16%. The near 2 percentage points reduction in smoking prevalence represents an additional 81,240 quitters and translates to a total lifetime medical cost savings (in 2016 present value) of $968 million, with 39% ($382 million) attributable to Tricare savings. Discussion: A comprehensive tobacco control policy within the DoD could significantly decrease the prevalence and lifetime medical cost of tobacco use. If the smoking prevalence among Prime beneficiaries could reach the Healthy People 2020 goal of 12%, through additional measures, the lifetime savings could mount to $2.08 billion. To achieve future savings, DoD needs to pay close attention to program design and implementation issues of any additional tobacco control initiatives. PMID- 29401347 TI - Implementation of a Screening and Management of Overweight and Obesity Clinical Practice Guideline in an Ambulatory Care Setting. AB - Introduction: Obesity is a rapidly growing health problem reaching epidemic levels around the world (World Health Organization, 2014). According to the World Health Organization, the current incident rate of obesity makes it the leading risk for deaths across the globe. The United States (USA) is amidst in this growing global epidemic. The obesity epidemic is a nondiscriminatory health problem affecting millions of individuals from a variety of backgrounds and social status. One group impacted by this disease is the US military. The health related consequences of overweight and obesity has increased our military health care expenditures and has a direct impact on our nation's military readiness (Veterans Affairs/Department of Defense, 2014). Materials and Methods: The purpose of this Doctor of Nursing Practice project was to implement the Veterans Affairs/Department of Defense's Clinical Practice Guideline on Screening and Management of Overweight and Obesity at a military treatment facility in the Midwest. The goal of the project was to reduce the incidence rate of overweight and obese active duty military service members assigned to a military installation in the Midwest. With institutional review board approval, project implementation results were analyzed with descriptive and inferential statistics (paired t- tests). Results: The goal to reduce the incident rate of overweight and obese by 5% was not achieved, but in turn the rate of overweight and obese increased by 1.57% over the 6-mo period. There were decreases in the normal with an increase in the overweight and obesity rate. This inverse outcome was unexpected and concerning. Conclusion: Based on the project's finding, there is a need to address the perceived barriers to maintaining healthy behaviors to plan future activities. An in-depth look at whether there is a knowledge deficit, a perceived lack of self-efficacy, competing life priorities preventing engagement in health promotion behaviors, or some other element influencing the motivation to change would be beneficial to understanding how to curb the growing rate of obesity. The utilization of the transtheoretical model of behavior change would make a sound theoretical framework to base such a new study, focusing on the stages of change as it relates to health promotion behaviors. PMID- 29401348 TI - Evaluation of the Group Lifestyle Balance Program in a Military Setting: An Investment Worth Expanding. AB - Introduction: The Diabetes Prevention Program (DPP) demonstrated that lifestyle intervention programs were effective in preventing or delaying the onset of diabetes. The Group Lifestyle Balance (GLB) program translated the DPP curriculum into a 12-wk group intervention for those at risk for diabetes. This retrospective evaluation examined clinical outcomes for patients in the Diabetes Center of Excellence GLB program located at Wilford Hall Ambulatory Surgical Center from 2009 to 2013. Objectives included determining rates of retention, demographic characteristics of program completers, and changes in metabolic surrogates of disease prevalence. Study Design: Adults with prediabetes or metabolic syndrome (MetS) were referred to the GLB program. Updated participant metabolic data were collected at regular intervals during their participation. Results: During the 5-yr study, 704 patients attended the initial class. Overall, 52% of all participants completed the program with the greatest decline in participation occurring by the fourth week (30%). Baseline prevalence of conditions of interest for those who completed the program was prediabetes (93.2%), obesity (56.1%), and MetS (31.5%). GLB completers were older and retired (p < 0.05). A significant number of active duty military members (44.9%, p < 0.01, n = 53) dropped out of the program before the fourth week. Furthermore, those who completed the program saw a 2.0% reduction in prediabetes prevalence (p < 0.001), obesity decreased by 8.7% (p < 0.001), and MetS decreased by 6.8% (p < 0.01). Significant differences were found for central obesity, triglycerides, and fasting blood sugar (p < 0.001). Conclusions: The GLB program is a valuable DPP and was effective at improving clinical outcomes and reducing the incidence of prediabetes, obesity, and MetS for participants who completed the program. Every effort should be made to support and encourage GLB participants to complete the program. PMID- 29401349 TI - Intracardiac Heterotopic Liver Presenting as a Right Atrial Myxoma: A Case Report. AB - Intracardiac heterotopic liver is a very rare entity. The most unique aspect of this entity is the increased carcinogenic potential of the tissue. This condition must be considered when assessing an intracardiac mass along with more common differential diagnoses such as neoplasms, thrombi, and vegetations. In this report, we present a case of a patient who presented to cardiac surgery for elective excision of a right atrial mass that was determined to be an accessory liver lobe. We discuss the diagnostic challenges, clinical management, and surgical and anesthetic implications of this rare finding. PMID- 29401350 TI - Academic Medicine in the Military Health System: Problems and Solutions for Academic Leadership Development. PMID- 29401351 TI - Emergency Department Waiting Times in an Israeli Children's Hospital During Times of Military Conflict. AB - Introduction: During military conflicts in southern Israel, many families moved north, and hospitals and primary care clinics under threat of missile attacks referred their patients to hospitals outside the combat zone, causing overcrowding of the emergency departments (ED). The study objective is to examine the effect of military conflicts on ED waiting time in a children's hospital outside the combat zone. Materials and Methods: A retrospective cohort study of patients admitted between January 2011 and December 2015 was conducted. Multivariable regression was used to examine the effect of age, gender, triage category, arrival time, weekday, and period of admission (peacetime and time of military conflict) on waiting time. Results: Totally, 79,825 children were admitted in peacetimes and 3,058 in times of military conflict. Factors that most influenced shorter waiting times were triage category 1 (change in waiting time: 25.5%; 95% confidence interval: -29.3 to -21.7) or triage category 2 (change in wait time: -21.8%; 95% confidence interval: -23.7 to -20.05). Arriving during times of military conflict did not influence ED waiting time (p=0.18). ED waiting times during times of peace and times of military conflict were 38 min of interquartile range (21-65) and 38 min of interquartile range (22-65), respectively. Conclusions: In this report of a large cohort of patients, waiting times were similar during periods of peace and periods of military conflict. The findings suggest that the 2012 and the 2014 military conflicts did not influence ED waiting times in a hospital outside the combat zone, despite the population shift that occurred during these conflicts. This study is the first to examine the association between periods of military conflict and ED waiting time in children. PMID- 29401352 TI - Fibrinogen Concentrate in the Special Operations Forces Environment. AB - Introduction: Hemorrhage is the most common cause of death among Special Operations Force (SOF) soldiers. Bringing remote damage control resuscitation into the far-forward combat environment is logistically challenging, as it requires blood products that generally require a robust cold chain. Alternatively, lyophilized products such as fibrinogen concentrate, which does not require thawing or blood group compatibility testing before use, might be advantageous in damage control resuscitation in the battlefield. In this report, we review the evidence for the use of fibrinogen concentrate in the Canadian SOF environment. Materials and Methods: The literature on the use of fibrinogen concentrate in the trauma setting was reviewed by Canadian Forces Services Working Group, in three separate meetings. Multiple stakeholders were consulted to obtain authoritative perspectives from subject matter experts on the use of fibrinogen concentrate in the Canadian SOF environment. We also conducted a comparison review of fibrinogen content, pathogen risk, shelf life, and methods required for use for fresh frozen plasma, cryoprecipitate, and fibrinogen concentrate relevant to their application in the far-forward combat environment. Results: Indications and a protocol for the use of fibrinogen as an adjunct to fresh whole blood were formulated based on a literature review and clinical expert opinion. Alternative strategies and other lyophilized blood products were considered before selecting fibrinogen concentrate as the lyophilized blood product of choice. Fibrinogen concentrate is an ABO-universal blood product with an excellent safety profile. Training was conducted by subject matter experts within civilian trauma centers and at military training facilities. The clinical efficacy and safety were confirmed by monitoring the use of fibrinogen concentrate in deployed combat settings. Conclusion: Fibrinogen concentrate is a useful adjunct to remote damage control resuscitation in the SOF environment. Fibrinogen concentrate was found to be robust for transport into the SOF environment and is widely accepted among SOF operators and medics. PMID- 29401353 TI - The Transcendental Meditation Program's Impact on the Symptoms of Post-traumatic Stress Disorder of Veterans: An Uncontrolled Pilot Study. AB - Background: Current treatments for post-traumatic stress disorder (PTSD) are only partially effective. This study evaluated whether an extensively researched stress reduction method, the Transcendental Meditation (TM) technique, can reduce the PTSD symptoms of veterans. Previous research suggested that TM practice can decrease veterans' PTSD symptoms. Methods: A one-group pretest-posttest design was used to evaluate the impact of TM practice on reducing PTSD symptoms. A convenience sample of 89 veterans completed PTSD Checklist-Civilian (PCL-5) questionnaires. Among those, 46 scored above 33, the threshold for provisional diagnosis of PTSD, and were included in this evaluation. The PCL-5 measured PTSD symptoms at baseline and 30 and 90 d after intervention. Regularity of TM practice was recorded. Paired sample t-tests were used to assess within-group changes from baseline to post-intervention periods. Analysis of variance was used to compare full-dose (two 20-min TM sessions per day) and half-dose (one 20-min TM session per day) groups. Findings: After 1 mo of TM practice, all 46 veterans responded; their PCL-5 average decreased from 51.52 in the pre-intervention period to a post-intervention mean of 23.43, a decline of 28.09 points (-54.5%); standard deviation: 14.57; confidence interval: 23.76-32.41; and effect size: 1.93; p < 0.0001. The median PTSD scores declined from 52.5 to 22.5, a decrease of 30 points (-57%), while 40 veterans (87%) had clinically significant declines (>10 points) in PTSD symptoms, and 37 (80%) dropped below the clinical level (<33). At the 90 d posttest, 31 of the 46 responded and three more dropped below the 33 threshold. Intent-to-treat analyses revealed clinically and statistically significant effects. A dose-response effect suggested a causal relationship. The full-dose group exhibited larger mean declines in PTSD symptoms than the half dose group. Averages of the 46 veterans' responses to 20 PCL-5 questions exhibited significant (p < 0.0001) declines from the pre-intervention period to the 30-d post-intervention assessment. Discussion: Results indicated that TM practice reduced PTSD symptoms without re-experiencing trauma. Because of the magnitude of these results and dose-response effect, regression to the mean, spontaneous remission of symptoms, and placebo effects are unlikely explanations for the results. Major limitations were absence of random assignment and lack of a control group. Participants chose to start and continue TM practice and to complete PCL-5 questionnaires. Those who self-selected to enter this study may not be representative of all veterans who have PTSD. Those who did not complete follow-up questionnaires at 90 d may or may not have had the same results as those who responded. The design and sampling method affect the generalizability of the results to wider populations. When taking into account these results and all previous research on the TM technique in reducing psychological and physiological stress, the convergence of evidence suggests that TM practice may offer a promising adjunct or alternative method for treating PTSD. Because of the widely recognized need to identify effective new approaches for treating PTSD, randomized research with control groups is warranted to further investigate the effectiveness of TM practice as a treatment for PTSD. PMID- 29401354 TI - Severe Sympathomimetic Toxidrome in a French Soldier: How Caffeine Overdose Can Lead to Severe Consequences. AB - We report the case of a French soldier, 29-yr-old, hospitalized in intensive care unit at Begin Military Hospital for the management of a sympathomimetic syndrome associated with severe metabolic disorders. Diagnosis of voluntary caffeine overdose was made. The evolution was favorable after metabolic disorders correction, without the need for dialysis. Caffeine is a molecule free of serious adverse effects when consumed at low doses. However, when consumed at high doses, it can become toxic and lead to death. Caffeine consumption has increased in recent years and especially in French Army. This toxicity remains unknown by a large part of population. We must be vigilant because this substance misuse can lead to serious consequences. PMID- 29401355 TI - Animal-Assisted Therapy for Post-traumatic Stress Disorder: Lessons from "Case Reports" in Media Stories. AB - Post-traumatic stress disorder (PTSD) can follow war trauma, sexual abuse, other traumas, and even be experienced by commanders for the PTSD of their subordinates. Medications and counseling are sometimes not effective, so new treatments are needed. Some years ago, I suggested that animal-assisted therapy (AAT) (pet therapy) might be beneficial for PTSD. A large randomized controlled trial is underway of canine-assisted therapy for PTSD. Randomized controlled trials are most useful in assessing the efficacy of a medical intervention as these trials control for known and unknown biases. However, due to their very nature and rigorous requirements, knowledge gained from randomized controlled trials may need to be supplemented from other kinds of studies. Here, I note that media reports of AAT for PTSD may effectively function as case reports and suggest further studies: For PTSD, these demonstrate that (1) AAT can be dramatically effective in improving PTSD symptoms; (2) there is the potential for benefit from AAT by multiple different animals besides canines for PTSD; and (3) AAT may have a role in preventing suicide in patients with PTSD. PMID- 29401356 TI - Patient-Clinician Communication About Pain: A Conceptual Model and Narrative Review. AB - Objective: Productive patient-clinician communication is an important component of effective pain management, but we know little about how patients and clinicians actually talk about pain in clinical settings and how it might be improved to produce better patient outcomes. The objective of this review was to create a conceptual model of patient-clinician communication about noncancer pain, review and synthesize empirical research in this area, and identify priorities for future research. Methods: A conceptual model was developed that drew on existing pain and health communication research. CINAHL, EMBASE, and PubMed were searched to find studies reporting empirical data on patient clinician communication about noncancer pain; results were supplemented with manual searches. Studies were categorized and analyzed to identify crosscutting themes and inform model development. Results: The conceptual model comprised the following components: contextual factors, clinical interaction, attitudes and beliefs, and outcomes. Thirty-nine studies met inclusion criteria and were analyzed based on model components. Studies varied widely in quality, methodology, and sample size. Two provisional conclusions were identified: contrary to what is often reported in the literature, discussions about analgesics are most frequently characterized by patient-clinician agreement, and self-presentation during patient-clinician interactions plays an important role in communication about pain and opioids. Conclusions: Published studies on patient-clinician communication about noncancer pain are few and diverse. The conceptual model presented here can help to identify knowledge gaps and guide future research on communication about pain. Investigating the links between communication and pain-related outcomes is an important priority for future research. PMID- 29401357 TI - Diagnosis, pathogenesis and outcome in leucocyte chemotactic factor 2 (ALECT2) amyloidosis. AB - Introduction: Renal biopsy series from North America suggest that leucocyte chemotactic factor 2 (ALECT2) amyloid is the third most common type of renal amyloid. We report the first case series from a European Centre of prevalence, clinical presentation and diagnostic findings in ALECT2 amyloidosis and report long-term patient and renal outcomes for the first time. Methods: We studied the clinical features, diagnostic investigations and the outcome of all patients with ALECT2 amyloidosis followed systematically at the UK National Amyloidosis Centre (NAC) between 1994 and 2015. Results: Twenty-four patients, all non-Caucasian, were diagnosed with ALECT2 amyloidosis representing 1.3% of all patients referred to the NAC with biopsy-proved renal amyloid. Diagnosis was made at median age of 62 years, usually from renal histology; immunohistochemical staining was definitive for ALECT2 fibril type. Median estimated glomerular filtration rate (GFR) at diagnosis was 33 mL/min/1.73 m2 and median proteinuria was 0.5 g/24 h. Hepatic amyloid was evident on serum amyloid P component (SAP) scintigraphy in 11/24 cases but was not associated with significant derangement of liver function. No patient had evidence of cardiac amyloidosis or amyloid neuropathy. Median follow-up was 4.8 (range 0.5-15.2) years, during which four patients died and four progressed to end-stage renal disease. The mean rate of GFR loss was 4.2 (range 0.5-9.6) mL/min/year and median estimated renal survival from diagnosis was 8.2 years. Serial SAP scans revealed little or no change in total body amyloid burden. Conclusions: ALECT2 amyloidosis is a relatively benign type of renal amyloid, associated with a slow GFR decline, which is reliably diagnosed on renal histology. Neither the molecular basis nor the factors underlying the apparent restriction of ALECT2 amyloidosis to non-Caucasian populations have been determined. PMID- 29401358 TI - Women and kidney disease: reflections on World Kidney Day 2018: Kidney Health and Women's Health: a case for optimizing outcomes for present and future generations. AB - Chronic kidney disease (CKD) affects ~10% of the world's adult population: it is one of the top 20 causes of death worldwide and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day coincide in 2018, thus offering an opportunity to reflect on the importance of women's health, and specifically their kidney health, on the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply these learnings more broadly. Girls and women, who make up ~50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for the diagnosis of kidney disease, and also a state where acute and chronic kidney diseases may manifest and that may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for childbearing and on the fetus. Women have different complications on dialysis than men and are more likely to be donors than recipients of kidney transplants. In this editorial we focus on what we do and do not know about women, kidney health and kidney disease and what we might learn in the future to improve outcomes worldwide. PMID- 29401359 TI - Anti-phospholipase A2 receptor antibodies in primary membranous nephropathy-10 key points. PMID- 29401360 TI - Using Web-Based Questionnaires to Assess Medication Use During Pregnancy: A Validation Study in 2 Prospectively Enrolled Cohorts. AB - Medication use is often underreported in paper-based questionnaires or interviews. Web-based questionnaires may improve recall of medication use, but data on their validity are currently lacking. Participants in the Pregnancy and Infant Development (PRIDE) Study (2014-2016; n = 557) and the Pregnancy Drug Registry (pREGnant) (2015-2016; n = 169) completed a 6-week paper-based medication diary during gestational weeks 19-24 or 26-31. In week 34, they completed a Web-based questionnaire with questions on medication names, time period and frequency of use, and quantity taken. To assess the degree of underreporting, we calculated the questionnaire's sensitivity using the medication diary as the reference standard. Sensitivity was high for many medication groups, including antiepileptic medication (sensitivity (Sn) = 0.96, 95% confidence interval (CI): 0.89, 1.00), antacids (Sn = 0.89, 95% CI: 0.86, 0.93), and iron preparations (Sn = 0.81, 95% CI: 0.64, 0.98). However, medications for short-term use were underreported more frequently, with sensitivities of 0.54 (95% CI: 0.35, 0.72) for antihistamines, 0.63 (95% CI: 0.57, 0.69) for analgesic and antipyretic agents, and 0.57 (95% CI: 0.51, 0.64) for acetaminophen. Shortening the period of time between exposure and questionnaire administration increased sensitivity substantially. In conclusion, underreporting in Web-based questionnaires is limited for many medication groups. In prospective studies, underreporting of medications for short-term use may be reduced by decreasing the interval between consecutive questionnaires. PMID- 29401361 TI - A Multiple-Imputation "Forward Bridging" Approach to Address Changes in the Classification of Asian Race/Ethnicity on the US Death Certificate. AB - The incomparability of old and new classification systems for describing the same data can be seen as a missing-data problem, and, under certain assumptions, multiple imputation may be used to "bridge" 2 classification systems. One example of such a change is the introduction of detailed Asian-American race/ethnicity classifications on the 2003 version of the US national death certificate, which was adopted for use by 38 states between 2003 and 2011. Using county- and decedent-level data from 3 different national sources for pre- and postadoption years, we fitted within-state multiple-imputation models to impute ethnicities for decedents classified as "other Asian" during preadoption years. We present mortality rates derived using 3 different methods of calculation: 1) including all states but ignoring the gradual adoption of the new death certificate over time, 2) including only the 7 states with complete reporting of all ethnicities, and 3) including all states and applying multiple imputation. Estimates from our imputation model were consistently in the middle of the other 2 estimates, and trend results demonstrated that the year-by-year estimates of the imputation model were more similar to those of the 7-state model. This work demonstrates how multiple imputation can provide a "forward bridging" approach to make more accurate estimates over time in newly categorized populations. PMID- 29401362 TI - Diversification of Pseudomonas aeruginosa within the cystic fibrosis lung and its effects on antibiotic resistance. AB - The evolution and diversification of bacterial pathogens within human hosts represent potential barriers to the diagnosis and treatment of life-threatening infections. Tremendous genetic and phenotypic diversity is characteristic of host adaptation in strains of Pseudomonas aeruginosa that infect the airways of individuals with chronic lung diseases and prove to be extremely difficult to eradicate. In this MiniReview, we examine recent advances in understanding within host diversity and antimicrobial resistance in P. aeruginosa populations from the lower airways of individuals with the fatal genetic disease cystic fibrosis and the potential impacts that this diversity may have on detecting and interpreting antimicrobial susceptibility within these populations. PMID- 29401363 TI - FORAGES AND PASTURES SYMPOSIUM: COVER CROPS IN LIVESTOCK PRODUCTION: WHOLE-SYSTEM APPROACH: Managing grazing to restore soil health and farm livelihoods. AB - To ensure long-term sustainability and ecological resilience of agroecosystems, agricultural production should be guided by policies to ensure regenerative cropping and grazing management protocols. Changing current unsustainable high input agricultural practices to low-input practices that regenerate ecosystem function will be necessary for sustainable, resilient agroecosystems. Effective soil management provides the greatest potential for achieving sustainable use of agricultural land with rapidly changing, uncertain and variable climate. With appropriate management of grazing enterprises, soil function can be regenerated to improve essential ecosystem services and farm profitability. Affected ecosystem services include carbon sequestration, water infiltration, soil fertility, nutrient cycling, soil formation, biodiversity, wildlife habitat, and increased ecosystem stability and resilience. Collectively, conservation agriculture managed regeneratively supports ecologically healthy, resilient agroecosystems and enhances watershed function. To accomplish this, it is important for scientists to partner with farmers who have improved the environment and excel financially to convert experimental results into sound environmental, social, and economic benefits regionally and globally. Benefits include addressing questions at commercial scale; integrating component science into whole-system responses; identifying emergent properties and unintended consequences; incorporating pro-active management to achieve desired goals under changing circumstances; and including the potential of the human element to achieve superior economic and environmental goals. Developing and implementing regenerative management protocols that include ruminant grazing animals will be necessary to ensure long-term sustainability and ecological resilience of agroecosystems. PMID- 29401364 TI - Effects of Elevated Atmospheric CO2 on Respiratory Rates in Mature Leaves of Two Rice Cultivars Grown at a Free-Air CO2 Enrichment Site and Analyses of the Underlying Mechanisms. AB - Respiratory CO2 efflux and O2 uptake rates in leaves change in response to the growth CO2 concentration ([CO2]). The degrees of change vary depending on the responses of cellular processes such as nitrogen (N) assimilation and accumulation of organic acids to growth [CO2]. However, the underlying mechanisms remain unclear. Here, we examined the respiratory characteristics of mature leaves of two rice varieties with different yield capacities at different growth stages under ambient and elevated [CO2] conditions at a free-air CO2 enrichment site. We also examined the effect of increased water temperature on leaf respiration. We measured the rates of CO2 efflux and O2 uptake, and determined N contents, primary metabolite contents and maximal activities of respiratory enzymes. The leaf CO2 efflux rates decreased in plants grown at elevated [CO2] in both varieties, and were higher in high-yielding Takanari than in Koshihikari. The leaf O2 uptake rates showed little change with respect to growth [CO2] and variety. The increased water temperature did not significantly affect the CO2 efflux and O2 uptake rates. The N and amino acid contents were significantly higher in Takanari than in Koshihikari. The enhanced N assimilation in Takanari may have consumed more respiratory NADH, leading to higher CO2 efflux rates. In Koshihikari, the ratio of tricarboxylic acid (TCA) cycle intermediates changed and maximal activities of enzymes in the TCA cycle decreased at elevated [CO2]. Therefore, the decreased rates of CO2 efflux in Koshihikari may be due to the decreased activities of TCA cycle enzymes at elevated [CO2]. PMID- 29401365 TI - 2017 Reviewers. PMID- 29401366 TI - High-Quality Orthopedic Research Is Having an Impact. PMID- 29401367 TI - Patient-Reported Outcome Measures in Perspective. PMID- 29401368 TI - Three-dimensional Technologies in Orthopedics. AB - New 3-dimensional digital technologies are revolutionizing orthopedic clinical practice, allowing structures of any complexity to be manufactured in just hours. Such technologies can make surgery for complex cases more precise, more cost effective, and possibly easier to perform. Applications include pre-operative planning, surgical simulation, patient-specific instrumentation and implants, bioprinting, prosthetics, and orthotics. The basic principles of 3- dimensional technologies, including imaging, design, numerical simulation, and printing, and their current applications in orthopedics are reviewed. [Orthopedics. 2018; 41(1):12-20.]. PMID- 29401369 TI - Prophylactic vitamin K for the prevention of vitamin K deficiency bleeding in preterm neonates. AB - BACKGROUND: Vitamin K is necessary for the synthesis of coagulation factors. Term infants, especially those who are exclusively breast fed, are deficient in vitamin K and consequently may have vitamin K deficiency bleeding (VKDB). Preterm infants are potentially at greater risk for VKDB because of delayed feeding and subsequent delay in the colonization of their gastrointestinal system with vitamin K producing microflora, as well as immature hepatic and hemostatic function. OBJECTIVES: To determine the effect of vitamin K prophylaxis in the prevention of vitamin K deficiency bleeding (VKDB) in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 11), MEDLINE via PubMed (1966 to 5 December 2016), Embase (1980 to 5 December 2016), and CINAHL (1982 to 5 December 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs of any preparation of vitamin K given to preterm infants. DATA COLLECTION AND ANALYSIS: We evaluated potential studies and extracted data in accordance with the recommendations of Cochrane Neonatal. MAIN RESULTS: We did not identify any eligible studies that compared vitamin K to no treatment.One study compared intravenous (IV) to intramuscular (IM) administration of vitamin K and compared various dosages of vitamin K. Three different prophylactic regimes of vitamin K (0.5 mg IM, 0.2 mg vitamin K1, or 0.2 mg IV) were given to infants less than 32 weeks' gestation. Given that only one small study met the inclusion criteria, we assessed the quality of the evidence for the outcomes evaluated as low.Intramuscular versus intravenousThere was no statistically significant difference in vitamin K levels in the 0.2 mg IV group when compared to the infants that received either 0.2 or 0.5 mg vitamin K IM (control) on day 5. By day 25, vitamin K1 levels had declined in all of the groups, but infants who received 0.5 mg vitamin K IM had higher levels of vitamin K1 than either the 0.2 mg IV group or the 0.2 mg IM group.Vitamin K1 2,3-epoxide (vitamin K1O) levels in the infants that received 0.2 mg IV were not statistically different from those in the control group on day 5 or 25 of the study. All of the infants had normal or supraphysiologic levels of vitamin K1 concentrations and either no detectable or insignificant amounts of prothrombin induced by vitamin K absence-II (PIVKA II).Dosage comparisonsDay 5 vitamin K1 levels and vitamin K1O levels were significantly lower in the 0.2 mg IM group when compared to the 0.5 mg IM group. On day 25, vitamin K1O levels and vitamin K1 levels in the 0.2 mg IM group and the 0.5 mg IM group were not significantly different. Presence of PIVKA II proteins in the 0.2 mg IM group versus the 0.5 mg IM group was not significantly different at day 5 or 25 of the study. AUTHORS' CONCLUSIONS: Preterm infants have low levels of vitamin K and develop detectable PIVKA proteins during the first week of life. Despite being at risk for VKDB, there are no studies comparing vitamin K versus non-treatment and few studies that address potential dosing strategies for effective treatment. Dosage studies suggest that we are currently giving doses of vitamin K to preterm infants that lead to supraphysiologic levels. Because of current uncertainty, clinicians will have to extrapolate data from term infants to preterm infants. Since there is no available evidence that vitamin K is harmful or ineffective and since vitamin K is an inexpensive drug, it seems prudent to follow the recommendations of expert bodies and give vitamin K to preterm infants. However, further research on appropriate dose and route of administration is warranted. PMID- 29401370 TI - Toward Enhancing Solar Cell Performance: An Effective and "Green" Additive. AB - Performance of bulk heterojunction polymer solar cells (PSCs) highly relies on the morphology of the photoactive layer involving conjugated polymers and fullerene derivatives as donors and acceptors, respectively. Herein, butylamine was found to be able to optimize the morphology of the donor/acceptor (D/A) film composed of a blend of poly(3-hexylthiophene-2,5-diyl) (P3HT) and phenyl-C61 butyric acid methyl ester (PCBM). Compared to the commonly used alkane dithiols and halogenated additives with high boiling points, butylamine has a much lower boiling point between 77 and 79 degrees C, and it is also much "greener". A specific interaction between butylamine and PCBM was demonstrated to account for the morphology improvement. Essentially, butylamine can selectively dissolve PCBM in the P3HT:PCBM blend and facilitate the diffusion of PCBM in the film fabrication processes. Atomic force microscopy and X-ray photoelectron spectroscopy investigations confirmed the formation of the P3HT-enriched top surface and the abundance of PCBM at the bottom side, i.e., the formation of vertical phase segregation, as a consequence of the specific PCBM-butylamine interaction. The D/A film with inhomogeneously distributed D and A components in the vertical film direction, with more P3HT at the hole extraction side and more PCBM at the electron extraction side, enables more efficient charge extraction in the D/A film, reflected by the largely enhanced fill factor. The power conversion efficiency of devices reached 4.03 and 4.61%, respectively, depending on the thickness of the D/A film, and these are among the best values reported for P3HT:PCBM-based devices. As compared to the devices fabricated without the introduction of butylamine under otherwise the same processing conditions, they represented 19.6 and 21.6% improvement in the efficiency, respectively. The discovery of butylamine as a new, effective additive in enhancing the performance of PSCs strongly suggests that the differential affinity of additives toward donors and acceptors likely plays a more important role in morphology optimization than their boiling point, different from what was reported previously. The finding provides useful information for realizing large-area PSC fabrication, where a "greener" additive is always preferred. PMID- 29401371 TI - Life Cycle Environmental Impacts of Disinfection Technologies Used in Small Drinking Water Systems. AB - : Small drinking water systems serve a fifth of the U.S. population and rely heavily on disinfection. While chlorine disinfection is common, there is interest in minimizing chemical addition, especially due to carcinogenic disinfection byproducts and chlorine-resistant pathogens, by using ultraviolet technologies; however, the relative, broader environmental impacts of these technologies are not well established, especially in the context of small (<10 000 people) water systems. The objective of this study was to identify environmental trade-offs between chlorine and ultraviolet disinfection via comparative life cycle assessment. The functional unit was the production of 1 m3 of drinking water to U.S. STANDARDS: Treatment included cartridge filtration followed by either chlorine disinfection or ultraviolet disinfection with chlorine residual addition. Environmental performance was evaluated for various chlorine contact zone materials (plastic, concrete, steel), ultraviolet validation factors (1.2 to 4.4), and electricity sources (renewable; U.S. average, high, and low impact grids). Performance was also evaluated when filtration and chlorine residual were not required. From a life cycle assessment perspective, replacing chlorine with UV was preferred only in a limited number of cases (i.e., high pumping pressure but filtration is not required). In all others, chlorine was environmentally preferred, although some contact zone materials and energy sources had an impact on the comparison. Utilities can use these data to inform their disinfection technology selection and operation to minimize environmental and human health impacts. PMID- 29401372 TI - Determinants of Photolyase's DNA Repair Mechanism in Mesophiles and Extremophiles. AB - Light-driven DNA repair by extremophilic photolyases is of tremendous importance for understanding the early development of life on Earth. The mechanism for flavin adenine dinucleotide repair of DNA lesions is the subject of debate and has been studied mainly in mesophilic species. In particular, the role of adenine in the repair process is poorly understood. Using molecular docking, molecular dynamics simulations, electronic structure calculations, and electron tunneling pathways analysis, we examined adenine's role in DNA repair in four photolyases that thrive at different temperatures. Our results indicate that the contribution of adenine to the electronic coupling between the flavin and the cyclobutane pyrimidine dimer lesion to be repaired is significant in three (one mesophilic and two extremophilic) of the four enzymes studied. Our analysis suggests that thermophilic and hyperthermophilic photolyases have evolved structurally to preserve the functional position (and thus the catalytic function) of adenine at their high temperatures of operation. Water molecules can compete with adenine in establishing the strongest coupling pathway for the electron transfer repair process, but the adenine contribution remains substantial. The present study also reconciles prior seemingly contradictory conclusions on the role of adenine in mesophile electron transfer repair reactions, showing how adenine-mediated superexchange is conformationally gated. PMID- 29401373 TI - Series of In Situ Photoinduced Polymer Graftings for Sensitive Detection of Protein Biomarkers via Cascade Amplification of Liquid Crystal Signals. AB - Developing of new polymeric materials for the sensitive and rapid detection of trace protein biomarkers has attracted increasing attention in biomedical fields. Herein, series of in situ photoinduced polymer graftings were developed for sensitive detection of protein biomarkers by using featured cascade amplification of liquid crystal (LC) signals. The limit-of-detection (LOD) for native bovine serum albumin (BSA) molecules is around 10 MUg/mL in a LC biosensor before signal amplification. Upon the cascade amplification using surface-grafted polymers, poly[poly(ethylene glycol) methacrylate] grafting ( s-P(PEGMA)) exhibits superior amplification ability (104-fold lower than native BSA) than the other two graftings of poly(2-hydroxyethyl methacrylate) ( s-PHEMA) and poly(methacrylic acid) ( s-PMAA; 102-fold lower than native BSA). The contact angles of water and LC on the s-P(PEGMA) grafting show significant difference in comparison with s PHEMA and s-PMAA graftings ( p < 0.05), implying interfacial energies of the grafted polymers may dictate the orientational transition of LCs. The clinical urine samples collected from the patients with proteinuria were also used to confirm the feasibility of the polymer-amplified LC sensors for practical protein assays. The present work reveals that in situ photoinduced polymer grafting is one promising method to amplify the signals of LC biosensors for the rapid and sensitive detection of trace protein biomarkers. PMID- 29401374 TI - Efficient Osmotic Pressure Calculations Using Coarse-Grained Molecular Simulations. AB - Osmotic pressure data is increasingly used to parametrize all-atom simulation Force Fields (FFs), leading to large computational cost for larger molecules. Here, we show that the osmotic pressure can be calculated precisely using transferable coarse-grained FFs obtained from short atomistic simulations using an inhomogeneously regularized coarse-graining procedure. This is demonstrated for carbohydrates, where compared to the equivalent atomistic system, an increase of the computational efficiency by a factor of ~500 is achieved. PMID- 29401375 TI - Different Phosphorus Supplies Altered the Accumulations and Quantitative Distributions of Phytic Acid, Zinc, and Iron in Rice (Oryza sativa L.) Grains. AB - Development of rice cultivars with low phytic acid (lpa) is considered as a primary strategy for biofortification of zinc (Zn) and iron (Fe). Here, two rice genotypes (XS110 and its lpa mutant) were used to investigate the effect of P supplies on accumulations and distributions of PA, Zn, and Fe in rice grains by using hydroponics and detached panicle culture system. Results showed that higher P level increased grain PA concentration on dry matter basis (g/kg), but it markedly decreased PA accumulation on per grain basis (mg/grain). Meanwhile, more P supply reduced the amounts and bioavailabilities of Zn and Fe both in milled grains and in brown grains. Comparatively, lpa mutant was more susceptive to exogenous P supply than its wild type. Hence, the appropriate P fertilizer application should be highlighted in order to increase grain microelement (Zn and Fe) contents and improve nutritional quality in rice grains. PMID- 29401376 TI - Rate-Limiting Step in Batteries with Metal Oxides as the Energy Materials. AB - Metal oxides are used as the energy materials in some aqueous and nonaqueous batteries. However, a large overpotential and poor rate-performance limit their wide application. Low electrical conductivity of the oxide is commonly considered to be the reason for these limitations. The present study specifically reveals the electrochemical reduction process of alpha-Fe2O3 particles by using a cyclic voltammetry technique combined with an electron spectroscopy technique. SEM and TEM observe the phase and crystal structure transformation process during alpha Fe2O3 reduction at the nanoscale, and EDS analyzes the composition change of particles at various periods. The surface of alpha-Fe2O3 particles is reduced to an amorphous compound first, and then O2- ions diffuse from the crystal matrix toward the outside simultaneously causing defects inside the particles. Experiments prove that gamma-Fe2O3, Fe3O4, CuO, and Bi2O3 have the same rate limiting step as alpha-Fe2O3; that is, O2- ions diffuse inside the oxide particles toward the outside. The diffusion coefficients of O2- in these metal oxides are also estimated. This study demonstrates that the ionic conductivity of metal oxides is the critical factor which affects the overpotential and rate performance of the batteries with these oxides as active material, and the O2- ion diffusion coefficient must be considered when selecting or designing metal oxides as energy material. The conclusion that O2- diffusion in oxides is the rate-limiting step of their reduction may be applicable to a group of oxides whose reduction reaction is not involved in ion diffusion from an electrolyte into their crystal matrix. PMID- 29401377 TI - Understanding the Mechanical Properties and Structure Transition of Antheraea pernyi Silk Fiber Induced by Its Contraction. AB - Like most major ampullate silks of spider, the length of Antheraea pernyi silkworm silk can shrink to a certain degree when the fiber is in contact with water. However, what happens in terms of molecule chain level and how it correlates to the mechanical properties of the silk during its contraction is not yet fully understood. Here, we investigate the water-induced mechanical property changes as well as the structure transition of two kinds of A. pernyi silk fiber, which are forcibly reeled from two different individuals (silkworm a and silkworm b; the silk fiber from either one represents the lower and upper limit of the distribution of mechanical properties, respectively). The tensile test results present that most of the mechanical parameters except the post-yield modulus and breaking strain for both silk fibers have the same variation trend before and after their water contraction. Synchrotron FTIR and Raman spectra show that the native filament from silkworm a contains more alpha-helix structures than that in silkworm b filament, and these alpha-helices are partially converted to beta sheet structures after the contraction of the fibers, while the order of both beta-sheet and alpha-helix slightly increase. On the other side, the content and orientation of both secondary structural components in silkworm b fiber keep unchanged, no matter if it is native or contracted. 13C CP/MAS NMR results further indicate that the alpha-helix/random coil to beta-sheet conformational transition that occurred in the silk of silkworm a corresponds the Ala residues. Based upon these results, the detailed structure transition models of both as reeled A. pernyi silk fibers during water contraction are proposed finally to interpret their properties transformation. PMID- 29401378 TI - CD44-Targeted Facile Enzymatic Activatable Chitosan Nanoparticles for Efficient Antitumor Therapy and Reversal of Multidrug Resistance. AB - Nanoparticles are attractive platforms for the delivery of various anticancer therapeutics. Nevertheless, their applications are still limited by the relatively low drug loading capacity and the occurrence of multidrug resistance (MDR) against chemotherapeutics. In this study, we report that the integration of d-alpha-tocopherol succinate (VES) residue with both chitosan and paclitaxel (PTX) led to significant improvement of drug loading capacity and drug loading efficiency through the enhancement of drug/carrier interaction. After the incorporation of hyaluronic acid containing PEG side chains (HA-PEG), higher serum stability and more efficient cellular uptake were obtained. Due to HA coating, VES residues and the enzymatic responsive drug release property, such facile nanoparticles actively targeted cancer cells that overexpress CD44 receptor and efficiently reversed the MDR of treated cells, but caused no significant toxicity to mouse fibroblast (NIH-3T3). More importantly, with HA-PEG coating, longer blood circulation and more effective tumor accumulation were achieved for prodrug nanoparticles. Finally, superior anticancer activity and excellent safety profile was demonstrated by HA-PEG coated enzymatically activatable prodrug nanoparticles compared to commercially available Taxol formulation. PMID- 29401379 TI - Computing the Free Energy without Collective Variables. AB - We introduce an approach for computing the free energy and the probability density in high-dimensional spaces, such as those explored in molecular dynamics simulations of biomolecules. The approach exploits the presence of correlations between the coordinates, induced, in molecular dynamics, by the chemical nature of the molecules. Due to these correlations, the data points lay on a manifold that can be highly curved and twisted, but whose dimension is normally small. We estimate the free energies by finding, with a statistical test, the largest neighborhood in which the free energy in the embedding manifold can be considered constant. Importantly, this procedure does not require defining explicitly the manifold and provides an estimate of the error that is approximately unbiased up to large dimensions. We test this approach on artificial and real data sets, demonstrating that the free energy estimates are reliable for data sets on manifolds of dimension up to ~10, embedded in an arbitrarily large space. In practical applications our method permits the estimation of the free energy in a space of reduced dimensionality without specifying the collective variables defining this space. PMID- 29401380 TI - Effective Recovery of Vanadium from Oil Refinery Waste into Vanadium-Based Metal Organic Frameworks. AB - Carbon black waste, an oil refinery waste, contains a high concentration of vanadium(V) leftover from the processing of crude oil. For the sake of environmental sustainability, it is therefore of interest to recover the vanadium as useful products instead of disposing of it. In this work, V was recovered in the form of vanadium-based metal-organic frameworks (V-MOFs) via a novel pathway by using the leaching solution of carbon black waste instead of commercially available vanadium chemicals. Two different types of V-MOFs with high levels of crystallinity and phase purity were fabricated in very high yields (>98%) based on a coordination modulation method. The V-MOFs exhibited well-defined and controlled shapes such as nanofibers (length: > 10 MUm) and nanorods (length: ~270 nm). Furthermore, the V-MOFs showed high catalytic activities for the oxidation of benzyl alcohol to benzaldehyde, indicating the strong potential of the waste-derived V-MOFs in catalysis applications. Overall, our work offers a green synthesis pathway for the preparation of V-MOFs by using heavy metals of industrial waste as the metal source. PMID- 29401381 TI - Scalable Top-Down Approach Tailored by Interferometric Lithography to Achieve Large-Area Single-Mode GaN Nanowire Laser Arrays on Sapphire Substrate. AB - GaN nanowires are promising for optical and optoelectronic applications because of their waveguiding properties and large optical band gap. However, developing a precise, scalable, and cost-effective fabrication method with a high degree of controllability to obtain high-aspect-ratio nanowires with high optical properties and minimum crystal defects remains a challenge. Here, we present a scalable two-step top-down approach using interferometric lithography, for which parameters can be controlled precisely to achieve highly ordered arrays of nanowires with excellent quality and desired aspect ratios. The wet-etch mechanism is investigated, and the etch rates of m-planes {1100} (sidewalls) were measured to be 2.5 to 70 nm/h depending on the Si doping concentration. Using this method, uniform nanowire arrays were achieved over a large area (>105 MUm2) with an spect ratio as large as 50, a radius as small as 17 nm, and atomic-scale sidewall roughness (<1 nm). FDTD modeling demonstrated HE11 is the dominant transverse mode in the nanowires with a radius of sub-100 nm, and single-mode lasing from vertical cavity nanowire arrays with different doping concentrations on a sapphire substrate was interestingly observed in photoluminescence measurements. High Q-factors of ~1139-2443 were obtained in nanowire array lasers with a radius and length of 65 nm and 2 MUm, respectively, corresponding to a line width of 0.32-0.15 nm (minimum threshold of 3.31 MW/cm2). Our results show that fabrication of high-quality GaN nanowire arrays with adaptable aspect ratio and large-area uniformity is feasible through a top-down approach using interferometric lithography and is promising for fabrication of III-nitride-based nanophotonic devices (radial/axial) on the original substrate. PMID- 29401382 TI - Micromachined Chip Scale Thermal Sensor for Thermal Imaging. AB - The lateral resolution of scanning thermal microscopy (SThM) has hitherto never approached that of mainstream atomic force microscopy, mainly due to poor performance of the thermal sensor. Herein, we report a nanomechanical system based thermal sensor (thermocouple) that enables high lateral resolution that is often required in nanoscale thermal characterization in a wide range of applications. This thermocouple-based probe technology delivers excellent lateral resolution (~20 nm), extended high-temperature measurements >700 degrees C without cantilever bending, and thermal sensitivity (~0.04 degrees C). The origin of significantly improved figures-of-merit lies in the probe design that consists of a hollow silicon tip integrated with a vertically oriented thermocouple sensor at the apex (low thermal mass) which interacts with the sample through a metallic nanowire (50 nm diameter), thereby achieving high lateral resolution. The efficacy of this approach to SThM is demonstrated by imaging embedded metallic nanostructures in silica core-shell, metal nanostructures coated with polymer films, and metal-polymer interconnect structures. The nanoscale pitch and extremely small thermal mass of the probe promise significant improvements over existing methods and wide range of applications in several fields including semiconductor industry, biomedical imaging, and data storage. PMID- 29401384 TI - Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid. AB - The self-assembly of insulin to form amyloid fibrils has been widely studied because it is a significant problem in the medical management of diabetes and is an important model system for the investigation of amyloid formation and its inhibition. A few inhibitors of insulin fibrillation have been identified with potencies that could be higher. Knowledge of how these work at the molecular level is not known but important for the development of more potent inhibitors. Here we show that rosmarinic acid completely inhibits amyloid formation by dimeric insulin at pH 2 and 60 degrees C. In contrast to other polyphenols, rosmarinic acid is soluble in water and does not degrade at elevated temperatures, and thus we were able to decipher the mechanism of inhibition by a combination of solution-state 1H NMR spectroscopy and molecular docking. On the basis of 1H chemical shift perturbations, intermolecular nuclear Overhauser effect enhancements between rosmarinic acid and specific residues of insulin, and slowed dynamics of rosmarinic acid in the presence of insulin, we show that rosmarinic acid binds to a pocket found on the surface of each insulin monomer. This results in the formation of a mixed tetramolecular aromatic network on the surface of insulin dimer, resulting in increased resistance of the amyloidogenic protein to thermal unfolding. This finding opens new avenues for the design of potent inhibitors of amyloid formation and provides strong experimental evidence for the role of surface aromatic clusters in increasing the thermal stability of proteins. PMID- 29401383 TI - Metabolomic "Dark Matter" Dependent on Peroxisomal beta-Oxidation in Caenorhabditis elegans. AB - Peroxisomal beta-oxidation (pbetao) is a highly conserved fat metabolism pathway involved in the biosynthesis of diverse signaling molecules in animals and plants. In Caenorhabditis elegans, pbetao is required for the biosynthesis of the ascarosides, signaling molecules that control development, lifespan, and behavior in this model organism. Via comparative mass spectrometric analysis of pbetao mutants and wildtype, we show that pbetao in C. elegans and the satellite model P. pacificus contributes to life stage-specific biosynthesis of several hundred previously unknown metabolites. The pbetao-dependent portion of the metabolome is unexpectedly diverse, e.g., intersecting with nucleoside and neurotransmitter metabolism. Cell type-specific restoration of pbetao in pbetao-defective mutants further revealed that pbetao-dependent submetabolomes differ between tissues. These results suggest that interactions of fat, nucleoside, and other primary metabolism pathways can generate structural diversity reminiscent of that arising from combinatorial strategies in microbial natural product biosynthesis. PMID- 29401386 TI - In-Situ Quantitative and Multiscale Structural Study of Starch-Based Biomaterials Immersed in Water. AB - The behavior upon immersion in water of two types of starchy materials of biomedical relevance, amorphous potato starch and glycerol-plasticized potato starch, is analyzed in depth. Synchrotron X-ray scattering, specifically wide angle X-ray scattering (WAXS), and magnetic resonance microimaging (MRMUI) are used as very precise and nondestructive quantitative methods to monitor water transfers and structure changes in the samples, with refined spatial and kinetics results. The ingress of water in the cylinder-shaped samples can be inferred from both techniques, and from this, a diffusion mechanism is deduced for each sample type. Qualitatively, scattering and imaging give comparable results: plasticized samples are shown to behave close to a Fickian diffusion case, amorphous samples close to a case II. WAXS results also provide an in-depth knowledge of the crystalline structures associated to each step of the water ingress, and these are in turn correlated to water diffusion. To refine these observations, a recrystallized starch sample is also analyzed via WAXS. This study gives better insight into the structure of a material with a huge biomedical potential (as implants, for example), and for such applications, the behavior upon immersion in water is particularly relevant. PMID- 29401385 TI - Artificial Metalloproteins Containing Co4O4 Cubane Active Sites. AB - Artificial metalloproteins (ArMs) containing Co4O4 cubane active sites were constructed via biotin-streptavidin technology. Stabilized by hydrogen bonds (H bonds), terminal and cofacial CoIII-OH2 moieties are observed crystallographically in a series of immobilized cubane sites. Solution electrochemistry provided correlations of oxidation potential and pH. For variants containing Ser and Phe adjacent to the metallocofactor, 1e-/1H+ chemistry predominates until pH 8, above which the oxidation becomes pH independent. Installation of Tyr proximal to the Co4O4 active site provided a single H-bond to one of a set of cofacial CoIII-OH2 groups. With this variant, multi-e-/multi-H+ chemistry is observed, along with a change in mechanism at pH 9.5 that is consistent with Tyr deprotonation. With structural similarities to both the oxygen-evolving complex of photosystem II (H-bonded Tyr) and to thin film water oxidation catalysts (Co4O4 core), these findings bridge synthetic and biological systems for water oxidation, highlighting the importance of secondary sphere interactions in mediating multi-e-/multi-H+ reactivity. PMID- 29401387 TI - Ex Vivo Detection of Circulating Tumor Cells from Whole Blood by Direct Nanoparticle Visualization. AB - The detection of circulating tumor cells (CTCs) from blood samples can predict prognosis, response to systemic chemotherapy, and metastatic spread of carcinoma. Therefore, approaches for CTC identification is an important aspect of current cancer research. Here, a method for the direct visualization of nanoparticle coated CTCs under dark field illumination is presented. A metastatic breast cancer cell line (4T1) was transduced with a non-native target protein (Thy1.1). Positive 4T1-Thy1.1 cells incubated with antibody-coated metallic nanoshells appeared overly bright at low magnification, allowing a quick screening of samples and easy visual detection of even single isolated CTCs. The use of a nontransduced cell line as control creates the ideal scenario to evaluate nonspecific binding. A murine metastatic tumor model with the 4T1-Thy1.1 cell line was also implemented. Blood was drawn from mice over the course of one month, and CTCs were successfully detected in all positive subjects. This work validates the use of metallic nanoshells as labels for direct visualization of CTCs while providing guidelines to a systematic development of nanotechnology based detection systems for CTCs. PMID- 29401388 TI - Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein-Protein Binding Affinity upon Mutation. AB - Computationally modeling changes in binding free energies upon mutation (interface DeltaDelta G) allows large-scale prediction and perturbation of protein-protein interactions. Additionally, methods that consider and sample relevant conformational plasticity should be able to achieve higher prediction accuracy over methods that do not. To test this hypothesis, we developed a method within the Rosetta macromolecular modeling suite (flex ddG) that samples conformational diversity using "backrub" to generate an ensemble of models and then applies torsion minimization, side chain repacking, and averaging across this ensemble to estimate interface DeltaDelta G values. We tested our method on a curated benchmark set of 1240 mutants, and found the method outperformed existing methods that sampled conformational space to a lesser degree. We observed considerable improvements with flex ddG over existing methods on the subset of small side chain to large side chain mutations, as well as for multiple simultaneous non-alanine mutations, stabilizing mutations, and mutations in antibody-antigen interfaces. Finally, we applied a generalized additive model (GAM) approach to the Rosetta energy function; the resulting nonlinear reweighting model improved the agreement with experimentally determined interface DeltaDelta G values but also highlighted the necessity of future energy function improvements. PMID- 29401389 TI - To Boil an Egg: Substrate Binding Affects Critical Stability in Thermal Unfolding of Proteins. AB - Thermal unfolding of proteins is used extensively in screening of drug candidates because molecular interactions with ligands and substrates affect strongly protein stability, transition temperature, and cooperativity. We use synchrotron radiation circular dichroism to monitor the thermal evolution of secondary structure in proteins as they approach the melting point and the impact of substrate on their thermal behavior. Using Landau free energy expansion, we quantify transition strength and proximity to a critical point through the relative separation tau+ between the transition temperature Tm and the spinodal T+, obtained from the equation of state. The weakest transition was observed in lysozyme with tau+ = -0.0167 followed by holo albumin with tau+ = -0.0208 with the strongest transition in monomeric apo albumin tau+ = -0.0242. A structural transition at 45 degrees C in apo albumin leads to a noncooperative melt with tau+ = -0.00532 and amyloidogenic increase in beta content. PMID- 29401390 TI - Formation of Methane Hydrate in the Presence of Natural and Synthetic Nanoparticles. AB - Natural gas hydrates occur widely on the ocean-bed and in permafrost regions, and have potential as an untapped energy resource. Their formation and growth, however, poses major problems for the energy sector due to their tendency to block oil and gas pipelines, whereas their melting is viewed as a potential contributor to climate change. Although recent advances have been made in understanding bulk methane hydrate formation, the effect of impurity particles, which are always present under conditions relevant to industry and the environment, remains an open question. Here we present results from neutron scattering experiments and molecular dynamics simulations that show that the formation of methane hydrate is insensitive to the addition of a wide range of impurity particles. Our analysis shows that this is due to the different chemical natures of methane and water, with methane generally excluded from the volume surrounding the nanoparticles. This has important consequences for our understanding of the mechanism of hydrate nucleation and the design of new inhibitor molecules. PMID- 29401391 TI - Systematic Computational Design and Identification of Low Picomolar Inhibitors of Aurora Kinase A. AB - Aurora kinase A (AKA) has served as an effective molecular target for the development of cancer therapeutics. A series of potent AKA inhibitors with the (4 methoxy-pyrimidin-2-yl)-phenyl-amine (MPPA) scaffold are identified using a systematic computer-aided drug design protocol involving structure-based virtual screening, de novo design, and free energy perturbation (FEP) simulations. To enhance the accuracy of the virtual screening to find a proper molecular core and de novo design to optimize biochemical potency, we preliminarily improved the scoring function by implementing a reliable hydration energy term. The overall design strategy proves successful to the extent that some inhibitors reveal exceptionally high potency at low picomolar levels; this was achieved by substituting phenyl, chlorine, and tetrazole moieties on the MPPA scaffold. The establishment of bidentate hydrogen bonds with backbone groups in the hinge region appears to be necessary for the high biochemical potency, consistent with the literature X-ray crystallographic data. The picomolar inhibitory activity also stems from the simultaneous formation of additional hydrogen bonds with the side chains of the hinge region and P-loop residues. The FEP simulation results show that the inhibitory activity surges to the low picomolar level because the interactions in the ATP-binding site of AKA become strong by structural modifications enough to overbalance the increase in dehydration cost. Because of the exceptionally high biochemical potency, the AKA inhibitors reported in this study are anticipated to serve as a new starting point for the discovery of anticancer medicine. PMID- 29401392 TI - Label-Free Imaging of Heme Dynamics in Living Organisms by Transient Absorption Microscopy. AB - Heme, a hydrophobic and cytotoxic macrocycle, is an essential cofactor in a large number of proteins and is important for cell signaling. This must mean that heme is mobilized from its place of synthesis or entry into the cell to other parts of the cell where hemoproteins reside. However, the cellular dynamics of heme movement is not well understood, in large part due to the inability to image heme noninvasively in live biological systems. Here, using high-resolution transient absorption microscopy, we showed that heme storage and distribution is dynamic in Caenorhabditis elegans. Intracellular heme exists in concentrated granular puncta which localizes to lysosomal-related organelles. These granules are dynamic, and their breaking down into smaller granules provides a mechanism by which heme stores can be mobilized. Collectively, these direct and noninvasive dynamic imaging techniques provide new insights into heme storage and transport and open a new avenue for label-free investigation of heme function and regulation in living systems. PMID- 29401393 TI - Effects of Magnesium Fertilizer on the Forage Crude Protein Content Depend upon Available Soil Nitrogen. AB - Magnesium (Mg) is important for both plant photosynthesis and protein synthesis. Nevertheless, latent Mg deficiencies are common, and Mg addition has shown an improved yield. Might such an increasing yield cause "hidden" hunger for microelements and protein, and if so, what is the mechanism? We conducted two greenhouse experiments using low-Mg soil to investigate (i) effects of five levels of Mg fertilizer (20-400 mg kg-1) on eight elements and crude protein concentrations in annual ryegrass and white clover and (ii) if any protein effects of the Mg fertilizer depend upon soil nitrogen (N). Mg addition significantly increased the yield in both species, simultaneously decreasing concentrations of crude protein, calcium (Ca), sodium, manganese, and potassium/Mg and Ca/Mg ratios caused by increased biomass dilution effects and increased [Mg]. Other mineral dilution effects of the Mg fertilizer depended upon species: the concentration of phosphorus decreased only in ryegrass, and the concentration of zinc decreased only in white clover. Mg addition in soil rich with available N (from N fertilizer in ryegrass or biological fixation in white clover) showed an increased crude protein content as well as increased yield in the forage of both species. These results suggest that the Mg fertilizer can affect the protein content positively or negatively depending upon available N in soil and that sufficiently available N must be ensured along with Mg addition in low Mg soils. PMID- 29401394 TI - Formation of Supported Graphene Oxide: Evidence for Enolate Species. AB - Graphene oxides are promising materials for novel electronic devices or anchoring of the active sites for catalytic applications. Here we focus on understanding the atomic oxygen (AO) binding and mobility on different regions of graphene (Gr) on Ru(0001). Differences in the Gr/Ru lattices result in the superstructure, which offers an array of distinct adsorption sites. We employ scanning tunneling microscopy and density functional theory to map out the chemical identity and stability of prepared AO functionalities in different Gr regions. The AO diffusion is utilized to establish that in the regions that are close to the metal substrate the terminally bonded enolate groups are strongly preferred over bridge-bonded epoxy groups. No oxygen species are observed on the graphene regions that are far from the underlying Ru, indicating their low relative stability. This study provides a clear fundamental basis for understanding the local structural, electronic factors and C-Ru bond strengthening/weakening processes that affect the stability of enolate and epoxy species. PMID- 29401395 TI - Structural and Spectral Features of 4'-Substituted 2'-Hydroxychalcones in Solutions and Crystals: Spectroscopic and Theoretical Investigations. AB - The article describes investigations of 2'-hydroxychalcone and its three derivatives bearing differently sized alkyloxy groups at position 4'. The compounds are investigated from the point of view of crystal structure, electronic absorption, fluorescence features in solutions and crystals using X ray diffraction and electronic spectroscopy methods, and quantum chemistry calculations. In general, both in solutions and in the crystal phase, the influence of substituents on absorption spectra of chalcones was found to be insignificant. Exclusively in the case of 4'-(4-methoxybenzyloxy)-2' hydroxychalcone, molecular packing influences the absorption features, which is because of the intermolecular interactions of substituent's phenyl ring and chromophore fragment of the neighboring molecules. The lack of fluorescence of the excited enol form of chalcones in solutions and crystals is mainly due to intersystem crossing and excited-state intramolecular proton transfer. Fluorescent properties of the phototautomer keto species formed by the proton transfer depend on molecular conformation. In solutions, the excited keto form is twisted and effectively deactivates nonradiatively due to conical intersection. In the crystal phase, the fixed planar geometry disables the conical intersection and the fluorescence of the keto form becomes detectable. PMID- 29401396 TI - Planar Tricyclic B8O8 and B8O8- Clusters: Boron Oxide Analogues of s-Indacene C12H8. AB - Boron clusters and their oxides are electron-deficient species with (pi and sigma) aromaticity and antiaromaticity, enabling a structural and bonding analogy between them and the aromatic hydrocarbons. s-Indacene C12H8 is normally considered as a border system between the classes of aromatic and antiaromatic hydrocarbons. We show herein, via computer global-minimum searches and B3LYP and single-point CCSD(T) calculations, that boron oxide clusters D2h B8O8 (1, 1Ag) and D2h B8O8- (2, 2B2g) adopt planar tricyclic structures, which feature fused heterocyclic B3O2/B4O2/B3O2 rings and two boronyl (BO) terminals, a structural pattern analogous to the C5/C6/C5 rings in s-indacene. Bonding analyses indicate that B8O8 (1) is a formally antiaromatic 12pi system, the molecular orbitals of which are largely similar to those of s-indacene. Infrared and ultraviolet visible spectra of B8O8 (1) neutral, as well as the photoelectron spectrum of B8O8- (2) anion, are predicted computationally. The latter spectrum shows a sizable energy gap of 3.5 eV for 2, demonstrating the electronic robustness of 1. Our bonding analyses also shed critical light on the nature of bonding in s indacene. PMID- 29401397 TI - Evidence that DeltaS? Controls Interfacial Electron Transfer Dynamics from Anatase TiO2 to Molecular Acceptors. AB - Recombination of electrons injected into TiO2 with molecular acceptors present at the interface represents an important loss mechanism in dye-sensitized water oxidation and electrical power generation. Herein, the kinetics for this interfacial electron transfer reaction to oxidized triphenylamine (TPA) acceptors was quantified over a 70 degrees temperature range for para-methyl-TPA (Me-TPA) dissolved in acetonitrile solution, 4-[N,N-di(p-tolyl)amino]benzylphosphonic acid (a-TPA) anchored to the TiO2, and a TPA covalently bound to a ruthenium sensitizer, [Ru(tpy-C6H4-PO3H2)(tpy-TPA)]2+ "RuTPA", where tpy is 2,2':6',2'' terpyridine. Activation energies extracted from an Arrhenius analysis were found to be 11 +/- 1 kJ mol-1 for Me-TPA and 22 +/- 1 kJ mol-1 for a-TPA, values that were insensitive to the identity of different sensitizers. Recombination to RuTPA+ proceeded with Ea = 27 +/- 1 kJ mol-1 that decreased to 19 +/- 1 kJ mol-1 when recombination occurred to an oxidized para-methoxy TPA (MeO-TPA) dissolved in CH3CN. Eyring analysis revealed a smaller entropy of activation |DeltaS?| when the a-TPA was anchored to the surface or covalently linked to the sensitizer, compared to that when Me-TPA was dissolved in CH3CN. In all cases, Eyring analysis provided large and negative DeltaS? values that point toward unfavorable entropic factors as the key contributor to the barrier that underlies the slow recombination kinetics that are generally observed at dye-sensitized TiO2 interfaces. PMID- 29401398 TI - Aircraft Measurements of Total Mercury and Monomethyl Mercury in Summertime Marine Stratus Cloudwater from Coastal California, USA. AB - Water samples from marine stratus clouds were collected during 16 aircraft flights above the Pacific Ocean near the Central California coast during the summer of 2016. These samples were analyzed for total mercury (THg), monomethyl mercury (MMHg), and 32 other chemical species in addition to aerosol physical parameters. The mean concentrations of THg and MMHg in the cloudwater samples were 9.2 +/- 6.0 ng L-1 (2.3-33.8 ng L-1) ( N = 97) and 0.87 +/- 0.66 ng L-1 (0.17-2.9 ng L-1) ( N = 22), respectively. This corresponds to 9.5% (3-21%) MMHg as a fraction of THg. Low and high nonsea salt calcium ion (nss-Ca2+) concentrations in cloudwater were used to classify flights as "marine" and "continental", respectively. Mean [MMHg]marine was significantly higher ( p < 0.05) than [MMHg]continental consistent with an ocean source of dimethyl Hg (DMHg) to the atmosphere. Mean THg in cloudwater was not significantly different between the two categories, indicating multiple emissions sources. Mean [THg]continental was correlated with pH, CO, NO3-, NH4+, and other trace metals, whereas [THg]marine was correlated with MMHg and Na+. THg concentrations were negatively correlated with altitude, consistent with ocean and land emissions, coupled with removal at the cloud-top due to drizzle formation. PMID- 29401399 TI - Spontaneous 15N Nuclear Spin Hyperpolarization in Metal-Free Activation of Parahydrogen by Molecular Tweezers. AB - The ability of frustrated Lewis pairs (FLPs) to activate H2 is of significant interest for metal-free catalysis. The activation of H2 is also the key element of parahydrogen-induced polarization (PHIP), one of the nuclear spin hyperpolarization techniques. It is demonstrated that o-phenylene-based ansa aminoboranes (AABs) can produce 1H nuclear spin hyperpolarization through a reversible interaction with parahydrogen at ambient temperatures. Heteronuclei are useful in NMR and MRI as well because they have a broad chemical shift range and long relaxation times and may act as background-free labels. We report spontaneous formation of 15N hyperpolarization of the N-H site for a family of AABs. The process is efficient at the high magnetic field of an NMR magnet (7 T), and it provides up to 350-fold 15N signal enhancements. Different hyperpolarization effects are observed with various AAB structures and in a broad temperature range. Spontaneous hyperpolarization, albeit an order of magnitude weaker than that for 15N, was also observed for 11B nuclei. PMID- 29401401 TI - Presence of archaea and selected bacteria in infected root canal systems. AB - Infections of the root canal have polymicrobial etiology. The main group of microflora in the infected pulp is bacteria. There is limited data that archaea may be present in infected pulp tissue. The aim of this study was to check the prevalence of archaea in necrotic root canal samples obtained from patients with primary or post-treatment infection. The prevalence of selected bacteria species (Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Synergistes sp.) in necrotic samples was evaluated as well. Sixty-four samples from root canal were collected for DNA and RNA extraction. A PCR assay based on the 16S rRNA gene was used to determine the presence of archaea and selected bacteria. Of the 64 samples, 6 were analyzed by semiquantitative reverse transcription PCR to estimate expression profiles of 16S rRNA, and another 9 were selected for direct sequencing. Archaea were detected in 48.4% samples. Statistical analysis indicated a negative association in coexistence between archaea and Treponema denticola (P < 0.05; Pearson's chi2 test). The main representative of the Archaea domain found in infected pulp tissue was Methanobrevibacter oralis. Archaea 16S rRNA gene expression was significantly lower than Synergistes sp., Porphyromonas gingivalis, and Tannerella forsythia (P < 0.05; Student's t test). Thus, it can be hypothesized that archaea may participate in the endodontic microbial community. PMID- 29401402 TI - Potential of Lactobacillus plantarum ZDY2013 and Bifidobacterium bifidum WBIN03 in relieving colitis by gut microbiota, immune, and anti-oxidative stress. AB - Ulcerative colitis (UC) is an inflammatory bowel disease that is difficult to cure, with rising incidence in recent decades. Probiotics have become a new strategy for UC treatment. In this study, we chose 2 new multisource probiotics, Lactobacillus plantarum ZDY2013 from acid beans and Bifidobacterium bifidum WBIN03 from infant feces, and a mixture of both, to investigate the anti inflammatory and antioxidant effect on H2O2-induced oxidative damage in a HT-29 cell model and dextran sodium sulfate (DSS)-induced UC in mice. Compared with the model group, the general relative indices results showed L. plantarum ZDY2013 and B. bifidum WBIN03 have a significant effect on DSS-induced UC in mice, by downregulating the pro-inflammatory cytokines (e.g., TNF-alpha) and upregulating antioxidant factors (e.g., SOD1, SOD2, GPX2) at the transcriptional level. By means of high-throughput sequencing (16S V3-V4) and systematical bioinformatics analyses, we found that colitis may be associated with the changes in intestinal flora, especially Firmicutes and Bacteroides. Administration of L. plantarum ZDY2013 increased the abundance of Lactobacillus animalis, whereas B. bifidum WBIN03 increased the abundance of Lachnospiraceae bacterium COE1. Our results revealed that a supplement of L. plantarum ZDY2013 and B. bifidum WBIN03 remit UC through modification of gut microbiota to regulate oxidative stress and inflammatory mediators. PMID- 29401400 TI - Cord Blood Metabolic Signatures of Birth Weight: A Population-Based Study. AB - Birth weight is an important indicator of maternal and fetal health and a predictor of health in later life. However, the determinants of variance in birth weight are still poorly understood. We aimed to identify the biological pathways, which may be perturbed by environmental exposures, that are important in determining birth weight. We applied untargeted mass-spectrometry-based metabolomics to 481 cord blood samples collected at delivery in four birth cohorts from across Europe: ENVIRONAGE (Belgium), INMA (Spain), Piccolipiu (Italy), and Rhea (Greece). We performed a metabolome-wide association scan for birth weight on over 4000 metabolic features, controlling the false discovery rate at 5%. Annotation of compounds was conducted through reference to authentic standards. We identified 68 metabolites significantly associated with birth weight, including vitamin A, progesterone, docosahexaenoic acid, indolelactic acid, and multiple acylcarnitines and phosphatidylcholines. We observed enrichment (p < 0.05) of the tryptophan metabolism, prostaglandin formation, C21 steroid hormone signaling, carnitine shuttle, and glycerophospholipid metabolism pathways. Vitamin A was associated with both maternal smoking and birth weight, suggesting a mediation pathway. Our findings shed new light on the pathways central to fetal growth and will have implications for antenatal and perinatal care and potentially for health in later life. PMID- 29401403 TI - Patellar Tendon Repair Augmentation With a Knotless Suture Anchor Internal Brace: A Biomechanical Cadaveric Study. AB - BACKGROUND: Patellar tendon repair with braided polyethylene suture alone is subject to knot slippage and failure. Several techniques to augment the primary repair have been described. Purpose/Hypothesis: The purpose was to evaluate a novel patellar tendon repair technique augmented with a knotless suture anchor internal brace with suture tape (SAIB). The hypothesis was that this technique would be biomechanically superior to a nonaugmented repair and equivalent to a standard augmentation with an 18-gauge steel wire. STUDY DESIGN: Controlled laboratory study. METHODS: Midsubstance patellar tendon tears were created in 32 human cadaveric knees. Two comparison groups were created. Group 1 compared #2 supersuture repair without augmentation to #2 supersuture repair with SAIB augmentation. Group 2 compared #2 supersuture repair with an 18-gauge stainless steel cerclage wire augmentation to #2 supersuture repair with SAIB augmentation. The specimens were potted and biomechanically loaded on a materials testing machine. Yield load, maximum load, mode of failure, plastic displacement, elastic displacement, and total displacement were calculated for each sample. Standard statistical analysis was performed. RESULTS: There was a statistically significant increase in the mean +/- SD yield load and maximum load in the SAIB augmentation group compared with supersuture alone (mean yield load: 646 +/- 202 N vs 229 +/- 60 N; mean maximum load: 868 +/- 162 N vs 365 +/- 54 N; P < .001). Group 2 showed no statistically significant differences between the augmented repairs (mean yield load: 495 +/- 213 N vs 566 +/- 172 N; P = .476; mean maximum load: 737 +/- 210 N vs 697 +/- 130 N; P = .721). CONCLUSION: Patellar tendon repair augmented with SAIB is biomechanically superior to repair without augmentation and is equivalent to repair with augmentation with an 18-gauge stainless steel cerclage wire. CLINICAL RELEVANCE: This novel patellar tendon repair augmentation is equivalent to standard 18-gauge wire augmentation at time zero. It does not require a second surgery for removal, and it is biomechanically superior to primary repair alone. PMID- 29401404 TI - Studies on the Tissue Localization of HKDC1, a Putative Novel Fifth Hexokinase, in Humans. AB - Hexokinase domain component 1 (HKDC1) is a recently discovered novel protein, which is being promoted as a putative fifth hexokinase. Although the exact role HKDC1 plays in physiology is still unclear, it has been shown to be important during pregnancy in the regulation of glucose homeostasis. In this study, we have comprehensively studied the expression pattern of HKDC1 in the human body. Using human tissue sample, immunohistochemistry imaging was performed. Our studies indicate that the tissues with highest HKDC1 expression were the brush border epithelium of the intestines, parts of the pancreas, and lung alveolar macrophages. Future directions will be to understand the role of this fifth hexokinase in these tissues, with a focus on its relative function as compared with other endogenously expressed hexokinases. PMID- 29401405 TI - Molecular analyses of the agouti allele in the Japanese house mouse identify a novel variant of the agouti gene. AB - It has been thought that the Japanese house mouse carries the Aw allele at the agouti locus causing light-colored bellies, but they do not always show this coloration. Thus, the presence of the Aw allele seems to be doubtful in them. To ascertain whether the Aw allele is present, a two-pronged approach was used. First, we compared lengths of DNA fragments obtained from three PCRs conducted on them to the known fragment sizes generated from mouse strains exhibiting homozygosities of either a/a, A/A, or Aw/Aw. PCR I, PCR II, and PCR III amplify only in the A and Aw alleles, the a and Aw alleles, and the a allele, respectively, and we detected amplifications in strains with A/A and Aw/Aw by PCR I, in those with a/a and the Japanese house mouse by PCR II, and in those with a/a by PCR III. Second, we sequenced the exon 1A region of the agouti gene and obtained sequences corresponding to the above strains and the Japanese house mouse, but their sequences were similar to those of the a allele. We concluded that their agouti allele is not identical to the Aw allele and seems to be a novel type similar to the a allele. PMID- 29401406 TI - The complete mitochondrial genome of the Dutch elm disease fungus Ophiostoma novo ulmi subsp. novo-ulmi. AB - Ophiostoma novo-ulmi, a member of the Ophiostomatales (Ascomycota), is the causal agent of the current Dutch elm disease pandemic in Europe and North America. The complete mitochondrial genome (mtDNA) of Ophiostoma novo-ulmi subsp. novo-ulmi, the European component of O. novo-ulmi, has been sequenced and annotated. Gene order (synteny) among the currently available members of the Ophiostomatales was examined and appears to be conserved, and mtDNA size variability among the Ophiostomatales is due in part to the presence of introns and their encoded open reading frames. Phylogenetic analysis of concatenated mitochondrial protein coding genes yielded phylogenetic estimates for various members of the Ophiostomatales, with strong statistical support showing that mtDNA analysis may provide valuable insights into the evolution of the Ophiostomatales. PMID- 29401407 TI - Microbial diversity and community structure in agricultural soils suffering from 4 years of Pb contamination. AB - Heavy metal pollution has become a widespread environmental problem due to rapid economic development. The phylogenetic diversity and structure of microbial communities in lead (Pb)-contaminated Lou soils were investigated using Illumina MiSeq sequencing of 16S rRNA genes. The presence of Pb2+ in soil showed weak impact on the diversity of soil bacteria community, but it influenced the abundance of some genera of bacteria, as well as soil physicochemical properties. We found significant differences in the relative abundances of heavy-metal resistant bacteria such as Bacillus, Streptococcus, and Arthrobacter at the genus level. Available Pb and total Pb negatively correlated with soil organic matter but positively affected available phosphorus. The abundance of main bacteria phyla was highly correlated with total Pb. The relative abundance of Gemmatimonadetes, Nitrospirae, and Planctomycetes was negatively correlated with total Pb. Collectively, Pb influences both the microbial community composition and physicochemical properties of soil. PMID- 29401408 TI - Preoperative KOOS and SF-36 Scores Are Associated With the Development of Symptomatic Knee Osteoarthritis at 7 Years After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are associated with the development of knee osteoarthritis despite ACL reconstruction surgery. However, little evidence is available to determine which patients will develop symptomatic knee osteoarthritis. PURPOSE: To determine if preoperative outcome measures-KOOS (Knee injury and Osteoarthritis Outcome Score) and SF-36 (36-item Short Form Health Survey)-were associated with the development of a symptomatic knee 7 years after ACL reconstruction. A secondary goal was to examine the relationship between imaging evidence of knee osteoarthritis and development of knee pain. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Prospectively collected data from 72 patients were reviewed with 7-year follow-up after unilateral ACL reconstruction. Patients were divided into symptomatic and asymptomatic groups based on the previously defined KOOS pain <=72. Demographic variables and preoperative KOOS and SF-36 scores were compared between groups. Radiographic and magnetic resonance imaging data were used to evaluate differences in joint space width, Osteoarthritis Research Society International radiographic score, and the Whole-Organ Magnetic Resonance Imaging Score between groups. Univariate and multivariate analyses were performed to identify potential predictors of pain at 7-year follow-up. Wilcoxon sum rank and t tests were used to compare imaging findings between the symptomatic and asymptomatic patients at 7 years. RESULTS: According to KOOS pain, 7 of the 72 patients available at 7 year follow-up formed the symptomatic group. No differences were found between groups in regard to demographic variables or intraoperative findings. In multivariate analysis, lower preoperative scores for KOOS sports/recreation ( P = .005) and SF-36 mental health ( P = .025) were associated with a painful knee at 7 years, with increased odds of 82% and 68% per 10-unit decrease, respectively. The Whole-Organ Magnetic Resonance Imaging Score at 7 years showed evidence of osteoarthritic changes in the symptomatic group as compared with the asymptomatic group ( P = .047). However, there were no significant differences in the Osteoarthritis Research Society International radiographic score ( P = .051) or joint space width ( P = .488) between groups. CONCLUSION: Lower preoperative KOOS and SF-36 scores were associated with those patients who developed symptomatic knee osteoarthritis 7 years after ACL reconstruction. PMID- 29401409 TI - Alternative splicing results in a lack of starch synthase IIa-D in Chinese wheat landrace. AB - We evaluated the SGP-1 protein composition of 368 Chinese wheat landraces using SDS-PAGE. The SGP-D1 null type was identified in three accessions (Xiaoqingmang, Pushanbamai, and P119). An 18-bp deletion and 9-bp variation were found at the junction region of the 7th intron and 8th exon, leading to deletion of the intron exon junction recognition site AG when aligned the 8261-bp DNA sequence of TaSSIIa-D in Pushanbamai with that of Chinese Spring. Four cDNA types with mis spliced isoforms were subsequently detected through amplification of TaSSIIa-D cDNAs. Among these, nine type II cDNAs with a 16-bp deletion in the 8th exon were detected, indicating that the major transcriptional pattern of TaSSIIa in Pushanbamai is type II. In the type IV cDNA, a 97-bp sequence remains undeleted in the end of the 5th exon. The amylose content in Pushanbamai was significantly higher than that in all control lines under field conditions, which suggested that deletion of SGP-D1 has an efficient impact on amylose content. As the TaSSIIa gene plays an important role in regulating the content of amylose, it is anticipated that these natural variants of TaSSIIa-D will provide useful resources for quality improvement in wheat. PMID- 29401410 TI - Lateral Augmentation Procedures in Anterior Cruciate Ligament Reconstruction: Anatomic, Biomechanical, Imaging, and Clinical Evidence. AB - BACKGROUND: There has been an increasing interest in lateral-based soft tissue reconstructive techniques as augments to anterior cruciate ligament reconstruction (ACLR). The objective of these procedures is to minimize anterolateral rotational instability of the knee after surgery. Despite the relatively rapid increase in surgical application of these techniques, many clinical questions remain. PURPOSE: To provide a comprehensive update on the current state of these lateral-based augmentation procedures by reviewing the origins of the surgical techniques, the biomechanical data to support their use, and the clinical results to date. STUDY DESIGN: Systematic review. METHODS: A systematic search of the literature was conducted via the Medline, EMBASE, Scopus, SportDiscus, and CINAHL databases. The search was designed to encompass the literature on lateral extra-articular tenodesis (LET) procedures and the anterolateral ligament (ALL) reconstruction. Titles and abstracts were reviewed for relevance and sorted into the following categories: anatomy, biomechanics, imaging/diagnostics, surgical techniques, and clinical outcomes. RESULTS: The search identified 4016 articles. After review for relevance, 31, 53, 27, 35, 45, and 78 articles described the anatomy, biomechanics, imaging/diagnostics, surgical techniques, and clinical outcomes of either LET procedures or the ALL reconstruction, respectively. A multitude of investigations were available, revealing controversy in addition to consensus in several categories. The level of evidence obtained from this search was not adequate for systematic review or meta-analysis; thus, a current concepts review of the anatomy, biomechanics, imaging, surgical techniques, and clinical outcomes was performed. CONCLUSION: Histologically, the ALL appears to be a distinct structure that can be identified with advanced imaging techniques. Biomechanical evidence suggests that the anterolateral structures of the knee, including the ALL, contribute to minimizing anterolateral rotational instability. Cadaveric studies of combined ACLR-LET procedures demonstrated overconstraint of the knee; however, these findings have yet to be reproduced in the clinical literature. The current indications for LET augmentation in the setting of ACLR and the effect on knee kinematic and joint preservation should be the subject of future research. PMID- 29401411 TI - Calculating metabolic energy expenditure across a wide range of exercise intensities: the equation matters. AB - We compared 10 published equations for calculating energy expenditure from oxygen consumption and carbon dioxide production using data for 10 high-caliber male distance runners over a wide range of running velocities. We found up to a 5.2% difference in calculated metabolic rate between 2 widely used equations. We urge our fellow researchers abandon out-of-date equations with published acknowledgments of errors or inappropriate biochemical/physical assumptions. PMID- 29401414 TI - Engineering Control over 3D Morphogenesis by Tissue Origami. AB - Controlled folding of tissues occurs in development and would enable advances in tissue engineering. In this issue of Developmental Cell, Hughes et al. (2018) use in vivo, in vitro, and in silico approaches to uncover blueprints of microscale mesenchymal cell distribution that robustly drives macroscopic 3D folding of tissues. PMID- 29401415 TI - A Dual Binding Receptor for ER-phagy. AB - Selective autophagy of the endoplasmic reticulum (ER)-ER-phagy-is mediated by multiple receptors. In this issue of Developmental Cell, Smith et al. (2018) identify ER membrane protein CCPG1 as an ER-phagy receptor that interacts with autophagy-related proteins GABARAPs and FIP200 and ensures ER protein homeostasis, especially in pancreatic acinar cells. PMID- 29401416 TI - Regulating beta-Catenin Nuclear Import with the Small GTPase Rap. AB - beta-catenin acts as a key mediator of Wnt signaling by migrating into the nucleus. In this issue of Developmental Cell, Griffin et al. (2018) propose that facilitated nuclear import of beta-catenin is actively regulated by the nuclear small GTPase Rap through its guanine nucleotide exchange factor, RAPGEF5. PMID- 29401417 TI - Sex, Gut, and Microglia. AB - Microglia are brain-resident macrophages whose function affects a myriad of physiological processes and can in turn be affected by peripheral factors. In a recent issue of Cell, Garel, Ginhoux and colleagues describe how gender, developmental stage, and microbiome contribute to the transcriptome of microglia (Thion et al., 2018). PMID- 29401419 TI - Feedback from Lateral Organs Controls Shoot Apical Meristem Growth by Modulating Auxin Transport. AB - Stem cells must balance self-renewal and differentiation; thus, their activities are precisely controlled. In plants, the control circuits that underlie division and differentiation within meristems have been well studied, but those that underlie feedback on meristems from lateral organs remain largely unknown. Here we show that long-distance auxin transport mediates this feedback in a non-cell autonomous manner. A low-auxin zone is associated with the shoot apical meristem (SAM) organization center, and auxin levels negatively affect SAM size. Using computational model simulations, we show that auxin transport from lateral organs can inhibit auxin transport from the SAM through an auxin transport switch and thus maintain SAM auxin homeostasis and SAM size. Genetic and microsurgical analyses confirmed the model's predictions. In addition, the model explains temporary change in SAM size of yabby mutants. Our study suggests that the canalization-based auxin flux can be widely adapted as a feedback control mechanism in plants. PMID- 29401421 TI - CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog. PMID- 29401420 TI - Cooperative Accumulation of Dynein-Dynactin at Microtubule Minus-Ends Drives Microtubule Network Reorganization. AB - Cytoplasmic dynein-1 is a minus-end-directed motor protein that transports cargo over long distances and organizes the intracellular microtubule (MT) network. How dynein motor activity is harnessed for these diverse functions remains unknown. Here, we have uncovered a mechanism for how processive dynein-dynactin complexes drive MT-MT sliding, reorganization, and focusing, activities required for mitotic spindle assembly. We find that motors cooperatively accumulate, in limited numbers, at MT minus-ends. Minus-end accumulations drive MT-MT sliding, independent of MT orientation, resulting in the clustering of MT minus-ends. At a mesoscale level, activated dynein-dynactin drives the formation and coalescence of MT asters. Macroscopically, dynein-dynactin activity leads to bulk contraction of millimeter-scale MT networks, suggesting that minus-end accumulations of motors produce network-scale contractile stresses. Our data provide a model for how localized dynein activity is harnessed by cells to produce contractile stresses within the cytoskeleton, for example, during mitotic spindle assembly. PMID- 29401422 TI - How Does Melittin Permeabilize Membranes? PMID- 29401423 TI - Essential Insights into Lipid Membrane Organization from Essential Fatty Acids. PMID- 29401418 TI - A Futile Battle? Protein Quality Control and the Stress of Aging. AB - There exists a phenomenon in aging research whereby early life stress can have positive impacts on longevity. The mechanisms underlying these observations suggest a robust, long-lasting induction of cellular defense mechanisms. These include the various unfolded protein responses of the endoplasmic reticulum (ER), cytosol, and mitochondria. Indeed, ectopic induction of these pathways, in the absence of stress, is sufficient to increase lifespan in organisms as diverse as yeast, worms, and flies. Here, we provide an overview of the protein quality control mechanisms that operate in the cytosol, mitochondria, and ER and discuss how they affect cellular health and viability during stress and aging. PMID- 29401424 TI - Brilliant Stimulation, One Cell at a Time. PMID- 29401425 TI - How to Connect Cardiac Excitation to the Atomic Interactions of Ion Channels. AB - Many have worked to create cardiac action potential models that explicitly represent atomic-level details of ion channel structure. Such models have the potential to define new therapeutic directions and to show how nanoscale perturbations to channel function predispose patients to deadly cardiac arrhythmia. However, there have been significant experimental and theoretical barriers that have limited model usefulness. Recently, many of these barriers have come down, suggesting that considerable progress toward creating these long sought models may be possible in the near term. PMID- 29401426 TI - A Preferred Curvature-Based Continuum Mechanics Framework for Modeling Embryogenesis. AB - Mechanics plays a key role in the development of higher organisms. However, understanding this relationship is complicated by the difficulty of modeling the link between local forces generated at the subcellular level and deformations observed at the tissue and whole-embryo levels. Here we propose an approach first developed for lipid bilayers and cell membranes, in which force-generation by cytoskeletal elements enters a continuum mechanics formulation for the full system in the form of local changes in preferred curvature. This allows us to express and solve the system using only tissue strains. Locations of preferred curvature are simply related to products of gene expression. A solution, in that context, means relaxing the system's mechanical energy to yield global morphogenetic predictions that accommodate a tendency toward the local preferred curvature, without a need to explicitly model force-generation mechanisms at the molecular level. Our computational framework, which we call SPHARM-MECH, extends a 3D spherical harmonics parameterization known as SPHARM to combine this level of abstraction with a sparse shape representation. The integration of these two principles allows computer simulations to be performed in three dimensions on highly complex shapes, gene expression patterns, and mechanical constraints. We demonstrate our approach by modeling mesoderm invagination in the fruit-fly embryo, where local forces generated by the acto-myosin meshwork in the region of the future mesoderm lead to formation of a ventral tissue fold. The process is accompanied by substantial changes in cell shape and long-range cell movements. Applying SPHARM-MECH to whole-embryo live imaging data acquired with light-sheet microscopy reveals significant correlation between calculated and observed tissue movements. Our analysis predicts the observed cell shape anisotropy on the ventral side of the embryo and suggests an active mechanical role of mesoderm invagination in supporting the onset of germ-band extension. PMID- 29401427 TI - Increasing the Time Resolution of Single-Molecule Experiments with Bayesian Inference. AB - Many time-resolved single-molecule biophysics experiments seek to characterize the kinetics of biomolecular systems exhibiting dynamics that challenge the time resolution of the given technique. Here, we present a general, computational approach to this problem that employs Bayesian inference to learn the underlying dynamics of such systems, even when they are much faster than the time resolution of the experimental technique being used. By accurately and precisely inferring rate constants, our Bayesian inference for the analysis of subtemporal resolution dynamics approach effectively enables the experimenter to super-resolve the poorly resolved dynamics that are present in their data. PMID- 29401428 TI - Simultaneous Multicolor Single-Molecule Tracking with Single-Laser Excitation via Spectral Imaging. AB - Single-molecule tracking (SMT) offers rich information on the dynamics of underlying biological processes, but multicolor SMT has been challenging due to spectral cross talk and a need for multiple laser excitations. Here, we describe a single-molecule spectral imaging approach for live-cell tracking of multiple fluorescent species at once using a single-laser excitation. Fluorescence signals from all the molecules in the field of view are collected using a single objective and split between positional and spectral channels. Images of the same molecule in the two channels are then combined to determine both the location and the identity of the molecule. The single-objective configuration of our approach allows for flexible sample geometry and the use of a live-cell incubation chamber required for live-cell SMT. Despite a lower photon yield, we achieve excellent spatial (20-40 nm) and spectral (10-15 nm) resolutions comparable to those obtained with dual-objective, spectrally resolved Stochastic Optical Reconstruction Microscopy. Furthermore, motions of the fluorescent molecules did not cause loss of spectral resolution owing to the dual-channel spectral calibration. We demonstrate SMT in three (and potentially more) colors using spectrally proximal fluorophores and single-laser excitation, and show that trajectories of each species can be reliably extracted with minimal cross talk. PMID- 29401430 TI - Destabilizing the AXH Tetramer by Mutations: Mechanisms and Potential Antiaggregation Strategies. AB - The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self association mechanisms and fibril formation of full-length ATX1. PMID- 29401429 TI - Helical Propensity Affects the Conformational Properties of the Denatured State of Cytochrome c'. AB - Changing the helical propensity of a polypeptide sequence might be expected to affect the conformational properties of the denatured state of a protein. To test this hypothesis, alanines at positions 83 and 87 near the center of helix 3 of cytochrome c' from Rhodopseudomonas palustris were mutated to serine to decrease the stability of this helix. A set of 13 single histidine variants in the A83S/A87S background were prepared to permit assessment of the conformational properties of the denatured state using histidine-loop formation in 3 M guanidine hydrochloride. The data are compared with previous histidine-heme loop formation data for wild-type cytochrome c'. As expected, destabilization of helix 3 decreases the global stabilities of the histidine variants in the A83S/A87S background relative to the wild-type background. Loop stability versus loop size data yields a scaling exponent of 2.1 +/- 0.2, similar to the value of 2.3 +/- 0.2 obtained for wild-type cytochrome c'. However, the stabilities of all histidine-heme loops, which contain the helix 3 sequence segment, are increased in the A83S/A87S background compared to the wild-type background. Rate constants for histidine-heme loop breakage are similar for the wild-type and A83S/A87S variants. However, for histidine-heme loops that contain the helix 3 sequence segment, the rate constants for loop formation increase in the A83S/A87S background compared to the wild-type background. Thus, residual helical structure appears to stiffen the polypeptide chain slowing loop formation in the denatured state. The implications of these results for protein folding mechanisms are discussed. PMID- 29401431 TI - Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1. AB - P-glycoprotein, also known as multidrug resistance protein 1 or ABCB1, can export a wide range of chemically unrelated compounds, including chemotherapeutic drugs. ABCB1 consists of two transmembrane domains that form the substrate binding and translocation domain, and of two cytoplasmic nucleotide binding domains (NBDs) that energize substrate transport by ATP binding and hydrolysis. ATP binding triggers dimerization of the NBDs, which switches the transporter from an inward facing to an outward facing transmembrane domain conformation. We performed MD simulations to study the dynamic behavior of the NBD dimer in the presence or absence of nucleotides. In the apo configuration, the NBDs were overall attractive to each other as shown in the potential of mean force profile, but the energy well was shallow and broad. In contrast, a sharp and deep energy minimum (~-42 kJ/mol) was found in the presence of ATP, leading to a well-defined conformation. Motif interaction network analyses revealed that ATP stabilizes the NBD dimer by serving as the central hub for interdomain connections. Simulations showed that forces promoting dimerization are multilayered, dominated by electrostatic interactions between the nucleotide and conserved amino acids of the signature sequence and the Walker A motif. In addition, direct and water bridged hydrogen bonds between NBDs provided conformation-defining interactions. Importantly, we characterized a largely unrecognized but essential contribution from hydrophobic interactions between the adenine moiety of the nucleotides and a hydrophobic surface of the X-loop to the stabilization of the nucleotide-bound NBD dimer. These hydrophobic interactions lead to a sharp energy minimum, thereby conformationally restricting the nucleotide-bound state. PMID- 29401432 TI - Dynamic and Irregular Distribution of RyR2 Clusters in the Periphery of Live Ventricular Myocytes. AB - Cardiac ryanodine receptors (RyR2s) are Ca2+ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca2+ release. The distribution of these Ca2+ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca2+ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes. Here, we used a knock-in mouse model expressing a green fluorescence protein (GFP)-tagged RyR2 to localize RyR2 clusters in live ventricular myocytes by virtue of their GFP fluorescence. Confocal imaging and total internal reflection fluorescence microscopy was employed to determine and compare the distribution of GFP-RyR2 in the interior and periphery of isolated live ventricular myocytes and in intact hearts. We found tightly ordered arrays of GFP-RyR2 clusters in the interior, as previously described. In contrast, irregular distribution of GFP-RyR2 clusters was observed in the periphery. Time lapse total internal reflection fluorescence imaging revealed dynamic movements of GFP-RyR2 clusters in the periphery, which were affected by external Ca2+ and RyR2 activator (caffeine) and inhibitor (tetracaine), but little detectable movement of GFP-RyR2 clusters in the interior. Furthermore, simultaneous Ca2+- and GFP-imaging demonstrated that peripheral RyR2 clusters with an irregular distribution pattern are functional with a Ca2+ release profile similar to that in the interior. These results indicate that the distribution of RyR2 clusters in the periphery of live ventricular myocytes is irregular and dynamic, which is different from that of RyR2 clusters in the interior. PMID- 29401434 TI - Melittin-Induced Permeabilization, Re-sealing, and Re-permeabilization of E. coli Membranes. AB - The permeabilization of model lipid bilayers by cationic peptides has been studied extensively over decades, with the bee-sting toxin melittin perhaps serving as the canonical example. However, the relevance of these studies to the permeabilization of real bacterial membranes by antimicrobial peptides remains uncertain. Here, we employ single-cell fluorescence microscopy in a detailed study of the interactions of melittin with the outer membrane (OM) and the cytoplasmic membrane (CM) of live Escherichia coli. Using periplasmic green fluorescent protein (GFP) as a probe, we find that melittin at twice the minimum inhibitory concentration first induces abrupt cell shrinkage and permeabilization of the OM to GFP. Within ~4 s of OM permeabilization, the CM invaginates to form inward facing "periplasmic bubbles." Seconds later the bubbles begin to leak periplasmic GFP into the cytoplasm. Permeabilization is localized, consistent with possible formation of toroidal pores. Within ~20 s, first the OM and then the CM re-seals to GFP. Some 2-20 min later, both CM and OM are re-permeabilized to GFP. We invoke a mechanism based on curvature stress concepts derived from model bilayer studies. The permeabilization and re-sealing events involve sequential, time-dependent build-up of melittin density within the outer and inner leaflets of each bilayer. We also propose a mechanical explanation for the early cell shrinkage event induced by melittin and a variety of other cationic peptides. As peptides gain access to the periplasm, they bind to the anionic peptido-crosslinks of the lipopolysaccharide layer, increasing its longitudinal elastic modulus. The cell wall shrinks because it can withstand the same turgor pressure with smaller overall extension. Shrinkage in turn induces invagination of the CM, preserving its surface area. We conclude by comparing the behavior of different peptides. PMID- 29401433 TI - Lipids Alter Rhodopsin Function via Ligand-like and Solvent-like Interactions. AB - Rhodopsin, a prototypical G protein-coupled receptor, is a membrane protein that can sense dim light. This highly effective photoreceptor is known to be sensitive to the composition of its lipidic environment, but the molecular mechanisms underlying this fine-tuned modulation of the receptor's function and structural stability are not fully understood. There are two competing hypotheses to explain how this occurs: 1) lipid modulation occurs via solvent-like interactions, where lipid composition controls membrane properties like hydrophobic thickness, which in turn modulate the protein's conformational equilibrium; or 2) protein-lipid interactions are ligand-like, with specific hot spots and long-lived binding events. By analyzing an ensemble of all-atom molecular dynamics simulations of five different states of rhodopsin, we show that a local ordering effect takes place in the membrane upon receptor activation. Likewise, docosahexaenoic acid acyl tails and phosphatidylethanolamine headgroups behave like weak ligands, preferentially binding to the receptor in inactive-like conformations and inducing subtle but significant structural changes. PMID- 29401435 TI - DHA Modifies the Size and Composition of Raftlike Domains: A Solid-State 2H NMR Study. AB - Docosahexaenoic acid is an omega-3 polyunsaturated fatty acid that relieves the symptoms of a wide variety of chronic inflammatory disorders. The structural mechanism is not yet completely understood. Our focus here is on the plasma membrane as a site of action. We examined the molecular organization of [2H31]-N palmitoylsphingomyelin (PSM-d31) mixed with 1-palmitoyl-2 docosahexaenoylphosphatylcholine (PDPC) or 1-palmitoyl-2 oleoylphosphatidylcholine (POPC), as a monounsaturated control, and cholesterol (chol) (1:1:1 mol) in a model membrane by solid-state 2H NMR. The spectra were analyzed in terms of segregation into ordered SM-rich/chol-rich (raftlike) and disordered PC-rich/chol-poor (nonraft) domains that are nanoscale in size. An increase in the size of domains is revealed when POPC was replaced by PDPC. Spectra that are single-component, attributed to fast exchange between domains (<45 nm), for PSM-d31 mixed with POPC and chol become two-component, attributed to slow exchange between domains (r > 30 nm), for PSM-d31 mixed with PDPC and chol. The resolution of separate signals from PSM-d31, and correspondingly from [3alpha-2H1]cholesterol (chol-d1) and 1-[2H31]palmitoyl-2 docosahexaenoylphosphatidylcholine (PDPC-d31), in raftlike and nonraft domains enabled us to determine the composition of the domains in the PDPC-containing membrane. Most of the lipid (28% SM, 29% chol, and 23% PDPC with respect to total lipid at 30 degrees C) was found in the raftlike domain. Despite substantial infiltration of PDPC into raftlike domains, there appears to be minimal effect on the order of SM, implying the existence of internal structure that limits contact between SM and PDPC. Our results suggest a significant refinement to the model by which DHA regulates the architecture of ordered, sphingolipid-chol-enriched domains (rafts) in membranes. PMID- 29401436 TI - Protein Rotational Dynamics in Aligned Lipid Membranes Probed by Anisotropic T1rho NMR Relaxation. AB - A membrane-bound form of Pf1 coat protein reconstituted in magnetically aligned DMPC/DHPC bicelles was used as a molecular probe to quantify for the viscosity of the lipid membrane interior by measuring the uniaxial rotational diffusion coefficient of the protein. Orientationally dependent 15N NMR relaxation times in the rotating frame, or T1rho, were determined by fitting individually the decay of the resolved NMR peaks corresponding to the transmembrane helix of Pf1 coat protein as a function of the spin-lock time incorporated into the 2D SAMPI4 pulse sequence. The T1rho relaxation mechanism was modeled by uniaxial rotational diffusion on a cone, which yields a linear correlation with respect to the bond factor sin4thetaB, where thetaB is the angle that the NH bond forms with respect to the axis of rotation. Importantly, the bond factors can be independently measured from the dipolar couplings in the separated local-field SAMPI4 spectra. From this dependence, the value of the diffusion coefficient D|| = 8.0 * 105 s-1 was inferred from linear regression of the experimental T1rho data even without any spectroscopic assignment. Alternatively, a close value of D|| = 7.7 * 105 s-1 was obtained by fitting the T1rho relaxation data for the assigned NMR peaks of the transmembrane domain of Pf1 to a wavelike pattern as a function of residue number. The method illustrates the use of single-helix transmembrane peptides as molecular probes to assess the dynamic parameters of biological membranes by NMR relaxation in oriented lipid bilayers. PMID- 29401437 TI - Motor Reattachment Kinetics Play a Dominant Role in Multimotor-Driven Cargo Transport. AB - Kinesin-based cargo transport in cells frequently involves the coordinated activity of multiple motors, including kinesins from different families that move at different speeds. However, compared to the progress at the single-molecule level, mechanisms by which multiple kinesins coordinate their activity during cargo transport are poorly understood. To understand these multimotor coordination mechanisms, defined pairs of kinesin-1 and kinesin-2 motors were assembled on DNA scaffolds and their motility examined in vitro. Although less processive than kinesin-1 at the single-molecule level, addition of kinesin-2 motors more effectively amplified cargo run lengths. By applying the law of total expectation to cargo binding durations in ADP, the kinesin-2 microtubule reattachment rate was shown to be fourfold faster than that of kinesin-1. This difference in microtubule binding rates was also observed in solution by stopped flow. High-resolution tracking of a gold-nanoparticle-labeled motor with 1 ms and 2 nm precision revealed that kinesin-2 motors detach and rebind to the microtubule much more frequently than does kinesin-1. Finally, compared to cargo transported by two kinesin-1, cargo transported by two kinesin-2 motors more effectively navigated roadblocks on the microtubule track. These results highlight the importance of motor reattachment kinetics during multimotor transport and suggest a coordinated transport model in which kinesin-1 motors step effectively against loads whereas kinesin-2 motors rapidly unbind and rebind to the microtubule. This dynamic tethering by kinesin-2 maintains the cargo near the microtubule and enables effective navigation along crowded microtubules. PMID- 29401438 TI - Cell Surface Deformation during an Action Potential. AB - The excitation of many cells and tissues is associated with cell mechanical changes. The evidence presented herein corroborates that single cells deform during an action potential. It is demonstrated that excitation of plant cells (Chara braunii internodes) is accompanied by out-of-plane displacements of the cell surface in the micrometer range (~1-10 MUm). The onset of cellular deformation coincides with the depolarization phase of the action potential. The mechanical pulse: 1) propagates with the same velocity as the electrical pulse (within experimental accuracy, ~10 mm s-1), 2) is reversible, 3) in most cases is of biphasic nature (109 out of 152 experiments), and 4) is presumably independent of actin-myosin-motility. The existence of transient mechanical changes in the cell cortex is confirmed by micropipette aspiration experiments. A theoretical analysis demonstrates that this observation can be explained by a reversible change in the mechanical properties of the cell surface (transmembrane pressure, surface tension, and bending rigidity). Taken together, these findings contribute to the ongoing debate about the physical nature of cellular excitability. PMID- 29401439 TI - Active Prestress Leads to an Apparent Stiffening of Cells through Geometrical Effects. AB - Tuning of active prestress, e.g., through activity of molecular motors, constitutes a powerful cellular tool to adjust cellular stiffness through nonlinear material properties. Understanding this tool is an important prerequisite for our comprehension of cellular force response, cell shape dynamics, and tissue organization. Experimental data obtained from cell mechanical measurements often show a simple linear dependence between mechanical prestress and measured differential elastic moduli. Although these experimental findings could point to stress-induced structural changes in the material, we propose a surprisingly simple alternative explanation in a theoretical study. We show how geometrical effects can give rise to increased cellular force response of cells in the presence of active prestress. The associated effective stress stiffening is disconnected from actual stress-induced changes of the elastic modulus, and should therefore be regarded as an apparent stiffening of the material. We argue that new approaches in experimental design are necessary to separate this apparent stress-stiffening due to geometrical effects from actual nonlinearities of the elastic modulus in prestressed cellular material. PMID- 29401440 TI - Friction from Transduction Channels' Gating Affects Spontaneous Hair-Bundle Oscillations. AB - Hair cells of the inner ear can power spontaneous oscillations of their mechanosensory hair bundle, resulting in amplification of weak inputs near the characteristic frequency of oscillation. Recently, dynamic force measurements have revealed that delayed gating of the mechanosensitive ion channels responsible for mechanoelectrical transduction produces a friction force on the hair bundle. The significance of this intrinsic source of dissipation for the dynamical process underlying active hair-bundle motility has remained elusive. The aim of this work is to determine the role of friction in spontaneous hair bundle oscillations. To this end, we characterized key oscillation properties over a large ensemble of individual hair cells and measured how viscosity of the endolymph that bathes the hair bundles affects these properties. We found that hair-bundle movements were too slow to be impeded by viscous drag only. Moreover, the oscillation frequency was only marginally affected by increasing endolymph viscosity by up to 30-fold. Stochastic simulations could capture the observed behaviors by adding a contribution to friction that was 3-8-fold larger than viscous drag. The extra friction could be attributed to delayed changes in tip link tension as the result of the finite activation kinetics of the transduction channels. We exploited our analysis of hair-bundle dynamics to infer the channel activation time, which was ~1 ms. This timescale was two orders-of-magnitude shorter than the oscillation period. However, because the channel activation time was significantly longer than the timescale of mechanical relaxation of the hair bundle, channel kinetics affected hair-bundle dynamics. Our results suggest that friction from channel gating affects the waveform of oscillation and that the channel activation time can tune the characteristic frequency of the hair cell. We conclude that the kinetics of transduction channels' gating plays a fundamental role in the dynamic process that shapes spontaneous hair-bundle oscillations. PMID- 29401441 TI - Diffusional and Electrical Properties of T-Tubules Are Governed by Their Constrictions and Dilations. AB - Cardiac t-tubules (TTs) form a network of complex surface membrane invaginations that is essential for proper excitation-contraction coupling. Although electron and optical microscopy studies provided a wealth of important information about the structure of TTs, assessing their functional properties remains a challenge. In this study, we investigated the diffusional accessibility of TTs in intact isolated adult mouse ventricular myocytes using, to our knowledge, a novel fluorescence-based assay. In this approach, a small part of TTs is first locally filled with fluorescent dextran and then its diffusion out of TTs is monitored after rapid removal of extracellular dextran. In normal cells, diffusion of 3 kDa dextran is characterized by an average time constant of 3.9 +/- 1.2 s with the data ranging from 1.8 to 10.5 s. The data are consistent with essentially free diffusion of dextran in TTs although measurable contribution of binding is also evident. TT fluorescence is abolished in cells treated with high concentration of formamide or after hyposmotic stress. Importantly, the assay we use allows for quantitative, repetitive measurements of subtle dynamic changes in TT structure of the same cell that are not possible to observe with other approaches. In particular, dextran diffusion rate decreases two-to-threefold during cell swelling, suggesting significant structural remodeling of TTs. Computer modeling shows that diffusional accessibility and electrical properties of TTs are primarily determined by the constrictions and dilations of individual TTs and that, from a functional perspective, TTs cannot be considered as a network of cylinders of the same average diameter. Constriction/dilation model of cardiac TTs is in a quantitative agreement with previous high-resolution microscopy studies of TT structure and alternative measurements of diffusional and electrical time constants of TTs. The data also show that the apparent electrical length constant of cardiac TTs is likely several-fold smaller than that estimated in earlier studies. PMID- 29401442 TI - Mechanisms of Plastic Deformation in Collagen Networks Induced by Cellular Forces. AB - Contractile cells can reorganize fibrous extracellular matrices and form dense tracts of fibers between neighboring cells. These tracts guide the development of tubular tissue structures and provide paths for the invasion of cancer cells. Here, we studied the mechanisms of the mechanical plasticity of collagen tracts formed by contractile premalignant acinar cells and fibroblasts. Using fluorescence microscopy and second harmonic generation, we quantified the collagen densification, fiber alignment, and strains that remain within the tracts after cellular forces are abolished. We explained these observations using a theoretical fiber network model that accounts for the stretch-dependent formation of weak cross-links between nearby fibers. We tested the predictions of our model using shear rheology experiments. Both our model and rheological experiments demonstrated that increasing collagen concentration leads to substantial increases in plasticity. We also considered the effect of permanent elongation of fibers on network plasticity and derived a phase diagram that classifies the dominant mechanisms of plasticity based on the rate and magnitude of deformation and the mechanical properties of individual fibers. Plasticity is caused by the formation of new cross-links if moderate strains are applied at small rates or due to permanent fiber elongation if large strains are applied over short periods. Finally, we developed a coarse-grained model for plastic deformation of collagen networks that can be employed to simulate multicellular interactions in processes such as morphogenesis, cancer invasion, and fibrosis. PMID- 29401443 TI - Sarcoplasmic Reticulum Ca2+ Release Uses a Cascading Network of Intra-SR and Channel Countercurrents. AB - In muscle, Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol is mediated through the ryanodine receptors (RyRs) and sustained by countercurrents that keep the SR membrane potential near 0 mV. Likewise, Ca2+ reuptake by the sarco/endoplasmic reticulum Ca2+ ATPase pump requires countercurrent. Although evidence has suggested that TRIC K+ channels and/or RyR K+ influx provide these countercurrents, the exact sources have not yet been determined. We used an equivalent circuit compartment model of a cardiac SR, the surrounding cytosol, and the dyadic cleft to probe the sources of countercurrent during a complete cardiac cycle. By removing and relocating TRIC K+ channels, as well as limiting when they are active, we explored the various possible sources of SR countercurrent under many conditions. Our simulations indicate that no single channel type is essential for countercurrent. Rather, a cascading network of countercurrents is present with anion fluxes within the SR redistributing charges throughout the full SR volume. This allows ion channels in the entire SR membrane, far from the Ca2+ fluxes through the RyRs in the junctional SR and sarco/endoplasmic reticulum Ca2+ ATPase pump in the nonjunctional SR, to mediate countercurrents that support Ca2+ release and reuptake. This multifactorial network of countercurrents allows Ca2+ release to be remarkably robust. PMID- 29401444 TI - The Competition between the Noise and Shear Motion Sensitivity of Cochlear Inner Hair Cell Stereocilia. AB - Acoustical excitation of the organ of Corti induces radial fluid flow in the subtectorial space (STS) that excites the hair bundles (HBs) of the sensory inner hair cell of the mammalian cochlea. The inner hair cell HBs are bathed in endolymphatic fluid filling a thin gap in the STS between the tectorial membrane and the reticular lamina. According to the fluctuation dissipation theorem, the fluid viscosity gives rise to mechanical fluctuations that are transduced into current noise. Conversely, the stochastic fluctuations of the mechanically gated channels of the HBs also induce dissipation. We develop an analytic model of the STS complex in a cross section of the gerbil organ of Corti. We predict that the dominant noise at the apex is due to the channel stochasticity whereas viscous effects dominate at the base. The net root mean square fluctuation of the HB motion is estimated to be at least 1.18 nm at the base and 2.72 nm at the apex. By varying the HB height for a fixed STS gap, we find that taller HBs are better sensors with lower thresholds. An integrated active HB model is shown to reduce the hydrodynamic resistance through a cycle-by-cycle power addition through adaptation, reducing the thresholds of hearing, hinting at one potential role for HB activity in mammalian hearing. We determine that a Couette flow approximation in the STS underestimates the dissipation and that modeling the entire STS complex is necessary to correctly predict the low-frequency dissipation in the cochlea. Finally, the difference in the noise budget at the base and the apex of the cochlea indicate that a sensing modality other than the shear motion of the TM that may be used to achieve low-noise acoustic sensing at the apex. PMID- 29401445 TI - Simulating Genetic Circuits in Bacterial Populations with Growth Heterogeneity. AB - We computationally study genetic circuits in bacterial populations with heterogeneities in the growth rate. To that end, we present a stochastic simulation method for gene circuits in populations of cells and propose an efficient implementation that we call the "Next Family Method". Within this approach, we implement different population setups, specifically Chemostat-type growth and growth in an ideal Mother Machine and show that the population structure and its statistics are different for the different setups whenever there is growth heterogeneity. Such dependence on the population setup is demonstrated, in the case of bistable systems with different growth rates in the stable states, to have distinctive signatures on quantities including the distributions of protein concentration and growth rates, and hysteresis curves. Applying this method to a bistable antibiotic resistance circuit, we find that as a result of the different statistics in different population setups, the estimated minimal inhibitory concentration of the antibiotic becomes dependent on the population setup in which it is measured. PMID- 29401447 TI - New Year Tidyings. PMID- 29401446 TI - A Distribution-Moment Approximation for Coupled Dynamics of the Airway Wall and Airway Smooth Muscle. AB - Asthma is fundamentally a disease of airway constriction. Due to a variety of experimental challenges, the dynamics of airways are poorly understood. Of specific interest is the narrowing of the airway due to forces produced by the airway smooth muscle wrapped around each airway. The interaction between the muscle and the airway wall is crucial for the airway constriction that occurs during an asthma attack. Although cross-bridge theory is a well-studied representation of complex smooth muscle dynamics, and these dynamics can be coupled to the airway wall, this comes at significant computational cost-even for isolated airways. Because many phenomena of interest in pulmonary physiology cannot be adequately understood by studying isolated airways, this presents a significant limitation. We present a distribution-moment approximation of this coupled system and study the validity of the approximation throughout the physiological range. We show that the distribution-moment approximation is valid in most conditions, and we explore the region of breakdown. These results show that in many situations, the distribution-moment approximation is a viable option that provides an orders-of-magnitude reduction in computational complexity; not only is this valuable for isolated airway studies, but it moreover offers the prospect that rich ASM dynamics might be incorporated into interacting airway models where previously this was precluded by computational cost. PMID- 29401448 TI - Crosslinking Mass Spectrometry Goes In-Tissue. AB - Chemical crosslinking combined with mass spectrometry provides information on protein conformations and protein-protein interactions in heart tissue. PMID- 29401449 TI - Principles of Systems Biology, No. 25. AB - This month: better ways of asking "who's there?" using rRNA sequencing (Albertsen); "humanizing" yeast chromatin (Boeke/Truong); the cargo spectrum of nuclear pores (Mackmull/Beck/Ori); exon-specific mutation rates (Sabarinathan/Gonzalez-Perez/Lopez-Bigas); synthetic virus-like particles (Lajoie/Butterfield); imaging the beating, developing heart (Scherf/Weber/Kohl/Huisken); and RNA-based FRET sensors (Jepsen/Andersen). PMID- 29401450 TI - Breaking New Ground in the Landscape of Single-Cell Analysis. AB - Here, we outline p-Creode, a new algorithm to construct multi-branching cell lineage trajectories from single-cell data. Application of this platform to diverse sources of single-cell data demonstrates its robustness and scalability, while the discovery of a new origin for rare gut tuft cells showcases the utility of p-Creode. PMID- 29401451 TI - Broad Views of Non-alcoholic Fatty Liver Disease. AB - Multi-omics multi-tissue data are used to interpret genome-wide association study results from mice to identify key driver genes of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat (steatosis) in the liver due to causes other than excessive alcohol consumption. The disease may progress to more severe forms of liver diseases, including non alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. In this issue of Cell Systems, Krishnan et al. (2018) reveal mechanisms underlying NAFLD by generating multi-omics data using liver and adipose tissues obtained from the Hybrid Mouse Diversity Panel, consisting of 113 mouse strains with various degrees of NAFLD. The study identified key driver genes of NAFLD that can be used in the development of efficient treatment strategies and illustrates the potential utility of systematic analysis of multi-layer biological networks. PMID- 29401452 TI - Advocates for Children's Health: Working Together to Reduce Harmful Environmental Exposures. PMID- 29401453 TI - A maximum-entropy model for predicting chromatin contacts. AB - The packaging of DNA inside a nucleus shows complex structure stabilized by a host of DNA-bound factors. Both the distribution of these factors and the contacts between different genomic locations of the DNA can now be measured on a genome-wide scale. This has advanced the development of models aimed at predicting the conformation of DNA given only the locations of bound factors-the chromatin folding problem. Here we present a maximum-entropy model that is able to predict a contact map representation of structure given a sequence of bound factors. Non-local effects due to the sequence neighborhood around contacting sites are found to be important for making accurate predictions. Lastly, we show that the model can be used to infer a sequence of bound factors given only a measurement of structure. This opens up the possibility for efficiently predicting sequence regions that may play a role in generating cell-type specific structural differences. PMID- 29401454 TI - Biophysical attributes that affect CaMKII activation deduced with a novel spatial stochastic simulation approach. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) holoenzymes play a critical role in decoding Ca2+ signals in neurons. Understanding how this occurs has been the focus of numerous studies including many that use models. However, CaMKII is notoriously difficult to simulate in detail because of its multi subunit nature, which causes a combinatorial explosion in the number of species that must be modeled. To study the Ca2+-calmodulin-CaMKII reaction network with detailed kinetics while including the effect of diffusion, we have customized an existing stochastic particle-based simulator, Smoldyn, to manage the problem of combinatorial explosion. With this new method, spatial and temporal aspects of the signaling network can be studied without compromising biochemical details. We used this new method to examine how calmodulin molecules, both partially loaded and fully loaded with Ca2+, choose pathways to interact with and activate CaMKII under various Ca2+ input conditions. We found that the dependence of CaMKII phosphorylation on Ca2+ signal frequency is intrinsic to the network kinetics and the activation pattern can be modulated by the relative amount of Ca2+ to calmodulin and by the rate of Ca2+ diffusion. Depending on whether Ca2+ influx is saturating or not, calmodulin molecules could choose different routes within the network to activate CaMKII subunits, resulting in different frequency dependence patterns. In addition, the size of the holoenzyme produces a subtle effect on CaMKII activation. The more extended the subunits are organized, the easier for calmodulin molecules to access and activate the subunits. The findings suggest that particular intracellular environmental factors such as crowding and calmodulin availability can play an important role in decoding Ca2+ signals and can give rise to distinct CaMKII activation patterns in dendritic spines, Ca2+ channel nanodomains and cytoplasm. PMID- 29401455 TI - Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans. AB - Mycolactone is the exotoxin produced by Mycobacterium ulcerans and is the virulence factor behind the neglected tropical disease Buruli ulcer. The toxin has a broad spectrum of biological effects within the host organism, stemming from its interaction with at least two molecular targets and the inhibition of protein uptake into the endoplasmic reticulum. Although it has been shown that the toxin can passively permeate into host cells, it is clearly lipophilic. Association with lipid carriers would have substantial implications for the toxin's distribution within a host organism, delivery to cellular targets, diagnostic susceptibility, and mechanisms of pathogenicity. Yet the toxin's interactions with, and distribution in, lipids are unknown. Herein we have used coarse-grained molecular dynamics simulations, guided by all-atom simulations, to study the interaction of mycolactone with pure and mixed lipid membranes. Using established techniques, we calculated the toxin's preferential localization, membrane translocation, and impact on membrane physical and dynamical properties. The computed water-octanol partition coefficient indicates that mycolactone prefers to be in an organic phase rather than in an aqueous environment. Our results show that in a solvated membrane environment the exotoxin mainly localizes in the water-membrane interface, with a preference for the glycerol moiety of lipids, consistent with the reported studies that found it in lipid extracts of the cell. The calculated association constant to the model membrane is similar to the reported association constant for Wiskott-Aldrich syndrome protein. Mycolactone is shown to modify the physical properties of membranes, lowering the transition temperature, compressibility modulus, and critical line tension at which pores can be stabilized. It also shows a tendency to behave as a linactant, a molecule that localizes at the boundary between different fluid lipid domains in membranes and promotes inter-mixing of domains. This property has implications for the toxin's cellular access, T-cell immunosuppression, and therapeutic potential. PMID- 29401456 TI - A phylogenetic method to perform genome-wide association studies in microbes that accounts for population structure and recombination. AB - Genome-Wide Association Studies (GWAS) in microbial organisms have the potential to vastly improve the way we understand, manage, and treat infectious diseases. Yet, microbial GWAS methods established thus far remain insufficiently able to capitalise on the growing wealth of bacterial and viral genetic sequence data. Facing clonal population structure and homologous recombination, existing GWAS methods struggle to achieve both the precision necessary to reject spurious findings and the power required to detect associations in microbes. In this paper, we introduce a novel phylogenetic approach that has been tailor-made for microbial GWAS, which is applicable to organisms ranging from purely clonal to frequently recombining, and to both binary and continuous phenotypes. Our approach is robust to the confounding effects of both population structure and recombination, while maintaining high statistical power to detect associations. Thorough testing via application to simulated data provides strong support for the power and specificity of our approach and demonstrates the advantages offered over alternative cluster-based and dimension-reduction methods. Two applications to Neisseria meningitidis illustrate the versatility and potential of our method, confirming previously-identified penicillin resistance loci and resulting in the identification of both well-characterised and novel drivers of invasive disease. Our method is implemented as an open-source R package called treeWAS which is freely available at https://github.com/caitiecollins/treeWAS. PMID- 29401457 TI - Ras/ERK-signalling promotes tRNA synthesis and growth via the RNA polymerase III repressor Maf1 in Drosophila. AB - The small G-protein Ras is a conserved regulator of cell and tissue growth. These effects of Ras are mediated largely through activation of a canonical RAF-MEK-ERK kinase cascade. An important challenge is to identify how this Ras/ERK pathway alters cellular metabolism to drive growth. Here we report on stimulation of RNA polymerase III (Pol III)-mediated tRNA synthesis as a growth effector of Ras/ERK signalling in Drosophila. We find that activation of Ras/ERK signalling promotes tRNA synthesis both in vivo and in cultured Drosophila S2 cells. We also show that Pol III function is required for Ras/ERK signalling to drive proliferation in both epithelial and stem cells in Drosophila tissues. We find that the transcription factor Myc is required but not sufficient for Ras-mediated stimulation of tRNA synthesis. Instead we show that Ras signalling promotes Pol III function and tRNA synthesis by phosphorylating, and inhibiting the nuclear localization and function of the Pol III repressor Maf1. We propose that inhibition of Maf1 and stimulation of tRNA synthesis is one way by which Ras signalling enhances protein synthesis to promote cell and tissue growth. PMID- 29401458 TI - Sem1 links proteasome stability and specificity to multicellular development. AB - The transition from vegetative growth to multicellular development represents an evolutionary hallmark linked to an oxidative stress signal and controlled protein degradation. We identified the Sem1 proteasome subunit, which connects stress response and cellular differentiation. The sem1 gene encodes the fungal counterpart of the human Sem1 proteasome lid subunit and is essential for fungal cell differentiation and development. A sem1 deletion strain of the filamentous fungus Aspergillus nidulans is able to grow vegetatively and expresses an elevated degree of 20S proteasomes with multiplied ATP-independent catalytic activity compared to wildtype. Oxidative stress induces increased transcription of the genes sem1 and rpn11 for the proteasomal deubiquitinating enzyme. Sem1 is required for stabilization of the Rpn11 deubiquitinating enzyme, incorporation of the ubiquitin receptor Rpn10 into the 19S regulatory particle and efficient 26S proteasome assembly. Sem1 maintains high cellular NADH levels, controls mitochondria integrity during stress and developmental transition. PMID- 29401459 TI - STERILE APETALA modulates the stability of a repressor protein complex to control organ size in Arabidopsis thaliana. AB - Organ size control is of particular importance for developmental biology and agriculture, but the mechanisms underlying organ size regulation remain elusive in plants. Meristemoids, which possess stem cell-like properties, have been recognized to play important roles in leaf growth. We have recently reported that the Arabidopsis F-box protein STERILE APETALA (SAP)/SUPPRESSOR OF DA1 (SOD3) promotes meristemoid proliferation and regulates organ size by influencing the stability of the transcriptional regulators PEAPODs (PPDs). Here we demonstrate that KIX8 and KIX9, which function as adaptors for the corepressor TOPLESS and PPD, are novel substrates of SAP. SAP interacts with KIX8/9 and modulates their protein stability. Further results show that SAP acts in a common pathway with KIX8/9 and PPD to control organ growth by regulating meristemoid cell proliferation. Thus, these findings reveal a molecular mechanism by which SAP targets the KIX-PPD repressor complex for degradation to regulate meristemoid cell proliferation and organ size. PMID- 29401460 TI - Zika virus like particles elicit protective antibodies in mice. AB - Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever. Since its recent emergence in 2014 in the American continent, ZIKV infection during pregnancy has been closely associated with a wide range of congenital abnormalities. To date, no vaccines or antivirals are publicly available. We developed Zika virus-like particles (VLPs) and evaluated their immunogenicity and protective efficacy in mouse models. ZIKV VLPs (ZIKVLPs) formulated with alum were injected into 6-8-week-old interferon deficient AG129 mice as well as wild type BALB/c mice. Control mice received PBS/alum. Animals were challenged with 200 PFU (>1000 AG129 LD50s) of ZIKV strain H/PF/2013. All vaccinated mice survived with no morbidity or weight loss while control animals either died at 9 days post challenge (AG129) or had increased viremia (BALB/c). Neutralizing antibodies were observed in all ZIKVLP vaccinated mice. The role of neutralizing antibodies in protecting mice was demonstrated by passive transfer. Our findings demonstrate the protective efficacy of the ZIKVLP vaccine and highlight the important role that neutralizing antibodies play in protection against ZIKV infection. PMID- 29401461 TI - Body fat distribution and risk of incident ischemic stroke in men and women aged 50 to 74 years from the general population. The KORA Augsburg cohort study. AB - BACKGROUND: It remains controversial whether measures of general or abdominal adiposity are better risk predictors for ischemic stroke. Furthermore, so far it is unclear whether body fat mass index (BFMI) and fat free mass index (FFMI) are risk predictors for ischemic stroke. This study examined the sex-specific relevance of body mass index (BMI), BROCA Index, waist circumference (WC), waist height ratio (WHtR), BFMI and FFMI for the development of ischemic stroke in a Caucasian population. MATERIAL AND METHODS: The prospective population-based cohort study was based on 1917 men and 1832 women (aged 50 to 74 years) who participated in the third (1994/95) or fourth (1999/2001) MONICA/KORA Augsburg survey. Subjects were free of stroke at baseline. Standardized anthropometric and bioelectric impedance measurements were obtained at baseline. Hazard ratios (HR) were estimated from Cox proportional hazard models. RESULTS: During a median follow-up of 9.3 years 128 ischemic strokes occurred in men and 81 in women, respectively. Coded as quartiles WC and WHtR were significantly associated with incident stroke in multivariable analyses in women (comparing the 4th vs. the bottom quartile), but none of the adiposity measures was significantly associated with incident stroke in multivariable adjusted analyses in men. When anthropometric measures were used as continuous variables, these findings were confirmed. After multivariable adjustment the associations between obesity measures and incident ischemic stroke were statistically significant only for WC (HR 1.39, 95%CI 1.12-1.72) and WHtR in women (HR 1.39, 95%CI 1.12-1.73) per increase of 1 standard deviation. In both sexes the measures BFMI and FFMI were no independent predictors for incident ischemic stroke. CONCLUSIONS: Abdominal obesity measures are independent predictors of incident ischemic stroke in women but not in men from the general adult population. Thus, it may be of particular importance for women to prevent central obesity in order to reduce their risk of ischemic stroke. PMID- 29401462 TI - Synthesis, stabilization, and characterization of the MR1 ligand precursor 5 amino-6-D-ribitylaminouracil (5-A-RU). AB - Mucosal-associated invariant T (MAIT) cells are an abundant class of innate T cells restricted by the MHC I-related molecule MR1. MAIT cells can recognize bacterially-derived metabolic intermediates from the riboflavin pathway presented by MR1 and are postulated to play a role in innate antibacterial immunity through production of cytokines and direct bacterial killing. MR1 tetramers, typically stabilized by the adduct of 5-amino-6-D-ribitylaminouracil (5-A-RU) and methylglyoxal (MeG), are important tools for the study of MAIT cells. A long standing problem with 5-A-RU is that it is unstable upon storage. Herein we report an efficient synthetic approach to the HCl salt of this ligand, which has improved stability during storage. We also show that synthetic 5-A-RU*HCl produced by this method may be used in protocols for the stimulation of human MAIT cells and production of both human and mouse MR1 tetramers for MAIT cell identification. PMID- 29401463 TI - Radiomic features analysis in computed tomography images of lung nodule classification. AB - PURPOSE: Radiomics, which extract large amount of quantification image features from diagnostic medical images had been widely used for prognostication, treatment response prediction and cancer detection. The treatment options for lung nodules depend on their diagnosis, benign or malignant. Conventionally, lung nodule diagnosis is based on invasive biopsy. Recently, radiomics features, a non invasive method based on clinical images, have shown high potential in lesion classification, treatment outcome prediction. METHODS: Lung nodule classification using radiomics based on Computed Tomography (CT) image data was investigated and a 4-feature signature was introduced for lung nodule classification. Retrospectively, 72 patients with 75 pulmonary nodules were collected. Radiomics feature extraction was performed on non-enhanced CT images with contours which were delineated by an experienced radiation oncologist. RESULT: Among the 750 image features in each case, 76 features were found to have significant differences between benign and malignant lesions. A radiomics signature was composed of the best 4 features which included Laws_LSL_min, Laws_SLL_energy, Laws_SSL_skewness and Laws_EEL_uniformity. The accuracy using the signature in benign or malignant classification was 84% with the sensitivity of 92.85% and the specificity of 72.73%. CONCLUSION: The classification signature based on radiomics features demonstrated very good accuracy and high potential in clinical application. PMID- 29401464 TI - Prevalence and correlates of hypertension in Maharashtra, India: A multilevel analysis. AB - BACKGROUND AND AIM: In the last few decades, the prevalence of hypertension has been drastically increased in India. The present study estimates the current prevalence of hypertension and its correlates in the state of Maharashtra. The variation in the prevalence of hypertension associated with individual-level characteristics is explained at the community and district level. METHODS: Data is used from the recent round of District Level Household & Facility Survey (DLHS 4), 2012-13. The DLHS-4 has used the nationally representative sample, collected through multistage stratified sampling procedure. A similar sampling frame, used in NSSO-2007-08, has been followed. The chi-square test is used to show the significance level of the association between the estimated prevalence of hypertension and its correlates. Multilevel regression analysis is carried out to investigate the effects of individual and community level factors on the prevalence of hypertension. RESULTS: The overall prevalence of hypertension is 25% in Maharashtra, and a huge variation in the prevalence of hypertension is found across the districts. Dhule, Gadchiroli (with a low HDI rank), Mumbai and Satara (with higher HDI rank) are the districts with the higher (above 30%) prevalence of high blood pressure. The prevalence also significantly varies according to different correlates. The prevalence of high blood pressure is higher among elderly population (40%), among males (28%), in the urban areas (27%) and in the richest wealth quintile (28%). The prevalence is also higher among cigarette smokers (31%), alcohol consumers (30%) and people with obesity (38%) as compared to their counterparts. The results of the multilevel analysis show that the older and obese persons are at four-time higher risk of hypertension. Again, age, sex, marital status, place of residence, wealth status, unhealthy habits (i.e. smoking and alcohol consumption) and BMI are significantly associated with hypertension. The results of VPC statistics show that 14% of hypertension prevalence could be attributed to differences at the community level. CONCLUSION: The prevalence of hypertension largely varies in the districts of Maharashtra irrespective of their level of socio-economic development (i.e. HDI rank). The variation in the rate of prevalence of hypertension is higher in the community (PSU) level as compared to the variation in the prevalence rate at the district level. Hypertension is attributable to the modifiable factors like risky lifestyle practices. PMID- 29401465 TI - Evaluation of a countrywide implementation of the world health organisation surgical safety checklist in Madagascar. AB - BACKGROUND: The 2009 World Health Organisation (WHO) surgical safety checklist significantly reduces surgical mortality and morbidity (up to 47%). Yet in 2016, only 25% of East African anesthetists regularly use the checklist. Nationwide implementation of the checklist is reported in high-income countries, but in low- and middle-income countries (LMICs) reports of successful implementations are sparse, limited to single institutions and require intensive support. Since checklist use leads to the biggest improvements in outcomes in LMICs, methods of wide-scale implementation are needed. We hypothesized that, using a three-day course, successful wide-scale implementation of the checklist could be achieved, as measured by at least 50% compliance with six basic safety processes at three to four months. We also aimed to determine predictors for checklist utilization. MATERIALS AND METHODS: Using a blended educational implementation strategy based on prior pilot studies we designed a three-day dynamic educational course to facilitate widespread implementation of the WHO checklist. The course utilized lectures, film, small group breakouts, participant feedback and simulation to teach the knowledge, skills and behavior changes needed to implement the checklist. In collaboration with the Ministry of Health and local hospital leadership, the course was delivered to 427 multi-disciplinary staff at 21 hospitals located in 19 of 22 regions of Madagascar between September 2015 and March 2016. We evaluated implementation at three to four months using questionnaires (with a 5-point Likert scale) and focus groups. Multivariate linear regression was used to test predictors of checklist utilization. RESULTS: At three to four months, 65% of respondents reported always using the checklist, with another 13% using it in part. Participant's years in practice, hospital size, or surgical volume did not predict checklist use. Checklist use was associated with counting instruments (p< 0.05), but not with verifying: patient identity, difficult intubation risk, risk of blood loss, prophylactic antibiotic administration, or counting needles and sponges. CONCLUSION: Use of a multi disciplinary three-day course for checklist implementation resulted in 78% of participants using the checklist, at three months; and an increase in counting surgical instruments. Successful checklist implementation was not predicted by participant length of medical service, hospital size or surgical volume. If reproducible in other countries, widespread implementation in LMICs becomes a realistic possibility. PMID- 29401466 TI - Ex vivo expansion of alveolar macrophages with Mycobacterium tuberculosis from the resected lungs of patients with pulmonary tuberculosis. AB - Tuberculosis (TB), with the Mycobacterium tuberculosis (Mtb) as the causative agent, remains to be a serious world health problem. Traditional methods used for the study of Mtb in the lungs of TB patients do not provide information about the number and functional status of Mtb, especially if Mtb are located in alveolar macrophages. We have developed a technique to produce ex vivo cultures of cells from different parts of lung tissues surgically removed from patients with pulmonary TB and compared data on the number of cells with Mtb inferred by the proposed technique to the results of bacteriological and histological analyses used for examination of the resected lungs. The ex vivo cultures of cells obtained from the resected lungs of all patients were largely composed of CD14 positive alveolar macrophages, foamy or not, with or without Mtb. Lymphocytes, fibroblasts, neutrophils, and multinucleate Langhans giant cells were also observed. We found alveolar macrophages with Mtb in the ex vivo cultures of cells from the resected lungs of even those TB patients, whose sputum smears and lung tissues did not contain acid-fast Mtb or reveal growing Mtb colonies on dense medium. The detection of alveolar macrophages with Mtb in ex vivo culture as soon as 16-18 h after isolation of cells from the resected lungs of all TB patients suggests that the technique proposed for assessing the level of infection in alveolar macrophages of TB patients has higher sensitivity than do prolonged bacteriological or pathomorphological methods. The proposed technique allowed us to rapidly (in two days after surgery) determine the level of infection with Mtb in the cells of the resected lungs of TB patients and, by the presence or absence of Mtb colonies, including those with cording morphology, the functional status of the TB agent at the time of surgery. PMID- 29401467 TI - Identification and characterisation of the ecdysone biosynthetic genes neverland, disembodied and shade in the salmon louse Lepeophtheirus salmonis (Copepoda, Caligidae). AB - The salmon louse is a marine ectoparasitic copepod on salmonid fishes. Its lifecycle consists of eight developmental stages, each separated by a molt. In crustaceans and insects, molting and reproduction is controlled by circulating steroid hormones such as 20-hydroxyecdysone. Steroid hormones are synthesized from cholesterol through catalytic reactions involving a 7,8-dehydrogenase Neverland and several cytochrome P450 genes collectively called the Halloween genes. In this study, we have isolated and identified orthologs of neverland, disembodied and shade in the salmon louse (Lepeophtheirus salmonis) genome. Tissue-specific expression analysis show that the genes are expressed in intestine and reproductive tissue. In addition, levels of the steroid hormones ecdysone, 20-hydroxyecdysone and ponasterone A were measured during the reproductive stage of adult females and in early life stages. PMID- 29401468 TI - Manual action verbs modulate the grip force of each hand in unimanual or symmetrical bimanual tasks. AB - Manual action verbs modulate the right-hand grip force in right-handed subjects. However, to our knowledge, no studies demonstrate the ability to accomplish this modulation during bimanual tasks nor describe their effect on left-hand behavior in unimanual and bimanual tasks. Using load cells and word playlists, we evaluated the occurrence of grip force modulation by manual action verbs in unimanual and symmetrical bimanual tasks across the three auditory processing phases. We found a significant grip force increase for all conditions compared to baseline, indicating the occurrence of modulation. When compared to each other, the grip force variation from baseline for the three phases of both hands in the symmetrical bimanual task was not different from the right-hand in the unimanual task. The left-hand grip force showed a lower amplitude for auditory phases 1 and 2 when compared to the other conditions. The right-hand grip force modulation became significant from baseline at 220 ms after the word onset in the unimanual task. This moment occurred earlier for both hands in bimanual task (160 ms for the right-hand and 180 for the left-hand). It occurred later for the left-hand in unimanual task (320 ms). We discuss the hypothesis that Broca's area and Broca's homologue area likely control the left-hand modulation in a unilateral or a bilateral fashion. These results provide new evidence for understanding the linguistic function processing in both hemispheres. PMID- 29401469 TI - Peri-implant conditions and marginal bone loss around cemented and screw-retained single implant crowns in posterior regions: A retrospective cohort study with up to 4 years follow-up. AB - The aim of the present study was to identify the peri-implant conditions (bleeding on probing (BOP), pocket probing depth (PPD), modified plaque index (mPI)) and marginal bone loss (MBL, marginal bone level change between follow-up and occlusal loading) around cemented and screw-retained posterior single crowns on tissue-level implants. The study was a retrospective cohort study with up to 4 years (mean 2.5 years) follow-up. Patients with either cemented or screw-retained crowns in posterior regions were included. Implant survival, technical complications, BOP, PPD, mPI, MBL, biologic complications (peri-implant mocositis and peri-implantitis) were evaluated. Mann-Whitney U test was used to test the difference between the screw-retained group (SG) and cemented group (CG). 176 patients (SG: 94, CG: 82) were included. The implant survival rates were 100% in SG and 98.8% in CG. Prosthetic screw loosening was found in 8 restorations (8.7%) at follow-up visit. Peri-implant mucositis rate was significantly higher in the SG group (42.1%) than that in the CG group (32.2%) (P = 0.04). Six patients (6.38%) in the screw-retained group and 5 patients (6.10%) in the cemented group were diagnosed with peri-implantitis, the difference did not reach statistical significance (P>0.05). No significant difference of PPD, mPI and MBL were found between two groups (P = 0.11, 0.13 and 0.08, respectively). High implant survival rates were achieved in both groups. Cemented single crowns on tissue-level implants showed comparable peri-implant conditions in comparison with two-piece screw-retained crowns. Well-designed prospective cohort or randomized controlled clinical trials with longer follow-up are needed to confirm the result. PMID- 29401470 TI - Phylogeny and source climate impact seed dormancy and germination of restoration relevant forb species. AB - For many species and seed sources used in restoration activities, specific seed germination requirements are often unknown. Because seed dormancy and germination traits can be constrained by phylogenetic history, related species are often assumed to have similar traits. However, significant variation in these traits is also present within species as a result of adaptation to local climatic conditions. A growing number of studies have attempted to disentangle how phylogeny and climate influence seed dormancy and germination traits, but they have focused primarily on species-level effects, ignoring potential population level variation. We examined the relationships between phylogeny, climate, and seed dormancy and germination traits for 24 populations of eight native, restoration-relevant forb species found in a wide range of climatic conditions in the Southwest United States. The seeds were exposed to eight temperature and stratification length regimes designed to mimic regional climatic conditions. Phylogenetic relatedness, overall climatic conditions, and temperature conditions at the site were all significantly correlated with final germination response, with significant among-population variation in germination response across incubation treatments for seven of our eight study species. Notably, germination during stratification was significantly predicted by precipitation seasonality and differed significantly among populations for seven species. While previous studies have not examined germination during stratification as a potential trait influencing overall germination response, our results suggest that this trait should be included in germination studies as well as seed sourcing decisions. Results of this study deepen our understanding of the relationships between source climate, species identity, and germination, leading to improved seed sourcing decisions for restorations. PMID- 29401471 TI - Clinical value of ALU concentration and integrity index for the early diagnosis of ovarian cancer: A retrospective cohort trial. AB - CA125 amounts have a large overlap in ovarian cancer and benign diseases. We conducted a retrospective cohort trial to assess the clinical value of circulating cell-free DNA concentration and integrity index for the diagnosis of ovarian cancer. A total of 150 patients were recruited. Plasma samples of 24 ovarian cancer patients, 12 benign ovarian cysts, and 12 healthy controls were assessed. By amplifying short ALU-115 repeat and long ALU-219 fragments, circulating cell-free DNA concentrations and integrity index were measured. Plasma ALU-219 fragment levels and integrity index were significantly higher in the ovarian cancer group compared with the benign disease and healthy control groups (p = 0.023 and p = 0.004, respectively). These findings indicated that plasma ALU-219 levels and integrity may have a clinical value in the early diagnosis of ovarian cancer. PMID- 29401472 TI - Mental health among children and adolescents: Construct validity, reliability, and parent-adolescent agreement on the 'Strengths and Difficulties Questionnaire' in Chile. AB - The Strengths and Difficulties Questionnaire (SDQ) is a screening tool used to measure psychological functioning among children and adolescents. It has been extensively used worldwide, but its psychometric properties, such as internal structure and reliability, seem to vary across countries. This is the first study exploring the construct validity and reliability of the Spanish version of SDQ among early adolescents (self-reported) and their parents in Latin America. A total of 1,284 early adolescents (9-15 years) and their parents answered the SDQ. We also collected demographic variables. A confirmatory factor analysis was conducted to assess the latent structure of the SDQ. We also used the multitrait multimethod analysis to separate the true variance on the constructs from variance resulting from measurement methods (self-report vs. parent report), and evaluated the agreement between adolescents and their parents. We found that the original five-factor model was a good solution and the resulting sub-scales had good internal consistency. We also found that the self-reported and parental versions of SDQ provide different information, which are complementary and provide a better picture of the emotional, social, and conduct problems of adolescents. We have added evidence for the construct validity and reliability of the Spanish self-reported and parental SDQ versions in a Chilean sample. PMID- 29401473 TI - Benefits of expressive writing in reducing test anxiety: A randomized controlled trial in Chinese samples. AB - PURPOSE: To explore the effect of expressive writing of positive emotions on test anxiety among senior-high-school students. METHODS: The Test Anxiety Scale (TAS) was used to assess the anxiety level of 200 senior-high-school students. Seventy five students with high anxiety were recruited and divided randomly into experimental and control groups. Each day for 30 days, the experimental group engaged in 20 minutes of expressive writing of positive emotions, while the control group was asked to merely write down their daily events. A second test was given after the month-long experiment to analyze whether there had been a reduction in anxiety among the sample. Quantitative data was obtained from TAS scores. The NVivo10.0 software program was used to examine the frequency of particular word categories used in participants' writing manuscripts. RESULTS: Senior-high-school students indicated moderate to high test anxiety. There was a significant difference in post-test results (P < 0.001), with the experimental group scoring obviously lower than the control group. The interaction effect of group and gender in the post-test results was non-significant (P > 0.05). Students' writing manuscripts were mainly encoded on five code categories: cause, anxiety manifestation, positive emotion, insight and evaluation. There was a negative relation between positive emotion, insight codes and test anxiety. There were significant differences in the positive emotion, anxiety manifestation, and insight code categories between the first 10 days' manuscripts and the last 10 days' ones. CONCLUSIONS: Long-term expressive writing of positive emotions appears to help reduce test anxiety by using insight and positive emotion words for Chinese students. Efficient and effective intervention programs to ease test anxiety can be designed based on this study. PMID- 29401474 TI - Medicine procurement in hospital pharmacies of Nepal: A qualitative study based on the Basel Statements. AB - BACKGROUND: Accessibility and affordability of evidence-based medicines are issues of global concern. For low-income countries like Nepal, it is crucial to have easy and reliable access to affordable, good-quality, evidence-based medicines, especially in the aftermath of natural or manmade disasters. Availability of affordable and evidence-based high quality medicines depends on the medicine procurement procedure, which makes it an important aspect of healthcare delivery. In this study, we aimed to investigate medicine procurement practices in hospital pharmacies of Nepal within the framework of International Pharmaceutical Federation [FIP] hospital pharmacy guidelines "the Basel Statements". METHOD: We conducted semi-structured interviews with hospital pharmacists or procurement officers in hospital pharmacies of four major regions in Nepal to explore procurement practices. Data were collected until saturation of themes, analysed using the framework approach, and organised around the statements within the procurement theme of the Basel Statements. RESULTS: Interviews conducted with 53 participants revealed that the procurement guidelines of the Basel Statements were adopted to a certain extent in hospital pharmacies of Nepal. It was found that the majority of hospital pharmacies in Nepal reported using an expensive direct-procurement model for purchasing medicines. Most had no formulary and procured medicines solely based on doctors' prescriptions, which were heavily influenced by pharmaceutical companies' marketing strategies. Whilst most procured only registered medicines, a minority reported purchasing unregistered medicines through unauthorised supply-chains. And although the majority of hospital pharmacies had some contingency plans for managing medicine shortages, a few had none. CONCLUSIONS: Procurement guidelines of the Basel Statements were thus found to be partially adopted; however, there is room for improvement in current procurement practices in hospital pharmacies of Nepal. Adoption and regulation of national and international policies is recommended for enhancing medicine accessibility, as well as improving preparedness for health emergencies during natural disasters and health epidemics. PMID- 29401475 TI - Overexpression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in boys with cryptorchidism. AB - BACKGROUND: The ubiquitin-proteasome system regulate p53, caspase and Bcl-2 family proteins, and is crucial for the degradation of the defective germ cells in testes. Purpose: to evaluate the concentration of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in the blood plasma of boys with cryptorchidism and if there is any correlation with patient age. METHODS: Patients-50 boys aged 1-4 years (median = 2,4y.) with unilateral cryptorchidism. Exclusion criteria were: previous human chorionic gonadotropin treatment, an abnormal karyotype, endocrine or immunological disorders or any long-term medication. The control group-50 healthy, age matched boys (aged 1-4 years, median = 2,1y.), admitted to the Pediatric Surgery Department for planned herniotomy. To investigate UCHL1 in blood plasma of boys with cryptorchidism, we used a novel technique Surface PLASMON RESONANCE Imaging (SPRI). RESULTS: The median concentration of UCHL1 in the blood plasma of boys with cryptorchidism, was 5-folds higher than in boys with inguinal hernia, whose testicles were located in the scrotum. We also noticed statistically significant difference between UCHL1 levels in boys with cryptorchidism up to 2 years old, and above 2 years old. Older boys, whose testicles since birth were located in the inguinal pouch or in the abdominal cavity, had higher concentration of UCHL1 in their blood plasma, than boys from younger group. In the group of cryptorchid boys, we also found slightly lower concentrations of INSL3, without statistical significance and no correlation with UCHL1 levels. CONCLUSIONS: Uchl1 concentrations in the blood plasma of boys with cryptorchidism, may reflect the heat-induced apoptosis of germ cells. Higher UCHL1 concentrations in older boys with undescended testicles, probably express intensity of germ cell apoptosis, more extensive when testicles are subjected to heat-stress for longer period. Further analyses of UCHL1 may help to elucidate its role in mechanisms influencing spermatogenesis. PMID- 29401476 TI - Pacing behaviour of players in team sports: Influence of match status manipulation and task duration knowledge. AB - The study aimed to identify the influence of prior knowledge of exercise duration associated with initial information about momentary match status (losing or winning) on the pacing behaviour displayed during soccer game-based activities. Twenty semi-professional male players participated in four game scenarios divided in two sessions. In the first game scenario, players were not informed about the time duration or initial match status. In the second, players were only informed they would be required to play a small-sided game for 12 minutes. In the third, players were told they would play a small-sided game for 12 minutes and that one of the teams was winning 2 to 0. Finally, in the fourth game scenario, players were instructed they would play a small-sided game for 12 minutes and the score lines used at the start of the previous game scenario were reversed. The results showed a tendency for the unknown task duration to elicit greater physical responses in all studied variables, compared with knowing the task duration. Knowing the task duration and starting the game winning or losing did not affect the players' activity profile between the two conditions. Thus, during small sided soccer games, knowledge (or not) about the exercise duration alters the pacing behaviour of the players. Moreover, short and undisclosed-length exercise durations resulted in the adoption of more aggressive pacing strategies, characterised by higher initial exercise intensities. Furthermore, previous information on match status does not seem to interfere with pacing patterns if the players are aware of the exercise duration. Coaches may use knowledge of exercise duration to manipulate the small-sided games' demands. PMID- 29401477 TI - Utility of Goldmann applanation tonometry for monitoring intraocular pressure in glaucoma patients with a history of laser refractory surgery. AB - The utility of Goldmann applanation tonometry (GAT) for monitoring intraocular pressure (IOP) in open-angle glaucoma (OAG) patients with a history of laser refractive surgery was investigated by comparing IOP fluctuations measured using GAT and dynamic contour tonometry (DCT) on the same day. In this retrospective study, patients were divided into one of two subgroups according to IOP fluctuation values using GAT: 43 eyes in the low IOP fluctuation group (LIFG [GAT fluctuation <=1.7 mmHg]); and 55 eyes in the high IOP fluctuation group (HIFG [GAT fluctuation >1.7 mmHg]). IOP fluctuation was defined as the standard deviation of all IOP values during follow-up. IOP parameters using GAT were compared with those of DCT. Correlation analyses were performed among IOP parameters, and between IOP fluctuation and associated factors including central corneal thickness, corneal curvature, and axial length. All IOP parameters demonstrated significantly high values in the HIFG compared with those in the LIFG. Mean and peak IOP using DCT were significantly higher than those using GAT in both groups. However, there were no significant differences in IOP fluctuation and reduction using both tonometry methods in the HIFG (p = 0.946 and p = 0.986, respectively). Bland-Altman analysis revealed similar fluctuations using GAT and DCT. In multivariate analyses, there was a significant correlation between fluctuations using GAT and DCT in the HIFG (p = 0.043). These results suggest that IOP monitoring using GAT is a reliable method of monitoring IOP change in glaucoma patients with a history of laser refractive surgery, especially those exhibiting high IOP fluctuation. Nevertheless, several factors, including central corneal thickness, corneal curvature, and axial length, should be considered when using GAT for IOP monitoring. PMID- 29401478 TI - Asymmetric cellular responses in primary human myoblasts using sera of different origin and specification. AB - For successful growth and maintenance of primary myogenic cells in vitro, culture medium and addition of sera are the most important factors. At present it is not established as to what extent sera of different origin and composition, supplemented in media or serum-free media conditions influence myoblast function and responses to different stimuli. By assessing markers of proliferation, differentiation/fusion, quiescence, apoptosis and protein synthesis the aim of the current study was to elucidate how primary human myoblasts and myotubes are modulated by different commonly used serum using FCS (foetal calf serum), (CS-FCS charcoal-stripped FCS, a manufacturing process to remove hormones and growth factors from sera), HS (horse serum) as well as in serum free conditions (DMEM). To characterise the biological impact of the different serum, myoblasts were stimulated with Insulin (100 nM) and Vitamin D (100 nM; 1alpha,25(OH)2D3, 1alpha,25-Dihydroxycholecalciferol, Calcitriol), two factors with characterised effects on promoting fusion and protein synthesis or quiescence, respectively in human myoblasts/myotubes. We demonstrate that sera of different origin/formulation differentially affect myoblast proliferation and myotube protein synthesis. Importantly, we showed that quantifying the extent to which Insulin effects myoblasts in vitro is highly dependent upon serum addition and which type is present in the media. Upregulation of mRNA markers for myogenic fusion, Myogenin, with Insulin stimulation, relative to DMEM, appeared dampened at varying degrees with serum addition and effects on p70S6K phosphorylation as a marker of protein synthesis could not be identified unless serum was removed from media. We propose that these asymmetric molecular and biochemical responses in human myoblasts reflect the variable composition of mitogenic and anabolic factors in each of the sera. The results have implications for both the reproducibility and interpretation of results from experimental models in myoblast cells/myotubes. PMID- 29401480 TI - Long-term kinetics of Salmonella Typhimurium ATCC 14028 survival on peanuts and peanut confectionery products. AB - Due to recent large outbreaks, peanuts have been considered a product of potential risk for Salmonella. Usually, peanut products show a low water activity (aw) and high fat content, which contribute to increasing the thermal resistance and survival of Salmonella. This study evaluated the long-term kinetics of Salmonella survival on different peanut products under storage at 28 degrees C for 420 days. Samples of raw in-shell peanuts (aw = 0.29), roasted peanuts (aw = 0.39), unblanched peanut kernel (aw = 0.54), peanut brittle (aw = 0.30), pacoca (aw = 0.40) and pe-de-moca (aw = 0.68) were inoculated with Salmonella Typhimurium ATCC 14028 at two inoculum levels (3 and 6 log cfu/ g). The Salmonella behavior was influenced (p<0.05) by aw, lipid, carbohydrate and protein content. In most cases for both inoculum levels, the greatest reductions were seen after the first two weeks of storage, followed by a slower decline phase. The lowest reductions were verified in pacoca and roasted peanuts, with counts of 1.01 and 0.87 log cfu/ g at low inoculum level and 2.53 and 3.82 log cfu/ g at high inoculum level at the end of the storage time. The highest loss of viability was observed in pe-de-moca, with absence of Salmonella in 10-g after 180 days at low inoculum level. The Weibull model provided a suitable fit to the data (R2>=0.81), with delta value ranging from 0.06 to 49.75 days. Therefore, the results demonstrated that Salmonella survives longer in peanut products, beyond the shelf life (>420 days), especially in products with aw around 0.40. PMID- 29401481 TI - Kinetic study of lipase-catalyzed glycerolysis of palm olein using Lipozyme TLIM in solvent-free system. AB - Diacylglycerol (DAG) and monoacylglycerol (MAG) are two natural occurring minor components found in most edible fats and oils. These compounds have gained increasing market demand owing to their unique physicochemical properties. Enzymatic glycerolysis in solvent-free system might be a promising approach in producing DAG and MAG-enriched oil. Understanding on glycerolysis mechanism is therefore of great importance for process simulation and optimization. In this study, a commercial immobilized lipase (Lipozyme TL IM) was used to catalyze the glycerolysis reaction. The kinetics of enzymatic glycerolysis reaction between triacylglycerol (TAG) and glycerol (G) were modeled using rate equation with unsteady-state assumption. Ternary complex, ping-pong bi-bi and complex ping-pong bi-bi models were proposed and compared in this study. The reaction rate constants were determined using non-linear regression and sum of square errors (SSE) were minimized. Present work revealed satisfactory agreement between experimental data and the result generated by complex ping-pong bi-bi model as compared to other models. The proposed kinetic model would facilitate understanding on enzymatic glycerolysis for DAG and MAG production and design optimization of a pilot-scale reactor. PMID- 29401479 TI - Detection of Zika virus using reverse-transcription LAMP coupled with reverse dot blot analysis in saliva. AB - In recent years, there have been increasing numbers of infectious disease outbreaks that spread rapidly to population centers resulting from global travel, population vulnerabilities, environmental factors, and ecological disasters such as floods and earthquakes. Some examples of the recent outbreaks are the Ebola epidemic in West Africa, Middle East respiratory syndrome coronavirus (MERS-Co) in the Middle East, and the Zika outbreak through the Americas. We have created a generic protocol for detection of pathogen RNA and/or DNA using loop-mediated isothermal amplification (LAMP) and reverse dot-blot for detection (RDB) and processed automatically in a microfluidic device. In particular, we describe how a microfluidic assay to detect HIV viral RNA was converted to detect Zika virus (ZIKV) RNA. We first optimized the RT-LAMP assay to detect ZIKV RNA using a benchtop isothermal amplification device. Then we implemented the assay in a microfluidic device that will allow analyzing 24 samples simultaneously and automatically from sample introduction to detection by RDB technique. Preliminary data using saliva samples spiked with ZIKV showed that our diagnostic system detects ZIKV RNA in saliva. These results will be validated in further experiments with well-characterized ZIKV human specimens of saliva. The described strategy and methodology to convert the HIV diagnostic assay and platform to a ZIKV RNA detection assay provides a model that can be readily utilized for detection of the next emerging or re-emerging infectious disease. PMID- 29401482 TI - Assets among low-income families in the Great Recession. AB - This paper examines the association between the Great Recession and real assets among families with young children. Real assets such as homes and cars are key indicators of economic well-being that may be especially valuable to low-income families. Using longitudinal data from the Fragile Families and Child Wellbeing Study (N = 4,898), we investigate the association between the city unemployment rate and home and car ownership and how the relationship varies by family structure (married, cohabiting, and single parents) and by race/ethnicity (White, Black, and Hispanic mothers). Using mother fixed-effects models, we find that a one percentage point increase in the unemployment rate is associated with a -0.5 percentage point decline in the probability of home ownership and a -0.7 percentage point decline in the probability of car ownership. We also find that the recession was associated with lower levels of home ownership for cohabiting families and for Hispanic families, as well as lower car ownership among single mothers and among Black mothers, whereas no change was observed among married families or White households. Considering that homes and cars are the most important assets among middle and low-income households in the U.S., these results suggest that the rise in the unemployment rate during the Great Recession may have increased household asset inequality across family structures and race/ethnicities, limiting economic mobility, and exacerbating the cycle of poverty. PMID- 29401483 TI - Alcohol consumption, but not smoking is associated with higher MR-derived liver fat in an asymptomatic study population. AB - BACKGROUND: The aim of our study was to determine the relation of alcohol consumption and cigarette smoking on continuous-measured hepatic fat fraction (HFF) in a population free of cardiovascular disease. We suggested a direct correlation of alcohol consumption with HFF and increased HFF in former smokers compared to current smokers. METHODS: Data from 384 subjects (mean age: 56 years, 58% men) of a population-based cohort study (KORA) were included in a cross sectional design. Liver fat was assessed by 3 Tesla magnetic resonance imaging (MRI) using a multi-echo Dixon sequence and T2-corrected single voxel multi-echo spectroscopy (1H-MRS). Smoking status was classified as never, former or current smoker and alcohol consumption as non-, moderate (0.1-39.9 g/day for men and 0.1 19.9 g/day for women), or heavy drinker (>= 40 g/day for men and >= 20 g/day for women). Fatty liver disease was defined as HFF>=5.56%. RESULTS: Average HFF was 8.8% by 1H-MRS and 8.5% by MRI. Former smokers showed a higher HFF (MRI: beta = 2.64; p = 0.006) and a higher FLD prevalence (MRI: OR = 1.91; p = 0.006) compared to never smokers. Current smokers showed decreased odds for FLD measured by 1H MRS after multivariable adjustment (OR = 0.37; p = 0.007) with never smoker as reference. Heavy drinking was positively associated with HFF (1H-MRS: beta = 2.99; p = 0.003) and showed highest odds for FLD (1H-MRS: OR = 3.05; p = 0.008) with non-drinker as reference. Moderate drinking showed a positive association with HFF (1H-MRS: beta = 1.54; p = 0.061 and MRI: beta = 1.75; p = 0.050). CONCLUSIONS: Our data revealed lowest odds for FLD in current smokers, moderate drinkers showing higher HFF than non-drinkers and heavy drinkers showing highest HFF and odds for FLD. These findings partly conflict with former literature and underline the importance of further studies to investigate the complex effects on liver metabolism. PMID- 29401484 TI - The critically endangered forest owlet Heteroglaux blewitti is nested within the currently recognized Athene clade: A century-old debate addressed. AB - Range-restricted species generally have specific niche requirements and may often have unique evolutionary histories. Unfortunately, many of these species severely lack basic research, resulting in poor conservation strategies. The phylogenetic relationship of the Critically Endangered Forest Owlet Heteroglaux blewitti has been the subject of a century-old debate. The current classifications based on non-phylogenetic comparisons of morphology place the small owls of Asia into three genera, namely, Athene, Glaucidium, and Heteroglaux. Based on morphological and anatomical data, H. blewitti has been alternatively hypothesized to belong within Athene, Glaucidium, or its own monotypic genus Heteroglaux. To test these competing hypotheses, we sequenced six loci (~4300 bp data) and performed phylogenetic analyses of owlets. Mitochondrial and nuclear trees were not congruent in their placement of H. blewitti. However, both mitochondrial and nuclear combined datasets showed strong statistical support with high maximum likelihood bootstrap (>/ = 90) and Bayesian posterior probability values (>/ = 0.98) for H. blewitti being nested in the currently recognized Athene group, but not sister to Indian A. brama. The divergence of H. blewitti from its sister taxa was between 4.3 and 5.7 Ma coinciding with a period of drastic climatic changes in the Indian subcontinent. This study presented the first genetic analysis of H. blewitti, a Critically Endangered species, and addressed the long debate on the relationships of the Athene-Heteroglaux-Glaucidium complex. We recommend further studies with more data and complete taxon sampling to understand the biogeography of Indian Athene species. PMID- 29401485 TI - RBFOX3/NeuN is dispensable for visual function. AB - RBFOX3/NeuN is a neuronal splicing regulator involved in neural circuitry balance, as well as neurogenesis and synaptogenesis. Rbfox3 is expressed in neurons; however, in the retina, expression is restricted to cells in the ganglion cell layer and some cells of the inner nuclear layer. Rbfox3 is expressed in a layer-specific manner in the retina, which implies a functional role, however, the role of RBFOX3 in the retina is unknown. Rbfox3 homozygous knockout (Rbfox3-/-) mice exhibit deficits in visual learning; therefore, understanding the role of RBFOX3 in the retina is critical for interpreting behavioral results. We found Rbfox3 expression was developmentally regulated in the retina and specifically expressed in ganglion cells, amacrine cells and horizontal cells of the retina. We demonstrate deletion of Rbfox3 resulted in a reduction in the thickness of the inner plexiform layer of the retina, where synapses are formed. Number of ganglion cells and amacrine cells is normal with loss of Rbfox3. Innervation of retinal ganglion cells into their targeted brain regions is normal in Rbfox3-/- mice. Importantly, Rbfox3-/- mice displayed normal non-image and image forming functions. Taken together, our results suggest RBFOX3 is dispensable for visual function. PMID- 29401487 TI - Correction: Ethical issues in the development and implementation of nutrition related public health policies and interventions: A scoping review. AB - [This corrects the article DOI: 10.1371/journal.pone.0186897.]. PMID- 29401486 TI - Acute and chronic rhinosinusitis and allergic rhinitis in relation to comorbidity, ethnicity and environment. AB - BACKGROUND: This study was conducted to assess the effect of comorbidity, ethnicity, occupation, smoking and place of residence on allergic rhinitis (AR), acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS). METHODS: A GA2LEN (The Global Allergy and Asthma European Network) screening questionnaire was sent to a random sample of the Dutch population (n = 16700) in three different areas of the Netherlands. RESULTS: Fifty percent (8347) of the questionnaires sent were returned. A total of 29% respondents (27-31% in different areas) met the criteria for AR, 18% (17-21%) for ARS and 16% (13-18%) for CRS. Risk factors for AR were itchy rash, eczema, adverse response after taking a painkiller, asthma, CRS and ARS. Moreover, the risk of AR was twice as low for full-time housewives/househusbands than for people with jobs. The risk of ARS or CRS was significantly higher in respondents with a doctor's diagnosis of CRS, AR, itchy rash or smoking. The risk of CRS was also significantly higher in respondents with an adverse response after taking painkillers, active smoking or asthma. Caucasians are generally less likely to have AR or CRS than Latin-Americans, Hindustani and African-Creoles, and more likely to have ARS than Asian, Hindustani, Mediterranean and African-Creoles. CONCLUSIONS: This study found shared and distinct risk factors for AR, ARS and CRS and therefore provides support for the belief that they have shared symptoms but are different diseases with different aetiologies. PMID- 29401488 TI - Hexons from adenovirus serotypes 5 and 48 differentially protect adenovirus vectors from neutralization by mouse and human serum. AB - Adenovirus vectors are widely used in gene therapy clinical trials, and preclinical studies with these vectors are often conducted in mice. It is therefore critical to understand whether mouse studies adequately predict the behavior of adenovirus vectors in humans. The most commonly-used adenovirus vectors are derived from adenovirus serotype 5 (Ad5). The Ad5 hexon protein can bind coagulation factor X (FX), and binding of FX has a major impact on vector interactions with other blood proteins. In mouse serum, FX protects Ad5 vectors from neutralization by natural antibodies and complement. In the current study, we similarly find that human FX inhibits neutralization of Ad5 vectors by human serum, and this finding is consistent among individual human sera. We show that human IgM and human IgG can each induce complement-mediated neutralization when Ad5 vectors are not protected by FX. Although mouse and human serum had similar effects on Ad5 vectors, we found that this was not true for a chimeric Ad5 vector that incorporated hexon regions from adenovirus serotype 48. Interestingly, this hexon-chimeric vector was neutralized by human serum, but not by mouse serum. These findings indicate that studies in mouse serum accurately predict the behavior of Ad5 vectors in human serum, but mouse serum is not an accurate model system for all adenovirus vectors. PMID- 29401489 TI - Quality of life as assessed by adults with cerebral palsy. AB - AIM: We explored the quality of life of adults with cerebral palsy without an intellectual disability and the predictors of quality of life. BACKGROUND: Because cerebral palsy is a disease that manifests in childhood, much of the research into quality of life for those dealing with it focuses on children; there are few studies that evaluate the quality of life of adults with cerebral palsy. Therefore, it is important to consider their perceptions in order to improve their general wellbeing and self-determination. DESIGN: This was a descriptive, cross-sectional study. METHOD: Quality of life was measured using the GENCAT Quality of Life Scale. Demographic and personal variables were also collected and examined. Participants comprised 75 adults (58.7 percent men, mean age = 40.84 years) with cerebral palsy who were members of the National Cerebral Palsy Association of Spain between 2014 and 2015. A linear multivariate model was examined as well. RESULTS: The overall mean score indicator of participants' quality of life was 103.29, which corresponds to the 56.6th percentile on the GENCAT scale. Examining the level of qualification, we found significant differences in the factors "personal development" and "self-determination," and those with a university education obtained higher scores than their less-educated counterparts. Having a partner was related to higher quality of life standard scores. After constructing a linear model, it was observed that maintaining sexual relationships was another factor that increased participants' quality of life. CONCLUSION: This study highlights the importance of social and romantic relationships to achieve a better quality of life in adults with cerebral palsy who do not have an intellectual disability. Social integration and sexuality education programs should be developed to improve their quality of life. PMID- 29401490 TI - Propionibacterium acnes-derived insoluble immune complexes in sinus macrophages of lymph nodes affected by sarcoidosis. AB - BACKGROUND: Propionibacterium acnes is thought to be a causative agent of sarcoidosis. Patients with sarcoidosis have circulating immune complexes. We attempted to detect P. acnes-derived immune complexes in sarcoid lesions. METHODS: We evaluated formalin-fixed and paraffin-embedded lymph node samples from 38 sarcoidosis patients and 90 non-sarcoidosis patients (27 patients with necrotizing lymphadenitis, 28 patients with reactive lymphadenitis, 16 patients with colon cancer, 19 patients with gastric cancer) by immunohistochemistry using anti-human immunoglobulins (IgG, IgA, and IgM) and complement (C1q and C3c) antibodies, and a P. acnes-specific monoclonal antibody (PAB antibody) that reacts with the membrane-bound lipoteichoic acid of P. acnes. RESULTS: Small round bodies (SRBs) bound to IgA, IgM, or IgG were detected in sinus macrophages, in 32 (84%), 32 (84%), or 11 (29%) sarcoid samples, respectively, and in 19 (21%), 26 (29%), or no (0%) control samples, respectively. Some of these insoluble immune complexes (IICs) also bound to C1q and C3c. We developed a microwave treatment followed by brief trypsin digestion (MT treatment) to detect PAB-reactive SRBs bound to immunoglobulins (IIC-forming P. acnes). MT treatment revealed abundant IIC-forming P. acnes in most (89%) of the sarcoid samples and sparse distribution in some (20%) of the control samples with lymphadenitis, but no IIC-forming P. acnes was detected in control samples without inflammation. IIC forming P. acnes were mostly bound to both IgA and IgM. The PAB-reactive antigen and immunoglobulins were both located at the peripheral rim of the IIC-forming P. acnes. Conventional electron microscopy identified many SRBs (0.5-2.0 MUm diameter) in sinus macrophages of sarcoid lymph nodes with many IIC-forming P. acnes, some of which were in phagolysosomes with a degraded and lamellar appearance. CONCLUSIONS: P. acnes-derived IICs in sinus macrophages were frequent and abundant in sarcoid lymph nodes, suggesting a potential etiologic link between sarcoidosis and this commensal bacterium. PMID- 29401491 TI - Urgent endoscopic retrograde cholangiopancreatography is not superior to early ERCP in acute biliary pancreatitis with biliary obstruction without cholangitis. AB - Acute pancreatitis is a common diagnosis worldwide, with gallstone disease being the most prevalent cause (50%). The American College of Gastroenterology recommends urgent endoscopic retrograde cholangiopancreatography (ERCP) (within 24 h) for patients with biliary pancreatitis accompanied by cholangitis. Most international guidelines recommend that ERCP be performed within 72 h in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, but the optimal timing for endoscopy is controversial. We investigated the optimal timing for ERCP in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, and whether performing endoscopy within 24 h is superior to performing it after 24 h. We analyzed the clinical data of 505 patients with newly diagnosed acute pancreatitis, from January 1, 2005 to December 31, 2014. We divided the patients into two groups according to the timing of ERCP: < 24 h (urgent) and 24-72 h (early).Among the 505 patients, 73 were diagnosed with biliary pancreatitis and a bile duct obstruction without cholangitis. The mean age of the patients was 55 years (range: 26-90 years). Bile duct stones and biliary sludge were identified on endoscopy in 45 (61.6%) and 11 (15.0%) patients, respectively. The timing of ERCP within 72 h was not associated with ERCP-related complications (P = 0.113), and the total length of hospital stay was not different between urgent and early ERCP (5.9 vs. 5.7 days, P = 0.174). No significant differences were found in total length of hospitalization or procedural-related complications, in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, according to the timing of ERCP (< 24 h vs. 24-72 h). PMID- 29401492 TI - Determinants of selective reporting: A taxonomy based on content analysis of a random selection of the literature. AB - BACKGROUND: Selective reporting is wasteful, leads to bias in the published record and harms the credibility of science. Studies on potential determinants of selective reporting currently lack a shared taxonomy and a causal framework. OBJECTIVE: To develop a taxonomy of determinants of selective reporting in science. DESIGN: Inductive qualitative content analysis of a random selection of the pertinent literature including empirical research and theoretical reflections. METHODS: Using search terms for bias and selection combined with terms for reporting and publication, we systematically searched the PubMed, Embase, PsycINFO and Web of Science databases up to January 8, 2015. Of the 918 articles identified, we screened a 25 percent random selection. From eligible articles, we extracted phrases that mentioned putative or possible determinants of selective reporting, which we used to create meaningful categories. We stopped when no new categories emerged in the most recently analyzed articles (saturation). RESULTS: Saturation was reached after analyzing 64 articles. We identified 497 putative determinants, of which 145 (29%) were supported by empirical findings. The determinants represented 12 categories (leaving 3% unspecified): focus on preferred findings (36%), poor or overly flexible research design (22%), high-risk area and its development (8%), dependence upon sponsors (8%), prejudice (7%), lack of resources including time (3%), doubts about reporting being worth the effort (3%), limitations in reporting and editorial practices (3%), academic publication system hurdles (3%), unfavorable geographical and regulatory environment (2%), relationship and collaboration issues (2%), and potential harm (0.4%). CONCLUSIONS: We designed a taxonomy of putative determinants of selective reporting consisting of 12 categories. The taxonomy may help develop theory about causes of selection bias and guide policies to prevent selective reporting. PMID- 29401493 TI - Global patterns and impacts of El Nino events on coral reefs: A meta-analysis. AB - Impacts of global climate change on coral reefs are being amplified by pulse heat stress events, including El Nino, the warm phase of the El Nino Southern Oscillation (ENSO). Despite reports of extensive coral bleaching and up to 97% coral mortality induced by El Nino events, a quantitative synthesis of the nature, intensity, and drivers of El Nino and La Nina impacts on corals is lacking. Herein, we first present a global meta-analysis of studies quantifying the effects of El Nino/La Nina-warming on corals, surveying studies from both the primary literature and International Coral Reef Symposium (ICRS) Proceedings. Overall, the strongest signal for El Nino/La Nina-associated coral bleaching was long-term mean temperature; bleaching decreased with decreasing long-term mean temperature (n = 20 studies). Additionally, coral cover losses during El Nino/La Nina were shaped by localized maximum heat stress and long-term mean temperature (n = 28 studies). Second, we present a method for quantifying coral heat stress which, for any coral reef location in the world, allows extraction of remotely sensed degree heating weeks (DHW) for any date (since 1982), quantification of the maximum DHW, and the time lag since the maximum DHW. Using this method, we show that the 2015/16 El Nino event instigated unprecedented global coral heat stress across the world's oceans. With El Nino events expected to increase in frequency and severity this century, it is imperative that we gain a clear understanding of how these thermal stress anomalies impact different coral species and coral reef regions. We therefore finish with recommendations for future coral bleaching studies that will foster improved syntheses, as well as predictive and adaptive capacity to extreme warming events. PMID- 29401494 TI - Changes in the geographical distribution of plant species and climatic variables on the West Cornwall peninsula (South West UK). AB - Recent climate change has had a major impact on biodiversity and has altered the geographical distribution of vascular plant species. This trend is visible globally; however, more local and regional scale research is needed to improve understanding of the patterns of change and to develop appropriate conservation strategies that can minimise cultural, health, and economic losses at finer scales. Here we describe a method to manually geo-reference botanical records from a historical herbarium to track changes in the geographical distributions of plant species in West Cornwall (South West England) using both historical (pre 1900) and contemporary (post-1900) distribution records. We also assess the use of Ellenberg and climate indicator values as markers of responses to climate and environmental change. Using these techniques we detect a loss in 19 plant species, with 6 species losing more than 50% of their previous range. Statistical analysis showed that Ellenberg (light, moisture, nitrogen) and climate indicator values (mean January temperature, mean July temperature and mean precipitation) could be used as environmental change indicators. Significantly higher percentages of area lost were detected in species with lower January temperatures, July temperatures, light, and nitrogen values, as well as higher annual precipitation and moisture values. This study highlights the importance of historical records in examining the changes in plant species' geographical distributions. We present a method for manual geo-referencing of such records, and demonstrate how using Ellenberg and climate indicator values as environmental and climate change indicators can contribute towards directing appropriate conservation strategies. PMID- 29401495 TI - Evaluating quality of life and cost implications of prophylactic radiotherapy in mesothelioma: Health economic analysis of the SMART trial. AB - BACKGROUND: The SMART trial is a UK-based, multicentre RCT comparing prophylactic radiotherapy and symptom-based (deferred) radiotherapy in 203 patients with Malignant Pleural Mesothelioma who had undergone large bore pleural interventions. Using costs and quality of life data collected alongside the clinical trial, we will estimate the cost-effectiveness of prophylactic radiotherapy compared to deferred radiotherapy over a 1-year period. METHODS: Healthcare utilization and costs were captured during the trial. Utility weights produced by the EQ-5D questionnaire were used to determine quality-adjusted life years (QALY) gained. The incremental cost-effectiveness ratio was calculated over the one-year trial period. RESULTS: Costs were similar in the immediate and deferred radiotherapy groups: L5480.40 (SD = L7040; n = 102) and L5461.40 (SD = L7770; n = 101) respectively. There was also no difference in QALY: 0.498 (95% CI: [0.45, 0.547]) in the prophylactic radiotherapy group versus 0.525 (95% CI: [0.471, 0.580]) in the deferred group. At a willingness to pay threshold of L30,000/QALY there was only a 24% chance that prophylactic radiotherapy was cost effective compared to deferred radiotherapy. CONCLUSIONS: There was no significant effect of prophylactic radiotherapy on quality of life in the intervention group, nor was there any discernable decrease in healthcare costs. There is little evidence to suggest that prophylactic radiotherapy is a cost effective intervention in this population. TRIAL REGISTRATION: ISRCTN72767336 with ISRCTN. PMID- 29401496 TI - Relationship among family environment, self-control, friendship quality, and adolescents' smartphone addiction in South Korea: Findings from nationwide data. AB - BACKGROUND: Many studies have examined the negative impact on smartphone addiction in adolescents. Recent concerns have focused on predictors of smartphone addiction. This study aimed to investigate the association of adolescents' smartphone addiction with family environment (specifically, domestic violence and parental addiction). We further investigated whether self-control and friendship quality, as predictors of smartphone addiction, may reduce the observed risk. METHODS: We used the 2013 national survey on internet usage and utilization data from the National Information Agency of Korea. Information on exposure and covariates included self-reported experience of domestic violence and parental addiction, sociodemographic variables, and other variables potentially related to smartphone addiction. Smartphone addiction was estimated using a smartphone addiction proneness scale, a standardized measure developed by national institutions in Korea. RESULTS: Adolescents who had experienced domestic violence (OR = 1.74; 95% CI: 1.23-2.45) and parental addiction (OR = 2.01; 95% CI: 1.24-3.27) were found to be at an increased risk for smartphone addiction after controlling for all potential variables. Furthermore, on classifying adolescents according to their level of self-control and friendship quality the association between domestic violence and parental addiction, and smartphone addiction was found to be significant in the group with adolescents with lower levels of self-control (OR = 2.87; 95% CI: 1.68-4.90 and OR = 1.95; 95% CI: 1.34 2.83) and friendship quality (OR = 2.33; 95% CI: 1.41-3.85 and OR = 1.83; 95% CI: 1.26-2.64). CONCLUSION: Our findings suggest that family dysfunction was significantly associated with smartphone addiction. We also observed that self control and friendship quality act as protective factors against adolescents' smartphone addiction. PMID- 29401497 TI - A novel solution configuration on liquid-based endometrial cytology. AB - OBJECTIVE: Early detection and diagnosis of endometrial carcinoma and precancerous change would undoubtedly become the most alluring part for researchers. With the emergence of endometrial brush samplers, a new upsurge in endometrial cytology is in the making. But endometrial specimens obtained by the endometrial brush samplers require special preservation solution. The objective of this study is to develop a new kind of endometrial-cell preservation solution and to test the availability compared with a patented liquid-based cell preservation solution. METHODS: In this controlled study, we had 5 endometrial cases collected with Li Brush from the First Affiliated Hospital of Xi'an Jiaotong University (09/2016 to 12/2016). The samples of each case were collected 2 times separately and perserved in different perservation solutions. One was a kind of novel endometrial cell preservation solution and the other was a kind of patented liquid-based cell (LBC) preservation solution. The endometrial cells were smeared on slides by using the ZP-C automated slide preparation system and stained with Papanicolaou stain. A semi-quantitative scoring system was used to analyze the quality of slides. Statistical analysis was performed using the Wilcoxon signed rank test on the SPSS program (SPSS 18.0). In all LBC preparations, endometrial cells from the novel endometrial cells preservation solution had more cell quantity, less red blood cell fragments, and the background was cleaner compared with control group. Although the novel endometrial-cell preservation solution showed cellularity and absence of blood and debris expressed by no statistically significant differences (p = 0.063 and 0.102 respectively). The preservation period of the two kinds of liquids was equivalent. CONCLUSIONS: The novel endometrial-cell preservation solution is superior to the liquid-base cell preservation solution for cervical cells, with clear background, diagnostic cells and low cost. PMID- 29401498 TI - Enhancement of pharmacokinetic and pharmacological behavior of ocular dorzolamide after factorial optimization of self-assembled nanostructures. AB - Dorzolamide hydrochloride is frequently administered for the control of the intra ocular pressure associated with glaucoma. The aim of this study is to develop and optimize self-assembled nanostructures of dorzolamide hydrochloride and L-alpha Phosphatidylcholine to improve the pharmacokinetic parameters and extend the drug pharmacological action. Self-assembled nanostructures were prepared using a modified thin-film hydration technique. The formulae compositions were designed based on response surface statistical design. The prepared self-assembled nanostructures were characterized by testing their drug content, particle size, polydispersity index, zeta potential, partition coefficient, release half-life and extent. The optimized formulae having the highest drug content, zeta potential, partition coefficient, release half-life and extent with the lowest particle size and polydispersity index were subjected to further investigations including investigation of their physicochemical, morphological characteristics, in vivo pharmacokinetic and pharmacodynamic profiles. The optimized formulae were prepared at pH 8.7 (F5 and F6) and composed of L-alpha-Phosphatidylcholine and drug mixed in a ratio of 1:1 and 2:1 w/w, respectively. They showed significantly higher Cmax, [Formula: see text] and [Formula: see text] at the aqueous humor with extended control over the intra-ocular pressure, when compared to the marketed product; Trusopt(r). The study introduced novel and promising self assembled formulae able to permeate higher drug amount through the cornea and achieve sustained pharmacological effect at the site of action. PMID- 29401499 TI - First typology of cacao (Theobroma cacao L.) systems in Colombian Amazonia, based on tree species richness, canopy structure and light availability. AB - AIM AND BACKGROUND: We present a typology of cacao agroforest systems in Colombian Amazonia. These systems had yet to be described in the literature, especially their potential in terms of biodiversity conservation. The systems studied are located in a post-conflict area, and a deforestation front in Colombian Amazonia. Cacao cropping systems are of key importance in Colombia: cacao plays a prime role in post conflict resolution, as cacao is a legal crop to replace illegal crops; cacao agroforests are expected to be a sustainable practice, promoting forest-friendly land use. MATERIAL AND METHODS: We worked in 50 x 2000 m2 agroforest plots, in Colombian Amazonia. A cluster analysis was used to build a typology based on 28 variables characterised in each plot, and related to diversity, composition, spatial structure and light availability for the cacao trees. We included variables related to light availability to evaluate the amount of transmitted radiation to the cacao trees in each type, and its suitability for cacao ecophysiological development. MAIN RESULTS: We identified 4 types of cacao agroforests based on differences concerning tree species diversity and the impact of canopy spatial structure on light availability for the cacao trees in the understorey. We found 127 tree species in the dataset, with some exclusive species in each type. We also found that 3 out of the 4 types identified displayed an erosion of tree species diversity. This reduction in shade tree species may have been linked to the desire to reduce shade, but we also found that all the types described were compatible with good ecophysiological development of the cacao trees. MAIN CONCLUSIONS AND PROSPECTS: Cacao agroforest systems may actually be achieving biodiversity conservation goals in Colombian Amazonia. One challenging prospect will be to monitor and encourage the conservation of tree species diversity in cacao agroforest systems during the development of these cropping systems, as a form of forest-friendly management enhancing sustainable peace building in Colombia. PMID- 29401500 TI - Mobile direct observation of therapy (MDOT) - A rapid systematic review and pilot study in children with asthma. AB - We describe, for the first time, the use of a mobile device platform for remote direct observation of inhaler use and technique. The research programme commenced with a rapid systematic review of mobile device (or videophone) use for direct observation of therapy (MDOT). Ten studies (mainly pilots) were identified involving patients with tuberculosis, sickle cell disease and Alzheimer's disease. New studies are ongoing (ClinicalTrials.gov website) in TB, stroke, sickle cell disease, HIV and opioid dependence. Having identified no prior use of MDOT in inhaler monitoring, we implemented a feasibility study in 12 healthy volunteer children (2-12 years; 8 females and 4 males) over a period of 14 days, with twice daily video upload of their 'dummy' inhaler use. Two children uploaded 100% of the requested videos, with only one child having an inhaler upload rate of <75%. The quality of uploaded videos was generally good (only 1.7% of unacceptable quality for evaluation). The final aspect of the research was a pilot study using MDOT (6 weeks) in 22 children with difficult to treat asthma. Healthcare professionals evaluated inhaler technique using uploaded videos and provided telephone instruction on improving inhaler use. The main outcomes were assessed at week 12 post initiation of MDOT. By week 5, all children still engaging in MDOT (n = 18) were judged to have effective inhaler technique. Spirometry values did not vary to a significantly significant degree between baseline and 12 weeks (P>0.05), however, mean fraction of exhaled nitric oxide (FeNO) values normalised (mean 38.7 to 19.3ppm) and mean Asthma Control Test values improved (13.1 to mean 17.8). Feedback from participants was positive. Overall the findings open up a new paradigm in device independent (can be used for any type of inhaler device) monitoring, providing a platform for evaluating / improving inhaler use at home. PMID- 29401501 TI - Neutrophil predominance in bronchoalveolar lavage fluid is associated with disease severity and progression of HRCT findings in pulmonary Mycobacterium avium infection. AB - Pulmonary Mycobacterium avium complex (MAC) infection is increasing in prevalence worldwide even in immunocompetent individuals. Despite its variable clinical course, the clinical and immunological factors associated with radiographical severity and progression are not largely unknown. We aimed to study the association between the inflammatory cell and cytokine profiles at the local infected site, and the radiological severity and/or progression of pulmonary MAC infection. In this retrospective cohort study, 22 healthy subjects and 37 consecutive patients who were diagnosed as having pulmonary MAC infection by positive cultures of bronchoalveolar lavage (BAL) fluids were enrolled. The 37 patients were divided into 2 groups based on the predominant BAL inflammatory cell type: the lymphocyte-dominant (LD) group and neutrophil-dominant (ND) groups. The high-resolution computed tomography score in both the lavaged segment and whole lung and cytokines profiles were compared between the 2 groups. The clinical course after the BAL procedure was also compared between the 2 groups. Both the segment and whole lung scores in the ND group were significantly higher than the LD group (P < 0.001). Levels of IL-8 in the BAL fluids were significantly higher in the ND group compared to the LD group (P = 0.01). In contrast, levels of IL-22 were significantly lower in the ND group compared to the LD group (P < 0.001). The prevalence of patients who showed deterioration of the disease was significantly higher in the ND group (83.3%) than the LD group (12.5%) (P < 0.01). Neutrophil-predominant inflammatory response at the infected site is associated with the radiographical severity and progression of pulmonary MAC infection. PMID- 29401503 TI - Unconscious response priming during continuous flash suppression. AB - Continuous flash suppression (CFS) has become a popular tool for studying unconscious processing, but the level at which unconscious processing of visual stimuli occurs under CFS is not clear. Response priming is a robust and well understood phenomenon, in which the prime stimulus facilitates overt responses to targets if the prime and target are associated with the same response. We used CFS to study unconscious response priming of shape: arrows with left or right orientation served as primes and targets. The prime was presented near the limen of consciousness and each trial was followed by subjective rating of visibility and a forced-choice response concerning the orientation of the prime in counterbalanced order. In trials without any reported awareness of the presence of the prime, discrimination of the prime's orientation was at chance level. However, priming was elicited in such unconscious trials. Unconscious priming was not influenced by the prime-target onset-asynchrony (SOA)/prime duration, whereas conscious processing, as indicated by the enhanced discriminability of the prime's orientation and conscious priming, increased at the longest SOAs/prime durations. These results show that conscious and unconscious processes can be dissociated with CFS and that CFS-masking does not completely suppress unconscious visual processing of shape. PMID- 29401502 TI - Attenuation of reactive gliosis in stroke-injured mouse brain does not affect neurogenesis from grafted human iPSC-derived neural progenitors. AB - Induced pluripotent stem cells (iPSCs) or their progeny, derived from human somatic cells, can give rise to functional improvements after intracerebral transplantation in animal models of stroke. Previous studies have indicated that reactive gliosis, which is associated with stroke, inhibits neurogenesis from both endogenous and grafted neural stem/progenitor cells (NSPCs) of rodent origin. Here we have assessed whether reactive astrocytes affect the fate of human iPSC-derived NSPCs transplanted into stroke-injured brain. Mice with genetically attenuated reactive gliosis (deficient for GFAP and vimentin) were subjected to cortical stroke and cells were implanted adjacent to the ischemic lesion one week later. At 8 weeks after transplantation, immunohistochemical analysis showed that attenuated reactive gliosis did not affect neurogenesis or commitment towards glial lineage of the grafted NSPCs. Our findings, obtained in a human-to-mouse xenograft experiment, provide evidence that the reactive gliosis in stroke-injured brain does not affect the formation of new neurons from intracortically grafted human iPSC-derived NSPCs. However, for a potential clinical translation of these cells in stroke, it will be important to clarify whether the lack of effect of reactive gliosis on neurogenesis is observed also in a human-to-human experimental setting. PMID- 29401504 TI - Anxiety, fatigue, and attentional bias toward threat in patients with hematopoietic tumors. AB - Cancer patients with hematopoietic tumors exhibit particularly high rates of anxiety disorders and depression, and often develop negative affect. In addition, psychological problems experienced by cancer patients impair their quality of life. When cancer patients feel anxious, they tend to direct their attention toward stimuli associated with threat in the surrounding environment. If attentional bias occurs in patients with hematopoietic tumors, who are at particular risk of developing negative affect, resolution of the bias could be useful in alleviating their anxiety. The current study examined the association between attentional bias and negative affect in patients with hematopoietic tumors and tested the hypothesis that negative affect would be more severe in those who exhibited greater attentional bias. Twenty-seven patients with hematopoietic tumors participated in the study. Reaction time (RT) was measured as the time between the presentation of the threatening and neutral images, and the subject's button press to indicate choice (neutral expressions). Eight combinations of "threatening" expressions with high emotional valence and "neutral" expressions with low emotional valence were presented. The images used to measure attentional bias were taken from the Japanese Female Facial Expression Database and had been rated as expressive of anger, sadness, or neutrality, with predetermined emotional valence. Psychological testing was performed with the Profile of Mood States (POMS). To examine the association between attentional bias and negative affect, we calculated Spearman's rank correlation coefficients for RTs and POMS. Subjects' mean RT was 882.9 (SD = 100.9) ms, and 19 of the 27 subjects exhibited slower RTs relative to healthy individuals. RT was significantly positively correlated with Tension-Anxiety (r = .679, p < .01) and Fatigue (r = .585, p < .01) subscale scores. The results of the study suggested that attentional bias toward threatening expressions could be positively correlated with the mental intensity of anxiety and fatigue in patients with hematopoietic tumors. PMID- 29401505 TI - Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. AB - OBJECTIVE: Obesity is associated with increased inflammation and insulin resistance. In conditions with chronic immune activation, low plasma vitamin B6 levels are described, as well as an increased kynurenine:tryptophan-ratio (KTR). We investigated circulating tryptophan, kynurenine and its metabolites, neopterin, B-vitamins, CRP, and HbA1c in individuals with obesity before and after bariatric surgery. METHODS: This longitudinal study included 37 patients with severe obesity, scheduled for bariatric surgery. Blood samples were taken at inclusion and at three months and one year postoperatively. RESULTS: We observed significant positive correlations between HbA1c and both 3-hydroxy-kynurenine and 3-hydroxyanthranilic acid at inclusion. After surgery, fasting glucose, HbA1C and triglycerides decreased, whereas HDL-cholesterol increased. Tryptophan, kynurenine and its metabolites, except for anthranilic acid, decreased during weight loss. The KTR and CRP decreased while vitamin B6 increased during the year following operation, indicating reduced inflammation (all p<0.05). CONCLUSIONS: In patients with obesity subjected to bariatric surgery, levels of 3 hydroxykynurenine and 3-hydroxyanthranilic acid seemed to be positively correlated to impaired glucose tolerance. One year following surgery, plasma levels of the kynurenine metabolites were substantially decreased, along with a metabolic improvement. The relation of circulating kynurenine pathway metabolites with biomarkers of metabolic impairment in patients with obesity needs further evaluation. PMID- 29401506 TI - Neighborhood-based physical activity differences: Evaluation of the effect of health promotion program. AB - INTRODUCTION: The practice of physical activity is an important factor in the prevention of health problems. However, a small portion of the population is physically active. Recent reviews show that physical activity classes in community settings have the potential to increase population levels of physical activity and reduce health inequalities. OBJECTIVE: To evaluate the effect of the Academias da Cidade Program in Belo Horizonte on the practice of physical activity in leisure time (PALT) by non-users living near the program centers. METHODS: We conducted a home-based health survey in Belo Horizonte (2008-2009) with 1,581 adults who were non-users of the program and who lived within a 1,500 meter radius of one active program center (exposed group) and two nonoperational centers with sites reserved for their construction (unexposed group). We collected data on PALT levels (>=150 minutes/week), which was measured with the Physical Activity International Questionnaire and analyzed with binary logistic regression using the Generalized Estimating Equations method. The propensity score was used as an adjustment variable to control the potential confusion in the measures of effect of exposure studied. RESULTS: The overall prevalence of the PALT was 26.5% in the exposed group and 22.7% in the unexposed group. The exposed group was more likely to be active in leisure time (OR = 1.05; CI 95%: 1.01-1.10). When considering the interaction between exposed group and distance, individuals in the exposed group who lived less than 500 meters from the program center were more likely to be active in leisure time (OR = 1.18, CI 95%: 1.03 1.35) compared to their counterparts. CONCLUSION: Promoting physical activity in the community can favorably affect PALT levels among residents, especially those living closest to intervention centers. We believe the Academias da Cidade Program is a promising strategy to facilitate the access to appropriate spaces for the practice of physical activity and contribute to increase the levels physical activity within populations. PMID- 29401507 TI - Turnover intentions in a call center: The role of emotional dissonance, job resources, and job satisfaction. AB - BACKGROUND: Turnover intentions refer to employees' intent to leave the organization and, within call centers, it can be influenced by factors such as relational variables or the perception of the quality of working life, which can be affected by emotional dissonance. This specific job demand to express emotions not felt is peculiar in call centers, and can influence job satisfaction and turnover intentions, a crucial problem among these working contexts. This study aims to detect, within the theoretical framework of the Job Demands-Resources Model, the role of emotional dissonance (job demand), and two resources, job autonomy and supervisors' support, in the perception of job satisfaction and turnover intentions among an Italian call center. METHOD: The study involved 318 call center agents of an Italian Telecommunication Company. Data analysis first performed descriptive statistics through SPSS 22. A path analysis was then performed through LISREL 8.72 and tested both direct and indirect effects. RESULTS: Results suggest the role of resources in fostering job satisfaction and in decreasing turnover intentions. Emotional dissonance reveals a negative relation with job satisfaction and a positive relation with turnover. Moreover, job satisfaction is negatively related with turnover and mediates the relationship between job resources and turnover. CONCLUSION: This study contributes to extend the knowledge about the variables influencing turnover intentions, a crucial problem among call centers. Moreover, the study identifies theoretical considerations and practical implications to promote well-being among call center employees. To foster job satisfaction and reduce turnover intentions, in fact, it is important to make resources available, but also to offer specific training programs to make employees and supervisors aware about the consequences of emotional dissonance. PMID- 29401508 TI - Taking an educational psychology course improves neuroscience literacy but does not reduce belief in neuromyths. AB - Educators are increasingly interested in applying neuroscience findings to improve educational practice. However, their understanding of the brain often lags behind their enthusiasm for the brain. We propose that educational psychology can serve as a bridge between basic research in neuroscience and psychology on one hand and educational practice on the other. We evaluated whether taking an educational psychology course is associated with increased neuroscience literacy and reduced belief in neuromyths in a sample of South Korean pre-service teachers. The results showed that taking an educational psychology course was associated with the increased neuroscience literacy, but there was no impact on belief in neuromyths. We consider the implications of these and other findings of the study for redesigning educational psychology courses and textbooks for improving neuroscience literacy. PMID- 29401509 TI - DNA methylation mediates the effect of maternal cognitive appraisal of a disaster in pregnancy on the child's C-peptide secretion in adolescence: Project Ice Storm. AB - Animal and human studies suggest that prenatal exposure to stress is associated with adverse health outcomes such as type 2 diabetes. Epigenetic modification, such as DNA methylation, is considered one possible underlying mechanism. The 1998 Quebec ice storm provides a unique opportunity to study an independent prenatal stressor on child outcomes. C-peptide is the best measure of endogenous insulin secretion and is widely used in the clinical management of patients with diabetes. The objectives of this study are to determine 1) the extent to which prenatal exposure to disaster-related stress (maternal objective hardship and maternal cognitive appraisal) influences children's C-peptide secretion, and 2) whether DNA methylation of diabetes-related genes mediates the effects of prenatal stress on C-peptide secretion. Children's (n = 30) C-peptide secretion in response to an oral glucose tolerance test were assessed in blood at 131/2 years. DNA methylation levels of selected type 1 and 2 diabetes-related genes were chosen based upon the genes associated with prenatal maternal objective hardship and/or cognitive appraisal levels. Bootstrapping analyses were performed to determine the mediation effect of DNA methylation. We found that children whose mothers experienced higher objective hardship exhibited higher C-peptide secretion. Cognitive appraisal was not directly associated with C-peptide secretion. DNA methylation of diabetes-related genes had a positive mediation effect of objective hardship on C-peptide secretion: higher objective hardship predicted higher C-peptide secretion through DNA methylation. Negative mediation effects of cognitive appraisal were observed: negative cognitive appraisal predicted higher C-peptide secretion through DNA methylation. However, only one gene, LTA, remained a significant mediator of cognitive appraisal on C-peptide secretion after the conservative Bonferroni multiple corrections. Our findings suggest that DNA methylation could act as an intervening variable between prenatal stress and metabolic outcomes, highlighting the importance of epigenetic mechanisms in response to environmental factors. PMID- 29401510 TI - Physiological joint line total knee arthroplasty designs are especially sensitive to rotational placement - A finite element analysis. AB - Mechanical and kinematical aligning techniques are the usual positioning methods during total knee arthroplasty. However, alteration of the physiological joint line and unbalanced medio-lateral load distribution are considered disadvantages in the mechanical and kinematical techniques, respectively. The aim of this study was to analyse the influence of the joint line on the strain and stress distributions in an implanted knee and their sensitivity to rotational mal alignment. Finite element calculations were conducted to analyse the stresses in the PE-Inlay and the mechanical strains at the bone side of the tibia component tibia bone interface during normal positioning of the components and internal and external mal-rotation of the tibial component. Two designs were included, a horizontal and a physiological implant. The loading conditions are based on internal knee joint loads during walking. A medialization of the stresses on the PE-Inlay was observed in the physiological implant in a normal position, accompanied by higher stresses in the mal-rotated positions. Within the tibia component-tibia bone interface, similar strain distributions were observed in both implant geometries in the normal position. However, a medialization of the strains was observed in the physiological implant in both mal-rotated conditions with greater bone volume affected by higher strains. Although evident changes due to mal-rotation were observed, the stresses do not suggest a local plastic deformation of the PE-Inlay. The strains values within most of the tibia component-tibia bone interface were in the physiological strain zone and no significant bone changes would be expected. The physiological cut on the articular aspect showed no detrimental effect compared to the horizontal implant. PMID- 29401511 TI - The pickup of visual information about size and location during approach to an obstacle. AB - The present study investigated differences in the pickup of information about the size and location of an obstacle in the path of locomotion. The main hypothesis was that information about obstacle location is most useful when it is sampled at a specific time during the approach phase, whereas information about obstacle size can be sampled at any point during the last few steps. Subjects approached and stepped over obstacles in a virtual environment viewed through a head-mounted display. In Experiment 1, a horizontal line on the ground indicating obstacle location was visible throughout the trial while information about obstacle height and depth was available only while the subject was passing through a viewing window located at one of four locations along the subject's path. Subjects exhibited more cautious behavior when the obstacle did not become visible until they were within one step length, but walking behavior was at most weakly affected in the other viewing window conditions. In Experiment 2, the horizontal line indicating obstacle location was removed, such that no information about the obstacle (size or location) was available outside of the viewing window. Subjects adopted a more cautious strategy compared to Experiment 1 and differences between the viewing window conditions and the full vision control condition were observed across several measures. The differences in walking behavior and performance across the two experiments support the hypothesis that walkers have greater flexibility in when they can sample information about obstacle size compared to location. Such flexibility may impact gaze and locomotor control strategies, especially in more complex environments with multiple objects and obstacles. PMID- 29401512 TI - Mechanical and geometrical determinants of wall stress in abdominal aortic aneurysms: A computational study. AB - An aortic aneurysm (AA) is a focal dilatation of the aortic wall. Occurrence of AA rupture is an all too common event that is associated with high levels of patient morbidity and mortality. The decision to surgically intervene prior to AA rupture is made with recognition of significant procedural risks, and is primarily based on the maximal diameter and/or growth rate of the AA. Despite established thresholds for intervention, rupture occurs in a notable subset of patients exhibiting sub-critical maximal diameters and/or growth rates. Therefore, a pressing need remains to identify better predictors of rupture risk and ultimately integrate their measurement into clinical decision making. In this study, we use a series of finite element-based computational models that represent a range of plausible AA scenarios, and evaluate the relative sensitivity of wall stress to geometrical and mechanical properties of the aneurysmal tissue. Taken together, our findings encourage an expansion of geometrical parameters considered for rupture risk assessment, and provide perspective on the degree to which tissue mechanical properties may modulate peak stress values within aneurysmal tissue. PMID- 29401513 TI - Context-dependent interactive effects of non-lethal predation on larvae impact adult longevity and body composition. AB - Predation impacts development, behavior and morphology of prey species thereby shaping their abundances, distribution and community structure. Non-lethal threat of predation, specifically, can have a strong influence on prey lifehistory characteristics. While investigations often focus on the impact of predation threat on prey in isolation, tests of its interactive effects with food availability and resource competition on prey survival and fitness can improve understanding of costs, benefits and trade-offs of anti-predator strategies. This study, involving Aedes aegypti mosquitoes as a model organism, investigates both simple and interactive effects of predation threat during the larval stage on survival, size at and time to maturity, stored teneral reserves of glycogen, protein and lipid in adults, and adult longevity. Our results show that development times of mosquito larvae were increased (by 14.84% in males and by 97.63% in females), and size of eclosing adults decreased (by 62.30% in males and by 58.33% in females) when exposed to lowered nutrition and elevated intraspecific competition, but that predation had no detectable effect on these simple traits. Teneral reserves of glycogen, protein and lipid and adult longevity were positively correlated with adult body size. Non-lethal predation threat had significant interactive effects with nutrition and larval competition on teneral reserves in males and adult longevity in males and females. The sexes responded differently to conditions encountered as larvae, with the larval environment affecting development and adult characteristics more acutely for females than for males. The outcome of this study shows how threat of predation on juveniles can have long-lasting effects on adults that are likely to impact mosquito population dynamics and that may impact disease transmission. PMID- 29401515 TI - Correction: Spatial and simultaneous representative seroprevalence of anti Toxoplasma gondii antibodies in owners and their domiciled dogs in a major city of southern Brazil. AB - [This corrects the article DOI: 10.1371/journal.pone.0180906.]. PMID- 29401514 TI - Patient and provider experiences with active surveillance: A scoping review. AB - OBJECTIVE: Active surveillance (AS) represents a fundamental shift in managing select cancer patients that initiates treatment only upon disease progression to avoid overtreatment. Given uncertain outcomes, patient engagement could support decision-making about AS. Little is known about how to optimize patient engagement for AS decision-making. This scoping review aimed to characterize research on patient and provider communication about AS, and associated determinants and outcomes. METHODS: MEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched from 2006 to October 2016. English language studies that evaluated cancer patient or provider AS views, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings. RESULTS: A total of 2,078 studies were identified, 1,587 were unique, and 1,243 were excluded based on titles/abstracts. Among 344 full-text articles, 73 studies were eligible: 2 ductal carcinoma in situ (DCIS), 4 chronic lymphocytic leukemia (CLL), 6 renal cell carcinoma (RCC) and 61 prostate cancer. The most influential determinant of initiating AS was physician recommendation. Others included higher socioeconomic status, smaller tumor size, comorbid disease, older age, and preference to avoid adverse treatment effects. AS patients desired more information about AS and reassurance about future treatment options, involvement in decision-making and assessment of illness uncertainty and supportive care needs during follow-up. Only three studies of prostate cancer evaluated interventions to improve AS communication or experience. CONCLUSIONS: This study revealed a paucity of research on AS communication for DCIS, RCC and CLL, but generated insight on how to optimize AS discussions in the context of routine care or clinical trials from research on AS for prostate cancer. Further research is needed on AS for patients with DCIS, RCC and CLL, and to evaluate interventions aimed at patients and/or providers to improve AS communication, experience and associated outcomes. PMID- 29401516 TI - Computational modelling of pathogenic protein spread in neurodegenerative diseases. AB - Pathogenic protein accumulation and spread are fundamental principles of neurodegenerative diseases and ultimately account for the atrophy patterns that distinguish these diseases clinically. However, the biological mechanisms that link pathogenic proteins to specific neural network damage patterns have not been defined. We developed computational models for mechanisms of pathogenic protein accumulation, spread and toxic effects in an artificial neural network of cortical columns. By varying simulation parameters we assessed the effects of modelled mechanisms on network breakdown patterns. Our findings suggest that patterns of network breakdown and the convergence of patterns follow rules determined by particular protein parameters. These rules can account for empirical data on pathogenic protein spread in neural networks. This work provides a basis for understanding the effects of pathogenic proteins on neural circuits and predicting progression of neurodegeneration. PMID- 29401517 TI - Role of alpha7nAChR-NMDAR in sevoflurane-induced memory deficits in the developing rat hippocampus. AB - Detrimental effects of volatile anaesthetics, including sevoflurane, on the structure and function of the developing brain have been reported. The internalization of N-methyl-D-aspartate receptors (NMDARs) contributes to anaesthetic neurotoxicity. Both nicotinic acetylcholine receptors (nAChRs) and NMDAR play a critical role in the development of the nervous system. Moreover, nAChR can interact with NMDAR, and previous studies have demonstrated modulation of NMDAR by nAChR. In our study, we used an alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonist and alpha7nAChR antagonist to explore the role of alpha7nAChR and NMDAR in sevoflurane-induced long-term effects on memory and dendritic spine both in vivo and in vitro. The results revealed that the activation of alpha7nAChR attenuated the development of sevoflurane-induced memory deficit and dendritic spine changes, which might be by regulating NR2B containing NMDAR trafficking from the intracellular pool to the cell surface pool in the hippocampus. Moreover, we demonstrated that alpha7nAChR could regulate NR2B-containing NMDAR via Src-family tyrosine kinase (SFK). Thus, our current study indicates that the trafficking of NR2B-containing NMDAR is regulated by alpha7nAChR via SFK in neonatal rat hippocampus, which may be secondary to sevoflurane-induced cognitive deficits in the developing hippocampus. PMID- 29401518 TI - Correction: First evidence of biogenic habitat from tubeworms providing a near absolute habitat requirement for high-intertidal Ulva macroalgae. AB - [This corrects the article DOI: 10.1371/journal.pone.0176952.]. PMID- 29401519 TI - Estimation of population mean in the presence of measurement error and non response under stratified random sampling. AB - In the present paper we propose an improved class of estimators in the presence of measurement error and non-response under stratified random sampling for estimating the finite population mean. The theoretical and numerical studies reveal that the proposed class of estimators performs better than other existing estimators. PMID- 29401521 TI - RLE plots: Visualizing unwanted variation in high dimensional data. AB - Unwanted variation can be highly problematic and so its detection is often crucial. Relative log expression (RLE) plots are a powerful tool for visualizing such variation in high dimensional data. We provide a detailed examination of these plots, with the aid of examples and simulation, explaining what they are and what they can reveal. RLE plots are particularly useful for assessing whether a procedure aimed at removing unwanted variation, i.e. a normalization procedure, has been successful. These plots, while originally devised for gene expression data from microarrays, can also be used to reveal unwanted variation in many other kinds of high dimensional data, where such variation can be problematic. PMID- 29401520 TI - Individual differences in first- and second-order temporal judgment. AB - The ability of subjects to identify and reproduce brief temporal intervals is influenced by many factors whether they be stimulus-based, task-based or subject based. The current study examines the role individual differences play in subsecond and suprasecond timing judgments, using the schizoptypy personality scale as a test-case approach for quantifying a broad range of individual differences. In two experiments, 129 (Experiment 1) and 141 (Experiment 2) subjects completed the O-LIFE personality questionnaire prior to performing a modified temporal-bisection task. In the bisection task, subjects responded to two identical instantiations of a luminance grating presented in a 4deg window, 4deg above fixation for 1.5 s (Experiment 1) or 3 s (Experiment 2). Subjects initiated presentation with a button-press, and released the button when they considered the stimulus to be half-way through (750/1500 ms). Subjects were then asked to indicate their 'most accurate estimate' of the two intervals. In this way we measure both performance on the task (a first-order measure) and the subjects' knowledge of their performance (a second-order measure). In Experiment 1 the effect of grating-drift and feedback on performance was also examined. Experiment 2 focused on the static/no-feedback condition. For the group data, Experiment 1 showed a significant effect of presentation order in the baseline condition (no feedback), which disappeared when feedback was provided. Moving the stimulus had no effect on perceived duration. Experiment 2 showed no effect of stimulus presentation order. This elimination of the subsecond order-effect was at the expense of accuracy, as the mid-point of the suprasecond interval was generally underestimated. Response precision increased as a proportion of total duration, reducing the variance below that predicted by Weber's law. This result is consistent with a breakdown of the scalar properties of time perception in the early suprasecond range. All subjects showed good insight into their own performance, though that insight did not necessarily correlate with the veridical bisection point. In terms of personality, we found evidence of significant differences in performance along the Unusual Experiences subscale, of most theoretical interest here, in the subsecond condition only. There was also significant correlation with Impulsive Nonconformity and Cognitive Disorganisation in the sub- and suprasecond conditions, respectively. Overall, these data support a partial dissociation of timing mechanisms at very short and slightly longer intervals. Further, these results suggest that perception is not the only critical mitigator of confidence in temporal experience, since individuals can effectively compensate for differences in perception at the level of metacognition in early suprasecond time. Though there are individual differences in performance, these are perhaps less than expected from previous reports and indicate an effective timing mechanism dealing with brief durations independent of the influence of significant personality trait differences. PMID- 29401522 TI - Different in the dark: The effect of habitat characteristics on community composition and beta diversity in bromeliad microfauna. AB - The mechanisms which structure communities have been the focus of a large body of research. Here, we address the question if habitat characteristics describing habitat quality may drive changes in community composition and beta diversity of bromeliad-inhabiting microfauna. In our system, changes in canopy cover along an environmental gradient may affect resource availability, disturbance in form of daily water temperature fluctuations and predation, and thus may lead to changes in community structure of bromeliad microfauna through differences in habitat quality along this gradient. Indeed, we observed distinct changes in microfauna community composition along the environmental gradient explained by changes in the extent of daily water temperature fluctuations. We found beta diversity to be higher under low habitat quality (low canopy cover) than under high habitat quality (high canopy cover), which could potentially be explained by a higher relative importance of stochastic processes under low habitat quality. We also partitioned beta diversity into turnover and nestedness components and we found a nested pattern of beta diversity along the environmental gradient, with communities from the lower-quality habitat being nested subsets of communities from the higher-quality habitat. However, this pattern resulted from an increase in microfauna alpha diversity with an increase in habitat quality. By providing insights into microfauna-environment relationships our results contribute to the mechanistic understanding of community dynamics in small freshwater bodies. Here, we highlight the importance of habitat characteristics representing habitat quality in structuring communities, and suggest that this information may help to improve conservation practices of small freshwater ecosystems. PMID- 29401523 TI - Survival and growth of Stenotrophomonas maltophilia in free-living amoebae (FLA) and bacterial virulence properties. AB - Stenotrophomonas maltophilia is found ubiquitously in the environment and is an important emerging nosocomial pathogen. S. maltophilia has been recently described as an Amoebae-Resistant Bacteria (ARB) that exists as part of the microbiome of various free-living amoebae (FLA) from waters. Co-culture approaches with Vermamoeba vermiformis demonstrated the ability of this bacterium to resist amoebal digestion. In the present study, we assessed the survival and growth of six environmental and one clinical S. maltophilia strains within two amoebal species: Acanthamoeba castellanii and Willaertia magna. We also evaluated bacterial virulence properties using the social amoeba Dictyostelium discoideum. A co-culture approach was carried out over 96 hours and the abundance of S. maltophilia cells was measured using quantitative PCR and culture approach. The presence of bacteria inside the amoeba was confirmed using confocal microscopy. Our results showed that some S. maltophilia strains were able to multiply within both amoebae and exhibited multiplication rates up to 17.5 and 1166 for A. castellanii and W. magna, respectively. In contrast, some strains were unable to multiply in either amoeba. Out of the six environmental S. maltophilia strains tested, one was found to be virulent. Surprisingly, this strain previously isolated from a soil amoeba, Micriamoeba, was unable to infect both amoebal species tested. We further performed an assay with a mutant strain of S. maltophilia BurA1 lacking the efflux pump ebyCAB gene and found the mutant to be more virulent and more efficient for intra-amoebal multiplication. Overall, the results obtained strongly indicated that free-living amoebae could be an important ecological niche for S. maltophilia. PMID- 29401524 TI - Impact of the choice of reference genome on the ability of the core genome SNV methodology to distinguish strains of Salmonella enterica serovar Heidelberg. AB - Salmonella enterica serovar Heidelberg (S. Heidelberg) is one of the top serovars causing human salmonellosis. The core genome single nucleotide variant pipeline (cgSNV) is one of several whole genome based sequence typing methods used for the laboratory investigation of foodborne pathogens. SNV detection using this method requires a reference genome. The purpose of this study was to investigate the impact of the choice of the reference genome on the cgSNV-informed phylogenetic clustering and inferred isolate relationships. We found that using a draft or closed genome of S. Heidelberg as reference did not impact the ability of the cgSNV methodology to differentiate among 145 S. Heidelberg isolates involved in foodborne outbreaks. We also found that using a distantly related genome such as S. Dublin as choice of reference led to a loss in resolution since some sporadic isolates were found to cluster together with outbreak isolates. In addition, the genetic distances between outbreak isolates as well as between outbreak and sporadic isolates were overall reduced when S. Dublin was used as the reference genome as opposed to S. Heidelberg. PMID- 29401525 TI - Long-term pathogenic response to Plasmodium relictum infection in Culex pipiens mosquito. AB - The transmission of Plasmodium within a vertebrate host population is strongly associated with the life history traits of its vector. Therefore the effect of malaria infection on mosquito fecundity and longevity has traditionally received a lot of attention. Several species of malaria parasites reduce mosquito fecundity, nevertheless almost all of the studies have focused only on the first gonotrophic cycle. Yet, during their lifetime, female mosquitoes go through several gonotrophic cycles, which raises the question of whether they are able to compensate the fecundity costs induced by the parasite. The impact of Plasmodium infection on female longevity is not so clear and has produced conflicting results. Here we measured the impact of Plasmodium relictum on its vector's longevity and fecundity during three consecutive gonotrophic cycles. In accordance with previous studies, we observed a negative impact of Plasmodium infection on mosquito (Culex pipiens) fecundity in the first gonotrophic cycle. Interestingly, despite having taken two subsequent uninfected blood meals, the negative impact of malaria parasite persisted. Nevertheless no impact of infection on mosquito longevity was observed. Our results are not in line with the hypothesis that the reduction of fecundity observed in infected mosquitoes is an adaptive strategy of Plasmodium to increase the longevity of its vector. We discuss the different underlying mechanisms that may explain our results. PMID- 29401526 TI - Consumer perceptions of strain differences in Cannabis aroma. AB - The smell of marijuana (Cannabis sativa L.) is of interest to users, growers, plant breeders, law enforcement and, increasingly, to state-licensed retail businesses. The numerous varieties and strains of Cannabis produce strikingly different scents but to date there have been few, if any, attempts to quantify these olfactory profiles directly. Using standard sensory evaluation techniques with untrained consumers we have validated a preliminary olfactory lexicon for dried cannabis flower, and characterized the aroma profile of eleven strains sold in the legal recreational market in Colorado. We show that consumers perceive differences among strains, that the strains form distinct clusters based on odor similarity, and that strain aroma profiles are linked to perceptions of potency, price, and smoking interest. PMID- 29401527 TI - [Administrative Prevalence and Health Care Situation of Dementia Patients in Acute Care Hospitals: An Epidemiological Health Care Study Based on Claims Data of Insured Persons in Saxony]. AB - OBJECTIVE: The increasing number of people with dementia will challenge the health care system, especially acute care. Using health insurance claims data, the study objective was to examine the regional patterns of the administrative prevalence of dementia, the prevalence of dementia in hospitals and the care situation in hospitals. METHODS: We used 2014 claims data from AOK PLUS, the largest statutory health insurance service in Saxony. If dementia was diagnosed either in an outpatient or inpatient setting in 3 of 4 quarters in a year, a person was categorised as a dementia case (n=61,700). The analysis of health care status included 61,239 patients with dementia and 183,477 control subjects. The control group was matched using the criteria of gender, age and region of residence. RESULTS: For those older than 65 years, the overall administrative prevalence rate of dementia was 9.3%. The estimated prevalence for those in hospitals was 16.7%. In 2014, there were 33% more admissions, 36% more hospital days and 18% higher costs per person-year among people diagnosed with dementia than the control subjects. The longer annual hospital stays and the higher costs were primarily caused by the greater number of admissions of people with dementia. Inpatient service use was, compared to people without dementia, characterized by a need for care and assistance, rather than by a need for medical therapeutic and diagnostic procedures. CONCLUSION: To improve the health care situation of people with dementia, to adapt to the challenges facing hospitals and to reduce the financial burden caused by dementia, more efforts are needed to improve the health care situation. Measures include, among others, improvements in recognition of dementia and reduction of unnecessary hospital stays. PMID- 29401528 TI - [Rare Paranasal Sinus Tumor]. PMID- 29401529 TI - [Tissue flossing as a recovery tool for the lower extremity after strength endurance intervals]. AB - CONTEXT: Tissue flossing is a technique used to improve range of motion, performance and regeneration, and to reduce pain, oedema and injury risks. PURPOSE: To analyse if tissue flossing is an effective therapeutic modality to improve regeneration after strength endurance exercises and to reduce delayed onset muscle soreness (DOMS). METHODS: 42 active, healthy female and male subjects were randomly assigned to either the control (n = 21) or the tissue flossing group (n = 21). All subjects followed the same testing protocol. On the leg press, participants performed as many one-legged repetitions as possible with 65 % of their one-repetition maximum (1 RM) at measurement point one (M1). Between M1 and M2, all subjects performed a strength endurance program until they were fully exhausted (three times as many repetitions as possible with 65 % of their 1 RM, one-legged on the leg press). At M2 (immediately after the strength endurance-to-exhausting program), M3 (30 minutes after the strength-endurance-to exhausting program) and M4 (60 minutes after the strength-endurance-to-exhausting program), the participants performed as many repetitions as possible with 65 % of their 1 RM on the leg press. Between M2 and M3, the tissue flossing group received three flossing treatments lasting two minutes each as a regeneration tool. Each subject completed the numeric rating scale (NRS) (0 - 10) and the "Likert muscle scale" 12 h, 24 h, 36 h, 48 h, 60 h and 72 h post M4. RESULTS: There were no significant effects over all four measurement points in favour of the tissue flossing group compared with the control group. No effects were found for the "Likert muscle scale". There was merely a significant effect on the NRS after 36 h (p = 0.044) in favour of the tissue flossing group. CONCLUSION: Tissue flossing neither improves nor delays regeneration after strength endurance intervals. Tissue flossing has no effect on DOMS reduction. PMID- 29401530 TI - Antiquitin Deficiency with Adolescent Onset Epilepsy: Molecular Diagnosis in a Mother of Affected Offsprings. AB - Antiquitin deficiency is the most prevalent form of pyridoxine-dependent epilepsy. While most patients present with neonatal onset of therapy-resistant seizures, a few cases with late-onset during infancy have been described. Here, we describe the juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency in an Indian female with homozygosity for the most prevalent ALDH7A1 missense mutation, c.1279G > C; p.Glu427Gln in exon 14. The diagnosis was established along familial cosegregation analysis for an affected offspring, that had neonatal pyridoxine responsive seizures and had been found to be compound heterozygous for c.1279G > C; p.Glu427Gln in exon 14 and a nonsense mutation c.796C > T; p.Arg266* in exon 9. While seizures in the mother had been incompletely controlled by levetiracetam, she remained seizure-free on pyridoxine monotherapy, 200 mg/day. Her fourth pregnancy resulted in a female affected offspring, who was treated prospectively and never developed seizures with a normal outcome at age 2 years while on pyridoxine. This report illustrates that the phenotypic spectrum of antiquitin deficiency is still underestimated and that this treatable inborn error of metabolism has to be considered in case of therapy resistant seizures even at older age. It furthermore supports prospective in utero treatment with pyridoxine in forthcoming pregnancies at risk. PMID- 29401538 TI - Effect of Conjugated Linoleic Acid on Leptin Level: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - The results of human clinical trials examining the effects of conjugated linoleic acid (CLA) on leptin concentration are inconsistent. Our objective was to elucidate the role of conjugated linoleic acid supplementation on leptin through a systematic review and a meta-analysis of available randomized placebo controlled trials (RCTs). We searched the PubMed, SCOPUS, and ISI web of science up to February2017, in English, to identify RCTs investigating the effect of CLA supplements on plasma leptin concentrations. Weighted mean differences (WMDs) and their respective 95% confidence intervals (CIs) were calculated to assess the efficacy of CLA on leptin concentration by using random effects. Statistical heterogeneity, study quality, meta-regression and publication bias were used based on standard methods. Nineteen RCTs (comprising 26 treatment arms) with 1045 subjects were included in this meta-analysis. Random-effect meta-analysis found a slight but not significant reduction in plasma leptin concentrations (WMD: -0.38 ng/ml, 95% CI: -1.08, 0.32, p=0.286); I2=53.24%, p=0.001), following CLA supplementation. The pooled effect size was robust and remained non-significant in the leave-one-out sensitivity analysis. Subgroup analysis based on BMI status showed that the CLA supplementation significantly reduces leptin when used for obese subjects (WMD: -1.47 ng/ml, 95% CI: -2.15, -0.79, p<0.001) and in the subset of trials lasting<24 weeks of duration (WMD: -0.76 ng/ml, 95% CI: -1.40, 0.12, p=0.019). CLA supplementation might moderately decrease circulatory leptin levels only among obese adults for shorter than 24 weeks. Additional high-quality studies are needed to replicate our results. PMID- 29401539 TI - Associations of TNFRSF1A Polymorphisms with Autoimmune Thyroid Diseases: A Case Control Study. AB - Previous studies have shown associations of polymorphisms in the tumor necrosis factor (TNF) receptor super family member 1A (TNFRSF1A) gene with several groups of inflammatory and autoimmune related diseases, but associations of TNFRSF1A polymorphisms with autoimmune thyroid diseases (AITD), mainly including two sub types of Hashimoto's thyroiditis (HT) and Graves' disease (GD), in the Chinese Han population is unclear. A case-control study of 1812 subjects (965 AITD patients and 847 unrelated healthy controls) was conducted to assess AITD associations with five single nucleotide polymorphisms (SNPs), including rs4149576, rs4149577, rs4149570, rs1800693, and rs767455 in the TNFRSF1A gene locus. Genotyping was performed and evaluated using the platform of ligase detection reaction. No significant difference was observed in the allele and genotype frequencies between HT or GD patients and controls in any of the five SNPs in the TNFRSF1A gene (all p values >0.05). However, a moderate association of rs4149570 with HT was found after adjusting for age and gender [odds ratio (OR)=1.40, p=0.03]. No obvious difference was found in the haplotype distribution of any of the five SNPs in the TNFRSF1A gene between the AITD patients and controls. These data suggest that these five SNPs in the TNFRSF1A gene are not associated with AITD in the Chinese Han population, but rs4149570 shows a weak association with HT after adjusting for gender and age. PMID- 29401540 TI - Eighteen-Year Effect of Androgen Therapy on Bone Mineral Density in Trans(gender) Men. AB - The study explores the influence of long-term androgen supplementation (18 years) on bone metabolism in trans(gender) men. Thirty five trans(gender) men aged (47+/ 4) were treated with adequate dose of testosterone. BMD was measured by DEXA at lumbar spine and neck and T score was determined. Biochemical parameters of bone turnover were measured in all patients. As compared with female and male age matched controls they showed a not significantly different T-score at spine [1.213+/-0.15 in trans(gender) men vs. 1.192+/-0.19 in females and 1.203+/-0.06 g/cm2 in males (p<0.01)]. BMD in the hip skeleton in trans(gender) men (0.950+/ g/cm2) was statistically higher than females (0.822+/-0.09) but not statistically different from normal males 0.988+/-0.06). Circulating biochemical markers of bone formation, and resorption were not different between the trans(gender) men, and matched controls. We conclude that BMD at the hip (site rich in cortical bone) after adequate dose of testosterone therapy is higher while it is not different at the spine (trabecular bone) in trans(gender) men even after 18 years of testosterone administration. PMID- 29401541 TI - [Editor's Comment]. PMID- 29401542 TI - ? PMID- 29401543 TI - ? PMID- 29401544 TI - ? PMID- 29401545 TI - ? PMID- 29401546 TI - [Medical Treatment of Thyroid Nodule]. AB - Whereas in regions with sufficient iodide intake treatment of thyroid nodules with levothyroxine has been almost completely abandoned and is also not further recommended by guidelines, medical treatment may be still indicated in Germany as recently demonstrated by randomized, placebo-controlled LISA study.A major reason for this is mild iodide deficiency in patients with thyroid nodules. In LISA study a combined therapy of levothyroxine and iodide resulted in an at least 50 % reduction of nodular volume in 21,6 % of treated patient compared to in only 5,2 % of placebo-treated patients.To avoid TSH suppression levothyroxine dose must be adjusted that TSH is in the lower reference range, since subclinical hyperthyroidism may result in cardiac adverse events as arrythmias.In the elderly the cardiac risk has to be considered and levothyroxine dose has frequently to be reduced or therapy even to be stopped. PMID- 29401547 TI - ? PMID- 29401548 TI - [Current Status of therapy and prophylaxis of oropharyngeal carcinoma]. AB - Incidence of oropharyngeal carcinoma (OPSCC) is increasing significantly worldwide. Due to its association with chronic tobacco/alcohol consumption, but increasingly also with the human papillomavirus HPV-16, oropharyngeal carcinoma is a genetically heterogeneous tumor group with high prognostic diversification. HPV-associated OPSCC respond significantly better to previous treatment concepts than non-HPV-associated. Both after primary surgical as well as after radiotherapie, radiochemotherapie and anti-EGFR treatment, this tumor group shows a significantly better survival. There is no evidence that in HPV association only primary radiotherapy concepts should be used. Currently, in the 8th edition of the TNM classification (UICC, AJCC), the HPV-associated different prognostic consideration with a rearrangement of the tumor stages and the N status was taken into account. Regardless of the known blur, p16 status detection is the most practicable and least expensive method of detection today, and is therefore consistently recommended (also by the AJCC and UICC TNM committees). HPV16 positive non-smokers differ from HPV-16 negative smokers by nearly 50 % in 5-year survival. Transoral robot surgery (TORS), which is highly acclaimed in the US today, with the Da Vinci Telemanipulator (Intuitive Surgical) has triggered a downright euphoric discussion on the minimally invasive surgery of resectable OPSCC. Based on a stable data set, it is now clear that an R0 resection must be sought regardless of the surgical procedure. Resection margins < 5 mm (R0 < 5 mm) are considered to be an "intermediate risk" situation and, like the N status, influence the adjuvant concept (radiochemotherapy). During and after transoral surgical procedures, the risk of rebleeding should never be underestimated and can not be ruled out with the utmost care. PMID- 29401549 TI - ? PMID- 29401550 TI - ? PMID- 29401551 TI - ? PMID- 29401552 TI - Characteristics and Immunological Roles of Surface Layer Proteins in Clostridium difficile. AB - Clostridium difficile is a major causative agent of antibiotic-associated diarrhea and has become the most common pathogen of healthcare-associated infection worldwide. The pathogenesis of C. difficile infection (CDI) is mediated by many factors such as colonization involving attachment to host intestinal epithelial cells, sporulation, germination, and toxin production. Bacterial cell surface components are crucial for the interaction between the bacterium and host cells. C. difficile has two distinct surface layer proteins (SLPs): a conserved high-molecular-weight SLP and a highly variable low-molecular-weight SLP. Recent studies have shown that C. difficile SLPs play roles not only in growth and survival, but also in adhesion to host epithelial cells and induction of cytokine production. Sequence typing of the variable region of the slpA gene, which encodes SLPs, is one of the methods currently used for typing C. difficile. SLPs have received much attention in recent years as vaccine candidates and new therapeutic agents in the treatment of C. difficile-associated diseases. Gaining mechanistic insights into the molecular functions of C. difficile SLPs will help advance our understanding of CDI pathogenesis and the development of vaccines and new therapeutic approaches. In this review, we summarize the characteristics and immunological roles of SLPs in C. difficile. PMID- 29401553 TI - Clinical Utility of a Diagnostic Approach to Detect Genetic Abnormalities in Multiple Myeloma: A Single Institution Experience. AB - BACKGROUND: The identification of genetic abnormalities in patients with multiple myeloma (MM) has gained emphasis because genetics-based risk stratification significantly affects overall survival (OS). We investigated genetic abnormalities using conventional cytogenetics and FISH and analyzed the prognostic significance of the identified additional abnormalities in MM. METHODS: In total, 267 bone marrow samples were collected from February 2006 to November 2013 from patients who were newly diagnosed as having MM in a tertiary care hospital in Korea. The clinical and laboratory data were retrospectively obtained. Cox proportional hazard regression was used to examine the relationship between clinical/genetic factors and survival outcome, using univariate and multivariate models. RESULTS: Using conventional cytogenetic analysis and FISH, 45% (120/267) and 69% (183/267) patients, respectively, were identified to harbor genetic abnormalities. In the univariate analysis, the following genetic variables were identified to affect OS: abnormal karyotype (P<0.001), aneuploidy (P=0.046), -13 or del(13q) (P=0.002), 1q amplification (P<0.001), and t(4;14) (P=0.020). In the multivariate analysis, the presence of -13 or del(13q) was the only significant genetic factor affecting OS (P=0.012) with a hazard ratio (HR) of 2.131 (95% confidence interval [CI], 1.185-3.832) in addition to the clinical factor of age (>65 years) (P=0.013) with an HR of 2.505 (95% CI, 1.218-5.151). CONCLUSIONS: Our findings highlight the importance of applying a comprehensive approach for detecting genetic abnormalities, which could be closely associated with the prognostic significance of MM. PMID- 29401554 TI - Prognostic Role of High-sensitivity Cardiac Troponin I and Soluble Suppression of Tumorigenicity-2 in Surgical Intensive Care Unit Patients Undergoing Non-cardiac Surgery. AB - BACKGROUND: The prognostic utility of cardiac biomarkers, high-sensitivity cardiac troponin I (hs-cTnI) and soluble suppression of tumorigenicity-2 (sST2), in non-cardiac surgery is not well-defined. We evaluated hs-cTnI and sST2 as predictors of 30-day major adverse cardiac events (MACE) in patients admitted to the surgical intensive care unit (SICU) following major non-cardiac surgery. METHODS: hs-cTnI and sST2 concentrations were measured in 175 SICU patients immediately following surgery and for three days postoperatively. The results were analyzed in relation to 30-day MACE and were compared with the revised Goldman cardiac risk index (RCRI) score. RESULTS: Overall, 30-day MACE was observed in 16 (9.1%) patients. hs-cTnI and sST2 concentrations differed significantly between the two groups with and without 30-day MACE (P<0.05). The maximum concentration of sST2 was an independent predictor of 30-day MACE (odds ratio=1.016, P=0.008). The optimal cut-off values of hs-cTnI and sST2 for predicting 30-day MACE were 53.0 ng/L and 182.5 ng/mL, respectively. A combination of hs-cTnI and sST2 predicted 30-day MACE better than the RCRI score. Moreover, 30-day MACE was observed more frequently with increasing numbers of above-optimal cut-off hs-cTnI and sST2 values (P<0.0001). Reclassification analyses indicated that the addition of biomarkers to RCRI scores improved the prediction of 30-day MACE. CONCLUSIONS: This study demonstrates the utility of hs cTnI and sST2 in predicting 30-day MACE following non-cardiac surgery. Cardiac biomarkers would provide enhanced risk stratification in addition to clinical RCRI scores for patients undergoing major non-cardiac surgery. PMID- 29401555 TI - Molecular Epidemiological Features and Antibiotic Susceptibility Patterns of Streptococcus dysgalactiae subsp. equisimilis Isolates from Korea and Japan. AB - BACKGROUND: The molecular characterization of Streptococcus dysgalactiae subsp. equisimilis (SDSE) has not yet been performed in Korea. This study aimed to find the differences or similarities in the clinical features, molecular epidemiological findings, and antimicrobial resistance patterns of SDSE from two countries (Korea and Japan). METHODS: SDSE isolates were collected from Korea (N=69) from 2012-2016 and Japan (N=71) from 2014-2016. Clinical characteristics, emm genotypes, and sequence types (STs) were compared. Microdilution tests were performed using different antimicrobials, and their resistance determinants were screened. RESULTS: Median ages were 69 years in Korea and 76 years in Japan. The most common underlying diseases were diabetes and malignancy. Blood-derived isolates comprised 36.2% and 50.7% of Korean and Japanese isolates, respectively; mortality was not different between the two groups (5.8% vs 9.9%, P=0.53). Among Korean isolates with 20 different combined ST-emm types, ST127-stG245 (N=16), ST128-stG485 (N=10), and ST138-stG652 (N=8) were prevalent. Among Japanese isolates with 29 different combined types, ST17-stG6792 (N=11), ST29-stG485 (N=7), and ST205-stG6792 (N=6) were prevalent. Resistance rates to erythromycin, clindamycin, and minocycline were 34.8%, 17.4%, and 30.4% in Korea and 28.2%, 14.1%, and 21.4% in Japan, respectively. CONCLUSIONS: SDSE infections commonly occurred in elderly persons with underlying diseases. There was a significant difference in the distribution of ST-emm types between the two countries. Antimicrobial resistance rates were comparable with different frequencies of resistance determinants in each country. PMID- 29401556 TI - Evaluation of a New Multiplex Real-Time PCR Assay for Detecting Gastroenteritis Causing Viruses in Stool Samples. AB - BACKGROUND: Diarrhea has been the second leading cause of death among children under the age of five, and the rapid and accurate pathogen diagnosis in patients with diarrhea is crucial for reducing morbidity and mortality. A newly developed one-step multiplex real-time PCR assay, the Allplex GI-Virus Assay, was evaluated for its ability to detect six diarrhea-causing viruses (rotavirus, norovirus genogroup I (GI) and genogroup II (GII), enteric adenovirus, astrovirus, and sapovirus) in stool samples. METHODS: The performance of the Allplex assay was compared with those of another multiplex PCR assay (Seeplex Diarrhea-V Ace Detection) and genotyping by sequencing, using 446 stool samples from patients with acute gastroenteritis. RESULTS: The overall agreement rates between the results of the Allplex and Seeplex assays were 98.7% for rotavirus, 99.1% for norovirus GI, 93.3% for norovirus GII, 98.0% for adenovirus, and 99.6% for astrovirus. The overall agreement rates between the Allplex assay and genotyping were 99.1% for rotavirus, 99.1% for norovirus GI, 98.7% for norovirus GII, 89.7% for adenovirus, 98.2% for astrovirus, and 99.8% for sapovirus. In addition, eight rotavirus genotypes, three norovirus GI genotypes, four norovirus GII genotypes, eight adenovirus genotypes, two astrovirus genotypes, and two sapovirus genotypes were detected. CONCLUSIONS: The Allplex assay showed high agreement with Seeplex and genotyping results, and was able to additionally detect sapoviruses. The Allplex assay could be useful in identifying viral gastrointestinal infections in patients with acute gastroenteritis symptoms. PMID- 29401557 TI - Comparison of Enterococcus faecium Bacteremic Isolates from Hematologic and Non hematologic Patients: Differences in Antimicrobial Resistance and Molecular Characteristics. AB - BACKGROUND: Enterococcus faecium, especially vancomycin-resistant E. faecium (VREfm), is a major concern for patients with hematologic diseases. Exposure to antibiotics including fluoroquinolone, which is used as a routine prophylaxis for patients with hematologic (MH) diseases, has been reported to be a risk factor for infection with vancomycin-resistant eneterocci. We compared the characteristics of E. faecium isolates according to their vancomycin susceptibility and patient group (MH vs non-MH patients). METHODS: A total of 120 E. faecium bacteremic isolates (84 from MH and 36 from non-MH patients) were collected consecutively, and their characteristics (susceptibility, multilocus sequence type [MLST], Tn1546 type, and the presence of virulence genes and plasmids) were determined. RESULTS: Among the vancomycin-susceptible E. faecium (VSEfm) isolates, resistance to ampicillin (97.6% vs 61.1%) and high-level gentamicin (71.4% vs 38.9%) was significantly higher in isolates from MH patients than in those from non-MH patients. Notably, hyl, esp, and pEF1071 were present only in isolates with ampicillin resistance. Among the VREfm isolates, ST230 (33.3%) and ST17 (26.2%) were predominant in MH patients, while ST17 (61.1%) was predominant in non-MH patients. Plasmid pLG1 was more prevalent in E. faecium isolates from MH patients than in those from non-MH patients, regardless of vancomycin resistance. Transposon analysis revealed five types across all VREfm isolates. CONCLUSIONS: The antimicrobial resistance profiles and molecular characteristics of E. faecium isolates differed according to the underlying diseases of patients within the same hospital. We hypothesize that the prophylactic use of fluoroquinolone might have an effect on these differences. PMID- 29401558 TI - Same-Day Identification and Antimicrobial Susceptibility Testing of Bacteria in Positive Blood Culture Broths Using Short-Term Incubation on Solid Medium with the MicroFlex LT, Vitek-MS, and Vitek2 Systems. AB - BACKGROUND: Early and appropriate antibiotic treatment improves the clinical outcome of patients with septicemia; therefore, reducing the turn-around time for identification (ID) and antimicrobial susceptibility test (AST) results is essential. We established a method for rapid ID and AST using short-term incubation of positive blood culture broth samples on solid media, and evaluated its performance relative to that of the conventional method using two rapid ID systems and a rapid AST method. METHODS: A total of 254 mono-microbial samples were included. Positive blood culture samples were incubated on blood agar plates for six hours and identified by the MicroFlex LT (Bruker Daltonics) and Vitek-MS (bioMerieux) systems, followed by AST using the Vitek2 System (bioMerieux). RESULTS: The correct species-level ID rates were 82.3% (209/254) and 78.3% (199/254) for the MicroFlex LT and Vitek-MS platforms, respectively. For the 1,174 microorganism/antimicrobial agent combinations tested, the rapid AST method showed total concordance of 97.8% (1,148/1,174) with the conventional method, with a very major error rate of 0.5%, major error rate of 0.7%, and minor error rate of 1.0%. CONCLUSIONS: Routine implementation of this short-term incubation method could provide ID results on the day of blood culture-positivity detection and one day earlier than the conventional AST method. This simple method will be very useful for rapid ID and AST of bacteria from positive blood culture bottles in routine clinical practice. PMID- 29401559 TI - Spectrum of MNX1 Pathogenic Variants and Associated Clinical Features in Korean Patients with Currarino Syndrome. AB - BACKGROUND: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS. METHODS: We enrolled 25 patients with CS, including 24 sporadic cases and one familial case. Direct sequencing of MNX1 and multiplex ligation-dependent probe amplification were performed. We also analyzed clinical phenotypes and evaluated genotype-phenotype correlations. RESULTS: We identified six novel variants amongst a total of six null variants, one missense variant, and one large deletion. The null variants included four frameshift variants (p.Gly98Alafs* 124, p.Gly145Alafs*77, p.Gly151Leufs*67, and p.Ala216Profs*5) and two nonsense variants (p.Tyr186* and p.Gln212*). The missense variant, p.Lys295Gln, was located in the highly-conserved homeobox domain and was predicted to be deleterious. A large deletion involving the 7q36 region was detected in one patient. Pathogenic variants in MNX1 were detected in 28% of all CS cases and 25% of sporadic cases. The clinical phenotype was variable in patients with and without pathogenic variants; no significant genotype-phenotype correlation was observed. CONCLUSIONS: This study revealed the spectrum and phenotypic variability of MNX1 pathogenic variants in the Korean population. PMID- 29401560 TI - Budget Impact of the Accreditation Program for Clinical Laboratories on Colorectal Cancer Screening via Fecal Immunochemical Testing: Results from the National Cancer Screening Program in Korea. AB - BACKGROUND: False-positive fecal immunochemical test (FIT) results in the National Cancer Screening Program (NCSP) for colorectal cancer may lead to unnecessary procedures, such as colonoscopies, increasing the medical costs. We estimated reductions in the cost of National Health Insurance according to the accreditation status of screening facilities participating in the NCSP for colorectal cancer. METHODS: We used data collected between 2007 and 2010 from NCSP and the Korea Central Cancer Registry to identify patients with colorectal cancer. We also ascertained the history of the accreditation of each facility by the Korean Laboratory Accreditation Program (KLAP). Budget impact was defined as a reduction in medical costs achieved when the false-positive rate of the non accredited facilities decreased relative to that of the accredited facilities. RESULTS: A total of 3,285 screening facilities participated in the NCSP. Of these, 196 were accredited by the KLAP. The false-positive rate of the accredited facilities was 2.47%, and that of the non-accredited facilities was 6.83%. Medical costs were estimated to be reduced by approximately 19 million US dollars (USD), and the cost of detecting one case of colorectal cancer was estimated to decrease from 9,212 USD to 7,332 USD if the false-positive rate of non-accredited facilities were decreased to that of the accredited facilities. Clinics were estimated to have the largest associated cost reduction. CONCLUSIONS: Quality assurance in clinical laboratories could lower false-positive rates and prevent the use of unnecessary procedures, ensuring patient safety and increasing the cost-effectiveness of FIT screening in the NCSP for colorectal cancer. PMID- 29401561 TI - Evaluation of Stability of Thiopurine Metabolites Using a Validated LC-MS/MS Method. AB - Measurement of thiopurine metabolites is helpful to monitor adverse effects and assess compliance in patients on thiopurine treatment. The purpose of this study was to develop and validate an analytical method for measurement of thiopurine metabolites, thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN), in RBCs. We developed and validated a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of 6-TGN and 6 MMPN and evaluated the stability of the thiopurine metabolites in RBC and whole blood states without any preprocessing at various storage conditions. The linear range was 0.1-10 MUmol/L and 0.5-100 MUmol/L for 6-TGN and 6-MMPN, respectively. The mean extraction recovery at the two concentrations was 71.0% and 75.0% for 6 TGN, and 102.2% and 96.4% for 6-MMPN. Thiopurine metabolites in preprocessed RBC samples were stable at 25 degrees C and 4 degrees C after storage for 4 hours and at -70 degrees C for up to 6 months. However, 6-TGN decreased by 30% compared with the initial concentration when stored at -20 degrees C for 180 days. In whole blood states, 6-TGN decreased by about 20% at four days after storage at 4 degrees C. We validated a reliable LC-MS/MS method and recommend that the patient's whole blood sample be preprocessed as soon as possible. PMID- 29401562 TI - Evaluation of the 1B Equation to Estimate Glomerular Filtration Rate in Pediatric Patients with Cancer. AB - The 1B equation is recommended for calculating the glomerular filtration rate (GFR) in children. Since few reports have evaluated the performance of the 1B equation, we investigated the performance of estimated GFR (eGFR) equations with the blood urea nitrogen (BUN) variable for pediatric cancer patients. In total, 203 children with cancer who underwent measured GFR (mGFR) assessment were enrolled. The median (range) mGFR and eGFR calculated using the updated Schwartz equation were 118 (43-241) and 135 (34-257) mL/min/1.73 m2, respectively. The bias, precision (root mean square error [RMSE]), and accuracy (P30, mGFR+/-30%) of three eGFR equations including updated Schwartz, 1B, and full age spectrum (FAS) were compared. The median bias (mL/min/1.73 m2) was: updated Schwartz, 8.5; 1B, -9.0; and FAS, 4.2. The biases for all three eGFR equations were significantly different from zero. The P30 was: updated Schwartz, 63.5%; 1B, 66.0%; and FAS, 66.0%. The RMSE was the lowest for the 1B equation (40.4), followed by FAS (42.3), and updated Schwartz (45.5). The median eGFR/mGFR ratio for the eGFR equations decreased with age and reduced kidney functions (i.e., increased creatinine and BUN concentrations). The bias may be further reduced by using the average from two equations, such as the updated Schwartz and 1B, or FAS equation, rather than using the updated Schwartz or 1B equation alone. The use of the 1B equation may underestimate the GFR. Using creatinine and BUN variables in the eGFR equation may yield a more accurate estimate of the GFR in pediatric cancer patients. PMID- 29401563 TI - Seasonal and Temperature-Associated Increase in Community-Onset Acinetobacter baumannii Complex Colonization or Infection. AB - Identifying the trends in community-onset Acinetobacter baumannii complex isolation and diversity according to temperature could help provide insight into the behavior of the A. baumannii complex. We performed a retrospective analysis of A. baumannii complex (Acinetobacter baumannii, Acinetobacter nosocomialis, Acinetobacter pittii, and Acinetobacter calcoaceticus) isolates obtained from patients at a Korean community hospital from 2006 to 2015 with reference to seasonal temperatures. The incidence rates were compared between warm (June September) and cold (November-March) months, defined as an average mean temperature >=20 degrees C and <=5 degrees C, respectively. Incidence rate was calculated as the number of cases per month, converted to cases/105 admissions for healthcare-acquired isolates and cases/103 outpatients for community-onset isolates. Approximately 3,500 A. baumannii complex cases were identified, and 26.2% of them were community-onset cases. The median (interquartile range) number of community-onset A. baumannii complex cases was significantly higher (P=0.0002) in warm months at 13.8 (9.5-17.6) than in cold months at 10.1 (6.3-13.2). There was a strong correlation between community-onset A. baumannii complex cases and temperature (Pearson's r=0.6805, P=0.0149). Thus, we identified a seasonality pattern for community-onset A. baumannii complex colonization or infection, but not for healthcare-acquired cases. PMID- 29401564 TI - Prevalence of Escherichia coli Carrying pks Islands in Bacteremia Patients. AB - Escherichia coli can harbor genomic pks islands that code for a polyketide peptide genotoxin known as colibactin. E. coli strains carrying pks islands trigger genetic instability. pks islands have been significantly associated with bacteremia. We investigated the molecular epidemiology of bacteremic E. coli isolates and the prevalence of bacteremia-causing E. coli carrying pks islands. A total of 146 E. coli isolates were collected at a tertiary-care hospital from January 2015 to December 2016. The phylogenetic groups were determined by multiplex PCR. All isolates were screened by PCR for sequence type 131 (ST131) associated single-nucleotide polymorphisms (SNPs) in mdh and gyrB. For detection of pks islands, we performed PCR for the clbB and clbN genes as colibactin system markers. Phylogenetic group B2 was the most common, accounting for 54.1% (N=79) of the isolates, followed by group D with 29.5% (N=43), group A with 11.6% (N=17), and group B1 with 4.8%. Of the group B2 isolates, 40.5% were ST131 strains and 32.9% carried pks islands. Only three ST131 isolates in group B2 carried the clbB and clbN genes, while the other 23 ST131 isolates did not. The pks gene might not be associated with ST131 strains. PMID- 29401565 TI - Circulating Microparticles and Coagulation Profiles in Patients with Advanced Stage Solid Tumors. PMID- 29401566 TI - NDM-5 and OXA-48 Co-producing Uropathogenic Escherichia coli Isolate: First Case in Korea. PMID- 29401567 TI - Clinical Significance of Anti-G Alloantibody and Serologic Interpretation Strategies for Patients with an Anti-C+D Pattern: First Report of Anti-G Alloantibody Identification in Korea. PMID- 29401568 TI - PITX2-related Axenfeld-Rieger Syndrome with a Novel Pathogenic Variant (c.475_476delCT). PMID- 29401569 TI - Erratum: Increasing Incidence of Listeriosis and Infection associated Clinical Outcomes. AB - This corrects the article on p. 102 in vol. 38, PMID: 29214753. PMID- 29401570 TI - Construction of a Transcriptome-Driven Network at the Early Stage of Infection with Influenza A H1N1 in Human Lung Alveolar Epithelial Cells. AB - We aimed to understand the molecular changes in host cells that accompany infection by the seasonal influenza A H1N1 virus because the initial response rapidly changes owing to the fact that the virus has a robust initial propagation phase. Human epithelial alveolar A549 cells were infected and total RNA was extracted at 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h post infection (h.p.i.). The differentially expressed host genes were clustered into two distinct sets of genes as the infection progressed over time. The patterns of expression were significantly different at the early stages of infection. One of the responses showed roles similar to those associated with the enrichment gene sets to known 'gp120 pathway in HIV.' This gene set contains genes known to play roles in preventing the progress of apoptosis, which infected cells undergo as a response to viral infection. The other gene set showed enrichment of 'Drug Metabolism Enzymes (DMEs).' The identification of two distinct gene sets indicates that the virus regulates the cell's mechanisms to create a favorable environment for its stable replication and protection of gene metabolites within 8 h. PMID- 29401571 TI - [Phenotypic and genetic changes of entomopathogenic ascomycete Beauveria Bassiana under passaging through various hosts]. AB - Phenotypic and genetic estimations of entomopathogenic ascomycete B.bassiana (strainSar-31) after 6-passaging through four hosts were shown. Increasing of virulence, changesin morpho-cultural characteristics and variations in Inter Simple Sequence Repeats(ISSR) assay between initial and reisolated cultures were registered.Six passages of entomopathogenic ascomycete Beauveria bassiana (strain Sar-31)through four hosts (Galleria mellonella, Tenebrio molitor, Leptinotarsa decemlineata, Locustamigratoria) and following estimation of phenotypic and genetic differences of theinitial strain and reisolated cultures were conducted. The passaging of strain through certainhost led to increasing of virulence for both this host and other test-insects. Unidirectionalchanges of morpho-cultural characteristics: colonies pigmentation and relief strengthening,increasing of conidia production and lipolytic activity were registered in all passagedcultures. Genetic analysis with 6 ISSR markers revealed variations between initial and reisolatedcultures in 3 markers. Taken together, the results of this study help us understandpotential ways of fungi strains changes during epizootic process and possibilities of ISSRassay applying for investigation of pathogen transmission. PMID- 29401572 TI - [Morphology of Cestode with Atypical Mode of Attachment]. AB - Morphological features of R a u s c h i ta e n ia a n c o ra (Mamaev, 1959), a cestode with atypicalmode of attachment ("anchoring" in the wall of the host intestine), are considered. AtI he center of the overgrown scolex there is a rostellum, size of which is close to that of thedeveloped metacestode. Large suckers are composed mainly of loose parenchyma and fineradial muscle fibers. Fragments of host tissue are noted in the suckers' cavity. Surface ofI he scolex is covered with large microtriches, which are in contact with the host tissue havingsigns of degradation. Distal cytoplasm is filled with vesicles coming from tegumentalcytons. Rostellar glands that are common to cyclophyllids are not found. Excretory canalscontain fluid (closer to the surface) and numerous lipid droplets (deeper located canals). PMID- 29401573 TI - [The number of larvae and period of its production of Cosmocerca Ornata females (Nematoda: Cosmocercidae)]. AB - The number of larvae in the Cosmocerca ornata (Dujardin, 1845) females from marshfrogs in vivo and period of larvae production of nematodes in vitro was studied. The numberof larvae in females of nematodes and quantity of born larvae depend on the size of parasites.The largest C. ornata females had the highest number of larvae and the longest periodof larvae production. The nematode sizes in its turn depends on density of infrapopulationof C. ornata and ambient temperature. The dependence of a number of the C. ornatalarvae on the host age and sex and on a season of the year was revealed. Different phenotypesof amphibians showed no influence on the number of larvae inside nematode females.In the experiment C. ornata females remained viable up to 8 days, producing larvae up to7 days. The optimum temperature for the larvae production constituted 24-28 degrees C. At atemperature of 12 degrees C and lower the nematode larvae output from females was stopped. PMID- 29401574 TI - [Exoskeleton anomalies among taiga tick males from populations of the Asiatic part of Russia]. AB - The taiga tick (Icodes persulcatus, Schulze, 1930) is the main and most epidemiologically dangerous vector of tick-born encephalitis virus (TBEV) and Borrelia in most parts of Russia's territory (Alekseev et al., 2008). The purpose of this article is to describe the incidence rate of I. persulcatus males with exoskeleton anomalies in populations of the Asiatic part of Russia. A total of 2630 taiga tick males were morphologically analyzed. They were collected in Far Eastern, Siberian and Ural Federal Districts (respectively, FEFD, SFD, UFD) in 15 geographically remote locations. It is shown that in all populations there are adult ticks with impaired exoskeleton, among which two types dominate: twin dents at the back of conscutum (P11), and uneven surface of conscutum - a "shagreen skin" (P9). The frequency of abnormalities in males from the areas with temperate monsoon and temperate continental climate (FEFD) was definitely lower (6.5 +/- 1.05 %), than in individuals from the territories of SFD (29.7 +/- 1.03 %) and UFD (25.8 +/- 3.93 %) with continental and sharply continental climate. FEFD territory is also characterized by a less number of males having two simultaneous exoskeleton anomalies. Similar district-preconditioned differences in the frequency of recorded body distortions are also typical of females, with a higher percentage of deviant individuals in comparison with males. Thus, the identified polymorphism of exoskeleton structure of the taiga tick may reflect the natural phenogeographical variability of this trait and might not be the result of human impact. PMID- 29401575 TI - [A case of the tick (Ixodidae) hiperinvasion of the tundra vole in magadan environs]. AB - A case of tundra vole death as a result its hyperinvasion by ticks Ixodes angustus on the northern periphery of the Asiatic range of the parasite is given. PMID- 29401576 TI - [Infection of the pacific saury Cololabis saira by acanthocephalans in the Kuril Islands area]. AB - The Pacific saury Cololabis saira (Brevoort, 1856) is one of the important target species of commercial fisheries. Food manufacturers and consumers encounter problems due to the infection of the saury by acanthocephalans, which are quite difficult to clean out completely during on-board catch processing. Infection of C. saira was not studied on a regular basis, therefore, our knowledge about the parasites of saury is fragmentary. This paper contains infection indices (only acanthocephalans) of the Pacific saury caught in the Kuril Islands area (Russian Exclusive Economic Zone) in 2015. PMID- 29401577 TI - The simplest "field" methods for extractin of nematodes from plants, wood, insects and soil, with additional description how to keep extracted nematodes alive for a long time. AB - The simplest modification of the dynamic extraction method using cottonwool filter based on the Baermann funnel principle, is described. This modification excludes the funnel because a great share of Sticky worms attach to sloping walls of a funnel and thus do not reach the collector Eppendorf tube. But the main principle of the Baermann funnel is used, I. e. sinking down of actively moving heavy narrow bodies via wide holes of filter and thus separating the active worms from passive non-Brownian moving substrate particles, which do not pass the filter and remain above it. This principle is illustrated because it has never been described before. In the proposed modification any sloping walls in the extraction paths are excluded and thus the probability to attach sticky nemotodes to walls is also excluded; only cylindrical equipment with abrupt vertical walls is used; procedures are extremely simplified to be user-friendly for beginners: only filter (cotton pads), Eppendorf tubes, plastic glasses and narrow PVC tubing are applied. The new simplified modification allows one to collect nematodes by non-professional workers, e. g. in Polar expeditions without microscopic study of results. As an addition, an efficient method to maintain extracted nematodes alive is proposed, using the "effect of water film" in foam rubber inside the Eppendorf tube. To maintain nematodes alive during several months it is recommended to suppress bacteria via addition of 0.2-0.4% formaldehyde solution and then keep the tube with nematodes in a refrigerator. PMID- 29401578 TI - Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia. AB - Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-gamma. Because the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, nCounter Inflammation Gene Array Analysis was used to build immune-related gene profiles of NK cells to comprehensively analyze the molecular signature of NK cells after ischemic brain injury. We observed distinct gene expression profiles reflecting different splenic NK-cell phenotypes and functional properties across the time course of transient middle cerebral artery occlusion (MCAO). Based on gene expression and pathway-network analysis, lower expression levels of signal transducer and activator of transcription-3 (STAT3) were observed in animals with MCAO compared with sham control animals. Genetic activation of STAT3 through the introduction of STAT3 clustered regularly interspaced short palindromic repeats (CRISPR) plasmid prevented the loss of NK-cell-derived IFN-gamma production after MCAO, together with reduced bacterial burden and mortality. Our data suggest that brain ischemia impairs NK-cell-mediated immune defense in the periphery, at least in part through the JAK-STAT3 pathway, which can be readdressed by modulating STAT3 activation status.-Jin, W.-N., Ducruet, A. F., Liu, Q., Shi, S. X.-Y., Waters, M., Zou, M., Sheth, K. N., Gonzales, R., Shi, F.-D. Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia. PMID- 29401579 TI - Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter. AB - Recent increases in fructose consumption have raised concerns about the potential adverse intergenerational effects of excess fructose intake. In the present study, we investigated whether excess maternal fructose intake affects hippocampal function in offspring. Female Sprague-Dawley rats were divided into 3 experimental groups: one group received distilled water, one group received 20% fructose water, and one group received 20% glucose water in addition to standard chow during gestation and lactation. Hippocampal function of offspring was evaluated by using novel object recognition and fear conditioning tests. Impaired cognitive performance was observed in the offspring of fructose-fed dams at postnatal d 60, potentially a result of decreased hippocampal neurogenesis. Real time PCR analysis demonstrated that offspring from fructose-fed dams exhibited decreased brain-derived neurotrophic factor ( BDNF) gene expression, whereas pyrosequencing assays revealed increased DNA methylation at the BDNF promoter. The potential association between BDNF transcription and levels of DNA methylation was confirmed on the basis of luciferase activity. Furthermore, longitudinal analysis revealed that increased methylation of the BDNF promoter region was maintained at least until rats reached maturity. These results indicate that epigenetic changes associated with BDNF may underlie hippocampal dysfunction that is induced by early-life exposure to excess maternal fructose consumption.-Yamazaki, M., Yamada, H., Munetsuna, E., Ishikawa, H., Mizuno, G., Mukuda, T., Mouri, A., Nabeshima, T., Saito, K., Suzuki, K., Hashimoto, S., Ohashi, K. Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter. PMID- 29401580 TI - Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet induced systemic inflammation, microglial activation, and reduced neuroplasticity. AB - The goal of this study was to identify the intrinsic links that explain the effect of a Western diet (WD) on cognitive dysfunction. Specific pathogen-free, wild-type mice were fed either a control diet (CD) or a high-fat, high-sucrose WD after weaning and were euthanized at 10 mo of age to study the pathways that affect cognitive health. The results showed that long-term WD intake reduced hippocampal synaptic plasticity and the level of brain-derived neurotrophic factor mRNA in the brain and isolated microglia. A WD also activated ERK1/2 and reduced postsynaptic density-95 in the brain, suggesting postsynaptic damage. Moreover, WD-fed mice had increased inflammatory signaling in the brain, ileum, liver, adipose tissue, and spleen, which was accompanied by microglia activation. In the brain, as well as in the digestive tract, a WD reduced signaling regulated by retinoic acid and bile acids (BAs), whose receptors form heterodimers to control metabolism and inflammation. Furthermore, a WD intake caused dysbiosis and dysregulated BA synthesis with reduced endogenous ligands for BA receptors, i.e., farnesoid X receptor and G-protein-coupled bile acid receptor in the liver and brain. Together, dysregulated BA synthesis and dysbiosis were accompanied by systemic inflammation, microglial activation, and reduced neuroplasticity induced by WD.-Jena, P. K., Sheng, L., Di Lucente, J., Jin, L.-W., Maezawa, I., Wan, Y. J. Y. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity. PMID- 29401581 TI - Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). AB - Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). PMID- 29401582 TI - Skeletal cell YAP and TAZ combinatorially promote bone development. AB - The functions of the paralogous transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in bone are controversial. Each has been observed to promote or inhibit osteogenesis in vitro, with reports of both equivalent and divergent functions. Their combinatorial roles in bone physiology are unknown. We report that combinatorial YAP/TAZ deletion from skeletal lineage cells, using Osterix-Cre, caused an osteogenesis imperfecta-like phenotype with severity dependent on allele dose and greater phenotypic expressivity with homozygous TAZ vs. YAP ablation. YAP/TAZ deletion decreased bone accrual and reduced intrinsic bone material properties through impaired collagen content and organization. These structural and material defects produced spontaneous fractures, particularly in mice with homozygous TAZ deletion and caused neonatal lethality in dual homozygous knockouts. At the cellular level in vivo, YAP/TAZ ablation reduced osteoblast activity and increased osteoclast activity, in an allele dose-dependent manner, impairing bone accrual and remodeling. Transcriptionally, YAP/TAZ deletion and small-molecule inhibition of YAP/TAZ interaction with the transcriptional coeffector TEAD reduced osteogenic and collagen-related gene expression, both in vivo and in vitro. These data demonstrate that YAP and TAZ combinatorially promote bone development through regulation of osteoblast activity, matrix quality, and osteoclastic remodeling.-Kegelman, C. D., Mason, D. E., Dawahare, J. H., Horan, D. J., Vigil, G. D., Howard, S. S., Robling, A. G., Bellido, T. M., Boerckel, J. D. Skeletal cell YAP and TAZ combinatorially promote bone development. PMID- 29401583 TI - Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy. AB - Argininosuccinate synthetase 1 (ASS1) is a rate-limited enzyme in arginine biosynthesis. The oncogenic potential of ASS1 in terms of prognosis and cancer metastasis in arginine prototrophic gastric cancer (GC) remains unclear at present. We identify differentially expressed proteins in microdissected GC tumor cells relative to adjacent nontumor epithelia by isobaric mass tag for relative and absolute quantitation proteomics analysis. GC cells with stable expression or depletion of ASS1 were further analyzed to identify downstream molecules. We investigated their effects on chemoresistance and cell invasion in the presence or absence of arginine. ASS1 was highly expressed in GC and positively correlated with GC aggressiveness and poor outcome. Depletion of ASS1 led to inhibition of tumor growth and decreased cell invasion via induction of autophagy-lysosome machinery, resulting in degradation of active beta-catenin, Snail, and Twist. Ectopic expression of ASS1 in GC cells reversed these effects and protected cancer cells from chemotherapy drug-induced apoptosis via activation of the AKT mammalian target of rapamycin signaling pathway. ASS1 contributes to GC progression by enhancing aggressive potential resulting from active beta-catenin, Snail, and Twist accumulation. Our results propose that ASS1 might contribute to GC metastasis and support its utility as a prognostic predictor of GC.-Tsai, C. Y., Chi, H.-C., Chi, L.-M., Yang, H.-Y., Tsai, M.-M., Lee, K.-F., Huang, H.-W., Chou, L.-F., Cheng, A.-J., Yang, C.-W., Wang, C.-S., Lin, K.-H. Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy. PMID- 29401584 TI - Deficiency of a novel gene, Yulink, predisposes to heart failure and ventricular arrhythmia. AB - Heart failure is a major cardiovascular disease and is associated with significant morbidity and mortality. Sudden cardiac death (SCD) in heart failure is a disastrous cardiovascular phenomenon. However, few studies have examined the genetic background that determines susceptibility to heart failure and SCD. We found that deficiency of a newly identified gene, Yulink, promoted cardiac alternans in zebrafish cardiomyocytes, and genetic knockdown (KD) resulted in pericardial edema, decreased cardiac output, and premature ventricular contractions. Yulink KD morphants exhibited irregular action potentials, slower Ca2+ reuptake, and alternans of Ca2+ transients and action potential duration, which are hallmarks for SCD susceptibility in heart failure. Similarly, KD of Yulink in mouse cardiomyocytes disrupted Ca2+ reuptake, reduced the expression of cardiac Serca2, and resulted in a reduction in peroxisome proliferator-activated receptor (PPAR)gamma activity. Expression of Serca2 was up-regulated by PPARgamma agonists and down-regulated by PPARgamma-short hairpin RNA KD, suggesting that Yulink regulates Serca2 expression through PPARgamma. Finally, Yulink and Serca2 were down-regulated in ventricular samples of hearts from patients with heart failure due to dilated cardiomyopathy. Our results highlight the interaction of Yulink with PPARgamma in regulating Serca2 expression and suggest a mechanistic role of the Yulink in the development of human heart failure and SCD.-Tsai, C. T., Kuo, M.-W., Lin, J.-L., Yu, A. L., Yu, J. Deficiency of a novel gene, Yulink, predisposes to heart failure and ventricular arrhythmia. PMID- 29401585 TI - The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation. AB - The disturbances of cellular proteostasis caused by the alteration in the ubiquitin-proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuroinflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y2R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitinG76V-green fluorescent protein (UbGFP mice)], we found that LPS-induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y2R. In this line, LPS-treated double transgenic UbGFP; P2Y2R-/- mice did not present a UPS impairment in astrocytes or a social interaction deficit as severe as that observed in LPS-treated UbGFP mice. In vivo administration of selective P2Y2R agonist diuridine tetraphosphate reversed the UPS impairment completely in astrocytes and partially in microglial cells, promoting increased expression of the proteasomal beta5 subunit by a mechanism dependent on the Src/PI3K/ERK pathway. Altogether, our results suggest that LPS induces unbalanced proteostasis in astrocytes by blocking P2Y2R. Finally, our findings point to the design of selective P2Y2R agonist drugs as a new therapeutic approach to treat the neuroinflammatory status.-De Diego Garcia, L., Sebastian-Serrano, A., Hernandez, I. H., Pintor, J., Lucas, J. J., Diaz-Hernandez, M. The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation. PMID- 29401586 TI - PolyQ-expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. AB - The components of ubiquitin (Ub)-proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub-related proteins remains elusive. Using N-terminal huntingtin (Htt-N552) and ataxin (Atx)-3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ-expanded proteins. We found that polyQ-expanded Htt-N552 and Atx-3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)-2, into inclusions. This sequestration effect is dependent on the UBA domains of Ub adaptors and the conjugated Ub of the aggregated proteins. Moreover, polyQ-expanded Htt-N552 and Atx-3 reduce the protein level of xeroderma pigmentosum group C (XPC) by sequestration of hHR23B, suggesting that this process may cut down the available quantity of hHR23B and thus affect its normal function in stabilizing XPC. Our findings demonstrate that polyQ-expanded proteins sequester Ub adaptors or other Ub-related proteins into aggregates or inclusions through ubiquitination of the pathogenic proteins. This study may also provide a common mechanism for the formation of Ub-positive inclusions in cells. Yang, H., Yue, H.-W., He, W.-T., Hong, J.-Y., Jiang, L.-L., Hu, H.-Y. PolyQ expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. PMID- 29401587 TI - Endoglin interacts with VEGFR2 to promote angiogenesis. AB - Endoglin, a TGF-beta coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promoted VEGF-induced tip cell formation. Mechanistically, endoglin interacted with VEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interact with VEGFR2 failed to sustain VEGFR2 on the cell surface and to promote VEGF-induced tip cell formation. Further, an endoglin-targeting monoclonal antibody (mAb), TRC105, cooperated with a VEGF-A targeting mAb, bevacizumab, to inhibit VEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-associated angiogenesis in a murine tumor model. This study demonstrate a novel mechanism by which endoglin initiates and regulates VEGF-driven angiogenesis while providing a rationale for combining anti-VEGF and anti endoglin therapy in patients with cancer.-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis. PMID- 29401588 TI - The role of AMP-activated protein kinase in the expression of the dystrophin associated protein complex in skeletal muscle. AB - Stimulation of AMPK induces the expression of dystrophin-associated protein complex (DAPC) components in skeletal muscle, whereas reductions in AMPK are associated with DAPC dysfunction. We sought to determine whether AMPK was necessary for the maintenance of DAPC expression in skeletal muscle. Fast, glycolytic extensor digitorum longus (EDL) and slow, oxidative soleus (Sol) muscles from wild-type mice and from littermates with skeletal muscle-specific knockout of the AMPK beta1 and beta2 subunits (AMPK beta1 beta2M-KO; MKO) were analyzed. DAPC mRNA and protein expression were similar between genotypes, with the exception of elevated neuronal nitric oxide synthase expression at the sarcolemma in MKO muscles. The content of transcriptional and post transcriptional regulators of the DAPC was also not affected by the loss of AMPK. However, MyoD and myogenin expression was diminished in MKO muscles, consistent with previous reports of myopathy in these animals. Furthermore, we observed decrements in extrasynaptic utrophin expression selectively in MKO Sol muscles, likely due to the adaptive accumulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha at the sarcolemma of MKO EDL muscles. Collectively, the evidence indicates that AMPK is sufficient but not essential for the maintenance of DAPC expression in skeletal muscle, yet it is required for preserving extrasynaptic utrophin levels in slow oxidative muscles.-Dial, A. G., Rooprai, P., Lally, J. S., Bujak, A. L., Steinberg, G. R., Ljubicic, V. The role of AMP-activated protein kinase in the expression of the dystrophin-associated protein complex in skeletal muscle. PMID- 29401589 TI - Staphylococcus aureus triggers a shift from influenza virus-induced apoptosis to necrotic cell death. AB - Superinfections with Staphylococcus aureus are a major complication of influenza disease, causing excessive inflammation and tissue damage. This enhanced cell damaging effect is also observed in superinfected tissue cultures, leading to a strong decrease in overall cell viability. In our analysis of the underlying molecular mechanisms, we observed that, despite enhanced cell damage in superinfection, S. aureus did not increase but rather inhibited influenza virus (IV)-induced apoptosis in cells on the level of procaspase-8 activation. This apparent contradiction was solved when we observed that S. aureus mediated a switch from apoptosis to necrotic cell death of IV-infected cells, a mechanism that was dependent on the bacterial accessory gene regulator ( agr) locus that promotes bacterial survival and spread. This so far unknown action may be a bacterial strategy to enhance dissemination of intracellular S. aureus and may thereby contribute to increased tissue damage and severity of disease.-Van Kruchten, A., Wilden, J. J., Niemann, S., Peters, G., Loffler, B., Ludwig, S., Ehrhardt, C. Staphylococcus aureus triggers a shift from influenza virus-induced apoptosis to necrotic cell death. PMID- 29401590 TI - Phospholipase Cbeta1 regulates proliferation of neuronal cells. AB - Cells have developed lineage-specific mechanisms to control proliferation and drive morphologic changes upon differentiation. A hallmark of differentiation is the assembly of signaling molecules that transduce extracellular signals, such as the production of the G protein-regulated enzyme phospholipase Cbeta (PLCbeta), which generates calcium signals from sensory stimuli. We found that in most cancerous cell lines there is positive correlation between PLCbeta1 levels and cell proliferation. In cells of neuronal lineage, however, reducing PLCbeta1 levels increases the rate of proliferation. Using a combination of biochemical and biophysical methods, we find that, in the G1 phase, a cytosolic population of PLCbeta1 associates with cyclin-dependent kinase 16 (CDK16), a neuron-specific enzyme that is activated by cyclin Y to inactivate the antioncogenic protein p27Kip1. Binding of PLCbeta1 directly inhibits CDK16 activity and in turn reduces the ability of cells to enter the S phase. Activation of Galphaq by carbachol causes movement of PLCbeta from the cytosol to the plasma membrane, reducing its association with CDK16. Similarly, the overexpression of activated Galphaq moves PLCbeta1 to the membrane, reverses G1 arrest, and promotes proliferation, thereby connecting external stimuli with cell proliferation. Our results present a model in which the transient high expression of PLCbeta1 that occurs at the onset of differentiation arrests cells in the G1 phase through its association with CDK16 and allows CDK16 to transition to its postmitotic function of neurite outgrowth and trafficking of synaptic vesicles. The novel role of PLCbeta1 in neuronal cell proliferation offers a unique interaction that can be manipulated to guide cells into a neuronal phenotype or to develop therapies for neuroblastomas.-Garwain, O., Valla, K., Scarlata, S. Phospholipase Cbeta1 regulates proliferation of neuronal cells. PMID- 29401591 TI - The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats. AB - Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Ruttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats. PMID- 29401592 TI - Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaking activity. AB - Spontaneous rhythmic action potential or pacemaking activity of pacemaker cells controls rhythmic signaling such as heartbeat. The mechanism underlying the origin of pacemaking activity is not well understood. In this study, we created human embryonic kidney (HEK) 293 cells that show pacemaking activity through heterologous expression of strong inward rectifier K+ subfamily 2 isoform 1 (Kir2.1) channels, hyperpolarization-activated cyclic nucleotide-gated isoform 2 (HCN2) nonselective cation channels, and voltage-gated Na+ subfamily 1 isoform 5 or Ca2+ subfamily 3 isoform 1 (Nav1.5 or Cav3.1) channels. A range of relative levels of Kir2.1 and HCN2 currents dynamically counterbalance, generating spontaneous rhythmic oscillation of resting membrane potential between -64 and 34 mV and determining oscillation rates. Each oscillation cycle begins with an autodepolarization phase, which slowly proceeds to the threshold potential that activates Nav1.5 or Cav3.1 channels and triggers action potential, causing engineered HEK293 cells to exhibit pacemaking activity at a rate of <=67 beats/min. Engineered HEK293 cells with Kir2.1 and either HCN3 or HCN4 also show the oscillation. Engineered HEK293 cells expressing HCN2 and other Kir2 channels, which lack Kir2.1-like complete inward rectification, do not show the oscillation. Therefore, Kir2.1-like inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate spontaneous rhythmic action potential and form an origin of pacemaking activity; Kir2 and HCN channels play essential roles in pacemaking activity.-Chen, K., Zuo, D., Wang, S.-Y. Chen, H. Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaking activity. PMID- 29401594 TI - Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice. AB - Lipids secreted from the meibomian gland (meibum) form the superficial layer of the tear film and prevent water evaporation from the ocular surface and infection. Here, we identified the fatty acid (FA) elongases responsible for the synthesis of very long-chain FAs (VLCFAs) that constitute the meibum lipids. Elongation of VLCFAs (ELOVL)1 is primarily responsible for the production of saturated VLCFAs, whereas ELOVL1, ELOVL3, and ELOVL4 redundantly participate in the synthesis of monounsaturated VLCFAs. Gene disruption of Elovl1 in mice shortened acyl moieties in the 2 major meibum lipids: cholesteryl esters and wax esters. These changes were associated with dry eye phenotypes, including increases in eye-blink frequency and water evaporation from the ocular surface at younger ages. Aged Elovl1 mutant mice developed corneal opacity with vascular invasion, accompanied by epidermalization of the cornea. Thus, in addition to the well-known VLC ceramides (acylceramides) in the epidermis, VLC meibum lipids are barrier-forming lipids.-Sassa, T., Tadaki, M., Kiyonari, H., Kihara, A. Very long chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice. PMID- 29401593 TI - MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production. AB - Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet unclear mechanisms. We report that matrix metalloproteinase 14 (MMP14) expression/activity are increased in bones from mice with genetic constitutive activation (ca) of the PTH receptor 1 (PTH1R) in Ots (caPTH1ROt) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1ROt). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1ROt mice. MMP14 activity increases soluble receptor activator of NF-kappaBeta ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1ROt mice or induced by chronic PTH elevation and decreased bone resorption but allowed full stimulation of bone formation induced by PTH injections, thereby potentiating bone gain. Thus, MMP14 is a new member of the intricate gene network activated in Ots by PTH1R signaling that can be targeted to adjust the skeletal responses to PTH in favor of bone preservation.-Delgado-Calle, J., Hancock, B., Likine, E. F., Sato, A. Y., McAndrews, K., Sanudo, C., Bruzzaniti, A., Riancho, J. A., Tonra, J. R., Bellido, T. MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production. PMID- 29401595 TI - Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice. AB - Thy1 (CD90), a glycosylated, glycophosphatidylinositol-anchored membrane protein highly expressed by subsets of mesenchymal stem cells and fibroblasts, inhibits adipogenesis. The role of Thy1 on bone structure and function has been poorly studied and represents a major knowledge gap. Therefore, we analyzed the long bones of wild-type (WT) and Thy1 knockout (KO) mice with micro-computed tomography (micro-CT) and histomorphometry to compare changes in bone architecture and overall bone structure. micro-CT analysis of long bones revealed Thy1 KO and WT mice fed a high-fat diet demonstrated bone structural parameters at 4 mo that differed significantly between WT and KO mice. A significant reduction in trabecular bone volume was noted in Thy1 KO mice. The most prominent differences were observed in trabecular bone volume ratio and trabecular bone connectivity density. Consistent with micro-CT measurements, histomorphometric analysis also showed decreased bone volume in the obese Thy1 KO mice compared to obese WT mice. In vitro assays revealed that osteogenic conditions increased Thy1 expression during OB differentiation and absence of Thy1 attenuated osteoblastogenesis. Together, these findings support the concept that Thy1 serves as a major mechanistic link to regulate bone formation and negatively regulate adipogenesis.-Paine, A., Woeller, C. F., Zhang, H., Garcia-Hernandez, M. L., Huertas, N., Xing, L., Phipps, R. P., Ritchlin, C. T. Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice. PMID- 29401596 TI - Prostaglandin E2 suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: implications for treatment of Mycobacterium tuberculosis infection. AB - Prostaglandin (PG)E2 is an arachidonic acid-derived lipid mediator that plays an important role in inflammation and immunity. In this study, we demonstrate that PGE2 suppresses basal and 1,25-dihydroxy vitamin D3 (VD3)-induced expression of hCAP18/LL-37 via E prostanoid (EP)2 and EP4 receptors. In humans, VD3 up regulates vitamin D receptor (VDR) expression and promotes transcription of the cathelicidin hCAP18/LL-37 gene, whereas PGE2 counteracts this effect. We find that PGE2 induces the cAMP/PKA-signaling pathway and enhances the expression of the inhibitory transcription factor cAMP-responsive modulator/inducible cAMP early repressor, which prevents VDR expression and induction of hCAP18/LL-37 in human macrophages. The negative regulation by PGE2 was evident in M1- and M2 polarized human macrophages, although PGE2 displayed more profound inhibitory effects in M2 cells. PGE2 impaired VD3-induced expression of cathelicidin and concomitant activation of autophagy during Mycobacterium tuberculosis (Mtb) infection and facilitated intracellular Mtb growth in human macrophages. An EP4 agonist also significantly promoted Mtb survival in human macrophages. Our results indicate that PGE2 inhibits hCAP18/LL-37 expression, especially VD3 induced cathelicidin and autophagy, which may reduce host defense against Mtb. Accordingly, antagonists of EP4 may constitute a novel adjunctive therapy in Mtb infection.-Wan, M., Tang, X., Rekha, R. S., Muvva, S. S. V. J. R., Brighenti, S., Agerberth, B., Haeggstrom, J. Z. Prostaglandin E2 suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: implications for treatment of Mycobacterium tuberculosis infection. PMID- 29401597 TI - VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia. AB - High-density lipoproteins augment hypoxia-induced angiogenesis by inducing the key angiogenic vascular endothelial growth factor A (VEGFA) and total protein levels of its receptor 2 (VEGFR2). The activation/phosphorylation of VEGFR2 is critical for mediating downstream, angiogenic signaling events. This study aimed to determine whether reconstituted high-density lipoprotein (rHDL) activates VEGFR2 phosphorylation and the downstream signaling events and the importance of VEGFR2 in the proangiogenic effects of rHDL in hypoxia. In vitro, rHDL increased VEGFR2 activation and enhanced phosphorylation of downstream, angiogenic signaling proteins ERK1/2 and p38 MAPK in hypoxia. Incubation with a VEGFR2 neutralizing antibody attenuated rHDL-induced phosphorylation of VEGFR2, ERK1/2, p38 MAPK, and tubule formation. In a murine model of ischemia-driven neovascularization, rHDL infusions enhanced blood perfusion and augmented capillary and arteriolar density. Infusion of a VEGFR2-neutralizing antibody ablated those proangiogenic effects of rHDL. Circulating Sca1+/CXCR4+ angiogenic progenitor cell levels, important for neovascularization in response to ischemia, were higher in rHDL-infused mice 3 d after ischemic induction, but that did not occur in mice that also received the VEGFR2-neutralizing antibody. In summary, VEGFR2 has a key role in the proangiogenic effects of rHDL in hypoxia/ischemia. These findings have therapeutic implications for angiogenic diseases associated with an impaired response to tissue ischemia.-Cannizzo, C. M., Adonopulos, A. A., Solly, E. L., Ridiandries, A., Vanags, L. Z., Mulangala, J., Yuen, S. C. G., Tsatralis, T., Henriquez, R., Robertson, S., Nicholls, S. J., Di Bartolo, B. A., Ng, M. K. C., Lam, Y. T., Bursill, C. A., Tan, J. T. M. VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia. PMID- 29401598 TI - Muscarinic receptors 2 and 5 regulate bitter response of urethral brush cells via negative feedback. AB - We have recently identified a cholinergic chemosensory cell in the urethral epithelium, urethral brush cell (UBC), that, upon stimulation with bitter or bacterial substances, initiates a reflex detrusor activation. Here, we elucidated cholinergic mechanisms that modulate UBC responsiveness. We analyzed muscarinic acetylcholine receptor (M1-5 mAChR) expression by using RT-PCR in UBCs, recorded [Ca2+]i responses to a bitter stimulus in isolated UBCs of wild-type and mAChR deficient mice, and performed cystometry in all involved strains. The bitter response of UBCs was enhanced by global cholinergic and selective M2 inhibition, diminished by positive allosteric modulation of M5, and unaffected by M1, M3, and M4 mAChR inhibitors. This effect was not observed in M2 and M5 mAChR-deficient mice. In cystometry, M5 mAChR-deficient mice demonstrated signs of detrusor overactivity. In conclusion, M2 and M5 mAChRs attenuate the bitter response of UBC via a cholinergic negative autocrine feedback mechanism. Cystometry suggests that dysfunction, particularly of the M5 receptor, may lead to such symptoms as bladder overactivity.-Deckmann, K., Rafiq, A., Erdmann, C., Illig, C., Durschnabel, M., Wess, J., Weidner, W., Bschleipfer, T., Kummer, W. Muscarinic receptors 2 and 5 regulate bitter response of urethral brush cells via negative feedback. PMID- 29401599 TI - Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo. AB - Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biologic functions, the contribution of endothelial TXNIP has not been well defined. To investigate the endothelial function of TXNIP, we generated a TXNIP knockout mouse on the Cdh5-cre background (TXNIPfl/fl cdh5cre). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5cre mice were fed a high protein-low carbohydrate (HP-LC) diet for 3 mo to induce metabolic stress. We found that TXNIPfl/fl and TXNIPfl/fl cdh5cre mice on an HP-LC diet displayed impaired glucose tolerance and dyslipidemia concretizing the metabolic stress induced. We evaluated the impact of this metabolic stress on mice with reduced endothelial TXNIP expression with regard to arterial structure and function. TXNIPfl/fl cdh5cre mice on an HP-LC diet exhibited less endothelial dysfunction than littermate mice on an HP-LC diet. These mice were protected from decreased aortic medial cell content, impaired aortic distensibility, and increased plasminogen activator inhibitor 1 secretion. This protective effect came with lower oxidative stress and lower inflammation, with a reduced NLRP3 inflammasome expression, leading to a decrease in cleaved IL-1beta. We also show the major role of TXNIP in inflammation with a knockdown model, using a TXNIP-specific, small interfering RNA included in a lipoplex. These findings demonstrate a key role for endothelial TXNIP in arterial impairments induced by metabolic stress, making endothelial TXNIP a potential therapeutic target.-Bedarida, T., Domingues, A., Baron, S., Ferreira, C., Vibert, F., Cottart, C.-H., Paul, J.-L., Escriou, V., Bigey, P., Gaussem, P., Leguillier, T., Nivet-Antoine, V. Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo. PMID- 29401600 TI - High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans. AB - High-fat, low-carbohydrate (CHO) diets increase whole-body rates of fat oxidation and down-regulate CHO metabolism. We measured substrate utilization and skeletal muscle mitochondrial respiration to determine whether these adaptations are driven by high fat or low CHO availability. In a randomized crossover design, 8 male cyclists consumed 5 d of a high-CHO diet [>70% energy intake (EI)], followed by 5 d of either an isoenergetic high-fat (HFAT; >65% EI) or high-protein diet (HPRO; >65% EI) with CHO intake clamped at <20% EI. During the intervention, participants undertook daily exercise training. On d 6, participants consumed a high-CHO diet before performing 100 min of submaximal steady-state cycling plus an ~30-min time trial. After 5 d of HFAT, skeletal muscle mitochondrial respiration supported by octanoylcarnitine and pyruvate, as well as uncoupled respiration, was decreased at rest, and rates of whole-body fat oxidation were higher during exercise compared with HPRO. After 1 d of high-CHO diet intake, mitochondrial respiration returned to baseline values in HFAT, whereas rates of substrate oxidation returned toward baseline in both conditions. These findings demonstrate that high dietary fat intake, rather than low-CHO intake, contributes to reductions in mitochondrial respiration and increases in whole-body rates of fat oxidation after a consuming a high-fat, low-CHO diet.-Leckey, J. J., Hoffman, N. J., Parr, E. B., Devlin, B. L., Trewin, A. J., Stepto, N. K., Morton, J. P., Burke, L. M., Hawley, J. A. High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans. PMID- 29401602 TI - Nanoparticles induced by embedding self-assembling cassette into glucagon-like peptide 1 for improving in vivo stability. AB - The multiple physiologic characteristics of glucagon-like peptide 1 (GLP-1) make it a promising drug candidate for treating type 2 diabetes mellitus. However, the half-life of GLP-1 is short as a result of degradation by dipeptidyl peptidase IV and renal clearance. Stabilizing GLP-1 is therefore critical for its use in drug development. Self-assembling peptides are a class of peptides that undergo spontaneous assembly into ordered nanostructures. Recently, studies of self assembling peptides as drug carriers have increased because of their enhanced stability. In the present study, GLP-1 was modified to incorporate the structural characteristics of self-assembling peptides aiming to generate a self-assembling GLP-1 derivative. Receptor binding capacity and insulinotropic effects were measured to investigate the physiologic functions of GLP-1, along with morphologic approaches to observe supramolecular formation on self-assembly at the nano scale. Finally, blood glucose regulation and body weight were monitored after administration of selected derivatives. Our findings revealed that cadyglp1e and cadyglp1m both exhibited improved stability even though different nanoshapes were observed for these two self-assembling peptides. Both cadyglp1e and cadyglp1m retained glucoregulatory activity after insulin stimulation and were potent drug candidates for long-acting GLP-1 derivatives to treat type 2 diabetes mellitus. Our findings support the feasibility of introducing self assembly functions into peptides with poor stabilities, such as GLP-1.-Li, Y., Cui, T., Kong, X., Yi, X., Kong, D., Zhang, J., Liu, C., Gong, M. Nanoparticles induced by embedding self-assembling cassette into glucagon-like peptide 1 for improving in vivo stability. PMID- 29401601 TI - Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease. AB - Sphingosine-1-phosphate (S1P) is a biolipid involved in chronic inflammation in several inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic, genetic disorder associated with severe chronic inflammation and tissue damage. We evaluated the effect of elevated S1P in chronic inflammation and tissue damage in SCD and underlying mechanisms. First, we demonstrated that interfering with S1P receptor signaling by FTY720, a U.S. Food and Drug Administration-approved drug, significantly reduced systemic, local inflammation and tissue damage without antisickling effects. These findings led us to discover that S1P receptor activation leads to substantial elevated local and systemic IL-6 levels in SCD mice. Genetic deletion of IL-6 in SCD mice significantly reduced local and systemic inflammation, tissue damage, and kidney dysfunction. At the cellular level, we determined that elevated IL-6 is a key cytokine functioning downstream of elevated S1P, which contributes to increased S1P receptor 1 ( S1pr1) gene expression in the macrophages of several tissues in SCD mice. Mechanistically, we revealed that S1P-S1PR1 signaling reciprocally up-regulated IL-6 gene expression in primary mouse macrophages in a JAK2-dependent manner. Altogether, we revealed that elevated S1P, coupled with macrophage S1PR1 reciprocally inducing IL-6 expression, is a key signaling network functioning as a malicious, positive, feed forward loop to sustain inflammation and promote tissue damage in SCD. Our findings immediately highlight novel therapeutic possibilities.-Zhao, S., Adebiyi, M. G., Zhang, Y., Couturier, J. P., Fan, X., Zhang, H., Kellems, R. E., Lewis, D. E., Xia, Y. Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease. PMID- 29401603 TI - Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway. AB - Hepatitis B virus core protein (HBc) is expressed preferentially in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). HBc can function as an oncogene arising from its gene regulatory properties, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of HBc during HBV-associated hepatocellular tumorigenesis. HBc increased tumor formation of hepatoma cells. Moreover, expression of HBc specifically promoted proliferation of hepatoma cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal switch from inactive Src to the active form of the kinase by HBc. HBc-mediated sarcoma (Src) kinase activation was associated with down-regulation of C-terminal Src kinase (Csk). In addition, HBc enhances Src expression by activation of alternative Src 1A promoter in an Sp1 transcription factor-dependent manner. Proliferation induced by stable HBc expression was associated with increased G1-S cell cycle progression mediated by Src kinase activation. HBc-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that HBc promotes tumorigenesis of hepatoma cells by enhancing the expression of total Src and the active form of the kinase and subsequently activates Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.-Liu, W., Guo, T.-F., Jing, Z.-T., Yang, Z., Liu, L., Yang, Y.-P., Lin, X., Tong, Q.-Y. Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway. PMID- 29401605 TI - Tau ablation in mice leads to pancreatic beta cell dysfunction and glucose intolerance. AB - The microtubule-associated protein tau is highly expressed in pancreatic islets. Abnormally phosphorylated tau aggregates assemble into neurofibrillary tangles linked to Alzheimer's disease pathology and has also been found in islets of patients with type 2 diabetes. However, the significance of tau in islet function remains relatively unexplored. Therefore, we investigated the role of tau on beta cell function and glucose homeostasis using tau knockout (tauKO) mice. TauKO mice were hyperglycemic and glucose intolerant at an early age. Islet insulin content was reduced and proinsulin levels were significantly elevated in tauKO mice, resulting in impaired glucose-stimulated insulin secretion. Loss of tau also resulted in increased epididymal fat mass and leptin levels, reduced glucose production, and insulin resistance at later ages, leading to complete onset of diabetes. Transgenic expression of human tau in islets was unable to rescue those defects in glucose regulation, indicating structural and/or functional differences between mouse and human tau. Cumulatively, these results suggest an important role for tau in the proper maintenance of pancreatic beta cell function and glucose homeostasis.-Wijesekara, N., Goncalves, R. A., Ahrens, R., De Felice, F. G., Fraser, P. E. Tau ablation in mice leads to pancreatic beta cell dysfunction and glucose intolerance. PMID- 29401606 TI - Cysteine-rich protein 61 regulates adipocyte differentiation from mesenchymal stem cells through mammalian target of rapamycin complex 1 and canonical Wnt signaling. AB - Emerging evidence suggests that cysteine-rich protein 61 (CYR61) plays a role in the differentiation and development of chondrocytes, osteoblasts, and osteoclasts; however, little is known about its role in adipogenesis. The current study indicates that the expression level of Cyr61 was altered in primary cultured marrow stromal cells and the established mesenchymal cell line, C3H10T1/2, after adipogenic treatment. Overexpressing Cyr61 repressed C3H10T1/2 and primary marrow stromal cells to differentiate into mature adipocytes. Conversely, inhibition of endogenous Cyr61 induced C3H10T1/2 and primary marrow stromal cells to fully differentiate. Mechanism investigations reveal that knockdown of Cyr61 inhibited the nuclear translocation of beta-catenin and decreased nuclear protein levels of beta-catenin and transcription factor 7-like 2. Moreover, the silencing of Cyr61 increased protein levels of phosphorylated ribosomal protein S6 kinase B1, mammalian target of rapamycin, eukaryotic translation initiation factor 4E-binding protein 1, and ribosomal protein S6-the major components of mammalian target of rapamycin complex 1 (mTORC1) signaling-in C3H10T1/2 cells. Additional investigations demonstrated that treatment with rapamycin significantly attenuated adipocyte formation that was induced by Cyr61 small interfering RNA (siRNA) transfection. Moreover, Cyr61 siRNA also lost its ability to stimulate adipocyte formation under the background of beta-catenin overexpression. Taken together, our study provides evidence that CYR61 regulates adipocyte differentiation via multiple signaling pathways that involve at least the inactivation of mTORC1 signaling and the activation of canonical Wnt signaling.-Yang, Y., Qi, Q., Wang, Y., Shi, Y., Yang, W., Cen, Y., Zhu, E., Li, X., Chen, D., Wang, B. Cysteine-rich protein 61 regulates adipocyte differentiation from mesenchymal stem cells through mammalian target of rapamycin complex 1 and canonical Wnt signaling. PMID- 29401607 TI - MSCs promote the development and improve the function of neonatal porcine islet grafts. AB - Deficient insulin secretion caused by immaturity is the predominant disadvantage of neonatal porcine islets (NPIs) when they serve as a source for islet xenotransplantation. We hypothesize that the transplantation of NPIs with a combination of mesenchymal stem cells (MSCs) can accelerate NPI maturation and improve the engraftment and function of NPIs. After indirect coculturing with monkey MSCs over 21 d, insulin secretion and the expression of regulatory genes relevant to development were assessed in NPIs. NPIs alone or in combination with allogeneic MSCs were intraportally transplanted into diabetic monkeys. Glycemic control was monitored, and graft function was evaluated. Our results suggest that MSCs benefit both the development and proliferation of NPIs in the coexisting systems in vitro and in vivo. These effects are dependent on platelet-derived growth factor receptor-alpha and are relevant to the inhibition of downstream target Notch1 signaling and the activation of PI3K/protein kinase B signaling. He, S., Wang, C., Du, X., Chen, Y., Zhao, J., Tian, B., Lu, H., Zhang, Y., Liu, J., Yang, G., Li, L., Li, H., Cheng, J., Lu, Y. MSCs promote the development and improve the function of neonatal porcine islet grafts. PMID- 29401604 TI - Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation. AB - Apolipoprotein A-I (apoA-I) shares with other exchangeable apolipoproteins a high level of structural plasticity. In the lipid-free state, the apolipoprotein amphipathic alpha-helices interact intra- and intermolecularly, providing structural stabilization by self-association. We have reported that lipid-free apoA-I becomes amyloidogenic upon physiologically relevant (myeloperoxidase mediated) Met oxidation. In this study, we established that Met oxidation promotes amyloidogenesis by reducing the stability of apoA-I monomers and irreversibly disrupting self-association. The oxidized apoA-I monomers also exhibited increased cellular cholesterol release capacity and stronger association with macrophages, compared to nonoxidized apoA-I. Of physiologic relevance, preformed oxidized apoA-I amyloid fibrils induced amyloid formation in nonoxidized apoA-I. This process was enhanced when self-association of nonoxidized apoA-I was disrupted by thermal treatment. Solid state NMR analysis revealed that aggregates formed by seeded nonoxidized apoA-I were structurally similar to those formed by the oxidized protein, featuring a beta-structure-rich amyloid fold alongside alpha-helices retained from the native state. In atherosclerotic lesions, the conditions that promote apoA-I amyloid formation are readily available: myeloperoxidase, active oxygen species, low pH, and high concentration of lipid-free apoA-I. Our results suggest that even partial Met oxidation of apoA-I can nucleate amyloidogenesis, thus sequestering and inactivating otherwise antiatherogenic and HDL-forming apoA-I.-Witkowski, A., Chan, G. K. L., Boatz, J. C., Li, N. J., Inoue, A. P., Wong, J. C., van der Wel, P. C. A., Cavigiolio, G. Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation. PMID- 29401608 TI - SUMOylation regulates cytochrome P450 2E1 expression and activity in alcoholic liver disease. AB - Alcohol acts through numerous pathways leading to alcoholic liver disease (ALD). Cytochrome P450 (CYP2E1), an ethanol-inducible enzyme, metabolizes ethanol producing toxic reactive oxygen species (ROS) and is regulated at the posttranslational level. Small ubiquitin-like modifier (SUMO)ylation is a posttranslational modification that involves the addition of SUMOs, which modulate protein stability, activity, and localization. We demonstrated that ubiquitin-conjugation enzyme 9, the SUMO-conjugating enzyme, is induced in the livers of an intragastric ethanol mouse model. Our aim is to examine whether SUMOylation could regulate ethanol-induced CYP2E1 expression in ALD and to elucidate the molecular mechanism(s). CYP2E1 and UBC9 expression in vitro and in vivo was detected by real-time PCR and immunoblotting/immunostaining. SUMOylation was assayed by mass spectrometry and coimmunoprecipitation. Ubc9 expression was induced in ethanol-fed mouse livers, and silencing inhibited ethanol-mediated CYP2E1 microsomal retention and enzymatic activity. CYP2E1 SUMOylation was found to be induced by ethanol in vitro and in vivo. Ubc9 silencing prevents ethanol induced lipid accumulation and ROS production. UBC9 was highly expressed in human ALD livers. Finally, we found that lysine 410 is a key SUMOylated residue contributing to CYP2E1 protein stability and activity preventing CYP2E1 SUMOylation. Ethanol-mediated up-regulation of CYP2E1 via SUMOylation enhancing its protein stability and activity and may have important implications in ALD. Tomasi, M. L., Ramani, K., Ryoo, M., Cossu, C., Floris, A., Murray, B. J., Iglesias-Ara, A., Spissu, Y., Mavila, N. SUMOylation regulates cytochrome P450 2E1 expression and activity in alcoholic liver disease. PMID- 29401609 TI - MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes. AB - Blood-brain barrier (BBB) disruption caused by reperfusion injury after ischemic stroke is an intractable event conducive to further injury. Brain pericytes play a vital role in maintaining BBB integrity by interacting with other components of the BBB. In this study, we found that sphingosine-1-phosphate receptor (S1PR)2 expressed in pericytes was significantly up-regulated after ischemia in vivo and in vitro. By using a S1PR2 antagonist (JTE-013), we showed that S1PR2 plays a critical role in the induction of BBB permeability of transient middle cerebral artery occlusion (tMCAO) rats and the in vitro BBB model. Furthermore, we discovered that S1PR2 may decrease N-cadherin expression and increase pericyte migration via NF-kappaB p65 signal and found that S1PR2 could be regulated by miR 149-5p negatively, which was decreased in the ischemic boundary zone and cultured pericytes after ischemia. Overexpression of miR-149-5p in cultured pericytes substantially increased N-cadherin expression and decreased pericyte migration, which decreased BBB leakage in the in vitro model. Up-regulating miR-149-5p by intracerebroventricular injection of agomir-149-5p attenuated BBB permeability and improved the outcomes of tMCAO rats significantly. Thus, our data suggest that miR-149-5p may serve as a potential target for treatment of BBB disruption after ischemic stroke.-Wan, Y., Jin, H.-J., Zhu, Y.-Y., Fang, Z., Mao, L., He, Q., Xia, Y.-P., Li, M., Li, Y., Chen, X., Hu, B. MicroRNA-149-5p regulates blood brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes. PMID- 29401610 TI - An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells. AB - Vimentin is a cytoskeletal intermediate filament protein that is expressed in mesenchymal cells and cancer cells during the epithelial-mesenchymal transition. The goal of this study was to identify vimentin-targeting small molecules by using the Tocriscreen library of 1120 biochemically active compounds. We monitored vimentin filament reorganization and bundling in adrenal carcinoma SW13 vimentin-positive (SW13-vim+) cells via indirect immunofluorescence. The screen identified 18 pharmacologically diverse hits that included 2 statins-simvastatin and mevastatin. Simvastatin induced vimentin reorganization within 15-30 min and significant perinuclear bundling within 60 min (IC50 = 6.7 nM). Early filament reorganization coincided with increased vimentin solubility. Mevastatin produced similar effects at >1 uM, whereas the structurally related pravastatin and lovastatin did not affect vimentin. In vitro vimentin filament assembly assays revealed a direct targeting mechanism, as determined biochemically and by electron microscopy. In SW13-vim+ cells, simvastatin, but not pravastatin, reduced total cell numbers (IC50 = 48.1 nM) and promoted apoptosis after 24 h. In contrast, SW13-vim- cell viability was unaffected by simvastatin, unless vimentin was ectopically expressed. Simvastatin similarly targeted vimentin filaments and induced cell death in MDA-MB-231 (vim+), but lacked effect in MCF7 (vim-) breast cancer cells. In conclusion, this study identified vimentin as a direct molecular target that mediates simvastatin-induced cell death in 2 different cancer cell lines.-Trogden, K. P., Battaglia, R. A., Kabiraj, P., Madden, V. J., Herrmann, H., Snider, N. T. An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells. PMID- 29401611 TI - Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver. AB - Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups ( 54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver. PMID- 29401612 TI - Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation. AB - Phagocytosis of silicon dioxide (SiO2) into lung cells causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that are present within mammalian cells; however, researchers have not determined whether circRNAs are involved in the pathophysiologic process of silicosis. To elucidate the role of these RNAs in SiO2-induced inflammation in pulmonary macrophages, we investigated the upstream molecular mechanisms and functional effects of circRNAs on cell apoptosis, proliferation, and migration. Primary cultures of alveolar macrophages from healthy donors and from patients and the RAW264.7 macrophage cell line were used to explore the functions of circZC3H4 RNA in macrophage activation. The experimental results indicated the following: 1) SiO2 concomitantly increased circZC3H4 RNA expression and increased ZC3H4 protein levels; 2) circular ZC3H4 (circZC3H4) RNA and ZC3H4 protein participated in SiO2 induced macrophage activation; and 3) SiO2-activated macrophages promoted fibroblast proliferation and migration via the circZC3H4 RNA/ZC3H4 pathway. The up-regulation of the ZC3H4 protein was confirmed in tissue samples from patients with silicosis. Our study elucidates a link between SiO2-induced macrophage activation and the circZC3H4 RNA/ZC3H4 pathway, thereby providing novel insight into the potential use of ZC3H4 to develop novel therapeutic strategies for silicosis.-Yang, X., Wang, J., Zhou, Z., Jiang, R., Huang, J., Chen, L., Cao, Z., Chu, H., Han, B., Cheng, Y., Chao, J. Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation. PMID- 29401613 TI - Receptor-specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3. AB - Bombesin receptor subtype 3 (BRS-3) is a GPCR that is expressed in the CNS, peripheral tissues, and tumors. Our understanding of BRS-3's role in physiology and pathophysiology is limited because its natural ligand is unknown. In an attempt to identify this ligand, we screened toad skin ( Bufo bufo gargarizans Cantor) extracts and identified prostaglandins as putative ligands. In BRS-3 transfected human embryonic kidney (HEK) cells, we found that prostaglandins, with prostaglandin E2 (PGE2) being the most potent, fulfill the pharmacologic criteria of affinity, selectivity, and specificity to be considered as agonists to the BRS-3 receptor. However, PGE2 is unable to activate BRS-3 in different cellular environments. We speculated that EP receptors might be the cause of this cellular selectivity, and we found that EP3 is the receptor primarily responsible for the differential PGE2 effect. Consequently, we reconstituted the HEK environment in Chinese hamster ovary (CHO) cells and found that BRS-3 and EP3 interact to potentiate PGE2 signaling. This potentiating effect is receptor specific, and it occurs only when BRS-3 is paired to EP3. Our study represents an example of functional crosstalk between two distantly related GPCRs and may be of clinical importance for BRS-3-targeted therapies.-Zhang, Y., Liu, Y., Wu, L., Fan, C., Wang, Z., Zhang, X., Alachkar, A., Liang, X., Civelli, O. Receptor specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3. PMID- 29401614 TI - Depletion of microglia augments the dopaminergic neurotoxicity of MPTP. AB - The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson's disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons. Further, depletion of microglia augmented the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. Microglia depletion-induced aggravation of MPTP neurotoxicity was also seen in lymphocyte-deficient mice. In addition, the depletion of microglia did not affect the production of brain-derived neurotrophic factor, but it dramatically augmented the production of inflammatory mediators by astrocytes after MPTP treatment. Our findings suggest microglia play a protective role against MPTP-induced neuroinflammation and dopaminergic neurotoxicity.-Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F.-D., Ma, C., Liu, Q. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP. PMID- 29401615 TI - Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. AB - Patients with cystic fibrosis (CF) experience chronic or recurrent bacterial and fungal lung infections. Many patients with CF cannot effectively clear Aspergillus from their lungs. This may result in IgE sensitization and the development of allergic bronchopulmonary aspergillosis, or invasive infections, such as Aspergillus bronchitis. Lung disease in patients with CF is associated with neutrophil-dominated inflammation and elevated levels of the serine protease, neutrophil elastase (NE). Various C-type lectin-like receptors (CLRs), including Dectin-1 and Dectin-2, are involved in the immune response to Aspergillus. Here, we show that purified NE cleaves Dectin-1 in an isoform specific manner. Bronchoalveolar lavage fluid from patients with CF, which contains high NE activity, induces Dectin-1 cleavage. Similarly, filtrate from a protease-producing strain of Aspergillus fumigatus induces isoform-specific cleavage of Dectin-1. Dectin-1 knockout (KO) cells and NE-treated cells demonstrated reduced phagocytosis of zymosan, a fungal cell wall preparation. In addition, NE cleaves 2 other CLRs, Dectin-2 and Mincle, and fungal-induced cytokine production was reduced in Dectin-1 KO cells, Dectin-2 KO cells, and NE treated cells. Thus, Dectin-1 and Dectin-2 cleavage by NE and/or A. fumigatus derived proteases results in an aberrant antifungal immune response that likely contributes to disease pathology in patients with CF.-Griffiths, J. S., Thompson, A., Stott, M., Benny, A., Lewis, N. A., Taylor, P. R., Forton, J., Herrick, S., Orr, S. J., McGreal, E. P. Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. PMID- 29401617 TI - REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. AB - REV-ERBs (REV-ERBalpha and REV-ERBbeta) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBalpha level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBalpha knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBbeta knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-kappaB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. PMID- 29401616 TI - New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models. AB - No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration. Abca4-/-Rdh8-/- mice, an accelerated model of retinal degeneration, were exposed to intense light after prophylactic injections of one of these compounds. Imaging and functional assessments of the retina indicated that these compounds successfully protected photoreceptor cells from degeneration to maintain a full-visual-field response. Furthermore, these compounds demonstrated a strong safety profile in wild-type mice and did not compromise visual function or damage the retina, despite repeated administration. These results indicate that modulating inhibitory GABA signaling can offer prophylactic protection against light-induced retinal degeneration.-Schur, R. M., Gao, S., Yu, G., Chen, Y., Maeda, A., Palczewski, K., Lu, Z.-R. New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models. PMID- 29401618 TI - Regulation of IL-1 signaling through control of focal adhesion assembly. AB - IL-1 signaling is adhesion-restricted in many cell types, but the mechanism that drives it is not defined. We screened for proteins recruited to nascent adhesions in IL-1-treated human fibroblasts with tandem mass tag-mass spectrometry. We used fibronectin bead preparations to enrich 10 actin-associated proteins. There was a 1.2 times log 2-fold enrichment of actin capping protein (ACP) at 30 min after IL 1 stimulation. Knockdown (KD) of ACP by siRNA reduced IL-1-induced ERK activation(by 56%, matrix metalloproteinase-3 (MMP-3) expression by 48%, and MMP 9 expression by 62% (in all reductions, P < 0.01). Confocal or structured illumination microscopy showed that ACP was diffused throughout the cytosol but strongly accumulated at the ruffled border of spreading cells. ACP colocalized with nascent paxillin- and vinculin-containing adhesions at the ruffled border, but not with mature adhesions in the center. ACP KD promoted the formation of large, stable adhesions. Immunoprecipitation and proximity ligation analysis showed that ACP was associated with the IL-1 signal transduction proteins myeloid differentiation factor 88 (MyD88) and IL-1 receptor-associated kinase (IRAK) at the ruffled border of the leading edge. IL-1-induced phospho-ERK and MyD88 or IRAK colocalized at the leading edge. We concluded that ACP is required for recruitment and function of IL-1 signaling complexes in nascent adhesions at the leading edge of the cell.-Wang, Q., Delcorde, J., Tang, T., Downey, G. P., McCulloch, C. A. Regulation of IL-1 signaling through control of focal adhesion assembly. PMID- 29401619 TI - Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates. AB - Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice. Previous studies have reported that knocking out Asah1 or Asah2 failed to reduce plasma SPH and S1P levels in mice. In this study, we show that knocking out Acer1 or Acer3 also failed to reduce the blood levels of SPH or S1P in mice. In contrast, knocking out Acer2 from either whole-body or the hematopoietic lineage markedly decreased the blood levels of SPH and S1P in mice. Of interest, knocking out Acer2 from whole-body or the hematopoietic lineage also markedly decreased the levels of dihydrosphingosine (dhSPH) and dihydrosphingosine-1-phosphate (dhS1P) in blood. Taken together, these results suggest that ACER2 plays a key role in the maintenance of high plasma levels of sphingoid base-1-phosphates-S1P and dhS1P-by controlling the generation of sphingoid bases-SPH and dhSPH-in hematopoietic cells.-Li, F., Xu, R., Low, B. E., Lin, C.-L., Garcia-Barros, M., Schrandt, J., Mileva, I., Snider, A., Luo, C. K., Jiang, X.-C., Li, M.-S., Hannun, Y. A., Obeid, L. M., Wiles, M. V., Mao, C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates. PMID- 29401620 TI - FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury. AB - Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury. PMID- 29401621 TI - IL-10 suppresses TNF-alpha-induced expression of human aromatase gene in mammary adipose tissue. AB - White adipose tissue inflammation is linked with increased aromatase gene expression and estrogen production, a major risk factor for breast cancer in obese postmenopausal women. TNF-alpha, a proinflammatory cytokine, is a key driver of aromatase promoter I.4-mediated expression in adipose tissue. In this study, we have shown that IL-10, an anti-inflammatory cytokine, suppressed both TNF-alpha-stimulated human aromatase reporter-luciferase (hARO-Luc) expression in mouse bone marrow mesenchymal stromal cells and aromatase gene expression in human breast adipose stromal cells (ASCs). IL-10 blocked TNF-alpha-stimulated ERK1/2 activation in ASCs, suggesting an inhibitory effect through the MAPK signaling pathway. The links among obesity, IL-10, and aromatase were confirmed in ovariectomized (OVX) hARO-Luc mice, where increased adiposity was associated with upregulation of aromatase reporter activity and reduced IL-10 level in the mammary fat pad. OVX mice also exhibited changes in gut microbiota, similar to that in obese women, indicating altered immune function. In summary, our results suggest that increased adiposity, induced by the lack of ovarian hormones, results in enhanced expression of aromatase in mammary adipose tissue, mediated by reduction in local IL-10. These findings may bring new insights into the mechanisms involved in the development of postmenopausal breast cancer, as well as novel approaches for prevention.-Martinez-Chacon, G., Brown, K. A., Docanto, M. M., Kumar, H., Salminen, S., Saarinen, N., Makela, S. IL-10 suppresses TNF alpha-induced expression of human aromatase gene in mammary adipose tissue. PMID- 29401623 TI - Hydroxysteroid (17beta) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility. AB - The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17beta-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.-Hakkarainen, J., Zhang, F.-P., Jokela, H., Mayerhofer, A., Behr, R., Cisneros-Montalvo, S., Nurmio, M., Toppari, J., Ohlsson, C., Kotaja, N., Sipila, P., Poutanen, M. Hydroxysteroid (17beta) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility. PMID- 29401622 TI - Dynamic structure mediates halophilic adaptation of a DNA polymerase from the deep-sea brines of the Red Sea. AB - The deep-sea brines of the Red Sea are remote and unexplored environments characterized by high temperatures, anoxic water, and elevated concentrations of salt and heavy metals. This environment provides a rare system to study the interplay between halophilic and thermophilic adaptation in biologic macromolecules. The present article reports the first DNA polymerase with halophilic and thermophilic features. Biochemical and structural analysis by Raman and circular dichroism spectroscopy showed that the charge distribution on the protein's surface mediates the structural balance between stability for thermal adaptation and flexibility for counteracting the salt-induced rigid and nonfunctional hydrophobic packing. Salt bridge interactions via increased negative and positive charges contribute to structural stability. Salt tolerance, conversely, is mediated by a dynamic structure that becomes more fixed and functional with increasing salt concentration. We propose that repulsive forces among excess negative charges, in addition to a high percentage of negatively charged random coils, mediate this structural dynamism. This knowledge enabled us to engineer a halophilic version of Thermococcus kodakarensis DNA polymerase. Takahashi, M., Takahashi, E., Joudeh, L. I., Marini, M., Das, G., Elshenawy, M. M., Akal, A., Sakashita, K., Alam, I., Tehseen, M., Sobhy, M. A., Stingl, U., Merzaban, J. S., Di Fabrizio, E., Hamdan, S. M. Dynamic structure mediates halophilic adaptation of a DNA polymerase from the deep-sea brines of the Red Sea. PMID- 29401624 TI - Insulin and IGF1 receptors are essential for the development and steroidogenic function of adult Leydig cells. AB - The insulin family of growth factors (insulin, IGF1, and IGF2) are critical in sex determination, adrenal differentiation, and testicular function. Notably, the IGF system has been reported to mediate the proliferation of steroidogenic cells. However, the precise role and contribution of the membrane receptors mediating those effects, namely, insulin receptor (INSR) and type-I insulin-like growth factor receptor (IGF1R), have not, to our knowledge, been investigated. We show here that specific deletion of both Insr and Igf1r in steroidogenic cells in mice leads to severe alterations of adrenocortical and testicular development. Double mutant mice display drastic size reduction of both adrenocortex and testes, with impaired corticosterone, testosterone, and sperm production. Detailed developmental analysis of the testes revealed that fetal Leydig cell (LC) function is normal, but there is a failure of adult LC maturation and steroidogenic function associated with accumulation of progenitor LCs (PLCs). Cell-lineage tracing revealed PLC enrichment is secondary to Insr and Igf1r deletion in differentiated adult LCs, suggesting a feedback mechanism between cells at different steps of differentiation. Taken together, these data reveal the cell-autonomous and nonautonomous roles of the IGF system for proper development and maintenance of steroidogenic lineages.-Neirijnck, Y., Calvel, P., Kilcoyne, K. R., Kuhne, F., Stevant, I., Griffeth, R. J., Pitetti, J.-L., Andric, S. A., Hu, M.-C., Pralong, F., Smith, L. B., Nef, S. Insulin and IGF1 receptors are essential for the development and steroidogenic function of adult Leydig cells. PMID- 29401625 TI - Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. AB - Sepsis-leading to septic shock-is the leading cause of death in intensive care units. The systemic inflammatory response to infection, which is initiated by activated myeloid cells, plays a key role in the lethal outcome. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory mediator, released by myeloid cells, that underlies a common genetic susceptibility to different infections and septic shock. Accordingly, strategies that are aimed at inhibiting the action of MIF have therapeutic potential. Here, we report the isolation and characterization of tailorable, small, affinity-matured nanobodies (Nbs; single-domain antigen-binding fragments derived from camelid heavy-chain Abs) directed against MIF. Of importance, these bioengineered Nbs bind both human and mouse MIFs with nanomolar affinity. NbE5 and NbE10 inhibit key MIF functions that can exacerbate septic shock, such as the tautomerase activity of MIF (by blocking catalytic pocket residues that are critical for MIF's conformation and receptor binding), the TNF-inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half-life extended construct (NbE10-NbAlb8-NbE10), attenuated lethality in murine endotoxemia when administered via single injection, either prophylactically or therapeutically. Hence, Nbs, with their structural and pharmacologic advantages over currently available inhibitors, may be an effective, novel approach to interfere with the action of MIF in septic shock and other conditions of inflammatory end-organ damage.-Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.-J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. PMID- 29401626 TI - Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet. AB - The breast cancer type 1 susceptibility protein (Brca1) is a regulator of DNA repair in mammary gland cells; however, recent cell culture evidence suggests that Brca1 influences other processes, including those in nonmammary cells. In this study, we sought to determine whether Brca1 is necessary for metabolic regulation of skeletal muscle using a novel in vivo mouse model. We developed an inducible skeletal muscle-specific Brca1knockout (BRCA1KOsmi) model to test whether Brca1 expression is necessary for maintenance of metabolic function of skeletal muscle when exposed to a high-fat diet (HFD). Our data demonstrated that deletion of Brca1 prevented HFD-induced alterations in glucose and insulin tolerance. Irrespective of diet, BRCA1KOsmi mice exhibited significantly lower ADP-stimulated complex I mitochondrial respiration rates compared to age-matched wild-type (WT) mice. The data show that Brca1 has the ability to localize to the mitochondria in skeletal muscle and that BRCA1KOsmi mice exhibit higher whole body CO2 production, respiratory exchange ratio, and energy expenditure, compared with the WT mice. Our results demonstrate that loss of Brca1 in skeletal muscle leads to dysregulated metabolic function, characterized by decreased mitochondrial respiration. Thus, any condition that results in loss of Brca1 function could induce metabolic imbalance in skeletal muscle.-Jackson, K. C., Tarpey, M. D., Valencia, A. P., Inigo, M. R., Pratt, S. J., Patteson, D. J., McClung, J. M., Lovering, R. M., Thomson, D. M., Spangenburg, E. E. Induced Cre mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet. PMID- 29401627 TI - Molecular basis for intestinal mucin recognition by galectin-3 and C-type lectins. AB - Intestinal mucins trigger immune responses upon recognition by dendritic cells via protein-carbohydrate interactions. We used a combination of structural, biochemical, biophysical, and cell-based approaches to decipher the specificity of the interaction between mucin glycans and mammalian lectins expressed in the gut, including galectin (Gal)-3 and C-type lectin receptors. Gal-3 differentially recognized intestinal mucins with different O-glycosylation profiles, as determined by mass spectrometry (MS). Modification of mucin glycosylation, via chemical treatment leading to a loss of terminal glycans, promoted the interaction of Gal-3 to poly- N-acetyllactosamine. Specific interactions were observed between mucins and mouse dendritic cell-associated lectin (mDectin)-2 or specific intercellular adhesion molecule-grabbing nonintegrin-related-1 (SIGN R1), but not mDectin-1, using a cell-reporter assay, as also confirmed by atomic force spectroscopy. We characterized the N-glycosylation profile of mouse colonic mucin (Muc)-2 by MS and showed that the interaction with mDectin-2 was mediated by high-mannose N-glycans. Furthermore, we observed Gal-3 binding to the 3 C-type lectins by force spectroscopy. We showed that mDectin-1, mDectin-2, and SIGN-R1 are decorated by N-glycan structures that can be recognized by the carbohydrate recognition domain of Gal-3. These findings provide a structural basis for the role of mucins in mediating immune responses and new insights into the structure and function of major mammalian lectins.-Leclaire, C., Lecointe, K., Gunning, P. A., Tribolo, S., Kavanaugh, D. W., Wittmann, A., Latousakis, D., MacKenzie, D. A., Kawasaki, N., Juge, N. Molecular basis for intestinal mucin recognition by galectin-3 and C-type lectins. PMID- 29401628 TI - Calmodulin regulates a TRP channel (ADF1) and phospholipase C (PLC) to mediate elevation of cytosolic calcium during acidic stress that induces deflagellation in Chlamydomonas. AB - Calcium has been implicated in the motility, assembly, disassembly, and deflagellation of the eukaryotic flagellum or cilium (exchangeable terms). Calmodulin (CaM) is known to be critical for flagellar motility; however, it is unknown whether and how CaM is involved in other flagella-related activities. We have studied CaM in Chlamydomonas, a widely used organism for ciliary studies. CaM is present in the cell body and the flagellum, with enrichment in the basal body region. Loss of CaM causes shortening of the nucleus basal body connector and impairs flagellar motility and assembly but not flagellar disassembly. Moreover, the cam mutant is defective in pH shock-induced deflagellation. The mutant deflagellates, however, upon mechanical shearing and treatment with mastoparan or detergent undergo permeabilization in the presence of calcium, indicating the cam mutant is defective in elevations of cytosolic calcium induced by pH shock, rather than by the deflagellation machinery. Indeed, the cam mutant fails to produce inositol 1,4,5-trisphosphate. Biochemical and genetic analysis showed that CaM does not directly activate PLC. Furthermore, CaM interacts with ADF1, a transient receptor channel that functions in acid-induced calcium entry. Thus, CaM is a critical regulator of flagellar activities especially those involved in modulating calcium homeostasis during acidic stress.-Wu, Q., Gao, K., Zheng, S., Zhu, X., Liang, Y., Pan, J. Calmodulin regulates a TRP channel (ADF1) and phospholipase C (PLC) to mediate elevation of cytosolic calcium during acidic stress that induces deflagellation in Chlamydomonas. PMID- 29401629 TI - Resistance training prevents muscle fibrosis and atrophy via down-regulation of C1q-induced Wnt signaling in senescent mice. AB - Increased complement component 1q (C1q) secretion with aging leads to muscle fibrosis and atrophy whereas resistance training attenuates circulating C1q levels. This study aimed to clarify whether resistance exercise-induced reduction of C1q secretion contributes to the inhibition of fibrosis and atrophy in aged muscles. Young (13-wk-old) and aged (38-wk-old) senescence-accelerated mouse prone 1 mice were randomly assigned to one of 4 groups: a young or aged sedentary control group, or a young or aged resistance training (climbing a ladder 3 d/wk for 12 wk) group. We found that resistance training ameliorated muscle fibrosis and atrophy in aged mice, concomitant with decreased circulating and muscle C1q levels and attenuated activation of muscle Wnt signaling (glycogen synthase kinase beta/beta-catenin), including beta-catenin in satellite (Pax7+/DAPI+) and fibroblast (vimentin+/DAPI+) cells. Furthermore, during muscle regeneration after mice were injured by cardiotoxin injection, we observed a reduction in circulating C1q levels, the inhibition of muscle fibrosis and repair, and decreased in the activation of muscle cytoplasmic and nuclear beta-catenin in aged mice from the resistance training group, but these effects were cancelled by a single preadministration of exogenous recombinant C1q. In addition, resistance training attenuated aging-related muscle loss concomitant with decreased expression of both muscle ring-finger protein 1 and muscle atrophy F-box in the muscle. Thus, resistance training-induced changes in circulating C1q levels may contribute to the prevention of muscle fibrosis and atrophy via muscle Wnt signaling in senescent mice.-Horii, N., Uchida, M., Hasegawa, N., Fujie, S., Oyanagi, E., Yano, H., Hashimoto, T., Iemitsu, M. Resistance training prevents muscle fibrosis and atrophy via down-regulation of C1q-induced Wnt signaling in senescent mice. PMID- 29401630 TI - Tetrandrine attenuates the bone erosion in collagen-induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase. AB - Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro, tetrandrine inhibited receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes. In bone marrow-derived macrophages and RAW264.7 cells, tetrandrine inhibited RANKL induced translocation of NF-kappaB-p65 and nuclear factor of activated T cell 1 (NFATc1) through suppressing spleen tyrosine kinase (Syk)-Bruton's tyrosine kinase-PLCgamma2-Ca2+ signaling. Of interest, tetrandrine did not affect the phosphorylation of immunoreceptor tyrosine-based activation motifs, the conventional upstream of Syk, but it inhibited the activity of Syk by enhancing its ubiquitination and degradation. The anti-osteoclastogenesis effect of tetrandrine nearly disappeared when it was used in combination with the Syk inhibitor piceatannol or in constitutively activated Syk-overexpressing cells. Taken together, tetrandrine attenuated CIA-induced bone destruction by inhibiting osteoclastogenesis through hindering the translocation of NF-kappaB-p65 and NFATc1 via reducing the activation of Syk.-Jia, Y., Miao, Y., Yue, M., Shu, M., Wei, Z., Dai, Y. Tetrandrine attenuates the bone erosion in collagen-induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase. PMID- 29401632 TI - Impaired prolactin actions mediate altered offspring metabolism induced by maternal high-fat feeding during lactation. AB - Maternal diet during lactation affects offspring metabolic health throughout life. Prolactin (PRL) is present in high quantities in maternal milk; however, the effects of milk PRL on the offspring remain poorly characterized. In this study, we evaluated whether feeding a high-fat diet (HFD) to rats during lactation alters PRL, both in the mother's serum and in milk, and whether this factor contributes to HFD-induced metabolic dysfunction in the offspring. Maternal HFD resulted in decreased PRL levels in milk (but not in serum), reduced mammary gland (MG) PRL receptor expression, and altered MG structure and function. Offspring from HFD-fed dams had increased body weight and adiposity, and developed fatty liver, hyperinsulinemia, and insulin resistance at weaning. Increasing PRL levels in the HFD-fed mothers by subcutaneous osmotic minipumps releasing PRL normalized MG function and PRL levels in milk. Moreover, PRL treatment in HFD-fed mothers, or directly in their pups via oral PRL administration, increased liver STAT5 phosphorylation, reduced visceral adiposity, ameliorated fatty liver, and improved insulin sensitivity in offspring. Our results show that HFD impairs PRL actions during lactation to negatively affect MG physiology and directly impair offspring metabolism.-De los Rios, E. A., Ruiz-Herrera, X., Tinoco-Pantoja, V., Lopez-Barrera, F., Martinez de la Escalera, G., Clapp, C., Macotela, Y. Impaired prolactin actions mediate altered offspring metabolism induced by maternal high-fat feeding during lactation. PMID- 29401631 TI - Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. AB - Obesity and diabetes are major challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-term adherence to this diet limits its translational potential. In this study, we develop a short-term methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growth factor (Fgf)-21-uncoupling protein (Ucp)-1 axis only in males. Methionine is an agonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects of MD. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of obesity and type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. PMID- 29401633 TI - Hydroxysteroid (17beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice. AB - Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13 knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial beta-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikela, H., Sobolewski, C., Portius, D., Maki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice. PMID- 29401634 TI - Formaldehyde induces diabetes-associated cognitive impairments. AB - Patients with type 2 diabetes mellitus (T2DM) often develop cognitive impairments and have an increased risk of developing Alzheimer's disease. Hyperglycemia is a major characteristic of T2DM, but how elevated glucose levels lead to cognitive decline remains elusive. Here, we report that patients with T2DM and mutations in the formaldehyde (FA)-degrading enzyme aldehyde dehydrogenase 2 ( ALDH2) gene had higher levels of FA and more severe dementia. Injection of FA induced hyperglycemia and cognitive deficits in rats. Ablation of gene expression of ALDH2, the main enzyme to oxidize FA, resulted in abnormally high levels of hippocampal FA, leading to hyperglycemia and cognitive impairments as well as potentiating streptozotocin-induced diabetes development in ALDH2 knockout mice. We found that FA interacts with insulin to form FA-insulin adducts, and these FA insulin adducts caused insulin deficiency, contributing to memory decline in diabetic rodent models. Reduction of FA by transgenic overexpression of human ALDH2 attenuates hyperglycemia and alleviates cognitive deficits in diabetic mouse models. These findings suggest that excess FA plays a critical role in mediating diabetes-related dementia. Targeting FA and its metabolizing enzyme ALDH2 may be a valid approach for preventing and treating dementia in diabetes mellitus.-Tan, T., Zhang, Y., Luo, W., Lv, J., Han, C., Hamlin, J. N. R., Luo, H., Li, H., Wan, Y., Yang, X., Song, W., Tong, Z. Formaldehyde induces diabetes associated cognitive impairments. PMID- 29401635 TI - Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils. AB - Amyloid fibrils are filamentous protein aggregates associated with the pathogenesis of a wide variety of human diseases. The formation of such aggregates typically follows nucleation-dependent kinetics, wherein the assembly and structural conversion of amyloidogenic proteins into oligomeric aggregates (nuclei) is the rate-limiting step of the overall reaction. In this study, we sought to gain structural insights into the oligomeric nuclei of the human prion protein (PrP) by preparing a series of deletion mutants lacking 14-44 of the C terminal 107 residues of PrP and examined the kinetics and thermodynamics of these mutants in amyloid formation. An analysis of the experimental data using the concepts of the Phi-value analysis indicated that the helix 2 region (residues 168-196) acquires an amyloid-like beta-sheet during nucleation, whereas the other regions preserves a relatively disordered structure in the nuclei. This finding suggests that the helix 2 region serves as the nucleation site for the assembly of amyloid fibrils.-Honda, R., Kuwata, K. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils. PMID- 29401636 TI - Analysis of Flow Cytometric Fluorescence Lifetime with Time-Delay Estimation of Pulse Signals. AB - The measurement of fluorescence lifetimes emerged in flow cytometry because it is not impacted by the non-linearity, which occurs in fluorescence intensity measurements. However, this significantly increases the cost and complexity of a traditional flow cytometer. This work reports a simple method of fluorescence lifetime measurement of a flow cytometer based on the cytometric fluorescence pulse time-delay estimation and hardware time-delay calibration. The modified chirp Z-transform (MCZT) algorithm, combined with the algorithm of fine interpolation of correlation peak (FICP), is applied to improve the temporal resolution of the cross-correlation function of the scattering and fluorescence signals, which in turn improves the time-delay estimation accuracy. The estimation accuracy is verified by Gauss fitting. Cells that were labeled simultaneously with three-color reagents are measured; the statistical results of 5000 cells are compared with reference values and are verified with the pulse width variation. The results show the potential of fluorescence lifetime measurements in the traditional flow cytometer. PMID- 29401637 TI - Speed Bump Detection Using Accelerometric Features: A Genetic Algorithm Approach. AB - Among the current challenges of the Smart City, traffic management and maintenance are of utmost importance. Road surface monitoring is currently performed by humans, but the road surface condition is one of the main indicators of road quality, and it may drastically affect fuel consumption and the safety of both drivers and pedestrians. Abnormalities in the road, such as manholes and potholes, can cause accidents when not identified by the drivers. Furthermore, human-induced abnormalities, such as speed bumps, could also cause accidents. In addition, while said obstacles ought to be signalized according to specific road regulation, they are not always correctly labeled. Therefore, we developed a novel method for the detection of road abnormalities (i.e., speed bumps). This method makes use of a gyro, an accelerometer, and a GPS sensor mounted in a car. After having the vehicle cruise through several streets, data is retrieved from the sensors. Then, using a cross-validation strategy, a genetic algorithm is used to find a logistic model that accurately detects road abnormalities. The proposed model had an accuracy of 0.9714 in a blind evaluation, with a false positive rate smaller than 0.018, and an area under the receiver operating characteristic curve of 0.9784. This methodology has the potential to detect speed bumps in quasi real time conditions, and can be used to construct a real-time surface monitoring system. PMID- 29401638 TI - Candidacidal Activity of a Novel Killer Toxin from Wickerhamomyces anomalus against Fluconazole-Susceptible and -Resistant Strains. AB - The isolation and characterization from the sand fly Phlebotomus perniciosus of a Wickerhamomyces anomalus yeast strain (Wa1F1) displaying the killer phenotype was recently reported. In the present work, the killer toxin (KT) produced by Wa1F1 was purified and characterized, and its antimicrobial activity in vitro was investigated against fluconazole- susceptible and -resistant clinical isolates and laboratory strains of Candida albicans and C. glabrata displaying known mutations. Wa1F1-KT showed a differential killing ability against different mutant strains of the same species. The results may be useful for the design of therapeutic molecules based on Wa1F1-KT and the study of yeast resistance mechanisms. PMID- 29401639 TI - Analysis of Lutein, Zeaxanthin, and Meso-Zeaxanthin in the Organs of Carotenoid Supplemented Chickens. AB - The macular carotenoids (i.e., lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ)) exhibit anti-inflammatory, antioxidant and optical properties that are believed to support human health and function. Studying the accumulation and distribution of these nutrients in tissues and organs, in addition to the eye, is an important step in understanding how these nutrients might support global human function and health (e.g., heart and brain). Chicken is an appropriate animal model with which to study the accumulation of these carotenoids in organs, as the relevant transport molecules and carotenoid binding proteins for L, Z and MZ are present in both humans and chickens. In this experiment, a sample of 3 chickens that were supplemented with L and MZ diacetate (active group) and a sample of 3 chickens that received a standard diet (control group) were analysed. Both groups were analysed for L, Z and MZ concentrations in the brain, eyes, heart, lung, duodenum/pancreas, jejunum/ileum, kidney and breast tissue. L, Z and MZ were identified in all the organs/tissues analysed from the active group. L and Z were identified in all of the organs/tissues analysed from the control group; while, MZ was identified in the eyes of these animals only. The discovery that MZ is accumulated in the tissues and organs of chickens supplemented with this carotenoid is important, given that it is known that a combination of L, Z and MZ exhibits superior antioxidant capacity when compared to any of these carotenoids in isolation. PMID- 29401640 TI - Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site. AB - DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors). NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA protein complex. In the present study, we used molecular dynamics (MD) simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B), whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total), screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase. PMID- 29401641 TI - Recent Advances in Detecting Mitochondrial DNA Heteroplasmic Variations. AB - The co-existence of wild-type and mutated mitochondrial DNA (mtDNA) molecules termed heteroplasmy becomes a research hot point of mitochondria. In this review, we listed several methods of mtDNA heteroplasmy research, including the enrichment of mtDNA and the way of calling heteroplasmic variations. At the present, while calling the novel ultra-low level heteroplasmy, high-throughput sequencing method is dominant while the detection limit of recorded mutations is accurate to 0.01% using the other quantitative approaches. In the future, the studies of mtDNA heteroplasmy may pay more attention to the single-cell level and focus on the linkage of mutations. PMID- 29401642 TI - Electrochemical Immunoassay Using Open Circuit Potential Detection Labeled by Platinum Nanoparticles. AB - In this work, a simple electrochemical immunoassay based on platinum nanoparticles (PtNPs) using open circuit potential (OCP) detection was developed. The detection of human chorionic gonadotropin hormone (hCG) as a model analyte, was demonstrated by direct electrical detection of PtNPs in hydrazine solution using OCP measurement without any application of either potential or current to the system. Disposable screen-printed carbon electrodes (SPCEs) were utilized for the development of our immunosensor, which required a sample volume as small as 2 MUL. After preparation of a sandwich-type immunosystem, hydrazine solution was dropped on the electrode's surface, which was followed immediately by electrical detection using OCP. The change of the OCP signal originated from electrocatalytic oxidation of the hydrazine on PtNPs. Under the optimal conditions of a pH of 6.0 and a hydrazine concentration of 1 mM, a detection limit of 0.28 ng mL-1 and a linearity of 0-10 ng mL-1 were obtained. The PtNP based OCP method is a simpler electrochemical detection procedure than those obtained from other electrochemical methods and has an acceptable sensitivity and reproducibility. The simplicity of the detection procedure and the cost effectiveness of the disposable SPCE illustrate the attractive benefits of this sensor. Moreover, it could be applied to a simplified and miniaturized diagnostic system with minimal user manipulation. PMID- 29401644 TI - The Biological Properties and Potential Interacting Proteins of d-Alanyl-d alanine Ligase A from Mycobacterium tuberculosis. AB - (1) Background: d-alanine-d-alanine ligase (DdlA), an effective target for drug development to combat against Mycobacterium tuberculosis (Mtb), which threatens human health globally, supplies a substrate of d-alanyl-d-alanine for peptidoglycan crosslinking by catalyzing the dimerization of two d-alanines. To obtain a better understanding of DdlA profiles and develop a colorimetric assay for high-throughput inhibitor screening, we focused on explicating and characterizing Tb-DdlA. (2) Methods and Results: Rv2981c (ddlA) was expressed in Escherichia coli, and the purified Tb-DdlA was identified using (anti) polyhistidine antibody followed by DdlA activity confirmation by measuring the released orthophosphate via colorimetric assay and the yielded d-alanyl-d-alanine through high performance thin layer chromatography (HP-TLC). The kinetic assays on Tb-DdlA indicated that Tb-DdlA exhibited a higher affinity to ATP (KmATP: 50.327 +/- 4.652 MUmol/L) than alanine (KmAla: 1.011 +/- 0.094 mmol/L). A colorimetric assay for Tb-DdlA activity was developed for high-throughput screening of DdlA inhibitors in this study. In addition, we presented an analysis on Tb-DdlA interaction partners by pull-down assay and MS/MS. Eight putative interaction partners of Tb-DdlA were identified. (3) Conclusions: Our dataset provided a valuable resource for exploring Tb-DdlA biology, and developed an easy colorimetric assay for screening of Tb-DdlA inhibitors. PMID- 29401643 TI - Review of Non-Respiratory, Non-Cancer Physical Health Conditions from Exposure to the World Trade Center Disaster. AB - After the World Trade Center attacks on 11 September 2001 (9/11), multiple cohorts were developed to monitor the health outcomes of exposure. Respiratory and cancer effects have been covered at length. This current study sought to review the literature on other physical conditions associated with 9/11-exposure. Researchers searched seven databases for literature published in English from 2002 to October 2017, coded, and included articles for health condition outcome, population, 9/11-exposures, and comorbidity. Of the 322 titles and abstracts screened, 30 studies met inclusion criteria, and of these, 28 were from three cohorts: the World Trade Center Health Registry, Fire Department of New York, and World Trade Center Health Consortium. Most studies focused on rescue and recovery workers. While many of the findings were consistent across different populations and supported by objective measures, some of the less studied conditions need additional research to substantiate current findings. In the 16 years after 9/11, longitudinal cohorts have been essential in investigating the health consequences of 9/11-exposure. Longitudinal studies will be vital in furthering our understanding of these emerging conditions, as well as treatment effectiveness. PMID- 29401646 TI - SNDR Limits of Oscillator-Based Sensor Readout Circuits. AB - This paper analyzes the influence of phase noise and distortion on the performance of oscillator-based sensor data acquisition systems. Circuit noise inherent to the oscillator circuit manifests as phase noise and limits the SNR. Moreover, oscillator nonlinearity generates distortion for large input signals. Phase noise analysis of oscillators is well known in the literature, but the relationship between phase noise and the SNR of an oscillator-based sensor is not straightforward. This paper proposes a model to estimate the influence of phase noise in the performance of an oscillator-based system by reflecting the phase noise to the oscillator input. The proposed model is based on periodic steady state analysis tools to predict the SNR of the oscillator. The accuracy of this model has been validated by both simulation and experiment in a 130 nm CMOS prototype. We also propose a method to estimate the SNDR and the dynamic range of an oscillator-based readout circuit that improves by more than one order of magnitude the simulation time compared to standard time domain simulations. This speed up enables the optimization and verification of this kind of systems with iterative algorithms. PMID- 29401645 TI - The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice. AB - The prebiotic inulin has proven effective at lowering inflammation and plasma lipid levels. As atherosclerosis is provoked by both inflammation and hyperlipidemia, we aimed to determine the effect of inulin supplementation on atherosclerosis development in hypercholesterolemic APOE*3-Leiden (E3L) mice. Male E3L mice were fed a high-cholesterol (1%) diet, supplemented with or without 10% inulin for 5 weeks. At week 3, a non-constrictive cuff was placed around the right femoral artery to induce accelerated atherosclerosis. At week 5, vascular pathology was determined by lesion thickness, vascular remodeling, and lesion composition. Throughout the study, plasma lipids were measured and in week 5, blood monocyte subtypes were determined using flow cytometry analysis. In contrast to our hypothesis, inulin exacerbated atherosclerosis development, characterized by increased lesion formation and outward vascular remodeling. The lesions showed increased number of macrophages, smooth muscle cells, and collagen content. No effects on blood monocyte composition were found. Inulin significantly increased plasma total cholesterol levels and total cholesterol exposure. In conclusion, inulin aggravated accelerated atherosclerosis development in hypercholesterolemic E3L mice, accompanied by adverse lesion composition and outward remodeling. This process was not accompanied by differences in blood monocyte composition, suggesting that the aggravated atherosclerosis development was driven by increased plasma cholesterol. PMID- 29401647 TI - Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features. AB - We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC. PMID- 29401648 TI - Chitosan Loaded into a Hydrogel Delivery System as a Strategy to Treat Vaginal Co Infection. AB - Polymeric hydrogels are common dosage forms designed for the topical administration of antimicrobial drugs to treat vaginal infections. One of the major advantages of using chitosan in these formulations is related to the intrinsic and broad antimicrobial activity exerted on bacteria and fungi by this natural polymer. Most vaginal yeast infections are caused by the pathogenic fungus Candida albicans. However, despite the anti-Candida activity towards and strains susceptibility to low molecular weight chitosan being documented, no information is available regarding the antimicrobial efficacy of mixed hydrogels in which chitosan is dispersed in a polymeric matrix. Therefore, the aim of the study is to evaluate the anti-Candida activity against eight different albicans and non-albicans strains of a mixed hydroxypropyl methylcellulose (HPMC)/chitosan hydrogel. Importantly, chitosan was dispersed in HPMC matrix either assembled in nanoparticles or in a monomolecular state to eventually correlate any variation in terms of rheological and mucoadhesive properties, as well as anti-Candida activity, with the chitosan form. Hydrogels containing 1% w/w chitosan, either as free polymer chain or assembled in nanoparticles, showed an improved mucoadhesiveness and an anti-Candida effect against all tested albicans and non albicans strains. Overall, the results demonstrate the feasibility of preparing HPMC/CS mixed hydrogels intended for the prevention and treatment of Candida infections after vaginal administration. PMID- 29401649 TI - Distributed Algorithm for Voronoi Partition of Wireless Sensor Networks with a Limited Sensing Range. AB - For Wireless Sensor Networks (WSNs), the Voronoi partition of a region is a challenging problem owing to the limited sensing ability of each sensor and the distributed organization of the network. In this paper, an algorithm is proposed for each sensor having a limited sensing range to compute its limited Voronoi cell autonomously, so that the limited Voronoi partition of the entire WSN is generated in a distributed manner. Inspired by Graham's Scan (GS) algorithm used to compute the convex hull of a point set, the limited Voronoi cell of each sensor is obtained by sequentially scanning two consecutive bisectors between the sensor and its neighbors. The proposed algorithm called the Boundary Scan (BS) algorithm has a lower computational complexity than the existing Range Constrained Voronoi Cell (RCVC) algorithm and reaches the lower bound of the computational complexity of the algorithms used to solve the problem of this kind. Moreover, it also improves the time efficiency of a key step in the Adjust Sensing-Radius (ASR) algorithm used to compute the exact Voronoi cell. Extensive numerical simulations are performed to demonstrate the correctness and effectiveness of the BS algorithm. The distributed realization of the BS combined with a localization algorithm in WSNs is used to justify the WSN nature of the proposed algorithm. PMID- 29401651 TI - Visual Estimation of Bacterial Growth Level in Microfluidic Culture Systems. AB - Microfluidic devices are an emerging platform for a variety of experiments involving bacterial cell culture, and has advantages including cost and convenience. One inevitable step during bacterial cell culture is the measurement of cell concentration in the channel. The optical density measurement technique is generally used for bacterial growth estimation, but it is not applicable to microfluidic devices due to the small sample volumes in microfluidics. Alternately, cell counting or colony-forming unit methods may be applied, but these do not work in situ; nor do these methods show measurement results immediately. To this end, we present a new vision-based method to estimate the growth level of the bacteria in microfluidic channels. We use Fast Fourier transform (FFT) to detect the frequency level change of the microscopic image, focusing on the fact that the microscopic image becomes rough as the number of cells in the field of view increases, adding high frequencies to the spectrum of the image. Two types of microfluidic devices are used to culture bacteria in liquid and agar gel medium, and time-lapsed images are captured. The images obtained are analyzed using FFT, resulting in an increase in high-frequency noise proportional to the time passed. Furthermore, we apply the developed method in the microfluidic antibiotics susceptibility test by recognizing the regional concentration change of the bacteria that are cultured in the antibiotics gradient. Finally, a deep learning-based data regression is performed on the data obtained by the proposed vision-based method for robust reporting of data. PMID- 29401650 TI - The Role of the Japanese Traditional Diet in Healthy and Sustainable Dietary Patterns around the World. AB - As incomes steadily increase globally, traditional diets have been displaced by diets that are usually animal-based with a high content of "empty calories" or refined sugars, refined fats, and alcohol. Dietary transition coupled with the expansion of urbanization and lower physical activity have been linked to the global growth in the prevalence of obesity, overweight and life style-related non communicable diseases. The challenge is in how to reverse the trend of high consumption of less healthy food by more healthful and more environmentally sustainable diets. The increasing recognition that each individual has specific needs depending on age, metabolic condition, and genetic profile adds complexity to general nutritional considerations. If we were to promote the consumption of low-energy and low salt but nutritious diets, taste becomes a relevant food quality. The Japanese traditional diet (Washoku), which is characterized by high consumption of fish and soybean products and low consumption of animal fat and meat, relies on the effective use of umami taste to enhance palatability. There may be a link between Washoku and the longevity of the people in Japan. Thus Washoku and umami may be valuable tools to support healthy eating. PMID- 29401652 TI - Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition. AB - Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta-flour beetle Tenebrio molitor model-has been used extensively for ecological and evolutionary host-parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7-10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition. PMID- 29401653 TI - MYC Regulates alpha6 Integrin Subunit Expression and Splicing Under Its Pro Proliferative ITGA6A Form in Colorectal Cancer Cells. AB - The alpha6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and beta4 integrin subunit (ITGB4) subunits of the alpha6beta4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood. Here, we show that the promoter activity of the ITGA6 gene is regulated by MYC. Pharmacological inhibition of MYC activity with the MYC inhibitor (MYCi) 10058-F4 or knockdown of MYC expression by short hairpin RNA (shRNA) both lead to a decrease in ITGA6 and ITGA6A levels in colorectal cancer cells, while overexpression of MYC enhances ITGA6 promoter activity. We also found that MYC inhibition decreases the epithelial splicing regulatory protein 2 (ESRP2) splicing factor at both the mRNA and protein levels. Chromatin immunoprecipitation revealed that the proximal promoter sequences of ITGA6 and ESRP2 were occupied by MYC and actively transcribed in colorectal cancer cells. Furthermore, expression studies in primary colorectal tumors and corresponding resection margins confirmed that the up-regulation of the ITGA6A subunit can be correlated with the increase in MYC and ESRP2. Taken together, our results demonstrate that the proto-oncogene MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2 to favor the production of the pro-proliferative ITGA6A variant in colorectal cancer cells. PMID- 29401655 TI - A Hybrid Readout Solution for GaN-Based Detectors Using CMOS Technology. AB - Gallium nitride (GaN) and its alloys are becoming preferred materials for ultraviolet (UV) detectors due to their wide bandgap and tailorable out-of-band cutoff from 3.4 eV to 6.2 eV. GaN based avalanche photodiodes (APDs) are particularly suitable for their high photon sensitivity and quantum efficiency in the UV region and for their inherent insensitivity to visible wavelengths. Challenges exist however for practical utilization. With growing interests in such photodetectors, hybrid readout solutions are becoming prevalent with CMOS technology being adopted for its maturity, scalability, and reliability. In this paper, we describe our approach to combine GaN APDs with a CMOS readout circuit, comprising of a linear array of 1 * 8 capacitive transimpedance amplifiers (CTIAs), implemented in a 0.35 um high voltage CMOS technology. Further, we present a simple, yet sustainable circuit technique to allow operation of APDs under high reverse biases, up to ~80 V with verified measurement results. The readout offers a conversion gain of 0.43 uV/e-, obtaining avalanche gains up to 103. Several parameters of the CTIA are discussed followed by a perspective on possible hybridization, exploiting the advantages of a 3D-stacked technology. PMID- 29401654 TI - The Optimal PEG for Kidney Preservation: A Preclinical Porcine Study. AB - University of Wisconsin (UW) solution is not optimal for preservation of marginal organs. Polyethylene glycol (PEG) could improve protection. Similarly formulated solutions containing either 15 or 20 g/L PEG 20 kDa or 5, 15 and 30 g/L PEG 35 kDa were tested in vitro on kidney endothelial cells, ex vivo on preserved kidneys, and in vivo in a pig kidney autograft model. In vitro, all PEGs provided superior preservation than UW in terms of cell survival, adenosine triphosphate (ATP) production, and activation of survival pathways. Ex vivo, tissue injury was lower with PEG 20 kDa compared to UW or PEG 35 kDa. In vivo, function recovery was identical between UW and PEG 35 kDa groups, while PEG 20 kDa displayed swifter recovery. At three months, PEG 35 kDa 15 and 30 g/L animals had worse outcomes than UW, while 5 g/L PEG 35 kDa was similar. PEG 20 kDa was superior to both UW and PEG 35 kDa in terms of function and fibrosis development, with low activation of damage pathways. PEG 20 kDa at 15 g/L was superior to 20 g/L. While in vitro models did not discriminate between PEGs, in large animal models of transplantation we showed that PEG 20 kDa offers a higher level of protection than UW and that longer chains such as PEG 35 kDa must be used at low doses, such as found in Institut George Lopez (IGL1, 1g/L). PMID- 29401656 TI - Integrated Change Detection and Classification in Urban Areas Based on Airborne Laser Scanning Point Clouds. AB - This paper suggests a new approach for change detection (CD) in 3D point clouds. It combines classification and CD in one step using machine learning. The point cloud data of both epochs are merged for computing features of four types: features describing the point distribution, a feature relating to relative terrain elevation, features specific for the multi-target capability of laser scanning, and features combining the point clouds of both epochs to identify the change. All these features are merged in the points and then training samples are acquired to create the model for supervised classification, which is then applied to the whole study area. The final results reach an overall accuracy of over 90% for both epochs of eight classes: lost tree, new tree, lost building, new building, changed ground, unchanged building, unchanged tree, and unchanged ground. PMID- 29401657 TI - Long-Term Effectiveness of Stress Management at Work: Effects of the Changes in Perceived Stress Reactivity on Mental Health and Sleep Problems Seven Years Later. AB - The reduction of stress reactivity resulting from stress management interventions prevents disorders and improves mental health, however, its long-term sustainability has been little examined. The objective of this study was, therefore, to determine the effectiveness of a stress management intervention, designed to improve stress reactivity, for mental health and sleep problems seven years later, using longitudinal data from 101 male industrial workers. Linear regressions estimated the adjusted effects of the changes in stress reactivity in general as well as in its six subdimensions (work overload, social conflict, social stress, failure at work, and anticipatory and prolonged reactivity) on depression, anxiety, and sleep problems seven years later. The improvement of the prolonged reactivity had positive effects on depression, anxiety, and sleep problems (unstandardized regression coefficients [Bs] >= 0.35, all p-values <= 0.01). Depression and sleep problems were further improved by a reduction of the reactivity to social conflicts (Bs >= 0.29, p-values < 0.05), and an improvement in the overall reactivity score positively influenced sleep problems (B = 0.07, p = 0.017). In conclusion, the improvement of stress reactivity resulting from a work stress intervention was effective and generally long-lasting in preventing mental health and sleep problems. The reduction of the prolonged reactivity seems of particular importance and efficient in inhibiting negative stress manifestations. PMID- 29401658 TI - Relative Contributions of Different Lifestyle Factors to Health-Related Quality of Life in the Elderly. AB - Much of the previous literature has studied the relationship between individual lifestyle factors and the health-related quality of life (HRQOL). However, only a few studies combined them to explore their relative importance to the HRQOL in the elderly. This study assesses the HRQOL of the urban, rural, and institutionalized Chinese elderly and explores the relative contributions of different lifestyle factors to their HRQOL. The SF-36v2 Health Survey, the WHOQOL OLD module, and the socio-demographic and lifestyle questionnaire were utilized in this study. Hierarchical regression was performed in order to analyze the results. The physical and mental component scores of the SF-36v2 survey were 47.05 +/- 9.95 and 54.92 +/- 9.92, respectively. The total score for the WHOQOL OLD module was 73.01 +/- 11.99, with institutionalized persons reporting lower scores. For the physical component of the elderly participants' HRQOL, the R2 value changed the most (0.116) when exercise-and-labor-related factors were added in. For the mental component, sleep-related (0.054), and leisure-time-activity related factors (0.053) caused the largest change of the R2 value. For the elderly-specific HRQOL, measured by the WHOQOL-OLD module, the leisure-time activity-related factors caused the largest change in the R2 value (0.119), followed by exercise-and-labor-related factors (0.078). Heterogeneity was present among the three subgroups. In sum, compared with their community-dwelling counterparts, the HRQOL of institutionalized older people was relatively poor and different lifestyle factors contributed to the HRQOL differently. PMID- 29401659 TI - Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines. AB - H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3 phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS 531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior. PMID- 29401660 TI - Epac Function and cAMP Scaffolds in the Heart and Lung. AB - Evidence collected over the last ten years indicates that Epac and cAMP scaffold proteins play a critical role in integrating and transducing multiple signaling pathways at the basis of cardiac and lung physiopathology. Some of the deleterious effects of Epac, such as cardiomyocyte hypertrophy and arrhythmia, initially described in vitro, have been confirmed in genetically modified mice for Epac1 and Epac2. Similar recent findings have been collected in the lung. The following sections will describe how Epac and cAMP signalosomes in different subcellular compartments may contribute to cardiac and lung diseases. PMID- 29401661 TI - Air Pollution and Otitis Media in Children: A Systematic Review of Literature. AB - Young children are particularly vulnerable to otitis media (OM) which globally affects over 80% of children below the age of 3 years. Although there is convincing evidence for an association between environmental tobacco smoke exposure and OM in children, the relationship with ambient air pollution is not clear. We aimed to systematically review the literature on the relationship between ambient air pollution exposure and OM in children. A systematic search was performed in PubMed and EMBASE databases. Of 934 references identified, 24 articles were included. There is an increasing body of evidence supporting an association between higher ambient air pollution exposure and a higher risk of OM in children. While NO2 showed the most consistent association with OM, other specific pollutants showed inconsistent associations. Studies were mainly conducted in high/middle income countries with limited evidence from low-income countries. Although there was a general consensus that higher air pollution exposure is associated with a greater prevalence of OM, the evidence for associations with specific pollutants is inconsistent. More well-designed studies on associations between specific air pollutants as risk factors for OM are warranted, especially in low income countries with high air pollution levels. PMID- 29401662 TI - A Novel Flavonoid Glucoside from the Fruits of Lycium ruthenicun. AB - A novel flavonoid glucoside, ruthenicunoid A (1), together with eight known substances, were isolated from the fruits of Lycium ruthenicun Murr. Their structures were elucidated by extensive spectroscopic data and chemical methods. Especially, the absolute configuration of glucose residue in 1 was assigned by acid hydrolysis followed by derivatization and GC analysis. Biological evaluation towards Sirtuin 1 (SIRT1) found that compounds 1 and 2 exhibit inhibitory activity against SIRT1 in a concentration-dependent manner, indicating its potential on SIRT1-associated disorders. PMID- 29401663 TI - Poly(Amide-imide) Aerogel Materials Produced via an Ice Templating Process. AB - Low density composites of sodium montmorillonite and poly(amide-imide) polymers have been created using an ice templating method, which serves as an alternative to the often-difficult foaming of high temperature/high performance polymers. The starting polymer was received in the poly(amic acid) form which can be cured using heat, into a water insoluble amide-imide copolymer. The resulting materials have densities in the 0.05 g/cm3 range and have excellent mechanical properties. Using a tertiary amine as a processing aid provides for lower viscosity and allows more concentrated polymer solutions to be used. The concentration of the amine relative to the acid groups on the polymer backbone has been found to cause significant difference in the mechanical properties of the dried materials. The synthesis and characterization of low density versions of two poly(amide-imide) polymers and their composites with sodium montmorillonite clay are discussed in the present work. PMID- 29401664 TI - A Simple Mechanism Based on Amino Acid Substitutions is not a Critical Determinant of High Mortality of Japanese Encephalitis Virus Infection in Mice. AB - For the development of effective treatment strategies for Japanese encephalitis (JE), it is important to identify the viral factors causing severe disease during JE virus (JEV) infection. In this study, we assessed whether amino acid substitutions are critical factors for higher mortality of JaTH160 compared with JaOArS982 in mice using the technique of infectious cDNA clones. We raised the possibility that two amino acids of C124 and NS3482 of JaTH160 may contribute to increased mortality in mice. However, simultaneous substitutions of these amino acids did not significantly increase the virulence of JaOArS982, suggesting that high mortality due to JaTH160 viral infection cannot be simply attributed to the specific amino acids. Multiple and complex, but not simple, mechanisms may induce the high mortality of JaTH160 infection in mice. PMID- 29401666 TI - Predicting Effects of the Self and Contextual Factors on Violence: A Comparison between School Students and Youth Offenders in Macau. AB - This study was designed to explore the self and contextual factors for violence in two samples of school students and youth offenders in Macau. There were 3085 participants who were between 12 and 20 years old; 48.3% of them were male and 51.7% female. Findings revealed that youth offenders exhibited more violence than school students. For the self factors, while lower self-esteem and higher self efficacy of school students were associated with more violent behavior, these two variables had no significant effects for youth offenders. For the contextual factors, family conflict was the strongest predictor of violence, and school commitment/attachment was the weakest predictor for both samples. For youth offenders, family conflict had the largest direct effect, followed by susceptibility to negative peer influence and influence of the Triad gangs, while school commitment/attachment had a significant though mild direct effect. For school students, family conflict mediated the effect of self-esteem and self efficacy on violence. While Triad gangs' influence was the second strongest predictor of violence, being exposed to Triad gangs' influence also mediated the effect of self-esteem and self-efficacy on violence. It is recommended that youth outreach services with a focus on family support and gang detachment for at-risk youth be strengthened. PMID- 29401665 TI - The Impact of Vitamin D in the Treatment of Essential Hypertension. AB - The aim of this review is to investigate, whether there is a possible link between vitamin D supplementation and the reduction of blood pressure in hypertensive patients. The renin-angiotensin-aldosterone system is known for being deeply involved in cardiovascular tonus and blood pressure regulation. Hence, many of the pharmaceutical antihypertensive drugs inhibit this system. Interestingly, experimental studies in mice have indicated that vitamin D supplementation significantly lowers renin synthesis and blood pressure. It is conceivable that similar mechanisms may be found in the human organism. Regarding this, large-scale cross-sectional studies suggest the serum 25(OH)D-level to be inversely correlated to the prevalence of hypertension. However, randomized controlled trials (RCTs) have not found a clear association between vitamin D supplementation and improvements in hypertension. Nevertheless, the missing association of vitamin D and hypertension in clinical trials can be due to suboptimal study designs. There are hints that restoration of serum 25(OH)D levels during vitamin D therapy is essential to achieve possible beneficial cardiovascular effects. It is important to perform long-term trials with a short dose interval and a high bioavailability of supplementation. Taken together, more RCTs are required to further investigate if vitamin D can be beneficial for the reduction of blood pressure. PMID- 29401668 TI - The Application of Social Characteristic and L1 Optimization in the Error Correction for Network Coding in Wireless Sensor Networks. AB - One of the remarkable challenges about Wireless Sensor Networks (WSN) is how to transfer the collected data efficiently due to energy limitation of sensor nodes. Network coding will increase network throughput of WSN dramatically due to the broadcast nature of WSN. However, the network coding usually propagates a single original error over the whole network. Due to the special property of error propagation in network coding, most of error correction methods cannot correct more than C/2 corrupted errors where C is the max flow min cut of the network. To maximize the effectiveness of network coding applied in WSN, a new error correcting mechanism to confront the propagated error is urgently needed. Based on the social network characteristic inherent in WSN and L1 optimization, we propose a novel scheme which successfully corrects more than C/2 corrupted errors. What is more, even if the error occurs on all the links of the network, our scheme also can correct errors successfully. With introducing a secret channel and a specially designed matrix which can trap some errors, we improve John and Yi's model so that it can correct the propagated errors in network coding which usually pollute exactly 100% of the received messages. Taking advantage of the social characteristic inherent in WSN, we propose a new distributed approach that establishes reputation-based trust among sensor nodes in order to identify the informative upstream sensor nodes. With referred theory of social networks, the informative relay nodes are selected and marked with high trust value. The two methods of L1 optimization and utilizing social characteristic coordinate with each other, and can correct the propagated error whose fraction is even exactly 100% in WSN where network coding is performed. The effectiveness of the error correction scheme is validated through simulation experiments. PMID- 29401667 TI - Infectious Agents as Stimuli of Trained Innate Immunity. AB - The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, beta-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation. PMID- 29401669 TI - Polymeric Flexible Immunosensor Based on Piezoresistive Micro-Cantilever with PEDOT/PSS Conductive Layer. AB - In this paper, a fully polymeric micro-cantilever with the surface passivation layer of parylene-C and the strain resistor of poly(3,4 ethylenedioxythiophene)/poly (styrene sulfonate) (PEDOT/PSS) was proposed and demonstrated for immunoassays. By optimizing the design and fabrication of the polymeric micro-cantilever, a square resistance of 220 Omega/? for PEDOT/PSS conductive layer have been obtained. The experimental spring constant and the deflection sensitivity were measured to be 0.017 N/m and 8.59 * 10-7 nm-1, respectively. The biological sensing performances of polymeric micro-cantilever were investigated by the immunoassay for human immunoglobulin G (IgG). The immunosensor was experimentally demonstrated to have a linear behavior for the detection of IgG within the concentrations of 10~100 ng/mL with a limit of detection (LOD) of 10 ng/mL. The experimental results indicate that the proposed polymeric flexible conductive layer-based sensors are capable of detecting trace biological substances. PMID- 29401672 TI - Two Solutions of Soil Moisture Sensing with RFID for Landslide Monitoring. AB - Two solutions for UHF RFID tags for soil moisture sensing were designed and are described in this paper. In the first, two conventional tags (standard transponders) are employed: one, placed close to the soil surface, is the sensor tag, while the other, separated from the soil, is the reference for system calibration. By transmission power ramps, the tag's turn-on power levels are measured and correlated with soil condition (dry or wet). In the second solution, the SL900A chip, which supports up to two external sensors and an internal temperature sensor, is used. An interdigital capacitive sensor was connected to the transponder chip and used for soil moisture measurement. In a novel design for an UHF RFID tag the sensor is placed below the soil surface, while the transponder and antenna are above the soil to improve communication. Both solutions are evaluated practically and results show the presence of water in soil can be remotely detected allowing for their application in landslide monitoring. PMID- 29401671 TI - Understanding Chinese Medicine Patterns of Rheumatoid Arthritis and Related Biomarkers. AB - Background: A considerable number of Rheumatoid Arthritis (RA) patients only experience side effects from treatment, with little to no actual pain relief. The combination of disease diagnosis in biomedicine and multi-disciplinary integrative approaches such as Chinese Medicine (CM), can help to identify different functional diagnosis of RA in the context of biomarker discovery. We aimed to analyse CM patterns in RA and their biomarker profiles. Methods: Four electronic databases (web of science, CINAHL, Scopus and PubMed) were searched. The reference list of all identified reports and articles were searched for additional studies. All study designs were included and no date limits were set. Studies were considered if they were published in English and explored the possible biomarkers profiles in RA patients, classified according to the American College of Rheumatology and categorized in CM as either cold, heat/hot or deficiency patterns. Methodological quality of included studies was assessed using checklists adapted from the (c)Critical Appraisal Skills Programme by two independent reviewers. A narrative synthesis was conducted, using thematic analysis. Results: A total of 10 articles were included. The studies examined 77 healthy volunteers and 1150 RA patients categorized as cold, heat/hot or deficiency pattern and related biomarkers were identified individually or concomitantly. Conclusions: CM pattern differentiation based on clinical signs and symptoms showed a diverse range of biomolecules, proteins and genes from RA patients correlated well with cold, heat/hot or deficiency phenotype-based CM patterns and could be used as diagnostic biomarkers for early detection, disease monitoring and therapeutic targets. PMID- 29401673 TI - Self-Test Procedures for Gas Sensors Embedded in Microreactor Systems. AB - Metal oxide (MOX) gas sensors sensitively respond to a wide variety of combustible, explosive and poisonous gases. However, due to the lack of a built in self-test capability, MOX gas sensors have not yet been able to penetrate safety-critical applications. In the present work we report on gas sensing experiments performed on MOX gas sensors embedded in ceramic micro-reaction chambers. With the help of an external micro-pump, such systems can be operated in a periodic manner alternating between flow and no-flow conditions, thus allowing repetitive measurements of the sensor resistances under clean air, R 0 , and under gas exposure, R g a s , to be obtained, even under field conditions. With these pairs of resistance values, eventual drifts in the sensor baseline resistance can be detected and drift-corrected values of the relative resistance response R e s p = ( R 0 - R g a s ) / R 0 can be determined. Residual poisoning induced changes in the relative resistance response can be detected by reference to humidity measurements taken with room-temperature-operated capacitive humidity sensors which are insensitive to the poisoning processes operative on heated MOX gas sensors. PMID- 29401670 TI - Converging Human and Malaria Vector Diagnostics with Data Management towards an Integrated Holistic One Health Approach. AB - Monitoring malaria prevalence in humans, as well as vector populations, for the presence of Plasmodium, is an integral component of effective malaria control, and eventually, elimination. In the field of human diagnostics, a major challenge is the ability to define, precisely, the causative agent of fever, thereby differentiating among several candidate (also non-malaria) febrile diseases. This requires genetic-based pathogen identification and multiplexed analysis, which, in combination, are hardly provided by the current gold standard diagnostic tools. In the field of vectors, an essential component of control programs is the detection of Plasmodium species within its mosquito vectors, particularly in the salivary glands, where the infective sporozoites reside. In addition, the identification of species composition and insecticide resistance alleles within vector populations is a primary task in routine monitoring activities, aiming to support control efforts. In this context, the use of converging diagnostics is highly desirable for providing comprehensive information, including differential fever diagnosis in humans, and mosquito species composition, infection status, and resistance to insecticides of vectors. Nevertheless, the two fields of human diagnostics and vector control are rarely combined, both at the diagnostic and at the data management end, resulting in fragmented data and mis- or non communication between various stakeholders. To this direction, molecular technologies, their integration in automated platforms, and the co-assessment of data from multiple diagnostic sources through information and communication technologies are possible pathways towards a unified human vector approach. PMID- 29401675 TI - The Taste of Commercially Available Clarithromycin Oral Pharmaceutical Suspensions in the Palestinian Market: Electronic Tongue and In Vivo Evaluation. AB - Background: The taste of oral liquid dosage forms is a crucial factor that impacts paediatric patient compliance. The electronic tongue (ET) is an emerging tool that could be useful in taste assessment in order to minimize the involvement of humans in such evaluations. Purpose: The aim of this study is to evaluate the taste of commercially available clarithromycin (CM) oral pharmaceutical suspensions in the Palestinian market. Method: Commercially available CM suspensions (the brand Klacid(r) and two generic K1 and K2) were assayed using the high performance liquid chromatography (HPLC) method. Then, the taste of these products was assessed using alpha-astree ET. In addition, an in vivo taste assessment was conducted on paediatric patients by a hedonic panel test. Moreover, volunteering community pharmacists were asked to rank the taste of these three products according to their experience from the best to the worst. Results: All suspension products had a CM concentration not less than 98% of the label amount. The ET results coupled with the principal component analysis (PCA) showed a very clear discrimination of the samples with different distances between groups (p-values < 0.001). Suspensions were in the following order in terms of taste: Klacid(r) > K1 > K2. Moreover, The pattern discrimination index between (K1 and Klacid(r)), (K1 and K2) and (Klacid(r) and K2) were 8.81%, 65.75%, and71.94%, respectively which suggests that K1 and Klacid(r) are the most similar preparations in terms of taste. Interestingly, these results were in excellent agreement with the pharmacist ranking and patient acceptance test. Conclusions: The evaluated preparations showed significantly different taste within the order of Klacid(r) > K1 > K2, as suggested by both the ET and in vivo results. Moreover, our results confirm the capability of alpha-astree ET in the taste assessment of oral suspensions and in predicting volunteer responses, which highlights its beneficial use as an in vitro taste assessment tool and as an alternative to human-based taste evaluations. PMID- 29401674 TI - Scandoside Exerts Anti-Inflammatory Effect Via Suppressing NF-kappaB and MAPK Signaling Pathways in LPS-Induced RAW 264.7 Macrophages. AB - The iridoids of Hedyotis diffusa Willd play an important role in the anti inflammatory process, but the specific iridoid with anti-inflammatory effect and its mechanism has not be thoroughly studied. An iridoid compound named scandoside (SCA) was isolated from H. diffusa and its anti-inflammatory effect was investigated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Its anti inflammatory mechanism was confirmed by in intro experiments and molecular docking analyses. As results, SCA significantly decreased the productions of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) and inhibited the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha and IL-6 messenger RNA (mRNA) expression in LPS-induced RAW 264.7 macrophages. SCA treatment suppressed the phosphorylation of inhibitor of nuclear transcription factor kappa-B alpaha (IkappaB-alpha), p38, extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK). The docking data suggested that SCA had great binding abilities to COX-2, iNOS and IkappaB. Taken together, the results indicated that the anti-inflammatory effect of SCA is due to inhibition of pro-inflammatory cytokines and mediators via suppressing the nuclear transcription factor kappa-B (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways, which provided useful information for its application and development. PMID- 29401676 TI - Interactive Cumulative Burden Assessment: Engaging Stakeholders in an Adaptive, Participatory and Transdisciplinary Approach. AB - Cumulative burden assessment (CuBA) has the potential to inform planning and decision-making on health disparities related to multiple environmental burdens. However, scholars have raised concerns about the social complexity to be dealt with while conducting CuBA, suggesting that it should be addressed in an adaptive, participatory and transdisciplinary (APT) approach. APT calls for deliberation among stakeholders by engaging them in a process of social learning and knowledge co-production. We propose an interactive stakeholder-based approach that facilitates a science-based stakeholder dialogue as an interface for combining different knowledge domains and engendering social learning in CuBA processes. Our approach allows participants to interact with each other using a flexible and auditable CuBA model implemented within a shared workspace. In two workshops we explored the usefulness and practicality of the approach. Results show that stakeholders were enabled to deliberate on cumulative burdens collaboratively, to learn about the technical uncertainties and social challenges associated with CuBA, and to co-produce knowledge in a realm of both technical and societal challenges. The paper identifies potential benefits relevant for responding to social complexity in the CuBA and further recommends exploration of how our approach can enable or constraint social learning and knowledge co production in CuBA processes under various institutional, social and political contexts. PMID- 29401678 TI - Design of Particulate-Reinforced Composite Materials. AB - A microstructure-based model is developed to study the effective anisotropic properties (magnetic, dielectric or thermal) of two-phase particle-filled composites. The Green's function technique and the effective field method are used to theoretically derive the homogenized (averaged) properties for a representative volume element containing isolated inclusion and infinite, chain structured particles. Those results are compared with the finite element approximations conducted for the assumed representative volume element. In addition, the Maxwell-Garnett model is retrieved as a special case when particle interactions are not considered. We also give some information on the optimal design of the effective anisotropic properties taking into account the shape of magnetic particles. PMID- 29401677 TI - Adverse Pregnancy Outcomes among Adolescents in Northwest Russia: A Population Registry-Based Study. AB - This study aimed to assess whether adolescents have an increased risk of adverse pregnancy outcomes (APO) compared to adult women. We used data on 43,327 births from the population-based Arkhangelsk County Birth Registry, Northwest Russia, for 2012-2014. The perinatal outcomes included stillbirth, preterm birth (<37 and <32 weeks), low and very low birthweight, 5 min Apgar score <7 and <4, perinatal infections, and the need for neonatal transfer to a higher-level hospital. Multivariable logistic regression was applied to assess the associations between age and APO. Altogether, 4.7% of deliveries occurred in adolescents. Both folic acid intake and multivitamin intake during pregnancy were more prevalent in adults. Adolescents were more likely to be underweight, to smoke, and to have infections of the kidney and the genital tract compared to adult women. Compared to adults, adolescents were at lower risk of low birthweight, a 5 min Apgar score <7, and need for neonatal transfer. Adolescents had no increased risk of other APO studied in the adjusted analysis, suggesting that a constellation of other factors, but not young age per se, is associated with APO in the study setting. PMID- 29401679 TI - Stepping It Up: Walking Behaviors in Children Transitioning from 5th to 7th Grade. AB - The purpose of this study was to (1) describe children's walking behaviors in 5th to 7th grade and change over time and (2) examine associations between walking behaviors and Walk Score(r). Participants consisted of n = 586 students from the Transitions and Activity Changes in Kids (TRACK) Study. Children reported any walking behavior (e.g., exercise and transportation) over the past five days. Walk Score was calculated based on children's home address. Descriptive statistics summarized walking behaviors by gender and time, and repeated measure mixed models examined the relationship between walking behaviors and Walk Score. Approximately 46.8% and 19.2% of 5th grade children reported walking for exercise and transportation, respectively, and these percentages declined through 7th grade. Girls reported higher levels of total walking behavior and walking for exercise than boys (p < 0.001). Girls with a higher Walk Score had 63% higher odds of reporting walking for transportation than girls with a lower Walk Score (OR = 1.63, 95% CI = 1.02, 2.62). Walking behaviors among children were infrequent with significant declines over time, and of the nine associations examined with Walk Score, only one was significant. Efforts should prioritize frequent walking behavior and community design to increase children's physical activity. PMID- 29401680 TI - Research on Synthetic Aperture Radar Processing for the Spaceborne Sliding Spotlight Mode. AB - Gaofen-3 (GF-3) is China' first C-band multi-polarization synthetic aperture radar (SAR) satellite, which also provides the sliding spotlight mode for the first time. Sliding-spotlight mode is a novel mode to realize imaging with not only high resolution, but also wide swath. Several key technologies for sliding spotlight mode in spaceborne SAR with high resolution are investigated in this paper, mainly including the imaging parameters, the methods of velocity estimation and ambiguity elimination, and the imaging algorithms. Based on the chosen Convolution BackProjection (CBP) and PFA (Polar Format Algorithm) imaging algorithms, a fast implementation method of CBP and a modified PFA method suitable for sliding spotlight mode are proposed, and the processing flows are derived in detail. Finally, the algorithms are validated by simulations and measured data. PMID- 29401681 TI - Deep Learning-Based Gaze Detection System for Automobile Drivers Using a NIR Camera Sensor. AB - A paradigm shift is required to prevent the increasing automobile accident deaths that are mostly due to the inattentive behavior of drivers. Knowledge of gaze region can provide valuable information regarding a driver's point of attention. Accurate and inexpensive gaze classification systems in cars can improve safe driving. However, monitoring real-time driving behaviors and conditions presents some challenges: dizziness due to long drives, extreme lighting variations, glasses reflections, and occlusions. Past studies on gaze detection in cars have been chiefly based on head movements. The margin of error in gaze detection increases when drivers gaze at objects by moving their eyes without moving their heads. To solve this problem, a pupil center corneal reflection (PCCR)-based method has been considered. However, the error of accurately detecting the pupil center and corneal reflection center is increased in a car environment due to various environment light changes, reflections on glasses surface, and motion and optical blurring of captured eye image. In addition, existing PCCR-based methods require initial user calibration, which is difficult to perform in a car environment. To address this issue, we propose a deep learning-based gaze detection method using a near-infrared (NIR) camera sensor considering driver head and eye movement that does not require any initial user calibration. The proposed system is evaluated on our self-constructed database as well as on open Columbia gaze dataset (CAVE-DB). The proposed method demonstrated greater accuracy than the previous gaze classification methods. PMID- 29401682 TI - Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer's and Vascular Dementia Drugs. AB - Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu) are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA). A further structural diversity of RA derivatives in some plants such as Salvia miltiorrhiza Bunge is a form of RA dimer, salvianolic acid-B (SA-B), that further give rise to diverse salvianolic acid derivatives. This review provides a comprehensive perspective on the chemistry and pharmacology of these compounds related to their potential therapeutic applications to dementia. The two common causes of dementia, Alzheimer's disease (AD) and stroke, are employed to scrutinize the effects of these compounds in vitro and in animal models of dementia. Key pharmacological mechanisms beyond the common antioxidant and anti-inflammatory effects of polyphenols are highlighted with emphasis given to amyloid beta (Abeta) pathologies among others and neuronal regeneration from stem cells. PMID- 29401685 TI - Effective Peroxidase-Like Activity of Co-Aminoclay [CoAC] and Its Application for Glucose Detection. AB - In this study, we describe a novel peroxidase-like activity of Co-aminoclay [CoAC] present at pH ~5.0 and its application to fluorescent biosensor for the determination of H2O2 and glucose. It is synthesized with aminoclays (ACs) entrapping cationic metals such as Fe, Cu, Al, Co., Ce, Ni, Mn, and Zn to find enzyme mimicking ACs by sol-gel ambient conditions. Through the screening of catalytic activities by the typical colorimetric reaction employing 2,2'-azino bis(3-ethylbenzo-thiazoline-6-sulfonic acid)diammonium salt (ABTS) as a substrate with or without H2O2, Fe, Cu, and CoACs are found to exhibit peroxidase-like activity, as well as oxidase-like activity was observed from Ce and MnACs. Among them, CoAC shows exceptionally high peroxidase-like activity, presumably due to its ability to induce electron transfer between substrates and H2O2. CoAC is then used to catalyze the oxidation of Amplex(r) UltraRed (AUR) into a fluorescent end product, which enables a sensitive fluorescent detection of H2O2. Moreover, a highly sensitive and selective glucose biosensing strategy is developed, based on enzyme cascade reaction between glucose oxidase (GOx) and CoAC. Using this strategy, a highly linear fluorescence enhancement is verified when the concentration of glucose is increased in a wide range from 10 MUM to 1 mM with a lower detection limit of 5 MUM. The practical diagnostic capability of the assay system is also verified by its use to detect glucose in human blood serum. Based on these results, it is anticipated that CoAC can serve as potent peroxidase mimetics for the detection of clinically important target molecules. PMID- 29401687 TI - Synthesis of Two Tetrasaccharide Pentenyl Glycosides Related to the Pectic Rhamnogalacturonan I Polysaccharide. AB - The synthesis of two protected tetrasaccharide pentenyl glycosides with diarabinan and digalactan branching related to the pectic polysaccharide rhamnogalacturonan I is reported. The strategy relies on the coupling of N-phenyl trifluoroacetimidate disaccharide donors to a common rhamnosyl acceptor. The resulting trisaccharide thioglycosides were finally coupled to an n-pentenyl galactoside acceptor to access the two protected branched tetrasaccharides. PMID- 29401684 TI - MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia. AB - Acute myeloid leukemias (AML) are clonal disorders of hematopoietic progenitor cells which are characterized by relevant heterogeneity in terms of phenotypic, genotypic, and clinical features. Among the genetic aberrations that control disease development there are microRNAs (miRNAs). miRNAs are small non-coding RNAs that regulate, at post-transcriptional level, translation and stability of mRNAs. It is now established that deregulated miRNA expression is a prominent feature in AML. Functional studies have shown that miRNAs play an important role in AML pathogenesis and miRNA expression signatures are associated with chemotherapy response and clinical outcome. In this review we summarized miRNA signature in AML with different cytogenetic, molecular and clinical characteristics. Moreover, we reviewed the miRNA regulatory network in AML pathogenesis and we discussed the potential use of cellular and circulating miRNAs as biomarkers for diagnosis and prognosis and as therapeutic targets. PMID- 29401686 TI - Evaluation of Polyphenol Anthocyanin-Enriched Extracts of Blackberry, Black Raspberry, Blueberry, Cranberry, Red Raspberry, and Strawberry for Free Radical Scavenging, Reactive Carbonyl Species Trapping, Anti-Glycation, Anti-beta-Amyloid Aggregation, and Microglial Neuroprotective Effects. AB - Glycation is associated with several neurodegenerative disorders, including Alzheimer's disease (AD), where it potentiates the aggregation and toxicity of proteins such as beta-amyloid (Abeta). Published studies support the anti glycation and neuroprotective effects of several polyphenol-rich fruits, including berries, which are rich in anthocyanins. Herein, blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts were evaluated for: (1) total phenolic and anthocyanins contents, (2) free radical (DPPH) scavenging and reactive carbonyl species (methylglyoxal; MGO) trapping, (3) anti-glycation (using BSA-fructose and BSA-MGO models), (4) anti-Abeta aggregation (using thermal- and MGO-induced fibrillation models), and, (5) murine microglia (BV-2) neuroprotective properties. Berry crude extracts (CE) were fractionated to yield anthocyanins-free (ACF) and anthocyanins-enriched (ACE) extracts. The berry ACEs (at 100 MUg/mL) showed superior free radical scavenging, reactive carbonyl species trapping, and anti-glycation effects compared to their respective ACFs. The berry ACEs (at 100 MUg/mL) inhibited both thermal- and MGO induced Abeta fibrillation. In addition, the berry ACEs (at 20 MUg/mL) reduced H2O2-induced reactive oxygen species production, and lipopolysaccharide-induced nitric oxide species in BV-2 microglia as well as decreased H2O2-induced cytotoxicity and caspase-3/7 activity in BV-2 microglia. The free radical scavenging, reactive carbonyl trapping, anti-glycation, anti-Abeta fibrillation, and microglial neuroprotective effects of these berry extracts warrant further in vivo studies to evaluate their potential neuroprotective effects against AD. PMID- 29401688 TI - Using Psychophysiological Sensors to Assess Mental Workload During Web Browsing. AB - Knowledge of the mental workload induced by a Web page is essential for improving users' browsing experience. However, continuously assessing the mental workload during a browsing task is challenging. To address this issue, this paper leverages the correlation between stimuli and physiological responses, which are measured with high-frequency, non-invasive psychophysiological sensors during very short span windows. An experiment was conducted to identify levels of mental workload through the analysis of pupil dilation measured by an eye-tracking sensor. In addition, a method was developed to classify mental workload by appropriately combining different signals (electrodermal activity (EDA), electrocardiogram, photoplethysmo-graphy (PPG), electroencephalogram (EEG), temperature and pupil dilation) obtained with non-invasive psychophysiological sensors. The results show that the Web browsing task involves four levels of mental workload. Also, by combining all the sensors, the efficiency of the classification reaches 93.7%. PMID- 29401689 TI - Gas Transport in Glassy Polymers: Prediction of Diffusional Time Lag. AB - The transport of gases in glassy polymeric membranes has been analyzed by means of a fundamental approach based on the nonequilibrium thermodynamic model for glassy polymers (NET-GP) that considers the penetrant chemical potential gradient as the actual driving force of the diffusional process. The diffusivity of a penetrant is thus described as the product of a purely kinetic quantity, the penetrant mobility, and a thermodynamic factor, accounting for the chemical potential dependence on its concentration in the polymer. The NET-GP approach, and the nonequilibrium lattice fluid (NELF) model in particular, describes the thermodynamic behavior of penetrant/polymer mixtures in the glassy state, at each pressure or composition. Moreover, the mobility is considered to follow a simple exponential dependence on penetrant concentration, as typically observed experimentally, using only two adjustable parameters, the infinite dilution penetrant mobility L10 and the plasticization factor beta, both determined from the analysis of the dependence of steady state permeability on upstream pressure. The available literature data of diffusional time lag as a function of penetrant upstream pressure has been reviewed and compared with model predictions, obtained after the values of the two model parameters (L10 and beta), have been conveniently determined from steady state permeability data. The model is shown to be able to describe very accurately the experimental time lag behaviors for all penetrant/polymer pairs inspected, including those presenting an increasing permeability with increasing upstream pressure. The model is thus more appropriate than the one based on Dual Mode Sorption, which usually provides an unsatisfactory description of time lag and required an ad hoc modification. PMID- 29401683 TI - Epigenetics and MicroRNAs in Cancer. AB - The ability to reprogram the transcriptional circuitry by remodeling the three dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells. PMID- 29401690 TI - Influence of Temperature on Corrosion Behavior of 2A02 Al Alloy in Marine Atmospheric Environments. AB - The corrosion behavior of 2A02 Al alloy under 4 mg/cm2 NaCl deposition at different temperatures (from 30 to 80 degrees C) has been studied. This corrosion behavior was researched using mass-gain, scanning electron microscopy SEM, laser scanning confocal microscopy-LSCM, X-ray photoelectron spectroscopy XPS and other techniques. The results showed and revealed that the corrosion was maximal at 60 degrees C after 200 h of exposure. The increase of temperature not only affected the solubility of oxygen gas in the thin film, but also promoted the transport of ions (such as Cl-), and the formation of protective AlO(OH), which further affects the corrosion speed. PMID- 29401691 TI - A New Reliability Analysis Model of the Chegongzhuang Heat-Supplying Tunnel Structure Considering the Coupling of Pipeline Thrust and Thermal Effect. AB - Based on the operating Chegongzhuang heat-supplying tunnel in Beijing, the reliability of its lining structure under the action of large thrust and thermal effect is studied. According to the characteristics of a heat-supplying tunnel service, a three-dimensional numerical analysis model was established based on the mechanical tests on the in-situ specimens. The stress and strain of the tunnel structure were obtained before and after the operation. Compared with the field monitoring data, the rationality of the model was verified. After extracting the internal force of the lining structure, the improved method of subset simulation was proposed as the performance function to calculate the reliability of the main control section of the tunnel. In contrast to the traditional calculation method, the analytic relationship between the sample numbers in the subset simulation method and Monte Carlo method was given. The results indicate that the lining structure is greatly influenced by coupling in the range of six meters from the fixed brackets, especially the tunnel floor. The improved subset simulation method can greatly save computation time and improve computational efficiency under the premise of ensuring the accuracy of calculation. It is suitable for the reliability calculation of tunnel engineering, because "the lower the probability, the more efficient the calculation." PMID- 29401692 TI - Modeling Electronic Skin Response to Normal Distributed Force. AB - The reference electronic skin is a sensor array based on PVDF (Polyvinylidene fluoride) piezoelectric polymers, coupled to a rigid substrate and covered by an elastomer layer. It is first evaluated how a distributed normal force (Hertzian distribution) is transmitted to an extended PVDF sensor through the elastomer layer. A simplified approach based on Boussinesq's half-space assumption is used to get a qualitative picture and extensive FEM simulations allow determination of the quantitative response for the actual finite elastomer layer. The ultimate use of the present model is to estimate the electrical sensor output from a measure of a basic mechanical action at the skin surface. However this requires that the PVDF piezoelectric coefficient be known a-priori. This was not the case in the present investigation. However, the numerical model has been used to fit experimental data from a real skin prototype and to estimate the sensor piezoelectric coefficient. It turned out that this value depends on the preload and decreases as a result of PVDF aging and fatigue. This framework contains all the fundamental ingredients of a fully predictive model, suggesting a number of future developments potentially useful for skin design and validation of the fabrication technology. PMID- 29401693 TI - Heat Coma Temperature and Supercooling Point in Oceanic Sea Skaters (Heteroptera, Gerridae). AB - Heat coma temperatures (HCTs) and super cooling points (SCPs) were examined for nearly 1000 oceanic sea skaters collected from in the Pacific and Indian Oceans representing four Halobates species; H. germanus, H. micans, H. sericeus, and H. sp. Analysis was conducted using the entire dataset because a negative correlation was seen between the HCTs and SCPs in all four species. A weak negative correlation was seen between HCTs and SCPs with a cross tolerance between warmer HCTs and colder SCPs. The weakness of the correlation may be due to the large size of the dataset and to the variability in ocean surface temperature. The negative correlation does however suggest that oceanic sea skaters may have some form of cross tolerance with a common physiological mechanism for their high and low temperature tolerances. PMID- 29401694 TI - Polymer-Based Nanocarriers for Co-Delivery and Combination of Diverse Therapies against Cancers. AB - Cancer gives rise to an enormous number of deaths worldwide nowadays. Therefore, it is in urgent need to develop new therapies, among which combined therapies including photothermal therapy (PTT) and chemotherapy (CHT) using polymer-based nanocarriers have attracted enormous interest due to the significantly enhanced efficacy and great progress has been made so far. The preparation of such nanocarriers is a comprehensive task involving the cooperation of nanomaterial science and biomedicine science. In this review, we try to introduce and analyze the structure, preparation and synergistic therapeutic effect of various polymer based nanocarriers composed of anti-tumor drugs, nano-sized photothermal materials and other possible parts. Our effort may bring benefit to future exploration and potential applications of similar nanocarriers. PMID- 29401695 TI - Influence of Graded Levels of l-Theanine Dietary Supplementation on Growth Performance, Carcass Traits, Meat Quality, Organs Histomorphometry, Blood Chemistry and Immune Response of Broiler Chickens. AB - l-theanine is a water-soluble non-proteinous amino acid mainly found in green tea leaves. Despite the availability of abundant literature on green tea, studies on the use of l-theanine as a feed additive in animals, and especially broilers are limited. The objective of this study was, therefore, to evaluate the effect of different dietary levels of l-theanine on meat quality, growth performance, immune response, and blood metabolites in broilers. A total of 400 day-old broiler chicks were randomly divided into four treatment groups using a completely randomized design; C-control, basal diet; 100LT-basal diet + 100 mg l theanine/kg diet; 200LT-basal diet + 200 mg l-theanine/kg diet; and 300LT-basal diet + 300 mg l-theanine/kg diet. Results revealed that the intermediate level of l-theanine (200 mg/kg diet) showed better results in terms of body weight gain (BWG), feed consumed (FC), and feed conversion ratio (FCR) as compared with the other supplemented groups and the control. The live weight eviscerated weight and gizzard weight were higher in all l-theanine levels as compared to those of the control group. Increased weight (p <= 0.05) of spleen and bursa were found in group 200LT (200 mg l-theanine/kg diet). Concerning meat color parameters, values for yellowness (b*), and redness (a*) were greater in l-theanine-supplemented groups than the control. Supplementing broiler diet with l-theanine reduced (p = 0.02) total serum cholesterol contents while increased HDL. Further analysis revealed lower relative serum cytokines (IL-2 and INF-gamma) and reduced mRNA expression of TNF-alpha and IL-6 in thymus, and IFN-gamma and IL-2 in spleen in the treated group. Moreover, supplementation with 200 mg/kg of l-theanine improved antioxidant status in blood by increasing SOD, GSH-Px, and relative CAT levels. It is concluded that the optimum supplementation level of l-theanine is 200 mg/kg of diet because it resulted in improved performance parameters in broilers. However, higher levels of l-theanine (300 mg/kg diet) may have deleterious effects on performance and health of broiler chickens. PMID- 29401696 TI - PIM Kinases and Their Relevance to the PI3K/AKT/mTOR Pathway in the Regulation of Ovarian Cancer. AB - Ovarian cancer is a medical term that includes a number of tumors with different molecular biology, phenotypes, tumor progression, etiology, and even different diagnosis. Some specific treatments are required to address this heterogeneity of ovarian cancer, thus molecular characterization may provide an important tool for this purpose. On a molecular level, proviral-integration site for Moloney-murine leukemia virus (PIM) kinases are over expressed in ovarian cancer and play a vital role in the regulation of different proteins responsible for this tumorigenesis. Likewise, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is also a central regulator of the ovarian cancer. Interestingly, recent research has linked the PIM kinases to the PI3K/AKT/mTOR pathway in several types of cancers, but their connection in ovarian cancer has not been studied yet. Once the exact relationship of PIM kinases with the PI3K/AKT/mTOR pathway is acquired in ovarian cancer, it will hopefully provide effective treatments on a molecular level. This review mainly focuses on the role of PIM kinases in ovarian cancer and their interactions with proteins involved in its progression. In addition, this review suggests a connection between the PIM kinases and the PI3K/AKT/mTOR pathway and their parallel mechanism in the regulation of ovarian cancer. PMID- 29401699 TI - The Effect of a Leisure Time Physical Activity Intervention Delivered via a Workplace: 15-Month Follow-Up Study. AB - In line with recommendations from both the World Health Organization and the European Union some employers encourage workplace health promotion through physical activity (PA) facilities and leisure time PA-initiatives. The current study describes a 15-month follow-up after an 8-week workplace delivered PA initiative, investigates if improvements in cardiovascular risk status are sustainable, and elucidates differences according to educational level. One hundred and twenty one employees (43 women) were examined before and after the 8 week PA-initiative and 94 at the 15-month follow-up. PA-levels, blood pressure, resting heart rate, lipids, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and selected markers of inflammation were registered at baseline, immediately after the 8-week PA-initiative, and 15 months after baseline. At the end of follow-up (15-month), PA-levels-increased during the 8-week intervention had returned to baseline values. None of the five improvements in cardiovascular markers (total cholesterol, low density lipoprotein (LDL), P-selectin, CD40Ligand (CD40L) and Monocyte chemoattractant protein-1 (MCP-1)) seen at the 8-week follow up were sustained. At the 15-month follow-up as compared to baseline HbA1c, CRP (log) and interleukin-6 (IL-6) were reduced by 0.06 mmol/L (95% CI -0.11,-0.01), 0.25 mg/L (95% CI -0.46,-0.04) and 0.39 pg/mL (95% CI -0.75, -0.04), respectively. At baseline, there were differences in cardiovascular risk factors comparing men with low versus high levels of education. No differences in changes in outcomes between these groups of men were found during follow-up. In this study highly educated men generally have lower levels of cardiovascular risk factors, but the effect of PA on such markers in this group do not differ from the effects seen in less educated men. PMID- 29401698 TI - Fat Mass Index and Body Mass Index Affect Peak Metabolic Equivalent Negatively during Exercise Test among Children and Adolescents in Taiwan. AB - Peak metabolic equivalent (MET) is the most reliable indicator of cardiorespiratory fitness (CRF). The aim of this study was to examine the association between CRF indicated by peak MET and body mass index (BMI) or fat mass index (FMI) in Taiwanese children and adolescents (C-A). Data of 638 C-A aged 10-18 that received symptom-limited treadmill exercise testing was analyzed. Anthropometry-body composition was measured by vector bioelectrical impedance analysis. BMI was defined as body weight (kg)/body height (m)2 and FMI was defined as fat mass (kg)/body height (m)2. BMI was grouped by Taiwanese obesity cut-off points. FMI Class-I was categorized by percentage of body fat. FMI Class II used the reference values from Korean C-A. Excess adiposity was defined as (1) "overweight" and "obesity" by BMI, (2) greater than the sex- and age-specific 75th percentile of whole subjects by FMI Class-I, and (3) greater than 95th percentiles of reference value by FMI Class-II. Boys had significantly higher fat mass and FMI, and had more excess adiposity than girls (all p < 0.05). Both boys and girls with excess adiposity (by any definition) had lower MET at anaerobic threshold (AT MET) and peak MET (all p < 0.001). BMI and FMI were significantly negatively associated with both AT MET and peak MET significantly (all p < 0.001). FMI (95% CI: -0.411~-0.548) correlated with peak MET more than BMI (95% CI: -0.134~ -0.372) did. Excess adiposity affected CRF negatively. It is concluded that weight management should start early in childhood. PMID- 29401700 TI - Prevalence of and Factors Associated with Work-Related Musculoskeletal Symptoms in Nursing Assistants Working in Nursing Homes. AB - The prevalence of work-related musculoskeletal symptoms (WRMSs) in different body parts for nursing assistants (NAs) working in nursing homes is currently unknown. The aim of this study was to determine the extent of WRMSs in nursing assistants and the factors associated with them. Four hundred and forty NAs from 52 nursing homes, recruited by convenience sampling, participated in this cross-sectional study in 2014-2015. A valid and reliable study questionnaire was used to collect data. The results of our study found that 88.4% of NAs reported at least one body part with WRMSs. These NAs reported more symptoms in the shoulders than lower back. Adverse workstyle (OR = 1.04, 95% CI = 1.01-1.08) was the only factor associated with WRMSs after adjustment for potential confounders using multivariable logistic regression. This adverse workstyle could be developed because of physical and psychological work demands. Efforts should be directed at integrating "workstyle intervention" into lifestyle physical activity training to this group of healthcare workers. PMID- 29401697 TI - Prediction of Disordered Regions and Their Roles in the Anti-Pathogenic and Immunomodulatory Functions of Butyrophilins. AB - Butyrophilins (BTNs) are a group of the moonlighting proteins, some members of which are secreted in milk. They constitute a large family of structurally similar type 1 transmembrane proteins from the immunoglobulin superfamily. Although the founding member of this family is related to lactation, participating in the secretion, formation and stabilization of milk fat globules, it may also have a cell surface receptor function. Generally, the BTN family members are known to modulate co-stimulatory responses, T cell selection, differentiation, and cell fate determination. Polymorphism of these genes was shown to be associated with the pathology of several human diseases. Despite their biological significance, structural information on human butyrophilins is rather limited. Based on their remarkable multifunctionality, butyrophilins seem to belong to the category of moonlighting proteins, which are known to contain intrinsically disordered protein regions (IDPRs). However, the disorder status of human BTNs was not systematically investigated as of yet. The goal of this study is to fill this gap and to evaluate peculiarities of intrinsic disorder predisposition of the members of human BTN family, and to find if they have IDPRs that can be attributed to the multifunctionality of these important proteins. PMID- 29401701 TI - Do Authoritarian Governments Respond to Public Opinion on the Environment? Evidence from China. AB - Given its serious impacts on the public's health, air pollution in China is a matter of strong public concern, particularly in reference to malodorous waste gas. Petition letters related to atmospheric pollution accounted for about 40% of the total petition cases. However, scholarly views differ on whether the Chinese government responds to public opinion on the environment and seeks to improve its environmental governance behavior. For this study, data from national surveys on the public's environmental satisfaction administered during the period 2011-2015 were analyzed to determine whether the public's dissatisfaction with the state of the environment in a given year resulted in increased investments by provincial governments in pollution governance during the following year. The study's findings revealed that governmental behavior in response to public opinion on the environment was selective within the field of environmental governance, with provincial governments being inclined to invest more in waste gas pollution control than in water pollution control. Furthermore, results from this study show that the Chinese government tends to put more efforts into the environmental field where it could more easily achieve short-term benefits. PMID- 29401703 TI - An Investigation of the Influence of Initial Roughness on the Friction and Wear Behavior of Ground Surfaces. AB - Friction and wear tests were performed on AISI 1045 steel specimens with different initial roughness parameters, machined by a creep-feed dry grinding process, to study the friction and wear behavior on a pin-on-disc tester in dry sliding conditions. Average surface roughness (Ra), root mean square (Rq), skewness (Rsk) and kurtosis (Rku) were involved in order to analyse the influence of the friction and wear behavior. The observations reveal that a surface with initial roughness parameters of higher Ra, Rq and Rku will lead to a longer initial-steady transition period in the sliding tests. The plastic deformation mainly concentrates in the depth of 20-50 MUm under the worn surface and the critical plastic deformation is generated on the rough surface. For surfaces with large Ra, Rq, low Rsk and high Rku values, it is easy to lose the C element in, the reciprocating extrusion. PMID- 29401702 TI - Bioactive Dietary VDR Ligands Regulate Genes Encoding Biomarkers of Skin Repair That Are Associated with Risk for Psoriasis. AB - Treatment with 1,25-dihydroxyvitamin D3 (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (LCE)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic deletion of LCE3B and LCE3C (LCE3C_LCE3B-del), we propose that certain dietary analogues of 1,25D activate the expression of residual LCE3A/LCE3D/LCE3E genes to compensate for the loss of LCE3B/LCE3C in the deletant genotype. Herein, human keratinocytes (HEKn) homozygous for LCE3C_LCE3B-del were treated with docosahexaenoic acid (DHA) and curcumin, two low-affinity, nutrient ligands for the vitamin D receptor (VDR). DHA and curcumin induce the expression of LCE3A/LCE3D/LCE3E mRNAs at concentrations corresponding to their affinity for VDR. Moreover, immunohistochemical quantitation revealed that the treatment of keratinocytes with DHA or curcumin stimulates LCE3 protein expression, while simultaneously opposing the tumor necrosis factor-alpha (TNFalpha)-signaled phosphorylation of mitogen activated protein (MAP) kinases, p38 and Jun amino terminal kinase (JNK), thereby overcoming inflammation biomarkers elicited by TNFalpha challenge. Finally, DHA and curcumin modulate two transcription factors relevant to psoriatic inflammation, the activator protein-1 factor Jun B and the nuclear receptor NR4A2/NURR1, that is implicated as a mediator of VDR ligand triggered gene control. These findings provide insights into the mechanism(s) whereby dietary VDR ligands alter inflammatory and barrier functions relevant to skin repair, and may provide a molecular basis for improved treatments for mild/moderate psoriasis. PMID- 29401705 TI - Direct Observation of Inner-Layer Inward Contractions of Multiwalled Boron Nitride Nanotubes upon in Situ Heating. AB - In situ heating transmission electron microscopy observations clearly reveal remarkable interlayer expansion and inner-layer inward contraction in multi walled boron nitride nanotubes (BNNTs) as the specimen temperature increases. We interpreted the observed inward contraction as being due to the presence of the strong constraints of the outer layers on radial expansion in the tubular structure upon in situ heating. The increase in specimen temperature upon heating can create pressure and stress toward the tubular center, which drive the lattice motion and yield inner diameter contraction for the multi-walled BNNTs. Using a simple model involving a wave-like pattern of layer-wise distortion, we discuss these peculiar structural alterations and the anisotropic thermal expansion properties of the tubular structures. Moreover, our in situ atomic images also reveal Russian-doll-type BN nanotubes, which show anisotropic thermal expansion behaviors. PMID- 29401704 TI - The Study of Anti-/Pro-Oxidant, Lipophilic, Microbial and Spectroscopic Properties of New Alkali Metal Salts of 5-O-Caffeoylquinic Acid. AB - Lithium, sodium, potassium, rubidium and caesium salts of 5-O-caffeoylquinic acid (chlorogenic acid, 5-CQA) were synthesized and described by FT-IR (infrared spectroscopy), FT-Raman (Raman spectroscopy), UV (UV absorption spectroscopy), 1H (400.15 MHz), 13C (100.63 MHz) NMR (nuclear magnetic resonance spectroscopy). The quantum-chemical calculations at the B3LYP/6-311++G** level were done in order to obtain the optimal structures, IR spectra, NBO (natural bond orbital) atomic charges, HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) orbitals and chemical reactivity parameters for 5-CQA and Li, Na and K 5-CQAs (chlorogenates). The DPPH (alpha, alpha-diphenyl-beta picrylhydrazyl) and FRAP (ferric reducing antioxidant power) assays were used for the preliminary estimation of the antioxidant properties of alkali metal chlorogenates and chlorogenic acid. In the DPPH assay the EC50 parameter were equal to 7.39 MUM for 5-CQA and was in the range of 4.50-5.89 MUM for salts. The FRAP values for two different concentrations (5 and 2.5 MUM) of the studied compounds were respectively 114.22 and 72.53 MUM Fe2+ for 5-CQA, whereas for salts they were 106.92-141.13 and 78.93-132.00 MUM Fe2+. The 5-CQA and its alkali metal salts possess higher antioxidant properties than commonly applied antioxidants (BHA, BHT, l-ascorbic acid). The pro-oxidant action of these compounds on trolox oxidation was studied in the range of their concentration 0.05-0.35 MUM. The lipophilicity (logkw) of chlorogenates and chlorogenic acid was determined by RP-HPLC (reverse phase-high performance liquid chromatography) using five different columns (C8, PHE (phenyl), CN (cyano), C18, IAM (immobilized artificial membrane)). The compounds were screened for their in vitro antibacterial activity against E. coli, Bacillus sp., Staphylococcus sp., Streptococcus pyogenes and antifungal activity against Candida sp. The 5-CQA possessed lower antibacterial (minimal inhibitory concentration, MIC = 7.06 mM) and antifungal (MIC = 14.11 mM) properties than its alkali metal salts (MIC values: 6.46-2.63 mM and 12.91-5.27mM, respectively). The synthesized chlorogenates possessed better antioxidant, lipophilic, antimicrobial as well as lower pro-oxidant properties than the ligand alone. Moreover, a systematic change of the activity of alkali metal salts along the series Li->Cs suggests that there are correlations between the studied biological properties. The type of metal cation in the carboxylate group of chlorogenate is crucial for the activity of studied compounds. PMID- 29401706 TI - Conceptualizing and Managing Medical Emergencies Where No Formal Paramedical System Exists: Perspectives from a Remote Indigenous Community in Canada. AB - (1) Background: Remote communities in Canada lack an equitable emergency medical response capacity compared to other communities. Community-based emergency care (CBEC) training for laypeople is a model that has the potential to enhance the medical emergency response capacity in isolated and resource-limited contexts. The purpose of this study was to understand the characteristics of medical emergencies and to conceptualize and present a framework for what a medical emergency is for one remote Indigenous community in northwestern Ontario, in order to inform the development of CBEC training. (2) Methods: This study adhered to the principles of community-based participatory research and realist evaluation; it was an integrated component of the formative evaluation of the second Sachigo Lake Wilderness Emergency Response Education Initiative (SLWEREI) training course in 2012. Twelve members of Sachigo Lake First Nation participated in the training course, along with local nursing staff, police officers, community Elders, and course instructors (n = 24 total), who participated in interviews, focus groups, and a collaborative discussion of local health issues in the development of the SLWEREI. (3) Results: The qualitative results are organized into sections that describe the types of local health emergencies and the informal response system of community members in addressing these emergencies. Prominent themes of health adversity that emerged were an inability to manage chronic conditions and fears of exacerbations, the lack of capacity for addressing mental illness, and the high prevalence of injury for community members. (4) Discussion: A three-point framework of what constitutes local perceptions of an emergency emerged from the findings in this study: (1) a sense of isolation; (2) a condition with a potentially adverse outcome; and (3) a need for help. PMID- 29401707 TI - In Vivo Evaluation of 3D-Printed Polycaprolactone Scaffold Implantation Combined with beta-TCP Powder for Alveolar Bone Augmentation in a Beagle Defect Model. AB - Insufficient bone volume is one of the major challenges encountered by dentists after dental implant placement. This study aimed to evaluate the efficacy of a customized three-dimensional polycaprolactone (3D PCL) scaffold implant fabricated with a 3D bio-printing system to facilitate rapid alveolar bone regeneration. Saddle-type bone defects were surgically created on the healed site after extracting premolars from the mandibles of four beagle dogs. The defects were radiologically examined using computed tomography for designing a customized 3D PCL scaffold block to fit the defect site. After fabricating 3D PCL scaffolds using rapid prototyping, the scaffolds were implanted into the alveolar bone defects along with beta-tricalcium phosphate powder. In vivo analysis showed that the PCL blocks maintained the physical space and bone conductivity around the defects. In addition, no inflammatory infiltrates were observed around the scaffolds. However, new bone formation occurred adjacent to the scaffolds, rather than directly in contact with them. More new bone was observed around PCL blocks with 400/1200 lattices than around blocks with 400/400 lattices, but the difference was not significant. These results indicated the potential of 3D printed porous PCL scaffolds to promote alveolar bone regeneration for defect healing in dentistry. PMID- 29401711 TI - Crowdsensing in Smart Cities: Overview, Platforms, and Environment Sensing Issues. AB - Evidence shows that Smart Cities are starting to materialise in our lives through the gradual introduction of the Internet of Things (IoT) paradigm. In this scope, crowdsensing emerges as a powerful solution to address environmental monitoring, allowing to control air pollution levels in crowded urban areas in a distributed, collaborative, inexpensive and accurate manner. However, even though technology is already available, such environmental sensing devices have not yet reached consumers. In this paper, we present an analysis of candidate technologies for crowdsensing architectures, along with the requirements for empowering users with air monitoring capabilities. Specifically, we start by providing an overview of the most relevant IoT architectures and protocols. Then, we present the general design of an off-the-shelf mobile environmental sensor able to cope with air quality monitoring requirements; we explore different hardware options to develop the desired sensing unit using readily available devices, discussing the main technical issues associated with each option, thereby opening new opportunities in terms of environmental monitoring programs. PMID- 29401710 TI - Dietary Iron Supplementation Alters Hepatic Inflammation in a Rat Model of Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease in the world. NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and eventually hepatocellular carcinoma. Acquired hepatic iron overload is seen in a number of patients with NAFLD; however, its significance in the pathology of NAFLD is still debated. Here, we investigated the role of dietary iron supplementation in experimental steatohepatitis in rats. Rats were fed a control, high-fat (HF), high-fat high-iron (HFHI) and high-iron (HI) diet for 30 weeks. Blood biochemical, histopathological and gut microbiota analyses were performed. Rats in HF and HFHI groups showed an ALT-dominant elevation of serum transaminases, hepatic steatosis, hepatic inflammation, and upregulation of proinflammatory cytokines. The number of large inflammatory foci, corresponding to lobular inflammation in NASH patients, was significantly higher in HFHI than in HF group; within the lesion, macrophages with intense iron staining were observed. Hepatic expression of TNFalpha was higher in HFHI than that in HF group. There was no significant change in hepatic oxidative stress, gut microbiota or serum endotoxin levels between HF and HFHI groups. These results suggested that dietary iron supplementation enhances experimental steatohepatitis induced by long-term high-fat diet feeding in rats. Iron-laden macrophages can play an important role in the enhancement of hepatic inflammation. PMID- 29401708 TI - Role of Cationic Side Chains in the Antimicrobial Activity of C18G. AB - Antimicrobial peptides (AMPs) have been an area of great interest, due to the high selectivity of these molecules toward bacterial targets over host cells and the limited development of bacterial resistance to these molecules throughout evolution. The peptide C18G has been shown to be a selective, broad spectrum AMP with a net +8 cationic charge from seven lysine residues in the sequence. In this work, the cationic Lys residues were replaced with other natural or non proteinogenic cationic amino acids: arginine, histidine, ornithine, or diaminopropionic acid. These changes vary in the structure of the amino acid side chain, the identity of the cationic moiety, and the pKa of the cationic group. Using a combination of spectroscopic and microbiological methods, the influence of these cationic groups on membrane binding, secondary structure, and antibacterial activity was investigated. The replacement of Lys with most other cationic residues had, at most, 2-fold effects on minimal inhibitory concentration against a variety of Gram-positive and Gram-negative bacteria. However, the peptide containing His as the cationic group showed dramatically reduced activity. All peptide variants retained the ability to bind lipid vesicles and showed clear preference for binding vesicles that contained anionic lipids. Similarly, all peptides adopted a helical conformation when bound to lipids or membrane mimetics, although the peptide containing diaminopropionic acid exhibited a decreased helicity. The peptides exhibited a wider variety of activity in the permeabilization of bacterial membranes, with peptides containing Lys, Arg, or Orn being the most broadly active. In all, the antibacterial activity of the C18G peptide is generally tolerant to changes in the structure and identity of the cationic amino acids, yielding new possibilities for design and development of AMPs that may be less susceptible to immune and bacterial recognition or in vivo degradation. PMID- 29401712 TI - What is Developmental Dyslexia? AB - Until the 1950s, developmental dyslexia was defined as a hereditary visual disability, selectively affecting reading without compromising oral or non-verbal reasoning skills. This changed radically after the development of the phonological theory of dyslexia; this not only ruled out any role for visual processing in its aetiology, but it also cast doubt on the use of discrepancy between reading and reasoning skills as a criterion for diagnosing it. Here I argue that this theory is set at too high a cognitive level to be explanatory; we need to understand the pathophysiological visual and auditory mechanisms that cause children's phonological problems. I discuss how the 'magnocellular theory' attempts to do this in terms of slowed and error prone temporal processing which leads to dyslexics' defective visual and auditory sequencing when attempting to read. I attempt to deal with the criticisms of this theory and show how it leads to a number of successful ways of helping dyslexic children to overcome their reading difficulties. PMID- 29401713 TI - Wafer-Scale Hierarchical Nanopillar Arrays Based on Au Masks and Reactive Ion Etching for Effective 3D SERS Substrate. AB - Two-dimensional (2D) periodic micro/nanostructured arrays as SERS substrates have attracted intense attention due to their excellent uniformity and good stability. In this work, periodic hierarchical SiO2 nanopillar arrays decorated with Ag nanoparticles (NPs) with clean surface were prepared on a wafer-scale using monolayer Au NP arrays as masks, followed by reactive ion etching (RIE), depositing Ag layer and annealing. For the prepared SiO2 nanopillar arrays decorated with Ag NPs, the size of Ag NPs was tuned from ca. 24 to 126 nanometers by controlling the deposition thickness of Ag film. Importantly, the SiO2 nanopillar arrays decorated with Ag NPs could be used as highly sensitive SERS substrate for the detection of 4-aminothiophenol (4-ATP) and rhodamine 6G (R6G) due to the high loading of Ag NPs and a very uniform morphology. With a deposition thickness of Ag layer of 30 nm, the SiO2 nanopillar arrays decorated with Ag NPs exhibited the best sensitive SERS activity. The excellent SERS performance of this substrate is mainly attributed to high-density "hotspots" derived from nanogaps between Ag NPs. Furthermore, this strategy might be extended to synthesize other nanostructured arrays with a large area, which are difficult to be prepared only via conventional wet-chemical or physical methods. PMID- 29401714 TI - Will Green CSR Enhance Innovation? A Perspective of Public Visibility and Firm Transparency. AB - In response to the asking and requiring of stakeholders to be more environmentally responsible, firms must commit to green corporate social responsibility (CSR). Firms being green and responsible always can acquire intangible resources that are important for firm innovation. Given the scarcity of existing research addressing relevant issues in depth, this paper expands our understanding of green CSR by revealing its antecedent effects on firm innovation performance. We also include public visibility and firm transparency as contingency factors to explore the relationship between green CSR and firm innovation performance. Using data collected from publicly listed firms in China, we find that greater innovation performance is associated with an increase in firm green CSR, and the positive relationship between green CSR and innovation performance is moderated by public visibility and firm transparency. Based on the results, theoretical contributions and practical implications are outlined. PMID- 29401709 TI - Role of Corneal Stromal Cells on Epithelial Cell Function during Wound Healing. AB - Following injury, corneal stromal keratocytes transform into repair-phenotype of activated stromal fibroblasts (SFs) and participate in wound repair. Simultaneously, ongoing bi-directional communications between corneal stromal epithelial cells also play a vital role in mediating the process of wound healing. Factors produced by stromal cells are known to induce proliferation, differentiation, and motility of corneal epithelial cells, which are also subsequently the main processes that occur during wound healing. In this context, the present study aims to investigate the effect of SFs conditioned medium (SFCM) on corneal epithelial cell function along with substance P (SP). Antibody microarrays were employed to profile differentially expressed cell surface markers and cytokines in the presence of SFCM and SP. Antibody microarray data revealed enhanced expression of the ITGB1 in corneal epithelial cells following stimulation with SP whereas SFCM induced abundant expression of IL-8, ITGB1, PD1L1, PECA1, IL-15, BDNF, ICAM1, CD8A, CD44 and NTF4. All these proteins have either direct or indirect roles in epithelial cell growth, movement and adhesion related signaling cascades during tissue regeneration. We also observed activation of MAPK signaling pathway along with increased expression of focal adhesion kinase (FAK), paxillin, vimentin, beta-catenin and vasodilator stimulated phosphoprotein (VASP) phosphorylation. Additionally, epithelial-to mesenchymal transition (EMT) regulating transcription factors Slug and ZEB1 expression were enhanced in the presence of SFCM. SP enriched the expression of integrin subunits alpha4, alpha5, alphaV, beta1 and beta3 whereas SFCM increased alpha4, alpha5, alphaV, beta1 and beta5 integrin subunits. We also observed increased expression of Serpin E1 following SP and SFCM treatment. Wound healing scratch assay revealed enhanced migration of epithelial cells following the addition of SFCM. Taken together, we conclude that SFCM-mediated sustained activation of ZEB1, Slug in combination with upregulated migration-associated integrins and ERK (Extracellular signal-regulated kinase)-FAK-paxillin axis, may lead to induce type 2 EMT-like changes during corneal epithelial wound healing. PMID- 29401715 TI - Studies of the Influence of Beam Profile and Cooling Conditions on the Laser Deposition of a Directionally-Solidified Superalloy. AB - In the laser deposition of single crystal and directionally-solidified superalloys, it is desired to form laser deposits with high volume fractions of columnar grains by suppressing the columnar-to-equiaxed transition efficiently. In this paper, the influence of beam profile (circular and square shapes) and cooling conditions (natural cooling and forced cooling) on the geometric morphology and microstructure of deposits were experimentally studied in the laser deposition of a directionally-solidified superalloy, IC10, and the mechanisms of influence were revealed through a numerical simulation of the thermal processes during laser deposition. The results show that wider and thinner deposits were obtained with the square laser beam than those with the circular laser beam, regardless of whether natural or forced cooling conditions was used. The heights and contact angles of deposits were notably increased due to the reduced substrate temperatures by the application of forced cooling for both laser beam profiles. Under natural cooling conditions, columnar grains formed epitaxially at both the center and the edges of the deposits with the square laser beam, but only at the center of the deposits with the circular laser beam; under forced cooling conditions, columnar grains formed at both the center and the edges of deposits regardless of the laser beam profile. The high ratios of thermal gradient and solidification velocity in the height direction of the deposits were favorable to forming deposits with higher volume fractions of columnar grains. PMID- 29401717 TI - Optimization of Polycistronic Anti-CCR5 Artificial microRNA Leads to Improved Accuracy of Its Lentiviral Vector Transfer and More Potent Inhibition of HIV-1 in CD4+ T-Cells. AB - C-C chemokine receptor type 5 (CCR5) is utilized by human immunodeficiency virus (HIV) as a co-receptor for cell entry. Suppression of the CCR5 gene by artificial microRNAs (amiRNAs) could confer cell resistance. In previous work, we created a lentivector that encoded the polycistron of two identical amiRNAs that could effectively suppress CCR5. However, tandem repeats in lentiviral vectors led to deletions of the repeated sequences during reverse transcription of the vector RNA. To solve this problem, we have created a new amiRNA against CCR5, mic1002, which has a different microRNA scaffold and targets a different sequence. Replacing one of the two identical tandem amiRNAs in the polycistron with the mic1002 amiRNA increased the accuracy of its lentiviral vector transfer while retaining its ability to effectively suppress CCR5. A lentiviral vector containing two heterogenic amiRNAs significantly inhibited HIV replication in a vector-transduced human CD4+ lymphocyte culture. PMID- 29401716 TI - Do Coffee Polyphenols Have a Preventive Action on Metabolic Syndrome Associated Endothelial Dysfunctions? An Assessment of the Current Evidence. AB - Epidemiologic studies from several countries have found that mortality rates associated with the metabolic syndrome are inversely associated with coffee consumption. Metabolic syndrome can lead to arteriosclerosis by endothelial dysfunction, and increases the risk for myocardial and cerebral infarction. Accordingly, it is important to understand the possible protective effects of coffee against components of the metabolic syndrome, including vascular endothelial function impairment, obesity and diabetes. Coffee contains many components, including caffeine, chlorogenic acid, diterpenes and trigonelline. Studies have found that coffee polyphenols, such as chlorogenic acids, have many health-promoting properties, such as antioxidant, anti-inflammatory, anti-cancer, anti-diabetes, and antihypertensive properties. Chlorogenic acids may exert protective effects against metabolic syndrome risk through their antioxidant properties, in particular toward vascular endothelial cells, in which nitric oxide production may be enhanced, by promoting endothelial nitric oxide synthase expression. These effects indicate that coffee components may support the maintenance of normal endothelial function and play an important role in the prevention of metabolic syndrome. However, results related to coffee consumption and the metabolic syndrome are heterogeneous among studies, and the mechanisms of its functions and corresponding molecular targets remain largely elusive. This review describes the results of studies exploring the putative effects of coffee components, especially in protecting vascular endothelial function and preventing metabolic syndrome. PMID- 29401718 TI - A Review of Microfiber-Based Temperature Sensors. AB - Optical microfiber-based temperature sensors have been proposed for many applications in a variety of industrial uses, including biomedical, geological, automotive, and defense applications. This increasing demand for these micrometric devices is attributed to their large dynamic range, high sensitivity, fast-response, compactness and robustness. Additionally, they can perform in-situ measurements remotely and in harsh environments. This paper presents an overview of optical microfibers, with a focus on their applications in temperature sensing. This review broadly divides microfiber-based temperature sensors into two categories: resonant and non-resonant microfiber sensors. While the former includes microfiber loop, knot and coil resonators, the latter comprises sensors based on functionally coated/doped microfibers, microfiber couplers, optical gratings and interferometers. In the conclusions, a summary of reported performances is presented. PMID- 29401719 TI - Nanomaterial-Based Sensing and Biosensing of Phenolic Compounds and Related Antioxidant Capacity in Food. AB - Polyphenolic compounds (PCs) have received exceptional attention at the end of the past millennium and as much at the beginning of the new one. Undoubtedly, these compounds in foodstuffs provide added value for their well-known health benefits, for their technological role and also marketing. Many efforts have been made to provide simple, effective and user friendly analytical methods for the determination and antioxidant capacity (AOC) evaluation of food polyphenols. In a parallel track, over the last twenty years, nanomaterials (NMs) have made their entry in the analytical chemistry domain; NMs have, in fact, opened new paths for the development of analytical methods with the common aim to improve analytical performance and sustainability, becoming new tools in quality assurance of food and beverages. The aim of this review is to provide information on the most recent developments of new NMs-based tools and strategies for total polyphenols (TP) determination and AOC evaluation in food. In this review optical, electrochemical and bioelectrochemical approaches have been reviewed. The use of nanoparticles, quantum dots, carbon nanomaterials and hybrid materials for the detection of polyphenols is the main subject of the works reported. However, particular attention has been paid to the success of the application in real samples, in addition to the NMs. In particular, the discussion has been focused on methods/devices presenting, in the opinion of the authors, clear advancement in the fields, in terms of simplicity, rapidity and usability. This review aims to demonstrate how the NM-based approaches represent valid alternatives to classical methods for polyphenols analysis, and are mature to be integrated for the rapid quality assessment of food quality in lab or directly in the field. PMID- 29401720 TI - Non-Covalent Supported of l-Proline on Graphene Oxide/Fe3O4 Nanocomposite: A Novel, Highly Efficient and Superparamagnetically Separable Catalyst for the Synthesis of Bis-Pyrazole Derivatives. AB - A superparamagnetic graphene oxide/Fe3O4/l-proline nano hybrid that was obtained from the non-covalent immobilization of l-proline on graphene oxide/Fe3O4 nanocomposite was used as a new magnetically separable catalyst for the efficient synthesis of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives. The prepared heterogeneous catalyst was characterized using FTIR, TGA, DTG, XRD, TEM, SEM, and elemental analysis techniques. Short reaction times (5-15 min), excellent yields (87-98%), and simple experimental procedure with an easy work-up are some of the advantages of the introduced catalyst. PMID- 29401722 TI - Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy. AB - The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE's unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives. PMID- 29401723 TI - Removal of Pharmaceutical and Personal Care Products (PPCPs) from Municipal Waste Water with Integrated Membrane Systems, MBR-RO/NF. AB - This study focuses on the application of combining membrane bioreactor (MBR) treatment with reverse osmosis (RO) or nanofiltration (NF) membrane treatment for removal of pharmaceuticals and personal care products (PPCPs) in municipal wastewater. Twenty-seven PPCPs were measured in real influent with lowest average concentration being trimethoprim (7.12 ng/L) and the highest being caffeine (18.4 ng/L). The results suggest that the MBR system effectively removes the PPCPs with an efficiency of between 41.08% and 95.41%, and that the integrated membrane systems, MBR-RO/NF, can achieve even higher removal rates of above 95% for most of them. The results also suggest that, due to the differences in removal mechanisms of NF/RO membrane, differences of removal rates exist. In this study, the combination of MBR-NF resulted in the removal of 13 compounds to below detection limits and MBR-RO achieved even better results with removal of 20 compounds to below detection limits. PMID- 29401721 TI - Cell Migration Related to MDR-Another Impediment to Effective Chemotherapy? AB - Multidrug resistance, mediated by members of the ATP-binding cassette (ABC) proteins superfamily, has become one of the biggest obstacles in conquering tumour progression. If the chemotherapy outcome is considered successful, when the primary tumour volume is decreased or completely abolished, modulation of ABC proteins activity is one of the best methods to overcome drug resistance. However, if a positive outcome is represented by no metastasis or, at least, elongation of remission-free time, then the positive effect of ABC proteins inhibition should be compared with the several side effects it causes, which may inflict cancer progression and decrease overall patient health. Clinical trials conducted thus far have shown that the tested ABC modulators add limited or no benefits to cancer patients, as some of them are merely toxic and others induce unwanted drug-drug interactions. Moreover, the inhibition of certain ABC members has been recently indicated as potentially responsible for increased fibroblasts migration. A better understanding of the complex role of ABC proteins in relation to cancer progression may offer novel strategies in cancer therapy. PMID- 29401725 TI - Modal Identification in an Automotive Multi-Component System Using HS 3D-DIC. AB - The modal characterization of automotive lighting systems becomes difficult using sensors due to the light weight of the elements which compose the component as well as the intricate access to allocate them. In experimental modal analysis, high speed 3D digital image correlation (HS 3D-DIC) is attracting the attention since it provides full-field contactless measurements of 3D displacements as main advantage over other techniques. Different methodologies have been published that perform modal identification, i.e., natural frequencies, damping ratios, and mode shapes using the full-field information. In this work, experimental modal analysis has been performed in a multi-component automotive lighting system using HS 3D-DIC. Base motion excitation was applied to simulate operating conditions. A recently validated methodology has been employed for modal identification using transmissibility functions, i.e., the transfer functions from base motion tests. Results make it possible to identify local and global behavior of the different elements of injected polymeric and metallic materials. PMID- 29401724 TI - Emerging Roles of Tumor Necrosis Factor-Stimulated Gene-6 in the Pathophysiology and Treatment of Atherosclerosis. AB - Tumor necrosis factor-stimulated gene-6 (TSG-6) is a 35-kDa glycoprotein that has been shown to exert anti-inflammatory effects in experimental models of arthritis, acute myocardial infarction, and acute cerebral infarction. Several lines of evidence have shed light on the pathophysiological roles of TSG-6 in atherosclerosis. TSG-6 suppresses inflammatory responses of endothelial cells, neutrophils, and macrophages as well as macrophage foam cell formation and vascular smooth muscle cell (VSMC) migration and proliferation. Exogenous TSG-6 infusion and endogenous TSG-6 attenuation with a neutralizing antibody for four weeks retards and accelerates, respectively, the development of aortic atherosclerotic lesions in ApoE-deficient mice. TSG-6 also decreases the macrophage/VSMC ratio (a marker of plaque instability) and promotes collagen fibers in atheromatous plaques. In patients with coronary artery disease (CAD), plasma TSG-6 levels are increased and TSG-6 is abundantly expressed in the fibrous cap within coronary atheromatous plaques, indicating that TSG-6 increases to counteract the progression of atherosclerosis and stabilize the plaque. These findings indicate that endogenous TSG-6 enhancement and exogenous TSG-6 replacement treatments are expected to emerge as new lines of therapy against atherosclerosis and related CAD. Therefore, this review provides support for the clinical utility of TSG-6 in the diagnosis and treatment of atherosclerotic cardiovascular diseases. PMID- 29401727 TI - Empirical Study on the Sustainability of China's Grain Quality Improvement: The Role of Transportation, Labor, and Agricultural Machinery. AB - As a major part of farming sustainability, the issues of grain production and its quality improvement have been important in many countries. This paper aims to address these issues in China. Based on the data from the main production provinces and by applying the stochastic frontier analysis methodology, we find that the improvement of transportation and the use of agricultural machinery have become the main driving forces for grain quality improvement in China. After further studying different provinces' potentials of grain quality improvement, we show that grain quality has increased steadily. Therefore, we can conclude China's grain quality improvement is indeed sustainable. Furthermore, different grains like rice, wheat, and corn share similar characteristics in terms of quality improvement, but the improvement rate for rice is relatively low, while those of corn and wheat are relatively high. Moreover, the overall change of efficiency gain of grain quality improvement is not significant for different provinces. The efficiency gains of the quality improvements for rice and wheat even decrease slightly. In addition, we find that only expanding grain quality improvement potential can simultaneously achieve the dual objectives of improving grain quality and increasing yield. PMID- 29401726 TI - Epidemiological Characteristics and Spatial-Temporal Distribution of Hand, Foot, and Mouth Disease in Chongqing, China, 2009-2016. AB - (1) Objective: Even with licensed vaccine for enterovirus 71 (EV71) put into market in 2016 in China, hand, foot, and mouth disease (HFMD) is still a threat for children's health in Chongqing. We described the epidemiological characteristics and spatial-temporal patterns of HFMD in Chongqing from 2009 to 2016, in order to provide information and evidence for guiding public health response and intervention. (2) Methods: We retrieved the HFMD surveillance data from January 2009 to December 2016 from "National Disease Reporting Information System", and then analyzed demographic and geographical information integrally. Descriptive analysis was conducted to evaluate the epidemic features of HFMD in Chongqing. The spatial-temporal methods were performed to explore the clusters at district/county level. (3) Results: A total of 276,207 HFMD cases were reported during the study period (total population incidence: 114.8 per 100,000 per year), including 641 severe cases (129 deaths). The annual incidence of HFMD sharply increased in even-numbered years, but remained stable or decreased in odd numbered years. A semiannual seasonality was observed during April to July, and October to December in each year. The male-to-female ratios of the mild and severe cases were 1.4:1 and 1.5:1, with the median age of 2.3 years and 1.9 years, respectively. More than 90% of the cases were children equal to and less than 5 years old. High-incidence clustered regions included the main urban districts and northeast regions according to incidence rates comparison or space time cluster analysis. A total of 19,482 specimen were collected from the reported cases and 13,277 (68.2%) were positive for enterovirus. EV71 was the major causative agent for severe cases, while other enteroviruses were the predominant serotype for mild cases. (4) Conclusions: The characteristics of HFMD in Chongqing exhibited a phenomenon of increasing incidence in two-year cycles and semiannual seasonality in time distribution. Children <=5 years old, especially boys, were more affected by HFMD. EV71 was the major causative agent for severe cases. We suggest initiating mass EV71 vaccination campaigns among children aged 6 months to 5 years in Chongqing, especially in the main urban districts and northern regions, in order to reduce case fatality, and take integrated measurements for controlling and preventing HFMD attributed to other enteroviruses. PMID- 29401728 TI - Antibacterial Effects of Chitosan/Cationic Peptide Nanoparticles. AB - This study attempted to develop chitosan-based nanoparticles with increased stability and antibacterial activity. The chitosan/protamine hybrid nanoparticles were formed based on an ionic gelation method by mixing chitosan with protamine and subsequently cross-linking the mixtures with sodium tripolyphosphate (TPP). The effects of protamine on the chemical structures, physical properties, and antibacterial activities of the hybrid nanoparticles were investigated. The antibacterial experiments demonstrated that the addition of protamine (125 ug/mL) in the hybrid nanoparticles (500 ug/mL chitosan and 166.67 ug/mL TPP) improved the antimicrobial specificity with the minimum inhibitory concentration (MIC) value of 31.25 ug/mL towards Escherichia coli (E. coli), while the MIC value was higher than 250 ug/mL towards Bacillus cereus. The chitosan/protamine hybrid nanoparticles induced the formation of biofilm-like structure in B. cereus and non-motile-like structure in E. coli. The detection of bacterial cell ruptures showed that the inclusion of protamine in the hybrid nanoparticles caused different membrane permeability compared to chitosan nanoparticles and chitosan alone. The chitosan/protamine nanoparticles also exhibited lower binding affinity towards B. cereus than E. coli. The results suggested that the hybridization of chitosan with protamine improved the antibacterial activity of chitosan nanoparticles towards pathogenic E. coli, but the inhibitory effect against probiotic B. cereus was significantly reduced. PMID- 29401729 TI - Follow-Up of Peripheral IL-1beta and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery. AB - Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1beta and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-kappaB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1beta and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-kappaB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-kappaB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation. PMID- 29401730 TI - Naive Bayes Bearing Fault Diagnosis Based on Enhanced Independence of Data. AB - The bearing is the key component of rotating machinery, and its performance directly determines the reliability and safety of the system. Data-based bearing fault diagnosis has become a research hotspot. Naive Bayes (NB), which is based on independent presumption, is widely used in fault diagnosis. However, the bearing data are not completely independent, which reduces the performance of NB algorithms. In order to solve this problem, we propose a NB bearing fault diagnosis method based on enhanced independence of data. The method deals with data vector from two aspects: the attribute feature and the sample dimension. After processing, the classification limitation of NB is reduced by the independence hypothesis. First, we extract the statistical characteristics of the original signal of the bearings effectively. Then, the Decision Tree algorithm is used to select the important features of the time domain signal, and the low correlation features is selected. Next, the Selective Support Vector Machine (SSVM) is used to prune the dimension data and remove redundant vectors. Finally, we use NB to diagnose the fault with the low correlation data. The experimental results show that the independent enhancement of data is effective for bearing fault diagnosis. PMID- 29401731 TI - BC-Box Motif-Mediated Neuronal Differentiation of Somatic Stem Cells. AB - Von Hippel-Lindau tumor suppressor protein (pVHL) functions to induce neuronal differentiation of neural stem/progenitor cells (NSCs) and skin-derived precursors (SKPs). Here we identified a neuronal differentiation domain (NDD) in pVHL. Neuronal differentiation of SKPs was induced by intracellular delivery of a peptide composed of the amino-acid sequences encoded by the NDD. Neuronal differentiation mediated by the NDD was caused by the binding between it and elongin C followed by Janus kinase-2 (JAK2) ubiquitination of JAK2 and inhibition of the JAK2/the signal transducer and activator of transcription-3(STAT)3 pathway. The NDD in pVHL contained the BC-box motif ((A,P,S,T)LXXX (A,C) XXX(A,I,L,V)) corresponding to the binding site of elongin C. Therefore, we proposed that other BC-box proteins might also contain an NDD; and subsequently also identified in them an NDD containing the amino-acid sequence encoded by the BC-box motif in BC-box proteins. Furthermore, we showed that different NDD peptide-delivered cells differentiated into different kinds of neuron-like cells. That is, dopaminergic neuron-like cells, cholinergic neuron-like cells, GABAnergic neuron-like cells or rhodopsin-positive neuron-like cells were induced by different NDD peptides. These novel findings might contribute to the development of a new method for promoting neuronal differentiation and shed further light on the mechanism of neuronal differentiation of somatic stem cells. PMID- 29401732 TI - Evaluation of the Effectiveness of Acupuncture in the Treatment of Knee Osteoarthritis: A Case Study. AB - Background: Osteoarthritis is a widespread chronic disease seen as a continuum of clinical occurrences within several phases, which go from synovial inflammation and microscopic changes of bone and cartilage to painful destructive changes of all the joint structures. Being the most common joint disease, it is the leading cause of disability in working individuals above 50 years of age. In some cases, conventional treatments produce just a mild and brief pain reduction and have considerable side-effects. Contemporary Traditional Chinese Medicine (TCM) is a model of systems biology based on a logically accessible theoretical background. It integrates several therapeutic approaches, among them acupuncture, which has shown effective results in the treatment of knee and hip osteoarthritis, minimizing pain, improving functionality and consequently leading to a better quality of life. Methods: The present case study included two patients with clinical signs of osteoarthritis and diagnosis of medial pain, as defined by the Heidelberg Model of TCM. Over 6 weeks, those patients were treated with acupuncture, with a frequency of one session a week. The sessions lasted for thirty minutes and were based on the needling of 4 local acupoints. Before and after each session, pain and mobility assessments were performed. Results: The results were positive, with significant reduction of pain and increased knee joint flexion amplitude and mobility. Conclusion: Acupuncture was effective as an alternative or complementary treatment of knee osteoarthritis, with high levels of improvement within a modest intervention period. PMID- 29401733 TI - An Active Learning Activity to Reinforce the Design Components of the Corticosteroids. AB - Despite the popularity of active learning applications over the past few decades, few activities have been reported for the field of medicinal chemistry. The purpose of this study is to report a new active learning activity, describe participant contributions, and examine participant performance on the assessment questions mapped to the objective covered by the activity. In this particular activity, students are asked to design two novel corticosteroids as a group (6-8 students per group) based on the design characteristics of marketed corticosteroids covered in lecture coupled with their pharmaceutics knowledge from the previous semester and then defend their design to the class through an interactive presentation model. Although class performance on the objective mapped to this material on the assessment did not reach statistical significance, use of this activity has allowed fruitful discussion of misunderstood concepts and facilitated multiple changes to the lecture presentation. As pharmacy schools continue to emphasize alternative learning pedagogies, publication of previously implemented activities demonstrating their use will help others apply similar methodologies. PMID- 29401734 TI - Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules. AB - Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ. PMID- 29401735 TI - Prediction of Effective Drug Combinations by an Improved Naive Bayesian Algorithm. AB - Drug combinatorial therapy is a promising strategy for combating complex diseases due to its fewer side effects, lower toxicity and better efficacy. However, it is not feasible to determine all the effective drug combinations in the vast space of possible combinations given the increasing number of approved drugs in the market, since the experimental methods for identification of effective drug combinations are both labor- and time-consuming. In this study, we conducted systematic analysis of various types of features to characterize pairs of drugs. These features included information about the targets of the drugs, the pathway in which the target protein of a drug was involved in, side effects of drugs, metabolic enzymes of the drugs, and drug transporters. The latter two features (metabolic enzymes and drug transporters) were related to the metabolism and transportation properties of drugs, which were not analyzed or used in previous studies. Then, we devised a novel improved naive Bayesian algorithm to construct classification models to predict effective drug combinations by using the individual types of features mentioned above. Our results indicated that the performance of our proposed method was indeed better than the naive Bayesian algorithm and other conventional classification algorithms such as support vector machine and K-nearest neighbor. PMID- 29401738 TI - Cytotoxicity Enhancement in Breast Cancer Cells with Carbonate Apatite Facilitated Intracellular Delivery of Anti-Cancer Drugs. AB - Pharmacotherapy as the mainstay in the management of breast cancer has demonstrated various drawbacks, including non-targeted bio distribution and narrow therapeutic and safety windows. Thus, enhancements in pharmacodynamic and pharmacokinetic profiles of the classical anti-cancer drugs could lead to improved efficacy against cancer cells. Therefore, inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized to efficiently deliver various drugs into cancer cells. Following characterization and various modifications in the structure of CA complexes with different drugs, lifted outcomes were achieved. Markedly, complexing paclitaxel with CA resulted in 20.71 +/- 4.34% loading efficiency together with 24.14 +/- 2.21% enhancement in cytotoxicity on MCF-7 cells plus superior in vivo anti-tumour efficacy compared to free paclitaxel. PMID- 29401736 TI - All-Round Manipulation of the Actin Cytoskeleton by HIV. AB - While significant progress has been made in terms of human immunodeficiency virus (HIV) therapy, treatment does not represent a cure and remains inaccessible to many people living with HIV. Continued mechanistic research into the viral life cycle and its intersection with many aspects of cellular biology are not only fundamental in the continued fight against HIV, but also provide many key observations of the workings of our immune system. Decades of HIV research have testified to the integral role of the actin cytoskeleton in both establishing and spreading the infection. Here, we review how the virus uses different strategies to manipulate cellular actin networks and increase the efficiency of various stages of its life cycle. While some HIV proteins seem able to bind to actin filaments directly, subversion of the cytoskeleton occurs indirectly by exploiting the power of actin regulatory proteins, which are corrupted at multiple levels. Furthermore, this manipulation is not restricted to a discrete class of proteins, but rather extends throughout all layers of the cytoskeleton. We discuss prominent examples of actin regulators that are exploited, neutralized or hijacked by the virus, and address how their coordinated deregulation can lead to changes in cellular behavior that promote viral spreading. PMID- 29401739 TI - Self-Organized Nanostructure Modified Microelectrode for Sensitive Electrochemical Glutamate Detection in Stem Cells-Derived Brain Organoids. AB - Neurons release neurotransmitters such as glutamate to communicate with each other and to coordinate brain functioning. As increased glutamate release is indicative of neuronal maturation and activity, a system that can measure glutamate levels over time within the same tissue and/or culture system is highly advantageous for neurodevelopmental investigation. To address such challenges, we develop for the first time a convenient method to realize functionalized borosilicate glass capillaries with nanostructured texture as an electrochemical biosensor to detect glutamate release from cerebral organoids generated from human embryonic stem cells (hESC) that mimic various brain regions. The biosensor shows a clear catalytic activity toward the oxidation of glutamate with a sensitivity of 93 +/- 9.5 nA.uM-1.cm-2. It was found that the enzyme-modified microelectrodes can detect glutamate in a wide linear range from 5 uM to 0.5 mM with a limit of detection (LOD) down to 5.6 +/- 0.2 uM. Measurements were performed within the organoids at different time points and consistent results were obtained. This data demonstrates the reliability of the biosensor as well as its usefulness in measuring glutamate levels across time within the same culture system. PMID- 29401740 TI - Primary Care Comprehensiveness Can Reduce Emergency Department Visits and Hospitalization in People with Hypertension in South Korea. AB - Hypertension has been the leading risk factor contributing to cardiovascular morbidity and mortality, which needs comprehensive measures to manage and can be controlled effectively in primary care. In the health care context of South Korea, where specialists can see patients directly at their own community clinics and there has been no consensus on the definition of primary care, the authors used the nationally representative 2013 Korea Health Panel data, categorized adults (>=18 years) with hypertension by types of usual source of care (USC), and analyzed the association of having a comprehensive community clinic (i.e., primary care) physician as a USC with experience of emergency department (ED) visits and hospitalization within a year. After adjusting for cofounding variables including Charlson comorbidity index scores, those having a primary care physician as a USC remained associated with a decrease in an experience of ED visits (OR: 0.61, 95% CI: 0.40-0.93) and hospitalization (OR: 0.69, 95% CI: 0.49-0.96), compared to those not having a usual physician. Health policies that promote having a primary care physician as a USC could decrease unnecessary experience of ED visits and hospitalization by adults with hypertension. This can partly reduce ED overcrowding and avoidable hospitalization in Korea. PMID- 29401737 TI - Neutrophils: Beneficial and Harmful Cells in Septic Arthritis. AB - Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host derived leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable in the first-line defense to kill invading pathogens in the early stage of disease. However, on the other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible damage to the infected joint, which is known as an important complication in septic arthritis patients. Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an efficient therapy to reduce tissue damage in septic arthritis. PMID- 29401741 TI - ABCA7 and Pathogenic Pathways of Alzheimer's Disease. AB - The ATP-binding cassette (ABC) reporter family functions to regulate the homeostasis of phospholipids and cholesterol in the central nervous system, as well as peripheral tissues. ABCA7 belongs to the A subfamily of ABC transporters, which shares 54% sequence identity with ABCA1. While ABCA7 is expressed in a variety of tissues/organs, including the brain, recent genome-wide association studies (GWAS) have identified ABCA7 gene variants as susceptibility loci for late-onset Alzheimer's disease (AD). More important, subsequent genome sequencing analyses have revealed that premature termination codon mutations in ABCA7 are associated with the increased risk for AD. Alzheimer's disease is a progressive neurodegenerative disease and the most common cause of dementia, where the accumulation and deposition of amyloid-beta (Abeta) peptides cleaved from amyloid precursor protein (APP) in the brain trigger the pathogenic cascade of the disease. In consistence with human genetic studies, increasing evidence has demonstrated that ABCA7 deficiency exacerbates Abeta pathology using in vitro and in vivo models. While ABCA7 has been shown to mediate phagocytic activity in macrophages, ABCA7 is also involved in the microglial Abeta clearance pathway. Furthermore, ABCA7 deficiency results in accelerated Abeta production, likely by facilitating endocytosis and/or processing of APP. Taken together, current evidence suggests that ABCA7 loss-of-function contributes to AD-related phenotypes through multiple pathways. A better understanding of the function of ABCA7 beyond lipid metabolism in both physiological and pathological conditions becomes increasingly important to explore AD pathogenesis. PMID- 29401743 TI - Current and Future Applications of Biomedical Engineering for Proteomic Profiling: Predictive Biomarkers in Neuro-Traumatology. AB - This systematic review aims to summarize the impact of nanotechnology and biomedical engineering in defining clinically meaningful predictive biomarkers in patients with traumatic brain injury (TBI), a critical worldwide health problem with an estimated 10 billion people affected annually worldwide. Data were collected through a review of the existing English literature performed on Scopus, MEDLINE, MEDLINE in Process, EMBASE, and/or Cochrane Central Register of Controlled Trials. Only experimental articles revolving around the management of TBI, in which the role of new devices based on innovative discoveries coming from the field of nanotechnology and biomedical engineering were highlighted, have been included and analyzed in this study. Based on theresults gathered from this research on innovative methods for genomics, epigenomics, and proteomics, their future application in this field seems promising. Despite the outstanding technical challenges of identifying reliable biosignatures for TBI and the mixed nature of studies herein described (single cells proteomics, biofilms, sensors, etc.), the clinical implementation of those discoveries will allow us to gain confidence in the use of advanced neuromonitoring modalities with a potential dramatic improvement in the management of those patients. PMID- 29401742 TI - Induced Salt Tolerance of Perennial Ryegrass by a Novel Bacterium Strain from the Rhizosphere of a Desert Shrub Haloxylon ammodendron. AB - Drought and soil salinity reduce agricultural output worldwide. Plant-growth promoting rhizobacteria (PGPR) can enhance plant growth and augment plant tolerance to biotic and abiotic stresses. Haloxylon ammodendron, a C4 perennial succulent xerohalophyte shrub with excellent drought and salt tolerance, is naturally distributed in the desert area of northwest China. In our previous work, a bacterium strain numbered as M30-35 was isolated from the rhizosphere of H. ammodendron in Tengger desert, Gansu province, northwest China. In current work, the effects of M30-35 inoculation on salt tolerance of perennial ryegrass were evaluated and its genome was sequenced to identify genes associated with plant growth promotion. Results showed that M30-35 significantly enhanced growth and salt tolerance of perennial ryegrass by increasing shoot fresh and dry weights, chlorophyll content, root volume, root activity, leaf catalase activity, soluble sugar and proline contents that contributed to reduced osmotic potential, tissue K+ content and K+/Na+ ratio, while decreasing malondialdehyde (MDA) content and relative electric conductivity (REC), especially under higher salinity. The genome of M30-35 contains 4421 protein encoding genes, 12 rRNA, 63 tRNA-encoding genes and four rRNA operons. M30-35 was initially classified as a new species in Pseudomonas and named as Pseudomonas sp. M30-35. Thirty-four genes showing homology to genes associated with PGPR traits and abiotic stress tolerance were identified in Pseudomonas sp. M30-35 genome, including 12 related to insoluble phosphorus solubilization, four to auxin biosynthesis, four to other process of growth promotion, seven to oxidative stress alleviation, four to salt and drought tolerance and three to cold and heat tolerance. Further study is needed to clarify the correlation between these genes from M30-35 and the salt stress alleviation of inoculated plants under salt stress. Overall, our research indicated that desert shrubs appear rich in PGPRs that can help important crops tolerate abiotic stress. PMID- 29401744 TI - Elevated Polyamines in Saliva of Pancreatic Cancer. AB - Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of PC detection in early stages. Polyamines have been reported as possible biomarkers in urine and saliva samples in various cancers. Here, we analyzed salivary metabolites, including polyamines, using capillary electrophoresis-mass spectrometry. Salivary samples were collected from patients with PC (n = 39), those with chronic pancreatitis (CP, n = 14), and controls (C, n = 26). Polyamines, such as spermine, N1 acetylspermidine, and N1-acetylspermine, showed a significant difference between patients with PC and those with C, and the combination of four metabolites including N1-acetylspermidine showed high accuracy in discriminating PC from the other two groups. These data show the potential of saliva as a source for tests screening for PC. PMID- 29401745 TI - Foil Strain Gauges Using Piezoresistive Carbon Nanotube Yarn: Fabrication and Calibration. AB - Carbon nanotube yarns are micron-scale fibers comprised by tens of thousands of carbon nanotubes in their cross section and exhibiting piezoresistive characteristics that can be tapped to sense strain. This paper presents the details of novel foil strain gauge sensor configurations comprising carbon nanotube yarn as the piezoresistive sensing element. The foil strain gauge sensors are designed using the results of parametric studies that maximize the sensitivity of the sensors to mechanical loading. The fabrication details of the strain gauge sensors that exhibit the highest sensitivity, based on the modeling results, are described including the materials and procedures used in the first prototypes. Details of the calibration of the foil strain gauge sensors are also provided and discussed in the context of their electromechanical characterization when bonded to metallic specimens. This characterization included studying their response under monotonic and cyclic mechanical loading. It was shown that these foil strain gauge sensors comprising carbon nanotube yarn are sensitive enough to capture strain and can replicate the loading and unloading cycles. It was also observed that the loading rate affects their piezoresistive response and that the gauge factors were all above one order of magnitude higher than those of typical metallic foil strain gauges. Based on these calibration results on the initial sensor configurations, new foil strain gauge configurations will be designed and fabricated, to increase the strain gauge factors even more. PMID- 29401747 TI - Evaluating the Hydrologic Performance of Low Impact Development Scenarios in a Micro Urban Catchment. AB - As urbanization progresses, increasingly impervious surfaces have changed the hydrological processes in cities and resulted in a major challenge for urban stormwater control. This study uses the urban stormwater model to evaluate the performance and costs of low impact development (LID) scenarios in a micro urban catchment. Rainfall-runoff data of three rainfall events were used for model calibration and validation. The pre-developed (PreDev) scenario, post-developed (PostDev) scenario, and three LID scenarios were used to evaluate the hydrologic performance of LID measures. Using reduction in annual runoff as the goal, the best solutions for each LID scenario were selected using cost-effectiveness curves. The simulation results indicated that the three designed LID scenarios could effectively reduce annual runoff volumes and pollutant loads compared with the PostDev scenario. The most effective scenario (MaxPerf) reduced annual runoff by 53.4%, followed by the sponge city (SpoPerf, 51.5%) and economy scenarios (EcoPerf, 43.1%). The runoff control efficiency of the MaxPerf and SpoPerf scenarios increased by 23.9% and 19.5%, respectively, when compared with the EcoPerf scenario; however, the costs increased by 104% and 83.6%. The reduction rates of four pollutants (TSS, TN, TP, and COD) under the MaxPerf scenario were 59.8-61.1%, followed by SpoPerf (53.9-58.3%) and EcoPerf (42.3-45.4%), and the costs of the three scenarios were 3.74, 3.47, and 1.83 million yuan, respectively. These results can provide guidance to urban stormwater managers in future urban planning to improve urban water security. PMID- 29401746 TI - Intracranial Pressure Monitoring-Review and Avenues for Development. AB - Intracranial pressure (ICP) monitoring is a staple of neurocritical care. The most commonly used current methods of monitoring in the acute setting include fluid-based systems, implantable transducers and Doppler ultrasonography. It is well established that management of elevated ICP is critical for clinical outcomes. However, numerous studies show that current methods of ICP monitoring cannot reliably define the limit of the brain's intrinsic compensatory capacity to manage increases in pressure, which would allow for proactive ICP management. Current work in the field hopes to address this gap by harnessing live-streaming ICP pressure-wave data and a multimodal integration with other physiologic measures. Additionally, there is continued development of non-invasive ICP monitoring methods for use in specific clinical scenarios. PMID- 29401748 TI - Key Aspects of Nucleic Acid Library Design for in Vitro Selection. AB - Nucleic acid aptamers capable of selectively recognizing their target molecules have nowadays been established as powerful and tunable tools for biospecific applications, be it therapeutics, drug delivery systems or biosensors. It is now generally acknowledged that in vitro selection enables one to generate aptamers to almost any target of interest. However, the success of selection and the affinity of the resulting aptamers depend to a large extent on the nature and design of an initial random nucleic acid library. In this review, we summarize and discuss the most important features of the design of nucleic acid libraries for in vitro selection such as the nature of the library (DNA, RNA or modified nucleotides), the length of a randomized region and the presence of fixed sequences. We also compare and contrast different randomization strategies and consider computer methods of library design and some other aspects. PMID- 29401751 TI - Calibration of Elasto-Magnetic Sensors on In-Service Cable-Stayed Bridges for Stress Monitoring. AB - The recent developments in measurement technology have led to the installation of efficient monitoring systems on many bridges and other structures all over the world. Nowadays, more and more structures have been built and instrumented with sensors. However, calibration and installation of sensors remain challenging tasks. In this paper, we use a case study, Adige Bridge, in order to present a low-cost method for the calibration and installation of elasto-magnetic sensors on cable-stayed bridges. Elasto-magnetic sensors enable monitoring of cable stress. The sensor installation took place two years after the bridge construction. The calibration was conducted in two phases: one in the laboratory and the other one on site. In the laboratory, a sensor was built around a segment of cable that was identical to those of the cable-stayed bridge. Then, the sample was subjected to a defined tension force. The sensor response was compared with the applied load. Experimental results showed that the relationship between load and magnetic permeability does not depend on the sensor fabrication process except for an offset. The determination of this offset required in situ calibration after installation. In order to perform the in situ calibration without removing the cables from the bridge, vibration tests were carried out for the estimation of the cables' tensions. At the end of the paper, we show and discuss one year of data from the elasto-magnetic sensors. Calibration results demonstrate the simplicity of the installation of these sensors on existing bridges and new structures. PMID- 29401749 TI - The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti Cancer Properties through Selective Sirtuin 1/2 Inhibition. AB - NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 uM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and alpha-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ? 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. PMID- 29401750 TI - Anti-Inflammatory Effect of Melittin on Porphyromonas Gingivalis LPS-Stimulated Human Keratinocytes. AB - Periodontitis is a chronic inflammatory disease that contributes to the destruction of the gingiva. Porphyromonas gingivalis (P. gingivalis) can cause periodontitis via its pathogenic lipopolysaccharides (LPS). Melittin, a major component of bee venom, is known to have anti-inflammatory and antibacterial effects. However, the role of melittin in the inflammatory response has not been elucidated in periodontitis-like human keratinocytes. Therefore, we investigated the anti-inflammatory effects of melittin on a P. gingivalis LPS (PgLPS)-treated HaCaT human keratinocyte cell line. The cytotoxicity of melittin was measured using a human keratinocyte cell line, HaCaT, and a Cell Counting Kit-8. The effect of melittin on PgLPS-induced inflammation was determined with Western blot, real-time quantitative PCT, and immunofluorescence. PgLPS increased the expression of toll-like receptor (TLR) 4 and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, and interferon gamma (IFN-gamma). Moreover, PgLPS induced activation of the nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB), extracellular signal regulated kinase (ERK), and protein kinase B/Akt. Melittin also inhibited the expression of proinflammatory cytokines by suppressing the activation of the NF kappaB signaling pathway, ERK, and Akt. Melittin attenuates the PgLPS-induced inflammatory response and could therefore be applied in the treatment of periodontitis for anti-inflammatory effects. PMID- 29401752 TI - Flexible Piezoelectric Sensor-Based Gait Recognition. AB - Most motion recognition research has required tight-fitting suits for precise sensing. However, tight-suit systems have difficulty adapting to real applications, because people normally wear loose clothes. In this paper, we propose a gait recognition system with flexible piezoelectric sensors in loose clothing. The gait recognition system does not directly sense lower-body angles. It does, however, detect the transition between standing and walking. Specifically, we use the signals from the flexible sensors attached to the knee and hip parts on loose pants. We detect the periodic motion component using the discrete time Fourier series from the signal during walking. We adapt the gait detection method to a real-time patient motion and posture monitoring system. In the monitoring system, the gait recognition operates well. Finally, we test the gait recognition system with 10 subjects, for which the proposed system successfully detects walking with a success rate over 93 %. PMID- 29401753 TI - Elsinopirins A-D, Decalin Polyketides from the Ascomycete Elsinoe pyri. AB - In course of our screening for new secondary metabolites from ecological niche specialized, phytopathogenic fungi, the plant pathogen Elsinoe pyri, strain 2203C, was found to produce four novel compounds (1-4), which were named elsinopirins A-D, in addition to the known metabolite elsinochrome A (5). After isolation by preparative high-performance liquid chromatography (HPLC), their structures, including relative stereochemistry, were elucidated by 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. Finally, absolute stereochemistry was assigned by chemical shifts of Mosher's esters (alpha-methoxy-alpha-trifluoromethylphenylacetic acid; MTPA) derivatives of elsinopirin B (2). The compounds were found to be devoid of significant antibacterial, antifungal, and cytotoxic activities. PMID- 29401754 TI - Implementation of a Surface Electromyography-Based Upper Extremity Exoskeleton Controller Using Learning from Demonstration. AB - Upper-extremity exoskeletons have demonstrated potential as augmentative, assistive, and rehabilitative devices. Typical control of upper-extremity exoskeletons have relied on switches, force/torque sensors, and surface electromyography (sEMG), but these systems are usually reactionary, and/or rely on entirely hand-tuned parameters. sEMG-based systems may be able to provide anticipatory control, since they interface directly with muscle signals, but typically require expert placement of sensors on muscle bodies. We present an implementation of an adaptive sEMG-based exoskeleton controller that learns a mapping between muscle activation and the desired system state during interaction with a user, generating a personalized sEMG feature classifier to allow for anticipatory control. This system is robust to novice placement of sEMG sensors, as well as subdermal muscle shifts. We validate this method with 18 subjects using a thumb exoskeleton to complete a book-placement task. This learning-from demonstration system for exoskeleton control allows for very short training times, as well as the potential for improvement in intent recognition over time, and adaptation to physiological changes in the user, such as those due to fatigue. PMID- 29401755 TI - Secure Indoor Localization Based on Extracting Trusted Fingerprint. AB - [-5]Indoor localization based on WiFi has attracted a lot of research effort because of the widespread application of WiFi. Fingerprinting techniques have received much attention due to their simplicity and compatibility with existing hardware. However, existing fingerprinting localization algorithms may not resist abnormal received signal strength indication (RSSI), such as unexpected environmental changes, impaired access points (APs) or the introduction of new APs. Traditional fingerprinting algorithms do not consider the problem of new APs and impaired APs in the environment when using RSSI. In this paper, we propose a secure fingerprinting localization (SFL) method that is robust to variable environments, impaired APs and the introduction of new APs. In the offline phase, a voting mechanism and a fingerprint database update method are proposed. We use the mutual cooperation between reference anchor nodes to update the fingerprint database, which can reduce the interference caused by the user measurement data. We analyze the standard deviation of RSSI, mobilize the reference points in the database to vote on APs and then calculate the trust factors of APs based on the voting results. In the online phase, we first make a judgment about the new APs and the broken APs, then extract the secure fingerprints according to the trusted factors of APs and obtain the localization results by using the trusted fingerprints. In the experiment section, we demonstrate the proposed method and find that the proposed strategy can resist abnormal RSSI and can improve the localization accuracy effectively compared with the existing fingerprinting localization algorithms. PMID- 29401756 TI - In-Depth Proteomic Characterization of Classical and Non-Classical Monocyte Subsets. AB - Monocytes are bone marrow-derived leukocytes that are part of the innate immune system. Monocytes are divided into three subsets: classical, intermediate and non classical, which can be differentiated by their expression of some surface antigens, mainly CD14 and CD16. These cells are key players in the inflammation process underlying the mechanism of many diseases. Thus, the molecular characterization of these cells may provide very useful information for understanding their biology in health and disease. We performed a multicentric proteomic study with pure classical and non-classical populations derived from 12 healthy donors. The robust workflow used provided reproducible results among the five participating laboratories. Over 5000 proteins were identified, and about half of them were quantified using a spectral counting approach. The results represent the protein abundance catalogue of pure classical and enriched non classical blood peripheral monocytes, and could serve as a reference dataset of the healthy population. The functional analysis of the differences between cell subsets supports the consensus roles assigned to human monocytes. PMID- 29401758 TI - Spatial multiplexing reconstruction for Fourier-transform ghost imaging via sparsity constraints. AB - A spatial multiplexing reconstruction method has been proposed to improve the sampling efficiency and image quality of Fourier-transform ghost imaging. In this method, the sensing equation of Fourier-transform ghost imaging is established based on recombination and reutilization of the correlated intensity distributions of light fields. It is theoretically proved that the scale of the sensing matrix in the sensing equation can be greatly reduced, and spatial multiplexing combined with this matrix reduction provides the feasibility of ghost imaging with just a few measurements. Experimental results show better visibility and signal-to-noise ratio in the Fourier spectrums reconstructed via spatial multiplexing compared with previous methods. The transmittance of an object is also recovered in spatial domain with better image quality based on its spectrum of spatial multiplexing reconstruction. This method is especially important to x-ray ghost imaging applications due to its potential for reducing radiation damage and achieving high quality images in x-ray microscopy. PMID- 29401759 TI - Phase retrieval in generalized optical interferometry systems. AB - Modal analysis of an optical field via generalized interferometry (GI) is a novel technique that treats said field as a linear superposition of transverse modes and recovers the amplitudes of modal weighting coefficients. We use phase retrieval by nonlinear optimization to recover the phase of these modal weighting coefficients. Information diversity increases the robustness of the algorithm by better constraining the solution. Additionally, multiple sets of random starting phase values assist the algorithm in overcoming local minima. The algorithm was able to recover nearly all coefficient phases for simulated fields consisting of up to 21 superpositioned Hermite Gaussian modes from simulated data and proved to be resilient to shot noise. PMID- 29401757 TI - Transcriptomic Analysis Provides Insights into Grafting Union Development in Pecan (Carya illinoinensis). AB - Pecan (Carya illinoinensis), as a popular nut tree, has been widely planted in China in recent years. Grafting is an important technique for its cultivation. For a successful grafting, graft union development generally involves the formation of callus and vascular bundles at the graft union. To explore the molecular mechanism of graft union development, we applied high throughput RNA sequencing to investigate the transcriptomic profiles of graft union at four timepoints (0 days, 8 days, 15 days, and 30 days) during the pecan grafting process. After de novo assembly, 83,693 unigenes were obtained, and 40,069 of them were annotated. A total of 12,180 differentially expressed genes were identified between by grafting. Genes involved in hormone signaling, cell proliferation, xylem differentiation, cell elongation, secondary cell wall deposition, programmed cell death, and reactive oxygen species (ROS) scavenging showed significant differential expression during the graft union developmental process. In addition, we found that the content of auxin, cytokinin, and gibberellin were accumulated at the graft unions during the grafting process. These results will aid in our understanding of successful grafting in the future. PMID- 29401760 TI - Mid-infrared upconversion based hyperspectral imaging. AB - Mid-infrared hyperspectral imaging has in the past decade emerged as a promising tool for medical diagnostics. In this work, nonlinear frequency upconversion based hyperspectral imaging in the 6 to 8 um spectral range is presented for the first time, using both broadband globar and narrowband quantum cascade laser illumination. AgGaS2 is used as the nonlinear medium for sum frequency generation using a 1064 nm mixing laser. Angular scanning of the nonlinear crystal provides broad spectral coverage at every spatial position in the image. This study demonstrates the retrieval of series of monochromatic images acquired by a silicon based CCD camera, using both broadband and narrowband illumination and a comparison is made between the two illumination sources for hyperspectral imaging. PMID- 29401761 TI - Wavelength division multiplexer based on cavity-resonator-integrated guided-mode resonance filters for a compact multi-wavelength light source. AB - Cavity-resonator-integrated guided-mode resonance filters (CRIGF) consisting of a grating coupler in a waveguide resonator formed by two distributed Bragg reflectors of different reflectances can act as a wavelength-selective reflector and an input waveguide coupler for an incident free-space wave. Integration of CRIGFs in a waveguide is proposed to give an array of external mirrors and a wavelength division multiplexer for constructing a compact multi-wavelength light source. Four CRIGFs of 10-MUm-size aperture with a wavelength spacing of 15 nm were designed and fabricated. The reflectance of 62% and output efficiency of higher than 18% were theoretically predicted. Multiplexing of four wavelengths was confirmed experimentally. PMID- 29401762 TI - Broadband 2-um emission on silicon chips: monolithically integrated Holmium lasers. AB - Laser sources in the mid-infrared are of great interest due to their wide applications in detection, sensing, communication and medicine. Silicon photonics is a promising technology which enables these laser devices to be fabricated in a standard CMOS foundry, with the advantages of reliability, compactness, low cost and large-scale production. In this paper, we demonstrate a holmium-doped distributed feedback laser monolithically integrated on a silicon photonics platform. The Al2O3:Ho3+ glass is used as gain medium, which provides broadband emission around 2 um. By varying the distributed feedback grating period and Al2O3:Ho3+ gain layer thickness, we show single mode laser emission at wavelengths ranging from 2.02 to 2.10 um. Using a 1950 nm pump, we measure a maximum output power of 15 mW, a slope efficiency of 2.3% and a side-mode suppression ratio in excess of 50 dB. The introduction of a scalable monolithic light source emitting at > 2 um is a significant step for silicon photonic microsystems operating in this highly promising wavelength region. PMID- 29401763 TI - Giant power enhancement for quasi-omnidirectional light radiation via epsilon near-zero materials. AB - We theoretically demonstrate a giant power enhancement effect for a line current source in a epsilon-near-zero (ENZ) two-dimensional (2D) shell with proper physical dimensions. Compared with the traditional high-epsilon dielectric approach, the ENZ scheme has the prominent advantage that the radiation performance is less sensitive to the outer radius of the shell, which is critically important for real applications where micro-nano fabrications are often involved. The enhancing performance is independent on the position of the source inside the ENZ shell and could be substantially strengthened by incorporating more sources, while the quasi-omnidirectional radiation pattern could be managed to have negligible variance, as evidenced by a particular example with an inner radius of the shell equal to 0.156lambda0. Compared with the single source case, two identical sources with a phase difference less than 134 degrees will raise the total radiation power more than 4 folds and the maxima will be about 30 when they are in phase. The field analysis shows that this quasi-isotropic radiation enhancement is mainly contributed by the amplification of the isotropic zeroth order mode radiation while the higher orders with anisotropic emission patterns are effectively suppressed by the specifically designed ENZ shell. In the end, a practicable device employing 4H silicon carbide (4H-SiC) naturally available with ENZ properties in the mid infrared regime is numerically proposed, which could provide more than 10 times of radiation enhancement through optimizing the permittivity of the inner dielectric cylinder. These results may find very important applications in the design of novel devices for mid-infrared photon sources or detectors. PMID- 29401764 TI - Analysis of the thickness dependence of metamaterial absorbers at terahertz frequencies. AB - Metamaterial absorbers typically consist of a metamaterial layer, a dielectric spacer layer, and a metallic ground plane. We have investigated the dependence of the metamaterial absorption maxima on the spacer layer thickness and the reflection coefficient of the metamaterial layer obtained in the absence of the ground plane layer. Specifically, we employ interference theory to obtain an analytical expression for the spacer thickness needed to maximize the absorption at a given frequency. The efficacy of this simple expression is experimentally verified at terahertz frequencies through detailed measurements of the absorption spectra of a series of metamaterials structures with different spacer thicknesses. Using an array of split-ring resonators (SRRs) as the metamaterial layer and SU8 as the spacer material we observe that the absorption peaks redshift as the spacer thickness is increased, in excellent agreement with our analysis. Our findings can be applied to guide metamaterial absorber designs and understand the absorption peak frequency shift of sensors based on metamaterial absorbers. PMID- 29401765 TI - Theoretical study of polarization dependence of carrier-induced refractive index change of quantum dot. AB - The influences of dot material component, barrier material component, aspect ratio and carrier density on the refractive index changes of TE mode and TM mode of columnar quantum dot are analyzed, and a multiparameter adjustment method is proposed to realize low polarization dependence of refractive index change. Then the quantum dots with low polarization dependence of refractive index change (<1.5%) within C-band (1530 nm - 1565 nm) are designed, and it shows that quantum dots with different material parameters are anticipated to have similar characteristics of low polarization dependence. PMID- 29401766 TI - Improvement of reliability in multi-interferometer-based counterfactual deterministic communication with dissipation compensation. AB - The direct counterfactual quantum communication (DCQC) is a surprising phenomenon that quantum information can be transmitted without using any carriers of physical particles. The nested interferometers are promising devices for realizing DCQC as long as the number of interferometers goes to be infinity. Considering the inevitable loss or dissipation in practical experimental interferometers, we analyze the dependence of reliability on the number of interferometers, and show that the reliability of direct communication is being rapidly degraded with the large number of interferometers. Furthermore, we simulate and test this counterfactual deterministic communication protocol with a finite number of interferometers, and demonstrate the improvement of the reliability using dissipation compensation in interferometers. PMID- 29401767 TI - Time- and frequency-resolved fluorescence with a single TCSPC detector via a Fourier-transform approach. AB - We introduce a broadband single-pixel spectro-temporal fluorescence detector, combining time-correlated single photon counting (TCSPC) with Fourier transform (FT) spectroscopy. A birefringent common-path interferometer (CPI) generates two time-delayed replicas of the sample's fluorescence. Via FT of their interference signal at the detector, we obtain a two-dimensional map of the fluorescence as a function of detection wavelength and emission time, with high temporal and spectral resolution. Our instrument is remarkably simple, as it only requires the addition of a CPI to a standard single-pixel TCSPC system, and it shows a readily adjustable spectral resolution with inherently broad bandwidth coverage. PMID- 29401768 TI - Cylindrical microlensing for enhanced collection efficiency of small pixel SPAD arrays in single-molecule localisation microscopy. AB - Single-photon avalanche photodiode (SPAD) image sensors offer time-gated photon counting, at high binary frame rates of >100 kFPS and with no readout noise. This makes them well-suited to a range of scientific applications, including microscopy, sensing and quantum optics. However, due to the complex electronics required, the fill factor tends to be significantly lower (< 10%) than that of EMCCD and sCMOS cameras (>90%), whilst the pixel size is typically larger, impacting the sensitivity and practicalities of the SPAD devices. This paper presents the first characterisation of a cylindrical-shaped microlens array applied to a small, 8 micron, pixel SPAD imager. The enhanced fill factor, ~50% for collimated light, is the highest reported value amongst SPAD sensors with comparable resolution and pixel pitch. We demonstrate the impact of the increased sensitivity in single-molecule localisation microscopy, obtaining a resolution of below 40nm, the best reported figure for a SPAD sensor. PMID- 29401769 TI - Engineering steady Knill-Laflamme-Milburn state of Rydberg atoms by dissipation. AB - The Knill-Laflamme-Milburn (KLM) states have been proved to be a useful resource for quantum information processing [Nature409, 46 (2001)]. For atomic KLM states, several schemes have been put forward based on the time-dependent unitary dynamics, but the dissipative generation of these states has not been reported. This work discusses the possibility for creating different forms of bipartite KLM states in neutral atom system, where the spontaneous emission of excited Rydberg states, combined with the Rydberg antiblockade mechanism, is actively exploited to engineer a steady KLM state from an arbitrary initial state. The numerical simulation of the master equation signifies that a fidelity above 99% is available with the current experimental parameters. PMID- 29401770 TI - Monte Carlo simulations of three-dimensional electromagnetic Gaussian Schell model sources. AB - This article presents a method to simulate a three-dimensional (3D) electromagnetic Gaussian-Schell model (EGSM) source with desired characteristics. Using the complex screen method, originally developed for the synthesis of two dimensional stochastic electromagnetic fields, a set of equations is derived which relate the desired 3D source characteristics to those of the statistics of the random complex screen. From these equations and the 3D EGSM source realizability conditions, a single criterion is derived, which when satisfied guarantees both the realizability and simulatability of the desired 3D EGSM source. Lastly, a 3D EGSM source, with specified properties, is simulated; the Monte Carlo simulation results are compared to the theoretical expressions to validate the method. PMID- 29401771 TI - Three-dimensional resolution-enhancement divided aperture correlation differential confocal microscopy with nanometer axial focusing capability. AB - Divided aperture confocal microscopy (DACM) provides an improved imaging depth, imaging contrast, and working distance at the expense of spatial resolution. Here, we present a new method-divided aperture correlation-differential confocal microscopy (DACDCM) to improve the DACM resolution and the focusing capability, without changing the DACM configuration. DACDCM divides the DACM image spot into two round regions symmetrical about the optical axis. Then the light intensity signals received simultaneously from two round regions by a charge-coupled device (CCD) are processed by correlation manipulation and differential subtraction to improve the DACM spatial resolution and axial focusing capability, respectively. Theoretical analysis and preliminary experiments indicate that, for the excitation wavelength of lambda = 632.8 nm, numerical aperture NA = 0.8, and normalized offset vM = 3.2 of the two regions, the DACDCM resolution is improved by 32.5% and 43.1% in the x and z directions, simultaneously, compared with that of the DACM. The axial focusing resolution used for the sample surface profile imaging was also significantly improved to 2 nm. PMID- 29401772 TI - Rate equation modeling of the frequency noise and the intrinsic spectral linewidth in quantum cascade lasers. AB - This work theoretically investigates the frequency noise (FN) characteristics of quantum cascade lasers (QCLs) through a three-level rate equation model, which takes into account both the carrier noise and the spontaneous emission noise through the Langevin approach. It is found that the power spectral density of the FN exhibits a broad peak due to the carrier noise induced carrier variation in the upper laser level, which is enhanced by the stimulated emission process. The peak amplitude is strongly dependent on the gain stage number and the linewidth broadening factor. In addition, an analytical formula of the intrinsic spectral linewidth of QCLs is derived based on the FN analysis. It is demonstrated that the laser linewidth can be narrowed by reducing the gain coefficient and/or accelerating the carrier scattering rates of the upper and the lower laser levels. PMID- 29401773 TI - Fabrication of hybrid optical line generator by direct machining. AB - In this study, a mold of a line generator consisting of a cylindrical lens array with a triangular diffractive grating was ultra-precision diamond machined with Moore 350FG 5-axis ultra-precision machine. The design and the simulation of the hybrid structure were performed using ray tracing and exact electromagnetic theory. The machined hybrid lens structure was replicated to a UV-curable polymer and was then characterized and tested. The optical measurements show that the hybrid element works as designed. PMID- 29401774 TI - Microwave spectroscopy measurement of ultracold ground state molecules produced via short-range photoassociation. AB - The high-resolution microwave (MW) spectroscopy is employed to measure the rotational structures of ultracold 85Rb133Cs molecules prepared in the X1Sigma+ (v = 0) ground state. These ground-state molecules are created using short-range photoassociation (PA) followed by the spontaneous emission. Using a combination of continuous-wave (CW) depletion spectroscopy and photoionization (PI) technique, we obtain the MW spectroscopy by coupling the neighboring rotational levels of ground-state molecules. Based on the frequency spacing obtained from the MW spectroscopy, the rotational constant of X1Sigma+ (v = 0) can be accurately determined with the rigid rotor model. The precision of the measurement by MW spectroscopy is found to be 3 orders of magnitude higher than the CW depletion spectroscopy. Our scheme provides a simple and highly accurate method for the measurement of molecular structure. PMID- 29401775 TI - Color dynamic holographic display with wide viewing angle by improved complex amplitude modulation. AB - An improved method of complex amplitude modulation (CAM) is proposed for color holographic display with a wide viewing angle. Bandlimited random initial phase is introduced to the CAM method, which overcomes the drawbacks brought by a constant initial phase and maintains the advantages of CAM. Modifications in CAM for color display are also explained. Both simulation and experimental results verify that the proposed method can reconstruct color 3D scenes successfully without the time-consuming process for encoding the computer-generated holograms. Compared with the display via traditional CAM, the results exhibit that the proposed method can reconstruct color 3D scenes with a better viewing effect. Because of the display effect improvement and the high calculation speed, this method can be applied to high performance holographic display. PMID- 29401776 TI - All-optical microscope autofocus based on an electrically tunable lens and a totally internally reflected IR laser. AB - Microscopic imaging at high spatial-temporal resolution over long time scales (minutes to hours) requires rapid and precise stabilization of the microscope focus. Conventional and commercial autofocus systems are largely based on piezoelectric stages or mechanical objective actuators. Objective to sample distance is either measured by image analysis approaches or by hardware modules measuring the intensity of reflected infrared light. We propose here a truly all optical microscope autofocus taking advantage of an electrically tunable lens and a totally internally reflected infrared probe beam. We implement a feedback-loop based on the lateral position of a totally internally reflected infrared laser on a quadrant photodetector, as an indicator of the relative defocus. We show here how to treat the combined contributions due to mechanical defocus and deformation of the tunable lens. As a result, the sample can be kept in focus without any mechanical movement, at rates up to hundreds of Hertz. The device requires only reflective optics and can be implemented at a fraction of the cost required for a comparable piezo-based actuator. PMID- 29401777 TI - Scattering media characterization with phase-only wavefront modulation. AB - A new experimental approach is demonstrated to probe the scattering properties of complex media. Using phase-only modulation of the light illuminating a random scattering sample, we induce and record fluctuations in the reflected speckle patterns. Using predictions from diffusion theory, we obtain the scattering and absorption coefficients of the sample from the average change in the speckle amplitude. Our approach, which is based on interference, is in principle able to give better signal to noise ratio as compared to an intensity modulation approach. We compare our results with those obtained from a knife-edge illumination method and enhanced back-scattering cone. Our work can find application in the non-invasive study of biological specimens as well as the study of light propagation in random scattering devices like solar cells or LEDs. PMID- 29401778 TI - Fluorescence emission difference with surface plasmon-coupled emission applied in confocal microscopy. AB - We combined confocal surface plasmon coupled emission microscopy (C-SPCEM) together with fluorescence emission difference (FED) technique to pursuit super resolution fluorescent image. Solid or hollow point spread function (PSF) for C SPCEM is achieved with radially-polarized or circularly-polarized illumination. The reason why PSF can be manipulated by the polarization of illumination light is corroborated by the interaction of fluorescent emitter with vector focal field on the plasmonic substrate. After introduction of FED technique, PSF for C-SPECM can shrunk to around lambda/4 in full-width half-maximum, which is unambiguously beyond Rayleigh's diffraction limit. The super-resolution capability of C-SPCEM with FED technique is experimentally demonstrated by imaging aggregated fluorescent beads with 150 nm in diameter. PMID- 29401779 TI - Design, fabrication and space suitability tests of wide field of view, ultra compact, and high resolution telescope for space application. AB - We report on the design, manufacture, and testing of an ultra-compact telescope for 16 unit (16U) CubeSats for Earth and space observation. This telescope provides 1 arcsec resolution at a 2.9 degree field of view. Dimensions are optimized to 230 * 230 * 330mm3 with a mass of less than 6kg including support structure. Our catadioptric 5-element design consists of a full-aperture corrector, a Mangin primary mirror (PM), a secondary mirror (SM), and a 2-lens field corrector. The focal length is 745mm, and squared-circular aperture has an equivalent diameter of 241mm. The designed modulation transfer function (MTF) is 0.275 for the entire unit including baffles at a Nyquist frequency of 161 cycles/mm for the 450-800nm band. As one of the distinguishing features of our state-of-the-art design, all optical surfaces are spherical to simplify adjustment. For the best thermal stability, all optical elements are produced from fused silica. We describe the details of design, adjustment, and laboratory performance tests for space environments in accordance with the requirements for in-orbit operation onboard Earth-observation micro-satellites to be launched in 2018. PMID- 29401780 TI - Assessing performance of modern Brillouin spectrometers. AB - Brillouin spectroscopy and imaging has experienced a renaissance in recent years seeing vast improvements in methodology and increasing number of applications. With this resurgence has come the development of new spontaneous Brillouin instruments that often tout superior performance compared to established conventional systems such as tandem Fabry-Perot interferometers (TFPI). The performance of these new systems cannot always be thoroughly examined beyond the scope of the intended application, as applications often take precedence in reports. We therefore present evaluation of three modern Brillouin spectrometers: two VIPA-based spectrometers with wavelength-specific notch filters, and one scanning 6-pass TFPI. Performance analysis is presented along with a discussion about the dependence of measurements on excitation laser source and the various susceptibilities of each system. PMID- 29401781 TI - Depth-resolved measurement of optical radiation-pressure forces with optical coherence tomography. AB - A weakly focused laser beam can exert sufficient radiation pressure to manipulate microscopic particles over a large depth range. However, depth-resolved continuous measurement of radiation-pressure force profiles over an extended range about the focal plane has not been demonstrated despite decades of research on optical manipulation. Here, we present a method for continuous measurement of axial radiation-pressure forces from a weakly focused beam on polystyrene micro beads suspended in viscous fluids over a depth range of 400 MUm, based on real time monitoring of particle dynamics using optical coherence tomography (OCT). Measurements of radiation-pressure forces as a function of beam power, wavelength, bead size, and refractive index are consistent with theoretical trends. However, our continuous measurements also reveal localized depth dependent features in the radiation-pressure force profiles that deviate from theoretical predictions based on an aberration-free Gaussian beam. The combination of long-range radiation pressure and OCT offers a new mode of quantitative optical manipulation and detection with extended spatial coverage. This may find applications in the characterization of optical tractor beams, or volumetric optical manipulation and interrogation of beads in viscoelastic media. PMID- 29401782 TI - 1000 fps computational ghost imaging using LED-based structured illumination. AB - Single-pixel imaging uses a single-pixel detector, rather than a focal plane detector array, to image a scene. It provides advantages for applications such as multi-wavelength, three-dimensional imaging. However, low frame rates have been a major obstacle inhibiting the use of computational ghost imaging technique in wider applications since its invention one decade ago. To address this problem, a computational ghost imaging scheme, which utilizes an LED-based, high-speed illumination module is presented in this work. At 32 * 32 pixel resolution, the proof-of-principle system achieved continuous imaging with 1000 fps frame rate, approximately two orders larger than those of other existing ghost imaging systems. The proposed scheme provides a cost-effective and high-speed imaging technique for dynamic imaging applications. PMID- 29401783 TI - Design of a compact CMOS-compatible photonic antenna by topological optimization. AB - Photonic antennas are critical in applications such as spectroscopy, photovoltaics, optical communications, holography, and sensors. In most of those applications, metallic antennas have been employed due to their reduced sizes. Nevertheless, compact metallic antennas suffer from high dissipative loss, wavelength-dependent radiation pattern, and they are difficult to integrate with CMOS technology. All-dielectric antennas have been proposed to overcome those disadvantages because, in contrast to metallic ones, they are CMOS-compatible, easier to integrate with typical silicon waveguides, and they generally present a broader wavelength range of operation. These advantages are achieved, however, at the expense of larger footprints that prevent dense integration and their use in massive phased arrays. In order to overcome this drawback, we employ topological optimization to design an all-dielectric compact antenna with vertical emission over a broad wavelength range. The fabricated device has a footprint of 1.78 um * 1.78 um and shows a shift in the direction of its main radiation lobe of only 4 degrees over wavelengths ranging from 1470 nm to 1550 nm and a coupling efficiency bandwidth broader than 150 nm. PMID- 29401784 TI - Thermally induced tunability of a terahertz metamaterial by using a specially designed nematic liquid crystal mixture. AB - The search for new low loss nematic liquid crystal mixtures with enhanced birefringence and low temperature of nematic-to-isotropic phase transition plays a pivotal role in a development of new applications in the emerging field of thermally tunable metamaterials. Here we maximize thermally induced tunability of a terahertz metamaterial by using a specially designed nematic liquid crystal mixture. It is shown that the resonant response of a metamaterial device can be effectively tuned both in terms of its magnitude and wavelength with the spectral tunability approaching the theoretical limit of 8 GHz. Electromagnetic simulations confirm our tests and match the experimental observations well. The suggested approach opens new routes for next-generation soft-matter-based filtering and sensing components and devices. PMID- 29401785 TI - On-chip integratable all-optical quantizer using cascaded step-size MMI. AB - We propose a novel all-optical phase shifted quantizer using cascade step-size MMI. The operation principle has been derived in detail. A 3-bit quantizer and a 5-bit quantizer are designed and simulated based on 220-nm SOI platform to verify the feasibility of the scheme, of which the lengths are all below 200 MUm. To the best of our knowledge, they have the most compact footprint compared to the existing all-optical quantizers. In the end, the fabrication error analyses of the proposed quantizers are carried out to verify their stability. PMID- 29401786 TI - Optimal design of a microring cavity optical modulator for efficient RF-to optical conversion. AB - The efficiency of optical sideband generation with a microring resonator modulator as a function of modulator parameters is studied taking into account the photon dynamics inside the resonator. The best achievable modulation efficiency is determined for any choice of the resonator intrinsic quality factor, and analytic solutions for the optimum modulator parameters, namely the coupling coefficient and the detuning between the frequencies of the input laser light and the microring resonance, are provided. This analysis is carried out both for a narrowband RF signal, in which case the modulator is optimized for the center frequency of this signal, and for wideband signals, when high conversion efficiency over a wide range of RF frequencies is desired. The obtained results are expected to be useful coherent optical links, direct detection RF receivers, and optical wavelength converters. PMID- 29401787 TI - Customizing longitudinal electric field profiles using spatial dispersion in dielectric wire arrays. AB - We show how spatial dispersion can be used as a mechanism to customize the longitudinal profiles of electric fields inside modulated wire media, using a fast and remarkably accurate 1D inhomogeneous model. This customization gives fine control of the sub-wavelength behaviour of the field, as has been achieved recently for transverse fields in simpler slotted-slab media. Our scheme avoids any necessity to run a long series of computationally intensive 3D simulations of specific structures, in order to iteratively converge (or brute-force search) to an empirical 'best-performance' design according to an abstract figure-of-merit. Instead, if supplied with an 'ideal waveform' profile, we could now calculate how to construct it directly. Notably, and unlike most work on photonic crystal structures, our focus is specifically on the field profiles because of their potential utility, rather than other issues such as band-gap control, and/or transmission and reflection coefficients. PMID- 29401788 TI - Theory and analysis of a large field polarization imaging system with obliquely incident light. AB - Polarization imaging technology provides information about not only the irradiance of a target but also the polarization degree and angle of polarization, which indicates extensive application potential. However, polarization imaging theory is based on paraxial optics. When a beam of obliquely incident light passes an analyser, the direction of light propagation is not perpendicular to the surface of the analyser and the applicability of the traditional paraxial optical polarization imaging theory is challenged. This paper investigates a theoretical model of a polarization imaging system with obliquely incident light and establishes a polarization imaging transmission model with a large field of obliquely incident light. In an imaging experiment with an integrating sphere light source and rotatable polarizer, the polarization imaging transmission model is verified and analysed for two cases of natural light and linearly polarized light incidence. Although the results indicate that the theoretical model is consistent with the experimental results, the theoretical model distinctly differs from the traditional paraxial approximation model. The results prove the accuracy and necessity of the theoretical model and the theoretical guiding significance for theoretical and systematic research of large field polarization imaging. PMID- 29401789 TI - Generation of high-field terahertz pulses in an HMQ-TMS organic crystal pumped by an ytterbium laser at 1030 nm. AB - We present the generation of high-peak-electric-field terahertz pulses via collinear optical rectification in a 2-(4-hydroxy-3-methoxystyryl)-1 methilquinolinium-2,4,6-trimethylbenzenesulfonate (HMQ-TMS) organic crystal. The crystal is pumped by an amplified ytterbium laser system, emitting 170-fs-long pulses centered at 1030 nm. A terahertz peak electric field greater than 200 kV/cm is obtained for 420 uJ of optical pump energy, with an energy conversion efficiency of 0.26% - about two orders of magnitude higher than in common inorganic crystals collinearly pumped by amplified femtosecond lasers. An open aperture Z-scan measurement performed on an n-doped InGaAs thin film using such terahertz source shows a nonlinear increase in the terahertz transmission of about 2.2 times. Our findings demonstrate the potential of this terahertz generation scheme, based on ytterbium laser technology, as a simple and efficient alternative to the existing intense table-top terahertz sources. In particular, we show that it can be readily used to explore nonlinear effects at terahertz frequencies. PMID- 29401790 TI - Numerical study of a DoFP polarimeter based on the self-organized nanograting array. AB - The self-organized nanograting manufactured by irradiating the transparent materials with the femtosecond laser has aroused wide interests in photonic applications in recent years. Although the mechanism of nanograting formatting has not yet been fully understood, the essential property of the optical birefringence can be precisely acquired by controlling the energy fluence of the femtosecond laser. In this paper, we proposed a novel application of the self organized nanograting in a division-of-focal-plane polarimeter. Based on the rigid-coupled-wave algorithm, the optical characteristics of the nanograting and the polarimeter were comprehensively analyzed and discussed. PMID- 29401791 TI - On-chip platform for a phased array with minimal beam divergence and wide field of-view. AB - Current silicon photonics phased arrays based on waveguide gratings enable beam steering with no moving parts. However, they suffer from a trade-off between beam divergence and field of view. Here, we show a platform based on silicon nitride/silicon that achieves simultaneously minimal beam divergence and maximum field of view while maintaining performance that is robust to fabrication variations. In addition, in order to maximize the emission from the entire length of the grating, we design the grating's strength by varying its duty cycle (apodization) to emit uniformly. We fabricate a millimeter long grating emitter with diffraction-limited beam divergence of 0.089 degrees . PMID- 29401792 TI - Method for simultaneous measurement of five DOF motion errors of a rotary axis using a single-mode fiber-coupled laser. AB - The rotary axis is the basis for rotational motion. Its motion errors have critical effects on the accuracy of the related equipment, such as a five-axis computer numerical control machine tool. There are several difficult problems in the implementation of high-precision and fast measurement of the multi-degree-of freedom motion errors of a rotary axis. In this paper, a novel method for the simultaneous measurement of five-degree-of-freedom motion errors of a rotary axis is proposed, which uses a single-mode fiber-coupled laser with a full-circle measuring range. It has the advantages of high efficiency, low cost, and it requires no decoupling calculation. An experimental system was built and a series of experiments were performed. The standard deviation of stability for 60 min of the five-degree-of-freedom measurement is 0.05 arcsec, 0.06 arcsec, 0.04 MUm, 0.03 MUm, and 0.19 arcsec, respectively. The repeatability deviation of measuring an indexing table is +/- 3.4 arcsec, +/- 4.6 arcsec, +/- 2.6 MUm, +/- 2.4 MUm, and +/- 3.2 arcsec. The maximum deviation of comparison is 3.9 arcsec and 3.2 arcsec. These results demonstrate the effectiveness of the proposed method; thus, a new approach of simultaneous measurement of the multi-degree-of-freedom motion errors of a rotary axis is provided. PMID- 29401793 TI - Probing changes in tilt angle with 20 nanoradian resolution using an extrinsic Fabry-Perot interferometer-based optical fiber inclinometer. AB - In this paper, we introduce and demonstrate a novel optical fiber extrinsic Fabry Perot interferometer (EFPI) for tilt measurements with 20 nrad resolution. Compared with in-line optical fiber inclinometers, an extrinsic sensing structure is used in the inclinometer reported herein. Our design greatly improves on the tilt angle resolution, the temperature stability, and the mechanical robustness of inclinometers with advanced designs. An EFPI cavity, which is formed between endfaces of a suspended rectangular mass block and a fixed optical fiber, is packaged inside a rectangular container box with an oscillation dampening mechanism. Importantly, the two reflectors of the EFPI sensor remain parallel while the cavity length of the EFPI sensor meters a change in tilt. According to the Fabry-Perot principle, the change in the cavity length can be determined, and the tilt angle of the inclinometer can be calculated. The sensor design and the measurement principle are discussed. An experiment based on measuring the tilt angle of a simply-supported 70-cm beam induced by a small load is presented to verify the resolution of our prototype inclinometer. The experimental results demonstrate significantly higher resolution (ca. 20 nrad) compared to commercial devices. The temperature cross-talk of the inclinometer was also investigated in a separate experiment and found to be 0.0041 MUrad / degrees C. Our inclinometer was also employed for monitoring the daily periodic variations in the tilt angle of a windowsill in a cement building caused by local temperature changes during a five-day period. The multi-day study demonstrated excellent stability and practicability for the novel device. The significant inclinometer improvements in differential tilt angle resolution, temperature compensation, and mechanical robustness also provide unique opportunities for investigating spatial-temporal modulations of gravitational fields. PMID- 29401794 TI - Surface modes in plasmonic Bragg fibers with negative average permittivity. AB - We investigate surface modes in plasmonic Bragg fibers composed of nanostructured coaxial cylindrical metal-dielectric multilayers. We demonstrate that the existence of surface modes is determined by the sign of the spatially averaged permittivity of the plasmonic Bragg fiber, epsilon-. Specifically, localized surface modes occur at the interface between the cylindrical core with epsilon-<0 and the outermost uniform dielectric medium, which is similar to the topologically protected plasmonic surface modes at the interface between two different one-dimensional planar metal-dielectric lattices with opposite signs of the averaged permittivity. Moreover, when increasing the number of dielectric metal rings, the propagation constant of surface modes with different azimuthal mode numbers is approaching that of surface plasmon polaritons formed at the corresponding planar metal/dielectric interface. Robustness of such surface modes of plasmonic Bragg fibers is demonstrated as well. PMID- 29401795 TI - Advanced RF and microwave functions based on an integrated optical frequency comb source. AB - We demonstrate advanced transversal radio frequency (RF) and microwave functions based on a Kerr optical comb source generated by an integrated micro-ring resonator. We achieve extremely high performance for an optical true time delay aimed at tunable phased array antenna applications, as well as reconfigurable microwave photonic filters. Our results agree well with theory. We show that our true time delay would yield a phased array antenna with features that include high angular resolution and a wide range of beam steering angles, while the microwave photonic filters feature high Q factors, wideband tunability, and highly reconfigurable filtering shapes. These results show that our approach is a competitive solution to implementing reconfigurable, high performance and potentially low cost RF and microwave signal processing functions for applications including radar and communication systems. PMID- 29401796 TI - Generation of arbitrary axisymmetrically polarized pulses by using the combination of 4-f spatial light modulator and common-path optical system. AB - We proposed and constructed a system to realize broadband generation of arbitrary axisymmetrically polarized (AP) pulses with spatial complex amplitude modulation. This system employs the combination of a spatial light modulator in the 4-f configuration (4-f SLM), and a space variant wave plate as a common path interferometer. The 4-f SLM and the common path interferometer offer compensation for spatial dispersion with respect to wavelength and stability to perturbation, respectively. We experimentally demonstrated the various AP pulses generation by applying modulations of fundamental and higher-order Laguerre-Gauss modes, whose radial indices were, respectively, p = 0 and 1, with high purity, which showed that we were able to generate arbitral AP pulses with spatial complex amplitude modulation. This technique is expected to be applied in both classical and quantum communications with higher-order modes. PMID- 29401797 TI - Virtual image determination for mirrored surfaces. AB - An object viewed via reflection from a mirrored surface is often perceived by the observer to be located behind the mirror's surface. The image of this object behind the mirror is known as its virtual image. Conventional methods for determining the location and shape of a virtual image for non-planar mirrors are complex and impractical unless both the observer and object are near the optical axis. We have developed a technique designed to be simple and practical for determining the location of a virtual image in a non-planar mirror far from the optical axis. Results using this technique were compared with known results from geometric optics for an object point on the optical axis of a parabola and for an object point imaged off the optical axis of a spherical mirror. These results were also in agreement with experimental measurements for a hemispherical mirror viewed at large angles with respect to its optical axis. This technique has applications for display devices or imaging tools utilizing curved, mirrored surfaces. PMID- 29401798 TI - Reconfigurable meta-mirror for wavefronts control: applications to microwave antennas. AB - A planar metasurface composed of electronically tunable meta-atoms incorporating voltage-controlled varactor diodes is proposed as a reconfigurable meta-mirror for wavefronts control in microwave antenna applications. The dispersion responses of the cells are individually tailored in the reconfigurable metasurface so as to overcome the bandwidth limitations of passive metasurfaces and also to control the phase characteristics. By controlling the bias voltage of the varactor diodes on the planar metasurface, the phase characteristics of reflectors can be engineered. The reconfigurable meta-mirror is utilized to implement three different types of reflectors. As such, a reflectarray, a cylindrical parabolic reflector and a dihedral reflector are numerically verified in microwave regime through finite element method. Moreover, experimental measurements are performed on a fabricated prototype to validate the proposed device. Frequency agility, beam deflection and beam focusing are the main functionalities demonstrated from the proposed reconfigurable meta-mirror. PMID- 29401799 TI - High-contrast front end based on cascaded XPWG and femtosecond OPA for 10-PW level Ti:sapphire laser. AB - By combining cross-polarized wave generation and femtosecond optical parametric amplification, a high-contrast front end featuring ultrahigh contrast, a broadband spectrum, an excellent beam profile, and good stability is built for a 10-PW-level Ti:sapphire laser in the Shanghai Superintense Ultrafast Laser Facility (SULF-10PW laser). The front end can deliver a cleaned pulse with a 110 MUJ energy at 1 kHz, and the bandwidth of the cleaned pulse exceeds 60 nm (FWHM), which can support a 17 fs compressed pulse duration. The measured output energy fluctuation in one hour is <1.8% in rms value. The measurement-limited contrast is 10-10 at 3 ps before the main pulse. Utilizing the high-contrast front end, single-shot contrast at 10-10 level has been demonstrated in the SULF-10PW laser at a 24 fs pulse duration. PMID- 29401800 TI - Determination of boron with molecular emission using laser-induced breakdown spectroscopy combined with laser-induced radical fluorescence. AB - Boron is an essential element for industry, but it is hard to accurately and rapidly determine high boron content with conventional laser-induced breakdown spectroscopy (LIBS), due to the matrix and self-absorption effect. Using molecular emission is an alternative method for boron content analysis, but its weak spectra are major challenges. Here, boron monoxide (BO) radicals were used to establish calibration assisted by LIBS and laser-induced radical fluorescence (LIBS-LIRF). Two types of BO radical excitations, vibrational ground state excitation (LIRFG) and vibrational excited state excitation (LIRFE), were compared. The results showed that LIRFG achieved better sensitivity with a limit of detection of 0.0993 wt.%, while the LIRFE was more accurate with a root mean square error of cross validation of 0.2514 wt.%. In conclusion, this work provided a potential approach for molecular emission analysis with LIBS-LIRF. PMID- 29401801 TI - High-speed "multi-grid" pulse-retrieval algorithm for frequency-resolved optical gating. AB - We use an algorithmic technique called "multi-grid" to improve the speed of convergence of the cross-correlation frequency-resolved-optical-gating (XFROG) pulse-retrieval algorithm for very complex pulses. The multi-grid approach uses a smaller trace (N/4 * N/4) drawn from the original N * N trace for initial iterations, yielding poorer resolution and range, but proceeding ~16 times faster for such iterations. The pulse field rapidly retrieved from this smaller array then provides the initial guess for the larger, full array, significantly reducing the number of iterations required on the full array. We first find that, for simple pulses and their resulting simple traces, the original generalized projections FROG and XFROG algorithms already converge in less time than is required to plot the retrieved pulse, so speed improvements for them appear irrelevant in general. Considering therefore only complex pulses and their resulting complex traces, we adapted the multi-grid algorithm to XFROG, the technique used for complex pulses whenever possible. We show that extending multi grid to even smaller arrays is not helpful, but intermediate-size arrays of N/2 * N/2 are, further reducing the number of iterations on the full array and further decreasing convergence time. We obtain a factor of ~7 improvement in speed for very complex pulses with time-bandwidth products of 50 to 90. This approach does not require modifications to the algorithm itself and so can be used in conjunction with essentially all FROG algorithms for improved speed. And it retains FROG's ability to determine the pulse-shape stability in multi-shot measurements. PMID- 29401802 TI - Surface gap solitons in a nonlinear fractional Schrodinger equation. AB - We address the propagation dynamics of gap solitons at the interface between uniform media and an optical lattice in the framework of a nonlinear fractional Schrodinger equation. Different families of solitons residing in the first and second bandgaps of the Floquet-Bloch spectrum are revealed. They feature a combination of the unique properties of fractional diffraction effects, surface waves and gap solitons. The instability of solitons can be remarkably suppressed by the decrease of Levy index, especially obvious for solitons in the second gaps. Additionally, we study the properties of multi-peaked solitons in fractional dimensions and find that they can be made completely stable in a wide region, provided that their power exceeds a critical value. Counterintuitively, at a small Levy index, the instability region shrinks with the increase of the number of soliton peaks. PMID- 29401803 TI - Fast coarse-fine locating method for phi-OTDR. AB - We proposed and demonstrated a coarse-fine method to achieve fast locating of external vibration for the phase-sensitive optical time-domain reflectometer (phi OTDR) sensing system. Firstly, the acquired backscattered traces from heterodyne coherent phi-OTDR systems are spatially divided into a few segments along a sensing fiber for coarse locating, and most of the acquired data can be excluded by comparing the phase difference between the endpoints in adjacent segments. Secondly, the amplitude-based locating is implemented within the target segments for fine locating. By using the proposed coarse-fine locating method, we have numerically and experimentally investigated a distributed vibration sensor based on the heterodyne coherent phi-OTDR system with a 50-km-long sensing fiber. We find that the computation cost of signal processing for locating is significantly reduced in the long-haul sensing fiber, showing a potential application in real time locating of external vibration. PMID- 29401804 TI - Enhanced underwater ranging using an optical vortex. AB - An optical vortex is used to enhance the ranging accuracy of an underwater pulsed laser ranging system. An experiment is conducted whereby an underwater object is illuminated by a pulsed Gaussian beam, and both the object-reflected and scattered light are passed through a diffractive spiral phase plate prior to being imaged at the receiver. An optical vortex is formed from the spatially coherent non-scattered component of the return, providing an effective way to discriminate the desired objected reflected light from the spatially incoherent scatter. Experimental results show that the optical vortex permits a spatially coherent ballistic target return to be more easily discriminated from spatially incoherent forward scattered light up to eight attenuation lengths. The results suggest new optical sensing techniques for underwater imaging or lidar. PMID- 29401805 TI - Suspended polarization beam splitter on silicon-on-insulator. AB - Polarization handling in suspended silicon photonics has the potential to enable new applications in fields such as optomechanics, photonic microelectromechanical systems, and mid-infrared photonics. In this work, we experimentally demonstrate a suspended polarization beam splitter on a silicon-on-insulator waveguide platform, based on an asymmetric directional coupler. Our device presents polarization extinction ratios above 10 and 15 dB, and insertion losses below 5 and 1 dB, for TM and TE polarized input, respectively, across a 40 nm wavelength range at 1550 nm, with a device length below 8 um. These results make our suspended polarization beam splitter a promising building block for future systems based on polarization diversity suspended photonics. PMID- 29401806 TI - Lippmann waveguide spectrometer with enhanced throughput and bandwidth for space and commercial applications. AB - This article presents an innovative high spectral resolution waveguide spectrometer, from the concept to the prototype demonstration and the test results. The main goal is to build the smallest possible Fourier transform spectrometer (FTS) with state of the art technology. This waveguide FTS takes advantage of a customized pattern of nano-samplers fabricated on the surface of a planar waveguide that allows the increase of the measurement points necessary for increasing the spectral bandwidth of the FTS in a fully static way. The use of a planar waveguide on the other hand allows enhancing the throughput in a waveguide spectrometer compared to the conventional devices made of single-mode waveguides. A prototype is made in silicon oxynitride/silicon dioxide technology and characterized in the visible range. This waveguide spectrometer shows a nominal bandwidth of 256~nm at a central wavelength of 633~nm thanks to a custom pattern of nanodisks providing a MUm sampling interval. The implementation of this innovative waveguide FTS for a real-case scenario is explored and further development of such device for the imaging FTS application is discussed. PMID- 29401807 TI - In situ retrieval and correction of aberrations in moldless lenses using Fourier ptychography. AB - Liquid droplets cured at low temperatures or using ultraviolet light are primary approaches for fabricating refractive lenses without molds. Until now the performance of moldless lens fabrication process relied heavily on this step to precisely control the shape of each liquid droplet. Hence, a major hurdle in lenses fabricated from liquid droplets is the large variability of droplet shapes because they are sensitive to small amounts of interfacial forces. The shape of the final droplet critically affects the imaging performance of the lenses and cannot be reversed easily. Here, we aim to overcome this hurdle by performing in situ aberration correction using Fourier ptychography techniques. We demonstrate, for the first time, that computational optics can reverse high amounts of optical aberrations in moldless lenses and achieve high resolution imaging. In terms of imaging resolution, we successfully increased the resolving power of low powered moldless elastomer lenses by almost three-fold, from a numerical aperture of 0.035 to 0.099. The computational approach directly elucidates the spatially varying wavefront aberrations from each lens using the same imaging system. This provides direct feedback of droplet lens fabrication techniques without the need for advanced wavefront correction methods. The application of computational imaging onto moldless lenses, using consumer digital imaging systems, lends itself to the global efforts in decentralising high resolution image intensive scientific tools to the wider community. PMID- 29401808 TI - Controlling multiple-dipole interactions mediated by nanophotonic structures and their application in W state generation. AB - We investigate cooperative behavior of three and four quantum emitters coupled to a common nanophotonic structure. We theoretically demonstrate that strong dipole dipole interaction is attainable for emitter distances on the order of the operating wavelength in a couple of judiciously designed systems, including epsilon-near-zero parallel plate waveguide, SOI microring resonator, and silicon microshell/silica core structure. We also show that a high-purity W state can be generated with high efficiency in such systems, making them promising candidates for the generation of long-range quantum entanglement between multiple qubits. PMID- 29401809 TI - Peculiar near-band-edge emission of polarization-dependent XEOL from a non-polar a-plane ZnO wafer. AB - Polarization-dependent hard X-ray excited optical luminescence (XEOL) was used to study not only the optical properties but also the crystallographic orientations of a non-polar a-plane ZnO wafer. In addition to a positive-edge jump and extra oscillations in the near-band-edge (NBE) XEOL yield, we observed a blue shift of the NBE emission peak that follows the polarization-dependent X-ray absorption near-edge structure (XANES) as the X-ray energy is tuned across the Zn K-edge. This NBE blue shift is caused by the larger X-ray absorption, generating higher free carriers to reduce the exciton-LO phonon coupling, which causes a decrease in the exciton activation energy. The extra oscillations in XANES and XEOL as the polarization is set parallel to the c-axis is attributed to simultaneous excitations of the Zn 4p - O 2ppi -bond along the c-axis and the bilayer sigma bond, whereas only the sigma-bond is excited when the polarization is perpendicular to the c-axis. The polarization-dependent XEOL spectra can be used to determine the crystallographic orientations. PMID- 29401810 TI - Super-resolution fluorescence blinking imaging using modified Fourier ptychography. AB - In this paper, we propose a new super-resolution imaging technique based on fluorescence blinking (SRFB). Contrary to structured illumination microscopy (SIM), SRFB considers the time-varying fluorescence distribution under a suitable density as the varying illuminated speckle pattern, and therefore, external speckle patterns or diffusers are not required. With several images recorded at different times, a super-resolution image can be obtained through an iterative algorithm modified from Fourier ptychography. Recorded image sequences in a microscopy imaging experiment based on photo switching or fluorescence blinking effects, such as STORM and SOFI, can be handled with SRFB and used to recover a super-resolution image. The simulation and experimental results confirm that the SRFB scheme can surpass the diffraction limit by a factor greater than two. PMID- 29401811 TI - Versatile reconstruction framework for diffraction tomography with intensity measurements and multiple scattering. AB - Taking benefit from recent advances in both phase retrieval and estimation of refractive indices from holographic measurements, we propose a unified framework to reconstruct them from intensity-only measurements. Our method relies on a generic and versatile formulation of the inverse problem and includes sparsity constraints. Its modularity enables the use of a variety of forward models, from simple linear ones to more sophisticated nonlinear ones, as well as various regularizers. We present reconstructions that deploy either the beam-propagation method or the iterative Lippmann-Schwinger model, combined with total-variation regularization. They suggest that our proposed (intensity-only) method can reach the same performance as reconstructions from holographic (complex) data. This is of particular interest from a practical point of view because it allows one to simplify the acquisition setup. PMID- 29401812 TI - Heralded generation of high-purity ultrashort single photons in programmable temporal shapes. AB - We experimentally demonstrate a source of nearly pure single photons in arbitrary temporal shapes heralded from a parametric down-conversion (PDC) source at telecom wavelengths. The technology is enabled by the tailored dispersion of in house fabricated waveguides with shaped pump pulses to directly generate the PDC photons in on-demand temporal shapes. We generate PDC photons in Hermite-Gauss and frequency-binned modes and confirm a minimum purity of 0.81, even for complex temporal shapes. PMID- 29401813 TI - Single-shot molecular orbital tomography with orthogonal two-color fields. AB - Molecular orbital tomography (MOT) based on high-order-harmonic generation opens a way to track the molecular electron dynamics or even follow a chemical reaction. However, the real-time imaging of the evolution of electron orbitals is hampered by the multi-shot measurement of high-order harmonics. Here, we report a single-shot MOT scheme with orthogonal two-color (OTC) fields. This scheme enables the tomographic imaging of molecular orbital with single-shot measurement in experiment, owing to the two-dimensional manipulation of the electron motion in OTC fields. Our work paves the way towards tracking the molecular electron dynamics with combined attosecond temporal and sub-Angstrom spatial resolutions. PMID- 29401814 TI - Temporal evolution of condensation and precipitation induced by a 22-TW laser. AB - Water condensation and precipitation induced by 22-TW 800-nm laser pulses at 1 Hz in an open cloud chamber were investigated in a time-resolved manner. Two parts of precipitation in two independent periods of time were observed directly following each laser shot. One part started around the filament zone at t < 500 MUs and ended at t ? 1.5 ms after the arrival of the femtosecond laser pulse. The other following the laser-induced energetic air motion (turbulence), started at t ? 20 ms and ended at t ? 120 ms. Meanwhile, the phase transitions of large-size condensation droplets with diameters of 400-500 MUm from liquid to solid (ice) in a cold area (T < -30 degrees C) were captured at t ? 20 ms. PMID- 29401815 TI - High key rate continuous-variable quantum key distribution with a real local oscillator. AB - Continuous-variable quantum key distribution (CVQKD) with a real local oscillator (LO) has been extensively studied recently due to its security and simplicity. In this paper, we propose a novel implementation of a high-key-rate CVQKD with a real LO. Particularly, with the help of the simultaneously generated reference pulse, the phase drift of the signal is tracked in real time and then compensated. By utilizing the time and polarization multiplexing techniques to isolate the reference pulse and controlling the intensity of it, not only the contamination from it is suppressed, but also a high accuracy of the phase compensation can be guaranteed. Besides, we employ homodyne detection on the signal to ensure the high quantum efficiency and heterodyne detection on the reference pulse to acquire the complete phase information of it. In order to suppress the excess noise, a theoretical noise model for our scheme is established. According to this model, the impact of the modulation variance and the intensity of the reference pulse are both analysed theoretically and then optimized according to the experimental data. By measuring the excess noise in the 25km optical fiber transmission system, a 3.14Mbps key rate in the asymptotic regime proves to be achievable. This work verifies the feasibility of the high key-rate CVQKD with a real LO within the metropolitan area. PMID- 29401816 TI - Spatial-mode-coupling-based dispersion engineering for integrated optical waveguide. AB - Dispersion ultimately limits the efficiency of the nonlinear process in the optical waveguide. Traditional dispersion engineering method is to tailor the cross-section of the waveguide with both of the height and width. However, the fabrication process limits the design freedom of the height in some cases. To solve the problem, we develop a dispersion engineering technique based on spatial mode coupling. Just by tailoring the width of waveguide without altering the height, the proposed method achieves anomalous dispersion with a range of 70 nm numerically and experimentally changes the dispersion of a micro-ring resonator from -750 +/- 30 ps/nm/km to 1300 +/- 200 ps/nm/km over a wavelength range of 25 nm with high Q of 0.8 million on the Si3N4/SiO2 waveguide platform. This technique overcomes the restrict from the fabrication process to the optical waveguide on the dispersion control and can enlarge application of the nonlinear optics on chip. PMID- 29401817 TI - Giant Goos-Hanchen shifts in non-Hermitian dielectric multilayers incorporated with graphene. AB - We theoretically investigate the Goos-Hanchen (GH) shifts of optical beam in a defective photonic crystal composed of dielectric multilayers and graphene. The system is non-Hermitian and possesses exceptional points (EPs) as the scattering matrix becomes defective at the zero points of reflection. The reflective wave at EPs experiences an abrupt phase change and there the eigenvalues of scattering matrix coalesce. The GH shifts are extremely large near EPs in parametric space composed of dielectric refractive index and incident angle. The positive and negative maxima of GH shifts could be as high as 103 times of the incident wavelength. The direction of GH shifts switches at EPs and the EPs position can be readily controlled by the chemical potential of graphene. Moreover, the GH shifts should remarkably change as the incident waves impinge on the structure from opposite directions. The study of GH shifts in the graphene incorporated multilayers may find great applications in highly sensitive sensors. PMID- 29401818 TI - Dynamics of a broad-band quantum cascade laser: from chaos to coherent dynamics and mode-locking. AB - The dynamics of a multimode quantum cascade laser, are studied in a model based on effective semiconductor Maxwell-Bloch equations, encompassing key features for the radiation-medium interaction such as an asymmetric frequency dependent gain and refractive index as well as the phase-amplitude coupling provided by the linewidth enhancement factor. By considering its role and that of the free spectral range, we find the conditions in which the traveling wave emitted by the laser at the threshold can be destabilized by adjacent modes, thus leading the laser emission towards chaotic or regular multimode dynamics. In the latter case our simulations show that the field oscillations are associated to self-confined structures which travel along the laser cavity, bridging mode-locking and solitary wave propagation. In addition, we show how a RF modulation of the bias current leads to active mode-locking yielding high-contrast, picosecond pulses. Our results compare well with recent experiments on broad-band THz-QCLs and may help in the understanding of the conditions for the generation of ultrashort pulses and comb operation in mid-IR and THz spectral regions. PMID- 29401819 TI - Channel likelihood correction for photon-counting array receivers in the presence of dead time and jitters. AB - This paper presents a modified channel likelihood model for optical communication systems with a photon-counting array receiver where photon-counting events are impaired by undesirable dead time and jitters. After the photon-counting detector detects a photon, the detector will go into a period of dead time under which it cannot detect any incident photons. In this context, the channel will have memory. We derive the channel likelihood in the presence of the detector dead time and the random jitter of the photon arrival. The impact of dead time and jitters on the performance of a pulse-position-modulated (PPM) optical communication system is also investigated. The simulation results indicate that the modified channel likelihood expressions can obtain a more obvious performance gain under the context of a stronger background noise, fewer detection elements, longer dead time and bigger jitter. PMID- 29401820 TI - Robust manipulation of light using topologically protected plasmonic modes. AB - We propose using a topological plasmonic crystal structure composed of an array of nearly parallel nanowires with unequal spacing for manipulating light. In the paraxial approximation, the Helmholtz equation that describes the propagation of light along the nanowires maps onto the Schrodinger equation of the Su-Schrieffer Heeger (SSH) model. Using a full three-dimensional finite difference time domain solution of the Maxwell equations, we verify the existence of topological defect modes, with sub-wavelength localization, bound to domain walls of the plasmonic crystal. We show that by manipulating domain walls we can construct spatial mode filters that couple bulk modes to topological defect modes, and topological beam splitters that couple two topological defect modes. Finally, we show that the structures are tolerant to fabrication errors with an inverse length-scale smaller than the topological band gap. PMID- 29401821 TI - Time-resolved tomography of ultrafast laser-matter interaction. AB - We demonstrate time-resolved tomography with 200 fs resolution for the three dimensional analysis of the non-linear dynamics of ultrafast laser-matter interaction inside the volume of transparent materials. We reconstruct as an example the three-dimensional spatial distribution of the transient extinction coefficient induced by focusing higher-order Bessel-Gaussian-beams into Gorilla glass. This approach can be employed to gaseous, liquid and transparent solid state matter which interact with laser light. PMID- 29401822 TI - 5 Gbps wireless transmission link with an optically pumped uni-traveling carrier photodiode mixer at the receiver. AB - We report the first demonstration of a uni-traveling carrier photodiode (UTC-PD) used as a 5 Gbps wireless receiver. In this experiment, a 35.1 GHz carrier was electrically modulated with 5 Gbps non-return with zero on-off keying (NRZ-OOK) data and transmitted wirelessly over a distance of 1.3 m. At the receiver, a UTC PD was used as an optically pumped mixer (OPM) to down-convert the received radio frequency (RF) signal to an intermediate frequency (IF) of 11.7 GHz, before it was down-converted to the baseband using an electronic mixer. The recovered data show a clear eye diagram, and a bit error rate (BER) of less than 10-8 was measured. The conversion loss of the UTC-PD optoelectronic mixer has been measured at 22 dB. The frequency of the local oscillator (LO) used for the UTC-PD is defined by the frequency spacing between the two optical tones, which can be broadly tuneable offering the frequency agility of this photodiode-based receiver. PMID- 29401823 TI - Large-volume, low-cost, high-precision FMCW tomography using stitched DFBs. AB - Optical frequency-modulated continuous-wave (FMCW) reflectometry is a ranging technique that allows for high-resolution distance measurements over long ranges. Similarly, swept-source optical coherence tomography (SS-OCT) provides high resolution depth imaging over typically shorter distances and higher scan speeds. In this work, we demonstrate a low-cost, low-bandwidth 3D imaging system that provides the high axial resolution imaging capability normally associated with SS OCT over typical FMCW ranging depths. The imaging system combines 12 distributed feedback laser (DFB) elements from a single butterfly module to provide an axial resolution of 27.1 MUm over 6 m of depth and up to 14 cubic meters of volume. Active sweep linearization is used, greatly reducing the signal processing overhead. Various sub-surface, OCT-style tomograms of semi-transparent objects are shown, as well as 3D maps of various objects over depths ranging from sub millimeter to several meters. Such imaging capability would make long-distance, high-resolution surface interrogation possible in a low-cost, compact package. PMID- 29401824 TI - High-quality trapped modes in all-dielectric metamaterials. AB - A planar all-dielectric metamaterial made of a double-periodic lattice whose unit cell consists of a single subwavelength dielectric particle having the form of a disk possessing a penetrating hole is considered. The resonant states in the transmitted spectra of the metamaterial are identified considering modes inherent to the individual cylindrical dielectric resonator. A correlation between the asymmetry in the particle's geometry, which arises from the off-centered displacement of the hole and the formation of the Mie-type and trapped modes, is established. The advantages of using a coaxial-sector notch instead of a round hole for the trapped mode excitation are explained. PMID- 29401825 TI - Anti-reflection coating design for metallic terahertz meta-materials. AB - We demonstrate a silicon-based, single-layer anti-reflection coating that suppresses the reflectivity of metals at near-infrared frequencies, enabling optical probing of nano-scale structures embedded in highly reflective surroundings. Our design does not affect the interaction of terahertz radiation with metallic structures that can be used to achieve terahertz near-field enhancement. We have verified the functionality of the design by calculating and measuring the reflectivity of both infrared and terahertz radiation from a silicon/gold double layer as a function of the silicon thickness. We have also fabricated the unit cell of a terahertz meta-material, a dipole antenna comprising two 20-nm thick extended gold plates separated by a 2 MUm gap, where the terahertz field is locally enhanced. We used the time-domain finite element method to demonstrate that such near-field enhancement is preserved in the presence of the anti-reflection coating. Finally, we performed magneto-optical Kerr effect measurements on a single 3-nm thick, 1-MUm wide magnetic wire placed in the gap of such a dipole antenna. The wire only occupies 2% of the area probed by the laser beam, but its magneto-optical response can be clearly detected. Our design paves the way for ultrafast time-resolved studies, using table-top femtosecond near-infrared lasers, of dynamics in nano-structures driven by strong terahertz radiation. PMID- 29401826 TI - Mie scattering of partially coherent light: controlling absorption with spatial coherence. AB - We study theoretically the absorbed power by a dielectric sphere when it is illuminated with partially coherent light coming from two pinholes. We present a general theory of Mie scattering of partially coherent light (based on the angular spectrum method); this theory is applied to the aforementioned particular scattering problem which is solved analytically. We found that, if the diameter of the sphere is smaller than the skin depth, the absorbed power by the sphere depends complicatedly on the degree of coherence of light between the pinholes. The absorbed power for coherent illumination can be smaller or greater than that for incoherent light between pinholes, depending on the geometrical configuration. Furthermore, there are particular setups in which the absorbed power is independent of the degree of coherence, despite that the intensity distribution of the electric field inside the sphere depends significantly on the spatial coherence. Hence, by tuning the coherence length between the pinholes, the absorbed power by the sphere can be controlled; if a whispering gallery mode is excited, the absorbed power can be varied over a wide range. Our study might have implications in the understanding of light absorption in photovoltaic nano devices. PMID- 29401827 TI - Surface and thickness measurement of transparent thin-film layers utilizing modulation-based structured-illumination microscopy. AB - In this research, an approach called modulation-based structured-illumination microscopy (MSIM) is proposed to measure the surface and thickness profile of thin film layers. With this method, a sinusoidal fringe pattern generated by digital micro-mirror devices (DMD) is projected on the sample. The modulation estimation of the reflected patterns is implemented for characterizing the surface and thickness profile of the sample. The measurement system is relatively simple and only an ordinary objective is enough to achieve imaging of the sample. In addition, the reflected signals come from the back surface of the film create less disturbance to the front surface compared with white-light interferometry. Consequently, they can be easily distinguished and achieve a successful measurement precisely. Both simulation and experiments are carried out to demonstrate the availability of this MISM method. The results are in excellent agreement with commercial stage profiler and the relative uncertainty is less than 10 nm. PMID- 29401828 TI - Effect of controllable parameter synchronization on the ensemble average bit error rate of space-to-ground downlink chaos laser communication system. AB - Chaotic modulation is a scheme used to enhance the information security through the configuration parameter synchronization. When chaotic modulation is adopted in the space-to-ground laser communication system, the traditional bit error rate (BER) calculation model for fiber-based chaos communication system is no longer available to depict the long-term communication performance. To solve this problem, we established a new ensemble average BER calculation model under the effects of intensity scintillation and pointing error. Based on this model, we conduct a simulation to research such a system, and our numerical results indicate that space-to-ground chaos laser communication system has a great anti interference against these two effects when the detector mismatch approaches zero. Our results display the advantages of chaotic modulation and also reflect the characteristics of space-to-ground chaos laser communication system. PMID- 29401829 TI - Superconducting nanowire single photon detection system for space applications. AB - Superconducting nanowire single photon detectors (SNSPDs) have advanced various frontier scientific and technological fields such as quantum key distribution and deep space communications. However, limited by available cooling technology, all past experimental demonstrations have had ground-based applications. In this work, we demonstrate a SNSPD system using a hybrid cryocooler that could ultimately be compatible with space applications. With a minimum operational temperature of 2.8 K, this SNSPD system presents a maximum system detection efficiency of over 50% and a timing jitter of 48 ps, which paves the way for various space applications. PMID- 29401830 TI - Buildup dynamics of dissipative soliton in an ultrafast fiber laser with net normal dispersion. AB - Taking advantage of technology of spatio-temporal reconstruction and dispersive Fourier transform (DFT), we experimentally observed the buildup dynamics of dissipative soliton in an ultrafast fiber laser in the net-normal dispersion regime. The soliton buildup dynamics were analyzed in both the spectral and temporal domains. We firstly revealed that the appearing of the spectral sharp peaks with oscillation structures during the mode-locking transition is caused by the formation of structural dissipative soliton. The experimental results were explained by the numerical simulations. These findings would give some new insights into the dissipative soliton buildup dynamics in ultrafast fiber lasers. PMID- 29401831 TI - Multiple surface expansion method for design of freeform imaging systems. AB - The relative aperture size and the field-of-view (FOV) are two significant parameters for optical imaging systems. However, it is difficult to improve relative aperture size and FOV simultaneously. In this paper, a freeform design method is proposed that is particularly effective for high performance systems. In this step-by-step method, the FOV is enlarged from a small initial value in equal-length steps until it reaches the full FOV; in each step, part of the area of one system surface is constructed. A freeform off-axis three-mirror imaging system with large relative aperture size and a wide FOV is designed as an example. The system operates at F/2.5 with 150 mm effective focal length and a 60 degrees * 1 degrees FOV. The average root-mean-square wavefront error of the system is 0.089lambda (working wavelength lambda = 530.5 nm). PMID- 29401832 TI - Polarization switch of four-wave mixing in a lawtunable fiber optical parametric oscillator. AB - We reported the simultaneous generation and selective manipulation of scalar and cross-phase modulation instabilities in a fiber optical parametric oscillator. Numerical and experimental results show independent control of parametric gain by changing the input pump polarization state. The resonant cavity enables power enhancement of 45 dB for the spontaneous sidebands, generating laser pulses tunable from 783 to 791 nm and 896 to 1005 nm due to the combination of four-wave mixing, cascaded Raman scattering and other nonlinear effects. This gain controlled, wavelength tunable, fiber-based laser source may find applications in the fields of nonlinear biomedical imaging and stimulated Raman spectroscopy. PMID- 29401833 TI - Clarification of surface modes of a periodic nanopatch metasurface. AB - We study the angle-dependent optical reflectance spectrum of a metasurface consisting of a periodic array of film-coupled plasmonic nanopatch particles. The nanopatch metasurface exhibits a strong, angle-independent absorption resonance at a wavelength defined by the nanopatch geometry and relative density. When the nanopatches are arranged in a regular lattice, a second, sharp absorption dip is present that varies strongly as a function of the incidence angle. This second resonance is a collective effect involving the excitation of surface plasmon modes and relates to a Wood's anomaly. Using an analytical model, we compute the surface modes of the structure and confirm details about the various mechanisms that contribute to the reflection spectra. The measured reflectance spectra are in excellent agreement with both analytical calculations and full-wave numerical simulations. PMID- 29401834 TI - Partial response signaling for improved chromatic dispersion tolerance in intensity modulation optical transmissions. AB - We investigate partial response signaling (PRS) as a way of increasing the transmission length achievable by direct detection optical systems. The performance of the duobinary and PRS modulations is evaluated against that of conventional on-off-keying (OOK). We prove by simulation and experimentally that duobinary increases the link distance by up to 1.5 times and PRS by up to 3 times, when no signal processing is employed. The gain is preserved even when equalization is used. PRS is employed also with 4-level pulse-amplitude modulation (PAM-4) and is shown to improve the transmission distance by almost 3 times. PMID- 29401835 TI - Tunable arbitrary unitary transformer based on multiple sections of multicore fibers with phase control. AB - In this paper, we propose a novel tunable unitary transformer, which can achieve arbitrary discrete unitary transforms. The unitary transformer is composed of multiple sections of multi-core fibers with closely aligned coupled cores. Phase shifters are inserted before and after the sections to control the phases of the waves in the cores. A simple algorithm is proposed to find the optimal phase setup for the phase shifters to realize the desired unitary transforms. The proposed device is fiber based and is particularly suitable for the mode division multiplexing systems. A tunable mode MUX/DEMUX for a three-mode fiber is designed based on the proposed structure. PMID- 29401836 TI - 3.2 Gigabit-per-second Visible Light Communication Link with InGaN/GaN MQW Micro photodetector. AB - This paper presents the first demonstration of InGaN multiple quantum well (MQW) based micro-photodetectors (uPD) used as the optical receiver in orthogonal frequency-division multiplexing (OFDM) modulated visible communication system (VLC). The 80-um diameter uPD exhibits a wavelength-selective responsivity in the near-UV to violet regime (374 nm - 408 nm) under a low reverse bias of -3 V. The modulation scheme of 16-quadrature amplitude modulation (16-QAM) OFDM enables the use of frequency response beyond -3 dB cutoff bandwidth of uPD. A record high data rate of 3.2 Gigabit per second (Gpbs) was achieved as a result, which provides the proof-of-concept verification of a viable high speed VLC link. PMID- 29401837 TI - All passive architecture for high efficiency cascaded Raman conversion. AB - Cascaded Raman fiber lasers have offered a convenient method to obtain scalable, high-power sources at various wavelength regions inaccessible with rare-earth doped fiber lasers. A limitation previously was the reduced efficiency of these lasers. Recently, new architectures have been proposed to enhance efficiency, but this came at the cost of enhanced complexity, requiring an additional low-power, cascaded Raman laser. In this work, we overcome this with a new, all-passive architecture for high-efficiency cascaded Raman conversion. We demonstrate our architecture with a fifth-order cascaded Raman converter from 1117nm to 1480nm with output power of ~64W and efficiency of 60%. PMID- 29401838 TI - Novel Rydberg eight-wave mixing process controlled in the nonlinear phase of a circularly polarized field. AB - Eight-wave mixing (EWM) is a seven-order nonlinear process that can reflect nonclassical features within multiple optical fields, thus imparting certain advantages. In this study, we directly observed the EWM spectrum and spatial images that show Rydberg atoms under a circularly polarized probe field in a five level coherently prepared atomic system. Such circular polarization dressing fields can obtain high-contrast Rydberg EWM overcome the difficulties of several multi-wave mixing (MWM) signals always coexist, and the multi-parameter controlling Rydberg EWM mechanism is established by changing the power and detuning and polarization of the dressing fields. These controllable high-order MWM processes present a contrast ratio of 96% and a narrow linewidth of <30 MHz compared with low-order mixing processes under identical conditions (e.g., six wave mixing). The corresponding MWM spatial images are presented, and they can partly reflect the underlying nonlinear phase variation, whereas the given theory can predict the experimental results. PMID- 29401839 TI - Enhancement of high-order harmonics in a plasma waveguide formed in clustered Ar gas. AB - Generation of high-order harmonics (HHs) is intensified by using a plasma waveguide created by a laser in a clustered gas jet. The formation of a plasma waveguide and the guiding of a laser beam are also demonstrated. Compared to the case without a waveguide, harmonics were strengthened up to nine times, and blue shifted. Numerical simulation by solving the time-dependent Schrodinger equation in strong field approximation agreed well with experimental results. This result reveals that the strengthening is the result of improved phase matching and that the blue shift is a result of change in fundamental laser frequency due to self phase modulation (SPM). PMID- 29401840 TI - Single-photodiode per polarization receiver with signal-signal beat interference suppression through heterodyne detection. AB - We show that a simplified, single-photodiode per polarization heterodyne receiver is able to directly suppress signal-signal beat interference (SSBI), without the need for cancellation in the digital domain. We characterize performance degradation due to SSBI, and show that a strong LO in the receiver can mitigate SSBI. Transmission of 400 Gb/s-class signals is shown over single fiber spans of up to 160 km, and over field-deployed metropolitan area fiber. These results indicate that a single photodiode can be used to receive complex optical signals in high speed fiber systems without the need for SSBI cancellation in the digital domain. PMID- 29401841 TI - Underwater wireless optical communication using an arrayed transmitter/receiver and optical superimposition-based PAM-4 signal. AB - In this work, we propose an underwater wireless optical communication (UWOC) system using an arrayed transmitter/receiver and optical superimposition-based pulse amplitude modulation with 4 levels (PAM-4). At the transmitter side, we design a spatial summing scheme using a light emitting diode (LED) array, which is divided into two groups in a uniformly interleaved manner. With on-off keying (OOK) modulation for each group, optical superimposition-based PAM-4 can be realized. It has enhanced tolerance to the modulation nonlinearities of LEDs. We numerically investigate the feasibility of the proposed spatial summing scheme in various underwater channels via Monte Carlo simulation. With the increase of divergence angle of LEDs and link distance, the optical power distribution tends to be more uniform at the reception plane. It can significantly relax the requirement on the link alignment. Furthermore, we conduct a proof-of-concept experiment employing two blue LEDs. A multi-pixel photon counter (MPPC), containing an array of single-photon avalanche diodes (SPADs), is used as the detector. It has a much higher sensitivity and can further relax the requirement for pointing. Over a 2-m tap water channel, data rates of 6.144 Mb/s, 8.192 Mb/s, and 12.288 Mb/s were achieved by using the PAM-4 signal generated by optical superimposition, within a 2.5-MHz system bandwidth. With 0.570-mg/L Mg(OH)2, the measured optical power is just 12.890 uW after a 2-m underwater channel. The corresponding bit error rate (BER) of the 12.288-Mbs PAM-4 signal is 2.9 * 10-3, which is still below the forward error correction (FEC) limit of 3.8 * 10-3. It implies that the UWOC system based on the high-sensitivity MPPC with array structure has superior power efficiency and robustness. PMID- 29401842 TI - Ultrasensitive sensing in air based on graphene-coated hollow core fibers. AB - The mismatching between permittivities of guided mode and air limits the operation of accurately monitoring the change in the refractive index of the surrounding air. To solve it, we propose a platform using a hollow core fiber with the integration of graphene coating. Experimental results demonstrate that the anti-resonant reflecting guidance has been enhanced while it induces sharply and periodically lossy dips in the transmission spectrum. We conclude a sensitivity of -365.9 dB/RIU and a high detection limit of 2.73 * 10-6 RIU by means of interrogating the intensity of the lossy dips. We believe that this configuration opens a direction for highly sensitive sensing in researches of chemistry, medicine, and biology. PMID- 29401843 TI - Iterative least-squares solver for generalized maximum-likelihood ptychography. AB - Although ptychography does not require a precise knowledge of the illumination wavefront, common implementations rely upon assumptions such as accurate knowledge of the scan positions and constant illumination. Limited validity of these assumptions results in deterioration of the reconstruction quality. We present a generalized ptychography method that optimizes the reconstruction along multiple directions. In our manuscript, we demonstrate that the additional flexibility not only helps to amend imprecisions of the ptychography model in a self-consistent way but additionally leads to faster convergence without a significant increase of the computational cost per iteration. PMID- 29401844 TI - Flat amplitude and wide multiwavelength Brillouin/erbium fiber laser based on Fresnel reflection in a micro-air cavity design. AB - In this report, we demonstrate a wide multiwavelength Brillouin-erbium fiber laser (MBEFL) with improved flatness that integrates a micro-air cavity. This air gap introduces a cavity loss to overcome the gain saturation as well as providing efficient pump recycling scheme through Fresnel back-reflection. In addition, the efficient four-wave mixing in the highly nonlinear fiber contributes to the self flattening of the output spectra. During operation, the optimized pumping values are set at 13 dBm Brillouin power and 600 mW erbium-ytterbium doped fiber amplifier when the air-gap length is fixed at 10 um. A total of 180 Stokes lines are produced with a channel spacing of 0.08 nm. The flat lasing bandwith is 14 nm that consists of 1557 to 1571 nm wavelengths within 3-dB span. The average optical signal-to-noise ratio is 18 dB, having high peak power of -8 dBm. To our knowledge, this is the best result attained in MBEFLs with respect to the spectral flatness. In fact, the power stability of 0.76 dB order over 45 minute durations merits it applications in optical fiber sensing and communications. PMID- 29401845 TI - Efficient 240W single-mode 1018nm laser from an Ytterbium-doped 50/400um all solid photonic bandgap fiber. AB - Lowering the quantum defect by tandem pumping with fiber lasers at 1018nm was critical for achieving the record 10kW single-mode ytterbium fiber laser. Here we report the demonstration of an efficient directly-diode-pumped single-mode ytterbium fiber laser with 240W at 1018nm. The key for the combination of high efficiency, high power and single-mode at 1018nm is an ytterbium-doped 50MUm/400MUm all-solid photonic bandgap fiber, which has a practical all-solid design and a pump cladding much larger than those used in previous demonstrations of single-mode 1018nm ytterbium fiber lasers, enabling higher pump powers. Efficient high-power single-mode 1018nm fiber laser is critical for further power scaling of fiber lasers and the all-solid photonic bandgap fiber can potentially be a significant enabling technology. PMID- 29401846 TI - Analysis of the nonlinear Kerr effects in optical transmission systems that deploy optical phase conjugation. AB - In this work, we will derive, validate, and analyze the theoretical description of nonlinear Kerr effects resulting from various transmission systems that deploy single or multiple optical phase conjugators (OPCs). We will show that the nonlinear Kerr compensation can be achieved, with various efficiencies, in both lumped and distributed Raman transmission systems. The results show that first order distributed Raman systems are superior to the discretely amplified systems in terms of the nonlinear Kerr compensation efficiency that a mid-link OPC can achieve. Also, we will show that the multi-OPC approach will diminish the nonlinearity compensation efficiency in any system as it will act as periodic dispersion compensators. PMID- 29401847 TI - Robust label-free biosensing using microdisk laser arrays with on-chip references. AB - Whispering-gallery mode (WGM) microdisk lasers show great potential for highly sensitive label-free detection in large-scale sensor arrays. However, when used in practical applications under normal ambient conditions, these devices suffer from temperature fluctuations and photobleaching. Here we demonstrate that these challenges can be overcome by a novel referencing scheme that allows for simultaneous compensation of temperature drift and photobleaching. The technique relies on reference structures protected by locally dispensed passivation materials, and can be scaled to extended arrays of hundreds of devices. We prove the viability of the concept in a series of experiments, demonstrating robust and sensitive label-free detection over a wide range of constant or continuously varying temperatures. To the best of our knowledge, these measurements represent the first demonstration of biosensing in active WGM devices with simultaneous compensation of both photobleaching and temperature drift. PMID- 29401848 TI - On the quantification of spatial resolution for three-dimensional computed tomography of chemiluminescence: erratum. AB - This erratum clarifies an accidental omission of a citation. PMID- 29401849 TI - Phase tuning by length contraction. AB - Typical integrated optical phase tuners alter the effective index. In this paper, we explore tuning by geometric deformation. We show that tuning efficiency, Vpi L, improves as the device size shrinks down to the optimal bend radius, contrary to conventional index-shift based approaches where Vpi L remains constant. We demonstrate that this approach is capable of ultra-low power tuning across a full FSR in a low-confinement silicon nitride based ring resonator of 580 MUm radius. We demonstrate record performance with VFSR = 16 V, Vpi L = 3.6 V dB, Vpi Lalpha = 1.1 V dB, tuning current below 10 nA, and unattenuated tuning response up to 1 MHz. We also present optimized designs for high confinement silicon nitride and silicon based platforms with radius down to 80 MUm and 45 MUm, respectively, with performance well beyond current state-of-the-art. Applications include narrow linewidth tunable diode lasers for spectroscopy and non-linear optics, optical phased array beamforming networks for RF antennas and LIDAR, and optical filters for WDM telecommunication links. PMID- 29401850 TI - Quantitative thermal imaging using single-pixel Si APD and MEMS mirror. AB - Accurate quantitative temperature measurements are difficult to achieve using focal-plane array sensors. This is due to reflections inside the instrument and the difficulty of calibrating a matrix of pixels as identical radiation thermometers. Size-of-source effect (SSE), which is the dependence of an infrared temperature measurement on the area surrounding the target area, is a major contributor to this problem and cannot be reduced using glare stops. Measurements are affected by power received from outside the field-of-view (FOV), leading to increased measurement uncertainty. In this work, we present a micromechanical systems (MEMS) mirror based scanning thermal imaging camera with reduced measurement uncertainty compared to focal-plane array based systems. We demonstrate our flexible imaging approach using a Si avalanche photodiode (APD), which utilises high internal gain to enable the measurement of lower target temperatures with an effective wavelength of 1 um and compare results with a Si photodiode. We compare measurements from our APD thermal imaging instrument against a commercial bolometer based focal-plane array camera. Our scanning approach results in a reduction in SSE related temperature error by 66 degrees C for the measurement of a spatially uniform 800 degrees C target when the target aperture diameter is increased from 10 to 20 mm. We also find that our APD instrument is capable of measuring target temperatures below 700 degrees C, over these near infrared wavelengths, with D* related measurement uncertainty of +/- 0.5 degrees C. PMID- 29401851 TI - On-chip calibration and control of optical phased arrays. AB - Optical phased arrays (OPAs) are important as they allow beam steering and scanning with no moving parts. As their channel count increases, the complexity of control and calibration becomes challenging. We propose an architecture and algorithm that provide rapid on-chip calibration and are scalable to arbitrary channel counts with significantly reduced chip area and reduced overall complexity compared to previously proposed approaches. The optimized phase shifter tuning algorithm - Deterministic Stochastic Gradient Descent (DSGD) - rapidly converges to the optimal state speeding up the digital-to-analog converter based control of large channel count OPAs. PMID- 29401852 TI - Nonlinear coupling states study of electromagnetic force actuated plasmonic nonlinear metamaterials. AB - Electromagnetic force actuated plasmonic nonlinear metamaterials have attracted a great deal of interest from the scientific community over the past several years, owing to the abundant interactions between the electromagnetically induced Ampere's force and the stored mechanical force within the meta-atoms. Despite this interest, a comprehensive study of such metamaterials is still lacking, especially for the nonlinear coupling states analysis. Here we fill this gap by extensively studying the physics of electromagnetic force actuated plasmonic nonlinear metamaterials and presenting a number of new significant findings. Our study will help physicists and engineers to better understand this hot topic and stimulate rapid developments of this promising nonlinear metamaterials. PMID- 29401853 TI - Carbon chloride-core fibers for soliton mediated supercontinuum generation. AB - We report on soliton-fission mediated infrared supercontinuum generation in liquid-core step-index fibers using highly transparent carbon chlorides (CCl4, C2Cl4). By developing models for the refractive index dispersions and nonlinear response functions, dispersion engineering and pumping with an ultrafast thulium fiber laser (300 fs) at 1.92 MUm, distinct soliton fission and dispersive wave generation was observed, particularly in the case of tetrachloroethylene (C2Cl4). The measured results match simulations of both the generalized and a hybrid nonlinear Schrodinger equation, with the latter resembling the characteristics of non-instantaneous medium via a static potential term and representing a simulation tool with substantially reduced complexity. We show that C2Cl4 has the potential for observing non-instantaneous soliton dynamics along meters of liquid core fiber opening a feasible route for directly observing hybrid soliton dynamics. PMID- 29401854 TI - Adjoint-based optimization of active nanophotonic devices. AB - We show that the adjoint variable method can be combined with the multi-frequency finite-difference frequency-domain method for efficient sensitivity calculations, enabling the systematic optimization of active nanophotonic devices. As a proof of principle demonstration, we have optimized a dynamic isolator structure in two dimensions, resulting in the reduction of the length of the modulated regions by a factor of two, while retaining good performance in the isolation ratio and insertion loss. PMID- 29401855 TI - Thermal noise in mid-infrared broadband upconversion detectors. AB - Low noise detection with state-of-the-art mid-infrared (MIR) detectors (e.g., PbS, PbSe, InSb, HgCdTe) is a primary challenge owing to the intrinsic thermal background radiation of the low bandgap detector material itself. However, researchers have employed frequency upconversion based detectors (UCD), operable at room temperature, as a promising alternative to traditional direct detection schemes. UCD allows for the use of a low noise silicon-CCD/camera to improve the SNR. Using UCD, the noise contributions from the nonlinear material itself should be evaluated in order to estimate the limits of the noise-equivalent power of an UCD system. In this article, we rigorously analyze the optical power generated by frequency upconversion of the intrinsic black-body radiation in the nonlinear material itself due to the crystals residual emissivity, i.e. absorption. The thermal radiation is particularly prominent at the optical absorption edge of the nonlinear material even at room temperature. We consider a conventional periodically poled lithium niobate (PPLN) based MIR-UCD for the investigation. The UCD is designed to cover a broad spectral range, overlapping with the entire absorption edge of the PPLN (3.5 - 5 um). Finally, an upconverted thermal radiation power of ~30 pW at room temperature (~30 degrees C) and a maximum of ~70 pW at 120 degrees C of the PPLN crystal are measured for a CW mixing beam of power ~60 W, supporting a good quantitative agreement with the theory. The analysis can easily be extended to other popular nonlinear conversion processes including OPO, DFG, and SHG. PMID- 29401856 TI - Simultaneous channel estimation and signal detection in wireless ultraviolet communications combating inter-symbol-interference. AB - One primary challenge in wireless ultraviolet communications (UVCs) is the inter symbol-interference (ISI), which may block the detection of current informative signal, especially when channel-related characteristics are unknown. In this paper, we propose a UV channel-related Bayesian scheme that can simultaneously estimate the channel characteristics and detect informative signals, which therefore can address the ISI disturbance. By investigating the UV single scattering photon model, the dynamic behaviors of the channel state information (CSI), which involve the uncertain signal and the unknown channel parameters are formulated. Hence, a sequential Bayesian process is suggested to estimate the UV CSI. Numerical analysis shows that the proposed scheme can obtain a promising estimation performance (i.e., the relative errors are less than 4%), and gain an extra 4dB detection performance compared with imperfect maximum-likelihood sequence detection (MLSD) scheme. PMID- 29401857 TI - Experimental investigation of extraordinary optical behaviors in a freestanding plasmonic cascade grating at visible frequency. AB - In this paper, we fabricate a freestanding plasmonic cascade grating and investigate the extraordinary optical behaviors associated with it. The structure consists of two identical metallic gratings with nearly perfect alignment on the lateral direction supported by a Si3N4 membrane. Two types of optical transmission resonances emerge in the fabricated sample at visible frequencies, corresponding to the electric and magnetic resonances in the cascaded structure. These resonances respectively originate from the near-field coupling of plasmonic symmetric and antisymmetric modes in the metal-dielectric-metal waveguide. Moreover, the influence of the incident angle and structure parameters on two resonant peaks are investigated. We envision that this type of plasmonic free standing cascaded nanostructure holds promise for a series of spectrum-dependent applications for the visible light. PMID- 29401858 TI - Tunable liquid-crystal microshell-laser based on whispering-gallery modes and photonic band-gap mode lasing. AB - The lasing behaviors of dye-doped cholesteric liquid crystal (DDCLC) microshells fabricated with silica-glass-microsphere coated DDCLCs were examined. Lasing characteristics were studied in a carrier medium with different refractive indices. The lasing in spherical cholesteric liquid crystals (CLCs) was attributed to two mechanisms, photonic band-gap (PBG) lasing and whispering gallery modes (WGMs), which can independently exist by varying the chiral agent concentration and pumping energy. It was also found that DDCLC microshells can function as highly sensitive thermal sensors, with a temperature sensitivity of 0.982 nm degrees C-1 in PBG modes and 0.156 nm degrees C-1 in WGMs. PMID- 29401859 TI - Tuning single-photon sources for telecom multi-photon experiments. AB - Multi-photon state generation is of great interest for near-future quantum simulation and quantum computation experiments. To-date spontaneous parametric down-conversion is still the most promising process, even though two major impediments still exist: accidental photon noise (caused by the probabilistic non linear process) and imperfect single-photon purity (arising from spectral entanglement between the photon pairs). In this work, we overcome both of these difficulties by (1) exploiting a passive temporal multiplexing scheme and (2) carefully optimizing the spectral properties of the down-converted photons using periodically-poled KTP crystals. We construct two down-conversion sources in the telecom wavelength regime, finding spectral purities of > 91%, while maintaining high four-photon count rates. We use single-photon grating spectrometers together with superconducting nanowire single-photon detectors to perform a detailed characterization of our multi-photon source. Our methods provide practical solutions to produce high-quality multi-photon states, which are in demand for many quantum photonics applications. PMID- 29401860 TI - Point-to-point overlay of a 100Gb/s DP-QPSK channel in LR-PONs for urban and rural areas. AB - The continuing growth in information demand from fixed and mobile end-users, coupled with the need to deliver this content in an economically viable manner, is driving new innovations in access networks. In particular, it is becoming increasingly important to find new ways to enable the coexistence of heterogeneous services types which may require different signal modulation formats over the same fiber infrastructure. For example, the same physical layer can potentially be used to deliver shared 10Gb/s services to residential customers, dedicated point-to-point (P2P) 100Gb/s services to business customers, and wireless fronthaul, in a highly cost-effective manner. In this converged scenario, the performance of phase modulated signals can be heavily affected by nonlinear crosstalk from co-propagating on-off-keying (OOK) channels. In this paper, the overlay of a 100G P2P dual-polarization quadrature phase-shift keying (DP-QPSK) channel in a long-reach passive optical network (LR-PON) in the presence of co-propagating 10Gb/s OOK neighboring channels is studied for two different PON topologies. The first LR-PON topology is particularly suited for densely populated areas while the second is aimed at rural, sparsely populated areas. The experimental results indicate that with an emulated load of 40 channels the urban architecture can support up to 100km span and 512 users, while the rural architecture can support up to 120km span and 1024 users. Finally, a system model is developed to predict the system performance and system margins for configurations different from the experimental setups and to carry out design optimization that could in principle lead to even more efficient and robust schemes. PMID- 29401862 TI - Symmetry enhanced non-reciprocal polarization rotation in a terahertz metal graphene metasurface. AB - In the present article we numerically investigated the magneto-optical behaviour of a sub-wavelength structure composed by a monolayer graphene and a metallic metasurface of optical resonators. Using this hybrid graphene-metal structure, a large increase of the non-reciprocal polarization rotation of graphene can be achieved over a broad range of terahertz frequencies. We demonstrate that the symmetry of the resonator geometry plays a key role for the performance of the system: in particular, increasing the symmetry of the resonator the non reciprocal properties can be progressively enhanced. Moreover, the possibility to exploit the metallic metasurface as a voltage gate to vary the graphene Fermi energy allows the system working point to be tuned to the desired frequency range. Another peculiar result is the achievement of a structure able to operate both in transmission and reflection with almost the same performance, but in a different frequency range of operation. The described system is hence a sub wavelength, tunable, multifunctional, effective non-reciprocal element in the terahertz region. PMID- 29401861 TI - Strong coupling in a microcavity containing beta-carotene. AB - We have fabricated an open-cavity microcavity structure containing a thin film of the biologically-derived molecule beta-carotene. We show that the beta-carotene absorption can be described in terms of a series of Lorentzian functions that approximate the 0-0, 0-1, 0-2, 0-3 and 0-4 electronic and vibronic transitions. On placing this molecular material into a microcavity, we obtain anti-crossing between the cavity mode and the 0-1 vibronic transition, however other electronic and vibronic transitions remain in the intermediate or weak-coupling regime due to their lower oscillator strength and broader linewidth. We discuss the consequences of strong-coupling for the possible modification of photosynthetic processes, or a re-ordering of allowed and optically-forbidden states. PMID- 29401863 TI - Metal-dielectric antennas for efficient photon collection from diamond color centers. AB - A central challenge in quantum technologies based on atom-like defects is the efficient collection of the emitter's fluorescence. Optical antennas are appealing as they offer directional emission together with spontaneous emission rate enhancement across a broad emitter spectrum. In this work, we introduce and optimize metal-dielectric nanoantenna designs recessed into a diamond substrate and aligned with quantum emitters. We analyze tradeoffs between external quantum efficiency, collection efficiency, radiative Purcell factor, and overall collected photon rate. This analysis shows that an optimized metal-dielectric hybrid structure can increase the collected photon rate from a nitrogen vacancy center by over two orders of magnitude compared to a bare emitter. PMID- 29401864 TI - 2D tomographic terahertz imaging using a single pixel detector. AB - A 2D tomographic terahertz imaging set-up using a single pixel imaging approach is realized, where a liquid helium cooled bolometer is utilized as a bucket detector and a mercury-arc lamp serves as a broadband terahertz source. The different patterns of the terahertz radiation, which are necessary for the single pixel imaging approach, are realized by spatially addressed photodoping of a high resistivity float zone silicon window, employing a near-infrared laser diode, which is spatially modulated by a digital micromirror device. The two investigated sample objects have cylindrical and cuboid shapes and consist of polypropylene. Both sample shapes cause strong influences of refraction, reflection and diffraction, which distort the measured projections and thus have to be considered in the tomographic reconstruction. In order to consider these effects, a model is developed which combines refraction and diffraction effects by a hybrid approach using ray tracing and scalar diffraction theory yielding finally projections of the sample objects. These simulated projections are compared to the measured projections and show a good agreement between the experimental results and the developed model. In accordance with this result, an optimization problem is formulated, which offers an approach for tomographic reconstruction using the developed model. PMID- 29401865 TI - Direct detection of the optical field beyond single polarization mode. AB - Direct detection is traditionally regarded as a detection method that recovers only the optical intensity. Compared with coherent detection, it owns a natural advantage-the simplicity-but lacks a crucial capability of field recovery that enables not only the multi-dimensional modulation, but also the digital compensation of the fiber impairments linear with the optical field. Full-field detection is crucial to increase the capacity-distance product of optical transmission systems. A variety of methods have been investigated to directly detect the optical field of the single polarization mode, which normally sends a carrier traveling with the signal for self-coherent detection. The crux, however, is that any optical transmission medium supports at least two propagating modes (e.g. single mode fiber supports two polarization modes), and until now there is no direct detection that can recover the complete set of optical fields beyond one polarization, due to the well-known carrier fading issue after mode demultiplexing induced by the random mode coupling. To avoid the fading, direct detection receivers should recover the signal in an intensity space isomorphic to the optical field without loss of any degrees of freedom, and a bridge should be built between the field and its isomorphic space for the multi-mode field recovery. Based on this thinking, we propose, for the first time, the direct detection of dual polarization modes by a novel receiver concept, the Stokes space field receiver (SSFR) and its extension, the generalized SSFR for multiple spatial modes. The idea is verified by a dual-polarization field recovery of a polarization-multiplexed complex signal over an 80-km single mode fiber transmission. SSFR can be applied to a much wider range of fields beyond optical communications such as coherent sensing and imaging, where simple field recovery without an extra local laser is desired for enhanced system performance. PMID- 29401866 TI - Skew line ray model of nonparaxial Gaussian beam. AB - Many ray-optics models have been proposed to describe the propagation of paraxial Gaussian beam. However, those paraxial ray-optics models are inapplicable to the beams that violate the paraxial condition. In this paper, we present a skew line ray (SLR) based model to represent the propagation properties of nonparaxial Gaussian beam under the oblate spheroidal coordinates. The free-space evolution of complex wavefront of the light beam including amplitude and phase is derived via this model. Our analysis demonstrates that the SLR model is available for both nonparaxial and paraxial conditions, and can be used to precisely describe the propagation of complex wavefront. Furthermore, this model changes the transverse density of rays while propagating. The behavior influences the transverse intensity distribution and makes the optical rays become concentrated towards the center. We believe that this ray-optics model can be further developed to describe other kind of structured beams such as Laguerre-Gauss and Bessel-Gauss beams. PMID- 29401867 TI - Reverse-mode PSLC multi-plane optical see-through display for AR applications. AB - In this paper we propose an optical see-through multi-plane display with reverse mode polymer-stabilized liquid crystal (PSLC). Our design solves the problem of accommodation-vergence conflict with correct focus cues. In the reverse mode PSLC system, power consumption could be reduced to ~1/(N-1) of that in a normal mode system if N planes are displayed. The PSLC films fabricated in our experiment exhibit a low saturation voltage ~20 Vrms, a high transparent-state transmittance (92%), and a fast switching time within 2 ms and polarization insensitivity. A proof-of-concept two-plane color display prototype and a four-plane monocolor display prototype were implemented. PMID- 29401868 TI - Multi-format signal generation using a frequency-tunable optoelectronic oscillator. AB - A novel photonic approach for multi-format signal generation based on a frequency tunable optoelectronic oscillator (OEO) is proposed using a dual-polarization quadrature phase shift-keying (DP-QPSK) modulator. The upper dual-parallel Mach Zehnder modulator (DP-MZM) integrated in the DP-QPSK modulator is properly biased to serve as an equivalent phase modulator, which functions in conjunction with a phase-shifted fiber Bragg grating (PS-FBG) in the OEO loop as a high-Q microwave photonic band-pass filter. The lower DP-MZM in the DP-QPSK modulator injected by the oscillation signal functions as a frequency multiplier, a phase-coded microwave signal generator or an optical frequency comb generator, respectively, with different signal injection methods. An experiment is performed. When the lower DP-MZM serves as a frequency multiplier, tunable frequency-doubled and quadrupled microwave signals up to 40 GHz are generated without using an optical notch filter; and if it functions as a phase-coded microwave signal generator, fundamental and frequency-doubled binary phase-coded microwave signals are generated with a tunable frequency. Furthermore, tunable five-line optical frequency combs are also generated using the compact system without an external RF source. The performance of the generated signals is also investigated. PMID- 29401869 TI - Single transverse mode laser in a center-sunken and cladding-trenched Yb-doped fiber. AB - We report a novel center-sunken and cladding-trenched Yb-doped fiber, which was fabricated by a modified chemical vapor deposition process with a solution-doping technique. The simulation results showed that the fiber with a core diameter of 40 um and a numerical aperture of 0.043 has a 1217 um2 effective mode area at 1080 nm. It is also disclosed that the leakage loss can be reduced lower than 0.01 dB/m for the LP01 mode, while over 80 dB/m for the LP11 mode by optimizing the bending radius as 14 cm. A 456 W laser output was observed in a MOPA structure. The laser slope efficiency was measured to be 79% and the M2 was less than 1.1, which confirmed the single mode operation of the large mode area center sunken cladding-trenched Yb-doped fiber. PMID- 29401870 TI - Effect of carrier transfer process between two kinds of localized potential traps on the spectral properties of InGaN/GaN multiple quantum wells. AB - Two InGaN/GaN multiple-quantum-well (MQW) samples with identical epitaxial structures are grown at different growth rates via metal-organic chemical vapor deposition system. The room temperature photoluminescence intensity of the fast grown sample is much stronger than that of the slow-grown one. In addition, the fast-grown sample has two luminescence peaks at low temperatures, and the height of main peak anomalously increases with increasing temperature below 100 K. Such improved emission efficiency and the untypical temperature-induced increase of peak height can be attributed to the carrier's transferring between two kinds of localized traps with different potential depth in the fast-grown sample, where the distribution of indium is seriously inhomogeneous. The enhanced fluctuation of indium is caused by the reduced migration time of adsorbed atoms due to the increased growth rate during the epitaxial growth of MQW region. PMID- 29401871 TI - Resonantly pumped eye-safe Er3+:YAG SPS-HIP ceramic laser. AB - We report for the first time laser action in resonantly-pumped transparent polycrystalline Er3+:YAG ceramic developed through a 2-step approach combining spark plasma sintering and HIP post treatment. Microstructural and spectroscopic properties, as well as the laser performance of large scale 0.5at.% Er:YAG transparent polycrystalline ceramic are discussed. A maximum slope efficiency of ~31% and optical-optical efficiency of 20% was measured. PMID- 29401872 TI - Electro optic sensor for high precision absolute distance measurement using multiwavelength interferometry. AB - A prototype multi-wavelength interferometric, phase shifting distance sensor based on linear electro optic effect has been demonstrated in this work to improve the measurement speed of a commercial four-wavelength interferometer. Experimental results revealed the phase modulation ability of the sensor, preserving equivalent efficiency for nanometer-scale absolute distance measurement similar to present piezoelectricity driven mechanical phase modulation. The electro optic sensor working under free beam propagation can significantly overcome the limitations experienced by mechanical phase modulation technique such as the restricted value for the modulating frequency and as well the high driving voltage requirement. PMID- 29401873 TI - Optical 3-D surface reconstruction with color binary speckle pattern encoding. AB - This paper proposes a novel 3-D surface profile measurement scheme by only a single-shot color binary speckle pattern (CBSP) and a temporal-spatial correlation matching algorithm, which can be applied to measurements of dynamic and static objects. R/G/B channels of CBSP are coupled with three carefully designed black and white binary speckle patterns (BWBSPs), whose physical features are associated with the system configuration parameters. We mathematically deduce the concrete details of how to design such a pattern and its relationship with the system parameters selected in the experiment. During 3 D reconstruction, we develop an extended temporal-spatial correlation framework to determine the correspondence between two stereo images sequences that are composed of R/G/B images separated from a captured color stereo image pair. Comparative experiments and analysis are implemented to assess the measurement accuracy using standard workpieces (dumbbell and optical flat). The results indicate that the proposed approach enjoys better performance than the conventional BWBSP-based method in terms of spatial resolution, accuracy, and efficient reconstructed points. An experiment of applying CBSP to measuring a moving A4 paper is also presented, demonstrating the success of our computational framework. Finally discussions concerning the limitations of this method are implemented. PMID- 29401874 TI - Flexible/curved backlight module with quantum-dots microstructure array for liquid crystal displays. AB - We present a backlight module (BLM) employing a photoluminescent quantum-dot microstructure array for flexible/curved liquid crystal displays (LCDs). Differently sized quantum-dot (QD) BLMs were prepared based on the theoretical spectral model and microstructure fabrication process. A 27-inch curved prototype showed a wide color gamut of 122.79% under the National Television Systems Committee standard while achieving high brightness of over 4000 cd/m2 and brightness/color uniformity of 85.21%/9.2 * 10-3. An LCD monitor prototype equipped with the proposed BLM was also assembled and tested, which showed higher visual performance when compared with a common commercial monitor. This method produces QD BLMs without the need of additional optical elements, and has good compatibility with traditional processes. PMID- 29401875 TI - Beat note stabilization in dual-polarization DFB fiber lasers by an optical phase locked loop. AB - A fully fibered microwave-optical source at 1.5 um is studied experimentally. It is shown that the beat note between two orthogonally polarized modes of a distributed-feedback fiber laser can be efficiently stabilized using an optical phase-locked loop. The pump-power-induced birefringence serves as the actuator. Beat notes at 1 GHz and 10 GHz are successfully stabilized to a reference synthesizer, passing from the 3 kHz free-running linewidth to a stabilized sub-Hz linewidth, with a phase noise as low as -75 dBc/Hz at 100 Hz offset from the carrier. Such dual-frequency stabilized lasers could provide compact integrated components for RF and microwave photonics applications. PMID- 29401876 TI - Plasmon-enhanced fluorescence of submonolayer porphyrins by silver-polymer core shell nanoparticles. AB - We investigate the fluorescence from submonolayer porphyrin molecules near silver polymer core-shell nanoparticles (NPs) at a well-controlled separation distance of about 1 nm - 5 nm. When porphyrin molecules are deposited on silver NPs with the plasmonic resonance peak at about 410 nm, which matches very closely with the 405-nm excitation laser and the absorption band of porphyrin molecules, their emission intensity is found to be enhanced due to the plasmonic resonant excitation enhancement, and shows a decline as the increasing polymer shell thickness. Meanwhile, the lifetime results demonstrate that there exists the fluorescence quenching due to the charge transfer and nonradiative energy transfer losses, which is also the main reason that the maximum enhancement factor obtained in experiment is only about 2.3, although the theoretical one is above 60 according to the electric field distribution near silver NPs calculated by finite-difference time-domain method. PMID- 29401877 TI - Optimization of laser emission at 2.8 MUm by Er:Lu2O3 ceramics. AB - We have demonstrated the continuous-wave operation of a highly efficient 2.8 MUm Er-doped Lu2O3 ceramic laser at room temperature. An Er:Lu2O3 ceramic with a doping concentration of 11 at.% afforded a slope efficiency of 29% and an output power of 2.3 W with pumping at 10 W. To our knowledge, these are the highest slope efficiency and output power obtained to date for an Er:Lu2O3 ceramic laser at 2.8 MUm. In addition, we prepared ceramics with various doping concentrations and determined their emission cross sections by fluorescence lifetime measurements and emission spectroscopy. PMID- 29401878 TI - Enhanced asymmetric transmissions attributed to the cavity coupling hybrid resonance in a continuous omega-shaped metamaterial. AB - In this paper, the infinite-length metallic bar is folded to a continuous omega shaped resonator and then arranged as a bi-layer metamaterial, which presents a hybrid resonance and a Fabry-Perot-like cavity mode. The asymmetric transmission (AT) for linearly polarized light is powerfully enhanced at a near-infrared regime by strongly coupling the hybrid resonance to the cavity, with the maximum value of the high-efficiency AT effect reaching 0.8 at around 1364 nm. At this near-infrared band, such a high-efficiency AT effect has never been realized previously by a bi-layer metamaterial. More importantly, we demonstrate that our design is robust to the misalignments, which greatly decreases the difficulties in sample fabrications. Accordingly, the proposed omega-shaped metamaterial provides potential applications in designing polarization filters, polarization switches, and other nano-devices. PMID- 29401879 TI - High-power high-brightness 980 nm lasers with >50% wall-plug efficiency based on asymmetric super large optical cavity. AB - High-power high-brightness super large optical cavity laser diodes with an optimized epitaxial structure are investigated at the wavelength of 980 nm range. The thicknesses of P- and N-waveguides are prudently chosen based on a systematic consideration about mode characteristics and vertical far-field divergences. Broad area laser diodes show a high internal quantum efficiency of 98% and a low internal optical loss of 0.58 cm-1. The ridge-waveguide laser with 7 MUm ridge and 3 mm cavity yields 1.9 W single spatial mode output with far-field divergence angles of 6.8 degrees in lateral and 11.5 degrees in vertical at full width at half maximum under 2 A CW operating current. The corresponding M2 values are 1.77 and 1.47 for lateral and vertical, respectively, and the corresponding brightness is 76.8 MW?cm-2?sr-1. The far-field divergence angles with 95% power content are in the range of 24.7 degrees to 26.1 degrees across the whole measured range. PMID- 29401880 TI - Electrical characteristics of silicon nanowire CMOS inverters under illumination. AB - In this study, we examine the electrical characteristics of complementary metal oxide-semiconductor (CMOS) inverters with silicon nanowire (SiNW) channels on transparent substrates under illumination. The electrical characteristics vary with the wavelength and power of light due to the variation in the generation rates of the electric-hole pairs. Compared to conventional optoelectronic devices that sense the on/off states by the variation in the current, our device achieves the sensing of the on/off states with more precision by using the voltage variation induced by the wavelength or intensity of light. The device was fabricated on transparent substrates to maximize the light absorption using conventional CMOS technologies. The key difference between our SiNW CMOS inverters and conventional optoelectronic devices is the ability to control the flow of charge carriers more effectively. The improved sensitivity accomplished with the use of SiNW CMOS inverters allows better control of the on/off states. PMID- 29401881 TI - Experimental and numerical comparison of probabilistically shaped 4096 QAM and a uniformly shaped 1024 QAM in all-Raman amplified 160 km transmission. AB - We describe an experimental and numerical comparison of a probabilistically shaped (PS) 4096 QAM signal and a uniformly shaped 1024 QAM signal. Both modulation formats have the same transmission rate and a spectral efficiency of 15.3 bit/s/Hz. In the computational simulation, we compared the generalized mutual information (GMI) of both modulation formats with bit-wise soft decision decoding and bit-wise hard decision decoding. For bit-wise hard decision decoding with an overhead of 7%, a shaping gain of 1.8 dB was attained. Then we successfully transmitted a single-channel PS-4096 QAM signal for the first time in an all-Raman amplified 160-km link, in which the transmission performance was improved compared with a uniformly shaped 1024 QAM with the same transmission rate. Transmissions with a high QAM multiplicity were achieved by using an optical phase-locked loop (OPLL) and a frequency stabilized fiber laser locked to an acetylene absorption line. Thanks to a shaping gain based on a bit-wise hard decision decoder, the 1.9-dB power margin, which agreed with the simulation result to within 0.1 dB, was increased after transmission. PMID- 29401882 TI - Optical design of soft multifocal contact lens with uniform optical power in center-distance zone with optimized NURBS. AB - This study aims to develop a new optical design method of soft multifocal contact lens (CLs) to obtain uniform optical power in large center-distance zone with optimized Non-Uniform Rational B-spline (NURBS). For the anterior surface profiles of CLs, the NURBS design curves are optimized to match given optical power distributions. Then, the NURBS in the center-distance zones are fitted in the corresponding spherical/aspheric curves for both data points and their centers of curvature to achieve the uniform power. Four cases of soft CLs have been manufactured by casting in shell molds by injection molding and then measured to verify the design specifications. Results of power profiles of these CLs are concord with the given clinical requirements of uniform powers in larger center-distance zone. The developed optical design method has been verified for multifocal CLs design and can be further applied for production of soft multifocal CLs. PMID- 29401883 TI - Fabrication and characterization of machined multi-core fiber tweezers for single cell manipulation. AB - Optical tweezing is a non-invasive technique that can enable a variety of single cell experiments; however, it tends to be based on a high numerical aperture (NA) microscope objective to both deliver the tweezing laser light and image the sample. This introduces restrictions in system flexibility when both trapping and imaging. Here, we demonstrate a novel, high NA tweezing system based on micro machined multicore optical fibers. Using the machined, multicore fiber tweezer, cells are optically manipulated under a variety of microscopes, without requiring a high NA objective lens. The maximum NA of the fiber-based tweezer demonstrated is 1.039. A stable trap with a maximum total power 30 mW has been characterized to exert a maximum optical force of 26.4 pN, on a trapped, 7 MUm diameter yeast cell. Single cells are held 15-35 MUm from the fiber end and can be manipulated in the x, y and z directions throughout the sample. In this way, single cells are controllably trapped under a Raman microscope to categorize the yeast cells as live or dead, demonstrating trapping by the machined multicore fiber-based tweezer decoupled from the imaging or excitation objective lens. PMID- 29401884 TI - Effects of carrier injection profile on low noise thin Al0.85Ga0.15As0.56Sb0.44 avalanche photodiodes. AB - : Avalanche photodiodes (APDs) with thin avalanche regions have shown low excess noise characteristics and high gain-bandwidth products, so they are suited for long-haul optical communications. In this work, we investigated how carrier injection profile affects the avalanche gain and excess noise factors of Al0.85Ga0.15As0.56Sb0.44 (lattice-matched to InP substrates) p-i-n and n-i-p diodes with total depletion widths of 145-240 nm. Different carrier injection profiles were achieved by using light with wavelengths of 420, 543 and 633nm. For p-i-n diodes, shorter wavelength light produces higher avalanche gains for a given reverse bias and lower excess noise factors at a given gain, compared to longer wavelength light. Thus, using 420 nm light on the p-i-n diodes, corresponding to pure electron injection conditions, gave the highest gain and lowest excess noise. In n-i-p diodes, pure hole injection yields significantly lower gain and higher excess noise, compared to mixed carrier injection. These show that the electron ionization coefficient, alpha, is higher than the hole ionization coefficient, beta. Using pure electron injection, excess noise factor characteristics with effective ionization ratios, keff, of 0.08-0.1 were obtained. This is significantly lower than those of InP and In0.52Al0.48As, the commonly used avalanche materials combined with In0.53Ga0.47As absorber. The data reported in this paper is available from the ORDA digital repository (DOI: 10.15131/shef. DATA: 5787318). PMID- 29401885 TI - Introduction: Nonlinear Optics (NLO) 2017 feature issue. AB - The editors introduce the feature issue on "Nonlinear Optics 2017," based on the topics presented at the NLO 2017 conference, which was held in Waikoloa, Hawaii, USA from July 17-21, 2017. This feature issue is jointly published by Optics Express and Optical Materials Express. PMID- 29401886 TI - Comparison of various excitation and detection schemes for dye-doped polymeric whispering gallery mode micro-lasers. AB - We compare different excitation and collection configurations based on free-space optics and evanescently coupled tapered fibers for both lasing and fluorescence emission from dye-doped doped polymeric whispering gallery mode (WGM) micro-disk lasers. The focus of the comparison is on the lasing threshold and efficiency of light collection. With the aid of optical fibers, we localize the pump energy to the cavity-mode volume and reduce the necessary pump energy to achieve lasing by two orders of magnitude. When using fibers for detection, the collection efficiency is enhanced by four orders of magnitude compared to a free-space read out perpendicular to the resonator plane. By enhancing the collection efficiency we are able to record a pronounced modulation of the dye fluorescence under continuous wave (cw) pumping conditions evoked by coupling to the WGMs. Alternatively to fibers as a collection tool, we present a read-out technique based on the detection of in-plane radiated light. We show that this method is especially beneficial in an aqueous environment as well as for size-reduced micro lasers where radiation is strongly pronounced. Furthermore, we show that this technique allows for the assignment of transverse electric (TE) and transverse magnetic (TM) polarization to the observed fundamental modes in a water environment by performing polarization-dependent photoluminescence (PL) spectroscopy. We emphasize the importance of the polarization determination for sensing applications and verify expected differences in the bulk refractive index sensitivity for TE and TM WGMs experimentally. PMID- 29401887 TI - Design of bifunctional metasurface based on independent control of transmission and reflection. AB - Multifunctional metasurface integrating different functions can significantly save the occupied space, although most of bifunctional metasurfaces reported to date only control the wave in either reflection or transmission regime. In this paper, we propose a scheme that allows one to independently control the reflection and transmission wavefront under orthogonal polarizations. For demonstration, we design a bifunctional metasurface that simultaneously realizes a diffusion reflection and a focusing transmission. The diffusion reflection is realized using a random phase distribution, which was implemented by randomly arranging two basic coding unit cells with the aid of an ergodic algorithm. Meanwhile, the hyperbolic phase distribution was designed to realize the focusing functionality in the transmission regime. To further show the potential applications, a high-gain lens antenna was designed by assembling the proposed metasurface with a proper feed. Both simulation and measurement results have been carried out, and the agreement between the two results demonstrates the validity of the performance as expected. The backward scattering can be reduced more than 5 dB within 6.4-10 GHz compared with the metallic plate. Moreover, the lens antenna has a gain of 20 dB (with around 13 dB enhancement in comparison with the bare feeding antenna) and an efficiency of 32.5%. PMID- 29401888 TI - Spectrometer-based refractive index and dispersion measurement using low coherence interferometry with confocal scanning. AB - This paper describes a technique for measuring refractive index and thickness of transparent plates using a fibre-optic low-coherence interferometer. The interferometer is used to independently measure quantities related to the phase and group refractive indices, np and ng, of the material under investigation. Additionally, the dispersion of the phase index dependent quantity is measured by taking advantage of the range of wavelengths available from a broadband source. These three quantities are related to simultaneously yield np and ng as well as the geometrical thickness t of the sample. Measurements are presented for a range of transparent materials including measurements of the ordinary and extraordinary refractive indices of a birefringent sapphire window. The mean percentage errors across all the samples tested were 0.09% for np, 0.08% for np, and 0.11% for t. PMID- 29401889 TI - Understanding and overcoming fundamental limits of asymmetric light-light switches. AB - The interplay between interference and absorption leads to interesting phenomena like coherent perfect absorption and coherent perfect transparency (CPA and CPT), which can be exploited for fully optical modulation. While it is known that it is possible to harness CPA and CPT for switching a strong signal beam with a weak control beam, it is not immediate that this process suffers from a fundamental compromise between the device efficiency (quantified by device loss and modulation depth) and the asymmetry between signal and control intensity desired for operation. This article quantifies this compromise and outlines a possible way to overcome it by means of a combination of optical gain and loss in the same photonic component. A general formulation and a specific device realization are both discussed. PMID- 29401890 TI - Aberration-controlled Bessel beam processing of glass. AB - It is known that Bessel beam generation with a non-ideal axicon induces beam pattern distortions. In this paper, we introduce a simple method for non-ideal axicon-generated Bessel beam reconstruction by tilting the axicon perpendicular to its optical axis. We found an optimum axicon tilt angle where beam distortions can be compensated by inducing additional astigmatic aberrations. At optimal tilt angle, the central spot symmetry and focal depth was increased. By this method we could control crack formation symmetry in the bulk of glass, which is essential for many transparent material processing applications. PMID- 29401891 TI - Six-beam homodyne laser Doppler vibrometry based on silicon photonics technology. AB - This paper describes an integrated six-beam homodyne laser Doppler vibrometry (LDV) system based on a silicon-on-insulator (SOI) full platform technology, with on-chip photo-diodes and phase modulators. Electronics and optics are also implemented around the integrated photonic circuit (PIC) to enable a simultaneous six-beam measurement. Measurement of a propagating guided elastic wave in an aluminum plate (speed ~ 909 m/s @ 61.5 kHz) is demonstrated. PMID- 29401892 TI - Development and characterization of an inexpensive single-particle fluorescence spectrometer for bioaerosol monitoring. AB - Laser-induced fluorescence (LIF) techniques to analyze atmospheric aerosols are commonly applied for research and human exposure monitoring, but are very expensive or offer poor spectral resolution. Here, we discuss how a recently proposed instrument can acquire resolved fluorescence spectra from many individual particles in a single camera image using four excitation wavelengths matched with common biological fluorophores for particle discrimination at lower cost. We discuss emission intensity calibration and demonstrate spectral differentiation among four species of pollen. These data provide context for how the instrument could be developed for pollen and mold-spore detection or for use by citizen scientists. PMID- 29401894 TI - Impact of substrate etching on plasmonic elements and metamaterials: preventing red shift and improving refractive index sensitivity. AB - We propose and demonstrate the elimination of substrate influence on plasmon resonance by using selective and isotropic etching of substrates. Preventing the red shift of the resonance due to substrates and improving refractive index sensitivity were experimentally demonstrated by using plasmonic nanostructures fabricated on silicon substrates. Applying substrate etching decreases the effective refractive index around the metal nanostructures, resulting in elimination of the red shift. Improvement of sensitivity to the refractive index environment was demonstrated by using plasmonic metamaterials with Fano resonance based on far field interference. Change in quality factors (Q-factors) of the Fano resonance by substrate etching was also investigated in detail. The presence of a closely positioned substrate distorts the electric field distribution and degrades the Q-factors. Substrate etching dramatically increased the refractive index sensitivity reaching to 1532 nm/RIU since the electric fields under the nanostructures became accessible through substrate etching. The FOM was improved compared to the case without the substrate etching. The method presented in this paper is applicable to a variety of plasmonic structures to eliminate the influence of substrates for realizing high performance plasmonic devices. PMID- 29401893 TI - Semi-random multicore fibre design for adaptive multiphoton endoscopy. AB - This paper reports the development, modelling and application of a semi-random multicore fibre (MCF) design for adaptive multiphoton endoscopy. The MCF was constructed from 55 sub-units, each comprising 7 single mode cores, in a hexagonally close-packed lattice where each sub-unit had a random angular orientation. The resulting fibre had 385 single mode cores and was double-clad for proximal detection of multiphoton excited fluorescence. The random orientation of each sub-unit in the fibre reduces the symmetry of the positions of the cores in the MCF, reducing the intensity of higher diffracted orders away from the central focal spot formed at the distal tip of the fibre and increasing the maximum size of object that can be imaged. The performance of the MCF was demonstrated by imaging fluorescently labelled beads with both distal and proximal fluorescence detection and pollen grains with distal fluorescence detection. We estimate that the number of independent resolution elements in the final image - measured as the half-maximum area of the two-photon point spread function divided by the area imaged - to be ~3200. PMID- 29401895 TI - Megawatt peak power tunable femtosecond source based on self-phase modulation enabled spectral selection. AB - Wavelength widely tunable femtosecond sources can be implemented by optically filtering the leftmost/rightmost spectral lobes of a broadened spectrum due to self-phase modulation (SPM) dominated fiber-optic nonlinearities. We numerically and experimentally investigate the feasibility of implementing such a tunable source inside optical fibers with negative group-velocity dispersion (GVD). We show that the spectral broadening prior to soliton fission is dominated by SPM and generates well-isolated spectral lobes; filtering the leftmost/rightmost spectral lobes results in energetic femtosecond pulses with the wavelength tuning range more than 400 nm. Employing an ultrafast Er-fiber laser and a dispersion shifted fiber with negative GVD, we implement an energetic tunable source that produces ~100-fs pulses tunable between 1.3 um and 1.7 um with up to ~16-nJ pulse energy. Further energy scaling is achieved by increasing the input pulse energy to ~1-MUJ and reducing the fiber length to 1.3 cm. The resulting source can produce >100-nJ femtosecond pulses at 1.3 um and 1.7 um with MW level peak power, representing an order of magnitude improvement of our previous results. Such a powerful source covers the 2nd and the 3rd biological transmission window and can facilitate multiphoton deep-tissue imaging. PMID- 29401896 TI - Active stabilization of alkali-atom vapor density with a solid-state electrochemical alkali-atom source. AB - We report a demonstration of vapor-phase Rubidium (Rb) density stabilization in a vapor cell using a solid-state electrochemical Rb source device. Clear Rb density stabilization is observed. Further demonstrations show that the temperature coefficient for Rb density can be reduced more than 100 times when locked and the device's power consumption is less than 10 mW. Preliminary investigation of the locking dynamic range shows that the Rb density is well stabilized when the initial density is five times higher (33 * 109 /cm3) than the set point density (6 * 109 /cm3). Active stabilization with this device is of high interest for portable cold-atom microsystems where large ambient temperature working ranges and low power consumption are required. PMID- 29401897 TI - Artificial dielectric stepped-refractive-index lens for the terahertz region. AB - In this paper we theoretically and experimentally demonstrate a stepped refractive-index convergent lens made of a parallel stack of metallic plates for terahertz frequencies based on artificial dielectrics. The lens consist of a non uniformly spaced stack of metallic plates, forming a mirror-symmetric array of parallel-plate waveguides (PPWGs). The operation of the device is based on the TE1 mode of the PPWG. The effective refractive index of the TE1 mode is a function of the frequency of operation and the spacing between the plates of the PPWG. By varying the spacing between the plates, we can modify the local refractive index of the structure in every individual PPWG that constitutes the lens producing a stepped refractive index profile across the multi stack structure. The theoretical and experimental results show that this structure is capable of focusing a 1 cm diameter beam to a line focus of less than 4 mm for the design frequency of 0.18 THz. This structure shows that this artificial dielectric concept is an important technology for the fabrication of next generation terahertz devices. PMID- 29401898 TI - Mechanism of propagating graphene plasmons excitation for tunable infrared photonic devices. AB - The mechanism of propagating graphene plasmons excitation using a nano-grating and a Fabry-Perot cavity as the optical coupling components is studied. It is demonstrated that the system could be well described within the temporal coupled mode theory using two phenomenological parameters, namely, the intrinsic loss rate and the coupling rate of a graphene plasmonic mode, and their analytical expressions are derived. It is found that the intrinsic loss rate is solely determined by the electron relaxation time of graphene, while independent of the field distributions of the modes. Such result originates from the negligible magnetic field energy of the graphene plasmonic mode. The coupling rate is governed by the optical coupling components parameters, and varies periodically with the Fabry-Perot cavity length. By modulating the two rates, quality factors and absorption rates can be adjusted. Furthermore, it is revealed that low refractive index of the Fabry-Perot cavity material is vital to the enlargement of tunable band, and the underlying physics is discussed. Such plasmon excitation configuration is insensitive to light incident angle and could serve as a platform for many tunable infrared photonic device, such as surface-enhanced infrared absorption spectroscopies, infrared detectors and modulators. PMID- 29401899 TI - Monolithic integration of GaN-based light-emitting diodes and metal-oxide semiconductor field-effect transistors: comment. AB - A potential erroneous and misleading result which is caused by the wrong calculation of current density and transconductance was found in a paper, namely [Opt. Express22, A1589 (2014)]. After checking the calculation, this paper points out the contradictory results existing in the MOSFET gate width as regards its actual layout and inconsistent I-V characteristics. Judging from the calculation result, we estimate that the author may confuse gate length with gate width in the calculation. Considering the author was conducting an interdisciplinary research and demonstrating a novel device design, these calculation errors may be trivial and comprehensible. But we still suggest that the author can make their work more accurate and comparable with other monolithic integration works by correcting the existing calculation errors. PMID- 29401900 TI - Monolithic integration of GaN-based light-emitting diodes and metal-oxide semiconductor field-effect transistors: reply. AB - We present some comments to the paper "Monolithic integration of GaN-based light emitting diodes and metal-oxide-semiconductor field-effect transistors: comment," [Opt. Express22, A1589 (2014)]. PMID- 29401901 TI - Strategy for tailoring the size distribution of nanospheres to optimize rough backreflectors of solar cells. AB - We study the light-trapping properties of surface textures generated by a bottom up approach, which utilizes monolayers of densely deposited nanospheres as a template. We demonstrate that just allowing placement disorder in monolayers from identical nanospheres can already lead to a significant boost in light-trapping capabilities. Further absorption enhancement can be obtained by involving an additional nanosphere size species. We show that the Power Spectral Density provides limited correspondence to the diffraction pattern and in turn to the short-circuit current density enhancement for large texture modulations. However, in predicting the optimal nanosphere size distribution, we demonstrate that full wave simulations of just a c-Si semi-infinite halfspace at a single wavelength in the range where light trapping is of main importance is sufficient to provide an excellent estimate. The envisioned bottom-up approach can thus reliably provide good light-trapping surface textures even with simple nanosphere monolayer templates defined by a limited number of control parameters: two nanosphere radii and their occurrence probability. PMID- 29401902 TI - Single scattering properties of non-spherical hydrosols modeled by spheroids. AB - The single scattering properties of hydrosols play an important role in the study of ocean optics, ocean color remote sensing, and ocean biogeochemistry research. Measurements show that hydrosols can be of various sizes and shapes, suggesting general non-spherical models should be considered for the study of single scattering properties of hydrosols. In this work, light scattering by non spherical hydrosols are modeled by randomly oriented spheroids with the Amsterdam discrete dipole approximation (ADDA) code. We have defined two new parameters to quantify the degree of optical non-sphericity (DONS) and investigated the dependence of DONS on refractive index, size, and aspect ratio. For particles with non-unitary aspect ratios, the magnitude of DONS increases as the refractive index and particle size increase. The dependence of the backscattering fraction on the non-sphericity, size, and refractive index of hydrosols is also studied. It is found that the backscattering fraction is larger for smaller particles as well as for particles with higher refractive indices. Absorptive hydrosols generally have a lower backscattering fraction than non-absorptive hydrosols. This study of light scattering by non-spherical hydrosols would lead to better radiative transfer models in ocean waters and new remote sensing techniques of hydrosol compositions. PMID- 29401903 TI - Tuning the correlated color temperature of white light-emitting diodes resembling Planckian locus. AB - We report a new electrically tunable color filter to actively adjust the correlated color temperature of white light-emitting diodes. With four passive cholesteric films and an active polarization rotator, both circular polarizations of the incident light are utilized to generate complementary blue and yellow colors. The blue/yellow ratio can be tuned by the applied voltage of the polarization rotator. In experiment, the tunable color filter offers a reasonably wide tuning range (1900 K and 2400 K), which resembles the Planckian locus. This design is promising for next generation smart lighting. PMID- 29401904 TI - Inkjet-printed perovskite distributed feedback lasers. AB - We report on digitally printed distributed feedback lasers on flexible polyethylene terephthalate substrates based on methylammonium lead iodide perovskite gain material. The perovskite lasers are printed with a digital drop on-demand inkjet printer, providing full freedom in the shape and design of the gain layer. We show that adjusting the perovskite ink increases the potential processing window and decreases the surface roughness of the active layer to less than 7 nm, which is essential for low lasing thresholds. Prototype inkjet-printed perovskite lasers processed on top of nanopatterned rigid as well as flexible substrates are demonstrated. Optimized perovskite gain layers printed on PET substrates demonstrated lasing and showed a linewidth of 0.4 nm and a lasing threshold of 270 kW/cm2. In addition, printing of a distinct shape shows a high level of uniformity, demonstrated by a low spatial resolved full width half maximum variation over the whole printing area. These results reveal the possibilities of digital printed perovskite layers towards large-scale and low cost laser applications of arbitrary shape. PMID- 29401905 TI - Feature issue introduction: halide perovskites for optoelectronics. AB - This joint Optics Express and Optical Materials Express feature issue presents a collection of nine papers on the topic of halide perovskites for optoelectronics. Perovskite materials have attracted significant attention over the past four years, initially for their outstanding performance in thin film solar cells, but more recently for applications in light-emitting devices (LEDs and lasers), photodetectors and nonlinear optics. At the same time, there is still much more to learn about the fundamental properties of these materials, and how these depend on composition, processing, and exposure to the environment. This feature issue provides a snapshot of some of the latest research in this rapidly-evolving multidisciplinary field. PMID- 29401906 TI - 50-GHz-spaced comb of high-dimensional frequency-bin entangled photons from an on chip silicon nitride microresonator. AB - Quantum frequency combs from chip-scale integrated sources are promising candidates for scalable and robust quantum information processing (QIP). However, to use these quantum combs for frequency domain QIP, demonstration of entanglement in the frequency basis, showing that the entangled photons are in a coherent superposition of multiple frequency bins, is required. We present a verification of qubit and qutrit frequency-bin entanglement using an on-chip quantum frequency comb with 40 mode pairs, through a two-photon interference measurement that is based on electro-optic phase modulation. Our demonstrations provide an important contribution in establishing integrated optical microresonators as a source for high-dimensional frequency-bin encoded quantum computing, as well as dense quantum key distribution. PMID- 29401907 TI - Silicon optical filter with transmission peaks in wide stopband obtained by anti symmetric photonic crystal with defect in multimode waveguides. AB - We experimentally demonstrate and characterize a wide optical stopband filter with transmission peaks constituted by two parallel rows of an anti-symmetric one dimensional (1D) photonic crystal with defect in a multimode waveguide. The working principle is based on mode coupling for the wavelengths that meet the phase matching condition as the fundamental mode is coupled to a higher-order mode and then filtered out with linear tapers as they are reflected back. The defect in the photonic crystal works as a Fabry-Perot like cavity that allows for localized states in the stopband to quantify the effects of the design parameters and we show a Fabry-Perot filter that extends through the 200 nm stopband. A compact 7 MUm2 device is demonstrated with standard fabrication techniques in Silicon-on-Insulator (SOI), and compared to Fabry-Perot filters in single mode waveguides, we obtain a larger bandwidth and lower back reflections. Applications include refractive index sensors, optical communications and on-chip spectroscopy. PMID- 29401908 TI - Transport-of-intensity-based phase imaging to quantify the refractive index response of 3D direct-write lithography. AB - Precise direct-write lithography of 3D waveguides or diffractive structures within the volume of a photosensitive material is hindered by the lack of metrology that can yield predictive models for the micron-scale refractive index profile in response to a range of exposure conditions. We apply the transport of intensity equation in conjunction with confocal reflection microscopy to capture the complete spatial frequency spectrum of isolated 10 MUm-scale gradient refractive index structures written by single-photon direct-write laser lithography. The model material, a high-performance two-component photopolymer, is found to be linear, integrating, and described by a single master dose response function. The sharp saturation of this function is used to demonstrate nearly binary, flat-topped waveguide profiles in response to a Gaussian focus. PMID- 29401909 TI - Highly stable and tunable white luminescence from Ag-Eu3+ co-doped fluoroborate glass phosphors combined with violet LED. AB - Ag-Eu3+ co-doped fluoroborate glass phosphors doped with various Eu3+ concentrations were prepared by a melt-quenching technique. The luminescent properties of these glass phosphors were characterized by excitation and emission spectra. Broad excitation and emission bands located, respectively, at 300-450 nm and 390-700 nm originating from silver aggregates were observed. Strong red emissions were detected under 404 nm violet light-emitting diode (LED) excitation for those Ag-Eu3+ co-doped samples. It was found that these red emissions of Eu3+ well compensated the deficiency of the red spectral components in glasses containing Ag aggregates. In addition, it was confirmed that stable white light could be achieved from the combination of a specific Ag-Eu3+ co-doped fluoroborate glass phosphor and LEDs with different output wavelengths. By adjusting the luminescence intensity ratio of the glass phosphor to the 404 nm violet LED, tunable emitting color was realized, and the studied glass phosphors showed excellent emitting color stability toward LED drive currents. Our results demonstrated that this kind of easy fabrication, low-cost, and highly stable Ag Eu3+ co-doped fluoroborate glass phosphors had potential application in white LED. PMID- 29401910 TI - Polarization control using passive and active crossed graphene gratings. AB - Graphene gratings provide a promising route towards the miniaturization of THz metasurfaces and other photonic devices, chiefly due to remarkable optical properties of graphene. In this paper, we propose novel graphene nanostructures for passive and active control of the polarization state of THz waves. The proposed devices are composed of two crossed graphene gratings separated by an insulator spacer. Because of specific linear and nonlinear properties of graphene, these optical metasurfaces can be utilized as ultrathin polarization converters operating in the THz frequency domain. In particular, our study shows that properly designed graphene polarizers can effectively select specific polarization states, their thickness being about a tenth of the operating wavelength and size more than 80* smaller than that of similar metallic devices. Equally important, we demonstrate that the nonlinear optical properties of graphene can be utilized to actively control the polarization state of generated higher harmonics. PMID- 29401911 TI - Centimeter-scale suspended photonic crystal mirrors. AB - Demand for lightweight, highly reflective and mechanically compliant mirrors for optics experiments has seen a significant surge. In this aspect, photonic crystal (PhC) membranes are ideal alternatives to conventional mirrors, as they provide high reflectivity with only a single suspended layer of patterned dielectric material. However, due to limitations in nanofabrication, these devices are usually not wider than 300 MUm. Here we experimentally demonstrate suspended PhC mirrors spanning areas up to 10 * 10 mm2. We overcome limitations imposed by the size of the PhC and measure reflectivities greater than 90 % on 56 nm thick mirrors at a wavelength of 1550 nm-an unrivaled performance compared to PhC mirrors with micro scale diameters. These structures bridge the gap between nano scale technologies and macroscopic optical elements. PMID- 29401912 TI - Novel optical fiber SPR temperature sensor based on MMF-PCF-MMF structure and gold-PDMS film. AB - In this paper, a novel optical fiber temperature sensor based on surface plasmon resonance (SPR) is presented. The sensor consists of multimode fiber-photonic crystal fiber-multimode fiber (MMF-PCF-MMF) structure coated with gold film, whose refractive index (RI) sensitivity was found to range from 1060.78 nm/RIU to 4613.73 nm/RIU in the RI range of 1.3330-1.3904. Through simulation and experimental results, the RI sensitivity of the MMF-PCF-MMF structure is found to be higher than that of multimode fiber-single mode fiber-multimode fiber (MMF-SMF MMF) structure. The sensing area was coated with polydimethylsiloxane (PDMS) that has a high thermal coefficient, obtaining a high temperature sensitivity of 1.551 nm/ degrees C in the temperature range of 35-100 degrees C, which means it has a broad application prospect in medical, environmental monitoring and manufacturing industry. PMID- 29401913 TI - Plasmonic interpretation of bulk propagating waves in hyperbolic metamaterial optical waveguides. AB - Hyperbolic metamaterials (HMMs) show great promise in photonics applications because their unconventional open isofrequency surface permits enlargement of wavenumbers without limitation. Although optical behaviors in HMMs can be macroscopically described by theoretical calculations with the effective medium approximation (EMA), neglect of microscopic phenomena in each layer leads to discrepancies from exact numerical results. We clarify the origin of bulk propagating waves in HMMs and we show that they can be classified into two modes: long- and short-range surface-plasmon-based coupled modes (LRSP and SRSP, respectively). Especially, we find that the ratio of the number of LRSP and SRSP couplings dominates the property of each propagation mode. This plasmonic interpretation bridges the gap between the EMA and numerical exact solutions, thereby facilitating studies on HMM applications. PMID- 29401914 TI - Wavelength diversification of high-power external cavity diamond Raman lasers using intracavity harmonic generation. AB - We report a high power quasi-continuous-wave (QCW) 620 nm laser from an external cavity diamond Raman laser utilizing intracavity frequency doubling in lithium triborate. Output power of 30 W for durations of 0.25 ms at 15% conversion efficiency was achieved with a beam quality factor M2 = 1.1 from a free-running Nd:YAG pump laser of M2 = 1.5. The critical design parameters that affect conversion efficiency and power were analysed with the aid of an analytical model. By adaptation to other pump technologies, the diamond approach provides a novel pathway towards high brightness CW beam generation in the visible and ultraviolet regions. PMID- 29401915 TI - Terahertz master-oscillator power-amplifier quantum cascade laser with a grating coupler of extremely low reflectivity. AB - A terahertz master-oscillation power-amplifier quantum cascade laser (THz-MOPA QCL) is demonstrated where a grating coupler is employed to efficiently extract the THz radiation. By maximizing the group velocity and eliminating the scattering of THz wave in the grating coupler, the residue reflectivity is reduced down to the order of 10-3. A buried DFB grating and a tapered preamplifier are proposed to improve the seed power and to reduce the gain saturation, respectively. The THz-MOPA-QCL exhibits single-mode emission, a single-lobed beam with a narrow divergence angle of 18 degrees * 16 degrees , and a pulsed output power of 136 mW at 20 K, which is 36 times that of a second order DFB laser from the same material. PMID- 29401916 TI - Transient establishment of the wavefronts for negative, zero, and positive refraction. AB - We quantitatively demonstrate transient establishment of wavefronts for negative, zero, and positive refraction through a wedge-shaped metamaterial consisting of periodically arranged split-ring resonators and metallic wires. The wavefronts for the three types of refractions propagate through the second interface of the wedge along positive refraction angles at first, then reorganize, and finally propagate along the effective refraction angles after a period of establishment time respectively. The establishment time of the wavefronts prevents violating causality or superluminal propagation for negative and zero refraction. The establishment time for negative or zero refraction is longer than that for positive refraction. For all three refraction processes, transient establishment processes precede the establishment of steady propagation. Moreover, some detailed characters are proven in our research, including infinite wavelength, uniform phase inside the zero-index material, and the phase velocity being antiparallel to the group velocity in the negative-index material. PMID- 29401917 TI - Parallel lensless compressive imaging via deep convolutional neural networks. AB - We report a parallel lensless compressive imaging system, which enjoys real-time reconstruction using deep convolutional neural networks. A prototype composed of a low-cost LCD, 16 photo-diodes and isolation chambers, has been built. Each of these 16 channels captures a fraction of the scene with 16*16 pixels and they are performing in parallel. An efficient inversion algorithm based on deep convolutional neural networks is developed to reconstruct the image. We have demonstrated encouraging results using only 2% (relative to pixel numbers, e.g. 5 for a block with 16*16 pixels) measurements per sensor for digits and around 10% measurements per sensor for facial images. PMID- 29401918 TI - High-resolution W-band ISAR imaging system utilizing a logic-operation-based photonic digital-to-analog converter. AB - W-band inverse synthetic aperture radar (ISAR) imaging systems are very useful for automatic target recognition and classification due to their high spatial resolution, high penetration and small antenna size. Broadband linear frequency modulated wave (LFMW) is usually applied to this system for its de-chirping characteristic. However, nearly all of the LFMW generated in electronic W-band ISAR system are based on multipliers and mixers, suffering seriously from electromagnetic interference (EMI) and timing jitter. And photonic-assisted LFMW generator reported before is always limited by bandwidth or time aperture. In this paper, for the first time, we propose and experimentally demonstrate a high resolution W-band ISAR imaging system utilizing a novel logic-operation-based photonic digital-to-analog converter (LOPDAC). The equivalent sampling rate of the LOPDAC is twice as large as the rate of the digital driving signal. Thus, a broadband LFMW with a large time aperture can be generated by the LOPDAC. This LFMW is up-converted to W band with an optical frequency comb. After photonic assisted de-chirping processing and data processing to the echo, a high resolution two-dimension image can be obtained. Experimentally, W-band radar with a time-bandwidth product (TBWP) as large as 79200 (bandwidth 8 GHz; temporal duration 9.9 us) is established and investigated. Results show that the two dimension (range and cross-range) imaging resolution is ~1.9 cm * ~1.6 cm with a sampling rate of 100 MSa/s in the receiver. PMID- 29401919 TI - High-sensitivity multi-channel probe beam detector towards MEG measurements of small animals with an optically pumped K-Rb hybrid magnetometer. AB - Multi-channel measurements with fine spatial resolution will make magnetoencephalograms (MEGs) possible with small animals using optically pumped magnetometers (OPMs). Therefore, we fabricated a 20-channel probe-beam detector that uses a K-Rb hybrid OPM to increase the spatial resolution. First, we investigated the sensitivity of the detector using the multi-channel measurements and demonstrated that the detector had a fine sensitivity (10-20 fT/Hz1/2 at 10 Hz). Subsequently, we measured magnetic field distribution generated from a loop coil and compared those measurements with analytically calculated distributions. The measurements were in good agreement with the theoretical predictions. The experimental results indicate that our newly developed multi-channel OPM detector has sufficient performance specifications for MEG measurements. PMID- 29401920 TI - Orbital angular momentum-enhanced measurement of rotation vibration using a Sagnac interferometer. AB - We construct an experimental measurement system for rotation vibration signal detection using the orbital angular momentum (OAM) of light in a Sagnac interferometer. Inputting light beams with different OAM, we demonstrate that the measured signal and signal-to-noise ratio can be increased by the OAM mode index l. In addition, the Sagnac interferometer can further improve the vibration signal and suppress the environmental noises. Such system has potential applications in high-precision sensing and monitoring of rotation vibrations. PMID- 29401921 TI - Nonlinear Cherenkov radiations modulated by mode dispersion in a Ti in-diffused LiNbO3 planar waveguide. AB - We report nonlinear Cherenkov radiations (NCRs) in a Ti in-diffused LiNbO3 planar waveguide. The radiations were modulated exploiting different polarizations and orders of the guided modes, the fundamental wavelengths and the working temperatures. Some characteristics related to NCRs, such as radiation angles and relative intensities were investigated in detail. The experimental results matched well with theoretical calculations. PMID- 29401922 TI - Fast and stable gratings inscription in POFs made of different materials with pulsed 248 nm KrF laser. AB - This paper presents fiber Bragg grating (FBG) inscription with a pulsed 248 nm UV KrF laser in polymer optical fibers (POFs) made of different polymers, namely polymethyl methacrylate (PMMA), cyclic-olefin polymer and co-polymer, and Polycarbonate. The inscribed gratings and the corresponding inscription parameters are compared with grating inscribed in POFs made of the aforementioned materials but with the hitherto most used laser for inscription, which is a continuous wave 325 nm UV HeCd laser. Results show a reduction of the inscription time of at least 16 times. The maximum time reduction is more than 130 times. In addition, a reflectivity and a bandwidth close to or higher than the ones with the 325 nm laser were obtained. The polymer optical fiber Bragg gratings (POFBGs) inscribed with the 248 nm laser setup present high stability with small variations in their central wavelength, bandwidth, and reflectivity after 40 days. PMID- 29401923 TI - High-alignment-accuracy transfer printing of passive silicon waveguide structures. AB - We demonstrate the transfer printing of passive silicon devices on a silicon-on insulator target waveguide wafer. Adiabatic taper structures and directional coupler structures were designed for 1310 nm and 1600 nm wavelength coupling tolerant for +/- 1 um misalignment. The release of silicon devices from the silicon substrate was realized by underetching the buried oxide layer while protecting the back-end stack. Devices were successfully picked by a PDMS stamp, by breaking the tethers that kept the silicon coupons in place on the source substrate, and printed with high alignment accuracy on a silicon photonic target wafer. Coupling losses of -1.5 +/- 0.5 dB for the adiabatic taper at 1310 nm wavelength and -0.5 +/- 0.5 dB for the directional coupler at 1600 nm wavelength are obtained. PMID- 29401924 TI - Mechano-optical effects in multiwall carbon nanotubes ethanol based nanofluids. AB - A highly sensitive technique for analyzing surface tension and dynamic viscosity of nanofluids was reported. Multiwall carbon nanotubes suspended in ethanol were evaluated. The assistance of a Fabry-Perot interferometer integrated by a small sample volume fluid allowed us to explore the stability and mechanical properties exhibited by the nanostructures. The surface tension and dynamic viscosity of the colloid was examined by using interferometric optical signals reflected from a remnant drop pending at the end of an optical fiber. Nanosecond pulses provided by a Nd:YAG laser source with 9.5 MW/mm2 at 532 nm wavelength were used to induce mechano-optical effects in the liquid drop. The mechanical parameters were approximated, taking into account single optical pulses interacting with an inelastic mass-spring-damper system. PMID- 29401925 TI - Point-by-point femtosecond laser micro-processing of independent core-specific fiber Bragg gratings in a multi-core fiber. AB - Four 3rd order fiber Bragg gratings were inscribed into separate cores of a 7 core multi-core fiber using the point-by-point inscription technique. A 1030 nm, 206 +/- 5 fs laser was used, operating at a frequency of 1 kHz and pulse energy of 2.1 +/- 0.2 uJ. Independent Bragg resonances at lambdaB = 1541.01 +/- 0.02, 1547.82 +/- 0.02, 1532.66 +/- 0.02, and 1537.42 +/- 0.02 nm and extinction ratios of 13.97 +/- 0.4, 16.02 +/- 0.4, 10.08 +/- 0.4 and 13.40 +/- 0.4 dB were recorded. Our data analysis shows that refractive index changes, Deltan, of the order 10-3 were induced. Core-specific inscription of fiber Bragg gratings in a multi-core fiber can provide a flexible and versatile platform to address the needs of recent space division multiplexed transmission and optical sensor networks. PMID- 29401926 TI - Coherent beam combination of multiple beams based on near-field angle modulation. AB - We proposed a new phase-locking technique for multibeam coherent beam combination. By near-field angle modulation and angular spectrum measurement, we obtained the relative phase between each pair of beams with one camera. This method is appropriate for multibeam schemes and possesses the advantages of high accuracy, resistance to energy fluctuation, and simplicity, as shown by the analysis in this study. In a proof-of-principle experiment, we realized the phase locking of three beams, achieving a Strehl ratio of 89.5%. Our method may supply a scheme for multibeam coherent combining of ultra-intense bulk laser systems. PMID- 29401927 TI - Enhanced sensing of millicharged particles using nonlinear effects in an optomechanical system. AB - Particles with electric charge 10-14 e in bulk mass are not excluded by present experiments. In the present letter we provide a feasible scheme to measure the millicharged particles via the optical cavity coupled to a levitated nanosphere. The results show that the optical probe spectrum of the nano-oscillator presents a tiny shift due to the existence of millicharged particles. Compare to the previous experiment the sensitivity can be improved by the using of a specific geometry to generate an electric field gradient and a pump-probe scheme to read the weak frequency shift. Owing to the very narrow linewidth(10-6 Hz) of the optical Kerr peak on the spectrum, this shift will be more obvious, which makes the millicharges more easy to be detectable. The technique proposed here paves the way for new applications for probing dark matter and nonzero charged neutrino in the condensed matter. PMID- 29401928 TI - Efficient full-spectrum utilization, reception and conversion of solar energy by broad-band nanospiral antenna. AB - In this work, the collection of solar energy by a broad-band nanospiral antenna is investigated in order to solve the low efficiency of the solar rectenna based on conventional nanoantennas. The antenna impedance, radiation, polarization and effective area are all considered in the efficiency calculation using the finite integral technique. The wavelength range investigated is 300-3000 nm, which corresponds to more than 98% of the solar radiation energy. It's found that the nanospiral has stronger field enhancement in the gap than a nanodipole counterpart. And a maximum harvesting efficiency about 80% is possible in principle for the nanospiral coupled to a rectifier resistance of 200 Omega, while about 10% for the nanodipole under the same conditions. Moreover, the nanospiral could be coupled to a rectifier diode of high resistance more easily than the nanodipole. These results indicate that the efficient full-spectrum utilization, reception and conversion of solar energy can be achieved by the nanospiral antenna, which is expected to promote the solar rectenna to be a promising technology in the clean, renewable energy application. PMID- 29401929 TI - Near-field thermophotovoltaic energy conversion using an intermediate transparent substrate. AB - We propose a scheme for near-field thermophotovoltaic (TPV) energy conversion, where thermal emission from an emitter is extracted by an intermediate transparent substrate attached to the top of a photovoltaic (PV) cell. The addition of an intermediate transparent substrate suppresses the unwanted heat transfer from the emitter to the PV cell due to the surface modes on the PV cell while maintaining the enhancement in the interband absorption. We confirm that our scheme is applicable for near-field TPV systems using a silicon (Si) or tungsten (W) emitter. As a specific example, we designed a near-field TPV system composed of a one-dimensional Si photonic crystal thermal emitter, an InGaAs PV cell, and an intermediate Si substrate, and displayed that our scheme could realize both high power density (>5 * 104 W/m2) and high power conversion efficiency (>40%) at a 50-nm gap between the emitter and the intermediate substrate. PMID- 29401930 TI - Near-field thermal rectification devices using phase change periodic nanostructure. AB - We theoretically analyze two near-field thermal rectification devices: a radiative thermal diode and a thermal transistor that utilize a phase change material to achieve dynamic control over heat flow by exploiting metal-insulator transition of VO2 near 341 K. The thermal analogue of electronic diode allows high heat flow in one direction while it restricts the heat flow when the polarity of temperature gradient is reversed. We show that with the introduction of 1-D rectangular grating, thermal rectification is dramatically enhanced in the near-field due to reduced tunneling of surface waves across the interfaces for negative polarity. The radiative thermal transistor also works around phase transition temperature of VO2 and controls heat flow. We demonstrate a transistor like behavior wherein heat flow across the source and the drain can be greatly varied by making a small change in gate temperature. PMID- 29401931 TI - Model-based self-optimization method for form correction in the computer controlled bonnet polishing of optical freeform surfaces. AB - Freeform surfaces have become increasingly widespread in the optical systems for enhanced performance and compact lightweight packaging. The geometrical complexity and high precision requirements of optical freeform surfaces for various functional optical applications, has posed great challenges in the design, precision machining, and measurement of these surfaces. This paper presents a model-based self-optimization approach for precision machining and measurement of optical freeform surfaces in the computer controlled bonnet polishing (CCBP) process. To realize the technical feasibility, the process parameters and motion control are accurately performed through modelling and simulation of machining processes, error compensation, and on-machine metrology. PMID- 29401932 TI - High-fidelity and low-latency mobile fronthaul based on segment-wise TDM and MIMO interleaved arraying. AB - In this paper, we firstly demonstrate an advanced arraying scheme in the TDM based analog mobile fronthaul system to enhance the signal fidelity, in which the segment of the antenna carrier signal (AxC) with an appropriate length is served as the granularity for TDM aggregation. Without introducing extra processing, the entire system can be realized by simple DSP. The theoretical analysis is presented to verify the feasibility of this scheme, and to evaluate its effectiveness, the experiment with ~7-GHz bandwidth and 20 8 * 8 MIMO group signals are conducted. Results show that the segment-wise TDM is completely compatible with the MIMO-interleaved arraying, which is employed in an existing TDM scheme to improve the bandwidth efficiency. Moreover, compared to the existing TDM schemes, our scheme can not only satisfy the latency requirement of 5G but also significantly reduce the multiplexed signal bandwidth, hence providing higher signal fidelity in the bandwidth-limited fronthaul system. The experimental result of EVM verifies that 256-QAM is supportable using the segment wise TDM arraying with only 250-ns latency, while with the ordinary TDM arraying, only 64-QAM is bearable. PMID- 29401933 TI - Linear optical sampling technique for simultaneously characterizing WDM signals with a single receiving channel. AB - Wavelength-division multiplexing (WDM) schemes have greatly increased optical transmission capacity, especially when using massively parallel optical frequency combs (OFCs) as carriers. In this paper, we show that linear optical sampling (LOS) is a kind of multiheterodyne process and it can be performed with arbitrary shaped periodic waveforms. Meanwhile, it can be used for characterizing WDM signals with only a single receiving channel. We successfully demonstrate an observation of 40 WDM channels with 1 THz total bandwidth and total 800 Gbit/s data rate by only using one sampling channel. We show that the adoption of the concept of multiheterodyne detection can improve the performance of LOS technique, and can also greatly simplify multi-channel WDM monitoring systems. PMID- 29401934 TI - 12.5 Gb/s multi-channel broadcasting transmission for free-space optical communication based on the optical frequency comb module. AB - A wide-spectrum, ultra-stable optical frequency comb (OFC) module with 100 GHz frequency intervals based on a quantum dot mode locked (QDML) laser is fabricated by our lab, and a scheme with 12.5 Gb/s multi-channel broadcasting transmission for free-space optical (FSO) communication is proposed based on the OFC module. The output power of the OFC is very stable, with the specially designed circuit and the flatness of the frequency comb over the span of 6 nm, which can be limited to 1.5 dB. Four channel wavelengths are chosen to demonstrate one-to-many channels for FSO communication, like optical wireless broadcast. The outdoor experiment is established to test the bit error rate (BER) and eye diagrams with 12.5 Gb/s on-off keying (OOK). The indoor experiment is used to test the highest traffic rate, which is up to 21 Gb/s for one-hop FSO communication. To the best of our knowledge, this scheme is the first to propose the realization of one-to many broadcasting transmission for FSO communication based on the OFC module. The advantages of integration, miniaturization, channelization, low power consumption, and unlimited bandwidth of one-to-many broadcasting communication scheme, shows promising results on constructing the future space-air-ground-ocean (SAGO) FSO communication networks. PMID- 29401935 TI - Intrinsic loss of few-mode fibers. AB - We summarize theoretical formulae for determining the intrinsic loss of few-mode fibers and compare intrinsic losses among step-index and parabolic graded-index few-mode fibers (FMF) with different dopants, and with single-mode fibers (SMF). The low-loss characteristics of pure-silica-core FMFs, in comparison with SMFs, give rise to additional motivations for pursuing mode-division multiplexed transmission over parallel-SMF transmission, and quasi-single-mode (QSM) transmission over ultra-large-area SMF transmission. PMID- 29401936 TI - Controlled nanostructures formation on stainless steel by short laser pulses for products protection against falsification. AB - The coloration of stainless steel surface due to the formation of spatially periodic structures induced by laser pulses of nanosecond duration is demonstrated. The period of microstructures corresponds to the laser wavelength, and their orientation angle depends on the adjustment of laser polarization. The marking algorithm for the development of authentication patterns is presented. Such patterns provide several levels of protection against falsification (visual, colorimetric and structural) along with high recording speed and capability of automated reading. PMID- 29401937 TI - Dual-wavelength off-axis digital holography using a single light-emitting diode. AB - We propose a new low-coherence interferometry system for dual-wavelength off-axis digital holography. By utilizing diffraction gratings, two beams with narrower bandwidths and different center wavelengths could be filtered in a single light emitting diode. The characteristics of the system are analytically determined to extend the coherence length and field-of-view enough for off-axis configuration. The proposed system enables the fast and accurate measurement of the surface profile with more than a micrometer step height and less noise. The performance of the system is verified by the experimental results of a standard height sample. PMID- 29401938 TI - Estimation of fluorescent Donaldson matrices using a spectral imaging system. AB - The present paper proposes a method to estimate the bispectral Donaldson matrices of fluorescent objects in a scene with a spectral imaging system. Multiple ordinary light sources with continuous spectral-power distributions are projected sequentially onto object surfaces without controlling the spectral shape of the illumination source. The estimation problem of the Donaldson matrices is solved as an optimization problem, where the residual error of observations by the spectral imaging system is minimized. The reflection, emission, and excitation spectral functions are estimated at each wavelength without using a basis function approximation. To improve the estimation efficiency, the output visible range is segmented into two types of wavelength ranges: one for only reflection and another for both reflection and emission. An iterative algorithm is then developed based on the wavelength segmentation and the physical excitation model. The usefulness of the proposed method is examined in experiments using different fluorescent objects and illuminants. We show the estimation accuracy of the Donaldson matrices, discuss the effective selection of illuminants, and demonstrate an application to spectral analysis and reconstruction of a fluorescent image. PMID- 29401939 TI - Time multiplexing technique of holographic view and Maxwellian view using a liquid lens in the optical see-through head mounted display. AB - We report a liquid lens based optical see-through head mounted display that can simultaneously display both a maxwellian view and a hologram. Holograms are reconstructed by an angular spectrum layer based synthesis method. A hologram and Maxwellian view are simultaneously displayed by focusing the liquid lens from 0 D to 20 D with 60 Hz. The hologram is reconstructed at a position 1.5 m from the eye, and it is confirmed that the Maxwellian view is clear, even if the focus of the eye changes from 50 cm to 1.7 m. In the proposed system, the liquid lens acts as a low-pass filter. Since the PSNR is about 23 dB in the currently used 10 mm diameter liquid lens, the image quality is not adequate. However, we successfully verify the feasibility of our proposed system. In addition, if a large diameter liquid lens of 30 mm or more is applied, excellent image quality of 30 dB or more can be realized. PMID- 29401940 TI - High performance InAs/InP quantum dot 34.462-GHz C-band coherent comb laser module. AB - We have developed an InAs/InP quantum dot (QD) C-band coherent comb laser (CCL) module with actively stabilized absolute wavelength and power, and channel spacing of 34.462 GHz with +/- 100 ppm accuracy. The total output power is up to 46 mW. The integrated average relative intensity noise (RIN) values of the lasing spectrum and a filtered single channel at 1540.19 nm were -165.6 dB/Hz and -130.3 dB/Hz respectively in the frequency range from 10 MHz to 10 GHz. The optical linewidth of the 45 filtered individual channels between 1531.77 nm to 1543.77 nm ranged from 850 kHz to 2.16 MHz. We have also analyzed the noise behaviors of each individual channel. PMID- 29401941 TI - Optical coherence grids and their propagation characteristics. AB - A novel class of partially coherent light sources termed optical coherence grids (OCGs) are introduced that can yield stable optical grids in the far field. The optical grids, of which the light distributes in a network of straight lines crossing each other to form a series of hollow cages, can be seen as a better controlled optical lattice. Propagation properties of OCG beams in free space, including spectral density, transverse coherence, and M2 factor, are investigated in detail. It is interesting that a periodic grid pattern is produced at a distance and remains stable on further propagation, and we stress that the structure of far-field optical grids can be flexibly tuned by modulating the correlation parameters of the source. In addition, by performing convolution of degree of coherence, we also propose perfect optical coherence grids (POCG). The far-field grid pattern of POCG is in a fully controllable fashion. This work is expected to find applications in cooling atoms, trapping microscopic particles, or assembling cells, etc. PMID- 29401942 TI - Scalable mode division multiplexed transmission over a 10-km ring-core fiber using high-order orbital angular momentum modes. AB - We propose and demonstrate a scalable mode division multiplexing scheme based on orbital angular momentum modes in ring core fibers. In this scheme, the high order mode groups of a ring core fiber are sufficiently de-coupled by the large differential effective refractive index so that multiple-input multiple-output (MIMO) equalization is only used for crosstalk equalization within each mode group. We design and fabricate a graded-index ring core fiber that supports 5 mode groups with low inter-mode-group coupling, small intra-mode-group differential group delay, and small group velocity dispersion slope over the C band for the high-order mode groups. We implement a two-dimensional wavelength- and mode-division multiplexed transmission experiment involving 10 wavelengths and 2 mode groups each with 4 OAM modes, transmitting 32 GBaud Nyquist QPSK signals over all 80 channels. An aggregate capacity of 5.12 Tb/s and an overall spectral efficiency of 9 bit/s/Hz over 10 km are realized, only using modular 4x4 MIMO processing with 15 taps to recover signals from the intra-mode-group mode coupling. Given the fixed number of modes in each mode group and the low inter mode-group coupling in ring core fibres, our scheme strikes a balance in the trade-off between system capacity and digital signal processing complexity, and therefore has good potential for capacity upscaling at an expense of only modularly increasing the number of mode-groups with fixed-size (4x4) MIMO blocks. PMID- 29401943 TI - Real-time normalization and nonlinearity evaluation methods of the PGC-arctan demodulation in an EOM-based sinusoidal phase modulating interferometer. AB - In order to reduce the nonlinearity caused by an error of phase modulation depth, carrier phase delay and non-ideal performance of the low pass filters in the sinusoidal phase modulating interferometer (SPMI), a modified EOM-based SPMI is proposed in this paper to realize real-time normalization of the quadrature components for the arctangent approach of phase generated carrier (PGC-Arctan) demodulation. To verify the effectiveness of the real-time normalization technique, a fixed-phase-difference detection method is presented to evaluate the periodic nonlinearity in real time. The modified EOM-based SPMI is consisted of a monitor interferometer and a probe interferometer. The two interferometers share a reference corner cube, which is mounted on a slowly moving stage, thus periodic interference signals are generated for real-time normalization of the quadrature components in PGC demodulation. Subtracting the demodulated phase of the monitor interferometer from the phase of the probe interferometer, the phase to be measured can be obtained. The fixed-phase-difference detection method is realized by detecting an interference signal with two photodetectors, which are placed at an interval of quarter fringe, and the variation of the fixed-phase-difference can reflect the nonlinear error in PGC demodulation. Experiments of real-time normalization, nonlinear error evaluation of PGC demodulation, and displacement measurement were implemented to demonstrate the effectiveness of the proposed method. Experimental results show that the nonlinear error of phase demodulation reduced to less than +/- 1 degrees with real-time normalization, and nanometer displacement measurement is realized. PMID- 29401944 TI - Overcoming the efficiency limit of organic light-emitting diodes using ultra-thin and transparent graphene electrodes. AB - We propose an effective way to enhance the out-coupling efficiencies of organic light-emitting diodes (OLEDs) using graphene as a transparent electrode. In this study, we investigated the detrimental adsorption and internal optics occurring in OLEDs with graphene anodes. The optical out-coupling efficiencies of previous OLEDs with transparent graphene electrodes barely exceeded those of OLEDs with conventional transparent electrodes because of the weak microcavity effect. To overcome this issue, we introduced an internal random scattering layer for light extraction and reduced the optical absorption of the graphene by reducing the number of layers in the multilayered graphene film. The efficiencies of the graphene-OLEDs increased significantly with decreasing the number of graphene layers, strongly indicating absorption reduction. The maximum light extraction efficiency was obtained by using a single-layer graphene electrode together with a scattering layer. As a result, a widened angular luminance distribution with a remarkable external quantum efficiency and a luminous efficacy enhancement of 52.8% and 48.5%, respectively, was achieved. Our approach provides a demonstration of graphene-OLED having a performance comparable to that of conventional OLEDs. PMID- 29401945 TI - Enhancement of electromagnetically induced transparency in metamaterials using long range coupling mediated by a hyperbolic material. AB - Near-field coupling is a fundamental physical effect, which plays an important role in the establishment of classical analog of electromagnetically induced transparency (EIT). However, in a normal environment the coupling length between the bright and dark artificial atoms is very short and far less than one wavelength, owing to the exponentially decaying property of near fields. In this work, we report the realization of a long range EIT, by using a hyperbolic metamaterial (HMM) which can convert the near fields into high-k propagating waves to overcome the problem of weak coupling at long distance. Both simulation and experiment show that the coupling length can be enhanced by nearly two orders of magnitude with the aid of a HMM. This long range EIT might be very useful in a variety of applications including sensors, detectors, switch, long-range energy transfer, etc. PMID- 29401946 TI - Designable cascaded nonlinear optical frequency conversion integrating multiple nonlinear interactions in two KTiOAsO4 crystals. AB - We demonstrated a novel cascaded nonlinear frequency conversion that integrated OPO, SFG and SRS in two KTA crystals, realizing an efficient wavelength conversion from 1064 nm to multi-wavelength around 630 nm. The OPO and SRS were both performed in an x-cut KTA crystal to realize a noncritically phase-matched OPO and X(ZZ)X Raman conversion. The SFG was achieved in a (theta = 90?, phi = 24.3?)-cut KTA crystal with a type-II phase-matching configuration. Benefitting from the strong pulse-narrowing induced by the combined effect of OPO and SRS, a minimum pulse width of 13.5 ns was obtained, corresponding to a pulse energy of 0.3 mJ and a pulse peak power of 22.2 kW. The multiple operation parameters of wavelength, average output power, pulse duration and repetition rate can be coordinated to explore new treatment plan in photodynamic therapy. Furthermore, the designability of cascaded nonlinear optical frequency conversion could make the nonlinear optical technology accessible to a much wider range of potential users. PMID- 29401947 TI - Controllable mode transformation in perfect optical vortices. AB - We report a novel method to freely transform the modes of a perfect optical vortex (POV). By adjusting the scaling factor of the Bessel-Gauss beam at the object plane, the POV mode transformation can be easily controlled from circle to ellipse with a high mode purity. Combined with the modulation of the cone angle of an axicon, the ellipse mode can be freely adjusted along the two orthogonal directions. The properties of the "perfect vortex" are experimentally verified. Moreover, fractional elliptic POVs with versatile modes are presented, where the number and position of the gaps are controllable. These findings are significant for applications that require the complex structured optical field of the POV. PMID- 29401948 TI - Tunable terahertz wave-plate based on dual-frequency liquid crystal controlled by alternating electric field. AB - In this work, the optically anisotropic property of dual-frequency liquid crystals (DFLC) in terahertz (THz) regime has been experimentally investigated, which indicates that the refractive index and birefringence of DFLC can be continuously modulated by both the alternating frequency and intensity of the alternating electric field. This tunability originates from the rotation of DFLC molecules induced by alternating electric fields. The results show that by modulating the alternating frequency from 1 kHz to 100 kHz under 30 kV/m electric field, the 600 MUm thickness DFLC cell can play as a tunable quarter-wave plate above 0.68 THz, or a half-wave plate above 1.33 THz. Besides, it can be viewed as a tunable THz phase shifter from 0 to pi. Therefore, due to its novel tuning mechanism, DFLC will be of great significance in dynamic manipulating on THz phase and polarization. PMID- 29401949 TI - Thermal poling of multi-wire array optical fiber. AB - We demonstrate in this paper thermal poling of multi-wire array fibers, which extends poling of fibers with two anodes to ~50 and ~500 wire array anodes. The second harmonic microscopy observations show that second order nonlinearity (SON) layers are developed surrounding all the rings of wires in the ~50 anode array fiber with poling of 1.8kV, 250 degrees C and 30min duration, and the outer rings of the ~500 anode array fiber at lower poling temperature. Our simulations based on a two-dimensional charge dynamics model confirm this can be explained by the self-adjustment mechanism, and show the SON layers are induced from the outer rings to the inner rings. PMID- 29401950 TI - Internal strain induced significant enhancement of deep ultraviolet light extraction efficiency for AlGaN multiple quantum wells grown by MOCVD. AB - In this work, combined analysis of internal strain effects on optical polarization and internal quantum efficiency (IQE) were conducted for the first time. Deep ultraviolet light extraction efficiency of AlGaN multiple quantum wells (MQWs) have been investigated by means of polarization-dependent photoluminescence (PD-PL) and temperature-dependent photoluminescence (TD-PL). With the increase of compressive internal strain applied to the MQWs by an underlying n-AlGaN layer, the degree of polarization (DOP) of the sample was improved from -0.26 to -0.06 leading to significant enhancement of light extraction efficiency (LEE) as the PL intensity increased by 29.2% even though the internal quantum efficiency declined by 7.7%. The results indicated that proper management of the internal compressive strain in AlGaN MQWs can facilitate the transverse electric (TE) mode and suppress the transverse magnetic (TM) mode which could effectively reduce the total internal reflection (TIR) and absorption. This work threw light upon the promising application of compressively strained MQWs to reduce the wave-guide effect and improve the LEE of deep ultraviolet light emitting diodes (DUV LEDs). PMID- 29401951 TI - Dynamic phase extraction in a modulated double-pulse phi-OTDR sensor using a stable homodyne demodulation in direct detection. AB - We propose and experimentally demonstrate a stable homodyne phase demodulation technique in a phi-OTDR using a double-pulse probe and a simple direct detection receiver. The technique uses selective phase modulation of one of a pair of pulses to generate a carrier for dynamic phase changes and involves an enhanced phase demodulation scheme suitable for distributed sensing by being robust against light intensity fluctuations, independent of the modulation depth, and convenient for analogue signal processing. The capability of the technique to quantify distributed dynamic phase change due to a generic external impact is experimentally demonstrated by measuring the phase change induced by a nonlinear actuator generating a 2 kHz perturbation at a distance of 1.5 km on a standard singlemode fiber with an SNR of ~24 dB. The demodulated nonlinear response is shown to have a spectrum consistent with one obtained using an FBG sensor and a commercial reading unit. PMID- 29401952 TI - Optical NP problem solver on laser-written waveguide platform. AB - Cognitive photonic networks are researched to efficiently solve computationally hard problems. Flexible fabrication techniques for the implementation of such networks into compact and scalable chips are desirable for the study of new optical computing schemes and algorithm optimization. Here we demonstrate a femtosecond laser-written optical oracle based on cascaded directional couplers in glass, for the solution of the Hamiltonian path problem. By interrogating the integrated photonic chip with ultrashort laser pulses, we were able to distinguish the different paths traveled by light pulses, and thus infer the existence or the absence of the Hamiltonian path in the network by using an optical correlator. This work proves that graph theory problems may be easily implemented in integrated photonic networks, down scaling the net size and speeding up execution times. PMID- 29401953 TI - Diurnal variations of the optical properties of phytoplankton in a laboratory experiment and their implication for using inherent optical properties to measure biomass. AB - Diurnal variations of phytoplankton size distributions, chlorophyll, carbon and nitrogen content, in vivo fluorescence and associated optical absorption and scattering properties were observed in the laboratory to help understand in situ and spatial observations. We grew triplicate semi-continuous cultures of T. pseudonana, D. tertiolecta, P. tricornutum and E. huxleyi under a sinusoidal light regime. We observed diurnal variations in the particulate absorption (ap), scattering (bp), attenuation (cp), and backscattering coefficients (bbp), which correlate with carbon and Chl concentrations. Relative variations from sunrise of bbp are slightly lower than those of cp, suggesting that bbp diurnal increases observed in nature are partly caused by phytoplankton. Non-concurrent changes of carbon and Chl-specific backscattering and scattering coefficients and optical cross-sections however indicates that using backscattering to infer scattering or biomass must be done with care. PMID- 29401954 TI - Mask-aligner lithography using a continuous-wave diode laser frequency-quadrupled to 193 nm. AB - We present a mask-aligner lithographic system operated with a frequency quadrupled continuous-wave diode laser emitting at 193 nm. For this purpose, a 772 nm diode laser is amplified by a tapered amplifier in the master-oscillator power-amplifier configuration. The emission wavelength is upconverted twice, using LBO and KBBF nonlinear crystals in second-harmonic generation enhancement cavities. An optical output power of 10 mW is achieved. As uniform exposure field illumination is crucial in mask-aligner lithography, beam shaping is realized with optical elements made from fused silica and CaF2 featuring a diffractive non imaging homogenizer. A tandem setup of shaped random diffusers, one static and one rotating, is used to control speckle formation. We demonstrate first experimental soft contact and proximity prints for a field size of 1 cm2 with a standard binary photomask and proximity prints with a two-level phase mask, both printed into 120 nm layers of photoresist on unstructured silicon substrates. PMID- 29401955 TI - Heuristic model for ballistic photon detection in collimated transmittance measurements. AB - An heuristic model for ballistic photon detection in continuous-wave measurements of collimated transmittance through a slab is presented. The model is based on the small angle approximation and the diffusion equation and covers all the ranges of optical thicknesses of the slab from the ballistic to the diffusive regime. The performances of the model have been studied by means of comparisons with the results of gold standard Monte Carlo simulations for a wide range of optical thicknesses and two types of scattering functions. For a non-absorbing slab and field of view of the receiver less than 3 degrees the model shows errors less than 15% for any value of the optical thickness. Even for an albedo value of 0.9, and field of view of the receiver less than 3 degrees the model shows errors less than 20%. These results have been verified for a large set of scattering functions based on the Henyey-Greenstein model and Mie theory for spherical scatterers. The latter has also been used to simulate the scattering function of Intralipid, a diffusive material widely used as reference standard for tissue simulating phantoms. The proposed model represents an effective improvement compared to the existing literature. PMID- 29401956 TI - Control of mode anticrossings in whispering gallery microresonators. AB - Optical microresonators attract strong interest because of exciting effects and applications ranging from sensing of single atoms and molecules to quantum and nonlinear optics. For all this, control and tuning of the discrete resonances are vital. In resonators made of anisotropic materials that are beneficial for nonlinear-optical applications, anticrossings of ordinarily (o) and extraordinarily (e) polarized modes occur regularly. This effect is badly understood and harmful for mode control and tuning. We show that the anticrossings are inherent in the o- and e-modes because of the vectorial properties of Maxwell's equations. Within a novel pertubative approach employing a strong localization of the modes near the resonator rim, we have quantified the anticrossings. The values of avoidance gaps strongly exceeding the linewidths and selection rules for the interacting modes are predicted. The inferred values of the avoidance gaps are confirmed experimentally in resonators made of lithium niobate. Furthermore, based on theory, we have eliminated the anticrossings completely by spatially-controlled introduction of defects. This paves the way for unperturbed tuning of anisotropic microresonators. PMID- 29401957 TI - Multiple aperture synthetic optical coherence tomography for biological tissue imaging. AB - An inherent compromise must be made between transverse resolution and depth of focus (DOF) in spectral domain optical coherence tomography (SD-OCT). Thus far, OCT has not been capable of providing a sufficient DOF to stably acquire cellular resolution images. We previously reported a novel technique named multiple aperture synthesis (MAS) to extend the DOF in high-resolution OCT [Optica4, 701 (2017)]. In this technique, the illumination beam is scanned across the objective lens pupil plane by being steered at the pinhole using a custom-made microcylindrical lens. Images captured via multiple distinctive apertures were digitally refocused, which is similar to synthetic aperture radar. In this study, we applied this technique for the first time to image both a homemade microparticle sample and biological tissue. The results demonstrated the feasibility and efficacy of high-resolution biological tissue imaging with a dramatic DOF extension. PMID- 29401958 TI - All-optical control of polarization splitting with a dielectric-clad azobenzene liquid crystal. AB - We report the design, fabrication, and characterization of an optically switchable polarizing beam splitter with a prism/azobenzene liquid crystal/prism hybrid structure. The beam splitter can operate in the polarization-splitting mode and the non-splitting mode. The switching between the modes is realized by the photoisomerization-induced phase transitions in the azobenzene liquid crystal, featuring all-optical control, bistability, and fast response. Such an active polarization-handling element is highly desirable as it not only simplifies and compacts sophisticated optical systems but also increases the degree of freedom in optical circuit design. PMID- 29401959 TI - Frequency comb generation in a silicon ring resonator modulator. AB - We report on the generation of an optical comb of highly uniform in power frequency lines (variation less than 0.7 dB) using a silicon ring resonator modulator. A characterization involving the measurement of the complex transfer function of the ring is presented and five frequency tones with a 10-GHz spacing are produced using a dual-frequency electrical input at 10 and 20 GHz. A comb shape comparison is conducted for different modulator bias voltages, indicating optimum operation at a small forward-bias voltage. A time-domain measurement confirmed that the comb signal was highly coherent, forming 20.3-ps-long pulses. PMID- 29401960 TI - Theoretical analysis of nonlinear surface wave absorbing metasurfaces. AB - In this paper, we provide a theoretical analysis and discussion of the fundamental principles of nonlinear surface wave absorbers, in which ideal diodes are used to rectify surface currents to produce nonlinear harmonic terms including DC, and higher order modes (2f0, and 4f0, ...). Interestingly, we find rectification converts most of the power to DC that can be completely absorbed by resistance in the surface, leading to advantages of nonlinear absorbers over conventional linear surface wave absorbers in both bandwidth and attenuation. We demonstrate the full-wave rectification case, and diode-rectifier-based nonlinear absorbing metasurfaces possess obvious advantages and can exceed the performance of linear absorbers, which relates the bandwidth and attenuation rate to the substrate thickness. For nonlinear metasurfaces, even with very thin substrates (for instance 0.35 mm thickness which is lambda0/143 for center frequency 6 GHz), we can potentially achieve more than 60% relative bandwidth, three times of that in linear metasurfaces. To visualize the practical working mechanism, the distributed nonlinear network using ideal diode model is presented, and the full wave simulations are demonstrated with nonlinear advantages. Differences between the theoretical case and practical case are addressed as well. PMID- 29401961 TI - Metamaterial-inspired compact optical coating for broadband polarization beam splitting. AB - A metal-dielectric is designed and fabricated as a compact polarization beam splitter. High p-polarized transmission is achieved by admittance matching, which is developed using a normalized admittance diagram. High s-polarized reflection is achieved with a metal-like equivalent s-polarized admittance which real part is much smaller than its imaginary part. An ultra-thin silver film with a thickness of around 11 nm is deposited to form an Ag-SiO2 multilayer. The polarization beam splitter requires only three or five layers of thin films to perform broadband beam splitting over wavelengths from 450 nm to 850 nm. PMID- 29401962 TI - Printed cylindrical lens pair for application to the seam concealment in tiled displays. AB - Seamless tiling of displays is one of the key enabling technologies for the next generation large-area electronics applications. In this paper, we propose a facile method to demonstrate a seamless display using cylindrical lens pair (CLP) fabricated by dispenser printing method. Optical properties of the printed CLP and corresponding capability of concealing seam in the display are analyzed by a set of luminance simulation and measurement in terms of geometric parameters of the lens. The seamless display with an optimized CLP features a viewing angle of the seam concealment of 40 degrees . PMID- 29401963 TI - Photonic magneto-Stark effect based on gradiently modulated magneto-optical medium. AB - Photons are neutral particles which cannot directly interact with an applied magnetic field, but recent studies show that an effective magnetic field can be created for photons by modulating the background permittivity or using magneto optical (MO) media. In this paper, we demonstrate that when the permittivity tensor of a MO medium is spatially modulated, it can create an effective magnetic field proportional to the gradient of gyrotropic ratio. This field induces a Lorentz force and gives rise to a photonic magneto-Stark (PMS) effect. We prove this effect occurs once the photon's wave vector and the gradient of gyrotropic ratio are non-parallel, and reaches the maximum when they are perpendicular. The PMS effect provides a new mechanism for wavelength modulation and controlling the direction-dependent propagation of photonic modes. PMID- 29401964 TI - Polarization chaos and random bit generation in nonlinear fiber optics induced by a time-delayed counter-propagating feedback loop. AB - In this manuscript, we experimentally and numerically investigate the chaotic dynamics of the state-of-polarization in a nonlinear optical fiber due to the cross-interaction between an incident signal and its intense backward replica generated at the fiber-end through an amplified reflective delayed loop. Thanks to the cross-polarization interaction between the two-delayed counter-propagating waves, the output polarization exhibits fast temporal chaotic dynamics, which enable a powerful scrambling process with moving speeds up to 600-krad/s. The performance of this all-optical scrambler was then evaluated on a 10-Gbit/s On/Off Keying telecom signal achieving an error-free transmission. We also describe how these temporal and chaotic polarization fluctuations can be exploited as an all-optical random number generator. To this aim, a billion-bit sequence was experimentally generated and successfully confronted to the dieharder benchmarking statistic tools. Our experimental analysis are supported by numerical simulations based on the resolution of counter-propagating coupled nonlinear propagation equations that confirm the observed behaviors. PMID- 29401965 TI - Photo-induced excitonic structure renormalization and broadband absorption in monolayer tungsten disulphide. AB - Atomically thin transition metal dichalcogenides (TMDCs) have emerged as a new class of two-dimensional (2D) material for novel optoelectronic applications. In particular, 2D TMDCs are viewed as intriguing and appealing materials to construct Q-switching and mode-locked modulators, due to their broadband saturable absorption even of photon energy below their excitonic energies. However, the dynamics and mechanism of saturable absorption inside TMDCs has yet to be investigated. In this paper, the relaxation dynamics of monolayer tungsten disulphide (WS2) was investigated considering different excitonic transitions. WS2 illustrates dramatic changes in optical responses when excited by intense laser pulses, which are characterized by the broadband photo-induced nonresonance absorption and the giant excitonic bands renormalization process. The experimental results show that strong photo-induced restructuring of excitonic bands has picosecond lifetime and full recovery of optical responses takes hundreds of picosecond. Additionally, our observations reveal that heavy renormalization and overlap of excitonic bands are induced by strong many-body Coulomb interactions. Moreover, the broadband absorption feature of WS2 opens up new applications in broadband saturable absorbers and ultrafast photonic devices. PMID- 29401966 TI - Graded SiGe waveguides with broadband low-loss propagation in the mid infrared. AB - Mid-infrared (mid-IR) silicon photonics is expected to lead key advances in different areas including spectroscopy, remote sensing, nonlinear optics or free space communications, among others. Still, the inherent limitations of the silicon-on-insulator (SOI) technology, namely the early mid-IR absorption of silicon oxide and silicon at lambda~3.6 um and at lambda ~8.5 um respectively, remain the main stumbling blocks that prevent this platform to fully exploit the mid-IR spectrum (lambda ~2-20 um). Here, we propose using a compact Ge-rich graded-index Si1-xGex platform to overcome this constraint. A flat propagation loss characteristic as low as 2-3 dB/cm over a wavelength span from lambda = 5.5 um to 8.5 um is demonstrated in Ge-rich Si1-xGex waveguides of only 6 um thick. The comparison of three different waveguides design with different vertical index profiles demonstrates the benefit of reducing the fraction of the guided mode that overlaps with the Si substrate to obtain such flat low loss behavior. Such Ge-rich Si1-xGex platforms may open the route towards the implementation of mid IR photonic integrated circuits with low-loss beyond the Si multi-phonon absorption band onset, hence truly exploiting the full Ge transparency window up to lambda ~15 um. PMID- 29401967 TI - Dynamic Stark induced vortex momentum of hydrogen in circular fields. AB - In this paper, we report our numerical simulation on the symmetry distortion and mechanism of the vortex-shaped momentum distribution of hydrogen atom by taking into account of the dynamic Stark effect. By deploying the strong field approximation (SFA) theory, we performed extensive simulation on the momentum pattern of hydrogen ionized by two time-delayed oppositely circularly polarized attosecond pulses. We deciphered that this distortion is originated from the temporal characteristics of the dynamic Stark phase which is nonlinear in time. PMID- 29401968 TI - Improvement in focusing accuracy of DNA sequencing microscope with multi-position laser differential confocal autofocus method. AB - High focusing accuracy in microscopes could improve the imaging quality to reduce the error rate in DNA sequencing. We propose a new feedback method to improve the focusing condition to a very high accuracy. A reference laser reflected by the sample is detected by two or more sensors around the confocal point. After acquiring the signals from the out-of-focus positions, online data processing is implemented to provide feedbacks for real-time focus-plane locking on the sample surface. This method provides an accuracy better than 1/10 of the objective depth of-focus. To balance optical aberrations, a specific optical feedback system should be designed, with athermal design considerations to adapt DNA sequencing work to temperature fluctuations. PMID- 29401969 TI - Ultra-low loss photonic circuits in lithium niobate on insulator. AB - Lithium niobate on insulator (LNOI) photonics promises to combine the excellent nonlinear properties of lithium niobate with the high complexity achievable by high contrast waveguides. However, to date, fabrication challenges have resulted in high-loss and sidewall-angled waveguides, limiting its applicability. We report LNOI single mode waveguides with ultra low propagation loss of 0.4 dB/cm and sidewall angle of 75 degrees . Our results open the route to a highly efficient photonic platform with applications ranging from high-speed telecommunication to quantum technology. PMID- 29401970 TI - Spin-controlled twisted laser beams: intra-cavity multi-tasking geometric phase metasurfaces. AB - Novel multi-tasking geometric phase metasurfaces were incorporated into a modified degenerate cavity laser as an output coupler to efficiently generate spin-dependent twisted light beams of different topologies. Multiple harmonic scalar vortex laser beams were formed by replacing the laser output coupler with a shared-aperture metasurface. A variety of distinct wave functions were obtained with an interleaving approach - random interspersing of geometric phase profiles within shared-aperture metasurfaces. Utilizing the interleaved metasurfaces, we generated vectorial vortices by coherently superposing of scalar vortices with opposite topological charges and spin states. We also generated multiple partially coherent vortices by incorporating harmonic response metasurfaces. The incorporation of the metasurface platforms into a laser cavity opens a pathway to novel types of nanophotonic functionalities and enhanced light-matter interactions, offering exciting new opportunities for light manipulation. PMID- 29401971 TI - Femtosecond laser Bessel beam welding of transparent to non-transparent materials with large focal-position tolerant zone. AB - It is known that ultrashort laser welding of materials requires an accurate laser beam focusing and positioning onto the samples interface. This puts forward severe challenges for controlling the focus position particularly considering that the tightly focused Gaussian beam has a short, micron-sized Rayleigh range. Here we propose a large-focal-depth welding method to bond materials by using non diffractive femtosecond laser Bessel beams. A zero-order Bessel beam is produced by an axicon and directly imaged on the interface between silicon and borosilicate glass to write welding lines, ensuring a non-diffractive length in the 500 MUm range and micron-sized FWHM diameter. The focal-position tolerant zone for effective welding increases thus many-fold compared to traditional Gaussian beam welding. The shear joining strength of the sample welded by this method could be as high as 16.5 MPa. The Raman spectrum and element distribution analyses within the cross section of welding line reveal that substance mixing has occurred during laser irradiation, which is considered as the main reason for femtosecond laser induced bonding. PMID- 29401972 TI - Hyperspectral absorption and backscattering coefficients of bulk water retrieved from a combination of remote-sensing reflectance and attenuation coefficient. AB - Absorption (a) and backscattering (bb) coefficients play a key role in determining the light field; they also serve as the link between remote sensing and concentrations of optically active water constituents. Here we present an updated scheme to derive hyperspectral a and bb with hyperspectral remote-sensing reflectance (Rrs) and diffuse attenuation coefficient (Kd) as the inputs. Results show that the system works very well from clear open oceans to highly turbid inland waters, with an overall difference less than 25% between these retrievals and those from instrument measurements. This updated scheme advocates the measurement and generation of hyperspectral a and bb from hyperspectral Rrs and Kd, as an independent data source for cross-evaluation of in situ measurements of a and bb and for the development and/or evaluation of remote sensing algorithms for such optical properties. PMID- 29401973 TI - Nanoscale displacement sensing based on the interaction of a Gaussian beam with dielectric nano-dimer antennas. AB - Measuring nanoscale displacement is crucial for optical nanometrology and optical calibration. Here, we present a comprehensive analysis of the far-field scattering of dielectric nano-dimer antennas excited precisely by a Gaussian beam. We demonstrated that the interaction of a Gaussian beam with a dielectric nanoantenna will lead to remarkable sensitivity of the far-field scattering to the displacement at a scale much smaller than the wavelength. The electric/magnetic dipole-dipole interaction model is drawn to analyze the far field scattering and the results are in good agreement with numerical simulations. This study will pave a simple way to a novel position detection and displacement sensing based on the interaction of general Gaussian beam with nanoantennas. PMID- 29401974 TI - Effect of insufficient temporal coherence on visibility contrast in X-ray grating interferometry. AB - X-ray grating interferometry, which has been spotlighted in the last decade as a multi-modal X-ray imaging technique, can provide three independent images, i.e., absorption, differential-phase, and visibility-contrast images. We report on a cause of the visibility contrast, an effect of insufficient temporal coherence, that can be observed when continuous-spectrum X-rays are used. This effect occurs even for a sample without unresolvable random structures, which are known as the main causes of visibility contrast. We performed an experiment using an acrylic cylinder and quantitatively explained the visibility contrast due to this effect. PMID- 29401975 TI - Electron-initiated low noise 1064 nm InGaAsP/InAlAs avalanche photodetectors. AB - We report an electron-initiated 1064 nm InGaAsP avalanche photodetectors (APDs) with an InAlAs multiplier. By utilizing a tailored digital alloy superlattice grading structure, a charge layer and a p type InAlAs multiplier, an unity gain quantum efficiency of 48%, a low room temperature dark current of 470 pA at 90% breakdown voltage, and a low multiplication noise with an effective k ratio of ~0.2 are achieved. The measured maximum gain factor is 5 at room temperature, which is currently limited by the non-optimized electric field profiles, and can be readily enhanced by modifying the doping and thickness parameters for the multiplier and the charge layer. PMID- 29401976 TI - Simultaneous location and size measurement of particles using extended glare point imaging technique. AB - Interferometric particle imaging (IPI) is a robust and popular technique for measuring particle size and velocity. A method based on a template matching algorithm and an auto-correlation method is proposed to simultaneously extract the location and the separation of doublet images of a particle from an IPI focused image. The position coordinate (x,y) of the particle can be determined with high accuracy, as evaluated by using a serial particle mask. Furthermore, the method can be employed to achieve sub-pixel spacing extraction when combined with Gaussian interpolation. The algorithm is tested using synthetic and experimental data. The results suggest that the method presented here is promising for its application to a high-density particle field, in accurately measuring both the particle size and its location. PMID- 29401977 TI - Non-radio-frequency signal tuned acousto-optic tunable filter. AB - As for the common acousto-optic tunable filter (AOTF), the optical wavelength is directly tuned by the frequency of the applied radio frequency (RF) signal. The working wavelength range of the RF controlled AOTF could be limited by the performance of the RF source, especially in the high frequency area. We have proposed a special noncollinear AOTF system, in which the central optical wavelength could be tuned continually by rotating the AOTF, rather than changing its RF. This arrangement is confirmed to be effective to broaden the work wavelength range of a traditional RF based AOTF with the high spectral resolution. Particularly, it is welcomed to the circumstance for the flexible spectral bandwidth. This work has presented not only an original way to tune the wavelength of the filtered optical signal but also a powerful supplement of the RF controlled AOTF. It can lead to a wider applications of a noncollinear AOTF in the field of spectral analysis, hyperspectral imaging, and etc. PMID- 29401978 TI - Compact titanium dioxide waveguides with high nonlinearity at telecommunication wavelengths. AB - Dense integration of photonic integrated circuits demands waveguides simultaneously fulfilling requirements on compactness, low loss, high nonlinearity, and capabilities for mass production. In this work, titanium dioxide waveguides with a thick core of 380 nm exhibiting a compact mode size (0.43 MUm2) and a low loss (5.4 +/- 1 dB/cm) at telecommunication wavelengths around 1550 nm have been fabricated and measured. A microring resonator having a 50 MUm radius has been measured to have a loaded quality factor of 53500. Four wave mixing experiments reveal a nonlinear parameter for the waveguides of 21-34 W-1 m-1 corresponding to a nonlinear index around 2.3-3.6 x 10-18 m2/W, which results in a wavelength conversion efficiency of -36.2 dB. These performances, together with the potentially simple dispersion engineering to the fabricated waveguides by the post processes, yield a strong promise for the titanium dioxide waveguides applied in photonic integrated circuits, especially for nonlinear implementations. PMID- 29401979 TI - Wide-angle broadband absorption in tapered patch antennas. AB - Strip array is a classical antenna structure, which provides an effective way to generate and explore new material properties and device functionalities. In this paper, we demonstrate wide-angle broadband absorption in patch antennas made of tapered strip arrays in the metal-insulator-metal geometry. By superimposing multiple resonances associated with the tapered width of the strips, near-perfect absorption is designed and realized over a wide bandwidth from 29.2 THz to 38 THz with efficiency exceeding 80% in the mid-infrared region. The strong absorption band is insensitive to incident angles up to 75 degrees . The angle-independent absorption is attributed to the unique mechanism of coupling between relevant magnetic resonances and free-space incident light. Our tapered patch antenna design offers the advantage of simplicity, and therefore flexibility in engineering natural materials for strong omnidirectional absorption with a variable and wide bandwidth, which could be of interest in applications such as bolometric sensing, camouflaging, and spectral filtering. PMID- 29401980 TI - Ultrafast volume holographic storage on PQ/PMMA photopolymers with nanosecond pulsed exposures. AB - Ultrafast holographic recording in bulk phenanthrenequinone dispersed poly (methyl methacrylate) photopolymers is experimentally examined under nanosecond pulsed exposure. A modified interference optical system is set to investigate the dark enhancement effect and real-time diffraction grating strength. Single transmission diffraction grating is recorded in a 6 nanosecond pulse exposure. Grating enhancement formation with different pulse quantity, repetition rate and spatial frequency are also measured. Diffraction efficiency is enhanced by increasing the pulse number as well as the single-pulse energy. The grating strength of 0.58 within 1.8 MUs cumulative exposure time is obtained. Moreover, holographic reciprocity failure occurring in the ultrafast holographic storage is analyzed. This paper presents a practical support for PQ/PMMA photopolymers in applications of transient information holographic storage. PMID- 29401981 TI - Saturable absorber based on a single mode fiber - graded index fiber - single mode fiber structure with inner micro-cavity. AB - An Er-doped mode-locked fiber laser with a saturable absorber based on single mode - graded index multimode - single mode fiber (SMF-GIMF-SMF) with inner micro cavity is demonstrated. The modulation depth of the saturable absorber was measured to be 1.9% when the SMF-GIMF-SMF structure is bent to a certain state. Such a simple saturable absorber enables the mode-locking operation in a ring Er doped fiber laser and ultrafast pulses with pulse energy of 0.026 nJ and pulse width of 528 fs at the fundamental repetition rate of 14.34 MHz can be generated. In addition, the harmonic mode-locking operation can also be achieved. PMID- 29401982 TI - Array-source X-ray velocimetry. AB - X-ray velocimetry (XV) has shown promise for investigations into various dynamic biological systems, including the motion of lungs and the flow of blood. Prior research in the field of XV has highlighted the need for both high spatial resolution to resolve features for tracking, and temporal resolution for accurate velocity measurement. In X-ray imaging systems, enhancement of spatial and temporal resolution requires a small focal spot size and high power output respectively, increasing anode power density requirements. In this paper, we present a multi-source XV regime whereby simultaneously illuminating a sample with multiple sources of small focal spot size, overall illumination can be increased whilst maintaining minimal source blurring without increasing power density requirements. Through a series of simulations, we demonstrate the capability for multi-source systems under various practical constraints, such as focal spot size and power density, to provide increased accuracy compared to single source systems. PMID- 29401984 TI - Time-resolved diffuse optical tomography system using an accelerated inverse problem solver. AB - A computationally efficient time-resolved diffuse optical tomography (TR-DOT) prototype was demonstrated using an accelerated inverse problem solver to reconstruct high quality 3D images of highly scattering media such as tissues. The inverse problem solver utilizes seven well-defined points on each experimentally recorded histogram of the distribution time-of-flight (DToF). In this work, the accuracy of the recovered optical properties, and the computational load and time of TR-DOT prototype were investigated using cylindrical turbid phantoms. These phantoms were measured using transmittance geometry under different conditions in multiple experiments to evaluate the performance of this prototype. Overall, the results of evaluation are important in the realization of a real-time and highly accurate TR-DOT system for diffuse optical imaging applications. PMID- 29401983 TI - Driving many distant atoms into high-fidelity steady state entanglement via Lyapunov control. AB - Based on Lyapunov control theory in closed and open systems, we propose a scheme to generate W state of many distant atoms in the cavity-fiber-cavity system. In the closed system, the W state is generated successfully even when the coupling strength between the cavity and fiber is extremely weak. In the presence of atomic spontaneous emission or cavity and fiber decay, the photon-measurement and quantum feedback approaches are proposed to improve the fidelity, which enable efficient generation of high-fidelity W state in the case of large dissipation. Furthermore, the time-optimal Lyapunov control is investigated to shorten the evolution time and improve the fidelity in open systems. PMID- 29401985 TI - Homogeneous spectral broadening of pulsed terahertz quantum cascade lasers by radio frequency modulation. AB - The authors present an experimental investigation of radio frequency modulation on pulsed terahertz quantum cascade lasers (QCLs) emitting around 4.3 THz. The QCL chip used in this work is based on a resonant phonon design which is able to generate a 1.2 W peak power at 10 K from a 400-um-wide and 4-mm-long laser with a single plasmon waveguide. To enhance the radio frequency modulation efficiency and significantly broaden the terahertz spectra, the QCLs are also processed into a double-metal waveguide geometry with a Silicon lens out-coupler to improve the far-field beam quality. The measured beam patterns of the double-metal QCL show a record low divergence of 2.6 degrees in vertical direction and 2.4 degrees in horizontal direction. Finally we perform the inter-mode beat note and terahertz spectra measurements for both single plasmon and double-metal QCLs working in pulsed mode. Since the double-metal waveguide is more suitable for microwave signal transmission, the radio frequency modulation shows stronger effects on the spectral broadening for the double-metal QCL. Although we are not able to achieve comb operation in this work for the pulsed lasers due to the large phase noise, the homogeneous spectral broadening resulted from the radio frequency modulation can be potentially used for spectroscopic applications. PMID- 29401986 TI - Time-bandwidth compression of microwave signals. AB - We report and demonstrate a reconfigurable photonic anamorphic stretch transform to realize time-bandwidth product (TBP) compression for microwave signals. A time spectrum convolution system is employed to provide an ultra-high nonlinear dispersion up to several nanoseconds per gigahertz, which is required for processing nanosecond-long microwave signals. The group delay of the system can be engineered easily by programming a WaveShaper. Based on the proposed scheme, the TBP of a double pulse microwave signal is compressed by 1.9 times. Our proposal can provide a more efficient way to sample, digitize and store high speed microwave signals, opening up entirely new perspectives for generation of many critical microwave signal processing modules. PMID- 29401987 TI - Comparative analysis of ferroelectric domain statistics via nonlinear diffraction in random nonlinear materials. AB - We present an indirect, non-destructive optical method for domain statistic characterization in disordered nonlinear crystals having homogeneous refractive index and spatially random distribution of ferroelectric domains. This method relies on the analysis of the wave-dependent spatial distribution of the second harmonic, in the plane perpendicular to the optical axis in combination with numerical simulations. We apply this technique to the characterization of two different media, Calcium Barium Niobate and Strontium Barium Niobate, with drastically different statistical distributions of ferroelectric domains. PMID- 29401988 TI - Optimization of Ag coated hydrogen silsesquioxane square array hybrid structure design for surface-enhanced Raman scattering substrate. AB - A computer-automated design process for a surface-enhanced Raman scattering (SERS) substrate using a particle swarm optimization algorithm is proposed. Nanostructured Ag coated hydrogen silsesquioxane nanopillar arrays of various sizes for SERS substrate applications are fabricated by direct Ag film deposition on substrates patterned by electron beam lithography and are investigated systematically. Good agreement is demonstrated between experimental and simulation results. The absorption spectra, charge distributions, and electric field distributions are calculated using finite-difference time-domain simulations to explain the field enhancement mechanism and indicate that this enhancement originates from plasmon resonance. Our work provides a guide towards optimum SERS substrate design. PMID- 29401989 TI - Thin-disk pumped optical parametric chirped pulse amplifier delivering CEP-stable multi-mJ few-cycle pulses at 6 kHz. AB - We present an optical parametric chirped pulse amplifier (OPCPA) delivering CEP stable ultrashort pulses with 7 fs, high energies of more than 1.8 mJ and high average output power exceeding 10 W at a repetition rate of 6 kHz. The system is pumped by a picosecond regenerative thin-disk amplifier and exhibits an excellent long-term stability. In a proof-of-principle experiment, high harmonic generation is demonstrated in neon up to the 61st order. PMID- 29401990 TI - Heterodyne interferometric signal retrieval in photoacoustic spectroscopy. AB - A new heterodyne interferometric method for optical signal detection in photoacoustic or photothermal spectroscopy is demonstrated and characterized. It relies on using one laser beam for the photoacoustic excitation of the gas sample that creates refractive index changes along the beam path, while another laser beam is used to measure these changes. A heterodyne-based detection of path length changes is presented that does not require the interferometer to be balanced or stabilized, which significantly simplifies the optical design. We discuss advantages of this new approach to photoacoustic signal detection and the new sensing arrangements that it enables. An open-path photoacoustic spectroscopy of carbon dioxide at 2003 nm and a novel sensing configuration that enables three dimensional spatial gas distribution measurement are experimentally demonstrated. PMID- 29401991 TI - IR-to-visible image upconverter under nonlinear crystal thermal gradient operation. AB - In this work we study the enhancement of the field-of-view of an infrared image up-converter by means of a thermal gradient in a PPLN crystal. Our work focuses on compact upconverters, in which both a short PPLN crystal length and high numerical aperture lenses are employed. We found a qualitative increase in both wavelength and angular tolerances, compared to a constant temperature upconverter, which makes it necessary a correct IR wavelength allocation in order to effectively increase the up-converted area. PMID- 29401992 TI - Double closed-loop control of integrated optical resonance gyroscope with mean square exponential stability. AB - A new double closed-loop control system with mean-square exponential stability is firstly proposed to optimize the detection accuracy and dynamic response characteristic of the integrated optical resonance gyroscope (IORG). The influence mechanism of optical nonlinear effects on system detection sensitivity is investigated to optimize the demodulation gain, the maximum sensitivity and the linear work region of a gyro system. Especially, we analyze the effect of optical parameter fluctuation on the parameter uncertainty of system, and investigate the influence principle of laser locking-frequency noise on the closed-loop detection accuracy of angular velocity. The stochastic disturbance model of double closed-loop IORG is established that takes the unfavorable factors such as optical effect nonlinearity, disturbed disturbance, optical parameter fluctuation and unavoidable system noise into consideration. A robust control algorithm is also designed to guarantee the mean-square exponential stability of system with a prescribed Hinfinity performance in order to improve the detection accuracy and dynamic performance of IORG. The conducted experiment results demonstrate that the IORG has a dynamic response time less than 76us, a long-term bias stability 7.04 degrees /h with an integration time of 10s over one hour test, and the corresponding bias stability 1.841 degrees /h based on Allan deviation, which validate the effectiveness and usefulness of the proposed detection scheme. PMID- 29401993 TI - Integrated 3D display and imaging using dual purpose passive screen and head mounted projectors and camera. AB - We propose an integrated 3D display and imaging system using a head-mounted device and a special dual-purpose passive screen that can simultaneously facilitate 3D display and imaging. The screen is mainly composed of two optical layers, the first layer is a projection surface, which are the finely patterned retro-reflective microspheres that provide high optical gain when illuminated with head-mounted projectors. The second layer is an imaging surface made up of an array of curved mirrors, which form the perspective views of the scene captured by a head-mounted camera. The display and imaging operation are separated by performing polarization multiplexing. The demonstrated prototype system consists of a head-worn unit having a pair of 15 lumen pico-projectors and a 24MP camera, and an in-house designed and fabricated 30cm * 24cm screen. The screen provides bright display using 25% filled retro-reflective microspheres and 20 different perspective views of the user/scene using 5 * 4 array of convex mirrors. The real-time implementation is demonstrated by displaying stereo-3D content providing high brightness (up to 240 cd/m2) and low crosstalk (<4%), while 3D image capture is demonstrated by performing the computational reconstruction of the discrete free-viewpoint stereo pair displayed on a desktop or virtual reality display. Furthermore, the capture quality is determined by measuring the imaging MTF of the captured views and the capture light efficiency is calculated by considering the loss in transmitted light at each interface. Further developments in microfabrication and computational optics can present the proposed system as a unique mobile platform for immersive human-computer interaction of the future. PMID- 29401994 TI - Reflection spectra and near-field images of a liquid crystalline half-Skyrmion lattice. AB - We investigate numerically the optical properties of a hexagonal half-Skyrmion lattice exhibited by a highly chiral liquid crystal confined between two parallel plates. Our study focuses on the near and far-field reflection for normally incident light with different polarizations. We show that, when the wavelength of the incident light is longer than a threshold value, the reflectivity is almost insensitive to the polarization of the incident light, although the intensity profiles of the reflected light, in particular in the near-field regime, depend significantly on the polarization. The former property is attributable to the quasi two-dimensional nature of the half-Skyrmion lattice, that is, almost uniform orientational order along the direction normal to the confining plates. Our results for the intensity of reflected light generated by evanescent as well as propagating contributions suggest that direct evidence of the formation and structure of half-Skyrmions could be provided by near-field optics with resolutions higher than that of conventional optical microscopy. PMID- 29401995 TI - Light modulation of top emission organic light emitting diodes showing strong microcavity effect by applying multilayered scattering film. AB - In order to suppress the viewing angle dependence of top emission organic light emitting diodes (TEOEDs) on a strong microcavity structure, we prepared multi layered nano scattering film which was consisted with transparent planarizing layer and hazy crosslinked scattering layer. Through such an approach, we could obtain not only a stable color shift and luminance distribution with viewing angle but also a negligible pixel blur level. Meanwhile, we investigated a black tint level of TEOLEDs after attachment of circular polarizer (CP) on various nano scattering films because nano scattering film deteriorates a black level. We found that the black level could be improved from the black tint by reducing the refractive index difference between planarizing layer and scattering layer. PMID- 29401996 TI - Tunable asymmetric transmission through tilted rectangular nanohole arrays in a square lattice. AB - Asymmetric transmission (AT) holds significant applications in controlling polarization and propagation directions of electromagnetic waves. In this paper, tilted rectangular nanohole (TRNH) arrays in a square lattice are proposed to realize an AT effect. Numerical results show two AT modes in the transmission spectrum, and they are ascribed to the localized surface plasmon resonances around the two ends of TRNH and surface plasmon polaritons on the golden film. AT properties of the TRNH strongly depend on structural parameters, such as width, length, thickness, and tilted angle of TRNH. Results provide a novel mechanism for generating AT effect and offer potential plasmonic device applications, such as asymmetric wave splitters and optical isolators. PMID- 29401997 TI - Snapshot compressive imaging using aberrations. AB - Based on compressed sensing, snapshot compressive imaging aims to optically compress high resolution images using low resolution detectors. The challenge is the generation of the simultaneous optical projections that can fulfill compressed sensing reconstruction requirements. We propose the use of aberrations to produce point spread functions that can simultaneously code and multiplex partial parts the scene. We explore different Zernike modes and analyze the corresponding coherence parameter. Simulation and experimental reconstruction results from 16X compressed measurements of natively sparse and natural scenes demonstrate the feasibility of using aberrations, in particular primary and secondary astigmatism, for simple, effective single-shot compressive imaging. PMID- 29401998 TI - Thermography based online characterization of conductive thin films in large scale electronics fabrication. AB - Flexible electronics is an emerging thin film based technology enabling completely new types of products and applications compared to conventional electronics. Since the quality of films defines the functionality of fabricated devices, the lack of suitable online manufacturing quality assessment tools has been identified to be a critical bottleneck while upscaling the volume and the yield of thin film electronics manufacturing. In order to solve that problem, a synchronized thermography (ST) based online measurement system was built. Applicability of proposed roll-to-roll compatible ST based system was demonstrated by characterizing a moving plastic film with conductive indium tin oxide on top. Obtained results show that ST can be utilized for online homogeneity characterization and sheet resistance estimation of large area thin films which are not possible with other existing methods. PMID- 29401999 TI - Nonlinear optical response during the electron transition process originated from 3D spin-orbit splitting in NiO nanosheets. AB - NiO, a 3d transition-metal oxide with the strong electron correlation, has attracted great physical attention due to the spin-orbit splitting of 3d electrons. By taking advantage of electron transition process originated from 3d spin-orbit splitting, it may be applied to many photonics areas by linear or nonlinear optical response. To further broaden the photonics applications of NiO, we originally explore the nonlinear optical response, saturable absorption, during the electronic transition due to 3d spin-orbit splitting under a strong optical field and successfully applied in the ultrafast photonics as a mode locker for the generation of visible laser pulses, which is the result of dynamic balancing process by the electron transition arising from ground state (3A2g) to excited state (1Eg) of spin-orbit splitting in the Ni2+ 3d configurations. With the NiO nanosheet film for saturable absorption, we experimentally realize a pulsed visible laser at a wavelength of 640.3 nm for the first time to our knowledge. These results indicate that the study of electron transition process generated by 3d spin-orbit splitting in 3d transition-metal oxides should be helpful for the development of ultrafast photonics and related devices design. PMID- 29402000 TI - Quantitative ptychographic bio-imaging in the water window. AB - Coherent X-ray ptychography is a tool for highly dose efficient lensless nano imaging of biological samples. We have used partially coherent soft X-ray synchrotron radiation to obtain a quantitative image of a laterally extended, dried, and unstained fibroblast cell by ptychography. We used data with and without a beam stop that allowed us to measure coherent diffraction with a high dynamic range of 1.7.106. As a quantitative result, we obtained the refractive index values for two regions of the cell with respect to a reference area. Due to the photon energy in the water window we obtained an extremely high contrast of 53% at 71 nm half-period resolution. The dose applied in our experiment was 9.5.104 Gy and is well below the radiation damage threshold. The concept for dynamic range improvement for low dynamic range detectors with a beam stop opens the path for high resolution nano-imaging of a variety of samples including cryo preserved, hydrated and unstained biological cells. PMID- 29402001 TI - Giant enhancement of stimulated Brillouin scattering with engineered phoxonic crystal waveguides. AB - Stimulated Brillouin scattering (SBS) is a third-order nonlinear process that involves the interaction of two light fields and an acoustic wave in a medium. It has been exploited for applications of optical communication, sensing, and signal processing. This effect, originally demonstrated in long optical fibers, has recently been realized in silicon waveguides on a chip-scale integrated platform. However, due to the weak per-unit-length SBS gain, the length of the silicon waveguides is usually several centimeters, which prevents device miniaturization for high-density integration. Here, we engineer a phoxonic crystal waveguide structure to achieve significantly enhanced SBS gain in the entire C band, by taking advantage of its simultaneous confinement of slow propagating optical and acoustic waves. The resulting SBS gain coefficient is greater than 3 * 104 W-1 m 1 in the wavelength range of 1520-1565 nm with the highest value beyond 106 W-1 m 1, which is at least an order of magnitude higher than the existing demonstrations. This giant enhancement of SBS gain enables ultracompact and high performance SBS-based integrated optoelectronic devices such as Brillouin lasers, amplifiers, and signal processors. PMID- 29402002 TI - Twin-mirror membrane distributed-reflector lasers using 20-MUm-long active region on Si substrates. AB - We demonstrate 20-MUm-long twin-mirror membrane distributed-reflector (DR) lasers for chip-to-chip optical interconnects. The lasers employ distributed Bragg reflectors (DBRs) at both ends of a 20-MUm-long lambda/4-phase shifted distributed feedback (DFB) section. We achieve single-mode lasing in a lambda/4 phase shifted DFB mode at room temperature with a threshold current of 0.39 mA. The lasing wavelength remains stable while the injected current is varied, and it is determined by the lambda/4 phase-shifted DFB. The modulation current efficiency is 11.4 GHz/mA1/2, which is measured by using relative intensity noise spectra. We also demonstrate the direct modulation of the DR lasers at a bit rate of 25.8 Gbit/s with an energy cost of 163 fJ/bit. PMID- 29402003 TI - Crystal growth, spectroscopy and laser performances of Pr3+:Sr0.7La0.3Mg0.3Al11.7O19 (Pr:ASL). AB - We report on the crystal growth, spectroscopic properties and visible laser performances of Pr3+-doped Sr0.7La0.3Mg0.3Al11.7O19 (ASL). ASL crystals doped with 2 at.% and 4 at.% Pr3+ were grown by Czochralski method. The laser experiments were carried out in a plane-concave resonator under excitation at 486 nm, provided from a 2omega-OPSL. Efficient laser emission was obtained with an 8 mm long sample of Pr(2at.%):ASL. The maximum output power amounted to 267 mW, 52 mW, and 318 mW at an absorbed power of 1.2W for red, orange, and deep red emission, respectively. PMID- 29402004 TI - Nonparaxial propagation of the chirped Airy vortex beams in uniaxial crystal orthogonal to the optical axis. AB - We study both analytically and numerically nonparaxial propagation dynamics of the Chirped Airy vortex (CAiV) beams in uniaxial crystal orthogonal to the optical axis. The propagation trajectory, the intensity, the radiation forces, the Poynting vector and the angular momentum (AM) of the CAiV beams are illustrated by numerical examples. The influences of the ratio of the extraordinary refractive index to the ordinary refractive index, the linear chirp factor and the quadratic chirp factor on the nonparaxial evolution of the CAiV beams are examined in detail. Results show that the linear chirp factor provides an intensity concentration, which is totally different with the influence of the quadratic chirp. Besides, the uniaxial crystals with different refractive index ratios can be used to control the intensity of optical lobes. Moreover, the value and the direction of the radiation forces depend on the propagation distance and the chirp factor. The chirp factor acting on the Poynting vector and the AM mainly occurs in the direction of vectors. The nonparaxial propagation characteristics of the CAiV beams provide a convenient method to the intensity modulation and the optical manipulation of micro particles. PMID- 29402005 TI - Integrated InP polarization rotator using the plasmonic effect. AB - we report on an integrated InP based polarization rotator scheme using the plasmonic effect. It operates as a half-wave retarder in ridge waveguide structure. The rotation angle of the eigenmode axes of the half-wave retarder waveguide is determined by the position off a bottom corner of a metal layer placed above the waveguide core in the upper cladding region. The simple rotator structure enables an easy and tolerant fabrication process. The length of the fabricated device is less than 50 MUm, and a polarization extinction ratio (PER) of 20 dB has been achieved. PMID- 29402006 TI - Fabrication of precise aperiodic multichannel fibre Bragg grating filters for spectral line suppression in hydrogenated standard telecommunications fibre. AB - We demonstrate the design and fabrication of multichannel fibre Bragg gratings (FBGs) with aperiodic channel spacings. These will be suitable for the suppression of specific spectral lines such as OH emission lines in the near infrared (NIR) which degrade ground based astronomical imaging. We discuss the design process used to meet a given specification and the fabrication challenges that can give rise to errors in the final manufactured device. We propose and demonstrate solutions to meet these challenges. PMID- 29402007 TI - Ultrafast spatial coherent control methods for transition pathway resolving spectroscopy of atomic rubidium. AB - We demonstrate the use of the ultrafast spatial coherent-control method to resolve the fine-structure two-photon transitions of atomic rubidium. Counter propagating ultrafast optical pulses with spectral phase and amplitude programmed with our optimized solutions successfully induced the two-photon transitions through 5S1/2-5P1/2-5D and 5S1/2-5P3/2-5D pathways, both simultaneously and at distinct spatial locations. Three different pulse-shaping solutions are introduced that combine amplitude shaping, which avoids direct intermediate resonances, and phase programming, which enables the remaining spectral components to be coherently interfered through the targeted transition pathways. Experiments were performed with a room-temperature vapor cell, and the results agree well with theoretical analysis. PMID- 29402008 TI - Interferometric snapshot spectro-ellipsometry. AB - We propose a snapshot spectroscopic ellipsometry and its applications for real time thin-film thickness measurement. The proposed system employs an interferometric polarization-modulation module that can measure the spectroscopic ellipsometric phase for thin-film deposited on a substrate with a measurement speed of around 20 msec. It requires neither moving parts nor time dependent modulation devices. The accuracy of the proposed interferometric snapshot spectro ellipsometer is analyzed through comparison with commercial equipment results. PMID- 29402009 TI - Surface-plasmon-induced ultra-broadband light absorber operating in the visible to infrared range. AB - We propose a novel broadband absorber that shows a strong absorption band much broader than that shown in previous work. In our proposed absorber, randomly arranged metal nanobumps are introduced in the incident-side metal layer of a metal/insulator / metal structure. The random structure converts broadband light into surface plasmons without any angular or polarization dependence. Using silver as the metal layer, we obtained an ultrawide region in which the absorption was higher than 50% in the wavelength region from 0.4 to 3.2 MUm, which corresponds to a three-octave bandwidth. PMID- 29402010 TI - Phase-engineered metalenses to generate converging and non-diffractive vortex beam carrying orbital angular momentum in microwave region. AB - In this paper, ultra-thin metalenses are proposed to generate converging and non diffractive vortex beam carrying orbital angular momentum (OAM) in microwave region. Phase changes are introduced to the transmission cross-polarized wave by tailoring spatial orientation of Pancharatnam-Berry phase unit cell. Based on the superposition of phase profile of spiral phase plate and that of a converging lens or an axicon, vortex beam carrying OAM mode generated by the metalens can also exhibit characteristics of a focusing beam or a Bessel beam. Measured field intensities and phase distributions at microwave frequencies verify the theoretical design procedure. The proposed method provides an efficient approach to control the radius of vortex beam carrying OAM mode in microwave wireless applications for medium-short range distance. PMID- 29402011 TI - Growth mechanism of one-step self-masking reactive-ion-etching (RIE) broadband antireflective and superhydrophilic structures induced by metal nanodots on fused silica. AB - This work presents a low-cost, simple, convenient, advanced technology to prepare large-area defect-free subwavelength structures (SWSs). SWSs were obtained by a metal-induced one-step self-masking RIE process on a fused-silica surface, in which metal-fluoride (mainly ferrous-fluoride) nanodots were used to induce and gather stable fluorocarbon polymer etching inhibitors in the RIE polymers as masks. The SWS growth processes are visible with an increase in etching time and some exhibit prominent broadband antireflective properties from the visible to the near-infrared wavelength range. Transmission in the 600-900-nm range increased from approximately 93% for the polished fused silica to above 99% for the double-side SWSs on fused silica. A theoretical simulation by a finite difference time-domain method agreed well with the experiments. Moreover, the surface of the SWSs exhibits excellent superhydrophilic properties. PMID- 29402012 TI - Embedding the photon with its relativistic mass as a particle into the electromagnetic wave. AB - The particle picture presented by the author in the paper "A particle picture of the optical resonator" [K. Altmann, ASSL 2014 Conference Paper ATu2A.29], which shows that the probability density of a photon propagating with a Gaussian wave can be computed by the use of a Schrodinger equation, is generalized to the case of a wave with arbitrary shape of the phase front. Based on a consideration of the changing propagation direction of the relativistic mass density propagating with the electromagnetic wave, a transverse force acting on the photon is derived. The expression obtained for this force makes it possible to show that the photon moves within a transverse potential that in combination with a Schrodinger equation allows to describe the transverse quantum mechanical motion of the photon by the use of matter wave theory, even though the photon has no rest mass. The obtained results are verified for the plane, the spherical, and the Gaussian wave. Additional verification could be provided also by the fact that the mathematical equation describing the Guoy phase shift could be derived from this particle picture in full agreement with wave optics. One more verification could be obtained by the fact that within the range of the validity of paraxial wave optics, Snell's law could also be derived from this particle picture. Numerical validation of the obtained results for the case of the general wave is under development. PMID- 29402013 TI - Quasi-static method and finite element method for obtaining the modifications of the spontaneous emission rate and energy level shift near a plasmonic nanostructure. AB - We provide numerical demonstrations of the applicability and accuracy of the quasi-static method and the finite-element method in the investigation of the modifications of the spontaneous emission rate and the energy level shift of an emitter placed near a silver-air interface or a silver nano-sphere. The analytical results are presented as a reference. Our calculations show that the finite element method is an accurate and general method. For frequency away from the radiative mode, the quasi-static method can be applied more effectively for calculating the energy level shift than the spontaneous emission rate. But for frequency around, there is a blue shift for both and this shift increases with the increasing of emitter-silver distance. Applying the theory to the nanosphere dimmer, we see similar phenomenon and find extremely large modifications of the spontaneous emission rate and energy level shift. These findings are instructive in the fields of quantum light-matter interactions. PMID- 29402014 TI - Mid-infrared ZGP OPO with divergence compensation and high beam quality. AB - Divergence compensation, optimization of the optical-to-optical efficiency, and high beam quality of signal and idler beams of a high-energy mid-infrared ZnGeP2 (ZGP) optical parametric oscillator (OPO) have been demonstrated by use of a Galilean telescope inside the nonplanar fractional-image-rotation enhancement (FIRE) ring resonator. With a small variation of the distance between the lenses of the telescope, the divergences of signal and idler beams could be adjusted. Up to 36 mJ of mid-infrared pulse energy in the 3-5 um wavelength range is obtained with 92 mJ of pump energy on crystal. The beam quality factors M2 are < 1.5 for the resonant signal beam and the non-resonant idler beam, respectively. Actually, this is an improvement of the beam quality by a factor 3 for the signal and ~2.7 for the idler beam compared without using a telescope inside the FIRE ring resonator. PMID- 29402015 TI - Novel thermal annealing methodology for permanent tuning polymer optical fiber Bragg gratings to longer wavelengths. AB - The Bragg wavelength of a polymer optical fiber Bragg grating can be permanently shifted by utilizing the thermal annealing method. In all the reported fiber annealing cases, the authors were able to tune the Bragg wavelength only to shorter wavelengths, since the polymer fiber shrinks in length during the annealing process. This article demonstrates a novel thermal annealing methodology for permanently tuning polymer optical fiber Bragg gratings to any desirable spectral position, including longer wavelengths. Stretching the polymer optical fiber during the annealing process, the period of Bragg grating, which is directly related with the Bragg wavelength, can become permanently longer. The methodology presented in this article can be used to multiplex polymer optical fiber Bragg gratings at any desirable spectral position utilizing only one phase mask for their photo-inscription, reducing thus their fabrication cost in an industrial setting. PMID- 29402016 TI - Photoalignment of dye-doped cholesteric liquid crystals for electrically tunable patterns with fingerprint textures. AB - We present a convenient photoalignment approach to fabricate rewritable fingerprint textures with designed geometrical patterns based on methyl red doped cholesteric liquid crystals (MDCLCs). MDCLC systems with/without nanoparticles of polyhedral oligomeric silsesquioxanes (POSS) were employed to realize two types of sophisticated binary patterns, respectively. Based on the understanding of involved mechanisms related to boundary conditions and middle-layer theory, we demonstrated the precise manipulation of fingerprint patterns by varying the fingerprint grating vectors in different domains. Notably, the hybrid-aligned liquid crystal configuration induced by POSS nanoparticles, which leads to the electrically rotatable grating, can be converted into the planar-aligned configuration by the adsorption of photoexcited methyl red molecules onto the indium-tin-oxide (ITO) surface. In this manner, the dynamic voltage-dependent behavior of fingerprint gratings is altered from the rotation mode (R-mode) to the on-off mode (O-mode). PMID- 29402017 TI - Observation of linear plasmonic breathers and adiabatic elimination in a plasmonic multi-level coupled system. AB - We provide experimental and numerical demonstrations of plasmonic propagation dynamics in a multi-level coupled system, and present the first observation of plasmonic breathers propagating in such systems. The effect is observed both for the simplest symmetric case of a thin metal layer surrounded by two identical dielectrics, and also for a more complex system that includes five and more layers. By a careful choice of the permittivities and thicknesses of the intermediate layers, we can adiabatically eliminate the plasmonic waves in all the intermediate interfaces, thus enabling efficient vertical delivery and extraction of plasmonic signals between the top layer and deeply buried layers. The observation relies on controlling the excited mode by breaking the symmetry of excitation, which is crucial for obtaining the results experimentally. We also observe this breathing effect for transversely shaped plasmonic beams, with Hermite-Gauss, Airy and Weber wavefronts, that despite the oscillatory nature of propagation in such systems, still preserve all their unique wavefront properties. Finally, we show that such approaches can be extended to plasmonic propagation in a general multi-layered system, opening a path for efficient three dimensional integrated plasmonic circuitry. PMID- 29402018 TI - Fast optimization method of designing a wideband metasurface without using the Pancharatnam-Berry phase. AB - Arbitrary control of electromagnetic waves remains a significant challenge although it promises many important applications. Here, we proposed a fast optimization method of designing a wideband metasurface without using the Pancharatnam-Berry (PB) phase, of which the elements are non-absorptive and capable of predicting the wideband and smooth phase-shift. In our design method, the metasurface is composed of low-Q-factor resonant elements without using the PB phase, and is optimized by the genetic algorithm and nonlinear fitting method, having the advantages that the far field scattering patterns can be quickly synthesized by the hybrid array patterns. To validate the design method, a wideband low radar cross section metasurface is demonstrated, showing good feasibility and performance of wideband RCS reduction. This work reveals an opportunity arising from a metasurface in effective manipulation of microwave and flexible fast optimal design method. PMID- 29402019 TI - Tailored Raman-resonant four-wave-mixing processes. AB - Nonlinear optical processes are strongly dominated by phase relationships among electromagnetic fields involved. In this paper, we theoretically and experimentally show that in a Raman-resonant four-wave-mixing process, the first anti-Stokes and Stokes generations can be tailored in a variety of ways by manipulating the phase relationships among the relevant electromagnetic fields. PMID- 29402020 TI - Accelerated computer generated holography using sparse bases in the STFT domain. AB - Computer-generated holography at high resolutions is a computationally intensive task. Efficient algorithms are needed to generate holograms at acceptable speeds, especially for real-time and interactive applications such as holographic displays. We propose a novel technique to generate holograms using a sparse basis representation in the short-time Fourier space combined with a wavefront recording plane placed in the middle of the 3D object. By computing the point spread functions in the transform domain, we update only a small subset of the precomputed largest-magnitude coefficients to significantly accelerate the algorithm over conventional look-up table methods. We implement the algorithm on a GPU, and report a speedup factor of over 30. We show that this transform is superior over wavelet-based approaches, and show quantitative and qualitative improvements over the state-of-the-art WASABI method; we report accuracy gains of 2dB PSNR, as well improved view preservation. PMID- 29402021 TI - High-speed and high-accuracy 3D surface measurement using a mechanical projector. AB - This paper presents a method to achieve high-speed and high-accuracy 3D surface measurement using a custom-designed mechanical projector and two high-speed cameras. We developed a computational framework that can achieve absolute shape measurement in sub-pixel accuracy through: 1) capturing precisely phase-shifted fringe patterns by synchronizing the cameras with the projector; 2) generating a rough disparity map between two cameras by employing a standard stereo-vision method using texture images with encoded statistical patterns; and 3) utilizing the wrapped phase as a constraint to refine the disparity map. The projector can project binary patterns at a speed of up to 10,000 Hz, and the camera can capture the required number of phase-shifted fringe patterns with 1/10,000 second, and thus 3D shape measurement can be realized as high as 10,000 Hz regardless the number of phase-shifted fringe patterns required for one 3D reconstruction. Experimental results demonstrated the success of our proposed method. PMID- 29402022 TI - Optical subcarrier processing for Nyquist SCM signals via coherent spectrum overlapping in four-wave mixing with coherent multi-tone pump. AB - As one of the promising multiplexing and multicarrier modulation technologies, Nyquist subcarrier multiplexing (Nyquist SCM) has recently attracted research attention to realize ultra-fast and ultra-spectral-efficient optical networks. In this paper, we propose and experimentally demonstrate optical subcarrier processing technologies for Nyquist SCM signals such as frequency conversion, multicast and data aggregation of subcarriers, through the coherent spectrum overlapping between subcarriers in four-wave mixing (FWM) with coherent multi tone pump. The data aggregation is realized by coherently superposing or combining low-level subcarriers to yield high-level subcarriers in the optical field. Moreover, multiple replicas of the data-aggregated subcarriers and the subcarriers carrying the original data are obtained. In the experiment, two 5 Gbps quadrature phase-shift keying (QPSK) subcarriers are coherently combined to generate a 10 Gbps 16 quadrature amplitude modulation (QAM) subcarrier with frequency conversions through the FWM with coherent multi-tone pump. Less than 1 dB optical signal-to-noise ratio (OSNR) penalty variation is observed for the synthesized 16QAM subcarriers after the data aggregation. In addition, some subcarriers are kept in the original formats, QPSK, with a power penalty of less than 0.4 dB with respect to the original input subcarriers. The proposed subcarrier processing technology enables flexibility for spectral management in future dynamic optical networks. PMID- 29402023 TI - Femtosecond laser written arrayed waveguide gratings with integrated photonic lanterns. AB - We demonstrate for the first time functional arrayed waveguide gratings (AWGs) fabricated using the femtosecond laser direct-write technique. This fabrication technique is a mask-less alternative to lithography enabling design flexibility and rapid prototyping. It is ideal for customized small scale production for new applications. The devices were demonstrated in the visible region at 632.8 nm with a measured free spectral range (FSR) of 22.2 nm, and 1.35 nm resolution. To highlight the advantages of using a 3-dimensional fabrication technique, a 3-port photonic lantern was integrated with an AWG in a single monolithic chip. Integration of this type is not feasible with lithography-based AWG fabrication and can increase the functionality of AWGs for sensing applications. PMID- 29402024 TI - Vectorial diffraction properties of THz vortex Bessel beams. AB - A vortex Bessel beam combines the merits of an optical vortex and a Bessel beam, including a spiral wave front and a non-diffractive feature, which has immense application potentials in optical trapping, optical fabrication, optical communications, and so on. Here, linearly and circularly polarized vortex Bessel beams in the terahertz (THz) frequency range are generated by utilizing a THz quarter wave plate, a spiral phase plate, and Teflon axicons with different opening angles. Taking advantage of a THz focal-plane imaging system, vectorial diffraction properties of the THz vortex Bessel beams are comprehensively characterized and discussed, including the transverse (Ex, Ey) and longitudinal (Ez) polarization components. The experimental phenomena are accurately simulated by adopting the vectorial Rayleigh diffraction integral. By varying the opening angle of the axicon, the characteristic parameters of these THz vortex Bessel beams are exhibited and compared, including the light spot size, the diffraction free range, and the phase evolution process. This work provides the precise experimental and theoretical bases for the comprehension and application of a THz vortex Bessel beam. PMID- 29402025 TI - Harmonically mode-locked Yb:CALGO laser pumped by a single-mode 1.2 W laser diode. AB - We present a SESAM mode locked Yb:CALGO laser with a harmonic repetition rate to the 300th order pumped by a single-mode fiber coupled laser diode. By fine tuning the internal angle between the laser beam and the normal axis through the gain medium, at pump power of 1.2 W, an average output power of 132 mW is achieved with a pulse duration of 777.6 fs and a repetition rate of 22.4 GHz. The amplification effect over several tens of roundtrips induced Fabry-Perot filtering of the anti-reflection (AR) coated gain medium is analyzed. The modulation depth increases and the FWHM of a passband Deltaupsiloncrystal decreases with increasing roundtrip numbers in the laser crystal. The intra cavity pulse shaping mechanism with a comb filter caused by the amplified etalon effect of the AR coated laser crystal leads to the overall mode spacing equal to the free spectral range of the gain medium other than the laser cavity and results in the high repetition rate running. PMID- 29402026 TI - Flattening axial intensity oscillations of a diffracted Bessel beam through a cardioid-like hole. AB - We present a new feasible way to flatten the axial intensity oscillations for diffraction of a finite-sized Bessel beam, through designing a cardioid-like hole. The boundary formula of the cardioid-like hole is given analytically. Numerical results by the complete Rayleigh-Sommerfeld method reveal that the Bessel beam propagates stably in a considerably long axial range, after passing through the cardioid-like hole. Compared with the gradually absorbing apodization technique in previous papers, in this paper a hard truncation of the incident Bessel beam is employed at the cardioid-like hole edges. The proposed hard apodization technique takes two advantages in suppressing the axial intensity oscillations, i.e., easier implementation and higher accuracy. It is expected to have practical applications in laser machining, light sectioning, or optical trapping. PMID- 29402027 TI - High-power stable continuous-wave single-longitudinal-mode Nd:YVO4 laser at 1342 nm. AB - A universal model about the sufficient condition of stable single-longitudinal mode (SLM) operation is established and applied to the theoretical analysis of a high power unidirectional ring Nd:YVO4 laser at 1342 nm with energy transfer upconversion and excited stimulated absorption taken into account. A stable continuous-wave SLM laser with 1342 nm power of 11.3 W and 671 nm power of 0.3 W is fabricated by optimizing the transmission of output coupler and the temperature of LiB3O5 crystal. Mode-hopping-free laser operation with a power stability better than +/- 0.5% and a frequency fluctuation less than +/- 88 MHz is achieved during a given three hours. PMID- 29402028 TI - Nanophotonic lithium niobate electro-optic modulators. AB - Since the emergence of optical fiber communications, lithium niobate (LN) has been the material of choice for electro-optic modulators, featuring high data bandwidth and excellent signal fidelity. Conventional LN modulators however are bulky, expensive and power hungry, and cannot meet the growing demand in modern optical data links. Chip-scale, highly integrated, LN modulators could offer solutions to this problem, yet the fabrication of low-loss devices in LN thin films has been challenging. Here we overcome this hurdle and demonstrate monolithically integrated LN electro-optic modulators that are significantly smaller and more efficient than traditional bulk LN devices, while preserving LN's excellent material properties. Our compact LN electro-optic platform consists of low-loss nanoscale LN waveguides, micro-ring resonators and miniaturized Mach-Zehnder interferometers, fabricated by directly shaping LN thin films into sub-wavelength structures. The efficient confinement of both optical and microwave fields at the nanoscale dramatically improves the device performances featuring a half-wave electro-optic modulation efficiency of 1.8 V?cm while operating at data rates up to 40 Gbps. Our monolithic LN nanophotonic platform enables dense integration of high-performance active components, opening new avenues for future high-speed, low power and cost-effective communication networks. PMID- 29402029 TI - Influence on the saturable absorption of the induced losses by photodeposition of zinc nanoparticles in an optical fiber. AB - In this work, the influence of induced losses on the saturable absorption by zinc nanoparticles photodeposited onto the core of an optical fiber end is reported. Samples with different losses were obtained by the photodeposition technique using a continuous wave laser at 1550 nm. The nonlinear absorption of the saturable absorber was characterized by the P-scan technique using a high-gain pulsed erbium-doped fiber amplifier. The results have demonstrated that for optical fibers with variable induced losses by deposited nanoparticles, the modulation depth increases proportionally based on the nonlinear absorption coefficient. With induced losses fixed at 3 dB, it was demonstrated that the modulation depth increased as a function of the optical power used in the photodeposition process. The saturation intensity of the saturable absorber presents small shifts for higher intensities. PMID- 29402030 TI - Demonstration of enhanced continuous-wave operation of blue laser diodes on a semipolar 202-1- GaN substrate using indium-tin-oxide/thin-p-GaN cladding layers. AB - The benefits of utilizing transparent conductive oxide on top of a thin p-GaN layer for continuous-wave (CW) operation of blue laser diodes (LDs) were investigated. A very low operating voltage of 5.35 V at 10 kA/cm2 was obtained for LDs with 250 nm thick p-GaN compared to 7.3 V for LDs with conventional 650 nm thick p-GaN. An improved thermal performance was also observed for the thin p GaN samples resulting in a 40% increase in peak light output power and a 32% decrease in surface temperature. Finally, a tradeoff was demonstrated between low operating voltage and increased optical modal loss in the indium tin oxide (ITO) with thinner p-GaN. LDs lasing at 445 nm with 150 nm thick p-GaN had an excess modal loss while LDs with an optimal 250 nm thick p-GaN resulted in optical output power of 1.1 W per facet without facet coatings and a wall-plug efficiency of 15%. PMID- 29402031 TI - Large area metalenses: design, characterization, and mass manufacturing. AB - Optical components, such as lenses, have traditionally been made in the bulk form by shaping glass or other transparent materials. Recent advances in metasurfaces provide a new basis for recasting optical components into thin, planar elements, having similar or better performance using arrays of subwavelength-spaced optical phase-shifters. The technology required to mass produce them dates back to the mid-1990s, when the feature sizes of semiconductor manufacturing became considerably denser than the wavelength of light, advancing in stride with Moore's law. This provides the possibility of unifying two industries: semiconductor manufacturing and lens-making, whereby the same technology used to make computer chips is used to make optical components, such as lenses, based on metasurfaces. Using a scalable metasurface layout compression algorithm that exponentially reduces design file sizes (by 3 orders of magnitude for a centimeter diameter lens) and stepper photolithography, we show the design and fabrication of metasurface lenses (metalenses) with extremely large areas, up to centimeters in diameter and beyond. Using a single two-centimeter diameter near infrared metalens less than a micron thick fabricated in this way, we experimentally implement the ideal thin lens equation, while demonstrating high quality imaging and diffraction-limited focusing. PMID- 29402032 TI - Realization of a compact one-seed laser system for atom interferometer-based gravimeters. AB - A simple and compact design of the laser system is important for realization of compact atom interferometers (AIs). We design and realize a simple fiber bench based 780-nm laser system used for 85Rb AI-based gravimeters. The laser system contains only one 780 nm seed laser, and the traditional frequency-doubling module is not used. The Raman beams are shared with one pair of the cooling beams by using a liquid crystal variable retarder based polarization control technique. This laser system is applied to a compact AI-based gravimeter, and a best gravity measurement sensitivity of 230 MUGal/Hz1/2 is achieved. The gravity measurements for more than one day are also performed, and the long-term stability of the gravimeter is 5.5 MUGal. PMID- 29402033 TI - Focusing behavior of the fractal vector optical fields designed by fractal lattice growth model. AB - We introduce a general fractal lattice growth model, significantly expanding the application scope of the fractal in the realm of optics. This model can be applied to construct various kinds of fractal "lattices" and then to achieve the design of a great diversity of fractal vector optical fields (F-VOFs) combinating with various "bases". We also experimentally generate the F-VOFs and explore their universal focusing behaviors. Multiple focal spots can be flexibly enginnered, and the optical tweezers experiment validates the simulated tight focusing fields, which means that this model allows the diversity of the focal patterns to flexibly trap and manipulate micrometer-sized particles. Furthermore, the recovery performance of the F-VOFs is also studied when the input fields and spatial frequency spectrum are obstructed, and the results confirm the robustness of the F-VOFs in both focusing and imaging processes, which is very useful in information transmission. PMID- 29402034 TI - 3D shape measurement of discontinuous specular objects based on advanced PMD with bi-telecentric lens. AB - This paper presents an advanced phase measuring deflectometry (PMD) method based on a novel mathematical model to obtain three dimensional (3D) shape of discontinuous specular object using a bi-telecentric lens. The proposed method uses an LCD screen, a flat beam splitter, a camera with a bi-telecentric lens, and a translating stage. The LCD screen is used to display sinusoidal fringe patterns and can be moved by the stage to two different positions along the normal direction of a reference plane. The camera captures the deformed fringe patterns reflected by the measured specular surface. The splitter realizes the fringe patterns displaying and imaging from the same direction. Using the proposed advanced PMD method, the depth data can be directly calculated from absolute phase, instead of integrating gradient data. In order to calibrate the relative orientation of the LCD screen and the camera, an auxiliary plane mirror is used to reflect the pattern on the LCD screen three times. After the geometric calibration, 3D shape data of the measured specular objects are calculated from the phase differences between the reference plane and the reflected surface. The experimental results show that 3D shape of discontinuous specular object can be effectively and accurately measured from absolute phase data by the proposed advanced PMD method. PMID- 29402035 TI - Strong coherent coupling between graphene surface plasmons and anisotropic black phosphorus localized surface plasmons. AB - The anisotropic plasmons properties of black phosphorus allow for realizing direction-dependent plasmonics devices. Here, we theoretically investigated the hybridization between graphene surface plasmons (GSP) and anisotropic black phosphorus localized surface plasmons (BPLSP) in the strong coupling regime. By dynamically adjusting the Fermi level of graphene, we show that the strong coherent GSP-BPLSP coupling can be achieved in both armchair and zigzag directions, which is attributed to the anisotropic black phosphorus with different in-plane effective electron masses along the two crystal axes. The strong coupling is quantitatively described by calculating the dispersion of the hybrid modes using a coupled oscillator model. Mode splitting energy of 26.5 meV and 19 meV are determined for the GSP-BPLSP hybridization along armchair and zigzag direction, respectively. We also find that the coupling strength can be strongly affected by the distance between graphene sheet and black phosphorus nanoribbons. Our work may provide the building blocks to construct future highly compact anisotropic plasmonics devices based on two-dimensional materials at infrared and terahertz frequencies. PMID- 29402036 TI - Multiple recollisions in nonsequential double ionization by counter-rotating two color circularly polarized laser fields. AB - With the three-dimensional (3D) classical ensemble method, we theoretically investigate the recollision dynamics in strong-field nonsequential double ionization (NSDI) of Ar by counter-rotating two-color circularly polarized laser fields. With the analysis of the NSDI trajectories, we find that not only multiple-recollision but also single-recollision processes occur in the double ionization events. Furthermore, the multiple-recollision and single-recollision processes both undergo the recollision-induced excitation with subsequent ionization (RESI) and recollision-induced ionization (RII). The angle between the momentum and the force of the laser field at the recollision moment can affect the times of the recollision. PMID- 29402037 TI - Wavefront control in adaptive microscopy using Shack-Hartmann sensors with arbitrarily shaped pupils. AB - In adaptive optical microscopy of thick biological tissue, strong scattering and aberrations can change the effective pupil shape by rendering some Shack-Hartmann spots unusable. The change of pupil shape leads to a change of wavefront reconstruction or control matrix that should be updated accordingly. Modified slope and modal wavefront control methods based on measurements of a Shack Hartmann wavefront sensor are proposed to accommodate an arbitrarily shaped pupil. Furthermore, we present partial wavefront control methods that remove specific aberration modes like tip, tilt and defocus from the control loop. The proposed control methods were investigated and compared by simulation using experimentally obtained aberration data. The performance was then tested experimentally through closed-loop aberration corrections using an obscured pupil. PMID- 29402039 TI - Ultra-thin and broadband tunable metamaterial graphene absorber. AB - A broadband tunable metamaterial graphene absorber is investigated in this paper. The unit cell of the proposed metamaterial graphene absorber is composed of four patch resonators. By tuning the chemical potential of graphene and the geometric size of each patch, the simulated total reflectivity is less than -10 dB from 22.02 to 36.61 THz and with the total thickness of 0.76 um (only 0.09lambda at the lowest frequency). The analysis of the surface current, magnetic field and power flow distributions has been performed to better understand the absorption mechanism. Moreover, this proposed absorber achieves its bandwidth tunable characteristics through a voltage biasing of the graphene's Fremi level. This proposed metamaterial graphene absorber (MGA) could be used as smart absorbers, photovoltaic devices and tunable sensors. PMID- 29402038 TI - Thermal nanoimprint lithography for drift correction in super-resolution fluorescence microscopy. AB - Localization-based super-resolution microscopy enables imaging of biological structures with sub-diffraction-limited accuracy, but generally requires extended acquisition time. Consequently, stage drift often limits the spatial precision. Previously, we reported a simple method to correct for this by creating an array of 1 MUm3 fiducial markers, every ~8 MUm, on the coverslip, using UV-nanoimprint lithography (UV-NIL). While this allowed reliable and accurate 3D drift correction, it suffered high autofluorescence background with shorter wavelength illumination, unstable adsorption to the substrate glass surface, and suboptimal biocompatibility. Here, we present an improved fiducial micro-pattern prepared by thermal nanoimprint lithography (T-NIL). The new pattern is made of a thermal plastic material with low fluorescence backgrounds across the wide excitation range, particularly in the blue-region; robust structural stability under cell culturing condition; and a high bio-compatibility in terms of cell viability and adhesion. We demonstrate drift precision to 1.5 nm for lateral (x, y) and 6.1 nm axial (z) axes every 0.2 seconds for a total of 1 min long image acquisition. As a proof of principle, we acquired 4-color wide-field fluorescence images of live mammalian cells; we also acquired super-resolution images of fixed hippocampal neurons, and super-resolution images of live glutamate receptors and postsynaptic density proteins. PMID- 29402040 TI - Ultraviolet-enhanced supercontinuum generation with a mode-locked Yb-doped fiber laser operating in dissipative-soliton-resonance region. AB - We experimentally demonstrate an all-fiber, ultraviolet-enhanced, supercontinuum generation in a specifically designed seven-core photonic crystal fiber pumped by a picosecond Yb-doped master oscillator power amplifier (MOPA). The MOPA source is seeded by a giant-chirped Yb-doped mode-locked fiber laser operating in the dissipative-soliton-resonance (DSR) region. The DSR is achieved by using a nonlinear optical loop mirror (NOLM) with a fundamental repetition rate of 4.5 MHz and a central wavelength of 1035 nm. An extremely wide optical spectrum spanning from 350 nm to 2400 nm is obtained with a total output power of 6.86 W. PMID- 29402041 TI - Decoupling substrate thickness and refractive index measurement in THz time domain spectroscopy. AB - Terahertz time-domain spectroscopy (THz-TDS) relies heavily on knowing precisely the thickness or refractive index of a material. In practice, one of these values is assumed to be known, or their product is numerically optimized to converge on suitable values. Both approaches are prone to errors and may mask some real features or properties of the material being studied. To eliminate these errors, we use THz-TDS in reflection geometry to accurately and independently determine both thickness and refractive index by illuminating the step-edge of a substrate atop a metal stage. This method relies solely on the relative time delay among three reflected pulses, and therefore forgoes the need for optimization or assumption of substrate parameters. PMID- 29402042 TI - Compact birefringent interferometer for Fourier transform hyperspectral imaging. AB - A compact birefringent interferometer (CBI) for Fourier transform hyperspectral imaging is presented. The CBI employs only two birefringent crystal plates: a shearing plate (SP) and a compensation plate (CP). The SP generates the optical path difference (OPD) associated with the field of view for broadband interference. The CP compensates the constant term and square term OPDs of the SP to adjust the position of the zero-order fringe pattern and suppress inconsistent total OPDs and other nonlinear OPDs. This paper details the theoretically deduced OPDs and then presents simulation analyses and verification experiments conducted to investigate the OPD distribution characteristics. To verify the CBI performance, experimental spectral measurements and hyperspectral imaging were performed. The experimental results demonstrate that the CBI can suppress inconsistent total OPDs and other nonlinear OPDs with only two birefringent crystal plates, and therefore offers much promise for miniature and high precision Fourier transform hyperspectral imaging. PMID- 29402043 TI - Assessing the depolarization capabilities of nonspherical particles in a super ellipsoidal shape space. AB - Here we use the state-of-the-art invariant imbedding T-matrix method to theoretically assess the backscattering linear depolarization ratio (LDR) of nonspherical particles in a super-ellipsoidal shape space. Super-ellipsoids have inherent flexibility to model the particle aspect ratio, roundness, and concavity, these being salient characteristics of most atmospheric particles (e.g., sea salt and dust aerosols). The complex refractive index of super ellipsoids was set up with the real part ranging from 1.1 to 2.0 and the imaginary part from 10-7 to 0.5. To constrain the computational burden, the maximum size parameters for spheroids and super-ellipsoids were set as 100 and 50, respectively. From the LDRs of spheroids, we found that enhanced LDRs (>~60%) are common for optically soft particles. However, as the real part of the refractive index increases (larger than ~1.33), the enhanced LDRs (>~60%) are in high probability observed for nearly-spherical particles, and then disappear as the refractive index exceeds 1.7. To produce the enhanced LDRs, the imaginary part of the refractive index should also be less than ~0.01 such that the backscattered waves from particle-to-air transmission have sizable contributions, as the external reflection of spheroids produces no depolarization. This finding has particular relevance to LiDAR observations of atmospheric particles because the refractive index of most aerosols and hydrometeors at the LiDAR wavelength (e.g., 0.532MUm) locates in this region, and aerosols and hydrometeors could have nearly-spherical morphologies. From the LDRs for general super-ellipsoids, we found that the enhanced LDRs (>~60%) exist for nearly-spherical particles with the aspect ratio close to unity, but disappear for super-ellipsoids with an aspect ratio at unity. In addition, the LDRs trend to decrease as the real part of the refractive index increases for convex super-ellipsoids, but show different features for concave super-ellipsoids. Furthermore, super-ellipsoids with different roundness parameters have a distinct dependence on the aspect ratio, which is significantly different from spheroids. The results presented here provide comprehensive references for understanding the LDR change of atmospheric aerosols as the particle shape and refractive index for interpreting LiDAR backscattering signals. PMID- 29402044 TI - Multimode optical feedback dynamics in InAs/GaAs quantum dot lasers emitting exclusively on ground or excited states: transition from short- to long-delay regimes. AB - The optical feedback dynamics of two multimode InAs/GaAs quantum dot lasers emitting exclusively on sole ground or excited lasing states is investigated. The transition from long- to short-delay regimes is analyzed, while the boundaries associated to the birth of periodic and chaotic oscillations are unveiled to be a function of the external cavity length. The results show that depending on the initial lasing state, different routes to chaos are observed. These results are of importance for the development of isolator-free transmitters in short-reach networks. PMID- 29402045 TI - Optical and thermal analysis of the light-heat conversion process employing an antenna-based hybrid plasmonic waveguide for HAMR. AB - We investigate a tapered, hybrid plasmonic waveguide which has previously been proposed as an optically efficient near-field transducer (NFT), or component thereof, in several devices which aim to exploit nanofocused light. We numerically analyze how light is transported through the waveguide and ultimately focused via effective-mode coupling and taper optimization. Crucial dimensional parameters in this optimization process are identified that are not only necessary to achieve maximum optical throughput, but also optimum thermal performance with specific application towards heat-assisted magnetic recording (HAMR). It is shown that existing devices constructed on similar waveguides may benefit from a heat spreader to avoid deformation of the plasmonic element which we achieve with no cost to the optical efficiency. For HAMR, our design is able to surpass many industry requirements in regard to both optical and thermal efficiency using pertinent figure of merits like 8.5% optical efficiency. PMID- 29402046 TI - Single-photon three-dimensional microfabrication through a multimode optical fiber. AB - Two-photon polymerization (TPP) processes have enabled the fabrication of advanced and functional microstructures. However, most TPP platforms are bulky and require the use of expensive femtosecond lasers. Here, we propose an inexpensive and compact alternative to TPP by adapting an endoscopic imaging system for single-photon three-dimensional microfabrication. The wavefront of a visible continuous-wave laser beam is shaped so that it focuses into a photoresist through a 5 cm long ultra-thin multimode optical fiber (?70 MUm, NA 0.64). Using this device, we show that single-photon polymerization can be confined to the phase-controlled focal spot thanks to the non-linearity of the photoresist, likely due to oxygen radical scavenging. Thus, by exploiting this non-linearity with a specific overcuring method we demonstrate single-photon three-dimensional fabrication of solid and hollow microstructures through a multimode fiber with a 1.0-MUm lateral and 21.5-MUm axial printing resolution. This opens up new possibilities for advanced and functional microfabrication through endoscopic probes with inexpensive laser sources. PMID- 29402047 TI - Impact of modulation bandwidth on multiplexing using principal modes in MMF links. AB - Multimode fibers (MMFs) are widely used for short fiber links. However, the data rates through MMFs is limited owing to modal dispersion. The so-called "principal modes" (PMs) permit transmission and multiplexing through the MMFs without modal dispersion for small modulation bandwidths. For larger modulation bandwidths, however, they lose their dispersion-free nature. In this paper, we model the impact of modulation bandwidth and mode coupling strength on the performance of PMs. We develop a simulator that characterizes the dispersion and cross-talk of the PMs of few-mode and large-core graded-index MMFs with mode-dependent losses (MDL). Simulations reveal that for fibers without MDL, for modulation frequencies beyond 10 GHz diminishes the PMs' frequency response by more than 1 dB for 100 m in large-core MMF links and 10 km few-mode fiber links. With MDL, simulations reveal that for modulation bandwidths beyond 2 GHz diminishes the frequency response by 3 dB for a 1 km few-mode fiber and by more than 4 dB for a 1 km large core multimode fiber. While multiplexing using PMs in large-core MMFs with MDL, we find that for modulation bandwidths beyond 3 GHz, the cross-talk is 20 dB in 1 km large-core MMF links, thereby limiting system performance. PMID- 29402048 TI - Dynamic shaping of orbital-angular-momentum beams for information encoding. AB - Shaping complex fields with a digital micromirror device (DMD) has attracted much attention recently due to its potential application in optical communication and microscopy. In this paper, we present an optimized Lee method to achieve dynamic shaping of orbital-angular-momentum (OAM) beams using a binary DMD. An error diffusion algorithm is introduced to enhance the accuracy for binary-amplitude hologram design, making it possible to achieve high fidelity wavefront shaping while retaining a high resolution. As a proof of concept, we apply this method to create different classes of OAM beams. The numerical simulations verify that a fidelity of F > 0.985 can be achieved for all the test OAM fields with fully independent phase and amplitude modulation. Moreover, we experimentally demonstrate the dynamic shaping of different OAM beams including pure modes and mixed modes with a switching rate of up to 17.8 kHz. On this basis, accurate information encoding into the generated multiplexed OAM beams is accomplished, which provides access to high speed classical and quantum communications that employ spatial mode encoding. PMID- 29402049 TI - Unlocking high spatial resolution in neutron imaging through an add-on fibre optics taper. AB - The demand for high resolution neutron imaging has been steadily increasing over the past years. The number of facilities offering cutting edge resolution is however limited, due to (i) the design complexity of an optimized device able to reach a resolution in the order of ~ 10 MUm and (ii) limitations in available neutron flux. Here we propose a simple addition, based on a Fibre Optics Taper (FOT), that can be easily attached to an already existing scintillator-camera imaging detector in order to efficiently increase its spatial resolution and hence boost the capability of an instrument into high resolution applications. PMID- 29402050 TI - Super flexible GaN light emitting diodes using microscale pyramid arrays through laser lift-off and dual transfer. AB - We demonstrated a method to obtain super flexible LEDs, based on high quality pyramid arrays grown directly on sapphire substrates. Laser lift-off (LLO) and dual transfer processes were applied to transfer pyramid arrays face up onto the flexible substrates, which is more efficient than back light emission. Ag grid and Ag nanowires were employed as the electrical connection. No significant performance reduction appeared until the device reached a curvature radius of 0.5 mm. The performance reduction results from cracks appearing at the junction of the Ag grid, which can be improved by replacing the Ag grid with a strip electrode. PMID- 29402051 TI - Predicting minimum uncertainties in the inversion of ocean color geophysical parameters based on Cramer-Rao bounds. AB - We present an analytical approach based on Cramer-Rao Bounds (CRBs) to investigate the uncertainties in estimated ocean color parameters resulting from the propagation of uncertainties in the bio-optical reflectance modeling through the inversion process. Based on given bio-optical and noise probabilistic models, CRBs can be computed efficiently for any set of ocean color parameters and any sensor configuration, directly providing the minimum estimation variance that can be possibly attained by any unbiased estimator of any targeted parameter. Here, CRBs are explicitly developed using (1) two water reflectance models corresponding to deep and shallow waters, resp., and (2) four probabilistic models describing the environmental noises observed within four Sentinel-2 MSI, HICO, Sentinel-3 OLCI and MODIS images, resp. For both deep and shallow waters, CRBs are shown to be consistent with the experimental estimation variances obtained using two published remote-sensing methods, while not requiring one to perform any inversion. CRBs are also used to investigate to what extent perfect a priori knowledge on one or several geophysical parameters can improve the estimation of remaining unknown parameters. For example, using pre-existing knowledge of bathymetry (e.g., derived from LiDAR) within the inversion is shown to greatly improve the retrieval of bottom cover for shallow waters. Finally, CRBs are shown to provide valuable information on the best estimation performances that may be achieved with the MSI, HICO, OLCI and MODIS configurations for a variety of oceanic, coastal and inland waters. CRBs are thus demonstrated to be an informative and efficient tool to characterize minimum uncertainties in inverted ocean color geophysical parameters. PMID- 29402052 TI - Oxidation of silicon nanowire can transport much more light into silicon substrate. AB - Silicon nanowire (SiNW) has been widely used for light-trapping in photovoltaics, optical sensors, and other optoelectronic devices. However, we found that 58.4% of the light trapped by a SiNW with a diameter of 60 nm and a length of 1 MUm will be wasted: 64.5% of the trapped light will be absorbed within itself, and 90.5% of carriers excited by this part of light will recombine before being transported to the silicon substrate. In this work, it is shown that oxidation of SiNW can transport much more light into the silicon substrate. At first, our simulation results demonstrate that oxidation can dramatically reduce the percentage of absorbed light. In an oxidized SiNW (O-SiNW) with a total and silicon core diameter of 60 nm and 30 nm, respectively, the percentage is about 44.5%. Next, a low carrier recombination ratio, about 27.3%, can be obtained in O SiNW due to the passivation effect of the oxide layer. As a result, oxidation of SiNW can reduce the proportion of wasted light from 58.4% to 12.1%. More importantly, oxidation almost doesn't sacrifice the light-trapping ability: experimental measurements demonstrate that the average reflectance of an O-SiNW array is only slightly higher than that of a SiNW array, 3.9% vs. 3.0%. Such O SiNW is promising to be used for low-loss light-trapping in specially designed photovoltaic devices. PMID- 29402053 TI - Bifacial CdS/CdTe thin-film solar cells using a transparent silver nanowire/indium tin oxide back contact. AB - A hybrid silver nanowires (AgNWs)/indium tin oxide (ITO) contact was used as a transparent back-electrode to fabricate a bifacial CdS/CdTe thin-film solar cell. The photovoltaic properties of the bifacial CdS/CdTe thin-film solar cell were investigated under front and back illumination conditions. The hybrid AgNWs/ITO back contact changed the average conversion efficiency from 0.4% (front) and 3.5% (rear) to 8.1% (front) and 0.9% (rear), respectively, improving the sum efficiency from 3.9% (ITO-only) to 9.0%. Our research demonstrates the use of a nanowire network as a transparent electrode in CdS/CdTe thin-film solar cells for bifacial or tandem applications. PMID- 29402054 TI - Quenching Mo optical losses in CIGS solar cells by a point contacted dual-layer dielectric spacer: a 3-D optical study. AB - A 3-D optical modelling was calibrated to calculate the light absorption and the total reflection of fabricated CIGS solar cells. Absorption losses at molybdenum (Mo) / CIGS interface were explained in terms of plasmonic waves. To quench these losses, we assumed the insertion of a lossless dielectric spacer between Mo and CIGS, whose optical properties were varied. We show that such a spacer with low refractive index and proper thickness can significantly reduce absorption in Mo in the long wavelength regime and improve the device's rear reflectance, thus leading to enhanced light absorption in the CIGS layer. Therefore, we optimized a realistic two-layer MgF2 / Al2O3 dielectric spacer to exploit (i) the passivation properties of ultra-thin Al2O3 on the CIGS side for potential high open-circuit voltage and (ii) the low refractive index of MgF2 on the Mo side to reduce its optical losses. Combining our realistic spacer with optically-optimized point contacts increases the implied photocurrent density of a 750 nm-thick CIGS layer by 10% for the wavelengths between 700 and 1150 nm with respect to the reference cell. The elimination of plasmonic resonances in the new structure leads to a higher electric field magnitude at the bottom of CIGS layer and justifies the improved optical performance. PMID- 29402055 TI - Catadioptric freeform optical system design for LED off-axis road illumination applications. AB - The aim of this paper is to develop a new composite structure of catadioptric optical system containing both freeform refractive surface and freeform total internal reflective (TIR) surface for LED road illumination applications. The role of freeform refractive part is to generate the shifted general rectangular illumination pattern to optimally match the shape of the road surface. The application of TIR mechanism is aimed to control the stray light in the sidewalk direction of the road luminaire and maximize the efficient energy efficiency. In this paper, we use the "double pole" ray mapping technique to design the refractive optical surface and the theta-phi coordinate ray mapping technique to derive the freeform TIR surface. The simulation shows that the novel catadioptric design has relatively high collection efficiency, thus high average illuminance level inside the effective illumination area. This lens also has good control of stray light on the backside of the road luminaire. PMID- 29402056 TI - Super air stable quasi-2D organic-inorganic hybrid perovskites for visible light emitting diodes. AB - Solution processed organic-inorganic hybrid perovskites are emerging as a new generation materials for optoelectronics. However, the electroluminescence is highly limited in light emitting diodes (LED) due to the low exciton binding energy and the great challenge in stability. Here, we demonstrate a super air stable quasi-two dimensional perovskite film employing hydrophobic fluorine containing organics as barrier layers, which can store in ambient for more than 4 months with no change. The dramatically reduced grain size of the perovskite crystal in contrast to three dimensional (3D) perovskites was achieved. Together with the natural quantum well of quasi-two dimensional perovskite confining the excitons to recombination, the LED exhibited the maximum luminance of 1.2 * 103 cd/m2 and current efficiency up to 0.3 cd/A, which is twenty fold enhancement than that of LED based on 3D analogues under the same condition. PMID- 29402057 TI - Random lasing in uniform perovskite thin films. AB - Following the very promising results obtained by the solar cell community, metal halide perovskite materials are increasingly attracting the attention of other optoelectronics researchers, especially for light emission applications. Lasing with both engineered and self-assembled resonator structures, such as microcrystal networks, has now been successfully observed, with the low cost and the simple solution-based process being a particular attraction. The ultimate in simplicity, however, would be to observe lasing from a continuous thin film, which has not been reported yet. Here, we show random lasing action from such a simple perovskite layer. Our lasers work at room temperature; they are deposited on unpatterned glass substrates and they exhibit a minimum threshold value of 10 uJ/cm2. By carefully controlling the solution processing conditions, we can determine whether random lasing occurs or not, using identical precursors. A rather special feature is that some of the films exhibit single and dual mode lasing action, which is rarely observed in random lasers. Our work fully exploits the simplicity of the solution-based process and thereby adds an important capability into the emerging field of perovskite-based light emitters. PMID- 29402058 TI - Evaluation of 3D printed optofluidic smart glass prototypes. AB - Smart glass or smart windows are an innovative technology used for thermal management, energy efficiency, and privacy applications. Notable commercially available smart glass relies on an electric stimuli to modulate the glass from a transparent to a translucent mode of operation. However, the current market technologies, such as electrochromic, polymer dispersed liquid crystal, and suspended particle devices are expensive and suffer from solar absorption, poor transmittance modulation, and in some cases, continuous power consumption. The authors of this paper present a novel optofluidic smart glass prototype capable of modulating visible light transmittance from 8% to 85%. PMID- 29402059 TI - On accurate simulations of thin-film solar cells with a thick glass superstrate. AB - The optical response of periodically nanotextured layer stacks with dimensions comparable to the wavelength of the incident light can be computed with rigorous Maxwell solvers, such as the finite element method (FEM). Experimentally, such layer stacks are often prepared on glass superstrates with a thickness, which is orders of magnitude larger than the wavelength. For many applications, light in these thick superstrates can be treated incoherently. The front side of thick superstrate is located far away from the computational domain of the Maxwell solvers. Nonetheless, it has to be considered in order to achieve accurate results. In this contribution, we discuss how solutions of rigorous Maxwell solvers can be corrected for flat front sides of the superstrates with an incoherent a posteriori approach. We test these corrections for hexagonal sinusoidal nanotextured silica-silicon interfaces, which are applied in certain silicon thin-film solar cells. These corrections are determined via a scattering matrix, which contains the full scattering information of the periodically nanotextured structure. A comparison with experimental data reveals that higher order corrections can predict the measured reflectivity of the samples much better than an often-applied zeroth-order correction. PMID- 29402061 TI - Unconventional, Yet Important, Risk Factors for Stroke. PMID- 29402060 TI - Penumbral Imaging-Based Thrombolysis with Tenecteplase Is Feasible up to 24 Hours after Symptom Onset. AB - BACKGROUND AND PURPOSE: Thrombolysis >4.5 hours after ischemic stroke onset is unproven. We assessed the feasibility of tenecteplase (TNK) treatment in patients with evidence of an ischemic penumbra 4.5 to 24 hours after onset. METHODS: Acute ischemic stroke patients underwent perfusion computed tomography (CT)/magnetic resonance imaging. Patients with cerebral blood volume (CBV) or diffusion weighted imaging Alberta Stroke Program Early CT Scores (ASPECTS) >6 and mismatch score >2 (defined as >2 ASPECTS regions with delay on mean transit time maps and normal CBV) were eligible for treatment with TNK (0.25 mg/kg). Patients with mismatch patterns enrolled in non-endovascular/non-thrombolysis trials and those without mismatch patterns served as comparators. RESULTS: The median (interquartile range) baseline National Institutes of Health Stroke Scale (NIHSS) in TNK treated patients (n=16) was 12 (range, 8 to 15). In the untreated mismatch (n=18) and nonmismatch (n=23) groups, the baseline NIHSS was 12 (range, 7 to 12) and 16 (range, 8 to 20; P=0.09) respectively. There was one symptomatic hemorrhage each in the TNK group (parenchymal hematoma [PH] 2) and non-mismatch group (PH 2). Penumbral salvage volumes were higher in TNK treated patients (48.3 mL [range, 24.9 to 80.4]) than the non-mismatch (-90.8 mL [range, -197 to -20]; P<0.0001) patients. CONCLUSIONS: This prospective, non-randomized study supports the feasibility of TNK therapy in patients with evidence of ischemic penumbra 4 to 24 hours after onset. PMID- 29402062 TI - Basilar Artery Plaque and Pontine Infarction Location and Vascular Geometry. AB - BACKGROUND AND PURPOSE: Subclinical atherosclerotic plaques are common in patients with pontine infarctions (PIs) but without basilar artery (BA) stenosis. We hypothesized that BA plaque locations may differ by PI type and vertical location as well as vertebrobasilar artery geometry. METHODS: Ninety-six patients with PI but without BA stenosis on magnetic resonance imaging (MRI) and magnetic resonance angiography were enrolled. PIs were classified by type (paramedian, deep, or lateral) and vertical location (rostral, middle, or caudal). Patients underwent high-resolution MRI to evaluate BA plaque location (anterior, posterior, or lateral). The mid-BA angle on anteroposterior view and angle between the BA and dominant vertebral artery (BA-VA angle) on lateral view were measured. RESULTS: The PIs were paramedian (72.9%), deep (17.7%), and lateral (9.4%) type with a rostral (32.3%), middle (42.7%), and caudal (25.0%) vertical location. The BA plaque locations differed by PI type (P=0.03) and vertical location (P<0.001); BA plaques were most frequent at the posterior wall in paramedian (37.1%) and caudal (58.3%) PIs and at the lateral wall in lateral (55.5%) and middle (34.1%) PIs. The BA-VA and mid-BA angles differed by BA plaque and PI vertical location; the greatest BA-VA angle was observed in patients with posterior plaques (P<0.001) and caudal PIs (P<0.001). Greatest mid-BA angles were observed with lateral BA plaques (P=0.03) and middlelocated PIs (P=0.03). CONCLUSIONS: Greater mid-BA angulation may enhance lateral plaque formation, causing lateral and middle PIs, whereas greater BA-VA angulation may enhance posterior plaque formation, causing paramedian or caudal PIs. PMID- 29402063 TI - Folic Acid in Stroke Prevention in Countries without Mandatory Folic Acid Food Fortification: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND AND PURPOSE: Additional folic acid (FA) treatment appears to have a neutral effect on reducing vascular risk in countries that mandate FA fortification of food (e.g., USA and Canada). However, it is uncertain whether FA therapy reduces stroke risk in countries without FA food fortification. The purpose of this study was to comprehensively evaluate the efficacy of FA therapy on stroke prevention in countries without FA food fortification. METHODS: PubMed, EMBASE, and clinicaltrials.gov from January 1966 to August 2016 were searched to identify relevant studies. Relative risk (RR) with 95% confidence interval (CI) was used as a measure of the association between FA supplementation and risk of stroke, after pooling data across trials in a random-effects model. RESULTS: The search identified 13 randomized controlled trials (RCTs) involving treatment with FA that had enrolled 65,812 participants, all of which stroke was reported as an outcome measure. After all 13 RCTs were pooled, FA therapy versus control was associated with a lower risk of any future stroke (RR, 0.85; 95% CI, 0.77 to 0.95). FA alone or combination of FA and minimal cyanocobalamin (<=0.05 mg/day) was associated with a lower risk of future stroke (RR, 0.75; 95% CI, 0.66 to 0.86) whereas combination of FA and cyanocobalamin (>=0.4 mg/day) was not associated with a lower risk of future stroke (RR, 0.95; 95% CI, 0.86 to 1.05). CONCLUSIONS: FA supplement reduced stroke in countries without mandatory FA food fortification. The benefit was found mostly in patients receiving FA alone or combination of FA and minimal cyanocobalamin. PMID- 29402064 TI - Low- versus Standard-Dose Intravenous Alteplase in the Context of Bridging Therapy for Acute Ischemic Stroke: A Korean ENCHANTED Study. AB - BACKGROUND AND PURPOSE: Following the positive results from recent trials on endovascular therapy (EVT), bridging therapy (intravenous alteplase plus EVT) is increasingly being used for the treatment of acute ischemic stroke. However, the optimal dose of intravenous alteplase remains unknown in centers where bridging therapy is actively performed. The optimal dose for eventual recanalization and positive clinical outcomes in patients receiving bridging therapy also remains unknown. METHODS: In this prospective Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) sub-study, we explored the outcomes following treatment with two different doses (low- [0.6 mg/kg] or standard-dose [0.9 mg/kg]) of intravenous alteplase across 12 Korean centers where EVT is actively performed. The primary endpoint was a favorable outcome at 90 days (modified Rankin Scale scores 0 to 1). Secondary endpoints included symptomatic intracerebral hemorrhage (ICH) in all patients, and the recanalization rate and favorable outcome in patients who underwent cerebral angiography for EVT (ClinicalTrials.gov, number NCT01422616). RESULTS: Of 351 patients, the primary outcome occurred in 46% of patients in both the standard-(80/173) and low-dose (81/178) groups (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.72 to 1.81; P=0.582), although ICHs tended to occur more frequently in the standard dose group (8% vs. 3%, P=0.056). Of the 67 patients who underwent cerebral angiography, there was no significant difference in favorable functional outcome between the standard- and low-dose groups (39% vs. 21%; OR, 2.39; 95% CI, 0.73 to 7.78; P=0.149). CONCLUSIONS: There was no difference in functional outcome between the patients receiving different doses of alteplase in centers actively performing bridging therapy. PMID- 29402065 TI - Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer. AB - BACKGROUND AND PURPOSE: Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA. METHODS: From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors. RESULTS: The final cohort consisted of 1,011 patients (59+/-13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01). CONCLUSIONS: Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA. PMID- 29402066 TI - Development of New Endovascular Devices for Aneurysm Treatment. AB - Since the first use of the Guglielmi detachable coil system for cerebral aneurysm embolization in 1990, various endovascular methods have been developed to treat large numbers of aneurysms. The main strategic and technical modifications introduced to date include balloon-assisted coil embolization, stent-assisted coil embolization, flow diverters, and flow disrupters. The development and introduction of such devices have been so persistent and rapid that new devices are being approved worldwide even before the earlier ones become available in some countries. However, even if some patient populations may possibly benefit from earlier introduction of new devices, the approval authorities should balance the available evidence of the safety and effectiveness of novel devices. This review aims to provide an overview of the recent innovations in endovascular treatment of cerebral aneurysms and a brief review of market access policies and regulations for importing high-risk medical devices, such as those used for endovascular aneurysm management, which correspond to class III devices, as defined by the U.S. Food and Drug Administration. We focus on the current situation in Korea and compare it with that in other Asian countries, such as China and Japan. PMID- 29402067 TI - Differences between the Molecular Mechanisms Underlying Ruptured and Non-Ruptured Carotid Plaques, and the Significance of ABCA1. AB - BACKGROUND AND PURPOSE: Carotid plaques are a strong risk factor for ischemic stroke, and plaque rupture poses an even higher risk. Although many studies have investigated the pathogenic mechanisms of carotid plaque formation, few have studied the differences in molecular mechanisms underlying the rupture and non rupture of carotid plaques. In addition, since early diagnosis and treatment of carotid plaque rupture are critical for the prevention of ischemic stroke, many studies have sought to identify the important target molecules involved in the rupture. However, a target molecule critical in symptomatic ruptured plaques is yet to be identified. METHODS: A total of 79 carotid plaques were consecutively collected, and microscopically divided into ruptured and non-ruptured groups. Quantitative polymerase chain reaction array, proteomics, and immunohistochemistry were performed to compare the differences in molecular mechanisms between ruptured and non-ruptured plaques. Enzyme-linked immunosorbent assay was used to measure the differences in ATP-binding cassette subfamily A member 1 (ABCA1) levels in the serum. RESULTS: The expression of several mRNAs and proteins, including ABCA1, was higher in ruptured plaques than non-ruptured plaques. In contrast, the expression of other proteins, including beta-actin, was lower in ruptured plaques than non-ruptured plaques. The increased expression of ABCA1 was consistent across several experiments, ABCA1 was positive only in the serum of patients with symptomatic ruptured plaques. CONCLUSIONS: This study introduces a plausible molecular mechanism underlying carotid plaque rupture, suggesting that ABCA1 plays a role in symptomatic rupture. Further study of ABCA1 is needed to confirm this hypothesis. PMID- 29402068 TI - Association of MicroRNA Biogenesis Genes Polymorphisms with Ischemic Stroke Susceptibility and Post-Stroke Mortality. AB - BACKGROUND AND PURPOSE: MicroRNA (miRNA) expression has been examined in multiple conditions, including various cancers, neurological diseases, and cerebrovascular diseases, particularly stroke. Existing evidence indicates that miRNA biosynthesis and function play crucial roles in ischemic stroke physiology and pathology. In this study, we selected six known polymorphisms in miRNA-biogenesis genes; DICER rs13078A>T, rs3742330A>G; DROSHA rs10719T>C, rs6877842G>C; Ran GTPase (RAN) rs14035C>T; exportin 5 (XPO5) rs11077A>C. METHODS: We analyzed the associations between these polymorphisms and disease status and clinical factors in 585 ischemic stroke patients and 403 controls. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The DICER rs3742330A>G (AA vs. AG+GG: adjusted odds ratio [AOR], 1.360; 95% confidence interval [CI], 1.024 to 1.807; P=0.034) and DROSHA rs10719T>C polymorphisms (TT vs. CC: AOR, 2.038; 95% CI, 1.113 to 3.730; P=0.021) were associated with ischemic stroke prevalence. During a mean follow-up of 4.80+/ 2.11 years, 99 (5.91%) of the stroke patients died. In multivariate Cox proportional hazard regression models, a significant association was found between RAN rs14035 and survival of large artery disease patients with ischemic stroke (CC vs. TT: adjusted hazard ratio, 5.978; P=0.015). CONCLUSIONS: An association was identified between the DICER and DROSHA polymorphisms and ischemic stroke. Specifically, polymorphisms (rs3742330 and rs10719) were more common in stroke patients, suggesting that they may be associated with an increased risk of ischemic stroke. PMID- 29402069 TI - Treatments to Promote Neural Repair after Stroke. AB - Stroke remains a major cause of human disability worldwide. In parallel with advances in acute stroke interventions, new therapies are under development that target restorative processes. Such therapies have a treatment time window measured in days, weeks, or longer and so have the advantage that they may be accessible by a majority of patients. Several categories of restorative therapy have been studied and are reviewed herein, including drugs, growth factors, monoclonal antibodies, activity-related therapies including telerehabilitation, and a host of devices such as those related to brain stimulation or robotics. Many patients with stroke do not receive acute stroke therapies or receive them and do not derive benefit, often surviving for years thereafter. Therapies based on neural repair hold the promise of providing additional treatment options to a majority of patients with stroke. PMID- 29402070 TI - Heart Failure as a Risk Factor for Stroke. AB - Heart failure (HF) is one of the major causes of death worldwide. Despite the high incidence of stroke in patients with HF, there has been a controversy as to whether HF itself is a risk factor for stroke. Recently, there is a great deal of evidence that HF itself increases the risk of stroke. In previous studies, the benefit of warfarin for stroke prevention in patients with HF was offset by the risk of bleeding. In the era of non-vitamin K antagonist oral anticoagulants with low bleeding profiles, we can expect a more effective stroke prevention in patients with HF by selective anticoagulation. The purpose of this review is to describe the relationship between stroke and HF, which could be an unconventional risk factor and a potential intervention target for stroke prevention. PMID- 29402073 TI - Ethnic Differences in Intracranial Artery Tortuosity: A Possible Reason for Different Locations of Cerebral Atherosclerosis. PMID- 29402074 TI - Multifunctional Porous Iron Oxide Nanoagents for MRI and Photothermal/Chemo Synergistic Therapy. AB - Nanoagents of integrating multiple imaging and therapeutic modalities have attracted tremendous attention for biomedical applications. Herein, we synthesize porous hollow Fe3O4 as a theranostic agent for MRI and combined photothermal/chemo cancer therapy. The as-prepared porous iron oxide nanoagents allow for T2-weighted MR imaging. Interestingly, we demonstrate that the porous structure endows the nanoagents an outstanding photothermal property for cancer cell killing, in comparison with other types of iron oxide nanomaterials. Under the exposure of an NIR laser, the heat produced by porous Fe3O4 can accelerate the release of the loaded drug (e.g., DOX) to enhance chemotherapeutic efficacy, promoting the ablation of cancer cells with synergistic photothermal/chemotherapy. PMID- 29402075 TI - Copper-Mediated Domino Cyclization/Trifluoromethylation of Propargylic N Hydroxylamines: Synthesis of 4-Trifluoromethyl-4-isoxazolines. AB - A Cu(OTf)2-mediated synthesis of trifluoromethylated 4-isoxazolines is described. In one step from readily available propargylic N-hydroxylamines, a domino 5-endo dig cyclization, followed by trifluoromethylation, takes place to construct the 4 isoxazoline core with concomitant installation of the CF3 group at the C-4 position. Such compounds could also be useful precursors for the preparation of alpha-trifluoromethyl beta-amino ketones. PMID- 29402072 TI - Air Pollution and Stroke. AB - The adverse health effects of air pollution have long been recognised; however, there is less awareness that the majority of the morbidity and mortality caused by air pollution is due to its effects on the cardiovascular system. Evidence from epidemiological studies have demonstrated a strong association between air pollution and cardiovascular diseases including stroke. Although the relative risk is small at an individual level, the ubiquitous nature of exposure to air pollution means that the absolute risk at a population level is on a par with "traditional" risk factors for cardiovascular disease. Of particular concern are findings that the strength of this association is stronger in low and middle income countries where air pollution is projected to rise as a result of rapid industrialisation. The underlying biological mechanisms through which air pollutants exert their effect on the vasculature are still an area of intense discussion. A greater understanding of the effect size and mechanisms is necessary to develop effective strategies at individual and policy levels to mitigate the adverse cardiovascular effects of air pollution. PMID- 29402076 TI - Indoor Chemistry. AB - This review aims to encapsulate the importance, ubiquity, and complexity of indoor chemistry. We discuss the many sources of indoor air pollutants and summarize their chemical reactions in the air and on surfaces. We also summarize some of the known impacts of human occupants, who act as sources and sinks of indoor chemicals, and whose activities (e.g., cooking, cleaning, smoking) can lead to extremely high pollutant concentrations. As we begin to use increasingly sensitive and selective instrumentation indoors, we are learning more about chemistry in this relatively understudied environment. PMID- 29402071 TI - Sleep Disturbances as a Risk Factor for Stroke. AB - Sleep, a vital process of human being, is carefully orchestrated by the brain and consists of cyclic transitions between rapid eye movement (REM) and non-REM (NREM) sleep. Autonomic tranquility during NREM sleep is characterized by vagal dominance and stable breathing, providing an opportunity for the cardiovascular neural axis to restore homeostasis, in response to use, distress or fatigue inflicted during wakefulness. Abrupt irregular swings in sympathovagal balance during REM sleep act as phasic loads on the resting cardiovascular system. Any causes of sleep curtailment or fragmentation such as sleep restriction, sleep apnea, insomnia, periodic limb movements during sleep, and shift work, not only impair cardiovascular restoration but also impose a stress on the cardiovascular system. Sleep disturbances have been reported to play a role in the development of stroke and other cardiovascular disorders. This review aims to provide updated information on the role of abnormal sleep in the development of stroke, to discuss the implications of recent research findings, and to help both stroke clinicians and researchers understand the importance of identification and management of sleep pathology for stroke prevention and care. PMID- 29402078 TI - Grain Boundaries Softening Thermoelectric Oxide BiCuSeO. AB - Engineering grain boundaries (GBs) are effective in tuning the thermoelectric (TE) properties of TE materials, but the role of GB on mechanical properties, which is important for their commercial applications, remains unexplored. In this paper, we apply ab initio method to examine the ideal shear strength and failure mechanism of GBs in TE oxide BiCuSeO. We find that the ideal shear strength of the GB is much lower than that of the ideal single crystal. The atomic rearrangements accommodating the lattice and neighbor structure mismatch between different grains leads to the much weaker GB stiffness compared with grains. Failure of the GBs arises from either the distortion of the Cu-Se layers or the relative slip between Bi-O and Cu-Se layers. This work is crucial to illustrate the deformation of GBs, laying the basis for the development and design of mechanically robust polycrystalline TE materials. PMID- 29402077 TI - Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma. AB - Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway. Here, we expanded our support for targeting Grp94 over cytosolic paralogs Hsp90alpha and Hsp90beta. We then developed a high-throughput screening assay to identify new chemical matter capable of disrupting the Grp94/OLF interaction. When applied to a blind, focused library of 17 Hsp90 inhibitors, our miniaturized single-read in vitro thioflavin T -based kinetics aggregation assay exclusively identified compounds that target the chaperone N-terminal nucleotide binding site. In follow up studies, one compound (2) decreased the extent of co-aggregation of Grp94 with OLF in a dose dependent manner in vitro, and enabled clearance of the aggregation-prone full length myocilin variant I477N in cells without inducing the heat shock response or causing cytotoxicity. Comparison of the co-crystal structure of compound 2 and another non-selective hit in complex with the N-terminal domain of Grp94 reveals a docking mode tailored to Grp94 and explains its selectivity. A new lead compound has been identified, supporting a targeted chemical biology assay approach to develop a protein degradation-based therapy for myocilin-associated glaucoma by selectively inhibiting Grp94. PMID- 29402079 TI - Monitoring the Stimulated Uncapping Process of Gold-Capped Mesoporous Silica Nanoparticles. AB - To establish a new method for tracking the interaction of nanoparticles with chemical cleaving agents, we exploited the optical effects caused by attaching 5 10 nm gold nanoparticles with molecular linkers to large mesoporous silica nanoparticles (MSN). At low levels of gold loading onto MSN, the optical spectra resemble colloidal suspensions of gold. As the gold is removed, by cleaving agents, the MSN revert to the optical spectra typical of bare silica. Time-lapse images of gold-capped MSN stationed in microchannels reveal that the rate of gold release is dependent on the concentration of the cleaving agent. The uncapping process was also monitored successfully for MSN endocytosed by A549 cancer cells, which produce the cleaving agent glutathione. These experiments demonstrate that the optical properties of MSN can be used to directly monitor cleaving kinetics, even in complex cellular settings. PMID- 29402080 TI - Power of Ultra Performance Liquid Chromatography/Electrospray Ionization-MS Reconstructed Ion Chromatograms in the Characterization of Small Differences in Polymer Microstructure. AB - From simple homopolymers to functionalized, 3-dimensional structured copolymers, the complexity of polymeric materials has become more and more sophisticated. With new applications, for instance, in the semiconductor or pharmaceutical industry, the requirements for the characterization have risen with the complexity of the used polymers. For each additional distribution, an additional dimension in analysis is needed. Small, often isomeric heterogeneities in topology or microstructure can usually not be simply separated chromatographically or distinguished by any common detector but affect the properties of materials significantly. For a drug delivery system, for example, the degree of branching and branching distribution is crucial for the formation of micelles. Instead of a complicated, time-consuming, and/or expensive 2D chromatography or ion mobility spectrometry (IMS) method, that also has its limitations, in this work, a simple approach using size exclusion chromatography (SEC) coupled with electrospray ionization (ESI) mass spectrometry is proposed. The online coupling allows the analysis of reconstructed ion chromatograms (RICs) of each degree of polymerization. While a complete separation often cannot be achieved, the derived retention times and peak widths lead to information on the existence and dispersity of heterogeneities. Although some microstructural heterogeneities like short chain branching can for large polymers be characterized with methods such as light scattering, for oligomers where the heterogeneities just start to form and their influence is at the maximum, they are inaccessible with these methods. It is also shown that with a proper calibration even quantitative information can be obtained. This method is suitable to detect small differences in, e.g., branching, 3D-structure, monomer sequence, or tacticity and could potentially be used in routine analysis to quickly determine deviations. PMID- 29402081 TI - Electrical Impedance Measurements of Biological Cells in Response to External Stimuli. AB - Dielectric spectroscopy (DS) is a noninvasive technique for real-time measurements of the impedance spectra of biological cells. DS enables characterization of cellular dielectric properties such as membrane capacitance and cytoplasmic conductivity. We have developed a lab-on-a-chip device that uses an electro-activated microwells array for capturing, DS measurements, and unloading of biological cells. Impedance measurements were conducted at 0.2 V in the 10 kHz to 40 MHz range with 6 s time resolution. An equivalent circuit model was developed to extract the cell membrane capacitance and cell cytoplasmic conductivity from the impedance spectra. A human prostate cancer cell line, PC-3, was used to evaluate the device performance. Suspension of PC-3 cells in low conductivity buffers (LCB) enhanced their dielectrophoretic trapping and impedance response. We report the time course of the variations in dielectric properties of PC-3 cells suspended in LCB and their response to sudden pH change from a pH of 7.3 to a pH of 5.8. Importantly, we demonstrated that our device enabled real-time measurements of dielectric properties of live cancer cells and allowed the assessment of the cellular response to variations in buffer conductivity and pH. These data support further development of this device toward single cell measurements. PMID- 29402082 TI - SnoopLigase Catalyzes Peptide-Peptide Locking and Enables Solid-Phase Conjugate Isolation. AB - Simple, efficient reactions for connecting biological building-blocks open up many new possibilities. Here we have designed SnoopLigase, a protein that catalyzes site-specific transamidation, forming an isopeptide bond with more than 95% efficiency between two peptide tags, SnoopTagJr and DogTag. We initially developed these components by three-part splitting of the Streptococcus pneumoniae adhesin RrgA. The units were then engineered, guided by structure, bioinformatic analysis of sequence homology, and computational prediction of stability. After engineering, SnoopLigase demonstrated high-yield coupling under a wide range of buffers and temperatures. SnoopTagJr and DogTag were functional at the N- or C-terminus, while DogTag was also functional at internal sites in proteins. Having directed reaction of SnoopTagJr and DogTag, SnoopLigase remained stably bound to the ligated product, thus reconstituting the parent domain. Separating products from unreacted starting material and catalyst is often as challenging as reactions themselves. However, solid-phase immobilization of SnoopLigase enabled the ligated SnoopTagJr-DogTag product to be eluted with high purity, free from SnoopLigase or unligated substrates. The solid-phase catalyst could then be reused multiple times. In search of a generic route to improve the resilience of enzymes, we fused SnoopTagJr to the N-terminus and DogTag to the C terminus of model enzymes, allowing cyclization via SnoopLigase. While wild-type phytase and beta-lactamase irreversibly aggregated upon heating, cyclization using SnoopLigase conferred exceptional thermoresilience, with both enzymes retaining solubility and activity following heat treatment up to 100 degrees C. SnoopLigase should create new opportunities for conjugation and nanoassembly, while illustrating how to harness product inhibition and extend catalyst utility. PMID- 29402083 TI - Synthesis of Highly Substituted 3-Pyrrolin-2-ones from N,N-Disubstituted alpha Amino Acids. AB - Highly functionalized 5-membered N-heterocyclic compounds, 4-aryl-3-chloro-5 methoxy-1-methyl-3-pyrrolin-2-ones, have been synthesized in moderate to high yields by the reaction of N,N-dimethylated aromatic alpha-amino acids with oxalyl chloride, followed by solvolysis with MeOH. The products possess a number of functional groups such as an amide, a mixed amido/alkoxy acetal, a vinyl halide, and an alkene and thus are promising candidates to be used as starting materials for the synthesis of diverse five-membered N-heterocyclic compounds. PMID- 29402084 TI - Human Perturbation of the Global Phosphorus Cycle: Changes and Consequences. AB - The phosphorus (P) cycle is an important Earth system process. While natural P mobilization is slow, humans have been altering P cycle by intensifying P releases from lithosphere to ecosystems. Here, we examined magnitudes of which humans have altered the P cycles by integrating the estimates from recent literatures, and furthermore illustrated the consequences. Based on our synthesis, human alterations have tripled the global P mobilization in land-water continuum and increased P accumulation in soil with 6.9 +/- 3.3 Tg-P yr-1. Around 30% of atmospheric P transfer is caused by human activities, which plays a significant role than previously thought. Pathways involving with human alterations include phosphate extraction, fertilizers application, wastes generation, and P losses from cropland. This study highlights the importance of sustainable P supply as a control on future food security because of regional P scarcity, food demand increase and continuously P intensive food production. Besides, accelerated P loads are responsible for enhanced eutrophication worldwide, resulting in water quality impairment and aquatic biodiversity losses. Moreover, the P enrichment can definitely stimulate the cycling of carbon and nitrogen, implying the great need for incorporating P in models predicting the response of carbon and nitrogen cycles to global changes. PMID- 29402085 TI - Filter-Based Protein Digestion (FPD): A Detergent-Free and Scaffold-Based Strategy for TMT Workflows. AB - High-throughput proteome profiling requires thorough optimization to achieve comprehensive analysis. We developed a filter aided sample preparation (FASP) like, detergent-free method, termed Filter-Based Protein Digestion (FPD). We compared FPD to protein extraction methods commonly used in isobaric tag-based proteome profiling, namely trichloroacetic acid (TCA) and chloroform-methanol (C M) precipitation. We divided a mammalian whole cell lysate from the SH-SY5Y neuroblastoma cell line for parallel protein processing with TCA (n = 3), C-M (n = 2), and FPD using either 10 kDa (n = 3) or 30 kDa (n = 3) molecular weight cutoff membranes. We labeled each sample with tandem mass tag (TMT) reagents to construct a TMT11-plex experiment. In total, 8654 proteins were quantified across all samples. Pairwise comparisons showed very little deviation for individual protein abundance measurements between the two FPD methods, whereas TCA and FPD showed the most difference. Specifically, membrane proteins were more readily quantified when samples were processed using TCA precipitation than other methods tested. However, globally, only 4% of proteins differed greater than 4-fold in the most divergent pair of protein extraction methods (i.e., FPD10 and TCA). We conclude that the detergent-free FPD strategy, particularly using the faster flowing 30 kDa filter, is a seamless alteration to high-throughput TMT workflows. PMID- 29402086 TI - Inkjet-Printed Biofunctional Thermo-Plasmonic Interfaces for Patterned Neuromodulation. AB - Localized heat generation by the thermo-plasmonic effect of metal nanoparticles has great potential in biomedical engineering research. Precise patterning of the nanoparticles using inkjet printing can enable the application of the thermo plasmonic effect in a well-controlled way (shape and intensity). However, a universally applicable inkjet printing process that allows good control in patterning and assembly of nanoparticles with good biocompatibility is missing. Here we developed inkjet-printing-based biofunctional thermo-plasmonic interfaces that can modulate biological activities. We found that inkjet printing of plasmonic nanoparticles on a polyelectrolyte layer-by-layer substrate coating enables high-quality, biocompatible thermo-plasmonic interfaces across various substrates (rigid/flexible, hydrophobic/hydrophilic) by induced contact line pinning and electrostatically assisted nanoparticle assembly. We experimentally confirmed that the generated heat from the inkjet-printed thermo-plasmonic patterns can be applied in micrometer resolution over a large area. Lastly, we demonstrated that the patterned thermo-plasmonic effect from the inkjet-printed gold nanorods can selectively modulate neuronal network activities. This inkjet printing process therefore can be a universal method for biofunctional thermo plasmonic interfaces in various bioengineering applications. PMID- 29402089 TI - Collision Frequency for Energy Transfer in Unimolecular Reactions. AB - Pressure dependence of unimolecular reaction rates is governed by the energy transfer in collisions of reactants with bath gas molecules. Pressure-dependent rate constants can be theoretically determined by solving master equations for unimolecular reactions. In general, master equation formulations describe energy transfer processes using a collision frequency and a probability distribution model of the energy transferred per collision. The present study proposes a novel method for determining the collision frequency from the results of classical trajectory calculations. Classical trajectories for collisions of several polyatomic molecules (ethane, methane, tetrafluoromethane, and cyclohexane) with monatomic colliders (Ar, Kr, and Xe) were calculated on potential energy surfaces described by the third-order density-functional tight-binding method in combination with simple pairwise interaction potentials. Low-order (including non integer-order) moments of the energy transferred in deactivating collisions were extracted from the trajectories and compared with those derived using some probability distribution models. The comparison demonstrates the inadequacy of the conventional Lennard-Jones collision model for representing the collision frequency and suggests a robust method for evaluating the collision frequency that is consistent with a given probability distribution model, such as the exponential-down model. The resulting collision frequencies for the exponential down model are substantially higher than the Lennard-Jones collision frequencies and are close to the (hypothetical) capture rate constants for dispersion interactions. The practical adequacy of the exponential-down model is also briefly discussed. PMID- 29402087 TI - Substrate Preferences Establish the Order of Cell Wall Assembly in Staphylococcus aureus. AB - The Gram-positive bacterial cell wall is a large supramolecular structure and its assembly requires coordination of complex biosynthetic pathways. In the step that merges the two major biosynthetic pathways in Staphylococcus aureus cell wall assembly, conserved protein ligases attach wall teichoic acids to peptidoglycan, but the order of biosynthetic events is a longstanding question. Here, we use a chemical approach to define which of the possible peptidoglycan intermediates are substrates for wall-teichoic acid ligases, thereby establishing the order of cell wall assembly. We have developed a strategy to make defined glycan chain-length polymers of either un-cross-linked or cross-linked peptidoglycan, and we find that wall teichoic acid ligases cannot transfer wall teichoic acid precursors to the cross-linked substrates. A 1.9 A crystal structure of a LytR-CpsA-Psr (LCP) family ligase in complex with a wall teichoic acid precursor defines the location of the peptidoglycan binding site as a long, narrow groove, and suggests that the basis for selectivity is steric exclusion of cross-linked peptidoglycan. Consistent with this hypothesis, we have found that chitin oligomers are good substrates for transfer, showing that LCPs do not discriminate cross-linked from un-cross-linked peptidoglycan substrates by recognizing features of the un-cross linked stem peptide. We conclude that wall teichoic acids are coupled to un-cross linked peptidoglycan chains at an early stage of peptidoglycan synthesis and may create marks that define the proper spacing of subsequent cross-links. PMID- 29402090 TI - Introducing Biochemistry to Bedside. PMID- 29402088 TI - Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization. AB - To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5 trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin. PMID- 29402091 TI - Combining CXCR4-targeted and nontargeted nanoparticles for effective unassisted in vitro magnetic hyperthermia. AB - The use of targeted nanoparticles for magnetic hyperthermia (MHT) increases MHT selectivity, but often at the expense of its effectiveness. Consequently, targeted MHT is typically used in combination with other treatment modalities. This work describes an implementation of a highly effective monotherapeutic in vitro MHT treatment based on two populations of magnetic particles. Cells were sequentially incubated with two populations of magnetic particles: nonfunctionalized superparamagnetic nanoparticles and anti-CXCR4-functionalized particles. After removing the excess of free particles, an alternating magnetic field (AMF) was applied to produce MHT. The induced cytotoxicity was assessed at different time-points after AMF application. Complete loss of cell viability was observed 72 h after MHT when the iron loading of the anti-CXCR4-functionalized particles was boosted by that of a nontargeted population. Additionally, induction of necrosis resulted in more efficient cell death than did induction of apoptosis. Achieving a uniquely high effectiveness in monotherapeutic MHT demonstrates the potential of this approach to achieve complete loss of viability of cancer cells while avoiding the side effects of dual-treatment strategies that use MHT only as a sensitizing therapy. PMID- 29402092 TI - Characterization of natural photonic crystals in iridescent wings of damselfly Chalcopteryx rutilans by FIB/SEM, TEM, and TOF-SIMS. AB - The iridescent wings of the Chalcopterix rutilans damselfly (Rambur) (Odonata, Polythoridae) are investigated with focused ion beam/scanning electron microscopy, transmission electron microscopy, and time-of-flight secondary ion mass spectrometry. The electron microscopy images reveal a natural photonic crystal as the source of the varying colors. The photonic crystal has a consistent number and thickness (~195 nm) of the repeat units on the ventral side of the wing, which is consistent with the red color visible from the bottom side of the wing in all regions. The dorsal side of the wing shows strong color variations ranging from red to blue depending on the region. In the electron microscopy images, the dorsal side of the wing exhibits varied number and thicknesses of the repeat units. The repeat unit spacings for the red, yellow/green, and blue regions are approximately 195, 180, and 145 nm, respectively. Three-dimensional analysis of the natural photonic crystals by time of-flight secondary ion mass spectrometry reveals that changes in the relative levels of Na, K, and eumelanin are responsible for the varying dielectric constant needed to generate the photonic crystal. The photonic crystal also appears to be assembled with a chemical tricomponent layer structure due to the enhancement of the CH6N3+ species at every other interface between the high/low dielectric constant layers. PMID- 29402093 TI - Clinical hypnosis in palliative care. PMID- 29402094 TI - Hypnosis in palliative care: from clinical insights to the science of self regulation. AB - Palliative care spans a wide-ranging spectrum: from pain-management to spiritual support. As the demand for end-of-life care increases, so does the demand for innovative, effective, interventions. Mind-body techniques seem especially advantageous in a palliative context. Here we show that hypnosis serves an excellent adjunct therapy in palliative care to boost the efficacy of standard treatments. With the overarching goal of bridging clinical and scientific insights, we outline how five core principles of hypnosis can benefit the diverse needs of palliative care. PMID- 29402095 TI - Community capacity development to enhance hospice palliative care in Alberta, Canada communities: evidence demonstrating the value of a community engaged model. AB - Our study explored the value of a community engaged model for good hospice care in three rural communities in Alberta, Canada. When communities are highly engaged in planning and implementing hospice care in their communities, our study discovered that they have key characteristics: that volunteerism needs to be balanced to prevent burnout; that the local knowledge of community members is used in a number of ways to plan and provide good hospice care; that a variety of resources, infrastructure, policies and expertise are used by the community to nurture community-focused palliative care initiatives. The value to the community or social capital, that accrues from these initiatives is not easily appreciated by the community members, and community-based initiatives benefit when this value is identified for them. In all three communities a focus group was conducted separately with the Hospice Society board and with family members and volunteers connected with the Hospice Society. Participants attending this oral presentation will learn how community palliative care is perceived by non-professional community leaders, as well as strategies that may help address barriers that are encountered when communities become engaged in addressing their own hospice and end of life care needs. PMID- 29402096 TI - Collaborative and participatory approaches to building community capacity for palliative and end of life care. AB - People living in rural and smaller urban areas near Calgary experience difficulty accessing palliative care services which are concentrated in metropolitan areas. The Cumming School of Medicine, Alberta Health Services and community hospice palliative care societies in two rural communities have been working to develop a partnership that incorporates local health system resources and community initiatives in supporting individuals and families living with progressive, life limiting illnesses. This presentation will provide an understanding of how academic institutions and health services can collaborate with community members to enhance capacity for end of life care, and enrich communities in the process. The Cumming School of Medicine, Alberta Health Services and community hospice palliative care societies have been collaboratively working together to enhance community capacity to support individuals and their families in providing end of life care. This presentation will explore this relationship and how it enriches communities in the process. PMID- 29402097 TI - Lessons we are learning: using participatory action research to integrate palliative care, health promotion and public health through the DoBra research program in Sweden. AB - Public health and health promotion approaches to end-of-life (EoL) research and care are still rare in Sweden. People remain generally ill-prepared for encounters with death and unable to advocate for quality EoL care; this may be reflected in Sweden's low scores for community engagement in the 2015 Quality of Death index. We have consolidated our endeavours into a cohesive national transdisciplinary research program, DoBra (a pun meaning both 'dying well' and 'awesome' in Swedish). In DoBra, we investigate how culture, the environment and conversation can promote constructive change and support better quality of life and death among the general population, in specific subgroups and in interventions directed to staff caring for dying individuals, their friends and families. DoBra uses ideas from new public health and the Ottawa Charter as umbrella theoretical frameworks and participatory action research as an overarching methodological approach. In DoBra we aim to achieve change in communities in a broad sense. In this interactive workshop, we therefore focus on the particular challenges we encounter in conducting stringent research when trying to catalyse, rather than control, change processes. We will share our ideas, experiences, reflections, tools and approaches as well as results, related to using a variety of strategies to bring together a broad range of stakeholders to co-create experience-based evidence through innovative approaches. We begin by linking theory, research and practice through discussion of the overarching ideas and individual projects, with the second part of the session based on audience engagement with various tools used in DoBra. PMID- 29402098 TI - A new method for developing compassionate communities and cities movement-"Todos Contigo" Programme (We are All With You): experience in Spain and Latin America countries. AB - Todos Contigo (We are All With You) is a programme for social awareness, training, and implementation of care networks for citizens to support, accompany and care for those who face advanced chronic disease and end of life situations. From New Health Foundation this programme collaborates with the Public Health and Palliative Care International Charter of Compassionate Communities. It seeks to promote a new integrated palliative care model in the daily lives of individuals, to make families and health/social professionals the main promoters of compassionate communities and compassionate cities movement. This workshop aims to: (I) describe the methodology of the programme: required tools and steps for building and developing a compassionate city or community; (II) identify stakeholders and organizations to join the compassionate community as networking agents; (III) sharing experiences from the implementation of this project in various contexts while providing specific examples and lessons learned from the perspective of various roles; (IV) explain the process of becoming a part of the project and of getting the official recognition for being a compassionate city. This workshop aims to share a new methodology "Todos Contigo" (We are all with you) Programme for the development of compassionate communities and cities movement. We describe our experiences in Spain and Latin American countries. The method is based on creating community networks, carrying out social awareness and training programmes related to end of life care. PMID- 29402099 TI - Celebrating indigenous communities compassionate traditions. AB - Living in a compassionate community is not a new practice in First Nations communities; they have always recognized dying as a social experience. First Nations hold extensive traditional knowledge and have community-based practices to support the personal, familial, and community experiences surrounding end-of life. However, western health systems were imposed and typically did not support these social and cultural practices at end of life. In fact, the different expectations of western medicine and the community related to end of life care has created stress and misunderstanding for both. One solution is for First Nations communities to develop palliative care programs so that people can receive care at home amongst their family, community and culture. Our research project "Improving End-of-Life Care in First Nations Communities" (EOLFN) was funded by the Canadian Institutes of Health Research [2010-2015] and was conducted in partnership with four First Nations communities in Canada (see www.eolfn.lakeheadu.ca). Results included a community capacity development approach to support Indigenous models of care at end-of-life. The workshop will describe the community capacity development process used to develop palliative care programs in First Nations communities. It will highlight the foundation to this approach, namely, grounding the program in community values and principles, rooted in individual, family, community and culture. Two First Nations communities will share stories about their experiences developing their own palliative care programs, which celebrated cultural capacity in their communities while enhancing medical palliative care services in a way that respected and integrated with their community cultural practices. This workshop shares the experiences of two First Nations communities who developed palliative care programs by building upon community culture, values and principles. The underlying model guiding development is shared. PMID- 29402100 TI - Collaborative model used to develop a resource guide for communities to enhance their palliative and end of life care: the case of Alberta, Canada. AB - In response to the desire of community organizations in Alberta for information and guidance as they seek to improve palliative and end of life care in their communities, a large number of organizations collaborated to develop a resource guide. In order to achieve this goal, it was first necessary to identify the common information needs of Alberta communities as they pursue their vision for improving local Palliative and End-of-Life Care. A committee comprised of representatives from Alberta Health Services, Alberta Health, Alberta Hospice Palliative Care Association, Hospice Societies, University researchers, Indigenous Health and Palliative Care physicians surveyed numerous community groups and stakeholders about their information needs. As a result of their feedback several themes were identified which formed the basis of the Resource Guide for Community-based Palliative and End-of-Life Care. This oral presentation will leave participants with a good understanding of how multiple stakeholders can work together to strengthen community-led palliative and end-of-life care, at a provincial level, when there is a common goal. PMID- 29402101 TI - Death literacy-developing a tool to measure the social impact of public health initiatives. AB - This presentation provides an overview of the development of the death literacy concept and of our recent research work to develop a death literacy benchmarking tool. The concept of 'death literacy' has four components; skills, knowledge, experiential learning and social action and all provide a framework for behavioural and systemic change. This tool will provide a national benchmark of death literacy in the general population, providing a way to measure the social impact of existing and new public health initiatives. The purpose of the GroundSwell Project (GSP) is to create a more death literate society, one where people and communities have the practical know-how needed to plan well for end of life. This means shifting focus from "talking about it" to transforming this conversation into one of deep community engagement, social action, insight and empowerment. Being death literate strengthens our ability to care, creating compassionate communities. This tool will provide a national benchmark of death literacy in the general population and will provide a way to measure the social impact of existing and new public health initiatives. Our goal is develop a tool that can be used by a number of stakeholders-funders, government and services. PMID- 29402102 TI - Public health by stealth. AB - What does it take to light a fire to create cultural change about the way we do death, dying and bereavement in Australia? The GroundSwell Project set out to embark on a bold journey to create cultural change in the death and dying space in Australia. For 7 years we have delivered over 55 arts/health projects and have punched well above our weight. What have we learned about change and innovation? We've learned that we had to set up a fiercely independent organisation, drawing on short term funding so that we were never locked into delivering results that perpetuated 'systemic malaise'. We grew a network of activators across Health and Palliative care, community as well as other non-health related workplaces. We sought to find the right people, likening them to 'positive outliers' and engaged their head, heart and hands so they may influence others for a ripple effect. We work well with power or rank, a critical skill when leaning into complex social change. We've learned that we must engage leaders not just in health but ALL sectors, institutions, all walks of life...why not make it possible for any change to be truly 'social'? In this presentation, you will glean highlights from a range of our innovations and our approach to leadership, social research and collaboration. You'll have pause to reflect on how in your current role in the health system, you too can create change, by drawing on non-health specific discourse, using a stronger social lens. Wanting to engage all walks of life to improve public health is one thing, doing it and maintaining momentum is another! Join Jessie from the GroundSwell Project, Australia to learn about what they have gleaned from 7 years of being just a little too ahead of their time. PMID- 29402103 TI - Proposal of a New Public Health End of Life approach for Brazil: how the Project EstaraoSeuLado-Primary Palliative Care is working and how it can help. AB - Brazil has 206 million people, and 1.2 million deaths and 600,000 new cases of cancer per year. Palliative Care services are patchily distributed. The Family Health Strategy, made up from 41,000 primary care teams across Brazil forms a comprehensive primary care network. The Project EstaraoSeuLado-Primary Palliative Care developed working from Community Centers. We created a model based on compassionate communities, with community carers working alongside primary care teams. We identified people who need palliative care, gave them specific care and enrolled their carers into a program of monthly meetings called "Comunidade Cuidador". We discussed caring at end of life and provided skills training. During 2015 we ran 8 training programmes with an average of 10 carers. The major themes of discussion were carer burnout, dealing with denial and skills needed daily. The effect of these meetings was better relations between carers and professionals with expansion of the naturally occurring supportive network. The results of this project have been remarkable. The joint working of professionals and supportive networks together is recognised as being transformational. Carers themselves spread this approach by recommending it to others they know with life limiting illness. We will discuss the model and how it can be replicated more broadly across Brazil. Family Health teams can use tools of identification, evaluation and assessment working with networks including the community as an important part. We will propose a new model of End-of-Life Care to be adopted as national policy. We have implemented a compassionate community programme in the area of Rio Grande in Brazil. This has been a combination of primary care working in harmony with communities, providing education, resources and training to enhance the skill of communities to care for their dying. This is a necessary solution for Brazil, where resources and access to healthcare is limited. Our model is successful and increasing. We propose wider adoption of this model across Brazil and will present figures on the size of the challenge we face. PMID- 29402104 TI - Developing an intervention for optimizing end of life care in any setting. AB - The gold standards of care created within the hospice setting are not always effectively influencing national, regional or local policy. This struggle is something which the public health sector has successfully contended with. In particular an approach known as Health in All Policies (HiAP) has been developed to lay down the rules of engagement and guide the exchange between organisations from all sectors. This synergy allows for an exploration of the possibilities of utilising HiAP within end of life care. In particular this study will look at how the HiAP can be adapted to better integrate end of life care throughout the population. Objectives are: (I) to investigate HiAP as an intervention; (II) to develop a framework for implementing a HiAP approach to end of life care; (III) to evaluate the possible impacts of changing the manner in which end of life care integrates within England. This presentation aims to unpick how HiAP guide exchanges between organisations from all sectors. Using this it then explores how we could use this to optimise end of life care. PMID- 29402105 TI - Linkage strategies for successful and sustainable partnerships: a practical framework for community engagement by palliative care services. AB - Partnerships are central to the success of linkages between palliative care services and the communities they support. The goal of partnership is to achieve more than individuals and groups can achieve on their own, yet the concept is often poorly understood. A clearly articulated understanding of partnership is a powerful step in transforming an organization's engagement with the community. The aim of this workshop is to enable participants to gain a clear understanding of partnership, understand the recognized evidence-based principles of establishing and maintaining partnerships, and identify practical approaches to partnering to take back to their organizations and communities. PMID- 29402106 TI - Creating a sustainable, participatory palliative care programme in an urban slum in Dhaka, Bangladesh. AB - The Centre for Palliative Care, based at the only medical university [Bangabandhu Sheikh Mujib Medical University (BSMMU)] in Dhaka, Bangladesh, in collaboration with Worldwide Hospice Palliative Care Alliance, piloted a one-year project focussed on improving the quality of life of 100 older people and their families in two slum settings in Dhaka. This project was developed following the identification of significant palliative care needs of older people in the slum settings. In addition, the project was formed in response to the absence of programmes delivering palliative care to the poorest and most marginalised in poor urban settings, in a sustainable manner within the context of the low development of palliative care and the human and financial resource limitations in Bangladesh. The programme was developed using a participatory approach which focussed on engaging members of the community in the delivery of the project through the identification and training of 8 palliative care assistants from the slum setting itself, who delivered basic care supported by health professionals, the development of palliative care activists within the community and the engagement of the slum community leadership. The impact of the project showed improved quality of life for the target population and the potential for further development as a sustainable, community owned model over a further 2 years, which could be translated into other urban settings. This presentation will highlight lessons learned from the development and implementation of the project, and findings from the independent evaluation completed in December 2016, overseen by Glasgow University. The presentation will outline the successes and challenges of developing a participatory, community owned palliative care service within a slum in Dhaka, Bangladesh for older people and their families. PMID- 29402107 TI - Embracing life-the Bethlehem Schools' Project, an "icebreaker" and "a foot in the door". AB - This workshop details a Partnership involving a High school, a Hospital (Calvary Health Care Bethlehem), La Trobe University and Palliative Care Victoria which seeks to support Community Capacity and resilience in dealing with Life-Limiting illness, death, dying and Loss. This alliance has produced an educational resource which may be used, not only as a tool to normalize death, but also as a means of exploring 'keys to well-being' at any stage of life, through any loss or challenge. This workshop features a template which has been trialled, adapted and evaluated in High School, workshop and Hospital induction settings within Australia. Responses thus far have been "overwhelmingly positive". Translating evidence of positive outcomes into Education & Health Care Systems, is a challenge-this workshop offers a means of approaching both. The conclusion of the workshop provides a number of insights: (I) engaging communities in discussions about well-being and harnessing the insights of youth is a palatable means of discussing well-being at end-of-life; (II) what we know, as a community about supporting people with life-limiting illness is applicable across the span of life-not just at the end; (III) just as it takes a village to raise a child-it takes a village to ensure a quality end-of life experience. What began as a one off hospital immersion for Secondary School students has grown to become a sustainable educational resource, applicable across a number of domains-with the capacity to become an evidence-based means of increasing community EOL capacity. This workshop details the evolution of a community partnership, which produced an evaluated, sustainable, educational resource encouraging conversations about death and loss whilst emphasizing the essentials of well-being. It is a potential "foot in the door" of the education system and an "ice-breaker" for new staff/students to Palliative care. PMID- 29402108 TI - The evolution of the Kelley community capacity development model for palliative care. AB - This oral presentation will describe the conceptual evolution of the Kelley model for Community Capacity Development [2000-2016]. It will illustrate how and why the model changed to become a powerful Canadian example of a public health approach to developing community based palliative care programs. Based on conducting participatory action research in rural, First Nations communities and long-term care homes, the perspective of "community" gradually expanded beyond health care professionals to include natural helpers, front line care providers, formal and informal community leaders, and social services. The Kelley model has potential to be applied internationally since it builds a context specific palliative care program that is grounded in the local community and uses existing informal and formal resources. The Kelley model is a theory of change and can be used to guide a process of developing community-based palliative care programs. The model includes a series of four incremental but non-linear phases. Development is a bottom-up process that is grounded in the unique needs, vision, culture and values of a specific community. Community change is made from inside the community and not from outside. Development builds on existing resources, relationships, strengths and assets. Based on participatory action research and applying the model in rural communities, First Nations communities and long term care homes, the definition of the "community" in the model gradually expanded from registered health care providers and health services only. Supportive community members, often taken for granted by health care professionals but critical to the success of community palliative care, gradually became more visible through the research. The Kelley model of the palliative care community grew to include natural helpers, front line providers such as personal support workers, formal and informal community leaders, and social services. The Kelley model is a Canadian model that can be used to guide community based palliative care development in many diverse geographic, organizational or cultural communities. It can be applied internationally since it creates a palliative care program that is grounded in a unique local community and uses existing informal and formal resources. PMID- 29402109 TI - Developing community apalliative care programs using a capacity building approach: the Northwestern Ontario experience. AB - Northwestern Ontario, Canada, is a large, sparsely populated geographic area with many small rural and remote communities. Most health services are delivered by primary care generalists. The goal of the North West LHIN Regional Palliative Care Program (RPCP) with St. Joseph's Care Group is to create an integrated system of palliative care accessible to all individuals in Northwestern Ontario who would benefit from a palliative approach, regardless of location, prognosis, or diagnosis. To achieve this goal and increase access to palliative care at the primary care level, the RPCP has used the Kelley Community Capacity Development Model to guide their process of developing palliative care programs in 8 different rural communities. In each community, a local community facilitator is identified and a palliative care committee is established. Subsequently, other community members and health care providers with an interest in death, dying, loss, and bereavement are engaged in a local workshop to discuss their community's strengths, identify areas of improvement, and develop a plan to implement their local palliative care program. Throughout, the RPCP team acts as a resource for the Kelley capacity development process, introduces tools and resources that have been created to support this work, and shares lessons learned from other communities. At the conference, rural community facilitators will share their experiences engaging their communities and highlight accomplishments in developing palliative care. Participants will discover how the Kelley community capacity building approach can mobilize rural, remote, and northern communities and improve access to a palliative approach to care. The North West LHIN RPCP has used the Kelley Community Capacity Development Model to guide development of palliative care programs in eight different rural communities. This workshop will describe the process, introduce tools that have been created to support this work, and share lessons learned from communities. PMID- 29402111 TI - MyGrief.ca. AB - Bereavement represents a significant public health concern as grievers often suffer from co-morbid health problems, increased use of health care resources, periodic hospitalizations, and even mortality in the first 2 years after the death. Furthermore, grievers frequently encounter major obstacles when seeking formal support, including lack of access to specialized grief support due to temporal, financial or geographic constraints. To address these gaps in service, the Canadian Virtual Hospice, in collaboration with pan-Canadian partners developed MyGrief.ca, the world's first evidence-based, online psycho-educational tool to support those who do not or cannot access existing in-person loss and grief supports and as a supplementary resource for those who do. The tool also serves as a rich educative tool for health providers. The content was developed with families and international leaders in the field of bereavement, with attentiveness to issues of cultural diversity. Funding was providing by the Canadian Partnership against Cancer. MyGrief.ca includes nine self-directed modules that cover a diversity of topics across the bereavement trajectory. Embedded within each module is a great variety of video testimonials detailing grief narratives that represent diverse age, cultural, gender, and sexual orientation groups. Attendees will be given an in-depth tour of MyGrief.ca, followed by an interactive conversation on the tool with a bereft family member, health provider and educator on their unique perspectives and the overall impact of using MyGrief.ca. Bereavement represents a significant public health issue with grievers often presenting with concurrent health difficulties in the first 2 years after the death. This workshop will present a novel tool developed by the Canadian Virtual Hospice, specifically an online self-directed bereavement resource to support patients, families and health providers. PMID- 29402110 TI - Addressing the cultural, spiritual and religious perspectives of palliative care. AB - Healthcare services are often out of sync with cultural, spiritual and religious perspectives on health, death, and grieving. This dissonance affects attitudes and behaviours in seeking and utilizing end-of-life health services and can lead to poor clinical communication, misunderstanding, and anxiety as patients, families and health providers interact during a serious illness. To address a gap in cultural-specific information Canadian Virtual Hospice launched LivingMyCulture.ca-an evidence-informed collection of videos of immigrants, refugees, and Indigenous people sharing their stories about the intersection of culture, spirituality, and religion with their experiences of advanced illness, palliative care, and grief. The video repository includes over 650 video clips, available in 11 different languages. These narratives empower and educate patients and their families by raising their awareness about accessing, advocating, and receiving culturally safe and inclusive care as they navigate the Canadian healthcare system. LivingMyCulture.ca also promotes culturally sensitive care among health providers to enhance their knowledge and skills in providing culturally safe and inclusive care in order to improve care outcomes. This presentation will introduce LivingMyCulture.ca, provide strategies for incorporating the tool into practice to support patient and family care and share summative evaluation results. A Somali-Canadian journalist and community leader will share her unique Muslim and Somali perspective about the way illness, dying and grief is approached and the impact of LivingMyCulture.ca in the community. Overviews of other culture groups' video resources will also be shared, reflecting Canada's rich cultural tapestry. This workshop will provide an overview of LivingMyCulture.ca, share video clips from the 11 cultures in the series and include a discussion with a Somali-Canadian journalist and community leader about the way people in her culture approach illness, dying and grief and the overall impact of LivingMyCulture.ca. PMID- 29402112 TI - The fiftieth anniversary of the Croatian scientific society for the history of health culture. AB - This paper presents the impressive activity of the Croatian Society for the History of Health Culture on the occasion of the half-century anniversary. The short overall historical review of the Society's history is given, and three particularly important projects are highlighted: the science conventions "Rijeka and its Citizens in Medical History" ("Rijeka i Rijecani u medicinskoj povjesnici"), the scientific journal AMHA - Acta medico-historica Adriatica, and the special section called "In honour of Asclepius and Orpheus" ("Asklepiju i Orfeju u cast"). PMID- 29402113 TI - [State school - polyclinic in Petrinja (1925-1945)]. AB - What has been researched and reconstructed, based on archival documents and data from professional literature, is the activity of the State school-polyclinic in Petrinja, from its foundation in 1925 to its termination in 1945. Key figures taking part in its activity have also been highlighted. Founded as one of the first school-polyclinics in Croatia, the State school-polyclinic in Petrinja developed complete preventive and curative health activities aimed at school population in Petrinja as well as at pupils from the village schools in Petrinja County. These activities were based on carrying out thorough check-ups, giving school children vaccination, and taking other counter-epidemic measures, providing health and sanitary education, exercising sanitary supervision of schools and pupils' homes, implementing remedial measures in the field, taking extra care of socially handicapped children, providing regular diet and healthy meals for the poorest (who got prescription glasses for free, as well as medicines, fish-liver oil, who got their teeth filled, hair cut and were given the opportunity to recuperate in the youth holiday camps at the seaside and in the mountains.) The activities also encompassed the efficient treatment of the sick, among whom the various infectious and internist diseases (anaemia, undernourishment, struma, rickets) and dental caries were prevalent. Its twenty year-old continuous activity aimed at providing school population with health care represents a successful synthesis of preventive and curative health principles based on progressive ideas of social medicine promoted by Andrija Stampar, who was a promoter and reformer of public health service in our regions. Due to being well-organized and the professional enthusiasm of its managers and staff, the State school-polyclinic in Petrinja efficiently promoted public hygiene and addressed the specific health needs of the school population. While promoting integral health care, maintaining and improving physical and mental health of children and youth in the schools in Petrinja and the other schools nearby, it raised the reputation of health care in Petrinja and contributed to the development of the Croatian school of medicine. PMID- 29402114 TI - Crime and madness at the opposite shores of the Adriatic: moral insanity in Italian and Croatian psychiatric discourses. AB - In the 19th century, fervid debates arose in the young psychiatric science about how to deal with and to scientifically categorize human behaviour which was perceived as dangerous to society, and as criminal. There were two concepts that stood out in these transnationally held discussions; namely moral insanity and later on, psychopathy. Following recent approaches in the cultural and social history of psychiatry, we understand moral insanity and psychopathy as social constructs, which are determined by the evolution in psychiatric knowledge, and also by laws, codes and social norms of particular historical timeframes. Our task is to discuss the evolution and adoption of these concepts in two linguistically different, but still historically profoundly entangled regions, namely in Italian and Croatian psychiatric discourses at the turn from the 19th to the 20th century. Our analysis of two of the most important medical and psychiatric journals of the time shows that psychiatric debates on antisocial and criminal behaviour were in numerous ways entangled and shaped by the way the two societies scientifically, legally, and institutionally struggled over the question of how to detect and control the mentally incapacitated criminal offender. PMID- 29402115 TI - Johann Gottlieb Walter (1734-1818) and the technical preparation of bones in an anatomical cabinet in the late eighteenth and nineteenth century. AB - This study aims to analyze Johann Gottlieb Walter's biography (1734-1818), a German physician that specialized in human anatomy, who received an award of the Gottingen Royal Academy of Sciences. Here, we describe his technique of preparing bones for educational purposes through the comparison of other widely used techniques. The article also focuses on the great historical, scientific and didactic values of the anatomical preparations. In Europe during the eighteenth century the activity of some anatomists and physiologists, who were dedicated to the realization of anatomical preparations, testified the progress of medicine in the study of the human body, fundamental knowledge for physician training. PMID- 29402116 TI - Rhazes, a pioneer in contribution to trials in medical practice. AB - Medical history explains that Persian physicians used scientific methods based on clinical experiences and observations for treatment from pre-Islamic time (before 637 AD) and centuries later (in the Islamic era). Rhazes was one of the Persian physicians acknowledged as a pharmacist, chemist and prominent scientific writer on various subjects of medicine and philosophy. In this study, we aimed to investigate clinical experiences, as well as the ethical and critical views of Rhazes in medical practice. Rhazes promoted ethics in the medical profession. He expressed critical key points about ancient written texts. He broke ancient physicians' taboos in medical theories and evaluated them based on his own experiences. He designed animal and preclinical evaluations for his theories and also performed the first clinical trials with control groups in the history. His critical views about medical sciences as well as his beliefs in experiments resulted in many medical, chemical and pharmaceutical findings. Therefore, in history, he can be considered as the pioneer in using trials and experiments for approving medical methods. PMID- 29402117 TI - [Renaissance medicine and the discovery of the lesser circulation: the role of Michael Servetus (1511-1553)]. AB - Human urine is currently the subject of biomedical investigations as a potential therapeutic resource and it continues to be used in remedies in different cultures and societies, including the Spanish culture. In this study we gather etnomedical knowledge about urotherapy and determine their associated symbolisms in Spain. A literature overview and a case study were carried out to compile urine-based remedies and as a direct analysis of symbolic systems. Urotherapy is widespread in Spanish folk medicine. Among the 204 collected remedies, those related to treatment of diseases or skin conditions predominate (63%). Remedies have been reported for the treatment of skin diseases such as eczema, chloasma, alopecia, etc. to treat or alleviate burns, chilblains, wounds or skin chapping, and as a treatment of venomous bites. Most of the collected remedies have an associated naturalist symbolism, based on local traditions and the transmission of empirical initial knowledge. The use of urine in Spain is a result of the interaction of two types of practice: a local and traditional urotherapy, rural and with a utilitarian purpose, and a technical urotherapy, limited to an urban environment and a naturopathic medicine. PMID- 29402118 TI - Devastating epidemics in recent ages Greek populations. AB - In the recent Greek ages the most devastating epidemics were plague, smallpox, leprosy and cholera. In 1816 plague struck the Ionian and Aegean Islands, mainland Greece, Constantinople and Smyrna. The Venetians ruling the Ionian Islands effectively combated plague in contrast to the Ottomans ruling all other regions. In 1922, plague appeared in Patras refugees who were expelled by the Turks from Smyrna and Asia Minor. Inoculation against smallpox was first performed in Thessaly by the Greek women, and the Greek doctors Emmanouel Timonis (1713, Oxford) and Jakovos Pylarinos (1715, Venice) made relevant scientific publications. The first leper colony opened in Chios Island. In Crete, Spinalonga was transformed into a leper island, which following the Independence War against Turkish occupation and the unification of Crete with Greece in 1913, was classified as an International Leper Hospital. Cholera struck Greece in 1853-1854 brought by the French troops during the Crimean War, and again during the Balkan Wars (1912-13) when the Bulgarian troops brought cholera to northern Greece. Due to successive wars, medical assistance was not always available, so desperate people turned many times to religion through processions in honor of local saints, for their salvation in epidemics. PMID- 29402119 TI - [Very late but too early... prof. Angelo Chiavaro and the Italian degree in dentistry]. AB - The birth of the Degree in Dentistry in Italy has been very troubled, and only in 1980 saw its effective implementation. Very "instructive" in this regard is the history on the establishment in 1924 (the period of the seizure of power by Fascism) of a "National School of Dentistry" at the University of Rome, which was withdrawn after only ten months. The biggest supporter and proponent of the School, Prof. Angelo Chiavaro, after a few years, was "punished" with the transfer from the University of Rome to that of Genoa. We present some brief notes on the biography of this courageous pioneer and the matter of which he was the protagonist. PMID- 29402120 TI - Nicolae Constantin Paulescu: the first explicit description of the internal secretion of the pancreas. AB - : The purpose of this article is to describe the research of Nicolae Constantin Paulescu and to emphasize his role in the discovery of insulin. METHODS: We made a thorough review of the literature and research in the Romanian Academy Archive in order to find adequate references. RESULTS: In 1912 N.C. Paulescu analysed the clinical and biochemical alterations in diabetic patients and in dogs after performing a pancreatectomy, that apart hyperglycemia and glycosuria (carbohydrate metabolism), had noted also changes in lipid and protein metabolism. In 1916 he started the experiments with a pancreas extract obtained by his original method, that was injected intravenously to the diabetic dogs. The results of his first experiments showed: "The pancreatic extract injected into a peripheral vein produce: 1) A diminution and even a temporary suppression of diabetic hyperglycemia, which may be replaced by hypoglycemia; 2) A diminution or even temporary suppression of glycosuria; 3) A diminution of blood urea; 4) A diminution of urinary urea. In other words, the intravenous injection of the pancreatic extract has as effect the disappearance of diabetic symptoms. The attenuation of the diabetic syndrome begins immediately after the injection. It reaches a maximum after 2 hours,- and it lasts for about 12 hours". He concluded as such: "This discovery,- which sheds a bright light over the pathogenesis of diabetes gives us also the key for the treatment of this syndrome". In 1921, Paulescu had published extensively his data in two outstanding French journals 8 months before the first publication of Banting and Best from February 1922. It is clear that insulin has been discovered in Europe. CONCLUSION: Paulescu thought that a new hormone - Pancreine, that he discovered is the key element in the treatment of diabetes, but his outstanding research was unfairly neglected. PMID- 29402121 TI - John C. Carapanayiotis (1909-1999): the Greek radiologist and pioneer of physiatry in Greece. AB - John C. Carapanayiotis was specialized in physical medicine and rehabilitation in the USA in 1948, at a time when the medical world in post-war Greece was ignorant of this specific medical specialty, and the political, economic and social backdrop was incapable of accepting and understanding the wealth of scientific knowledge that he was trying to introduce. At this point it should be noted that the specialty of Physical Medicine and Rehabilitation was established in Greece in 1973. John C. Carapanayiotis was a member of the American Congress of Physical Medicine during the 1950's. In the same period, he expressed interest, on behalf of the New York University, in the establishment of a Physical Therapy Clinic in Greece, which would be granted unlimited funding by the Marshal Plan. His efforts clashed constantly with the backward mentality of his time, with the entrenched conservatism and with the bureaucratic red tape. Unfortunately, he was far ahead of his time and was condemned to the same fate as all other visionaries and pioneers in the way that his knowledge and scientific background were not put into practice for decades to come. PMID- 29402122 TI - Detailed analysis of research and practice in the life of a pediatric surgeon in East Central Europe in the 20th century - an example of prof. Zofia Umiastowska Sawicka. AB - Professor Zofia Umiastowska Sawicka laid the foundations for modern pediatric surgery in Poland, first in Bialystok, and subsequently in Kielce. She was a student of Prof. Jan Kossakowski from Warsaw Medical University to be counted among his most talented and skilled disciples. Professor Umiastowska became the head of the first Department of Pediatric Surgery in Bialystok, which was later incorporated into the Medical Academy of Bialystok. In 1977 she moved to Kielce to run the Department of Pediatric Surgery until her retirement in 1991. In these locations she was the one who trained generations of pediatric surgeons with special emphasis on surgical management of exstrophy of the bladder, vaginal labial adhesion (synechia), injuries of the male urethra, liver and hepatic ligament. During her professional lifetime she focused on congenital diaphragmatic hernia, Meckel's diverticulum, and some aspects of pediatric oncology as well. Every school she attended enriched her with the best of knowledge and skills that made her a perfect teacher for others. However, the Warsaw Medical University essentially played the main role at the core of her surgical training: here she was taught and she learnt how to be pediatric surgeon for good of public health of the society in concord with the motto of the Warsaw Medical University: Saluti publicae. PMID- 29402124 TI - An Evaluation of Army Wellness Center Clients' Health-Related Outcomes. AB - PURPOSE: To examine whether Army community members participating in a best practice based workplace health promotion program (WHPP) experience goal moderated improvements in health-related outcomes. DESIGN: Pretest/posttest outcome evaluation examining an autonomously participating client cohort over 1 year. SETTING: Army Wellness Center facilities on 19 Army installations. PARTICIPANTS: Army community members sample (N = 5703), mostly Active Duty Soldiers (64%). INTERVENTION: Assessment of health risks with feedback, health assessments, health education classes, and health coaching sessions conducted by health educators at a recommended frequency of once a month for 3 to 12 months. MEASURES: Initial and follow-up outcome assessments of body mass index (BMI), body fat, cardiorespiratory fitness, blood pressure, and perceived stress. ANALYSIS: Mixed model linear regression testing for goal-moderated improvements in outcomes. RESULTS: Clients experienced significant improvements in body fat ( 2% change), perceived stress (-6% to -12% change), cardiorespiratory fitness (+6% change), and blood pressure (-1% change) regardless of health-related goal. Only clients with a weight loss goal experienced BMI improvement (-1% change). Follow up outcome assessment rates ranged from 44% (N = 2509) for BMI to 6% (N = 342) for perceived stress. CONCLUSION: Army Wellness Center clients with at least 1 follow-up outcome assessment experienced improvements in military readiness correlates and chronic disease risk factors. Evaluation design and follow-up related limitations notwithstanding results suggest that best practices in WHPPs can effectively serve a globally distributed military force. PMID- 29402125 TI - Management of infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: current evidence and future prospects. AB - INTRODUCTION: The spread of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae has become a major public health threat worldwide. Area covered: A thorough systematic literature review describing the current evidence and future prospects of therapeutic options for infections caused by ESBL producing Enterobacteriaceae. Expert commentary: The methods of detecting ESBLs have been evolving. The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing lowered the MIC breakpoints of cephalosporins against ESBL-producing Enterobacteriaceae in 2010. Phenotypic testing for ESBLs is no longer recommended. Instead, the selection of appropriate antimicrobial agents largely depends on the report of minimum inhibitory concentrations (MICs). To date, therapeutic options for these multidrug-resistant organisms remain limited. The clinical efficacy of piperacillin/tazobactam and cefepime on in vitro-susceptible ESBL-producing Enterobacteriaceae remains a concern. Many studies found an in vitro-in vivo discordance based on current breakpoints. Carbapenems are the most reliable antibiotics for severe infections caused by ESBL-producing Enterobacteriaceae. However, their overuse has led to a serious problem of increasing drug resistance. Recently, ceftolozane/tazobactam and ceftazidime/avibactam have been approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. The introduction of these new beta lactam/beta-lactamase inhibitor combinations offers new carbapenem-sparing options for the treatment of ESBL infections. PMID- 29402126 TI - Evolution of compstatin family as therapeutic complement inhibitors. AB - INTRODUCTION: Therapeutic modulation of complement activation is considered as a promising approach for the treatment of host tissue damage in several inflammatory and autoimmune diseases. Complement component protein C3 is a particularly attractive drug target for complement inhibitors, due to its central role in three pathways of complement activation cascade. Areas covered: The author provides a comprehensive review on compstatin family peptides which have been discovered and optimized as potent and selective C3 inhibitors via a combination of chemical, biophysical and computational approaches. New generations of the compstatin family with improved potency and therapeutic properties have been developed in recent years. Over two decades, compstatin demonstrated therapeutic potential as a first-of-its-kind complement inhibitor in a series of disease models, with encouraging efforts in clinical trials. Expert opinion: Compstatin holds promise for new therapeutic implications in blocking the effect of the complement cascade in a variety of disease conditions. The development of cost-effective treatment options with suitable dosing route and schedule will be critical for patients with complement mediated chronic diseases. PMID- 29402127 TI - Deguelin Impairs Cell Adhesion, Migration and Invasion of Human Lung Cancer Cells through the NF-[Formula: see text]B Signaling Pathways. AB - Deguelin, a rotenoid, is isolated from a natural plant species, and has biological activities including antitumor function. In the present study, we investigated the effect of deguelin on the cell adhesion, migration and invasion of NCI-H292 human lung cancer cells in vitro. Cell viability was analyzed by using flow cytometer. Cell adhesion was determined by using the cell-matrix adhesion assay. Wound healing assay was used to examine cell migration. Cell migration and invasion were investigated using a Boyden chamber assay. The protein expression was measured by Western blotting and confocal laser microscopy. The electrophoretic mobility shift assay was used to measure NF [Formula: see text]B p65 binding to DNA.We selected the concentrations of deguelin at 0, 0.5, 1.0, 1.5, 2.0 and 2.5[Formula: see text][Formula: see text]M and we found that those concentrations of deguelin did not induce significant cytotoxic effects on NCI-H292 cells. Thus, we selected those concentrations of deguelin for metastasis assay. We found that deguelin inhibited cell adhesion, migration and invasion in dose-dependent manners that was assayed by wound healing and transwell methods, respectively. Deguelin decreased the expression of MMP-2/-9, SOS 1, Rho A, p-AKT (Thr308), p-ERK1/2, p-p38, p-JNK, NF-[Formula: see text]B (p65) and uPA in NCI-H292 cells. Deguelin suppressed the expression of PI3K, SOS 1, NF-[Formula: see text]B (p65), but did not significantly affect PKC and Ras in the nuclei of NCI-H292 cells that were confirmed by confocal laser microscopy. We suggest that deguelin may be used as a novel anticancer metastasis of lung cancer in the future. PMID- 29402128 TI - Systematic review and benchmarking of Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) in oncology. AB - INTRODUCTION: The Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) has been used to evaluate the clinical benefits and risks of oncology treatments. However, limited information is available to interpret and contextualize Q-TWiST results. Areas covered: A systematic review of Q-TWiST literature was conducted to provide contextualizing benchmarks for future studies. 51 articles with 81 unique Q-TWiST comparisons were identified. The mean (95% CI) and median absolute Q-TWiST gains for treatment versus control arms were 2.78 (1.82-3.73) months and 2.20 months across all cancers, respectively. The mean (median) relative Q-TWiST gains were 7.8% (7.2%) across all cancers. Most (88%) studies reported positive gains. The percentage of studies with relative Q-TWiST gains >=10% (ie, clinically important difference) and >=15% (ie, clearly clinically important difference) were 40.0% and 22.7%, respectively. Expert commentary: The relevance of Q-TWiST in assessing net clinical benefits of cancer therapy has not diminished, despite an arguably low number of published studies. The interest in such assessment is highlighted by the recent emergence of oncology value frameworks. The Q-TWiST should be compelling to clinicians as it integrates clinical information (ie, toxicity, relapse/progression, and survival) and patient preferences for each of these states into a single meaningful index. PMID- 29402129 TI - Reduction kinetics and electrochemistry of tetracarboxylate nitroxides. AB - Tetracarboxylate pyrroline nitroxides undergo very fast reduction with ascorbate/glutathione (GSH), with second-order rate constants that are five orders of magnitude greater than those for gem-diethyl pyrroline nitroxides. For tetracarboxylate nitroxides, the electrochemical reduction potentials, measured by square wave voltammetry, are much less negative (by about 0.8 V), compared with the corresponding gem-diethyl nitroxides, while the oxidation potentials become more positive (by about 0.7 V). Electrochemical potentials correlate well via simple regressions with field/inductive parameters such as Swain/Lupton F parameters (and/or Charton sigmaI-parameters). Rates of reduction with ascorbate/GSH similarly correlate well for four pyrroline nitroxides, except for the slowest reducing gem-diethyl nitroxide. These results suggest that the electron withdrawing groups adjacent to the nitroxide moiety have a strong accelerating impact on the reduction rates, and thus they are not suitable for the design of hydrophilic nitroxides for in vivo applications. PMID- 29402130 TI - Behavioral and hematological responses of broiler chickens administered with betaine and ascorbic acid during hot-dry season. AB - Heat stress is a major problem in poultry production in tropical regions. Assessing the impact of thermally stressful environmental conditions on the welfare of broiler chickens is of great importance. Behavioral responses in a novel environment and hematology of broiler chickens administered with betaine and/or ascorbic acid (AA) during the hot-dry season were evaluated. Broiler chickens were randomly divided into four groups: Group I (control) was given sterile water, Group II was given betaine, Group III was given AA, and Group IV received betaine + AA orally and daily for 42 days. An open-field test was used to assess behavior. Hematological parameters were obtained using a hematology auto-analyzer. The natural environmental conditions were predominantly outside the thermoneutral zone for broiler chickens. Results demonstrated that treated groups exhibited improved ability to adjust faster to a new environment and better hematological responses than controls, evidenced by enhanced behavioral responses, oxygen-carrying capacity, and immune responses of broiler chickens under unfavorable environmental conditions. Betaine and/or AA administration to broiler chickens improved some behavioral responses, hemoglobin concentrations, packed cell volume, and total leukocyte count during the hot-dry season. PMID- 29402132 TI - Rasch analysis and ordinal-to-interval conversion tables for the Depression, Anxiety and Stress Scale. AB - This study conducted Rasch analysis of the Depression, Anxiety and Stress Scale using responses of 400 participants to produce ordinal-to-interval conversion algorithms not available to date. Minor modifications such as removing the non fitting item 5 and combining subscales items into super-items were necessary to achieve the best model fit ( chi2(15) = 20.28, p = 0.16). The results support internal validity of the modified 20-item Depression, Anxiety and Stress Scale and include ordinal-to-interval conversion tables for use with non-clinical populations that improve reliability and precision of the measure. PMID- 29402134 TI - Depression literacy and help-seeking in Australian police. AB - OBJECTIVE:: To assess depression literacy, help-seeking and help-offering to others in members of the police force in the state of Victoria, Australia. METHODS:: All staff in police stations involved in a cluster randomised controlled trial of an integrated workplace mental health intervention were invited to participate. Survey questions covered sociodemographic and employment information, recognition of depression in a vignette, stigma, treatment beliefs, willingness to assist co-workers with mental health problems, help-giving and help-seeking behaviours, and intentions to seek help. Using the baseline dataset associated with the trial, the paper presents a descriptive analysis of mental health literacy and helping behaviours, comparing police station leaders and lower ranks. RESULTS:: Respondents were 806 staff, comprising 618 lower-ranked staff and 188 leaders. Almost 84% of respondents were able to correctly label the problem described in the vignette. Among those who had helped someone with a mental health problem, both lower ranks and leaders most commonly reported 'talking to the person' although leaders were more likely to facilitate professional help. Leaders' willingness to assist the person and confidence in doing so was very high, and over 80% of leaders appropriately rated police psychologists, general practitioners, psychologists, talking to a peer and contacting welfare as helpful. However, among both leaders and lower ranks with mental health problems, the proportion of those unlikely to seek professional help was greater than those who were likely to seek it. CONCLUSION:: Knowledge about evidence-based interventions for depression was lower in this police sample than surveys in the general population, pointing to the need for education and training to improve mental health literacy. Such education should also aim to overcome barriers to professional help-seeking. Interventions that aim to improve mental health literacy and help-seeking behaviour appear to be suitable targets for better protecting police member mental health. PMID- 29402133 TI - Featured Article: Immunomodulatory effect of hemozoin on pneumocyte apoptosis via CARD9 pathway, a possibly retarding pulmonary resolution. AB - Plasmodium falciparum, the most virulent malaria parasite species, causes severe symptoms especially acute lung injury (ALI), of which characterized by alveolar epithelium and endothelium destruction and accelerated to blood-gas-barrier breakdown. Parasitized erythrocytes, endothelial cells, monocytes, and cytokines are all involved in this mechanism, but hemozoin (HZ), the parasitic waste from heme detoxification, also mainly contributes. In addition, it is not clear why type II pneumocyte proliferation, alveolar restorative stage, is rare in malaria associated ALI. To address this, in vitro culture of A549 cells with Plasmodium HZ or with interleukin (IL)-1beta triggered by HZ and monocytes (HZ-IL-1beta) was conducted to determine their alveolar apoptotic effect using ethidium bromide/acridine orange staining, annexin-V-FITC/propidium iodide staining, and electron mircroscopic study. Caspase recruitment domain-containing protein 9 ( CARD9), the apoptotic regulator gene, and IL-1beta were quantified by reverse transcriptase PCR. Junctional cellular defects were characterized by immunohistochemical staining of E-cadherin. The results revealed that cellular apoptosis and CARD9 expression levels were extremely high 24 h after induction by HZ-IL-1beta when compared to the HZ- and non-treated groups. E-cadherin was markedly down-regulated by HZ-IL-1beta and HZ treatments. CARD9 expression was positively correlated with IL-1beta expression and the number of apoptotic cells. Interestingly, the localization of HZ in the vesicular surfactant of apoptotic pneumocyte was also identified and submitted to be a cause of alveolar resolution abnormality. Thus, HZ triggers monocytes to produce IL-1beta and induces pneumocyte type II apoptosis through CARD9 pathway in association with down regulated E-cadherin, which probably impairs alveolar resolution in malaria associated ALI. Impact statement The present work shows the physical and immunomodulatory properties of hemozoin on the induction of pneumocyte apoptosis in relation to IL-1beta production through the CARD9 pathway. This occurrence may be a possible pathway for the retardation of lung resolution leading to blood-gas barrier breakdown. Our findings lead to the understanding of the host-parasite relationship focusing on the dysfunction in ALI induced by HZ, a possible pathway of the recovering lung epithelial retardation in malaria-associated ARDS. PMID- 29402135 TI - Various physicochemical and surface properties controlling the bioactivity of cerium oxide nanoparticles. AB - Amidst numerous emerging nanoparticles, cerium oxide nanoparticles (CNPs) possess fascinating pharmacological potential as they can be used as a therapeutic for various oxidative stress-associated chronic diseases such as cancer, inflammation and neurodegeneration due to unique redox cycling between Ce3+ and Ce4+ oxidation states on their surface. Lattice defects generated by the formation of Ce3+ ions and compensation by oxygen vacancies on CNPs surface has led to switching between CeO2 and CeO2-x during redox reactions making CNPs a lucrative catalytic nanoparticle capable of mimicking key natural antioxidant enzymes such as superoxide dismutase and catalase. Eventually, most of the reactive oxygen species and nitrogen species in biological system are scavenged by CNPs via an auto-regenerative mechanism in which a minimum dose can exhibit catalytic activity for a longer duration. Due to the controversial outcomes on CNPs toxicity, considerable attention has recently been drawn towards establishing relationships between the physicochemical properties of CNPs obtained by different synthesis methods and biological effects ranging from toxicity to therapeutics. Unlike non-redox active nanoparticles, variations in physicochemical properties and the surface properties of CNPs obtained from different synthesis methods can significantly affect their biological activity (inactive, antioxidant, or pro-oxidant). Moreover, these properties can influence the biological identity, cellular interactions, cellular uptake, biodistribution, and therapeutic efficiency. This review aims to highlight the critical role of various physicochemical and the surface properties of CNPs controlling their biological activity based on 165 cited references. PMID- 29402136 TI - Comorbidity of depressive symptoms among primary care patients with diabetes in a federally qualified health center. AB - Depression is frequently comorbid with diabetes; however, less is known about this comorbidity in socially disadvantaged populations. This cross-sectional study examined depressive symptomatology among 424 patients with prediabetes or type 2 diabetes mellitus at a federally qualified health center. Prevalence of clinically significant depressive symptoms was assessed using the World Health Organization Five-Item Well-Being Index. The majority (67.7%) endorsed depressive symptoms, with greater prevalence among middle-aged adults (45-64 years) than younger or older counterparts. More women than men endorsed depressive symptoms. Findings suggest the need for routine depression screening in both prediabetes and type 2 diabetes mellitus, particularly among middle-aged and low-income individuals. PMID- 29402138 TI - Crosstalk between prognostic long noncoding RNAs and messenger RNAs as transcriptional hallmarks in gastric cancer. AB - AIM: Our study investigated the significance of the crosstalk between long noncoding RNAs (lncRNAs) and mRNAs in gastric cancer (GC). METHODS: lncRNA and mRNA expression profiling data in 671 GC tumors and 77 nontumorous gastric tissues were retrieved from the gene expression omnibus database: GSE54129, GSE13911, GSE19826, GSE79973, GSE15459 and GSE66229. Differentially expressed analysis, RNA coexpression network construction, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were conducted in this study. RESULTS: Using differentially expressed and prognostic lncRNAs or mRNAs in GC, we constructed the lncRNA-mRNA coexpression networks. This network involved with vital GO and KEGG pathways. CONCLUSION: Our study reveals coexpressed lncRNAs and mRNAs as transcriptional hallmarks in GC patients which provide interesting information regarding the incidence and outcome of GC. PMID- 29402137 TI - Perceived Stress, Its Physiological Correlates, and Quality of Life in Patients With Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is a chronic, common disorder of the gastrointestinal tract associated with high psychological comorbidity and diminished quality of life. Patients with IBS display a heightened sensitivity to stress, although the literature is inconsistent as to whether they have a dysregulated stress response. The purpose of the present investigation, a substudy of a larger research effort, was to examine physiological correlates of perceived stress in patients with IBS (cortisol and adrenocorticotropic hormone) and to explore associations between perceived stress and quality of life. A total of 101 participants (35 with IBS [predominant subtypes IBS-constipation and IBS diarrhea] and 66 healthy controls [HCs]) completed self-report inventories regarding perceived stress and quality of life, and fasting peripheral blood was drawn. Participants with IBS did not differ from the HC in demographic or physiological measures but did differ in psychological measures, reporting significantly higher levels of perceived stress and lower levels of quality of life. Perceived stress and quality of life were not significantly associated in IBS participants. However, differential findings of the stress response were found within IBS participants by sex, race, and subtype. These findings illustrate the heterogeneity of the IBS patient population, underscore the necessity of evaluating larger sample sizes and increasing the diversity of such samples to include males and ethnic minorities, and demonstrate the importance of taking an individualized approach to evaluation and treatment in the IBS patient population. PMID- 29402139 TI - 'I don't even know how to start that kind of conversation': HIV communication between mothers and adolescents with perinatally acquired HIV. AB - Young people with perinatally acquired HIV are now surviving into late adolescence and adulthood. We explored HIV communication within mother/adolescent dyads following naming of the adolescents' HIV. Five adolescents with perinatally acquired HIV (14-16 years) and their biological mothers were interviewed separately. HIV communication between mothers and children was rare. Discussion most commonly related to biomedical aspects of HIV. Onward HIV disclosure was discouraged by mothers, which often contrasted with adolescents' beliefs. Discussing emotional and sexual aspects of HIV was mutually avoided. Culturally sensitive support and guidance should be offered to families about discussing HIV, considering potentially differing perspectives. PMID- 29402131 TI - Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress. AB - SIGNIFICANCE: Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. CRITICAL ISSUES: In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. FUTURE DIRECTIONS: Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703. PMID- 29402140 TI - Health anxiety and associated constructs in children and adolescents with congenital heart disease: A CHAMPS cohort study. AB - This study explored health anxiety and associated constructs in children and adolescents with congenital heart disease and typically developing children and adolescents. A total of 84 participants (7-16 years) completed measures of health anxiety, intolerance of uncertainty, anxiety sensitivity, and DSM-IV anxiety disorder symptom categories. Results demonstrated that children and adolescents with congenital heart disease experienced significantly higher levels of health anxiety and associated constructs compared to typically developing children and adolescents. Our findings highlight a specific chronic physical health population who may be at risk of clinical levels of health anxiety and related psychopathology and require appropriate intervention. PMID- 29402141 TI - VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics. AB - OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation. METHODS: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125 mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500 mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline. RESULTS: Data collection will be complete in the fourth quarter of 2017. CONCLUSIONS: VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS. PMID- 29402142 TI - Factor structure, correlates, and incremental validity of the Pain Appraisal Inventory-Short Form. AB - We assessed the factor structure, correlates, and incremental validity of the Pain Appraisal Inventory in Chinese adult chronic pain samples. In an initial exploratory factor analysis sample ( N = 301), the original two-component (threat, challenge) 16-item Pain Appraisal Inventory and a 10-item short form (Pain Appraisal Inventory-Short Form) were supported. Within a confirmatory factor analysis sample ( N = 285), uniformly acceptable fits were observed only for the Pain Appraisal Inventory-Short Form. Furthermore, Pain Appraisal Inventory-Short Form threat and challenge subscales had significant correlations with conceptually related measures and added to prediction models for pain related coping and adjustment, independent of other pain belief scales. Together, results indicated that the Pain Appraisal Inventory-Short Form has utility in Chinese chronic pain samples. PMID- 29402143 TI - The Social Provisions Scale: psychometric properties of the SPS-10 among participants in nature-based services. AB - PURPOSE: This article analyses the psychometric properties of the Social Provisions Scale 10-items version. METHODS: The Social Provisions Scale was analysed by means of the polytomous Rasch model, applied to data on 93 young adults (16-30 years) out of school or work, participating in different nature based services, due to mental or drug-related problems. RESULTS: The psychometric analysis concludes that the original scale has difficulties related to targeting and construct validity. In order to improve the psychometric properties, the scale was modified to include eight items measuring functional support. The modification was based on theoretical and statistical considerations. CONCLUSION: After modifications the scale showed not only satisfying psychometric properties, but it also clarified uncertainties regarding construct validity of the measure. However, further analysis on larger samples are required. Implications for Rehabilitation Social support is important for a variety of rehabilitation outcomes and for different patient groups in the rehabilitation context, including people with mental health or drug-related problems. Social Provisions Scale may be used as a screening tool to assess social support of participants in rehabilitation, and the scale may also be an important instrument in rehabilitation research. There might be issues measuring structural support using a 10-items version of the Social Provisions Scale but it seemed to work well as an 8-item scale measuring functional support. PMID- 29402144 TI - Mitochondrial Ferritin Is a Hypoxia-Inducible Factor 1alpha-Inducible Gene That Protects from Hypoxia-Induced Cell Death in Brain. AB - AIMS: Mitochondrial ferritin (protein [FtMt]) is preferentially expressed in cell types of high metabolic activity and oxygen consumption, which is consistent with its role of sequestering iron and preventing oxygen-derived redox damage. As of yet, the mechanisms of FtMt regulation and the protection FtMt affords remain largely unknown. RESULTS: Here, we report that hypoxia-inducible factor 1alpha (HIF-1alpha) can upregulate FtMt expression. We verify one functional hypoxia response element (HRE) in the positive regulatory region and two HREs possessing HIF-1alpha binding activity in the minimal promoter region of the human FTMT gene. We also demonstrate that FtMt can alleviate hypoxia-induced brain cell death by sequestering uncommitted iron, whose levels increase with hypoxia in these cells. INNOVATION: In the absence of FtMt, this catalytic metal excess catalyzes the production of cytotoxic reactive oxygen species. CONCLUSION: Thus, the cell ability to increase expression of FtMt during hypoxia may be a skill to avoid tissue damage derived from oxygen limitation. Antioxid. Redox Signal. 00, 000-000. PMID- 29402146 TI - Incremental validity of the comprehensive inventory of thriving in predicting self-reporting mental and physical health among community populations. AB - This study examined psychometric properties and 1-year predictive validity of the Comprehensive Inventory of Thriving in China. In total, 556 participants in Chinese communities completed the Comprehensive Inventory of Thriving for confirmatory factor analysis. The other 533 individuals further completed the Flourishing Scale and Satisfaction With Life Scale and reported their physical and mental health 1 year later. The 18-factor correlated model showed a better goodness-of-fit than the seven-factor second-order related model. Thriving had higher correlation coefficients with depression, anxiety, stress, and doctor visits. The Comprehensive Inventory of Thriving is an efficient screening tool to differentiate the risk group from other groups and can predict health outcomes among community populations for active interventions. PMID- 29402145 TI - High NUP43 expression might independently predict poor overall survival in luminal A and in HER2+ breast cancer. AB - AIM: To explore the independent prognostic value of NUP43 in terms of overall survival (OS) and the mechanisms of its dysregulation in breast cancer. PATIENTS & METHODS: Bioinformatic analysis was performed by using data from The Cancer Genome Atlas-breast invasive carcinoma. RESULTS: High NUP43 expression was an independent prognostic factor of poor OS in luminal A subtype (HR: 2.400; 95% CI: 1.070-5.379; p = 0.034) and in HER2+ subtype (HR: 10.578; 95% CI: 1.850-60.473; p = 0.008). NUP43 DNA amplification was associated with elevated NUP43 expression, while DNA deletion was associated with decreased NUP43 transcription. CONCLUSION: NUP43 upregulation was related to DNA amplification and might independently predict poor OS in luminal A and in HER2+ breast tumors. PMID- 29402147 TI - Carotid IM-GSM is better than IMT for identifying patients with multiple arterial disease. AB - OBJECTIVE: Atherosclerosis is a systemic inflammatory disease that can affect more than one arterial bed simultaneously. The aim of this study was to determine the relationship between ultrasound markers of atherosclerosis and multiple arterial disease. DESIGN: We have included 87 currently asymptomatic carotid disease patients (mean age 69 +/- 6 year, 34% females) in this study. Intima media thickness (IMT) and intima media-grey scale median (IM-GSM) were measured in the common carotid artery (CCA), and correlated with previous and/or current atherosclerotic vascular disease in the coronary, carotid and lower extremities. Patients were divided into three groups: (1) asymptomatic, (2) previous symptoms in one arterial territory and (3) previous symptoms in multiple arterial territories. RESULTS: Patients with previous disease in the coronary arteries had higher IMT (p = .034) and lower IM-GSM (p < .001), and those with prior stroke had lower IM-GSM (p = .007). Neither IMT nor IM-GSM was different between patients with and without previous lower extremity vascular disease. IM-GSM was significantly different between groups, it decreased significantly with increasing number of arterial territories affected (37.7 +/- 15.4 vs. 29.3 +/- 16.4 vs. 20.7 +/- 12.9) p < .001, for asymptomatic, symptoms in one and in multiple arterial systems, respectively. Conventional IMT was not significantly different between groups p = .49. CONCLUSION: Carotid IMT was higher and IM-GSM lower in patients with symptomatic nearby arterial territories but not in those with peripheral disease. In contrast to conventional IMT, IM-GSM can differentiate between numbers of arterial territories affected by atherosclerosis, suggesting that it is a better surrogate for monitoring multiple arterial territory disease. PMID- 29402148 TI - Urinary tract infection during pregnancy: current concepts on a common multifaceted problem. AB - Urinary tract infections (UTIs) are the most common bacterial infection in pregnancy, increasing the risk of maternal and neonatal morbidity and mortality. Urinary tract infections may present as asymptomatic bacteriuria, acute cystitis or pyelonephritis. Escherichia coli is the most common pathogen associated with both symptomatic and asymptomatic bacteriuria. If asymptomatic bacteriuria is untreated, up to 30% of mothers develop acute pyelonephritis, with an increased risk of multiple maternal and neonatal complications, such as preeclampsia, preterm birth, intrauterine growth restriction and low birth weight. Urinary tract infection is a common, but preventable cause of pregnancy complications, thus urinary tests, such as urine culture or new technologies such as high throughput DNA sequence-based analyses, should be used in order to improve antenatal screening of pregnant women. PMID- 29402149 TI - Ex vivo comparison between thyroid-dedicated bipolar and monopolar radiofrequency electrodes. AB - PURPOSE: This study evaluated the characteristics of a thyroid-dedicated bipolar RF electrode (BRFE) and compared its ablation performance with that of monopolar RF electrodes (MRFEs) in normal bovine liver blocks. METHODS: BRFE was tested on 60 bovine liver blocks with six different time-power combinations, applying 20, 30 and 40 W for 60 and 120 s. Subsequently, BRFE and MRFEs with 0.5-, 0.7- and 1 cm active tips were applied on 160 bovine liver blocks, creating 16 time electrode combinations (10, 30, 60 and 120 s). The ablation characteristics, RF efficacy and true RF efficacy of each electrode group were then evaluated and compared. True RF efficacy was defined as the total ablation volume created within the total time during which valid RF current was generated. RESULTS: The true RF efficacy of BRFE with 30 W at 60 s was significantly higher than that of BRFE with 20 W and 40 W during the preliminary experiment (p = 0.011). BRFE showed larger vertical and transverse diameters (DT1, DT2) than MRFE with a 0.5 cm active tip (all p values < 0.001, except 10 s). By contrast, MRFE with a 0.7 cm active tip created a larger DT1, DT2, volume, efficacy and true efficacy than BRFE (maximum p value = 0.011). The shape ratio of BRFE was significantly higher than that of MRFEs with 0.5-cm and 0.7-cm tips (all p < 0.001). CONCLUSIONS: Application of BRFE with 30 W could achieve a median ablation volumes and efficacy between that of MRFEs with 0.5-cm and 0.7-cm active tips and created a more ellipsoid-shaped ablation zone. PMID- 29402150 TI - In vivo monitoring of microwave ablation in a porcine model using ultrasonic differential attenuation coefficient intercept imaging. AB - In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Deltaalpha0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Deltaalpha0 is estimated by subtracting an initial value of Deltaalpha0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Deltaalpha0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Deltaalpha0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Deltaalpha0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Deltaalpha0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA. PMID- 29402151 TI - Prolonged Elevated Heart Rate and 90-Day Survival in Acutely Ill Patients: Data From the MIMIC-III Database. AB - PURPOSE: We sought to evaluate the association of prolonged elevated heart rate (peHR) with survival in acutely ill patients. METHODS: We used a large observational intensive care unit (ICU) database (Multiparameter Intelligent Monitoring in Intensive Care III [MIMIC-III]), where frequent heart rate measurements were available. The peHR was defined as a heart rate >100 beats/min in 11 of 12 consecutive hours. The outcome was survival status at 90 days. We collected heart rates, disease severity (simplified acute physiology scores [SAPS II]), comorbidities (Charlson scores), and International Classification of Diseases (ICD) diagnosis information in 31 513 patients from the MIMIC-III ICU database. Propensity score (PS) methods followed by inverse probability weighting based on the PS was used to balance the 2 groups (the presence/absence of peHR). Multivariable weighted logistic regression was used to assess for association of peHR with the outcome survival at 90 days adjusting for additional covariates. RESULTS: The mean age was 64 years, and the most frequent main disease category was circulatory disease (41%). The mean SAPS II score was 35, and the mean Charlson comorbidity score was 2.3. Overall survival of the cohort at 90 days was 82%. Adjusted logistic regression showed a significantly increased risk of death within 90 days in patients with an episode of peHR ( P < .001; odds ratio for death 1.79; confidence interval, 1.69-1.88). This finding was independent of median heart rate. CONCLUSION: We found a significant association of peHR with decreased survival in a large and heterogenous cohort of ICU patients. PMID- 29402153 TI - Psychological factors influencing choice of prenatal diagnosis in Chinese multiparous women with advanced maternal age. AB - OBJECTIVES: To investigate the psychological predictors in Chinese multiparous pregnant women of advanced maternal age (AMA) for choosing aneuploidy screening or diagnostic testing. METHODS: A total of 84 pregnant women of AMA were consecutively enrolled from Renming Hospital, Wuhan University. All participants completed three questionnaires: Zung Self-Rating Anxiety Scale (SAS), Zung Self Rating Depression Scale (SDS), and Pregnancy Stress Rating Scale (PSRS). Demographic information and the choice of noninvasive prenatal testing (NIPT) versus invasive prenatal diagnosis (PND) were also collected. RESULTS: Thirty seven chose to have invasive PND, and 47 chose NIPT. Choosing invasive PND, as opposed to NIPT, was associated with lower educational background (chi2 = -2.269, p = .023), higher SAS scores (47.62 +/- 7.96 versus 44.21 +/- 6.10, p = .029), and higher SDS scores (50.41 +/- 9.80 versus 45.96 +/- 11.05, p = .058). Logistic regression analysis further showed that the decisive predictors for invasive PND are SAS (OR =1.106, p = .008) scores, scores of factor 3 in PSRS and the stress from changes of shape and motility (OR =0.471, p = .038). Subgroup analysis showed that women with previous negative pregnancy experience had higher scores in factor 2-stress (guarantee of maternal-fetal safety: 1.96 +/- 0.63 versus 2.49 +/- 0.65, p = .004) and total PSRS scores (1.60 +/- 0.4 versus 1.83 +/- 0.31, p = .044) than those without. Additionally, unemployment post pregnancy was associated with marginally significant higher PSRS scores (p = .083). CONCLUSIONS: The decision for invasive PND might be swayed by anxiety and attenuated by pregnancy stress originating from worry about changes in fetal shape and motility (measured by SAS and factor 3 score of PSRS, respectively). PMID- 29402152 TI - A signal detection-item response theory model for evaluating neuropsychological measures. AB - INTRODUCTION: Models from signal detection theory are commonly used to score neuropsychological test data, especially tests of recognition memory. Here we show that certain item response theory models can be formulated as signal detection theory models, thus linking two complementary but distinct methodologies. We then use the approach to evaluate the validity (construct representation) of commonly used research measures, demonstrate the impact of conditional error on neuropsychological outcomes, and evaluate measurement bias. METHOD: Signal detection-item response theory (SD-IRT) models were fitted to recognition memory data for words, faces, and objects. The sample consisted of U.S. Infantry Marines and Navy Corpsmen participating in the Marine Resiliency Study. Data comprised item responses to the Penn Face Memory Test (PFMT; N = 1,338), Penn Word Memory Test (PWMT; N = 1,331), and Visual Object Learning Test (VOLT; N = 1,249), and self-report of past head injury with loss of consciousness. RESULTS: SD-IRT models adequately fitted recognition memory item data across all modalities. Error varied systematically with ability estimates, and distributions of residuals from the regression of memory discrimination onto self-report of past head injury were positively skewed towards regions of larger measurement error. Analyses of differential item functioning revealed little evidence of systematic bias by level of education. CONCLUSIONS: SD-IRT models benefit from the measurement rigor of item response theory-which permits the modeling of item difficulty and examinee ability-and from signal detection theory which provides an interpretive framework encompassing the experimentally validated constructs of memory discrimination and response bias. We used this approach to validate the construct representation of commonly used research measures and to demonstrate how nonoptimized item parameters can lead to erroneous conclusions when interpreting neuropsychological test data. Future work might include the development of computerized adaptive tests and integration with mixture and random-effects models. PMID- 29402154 TI - Unfamiliar Face Matching With Frontal and Profile Views. AB - Research has systematically examined how laboratory participants and real-world practitioners decide whether two face photographs show the same person or not using frontal images. In contrast, research has not examined face matching using profile images. In Experiment 1, we ask whether matching unfamiliar faces is easier with frontal compared with profile views. Participants completed the original, frontal version of the Glasgow Face Matching Test, and also an adapted version where all face pairs were presented in profile. There was no difference in performance across the two tasks, suggesting that both views were similarly useful for face matching. Experiments 2 and 3 examined whether matching unfamiliar faces is improved when both frontal and profile views are provided. We compared face matching accuracy when both a frontal and a profile image of each face were presented, with accuracy using each view alone. Surprisingly, we found no benefit when both views were presented together in either experiment. Overall, these results suggest that either frontal or profile views provide substantially overlapping information regarding identity or participants are unable to utilise both sources of information when making decisions. Each of these conclusions has important implications for face matching research and real-world identification development. PMID- 29402155 TI - Duck Eats Rabbit: Exactly Which Type of Relational Phrase Can Disambiguate the Perception of Identical Side by Side Ambiguous Figures? AB - Many individuals cannot at first see two ambiguous figures as different interpretations simultaneously, even with effort. Here in a large sample replication, we find that the phrase "duck eats rabbit" allows those who could not see a duck and rabbit side by side to do so. In a second experiment, we show that a relational phrase "next to" that does not disambiguate the spatial position interpretation does not similarly allow the duck to be seen next to the rabbit, supporting the proposal that top-down semantic-framing can influence perception of ambiguous figures. PMID- 29402156 TI - Donor Body Mass Index as a Risk Factor for Delayed Onset of Graft Function. AB - Delayed graft function continues to pose a significant challenge to clinicians in the context of kidney transplantation. The objective of this retrospective, 5 year analysis is to identify the parameters of beating heart donors and those of recipients that affect the delayed development of graft function. The monitored group was composed of 152 beating heart donors and 179 recipients. Delayed graft function was identified in 32 (17%) patients. The predictor for development of delayed graft function was the body mass index of the donor (odds ratio: 1.1473; 95% confidence interval [CI]: 1.0017-1.3140; P = .0472), and the independent risk factors were donor body mass index 30 to 34.9 kg/m2 (hazard ratio [HR]: 6.0215; 95% CI: 1.4188-25.556; P = .0149), donor body mass index >=35 kg/m2 (HR: 13.5484; 95% CI: 1.4575-125.938; P = .0220), and abuse of alcohol in the donor's history (HR: 1.779; 95% CI: 1.0679-2.964; P = .0270). PMID- 29402157 TI - Alternative approaches to surgical hemostasis in patients with morbidly adherent placenta undergoing fertility-sparing surgery. AB - AIM: To evaluate the efficacy of different methods of surgical hemostasis, including the ligation of internal iliac arteries (IIA), temporary occlusion of the common iliac artery (CIA) and combined compression hemostasis, during cesarean section in patients with morbidly adherent placenta (MAP). MATERIALS AND METHODS: The study included 54 patients with MAP. All patients underwent cesarean section with application of surgical hemostasis techniques. In Group 1 (n = 15), ligation of IIA was performed, in Group 2 (n = 18) extravasal temporary occlusion of CIA, and in Group 3 (n = 21) combined compression hemostasis was applied. The latter technique included placement of bilateral tourniquets on the upper uterine pedicles and on the cervicoisthmic segment, and controlled Zhukovsky balloon tamponade of the uterus, with subsequent resection of the uterine wall with abnormal placental invasion, evacuation of placenta from the uterine cavity and closure of the uterine wall defect with a double suture. The studied outcomes were total blood loss, duration of surgery, the hemoglobin level alteration, hysterectomy rate, and length of postoperative hospital stay. RESULTS: Total blood loss in Group 1 was 2440 +/- 1215 ml, in Group 2 - 2186 +/- 1353 ml, and in Group 3 - 1295 +/- 520.3 ml (p = .0045). In Group 3, the lowest number of cases with blood loss >2000 ml was observed [8 (53.3%) versus 9 (50.0%) and 2 (9.5%), respectively; p = .0411]. The duration of surgery, the hemoglobin level alteration, hysterectomy rate, and length of hospital stay after delivery did not differ significantly between the groups. CONCLUSIONS: All surgical techniques used in the study were effective to decrease the blood loss during cesarean section in patients with MAP; however, the combined compression hemostasis showed the highest efficacy. PMID- 29402158 TI - Obstetric outcomes and placental findings in gestational diabetes patients according to maternal prepregnancy weight and weight gain. AB - OBJECTIVE: We assessed clinical outcomes and placental pathology among pregnancies complicated with gestational diabetes mellitus (GDM) according to their pregestational body mass index (BMI) and weight gain during pregnancy. STUDY DESIGN: Pregnancy outcome and placental pathological reports of all GDM deliveries, during 2009-2015, were reviewed. We compared women with pregestational BMI > 30 and or gestational weight gain >20 kg (high-BMI group), and women with pregestational BMI < 30 and weight gain less than 20 kg (normal BMI group). RESULTS: Out of the 429 women with GDM, 221 (51.5%) were in the high BMI group and 208 (48.3%) were in the normal BMI group. As compared to the normal BMI group, the high-BMI group displayed a higher rate of GDMA2 41.6 versus 30.2%, p = .01, higher birth weight, 3475 +/- 508 g versus 3242 +/- 503 g, p < .001, more large for gestational age neonates, 33.1 versus 13.9%, p < .001, and a trend for more cesarean deliveries (CD), 49.3 versus 40.8%, p = .07, respectively. By logistic regression analysis, past CD and high BMI were independently associated with CD, while GDM type and birth weight were nonsignificant. Pathological reports were available for 143 of these patients. Placental weight was increased among the high-BMI group, but did not retain significance after adjustment for birth weight, and GDM type. No differences were demonstrated in other placental histological findings. CONCLUSIONS: GDM pregnancies accompanied by increased weight gain or elevated pregestational BMI are associated with adverse obstetric outcomes, despite similar placental findings. Patient should be advised accordingly, as gestational weight gain may determine delivery mode. PMID- 29402159 TI - Death Is Not the End: A Register-Based Study of the Effect of Parental Death on Adult Children's Childbearing Behavior in Sweden. AB - Macro-level studies have shown that rapid increases in mortality can affect fertility rates. Parental death has also been linked to negative psychological and physical outcomes, reduced relationship quality, and making bereaved children attach more importance to their families. No prior study has examined whether parental death influences adult children's fertility at the microlevel. This study applies event history techniques to Swedish multigeneration registers listing 1.5 million individuals with micro data on mortality and fertility to investigate short-term (first birth risk) and long-term (childlessness at age 45) effects of parental death on adult children's fertility. The principal finding is that parental death during reproductive age affects children's fertility and this effect is mainly short term. The effects differ to some degree between men and women and depend on the stage of the life course in which the bereavement occurs. Younger individuals experiencing a parental death have a significantly higher first birth risk after the parental death compared with peers who did not experience a parental death. Individuals older than 23 who experience a parental death have no or lower first birth risk after the parental death compared with baseline. Men, compared with women, are more likely to end childless if they experience a parental death. PMID- 29402160 TI - Medically Timed Death as an Enactment of Good Death: An Ethnographic Study of Three European Intensive Care Units. AB - The article is based on ethnographic observation and semistructured interviews with personnel in three European adult intensive care units. Intensive care is a domain of contemporary biomedicine centered on invasive and intense efforts to save lives in acute, critical conditions. It echoes our culture's values of longevity. Nevertheless, mortality rates are elevated. Many deaths follow from nontreatment decisions. Medicalized dying in technological medical settings are often presented as unnatural, impersonal, and undesirable ways of dying. How does this affect the way in which death is experienced by intensive care professionals? What might the enactment of dying in intensive care reveal about our cultural values of good and bad dying? PMID- 29402161 TI - The relationship between Type D personality and physical health complaints is mediated by perceived stress and anxiety but not diurnal cortisol secretion. AB - Type D personality has been associated with minor health complaints in the general population and dysregulation of basal cortisol secretion in coronary patients. The aims of the present study were to investigate (i) whether there is an association between Type D personality and basal cortisol secretion in the general population, and (ii) whether subjective measures of stress and anxiety, as well as indices of basal cortisol secretion, mediate the relationship between Type D personality and self-reported physical symptoms in this group. Self-report measures of stress, trait anxiety and physical symptoms were provided by 101 individuals aged 18-45 years. Saliva samples were also provided over two consecutive "typical" days, to enable indices of the cortisol awakening response and diurnal cortisol profile to be determined. There was a significant relationship between Type D personality and self-reported physical symptoms, which was fully mediated by subjective stress and anxiety. However, there were no significant relationships between Type D personality and the basal cortisol indices. These findings suggest that the association between Type D personality and minor health complaints in the general population can be explained by feelings of stress and anxiety, but a precise biological mechanism for this link is yet to be elucidated. PMID- 29402162 TI - Effects of a proposed quality improvement process in the proportion of the reported ultrasound findings unsupported by stored images. AB - OBJECTIVES: To investigate the proportion of documented ultrasound findings that were unsupported by stored ultrasound images in the obstetric ultrasound unit, before and after the implementation of a quality improvement process consisting of a checklist and feedback. METHODS: A quality improvement process was created involving utilization of a checklist and feedback from physician to sonographer. The feedback was based on findings of the physician's review of the report and images using a check list. To assess the impact of this process, two groups were compared. Group 1 consisted of 58 ultrasound reports created prior to initiation of the process. Group 2 included 65 ultrasound reports created after process implementation. Each chart was reviewed by a physician and a sonographer. Findings considered unsupported by stored images by both reviewers were used for analysis, and the proportion of unsupported findings was compared between the two groups. Results are expressed as mean +/- standard error. A p value of < .05 was used to determine statistical significance. RESULTS: Univariate analysis of baseline characteristics and potential confounders showed no statistically significant difference between the groups. The mean proportion of unsupported findings in Group 1 was 5.1 +/- 0.87, with Group 2 having a significantly lower proportion (2.6 +/- 0.62) (p value = .018). CONCLUSIONS: Results suggest a significant decrease in the proportion of unsupported findings in ultrasound reports after quality improvement process implementation. Thus, we present a simple yet effective quality improvement process to reduce unsupported ultrasound findings. PMID- 29402163 TI - Do Persian Native Speakers Prosodically Mark Wh-in-situ Questions? AB - It has been shown that prosody contributes to the contrast between declarativity and interrogativity, notably in interrogative utterances lacking lexico-syntactic features of interrogativity. Accordingly, it may be proposed that prosody plays a role in marking wh-in-situ questions in which the interrogativity feature (the wh phrase) does not move to sentence-initial position, as, for example, in Persian. This paper examines whether prosody distinguishes Persian wh-in-situ questions from declaratives in the absence of the interrogativity feature in the sentence initial position. To answer this question, a production experiment was designed in which wh-questions and declaratives were elicited from Persian native speakers. On the basis of the results of previous studies, we hypothesize that prosodic features mark wh-in-situ questions as opposed to declaratives at both the local (pre- and post-wh part) and global level (complete sentence). The results of the current study confirm our hypothesis that prosodic correlates mark the pre-wh part as well as the complete sentence in wh-in-situ questions. The results support theoretical concepts such as the frequency code, the universal dichotomous association between relaxation and declarativity on the one hand and tension and interrogativity on the other, the relation between prosody and pragmatics, and the relation between prosody and encoding and decoding of sentence type. PMID- 29402164 TI - Shhh... I Need Quiet! Children's Understanding of American, British, and Japanese accented English Speakers. AB - Children's ability to understand speakers with a wide range of dialects and accents is essential for efficient language development and communication in a global society. Here, the impact of regional dialect and foreign-accent variability on children's speech understanding was evaluated in both quiet and noisy conditions. Five- to seven-year-old children ( n = 90) and adults ( n = 96) repeated sentences produced by three speakers with different accents-American English, British English, and Japanese-accented English-in quiet or noisy conditions. Adults had no difficulty understanding any speaker in quiet conditions. Their performance declined for the nonnative speaker with a moderate amount of noise; their performance only substantially declined for the British English speaker (i.e., below 93% correct) when their understanding of the American English speaker was also impeded. In contrast, although children showed accurate word recognition for the American and British English speakers in quiet conditions, they had difficulty understanding the nonnative speaker even under ideal listening conditions. With a moderate amount of noise, their perception of British English speech declined substantially and their ability to understand the nonnative speaker was particularly poor. These results suggest that although school-aged children can understand unfamiliar native dialects under ideal listening conditions, their ability to recognize words in these dialects may be highly susceptible to the influence of environmental degradation. Fully adult like word identification for speakers with unfamiliar accents and dialects may exhibit a protracted developmental trajectory. PMID- 29402165 TI - A Deterioration in Hearing Is Associated With Functional and Cognitive Impairments, Difficulty With Communication, and Greater Health Instability. AB - OBJECTIVES: To examine the relationship between hearing deterioration and several health-related outcomes among home care clients in Ontario. DESIGN: Longitudinal analysis was completed for clients with at least two comprehensive assessments. Hearing status, based on a single item, ranged from zero (no impairment) to three (highly impaired). Hearing deterioration was defined as at least a 1-point decline between subsequent assessments. RESULTS: Seven percent experienced a 1 point deterioration in hearing and roughly 1% had a 2/3-point decline. After adjusting for other covariates, increasing age (odds ratio = 1.94; 95% confidence intervals [CIs] = [1.45, 2.61]) and a diagnosis of Alzheimer's disease (1.37; CI = [1.04, 1.80]) and other dementias (1.32; CI = [1.07, 1.63]) increased the risk of a 2/3-point deterioration. CONCLUSION: These findings can assist home care professionals and policy makers in creating and refining interventions to meet the needs of older adults with hearing difficulties. PMID- 29402166 TI - In-home contextual reality: a qualitative analysis using the Multiple Errands Test Home Version (MET-Home). AB - Adults with stroke frequently experience executive dysfunction. Despite the range of assessments that examine the effects of executive dysfunction on daily tasks, there remains a paucity of literature that examines the influence of the environment on performance in the community. The MET-Home is an ecologically valid assessment for examining post-stroke executive dysfunction in the home environment. This qualitative study explores the relationship between the environment and MET-Home performance among home-dwelling adults with stroke and matched controls. Using a descriptive qualitative approach, we analysed video, interview, and observation notes from a MET-Home validation study. An overarching theme of interplay between everyday task performance and the home environment produced further themes: naturalistically emerging supports and barriers and environment as strategy. Within naturalistically emerging supports and barriers, five contextual sub-themes were discovered: physical environment, social environment, temporal context, virtual context, and personal context. Within environment as strategy, we identified four sub-themes: reducing distractions, using everyday technologies, planning in context, and seeking social support. These findings extend the conceptualisation of how we evaluate executive dysfunction in the context of the community to also consider the inherent influence of the environment. PMID- 29402167 TI - Differential Adaptations of the Musculoskeletal System after Spinal Cord Contusion and Transection in Rats. AB - Spinal cord injury (SCI) causes impaired neuronal function with associated deficits in the musculoskeletal system, which can lead to permanent disability. Here, the impact of SCI on in vivo musculoskeletal adaptation was determined by studying deficits in locomotor function and analyzing changes that occur in the muscle and bone compartments within the rat hindlimb after contusion or transection SCI. Analyses of locomotor patterns, as assessed via the Basso, Beattie, and Bresnahan (BBB) rating scale, revealed that transection animals showed significant deficits, while the contusion group had moderate deficits, compared with naive groups. Muscle myofiber cross-sectional areas (CSA) of both the soleus and tibialis anterior muscles were significantly decreased three months after contusion SCI. Such decreases in CSA were even more dramatic in the transection SCI group, suggesting a dependence on muscle activity, which is further validated by the correlation analyses between BBB score and myofiber CSA. Bone compartment analyses, however, revealed that transection animals showed the most significant deficits, while contusion animals showed no significant differences in the trabecular bone content within the proximal tibia compartment. In general, values of bone volume per total bone volume (BV/TV) were similar across the SCI groups. Significant decreases were observed, however, in the transection animals for bone mineral content, bone mineral density, and three dimensional trabecular structure parameters (trabecular number, thickness, and spacing) compared with the naive and contusion groups. Together, these findings suggest an altered musculoskeletal system can be correlated directly to motor dysfunctions seen after SCI. PMID- 29402168 TI - Could stool collection devices help increase uptake in bowel cancer screening programmes? AB - OBJECTIVE: To understand the usage and acceptability of a faecal collection device amongst participants in the National Health Service Bowel Cancer Screening Programme, with the aim of influencing future uptake. SETTING: Participants completing faecal occult blood test retests as part of the routine Bowel Cancer Screening Programme in Eastern England. METHODS: A faecal collection device and questionnaire were sent to all potential retest participants during a one-month period to collect information on prior stool collection methods and ease of use and usefulness of the enclosed faecal collection device. RESULTS: Out of 1087 participants invited, 679 (62.5%) returned their questionnaire. Of these, 429 (63.2%) trialled the faecal collection device at least once, 163 (38.4%) found the device made collecting their sample easier than previously, 189 (44.6%) found it made collection more difficult and 72 (17.0%) said it made no difference. Similar numbers reported finding that the faecal collection device made collecting the sample more pleasant (130, 31.5%), less pleasant (103, 25.0%) and no different (179, 43.4%) compared with previous collection without a faecal collection device. CONCLUSION: Although a small proportion of participants found the faecal collection device helpful, a considerable majority did not or did not use it at all. Offering faecal collection devices is unlikely to produce a substantial increase in bowel cancer screening uptake. PMID- 29402169 TI - Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure. AB - Purine nucleotides transduce cell membrane receptor responses and modulate ion channel activity. This is accomplished through conformational change in the structure of nucleotides and cell membrane associated proteins. The aim of this study is to enhance our understanding of nucleotide dependence in regard to signal transduction events, drug action and pharmacological promiscuity. Nucleotides and ligand structures regulating Galpha protein subunits, voltage- and ligand-gated ion channels are investigated for molecular similarity using a computational program. Results differentiate agonist and antagonist structures, identify molecular similarity within nucleotide and ligand structures and demonstrate the potential of ligands to regulate nucleotide conformational change. Relative molecular similarity within nucleotides and the ligands of the major receptor classes provides insight into mechanisms of receptor and ion channel regulation. The nucleotide template model has some merit as an initial screening tool in the study and comparison of drug and hormone structures. PMID- 29402170 TI - Residual limb fluid volume change and volume accommodation: Relationships to activity and self-report outcomes in people with trans-tibial amputation. AB - BACKGROUND: Fluctuations in limb volume degrade prosthesis fit and require users to accommodate changes using management strategies, such as donning and doffing prosthetic socks. OBJECTIVES: To examine how activities and self-report outcomes relate to daily changes in residual limb fluid volume and volume accommodation. STUDY DESIGN: Standardized, two-part laboratory protocol with an interim observational period. METHODS: Participants were classified as "accommodators" or "non-accommodators," based on self-report prosthetic sock use. Participants' residual limb fluid volume change was measured using a custom bioimpedance analyzer and a standardized in-laboratory activity protocol. Self-report health outcomes were assessed with the Socket Comfort Score and Prosthesis Evaluation Questionnaire. Activity was monitored while participants left the laboratory for at least 3 h. They then returned to repeat the bioimpedance test protocol. RESULTS: Twenty-nine people were enrolled. Morning-to-afternoon percent limb fluid volume change per hour was not strongly correlated to percent time weight bearing or to self-report outcomes. As a group, non-accommodators ( n = 15) spent more time with their prosthesis doffed and reported better outcomes than accommodators. CONCLUSION: Factors other than time weight-bearing may contribute to morning-to-afternoon limb fluid volume changes and reported satisfaction with the prosthesis among trans-tibial prosthesis users. Temporary doffing may be a more effective and satisfying accommodation method than sock addition. Clinical relevance Practitioners should be mindful that daily limb fluid volume change and prosthesis satisfaction are not dictated exclusively by activity. Temporarily doffing the prosthesis may slow daily limb fluid volume loss and should be investigated as an alternative strategy to sock addition. PMID- 29402171 TI - Three-dimensional analysis of deformities of the radius and ulna in congenital proximal radioulnar synostosis. AB - We reconstructed three-dimensional images of radius and ulna in 38 forearms of 25 patients with congenital proximal radioulnar synostosis from their computed tomographic studies. We also analysed correlations between the deformities of radius and ulna and degrees of fixed pronation of these forearms. The average ulnar deviation, flexion and internal rotation deformities of the radius were 6 degrees , 3 degrees and 18 degrees , respectively. The average radial deviation, extension and internal rotation deformities of the ulna were 3 degrees , 4 degrees and 30 degrees , respectively. The flexion deformity of the radius and the internal rotation deformity of the radius and ulna were correlated significantly with degree of fixed pronation. We conclude that the patients with congenital proximal radioulnar synostosis have remarkable flexion deformity of the radius and internal rotation deformity of the radius and ulna, which might impede forearm rotation after corrective surgery in the proximal part of the forearm. PMID- 29402172 TI - Teaching of distal radius shortening osteotomy: three-dimensional procedural simulator versus bone procedural simulator. AB - In order to facilitate the learning of distal radius shortening osteotomy by junior surgeons, the main assumption was that using a three-dimensional procedural simulator was better than a bone procedural simulator. After viewing a video, ten junior surgeons performed a distal radius shortening osteotomy: five with a bone procedural simulator (Group 1) and five with a three-dimensional procedural simulator (Group 2). All subsequently performed the same surgery on fresh cadaveric bones. The duration of the procedure, shortening of the radius, and the level of osteotomy were significantly better in Group 2. The three dimensional procedural simulator seems to teach distal radius osteotomy better than a bone model and could be useful in teaching and learning bone surgery of the wrist. PMID- 29402173 TI - Coping strategy and social support modify the association between perceived stress and C-reactive protein: a longitudinal study of healthy men and women. AB - Inconsistent associations have been reported between perceived stress and C reactive protein (CRP), a marker of systemic inflammation. We previously observed a male-specific inverse relationship between perceived stress and CRP in a cross sectional study. In the present study, we examined the longitudinal association between changes in perceived stress and CRP, and further analyzed whether changes in coping strategies and social support modify this association. This study included 8454 participants in both a baseline survey and a follow-up survey 5 years later. Psychosocial measures (i.e. perceived stress, coping strategies, and social support) and CRP concentrations were measured by identical means in both surveys. Consistent with our previous findings, increased perceived stress was significantly associated with lower CRP in men (ptrend = .037), but not in women. Increased "emotional expression," a coping strategy, was also associated with lower CRP in women (ptrend = .024). Furthermore, interactions between perceived stress and a coping strategy (positive reappraisal) or social support on CRP were found in men (pinteraction = .007 and .038, respectively); the above inverse association between stress and CRP was not detected for participants with diminished positive reappraisal or social support. In conclusion, increases in perceived stress during a 5-year period were associated with decreases in CRP among healthy men, and the observed association was possibly modified by coping strategy or social support. PMID- 29402174 TI - Online data to contextualize waterpipe tobacco smoking establishments surrounding large US universities. AB - Waterpipe tobacco smoking has grown in popularity among US college students and is associated with serious health risks. Much of the waterpipe tobacco smoking takes place in establishments such as "hookah bars" or in lounge settings. Web based data platforms such as Yelp have demonstrated utility in locating these establishments but are prone to over- and underestimation. The purpose of this study was to optimize strategies for algorithmically estimating the prevalence of waterpipe tobacco smoking establishments. We conducted searches for potential waterpipe tobacco smoking establishments near highly residential US universities ( N = 41). Of 521 potential establishments, independent coders confirmed 257 as permitting waterpipe tobacco smoking. We compared four strategies for using Yelp metadata to estimate the number of confirmed waterpipe tobacco smoking establishments by location. An accuracy-weighted approach generated estimates that closely matched confirmed data without significant over- or underestimation. The use of algorithms such as these may dramatically improve the feasibility and efficacy of future research linking environmental data and health outcomes. PMID- 29402175 TI - Imprinting Status in Two Human Parthenogenetic Embryonic Stem Cell Lines: Analysis of 63 Imprinted Gene Expression Levels in Undifferentiated and Early Differentiated Stages. AB - Human parthenogenetic embryonic stem cells (hPESCs) represent a source of histocompatible tissues for transplantation and carry two copies of the maternal genome, but lack the paternal genome. In this study, we selected 63 known human imprinted genes to investigate the imprinting status of hPESC. The expression level of these genes, including 27 maternally and 36 paternally imprinted were illustrated in hPESC and human embryonic stem cells (hESCs) derived from fertilized embryo lines. The expression activity changes of these genes were analyzed in undifferentiated and early differentiated hPESC lines. In addition, the methylation status of four differentially methylated regions (DMRs) of the imprinted genes was analyzed in undifferentiated and early differentiated hPESC and hESC lines. As a result, we found that all the maternally imprinted genes were expressed at similar levels in the undifferentiated hPESC lines and the hESC lines, except ZNF264 and ATP10A. Twenty-one analyzed paternal imprinted genes were expressed at the same level in two separated hPESC lines as well as compared with the hESC lines, whereas 15 other paternal imprinted genes were significantly downregulated or inactivated in hPESC lines as compared with the hESC line. During prolonged passage, the expression levels of the majority of imprinted genes remained stable in two hPESC lines. The four DMRs, including PEG3/ZIM2 (DMRs), SNURF/SNRPN DMRs, and KVDMR1 DMRs are highly methylated in the genes of two undifferentiated hPESCs and its embryonic bodies (EBs), whereas the genes of the undifferentiated hESCs and its EBs are half methylated. During the early differentiation stage, the imprinted genes showed the same expression trend and the expression levels of H19, IGF2, SLC22A2, SLC22A3/SLC22A18, and CPA4 were significantly upregulated in both hPESC lines. As conclusion, hPESCs show a substantial degree of epigenetic stability with respect to some imprinted genes. PMID- 29402176 TI - Estimating the frequency of indolent breast cancer in screening trials. AB - Cancer screening can detect cancer that would not have been detected in a patient's lifetime without screening. Standard methods for analyzing screening data do not explicitly account for the possibility that a fraction of tumors may remain latent indefinitely. We extend these methods by representing cancers as a mixture of those that progress to symptoms (progressive) and those that remain latent (indolent). Given sensitivity of the screening test, we derive likelihood expressions to simultaneously estimate (1) the rate of onset of preclinical cancer, (2) the average preclinical duration of progressive cancers, and (3) the fraction of preclinical cancers that are indolent. Simulations demonstrate satisfactory performance of the estimation approach to identify model parameters subject to precise specifications of input parameters and adequate numbers of interval cancers. In application to four breast cancer screening trials, the estimated indolent fraction among preclinical cancers varies between 2% and 35% when assuming 80% test sensitivity and varying specifications for the earliest time that participants could plausibly have developed cancer. We conclude that standard methods for analyzing screening data can be extended to allow some indolent cancers, but accurate estimation depends on correctly specifying key inputs that may be difficult to determine precisely in practice. PMID- 29402178 TI - Social Decision Making in Adolescents and Young Adults: Evidence From the Ultimatum Game and Cognitive Biases. AB - During adolescence and early adulthood, individuals deal with important developmental changes, especially in the context of complex social interactions. Previous studies demonstrated that those changes have a significant impact on the social decision making process, in terms of a progressive increase of intentionality comprehension of others, of the sensitivity to fairness, and of the impermeability to decisional biases. However, neither adolescents nor adults reach the ideal level of maximization and of rationality of the homo economicus proposed by classical economics theory, thus remaining more close to the model of the "bounded rationality" proposed by cognitive psychology. In the present study, we analyzed two aspects of decision making in 110 participants from early adolescence to young adulthood: the sensitivity to fairness and the permeability to decisional biases (Outcome Bias and Hindsight Bias). To address these questions, we adopted a modified version of the Ultimatum Game task, where participants faced fair, unfair, and hyperfair offers from proposers described as generous, selfish, or neutral. We also administered two behavioral tasks testing the influence of the Outcome Bias and of the Hindsight Bias in the evaluation of the decision. Our behavioral results highlighted that the participants are still partially consequentialist, as the decisional process is influenced by a complex balance between the outcome and the psychological description of the proposer. As regards cognitive biases, the Outcome Bias and the Hindsight Bias are present in the whole sample, with no relevant age differences. PMID- 29402177 TI - In Vitro Modeling of Leucine-Rich Repeat Kinase 2 G2019S-Mediated Parkinson's Disease Pathology. AB - Leucine-rich repeat kinase 2 (LRRK2) G2019S (glycine to serine) is the most common mutation associated with sporadic and familial Parkinson's disease (PD) with 80% penetrance by age 70. This mutation is found worldwide, with up to 40% of individuals in the North African Arab population carrying the mutation. Induced pluripotent stem cells derived from fibroblasts of patients carrying the LRRK2 G2019S mutation have been a critical source of cells for generating dopaminergic neurons and studying G2019S-related pathology. These studies have elucidated LRRK2-related mechanisms of mitochondrial dysregulation, increased reactive oxygen species, truncated and simplified neurites, and cell death. These phenotypes are thought to result from the G2019S mutation increasing substrate access and therefore increasing the catalytic rate of the serine/threonine kinase. In this article, we critically review the contributions of in vitro modeling to the current knowledge on LRRK2 G2019S. We also analyze the role of patient-derived cell lines for the identification and validation of therapeutic targets, emphasizing their importance as part of a 3R approach to translational research and personalized medicine. PMID- 29402179 TI - The Moderating Effect of Mental Toughness: Perception of Risk and Belief in the Paranormal. AB - This research demonstrates that higher levels of mental toughness provide cognitive-perceptual processing advantages when evaluating risk. No previous research, however, has examined mental toughness in relation to perception of risk and paranormal belief (a variable associated with distorted perception of causality and elevated levels of perceived risk). Accordingly, the present paper investigated relationships between these factors. A sample of 174 participants completed self-report measures assessing mental toughness, general perception of risk, and paranormal belief. Responses were analyzed via correlations and moderation analyses. Results revealed that mental toughness correlated negatively with perception of risk and paranormal belief, whereas paranormal belief correlated positively with perception of risk. For the moderation effects, simple slopes analyses indicated that high levels of MT and subfactors of commitment and confidence reduced the strength of association between paranormal belief and perceived risk. Therefore, MT potentially acts as a protective factor among individuals who believe in the paranormal, reducing the tendency to perceive elevated levels of risk. PMID- 29402180 TI - The Security Scale as a measure of attachment: meta-analytic evidence of validity. AB - This meta-analysis evaluated the psychometric properties of the Security Scale (SS; k = 57 studies), a measure specifically designed to assess attachment in middle childhood, using several criteria: stability over time, associations with other attachment measures, relations with caregiver sensitivity, and associations with theoretically driven outcomes. The SS demonstrated moderate stability and meaningful associations with other attachment measures and caregiver sensitivity. Furthermore, the SS showed significant associations with developmental correlates of attachment: school adaptation, emotional and peer social competence, self esteem, and behavioral problem. Some effect sizes varied as a function of socioeconomic status (SES; peer social competence and maladjustment) and publication status (emotional competence, peer social competence, and self esteem). The association between the SS and our constructs of interest were, for the most part, independent of geographical location and child gender or age. Overall, findings suggest that the SS is a robust measure of attachment in middle childhood and early adolescence. PMID- 29402181 TI - Home is where the head is: a distributed cognition account of personal health information management in the home among those with chronic illness. AB - Managing chronic illness requires personal health information management (PHIM) to be performed by lay individuals. Paramount to understanding the PHIM process is understanding the sociotechnical system in which it frequently occurs: the home environment. We combined distributed cognition theory and the patient work system model to investigate how characteristics of the home interact with the cognitive work of PHIM. We used a 3D virtual reality CAVE that enabled participants who had been diagnosed with diabetes (N = 20) to describe how they would perform PHIM in the home context. We found that PHIM is distinctly cognitive work, and rarely performed 'in the head'. Rather, features of the physical environment, tasks, people, and tools and technologies present, continuously shape and are shaped by the PHIM process. We suggest that approaches in which the individual (sans context) is considered the relevant unit of analysis overlook the pivotal role of the environment in shaping PHIM. Practitioner Summary: We examined how Personal Health Information Management (PHIM) is performed in the homes of diabetic patients. We found that approaches to studying cognition that focus on the individual, to the exclusion of their context, overlook the pivotal role of environmental, social, and technological features in shaping PHIM. PMID- 29402183 TI - Temporal Trends in the Presentation, Treatment, and Outcome of Medullary Thyroid Carcinoma: An Israeli Multicenter Study. AB - BACKGROUND: The widespread use of neck sonography in recent years has led to a dramatic increase in the detection of thyroid cancer, accompanied by changes in the clinicopathologic features of the disease. However, small papillary carcinomas account for the bulk of this increase, while little is known about temporal changes in medullary thyroid carcinoma (MTC). The aim of this study was to evaluate trends in the presentation, treatment, and outcome of MTC. METHODS: Patients treated for MTC at four medical centers in Israel were divided into three groups by year of diagnosis: 19811995 (period A), 1996-2005 (period B), and 2006-2016 (period C). Clinicopathologic and survival data were collected retrospectively from the medical files and compared between the groups. RESULTS: The cohort included 182 patients (54.9% female) with a mean age of 49.2 +/- 18.7 years: 43 (23.6%) diagnosed in period A, 54 (29.7%) in period B, and 85 (46.7%) in period C. No significant differences were found between the groups in primary tumor size (25.7 +/- 18.9 mm, 26.6 +/- 18 mm, and 23.7 +/- 17.6 mm, respectively), proportion of micro-MTC (30.8%, 20.0%, and 25.3%, respectively), or TNM staging. Age at diagnosis significantly increased over time (38.7 +/- 17.2 years, 51.7 +/- 18.4 years, and 53.7 +/- 17.7 years, respectively; p < 0.001), and the rate of familial MTC significantly decreased (41.9%, 14.8%, and 8.2%, respectively; p = 0.002). Although the implementation of cervical lymph node dissection increased (62.1%, 78.4%, and 85%, respectively; p = 0.01), detection of metastatic lymph nodes decreased from 88.9% in period A to 65.0% in periods B and C (p = 0.06). There was no difference between the groups in disease-specific survival or disease-free state at one year from diagnosis (37.5%, 43.1%, and 50%, respectively) and last follow-up (27%, 41.2%, and 48%, respectively). Similar findings on MTC presentation and outcomes were obtained when only patients with non-familial MTC were analyzed. CONCLUSIONS: Unlike differentiated thyroid cancer, most of the presenting features of MTC have not changed over time. The most significant temporal change is a decreased rate of familial MTC. Despite more extensive surgery and the use of new treatment modalities in recent years, significant improvement in disease-related outcomes were not found. PMID- 29402184 TI - Longitudinal analysis of HIV risk behaviour patterns and their predictors among public primary care patients with tuberculosis in South Africa. AB - The goal of this study was to identify various HIV risk behaviours among tuberculosis (TB) patients in a longitudinal study design in South Africa. In 42 public primary healthcare facilities in three districts in three provinces, adult new TB and TB retreatment patients with hazardous or harmful alcohol use were interviewed within 1 month of initiation of anti-TB treatment and were followed up at 6 months. The total sample with a complete 6-month follow-up assessment was 853. At the follow-up assessment, several HIV risk behaviours significantly reduced from baseline to follow-up. In multivariate Generalized Estimating Equations logistic regression analyses, high poverty (odds ratio (OR): 2.68, 95% confidence interval (CI): 1.56-4.62), Posttraumatic Stress Disorder (PTSD) symptoms (OR = 1.55, 95% CI = 1.03-2.36), and sexual partner on antiretroviral therapy (ART) (OR = 1.84, 95% CI = 1.09-3.10) were associated with a higher odds, and excellent/very good perceived health status (OR: 0.61, 95% CI: 0.37-0.98), severe psychological stress (OR = 0.51, 95% CI = 0.34-0.77), and HIV non disclosure to most recent sexual partner (OR = 0.40, 95% CI = 0.25-0.65) were associated with a lower odds of inconsistent condom use. Being HIV positive (OR = 4.18, 95% CI = 2.68-6.53) and excellent/very subjective health status (OR = 2.98, 95% CI = 1.73-5.13) were associated with a higher odds, and having PTSD symptoms (OR = 0.60, 95% CI = 0.36-0.99), being on ART (OR = 0.48, 95% CI = 0.25-0.95), having a sexual partner on ART (OR = 0.41, 95% CI = 0.18-0.96), and HIV status non-disclosure (OR = 0.25, 95% CI = 0.15-0.41) were associated with a lower odds of having sex with an HIV-positive or HIV status unknown person. High poverty index (OR = 1.97, 95% CI = 1.19-3.25) and having a sexual partner on ART (OR = 4.37, 95% CI = 1.82-10.48) were associated with a higher odds, and having a partner with HIV-negative status (OR = 0.29, 95% CI = 0.16-0.51) and inconsistent condom use (OR = 0.39, 95% CI = 0.24-0.64) were associated with a lower odds of HIV status non-disclosure at last sex. The study found that among TB patients with problem drinking over a 6-month TB treatment period, the frequency of some HIV risk behaviours (inconsistent condom use) declined (OR = 0.64, 95% CI = 0.41 0.98), but also persisted at a high-level calling for a strengthening and integration of HIV prevention into TB management. PMID- 29402182 TI - Harnessing centred identity transformation to reduce executive function burden for maintenance of health behaviour change: the Maintain IT model. AB - The inability to produce sustainable lifestyle modifications (e.g., physical activity, healthy diet) remains a major barrier to reducing morbidity and mortality from prevalent, preventable conditions. The objective of this paper is to present a model that builds on and extends foundational theory and research to suggest novel approaches that may help to produce lasting behaviour change. The model aims to integrate factors not typically examined together in order to elucidate potential processes underlying a shift from behaviour initiation to long-term maintenance. The central premise of the Maintain IT model builds on approaches demonstrating that in-tact executive function (EF) is critical for health behaviour initiation, for more complex behaviours beyond initiation, and in unsupportive environments and circumstances, but successful recruitment of EF is effortful and prone to error. Enduring changes are more likely if the underlying cognitive processes can become less effortful (non-conscious, automatic). The Maintain IT model posits that a centred identity transformation is one path leading to less effortful processing and facilitating successful recruitment of EF when necessary over the long term, increasing the sustainability of health behaviour change. A conceptual overview of the literature supporting the utility of this integrative model, future directions, and anticipated challenges are presented. PMID- 29402185 TI - The Common Sense Model of Self-Regulation and Acceptance and Commitment Therapy: integrating strategies to guide interventions for chronic illness. AB - Most health behaviour intervention efforts are adapted from the typical psychological treatment experience and may not take into serious consideration theories specifically developed to describe the process of adaptation to illness. This paper presents a proposal for the combination of a theory about the experience of and adaptation to illness, that is, the Common Sense Model of Self Regulation (CSM), and an efficient psychological theory and therapy, Acceptance and Commitment Therapy (ACT). Past combinations of CSM with cognitive or cognitive-behavioural interventions have focussed almost only on specific aspects of this model (mostly, illness representations and action plans) and left out other, equally important for a fruitful adaptation to illness, recommendations of the model (e.g., regarding the system coherence). Therefore, the development of the proposed combination is to try to match a broad array of the CSM aspects with the principles, intervention techniques and methods employed by ACT, in order to produce a 'double-pillared' intervention strategy that may prove especially effective for promoting patients' adaptation to a chronic condition and enhancing their well-being and health. PMID- 29402186 TI - Equilibrium disorders in workers exposed to mixed solvents. AB - BACKGROUND: Organic solvents cause diseases of the vestibular system. However, little is known regarding the correlation between vestibular damage and exposure to organic solvents below threshold limit values. The best measure by which to evaluate vestibular disorders is static and dynamic posturography. OBJECTIVE: The aim of this study was to evaluate equilibrium disorders via static and dynamic posturography in workers without clear symptoms and exposed to low doses of mixed solvents. METHODS: 200 subjects were selected. Using an Otometrics device (Madsen, Denmark), all subjects endured static and dynamic posturography testing with both eyes-open and eyes-closed conditions. Results were compared with a control group of unexposed individuals. RESULT: Based on the obtained data, the following results can be drawn: (a) subjects exposed to mixtures of solvents show highly significant differences regarding all static and dynamic posturography parameters in comparison to the control group; (b) posturography testing has proven to be a valid means by which to detect subliminal equilibrium disorders in subjects exposed to solvents. CONCLUSION: We can confirm that refinery workers exposed to mixtures of solvents can present subliminal equilibrium disorders. Early diagnosis of the latter is made possible by static and dynamic posturography. PMID- 29402187 TI - Enhanced inpatient rounds, appointment reminders, and patient education improved HIV care engagement following hospital discharge. AB - Human immunodeficiency virus (HIV) care engagement post hospital discharge is often suboptimal. Strategies to improve follow-up are needed. A quasi experimental study was conducted among hospitalized HIV-infected patients between the period from 1 January 2013 to 30 June 2014 (preintervention period) and 1 July 2014 to 31 December 2015 (intervention period). During the intervention period, an HIV care team consisting of an Infectious Diseases physician, a nurse, a pharmacist, a social worker, and an HIV-infected volunteer made daily inpatient rounds. Prior to discharge, patients received a structured HIV education session and an outpatient appointment was scheduled for them with two telephone reminder calls following discharge. There were 240 HIV-infected patients enrolled (120 in each study period), of which the median age was 37 years (interquartile range [IQR] 28-44 years), 58% were male, 39% were newly diagnosed with HIV infection, 46% were hospitalized because of AIDS-related conditions, and the median CD4 cell count on admission was 158 cells/ul (IQR 72-382 cells/ul). The rate of HIV care engagement within 30 days after discharge was significantly higher in the intervention period compared to the preintervention period (95% versus 69%; P < 0.001). Independent factors associated with no care engagement within 30 days were patients in the preintervention period (adjusted odds ratio [aOR] 6.36; P < 0.001) and new diagnosis of HIV infection (aOR 2.77; P = 0.009). The study findings suggest that enhanced inpatient rounds, appointment reminders, and patient education were shown to be associated with improved HIV care engagement after hospital discharge. Patients with a new diagnosis of HIV infection benefit from more intense outreach. ClinicalTrials.gov Identifier: NCT02578654. PMID- 29402188 TI - Middle Childhood Attachment Strategies: validation of an observational measure. AB - The purpose of this study was to assess behavioral manifestations of attachment in middle childhood, and to evaluate their relations with key theoretical correlates. The sample consisted of 87 children (aged 10-12 years) and their mothers. Dyads participated in an 8-min videotaped discussion of a conflict in their relationships, later scored with the Middle Childhood Attachment Strategies Coding System (MCAS) for key features of all child attachment patterns described in previous literature (secure, ambivalent, avoidant, disorganized-disoriented, caregiving/role-confused, hostile/punitive). To assess validity, relations among MCAS dimensions and other measures of attachment, parenting, and psychological adjustment were evaluated. Results provide preliminary evidence for the psychometric properties of the MCAS in that its behaviorally assessed patterns were associated with theoretically relevant constructs, including maternal warmth/acceptance and psychological control, and children's social competence, depression, and behavioral problems. The MCAS opens new grounds for expanding our understanding of attachment and its outcomes in middle childhood. PMID- 29402190 TI - Quantile residual lifetime regression with functional principal component analysis of longitudinal data for dynamic prediction. AB - Optimal therapeutic decisions can be made according to disease prognosis, where the residual lifetime is extensively used because of its straightforward interpretation and formula. To predict the residual lifetime in a dynamic manner, a longitudinal biomarker that is repeatedly measured during the post-baseline follow-up period should be included. In this article, we use functional principal component analysis, a powerful and flexible tool, to handle irregularly measured longitudinal data and extract the dominant features over a specific time interval. To capture the time-dependent trajectory pattern, a series of moving time windows are used to estimate window-specific functional principal component analysis scores, which are then combined with a quantile residual lifetime regression model to facilitate dynamic prediction. Estimation of this regression model can be achieved by solving estimating equations with the help of locating the minimizer of the L1-type function. Simulation studies demonstrate the advantages of our proposed method in both calibration and discrimination under various scenarios. The proposed method is applied to data from patients with chronic myeloid leukemia to illustrate its practicality, where we dynamically predict quantile residual lifetimes with longitudinal expression levels of an oncogene, BCR-ABL. PMID- 29402189 TI - Simplified Footprint-Free Cas9/CRISPR Editing of Cardiac-Associated Genes in Human Pluripotent Stem Cells. AB - Modeling disease with human pluripotent stem cells (hPSCs) is hindered because the impact on cell phenotype from genetic variability between individuals can be greater than from the pathogenic mutation. While "footprint-free" Cas9/CRISPR editing solves this issue, existing approaches are inefficient or lengthy. In this study, a simplified PiggyBac strategy shortened hPSC editing by 2 weeks and required one round of clonal expansion and genotyping rather than two, with similar efficiencies to the longer conventional process. Success was shown across four cardiac-associated loci (ADRB2, GRK5, RYR2, and ACTC1) by genomic cleavage and editing efficiencies of 8%-93% and 8%-67%, respectively, including mono- and/or biallelic events. Pluripotency was retained, as was differentiation into high-purity cardiomyocytes (CMs; 88%-99%). Using the GRK5 isogenic lines as an exemplar, chronic stimulation with the beta-adrenoceptor agonist, isoprenaline, reduced beat rate in hPSC-CMs expressing GRK5-Q41 but not GRK5-L41; this was reversed by the beta-blocker, propranolol. This shortened, footprint-free approach will be useful for mechanistic studies. PMID- 29402191 TI - Post-menopausal bleeding - Is transvaginal ultrasound a useful first-line investigation in tamoxifen users? AB - Objective To evaluate the role of transvaginal ultrasound triage in women with a history of tamoxifen treatment who present with post-menopausal bleeding. Study design A retrospective review was undertaken of patients who presented with symptoms of post-menopausal bleeding and underwent ultrasound triage. Endometrial thickness and ultrasonographic features were then correlated with hysteroscopic and histopathological outcome data. The findings and outcomes for women with a history of tamoxifen use (tamoxifen group) were compared to those who had not taken tamoxifen (non-tamoxifen group). Results A total of 614 women with post menopausal bleeding underwent transvaginal ultrasound triage, of whom 53 had a history of current or previous tamoxifen treatment. An endometrial thickness of >=5 mm or the presence of other abnormal features was used to triage women to further investigation by hysteroscopy and biopsy. Endometrial thickness was significantly greater in the tamoxifen group (11 mm vs. 6 mm). Nearly all of the tamoxifen group were triaged to further investigation (98.1%), compared with significantly fewer in the non-tamoxifen group (68.3%) Overall, the incidence of endometrial pathology was also significantly higher in tamoxifen patients (43.4% vs. 31.7%). Conclusion For women presenting with post-menopausal bleeding, the use of transvaginal ultrasound as a triage tool is rarely helpful in evaluating women who have a history as tamoxifen use, as most will require further investigation with hysteroscopy and biopsy. A post-menopausal bleeding protocol that omits transvaginal ultrasound for women with a history of tamoxifen use may be an appropriate and effective pathway for managing these patients. PMID- 29402192 TI - Performance Measurement and Comparative Transcriptome Analysis Revealed the Efforts on Hybrid Improvement of Qinchuan Cattle. AB - Crossbreeding can provide productive gains through heterosis, however, surveys about the effects of crossbreeding through global transcriptomic sequencing are few. This study revealed that Angus * Qinchuan cattle (AQF) have improved performance characteristics compared to Qinchuan cattle (QCF). We performed RNA seq on the subcutaneous fat tissue of QCF and AQF. More than 42.2 million clean reads were obtained in each sample. We detected 40 and 21 breed-specific highly expressed genes (FPKM > 500) in QCF and AQF, respectively. Furthermore, a total of 353 differentially expressed genes (DEGs, |log2 ratio| >= 1 and Probability >= 0.8) were found between these two groups, of which 227 genes were upregulated in AQF and 126 genes were upregulated in QCF. Functional enrichment analyses showed that breed-specific highly expressed genes and DEGs were closely related to terms such as development in AQF, and adaption or immune in QCF. In addition, we also identified the novel transcript units, alternative splicing events, single nucleotide polymorphisms and Indels. Our results revealed differences in inherent characteristics and genetic differences when comparing QCF with AQF. PMID- 29402193 TI - Can We Really Discuss About RRT Starting Time Before We Have a Recovery Biomarker? PMID- 29402194 TI - "Can We Discuss About RRT Starting Time Before We Have a Recovery Biomarker"-Yes, We Can. PMID- 29402197 TI - Hysteroscopic Corrections for Complete Septate and T-Shaped Uteri Have Similar Surgical and Reproductive Outcome. AB - AIM:: To compare the surgical results and reproductive performances of patients with ESHRE/ESGE (European Society for Human Reproduction and Embryology/European Society for Gynaecologic Endoscopy) class U1a and U2b uterine anomalies after hysteroscopic correction. METHODS:: A retrospective cohort study was conducted at a university hospital infertility clinic. Ninety-six patients with class U2b (complete septate uterus) and 78 patients with class U1a (T-shaped uterus) uterine anomalies who underwent hysteroscopic correction between January 2009 and December 2015 were recruited. RESULTS:: The operation time was significantly longer in class U2b anomalies (26.5 +/- 5.3 minutes) than class U1a anomalies (22.8 +/- 5.8 minutes; mean difference [95% confidence interval [CI]: 3.6 +/- 0.9 [1.8-5.3]; P < .001). Six out of all complete septate patients and 3 of T-shaped patients were reoperated due to postoperative synechia or to further enlarge the cavity. There were no differences between the groups regarding intraoperative (blood loss and uterine rupture) and postoperative (bleeding and infection) complications. After surgical correction, the term delivery rates increased from 3% to 71% ( P < .001) in class U2b and from 4% to 62.1% ( P < .001) in class U1a. The chance of live birth significantly increased after hysteroscopic correction both in class U2b (odds ratio [OR] 106.1; 95% CI, 29.1-387.1; P < .001) and class U1a (OR 35.7; 95% CI, 11.6-109.9; P < .001). The postoperative reproductive performances of both anomalies were similar. CONCLUSION:: Both types of anomalies seem to have similar severity and prognosis. Patients with both types of anomalies have excellent reproductive outcome after hysteroscopic correction. PMID- 29402196 TI - Peripheral artery disease is associated with frailty in chronic hemodialysis patients. AB - Objectives The clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients. Methods A total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index <0.9. Results Of 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P < 0.0001). Thigh circumferences were also significantly larger in the Non-peripheral artery disease group (41.7 cm vs. 39.7 cm, P = 0.0054). A multivariate logistic regression analysis demonstrated that the factors independently associated with peripheral artery disease were as follows: frailty (odds ratio = 2.06, 95% confidence interval 1.09-3.89) and myocardial infarction (odds ratio = 3.74, 95% confidence interval 2.05-6.83). Conclusions It is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients. PMID- 29402198 TI - The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis. AB - Endometriotic stromal cells synthesize estradiol via the steroidogenic pathway. Nuclear receptor subfamily 5, group A, member 1 (NR5A1) is critical, but alone not sufficient, in activating this cascade that involves at least 5 genes. To evaluate whether another transcription factor is required for the activation of this pathway, we examined whether GATA Binding Protein 6 (GATA6) can transform a normal endometrial stromal cell (NoEM) into an endometriotic-like cell by conferring an estrogen-producing phenotype. We ectopically expressed GATA6 alone or with NR5A1 in NoEM or silenced these transcription factors in endometriotic stromal cells (OSIS) and assessed the messenger RNAs or proteins encoded by the genes in the steroidogenic cascade. Functionally, we assessed the effects of GATA6 expression or silencing on estradiol formation. In OSIS, GATA6 was necessary for catalyzing the conversion of progesterone to androstenedione (CYP17A1; P < .05). In NoEM, ectopic expression of GATA6 was essential for converting pregnenolone to estrogen (HSD3B2, CYP17A1, and CYP19A1; P < .05). However, simultaneous ectopic expression of both GATA6 and NR5A1 was required and sufficient to confer induction of all 5 genes and their encoded proteins that convert cholesterol to estrogen. Functionally, only simultaneous knockdown of GATA6 and NR5A1 blocked estradiol formation in OSIS ( P < .05). The presence of both transcription factors was required and sufficient to transform endometrial stromal cells into endometriotic-like cells that produced estradiol in large quantities ( P < .05). In summary, GATA6 alone is essential but not sufficient for estrogen formation in endometriosis. However, simultaneous addition of GATA6 and NR5A1 to an endometrial stromal cell is sufficient to transform it into an endometriotic-like cell, manifested by the activation of the estradiol biosynthetic cascade. PMID- 29402199 TI - Fertility-Sparing Treatment of Adenomyosis in Patients With Infertility: A Systematic Review of Current Options. AB - Adenomyosis is a benign gynecological disease observed in women in their reproductive age. Recent studies have shown that adenomyosis might be a relevant factor for infertility, either impairing implantation or leading to early miscarriage. However, conservative treatment of infertility related to adenomyosis is still unclear. This study systematically reviews the literature for the reproductive outcomes of the available conservative treatments for patients with adenomyosis-associated infertility. We conducted a search in PubMed/Medline for studies in English published in the last 7 years and included 16 studies. Six studies evaluated surgical treatments of adenomyosis. When considering only spontaneous pregnancies, the overall clinical pregnancy rate was very low (18.2%). However, when using GnRH analogues for 24 weeks after surgery, the pooled spontaneous pregnancy rate was higher (40.7% vs 15.0%; P = .002). No significant difference was observed in the other outcomes. Ten studies evaluated exclusive assisted reproductive techniques for infertility related to adenomyosis and showed that the long stimulation protocol had better outcomes compared to short stimulation protocol in pregnancy rate (43.3% vs 31.8%; P = .0001), live birth (43.0% vs 23.1%; P = .005), and miscarriage (18.5% vs 31.1%; P < .0001). PMID- 29402200 TI - Association Between Genetic Polymorphisms of WNT1 Inducible Signaling Pathway Protein 1 and Uterine Cervical Cancer. AB - To date, no study has investigated the involvement of the single-nucleotide polymorphisms (SNPs) of WNT1 inducible signaling pathway protein 1 (WISP1) in uterine cervical cancer. Therefore, we conducted this study to explore the clinical implications of WISP1 SNPs in cervical cancer. One hundred and fifteen patients with invasive cervical cancer, 95 patients with preinvasive lesions, and 316 normal controls were enrolled. The WISP1 SNPs rs62514004, rs2929973, rs2977530, and rs2977537 were selected, and their genotypic distributions were determined through real-time polymerase chain reaction. Our findings showed that genotypes AG/GG in WISP1 SNP rs2977530 reduced the risk of invasive cervical cancer with AA as a reference; however, these genotypes did not reduce the risk of preinvasive lesions. By contrast, genotype AA in WISP1 SNP rs2977537 elevated the risk of invasive cervical cancer with GG/GA as a reference, but it did not elevate the risk of preinvasive lesions. Moreover, an additional integrated in silico analysis indicated that WISP1 rs2977537 altered the WISP1 expression recorded in the Genotype-Tissue Expression database. In conclusion, genotypes AG/GG in WISP1 SNP rs2977530 reduce the susceptibility of Taiwanese women to invasive cervical cancer, whereas genotype AA in rs2977537 increases the said risk. PMID- 29402201 TI - Similar Characteristics of Endometrial and Endometriotic Epithelial Cells. AB - Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial and acquisition of mesenchymal cell characteristics. Our aim was to assess the epithelial phenotype in the pathogenesis of endometriosis with epithelial and mesenchymal markers. We used 2 structural (keratin-18, -19 [K18, K19]), 1 membrane-associated (mucin-1 [MUC1]), and 2 mesenchymal proteins (vimentin; zinc finger E-box-binding homeobox 1, [ZEB1]) to compare epithelial and mesenchymal characteristics in eutopic endometrium with the 3 endometriotic entities, peritoneal, ovarian, and deep infiltrating endometriosis (DIE). Quantitation showed no differences for K18, K19, and MUC1 between endometrium with and without endometriosis. Also, K18 was not different between endometrium and endometriotic lesions. In contrast, K19 and MUC1 were modestly but significantly decreased in the endometriotic lesions compared to endometrium. However, the maintained expression of epithelial markers in all investigated tissues, regardless of the pathological condition, clearly indicates no loss of the epithelial phenotype. This is further supported by the reduced presence of epithelial vimentin in endometriotic lesions which is in contrast to an increase in stromal vimentin in ectopic endometrium, especially in ovarian endometriosis. The ZEB1 increase in endometriotic lesions, especially in DIE, on the other hand suggests a role of partial EMT in the development of endometriotic lesions, possibly connected with the gain of invasive capabilities or stemness. Taken together, although we found some hints for at least a partial EMT, we did not observe a severe loss of the epithelial cell phenotype. Thus, we propose that EMT is not a main factor in the pathogenesis of endometriosis. PMID- 29402202 TI - Predicting Factors for High-Grade Cervical Dysplasia in Women With Low-Grade Cervical Cytology and Nonvisible Squamocolumnar Junction. AB - OBJECTIVE: To assess the risk of developing high-grade cervical dysplasia among women with low-grade cervical cytology and nonvisible squamocolumnar junction (SCJ) at colposcopic examination. METHODS: Data of consecutive women with low grade intraepithelial lesion(<=LSIL) undergoing colposcopic examination, which was unsatisfactory (due to the lack of the visualization of the entire SCJ), were retrospectively reviewed. The risk of developing high-grade cervical intraepithelial neoplasia (CIN2+) was assessed using Kaplan-Meier and Cox models. RESULTS: Data of 86 women were retrieved. Mean (standard deviation [SD]) age was 36.3 (13.4) years. A total of 71 (82.5%) patients had high-risk human papillomavirus (HR-HPV) at the time of diagnosis. Among the 63 patients undergoing repetition of HPV testing, 15 (24%) and 48 (76%) women had positive and negative tests for HR-HPV at 12 months, respectively. We observed that 5 (33%) of 15 patients with HPV persistence developed CIN2+, while only 1 (2%) patient of 48 patients without HPV persistence developed CIN2+ (odds ratio [OR]: 23.5; 95% confidence interval [CI]: 2.46-223.7; P < .001). The length of HR-HPV persistence correlated with an increased risk of developing CIN2+ ( P < .001; P for trend). High-risk HPV persistence is the only factor predicting for CIN2+ (hazard ratio: 3.19; 95% CI: 1.55-6.57; P = .002). CONCLUSIONS: High-risk HPV persistence predicts the risk of developing CIN2+ in patients with unsatisfactory colposcopic examination. Further studies are warranted in order to implement the use of HPV testing in patients with unsatisfactory colposcopy. PMID- 29402203 TI - Human Umbilical Cord Perivascular Cells and Human Bone Marrow Mesenchymal Stromal Cells Transplanted Intramuscularly Respond to a Distant Source of Inflammation. AB - Intravenously administered mesenchymal stromal cells (MSCs) are rapidly entrapped in the lungs, where they display an anti-inflammatory phenotype. Intramuscular (IM) delivery provides an increased MSC dwell-time, which could result in a sustained modulation of an inflammatory milieu. We studied the therapeutic effects of IM delivered MSCs to treat a distant (contralateral) inflammation, and compared the efficacy of neonatal (umbilical cord) and adult bone marrow MSCs (BMMSCs). Inflammation decreased over 48 h, but neonatal cells showed an earlier response than BMMSCs. Tumor necrosis factor-induced gene-6 (TSG-6) was released at the site of MSC delivery, while neutrophil infiltration was abrogated and inflammation reduced at the contralateral site. MSCs did not distribute to the organs or to the site of inflammation. Thus, IM delivery presents a promising alternative for the treatment of inflammation, and neonatal MSCs may represent a stronger candidate than those derived from adult BM to treat inflammatory diseases. PMID- 29402204 TI - Glomeruloid Microvascular Proliferation, Desmoplasia, and High Proliferative Index as Potential Indicators of High Grade Canine Choroid Plexus Tumors. AB - Choroid plexus tumors (CPT) are intraventricular neoplasms accounting for 10% of all primary central nervous system tumors in dogs. They are frequently classified according to the human WHO classification into choroid plexus papilloma (CPP, grade I), atypical CPP (aCPP, grade II), and choroid plexus carcinoma (CPC, grade III). Histological features observed in canine CPT such as increased vascular density (IVD) and glomeruloid microvascular proliferation (GMVP) are not part of the WHO classification. This multi-centric study aimed to investigate tumor associated vascular hyperplasia in dogs by determining the prevalence of GMVP and IVD in 52 canine CPT and their association with tumor grade. In addition, the expression of angiogenic factors was assessed by immunohistochemistry in 25 tumors to investigate the pathogenesis of tumor-associated vascular hyperplasia. Based on the classical histological hallmarks, this study of 52 CPT identified 22 (42%) CPP (grade I) and 30 of (58%) CPC (grade III). GMVP was more prevalent in CPC (13/30; 43%) than CPP (1/22; 4%), whereas IVD occurred to a similar extent in CPP and CPC. Desmoplasia was more common in CPC (19/30; 63%) than CPP (2/22; 9%), and similarly, the proliferative index (PI) of neoplastic epithelium was significantly higher in CPC (5.14%) than CPP (0.94%). The majority of CPT expressed platelet-derived growth factor (PDGF), PDGFRalpha, PDGFRbeta, and vascular endothelial growth factor (VEGF) irrespective of tumor grade or tumor associated vascular hyperplasia. These results suggest that tumor-associated GMVP, desmoplasia, and PI may serve as histological indicators of malignancy in CPT. PMID- 29402205 TI - Prostatic Lesions in Odontocete Cetaceans. AB - The prostate is the only accessory male genital gland described in cetaceans. Although few studies describe the gross and histologic anatomy of the prostate in cetaceans, there is no information on pathological findings involving this organ. The prostate glands of 45 cetaceans, including 8 different odontocete species ( n = 44) and 1 mysticete, were evaluated. The main pathologic diagnoses were verminous prostatitis, septic prostatitis, viral prostatitis, benign prostatic hyperplasia, and prostatitis of unknown etiology. Verminous prostatitis ( n = 12) was caused by nematodes of the genus Crassicauda, and different presentations were observed. Septic prostatitis, identified in 2 cases, both involved nematode infestation and Clostridium spp coinfection. One case of viral prostatitis was identified and was associated with morbillivirus infection. In prostatitis of unknown cause ( n = 7), varying degrees of prostatic lesions, mostly chronic inflammation, were identified. Impacts at individual levels (eg, localized disease, loss of reproductive capacity) and population levels (eg, decreased reproductive success) are plausible. Our results indicate a high occurrence of prostatic lesions in free-ranging odontocetes. For this reason, the prostate should be routinely inspected and sampled during necropsy of odontocete cetaceans. PMID- 29402206 TI - Validation of Digital Microscopy Compared With Light Microscopy for the Diagnosis of Canine Cutaneous Tumors. AB - Integration of new technologies, such as digital microscopy, into a highly standardized laboratory routine requires the validation of its performance in terms of reliability, specificity, and sensitivity. However, a validation study of digital microscopy is currently lacking in veterinary pathology. The aim of the current study was to validate the usability of digital microscopy in terms of diagnostic accuracy, speed, and confidence for diagnosing and differentiating common canine cutaneous tumor types and to compare it to classical light microscopy. Therefore, 80 histologic sections including 17 different skin tumor types were examined twice as glass slides and twice as digital whole-slide images by 6 pathologists with different levels of experience at 4 time points. Comparison of both methods found digital microscopy to be noninferior for differentiating individual tumor types within the category epithelial and mesenchymal tumors, but diagnostic concordance was slightly lower for differentiating individual round cell tumor types by digital microscopy. In addition, digital microscopy was associated with significantly shorter diagnostic time, but diagnostic confidence was lower and technical quality was considered inferior for whole-slide images compared with glass slides. Of note, diagnostic performance for whole-slide images scanned at 200* magnification was noninferior in diagnostic performance for slides scanned at 400*. In conclusion, digital microscopy differs only minimally from light microscopy in few aspects of diagnostic performance and overall appears adequate for the diagnosis of individual canine cutaneous tumors with minor limitations for differentiating individual round cell tumor types and grading of mast cell tumors. PMID- 29402207 TI - Congenital Hepatic Fibrosis in a Purebred Spanish Horse Foal: Pathology and Genetic Studies on PKHD1 Gene Mutations. AB - A 1-month-old Purebred Spanish Horse (PSH) foal presented with progressive hepatic failure culminating in death. Hepatic lesions were consistent with congenital hepatic fibrosis (CHF). Genetic studies in the PKHD1 gene in the affected foal revealed that it was heterozygous for the 2 previously described single-nucleotide polymorphisms (SNPs) linked to CHF in Swiss Franches-Montagnes (SFM) horses. In addition, 2 novel mutations were detected, the foal being homozygous for one of them and heterozygous for the other. Genetic studies in a healthy PSH population ( n = 35) showed a 3-fold higher genotypic frequency for PKHD1 SNP g.49,630,834G>A and a 5-fold higher genotypic frequency for PKHD1 SNP g.49,597,760A>T compared with those reported for SFM horses. SNPs in the PKHD1 gene in CHF-affected SFM horses might not fully explain the CHF observed in the PSH. Other mutations in the PKHD1 gene could play a more important role in the PSH. PMID- 29402208 TI - Border Disease Virus Infection of Bovine Placentas. AB - Subsequent to a previous study of border disease virus (BDV) horizontal transmission from a persistently BDV-infected calf to 6 seronegative pregnant heifers, the heifers were slaughtered 60 days after exposure to the infected calf, and their fetuses and placentas were examined. Immunohistochemical examination of fetal organs and placenta showed positive labeling of moderate intensity for pestivirus antigen in 3 of 6 heifers. BDV infection in these 3 animals was confirmed by the detection of BDV RNA in different organs using reverse transcription quantitative polymerase chain reaction. In the placenta, the positive cells were visualized mostly on the fetal side. In those 3 heifers that harbored an infected fetus, the placental tissue in the placentome region showed a moderate to severe mononuclear and fibrosing placentitis and, in severe cases, necrotic areas. The inflammatory population was composed predominantly of T and B cells, a substantial number of macrophages, and, to a lesser extent, plasma cells. This is a novel report of placentitis in persistently BDV-infected fetuses from pregnant heifers that became acutely infected by cohousing with a calf persistently infected with BDV, which extends previous reports on bovine viral diarrhea virus-infected and BDV-infected cattle and sheep, respectively. PMID- 29402209 TI - Breeding consequences of flavivirus infection in the collared flycatcher. AB - BACKGROUND: The breeding consequences of virus infections have rarely been studied in avian natural breeding populations. In this paper we investigated the links between humoral immunity following a natural flavivirus infection and reproduction in a wild bird population of collared flycatcher (Ficedula albicollis). We analyzed plasma from 744 birds for antibodies and correlated these results to a number of reproductive components. RESULTS: Nearly one third (27.8%) of the sampled collared flycatchers were found seropositive for flavivirus. Males had significantly more frequently flavivirus antibodies (32.3%) than females (25.1%). Seropositive females differed significantly from seronegative females in four traits: they had earlier lay date, higher body weight, higher survival rate and were older than seronegative females. The females did not differ in clutch size, number of fledged young or number of recruited young. Seropositive males had female partners with earlier lay date, i.e. the males bred earlier and they also produced more fledged young than seronegative males. In contrast, the males did not differ in clutch size, number of recruited young, male weight, age or survival. Interestingly, seropositive males had larger ornament, forehead badge size, than seronegative males. CONCLUSIONS: Collared flycatchers with an antibody response against flavivirus were more successful than birds with no antibody response, for any of the measured life history traits. The positive link between flavivirus antibody presence and life-history trait levels suggest that it is condition dependent in the collared flycatcher. PMID- 29402211 TI - Phylogenomics of a rapid radiation: the Australian rainbow skinks. AB - BACKGROUND: The application of target capture with next-generation sequencing now enables phylogenomic analyses of rapidly radiating clades of species. But such analyses are complicated by extensive incomplete lineage sorting, demanding the use of methods that consider this process explicitly, such as the multispecies coalescent (MSC) model. However, the MSC makes strong assumptions about divergence history and population structure, and when using the full Bayesian implementation, current computational limits mean that relatively few loci and samples can be analysed for even modest sized radiations. We explore these issues through analyses of an extensive (> 1000 loci) dataset for the Australian rainbow skinks. This group consists of 3 genera and 41 described species, which likely diversified rapidly in Australia during the mid-late Miocene to occupy rainforest, woodland, and rocky habitats with corresponding diversity of morphology and breeding colouration. Previous phylogenetic analyses of this group have revealed short inter-nodes and high discordance among loci, limiting the resolution of inferred trees. A further complication is that many species have deep phylogeographic structure - this poses the question of how to sample individuals within species for analyses using the MSC. RESULTS: Phylogenies obtained using concatenation and summary coalescent species tree approaches to the full dataset are well resolved with generally consistent topology, including for previously intractable relationships near the base of the clade. As expected, branch lengths at the tips are substantially overestimated using concatenation. Comparisons of different strategies for sampling haplotypes for full Bayesian MSC analyses (for one clade and using smaller sets of loci) revealed, unexpectedly, that combining haplotypes across divergent phylogeographic lineages yielded consistent species trees. CONCLUSIONS: This study of more than 1000 loci provides a strongly-supported estimate of the phylogeny of the Australian rainbow skinks, which will inform future research on the evolution and taxonomy of this group. Our analyses suggest that species tree estimation with the MSC can be quite robust to violation of the assumption that the individuals representing a taxon are sampled from a panmictic population. PMID- 29402210 TI - Defiant: (DMRs: easy, fast, identification and ANnoTation) identifies differentially Methylated regions from iron-deficient rat hippocampus. AB - BACKGROUND: Identification of differentially methylated regions (DMRs) is the initial step towards the study of DNA methylation-mediated gene regulation. Previous approaches to call DMRs suffer from false prediction, use extreme resources, and/or require library installation and input conversion. RESULTS: We developed a new approach called Defiant to identify DMRs. Employing Weighted Welch Expansion (WWE), Defiant showed superior performance to other predictors in the series of benchmarking tests on artificial and real data. Defiant was subsequently used to investigate DNA methylation changes in iron-deficient rat hippocampus. Defiant identified DMRs close to genes associated with neuronal development and plasticity, which were not identified by its competitor. Importantly, Defiant runs between 5 to 479 times faster than currently available software packages. Also, Defiant accepts 10 different input formats widely used for DNA methylation data. CONCLUSIONS: Defiant effectively identifies DMRs for whole-genome bisulfite sequencing (WGBS), reduced-representation bisulfite sequencing (RRBS), Tet-assisted bisulfite sequencing (TAB-seq), and HpaII tiny fragment enrichment by ligation-mediated PCR-tag (HELP) assays. PMID- 29402212 TI - Bio-SimVerb and Bio-SimLex: wide-coverage evaluation sets of word similarity in biomedicine. AB - BACKGROUND: Word representations support a variety of Natural Language Processing (NLP) tasks. The quality of these representations is typically assessed by comparing the distances in the induced vector spaces against human similarity judgements. Whereas comprehensive evaluation resources have recently been developed for the general domain, similar resources for biomedicine currently suffer from the lack of coverage, both in terms of word types included and with respect to the semantic distinctions. Notably, verbs have been excluded, although they are essential for the interpretation of biomedical language. Further, current resources do not discern between semantic similarity and semantic relatedness, although this has been proven as an important predictor of the usefulness of word representations and their performance in downstream applications. RESULTS: We present two novel comprehensive resources targeting the evaluation of word representations in biomedicine. These resources, Bio-SimVerb and Bio-SimLex, address the previously mentioned problems, and can be used for evaluations of verb and noun representations respectively. In our experiments, we have computed the Pearson's correlation between performances on intrinsic and extrinsic tasks using twelve popular state-of-the-art representation models (e.g. word2vec models). The intrinsic-extrinsic correlations using our datasets are notably higher than with previous intrinsic evaluation benchmarks such as UMNSRS and MayoSRS. In addition, when evaluating representation models for their abilities to capture verb and noun semantics individually, we show a considerable variation between performances across all models. CONCLUSION: Bio-SimVerb and Bio SimLex enable intrinsic evaluation of word representations. This evaluation can serve as a predictor of performance on various downstream tasks in the biomedical domain. The results on Bio-SimVerb and Bio-SimLex using standard word representation models highlight the importance of developing dedicated evaluation resources for NLP in biomedicine for particular word classes (e.g. verbs). These are needed to identify the most accurate methods for learning class-specific representations. Bio-SimVerb and Bio-SimLex are publicly available. PMID- 29402213 TI - xenoGI: reconstructing the history of genomic island insertions in clades of closely related bacteria. AB - BACKGROUND: Genomic islands play an important role in microbial genome evolution, providing a mechanism for strains to adapt to new ecological conditions. A variety of computational methods, both genome-composition based and comparative, have been developed to identify them. Some of these methods are explicitly designed to work in single strains, while others make use of multiple strains. In general, existing methods do not identify islands in the context of the phylogeny in which they evolved. Even multiple strain approaches are best suited to identifying genomic islands that are present in one strain but absent in others. They do not automatically recognize islands which are shared between some strains in the clade or determine the branch on which these islands inserted within the phylogenetic tree. RESULTS: We have developed a software package, xenoGI, that identifies genomic islands and maps their origin within a clade of closely related bacteria, determining which branch they inserted on. It takes as input a set of sequenced genomes and a tree specifying their phylogenetic relationships. Making heavy use of synteny information, the package builds gene families in a species-tree-aware way, and then attempts to combine into islands those families whose members are adjacent and whose most recent common ancestor is shared. The package provides a variety of text-based analysis functions, as well as the ability to export genomic islands into formats suitable for viewing in a genome browser. We demonstrate the capabilities of the package with several examples from enteric bacteria, including an examination of the evolution of the acid fitness island in the genus Escherichia. In addition we use output from simulations and a set of known genomic islands from the literature to show that xenoGI can accurately identify genomic islands and place them on a phylogenetic tree. CONCLUSIONS: xenoGI is an effective tool for studying the history of genomic island insertions in a clade of microbes. It identifies genomic islands, and determines which branch they inserted on within the phylogenetic tree for the clade. Such information is valuable because it helps us understand the adaptive path that has produced living species. PMID- 29402215 TI - Adaptive genomic evolution of opsins reveals that early mammals flourished in nocturnal environments. AB - BACKGROUND: Based on evolutionary patterns of the vertebrate eye, Walls (1942) hypothesized that early placental mammals evolved primarily in nocturnal habitats. However, not only Eutheria, but all mammals show photic characteristics (i.e. dichromatic vision, rod-dominated retina) suggestive of a scotopic eye design. RESULTS: Here, we used integrative comparative genomic and phylogenetic methodologies employing the photoreceptive opsin gene family in 154 mammals to test the likelihood of a nocturnal period in the emergence of all mammals. We showed that mammals possess genomic patterns concordant with a nocturnal ancestry. The loss of the RH2, VA, PARA, PARIE and OPN4x opsins in all mammals led us to advance a probable and most-parsimonious hypothesis of a global nocturnal bottleneck that explains the loss of these genes in the emerging lineage (> > 215.5 million years ago). In addition, ancestral character reconstruction analyses provided strong evidence that ancestral mammals possessed a nocturnal lifestyle, ultra-violet-sensitive vision, low visual acuity and low orbit convergence (i.e. panoramic vision). CONCLUSIONS: Overall, this study provides insight into the evolutionary history of the mammalian eye while discussing important ecological aspects of the photic paleo-environments ancestral mammals have occupied. PMID- 29402216 TI - A comparison of symptoms in older hospitalised cancer and non-cancer patients in need of palliative care: a secondary analysis of two cross-sectional studies. AB - BACKGROUND: Evidence on the differences in symptom patterns between older palliative cancer and non-cancer patients is lacking. The purpose of the study was to determine the differences in symptoms between older hospitalised palliative cancer and non-cancer patients. METHODS: A secondary analysis of two multi-centre cross-sectional studies was performed. A validated instrument was used to assess the frequency and intensity of 40 symptoms in older hospitalised palliative cancer patients (n = 100) and older palliative non-cancer patients (n = 100). The data were collected between March 2013 and June 2015. Differences between groups were measured statistically. RESULTS: Overall, similarities in symptom patterns were observed between cancer and non-cancer patients. Some minor differences were detected between the groups. Non-cancer patients experienced significantly more physical symptoms and functional dependence than cancer patients. Patients with cancer experienced higher levels of frequency and intensity of psychological symptoms compared to non-cancer patients. CONCLUSIONS: Healthcare professionals should be aware of the high occurrence of symptoms in both cancer and non-cancer patients, and they should be educated about the systematic assessment of symptoms in multiple domains by accounting for the occurrence of generic symptoms and disease-specific symptoms. PMID- 29402214 TI - Sequence analysis of European maize inbred line F2 provides new insights into molecular and chromosomal characteristics of presence/absence variants. AB - BACKGROUND: Maize is well known for its exceptional structural diversity, including copy number variants (CNVs) and presence/absence variants (PAVs), and there is growing evidence for the role of structural variation in maize adaptation. While PAVs have been described in this important crop species, they have been only scarcely characterized at the sequence level and the extent of presence/absence variation and relative chromosomal landscape of inbred-specific regions remain to be elucidated. RESULTS: De novo genome sequencing of the French F2 maize inbred line revealed 10,044 novel genomic regions larger than 1 kb, making up 88 Mb of DNA, that are present in F2 but not in B73 (PAV). This set of maize PAV sequences allowed us to annotate PAV content and to analyze sequence breakpoints. Using PAV genotyping on a collection of 25 temperate lines, we also analyzed Linkage Disequilibrium in PAVs and flanking regions, and PAV frequencies within maize genetic groups. CONCLUSIONS: We highlight the possible role of MMEJ type double strand break repair in maize PAV formation and discover 395 new genes with transcriptional support. Pattern of linkage disequilibrium within PAVs strikingly differs from this of flanking regions and is in accordance with the intuition that PAVs may recombine less than other genomic regions. We show that most PAVs are ancient, while some are found only in European Flint material, thus pinpointing structural features that may be at the origin of adaptive traits involved in the success of this material. Characterization of such PAVs will provide useful material for further association genetic studies in European and temperate maize. PMID- 29402217 TI - Systematic comparison of small RNA library preparation protocols for next generation sequencing. AB - BACKGROUND: Next-generation sequencing technologies have revolutionized the study of small RNAs (sRNAs) on a genome-wide scale. However, classical sRNA library preparation methods introduce serious bias, mainly during adapter ligation steps. Several types of sRNA including plant microRNAs (miRNA), piwi-interacting RNAs (piRNA) in insects, nematodes and mammals, and small interfering RNAs (siRNA) in insects and plants contain a 2'-O-methyl (2'-OMe) modification at their 3' terminal nucleotide. This inhibits 3' adapter ligation and makes library preparation particularly challenging. To reduce bias, the NEBNext kit (New England Biolabs) uses polyethylene glycol (PEG), the NEXTflex V2 kit (BIOO Scientific) uses both randomised adapters and PEG, and the novel SMARTer (Clontech) and CATS (Diagenode) kits avoid ligation altogether. Here we compared these methods with Illumina's classical TruSeq protocol regarding the detection of normal and 2' OMe RNAs. In addition, we modified the TruSeq and NEXTflex protocols to identify conditions that improve performance. RESULTS: Among the five kits tested with their respective standard protocols, the SMARTer and CATS kits had the lowest levels of bias but also had a strong formation of side products, and as a result performed relatively poorly with biological samples; NEXTflex detected the largest numbers of different miRNAs. The use of a novel type of randomised adapters called MidRand-Like (MRL) adapters and PEG improved the detection of 2' OMe RNAs both in the TruSeq as well as in the NEXTflex protocol. CONCLUSIONS: While it is commonly accepted that biases in sRNA library preparation protocols are mainly due to adapter ligation steps, the ligation-free protocols were not the best performing methods. Our modified versions of the TruSeq and NEXTflex protocols provide an improved tool for the study of 2' OMe RNAs. PMID- 29402218 TI - Diabetes and the occurrence of infection in primary care: a matched cohort study. AB - BACKGROUND: People with diabetes may be at higher risk for acquiring infections through both glucose-dependent and biologic pathways independent of glycemic control. Our aim was to estimate the association between diabetes and infections occurring in primary care. METHODS: Using the Newfoundland and Labrador Sentinel of the Canadian Primary Care Sentinel Surveillance Network, patients with diabetes >=18 years between 1 January 2008 and 31 March 2013 were included with at least 1-year of follow-up. We randomly matched each patient with diabetes on the date of study entry with up to 8 controls without diabetes. Primary outcome was the occurrence of >=1 primary care physician visits for any infectious disease. Secondary outcomes included primary visits for head & neck, respiratory, gastrointestinal, genitourinary, skin and soft tissue, musculoskeletal, and viral infections. Using multivariable conditional logistic regression analysis, we measured the independent association between diabetes and the occurrence of infections. RESULTS: We identified 1779 patients with diabetes who were matched to 11,066 patients without diabetes. Patients with diabetes were older, had a higher prevalence of comorbidities, and were more often referred to specialists. After adjusting for potential confounders, patients with diabetes had an increased risk of any infection compared to patients without diabetes (adjusted odds ratio = 1.21, 95% confidence interval 1.07-1.37). Skin and soft tissue infections had the strongest association, followed by genitourinary, gastrointestinal, and respiratory infections. Diabetes was not associated with head and neck, musculoskeletal, or viral infections. CONCLUSION: Patients with diabetes appear to have an increased risk of certain infections compared to patients without diabetes. PMID- 29402220 TI - Design of a Novel Multifunction Decision Support Display for Anesthesia Care: AlertWatch(r) OR. AB - BACKGROUND: This paper describes the design of a multifunction alerting display for intraoperative anesthetic care. The design was inspired by the multifunction primary flight display used in modern aviation. RESULTS: The display retrieves live data from multiple sources; the physiologic monitors, the anesthesia information management system, the laboratory values and comorbidities from patient's problem summary list, medical history or history & physical. This information is integrated into a display composed of readily identifiable icons of organ systems, which are color coded to signify normal range, marginal range, abnormal range (by green, yellow, red respectively) and orange outlines for comorbidities/risk factors. There are dozens of text alerts, which can be presented as black text (informational), red text (important information) and red scrolling text (highest importance information). The alerts are derived from current standards in the literature and some involve complex calculations being conducted in the background. CONCLUSIONS: The goal of such a system is to improve the quality and safety of anesthetic care by providing enhanced situational awareness in a fashion analogous to the "glass cockpit" and its primary flight display which has improved aviation safety. PMID- 29402219 TI - Clinical characteristics of distal gastric cancer in young adults from Northeastern Brazil. AB - BACKGROUND: It has been suggested that distal gastric carcinoma (GC) in younger patients has a more aggressive outcome than in older patients, however this is a controversial issue. The aim of this study was to compare clinicopathological features between younger and older patients with GC in Northeastern Brazil. METHODS: A total of 207 patients with distal GC (41 patients <=45 years, considered younger group, and 166 > 45 years, considered older group) were evaluated prospectively during a 6 year period. RESULTS: The mean patient age in the young group was 37.41 years old and 64.43 years in the older group. No significant difference was found regarding gender, area of residence, history of alcohol consumption, chronic tobacco smoking. Prevalence of first-degree GC history was 12.5% (7.3% in younger group vs. 13.9% in older; p < 0.46). The most frequent symptom was gastric pain and weight loss. Diffuse infiltrative cancer was more frequently seen in younger patients (70.70% vs. 33.70%, respectively; p < 0.01), as was histologically less differentiated tumors (63.40% vs. 33.10%; p < 0.01) and stage IV of GC (48.80% vs. 30.70%; p < 0.015). Five-year survival, evaluated in 82 patients, was lower in younger patients (p = 0.045); however, after adjusting for stage of GC in the multivariate analysis, this association did not remain significant. Family history of GC and gender had no impact on survival. CONCLUSIONS: Younger patients showed higher prevalence of diffuse type of Lauren and lower survival that was attributed to higher rate of advanced stage of GC. Gastric cancer screening strategies should also be considered in younger individuals, especially in areas of high prevalence. Further studies are warranted to determine risk factors associated with gastric cancer in young adults. PMID- 29402221 TI - Transcriptome analysis reveals potential mechanisms for different grain size between natural and resynthesized allohexaploid wheats with near-identical AABB genomes. AB - BACKGROUND: Common wheat is a typical allohexaploid species (AABBDD) derived from the interspecific crossing between allotetraploid wheat (AABB) and Aegilops tauschii (DD). Wide variation in grain size and shape observed among Aegilops tauschii can be retained in synthetic allohexaploid wheats, but the underlying mechanism remains enigmatic. Here, the natural and resynthesized allohexaploid wheats with near-identical AB genomes and different D genomes (TAA10 and XX329) were employed for analysis. RESULTS: Significant differences in grain size and weight between TAA10 and XX329 were observed at the early stages of development, which could be mainly attributed to the higher growth rates of the pericarp and endosperm cells in XX329 compared to TAA10. Furthermore, comparative transcriptome analysis identified that 8891 of 69,711 unigenes (12.75%) were differentially expressed between grains at 6 days after pollination (DAP) of TAA10 and XX329, including 5314 up-regulated and 3577 down-regulated genes in XX329 compared to TAA10. The MapMan functional annotation and enrichment analysis revealed that the differentially expressed genes were significantly enriched in categories of cell wall, carbohydrate and hormone metabolism. Notably, consistent with the up-regulation of sucrose synthase genes in resynthesized relative to natural allohexaploid wheat, the resynthesized allohexaploid wheat accumulated much higher contents of glucose and fructose in 6-DAP grains than those of the natural allohexaploid wheat. CONCLUSIONS: These data indicated that the genetic variation of the D genome induced drastic alterations of gene expression in grains of the natural and resynthesized allohexaploid wheats, which may contribute to the observed differences in grain size and weight. PMID- 29402222 TI - Large-scale genomic analysis shows association between homoplastic genetic variation in Mycobacterium tuberculosis genes and meningeal or pulmonary tuberculosis. AB - BACKGROUND: Meningitis is the most severe manifestation of tuberculosis. It is largely unknown why some people develop pulmonary TB (PTB) and others TB meningitis (TBM); we examined if the genetic background of infecting M. tuberculosis strains may be relevant. METHODS: We whole-genome sequenced M. tuberculosis strains isolated from 322 HIV-negative tuberculosis patients from Indonesia and compared isolates from patients with TBM (n = 106) and PTB (n = 216). Using a phylogeny-adjusted genome-wide association method to count homoplasy events we examined phenotype-related changes at specific loci or genes in parallel branches of the phylogenetic tree. Enrichment scores for the TB phenotype were calculated on single nucleotide polymorphism (SNP), gene, and pathway level. Genetic associations were validated in an independent set of isolates. RESULTS: Strains belonged to the East-Asian lineage (36.0%), Euro American lineage (61.5%), and Indo-Oceanic lineage (2.5%). We found no association between lineage and phenotype (Chi-square = 4.556; p = 0.207). Large genomic differences were observed between isolates; the minimum pairwise genetic distance varied from 17 to 689 SNPs. Using the phylogenetic tree, based on 28,544 common variable positions, we selected 54 TBM and 54 PTB isolates in terminal branch sets with distinct phenotypes. Genetic variation in Rv0218, and absence of Rv3343c, and nanK were significantly associated with disease phenotype in these terminal branch sets, and confirmed in the validation set of 214 unpaired isolates. CONCLUSIONS: Using homoplasy counting we identified genetic variation in three separate genes to be associated with the TB phenotype, including one (Rv0218) which encodes a secreted protein that could play a role in host-pathogen interaction by altering pathogen recognition or acting as virulence effector. PMID- 29402223 TI - MORG1+/- mice are protected from histological renal damage and inflammation in a murine model of endotoxemia. AB - BACKGROUND: The MAPK-organizer 1 (MORG1) play a scaffold function in the MAPK and/or the PHD3 signalling paths. Recently, we reported that MORG1+/- mice are protected from renal injury induced by systemic hypoxia and acute renal ischemia reperfusion injury via increased hypoxia-inducible factors (HIFs). Here, we explore whether MORG1 heterozygosity could attenuate renal injury in a murine model of lipopolysaccharide (LPS) induced endotoxemia. METHODS: Endotoxemia was induced in mice by an intraperitoneal (i.p) application of 5 mg/kg BW LPS. The renal damage was estimated by periodic acid Schiff's staining; renal injury was evaluated by detection of urinary and plasma levels of neutrophil gelatinase associated lipocalin and albumin/creatinine ratio via ELISAs. Renal mRNA expression was assessed by real-time PCR, whereas the protein expression was determined by immunohistochemistry or Western blotting. RESULTS: LPS administration increased tubular injury, microalbuminuria, IL-6 plasma levels and renal TNF-alpha expression in MORG1 +/+ mice. This was accompanied with enhanced infiltration of the inflammatory T-cells in renal tissue and activation of the NF kappaB transcription factors. In contrast, endotoxemic MORG1 +/- showed significantly less tubular injury, reduced plasma IL-6 levels, significantly decreased renal TNF-alpha expression and T-cells infiltration. In support, the renal levels of activated caspase-3 were lower in endotoxemic MORG1 +/- mice compared with endotoxemic MORG1 +/+ mice. Interestingly, LPS application induced a significantly higher accumulation of renal HIF-2alpha in the kidneys of MORG1+/ mice than in wild-type mice, accompanied with a diminished phosphorylation of IkappaB-alpha and IKK alpha,beta and decreased iNOS mRNA in the renal tissues of the LPS-challenged MORG1+/- mice, indicating an inhibition of the NF-kappaB transcriptional activation. CONCLUSIONS: MORG1 heterozygosity protects against histological renal damage and shows anti-inflammatory effects in a murine endotoxemia model through modulation of HIF-2alpha stabilisation and/or simultaneous inhibition of the NF-kappaB signalling. Here, we show for the first time that MORG1 scaffold could represent the missing link between innate immunity and inflammation. PMID- 29402224 TI - The optimal CO2 concentrations for the growth of three perennial grass species. AB - BACKGROUND: Grasslands are one of the most representative vegetation types accounting for about 20% of the global land area and thus the response of grasslands to climate change plays a pivotal role in terrestrial carbon balance. However, many current climate change models, based on earlier results of the doubling-CO2 experiments, may overestimate the CO2 fertilization effect, and as a result underestimate the potentially effects of future climate change on global grasslands when the atmospheric CO2 concentration goes beyond the optimal level. Here, we examined the optimal atmospheric CO2 concentration effect on CO2 fertilization and further on the growth of three perennial grasses in growth chambers with the CO2 concentration at 400, 600, 800, 1000, and 1200 ppm, respectively. RESULTS: All three perennial grasses featured an apparent optimal CO2 concentration for growth. Initial increases in atmospheric CO2 concentration substantially enhanced the plant biomass of the three perennial grasses through the CO2 fertilization effect, but this CO2 fertilization effect was dramatically compromised with further rising atmospheric CO2 concentration beyond the optimum. The optimal CO2 concentration for the growth of tall fescue was lower than those of perennial ryegrass and Kentucky bluegrass, and thus the CO2 fertilization effect on tall fescue disappeared earlier than the other two species. By contrast, the weaker CO2 fertilization effect on the growth of perennial ryegrass and Kentucky bluegrass was sustained for a longer period due to their higher optimal CO2 concentrations than tall fescue. The limiting effects of excessively high CO2 concentrations may not only associate with changes in the biochemical and photochemical processes of photosynthesis, but also attribute to the declines in stomatal conductance and nitrogen availability. CONCLUSIONS: In this study, we found apparent differences in the optimal CO2 concentrations for the growth of three grasses. These results suggest that the growth of different types of grasses may respond differently to future elevated CO2 concentrations through the CO2 fertilization effect, and thus potentially alter the community composition and structure of grasslands. Meanwhile, our results may also be helpful for improving current process-based ecological models to more accurately predict the structure and function of grassland ecosystems under future rising atmospheric CO2 concentration and climate change scenarios. PMID- 29402225 TI - The perceived impact of family physicians on the district health system in South Africa: a cross-sectional survey. AB - BACKGROUND: Evidence from first world contexts support the notion that strong primary health care teams contain family physicians (FPs). African leaders are looking for evidence from their own context. The roles and scope of practice of FPs are also contextually defined. The South African family medicine discipline has agreed on six roles. These roles were incorporated into a family physician impact assessment tool, previously validated in the Western Cape Province. METHODS: A cross-sectional study design was used to assess the perceived impact of family physicians across seven South African provinces. All FPs working in the district health system (DHS) of these seven provinces were invited to participate. Sixteen respondents (including the FP) per enrolled FP were asked to complete the validated 360-degree assessment tool. RESULTS: A total number of 52 FPs enrolled for the survey (a response rate of 56.5%) with a total number of 542 respondents. The mean number of respondents per FP was 10.4 (SD = 3.9). The perceived impact made by FPs was high for five of the six roles. Co-workers rated their FP's impact across all six roles as higher, compared to the other doctors at the same facility. The perceived beneficial impact was experienced equally across the whole study setting, with no significant differences when comparing location (rural vs. metropolitan), facility type or training model (graduation before and >= 2011). CONCLUSIONS: The findings support the need to increase the deployment of family physicians in the DHS and to increase the number being trained as per the national position paper. PMID- 29402226 TI - Cross-sectional survey of knowledge of obstetric danger signs among women in rural Madagascar. AB - BACKGROUND: Antenatal care (ANC) has the potential to identify and manage obstetric complications, educate women about risks during pregnancy and promote skilled birth attendance during childbirth. The aim of this study was to assess women's knowledge of obstetric danger signs and factors associated with this knowledge in Ambanja, Madagascar. It also sought to evaluate whether the participation in a mobile health (mHealth) project that aimed to provide comprehensive ANC to pregnant women in remote areas influenced women's knowledge of obstetric danger signs. METHODS: From April to October 2015, a non-random, convenience sample of 372 women in their first year postpartum were recruited, including 161 who had participated in the mHealth project. Data were analyzed using bivariate and multivariate logistic regression. RESULTS: Knowledge of at least one danger sign varied from 80.9% of women knowing danger sign(s) in pregnancy, to 51.9%, 50.8% and 53.2% at delivery, postpartum and in the newborn, respectively. Participation in the mHealth intervention, higher household income, and receipt of information about danger signs during pregnancy were associated with knowledge of danger signs during delivery, in bivariate analysis; only higher household income and mHealth project participation were independently associated. Higher educational attainment and receipt of information about danger signs in antenatal care were associated with significantly higher odds of knowing danger sign(s) for the newborn in both bivariate and multivariate analysis. CONCLUSIONS: Knowledge of obstetric danger signs is low. Information provision during pregnancy and with mHealth is promising. TRIAL REGISTRATION: This trial was retrospectively registered at the International Standard Randomized Controlled Trial Register (identifier ISRCTN15798183 ; August 22, 2015). PMID- 29402227 TI - CoVaCS: a consensus variant calling system. AB - BACKGROUND: The advent and ongoing development of next generation sequencing technologies (NGS) has led to a rapid increase in the rate of human genome re sequencing data, paving the way for personalized genomics and precision medicine. The body of genome resequencing data is progressively increasing underlining the need for accurate and time-effective bioinformatics systems for genotyping - a crucial prerequisite for identification of candidate causal mutations in diagnostic screens. RESULTS: Here we present CoVaCS, a fully automated, highly accurate system with a web based graphical interface for genotyping and variant annotation. Extensive tests on a gold standard benchmark data-set -the NA12878 Illumina platinum genome- confirm that call-sets based on our consensus strategy are completely in line with those attained by similar command line based approaches, and far more accurate than call-sets from any individual tool. Importantly our system exhibits better sensitivity and higher specificity than equivalent commercial software. CONCLUSIONS: CoVaCS offers optimized pipelines integrating state of the art tools for variant calling and annotation for whole genome sequencing (WGS), whole-exome sequencing (WES) and target-gene sequencing (TGS) data. The system is currently hosted at Cineca, and offers the speed of a HPC computing facility, a crucial consideration when large numbers of samples must be analysed. Importantly, all the analyses are performed automatically allowing high reproducibility of the results. As such, we believe that CoVaCS can be a valuable tool for the analysis of human genome resequencing studies. CoVaCS is available at: https://bioinformatics.cineca.it/covacs . PMID- 29402228 TI - Economic evaluation of an extended nutritional intervention in older Australian hospitalized patients: a randomized controlled trial. AB - BACKGROUND: Prevalence of malnutrition in older hospitalized patients is 30%. Malnutrition is associated with poor clinical outcomes in terms of high morbidity and mortality and is costly for hospitals. Extended nutrition interventions improve clinical outcomes but limited studies have investigated whether these interventions are cost-effective. METHODS: In this randomized controlled trial, 148 malnourished general medical patients >=60 years were recruited and randomized to receive either an extended nutritional intervention or usual care. Nutrition intervention was individualized and started with 24 h of admission and was continued for 3 months post-discharge with a monthly telephone call whereas control patients received usual care. Nutrition status was confirmed by Patient generated subjective global assessment (PG-SGA) and health-related quality of life (HRQoL) was measured using EuroQoL 5D (EQ-5D-5 L) questionnaire at admission and at 3-months follow-up. A cost-effectiveness analysis was conducted for the primary outcome (incremental costs per unit improvement in PG-SGA) while a cost utility analysis (CUA) was undertaken for the secondary outcome (incremental costs per quality adjusted life year (QALY) gained). RESULTS: Nutrition status and HRQoL improved in intervention patients. Mean per included patient Australian Medicare costs were lower in intervention group compared to control arm (by $907) but these differences were not statistically significant (95% CI: -$2956 to $4854). The main drivers of higher costs in the control group were higher inpatient ($13,882 versus $13,134) and drug ($838 versus $601) costs. After adjusting outcomes for baseline differences and repeated measures, the intervention was more effective than the control with patients in this arm reporting QALYs gained that were higher by 0.0050 QALYs gained per patient (95% CI: -0.0079 to 0.0199). The probability of the intervention being cost-effective at willingness to pay values as low as $1000 per unit improvement in PG-SGA was > 98% while it was 78% at a willingness to pay $50,000 per QALY gained. CONCLUSION: This health economic analysis suggests that the use of extended nutritional intervention in older general medical patients is likely to be cost-effective in the Australian health care setting in terms of both primary and secondary outcomes. TRIAL REGISTRATION: ACTRN No. 12614000833662 . Registered 6 August 2014. PMID- 29402229 TI - Estimation of the incidence of severe fever with thrombocytopenia syndrome in high endemic areas in China: an inpatient-based retrospective study. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a severe viral disease caused by SFTSV. It is important to estimate the rate of missed SFTS diagnosis and to further understand the actual incidence in high endemic areas in China. METHODS: This study was conducted in two high SFTS endemic provinces in 2015. Patients hospitalized in 2014 or within 1 year before investigation were selected after considering their clinical manifestations, specifically, fever, platelet, and white blood cell. During retrospective investigation, sera were collected to detect SFTSV antibodies to assess SFTSV infection. To further understand SFTSV infection, acute phase sera were detected; SFTSV infection rate among a healthy population was also investigated to determine the basic infection level. RESULTS: In total, 246 hospitalized cases were included, including 83 cases (33.7%) with fever, thrombocytopenia and leukopenia, 38 cases (15.4%) with fever and thrombocytopenia but without leukopenia, and 125 cases (50.8%) without fever but with thrombocytopenia and leukopenia. In total, 13 patients (5.3%) were SFTSV IgM antibody-positive, 48 (19.5%) were IgG-positive. Of the 13 IgM-positive cases, 11 (84.6%) were IgG-positive (9 with titres >=1:400). Seropositive rates of antibodies were high (8.4% for IgM and 30.1% for IgG) in patients with fever, thrombocytopenia and leukopenia. Furthermore, among IgG-positive cases in this group, 76% (19/25) of patients' IgG antibody titres were >=1:400. Additionally, 28 of 246 cases were initially diagnosed with suspected SFTS and were then excluded, and 218 patients were never diagnosed with SFTS; the seropositive rates of IgM and IgG in these two groups were 25% and 67.9% and 2.8% and 13.3%, respectively. These rates were 64.3% and 21.4% in 14 sera collected during acute phase of the 28 cases mentioned above. Seropositive rate of SFTSV IgG was only 1.3% in the patient-matched healthy group, and no IgM antibody was detected. A preliminary estimate of 8.3% of SFTS cases were missed in SFTS high endemic provinces. CONCLUSIONS: The actual SFTS incidence was underestimated. Effective measures such as adding a new SFTS case category - "SFTS clinical diagnosis cases" or using serological detection methods during acute phase should be considered to avoid missed diagnoses. PMID- 29402230 TI - Ongoing niche differentiation under high gene flow in a polymorphic brackish water threespine stickleback (Gasterosteus aculeatus) population. AB - BACKGROUND: Marine threespine sticklebacks colonized and adapted to brackish and freshwater environments since the last Pleistocene glacial. Throughout the Holarctic, three lateral plate morphs are observed; the low, partial and completely plated morph. We test if the three plate morphs in the brackish water Lake Engervann, Norway, differ in body size, trophic morphology (gill raker number and length), niche (stable isotopes; delta15N, delta13C, and parasites (Theristina gasterostei, Trematoda spp.)), genetic structure (microsatellites) and the lateral-plate encoding Stn382 (Ectodysplasin) gene. We examine differences temporally (autumn 2006/spring 2007) and spatially (upper/lower sections of the lake - reflecting low versus high salinity). RESULTS: All morphs belonged to one gene pool. The complete morph was larger than the low plated, with the partial morph intermediate. The number of lateral plates ranged 8-71, with means of 64.2 for complete, 40.3 for partial, and 14.9 for low plated morph. Stickleback delta15N was higher in the lower lake section, while delta13C was higher in the upper section. Stickleback isotopic values were greater in autumn. The low plated morph had larger variances in delta15N and delta13C than the other morphs. Sticklebacks in the upper section had more T. gasterostei than in the lower section which had more Trematoda spp. Sticklebacks had less T. gasterostei, but more Trematoda spp. in autumn than spring. Sticklebacks with few and short rakers had more T. gasterostei, while sticklebacks with longer rakers had more Trematoda. spp. Stickleback with higher delta15N values had more T. gasterostei, while sticklebacks with higher delta15N and delta13C values had more Trematoda spp. The low plated morph had fewer Trematoda spp. than other morphs. CONCLUSIONS: Trait-ecology associations may imply that the three lateral plate morphs in the brackish water lagoon of Lake Engervann are experiencing ongoing divergent selection for niche and migratory life history strategies under high gene flow. As such, the brackish water zone may generally act as a generator of genomic diversity to be selected upon in the different environments where threespine sticklebacks can live. PMID- 29402231 TI - The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators. AB - BACKGROUND: Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. MAIN BODY: A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments. The meeting focused on developing a consensus among all stakeholders as to how best to achieve a more fundamental and profound understanding of SYNGAP1 biology and its role in human disease. SHORT CONCLUSION: From all of these proceedings, several areas of consensus emerged. The clinicians and geneticists agreed that the prevalence of epilepsy and sensory processing impairments in SYNGAP1-related brain disorders approached 100%. The neurobiologists agreed that more basic research is needed to better understand the molecular and cellular functions of the Syngap1 gene, which will lead to targets for therapeutic intervention. Finally, everyone agreed that there is a pressing need to form a robust patient registry as an initial step toward a prospective natural history study of patients with pathogenic SYNGAP1 variants. PMID- 29402232 TI - Evolution of quality of life in patients with breast cancer during the first year of follow-up in Morocco. AB - BACKGROUND: Quality of life has an important place in the future of patients with breast cancer. The objective of this study is to assess the evolution of the patient's quality of life with breast cancer in Morocco after a year of follow up. METHODS: This study involved the patients with breast cancer with all types of treatment as determined by their physicians. Patient's quality of life was assessed with the Moroccan Arabic version of QLQ- EORTC QLQ C30 and EORTC-BR23 questionnaires. Data were analyzed using SPSS Version 20 software. RESULTS: Regarding EOTRC questionnaires QLQ C-30, there was a significant improvement in global health status and all scales of the functional dimension except the social functional where there was a trend towards improvement and the financial impact of the disease where the situation has deteriorated. Quality of life was improved for most symptom-sized scales dimension of EORTC QLQ- C30 with the exception of diarrhea where it was observed degradation. Most of the EORTC QLQ-scales BR23 questionnaires showed a favorable trend in the quality of life except those of sexual functioning, sexual enjoyment, hair loss and the side effects of systemic therapy. CONCLUSION: The quality of life of the patient is significantly improved after 1 year of follow up. Quality of life instruments can be useful in the early identification of patients whose score low on functional scales and symptoms. PMID- 29402233 TI - A population-based screening study for cardiovascular diseases and diabetes in Danish postmenopausal women: acceptability and prevalence. AB - BACKGROUND: Reducing women's cardiovascular risk and the economic costs associated with cardiovascular diseases (CVD) and diabetes (DM) continues to be a challenge. Whether a multifaceted CVD screening programme is beneficial as a preventive strategy in women remains uncertain. The aim of this study was to investigate the prevalence of CVD and DM as well as the acceptability toward screening and preventive actions. METHODS: An observational study was performed among all women born in 1936, 1941, 1946 and 1951 living in Viborg Municipality, Denmark, from October 2011. In total, 1984 were invited to screening for abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), carotid plaque (CP), hypertension (HT), atrial fibrillation (AF), DM and dyslipidaemia. Participants with positive tests were offered prophylactic intervention including follow-up consultations in case of AAA, PAD and/or CP. Participants with AAA >= 50 mm were referred to specialists in vascular surgery. Women with AF or potential familial hypercholesterolaemia (FH) were referred to cardiology work up. RESULTS: Among those invited, 1474 (74.3%) attended screening, but the attendees' share decreased with increasing age groups (p < 0.001). AAA was diagnosed in 10 (0.7%) women, PAD in 101 (6.9%) and CP in 602 (40.8%). The percentage of women with these conditions rose with increasing age group (p < 0.05). Unconfirmed potential HT was observed in 94 (6.4%), unknown AF in 6 (0.4%), DM in 14 (1%) and potential FH in 35 (2.4%). None of these findings differed across age groups. Among the 631 women diagnosed with AAA, PAD and/or CP, 182 (28.8%) were already in antiplatelet and 223 (35.3%) in lipid-lowering therapy prior to screening. Antiplatelet therapy was initiated in 215 (34.1%) and lipid-lowering therapy in 191 (30.3%) women. Initiation of antiplatelet and lipid lowering therapy was further recommended to 134 (21.2%) and 141 (22.4%) women, respectively, who hesitated to follow the recommendation. CONCLUSIONS: The study recorded an acceptable total attendance rate, even though a significantly lower attendance rate was observed in the eldest women. The identified hesitation towards prophylactic therapy may affect the rationale and effectiveness of CVD screening, and hesitation seems a critical issue that should be addressed in the design of future screening programmes. PMID- 29402235 TI - What gives rise to clinician gut feeling, its influence on management decisions and its prognostic value for children with RTI in primary care: a prospective cohort study. AB - BACKGROUND: The objectives were to identify 1) the clinician and child characteristics associated with; 2) clinical management decisions following from, and; 3) the prognostic value of; a clinician's 'gut feeling something is wrong' for children presenting to primary care with acute cough and respiratory tract infection (RTI). METHODS: Multicentre prospective cohort study where 518 primary care clinicians across 244 general practices in England assessed 8394 children aged >=3 months and < 16 years for acute cough and RTI. The main outcome measures were: Self-reported clinician 'gut feeling'; clinician management decisions (antibiotic prescribing, referral for acute admission); and child's prognosis (reconsultation with evidence of illness deterioration, hospital admission in the 30 days following recruitment). RESULTS: Clinician years since qualification, parent reported symptoms (illness severity score >= 7/10, severe fever < 24 h, low energy, shortness of breath) and clinical examination findings (crackles/ crepitations on chest auscultation, recession, pallor, bronchial breathing, wheeze, temperature >= 37.8 degrees C, tachypnoea and inflamed pharynx) independently contributed towards a clinician 'gut feeling that something was wrong'. 'Gut feeling' was independently associated with increased antibiotic prescribing and referral for secondary care assessment. After adjustment for other associated factors, gut feeling was not associated with reconsultations or hospital admissions. CONCLUSIONS: Clinicians were more likely to report a gut feeling something is wrong, when they were more experienced or when children were more unwell. Gut feeling is independently and strongly associated with antibiotic prescribing and referral to secondary care, but not with two indicators of poor child health. PMID- 29402234 TI - Randomised controlled trial protocol (GRIP study): examining the effect of involvement of a general practitioner and home care oncology nurse after a cancer diagnosis on patient reported outcomes and healthcare utilization. AB - BACKGROUND: Due to the ageing population and improving diagnostics and treatments, the number of cancer patients and cancer survivors is increasing. Policymakers, patients and professionals advocate a transfer of (part of) cancer care from the hospital environment to the primary care setting, as this could stimulate personalized and integrated care, increase cost-effectiveness and would better meet the patients' needs and expectations. The effects of structured active follow-up from primary care after cancer diagnosis have not been studied yet. Therefore the GRIP study aims to assess the effects of structured follow-up after a cancer diagnosis, by a primary care team including a general practitioner (GP) and a home care oncology nurse (HON), on satisfaction and healthcare utilization of patients treated with curative intent. METHODS: We will conduct a multicentre, two-arm randomised controlled trial in The Netherlands. We plan to include 150 patients who will be treated with curative intent for either breast, lung, colorectal, gynaecologic cancer, or melanoma. Further inclusion criteria are: age 18 years and older, able to answer questionnaires in Dutch, GP agrees to participate and the possibility to include the patient before the start of treatment. All patients receive care as usual. The intervention arm will receive additional structured follow-up consisting of a GP consultation before onset of treatment to empower the patient for shared decision making with the specialist and a minimum of three contacts with the HON during and after treatment. Primary outcomes are: patient satisfaction with care at the level of specialist, GP and nurse and healthcare utilization. Secondary outcomes include: quality of life, employment status, patient empowerment, shared decision making, mental health and satisfaction with given information. Repeated questionnaires, filled in by the participants, will be assessed within the 1-year study period. DISCUSSION: This randomised controlled trial will evaluate the effects of structured follow-up after a cancer diagnosis by a primary care team including a GP and HON, for patients undergoing treatment with curative intent. Results from the present study may provide the evidence needed to optimally rearrange responsibilities in cancer care delivery and consequently improve cancer care and patient related outcomes. TRIAL REGISTRATION: Trial number: NTR5909 . PMID- 29402236 TI - Investigations of organ and effective doses of abdominal cone-beam computed tomography during transarterial chemoembolization using Monte Carlo simulation. AB - BACKGROUND: To investigate the organ dose, effective dose (ED), conversion factor, and the C-arm rotation angle effects on dose variations of abdominal C arm cone-beam computed tomography (CBCT) during transarterial chemoembolization (TACE). METHODS: The organ doses and EDs for abdominal C-arm CBCT were retrospectively calculated according to a Monte Carlo technique for 80 patients. Dose variations from projections, ED to dose-area product (DAP) ratios, and effects of body mass index (BMI) on the ED and ED to DAP ratios were also analyzed. RESULTS: The kidney received the highest dose (14.6 +/- 1.2 mSv). Organ dose deviations among C-arm rotation angles was highest for stomach (CV = 0.71). The mean ED of the the CBCT run during TACE was 3.5 +/- 0.5 mSv, and decreased with increased BMI (R2 = 0.45, p < 0.001). The mean ED to DAP ratio was 0.27 +/- 0.04 mSv.Gy- 1.cm- 2 and tended to decrease with increased BMI (R2 = 0.55, p < 0.001). The mean ED to DAP ratios were 0.29 +/- 0.02, 0.26 +/- 0.02, and 0.23 +/- 0.03 mSv.Gy- 1.cm- 2 for patients with BMI < 25 kg/m2, 25-30 kg/m2, and >=30 kg/m2, respectively. CONCLUSIONS: Suitable conversion factors for C-arm CBCT facilitate the use of DAPs for estimating the ED. The patient dose can be varied by adjusting the CBCT rotation angle setting, and dose reduction strategies can be further manipulated. PMID- 29402237 TI - A simple filter model to guide the allocation of healthcare resources for improving the treatment of depression among cancer patients. AB - BACKGROUND: Depression is highly prevalent yet often poorly detected and treated among cancer patients. In light of the move towards evidence-based healthcare policy, we have developed a simple tool that can assist policy makers, organisations and researchers to logically think through the steps involved in improving patient outcomes, and to help guide decisions about where to allocate resources. METHODS: The model assumes that a series of filters operate to determine outcomes and cost-effectiveness associated with depression care for cancer patients, including: detection of depression, provider response to detection, patient acceptance of treatment, and effectiveness of treatment provided. To illustrate the utility of the model, hypothetical data for baseline and four scenarios in which filter outcomes were improved by 15% were entered into the model. RESULTS: The model provides outcomes including: number of people successfully treated, total costs per scenario, and the incremental cost effectiveness ratio per scenario compared to baseline. The hypothetical data entered into the model illustrate the relative effectiveness (in terms of the number of additional incremental successes) and relative cost-effectiveness (in terms of cost per successful outcome and total cost) of making changes at each step or filter. CONCLUSIONS: The model provides a readily accessible tool to assist decision makers to think through the steps involved in improving depression outcomes for cancer patents. It provides transparent guidance about how to best allocate resources, and highlights areas where more reliable data are needed. The filter model presents an opportunity to improve on current practice by ensuring that a logical approach, which takes into account the available evidence, is applied to decision making. PMID- 29402238 TI - Effect of oral Colchicine on Peripapillary retinal nerve fiber layer thickness in patients with familial Mediterranean fever. AB - BACKGROUND: The purpose of this study is to investigate whether oral colchicine has an effect on peripapillary retinal nerve fiber layer (pRNFL) thickness of familial Mediterranean fever (FMF) patients. METHODS: We conducted a cross sectional study by comparing pRNFL thickness of FMF patients on colchicine (treated group), newly diagnosed colchicine naive FMF patients (untreated group) and healthy controls. The study included 66 FMF patients and 32 healthy control subjects. Treated FMF patients were grouped according to colchicine use, duration of use and dosage. pRNFL thickness of the patients and controls were measured by using optical coherence tomography and the measurements were compared. RESULTS: No statistically significant difference was found between the pRNFL thickness in untreated group, treated group and the healthy control group (all p > 0.05). No statistically significant difference was found between pRNFL thickness in the healthy control group and FMF patients grouped according to duration or dosage of colchicine use (all p > 0.05). CONCLUSIONS: According to our study, FMF and oral colchicine use had no statistically significant effect on pRNFL thickness. PMID- 29402239 TI - Primary extra-uterine and extra-ovarian mullerian adenosarcoma: case report and literature review. AB - BACKGROUND: Extra-uterine mullerian adenosarcomas have varying biological behaviours depending on the presence of endometriosis or sarcomatous overgrowth. These behaviours manifest according to the tumours' histological characteristics and sites of origin. The best treatment and oncologic outcome have not been clarified because only a few cases of extra-uterine and extra-ovarian adenosarcoma have been described in the literature. Here, we report a case of primary peritoneal adenosarcoma with sarcomatous overgrowth and review all reported cases of adenosarcomas arising outside of the uterus and outside the ovaries to identify the best treatment options and clarify outcomes. CASE PRESENTATION: A 79-year-old woman was referred to our Department with an abdominal mass resembling a fibroid with a haemorrhage. Her gynaecological history was negative. A transvaginal and transabdominal ultrasound examination revealed a multicystic mass resembling an ovarian tumour arising from the pelvis and extending up to the abdomen. At laparotomy a peritoneal mass arising from Douglas peritoneum was resected. The uterus and adnexa appeared normal, and a supra-cervical hysterectomy with bilateral salpingo-oophorectomy was performed. No macroscopic residual disease was present. Final pathology diagnosed a malignant peripheral nerve sheath tumors with divergent differentiation. Four weeks later a new, multicystic mass was found. Due to the progressive poor condition, the patient died four months after diagnosis. Histological slides were reviewed by external expert pathologists and the final diagnosis was of extra genital adenosarcoma with sarcomatous overgrowth. Furthermore, we also collected and analysed articles written in English regarding extra-uterine and extra ovarian adenosarcomas published between January 1974 and October 2016. PubMed was used as a database for this search. Clinical and pathological characteristics, treatments and outcomes were assessed. CONCLUSIONS: Only 41 cases has been reported in literature. Previous endometriosis and sarcomatous overgrowth showed an inverse effect on prognosis. Endometriosis was confirmed to have a positive effect on disease free survival Complete surgical resection is the mainstay of treatment. A worldwide registry is urgently required to collect data to standardize treatment and to obtain reliable data on prognosis. PMID- 29402240 TI - Internal structure and reliability of the Attachment Insecurity Screening Inventory (AISI) for children age 6 to 12. AB - BACKGROUND: The aim of the present study was to examine the internal structure and reliability of the Attachment Insecurity Screening Inventory (AISI) 6-12. The AISI 6-12 years is a parent-report questionnaire for assessing the parents' perspective on the quality of the attachment relationship with their child aged between 6 and 12 years. METHODS: The sample consisted of 681 mothers and fathers reporting on 372 children (72.3% adoption parents, 14.9% non-biological primary care takers including foster parents, and 12.8% biological parents). The internal structure was assessed with multilevel confirmatory factor analyses (CFA) and the reliability of the scores with Cronbach's and ordinal alphas. RESULTS: Multilevel CFA confirmed a three-factor model of avoidant, ambivalent/resistant and disorganized attachment. Multi-group CFA indicated full configural and metric measurement invariance, and partial scalar and strict measurement invariance across mothers and fathers. Reliability coefficients were found to be sufficient. CONCLUSIONS: This study showed the potential of using parental reports in the initial screening of attachment related problems, especially considering the practical approach of parental reports. However, further development of the AISI 6-12 years seems important to increase the validity of the AISI 6-12 years. In addition, future studies are necessary to replicate the current findings, and to strengthen the evidence that the AISI 6-12 years is appropriate for the use in middle childhood and validly assesses the parents' perspective on attachment insecurities in their child. PMID- 29402241 TI - Trial protocol: a parallel group, individually randomized clinical trial to evaluate the effect of a mobile phone application to improve sexual health among youth in Stockholm County. AB - BACKGROUND: Genital Chlamydia trachomatis infection is a major public health problem worldwide affecting mostly youth. Sweden introduced an opportunistic screening approach in 1982 accompanied by treatment, partner notification and case reporting. After an initial decline in infection rate till the mid-90s, the number of reported cases has increased over the last two decades and has now stabilized at a high level of 37,000 reported cases in Sweden per year (85% of cases in youth). Sexual risk-taking among youth is also reported to have significantly increased over the last 20 years. Mobile health (mHealth) interventions could be particularly suitable for youth and sexual health promotion as the intervention is delivered in a familiar and discrete way to a tech savvy at-risk population. This paper presents a protocol for a randomized trial to study the effect of an interactive mHealth application (app) on condom use among the youth of Stockholm. METHODS: 446 youth resident in Stockholm, will be recruited in this two arm parallel group individually randomized trial. Recruitment will be from Youth Health Clinics or via the trial website. Participants will be randomized to receive either the intervention (which comprises an interactive app on safe sexual health that will be installed on their smart phones) or a control group (standard of care). Youth will be followed up for 6 months, with questionnaire responses submitted periodically via the app. Self-reported condom use over 6 months will be the primary outcome. Secondary outcomes will include presence of an infection, Chlamydia tests during the study period and proxy markers of safe sex. Analysis is by intention to treat. DISCUSSION: This trial exploits the high mobile phone usage among youth to provide a phone app intervention in the area of sexual health. If successful, the results will have implications for health service delivery and health promotion among the youth. From a methodological perspective, this trial is expected to provide information on the strength and challenges of implementing a partially app (internet) based trial in this context. TRIAL REGISTRATION: ISRCTN 13212899, date of registration June 22, 2017. PMID- 29402242 TI - Transitions as experienced by persons in palliative care circumstances and their families - a qualitative meta-synthesis. AB - BACKGROUND: When receiving palliative care, patients and their families experience altered life situations in which they must negotiate challenges in daily life, increased care and new roles. With limited time, they also experience emotional changes that relate to their uncertain future. Transitions experienced in such situations are often studied by focusing on individual aspects, which are synthesized in the following study. The aim was to conduct a qualitative meta synthesis to explore the experiences patients and their families gain during transitions in palliative care circumstances. METHODS: A qualitative meta synthesis was conducted following an inductive approach as proposed by Sandelowski and Barroso. Inclusion criteria were studies with adult persons in palliative situations and articles published in English or German. Relevant articles were identified by researching the Pubmed and Cinahl databases, as well as by hand searches in journals and reference lists for the period 2000-2015. The findings of each study were analyzed using initial coding, followed by axial and selective coding in this order. Consequently, a conceptual model was derived from the categories. RESULTS: In total 2225 articles were identified in the literature search. Finally, 14 studies were included after the selection process. The central phenomenon observed among palliative care patients and their families was maintaining normality during transitions. Transitions are initially experienced unconsciously until a crisis occurs and responsive actions are necessary, which encourages patients and families to perceive the situation consciously and develop strategies for its negotiation. Patients remain caught between hopelessness and valuing their remaining time alive. As the illness progresses, informal caregivers reprioritize and balance their roles, and after death, family members inevitably find themselves in changed roles. CONCLUSIONS: In palliative care situations, transitions are experienced differently by patients and their families in a constant phenomenon that oscillates between unconscious and conscious perceptions of transitions. The derived conceptual model offers an additional perspective to existing models and helps to clarify the phenomenon in practical settings. The study promotes a differentiated conceptual view of transitions and emphasizes patients' and families' perspectives. PMID- 29402243 TI - Treatment decisions, clinical outcomes, and pharmacoeconomics in the treatment of patients with EGFR mutated stage III/IV NSCLC in Germany: an observational study. AB - BACKGROUND: We evaluated treatment decisions and outcomes in a cohort of predominately Caucasian patients with EGFR mutation-positive (EGFR Mut+) non small-cell lung cancer (NSCLC). METHODS: REASON (NCT00997230) was a non interventional study in German patients with stage IIIB/IV NSCLC. Secondary endpoints for EGFR Mut + NSCLC included progression-free survival (PFS), overall survival (OS), adverse event (AE) management, and pharmacoeconomic outcomes. RESULTS: Among 334 patients with EGFR Mut + NSCLC, tyrosine kinase inhibitors (TKIs) were the most common first-line therapy (56.6%, 53.0% gefitinib). Among patients who received TKIs/gefitinib before first disease progression, PFS was longer compared with those who did not receive a TKI (median 10.1/10.0 vs. 7.0 months; HR 0.67/0.69; log-rank p = 0.012/p = 0.022). OS was longer for those patients who ever received a TKI/gefitinib during their complete therapy course compared with those who never received a TKI (median 18.4/18.1 vs. 13.6 months; HR 0.53/0.55; p = 0.003/p = 0.005). Total mean first-line treatment healthcare costs per person were higher for those receiving TKIs (?46,443) compared with those who received chemotherapy (?27,182). Mean outpatient and inpatient costs were highest with chemotherapy. Rash, diarrhea, and dry skin were the most commonly reported AEs for patients receiving gefitinib. CONCLUSIONS: In REASON, TKI therapy was the most common first- and second-line treatment for EGFR Mut + NSCLC, associated with increased drug costs compared with chemotherapy. Patients who received gefitinib or a TKI ever during their complete therapy course had prolonged PFS and OS compared with patients who did not receive a TKI. TRIAL REGISTRATION: The trial was registered on October, 2009 with ClinicalTrials.gov : https://clinicaltrials.gov/ct2/show/NCT00997230?term=NCT00997230&rank=1. PMID- 29402244 TI - Changes in CT morphology can be an independent response marker for patients receiving regorafenib for colorectal liver metastases: retrospective pilot study. AB - BACKGROUND: Regorafenib is a multi-kinase inhibitor, which was shown to be effective for patients with metastatic colorectal cancer refractory to standard therapies. However, its patterns of response has not yet been fully understood. METHODS: Clinical records of 10 patients who received regorafenib for evaluable colorectal liver metastases were reviewed. Response to chemotherapy was evaluated with the RECIST and morphologic response criteria, and its clinical relevance was analyzed. RESULTS: All patients received multiple lines of fluorouracil-based chemotherapy before regorafenib. The median follow-up duration after introduction of regorafenib was 4.9 months (range, 2 to 12.5 months). Median number of chemotherapy cycles was 2 (range, 1 to 15). In size-based response evaluation, 4 patients presented SD and 6 patients showed PD according to the RECIST. In non size-based response evaluation, 3 patients were classified as optimal morphologic response and 7 patients were categorized as suboptimal morphologic response. Patients who presented optimal morphologic response showed significantly longer progression-free survival compared with those presented suboptimal response (median, 4.9 months vs. 0.7 months; P = 0.028), while size-based response evaluation could not well stratify patient prognosis. CONCLUSION: Non-size-based CT morphologic response could be a potential alternative response marker for patients treated with regorafenib. PMID- 29402245 TI - Next wave of interventions to reduce under-five mortality in Rwanda: a cross sectional analysis of demographic and health survey data. AB - BACKGROUND: Sustained investments in Rwanda's health system have led to historic reductions in under five (U5) mortality. Although Rwanda achieved an estimated 68% decrease in the national under U5 mortality rate between 2002 and 2012, according to the national census, 5.8% of children still do not reach their fifth birthday, requiring the next wave of child mortality prevention strategies. METHODS: This is a cross-sectional study of 9002 births to 6328 women age 15-49 in the 2010 Rwanda Demographic and Health Survey. We tested bivariate associations between 29 covariates and U5 mortality, retaining covariates with an odds ratio p < 0.1 for model building. We used manual backward stepwise logistic regression to identify correlates of U5 mortality in all children U5, 0-11 months, and 12-59 months. Analyses were performed in Stata v12, adjusting for complex sample design. RESULTS: Of 14 covariates associated with U5 mortality in bivariate analysis, the following remained associated with U5 mortality in multivariate analysis: household being among the poorest of the poor (OR = 1.98), child being a twin (OR = 2.40), mother having 3-4 births in the past 5 years (OR = 3.97) compared to 1-2 births, mother being HIV positive (OR = 2.27), and mother not using contraceptives (OR = 1.37) compared to using a modern method (p < 0.05 for all). Mother experiencing physical or sexual violence in the last 12 months was associated with U5 mortality in children ages 1-4 years (OR = 1.48, p < 0.05). U5 survival was associated with a preceding birth interval 25-50 months (OR = 0.67) compared to 9-24 months, and having a mosquito net (OR = 0.46) (p < 0.05 for both). CONCLUSIONS: In the past decade, Rwanda rolled out integrated management of childhood illness, near universal coverage of childhood vaccinations, a national community health worker program, and a universal health insurance scheme. Identifying factors that continue to be associated with childhood mortality supports determination of which interventions to strengthen to reduce it further. This study suggests that Rwanda's next wave of U5 mortality reduction should target programs in improving neonatal outcomes, poverty reduction, family planning, HIV services, malaria prevention, and prevention of intimate partner violence. PMID- 29402246 TI - Personal social networks and organizational affiliation of South Asians in the United States. AB - BACKGROUND: Understanding the social lives of South Asian immigrants in the United States (U.S) and their influence on health can inform interpersonal and community-level health interventions for this growing community. This paper describe the rationale, survey design, measurement, and network properties of 700 South Asian individuals in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) social networks ancillary study. METHODS: MASALA is a community-based cohort, established in 2010, to understand risk factors for cardiovascular disease among South Asians living in the U.S. Survey data collection on personal social networks occurred between 2014 and 2017. Network measurements included size, composition, density, and organizational affiliations. Data on participants' self-rated health and social support functions and health-related discussions among network members were also collected. RESULTS: Participants' age ranged from 44 to 84 (average 59 years), and 57% were men. South Asians had large (size=5.6, SD=2.6), kin-centered (proportion kin=0.71, SD=0.28), and dense networks. Affiliation with religious and spiritual organizations was perceived as beneficial to health. Emotional closeness with network members was positively associated with participants' self rated health (p-value <0.001), and networks with higher density and more kin were significantly associated with health-related discussions. DISCUSSION: The MASALA networks study advances research on the cultural patterning of social relationships and sources of social support in South Asians living in the U.S. Future analyses will examine how personal social networks and organizational affiliations influence South Asians' health behaviors and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02268513. PMID- 29402247 TI - The power of support from companion animals for people living with mental health problems: a systematic review and narrative synthesis of the evidence. AB - BACKGROUND: There is increasing recognition of the therapeutic function pets can play in relation to mental health. However, there has been no systematic review of the evidence related to the comprehensive role of companion animals and how pets might contribute to the work associated with managing a long-term mental health condition. The aim of this study was to explore the extent, nature and quality of the evidence implicating the role and utility of pet ownership for people living with a mental health condition. METHODS: A systematic search for studies exploring the role of companion animals in the management of mental health conditions was undertaken by searching 9 databases and undertaking a scoping review of grey literature from the earliest record until March 2017. To be eligible for inclusion, studies had to be published in English and report on primary data related to the relationship between domestic animal ownership and the management of diagnosable mental health conditions. Synthesis of qualitative and quantitative data was undertaken in parallel using a narrative synthesis informed by an illness work theoretical framework. RESULTS: A total of 17 studies were included in the review. Quantitative evidence relating to the benefits of pet ownership was mixed with included studies demonstrating positive, negative and neutral impacts of pet ownership. Qualitative studies illuminated the intensiveness of connectivity people with companion animals reported, and the multi-faceted ways in which pets contributed to the work associated with managing a mental health condition, particularly in times of crisis. The negative aspects of pet ownership were also highlighted, including the practical and emotional burden of pet ownership and the psychological impact that losing a pet has. CONCLUSION: This review suggests that pets provide benefits to those with mental health conditions. Further research is required to test the nature and extent of this relationship, incorporating outcomes that cover the range of roles and types of support pets confer in relation to mental health and the means by which these can be incorporated into the mainstay of support for people experiencing a mental health problem. PMID- 29402249 TI - A web tool for designing and conducting phase I trials using the continual reassessment method. AB - BACKGROUND: Broad implementation of model-based dose-finding methods, such as the continual reassessment method (CRM), has been limited, with traditional or modified 3 + 3 designs remaining in frequent use. Part of the reason is the lack of reliable, easy-to-use, and robust software tools for designing and implementing more efficient designs. RESULTS: With the aim of augmenting broader implementation of model-guided methods, we have developed a web application for the Bayesian CRM in the R programming language using the Shiny package. The application has two components, simulation and implementation. Within the application, one has the ability to generate simulated operating characteristics for the study design phase, and to sequentially provide the next dose recommendation for each new accrual or cohort based on the current data for the study implementation phase. At the conclusion of the study, it can be used to estimate the maximum tolerated dose (MTD). The web tool requires no programming knowledge, and it is free to access on any device with an internet browser. CONCLUSIONS: The application provides the type of simulation information that aid clinicians and reviewers in understanding operating characteristics for the accuracy and safety of the CRM, which we hope will augment phase I trial design. We believe that the development of this software will facilitate more efficient collaborations within study teams conducting single-agent dose-finding trials. PMID- 29402248 TI - Acute and sub-acute oral toxicity of Dracaena cinnabari resin methanol extract in rats. AB - BACKGROUND: Dracaena cinnabari (DC) is a perennial tree that located on the Southern coast of Yemen native to the Socotra Island. This tree produces a deep red resin known as the Dragon's blood, the Twobrother's Blood or Damm Alakhwain. The current study performed to evaluate the safety of the DC resin methanol extract after a single or 28 consecutive daily oral administrations. METHODS: In assessing the safety of DC resin methanol extract, acute and sub-acute oral toxicity tests performed following OECD guidelines 423 and 407, respectively, with slight modifications. In acute oral toxicity test, DC resin methanol extract administered to female Sprague Dawley rats by oral gavage at a single dose of 300 and 2000 mg/kg body weight. Rats observed for toxic signs for 14 days. In sub acute oral toxicity test, DC resin methanol extract administered to the rats by oral gavage at 500, 1000, and 1500 mg/kg body weight daily up to 28 days to male and female Spradgue Dawley rats. The control and high dose in satellite groups were also maintained and handled as the previous groups to determine the late onset toxicity of DC resin methanol extract. At the end of each test, hematological and biochemical analysis of the collected blood were performed as well as gross and microscopic pathology. RESULTS: In acute oral toxicity, no treatment-related death or toxic signs were observed. It revealed that the DC resin methanol extract could be well tolerated up to the dose 2000 mg/kg body weight and could be classified as Category 5. The sub-acute test observations indicated that there are no treatment-related changes up to the high dose level compared to the control. Food consumption, body weight, organ weight, hematological parameters, biochemical parameters and histopathological examination (liver, kidney, heart, spleen and lung) revealed no abnormalities. Water intake was significantly higher in the DC resin methanol extract treated groups compared to the control. CONCLUSION: This study demonstrates tolerability of DC resin methanol extract administered daily for 28 days up to 1500 mg/kg dose. PMID- 29402250 TI - Prevalence and factors associated with sleep disorders among children with cerebral palsy in Uganda; a cross-sectional study. AB - BACKGROUND: Sleep plays a prominent role in the growth and development of children. Children with cerebral palsy (CP) are more prone to sleep disorders (SDs) than their peers. Children with CP, have a higher prevalence of disorders involving; initiation and maintenance of sleep, sleep-wake transition, excessive sleepiness and arousal. These sleep disorders impact on the quality of life of these children. Despite, having a high prevalence of CP in Uganda, there is a paucity of data that focuses on sleep disorders in CP, including a lack of prevalence estimates of sleep breathing disorder (SBD) in CP. Understanding the prevalence and disorders of sleep within this population would help advise on the development of tailored interventions to address the needs of these children and improve their quality of life. This study determined the prevalence and associated factors of sleep disorders among children aged 2 - 12 years with cerebral palsy in Uganda. METHODS: This was a cross sectional study. All participants had a physical examination and screening with the Sleep Disturbances Scale for Children (SDSC) questionnaire to determine the prevalence of sleeps disorders. A total score (TS) >= 51 on the Sleep Disturbances Scale for Children was regarded as abnormal. RESULTS: A total of 135 participants were recruited. The prevalence of sleep disorders was 43/135 (32%) with 95% CI: (24.0-39.7). The most common type of sleep disorders was a disorder of initiating and maintaining sleep 37(27%). The factors associated with sleep disorders among children with cerebral palsy were bilateral spasticity (p = 0.004); OR:(95%CI), 11.193: (2.1 - 59.0), lowest levels of gross motor function V (p = < 0.001); OR:(95%CI), 13.182: (3.7 - 47.0) or IV (p = 0.007); OR:(95%CI), 12.921: (2.0 - 82.3), lowest level of manual ability V (p = 0.004); OR:(95%CI), 11.162: (2.2 - 56.4) and presence of epilepsy (p = 0.011); OR:(95%CI), 3.865: (1.4 - 10.9). CONCLUSIONS: The prevalence of sleep disorders among children with cerebral palsy in Uganda is high. Severe disability and presence of epilepsy were associated with sleep disorders among children with cerebral palsy. PMID- 29402251 TI - Varicella zoster virus-associated Chorioretinitis: a case report. AB - BACKGROUND: Chorioretinitis is an unusual form of varicella zoster virus (VZV) associated uveitis, and no report has described VZV-associated chorioretinitis using serial optical coherence tomography (OCT) images obtained during the course of resolution. CASE PRESENTATION: A 61-year-old woman presented with acute, unilateral vision loss in her right eye. Her visual acuity was count fingers in the right eye and 16/20 in the left eye, and she exhibited skin vesicles on her right forehead. Slit lamp biomicroscopy, funduscopy, OCT, and intraocular fluid analysis were performed. The right eye exhibited multiple inflammatory lesions at the posterior pole, macular edema, and disc swelling on the fundus examination. OCT revealed predominant involvement of the choroid and the retinal pigment epithelium (RPE). Intraocular fluid analysis showed positivity for VZV. The patient was admitted and treated with intravenous acyclovir. Additional oral prednisolone was used to reduce the inflammatory reaction. After 2 weeks of treatment with acyclovir, the lesion resolved, with undulation of the RPE. Her final visual acuity was 20/20. CONCLUSIONS: VZV-associated posterior uveitis may present as multifocal chorioretinitis. Intraocular fluid analysis is important to detect an infectious origin. PMID- 29402252 TI - Pre-operative and intra-operative detection of axillary lymph node metastases in 108 patients with invasive lobular breast cancer undergoing mastectomy. AB - BACKGROUND: Despite the recent changes in the treatment of the axilla in selected breast cancer patient, positive sentinel lymph node (SLN) in patients undergoing mastectomy still necessitates axillary lymph node dissection (ALND). In invasive lobular carcinoma (ILC), pre-operative detection of the lymph node metastasis may be demanding due to its unique morphology. The aim of this study was to examine the benefit of preoperative axillary ultrasound (AUS), ultrasound-guided fine needle aspiration biopsy (US-FNAB), and intra-operative imprint cytology (IIC), in order to avoid two-stage axillary surgery in patients with ILC undergoing mastectomy. METHODS: The object of this study were 102 patients (median age 52, range 34-73 years) with clinically non-suspicious axilla in whom 108 mastectomies were performed after a pre-operative AUS investigation. Whenever a metastasis was detected in a sentinel lymph node, ALND was done. Reports of the pre-operative AUS investigation, US-FNAB, and IIC were compared with definitive histopathological reports of surgical specimens. RESULTS: In 46 cases lymph node metastases were diagnosed. AUS suspicious lymph nodes were found in 29/108 cases and histopathology confirmed metastases in 22/30 cases. US-FNAB was performed in 29 cases with AUS suspicious lymph nodes. Cytology proved metastases in 11/29 cases. Histopathology confirmed metastases in 10/11 cases with only isolated tumor cells found in one case. IIC investigation was performed in 63 cases and in 10/27 cases metastases were confirmed by histopathology. Pre-operative AUS, US FNAB, and/or IIC investigation enabled ALND during a single surgical procedure in 20/46 patients with metastases in lymph nodes. CONCLUSION: Pre-operative AUS, US FNAB, and/or IIC are/is beneficial in patients with ILC planned for mastectomy in order to decrease the number of two stage axillary procedures. PMID- 29402253 TI - Design of a study evaluating the effects, health economics, and stakeholder perspectives of a multi-component occupational rehabilitation program with an added workplace intervention - a study protocol. AB - BACKGROUND: Recent research has suggested that interventions at the workplace might be the most potent ingredient in return to work interventions, but few studies have investigated the different effects of workplace interventions as part of occupational rehabilitation programs. The comprehensive design described in this article includes effect (on return to work and health outcomes), and health economic evaluations of a workplace intervention added to a multicomponent rehabilitation program. Qualitative and mixed method studies will investigate sick-listed persons', rehabilitation therapists' and employers' perspectives on the usability and outcomes of the rehabilitation program and the workplace intervention. The program and intervention are provided to patients with musculoskeletal, psychological or general and unspecified diagnoses. The program is multi-component and includes Acceptance and Commitment Therapy, physical exercise, patient education and creating a plan for increased work participation. METHODS: Persons who are employed, aged from 18 to 60 years, with a current sick leave status of 50% or more and a diagnosis within the musculoskeletal, psychological or general and unspecified chapters of International Classification of Primary Care-2 (ICPC-2) will be recruited to a researcher-blinded parallel group randomized controlled trial. All participants take part in an in-patient occupational rehabilitation program, while the intervention group also takes part in an intervention at the workplace. The effect and economic evaluation will investigate the effect of the added workplace intervention. The primary outcome measures will be time until full sustainable return to work and total number of sickness absence days in the 12 months after inclusion. Health economic evaluations will investigate the cost-effectiveness and cost-utility. Qualitative studies will investigate rehabilitation therapists' experiences with working towards return to work within an ACT-approach and stakeholders' experiences with the workplace intervention. A mixed methods study will combine quantitative and qualitative findings on the participants' expectations and motivation for return to work. DISCUSSION: The outline of this comprehensive study could represent an important addition to the standard designs of return to work evaluation. The mixed methods design, with qualitative approaches as well as a rigorous randomized controlled trial, might prove useful to shed light on contextual factors. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02541890 . September 4, 2015. PMID- 29402254 TI - Serum and synovial fluid cytokine profiling in hip osteoarthritis: distinct from knee osteoarthritis and correlated with pain. AB - BACKGROUND: Inflammation is associated with the onset and progression of osteoarthritis in multiple joints. It is well known that mechanical properties differ between different joints, however, it remains unknown if the inflammatory process is similar/distinct in patients with hip vs. knee OA. Without complete understanding of the role of any specific cytokine in the inflammatory process, understanding the 'profile' of inflammation in a given patient population is an essential starting point. The aim of this study was to identify serum cytokine profiles in hip Osteoarthritis (OA), and investigate the association between cytokine concentrations and clinical measurements within this patient population and compare these findings to knee OA and healthy control cohorts. METHODS: In total, 250 serum samples (100 knee OA, 50 hip OA and 100 control) and 37 synovial fluid samples (8 knee OA, 14 hip OA and 15 control) were analyzed using a multiplex ELISA based approach. Synovial biopsies were also obtained and examined for specific cytokines. Pain, physical function and activity within the hip OA cohort were examined using the HOOS, SF-36, HHS and UCLA outcome measures. RESULTS: The three cohorts showed distinct serum cytokine profiles. EGF, FGF2, MCP3, MIP1alpha, and IL8 were differentially expressed between hip and knee OA cohorts; while FGF2, GRO, IL8, MCP1, and VEGF were differentially expressed between hip OA and control cohorts. Eotaxin, GRO, MCP1, MIP1beta, VEGF were differentially expressed between knee OA and control cohorts. EGF, IL8, MCP1, MIP1beta were differentially expressed in synovial fluid from a sub-set of patients from each cohort. Specifically within the hip OA cohort, IL-6, MDC and IP10 were associated with pain and were also found to be present in synovial fluid and synovial membrane (except IL-6) of patients with hip OA. CONCLUSION: OA may include different inflammatory subtypes according to affected joints and distinct inflammatory processes may drive OA in these joints. IL6, MDC and IP10 are associated with hip OA pain and these proteins may be able to provide additional information regarding pain in hip OA patients. PMID- 29402255 TI - Prevalence of positive depression screen among post miscarriage women- A cross sectional study. AB - BACKGROUND: Miscarriages are a common pregnancy complication affecting about 10 15% of pregnancies. Miscarriages may be associated with a myriad of psychiatric morbidity at various timelines after the event. Depression has been shown to affect about 10-20% of all women following a miscarriage. However, no data exists in the local setting informing on the prevalence of post-miscarriage depression. We set out to determine the prevalence of positive depression screen among women who have experienced a miscarriage at the Aga Khan University hospital, Nairobi. METHODS: The study was cross-sectional in design. Patients who had a miscarriage were recruited at the post-miscarriage clinic review at the gynecology clinics at Aga Khan University Hospital, Nairobi. The Edinburgh postpartum depression scale was used to screen for depression in the patients. Prevalence was calculated from the percentage of patients achieving the cut -off score of 13 over the total number of patients. RESULTS: A total of 182 patients were recruited for the study. The prevalence of positive depression screen was 34.1% since 62 of the 182 patients had a positive depression screen. Moreover, of the patients who had a positive depression screen, 21(33.1%) had thoughts of self-harm. CONCLUSION: A positive depression screen is present in 34.1% of women in our population two weeks after a miscarriage. Thoughts of self-harm are present in about a third of these women (33.1%) hence pointing out the importance of screening these women using the EPDS after a miscarriage. PMID- 29402256 TI - A qualitative analysis exploring preferred methods of peer support to encourage adherence to a Mediterranean diet in a Northern European population at high risk of cardiovascular disease. AB - BACKGROUND: Epidemiological and randomised controlled trial evidence demonstrates that adherence to a Mediterranean diet (MD) can reduce cardiovascular disease (CVD) risk. However, methods used to support dietary change have been intensive and expensive. Peer support has been suggested as a possible cost-effective method to encourage adherence to a MD in at risk populations, although development of such a programme has not been explored. The purpose of this study was to use mixed-methods to determine the preferred peer support approach to encourage adherence to a MD. METHODS: Qualitative (focus groups) and quantitative methods (questionnaire and preference scoring sheet) were used to determine preferred methods of peer support. Sixty-seven high CVD risk participants took part in 12 focus groups (60% female, mean age 64 years) and completed a questionnaire and preference scoring sheet. Focus group data were transcribed and thematically analysed. RESULTS: The mean preference score (1 being most preferred and 5 being least preferred) for group support was 1.5, compared to 3.4 for peer mentorship, 4.0 for telephone peer support and 4.0 for internet peer support. Three key themes were identified from the transcripts: 1. Components of an effective peer support group: discussions around group peer support were predominantly positive. It was suggested that an effective group develops from people who consider themselves similar to each other meeting face-to-face, leading to the development of a group identity that embraces trust and honesty. 2. Catalysing Motivation: participants discussed that a group peer support model could facilitate interpersonal motivations including encouragement, competitiveness and accountability. 3. Stepping Stones of Change: participants conceptualised change as a process, and discussed that, throughout the process, different models of peer support might be more or less useful. CONCLUSION: A group-based approach was the preferred method of peer support to encourage a population at high risk of CVD to adhere to a MD. This finding should be recognised in the development of interventions to encourage adoption of a MD in a Northern European population. PMID- 29402257 TI - Correction to: Tracking physical activity in different settings from late childhood to early adulthood in Germany: the MoMo longitudinal study. AB - CORRECTION: After publication of the article [1], it has been brought to our attention that the values cited under "indices t1-t0" have been reversed and should be displayed in the opposite order. The corrected Table 1 would appear as follows. PMID- 29402259 TI - Correction to: Retinal complications of gout: a case report and review of the literature. AB - CORRECTION: After publication of the article [1], it has been brought to our attention that the images displayed in Figs. 1, 2 and 3 have been transposed. PMID- 29402258 TI - Effects of home-based play-assisted stimulation on developmental performances of children living in extreme poverty: a randomized single-blind controlled trial. AB - BACKGROUND: Children living with foster families in a resource-limited setting such as Ethiopia are at risk of developmental problems. It is not yet clear whether intensive home-based developmental stimulation assisted by play can reduce these problems. The main objective of this study was to examine the effects of play-assisted intervention integrated into basic services on the developmental performance of children living with foster families in extreme poverty. METHODS: A randomized single-blind (investigator) controlled trial design was used. The study was conducted in Jimma, South West Ethiopia. Using computer-generated codes, eligible children of 3-59 months in age were randomly allocated to intervention (n = 39) and control (n = 39) groups at a 1:1 ratio. Children in the intervention group received home-based play-assisted stimulation in addition to the basic services provided to children in both groups. The intervention consisted of an hour of play stimulation conducted during a weekly home visit over the course of six months. Personal-social, language, fine and gross motor outcomes were assessed using Denver II-Jimma, and social-emotional outcome was obtained using an adapted Ages and Stages Questionnaire: Social Emotional (ASQ: SE). Information about sociodemographic characteristics was collected using a structured questionnaire. Anthropometric methods were used to determine nutritional status. The effects of the intervention on the abovementioned outcomes over the study period and group differences in change over time were examined using Generalized Estimating Equations (GEE). RESULTS: Statistically significant intervention effects were found for language (P = 0.0014), personal-social (P = 0.0087) and social-emotional (P < 0.0001) performances. At the midline of the study, language (effect size = 0.34) and social-emotional (effect size = - 0.603) benefits from the play-assisted stimulation had already been observed for the children in the intervention group. For language, the intervention effect depended on the child's sex (P = 0.0100) and for personal-social performance, on family income (P = 0.0300). CONCLUSIONS: Intensive home-based play-assisted stimulation reduced the developmental problems of children in foster families in the context of extreme poverty. Longer follow up may reveal further improvements in the developmental performance of the children. TRIAL REGISTRATION: The study was retrospectively registered on ClinicalTrials.gov on 17 November 2016, Study Identifier: NCT02988180 . PMID- 29402260 TI - Equity and efficiency of medical service systems at the provincial level of China's mainland: a comparative study from 2009 to 2014. AB - BACKGROUND: The astonishing economic achievements of China in the past few decades have remarkably increased not only the quantity and quality of medical services but also the inequalities in health resources allocation across regions and inefficiency of the medical service delivery. METHODS: A descriptive analysis was used to compare the inequities in inputs and outputs of the provincial medical service systems, a non-radial super-efficiency data envelopment analysis model was then used to estimate the efficiency, and a regression analysis of the panel data was used to explore the determinants. RESULTS: The inputs and outputs of most provincial medical service systems increased gradually from 2009 to 2014. Overall, the eastern region allocated more human and capital resources than the other two regions, and produced more than 50% of the total outpatient and emergency room visits, whereas the western region produced more inpatient services (about 30% of the total volume of inpatient services) according to the distribution of the population. The average efficiency scores of the provincial medical systems in China's mainland were 0.895, 0.927, 0.929, 0.963, 0.977 and 0.968 from 2009 to 2014, with a slight average improvement of 1.60%. The efficiency score of each provincial medical service system varied greatly from one another: Tibet (1.475 +/- 0.057) performed extremely well, whereas several others including Heilongjiang (0.579 +/- 0.001) performed poorly. Furthermore, the proportion of high-class medical facilities was negatively associated with efficiency, whereas the proportion of the vulnerable population, the per capita Gross Domestic Product, the proportion of the illiterate population and the improvement of primary health care had positive effects on efficiency. CONCLUSION: Inequity in health resources allocation and service provision existed across the regions, but not all the gaps have begun to narrow since 2009. The difference of efficiency was great among provincial medical service systems but minor across regions, and the score changed very little over time. More importantly, the central region held the lowest average efficiency score in the past 6 years, while the western region held the largest average efficiency score at the first 5 years, which should receive enough attention of the government and decision-makers. In practice, efficiency was related to many complicated factors, indicating that the improvement of efficiency is a complex and iterative process that requires the strong cooperation of many sectors. PMID- 29402261 TI - Biomechanical effects of metastasis in the osteoporotic lumbar spine: A Finite Element Analysis. AB - BACKGROUND: Cancer patients are likely to undergo osteoporosis as consequence of hormone manipulation and/or chemotherapy. Little is known about possible increased risk of fracture in this population. The aim of this study was to describe the biomechanical effect of a metastatic lesion in an osteoporotic lumbar spine model. METHODS: A finite element model of two spinal motion segments (L3-L5) was extracted from a previously developed L3-Sacrum model and used to analyze the effect of metastasis size and bone mineral density (BMD) on Vertebral bulge (VB) and Vertebral height (VH). VB and VH represent respectively radial and axial displacement and they have been correlated to burst fracture. A total of 6 scenarios were evaluated combining three metastasis sizes (no metastasis, 15% and 30% of the vertebral body) and two BMD conditions (normal BMD and osteoporosis). RESULTS: 15% metastasis increased VB and VH by 178% and 248%, respectively in normal BMD model; while VB and VH increased by 134% and 174% in osteoporotic model. 30% metastasis increased VB and VH by 88% and 109%, respectively, when compared to 15% metastasis in normal BMD model; while VB and VH increased by 59% and 74% in osteoporotic model. CONCLUSION: A metastasis in the osteoporotic lumbar spine always leads to a higher risk of vertebral fracture. This risk increases with the size of the metastasis. Unexpectedly, an increment in metastasis size in the normal BMD spine produces a greater impact on vertebral stability compared to the osteoporotic spine. PMID- 29402262 TI - Effects of Panax notoginseng saponins on severe acute pancreatitis through the regulation of mTOR/Akt and caspase-3 signaling pathway by upregulating miR-181b expression in rats. AB - BACKGROUND: In China, Panax notoginseng has been used to treat oxidative stress related diseases for a long time. Panax notoginseng saponins is an extract from Panax notoginseng Ledeb. Its therapeutic potential is related to antioxidant activity, but related mechanisms are still unclear. The study aims to assess the protection effects of Panax notoginseng saponins in the taurocholate-induced rat model of acute pancreatitis (AP) and explore underlying mechanisms. METHODS: A rat model of severe acute pancreatitis (SAP) was established in rats induced with taurocholate. Panax notoginseng saponins was firstly administered in the treatment group via intravenous injection. After 2 h, taurocholate administration was performed. After 24 h, the expression levels of miR-181b, Beclin1, LC3-II, Akt and mTOR from pancreas tissues were measured by Western Blotting and RT-PCR. Then the expression levels of Caspase-3 and Blc-2 were determined by immunohistochemistry. Apoptosis was assessed by the TUNEL assay. Amylase and lipase in serum were determined by ELISA and pancreatic water contents in pancreatic tissue were measured. After eosin and hematoxylin staining, the histologic analysis was performed. RESULTS: After SAP induction by taurocholate and the treatment with Panax notoginseng saponins for 24 h, we detected the up regulated miR-181b, the reduced Bcl-2 expression, the increased activity of mTOR/Akt, the blocked Beclin1 and LC3-II expressions, and the enhanced Caspase-3 expression. Serum lipase and amylase levels were significantly decreased in the treatment group of Panax notoginseng saponins compared to the control group. Histological analysis results verified the attenuation effects of Panax notoginseng saponins on taurocholate-induced pancreas injury, apoptosis, and autophagy. CONCLUSION: By up-regulating the miR-181b expression level, Panax notoginseng saponins significantly reduced taurocholate-induced pancreas injury and autophagy and increased apoptosis. The significant protection effects of Panax notoginseng saponins suggested its potential in treating taurocholate induced-acute pancreatitis. PMID- 29402263 TI - Effect of the 2015 earthquake on pediatric inpatient pattern at a tertiary care hospital in Nepal. AB - BACKGROUND: Earthquakes impact child health in many ways. Diseases occurring immediately following an earthquake have been studied in field based hospitals but studies on the inpatient disease pattern among children without trauma in a permanent hospital setup is lacking. METHODS: We examined the diagnoses of all children without trauma, admitted to Kanti Children's Hospital, Kathmandu for fifteen-week duration (from 4th week to end of the 18th week) following the 7.8 magnitude Nepal earthquake on 25th April 2015. The admitted children were grouped based on direct effect of earthquake on their family (house damaged or family member injured or dead) and on whether their place of residence was located in an earthquake affected district. Most common diagnoses were identified and their distribution between the aforementioned groups analyzed to examine differences, if any, in disease occurrence or presentation. The fifteen weeks study duration was divided into three parts of five weeks each, to study trends in illness presentation. Variables were compared among various groups using appropriate statistical tests (p < 0.05). RESULTS: A total of 1057 patients were admitted. The proportion of patients requiring admission for pneumonia, acute gastroenteritis and acute or poststreptococcal glomerulonephritis (AGN/PSGN) was significantly higher among children belonging to earthquake affected districts. Proportion of patients with any infective condition was also significantly higher in this group. Acute gastroenteritis and any infective condition were significantly higher among children from substantially affected families. The proportion of AGN/PSGN among admitted patients increased in successive time categories among patients from affected districts and from substantially affected families. Urinary Tract Infection, bronchiolitis, tuberculosis, pleural effusion, protein energy malnutrition/failure to thrive, nephrotic syndrome, meningitis/meningoencephalitis, epilepsy or seizure disorders, leukemia/malignancies, enteric fever, infective hepatitis and congenital heart disease were not significantly different among children from affected and not affected districts or between substantially affected and not affected families. Patients from substantially affected families were admitted to semi-intensive care ward or ICU in significantly higher proportions (12.6% vs 7.8%, p = 0.014). CONCLUSION: Children seeking care for certain diseases were more likely to be from earthquake affected families and districts. Those from affected families required critical care more often. PMID- 29402264 TI - Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients. AB - BACKGROUND: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients. METHODS: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence free (RFS) and distant metastasis-free (DMFS) survival. RESULTS: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). CONCLUSIONS: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively. PMID- 29402265 TI - A qualitative study of developing beliefs about health, illness and healthcare in migrant African women with gestational diabetes living in Sweden. AB - BACKGROUND: Gestational diabetes (GDM) is associated with health risks for both mother and child, and is particularly relevant to migrant women and women of African origin. With today's extensive global migration, contact with the new society and health system confronts the migrant's culture of origin with the culture of the host country. The question is whether immigrants' patterns of beliefs about health, illness, and health-related behaviour change over time, as no previous studies have been found on this topic. The purpose was to explore development over time, during and after pregnancy, of beliefs about health, illness and healthcare in migrant women with GDM born in Africa living in Sweden, and study the influence on self-care and care seeking. METHODS: Qualitative prospective study. Semi-structured interviews, with 9 women (23-40 years), on three different occasions: during pregnancy (gestational weeks 34-38), and 3 and 14 months after delivery managed at an in-hospital diabetes specialist clinic in Sweden. RESULTS: Beliefs were rather stable over time and mainly related to individual and social factors. GDM was perceived as a transient condition as health professionals had informed about it, which made them calm. None, except one, expressed worries about relapse and the health of the baby. Instead women worried about being unable to live an ordinary life and being bound to lifestyle changes, particularly diet, developing diabetes and needing insulin injections. Over time knowledge of appropriate diet improved, although no advice was experienced given by the clinic after delivery. The healthcare model was perceived as well functioning with easy access but regular follow-ups were requested as many (decreasing over time) were unsure whether they still had GDM and lacked information about GDM and diet. During pregnancy information was also requested about the healthcare system before/after delivery. CONCLUSIONS: Beliefs changed to a limited extent prospectively, indicated low risk awareness, limited knowledge of GDM, irrelevant worries about future health, and being unable to live a normal life, associated with problematic lifestyle changes. Beliefs about the seriousness of GDM in health professionals influenced patients' beliefs and health-related behaviour. The healthcare organisation urgently needs to be improved to deliver appropriate and timely information through competent staff. PMID- 29402266 TI - The gravitational force of mental health services: distance decay effects in a rural Swiss service area. AB - BACKGROUND: Previous research suggested a distance decay effect in health services systems, with people living closer to service facilities being more likely to use them. METHOD: In this ecological cross sectional study, we conducted spatial and statistical analyses in a Swiss mental health services system being legally bound to provide primary mental health care to approximately 620,000 inhabitants. We examined a cohort of all patients who were over 18 years old and who were treated in the mental health services system between January and December 2011. RESULTS: There were 5574 treatment cases during the 12-month period, 2161 inpatient cases and 3413 outpatient cases. Travel time by public transportation between patients' residence and the closest mental health service facility negatively predicted the utilization of outpatient services for all mental disorders, even after controlling for variability in ecological (e.g. socioeconomic) characteristics of the communities in the service provision area. For utilization of inpatient wards no geographical distance decay effect was observed, except for organic mental disorders. CONCLUSIONS: Based on these findings, outpatient clinics should be most effectively located decentralized and in the largest communities to meet the needs of the population as close as possible to where people live and to avoid remote areas being insufficiently supplied with mental health care. For mental hospitals and inpatient services decentralized location seems to be less important. PMID- 29402267 TI - In vivo validation of anti-malarial activity of crude extracts of Terminalia macroptera, a Malian medicinal plant. AB - BACKGROUND: Plasmodium falciparum malaria is still one of the most deadly pathology worldwide. Efficient treatment is jeopardized by parasite resistance to artemisinin and its derivatives, and by poor access to treatment in endemic regions. Anti-malarial traditional remedies still offer new tracks for identifying promising antiplasmodial molecules, and a way to ensure that all people have access to care. The present study aims to validate the traditional use of Terminalia macroptera, a Malian plant used in traditional medicine. METHODS: Terminalia macroptera was collected in Mali. Leaves (TML) and roots ethanolic extracts (TMR) were prepared and tested at 2000 mg/kg for in vivo acute toxicity in Albino Swiss mice. Antiplasmodial activity of the extracts was assessed against a chloroquine resistant strain P. falciparum (FcB1) in vitro. In vivo, anti-malarial efficacy was assessed by a 4-day suppressive test at 100 mg/kg in two malaria murine models of uncomplicated malaria (Plasmodium chabaudi chabaudi infection) and cerebral malaria (Plasmodium berghei strain ANKA infection). Constituents of TMR were characterized by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation pattern. RESULTS: Lethal dose of TML and TMR were greater than 2000 mg/kg in Albino Swiss mice. According to the OECD's Globally Harmonized System of Classification, both extracts are non-toxic orally. Antiplasmodial activity of T. macroptera extracts was confirmed in vitro against P. falciparum FcB1 strain with IC50 values of 1.2 and 1.6 ug/mL for TML and TMR, respectively. In vivo, oral administration of TML and TMR induced significant reduction of parasitaemia (37.2 and 46.4% respectively) in P. chabaudi chabaudi infected mice at the 7th day of infection compared to untreated mice. In the cerebral malaria experimental model, mice treated with TMR and TML presented respectively 50 and 66.7% survival rates at day 9 post-infection when all untreated mice died. Eleven major compounds were found in TMR. Among them, several molecules already known could be responsible for the antiplasmodial activity of the roots extract of T. macroptera. CONCLUSIONS: This study confirms both safety and anti-malarial activity of T. macroptera, thus validating its traditional use. PMID- 29402268 TI - True malaria prevalence in children under five: Bayesian estimation using data of malaria household surveys from three sub-Saharan countries. AB - BACKGROUND: Malaria is one of the major causes of childhood death in sub-Saharan countries. A reliable estimation of malaria prevalence is important to guide and monitor progress toward control and elimination. The aim of the study was to estimate the true prevalence of malaria in children under five in the Democratic Republic of the Congo, Uganda and Kenya, using a Bayesian modelling framework that combined in a novel way malaria data from national household surveys with external information about the sensitivity and specificity of the malaria diagnostic methods used in those surveys-i.e., rapid diagnostic tests and light microscopy. METHODS: Data were used from the Demographic and Health Surveys (DHS) and Malaria Indicator Surveys (MIS) conducted in the Democratic Republic of the Congo (DHS 2013-2014), Uganda (MIS 2014-2015) and Kenya (MIS 2015), where information on infection status using rapid diagnostic tests and/or light microscopy was available for 13,573 children. True prevalence was estimated using a Bayesian model that accounted for the conditional dependence between the two diagnostic methods, and the uncertainty of their sensitivities and specificities obtained from expert opinion. RESULTS: The estimated true malaria prevalence was 20% (95% uncertainty interval [UI] 17%-23%) in the Democratic Republic of the Congo, 22% (95% UI 9-32%) in Uganda and 1% (95% UI 0-3%) in Kenya. According to the model estimations, rapid diagnostic tests had a satisfactory sensitivity and specificity, and light microscopy had a variable sensitivity, but a satisfactory specificity. Adding reported history of fever in the previous 14 days as a third diagnostic method to the model did not affect model estimates, highlighting the poor performance of this indicator as a malaria diagnostic. CONCLUSIONS: In the absence of a gold standard test, Bayesian models can assist in the optimal estimation of the malaria burden, using individual results from several tests and expert opinion about the performance of those tests. PMID- 29402269 TI - Expression of a recombinant hybrid antimicrobial peptide magainin II-cecropin B in the mycelium of the medicinal fungus Cordyceps militaris and its validation in mice. AB - BACKGROUND: Antibiotic residues can cause antibiotic resistance in livestock and their food safety-related issues have increased the consumer demand for products lacking these residues. Hence, developing safe and effective antibiotic alternatives is important to the animal feed industry. With their strong antibacterial actions, antimicrobial peptides have potential as antibiotic alternatives. RESULTS: We investigated the antibacterial and immunomodulatory activities and the mechanisms of action of an antimicrobial peptide. The hybrid antimicrobial peptide magainin II-cecropin B (Mag II-CB) gene was transformed into the medicinal Cordyceps militaris fungus. Recombinant Mag II-CB exhibited broad-spectrum antibacterial activity in vitro and its antibacterial and immunomodulatory functions were evaluated in BALB/c mice infected with Escherichia coli (ATCC 25922). Histologically, Mag II-CB ameliorated E. coli related intestinal damage and maintained the integrity of the intestinal mucosal barrier by up-regulating tight junction proteins (zonula occludens-1, claudin-1 and occludin). The intestinal microbial flora was positively modulated in the Mag II-CB-treated mice infected with E. coli. Mag II-CB treatment also supported immune functioning in the mice by regulating their plasma immunoglobulin and ileum secreted immunoglobulin A levels, by attenuating their pro-inflammatory cytokine levels, and by elevating their anti-inflammatory cytokines levels. Moreover, directly feeding the infected mice with the C. militaris mycelium producing Mag II-CB further proofed the antibacterial and immunomodulatory functions of recombinant hybrid antimicrobial peptide. CONCLUSION: Our findings suggest that both purified recombinant AMPs and C. militaris mycelium producing AMPs display antibacterial and immunomodulatory activities in mice. And C. militaris producing AMPs has the potential to become a substitute to antibiotics as a feed additive for livestock in future. PMID- 29402270 TI - Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE). AB - BACKGROUND: Ultrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM). METHODS: This is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period. RESULTS: The mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted DeltaGSM = 2.40 +/- 1.19 [mean +/- SE], p = 0.044) but not in the conventional treatment group (adjusted DeltaGSM = 1.32 +/- 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups. CONCLUSIONS: A post hoc sub analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings. Trial registration UMIN000028664, Registered 15 August 2017 ("retrospectively registered"). PMID- 29402271 TI - Effect of diagnosis related groups implementation on the intensive care unit of a Swiss tertiary hospital: a cohort study. AB - BACKGROUND: In 2013 the Swiss Diagnosis Related Groups ((Swiss)-DRG) was implemented in Intensive Care Units (ICU). Its impact on hospitalizations has not yet been examined. We compared the number of ICU admissions, according to clinical severity and referring institution, and screened whether implementation of Swiss-DRG affected admission policy, ICU length-of-stay (ICU-LOS) or ICU mortality. METHODS: Retrospective, single centre, cohort study conducted at the University Hospital Zurich, Switzerland between January 2009 and end of September 2013. Demographic and clinical data was retrieved from a quality assurance database. RESULTS: Admissions (n = 17,231) before the introduction of Swiss-DRG were used to model expected admissions after DRG, and then compared to the observed admissions. Forecasting matched observations in patients with a high clinical severity admitted from internal units and external hospitals (admitted / predicted: 709 / 703, [95% Confidence Interval (CI), 658-748] and 302 / 332, [95% CI, 269-365] respectively). In patients with low severity of disease, in-house admissions became more frequent than expected and external admission were less frequent (admitted / predicted: 1972 / 1910, [95% CI, 1898-1940] and 436 / 518, [95% CI, 482-554] respectively). Various mechanisms related to Swiss-DRG may have led to these changes. DRG could not be linked to significant changes in regard to ICU-LOS and ICU mortality. CONCLUSIONS: DRG introduction had not affected ICU admissions policy, except for an increase of in-house patients with a low clinical severity of disease. DRG had neither affected ICU mortality nor ICU-LOS. PMID- 29402272 TI - Molecular analysis of carnivore Protoparvovirus detected in white blood cells of naturally infected cats. AB - BACKGROUND: Cats are susceptible to feline panleukopenia virus (FPV) and canine parvovirus (CPV) variants 2a, 2b and 2c. Detection of FPV and CPV variants in apparently healthy cats and their persistence in white blood cells (WBC) and other tissues when neutralising antibodies are simultaneously present, suggest that parvovirus may persist long-term in the tissues of cats post-infection without causing clinical signs. The aim of this study was to screen a population of 54 cats from Sardinia (Italy) for the presence of both FPV and CPV DNA within buffy coat samples using polymerase chain reaction (PCR). The DNA viral load, genetic diversity, phylogeny and antibody titres against parvoviruses were investigated in the positive cats. RESULTS: Carnivore protoparvovirus 1 DNA was detected in nine cats (16.7%). Viral DNA was reassembled to FPV in four cats and to CPV (CPV-2b and 2c) in four cats; one subject showed an unusually high genetic complexity with mixed infection involving FPV and CPV-2c. Antibodies against parvovirus were detected in all subjects which tested positive to DNA parvoviruses. CONCLUSIONS: The identification of FPV and CPV DNA in the WBC of asymptomatic cats, despite the presence of specific antibodies against parvoviruses, and the high genetic heterogeneity detected in one sample, confirmed the relevant epidemiological role of cats in parvovirus infection. PMID- 29402273 TI - In vitro assessment of nutraceutical compounds and novel nutraceutical formulations in a liver-steatosis-based model. AB - BACKGROUND: Steatosis is a chronic liver disease that depends on the accumulation of intracellular fatty acids. Currently, no drug treatment has been licensed for steatosis; thus, only nutritional guidelines are indicated to reduce its progression. The aim of this study is to combine different nutraceutical compounds in order to evaluate their synergistic effects on a steatosis in vitro model compared to their separate use. In particular, three different formulations based on silymarin, curcumin, vitamin E, docosahexaenoic acid (DHA), choline, and phosphatidylcholine were assayed. METHODS: Human hepatocellular carcinoma cells (HepG2 cell line) were treated with a mixture of fatty acids in order to induce an in vitro model of steatosic cells, and then the amount of intracellular fat was evaluated by Oil Red O staining. The peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and gamma) expression, closely correlated to lipid metabolism, was evaluated. The efficiency of these receptors was evaluated through the study of LPL mRNA expression, a marker involved in the lipolysis mechanism. Superoxide dismutase (SOD-2) and malondialdehydes (MDA) in lipid peroxidation were assayed as specific biomarkers of oxidative stress. In addition, experiments were performed using human liver cells stressed to obtain a steatosis model. In particular, the content of the intracellular fat was assayed using Oil Red O staining, the activation of PPARalpha and gamma was evaluated through western blotting analyses, and the LPL mRNA expression level was analyzed through qRT-PCR. RESULTS: All formulations proved effective on lipid content reduction of about 35%. The oxidative stress damage was reduced by all the substances separately and even more efficiently by the same in formulation (i.e. Formulation 1 and Formulation 3, which reduced the SOD-2 expression and induced the PPARs activation). Lipid peroxidation, was reduced about 2 fold by foormulation2 and up to 5 fold by the others compared to the cells pretreated with H2O2.Formulation 1, was more effective on PPARgamma expression (2.5 fold increase) respect to the other compounds on FA treated hepathocytes. Beside, LPL was activated also by Formulation 3 and resulted in a 5 to 9 fold-increase respect to FA treated control. CONCLUSIONS: Our results proved that the formulations tested could be considered suitable support to face steatosis disease beside the mandatory dietetic regimen. PMID- 29402274 TI - Entomological impact of indoor residual spraying with pirimiphos-methyl: a pilot study in an area of low malaria transmission in Senegal. AB - BACKGROUND: Scaling-up of effective anti-malarial control strategies in Central West region of Senegal has resulted in the sharp decline in malaria prevalence in this area. However, despite these strategies, residual malaria transmission has been observed in some villages (hot spots). The objective of this study was to assess the impact of indoor residual spraying (IRS) with pirimiphos-methyl on malaria transmission in hot spot areas. METHODS: The malaria vector population dynamics were monitored in each of the six selected villages (4 of which used IRS, 2 were unsprayed control areas) using overnight human landing catches (HLC) and pyrethrum spray catches (PSC). The host source of blood meals from freshly fed females collected using PSC was identified using the direct ELISA method. Females caught through HLC were tested by ELISA for the detection of Plasmodium falciparum circumsporozoite protein and Anopheles gambiae complex was identified using PCR. RESULTS: Preliminary data shown that the densities of Anopheles populations were significantly lower in the sprayed areas (179/702) compared to the control. Overall, malaria transmission risk was 14 times lower in the intervention zone (0.94) compared to the control zone (12.7). In the control areas, three Anopheles species belonging to the Gambiae complex (Anopheles arabiensis, Anopheles coluzzii and Anopheles melas) maintained the transmission, while only An. coluzzii was infective in the sprayed areas. CONCLUSION: The preliminary data from this pilot study showed that IRS with the CS formulation of pirimiphos-methyl is likely very effective in reducing malaria transmission risk. However, additional studies including further longitudinal entomological surveys as well as ecological and ethological and genetical characterization of vectors species and their populations are needed to better characterize the entomological impact of indoor residual spraying with pirimiphos-methyl in the residual transmission areas of Senegal. PMID- 29402276 TI - Establishment of a yeast-based VLP platform for antigen presentation. AB - BACKGROUND: Chimeric virus-like particles (VLP) allow the display of foreign antigens on their surface and have proved valuable in the development of safe subunit vaccines or drug delivery. However, finding an inexpensive production system and a VLP scaffold that allows stable incorporation of diverse, large foreign antigens are major challenges in this field. RESULTS: In this study, a versatile and cost-effective platform for chimeric VLP development was established. The membrane integral small surface protein (dS) of the duck hepatitis B virus was chosen as VLP scaffold and the industrially applied and safe yeast Hansenula polymorpha (syn. Pichia angusta, Ogataea polymorpha) as the heterologous expression host. Eight different, large molecular weight antigens of up to 412 amino acids derived from four animal-infecting viruses were genetically fused to the dS and recombinant production strains were isolated. In all cases, the fusion protein was well expressed and upon co-production with dS, chimeric VLP containing both proteins could be generated. Purification was accomplished by a downstream process adapted from the production of a recombinant hepatitis B VLP vaccine. Chimeric VLP were up to 95% pure on protein level and contained up to 33% fusion protein. Immunological data supported surface exposure of the foreign antigens on the native VLP. Approximately 40 mg of chimeric VLP per 100 g dry cell weight could be isolated. This is highly comparable to values reported for the optimized production of human hepatitis B VLP. Purified chimeric VLP were shown to be essentially stable for 6 months at 4 degrees C. CONCLUSIONS: The dS based VLP scaffold tolerates the incorporation of a variety of large molecular weight foreign protein sequences. It is applicable for the display of highly immunogenic antigens originating from a variety of pathogens. The yeast-based production system allows cost-effective production that is not limited to small scale fundamental research. Thus, the dS-based VLP platform is highly efficient for antigen presentation and should be considered in the development of future vaccines. PMID- 29402277 TI - Live birth after Laser Assisted Viability Assessment (LAVA) to detect pentoxifylline resistant ejaculated immotile spermatozoa during ICSI in a couple with male Kartagener's syndrome. AB - Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive disease with abnormalities in the structure of cilia, causing impairment of muco-ciliary clearance with respiratory tract infections, heterotaxia and abnormal sperm motility with male infertility. Here, with a comprehensive literature review, we report a couple with an infertility history of 9 years and three unsuccessful IVF treatments, where male partner has Kartagener's Syndrome, a subtype of PCD, displaying recurrent respiratory infections, dextrocardia and total asthenozoospermia. His diagnosis was verified with transmission electron microscopy and genetic mutation screening, revealing total absence of dynein arms in sperm tails and homozygous mutation in the ZMYND10, heterozygous mutations in the ARMC4 and DNAH5 genes. Laser assisted viability assay (LAVA) was performed by shooting the sperm tails during sperm retrieval for microinjection, following detection of pentoxifylline resistant immotile sperm. Live births of healthy triplets, one boy and two monozygotic girls, was achieved after double blastocyst transfer. PMID- 29402275 TI - Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion. AB - BACKGROUND: The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) has been shown to stimulate early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation. The aim of the present study is to probe the possibility to prevent the molecular changes induced by the BCCAO/R with dietary natural compounds known to possess anti-inflammatory activity, such as the phytocannabinoid beta caryophyllene (BCP). METHODS: Two groups of adult Wistar rats were used, sham operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half of the rats were gavage-fed with a single dose of BCP (40 mg/per rat in 300 MUl of sunflower oil as vehicle), while the second half were pre-treated with the vehicle alone. HPLC, Western Blot and immunohistochemistry were used to analyze cerebral cortex and plasma. RESULTS: After BCCAO/R, BCP prevented the increase of lipoperoxides occurring in the vehicle-treated rats in both cerebral cortex and plasma. In the frontal cortex, BCP further prevented activation of the endocannabinoid system (ECS), spared the docosahexaenoic acid (DHA), appeared to prevent the increase of cyclooxygenase-2 and increased the peroxisome proliferator activated receptor-alpha (PPAR-alpha) protein levels, while, in plasma, BCP induced the reduction of arachidonoylethanolamide (AEA) levels as compared to vehicle-treated rats. CONCLUSIONS: Collectively, the pre-treatment with BCP, likely acting as agonist for CB2 and PPAR-alpha receptors, modulates in a beneficial way the ECS activation and the lipoperoxidation, taken as indicative of oxidative stress. Furthermore, our results support the evidence that BCP may be used as a dietary supplement to control the physiological response to the hypoperfusion/reperfusion-induced oxidative stress. PMID- 29402278 TI - Participants' perceptions of interactions with community health workers who promote behavior change: a qualitative characterization from participants with normal, depressive and anxious mood states. AB - BACKGROUND: Interventions that promote healthier lifestyles among Latinos often involve community health workers (CHWs). CHWs can effectively advocate for healthier lifestyles and may be pivotal in addressing such mental health conditions as depression and anxiety. The goal of this study was to characterize the relationship dynamics between Latino participants and CHWs, from the participant's perspective. We aimed to determine if CHW-delivered community interventions effected behavior change, especially among participants who reported anxiety and depression. METHODS: Semi-structured interviews were conducted with a purposive sample of 28 Latino participants that was based on a mental health scoring strata. Participants completed a lifestyle intervention that included multiple home visits from CHWs to promote physical activity and healthful food choice. Interviews were conducted in the participant's preferred language (English or Spanish). Transcribed interviews were analyzed using a grounded theory approach until concept saturation was achieved. RESULTS: The sample was primarily female (82%), lower socioeconomic status (64%), and mean age of 50 years. Participants discussed the rapport building and professionalism of CHWs as a feature that facilitated strong, positive relationships and lifestyle behavior changes. Participants described how CHWs patterned their change approaches, which were similar to commonly used therapeutic techniques in the treatment of anxiety and depression. While anxiety and depression were described as having an impact on behavior change, most, but not all, participants who reported negative mood states said that the CHW relationship helped in changing that state to some extent. CONCLUSIONS: Participants' perceptions indicated that positive personal changes were influenced by CHWs. Only participants who reported consistently poor scores for depression, anxiety or both reported negative or neutral experiences with the CHWs. This study lends qualitative support to the use of CHWs as extenders of care, particularly in areas that have a shortage of primary and mental health care providers. PMID- 29402279 TI - Increase in relative skeletal muscle mass over time and its inverse association with metabolic syndrome development: a 7-year retrospective cohort study. AB - BACKGROUND: Skeletal muscle mass was negatively associated with metabolic syndrome prevalence in previous cross-sectional studies. The aim of this study was to investigate the impact of baseline skeletal muscle mass and changes in skeletal muscle mass over time on the development of metabolic syndrome in a large population-based 7-year cohort study. METHODS: A total of 14,830 and 11,639 individuals who underwent health examinations at the Health Promotion Center at Samsung Medical Center, Seoul, Korea were included in the analyses of baseline skeletal muscle mass and those changes from baseline over 1 year, respectively. Skeletal muscle mass was estimated by bioelectrical impedance analysis and was presented as a skeletal muscle mass index (SMI), a body weight-adjusted appendicular skeletal muscle mass value. Using Cox regression models, hazard ratio for developing metabolic syndrome associated with SMI values at baseline or changes of SMI over a year was analyzed. RESULTS: During 7 years of follow-up, 20.1% of subjects developed metabolic syndrome. Compared to the lowest sex specific SMI tertile at baseline, the highest sex-specific SMI tertile showed a significant inverse association with metabolic syndrome risk (adjusted hazard ratio [AHR] = 0.61, 95% confidence interval [CI] 0.54-0.68). Furthermore, compared with SMI changes < 0% over a year, multivariate-AHRs for metabolic syndrome development were 0.87 (95% CI 0.78-0.97) for 0-1% changes and 0.67 (0.56 0.79) for > 1% changes in SMI over 1 year after additionally adjusting for baseline SMI and glycometabolic parameters. CONCLUSIONS: An increase in relative skeletal muscle mass over time has a potential preventive effect on developing metabolic syndrome, independently of baseline skeletal muscle mass and glycometabolic parameters. PMID- 29402280 TI - Health status and air pollution related socioeconomic concerns in urban China. AB - BACKGROUND: China is experiencing environmental issues and related health effects due to its industrialization and urbanization. The health effects associated with air pollution are not just a matter of epidemiology and environmental science research, but also an important social science issue. Literature about the relationship of socioeconomic factors with the environment and health factors is inadequate. The relationship between air pollution exposure and health effects in China was investigated with consideration of the socioeconomic factors. METHODS: Based on nationwide survey data of China in 2014, we applied the multilevel mixed effects model to evaluate how socioeconomic status (represented by education and income) contributed to the relationship between self-rated air pollution and self rated health status at community level and individual level. RESULTS: The findings indicated that there was a non-linear relationship between the community socioeconomic status and community air pollution in urban China, with the highest level of air pollution presented in the communities with moderate socioeconomic status. In addition, health effects associated air pollution in different socioeconomic status groups were not equal. Self-rated air pollution had the greatest impact on self-rated health of the lower socioeconomic groups. With the increase of socioeconomic status, the effect of self-rated air pollution on self rated health decreased. CONCLUSIONS: This study verified the different levels of exposure to air pollution and inequality in health effects among different socioeconomic groups in China. It is imperative for the government to urgently formulate public policies to enhance the ability of the lower socioeconomic groups to circumvent air pollution and reduce the health damage caused by air pollution. PMID- 29402281 TI - Combining value of information analysis and ethical argumentation in decisions on participation of vulnerable patients in clinical research. AB - BACKGROUND: The participation of vulnerable patients in clinical research poses apparent ethical dilemmas. Depending on the nature of the vulnerability, their participation may challenge the ethical principles of autonomy, non-maleficence, or justice. On the other hand, non-participation may preclude the building of a knowledge base that is a prerequisite for defining the optimal clinical management of vulnerable patients. Such clinical uncertainty may also incur substantial economic costs. MAIN TEXT: We present the participation of pre menopausal women with atrial fibrillation in trials of novel oral anticoagulant drugs as a case study. Due to their non-participation in pivotal trials, it is uncertain whether for them, the risks that are associated with these drugs are outweighed by the advantages compared with conventional treatment. We addressed the question whether research of this new class of drugs in this subgroup would be appropriate from both, an ethical as well an economic perspective. We used the method of specifying norms as a wider framework to resolve the apparent ethical dilemma, while incorporating the question whether research of oral anticoagulants in premenopausal women with atrial fibrillation can be justified on economic grounds. For the latter, the results of a value-of-information analysis were used. CONCLUSIONS: Further clinical research on NOACs in premenopausal women with atrial fibrillation can be justified on both, ethical and economic grounds. Addressing apparent ethical dilemmas by invoking a method such as specifying norms can improve the quality of public practical reasoning. As such, the method should also prove valuable to committees that have formally been granted the authority to review trial protocols and proposals for scientific research. PMID- 29402282 TI - Clinical consequences of submicroscopic malaria parasitaemia in Uganda. AB - BACKGROUND: Submicroscopic malaria parasitaemia is common in both high- and low endemicity settings, but its clinical consequences are unclear. METHODS: A cohort of 364 children (0.5-10 years of age) and 106 adults was followed from 2011 to 2016 in Tororo District, Uganda using passive surveillance for malaria episodes and active surveillance for parasitaemia. Participants presented every 90 days for routine visits (n = 9075); a subset was followed every 30 days. Participants who presented with fever and a positive blood smear were treated for malaria. At all routine visits microscopy was performed and samples from subjects with a negative blood smear underwent loop-mediated isothermal amplification for detection of plasmodial DNA. RESULTS: Submicroscopic parasitaemia was common; the proportion of visits with submicroscopic parasitemia was 25.8% in children and 39.2% in adults. For children 0.5-10 years of age, but not adults, having microscopic and submicroscopic parasitaemia at routine visits was significantly associated with both fever (adjusted risk ratios [95% CI], 2.64 [2.16-3.22], 1.67 [1.37-2.03]) and non-febrile illness (aRR [CI], 1.52 [1.30-1.78], 1.26 [1.09 1.47]), compared to not having parasitaemia. After stratifying by age, significant associations were seen between submicroscopic parasitaemia and fever in children aged 2-< 5 and 5-10 years (aRR [CI], 1.42 [1.03-1.98], 2.01 [1.49 2.71]), and submicroscopic parasitaemia and non-febrile illness in children aged 5-10 years (aRR [CI], 1.44 [1.17-1.78]). These associations were maintained after excluding individuals with a malaria episode within the preceding 14 or following 7 days, and after adjusting for household wealth. CONCLUSIONS: Submicroscopic malaria infections were associated with fever and non-febrile illness in Ugandan children. These findings support malaria control strategies that target low density infections. PMID- 29402283 TI - High prevalence of malaria in a non-endemic setting: comparison of diagnostic tools and patient outcome during a four-year survey (2013-2017). AB - BACKGROUND: Malaria is no longer endemic in Italy since 1970 when the World Health Organization declared Italy malaria-free, but it is now the most commonly imported disease. The aim of the study was to analyse the trend of imported malaria cases in Parma, Italy, during January 2013-June 2017, reporting also the treatment and the outcome of cases, exploring the comparison of the three diagnostic tests used for malaria diagnosis: microscopy, immunochromatographic assay (ICT) (BinaxNOW(r)) and Real-time PCR assays detecting Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium knowlesi. RESULTS: Of the 288 patients with suspected malaria, 87 were positive by microscopy: 73 P. falciparum, 2 P. vivax, 8 P. ovale, 1 P. vivax/P. ovale, 1 P. malariae and 2 Plasmodium sp. All samples were positive by ICT except 6. Plasmodial DNA was revealed in the 87 cases and in 2 additional cases showing P. falciparum-specific bands by ICT, as follows: 75 P. falciparum, 2 P. vivax, 6 P. ovale curtisi, 3 P. ovale wallikeri, 1 P. malariae, and 2 mixed infections. 72 patients were foreigners and 17 Italians travelling for tourism or business. The majority of these patients presented with fever at blood collection and did not have chemoprophylaxis. No fatal cases were observed and the drug mostly used was quinine observing a negative blood smear or a parasitaemia < 0.001% after 48-72 h' therapy. CONCLUSIONS: The study shows an update and a thorough analysis of imported malaria cases in the area of Parma during 4.5 years from the point of view of the total case management, clinical and diagnostic. The prevalence of malaria in such area in the considered period was especially due to immigrants mostly from Africa. Molecular methods were more sensitive and specific than microscopy and ICT, both detecting additional cases of P. falciparum malaria missed by microscopy and correctly identifying the Plasmodium species of medical interest. The data reported in this study may stimulate the clinicians in non-endemic areas to suspect malaria also in cases, where the most typical symptoms are absent, and the parasitologists to confirm the results of microscopy, remaining the reference method, with molecular methods to avoid misdiagnosis. PMID- 29402284 TI - Metabolic characterization of menopause: cross-sectional and longitudinal evidence. AB - BACKGROUND: Women who experience menopause are at higher cardiometabolic risk and often display adverse changes in metabolic biomarkers compared with pre menopausal women. It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging. Well-conducted longitudinal studies are required to determine this. The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status, defined according to the 2012 Stages of Reproductive Aging Workshop criteria, with 74 metabolic biomarkers, and establish whether any associations are independent of age-related changes. METHODS: We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women. In a subgroup of 1,492 women who had repeat assessments after 2.5 years, we assessed how the change in reproductive status was associated with the changes in metabolic biomarkers. Metabolic profiles were measured by high-throughput quantitative nuclear magnetic resonance metabolomics. In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive-status category change to that of the reference of being pre-menopausal at both time points. As all women aged by a similar amount during follow-up, these analyses contribute to distinguishing age related changes from those related to change in reproductive status. RESULTS: Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting the transition to menopause induces multiple metabolic changes independent of chronological aging. The metabolic changes included increased concentrations of very small very low density lipoproteins, intermediate-density lipoproteins, low-density lipoproteins (LDLs), remnant, and LDL cholesterol, and reduced LDL particle size, all toward an atherogenic lipoprotein profile. Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein. Also, levels of glutamine and albumin increased during the transition. Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years. CONCLUSIONS: The transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory. The adverse changes in multiple apolipoprotein-B-containing lipoprotein subclasses and increased inflammation may underlie women's increased cardiometabolic risk in their post menopausal years. PMID- 29402285 TI - 18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis. AB - BACKGROUND: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F VC701, in combination with magnetic resonance imaging (MRI). METHODS: MOG35 55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. RESULTS: In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels. PMID- 29402286 TI - A review of the experimental evidence on the toxicokinetics of carbon monoxide: the potential role of pathophysiology among susceptible groups. AB - BACKGROUND: Acute high level carbon monoxide (CO) exposure can cause immediate cardio-respiratory arrest in anyone, but the effects of lower level exposures in susceptible persons are less well known. The percentage of CO-bound hemoglobin in blood (carboxyhemoglobin; COHb) is a marker of exposure and potential health outcomes. Indoor air quality guidelines developed by the World Health Organization and Health Canada, among others, are set so that CO exposure does not lead to COHb levels above 2.0%, a target based on experimental evidence on toxicodynamic relationships between COHb and cardiac performance among persons with cardiovascular disease (CVD). The guidelines do not consider the role of pathophysiological influences on toxicokinetic relationships. Physiological deficits that contribute to increased CO uptake, decreased CO elimination, and increased COHb formation can alter relationships between CO exposures and resulting COHb levels, and consequently, the severity of outcomes. Following three fatalities attributed to CO in a long-term care facility (LTCF), we queried whether pathologies other than CVD could alter CO-COHb relationships. Our primary objective was to inform susceptibility-specific modeling that accounts for physiological deficits that may alter CO-COHb relationships, ultimately to better inform CO management in LTCFs. METHODS: We reviewed experimental studies investigating relationships between CO, COHb, and outcomes related to health or physiological outcomes among healthy persons, persons with CVD, and six additional physiologically susceptible groups considered relevant to LTCF residents: persons with chronic obstructive pulmonary disease (COPD), anemia, cerebrovascular disease (CBD), heart failure, multiple co-morbidities, and persons of older age (>= 60 years). RESULTS: We identified 54 studies published since 1946. Six studies investigated toxicokinetics among healthy persons, and the remaining investigated toxicodynamics, mainly among healthy persons and persons with CVD. We identified one study each of CO dynamics in persons with COPD, anemia and persons of older age, and no studies of persons with CBD, heart failure, or multiple co-morbidities. Considerable heterogeneity existed for exposure scenarios and outcomes investigated. CONCLUSIONS: Limited experimental human evidence on the effects of physiological deficits relevant to CO kinetics exists to support indoor air CO guidelines. Both experimentation and modeling are needed to assess how physiological deficits influence the CO-COHb relationship, particularly at sub-acute exposures relevant to indoor environments. Such evidence would better inform indoor air quality guidelines and CO management in indoor settings where susceptible groups are housed. PMID- 29402287 TI - Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells. AB - BACKGROUND: Despite the implications for tumor growth and cancer drug resistance, the mechanisms underlying differences in energy metabolism among cells remain unclear. METHODS: To analyze differences between cell types, cell viability, ATP and alpha-ketoglutaric acid levels, the oxygen consumption rate and extracellular acidification rate, and the expression of key enzymes involved in alpha-KG metabolism and transfer were examined. Additionally, UPLC-MS/MS was used to determine the doxorubicin (DOX) content in SMMC-7721 and SMMC-7721/DOX cells. RESULTS: We found that energy metabolism in SMMC-7721 cells is mainly dependent on the glycolysis pathway, whereas SMMC-7721/DOX cells depend more heavily on the oxidative phosphorylation pathway. Cell viability and intracellular ATP levels in SMMC-7721/DOX cells were significantly reduced by rotenone and oligomycin, inhibitors of oxidative phosphorylation. However, SMMC-7721 cell properties were more strongly influenced by an inhibitor of glycolysis, 2-deoxy-D-glucose. Furthermore, the suppressive effect of alpha-KG on ATP synthase plays an important role in the low levels of oxidative phosphorylation in SMMC-7721 cells; this effect could be strengthened by the metabolic poison methotrexate and reversed by L-(-)-malic acid, an accelerator of the malate-aspartate cycle. CONCLUSIONS: The inhibitory effect of alpha-KG on ATP synthase was uncoupled with the tricarboxylic acid cycle and oxidative phosphorylation in SMMC-7721 cells; accordingly, energy metabolism was mainly determined by glycolysis. In drug resistant cells, a remarkable reduction in the inhibitory effects of alpha-KG on ATP synthase resulted in better coordination among the TCA cycle, oxidative phosphorylation, and glycolysis, providing novel potential strategies for clinical treatment of liver cancer resistance. PMID- 29402288 TI - Trends in parasite prevalence following 13 years of malaria interventions on Bioko island, Equatorial Guinea: 2004-2016. AB - BACKGROUND: Whilst there have been substantial reductions in malaria transmission over the past decade, in many countries in West and Central Africa the malaria burden remains high. Monitoring and evaluation of malaria transmission trends and intervention strategies are key elements for malaria control programmes. This study uses a time series of annual malaria indicator surveys to track the progress of malaria control in Bioko Island, Equatorial Guinea, over a 13 year period of intensive interventions. Malaria infection and haemoglobin were measured annually in children (1 to 14 years) in cross-sectional household surveys from 2004 to 2016 in 18 sentinel sites across the island. Trends in transmission patterns were assessed and the impact of the vector control interventions (net use and spray coverage) was evaluated. RESULTS: Between 2004 and 2016 approximately 106,500 individual tests for parasitaemia were conducted using rapid diagnostic tests. Although spray coverage remained relatively high (> 70%) over the time period, reported net usage was generally below 40%. Parasite prevalence reduced from 43.3 to 10.5% between 2004 and 2016. The prevalence of moderate to severe anaemia in children aged 1-5 years reduced from 14.9 to 1.6%. Impact in individual sites ranged from 57 to 100% reductions in parasite prevalence between 2004 and 2016. Sleeping under a net and living in a house that had been sprayed in the past 12 months were independently protective against infection (OR = 0.69 [95%CI 0.61-0.80] and OR = 0.87 [95% CI 0.78-0.97], respectively), whilst recent travel to the mainland increased the odds of infection nearly fourfold (OR = 3.94 [95%CI 2.79-5.56]). CONCLUSION: Island-wide interventions have resulted in a substantial reduction in malaria transmission on Bioko Island. This unique time series of 13 consecutive annual malaria indicator surveys clearly demonstrates the long-term effectiveness of the sustained use of two vector control interventions, indoor residual spraying and LLINs, and the value of comprehensive and sustained surveillance. Despite considerable success in reducing the burden on the island, malaria is still endemic, with populations in some areas remaining at high risk of infection. PMID- 29402289 TI - A comparison of five methods of measuring mammographic density: a case-control study. AB - BACKGROUND: High mammographic density is associated with both risk of cancers being missed at mammography, and increased risk of developing breast cancer. Stratification of breast cancer prevention and screening requires mammographic density measures predictive of cancer. This study compares five mammographic density measures to determine the association with subsequent diagnosis of breast cancer and the presence of breast cancer at screening. METHODS: Women participating in the "Predicting Risk Of Cancer At Screening" (PROCAS) study, a study of cancer risk, completed questionnaires to provide personal information to enable computation of the Tyrer-Cuzick risk score. Mammographic density was assessed by visual analogue scale (VAS), thresholding (Cumulus) and fully automated methods (Densitas, Quantra, Volpara) in contralateral breasts of 366 women with unilateral breast cancer (cases) detected at screening on entry to the study (Cumulus 311/366) and in 338 women with cancer detected subsequently. Three controls per case were matched using age, body mass index category, hormone replacement therapy use and menopausal status. Odds ratios (OR) between the highest and lowest quintile, based on the density distribution in controls, for each density measure were estimated by conditional logistic regression, adjusting for classic risk factors. RESULTS: The strongest predictor of screen-detected cancer at study entry was VAS, OR 4.37 (95% CI 2.72-7.03) in the highest vs lowest quintile of percent density after adjustment for classical risk factors. Volpara, Densitas and Cumulus gave ORs for the highest vs lowest quintile of 2.42 (95% CI 1.56-3.78), 2.17 (95% CI 1.41-3.33) and 2.12 (95% CI 1.30-3.45), respectively. Quantra was not significantly associated with breast cancer (OR 1.02, 95% CI 0.67-1.54). Similar results were found for subsequent cancers, with ORs of 4.48 (95% CI 2.79-7.18), 2.87 (95% CI 1.77-4.64) and 2.34 (95% CI 1.50 3.68) in highest vs lowest quintiles of VAS, Volpara and Densitas, respectively. Quantra gave an OR in the highest vs lowest quintile of 1.32 (95% CI 0.85-2.05). CONCLUSIONS: Visual density assessment demonstrated a strong relationship with cancer, despite known inter-observer variability; however, it is impractical for population-based screening. Percentage density measured by Volpara and Densitas also had a strong association with breast cancer risk, amongst the automated measures evaluated, providing practical automated methods for risk stratification. PMID- 29402290 TI - Clinical results of proton beam therapy for elderly patients with non-small cell lung cancer. AB - BACKGROUND: The purpose of the present study was to evaluate retrospectively the efficacy and safety of proton beam therapy for elderly patients (>=80 years of age) with non-small cell lung cancer. METHODS: Patients diagnosed with T1-4 N0 M0 non-small cell lung cancer and treated with proton beam therapy between January 2009 and 2015 were recruited from our database retrospectively. Toxicity was evaluated using The Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Thirty-five patients, including 25 (71%) with clinically inoperable lung cancer, were administered proton beam therapy. The median age was 82 years (range: 80-87 years), and the median follow-up time was 34 months (range: 10-72 months). The median dose of proton beam therapy was 80.0 Gy relative biological effectiveness (RBE) (range: 60.0-80.0 Gy [RBE]), and all patients completed the treatments. All patients were followed for at least 23 months or until their death. The 3-year overall survival rate was 67.2% (90.0% in patients with operable lung cancer, and 58.2% in those with inoperable lung cancer). The 3-year local control rate was 86.5%. Two patients presented with grade 2 pneumonitis. The occurrence rate of grade 2 pneumonitis was significantly correlated with a high lung V20 (p = 0.030), and a high mean lung dose (p = 0.030), and a low ratio of lung volume spared from 0.05 Gy (RBE) dose (total lung volume minus lung volume irradiated at least 0.05 Gy [RBE]) (p = 0.030). However, there were no cases of grade 3 or higher radiation pneumonitis. CONCLUSIONS: This study suggests that the proton beam therapy was feasible for elderly patients with non small cell lung cancer and can be considered as one of the treatment choices for elderly patients with lung cancer. PMID- 29402291 TI - Evaluating a dementia learning community: exploratory study and research implications. AB - BACKGROUND: Access times for, the costs and overload of hospital services are an increasingly salient issue for healthcare managers in many countries. Rising demand for hospital care has been attributed partly to unplanned admissions for older people, and among these partly to the increasing prevalence of dementia. The paper makes a preliminary evaluation of the logic model of a Dementia Learning Community (DLC) intended to reduce unplanned hospital admissions from care homes of people with dementia. A dementia champion in each DLC care home trained other staff in dementia awareness and change management with the aims of changing work routines, improving quality of life, and reducing demands on external services. METHODS: Controlled mixed methods realistic evaluation comparing 13 intervention homes with 10 controls in England during 2013-15. Each link in the assumed logic model was tested to find whether that link appeared to exist in the DLC sites, and if so whether its effects appeared greater there than in control sites, in terms of selected indicators of quality of life (DCM Well/Ill-Being, QUALID, end-of-life planning); and impacts on ambulance call-outs and hospital admissions. RESULTS: The training was implemented as planned, and triggered cycles of Plan-Do-Study-Act activity in all the intervention care homes. Residents' well-being scores, measured by dementia care mapping, improved markedly in half of the intervention homes but not in the other half, where indeed some scores deteriorated markedly. Most other care quality indicators studied did not significantly improve during the study period. Neither did ambulance call-out or emergency hospital admission rates. CONCLUSIONS: PDSA cycles appeared to be the more 'active ingredient' in this intervention. The reasons why they impacted on well-being in half of the intervention sites, and not the others, require further research. A larger, longer study would be necessary to measure definitively any impacts on unplanned hospital admissions. Our evidence suggested revising the DLC logic model to include care planning and staff familiarisation with residents' personal histories and needs as steps towards improving residents' quality of life. PMID- 29402292 TI - Geographic variation in health insurance benefits in Qianjiang District, China: a cross-sectional study. AB - BACKGROUND: Health insurance contributes to reducing the economic burden of disease and improving access to healthcare. In 2016, the Chinese government announced the integration of the New Cooperative Medical Scheme (NCMS) and Urban Resident Basic Medical Insurance (URBMI) to reduce system segmentation. Nevertheless, it was unclear whether there would be any geographic variation in health insurance benefits if the two types of insurance were integrated. The aim of this study was to identify the potential geographic variation in health insurance benefits and the related contributing factors. METHODS: This cross sectional study was carried out in Qianjiang District, where the NCMS and URBMI were integrated into Urban and Rural Resident Basic Medical Insurance Scheme (URRBMI) in 2010. All beneficiaries under the URRBMI were hospitalized at least once in 2013, totaling 445,254 persons and 65,877 person-times, were included in this study. Town-level data on health insurance benefits, healthcare utilization, and socioeconomic and geographical characteristics were collected through health insurance system, self-report questionnaires, and the 2014 Statistical Yearbook of Qianjiang District. A simplified Theil index at town level was calculated to measure geographic variation in health insurance benefits. Colored maps were created to visualize the variation in geographic distribution of benefits. The effects of healthcare utilization and socioeconomic and geographical characteristics on geographic variation in health insurance benefits were estimated with a multiple linear regression analysis. RESULTS: Different Theil index values were calculated for different towns, and the Theil index values for compensation by person-times and amount were 2.5028 and 1.8394 in primary healthcare institutions and 1.1466 and 0.9204 in secondary healthcare institutions. Healthcare-seeking behavior and economic factors were positively associated with health insurance benefits in compensation by person-times significantly, meanwhile, geographical accessibility and economic factors had positive effects (p < 0.05). CONCLUSIONS: The geographic variation in health insurance benefits widely existed in Qianjiang District and the distribution of health insurance benefits for insured inpatients in primary healthcare institutions was distinctly different from that in secondary healthcare institutions. When combining the NRCM and URMIS in China, the geographical accessibility, healthcare-seeking behavior and economic factors required significant attention. PMID- 29402293 TI - Genetic variants of RNASE3 (ECP) and susceptibility to severe malaria in Senegalese population. AB - BACKGROUND: Severe forms of malaria (SM) are an outcome of Plasmodium falciparum infection and can cause death especially in children under 4 years of age. RNASE3 (ECP) has been identified as an inhibitor of Plasmodium parasites growth in vitro, and genetic analysis in hospitalized Ghanaian subjects has revealed the RNASE3 +371G/C (rs2073342) polymorphism as a susceptibility factor for cerebral malaria. The +371 C allele results in an Arg/Thr mutation that abolishes the cytotoxic activity of the ECP protein. The present study aims to investigate RNASE3 gene polymorphisms and their putative link to severe malaria in a malaria cohort from Senegal. METHODS/RESULTS: Patients enrolled from hospitals were classified as having either uncomplicated (UM) or severe malaria (SM). The analysis of the RNASE3 gene polymorphisms was performed in 241 subjects: 178 falciparum infected (96 SM, 82 UM) and 63 non-infected subjects as population control group (CTR). Six frequent SNPs (MAF > 3%) were identified, and one SNP was associated with malaria severity by performing a logistic regression analysis SM vs.UM: RNASE3 +499G/C (rs2233860) under age, sex as covariates and HbS/HbC polymorphisms adjustment (p = 0.003, OR 0.43, CI 95% 0.20-0.92). The polymorphisms: +371G/C (rs2073342), +499G/C (rs2233860) and +577A/T (rs8019343) defined a haplotype risk (G-G-T) for malaria severity (Fisher exact test, p = 0.03) (OR 4.1, IC 95% (1.1-14.9). CONCLUSION: In addition to the previously described association of +371G/C polymorphism in Ghanaians cohort, the RNASE3 +499G/C polymorphism was associated with susceptibility to SM in a Senegalese population. The haplotype +371G/+499G/+577T defined by RNASE3 polymorphisms was associated with severity. The genetic association identified independently in the Senegalese population provide additional evidence of a role of RNASE3 (ECP) in malaria severity. PMID- 29402294 TI - An epidemiologic study of antimicrobial resistance of Staphylococcus species isolated from equine samples submitted to a diagnostic laboratory. AB - BACKGROUND: Antimicrobial resistance limits traditional treatment options and increases costs. It is therefore important to estimate the magnitude of the problem so as to provide empirical data to guide control efforts. The aim of this study was to investigate the burden and patterns of antimicrobial resistance (AMR) among equine Staphylococcus samples submitted to the University of Kentucky Veterinary Diagnostic Laboratory (UKVDL) from 1993 to 2009. Retrospective data of 1711 equine Staphylococcus samples submitted to the UKVDL during the time period 1993 to 2009 were included in the study. Antimicrobial susceptibility testing, that included 16 drugs, were performed using cultures followed by the Kirby-Bauer disk diffusion susceptibility test. The proportion of resistant isolates by animal breed, species of organism, sample source, and time period were computed. Chi-square and Cochran-Armitage trend tests were used to identify significant associations and temporal trends, respectively. Logistic regression models were used to investigate predictors of AMR and multidrug resistance (MDR). RESULTS: A total of 66.3% of the isolates were resistant to at least one antimicrobial, most of which were Staphylococcus aureus (77.1%), while 25.0% were MDR. The highest level of resistance was to penicillins (52.9%). Among drug classes, isolates had the highest rate of AMR to at least one type of beta-lactams (49.2%), followed by aminoglycosides (30.2%). Significant (p < 0.05) associations were observed between odds of AMR and horse breed, species of organism and year. Similarly, significant (p < 0.05) associations were identified between odds of MDR and breed and age. While some isolates had resistance to up to 12 antimicrobials, AMR profiles featuring single antimicrobials such as penicillin were more common than those with multiple antimicrobials. CONCLUSION: Demographic factors were significant predictors of AMR and MDR. The fact that some isolates had resistance to up to 12 of the 16 antimicrobials assessed is quite concerning. To address the high levels of AMR and MDR observed in this study, future studies will need to focus on antimicrobial prescription practices and education of both practitioners and animal owners on judicious use of antimicrobials to slow down the development of resistance. PMID- 29402295 TI - Thermal experiments with the Asian bush mosquito (Aedes japonicus japonicus) (Diptera: Culicidae) and implications for its distribution in Germany. AB - BACKGROUND: As ectothermic animals, temperature influences insects in almost every aspect. The potential disease spreading Asian bush mosquito (Aedes japonicus japonicus) is native to temperate East Asia but invasive in several parts of the world. We report on the previously poorly understood temperature dependence of its life history under laboratory conditions to understand invasion processes and to model temperature niches. RESULTS: To evaluate winter survival, eggs were exposed between 1 day and 14 days to low temperatures (5 degrees C, 0 degrees C, -5 degrees C and -9 degrees C). Hatching success was drastically decreased after exposure to 0 degrees C and -5 degrees C, and the minimal hatching success of 0% was reached at -9 degrees C after two days. We then exposed larvae to 14 temperatures and assessed their life trait parameters. Larval survival to adulthood was only possible between 10 degrees C and 31 degrees C. Based on this, we modelled the optimal (25 degrees C), minimal (7 degrees C) and maximal (31 degrees C) temperature for cumulative female survival. The time to adult emergence ranges from 12 days to 58 days depending on temperature. We used an age-at-emergence-temperature model to calculate the number of potential generations per year for the Asian bush mosquito in Germany with an average of 4.72 potential generations. At lower temperatures, individuals grew larger than at higher temperatures with female R1 length ranging from 3.04 +/- 0.1 mm at 31 degrees C to 4.26 +/- 0.2 mm at 15 degrees C. CONCLUSIONS: Reduced egg hatch after exposure to sub-zero temperatures prohibits the establishment of the Asian bush mosquito in large parts of Germany. Larval overwintering is not possible at temperature <= 5 degrees C. The many potential generations displayed per year may contribute to the species' invasion success. This study on the thermal ecology of the Asian bush mosquito adds to our knowledge on the temperature dependence of the species and data could be incorporated in epidemiological and population dynamic modelling. PMID- 29402296 TI - Sex disparity in the management and outcomes of dyslipidemia of diabetic patients in the Arabian Gulf: findings from the CEPHEUS study. AB - BACKGROUND: Little is known about sex gap in the management and outcomes of dyslipidemia among diabetics in the Arabian Gulf. The aim if this study was to determine sex differences in the management and outcomes of dyslipidemia in diabetic patients in the Arabian Gulf. METHODS: This study was derived from the Centralized Pan-Middle-East Survey on the management of hypercholesterolemia. Patients recruited were aged >=18 years on lipid lowering drugs for >=3 months (stable medication for >=6 weeks). Outcomes were based on the joint Consensus Statement of the American Diabetes Association and American College of Cardiology Foundation. Analyses were performed using univariate and multivariate logistic regression techniques. RESULTS: The mean age of the cohort (n = 3336) was 57 +/- 11 years and 45% (n = 1486) were females. Females were less likely to be on rosuvastatin (7.6% vs 12%; P < 0.001), atorvastatin (41% vs 46%; P = 0.005) and combination hypolipidemic therapy (5.6% vs 2.8%; P < 0.001) but more likely to be on simvastatin (51% vs 39%; P < 0.001) than males. Females, especially those with very high atherosclerotic cardiovascular disease (ASCVD) risk status, were also less likely to achieve LDL-cholesterol [adjusted odds ratio (aOR), 0.58; 95% confidence interval (CI): 0.40-0.86; P = 0.006], non-HDL-cholesterol [aOR, 0.68; 95% CI: 0.46-0.99; P = 0.048] and apolipoprotein B [aOR, 0.64; 95% CI: 0.44-0.92; P = 0.016] lipid targets. CONCLUSIONS: Diabetic women were less likely to be on optimal hypolipemic therapy and consequently less likely to attain lipid goals compared to men. This shows a sex gap on dyslipidemia treatment in the region. Diabetic women with very high ASCVD risk status need to be aggressively treated to lower their risk of cardiovascular events. PMID- 29402297 TI - COS-7-based model: methodological approach to study John Cunningham virus replication cycle. AB - John Cunningham virus (JCV) is a human neurotropic polyomavirus whose replication in the Central Nervous System (SNC) induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV propagation and PML investigation have been severely hampered by the lack of an animal model and cell culture systems to propagate JCV have been very limited in their availability and robustness. We previously confirmed that JCV CY strain efficiently replicated in COS-7 cells as demonstrated by the progressive increase of viral load by quantitative PCR (Q-PCR) during the time of transfection and that archetypal regulatory structure was maintained, although two characteristic point mutations were detected during the viral cycle. This short report is an important extension of our previous efforts in defining our reliable model culture system able to support a productive JCV infection.Supernatants collected from transfected cells have been used to infect freshly seeded COS-7 cell line. An infectious viral progeny was obtained as confirmed by Western blot and immunofluorescence assay. During infection, the archetype regulatory region was conserved.Importantly, in this study we developed an improved culture system to obtain a large scale production of JC virus in order to study the genetic features, the biology and the pathogenic mechanisms of JC virus that induce PML. PMID- 29402298 TI - Laparoscopic low anterior resection for rectal cancer with rectal prolapse: a case report. AB - BACKGROUND: Rectal cancer with rectal prolapse is rare, described by only a few case reports. Recently, laparoscopic surgery has become standard procedure for either rectal cancer or rectal prolapse. However, the use of laparoscopic low anterior resection for rectal cancer with rectal prolapse has not been reported. CASE PRESENTATION: A 63-year-old Japanese woman suffered from rectal prolapse, with a mass and rectal bleeding for 2 years. An examination revealed complete rectal prolapse and the presence of a soft tumor, 7 cm in diameter; the distance from the anal verge to the tumor was 5 cm. Colonoscopy demonstrated a large villous tumor in the lower rectum, which was diagnosed as adenocarcinoma on biopsy. We performed laparoscopic low anterior resection using the prolapsing technique without rectopexy. The distal surgical margin was more than 1.5 cm from the tumor. There were no major perioperative complications. Twelve months after surgery, our patient is doing well with no evidence of recurrence of either the rectal prolapse or the cancer, and she has not suffered from either fecal incontinence or constipation. CONCLUSIONS: Laparoscopic low anterior resection without rectopexy can be an appropriate surgical procedure for rectal cancer with rectal prolapse. The prolapsing technique is useful in selected patients. PMID- 29402299 TI - The significance of tumour microarchitectural features in breast cancer prognosis: a digital image analysis. AB - BACKGROUND: As only a minor portion of the information present in histological sections is accessible by eye, recognition and quantification of complex patterns and relationships among constituents relies on digital image analysis. In this study, our working hypothesis was that, with the application of digital image analysis technology, visually unquantifiable breast cancer microarchitectural features can be rigorously assessed and tested as prognostic parameters for invasive breast carcinoma of no special type. METHODS: Digital image analysis was performed using public domain software (ImageJ) on tissue microarrays from a cohort of 696 patients, and validated with a commercial platform (Visiopharm). Quantified features included elements defining tumour microarchitecture, with emphasis on the extent of tumour-stroma interface. The differential prognostic impact of tumour nest microarchitecture in the four immunohistochemical surrogates for molecular classification was analysed. Prognostic parameters included axillary lymph node status, breast cancer-specific survival, and time to distant metastasis. Associations of each feature with prognostic parameters were assessed using logistic regression and Cox proportional models adjusting for age at diagnosis, grade, and tumour size. RESULTS: An arrangement in numerous small nests was associated with axillary lymph node involvement. The association was stronger in luminal tumours (odds ratio (OR) = 1.39, p = 0.003 for a 1-SD increase in nest number, OR = 0.75, p = 0.006 for mean nest area). Nest number was also associated with survival (hazard ratio (HR) = 1.15, p = 0.027), but total nest perimeter was the parameter most significantly associated with survival in luminal tumours (HR = 1.26, p = 0.005). In the relatively small cohort of triple-negative tumours, mean circularity showed association with time to distant metastasis (HR = 1.71, p = 0.027) and survival (HR = 1.8, p = 0.02). CONCLUSIONS: We propose that tumour arrangement in few large nests indicates a decreased metastatic potential. By contrast, organisation in numerous small nests provides the tumour with increased metastatic potential to regional lymph nodes. An outstretched pattern in small nests bestows tumours with a tendency for decreased breast cancer-specific survival. Although further validation studies are required before the argument for routine quantification of microarchitectural features is established, our approach is consistent with the demand for cost effective methods for triaging breast cancer patients that are more likely to benefit from chemotherapy. PMID- 29402300 TI - Variability in gut mucosal secretory IgA in mice along a working day. AB - OBJECTIVE: To assess the variability of secretory immunoglobulin A (S-IgA) in the lumen and feces of mice along a working day. RESULTS: Mice were maintained under a 12 h light-dark cycle, light period starting at 8 AM. S-IgA was determined in feces and intestinal content (after one or three washes) at three points along the day: at the beginning, in the middle and at the end of the light period (ELP). Significant reduction in the content of S-IgA in the small intestine fluid and in feces was observed at the end of the light cycle, which coincides with the end of a regular working day (8 PM) in any given animal facility. It was also observed that three washes of the small intestine were more effective than one flush to recover a significant higher amount of S-IgA, with the smallest coefficient of variation observed by the ELP. A smaller CV would imply a reduced number of animals needed to achieve the same meaningful results. The results may be useful when designing animal trials for the selection of probiotic candidates based on their capacity of activating S-IgA, since it would imply a more rational use of experimental animals. PMID- 29402301 TI - Sialylation of EGFR by the ST6Gal-I sialyltransferase promotes EGFR activation and resistance to gefitinib-mediated cell death. AB - BACKGROUND: The ST6Gal-I sialyltransferase is upregulated in numerous cancers, and high expression of this enzyme correlates with poor patient prognosis in various malignancies, including ovarian cancer. Through its sialylation of a select cohort of cell surface receptors, ST6Gal-I modulates cell signaling to promote tumor cell survival. The goal of the present study was to investigate the influence of ST6Gal-I on another important receptor that controls cancer cell behavior, EGFR. Additionally, the effect of ST6Gal-I on cancer cells treated with the common EGFR inhibitor, gefitinib, was evaluated. RESULTS: Using the OV4 ovarian cancer cell line, which lacks endogenous ST6Gal-I expression, a kinomics assay revealed that cells with forced overexpression of ST6Gal-I exhibited increased global tyrosine kinase activity, a finding confirmed by immunoblotting whole cell lysates with an anti-phosphotyrosine antibody. Interestingly, the kinomics assay suggested that one of the most highly activated tyrosine kinases in ST6Gal-I-overexpressing OV4 cells was EGFR. Based on these findings, additional analyses were performed to investigate the effect of ST6Gal-I on EGFR activation. To this end, we utilized, in addition to OV4 cells, the SKOV3 ovarian cancer cell line, engineered with both ST6Gal-I overexpression and knockdown, as well as the BxPC3 pancreatic cancer cell line with knockdown of ST6Gal-I. In all three cell lines, we determined that EGFR is a substrate of ST6Gal-I, and that the sialylation status of EGFR directly correlates with ST6Gal-I expression. Cells with differential ST6Gal-I expression were subsequently evaluated for EGFR tyrosine phosphorylation. Cells with high ST6Gal-I expression were found to have elevated levels of basal and EGF-induced EGFR activation. Conversely, knockdown of ST6Gal-I greatly attenuated EGFR activation, both basally and post EGF treatment. Finally, to illustrate the functional importance of ST6Gal-I in regulating EGFR-dependent survival, cells were treated with gefitinib, an EGFR inhibitor widely used for cancer therapy. These studies showed that ST6Gal-I promotes resistance to gefitinib-mediated apoptosis, as measured by caspase activity assays. CONCLUSION: Results herein indicate that ST6Gal-I promotes EGFR activation and protects against gefitinib-mediated cell death. Establishing the tumor-associated ST6Gal-I sialyltransferase as a regulator of EGFR provides novel insight into the role of glycosylation in growth factor signaling and chemoresistance. PMID- 29402302 TI - Identification of a major quantitative trait locus underlying salt tolerance in 'Jidou 12' soybean cultivar. AB - BACKGROUND: Identification of the quantitative trait locus (QTL) underlying salt tolerance is a prerequisite for marker-assisted selection in the salt-tolerant breeding process. METHODS: In this study, the recombinant inbred lines derived from the salt-tolerant elite soybean cultivar 'Jidou 12' and the salt-sensitive elite cultivar 'Ji NF 58' were used to identify the QTL associated with salt tolerance, using both salt tolerance rating (STR) and leaf chlorophyll content (SPAD) as indicators. RESULTS: A major salt-tolerant QTL, which was flanked by SSR markers GMABAB and Barcsoyssr_03_1421 on chromosome 3, was identified based on single-marker regression, single trait composite interval mapping, and multiple interval mapping analysis. For STR, the LOD ranged from 19.8 to 20.1; R2 ranged from 44.3 to 44.7%; and the additive effect ranged from 0.876 to 0.885 among the three mapping methods. For SPAD, the LOD ranged from 10.6 to 11.0; R2 ranged from 27.0 to 27.6%; and the additive effect ranged from 1.634 to 1.679 among the three mapping methods. CONCLUSIONS: In this study, a major QTL conditioning salt tolerance on chromosome 3 was identified. The DNA markers closely associated with the QTLs might be useful in marker-assisted selection for soybean salt tolerance improvement in Huanghuaihai, China. PMID- 29402303 TI - Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation: study protocol for a randomized controlled trial. AB - BACKGROUND: Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due to the lack of high quality evidence. METHODS: An individual level, stepped-wedge randomised trial has been designed to allow observer-blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) pre-operative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates. DISCUSSION: An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks). TRIAL REGISTRATION: ISRCTN registry, ISRCTN11747152 . Registered on 30 September 2015. The trial was prospectively registered (first patient enrolled on 21 March 2016). PMID- 29402304 TI - Comprehensive characterization of chorionic villi-derived mesenchymal stromal cells from human placenta. AB - BACKGROUND: Studies in which mesenchymal stromal cells (MSC) from the placenta are compared with multiple MSC types from other sources are rare. The chorionic plate of the human placenta is mainly composed of fetal blood vessels embedded in fetal stroma tissue, lined by trophoblastic cells and organized into chorionic villi (CV) structures. METHODS: We comprehensively characterized human MSC collected from postnatal human chorionic villi of placenta (CV-MSC) by analyzing their growth and proliferation potential, differentiation, immunophenotype, extracellular matrix production, telomere length, aging phenotype, and plasticity. RESULTS: Immunophenotypic characterization of CV-MSC confirmed the typical MSC marker expression as defined by the International Society for Cellular Therapy. The surface marker profile was consistent with increased potential for proliferation, vascular localization, and early myogenic marker expression. CV-MSC retained multilineage differentiation potential and extracellular matrix remodeling properties. They have undergone reduced telomere loss and delayed onset of cellular senescence as they aged in vitro compared to three other MSC sources. We present evidence that increased human telomerase reverse transcriptase gene expression could not explain the exceptional telomere maintenance and senescence onset delay in cultured CV-MSC. Our in-vitro tumorigenesis detection assay suggests that CV-MSC are not prone to undergo malignant transformation during long-term in-vitro culture. Besides SOX2 expression, no other pluripotency features were observed in early and late passages of CV-MSC. CONCLUSIONS: Our work brings forward two remarkable characteristics of CV-MSC, the first being their extended life span as a result of delayed replicative senescence and the second being a delayed aged phenotype characterized by improved telomere length maintenance. MSC from human placenta are very attractive candidates for stem cell-based therapy applications. PMID- 29402305 TI - Assessment of the gorilla gut virome in association with natural simian immunodeficiency virus infection. AB - BACKGROUND: Simian immunodeficiency viruses (SIVs) of chimpanzees and gorillas from Central Africa crossed the species barrier at least four times giving rise to human immunodeficiency virus type 1 (HIV-1) groups M, N, O and P. The paradigm of non-pathogenic lentiviral infections has been challenged by observations of naturally infected chimpanzees with SIVcpz associated with a negative impact on their life span and reproduction, CD4+ T-lymphocyte loss and lymphoid tissue destruction. With the advent and dissemination of new generation sequencing technologies, novel promising markers of immune deficiency have been explored in human and nonhuman primate species, showing changes in the microbiome (dysbiosis) that might be associated with pathogenic conditions. The aim of the present study was to identify and compare enteric viromes of SIVgor-infected and uninfected gorillas using noninvasive sampling and ultradeep sequencing, and to assess the association of virome composition with potential SIVgor pathogenesis in their natural hosts. RESULTS: We analyzed both RNA and DNA virus libraries of 23 fecal samples from 11 SIVgor-infected (two samples from one animal) and 11 uninfected western lowland gorillas from Campo-Ma'an National Park (CP), in southwestern Cameroon. Three bacteriophage families (Siphoviridae, Myoviridae and Podoviridae) represented 67.5 and 68% of the total annotated reads in SIVgor-infected and uninfected individuals, respectively. Conversely, mammalian viral families, such as Herpesviridae and Reoviridae, previously associated with gut- and several mammalian diseases were significantly more abundant (p < 0.003) in the SIVgor infected group. In the present study, we analyzed, for the first time, the enteric virome of gorillas and their association with SIVgor status. This also provided the first evidence of association of specific mammalian viral families and SIVgor in a putative dysbiosis context. CONCLUSIONS: Our results suggested that viromes might be potentially used as markers of lentiviral disease progression in wild gorilla populations. The diverse mammalian viral families, herein described in SIVgor-infected gorillas, may play a pivotal role in a disease progression still unclear in these animals but already well characterized in pathogenic lentiviral infections in other organisms. Larger sample sets should be further explored to reduce intrinsic sampling variation. PMID- 29402306 TI - Sustainable reduction of antibiotic-induced antimicrobial resistance (ARena) in German ambulatory care: study protocol of a cluster randomised trial. AB - BACKGROUND: Despite many initiatives to enhance the rational use of antibiotics, there remains substantial room for improvement. The overall aim of this study is to optimise the appropriate use of antibiotics in German ambulatory care in patients with acute non-complicated infections (respiratory tract infections, such as bronchitis, sinusitis, tonsillitis and otitis media), community-acquired pneumonia and non-complicated cystitis, in order to counter the advancing antimicrobial resistance development. METHODS: A three-armed cluster randomised trial will be conducted in 14 practice networks in two German federal states (Bavaria and North Rhine-Westphalia) and an added cohort that reflects standard care. The trial is accompanied by a process evaluation. Each arm will receive a different set of implementation strategies. Arm A receives a standard set, comprising of e-learning on communication with patients and quality circles with data-based feedback for physicians, information campaigns for the public, patient information material and performance-based additional reimbursement. Arm B receives this standard set plus e-learning on communication with patients and quality circles with data-based feedback tailored for non-physician health professionals of the practice team and information material for tablet computers (culture sensitive). Arm C receives the standard set as well as a computerised decision support system and quality circles in local multidisciplinary groups. The study aims to recruit 193 practices which will provide data on 23,934 patients each year (47,867 patients in total). The outcome evaluation is based on claims data and refers to established indicators of the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). Primary and secondary outcomes relate to prescribing of antibiotics, which will be analysed in multivariate regression models. The process evaluation is based on interviews with surveys among physicians, non-physician health professionals of the practice team and stakeholders. A patient survey is conducted in one of the study arms. Interview data will be qualitatively analysed using thematic framework analysis. Survey data of physicians, non-physician health professionals of the practice team and patients will use descriptive and exploratory statistics for analysis. DISCUSSION: The ARena trial will examine the effectiveness of large scale implementation strategies and explore their delivery in routine practice. TRIAL REGISTRATION: ISRCTN, ISRCTN58150046 . Registered 24 August 2017. PMID- 29402307 TI - Water intake among Ghanaian youth aged 15-34 years: quantitative and qualitative evidence. AB - BACKGROUND: The prevalence of obesity is on the increase in Ghana, and the intake of sugar-sweetened beverages may be a determinant. The aim of this study is to use quantitative and qualitative data to investigate water intake among Ghanaian youth 15-34 years old. METHODS: The 2008 Ghana Demographic and Health Survey data is used to investigate the effects of socio-demographic factors on water intake behaviours of a sample of 2771 male and 2806 female youth aged 15-34 years old in Ghana. Additionally, data from focus group discussions are used to examine perceptions with regard to water intake. In terms of the analysis, the quantitative bit of the data utilised Stata software and the qualitative data used the Atlas Ti software. Percentages, means, standard deviations, t test, one way ANOVA, Tukey's post hoc test and Poisson regression were used for the quantitative analysis while the qualitative data was analysed thematically. RESULTS: Quantitative results found that age (IRR = 1.112, 95% CI 1.070-1.156) and region of residence (IRR = 0.855, 95% CI 0.780-0.937; IRR = 0.910, 95% CI 0.834-0.993) were important predictors of water intake in males, while age (IRR = 1.103, 95% CI 1.054-1.153), region of residence (IRR = 0.907, 95% CI 0.844-0.975; IRR = 1.258, 95% CI 1.130-1.400), ethnicity (IRR = 0.919, 95% CI 0.834-1.013) and marital status (IRR = 1.051, 95% CI 0.999-1.106) were found to be important predictors of water intake among females. From the focus group discussion, accessibility and physiological factors were mentioned as issues hampering adequate water intake. CONCLUSION: The similarities and differences between males and females should sensitise policy makers to the need for more gender-specific interventions to encourage water intake for the purposes of preventing non communicable diseases. Moreover, intervention(s) to promote water intake should address issues of accessibility, physiological factors, weather and weight management. PMID- 29402308 TI - Cavernous sinus involvement is not a risk factor for the primary tumor site treatment outcome of Sinonasal adenoid cystic carcinoma. AB - BACKGROUND: Sinonasal adenoid cystic carcinoma is a rare malignancy of the head and neck. Cavernous sinus invasion from sinonasal adenoid cystic carcinoma and its related management have rarely been investigated. This study evaluated the relationship between treatment outcome and cavernous sinus involvement in addition to other parameters. METHODS: A retrospective case series study was conducted at a tertiary referral center. The medical records of 47 patients diagnosed with primary sinonasal adenoid cystic carcinoma between 1984 and 2015 were retrospectively reviewed. The survival impact of the primary treatment modalities and the anatomic sites of tumor involvement were analyzed. RESULTS: Cavernous sinus invasion was observed in 8 patients (17%), of whom 7 had ACC tumors originating from the maxillary sinus. The results of univariate analysis revealed that tumor stage, primary surgery, and the absence of skull-base and infratemporal fossa invasion were associated with better overall survival (P = 0.033, P = 0.012, P = 0.011, and P = 0.040, respectively) and better disease-free survival (P = 0.019, P = 0.001, P = 0.017, and P = 0.029, respectively). Multivariate analysis identified primary surgery as the only independent prognostic factor for disease-free survival (P = 0.026). Cavernous sinus invasion by sinonasal adenoid cystic carcinoma was not associated with worse overall survival or disease-free survival (P = 0.200 and P = 0.198, respectively). CONCLUSIONS: Because maxillary adenoid cystic carcinoma is associated with a higher rate of cavernous sinus invasion, such cases warrant caution during preoperative planning. Primary surgery as the initial therapy provides better locoregional control and survival for patients with sinonasal adenoid cystic carcinoma. Cavernous sinus invasion did not significantly impact survival; thus, it should not be regarded as a contraindication for curative treatment. PMID- 29402309 TI - Embryonic stem cell-derived cardiomyocytes for the treatment of doxorubicin induced cardiomyopathy. AB - BACKGROUND: Doxorubicin (Dox) is a chemotherapy drug with limited application due to cardiotoxicity that may progress to heart failure. This study aims to evaluate the role of cardiomyocytes derived from mouse embryonic stem cells (CM-mESCs) in the treatment of Dox-induced cardiomyopathy (DIC) in mice. METHODS: The mouse embryonic stem cell (mESC) line E14TG2A was characterized by karyotype analysis, gene expression using RT-PCR and immunofluorescence. Cells were transduced with luciferase 2 and submitted to cardiac differentiation. Total conditioned medium (TCM) from the CM-mESCs was collected for proteomic analysis. To establish DIC in CD1 mice, Dox (7.5 mg/kg) was administered once a week for 3 weeks, resulting in a cumulative Dox dose of 22.5 mg/kg. At the fourth week, a group of animals was injected intramyocardially with CM-mESCs (8 * 105 cells). Cells were tracked by a bioluminescence assay, and the body weight, echocardiogram, electrocardiogram and number of apoptotic cardiomyocytes were evaluated. RESULTS: mESCs exhibited a normal karyotype and expressed pluripotent markers. Proteomic analysis of TCM showed proteins related to the negative regulation of cell death. CM-mESCs presented ventricular action potential characteristics. Mice that received Dox developed heart failure and showed significant differences in body weight, ejection fraction (EF), end-systolic volume (ESV), stroke volume (SV), heart rate and QT and corrected QT (QTc) intervals when compared to the control group. After cell or placebo injection, the Dox + CM-mESC group showed significant increases in EF and SV when compared to the Dox + placebo group. Reduction in ESV and QT and QTc intervals in Dox + CM-mESC-treated mice was observed at 5 or 30 days after cell treatment. Cells were detected up to 11 days after injection. The Dox + CM-mESC group showed a significant reduction in the percentage of apoptotic cardiomyocytes in the hearts of mice when compared to the Dox + placebo group. CONCLUSIONS: CM-mESC transplantation improves cardiac function in mice with DIC. PMID- 29402310 TI - fNIRS-based Neurorobotic Interface for gait rehabilitation. AB - BACKGROUND: In this paper, a novel functional near-infrared spectroscopy (fNIRS) based brain-computer interface (BCI) framework for control of prosthetic legs and rehabilitation of patients suffering from locomotive disorders is presented. METHODS: fNIRS signals are used to initiate and stop the gait cycle, while a nonlinear proportional derivative computed torque controller (PD-CTC) with gravity compensation is used to control the torques of hip and knee joints for minimization of position error. In the present study, the brain signals of walking intention and rest tasks were acquired from the left hemisphere's primary motor cortex for nine subjects. Thereafter, for removal of motion artifacts and physiological noises, the performances of six different filters (i.e. Kalman, Wiener, Gaussian, hemodynamic response filter (hrf), Band-pass, finite impulse response) were evaluated. Then, six different features were extracted from oxygenated hemoglobin signals, and their different combinations were used for classification. Also, the classification performances of five different classifiers (i.e. k-Nearest Neighbour, quadratic discriminant analysis, linear discriminant analysis (LDA), Naive Bayes, support vector machine (SVM)) were tested. RESULTS: The classification accuracies obtained from SVM using the hrf were significantly higher (p < 0.01) than those of the other classifier/ filter combinations. Those accuracies were 77.5, 72.5, 68.3, 74.2, 73.3, 80.8, 65, 76.7, and 86.7% for the nine subjects, respectively. CONCLUSION: The control commands generated using the classifiers initiated and stopped the gait cycle of the prosthetic leg, the knee and hip torques of which were controlled using the PD CTC to minimize the position error. The proposed scheme can be effectively used for neurofeedback training and rehabilitation of lower-limb amputees and paralyzed patients. PMID- 29402311 TI - Hepatic stem cells with self-renewal and liver repopulation potential are harbored in CDCP1-positive subpopulations of human fetal liver cells. AB - BACKGROUND: Mature human hepatocytes are critical in preclinical research and therapy for liver disease, but are difficult to manipulate and expand in vitro. Hepatic stem cells (HpSCs) may be an alternative source of functional hepatocytes for cell therapy and disease modeling. Since these cells play an import role in regenerative medicine, the precise characterization that determines specific markers used to isolate these cells as well as whether they contribute to liver regeneration still remain to be shown. METHOD: In this study, human HpSCs were isolated from human primary fetal liver cells (FLCs) by flow cytometry using CDCP1, CD90, and CD66 antibodies. The isolated CDCP1+CD90+CD66- HpSCs were cultured on dishes coated with type IV collagen in DMEM nutrient mixture F-12 Ham supplemented with FBS, human gamma-insulin, nicotinamide, dexamethasone, and L glutamine for at least 2 weeks, and were characterized by transcriptomic profiling, quantitative real-time PCR, immunocytochemistry, and in-vivo transplantation. RESULTS: The purified CDCP1+CD90+CD66- subpopulation exhibited clonal expansion and self-renewal capability, and bipotential capacity was further identified in single cell-derived colonies containing distinct hepatocytes and cholangiocytes. Moreover, in-vivo liver repopulation assays demonstrated that human CDCP1+CD90+CD66- HpSCs repopulated over 90% of the mouse liver and differentiated into functional hepatocytes with drug metabolism activity. CONCLUSIONS: We identified a human hepatic stem/progenitor population in the CDCP1+CD90+CD66- subpopulation in human FLCs, indicating CDCP1 marker could potentially be utilized to identify and isolate HpSCs for further cytotherapy of liver disease. PMID- 29402312 TI - Perceptions and experiences of community first responders on their role and relationships: qualitative interview study. AB - BACKGROUND: Community First Responders (CFRs) are lay volunteers who respond to medical emergencies. We aimed to explore perceptions and experiences of CFRs in one scheme about their role. METHODS: We conducted semi-structured interviews with a purposive sample of CFRs during June and July 2016 in a predominantly rural UK county. Interviews were transcribed verbatim and analysed using the Framework method, supported by NVivo 10. RESULTS: We interviewed four female and 12 male adult CFRs aged 18-65+ years with different levels of expertise and tenures. Five main themes were identified: motivation and ongoing commitment; learning to be a CFR; the reality of being a CFR; relationships with statutory ambulance services and the public; and the way forward for CFRs and the scheme. Participants became CFRs mainly for altruistic reasons, to help others and put something back into their community, which contributed to personal satisfaction and helped maintain their involvement over time. CFRs valued scenario-based training and while some were keen to access additional training to enable them to attend a greater variety of incidents, others stressed the importance of maintaining existing abilities and improving their communication skills. They were often first on scene, which they recognised could take an emotional toll but for which they found informal support mechanisms helpful. Participants felt a lack of public recognition and sometimes were undervalued by ambulance staff, which they thought arose from a lack of clarity over their purpose and responsibilities. Although CFRs perceived their role to be changing, some were fearful of extending the scope of their responsibilities. They welcomed support for volunteers, greater publicity and help with fundraising to enable schemes to remain charities, while complementing the role of ambulance services. DISCUSSION: CFR schemes should consider the varying training, development and support needs of staff. CFRs wanted schemes to be complementary but distinct from ambulance services. Further information on outcomes and costs of the CFR contribution to prehospital care is needed. CONCLUSION: Our findings provide insight into the experiences of CFRs, which can inform how the role might be better supported. Because CFR schemes are voluntary and serve defined localities, decisions about levels of training, priority areas and targets should be locally driven. Further research is required on the effectiveness, outcomes, and costs of CFR schemes and a wider understanding of stakeholder perceptions of CFR and CFR schemes is also needed. PMID- 29402314 TI - Identifying priority technical and context-specific issues in improving the conduct, reporting and use of health economic evaluation in low- and middle income countries. AB - BACKGROUND: The use of economic evaluation in healthcare policies and decision making, which is limited in low- and middle-income countries (LMICs), might be promoted through the improvement of the conduct and reporting of studies. Although the literature indicates that there are many issues affecting the conduct, reporting and use of this evidence, it is unclear which factors should be prioritised in finding solutions. This study aims to identify the top priority issues that impede the conduct, reporting and use of economic evaluation as well as potential solutions as an input for future research topics by the international Decision Support Initiative and other movements. METHODS: A survey on issues regarding the conduct, reporting and use of economic evaluation as well as on potential solutions was conducted using an online questionnaire among researchers who have experience in conducting economic evaluations in LMICs. The respondents were requested to consider the list of issues provided, rank the most important ones and propose solutions. A scoring system was applied to derive the ranking of difficulties according to researchers' responses. Issues were grouped into technical and context-specific difficulties and analysed separately as a whole and by region. RESULTS: Researchers considered the lack of quality local clinical data, poor reporting and insufficient data to conduct the analysis from the chosen perspective as the most important technical difficulties. On the other hand, the non-integration of economic evaluations into decision-making was considered the most important context-specific issue. Finally, context-specific issues were considered the larger barrier to the use of economic evaluation. CONCLUSION: The technical issues that were considered most important were closely linked with the lack of an appropriately functioning information system as well as the capacity to generate essential contextual information (e.g. data and locally relevant utility values), especially when the methodology is complex. To overcome this, simpler approaches to collect data that yields information of comparable quality to more rigorous methods should be developed. The international community can play a major role through research on methodologies feasible for LMIC settings as well as in building research capacity in countries. Context-specific issues, which were recognised as larger barriers, should be improved in parallel. PMID- 29402313 TI - The IMPROVE-GAP Trial aiming to improve evidence-based management of community acquired pneumonia: study protocol for a stepped-wedge randomised controlled trial. AB - BACKGROUND: Community-acquired pneumonia is a leading worldwide cause of hospital admissions and healthcare resource consumption. The largest proportion of hospitalisations now occurs in older patients, with high rates of multimorbidity and complex care needs. In Australia, this population is usually managed by hospital inpatient general internal medicine units. Adherence to consensus best practice guidelines is poor. Ensuring evidence-based care and reducing length of stay may improve patient outcomes and reduce organisational costs. This study aims to evaluate an alternative model of care designed to improve adherence to four Level 1 or 2 evidence-supported interventions (routine corticosteroids, early switch to oral antibiotics, early mobilisation and routine malnutrition screening). METHODS/DESIGN: The IMPROVing Evidence-based treatment Gaps and outcomes in community-Acquired Pneumonia (IMPROVE-GAP) trial is a pragmatic, investigator-initiated, stepped-wedge randomised trial. Patients hospitalised under a general internal medicine unit who meet a standard case definition for community-acquired pneumonia will be included. Eight general internal medicine units at two Australian hospitals in a single health service will be randomised using concealed allocation to: (i) usual medical, nursing and allied health care delivered according to existing organisational practice or (ii) care supported by a dedicated "community-acquired pneumonia service": a multidisciplinary team deploying algorithm-based implementation of a bundle of the four evidence-based interventions. The primary outcome measure will be length of hospital stay. Secondary outcome measures include inpatient mortality, 30 and 90 day readmission rates and mortality and health-service utilisation costs. Protocol adherence will be measured and reported, and serious adverse events (rates of hyperglycaemia requiring new insulin; falls during mobilisation) will be collected and reported. DISCUSSION: IMPROVE-GAP represents an important and unique precedent for testing a new service-delivery model for improving compliance with a number of evidence based interventions. Its stepped-wedge randomised controlled trial design provides a means to address some significant ethical, organisational and other methodological challenges to evaluating the effectiveness of health-service interventions in complex hospital populations. The new service-delivery model will effectively be fully implemented by trial completion, facilitating rapid, seamless translation into practice should care outcomes be superior. This trial is currently recruiting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02835040. Prospectively registered on 22 May 2016. PMID- 29402315 TI - Professionalism and non-technical skills in Radiology in the UK: a review of the national curriculum. AB - OBJECTIVE: To drive quality and safe clinical practice, professional values and non-technical skills need to be explicit in all postgraduate medical curricula and appropriate assessment tools should be available for teachers to apply. We interrogate a national Radiology curriculum for content on professionalism and assessment tools, comparing it with the Royal College of Physicians' 2005 document. RESULTS: We found that whilst the knowledge for practising with professional values is embedded in the curriculum, the skills that have to be acquired have not been comprehensively developed. This is reflected in the restricted assessment tools that are mapped to each generic area. The terminology used in the Radiology curriculum was varied and the most frequently used descriptor for professionalism or behaviours pertaining to non-technical aspects was Good Medical Practice; a term used by our regulator, the General Medical Council, and to which our curriculum is mapped. If terminology is to be standardized in Britain collaboration with our regulator is key. We need standardized terminology to permit effective research and sharing of best practice. The Radiology curriculum encompasses all the values set out in the seminal document produced by the Royal College of Physicians in 2005, Doctors in society: medical professionalism in a changing world. PMID- 29402317 TI - Predictors of therapy failure in newly diagnosed pulmonary tuberculosis cases in Beira, Mozambique. AB - OBJECTIVE: Tuberculosis (TB) remains a major global health issue, ranking in the top ten causes of death worldwide. A deep understanding of factors influencing poor treatment outcomes may allow the development of additional treatment strategies, focused on the most vulnerable groups. Aims of the study were: (i) to evaluate the treatment outcome among TB subjects followed in an outpatient setting and (ii) to analyze factors associated with treatment failure in newly diagnosed patients with pulmonary TB in Beira, the second largest city of Mozambique. RESULTS: A total of 301 TB adult patients (32.6% females) were enrolled. Among them, 62 (20.6%) experienced a treatment failure over a 6 months follow-up. On multivariate model, being males (O.R. = 1.73; 95% CI 1.28-2.15), absence of education (O.R. = 1.85; 95% CI 1.02-2.95), monthly income under 50 dollars (O.R. = 1.74; 95% CI 1.24-2.21) and being employed (O.R. = 1.57; 95% CI 1.21-1.70), low body mass index values (O.R. = 1.42; 95% CI 1.18-1.72) and HIV status (O.R. = 1.42; 95% CI 1.10-1.78) increased the likelihood of therapy failure over 6 months of follow-up. In this study, patients who need more medical attention were young males, malnourished, with low income and low educational degree and HIV positive. These subjects were more likely to fail therapy. PMID- 29402316 TI - Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer. AB - BACKGROUND: Polo-like kinase 1 (Plk1) is a serine/threonine kinase that is a key regulator of multiple stages of mitotic progression. Plk1 is upregulated in many tumor types including colorectal cancer (CRC) and portends a poor prognosis. TAK 960 is an ATP-competitive Plk1 inhibitor that has demonstrated efficacy across a broad range of cancer cell lines, including CRC. In this study, we investigated the activity of TAK-960 against a large collection of CRC models including 55 cell lines and 18 patient-derived xenografts. METHODS: Fifty-five CRC cell lines and 18 PDX models were exposed to TAK-960 and evaluated for proliferation (IC50) and Tumor Growth Inhibition Index, respectively. Additionally, 2 KRAS wild type and 2 KRAS mutant PDX models were treated with TAK-960 as single agent or in combination with cetuximab or irinotecan. TAK-960 mechanism of action was elucidated through immunoblotting and cell cycle analysis. RESULTS: CRC cell lines demonstrated a variable anti-proliferative response to TAK-960 with IC50 values ranging from 0.001 to > 0.75 MUmol/L. Anti-proliferative effects were sustained after removal of drug. Following TAK-960 treatment a highly variable accumulation of mitotic (indicating cell cycle arrest) and apoptotic markers was observed. Cell cycle analysis demonstrated that TAK-960 treatment induced G2/M arrest and polyploidy. Six out of the eighteen PDX models responded to single agent TAK-960 therapy (TGII< 20). The addition of TAK-960 to standard of care chemotherapy resulted in largely additive antitumor effects. CONCLUSION: TAK-960 is an active anti-proliferative agent against CRC cell lines and PDX models. Collectively, these data suggest that TAK-960 may be of therapeutic benefit alone or in combination with other agents, although future work should focus on the development of predictive biomarkers and hypothesis-driven rational combinations. PMID- 29402318 TI - Differences in the expression profiles of claudin proteins in human nasopharyngeal carcinoma compared with non-neoplastic mucosa. AB - BACKGROUND: Several studies have suggested that claudin proteins, which are the main components of tight junction structures, are related to the regulation of cell polarity and cell differentiation. METHOD: To explore the expression profiles of the tight junction proteins claudin-2, - 5, - 8 and - 9 in nasopharyngeal carcinoma, IHC (immunohistochemical analysis), Western blot and real-time PCR were used to detect the expression profiles of these claudin proteins in nasopharyngeal carcinoma tissues and in non-neoplastic mucosal tissues. RESULTS: According to our study, the expression levels of claudin-2 and claudin-5 were reduced, while the expression of claudin-8 was increased in nasopharyngeal carcinoma tissues in comparison with non-neoplastic mucosal tissues. Correlations between claudin-2 and -5 expression and metastatic progression in nasopharyngeal carcinoma patients were also found. CONCLUSION: In summary, our research reveals distinct expression profiles of claudin-2, - 5 and 8 in non-neoplastic mucosal tissues and nasopharyngeal carcinoma tissues. In addition, the expression of these claudin proteins was highly correlated with metastatic progression and prognosis in patients with nasopharyngeal carcinoma and had predictive value for the metastasis and survival of nasopharyngeal carcinoma patients. PMID- 29402319 TI - Makes FLASH the difference between the intervention group and the treatment-as usual group in an evaluation study of a structured education and treatment programme for flash glucose monitoring devices in people with diabetes on intensive insulin therapy: study protocol for a randomised controlled trial. AB - BACKGROUND: People with diabetes on intensive insulin therapy need sufficient glycaemic control to prevent the onset or progression of diabetic complications. The burden of multiple daily blood glucose self-testing can be lessened by novel diabetes technology like flash glucose monitoring systems which provide more information compared to self-monitoring of blood glucose. Despite this delivered additional information studies are showing no significant effect on HbA1c reduction, but a reduced time spent in a hypoglycaemic glucose range. We assume that users of these devices need additional education and training to integrate the delivered information into treatment decisions. Therefore, FLASH, an education and treatment programme, was developed. The programme evaluation follows herein. METHODS/DESIGN: Patients are recruited through 40 diabetes outpatient study centres located across Germany. They will be randomly assigned to participate in the education and treatment programme (intervention group) or to obtain treatment as usual (control group). All patients have to give blood samples and to answer a bench of questionnaires during baseline assessment, at the end of the intervention, and 6 months after the end of the intervention. Physicians will be asked to declare some additional clinical data (such as details of the diabetes therapy) for every patient at every one of the three assessment points. DISCUSSION: This study is conducted as a randomised controlled trial to test the hypothesis that the newly developed education and treatment programme combined with the use of a flash glucose monitoring device (intervention group) is superior to reduce HbA1c compared to the use of flash glucose monitoring alone (control group). The first results will be expected in 2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03175315 . Registered on 2 May 2017. PMID- 29402320 TI - Women's contraceptive discontinuation and switching behavior in urban Senegal, 2010-2015. AB - BACKGROUND: With the focus of global and national family planning initiatives on reaching "additional user" targets, it is increasingly important for programs to assess contraceptive method discontinuation and switching. This analysis calculated the discontinuation rate and method-specific discontinuation rates, examined reasons given for contraceptive discontinuation, and assessed characteristics associated with subsequent contraceptive switching and abandonment among women living in urban areas of Senegal. METHODS: Data came from the Measurement, Learning & Evaluation project's 2015 survey of 6927 women of reproductive age living in six urban sites (Dakar, Pikine, Guediawaye, Mbao, Kaolack and Mbour). Information on contraceptive use and discontinuation for the five years preceding the survey were recorded in a monthly calendar. Single decrement life tables were used to calculate discontinuation rates. Descriptive analyses were used to assess reasons for discontinuation and method switching after discontinuation. A multinomial logistic regression was used to estimate the likelihood of being a non-user in-need of contraception, a non-user not in-need of contraception, or a method switcher in the month after discontinuation, by sociodemographic and other characteristics. RESULTS: The 12-month discontinuation rate for all methods was 34.7%. Implants had the lowest one-year discontinuation rates (6.3%) followed by the intrauterine device (IUD) (18.4%) while higher rates were seen for daily pills (38%), injectables (32.7%), and condoms (62.9%). The most common reasons for discontinuation were reduced need (45.6%), method problems (30.1%), and becoming pregnant while using (10.0%). Only 17% of discontinuations were followed by use of another method; most often daily pills (5.2%) or injectables (4.2%). In the multivariate analysis, women with any formal education (primary, secondary or higher) were more than 50% more likely to switch methods than remain in need of contraception after discontinuation than women with no education or Koranic-only education (RRR = 1.59, p-value = 0.004; RRR = 1.55, p-value = 0.031). The likelihood of switching compared to being "in need" was also significantly higher for women who were married and who discontinued traditional methods. CONCLUSIONS: To support increased contraceptive method use, women with no education and unmarried women are priorities for counseling and information about side effects and method switching at the time of method adoption. PMID- 29402321 TI - A cross-sectional study assessing the association between online ratings and clinical quality of care measures for US hospitals: results from an observational study. AB - BACKGROUND: Little is known about the usefulness of online ratings when searching for a hospital. We therefore assess the association between quantitative and qualitative online ratings for US hospitals and clinical quality of care measures. METHODS: First, we collected a stratified random sample of 1000 quantitative and qualitative online ratings for hospitals from the website RateMDs. We used an integrated iterative approach to develop a categorization scheme to capture both the topics and sentiment in the narrative comments. Next, we matched the online ratings with hospital-level quality measures published by the Centers for Medicare and Medicaid Services. Regarding nominally scaled measures, we checked for differences in the distribution among the online rating categories. For metrically scaled measures, we applied the Spearman rank coefficient of correlation. RESULTS: Thirteen of the twenty-nine quality of care measures were significantly associated with the quantitative online ratings (Spearman p = +/-0.143, p < 0.05 for all). Thereof, eight associations indicated better clinical outcomes for better online ratings. Seven of the twenty-nine clinical measures were significantly associated with the sentiment of patient narratives (p = +/-0.114, p < 0.05 for all), whereof four associations indicated worse clinical outcomes in more favorable narrative comments. CONCLUSIONS: There seems to be some association between quantitative online ratings and clinical performance measures. However, the relatively weak strength and inconsistency of the direction of the association as well as the lack of association with several other clinical measures may not enable the drawing of strong conclusions. Narrative comments also seem to have limited potential to reflect the clinical quality of care in its current form. Thus, online ratings are of limited usefulness in guiding patients towards high-performing hospitals from a clinical point of view. Nevertheless, patients might prefer different aspects of care when choosing a hospital. PMID- 29402322 TI - Cochlear implants and 1.5 T MRI scans: the effect of diametrically bipolar magnets and screw fixation on pain. AB - BACKGROUND: The probability that a patient will need an MRI scan at least once in a lifetime is high. However, MRI scanning in cochlear implantees is associated with side effects. Moreover, MRI scan-related artifacts, dislodging magnets, and pain are often the most frequent complications. The aim of this study was to evaluate the occurrence of pain in patients with cochlear implant systems using 1.5T MRI scans. METHODS: In a prospective case study of 10 implantees, an MRI scan was performed and the degree of pain was evaluated by a visual analog scale. Scans were performed firstly with and depending on the degree of discomfort/pain, without a headband. Four of the cochlear implants contained a screw fixation. Six cochlear implants contained an internal diametrically bipolar magnet. MRI observations were performed with a 1.5 T scanner. RESULTS: MRI scans were performed on all patients without causing any degree of pain, even without the use of a headband. CONCLUSION: Patients undergoing 1.5 T MRIs with devices including a diametrically bipolar magnet or a rigid implant screw fixation, experienced no pain, even without headbands. PMID- 29402323 TI - Equivocal tests after contrast stress-echocardiography compared with invasive coronary angiography or with CT angiography: CT calcium score in mildly positive tests may spare unnecessary coronary angiograms. AB - BACKGROUND: Imaging stress tests are not ideally accurate to predict anatomically obstructive CAD, leading to a non-trivial rate of unnecessary iCA. This may depend on the threshold used to indicate iCA, and maybe CTA or, one step earlier, CT calcium score could spare most unnecessary iCA in only mildly positive cSE. We assessed the diagnostic accuracy of contrast stress-echocardiography (cSE) in comparison with invasive coronary angiography (iCA), and CT angiography (CTA) only in case of equivocal tests, to find hints helping reduce falsely positive cSE in the suspicion of coronary artery disease (CAD). METHODS: Patients who were indicated cSE for suspected CAD between 2012 and 2016, who also underwent iCA were selected and diagnostic results compared. A second group, specifically with equivocal cSE who underwent CTA was also analyzed. RESULTS: 137 subjects with equivocal cSE and CTA and 314 with cSE (any result) and iCA were selected. In the CTA-equivocal cSE group, an Agatston score < 105 and a coronary flow reserve (CFR LAD) <1.7 had very high negative predictive value (99%, 92% respectively) to exclude obstructive CAD. The Agatston score was the most significant incremental predictor of CAD beyond clinical variables (chi square 31 to 47, p < 0.001). In the iCA group a more-than-mild reversible wall motion abnormality (WMA) demonstrated high positive predictive value for CAD (89%), while CFR-LAD appeared less useful. More-than-mild reversible WMA was the most significant predictor of CAD beyond clinical variables (chi square 37.5 to 56, p < 0.001). CONCLUSIONS: Our data suggest iCA should be indicated only for more-than-mild reversible WMA at cSE, due to the very high positive predictive value for CAD of this finding, while mildly positive tests should be shifted to non-invasive CT, with CTA performed only for coronary calcium Agatston score > 100, since lower scores demonstrated very high negative predictive value for CAD, not justifying proceeding to CTA and even less to iCA. PMID- 29402324 TI - Herbal compound 861 prevents hepatic fibrosis by inhibiting the TGF beta1/Smad/SnoN pathway in bile duct-ligated rats. AB - BACKGROUND: This study was to evaluate the effects of herbal compound 861 (Cpd861) on ski-related novel protein N (SnoN) and transforming growth factor beta1 (TGF-beta1) /Smad signaling in rats with bile duct ligation (BDL)-induced hepatic fibrosis, and to explore the mechanisms of Cpd861 on hepatic fibrosis. METHODS: Thirty Wistar male rats were randomly divided into three groups: sham operation, BDL, and Cpd861. To induce hepatic fibrosis, BDL and Cpd861 group rats underwent bile duct ligation. Cpd861 at 9 g/kg/d or an equal volume of normal saline was administered intragastrically for 28 days. Liver injury was assessed biochemically and histologically. Protein and mRNA changes for SnoN and TGF beta1/Smad signaling (TGF-beta1, Smad2, phosphorylated Smad2 [p-Smad2], phosphorylated Smad3 [p-Smad3], fibronectin, and collagen III) were determined by Western blotting and quantitative real-time PCR. RESULTS: BDL rats treated with Cpd861 had significantly alleviated hepatic fibrosis compared to BDL rats not receiving Cpd861 treatment. Moreover, Cpd861 decreased the expression of fibrosis associated proteins fibronectin and collagen III in liver tissue. Cpd861 administration increased the expression of SnoN protein, did not change SnoN mRNA level, and decreased TGF-beta1, p-Smad2, and p-Smad3 protein expression compared to BDL without Cpd861 treatment. CONCLUSIONS: Cpd861 attenuates hepatic fibrosis by increasing SnoN protein expression and inhibiting the TGF-beta1/Smad signaling pathway. PMID- 29402325 TI - Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder. AB - BACKGROUND: Evidence suggests that nearly half of patients with major depressive disorder (MDD) do not achieve an adequate response to antidepressant treatments (ADTs), which impacts patients' functioning, quality of life (QoL), and well being. This patient survey aimed to better understand patient perspectives on the emotional impact of experiencing an inadequate response to ADTs. METHODS: An online survey was conducted in 6 countries with respondents diagnosed with MDD and experiencing an inadequate response to ADTs. The survey was designed to explore how patients felt about their medications and health care provider (HCP). Those indicating they were 'frustrated' with their medications and/or HCP were asked to provide reasons for their frustration and its impact on their relationship with their HCP and decisions about their treatment. RESULTS: Overall, 2096 respondents with MDD and inadequate response to ADT completed the survey. The most frequent emotion reported by patients regarding their medication was frustration (29.8% of respondents) followed by hopeless (27.4%) and apprehensive/anxious/scared (27.4%). Regarding their HCP, patients reported feeling understood (31.6%) and trusting/confident (28.8%) most often; however, 19.2% reported feelings of frustration. Main reasons for frustration with medication were poor symptom control/lack of efficacy (59.3%) and tolerability issues (19.7%), and the main reasons for frustration with their HCP were not feeling heard (22.4%), ineffective treatment (13.5%) and feeling rushed/lack of quality visit (12.5%). The longer the current episode duration and the greater the disruption to daily living, the more likely the respondents experienced feelings of frustration with medication. Feelings of frustration lead to adherence issues, with 33.3 and 27.3% of respondents indicating their frustration with their medication and HCP, respectively, made them want to quit their medication. Approximately one in six patients frustrated with either their medication and/or HCP indicated their frustration had resulted in them not taking their medication regularly. Frustration with their HCP also impacted patient's confidence in HCPs abilities (34.7%), sharing less information with their HCP (28.9%) as well as missing appointments (17.4%) and medications (14.5%). CONCLUSIONS: Feelings of frustration are frequent in patients with inadequate response to ADT and this frustration may impact treatment adherence and the patient-HCP relationship. PMID- 29402326 TI - Treatment of gingival defects with gingival mesenchymal stem cells derived from human fetal gingival tissue in a rat model. AB - BACKGROUND: The study aimed to evaluate the efficacy and safety of gingival mesenchymal stem cells (GMSCs) from human fetal gingival tissue used for treating gingival defects in a rat model. METHODS: GMSCs were isolated from human fetal gingival tissue and identified by flow cytometry for nestin, Oct4, vimentin, NANOG, CD105, and CD90. The immunogenicity of GMSCs was analyzed by mixed lymphocyte reactions; the tumorigenicity of GMSCs was evaluated by xenotransplanting into nude mice. The gingival defect animal model was established by mechanical resection in rats. GMSCs were transplanted into the defective area, and the regeneration of gingival tissue was observed twice weekly. Four weeks after transplantation, the gingival tissue was surgically cut down, and the graft was analyzed by immunohistochemistry staining for human mitochondrial antigens and rat CD3 and CD20. RESULTS: GMSCs from human fetal gingival tissue positively expressed nestin, Oct4, vimentin, NANOG, CD105, and CD90. There was no cell aggregation after mixed lymphocyte reactions, and interleukin-2 did not increase. Inoculation of GMSCs into nude mice for 6 months showed no tumor formation. GMSCs were transplanted into the gingiva defects of rats. One week after transplantation, the defect area was reduced, and after 3 weeks the morphology and color of local gingival tissue was similar to normal gingival tissue, and gingival height was the same as the normal control group. CONCLUSIONS: Using GMSCs from human fetal gingival tissue to treat gingival defects is a safe and effective innovative treatment method. PMID- 29402327 TI - Mapping educational opportunities for healthcare workers on antimicrobial resistance and stewardship around the world. AB - BACKGROUND: Antimicrobial resistance is an important global issue facing society. Healthcare workers need to be engaged in solving this problem, as advocates for rational antimicrobial use, stewards of sustainable effectiveness, and educators of their patients. To fulfill this role, healthcare workers need access to training and educational resources on antimicrobial resistance. METHODS: To better understand the resources available to healthcare workers, we undertook a global environmental scan of educational programs and resources targeting healthcare workers on the topic of antimicrobial resistance and antimicrobial stewardship. Programs were identified through contact with key experts, web searching, and academic literature searching. We summarized programs in tabular form, including participating organizations, region, and intended audience. We developed a coding system to classify programs by program type and participating organization type, assigning multiple codes as necessary and creating summary charts for program types, organization types, and intended audience to illustrate the breadth of available resources. RESULTS: We identified 94 educational initiatives related to antimicrobial resistance and antimicrobial stewardship, which represent a diverse array of programs including courses, workshops, conferences, guidelines, public outreach materials, and online-resource websites. These resources were developed by a combination of government bodies, professional societies, universities, non-profit and community organizations, hospitals and healthcare centers, and insurance companies and industry. Most programs either targeted healthcare workers collectively or specifically targeted physicians. A smaller number of programs were aimed at other healthcare worker groups including pharmacists, nurses, midwives, and healthcare students. CONCLUSIONS: Our environmental scan shows that there are many organizations working to develop and share educational resources for healthcare workers on antimicrobial resistance and antimicrobial stewardship. Governments, hospitals, and professional societies appear to be driving action on this front, sometimes working with other types of organizations. A broad range of resources have been made freely available; however, we have noted several opportunities for action, including increased engagement with students, improvements to pre-service education, recognition of antimicrobial resistance courses as continuing medical education, and better platforms for resource-sharing online. PMID- 29402329 TI - Effectiveness of a new long-lasting insecticidal nets delivery model in two rural districts of Mozambique: a before-after study. AB - BACKGROUND: In 2015, Mozambique piloted a new model of long-lasting insecticidal nets (LLINs) delivery in a campaign. The new delivery model was used in two rural districts were, and two others were considered as control, maintaining the old delivery model. The aim of this study is to compare the coverage of ownership and use of LLINs in intervention and control districts in Mozambique. METHODS: A before-after design with control group was carried out 6 months after LLINs distribution. Using systematic probabilistic sampling, 1547 households were surveyed by means of a questionnaire. To find associations between the district categories (intervention and control) and the main outcomes of the study (LLIN ownership, use, and universal coverage achievement), odds ratio (OR) and respective confidence intervals were calculated. RESULTS: Of the 760 households surveyed in the intervention districts, 98.8% had at least one LLIN; of the 787 households surveyed in the control districts, 89.6% had at least one LLIN [OR: 9.7, 95% (CI 4.84-19.46)]. Around 95 and 87% of households owning at least one LLIN reported having slept under the LLIN the previous night in the intervention and control districts, respectively [OR: 3.2; 95% (CI 2.12-4.69)]. Seventy-one percent of the households surveyed achieved universal coverage in the intervention districts against 59.6% in the control districts [OR: 1.6; 95% (CI 1.33-2.03)]. CONCLUSIONS: The universal coverage campaign piloted with the new delivery model has increased LLINs ownership, use, and progression for reaching universal coverage targets in the community. PMID- 29402328 TI - Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first line chemotherapy. AB - BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. METHODS: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan-Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS). RESULTS: We observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZpos/WNTmut) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZpos/WNTmut signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27-4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41-5.29, p = 0.003). Finally, the TAZpos/WNTmut signature negatively impacted overall survival. CONCLUSIONS: Collectively, our findings indicate that the oncogenic YAP/TAZ-Wnt crosstalk may be active in GC, conferring chemoresistant traits that translate into adverse survival outcomes. PMID- 29402330 TI - Impact of diabetes and early revascularization on the need for late and repeat procedures. AB - BACKGROUND: Coronary artery disease often progresses more rapidly in diabetics, but the integrated impact of diabetes and early revascularization status on late or repeat revascularization in the contemporary era is less clear. METHODS: Coronary angiography was performed in 12,420 patients between the years 2000-2015 and early revascularization status [none, percutaneous coronary intervention (PCI) or bypass surgery (CABG)] was determined. Subsequent revascularization procedures were recorded over a median follow-up of 67 months and its relation to diabetic and baseline revascularization status was studied. RESULTS: Early revascularization status was none in 5391, PCI in 5682 and CABG in 1347 patients. Late revascularization rates were 10, 26 and 11.1% respectively. Diabetes was present in 37%; a stepwise relationship of diabetic status with late revascularization was observed: no diabetes (reference) 14.4%, non-insulin treated diabetes 21% (adjusted HR 1.35, 95% CI 1.23-1.49, p < 0.001) and insulin treated diabetes 32.8% (adjusted HR 2.20, 95% CI 1.91-2.54, p < 0.001), which was similar in magnitude for each early revascularization state (none, PCI or CABG). Further revascularizations (>= 2) were also significantly more common in diabetics, in particular if insulin-treated. Glycosylated hemoglobin level was moderately associated with late revascularization in diabetics after early PCI but not following diagnostic catheterization or CABG. CONCLUSIONS: Diabetic status graded by treatment, and in particular insulin therapy, is a strong predictor for late or repeat revascularization irrespective of early revascularization status. The high rate of repeat revascularization in diabetics following PCI remains a challenging issue. PMID- 29402331 TI - Spatial scale affects the relative role of stochasticity versus determinism in soil bacterial communities in wheat fields across the North China Plain. AB - BACKGROUND: The relative importance of stochasticity versus determinism in soil bacterial communities is unclear, as are the possible influences that alter the balance between these. Here, we investigated the influence of spatial scale on the relative role of stochasticity and determinism in agricultural monocultures consisting only of wheat, thereby minimizing the influence of differences in plant species cover and in cultivation/disturbance regime, extending across a wide range of soils and climates of the North China Plain (NCP). We sampled 243 sites across 1092 km and sequenced the 16S rRNA bacterial gene using MiSeq. We hypothesized that determinism would play a relatively stronger role at the broadest scales, due to the strong influence of climate and soil differences in selecting many distinct OTUs of bacteria adapted to the different environments. In order to test the more general applicability of the hypothesis, we also compared with a natural ecosystem on the Tibetan Plateau. RESULTS: Our results revealed that the relative importance of stochasticity vs. determinism did vary with spatial scale, in the direction predicted. On the North China Plain, stochasticity played a dominant role from 150 to 900 km (separation between pairs of sites) and determinism dominated at more than 900 km (broad scale). On the Tibetan Plateau, determinism played a dominant role from 130 to 1200 km and stochasticity dominated at less than 130 km. Among the identifiable deterministic factors, soil pH showed the strongest influence on soil bacterial community structure and diversity across the North China Plain. Together, 23.9% of variation in soil microbial community composition could be explained, with environmental factors accounting for 19.7% and spatial parameters 4.1%. CONCLUSIONS: Our findings revealed that (1) stochastic processes are relatively more important on the North China Plain, while deterministic processes are more important on the Tibetan Plateau; (2) soil pH was the major factor in shaping soil bacterial community structure of the North China Plain; and (3) most variation in soil microbial community composition could not be explained with existing environmental and spatial factors. Further studies are needed to dissect the influence of stochastic factors (e.g., mutations or extinctions) on soil microbial community distribution, which might make it easier to predictably manipulate the microbial community to produce better yield and soil sustainability outcomes. PMID- 29402332 TI - The Efficacy and Mechanism Evaluation of Treating Idiopathic Pulmonary fibrosis with the Addition of Co-trimoxazole (EME-TIPAC): study protocol for a randomised controlled trial. AB - BACKGROUND: We hypothesise, based upon the findings from our previous trial, that the addition of co-trimoxazole to standard therapy is beneficial to patients with moderate to severe idiopathic pulmonary fibrosis (IPF). We aim to investigate this by assessing unplanned hospitalisation-free survival (defined as time from randomisation to first non-elective hospitalisation, lung transplant or death) and to determine whether any effect relates to changes in infection and/or markers of disease control and neutrophil activity. METHODS/DESIGN: The EME-TIPAC trial is a double-blind, placebo-controlled, randomised, multicentre clinical trial. A total of 330 symptomatic patients, aged 40 years old or older, with IPF diagnosed by a multidisciplinary team (MDT) according to international guidelines and a FVC <= 75% predicted will be enrolled. Patients are randomised equally to receive either two tablets of co-trimoxazole 480 mg or two placebo tablets twice daily over a median treatment period of 27 (range 12-42) months. All patients receive folic acid 5 mg daily whilst on the trial IMP to reduce the risk of bone marrow depression. The primary outcome for the trial is a composite endpoint consisting of the time to death, transplant or first non-elective hospital admission and will be determined from adverse event reporting, hospital databases and the Office of National Statistics with active tracing of patients missing appointments. Secondary outcomes include the individual components of the primary outcome, (1) King's Brief Interstitial Lung Disease Questionnaire, (2) MRC Dyspnoea Score, (3) EQ5D, (4) spirometry, (5) total lung-diffusing capacity and (6) routine sputum microbiology. Blood will be taken for cell count, biochemistry and analysis of biomarkers including C-reactive protein and markers of disease. The trial will last for 4 years. Recruitment will take place in a network of approximately 40 sites throughout the UK (see Table 1 for a full list of participating sites). We expect recruitment for 30 months, follow-up for 12 months and trial analysis and reporting to take 4 months. DISCUSSION: The trial is designed to test the hypothesis that treating IPF patients with co-trimoxazole will increase the time to death (all causes), lung transplant or first non elective hospital admission compared to standard care ( https://www.nice.org.uk/guidance/cg163 ), in patients with moderate to severe disease. The mechanistic aims are to investigate the effect on lung microbiota and other measures of infection, markers of epithelial injury and markers of neutrophil activity. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 17464641 . Registered on 29 January 2015. PMID- 29402334 TI - Developing prehospital clinical practice guidelines for resource limited settings: why re-invent the wheel? AB - OBJECTIVES: Methods on developing new (de novo) clinical practice guidelines (CPGs) have received substantial attention. However, the volume of literature is not matched by research into alternative methods of CPG development using existing CPG documents-a specific issue for guideline development groups in low- and middle-income countries. We report on how we developed a context specific prehospital CPG using an alternative guideline development method. Difficulties experienced and lessons learnt in applying existing global guidelines' recommendations to a national context are highlighted. RESULTS: The project produced the first emergency care CPG for prehospital providers in Africa. It included > 270 CPGs and produced over 1000 recommendations for prehospital emergency care. We encountered various difficulties, including (1) applicability issues: few pre-hospital CPGs applicable to Africa, (2) evidence synthesis: heterogeneous levels of evidence classifications and (3) guideline quality. Learning points included (1) focusing on key CPGs and evidence mapping, (2) searching other resources for CPGs, (3) broad representation on CPG advisory boards and (4) transparency and knowledge translation. Re-inventing the wheel to produce CPGs is not always feasible. We hope this paper will encourage further projects to use existing CPGs in developing guidance to improve patient care in resource-limited settings. PMID- 29402333 TI - Clinical results of multidisciplinary therapy including palliative posterior spinal stabilization surgery and postoperative adjuvant therapy for metastatic spinal tumor. AB - BACKGROUND: Surgeries performed for metastatic spinal tumor are mostly palliative and are controversial for patients with short life expectancy. We investigated whether palliative posterior spinal stabilization surgery with postoperative multidisciplinary therapy results in improvement of life prognosis and activities of daily living (ADL) in patients with metastatic spinal tumor. METHODS: The subjects were 55 patients who underwent palliative posterior-only instrumentation surgery for metastatic spinal tumor at our hospital between 2012 and 2015. Postoperative survival, early paralysis improvement, ADL improvement, and rate of discharge to home were examined. RESULTS: The patients included 37 males and 18 females, and the mean age at the time of surgery was 66.8 years old. The mean Tokuhashi score was 7.1, the mean spinal instability neoplastic score (SINS) was 9.4, and the epidural spinal cord compression scale (ESCCS) was grade 3 in 20 patients (36.3%). The mean Barthel index for ADL was 48.7. The median postoperative survival time determined using the Kaplan-Meier method was 12.0 months (95% confidence interval 2.4-21.5). Regarding improvement of paralysis, the modified Frankel scale was improved by one grade or more or grade E was maintained in 35 patients (63.6%), whereas paralysis aggravated in 2 (3.6%). In surgery, conventional posterior decompression and fixation were applied in 31 patients (56.3%), and minimally invasive spine stabilization was applied in 24 (43.6%). Postoperative chemotherapy was performed in 31 patients (56.3%), radiotherapy was used in 38 (69.0%), and a bone-modifying agent was administered in 39 (70.2%). Regarding ADL, the mean Barthel index improved from 48.5 before surgery to 74.5 after surgery. Thirty-seven patients (67.2%) were discharged to home. CONCLUSIONS: ADL improved and allowed discharge to home, and postoperative adjuvant therapy could be administered at a high rate in patients who received palliative posterior spinal stabilization surgery. Survival time extended beyond the preoperative life expectancy in many patients. Patients with a metastatic spinal tumor have short life expectancy and paralysis caused by spinal instability and spinal cord compression. However, multidisciplinary therapy including palliative posterior spinal stabilization surgery with reduced invasiveness and postoperative adjuvant therapy are effective in these patients. PMID- 29402335 TI - ON IMPACT AND IMPACT FACTORS. AB - The International Journal of Technology Assessment in Health Care (IJTAHC) is part of the so-called Cambridge Core, the "home of academic content" (1). As such, not surprisingly, it is judged by standard scientific standards such as the Journal's Impact Factor (IF). Although on the rise, there is still significant room for improvement (2). In this Editorial, I will discuss the relevance of the IF to the Journal and offer some suggestions as to how it might be given new impetus. I will conclude by briefly discussing some challenges associated with assessing impact in the context of health technology assessment (HTA). PMID- 29402336 TI - Natural biological control of Chrysodeixis includens. AB - A wide variety of abiotic and biotic factors act on insect pests to regulate their populations. Knowledge of the time and magnitude of these factors is fundamental to understanding population dynamics and developing efficient pest management systems. We investigate the natural mortality factors, critical pest stages, and key mortality factors that regulate Chrysodeixis includens populations via ecological life tables. The total mortality caused by natural factors was 99.99%. Natural enemies were the most important mortality factors in all pest stages. The critical stages of C. includens mortality were second and fourth instars. The key mortality factors were predation by ants in the second instar and predation by Vespidae in the fourth instar. The elimination of these factors can cause an increase of 77.52 and 85.17% of C. includens population, respectively. This study elucidates the importance of natural enemies and other natural mortality factors in C. includens population regulation. These factors should be considered in developing and implementing C. includens management strategies and tactics in order to achieve effective and sustainable pest control. PMID- 29402337 TI - COMPLETED FERTILITY DURING THE TWENTIETH CENTURY: AN EXAMPLE FROM SIX SETTLEMENTS IN NORTHERN GREECE. AB - This study aimed to delineate temporal trends and differentials of completed fertility and their relationship with some characteristics of the marriage system in specific anthropological populations of northern Greece. The analysis was based on the life history of quinquennial and decennial birth cohorts of married women born in the 20th century who reproduced solely within the settlements studied. The variables studied were: children ever born, mean age of mother at first marriage, mean age of mother at first child (live birth), mean age of mother at last child and reproductive span. The results indicated that there were significant differences in the demographic characteristics of marriage and that there was an ongoing fertility transition in the 20th century in the populations studied. The mechanism of fertility decline was connected with the gradual reduction of the mean age of the mother at last child, the parallel decrease in the mean age at childbearing and a shortening of the reproductive span. Fertility levels at all times maintained a dynamic character imposed by local cultural, economic and social structures, which, in turn, were part of broader national and international structures, in all the populations studied. A strong trend of convergence of fertility levels was observed among the populations studied. PMID- 29402338 TI - ppGpp and cytotoxicity diversity in Shiga toxin-producing Escherichia coli (STEC) isolates - CORRIGENDUM - ERRATUM. PMID- 29402339 TI - Knowledge, Attitudes, and Practices Regarding Antimicrobial Use and Stewardship Among Prescribers at Acute-Care Hospitals. AB - OBJECTIVE To assess antimicrobial prescriber knowledge, attitudes, and practices (KAP) regarding antimicrobial stewardship (AS) and associated barriers to optimal prescribing. DESIGN Cross-sectional survey. SETTING Online survey. PARTICIPANTS A convenience sample of 2,900 US antimicrobial prescribers at 5 acute-care hospitals within a hospital network. INTERVENTION The following characteristics were assessed with an anonymous, online survey in February 2015: attitudes and practices related to antimicrobial resistance, AS programs, and institutional AS resources; antimicrobial prescribing and AS knowledge; and practices and confidence related to antimicrobial prescribing. RESULTS In total, 402 respondents completed the survey. Knowledge gaps were identified through case based questions. Some respondents sometimes selected overly broad therapy for the susceptibilities given (29%) and some "usually" or "always" preferred using the most broad-spectrum empiric antimicrobials possible (32%). Nearly all (99%) reported reviewing antimicrobial appropriateness at 48-72 hours, but only 55% reported "always" doing so. Furthermore, 45% of respondents felt that they had not received adequate training regarding antimicrobial prescribing. Some respondents lacked confidence selecting empiric therapy using antibiograms (30%), interpreting susceptibility results (24%), de-escalating therapy (18%), and determining duration of therapy (31%). Postprescription review and feedback (PPRF) was the most commonly cited AS intervention (79%) with potential to improve patient care. CONCLUSIONS Barriers to appropriate antimicrobial selection and de-escalation of antimicrobial therapy were identified among front-line prescribers in acute-care hospitals. Prescribers desired more AS-related education and identified PPRF as the most helpful AS intervention to improve patient care. Educational interventions should be preceded by and tailored to local assessment of educational needs. Infect Control Hosp Epidemiol 2018;39:316 322. PMID- 29402340 TI - Whole-exome sequencing identifies a Novel SCN5A mutation (C335R) in a Chinese family with arrhythmia. AB - BACKGROUND: SCN5A encodes sodium-channel alpha-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia. METHODS: Genomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes. Sanger sequencing was applied to verify the mutation co-segregated in the family.Results and conclusionsA novel missense mutation in SCN5A (C335R) was identified, and this mutation co-segregated within the affected family members. This missense mutation was predicted to result in amplitude reduction in peak Na+ current, further leading to channel protein dysfunction. Our study expands the spectrum of SCN5A mutations and contributes to genetic counselling of families with arrhythmia. PMID- 29402341 TI - Performance, profitability and greenhouse gas emissions of alternative finishing strategies for Holstein-Friesian bulls and steers. AB - Modifying finishing strategies within established production systems has the potential to increase beef output and farm profit while reducing greenhouse gas (GHG) emissions. Thus, the objectives of this study were to investigate the effects of finishing duration on animal performance of Holstein-Friesian (HF) bulls and steers and evaluate the profitability and GHG emissions of these finishing strategies. A total of 90 HF calves were assigned to a complete randomised block design; three bull and three steer finishing strategies. Calves were rotationally grazed in a paddock system for the first season at pasture, housed and offered grass silage ad libitum plus 1.5 kg DM of concentrate per head daily for the first winter and returned to pasture for a second season. Bulls were slaughtered at 19 months of age and either finished indoors on concentrates ad libitum for 100 days (19AL), finished at pasture supplemented with 5 kg DM of concentrate per head daily for 100 (19SP) or 150 days (19LP). Steers were slaughtered at 21 months of age and finished at pasture, supplemented with 5 kg DM of concentrate per head daily for 60 (21SP) and 110 days (21LP) or slaughtered at 24 months of age and finished indoors over the second winter on grass silage ad libitum plus 5 kg DM of concentrate per head daily (24MO). The Grange Dairy Beef Systems Model and the Beef Systems Greenhouse Gas Emissions Model were used to evaluate profitability and GHG emissions, respectively. Average daily gain during the finishing period (P<0.001), live weight at slaughter (P<0.01), carcass weight (P<0.05) and fat score (P<0.001) were greater for 19AL than 19SP and 19LP, respectively. Similarly, concentrate dry matter intake was greater for 19AL than 19SP; 19LP was intermediate (P<0.001). Live weight at slaughter (P<0.001), carcass weight (P<0.001), conformation score (P<0.05) and fat score (P<0.001) were greater for 24MO than 21SP and 21LP, respectively. During the finishing period concentrate dry matter intake was greater for 21LP than 21SP with 24MO intermediate; 542, 283 and 436 kg DM, respectively. Although pasture-based finishing strategies had lower gross output values, concentrate feed costs were also reduced thus net margin was greater than indoor finishing strategies. Reducing concentrate input increased GHG emissions for bulls and steers slaughtered at the same age, respectively. Although prolonging the finishing duration reduced GHG emissions for bull and steer production systems, finishing bulls and steers over a longer period at pasture did not enhance animal performance and profit. PMID- 29402342 TI - Propofol inhibits lung cancer A549 cells growth and epithelial-mesenchymal transition process by up-regulation of microRNA-1284. AB - Propofol has been widely used in lung cancer resections. Some studies have demonstrated that the effects of propofol might be mediated by microRNAs (miRNAs). This study aimed to investigate the effects and mechanisms of propofol on lung cancer cells by regulation of miR-1284. A549 cells were treated with different concentrations of propofol, while transfected with miR-1284 inhibitor, si-FOXM1 and their negative controls. Cell viability, migration, invasion, the expression of miR-1284, FOXM1 and epithelial mesenchymal transition (EMT) factors were respectively detected by CCK8, Transwell, qRT-PCR and western blot assays. In addition, the regulatory and binding relationships among propofol, miR-1284 and FOXM1 were assessed, respectively. Results showed that propofol suppressed A549 cells viability, migration and invasion, up-regulated E-cadherin, while down regulated N-cadherin, Vimentin and Snail expressions. Moreover, propofol significantly promoted the expression of miR-1284. MiR-1284 suppression abolished propofol-induced decreases of cell viability, migration and invasion, and increased FOXM1 expression and the luciferase activity of FOXM1-wt. Further, miR 1284 negatively regulated FOXM1 expression. FOXM1 knockdown reduced cell viability, migration and invasion by propofol treatment plus miR-1284 suppression. In conclusion, our study indicated that propofol could inhibit cell viability, migration, invasion and EMT process in lung cancer cells by regulation of miR-1284. PMID- 29402343 TI - MicroRNA-204 Inhibits the Growth and Motility of Colorectal Cancer Cells by Downregulation of CXCL8. AB - Among all of the miRNAs, miR-204 has gained considerable attention in the field of cancer research. This study aimed to reveal the detailed functions and the underlying mechanism of miR-204 in colorectal cancer (CRC) cells. The expressions of miR-204 in CRC tumor tissues and cell lines were monitored. Expressions of miR 204 and CXCL8 in Caco-2 and HT-29 cells were altered by transfection, and then cell viability, apoptosis, migration, invasion, EMT-related protein expression, and PI3K/AKT/mTOR pathway protein expression were assessed. We found that miR-204 was expressed at low levels in CRC tumor tissues and cell lines when compared to their normal controls. miR-204 overexpression reduced the viability, migration, and invasion of Caco-2 and HT-29 cells while significantly inducing apoptosis. miR-204 overexpression upregulated E-cadherin expression and downregulated N cadherin and vimentin expressions. CXCL8 was a target of miR-204, and miR-204 suppression could not increase cell viability, migration, invasion, and EMT procedure when CXCL8 was silenced. Moreover, miR-204 overexpression decreased the phosphorylated levels of PI3K, AKT, and mTOR. The increased phosphorylations of PI3K, AKT, and mTOR, and the upregulation of CXCL8 induced by miR-204 suppression were all abolished by the addition of LY294002 and AZD8055 (inhibitors of PI3K/AKT and mTOR, respectively). To conclude, we demonstrated a tumor suppressive miRNA in CRC cell lines, miR-204, which is poorly expressed in CRC tissues and cell lines. miR-204 exerted antigrowth, antimigration, anti-invasion, and anti-EMT activities, which might be via deactivating the PI3K/AKT/mTOR pathway and repressing CXCL8 expression. PMID- 29402344 TI - Impact of switching from Caucasian to Indian reference equations for spirometry interpretation. AB - BACKGROUND: In the absence of ethnically appropriate prediction equations, spirometry data in Indian subjects are often interpreted using equations for other ethnic populations. OBJECTIVES: To evaluate the impact of switching from Caucasian (National Health and Nutrition Examination Survey III [NHANES III] and Global Lung Function Initiative [GLI]) equations to the recently published North Indian equations on spirometric interpretation, and to examine the suitability of GLI-Mixed equations for this population. MATERIALS AND METHODS: Spirometry data on 12 323 North Indian patients were analysed using the North Indian equations as well as NHANES III, GLI-Caucasian and GLI-Mixed equations. Abnormalities and ventilatory patterns were categorised and agreement in interpretation was evaluated. RESULTS: The NHANES III and GLI-Caucasian equations and, to a lesser extent, the GLI-Mixed equations, predicted higher values and labelled more measurements as abnormal. In up to one third of the patients, these differed from Indian equations in the categorisation of ventilatory patterns, with more patients classified as having restrictive and mixed disease. CONCLUSION: The NHANES III and GLI-Caucasian equations substantially overdiagnose abnormalities and misclassify ventilatory patterns on spirometry in Indian patients. Such errors of interpretation, although less common with the GLI-Mixed equations, remain substantial and are clinically unacceptable. A switch to Indian equations will have a major impact on interpretation. PMID- 29402345 TI - Updated Review of Fish Analgesia. AB - Analgesics are an integral part of routine pain management in mammals, yet their use in fish is still limited. Some recommendations on the use of analgesics in fish are currently in the literature; however, information on the properties of analgesic drugs in most fish species is still scarce and sometimes misleading. The present review of information on the use of analgesics in fish was thus compiled to help clinicians make an informed decision as to which drug and dose to use. The main agents that have been investigated are opioids, NSAID, and local anesthetics, primarily in rainbow trout and zebrafish. There is presently no overwhelming evidence of efficacy for most analgesics in fish, although beneficial effects on behavior and physiologic parameters have been reported in many instances, especially associated with morphine administration. Furthermore, most analgesics did not result in significant adverse side effects. Thus, analgesics could be administered whenever it is considered that an animal might experience pain, given that the drugs appear not to cause harm and may be beneficial. However, caution must be advised because 1) important interspecies variation has been reported and 2) unforeseen effects could affect experimental results. Further research is needed to investigate analgesic use in fish. This should be accompanied by research aimed at improving our knowledge of the various species of fish. The current lack of a validated approach to assessing pain in fish limits our ability to evaluate the efficacy of analgesics in fish. PMID- 29402347 TI - Effects of Intracage Ammonia on Markers of Pulmonary Endothelial Integrity in Mice Housed in Static Microisolation Cages. AB - Time-weighted exposure limits to ammonia are established for humans; however similar guidelines have not been defined for laboratory rodents. The Guide recommends maintaining air pollutants at concentrations below levels irritating to mucous membranes but does not provide specific values. Numerous studies have examined ammonia and its effects on animal health, yet none have assessed the effects of naturally occurring intracage ammonia on the lower pulmonary tree and pulmonary endothelial and epithelial integrity in mice. We performed several assays commonly used in mouse acute lung-injury studies (bronchoalveolar lavage fluid [BAL] cell counts and protein concentration, excess lung water content [ELW], Evans blue permeability assay [EBA], lung tissue myeloperoxidase assay [MPO], and lung histopathology) to evaluate the effects of exposure to cyclical, naturally occurring ammonia levels on pulmonary integrity and inflammation. C57BL/6 mice were maintained in static microisolation or open-top cages. Cages were changed weekly, and ammonia levels were measured for 6 wk on days 0, 1, 3, 5, and 7 of each cage-change cycle. Ammonia levels in static microisolation cages began to increase on day 3 and peaked at a mean of 141.3 ppm on day 7. Ammonia levels in open-top cages never exceeded 5 ppm. Neither BAL cell counts, protein concentration, ELW, EBA, nor MPO differed significantly between groups. Lung histopathology showed minimal, incidental changes in all mice. Our findings indicate that the ammonia concentrations in the static microisolation cages we used did not alter the integrity of the lower pulmonary tract nor influence key indicators used to assess acute lung injury. PMID- 29402346 TI - Standard Electrocardiographic Data from Capuchin Monkeys (Cebus apella, Linnaeus, 1758). AB - Capuchin monkeys are a species of arboreal primate found in all South American countries. These monkeys have been highlighted for their potential for biomedical research due to their anatomic and physiologic similarities and genetic homology with humans. Here we characterized the electrocardiographic tracings from 12 healthy, young capuchin monkeys that were restrained with ketamine and midazolam. All 12 monkeys had normal sinus rhythms. Neither P-wave duration, PR interval, QT interval, nor P- or R-wave amplitude (in millivolts) differed between males and females. The P waves were small, monophasic, and positive in all animals. The QRS complex showed positive polarity in the D1, D2, aVL, aVF, V2, V4, and V10 derivations and negative polarity in the D3, aVR, and rV2 leads. The T wave exhibited a negative polarity only in the aVR derivation in all animals in the study, and no significant difference was present between sexes. The ST segment was isoelectric in both sexes and lacked reductions and elevations. The anesthetic protocol was well tolerated all of the monkeys and allowed for diagnostic-quality acquisition, measurement, and characterization of the electrocardiogram and establishment of the normal electrocardiographic parameters of chemically restrained capuchin monkeys. PMID- 29402348 TI - Evaluation of 6 Methods for Aerobic Bacterial Sanitization of Smartphones. AB - Smartphones are ubiquitous devices that offer a variety of useful applications for human and veterinary medical professionals and the biomedical research community. Smartphones can serve as fomites and potentially transmit pathogens, including bacterial species such as methicillin-resistant Staphylococcus aureus. The goal of this study was to evaluate 6 methods to decrease aerobic bacterial colonies on smartphones, including two 254-nm UVC devices, 70% ethanol spray, quaternary ammonium disinfectant spray, sodium hypochlorite-impregnated wipes, and delicate-task wipes. All methods were individually effective at decreasing aerobic bacterial counts after sanitization. In addition, 254-nm UVC devices providing a dose of 60 mJ/cm2, with UVC bulbs exposing both sides of the smartphone, were an effective nonliquid method for smartphone sanitization. PMID- 29402349 TI - Evaluation of a Commercially Available Euthanasia Solution as a Voluntarily Ingested Euthanasia Agent in Laboratory Mice. AB - All currently accepted methods of euthanasia for laboratory mice involve some degree of stress, fear, anxiety, or pain. We evaluated the voluntary oral administration of a euthanasia drug in 99 male and 81 female mice of various strains. We first explored the palatability of sugar-cookie dough with various flavorings added. We placed the cookie dough in the cage with an adult mouse and recorded the amount ingested after 1 h. Mice readily ingested all flavors of sugar-cookie dough. We then added a euthanasia solution containing pentobarbital and phenytoin to all flavors of cookie dough and placed a small bolus in the cage of each mouse or mouse pair. We observed the mice for 1 h for clinical signs of pentobarbital intoxication and then weighed uneaten dough to determine the dose of pentobarbital ingested. Palatability declined sharply when euthanasia solution was present. Mice ingested higher doses of pentobarbital in cookie dough during the dark phase and after fasting. Ingestion caused ataxia in some mice but was not sufficient to cause loss of righting reflex, unconsciousness, or death in any mouse. We successfully identified sugar cookie dough as a drug vehicle that was readily and rapidly eaten by mice without the need for previous exposure. Additional research is needed to identify euthanasia compounds for mice that do not affect the palatability of cookie dough. PMID- 29402350 TI - Evaluation of Volume of Intramuscular Injection into the Caudal Thigh Muscles of Female and Male BALB/c Mice (Mus musculus). AB - This study presents recommendations for intramuscular injection into the caudal thigh muscle of mice according to analysis of in vivo imaging of intramuscularly injected iohexol, a radiocontrast agent commonly used in CT imaging. An experienced laboratory animal technician using a Hamilton syringe intramuscularly injected iohexol into isoflurane-anesthetized female and male BALB/c mice. Injected volumes (25, 50, 100, and 200 MUL) underwent CT scanning at 9 time points over a 3-h period. The distribution of the injectate in the muscles of the rear leg was examined over time for each volume group. Results indicated that 25- and 50-MUL volumes remain intramuscularly. At 100 MUL, mild to moderate leakage into the extramuscular tissues occurred. At 200 MUL, leakage into the extramuscular tissues was moderate to severe. Our results suggest volumes of 50 MUL or less are recommended for the caudal thigh muscles of mice when intramuscular pharmacokinetics are needed; volumes greater than 50 MUL display variable distribution into extramuscular tissues, thus potentially yielding different pharmacokinetic profiles. PMID- 29402351 TI - Accuracy of 5 Point-of-Care Glucometers in C57BL/6J Mice. AB - Despite few published studies that assess the accuracy of glucometers in laboratory animals, glucometers are commonly used in animal research. We set out to determine the accuracy of 5 point-of-care glucometers (POCG) when used to evaluate murine whole blood, plasma, and serum samples. The POCG tested included one veterinary device (POCG A) and 4 humanuse instruments (POCG B through E). Whole blood, plasma, and serum samples from 50 female C57BL/6J mice were analyzed on all POCG, and serum was analyzed on a reference biochemical analyzer. The mean blood glucose concentration (BGC) measured in whole blood by using POCG A was greater than that on the biochemical analyzer, whereas the mean BGC in whole blood according to POCG B through E did not differ significantly from that on the biochemical analyzer. Mean BGC in plasma and serum did not differ between POCG B and E and the biochemical analyzer, whereas the plasma and serum BGC values from POCG C and D were greater than the mean BGC from the biochemical analyzer. The accuracy of each POCG for each sample type was evaluated by analyzing mean differences, correlations, and Bland-Altman graphs. We found that the 4 human-use POCG are appropriate for use with whole blood from female C57BL/6J mice, whereas only 2 of the evaluated POCG were sufficiently accurate for use with plasma or serum. PMID- 29402352 TI - Hydrophobic Sand Versus Metabolic Cages: A Comparison of Urine Collection Methods for Rats (Rattus norvegicus). AB - A common method for urine collection from rats requires the use of a metabolic cage, thus exposing animals to extended periods of isolation in an unfamiliar cage with a wire-mesh floor. A new method involving hydrophobic sand, a material more similar to bedding, has become available recently but has not been extensively compared with metabolic cages in regard to collection efficiency or stress. Using a within-subjects crossover design, we examined differences in stress markers, urinary markers, and urine volume of clinically healthy male Sprague-Dawley rats during 2-, 4-, and 6-h collection sessions in hydrophobic sand and metabolic cages. Stress response markers of weight loss, fecal pellet output, or corticosterone did not differ between hydrophobic sand and metabolic cages, and observed behavior suggested that sand may be less stressful than metabolic cages. All clinically relevant urinary markers examined were normal, with no differences between collection methods. Total urine volume collected was greater from the metabolic cage than sand in 3 of the 5 sessions, but the volume collected during the shortest session (2 h) did not differ between methods and accounted for 62% of the total volume collected during the longest session (6 h). Our results suggest that hydrophobic sand is a refinement of urine collection methods for rats that decreases isolation time, risk of injury, and stress and maintains the integrity of urine samples. PMID- 29402353 TI - Effectiveness of Rapid Cooling as a Method of Euthanasia for Young Zebrafish (Danio rerio). AB - Despite increased use of zebrafish (Danio rerio) in biomedical research, consistent information regarding appropriate euthanasia methods, particularly for embryos, is sparse. Current literature indicates that rapid cooling is an effective method of euthanasia for adult zebrafish, yet consistent guidelines regarding zebrafish younger than 6 mo are unavailable. This study was performed to distinguish the age at which rapid cooling is an effective method of euthanasia for zebrafish and the exposure times necessary to reliably euthanize zebrafish using this method. Zebrafish at 3, 4, 7, 14, 16, 19, 21, 28, 60, and 90 d postfertilization (dpf) were placed into an ice water bath for 5, 10, 30, 45, or 60 min (n = 12 to 40 per group). In addition, zebrafish were placed in ice water for 12 h (age <=14 dpf) or 30 s (age >=14 dpf). After rapid cooling, fish were transferred to a recovery tank and the number of fish alive at 1, 4, and 12 24 h after removal from ice water was documented. Euthanasia was defined as a failure when evidence of recovery was observed at any point after removal from ice water. Results showed that younger fish required prolonged exposure to rapid cooling for effective euthanasia, with the required exposure time decreasing as fish age. Although younger fish required long exposure times, animals became immobilized immediately upon exposure to the cold water, and behavioral indicators of pain or distress rarely occurred. We conclude that zebrafish 14 dpf and younger require as long as 12 h, those 16 to 28 dpf of age require 5 min, and those older than 28 dpf require 30 s minimal exposure to rapid cooling for reliable euthanasia. PMID- 29402355 TI - Abstracts of Scientific Papers 2017 Association of Primate Veterinarians Workshop. PMID- 29402354 TI - Comparison of Direct and Indirect Methods of Measuring Arterial Blood Pressure in Healthy Male Rhesus Macaques (Macaca mulatta). AB - Blood pressure is a critical parameter for evaluating cardiovascular health, assessing effects of drugs and procedures, monitoring physiologic status during anesthesia, and making clinical decisions. The placement of an arterial catheter is the most direct and accurate method for measuring blood pressure; however, this approach is invasive and of limited use during brief sedated examinations. The objective of this study was to determine which method of indirect blood pressure monitoring was most accurate compared with measurement by direct arterial catheterization. In addition, we sought to determine the relative accuracy of each indirect method (compared with direct arterial measurement) at a given body location and to assess whether the accuracy of each indirect method was dependent on body location. We compared direct blood pressure measurements by means of catheterization of the saphenous artery with oscillometric and ultrasonic Doppler flow detection measurements at 3 body locations (forearm, distal leg, and tail base) in 16 anesthetized, male rhesus macaques. The results indicate that oscillometry at the forearm is the best indirect method and location for accurately and consistently measuring blood pressure in healthy male rhesus macaques. PMID- 29402356 TI - [BRL-44408 maleate, the antagonist of alpha2A-adrenoceptor, attenuates endogenous lipopolysacchride-induced acute lung injury through inhibiting the mitogen activated protein kinase kinase/extracellular regulated protein kinases signaling pathway in mice]. AB - OBJECTIVE: To explore the effects and mechanism of alpha2A-adrenergic receptor (alpha2A-AR) antagonist BRL-44408 maleate on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Sixty male C57BL/6 mice were randomly divided into three groups (n = 20): sham group, LPS group and BRL-44408 maleate pre-treated group (BRL+LPS group). The model of ALI was replicated by intratracheally administrated of LPS (5 mg/kg), and the mice in the sham group were received an equal volume of saline. Mice in the BRL+LPS group were treated with additionally BRL-44408 maleate (5 mg/kg, i.p) at 4 hours before LPS administration. The mice were sacrificed at 6 hours and 24 hours after LPS administration in each group. Among them, 5 mice were used to collect the bronchoalveolar lavage fluid (BALF) and the other 5 mice were sacrificed for lung tissues. The levels of norepinephrine (NE), tumor necrosis factor-alpha (TNF alpha), interleukins (IL-6, IL-10) in BALF were measured by enzyme linked immunosorbent assay (ELISA). The level of protein in BALF was measured by bicinchoninic acid (BCA) method. The histopathological changes and wet/dry (W/D) ratio of lung tissue were observed. The expression of lung phosphorylated mitogen activated protein kinase kinase (p-MEK) and phosphorylated extracellular regulated protein kinases (p-ERK) were detected by Western Blot. RESULTS: Compared with the sham group, the lung histopathological injury was significantly aggravated, and the histopathological injury score was significantly increased, the lung W/D ratio, and total protein content, NE, TNF-alpha, IL-6, IL-10 in BALF, and p-MEK and p-ERK expressions were significantly increased in LPS group at 6 hours after model setup [the lung histopathological injury score: 0.70+/ 0.04 vs. 0.14+/-0.13, W/D ratio: 4.79+/-0.15 vs. 4.35+/-0.17, protein content (g/L): 1.51+/-0.36 vs. 0.46+/-0.13, NE (ng/L): 85.02+/-11.28 vs. 47.18+/-10.30, TNF-alpha (ng/L): 186.61+/-21.93 vs. 9.18+/-2.86, IL-6 (ng/L): 193.45+/-26.54 vs. 13.58+/-2.54, IL-10 (ng/L): 113.46+/-31.23 vs. 25.66+/-9.41, p-MEK/beta-actin: 0.246+/-0.019 vs. 0.178+/-0.030, p-ERK/beta-actin: 0.257+/-0.013 vs. 0.175+/ 0.014, all P < 0.05], and increase with time after model setup. Compared with the LPS group, BRL-44408 maleate pretreatment for 6 hours could significantly improve the degree of lung injury and reduce the lung histopathological injury score (0.61+/-0.05 vs. 0.70+/-0.04), reduce lung W/D weight ratio (4.51+/-0.22 vs. 4.79+/-0.15); the expression of NE, TNF-alpha, IL-6 in BALF were inhibited [NE (ng/L): 55.77+/-15.86 vs. 85.02+/-11.28, TNF-alpha(ng/L): 54.79+/-12.68 vs. 186.61+/-21.93, IL-6 (ng/L): 67.66+/-20.08 vs. 193.45+/-26.54], in addition, the up-regulation of p-MEK, p-ERK were significantly inhibited (p-MEK/beta-actin: 0.204+/-0.008 vs. 0.246+/-0.019, p-ERK/beta-actin: 0.186+/-0.024 vs. 0.257+/ 0.013), with statistically significant differences (all P < 0.05). The protein content and the expression of IL-10 in BALF showed no significant difference. CONCLUSIONS: alpha2A-AR blocker BRL-44408 maleate could alleviate endogenous ALI induced by LPS in mice by inhibiting the MEK/ERK pathway. PMID- 29402357 TI - [Predictive factors for failure of non-invasive positive pressure ventilation in immunosuppressed patients with acute respiratory failure]. AB - OBJECTIVE: To evaluate the predictive factors for failure of non-invasive positive pressure ventilation (NIPPV) in immunosuppressed patients with acute respiratory failure (ARF). METHODS: The clinical data of 118 immuno-deficient patients treated with NIPPV in the respiratory and intensive care unit (RICU) of the First Affiliated Hospital of Xinjiang Medical University from January 2012 to August 2017 were retrospectively analyzed. The patients were divided into a non endotracheal intubation (ETI) group (n = 62) and ETI group (n = 56) according to whether ETI was performed during the hospitalization period or not. Each observed indicator was analyzed by univariate analysis, and factors leading to failure of NIPPV were further analyzed by Logistic regression. Receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of risk factors for failure of NIPPV in immunosuppressed patients with ARF. RESULTS: The non-intubation rate for NIPPV in immunosuppressed patients was 50.8% (60/118). Compared with the non-ETI group, the body temperature, pH value in the ETI group were significantly increased, the partial pressure of arterial carbon dioxide (PaCO2) was significantly decreased, the ratio of oxygenation index (PaO2/FiO2) < 100 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluation II (APACHE II) score >= 20, and the number of cases requiring catecholamine were significantly increased, the mortality was significantly increased. Multivariate Logistic regression analysis showed that the APACHE II score >= 20 [odds ratio (OR) = 15.274, 95% confidence internal (95%CI) = 2.175-107.252, chi2 = 7.516, P = 0.006], PaO2/FiO2 < 100 mmHg (OR = 0.075, 95%CI = 0.014-0.408, chi2 = 8.968, P = 0.003), and need for catecholamine (OR = 35.736, 95%CI = 6.974-183.124, chi2 = 18.400, P < 0.001) were independent risk factors for failure of NIPPV. ROC curve analysis showed that the APACHE II score >= 20 and PaO2/FiO2 < 100 mmHg could predict failure of NIPPV, the area under ROC curve (AUC) of the APACHE II score >= 20 was 0.787, the sensitivity was 83.93%, the specificity was 69.35%, the positive predict value (PPV) was 71.21%, the negative predict value (NPV) was 82.69%, the positive likelihood ratio (PLR) was 2.74, the negative likelihood ratio (NLR) was 0.23, and Youden index was 0.53; the AUC of PaO2/FiO2 < 100 mmHg was 0.757, the sensitivity was 80.65%, the specificity was 66.07%, the PPV was 68.18%, the NPV was 78.85%, the PLR was 2.38, the NLR was 0.29, and Youden index was 0.47. CONCLUSIONS: 50.8% of immunocompromised and ARF patients treated with NIPPV did not require ETI, which is independent of the etiology of ARF. APACHE II score >= 20, PaO2/FiO2 < 100 mmHg, and the need for catecholamine are predictive factors for failure of NIPPV in immunocompromised patients. PMID- 29402358 TI - [Effect of early mobilization on diaphragmatic function in patients with mechanical ventilation: a prospective randomized controlled study]. AB - OBJECTIVE: To investigate the effect of early mobilization on diaphragmatic function in patients with mechanical ventilation (MV). METHODS: Sixty chronic obstructive pulmonary disease with acute exacerbation (AECOPD) patients with respiratory failure (RF) and underwent MV admitted to intensive care unit (ICU) of Huxi Affiliated Hospital of Jining Medical College from January 2016 to January 2017 were enrolled. The patients were divided into treatment group (n = 30) and control group (n = 30) by randomly number table method. The two groups were given analgesia, sedation, MV, antibiotics, nutritional support and other treatments. An implementation plan was developed based on the clinical practice of pain, irritability and delirium in adult patients (PAD) with ICU, while the treatment group was given early mobilization (such as joint activity, stand to the bed, 3 times a day). The diaphragmatic thickness at the end of expiration (DTee), diaphragmatic thickness at the end of inspiration (DTei) and diaphragmatic thickening fraction (DTF) were measured by bedside ultrasonography before and 24 hours, 48 hours, 3 days and 5 days after treatment respectively. RESULTS: There were no significant differences in the parameters of the diaphragm before treatment between the two groups. In the control group, DTee was gradually decreased at 5 days after treatment and was significantly lower than that before treatment (cm: 0.26+/-0.06 vs. 0.28+/-0.08, t = 3.045, P = 0.005). While there was no significant change in DTee in the treatment group. There was no significant difference in DTee between the two groups at different time points after treatment. DTei and DTF were significantly increased in the two groups after treatment, and reached the peak value at 48 hours; with the prolonged of MV time, DTei and DTF in the control group at 3 days and 5 days were significantly lower than those at 48 hours [DTei (cm): 0.35+/-0.07, 0.34+/-0.07 vs. 0.36+/ 0.08; DTF: (29.29+/-11.01)%, (28.62+/-11.97)% vs. (32.48+/-15.63)%, all P < 0.01]; there were no significant changes in the treatment group. DTF in the treatment group at 3 days and 5 days was significantly higher than that in the control groups [(38.53+/-11.39)% vs. (29.29+/-11.01)%, (37.27+/-11.26)% vs. (28.62+/-11.97)%, both P < 0.01]. CONCLUSIONS: MV can lead to diaphragmatic dysfunction, while early mobilization can delay diaphragmatic atrophy and systolic dysfunction in MV patients. PMID- 29402359 TI - [Predictive value of partial pressure of end-tidal carbon dioxide on the effect of active abdominal compression-decompression cardiopulmonary resuscitation and serum S100B protein on cerebral function]. AB - OBJECTIVE: To explore the predictive value of partial pressure of end-tidal carbon dioxide (PETCO2) on the effect of active abdominal compression decompression cardiopulmonary resuscitation (AACD-CPR) and serum S100B protein on cerebral function. METHODS: 142 adult patients with in-hospital cardiac arrest (IHCA) AACD-CPR in Zhengzhou People's Hospital, Affiliated Southern Medical University from September 2014 to December 2017 were enrolled. Patients were divided into successful group and failure group according to restoration of spontaneous circulation (ROSC) or not; and then according to Glasgow-Pittsburgh cerebral performance categories (CPC) one month after ROSC, the successful group was divided into good prognosis group (CPC 1-2) and poor prognosis group (CPC 3 5) further. The variations of hemodynamic, arterial blood gas index, PETCO2 and serum S100B protein level (25 healthy subjects as normal S100B protein level reference value) during the recovery were analyzed. The predictive value of PETCO2 on the effect of AACD-CPR and serum S100B protein on cerebral function of successful resuscitation patients were analyzed by receiver operating characteristic curve (ROC). RESULTS: (1) According to the traditional qualitative indexes, such as pulsation of the large artery, redness of lips and extremities, spontaneous fluctuation of chest, narrowing of pupil, existence of shallow reflex, etc, 54 in 142 patients with IHCA were successfully resuscitated; 57 cases were successfully resuscitated through the guidance of PETCO2, there was no significant difference between the two groups (chi2 = 0.133, P = 0.715). With the AACD-CPR, 142 CA patients' arterial partial pressure of oxygen (PaO2), arterial blood carbon dioxide partial pressure (PaCO2) were all improved with different degrees; heart rate (HR), mean arterial pressure (MAP), PaO2 and PaCO2 were further improved at 20 minutes after ROSC. At beginning of AACD-CPR, PETCO2 of both groups were about 10 mmHg (1 mmHg = 0.133 kPa). PETCO2 was gradually rising to above 20 mmHg in successful group during AACD-CPR process; the failed group increased slightly within 2-5 minutes, then gradually decreased to below 20 mmHg, there was a significant difference in PETCO2 between the two groups at each time. The area under the ROC (AUC) of PETCO2 at CPR 20 minutes in predicting the outcome of the resuscitation was 0.969, 95% confidence interval (95%CI) was 0.943 0.995 (P = 0.000), when the cut-off value of PETCO2 was 24.25 mmHg, the sensitivity was 90.7%, and the specificity was 96.6%. (2) The level of serum S100B protein at 0.5 hour after ROSC in the good prognosis group and the poor prognosis group were significant higher than that of the normal control group; there was no significant difference between poor prognosis group and good prognosis group. S100B protein concentration of the poor prognosis group reached the peak within 3-6 hours, then gradually decreased, and was higher than that of the normal control group at ROSC 72 hours; the good prognosis was gradually decreased and recovered to normal control group within ROSC 72 hours. The AUC of S100B at 3 hours after ROSC on cerebral function prognosis prediction was 0.925, 95%CI was 0.867-0.984 (P = 0.000), when the cut-off value of S100B protein was 1.215 MUg/L, the sensitivity was 85.2%, and the specificity was 85.5%. CONCLUSIONS: The variation of PETCO2 can be used as an objective index to predict the success of AACD-CPR, and serum S100B protein can be used as an objective clinical index to predict cerebral function after AACD-CPR, both of which have some reference and guiding significance for clinical treatment. PMID- 29402360 TI - [Effect of lactic acid levels on the prognosis of critically ill patients after cardiac and non-cardiac surgery: an analysis of 549 cases]. AB - OBJECTIVE: To compare the impact of mean lactate concentration and lactate variability on postoperative outcome after cardiac surgery and non-cardiac surgery in critical patients, and to explore the prognostic value of the first lactate and the highest lactate during the first 24 hours in intensive care unit (ICU). METHODS: A retrospective study was conducted. The postoperative patients of cardiac surgery and non-cardiac surgery who were transferred to ICU immediately, and who were at least 18 years old and whose ICU lengths of stay were at least 1 day, and who were admitted to ICU of the First Affiliated Hospital of Zhengzhou University from September 2014 to September 2016 were enrolled. According to the mean lactate concentration, the patients were divided into normal lactate group (0-2 mmol/L), relatively high lactate group (2-4 mmol/L), and absolute high lactate group (> 4 mmol/L), and the relationship between the mean lactate concentration and the prognosis of patients was analyzed. According to the degree of lactate variability, the patients were divided into four groups, and multivariate regression models were used to assess the risk of death in three different lactate variability groups. The value of the first lactate value and the highest lactate value during the first 24 hours in ICU were evaluated to predict the prognosis by the receiver operating characteristic (ROC) curve. RESULTS: 268 postoperative patients of cardiac surgery and 281 cases of non-cardiac surgery were selected, and the characteristic of the baseline data in the two groups was balanced. (1) Mean lactate concentration and mortality in ICU: in the normal lactate group (0-2 mmol/L), there was no significant difference in mortality between the post cardiac operative group and post-non-cardiac operative group [7.9% (14/177) vs. 6.5% (14/217), odds ratio (OR) = 1.245, P = 0.694]. In the relatively high lactate group (2-4 mmol/L), there was no significant difference between the two groups, either [33.3% (12/36) vs. 23.7% (9/38), OR = 1.611, P = 0.442]. In the absolute high lactate group (> 4 mmol/L), ICU mortality in post-non-cardiac operative group was obviously higher than that of post-cardiac operative group [69.2% (18/26) vs. 43.6% (24/55), OR = 0.344, P = 0.036]. (2) The ranges of lactate variability per quartile (mmol*L-1*d-1) and ICU mortality risk: there was a linear relationship between lactate variability and ICU mortality in post-non cardiac operative group, < 0.50 (reference), 0.50-0.85 (OR = 1.17, P = 0.87), 0.85-1.44 (OR = 4.86, P = 0.04), > 1.44 (OR = 22.66, P < 0.01) , and there was a significant difference between the two groups in the high degree of variability (0.85-1.44 and > 1.44). The risk of death after cardiac surgery tended to increase, < 0.55 (reference), 0.55-1.25 (OR = 0.61, P = 0.61), 1.25-2.43 (OR = 3.46, P = 0.10), > 2.43 (OR = 12.14, P < 0.01), and the risk of death only showed difference in the highest degree of variation (> 2.43). (3) ROC curve showed that the area under ROC curves (AUC) of the highest lactate in 24 hours were larger than that of the first lactate in both groups, with higher sensitivity and specificity. In the post-cardiac operative group and post-non-cardiac operative group, the AUC of the highest lactate in the first 24 hours were 0.877 and 0.875, the cut-off values were 5.35 mmol/L and 5.65 mmol/L, the sensitivity were 81.4% and 67.9%, and the specificity were 93.8% and 96.1%, respectively. CONCLUSIONS: Patients with post-non-cardiac operation should be more active in controlling hyperlactatemia and lactate variability. The highest lactate in the first 24 hours maybe one of the indicator for the assessment of the prognosis of the postoperative patients. PMID- 29402361 TI - [Meta-analysis of the effects between endotracheal intubation and laryngeal mask airway for patients with out-of-hospital cardiac arrest]. AB - OBJECTIVE: To comprehensively evaluate the resuscitation effect of endotracheal intubation (ETI) ventilation and laryngeal mask airway (LMA) for out-of-hospital cardiac arrest (OHCA). METHODS: Databases such as Cochrane Library, PubMed, Embase, Ebsco, Elsevier, OVID, Springer, Proquest, and China biomedical literature database (CBMdisc), CNKI, Wanfang database, Chinese Science and Technology Journal Full-text Database, VIP Chinese biomedical journal database were searched from the establishment of literature database to December 2017 to study the difference of effects between ETI and LMA for patients with OHCA. The effect determination indexes included the return of spontaneous circulation (ROSC) rate, 1-month survival and 1-month neurological recovery. After evaluation of the quality of included studies and extraction of the data, the software of RevMan 5.3 was used to analyze those outcomes. RESULTS: A total of 9 articles, including 7 English, 2 Chinese; 5 prospective studies and 4 retrospective studies were included. All of the literatures had high quality, and the Newcastle Ottawa scale (NOS) scored 7-9 points. The Meta-analysis showed that ETI was significantly more beneficial than LMA in improving the rate of ROSC [odds ratio (OR) = 1.51, 95% confidence interval (95%CI) = 1.42-1.62, Z = 12.35,P < 0.01], and 1-month survival (OR = 1.16, 95%CI = 1.06-1.26, Z = 3.41, P < 0.01), and there was no significant difference in 1-month neurological recovery (OR = 1.13, 95%CI = 0.96-1.32, Z = 1.49, P = 0.14). CONCLUSIONS: ETI has higher recovery success rate and survival rate than LMA for the rescue of OHCA adult patients, but the improvement of the nervous system is unclear. PMID- 29402362 TI - [Effects of mild hypothermia on beta-adrenergic signaling pathway in a cardiac arrest swine model]. AB - OBJECTIVE: To observe the effect of mild hypothermia on myocardial beta adrenergic receptor (beta-AR) signal pathway after cardiopulmonary resuscitation (CPR) in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Healthy male Landraces were collected for reproducing the CA CPR model (after 8-minute untreated ventricular fibrillation, CPR was implemented). The animals were divided into two groups according to random number table (n = 8). In the mild hypothermia group, the blood temperature of the animals was induced to 33 centigrade and maintained for 6 hours within 20 minutes after return of spontaneous circulation (ROSC) by using a hypothermia therapeutic apparatus. In the control group, the body temperature of the animals was maintained at (38.0+/-0.5)centigrade with cold and warm blankets. The heart rate (HR), mean arterial pressure (MAP), the maximum rate of increase or decrease in left rentricular pressure (+dp/dt max) were measured during the course of the experiment. The cardiac output (CO) was measured by heat dilution methods before CA (baseline), and 0.5, 1, 3, 6 hours after ROSC respectively, the venous blood was collected to detect the concentration of cTnI. Left ventricular ejection fraction (LVEF) was measured with cardiac ultrasound before CA and 6 hours after ROSC. Animals were sacrificed at 6 hours after ROSC and the myocardial tissue was harvested quickly, the mRNA expression of beta1-AR in myocardium was detected by reverse transcription-polymerase chain reaction (RT-PCR), the contents of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) were detected by enzyme linked immunosorbent assay (ELISA), the protein content of G protein coupled receptor kinase 2 (GRK2) was detected by Western Blot. RESULTS: After successful resuscitation, the HR of both groups were significantly higher than the baseline values, CO, +/-dp/dt max were significantly decreased, MAP were not significantly changed, serum cTnI levels were significantly increased. Compared with the control group, HR at 0.5, 1, 3 hours after ROSC were significantly decreased in mild hypothermia group (bpm: 142.80+/-12.83 vs. 176.88+/-15.14, 115.80+/-11.48 vs. 147.88+/-18.53, 112.60+/-7.40 vs. 138.50+/-12.02, all P < 0.01), CO was significantly increased at 1 hours and 3 hours after ROSC (L/min: 3.97+/-0.40 vs. 3.02+/-0.32, 4.00+/-0.11 vs. 3.11+/-0.59, both P < 0.01), +dp/dt max at 3 hours and 6 hours was also significantly increased after ROSC [+dp/dt max (mmHg/s): 3 402.5+/-612.7 vs. 2 130.0+/-450.6, 3 857.5+/-510.4 vs. 2 562.5+/ 633.9; -dp/dt max (mmHg/s): 2 935.0+/-753.2 vs. 1 732.5+/-513.6, 3 520.0+/-563.6 vs. 2 510.0+/-554.3, all P < 0.05], the cTnI was significantly decreased at 3 hours and 6 hours afher ROSC (MUg/L: 1.39+/-0.40 vs. 3.24+/-0.78, 1.46+/-0.35 vs. 3.78+/-0.93, both P < 0.01). The left at 6 hours after ROSC in both groups was decreased as compared with that before CA. The LVEF in the mild hypothermia group was higher than that in the control group (0.52+/-0.04 vs. 0.40+/-0.05, P < 0.05). The mRNA expression of beta1-AR, and concentrations of AC and cAMP in hypothermia group were significantly higher than those in control group [beta1-AR mRNA (2-DeltaDeltaCT): 1.18+/-0.39 vs. 0.55+/-0.17, AC (ng/L): 197.0+/-10.5 vs. 162.0+/-6.3, cAMP (nmol/L): 1 310.58+/-48.82 vs. 891.25+/-64.95, all P < 0.05], GRK2 was lower than that in the control group (GRK2/GAPDH: 0.45+/-0.05 vs. 0.80+/ 0.08, P < 0.05). CONCLUSIONS: Mild hypothermia can reduce the degree of cardiac function injury after CPR, and its mechanism may be related to the reduction of impaired myocardial beta-AR signaling after CPR. PMID- 29402363 TI - [Effect of neuregulin-1 on heart function and inflammatory mediators in rats with sepsis]. AB - OBJECTIVE: To explore the protective effect of neuregulin-1 (NRG-1) on heart function and myocardium in rats with sepsis and its mechanism. METHODS: Healthy male Sprague-Dawly (SD) rats were divided into three groups according to random number table method, with 6 rats in each group. Sepsis model was established by cecal ligation and puncture (CLP group); rats in sham operation group (sham group) underwent the same procedure except ligation. Rats in NRG-1 pre-treatment group (NRG group) were intravenously injected with recombinant human NGR-1 (rhNRG 1) at the dose of 10 MUg/kg through tail vein; rats in CLP group and sham group were treated with the same amount of saline. At 24 hours after CLP, hemodynamic method was used to evaluate the cardiac function, and myocardial morphology was observed with hematoxylin and eosin (HE) staining, enzyme linked immunosorbent assay (ELISA) was used to detect the levels of cardiac troponin T (cTnT), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) in serum and macrophage migration inhibitor factor (MIF) in myocardial tissue. RESULTS: (1) heart function: compared with the sham group, the mean arterial pressure (MAP), left ventricular systolic pressure (LVSP) and left ventricular pressure maximal rate of rise and fall (+/-dp/dt max) were significantly decreased in CLP group and NRG group, while the MAP, LVSP and +/-dp/dt max in NRG group were significantly higher than those in CLP group [MAP (mmHg, 1 mmHg = 0.133 kPa): 125.78+/-8.15 vs. 113.05+/-5.85, LVSP (mmHg): 151.27+/-6.79 vs. 139.39+/-8.05, +dp/dt max (kPa/s): 4 389.59+/-332.38 vs. 3 706.85+/-451.31, -dp/dt max (kPa/s): 4 291.42+/-323.72 vs. 3 691.17+/-515.44, all P < 0.05]. (2) Myocardial injury: compared with the sham group, the levels of serum cTnT in CLP group and NRG group were significantly increased, while the levels of serum cTnT in NRG group were significantly lower than those in CLP group (ng/L: 206.37+/-67.28 vs. 344.13+/ 80.95, P < 0.05), and the HE staining showed that myocardial pathological changes in NRG group were improved compared with the CLP group. (3) Inflammatory mediators level: compared with the sham group, the levels of serum TNF-alpha, IL 1beta and myocardial MIF were significantly increased in CLP group and NRG group, while the indicators in NRG group were lower than those in CLP group [TNF-alpha (ng/L): 52.77+/-3.43 vs. 97.19+/-13.98, IL-1beta (ng/L): 40.25+/-5.48 vs. 56.05+/ 6.88, MIF (MUg/L): 1.92+/-0.16 vs. 2.87+/-0.10, all P < 0.05]. CONCLUSIONS: NRG-1 can reduce circulating levels of inflammatory factors in rats with sepsis, adjust myocardial MIF level, and alleviate myocardial cell injury, thereby improving cardiac function, and play a role in myocardial protection. PMID- 29402364 TI - [Role of microRNA-1-mediated AMP-activated protein kinase pathway in cardiac fibroblasts induced by high glucose in rats]. AB - OBJECTIVE: To investigate the role of microRNA-1 (miR-1) in cardiac fibroblasts induced by high glucose in rats. METHODS: The primary fibroblasts were cultured from the apical tissue of 1-3 day-old Sprague-Dawley (SD) rats. The cells which were passaged to generation 3 or 4, were randomly divided into normal glucose+lentivector-vehicle group (CON+Lv-Vehicle group), normal glucose+lentivector-miR-1 group (CON+Lv-miR1 group), high glucose+lentivector vehicle group (HG+Lv-Vehicle group), high glucose+lentivector-miR-1 group (HG+Lv miR1 group), high glucose+Lv-Vehicle+inhibitor group (HG+Lv-Vehicle+CC group), and high glucose+lentivector-miR-1+inhibitor group (HG+Lv-miR1+CC group). The myocardial fibroblasts were cultured in the concentration of 5.5 mmol/L glucose (normal glucose) or 25.0 mmol/L (high glucose) DMEM medium. Then lentiviral vector containing miR-1 silent sequence or the same volume of lentiviral vector was inoculated into the cells. The AMP activated protein kinase (AMPK) inhibitor Compound C (20 MUmol/L) was added to the medium at 12 hours before sampling in inhibitor groups. The expression of phosphorylation of AMPK (p-AMPK), collagenIandIII, matrix metalloproteinase (MMP-2, MMP-9), and autophagy flux related protein LC3B-II and p62/SQSTM1 were measured by Western Blot. RESULTS: The purity of rat myocardial fibroblasts in vitro was 97%. Compared with CON+Lv Vehicle group, there was no significant difference in the expression of p-AMPK in CON+Lv-miR1 group, the expression of p-AMPK in HG+Lv-Vehicle group was significantly decreased (p-AMPK/t-AMPK: 44.72+/-3.29 vs. 100.00+/-7.77, P < 0.01). The expression of p-AMPK in HG+Lv-miR1 group was higher than that in HG+Lv Vehicle group (p-AMPK/t-AMPK: 60.52+/-5.16 vs. 44.72+/-3.29, P < 0.05). Compared with HG+Lv-Vehicle group, the expressions of collagen, MMP, LC3B-II and p62/SQSTM1 in HG+Lv-miR1 group were significantly decreased; after the treatment with AMPK inhibitor, the expressions of collagen, MMP, LC3B-II, p62/SQSTM1 were significantly increased (HG+Lv-Vehicle+CC group vs. HG+Lv-Vehicle group: collagen I/beta-actin: 158.74+/-13.21 vs. 100.00+/-7.64, collagen III/beta-actin: 177.38+/ 17.31 vs. 100.00+/-5.18, MMP-2/beta-actin: 130.09+/-14.31 vs. 100.00+/-10.47, MMP 9/beta-actin: 215.54+/-20.92 vs. 100.00+/-11.28, LC3B-II/beta-actin: 159.34+/ 13.83 vs. 100.00+/-6.44, p62/SQSTM1/beta-actin: 201.01+/-24.02 vs. 100.00+/-8.62; HG+Lv-miR1+CC group vs. HG+Lv-miR1 group: collagen I/beta-actin: 108.69+/-9.93 vs. 80.83+/-7.24, collagen III/beta-actin: 127.68+/-10.46 vs. 81.56+/-9.97, MMP 2/beta-actin: 106.66+/-10.21 vs. 74.80+/-7.43, MMP-9/ beta-actin: 145.65+/-11.56 vs. 74.63+/-10.55, LC3B-II/beta-actin: 150.15+/-13.28 vs. 22.98+/-2.87, p62/SQSTM1/beta-actin: 130.48+/-10.74 vs. 49.90+/-2.27, all P < 0.05). CONCLUSIONS: miR-1 gene silencing inhibits myocardial fibrosis induced by high glucose, its mechanism may be related to the up-regulation of p-AMPK, which can recover autophagy flux. PMID- 29402365 TI - [Effect and mechanism of dexmedetomidine on lungs in patients of sepsis complicated with acute respiratory distress syndrome]. AB - OBJECTIVE: To investigate the mechanisms of protective effects of dexmedetomidine on lungs in patients of sepsis complicated with acute respiratory distress syndrome (ARDS). METHODS: The adult patients with sepsis complicated with ARDS, the oxygenation index (PaO2/FiO2) was 150-200 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluation II (APACHE II) score was 10-20, need mechanical ventilation (MV) treatment > 72 hours, and admitted to intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from September 2013 to June 2017 were enrolled. According to the random number table method, the patients were divided into three groups (n = 80): no sedation group, propofol group (0.3-4.0 mg*kg-1*h-1) and dexmedetomidine group (0.2-0.7 MUg*kg 1*h-1). The three groups were adequately analgesic treated with remifentanil. The sedation target was -1-0 of Richmond agitation-sedation score (RASS). The levels of interlenkin-6 (IL-6) and tumor necrosis factor-alpha (INF-alpha) were determined by enzyme linked immunosorbent assay (ELISA) before sedation, and 24, 48, 72 hours after sedation. The expressions of inflammatory signaling proteins in bronchoalveolar lavage fluid (BALF) were determined by Western Blot before sedation and 72 hours after sedation. RESULTS: There were no significant changes for inflammatory factors in serum, and inflammatory signaling proteins and anti apoptotic signaling proteins in alveolar exfoliated cells in no sedation group. The levels of IL-6 and TNF-alpha in serum and the expressions of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and phosphorylated c Jun N-terminal kinase (p-JNK) in alveolar cells in propofol group and dexmedetomidine group were all significantly reduced after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group [48 hours: TNF-alpha (ng/L) was 153.76+/-29.16 vs. 179.82+/-30.28; 72 hours: IL-6 (ng/L) was 272.18+/-42.76 vs. 304.49+/-44.93, TNF-alpha (ng/L) was 102.18+/-30.25 vs. 140.28+/-28.92, TLR4 (IA value) was 0.288+/-0.034 vs. 0.648+/-0.029, MyD88 (IA value): 0.356+/-0.030 vs. 0.752+/-0.044, p-JNK (IA value): 0.256+/-0.027 vs. 0.303+/-0.034, all P < 0.05]. The expression of p-Akt in alveolar cells in propofol group and dexmedetomidine group was all significant increased after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group (IA value: 1.032+/-0.030 vs. 0.743+/-0.028, P < 0.05). CONCLUSIONS: Dexmedetomidine exerts the protective effects on lungs in patients of sepsis complicated with ARDS through the TLR4-MyD88-JNK signaling pathway. PMID- 29402366 TI - [Diagnostic value of lung ultrasound B-line score in acute heart failure]. AB - OBJECTIVE: To investigate the value of bedside lung ultrasound B-line score in the diagnosis of acute heart failure (AHF). METHODS: A retrospectively analysis was conducted. The adult patients presenting with acute dyspnea in intensive care unit (ICU) of Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2016 to June 2017 were enrolled. An 8-zone lung ultrasound was performed and plasma B-type natriuretic peptide (BNP) level was tested in all patients. AHF was determined as the final diagnosis by two experienced ICU doctors according to the diagnostic criteria of AHF. Patients were divided into two groups: AHF group and non-AHF group. The levels of BNP and B-line score were compared between the two groups, and the diagnostic value of BNP and B-line score in AHF was evaluated. RESULTS: Fifty-six patients were included in this study, with 32 of men and 24 of women, and with an average age of 77.3+/-8.8. Thirty-six patients were diagnosed as AHF. The level of BNP and lung ultrasound B-line score in AHF group were higher than those in non-AHF group [BNP (ng/L): 1 640.4+/-1 078.4 vs. 236.9+/-124.9, B line score: 12.8+/-5.3 vs. 5.4+/-1.8, both P < 0.01]. There was a strong correlation between elevated BNP levels and an increased B lines score (R2 = 0.712, P = 0.000). The receiver operating characteristic curve (ROC) showed that when the cut-off of lung ultrasound B-line score was 8.5, AHF could be discriminated from dyspnea caused by other diseases (sensitivity was 77.8%, specificity was 95%, positive likelihood ratio was 15.56, negative likelihood ratio was 0.23). The area under the ROC curve (AUC) of lung ultrasound B-line score was 0.917 [95% confidence interval (95%CI) = 0.847-0.987, P = 0.000], slightly lower than that of plasma BNP [0.979 (95%CI = 0.951-1.008)]. CONCLUSIONS: Lung ultrasound B-line score was highly specific, but moderately sensitive for identifying patients with AHF. PMID- 29402367 TI - [Continuous contrast-enhanced ultrasound applied to acute kidney injury caused by sepsis: a diagnostic clinical study]. AB - OBJECTIVE: To evaluate the diagnostic value of contrast-enhanced ultrasound in acute kidney injury (AKI) caused by sepsis. METHODS: The sepsis patients admitted to intensive care unit of Tianjin Third Central Hospital from January 2015 to June 2017 were enrolled. All of the patients were completed the 6-hour Bundle treatment and the bilateral renal contrast-enhanced ultrasound within 24 hours, and the peak signal intensity (PSI), peak intensity time (PIT), wash internal rate (WIR) and renal function parameters were measured at the same time. The patients were divided into AKI 24 hours group and non-AKI 24 hours group according to Kidney Disease: Improving Global Outcomes (KDIGO)-AKI diagnostic criteria, and the parameters differences were compared between the two groups. The receiver operating characteristic (ROC) curve were used to analyze the diagnostic value of the parameters. Renal function of the non-AKI group patients was measured again 7 days after hospital admission, and patients were divided into AKI 7 days group and non-AKI 7 days group, and the related parameters of the two groups measured within 24 hours were compared. RESULTS: (1) Ninety-six patients were enrolled, with 39 cases of AKI occurred within 24 hours after admission, and with an incidence of 40.6%. Contrast-enhanced ultrasound showed that the time-intensity curve (TIC) of non-AKI patients manifested as a slow down after rapid rise to the peak, but the AKI patients showed as slow rise to the peak and more slow decrease. Compared with non-AKI 24 hours group, AKI 24 hours group performance as PSI weakened, PIT extended and WIR decreased [PSI (dB): 114.41+/-19.38 vs. 141.24+/-24.65, PIT (s): 22.86+/-4.29 vs. 17.39+/-3.68, WIR (dB/s): 5.53+/-4.17 vs. 7.85+/-1.84, all P < 0.01]. ROC curve analysis showed that area under the ROC curve (AUC) of WIR, PIT, PSI was 0.85, 0.84, 0.82 respectively (all P < 0.01), the cut-off value of WIR was 7.18 dB/S, the sensitivity, specificity and accuracy were 82.05%, 80.70% and 81.25% respectively; the cut-off value of PIT was 18.45 s, the sensitivity, specificity and accuracy were 74.35%, 73.68% and 73.95% respectively; the cut-off values of PSI was 121.21 dB, the sensitivity, specificity and accuracy were 71.79%, 87.72% and 81.25% respectively. (2) The incidence of AKI within 7 days in non-AKI patients was 26.3% (15/57). There were significant differences in PIT, WIR and PSI between AKI 7 days group and non-AKI 7 days group [PSI (dB): 124.97+/-26.64 vs. 147.02+/-21.51, PIT (s): 20.61+/-3.27 vs. 16.24+/-3.13, WIR (dB/s): 6.81+/ 1.76 vs. 8.22+/-1.75, all P < 0.05]. However, there was no significant difference in serum creatinine (SCr), blood urea nitrogen (BUN) and creatinine clearance rate (CCr). CONCLUSIONS: Compared to SCr and BUN, contrast-enhanced ultrasound parameters can early response to renal dysfunction, and contribute to early diagnosis of sepsis induced AKI. PMID- 29402368 TI - [Efficacy and safety of simulated artificial pancreas in modulating stress hyperglycemia in critically ill patients: a prospective randomized controlled study]. AB - OBJECTIVE: To explore efficacy and safety of simulated artificial pancreas in modulating stress hyperglycemia in critically ill patients. METHODS: A prospective randomized controlled study was performed. Seventy-two critically ill patients with stress hyperglycemia, aged 18-85 years, acute physiology and chronic health evaluation II (APACHE II) score over 15, two consecutive random blood glucose 11.1 mmol/L or higher, glycated hemoglobin (HbA1C) below 0.065, unable to eat food for 3 days after inclusion, or only accepting parenteral nutrition, admitted to intensive care unit (ICU) in Shanghai Punan Hospital of Pudong New District from January 1st, 2015 to June 30th, 2017 were enrolled. The patients were divided into three groups according to the random number table method, high-intensity group and low-intensity group were injected Novolin R (high-intensity group 2/3 dosage, low-intensity group 1/3 dosage) to modulate stress hyperglycemia by simulated artificial pancreas. Simulated artificial pancreas consisted of Guardian real time glucose monitoring system (GRT system), close-circle control algorithm and micro-pump; subcutaneous injection of Humulin 70/30 was applied to modulate stress hyperglycemia in humulin group. Real-time glucose levels of interstitial fluid in abdominal wall, equivalent to blood glucose levels, 10 minutes each time, were monitored by using of GRT system for all patients in three groups. Fasting serum levels of stress hormones including epinephrine and cortisol and insulin resistance index (IRI) were recorded within 24 hours after inclusion. Mean blood glucose, blood glucose variation coefficient, blood glucose target-reaching rate, blood glucose target-reaching time, hypoglycemia rate and 6-month mortality were measured. Twenty healthy adults from health administration department of the hospital were recruited as healthy control group. RESULTS: A total of 60 eligible critically ill patients were included in this study, each group with 20 patients. There was no significant difference in gender, age, APACHE II scores among three groups. The levels of serum epinephrine, cortisol and IRI within 24 hours after inclusion in the three groups were significantly higher than those in healthy control group. The mean blood glucose levels of humulin group, low-intensity group, high intensity group were decreased (mmol/L: 10.2+/-3.2, 8.4+/-2.6, 8.1+/-2.2), the blood glucose target-reaching rate were increased [40.2% (3 295/8 196), 71.1% (5 393/7 585), 80.4% (6 286/7 818)], the blood glucose target-reaching time were shortened (hours: 49.1+/-5.8, 24.6+/-4.6, 17.5+/-4.2), the hypoglycemia rates were increased respectively [1.3% (108/8 196), 2.8% (211/7 585), 4.0% (313/7 818)], with statistically significant differences (all P = 0.000). There was no significant difference in blood glucose variation coefficient and 6-month mortality among three groups [blood glucose variation coefficient: (29.4+/-3.7)%, (28.5+/-5.3)%, (26.1+/-4.6)%, 6-month mortality: 55.0%, 45.0%, 40.0%, all P > 0.05]. CONCLUSIONS: Simulated artificial pancreas could effectively and safely modulate stress hyperglycemia in critically ill patients, high-intensity modulation could bring about better efficacy in the regulation of hyperglycemia. High-frequency blood glucose monitoring by using GRT system could promptly identify hypoglycemia and help it to be corrected. PMID- 29402369 TI - [Effect of silencing aquaporin 4 on learning and memory dysfunction in rats with traumatic brain injury]. AB - OBJECTIVE: To observe the protein expression related to cognitive and learning memory function, and to investigate the effect of aquaporin 4 (AQP4) silence on learning and memory function in traumatic brain injury (TBI) rats. METHODS: Ninety-six healthy adult male Wistar rats were divided into groups according to the random number table. (1) Forty-eight rats were divided into sham operation (sham) group, TBI group (by using modified Feeney method), AQP4 RNA interference (RNAi) negative group [TBI+meaningless small interfering RNA (siRNA)-AQP4 liposome solution 10 MUL], and AQP4 RNAi group (TBI+siRNA-AQP4 liposome solution 10 MUL). In each group, brain tissues of 4 rats were harvested at 1, 6 and 12 hours respectively. The protein expressions of hippocampus AQP4, general control nonderepressible 2 kinase (GCN2), cyclic adenosine monophosphate response element binding protein (CREB) and phosphorylated CREB (p-CREB) were detected by Western Blot. (2) In addition, 48 rats were divided into normal control group (control group), sham group, TBI group and AQP4 RNAi group, brain water content were measured in 6 of them after 12 hours of injury, and 6 were used in Morris water maze test. RESULTS: (1) The protein expressions of hippocampus AQP4 and GCN2 in TBI group were significantly higher than those in sham group, and increased gradually with time with statistical difference at 12 hours (AQP4 protein: 5.03+/ 0.09 vs. 1, GCN2 protein: 4.01+/-0.13 vs. 1, both P < 0.01); the protein expressions of hippocampus CREB and p-CREB were significantly lower than those in sham group, and decreased gradually with time with statistical difference at 12 hours (CREB protein: 0.38+/-0.03 vs. 1, p-CREB protein: 0.38+/-0.03 vs. 1, both P < 0.01). Compared with TBI group, the protein expressions of AQP4 in AQP4 RNAi group was significantly decreased (1 hour: 1.02+/-0.04 vs. 2.23+/-0.05, 6 hours: 1.23+/-0.03 vs. 2.59+/-0.04, 12 hours: 2.20+/-0.08 vs. 5.03+/-0.09, all P < 0.01), but there were no significant difference in the expressions of GCN2, CREB or p-CREB. There was no significant difference in the expression of protein between AQP4 RNAi negative group and TBI group. (2) The brain water content in TBI group was significantly higher than that in control group and sham group [(83.7+/-0.4)% vs. (76.2+/-0.2)%, (76.2+/-0.3)%, both P < 0.01]. The brain water content in AQP4 RNAi group [(78.8+/-0.3)%] was significantly decreased as compared with that in TBI group (P < 0.01). The latency of Morris water maze test was significantly prolonged in the day 11, 13 and 15 after the injury of the TBI group and AQP4 RNAi group, and the exploration time was significantly shortened. Compared with TBI group, the incubation period of AQP4 RNAi group was significantly shortened at 15 days (s: 60.2+/-11.1 vs. 62.0+/-11.5, P < 0.05), and the exploration time was significantly prolonged (s: 37.0+/-8.5 vs. 32.7+/ 9.2, P < 0.05). CONCLUSIONS: The impairment of cognitive and learning memory function in rats after TBI was significantly related to the changes in CREB and GCN2 in cognitive and learning memory function. After RNAi treatment, the cognitive and learning and memory function of rats was not improved obviously, but the brain edema could be alleviated. PMID- 29402370 TI - [Impact of permissive underfeeding versus standard enteral feeding on outcomes in critical patients requiring mechanical ventilation: a prospective randomized controlled study]. AB - OBJECTIVE: To compare the impact of permissive underfeeding versus standard enteral feeding on outcomes in critical patients requiring mechanical ventilation (MV). METHODS: A prospective randomized controlled study was conducted. Eighty two patients requiring MV admitted to intensive care unit (ICU) of Anji People's Hospital from January 2015 to March 2017 were enrolled, and they were randomly divided into the permissive underfeeding group (n = 40, non-protein heat was 52.3 62.8 kJ*kg-1*d-1, protein was 1.2-1.5 g*kg-1*d-1) and standard enteral feeding group (n = 42, non-protein heat was 104.6-125.5 kJ*kg-1*d-1, protein was 1.2-1.5 g*kg-1*d-1). Permissive underfeeding group received 50% of their daily energy expenditure via enteral nutrition (EN) and standard enteral feeding group received 100% of their daily energy expenditure via EN in 24-48 hours after admitted to ICU. Nutritional status [pro-albumin (PA), serum albumin (ALB)], inflammation state [procalcitonin (PCT), hypersensitive C-reactive protein (hs CRP)] were detected before treatment and 7 days after treatment. Duration of MV, length of ICU stay, daily insulin dosage, 28-day mortality, hospital acquired pneumonia (HAP), urinary tract infection, septic shock and other secondary infection, and the nutrition related complications were recorded. RESULTS: Compared with before treatment, the levels of serum PA (mg/L) and ALB (g/L) were significantly increased, the levels of PCT (ng/L) and hs-CRP (mg/L) were significantly decreased at 7 days after treatment in both groups [permissive underfeeding group: PA was 127.42+/-65.83 vs. 80.92+/-60.14, ALB was 30.16+/-4.32 vs. 25.36+/-6.21, PCT was 375.8+/-227.2 vs. 762.3+/-314.5, hs-CRP was 32.19+/ 7.53 vs. 120.48+/-60.24; standard enteral feeding group: PA was 132.56+/-61.32 vs. 86.78+/-47.06, ALB was 31.25+/-4.63 vs. 26.71+/-5.48, PCT was 412.1+/-323.4 vs. 821.7+/-408.6, hs-CRP was 35.86+/-5.69 vs. 116.38+/-72.16, all P < 0.05], but there was no significant difference in PA, ALB, PCT or hs-CRP at 7 days after treatment between two groups (all P > 0.05). There was no significant difference in the duration of MV, length of ICU stay, 28-day mortality or ICU-associated infection between two groups [duration of MV (hours): 162.35+/-20.37 vs. 153.48+/ 18.65, length of ICU stay (days): 7.52+/-1.61 vs. 6.34+/-1.87, 28-day mortality: 17.5% vs. 19.0%, ICU-associated infection: 45.0% vs. 47.6%, all P > 0.05]. Compared with standard enteral feeding, insulin demand was significantly decreased (U/d: 13.68+/-10.36 vs. 26.24+/-18.53), and gastrointestinal intolerance was less frequent (32.5% vs. 54.8%) in the permissive underfeeding group (both P < 0.05). Kaplan-Meier survival curve analysis showed that there was no significant difference between the two groups (chi2 = 3.216, P = 0.068). CONCLUSIONS: The curative effect and prognosis of MV severe patients receiving permissive underfeeding are similar to those of standard enteral feeding, but it can reduce the dosage of insulin with better gastrointestinal tolerance. PMID- 29402371 TI - [Assessing nutritional status of severe malnutrition patients by bioelectrical impedance technique: a multicenter prospective study]. AB - OBJECTIVE: To assess the nutritional status of severe malnutrition patients with anorexia nervosa by multi-frequency bioelectrical impedance technique, and to provide the basis for nutritional support therapy. METHODS: A prospective study was conducted. Twenty-six severe malnutrition patients with anorexia nervosa, body mass index (BMI) <= 16 kg/m2 admitted to intensive care unit (ICU) of Peking University Third Hospital and general three ward of Peking University Sixth Hospital from June 1st to September 30th, 2017 were enrolled. The extracellular water (ECW), intracellular water (ICW), ECW/ICW ratio, adipose tissue mass (ATM), lean tissue mass (LTM), total body water/body weight (TBW/WT), ATM/WT, and LTM/WT were measured by multi-frequency bioelectrical impedance meter. Thirty-eighty healthy volunteers with normal nutritional status (23.0 kg/m2 > BMI > 18.5 kg/m2) matched by gender and height were enrolled as healthy control group. The predictive value of main body composition for nutritional status were analyzed by receiver operating characteristic (ROC) curve. RESULTS: All the patients were female. There was no significant difference in height between two groups, but WT and BMI in the severe malnutrition group were significantly higher than those in the healthy control group [WT (kg): 38.1+/-4.9 vs. 54.2+/-3.3, BMI (kg/m2): 13.6+/-2.5 vs. 21.2+/-1.1, both P < 0.01]. Compared with the healthy control group, the ECW, ICW, ATM, LTM, ATM/WT and LTM/WT were significantly decreased in the severe malnutrition group [ECW (L): 9.02+/-0.42 vs. 10.19+/-0.77, ICW (L): 12.6+/-0.9 vs.19.1+/-1.3, ATM (kg): 9.3+/-1.1 vs. 16.6+/-1.9, LTM (kg): 16.5+/ 1.5 vs. 26.1+/-1.7, ATM/WT: 0.26+/-0.02 vs. 0.30+/-0.02, LTM/WT: 0.22+/-0.02 vs. 0.26+/-0.01, all P < 0.01], the ECW/ICW and TBW/WT were significantly increased in the severe malnutrition group (ECW/ICW: 0.72+/-0.06 vs. 0.54+/-0.06, TBW/WT: 0.58+/-0.02 vs. 0.52+/-0.02, both P < 0.01). It was shown by ROC curve analysis that the area under ROC curve (AUC) of TBW/WT, ATM/WT, LTM/WT for evaluating severe malnutrition were 0.999, 0.919, 0.954 respectively; when the cut-off of TBW/WT, ATM/WT, LTM/WT were 0.58, 0.28, 0.24 respectively, the sensitivity were 100%, 85%, 80% respectively, and the specificity were 95%, 80%, 91% respectively. CONCLUSIONS: Main body composition of severe malnutrition patients with anorexia nervosa changed significantly. Bioelectrical impedance technology can be an effective assessment tool for the nutritional status of such patients. PMID- 29402372 TI - [Advances in the research of the relationship between interferon-inducible protein-10 and liver injury]. AB - OBJECTIVE: The pathogenesis of liver failure is extremely complex. In recent years, the role of chemokines in viral hepatitis has been widely concerned. A large number of studies have confirmed that the abnormal expression of chemokines is closely related to the process of viral hepatitis and other types of hepatitis. Interferon-inducible protein-10 (IP-10) is a good indicator of the specificity and sensitivity of inflammatory liver injury. In this paper, IP-10 in different types of liver injury in the pathogenesis of research progress were reviewed to provide valuable indicators for clinical diagnosis, treatment strategy and prognosis evaluation of liver injury. PMID- 29402373 TI - [Role of mitochondrial dysfunction in the pathogenesis of septic cardiomyopathy]. AB - OBJECTIVE: The incidence and mortality of septic cardiomyopathy were high, which is the common cause of death in the patients with sepsis. The pathogenesis of sepsis induced myocardial injury is still unclear. The mitochondrial dysfunction of myocardial cells plays a very important role in the pathophysiological mechanism. This review attempts to introduce the mitochondrial damage of cardiomyocyte from the regulation of mitochondrial energy metabolism, the mechanism of mitochondrial damage, the role of aquaporin and the adjustment of mitochondrial dynamic, in order to provide help for the early prevention of septic cardiomyopathy. PMID- 29402374 TI - Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis. AB - BACKGROUND: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. METHODS: We first conducted a case-control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. RESULTS: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference -0.48, 95% confidence interval [CI] -0.57 to -0.39, p = 9.8 * 10-24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65-1.51, p = 0.96). LIMITATIONS: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. CONCLUSION: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach. PMID- 29402375 TI - Neuroanatomical phenotypes in mental illness: identifying convergent and divergent cortical phenotypes across autism, ADHD and schizophrenia. AB - BACKGROUND: There is evidence suggesting neuropsychiatric disorders share genomic, cognitive and clinical features. Here, we ask if autism-spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and schizophrenia share neuroanatomical variations. METHODS: First, we used measures of cortical anatomy to estimate spatial overlap of neuroanatomical variation using univariate methods. Next, we developed a novel methodology to determine whether cortical deficits specifically target or are "enriched" within functional resting-state networks. RESULTS: We found cortical anomalies were preferentially enriched across functional networks rather than clustering spatially. Specifically, cortical thickness showed significant enrichment between patients with ASD and those with ADHD in the default mode network, between patients with ASD and those with schizophrenia in the frontoparietal and limbic networks, and between patients with ADHD and those with schizophrenia in the ventral attention network. Networks enriched in cortical thickness anomalies were also strongly represented in functional MRI results (Neurosynth; r = 0.64, p = 0.032). LIMITATIONS: We did not account for variable symptom dimensions and severity in patient populations, and our cross-sectional design prevented longitudinal analyses of developmental trajectories. CONCLUSION: These findings suggest that common deficits across neuropsychiatric disorders cannot simply be characterized as arising out of local changes in cortical grey matter, but rather as entities of both local and systemic alterations targeting brain networks. PMID- 29402377 TI - Towards a continuum of care concerning chemsex issues. AB - In response to the apparent rise in chemsex in the Netherlands Mainline Foundation interviewed 27 MSM about their crystal meth use and/or experience with injecting in a sexual context. These men were interviewed about their motivation for methamphetamine use, their sexual risk-taking behaviour, methods and context of their drug use, and their information- and care needs. In 2015 this resulted in the status report Tina and Slamming: MSM, Crystal Meth Use and Intravenous Drug Use in a Sexual Context. Following the publication of this report Mainline foundation has been offering harm-reduction intervention for MSM and promoting the development of a continuum of care by building networks, training professionals and investing in advocacy. In our view, a continuum of care means the availability of a sufficient level of qualitative and effective preventive interventions, harm reduction services and treatment facilities that are connected, can track and intervene in the 'lifecycle' of individual drug use, and are easily accessible by the target group. This case study describes the various interventions of Mainline foundation, that make up their continuum of care approach concerning chemsex issues. PMID- 29402376 TI - PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality 18fluorine-2-fluoro-2-deoxy-d glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer. AB - BACKGROUND: Pancreatic cancer diagnosis and staging can be difficult in 10-20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer. OBJECTIVE: To determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer. DESIGN: A multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy. PARTICIPANTS: Patients with suspected pancreatic malignancy. INTERVENTIONS: All patients to undergo PET/CT following standard diagnostic work-up. MAIN OUTCOME MEASURES: The primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients' diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours. RESULTS: Between 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUVmax.) for a pancreatic cancer diagnosis was 7.5. PET/CT demonstrated a significant improvement in relative sensitivity (p = 0.01) and specificity (p = 0.023) compared with MDCT. Incremental likelihood ratios demonstrated that PET/CT significantly improved diagnostic accuracy in all scenarios (p < 0.0002). PET/CT correctly changed the staging of pancreatic cancer in 56 patients (p = 0.001). PET/CT influenced management in 250 (45%) patients. PET/CT stopped resection in 58 (20%) patients who were due to have surgery. The benefit of PET/CT was limited in patients with chronic pancreatitis or other pancreatic tumours. PET/CT was associated with a gain in quality-adjusted life-years of 0.0157 (95% confidence interval -0.0101 to 0.0430). In the base-case model PET/CT was seen to dominate MDCT alone and is thus highly likely to be cost-effective for the UK NHS. PET/CT was seen to be most cost-effective for the subgroup of patients with suspected pancreatic cancer who were thought to be resectable. CONCLUSION: PET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer. STUDY REGISTRATION: Current Controlled Trials ISRCTN73852054 and UKCRN 8166. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29402378 TI - Chemsex case study: is it time to recommend routine screening of sexualised drug use in men who have sex with men? AB - This case discusses a gay male participating in sexualised drug use. It raises several important issues and strengthens the case for routine screening for sexualised drug use in men who have sex with men so that healthcare professionals can provide better-informed and higher-quality health care to this population. PMID- 29402379 TI - The last common ancestor of animals lacked the HIF pathway and respired in low oxygen environments. AB - Animals have a carefully orchestrated relationship with oxygen. When exposed to low environmental oxygen concentrations, and during periods of increased energy expenditure, animals maintain cellular oxygen homeostasis by enhancing internal oxygen delivery, and by enabling the anaerobic production of ATP. These low oxygen responses are thought to be controlled universally across animals by the hypoxia-inducible factor (HIF). We find, however, that sponge and ctenophore genomes lack key components of the HIF pathway. Since sponges and ctenophores are likely sister to all remaining animal phyla, the last common ancestor of extant animals likely lacked the HIF pathway as well. Laboratory experiments show that the marine sponge Tethya wilhelma maintains normal transcription under oxygen levels down to 0.25% of modern atmospheric saturation, the lowest levels we investigated, consistent with the predicted absence of HIF or any other HIF-like pathway. Thus, the last common ancestor of all living animals could have metabolized aerobically under very low environmental oxygen concentrations. PMID- 29402380 TI - Evolution: Oxygen and early animals. AB - The biology of sponges provides clues about how early animals may have dealt with low levels of oxygen. PMID- 29402382 TI - Language ENvironment analysis (LENA) system investigation of day long recordings in children: A literature review. AB - The Language ENvironment Analysis (LENA) System is a relatively new recording technology that can be used to investigate typical child language acquisition and populations with language disorders. The purpose of this paper is to familiarize language acquisition researchers and speech-language pathologists with how the LENA System is currently being used in research. The authors outline issues in peer-reviewed research based on the device. Considerations when using the LENA System are discussed. PMID- 29402383 TI - Distributed robust adaptive control of high order nonlinear multi agent systems. AB - In this paper, a robust adaptive neural network based controller is presented for multi agent high order nonlinear systems with unknown nonlinear functions, unknown control gains and unknown actuator failures. At first, Neural Network (NN) is used to approximate the nonlinear uncertainty terms derived from the controller design procedure for the followers. Then, a novel distributed robust adaptive controller is developed by combining the backstepping method and the Dynamic Surface Control (DSC) approach. The proposed controllers are distributed in the sense that the designed controller for each follower agent only requires relative state information between itself and its neighbors. By using the Young's inequality, only few parameters need to be tuned regardless of NN nodes number. Accordingly, the problems of dimensionality curse and explosion of complexity are counteracted, simultaneously. New adaptive laws are designed by choosing the appropriate Lyapunov-Krasovskii functionals. The proposed approach proves the boundedness of all the closed-loop signals in addition to the convergence of the distributed tracking errors to a small neighborhood of the origin. Simulation results indicate that the proposed controller is effective and robust. PMID- 29402381 TI - Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance. AB - Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance. PMID- 29402384 TI - Reply. PMID- 29402385 TI - [Seclusion and restraint: From prescription to decision]. AB - Psychiatric care has always included patients in crisis who are potentially dangerous or agitated. Faced with the many issues they may encounter, the therapeutic relationship has always been prioritized over all other considerations. However, the practice of seclusion and restraint has been steadily increasing in the past few decades. Their use is becoming customary rather than exceptional and consequently fosters less thought by the care teams. In the Healthcare System Modernization Act of January 26th, 2016, the lawmakers sought to underline the freedom-destroying nature of these practices and the necessity of their regulation. This law represents a fundamental change in the nature of seclusion and restraint. What was but a simple prescription becomes a conscious decision of depriving someone of her or his freedom and must only be considered as a last resort. The changes in the Law and the recent changes in the recommendations for clinical practice by the French National Institute of Health invite reflection. Many questions remain about the origins of violence, the reasons for the increasing use of seclusion and restraint measures, and the alternatives that have been developed. Many theories suggest that the less stressful and constrained an environment is, the more empowered the patient will be. He is an actor in his own care and is considered a full active participant. The Law is reconciled with caregivers initiating a reflection on the benefits of these measures regarding the violation of fundamental freedoms. Reflection on psychiatric care and the quality of its management must be the focus when caring for patients in crisis. PMID- 29402386 TI - Treating borderline personality disorder with oxytocin: An enthusiastic note of caution. Commentary to Servan et al. The effect of oxytocin in borderline personality disorder. PMID- 29402387 TI - Commentary on: Non-interpretive radiology: an Irish perspective. PMID- 29402388 TI - Ignoring versus updating in working memory reveal differential roles of attention and feature binding. AB - Ignoring distracting information and updating current contents are essential components of working memory (WM). Yet, although both require controlling irrelevant information, it is unclear whether they have the same effects on recall and produce the same level of misbinding errors (incorrectly joining the features of different memoranda). Moreover, the likelihood of misbinding may be affected by the feature similarity between the items already encoded into memory and the information that has to be filtered out (ignored) or updated into memory. Here, we investigate these questions. Participants were sequentially presented with two pairs of arrows. The first pair of arrows always had to be encoded into memory, but the second pair either had to be ignored (ignore condition) or allowed to displace the previously encoded items (update condition). To investigate the effect of similarity on recall, we also varied, in a factorial manner, whether the items that had to be ignored or updated were presented in the same or different colours and/or same or different spatial locations to the original memoranda. By applying a computational model, we were able to quantify the levels of misbinding. Ignoring, but not updating, increased overall recall error as well as misbinding rates, even when accounting for the retention period. This indicates that not all manipulations of attention in WM are equal in terms of their effects on recall and misbinding. Misbinding rates in the ignore condition were affected by the colour and spatial congruence of relevant and irrelevant information to a greater extent than in the update condition. This finding suggests that attentional templates are used to evaluate relevant and irrelevant information in different ways during ignoring and updating. Together, the results suggest that differences between the two functions might occur due to higher levels of attentional compartmentalisation - or protection - during updating compared to ignoring. PMID- 29402389 TI - Delineating the burden of chronic post-operative pain in patients undergoing open repair of complex ventral hernias. AB - BACKGROUND: After open complex ventral hernia repair (cVHR), chronic pain has a significant impact on quality of life and processes of care. METHODS: Records of 177 patients undergoing cVHR were reviewed in order to characterize the burden of managing postoperative pain in the first post-operative year following open cVHR. RESULTS: In this cohort, 91 patients initiated at least one unsolicited complaint of pain, though phone call (37), unscheduled clinic visit (45) or evaluation in the emergency room (9); among these an actionable diagnosis was found in 38 (41.8%). Among 41 patients who initiated additional unsolicited complaints of pain, an actionable diagnosis was found in only 3 patients. Risk factors for such complaints included pre-operative pain and the use of synthetic mesh. CONCLUSIONS: Even in the absence of an actionable diagnosis, significant resources are utilized in evaluation and management of unsolicited complaints of pain in the first year after cVHR. PMID- 29402390 TI - Effect of milk protein composition of a model infant formula on the physicochemical properties of in vivo gastric digestates. AB - We investigated the effect of protein composition and, in particular, the presence of whey proteins or beta-casein on the digestion behavior of a model infant formula using an in vivo piglet model. Three isocaloric diets optimized for piglets were prepared with the same concentrations of protein. For protein source, 1 diet contained only whey proteins and 2 contained a casein:whey protein ratio of 40:60 but differed in the amount of beta-casein. To obtain the desired protein compositions, skim milk was microfiltered at 7 or 22 degrees C, and retentates and permeates were combined with whey protein isolate. The diets were optimized to the nutritional needs of the piglets and fed to 24 newborn piglets for 18 d. Eight piglets were also fed ad libitum with sow milk and considered only as reference (not included in the statistical analysis). The study was carried out in 2 blocks, killing the animals 60 and 120 min after the last meal. All gastric contents, regardless of diet, showed a wide range of pH. Postprandial time did not affect the pH or physical properties of the gastric digesta. The digesta from whey protein-casein formulas showed significantly higher viscosity, a higher storage modulus, and a denser microstructure than digesta obtained from piglets fed whey protein formula. The beta-casein:total casein ratio at the level used in this study did not significantly affect the physical and chemical properties of the stomach digestate. Although caseins showed extensive gastric hydrolysis, whey proteins remained largely intact at both postprandial times. The results indicate that the presence of different concentrations of milk proteins can be critical to the digestion properties of the food matrix and may affect the nutritional properties of the components. PMID- 29402392 TI - Phenotypic novelty by CRISPR in plants. AB - Genome editing by CRISPR is now routinely used in plant biology for unravelling gene functions and improving agronomical traits. CRISPR opens up the possibility of genome manipulations which would have been unthinkable a few years ago. In this perspective, we discuss and suggest CRISPR-mediated approaches for steering plant development, also highlighting potential challenges. PMID- 29402391 TI - IFN-gamma and tumor gangliosides: Implications for the tumor microenvironment. AB - Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-gamma (IFN-gamma) may boost antitumor immune responses. Thus we wondered whether IFN-gamma would counteract tumor ganglioside mediated immune suppression. To test this hypothesis, we exposed human monocyte derived LPS-activated dendritic cells (DC) to IFN-gamma and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro inflammatory surface markers and cytokines. Strikingly, while increasing LPS dependent DC responses, IFN-gamma unexpectedly did not counteract the inhibitory effects of GD1a. Rather, induction of indoleamine 2,3-dioxygenase (IDO1), and expression of STAT1/IRF-1 and programmed cell death ligand (PD-L1), indicated that the immunoinhibitory, not an immune stimulatory, IFN-gamma-signaling axis, was active. The combination, IFN-gamma and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8+ T-cells. We suggest that gangliosides and IFN-gamma may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression. PMID- 29402393 TI - Acute Generalized Exanthematous Pustulosis Simulating Toxic Epidermal Necrolysis: Overlapping Processes. PMID- 29402394 TI - Microbial biopesticides for invertebrate pests and their markets in the United States. AB - Microbial pesticides based on bacteria, fungi and viruses or their bioactive compounds have long been developed as alternatives for synthetic pesticides to control invertebrate pests. However, concern for environmental and human health from excessive reliance on chemical pesticides, changes in residue standards, and increased demand for organically grown produce has contributed to a considerable growth in their use in recent years. There are currently 356 registered biopesticide active ingredients in the U.S., including 57 species and/or strains of microbes or their derivatives, labelled for use against pestiferous insects, mites and nematodes. Strains of Bacillus thuringiensis for Lepidoptera remain the most popular products, but newer bacterial strains and their metabolites have been developed against a wider range of arthropods for use on fruit, vegetable and ornamental crops. Currently, ten fungal species/strains are registered against thrips, whiteflies, aphids, or other sucking pests and plant parasitic nematodes in greenhouse, nursery and field crops, while five nucleopolyhedroviruses and three granuloviruses are registered for Lepidoptera in field and greenhouse grown vegetables and ornamentals, tree fruit and nuts, forestry, and stored products. Many of these products are organic listed and most have 4 h or less reentry and no pre-harvest restrictions. Investment by multinational companies, advances in screening, industrial fermentation and storage of new microorganisms, are increasing the market share for microbials. Here, we summarize the market for microbial-based pesticides labelled for invertebrates in the U.S. We cover current uses and recent advances that further advance their use in additional markets in the coming decades. PMID- 29402395 TI - Intestinal worms eating neuropsychiatric disorders? Apparently so. AB - A number of factors in Western society, including inflammatory diets, sedentary lifestyles, vitamin D deficiency and chronic psychological stress, are known to induce inflammation and to be associated with neuropsychiatric disorders. One factor that is emerging as a potential inflammation inducing factor is biota depletion, or loss of biodiversity from the ecosystem of the human body as a result of industrialization. Originally known as the "hygiene hypothesis", biota alteration theory describes the effects of biota alteration on the human immune system. Work on this topic has pinpointed depletion of helminths as a key loss to the body's ecosystem in Western society, and suggests that some exposure to helminths, ubiquitous prior to the modern era, may be necessary for normal immune system development. Socio-medical studies of humans "self-treating" with helminths as well as limited studies in animal models strongly suggest that helminth therapy may be a productive approach toward treating a range of neuropsychiatric disorders, including chronic fatigue, migraine headaches, depression and anxiety disorders. However, helminth therapy faces some daunting hurdles, including the lack of a financial incentive for development, despite a tremendous potential market for the organisms. It is argued that benevolent donation for early trials as well as changes in regulatory policy to accommodate helminth therapy may be important for the field to develop. It is hoped that future success with some high-profile trials can propel the field, now dominated more by self-treatment than by clinical trials, forward into the main stream of medicine. PMID- 29402396 TI - Total occlusion of the left main coronary artery presenting as ST-elevation myocardial infarction. AB - An ECG pattern of widespread ST depression in six or more precordial and inferior leads, accompanied by ST-segment elevation in the aVR and/or V1 leads, is typical of the non-ST-segment elevation myocardial infarction (NSTEMI) pattern associated left main (LM) artery occlusion, but this ECG pattern is really associated with a subocclusion of the LM, or in the case that the LM was occluded with the presence of collateral circulation. There are few reports of ST-elevation myocardial infarction (STEMI) due to acute total LM occlusion. We report a case of STEMI pattern due to acute total LM occlusion. PMID- 29402397 TI - Task-shifting of CD4 T cell count monitoring by the touchscreen-based MuseTM Auto CD4/CD4% single-platform system for CD4 T cell numeration: Implication for decentralization in resource-constrained settings. AB - BACKGROUND: The accuracy of CD4 T cell monitoring by the recently developed flow cytometry-based CD4 T cell counting MuseTM Auto CD4/CD4% Assay analyzer (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany) was evaluated in trained lay providers against laboratory technicians. METHODS: After 2 days of training on the MuseTM Auto CD4/CD4% analyzer, EDTA-blood samples from 6 HIV-positive and 4 HIV-negative individuals were used for CD4 T cell counting in triplicate in parallel by 12 trained lay providers as compared to 10 lab technicians. RESULTS: Mean number of CD4 T cells in absolute number was 829 +/- 380 cells/MUl by lay providers and 794 +/- 409 cells/MUl by technicians (P > 0.05); and in percentage 36.2 +/- 14.8%CD4 by lay providers and 36.1 +/- 15.0%CD4 by laboratory technician (P > 0.05). The unweighted linear regression and Passing Bablok regression analyses on CD4 T cell results expressed in absolute count revealed moderate correlation between CD4 T cell counts obtained by lay providers and lab technicians. The mean absolute bias measured by Bland-Altman analysis between CD4 T cell/MUl obtained by lay providers and lab technicians was -3.41 cells/MUl. Intra-assay coefficient of variance (CV) of MuseTM Auto CD4/CD4% in absolute number was 10.1% by lay providers and 8.5% by lab technicians (P > 0.05), and in percentage 5.5% by lay providers and 4.4% by lab technicians (P > 0.05). The inter-assay CV of MuseTM Auto CD4/CD4% in absolute number was 13.4% by lay providers and 10.3% by lab technicians (P > 0.05), and in percentage 7.8% by lay providers and 6.9% by lab technicians (P > 0.05). CONCLUSIONS: The study demonstrates the feasibility of CD4 T cell counting using the alternative flow cytometer MuseTM Auto CD4/CD4% analyzer by trained lay providers and therefore the practical possibility of decentralization CD4 T cell counting to health community centers. PMID- 29402398 TI - [Can medical oncologists talk about cure to their patient after localized breast cancer treatment?] AB - INTRODUCTION: Despite ongoing therapeutic advances in oncology, the use of the term cure in front of patients remains controversial. The word remission is often preferred in clinical practice. The purpose of this research is to explore how oncologists vary in their usage and definition of the word cure when talking to patients. METHODS: Qualitative and exploratory pilot study conducted by semi structured interviews with a group of French oncologists about a clinical vignette of localized breast cancer treated by surgery and complete adjuvant treatment. RESULTS: Thirteen oncologists participated in this study between January and March 2016. They were divided into two groups according to whether or not they use the term cure in their clinical practice. A first group of five doctors define the word cure as the lasting absence of relapse of the disease. Because of their duty of transparency and the uncertainty of post-therapeutic relapse, these five doctors tend to never use the word cure. The analysis of the second group of eight doctors, who do use of the word cure in their practice, highlighted an absence of consensus on its definition. However, all of them justify their use of it with the importance of expressing positive emotions such as hope to patients. DISCUSSION: Our findings confirm that there are divergent understandings of the concept of cure between oncologists and how they manage prognosis uncertainty. Medical language is thus influenced by scientific knowledge, but also by doctors' personal values and ways of thinking, perhaps influencing the doctor-patient relationship in turn. This exploratory study will be extended on a wider scale to explore the coexistence of other elements of diversity. PMID- 29402399 TI - Tick borne illness-Lyme disease. AB - Lyme disease is the most commonly reported tick-borneillness in the United States. Thecausative spirochete, Borrelia burgdorferi is transmitted by 4 species of Ixodes tick species. Over 90% of US cases occur in northeasternstates from Maine to Virginia, and in Wisconsin, Minnesota, and Michigan. Infection also takes place in northern California and Oregon. Lyme borreliosis is also diagnosed in parts of Europe, China, and Japan. The white-footed mouse is the primary animal reservoir for B. burgdorferi in the U.S. and the preferred host for nymphal and larval forms of the deer tick. Deer are hosts for the adult ticks but do not carry the spirochete. Signs and symptomsof infection occur in 3 stages; early localized, typified by erythema migrans; early disseminated with a flu-like syndrome, neurologic, and cardiac manifestations; and late, characteristically with arthritis. Although, the term 'Chronic Lyme Disease' has been assigned to many patients with a variety of unexplained symptoms, experts in the field question the validity of this diagnosis and warn against prolonged unproven antimicrobial therapies. Diagnosis relies upon clinical evaluation and is supported by serologic testing using a 2-step process which requires careful interpretation. Treatmentvaries with stage of disease, but normally includes doxycycline, amoxicillin,and ceftriaxone. Currently, no preventative vaccine is available. In some geographic areas, patients may be confected with Babesia, Ehrlichia, and Anaplasma since the same Ixodes ticks transmit these pathogens. PMID- 29402400 TI - How much is left in your "sleep tank"? Proof of concept for a simple model for sleep history feedback. AB - Technology-supported methods for sleep recording are becoming increasingly affordable. Sleep history feedback may help with fatigue-related decision making Should I drive? Am I fit for work? This study examines a "sleep tank" model (SleepTankTM), which is analogous to the fuel tank in a car, refilled by sleep, and depleted during wake. Required inputs are sleep period time and sleep efficiency (provided by many consumer-grade actigraphs). Outputs include suggested hours remaining to "get sleep" and percentage remaining in tank (Tank%). Initial proof of concept analyses were conducted using data from a laboratory-based simulated nightshift study. Ten, healthy males (18-35y) undertook an 8h baseline sleep opportunity and daytime performance testing (BL), followed by four simulated nightshifts (2000 h-0600 h), with daytime sleep opportunities (1000 h-1600 h), then an 8 h night-time sleep opportunity to return to daytime schedule (RTDS), followed by daytime performance testing. Psychomotor Vigilance Task (PVT) and Karolinska Sleepiness Scale were performed at 1200 h on BL and RTDS, and at 1830 h, 2130 h 0000 h and 0400 h each nightshift. A 40-minute York Driving Simulation was performed at 1730 h, 2030 h and 0300 h on each nightshift. Model outputs were calculated using sleep period timing and sleep efficiency (from polysomnography) for each participant. Tank% was a significant predictor of PVT lapses (p < 0.001), and KSS (p < 0.001), such that every 5% reduction resulted in an increase of two lapses, or one point on the KSS. Tank% was also a significant predictor of %time in the Safe Zone from the driving simulator (p = 0.001), such that every 1% increase in the tank resulted in a 0.75% increase in time spent in the Safe Zone. Initial examination of the correspondence between model predictions and performance and sleepiness measures indicated relatively good predictive value. Results provide tentative evidence that this "sleep tank" model may be an informative tool to aid in individual decision-making based on sleep history. PMID- 29402401 TI - Effects of methodological decisions on rainfall-related crash relative risk estimates. AB - Numerous studies have examined the influence of rainfall on the relative risk of crash, and they all agree that rainfall leads to an increase in relative risk as compared to dry conditions; what they do not agree on is the magnitude of these increases. Here we consider three methodological decisions made in computing the relative risk and examine their impacts: the inclusion or exclusion of zero total events (where no crashes occur during event or control periods), the temporal scale of analysis, and the use of information on pavement and weather conditions contained with the crash reports to determine relative risk. Our analyses are based on several years of data from six U.S. states (Arkansas, Georgia, Illinois, Maryland, Minnesota and Ohio). Zero total events in the context of weather related crash studies typically provide no information on the actual crash odds and greatly alter the distribution of relative risk estimates and should be removed from the analysis. While the use of a daily time step provides an estimate of relative risk that is not significantly different from an hourly time step for the majority of rural counties in our study area, the same is true of only 39% of the urban counties. Finally, the use of pavement and weather condition information from the crash reports results in relative risk estimates that are lower than the standard approach, however this difference decreases as rainfall totals increase. By highlighting the influence of methodological choices, we hope to pave the way towards the potential reduction in uncertainties in weather-related relative risk estimates. PMID- 29402402 TI - Effects of strategic early-morning caffeine gum administration on association between salivary alpha-amylase and neurobehavioural performance during 50 h of sleep deprivation. AB - Self-assessment is the most common method for monitoring performance and safety in the workplace. However, discrepancies between subjective and objective measures have increased interest in physiological assessment of performance. In a double-blind placebo-controlled study, 23 healthy adults were randomly assigned to either a placebo (n = 11; 5 F, 6 M) or caffeine condition (n = 12; 4 F, 8 M) while undergoing 50 h (i.e. two days) of total sleep deprivation. In previous work, higher salivary alpha-amylase (sAA) levels were associated with improved psychomotor vigilance and simulated driving performance in the placebo condition. In this follow-up article, the effects of strategic caffeine administration on the previously reported diurnal profiles of sAA and performance, and the association between sAA and neurobehavioural performance were investigated. Participants were given a 10 h baseline sleep opportunity (monitored via standard polysomnography techniques) prior to undergoing sleep deprivation (total sleep time: placebo = 8.83 +/- 0.48 h; caffeine = 9.01 +/- 0.48 h). During sleep deprivation, caffeine gum (200 mg) was administered at 01:00 h, 03:00 h, 05:00 h, and 07:00 h to participants in the caffeine condition (n = 12). This strategic administration of caffeine gum (200 mg) has been shown to be effective at maintaining cognitive performance during extended wakefulness. Saliva samples were collected, and psychomotor vigilance and simulated driving performance assessed at three-hour intervals throughout wakefulness. Caffeine effects on diurnal variability were compared with previously reported findings in the placebo condition (n = 11). The impact of caffeine on the circadian profile of sAA coincided with changes in neurobehavioural performance. Higher sAA levels were associated with improved performance on the psychomotor vigilance test during the first 24 h of wakefulness in the caffeine condition. However, only the association between sAA and response speed (i.e. reciprocal-transform of mean reaction time) was consistent across both days of sleep deprivation. The association between sAA and driving performance was not consistent across both days of sleep deprivation. Results show that the relationship between sAA and reciprocal-transform of mean reaction time on the psychomotor vigilance test persisted in the presence of caffeine, however the association was relatively weaker as compared with the placebo condition. PMID- 29402403 TI - Statistical shape modeling characterizes three-dimensional shape and alignment variability in the lumbar spine. AB - The mechanics of the lumbar spine are heavily dependent on the underlying anatomy. Anatomical measures are used to assess the progression of pathologies related to low back pain and to screen patients for surgical treatment options. To describe anatomical norms and pathological differences for the population, statistical shape modeling, which uses full three-dimensional representations of bone morphology and relative alignment, can capture intersubject variability and enable comparative evaluations of subject to population. Accordingly, the objective of this study was to develop a comprehensive set of three-dimensional statistical models to characterize anatomical variability in the lumbar spine, by specifically describing the shape of individual vertebrae, and shape and alignment of the entire lumbar spine (L1-S1), with a focus on the L4-L5 and L5-S1 functional spinal units (FSU). Using CT scans for a cohort of 52 patients, lumbar spine geometries were registered to a template to establish correspondence and a principal component analysis identified the primary modes of variation. Scaling was the most prevalent mode of variation for all models. Subsequent modes of the statistical shape models of the individual bones characterized shape variation within the processes. Subsequent modes of variation for the FSU and entire spine models described alignment changes associated with disc height and lordosis. Quantification of anatomical variation in the spine with statistical models can inform implant design and sizing, assist clinicians in diagnosing pathologies, screen patients for treatment options, and support pre-operative planning. PMID- 29402404 TI - Prognostic value of suPAR and hs-CRP on cardiovascular disease. AB - BACKGROUND AND AIMS: Studies have shown that soluble urokinase Plasminogen Activator Receptor (suPAR) and CRP (both inflammatory markers) and coronary artery calcification (CAC) are independent risk predictors for cardiovascular (CV) disease. The aim of this study is to assess whether suPAR and CRP have an increased predictive prognostic value beyond the traditional CV risk factors and the CAC score. METHODS: A population sample of 1179 subjects, free of CV disease was included. The subjects underwent traditional CV risk evaluation, CAC assessment and blood sampling for suPAR and CRP. CV events were extracted from The Danish National Patient Register after 6.5 years. The additive values of suPAR and CRP were evaluated by unadjusted Kaplan Meier analysis, adjusted hazard ratio and ROCAUC models. RESULTS: 1179 participants (47.6% males, mean age 55 years) were included. 73 events occurred. In Kaplan Meier analyses, suPAR and CRP were significantly associated with CV events (p = 0.03 and p = 0.002). Adjusted for the CV risk factors and the CAC score, the hazard ratios for suPAR and CRP were 1.17 (95% confidence interval [CI] 1.01-1.34) and 1.04 (95% CI 1.01-1.06), respectively. suPAR was associated with a substantial risk among women (2.03; 95% CI 1.45-2.84) and 60-year-old subjects (1.44; 95% CI 1.09-1.90). By ROCAUC, neither suPAR nor CRP provided significant estimates (0.7100 and 0.7054) compared to the traditionally CV risk factors (0.6952, p = 0.24 and p = 0.16) and CAC score (0.7481, p = 0.33 and p = 0.32). CONCLUSIONS: Adjusted for traditional CV risk factors and CAC score, suPAR and CRP were of minor importance in risk prediction. PMID- 29402406 TI - Secretion of GLP-1 but not GIP is potently stimulated by luminal d-Allulose (d Psicose) in rats. AB - Glucagon-like peptide 1 (GLP-1), an incretin gastrointestinal hormone, is secreted when stimulated by nutrients including metabolizable sugars such as glucose and fructose. d-Allulose (allulose), also known as d-psicose, is a C-3 isomer of d-fructose and a rare sugar with anti-diabetic or anti-obese effects in animal models. In the present study, we examined whether an oral administration of allulose could stimulate GLP-1 secretion in rats, and investigated the underlying mechanisms. Oral, but not intraperitoneal, administration of allulose (0.5-2.0 g/kg body weight) elevated plasma GLP-1 levels for more than 2 h in a dose-dependent manner. The effects of allulose on GLP-1 secretion were higher than that of dextrin, fructose, or glucose. In addition, oral allulose increased total and active GLP-1, but not glucose-dependent insulinotropic polypeptide (GIP), levels in the portal vein. In anesthetized rats equipped with a portal catheter, luminal (duodenum and ileum) administration of allulose increased portal GLP-1 levels, indicating the luminal effect of allulose. Allulose-induced GLP-1 secretion was abolished in the presence of xanthohumol (a glucose/fructose transport inhibitor), but not in the presence of inhibitors of the sodium dependent glucose cotransporter 1 or the sweet taste receptor. These results demonstrate a potent and lasting effect of orally administered allulose on GLP-1 secretion in rats, without affecting GIP secretion. The potent and selective GLP 1-releasing effect of allulose holds promise for the prevention and treatment of glucose intolerance through promoting endogenous GLP-1 secretion. PMID- 29402405 TI - SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development. AB - Sirtuins (SIRT1-7) are NAD+-dependent deacetylase/deacylases that regulate a wide variety of biological functions. Although the roles of sirtuins in cartilage homeostasis and cartilage diseases have been well studied, there is no information on the contribution of SIRT7 to cartilage homeostasis and osteoarthritis (OA) pathologies. Here, we demonstrate that Sirt7 knockout mice are resistant to the development of aging-associated OA and forced exercise induced OA. Attenuation of Sirt7 in the murine chondrogenic cell line ATDC5 increased the deposition of a glycosaminoglycan-rich extracellular matrix and the mRNA expression of extracellular matrix components such as Col2a1 and Acan. Mechanistically, we found that SIRT7 suppressed the transcriptional activity of SOX9, which is an important transcription factor in chondrocytes, and that the enzymatic activity of SIRT7 was required for its function. Our results indicate that SIRT7 is a novel important regulator of cartilage homeostasis and OA development. PMID- 29402407 TI - Retina-derived endogenous sulfur dioxide might be a novel anti-apoptotic factor. AB - Endogenous sulfur dioxide (SO2) was found to be generated from the enzymatic reaction catalysed by aspartate transference 1 (AAT1) in the mammals and play importantly biological effects. In the present study, we explored the existence of endogenous SO2 pathway in mouse retinal tissues and 661w photoreceptor cell and investigated its possible pathophysiological role in the hydrogen peroxide (H2O2)-induced mouse photoreceptor cell apoptosis. The data showed that endogenous SO2 pathway including AAT1 expression and SO2 content was found to be presented in mouse photoreceptor cells. AAT1 protein and SO2 were mainly distributed in the cytoplasm, while a small amount of AAT1 protein and SO2 was found in the nucleus of 661W photoreceptor cells. H2O2 significantly decreased the SO2 content and AAT1 expression, but increased the cleaved caspase-3 protein level and the apoptotic index, and the number of TUNEL-positive cells in the 661W photoreceptor cells. Moreover, an AAT inhibitor HDX treatment inhibited SO2 synthesis and mimicked H2O2-induced apoptosis in 661W cells. In conclusion, the endogenous SO2/AAT1 pathway is firstly found to be present in mouse photoreceptor cells, and might play an important role in the prevention from mouse photoreceptor cell apoptosis. PMID- 29402408 TI - CC-223 inhibits human head and neck squamous cell carcinoma cell growth. AB - mTOR over-activation is associated with the progression of head and neck squamous cell carcinoma (HNSCC). CC-223 is a novel and potent mTOR kinase inhibitor. Its activity against human HNSCC cells is studied here. In established SCC-9 cells and primary human oral cavity carcinoma (OCC) cells, CC-223 treatment at only nM concentrations significantly inhibited survival, proliferation and cell cycle progression. Furthermore, CC-223 provoked apoptosis activation in human HNSCC cells. CC-223 is more efficient in killing HNSCC cells than other known Akt-mTOR inhibitors: RAD001, MK-2206 and AZD-2014. CC-223 was however non-cytotoxic to the primary human oral epithelial cells. Further studies demonstrate that CC-223 almost completely blocked mTOR complex 1 (mTORC1) and mTORC2 activation in SCC-9 cells and primary OCC cells. In vivo, oral administration of CC-223 at well tolerated doses potently inhibited SCC-9 xenograft tumor growth in severe combined immunodeficient mice. mTORC1 and mTORC2 activation was largely inhibited in CC-223-treated tumor tissues. Overall, targeting the mTOR kinase by CC-223 inhibits human HNSCC cell growth in vitro and in vivo. CC-223 might have a translational value for the treatment of HNSCC. PMID- 29402409 TI - Autophagy activated by SIRT6 regulates Abeta induced inflammatory response in RPEs. AB - Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-beta is accumulated and in amyloid-beta stimulated RPEs. In addition, gain and loss-of-function studies confirmed the positive role of SIRT6 in regulating autophagy. Interesting, inhibition of autophagy attenuates amyloid beta stimulated inflammatory response in RPEs. Collectively, our findings uncover the autophagy modulated by SIRT6 may be a proinflammatory mechanism for amyloid beta induced RPE dysfunction. PMID- 29402410 TI - Immunomodulatory effects of polysaccharide fraction isolated from Fagopyrum esculentum on innate immune system. AB - The present study investigates the immunomodulatory activities of buckwheat polysaccharide fraction (BPF) from the seed of Fagopyrum esculentum on RAW 264.7 macrophage cell line and Cyclophosphamide-induced immunosuppressed conditions in mice models. The results of in vitro showed that treatment with 0.5-10 MUg/mL of BPF can modulate immune responses. MTT assay and nitric oxide production and immune-related cytokine levels were conducted. Treatment with BPF at a dose of 10 MUg/mL of BPF increased immune responses on macrophages. Moreover, natural killer (NK) cell cytotoxicity was conducted. The apoptosis of YAC-1 cells increased as the co-culture ratio between spleen cells and YAC-1 cells increased approximately 4- fold compared to the control group from 12.5:1 to 50.0:1. The in-vivo immunomodulatory effects of BPF were evaluated by cyclophosphamide-induced mice model. The immune response of BPF was determined against cyclophosphamide (100 mg/kg) immunosuppressed mice at doses of 50 mg/kg and 100 mg/kg of BPF as compared to control. The results of this study showed that BPF administration increased spleen and thymus indices as well as the leukocytes count in the blood of immunosuppressed mice. All of results suggested that BPF are potentially acts as immunomodulator for activation of immune responses. PMID- 29402411 TI - Epigallocatechin-3-gallate attenuates acute and chronic psoriatic itch in mice: Involvement of antioxidant, anti-inflammatory effects and suppression of ERK and Akt signaling pathways. AB - Chronic itch is a distressing symptom of many skin diseases and negatively impacts quality of life. However, there is no medication for most forms of chronic itch, although antihistamines are often used for anti-itch treatment. Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, exhibits anti oxidative and anti-inflammatory properties. Our previous studies highlighted a key role of oxidative stress and proinflammatory cytokines in acute and chronic itch. Here, we evaluated the effects of green tea polyphenon 60 and EGCG on acute and chronic itch in mouse models and explored its potential mechanisms. The effects of EGCG were determined by behavioral tests in mouse models of acute and chronic itch, which were induced by compound 48/80, chloroquine (CQ), and 5% imiquimod cream treatment, respectively. We found that systemic or local administration of green tea polyphenon 60 or EGCG significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner in mice. Incubation of EGCG significantly decreased the accumulation of intracellular reactive oxygen species (ROS) directly induced by compound 48/80 and CQ in cultured ND7-23 cells, a dorsal root ganglia derived cell line. EGCG also attenuated imiquimod-induced chronic psoriatic itch behaviors and skin epidermal hyperplasia in mice. In addition, EGCG inhibited the expression of IL 23 mRNA in skin and TRPV1 mRNA in dorsal root ganglia (DRG). Finally, EGCG remarkably inhibited compound 48/80-induced phosphorylation of extracellular signal-regulated kinase (ERK) and imiquimod-induced p-AKT in the spinal cord of mice, respectively. Collectively, these results indicated EGCG could be a promising strategy for anti-itch therapy. PMID- 29402412 TI - MiR-183 inhibits osteosarcoma cell growth and invasion by regulating LRP6 Wnt/beta-catenin signaling pathway. AB - Recent studies have demonstrated that microRNA-183 (miR-183) deregulates and plays major roles in many tumors. However, the role of miR-183 in osteosarcoma (OS) pathogenesis is still largely unknown. In this study, we first over expressed and knocked down miR-183 in MG63 and U20S cells, respectively. Functional analyses showed that ectopic expression of miR-183 suppressed MG63 cell growth, migration, and invasion in vitro and in vivo, whereas knockdown of endogenous miR-183 in U20S cells significantly enhanced these abilities. Next, we characterized low density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-183 that interacted with the 3'-untranslated region of LRP6. Furthermore, ectopic expression of LRP6 significantly abrogated the tumor suppressive effect induced by miR-183. Finally, miR-183 regulated the tumor suppressive functions in MG63 cells by suppressing the LRP6-Wnt/beta-catenin signaling pathway. Therefore, our study demonstrates that miR-183 is a tumor suppressor microRNA that plays a major role in OS. PMID- 29402413 TI - Inhibition of CREPT restrains gastric cancer growth by regulation of cycle arrest, migration and apoptosis via ROS-regulated p53 pathway. AB - CREPT (cell-cycle related and expression-elevated protein in tumor) was reported to be associated with growth of several human cancers; however, its clinical significance and regulatory mechanism still remain unclear in human gastric cancer. In the present study, we found CREPT was significantly increased in gastric cancer tissues compared to the matched adjacent normal tissues. CREPT silence inhibited the proliferation of gastric cancer cells through inducing G0/G1 phase cell cycle arrest, which was linked to the reduction of Cyclin D1 and Cyclin D-dependent kinase 4 (CDK4), and the elevation of p53 and p21. In addition, CREPT knockdown (KD) decreased migration of gastric cancer cells through up-regulating E-cadherin and down-regulating vimentin, N-cadherin and matrix metalloproteinase 1 (MMP-1) expressions. Further, CREPT KD induced apoptosis in gastric cancer cells, as evidenced by the increase of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). Intriguingly, suppressing p53 expressions significantly abolished CREPT silence-induced apoptosis, and reduction of cell viability. Moreover, CREPT KD caused reactive oxygen species (ROS) generation using discounted cash flow (DCF) analysis, which was reversed by ROS scavenger, N-acetyl-l-cysteine (NAC), pretreatment. Of note, NAC pretreatment abrogated apoptotic cell death in CREPT KD gastric cancer cells. In vivo, suppressing CREPT reduced the gastric tumor growth in gastric cancer xenograft models. Altogether, our results provided a novel insight into CREPT in regulating gastric cancer progression through apoptosis regulated by ROS/p53 pathways. PMID- 29402414 TI - CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy. AB - AIMS: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). METHODS AND RESULTS: In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1-5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. CONCLUSIONS: In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia. PMID- 29402415 TI - Determining the utility of creatinine delta checks: A large retrospective analysis. AB - INTRODUCTION: Delta checks are a long-standing practice for identifying errors in the laboratory. However, with the decrease in errors due to laboratory automation, their utility is unclear. The objective of this retrospective analysis was to determine whether establishment of a creatinine delta check would be an effective means for capturing true laboratory error. METHODS: All patients with a minimum of two creatinine results during March of 2015 were selected for review (n = 23,410 creatinine results). The lowest % change for a previously confirmed creatinine error in our laboratory was approximately 60%; therefore only results that changed by at least +/-60% (n = 254) were reviewed. The etiology of creatinine value change was categorized as laboratory error, pathologic change, or non-pathologic change, based upon chart review. RESULTS: 1.2% (3/254) of reviewed delta checks were determined to reflect 2 instances of true laboratory error that went unrecognized by laboratory staff. 91.3% (232/254) of the delta checks were determined to reflect a pathologic or dialysis-related change in creatinine levels. The remaining 7.5% of delta checks (19/234) were deemed to be non-pathologic changes in creatinine. DISCUSSION: This study identified two instances of laboratory error reflected by 3 delta checks (1.2%); the vast majority (91.3%) of creatinine results that changed by +/-60% were pathologic or dialysis-related. Thus, establishment of a +/-60% delta check for creatinine would overwhelmingly flag true biological change and would not be an efficient means for identifying rare laboratory errors. Clinical laboratories should perform similar retrospective analyses prior to enacting delta checks to determine whether they will effectively capture laboratory error. PMID- 29402416 TI - What information on measurement uncertainty should be communicated to clinicians, and how? AB - The communication of laboratory results to physicians and the quality of reports represent fundamental requirements of the post-analytical phase in order to assure the right interpretation and utilization of laboratory information. Accordingly, the International Standard for clinical laboratories accreditation (ISO 15189) requires that "laboratory reports shall include the information necessary for the interpretation of the examination results". Measurement uncertainty (MU) is an inherent property of any quantitative measurement result which express the lack of knowledge of the true value and quantify the uncertainty of a result, incorporating the factors known to influence it. Even if the MU is not included in the report attributes of ISO 15189 and cannot be considered a post-analytical requirement, it is suggested as an information which should facilitate an appropriate interpretation of quantitative results (quantity values). Therefore, MU has two intended uses: for laboratory professionals, it gives information about the quality of measurements, providing evidence of the compliance with analytical performance characteristics; for physicians (and patients) it may help in interpretation of measurement results, especially when values are compared with reference intervals or clinical decision limits, providing objective information. Here we describe the way that MU should be added to laboratory reports in order to facilitate the interpretation of laboratory results and connecting efforts performed within laboratory to provide more accurate and reliable results with a more objective tool for their interpretation by physicians. PMID- 29402417 TI - A novel method for quantitation of acylglycines in human dried blood spots by UPLC-tandem mass spectrometry. AB - BACKGROUND: Several acylcarnitines used as primary markers on dried blood filter papers (DBS) for newborn screening lack specificity and contribute to a higher false positive rate. The analysis of urine acylglycines is useful in the diagnosis of inborn errors of metabolism (IEM) including medium chain acyl-CoA dehydrogenase deficiency (MCADD), isovaleric acidemia, and beta-ketothiolase deficiency (BKTD). Currently, no method for analyzing acylglycines from DBS has been published. METHODS: Acylglycines were extracted from two 3.2 mm DBS punches and butylated using Butanol-HCl. Ultra Performance Liquid Chromatography (UPLC MS/MS) with run time of 10 min permits resolution and quantitation of 15 acylglycines; including several isobaric. Method development was completed. Reference intervals (n = 573) were established for four birth weight groups. Furthermore, samples from patients with a confirmed IEM (n = 11), and false positive screens (n = 78) were analyzed to validate the interpretation obtained from the newly established reference intervals. RESULTS: Calibration curves were linear from 0.005 to 25.0 MUM. Ion suppression was evaluated as minimal (2 to 10%). Samples from known patients were used to validate the reference intervals. For C5OH-related disorders, tiglylglycine (TG), TG/acetylglycine (AG) ratio, 3methylcrotonylglycine (3MCG) and 3MCG/AG ratio increased specificity. Propionylglycine (PG) and PG/acetylglycine ratio were two discriminatory markers in the investigation of C3-related disorders. Hexanoylglycine (HG), octanoylglycine (OG), suberylglycine (SG), and the ratios HG/AG, OC/AG and SG/AG were excellent markers of MCADD deficiency. CONCLUSION: This method shows potential application as a second tier screen in order to reduce the false positive rate for a number of IEM targeted by newborn screening. PMID- 29402418 TI - Description of a Method to Obtain Complete One-Year Follow-Up in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - The Centers for Medicare and Medicaid Services National Coverage Determination requires centers performing transcatheter aortic valve implantation (TAVI) to report clinical outcomes up to 1 year. Many sites encounter challenges in obtaining complete 1-year follow-up. We report our process to address this challenge. A multidisciplinary process involving clinical personnel, data and quality managers, and research coordinators was initiated to collect TAVI data at baseline, 30 days, and 1 year. This process included (1) planned clinical follow up of all patients at 30 days and 1 year; (2) query of health-care system-wide integrated data warehouse (IDW) to ascertain last date of clinical contact within the system for all patients; (3) online obituary search, cross-referencing for unique patient identifiers to determine if mortality occurred in remaining unknown patients; and (4) phone calls to remaining unknown patients or patients' families. Between January 2012 and December 2016, 744 patients underwent TAVI. All 744 patients were eligible for 30-day follow-up and 546 were eligible for 1 year follow-up. At routine clinical follow-up of 22 of 744 (3%) patients at 30 days and 180 of 546 (33%) patients at 1 year had unknown survival status. The integrated data warehouse query confirmed status-alive for an additional 1 of 22 patients at 30 days (55%) and 91 of 180 patients at 1 year (51%). Obituaries were identified for 23 of 180 additional patients at 1 year (13%). Phone contact identified the remaining unknown patients at 30 days and 1 year, resulting in 100% known survival status for patients at 30 days (744 of 744) and at 1 year (546 of 546). In conclusion, using a comprehensive approach, we were able to determine survival status in 100% of patients who underwent TAVI. PMID- 29402419 TI - Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists. AB - Vitamin K antagonist (VKA) is a commonly prescribed anticoagulant with a narrow therapeutic window. Genetic polymorphisms account for high VKA dosage variability. Hence, we performed an updated meta-analysis of all randomized clinical trials (RCTs) comparing genotype-guided VKA versus standard dosing algorithms. We conducted a systematic search of electronic databases from inception to October 2017 for all RCTs. The primary outcome was the percentage of time in therapeutic range (TTR). Secondary outcomes were international normalized ratio >4, major and all bleeding events, thromboembolism, adverse and serious adverse events, and all-cause mortality. We calculated the weighted mean difference for the primary outcome and risk ratio (RR) for secondary outcomes using a random-effect model. We included 20 RCTs and analyzed a total of 5,980 adult patients. Our pooled analysis showed greater improvement in TTR for the genotype-guided group in comparison with the standard group (mean difference 3.41%, 95% confidence interval [CI] 0.71 to 6.10, p = 0.01). In addition, there were significant reductions in major and all bleeding events ((RR 0.35, 95% CI 0.20 to 0.63, p = 0.0004) and (RR 0.79, 95% CI 0.66 to 0.95, p = 0.01), respectively). However, there were no significant differences between the groups for international normalized ratio >4 (RR 0.89, 95% CI 0.80 to 1.00, p = 0.06), thromboembolism (RR 0.81, 95% CI 0.56 to 1.17, p = 0.25), serious adverse events (RR 0.79, 95% CI 0.61 to 1.03, p = 0.08), any adverse events (RR 0.94, 95% CI 0.88 to 1.01, p = 0.07), or all-cause mortality (RR 0.73, 95% CI 0.32 to 1.66, p = 0.46). In conclusion, genotype-guided VKA dosing can improve the TTR and reduce the risk for bleeding episodes, in comparison with standard dosing algorithms. PMID- 29402420 TI - Effect of Optimization of Medical Treatment on Long-Term Survival of Patients With Heart Failure After Implantable Cardioverter Defibrillator and Cardiac Resynchronization Device Implantation (from the French National EGB Database). AB - Prognosis of heart failure with reduced ejection fraction (HFrEF) is improved by drug optimization according to guidelines; however, little is known regarding such optimization in HFrEF patients with an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT). This study aimed to describe implementation of this optimized strategy and its impact in patients implanted with an ICD/CRT. Using a 1/97th representative sample of the French national health-care insurance system claims database, a retrospective cohort study was conducted including HFrEF patients implanted with ICD or CRT between January 2009 and December 2014. HFrEF treatments were analyzed before and after ICD/CRT implantation. Heart failure (HF) hospitalization and survival were examined at 1, 3, and 5 years: 378 patients (135 CRT, 243 ICD) with a mean age of 68 +/- 13 years were included. Mean follow-up was 23 months [11-42]. At baseline, 36% of patients had no or only 1 HFrEF drug among beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists, whereas 26% of patients received an optimal treatment (all 3 classes). At 3 months after ICD/CRT implantation, the prescription rate of HFrEF drugs was higher than baseline but returned to preimplantation levels at the end of follow-up. HF hospitalization rate was higher in the nonoptimized patient group (28% vs 14%, p = 0.001). Optimal HFrEF treatment was associated with better survival (hazard ratio = 0.59 [0.4-0.86], p = 0.006). In conclusion, HFrEF drugs are underprescribed before and after ICD/CRT implantation despite the demonstration that HFrEF drug optimization also reduces death and HF hospitalization in this population. PMID- 29402421 TI - Relation of Bleeding Events to Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention (a DANAMI-3 Substudy). AB - Bleeding events in relation to treatment of ST-segment elevation myocardial infarction (STEMI) have previously been associated with mortality. In this study, we investigated the incidence and prognosis of, and variables associated with serious bleedings within 30 days after primary percutaneous coronary intervention in patients from The Third Danish Study of Optimal Acute Treatment of Patients with ST-Segment Elevation Myocardial Infarction (DANAMI-3) (n = 2,217). Hospital charts were read within 30 days postadmission to assess bleeding events using thrombolysis in myocardial infarction (TIMI) and Bleeding Academic Research Consortium criteria. TIMI minor/major bleeding (TMMB) occurred in 59 patients (2.7%). Variables associated with TMMB were female gender (hazard ratio [HR] 3.9, 95% confidence interval [CI] 2.2 to 6.7, p <0.0001), symptom-to-catheterization time >3 hours (HR 1.9, 95% CI 1.1 to 3.3, p = 0.02), use of glycoprotein IIb/IIIa inhibitor (HR 2.1, 95% CI 1.2 to 3.7, p = 0.01), and increasing S-creatinine (HR 1.1, 95% CI 1.0 to 1.2, p = 0.001). Undergoing 2 in-hospital procedures were not associated with increased risk of TMMB. TMMB was strongly associated with 30-day mortality in multivariable analysis (HR 4.8, 95% CI 2.2 to 10.4, p <0.0001) but not with mortality days 31 to 365. When excluding fatal bleedings from the analysis, a TMMB was no longer associated with 30-day mortality. In conclusion, we found that in a contemporary STEMI-population, the incidence of 30-day TMMB was low. A TMMB was strongly associated with 30-day mortality but not with mortality days 31 to 365. If patients survived a serious bleeding, their short- and long-term prognoses were not affected. PMID- 29402422 TI - Comparison of Outcomes and Costs Associated With Aspirin +/- Clopidogrel After Coronary Artery Bypass Grafting. AB - Optimal antiplatelet therapy after coronary artery bypass graft (CABG) surgery remains controversial. This study evaluated the role of dual antiplatelet therapy using aspirin and clopidogrel (DAPT) versus antiplatelet therapy using aspirin only (ASA) on post-CABG clinical outcomes and costs. In the Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial, clopidogrel use after CABG was prospectively collected beginning in year 2 of this study to include 1,525 of the 2,203 original ROOBY patients who received aspirin after CABG. Discretionarily, surgeons after CABG administered either DAPT or ASA treatments. The ROOBY trial's primary 30-day composite (mortality or perioperative morbidity), 1-year composite (all-cause death, repeat revascularization, or nonfatal myocardial infarction), and costs were compared for these 2 strategies. Of the 1,525 subjects, 511 received DAPT and 1,014 received ASA. DAPT subjects, compared with ASA subjects, had lower rates of preoperative left ventricular ejection fraction of >=45% (78.8% vs 85.7%, p <0.001), on-pump CABG (36.6% vs 57.1%, p = 0.001), and endoscopic vein harvesting (30.0% vs 42.8%, p <0.001). ASA patients were more likely to have earlier aspirin administration and receive 325 versus 81 mg dosages. The 30-day composite outcome rate was significantly lower for DAPT patients compared with ASA patients (3.3% vs 7.1%, p = 0.003), but the 1 year composite outcome was equal between the 2 groups (12.0% vs12.0%, p = 1.0). At 1 year, there were no cost differences between the 2 groups. Propensity analyses did not significantly alter the results. In conclusion, DAPT appeared safe and was associated with fewer 30-day adverse outcomes than aspirin only and with no 1-year outcome or cost differences. PMID- 29402423 TI - Management of blunt cerebrovascular injury (BCVI) in the multisystem injury patient with contraindications to immediate anti-thrombotic therapy. PMID- 29402424 TI - Can intermittent pneumatic compression (IPC) reduce time to surgery for malleolar fractures? PMID- 29402425 TI - Surgical treatment of rib fracture nonunion: A single center experience. AB - INTRODUCTION: In contrast to the emerging evidence on the operative treatment of flail chest, there is a paucity of literature on the surgical treatment of rib fracture nonunion. The purpose of this study was to describe our standardized approach and report the outcome (e.g. patient satisfaction, pain and complications) after surgical treatment of a rib fracture nonunion. METHODS: A single centre retrospective cohort study was performed at a level 1 trauma centre. Symptomatic rib nonunion was defined as a severe persistent localized pain associated with the nonunion of one or more rib fractures on a chest CT scan at least 3 months after the initial trauma. Patients after initial operative treatment of rib fractures were excluded. RESULTS: Nineteen patients (11 men, 8 women), with symptomatic nonunions were included. Fourteen patients were referred from other hospitals and 8 patients received treatment from a pain medicine specialist. The mean follow-up was 36 months. No in-hospital complications were observed. In 2 patients, new fractures adjacent to the implant, without new trauma were observed. Furthermore 3 patients requested implant removal with a persistent nonunion in one patient. There was a mean follow-up of 36 months, the majority of patients (n = 13) were satisfied with the results of their surgical treatment and all patients experienced a reduction in the number of complaints. Persisting pain was a common complaint. Three patients reporting severe pain used opioid analgesics on a daily or weekly basis. Only 1 patient needed ongoing treatment by a pain medicine specialist. CONCLUSION: Surgical fixation of symptomatic rib nonunion is a safe and feasible procedure, with a low perioperative complication rate, and might be beneficial in selected symptomatic patients in the future. In our study, although the majority of patients were satisfied and the pain level subjectively decreases, complaints of persistent pain were common. PMID- 29402426 TI - Thoracic injury rule out criteria and NEXUS chest in predicting the risk of traumatic intra-thoracic injuries: A diagnostic accuracy study. AB - INTRODUCTION: This study aimed to compare the diagnostic accuracy of NEXUS chest and Thoracic Injury Rule out criteria (TIRC) models in predicting the risk of intra-thoracic injuries following blunt multiple trauma. METHODS: In this diagnostic accuracy study, using the 2 mentioned models, blunt multiple trauma patients over the age of 15 years presenting to emergency department were screened regarding the presence of intra-thoracic injuries that are detectable via chest x-ray and screening performance characteristics of the models were compared. RESULTS: In this study, 3118 patients with the mean (SD) age of 37.4 (16.9) years were studied (57.4% male). Based on TIRC and NEXUS chest, respectively, 1340 (43%) and 1417 (45.4%) patients were deemed in need of radiography performance. Sensitivity, specificity, and positive and negative predictive values of TIRC were 98.95%, 62.70%, 21.19% and 99.83%. These values were 98.61%, 59.94%, 19.97% and 99.76%, for NEXUS chest, respectively. Accuracy of TIRC and NEXUS chest models were 66.04 (95% CI: 64.34-67.70) and 63.50 (95% CI: 61.78-65.19), respectively. CONCLUSION: TIRC and NEXUS chest models have proper and similar sensitivity in prediction of blunt traumatic intra-thoracic injuries that are detectable via chest x-ray. However, TIRC had a significantly higher specificity in this regard. PMID- 29402427 TI - Novel implant for peri-prosthetic proximal tibia fractures. AB - BACKGROUND: Repair of peri-prosthetic proximal tibia fractures is very challenging in patients with a total knee replacement or arthroplasty. The tibial component of the knee implant severely restricts the fixation points of the tibial implant to repair peri-prosthetic fractures. A novel implant has been designed with an extended flange over the anterior of tibial condyle to provide additional points of fixation, overcoming limitations of existing generic locking plates used for proximal tibia fractures. Furthermore, the screws fixed through the extended flange provide additional support to prevent the problem of subsidence of tibial component of knee implant. METHODS: The design methodology involved extraction of bone data from CT scans into a flexible CAD format, implant design and structural evaluation and optimisation using FEM as well as prototype development and manufacture by selective laser melting 3D printing technology with Ti6Al4 V powder. RESULTS: A prototype tibia implant was developed based on a patient-specific bone structure, which was regenerated from the CT images of patient's tibia. The design is described in detail and being applied to fit up to 80% of patients, for both left and right sides based on the average dimensions and shape of the bone structure from a wide range of CT images. CONCLUSION: A novel tibial implant has been developed to repair peri-prosthetic proximal tibia fractures which overcomes significant constraints from the tibial component of existing knee implant. PMID- 29402428 TI - Period prevalence and factors associated with road traffic crashes among young adults in Kuwait. AB - OBJECTIVES: This cross-sectional study assessed one-year period prevalence of road traffic crashes (RTCs) and examined the factors associated with RTCs among young adults in Kuwait. DESIGN AND SETTINGS: During December 2016, 1500 students enrolled in 15 colleges of Kuwait University were invited to participate in the study. Students 18 years old or older and who drive by themselves were eligible. Data were collected using a structured self-administered questionnaire. One-year period prevalence of RTCs (>=1 vs. none) was computed. Multivariable log-binomial regression model was used to identify the risk factors associated with one-year period prevalence of RTCs. RESULTS: Of 1500 invited individuals, 1465 (97.7%) participated, of which 71.4% (1046/1465) were female, 56.4% (804/1426) were aged between 21 and 25 years, and 67.1% (980/1460) were Kuwaitis. One-year period prevalence of RTC was 38.9%. The final multivariable log-binomial regression model showed that after adjusting for the influences of other variables in the model, participants were more likely to have had at least one RTC during the past year, if they habitually sped over limit (adjusted PR = 1.19; 95% confidence interval (CI): 1.04-1.36), crossed a red light (adjusted PR = 1.33; 95% CI: 1.16 1.52), or if they have had three or more speeding tickets (adjusted PR = 1.40; 95% CI: 1.13-1.73) compared to those who reportedly had no RTC during the same period. CONCLUSION: One-year period prevalence of RTCs among university students in Kuwait, though relatively lower than the reported figures in similar populations elsewhere in the region, is yet high enough to warrant diligent attention. Habitual speeding, having had three or more speeding tickets, and the practice of crossing a red light were significantly and independently associated with at least one RTC during the past year. Targeted education and enforcement of existing traffic laws may reduce the RTCs frequency in this relatively young population. Future studies may look at impact of such interventions. PMID- 29402429 TI - Letter to the editor concerning "A biomechanical study comparing proximal femur nail and proximal femur locking compression plate in fixation of reverse oblique proximal femur fractures". PMID- 29402431 TI - Limiting the impacts of child abuse and neglect by understanding which supports matter most: A differential impact approach. PMID- 29402430 TI - Application of mesoporous carbon-polymer monolith for the extraction of phenolic acid in food samples. AB - In this study, activated carbon-organic polymer (AC-polymer) extraction columns were prepared via microwave-assisted polymerization. The AC-polymer was applied in polymer monolith microextraction (PMME) of phenolic acids (PAs) in food samples. Structural characterization using Raman and Fourier transform infrared (FTIR) spectroscopy revealed the successful incorporation of AC into polymer monolith. In contrast to neat polymer in which low extraction efficiency (17.0 57.7%) was observed, the AC-polymer (8 mg AC, 4 cm column length) afforded better extraction efficiency for PAs ranging from 75.8 to 99.8% for intra-day with less than 1.4% relative standard deviations (RSDs) and inter-day precision ranging from 74.3 to 100.1% (<2.7% RSDs). The extraction efficiency for column-to-column were found to be in the range of 72.8-100.5% (<2.0% RSDs) (n = 3). Under the optimized conditions, the AC-polymer monolithic column was successfully applied in PMME of PAs in fruit wine and cranberry juice samples at concentrations of <4.8 mg L-1 and 26.54 mg L-1, respectively. PMID- 29402432 TI - Type I interferon suppression-negative and host mRNA nuclear retention-negative mutation in nsp1beta confers attenuation of porcine reproductive and respiratory syndrome virus in pigs. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has the ability to suppress the type I interferons (IFNs-alpha/beta) induction to facilitate its survival during infection, and the nsp1 protein of PRRSV has been identified as the potent IFN antagonist. The nsp1beta subunit of nsp1 has also been shown to block the host mRNA nuclear export as one of the mechanisms to suppress host antiviral protein production. The SAP motif in nsp1beta is the functional motif for both IFN suppression and host mRNA nuclear retention, and using infectious clones, two mutant viruses vL126A and vL135A have been generated. These mutants retain the infectivity, but the phenotype is negative for both IFN suppression and host mRNA nuclear retention due to the loss of the SAP motif. To examine the pathogenic role of IFN suppression in pigs, 40 piglets were allotted to four groups and each group was intramuscularly infected with vL126A, vL135A, wild-type (WT) PRRSV, and placebo. Pigs infected with vL126A or vL135A exhibited mild clinical signs with low viral titers and short duration of viremia. The levels of PRRSV-specific antibody remained comparable in all infected groups but the neutralizing antibody titers were high in vL126A-infected or vL135A-infected pigs. The IFN-alpha concentration was also high in pigs infected with the SAP mutants. Reversion to WT sequence was observed in the SAP motif in some animals, and the revertants regained the function to suppress IFN production and host mRNA nuclear export, indicating strong selection pressure in the SAP motif of nsp1beta. Together, our data demonstrate that the IFN antagonism and host mRNA nuclear retention mediated by nsp1beta contributes to viral virulence, and loss of these functions confers PRRSV attenuation. PMID- 29402433 TI - Hedging our bets. PMID- 29402434 TI - Congenital hemifacial hyperplasia. PMID- 29402435 TI - Behcet's disease. PMID- 29402436 TI - Body composition in acute heart failure patients: Relationship with gender and left ventricular ejection fraction. PMID- 29402438 TI - Resolution of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) during Nivolumab therapy for non-small cell lung cancer: a case report. PMID- 29402437 TI - Auditory prediction during speaking and listening. AB - In the present EEG study, the role of auditory prediction in speech was explored through the comparison of auditory cortical responses during active speaking and passive listening to the same acoustic speech signals. Two manipulations of sensory prediction accuracy were used during the speaking task: (1) a real-time change in vowel F1 feedback (reducing prediction accuracy relative to unaltered feedback) and (2) presenting a stable auditory target rather than a visual cue to speak (enhancing auditory prediction accuracy during baseline productions, and potentially enhancing the perturbing effect of altered feedback). While subjects compensated for the F1 manipulation, no difference between the auditory-cue and visual-cue conditions were found. Under visually-cued conditions, reduced N1/P2 amplitude was observed during speaking vs. listening, reflecting a motor-to sensory prediction. In addition, a significant correlation was observed between the magnitude of behavioral compensatory F1 response and the magnitude of this speaking induced suppression (SIS) for P2 during the altered auditory feedback phase, where a stronger compensatory decrease in F1 was associated with a stronger the SIS effect. Finally, under the auditory-cued condition, an auditory repetition-suppression effect was observed in N1/P2 amplitude during the listening task but not active speaking, suggesting that auditory predictive processes during speaking and passive listening are functionally distinct. PMID- 29402439 TI - Drug development and clinical trial design in pancreatico-biliary malignancies. AB - Pancreatico-biliary (P-B) tumors arise from the pancreas, bile duct, and ampulla of Vater. Despite their close anatomical location, they have different etiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging and surgical techniques, and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger phase III trials, raising the valid question of how drug development can be optimized for patients with pancreatic adenocarcinoma and biliary tract malignancies. In this article we summarize the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as phase I and non-randomised phase II trials, within the clinical context and current therapeutic landscape of P-B tumors and postulate how translational studies and trial design may enable better realization of emerging targets together with a proposed model for future patient management. A detailed summary of current phase I clinical trials in P-B tumors is provided. PMID- 29402440 TI - [Pain management in children with erythromelalgia: case report]. AB - Erythromelalgia is a neuropathic pain syndrome due to an autosomal dominant gene, characterized by erythema, increased skin temperature and burning pain in hands and feet, whose treatment is often unsatisfactory. In this paper, we report a case of a 9 years old female patient whose first episode of burning pain, erythema and edema of the hands, without triggering factors, had instant relief after immersion in cold water. She presented with systemic arterial hypertension and had seizures. The patient was treated with gabapentin (150mg.8h-1) and amitriptyline (12.5mg) orally, intravenous lidocaine infusion (120mg), without relieving pain complaints. Due to the lack of response to the proposed treatment, it was decided to gradually reduce these medications and to introduce carbamazepine (200mg) orally and, after 4 days of treatment, there was complete relief of the manifestations. PMID- 29402441 TI - [Ropivacaine use in transnasal sphenopalatine ganglion block for post dural puncture headache in obstetric patients - case series]. AB - PURPOSE: Sphenopalatine ganglion block is widely accepted in chronic pain; however it has been underestimated in post dural puncture headache treatment. The ganglion block does not restore normal cerebrospinal fluid dynamics but effectively reduces symptoms associated with resultant hypotension. When correctly applied it may avoid performance of epidural blood patch. The transnasal approach is a simple and minimally invasive technique. In the cases presented, we attempted to perform and report the ganglion block effectiveness and duration, using ropivacaine. CLINICAL FEATURES: We present four obstetrics patients with post dural puncture headache, after epidural or combined techniques, with Tuohy needle 18G that underwent a safe and successful sphenopalatine ganglion block. We performed the block 24-48h after dural puncture, with 4mL of ropivacaine 0.75% in each nostril. In three cases pain recurred within 12-48h, although less intense. In one patient a second block was performed with complete relief and without further recurrence. In the other two patients a blood patch was performed without success. All patients were asymptomatic within 7 days. CONCLUSION: The average duration of analgesic effect of the block remains poorly defined. In the cases reported, blocking with ropivacaine was a simple, safe and effective technique, with immediate and sustained pain relief for at least 12-24h. PMID- 29402442 TI - Distribution, source identification and health risk assessment of PFASs and two PFOS alternatives in groundwater from non-industrial areas. AB - Little research has been carried out for the per- and polyfluoroalkyl substances (PFASs) in groundwater from non-industrial areas, even though it has been proved that PFASs can transport for long distance. In this study, the concentration profiles and geographical distribution of 14 PFASs, including two alternatives of perfluorooctane sulfonate (PFOS), 6:2 fluorotelomer sulfonate (6:2 FTS) and potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F-53B), were analyzed in groundwater samples (n = 102) collected from water wells in non-industrial areas. The total concentrations of PFASs (Sigma14PFASs) in groundwater samples ranged from 2.69 to 556 ng/L (mean 43.1 ng/L). The detection rates of shorter chain (C4-C9) PFASs were 62.75-100%, higher than those of long chain (> C10) PFASs with detection rates of less than 40%. The source identification using hierarchical cluster analysis and Spearman rank correlation analysis suggested that domestic sewage and atmospheric deposition may contribute significantly to the PFAS occurrence in groundwater in non-industrial areas, while the nearby industrial parks may contribute some, but not at a significant level. Furthermore, the human health risk assessment analysis shows that the health hazards associated with perfluorooctanoic acid (PFOA) and PFOS, two of the main PFAS constituents in groundwater from non-industrial areas, were one or two orders of magnitude higher than those in a previous study, but were unlikely to cause long-term harm to the residents via the drinking water exposure pathway alone. PMID- 29402443 TI - AAHFN leadership message. PMID- 29402444 TI - Comparison of nasal and forehead oximetry accuracy and pressure injury in critically ill patients. AB - BACKGROUND: In critically ill patients, clinicians can have difficulty obtaining accurate oximetry measurements. OBJECTIVE: To compare the accuracy of nasal alar and forehead sensor measurements and incidence of pressure injury. METHODS: 43 patients had forehead and nasal alar sensors applied. Arterial samples were obtained at 0, 24, and 120 hours. Oxygen saturations measured by co-oximetry were compared to sensor values. Skin was assessed every 8 hours. RESULTS: Oxygen saturations ranged from 69.8%-97.8%, with 18% of measures < 90%. Measurements were within 3% of co-oximetry values for 54% of nasal alar compared to 35% of forehead measurements. Measurement failures occurred in 6% for nasal alar and 22% for forehead. Three patients developed a pressure injury with the nasal alar sensor and 13 patients developed a pressure injury with the forehead sensor (chi2 = 7.68; p = .006). CONCLUSIONS: In this group of patients with decreased perfusion, nasal alar sensors provided a potential alternative for continuous monitoring of oxygen saturation. PMID- 29402445 TI - Corrigendum to "Testosterone inhibits facilitating effects of parenting experience on parental behavior and the oxytocin system in mice" [Physiol. Behav. 118 (2013) 159-164]. PMID- 29402446 TI - Getting a kinematic handle on reach-to-grasp: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Reach-to-grasp is an essential everyday activity that is often impaired after stroke. The objectives of this review are: (1) identify differences in the kinematic characteristics of reach-to-grasp between individuals with and without stroke, and (2) determine the influence of object location on kinematics. DATA SOURCES: MEDLINE, AMED, and Embase databases. ELIGIBILITY CRITERIA: Studies investigating individuals with stroke and neurologically intact control participants completing reach-to-grasp (paretic upper limb) of an object assessed via kinematic assessment (motion analysis). REVIEW METHODS: Following Cochrane Collaboration guidelines a meta-analysis comparing kinematic characteristics of reach-to-grasp between individuals with and without stroke. Potential risk of bias was assessed using the Down's and Black Tool. Data were synthesised by calculating the standardised mean difference (SMD) in kinematic characteristics between adults with and without stroke. RESULTS: Twenty-nine studies met the review criteria, mainly of observational design; 460 individuals with stroke and 324 control participants. Kinematic differences in reach-to-grasp were identified in the central and ipsilateral workspace for example, individuals with stroke exhibited significantly lower peak velocity SMD -1.48 (95% CI -1.94, -1.02), and greater trunk displacement SMD 1.55 (95% CI 0.85, 2.25) than control participants. Included studies were assessed as demonstrating unclear or high potential risk-of-bias. CONCLUSIONS: Differences in kinematic characteristics between individuals with and without stroke were identified which may be different reaching in the ipsilateral and central workspace. Suggesting, that object location may influence some kinematic characteristics and not others which may be pertinent when re-training reach-to grasp. PROSPERO: CRD42014009479. PMID- 29402447 TI - Nonoperative management of pilonidal sinus disease: one more step toward the ideal management therapy-a randomized controlled trial. AB - BACKGROUND: Pilonidal sinus disease is a common perianal inflammatory condition. Currently, operative therapy is the standard management strategy. The aim of this study is to investigate the efficacy of a preparation with antimicrobial, sclerosing, and wound-enhancing properties in the nonoperative management of pilonidal sinus disease. METHODS: A parallel randomized controlled trial was conducted between January 2013 and January 2017 to investigate the effect of a mixture of sclerosing agent and herbal product (Lawsonia inermis powder) in the management of sacrococcygeal pilonidal sinus disease. The patients were allocated randomly into the study group (group receiving injection of the mixture into the sinus track) and the control group (group receiving the classic technique of operative excision and primary closure). RESULTS: This study was conducted among 400 patients, 316 (79%) male, 84 (21%) female. The age range was 18 to 40 years with a mean age of 27.1 years (standard deviation, +/-2.4); each group included 200 patients. None of the patients had an abscess or complicated pilonidal disease. Cure rate, defined as complete healing of the sinus, was high among both groups after the first intervention (94% for control group and 89% for the test group, respectively; P = .051). In the study group, there was a statistically significant decrease in hospital stay, cost, perioperative pain, duration of absence from work, and duration of the procedure. CONCLUSION: According to this trial, the injection of this mixture appears to be better than the other therapeutic options for pilonidal sinus disease in terms of cost effectiveness, time off work, rate of complication, and perioperative pain. PMID- 29402448 TI - Effect of triclosan-coated sutures on the incidence of surgical site infection after abdominal wall closure in gastroenterological surgery: a double-blind, randomized controlled trial in a single center. AB - BACKGROUND: Surgical site infection is one of the most common postoperative complications after gastroenterologic surgery. This study investigated the effect of triclosan-coated sutures in decreasing the incidence of surgical site infections after abdominal wall closure in gastroenterologic surgery. METHODS: A prospective, double-blind, randomized, controlled parallel adaptive group sequential superiority trial was conducted from March 2014 to March 2017 in a single center. Eligible patients were those who underwent gastroenterologic surgery. Patients were allocated randomly to receive either abdominal wall closure with triclosan-coated sutures (the study group) or sutures without triclosan (the control group). The primary end point was the incidence of superficial or deep surgical site infections within 30 days after operation. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/), identification number UMIN000013054. RESULTS: A total of 1,013 patients (study group, 508 patients; control group, 505 patients) were analyzed by a modified intention-to-treat approach. The wounds in 990 (97.7%) of the 1,013 patients were classified as clean-contaminated. The primary end point (incidence of superficial or deep surgical site infections) was 35 (6.9%) of 508 patients in the study group and 30 (5.9%) of 505 in the control group. The incidence of surgical site infections did not differ markedly between the 2 groups (95% confidence interval: 0.686-2.010, P = .609). Of the 65 infections, 42 (64.6%) were superficial surgical site infections, with similar frequencies in the 2 groups, and 23 (35.4%) were deep surgical site infections, again with similar frequencies in the 2 groups. CONCLUSION: Triclosan-coated sutures did not decrease the incidence of surgical site infections after abdominal wall closure in gastroenterologic surgery. PMID- 29402449 TI - Databases for surgical health services research: American College of Surgeons National Surgical Quality Improvement Program. PMID- 29402450 TI - Vascular ring: Early and long-term mortality and morbidity after surgical repair. AB - BACKGROUND: Vascular ring is a rare cause of recurrent respiratory infections, dysphagia and stridor. Surgical repair is considered safe but the long-term outcomes are unclear. The purpose of this study was to investigate the mortality and morbidity following vascular ring surgery in a single institution. MATERIALS AND METHODS: This retrospective study covers operations done at Aarhus University Hospital, Denmark between October 1983 and May 2015. Medical records were reviewed focusing on early complications and long-term complaints up to September 2017. RESULTS: A total of 23 patients with median age of 1.4 years (range 0.008 64 years) were operated for vascular ring. Median follow-up was 6.8 years (range 2.4-34 years). Presenting symptoms were stridor (52%), dysphagia or vomiting (52%) and recurrent respiratory infections (48%). There were no early or late deaths. Three months postoperatively, 59% reported no respiratory complaints and 50% reported normal eating habits. Long term, only 14% had no complaints. In particular, asthma (36%), persistent stridor (18%) and recurrent respiratory infections (32%) were frequent. A high number of patients developed mental illness (27%). CONCLUSION: Surgery for vascular ring can be performed with low early and long-term mortality. Despite good three months outcome, the majority of patients had long-term respiratory issues. Oesophageal morbidity was low. LEVEL OF-EVIDENCE: 2B. PMID- 29402451 TI - Turkish Medical Association central council detained for demanding peace. PMID- 29402452 TI - Impacts of stress on reproductive and social behaviors. AB - Impacts of steroid stress hormones on the brain have provided multiple opportunities for linking specific molecular phenomena to behavioral state. The negative impacts of stress on female reproductive biological processes have been documented thoroughly at the endocrine and behavioral levels. More recently, a '3 hit' theory of autism has identified early stress as one of the hits. The multiple biochemical effects of endotoxin (lipopolysaccharide, LPS) indicated that it would serve as a powerful maternal immune activator. The prenatal exposure to LPS coupled with the other two 'hits'- an autism-related mutation and the Y chromosome - - heightened certain autism-like signs in mouse behavior. PMID- 29402453 TI - Primary Psychiatric Manifestations of Subacute Sclerosing Panencephalitis: A Case Report and Literature Review. PMID- 29402454 TI - Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure Associated Liver Disease in Surgical Infants. AB - OBJECTIVE: To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure-associated liver disease (IFALD) among infants. STUDY DESIGN: Two cohorts of infants <6 months old undergoing intestinal surgery were compared: preguideline (retrospective data from 2007 to 2013; n = 83) and postguideline (prospective data from 2013 to 2016; n = 81). The guidelines included greater initial enteral nutrition volumes of 20 mL/kg/d and daily feeding advancement if tolerated. The primary outcomes were incidence of IFALD (peak direct bilirubin [DB] >2 mg/dL) and severity (DB >5 mg/dL for moderate-severe). Multiple logistic regression was used to determine the odds of developing IFALD. Other outcomes were time to reach 50% and 100% goal calories from enteral nutrition and the incidence of necrotizing enterocolitis after feeding. RESULTS: The incidence of IFALD decreased from 71% to 51% (P = .031), and median peak DB decreased from 5.7 to 2.4 mg/dL (P = .001). After adjusting for diagnosis and prematurity, the odds of developing IFALD of any severity were reduced by 60% (OR 0.40, 95% CI 0.20-0.85), and the odds of developing moderate-to-severe IFALD were reduced by 72% (OR 0.28, 95% CI 0.13 0.58) with guideline use. Time to reach 50% enteral nutrition decreased from a median of 10 to 6 days (P = .020) and time to reach 100% enteral nutrition decreased from 35 to 21 days (P = .035) with guideline use. The incidence of necrotizing enterocolitis after initiating enteral nutrition did not change (5% vs 9%, P = .346). CONCLUSIONS: Implementation of feeding guidelines reduced time to reach feeding goals, significantly reducing IFALD incidence and severity. PMID- 29402455 TI - Routine Supplementation of Lactobacillus rhamnosus GG and Risk of Necrotizing Enterocolitis in Very Low Birth Weight Infants. AB - OBJECTIVE: To evaluate if routine supplementation of Lactobacillus rhamnosus GG ATCC 53103 (LGG) is associated with a decreased risk of necrotizing enterocolitis in very low birth weight (VLBW) infants. STUDY DESIGN: Retrospective observational cohort study of VLBW (<1500 g) infants at a single center from 2008 to 2016. LGG supplementation with Culturelle at a dose of 2.5 to 5 * 109 CFU/day began in 2014. We used multivariable logistic regression to evaluate the association between LGG supplementation and necrotizing enterocolitis (modified Bell stage IIA or greater), after adjusting for potential confounders. We also compared changes in necrotizing enterocolitis incidence before and after implementation of LGG using a statistical process control chart. RESULTS: We evaluated 640 VLBW infants with a median gestational age of 28.7 weeks (IQR 26.3 30.6); 78 (12%) developed necrotizing enterocolitis. The median age at first dose of LGG was 6 days (IQR 3-10), and duration of supplementation was 32 days (IQR 18 45). The incidence of necrotizing enterocolitis in the epoch before LGG implementation was 10.2% compared with 16.8% after implementation. In multivariable analysis, LGG supplementation was associated with a higher risk of necrotizing enterocolitis (aOR 2.10, 95 % CI 1.25-3.54, P = .005). We found no special cause variation in necrotizing enterocolitis after implementation of LGG supplementation. There were no episodes of Lactobacillus sepsis during 5558 infant days of LGG supplementation. CONCLUSIONS: In this study, routine LGG supplementation was not associated with a decreased risk of necrotizing enterocolitis. Our findings do not support the use of the most common probiotic preparation currently supplemented to VLBW infants in the US. PMID- 29402456 TI - Identification of prolargin expression in articular cartilage and its significance in rheumatoid arthritis pathology. AB - Qualitative 2D gel-electrophoresis (2DE) protein profiling for osteoarthritis (OA) and rheumatoid arthritis (RA) is challenging because of selective protein loss due to discrepancies in protein precipitation methodologies. Thus, we aimed at developing qualitative protein representation from OA/RA articular cartilage without protein precipitation towards identification of clinically relevant proteins. Chondroitinase digested human articular cartilages from RA patients were subjected to protein extraction using guanidinium hydrochloride (GuHCl) or 8 M urea with 10 or 2% ASB-14-4 or 0.45 M urea with 2% ASB-14-4 with cetylpyridinium chloride (CPC). The GuHCl extract is further protein precipitated with acetone or ammonium acetate-methanol or centricon-fractionated using 100 kDa cut filters and protein precipitated using ethanol. Processed extracts were subjected to 2DE to identify protein profiles. Poor proteins representations were observed in 2D gels with protein precipitated samples compared to qualitative protein representations seen in 2D gels of 0.45 M urea and 2%ASB-14-4 extraction procedure reproducibly. The strategy circumventing protein precipitation generated qualitative 2D gels. RA vs OA gel comparison showed elevated prolargin levels in RA with biglycan levels remaining unaltered. Up regulation of prolargin in RA suggests the likelihood of an adaptive mechanism to control the increased osteoclastogenesis in RA and may have therapeutic value in controlling the disease. PMID- 29402458 TI - Corrigendum to "Intervention studies to foster resilience - A systematic review and proposal for a resilience framework in future intervention studies" [Clinical Psychology Review 59 (2018) 78-100]. PMID- 29402457 TI - Enhanced oral bioavailability of an antipsychotic drug through nanostructured lipid carriers. AB - Olanzapine is an atypical antipsychotic, undergoes extensive first pass metabolism, also has poor aqueous solubility and belongs to BCS (Biopharmaceutical Classification System) Class II drug) exhibit low oral bioavailability. To overcome this and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited through Nano structured lipid carriers (NLCs). The NLCs were formulated by solvent diffusion method using solid lipid (glyceryl tripalmitate), liquid lipid (castor oil) and surfactants (Pluronic F-68, Soylecithin). The formulated NLCs were characterized for physico chemical properties, in-vitro release studies and in-vivo oral bioavailability. F6 has shown average particle size of 158.5 nm with PI of 0.115 indicating narrow particle size distribution and follows uni modal distribution. It was found that the batch with stearyl amine has a zeta potential of 28.39 mV which confers stability to the dispersion. Bioavailability studies indicate that there was more than 51/2-fold increase in oral bioavailability in case of NLCs (F6) compared to olanzapine suspension which indicates that NLCs provided sustained release of the drugs, and these systems can be the preferred as drug carriers for lipophilic drugs in long term disease conditions such as schizophrenia for enhanced bioavailability. PMID- 29402459 TI - Main causes of family refusal to organ and tissue donation: 10 years of experience in a latin american center. PMID- 29402460 TI - Bile cast nephropathy associated with severe liver dysfunction caused by anabolic steroids. PMID- 29402461 TI - Mesenchymal stromal/stem cells as potential therapy in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a multifactorial microvascular disease induced by hyperglycemia and subsequent metabolic abnormalities. The resulting cell stress causes a sequela of events that ultimately can lead to severe vision impairment and blindness. The early stages are characterized by activation of glia and loss of pericytes, endothelial cells (EC) and neuronal cells. The integrity of the retinal microvasculature becomes affected, and, as a possible late response, macular edema may develop as a common reason for vision loss in patients with non proliferative DR. Moreover, the local ischemia can trigger vasoproliferation leading to vision-threating proliferative DR (PDR) in humans. Available treatment options include control of metabolic and hemodynamic factors. Timely intervention of advanced DR stages with laser photocoagulation, intraocular anti-vascular endothelial growth factor (VEGF) or glucocorticoid drugs can reduce vision loss. As the pathology involves cell loss of both the vascular and neuroglial compartments, cell replacement strategies by stem and progenitor cells have gained considerable interest in the past years. Compared to other disease entities, so far little is known about the efficacy and potential mode of action of cell therapy in treatment of DR. In preclinical models of DR different cell types have been applied ranging from embryonic or induced pluripotent stem cells, hematopoietic stem cells, and endothelial progenitor cells to mesenchymal stromal cells (MSC). The latter cell population can combine various modes of action (MoA), thus they are among the most intensely tested cell types in cell therapy. The aim of this review is to discuss the rationale for using MSC as potential cell therapy to treat DR. Accordingly, we will revise identified MoA of MSCs and speculate how these may support the repair of the damaged retina. PMID- 29402462 TI - Which Coexistence Mechanisms Should Biogeographers Quantify? A Reply to Alexander et al. PMID- 29402463 TI - 20 Years Spatial-Temporal Analysis of Dengue Fever and Hemorrhagic Fever in Mexico. AB - BACKGROUND AND AIM: Dengue Fever (DF) is a human vector-borne disease and a major public health problem worldwide. In Mexico, DF and Dengue Hemorrhagic Fever (DHF) cases have increased in recent years. The aim of this study was to identify variations in the spatial distribution of DF and DHF cases over time using space time statistical analysis and geographic information systems. METHODS: Official data of DF and DHF cases were obtained in 32 states from 1995-2015. Space-time scan statistics were used to determine the space-time clusters of DF and DHF cases nationwide, and a geographic information system was used to display the location of clusters. RESULTS: A total of 885,748 DF cases was registered of which 13.4% (n = 119,174) correspond to DHF in the 32 states from 1995-2015. The most likely cluster of DF (relative risk = 25.5) contained the states of Jalisco, Colima, and Nayarit, on the Pacific coast in 2009, and the most likely cluster of DHF (relative risk = 8.5) was in the states of Chiapas, Tabasco, Campeche, Oaxaca, Veracruz, Quintana Roo, Yucatan, Puebla, Morelos, and Guerrero principally on the Gulf coast over 2006-2015. CONCLUSION: The geographic distribution of DF and DHF cases has increased in recent years and cases are significantly clustered in two coastal areas (Pacific and Gulf of Mexico). This provides the basis for further investigation of risk factors as well as interventions in specific areas. PMID- 29402464 TI - [Case report: Intraocular foreign body masquerading as toxoplasma chorioretinitis]. PMID- 29402465 TI - [Topical cyclosporine A and risk of ocular surface neoplasia]. AB - INTRODUCTION: Cyclosporine A (CsA) has well-known cutaneous carcinogenic effects when administered systemically. In ophthalmology, it is increasingly used in the form of eye drops since its indication for moderate to severe eye dry eye. The goal of this review of the literature is to evaluate a possible link between topical ocular CsA use and the occurrence of ocular surface neoplasia. MATERIALS AND METHODS: A literature review was performed. Publications evaluating the safety and efficacy of topical CsA as well as studies on the epidemiology and risk factors for conjunctival neoplasia and cases of conjunctival neoplasia were analyzed. Finally, post-market surveillance data from commercially available CsA eye drops were also evaluated. RESULTS: Five cases of conjunctival neoplasia in patients treated with systemic and/or topical CsA have been described in the literature, three with systemic administration alone, another with combined systemic and local administration, and one case of local administration alone. In these cases, no direct link with the administration of ocular topical CsA could be determined. Among the numerous prospective studies evaluating the safety and efficacy of topical CsA as well as the case-control studies evaluating the risk factors for developing conjunctival neoplasia, no relationship between the occurrence of conjunctival neoplasia and the use of topical ocular CsA was observed. CONCLUSION: Despite plausible pathophysiologic mechanisms, to date there is no evidence of an increased risk of ocular surface neoplasia with the use of topical ocular CsA. Further studies specifically addressing this question and with a longer duration are needed in order to precisely evaluate this theoretical risk. PMID- 29402466 TI - The Cu(II) affinity of the N-terminus of human copper transporter CTR1: Comparison of human and mouse sequences. AB - Copper Transporter 1 (CTR1) is a homotrimeric membrane protein providing the main route of copper transport into eukaryotic cells from the extracellular milieu. Its N-terminal extracellular domain, rich in His and Met residues, is considered responsible for directing copper into the transmembrane channel. Most of vertebrate CTR1 proteins contain the His residue in position three from N terminus, creating a well-known Amino Terminal Cu(II)- and Ni(II)-Binding (ATCUN) site. CTR1 from humans, primates and many other species contains the Met-Asp-His (MDH) sequence, while some rodents including mouse have the Met-Asn-His (MNH) N terminal sequence. CTR1 is thought to collect Cu(II) ions from blood copper transport proteins, including albumin, but previous reports indicated that the affinity of N-terminal peptide/domain of CTR1 is significantly lower than that of albumin, casting serious doubt on this aspect of CTR1 function. Using potentiometry and spectroscopic techniques we demonstrated that MDH-amide, a tripeptide model of human CTR1 N-terminus, binds Cu(II) with K of 1.3 * 1013 M-1 at pH 7.4, ~13 times stronger than Human Serum Albumin (HSA), and MNH-amide is even stronger, K of 3.2 * 1014 M-1 at pH 7.4. These results indicate that the N terminus of CTR1 may serve as intermediate binding site during Cu(II) transfer from blood copper carriers to the transporter. MDH-amide, but not MNH-amide also forms a low abundance complex with non-ATCUN coordination involving the Met amine, His imidazole and Asp carboxylate. This species might assist Cu(II) relay down the peptide chain or its reduction to Cu(I), both steps necessary for the CTR1 function. PMID- 29402467 TI - Effect of ionic strength on barium transport in porous media. AB - Hydraulic fracturing (or fracking) is a well stimulation technique used to extract resources from a low permeability formation. Currently, the most common application of fracking is for the extraction of oil and gas from shale. During the operation, a large volume of brine, rich in hazardous chemicals, is produced. Spills of brine from wells or pits might negatively impact underground water resources and, in particular, one of the major concerns is the migration of radionuclides, such as radium (Ra2+), into the shallow subsurface. However, the transport behaviour of Ra2+ through a reactive porous medium under conditions typical of a brine, i.e., high salinity, is not well understood, yet. Here, a study on the transport behaviour of barium (Ba2+, congener of radium) through a porous medium containing a common mineral such as goethite (FeO(OH)) is presented. Batch and column flood tests were carried out at conditions resembling the produced brine, i.e., large values of ionic strength (I), namely, 1 to 3mol/kg. The measurements were described with the triple layer surface complexation model coupled with the Pitzer activity coefficient method and a reactive transport model, in the case of the transport tests. The experimental results show that the adsorption of Ba2+ onto FeO(OH) increases with pH but decreases with I and it becomes negligible at the brine conditions. Moreover, even if isotherms show adsorption at large I, at the same conditions during transport, Ba2+ travels without retardation through the FeO(OH) porous medium. The triple layer model agrees very well with all batch data but it does not describe well the transport tests in all cases. In particular, the model cannot match the pH measurements at large I values. This suggests that the chemical reactions at the solid-liquid interface do not capture the mechanism of Ba2+ adsorption onto FeO(OH) at large salinity. Finally, this study suggests that barium, and potentially its congeners, namely, radium, calcium, magnesium, and strontium, may travel at the average flow velocity through a soil where the dominant reactive mineral is goethite. PMID- 29402468 TI - Effects of aerobic exercise on white matter hyperintensities: An exploratory analysis. PMID- 29402469 TI - The impact of health discipline designation on psychological assessments prior to bariatric surgery. PMID- 29402470 TI - A qualitative signature for predicting pathological response to neoadjuvant chemoradiation in locally advanced rectal cancers. AB - BACKGROUND AND PURPOSE: The standard therapy for locally advanced rectal cancers (LARCs) is neoadjuvant chemoradiation (nCRT) followed by surgical resection. Pathological response to nCRT varies among patients, and it remains a challenge to predict pathological response to nCRT in LARCs. MATERIAL AND METHODS: Using 42 samples as the training cohort, we searched a signature by screening the gene pairs whose within-sample relative expression orderings are significantly correlated with the pathological response. The signature was validated in both a public cohort of 46 samples and a cohort of 33 samples measured at our laboratory. RESULTS: A signature consisting of 27 gene pairs was identified in the training cohort with an accuracy of 92.86% and an area under the receiver operating characteristic curve (AUC) of 0.95. The accuracy was 89.13% for the public test cohort and 90.91% for the private test cohort, with AUC being 0.95 and 0.91, respectively. Furthermore, the signature was used to predict disease free survival benefits from 5Fu-based chemotherapy in 285 locally advanced colorectal cancers. CONCLUSIONS: The signature consisting of 27 gene pairs can robustly predict clinical response of LARCs to nCRT. PMID- 29402471 TI - Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review. AB - Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of venous thromboembolism (VTE). However, the use of DOACs in unusual VTE, including cerebral venous thrombosis (CVT) and splanchnic venous thrombosis (SVT), and in patients with biological thrombophilia including minor thrombophilia (Factor V Leiden and prothrombin G20210A), major innate thrombophilia (protein C and S deficiency, and antithrombin) and major acquired thrombophilia (antiphospholipid syndrome [APS]), remains controversial due to the paucity of available data. There are some reports of DOACs use in the initial treatment or long-term maintenance of patients with either CVT or SVT, but their efficacy remains unclear. The efficacy of DOACs may be suitable in patients with biological minor or major thrombophilia. The use of DOACs for the long-term maintenance of patients with APS is more contentious. Randomized clinical trials, which are currently underway, should offer definitive insight into the efficacy and safety profiles of DOACs in these patient populations. PMID- 29402472 TI - [End-of-life decisions: results of the expert-validated questionnaire]. AB - OBJECTIVE: To assess the attitudes and knowledge in the life's end about palliative care, advance directives, psychological-physical care, medically assisted suicide and spiritual accompaniment. METHOD: A cross-sectional study performed in the population at primary health care center of the Autonomous Region of Madrid (Spain). It participated 425 selected people that a simple random was applied in the consultation sheets of health professionals. They analyzed 42 variables of self-administered questionnaire. RESULTS: The surveyed population of Madrid displayed the following characteristics: university studies 58%, 51-70 years 47%, married 60%, and women 61%. 91% would like to decide about their care at life's end. 58% of respondents are aware of palliative care and 53% would request spiritual accompaniment. They know advance directives (50%) but have not made the document. 54% are in favor of legalizing the euthanasia and 42% the assisted suicide. CONCLUSION: Madrid's people state they would like to decide what care they will receive at life's end and request spiritual accompaniment. Outstanding advocates of euthanasia against assisted suicide. They would like to receive palliative care and complete advance directives documents. To draw comparisons within the population, thereby increasing awareness about social health care resources in Autonomous Region of Madrid, surveys should be conducted in different primary health care centers areas of Madrid. PMID- 29402473 TI - 3D Printing of Bacteria: The Next Frontier in Biofabrication. AB - Bacterial species are now being mixed with various bioinks to produce functional complex materials using 3D printing. These systems show enormous potential in applications such as bioremediation, sensors that can detect toxic chemicals, oil spill filters, and wound dressings. In particular, 3D-printed minibiofactories represent a potential paradigm shift in biotechnology. PMID- 29402474 TI - Cerebral aspergillosis: An emerging opportunistic infection in patients receiving ibrutinib for chronic lymphocytic leukemia? PMID- 29402475 TI - Intensive care admission for Coronavirus OC43 respiratory tract infections. AB - BACKGROUND: Coronavirus OC43 infection causes severe pneumonia in patients presenting with comorbidities, but clinical signs alone do not allow for viral identification. OBJECTIVES: To analyze acute manifestations of Coronavirus OC43 infections and outcomes of patients admitted to an intensive care unit (ICU). PATIENTS AND METHODS: Retrospective and monocentric study performed during a Coronavirus OC43 outbreak. We used multiplex PCR to detect an OC43 outbreak in Reunion Island during the 2016 Southern Hemisphere's winter: seven admissions to the ICU. RESULTS: Mean age of patients was 71 [67;76] years, SAPS II was 42 [28;53], pneumonia severity index 159 [139;182] vs 73 [40.5;107] for patients in medical wards, and 43% required mechanical ventilation. Comorbidities were diabetes mellitus (87%), chronic respiratory failure (57%), and chronic renal failure (29%). One patient died from Haemophilus influenzae co-infection. CONCLUSION: As for MERS Co-V infections, underlying comorbidities impacted the clinical outcomes of OC43 infections. PMID- 29402476 TI - AMS assessment of U-contamination of structural materials of the Garigliano NPP under decommissioning. AB - The assessment of the radiological impact of decommissioning activities at a Nuclear Power Plant requires a detailed mapping of the distribution of radionuclides both in the environment surrounding the NPP and in its structural material. The detection of long-lived actinide isotopes and possibly the identification of their origin is particularly interesting and valuable if ultrasensitive measurement of the relative abundance of U isotopes is performed via Accelerator Mass Spectrometry (AMS). In this paper we present an investigation carried out on the structural materials of the Garigliano NPP aiming to determine the abundance of 235,236,238U in the various compartments of the plant buildings under decommissioning. Since the expected values both for isotopic ratios and total U concentrations range over different orders of magnitude, we have developed a novel methodology for the measurement of 234,235U/238U isotopic ratios in low U concentration samples. This allowed a systematic investigation of the distribution of all U isotopes in concrete and metal matrices of the NPP. The behavior of 235,236U/238U isotopic ratios in the different compartments of the NPP is discussed. The correlation of these ratios with 60Co and 137Cs specific activities is also studied to show a different behavior for concrete and metal samples. These data represent a very valuable information to direct the decommissioning procedures under course. PMID- 29402477 TI - Analytical method for evaluating (and correcting) the impact of outdoor radon concentration on the estimates of percentage of dwellings exceeding reference levels. AB - Outdoor radon concentration contributes to indoor radon levels, generally causing a shift from lognormal distribution of measured radon concentration data distribution, and it makes more challenging the estimation of radon distribution parameters on the basis of the lognormal assumption. In particular, lognormal assumption with no correction could lead to a significantly biased estimate of the percentage of dwellings exceeding a certain level, e.g. a reference level (RL), since this is based on biased estimates of geometric mean (GM) and geometric standard deviation (GSD) of radon concentration distribution. Subtracting to each measured data a constant outdoor radon level can usually compensate data distribution departure from log-normality (except for low radon levels), if the appropriate outdoor level value is chosen by means of a lognormal fit of the data. This approach - already (but not always) used in literature - cannot be applied in cases where all the data of radon concentrations are not available (e.g., for a review study). For these cases, this work presents an analytical method to quantitatively evaluate and correct the impact of outdoor on the lognormal distribution parameter estimates and, in particular, on the percentages of dwellings exceeding radon reference levels. The proposed method is applied to a number of possible situations, with different values of outdoor radon level, GM and GSD. The results show that outdoor radon levels generally produce an underestimation of the actual GSD parameter, which increases as the outdoor level increases, and in the worse cases, could lead to an underestimation higher than 50%. Consequently, if the outdoor contribution is not properly taken into account, the percentage of dwellings exceeding a certain RL is almost always underestimated, even by 80%-90% for RL equal to 300 Bq/m3. This could have implications for the classification of areas as regards radon concentration and for the estimation of avertable lung cancers attributable to radon levels higher than some possible RLs. PMID- 29402478 TI - Probiotic Use in Equine Gastrointestinal Disease. AB - Probiotics are commonly used in human and veterinary medicine due to their postulated positive effects on overall and specifically gastrointestinal health. Although some beneficial effects have been shown in several human diseases, a general beneficial effect of probiotics is currently not supported. In horses, well-designed studies to date are few, results are conflicting, and the effects of probiotics are questionable. Adverse effects are rare; however, intestinal adverse effects (diarrhea) have been reported in foals. Quality control of over the-counter probiotics is not tightly regulated, and labels often do not reflect the content. PMID- 29402479 TI - Advances in Diagnostics and Treatments in Horses with Acute Colic and Postoperative Ileus. AB - Differentiating between medical and surgical causes of colic is one of the primary goals of the colic workup, because early surgical intervention improves prognosis in horses requiring surgery. Despite the increasing availability of advanced diagnostics (hematologic analyses, abdominal ultrasound imaging, etc), the most accurate indicators of the need for surgery remain the presence of moderate to severe signs of abdominal pain, recurrence of pain after appropriate analgesic therapy, and the absence of intestinal borborygmi. Investigation of novel biomarkers, which may help to differentiate surgical lesions from those that can be managed medically, continues to be an active area of research. PMID- 29402480 TI - Understanding the Intestinal Microbiome in Health and Disease. AB - This article provides readers with the basic concepts necessary to understand studies using recent molecular methods performed in intestinal microbiome assessment, with special emphasis on the high throughput sequencing. This review also summarizes the current knowledge on this topic and discusses future insights on the interaction between the intestinal microbiome and equine health. PMID- 29402481 TI - Techniques and Accuracy of Abdominal Ultrasound in Gastrointestinal Diseases of Horses and Foals. AB - Diagnostic ultrasonography has been used as a test to determine the presence or absence of gastrointestinal disease in horses and foals. General techniques and anatomic landmarks are reviewed. Many clinical reports that have included diagnostic ultrasound as part of their diagnostic process and accuracy studies are necessary to determine the usefulness of diagnostic ultrasound in clinical practice. PMID- 29402482 TI - Taxifolin suppresses rat and human testicular androgen biosynthetic enzymes. AB - Taxifolin is a flavonoid. It has been used as a chemopreventive agent and supplement. It may have some beneficial effects to treat prostate cancer by suppressing androgen production in Leydig cells. The objective of the present study was to study the effects of taxifolin on androgen production of rat Leydig cells isolated from immature testis and some rat and human testosterone biosynthetic enzyme activities. Rat Leydig cells were incubated with 100MUM taxifolin without (basal) or with 10ng/ml luteinizing hormone (LH), 10mM 8 bromoadenosine 3',5'-cyclic monophosphate (8BR), and steroid enzyme substrates (20MUM): 22R-hydroxychloesterol, pregnenolone, progesterone, and androstenedione. The medium concentrations of 5alpha-androstane-3alpha, 17beta-diol (DIOL) and testosterone were measured. Taxifolin significantly suppressed basal, LH stimulated, 8BR-stimulated, pregnenolone-mediated, and progesterone-mediated androgen production by Leydig cells. Further study demonstrated that taxifolin inhibited rat 3beta-hydroxysteroid dehydrogenase and 17alpha-hydroxylase/17, 20 lyase with IC50 values of 14.55+/-0.013 and 16.75+/-0.011MUM, respectively. Taxifolin also inhibited these two enzyme activities in human testis with IC50 value of about 100MUM. Taxifolin was a competitive inhibitor for these two enzymes when steroid substrates were used. In conclusion, taxifolin may have benefits for the treatment of prostate cancer. PMID- 29402483 TI - Nomenclature for factors of the HLA system, update November 2017. PMID- 29402484 TI - Messengers of tolerance. AB - The use of immunosuppressant drugs after organ transplantation has brought great success in the field of organ transplantation with respect to short-term outcome. However, major challenges (i.e., limited improvement of long-term survival, immunosuppressant toxicity, infections and carcinoma) demand alternate treatment approaches that minimizes the use of immunosuppressants. Interestingly, few studies have identified groups of transplant patients who developed operational tolerance and thereby keep their allograft without complications in absence of immunosuppressants. These rare groups of patients are of particular interest as study subjects for understanding mechanisms of graft tolerance that could be leveraged in future for inducing tolerance and for understanding mechanisms involved in improving long-term allograft outcomes. Also, biomarkers from these studies could benefit the larger transplant population by their application in immunosuppressant tailoring and identification of tolerant patients among patients with stably functioning allografts. This review compiles several gene expression studies performed in samples from tolerant patients in different solid organ transplantations to identify key genes and associated molecular pathways relevant to tolerance. This review is aimed at putting forth all this important work done thus far and to identify research gaps that need to be filled, in order to achieve the greater purpose of these studies. PMID- 29402485 TI - Multidirectional Estimation of Arterial Stiffness Using Vascular Guided Wave Imaging with Geometry Correction. AB - We previously found that vascular guided wave imaging (VGWI) could non-invasively quantify transmural wall stiffness in both the longitudinal (r-z plane, 0 degrees ) and circumferential (r-theta plane, 90 degrees ) directions of soft hollow cylinders. Arterial stiffness estimation in multiple directions warrants further comprehensive characterization of arterial health, especially in the presence of asymmetric plaques, but is currently lacking. This study therefore investigated the multidirectional estimation of the arterial Young's modulus in a finite element model, in vitro artery-mimicking phantoms and an excised porcine aorta. A longitudinal pre-stretch of 20% and/or lumen pressure (15 or 70 mm Hg) was additionally introduced to pre-condition the phantoms for emulating the intrinsic mechanical anisotropy of the real artery. The guided wave propagation was approximated by a zero-order antisymmetric Lamb wave model. Shape factor, which was defined as the ratio of inner radius to thickness, was calculated over the entire segment of each planar cross section of the hollow cylindrical structure at a full rotation (0 degrees -360 degrees at 10 degrees increments) about the radial axis. The view-dependent geometry of the cross segment was found to affect the guided wave propagation, causing Young's modulus overestimation in four angular intervals along the propagation pathway, all of which corresponded to wall regions with low shape factors (<1.5). As validated by mechanical tensile testing, the results indicate not only that excluding the propagation pathway with low shape factors could correct the overestimation of Young's modulus, but also that VGWI could portray the anisotropy of hollow cylindrical structures and the porcine aorta based on the derived fractional anisotropy values from multidirectional modulus estimates. This study may serve as an important step toward 3-D assessment of the mechanical properties of the artery. PMID- 29402486 TI - Could Ultrasound Elastography Reflect Liver Function? AB - The purpose of this study was to investigate whether ultrasound elastography reflects liver function reserve relative to liver fibrosis histology. Sixty-five New Zealand rabbits were divided into an experimental group (n = 45) and a control group (n = 20). In the experimental group, liver fibrosis (F1-F4) was induced by subcutaneous injection of carbon tetrachloride. Point shear wave elastography and the indocyanine green (ICG) elimination test were performed for the two groups at 4-wk intervals for 56 wk. The liver stiffness value (LSV) and the ICG retention rate at 15 min (ICGR15) were obtained, and the correlation between them was investigated. The median LSVs of stages F0-F4 were 3.92 kPa (1.91-8.53 kPa), 5.02 kPa (2.39-8.91 kPa), 7.87 kPa (5.21-12.26 kPa), 12.83 kPa (5.92-16.79 kPa) and 16.64 kPa (9.76-29.50 kPa), respectively. The median ICGR15 values of stages F0-F4 were 8.7% (4.8%-15.6%), 10.8% (5.6%-20.3%), 19.2% (12.3% 26.7%), 31.0% (20.9%-41.0%) and 45.6% (22.1%-60.9%). There were significant differences in LSVs and ICGR15 values among the different stages of liver fibrosis (p <0.01). A positive correlation was observed between LSV and ICGR15 (r = 0.7497, p < 0.0001). A strong correlation was observed between liver stiffness and liver function reserve, indicating ultrasound elastography may reflect liver function reserve in different degrees of liver fibrosis. PMID- 29402487 TI - [About atypic tissular mass]. PMID- 29402488 TI - [Clinical and microbiological profile of patients experiencing relapses of tuberculosis in Tunisia]. AB - INTRODUCTION: Relapse of tuberculosis (TB) is known to be as one of the major risk factors for resistant TB. The aim of this study is to focus on clinical, radiological and bacteriological features of patients with pulmonary TB relapse. METHODS: We performed a retrospective survey in the respiratory department of the teaching hospital La Rabta in Tunis between January 2000 and December 2014. Data of patients with a pulmonary TB relapse were analyzed. RESULTS: During the study period, among 1250 patients hospitalized for pulmonary TB, 44 had a TB relapse. The TB relapse rate was estimated to be at 3.5%. The average age was 43.95+/-16.7 years. Sex ratio was 5,2. Eighty one percent of patients were current smokers. Alcoholism was found in 40.9% of cases. The mean time to relapse was 6.37+/-3.7 years. The radiological lesions were moderately extended at least in 54.6% of cases. A resistant TB was found in 33% of cases (mono-resistance: 33.3%, multi drug resistance (TB-MR): 11,1%, poly-resistance: 55.5%). The most incriminated drugs were isoniazid, rifampicin and pyrazinamide. One patient received TB-MR treatment regimen for 18 months. In the other cases, the duration of treatment was prolonged. Recovery was obtained in 72.7% of cases, two patients died and 22.7% of patients were lost to follow up. CONCLUSION: In Tunisia, TB relapse usually affects young male patients who are often alcoholic and smokers. Resistant TB is frequent among these patients. These findings lead us to emphasize the need of rapid diagnosis tools and adapted treatment regimen in these patients. PMID- 29402489 TI - [Effectiveness of Beauveria bassiana (Baubassil(r)) on the common cattle tick Rhipicephalus microplus in the Department of Guajira, Colombia]. AB - The effectiveness of Baubassil(r)(Beauveria bassiana) on the tick Rhipicephalus (Boophilus) microplus was evaluated. In the in vitro phase, the optimal germination temperature of the fungus was determined by microcultures at 25, 30 and 35 degrees C and the mortality of ticks. In the field, in a randomized design, 30 cebuine cows; 15 cows were treated with Baubassil(r) once a week at a 1*106 conidia/ml, and a control group was left untreated. It was observed that at temperatures of 25, 30 and 35 degrees C, germination of the entomopathogen was 97.5, 94.7 and 6.3%, respectively. In animals treated with Baubassil(r) obtained a corrected effectiveness of 96.8% on ticks in the fifth week of application. The use of Baubassil(r) would be a valid alternative for controlling the cattle tick under the agroecological conditions of the Dry Caribbean. PMID- 29402490 TI - In the Setting of Negative Mammogram, Is Additional Breast Ultrasound Necessary for Evaluation of Breast Pain? AB - PURPOSE: To evaluate whether in the setting of negative diagnostic mammogram for breast pain additional ultrasound is necessary. METHODS: Retrospective IRB approved review of our database identified 8085 women who underwent ultrasound evaluation for breast pain from 1/1/2013-12/31/2013. Of 8085 women, 559 women had mammogram evaluation preceding the ultrasound and these women comprise the basis of this study. The patient's age, type of mammogram examination (screening or diagnostic), Breast Imaging-Reporting and Data System (BI-RADS) breast density (BD), type of breast pain (focal, diffuse, cyclical, unilateral, bilateral), additional breast symptoms (palpable concern, nipple discharge, skin changes, others), mammogram or ultrasound findings and final BI-RADS assessment, follow-up imaging, and follow-up biopsy results were reviewed and recorded. RESULTS: The median age of patients was 46 years old (range: 27-97). Patients recalled from negative screening mammogram were 29.8% (167/559). Patients with preceding negative diagnostic mammogram were 70.2% (392/559). The BI-RADS BD distribution was BD1: 5.5%, BD2: 39.9%, BD3: 46.0%, BD4: 8.6%. Final BI-RADS assessments were BI-RADS 1/2 (79%), BI-RADS 3 (12.9%), BI-RADS 4 (8.1%), BI-RADS 5 (0%). Majority (66.9%, 374/559) of the patient had breast pain alone. Additional breast symptoms were also noted as follows: palpable concern (24%), nipple discharge (3.9%), skin changes or other (5.2%). On follow-up evaluation, 26 findings were recommended for tissue sampling yielding 2 malignancies (0.4%, 2/559) in 2 patients. In the setting of negative mammogram and clinical symptom of breast pain alone yielded no malignances (NPV, 100%, 374/374) and was not impacted by BD. In patients with additional symptoms accompanying pain, malignancies were present despite negative mammogram in 2 patients; nipple discharge (4.5%, 1/22), and palpable concern (0.7%, 1/134). CONCLUSION: In the setting of negative mammogram and breast pain alone, additional evaluation with ultrasound is likely low yield and may be unnecessary. However, with additional symptoms such as palpable concern or nipple discharge, ultrasound is likely an important adjunct modality for identifying mammographically occult tumors. PMID- 29402491 TI - WASP (Write a Scientific Paper): Understanding research metrics. AB - Research metrics are quantitative measurements that identify and acknowledge research output while enhancing article, author and journal impact within the academic community. The article impact depends on the number of times that same article is cited by other authors, while an author's impact depends on the number of citations received on the total number of published articles by the same author. With the advancement in technology and the increased availability of open access journals, article-level metrics has become a popular metric. This is the aggregation of the traditional article citations and the article online presence through blogs, tweets and newspapers, which further enhances the author's impact within the academic community. A journal's impact will depend on the average number of citations received by the articles published within the journal over a period of time. The academic reputation within the academic community will therefore depend on both article and author metrics and is further enhanced by publishing in high impact journals. PMID- 29402492 TI - Agrobacterium bohemicum sp. nov. isolated from poppy seed wastes in central Bohemia. AB - Two non-pathogenic strains R89-1 and R90T isolated from poppy seed (Papaver somniferum L.) wastes were phenotypically and genotypically characterized. Multilocus sequence analysis (MLSA) was conducted with six genes (atpD, glnA, gyrB, recA, rpoB, 16S rRNA). The strains represented a new species which clustered with Agrobacterium rubi NBRC 13261T and Agrobacterium skierniewicense Ch11T type strains. MLSA was further accompanied by whole-genome phylogeny, in silico DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) analyses for both strains. ANI and dDDH values were deep below the species delineation threshold. Phenotypic features of the novel strains unequivocally allowed their differentiation from all other Agrobacterium species. Unlike other agrobacteria, the strains were salt sensitive and were able to biotransform morphine alkaloids. The dominant cellular fatty acids are 18:1 w7c, 16:0 and 12:0 aldehyde/16:1 iso I/14:0 3OH summed in feature 2 and the major respiratory quinine is Q-10 (87%). The DNA G+C content is 56mol%. Microbial community analysis indicated probable association with P. somniferum plant material. Altogether, these characteristics showed that strains R90T and R89-1 represent a new species of the genus Agrobacterium which we propose to name Agrobacterium bohemicum. The type strain of A. bohemicum is R90T (=CCM 8736T=DSM 104667T). PMID- 29402493 TI - A rare case of post cesarean duodenal perforation diagnosed by laparoscopy. PMID- 29402494 TI - Activation of bombesin receptor Subtype-3 by [D-Tyr6,beta Ala11,Phe13,Nle14]bombesin6-14 increased glucose uptake and lipogenesis in human and rat adipocytes. AB - BRS-3 has an important role in glucose homeostasis. Its expression was reduced in skeletal muscle from obese and/or diabetic patients, and BRS-3 KO-mice developed obesity. In this work, focused on rat/human adipose tissue, BRS-3 gene-expression was lower than normal-levels in hyperlipidemic, type-2-diabetic (T2D), and type-1 diabetic rats and also in obese (OB) and T2D patients. Moreover, BRS-3 protein levels were decreased in diabetic rat and in obese and diabetic human fat pieces; but neither mutation nor even polymorphism in the BRS-3-gene was found in OB or T2D patients. Interestingly, in rat and human adipocytes, without metabolic alterations, [D-Tyr6,beta-Ala11,Phe13,Nle14]bombesin6-14 -BRS-3-agonist-, as insulin, enhanced BRS-3 gene/protein expression, increased, PKB, p70s6K, MAPKs and p90RSK1 phosphorylation-levels, and induced a concentration-related stimulation of glucose transport, GLUT-4 membrane translocation and lipogenesis, exclusively mediated by BRS-3, and abolished by wortmannin, PD98059 or rapamacyn. These results confirm that BRS-3 and/or its agonist are a potential therapeutic tool for obesity/diabetes. PMID- 29402496 TI - Comment on "One-year outcomes of the treat-and-extend approach with aflibercept in age-related macular degeneration: Effects on typical choroidal neovascularization and retinal angiomatous proliferation". PMID- 29402495 TI - Effect of inhaled medication on dental caries index in asthmatic children. AB - INTRODUCTION: Asthma is a chronic inflammatory disease of airways with a high prevalence among children in pre-school ages. Considering controversial results in different studies about the effect of this disease on the indices of dental caries, the aim of this study was to compare dmft (decay, missing, filling teeth) situation in asthmatic and non-asthmatic 6-12-year-old children. METHODS: This was a case-control study on 46 asthmatic and 47 non-asthmatic children aged 6-12 years. In asthmatic children, the severity of disease, type and dose of the administered inhalational drug, duration of drug consumption, times and technique of drug administration, and washing the mouth after drug consumption was assessed. The index of primary teeth decay or dmft, dental plaque and gingival inflammation were recorded in both groups. Data were analysed by SPSS (ver. 22) using Student's T-test, chi-square test and linear regression. FINDINGS: dmft in case and control groups was 5.25+/-2.25 and 4.15+/-3.27, respectively and the difference was not statistically significant (P=0.062). None of the variables related to asthma affected dmft (P>0.05). CONCLUSION: Suffering from asthma does not affect the risk of decay in primary teeth. PMID- 29402497 TI - Diagnosis of ocular toxocariasis by detecting antibodies in the vitreous humor. AB - OBJECTIVES: To demonstrate the production of the local toxocara antibodies in the vitreous of patients with negative serology. MATERIAL AND METHODS: Retrospective review of the medical records of patients seen in a Tertiary Referral Hospital, and at an Eye Institute, with an ocular diagnosis of toxocariasis who had a negative serology and positive titres in the vitreous. RESULTS: After reviewing the medical records of 40 patients with a diagnosis of ocular toxocariasis, a total of six cases (15%) were found with a negative serology and a positive vitreous titre for toxocara antibody, both of them performed using an ELISA procedure. The mean age was 18 years, there were no differences observed between males and females. A peripheral granuloma was the most common clinic finding, and all patients underwent vitrectomy either to remove epiretinal membranes or to repair retinal detachments. CONCLUSION: A negative serology does not rule out a diagnosis of ocular toxocariasis. Vitreous samples may be necessary to confirm a clinical diagnosis. PMID- 29402498 TI - Ocriplasmin retinopathy: Possible cause of macular hole closure failure. AB - CASE REPORT: A 53 year-old woman with a stage 2 macular hole received ocriplasmin injection as a first approach. She subsequently underwent pars plana vitrectomy due to enlargement of the hole post-injection. The visual gain following the surgery was minimal despite closure of the hole. This could be explained by outer retina atrophy as a consequence of potential toxic mechanisms related to ocriplasmin. DISCUSSION: Further studies may be warranted to fully understand the impact of ocriplasmin on long-term visual function. PMID- 29402499 TI - Editorial overview: Neurobiology of disease (2018). PMID- 29402500 TI - Increasing genetic counseling referral rates through bundled interventions after ovarian cancer diagnosis. AB - OBJECTIVE: To increase genetic counseling referrals for patients with newly diagnosed epithelial ovarian cancer (EOC). METHODS: A practice-gap analysis was performed after measuring baseline genetic counseling referral rates to identify barriers to referral from the multidisciplinary single institution EOC care group. A Genetics Referral Toolkit consisting of a referral template, a genetic risk checklist, family history worksheet and provider and patient awareness was developed to address identified gaps with the goal of increasing referral rates. Clinical characteristics, referral placement, completion of genetic counseling/testing were abstracted for a historic cohort and intervention cohort. Data for the two cohorts were compared using chi-square, Fisher's exact test, or t-test. Association with referral was determined by univariate logistic regression. RESULTS: Eighty one patients from July through December 2013 (historic cohort) and 62 patients from July through December 2015 (intervention cohort) were identified as having a new diagnosis of EOC. Among these women, genetic counseling referral rates increased from 48.1% (39/81) in 2013 to 74.2% (46/62) in 2015 (p=0.002) after implementation of the toolkit. In a subset of patients without a previous genetic counseling referral, 87.9% (29/33) completed counseling and 79.3% (23/29) pursued testing from the historic cohort. In the intervention cohort, 60% (24/40) were seen for counseling and 100% (24/24) had testing. CONCLUSION: Application of a quality improvement process to create a Genetics Referral Toolkit increased the genetic counseling referral rate in patients with a new diagnosis of EOC. The majority of patients who were referred completed genetics consultation and elected genetic testing. PMID- 29402501 TI - HOXA4/HOXB3 gene expression signature as a biomarker of recurrence in patients with high-grade serous ovarian cancer following primary cytoreductive surgery and first-line adjuvant chemotherapy. AB - OBJECTIVES: Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear. METHODS: HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples (n=71). A prognostic model for PFS was developed using univariate and multivariate Cox regression. Patients were stratified into risk groups that optimized the test statistic. The model was tested in an independent HGSOC cohort from The Cancer Genome Atlas (TCGA) (n=320). The effect of selected HOX genes on drug sensitivity and reactive oxygen species (ROS) accumulation was examined in vitro. RESULTS: Of 23 HOX genes tested in the training cohort, HOXA4 (HR=1.20, 95% CI=1.07-1.34, P=0.002) and HOXB3 (HR=1.09, 95% CI=1.01-1.17, P=0.027) overexpression were significantly associated with shorter PFS in multivariate analysis. Based on the optimal cutoff of the HOXA4/HOXB3 risk score, median PFS was 16.9months (95% CI=14.6-21.2months) and not reached (>80months) for patients with high and low risk scores, respectively (HR=8.89, 95% CI=2.09-37.74, P<0.001). In TCGA, the HOXA4/HOXB3 risk score was significantly associated with disease-free survival (HR=1.44, 95% CI=1.00-2.09, P=0.048). HOXA4 or HOXB3 overexpression in ovarian cancer cells decreased sensitivity to cisplatin and attenuated the generation of cisplatin-induced ROS (P<0.05). CONCLUSIONS: HOXA4/HOXB3 gene expression-based risk score may be useful for prognostic risk stratification and warrants prospective validation in HGSOC patients. PMID- 29402502 TI - Influence of zinc supplementation on immune parameters in weaned pigs. AB - Zinc is an essential trace element, highly important for a well functioning immune system. In case of zinc deficiency, proper immune functions are not ensured thus leading to various diseases. Weaning of pigs from the sow causes stress, increasing susceptibility to infections. Moreover, low feed intake during the first two weeks post-weaning, accompanied by low zinc intake, results in temporary zinc deficiency. Therefore, supporting the immune system by zinc supplementation might improve its function and thereby the pigs' health and well being. In this study, the immune status of weaned pigs was analyzed under different conditions of zinc supplementation. More precisely, the daily porcine diet was either left unsupplemented (0 ppm), or was supplemented with low (100 ppm), or high (2500 ppm) amounts of additional zinc in the form of zinc oxide (ZnO) (Zn0, Zn100, and Zn2500, respectively). Porcine innate and adaptive immune cells of the different dietary groups were analyzed. Results revealed an improved innate immune capacity, represented by increased phagocytosis and slightly increased oxidative burst in cells from the Zn2500 pigs and Zn100 pigs, respectively. Apart from that, zinc supplementation improved adaptive immunity, as seen by increased numbers of CD3+ T cells as well as increased numbers of CD3+CD4+Foxp3+ regulatory T cells, elevated interleukin (IL)-2 production and decreased IL-10 production. Although not significant, supplementing 2500 ppm zinc slightly decreased killing activity of natural killer (NK) cells. Thus, the optimal concentration for zinc supplementation of weaned pigs two weeks post weaning needs to be further studied, presumably establishing an optimal concentration between 100 ppm and 2500 ppm zinc. Genome comparisons indicate that the porcine genome is more closely related to the human genome than the murine genome is related to the human genome. Therefore, the pig seems to be a suitable organism to study human immunity and diseases. Results obtained in the current study might therefore be transferable to the human immune system. PMID- 29402503 TI - Environmental training is beneficial to clinical symptoms and cortical presynaptic defects in mice suffering from experimental autoimmune encephalomyelitis. AB - The effect of "prophylactic" environmental stimulation on clinical symptoms and presynaptic defects in mice suffering from the experimental autoimmune encephalomyelitis (EAE) at the acute stage of disease (21 +/- 1 days post immunization, d.p.i.) was investigated. In EAE mice raised in an enriched environment (EE), the clinical score was reduced when compared to EAE mice raised in standard environment (SE).Concomitantly, gain of weight and increased spontaneous motor activity and curiosity were observed, suggesting increased well being in mice. Impaired glutamate exocytosis and cyclic adenosine monophosphate (cAMP) production in cortical terminals of SE-EAE mice were evident at 21 +/- 1 d.p.i.. Differently, the 12 mM KCl-evoked glutamate exocytosis from cortical synaptosomes of EE-EAE mice was comparable to that observed in SE and EE-control mice, but significantly higher than that in SE-EAE mice. Similarly, the 12 mM KCl evoked cAMP production in EE-EAE mice cortical synaptosomes recovered to the level observed in SE and EE-control mice. MUNC-18 and SNAP25 contents, but not Syntaxin-1a and Synaptotagmin 1 levels, were increased in cortical synaptosomes from EE-EAE mice when compared to SE-EAE mice. Circulating IL-1beta was increased in the spinal cord, but not in the cortex, of SE-EAE mice, and it did not recover in EE-EAE mice. Inflammatory infiltrates were reduced in the cortex but not in the spinal cord of EE-EAE mice. Demyelination was observed in the spinal cord; EE significantly diminished it. We conclude that "prophylactic" EE is beneficial to synaptic derangements and preserves glutamate transmission in the cortex of EAE mice. PMID- 29402504 TI - Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. AB - Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson' disease. Novel dual GLP-1/GIP receptor agonists have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the blood -brain barrier. They show clear neuroprotective effects by reducing inflammation and oxidative stress and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, dopaminergic neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29402505 TI - Morphologic Analysis of the Normal Right Ventricle Using Three-Dimensional Echocardiography-Derived Curvature Indices. AB - BACKGROUND: Right ventricular (RV) remodeling involves changes in size, wall thickness, function, and shape. Previous studies have suggested that regional curvature indices (rCI) may be useful for RV shape analysis. The aim of this study was to establish normal three-dimensional echocardiographic values of rCI in a large group of healthy subjects to facilitate future three-dimensional echocardiographic study of adverse RV remodeling. METHODS: RV endocardial surfaces were reconstructed at end-diastole and end-systole in 245 healthy subjects (mean age, 42 +/- 12 years) and analyzed using custom software to calculate mean curvature in six regions: RV inflow tract (RVIT) and RV outflow tract, apex, and body (both divided into free wall and septal regions). Associations with age and gender were studied. RESULTS: The apical free wall was convex, while the septum (apex and body) was more concave than the body free wall. Septal curvature did not change significantly from end-diastole to end systole. The RV outflow tract and RVIT became flatter from end-diastole to end systole. In keeping with the "bellows-like" action of RV contraction, the body free wall became flatter, while the apex free wall changed to a more convex surface. There were no intergender differences in rCI. In older subjects (>=55 years of age), the RV free wall and RV outflow tract were flatter, and from end diastole to end-systole, the RVIT became less flattened and the apex less pointed. These changes suggest that the right ventricle is stiffer in older subjects, with less dynamic contraction of the RVIT and less bellows-like movement. CONCLUSIONS: This study established normal three-dimensional echocardiographic values for RV rCI, which are needed to further study RV diastolic dysfunction and remodeling with disease. PMID- 29402507 TI - Pulmonary nodules and immunotherapy: disease progression or toxicity of anti PD1/anti-PDL1 checkpoint inhibitors? PMID- 29402506 TI - Unidimensional Longitudinal Strain: A Simple Approach for the Assessment of Longitudinal Myocardial Deformation by Echocardiography. AB - BACKGROUND: Impaired left ventricular (LV) longitudinal function (LF) is a known predictor of cardiac events in patients with heart failure, but two-dimensional strain imaging, the reference method to measure myocardial deformation, is not always feasible or available. Therefore, reliable and reproducible alternatives are needed. The aim of the present study was to evaluate unidimensional longitudinal strain (ULS) as a simple echocardiographic parameter for the assessment of LV LF. METHODS: Two hundred two patients with dilated cardiomyopathy who had their first presentation in the authors' cardiology department, as well as the same number of age- and gender-matched control subjects, were prospectively included in this study. ULS was compared with global longitudinal strain (GLS), the current gold standard for LV LF assessment by echocardiography. Uni- and multivariate Cox regression analyses were conducted to evaluate the prognostic value of ULS. RESULTS: LV LF was higher in the control group compared with patients: GLS -19.5 +/- 1.7% versus -12.6 +/- 4.8% and ULS 16.3 +/- 1.5% versus -10.2 +/- 3.9% (P < .001 for each). Correlation between ULS and GLS was excellent (r = 0.94), while Bland-Altman plots revealed lower values for ULS (bias -2.76%, limits of agreement +/-3.31%). During a mean follow-up time of 39 months, the combined end point of cardiovascular death or hospitalization for acute cardiac decompensation was reached by 28 patients (13.9%). GLS (hazard ratio, 1.21; 95% CI, 1.10-1.34; P < .001) and ULS (hazard ratio, 1.24; 95% CI, 1.12-1.39; P < .001) had comparable prognostic impact on patient outcomes. CONCLUSIONS: ULS might be an alternative echocardiographic method for the assessment of LV LF, with similar diagnostic and prognostic value compared with GLS. PMID- 29402508 TI - Recurrent and persistent pneumonia. PMID- 29402509 TI - Effects of aerobic or resistance exercise training on cardiovascular autonomic function of subjects with type 2 diabetes: A pilot study. AB - BACKGROUND AND AIMS: Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects. METHODS AND RESULTS: Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences. CONCLUSION: Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out. CLINICAL TRIAL REGISTRATION NUMBER: NCT01182948, clinicaltrials.gov. PMID- 29402510 TI - Pleural manometry in patients with pleural diseases - the usefulness in clinical practice. AB - Although pleural manometry is a relatively simple medical procedure it is only occasionally used to follow pleural pressure (Ppl) changes during a therapeutic thoracentesis and pneumothorax drainage. As some studies showed that pleural pressure monitoring might be associated with significant advantages, pleural manometry has been increasingly evaluated in the last decade. The major clinical applications of pleural pressure measurements include: the prevention of complications associated with large volume thoracentesis, diagnosis and differentiation between various types of an unexpandable lung and a possible prediction of the efficacy of chest tube drainage in patients with spontaneous pneumothorax. It is well known that the therapeutic thoracentesis might be complicated by cough, chest discomfort, and rarely, by a life threatening condition called reexpansion pulmonary edema (RPE). The serious adverse events of thoracentesis are related to pleural pressure drop rather than to the volume of removed pleural effusion. The use of pleural manometry during pleural fluid withdrawal enables the evaluation of the relationship between withdrawn pleural fluid volume, pleural pressure changes and procedure related complications. Pleural pressure measurement is also an important tool to study the different mechanism of pneumothorax complicating the thoracentesis. Pleural manometry is critical for measurement of pleural elastance, diagnosis of an unexpandable lung and differentiation between trapped lung and lung entrapment. This usually has significant clinical implications in terms of further management of patients with pleural effusion. The paper is a comprehensive review presenting different aspects of pleural pressure measurement in clinical practice. PMID- 29402511 TI - Cross-cultural Adaption and Validation of the Danish Voice Handicap Index. AB - OBJECTIVES: We aimed to assess psychometric properties, including internal consistency, reliability, and clinical validity of the Danish version of the Voice Handicap Index (VHI). STUDY DESIGN: A cross-sectional survey study was carried out. METHODS: For validation, the existing nonvalidated Danish version of the VHI was used. Data from 208 patients with voice disorders of different etiology (neurogenic, functional, and structural) and a control group of 85 vocally healthy individuals were included. A test-retest reliability analysis of 42 patients and 45 control persons was performed. The internal consistency, test retest reliability, and clinical validity of the questionnaire were assessed. RESULTS: Internal consistency was high with a Cronbach alpha >0.90 for both the patient and control group. Test-retest reliability measured as intraclass correlation coefficient was good with 0.93 (95% confidence interval [95% confidence interval]: 0.87-0.96) for patients and 0.78 (95% confidence interval: 0.63-0.87) for the control group which indicates sufficient reliability of the questionnaire. The Danish VHI has good clinical validity as it has a strong correlation between patient's perception of the severity of their voice disorder and the VHI score from the Spearman correlation of 0.69. CONCLUSION: The existing Danish version of the VHI has been thoroughly validated and found to be in line with the original VHI from Jacobsen et al. It showed good internal consistency, test-retest reliability, and clinical validity. It is suitable for use in daily practice and in research projects as it is able to assess patients' perception of their voice disorder severity. PMID- 29402512 TI - Paradoxical insomnia and subjective-objective sleep discrepancy: A review. AB - Paradoxical insomnia is characterized by discrepancy between subjective and objective assessments of sleep and is challenging to diagnosis and treat. Typically, polysomnographic (PSG) findings show significantly longer total sleep time than patients' report of sleep, and the difference between subjective and PSG sleep is greater than that seen in other insomnia subtypes. Subjective objective sleep discrepancy may also present in different clinical pictures, as marked discrepancies between patients' perception of sleep and objective findings are common in a variety of medical, sleep and psychiatric disorders. However, there is a paucity of literature about the etiology and treatment of sleep discrepancy and paradoxical insomnia. Therefore, the underlying neurophysiological mechanisms of sleep discrepancy and paradoxical insomnia should be further investigated. Additionally, well-controlled clinical trials are needed to establish an evidence based intervention for treatment. PMID- 29402513 TI - Does platelet-rich fibrin have a role in osseointegration of immediate implants? A randomized, single-blind, controlled clinical trial. AB - Immediate implants are a valuable treatment option to replace natural teeth in the aesthetic region. The hypothesis of this randomized controlled clinical trial was that immediate implants grafted with autologous platelet-rich fibrin (PRF) have better clinical and radiographic outcomes than non-grafted controls. Forty one implants were placed in 31 subjects with one or more non-restorable single rooted teeth. Autologous PRF was placed in the peri-implant region of the study group (n=21) and no augmentation was done in the control group (n=20). A staged protocol was followed for implant restoration. The patients received a definitive restoration after 3 months and were followed up for a period of 1year. The statistical analysis included 39 implants sites in 29 subjects. A significant increase in implant stability was noted in both groups over the 3-month period (implant stability quotient: study group 56.58+/-18.81 to 71.32+/-7.82; control group 60.61+/-11.49 to 70.06+/-8.96; P=0.01). No significant difference was observed between the groups in terms of implant stability. The hypothesis was thus rejected, as there was no significant effect of PRF on immediate implants with adequate primary stability. PMID- 29402514 TI - Dynamic analysis of maxillary perfusion during Le Fort I osteotomy using indocyanine green. AB - The aim of this study was to evaluate the dynamic perfusion of the maxilla during various stages of a Le Fort I osteotomy using indocyanine green (ICG) dye angiography. This was a retrospective evaluation of patients who underwent a Le Fort I osteotomy. ICG was used to assess perfusion at specific time points during the procedure. Twenty-four patients underwent a Le Fort I osteotomy with dynamic perfusion ICG angiography. Statistically significant differences in perfusion were noted at all three locations assessed between preoperative (T0), post down fracture (T1), and postoperative (T2) time points. When controlling for mean arterial pressure, statistically significant differences were noted at all three locations assessed between T0 and T1, and between T0 and T2. There were no statistically significant differences in patient age, heart rate, preservation or sacrifice of the descending palatine arteries, or conventional vs. segmental Le Fort I osteotomies across T0, T1, and T2. In conclusion, there was a statistically significant decrease in perfusion, as assessed by intraoperative dynamic angiography, to the anterior maxilla following maxillary down-fracture. Patient age, conventional vs. segmental Le Fort I osteotomy, changes in mean arterial pressure and/or heart rate, and preservation of the descending palatine vessels had no statistically significant effect on perfusion. PMID- 29402515 TI - Standard morphology of the oral commissure and changes resulting from reconstruction for defects involving the commissure. AB - The aim of this study was to characterize the standard morphology of the oral commissure and to describe the changes after reconstruction in patients with through-and-through cheek defects involving the oral commissure. Indices for the morphological analyses of the commissure were derived from examinations of 50 normal Japanese volunteers. Ten patients with full-thickness cheek defects involving the commissure were then evaluated. All of these patients underwent free flap reconstruction with vermilion advancement flaps from the remaining vermilion. The morphology of the commissure with the mouth closed was classified based on the point of entrance of the vermilion into the oral cavity. In normal volunteers, the commissure pattern consisting of the entrance of the upper vermilion into the oral cavity before the lower vermilion and just prior to forming the oral commissure was considered to be the standard. However, in the reconstructed cases, there was an increase in the pattern in which the lower vermilion enters the oral cavity before the upper vermilion for the remaining commissure postoperatively, especially when the lower lip defects were greater than those of the upper lip. It is important to refer not only to the standard morphology of the commissure, but also to the changes according to the extent of resection and the method of reconstruction. PMID- 29402516 TI - Factors influencing nursing students' intention to comply with infection control practices. AB - The purpose of this study was to examine how nursing students' intention to comply with infection control practices (ICPs) is affected by their awareness of ICPs and by their observations of staff nurses' noncompliance with ICPs. The subjects were 350 nursing students from 8 universities in Korea. Hierarchical multiple linear regression analysis was used to determine the predictive factors of compliance intention with ICPs. We found that nursing students' awareness of ICPs was the most significant influencing factor affecting their compliance with ICPs. Students' observation of staff nurses' noncompliance with ICPs was the second most significant influencing factor. PMID- 29402517 TI - Protection alone may not promote natural recovery of biogenic habitats of high biodiversity damaged by mobile fishing gears. AB - The horse mussel Modiolus modiolus (L.) is a large marine bivalve that aggregates to create complex habitats of high biodiversity. As a keystone species, M. modiolus is of great importance for the functioning of marine benthic ecosystems, forming biogenic habitats used to designate Marine Protected Areas (MPAs). The present study investigates the condition of M. modiolus beds historically subjected to intense scallop fishing using mobile fishing gears. The study, conducted seven years after the introduction of legislation banning all forms of fishing, aimed to establish whether natural habitat recovery occurs after protection measures are put in place. Lower biodiversity and up to 80% decline in densities of M. modiolus were recorded across the current distributional range of the species in Strangford Lough, Northern Ireland. The decline in biodiversity in most areas surveyed was consistent with that observed in biogenic reefs impacted by mobile fishing gears elsewhere. Epifauna, including sponges, hydroids and tunicates, experienced the most substantial decline in biodiversity, with up to 64% fewer taxa recorded in 2010 compared with 2003. Higher variability in community composition and a shift towards faunal assemblages dominated by opportunistic infaunal species typical of softer substrata were also detected. Based on these observations we suggest that, for biogenic habitats, the designation of MPAs and the introduction of fishing bans alone may not be sufficient to reverse or halt the negative effects caused by past anthropogenic impacts. Direct intervention, including habitat restoration based on translocation of native keystone species, should be considered as part of management strategies for MPAs which host similar biogenic reef habitats where condition and natural recovery have been compromised. PMID- 29402518 TI - Effects of the toxic benthic dinoflagellate Ostreopsis cf. ovata on fertilization and early development of the sea urchin Lytechinus variegatus. AB - Blooms of the benthic dinoflagellate Ostreopsis cf. ovata have been recorded with increasing frequency, intensity and geographic distribution. This dinoflagellate produces potent toxins that may cause mortality of marine invertebrates. Adults of sea urchins are commonly affected by O. cf. ovata exposure with evidence of spines loss and high mortality during periods of high dinoflagellate abundances. Here, we report on the effects of the toxic dinoflagellate O. cf. ovata on fertilization and early development of the sea urchin Lytechinus variegatus, a key ecological herbivore. Lytechinus variegatus eggs and sperm were experimentally exposed to different concentrations of Ostreopsis cf. ovata (4, 40, 400, and 4000 cells ml-1) to test the hypothesis that fertilization success, embryonic and larval development of the sea urchin are negatively affected by the toxic dinoflagellate even at low abundances. Reduced fertilization, developmental failures, embryo and larval mortality, and occurrence of abnormal offspring were evident after exposure to O. cf. ovata. Fertilization decreased when gametes were exposed to high O. cf. ovata abundances (400 and 4000 cells ml-1), but just the exposure to the highest abundance significantly reduced fertilization success. Sea urchin early development was affected by O. cf. ovata in a dose-dependent way, high dinoflagellate abundances fully inhibited the early development of L. variegatus. Ostreopsis cf. ovata significantly increased the mortality of sea urchin eggs and embryos in the first hours of exposure (~1-3 h), regardless of dinoflagellate abundance. Abundances of 400 and 4000 O. cf. ovata cells ml-1 induced significantly higher mortality on sea urchin initial stages in the first hours, and no egg or embryo was found in these treatments after 18 h of incubation. The early echinopluteus larva was only reached in the control and in treatments with low Ostreopsis cf. ovata abundances (4 and 40 cells ml-1). The exposure to O. cf. ovata led to significantly higher occurrence of skeletal anomalies in the early larva of L. variegatus. Interactions of sea urchin gametes and Ostreopsis cells may naturally occur in coastal areas due to the match between O. cf. ovata blooms and L. variegatus reproductive period. Reduced larval density and increased larval abnormalities were observed even at low abundances (4 and 40 cells ml-1) frequently found in tropical environments all year round. The chronic exposure to O. cf. ovata could significantly impact larval fitness, thus compromising recruitment success, and highlight the negative effects of benthic HABs on sea urchin populations and its possible broader ecological implications. PMID- 29402519 TI - Metal interactions between the polychaete Branchipolynoe seepensis and the mussel Bathymodiolus azoricus from Mid-Atlantic-Ridge hydrothermal vent fields. AB - The vent blood-red commensal polynoid polychaete Branchipolynoe seepensis is commonly found in the pallial cavity of the vent mussel Bathymodiolus azoricus, the dominant bivalve species along the Mid-Atlantic-Ridge (MAR) and is known to be kleptoparasitic. Mussels were collected from three hydrothermal vent fields in the MAR: Menez Gwen (850 m depth, MG2, MG3 and MG4), Lucky Strike (1700 m depth, Montsegur-MS and Eiffel Tower-ET) and Rainbow (2300 m depth). Polychaetes were absent in all Menez Gwen vent mussels, while the highest percentage was detected in mussels from Lucky Strike, where more than 70% of the mussels had at least one polychaete in their mantle cavity, followed by Rainbow with 33% of mussels with polychaetes. Total metal concentrations (Ag, Cd, Co, Cu, Fe, Mn, Ni and Zn) were determined in polychaetes whole body and in the mussel tissues (gills, digestive gland and mantle). To understand the possible metal interactions between symbiont and host, the activity of antioxidant defence (catalase (CAT), metallothioneins (MTs)), biotransformation enzymes (glutathione-s-transferases (GST)) activities and lipid peroxidation (LPO) were determined in polychaete whole soft tissues and in mussel tissues (gills, digestive gland and mantle). Metal concentrations in polychaetes and mussels tissues indicated that the accumulation patterns were species specific and also influenced by, and possibly dependent upon, the inter- and intra-variation of vent physico-chemistry between hydrothermal fields. Despite not detecting any strong correlations between metal and enzymes activities in polychaetes and mussels, when in presence of polychaetes, mussels presented less metal concentrations in the gills and digestive gland and lower activity of enzymatic biomarkers. This leads to infer that the polychaete plays a role on the detoxification process, and the interaction between the polychaete mussel association is probably an adaptation to metals concentrations at the vent sites. PMID- 29402520 TI - Diel and seasonal changes in the spatial behaviour of a soft-sediment fish (Solea senegalensis) inside a marine reserve. AB - The protection provided by marine reserves directly depends on the short and long term movement patterns of local organisms. Although there has been an increase in research assessing the behavioural patterns of fishes in reef-based habitats, there is still a paucity of studies addressing the benefits of marine protected areas (MPAs) for soft-sediment species. Here, we investigated both diel and seasonal shifts in spatial behaviour of the Senegalese sole, Solea senegalensis, within a recently-established marine reserve using long-term passive acoustic telemetry. Results showed variable levels of site attachment, with nearly half of the fish (n = 8) disappearing from the monitored area within 30 days, and the remaining (n = 9) being detected for periods up to 293 days and spending 95% of their time within an average area of 0.88 +/- 0.46 km2. Although detection frequency was higher during daytime periods, the larger home range areas and greater movement observed during nighttime periods are consistent with a nocturnal activity regime, which might increase the vulnerability of S. senegalensis to illegal fishing. Additionally, patterns observed during the spawning season suggest the existence of shifts in habitat use linked with reproductive activity, opening the door to further research on soles' fine-scale interaction dynamics. Overall, this study provides novel insights into the ecology of a flatfish species and suggests that small no-take areas encompassing suitable soft-sediment habitats can offer adequate protection to at least part of the Senegalese sole population. PMID- 29402521 TI - Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglutamate Pharmacokinetics, Adalimumab Pharmacokinetics, and Efficacy: Pharmacokinetic and Exposure-response Analysis of the CONCERTO Trial. AB - PURPOSE: Methotrexate (MTX) and adalimumab are well-recognized treatments of rheumatoid arthritis (RA), the efficacy of which may be driven by intracellular polyglutamates (PGs). The aim of this analysis was to characterize MTX PG concentrations and adalimumab pharmacokinetics in the CONCERTO trial. In addition, the relationships between MTX dose/pharmacokinetics, adalimumab pharmacokinetics, and efficacy were evaluated. METHODS: CONCERTO was a double blind, parallel-arm study in patients with early RA randomized to adalimumab 40 mg SC every other week plus blinded MTX 2.5, 5, 10, or 20 mg PO once weekly, for 26 weeks. Blood samples were obtained through week 26 for the determination of concentrations of MTX PG, adalimumab, and anti-adalimumab antibody (AAA). Clinical outcomes were also assessed. FINDINGS: A total of 395 patients were included in the analysis (MTX, 329; adalimumab, 395). The mean time to steady state MTX PG concentration was increased with MTX dose, from 8 to >26 weeks, depending on PG chain length. Dose proportionality changed with PG chain length. As MTX dose was increased, the percentage of short-chain PGs increased less than dose proportionally, while the percentage of long-chain PGs increased more than dose proportionally. For very-long-chain PGs, dose proportionality could not be assessed due to the nonmeasurable concentrations in the 2.5- and 5-mg MTX dose groups. As MTX dose increased, mean adalimumab concentrations also increased (P < 0.001). The percentage of patients with AAA decreased with increasing MTX dose, and at week 26, AAA+ status was significantly correlated with MTX dose level (P = 0.005). In general, rates of response, defined using the 28-joint count disease activity score based on C-reactive protein (DAS28[CRP]; response, <3.2), were greater in the subgroup without AAA. The likelihood of a patient achieving a DAS28(CRP) response was related to the baseline measurement (P < 0.001) and to the concentration of adalimumab (P = 0.001), but not to the MTX regimen (P = 0.689). IMPLICATIONS: The dose-response characteristics of MTX PG pharmacokinetics and the resultant effects of MTX on adalimumab exposures should be considered when determining the benefit-risk profile of MTX and adalimumab combination therapy in patients with early RA. ClinicalTrials.gov identifier: NCT01185301. PMID- 29402523 TI - Surgical indications or inclusion/exclusion criteria of explorative tympanotomy on sudden sensorineural hearing. PMID- 29402522 TI - A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial. AB - PURPOSE: Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia. METHODS: I-ROSETTE (Ildong ROSuvastatin & ezETimibe for hypercholesTElolemia) was an 8-week, double-blind, multicenter, Phase III randomized controlled trial conducted at 20 hospitals in the Republic of Korea. Patients with hypercholesterolemia who required medical treatment according to National Cholesterol Education Program Adult Treatment Panel III guidelines were eligible for participation in the study. Patients were randomly assigned to receive ezetimibe 10 mg/rosuvastatin 20 mg, ezetimibe 10 mg/rosuvastatin 10 mg, ezetimibe 10 mg/rosuvastatin 5 mg, rosuvastatin 20 mg, rosuvastatin 10 mg, or rosuvastatin 5 mg in a 1:1:1:1:1:1 ratio. The primary end point was the difference in the mean percent change from baseline in LDL-C level after 8 weeks of treatment between the ezetimibe/rosuvastatin and rosuvastatin treatment groups. All patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS: Of 396 patients, 389 with efficacy data were analyzed. Baseline characteristics among 6 groups were similar. After 8 weeks of double-blind treatment, the percent changes in adjusted mean LDL-C levels at week 8 compared with baseline values were -57.0% (2.1%) and -44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively (P < 0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. The mean percent change in LDL-C level in all ezetimibe/rosuvastatin combination groups was >50%. The number of patients who achieved target LDL-C levels at week 8 was significantly greater in the ezetimibe/rosuvastatin group (180 [92.3%] of 195 patients) than in the rosuvastatin monotherapy group (155 [79.9%] of 194 patients) (P < 0.001). There were no significant differences in the incidence of overall AEs, adverse drug reactions, and serious AEs; laboratory findings, including liver function test results and creatinine kinase levels, were comparable between groups. IMPLICATIONS: Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT02749994. PMID- 29402524 TI - Going beyond morphology in Ebstein's anomaly. PMID- 29402526 TI - The Yellow Scale Is Superior to the Gray Scale for Detecting Acute Ischemic Stroke on a Monitor Display in Computed Tomography. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare the efficacy of the color scale with regard to focal detection with computed tomography in acute ischemic stroke. MATERIALS AND METHODS: Computed tomography images of the brain of 19 patients diagnosed with acute stroke, based on magnetic resonance diffusion-weighted images obtained within an onset of 24 hours, and the images of five normal patients were displayed in each color look-up table on a monitor. The detection of acute stroke was compared among 15 radiologists. The images were compared in the gray, green, yellow, red, and blue scales of the look-up tables. The observers recorded acute ischemic stroke as "present" or "absent." They also located the position of the stroke lesion and described the degree of their conviction as to whether a lesion existed. Detection was evaluated by receiver operating characteristic analysis. The area under the receiver operating characteristic curves was compared. In addition, reduced fatigue and the ease in image observation were compared. RESULTS: Compared to the other scales, the yellow scale had a significantly higher area under the receiver operating characteristic curve, which indicated that this scale allowed better detection of acute ischemic stroke. The gray scale produced the least fatigue in image observation. CONCLUSIONS: The detection of acute ischemic stroke is improved by changing the display monitor from the gray scale to the yellow scale. From the perspective of color psychology, yellow is associated with higher arousal, cheerfulness, confidence, creativity, and excitement. Therefore, the yellow scale may be suitable for a medical imaging display. PMID- 29402525 TI - Atrio-ventricular deformation and heart failure in Ebstein's Anomaly - A cardiovascular magnetic resonance study. AB - PURPOSE: We aimed to quantify atrial and ventricular myocardial deformation in Ebstein's Anomaly (EA) in a case-control study with cardiovascular magnetic resonance (CMR) feature tracking and to correlate changes in cardiac performance with the severity of disease and clinical heart failure parameters. MATERIALS AND METHODS: Atrial and ventricular deformation was measured using CMR feature tracking in 30 EA and 20 healthy control subjects. Atrial performance was characterized using longitudinal strain and strain rate parameters for reservoir function, conduit function and booster pump function. Ventricular performance was characterized using RV and LV global longitudinal strain (epsilonl) and LV circumferential and radial strain (epsilonc and epsilonr). Volumetric measurements for the ventricles including the Total Right/Left-Volume-Index (R/L Volume-Index) and heart failure markers (BNP, NYHA class) were also quantified. RESULTS: EA patients showed significantly impaired right atrial performance, which correlated with heart failure markers (NYHA, BNP, R/L-Volume-Index). LA function in EA patients was also impaired with atrial contractile function correlating with NYHA class. EA patients exhibited impaired RV myocardial deformation, also with a significant correlation with heart failure markers. CONCLUSION: CMR feature tracking can be used to quantify ventricular and atrial function in a complex cardiac malformation such as EA. EA is characterized by impaired quantitative right heart atrio-ventricular deformation, which is associated with heart failure severity. While LV function remains preserved, there is also significant impairment of LA function. These quantitative performance parameters may represent early markers of cardiac deterioration of potential value in the clinical management of EA. PMID- 29402527 TI - Humidification of Blow-By Oxygen During Recovery of Postoperative Pediatric Patients: One Unit's Journey. AB - PURPOSE: To examine the practice of nebulizer cool mist blow-by oxygen administered to spontaneously breathing postanesthesia care unit (PACU) pediatric patients during Phase one recovery. DESIGN: Existing evidence was evaluated. Informal benchmarking documented practices in peer organizations. An in vitro study was then conducted to simulate clinical practice and determine depth and amount of airway humidity delivery with blow-by oxygen. METHODS: Informal benchmarking information was obtained by telephone interview. Using a three dimensional printed simulation model of the head connected to a breathing lung simulator, depth and amount of moisture delivery in the respiratory tree were measured. FINDINGS: Evidence specific to PACU administration of cool mist blow-by oxygen was limited. Informal benchmarking revealed that routine cool mist oxygenated blow-by administration was not widely practiced. The laboratory experiment revealed minimal moisture reaching the mid-tracheal area of the simulated airway model. CONCLUSIONS: Routine use of oxygenated cool mist in spontaneously breathing pediatric PACU patients is not supported. PMID- 29402528 TI - Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. AB - Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS)-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 MUM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity. PMID- 29402529 TI - Psychometric properties of neural responses to monetary and social rewards across development. AB - Reward-related event-related potentials (ERPs) are often used to index individual differences that signal the presence or predict the onset of psychopathology. However, relatively little research has explored the psychometric properties of reward-related ERPs. Without understanding their psychometric properties, the value of using ERPs as biomarkers for psychopathology is limited. The present study, therefore, sought to establish the internal consistency reliability and convergent validity of the reward positivity (RewP) and feedback negativity (FN) elicited by two types of incentives commonly used in individual differences research - monetary and social rewards. A large, developmentally-diverse sample completed a forced-choice guessing task in which they won or lost money, as well as a social interaction task in which they received acceptance and rejection feedback. Data were analyzed at both Cz and at a frontocentral region of interest (ROI) using techniques derived from classical test theory and generalizability theory. Results demonstrated good to excellent internal consistency of the RewP and FN within 20 trials in both tasks, in addition to convergent validity between the two tasks. Results from a regression-based approach to isolating activity specific to a single response demonstrated acceptable to good internal consistency within 20 trials in both tasks, while a subtraction-based approach (?RewP) did not achieve acceptable internal consistency in either task. Internal consistency was not moderated by age and did not differ between Cz and the frontocentral ROI; however, the magnitudes of the RewP and FN were significantly associated with age at Cz but not at the ROI. This work replicates previous studies demonstrating good psychometric properties of the monetary RewP/FN and provides novel information about the psychometric properties of the social RewP/FN. These data support the use of reward-related ERPs elicited by multiple reward types in studies of biomarkers of psychopathology. PMID- 29402530 TI - Subconcussive head impacts in sport: A systematic review of the evidence. AB - PURPOSE: To identify and evaluate the evidence that examines subconcussive impacts in sport-specific settings, and address two objectives: a) to determine how 'subconcussion' is characterized in the current literature, and b) to identify directions for future research. RESEARCH DESIGN: Systematic review. METHODS AND PROCEDURES: CINAHL, EMBASE, MedLine, PsycINFO, SportDiscus, and Web of Science were searched for articles that sought to assess subconcussive impacts or outcomes related to non-concussive head impact exposure. Eligible articles were reviewed and evaluated with three quality assessment tools by rotating pairs of reviewers. RESULTS: A total of 1966 articles were screened. Fifty-six studies met the inclusion criteria. Studies were classified into three main categories based on primary focus: neurobiological, neuropsychological, and impact exposure metrics. The neurobiological studies suggested that in male athletes, functional and microstructural deterioration was associated with repetitive head impacts. There was insufficient to weak evidence for the relationship between repetitive hits to the head and deterioration in neurocognitive performance. Studies of impact exposure metrics examined various indices, including linear acceleration, rotational acceleration, and location and frequency of hits. Insufficient evidence was presented to determine a minimal injury threshold for repetitive hits to the head. Across all categories of studies there was a lack of consistency and clarity in defining and measuring variables related to the concept of 'subconcussion'. CONCLUSIONS: Evidence reviewed predominantly from studies of male athletes in contact and collision sports identifies that repetitive hits to the head are associated with microstructural and functional changes in the brain. Whether these changes represent injury is unclear. We determined the term 'subconcussion' to be inconsistently used, poorly defined, and misleading. Future research is needed to characterize the phenomenon in question. PMID- 29402531 TI - Short-Term Preoperative Weight Loss and Postoperative Outcomes in Bariatric Surgery. AB - BACKGROUND: Preoperative weight loss is often encouraged before undergoing weight loss surgery. Controversy remains as to its effect on postoperative outcomes. The aim of this study was to determine what impact short-term preoperative excess weight loss (EWL) has on postoperative outcomes in patients undergoing primary vertical sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). STUDY DESIGN: All patients who underwent SG (n = 167) or RYGB (n = 188) between 2014 and 2016 and who completed our program-recommended low calorie diet (LCD) for 4 weeks immediately preceding surgery were included. These patients (N = 355) were then divided into 2 cohorts and analyzed according to those who achieved >=8% EWL (n = 224) during the 4-week LCD period and those who did not (n = 131). Primary endpoints included percent excess weight loss (% EWL) at 1, 3, 6, and 12 months postoperatively. RESULTS: Patients achieving >=8% EWL preoperatively experienced a greater % EWL at postoperative month 3 (42.3 +/- 13.2% vs 36.1 +/- 10.9%, p < 0.001), month 6 (56.0 +/- 18.1% vs 47.5 +/- 14.1%, p < 0.001), and month 12 (65.1 +/- 23.3% vs 55.7 +/- 22.2%, p = 0.003). Median operative duration (117 minutes vs 125 minutes; p = 0.061) and mean hospital length of stay (1.8 days vs 2.1 days; p = 0.006) were also less in patients achieving >=8% EWL. No significant differences in follow-up, readmission, or reoperation rates were seen. Linear regression analysis revealed that patients who achieved >=8% EWL during the 4 week LCD lost 7.5% more excess weight at postoperative month 12. CONCLUSIONS: Based on these data, preoperative weight loss of >=8% excess weight, while following a 4-week LCD, is associated with a significantly greater rate of postoperative EWL over 1 year, as well as shorter operative duration and hospital length of stay. PMID- 29402532 TI - Protecting Your Patients' Interests in the Era of Big Data, Artificial Intelligence, and Predictive Analytics. AB - The Hippocratic oath and the Belmont report articulate foundational principles for how physicians interact with patients and research subjects. The increasing use of big data and artificial intelligence techniques demands a re-examination of these principles in light of the potential issues surrounding privacy, confidentiality, data ownership, informed consent, epistemology, and inequities. Patients have strong opinions about these issues. Radiologists have a fiduciary responsibility to protect the interest of their patients. As such, the community of radiology leaders, ethicists, and informaticists must have a conversation about the appropriate way to deal with these issues and help lead the way in developing capabilities in the most just, ethical manner possible. PMID- 29402533 TI - Artificial Intelligence and Machine Learning in Radiology: Opportunities, Challenges, Pitfalls, and Criteria for Success. AB - Worldwide interest in artificial intelligence (AI) applications, including imaging, is high and growing rapidly, fueled by availability of large datasets ("big data"), substantial advances in computing power, and new deep-learning algorithms. Apart from developing new AI methods per se, there are many opportunities and challenges for the imaging community, including the development of a common nomenclature, better ways to share image data, and standards for validating AI program use across different imaging platforms and patient populations. AI surveillance programs may help radiologists prioritize work lists by identifying suspicious or positive cases for early review. AI programs can be used to extract "radiomic" information from images not discernible by visual inspection, potentially increasing the diagnostic and prognostic value derived from image datasets. Predictions have been made that suggest AI will put radiologists out of business. This issue has been overstated, and it is much more likely that radiologists will beneficially incorporate AI methods into their practices. Current limitations in availability of technical expertise and even computing power will be resolved over time and can also be addressed by remote access solutions. Success for AI in imaging will be measured by value created: increased diagnostic certainty, faster turnaround, better outcomes for patients, and better quality of work life for radiologists. AI offers a new and promising set of methods for analyzing image data. Radiologists will explore these new pathways and are likely to play a leading role in medical applications of AI. PMID- 29402535 TI - Stakeholder Perceptions of Cyberbullying Cases: Application of the Uniform Definition of Bullying. AB - PURPOSE: The Uniform Definition of Bullying was developed to address bullying and cyberbullying, and to promote consistency in measurement and policy. The purpose of this study was to understand community stakeholder perceptions of typical cyberbullying cases, and to evaluate how these case descriptions align with the Uniform Definition. METHODS: In this qualitative case analysis we recruited stakeholders commonly involved in cyberbullying. We used purposeful sampling to identify and recruit adolescents and young adults, parents, and professionals representing education and health care. Participants were asked to write a typical case of cyberbullying and descriptors in the context of a group discussion. We applied content analysis to case excerpts using inductive and deductive approaches, and chi-squared tests for mixed methods analyses. RESULTS: A total of 68 participants contributed; participants included 73% adults and 27% adolescents and young adults. A total of 650 excerpts were coded from participants' example cases and 362 (55.6%) were consistent with components of the Uniform Definition. The most frequently mentioned component of the Uniform Definition was Aggressive Behavior (n = 218 excerpts), whereas Repeated was mentioned infrequently (n = 19). Most participants included two to three components of the Uniform Definition within an example case; none of the example cases included all components of the Uniform Definition. CONCLUSIONS: We found that most participants described cyberbullying cases using few components of the Uniform Definition. Findings can be applied toward considering refinement of the Uniform Definition to ensure stakeholders find it applicable to cyberbullying. PMID- 29402534 TI - Association among metabolic syndrome, inflammation, and survival in prostate cancer. AB - BACKGROUND: Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. METHODS: We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016. MS was defined by modified adult treatment panel-III criteria. INF was characterized by at least one of these criteria: neutrophil to lymphocyte ratio >= 3, elevated erythrocyte sedimentation rate or C-reactive protein. RESULTS: Eighty-three of 551 (15.1%) patients met MS criteria at baseline and 34 (6.2%) during treatment. MS patients (MS+) presented a greater INF profile compared to MS- (P<0.0001). Median PFS was 3.7 for MS+ vs. 8.7 months for MS- (hazard ratio [HR] = 2.77; 95% CI: 2.12-3.61; P<0.0001). Median OS was 6.9 and 19 months in MS+ and MS-, respectively (HR = 3.43; 95% CI: 2.56-4.58; P<0.0001). We also demonstrated INF led to shorter PFS and OS (4.5 vs. 8.5 months, HR = 1.48, 95% CI: 1.15-1.90, P = 0.002, and 11.2 vs. 18.8 months, HR =1.66, 95% CI: 1.26-2.18, P = 0.0003, respectively). The combination of MS with INF provided the identification of high-risk prognostic group (MS+/INF+ vs. MS-/INF-) with worse PFS (3.7 vs. 9 months, HR = 2.7, 95% CI: 1.88-3.89, P<0.0001) and OS (6.3 vs. 20.4 months, HR = 4.04, 95% CI: 2.75-5.93, P<0.0001). Multivariable analysis confirmed that MS was independently associated with PFS (HR = 2.07; 95% CI: 1.03 4.18; P = 0.041) and OS (HR = 4.87; 95% CI: 2.36-10.03; P<0.0001). The absence of INF as an independent predictor of survival underlined the correlation between MS/INF. CONCLUSIONS: Pretreatment identification of MS and INF alterations might represent an available and easy tool for better prognostication of patients with mCRPC. A prospective evaluation is warranted. PMID- 29402536 TI - A demographic, clinical, and behavioral typology of obesity in the United States: an analysis of National Health and Nutrition Examination Survey 2011-2012. AB - PURPOSE: Public health reporting, randomized trials, and epidemiologic studies of obesity tend to consider it as a homogeneous entity. However, obesity may represent a heterogeneous condition according to demographic, clinical, and behavioral factors. We assessed the heterogeneity of individuals with obesity in the United States. METHODS: We analyzed data from the 2011-2012 wave of the National Health and Nutrition Examination Survey, a nationally representative sample of adults in the United States with detailed physical examination and clinical data (n = 1380). We used cluster analysis to identify subgroups classified as obese according to demographic factors, clinical conditions, and behavioral characteristics. RESULTS: We found significant heterogeneity among participants with obesity according to six distinct clusters (P < .001): affluent men with sleep disorders (16% of sample); older smokers with cardiovascular disease (16%); older women with high comorbidity (20%); healthy white women (13%); healthy non-white women (14%); and active men who drink higher amounts of alcohol (21%). CONCLUSIONS: Obesity in the United States is not a homogeneous condition. Current research and treatment may fail to account for complex and interrelated factors, with implications for prevention strategies and diverse risks of obesity. PMID- 29402537 TI - Optical properties of composite restorations influenced by dissimilar dentin restoratives. AB - OBJECTIVES: To evaluate optical properties (color and translucency) of 'sandwich' restorations of resin-based composites and esthetically unfavorable dentin restoratives. METHODS: Cylindrical 'dentin' specimens (8mm in diameter and 2mm thick, N=5/group) were prepared using EverX Posterior (GC), Biodentine (Septodont), experimental hydroxyapatite (HAP) or conventional composites (Gradia Direct Posterior, GC; Filtek Z250 and Filtek Z500, 3M ESPE). Capping 'enamel' layers were prepared using composites (Gradia Direct Posterior, Filtek Z250 or Z550) of A1 or A3 shade and the following thickness: 0.6, 1 or 2mm. Color (DeltaE) and translucency parameter (TP) were determined using a spectrophotometer (VITA Easyshade Advance 4.0, VITA Zahnfabrik). Data were statistically analyzed using analysis of variance with Tukey's post-hoc tests (alpha=0.05). RESULTS: TP was greatly affected by layer thickness, whilst DeltaE depended on shade and layer thickness of the capping composite. HAP and Biodentine showed significantly lower TP and higher DeltaE (deviation from 'ideal white') than composites (p<0.05). Greater TP was seen in EverX_composite groups than in corresponding control groups of the same shade and thickness. TP of composites combined with Biodentine or HAP was below 2, lower than the corresponding control groups (p<0.05). Within-group differences of DeltaE were greatest in HAP_composite groups. EverX_Gradia and EverX_FiltekZ250 combinations showed the most comparable DeltaE with the control groups. SIGNIFICANCE: A 2mm thick layer of composite covering dentin restoratives with unfavorable esthetics is recommended for a final 'sandwich' restoration that is esthetically comparable to a conventional, mono-composite control restoration. PMID- 29402538 TI - Approximate relative fatigue life estimation methods for thin-walled monolithic ceramic crowns. AB - OBJECTIVES: The objective is to establish an approximate relative fatigue life estimation method under simulated mastication load for thin-walled monolithic restorations. METHODS: Experimentally measured fatigue parameters of fluormica, leucite, lithium disilicate and yttrium-stabilized zirconia in the existing literature were expressed in terms of the maximum cyclic stress and stress corresponding to initial crack size prior to N number of loading cycles to assess their differences. Assuming that failures mostly originate from high stress region, an approximate restoration life method was explored by ignoring the multi axial nature of stress state. Experiments utilizing a simple trilayer restoration model with ceramic LD were performed to test the model validity. RESULTS: Ceramic fatigue was found to be similar for clinically relevant loading range and mastication frequency, resulting in the development of an approximate fatigue equation that is universally applicable to a wide range of dental ceramic materials. The equation was incorporated into the approximate restoration life estimation, leading to a simple expression in terms of fast fracture parameters, high stress area DeltaA, the high stress averaged over DeltaA and N. The developed method was preliminarily verified by the experiments. The impact of fast fracture parameters on the restoration life was separated from other factors, and the importance of surface preparation was manifested in the simplified equation. Both the maximum stress and the area of high stress region were also shown to play critical roles. SIGNIFICANCE: While nothing can replace actual clinical studies, this method could provide a reasonable preliminary estimation of relative restoration life. PMID- 29402539 TI - Predicting refractive index of fluoride containing glasses for aesthetic dental restorations. AB - OBJECTIVE: Dental restoration aesthetics, particularly the translucency of modern dental restorative filling materials depends on the refractive index (RI) match between the different components in the material. In the case of dental composites (DC), the RI of the polymer must match the RI of the filler otherwise the material is optically opaque and has limited depth of cure. In the case of glass ionomer cements (GICs), the RI of the ion-leachable glass must match the RI of the polysalts to engineer a smart material with a tooth-like appearance. The RI of oxide glasses can be calculated by means of Appen factors. However, no Appen factors are available for the fluoride components in dental glasses. Therefore, the objective of this study is to empirically derive composition specific Appen factors for the metal fluorides in complex multicomponent glasses for use in dentistry. METHODS: Two series of bioactive glasses and two series of ionomer-type glasses were produced for this study. Refractive indices of all glasses were then measured by the Becke Line technique. Thereafter, composition specific factors for the metal fluorides were derived. RESULTS: It was found that increasing metal fluoride content reduces the RI of multicomponent dental glasses linearly. A series-specific Appen factors for the metal fluorides were successfully derived and allow RI calculation to within 0.005. SIGNIFICANCE: This paper proposes a modified Appen Model with composition-specific Appen factors for the metal fluorides for the development of dental restoratives with enhanced aesthetics and improved depth of cure of dental composites. PMID- 29402540 TI - Nano-graphene oxide incorporated into PMMA resin to prevent microbial adhesion. AB - OBJECTIVE: Although polymethyl methacrylate (PMMA) is widely used as a dental material, a major challenge of using this substance is its poor antimicrobial (anti-adhesion) effects, which increase oral infections. Here, graphene-oxide nanosheets (nGO) were incorporated into PMMA to introduce sustained antimicrobial adhesive effects by increasing the hydrophilicity of PMMA. METHODS: After characterizing nGO and nGO-incorporated PMMA (up to 2wt%) in terms of morphology and surface characteristics, 3-point flexural strength and hardness were evaluated. The anti-adhesive effects were determined for 4 different microbial species with experimental specimens and the underlying anti-adhesive mechanism was investigated by a non-thermal oxygen plasma treatment. Sustained antimicrobial-adhesive effects were characterized with incubation in artificial saliva for up to 28 days. RESULTS: The typical nanosheet morphology was observed for nGO. Incorporating nGO into PMMA roughened its surface and increased its hydrophilicity without compromising flexural strength or surface hardness. An anti-adhesive effect after 1h of exposure to microbial species in artificial saliva was observed in nGO-incorporated specimens, which accelerated with increasing levels of nGO without significant cytotoxicity to oral keratinocytes. Plasma treatment of native PMMA demonstrated that the antimicrobial-adhesive effects of nGO incorporation were at least partially due to increased hydrophilicity, not changes in the surface roughness. A sustained antimicrobial adhesive property against Candida albicans was observed in 2% nGO for up to 28 days. SIGNIFICANCE: The presence of sustained anti-adhesion properties in nGO incorporated PMMA without loading any antimicrobial drugs suggests the potential usefulness of this compound as a promising antimicrobial dental material for dentures, orthodontic devices and provisional restorative materials. PMID- 29402541 TI - Synthesis and characterization of Ciprofloxacin-containing divinyl oligomers and assessment of their biodegradation in simulated salivary esterase. AB - OBJECTIVE: Two leading causes contributing to dental restoration replacement are the marginal breakdown at the composite/dentin interface and secondary caries mediated by bacteria. The objective of the present study was to synthesize oligomers which incorporated enhanced bio-stability but would also be able to generate antimicrobial function if they underwent degradation. METHODS: Stability was incorporated into the oligomers by generating structural features that would physically hinder the availability of hydrolytically sensitive groups in the oligomers. As a proof-of concept for the antibacterial feature, antimicrobial function was achieved by covalently incorporating Ciprofloxacin (CF) into the backbone of cross-linking divinyl oligomers (referred to as EDV and HLH-CFPEG). The hydrolytic stability of the oligomers was studied in simulated human salivary esterase and compared to the commercial monomer 2,2-bis[4(2-hydroxy-3 methacryloxypropoxy)-phenyl]propane (BisGMA). RESULTS: Both drug oligomers were found to be significantly more stable than BisGMA. Upon degradation, both drug oligomers released CF differentially in free form. Polymer synthesis from resin formulations containing 15wt% HLH-CFPEG showed a high degree of vinyl group conversion and gel content, and under hydrolytic conditions showed the release of CF during a 28-day monitoring study period. SIGNIFICANCE: HLH-CFPEG can be used in dental resin adhesive systems for local delivery of CF to the marginal interface. Minimizing the growth of Streptococcus mutans at the marginal site can improve longevity by reducing esterase activity derived specifically from S. mutans. PMID- 29402542 TI - Early responses of human pulp to direct capping with resin adhesive systems and calcium hydroxide. AB - OBJECTIVE: Early responses of human pulp to Prime&Bond/phosphoric acid, Clearfil SE Bond, Clearfil S3 Bond and Dycal were investigated ex vivo. MATERIALS AND METHODS: The three adhesives, Dycal or buffer (DPBS) were applied directly onto the pulp of human teeth slices that were placed in culture for 4 days. Cell viability was monitored by the MTT assay during the culture period. After 4 days, tissue integrity was examined by hematoxylin-eosin staining. Vimentin levels were assessed by Western blotting. TUNEL assay was applied for apoptotic cell detection at specific pulp areas. RESULTS: Profound reduction of cell viability and tissue integrity was observed in adhesive-treated groups, while the impact of Dycal was found to be less harmful. Extended apoptosis was caused mostly by the Clearfil SE and Prime&Bond. All adhesives reduced Vimentin levels. SIGNIFICANCE: The study provides evidence that early pulp responses to direct capping with different adhesive systems or calcium hydroxide may vary significantly and underline the need for further studies in relevant ex vivo systems. PMID- 29402543 TI - 44Ca doped remineralization study on dentin by isotope microscopy. AB - OBJECTIVE: The dental caries is developed as a result of an alternative course of mineral gain and loss. In order to distinguish between intrinsic Ca (tooth derived mineral) and extrinsic Ca (solution-derived mineral) uptakes, a 44Ca doped pH-cycling was performed using 44Ca (a stable calcium isotope) remineralization solution. METHODS: The natural abundance of 40Ca and 44Ca is 96.9% and 2.1%, respectively. The remineralization solution was prepared using 44Ca to contain 1.5mmol/L CaCl2 (44Ca), 0.9mmol/L KH2PO4, 130mmol/L KCl, 20mmol/L HEPES at pH 7.0. The pH-cycling was conducted on bovine root dentin daily by demineralization (pH 5.0) for 2h, incubation in 0% (control) and 0.2% NaF (900ppm fluoride) for 2h and 44Ca doped remineralization for 20h. After 14days pH cycling, the specimens were sectioned longitudinally. On the sectioned surface, isotope imaging of 40Ca and 44Ca labeled mineral distribution was observed by a high mass-resolution stigmatic secondary ion 77 (Camera IMS 1270, Gennevilliers Cedex, France). RESULTS: Uptake of 44Ca was greater in intensity for the 0.2% fluoride group than the control, especially in the superficial lesions. The control group showed 40Ca (intrinsic) distribution in the subsurface lesions and in the superficial lesions, meanwhile the fluoride group showed 40Ca distribution limited in subsurface lesions. The total Ca (44Ca+40Ca) image revealed more homogeneously for the control than the fluoride group. SIGNIFICANCE: Since the fluoride-treated surface is more acid-resistant than intrinsic dentin, alternative minerals were dissolved from the intact intrinsic lesion in the demineralization cycle. PMID- 29402544 TI - [Facial injections of hyaluronic acid-based fillers for malformations. Preliminary study regarding scar tissue improvement and cosmetic betterment]. AB - BACKGROUND: Cross-linked hyaluronic acid-based fillers have gained rapid acceptance for treating facial wrinkles, deep tissue folds and sunken areas due to aging. This study evaluates, in addition to space-filling properties, their effects on softness and elasticity as a secondary effect, following injection of 3 commercially available cross-linked hyaluronic acid-based fillers (15mg/mL, 17,5mg/mL and 20mg/mL) in patients presenting with congenital or acquired facial malformations. PATIENTS ET METHODS: We started injecting gels of cross-linked hyaluronic acid-based fillers in those cases in 2013; we performed 46 sessions of injections in 32 patients, aged from 13-32. Clinical assessment was performed by the patient himself and by a plastic surgeon, 15 days after injections and 6-18 months later. RESULTS: Cross-linked hyaluronic acid-based fillers offered very subtle cosmetic results and supplemented surgery with a very high level of satisfaction of the patients. When injected in fibrosis, the first session enhanced softness and elasticity; the second session enhanced the volume. Cross linked hyaluronic acid-based fillers fill sunken areas and better softness and elasticity of scar tissues. CONCLUSION: In addition to their well-understood space-filling function, as a secondary effect, the authors demonstrate that cross linked hyaluronic acid-based fillers improve softness and elasticity of scarring tissues. Many experimental studies support our observations, showing that cross linked hyaluronic acid stimulates the production of several extra-cellular matrix components, including dermal collagen and elastin. PMID- 29402546 TI - Reconstruction of an anterior chest wall radionecrosis defect by a contralateral latissimus dorsi flap: A case report. AB - INTRODUCTION: Soft tissue and bone radionecrosis are rare but serious complications may occur late after radiotherapy. CASE REPORT: We report the case of an 86-year-old woman with a history an infiltrating ductal carcinoma of the left breast, treated by total mastectomy, left axillary dissection and adjuvant radiotherapy. Eighteen years later, the first radionecrosis lesions appeared and grew progressively in a 6-month period. These lesions are deep, involving the anterior aspect of the 4th to the 6th ribs and infiltrating the chest wall to the left cardio-thoracic space communicating largely with the pericardium. During axillary dissection, the neurovascular pedicle of the left latissimus dorsi muscle had been severed. The first part of the operation consisted of performing a left side parietectomy of the thoracic wall with a large resection of pericardial tissue and a small myocardial patch. The second step consisted of repairing the thoracic wall defect with a contralateral musculocutaneous latissimus dorsi flap. CONCLUSION: Due to its significant axis of rotation, the latissimus dorsi muscle flap must be considered in the therapeutic algorithm for covering of contralateral anterior chest wall defects. PMID- 29402545 TI - The ongoing emergence of robotics in plastic and reconstructive surgery. AB - Robot-assisted surgery is more and more widely used in urology, general surgery and gynecological surgery. The interest of robotics in plastic and reconstructive surgery, a discipline that operates primarily on surfaces, has yet to be conclusively proved. However, the initial applications of robotic surgery in plastic and reconstructive surgery have been emerging in a number of fields including transoral reconstruction of posterior oropharyngeal defects, nipple sparing mastectomy with immediate breast reconstruction, microsurgery, muscle harvesting for pelvic reconstruction and coverage of the scalp or the extremities. PMID- 29402547 TI - Re: Retropubic Tissue Fixation System Tensioned Mini-sling Carried out Under Local Anesthesia Cures Stress Urinary Incontinence and Intrinsic Sphincter Deficiency: 1-year Data. PMID- 29402548 TI - Magnetic Resonance Imaging of Sentinel Lymph Nodes Using Intraprostatic Injection of Superparamagnetic Iron Oxide Nanoparticles in Prostate Cancer Patients: First in-human Results. PMID- 29402550 TI - Angiolymphoid Hyperplasia With Eosinophilia of the Lung. PMID- 29402551 TI - Transdermal scopolamine for the prevention of a salivary fistula after parotidectomy. AB - Our aim was to investigate whether perioperative transdermal application of scopolamine could help to prevent fistulas after parotidectomy, and to this end we retrospectively studied the records of all patients (n=645) who had benign parotid tumours treated by partial parotidectomy between 2011 and 2016. We found that scopolamine led to a significant decrease in the incidence of salivary fistulas from 54/371(15%) in the group not given it to 10/274 (4%) in the group given it (p<0.0001). The "number needed to treat" was 9.17. There was a relatively low incidence of all adverse effects after scopolamine. Our results are encouraging. Thorough consideration of the contraindications and a knowledge of the potential adverse effects are crucial for its successful implementation. PMID- 29402549 TI - The Effect of Size and Shape of RNA Nanoparticles on Biodistribution. AB - Drugs with ideal pharmacokinetic profile require long half-life but little organ accumulation. Generally, PK and organ accumulation are contradictory factors: smaller size leads to faster excretion and shorter half-lives and thus a lower tendency to reach targets; larger size leads to longer circulation but stronger organ accumulation that leads to toxicity. Organ accumulation has been reported to be size dependent due in large part to engulfing by macrophages. However, publications on the size effect are inconsistent because of complication by the effect of shape that varies from nanoparticle to nanoparticle. Unique to RNA nanotechnology, size could be tuned without a change in shape, resulting in a true size comparison. Here we investigated size effects using RNA squares of identical shape but varying size and shape effects using RNA triangles, squares, and pentagons of identical size but varying shape. We found that circulation time increased with increasing RNA nanoparticle size from 5-25 nm, which is the common size range of therapeutic RNA nanoparticles. Most particles were cleared from the body within 2 hr after systemic injection. Undetectable organ accumulation was found at any time for 5 nm particles. For 20 nm particles, weak signal was found after 24 hr, while accumulation in tumor was strongest during the entire study. PMID- 29402552 TI - Patient Concerns Inventory (at diagnosis) and intention to treat. PMID- 29402554 TI - Corrigendum to "Long-term mortality and morbidity among 30-day survivors after in hospital cardiac arrests-A Swedish cohort study" [Resuscitation 124 (2018) 76 79]. AB - OBJECTIVES: Resuscitation on in-hospital cardiac arrest (IHCA) is estimated to occur in 200,000 hospitalised patients annually in the US and short-term survival, i.e. 30 days, is reported to be around 15-20%. Even if 30-day survival is a good measure of successful resuscitation, the number of survivors is quite high and a perspective on longer-term outcomes is relevant. AIM: To assess long term mortality among 30-day survivors after an IHCA. MATERIAL AND METHODS: All patients >=18 years surviving for at least 30 days after an IHCA at Karolinska University Hospital between 1st January 2007 and 31st December 2014 were included. Data regarding the IHCA, patient characteristics, new cardiac, pulmonary or neurological diagnosis and death dates were obtained from complete Swedish national registries. Censor date was set as 10th February 2017. Differences in long-term survival between those with shockable compared to those with non-shockable first rhythm were assessed with Kaplan Meier survival curves, with adjustment for age-adjusted Charlson Co-morbidity Index (AccI). RESULTS: In all, 1019 patients suffered an IHCA, of whom 267 (26%) survived for at least 30 days. Out of the 267 patients, 158 (59%) were still alive at the censor date, i.e. 3-10 years after their IHCA. The three year survival ratio was 72%. There was a significant better long-term survival among those with shockable initial rhythm than those with a non-shockable first rhythm that persisted after adjustment for ACCI (adjusted 10-year survival; >75% and >50% respectively, p value < .01). CONCLUSION: In conclusion, long-term survival after an IHCA is quite good irrespective of initial rhythm but is related to the burden of baseline co-morbidities. PMID- 29402553 TI - Impacts of rural worker migration on ambient air quality and health in China: From the perspective of upgrading residential energy consumption. AB - In China, rural migrant workers (RMWs) are employed in urban workplaces but receive minimal resources and welfare. Their residential energy use mix (REM) and pollutant emission profiles are different from those of traditional urban (URs) and rural residents (RRs). Their migration towards urban areas plays an important role in shaping the magnitudes and spatial patterns of pollutant emissions, ambient PM2.5 (fine particulate matter with a diameter smaller than 2.5 MUm) concentrations, and associated health impacts in both urban and rural areas. Here we evaluate the impacts of RMW migration on REM pollutant emissions, ambient PM2.5, and subsequent premature deaths across China. At the national scale, RMW migration benefits ambient air quality because RMWs tend to transition to a cleaner REM upon arrival at urban areas-though not as clean as urban residents'. In 2010, RMW migration led to a decrease of 1.5 MUg/m3 in ambient PM2.5 exposure concentrations (Cex) averaged across China and a subsequent decrease of 12,200 (5700 to 16,300, as 90% confidence interval) in premature deaths from exposure to ambient PM2.5. Despite the overall health benefit, large-scale cross-province migration increased megacities' PM2.5 levels by as much as 10 MUg/m3 due to massive RMW inflows. Model simulations show that upgrading within-city RMWs' REMs can effectively offset the RMW-induced PM2.5 increase in megacities, and that policies that properly navigate migration directions may have potential for balancing the economic growth against ambient air quality deterioration. Our study indicates the urgency of considering air pollution impacts into migration related policy formation in the context of rapid urbanization in China. PMID- 29402555 TI - The development and validation of a novel model for predicting surgical complications in colorectal cancer of elderly patients: Results from 1008 cases. AB - OBJECTIVE: To establish predicting models of surgical complications in elderly colorectal cancer patients. BACKGROUND: Surgical complications are usually critical and lethal in the elderly patients. However, none of the current models are specifically designed to predict surgical complications in elderly colorectal cancer patients. METHODS: Details of 1008 cases of elderly colorectal cancer patients (age >= 65) were collected retrospectively from January 1998 to December 2013. Seventy-six clinicopathological variables which might affect postoperative complications in elderly patients were recorded. Multivariate stepwise logistic regression analysis was used to develop the risk model equations. The performance of the developed model was evaluated by measures of calibration (Hosmer-Lemeshow test) and discrimination (the area under the receiver-operator characteristic curve, AUC). RESULTS: The AUC of our established Surgical Complication Score for Elderly Colorectal Cancer patients (SCSECC) model was 0.743 (sensitivity, 82.1%; specificity, 78.3%). There was no significant discrepancy between observed and predicted incidence rates of surgical complications (AUC, 0.820; P = .812). The Surgical Site Infection Score for Elderly Colorectal Cancer patients (SSISECC) model showed significantly better prediction power compared to the National Nosocomial Infections Surveillance index (NNIS) (AUC, 0.732; P ? 0.001) and Efficacy of Nosocomial Infection Control index (SENIC) (AUC; 0.686; P?0.001) models. CONCLUSIONS: The SCSECC and SSISECC models show good prediction power for postoperative surgical complication morbidity and surgical site infection in elderly colorectal cancer patients. PMID- 29402556 TI - Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study. AB - BACKGROUND AND OBJECTIVES: Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy. PATIENTS AND METHODS: Electrochemotherapy with bleomycin was performed on 17 hepatocellular carcinomas in 10 patients using a previously established protocol. The procedure was performed during open surgery and the patients were followed for median 20.5 months. RESULTS: Electrochemotherapy was feasible for all 17 lesions, and no treatment-related adverse events or major post-operative complications were observed. The median size of the treated lesions was 24 mm (range 8-41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally. The complete response rate at 3-6 months was 80% per patient and 88% per treated lesion. CONCLUSIONS: Electrochemotherapy of hepatocellular carcinoma proved to be a feasible and safe treatment in all 10 patients included in this study. To evaluate the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment are encouraging, in 15 out of 17 lesions complete response was obtained. Electrochemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/perioperative risk for high morbidity and mortality. PMID- 29402557 TI - Optimization of the risk-benefit ratio of differentiated thyroid cancer treatment. AB - The vast majority of differentiated thyroid cancers (DTC) are characterized by an innocuous nature, excellent patient survival, and limited treatment requirement. However, a significant proportion of affected patients is prone to receiving overtreatment, due to undertreatment concerns associated with the difficulty to differentiate them from a small minority affected by aggressive DTC. Identification of prognostic factors and development of staging systems has helped to reduce the proportion of overtreatment in DTC. However, the absolute number of overtreated patients continues to increase, as a result of an on-going incidence surge in early DTC associated with the increased application and sensitivity of modern diagnostic tools. In the present paper, we describe how DTC treatment can be optimized by thoughtful evidence-based balancing of oncologic safety against treatment associated morbidity. PMID- 29402558 TI - Pigmented Purpuric Dermatosis in Adults Treated with Herbal Medicine: Report of Five Cases. AB - BACKGROUND: The purpose of this report is to demonstrate the clinical effect of Korean medicine treatment for pigmented purpuric dermatosis (PPD). METHODS: Five cases of PPD with skin purpura and blood heat due to blood deficiency were evaluated. All patients had been in a chronic disease state for at least 1 year. The treatment consisted only of the Korean herbal medicine Gami-Samultang (GS). The degree of symptoms that the patients experienced when they first visited our clinic was set at a visual analog scale (VAS) score of 10. RESULTS: After treatment, body purpura disappeared in all cases. In contrast, the patients' symptoms had not resolved following previous steroid treatment. All patients were satisfied with the treatment results and showed a VAS score of 0 for purpura. CONCLUSION: This report suggests that GS can be used to effectively treat PPD. Additional clinical studies on PPD are needed to develop more comprehensive treatment guidelines. PMID- 29402559 TI - Spectra-structure correlations in NIR region: Spectroscopic and anharmonic DFT study of n-hexanol, cyclohexanol and phenol. AB - We investigated near-infrared (7500-4000 cm-1) spectra of n-hexanol, cyclohexanol and phenol in CCl4 (0.2 M) by using anharmonic quantum calculations. These molecules represent three major kinds of alcohols; linear and cyclic aliphatic, and aromatic ones. Vibrational second-order perturbation theory (VPT2) was employed to calculate the first overtones and binary combination modes and to reproduce the experimental NIR spectra. The level of conformational flexibility of these three alcohols varies from one stable conformer of phenol through four conformers of cyclohexanol to few hundreds conformers in the case of n-hexanol. To take into account the most relevant conformational population of n-hexanol, a systematic conformational search was performed. Accurate reproduction of the experimental NIR spectra was achieved and detailed spectra-structure correlations were obtained for these three alcohols. VPT2 approach provides less reliable description of highly anharmonic modes, i.e. OH stretching. In the present work this limitation was manifested in erroneous results yielded by VPT2 for 2nuOH mode of cyclohexanol. To study the anharmonicity of this mode we solved the corresponding time-independent Schrodinger equation based on a dense-grid probing of the relevant vibrational potential. These results allowed for significant improvement of the agreement between the calculated and experimental 2nuOH band of cyclohexanol. Various important biomolecules include similar structural units to the systems investigated here. A detailed knowledge on spectral properties of these three types of alcohols is therefore essential for advancing our understanding of NIR spectroscopy of biomolecules. PMID- 29402560 TI - Raman, AFM and SNOM high resolution imaging of carotene crystals in a model carrot cell system. AB - Three non-destructive and complementary techniques, Raman imaging, Atomic Force Microscopy and Scanning Near-field Optical Microscopy were used simultaneously to show for the first time chemical and structural differences of carotenoid crystals. Spectroscopic and microscopic scanning probe measurements were applied to the released crystals or to crystals accumulated in a unique, carotenoids rich callus tissue growing in vitro that is considered as a new model system for plant carotenoid research. Three distinct morphological crystal types of various carotenoid composition were identified, a needle-like, rhomboidal and helical. Raman imaging using 532 and 488 nm excitation lines provided evidence that the needle-like and rhomboidal crystals had similar carotenoid composition and that they were composed mainly of beta-carotene accompanied by alpha-carotene. However, the presence of alpha-carotene was not identified in the helical crystals, which had the characteristic spatial structure. AFM measurements of crystals identified by Raman imaging revealed the crystal topography and showed the needle-like and rhomboidal crystals were planar but they differed in all three dimensions. Combining SNOM and Raman imaging enabled indication of carotenoid rich structures and visualised their distribution in the cell. The morphology of identified subcellular structures was characteristic for crystalline, membraneous and tubular chromoplasts that are plant organelles responsible for carotenoid accumulation in cells. PMID- 29402562 TI - Commentary to "Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent?" PMID- 29402561 TI - The single mandibular implant study - Short-term effects of the loading protocol on Oral Health-related Quality of Life. AB - PURPOSE: A single implant can be placed to retain an overdenture in the edentulous mandible. This study aimed at the development of Oral Health-related Quality of Life comparing immediate and delayed implant loading, i.e., loading after 3 months of submerged healing. METHODS: In a randomized controlled trial, 158 participants received a single mandibular implant in the midline. Quality of life was measured using the summary score of the German 49-item Oral Health Impact Profile at baseline, one month after implant placement (direct loading group) as well as one and four months after loading. RESULTS: Mean scores at baseline were comparable. Four months after implantation, a decrease of mean scores was recognized for both groups, indicating a significantly enhanced quality of life after treatment. When comparing the groups after both 1 and 4 months of loading, quality of life was insignificantly higher in the delayed loading group (1 month: 42.1 vs. 32.3; 4 months: 33.6 vs. 27.7). For immediate loading, an insignificant tendency to an earlier improvement was recognized (Delta1month-baseline: 9.7, compared to Delta1month-baseline: 6.4). CONCLUSIONS: The single mandibular implant concept was associated with a positive impact on quality of life. However, no statistically significant influence of implant loading on quality of life was found. PMID- 29402563 TI - A response surface analysis of expected and received support for smoking cessation: Expectancy violations predict greater relapse. AB - People attempting to stop smoking cigarettes (quitters) hold expectations about the extent to which their partner will provide helpful support during a quit attempt. However, these expectations may not align with their perceptions of the helpfulness of the support they receive. We examine expected and received helpful support during a quit attempt. We hypothesized that receiving less helpful support than expected (i.e., creating an expectancy violation) would be associated with the greatest return to smoking. Sixty-two quitters completed a 21 day ecological momentary assessment (EMA) study. They reported expected support at baseline and support receipt and smoking during the EMA phase. At follow-up, they completed an expelled breath carbon monoxide test. Analyses using polynomial generalized linear models with response surface analysis indicated that smoking outcomes depended on the joint influence of expected and received helpful support. As hypothesized, when quitters expected more helpful support than they received, they were more likely to smoke in the first 24h and the last seven days of the EMA, and they provided higher carbon monoxide readings at follow-up. These results are consistent with an expectancy violation explanation: quitters are more likely to smoke when they perceive their partner has failed to provide support that is as helpful as expected. Given the importance of support for smoking cessation, many researchers have attempted to experimentally increase provision of support. The current findings suggest that partner support interventions might backfire if the quitter is led to expect more helpful support than the partner is able to provide. PMID- 29402564 TI - Malaria in Italy - Migrants Are Not the Cause. AB - Recently, five cases of malaria were reported in Italy. These people had not travelled abroad, prompting some media and political organizations to fuel a climate of fear by connecting the cases with migrants coming into the country. Here, we discuss scientific data highlighting the limited risk of malaria reintroduction in Italy. PMID- 29402565 TI - Advantages of an on-the-screwhead crosslink connector for atlantoaxial fixation using the Goel/Harms technique. AB - The goal of fixation surgery for atlantoaxial instability is to achieve solid bony fusion. Achieving bony fusion as early as possible is beneficial for patients. Although placement of a transverse cross-link connector (XL) provides greater biomechanical strength, XLs have not been able to be placed when performing the Goel/Harms procedure. Recently, placing a XL on the screw head (on the-head XL [OH-XL]) has become a viable option during the Goel/Harms procedure. However, there is little evidence demonstrating whether applying an OH-XL achieves early solid bony union. A matched-control study was conducted to investigate whether placing an OH-XLs in C1/2 fixation surgery provides earlier bone union or not. Eighteen patients who underwent atlantoaxial fusion with OH XLs (X-group), and 17 age and sex-matched patients without OH-XLs (NX-group) were compared. Bony union was assessed using reconstructed sagittal and coronal computed tomography images. Six months after surgery, six patients in the X-group and one patient in the NX-group achieved bony union (p = .0338). One year after surgery, 14 patients in the X-group and 4 patients in the NX-group achieved bone union (p = .0010). Two years after surgery, 17 patients in the X-group and 9 patients in the NX-group achieved bony union (p = .0011). This is the first report of the clinical application of OH-XLs for the Goel/Harms procedure. OH-XLs yield earlier bony fusion; thus, placing OH-XLs is beneficial for atlantoaxial fixation surgery using lateral mass screws of the atlas. PMID- 29402566 TI - Application of a newly developed upper limb single-joint hybrid assistive limb for postoperative C5 paralysis: An initial case report indicating its safety and feasibility. AB - Postoperative C5 paralysis is a serious complication of cervical spine surgery, with no established method for effective rehabilitation. A 67-year-old man presented with postoperative bilateral C5 paralysis following cervicothoracic surgery for ossification of the posterior longitudinal ligament (OPLL). Starting 15 days after surgery, left elbow joint training was performed 2-3 times weekly, for a total of 10 sessions, using an upper limb single-joint hybrid assistive limb (upper limb HAL-SJ). Right elbow joint training was also performed 5 times weekly starting 38 days after surgery, for a total of 10 sessions, using the upper limb HAL-SJ. No serious adverse events were noted during treatment with the upper limb HAL-SJ. Manual muscle testing showed no apparent change in deltoid and biceps strength on either side during use of the upper limb HAL-SJ; however, hand held dynamometer testing showed improvement over time in both muscles. At 12 months after surgery, the patient was able to elevate both arms. The present case indicates initial safety and feasibility of treatment for postoperative C5 paralysis with an upper limb HAL-SJ. PMID- 29402567 TI - Dysgeusia in deep brain stimulation for essential tremor. AB - Dysgeusia, or foul taste, is a rarely reported side effect in patients who have undergone deep brain stimulation (DBS) in the thalamus for essential tremor. This retrospective study evaluated the incidence, nature, neurophysiological and anatomical location of dysgeusia following DBS. Of 52 patients who had undergone DBS for essential tremor, eight (15%) reported dysgeusia, which was described as a "metallic," "sour," "foul," or "cold" taste in the mouth. Dysgeusia was separate and distinguishable from paresthesia. Dysgeusia was more frequently reported with bilateral than unilateral DBS implants (6 of 27 (22%) vs. 2 of 25 (8%) patients, respectively). The anatomical locations of the contacts causing dysgeusia were measured on postoperative MRI, and compared to those from seven control patients who did not experience dysgeusia after receiving bilateral DBS implants. Leads causing dysgeusia were more posterior than non-dysgeusia associated leads (4.5 +/- 1.2 vs. 5.7 +/- 1.8 mm anterior to the posterior commissure, respectively, P < .001). Intraoperative microelectrode recording indicated that these contacts were in the sensory region of the thalamus. Intraoperative testing found that low sensory threshold for paresthesia predicted the development of dysgeusia postoperatively (1.5 +/- 0.5 V vs. 3.3 +/- 1.9 V; P < .05). These data indicate that taste perception can be altered in the human through DBS, with posterior leads likely within the sensory region of the thalamus. Dysgeusia can be reduced by changing stimulation parameters, or surgical revision of the lead. PMID- 29402568 TI - 3,4-Diaminopyridine for the treatment of myasthenia gravis with electrophysiological patterns of Lambert-Eaton myasthenic syndrome. AB - 3,4-Diaminopyridine (34DAP) is a presynaptic transmission enhancer. Its efficacy for Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG) was demonstrated. However, there are cases sharing the characteristics of both disease and the effect of 34DAP in "gray zone" patients is sparse. Recently, we prescribed 34DAP to five anti-acetylcholine receptor antibody-positive MG patients with electrophysiological LEMS patterns and three LEMS patients, and carefully monitored the responses. Sero-positive MG patients exhibited more favorable responses than LEMS patients. The combination of 34DAP and pyridostigmine resulted in the best outcomes. No significant side effects were recorded during the follow-up period. In conclusion, this study results provide evidence that 34DAP could be effective in sero-positive MG patients with pre synaptic dysfunction. PMID- 29402569 TI - Unusual paediatric spinal myxopapillary ependymomas: Unique molecular entities or pathological variations on a theme? AB - Ependymomas are the commonest type of spinal glioma which represent a group of relatively benign tumours. Myxopapillary ependymoma (MPE) is a common variant found within the distal spinal cord around the conus. These two entities are clearly differentiated on the basis of their characteristic histological and molecular features. Rare variants of MPE's are described in the literature to have the propensity to metastasise and grow in extraspinal locations despite appearing histologically identical to their more benign relatives. Here, we describe two unusual cases of MPE and utilise DNA methylation analyses to compare their molecular signatures with known molecular subtypes of ependymoma in an attempt to distinguish whether these tumours represent a unique subset of disease. PMID- 29402570 TI - Improving youth question-asking and provider education during pediatric asthma visits. AB - OBJECTIVE: We conducted a pragmatic randomized controlled trial to test the effectiveness of an asthma question prompt list with video intervention to increase youth question-asking and provider education during visits. METHODS: English or Spanish-speaking youth ages 11-17 with persistent asthma and their parents were enrolled from four rural and suburban pediatric clinics. Youth were randomized to the intervention or usual care groups. Intervention group adolescents watched the video on an iPad and then completed an asthma question prompt list before their visits. Generalized estimating equations were used to analyze the data. RESULTS: Forty providers and 359 patients participated. Intervention group youth were significantly more likely to ask one or more questions about medications, triggers, and environmental control than usual care youth. Providers were significantly more likely to educate intervention group youth about rescue medications, triggers, and environmental control. Intervention group caregivers were not significantly more likely to ask questions. CONCLUSION: The intervention increased youth question-asking and provider education about medications, triggers, and environmental control. The intervention did not impact caregiver question-asking. PRACTICE IMPLICATIONS: Providers/practices should consider having youth complete question prompt lists and watch the video with their parents before visits to increase youth question-asking during visits. PMID- 29402571 TI - Health economic evaluations of patient education interventions a scoping review of the literature. AB - OBJECTIVES: To provide a comprehensive overview of health economic evaluations of patient education interventions for people living with chronic illness. METHODS: Relevant literature published between 2000 and 2016 has been comprehensively reviewed, with attention paid to variations in study, intervention, and patient characteristics. RESULTS: Of the 4693 titles identified, 56 articles met the inclusion criteria and were included in this scoping review. Of the studies reviewed, 46 concluded that patient education interventions were beneficial in terms of decreased hospitalization, visits to Emergency Departments or General Practitioners, provide benefits in terms of quality-adjusted life years, and reduce loss of production. Eight studies found no health economic impact of the interventions. CONCLUSIONS: The results of this review strongly suggest that patient education interventions, regardless of study design and time horizon, are an effective tool to cut costs. This is a relatively new area of research, and there is a great need of more research within this field. PRACTICE IMPLICATIONS: In bringing this evidence together, our hope is that healthcare providers and managers can use this information within a broad decision-making process, as guidance in discussions of care quality and of how to provide appropriate, cost effective patient education interventions. PMID- 29402572 TI - Motivational interviewing and screening colonoscopy in high-risk individuals. A randomized controlled trial. AB - OBJECTIVE: To measure the impact of motivational interviewing (MI) on cancer knowledge and screening practice among first degree relatives (FDRs) of patients with colon cancer. METHODS: This randomized controlled trial targeted patients with colon cancer first to recruit their possible FDRs. Digit randomization of the eligible index patients into intervention or control groups resulted in allocating their belonging FDRs to the same study arm. FDRs (n = 120) in intervention arm received MI counseling on phone by a trained oncology nurse and FDRs (n = 120) in control group received standard generic information by a physician on phone. Primary outcome was the rate of documented colonoscopy in FDRs within six months after the baseline. RESULTS: A total of 227 FDRs were followed up, 115 in the intervention and 112 in the control group. At follow-up, the uptake of screening colonoscopy in the intervention group was 83.5% versus 48.2% in controls (crude odds ratio, 5.4; 95% confidence interval, 2.9-10.0, P < .001). CONCLUSION: This was the first randomized controlled trial in Iran that confirmed the efficaciousness of a phone-based MI counseling in improving colonoscopy uptake among family members of patients with colon cancer. PRACTICE IMPLICATIONS: Phone-based motivational counseling that involves trained nurses or health providers seems to be feasible approach in Iran health system and enhances screening for colon cancer. PMID- 29402573 TI - Informal interpreting in general practice: Are interpreters' roles related to perceived control, trust, and satisfaction? AB - OBJECTIVE: The aim of this observational study was twofold. First, we examined how often and which roles informal interpreters performed during consultations between Turkish-Dutch migrant patients and general practitioners (GPs). Second, relations between these roles and patients' and GPs' perceived control, trust in informal interpreters and satisfaction with the consultation were assessed. METHODS: A coding instrument was developed to quantitatively code informal interpreters' roles from transcripts of 84 audio-recorded interpreter-mediated consultations in general practice. Patients' and GPs' perceived control, trust and satisfaction were assessed in a post consultation questionnaire. RESULTS: Informal interpreters most often performed the conduit role (almost 25% of all coded utterances), and also frequently acted as replacers and excluders of patients and GPs by asking and answering questions on their own behalf, and by ignoring and omitting patients' and GPs' utterances. The role of information source was negatively related to patients' trust and the role of GP excluder was negatively related to patients' perceived control. CONCLUSION: Patients and GPs are possibly insufficiently aware of the performed roles of informal interpreters, as these were barely related to patients' and GPs' perceived trust, control and satisfaction. PRACTICE IMPLICATIONS: Patients and GPs should be educated about the possible negative consequences of informal interpreting. PMID- 29402575 TI - Do you define the limits of normalcy from looking at the patient or the healthy subject? PMID- 29402574 TI - Family companions' involvement during pre-surgical consent visits for major cancer surgery and its relationship to visit communication and satisfaction. AB - OBJECTIVE: To examine the association between family companion presence during pre-surgical visits to discuss major cancer surgery and patient-provider communication and satisfaction. METHODS: Secondary analysis of 61 pre-surgical visit recordings with eight surgical oncologists at an academic tertiary care hospital using the Roter Interaction Analysis System (RIAS). Surgeons, patients, and companions completed post-visit satisfaction questionnaires. Poisson and logistic regression models assessed differences in communication and satisfaction when companions were present vs. absent. RESULTS: There were 46 visits (75%) in which companions were present, and 15 (25%) in which companions were absent. Companion communication was largely emotional and facilitative, as measured by RIAS. Companion presence was associated with more surgeon talk (IRR 1.29, p = 0.006), and medical information-giving (IRR 1.41, p = 0.001). Companion presence was associated with less disclosure of lifestyle/psychosocial topics by patients (IRR 0.55, p = 0.037). In adjusted analyses, companions' presence was associated with lower levels of patient-centeredness (IRR 0.77, p 0.004). There were no differences in patient or surgeon satisfaction based on companion presence. CONCLUSION: Companions' presence during pre-surgical visits was associated with patient-surgeon communication but was not associated with patient or surgeon satisfaction. PRACTICE IMPLICATIONS: Future work is needed to develop interventions to enhance patient-companion-provider interactions in this setting. PMID- 29402576 TI - Readability of Spanish language online information for the initial treatment of burns. AB - OBJECTIVE: This study's aim is to identify the most popular online resources for burn treatment information available in the Spanish language, and to evaluate the readability of this information. METHODS: The phrase "tratamiento de quemaduras" (burn treatment) was entered into search engines Google and Bing on 9/15/2014 and 9/13/2017. The top 12 Spanish web results on each site were identified and analyzed using Readability Studio Professional Edition v2012.1. The software generated a "mean grade reading level" for each article, or the grade of students that could be expected to understand the article's language. RESULTS: 21 distinct articles were identified at T1 and 17 at T2, with seven overlapping between T1 and T2. The average grade reading level of all the websites ranged from 7.8 to 13.8 at T1 (approximately 8th grade to sophomore year of college) and 7.8 to 12.2 at T2. CONCLUSIONS: No websites were within 1 standard deviation of the American Medical Association recommended 6th grade reading level. With readability showing little improvement during the past three years, providers should be aware of the complexity of online literature, and the potential complications this presents to patients. Additionally, burn centers should prioritize generating more accessible information for the Spanish speaking public. PMID- 29402577 TI - High-voltage electric stimulation of the donor site of skin grafts accelerates the healing process. A randomized blinded clinical trial. AB - INTRODUCTION: Severe burns benefit from skin grafting, and grafting surgery is of great importance in the treatment of these injuries. As a result, there is formation of an additional wound at the donor site, which is painful and susceptible to infection. However, the therapeutic approach to these problems at donor sites for skin grafting is insufficiently explored in the literature. AIM: To evaluate electrical stimulation of the donor sites of burn patients treated by grafting surgery. METHODS: This work evaluated 30 donor sites of cutaneous graft burn patients treated with high-voltage electrical stimulation. Subjects were randomized into two groups: electrical stimulation (GES), treated with electrostimulation (50min, 100Hz, twin pulses 15 us, monophasic), and the sham group (GS), treated by the same procedures but without current. Pain was assessed by visual analog scale daily before and after the electrical stimulation. The time elapsed until complete epithelization was evaluated (time of primary dressing detached spontaneously). Skin temperature was measured by thermography. The characteristics of donor sites were qualitatively evaluated using images and the plug-in CaPAS(r) (Carotid Plaque Analysis Software). RESULTS: The results showed a significant decrease in pain, which was absent on the third day in the GES and the sixth day in the GS. The time the primary dressing detached spontaneously in days decreased (p<0.05) (4.7+/-0.2) compared to the GS group (7.0+/-1.3). Donor site healing characteristics such as vascularization, pigmentation, height, the quantity of crust formed, irregularities, and the quality of healing was better in the GES; moreover, homogeneity and inertia of the images confirmed higher healing quality. CONCLUSION: As a result of the study, the technology shows promise and merits a larger study with objective assessments and different physical variables. PMID- 29402579 TI - The effect of SPARK on social and motor skills of children with autism. AB - BACKGROUND: This study aimed to evaluate the effectiveness of a selected group exercise known as Sports, Play and Active Recreation for Kids (SPARK) on the motor and behavioral skills of children with autism spectrum disorder (ASD) using a quasi-experimental design with repeated measures. METHODS: Twenty-eight children with ASD (age range of 5e12 years) participated in this study. The participants were examined at baseline, pre-test, and post-test using Bruininks Oseretsky Test of Motor Proficiency (BOTMP), Autism treatment evaluation checklist (ATEC), and Gilliam Autism Rating Scale-second edition (GARS-2). RESULTS: The results showed that the SPARK program significantly improved balance (static and dynamic), bilateral coordination and social interaction (p < 0.05) in children with ASD. CONCLUSION: The results of this study suggest that the SPARK's training can be considered as a therapeutic option not only for motor enhancement but also for improving social skills in children with ASD. PMID- 29402578 TI - Influenza vaccine effectiveness in older adults compared with younger adults over five seasons. AB - BACKGROUND: There have been inconsistent reports of decreased vaccine effectiveness (VE) against influenza viruses among older adults (aged >= 65 years) compared with younger adults in the United States. A direct comparison of VE over multiple seasons is needed to assess the consistency of these observations. METHODS: We performed a pooled analysis of VE over 5 seasons among adults aged >= 18 years who were systematically enrolled in the U.S. Flu VE Network. Outpatients with medically-attended acute respiratory illness (cough with illness onset <= 7 days prior to enrollment) were tested for influenza by reverse transcription polymerase chain reaction. We compared differences in VE and vaccine failures among older adult age group (65-74, >=75, and >= 65 years) to adults aged 18-49 years by influenza type and subtype using interaction terms to test for statistical significance and stratified by prior season vaccination status. RESULTS: Analysis included 20,022 adults aged >= 18 years enrolled during the 2011-12 through 2015-16 influenza seasons; 4,785 (24%) tested positive for influenza. VE among patients aged >= 65 years was not significantly lower than VE among patients aged 18-49 years against any subtype with no significant interaction of age and vaccination. VE against A(H3N2) viruses was 14% (95% confidence interval [CI] -14% to 36%) for adults >= 65 years and 21% (CI 9-32%) for adults 18-49 years. VE against A(H1N1)pdm09 was 49% (95% CI 22-66%) for adults >= 65 years and 48% (95% CI 41-54%) for adults 18-49 years and against B viruses was 62% (95% CI 44-74%) for adults >= 65 years and 55% (95% CI 45-63%) for adults 18-49 years. There was no significant interaction of age and vaccination for separate strata of prior vaccination status. CONCLUSIONS: Over 5 seasons, influenza vaccination provided similar levels of protection among older and younger adults, with lower levels of protection against influenza A(H3N2) in all ages. PMID- 29402580 TI - Life on Phosphite: A Metagenomics Tale. AB - Phosphite, a species of phosphorus in a P3+ oxidation state, is believed to have played an important role in the primordial Earth. Figueroa et al. used metagenomics to uncover anaerobic bacterial communities from waste water waste sludge that sustain life from energy provided by phosphite. PMID- 29402581 TI - Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder. AB - This study investigated adolescent cannabis use as a risk factor for schizophrenia spectrum disorder (SSD). Motives for early cannabis use and resulting usage patterns were examined alongside clinical measures of SSD onset and symptomatology. Participants (N = 178) were recruited for two samples, 1: healthy controls (HC) with cannabis use, 2: schizophrenia patients (SSD) with cannabis use. Structured interviews of participants and family informants were used to obtain diagnostic and biographical information. Factor-analysis of reported motives for initiating cannabis use produced four groups; sedation, stimulation, social pressure, and recreation. Regression analyses revealed significant relationships between these groups and SSD. Most notably, reason group factor scores predict SSD risk as well as schizotypal symptom severity. Findings also indicate that these factors follow a hierarchical structure, which explains their relative involvement in increased SSD risk. We suggest that adolescent cannabis use both hastens the onset and amplifies the severity of SSD. In response we propose a model for identifying at risk individuals, predicting the onset and severity of SSD, and potentially mitigating the associated psychiatric impairments. PMID- 29402582 TI - Birth experiences, trauma responses and self-concept in postpartum psychotic-like experiences. AB - The frequency of psychotic-like experiences (PLEs) amongst new mothers is beginning to be explored but the mechanisms underlying such experiences are yet to be understood. First time mothers (N=10,000) receiving maternity care via the UK National Health Service were contacted postnatally via Emma's Diary, an online resource for mothers. Measures assessed birth experience, trauma appraisals, post traumatic stress symptoms, adjustment to motherhood, self-concept clarity and PLEs (in the form of hallucinations and delusions). There was a 13.9% response rate (N=1393) and 1303 participants reported experiencing at least one PLE (93.5%). Three competing nested path models were analysed. A more negative birth experience directly predicted delusions, but not hallucinations. Trauma appraisals and poorer adjustment to motherhood indirectly predicted PLEs, via disturbed self-concept clarity. Post-traumatic stress symptoms directly predicted the occurrence of all PLEs. PLEs in first time mothers may be more common than previously thought. A key new understanding is that where new mothers have experienced birth as traumatic and are struggling with adjustment to their new role, this can link to disturbances in a coherent sense of self (self-concept clarity) and be an important predictor of PLEs. Understanding the development of PLEs in new mothers may be helpful in postnatal care, as would public health interventions aimed at reducing the sense of abnormality or stigma surrounding such experiences. PMID- 29402583 TI - Diagnostic Accuracy of Sequential Arthroscopic Approach for Ramp Lesions of the Posterior Horn of the Medial Meniscus in Anterior Cruciate Ligament-Deficient Knee. AB - PURPOSE: To document the diagnostic accuracy and steps for sequential arthroscopic exploration of ramp lesions-peripheral tear within 4 mm of meniscocapsular junction of medial meniscus-associated with anterior cruciate ligament (ACL) injury. METHODS: This was a prospective consecutive study of 195 primary ACL reconstructions with arthroscopic exploration for ramp lesion in 4 steps: (1) standard exploration through the anterolateral portal, (2) through the intercondylar space using a 30 degrees arthroscope, (3) through the intercondylar space using a 70 degrees arthroscope, and (4) after creation of a posteromedial portal. Acute (<3 months) and chronic case (>3 months) groups were compared, and the sensitivity and specificity of magnetic resonance imaging (MRI) were assessed. RESULTS: Overall, 50 patients (26.6%) were confirmed as having a ramp lesion. After step 1, only 19 cases (38%) were identified as a ramp lesion. After step 2, 24 cases (48%) were found, and the sensitivity of step 2 was estimated at 48%. After step 3, an additional 26 cases (52%) were identified. No more additional cases of ramp lesion were found after step 4. There were statistically significant differences between steps 2 and 3 (P = .001), but no differences between steps 1 and 2, or steps 3 and 4. Although there were no statistical differences in overall prevalence for acute (28/128, 21.8%) and chronic (22/67, 32.8%) groups (P = .136), the incidence of ramp lesion confirmed through the standard portal approach was found to be significantly correlated with chronic group (odds ratio: 2.95, P = .023). The sensitivity and specificity of preoperative MRI were 84% and 95.17%. CONCLUSIONS: Many ramp lesions could not be diagnosed through the standard portal and intercondylar space using a 30 degrees arthroscope. Posteromedial inspection using a 70 degrees arthroscope has improved the diagnostic accuracy for ramp lesion without direct exploration through the posteromedial portal. Care should be taken to identify ramp lesions when ACL reconstruction is performed. LEVEL OF EVIDENCE: Level I, diagnostic study of consecutive patients. PMID- 29402584 TI - Anteromedial Meniscofemoral Ligament of the Anterior Horn of the Medial Meniscus: Clinical, Magnetic Resonance Imaging, and Arthroscopic Features. AB - PURPOSE: To describe the clinical, arthroscopic, and magnetic resonance imaging (MRI) findings of knees with anomalous insertion of the anterior horn of the medial meniscus (AHMM) into the intercondylar notch via an anteromedial meniscofemoral ligament (AMMFL). METHODS: A total of 2,503 arthroscopic knee surgeries performed from July 2003 to October 2016 were reviewed retrospectively to identify knees with an AMMFL. Medical records, arthroscopic photographs, and MRI of identified cases were analyzed. Meniscus width and extrusion were measured on MRI. Fifty patients with a normal meniscus were selected as a control group. RESULTS: A total of 13 (0.52%) patients had an AMMFL with insertion at the intercondylar notch. All cases were diagnosed incidentally during arthroscopy. The characteristics of knee pain were related to surgical pathology. Arthroscopic examination revealed the AMMFL as a band-like structure covering the anterior cruciate ligament. In all cases, the AHMM had no bony attachment to the tibia, and increased mobility was observed on probing of the AHMM. The medial meniscus (MM) was significantly larger than the general size in 8 cases (61.5%). Twelve knees (92.3%) had meniscus tears. On MRI, the AMMFL appeared as a low-signal linear structure arising at the AHMM and coursing superiorly along the anterior cruciate ligament. The mean MM width was greater than that in the control group at the mid-body (P = .030), anterior horn (P = .002), and posterior horn (P = .001). CONCLUSIONS: All cases of AMMFL were found incidentally during arthroscopic surgery, and the AMMFL was a silent lesion. There was no significant meniscal extrusion, although the AHMM had no bony attachment. This is because the AMMFL may act as an anchor for the AHMM. Therefore, the AMMFL should not always be removed. The MM with an AMMFL tended to be larger than the typical MM and may be related to some degree of hypermobility, which raises the risk of meniscal tears. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29402585 TI - Modified Latarjet Procedure Without Capsulolabral Repair for the Treatment of Failed Previous Operative Stabilizations in Athletes. AB - PURPOSE: To analyze time to return to sport, functional outcomes, and recurrences of the modified Latarjet procedure without capsulolabral repair in athletes with recurrent anterior shoulder instability after a failed previous operative stabilization. METHODS: We included athletes with recurrent anterior shoulder instability with a previous failed operative stabilization treated with the modified Latarjet procedure without capsulolabral repair with a minimum of 2-year follow-up. Return to sports, range of motion, the Rowe score, a visual analog scale for pain in sport activity, and the Athletic Shoulder Outcome Scoring System were used to assess functional outcomes. Recurrences were also evaluated. The postoperative bone block position and consolidation were assessed with computed tomography. RESULTS: Between June 2008 and June 2015, 68 athletes were treated with the modified Latarjet procedure without capsulolabral reconstruction for recurrent shoulder instability after a previous failed stabilization surgery. The mean follow-up was 44 months (range, 24-108 months), and the mean age at the time of operation was 26.8 years (range, 17-35 years). All the patients returned to sports, and 95% returned to the same sport they practiced before the surgery, all to the same level. No significant difference in shoulder range of motion was found between preoperative and postoperative results. The Rowe score, visual analog scale, and Athletic Shoulder Outcome Scoring System showed statistical improvement after operation (P < .001). There was no recurrence of shoulder dislocation or subluxation. The bone block healed in 92% of patients. There were 8 complications (12.3%) and 2 reoperations (3%). CONCLUSIONS: In athletes with previous failed operative stabilization procedures, the modified Latarjet without capsulolabral repair produced excellent functional outcomes with most athletes returning to sport at the same level they had before the surgery without recurrences. LEVEL OF EVIDENCE: Level IV, therapeutic, case series study. PMID- 29402586 TI - High Rate of Return to Swimming After Hip Arthroscopy for Femoroacetabular Impingement. AB - PURPOSE: To evaluate patients' ability to return to swimming after hip arthroscopy for femoroacetabular impingement syndrome (FAIS) with capsular closure. METHODS: Consecutive FAIS patients who had undergone hip arthroscopy for the treatment of FAIS by a single fellowship-trained surgeon were reviewed. The inclusion criteria included patients with a diagnosis of FAIS who self-reported being swimming athletes with a minimum clinical follow-up duration of 2 years. For all patients, we assessed demographic data; preoperative physical examination findings, imaging findings, and patient-reported outcome (PRO) scores including the modified Harris Hip Score, Hip Outcome Score-Activities of Daily Living subscale, Hip Outcome Score-Sports-Specific subscale, and visual analog scale for pain; and postoperative examination findings and PROs at a minimum of 2 years after surgery, including a swimming-specific questionnaire. RESULTS: The study included 26 patients (62% female patients; average age, 31.3 +/- 7.2 years; average body mass index, 24.2 +/- 2.7 kg/m2). Preoperatively, 24 patients (92%) were unable to swim at their preinjury level, and swimming was either decreased or discontinued entirely at an average of 6.0 +/- 4.0 months before surgery. All 26 patients (100%) returned to swimming at an average of 3.4 +/- 1.7 months after surgery, including 14 (54%) who returned at a higher level of performance than their preoperative state, 10 (38%) who returned to the same level, and 2 (7%) who returned at a lower level. The ability to return at a higher level of performance was not associated with age (P = .81), sex (P = .62), or body mass index (P = .16). At an average of 31.2 +/- 4.95 months' follow-up, postoperative PRO scores improved significantly from preoperative values (Hip Outcome Score-Activities of Daily Living subscale from 68.5 +/- 19.9 to 93.9 +/- 5.7, P < .0001; Hip Outcome Score-Sports-Specific subscale from 44.0 +/- 21.0 to 85.2 +/- 16, P < .0001; and modified Harris Hip Score from 59.5 +/- 12.1 to 94 +/- 8.6, P < .0001). The average patient satisfaction level was 93% +/- 9%. CONCLUSIONS: Recreational and amateur swimmers return to swimming 100% of the time after hip arthroscopy for FAIS, with just over half returning at a higher level, and most of these patients return within 4 months after surgery. This information is critical in counseling patients on their expectations with respect to returning to swimming after hip arthroscopy for FAIS. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29402587 TI - Prevalence and Consistency in Surgical Outcome Reporting for Femoroacetabular Impingement Syndrome: A Scoping Review. AB - PURPOSE: The purposes of this review were (1) to collate and synthesize research studies reporting any outcome measure on both open and arthroscopic surgical treatment of femoroacetabular impingement (FAI) syndrome and (2) to report the prevalence and consistency of outcomes across the included studies. METHODS: A computer-assisted literature search of the MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Embase databases was conducted using keywords related to FAI syndrome and both open and arthroscopic surgical outcomes, resulting in 2,614 studies, with 163 studies involving 14,824 subjects meeting the inclusion criteria. Two authors independently reviewed study inclusion and data extraction with independent verification. The prevalence of reported outcomes was calculated and verified by separate authors. RESULTS: Between 2004 and 2016, there has been a 2,600% increase in the publication of surgical outcome studies. Patients had a mean duration of symptoms of 27.7 +/- 21.5 months before surgery. Arthroscopy was the surgical treatment used in 71% of studies. The mean final follow-up period after surgery was 32.2 +/- 17.3 months. Follow-up time frames were reported in 78% of studies. Ten different patient reported outcome measures were reported. The alpha angle was reported to be measured 42% less frequently as a surgical outcome than as a surgical indication. Surgical complications were addressed in only 53% of studies and failures in 69%. Labral pathology (91% of studies reporting) and chondral pathology (61%) were the primary coexisting pathologies reported. Clinical signs, as defined by the Warwick Agreement on FAI syndrome, were reported in fewer than 25% of studies. CONCLUSIONS: Most FAI syndrome patients have longstanding pain and potential coexisting pathology. Patient-reported outcome measures and diagnostic imaging are the most frequently reported outcomes. Measures of hip strength and range of motion are under-reported. It is unclear whether the inconsistency in reporting is because of lack of measurement or lack of reporting of specific outcomes in these studies. Current surgical outcomes are limited to mid-term surgical follow up time frames and inconsistent outcome reporting. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies. PMID- 29402589 TI - Dysomma alticorpus, a new species of cutthroat eel from the Gulf of Aqaba, Red Sea (Teleostei: Synaphobranchidae). AB - The cutthroat eel Dysomma alticorpus n. sp. is described based on a single specimen collected in a trammel net at a depth of 350m off Eilat, Israel, Gulf of Aqaba, Red Sea. The new species belongs to the Dysomma anguillare species complex, which comprises species possessing a well-developed pectoral fin, intermaxillary teeth, a uniserial row of 7-15 large compound teeth in the lower jaw (which may be followed by a few smaller teeth), and an anteriorly situated anus with the trunk shorter than the head length. It is characterised by a combination of the following characters: origin of the dorsal fin well anterior to the base of the pectoral fin, predorsal length 13.8% TL; preanal length 22.8% TL; three compound teeth on the vomer; head pores: IO 4, SO 3; M 6; POP 0; AD 1, F 0, ST 0; lateral-line pores: predorsal 4, prepectoral 8, preanal 14, total 57 58, the last at the posterior two-thirds of the total length; MVF 7-16-115; total vertebrae 115. Dysomma alticorpus n. sp. is compared with other species of the genus. A revised key to the species of the genera Dysomma and Dysommina is provided. PMID- 29402590 TI - A euryhaline fish, lost in the desert: The unexpected metapopulation structure of Coptodon guineensis (Gunther, 1862) in the Sebkha of Imlili. AB - Euryhaline Cichlid fish of the species Coptodon guineensis are present in different water holes situated in a dried depression in the desert in the extreme South of Morocco, the Sebkha of Imlili. A genetic survey of this population, using complete sequences of the ND2 gene (mtDNA) and sixteen microsatellite loci, revealed that the fish in the sebkha did not form a single population, but rather a metapopulation. This metapopulational structure may be regarded as good news from the point of view of the conservation of fish in the sebkha. Although small individual populations may have short, finite life spans, the metapopulation as a whole is more stable, because immigrants from one population are likely to re colonize the habitat, left open by the extinction of another. PMID- 29402588 TI - TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion. AB - OBJECTIVE: Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K+ (K2P) channel TALK-1 is abundantly expressed in somatostatin-secreting delta-cells. However, a physiological role for TALK-1 in delta-cells remains unknown. We previously determined that in beta cells, K+ flux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Ca2+ leak, modulating Ca2+ handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca2+-induced Ca2+ release (CICR) from the delta-cell ER, we investigated whether TALK-1 modulates delta cell Ca2+ handling and somatostatin secretion. METHODS: To define the functions of islet delta-cell TALK-1 channels, we generated control and TALK-1 channel deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in delta and alpha-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca2+ imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts delta- and alpha-cell function. RESULTS: TALK-1 channels are expressed in both mouse and human delta-cells, where they modulate glucose-stimulated changes in cytosolic Ca2+ and somatostatin secretion. Measurement of cytosolic Ca2+ levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO delta cells that could be abolished by depleting ER Ca2+ with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and alpha cell Ca2+ oscillations in TALK-1 KO islets, and found that blockade of alpha-cell somatostatin signaling with a somatostatin receptor 2 (SSTR2) antagonist restored glucagon secretion in TALK-1 KO islets. CONCLUSIONS: These data indicate that TALK-1 reduces delta-cell cytosolic Ca2+ elevations and somatostatin release by limiting delta-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion. PMID- 29402591 TI - Unusual Cause of Heart Failure in an Elderly Patient. PMID- 29402592 TI - Selection of the Best of 2017 in Clinical Arrhythmology. PMID- 29402594 TI - [The treatment of attention deficit hyperactivity disorder in children and adolescents: epidemiology, multimorbidity and integrated health services]. PMID- 29402593 TI - [Five cases of aplasia cutis congenita]. PMID- 29402595 TI - Lower rate of early pregnancy loss in patients experiencing early-onset low LH in GnRH antagonist cycles supplemented with menotropin. AB - BACKGROUND/PURPOSE: The role of LH during controlled ovarian stimulation (COS) in the general population remains contentious. There is no consensus on the indications for LH supplementation during COS. The purpose of this study is to determine whether menotropin supplement is associated with decreases in early pregnancy loss rates in patients exhibiting low endogenous LH during COS. METHOD: This is a single-center, retrospective cohort from a university-affiliated hospital. Patients were enrolled from the in-vitro fertilization center from January, 2011 to December, 2014. Patients who experienced a LH level ? 0.8 mIU/mL during stimulation were identified, and patients that received menotropin supplementation were compared to those without menotropin supplementation. Outcome variables, including the number of oocytes retrieved, embryos obtained, implantation rates, pregnancy rates and early pregnancy loss rates, were compared. RESULTS: Patients that experienced low LH during GnRH antagonist protocol and were supplemented with menotropin were associated with lower early pregnancy loss when compared with patients without menotropin supplementation (26.7% vs. 11.5%, p = 0.045). More specifically, in patients who exhibited early onset low LH, before the use of GnRH antagonists, menotropin supplementation was associated with significantly lower early pregnancy loss compared with non supplemented patients (3.3% vs. 29.0%, OR: 0.08, p = 0.012). Beneficial effects persisted after adjusting for confounders (aOR: 0.103, 95% CI: 0.011-0.933). CONCLUSIONS: Menotropin supplementation is associated with decreased early pregnancy loss in patient who exhibited low LH during GnRH antagonist cycles. This effect is especially prominent in patients who experience low LH before the start of GnRH antagonists. PMID- 29402596 TI - Gradual increase in advanced glycation end-products from no diabetes to early and regular gestational diabetes: A case-control study. PMID- 29402597 TI - Shifting to triple value healthcare: Reflections from England. AB - Increasing need and demand because of growing and aging populations combined with stagnant or decreasing resources being invested into healthcare globally mean that a radical shift is needed to ensure that healthcare systems can meet current and future challenges. Quality-, safety- and efficiency-improvement approaches have been used as means to address many problems in healthcare and while they are essential and necessary, they are not sufficient to meet our current challenges. To build resilient and sustainable healthcare systems, we need a shift to focus on triple value healthcare, which will help healthcare professionals improve outcomes at the process, patient and population levels while also optimising resource utilisation. Here we present a brief history of the Quality and Evidence based Healthcare model and then describe how value emerged as a predominant theme in England. We then highlight the four solutions that we, as part of the RightCare programme, designed and refined in the English NHS to turn theory into practice: We end with a description of how triple value is being introduced into Germany and steps that can be taken to facilitate its adoption. PMID- 29402598 TI - Clinical Indications for Carbon Ion Radiotherapy. AB - Compared with photon and proton therapy, carbon ion radiotherapy (CIRT) offers potentially superior dose distributions, which may permit dose escalation with the potential for improved sparing of adjacent normal tissues. CIRT has increased biological effectiveness leading to increased tumour killing compared with other radiation modalities. Here we review these biophysical properties and provide a comprehensive evaluation of the current clinical evidence available for different tumour types treated with CIRT. We suggest that patient selection for CIRT should move away from the traditional viewpoint, which confines use to deep-seated hypoxic tumours that are adjacent to radiosensitive structures. A more integrated translational approach is required for the future as densely ionising C-ions elicit a distinct signal response pathway compared with sparsely ionising X-rays. This makes CIRT a biologically distinct treatment compared with conventional radiotherapy. PMID- 29402599 TI - Pembrolizumab in Combination with Radiotherapy for Metastatic Melanoma - Introducing the PERM Trial. PMID- 29402600 TI - Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine. AB - AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma. PMID- 29402601 TI - Mitophagy in three cases of immune-mediated necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: ultrastructural and immunohistochemical studies. AB - Immune-mediated necrotizing myopathy (IMNM) associated with anti-3-hydroxy-3 methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies occurs in patients both with and without history of statin-intake. The mechanisms of muscle fiber degeneration in this condition remain unknown. We studied pathological changes in muscle biopsies from three patients lacking history of statin-intake. Ultrastructural observations showed accumulation of degenerating mitochondria, glycogen granules and autophagic vacuoles, forming large composites in three cases, along with various nonspecific changes. The autophagic vacuoles often contained remnants of mitochondria, indicating mitophagy. Furthermore, upregulation of B-cell lymphoma 2/adenovirus E1B 19 kD-interacting protein 3 (BNIP3), a protein involved in mitophagy, was observed in two cases examined. In three cases of sporadic inclusion body myositis, two polymyositis, and three IMNM with anti-signal recognition particle antibody, BNIP3 was upregulated less frequently, and ultrastructural change of mitophagy was rarely seen. These findings suggested that mitophagy plays an important role in muscle fiber degeneration in IMNM with anti-HMGCR autoantibodies. PMID- 29402602 TI - Genotype and phenotype analysis of 43 Iranian facioscapulohumeral muscular dystrophy patients; Evidence for anticipation. AB - Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary myopathy (prevalence 1/8300-1/20,000). It is typically characterized by progressive weakness of facial, scapular and humeral muscles. Pelvic, abdominal and lower limbs muscles may eventually be affected. FSHD is classified into two subgroups, FSHD1 and FSHD2. FSHD1 is due to a reduction in the copy number of D4Z4 macrosatellites on chromosome 4q35 (11-100 repeats in normal individuals and 1-10 repeats in patients), and FSHD2 is caused by mutations in SMCHD1 or DNMT3B. Here, we present clinical features and results of genetic analysis on 43 Iranian FSHD patients. Forty patients carried 2-7 D4Z4 repeats based on Southern blot analysis, thus confirming FSHD1 diagnosis in these patients. The number of patients with D4Z4 repeats in the range of 1-3, 4-6 and 7-9 were, respectively, 22, 17 and one. Patients with the lower number of D4Z4 repeats generally showed earlier onset and more severe disease presentations. Anticipation was observed in 14 multi-generational families. To the best of our knowledge, this is the first phenotype and genotype analysis of FSHD patients in the Iranian population. The results of this study will be beneficial for genetic counselling of FSHD patients and their families, and for the establishment of a simple affordable genetic test for Iranians as the majority of patients had 1-5 D4Z4 repeats. PMID- 29402603 TI - Monosodium glutamate impairs the contraction of uterine visceral smooth muscle ex vivo of rat through augmentation of acetylcholine and nitric oxide signaling pathways. AB - The aim of the study was to examine the toxic effects of Monosodium glutamate (MSG), an extensively used food additive, on the contraction of uterine visceral smooth muscle (UVSM) in rat and to elucidate the probable neurocrine mechanism involved in it. MSG produced significant potentiation of the force and inhibition of frequency of uterus recorded ex vivo in chronic MSG exposure and in single dose acute experiments. MSG also produced significant potentiation of force of acetylcholine induced contraction and no alterations in atropine induced contraction of uterus. Further, MSG produced significant increase in force and frequency of contraction of neostigmine incubated uterus. We have found significant potentiation of the post pause force of contraction of uterus when MSG was applied in adrenaline incubated uterus. MSG also produced significant decrease in frequency of contraction of sodium nitroprusside incubated uterus; increase in frequency of N-omega-Nitro-l-Arginine Methyl Ester incubated uterus and no significant changes in frequency of contraction of methylene blue incubated uterus. These results indicate that MSG potentiates the force of contraction of UVSM predominantly by augmenting the activity of cholinergic intrinsic efferents and inhibits the frequency of contraction probably by augmenting the activity of nitrergic efferents. In conclusion, MSG potentiates the force and inhibits the frequency of contraction of UVSM, and the MSG induced effect is probably mediated through the augmentation of acetylcholine and nitric oxide signaling pathways. PMID- 29402604 TI - Limited usefulness of endoscopic evaluation in patients with continuous-flow left ventricular assist devices and gastrointestinal bleeding. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is a frequent cause of re-admission in patients with continuous-flow left ventricular assist devices (CF-LVADs) and is associated with multiple endoscopic procedures and high resource utilization. Our aim was to determine the diagnostic and therapeutic yield of endoscopy and to develop a more cost-effective approach for the management of GIB in CF-LVAD recipients. METHODS: We retrospectively reviewed 428 patients implanted with a CF LVAD between 2009 and 2016 at the Columbia University Medical Center and identified those hospitalized for GIB. Patients were categorized into upper GIB (UGIB), lower GIB (LGIB) and occult GIB (OGIB), based on clinical presentation. RESULTS: Eighty-seven CF-LVAD patients underwent a total of 164 GIBs, resulting in 239 endoscopies. Index presentation was consistent with UGIB in 30 (34.5%), LGIB in 19 (21.8%) and OGIB in 38 (43.7%) patients. On the first GIB, 147 endoscopies localized a bleeding source in 49 (30%), resulting in 24 (16.3%) endoscopic interventions. Of 45 lesions identified, arteriovenous malformations (AVMs) were the most common (22, 48.9%). A gastric or small bowel source (HR 2.8, p = 0.003) and an endoscopic intervention (HR 1.9, p = 0.04) predicted recurrent GIB. The proposed algorithm may reduce the number of endoscopic procedures by 45% and costs by 35%. CONCLUSIONS: Occult GIB is the most common presentation in CF LVAD patients and carries the lowest diagnostic and therapeutic yield of endoscopy. Performing an intervention was among the strongest predictors of recurrent GIB. Our proposed algorithm may decrease the number of low-yield procedures and improve resource utilization. PMID- 29402605 TI - Botulinum toxin B suppresses the pressure ulcer formation in cutaneous ischemia reperfusion injury mouse model: Possible regulation of oxidative and endoplasmic reticulum stress. AB - BACKGROUND: We previously identified that botulinum toxin A (BTX-A) suppressed pressure ulcer (PU) formation after cutaneous ischemia-reperfusion (I/R) injury; however, regulation of cutaneous I/R-induced oxidative and endoplasmic reticulum (ER) stress by BTX-B was not investigated. Additionally, the efficacy of BTX-B injection has never been examined. OBJECTIVE: Objective was to assess the effects of BTX-B on the formation of PU by cutaneous I/R injury, and the regulation of oxidative and ER stress in I/R injury by BTX-B. METHODS: BTX-B was subcutaneously injected into I/R area, and wound size, vascular damage, hypoxic area, and apoptotic cells in I/R area were analyzed. We evaluated the extent of oxidative and ER stress in I/R area by using OKD48 mice and ERAI mice, respectively, which enabled evaluating oxidative and ER stress through bioluminescence detection. RESULTS: BTX-B injection significantly suppressed the formation of PU by cutaneous I/R injury. Cutaneous I/R-induced vascular damage, hypoxic area, and number of oxidative-damaged cells and apoptotic cells were suppressed by BTX-B injection. BTX-B administration significantly inhibited I/R-induced oxidative stress signal in OKD48 mice. BTX-B reduced the I/R-induced oxidative stress associated factors. BTX-B significantly inhibited the oxidant-induced reactive oxygen species and apoptosis of endothelial cells and fibroblasts. BTX-B significantly inhibited I/R-induced ER stress signal in ERAI mice. Cutaneous I/R injury-induced ER stress-response factors and GRP78/BiP and CHOP-positive cells in I/R area were significantly decreased by BTX-B injection. CONCLUSION: BTX-B injection might have protective effects against PU formation after cutaneous I/R injury by reducing vascular damage, hypoxia-induced oxidative and ER stress, and apoptosis. PMID- 29402606 TI - Prognostic value of the blink reflex test in Bell's palsy and Ramsay-Hunt syndrome. AB - OBJECTIVE: This study was designed to evaluate the prognostic value of the blink reflex (BR) test in patients with Bell's palsy (BP) or Ramsay Hunt syndrome (RHS). METHODS: The House-Brackmann (HB) grade of patients diagnosed with BP and RHS was determined at first visit and 3 months later. Final HB grade III-VI was defined as an incomplete recovery. Factors evaluated as prognostic of poor recovery included electroneurography (ENoG) degeneration rate (DR)>90%, and absence of BR. Rates of complete and incomplete recovery were calculated and the associations between prognostic factors and recovery were determined. RESULTS: Of the 129 included patients, 98 (76%) had BP and 31 (24%) had RHS. Absence of BR and low mean ENoG value were significantly associated with incomplete recovery in both the BP and RHS groups (p<0.05 each). Initial HB grade V-VI was significantly associated with rate of incomplete recovery in patients with RHS (p<0.05 each). Severe residual palsy (final HB grade V-VI) in the absence of BR was significantly more frequent in patients with RHS than with BP (p<0.05). CONCLUSION: BR test results were a good prognostic indicator in patients with BP and RHS, as were ENoG value. Absence of BR was more frequently associated with severe residual palsy in RHS than in BP. PMID- 29402607 TI - Conservative treatment for cutaneous fistula resulted from abscess formation in patients with tuberculous cervical lymphadenitis. AB - OBJECTIVE: This study describes the clinical characteristics and course of conservative treatment using anti-Tb medication and dressing in patients with tuberculous cervical fistula resulting from abscess formation, and to investigate factors prognostic of dressing and treatment duration. METHODS: The medical records of patients with tuberculous cervical lymphadenitis were reviewed, and 38 of these patients who presented with cutaneous fistula that resulted from abscess formation were included in the study. RESULTS: The mean duration of dressing until fistula closure was 3.7+/-2.0months (range 0.2-8.5), and the mean duration of treatment with anti-Tb medication was 10.6+/-2.6months (range 6.0-16.0). Patients with concomitant Tb, beyond the cervical lymph nodes showed significantly prolonged duration of dressing (4.6 months vs. 3.2 months, p=0.025) and anti-Tb medication (11.8 months vs. 9.8 months, p=0.015). CONCLUSION: Our results indicate that about 3.7 months of dressing was required for fistula closure. Tuberculous cervical lymphadenitis patients with fistula who had Tb beyond the cervical lymph nodes could be expected to require dressing for 4.6 months and prolonged and anti-Tb medication treatment. PMID- 29402608 TI - Instrumental head impulse test changes after intratympanic gentamicin for unilateral definite Meniere's disease: A systematic review and meta-analysis. AB - OBJECTIVE: To estimate how much could intratympanic gentamicin (ITG) interfere with the vestibular-ocular reflex (VOR) parameters on instrumental head impulse test (HIT), either with scleral search coil or video head impulse test and, eventually, foresee the control of vertigo crisis in unilateral intractable Meniere's disease (MD). METHODS: A literature search was conducted in PubMed, Scopus, Web of Science and Cochrane search engines. The search terms used were "vestibular ocular reflex", "head impulse test", "gentamicin," and "Meniere's disease". Limitations included text availability to be full text, species to be humans and language to be English. All study types were included. 89 articles were screened identifying four eligible studies were identified. Studies were included after consensus of the authors. Meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data was analysed using Review Manager software. RESULTS: Instrumental HIT, after ITG for MD, demonstrated, in the treated ear, a decreased gain in the horizontal, posterior and superior semicircular canals (SCC), of 0.36 (0.26; 0.47; 95% CI), 0.35 (0.22; 0.48; 95% CI) and 0.28 (0.21; 0.35; 95% CI), respectively. Gain asymmetry increases between the treated and non-treated ear of 23.78 (7.22; 40.35; 95% CI), 32.01 (12.27; 51.76; 95% CI) and 17.49 (9.99; 24.99; 95% CI), were similarly detected in the horizontal, posterior and superior SCC, respectively. Significantly smaller gain values after the first treatment were observed for a single injection group versus multiple injection group in the horizontal (p=0.002) and superior SCCs (p=0.016). CONCLUSIONS: Instrumental HIT is effective in evaluating the SCC function after ITG for intractable unilateral MD. VOR gain changes in the direction of the treated ear in the three SCC have been clearly registered. An increased reduction of the VOR gain in the horizontal and anterior SCC also seemed to foresee the control of vertigo crisis. Still, after meta-analysis, the small number of patients' data available did not allow to define a treatment end-point value. This review also indicated that further and better-designed studies are warranted. PMID- 29402609 TI - Combined transoral-transhyoid endoscopic approach for hypopharyngeal cancer. AB - Endoscopic transoral surgery for hypopharyngeal cancer is an effective treatment option to avoid invasive open surgery or chemoradiation. Here we describe the case of a 66-year-old patient with cT2N0M0 pyriform sinus cancer whom we treated using a transoral-transhyoid endoscopic approach. Using this approach, a transhyoid route was created in addition to the transoral route and used to extirpate the tumor. En bloc resection of the tumor was completed without difficulty. A combined transoral-transhyoid approach is a useful surgical option for treatment of selected patients with hypopharyngeal cancer. This technique is straightforward to perform and can be used as a backup technique in endoscopic transoral surgery. Also, more complicated lesions can be resected by this approach than by a single-route transoral approach. PMID- 29402610 TI - Synthesis of chondroitin sulfate CC and DD tetrasaccharides and interactions with 2H6 and LY111. AB - We synthesized the biotinylated chondroitin sulfate tetrasaccharides CS-CC [ 3)betaGalNAc6S(1-4)betaGlcA(1-]2 and CS-DD [-3)betaGalNAc6S(1-4)betaGlcA2S(1-]2 which possess sulfate groups at O-6 of GalNAc and an additional sulfate group at O-2 of GlcA, respectively. We also analyzed interactions among CS-CC and CS-DD and the antibodies 2H6 and LY111, both of which are known to bind with CS-A, while CS-DD was shown for the first time to bind with both antibodies. PMID- 29402611 TI - Structure-activity studies of a macrocyclic peptide inhibitor of histone lysine demethylase 4A. AB - The combination of genetic code reprogramming and mRNA display is a powerful approach for the identification of macrocyclic peptides with high affinities to a target of interest. We have previously used such an approach to identify a potent inhibitor (CP2) of the human KDM4A and KDM4C lysine demethylases; important regulators of gene expression. In the present study, we have used genetic code reprogramming to synthesise very high diversity focused libraries (>1012 compounds) based on CP2 and, through affinity screening, used these to delineate the structure activity relationship of CP2 binding to KDM4A. In the course of these experiments we identified a CP2 analogue (CP2f-7) with ~4-fold greater activity than CP2 in in vitro inhibition assays. This work will facilitate the development of more potent, selective inhibitors of lysine demethylases. PMID- 29402613 TI - Macronutrient intake and oxidative stress/inflammation in type 1 diabetes. PMID- 29402612 TI - Sensitivity and Reproducibility of Automated Feeding Artery Detection Software during Transarterial Chemoembolization of Hepatocellular Carcinoma. AB - PURPOSE: To evaluate the performance of automated feeder detection (AFD) software (EmboGuide; Philips Healthcare, Best, The Netherlands) on hepatocellular carcinoma (HCC) tumors during transarterial chemoembolization. MATERIALS AND METHODS: Forty-four first-time transarterial chemoembolization patients (37 men; mean age, 62 +/- 11 years) were enrolled between May 2012 and July 2013. A total of 86 HCC lesions were treated (2.0 +/- 1.4 lesions per patient; 27.6 +/- 15.9 mm maximum diameter). One hundred forty-seven feeding arteries were found with digital subtraction angiography (DSA), cone-beam computed tomography (CT), and AFD software with the option of manual adjustment (MA). Three independent interventional radiologists analyzed the cone-beam CT images retrospectively with and without AFD and MA. Compared with the number of treated vessels, the number of true positives, false positives, false negatives, sensitivity, and interreader agreement were determined using clustered binary data analysis. RESULTS: Cone beam CT enabled detection of 100 +/- 3.5 feeding arteries (70% sensitivity) with 68.6% agreement among readers. AFD software significantly improved detection to 127+/-0.6 feeding arteries (86% sensitivity, P = .008) with 99.7% reader agreement and reduced the number of false negatives from an average of 47 +/- 3.5 to 20 +/- 0.6 (P = .008). MA of the AFD results produced similar feeding artery detection rates (127 +/- 5.1, 86% sensitivity, P = .8), with lower interreader agreement (91.6%) and slightly fewer false positives (16 +/- 0.0 to 14 +/- 2.5, P = .4). CONCLUSIONS: AFD software significantly improved feeding artery detection rates during transarterial chemoembolization of HCC lesions with better user reproducibility compared with cone-beam CT alone. In conjunction with DSA, AFD enables maximum feeding artery detection in this setting. PMID- 29402614 TI - Tissue Plasminogen Activator to Treat a Stroke after Foam Sclerotherapy in a Woman with a Patent Foramen Ovale. AB - Although foam sclerotherapy to varicose veins is now a popular treatment because of its high efficacy and safety, some neurologic complications have recently been reported. Presently, the effectiveness and safety of intravenous recombinant tissue-type plasminogen activator therapy to stroke following foam sclerotherapy remain unclear. Here, we report the case of a 68-year-old woman whose ischemic symptoms following foam sclerotherapy were treated by intravenous recombinant tissue-type plasminogen activator. After she was admitted, the venous thrombosis in her right soleus vein and a patent foramen ovale causing the right-to-left shunt were revealed. Thus, we diagnosed the ischemic symptoms were due to paradoxical embolism following foam sclerotherapy. After intravenous recombinant tissue-type plasminogen activator therapy, there was no complication and the outcome was good. Our case suggests the effectiveness and the safety of intravenous recombinant tissue-type plasminogen activator therapy to paradoxical embolism following foam sclerotherapy. PMID- 29402615 TI - Improving Call-to-Door Time Using School-Based Intervention by Emergency Medical Technicians: The Akashi Project. AB - BACKGROUND: Identification of stroke signs by emergency medical technicians (EMTs) is important for initiating the "stroke chain of survival." The aim of the present study was to clarify the effect of EMT-led lessons on stroke awareness for schoolchildren in the Akashi project on the transportation time to arrive at the hospital. METHODS: Stroke lessons were given by EMTs to 887 elementary school children in elementary schools between September 2014 and October 2015. Data on transportation times from prehospital records and final diagnoses at discharge were collected from both pre- (period 1; January-June 2014) and posteducation (period 2; January-June 2016) periods. Transportation time or onset-to-door time was divided into two parts: the onset-to-call time and the call-to-door time. RESULTS: One hundred forty-four patients in period 1 and 143 in period 2 were transported with potential strokes identified by EMTs. Among these, 119 (83%) in period 1 and 114 (80%) in period 2 had final diagnosis of stroke or transient ischemic attack. The mean age in period 2 was older than that in period 1 (75 years old versus 72 years old); however, there were no significant differences in gender and consciousness level between the 2 periods. The median call-to-door time of 28 minutes for period-2 patients was significantly shorter than that for period-1 patients (32 minutes, P = .0057). There were no differences in median onset-to-door times and onset-to-call times between the 2 periods. CONCLUSIONS: School-based education about stroke conducted by EMTs may be a promising strategy to cut the prehospital delay and to widely spread stroke awareness via school children and EMTs. PMID- 29402616 TI - Identifying areas under potential risk of illegal construction and demolition waste dumping using GIS tools. AB - Construction and demolition (C&D) waste, dumped illegally in ravines and open areas, contaminates soil and can cause underground water pollution and forests fires. Yet, effective monitoring of illegal C&D waste dumping and enforcing legislation against the offenders are often a difficult task due to the large size of geographic areas that need to be monitored, and limited human and financial resources available to environmental law enforcement agencies. In this study, we use Geographic Information System (GIS) tools and geo-statistical modelling to identify the areas under potentially elevated risk of illegal C&D waste dumping in the Haifa district of Israel. As our analysis shows, locational factors, significantly associated with the accumulated amount of waste in the existing illegal C&D waste sites, include: distance to the nearest main road, depth of the ravine present at the site (p<0.01), and forest proximity (p<0.05). Using the model incorporating these locational parameters, we mapped the areas under the elevated risk of illegal C&D waste dumping for future monitoring. As we suggest, the proposed approach may be useful for environmental law enforcement authorities, by helping them to focus on specific sites for inspection, save resources, and act against the offenders more efficiently. PMID- 29402617 TI - Spatial and temporal distribution of pore gas concentrations during mainstream large-scale trough composting in China. AB - With the advantages of high treatment capacity and low operational cost, large scale trough composting has become one of the mainstream composting patterns in composting plants in China. This study measured concentrations of O2, CO2, CH4 and NH3 on-site to investigate the spatial and temporal distribution of pore gas concentrations during mainstream large-scale trough composting in China. The results showed that the temperature in the center of the pile was obviously higher than that in the side of the pile. Pore O2 concentration rapidly decreased and maintained <5% (in volume) for 38 days or more in both the center and side of the pile and effective O2 diffusion occurred at most in every two contiguous layers. Pore CO2 and CH4 concentrations at each measurement point were positively correlated (0.436 <= r <= 0.570, P < 0.01) and the concentrations in the side of the pile were obviously lower than those in the center. The top layer exhibited highest pore O2 concentration and lowest CO2 and CH4 concentrations, and the bottom layer was on the contrary. No significant differences in pore NH3 concentrations between different layers or between different measurement points in the same layer were found. Therefore, mixing the center and the side of the pile when mechanical turning and adjusting the height of the pile according to the physical properties of bulking agents are suggested to optimize the oxygen distribution and promote the composting process during large-scale trough composting when the pile was naturally aerated, which will contribute to improving the current undesirable atmosphere environment in China. PMID- 29402618 TI - Insights into the effect of chlorine on arsenic release during MSW incineration: An on-line analysis and kinetic study. AB - The effect of chlorine on arsenic (As) release dynamics during municipal solid waste (MSW) incineration in a fluidized bed was studied on the basis of an on line analysis system. This system can continuously and quantitatively measure the concentrations of trace elements in flue gas. Chlorine addition increases obviously the concentration of arsenic in flue gas, indicating a promoting effect of chlorine on arsenic release during MSW incineration. Based on the temporal concentration of arsenic in flue gas, the overall kinetic parameters of arsenic release during MSW incineration were calculated. A second-order kinetic law r(x) = 81.6e-66.9/RT (-1.05x2 - 0.01x + 1.03) was ascertained for arsenic release during MSW incineration without chlorine addition, and r(x) = 177.3e-65.3/RT ( 0.68x2 - 0.43x + 1.08) for arsenic release with chlorine addition. Thermodynamic calculations were performed to predict the partitioning behavior of arsenic during MSW incineration. The addition of chlorine can not only compete with gaseous arsenic to react with mineral, but is also able to increase the volatilization of arsenic by forming volatile arsenic chlorides, thereby affecting the release kinetics of arsenic during MSW incineration. PMID- 29402619 TI - Pyrolysis of the mixture of MSWI fly ash and sewage sludge for co-disposal: Effect of ferrous/ferric sulfate additives. AB - Co-pyrolysis with sewage sludge was proved to be an efficient pre-treatment for sanitary landfill of municipal solid waste incineration (MSWI) fly ash (FA). In this study, to improve the stabilization effect of heavy metals, mixed ferrous/ferric sulfate was added into the FA/SS mixture before pyrolysis. To examine the feasibility of the landfill of co-pyrolysis char, toxicity characteristic leaching procedure (HJ/T300) was conducted. In addition, physio chemical characteristics of char were also tested to explain the stability of heavy metals, including the speciation, mineralogical composition and the morphological features of them. The results indicated that within the range that the obtained char could meet the standard for landfill (GB16889-2008), the appropriate addition of mixed ferrous/ferric sulfates benefit to raising the FA ratio in the FA/SS mixture. The maximum ratio of 67 wt% is achieved when the additive was 1.5 wt% of dried SS (based on iron element) and the pyrolysis temperature was 500 degrees C. PMID- 29402620 TI - Monitoring of mycoflora in outdoor air of different localities of Ahvaz, Iran. AB - INTRODUCTION: Airborne fungi are considered important causes of respiratory allergy and diseases. The knowledge of these fungi in a city or region is important for the ecological diagnosis and specific treatment of respiratory manifestations induced by inhalation of fungal agents. Therefore, in recent years bioaerosols and their density in the air is highly regarded. Identifying fungi with common mycological methods as well as molecular about 5% of people are prone to allergic symptoms of the respiratory tract caused by molds during their lives. Fungi are being considered as one of the most common triggers of asthma, allergic rhinitis and other respiratory problems. AIMS: We aimed at the investigation of the airborne fungi of Ahvaz, Khuzestan province, Iran, during spring and autumn months. MATERIALS AND METHODS: A total of 224 Petri dishes with Sabouraud dextrose agar medium containing chloramphenicol were exposed at seven different regions in the city. Two hundred and twenty-four samples (112 samples per season) were taken from outdoor air seven areas of Ahvaz using microbial sampler (Quick Take-30, SKC, USA) with Debbi 14.3L/min during 5minutes directly on Sabouraud dextrose agar medium with Chloramphenicol and Dechlorane. The effects of environmental factors such as temperature, humidity and wind velocity on bioaerosol concentrations were studied. RESULTS: The dishes exposed yielded 1240 fungal colonies of 24 genera. The most predominant were: Cladosporium spp. (37.1%), Alternaria spp. (25.7%), Aspergillus spp. (13.5%), Penicillium spp. (5.9%), Drechslera spp. (3.46%) and Stemphylium spp. (3.46%). The maximum and minimum numbers of airborne fungi were isolated from humid (32.3%) and industrial (17%) environments, respectively. In addition, positive correlation was observed between the number of fungi and relative humidity (r=0.476, P=0.000) in spring and autumn seasons. CONCLUSION: This study indicated that the incidence of airborne fungi with clinical significance had a direct relationship with the variation of environmental conditions. PMID- 29402621 TI - Evaluation of anti-enzyme properties of Origanum vulgare essential oil against oral Candida albicans. AB - This study aimed to evaluate the anti-enzymatic activity of Origanum vulgare (oregano) essential oil against 15 strains of Candida albicans. Candida albicans samples were isolated from the oral mucosa of patients with denture stomatitis treated in a Dentistry school on a public university. Preparation of the inoculum was performed with a suspension of C. albicans reactivated 24h earlier in 5mL of sterile phosphate buffer saline (PBS) adjusted to a 0.5-turbidity on the MacFarland scale (1,5*108UFC/mL). The essential oil was obtained by hydrodistillation in a Clevenger-type machine and analyzed by gas chromatography. Enzymatic assay was performed to test phospholipase anti-enzymatic properties. Chromatography analysis revealed that the main compounds present in the essential oil were 4-terpineol (41.17%), thymol (21.95%), gamma-terpinene (5.91%) and carvacrol (4.71%). For the anti-enzymatic test, the statistical analysis showed that there was found statistically significant interactions between the factors time and concentration (P<=0,001). Thus, essential oil of oregano at 1%, 5% and 10% presented significant reductions in the production of the phospholipase enzyme produced by Candida albicans strains. However, the longer the incubation time of the essential oil, there is a relatively moderate reduction in its anti enzymatic activity. PMID- 29402622 TI - Retained Paravertebral Catheter Fragment during Removal. A Rare Event without Damage for the Patient. PMID- 29402623 TI - Association of red blood cell transfusion and short- and longer-term mortality after coronary artery bypass graft surgery. AB - OBJECTIVE: Red blood cell (RBC) transfusion has been linked to increased morbidity and mortality. However, strict RBC transfusion recommendations recently have been questioned. The aim of this study was to investigate the short- and long-term mortality outcomes after RBC transfusion in patients undergoing coronary artery bypass graft surgery (CABG). DESIGN: This was a retrospective medical record review. SETTING: Tertiary care academic medical center. PARTICIPANTS: The study included patients who underwent CABG from June 2006 to May 2013. INTERVENTION: Adult (>18 years) cardiac surgery patients who were admitted to the cardiothoracic intensive care unit in a tertiary care academic medical center from June 2006 to May 2013 were collected. In all, 2,180 patients who underwent CABG surgery were included into propensity-score matching analyses, which were matched 1:1. Patients who did not receive transfusion of packed red blood cells (PRBC) (n = 937) were compared with those who received 1 to 5 U (n = 1,113). The study outcomes included mortality rates at 1, 3, and 6 months (short term) and 1, 2, 3, and 4 years (long-term). RESULTS: No statistical significant differences were found for the 1-month (2% v 1.1%, p = 0.292), 3-month (2.9% v 2%, p = 0.396), or 6-month mortality rate (4.3% v 3.4%, p = 0.602) in 446 patients with 1 to 5 U versus 446 matched patients with no PRBC transfusion. Patients in the transfused group compared with those in the no-transfusion group had statistically significant higher 3-year mortality rate (11% v 6.7%; hazard ratio, 1.64; 95% confidence interval, 1.03-2.63; p = 0.038). CONCLUSION: In the present study, patients undergoing CABG surgery and receiving <6 U of PRBC did not have statistically increased risk for in-hospital mortality and up to 2 years postoperatively. A modestly statistically significant difference was noted at 3 years. However, cumulatively, there was no statistical difference between the transfused and nontransfused groups at 4 years. Further studies are needed to confirm the findings and define the population that will benefit the most from blood transfusion. PMID- 29402624 TI - Intraoperative Grading of Mitral Regurgitation During General Anesthesia: Is Hemodynamic Matching Useful? PMID- 29402625 TI - In Reply to "Letter to the Editor: Surgical Start Times and Outcomes: It's Not Just the Hour, but the Day as Well". PMID- 29402626 TI - The Perfect Storm: Carcinoid Heart Disease and Acute Right Ventricular Failure. PMID- 29402627 TI - Survey of Postoperative Regional Analgesia for Thoracoscopic Surgeries in Canada. AB - OBJECTIVES: To determine the preferences and perceptions regarding analgesic options for video-assisted thoracic surgery (VATS) among thoracic anesthesiologists in Canada. DESIGN: A cross-sectional survey of thoracic anesthesiologists with 30 multiple choice questions was e-mailed through an online survey tool called FluidSurveys was performed to members of the Canadian Anesthesiologists' Society. SETTING: A nationwide survey. PARTICIPANTS: Members of Canadian Anesthesiologists' Society who provide thoracic anesthesia INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participant characteristics and outcomes are described using counts and percentages. The frequency of use of each technique for each surgical category is described in percentages and 95% confidence intervals. Based on the responses obtained from individual centers, approximately 469 anesthesiologists provided thoracic care in Canada at the time of the survey. The response rate to the survey was 19% (n = 89). Epidural analgesia was preferred by 93.42% (95% CI 85-98) for open surgeries compared with 41% (30-52) for VATS lobectomies. The difference was statistically significant 52% (37-67). Patient-controlled analgesia was preferred by 27% (19-39) for VATS lobectomies and 46% (35-57) for VATS minor resections. Only 14% preferred paravertebral block for any VATS surgeries. CONCLUSIONS: The use of analgesic techniques for VATS surgeries is variable and largely dictated by provider preferences. The majority still prefer epidural analgesia compared with paravertebral catheter (placed either by the anesthesiologist or surgeon). A broadly acceptable choice that is effective, safe, and technically less demanding requires comparative effectiveness studies and more uniform training for physicians. PMID- 29402628 TI - Total Intravenous Versus Volatile Induction and Maintenance of Anesthesia in Elective Carotid Endarterectomy: Effects on Cerebral Oxygenation and Cognitive Functions. AB - OBJECTIVE: Carotid endarterectomy (CEA) is effective for the prevention of stroke, yet can be associated with a postoperative cognitive dysfunction (POCD) that may be affected by the type of anesthesia. The aim of the study was to compare the effects of total intravenous anesthesia (TIVA) with propofol to volatile induction and maintenance of anesthesia (VIMA) with sevoflurane on cerebral tissue oxygen saturation (SctO2) and POCD. DESIGN: Single-center, pilot randomized prospective study. SETTINGS: Single-center, 1,000-bed clinical hospital. PARTICIPANTS: The study included 40 adult male patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were randomized to the TIVA (n = 20) or the VIMA (n = 20) groups. Cardiorespiratory parameters and SctO2 were monitored during CEA and through 20 hours postoperatively. Cognitive functions were assessed preoperatively and on days 1 and 5 after CEA using the Montreal Cognitive Assessment Score (MoCA). In both groups, the ipsilateral SctO2 decreased after clamping, whereas the contralateral SctO2 asymmetrically decreased in the TIVA group only compared both with baseline and with the VIMA group. The changes in MoCA by day 1 correlated with the relative change in the ipsilateral SctO2 after the clamping in the TIVA group (rho = 0.54, p = 0.015). The improvement of MoCA from days 1 to 5 was related to the relative decline in MAP after the clamping. Better cognitive function was observed by day 5 after sevoflurane VIMA compared with TIVA. CONCLUSION: In CEA, VIMA with sevoflurane might preserve oxygenation in the contralateral hemisphere, suppress an asymmetry of cerebral oxygenation, and improve the early postoperative cognition compared with propofol anesthesia. PMID- 29402629 TI - Point-shear wave elastography predicts liver hypertrophy after portal vein embolization and postoperative liver failure. AB - PURPOSE: To correlate point-shear wave elastography (SWE) with liver hypertrophy after right portal vein embolization (RPVE) and to determine its usefulness in predicting postoperative liver failure in patients undergoing partial liver resection. PATIENTS AND METHODS: Point-SWE was performed the day before RPVE in 56 patients (41 men) with a median age of 66 years. The percentage (%) of future remnant liver (FRL) volume increase was defined as: %FRLpost-%FRLpre%FRLpre*100 and assessed on computed tomography performed 4 weeks after RPVE. RESULTS: Median (range) %FRLpre and %FRLpost was respectively, 31.5% (12-48%) and 41% (23-61%) (P<0.001), with a median %FRL volume increase of 25.6% (-8; 123%). SWE correlated with %FRL volume increase (P=-0.510; P<0.001). SWV (P=0.003) and %FRLpre (P<0.001) were associated with %FRL volume increase at multivariate regression analysis. Forty-three patients (77%) were operated. Postoperative liver failure occurred in 14 patients (32.5%). Median SWE was different between the group with (1.68m/s) and without liver failure (1.07m/s) (P=0.018). The AUROC of SWE predicting liver failure was 0.724 with a best cut-off of 1.31m/s, corresponding to a sensitivity of 21%, specificity of 96%, positive predictive value 75% and negative predictive value of 72%. SWE was the single independent preoperative variable associated with liver failure. CONCLUSIONS: SWE assessed by point-SWE is a simple and useful tool to predict the FRL volume increase and postoperative liver failure in a population of patients with liver tumor. PMID- 29402630 TI - Implicit attentional bias for facial emotion in dissociative seizures: Additional evidence. AB - This study sought to extend knowledge about the previously reported preconscious attentional bias (AB) for facial emotion in patients with dissociative seizures (DS) by exploring whether the finding could be replicated, while controlling for concurrent anxiety, depression, and potentially relevant cognitive impairments. Patients diagnosed with DS (n=38) were compared with healthy controls (n=43) on a pictorial emotional Stroop test, in which backwardly masked emotional faces (angry, happy, neutral) were processed implicitly. The group with DS displayed a significantly greater AB to facial emotion relative to controls; however, the bias was not specific to negative or positive emotions. The group effect could not be explained by performance on standardized cognitive tests or self-reported depression/anxiety. The study provides additional evidence of a disproportionate and automatic allocation of attention to facial affect in patients with DS, including both positive and negative facial expressions. Such a tendency could act as a predisposing factor for developing DS initially, or may contribute to triggering individuals' seizures on an ongoing basis. Psychological interventions such as Cognitive Behavioral Therapy (CBT) or AB modification might be suitable approaches to target this bias in clinical practice. PMID- 29402631 TI - A brief history of typical absence seizures - Petit mal revisited. AB - In this article, we have traced back the history of typical absence seizures, from their initial clinical description to the more recent nosological position. The first description of absence seizures was made by Poupart in 1705 and Tissot in 1770. In 1824, Calmeil introduced the term "absences", and in 1838, Esquirol for the first time used the term petit mal. Reynolds instead used the term "epilepsia mitior" (milder epilepsy) and provided a comprehensive description of absence seizures (1861). In 1854, Delasiauve ranked absences as the seizure type with lower severity and introduced the concept of idiopathic epilepsy. Otto Binswanger (1899) discussed the role of cortex in the pathophysiology of "abortive seizures", whereas William Gowers (1901) emphasized the importance of a detailed clinical history to identify nonmotor seizures or very mild motor phenomena which otherwise may go unnoticed or considered not epileptic. At the beginning of the 20th Century, the term pyknolepsy was introduced, but initially was not universally considered as a type of epilepsy; it was definitely recognized as an epileptic entity only in 1945, based on electroencephalogram (EEG) recordings. Hans Berger, the inventor of the EEG, made also the first EEG recording of an atypical absence (his results were published only in 1933), whereas the characteristic EEG pattern was reported by neurophysiologists of the Harvard Medical School in 1935. The discovery of EEG made it also possible to differentiate absence seizures from so called "psychomotor" seizures occurring in temporal lobe epilepsy. Penfield and Jasper (1938) considered absences as expression of "centrencephalic epilepsy". Typical absences seizures are now classified by the International League Against Epilepsy among generalized nonmotor (absence) seizures. PMID- 29402632 TI - Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome. AB - OBJECTIVE: Phelan-McDermid Syndrome (PMS) is a rare genetic condition associated with loss of function mutations, including deletions, in the chromosome 22q13 region. This PMS phenotype includes intellectual disability, often minimal to absent verbal skills, and other neurologic features including autism spectrum disorder and seizures. Reports indicate seizures and abnormal electroencephalograms (EEGs) in this population, but previous studies do not describe EEG findings during sleep or prognostic value of abnormal EEG over any time period. METHODS: During a natural history study, 16 consecutively enrolled participants (mean age 10years) with PMS underwent both routine (approximately 25min) and overnight (average 9.65h) video-EEG, in addition to genetic testing, neurodevelopmental assessment, neurological examination, and epilepsy phenotyping. Over 240h of EEG, data was recorded. Comparison of findings from the routine EEG was made with prolonged EEG acquired during awake and sleep the same night. In a subset of nine participants, the overnight EEG was repeated one or more years later to observe the natural evolution and prognostic value of any abnormalities noted at baseline. RESULTS: A history of epilepsy, with multiple seizure types, was confirmed in seven of the 16 participants, giving a prevalence of 43.8% in this cohort. All but one EEG was abnormal (15 of 16), and 75% (12 of 16) showed epileptiform activity. Of these, only 25% of participants (3 of 12) showed definitive epileptiform discharges during the routine study. Overnight EEGs (sleep included) did not show any clinical events consistent with seizures or electrophic seizures, however, overnight EEG showed either more frequent and/or more definitive epileptiform activity in 68.75% (11 of 16) participants. All seven of the 16 participants who had previously been diagnosed with epilepsy showed epileptiform abnormalities. In addition to a wide range of epileptiform activity observed, generalized slowing with poor background organization was frequently noted. Follow-up EEG confirmed persistence of abnormal discharges, but none of the abnormal EEGs showed evolution to electrographic seizures. Clinically, there was no emergence of epilepsy or significant developmental regression noted in the time frame observed. CONCLUSIONS: This is the first and most abundant prolonged awake and sleep video-EEG data recorded in a PMS cohort to date. The importance of overnight prolonged EEGs is highlighted by findings from this study, as they can be used to document the varied topographies of EEG abnormalities in conditions such as PMS, which are often missed during routine EEG studies. While the long-term significance of the EEG abnormalities found (beyond 1year) remains uncertain despite their persistence over time, these findings do underscore the current clinical recommendation that overnight prolonged EEG studies (with sleep) should be conducted in individuals with PMS. PMID- 29402633 TI - First-aid management of tonic-clonic seizures among healthcare personnel: A survey by the Apulian section of the Italian League Against Epilepsy. AB - INTRODUCTION: To evaluate the knowledge of healthcare workers about first-aid measures to be performed during and after a tonic-clonic seizure. METHODS: One hundred and fifty-four healthcare workers (86 physicians) working at 8 tertiary hospitals in the Apulia region, Italy, responded to a questionnaire comprising of 28 questions based on available Italian and international recommendations about what to do during a tonic-clonic seizure. RESULTS: One hundred and fifty-four healthcare workers completed and returned surveys with a response rate of 96.25%. There were 55 nurses (35.7%), 86 physicians (55.8%), and 13 healthcare workers with different roles (Electroencephalograph technicians, psychologists, social workers). Among physicians, there were 7 cardiologists, 3 surgeons, 12 infectious disease specialists, 11 internal medicine specialists, 2 psychiatrists, 2 gynecologists, 27 specialists working in the emergency department, and 22 physicians with different specializations. Nearly 90% of the respondents identified head protection as important first aid, while 100% responded to not keep the legs elevated. To avoid tongue bite, both physicians and other healthcare workers would put something in the mouth (54.0%), like a Guedel cannula (71.0%) fingers (29.5%). Grabbing arms and legs, trying to stop the seizure, would be potentially performed by 11.6% of our sample. Physicians would administer a benzodiazepine during the seizure (65.7%) and during the postictal phase (29.2%), even if the patient is known to have epilepsy (23.7%), and in this case, 11.3% of respondents would administer the usual antiepileptic medications. More than half of respondents would call the emergency telephone number, because of necessary hospitalization in case of tonic-clonic seizure, even if it is experienced by a patient known to have epilepsy. CONCLUSION: Our survey suggests the need for epilepsy educational programs on first-aid management of seizures among healthcare workers. PMID- 29402634 TI - A CYP2B6-humanized mouse model and its potential applications. AB - CYP2B6 is a human microsomal cytochrome P450 enzyme with broad substrate selectivity. CYP2B6 is the only functional member of the human CYP2B gene subfamily, which differs from the situation in rodents, such as mouse, where multiple functional Cyp2b genes are expressed. Recent studies with Cyp2b knockout or knockdown mouse models have yielded insights into the in vivo roles of mouse CYP2B enzymes in drug disposition and xenobiotic toxicity. A CYP2B6-humanized mouse model (CYP2A13/2B6/2F1-transgenic/Cyp2abfgs-null), which expresses human CYP2B6 in the liver, and human CYP2A13 and CYP2F1 in the respiratory tract, but not any of the mouse Cyp2b genes, has also been established. In the CYP2B6 humanized mouse, the CYP2B6 transgene is expressed primarily in the liver, where it was found to be active toward prototype CYP2B6 substrate drugs. The regulatory elements of the CYP2B6 transgene appear to be compatible with mouse nuclear receptors that mediate CYP2B induction. Therefore, the CYP2B6-humanized mouse is a valuable animal model for studying the impact of CYP2B6 expression or induction on drug metabolism, drug efficacy, drug-drug interaction, and drug/xenobiotic toxicity. In this mini-review, we provide a brief background on CYP2B6 and the Cyp2b-knockout and CYP2B6-humanized mice, and discuss the potential applications and limitations of the current models. PMID- 29402635 TI - Disposal of the residual autologous HSC units: Results of a survey carried out two years after the publication of a national policy in Italy. PMID- 29402636 TI - Elimination of lymphatic filariasis in west African urban areas: is implementation of mass drug administration necessary? AB - Lymphatic filariasis in Africa is caused by the parasite Wuchereria bancrofti and remains a major cause of morbidity and disability in 74 countries globally. A key strategy of the Global Programme for the Elimination of Lymphatic Filariasis, which has a target elimination date of 2020, is the treatment of entire endemic communities through mass drug administration of albendazole in combination with either ivermectin or diethylcarbamazine. Although the strategy of mass drug administration in combination with other interventions, such as vector control, has led to elimination of the infection and its transmission in many rural communities, urban areas in west Africa present specific challenges to achieving the 2020 targets. In this Personal View, we examine these challenges and the relevance of mass drug administration in urban areas, exploring the rationale for a reassessment of policy in these settings. The community-based mass treatment approach is best suited to rural areas, is challenging and costly in urban areas, and cannot easily achieve the 65% consistent coverage required for elimination of transmission. In our view, the implementation of mass drug administration might not be essential to interrupt transmission of lymphatic filariasis in urban areas in west Africa. Evidence shows that transmission levels are low and that effective mass drug distribution is difficult to implement, with assessments suggesting that specific control measures against filariasis in such dynamic settings is not an effective use of limited resources. Instead, we recommend that individuals who have clinical disease or who test positive for W bancrofti infection in surveillance activities should be offered antifilarial drugs through a passive surveillance approach, as well as morbidity management for their needs. We also recommend that more precise studies are done, so that mass drug administration in urban areas is considered if sustainable transmission is found to be ongoing. Otherwise, the limited resources should be directed towards other elements of the lymphatic filariasis programme. PMID- 29402637 TI - Endometrial blood perfusion as assessed using a novel laser Doppler technique in Angus cows. AB - Previous studies have characterized ovarian steroid synthesis which directly affects uterine environment and blood flow. Clearance of steroids occurs primarily in hepatic tissues, however, it was discovered that there is an abundant activity of the phase II steroid metabolizing enzyme UDP glucuronosyltransferase (UGT) in uterine biopsies. No minimally invasive techniques for collecting endometrial perfusion, which is affected by steroids and indicative of reproductive health, have been developed for livestock. The objective of the present study was to characterize UGT activity and endometrial blood perfusion during a normal estrous cycle of cattle. It was hypothesized that there would be increased steroid metabolism during the luteal phase of the estrous cycle and in the uterine horn ipsilateral to the corpus luteum (CL). During the first synchronized estrous cycle, progesterone and UGT activity increased on Day 6 compared with 0 and 3, with the first day of estrus being considered Day 0 of the study. Endometrial perfusion was greater ipsilateral to the CL compared with contralateral on Day 12, and was less ipsilateral to the CL compared with contralateral on Day 18. Similar to perfusion results, nitric oxide metabolites (nitrites) were greatest in the endometrium ipsilateral as compared with contralateral to the CL. Moreover, there was a positive correlation (r = 0.28; P = .04) between endometrial perfusion and nitrite concentration. It is concluded that activity of UGT within the endometrium is affected by the contralateral or ipsilateral location of the CL, and collection of endometrial perfusion data using a laser Doppler probe could be a viable measurement technique as indicated by associated nitrite concentrations in the present study. PMID- 29402638 TI - Regulation of conceptus interferon-tau gene subtypes expressed in the uterus during the peri-implantation period of cattle. AB - Conceptus interferon tau (IFNT), produced by the embryonic trophectoderm, is known as a major signaling protein essential for the process of maternal recognition of pregnancy in ruminants. Similar to other IFN gene families such as IFNA and IFNB, multiple IFNT genes exist. The number of IFNT genes actively transcribed and regulated in conceptuses of cattle has, however, not been well characterized. In this study, IFNT transcripts in utero were studied through the use of next generation sequencer. Among 38 IFN genes registered and eight annotated as IFNT, only two transcripts, IFNT1 and IFNTc1, were found in conceptuses in utero. Relative abundance of transcription factor(s) involved in the regulation of IFNT genes were investigated by real-time PCR. Transcriptional activity of IFNT1 and IFNTc1 were investigated using bovine non-trophoblast ear fibroblast (EF) cells, which were co-transfected with luciferase reporter constructs with upstream (-631 to -51) promoter regions of IFNT1 or IFNTc1 and various transcription factor expression plasmids, CDX2, AP1 (JUN), ETS2 and/or CREBBP. CDX2 with AP1 and ETS2 was found to increase luciferase activity of IFNT1 and IFNTc1 approximately 14- and 11-fold, respectively, in EF cells, which do not express the CDX2 gene. These results indicated that two isoforms of conceptus IFNT genes of cattle could be regulated differently in utero. Furthermore, IFNT1 and IFNTc1 were found to have similar antiviral activity, suggesting that both IFNT genes could function to increase conceptus signaling to the uterine endometrium for the process of maternal recognition of pregnancy during the pre implantation period. PMID- 29402639 TI - Reproductive responses to sexually active buck of does treated with melatonin when body weight/body condition is increasing or decreasing. AB - When the sexual activity of bucks is minimal, there is a minimal male effect on does regardless of their body weight (BW)/body condition (BC) and whether does are treated with melatonin or not. The study examines whether sexually active bucks can induce an adequate male effect in does with an increasing or decreasing trajectory of change in BW/BC when does are or not treated with melatonin. During natural anoestrus, 46 Blanca Andaluza does were assigned to two groups: 1) low BW/low BC group in which does were fed 1.9 times maintenance requirements for dietary energy for gaining BW/BC (LLg group; n = 23); or 2) a high BW/high BC group in which the does were fed 0.4 times maintenance requirements for dietary energy that resulted in a loss of BW/BC (HHl group; n = 23). There were similar numbers of does in each group that were treated or not treated with melatonin (MEL). Following 48 days of isolation from bucks, four sexually active individuals fitted with marking harnesses were transferred to the paddock containing the does of each group. Blood samples were collected by jugular venipuncture (before the distribution of concentrate) twice per week. The effect of the treatments (increasing or decreasing BW/BC and melatonin) on the different variables that were assessed were analysed using an ANOVA or the Fisher-Freeman Halton exact probability test as necessary. During the 35 days after treatments were applied, the percentage of females expressing oestrous and having an ovulation were greater in the LLg + MEL than HHl-MEL subgroup (P < 0.05). The interaction of nutrition * melatonin treatment had a significant effect on reproduction of does (P < 0.05). This could be explained by the greater plasma glucose and IGF-1 and lesser plasma non-esterified fatty acid concentrations in does with increasing BW/BC (P < 0.01), and the greater IGF-1 concentrations of MEL-treated females (P < 0.01). The LH concentration and pulsatile release of this hormone from the pituitary were also modified by the presence of the males (P < 0.01). Furthermore, the LLg + MEL-treated does were responsive to the presence of bucks (P < 0.05). The present results indicate sexually active males cannot induce an adequate reproductive response in females with decreasing BW/BC even when does are being treated with melatonin. The presence of bucks enhanced the doe reproductive response when does were treated with melatonin and a pattern of increasing BW/BC. PMID- 29402640 TI - Effect of thickness on optical properties of monolithic CAD-CAM ceramics. AB - OBJECTIVE: To compare the effect of material and thickness on the color stability and relative translucency parameters (RTP) for monolithic ceramics subjected to coffee thermocycling. METHODS: Four specimens each at thicknesses of 0.5, 0,7 and 1 mm were sectioned from monolithic ceramics [preshaded monolithic zirconia (MonZr), lithium disilicate (LDS) and zirconia reinforced lithium silicate (ZLS)]. The specimens were glazed and subjected to 5000 coffee thermocycling. The color coordinates of specimens were determined with a spectroradiometer and color differences and RTP values were calculated with CIEDE2000 color difference and TPCIEDE2000 formulas. ANOVA was used to analyze CIEDE2000 color difference and RTP values (alpha = .05). RESULTS: For the color difference data, the 2-way ANOVA revealed a significant interaction between material and different thickness (P = .002). Except for 0.5 mm thick ZLS material, all materials in all thicknesses studied presented color changes within the clinically acceptable limits after coffee thermocycling. For the RTP data, the 3-way ANOVA revealed a highly significant interaction between material and different thicknesses (P < .001). CONCLUSIONS: Material type and thickness can be expected to affect color change and relative translucency of the restorations made with preshaded MonZr, LDS and ZLS materials. Except for 0.5 mm thick ZLS material, color changes of all studied materials were within the clinically acceptable limits. Except ZLS material, color changes of other materials were not significantly affected by thickness. Staining in coffee was not found to affect translucency, and the materials' translucency parameters were ranked from high to low as LDS, ZLS and MonZr at each thickness studied. PMID- 29402641 TI - [Emphysema, did you say emphysema?] AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common condition that may initially look simple but may conceal other diseases capable of accelerating its natural history or even simulating it. We describe four cases presenting as COPD with emphysema that were reclassified on the basis of certain clinical characteristics and the radiological pattern. CASE REPORTS: A 52 year old never smoking woman presenting with emphysema was eventually diagnosed as having lymphangioleiomyomatosis on the basis of an abdominal CT scan showing kidney angiomyolipomas. A 44 years old smoker presenting with rapidly evolving emphysema was eventually diagnosed as having Langerhans cell histiocytosis on the basis of a previous chest CT (four years earlier) showing cavitating nodules. An airport refueler, 73 years old, with severe emphysema despite never having smoked, was eventually diagnosed as suffering from alpha-1 antitrypsin deficiency. The last patient was a 54 year old man, a never smoker, who presented with severe airflow limitation and multilobar hyperlucency, with bronchiectasis in the same areas. He was eventually diagnosed as having a severe form of the Swyer-James-MacLeod syndrome. CONCLUSION: These four case reports underline the importance of questioning the diagnosis of COPD when certain particular phenotypic characteristics are identified. PMID- 29402642 TI - [Study about the prevalence of the obstructive sleep apnoea syndrome in Vietnam]. AB - INTRODUCTION: Epidemiological studies on obstructive sleep apnoea syndrome (OSAS) in Asia, South East Asia in particular, are few. The EPSASIE study aimed to determine the prevalence of OSAS in an adult Vietnamese population and to describe its characteristics. METHODS: This is a prospective, observational, multicenter study. Nocturnal ventilatory polygraphy (PV) or polysomnography (PSG) were performed in patients having symptoms evocative of the SAS syndrome and an index of respiratory events (IER)>10/h or>25 in one hour, measured by RU Sleeping. RESULTS: A total of 667/750 validated questionnaires were received. The mean age of the study population was 44+/-12 years with a mean body mass index of 21.6+/-5.2kg/m2. PV or PSG were performed on 93 subjects after positive screening by RU Sleeping. OSAS with an apnoea-hypopnoea index (AHI)>5 was found in 57 subjects (8.5%) and in 35 subjects with AHI>15 (5.2% of cases). CONCLUSION: The prevalence of OSAS is quite high in the Vietnamese population and comparable with current literature data. PMID- 29402643 TI - [Adherence to treatment with continuous positive airways pressure]. AB - INTRODUCTION: Continuous positive airways pressure (CPAP) is the standard treatment for obstructive sleep apnea syndrome (OSAS). It produces substantial benefits if used for the appropriate indication and if patients adhere to treatment. METHODS: We conducted a prospective study of 103 patients treated with CPAP over four years follow-up. RESULTS: Our population had a mean age of 52 years with a sex ratio of 0.63. Face to face, individual education was provided in all cases. CPAP titration was performed by an unattended domiciliary autoadjusted CPAP device in 83.5% of patients for 15 days to one month. Twenty patients refused CPAP treatment after the period of titration. Eighty two patients (98.8%) were treated by constant CPAP. Seventy five percent of the patients complained of at least one side effect. The more common were nasal (56.6%) and mask related problems (40%). Seventy six percent of patients used CPAP for more than 4hours per day. Eleven patients stopped CPAP therapy because of intolerance (10 cases) and reluctance to instrumental therapy (one case). Adherence to CPAP therapy was associated with the severity of OSAS, the level of daytime sleepiness, higher pressures, repeated education during the course of follow up, clinical efficacy and the presence of fewer side-effects. CONCLUSIONS: We obtained satisfactory rates of adherence and tolerance of CPAP assisted by regular medical and technical follow-up of patients. PMID- 29402644 TI - gammadelta T cell responses: How many ligands will it take till we know? AB - gammadelta T cells constitute a sizeable and non-redundant fraction of the total T cell pool in all jawed vertebrates, but in contrast to conventional alphabeta T cells they are not restricted by classical MHC molecules. Progress in our understanding of the role of gammadelta T cells in the immune system has been hampered, and is being hampered, by the considerable lack of knowledge regarding the antigens gammadelta T cells respond to. The past few years have seen a wealth of data regarding the TCR repertoires of distinct gammadelta T cell populations and a growing list of confirmed and proposed molecules that are recognised by gammadelta T cells in different species. Yet, the physiological contexts underlying the often restricted TCR usage and the chemical diversity of gammadelta T cell ligands remain largely unclear, and only few structural studies have confirmed direct ligand recognition by the TCR. We here review the latest progress in the identification and validation of putative gammadelta T cell ligands and discuss the implications of such findings for gammadelta T cell responses in health and disease. PMID- 29402645 TI - Large-scale expansion of Vgamma9Vdelta2 T cells with engineered K562 feeder cells in G-Rex vessels and their use as chimeric antigen receptor-modified effector cells. AB - Vgamma9Vdelta2 T cells are a minor subset of lymphocytes in the peripheral blood that has been extensively investigated for their tolerability, safety and anticancer efficacy. A hindrance to the broad application of these cells for adoptive cellular immunotherapy has been attaining clinically appropriate numbers of Vgamma9Vdelta2 T cells. Furthermore, Vgamma9Vdelta2 T cells exist at low frequencies among cancer patients. We, therefore, sought to conceive an economical method that allows for a quick and robust large-scale expansion of Vgamma9Vdelta2 T cells. A two-step protocol was developed, in which peripheral blood mononuclear cells (PBMCs) from healthy donors or cancer patients were activated with Zometa and interleukin (IL)-2, followed by co-culturing with gamma irradiated, CD64-, CD86- and CD137L-expressing K562 artificial antigen-presenting cells (aAPCs) in the presence of the anti-CD3 antibody OKT3. We optimized the co culture ratio of K562 aAPCs to immune cells, and migrated this method to a G-Rex cell growth platform to derive clinically relevant cell numbers in a Good Manufacturing Practice (GMP)-compliant manner. We further include a depletion step to selectively remove alphabeta T lymphocytes. The method exhibited high expansion folds and a specific enrichment of Vgamma9Vdelta2 T cells. Expanded Vgamma9Vdelta2 T cells displayed an effector memory phenotype with a concomitant down-regulated expression of inhibitory immune checkpoint receptors. Finally, we ascertained the cytotoxic activity of these expanded cells by using nonmodified and chimeric antigen receptor (CAR)-engrafted Vgamma9Vdelta2 T cells against a panel of solid tumor cells. Overall, we report an efficient approach to generate highly functional Vgamma9Vdelta2 T cells in massive numbers suitable for clinical application in an allogeneic setting. PMID- 29402646 TI - Fall-Risk-Increasing Drugs: A Systematic Review and Meta-analysis: III. Others. AB - BACKGROUND AND OBJECTIVE: The use of psychotropic medication and cardiovascular medication has been associated with an increased risk of falling. However, other frequently prescribed medication classes are still under debate as potential risk factors for falls in the older population. The aim of this systematic review and meta-analysis is to evaluate the associations between fall risk and nonpsychotropic and noncardiovascular medications. METHODS AND DESIGN: A systematic review and meta-analysis. A search was conducted in Medline, PsycINFO, and Embase. Key search concepts were "falls," "aged," "medication," and "causality." Studies were included that investigated nonpsychotropic and noncardiovascular medications as risk factors for falls in participants >=60 years or participants with a mean age >=70 years. A meta-analysis was performed using the generic inverse variance method, pooling unadjusted and adjusted odds ratio (OR) estimates separately. RESULTS: In a qualitative synthesis, 281 studies were included. The results of meta-analysis using adjusted data were as follows (a pooled OR [95% confidence interval]): analgesics, 1.42 (0.91-2.23); nonsteroidal anti-inflammatory drugs (NSAIDs), 1.09 (0.96-1.23); opioids, 1.60 (1.35-1.91); anti-Parkinson drugs, 1.54 (0.99-2.39); antiepileptics, 1.55 (1.25 1.92); and polypharmacy, 1.75 (1.27-2.41). Most of the meta-analyses resulted in substantial heterogeneity that did not disappear after stratification for population and setting in most cases. In a descriptive synthesis, consistent associations with falls were observed for long-term proton pump inhibitor use and opioid initiation. Laxatives showed inconsistent associations with falls (7/20 studies showing a positive association). CONCLUSION: Opioid and antiepileptic use and polypharmacy were significantly associated with increased risk of falling in the meta-analyses. Long-term use of proton pump inhibitors and opioid initiation might increase the fall risk. Future research is necessary because the causal role of some medication classes as fall-risk-increasing drugs remains unclear, and the existing literature contains significant limitations. PMID- 29402647 TI - Frailty Screening (FRAIL-NH) and Mortality in French Nursing Homes: Results From the Incidence of Pneumonia and Related Consequences in Nursing Home Residents Study. AB - OBJECTIVES: To investigate the ability of the fatigue, resistance, ambulation, incontinence or illness, loss of weight, nutritional approach, and help with dressing (FRAIL-NH) tool to predict mortality. DESIGN: The Incidence of Pneumonia and Related Consequences in Nursing Home Residents (INCUR) study database was used. This was an observational cohort study in French nursing homes conducted over 12 months in 2012. PARTICIPANTS: A total of 788 residents aged 60 years or older, from 13 randomly selected French nursing homes. MEASUREMENTS: FRAIL-NH was generated from the available variables at baseline. FRAIL-NH scores ranged from 0 to 14 and people were categorized as nonfrail (0-1), frail (2-5), and most frail (6-14). Mortality data were obtained from medical charts and confirmed by the nursing home administrative documentation. RESULTS: Mean age of the participants was 86.2 +/- 7.5 years, and 74.5% were women. The prevalence of persons with FRAIL-NH score greater than 1 was 88.8%, with 54.2% and 34.6% of residents identified as most frail and frail, respectively. The mean FRAIL-NH score was 6.0 +/- 3.4. Women (N = 583) were frailer (6.1 +/- 3.4) than men (N = 200, 5.5 +/- 3.4; P = .027). Overall, 136 residents died over the 1-year follow-up period. The FRAIL-NH score was a predictor of mortality (adjusted hazard ratios: for frail group 1.15, 95% confidence interval 0.55-2.41; for most frail group 2.14, 95% confidence interval 1.07- 4.27). CONCLUSIONS: FRAIL-NH is a predictor of mortality in nursing home residents and the score could assist with guiding appropriate care planning. PMID- 29402648 TI - Treatment of Cardiovascular Diseases Among Elderly Residents of Long-term Care Facilities. AB - BACKGROUND: The prevalence of cardiovascular diseases among nursing home residents is high but little is known whether pharmacologic therapy recommended by actual medication guidelines is followed by facility's staff. AIM: To evaluate the adherence to actual guidelines for treatment of cardiovascular diseases among older adult residents of long-term care (LTC) facilities. MATERIAL AND METHODS: The cross-sectional study was performed from December 2009 to November 2010 among 189 elderly residents aged >=60 years in 3 LTC facilities in Poland: 1 long-term care hospital (LTCH) and 2 nursing homes (NHs). The initial evaluation included analysis of medical documentation (all diagnosed diseases and used drugs), blood pressure (BP) measurements and performance of Mini Nutritional Assessment Short Form (MNA-SF), Abbreviated Mental Test Score (AMTS), Activities of Daily Living (ADL) score, and Barthel Index. Prescribed medication for hypertension (HT), heart failure (HF), and coronary heart disease (CHD) were compared to current European Cardiology Society (ESC), and European Society of Hypertension (ESH) medication guidelines. Residents were divided into 3 subgroups: with HT, HF, and CHD. Results were presented as means and standard deviation. Groups were compared using Mann-Whitney U test for nonparametric data and chi-square test to assess differences in distribution of categorical variables. P values <.05 were considered statistically significant. RESULTS: CHD was diagnosed among 114 residents (60.3%) but only 60.5% of them were treated with aspirin (ASA), 45.6% with beta-blockers (BBs), 60.5% with angiotensin-converting enzyme inhibitor (ACEI), and 24.6% with statins. HF observed in 75% of cases was treated by using ACEI (54.7%), BBs (45.3%), loop diuretics (LDs, 36%), mineralocorticoid-receptor antagonists (MRAs, 21.3%). HT was diagnosed among 98 study participants (51.9%) and in the majority of cases (76.6%) was well controlled (mean BP: 133.7 +/- 17.6/73.8 +/- 10.2 mmHg). The most popular antihypertensive drugs were ACEIs (77.6%), BBs (40.8%) and calcium channel blockers (CCBs, 26.5%) whereas thiazides, alpha-blockers (ABs), and angiotensin receptor blockers (ARBs) were used less frequently. CONCLUSION: In summary, the study showed that insufficient treatment of cardiovascular diseases among elderly residents of LTC facilities could be a potential risk factor of poor prognosis. PMID- 29402649 TI - Is Neighborhood Green Space Associated With Less Frailty? Evidence From the Mr. and Ms. Os (Hong Kong) Study. AB - OBJECTIVES: To examine whether neighborhood green space was related to frailty risk longitudinally and to examine the relative contributions of green space, physical activity, and individual health conditions to the frailty transitions. DESIGN, SETTING, AND PARTICIPANTS: Four thousand community-dwelling Chinese adults aged >=65 years participating in the Mr. and Ms. Os (Hong Kong) study in 2001-2003 were followed up for 2 years. METHODS: The percentage of green space within a 300-meter radial buffer around the participants' place of residence was derived for each participant at baseline based on the normalized difference vegetation index. Frailty status was classified according to the Fried criteria at baseline and after 2 years. Ordinal logistic regression and path analysis were used to examine associations between green space and the frailty transitions, adjusting for demographics, socioeconomic status, lifestyle factors, health conditions, and baseline frailty status. RESULTS: At baseline, 53.5% of the participants met the criterion for robust, 41.5% were classified as prefrailty, and 5.0% were frail. After 2 years, 3240 participants completed all the measurements. Among these, 18.6% of prefrail or frail participants improved, 66% remained in their frailty state, and 26.8% of robust or prefrail participants progressed in frailty status. In multivariable models, the frailty status of participants living in neighborhoods with more than 34.1% green space (the highest quartile) at baseline was more likely to improve at the 2-year follow-up than it was for those living in neighborhoods with 0 to 4.5% (the lowest quartile) [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.04-1.60; P for trend: 0.022]. When men and women were analyzed separately, the association between green space and frailty remained significant in men (OR: 1.40, 95% CI: 1.03-1.90) but not in women. Path analysis showed that green space directly affects frailty transitions (beta = 0.041, P < .05) and also exerts an effect through physical activity (beta = 0.034, P < .05). Physical activity directly affects frailty (beta = 0.134, P < .05), and also indirectly affects frailty through health conditions including number of diseases (beta = -0.057, P < .05) and cognitive functions (beta = 0.041, P < .05). The magnitude of the direct effect of green space on the 2-year frailty transitions is comparable to those of the indirect effect through physical activity. CONCLUSION: Older people living in neighborhoods with a higher percentage of green space were associated with improvement in frailty status, independent of a wide range of individual characteristics. PMID- 29402650 TI - A Quality Improvement System to Manage Feeding Assistance Care in Assisted Living. AB - PURPOSE: To describe a feasible quality improvement system to manage feeding assistance care processes in an assisted living facility (ALF) that provides dementia care and the use of these data to maintain the quality of daily care provision and prevent unintentional weight loss. DESIGN AND METHODS: Supervisory ALF staff used a standardized observational protocol to assess feeding assistance care quality during and between meals for 12 consecutive months for 53 residents receiving dementia care. Direct care staff received feedback about the quality of assistance and consistency of between-meal snack delivery for residents with low meal intake and/or weight loss. RESULTS: On average, 78.4% of the ALF residents consumed more than one-half of each served meal and/or received staff assistance during meals to promote consumption over the 12 months. An average of 79.7% of the residents were offered snacks between meals twice per day. The prevalence of unintentional weight loss averaged 1.3% across 12 months. IMPLICATIONS: A quality improvement system resulted in sustained levels of mealtime feeding assistance and between-meal snack delivery and a low prevalence of weight loss among ALF residents receiving dementia care. Given that many ALF residents receiving dementia care are likely to be at risk for low oral intake and unintentional weight loss, ALFs should implement a quality improvement system similar to that described in this project, despite the absence of regulations to do so. PMID- 29402651 TI - Progressive Resistance and Balance Training for Falls Prevention in Long-Term Residential Aged Care: A Cluster Randomized Trial of the Sunbeam Program. AB - BACKGROUND: Falls prevention is an international priority, and residents of long term aged care fall approximately 3 times more often than community dwellers. There is a relative scarcity of published trials in this setting. OBJECTIVES: Our objective was to undertake a randomized controlled trial to test the effect of published best practice exercise in long-term residential aged care. The trial was designed to determine if combined high level balance and moderate intensity progressive resistance training (the Sunbeam Program) is effective in reducing the rate of falls in residents of aged care facilities. METHOD: A cluster randomized controlled trial of 16 residential aged care facilities and 221 participants was conducted. The broad inclusion criterion was permanent residents of aged care. Exclusions were diagnosed terminal illness, no medical clearance, permanent bed- or wheelchair-bound status, advanced Parkinson's disease, or insufficient cognition to participate in group exercise. Assessments were taken at baseline, after intervention, and at 12 months. Randomization was performed by computer-generated sequence to receive either the Sunbeam program or usual care. A cluster refers to an aged care facility. INTERVENTION: The program consisted of individually prescribed progressive resistance training plus balance exercise performed in a group setting for 50 hours over a 25-week period, followed by a maintenance period for 6 months. OUTCOME MEASURES: The primary outcome measure was the rate of falls (number of falls and days followed up). Secondary outcomes included physical performance (Short Physical Performance Battery), quality of life (36-item Short-Form Health Survey), functional mobility (University of Alabama Life Space Assessment), fear of falling (Falls Efficacy Scale International), and cognition (Addenbrooke's Cognitive Evaluation-revised). RESULTS: The rate of falls was reduced by 55% in the exercise group (incidence rate ratio = 0.45, 95% confidence interval 0.17-0.74); an improvement was also seen in physical performance (P = .02). There were no serious adverse events. CONCLUSION: The Sunbeam Program significantly reduced the rate of falls and improved physical performance in residents of aged care. This finding is important as prior work in this setting has returned inconsistent outcomes, resulting in best practice guidelines being cautious about recommending exercise in this setting. This work provides an opportunity to improve clinical practice and health outcomes for long-term care residents. PMID- 29402652 TI - Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: II. Psychotropics. AB - BACKGROUND AND OBJECTIVE: Falls are a major public health problem in older adults. Earlier studies showed that psychotropic medication use increases the risk of falls. The aim of this study is to update the current knowledge by providing a comprehensive systematic review and meta-analysis on psychotropic medication use and falls in older adults. METHODS AND DESIGN: This study is a systematic review and meta-analysis. A search was conducted in Medline, PsycINFO, and Embase. Key search concepts were "falls," "aged," "medication," and "causality." Studies were included that investigated psychotropics (antipsychotics, antidepressants, anxiolytics, sedatives, and hypnotics) as risk factors for falls in participants >=60 years of age or participants with a mean age of >=70 years. Meta-analyses were performed using generic inverse variance method pooling unadjusted and adjusted odds ratio (OR) estimates separately. RESULTS: In total, 248 studies met the inclusion criteria for qualitative synthesis. Meta-analyses using adjusted data showed the following pooled ORs: antipsychotics 1.54 [95% confidence interval (CI) 1.28-1.85], antidepressants 1.57 (95% Cl 1.43-1.74), tricyclic antidepressants 1.41 (95% CI 1.07-1.86), selective serotonin reuptake inhibitors 2.02 (95% CI 1.85-2.20), benzodiazepines 1.42 (95%, CI 1.22-1.65), long-acting benzodiazepines 1.81 (95%, CI 1.05-3.16), and short-acting benzodiazepines 1.27 (95%, CI 1.04-1.56) Most of the meta analyses resulted in substantial heterogeneity that did not disappear after stratification for population and healthcare setting. CONCLUSIONS: Antipsychotics, antidepressants, and benzodiazepines are consistently associated with a higher risk of falls. It is unclear whether specific subgroups such as short-acting benzodiazepines and selective serotonin reuptake inhibitors are safer in terms of fall risk. Prescription bias could not be accounted for. Future studies need to address pharmacologic subgroups as fall risk may differ depending on specific medication properties. Precise and uniform classification of target medication (Anatomical Therapeutic Chemical Classification) is essential for valid comparisons between studies. PMID- 29402653 TI - Fifteen Minutes Daily Brisk Walk May Be a New Best Target in Very Old Adults: Age Is Not an Excuse to Not Exercise. PMID- 29402654 TI - Reprint of: XPA is primarily cytoplasmic but is transported into the nucleus upon UV damage in a cell cycle dependent manner. PMID- 29402655 TI - Haplotype structure of 27 Yfiler(r)Plus loci in Chinese Dongxiang ethnic group and its genetic relationships with other populations. PMID- 29402656 TI - Corrigendum to "Sulforaphane attenuates postnatal proteasome inhibition and improve spatial learning in adult mice" [J Nutr Biochem 51 (2018) 69-79]. PMID- 29402657 TI - Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease. AB - INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them. STUDY DESIGN: Prospective observational study. MATERIAL AND METHODS: The study was conducted on 300 patients with type 2 diabetes mellitus attending the outpatient department of a tertiary care teaching hospital. All patients underwent hepatic ultrasonography to look for hepatic steatosis. Among the 300 patients, 124 were divided into NAFLD and non-NAFLD groups based on the ultrasound findings. These patients were subjected to electrocardiogram, 2D echocardiogram, carotid intima media thickness (CIMT) measurement and ankle brachial pressure index measurement along with measurement of markers of oxidative stress. RESULTS: Hepatic steatosis was present in 61% of diabetic patients in this study. Cardiovascular disease was not found to be significantly associated in diabetic patients with NAFLD. However, cardiovascular risk factors like CIMT, high sensitivity c-reactive protein (hs-CRP) and malondialdehyde (MDA) were elevated in these patients. hs-CRP and MDA levels were found to be significantly associated with the severity of NAFLD. CONCLUSION: There is a high prevalence of NAFLD in type 2 diabetic patients. No correlation was detected between the presence of NAFLD and cardiovascular disease in them; although there was an association between cardiovascular risk factors and NAFLD. PMID- 29402658 TI - The Cost of Caring: An Exploration of Compassion Fatigue, Compassion Satisfaction, and Job Satisfaction in Pediatric Nurses. AB - PURPOSE: The purpose of this study was to describe levels of compassion satisfaction, compassion fatigue, and job satisfaction among pediatric nurses in the United States and determine if there was a relationship among these constructs. DESIGN AND METHODS: All members Society of Pediatric Nurses were sent an electronic invitation to participate, and those who consented received three measures; a demographic questionnaire, the Job Satisfaction Survey (JSS) and the Professional Quality of Life (ProQOL) measure. RESULTS: Three hundred eighteen (10.6%) of members of the Society of Pediatric Nurses participated in the study: Over three quarters (245, 76%) of the sample had another career before nursing. The sample's mean job satisfaction level was 149.8 (SD=29.74), which was significantly higher than published reported means for nurses. Bivariate analyses revealed a significant relationship between gender and the compassion satisfaction, in that women were more likely to evidence compassion satisfaction than men (t=1.967, p=.05, df=298). No other significant relationships were found. CONCLUSIONS: The majority of nurses had high levels of compassion satisfaction and job satisfaction; further, female gender was associated with higher levels of compassion satisfaction. PRACTICE IMPLICATIONS: This current study had a very high response from second-career nurses (n=245, 76.8%) and overall, the sample had higher levels of compassion satisfaction. It is possible that second career nurses are better equipped in some way that helps them mediate negative responses of caring as a pediatric nurse and future research should explore this. Due to the significant financial costs to institutions of having nurses who have low levels of job satisfaction and high levels on compassion fatigue, it is imperative for hospital administrators to develop infrastructures to support employees. PMID- 29402660 TI - Improving the Discharge to Home Experience for Pediatric Heart Center Patients and Families. AB - PURPOSE: The purpose of this study was to determine if implementation of the discharge specialist role improves family perception of discharge readiness and determines whether the use of the role decreases the number of tasks needing completion on the day of discharge. DESIGN AND METHODS: A prospective descriptive study was designed to compare parent readiness for discharge from two groups of participants. One group had a discharge specialist the day of discharge. The other group did not have the assistance of the discharge specialist on the day of discharge. Participants were contacted after discharge and surveyed on their perception of readiness for discharge based on a modified version of the Care Transitions Method Survey. Patient responses were either Strongly Agree or Less than Strongly Agree. RESULTS: A total of 60 patients (30 in each group) were analyzed. There were no statistically significant differences in demographic variables between the two groups. The overall average score of the composite proportion responding with Strongly Agree was higher among caregivers using a discharge specialist (Mean = 88.2) as compared to those without (Mean = 55.9, U = 157.0, p < .001). CONCLUSION: The use of a discharge specialist on the day of discharge resulted in a higher parent perception of discharge readiness in this sample of children with complex cardiac diagnosis. PRACTICE IMPLICATIONS: The use of a discharge specialist in the heart center can assist with the successful transition from hospital to home. Future research should examine the effect of the discharge specialist on hospital re-admission rates and clinical outcomes. PMID- 29402659 TI - The Effect of Nutrition and Sleep Habits on Predisposition for Metabolic Syndrome in Greek Children. AB - PURPOSE: To investigate the effect of lifestyle habits in childhood Metabolic Syndrome (MTS). DESIGN AND METHODS: Descriptive correlation study with 480 participants (5-12 years old) using a specially designed questionnaire was conducted. Anthropometric and biochemical analyses were performed. RESULTS: Fifteen percent of children exhibited predisposition for MTS. Regarding sleep habits, logistic regression analysis (LRA) showed that hour of sleep -before 22:00- was associated with decreased waist circumference (WC%) (p = .026). Midday siesta was negatively correlated with systolic (SBP) (p = .001) and diastolic blood pressure (DBP) (p = .046). In children without MTS, lack of sleep and night time sleep was positively correlated with DBP (p = .044) and fasting blood glucose (FBG) (p = .005). Regarding nutrition habits, fast food consumption was positively correlated with SBP (p = .006) and meat consumption was positively correlated with both Body Mass Index% (BMI%) (p = .038) and WC% (p = .023). LRA showed that fruit (p = .001) and legume (p = .040) consumption was associated with decreased FBG; fish consumption with decreased Low Density Lipoprotein (LDL) cholesterol (p = .031), vegetable (p = .054) and cereal consumption (p = .012) with decreased DBP. In children with MTS, fruits were associated with increased FBG (p = .034). In children without MTS, meat consumption was associated with increased LDL (p = .024), cereal with increased WC% (p = .002) and olive products with increased High Density Lipoprotein (HDL) cholesterol and BMI% (p = .037). CONCLUSIONS: The adoption of both balanced diet and sleep habits seemed to be crucial for the prevention of MTS. PRACTICE IMPLICATIONS: Clinical health nurses could develop and implement preventive intervention programs in order to avoid metabolic complications in adulthood. PMID- 29402661 TI - A mechanism of interleukin-25 production from airway epithelial cells induced by Japanese cedar pollen. AB - IL-25 likely has vital roles in initiating and activating type-2 immune responses in AR. We hypothesized that the molecules produced IL-25 by allergen-producing organisms such as JC is involved in the pathogenesis of AR. Participants included 13 patients with Japanese cedar pollinosis and 10 HCs. We measured the IL-25 protein concentration in nasal secretions and in culture supernatants of PNECs. NHBE cells were stimulated with pharmacological and immunological agents and JC. The IL-25 concentration in nasal secretions was significantly higher in patients with Japanese cedar pollinosis than in HCs. JC stimulated IL-25 production from PNECs. TNF-alpha, IL-4, and IL-13 significantly enhanced JC-induced IL-25 production; their activation by serine proteases was sufficient to enhance IL-25 production. Furthermore, the NADPH oxidase activity, including JC enhanced IL-25 production. A better understanding of JC-induced IL-25 production by epithelial cells may allow the development of novel therapeutic and preventive strategies for Japanese cedar pollinosis. PMID- 29402662 TI - Pharmacist-managed short-acting beta agonist refill service in a general pediatric clinic. AB - OBJECTIVES: To use a pharmacist-managed short-acting beta agonist (SABA) service (1) to determine the patient's rationale for SABA refill requests, (2) to assess adherence to current controller therapy and current level of disease control, and (3) to characterize the pharmacist's recommendations made in response to a patient's SABA refill request. SETTING: An academic-based general pediatric clinic. PRACTICE DESCRIPTION: SABA overuse is a marker of increased morbidity and mortality in children with asthma. This article describes a pharmacist-managed SABA refill telephone service. PRACTICE INNOVATION: The pediatric ambulatory care pharmacy team assessed and authorized (or denied) all SABA refill requests, provided education, and facilitated appropriate follow-up using a telephone service. INTERVENTIONS: Upon receiving a patient-requested SABA refill, the pharmacist identified the reason for the SABA request, assessed asthma control, and determined adherence to daily controllers or spacer use, if applicable. Education was also provided. Data obtained were used to determine SABA refill approval. EVALUATION: Primary reasons for SABA refill request were for (1) current symptom management and (2) no refills remaining in the absence of symptoms. Forty-two (50%) SABA refill requests were eligible for refill per the clinic algorithm, yet 70% actually received a refill after assessment by the pharmacist. Asthma control was assessed as 26% well controlled, 38% not well controlled, and 36% very poorly controlled. Forty-eight percent of patients prescribed daily controller medications were deemed adherent. Spacers were used in 43 of 76 (56%) patients using metered dose inhalers. Education was provided to 82% of caregivers. Pharmacists facilitated asthma follow-up visits in 41 of 84 (49%) patients contacted, and 61% of those appointments were kept. CONCLUSIONS: Pharmacist management of a SABA refill telephone service provides an additional means for delivery of asthma education, facilitates follow-up asthma care, helps to identify patients at risk for increased morbidity and mortality due to the overuse of SABAs, and provides another mechanism for medication refills. PMID- 29402663 TI - Dying better. PMID- 29402664 TI - Osteopontin may be a driver of abdominal aortic aneurysm formation. AB - OBJECTIVE: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation-suppressing lymphocytes present in the human AAA condition was investigated and presented herein. METHODS: Serum OPN concentrations were measured in healthy, risk factor-matched non-AAA and AAA patients by enzyme linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence-activated cell sorting. RESULTS: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction. CONCLUSIONS: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation. PMID- 29402665 TI - Malpractice litigation in the endovascular era. AB - OBJECTIVE: The standard of care in the treatment of vascular disease continues to evolve as endovascular therapies develop. Currently, it is unclear how medical malpractice litigation has adapted to the "endovascular era." This retrospective case review is the most comprehensive analysis to date of malpractice actions involving endovascular procedures performed by vascular surgeons (VSs), interventional radiologists (IRs), interventional cardiologists (ICs), and cardiothoracic surgeons (CTSs). METHODS: The legal databases LexisNexis and Westlaw were searched for all published legal cases in the United States involving endovascular procedures. The search was limited to state and federal cases up to and including the year 2016. Keywords included "malpractice," "vascular," "endovascular," "catheter," "catheterization," "stent," "angiogram," "angiography," and "surgery." Cases involving tax revenue, insurance disputes, Social Security Disability, and hospital employment contract disputes were excluded. Data were analyzed using chi2 test. RESULTS: There were 2115 initial search results identified, and 369 cases were included in final analysis. The rate of endovascular procedure-related lawsuits (per 1000 active physicians in the specialty) was highest for ICs (105.56), whereas rates for VSs and IRs were comparable (18.47 and 16.85, respectively); 93% of the IC cases were related to coronary interventions. Overall, 55% (148/271 classifiable cases) of actions were related to elective procedures. For VSs specifically, 46% (25/54) of cases arose from diagnostic angiography and inferior vena cava filter placement, two relatively minor procedure types. Overall, 83% (176/211 finalized cases) of verdicts favored defendants, with no significant differences across the specialties; 43% (157/368) of total cases involved death of the patient. Among the four specialties, there was a significant (P = .0004) difference in the primary allegation (informed consent, preprocedure negligence, intraprocedure complications, or postprocedure complications) underlying the litigation. For CTSs and VSs, there was a predominance of informed consent and preprocedure negligence allegations (70% [7/10] and 52% [28/54], respectively). Intraprocedure negligence was the most common allegation for IRs (59% [23/39]), whereas allegations were more evenly distributed among ICs. CONCLUSIONS: Key issues were identified regarding malpractice litigation involving the specialties that commonly perform endovascular procedures. Despite the increasing number of ICs doing peripheral interventions, a large majority of IC cases were related to coronary treatments. A surprisingly large percentage of VS cases were related to seemingly minor cases. There were significant interspecialty differences in the primary underlying allegations. As the scope of endovascular procedures broadens and deepens, it is important for clinicians to be aware of legal considerations relevant to their practice. PMID- 29402666 TI - Reduction of the DIEP flap donor site morbidity through a minimally invasive pedicle harvest with Jacob's ladder incisions. PMID- 29402667 TI - Time to re-group and save: Do we routinely need to perform group-and-save in patients undergoing free deep inferior epigastric perforator (DIEP) flap breast reconstruction? PMID- 29402668 TI - Female Surgeons as Counter Stereotype: The Impact of Gender Perceptions on Trainee Evaluations of Physician Faculty. AB - OBJECTIVE: Similar to women in Science, Technology, Engineering and Mathematics disciplines, women in medicine are subject to negative stereotyping when they do not adhere to their sex-role expectations. These biases may vary by specialty, largely dependent on the gender's representation in that specialty. Thus, females in male-dominated surgical specialties are especially at risk of stereotype threat. Herein, we present the role of gender expectations using trainee evaluations of physician faculty at a single academic center, over a 5-year period (2010-2014). DESIGN: Using Graduate Medical Education evaluation data of physician faculty from MedHub, we examined the differences in evaluation scores for male and female physicians within specialties that have traditionally had low female representation (e.g., surgical fields) compared to those with average or high female representation (e.g., pediatrics). SETTING: Stanford Medicine residents and fellows' MedHub ratings of their physician faculty from 2010 to 2014. PARTICIPANTS: A total of 3648 evaluations across 1066 physician faculty. RESULTS: Overall, female physicians received lower median scores than their male counterparts across all specialties. When using regression analyses controlling for race, age, rank, and specialty-specific characteristics, the negative effect persists only for female physicians in specialties with low female representation. CONCLUSIONS: This finding suggests that female physicians in traditionally male-dominated specialties may face different criteria based on sex role expectations when being evaluated by trainees. As trainee evaluations play an important role in career advancement decisions, dictate perceptions of quality within academic medical centers and affect overall job satisfaction, we propose that these differences in evaluations based merely on gender stereotypes could account, in part, for the narrowing pipeline of women promoted to higher ranks in academic medicine. PMID- 29402669 TI - Comparative Analysis of Porcine and Human Thoracic Aortic Stiffness. AB - OBJECTIVES: To compare porcine and human thoracic aortic stiffness using the available literature. METHODS: The available literature was searched for studies reporting data on porcine or human thoracic aortic mechanical behaviour. A four fibre constitutive model was used to transform the data from included studies. Thus, equi-biaxial stress stretch curves were generated to calculate circumferential and longitudinal aortic stiffness. Analysis was performed separately for the ascending and descending thoracic aorta. Data on human aortic stiffness were divided by age <60 or >=60 years. Porcine and human aortic stiffness were compared. RESULTS: Eleven studies were included, six reported on young porcine aortas, four on human aortas of various ages, and one reported on both. In the ascending aorta, circumferential and longitudinal stiffness were 0.42+/-0.08 MPa and 0.37+/-0.06 MPa for porcine aortas (4-9 months) versus 0.55+/ 0.15 MPa and 0.45+/-0.08 MPa for humans <60 years, and 1.02+/-0.59 MPa and 1.03+/ 0.54 MPa for humans >=60 years. In the descending aorta, circumferential and longitudinal stiffness were 0.46+/-0.03 MPa and 0.44+/-0.01 MPa for porcine aortas (4-10 months) versus 1.04+/-0.70 MPa and 1.24+/-0.76 MPa for humans <60 years, and 3.15+/-3.31 MPa and 1.17+/-0.31 MPa for humans >=60 years. CONCLUSIONS: The stiffness of young porcine aortic tissue shows good correspondence with human tissue aged <60 years, especially in the ascending aorta. Young porcine aortic tissue is less stiff than human aortic tissue aged >=60 years. PMID- 29402670 TI - Infrapopliteal Angioplasty of One or More than One Artery for Critical Limb Ischaemia: A Randomised Clinical Trial. AB - OBJECTIVE: The aim was to analyse the effect of the treatment of more than one infrapopliteal artery with respect to wound healing and limb salvage. METHODS: Seventy-eight patients were enrolled prospectively for 80 procedures (80 limbs) that were randomly divided into two groups: 40 in the single vessel (SV) group and 40 in the multiple vessel group (MV). All patients had tissue loss. The choice of the first artery to treat was based on an analysis of two factors: the ease of the required endovascular technique and the presence of adequate distal outflow. The randomisation point was after the first successful distal artery angioplasty. The primary endpoints were the wound healing rate and limb salvage. RESULTS: The mean age of the patients was 69.1 +/- 4.3 years, and 56% were male. Concomitant treatment of the femoral and popliteal arteries was performed in 38.8% of patients. All demographic characteristics and technical aspects were statistically comparable for both groups. Successful recanalisation was achieved in 95.8%, 86.2%, 86.9%, and 92.5% for the tibio-fibular trunk, anterior tibial, posterior tibial, and fibular artery, respectively. In the MV group, a higher contrast volume (29 mL more; p = .049), longer procedure time (p = .01), and higher radiation exposure (p = .04) were noted. There was no difference in renal function between the groups either before or 30 days after the procedure (p = .165). The limb salvage rates after 1 and 3 years, respectively, were 75.9% and 67% for the SV group and 91.1% and 91.1% for the MV group (log rank p = .052). The wound healing rates after 1 and 3 years, respectively, were 33.6% and 70.9% for the SV and 63.9% and 78.4% for MV group (log rank p = .006). Wound healing was faster in MV (2.11 cm2/month) than SV group (0.62 cm2/month; p = .004). CONCLUSION: Endovascular treatment of more than one artery was associated with better wound healing rates but not with better limb salvage. PMID- 29402672 TI - Social network as teaching material in medical school: Review and perspectives. PMID- 29402673 TI - Idiopathic unilateral vocal-fold paralysis in the adult. AB - GOAL: To analyze the characteristics of adult idiopathic unilateral vocal-fold paralysis. MATERIAL AND METHODS: Retrospective study of diagnostic problems, clinical data and recovery in an inception cohort of 100 adult patients with idiopathic unilateral vocal-fold paralysis (Group A) and comparison with a cohort of 211 patients with isolated non-idiopathic non-traumatic unilateral vocal-fold paralysis (Group B). RESULTS: Diagnostic problems were noted in 24% of cases in Group A: eight patients with concomitant common upper aerodigestive tract infection, five patients with a concomitant condition liable to induce immunodepression and 11 patients in whom a malignant tumor occurred along the path of the ipsilateral vagus and inferior laryngeal nerves or in the ipsilateral paralyzed larynx. There was no recovery of vocal-fold motion beyond 51 months after onset of paralysis. The 5-year actuarial estimate for recovery differed significantly (P<0.0001): 53.2% in Group A versus 17.9% in Group B. In Group A, recovery occurred before the end of the second year following paralysis onset in 93% of cases. On univariate analysis, recovery in Group A was associated with younger age (P=0.0033), shorter time to consultation (P<0.0001), and absence of oncologic history (P<0.028). In case of non-recovery in Group A, malignant tumor along the ipsilateral vagus or inferior laryngeal nerve was found in 17.2% of cases, 81% of which manifesting during the 30 months following the onset of vocal fold paralysis. CONCLUSION: In non-traumatic vocal-fold paralysis in adult patients, without recovery of vocal-fold motion, a minimum three years' regular follow-up is recommended. PMID- 29402671 TI - Management of antiplatelet therapy in patients undergoing elective invasive procedures: Proposals from the French Working Group on perioperative hemostasis (GIHP) and the French Study Group on thrombosis and hemostasis (GFHT). In collaboration with the French Society for Anesthesia and Intensive Care (SFAR). PMID- 29402674 TI - International consensus (ICON) on the ENT role in diagnosis of obstructive sleep apnea syndrome. AB - During the 2017 IFOS ENT World Congress, an international expert panel was asked to clarify the role of ENT in the diagnosis process of the obstructive sleep apnea syndrome (OSA) in adults around the world. OSA is a major public health issue throughout the world. OSA is a highly prevalent disease with heavy clinical, social and economical outcomes. This high prevalence raises serious difficulties of diagnosis accessibility if only somnologists are able to confirm OSA diagnosis. First of all, the panellists reviewed the impact of OSA. Secondly, they defined the ENT role stressing ENT legitimacy, professional expertise and academic and institutional tasks. They also defined when somnologists were necessary. For the international panel, the ENT is a major player in the OSA diagnosis process. PMID- 29402675 TI - The provision of cell phones as a recruitment and retention strategy for people who inject drugs enrolling in a randomized trial. AB - BACKGROUND: Studies of drug-using populations often restrict enrollment by limiting participation to those with a working telephone. It is unknown whether supplying phones could broaden recruitment and sustain retention among an urban population of people who inject drugs (PWID). We compare the feasibility of offering pay-by-month phones to gift card compensation as part of an ongoing randomized controlled trial of hospitalized PWID. METHODS: Participants were recruited from inpatient services at an urban hospital in Boston, MA to participate in an ongoing randomized trial testing a motivational interviewing (MI) intervention. Participants who did not have their own phone at the time of enrollment were offered a pay-by-month phones as compensation for study participation. RESULTS: Eighty-one participants met study criteria, were enrolled, and completed the study at the time of analysis. We used a generalized estimating equation to compare the overall likelihood of attending interviews during the 12-month follow-up period. Participants receiving phones tended to have lower mean educational attainment (11.4 years vs. 12.1 years), were significantly (Fisher's exact p < 0.001) more likely to report homelessness during the past 90 days (86.7% vs. 37.3%), and were significantly less likely (Fisher's exact p = .044) to be employed (3.3% vs. 20.4%) compared to those receiving gift cards. Participants in each group were equally likely to attend follow-up interviews during the study (83.3% vs. 88.3%, p = 0.53). CONCLUSION: Offering phones as a compensation method allows recruitment of a more disenfranchised population without impacting study retention and therefore may improve generalizability of study results. PMID- 29402676 TI - Features of prescription drug monitoring programs associated with reduced rates of prescription opioid-related poisonings. AB - BACKGROUND: The United States is in the midst of an opioid epidemic. In addition to other system-level interventions, all states have responded during the crisis by implementing prescription drug monitoring programs (PDMPs). This study examines associations between specific administrative features of PDMPs and changes in the risk of prescription opioid-related poisoning (RxORP) over time. METHODS: This longitudinal, observational study utilized a 'natural experiment' design to assess associations between PDMP features and risk of RxORP in a nationally-representative population of privately-insured adults from 2004 to 2014. Administrative health claims data were used to identify inpatient hospital admissions and emergency department visits related to RxORP. Generalized estimating equation Poisson regression models were used to examine associations between specific PDMP features and changes in relative risk (RR) of RxORP over time. RESULTS: In adjusted analyses, states without PDMPs experienced an average annual increase in the rate of RxORP of 9.51% over the study period, while states with operational PDMPs experienced an average annual increase of 3.17%. The increase in RR of RxORP over time in states with operational PDMPs was significantly less than increases in states without PDMPs. States with specific features, including those that monitored more schedules or required more frequent data reporting, experienced stronger protective effects on the RR of RxORP over time. CONCLUSION: This study examined associations between specific PDMP features and RxORP rates in a nationally-representative population of privately-insured adults. Results of this study may be used as empirical evidence to guide PDMP best practices. PMID- 29402678 TI - The Galician Beverage Picture Set (GBPS): A standardized database of alcohol and non-alcohol images. AB - BACKGROUND: The available picture sets in alcohol research are scarce and display a number of limitations, including poor picture quality, limited number of stimuli and absence of non-alcohol and/or real-life images. In the present study, we developed the Galician Beverage Picture Set (GBPS), a database of high-quality alcohol and non-alcohol pictures embedded in real-life scenarios. METHODS: A total of 201 college students (~59% females) were assessed by the Alcohol Use Disorders Identification Test, ~54% being characterized as no/low drinkers (N/LDs) and ~46% as risky drinkers (RDs). The GBPS included six types of beverages: beer, wine, liquor (alcoholic drinks); water, juice, milk (non alcoholic drinks). Additionally, two subcategories were considered: orientation (landscape, portrait) and number of people (0, 1, >=2 people). Participants rated the images for valence, arousal and visual complexity. Objective measures of brightness and color and recognition rates were also assessed. Internal consistency was estimated using Cronbach's alpha coefficient. RESULTS: There was a high degree of internal consistency within each category (alcoholic and non alcoholic drinks) for valence, arousal and visual complexity scores. A mixed model ANOVA revealed that RDs rated alcohol pictures as more pleasant and arousing than N/LDs. Conversely, N/LDs displayed greater valence and arousal ratings than RDs for non-alcohol pictures. CONCLUSIONS: The GBPS provides normative data on affective (valence/arousal), perceptual (visual complexity) and physical (brightness/color) values for a large number of images that may be useful for alcohol-related research. Differences in subjective assessments between N/LDs and RDs support the picture set's suitability for studies in young drinkers. PMID- 29402677 TI - Associations between childhood ADHD, gender, and adolescent alcohol and marijuana involvement: A causally informative design. AB - BACKGROUND: We report whether the etiology underlying associations of childhood ADHD with adolescent alcohol and marijuana involvement is consistent with causal relationships or shared predispositions, and whether it differs by gender. METHODS: In three population-based twin samples (N = 3762; 64% monozygotic), including one oversampling females with ADHD, regressions were conducted with childhood inattentive or hyperactive-impulsive symptoms predicting alcohol and marijuana outcomes by age 17. To determine whether ADHD effects were consistent with causality, twin difference analyses divided effects into those shared between twins in the pair and those differing within pairs. RESULTS: Adolescents with more severe childhood ADHD were more likely to initiate alcohol and marijuana use earlier, escalate to frequent or heavy use, and develop symptoms. While risks were similar across genders, females with more hyperactivity impulsivity had higher alcohol consumption and progressed further toward daily marijuana use than did males. Monozygotic twins with more severe ADHD than their co-twins did not differ significantly on alcohol or marijuana outcomes, however, suggesting a non-causal relationship. When co-occurring use of other substances and conduct/oppositional defiant disorders were considered, hyperactivity impulsivity remained significantly associated with both substances, as did inattention with marijuana, but not alcohol. CONCLUSIONS: Childhood ADHD predicts when alcohol and marijuana use are initiated and how quickly use escalates. Shared familial environment and genetics, rather than causal influences, primarily account for these associations. Stronger relationships between hyperactivity-impulsivity and heavy drinking/frequent marijuana use among adolescent females than males, as well as the greater salience of inattention for marijuana, merit further investigation. PMID- 29402680 TI - A randomized, open label trial of methadone continuation versus forced withdrawal in a combined US prison and jail: Findings at 12 months post-release. AB - Recently, incarcerated individuals are at increased risk of opioid overdose. Methadone maintenance treatment (MMT) is an effective way to address opioid use disorder and prevent overdose; however, few jails and prisons in the United States initiate or continue people who are incarcerated on MMT. In the current study, the 12 month outcomes of a randomized control trial in which individuals were provided MMT while incarcerated at the Rhode Island Department of Corrections (RIDOC) are assessed. An as-treated analysis included a total of 179 participants-128 who were, and 51 who were not, dosed with methadone the day before they were released from the RIDOC. The results of this study demonstrate that 12 months post-release individuals who received continued access to MMT while incarcerated were less likely to report using heroin and engaging in injection drug use in the past 30 days. In addition, they reported fewer non fatal overdoses and were more likely to be continuously engaged in treatment in the 12-month follow-up period compared to individuals who were not receiving methadone immediately prior to release. These findings indicate that providing incarcerated individuals continued access to MMT has a sustained, long-term impact on many opioid-related outcomes post-release. PMID- 29402681 TI - Sexual minority youth continue to smoke cigarettes earlier and more often than heterosexuals: Findings from population-based data. AB - BACKGROUND: An established body of research documents that sexual minority (i.e., lesbian, gay, and bisexual) populations are at higher risk for several adverse health behaviors and outcomes compared to their heterosexual counterparts. Smoking is one behavior where the gap is especially large, particularly among youth. Researchers have increasingly drawn attention to contextual determinants of health behaviors affecting sexual minority youth. PURPOSE: Although these factors have evolved over time, few scholars have examined time as a contextual factor that affects sexual minority health behaviors or the level of inequality with heterosexual populations. We aimed to fill this gap. PROCEDURES: We used eight years of data from the Massachusetts Youth Risk Behavior Survey (MYRBS), pooled into four waves, to determine whether gaps between sexual minority and heterosexual youth have widened or narrowed for three different indicators of smoking: having ever smoked, early onset smoking, and daily cigarette smoking in the past 30 days. RESULTS: We find that, though rates of smoking for all youth in Massachusetts have declined since the late 1990s, significant disparities remain between sexual minority and heterosexual youth. CONCLUSIONS: Findings may suggest that targeted tobacco control programs in Massachusetts are needed; perhaps shifts in social attitudes toward smoking have affected smoking behaviors in diverse segments of society. PMID- 29402679 TI - Early onset tobacco cigarette smokers exhibit deficits in response inhibition and sustained attention. AB - BACKGROUND: Initiation of cigarette smoking during adolescence coincides with structural and cognitive neuromaturation. Thus, early onset smokers (EOS; initiated <16 years old) may be at unique risk of altered development of executive function relative to late onset smokers (LOS; initiated >16 years old). This study quantified the effects of age of smoking onset on response impulsivity and inhibitory control using a novel smoking Go/NoGo task (Luijten et al., 2011). METHODS: Nicotine deprived adult EOS (n = 10) and LOS (n = 10) and adult healthy non-smokers (HNS; n = 10) were shown smoking-related and neutral images with either a blue (Go) or yellow (NoGo) frame. Participants were instructed to respond to blue-framed Go trials quickly and accurately, and withhold responding for yellow-framed NoGo trials. RESULTS: EOS made more Go response accuracy errors (p <= 0.02) and failed more frequently to inhibit responses to NoGo trials (p < 0.02) than LOS and HNS. EOS also made more errors in inhibiting responses to smoking-related (p <= 0.02) and neutral (p <= 0.02) NoGo trials. EOS reported greater baseline craving for cigarette smoking than LOS (p < 0.04), and craving was significantly associated with greater omission errors (p <= 0.04). CONCLUSIONS: EOS exhibited greater difficulty than LOS in responding accurately to Go stimuli and withholding responses to both smoking and neutral NoGo stimuli, indicating greater response impulsivity, poor attention, and deficits in response inhibition. These findings suggest that EO smoking, in particular, contributes to diminished task-related attention and inhibitory control behaviors in adulthood and provide support for the tobacco-induced neurotoxicity of adolescent cognitive development (TINACD) theory (DeBry and Tiffany, 2008). PMID- 29402682 TI - Association between patient classification systems and nurse staffing costs in intensive care units: An exploratory study. AB - OBJECTIVES: Nurse staffing costs represent approximately 60% of total intensive care unit costs. In order to analyse resource allocation in intensive care, we examined the association between nurse staffing costs and two patient classification systems: the nursing activities score (NAS) and nine equivalents of nursing manpower use score (NEMS). RESEARCH METHODOLOGY/DESIGN: A retrospective descriptive correlational analysis of nurse staffing costs and data of 6390 patients extracted from a data warehouse. SETTING: Three intensive care units in a university hospital and one in a regional hospital in Norway. MAIN OUTCOME MEASURES: Nurse staffing costs, NAS and NEMS. RESULTS: For merged data from all units, the NAS was more strongly correlated with monthly nurse staffing costs than was the NEMS. On separate analyses of each ICU, correlations were present for the NAS on basic costs and external overtime costs but were not significant. The annual mean nurse staffing cost for 1% of NAS was 20.9-23.1 euros in the units, which was comparable to 53.3-81.5 euros for 1 NEMS point. CONCLUSION: A significant association was found between monthly costs, NAS, and NEMS. Cost of care should be based on individual patients' nursing care needs. The NAS makes nurses' workload visible and may be a helpful classification system in future planning and budgeting of intensive care resources. PMID- 29402683 TI - Prevalence of drug use during sex amongst MSM in Europe: Results from a multi site bio-behavioural survey. AB - BACKGROUND: Substance use has been consistently reported to be more prevalent amongst Men who have Sex with Men (MSM) compared to the general population. Substance use, in particular polydrug use, has been found to be influenced by social and contextual factors and to increase the risk of unprotected intercourse among MSM. The objective of this analysis was to investigate the prevalence and predictors of drug use during a sexual encounter and to identify specific prevention needs. METHODS/DESIGN: A multi-site bio-behavioural cross-sectional survey was implemented in 13 European cities, targeting MSM and using Time Location Sampling and Respondent-Driven Sampling methods Multivariable multi level logistic random-intercept model (random effect of study site) was estimated to identify factors associated with the use of alcohol, cannabis, party drugs, sexual performance enhancement drugs and chemsex drugs. RESULTS: Overall, 1261 (30.0%) participants reported drug use, and 436 of 3706 (11.8%) reported the use of two or more drugs during their last sexual encounter. By drug class, 966 (23.0%) reported using sexual performance enhancement drugs, 353 (8.4%) - party drugs, and 142 (3.4%) the use of chemsex drugs. Respondents who reported drug use were more frequently diagnosed with HIV (10.5% vs. 3.9%) before and with other STIs during the 12 months prior to the study (16.7% vs. 9.2%). The use of all the analysed substances was significantly associated with sexual encounter with more than one partner. DISCUSSION: Substance and polydrug use during sexual encounters occurred amongst sampled MSM across Europe although varying greatly between study sites. Different local social norms within MSM communities may be important contextual drivers of drug use, highlighting the need for innovative and multi faceted prevention measures to reduce HIV/STI risk in the context of drug use. PMID- 29402684 TI - Implications of survey labels and categorisations for understanding drug use in the context of sex among gay and bisexual men in Melbourne, Australia. AB - BACKGROUND: Reliably measuring drug use by gay, bisexual and other men who have sex with men (GBM) in the context of sex can inform sexual health service responses. We report changing drug use patterns among GBM testing for HIV at a community-based service in Melbourne in response to behavioural survey modifications. METHODS: Surveys were completed by GBM prior to all HIV tests. Survey one asked about use of "party drugs for the purpose of sex" and survey two asked about specific drug use (alcohol, amyl nitrate, methamphetamine, cocaine, ecstasy, GHB, Viagra(r)/Cialis(r)) before or during sex. Differences in drug use prevalence and demographic and sexual risk correlates are reported. RESULTS: Reported drug use increased from 16.9% in survey one to 54.0% in survey two. Among GBM completing both surveys, 45% who reported no drug use in survey one reported drug use in survey two. Drug use was associated with high HIV risk behaviours across both surveys. CONCLUSION: Survey modification improved ascertainment of drug use in the context of sex among GBM. Continued monitoring of drug use in this setting will improve our understanding the relationship between use of specific drugs and sexual health and help inform client focused health promotion. PMID- 29402685 TI - Is computed tomography tractography reliable in patients with anterior abdominal stab wounds? AB - INTRODUCTION: The current literature and guidelines recommend that determination of peritoneal violation is done first in cases of anterior abdominal stab wounds. The primary endpoint of this study was to determine the reliability of computed tomographic (CT) tractography to assess peritoneal violation in anterior abdominal stab wounds. The secondary endpoint is to compare local wound exploration between conventional CT and CT tractography in the evaluation of peritoneal violation. MATERIAL AND METHODS: A total of 252 patients who were referred with anterior abdominal stab wounds were included in this prospective observational study. Three techniques (local wound exploration, conventional abdominal tomography, and CT tractography) were used to evaluate peritoneal violation. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for each technique to determine peritoneal violation. RESULTS: The results for the local wound exploration were 100% sensitivity, 100% specificity, 100% PPV, 100% NPV, and 100% accuracy. The results for CT tractography were 95% sensitivity, 100% specificity, 100% PPV, 80% NPV, and 96% accuracy. Conventional abdominal tomography results were 87% sensitivity, 50% specificity, 91% PPV, 40% NPV, and 82% accuracy. CONCLUSION: Local wound exploration is 100% effective in determining peritoneal violation with anterior abdominal stab wounds. CT tractography is better than conventional CT in detecting peritoneal violation. However, we do not recommend CT tractography in anterior abdominal stab wounds due to the false-negative results. PMID- 29402686 TI - Paramedics attitudes toward endotracheal intibation. PMID- 29402687 TI - The application of gap analysis to develop a call out/call back airway checklist: An ED quality improvement study. PMID- 29402688 TI - Respiratory oxygen uptake is associated with survival in a cohort of ventilated trauma and burn patients. AB - BACKGROUND: Little data is available in the literature about the role of end tidal oxygen in critically ill patients. We sought to identify the association between the level of respiratory oxygen and clinical outcomes in critically-ill ventilated trauma and burn patients. METHODS: A retrospective cohort of 55 trauma and burn patients from 2010 to 2016 was collected. Exposures of interest included a) expiratory end tidal oxygen (ETO2) and b) the difference between FiO2 and ETO2 (uptake). Associations of clinical characteristics with ETO2 and oxygen uptake were examined using a Spearman correlation. The relationships between discharge status, demographics, injury type, severity, and clinical characteristics were examined using chi-square (or Fisher's exact) tests and two-sample t-tests. Multivariable analyses using linear and logistic regression were performed to determine whether expiratory end tidal oxygen or oxygen uptake was an independent predictor of clinical outcomes. RESULTS: Mean age for the patients was 46.3+/ 18.2years with 41 (74.6%) male and 34 (61.8%) white. In the cohort, 27 (49.1%) of patients had burns and 28 (50.9%) blunt trauma. Oxygen uptake was negatively correlated with lactic acid, minute ventilation, total ICU days, and ventilator days (p<0.05). Patients who died demonstrated lower oxygen uptake than those alive, oxygen uptake remained significantly associated with discharge status after adjusting for potential confounders (p=0.028). CONCLUSION: A narrowed difference between ETO2 and inspiratory oxygen is associated with increased mortality in a cohort of ventilated trauma and burn patients. Future research is needed to further elucidate the role of respiratory oxygen level in larger, prospective studies. PMID- 29402690 TI - Outcomes of Heart Block in Myocarditis: A Review of 31,760 Patients. AB - BACKGROUND: Various electrocardiographic abnormalities, including atrioventricular conduction block, have been reported in patients with myocarditis. We performed an observation study to describe the characteristics and outcomes of inpatients diagnosed with myocarditis complicated by heart block (HB) in a large national cohort. METHODS: We identified patients with primary ICD 9 codes for myocarditis HB from the Nationwide Inpatient Survey (NIS) Database from 1998 to 2013. We compared the baseline characteristics and compared clinical outcomes between patients with and without HB, and in patients with/without high degree atrioventricular block (HDAVB). RESULTS: From the NIS database, 31,760 patients had a principal diagnosis of myocarditis and HB was reported in 1.7% of these patients (n=540). Female gender and Asian race were independently associated with HB. Out of 540 patients, 363 patients had HDAVB (67.2%) and 177 patients had not advanced HB (32.8%). Not advanced HB was not associated with an increased mortality rate compared to patients without HB (0% vs. 2.7%, p=0.315). On the other hand, the incidence of cardiogenic shock, respiratory failure and renal failure were higher in patients with HDAVB (26.2% vs. 5.0%, 33.9% vs. 5.9% and 29.2% vs. 5.5%, p<0.001 respectively). Patients with HDAVB required more procedural support (incidence of intra-aortic balloon pump 17.8% vs. 3.3%). They also had significantly longer lengths of hospital stay (9.4+/-9.4 vs. 4.3+/-8.4, p<0.001) and higher mortality (15.5% vs. 2.7%, p<0.001). Compared to myocarditis patients without HB, the odds for mortality in myocarditis patients with HDAVB 1.58 (95% CI=1.03-2.49, p=0.039). CONCLUSIONS: The incidence of HB and HDAVB among patients with acute myocarditis was 1.7% and 1.1% respectively. Female gender and Asian race were both independently associated with significant odds for the occurrence of HB and HDAVB. High degree atrioventricular block was independently associated with increased morbidity and mortality. PMID- 29402689 TI - Patient, provider, and environmental factors associated with adherence to cardiovascular and cerebrovascular clinical practice guidelines in the ED. AB - OBJECTIVES: Myocardial infarction and stroke are two of the leading causes of death in the U.S. Both diseases have clinical practice guidelines (CPGs) specific to the emergency department (ED) that improve patient outcomes. Our primary objectives were to estimate differences in ED adherence across CPGs for these diseases and identify patient, provider, and environmental factors associated with adherence. METHODS: Design: Retrospective study at 3 hospitals in Colorado using standard medical record review. POPULATION: Consecutive adults (>=18) hospitalized for acute coronary syndrome (ACS), ST-elevation myocardial infarction (STEMI), or acute ischemic stroke (AIS), who were admitted to the hospital from the ED and for whom the ED diagnosed or initiated treatment. OUTCOME: ED adherence to the CPG (primary); in-hospital mortality and length-of stay (secondary). ANALYSIS: Multivariable logistic regression using generalized estimating equations was used. RESULTS: Among 1053 patients, ED care was adherent in 84% with significant differences in adherence between CPGs (p<0.001) and across institutions (p=0.04). When patients presented with atypical chief complaints, the odds of receiving adherent care was 0.6 (95% CI 0.4-0.9). When the primary ED diagnosis was associated but not specific to the CPG, the odds of receiving adherent care was 0.5 (95% CI 0.3-0.9) and 0.3 (95% CI 0.2-0.5) for unrelated primary diagnoses. CONCLUSIONS: Adherence to ED CPGs for ACS, STEMI and AIS differs significantly between cardiovascular and cerebrovascular diseases and is more likely to occur when the diagnosis is highly suggested by the patient's complaint and acknowledged as the primary diagnosis by the treating ED physician. PMID- 29402691 TI - Recurrent Left Ventricular Myxoma. PMID- 29402692 TI - Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. AB - AIM: We now know that 20-40% of patients with a single ventricle will develop heart failure after the second decade post-Fontan surgery. However, we remain unable to risk-stratify the cohort to identify patients at highest risk of late failure and death. We conducted a systematic review of all reported late outcomes for patients with a Fontan circulation to identify predictors of late death. METHODS: We searched MEDLINE, Embase and PubMed with subject terms ("single ventricle", "Hypoplastic left heart syndrome", "congenital heart defects" or "Fontan procedure") AND ("heart failure", "post-operative complications", "death", "cause of death", "transplantation" or "follow-up studies") for relevant studies between January 1990 and December 2015. Variables identified as significant predictors of late death on multivariate analysis were collated for meta-analysis. Survival data was extrapolated from Kaplan-Meier survival curves to generate a distribution-free summary survival curve. RESULTS: Thirty-four relevant publications were identified, with a total of 7536 patients included in the analysis. Mean follow-up duration was 114 months (range 24-269 months). There were 688 (11%) late deaths. Predominant causes of death were late Fontan failure (34%), sudden death (19%) and perioperative death (16%). Estimated mean survival at 5, 10 and 20 years post Fontan surgery were 95% (95%CI 93-96), 91% (95%CI 89 93) and 82% (95%CI 77-85). Significant predictors of late death include prolonged pleural effusions post Fontan surgery (HR1.18, 95%CI 1.09-1.29, p<0.001), protein losing enteropathy (HR2.19, 95%CI 1.69-2.84, p<0.001), increased ventricular end diastolic volume (HR1.03 per 10ml/BSA increase, 95%CI 1.02-1.05, p<0.001) and having a permanent pacemaker (HR12.63, 95%CI 6.17-25.86, p<0.001). CONCLUSIONS: Over 80% of patients who survive Fontan surgery will be alive at 20 years. Developing late sequelae including protein losing enteropathy, ventricular dysfunction or requiring a pacemaker predict a higher risk of late death. PMID- 29402693 TI - Left Atrial Appendage Exclusion Using the AtriClip Device: A Case Series. AB - BACKGROUND: Atrial fibrillation (AF) affects 1.5-2% of the population and is associated with a five-fold increased lifetime risk of stroke [1]. The left atrial appendage (LAA) is the source of embolic strokes in up to 90% of patients with non-valvular AF with clots in the left atrium [2]. METHODS: We reviewed the clinical notes and echocardiographic findings of 20 patients who underwent open cardiac surgery in which concurrent AtriClip (Atricure Inc, Westchester, Ohio, USA) device insertion was attempted at our institution from July 2013 to February 2015. This was to examine the safety and efficacy of LAA exclusion with clip devices during open cardiac surgery. Indications for LAA exclusion included a history or suspicion of atrial arrhythmia, left ventricular dilatation, or a history of transient ischaemic attacks. RESULTS: All 20 of the 20 participants had successful placement of the clip device (100% success rate). There were no adverse events related to the device and no perioperative mortality. There were three late deaths due to chronic obstructive pulmonary disease (COPD), leukaemia, and refractory congestive cardiac failure. No late device related complications were found on follow-up imaging in the remaining patients. CONCLUSIONS: The results of our study demonstrate the LAA exclusion during open cardiac surgery with the AtriClip device is safe, has a 100% success rate, and appears to be stable over time. PMID- 29402695 TI - Differential removal of human pathogenic viruses from sewage by conventional and ozone treatments. AB - Sewage contains a mixed ecosystem of diverse sets of microorganisms, including human pathogenic viruses. Little is known about how conventional as well as advanced treatments of sewage, such as ozonation, reduce the environmental spread of viruses. Analyses for viruses were therefore conducted for three weeks in influent, after conventional treatment, after additional ozonation, and after passing an open dam system at a full-scale treatment plant in Knivsta, Sweden. Viruses were concentrated by adsorption to a positively charged filter, from which they were eluted and pelleted by ultracentrifugation, with a recovery of about 10%. Ion Torrent sequencing was used to analyze influent, leading to the identification of at least 327 viral species, most of which belonged to 25 families with some having unclear classification. Real-time PCR was used to test for 21 human-related viruses in inlet, conventionally treated, and ozone-treated sewage and outlet waters. The viruses identified in influent and further analyzed were adenovirus, norovirus, sapovirus, parechovirus, hepatitis E virus, astrovirus, pecovirus, picobirnavirus, parvovirus, and gokushovirus. Conventional treatment reduced viral concentrations by one to four log10, with the exception of adenovirus and parvovirus, for which the removal was less efficient. Ozone treatment led to a further reduction by one to two log10, but less for adenovirus. This study showed that the amount of all viruses was reduced by conventional sewage treatment. Further ozonation reduced the amounts of several viruses to undetectable levels, indicating that this is a promising technique for reducing the transmission of many pathogenic human viruses. PMID- 29402694 TI - Prenatal organophosphate insecticide exposure and infant sensory function. AB - BACKGROUND: Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early life exposure on visual and auditory function are unknown. Here we examined associations between prenatal OP exposure and grating visual acuity (VA) and auditory brainstem response (ABR) during infancy. METHODS: 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Grating visual acuity (VA) (n = 179-200) and auditory brainstem response (ABR) (n = 139-183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and central conduction time, and head circumference (HC). Associations between sensory outcomes during infancy and cord OPs were examined using linear mixed models. RESULTS: Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate (p = 0.04), respectively. CONCLUSIONS: We found deficits in grating VA and HC in 9 month-old infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in infancy could potentially negatively affect downstream cognitive development. PMID- 29402696 TI - Towards 5G communication systems: Are there health implications? AB - The spread of radiofrequency electromagnetic fields (RF-EMF) is rising and health effects are still under investigation. RF-EMF promote oxidative stress, a condition involved in cancer onset, in several acute and chronic diseases and in vascular homeostasis. Although some evidences are still controversial, the WHO IARC classified RF-EMF as "possible carcinogenic to humans", and more recent studies suggested reproductive, metabolic and neurologic effects of RF-EMF, which are also able to alter bacterial antibiotic resistance. In this evolving scenario, although the biological effects of 5G communication systems are very scarcely investigated, an international action plan for the development of 5G networks has started, with a forthcoming increment in devices and density of small cells, and with the future use of millimeter waves (MMW). Preliminary observations showed that MMW increase skin temperature, alter gene expression, promote cellular proliferation and synthesis of proteins linked with oxidative stress, inflammatory and metabolic processes, could generate ocular damages, affect neuro-muscular dynamics. Further studies are needed to better and independently explore the health effects of RF-EMF in general and of MMW in particular. However, available findings seem sufficient to demonstrate the existence of biomedical effects, to invoke the precautionary principle, to define exposed subjects as potentially vulnerable and to revise existing limits. An adequate knowledge of pathophysiological mechanisms linking RF-EMF exposure to health risk should also be useful in the current clinical practice, in particular in consideration of evidences pointing to extrinsic factors as heavy contributors to cancer risk and to the progressive epidemiological growth of noncommunicable diseases. PMID- 29402697 TI - Impact of BRCA Mutation Status on Survival of Women With Triple-negative Breast Cancer. AB - INTRODUCTION: The effect of germline BRCA mutations on the outcomes of patients with triple-negative breast cancer (TNBC) is not well understood. MATERIALS AND METHODS: The present retrospective study included women with newly diagnosed TNBC from January 1, 2004 to December 30, 2013. The demographic and tumor characteristics, genetic testing results, and outcomes were collected by a review of the patients' medical records. The outcomes were compared between the BRCA+ and BRCA- women. Kaplan-Meier curves were plotted for survival analysis, and Cox proportional hazard regression was used to determine the predictors of recurrence free survival. RESULTS: A total of 266 TNBC patients who had undergone BRCA testing were included in the final analysis. Of the 266 patients, 72 (27.0%) tested positive for a pathogenic BRCA mutation and 194 (73.0%) tested negative. BRCA+ women were more likely to be diagnosed with breast cancer at a younger age than were the BRCA- women. Mutation carriers were also more likely to undergo bilateral mastectomy and less likely to receive radiation. The 2- and 5-year overall survival in BRCA+ women was 97.1% and 83.1% and was 97.3% and 89.7% in the BRCA- women, respectively. No statistically significant difference was found in overall survival between the BRCA+ and BRCA- group. No statistically significant difference was noted in the rate of locoregional recurrence, distant recurrence, or recurrence-free survival between the BRCA+ and BRCA- women. CONCLUSION: Our study has demonstrated that BRCA mutation carrier status does not affect overall survival or recurrence-free survival in patients with TNBC. PMID- 29402698 TI - Subcortical neurodegeneration in chorea: Similarities and differences between chorea-acanthocytosis and Huntington's disease. AB - INTRODUCTION: Chorea-acanthocytosis (ChAc) and Huntington's disease (HD) are neurodegenerative conditions that share clinical and neuropathological features, despite their distinct genetic etiologies. METHODS: In order to compare these neuropathologies, serial gallocyanin-stained brain sections from three subjects with ChAc were analyzed and compared with our previous studies of eight HD cases, in addition to three hemispheres from two male controls. RESULTS: Astrogliosis was much greater in the ChAc striatum, as compared to that found in HD, with dramatic increase in total striatal glia numbers and the number of glia per striatal neuron. Striatal astrocytes are most likely derived from the striatal subependymal layer in ChAc, which showed massive proliferation. The thalamic centromedian-parafascicular complex is reciprocally connected to the striatum and is more heavily affected in HD than in ChAc. CONCLUSION: The distinct patterns of selective vulnerability and gliosis observed in HD and ChAc challenge simplistic views on the pathogenesis of these two diseases with rather similar clinical signs. The particular roles played by astroglia in ChAc and in HD clearly need to be elucidated in more detail. PMID- 29402699 TI - Next-generation nuclear morphology to grade solid tumours. PMID- 29402700 TI - Chromatin organisation and cancer prognosis: a pan-cancer study. AB - BACKGROUND: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. METHODS: Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. FINDINGS: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1.7, 95% CI 1.2-2.5, in the discovery cohort; 1.8, 1.0-3.0, in the Gloucester validation cohort; 2.2, 1.1-4.5, in the QUASAR 2 validation cohort; 3.1, 1.9-5.0, in the ovarian carcinoma cohort; 2.5, 1.8-3.4, in the uterine sarcoma cohort; 2.3, 1.2-4.6, in the prostate carcinoma cohort; and 4.3, 2.8-6.8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1.7, 95% CI 1.1-2.5, in the discovery cohort; 1.9, 1.1-3.2, in the Gloucester validation cohort; 2.6, 1.2 5.6, in the QUASAR 2 cohort; 1.8, 1.1-3.0, for ovarian carcinoma; 1.6, 1.0-2.4, for uterine sarcoma; 1.43, 0.68-2.99, for prostate carcinoma; and 1.9, 1.1-3.1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2.9, 95% CI 1.0-8.4) and microsatellite stable (1.8, 1.2-2.7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1.3, 0.7-2.4) or chromatin heterogeneous (0.8, 0.3-2.0) stage II colorectal cancer. INTERPRETATION: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings. FUNDING: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust. PMID- 29402701 TI - Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial. AB - BACKGROUND: The benefit of early integration of palliative care into oncological care is suggested to be due to increased psychosocial support. In Belgium, psychosocial care is part of standard oncological care. The aim of this randomised controlled trial is to examine whether early and systematic integration of palliative care alongside standard psychosocial oncological care provides added benefit compared with usual care. METHODS: In this randomised controlled trial, eligible patients were 18 years or older, and had advanced cancer due to a solid tumour, an European Cooperative Oncology Group performance status of 0-2, an estimated life expectancy of 12 months, and were within the first 12 weeks of a new primary tumour or had a diagnosis of progression. Patients were randomly assigned (1:1), by block design using a computer-generated sequence, either to early and systematic integration of palliative care into oncological care, or standard oncological care alone in a setting where all patients are offered multidisciplinary oncology care by medical specialists, psychologists, social workers, dieticians, and specialist nurses. The primary endpoint was change in global health status/quality of life scale assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ C30) at 12 weeks. The McGill Quality of Life Questionnaire (MQOL), which includes the additional existential wellbeing dimension, was also used. Analysis was by intention to treat. This trial is ongoing, but closed for accrual, and is registered with ClinicalTrials.gov, number NCT01865396. FINDINGS: From April 29, 2013, to Feb 29, 2016, we screened 468 patients for eligibility, of whom 186 were enrolled and randomly assigned to the early and systematic palliative care group (92 patients) or the standard oncological care group (94). Compliance at 12 weeks was 71% (65 patients) in the intervention group versus 72% (68) in the control group. The overall quality of life score at 12 weeks, by the EORTC QLQ C30, was 54.39 (95% CI 49.23-59.56) in the standard oncological care group versus 61.98 (57.02-66.95) in the early and systematic palliative care group (difference 7.60 [95% CI 0.59-14.60]; p=0.03); and by the MQOL Single Item Scale, 5.94 (95% CI 5.50-6.39) in the standard oncological care group versus 7.05 (6.59-7.50) in the early and systematic palliative care group (difference 1.11 [95% CI 0.49-1.73]; p=0.0006). INTERPRETATION: The findings of this study show that a model of early and systematic integration of palliative care in oncological care increases the quality of life of patients with advanced cancer. Our findings also show that early and systematic integration of palliative care is more beneficial for patients with advanced cancer than palliative care consultations offered on demand, even when psychosocial support has already been offered. Through integration of care, oncologists and specialised palliative care teams should work together to enhance the quality of life of patients with advanced cancer. FUNDING: Research Foundation Flanders, Flemish Cancer Society (Kom Op Tegen Kanker). PMID- 29402702 TI - Early integration of palliative care-new evidence and old questions. PMID- 29402703 TI - Tibial Nerve Stimulation to Drive Genital Sexual Arousal in an Anesthetized Female Rat. AB - BACKGROUND: There is clinical evidence that percutaneous tibial nerve stimulation can positively benefit women with female sexual interest/arousal disorder, yet no studies have explored the potential mechanisms further. AIM: To investigate the effect of tibial nerve stimulation on vaginal blood perfusion (VBP) in an anesthetized rat model. METHODS: 16 ketamine-anesthetized rats were surgically implanted with a nerve cuff electrode on 1 tibial nerve. The tibial nerve was stimulated for 30 minutes continuously or non-continuously at a frequency of 10 to 25 Hz. OUTCOMES: VBP was measured with laser Doppler flowmetry and analyzed using a wavelet transform of time-frequency representations with a focus on the neurogenic energy range (0.076-0.200 Hz). RESULTS: 25 of 33 (75.8%) stimulation periods had at least a 500% increase in laser Doppler flowmetry neurogenic energy compared with baseline. This increase was most common within 20 to 35 minutes after the start of stimulation. There was no statistically significant difference for frequency used or estrous cycle stage. CLINICAL TRANSLATION: The results of this study provide further support for percutaneous tibial nerve stimulation as an alternative treatment option for women with genital arousal aspects of female sexual interest/arousal disorder. STRENGTHS AND LIMITATIONS: This study successfully demonstrates the ability of tibial nerve stimulation to increase VBP. However, further studies to determine parameter optimization and to illuminate neural mechanisms are needed. Further studies also are necessary to determine effects of repeated stimulation sessions. CONCLUSION: Long-duration tibial stimulation was successful at driving increases in the neurogenic component of VBP, providing evidence that tibial nerve stimulation could be used to treat genital arousal aspects of female sexual interest/arousal disorder by improving pelvic blood flow. Zimmerman LL, Rice IC, Berger MB, Bruns TM. Tibial Nerve Stimulation to Drive Genital Sexual Arousal in an Anesthetized Female Rat. J Sex Med 2018;15:296-303. PMID- 29402704 TI - Long-term efficacy: The Achille's heel of the male sling? PMID- 29402705 TI - Treatment tailoring for factor V deficient patients and perioperative management using global hemostatic coagulation assays. AB - INTRODUCTION: Congenital factor V deficiency (FVD) is a rare bleeding disorder with an estimated incidence of 1 in 1000,000 in the general population. Since the common coagulation tests do not correlate with the bleeding tendency there is an unmet need to predict FVD patients' bleeding hazard prior to surgical interventions. AIM: To optimize treatment prior to surgical interventions, using global coagulation assays, thrombin generation (TG) and rotating thromboelastogram (ROTEM). METHODS: Our cohort included 5 patients with FVD, 4 severe and one mild. Two of them underwent TG and ROTEM prior to surgical interventions, including ex vivo spiking assays using bypass agents and platelets spiking. RESULTS: All five patients exhibited prolonged PT and PTT, non-dependent on their bleeding tendency. Patient 1, who demonstrated severe bleeding phenotype, underwent surgery treated by combination of APCC (FEIBA) and platelet transfusion. Therapy was guided by global tests (TG as well as ROTEM) results. During the pre and post-operative period neither excessive bleeding nor any thrombosis was noted. In contrast, TG and ROTEM analysis of patient 4 has lead us to perform the surgery without any blood products' support. Indeed, the patient did not encounter any bleeding. CONCLUSION: Global coagulation assays may be useful ancillary tools guiding treatment decisions in FVD patients undergoing surgical procedures. PMID- 29402706 TI - Association Between Pretreatment Neutrophil-to-Lymphocyte Ratio and Outcome of Patients With Metastatic Renal-Cell Carcinoma Treated With Nivolumab. AB - BACKGROUND: Biomarkers to guide treatment in metastatic renal-cell carcinoma (mRCC) are lacking. We aimed to investigate the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving nivolumab. PATIENTS AND METHODS: Through retrospective chart review, we identified 38 patients with mRCC treated with standard-of-care nivolumab between 2015 and 2016 at Winship Cancer Institute of Emory University. NLR was determined from complete blood count collected before starting treatment, and imaging was performed to assess progression. The NLR cutoff value of 5.5 was determined by log-rank test, and the univariate association with overall survival (OS) or progression-free survival (PFS) was assessed by the Cox proportional hazard model and Kaplan-Meier method. RESULTS: The 38 patients had a median age of 69 years. The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The median PFS was 2.6 months in the high NLR group but not reached in the low NLR group. Low NLR was strongly associated with increased PFS with hazard ratio of 0.20 (95% confidence interval, 0.07-0.64; P = .006). The median OS was 2.7 months in the high NLR group but not reached in the low NLR group. Low NLR was significantly associated with a prolonged OS with hazard ratio of 0.06 (95% confidence interval, 0.01-0.55; P = .012). CONCLUSION: Pretreatment NLR < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies. PMID- 29402707 TI - Bone Talk: Activated Osteoblasts Promote Lung Cancer Growth. AB - Cancer cells can directly stimulate the generation and recruitment of tumor supportive bone marrow-derived cells (BMDCs), including neutrophils, via secreted factors. A new study demonstrates that lung tumors also remotely activate bone residing osteoblasts, which in turn promote neutrophil production. This is a multistep mechanism of establishing a supportive tumor microenvironment. PMID- 29402708 TI - Study on the discrimination between Corydalis Rhizoma and its adulterants based on HPLC-DAD-Q-TOF-MS associated with chemometric analysis. AB - Corydalis Rhizoma (Yanhuso), is a crucial antianalgesic Traditional Chinese Medicine in clinic. Its adulterants (Northeast Yanhusuo), which are also from Corydalis and distributed in Northeast area of China, are used instead of Corydalis Rhizoma in the local places with a long history. In this paper, we compared the chemical differences of Corydalis Rhizoma and its seven adulterants by HPLC-DAD-Q-TOF-MS associated with chemometric analysis. 48 alkaloids are identified from them, and 14 alkaloids are reported for the first time based on the Mass data. The classification of different species is verified through PLS-DA and Hierarchical Clustering Heatmap analysis based on 26 samples. We find that large discrimination existing in the categories and content of the alkaloids between different species. C.y. is similar with C.t., which mainly contains protoberberine, tetrahydroprotoberberine and protopine types of alkaloids. Six other Northeast Yanhusuo, including C.r., C.w., C.a. as well as its three formas, can be classified into one category, because they mainly contained benzophenanthridines and aprophines. PMID- 29402709 TI - Spontaneous dissection of the left main coronary artery: Case report and brief review. PMID- 29402710 TI - Safety and utility of dobutamine and pressure wire use in the hemodynamic assessment of low-flow, low-gradient aortic stenosis with reduced left ventricular ejection fraction. AB - BACKGROUND: The ACC/AHA guidelines recommend low-dose dobutamine challenge for hemodynamic assessment of the severity of AS in patients with low flow, low gradient aortic stenosis with reduced ejection fraction (EF) (LFLG-AS; stage D2). Inherent pitfalls of echocardiography could result in inaccurate aortic valve areas (AVA), which have downstream prognostic implications. Data on the safety and efficacy of coronary pressure wire and fluid-filled catheter use for low dose dobutamine infusion is sparse. METHODS: We retrospectively analyzed 39 consecutive patients with EF<50%, AVA<1cm2 and SVI<35ml/m2 on echocardiography who underwent simultaneous right and left heart catheterization. Hemodynamic assessments were performed at baseline and at every increment in the dobutamine infusion rate (The infusion was continued until maximal dose of dobutamine or a mean AV gradient>40mmHg was attained. The occurrence of sustained ventricular arrhythmias, symptomatic hypotension or intolerable symptoms leading to cessation of infusion was recorded. Transient ischemic attacks (TIAs) or clinically apparent strokes periprocedurally or up to 30days after the procedure were recorded. RESULTS: Dobutamine challenge confirmed true AS in 26 patients (67%) and pseudosevere AS in 34%. No sustained arrhythmias, hypotension or cessation of infusion from intolerable symptoms were observed. No clinical strokes or TIAs were observed up to 30days after procedure in any of these patients. CONCLUSIONS: Hemodynamic assessment of AS using a pressure wire with dobutamine challenge is a safe and effective tool in identifying truly severe AS in patients with LFLG-AS with reduced EF. PMID- 29402711 TI - Comparison of chronological changes in urinary function in patients who underwent low-dose-rate brachytherapy for prostate cancer-A randomized controlled trial of alpha-1 adrenoceptor antagonist alone versus combination with cyclooxygenase-2 inhibitor. AB - PURPOSE: To evaluate the add-on efficacy of a cyclooxygenase (COX)-2 inhibitor on the chronological changes in urinary function in patients who underwent low-dose rate prostate brachytherapy. METHODS AND MATERIALS: A total of 310 patients with prostate cancer who underwent low-dose-rate-brachytherapy were enrolled. Patients were randomized and allocated to the monotherapy group (tamsulosin alone: 0.2 mg/d) and the combination group (tamsulosin 0.2 mg/d plus celecoxib: 200 mg/d). We compared the chronological change in the international prostate symptom score (IPSS), the overactive bladder symptom score (OABSS), uroflowmetric parameters, and the frequency volume chart. RESULTS: There was not a significant difference between the two groups in the chronological changes in IPSS and OABSS for 12 months after implantation. Regarding the frequency volume chart assessment, the mean daytime urinary frequency in the combination group at 3 and 6 months after implantation was significantly lower than that in the monotherapy group. Regarding IPSS recovery at 3 months after implantation, higher baseline IPSS and nonuse of external beam radiation therapy were independent factors, while smaller prostate volume and higher baseline IPSS were independent factors of IPSS recovery at 12 months after implantation based on multivariate analyses. CONCLUSIONS: There was not an additional effect of a COX-2 inhibitor to the action of an alpha-1 adrenoceptor antagonist on concerning the chronological changes in IPSS and OABSS. The use of a COX-2 inhibitor reduced the daytime urinary frequency and postvoid residual after seed implantation. PMID- 29402712 TI - Patients at Risk: Preoperative Opioid Use Affects Opioid Prescribing, Refills, and Outcomes After Total Knee Arthroplasty. AB - BACKGROUND: The purpose of this study was to evaluate the effect of preoperative opioid use on opioid prescriptions, refills, and clinical outcomes after total knee arthroplasty (TKA). METHODS: A retrospective review identified 53 patients on preoperative opioids who were matched 1:2 to 106 opioid-naive patients undergoing primary TKA with at least 2-year follow-up. Opioid refills, Knee Society Score (preoperative and follow-up), morphine equivalent dose (MED) prescribed, and persistent opioid use were compared between groups. RESULTS: The average total MED prescribed at discharge was 1248 mg, ranging from 0 to 5600 mg. The average daily MED used before discharge was greater in the preoperative opioid group compared to the opioid-naive group (90 +/- 75 mg vs 54 +/- 42 mg; P = .001). The preoperative opioid group and opioid-naive group differed in terms of refills (1.3 +/- 1.6 vs 0.4 +/- 0.6; P = .0001), persistent opioid use (21 [39%] vs 5 [4%], P = .0001), postoperative KSS (85 +/- 11 vs 90 +/- 13; P = .01), and manipulations under anesthesia (4 [8%] vs 1 [1%], P = .03). Preoperative tramadol users had the same risk of refills, persistent opioid use, reduced KSS, and manipulation under anesthesia as those taking other opioids. CONCLUSION: Preoperative opioid users were discharged with less opioids, required more refills, were more likely to remain on opioids, and required more manipulations under anesthesia than opioid-naive patients. These risks extended to preoperative tramadol users. PMID- 29402713 TI - Chronic Obstructive Pulmonary Disease Is Associated With Short-Term Complications Following Total Hip Arthroplasty. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. Furthermore, COPD patients are at increased risk of complications following surgery. The purpose of this study was to evaluate the postoperative total hip arthroplasty (THA) outcomes of COPD patients. Specifically, we asked the following questions: (1) Is COPD associated with adverse perioperative outcomes and (2) Does COPD increase the risk of short-term complications following THA? METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify 64,796 patients who underwent THA between 2008 and 2014. A total of 2426 patients with COPD were identified. COPD and non-COPD cohorts were compared based on the following outcomes: hospital length-of-stay, operative times, discharge disposition, and 30-day postoperative complications. RESULTS: COPD patients were found to have a longer length-of-stay and be discharged to an extended care facility (P < .001). COPD patients were also at significantly (P < .05) increased risk for any complication, such as mortality, myocardial infarction, pneumonia, septic shock, unplanned reintubation, use of a mechanical ventilator >48 hours, deep infection, require a blood transfusion, return to operating room, and a readmission within 30 days postoperatively. CONCLUSIONS: COPD patients are more likely to suffer from postoperative complications following THA when compared to non-COPD patients. Many of these complications are medical, pulmonary evaluation and medical optimization are a critical step in preoperative management for these patients. PMID- 29402714 TI - Retrieval Analysis of Large-Head Modular Metal-on-Metal Hip Replacements of a Single Design. AB - BACKGROUND: There are limited publications examining modular metal-on-metal (MoM) total hip implants in which a comprehensive analysis of retrieved components is performed. This study examines 24 retrieved modular MoM implants from a single manufacturer and compares retrieval analytics; bearing surface damage, wear, and modular taper corrosion against patient, surgical and implant characteristics to elucidate significant associations. METHODS: Clinical, patient, and surgical data were collected including age, body mass index, blood metal ion levels, and cup inclination. Damage assessment was performed visually in addition to surface profilometry. Acetabular liners and femoral heads were measured for volumetric wear. Femoral head taper bores were similarly measured for material removal due to corrosion and fretting. RESULTS: Patients with MoM-related reasons for revision showed significantly higher levels of blood metal ion levels. Bearing wear was strongly associated with blood metal ion levels and was significantly increased in cups placed more vertically. Younger patients tended to have higher body mass indices as well as poorer cup placement. CONCLUSION: This work details a broad range of analyses on a series of modular MoM total hip implants from a single manufacturer of which there are few published studies. Acetabular cup inclination angle was deemed a primary cause of revision surgery through increased MoM wear, high metal ion levels in the blood, and subsequent adverse local tissue reactions. Heavy patients can increase the surgical difficulty which was shown to be related to poor cup placement in this cohort. PMID- 29402715 TI - Does Parkinson Disease Increase the Risk of Perioperative Complications After Total Hip Arthroplasty? A Nationwide Database Study. AB - BACKGROUND: Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States, affecting over 1 million people. As part of the disease process, PD can cause poor bone quality and other musculoskeletal problems that can affect a patient's quality of life. With advances in treatment, PD patients can be more active and may be candidates for total hip arthroplasty (THA). However, there is a paucity of literature on the outcomes of THA in PD patients. Therefore, the purpose of this study was to evaluate the perioperative outcomes of PD patients who underwent THA. Specifically, we assessed: (1) perioperative surgical and medical complications; (2) lengths of stay (LOSs); and (3) total hospital charges. METHODS: Using the Nationwide Inpatient Sample, patients who had PD and underwent THA between 2002 and 2013 were identified. With the use of propensity scores, PD patients were matched in a 1:3 ratio to patients without PD by the year of surgery, age, gender, race, Charlson/Deyo score, and insurance type. This yielded a total of 10,519 PD and 31,679 non-PD THA patients. Regression analyses were used to compare the risk of perioperative complications (any, surgical, medical), the percent differences in mean LOS, and the percent differences in total hospital charges. RESULTS: Compared with the matched cohort, PD patients had a 52% higher risk for any complication (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.37-1.69), a 30% higher risk for any surgical complication (OR = 1.30; 95% CI: 0.88-1.91), and a 54% higher risk for any medical complication (OR = 1.54; 95% CI, 1.38-1.71). Specifically, PD patients were more likely to have postoperative delirium (OR = 2.61; 95% CI: 1.77-3.85), altered mental status (OR = 3.01; 95% CI: 1.35-6.71), urinary tract infection (OR = 1.34; 95% CI: 1.09-1.76), and blood transfusion (OR = 1.62; 95% CI: 1.44-1.82). Also, PD patients had a mean LOS that was 8.57% longer (P < .0001), and mean total hospital charges that were 3.85% higher (P < .0001). CONCLUSION: Orthopedic surgeons and neurologists should be involved in the preoperative counseling of PD patients regarding their potential increased risks associated with THA, which could help optimize their preoperative care. Furthermore, the risk of complications and higher costs could potentially lead to the development of different reimbursement methods in this population of patients. PMID- 29402716 TI - Gait Analysis of Leg Length Discrepancy-Differentiated Hip Replacement Patients With Developmental Dysplasia: A Midterm Follow-Up. AB - BACKGROUND: Few studies investigate gait characteristics and symmetry of developmental dysplasia of the hip patients (Crowe II and III) after total hip arthroplasty (THA) whose leg length discrepancy (LLD) is within 20 mm. Our study aimed to explore whether gait analysis parameters in these patients can return to the level of unaffected people and how bodies compensate for the discrepancy. METHOD: A total of 45 patients who underwent cementless THA and 20 healthy controls were involved in this study prospectively. Group 1 includes patients whose LLD is <10 mm and group 2 includes patients whose LLD is 10-20 mm. Gait analysis was performed during 5-year midterm postoperative follow-up. RESULT: The parameters, particularly the range of motion (ROM) in the hip, in both experimental groups (1 and 2) were significantly lower than healthy control group. For the nonoperated side, group 1 displayed significantly reduced ROM in the hip and knee compared with the age-matched controls. This was not observed in group 2. Greater bilateral symmetry can be seen in group 1 compared with group 2. CONCLUSION: Despite LLD being limited to within 20 mm, THA patients in both groups showed a less efficient gait than that of healthy controls on 5-year midterm follow-up. The increased ROM in the nonoperated hip may act as a compensatory mechanism. LLD of 10 mm may be a cutoff value to assess whether compensation occurs in the contralateral limb. Reconstruction of equal limb length is recommended when surgeons perform THA for dysplastic hips. PMID- 29402717 TI - The relationship between workplace violence, perceptions of safety, and Professional Quality of Life among emergency department staff members in a Level 1 Trauma Centre. AB - BACKGROUND: Emergency department staff members are frequently exposed to workplace violence which may have physical, psychological, and workforce related consequences. The purpose of this study was to examine the relationships between exposure to workplace violence, tolerance to violence, expectations of violence, perceptions of workplace safety, and Professional Quality of Life (compassion satisfaction - CS, burnout - BO, secondary traumatic stress - STS) among emergency department staff members. METHODS: A cross-sectional design was used to survey all emergency department staff members from a suburban Level 1 Trauma Centre in the western United States. RESULTS: All three dimensions of Professional Quality of Life were associated with exposure to non-physical patient violence including: general threats (CS p = .012, BO p = .001, STS p = .035), name calling (CS p = .041, BO p = .021, STS p = .018), and threats of lawsuit (CS p = .001, BO p = .001, STS p = .02). Tolerance to violence was associated with BO (p = .004) and CS (p = .001); perception of safety was associated with BO (p = .018). CONCLUSION: Exposure to non-physical workplace violence can significantly impact staff members' compassion satisfaction, burnout and secondary traumatic stress. Greater attention should be paid to the effect of non-physical workplace violence. Additionally, addressing tolerance to violence and perceptions of safety in the workplace may impact Professional Quality of Life. PMID- 29402718 TI - Does age, time since injury and meniscal injury affect short term functional outcomes in arthroscopic single bundle anterior cruciate ligament reconstruction? AB - PURPOSE: We conducted this study to correlate the short term clinical outcomes after anterior cruciate ligament (ACL) reconstruction with patients' age, time since injury and associated meniscal injury. METHODS: A total of 43 patients who underwent ACL reconstruction between October 2013 and February 2015 were taken for the study. Preoperative demographic data, clinical scores (Lysholm, IKDC) were recorded for each patient. Time since injury and associated meniscal injuries were recorded. Then a standardized surgical technique was used for each graft type. They were followed up for 6 months and the Lysholm and IKDC scores were evaluated. RESULTS: Only 33 patients completed 6 months follow-up at the end of this study. Twenty-four patients (72.7%) were in the age group of 18-30 years. Nine patients belonged to age group 30-50 years (27.3%). The p value for differences in Lysholm scores between the two age groups was not significant (0.339). The p value for differences in IKDC scores between the two age groups was not significant either (0.138). The mean Lysholm scores were 93.86 +/- 3.024 for the group who presented <6 months post-injury, 92 +/- 5.494 for the group who presented between 6 months and 1 year and 94.64 +/- 3.104 for the group who presented after 1 year; whereas the mean IKDC scores were 92.43 +/- 0.793, 90.64 +/- 6.598 and 90.89 +/- 2.113 respectively. The correlation of outcomes with meniscal injury had no statistical significance. CONCLUSION: Based on our study, we conclude that age, time since injury and associated meniscal injury does not affect short term functional outcome in ACL reconstruction. PMID- 29402719 TI - Intramedullary devices in the management of Judet III and IV paediatric radial neck fractures. AB - PURPOSE: The aim of this study is to discuss the results of different intramedullary devices used in the management of paediatric radial neck fractures and to suggest methods to avoid the pitfalls of the technique. METHODS: Thirty patients with isolated Judet III and IV fractures were included in this prospective study. Judet I and II fractures and radial neck fractures associated with other injuries were excluded. The final results were graded using the Metaizeau functional scoring system and Oxford Elbow Score. RESULTS: The functional result was good to excellent in 24 of 30 cases (80%). The mean Oxford Elbow Score was 44.32. The mean follow-up was 40.11 months. The complications seen were radiocapitellar joint penetration - 6 cases at mean 4.87 weeks, redisplacement - 6, radial epiphyseal sclerosis - 5, and heterotopic ossification - 1 case. CONCLUSION: Intramedullary K wires may result in radiocapitellar joint penetration. Titanium Elastic Nail System should not be used as purely fixation devices as they may not prevent redisplacement. Regular follow-up until at least 6 weeks is essential. Patients who have a Judet IV fracture and need open reduction should be given a guarded prognosis. The paper highlights the pitfalls of the technique and makes recommendations regarding the type of implant, follow up and patient counselling in Judet IV fractures. PMID- 29402720 TI - A review of upper limb injuries in bear maul victims: Consistent pattern and inverse relation in severity with facial and scalp injuries. AB - PURPOSE: Bear maul injuries are the most common wild animal inflicted injuries in India. More than 300 bear maul injuries report to our hospital per year. METHODS: Twenty-one consecutive patients over a period of 1 year reported to our department for orthopaedic management of bear maul injuries. All the patients were referred either from peripheral hospitals or from other surgical departments of our hospital. RESULTS: All the patients had facial/scalp injuries of variable severity. In all the patients the severity of limb and facial trauma was inversely proportional to each other. Pattern of upper limb trauma in most of the patients was similar. Fifteen patients had either fractures of distal humerus or mid shaft/proximal forearm bone fracture. Two had distal forearm bone fracture, 2 had carpal/metacarpal fractures and 1 had clavicle fracture. Only 1 had lower limb fracture. Thirteen out of 21 patients had associated neurovascular injury of the involved limb. The characteristic feature was extensive soft tissue involvement of the affected limb. CONCLUSION: Upper limb injuries in bear maul patients usually have similar pattern. The severity of upper limb and facial/scalp trauma is inversely proportional to each other. Multistage orthopaedic surgeries are needed for such complex limb injuries. PMID- 29402721 TI - Optimized administration of hetIL-15 expands lymphocytes and minimizes toxicity in rhesus macaques. AB - The common gamma-chain cytokine interleukin-15 (IL-15) plays a significant role in regulating innate and adaptive lymphocyte homeostasis and can stimulate anti tumor activity of leukocytes. We have previously shown that the circulating IL-15 in the plasma is the heterodimeric form (hetIL-15), produced upon co-expression of IL-15 and IL-15 Receptor alpha (IL-15Ralpha) polypeptides in the same cell, heterodimerization of the two chains and secretion. We investigated the pharmacokinetic and pharmacodynamic profile and toxicity of purified human hetIL 15 cytokine upon injection in rhesus macaques. We compared the effects of repeated hetIL-15 administration during a two-week dosing cycle, using different subcutaneous dosing schemata, i.e. fixed doses of 0.5, 5 and 50 ug/kg or a doubling step-dose scheme ranging from 2 to 64 ug/kg. Following a fixed-dose regimen, dose-dependent peak plasma IL-15 levels decreased significantly between the first and last injection. The trough plasma IL-15 levels measured at 48 h after injections were significantly higher after the first dose, compared to subsequent doses. In contrast, following the step-dose regimen, the systemic exposure increased by more than 1 log between the first injection given at 2 ug/kg and the last injection given at 64 ug/kg, and the trough levels were comparable after each injection. Blood lymphocyte cell count, proliferation, and plasma IL-18 levels peaked at day 8 when hetIL-15 was provided at fixed doses, and at the end of the cycle following a step-dose regimen, suggesting that sustained expansion of target cells requires increasing doses of cytokine. Macaques treated with a 50 ug/kg dose showed moderate and transient toxicity, including fever, signs of capillary leak syndrome and renal dysfunction. In contrast, these effects were mild or absent using the step-dose regimen. The results provide a new method of optimal administration of this homeostatic cytokine and may have applications for the delivery of other cytokines. PMID- 29402723 TI - Reduction of respiratory infections in asthma patients supplemented with vitamin D is related to increased serum IL-10 and IFNgamma levels and cathelicidin expression. AB - BACKGROUND: Vitamin D is a molecule that modulates the immune response and shows anti-inflammatory effects that are beneficial for the control of chronic diseases such as asthma. The trial aim was to explore the effect of vitamin D supplementation on the colonization of pathogenic bacteria in the upper respiratory tract of allergic asthmatic patients. METHODS: This study was conducted in 86 patients between 18 and 50 years of age who were randomly divided into two groups. Both groups received the treatment recommended by the Global Initiative for Asthma (GINA). One group also received calcitriol (1,25-(OH)2D3), and the other group received a placebo. At baseline and 6 months, skin prick tests were conducted, pharyngeal bacterial cultures were performed, and cathelicidin LL-37 was measured in sputum. Serum levels of IgE, eosinophils, IL 5, IL-9, IL-10, IL-13, and IFNgamma were quantified at the beginning and the end of the study. RESULTS: Serum levels of IL-10 and IFNgamma increased significantly in the group of patients with vitamin D supplementation, while IL-5, IL-9, and IL 13 decreased significantly. At the end of the trial, IgE and eosinophil levels significantly decreased but allergen sensitivity did not show any changes from baseline. Respiratory infections were drastically reduced, and this decrease was related to the number of patients who had high serum levels of IL-10 and IFNgamma and expressed LL-37 in their sputum. CONCLUSION: Treatment of asthma patients with vitamin D reduced respiratory infections, and this effect was related to the increase of cathelicidin LL-37. PMID- 29402722 TI - CD80/CD86 signaling contributes to the proinflammatory response of Staphylococcus aureus in the airway. AB - It was posited that the initial host response to Staphylococcus aureus is a contributing factor in the pathogenesis of acute pneumonia. Having previously observed that T cells play a negative role in the pathogenesis of acute pneumonia to S. aureus the contribution of the CD80/CD86 pathway in pathogenesis was investigated. Mice lacking CD80 and CD86 had significantly improved survival in a mouse model of acute S. aureus pneumonia. This was accompanied by significant reductions in several proinflammatory cytokines, including TNF, MIP-2, IL-1beta, IL-17 and IL-6, as well as increased numbers of viable alveolar macrophages. Early during infection reductions in cytokine production were evident and cytokine production in response to S. aureus in bone marrow derived macrophages showed decreases in TNF, KC, IL-1alpha and GM-CSF. Our data suggest that CD80/CD86 signaling plays a significant role in the initial inflammatory response to S. aureus in the airway and could be a potential acute target to reduce the initial inflammatory insult. PMID- 29402724 TI - Effects of acute or chronic heat exposure, exercise and dehydration on plasma cortisol, IL-6 and CRP levels in trained males. AB - This study examined the acute and chronic effects of euhydrated and hypohydrated heat exposure, on biomarkers of stress and inflammation. Eight trained males [mean (SD) age: 21 (3) y; mass: 77.30 (4.88) kg; VO2max: 56.9 (7.2) mL kg-1 min 1] undertook two heat acclimation programmes (balanced cross-over design), once drinking to maintain euhydration and once with restricted fluid-intake (permissive dehydration). Days 1, 6, and 11 were 60 min euhydrated exercise-heat stress tests (40 degrees C; 50% RH, 35% peak power output), days 2-5 and 7-10 were 90 min, isothermal-strain (target rectal temperature: 38.5 degrees C) exercise-heat sessions. Plasma was obtained pre- and post- exercise on day 1, 2, and 11 and analysed for cortisol, interleukin-6 (IL-6), and C-reactive protein (CRP). Cortisol and CRP were also assessed on day 6. IL-6 was elevated following the initial (acute) 90 min isothermal heat strain exercise-heat exposure (day 2) with permissive dehydration ((pre exercise: 1.0 pg mL-1 [0.9], post-exercise: 1.8 pg mL-1 [1.0], P = .032) and when euhydrated (pre-exercise: 1.0 pg mL-1 [1.4], post-exercise: 1.6 pg mL-1 [2.1], P = .048). Plasma cortisol levels were also elevated but only during permissive dehydration (P = .032). Body mass loss was strongly correlated with Deltacortisol (r = -0.688, P = .003). Although there was a trend for post-exercise cortisol to be decreased following both heat acclimation programmes (chronic effects), there were no within or between intervention differences in IL-6 or CRP. In conclusion, acute exercise in the heat increased IL-6 and cortisol only when fluid-intake is restricted. There were no chronic effects of either intervention on biomarkers of inflammation as evidenced by IL-6 and CRP returning to basal level at the end of heat acclimation. PMID- 29402725 TI - CCL18 - Beyond chemotaxis. AB - The chemokine CCL18 is constitutively expressed in human lung and serum, and is further elevated during pathologic conditions such as allergy, fibrosis and cancer, suggesting that it may participate in both homeostatic and inflammatory processes. Under steady state conditions, CCL18 has chemotactic activity, albeit modest, toward naive T cells and as such, may be involved in the initiation of the adaptive response. Its chemotactic effect on inflammatory cells is ambiguous as it attracts both regulatory and inflammatory immune cells. CCL18 can also modulate tissue inflammation by inhibiting cell recruitment through binding to glycosaminoglycans with high affinity, thereby displacing other chemokines bound to the endothelial surface. CCL18 induces regulatory phenotype and function of immune cells through direct activation and plays a major role in fibrotic processes, particularly in the lung. Finally, CCL18 is involved in cancer cell activation and migration and also participates in immune tolerance toward cancer. Its high constitutive expression levels and its further up-regulation in many diseases, together with its moderate chemoattractant properties support the fact that this chemokine has activities beyond cell recruitment. PMID- 29402726 TI - High Expression of TET1 Predicts Poor Survival in Cytogenetically Normal Acute Myeloid Leukemia From Two Cohorts. AB - Ten-Eleven-Translocation 1 (TET1) plays a role in the DNA methylation process and gene activation. Recent reports suggest TET1 acts as an oncogene in leukemia development. However, the clinical relevance and biological insight of TET1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) is unknown. In this study, quantification of TET1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 360 CN-AML patients. As a result, high TET1 expression was more common in M0/M1 morphology and genes of NPM1 mutations, and underrepresented in CEBPA double allele mutations in our AML patients. In addition, we found overexpression of TET1 was associated with an inferior overall survival and event free survival in the two independent cohorts. Notably, mRNA and miRNA integrative analyses showed aberrant expression of several hub oncogenes appear to be regulated by some miRNAs like miR-127-5p, miR-494, miR-21 and miR-616 in high TET1 expressers. In conclusion, the TET1 gene expression might serve as a reliable predictor for patients survival in AML. PMID- 29402727 TI - Salivary Glycopatterns as Potential Biomarkers for Screening of Early-Stage Breast Cancer. AB - OBJECTIVE: We systematically investigated and assessed the alterations of salivary glycopatterns and possibility as biomarkers for diagnosis of early-stage breast cancer. DESIGN: Alterations of salivary glycopatterns were probed using lectin microarrays and blotting analysis from 337 patients with breast benign cyst or tumor (BB) or breast cancer (I/II stage) and 110 healthy humans. Their diagnostic models were constructed by a logistic stepwise regression in the retrospective cohort. Then, the performance of the diagnostic models were assessed by ROC analysis in the validation cohort. Finally, a double-blind cohort was tested to confirm the application potential of the diagnostic models. RESULTS: The diagnostic models were constructed based on 9 candidate lectins (e.g., PHA-E+L, BS-I, and NPA) that exhibited significant alterations of salivary glycopatterns, which achieved better diagnostic powers with an AUC value >0.750 (p<0.001) for the diagnosis of BB (AUC: 0.752, sensitivity: 0.600, and specificity: 0.835) and I stage breast cancer (AUC: 0.755, sensitivity: 0.733, and specificity: 0.742) in the validation cohort. The diagnostic model of I stage breast cancer exhibited a high accuracy of 0.902 in double-blind cohort. CONCLUSIONS: This study could contribute to the screening for patients with early stage breast cancer based on precise alterations of salivary glycopatterns. PMID- 29402728 TI - From Tissue Engineering to Regenerative Surgery. PMID- 29402729 TI - Radiologic correlation between the thickness of the roof of the glenoid fossa and that of the bony covering of the superior semicircular canal. AB - OBJECTIVES: Dehiscence of the superior semicircular canal (SSC) has been associated with alteration of the temporomandibular joint, although data explaining this association are lacking. The present study examined the correlations between the presence of dehiscences and thickness of the bone covering the SSC and the roof of the glenoid fossa (RGF). STUDY DESIGN: Computed tomography was used in a cross-sectional analysis of the presence of dehiscences and thickness of the bone overlying the SCC and RGF in 156 temporal bones of 78 patients. The correlations of the presence of dehiscences in the SSC and ipsilateral RGF and the thickness of bone covering the SSC and RGF were analyzed by using the chi2 or Fisher's exact test. The relationship between the thickness of the bone overlying the SCC and RGF was analyzed by using the Spearman correlation coefficient and the Kruskal-Wallis test. The relationship between the thickness of the RGF and the covering of the SCC and patient age and gender was analyzed with the general linear model. RESULTS: Significant correlations were found between the presence of dehiscences and thickness of the bone overlying the SSC and RGF (P < .001). CONCLUSIONS: There is a morphologic relationship between the structure of the SSC and RGF. PMID- 29402730 TI - Clinical complications in the application of polyglycolic acid sheets with fibrin glue after resection of mucosal lesions in oral cavity. AB - OBJECTIVES: Covering open wounds with a polyglycolic acid (PGA) sheet using fibrin glue after resection of oral mucosal lesions is reportedly useful. We focused on clinical complications of this procedure: development of marked granuloma-like neoplasm (GLN) and abnormal postoperative bleeding (APB) on the resected region. STUDY DESIGN: The characteristics of 100 cases with PGA sheet application after the resection of oral mucosal lesion were examined retrospectively by the medical records and/or oral photographs at our department between 2010 and 2016. RESULTS: Our retrospective analysis identified included 8 cases of GLN development and 7 cases of APB. There was a significantly higher risk of GLN development when the PGA sheet was applied to the raw surface of the tongue. There were no immediate APBs, but 4 APBs occurred several hours after surgery. All APB cases involved the tongue. CONCLUSIONS: Both GLNs and APBs are minor complications. Although all cases of GLNs did not involve the recurrence of a tumor, follow-up with incisional or excisional biopsy should be performed. APB in the oral cavity induced by the PGA sheet peeling due to fluctuating adhesive force of the PGA sheets and fibrin glue can sometimes induce life-threatening events. PMID- 29402731 TI - Electromagnetic navigated condylar positioning after high oblique sagittal split osteotomy of the mandible: a guided method to attain pristine temporomandibular joint conditions. AB - OBJECTIVES: Reproduction of the exact preoperative proximal-mandible position after osteotomy in orthognathic surgery is difficult to achieve. This clinical pilot study evaluated an electromagnetic (EM) navigation system for condylar positioning after high-oblique sagittal split osteotomy (HSSO). STUDY DESIGN: After HSSO as part of 2-jaw surgery, the position of 10 condyles was intraoperatively guided by an EM navigation system. As controls, 10 proximal segments were positioned by standard manual replacement. Accuracy was measured by pre- and postoperative cone beam computed tomography imaging. RESULTS: Overall, EM condyle repositioning was equally accurate compared with manual repositioning (P > .05). Subdivided into 3 axes, significant differences could be identified (P < .05). Nevertheless, no significantly and clinically relevant dislocations of the proximal segment of either the EM or the manual repositioning method could be shown (P > .05). CONCLUSIONS: This pilot study introduces a guided method for proximal segment positioning after HSSO by applying the intraoperative EM system. The data demonstrate the high accuracy of EM navigation, although manual replacement of the condyles could not be surpassed. However, EM navigation can avoid clinically hidden, severe malpositioning of the condyles. PMID- 29402732 TI - Female Sexual Dysfunction: A Systematic Review of Outcomes Across Various Treatment Modalities. AB - BACKGROUND: Female sexual dysfunction (FSD) is a highly prevalent condition. Nevertheless, the scientific literature has only recently begun to accumulate evidence for treatment modalities that address the underlying etiologies of FSD. AIM: The purpose of this systematic review is to elucidate what treatments are effective across the various symptom complexes of FSD. METHODS: Utilizing Meta analysis of Observational Studies in Epidemiology guidelines, we conducted a systematic review of PubMed, EMBASE, clinicaltrials.gov, and the Cochrane Review databases. Eleven search strings, encompassing the terms "female sexual dysfunction" and "treatment," in combination with "vulvovaginal atrophy," "vaginismus," "vaginal atrophy," "vulvodynia," "vestibulitis," "hypoactive sexual desire," "arousal disorder," "sexual pain disorder," "genitourinary syndrome of menopause," and "orgasmic disorder" were utilized. 605 Relevant articles were retrieved. A total of 103 original studies met inclusion criteria. OUTCOMES: We assess peer-reviewed literature. RESULTS: 42 Treatment modalities were utilized, including 26 different classes of medications. Although outcome measures varied, the most substantial improvement across multiple studies was noted with various hormonal regimens. The most common treatments included hormonal therapy (25 studies), phosphodiesterase type-5 inhibitors (9 studies), botulinum toxin A (5 studies), and flibanserin (5 studies). The psychotherapeutic approach was detailed in 36 articles while 3 studies utilized homeopathic treatments. Numerous treatments showed efficacy in a single case series, including the promising results associated with the micro-ablative carbon-dioxide laser. Despite the marked improvement in specific FSD domains, neither pharmacologic treatments nor psychotherapeutic interventions demonstrate consistent disease resolution. CONCLUSIONS: Treatment of FSD is multi-factorial; medications alone do not resolve FSD. The wide variability of treatment and outcome measures across the literature attests to the complexity of FSD and the need for a treatment algorithm that addresses all 4 domains of FSD. Weinberger JM, Houman J, Caron AT, et al. Female Sexual Dysfunction: A Systematic Review of Outcomes Across Various Treatment Modalities. Sex Med Rev 2018;XX:XXX-XXX. PMID- 29402733 TI - Impact of isotropic constitutive descriptions on the predicted peak wall stress in abdominal aortic aneurysms. AB - Biomechanics-based assessment of Abdominal Aortic Aneurysm (AAA) rupture risk has gained considerable scientific and clinical momentum. However, computation of peak wall stress (PWS) using state-of-the-art finite element models is time demanding. This study investigates which features of the constitutive description of AAA wall are decisive for achieving acceptable stress predictions in it. Influence of five different isotropic constitutive descriptions of AAA wall is tested; models reflect realistic non-linear, artificially stiff non-linear, or artificially stiff pseudo-linear constitutive descriptions of AAA wall. Influence of the AAA wall model is tested on idealized (n=4) and patient-specific (n=16) AAA geometries. Wall stress computations consider a (hypothetical) load-free configuration and include residual stresses homogenizing the stresses across the wall. Wall stress differences amongst the different descriptions were statistically analyzed. When the qualitatively similar non-linear response of the AAA wall with low initial stiffness and subsequent strain stiffening was taken into consideration, wall stress (and PWS) predictions did not change significantly. Keeping this non-linear feature when using an artificially stiff wall can save up to 30% of the computational time, without significant change in PWS. In contrast, a stiff pseudo-linear elastic model may underestimate the PWS and is not reliable for AAA wall stress computations. PMID- 29402735 TI - The mindedness of maternal touch: An investigation of maternal mind-mindedness and mother-infant touch interactions. AB - Increasing evidence shows that maternal touch may promote emotion regulation in infants, however less is known about how parental higher-order social cognition abilities are translated into tactile, affect-regulatory behaviours towards their infants. During 10 min book-reading, mother-infant sessions when infants were 12 months old (N = 45), we investigated maternal mind-mindedness (MM), the social cognitive ability to understand an infant's mental state, by coding the contingency of maternal verbal statements towards the infants' needs and desires. We also rated spontaneous tactile interactions in terms of their emotional contingency. We found that frequent non-attuned mind-related comments were associated with touch behaviours that were not contingent with the infant's emotions; ultimately discouraging affective tactile responses from the infant. However, comments that were more appropriate to infant's mental states did not necessarily predict more emotionally-contingent tactile behaviours. These findings suggest that when parental high-order social cognitive abilities are compromised, they are also likely to translate into inappropriate, tactile attempts to regulate infant's emotions. PMID- 29402734 TI - Maternal Exercise Improves the Metabolic Health of Adult Offspring. AB - The intrauterine environment can modulate the course of development and confer an enduring effect on offspring health. The effects of maternal diet to impair offspring metabolic health are well established, but the effects of maternal exercise on offspring metabolic health have been less defined. Because physical exercise is a treatment for obesity and type 2 diabetes (T2D), maternal exercise is an appealing intervention to positively influence the intrauterine environment and improve the metabolic health of offspring. Recent research has provided insights into the effects of maternal exercise on the metabolic health of adult offspring, which is the focus of this review. PMID- 29402736 TI - Automated three-dimensional tracking of the left ventricular myocardium in time resolved and dose-modulated cardiac CT images using deformable image registration. AB - BACKGROUND: Assessment of myocardial deformation from time-resolved cardiac computed tomography (4D CT) would augment the already available functional information from such an examination without incurring any additional costs. A deformable image registration (DIR) based approach is proposed to allow fast and automatic myocardial tracking in clinical 4D CT images. METHODS: Left ventricular myocardial tissue displacement through a cardiac cycle was tracked using a B spline transformation based DIR. Gradient of such displacements allowed Lagrangian strain estimation with respect to end-diastole in clinical 4D CT data from ten subjects with suspected coronary artery disease. Dice similarity coefficient (DSC), point-to-curve error (PTC), and tracking error were used to assess the tracking accuracy. Wilcoxon signed rank test provided significance of tracking errors. Topology preservation was verified using Jacobian of the deformation. Reliability of estimated strains and torsion (normalized twist angle) was tested in subjects with normal function by comparing them with normal strain in the literature. RESULTS: Comparison with manual tracking showed high accuracy (DSC: 0.99+/-0.05; PTC: 0.56mm+/-0.47 mm) and resulted in determinant(Jacobian)>0 for all subjects, indicating preservation of topology. Average radial (0.13 mm), angular (0.64) and longitudinal (0.10 mm) tracking errors for the entire cohort were not significant (p > 0.9). For patients with normal function, average strain [circumferential, radial, longitudinal] and peak torsion estimates were: [-23.5%, 31.1%, -17.2%] and 7.22 degrees , respectively. These estimates were in conformity with the reported normal ranges in the existing literature. CONCLUSIONS: Accurate wall deformation tracking and subsequent strain estimation are feasible with the proposed method using only routine time-resolved 3D cardiac CT. PMID- 29402737 TI - Anxiety and Threat-Related Attention: Cognitive-Motivational Framework and Treatment. AB - Research in experimental psychopathology and cognitive theories of anxiety highlight threat-related attention biases (ABs) and underpin the development of a computer-delivered treatment for anxiety disorders: attention-bias modification (ABM) training. Variable effects of ABM training on anxiety and ABs generate conflicting research recommendations, novel ABM training procedures, and theoretical controversy. This article summarises an updated cognitive motivational framework, integrating proposals from cognitive models of anxiety and attention, as well as evidence of ABs. Interactions between motivational salience-driven and goal-directed influences on multiple cognitive processes (e.g., stimulus evaluation, inhibition, switching, orienting) underlie anxiety and the variable manifestations of ABs (orienting towards and away from threat; threat-distractor interference). This theoretical analysis also considers ABM training as cognitive skill training, describes a conceptual framework for evaluating/developing novel ABM training procedures, and complements network based research on reciprocal anxiety-cognition relationships. PMID- 29402738 TI - Potentiation of the activity of beta-lactam antibiotics by farnesol and its derivatives. AB - Farnesol, a sesquiterpene alcohol, potentiates the activity of beta-lactam antibiotics against antibiotic-resistant bacteria. We document that farnesol and two synthetic derivatives (compounds 2 and 6) have poor antibacterial activities of their own, but they potentiate the activities of ampicillin and oxacillin against Staphylococcus aureus strains (including methicillin-resistant S. aureus). These compounds attenuate the rate of growth of bacteria, which has to be taken into account in assessment of the potentiation effect. PMID- 29402739 TI - Determination of L-AP4-bound human mGlu8 receptor amino terminal domain structure and the molecular basis for L-AP4's group III mGlu receptor functional potency and selectivity. AB - L-2-Amino-4-phosphonobutyric acid (L-AP4) is a known potent and selective agonist for the Group III mGlu receptors. However, it does not show any selectivity among the individual group III mGlu subtypes. In order to understand the molecular basis for this group selectivity, we solved the first human mGlu8 amino terminal domain (ATD) crystal structures in complex with L-glu and L-AP4. In comparison with other published L-glu-bound mGlu ATD structures, we have observed L-glu binds in a significantly different manner in mGlu1. Furthermore, these new structures provided evidence that both the electronic and steric nature of the distal phosphate of L-AP4 contribute to its exquisite Group III functional agonist potency and selectivity. PMID- 29402740 TI - Synthesis of novel multivalent fluorescent inhibitors with high affinity to prostate cancer and their biological evaluation. AB - Prostate-specific membrane antigen (PSMA) is an important biological target for therapy and diagnosis of prostate cancer. In this study, novel multivalent PSMA inhibitors with glutamate-urea-lysine structures were designed to improve inhibition characteristics. Precursors of the novel inhibitors were prepared from glutamic acid with di-tert-butyl ester. A near-infrared molecular dye, sulfo Cy5.5, was introduced into the precursors to generate the final PSMA fluorescent inhibitors, compounds 12-14, to visualize prostate cancer. Biological behaviors of the inhibitors were evaluated using in vitro inhibition assays, in vivo fluorescent imaging, and ex vivo biodistribution assays. Ki values from inhibition studies indicated that dimeric inhibitor 13 with a glutamine linker showed approximately 3-fold more inhibitory activity than monomeric inhibitor 12. According to other biological studies using a mouse model of prostate cancer, dimeric inhibitor compounds 13 and 14 had higher tumor accumulation than the monomer. However, glutamine-based dimeric inhibitor 13 showed lower liver uptake than dimeric inhibitor 14, which had a benzene structure. Thus, these studies suggest that glutamine-based dimeric inhibitor 13 can be a promising optical inhibitor of prostate cancer. PMID- 29402741 TI - Design, synthesis, and structure-activity relationships of new benzofuro[3,2 b]pyridin-7-ols as DNA topoisomerase II inhibitors. AB - Human DNA topoisomerases have become attractive targets for developing more effective anticancer drugs. In this study, a series of new benzofuro[3,2 b]pyridin-7-ols were designed and synthesized for the first time and screened for their topoisomerase I and II inhibitory and antiproliferative activity. Structure activity relationships revealed the position of ortho- and para-hydroxyl group at 2-phenyl ring, and meta-hydroxyl group at 4-phenyl ring of benzofuro[3,2 b]pyridin-7-ol are important for potent and selective topo II inhibitory activity. Compound 11 showed the most selective and potent topo II inhibition (100% inhibition at 100 uM) and strongest antiproliferative activity (IC50 = 0.86 uM) than all the positive controls in HeLa cell line. PMID- 29402742 TI - Novel SIRT1 activator MHY2233 improves glucose tolerance and reduces hepatic lipid accumulation in db/db mice. AB - The NAD+-dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1 month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233. In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance. PMID- 29402743 TI - Formoxanthone C, isolated from Cratoxylum formosum ssp. pruniflorum, reverses anticancer drug resistance by inducing both apoptosis and autophagy in human A549 lung cancer cells. AB - Multidrug resistance (MDR) cancer toward cancer chemotherapy is one of the obstacles in cancer therapy. Therefore, it is of interested to use formoxanthone C (1,3,5,6-tetraoxygenated xanthone; XanX), a natural compound, which showed cytotoxicity against MDR human A549 lung cancer (A549RT-eto). The treatment with XanX induced not only apoptosis- in A549RT-eto cells, but also autophagy-cell death. Inhibition of apoptosis did not block XanX-induced autophagy in A549RT-eto cells. Furthermore, suppression of autophagy by beclin-1 small interfering RNAs (siRNAs) did not interrupt XanX-induced apoptosis, indicating that XanX can separately induce apoptosis and autophagy. Of interest, XanX treatment reduced levels of histone deacetylase 4 (HDAC4) protein overexpressed in A549RT-etocells. The co-treatment with XanX and HDAC4 siRNA accelerated both autophagy and apoptosis more than that by XanX treatment alone, suggesting survival of HDAC4 in A549RT-eto cells. XanX reverses etoposide resistance in A549RT-eto cells by induction of both autophagy and apoptosis, and confers cytotoxicity through down regulation of HDAC4. PMID- 29402744 TI - Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents. AB - Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure-activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules. PMID- 29402746 TI - Isoxazole-containing neonicotinoids: Design, synthesis, and insecticidal evaluation. AB - A series of novel isoxazole-containing neonicotinoids were synthesized from nitromethylene analogues and aromatic aldehydes in the presence of l proline/K2CO3. Bioassays indicated that several synthesized compounds showed 40 70% mortality against brown planthopper (Nilaparvata lugens) under the concentration of 4mgL-1, higher than that of imidacloprid (20%). Against cowpea aphid (Aphis craccivora), the best activity of title compounds reached 90% at the concentration of 20mgL-1. PMID- 29402745 TI - Design, synthesis and antibacterial evaluation of honokiol derivatives. AB - Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1*MIC and 4*MIC. PMID- 29402747 TI - Estrogenic activity of constituents from the rhizomes of Rheum undulatum Linne. AB - Stilbenes have been reported to be phytoestrogen compounds owing to its structural similarity to the estrogenic agent diethylstilbestrol. To find new stilbene-derivative phytoestrogens, isolation of stilbene-rich R. undulatum was performed and led to identify six new compounds (1-5 and 28), one newly determined absolute configurations compound (27) together with 21 previously reported compounds (6-26). The structures of compounds were determined on the basis of extensive spectroscopic methods including 1D and 2D NMR and CD spectra data. All the isolated compounds were tested for their estrogenic activities in HepG2 cells transiently transfected with ERalpha, ERbeta and ERE-reporter plasmid. Among them, stilbene-derivatives, piceatannol 3'-O-beta-d-xylopyranoside (12), cis-rhaponticin (16) and rhapontigenin 3'-O-beta-d-glucopyranoside (17), showed the more potent binding affinity for estrogen receptors than 17beta estrodiol. PMID- 29402748 TI - Cultural sciences and representation of culture in the mind, and body: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29402749 TI - Improving the accuracy of the nearest neighbor model of DNA melting: Comment on "DNA melting and energetics of the double helix" by Alexander Vologodskii and Maxim D. Frank-Kamenetskii. PMID- 29402750 TI - A bridge towards a mathematical theory of living systems: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by F. Schoeller, L. Perlovsky, and D. Arseniev. PMID- 29402751 TI - Australian state of Victoria passes assisted dying bill. PMID- 29402753 TI - Upfront Alcian Blue-periodic acid Schiff stain for the assessment of upper gastrointestinal disorders. PMID- 29402752 TI - Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: A French randomised double-blind phase III trial (PRODIGE 50 ASPIK). AB - Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence. We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20, stage III or high risk stage II. The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HR = 0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3-4 severe bleeding. PMID- 29402754 TI - Mitochondrial responses to anoxia exposure in red eared sliders (Trachemys scripta). AB - When deprived oxygen, mitochondria from most vertebrates transform from the main site of ATP production to the dominant site of cellular ATP use due to the reverse functioning of the F1FO-ATPase (complex V). The anoxia-tolerant freshwater turtle Trachemys scripta however, has previously been shown to inhibit complex V activity in heart and brain in response to anoxia exposure, but the regulatory mechanism is unknown. To gain insight into the putative regulatory mechanisms underlying the anoxia-induced inhibition of complex V in T. scripta, we examined the effects of two weeks anoxia exposure at 4 degrees C on the mitochondrial proteome and candidate mechanisms that have been shown to regulate complex V in other organisms. In T. scripta, we confirmed that anoxia exposure resulted in a >80% inhibition of complex V in heart, brain and liver. Incubation of mitochondria with the nitric oxide donor, s-nitrosoglutathione, did not affect complex V activity despite showing the expected inhibition in mice. Proteomics analysis showed anoxia-induced decreases in three peripheral stalk subunits of complex V, possibly pointing to a unique site of regulation. Proteomics analysis also revealed differential expression of numerous enzymes involved with the electron transport system, the tricarboxylic acid cycle, as well as lipid and amino acid metabolism in response to anoxia exposure. PMID- 29402755 TI - MedAd-AppQ: A quality assessment tool for medication adherence apps on iOS and android platforms. AB - BACKGROUND: With the recent proliferation of smartphone medication adherence applications (apps), it is increasingly more difficult for patients and clinicians to identify the most useful app. OBJECTIVE: To develop a quality assessment tool for medication adherence apps, and evaluate the quality of such apps from the major app stores. METHODS: In this study, a Medication Adherence App Quality assessment tool (MedAd-AppQ) was developed and two evaluators independently assessed apps that fulfilled the following criteria: availability in English, had at least a medication reminder feature, non-specific to certain disease conditions (generic apps), free of technical malfunctions and availability on both the iPhone Operating System (iOS) and Android platforms. Descriptive statistics, Mann-Whitney U test, Pearson product moment correlation and Spearman rank-order correlation were used for statistical analysis. RESULTS: MedAd-AppQ was designed to have 24 items (total 43 points) categorized under three sections: content reliability (11 points), feature usefulness (29 points) and feature convenience (3 points). The three sections of MedAd-AppQ were found to have inter-rater correlation coefficients of 0.801 (p-value < .001) or higher. Based on analysis of 52 apps (27 iOS and 25 Android), quality scores ranged between 7/43 (16.3%) and 28/43 (65.1%). There was no significant difference between the quality scores of the Android and iOS versions. None of the apps had features for self-management of side effects. Only two apps in each platform provided disease-related and/or medication information. CONCLUSIONS: MedAd-AppQ can be used to reliably assess the quality of adherence apps. Clinicians can use the tool in selecting apps for use by patients. Developers of adherence apps should consider features that provide therapy-related information and help patients in medications and side-effects management. PMID- 29402756 TI - A Novel Approach for Apical Dissection During Robot-assisted Radical Prostatectomy: The "Collar" Technique. AB - BACKGROUND: Apical dissection in robot-assisted radical prostatectomy (RARP) affects not only cancer control, but also continence recovery. OBJECTIVE: To describe a novel approach for apical dissection, the collar technique, to reduce apical positive surgical margins (PSMs). DESIGN, SETTING, AND PARTICIPANTS: A total of 189 consecutive patients (81 in the control group, 108 in the collar technique group) underwent RARP at a single center. PRIMARY OUTCOME: rates of apical PSMs; secondary outcome: urinary continence. INTERVENTION: The urethral sphincter complex is incised 2-3mm distally to the apex, to stay farther from it and reduce PSMs; the underlying smooth muscle is exposed and incised closer to the apex to preserve the maximal length of the lissosphincter. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mann-Whitney U and chi-square tests compared median and proportions between the two groups, respectively. Univariate logistic regression tested the association between technique employed and risk of apical PSMs. RESULTS AND LIMITATIONS: Fourteen patients (7.4%) revealed apical PSMs (9.9% in the control group, 5.6% in the collar group; p=0.7). When the collar technique was used, significantly lower rates of apical PSMs occurred in pT2 disease (0% vs 7.1%; p=0.03). In case of apical tumor at preoperative magnetic resonance imaging (MRI; n=43), the collar technique determined significantly lower overall (9.7% vs 42%) and apical (3.2% vs 42%) PSMs (all p<=0.02). Continence recovery in the collar and control groups was similar. When preoperative MRI showed an apical tumor, the collar technique had a significantly lower risk of apical PSMs (odds ratio: 0.05, p=0.009). CONCLUSIONS: The collar technique reduces the rates of apical PSMs in case of apical tumor, preserving the length of the lissosphincter. PATIENT SUMMARY: We describe a novel approach for apical dissection during robot-assisted radical prostatectomy. Our technique reduces the rates of apical surgical margins in case of apical tumor at preoperative magnetic resonance imaging and leads to optimal continence recovery. PMID- 29402757 TI - Effect of social leisure activities on object naming in healthy aging A multimodal approach. AB - Environmental factors contribute to the constitution and maintenance of the cognitive reserve and partially explain the variability of cognitive performance in older individuals. We assessed the role of leisure activities - social and individual - on the access to lexico-semantic representations evaluated through a task of object naming (ON). We hypothesize that compared to individual, social leisure activities explain better the ON performance in the older adults, which is explained by a mechanism of neural reserve. Our results in older adults indicate (a) a significant correlation between leisure social activities and the response time for ON, (b) a significant correlation between link the neural activity of the left superior and medial frontal (SmFG) for ON and leisure social activities. Interestingly, the activity of the left SmFG partially mediates the relationship between social activities and OD performance. We suggest that social leisure activities may contribute to maintain ON performances in healthy aging, through a neural reserve mechanism, in relation with left SmFG activity. This region is typically involved in the access to semantic representations, guided by the emotional state. These results open interesting perspectives on the role of social leisure activities on lexical production during aging. PMID- 29402758 TI - Self-expressed patient preferences for the treatment of actinic keratosis: results from a non-interventional study based on a real-life setting in Spain. PMID- 29402759 TI - Health Information Technology Continues to Show Positive Effect on Medical Outcomes: Systematic Review. AB - BACKGROUND: Health information technology (HIT) has been introduced into the health care industry since the 1960s when mainframes assisted with financial transactions, but questions remained about HIT's contribution to medical outcomes. Several systematic reviews since the 1990s have focused on this relationship. This review updates the literature. OBJECTIVE: The purpose of this review was to analyze the current literature for the impact of HIT on medical outcomes. We hypothesized that there is a positive association between the adoption of HIT and medical outcomes. METHODS: We queried the Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Medical Literature Analysis and Retrieval System Online (MEDLINE) by PubMed databases for peer-reviewed publications in the last 5 years that defined an HIT intervention and an effect on medical outcomes in terms of efficiency or effectiveness. We structured the review from the Primary Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and we conducted the review in accordance with the Assessment for Multiple Systematic Reviews (AMSTAR). RESULTS: We narrowed our search from 3636 papers to 37 for final analysis. At least one improved medical outcome as a result of HIT adoption was identified in 81% (25/37) of research studies that met inclusion criteria, thus strongly supporting our hypothesis. No statistical difference in outcomes was identified as a result of HIT in 19% of included studies. Twelve categories of HIT and three categories of outcomes occurred 38 and 65 times, respectively. CONCLUSIONS: A strong majority of the literature shows positive effects of HIT on the effectiveness of medical outcomes, which positively supports efforts that prepare for stage 3 of meaningful use. This aligns with previous reviews in other time frames. PMID- 29402760 TI - Lessons From Recruitment to an Internet-Based Survey for Degenerative Cervical Myelopathy: Comparison of Free and Fee-Based Methods. AB - BACKGROUND: Degenerative Cervical Myelopathy (DCM) is a syndrome of subacute cervical spinal cord compression due to spinal degeneration. Although DCM is thought to be common, many fundamental questions such as the natural history and epidemiology of DCM remain unknown. In order to answer these, access to a large cohort of patients with DCM is required. With its unrivalled and efficient reach, the Internet has become an attractive tool for medical research and may overcome these limitations in DCM. The most effective recruitment strategy, however, is unknown. OBJECTIVE: To compare the efficacy of fee-based advertisement with alternative free recruitment strategies to a DCM Internet health survey. METHODS: An Internet health survey (SurveyMonkey) accessed by a new DCM Internet platform (myelopathy.org) was created. Using multiple survey collectors and the website's Google Analytics, the efficacy of fee-based recruitment strategies (Google AdWords) and free alternatives (including Facebook, Twitter, and myelopathy.org) were compared. RESULTS: Overall, 760 surveys (513 [68%] fully completed) were accessed, 305 (40%) from fee-based strategies and 455 (60%) from free alternatives. Accounting for researcher time, fee-based strategies were more expensive ($7.8 per response compared to $3.8 per response for free alternatives) and identified a less motivated audience (Click-Through-Rate of 5% compared to 57% using free alternatives) but were more time efficient for the researcher (2 minutes per response compared to 16 minutes per response for free methods). Facebook was the most effective free strategy, providing 239 (31%) responses, where a single message to 4 existing communities yielded 133 (18%) responses within 7 days. CONCLUSIONS: The Internet can efficiently reach large numbers of patients. Free and fee-based recruitment strategies both have merits. Facebook communities are a rich resource for Internet researchers. PMID- 29402762 TI - Effect on the Metabolic Biomarkers in Schoolchildren After a Comprehensive Intervention Using Electronic Media and In-Person Sessions to Change Lifestyles: Community Trial. AB - BACKGROUND: Obesity is a chronic low-intensity state of inflammation with metabolic alterations that, when acquired during childhood, lead to severe illness in adults. Encouraging healthy eating habits and physical activity is the basis for preventing and treating obesity and its complications. OBJECTIVE: To evaluate how a comprehensive intervention promoting healthy eating habits and physical activities in schools affects children's metabolic biomarkers. METHODS: Of four Mexico City primary schools in this study, two groups of children that were recruited at their schools were assigned to a 12-month intervention group (IG) and the other two were assigned to control groups (CGs). The intervention had two components: (1) parents/schoolchildren attended in-person educational sessions promoting healthy eating and physical activity habits, and were provided printed information; and (2) parents were able to seek information through a website, and also received brief weekly mobile phone text messages. Anthropometric measurements and fasting blood samples were taken from both groups of children at baseline and again after 12 months. RESULTS: The study involved 187 children in the IG and 128 in the CG. Regardless of each child's nutritional status at the beginning of the study, the intervention improved metabolic parameters; the IG showed a negative effect on glucose concentrations (-1.83; CI 95% -3.06 to -0.60), low-density lipoprotein-cholesterol (-2.59; CI 95% -5.12 to 0.06), insulin (-0.84; CI 95% -1.31 to -0.37), and homeostasis model to assess the insulin resistance index (HOMA-IR; -0.21; CI 95% -0.32 to -0.09) in comparison to the CG. HOMA-IR improved in children who had higher than baseline body mass index z-scores. CONCLUSIONS: Intervention through multiple components that promoted healthier eating and physical activity habits improved the metabolic parameters of the children in the study after one year, regardless of their nutritional status. PMID- 29402761 TI - Patterns of Fitbit Use and Activity Levels Throughout a Physical Activity Intervention: Exploratory Analysis from a Randomized Controlled Trial. AB - BACKGROUND: There has been a rapid increase in the use of technology-based activity trackers to promote behavior change. However, little is known about how individuals use these trackers on a day-to-day basis or how tracker use relates to increasing physical activity. OBJECTIVE: The aims were to use minute level data collected from a Fitbit tracker throughout a physical activity intervention to examine patterns of Fitbit use and activity and their relationships with success in the intervention based on ActiGraph-measured moderate to vigorous physical activity (MVPA). METHODS: Participants included 42 female breast cancer survivors randomized to the physical activity intervention arm of a 12-week randomized controlled trial. The Fitbit One was worn daily throughout the 12-week intervention. ActiGraph GT3X+ accelerometer was worn for 7 days at baseline (prerandomization) and end of intervention (week 12). Self-reported frequency of looking at activity data on the Fitbit tracker and app or website was collected at week 12. RESULTS: Adherence to wearing the Fitbit was high and stable, with a mean of 88.13% of valid days over 12 weeks (SD 14.49%). Greater adherence to wearing the Fitbit was associated with greater increases in ActiGraph-measured MVPA (binteraction=0.35, P<.001). Participants averaged 182.6 minutes/week (SD 143.9) of MVPA on the Fitbit, with significant variation in MVPA over the 12 weeks (F=1.91, P=.04). The majority (68%, 27/40) of participants reported looking at their tracker or looking at the Fitbit app or website once a day or more. Changes in Actigraph-measured MVPA were associated with frequency of looking at one's data on the tracker (b=-1.36, P=.07) but not significantly associated with frequency of looking at one's data on the app or website (P=.36). CONCLUSIONS: This is one of the first studies to explore the relationship between use of a commercially available activity tracker and success in a physical activity intervention. A deeper understanding of how individuals engage with technology based trackers may enable us to more effectively use these types of trackers to promote behavior change. TRIAL REGISTRATION: ClinicalTrials.gov NCT02332876; https://clinicaltrials.gov/ct2/show/NCT02332876?term=NCT02332876 &rank=1 (Archived by WebCite at http://www.webcitation.org/6wplEeg8i). PMID- 29402763 TI - Engaging a Community for Rare Genetic Disease: Best Practices and Education From Individual Crowdfunding Campaigns. AB - BACKGROUND: Genetic sequencing is critically important to diagnostic health care efforts in the United States today, yet it is still inaccessible to many. Meanwhile, the internet and social networking have made crowdfunding a realistic avenue for individuals and groups hoping to fund medical and research causes, including patients in need of whole exome genetic sequencing (WES). OBJECTIVE: Amplify Hope is an educational program designed to investigate what factors affect the success of medical crowdfunding campaigns. We conducted a needs assessment, a series of 25 interviews concerning crowdfunding, and provided training on best practices identified through our assessment for 11 individuals hoping to run their medical crowdfunding campaigns to raise money for patients to access trio WES to identify the mutated proteins that caused their apparent inherited disease. METHODS: The crowdfunding education was given in a 30-day training period with resources such as webinars, fact sheets and a crowdfunding training guide emailed to each participant. All campaigns were launched on the same date and were given 30 days to raise the same goal amount of US $5000. Reviewing the 4 crowdfunding campaigns that raised the goal amount within the 30 day period, we sought to identify features that made the 4 crowdfunding campaigns successful. In addition, we sought to assess which factors the resulting 75 donors report as influencing their decision to donate to a campaign. Finally, we investigated whether crowdfunding campaigns for exome sequencing had an impact on increasing applicant's and donors' knowledge of genomics. RESULTS: Of the 86 study inquiries, 11 participants submitted the required forms and launched their crowdfunding campaigns. A total of 4 of the 11 campaigns raised their goal amounts within 30 days. CONCLUSIONS: We found that social media played an important role in all campaigns. Specifically, a strong social media network, an active outreach process to networks, as well as engagement within the study all correlated with a higher success rate. Amplify Hope donors were more likely to support projects that were near their fundraising goals, and they found video far more effective for learning about genomics than any other medium. PMID- 29402764 TI - Comparative Analysis of miRNA Expression Profiles of Multiple Myeloma with 1q21 Gains and Normal FISH. AB - BACKGROUND: Multiple myeloma (MM) with 1q21 gains invariably has a poor prognosis. Many recent studies have reported the relationship between micro (mi)RNA expression and MM prognosis. However, there is little information on the association between miRNA alterations and 1q21 gains. METHODS: We compared the miRNA expression profiles of MM with 1q21 gains and MM with normal fluorescence in situ hybridisation (FISH) by gene expression array. Differentially expressed miRNAs were identified using Affymetrix TAC software. Thresholds were defined as a false discovery rate <0.05, p value <0.05, and n-fold change >2. RESULTS: Six miRNAs (let-7f-5p and -7g-5p, and miR-29a-3p, -29b-1-5p, -331-3p, and -223-3p) were downregulated and 4 (miR-30e-5p, -17-3p, -18b-5p, and -19a-3p) were upregulated in MM with 1q21 gains relative to MM with normal FISH. CONCLUSIONS: The identified set of miRNAs can serve as biomarkers for distinguishing MM with 1q21 gains from MM with normal FISH. PMID- 29402765 TI - Computed Tomography Perfusion Derived Blood-Brain Barrier Permeability Does Not Yet Improve Prediction of Hemorrhagic Transformation. AB - INTRODUCTION: Hemorrhagic transformation (HT) in acute ischemic stroke can occur as a result of reperfusion treatment. While withholding treatment may be warranted in patients with increased risk of HT, prediction of HT remains difficult. Nonlinear regression analysis can be used to estimate blood-brain barrier permeability (BBBP). The aim of this study was to identify a combination of clinical and imaging variables, including BBBP estimations, that can predict HT. MATERIALS AND METHODS: From the Dutch acute stroke study, 545 patients treated with intravenous recombinant tissue plasminogen activator and/or intra arterial treatment were selected, with available admission extended computed tomography (CT) perfusion and follow-up imaging. Patient admission treatment characteristics and CT imaging parameters regarding occlusion site, stroke severity, and BBBP were recorded. HT was assessed on day 3 follow-up imaging. The association between potential predictors and HT was analyzed using univariate and multivariate logistic regression. To compare the added value of BBBP, areas under the curve (AUCs) were created from 2 models, with and without BBBP. RESULTS: HT occurred in 57 patients (10%). In univariate analysis, older age (OR 1.03, 95% CI 1.006-1.05), higher admission National Institutes of Health Stroke Scale (NIHSS; OR 1.13, 95% CI 1.08-1.18), higher clot burden (OR 1.28, 95% CI 1.16-1.41), poor collateral score (OR 3.49, 95% CI 1.85-6.58), larger Alberta Stroke Program Early CT Score cerebral blood volume deficit size (OR 1.26, 95% CI 1.14-1.38), and increased BBBP (OR 2.22, 95% CI 1.46-3.37) were associated with HT. In multivariate analysis with age and admission NIHSS, the addition of BBBP did not improve the AUC compared to both independent predictors alone (AUC 0.77, 95% CI 0.71-0.83). CONCLUSION: BBBP predicts HT but does not improve prediction with age and admission NIHSS. PMID- 29402766 TI - Acute Pancreatitis Associated with Ixazomib in a Multiple Myeloma Patient. AB - BACKGROUND: Acute pancreatitis is an uncommon complication of anti-myeloma agents. Ixazomib is a first-in-class oral proteasome inhibitor to receive regulatory approval for the treatment of multiple myeloma. This case report describes the first case of ixazomib-associated pancreatitis. CASE PRESENTATION: An 80-year-old female with relapsed multiple myeloma presented with severe diarrhea, nausea, vomiting, abdominal pain, and acute renal failure 3 weeks after starting ixazomib and dexamethasone for disease progression. An extensive workup revealed acute pancreatitis without a definitive cause. Her condition improved with supportive measures and the discontinutation of ixazomib. The latter was suspected as the probable etiology of the patient's acute pancreatitis, given no clear alternative causes and the temporal relationship between initiating ixazomib and the development of her symptoms. CONCLUSIONS: Practitioners should include acute pancreatitis as part of their differential diagnosis in patients on ixazomib treatment who present with gastrointestinal symptoms. PMID- 29402767 TI - Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes: Post-Hoc Analyses from Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Study. AB - BACKGROUND: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney function induced by bardoxolone methyl. METHODS: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive once-daily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of >=30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation). RESULTS: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001). CONCLUSIONS: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD. PMID- 29402768 TI - Spotty Carotid Plaques Are Associated with Inflammation and the Occurrence of Cerebrovascular Symptoms. AB - BACKGROUND: Echolucent carotid plaques have been related to an increased risk of ischemic cerebrovascular events. The aim of the present study was to evaluate whether a new objective ultrasonographic parameter, the statistical geometric feature (SGF), reflecting spottiness of carotid plaques, can be associated with cerebrovascular symptoms and with a rupture-prone plaque phenotype. METHODS: The plaques of 144 patients who underwent carotid endarterectomy were included in this study. SGF and plaque area were estimated by outlining the plaque on ultrasound (US) images. The correlation coefficient for inter- and intraobserver variability was 0.69 and 0.93, respectively. The SGF values were normalized to the degree of stenosis (SGF/DS). The plaques collected at surgery 1 day after the US were analyzed histologically, and inflammatory markers and matrix metalloproteinases (MMPs) were measured. RESULTS: Patients with ipsilateral hemispheric symptoms had higher SGF/DS compared to patients without symptoms (0.82 [0.59-1.16] vs. 0.70 [0.56-0.89], p = 0.01). Analysis of plaque components revealed a positive correlation between SGF/DS and the percentage of the plaque area stained for lipids, macrophages, and hemorrhage. A correlation was also found between SGF/DS and plaque expression of interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, vascular endothelial growth factor A, C-C motif chemokine 3 and 20, and MMP-9. An inverse correlation was found with plaque levels of osteoprotegerin. CONCLUSIONS: The present study supports the concept that spottiness is a feature of the carotid plaques rich in inflammation and can be associated with the typical phenotype of high-risk plaques. PMID- 29402769 TI - Upregulated Serum MiR-146b Serves as a Biomarker for Acute Ischemic Stroke. AB - BACKGROUND/AIMS: Stroke is a major cerebrovascular disease threatening human health and life with high morbidity, disability and mortality. It is aimed to find effective biomarkers for the early diagnosis on stroke. METHODS: The expressions of 17 previously reported stroke-associated miRNAs were measured using quantitative RT-PCR and the expressions of plasma high-sensitivity C reactive protein (hs-CRP) and serum interleukin 6 (IL-6), the pro-inflammation markers in brain injury, were examined using enzyme-linked immunosorbent assay in 128 acute ischemic stroke (AIS) patients and control group. RESULTS: Serum miR 146b expression was significantly increased within 24 hours after stroke onset in patients compared with control group. In addition, the upregulation of serum miR 146b was strong positively correlated with plasma hs-CRP, infarct volume and National Institutes of Health Stroke Scale (NIHSS) score, and moderate positively correlated with serum IL-6 of patients. Importantly, the combination of plasma hs CRP and serum miR-146b gained a better sensitivity/specificity for prediction of AIS (AUC from 0.782 to 0.863). CONCLUSION: Our preliminary findings suggested that upregulated serum miR-146b in acute ischemic stroke might be a potential biomarker for AIS evaluation. PMID- 29402770 TI - Cord Blood Lysophosphatidylcholine 16: 1 is Positively Associated with Birth Weight. AB - BACKGROUND/AIMS: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. METHODS: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. RESULTS: After FDR adjustment using the Benjamini Hochberg procedure lysophosphatidylcholines (LPC) 14: 0, 16: 1, and 18: 1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94*10-11 ). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: -258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). CONCLUSIONS: After correction for multiple testing and adjustment for potential confounders, LPC 16: 1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies. PMID- 29402771 TI - Micro Integral Membrane Protein (MIMP), a Newly Discovered Anti-Inflammatory Protein of Lactobacillus Plantarum, Enhances the Gut Barrier and Modulates Microbiota and Inflammatory Cytokines. AB - BACKGROUND/AIMS: Recent studies have demonstrated that the manipulation of the gut microbiome represents a promising treatment for inflammatory bowel disease (IBD). We previously identified micro integral membrane protein (MIMP) as the smallest domain of surface layer protein from Lactobacillus Plantarum. However, the therapeutic relevance of MIMP in IBD remains unknown. METHODS: We initially employed a dextran sodium sulphate (DSS)-induced colitis model and evaluated the effect of MIMP on the inflammation response, intestinal barrier and gut microbiota using histological examination, Fluorescein isothiocyanate-Dextran detection and pyrosequencing analysis respectively. We then established peripheral blood mononuclear cells (PBMCs) and an epithelial CaCO-2 co-culture model to investigate the regulatory role of MIMP in inflammatory cytokines. The level changes of inflammatory cytokines were detected using Enzyme-linked immunosorbent and real-time polymerase chain reaction assay. The involved regulatory mechanisms were investigated mainly using dual luciferase reporter and chromatin immunoprecipitation assay. RESULTS: In the DSS-induced colitis model, we observed that MIMP intervention effectively improved the body weight loss, increased the colon length and decreased disease activity index. Consistently, the inflammation scores in the MIMP treatment group were significantly lower than those in the DSS treatment group. Furthermore, MIMP intervention was found to successfully neutralize DSS treatment by decreasing the expression of pro inflammatory cytokines (IFN-gamma, IL-17 and IL-23) and increasing the expression of anti-inflammatory cytokines (IL-4 and IL-10). Notably, the permeability assay demonstrated that the MIMP treatment group was remarkably lower than that in the DSS treatment group. We also showed that MIMP improved gut microbiota dysbiosis caused by DSS-induced inflammation. Additionally, in PBMCs and the CaCO-2 co culture model, MIMP showed an obvious suppressive effect on lipopolysaccharide induced inflammation in a time- and dose-dependent manner. Furthermore, we revealed that MIMP could modulate inflammatory cytokine expression through the toll-like receptor 4 pathway and histone acetylation. CONCLUSIONS: Our results suggested that MIMP showed a significant anti-inflammatory effect through regulating the gut barrier, microbiota and inflammatory cytokines. MIMP may have translational relevance as clinically relevant therapy for IBD patients. PMID- 29402772 TI - Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice. AB - BACKGROUND/AIMS: Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. METHODS: The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. RESULTS: Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. CONCLUSION: The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility. PMID- 29402773 TI - Protective Effects of Let-7b on the Expression of Occludin by Targeting P38 MAPK in Preventing Intestinal Barrier Dysfunction. AB - BACKGROUND/AIMS: Let-7b was dramatically reduced after a dicer knockout of mice with intestinal barrier function injuries. This paper aims to investigate the molecular mechanism of let-7b by targeting p38 MAPK in preventing intestinal barrier dysfunction. METHODS: A total of 186 patients were enrolled, with 93 in the control group and 93 in the PRO group. Only 158 patients completed the entire study, whereas the others either did not meet the inclusion criteria or refused to participate. To further verify the role of let-7b, intestinal epithelial conditional knockout (IKO) mice of mmu-let-7b model were established. Serum let 7b, zonulin, IL-6, and TNF-alpha concentrations were measured by ELISA or quantitative RT-PCR. Permeability assay was done by ussing chamber. The apoptotic cells were identified using an In Situ Cell Death Detection Kit. Protein was detected by western blot. RESULTS: Probiotics can lower infection-related complications, as well as increase the serum and tissue let-7b levels. P38 MAPK was identified as the target of let-7b, as verified by NCM460 cells. P38 MAPK expression was increased, whereas tight-junction (TJ) proteins were significantly decreased in let-7b IKO mice (both P<0.05). Negative regulation of p38 MAPK molecular signaling pathways was involved in the protective effects of let-7b on intestinal barrier function. CONCLUSION: Let-7b was identified as a novel diagnosis biomarker or a potential treatment target for preventing intestinal barrier dysfunction. PMID- 29402774 TI - TRPC3 Overexpression Promotes the Progression of Inflammation-Induced Preterm Labor and Inhibits T Cell Activation. AB - BACKGROUND/AIMS: To detect the expression of the TRPC3 channel protein in the tissues of women experiencing preterm labor and investigate its interaction with T lymphocytes, providing a theoretical basis for the clinical prevention of threatened preterm labor and the development of drug-targeted therapy. METHODS: Forty-seven women experiencing preterm labor and 47 women experiencing normal full-term labor were included in this study. All included women underwent delivery via cesarean section; uterine samples were obtained at delivery. The expression of TRPC3 in uterine tissue was detected by immunohistochemistry, real time quantitative reverse transcription-PCR, and western blot assay. Activation of T lymphocytes in peripheral blood and uterine tissue were detected by flow cytometry. A TRPC3-/- mouse model of inflammation-induced preterm labor was established; expression of TRPC3, Cav3.1, and Cav3.2 were analyzed in mouse uterine tissue. Activation of T lymphocytes in female mouse and human peripheral blood samples was determined using flow cytometry. RESULTS: In women experiencing preterm labor, expression of TRPC3 and the Cav3.1 and Cav3.2 proteins was significantly increased; in addition, the percentage of CD3+, CD4+, and CD8+ T cells in peripheral blood was significantly decreased. TRPC3 knockout significantly delayed the occurrence of preterm labor in mice. The muscle tension of ex vivo uterine strips was lower, Cav3.1 and Cav3.2 protein expression was lower, and the percentage of CD8+ T lymphocytes was significantly increased in wild-type mice subjected to an inflammation-induced preterm labor than in wild type mice experiencing normal full-term labor. CONCLUSION: TRPC3 is closely related to the initiation of labor. TRPC3 relies on Cav3.1 and Cav3.2 proteins to inhibit inflammation-induced preterm labor by inhibiting the activation of T cells, in particular CD8+ T lymphocytes. PMID- 29402775 TI - Intradialytic Hypotension as an Independent Risk Factor for Long-Term Mortality in Maintaining Hemodialysis Patients: A 5-Year Follow-Up Cohort Study. AB - AIMS: This study aimed to assess risk factors of intradialytic hypotension (IDH) and the association of prognosis and IDH among maintenance hemodialysis (MHD) patients. METHODS: Among 293 patients, 117 were identified with IDH (more than 4 hypotensive events during 3 months). The association between IDH and survival was evaluated. RESULTS: The incidence of IDH was 39.9%. Age, ultrafiltration rate, N terminal pro-B-type natriuretic peptide (NT-proBNP), albumin, beta2-microglobulin (beta2MG), and aortic root inside diameter (AoRD) were independently associated with IDH. During the 5-year follow-up, 84 patients died with a mortality rate 5.2 per 100 person-year. IDH-prone patients had a higher all-cause mortality rate. IDH and left ventricular mass index were independent risk factors for death (HR 1.655, 95% CI 1.061-2.580; HR 1.008, 95% CI 1.001-1.016). CONCLUSION: IDH is an independent risk factor for long-term mortality in MHD patients. Patients with older age, high ultrafiltration rate, high level of serum NT-proBNP and beta2MG, hypoalbuminemia, and shorter AoRD are at high risk of IDH. PMID- 29402777 TI - Correlation of Insulin-Like Growth Factor-I and -II Concentrations at Birth Measured by Mass Spectrometry and Growth from Birth to Two Months. AB - BACKGROUND: Immunoassays used to measure insulin-like growth factor (IGF)-I and II concentrations are susceptible to interference from IGF-binding proteins. The aim of this study was to investigate the association of IGF-I and -II concentrations at birth with neonatal anthropometry using a liquid chromatography/mass spectrometry (LCMS) assay. METHODS: LCMS was used to measure IGF-I and -II concentrations in umbilical cord blood of term, healthy infants enrolled in the Cork BASELINE Birth Cohort Study. Weight, length, and occipitofrontal head circumference (OFC) were measured at birth and 2 months. RESULTS: Cord blood IGF-I and -II concentrations were measured in 1,100 infants. Mean (SD) IGF-I and -II concentrations were 52.5 (23.9) ng/mL and 424.3 (98.2) ng/mL, respectively. IGF-I and -II concentrations at birth were associated (p < 0.05) with weight (R2 = 0.19, R2 = 0.01), length (R2 = 0.07, R2 = 0.004), and OFC (R2 = 0.03, R2 = 0.04) at birth. Low IGF-I concentrations at birth were associated with increases in weight (p < 0.001) and OFC (p < 0.01) Z-scores in the first 2 months. CONCLUSION: Using an LCMS assay, we have shown that anthropometric parameters at birth are associated with IGF-I and weakly with IGF II concentrations. This indicates that, at the time of birth, IGF-I is the more important growth factor for regulating infant growth. PMID- 29402778 TI - Interaction of Vitamin E Intake and Pro12Ala Polymorphism of PPARG with Adiponectin Levels. AB - BACKGROUND/AIM: One of the beneficial effects associated with vitamin E intake is the enhancement of peroxisome proliferator-activated receptor gamma (PPARgamma) activity and the consequent upregulation of adiponectin expression. The aim of this study was to analyze the adiponectin levels in subjects with the Pro12Ala polymorphism of PPARG according to vitamin E intake. METHODS: A total of 283 subjects were enrolled. Total vitamin E intake was estimated based on a validated 3-day food consumption record and analyzed using Nutritionist ProTM software. The Pro12Ala polymorphism (rs1801282) was determined by allelic discrimination. The adiponectin levels were measured by an ELISA assay. RESULTS: Vitamin E intake was deficient in all subjects (1.50 +/- 1.78 mg/day). Subjects with higher vitamin E intake levels and the Pro12Ala/Ala12Ala genotype had statistically significant higher levels of serum adiponectin than subjects with the Pro12Pro genotype (4.4 [3.2-5.7] vs. 2.7 [2.0-3.5] MUg/mL; p = 0.024). CONCLUSIONS: Our results suggest that increased consumption of vitamin E should be encouraged since it has been reported that vitamin E promotes adiponectin expression via PPARgamma activation. Subjects with Pro12Pro genotype had lower serum adiponectin levels than subjects with Pro12Ala/Ala12Ala genotype; therefore, they might be at higher risk of developing metabolic complications. PMID- 29402776 TI - Association of FTO rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern? AB - OBJECTIVE: To investigate the effect of the common fat mass and obesity associated (FTO) gene polymorphism rs9939609 on body mass index (BMI) in one of the most obese populations worldwide. SUBJECTS AND METHODS: Genotypic data for FTO rs9939609 were available for 1,034 unrelated Kuwaiti adults obtained from Kuwait's Dasman Diabetes Institute and Kuwait University. The association between the FTO polymorphism with BMI as continuous and categorical (normal BMI [< 25] vs. overweight/obese [> 25]) variables was analyzed using both linear and logistic regression models, respectively, with the assumption of both dominant and additive genetic models performed using the SNPassoc package from R statistics. RESULTS: The A allele was associated with increased BMI (beta = 1.21; 95% CI = 0.16-2.26; p = 0.023). In concordance, the categorical BMI (normal vs. overweight/obese) also showed a significant association between the A allele and overweight/obesity (OR = 1.47; 95% CI = 1.01-2.12; p = 0.041). However, no association between the FTO variant was observed with cardiometabolic traits. CONCLUSION: We observed an association between the common FTO rs9939609 polymorphism and increased BMI (overweight/obesity) in Kuwaiti adults, which is consistent with previous research in other populations. Our findings encourage further investigation of genetic variants to elucidate the mechanisms involved in the development of obesity in such an obesogenic population. PMID- 29402779 TI - The Combined Effects of Genetic Variation in the CNDP1 and CNDP2 Genes and Dietary Carbohydrate and Carotene Intake on Obesity Risk. AB - BACKGROUND/AIMS: It is possible that carnosinase (CNDP1) and cellular nonspecific dipeptidase (CNDP2) have important roles in protecting cells and tissues against the damage of oxidative stress. Oxidative stress and subsequent inflammation are key factors in the development of common chronic metabolic diseases, such as obesity. We aimed to investigate the combined effects of genetic variations in CNDP1 and CNDP2 and dietary carbohydrate and carotene intake on obesity risk. METHODS: A total of 1,059 Japanese men were randomly selected from participants who visited a medical center for routine medical checkups. We analyzed the relationships between the genotypes of 4 single-nucleotide polymorphisms (SNPs) (rs12605520, rs7244647, rs4891558, and rs17089368) in the CNDP1/CNDP2 locus and body mass index or prevalence of obesity/overweight taking into account dietary carbohydrate and carotene intake. RESULTS: We found that 2 SNPs (rs7244647 in CNDP1 and rs4891558 in CNDP2) were associated with obesity risk. In addition, these associations were observed only in the group with high carbohydrate and low carotene intake but not in the group with low carbohydrate and high carotene intake. CONCLUSIONS: Our findings indicate that the combination of genetic variations in CNDP1 and CNDP2 and dietary carbohydrate/carotene intake modulate obesity risk. PMID- 29402782 TI - Sex Differences in the Impact of BDNF Genotype on the Longitudinal Relationship between Physical Activity and Cognitive Performance. AB - BACKGROUND: Physical activity may preserve cognitive function in older adults, but benefits vary by sex and genetic factors. OBJECTIVE: We tested the longitudinal association between physical activity and cognitive performance to de termine whether a common genetic polymorphism for brain-derived neurotrophic factor (BDNF Val66Met) moderated this effect. METHODS: In a 12-year longitudinal population-based sample of older adults (n = 2,218), we used growth curve modeling to investigate whether the benefits of physical activity on cognitive preservation differed by BDNF genotype and sex across multiple cognitive domains including processing speed, attention, working memory, and episodic verbal memory. RESULTS: The relationship between physical activity and cognitive performance was dependent on BDNF carrier status in males (Deltachi2 [Deltadf] = 12.94 [4], p = 0.01), but not in females (Deltachi2 [Deltadf] = 4.38 [4], p = 0.36). Cognition benefited from physical activity in male BDNF met noncarriers, but not met carriers, whereas cognition was not statistically significantly related to physical activity in females regardless of genotype. CONCLUSION: We observed longitudinal, but not cross-sectional, effects of physical activity on cognitive performance. Our study highlights the importance of longitudinal follow up and consideration of sex differences in the relationships between physical activity, BDNF genotype, and cognitive decline. The findings contribute to understanding gene-lifestyle interactions in promoting cognitive health. PMID- 29402780 TI - Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta. AB - BACKGROUND/AIMS: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. METHODS: Gene expression of 50 ABC transporters was assessed using TaqMan(r) Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P glycoprotein (P-gp) were examined by qPCR. RESULTS: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). CONCLUSIONS: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD. PMID- 29402781 TI - The Effects of Heat Exposure on Vaginal Smooth Muscle Cells: Elastin and Collagen Production. AB - AIMS: To evaluate smooth muscle cells (SMCs) proliferation and elastin and collagen production after heat exposure (65 degrees C). METHODS: Samples were taken from the anterior vaginal wall, SMCs were cultured, and heated to 65 degrees C for 30 and 60 s. Cell proliferation was assessed; tropoelastin and collagen production was measured. RESULTS: Heat does not affect SMC proliferation at 65 degrees C neither at 30 nor at 60 s. Surface-deposited elastin level was significantly increased after heat exposure (mean +/- SD, 30 s 155 +/- 5% of control [p < 0.01] and 60 s 516 +/- 40% of control [p < 0.01]). Tropoelastin levels in the culture media were significantly lower after 60 s of heat exposure (mean +/- SD, 30 s 102 +/- 5% of control [p = ns] and 60 s 70 +/- 2% of control [p = 0.04]). Significant increase in surface-deposited collagen production was found (mean +/- SD, 30 s 170 +/- 6% of control [p < 0.01] and 60 s 123 +/- 6% of control [p < 0.01]), but no such elevation was measured in the media after heat exposure (mean +/- SD, 30 s 120 +/- 20% of control [p = ns] and 60 s 100 +/- 20% of control [p = ns]). CONCLUSION: When SMCs are exposed to heat there is significant elevation in collagen and elastin production. Changes in the composition of the extracellular matrix after heat exposure may contribute to vaginal wall remodeling. PMID- 29402783 TI - Monoclonal Gammopathy Responsive to Decitabine Given for Acute Myeloid Leukemia in a Frail Patient. PMID- 29402785 TI - Family Physician-Led Group Visits for Lifestyle Modification in Women with Weight Problems: A Pilot Intervention and Follow-Up Study. AB - OBJECTIVE: Lifestyle modification requires extensive information sharing and counseling. However, one-on-one primary care consultations are lacking to cover all necessary components due to time constraints. This preliminary study aims to investigate the feasibility and effects of lifestyle-changing intervention by family physician-led group visits (GVs) on weight management in overweight and obese women. METHODS: 60 volunteers fulfilling the inclusion criteria were enrolled. Baseline and 6th month assessments consisted of anthropometric measurements, SF-36 Health Survey, blood variables, exercise test, and resting metabolic rate. Weight maintenance was controlled at the 12th month. RESULTS: Although weight loss among participants varied, the mean body weights were significantly decreased by 8.2% in full-attenders (n = 30). A significant increase in HDL-cholesterol and decreases in heart rate and blood pressure were found. SF-36 summary scales were significantly improved. Weight change was moderately correlated with exercise duration, compliance to diet, and baseline mental component score. It was determined that 62.5% of the participants either lost or maintained body weight at the 12th month. CONCLUSION: Significant weight loss and quality of life improvement was achieved in this pilot study. GVs may be a promising alternative to primary care consultations for obesity management; however, the high dropout level and diverse outcomes need further assessment. PMID- 29402786 TI - Rigid Triple Endoscopy Improves Clinical Staging of Primary Head and Neck Cancer. AB - BACKGROUND: Correct pre-therapeutic staging of the first primary carcinoma (FPC) and detection of simultaneous second primary carcinomas (SSPCs) decisively influence therapy and prognosis of head and neck squamous cell carcinomas (HNSCC). The aim of this study was to determine the benefit of pre-therapeutic triple endoscopy for detection of SSPC and pre-therapeutic T category. METHODS: A cohort of 234 HNSCC patients with completed triple endoscopy was reviewed, focusing on pre-therapeutic T category and SSPC. Risk stratification for different subsites was evaluated. RESULTS: The risk for SSPC was 5.56%. FPC of the oral cavity and oropharynx had the highest prevalence of SSPC (46.15%, 38.46%); most SSPCs were found in the hypopharynx. No SSPCs were found in the oral cavity, nasopharynx and oesophagus. Significant results in correct pre therapeutic T staging have been achieved for the larynx (p = 0.021) and the oropharynx (p = 0.001). CONCLUSIONS: Triple endoscopies seem to be inadequate for SSPC detection in HNSCC patients. Endoscopies of the trachea and oesophagus should be reconsidered. Alternatively, risk-directed endoscopies of the hypopharynx might be performed in patients with oral cancer. For evaluation of resectability, conducting triple endoscopy could be reduced to a single endoscopy because the complication rate is low and pre-therapeutic T staging can be improved. PMID- 29402788 TI - Extracorporeal Hemoperfusion as a Potential Therapeutic Option for Critical Accumulation of Rivaroxaban. PMID- 29402784 TI - Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake. AB - BACKGROUND: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. METHODS: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. RESULTS: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. CONCLUSIONS: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction. PMID- 29402790 TI - Unravelling Pathophysiology of Crystalline Nephropathy in Ceftriaxone-Associated Acute Kidney Injury: A Cellular Proteomic Approach. AB - BACKGROUND: Previous studies showed that ceftriaxone can cause acute kidney injury (AKI) in the pediatric population. This study proposed a cellular model of crystalline nephropathy in ceftriaxone-associated AKI and explored the related pathophysiology by using a proteomic approach. METHODS: Ceftriaxone was crystallized with calcium in artificial urine. Madin-Darby Canine Kidney (MDCK) cells, a model of distal renal tubular cell, were cultured in the absence (untreated control) or presence of ceftriaxone crystals for 48-h (n = 5 each). MDCK cells were harvested and subsequently analyzed by proteomic analysis. Protein bioinformatics (i.e., STRING and Reactome) was used to predict functional alterations, and subsequently validated by Western blotting and cellular studies. p < 0.05 was considered statistically significant. RESULTS: Phase-contrast microscopy showed increased intracellular vesiculation and cell enlargement as a result of ceftriaxone crystal exposure. Proteome analysis revealed a total of 20 altered proteins (14 increased, 5 decreased and 1 absent) in ceftriaxone crystal treated MDCK cells as compared to untreated cells (p < 0.05). Protein bioinformatics and validation studies supported heat stress response mediated by heat shock protein 70 (Hsp70) and downregulation of annexin A1 as the proposed pathophysiology of crystalline nephropathy in ceftriaxone-associated AKI, in which impaired proliferation and wound healing of crystal-induced distal tubular cells were outcomes. CONCLUSIONS: This study, for the first time, used the in vitro model of crystalline nephropathy to investigate the underlying pathophysiology of ceftriaxone-associated AKI, which should be investigated in vivo for potential clinical benefits in the future. PMID- 29402789 TI - Hyoscine N-Butylbromide for Preventing Propofol Injection Pain: A Randomized, Placebo-Controlled and Double-Blind Study. AB - OBJECTIVE: In this study, the aim was to investigate the effect of hyoscine N butylbromide (HnBB) pretreatment on pain during propofol injection. SUBJECTS AND METHODS: In this prospective, randomized, placebo-controlled and double-blind trial, 60 patients scheduled to undergo routine outpatient surgery under general anesthesia were randomly allocated to 2 groups, the HnBB (n = 30) and sodium chloride (n = 30) groups. Twenty seconds after the injection of 20 mg HnBB or 0.9 % sodium chloride, a 50-mg dose of propofol was injected in 2-3 s. Ten seconds later, the pain intensity was assessed using a 4-point scale: no pain (0), mild (1), moderate (2), and severe (3) pain. The Student t test was used for the analysis of parametric data and the Pearson chi2 test for categorical data. RESULTS: The occurrence of pain in the HnBB group (43.3%) was significantly lower than the control group (73.3%) (p < 0.018). Of the 30 patients in each group, 10 in the control group and 3 in the HnBB group experienced severe pain (p = 0.001). CONCLUSIONS: Pretreatment with 20 mg HnBB significantly reduced propofol injection pain compared to placebo. PMID- 29402791 TI - Postpartum Weight Retention Risk Factors in a Taiwanese Cohort Study. AB - OBJECTIVE: Excess postpartum weight retention (PPWR) is related to long-term weight gain. Therefore, this study was conducted to identify the risk factors for PPWR to provide guidance for preventive strategies. METHODS: This cohort study surveyed 461 women who gave birth at a medical center between March 2014 and March 2016. The participants completed a questionnaire within 1 month of delivery, and their 6-month postpartum weight was tracked. RESULTS: The results showed that the mean pre-pregnancy BMI was 21.4 +/- 3.3 kg/m2, and the mean gestational weight gain (GWG) was 12.8 +/- 4.1 kg. The mean PPWR was 4.6 +/- 3.5 kg at 1 month and 2.1 +/- 3.3 kg at 6 months. Multivariate analysis revealed that GWG (adjusted OR: 1.92 (1.70-2.17)), pre-pregnancy BMI (adjusted OR: 0.85 (0.77 0.94)), and exclusive breastfeeding (adjusted OR: 0.55 (0.32-0.94)) were significantly correlated with a 1-month PPWR higher than the median value. In addition, GWG (adjusted OR: 1.30 (1.22-1.39)) and exclusive breastfeeding (adjusted OR: 0.37 (0.24-0.58)) were significantly correlated with a 6-month PPWR higher than the median value. CONCLUSION: Our findings indicate that the key to reducing PPWR is to control GWG and engage in exclusive breastfeeding. PMID- 29402792 TI - Hospital Readmission among New Dialysis Patients Associated with Young Age and Poor Functional Status. AB - BACKGROUND/AIMS: Over one-third of hospital discharges among dialysis patients are followed by 30-day readmission. The first year after dialysis start is a high risk time frame. We examined the rate, causes, timing, and predictors of 30-day readmissions among adult, incident dialysis patients. METHODS: Hospital readmissions were assessed from the 91st day to the 15th month after the initiation of dialysis using a Mayo Clinic registry linkage to United States Renal Data System claims during the period January 2001-December 2010. RESULTS: Among 1,727 patients with >=1 hospitalization, 532 (31%) had >=1, and 261 (15%) had >=2 readmissions. Readmission rate was 1.1% per person-day post-discharge, and the highest rates (2.5% per person-day) occurred <=5 days after index admission. The overall cumulative readmission rate was 33.8% at day 30. Common readmission diagnoses included cardiac issues (22%), vascular disorders (19%), and infection (13%). Similar-cause readmissions to index hospitalization were more common during days 0-14 post-discharge than days 15-30 (37.5 vs. 22.9%; p = 0.004). Younger age at dialysis initiation, inability to transfer/ambulate, serum creatinine <=5.3 mg/dL, higher number of previous hospitalizations, and longer duration on dialysis were associated with higher readmission rates in multivariable analyses. Patients aged 18-39 were few (8.3%) but comprised 17.7% of "high-readmission" users such that a 30-year-old patient had an 87% chance of being readmitted within 30 days of any hospital discharge, whereas an 80-year-old patient had a 25% chance. CONCLUSIONS: Overall, 30-day readmissions are common within the first year of dialysis start. The first 10-day period after discharge, young patients, and those with poor functional status represent key areas for targeted interventions to reduce readmissions. PMID- 29402793 TI - Regulation of Endothelial Permeability by Glutathione S-Transferase Pi Against Actin Polymerization. AB - BACKGROUND/AIMS: Inflammation-induced injury of the endothelial barrier occurs in several pathological conditions, including atherosclerosis, ischemia, and sepsis. Endothelial cytoskeleton rearrangement is an important pathological mechanism by which inflammatory stimulation triggers an increase of vascular endothelial permeability. However, the mechanism maintaining endothelial cell barrier function against inflammatory stress is not fully understood. Glutathione S transferase pi (GSTpi) exists in various types of cells and protects them against different stresses. In our previous study, GSTpi was found to act as a negative regulator of inflammatory responses. METHODS: We used a Transwell permeability assay to test the influence of GSTpi and its transferase activity on the increase of endothelial permeability induced by tumor necrosis factor alpha (TNF-alpha). TNF-alpha-induced actin remodeling and the influence of GSTpi were observed by using laser confocal microscopy. Western blotting was used to test the influence of GSTpi on TNF-alpha-activated p38 mitogen-activated protein kinase (MAPK)/MK2/heat shock protein 27 (HSP27). RESULTS: GSTpi reduced TNF-alpha induced stress fiber formation and endothelial permeability increase by restraining actin cytoskeleton rearrangement, and this reduction was unrelated to its transferase activity. We found that GSTpi inhibited p38MAPK phosphorylation by directly binding p38 and influenced downstream substrate HSP27-induced actin remodeling. CONCLUSION: GSTpi inhibited TNF-alpha-induced actin remodeling, stress fiber formation and endothelial permeability increase by inhibiting the p38MAPK/HSP27 signaling pathway. PMID- 29402794 TI - BDNF VAL66MET Polymorphism Elevates the Risk of Bladder Cancer via MiRNA-146b in Micro-Vehicles. AB - BACKGROUND/AIMS: Emerging studies on brain-derived neurotrophic factor (BDNF) have shown that might be novel biomarkers and therapeutic targets for cancer. We explore the role of BDNF in the tumorigenesis of bladder cancer and the underlying molecular mechanism. METHODS: 368 patients with diagnosed bladder cancer and 352 healthy controls were enrolled to evaluate the association of BDNF and the miR-146b. Bioinformatics algorithm analysis and luciferase assay were performed to identify the target genes of miR-146b. Real-time PCR and western blot were carried out to validate the relationship between miR-146b and CRK. MTT assay and FACS were used to evaluated the proliferation and apoptosis of cancer cells. MVs were isolated and transfect into the culture cells to confirm the above observation. RESULTS: The clinical study shows that BDNF Met/Met was significantly associated with the risk of bladder cancer. In addition, comparing with Val/Val and Val/Met, Met/Met has lower miR-146b level. Luciferase assay shows that BDNF Val/Val is apparently enhanced miR-146b promoter-luciferase, but not BDNF Met/Met. Based on luciferase assay, CRK is a direct target gene of miR 146b. MiR-146b mimics significantly inhibited the expression of CRK and activation of AKT level. The expression of CRK and the activation of AKT (p-AKT) were significantly inhibited by MV-BDNF Val/Val-miR-146b or MV-BDNF Val/Met-miR 146b, but not MV-BDNF Met/Met-miR-146b. MV-BDNF Val/Val-miR-146b or Val/Met-miR 146b obviously inhibited cell proliferation, which eliminated by CRK. Meanwhile, with MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not affect the proliferation. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b enhanced cell apoptosis, which could be eliminated by CRK. Meanwhile, MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not promote apoptosis. CONCLUSION: BDNF VAL66MET polymorphism is associated with miR-146b and its target gene CRK. MiR-146b and CRK mediated BDNF VAL66MET polymorphism associated proliferation and apoptosis via activation of AKT. Thus, BDNF Val66Met is associated with the risk of bladder cancer, and the BDNF variant could be used a biomarker for the diagnosis of bladder cancer. PMID- 29402795 TI - The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression. AB - Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the tumor microenvironment, and they play a pivotal role in prompting the various tumor growth. However, the role of TAMs in colorectal carcinoma (CRC) is controversial, because a few papers report that TAMs is beneficial to CRC patients. In this review, we discuss the good or bad roles of TAMs in CRC progression. Interestingly, recent studies provide strong evidence that TAMs facilitate CRC growth, but do not exert tumor suppressive activities. TAMs can stimulate CRC growth by altering extracellular matrix remodeling, tumor metabolism, angiogenesis, as well as the tumor microenvironment. Therefore, TAMs could serve as a target for CRC therapeutic treatment. PMID- 29402796 TI - Oral Brush Liquid-Based Cytology: A Study of Concordance between a Cytotechnologist and a Cytopathologist. AB - OBJECTIVE: Oral cancer accounts for almost 40% of all cancers in the Indian subcontinent. Techniques like oral scrape cytology are helpful in early diagnosis of premalignant lesion and thus prevention of malignant transformation. The purpose of this study is to evaluate the performance of cytotechnologists in assessing the adequacy and preliminary diagnostic accuracy of oral brush liquid based cytology. STUDY DESIGN: 110 oral brush liquid-based cytology smears were prospectively screened by a cytotechnologist for adequacy assessment, and a preliminary diagnosis was recorded. Smears were subsequently studied by the reporting cytopathologist for the final diagnosis. The performance of the cytotechnologist in the assessment of adequacy and the preliminary diagnosis were compared with the final interpretation rendered by the cytopathologist. RESULTS: There was no significant difference in adequacy assessment between both observers, and good concordance was observed in the identification of frankly malignant lesions; however, in premalignant cases, complete agreement in all the cases was not observed. Maximum numbers of discrepant cases were seen in high grade squamous intraepithelial lesions, 4/17 were downgraded to low-grade squamous intraepithelial lesions and 2/17 to negative for intraepithelial lesion or malignancy, respectively. CONCLUSION: Trained cytotechnologists are capable of assessing the adequacy and identifying the malignancy in oral brush liquid-based cytology smears, and hence there is potential for them to perform initial screening of such cases. PMID- 29402797 TI - Angiotensin II Silencing Alleviates Erectile Dysfunction Through Down-Regulating the Rhoa/Rho Kinase Signaling Pathway in Rats with Diabetes Mellitus. AB - BACKGROUND/AIMS: We aim to explore the role of angiotensin (Ang)II and the RhoA/Rho kinase signaling pathway in the pathogenesis of erectile dysfunction in diabetes mellitus (DM). METHODS: Male Sprague-Dawley (SD) rats were used for experiments and short hairpin RNA (shRNA) was used to silence the AngII gene. The erectile function of rats was observed and intracavernous pressure and mean arterial pressure (ICP/MAP) were measured after electrical stimulation. Relaxation and contraction of smooth muscle in the corpus cavernosum were tested. Western blotting and quantitative RT-PCR were applied to measure the expressions of RhoA, Rho-associated kinase (ROCK)1 and ROCK2. Radioimmunoassay was applied to detect the levels of AngII. RESULTS: Rats in the control group had the most erectile times, followed by AngII-silenced rats with DMED and rats with DMED. Rats with DMED had worse ICP and MAP than AngII-silenced rats. The contraction ability was markedly improved and relaxation ability was decreased in AngII silenced rats with DMED as compared with rats with DMED. The levels of AngII were significantly increased in DMED rats while significantly decreased after AngII silencing. The mRNA and proteins of RhoA and ROCK2 were expressed in a similar way. CONCLUSION: AngII silencing improves erectile dysfunction via down regulating the RhoA/Rho kinase signaling pathway. PMID- 29402798 TI - Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia. AB - BACKGROUND/AIMS: Ischemic stroke is a major cause of disability and mortality worldwide, while effective restorative treatments are limited at present. Stem cell transplantation holds therapeutic potential for ischemic vascular diseases and may provide an opportunity for neural regeneration. Dental pulp stem cells (DPSCs) origin from neural crest and have neuro-ectodermal features including proliferation and multilineage differentiation potentials. METHODS: The rat model of middle cerebral artery occlusion (MCAO) was used to evaluate whether intravenous administration of DPSCs can reduce infarct size and to estimate the migration and trans-differentiation into neuron-like cells in focal cerebral ischemia models. Brain tissues were collected at 4 weeks following cell transplantation and analyzed with immunofluorescence, immunohistochemistry and real-time polymerase chain reaction (RT-PCR) methods. RESULTS: Intravenously administration of rat-derived DPSCs were found to migrate into the boundary of ischemic areas and expressed neural specific markers, reducing infarct volume and cerebral edema. CONCLUSIONS: These results suggest that DPSCs treatment may serve as a potential therapy for clinical stroke patients in the future. PMID- 29402800 TI - Is Surgical Excision Necessary in Breast Papillomas 10 mm or Smaller at Core Biopsy. AB - BACKGROUND: The objective of this study was to propose managements for breast papillomas of 10 mm or smaller initially diagnosed at core biopsy. METHOD: We reviewed the data of patients in our center from 2004 to 2013. 116 lesions of 10 mm or smaller as measured by ultrasound (US) were diagnosed as papillomas at core needle biopsy (CNB) or vacuum-assisted biopsy (VAB). 74 of the papillomas diagnosed by CNB were surgically excised, the others were followed by imaging surveillance. RESULT: 13 of 116 lesions were found to be malignant, with an upgrade rate of 11.2%. Analyzing the difference between malignant and nonmalignant lesions, patients with malignant lesions were older than those with nonmalignant lesions (56.6 vs. 46.6 years, p = 0.002). Papillomas with atypia had a significantly higher upgrade rate than without, both in the surgical results (p = 0.030) and overall (p = 0.0392). None of 16 papillomas larger than 5 mm upgraded to malignancy. Breast papillomas diagnosed by CNB had a significantly higher upgrade rate (16.5%) than those diagnosed by VAB (0%) (p = 0.021). CONCLUSION: Our finding suggests that breast papillomas of 6-10 mm at initial CNB need additional surgical excision, but imaging surveillance may be suitable for papillomas no larger than 5 mm and papillomas detected by VAB. PMID- 29402799 TI - Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats. AB - BACKGROUND/AIMS: Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. METHODS: A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-alpha in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. RESULTS: The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-alpha significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-alpha. CONCLUSIONS: All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti apoptotic and anti-inflammatory action. PMID- 29402801 TI - Second Autologous Hematopoietic Stem Cell Transplant as Salvage Therapy for Relapsed Multiple Myeloma: A Global Treatment Option for Eligible Patients. PMID- 29402802 TI - Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) have been described to have important roles in primary immune thrombocytopenia (ITP). To gain additional understanding, we have now further evaluated the involvement of miRNAs in ITP. METHODS: Microarray experiments were performed to examine the expression profiles of miRNAs and mRNAs in samples from subjects with newly diagnosed ITP (G1), chronic ITP (G2), and normal controls. The systematic Pipeline of Outlier MicroRNA Analysis framework was applied to identify key miRNAs expressed in the G1 and G2 samples. Quantitative PCR and receiver operator characteristic curves were used to confirm the performance of key miRNAs. RESULTS: Compared with normal controls, 14 miRNAs (12 over-expressed and 2 under-expressed) and 7 over-expressed miRNAs were identified as key in G1 and G2 samples, respectively. miR-106b-5p, miR-200c-3p, and miR-92a-3p exhibited significantly different expression profiles among the groups. In particular, miR-106b-5p and miR-200c-3p were expressed at higher levels in patients with ITP compared to the normal controls. Furthermore, these two miRNAs expressions were even higher in patients with chronic ITP. CONCLUSION: MiR-106b-5p and miR-200c-3p may represent valuable biomarkers of ITP, although further studies are needed to confirm and assess the value of these potential biomarkers at various stages of ITP. PMID- 29402803 TI - Identification of Immunoglobulin E-Binding Proteins of the Xerophilic Fungus Aspergillus penicillioides Crude Mycelial Mat Extract and Serological Reactivity Assessment in Subjects with Different Allergen Reactivity Profiles. AB - BACKGROUND: Aspergillus penicillioides is a very common indoor xerophilic fungus and potential causative agent of respiratory conditions. Although people are constantly exposed to A. penicillioides, no proteins with allergenic potential have been described. Therefore, we aim to confirm allergic sensitization to A. penicillioides through reactivity in serological assays and detect immunoglobulin E (IgE)-binding proteins. METHODS: In an indirect ELISA, we compared the serological reactivity to A. penicillioides between subjects with specific IgE (sIgE) (group 1, n = 54) and no sIgE reactivity (group 2, n = 15) against commercial allergens. Correlations and principal component analysis were performed to identify associations between reactivity to commercial allergens and A. penicillioides. IgE-binding proteins in A. penicillioides were visualized using Western blotting (WB) in group 1. The IgE-binding proteins with the highest reactivity were analyzed by mass spectrometry and confirmed by transcript matching. RESULTS: There was no statistical significance (p = 0.1656) between the study groups in serological reactivity. Correlations between reactivity to A. penicillioides, dog epithelia, Aspergillus fumigatus, and Penicillium chrysogenum were observed. WB experiments showed 6 IgE-binding proteins with molecular weights ranging from 45 to 145 kDa. Proteins of 108, 83, and 56 kDa showed higher reactivity. Mass spectrometry analysis of these 3 proteins led to the putative identification of NADP-specific glutamate dehydrogenase and catalase B. This was confirmed with transcriptome analysis. CONCLUSIONS: These results provide evidence of the presence of potential allergenic components in A. penicillioides. Further analysis of the putatively identified proteins should reveal their allergenic potential. PMID- 29402804 TI - Platinum-Based Neoadjuvant Chemotherapy versus Primary Surgery in Ovarian Carcinoma International Federation of Gynecology and Obstetrics Stages IIIc and IV: A Systematic Review and Meta-Analysis. AB - BACKGROUND/AIM: This study aimed to compare neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) with primary debulking surgery (PDS) followed by chemotherapy in patients with advanced ovarian carcinoma International Federation of Gynecology and Obstetrics (FIGO) stages IIIc and IV. METHODS: PubMed, the Cochrane Library, and manual searches were applied to discriminate potentially eligible studies published before June 30, 2016. RESULTS: A total of 12 comparative studies were finally included; 1,372 patients underwent NAC followed by IDS, and 2,680 patients underwent PDS followed by chemotherapy. For overall pooled estimates, significant between-trial differences were found in the optimal debulking rate, grade 3-5 postoperative adverse reactions, and median overall survival (OS), but no difference was found in the median progression-free survival (PFS). Moreover, a significantly higher incidence was identified in major infections, vascular events, and wound complications for patients in the PDS group. CONCLUSIONS: This study suggested that NAC followed by IDS could improve the optimal debulking rate and decrease the postoperative adverse reactions for the current studies, but whether it could improve the OS and PFS compared with PDS followed by chemotherapy in patients with ovarian carcinoma FIGO stages IIIc and IV were still needed to be verified by conducting more randomized controlled trials. PMID- 29402805 TI - Tick-Tock Chimes the Kidney Clock - from Biology of Renal Ageing to Clinical Applications. AB - Ageing of the kidney is a multi-dimensional process that occurs simultaneously at the molecular, cellular, histological, anatomical and physiological level. Nephron number and renal cortical volume decline, renal tubules become atrophic and glomeruli become sclerotic with age. These structural changes are accompanied by a decline in glomerular filtration rate, decreased sodium reabsorption and potassium excretion, reduced urinary concentrating capacity and alterations in the endocrine activity of the kidney. However, the pace of progression of these changes is not identical in everyone - individuals of the same age and seemingly similar clinical profile often exhibit stark differences in the age-related decline in renal health. Thus, chronological age poorly reflects the time dependent changes that occur in the kidney. An ideal measure of renal vitality is biological kidney age - a measure of the age-related changes in physiological function. Replacing chronological age with biological age could provide numerous clinical benefits including improved prognostic accuracy in renal transplantation, better stratification of risk and identification of those who are on a fast trajectory to an age-related drop in kidney health. PMID- 29402806 TI - Gastric Neuroendocrine Tumors (G-Nets): Incidence, Prognosis and Recent Trend Toward Improved Survival. AB - BACKGROUND/AIMS: Gastric neuroendocrine tumors (G-NETs) are uncommon neoplasms that can present with or without clinical symptoms. In this study, we evaluated the incidence, prognosis, and temporal trends of G-NETs. METHODS: We analyzed all cases of G-NETs registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2014. Incidence was estimated by age and joinpoint analyses. Survival rates were calculated and survival trends over time were evaluated. RESULTS: A total of 3740 eligible patients were enrolled in the study. G-NETs incidence increased from 0.31 per 1 000 000 patients in 1975 to 4.85 in 2014, with an annual percentage changes (APCs) of 8.9% (95% confidence interval [CI] = 7.7% to 10.21%, P < 0.001, t test (29) from 1975 to 2001 and 3.6% from 2002 to 2014 (95% CI= 2.3% to 4.9%, P < 0.001). For cases diagnosed between 1973 and 1982, five-year survival was 62.8% +/- 7.0% (Standard error, SE) and increased to 86.7% +/- 0.7% for cases diagnosed between 2003 and 2012 (P < 0.001). Years of diagnosis, gender, age at diagnosis, marital status, grade, tumor size, tumor stage, and surgery performed or not were the strongest predictors of worse survival in both univariate and multivariate analysis (P<0.05). CONCLUSION: G-NETs are uncommon neoplasms but the incidence is growing. Survival has improved in the past decades. Years of diagnosis, gender, age at diagnosis, marital status, grade, tumor size, tumor stage, and surgery status predict survival in patients with G-NETs. PMID- 29402807 TI - Recent Advances and Future Opportunities to Address Challenges in Offloading Diabetic Feet: A Mini-Review. AB - Diabetic foot ulcers (DFU) are a substantial dilemma for geriatric individuals with diabetes. The breakdown in tissue associated with DFU is typically a result of repetitive cycles of physical stress placed on the feet during weight-bearing activity. Accordingly, a key tenet in healing as well as preventing DFU is the use of offloading footwear to redistribute physical stress away from high stress locations such as bony prominences. Over the last several years there has been a substantial amount of effort directed at better understanding and implementing the practice of offloading. A review of this work as well as relevant technological advances is presented in this paper. Specifically, we will discuss the following topics in association with offloading diabetic feet: achieving optimal offloading, dosing activity/physical stress, thermal monitoring to detect preulcerative tissue damage, adherence with offloading devices, and optimizing the user experience. In addition to presenting progress to date, potential directions for further advancement are discussed. PMID- 29402808 TI - Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR. AB - BACKGROUND/AIMS: This study aimed to explore the effect of microRNA-592-5p (miR 592-5p) on hypoxic-ischemic brain damage (HIBD)-induced hippocampal neuronal injury in a neonatal mouse model relative to the involvement of one target gene, PTGDR, and the PGD2/ DP signaling pathway. METHODS: A total of 30 neonatal mice aged 7 days were randomly selected to establish an HIBD mouse model. Hippocampal neuronal cells were transfected into a control group, a blank group, a negative control (NC) group, an miR-592-5p mimics group, an miR-592-5p inhibitors group, an siRNA-PTGDR group and an miR-592-5p inhibitors + siRNA-PTGDR group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses were performed to detect the expression levels of miR-592-5p, PTGDR, DP2, Bcl-2 and Bax in tissues and cells. Cell proliferation, cell cycle and apoptosis were detected by MTT assay and flow cytometry, respectively. RESULTS: The expression levels of miR-592-5p and Bcl-2 decreased, while the expression levels of PTGDR, DP2 and Bax increased in the HIBD group. PTGDR is a target gene of miR-592-2p. Compared with the NC and blank groups, the expression levels of PTGDR, DP2 and Bax decreased, while the expression levels of miR-592-5p and Bcl-2 increased in the miR-592-5p mimics group. The siRNA-PTGDR group showed the same trend as that observed in the miR-592-5p mimics group, except with no difference in miR-592-5p expression. The miR-592-5p inhibitors group showed an opposite gene expression trend compared to that in the miR-592-5p mimics group. The S phase of the cell cycle was prolonged, the G1 phase was reduced, proliferation was increased, and the apoptosis rate was decreased in the siRNA-PTGDR and miR-592-5p mimics groups. Opposite trends for cell cycle, proliferation and apoptosis were observed in the miR-592-5p inhibitors group. CONCLUSIONS: Our study suggests that miR-592-5p upregulation protects against hippocampal neuronal injury caused by HIBD by targeting PTGDR and inhibiting the PGD2/DP signaling pathway. PMID- 29402809 TI - Questionnaire-Based Survey on Gastrointestinal Bleeding and Management of Antithrombotic Agents during Endoscopy Among Asian Countries. AB - OBJECTIVE: Guidelines on the management of antithrombotic therapy for endoscopic procedures vary among countries. Differences in the management of antithrombotic agents for endoscopic procedures between Western and Eastern countries have already been reported. However, no study has investigated the differences among Asian countries. The aim of this study was to examine the differences in the etiology of gastrointestinal bleeding and management of antithrombotic agents during endoscopic procedures between Japan and other Asian countries (OAC). METHODS: Questionnaires regarding gastrointestinal bleeding in clinical practice and management of antithrombotic agents during endoscopy were distributed to members of the International Gastroenterology Consensus Symposium Study Group. We analyzed the questionnaire answers and compared the results between Japan and OAC. RESULTS: The cause of and treatment methods for gastrointestinal bleeding differed between Japan and OAC. In Japan, the trend was to continue drugs at the time of biopsy and endoscopic therapy. Even in cases of discontinuation, the drug withdrawal period was as short as <3 days. Thrombotic complications caused by the withdrawal of antithrombotic agents were observed more frequently in Japan (34.78%) than in OAC (22.46%; p = 0.016). CONCLUSION: Due to differences in guidelines and complications associated with discontinuation of drugs, the antithrombotic withdrawal period in Japan tended to be shorter than that in OAC. PMID- 29402810 TI - Basophil Membrane Expression of Epithelial Cytokine Receptors in Patients with Severe Asthma. AB - BACKGROUND: Severe asthma is a heterogeneous disease, which is characterized by airway damage and remodeling. All triggers of asthma, such as allergens, bacteria, viruses, and pollutants, interact with the airway epithelial cells, which drive the airway inflammatory response through the release of cytokines, particularly IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). OBJECTIVES AND METHODS: To investigate whether the expression of the IL-25, IL-33, and TSLP receptors on the basophil membrane are associated with asthma severity. Twenty six patients with asthma (11 severe and 15 moderate/mild) and 10 healthy subjects (controls) were enrolled in the study. The results of the basophil activation test and flow cytometry analysis were assessed to investigate basophil membrane expression of IL-25, TSLP, and IL-33 receptors before and after IgE stimulation. RESULTS: IL-25 and IL-33 receptor expression on the basophil membrane at baseline were significantly higher in patients with severe asthma than in those with mild/moderate asthma or healthy subjects, independent of atopy, eosinophilia, asthma control, and exacerbation frequency. Following IgE stimulation, a significantly higher increase in the IL-25 and IL-33 receptors was observed in mild/moderate versus severe asthma. CONCLUSIONS: The high expression of the IL-25 and IL-33 receptors on the basophil membrane of patients with severe asthma indicates an overstimulation of basophils by these cytokines in severe asthma. This finding can possibly be used as a biomarker of asthma severity. PMID- 29402811 TI - Evaluation of Direct and Indirect Methods of Sub-Neoglottic Pressure Measurement in Tracheoesophageal Speakers: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Tracheoesophageal (TE) prosthetic voice is one of the voice restoration options for individuals who have undergone a total laryngectomy. Aerodynamic analysis of the TE voice provides insight into the physiological changes that occur at the level of the neoglottis with voice prosthesis in situ. The present study is a systematic review and meta-analysis of sub-neoglottic pressure (SNP) measurement in TE speakers by direct and indirect methods. PATIENTS AND METHODS: The screening of abstracts and titles was carried out for inclusion of articles using 10 electronic databases spanning the period from 1979 to 2016. Ten articles which met the inclusion criteria were considered for meta analysis with a pooled age range of 40-83 years. RESULTS: The pooled mean SNP obtained from the direct measurement method was 53.80 cm H2O with a 95% confidence interval of 21.14-86.46 cm H2O, while for the indirect measurement method, the mean SNP was 23.55 cm H2O with a 95% confidence interval of 19.23 27.87 cm H2O. CONCLUSION: Based on the literature review, the various procedures followed for direct and indirect measurements of SNP contributed to a range of differences in outcome measures. The meta-analysis revealed that the "interpolation method" for indirect estimation of SNP was the most acceptable and valid method in TE speakers. PMID- 29402812 TI - Contrast-Induced Encephalopathy following Coronary Angiography with No Radiological Features: A Case Report and Literature Review. AB - Contrast-induced encephalopathy (CIE) following coronary angiography (CAG) is a very rare complication. Radiological signs such as cerebral oedema and cortical enhancement are of great importance in the diagnosis. We report a case of probable CIE in a 76-year-old gentleman following a normal diagnostic CAG that involved 120 mL of the iodinated contrast agent iohexol (Omnipaque 300). At 90 min postprocedure he became acutely confused with a normal non-contrast CT of the head. After 9 days of conservative treatment, the patient recovered spontaneously with no neurological deficits. This case and a review of the literature highlights that contrast-induced neurotoxicity may not always present with the typical radiological signs that are described in association with CIE. Given the excellent prognosis with supportive management only, interventional cardiologists should be well aware of this condition despite the absence of radiological features. PMID- 29402813 TI - Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities? AB - BACKGROUND: Growth hormone (GH) treatment may unmask central hypothyroidism (CeH). This was first observed in children with GH deficiency (GHD), later also in adults with GHD due to acquired "organic" pituitary disease. We hypothesized that newly diagnosed CeH in children after starting GH treatment for nonacquired, apparent isolated GHD points to congenital "organic" pituitary disease. METHODS: Nationwide, retrospective cohort study including all children with nonacquired GHD between 2001 and 2011 in The Netherlands. The prevalence of CeH, hypothalamic pituitary (HP) abnormalities, and neonatal congenital hypothyroidism screening results were evaluated. RESULTS: Twenty-three (6.3%) of 367 children with apparent isolated GHD were prescribed LT4 for presumed CeH within 2 years after starting GH treatment. Similarly to children already diagnosed with multiple pituitary hormone deficiency, 75% of these 23 had structural HP abnormalities. In children not prescribed LT4, low pre- or post-GH treatment FT4 concentrations were also associated with structural HP abnormalities. Neonatal screening results of only 4 of the 23 children could be retrieved. CONCLUSION: In children with nonacquired, apparent isolated GHD, a diagnosis of CeH after, or a low FT4 concentration around the start of GH treatment, is associated with congenital structural HP abnormalities, i.e., "organic" pituitary disease. Neonatal values could not be judged reliably. PMID- 29402814 TI - Association of Ultrafiltration Rate with Mortality in Incident Hemodialysis Patients. AB - BACKGROUND/AIMS: Ultrafiltration rate (UFR) appears to be associated with mortality in prevalent hemodialysis (HD) patients. However, the association of UFR with mortality in incident HD patients remains unknown. METHODS: We examined a US cohort of 110,880 patients who initiated HD from 2007 to 2011. Baseline UFR was divided into 5 groups (<4, 4 to <6, 6 to <8, 8 to <10, and >=10 mL/h/kg body weight [BW]). We examined predictors of higher baseline UFR using logistic regression and the association of baseline UFR and all-cause and cardiovascular (CV) mortality using Cox proportional hazard models with adjustments for demographics, comorbidities, and markers of malnutrition-inflammation-cachexia syndrome. RESULTS: Patients were 63 +/- 15 years, with 43% women, 32% African Americans, and had a mean baseline UFR of 7.5 +/- 3.1 mL/h/kg BW. In the fully adjusted logistic regression models, factors associated with higher UFR (>=7.5 mL/h/kg BW) included Hispanic ethnicity, diabetes, and higher dietary protein intake. There was a linear association between UFR and all-cause and CV mortality, where UFR >=10 mL/h/kg BW (reference UFR 6-<8 mL/h/kg BW) conferred the highest risk in both unadjusted (HR 1.15 [95% CI 1.10-1.19]) and adjusted models (HR 1.23 [95% CI 1.16-1.31]). The linear association with all-cause mortality remained consistent across strata of age, urine volume, and treatment time. CONCLUSIONS: Higher UFR is independently associated with higher all-cause and CV mortality in incident HD patients. Clinical trials are warranted to examine the effects of lowering UFR on outcomes. PMID- 29402815 TI - Introducing a Virtual Lesion Model of Dysphagia Resulting from Pharyngeal Sensory Impairment. AB - BACKGROUND/AIMS: Performing neurophysiological and functional imaging studies in severely affected patients to investigate novel neurostimulation techniques for the treatment of neurogenic dysphagia is difficult. Therefore, basic research needs to be conducted in healthy subjects. Swallowing is a motor function highly dependent on sensory afferent input. Here we propose a virtual peripheral sensory lesion model to mimic pharyngeal sensory impairment, which is known as a major contributor to dysphagia in neurological disease. METHODS: In this randomized crossover study on 11 healthy volunteers, cortical activation during pneumatic pharyngeal stimulation was measured applying magnetoencephalography in two separate sessions, with and without pharyngeal surface anesthesia. RESULTS: Stimulation evoked bilateral event-related desynchronization (ERD) mainly in the caudolateral pericentral cortex. In comparison to the no-anesthesia condition, topical anesthesia led to a reduction of ERD in beta (13-30 Hz) and low gamma (30 60 Hz) frequency ranges (p<0.05) in sensory but also motor cortical areas. CONCLUSIONS: Withdrawal of sensory afferent information by topical anesthesia leads to reduced response to pneumatic pharyngeal stimulation in a distributed cortical sensorimotor network in healthy subjects. The proposed paradigm may serve to investigate the effect of neuromodulatory treatments specifically on pharyngeal sensory impairment as relevant cause of neurogenic dysphagia. PMID- 29402816 TI - Further Evidence of the Positive Influence of Repetitive Transcranial Magnetic Stimulation on Speech and Language in Patients with Aphasia after Stroke: Results from a Double-Blind Intervention with Sham Condition. AB - BACKGROUND: After a stroke, up to 20% of patients suffer from aphasia. The preferred treatment for stroke-related aphasia (SRA) is regular speech and language training (SLT). In the present study, we investigated to what extent adjuvant repetitive transcranial magnetic stimulation (rTMS) might enhance recovery. While there is growing evidence of the positive effect of adjuvant rTMS on aphasia, no study has yet been based on an Iranian sample. METHOD: A total of 12 patients (mean age: 55 years; right-handed; 7 women) underwent treatment for SRA 1 month after stroke. The standard treatment consisted of regular 45-min SLT sessions 5 times a week for 2 consecutive weeks. Additionally, patients were randomly assigned either to adjuvant rTMS (5 times a week for 30 min) or to a sham condition (5 times a week for 30 min). At baseline and after 2 weeks of intervention, the degree of aphasia was assessed with the Farsi version of the Western Aphasia Battery. rTMS was applied to the inferior posterior frontal gyrus of the right hemisphere. RESULTS: Speech and language improved over time, but more so in the rTMS than in the sham condition. Large effect sizes were observed for content, fluency, and the aphasia quotient; medium effect sizes were observed for command comprehension and repetition, while effect sizes were small for auditory comprehension and naming. CONCLUSIONS: Among patients with SRA, compared to a sham condition, adjuvant rTMS improved speech and language skills. The present results add to the accumulating evidence that rTMS as a neuromodulation technique has the capacity to enhance the effect of conventional SLT. PMID- 29402817 TI - Treatment of Metastatic Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE) - Long-Term Disease Control by Multimodal Therapy. AB - BACKGROUND: Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor that occurs mainly in pediatric patients and young adults. Only few of these patients develops metastatic disease; therefore, clinical data regarding treatment and outcome of metastatic SETTLE are extremely limited. Several chemotherapy agents have been used in SETTLE but due to the limited number of patients no evidence-based therapy exists. CASE REPORT: We present a case of metastatic SETTLE presenting with high tumor burden and paraneoplastic hypercalcemia. Prolonged disease control with several lines of platinum-based chemotherapy, anti-epidermal growth factor receptor therapy and additional radiotherapy was achieved. CONCLUSION: Multi-agent chemotherapy is an active treatment in metastatic SETTLE and can induce sustained tumor control. PMID- 29402818 TI - Maternal Vitamin D Status and Risk of Gestational Diabetes: a Meta-Analysis. AB - BACKGROUND/AIMS: Whether maternal vitamin D deficiency is associated with gestational diabetes remains controversial. This meta-analysis aimed to systematically evaluate published evidence on the association between maternal vitamin D status and the risk of gestational diabetes. METHODS: We retrieved relevant articles from the PubMed, Medline and Embase databases up to May 2017 for observational studies investigating the association between vitamin D status and the risk of gestational diabetes. Odds ratios (OR) or risk ratios (RR) from individual studies were pooled using the fixed and random effect models. RESULTS: The meta-analysis of 29 observational studies included 28,982 participants, of which 4,634 were diagnosed with gestational diabetes, and showed that maternal vitamin D insufficiency was associated with a significantly increased risk of gestational diabetes by 39% (pooled OR = 1.39, 95%CI = 1.20-1.60) with moderate heterogeneity (I2 = 50.2%; P = 0.001). Moreover, the 25(OH)D level was significantly lower in gestational diabetes cases than in controls with a pooled effect of -4.79 nmol/L (95% CI = -6.43, -3.15). Significant heterogeneity was also detected (I2 = 65.0%, P < 0.001). Further subgroup analysis indicated that this association was also evident in most subpopulations. CONCLUSION: This meta analysis indicated a significant association between vitamin D insufficiency and increased risk of gestational diabetes. Further well-designed large-scale clinical trials are essential to verify this association. PMID- 29402819 TI - Clinical Heterogeneity in Familial IgA Nephropathy. AB - BACKGROUND: IgA nephropathy is the most common primary glomerulonephritis worldwide and a significant cause of end-stage renal disease (ESRD). While most cases of IgA nephropathy are considered sporadic, familial cases have been reported. METHODS: We performed a national audit of 1,809 patients attending renal clinics and dialysis units to identify a family history among patients with kidney disease. We reviewed all renal biopsies performed at our institution spanning a 30-year period. Paediatric cases were not included. RESULTS: We identified 14 families involving 41 affected individuals with biopsy-proven IgA nephropathy and at least one other member with either biopsy-proven IgA nephropathy or ESRD. Detailed family histories were obtained, medical records reviewed and family pedigrees constructed. Retrospective application of the MESTC criteria to all familial IgA biopsies was performed. Seven families had 2 or more members with biopsy-proven IgA nephropathy, equating to 23 (1.8%) of 1,283 biopsies with IgA nephropathy over the last 30 years. A complex inheritance pattern was observed, with autosomal dominant and autosomal recessive families identified with varying penetrance. There was a male preponderance (68%), and a complex heterogeneity in the clinical and histopathological features of familial IgA patients (age range 16-60 years; creatinine range 60-350 MUmol/L). We observed a high rate (66%) of progression to ESRD, with a mean time to progression of 5.13 years (SD 1.8 years; range 2-8 years). Among those patients who had undergone transplantation, recurrence of disease was reported in 5 (50%) cases. CONCLUSION: These data suggests familial aggregation of IgA nephropathy, confirm the clinical and histopathological heterogeneity and raise the possibility of monogenic inheritance. PMID- 29402820 TI - Primary Fused Teeth and Findings in Permanent Dentition. AB - OBJECTIVE: The aim of this study was to investigate the characteristics of primary fused teeth (PFT) and their effect on permanent dentition in a group of Turkish children. SUBJECTS AND METHODS: Dental records of 13,450 pediatric patients who attended the Pediatric Dental Clinic in northern Turkey between 2015 and 2017 were reviewed. Forty patients had been diagnosed with PFT and were included in the study. Clinical and radiographic examinations were conducted, and the distribution of PFT was calculated by type, sex, affected jaw, associated dental anomalies, and clinical complications. Data analysis involved descriptive statistics. RESULTS: A total of 50 PFT were detected in the 40 patients. The mean age of patients was 6.7 +/- 0.3 years (range 3-10 years). The most common PFT were the mandibular lateral incisors and canines (34, 68%). The most prevalent type of PFT was type III (20, 40%). Of the 40 patients with PFT, 34 (85%) also ex hibited other dental anomalies such as tooth aplasia, peg-shaped incisors, talon cusps, ectopic eruption, and delayed eruption in both related and unrelated areas. The most common complications of PFT were fusion-related tooth aplasia (n = 26 [76%]) and caries formation in the affected teeth (24 [48%]). CONCLUSION: In this study, PFT were frequently observed in the mandibular anterior region. Caries formation and dental anomalies, especially permanent tooth aplasia, were often encountered in areas where PFT were seen. Hence, parents should be informed about possible dental problems associated with PFT and be encouraged to schedule regular follow-up appointments. PMID- 29402821 TI - Completeness and Legibility of Handwritten Prescriptions in Sana'a, Yemen. AB - OBJECTIVE: The aim of this study was to investigate the completeness and legibility of prescriptions dispensed in community pharmacies located in Sana'a, Yemen. MATERIALS AND METHODS: A cross-sectional study was conducted at 23 randomly selected community pharmacies throughout the capital city of Sana'a, Yemen, from May 2015 to January 2016. A total of 2,178 prescriptions were analyzed for the essential elements of a complete prescription using a validated checklist. RESULTS: Of the 2,178 prescriptions, 19 (0.87%) were considered to be of good quality. The remaining 2,159 (99.12%) were considered as being of very poor quality. Writing errors relating to patients and prescribed medications were the most common errors. CONCLUSION: In this study, the quality of prescription writing was found to be very poor. Hence, continuous professional development programs are recommended to improve the quality of prescription writing among physicians. Future studies in other cities and investigation of the impact of continuous educational programs on the quality of prescription writing are strongly recommended. PMID- 29402823 TI - Extremely Long Survival under Combined Immunotherapy in a Metastatic Functional Neuroendocrine Neoplasia Patient. AB - Treatment and prognosis of neuroendocrine neoplasia depends on tumor size, stage, grade, resectability, and extent of distant metastasis. In most cases a multimodality approach including surgical, locally invasive procedures, peptide guided radioreceptor therapy (PRRT), and medical therapies represent the mainstay of treatment in advanced disease. In the reported case, a 68-year-old man was diagnosed in 2010 with an initially functional (histamine) neuroendocrine tumor of gastric type III, G2, stage IVB, cT4cN1cM1 (hepatic, peritoneal, nodal, osseous), including a hepatic tumor load of 25%. Intensive multimodality approaches including combined immunotherapy (vaccination and PD-1/CTLA-4 blockade) led to a survival of 8 years until now with a high quality of life and minimal residual disease (only a single, small paragastric recurrence) despite the dedifferentiation of the tumor into a neuroendocrine carcinoma G3 (Ki-67 of 80%) including a nonfunctional stage. PMID- 29402822 TI - Metabolic Syndrome Is Associated with Health-Related Quality of Life in Suspected Patients with Nonalcoholic Steatohepatitis. AB - OBJECTIVE: This study was designed to examine the effect of metabolic syndrome (MetS) on health-related quality of life (HRQOL) in patients with suspected nonalcoholic steatohepatitis (NASH). SUBJECTS AND METHODS: Three hundred thirty two patients (236 males and 96 females) with suspected NASH from the Amol cohort study were included in this study. MetS was diagnosed based on Adult Treatment Panel III criteria and HRQOL was measured using the 12-Item Short-Form Health Survey (SF-12) questionnaire (with 8 subscales and 2 summary components). A multivariable linear regression model was used to assess the independent effect of MetS on HRQOL. RESULTS: The mean age of the study population was 42 +/- 13 years (range 18-82). The prevalence of MetS was 43.4% (n = 144) and the mean scores on the Physical Component Summary (PCS) and the Mental Component Summary were 72.4 +/- 20.86 and 42.7 +/- 12.42, respectively. The multivariable linear regression model showed that MetS was negatively associated with 4 subscales of HRQOL that included: role limitations due to physical problems (RP) (B = -14.05, p = 0.004), bodily pain (BP) (B = -7.37, p = 0.02), vitality (VT) (B = -7.72, p = 0.022), and role limitations due to emotional problems (RE) (B = -12.67, p = 0.005) after adjustment for other variables. Also, MetS had a borderline association with the general health and mental health subscales and the PCS (p < 0.1). CONCLUSION: In this study, there was a strong association between MetS and 4 subscales (RP, BP, VT, and RE) of HRQOL in patients with suspected NASH; this could be considered as a part of health policy to improve general health. PMID- 29402824 TI - Black Hole Sign Predicts Poor Outcome in Patients with Intracerebral Hemorrhage. AB - BACKGROUND: In spontaneous intracerebral hemorrhage (ICH), black hole sign has been proposed as a promising imaging marker that predicts hematoma expansion in patients with ICH. The aim of our study was to investigate whether admission CT black hole sign predicts hematoma growth in patients with ICH. METHODS: From July 2011 till February 2016, patients with spontaneous ICH who underwent baseline CT scan within 6 h of symptoms onset and follow-up CT scan were recruited into the study. The presence of black hole sign on admission non-enhanced CT was independently assessed by 2 readers. The functional outcome was assessed using the modified Rankin Scale (mRS) at 90 days. Univariate and multivariable logistic regression analyses were performed to assess the association between the presence of the black hole sign and functional outcome. RESULTS: A total of 225 patients (67.6% male, mean age 60.3 years) were included in our study. Black hole sign was identified in 32 of 225 (14.2%) patients on admission CT scan. The multivariate logistic regression analysis demonstrated that age, intraventricular hemorrhage, baseline ICH volume, admission Glasgow Coma Scale score, and presence of black hole sign on baseline CT independently predict poor functional outcome at 90 days. There are significantly more patients with a poor functional outcome (defined as mRS >=4) among patients with black hole sign than those without (84.4 vs. 32.1%, p < 0.001; OR 8.19, p = 0.001). CONCLUSIONS: The CT black hole sign independently predicts poor outcome in patients with ICH. Early identification of black hole sign is useful in prognostic stratification and may serve as a potential therapeutic target for anti-expansion clinical trials. PMID- 29402825 TI - Relationship between Activity Noise, Voice Parameters, and Voice Symptoms among Female Teachers. AB - OBJECTIVE: Our interest was in how teachers' voices behave during the delivery of lessons in core subjects (e.g., mathematics, science, etc.). We sought to evaluate the relationship between voice sound pressure level (SPL), vocal fundamental frequency (F0), voice symptoms, activity noise, and differences therein during the first and the last lessons in core subjects of the day. PATIENTS AND METHODS: The participants were 24 female elementary school teachers. Voice symptoms were evaluated by questionnaire. The data were recorded on 2 portable voice accumulators (VoxLog) from the first and last lessons of the day. The versions of accumulators differed by frequency weighting; therefore, the analysis and the results of noise and voice SPL were treated separately: unweighted (group 1) and A-weighted (group 2). RESULTS: Difference in voice SPL followed difference in activity noise. F0 increased between the first and last lessons. Correlations were found between differences in the noise and the voice symptoms of tiredness and dryness. Irritating mucus was associated with high F0 during the first lesson. CONCLUSION: An apparent increase in voice loading due to the activity noise was observed during lessons in core subjects. Collaboration between specialists in voice and acoustics and teachers and pupils is needed to reduce this voice loading. PMID- 29402826 TI - When to Screen Ischaemic Stroke Patients for Cancer. AB - BACKGROUND AND PURPOSE: Ischemic stroke can be the first manifestation of cancer and it is therefore important to ascertain which stroke patients should be considered for cancer-diagnostic investigations. We aimed to determine the frequency of active cancer in patients with acute ischemic stroke and to compare clinical findings in stroke patients with active cancer to ischemic stroke patients with no history of cancer. Finally, we aimed to develop a predictive and feasible score for clinical use to uncover underlying malignancy. METHODS: All ischemic stroke patients admitted to the stroke unit in the Department of Neurology, Haukeland University Hospital were consecutively included in the Norwegian Stroke Research Registry (NORSTROKE). Stroke etiology was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Data on cancer diagnoses was obtained from patients' medical records and the Cancer Registry of Norway. Active cancer was defined as cancer diagnosis, metastasis of known cancer, recurrent cancer or receiving cancer treatment, all within 12 months before or after the index stroke. Based on variables independently associated with active cancer, a predictive score was developed using the area under the receiver operating characteristic (AUC-ROC) curves. Bayes' theorem was used to calculate post-test probabilities of active cancer. RESULTS: Of the 1,646 ischemic stroke patients included, 82 (5.0%) had active cancer. Increased D-dimer (OR = 1.1, 95% CI: 1.1-1.2, p = <0.001), lower Hb (OR = 0.6, 95% CI: 0.5-0.7, p = <0.001), smoking (OR = 2.2, 95% CI: 1.2-4.3, p = 0.02) and suffering a stroke of undetermined etiology (OR = 1.9, 95% CI: 1.1-3.3, p = 0.03) were factors independently associated with active cancer. These were included in the final predictive score which gave an AUC of 0.73 (95% CI: 0.65-0.81) in patients younger than 75 years of age. Assuming the prevalence of cancer to be 5%, the score shows that if a patient fulfills all 3 score points, the probability of active cancer is 53%. CONCLUSIONS: Active cancer was found in 5% of our ischemic stroke patients. We found that a clinical score comprising elevated D-dimer >=3 mg/L, lower Hb <=12.0 g/dL and previous or current smoking is feasible for predicting active cancer in ischemic stroke patients. PMID- 29402827 TI - Expanded Haemodialysis Therapy of Chronic Haemodialysis Patients Prevents Calcification and Apoptosis of Vascular Smooth Muscle Cells in vitro. AB - BACKGROUND: Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes. Recent trials demonstrated a reduction of inflammation in VSMC by use of dialysis membranes with a higher and steeper cut off. These membranes caused significant albumin loss. Therefore, the effect of high retention Onset (HRO) dialysis membranes on vascular calcification and its implications in vitro was evaluated. METHODS: In the PERCI II trial, 48 chronic dialysis patients were dialyzed using HF and HRO dialyzers and serum samples were collected. Calcifying VSMC were incubated with the serum samples. Calcification was determined using alizarin red staining (AZR) and determination of alkaline phosphatase (ALP) activity. Furthermore, apoptosis was evaluated, and release of matrix Gla protein (MGP), osteopontin (OPN) and growth differentiation factor 15 (GDF-15) were measured in cell supernatants. RESULTS: Vascular calcification in vitro was significantly reduced by 24% (ALP) and 36% (AZR) after 4 weeks of HRO dialysis and by 33% (ALP) and 48% (AZR) after 12 weeks of dialysis using HRO membranes compared to HF dialysis. Apoptosis was significantly lower in the HRO group. The concentrations of MGP and OPN were significantly elevated after incubation with HF serum compared to HRO serum and healthy controls. Similarly, GDF-15 release in the supernatant was elevated after incubation with HF serum, an effect significantly ameliorated after treatment with HRO medium. CONCLUSIONS: Expanded haemodialysis therapy reduces the pro-calcific potential of serum from dialysis patients in vitro. With a markedly reduced albumin filtration compared to high cut-off dialysis, use of the HRO dialyzers may possibly provide a treatment option for chronic dialysis patients to reduce the progression of vascular calcification. PMID- 29402829 TI - A Continuous Renal Replacement Therapy Protocol on the Updated Nikkiso Aquarius Platform Using Regional Citrate as First-Line Anticoagulation Significantly Improves Filter Life Span but the Position of the Vascular Access is Key. PMID- 29402828 TI - Erythrocyte-Rich Thrombus Is Associated with Reduced Number of Maneuvers and Procedure Time in Patients with Acute Ischemic Stroke Undergoing Mechanical Thrombectomy. AB - BACKGROUND: Only few studies have investigated the relationship between the histopathology of retrieved thrombi and clinical outcomes. This study aimed to evaluate thrombus composition and its association with clinical, laboratory, and neurointerventional findings in patients treated by mechanical thrombectomy due to acute large vessel occlusion. METHODS: At our institution, 79 patients were treated by mechanical thrombectomy using a stent retriever and/or aspiration catheter between August 2015 and August 2016. The retrieved thrombi were quantitatively analyzed to quantify red blood cells, white blood cells, and fibrin by area. We divided the patients into two groups - a fibrin-rich group and an erythrocyte-rich group - based on the predominant composition in the thrombus. The groups were compared for imaging, clinical, and neurointerventional data. RESULTS: The retrieved thrombi from 43 patients with acute stroke from internal carotid artery, middle cerebral artery, or basilar artery occlusion were histologically analyzed. Erythrocyte-rich thrombi were present in 18 cases, while fibrin-rich thrombi were present in 25 cases. A cardioembolic etiology was significantly more prevalent among the patients with fibrin-rich thrombi than among those with erythrocyte-rich thrombi. Attenuation of thrombus density as shown on computed tomography images was greater in patients with erythrocyte-rich thrombi than in those with fibrin-rich thrombi. All other clinical and laboratory characteristics remained the same. Patients with erythrocyte-rich thrombi had a smaller number of recanalization maneuvers, shorter procedure times, a shorter time interval between arrival and recanalization, and a higher percentage of stent retrievers in the final recanalization procedure. The occluded vessels did not differ significantly. CONCLUSIONS: In this study, erythrocyte-rich thrombus was associated with noncardioembolic etiology, higher thrombus density, and reduced procedure time. PMID- 29402830 TI - Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives. AB - With the widespread use of genetic diagnostic technologies, many novel mutations have been identified in hereditary spherocytosis (HS)-related genes, including SPTA1, SPTB, ANK1, SLC4A1, and EPB42. However, mutations in HS-related genes are dispersed and nonspecific in the diagnosis of some HS patients, indicating significant heterogeneity in the molecular deficiency of HS. It is necessary to provide the molecular and genetic characteristics of these 5 genes for clinicians to examine HS. Here, we reviewed the recent proposed molecular genetic mechanisms of HS. PMID- 29402831 TI - NF-kappaB-Induced MicroRNA-211 Inhibits Interleukin-10 in Macrophages of Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome. AB - BACKGROUND/AIMS: The present study addressed the potential involvement of microRNAs in acute respiratory distress syndrome (ARDS)-related inflammation and elucidates the underlying molecular mechanism. METHODS: ARDS rat model was established by lipopolysaccharide, with compromised gas exchange capacity and lung edema. The inflammatory cells from bronchoalveolar lavage fluid (BALF) were profiled with automatic blood cell analyzer. The relative fluorescence intensity of BALF-derived macrophages was analyzed by flow cytometry. The relative microRNA expression was determined using microarray and Taqman assay. The secretory interleukin (IL)-10 was measured by enzyme-linked immunosorbent assay. Luciferase reporter assay was performed to determine the regulatory effects of miR-211 and NF-kappaB on IL-10 and miR-211 expressions, respectively. Chromatin immunoprecipitation (ChIP) was conducted to detect the direct binding of NK kappaB on miR-211 promoter. The protein level was determined by Western blot. RESULTS: The provoked acute inflammation was characterized with increased total cells, macrophages, neutrophils and lymphocytes. The relative expression of miR 211 was aberrantly up-regulated in BALF-derived macrophages from ARDS rats, which was accompanied with reduction of secretory IL-10. We further demonstrated that miR-211 inhibited IL-10 expression by binding to its 3'-UTR. The expression of miR-211 was modulated by NF-kappaB. CONCLUSION: Here we elucidated a crucial role of NF-kappaB/miR-211/IL-10 signaling axis in ARDS-related inflammation. PMID- 29402832 TI - The CFTR-Associated Ligand Arrests the Trafficking of the Mutant DeltaF508 CFTR Channel in the ER Contributing to Cystic Fibrosis. AB - BACKGROUND/AIMS: The CFTR-Associated Ligand (CAL), a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL's regulatory effect on DeltaF508 CFTR has remained almost entirely uninvestigated. METHODS: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of DeltaF508 CFTR through arrest of DeltaF508 CFTR trafficking in the endoplasmic reticulum (ER) using a combination of cell biology, biochemistry and electrophysiology. RESULTS: We demonstrate that CAL is an ER localized protein that binds to DeltaF508 CFTR and is degraded in the 26S proteasome. When CAL is inhibited, DeltaF508 CFTR retention in the ER decreases and cell surface expression of mature functional DeltaF508 CFTR is observed alongside of enhanced expression of plasma membrane scaffolding protein NHERF1. Chaperone proteins regulate this novel process, and DeltaF508 CFTR binding to HSP40, HSP90, HSP70, VCP, and Aha1 changes to improve DeltaF508 CFTR cell surface trafficking. CONCLUSION: Our results reveal a pathway in which CAL regulates the cell surface availability and intracellular retention of DeltaF508 CFTR. PMID- 29402833 TI - Usefulness of Serum Omentin-1 Levels for the Prediction of Adverse Cardiac Events in Patients with Hypertrophic Cardiomyopathy. AB - OBJECTIVE: To investigate the association between serum omentin-1 levels and adverse cardiac events in patients with hypertrophic cardiomyopathy (HCM). SUBJECTS AND METHODS: This prospective, observational study included 87 patients with HCM and 50 age- and sex-matched control subjects. Serum omentin-1 and brain natriuretic peptide (BNP) levels were measured in all subjects, using enzyme linked immunosorbent assay and electrochemiluminescence, respectively. Patients with HCM were divided into 2 groups according to their omentin levels, i.e., low: <=291 ng/mL (n = 48) and high: > 291 ng/mL (n = 39). Cardiac mortality, hospitalization due to heart failure, and implantable cardioverter-defibrillator (ICD) implantation were considered adverse cardiac events. Statistical analysis included uni- and multivariant logistic regression, receiver-operating characteristic (ROC) analysis, and the Kaplan-Meier method. RESULTS: Serum omentin-1 levels were significantly lower in the obstructive (253.9 +/- 41.3 ng/mL) and nonobstructive (301.9 +/- 39.8 ng/mL) HCM groups than in the control group (767.1 +/- 56.4 ng/mL), p < 0.001, respectively. The BNP levels were higher in the obstructive and nonobstructive HCM groups than in the control group (269.5 +/- 220, 241.0 +/- 227, and 24.0 +/- 18.9 pg/mL, respectively, p < 0.001). The Kaplan-Meier analysis indicated that patients with low omentin-1 levels showed a significantly higher (48.2%) 2-year cumulative incidence of overall adverse cardiac events than those with high omentin-1 levels (16.2%) (log-rank test, p = 0.001). In the multivariate logistic regression analysis, omentin-1, interventricular septum (IVS) thickness, and male gender were independent predictors of adverse cardiac events in the follow-up. CONCLUSION: Omentin-1 levels were lower in patients with HCM than in the control group, and this was associated with worse cardiac outcomes. PMID- 29402834 TI - Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation. AB - BACKGROUND/AIMS: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. METHODS: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. RESULTS: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. CONCLUSION: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis. PMID- 29402835 TI - Voltage-Gated Na+ Channels are Modulated by Glucose and Involved in Regulating Cellular Insulin Content of INS-1 Cells. AB - BACKGROUND/AIMS: Islet beta cells (beta-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in beta-cells, such as K+ and Ca2+ channels, contribute to insulin secretion. The response of voltage-gated Na+ channels (VGSCs) in beta-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. METHODS: The effect of glucose on VGSC currents (INa) was investigated in insulin-secreting beta-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and Methylthiazolyldiphenyl-tetrazolium Bromide (MTT) assay methods respectively. RESULTS: Our results show that extracellular glucose application can inhibit the peak of INa in a concentration-dependent manner. Glucose concentration of 18 mM reduced the amplitude of INa, suppressed the INa of steady state activation, shifted the steady-state inactivation curves of INa to negative potentials, and prolonged the time course of INa recovery from inactivation. Glucose also enhanced the activity-dependent attenuation of INa and reduced the fraction of activated channels. Furthermore, 18 mM glucose or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited the activity of VGSC and also improved insulin synthesis. CONCLUSION: These results revealed that extracellular glucose application enhances the insulin synthesis in INS-1 cells and the mechanism through the partial inhibition on INa channel is involved. Our results innovatively suggest that VGSC plays a vital role in modulating glucose homeostasis. PMID- 29402836 TI - Correlation Between Baseline Osteoprotegerin Serum Levels and Prognosis of Advanced-Stage Colorectal Cancer Patients. AB - BACKGROUND/AIMS: Osteoprotegerin (OPG) is a soluble receptor of the pro-apoptotic cytokine TRAIL which is thought to contribute to tumour development by inhibiting apoptosis or affecting other aspects of tumour biology, including cell proliferation and immune response. Although immunohistochemical studies suggest that OPG correlates with survival in metastatic colorectal cancer (mCRC), only scarce data are available on serum OPG in CRC patients. METHODS: In this pilot study, we assessed the prognostic significance of serum OPG and CEA (Carcinoembryonic antigen) in 81 patients with UICC (Union for International Cancer Control) stage-IV mCRC. OPG was additionally assessed by immunohistochemistry in primary tissue samples from 33 patients of the same cohort. RESULTS: Baseline serum OPG correlated with CEA (r=0.36, p=0.0011), but independently predicted survival of mCRC patients. Life expectancy was poorer in patients with OPG levels above the median concentration of 51ng/ml (median overall survival [95% confidence interval] 1.8 years [1.3-3.0] vs. 1.0 [0.7-1.2] p=0.013). Patients with high levels of both OPG and CEA had an even poorer life expectancy vs. low-OPG/low-CEA patients (0.9 years [0.6-1.5] vs. 3 years [1.2 4.4], p=0.015), indicating that CEA and OPG have additive prognostic significance. Immunohistochemical analysis of OPG failed to show a correlation between OPG staining and survival (p=0.055) or OPG concentration from matched serum samples. CONCLUSIONS: This pilot study provides evidence of independent prognostic significance of serum OPG in patients with advanced mCRC and warrants its further prospective validation. PMID- 29402837 TI - Protective Effects of Oxymatrine on Vascular Endothelial Cells from High-Glucose Induced Cytotoxicity by Inhibiting the Expression of A2B Receptor. AB - BACKGROUND/AIMS: Diabetes mellitus (DM) has become an increasingly epidemic metabolic disease. Vascular endothelial cells play a key role in developing the cardiovascular complications of DM. The A2B receptor is expressed in vascular endothelial cells, and may help regulate the function of endothelial cells. The aim of this study was to investigate the protective effects of oxymatrine (OMT) on human umbilical vein endothelial cells (HUVECs) from high glucose-induced cytotoxicity. METHODS: Homology modeling and molecular docking analysis were used to detect the binding sites between the adenosine A2B receptor and OMT. HUVECs were cultured with control (5.5 mM) or elevated glucose (22.2 mM) in the presence or absence of 3 uM OMT or A2B siRNA for 3 days. The MTS cell viability assay was used to measure the toxicity of high glucose on HUVECs and the protective effect of OMT or A2B siRNA. The expression of the adenosine A2B receptor and CCL5 in HUVECs was detected with real-time quantitative PCR (qPCR) and Western blotting methods in each group. Levels of IL-1beta and TNF-alpha were measured using an enzyme-linked immunosorbent assay (ELISA) kit, and the concentration of NO was detected with the nitrate reductase method. Monocyte chemotactic activity in each group was detected using Transwell chambers. Furthermore, the phosphorylation of p38 and ERK1/2 in each group was observed through the Western blotting method. RESULTS: Homology modeling and molecular docking analysis showed that OMT contains well-fitted binding sites to the A2B receptor. After chronic culture at high glucose, the rate of cell viability was significantly lower than that of the control group. After co-treatment with OMT or A2B siRNA, cell viability was significantly increased compared with the high-glucose group. The results from real-time quantitative RT-PCR (qRT-PCR) and Western blotting indicated that high glucose could increase the expression of A2B receptors in HUVECs, an effect that was inhibited by OMT. In addition, the results revealed that the expression of CCL5, IL-1beta and TNF-alpha was increased in the high-glucose group, and that the NO produced by HUVECs decreased due to hyperglycemia; however, co-culture with OMT or A2B siRNA abolished these effects. Meanwhile, the chemotaxis activity of monocytes to HUVECs cultured in high-glucose medium was enhanced 2.59-fold compared to the control cells. However, the inflammatory reactions in HUVECs were completely relieved by co-treatment with OMT or A2B siRNA. Moreover, the phosphorylation of p38 and ERK1/2 in HUVECs in the high-glucose group was significantly higher than that of the control group; these effects were reversed after co-treatment with OMT or A2B siRNA. CONCLUSION: OMT may protect the HUVECs from high glucose-induced cytotoxicity through inhibitting the expression of A2B receptor and inflammatory factors as well as decreasing the phosphorylation of p38 and ERK1/2. PMID- 29402838 TI - Antispasmodic Effect of Blackcurrant (Ribes nigrum L.) Juice and Its Potential Use as Functional Food in Gastrointestinal Disorders. AB - OBJECTIVE: The purpose of this study was to investigate the relaxative effects of blackcurrant juice on the gastrointestinal smooth muscle in vitro. MATERIALS AND METHODS: Berries of the blackcurrant cultivar Ometa were used for the preparation of the juice used. The spasmolytic activity of blackcurrant juice was tested on rat ileum isolated from male Wistar rats by monitoring its influence on spontaneous contractions, as well as contractions induced by potassium chloride (KCl), barium chloride (BaCl2), calcium chloride (CaCl2), and acetylcholine (Ach). The results are expressed as the mean +/- standard deviation obtained in 6 measurements and statistical significance was determined by the Student t test, with p < 0.05 taken as significant. RESULTS: The blackcurrant cultivar Ometa significantly reduced the frequency and the amplitude of spontaneous contractions (57.94 +/- 3.44%) and Ach-induced contractions (42.74 +/- 5.36%; p < 0.05) of the isolated rat ileum. Cumulative concentrations (0.01-3 mg/mL) of the Ometa juice also reduced contractions of the isolated rat ileum stimulated by KCl (51.46 +/- 6.87%), CaCl2 (57.54 +/- 6.47%), and BaCl2 (58.54 +/- 10.55%). The inhibitory effects of the juice were proportional to the applied concentration. CONCLUSION: The antispasmodic effect of Ometa cultivar shows that common gastrointestinal disorders could be treated by the functional food. PMID- 29402839 TI - Social Dimensions of Personal Growth following Widowhood: A Three-Wave Study. AB - BACKGROUND: Losing one's spouse is one of the most stressful life events in old age, yet research on positive consequences of overcoming critical life events describes experiences of personal growth for survivors. OBJECTIVE: Because prior studies conceptualized personal growth as a stable accomplishment of an individual, our study challenges this assumption by examining trajectories of personal growth and its links to two aspects of social support. We assume that personal growth is boosted by heightened levels of loss-related social support seeking during early years of widowhood. However, toward the later stages in the bereavement process, we expect personal growth to be fostered by perceived social embeddedness. DATA AND METHOD: Data stem from a survey on relationships in later life conducted in 2012, 2014, and 2016 in Switzerland. The final analytical sample consisted of 508 individuals aged 50+ years, who were on average 73 years old and widowed for about 3 years at baseline. Longitudinal explorative factor analyses yielded a 3-factorial solution for personal growth. Random-effects group specific growth curves were used to examine the trajectories of personal growth and its subdimensions, by different levels of loss-related social support seeking and embeddedness in a supportive network, over the first 8 years of widowhood. Our analyses included time-invariant and time-varying covariates. RESULTS: On average, our findings point to a stable trajectory of personal growth after having become widowed in later life. Group-specific analyses, however, showed different courses in the trajectories for specific subdimensions of personal growth - particularly for spiritual change and appreciation of life. Average marginal effects also yielded group differences by loss-related support seeking in the level of personal growth over time, which highlight the importance of social support seeking, rather than social embeddedness, at all stages of the bereavement process. CONCLUSION: Findings underline the importance of a longitudinal and linked-lives perspective on personal growth and point to different pathways regarding its various subdimensions. Future research should further examine the validity of personal growth scales for other populations and consider the possibility to experience personal growth already during the anticipation of a traumatic event (e.g., in the case of long-term caretaking). PMID- 29402840 TI - Elevations of Thrombotic Biomarkers in Hemoglobin H Disease. AB - BACKGROUND: Thalassemia is a group of hereditary hemoglobinopathies caused by decreased or absent synthesis of alpha and/or beta globin chains. Studies have shown that hypercoagulability and thrombosis are common clinical symptoms in beta thalassemia, especially beta-thalassemia intermedia, but little is known about in alpha-thalassemia. This study aims to examine phosphatidylserine (PS) levels, platelet activation, and coagulation markers in splenectomized (S) and nonsplenectomy (NS) patients with hemoglobin (Hb) H disease. METHODS: The NS group comprised 20 patients (median age 15.0 years, range, 14-16.5 years), and the S group consisted of 11 patients (median age 16.4 years, range, 14-19.9 years) with Hb H disease; the control group consisted of 20 normal subjects. Hematological parameters were collected. Flow cytometry was used to measure PS exposure on red blood cells. The levels of intercellular adhesive molecule (ICAM) 1, tumor necrosis factor alpha (TNFalpha), beta-thromboglobulin (TG) and prothrombin fragment 1 + 2 (F1.2) were determined using ELISA test kits. RESULTS: Significant increases in the levels of PS, ICAM-1, TNFalpha, beta-TG, and F1.2 were observed in both patient groups compared to normal controls (p < 0.01). CONCLUSION: This observation indicates blood coagulation, endothelial injury, chronic low-grade inflammation, platelet activation, and thrombin generation are present in Hb H disease; these findings merit further assessment in a larger prospective cohort to establish possible links with thrombotic manifestations. PMID- 29402842 TI - A Pooled Analysis of Pharmacokinetic Variability Information for Common Probe Substrates Used in Drug-Drug Interaction Studies. AB - Sample size estimates for drug-drug interaction (DDI) studies are often based on variability information from the literature or from historical studies, but small sample sizes in these sources may limit the precision of the estimates obtained. This project aimed to create an intra-subject variability library of the pharmacokinetic (PK) exposure parameters, area under the curve, and maximum plasma concentration, for probes commonly used in DDI studies. Data from 66 individual DDI studies in healthy subjects relating to 18 common probe substrates were pooled to increase the effective sample size for the identified probes by 1.5- to 9-fold, with corresponding improvements in precision of the intra-subject PK variability estimates in this library. These improved variability estimates will allow better assessment of the sample sizes needed for DDI studies in future. PMID- 29402841 TI - The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-beta1 in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients. AB - OBJECTIVE: To investigate the possible role of signal transducer and activator of transcription 5 (STAT5) in the pathogenesis of liver fibrosis in Egyptian patients with chronic hepatitis C (CHC) virus infection and its relation to hepatic stellate cells (HSC). SUBJECTS AND METHODS: Sixty-five patients (46 males and 19 females) were divided into 4 groups based on the severity of fibrosis as detected by Fibroscan as follows: F1, n = 15; F2, n = 21; F3, n = 13; and F4, n = 16. Twenty age- and gender-matched healthy persons volunteered as controls. The serum levels of STAT5, TGF-beta1, alpha-smooth muscle actin (alpha-SMA), fasting blood sugar, and fasting insulin, as well as homeostasis model assessment of insulin resistance (HOMA-IR), were determined and compared for all groups. The usefulness of the studied serum biomarkers for predicting liver fibrosis was evaluated using a receiver operating characteristic curve. RESULTS: Serum levels of STAT5 were significantly lower in patients compared to controls (9.69 +/- 5.62 vs. 14.73 +/- 6.52, p <= 0.001); on the contrary, TGF-beta1, alpha-SMA, and HOMA IR were significantly higher in patients compared to controls (mean: 1,796.04 vs. 1,636.94; 14.94 vs. 8.1; and 7.91 vs. 4.18; p <= 0.01 and 0.001, respectively). TGF-beta1 and alpha-SMA showed a progressive increase with advancing severity of hepatic fibrosis (mean TGF-beta1: 2,058.4 in F1-F2 and 1,583.8 in F3-F4, p <= 0.04; mean alpha-SMA: 13.59 in F1-F2 and 16.62 in F3-F4, p <= 0.05). STAT5 had a significant negative correlation with TGF-beta1 (p <= 0.001), while no correlation was detected with alpha-SMA (p <= 0.8). CONCLUSIONS: STAT5 may play a significant role in hepatic fibrogenesis through the induction of TGF-beta1 but not through the activation of hepatic stellate cells. PMID- 29402843 TI - Sensitive Detection of Atrial Fibrillation in Acute Stroke Patients by Short-Term Bedside Electrocardiography Monitoring Software Analysis. AB - BACKGROUND: Atrial fibrillation (AF) is an important cause of stroke. Continuous electrocardiography (ECG) monitoring with software-based analysis algorithms has been suggested to enhance the AF detection rate. We investigated the ability of stroke risk analysis (SRA) in the detection of AF in acute stroke patients. METHODS: Consecutive stroke patients numbering 1,153 were screened. Patients with cardioembolic stroke related to AF (n = 296, paroxysmal n = 63, persistent n = 233) and patients with cryptogenic stroke (n = 309) after standard diagnostic work-up (bedside ECG monitoring, ultrasound, transesophageal echocardiography, 24 h Holter ECG) received SRA during their stay at the Stroke Unit. Determination of AF risk by SRA in the patients with AF and in the patient group with cryptogenic stroke was assessed and compared. RESULTS: Median SRA monitoring analysis time was 16 h (range 2-206 h, interquartile range 10-36). In AF patients, SRA also detected a possible or definitive AF in 98%. The overall sensitivity of SRA to detect possible or definitive AF in patients with proven AF by standard diagnostic work up and cryptogenic stroke was 98%, specificity 27%, positive predictive value 56%, and the negative predictive value (NPV) was 92%. Area under ROC curve was 0.622. CONCLUSION: SRA was found to be highly sensitive to detect possible or definitive AF in clinical routine within a short monitoring time. However, low specificity and poor accuracy do not allow diagnosing AF by SRA alone, but with the high NPV compared to current diagnostic standard, it is a valid diagnostic tool to rule out AF. Thereby, SRA is a contribution to clarify stroke etiology. PMID- 29402844 TI - Chlormethine Hydrochloride is Not Inferior to Tacrolimus in Treating Steroid Resistant Nephrotic Syndrome. AB - BACKGROUND/AIMS: The present study aimed to explore the equivalence of CHL and tacrolimus (TAC), despite reports regarding the efficacy and safety of TAC in treating SRNS patients. METHODS: A retrospective cohort study of CHL or TAC treatment was performed by collecting the medical records of SRNS patients with a pathological classification of focal segmental glomurular sclerosis (FSGS) or membranous nephropathy (MN) from December 2008 to December 2014 in a 3A grade hospital in southern China. The treatment regimen includes 6 months of induction therapy and a subsequent 6 to 30 months of maintenance therapy, which were evaluated by the scheduled follow-up and the detection of proteinuria and serum creatinine levels. The treatment outcomes were classified as complete remission, partial remission or no remission. RESULTS: In a total of 146 SRNS patients, CHL treatment showed a higher proportion of complete remission (27.8% vs 14.9%) or partial remission (52.8% vs 37.8%) compared to TAC treatment (P < 0.10) at the stage of induction therapy. The CHL treatment of SRNS patients with FSGS showed better efficacy than treatment of the TAC group, but the difference of efficacy in the pathological type of MN between CHL and TAC group was not significant (P > 0.10). During maintenance therapy, the difference between the CHL and TAC groups was not significant in the SRNS patients with FSGS or MN (P > 0.10). In addition, the difference of adverse effects between CHL and TAC group was not significant (P > 0.10), although there was a slightly higher proportion of nausea and vomiting in the CHL group. CONCLUSION: The non-inferior efficacy of CHL treatment on the SRNS patients with FSGS or MN compared to TAC treatment, which highlighted CHL can be considered to be alternative treatment for SRNS patients in the clinical setting. PMID- 29402845 TI - Key Proteins Involved in Spheroid Formation and Angiogenesis in Endothelial Cells After Long-Term Exposure to Simulated Microgravity. AB - BACKGROUND/AIMS: Cardiovascular complications are common in astronauts returning from a prolonged spaceflight. These health problems might be driven by complex modulations of gene expression and protein synthesis in endothelial cells (ECs). Studies on the influence of microgravity on phenotype, growth pattern and biological processes of ECs can help to understand these complications. METHODS: We exposed ECs (EA.hy926) to a Random Positioning Machine (RPM). Proteins associated with cell structure, angiogenesis and endothelial dysfunction were investigated in distinct pools of multicellular spheroids (MCS), adherent cells (AD) and tubular structures (TS) formed after a 35-day RPM-exposure. RESULTS: Combining morphological and molecular approaches, we found AD, MCS and TS with changes in the synthesis and release of proteins involved in three-dimensional growth. Fibronectin and monocyte chemoattractant protein-1 (MCP-1) mRNAs and protein contents were elevated along with an increased secretion of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, MCP-1, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL) and regulated on activation, normal T cell expressed and secreted (RANTES) proteins in the culture supernatant as determined by multianalyte profiling technology. Together they form a network of interaction. CONCLUSIONS: These results show that a prolonged RPM-exposure of ECs induced TS and MCS formation. The factors VEGF, NGAL, IL-6, IL-8, MCP-1, VCAM 1, ICAM-1, fibronectin and RANTES seem to be affected when gravity is omitted. PMID- 29402846 TI - Rs1520220 and Rs2195239 Polymorphisms of IGF-1 Gene Associated with Histopathological Grades in IgA Nephropathy in Northwestern Chinese Han Population. AB - BACKGROUND/AIMS: Insulin-like growth factor-1 (IGF-1) plays important roles in cellular proliferation, differentiation, and growth. Previous studies showed that single-nucleotide polymorphisms (SNPs) of IGF-1 are associated with various diseases. This case-control study aimed to examine the relationship between IGF-1 polymorphisms and IgA nephropathy (IgAN) risk in a Chinese Han population. METHODS: We recruited 351 IgAN patients and 310 healthy controls from Northwestern China. Sequenom MassARRAY was utilized to examine the genotypes of two common IGF-1 SNPs (rs1520220 and rs2195239). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by the Chi square test to evaluate the associations between IGF-1 and IgAN. RESULTS: Our study demonstrated that IGF 1 gene rs1520220 and rs2195239 polymorphisms did not confer susceptibility to IgAN. We found no correlation between gender, blood pressure, proteinuria, eGFR, and IgAN in both SNPs. However, the rs1520220 and rs2195239 variants were correlated with M1 and E1 in patients with IgAN (M0/M1: CC vs. CG+GG: OR = 1.62, P = 0.04; E0/E1: CC vs. CG+GG: OR = 1.95, P = 0.004; GG vs. GC+CC: OR = 1.90, P = 0.004, respectively). CONCLUSION: These results indicate that IGF-1 gene polymorphisms play crucial roles in the histopathological progression of IgAN in the Chinese Han population. PMID- 29402847 TI - Extravascular CD3+ T Cells in Brains of Alzheimer Disease Patients Correlate with Tau but Not with Amyloid Pathology: An Immunohistochemical Study. AB - BACKGROUND: Strong genetic and epidemiological evidence points to a crucial role of the immune system in the development of Alzheimer disease (AD). CD3+ T lymphocytes have been described in brains of postmortem AD patients and in transgenic models of AD-like cerebral amyloidosis and tau pathology. However, the occurrence of T cells in AD brains is still controversial; furthermore, the relationship between T cells and hallmarks of AD pathology (amyloid plaques and neurofibrillary tangles) remains to be established. OBJECTIVES: We have studied the occurrence of T cells in postmortem hippocampi and mid frontal gyrus (MFG) samples of AD patients (Braak stage V-VI) and nondemented control subjects and correlated it with amyloid and tau pathology burden. METHODS: Confocal microscopy and bright-field immunohistochemistry were used to identify brain-associated T cells. Extravascular CD3+ T cells were quantified and compared to nondemented controls. In addition, numbers of extravascular CD3+ T cells were correlated with amyloid (6E10 staining) and tau pathology (AT8 staining) in the same sections. RESULTS: Several CD3+, extravascular T cells were observed in the brains of AD patients, mostly of the CD8+ subtype. AD hippocampi harbored significantly increased numbers of extravascular CD3+ T cells compared to nondemented controls. CD3+ T cells significantly correlated with tau pathology but not with amyloid plaques in AD samples. CONCLUSIONS: Our data support the notion of T-cell occurrence in AD brains and suggest that, in advanced stages of AD, T-cell extravasation is driven by tau-related neurodegenerative changes rather than by cerebral amyloidosis. T cells could be crucial for driving the amyloid independent phase of the AD pathology. PMID- 29402849 TI - Association between IL-13 Gene rs20541 Polymorphism and Glioma Susceptibility: A Meta-Analysis. AB - OBJECTIVE: We performed a meta-analysis to estimate the association between IL-13 gene rs20541 (R130Q) polymorphism and the susceptibility of glioma. PATIENTS AND METHODS: Potentially eligible studies published before February 1, 2016 were searched in 4 databases including PubMed, EMBASE, EBSCO, and Ovid. Odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were used to estimate the strength of relationship between the IL-13 gene rs20541 polymorphism and glioma susceptibility. Stata 11.0 software was used to perform the present meta-analysis. RESULTS: In total, 10 case-control studies with 13 datasets including 3,123 cases and 5,390 controls were identified. A significant increase in glioma susceptibility was found in the dominant model (AA + AG vs. GG: OR = 1.14, 95% CI 1.01-1.29; P = 0.031). Significantly decreasing glioma susceptibility was found for Asians in the heterozygote comparison (AG vs. GG: OR = 0.74, 95% CI 0.55-0.99; P = 0.042) and the allele contrast genetic model (A vs. G: OR = 0.67, 95% CI 0.47-0.96; P = 0.028). By contrast, in Caucasians, a significant increase in glioma susceptibility was found in the dominant model (AA + AG vs. GG: OR = 1.25, 95% CI 1.11-1.41; P = 0.000). CONCLUSION: There may be a weak association between the IL-13 gene rs20541 polymorphism and glioma susceptibility, and the associations may be different between ethnicities. PMID- 29402848 TI - Do Statins Affect Thyroid Volume and Nodule Size in Patients with Hyperlipidemia in a Region with Mild-to-Moderate Iodine Deficiency? A Prospective Study. AB - OBJECTIVE: The objective of this study was to assess the antiproliferative pleiotropic effects of statins on thyroid function, volume, and nodularity. SUBJECTS AND METHODS: One hundred and six hyperlipidemic patients were included in this prospective study. The 69 patients in the statin groups received atorvastatin (16 received 10 mg and 18 received 20 mg) or rosuvastatin (20 received 10 mg and 15 received 20 mg). The 37 patients in the control group, assessed as not requiring drugs, made only lifestyle changes. Upon admission and after 6 months, all patients were evaluated by ultrasonography as well as for lipid variables (total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides) and thyroid function and structure. RESULTS: After 6 months, no differences in thyroid function, thyroid volume, the number of thyroid nodules, or nodule size were observed in the statin and control groups. In a subgroup analysis, total thyroid volume had decreased more in patients receiving 20 mg of rosuvastatin than that in the control group (p < 0.05). Maximum nodule size had decreased more in those receiving 10 mg of rosuvastatin (p < 0.05). CONCLUSIONS: Our results suggest an association between rosuvastatin treatment and smaller thyroid volume and maximum nodule diameter; this could be attributable to the antiproliferative effects of statin therapy on the thyroid. PMID- 29402850 TI - Fetal Serum Metabolites Are Independently Associated with Gestational Diabetes Mellitus. AB - BACKGROUND/AIMS: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. METHODS: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. RESULTS: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32: 1 and proline still showed an independent association with GDM. CONCLUSIONS: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. PMID- 29402851 TI - Intracranial Arterial Calcification in Black Africans with Acute Ischaemic Stroke. AB - BACKGROUND: Intracranial arterial calcification (IAC), a recognized marker of atherosclerosis on cranial computed tomography (CT), is an independent risk factor for ischaemic stroke. This study aimed to determine the prevalence, distribution, severity, and associations of IAC in adults with acute ischaemic stroke (AIS) at the University College Hospital, Ibadan, Nigeria. METHODS: Cranial CT images of 130 consecutive adults who presented with AIS were acquired on a 64-slice multi-detector Toshiba Aquilion scanner and evaluated for IAC in bone window on Vitrea(r) software using a semi-quantitative scoring method for extent, thickness, and length of calcifications in the large intracranial arteries. Associations of IAC with clinical and laboratory data were determined by statistical analysis at p < 0.05. RESULTS: There were 71 males (54.6%), and the mean age of all patients was 63.0 +/- 13.2 years. Hypertension was the most common risk factor (83.1%). IAC was found in 121 patients (93.1%), predominantly in the carotid siphon (86.1%) followed by the intracranial vertebral arteries (9.3%), middle cerebral arteries (2.4%), basilar artery (1.2%), and the anterior cerebral arteries (1%). The burden of IAC ranged from mild (17.4%) to moderate (52.1%) to severe (30.6%). Age (p < 0.001), diastolic blood pressure (p = 0.037), and alcohol use (0.046) were significantly different among the patients with mild, moderate, and severe degrees of IAC. IAC was associated with age (p < 0.001), hypertension (p = 0.03), diabetes mellitus (p = 0.02), hyperlipidaemia (p = 0.04), and alcohol use (p < 0.001) but not with sex (p = 0.35). CONCLUSIONS: The burden of IAC is very high among native African patients with AIS and preferentially involves proximal inflow arteries. Therefore, the role of large vessel atherosclerosis in ischaemic stroke in native Africans should be explored in future multinational, multimodality studies. PMID- 29402852 TI - Cytomegalovirus Glycoprotein B Genotype Distribution in Italian Transplant Patients. AB - BACKGROUND: The cytomegalovirus (CMV) UL55 gene encodes for a glycoprotein implicated in virus pathogenesis. Based on UL55 polymorphism, CMV has been divided into 4 genotypes. Previous studies investigated the possible role of genotypes in the clinical outcome of infection in different categories of patients; however, few data are available, particularly in the transplant setting and Italian case records. METHODS: Phylogenetic analysis through a maximum likelihood tree was used to evaluate the prevalence and distribution of CMV genotypes in whole blood specimens from 47 transplant patients and investigate the relation with demographic and clinical features. RESULTS: Overall, 40.4% of patients were classified as single genotype (12.8% gB1, 23.4% gB2, 4.2% gB3); mixed genotypes were detected in 59.6%. Genotype 4 was detected only in mixed cases. In comparison to single genotypes, mixed genotypes were more frequently associated with a higher duration of DNA viremia and higher peak viral load. CONCLUSIONS: Mixed infections seem to be prevalent in Italian transplant patients; it is likely that mixed infections are more difficult to control by immunological response in comparison to single genotype infections. In this context, the genetic profile of infecting viruses and relation to clinical outcome should be investigated, also taking into account the CMV-specific cellular immune response. PMID- 29402853 TI - Oxaliplatin-Induced Acute ST Segment Elevation Mimicking Myocardial Infarction: A Case Report. AB - BACKGROUND: Oxaliplatin is a platinum-based antineoplastic agent used for the treatment of colorectal cancer and other gastrointestinal tumors. In combination with 5-fluorouracil for instance it is given in the so-called FOLFOX regimen in patients with colorectal cancer in the adjuvant as well as the palliative treatment setting. Cumulative neuropathy is a common cause of treatment discontinuation. Other toxicities are generally tolerable and managed by dose reductions and/or supportive treatment. While chronic cardiotoxic effects of cytostatics are well described, there are few reports on acute cardiotoxic reactions. CASE REPORT: The present case describes the sudden development of a transient coronary vasospasm in a 56-year-old male patient mimicking an acute ST segment elevation myocardial infarction during systemic treatment with oxaliplatin. CONCLUSION: Oxaliplatin is one of the most commonly used cytostatics for gastrointestinal cancer. Coronary vasospasm has never been reported for oxaliplatin. Thus it is crucial to keep in mind that acute cardiotoxic side effects may occur, even with chemotherapeutic agents without a prior evidence based description of such events. PMID- 29402854 TI - Feasibility, Validity, and Reliability of the Italian Pediatric Quality of Life Inventory Multidimensional Fatigue Scale for Adults in Inpatients with Severe Obesity. AB - OBJECTIVE: This study was aimed to examine the feasibility, validity, and reliability of the Italian Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQLTM MFS) for adult inpatients with severe obesity. METHODS: 200 inpatients (81% females) with severe obesity (BMI >= 35 kg/m2) completed the PedsQL MFS (General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue domains), the Fatigue Severity Scale, and the Center for Epidemiologic Studies Depression Scale immediately after admission to a 3-week residential body weight reduction program. A randomized subsample of 48 patients re-completed the PedsQL MFS after 3 days. RESULTS: Confirmatory factor analysis showed that a modified hierarchical model with two items moved from the Sleep/Rest Fatigue domain to the General Fatigue domain and a second-order latent factor best fitted the data. Internal consistency and test-retest reliabilities were acceptable to high in all scales, and small to high statistically significant correlations were found with all convergent measures, with the exception of BMI. Significant floor effects were found in two scales (Cognitive Fatigue and Sleep/Rest Fatigue). CONCLUSION: The Italian modified PedsQL MFS for adults showed to be a valid and reliable tool for the assessment of fatigue in inpatients with severe obesity. Future studies should assess its discriminant validity as well as its responsiveness to weight reduction. PMID- 29402855 TI - Vinflunine in Advanced Transitional Cell Cancer of the Urothelial Tract: A Potential Option for Maintenance Therapy? A Case Series. AB - INTRODUCTION: Vinflunine is a microtubule inhibitor approved in Europe as second line treatment of advanced transitional cell cancer of the urothelium (TCCU). The inability to continue with a first-line platinum-based regimen beyond 6 cycles suggested investigating the use of vinflunine as switch maintenance therapy in patients with response or stable disease after first-line therapy. METHODS: Patients with advanced TCCU and documented disease control after 3-6 cycles of first-line platinum-based chemotherapy received vinflunine maintenance therapy within 6 weeks of the last cycle. Our analysis aimed to examine the performance of vinflunine in terms of activity and safety in such a patient population. RESULTS: 28 consecutive patients were studied. After a median follow-up of 25 months, vinflunine was associated with a median progression-free survival of 9 months (range 4 to > 16 months) and a disease control rate of 64%; median overall survival was not reached. Treatment was well tolerated, with no unexpected safety events. The most common adverse events of grade >= 3 were neutropenia (21%) and constipation (14%); no toxicity-related death occurred. CONCLUSIONS: Our results suggest that vinflunine may be a suitable maintenance treatment option for TCCU patients who received a maximum of 6 cycles of platinum-based chemotherapy commonly used as first-line treatment. PMID- 29402857 TI - Association between COMT Polymorphism Val158Met and Opioid Consumption in Patients with Postoperative Pain: A Meta-Analysis. AB - BACKGROUND/AIMS: Several factors influencing postoperative pain and the effect of opioid analgesics have been investigated on an individual level. The aim of this study was to clarify the impact of catecholamine-O-methyltransferase (COMT) gene Val158Met on opioid consumption in postoperative patients. METHODS: A systematic review and meta-analysis of the literature up to September 30, 2017, were performed by using PubMed, Cochrane Library, ISI Web of Science, and Chinese National Knowledge Infrastructure (CNKI) database. The meta-analysis examined all studies involving the association between genetic polymorphisms of COMT Val158Met and opioid consumption during the acute postoperative period. RESULTS: Of the 153 identified studies, 23 studies were retrieved for systematic review and 10 studies were retrieved for meta-analysis. However, it was impossible to conduct meta-analysis on the association between COMT Val158Met polymorphism and postoperative pain because of heterogeneity of the data. Overall, meta-analysis showed that COMT Val/Met carriers consumed less opioid for analgesia within the first 24 hours after surgery (SMD = 0.14, 95% CI = [0.03, 0.25], P = 0.01) but not within 48 hours (SMD = 0.14, 95% CI = [0.08, 0.36], P = 0.21). There was no significant difference in opioid consumption between Val/ Val and Met/Met patients. CONCLUSION: Patients with Val/Met but not Met/Met allele variant consumed less opioid, though larger and better-designed studies are required to obtain an exclusive conclusion about the correlation between postoperative pain and COMT Val158Met polymorphism. PMID- 29402856 TI - Dynamic Thiol/Disulphide Homeostasis in Children and Adolescents with Non Autoimmune Subclinical Hypothyroidism. AB - OBJECTIVE: To evaluate the thiol/disulphide homeostasis in children with non autoimmune subclinical hypothyroidism (SHT). SUBJECTS AND METHODS: Thiol/disulphide homeosta sis, involving native thiol (SH), disulphide (SS), and total thiol (SS + SH), was evaluated in 60 children and adolescents who were negative for thyroid auto-antibodies (anti-thyroid peroxidase, anti thyroglobulin) and had a thyroid-stimulating hormone (TSH) value of > 5 mIU/L, and in 40 sex- and age-matched healthy control subjects who were negative for thyroid autoantibodies and had normal TSH levels. Lipid profiles and urine iodine levels were also determined. RESULTS: SH (466 +/- 32.8 vs. 462 +/- 32.1 MUmol/L p = 0.59), SH + SS (508 +/- 34.0 vs. 506 +/- 32.7 MUmol/L, p = 0.81), SS (21 +/- 5.5 vs. 22 +/- 5.8 MUmol/L, p = 0.41), SS/SH (4.5 +/- 1.2 vs. 4.8 +/- 1.3%, p = 0.36), SS/SH + SS (4.1 +/- 1.0 vs. 4.3 +/- 1.1%, p = 0.36) and SH/SH + SS (91 +/- 2.1 vs. 91 +/- 2.1%, p = 0.31) levels were similar in children with SHT and control subjects (p > 0.05). There was no difference between total cholesterol, triglyceride, and low-density lipoprotein levels in SHT patients and controls. No difference was detected between the patients with or without iodine deficiency in the SHT group in terms of thiol/disulphide homeostasis parameters. CONCLUSION: The status of dynamic thiol/disulphide homeostasis did not change in children and adolescents with non-autoimmune SHT. Future studies are needed for the evaluation of oxidative stress in patients with long-standing non-autoimmune SHT. PMID- 29402858 TI - Skeletal Extracellular Matrix Supports Cardiac Differentiation of Embryonic Stem Cells: a Potential Scaffold for Engineered Cardiac Tissue. AB - BACKGROUND/AIMS: Decellularized cardiac extracellular matrix (cECM) has been widely considered as an attractive scaffold for engineered cardiac tissue (ECT), however, its application is limited by immunogenicity and shortage of organ donation. Skeletal ECM (sECM) is readily available and shows similarities with cECM. Here we hypothesized that sECM might be an alternative scaffold for ECT strategies. METHODS: Murine ventricular tissue and anterior tibial muscles were sectioned into 300 mm-thick, and then cECM and sECM were acquired by pretreatment/SDS/TritonX-100 three-step-method. Acellularity and morphological properties of ECM was assessed. SECM was recellularized with murine embryonic stem cells (mESCs) or mESC-derived cardiomyocytes (mESC-CMs), and was further studied by biocompatibility assessment, immunofluorescent staining, quantitative real-time PCR and electrophysiological experiment. RESULTS: The relative residual contents of DNA, protein and RNA of sECM were comparable with cECM. The morphological properties and microstructure of sECM were similar to cECM. SECM supported mESCs to adhere, survive, proliferate and differentiate into functional cardiac microtissue with both electrical stimulated response and normal adrenergic response. Purified mESC-CMs also could adhere, survive, proliferate and form a sECM-based ECT with synchronized contraction within 6 days of recellularization. CONCLUSION: ECMs from murine skeletal muscle support survival and cardiac differentiation of mESCs, and are suitable to produce functional ECT patch. This study highlights the potential of patient specific of sECM to replace cECM for bioengineering ECT. PMID- 29402859 TI - Ventricular Arrhythmic Storm after Initiating Sacubitril/Valsartan. AB - OBJECTIVES: Sacubitril/valsartan was approved recently for the treatment of patients with heart failure and reduced ejection fraction. We present 6 cases of ventricular arrhythmia, that occurred shortly after sacubitril/valsartan initiation, that required drug withdrawal. Other potential triggering factors of electrical storm were ruled out and, from the arrhythmic perspective, all of the patients were stable in the previous year. Our aim is to describe the possible association of sacubitril/valsartan with arrhythmic storm. METHODS: This was an observational monocentric study performed in the first 7 months of sacubitril/valsartan commercialization in Spain (October 2016). All patients were included in the SUMA (Sacubitril/Varsartan Usado Ambulatoriamente en Madrid [Sacubitril/Valsartan Used in Outpatients in Madrid]) registry. Patients were consecutively enrolled on the day they started the drug. Ventricular arrhythmic storm was defined as >=2 episodes of sustained ventricular arrhythmia or defibrillator therapy application in 24 h. RESULTS: From 108 patients who received the drug, 6 presented with ventricular arrhythmic storm (5.6%). Baseline characteristics were similar in the patients with and without ventricular arrhythmic storm. The total number of days that sacubitril/valsartan was administered to each patient was 5, 6, 44 (8 since titration), 84, 93, and 136 (105 since titration), respectively. CONCLUSIONS: Our data are not enough to infer a cause-and-effect relationship. Further investigations regarding a potential proarrhythmic effect of sacubitril/valsartan are probably needed. PMID- 29402860 TI - Effect of Sedative-Hypnotic Medicines on Mortality in Peritoneal Dialysis Patients with Sleep Disorders: A Retrospective Cohort Study. AB - BACKGROUND: Sedative-hypnotic medication is widely used among continuous ambulatory peritoneal dialysis (CAPD) patients with sleep disorders; however, its effect on mortality has rarely been investigated. METHODS: Logistic regression was employed to identify factors associated with sedative-hypnotic medication, whose effect on mortality was evaluated by Cox proportional hazards models. RESULTS: A total of 146 CAPD patients with sleep disorders were recruited, of which 46 patients (31.5%) used either benzodiazepines or zolpidem. Sedative hypnotic medication was more frequently used by older patients and those with longer duration of CAPD therapy and there was no significant association between sedative-hypnotic medicines and all-cause mortality after adjusting for age, gender, diabetes, cardiovascular disease, and duration of CAPD. CONCLUSION: Sedative-hypnotic medication was more often used by older patients and patients with a longer duration of CAPD. There was no association between these agents and all-cause mortality in CAPD patients with sleep disorders. PMID- 29402861 TI - Prognostic Value of miR-375 for Survival Outcomes in Various Cancers: A Systematic Review and Meta-Analysis. AB - BACKGROUND: miR-375 plays a role in tumor progression; however, its potential as a prognostic factor in cancer remains unclear. This meta-analysis assessed the value of miR-375 as a global prognostic biomarker in human cancer. METHODS: A systematic literature review was performed to retrieve publications with relevant survival data. Pooled hazard ratios (HRs) were calculated for low miR-375 expression. Publication bias was examined. RESULTS: Data were extracted from 11 studies of 1,797 patients (low expression in 769 cases; high in 1,028 cases). The pooled HR for overall/cumulative survival (OS/CS) was 1.90 (95% confidence interval (CI) 1.57-2.29) and the pooled HR for disease-free, recurrence-free or progression-free survival (DFS/RFS/PFS) was 1.93 (95% CI 1.39-2.67), indicating low miR-375 expression was associated with significantly poorer outcomes compared to normal/high miR-375 expression. Subgroup analysis revealed miR-375 might be a good prognostic factor in cancer, regardless of population, sample type, and cancer type. The prognostic value of miR-375 in non-Chinese patients was particularly high (pooled HR > 2). CONCLUSION: Low miR-375 expression could represent a valuable prognostic marker in various cancers. Circulating miR-375 levels may provide a useful non-invasive, practical prognostic biomarker. However, the prognostic value of miR-375 in specific cancer types remains unclear; further studies are warranted. PMID- 29402862 TI - Four-Week Strategy-Based Training to Enhance Prospective Memory in Older Adults: Targeting Intention Retention Is More Beneficial than Targeting Intention Formation. AB - BACKGROUND: So far, training of prospective memory (PM) focused on very short instances (single sessions) and targeted the intention-formation phase only. OBJECTIVE: We aimed to compare the effectiveness of 2 different 4-week strategy based PM training types, namely imagery training (targeting the encoding of the PM intention in the intention-formation phase) versus rehearsal training (targeting the maintenance of the PM intention in the intention-retention phase) in older adults. METHODS: We used a 4-week training protocol (8 sessions in total, 2 sessions per week). From the 44 participants, 21 were randomly assigned to the imagery training (vividly imagining a mental picture to memorize the connection between the PM cue words and related actions during intention formation) and 23 to the rehearsal training (rehearsing the PM cue words during intention retention). The criterion PM task was assessed before and after the training. RESULTS: Comparing the effectiveness of both training types, we found a significant time by training type interaction on PM accuracy in terms of PM cue detection, F(1, 42) = 6.07, p = 0.018, eta2p = 0.13. Subsequent analyses revealed that the rehearsal training was more effective in enhancing PM accuracy in terms of PM cue detection than the imagery training. CONCLUSION: Strategy-based PM training in older adults targeting the maintenance of the PM intention in the intention-retention phase may be more effective in enhancing PM accuracy in terms of PM cue detection than the strategy targeting the encoding of the PM intention in the intention-formation phase. This suggests that for successful prospective remembering, older adults may need more support to keep the PM cues active in memory while working on the ongoing task than to initially encode the PM intention. PMID- 29402863 TI - Antibacterial Activity, Cytotoxicity, and the Mechanism of Action of Bacteriocin from Bacillus subtilis GAS101. AB - OBJECTIVE: The aim of this study was to purify and characterize bacteriocin from the soil isolate Bacillus subtilis GAS101, and to determine its antimicrobial as well as antibiofilm potential. The purified bacteriocin was further analyzed and evaluated for mammalian cell cytotoxicity and the possible mode of action. MATERIAL AND METHODS: Bacteriocin from B. subtilis GAS101 (an animal husbandry soil isolate) was partially purified and checked for antimicrobial and antibiofilm activity against gram-positive and gram-negative bacteria. The molecular weight of bacteriocin was determined using tricine SDS-PAGE gel. The stability of bacteriocin was investigated at various temperatures and pH levels, and its sensitivity towards 8 enzymes and 6 chemicals was determined. Cytotoxicity analysis was performed on a Vero cell line by a tetrazolium dye based assay. Scanning electron microscopy (SEM) of bacteriocin-treated bacteria was carried out to determine the possible mode of action. RESULTS: Bacteriocin from B. subtilis GAS101 was a potential inhibitor of both the indicator organisms (Staphylococcus epidermidis and Escherichia coli), and had a molecular weight of approximately 6.5 kDa. An in situ gel assay showed a zone of inhibition corresponding to the estimated protein band size. Bacteriocin was stable and showed antibacterial activity in broad ranges of temperature (30-121 degrees C) and pH (2-12). It was sensitive to 4 proteolytic enzymes, which indicated its proteinaceous nature. Bacteriocin showed > 70% cell viability on the mammalian Vero cell line. SEM depicted that the bacteriocin was able to disrupt the bacterial cell membrane as its probable mode of action. CONCLUSION: Thermostable and pH-tolerant bacteriocin from B. subtilis GAS101, of about 6.5 kDa, showed broad-spectrum antimicrobial and antibiofilm activity. PMID- 29402865 TI - Concluding Remarks - From Bench to Bed. PMID- 29402864 TI - Alpha-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood Retinal Barrier Breakdown and Vascular Leakage via MC4R. AB - BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of alpha-Melanocyte stimulating hormone (alpha-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the alpha-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). METHODS: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with alpha-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of alpha-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the alpha-MSH's anti hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating alpha-MSH's protection. RESULTS: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by alpha-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in alpha-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by alpha-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in alpha-MSH-treated diabetic retinas. Mechanistically, alpha-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. CONCLUSIONS: This study showed previously undescribed protective effects of alpha-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro inflammatory factors and augmenting tight junctions. alpha-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells. PMID- 29402866 TI - Paediatric Endocrinology Subspecialty - The European Map, 55 Years Later. PMID- 29402867 TI - Focal Encephalitis, Meningitis, and Acute Respiratory Distress Syndrome Associated with Influenza A Infection. AB - OBJECTIVE: To present a case of influenza A infection complicated with focal encephalitis, meningitis, and acute respiratory distress syndrome. CLINICAL PRESENTATION AND INTERVENTION: A 35-year-old woman presented with fever, headache, cough, and body aches. Seizures, altered consciousness, and dyspnea occurred later. A nasopharyngeal swab revealed a positive reaction for the influenza A antigen. Magnetic resonance imaging scans showed a T2 prolongation in the left frontoparietal subcortical white matter, which was consistent with focal encephalitis. She recovered after treatment with oseltamivir and antibiotics. CONCLUSION: This case report highlights focal encephalitis with concomitant pulmonary complications after influenza A infection. PMID- 29402868 TI - Change of Peripheral Blood Treg/Thl7 in Cognitive Impairment with Chronic Renal Failure Patients. AB - BACKGROUND/AIMS: To investigate the changes in peripheral blood Treg/Th17 cell balance and its significance in patients with chronic renal failure (CRF) and cognitive impairment. METHODS: A total of 71 patients with CRF were enrolled as a study group. The patients were divided into a cognitive impairment group and a normal cognitive function group according to the Mini-Mental State Examination (MMSE). Peripheral blood Treg and Th17 cells were analyzed by flow cytometry and their relevant cytokines (IL-17, IL-10 and TGF-beta) and other biochemical indicators, including C-reactive protein (CRP) and IL-6, were determined by ELISA. RESULTS: Thepatients with both CRF and cognitive impairment were older than the cognitive normal groups. Peripheral blood Treg cells by Flow cytometry (the CRF cognitive impairment group 5.57+/-1.3%, CRF group with normal cognitive function 7.5 +/- 0.9% and normal control group 9.7 +/- 1.7%,P<0.05) and its related cytokines (IL-10 and TGF-beta) by ELISA detection were lower in the group with cognitive impairment than in the group without cognitive impairment ( IL-10, 7.4+/-4.2 pg/mL, 13.8+/-3.9 pg/mL, 18.3+/-3.2 pg/mL; TGF-beta 335.6+/-175.3 pg/mL, 512.7 +/- 114.6 pg/mL, 953.8+/-373.4 pg/mL P < 0.05, respectively).However, Th17 cell numbers (the CRF cognitive impairment group 3.3 +/- 0.7%, CRF group with normal cognitive function2.2 +/- 0.5% and normal control group 1.5 +/- 0.3%),and cytokine levels (IL-17, IL-6 and CRP) were higher in the group with cognitive impairment IL-6 (21.3 +/- 5.1 pg/mL), IL-17 (18.5 +/- 4.2 pg/mL) and CRP (20.3 +/- 5.9 mg/L) in the CRF group with cognitive impairment when compared with the CRF group and normal cognitive function (12.2 +/- 4.5 pg/mL, 12.1 +/- 3.7 pg/mL and 13.5 +/- 4.6 mg/L, respectively) or the normal control group (9.2 +/- 5.8 pg/mL, 7.4 +/- 2.6 pg/mL and 3.2 +/- 1.3 mg/L, respectively, P<0.05). The frequencies of Treg in patients with CRF were positively correlated with the MMSE scores ((r = 0.518, P < 0.05), but the Th17 numbers were negatively correlated (r = -0.435, P < 0.05). CONCLUSION: An imbalance of peripheral blood Treg/Th17 cells is associated with cognitive impairment in patients with CRF. PMID- 29402869 TI - Treatment of Hypertension in Renal Transplant Recipients in Four Independent Cross-Sectional Analyses. AB - BACKGROUND/AIMS: This retrospective study analysed hypertension management and adherence to blood pressure (BP) targets among renal transplant recipients (RTRs) under specialized care in the Outpatient Transplantation Unit in the Department of Nephrology, Transplantology and Internal Medicine at Gdansk University Hospital. METHODS: Medical records of 101, 316, 639 and 818 RTRs diagnosed with hypertension, who received outpatient care in 2001, 2006, 2011 and 2014, respectively were analysed in four independent cross-sectional surveys. All RTRs received antihypertensive regimens. RESULTS: The overall most commonly used antihypertensive agents were beta-blockers (BB) (range 66.3-82.5%) followed by calcium channel blockers (CCB) (range 52.8-64.2%). Whilst a significant, upward tendency of BB usage (p<0.01) was observed, CCB usage (p<0.001) displayed a downward tendency as a first line therapy in the subsequent years. The average number of antihypertensive agents used per patient increased significantly from 2.24+/-1.03 in 2001 to 2.55+/-1.25 in 2014 (p<0.05). The most frequently used combination of hypotensive therapy consisted of two or three antihypertensive drugs depending on the survey. The most common two drug combination consisted of BB and CCB followed by BB accompanied by angiotensin converting enzyme inhibitors. A significant, upward tendency in the use of four (p<0.001) and five (p<0.05) antihypertensive drugs simultaneously, was observed in subsequent years. The target values of BP i.e. <140/90 mmHg were accomplished in 47, 58, 60 and 46% of RTRs in subsequent years. In a secondary - stratified analysis of data from 2014, younger patients (p<0.05), patients with better graft function (p<0.001), patients treated with a higher number of antihypertensive agents (p<0.001) and those not treated with BB (p<0.01) were shown to reach the BP target of below 140/90 mmHg more often. CONCLUSION: The study showed intensification of hypertension treatment in RTRs in subsequent years with BB assuming a dominant role. PMID- 29402870 TI - Mentalization-Based Treatment for Concurrent Borderline Personality Disorder and Substance Use Disorder: A Randomized Controlled Feasibility Study. AB - AIMS: There is a scarcity of clinical trials on psychological treatments for concurrent borderline personality disorder (BPD) and substance use disorder (SUD). Mentalization-based treatment (MBT) have shown efficacy in several trials on BPD. The aim of the present study was to examine the feasibility and effectiveness of MBT for concurrent BPD and SUD. METHODS: Patients (n = 46) with concurrent BPD and SUD were randomized either to MBT in combination with SUD treatment (n = 24) or to SUD treatment alone (n = 22). Outcome was measured after 18 months using objective data, as well as interview and self-report measures. RESULTS: There was no significant difference between the groups on any outcome variable. No suicide attempts occurred in the MBT group in contrast to 4 suicide attempts that occurred in the control group - a difference that did not reach statistical significance (p = 0.06). A majority of the therapists did not show sufficient MBT adherence and quality. CONCLUSION: MBT for patients with concurrent BPD and SD does not appear to be harmful; on the other hand, it is possibly helpful in reducing the risk involved in suicide attempts. PMID- 29402872 TI - Exercise Training Restores the Cardiac Microrna-16 Levels Preventing Microvascular Rarefaction in Obese Zucker Rats. AB - OBJECTIVE: To evaluate the effects of aerobic exercise training (AET) on cardiac miRNA-16 levels and its target gene VEGF related to microvascular rarefaction in obese Zucker rats (OZR). METHODS: OZR (n = 11) and lean (L; n = 10) male rats were assigned into 4 groups: OZR, trained OZR (OZRT), L and trained L (LT). Swimming exercise training lasted 60 min, 1*/day/10 weeks, with 4% body weight workload. Cardiac angiogenesis was assessed by histological analysis (periodic acid-Schiff) by calculating the capillary/fiber ratio. The protein expressions of VEGF, VEGFR2, and CD31 were evaluated by western blot. The expression of miRNA-16 was evaluated by real-time PCR. RESULTS: Heart rate decreased in the trained groups compared to sedentary groups. The cardiac capillary/fiber ratio was reduced in OZR compared to L, LT and OZRT groups, indicating that aerobic exercise training (AET) was capable of reversing the microvascular rarefaction in the obese animals. miRNA-16 expression was increased in OZR compared to L, LT and OZRT. In contrast, its target, VEGF protein expression was 24% lower in OZR compared to L group, which has been normalized in OZRT group. VEGFR2 protein expression was increased in trained groups compared to their controls. CD31, a endothelial cells marker, showed increased expression in OZRT compared to OZR, indicating greater vascularization in OZRT group. CONCLUSION: AET induced cardiac angiogenesis in obese animals. This revascularization is associated with a decrease in miRNA-16 expression permissive for increased VEGF protein expression, suggesting a mechanism for potential therapeutic application in vascular diseases. PMID- 29402871 TI - Oral Health and Brain Injury: Causal or Casual Relation? AB - BACKGROUND: To systematically review the current literature investigating the association between oral health and acquired brain injury. METHODS: A structured search strategy was applied to PubMed, Embase, Web of Science, and CENTRAL electronic databases until March 2017 by 2 independent reviewers. The preferred reporting items for systematic review and meta-analysis guidelines were used for systematic review. RESULTS: Even though the objective was to assess the association between oral health and acquired brain injury, eligible studies focused solely on different forms of stroke and stroke subtypes. Stroke prediction was associated with various factors such as number of teeth, periodontal conditions (even after controlling for confounding factors), clinical attachment loss, antibody levels to Aggregatibacter actinomycetemcomitans and Prevotella intermedia. The literature showed no consensus on the possible association between gingivitis and stroke. Patients with stroke generally had poorer oral hygiene practices and oral health. Dental prophylaxis and professional intervention reduced the incidence of stroke. CONCLUSIONS: Overall, oral health and stroke were related. Periodontitis and tooth loss were independently associated with stroke. However, prevention and timely intervention may reduce the risk of stroke. Stroke was the main cerebral lesion studied in the literature, with almost no publications on other brain lesions. PMID- 29402874 TI - Rational Approaches Targeting the Prevention of Cardiovascular Calcification: The Evolving Field of Osteocardiology. PMID- 29402873 TI - Repeated Dexamethasone Intravitreal Implant for the Treatment of Diabetic Macular Oedema Unresponsive to Anti-VEGF Therapy: Outcome and Predictive SD-OCT Features. AB - PURPOSE: To investigate dexamethasone intravitreal implant 0.7 mg (DEX implant) for the treatment of diabetic macular oedema (DME) refractory to anti-vascular endothelial growth factor (anti-VEGF) therapy and evaluate predictive factors. METHODS: Two-centre retrospective interventional case series, including 40 eyes of 31 patients treated with DEX implant for at least 2 consecutive cycles. RESULTS: Mean +/- SD intervals from implantation to recurrence in the first (4.2 +/- 1.0 months) and second cycles (4.0 +/- 0.9 months) were not significantly different. Best corrected visual acuity improved significantly (p < 0.001) by 7.0 +/- 8.4 letters from baseline to month 2, and by 5.1 +/- 6.9 letters between the first and second cycles. Central retinal thickness reduction 2 months after implantation was greater after the first (-194 +/- 172 um) than the second cycle (-134 +/- 150 um). Ellipsoid zone-external limiting membrane (EZ-ELM) disruption score decreased from 1.39 +/- 1.16 at baseline to 1.24 +/- 1.16 (p = 0.0832) after cycle 1 and remained stable 2 months after cycle 2. Eyes with persisting severe EZ-ELM disruption (score >2, n = 10) 2 months after the first DEX implant showed significantly (p = 0.0153) smaller visual acuity (VA) gains than eyes with less severe (score <=2) EZ-ELM disruption. CONCLUSION: Repeated intravitreal DEX injections with average intervals of 4 months are valuable in patients with DME refractory to anti-VEGF therapy. Disorganization of outer retinal layers (EZ-ELM) may predict smaller VA gains if evaluated after initial reduction of macular oedema. PMID- 29402875 TI - Effect of Transversus Abdominis Plane Block on Postoperative Pain after Colorectal Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: To assess the analgesic efficacy of transversus abdominis plane (TAP) block in patients undergoing colorectal surgery (CRS). MATERIALS AND METHODS: The databases of PubMed, ISI Web of Science, and Embase were searched, and randomized controlled studies (RCTs) that compared TAP block to control for relief of postoperative pain in patients who underwent CRS were included. Outcomes, including postoperative pain at rest and with movement, morphine use, postoperative nausea and vomiting, and the length of hospital stay, were analyzed using STATA software. The weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) or relative risk with 95% CI were used to present the strength of associations. RESULTS: A total of 7 RCTs with 511 patients were included. The results of this study suggested that TAP block significantly relieved postoperative pain during postanesthetic recovery after CRS at rest and during movement (WMDs were -0.98 [95% CI -1.57 to -0.38] and -0.68 [-1.07 to 0.30], respectively), and also decreased pain intensity during movement 24 h after CRS (WMD: -0.57 [95% CI -1.06 to -0.08]). TAP block significantly reduced opioid consumption within 24 h when compared to controls, with a WMD of 15.66 (95% CI -23.93 to -7.39). However, TAP block did not shorten the length of hospital stay. CONCLUSIONS: TAP block was an effective approach for relief of postoperative pain and reduced postoperative consumption of morphine. More RCTs with large sample sizes are required to confirm these findings. PMID- 29402876 TI - Reporting of Adverse Drug Reactions in Primary Care Settings in Kuwait: A Comparative Study of Physicians and Pharmacists. AB - OBJECTIVE: To investigate and compare knowledge, attitudes, and practices regarding pharmacovigilance (PV) and the reporting of adverse drug reactions (ADR) among physicians and pharmacists in primary care settings. SUBJECTS AND METHODS: A cross-sectional study was conducted, in which a validated self administered questionnaire was distributed to 386 physicians and 197 pharmacists in 38 primary care clinics in Kuwait. Categorical variables were described using numbers and percentages. The Pearson chi2 test, Fisher exact test, and Mann Whitney U test were used as appropriate. p < 0.05 was considered statistically significant. RESULTS: Of the 583 questionnaires distributed, 485 were completed (by 318 physicians and 167 pharmacists), giving an overall response rate of 83.2%. A total of 52.8% (n = 256) and 70.5% (n = 341) of the study participants were knowledgeable about the definitions of PV and ADR, respectively, with pharmacists demonstrating significantly better knowledge of PV (n = 105/167 vs. 151/318, i.e., 62.9 vs. 47.5%; p < 0.001) and purpose (n = 123/167 vs. 177/318, i.e., 74.1 vs. 55.7%; p < 0.001). However, the majority (n = 434/485; 89.4%) were not aware of an ADR reporting system in Kuwait. Almost every participant (n = 474/485; 97.7%) thought it was necessary to report ADR. However, significantly fewer physicians than pharmacists (n = 248/318 vs. 147/167, i.e., 78.0 vs. 88.0%; p < 0.01) believed that ADR reporting was a professional obligation. Only 27.8% (n = 133/485) had reported ADR, with pharmacists having reported significantly fewer than physicians (n = 35/167 vs. 98/318, i.e., 21.7 vs. 30.8%; p = 0.036). CONCLUSIONS: This study indicated that the attitude was positive but there was suboptimal knowledge and poor practice among primary care physicians and pharmacists with regard to ADR reporting. Targeted training about ADR reporting while ensuring a robust regulatory framework would encourage ADR reporting practices in the primary health care setting in Kuwait. PMID- 29402877 TI - Functional Neuroanatomy of Secondary Self-Injurious Behavior. AB - BACKGROUND: Secondary self-injurious behavior (SSIB) is underreported and predominantly not associated with suicide. In both adults and children, SSIB can cause intractable self-harm and is associated with a variety of clinical disorders, particularly those involving dysfunctional motor control. METHODS: We performed a literature review evaluating the clinical efficacy of deep-brain stimulation (DBS) as modulating SSIB observations and review current progress in preclinical SSIB animal studies. RESULTS: Neuromodulation is an effective therapeutic option for several movement disorders. Interestingly, this approach is emerging as a potentially effective treatment for movement disorder-associated SSIB (secondary); however, it is important to understand the neuroanatomy, clinical appraisal, and outcome data when considering surgical therapy for SSIB. CONCLUSION: The current review examines the literature encompassing animal models and human case studies while identifying existing hypotheses from cytoarchitectonic-based targeting to neurotransmitter-based pathways. This review also highlights the need for awareness of an underrecognized pathology that may be amenable to DBS. PMID- 29402878 TI - Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression. AB - BACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm3. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used. PMID- 29402879 TI - Effects of High-Frequency Repetitive Transcranial Magnetic Stimulation Combined with Task-Oriented Mirror Therapy Training on Hand Rehabilitation of Acute Stroke Patients. AB - BACKGROUND Impairments of hand function make it difficult to perform daily life activities and to return to work. The aim of this study was to investigate the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) combined with task-oriented mirror therapy (TOMT) on hand rehabilitation in acute stroke patients. MATERIAL AND METHODS Twenty subacute stroke patients in the initial stages (<3 months) participated in the study. Subjects were allocated to 2 groups: the experimental group received HF-rTMS + TOMT and the control group received HF-rTMS. TOMT training was conducted in 10 sessions over 2 weeks for 30 min. rTMS was applied at a 20 Hz frequency over the hand motor area in the cortex of the affected hemisphere for 15 min. Outcomes, including motor-evoked potential (MEP), pinch grip, hand grip, and box and block test, were measured before and after training. RESULTS Significant improvements in the MEP and hand function variables were observed in both groups (p<0.05). In particular, hand functions (pinch grip and box and block test) were significantly different between the 2 groups (p<0.05). CONCLUSIONS HF-rTMS combined with TOMT had a positive effect on hand function and can be used for the rehabilitation of precise hand movements in acute stroke patients. PMID- 29402880 TI - Adenocarcinoma in a Blind Loop of the Ileum 53 Years After an Ileotransversostomy Procedure. AB - BACKGROUND Primary small bowel cancer is a rare malignancy; the common histopathological types are carcinoid and adenocarcinoma. Inflammatory bowel diseases and familial adenomatous polyposis are known risk factors for small bowel cancer. Additionally, cases of surgery-induced small bowel adenocarcinoma are sometimes reported after ileostomy. CASE REPORT A 84-year-old woman, who had undergone ileotransversostomy for intestinal obstruction due to postoperative adhesion following appendectomy at the age of 31 years, was referred to our hospital for further examination after experiencing abdominal pain in the right lower quadrant for 2 weeks. Laboratory data showed elevated serum levels of carcinoembryonic antigen (CEA, 102.9 ng/ml) and carbohydrate antigen 19-9 (CA19 9, 104 U/ml). Enhanced computed tomography (CT) revealed a 10-cm mass in the terminal ileum and a distention of the ileum and colon in the blind loop, with retention of feces. The patient was suspected of having ileal cancer by preoperative examination; therefore, right hemicolectomy with en bloc resection was performed. The tumor was histopathologically diagnosed as a well differentiated and mucinous adenocarcinoma of the ileum. At over 12 months after surgery, tumor recurrence had not been observed. CONCLUSIONS Difficulties in diagnosis can cause delays in treatment and lead to poor prognosis, mainly because tumors in the small bowel rarely cause clinical symptoms. Adenocarcinoma of the ileum should be considered in postoperative patients with ileotransversostomy. PMID- 29402881 TI - Tunable metal-insulator transition, Rashba effect and Weyl Fermions in a relativistic charge-ordered ferroelectric oxide. AB - Controllable metal-insulator transitions (MIT), Rashba-Dresselhaus (RD) spin splitting, and Weyl semimetals are promising schemes for realizing processing devices. Complex oxides are a desirable materials platform for such devices, as they host delicate and tunable charge, spin, orbital, and lattice degrees of freedoms. Here, using first-principles calculations and symmetry analysis, we identify an electric-field tunable MIT, RD effect, and Weyl semimetal in a known, charge-ordered, and polar relativistic oxide Ag2BiO3 at room temperature. Remarkably, a centrosymmetric BiO6 octahedral-breathing distortion induces a sizable spontaneous ferroelectric polarization through Bi3+/Bi5+ charge disproportionation, which stabilizes simultaneously the insulating phase. The continuous attenuation of the Bi3+/Bi5+ disproportionation obtained by applying an external electric field reduces the band gap and RD spin splitting and drives the phase transition from a ferroelectric RD insulator to a paraelectric Dirac semimetal, through a topological Weyl semimetal intermediate state. These findings suggest that Ag2BiO3 is a promising material for spin-orbitonic applications. PMID- 29402883 TI - Publisher Correction: Electric-field control of ferromagnetism through oxygen ion gating. AB - In the original version of this Article, Figs. 4c and 4d contained incorrectly sized error bars. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29402882 TI - Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes. AB - The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29402884 TI - Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes. AB - Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug-target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors. PMID- 29402885 TI - Transcriptional decomposition reveals active chromatin architectures and cell specific regulatory interactions. AB - Transcriptional regulation is tightly coupled with chromosomal positioning and three-dimensional chromatin architecture. However, it is unclear what proportion of transcriptional activity is reflecting such organisation, how much can be informed by RNA expression alone and how this impacts disease. Here, we develop a computational transcriptional decomposition approach separating the proportion of expression associated with genome organisation from independent effects not directly related to genomic positioning. We show that positionally attributable expression accounts for a considerable proportion of total levels and is highly informative of topological associating domain activities and organisation, revealing boundaries and chromatin compartments. Furthermore, expression data alone accurately predict individual enhancer-promoter interactions, drawing features from expression strength, stabilities, insulation and distance. We characterise predictions in 76 human cell types, observing extensive sharing of domains, yet highly cell-type-specific enhancer-promoter interactions and strong enrichments in relevant trait-associated variants. Overall, our work demonstrates a close relationship between transcription and chromatin architecture. PMID- 29402886 TI - Creation of a long-acting nanoformulated dolutegravir. AB - Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, a long-acting parenteral DTG was created through chemical modification to improve treatment outcomes. A hydrophobic and lipophilic modified DTG prodrug is encapsulated into poloxamer nanoformulations (NMDTG) and characterized by size, shape, polydispersity, and stability. Retained intracytoplasmic NMDTG particles release drug from macrophages and attenuate viral replication and spread of virus to CD4+ T cells. Pharmacokinetic tests in Balb/cJ mice show blood DTG levels at, or above, its inhibitory concentration90 of 64 ng/mL for 56 days, and tissue DTG levels for 28 days. NMDTG protects humanized mice from parenteral challenge of the HIV-1ADA strain for two weeks. These results are a first step towards producing a long-acting DTG for human use by affecting drug apparent half-life, cell and tissue drug penetration, and antiretroviral potency. PMID- 29402887 TI - Elucidation of the origin of chiral amplification in discrete molecular polyhedra. AB - Chiral amplification in molecular self-assembly has profound impact on the recognition and separation of chiroptical materials, biomolecules, and pharmaceuticals. An understanding of how to control this phenomenon is nonetheless restricted by the structural complexity in multicomponent self assembling systems. Here, we create chiral octahedra incorporating a combination of chiral and achiral vertices and show that their discrete nature makes these octahedra an ideal platform for in-depth investigation of chiral transfer. Through the construction of dynamic combinatorial libraries, the unique possibility to separate and characterise each individual assembly type, density functional theory calculations, and a theoretical equilibrium model, we elucidate that a single chiral unit suffices to control all other units in an octahedron and how this local amplification combined with the distribution of distinct assembly types culminates in the observed overall chiral amplification in the system. Our combined experimental and theoretical strategy can be applied generally to quantify discrete multi-component self-assembling systems. PMID- 29402889 TI - Disentangling entanglements in biopolymer solutions. AB - Reptation theory has been highly successful in explaining the unusual material properties of entangled polymer solutions. It reduces the complex many-body dynamics to a single-polymer description, where each polymer is envisaged to be confined to a tube through which it moves in a snake-like fashion. For flexible polymers, reptation theory has been amply confirmed by both experiments and simulations. In contrast, for semiflexible polymers, experimental and numerical tests are either limited to the onset of reptation, or were performed for tracer polymers in a fixed, static matrix. Here, we report Brownian dynamics simulations of entangled solutions of semiflexible polymers, which show that curvilinear motion along a tube (reptation) is no longer the dominant mode of dynamics. Instead, we find that polymers disentangle due to correlated constraint release, which leads to equilibration of internal bending modes before polymers diffuse the full tube length. The physical mechanism underlying terminal stress relaxation is rotational diffusion mediated by disentanglement rather than curvilinear motion along a tube. PMID- 29402888 TI - Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor. AB - The two highly homologous subtypes of stimulatory G proteins Galphas (Gs) and Galphaolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction. PMID- 29402890 TI - Beclin1 circulating levels and accelerated aging markers in COPD. PMID- 29402892 TI - Methods for Sterilizing Clinically Relevant Wear Particles Isolated from Metal-on Metal Hip Implants. AB - Engineered or incidental particles may contain endotoxin from contaminated environments associated with generation, production, or handling activities. Endotoxins are ubiquitous contaminants that may yield false positive responses in immunological assays if present. The purpose of this study was to develop a sterilization method for removal of endotoxin from clinically relevant wear particles isolated from metal-on-metal (MoM) hip implant lubricant. In this case, the goal of particle sterilization was to sufficiently reduce endotoxin levels to acceptable levels for sensitive biological assays while retaining the physical and chemical characteristics of the original particles. Optimization of treatment with 0.05 NaOH in 50% ethanol successfully achieved a 5-log (>99.999%) reduction of endotoxin content while retaining the size and chemistry of MoM hip implant wear particles. Using the optimized method, the concentration of endotoxin was reduced from 161,000 to 1.19 EU/mL. As particle types can vary, sterilization strategies will also differ to optimize endotoxin removal while retaining key particle characteristics. To our knowledge, this study represents the first published sterilization method for clinically relevant MoM hip implant wear particles isolated from serum-rich lubricant. PMID- 29402891 TI - Ecophysiological response of native and exotic salt marsh vegetation to waterlogging and salinity: Implications for the effects of sea-level rise. AB - The ecophysiological characteristics of native Phragmites australis and exotic Spartina alterniflora grown under waterlogging and salinity were investigated to explore their adaptation potential to sea level rise. The seasonal course of phenotypic traits, photosynthetic activity and chlorophyll fluorescence parameters of P. australis did not change remarkably under shallow flooding, whereas these variables were sensitive to increasing salinity. Waterlogging exacerbated the negative effects of salinity on shoot growth and photosynthetic activity of P. australis, and the combined stresses led to an absence of tassel and reproductive organs. By contrast, S. alterniflora performed well under both stresses and showed an obvious adaptation of salt secretion with increasing salinity. Light salinity was the optimal condition for S. alterniflora, and the tassel growth, chlorophyll content and fluorescence characters under moderate stresses did not differ notably. The Na+ and Cl- concentrations in leaves of both species increased, and the K+ content decreased in response to salinity. Under moderate and high saline levels, the ion concentrations in S. alterniflora were maintained at relatively consistent levels with increased salt secretion. We expect the degradation of P. australis and further colonization of S. alterniflora under prolonged flooding and saltwater intrusion from sea level rise on the coastline of China. PMID- 29402893 TI - Magnetism of coupled spin tetrahedra in ilinskite-type KCu5O2(SeO3)2Cl3. AB - Synthesis, thermodynamic properties, and microscopic magnetic model of ilinskite type KCu5O2(SeO3)2Cl3 built by corner-sharing Cu4 tetrahedra are reported, and relevant magnetostructural correlations are discussed. Quasi-one-dimensional magnetic behavior with the short-range order around 50 K is rationalized in terms of weakly coupled spin ladders (tubes) having a complex topology formed upon fragmentation of the tetrahedral network. This fragmentation is rooted in the non trivial effect of the SeO3 groups that render the Cu-O-Cu superexchange strongly ferromagnetic even at bridging angles exceeding 110 degrees . PMID- 29402895 TI - Visualization and quantification of dynamic STAT3 homodimerization in living cells using homoFluoppi. AB - Dimerization in signal transduction is a dynamically regulated process and a key regulatory mechanism. Signal transducer and activator of transcription 3 (STAT3) dimerizes after tyrosine phosphorylation upon cytokine stimulation. Because only the STAT3 dimer possesses the trans-activation activity, dimerization is an indispensable process for cytokine signaling. Here we report the detection of dynamic STAT3 dimerization in living cells using the homoFluoppi system. This method allowed us to validate the presence of an intact Src homology 2 domain and STAT3 Tyr705 phosphorylation, which facilitate puncta formation and homodimerization. Puncta formation was reversible, as determined by a decreased punctate signal after washout of oncostatin M. We analyzed STAT3 mutants, which have been reported in patients with hyper IgE syndrome and inflammatory hepatocellular adenoma (IHCA). Analysis of the IHCA mutants using homoFluoppi revealed constitutive activity independent of cytokine stimulation and novel insight into kinetics of dimer dissociation process. Next, we used homoFluoppi to screen for inhibitors of STAT3 dimerization, and identified 3,4-methylenedioxy beta-nitrostyrene as a novel inhibitor. The results of this study show that homoFluoppi is a useful research tool for the analysis of proteins like STAT3 that dynamically dimerize, and is applicable for the screening of dimerization modulators. PMID- 29402894 TI - Comprehensive network of miRNA-induced intergenic interactions and a biological role of its core in cancer. AB - MicroRNAs (miRNAs) are a family of short noncoding RNAs that posttranscriptionally regulate gene expression and play an important role in multiple cellular processes. A significant percentage of miRNAs are intragenic, which is often functionally related to their host genes playing either antagonistic or synergistic roles. In this study, we constructed and analyzed the entire network of intergenic interactions induced by intragenic miRNAs. We further focused on the core of this network, which was defined as a union of nontrivial strongly connected components, i.e., sets of nodes (genes) mutually connected via directed paths. Both the entire network and its core possessed statistically significant non-random properties. Specifically, genes forming the core had high expression levels and low expression variance. Furthermore, the network core did not split into separate components corresponding to individual signalling or metabolic pathways, but integrated genes involved in key cellular processes, including DNA replication, transcription, protein homeostasis and cell metabolism. We suggest that the network core, consisting of genes mutually regulated by their intragenic miRNAs, could coordinate adjacent pathways or homeostatic control circuits, serving as a horizontal inter-circuit link. Notably, expression patterns of these genes had an efficient prognostic potential for breast and colorectal cancer patients. PMID- 29402896 TI - Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development. AB - The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural precursor differentiation, providing a potential explanation of why CHC22 deficient patients are unable to feel touch or pain. We show the CHC22 effect on neural differentiation is independent of the more common clathrin heavy chain CHC17, and that CHC22-dependent differentiation is mediated through an autocrine/paracrine mechanism. Using quantitative proteomics, we define the composition of clathrin-coated vesicles in SH-SY5Y cells, and determine proteome changes induced by CHC22 depletion. In the absence of CHC22 a subset of dense core granule (DCG) neuropeptides accumulated, were processed into biologically active 'mature' forms, and secreted in sufficient quantity to trigger neural differentiation. When CHC22 is present, however, these DCG neuropeptides are directed to the lysosome and degraded, thus preventing differentiation. This suggests that the brief reduction seen in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway. PMID- 29402897 TI - Neuroprotective effects of pifithrin-alpha against traumatic brain injury in the striatum through suppression of neuroinflammation, oxidative stress, autophagy, and apoptosis. AB - Cortical and hippocampal neuronal damages caused by traumatic brain injury (TBI) are associated with motor and cognitive impairments; however, only little attention paid to the striatal damage. It is known that the p53 tumor-suppressor transcription factor participated in TBI-induced secondary brain damage. We investigated how the p53 inactivator pifithrin (PFT)-alpha affected TBI-induced striatal neuronal damage at 24 h post-injury. Sprague-Dawley rats subjected to a controlled cortical impact were used as TBI models. We observed that p53 mRNA significantly increased, whereas p53 protein expression was distributed predominantly in neurons but not in glia cells in striatum after TBI. PFT-alpha improved motor deficit following TBI. PFT-alpha suppressed TBI-induced striatal glial activation and expression of proinflammatory cytokines. PFT-alpha alleviated TBI-induced oxidative damage TBI induced autophagy was evidenced by increased protein expression of Beclin-1 and shift of microtubule-associated light chain (LC)3-I to LC3-II, and decreased p62. These effects were reduced by PFT-alpha. Post-injury PFT-alpha treatment reduced the number of degenerating (FJC-positive) and apoptotic neurons. Our results suggest that PFT-alpha may provide neuroprotective effects via p53-dependent or -independent mechanisms depending on the cell type and timing after the TBI and can possibly be developed into a novel therapy to ameliorate TBI-induced neuronal damage. PMID- 29402898 TI - Exploring coral microbiome assemblages in the South China Sea. AB - Coral reefs are significant ecosystems. The ecological success of coral reefs relies on not only coral-algal symbiosis but also coral-microbial partnership. However, microbiome assemblages in the South China Sea corals remain largely unexplored. Here, we compared the microbiome assemblages of reef-building corals Galaxea (G. fascicularis) and Montipora (M. venosa, M. peltiformis, M. monasteriata) collected from five different locations in the South China Sea using massively-parallel sequencing of 16S rRNA gene and multivariate analysis. The results indicated that microbiome assemblages for each coral species were unique regardless of location and were different from the corresponding seawater. Host type appeared to drive the coral microbiome assemblages rather than location and seawater. Network analysis was employed to explore coral microbiome co occurrence patterns, which revealed 61 and 80 co-occurring microbial species assembling the Galaxea and Montipora microbiomes, respectively. Most of these co occurring microbial species were commonly found in corals and were inferred to play potential roles in host nutrient metabolism; carbon, nitrogen, sulfur cycles; host detoxification; and climate change. These findings suggest that the co-occurring microbial species explored might be essential to maintain the critical coral-microbial partnership. The present study provides new insights into coral microbiome assemblages in the South China Sea. PMID- 29402899 TI - Comparison of Environmental Impact and Nutritional Quality among a European Sample Population - findings from the Food4Me study. AB - This study evaluates the relationship between environmental impacts and diet quality through several environmental and nutritional indicators, using data from over 1400 participants across seven European countries in the Food4Me study. Comparisons of environmental impacts and dietary quality were evaluated across country, gender groups, and dietary patterns. While there was clear variability within the different subsets, there were large differences observed in both dietary quality and environmental impacts between cultures, genders, and dietary patterns. Individuals abstaining from red meat consistently had lower impacts in combination with lower consumption of harmful nutrients (saturated fats, sodium, and sugars) while maintaining average intake of beneficial nutrients. A 'best practice' diet with low impacts, adequate nutrient intake, and low saturated fats, sodium, and sugars, was constructed from the sample and used as a benchmark. Recorded eating patterns were compared to this recommended diet. On average, intakes of sweets, meats, and drinks should be decreased and intakes of vegetables and cereals increased, at varying rates depending on country and gender. However, the study shows a large spread of eating patterns and recommendations for lowering environmental impacts and increasing nutritional quality vary greatly among individuals. PMID- 29402900 TI - Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. AB - Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes. CANA treatment for 20 weeks inhibited the development of hepatic fibrosis in WD-fed MC4R-KO mice. After one year of CANA treatment, the number of liver tumors was significantly reduced in WD-fed MC4R-KO mice. In adipose tissue, CANA suppressed the ratio of oxidative to reduced forms of glutathiones (GSSG/GSH) in WD-fed MC4R KO mice. Treatment with GSH significantly attenuated the H2O2-induced upregulation of genes related to NADPH oxidase in 3T3-L1 adipocytes, and that of Il6, Tgfb, and Pdgfb in RAW264.7 cells. This study provides evidence that SGLT2 inhibitors represent the unique class of drugs that can attenuate or delay the onset of NASH and eventually hepatocellular carcinoma, at least partly, through "healthy adipose expansion". PMID- 29402901 TI - Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. AB - Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1alpha by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells. PMID- 29402902 TI - Excitation of epsilon-near-zero resonance in ultra-thin indium tin oxide shell embedded nanostructured optical fiber. AB - We report a novel optical waveguide design of a hollow step index fiber modified with a thin layer of indium tin oxide (ITO). We show an excitation of highly confined waveguide mode in the proposed fiber near the wavelength where permittivity of ITO approaches zero. Due to the high field confinement within thin ITO shell inside the fiber, the epsilon-near-zero (ENZ) mode can be characterized by a peak in modal loss of the hybrid waveguide. Our results show that such in-fiber excitation of ENZ mode is due to the coupling of the guided core mode to the thin-film ENZ mode. We also show that the phase matching wavelength, where the coupling takes place, varies depending on the refractive index of the constituents inside the central bore of the fiber. These ENZ nanostructured optical fibers have many potential applications, for example, in ENZ nonlinear and magneto-optics, as in-fiber wavelength-dependent filters, and as subwavelength fluid channel for optical and bio-photonic sensing. PMID- 29402903 TI - Loss-of-function uORF mutations in human malignancies. AB - Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis. PMID- 29402904 TI - In vitro RNA-seq-based toxicogenomics assessment shows reduced biological effect of tobacco heating products when compared to cigarette smoke. AB - The battery of regulatory tests used to evaluate the risk of novel tobacco products such as heated tobacco products (THPs) presents some limitations including a bias towards the apical endpoint tested, and limited information on the mode of action. This is driving a paradigm shift to more holistic systems biology approaches. In this study, we used RNA-sequencing to compare the transcriptomic perturbations following acute exposure of a 3D airway tissue to the aerosols from two commercial THPs and a reference 3R4F cigarette. 2809 RNAs were differentially expressed for the 3R4F treatment and 115 and 2 RNAs for the two THPs (pFDR < 0.05, FC > 1.5), respectively. The relationship between the identified RNA features and gene ontologies were mapped showing a strong association with stress response, xenobiotics metabolism, and COPD-related terms for 3R4F. In contrast, fewer ontologies were found enriched for the THPs aerosols. "Response to wounding" was a common COPD-related term over-represented for the two THPs but at a reduced significance. Quantification of a cytokine panel post-exposure confirmed a pro-inflammatory effect of cigarette smoke but not for THPs. In conclusion, THPs have a reduced impact on gene expression compared to 3R4F. PMID- 29402905 TI - Improved Tapaswini having four BB resistance genes pyramided with six genes/QTLs, resistance/tolerance to biotic and abiotic stresses in rice. AB - Rice, a major food crop, is grown in a wide range of ecological conditions and suffers significant yield losses as it is constantly exposed to a wide range of environmental and biotic stresses. The prevalence of different biotypes/strains has necessitated assembling of numerous resistance genes/QTLs into elite genotypes to confer a broader scale of resistance. The current study reports successful pyramiding of genes/QTLs that confer tolerance/resistance to submergence (Sub1), salinity (Saltol), blast (Pi2, Pi9) and gall midge (Gm1, Gm4) to supplement the four bacterial blight resistance genes (Xa 4, xa5, xa13, Xa21) present in Improved Tapaswini, an elite cultivar. The precise transfer of genes/QTLs was accomplished through effective foreground selection and suitable gene pyramids were identified. Background selection was practiced using morphological and grain quality traits to enhance the recovery of the recurrent parental genome. In the bioassays, the pyramids exhibited higher levels of resistance/ tolerance against the target stresses. The novel feature of the study was successful pyramidization and demonstration of the function of ten genes/QTLs in a new genotype. This success can stimulate several such studies to realize the full potential of molecular plant breeding as the foundation for rice improvement. PMID- 29402906 TI - Full-Stokes polarization imaging method based on the self-organized grating array in fused silica. AB - A full-Stokes polarization imaging method based on the self-organized grating array was presented. By focusing the ultra-fast laser with moderate fluence into fused silica, the self-organized grating array was fabricated, featuring the optical properties similar to wave plates. A set of four independent polarization measurements were simultaneously acquired with designed grating array mounted in the focal plane of an imaging detector. Experimental results including the device fabrication, calibration and optimization were presented. Finally, a principle verification experiment was implemented for our polarization imaging method. PMID- 29402907 TI - Statistical Approach for Gene Set Analysis with Trait Specific Quantitative Trait Loci. AB - The analysis of gene sets is usually carried out based on gene ontology terms and known biological pathways. These approaches may not establish any formal relation between genotype and trait specific phenotype. In plant biology and breeding, analysis of gene sets with trait specific Quantitative Trait Loci (QTL) data are considered as great source for biological knowledge discovery. Therefore, we proposed an innovative statistical approach called Gene Set Analysis with QTLs (GSAQ) for interpreting gene expression data in context of gene sets with traits. The utility of GSAQ was studied on five different complex abiotic and biotic stress scenarios in rice, which yields specific trait/stress enriched gene sets. Further, the GSAQ approach was more innovative and effective in performing gene set analysis with underlying QTLs and identifying QTL candidate genes than the existing approach. The GSAQ approach also provided two potential biological relevant criteria for performance analysis of gene selection methods. Based on this proposed approach, an R package, i.e., GSAQ ( https://cran.r project.org/web/packages/GSAQ ) has been developed. The GSAQ approach provides a valuable platform for integrating the gene expression data with genetically rich QTL data. PMID- 29402908 TI - Enhanced Reality Showing Long-Lasting Analgesia after Total Knee Arthroplasty: Prospective, Randomized Clinical Trial. AB - To overcome the limitation of short-term efficacy of virtual reality (VR), an enhanced reality (ER) analgesia, (combination of the VR, real-time motion capture, mirror therapy [MT]) involving a high degree of patients' presence or embodiment was explored. Patients, who underwent unilateral total knee arthroplasty (TKA), received ER analgesia. The duration was 5 times a week, for 2 weeks for one group and 5 times a week, for 1 week in the other. Visual Analogue Scale (VAS) at rest and during movement, active knee range of motion (ROM) for flexion and extension were measured repeatedly. After screening 157 patients, 60 were included. Pre-interventional evaluation was performed at 6.7 days and ER was initiated at 12.4 days after surgery. Evaluation was performed at 5, 12, 33 days after the initiation of ER. Analgesia in the 2 week therapy group was effective until the third evaluation (p = 0.000), whereas in the other group, it was effective only until the second evaluation (p = 0.010). Improvement in ROM in the 2 week group was also maintained until the third evaluation (p = 0.037, p = 0.009). It could lay the foundations for the development of safe and long-lasting analgesic tools. PMID- 29402909 TI - Spatial and Temporal Characteristics of 2014 Dengue Outbreak in Guangdong, China. AB - The record-breaking number of dengue cases reported in Guangdong, China in 2014 has been topic for many studies. However, the spatial and temporal characteristics of this unexpectedly explosive outbreak are still poorly understood. We adopt an integrated approach to ascertain the spatial-temporal progression of the outbreak in each city in Guangdong as well as in each district in Guangzhou, where the majority of cases occurred. We utilize the Richards model, which determines the waves of reported cases at each location and identifies the turning point for each wave, in combination with a spatial association analysis conducted by computing the standardized G* statistic that measures the degree of spatial autocorrelation of a set of geo-referenced data from a local perspective. We found that Yuexiu district in Guangzhou was the initial hot spot for the outbreak, subsequently spreading to its neighboring districts in Guangzhou and other cities in Guangdong province. Hospital isolation of cases during early stage of outbreak in neighboring Zhongshan (in effort to prevent disease transmission to the vectors) might have played an important role in the timely mitigation of the disease. Integration of modeling approach and spatial association analysis allows us to pinpoint waves that spread the disease to communities beyond the borders of the initially affected regions. PMID- 29402910 TI - Author Correction: RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin. AB - In the original version of this Article, the affiliation details for Antoine Aze, Michalis Fragkos, Stephane Bocquet, Julien Cau and Marcel Mechali incorrectly omitted 'CNRS and the University of Montpellier'. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29402911 TI - River self-organisation inhibits discharge control on waterfall migration. AB - The action of rivers within valleys is fundamentally important in controlling landscape morphology, and how it responds to tectonic or climate change. The response of landscapes to external forcing usually results in sequential changes to river long profiles and the upstream migration of waterfalls. Currently, models of this response assume a relationship between waterfall retreat rate and drainage area at the location of the waterfall. Using an experimental study, we show that this assumption has limited application. Due to a self-regulatory response of channel geometry to higher discharge through increasing channel width, the bed shear stress at the lip of the experimental waterfall remains almost constant, so there was no observed change in the upstream retreat rate despite an order of magnitude increase in discharge. Crucially, however, the strength of the bedrock material exhibits a clear control on the magnitude of the mean retreat rate, highlighting the importance of lithology in setting the rate at which landscapes respond to external forcing. As a result existing numerical models of landscape evolution that simulate the retreat of waterfalls as a function of drainage area with a fixed erodibility constant should be re evaluated to consider spatial heterogeneity in erodibility and channel self organisation. PMID- 29402912 TI - Dispersion of the soybean root rot by Cycloneda sanguinea (Coleoptera: Coccinellidae). AB - The dispersion of pathogenic microorganisms consists of the transport of pathogens from their source to inoculate a new host. Agricultural and economic importance of the Soybean root rot justifies studying this disease, especially the role of insects as dispersers. The aim of this study was to evaluate the role of the ladybird beetle, Cycloneda sanguinea Linnaeus (Coleoptera: Coccinellidae) in the dispersion of pathogens that cause Soybean root rot. Three pathogen species, Macrophomina phaseolina (Tassi) (Sphaeropsidales: Botryosphaeriaceae), Fusarium incarnatum-equiseti species complex (FIESC), and F. commune (Skovgaard) O'Donnell & Nirenberg were isolated from the midgut of ladybird beetles and cultured. Macrophomina phaseolina was identified by morphology while for the other two species, DNA was sequenced. The DNA extracted was amplified in the Internal Transcriber Spacer (ITS) region, sequenced and compared to voucher sequences deposited in the GenBank. Sequences of nucleotide ITS1-5.8 S were identified in the regions of rDNA-ITS4 ribosomal DNA. This is the first report of Macrophomina phaseolina (Tassi) (Sphaeropsidales: Botryosphaeriaceae), Fusarium incarnatum-equiseti species complex (FIESC), and F. commune (Skovgaard) O'Donnell & Nirenberg, being dispersed by C. sanguinea in Brazilian soybean fields. PMID- 29402913 TI - Combining Turing and 3D vertex models reproduces autonomous multicellular morphogenesis with undulation, tubulation, and branching. AB - This study demonstrates computational simulations of multicellular deformation coupled with chemical patterning in the three-dimensional (3D) space. To address these aspects, we proposes a novel mathematical model, where a reaction-diffusion system is discretely expressed at a single cell level and combined with a 3D vertex model. To investigate complex phenomena emerging from the coupling of patterning and deformation, as an example, we employed an activator-inhibitor system and converted the activator concentration of individual cells into their growth rate. Despite the simplicity of the model, by growing a monolayer cell vesicle, the coupling system provided rich morphological dynamics such as undulation, tubulation, and branching. Interestingly, the morphological variety depends on the difference in time scales between patterning and deformation, and can be partially understood by the intrinsic hysteresis in the activator inhibitor system with domain growth. Importantly, the model can be applied to 3D multicellular dynamics that couple the reaction-diffusion patterning with various cell behaviors, such as deformation, rearrangement, division, apoptosis, differentiation, and proliferation. Thus, the results demonstrate the significant advantage of the proposed model as well as the biophysical importance of exploring spatiotemporal dynamics of the coupling phenomena of patterning and deformation in 3D space. PMID- 29402914 TI - Neuroprotection of the hypoxic-ischemic mouse brain by human CD117+CD90+CD105+ amniotic fluid stem cells. AB - Human amniotic fluid contains two morphologically-distinct sub-populations of stem cells with regenerative potential, spindle-shaped (SS-hAFSCs) and round shaped human amniotic fluid stem cells (RS-hAFSCs). However, it is unclear whether morphological differences correlate with functionality, and this lack of knowledge limits their translational applications. Here, we show that SS-hAFSCs and RS-hAFSCs differ in their neuro-protective ability, demonstrating that a single contralateral injection of SS-hAFSCs into hypoxic-ischemic P7 mice conferred a 47% reduction in hippocampal tissue loss and 43-45% reduction in TUNEL-positive cells in the hippocampus and striatum 48 hours after the insult, decreased microglial activation and TGFbeta1 levels, and prevented demyelination. On the other hand, RS-hAFSCs failed to show such neuro-protective effects. It is possible that SS-hAFSCs exert their neuroprotection via endoglin-dependent inhibition of TGFbeta1 signaling in target cells. These findings identify a sub population of CD117+CD90+CD105+ stem cells as a promising source for the neuro protection of the developing brain. PMID- 29402915 TI - Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. AB - Mutations in either cubilin (CUBN) or amnionless (AMN) genes cause Imerslund Grasbeck syndrome (IGS), a hereditary disease characterised by anaemia attributed to selective intestinal malabsorption of cobalamin and low-molecular weight proteinuria. Although cubilin protein does not have a transmembrane segment, it functions as a multi-ligand receptor by binding to the transmembrane protein, amnionless. We established a system to quantitatively analyse membrane targeting of the protein complex in cultured renal and intestinal cells and analysed the pathogenic mechanisms of mutations found in IGS patients. A novel CUBN mutation, several previously reported CUBN missense mutations and all previously reported AMN missense mutations resulted in endoplasmic reticulum (ER) retention and completely inhibited amnionless-dependent plasma membrane expression of cubilin. The ER retention of cubilin and amnionless was confirmed in renal proximal tubular cells of a patient with IGS. Notably, the interaction between cubilin and amnionless was not sufficient, but amnionless-mediated glycosylation of cubilin was necessary for their surface expression. Quantitative mass spectrometry and mutagenesis demonstrated that N-linked glycosylation of at least 4 residues of cubilin protein was required for its surface targeting. These results delineated the molecular mechanisms of membrane trafficking of cubilin in renal and intestinal cells. PMID- 29402916 TI - Transcriptomic changes in the pre-implantation uterus highlight histotrophic nutrition of the developing marsupial embryo. AB - Early pregnancy is a critical time for successful reproduction; up to half of human pregnancies fail before the development of the definitive chorioallantoic placenta. Unlike the situation in eutherian mammals, marsupial pregnancy is characterised by a long pre-implantation period prior to the development of the short-lived placenta, making them ideal models for study of the uterine environment promoting embryonic survival pre-implantation. Here we present a transcriptomic study of pre-implantation marsupial pregnancy, and identify differentially expressed genes in the Sminthopsis crassicaudata uterus involved in metabolism and biosynthesis, transport, immunity, tissue remodelling, and uterine receptivity. Interestingly, almost one quarter of the top 50 genes that are differentially upregulated in early pregnancy are putatively involved in histotrophy, highlighting the importance of nutrient transport to the conceptus prior to the development of the placenta. This work furthers our understanding of the mechanisms underlying survival of pre-implantation embryos in the earliest live bearing ancestors of mammals. PMID- 29402918 TI - Droplet microfluidics for the highly controlled synthesis of branched gold nanoparticles. AB - The synthesis of anisotropic metallic nanoparticles (NPs) has been a field of intense and challenging research in the past decade. In this communication, we report on the reproducible and highly controllable synthesis of monodisperse branched gold nanoparticles in a droplet-based microfluidics platform. The process has been automated by adapting two different bulk synthetic strategies to microdroplets, acting as microreactors, for NP synthesis: a surfactant-free synthesis and a surfactant-assisted synthesis. Microdroplets were generated in two different microfluidic devices designed to accommodate the requirements of both bulk syntheses. The epitaxial growth of AuNSTs inside the microdroplets allowed for a fine control of reagent mixing and local concentrations during particle formation. This is the first time branched gold NPs have been synthesised in a microfluidics platform. The monodispersity of the product was comparable to the synthesis in bulk, proving the potential of this technology for the continuous synthesis of high quality anisotropic NPs with improved reproducibility. PMID- 29402917 TI - Insulin-degrading enzyme is not secreted from cultured cells. AB - Insulin-degrading enzyme (IDE) functions in the catabolism of bioactive peptides. Established roles include degrading insulin and the amyloid beta peptide (Abeta), linking it to diabetes and Alzheimer's disease. IDE is primarily located in the cytosol, and a longstanding question is how it gains access to its peptide substrates. Reports suggest that IDE secreted by an unconventional pathway participates in extracellular hydrolysis of insulin and Abeta. We find that IDE release from cultured HEK-293 or BV-2 cells represents only ~1% of total cellular IDE, far less than has been reported previously. Importantly, lactate dehydrogenase (LDH) and other cytosolic enzymes are released at the same relative level, indicating that extracellular IDE results from a loss of cell integrity, not secretion. Lovastatin increases IDE release from BV-2 cells as reported, but this release is mirrored by LDH release. Cell viability assays indicate lovastatin causes a loss of cell integrity, explaining its effect on IDE release. IDE is present in an exosome-enriched fraction from BV-2 cell conditioned media, however it represents only ~0.01% of the total cellular enzyme and is unlikely to be a significant source of IDE. These results call into question the secretion of IDE and its importance in extracellular peptide degradation. PMID- 29402919 TI - Long non-coding and coding RNAs characterization in Peripheral Blood Mononuclear Cells and Spinal Cord from Amyotrophic Lateral Sclerosis patients. AB - Alteration in RNA metabolism, concerning both coding and long non-coding RNAs (lncRNAs), may play an important role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. In this work, we performed a whole transcriptome RNA-seq analysis to investigate the regulation of non-coding and coding RNAs in Sporadic ALS patients (SALS), mutated ALS patients (FUS, TARDBP and SOD1) and matched controls in Peripheral Blood Mononuclear Cells (PBMC). Selected transcripts were validated in spinal cord tissues. A total of 293 differentially expressed (DE) lncRNAs was found in SALS patients, whereas a limited amount of lncRNAs was deregulated in mutated patients. A total of 87 mRNAs was differentially expressed in SALS patients; affected genes showed an association with transcription regulation, immunity and apoptosis pathways. Taken together our data highlighted the importance of extending the knowledge on transcriptomic molecular alterations and on the significance of regulatory lncRNAs classes in the understanding of ALS disease. Our data brought the light on the importance of lncRNAs and mRNAs regulation in central and peripheral systems, offering starting points for new investigations about pathogenic mechanism involved in ALS disease. PMID- 29402920 TI - Parental age and gene expression profiles in individual human blastocysts. AB - The epigenetic status of the genome changes dynamically from fertilization to implantation. In addition, the physiological environment during the process of gametogenesis, including parental age, may affect the epigenome of the embryo after fertilization. It is important to clarify the influence of parental age on gene expression in the embryo in terms of transgenerational epigenetics to improve the techniques currently used in assisted reproductive medicine. Here, we performed single-embryo RNA-seq analysis on human blastocysts fertilized by intracytoplasmic sperm injection, including from relatively elderly mothers, to elucidate the effects of parental age on the embryonic gene expression profile. We identified a number of genes in which the expression levels were decreased with increasing maternal age. Among these genes, several are considered to be important for meiotic chromosomal segregation, such as PTTG1, AURKC, SMC1B and MEIKIN. Furthermore, the expression levels of certain genes critical for autophagy and embryonic growth, specifically GABARAPL1 and GABARAPL3, were negatively correlated with advanced paternal age. In addition, levels of transcripts derived from major satellite repeats also decreased as the maternal age increased. These results suggest that epigenetic modifications of the oocyte genome may change with parental age and be transmitted to the next generation. PMID- 29402921 TI - Effects of dietary lysine restriction on inflammatory responses in piglets. AB - The aim of this study was to investigate the effects of lysine restriction on inflammatory responses in piglets. 38 male piglets with similar body weight of 9.62 kg were randomly divided into control group (basal diet) and lysine restricted group (diet containing 70% lysine of the control diet). The results showed that lysine restriction increased the serum concentration of IgG an IgM. Piglets fed the lysine-restricted diet exhibited overexpression of interleukin-8 (IL-8) in the kidney (P < 0.05) and IL-6 and IL-4 in the spleen (P < 0.05). The mRNA abundances of IL-4 in the kidney (P < 0.05) and IL-10 in the liver (P < 0.05) were significantly lower in the lysine-restricted group compared with the control group. Meanwhile, lysine restriction increased the mRNA level of Tlr8 in the kidney (P < 0.05) but decreased the mRNA level of Tlr8 in the liver (P < 0.05). Finally, lysine restriction markedly enhanced extracellular signal regulated kinases 1/2 (ERK1/2) phosphorylation in the kidney and liver and nuclear transcription factor kappa B (NF-kappaB) was activated in the liver and spleen in response to dietary lysine restriction. In conclusion, lysine restriction affected inflammatory responses in the kidney, liver, and spleen via mediating serum antibody volume, inflammatory cytokines, Tlrs system, and ERK1/2 and NF-kappaB signals in piglets. PMID- 29402922 TI - A Novel Mitochondrial Serine O-Acetyltransferase, OpSAT1, Plays a Critical Role in Sulfur Metabolism in the Thermotolerant Methylotrophic Yeast Ogataea parapolymorpha. AB - In most bacteria and plants, direct biosynthesis of cysteine from sulfide via O acetylserine (OAS) is essential to produce sulfur amino acids from inorganic sulfur. Here, we report the functional analysis of a novel mitochondrial serine O acetyltransferase (SAT), responsible for converting serine into OAS, in the thermotolerant methylotrophic yeast Ogataea parapolymorpha. Domain analysis of O. parapolymorpha SAT (OpSat1p) and other fungal SATs revealed that these proteins possess a mitochondrial targeting sequence (MTS) at the N-terminus and an alpha/beta hydrolase 1 domain at the C-terminal region, which is quite different from the classical SATs of bacteria and plants. Noticeably, OpSat1p is functionally interchangeable with Escherichia coli SAT, CysE, despite that it displays much less enzymatic activity, with marginal feedback inhibition by cysteine, compared to CysE. The Opsat1Delta-null mutant showed remarkably reduced intracellular levels of cysteine and glutathione, implying OAS generation defect. The MTS of OpSat1p directs the mitochondrial targeting of a reporter protein, thus, supporting the localization of OpSat1p in the mitochondria. Intriguingly, the OpSat1p variant lacking MTS restores the OAS auxotrophy, but not the cysteine auxotrophy of the Opsat1Delta mutant strain. This is the first study on a mitochondrial SAT with critical function in sulfur assimilatory metabolism in fungal species. PMID- 29402923 TI - Handling method alters the hedonic value of reward in laboratory mice. AB - Mice are the most widely used model species for drug discovery and scientific research. Consequently, it is important to refine laboratory procedures and practices to ensure high standards of welfare and scientific data quality. Recent studies have identified that the standard practice of handling laboratory mice by their tails increases behaviours indicative of anxiety, which can be overcome by handling mice using a tunnel. However, despite clear negative effects on mice's behaviour, tunnel handling has yet to be widely implemented. In this study, we provide the first evidence that tail handling also reduces mice's responses to reward. Anhedonia is a core symptom of clinical depression, and is measured in rodents by assessing how they consume a sucrose solution: depressed mice consume less sucrose and the size of their licking bouts when drinking (their 'lick cluster sizes') also tend to be smaller. We found that tail handled mice showed more anhedonic responses in both measures compared to tunnel handled mice, indicative of a decreased responsiveness to reward and potentially a more depressive-like state. Our findings have significant implications for the welfare of laboratory mice as well as the design and interpretation of scientific studies, particularly those investigating or involving reward. PMID- 29402924 TI - Transcriptome sequence analysis and mining of SSRs in Jhar Ber (Ziziphus nummularia (Burm.f.) Wight & Arn) under drought stress. AB - Ziziphus nummularia (Burm.f.) Wight & Arn., a perennial shrub that thrives in the arid regions, is naturally tolerant to drought. However, there are limited studies on the genomics of drought tolerance in Ziziphus sp. In this study, RNA sequencing of one month old seedlings treated with PEG 6000 was performed using Roche GS-FLX454 Titanium pyrosequencing. A total of 367,176 raw sequence reads were generated, and upon adapter trimming and quality filtration 351,872 reads were assembled de novo into 32,739 unigenes. Further characterization of the unigenes indicated that 73.25% had significant hits in the protein database. Kyoto encyclopedia of genes and genomes database (KEGG) identified 113 metabolic pathways from the obtained unigenes. A large number of drought-responsive genes were obtained and among them differential gene expression of 16 highly induced genes was validated by qRT-PCR analysis. To develop genic-markers, 3,425 simple sequence repeats (SSRs) were identified in 2,813 unigene sequences. The data generated shall serve as an important reservoir for the identification and characterization of drought stress responsive genes for development of drought tolerant crops. PMID- 29402925 TI - Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems. AB - The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5-10 uM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human in vivo metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human in vivo amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human in vivo hydrolytic metabolism of the aromatic amide compounds tested. PMID- 29402926 TI - Cryptic Biological Invasions: a General Model of Hybridization. AB - The dispersal of non-native genes due to hybridization is a form of cryptic invasion with growing concern in evolution and conservation. This includes the spread of transgenic genes and antibiotic resistance. To investigate how genes and phenotypes are transmitted, we developed a general model that, for the first time, considers concurrently: multiple loci, quantitative and qualitative gene expression, assortative mating, dominance/recessivity inheritance and density dependent demographic effects. Selection acting on alleles or genotypes can also be incorporated. Our results reveal that the conclusions about how hybridization threatens a species can be biased if they are based on single-gene models, while considering two or more genes can correct this bias. We also show that demography can amplify or balance the genetic effects, evidencing the need of jointly incorporating both processes. By implementing our model in a real case, we show that mallard ducks introduced in New Zealand benefit from hybridization to replace native grey-ducks. Total displacement can take a few generations and occurs by interspecific competition and by competition between hybrids and natives, demonstrating how hybridization may facilitate biological invasions. We argue that our general model represents a powerful tool for the study of a wide range of biological and societal questions. PMID- 29402927 TI - Salmonella Enteritidis ST183: emerging and endemic biotypes affecting western European hedgehogs (Erinaceus europaeus) and people in Great Britain. AB - The impacts of hedgehog (Erinaceus europaeus) Salmonella infection on public health and on animal welfare and conservation are unknown. We isolated Salmonella Enteritidis multi-locus sequence-type (ST)183 from 46/170 (27%) hedgehog carcasses (27 S. Enteritidis phage type (PT)11, 18 of a novel PT66 biotype and one with co-infection of these PTs) and from 6/208 (3%) hedgehog faecal samples (4 PT11, 2 PT66) from across Great Britain, 2012-2015. Whole genome phylogenetic analysis of the hedgehog isolates and ST183 from people in England and Wales found that PT11 and PT66 form two divergent clades. Hedgehog and human isolates were interspersed throughout the phylogeny indicating that infections in both species originate from a common population. PT11 was recovered from hedgehogs across England and Scotland, consistent with endemic infection. PT66 was isolated from Scotland only, possibly indicating a recent emergence event. People infected with ST183 were four times more likely to be aged 0-4 years than people infected by the more common ST11 S. Enteritidis. Evidence for human ST183 infection being non-foodborne included stronger correlation between geographic and genetic distance, and significantly increased likelihood of infection in rural areas, than for ST11. These results are consistent with hedgehogs acting as a source of zoonotic infection. PMID- 29402928 TI - A novel small deletion in the NHS gene associated with Nance-Horan syndrome. AB - Nance-Horan syndrome is a rare X-linked recessive inherited disease with clinical features including severe bilateral congenital cataracts, characteristic facial and dental abnormalities. Data from Chinese Nance-Horan syndrome patients are limited. We assessed the clinical manifestations of a Chinese Nance-Horan syndrome pedigree and identified the genetic defect. Genetic analysis showed that 3 affected males carried a novel small deletion in NHS gene, c.263_266delCGTC (p.Ala89TrpfsTer106), and 2 female carriers were heterozygous for the same variant. All 3 affected males presented with typical Nance-Horan syndrome features. One female carrier displayed lens opacities centered on the posterior Y suture in both eyes, as well as mild dental abnormalities. We recorded the clinical features of a Chinese Nance-Horan syndrome family and broadened the spectrum of mutations in the NHS gene. PMID- 29402929 TI - Generation of a rod-specific NRL reporter line in human pluripotent stem cells. AB - Reporter lines generated in human pluripotent stem cells can be highly useful for the analysis of specific cell types and lineages in live cultures. We created the first human rod reporter line using CRISPR/Cas9 genome editing to replace one allele of the Neural Retina Leucine zipper (NRL) gene with an eGFP transgene in the WA09 human embryonic stem cell (hESC) line. After confirming successful targeting, three-dimensional optic vesicle structures were produced to examine reporter specificity and to track rod differentiation in culture. The NRL+/eGFP hESC line robustly and exclusively labeled the entirety of rods throughout differentiation, eventually revealing highly mature structural features. This line provides a valuable tool for studying human rod development and disease and testing therapeutic strategies for retinitis pigmentosa. PMID- 29402930 TI - Intracellular tracing of amyloid vaccines through direct fluorescent labelling. AB - Alzheimer's disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Abeta as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation. However, the intrinsic phagocytic properties of such cells have pre-disposed them to internalise misfolded amyloidogenic peptides that could act as seeds capable of nucleating amyloid formation in the brain. Mechanisms governing the cellular fate of amyloid therefore, may prove to be key in the development of future vaccination regimes. Herein, we have developed unequivocal and direct conformation-sensitive fluorescent molecular probes that reveal the intracytoplasmic and intranuclear persistence of amyloid in a monocytic T helper 1 (THP-1) cell line. Use of the pathogenic Abeta42 species as a model antigen in simulated vaccine formulations suggested differing mechanisms of cellular internalisation, in which fibrillar amyloid evaded lysosomal capture, even when co-deposited on particulate adjuvant materials. Taken collectively, direct fluorescent labelling of antigen-adjuvant complexes may serve as critical tools in understanding subsequent immunopotentiation in vaccines directed against amyloidosis and wider dementia. PMID- 29402931 TI - Steric exclusion and protein conformation determine the localization of plasma membrane transporters. AB - The plasma membrane (PM) of Saccharomyces cerevisiae contains membrane compartments, MCC/eisosomes and MCPs, named after the protein residents Can1 and Pma1, respectively. Using high-resolution fluorescence microscopy techniques we show that Can1 and the homologous transporter Lyp1 are able to diffuse into the MCC/eisosomes, where a limited number of proteins are conditionally trapped at the (outer) edge of the compartment. Upon addition of substrate, the immobilized proteins diffuse away from the MCC/eisosomes, presumably after taking a different conformation in the substrate-bound state. Our data indicate that the mobile fraction of all integral plasma membrane proteins tested shows extremely slow Brownian diffusion through most of the PM. We also show that proteins with large cytoplasmic domains, such as Pma1 and synthetic chimera of Can1 and Lyp1, are excluded from the MCC/eisosomes. We hypothesize that the distinct localization patterns found for these integral membrane proteins in S. cerevisiae arises from a combination of slow lateral diffusion, steric exclusion, and conditional trapping in membrane compartments. PMID- 29402933 TI - Tripartite symbiosis of plant-weevil-bacteria is a widespread phenomenon in the Negev Desert. AB - The weevil Conorhynchus palumbus develops in a mud chamber affixed to the roots of the summer annual plant Salsola inermis in the Negev Desert of Israel. The weevil carries nitrogen fixing bacteria, and evidence suggests that plants with weevils utilize the fixed nitrogen. To characterize the distribution, abundance and significance of this unique interaction, we surveyed Salsola plants in 16 sites throughout the Negev Desert. We excavated ~100 plants from each site, recorded the presence of weevils in their roots, and characterized the soil properties in each site. Weevil mud chambers were present in all of the sampled sites and their abundance was positively correlated with soil nitrogen content and with plant size, and negatively correlated with soil grain-size. Intriguingly, we found two additional weevil species-Menecleonus virgatus and Maximus mimosae-residing in mud chambers on Salsola roots, and found one additional Salsola species-S. incanescens-accommodating weevils. Nitrogen fixing bacteria were found in weevil larvae of the two additional species and at multiple sites. Overall, our findings suggest that potentially beneficial associations between weevils and plants may be more common than previously acknowledged, and may play an important role in this desert ecosystem. PMID- 29402932 TI - BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1. AB - BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth. PMID- 29402934 TI - Size at emergence improves accuracy of age estimates in forensically-useful beetle Creophilus maxillosus L. (Staphylinidae). AB - Insects colonizing human or animal cadavers may be used to estimate post-mortem interval (PMI) usually by aging larvae or pupae sampled on a crime scene. The accuracy of insect age estimates in a forensic context is reduced by large intraspecific variation in insect development time. Here we test the concept that insect size at emergence may be used to predict insect physiological age and accordingly to improve the accuracy of age estimates in forensic entomology. Using results of laboratory study on development of forensically-useful beetle Creophilus maxillosus (Linnaeus, 1758) (Staphylinidae) we demonstrate that its physiological age at emergence [i.e. thermal summation value (K) needed for emergence] fall with an increase of beetle size. In the validation study it was found that K estimated based on the adult insect size was significantly closer to the true K as compared to K from the general thermal summation model. Using beetle length at emergence as a predictor variable and male or female specific model regressing K against beetle length gave the most accurate predictions of age. These results demonstrate that size of C. maxillosus at emergence improves accuracy of age estimates in a forensic context. PMID- 29402935 TI - Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. AB - Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to alpha-synuclein-dependent degeneration in RBD patients. PMID- 29402936 TI - Microscale Gene Expression Analysis of Tumor-Associated Macrophages. AB - Macrophages, apart from being the key effector cells of the innate immune system, also play critical roles during the development and progression of various complex diseases, including cancer. Tumor-associated macrophages, infiltrate tumors during different stages of cancer progression to regulate motility, invasion, and intravasation to metastatic sites. Macrophages can exist in different polarization states associated with unique function in tumors. Since tumor-associated macrophages constitute a very small proportion of tumor cells, analysis of gene expression pattern using normal extraction buffer-based methods remains a challenging task. Therefore, it is imperative to develop low-throughput strategies to investigate transcriptional regulations from a small number of immune cells. Here, we describe an efficient, sensitive, and cost-effective approach for gene expression analysis of a small number of fluorescence-activated sorted tumor-associated macrophages. Our analyses from the different number of stable, primary, and sorted macrophages suggest 5,000 cells is an optimal number for performing quantitative, real-time PCR analysis of multiple genes. Our studies could detect expression of macrophage-specific genes from cultured primary macrophages, and FACS-sorted macrophages from different biological tissues without introducing biases in comparative gene expression ratios. In conclusion, our kit-based method for quantitative gene expression analysis from a small number of cells found in biological tissues will provide an opportunity to study cell-specific, transcriptional changes. PMID- 29402937 TI - Comparative study on nutrient depletion-induced lipidome adaptations in Staphylococcus haemolyticus and Staphylococcus epidermidis. AB - Staphylococcus species are emerging opportunistic pathogens that cause outbreaks of hospital and community-acquired infections. Some of these bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are difficult to treat due to their resistance to multiple antibiotics. We carried out a comparative study on the lipidome adaptations in response to starvation in the two most common coagulase-negative Staphylococcus species: a S. epidermidis strain sensitive to ampicillin and erythromycin and a S. haemolyticus strain resistant to both. The predominant fatty acid composition in glycerolipids was (17:0-15:0) in both bacteria. During the exponential phase, the two bacterial lipidomes were similar. Both were dominated by diacylglycerol (DAG), phosphatidylglycerol (PG), lysyl phosphatidylglycerol (Lysyl-PG) and Diglucosyl-diacylglycerol (DGDG). Alanyl-PG was detected in small amounts in both bacterial lipids. N-succinyl-lysyl-PG was detected only in S. haemolyticus, while lysyl-DAG only in S. epidermidis. As the two bacteria entered stationary phase, both lipidomes became essentially nitrogen free. Both bacteria accumulated large amounts of free fatty acids. Strikingly, the lipidome of S. epidermidis became dominated by cardiolipin (CL), while that of S. haemolyticus was simplified to DGDG and PG. The S. epidermidis strain also produced acyl-phosphatidylglycerol (APG) in the stationary phase. PMID- 29402938 TI - The spin structures of interlayer coupled magnetic films with opposite chirality. AB - Using Monte-Carlo simulations and micromagnetic simulations, we reveal how the spin structural correlation and the skyrmion dynamics are affected by the interlayer coupling in a chiral magnetic bilayer system, in which the two layers have opposite chirality. The interaction through interlayer coupling between chiral magnetic structures influences the static and dynamics properties profoundly. The competition between the Dzyaloshinskii-Moriya interaction and the interlayer interaction allows multiple magnetic structures to be energetically stable, which includes sole skyrmion states (skyrmion appears in only one of the layers) and skyrmion pair states (coupled skyrmions in top and bottom layers). When current driven spin transfer torques are applied to each state, the sole skyrmion state is mainly propelled by a spin transfer torque causing the skyrmion hall effect, but the skyrmion pair state is propelled by a torque from skyrmion skyrmion interaction and not influenced by the skyrmion hall effect. Also upon application of an external magnetic field, we found the skyrmions in a skyrmion pair state extinguish in an exclusive way, as the annihilation of a skyrmion in one of the layers stabilizes the once paired skyrmion in the other layer, i.e. the skyrmion lattice sites have only one skyrmion in either layer. PMID- 29402939 TI - p38 activation induces production of miR-146a and miR-31 to repress E-selectin expression and inhibit transendothelial migration of colon cancer cells. AB - Extravasation of circulating cancer cells determines their metastatic potential. This process is initiated by the adhesion of cancer cells to vascular endothelial cells through specific interactions between endothelial adhesion receptors such as E-selectin and their ligands on cancer cells. In the present study, we show that miR-146a and miR-181b impede the expression of E-selectin by repressing the activity of its transcription factor NF-kappaB, thereby impairing the metastatic potentials of colon cancer cells by decreasing their adhesion to, and migration through, the endothelium. Among the two microRNAs, only miR-146a is activated by IL-1beta, through the activation of p38, ERK and JNK MAP kinases, as well as their downstream transcription factors GATA2, c-Fos and c-Jun. Inhibiting p38 MAP kinase increases NF-kappaB activity, at least partially via miR-146a. Inhibiting p38 also increases the expression of E-selectin at the post-transcriptional level via decreasing miR-31, which targets E-selectin mRNA and also depends on p38 for its expression. In response to IL-1beta, p38 MAP kinase hence represses the expression of E-selectin at the transcriptional and the post-transcriptional levels, via miR-146a and miR-31, respectively. These results highlight novel mechanisms by which p38 downregulates the expression of E-selectin through different microRNAs following inflammatory stimuli associated to cancer progression. PMID- 29402940 TI - 3D Printed Auxetic Mechanical Metamaterial with Chiral Cells and Re-entrant Cores. AB - By combining the two basic deformation mechanisms for auxetic open-cell metamaterials, re-entrant angle and chirality, new hybrid chiral mechanical metamaterials are designed and fabricated via a multi-material 3D printer. Results from mechanical experiments on the 3D printed prototypes and systematic Finite Element (FE) simulations show that the new designs can achieve subsequential cell-opening mechanism under a very large range of overall strains (2.91%-52.6%). Also, the effective stiffness, the Poisson's ratio and the cell opening rate of the new designs can be tuned in a wide range by tailoring the two independent geometric parameters: the cell size ratio [Formula: see text], and re entrant angle theta. As an example application, a sequential particle release mechanism of the new designs was also systematically explored. This mechanism has potential application in drug delivery. The present new design concepts can be used to develop new multi-functional smart composites, sensors and/or actuators which are responsive to external load and/or environmental conditions. PMID- 29402941 TI - Eis, a novel family of arylalkylamine N-acetyltransferase (EC 2.3.1.87). AB - Enhanced intracellular survival (Eis) proteins were found to enhance the intracellular survival of mycobacteria in macrophages by acetylating aminoglycoside antibiotics to confer resistance to these antibiotics and by acetylating DUSP16/MPK-7 to suppress host innate immune defenses. Eis homologs composing of two GCN5 N-acetyltransferase regions and a sterol carrier protein fold are found widely in gram-positive bacteria. In this study, we found that Eis proteins have an unprecedented ability to acetylate many arylalkylamines, are a novel type of arylalkylamine N-acetyltransferase AANAT (EC 2.3.1.87). Sequence alignment and phyletic distribution analysis confirmed Eis belongs to a new aaNAT like cluster. Among the cluster, we studied three typical Eis proteins: Eis_Mtb from Mycobacterium tuberculosis, Eis_Msm from Mycobacterium smegmatis, and Eis_Sen from Saccharopolyspora erythraea. Eis_Mtb prefers to acetylate histamine and octopamine, while Eis_Msm uses tyramine and octopamine as substrates. Unlike them, Eis_Sen exihibits good catalytic efficiencies for most tested arylalkylamines. Considering arylalkylamines such as histamine plays a fundamental role in immune reactions, future work linking of AANAT activity of Eis proteins to their physiological function will broaden our understanding of gram-positive pathogen-host interactions. These findings shed insights into the molecular mechanism of Eis, and reveal potential clinical implications for many gram-positive pathogens. PMID- 29402943 TI - Coffee Intake as a Risk Indicator for Tooth Loss in Korean Adults. AB - The aim of this study was to examine the association between coffee intake and tooth loss. This study hypothesized that the intake of coffee would increase the prevalence of tooth loss in Korean adults. Subject information was obtained from the Korea National Health and Nutrition Examination Survey conducted in 2010 2011. Sociodemographic and lifestyle variables, anthropometric and biochemical status, metabolic health and glucose tolerance status, as well as oral health behaviors were evaluated. The number of remaining teeth was negatively associated with the frequency of coffee intake (p-value < 0.05). Daily coffee consumers had significantly higher levels of body mass index (BMI), waist circumference (WC), total cholesterol, and low density lipoprotein cholesterol (LDL-C) (all p-value < 0.05). Individuals with less than 20 remaining teeth had higher BMI, WC, diastolic blood pressure, and LDL-C (all p-value < 0.05). Finally, participants who drank coffee on a daily basis were more likely to have fewer remaining teeth. The prevalence of having less than 20 remaining teeth was 69% higher in groups with daily coffee intake than those with coffee intake of less than once a month after adjustment for potential covariates (Odds Ratio [95% CI] = 1.69 [1.35, 2.13]). In conclusion, daily coffee consumption is closely associated with tooth loss in Korean adults. PMID- 29402942 TI - Higher-generation type III-B rotaxane dendrimers with controlling particle size in three-dimensional molecular switching. AB - Type III-B rotaxane dendrimers (T3B-RDs) are hyperbranched macromolecules with mechanical bonds on every branching unit. Here we demonstrate the design, synthesis, and characterization of first to third (G1-G3), and up to the fourth (G4) generation (MW > 22,000 Da) of pure organic T3B-RDs and dendrons through the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. By utilizing multiple molecular shuttling of the mechanical bonds within the sphere-like macromolecule, a collective three-dimensional contract-extend molecular motion is demonstrated by diffusion ordered spectroscopy (DOSY) and atomic force microscopy (AFM). The discrete T3B-RDs are further observed and characterized by AFM, dynamic light scattering (DLS), and mass spectrometry (MS). The binding of chlorambucil and pH-triggered switching of the T3B-RDs are also characterized by 1H-NMR spectroscopy. PMID- 29402944 TI - Corium lavas: structure and properties of molten UO2-ZrO2 under meltdown conditions. AB - In the exceedingly rare event of nuclear reactor core meltdown, uranium dioxide fuel reacts with Zircaloy cladding to produce eutectic melts which can subsequently be oxidized by coolant/moderator water. Oxidized corium liquids in the xUO2.(100 - x)ZrO2 system were produced via laser melting of UO2-ZrO2 mixtures to temperatures in excess of 3000 K. Contamination was avoided by floating the droplets on a gas stream within an aerodynamic levitator and in-situ high-energy x-ray diffraction experiments allowed structural details to be elucidated. Molecular dynamics simulations well reproduced diffraction and density data, and show less compositional variation in thermal expansion and viscosity than suggested by existing measurements. As such, corium liquids maintain their highly penetrating nature irrespective of the amount of oxidized cladding dissolved in the molten fuel. Metal-oxygen coordination numbers vary with both composition and temperature. The former is due to mismatch in native values, nUO(x = 100) ~ 7 and nZrO(x = 0) ~ 6, and the requirement for oxygen site stabilization. The latter provides a thermal expansion mechanism. PMID- 29402945 TI - Ubiquinone binding site of yeast NADH dehydrogenase revealed by structures binding novel competitive- and mixed-type inhibitors. AB - Yeast Ndi1 is a monotopic alternative NADH dehydrogenase. Its crystal structure in complex with the electron acceptor, ubiquinone, has been determined. However, there has been controversy regarding the ubiquinone binding site. To address these points, we identified the first competitive inhibitor of Ndi1, stigmatellin, along with new mixed-type inhibitors, AC0-12 and myxothiazol, and thereby determined the crystal structures of Ndi1 in complexes with the inhibitors. Two separate binding sites of stigmatellin, STG-1 and STG-2, were observed. The electron density at STG-1, located at the vicinity of the FAD cofactor, further demonstrated two binding modes: STG-1a and STG-1b. AC0-12 and myxothiazol are also located at the vicinity of FAD. The comparison of the binding modes among stigmatellin at STG-1, AC0-12, and myxothiazol revealed a unique position for the aliphatic tail of stigmatellin at STG-1a. Mutations of amino acid residues that interact with this aliphatic tail at STG-1a reduced the affinity of Ndi1 for ubiquinone. In conclusion, the position of the aliphatic tail of stigmatellin at STG-1a provides a structural basis for its competitive inhibition of Ndi1. The inherent binding site of ubiquinone is suggested to overlap with STG-1a that is distinct from the binding site for NADH. PMID- 29402946 TI - Nature of spiral state and absence of electric polarisation in Sr-doped YBaCuFeO5 revealed by first-principle study. AB - Experimental results on YBaCuFeO5, in its incommensurate magnetic phase, appear to disagree on its ferroelectric response. Ambiguity exists on the nature of the spiral magnetic state too. Using first-principles density functional theory (DFT) calculations for the parent compound within LSDA + U + SO approximation, we reveal the nature of spiral state. The helical spiral is found to be more stable below the transition temperature as spins prefer to lie in ab plane. Dzyaloshinskii-Moriya (DM) interaction turns out to be negligibly small and the spin current mechanism is not valid in the helical spiral state, ruling out an electric polarisation from either. These results are in very good agreement with the recent, high quality, single-crystal data. We also investigate the magnetic transition in YBa1-xSrxCuFeO5 for the entire range (0 <= x <= 1) of doping. The exchange interactions are estimated as a function of doping and a quantum Monte Carlo (QMC) calculation on an effective spin Hamiltonian shows that the paramagnetic to commensurate phase transition temperature increases with doping till x = 0.5 and decreases beyond. These observations are consistent with experimental findings. PMID- 29402947 TI - Intracellular calcium signal at the leading edge regulates mesodermal sheet migration during Xenopus gastrulation. AB - During the gastrulation stage in animal embryogenesis, the cells leading the axial mesoderm migrate toward the anterior side of the embryo, vigorously extending cell protrusions such as lamellipodia. It is thought that the leading cells sense gradients of chemoattractants emanating from the ectodermal cells and translate them to initiate and maintain the cell movements necessary for gastrulation. However, it is unclear how the extracellular information is converted to the intracellular chemical reactions that lead to motion. Here we demonstrated that intracellular Ca2+ levels in the protrusion-forming leading cells are markedly higher than those of the following cells and the axial mesoderm cells. We also showed that inhibiting the intracellular Ca2+ significantly retarded the gastrulation cell movements, while increasing the intracellular Ca2+ with an ionophore enhanced the migration. We further found that the ionophore treatment increased the active form of the small GTPase Rac1 in these cells. Our results suggest that transient intracellular Ca2+ signals play an essential role in the active cell migration during gastrulation. PMID- 29402948 TI - Metabolomics profiling reveals differential adaptation of major energy metabolism pathways associated with autophagy upon oxygen and glucose reduction. AB - The ability of cells to rearrange their metabolism plays an important role in compensating the energy shortage and may provide cell survival. Our study focuses on identifing the important adaptational changes under the conditions of oxygen and glucose reduction. Employing mass spectrometry-based metabolomics in combination with biochemistry and microscopy techniques we identified metabolites, proteins and biomolecular pathways alterations in primary human IMR90 fibroblasts upon energy deficits. Multivariate statistical analyses revealed significant treatment-specific metabolite level and ratio alterations as well as major energy metabolism pathways like 'glycolysis', 'pentose phosphate pathway', 'mitochondrial electron transport chain' and 'protein biosynthesis (amino acids)' indicating an activation of catabolism and reduction of anabolism as important mechanisms of adaptation towards a bioenergetic demand. A treatment specific induction of the autophagic and mitophagic degradation activity upon oxygen reduction, glucose reduction as well as oxygen-glucose reduction further supports our results. Therefore, we suggest that the observed alterations represent an adaptive response in order to compensate for the cells' bioenergetics needs that ultimately provide cell survival. PMID- 29402950 TI - Variation in Raw Milk Microbiota Throughout 12 Months and the Impact of Weather Conditions. AB - Milk microbiota has a great influence on the safety and quality of dairy products. However, few studies have investigated the variations of bacterial composition in raw milk. In this study, raw milk samples were collected in 12 successive months, and their bacterial compositions were determined by 16 S rRNA gene sequencing. The highest diversity of bacterial composition was detected in June, while the lowest was in December. Firmicutes, Proteobacteria and Actinobacteria were the most abundant phyla and exhibited a counter-balanced relationship. Pseudomonas, Lactococcus and Acinetobacter were the most prevalent genera (>1%), and a tiny core microbiota (Acinetobacter and Pseudomonas) was observed. Temperature and humidity were the determining factors for most variation in bacterial compositions at both the phylum and genus levels. Higher abundances of Pseudomonas, Propionibacterium and Flavobacterium were correlated with low temperature. Furthermore, Pseudomonas/Propionibacterium and Lactobacillus/Bifidobacterium were two pairs of genera that had synergistic effects. Associations between the microbiota and milk quality parameters were analyzed. The abundances of Propionibacterium and Pseudoalteromonas were negatively correlated to total bacterial count, which meant that they helped to maintain milk quality, while a series of environmental microorganisms contributed to the spoilage of raw milk. PMID- 29402949 TI - Interaction of genotype and diet on small intestine microbiota of Japanese quail fed a cholesterol enriched diet. AB - Our previous study has shown that genetic selection for susceptibility/resistance to diet-induced atherosclerosis has affected the Japanese quail's cecal environment to accommodate distinctly different cecal microbiota. In this study, we fed the Atherosclerosis-resistant (RES) and -susceptable (SUS) quail a regular and a cholesterol enriched diet to examine the interaction of host genotype and diet on the diversity, composition, and metabolic functions of the duodenal and ileal microbiota with relations to atherosclerosis development. In the duodenal content, 9 OTUs (operational taxonomic units) were identified whose abundance had significant positive correlations with plasma total cholesterol, LDL level and/or LDL/HDL ratio. In the ileal content, 7 OTUs have significant correlation with plasma HDL. Cholesterol fed RES hosted significantly less Escherichia and unclassified Enterobacteriaceae (possibly pathogenic) in their duodenum than SUS fed the same diet. Dietary cholesterol significantly decreased the duodenal microbiome of SUS's biosynthesis of Ubiquinone and other terpenoid-quinone. Cholesterol fed RES had significantly more microbiome genes for Vitamin B6, selenocompound, taurine and hypotaurine, and Linoleic acid metabolism; Bisphenol degradation; primary bile acid, and butirosin and neomycin biosynthesis than SUS on the same diet. Microbiome in the ileum and ceca of RES contributed significantly towards the resistance to diet induced atherosclerosis. PMID- 29402951 TI - Presence and molecular characterization of Cryptosporidium and Giardia in recreational lake water in Tianjin, China: a preliminary study. AB - Little is known about the occurrence of Cryptosporidium and Giardia in recreational water in China. A total of 52 samples were collected from recreational lakes in Tianjin during a high-occurrence season (June-October) for the waterborne cryptosporidiosis and giardiasis, and the occurrence and genotypes of Cryptosporidium and Giardia were investigated. The results showed that 82.7% (43) and 98.1% (51) of samples were positive for Cryptosporidium oocyst and Giardia cysts, respectively. The mean concentration of parasites was 3.65 oocysts/10 L and 12.58 cysts/10 L, respectively. Molecular characterization revealed that the presence of Cryptosporidium parvum, C. andersoni, C. hominis, C. meleagridis, C. fragile, C. ubiquitum, and Giardia lamblia assemblage A, B and D. The protozoan contamination in the studied lakes may originate from animal feces on ground, which was washed into the lake by stormwater runoff. Nevertheless, there is a potential risk of infection during recreational activities in the lake because the dominant detected protozoan genotypes are common human pathogens. Moreover, microbial indicators analysis does not adequately indicate the protozoan contamination in recreational water. The information from this study will be valuable for future protozoan source tracking, and any further control interventions against Cryptosporidium and/or Giardia infection associated with recreational water. PMID- 29402952 TI - Histone H5 is a potent Antimicrobial Agent and a template for novel Antimicrobial Peptides. AB - Modern medicine is challenged continuously by the increasing prevalence of antibiotic resistant bacteria. Cationic antimicrobial peptides and their derivatives are interesting potential alternatives to antibiotics due to their rapid action, broad-spectrum of antimicrobial activity and limited emergence of bacterial resistance. This study reports the novel antimicrobial properties of histone H5, purified from chicken erythrocytes, and histone H5-derived synthetic peptides. Broth microdilution assays revealed that histone H5 has potent broad spectrum antimicrobial activity against Gram-positive and Gram-negative planktonic bacteria (MIC range: 1.9 +/- 1.8 to 4.9 +/- 1.5 ug/mL), including vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Moreover, histone H5 displayed anti-biofilm activity against established Listeria monocytogenes and Pseudomonas aeruginosa biofilms. Scanning electron microscopy demonstrated bacterial membrane damage after histone H5 treatment, while a hemolytic assay revealed that histone H5 is non-toxic towards mammalian erythrocytes, even at a concentration of 1 mg/mL. Although the predicted H5-derived antimicrobial peptides tested in this study were located within the antimicrobial domain of histone H5, their synthetic versions did not possess more potent antimicrobial activity than the full length protein. Overall, this study demonstrates that histone H5 is a potent antimicrobial and therefore a promising template for the development of novel histone H5-derived antimicrobial peptides. PMID- 29402953 TI - Development of chipless, wireless current sensor system based on giant magnetoimpedance magnetic sensor and surface acoustic wave transponder. AB - A chipless, wireless current sensor system was developed using a giant magnetoimpedance (GMI) magnetic sensor and one-port surface acoustic wave (SAW) reflective delay line for real-time power monitoring in a current-carrying conductor. The GMI sensor has a high-quality crystalline structure in each layer, which contributes to a high sensitivity and good linearity in a magnetic field of 3-16 Oe. A 400 MHz RF energy generated from the interdigital transducer (IDT) type reflector on the one-port SAW delay line was used as an activation source for the GMI magnetic sensor. The one-port SAW delay line replaces the presently existing transceiver system, which is composed of thousands of transistors, thus enabling chipless and wireless operation. We confirmed a large variation in the amplitude of the SAW reflection peak with a change in the impedance of the GMI sensor caused by the current flow through the conductor. Good linearity and sensitivity of ~0.691 dB/A were observed for currents in the range 1-12 A. Coupling of Mode (COM) modeling and impedance matching analysis were also performed to predict the device performance in advance and these were compared with the experimental results. PMID- 29402954 TI - Randomized controlled clinical trial on bleaching sensitivity and whitening efficacy of hydrogen peroxide versus combinations of hydrogen peroxide and ozone. AB - The clinical efficacy regarding bleaching sensitivity and tooth shade lightening using a standard hydrogen peroxide (H2O2) bleaching gel was compared with the additional use of ozone either before or after application of H2O2. Using computer-generated tables, 45 participants were randomly allocated into three groups (n = 15 each) in this investigator-driven, single-centre trial. In Group 1, upper anterior teeth were bleached using ozone (produced via a healOzone X4 device) for 60 seconds, then 38% H2O2 for 20 minutes; in Group 2, 38% H2O2 application (20 min) was followed by ozone (60 s); air produced by the healOzone machine (60 s) followed by 38% H2O2 (20 min) was used in Group 3 (control). Bleaching sensitivity was evaluated via visual analogue scales, and a treatment blinded reader objectively recorded tooth shades using a colorimeter before and 24 hours after bleaching (at alpha = 0.05). The H2O2/ozone combination did not result in pain sensations, while both ozone/H2O2 and H2O2 alone increased bleaching sensitivity (p < 0.001). Teeth achieved lighter shades (higher L*/lower b* values) after bleaching in all groups (p < 0.001), while Ozone boosted lighter tooth shades, irrespective of its use before or after H2O2 (p < 0.05). Due to the complimentary effects, applying ozone after H2O2 seems preferable for bleaching. PMID- 29402955 TI - The limited prosocial effects of meditation: A systematic review and meta analysis. AB - Many individuals believe that meditation has the capacity to not only alleviate mental-illness but to improve prosociality. This article systematically reviewed and meta-analysed the effects of meditation interventions on prosociality in randomized controlled trials of healthy adults. Five types of social behaviours were identified: compassion, empathy, aggression, connectedness and prejudice. Although we found a moderate increase in prosociality following meditation, further analysis indicated that this effect was qualified by two factors: type of prosociality and methodological quality. Meditation interventions had an effect on compassion and empathy, but not on aggression, connectedness or prejudice. We further found that compassion levels only increased under two conditions: when the teacher in the meditation intervention was a co-author in the published study; and when the study employed a passive (waiting list) control group but not an active one. Contrary to popular beliefs that meditation will lead to prosocial changes, the results of this meta-analysis showed that the effects of meditation on prosociality were qualified by the type of prosociality and methodological quality of the study. We conclude by highlighting a number of biases and theoretical problems that need addressing to improve quality of research in this area. PMID- 29402956 TI - Optimization by Self-Organized Criticality. AB - Self-organized criticality (SOC) is a phenomenon observed in certain complex systems of multiple interacting components, e.g., neural networks, forest fires, and power grids, that produce power-law distributed avalanche sizes. Here, we report the surprising result that the avalanches from an SOC process can be used to solve non-convex optimization problems. To generate avalanches, we use the Abelian sandpile model on a graph that mirrors the graph of the optimization problem. For optimization, we map the avalanche areas onto search patterns for optimization, while the SOC process receives no feedback from the optimization itself. The resulting method can be applied without parameter tuning to a wide range of optimization problems, as demonstrated on three problems: finding the ground-state of an Ising spin glass, graph coloring, and image segmentation. We find that SOC search is more efficient compared to other random search methods, including simulated annealing, and unlike annealing, it is parameter free, thereby eliminating the time-consuming requirement to tune an annealing temperature schedule. PMID- 29402957 TI - Selective Inhibition of Succinate Dehydrogenase in Reperfused Myocardium with Intracoronary Malonate Reduces Infarct Size. AB - Inhibition of succinate dehydrogenase (SDH) with malonate during reperfusion reduces infarct size in isolated mice hearts submitted to global ischemia. However, malonate has toxic effects that preclude its systemic administration in animals. Here we investigated the effect of intracoronary malonate on infarct size in pigs submitted to transient coronary occlusion. Under baseline conditions, 50 mmol/L of intracoronary disodium malonate, but not lower concentrations, transiently reduced systolic segment shortening in the region perfused by the left anterior descending coronary artery (LAD) in open-chest pigs. To assess the effects of SDH inhibition on reperfusion injury, saline or malonate 10 mmol/L were selectively infused into the area at risk in 38 animals submitted to ischemia-reperfusion. Malonate improved systolic shortening in the area at risk two hours after 15 min of ischemia (0.18 +/- 0.07 vs 0.00 +/- 0.01 a.u., p = 0.025, n = 3). In animals submitted to 40 min of ischemia, malonate reduced reactive oxygen species production (MitoSOX staining) during initial reperfusion and limited infarct size (36.46 +/- 5.35 vs 59.62 +/- 4.00%, p = 0.002, n = 11), without modifying reperfusion arrhythmias. In conclusion, inhibition of SDH with intracoronary malonate during early reperfusion limits reperfusion injury and infarct size in pigs submitted to transient coronary occlusion without modifying reperfusion arrhythmias or contractile function in distant myocardium. PMID- 29402958 TI - Cell fate in antiviral response arises in the crosstalk of IRF, NF-kappaB and JAK/STAT pathways. AB - The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-kappaB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-kappaB, a requirement for induction of IFNbeta expression. Autocrine IFNbeta initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-kappaB in first responder cells. Paracrine IFNbeta, in turn, sensitises second responder cells through a JAK/STAT-mediated positive feedforward pathway that upregulates the positive-feedback components: RIG-I, PKR and OAS1A. In these sensitised cells, the 'live-or-die' decision phase following poly(I:C) exposure is shorter they rapidly produce antiviral responses and commit to apoptosis. The interlinked positive feedback and feedforward signalling is key for coordinating cell fate decisions in cellular populations restricting pathogen spread. PMID- 29402959 TI - Dietary changes needed to improve diet sustainability: are they similar across Europe? AB - BACKGROUND/OBJECTIVES: It is not known whether dietary changes able to simultaneously achieve nutritional adequacy and reduce diet-related greenhouse gas emissions (GHGE) are similar across Europe when cultural and gender specificities are taken into account. SUBJECTS/METHODS: Starting from each mean observed diet in five European countries (France, UK, Italy, Finland, and Sweden) and for each gender, nutritionally adequate diets departing the least from observed diet were designed with linear programming by applying stepwise 10% GHGE reductions. Other models directly minimized GHGE. RESULTS: For most countries and whatever the gender, achieving nutritional adequacy implied between-food-group subtitutions (i.e., replacing items from the sugar/fat/alcohol food-group with items from the fruit and vegetables and starchy food-groups), but increased GHGE. Once nutritional adequacy was met, to decrease GHGE, the optimization process further induced within-food-groups substitutions that were reinforced by stepwise GHGE reductions. Diet modeling results showed the need for changes in consumption of animal-based products but those changes differed according to country and gender, particularly for fish, poultry, and non-liquid milk dairy. Depending on country and gender, maximal GHGE reductions achievable ranged from 62% to 78% but they induced large departures from observed diets (at least 2.8 kg/day of total absolute weight change) by modifying the quantity of at least 99% of food items. CONCLUSIONS: Setting nutritional goals with no consideration for the environment may increase GHGE. However, diet sustainability can be improved by substituting food items from the sugar/fat/alcohol food group with fruit, vegetables, and starches, and country-specific changes in consumption of animal-based products. Standardized surveys and individual diet modeling are promising tools for further exploring ways to achieve sustainable diets in Europe. PMID- 29402960 TI - Spatiotemporal organization of cilia drives multiscale mucus swirls in model human bronchial epithelium. AB - Mucociliary clearance is a biomechanical mechanism of airway protection. It consists of the active transport along the bronchial tree of the mucus, a fluid propelled by the coordinated beating of a myriad of cilia on the epithelial surface of the respiratory tract. The physics of mucus transport is poorly understood because it involves complex phenomena such as long-range hydrodynamic interactions, active collective ciliary motion, and the complex rheology of mucus. We propose a quantitative physical analysis of the ciliary activity and mucus transport on a large panel of human bronchial cultures from control subjects, patients with asthma and chronic obstructive pulmonary disease obtained from endobronchial biopsies. Here we report on the existence of multiple ciliary domains with sizes ranging from the tens of a micron to the centimeter, where ciliary beats present a circular orientational order. These domains are associated with circular mucus flow patterns, whose size scales with the average cilia density. In these domains, we find that the radial increase of the ciliated cell density coupled with the increase in the orientational order of ciliary beats result in a net local force proportional to the mucus velocity. We propose a phenomenological physical model that supports our results. PMID- 29402962 TI - Interatomic Potentials Transferability for Molecular Simulations: A Comparative Study for Platinum, Gold and Silver. AB - A perfectly transferable interatomic potential that works for different materials and systems of interest is lacking. This work considers the transferability of several existing interatomic potentials by evaluating their capability at various temperatures, to determine the range of accuracy of these potentials in atomistic simulations. A series of embedded-atom-method (EAM) based interatomic potentials has been examined for three precious and popular transition metals in nanoscale studies: platinum, gold and silver. The potentials have been obtained from various credible and trusted repositories and were evaluated in a wide temperature range to tackle the lack of a transferability comparison between multiple available force fields. The interatomic potentials designed for the single elements, binary, trinary and higher order compounds were tested for each species using molecular dynamics simulation. Validity of results arising from each potential was investigated against experimental values at different temperatures from 100 to 1000 K. The data covers accuracy of all studied potentials for prediction of the single crystals' elastic stiffness constants as well as the bulk, shear and Young's modulus of the polycrystalline specimens. Results of this paper increase users' assurance and lead them to the right model by a way to easily look up data. PMID- 29402961 TI - ITGB1-dependent upregulation of Caveolin-1 switches TGFbeta signalling from tumour-suppressive to oncogenic in prostate cancer. AB - Caveolin-1 (CAV1) is over-expressed in prostate cancer (PCa) and is associated with adverse prognosis, but the molecular mechanisms linking CAV1 expression to disease progression are poorly understood. Extensive gene expression correlation analysis, quantitative multiplex imaging of clinical samples, and analysis of the CAV1-dependent transcriptome, supported that CAV1 re-programmes TGFbeta signalling from tumour suppressive to oncogenic (i.e. induction of SLUG, PAI-1 and suppression of CDH1, DSP, CDKN1A). Supporting such a role, CAV1 knockdown led to growth arrest and inhibition of cell invasion in prostate cancer cell lines. Rationalized RNAi screening and high-content microscopy in search for CAV1 upstream regulators revealed integrin beta1 (ITGB1) and integrin associated proteins as CAV1 regulators. Our work suggests TGFbeta signalling and beta1 integrins as potential therapeutic targets in PCa over-expressing CAV1, and contributes to better understand the paradoxical dual role of TGFbeta in tumour biology. PMID- 29402963 TI - Fast assessment of lipid content in arteries in vivo by intravascular photoacoustic tomography. AB - Intravascular photoacoustic tomography is an emerging technology for mapping lipid deposition within an arterial wall for the investigation of the vulnerability of atherosclerotic plaques to rupture. By converting localized laser absorption in lipid-rich biological tissue into ultrasonic waves through thermoelastic expansion, intravascular photoacoustic tomography is uniquely capable of imaging the entire arterial wall with chemical selectivity and depth resolution. However, technical challenges, including an imaging catheter with sufficient sensitivity and depth and a functional sheath material without significant signal attenuation and artifact generation for both photoacoustics and ultrasound, have prevented in vivo application of intravascular photoacoustic imaging for clinical translation. Here, we present a highly sensitive quasi collinear dual-mode photoacoustic/ultrasound catheter with elaborately selected sheath material, and demonstrated the performance of our intravascular photoacoustic tomography system by in vivo imaging of lipid distribution in rabbit aortas under clinically relevant conditions at imaging speeds up to 16 frames per second. Ex vivo evaluation of fresh human coronary arteries further confirmed the performance of our imaging system for accurate lipid localization and quantification of the entire arterial wall, indicating its clinical significance and translational capability. PMID- 29402964 TI - Modeling the Intervention of HIV Transmission across Intertwined Key Populations. AB - The HIV transmissions between multiple key populations make interventions difficult, particularly with multiple transmission behaviors. It remains unclear how significant the role of bridge individuals (who connect multiple communities) is in HIV transmission, and how to develop more effective intervention strategies targeting different transmission modes across key populations. In this research, we proposed a 2-layer social network framework to simulate the HIV transmissions across female sex workers (FSWs) and persons who inject drugs (PWID) through two behaviors: unprotected sex and needle-sharing. We proposed a set of intervention strategies based on the topological properties of individuals in the social network and estimated the efficacy of these strategies. Simulation studies demonstrated that bridge individuals played a significant role in HIV transmissions across the two networks. Prevention on such bridge individuals could help reduce both the scale and speed of HIV transmissions. PMID- 29402965 TI - Characterizations of distinct parallel and antiparallel G-quadruplexes formed by two-repeat ALS and FTD related GGGGCC sequence. AB - The large expansion of GGGGCC (G4C2) repeats of the C9orf72 gene have been found to lead to the pathogenesis of devastating neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The structural polymorphisms of C9orf72 HRE DNA and RNA may cause aberrant transcription and contribute to the development of ALS and FTD. Here we showed that the two-repeat G4C2 DNA, d(G4C2)2, simultaneously formed parallel and antiparallel G-quadruplex conformations in the potassium solution. We separated different folds of d(G4C2)2 by anion exchange chromatography, followed with characterizations by circular dichroism and nuclear magnetic resonance spectroscopy. The parallel d(G4C2)2 G quadruplex folded as a symmetric tetramer, while the antiparallel d(G4C2)2 adopted the topology of an asymmetric dimer. These folds are distinct from the antiparallel chair-type conformation we previously identified for the d(G4C2)4 G quadruplex. Our findings have demonstrated the conformational heterogeneity of the C9orf72 HRE DNA, and provided new insights into the d(G4C2)n folding. Meanwhile, the purified d(G4C2)2 G-quadruplex samples are suitable for further three-dimensional structure characterizations, which are required for the structure-based design of small molecules targeting ALS and FTD related C9orf72 HRE. PMID- 29402966 TI - Tracking hidden organic carbon in rocks using chemometrics and hyperspectral imaging. AB - Finding traces of life or organic components of prebiotic interest in the rock record is an appealing goal for numerous fields in Earth and space sciences. However, this is often hampered by the scarceness and highly heterogeneous distribution of organic compounds within rocks. We assess here an innovative analytical strategy combining Synchrotron radiation-based Fourier-Transform Infrared microspectroscopy (S-FTIR) and multivariate analysis techniques to track and characterize organic compounds at the pore level in complex oceanic rocks. S FTIR hyperspectral images are analysed individually or as multiple image combinations (multiset analysis) using Principal Component Analyses (PCA) and Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS). This approach allows extracting simultaneously pure organic and mineral spectral signatures and determining their spatial distributions and relationships. MCR-ALS analysis provides resolved S-FTIR signatures of 8 pure mineral and organic components showing the close association at a micrometric scale of organic compounds and secondary clays formed during rock alteration and known to catalyse organic synthesis. These results highlights the potential of the serpentinizing oceanic lithosphere to generate and preserve organic compounds of abiotic origin, in favour of the hydrothermal theory for the origin of life. PMID- 29402967 TI - Optimization of Gas Composition Used in Plasma Chemical Vaporization Machining for Figuring of Reaction-Sintered Silicon Carbide with Low Surface Roughness. AB - In recent years, reaction-sintered silicon carbide (RS-SiC) has been of interest in many engineering fields because of its excellent properties, such as its light weight, high rigidity, high heat conductance and low coefficient of thermal expansion. However, RS-SiC is difficult to machine owing to its high hardness and chemical inertness and because it contains multiple components. To overcome the problem of the poor machinability of RS-SiC in conventional machining, the application of atmospheric-pressure plasma chemical vaporization machining (AP PCVM) to RS-SiC was proposed. As a highly efficient and damage-free figuring technique, AP-PCVM has been widely applied for the figuring of single-component materials, such as Si, SiC, quartz crystal wafers, and so forth. However, it has not been applied to RS-SiC since it is composed of multiple components. In this study, we investigated the AP-PCVM etching characteristics for RS-SiC by optimizing the gas composition. It was found that the different etching rates of the different components led to a large surface roughness. A smooth surface was obtained by applying the optimum gas composition, for which the etching rate of the Si component was equal to that of the SiC component. PMID- 29402968 TI - Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies. AB - RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation. PMID- 29402969 TI - Unidirectional molecular assembly alignment on graphene enabled by nanomechanical symmetry breaking. AB - Precise fabrication of molecular assemblies on a solid surface has long been of central interest in surface science. Their perfectly oriented growth only along a desired in-plane direction, however, remains a challenge, because of the thermodynamical equivalence of multiple axis directions on a solid-surface lattice. Here we demonstrate the successful fabrication of an in-plane, unidirectional molecular assembly on graphene. Our methodology relies on nanomechanical symmetry breaking effects under atomic force microscopy tip scanning, which has never been used in molecular alignment. Individual one dimensional (1D) molecular assemblies were aligned along a selected symmetry axis of the graphene lattice under finely-tuned scanning conditions after removing initially-adsorbed molecules. Experimental statistics and computational simulations suggest that the anisotropic tip scanning locally breaks the directional equivalence of the graphene surface, which enables nucleation of the unidirectional 1D assemblies. Our findings will open new opportunities in the molecular alignment control on various atomically flat surfaces. PMID- 29402970 TI - The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction. AB - The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype. PMID- 29402971 TI - Identification and caste-dependent expression patterns of DNA methylation associated genes in Bombus terrestris. AB - DNA methylation has been proposed to play critical roles in caste fate and behavioral plasticity in bumblebees, however, there is little information on its regulatory mechanisms. Here, we identified six important genes mediating the modification of DNA methylation and determined their expression patterns in the bumblebee Bombus terrestris. There is a complete functional DNA methylation system, including four DNA methyltransferases (DNMT1a, DNMT1b, DNMT2, and DNMT3), a DNA demethylase (Ten-eleven translocation), and a methyl-CpG-binding domain protein in B. terrestris. Most of these genes were highly expressed in fat bodies and gonads but lowly expressed in antennae and brains of bumblebee adults. Besides, these genes exhibited caste-specific expression patterns in bumblebees, with higher transcription levels in queens than workers and drones. Whereas their expression levels showed no remarkable difference in queenright and queenless workers. These results suggested potential roles of DNA methylation-related genes in caste differentiation in bumblebees. PMID- 29402972 TI - Publisher Correction: Ballistic geometric resistance resonances in a single surface of a topological insulator. AB - In the original version of this Article, the second and third sentences of the first paragraph of the "Gate voltage and antidot period dependencies" section of the Results originally incorrectly read "The characteristic evolution of the sheet resistance rho?=rho? (B=0) with Vg shown for three antidot samples and an unpatterned reference sample in Fig. 3a. The maxima of rhoxx, located between Vg~0.5 and 1 V, reflect the charge neutrality point (CNP), corresponding to an EF position located slightly in the valence band (see band structure in Fig. 3b)." In the corrected version, "[Formula: see text]" is replaced by "[Formula: see text]", and "The maxima of [Formula: see text]" is replaced by "The maxima of [Formula: see text]". PMID- 29402973 TI - Silver nanoparticles have lethal and sublethal adverse effects on development and longevity by inducing ROS-mediated stress responses. AB - Silver nanoparticles (AgNPs) are widely used in the household, medical and industrial sectors due to their effective bactericidal activities and unique plasmonic properties. Despite the promising advantages, safety concerns have been raised over the usage of AgNPs because they pose potential hazards. However, the mechanistic basis behind AgNPs toxicity, particularly the sublethal effects at the organismal level, has remained unclear. In this study, we used a powerful in vivo platform Drosophila melanogaster to explore a wide spectrum of adverse effects exerted by dietary AgNPs at the organismal, cellular and molecular levels. Lethal doses of dietary AgNPs caused developmental delays and profound lethality in developing animals and young adults. In contrast, exposure to sublethal doses, while not deadly to developing animals, shortened the adult lifespan and compromised their tolerance to oxidative stress. Importantly, AgNPs mechanistically resulted in tissue-wide accumulation of reactive oxygen species (ROS) and activated the Nrf2-dependent antioxidant pathway, as demonstrated by an Nrf2 activity reporter in vivo. Finally, dietary AgNPs caused a variety of ROS mediated stress responses, including apoptosis, DNA damage, and autophagy. Altogether, our study suggests that lethal and sublethal doses of AgNPs, have acute and chronic effects, respectively, on development and longevity by inducing ROS-mediated stress responses. PMID- 29402974 TI - Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster. AB - Genetic variability affects the response to numerous xenobiotics but its role in the clinically-observed irregular responses to general anesthetics remains uncertain. To investigate the pharmacogenetics of volatile general anesthetics (VGAs), we developed a Serial Anesthesia Array apparatus to expose multiple Drosophila melanogaster samples to VGAs and behavioral assays to determine pharmacokinetic and pharmacodynamic properties of VGAs. We studied the VGAs isoflurane and sevoflurane in four wild type strains from the Drosophila Genetic Reference Panel, two commonly used laboratory strains (Canton S and w 1118 ), and a mutant in Complex I of the mitochondrial electron transport chain (ND23 60114 ). In all seven strains, isoflurane was more potent than sevoflurane, as predicted by their relative lipid solubilities, and emergence from isoflurane was slower than from sevoflurane, reproducing cardinal pharmacokinetic and pharmacodynamic properties in mammals. In addition, ND23 60114 flies were more sensitive to both agents, as observed in worms, mice, and humans carrying Complex I mutations. Moreover, we found substantial variability among the fly strains both in absolute and in relative pharmacokinetic and pharmacodynamic profiles of isoflurane and sevoflurane. These data indicate that naturally occurring genetic variations measurably influence cardinal pharmacologic properties of VGAs and that flies can be used to identify relevant genetic variations. PMID- 29402975 TI - Primate modularity and evolution: first anatomical network analysis of primate head and neck musculoskeletal system. AB - Network theory is increasingly being used to study morphological modularity and integration. Anatomical network analysis (AnNA) is a framework for quantitatively characterizing the topological organization of anatomical structures and providing an operational way to compare structural integration and modularity. Here we apply AnNA for the first time to study the macroevolution of the musculoskeletal system of the head and neck in primates and their closest living relatives, paying special attention to the evolution of structures associated with facial and vocal communication. We show that well-defined left and right facial modules are plesiomorphic for primates, while anthropoids consistently have asymmetrical facial modules that include structures of both sides, a change likely related to the ability to display more complex, asymmetrical facial expressions. However, no clear trends in network organization were found regarding the evolution of structures related to speech. Remarkably, the increase in the number of head and neck muscles - and thus of musculoskeletal structures - in human evolution led to a decrease in network density and complexity in humans. PMID- 29402976 TI - Nitrogen Fixation by Trichodesmium and unicellular diazotrophs in the northern South China Sea and the Kuroshio in summer. AB - Distribution of diazotrophs and their nitrogen fixation activity were investigated in the northern South China Sea (nSCS) and the Kuroshio from July 16th to September 1st, 2009. N2 fixation activities in whole seawater and <10 MUm fraction at the surface were measured by acetylene reduction assay. Higher activities were observed at the East China Sea (ECS) Kuroshio and the nSCS shelf. The nSCS basin showed a low N2 fixation activity. The <10 MUm fractions (unicellular diazotrophs) contributed major portion to the whole-water activity in the survey time, indicating that nanoplanktonic cyanobacterias were the major diazotrophs in the survey area. Daily N2 fixation rates of Trichodesmium ranged from 0.11 to 9.83 pmolNtrichome-1 d-1 with an average of 4.03 pmolNtrichome-1 d 1. The Luzon Strait and the ECS Kuroshio had higher N2 fixation rates of Trichodesmium than the nSCS shelf and basin. Calculated activities of Trichodesmium at most stations were moderately low compared with that of the whole-water. The contribution of N2 fixation by the whole-water to primary production ranged from 1.7% to 18.5%. The estimated amount of new nitrogen introduced by Trichodesmium contributed up to 0.14% of the total primary production and 0.41% of the new production in the Luzon Strait. PMID- 29402977 TI - Direct imaging of the electron liquid at oxide interfaces. AB - The breaking of symmetry across an oxide heterostructure causes the electronic orbitals to be reconstructed at the interface into energy states that are different from their bulk counterparts 1 . The detailed nature of the orbital reconstruction critically affects the spatial confinement and the physical properties of the electrons occupying the interfacial orbitals2-4. Using an example of two-dimensional electron liquids forming at LaAlO3/SrTiO3 interfaces5,6 with different crystal symmetry, we show that the selective orbital occupation and spatial quantum confinement of electrons can be resolved with subnanometre resolution using inline electron holography. For the standard (001) interface, the charge density map obtained by inline electron holography shows that the two-dimensional electron liquid is confined to the interface with narrow spatial extension (~1.0 +/- 0.3 nm in the half width). On the other hand, the two dimensional electron liquid formed at the (111) interface shows a much broader spatial extension (~3.3 +/- 0.3 nm) with the maximum density located ~2.4 nm away from the interface, in excellent agreement with density functional theory calculations. PMID- 29402978 TI - Searching for materials with reduced dimension. PMID- 29402979 TI - Human Neurospheroid Arrays for In Vitro Studies of Alzheimer's Disease. AB - Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of concept experiments, we validate the neurospheroids array as a sensitive and robust tool for screening compounds over extended time. We show that when suspended in three-dimensional extracellular matrix up to several weeks, the stem cell-derived neurospheroids display extensive neurite outgrowth and extend thick bundles of dendrites outward. We also cultivate genetically-engineered stem cell-derived neurospheroids with familial Alzheimer's disease mutations for eight weeks in our microarray system. Interestingly, we observed robust accumulation of amyloid-beta and phosphorylated tau, key hallmarks of Alzheimer's disease. Overall, our in vitro model for engineering neurospheroid arrays is a valuable tool for studying complex neurodegenerative diseases and accelerating drug discovery. PMID- 29402981 TI - Clinical features and therapeutic perspectives on hypertension in diabetics. AB - Over 50% of patients with diabetes mellitus, either type 1 or 2, ultimately develop hypertension as a complication. In diabetics, this further increases the incidence of cardiovascular disease (CVD) by 2- to 3-fold and accelerates the progression of diabetic nephropathy. Arteriosclerosis, a clinical feature of hypertension in diabetics, develops and advances from a young age. Therefore, in providing treatment, it is necessary to evaluate the degree of arteriosclerosis. Diabetic patients are encouraged to strictly control their blood glucose levels. Recently developed drugs, such as GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors, also have hypotensive actions, making them ideal for use in diabetics with hypertension. SGLT2 inhibitors and GLP-1 receptor agonists reportedly suppress the onset and progression of CVD, as well as diabetic nephropathy. The possibility of hypoglycemia triggering blood pressure elevation and arrhythmia has been noted, so a key point here is not to cause hypoglycemia. In selecting hypotensive agents, we must choose types that do not aggravate insulin resistance and engage in hypotensive treatment that also considers both nocturnal and morning hypertension. In addition, facing the onset of an aging society, there is a growing need for treatments that do not cause excessive blood pressure reduction or hypoglycemia. Favorable lifelong blood pressure and glucose control are increasingly important for the treatment of diabetes accompanied by hypertension. PMID- 29402980 TI - Mendelian randomisation study of the relationship between vitamin D and risk of glioma. AB - To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM. PMID- 29402982 TI - Microparticles produced by human papillomavirus type 16 E7-expressing cells impair antigen presenting cell function and the cytotoxic T cell response. AB - High-risk, cancer-causing human papillomaviruses (HPV) cause infections of the epidermis that may progress to cancer, including cervical cancer. Viral persistence, contributed to by viral evasion of the host immune response, is associated with the likelihood of cancer developing. Langerhans cells (LCs) are the only professional antigen presenting cells located in the epidermis, therefore may influence the antiviral immune response. Microparticles, or microvesicles, are small membrane particles shed by cells that can exert effects on other cells at both a local and systemic level. We found increased numbers of microparticles were shed from human or mouse keratinocytes expressing the HPV16 E7 oncoprotein, compared with control keratinocytes. Co-culture of LCs with microparticles from E7-expressing cells suppressed the cytotoxic T cell response. We attributed this, at least in part, to the reduction in surface of CD40 and intracellular pro-inflammatory cytokine IL-12 p40 subunit that we measured in the LCs. The evidence provided here shows that co-culture of E7-microparticles with LCs inhibits antigen-specific cytotoxicity. This is an important finding, suggesting that microparticles from HPV-infected cells could suppress the T cell response by regulating LCs, potentially contributing to persistence of HPV infection and cancer. PMID- 29402983 TI - Prediction of HIV-1 and HIV-2 proteins by using Chou's pseudo amino acid compositions and different classifiers. AB - Human immunodeficiency virus (HIV) is the retroviral agent that causes acquired immune deficiency syndrome (AIDS). The number of HIV caused deaths was about 4 million in 2016 alone; it was estimated that about 33 million to 46 million people worldwide living with HIV. The HIV disease is especially harmful because the progressive destruction of the immune system prevents the ability of forming specific antibodies and to maintain an efficacious killer T cell activity. Successful prediction of HIV protein has important significance for the biological and pharmacological functions. In this study, based on the concept of Chou's pseudo amino acid (PseAA) composition and increment of diversity (ID), support vector machine (SVM), logisitic regression (LR), and multilayer perceptron (MP) were presented to predict HIV-1 proteins and HIV-2 proteins. The results of the jackknife test indicated that the highest prediction accuracy and CC values were obtained by the SVM and MP were 0.9909 and 0.9763, respectively, indicating that the classifiers presented in this study were suitable for predicting two groups of HIV proteins. PMID- 29402984 TI - Clinical-pathological study on beta-APP, IL-1beta, GFAP, NFL, Spectrin II, 8OHdG, TUNEL, miR-21, miR-16, miR-92 expressions to verify DAI-diagnosis, grade and prognosis. AB - Traumatic brain injury (TBI) is one of the most important death and disability cause, involving substantial costs, also in economic terms, when considering the young age of the involved subject. Aim of this paper is to report a series of patients treated at our institutions, to verify neurological results at six months or survival; in fatal cases we searched for betaAPP, GFAP, IL-1beta, NFL, Spectrin II, TUNEL and miR-21, miR-16, and miR-92 expressions in brain samples, to verify DAI diagnosis and grade as strong predictor of survival and inflammatory response. Concentrations of 8OHdG as measurement of oxidative stress was performed. Immunoreaction of beta-APP, IL-1beta, GFAP, NFL, Spectrin II and 8OHdG were significantly increased in the TBI group with respect to control group subjects. Cell apoptosis, measured by TUNEL assay, were significantly higher in the study group than control cases. Results indicated that miR-21, miR-92 and miR 16 have a high predictive power in discriminating trauma brain cases from controls and could represent promising biomarkers as strong predictor of survival, and for the diagnosis of postmortem traumatic brain injury. PMID- 29402985 TI - Impact of overexpression of cytosolic isoform of O-acetylserine sulfhydrylase on soybean nodulation and nodule metabolome. AB - Nitrogen-fixing nodules, which are also major sites of sulfur assimilation, contribute significantly to the sulfur needs of whole soybean plants. Nodules are the predominant sites for cysteine accumulation and the activity of O acetylserine(thiol)lyase (OASS) is central to the sulfur assimilation process in plants. Here, we examined the impact of overexpressing OASS on soybean nodulation and nodule metabolome. Overexpression of OASS did not affect the nodule number, but negatively impacted plant growth. HPLC measurement of antioxidant metabolites demonstrated that levels of cysteine, glutathione, and homoglutathione nearly doubled in OASS overexpressing nodules when compared to control nodules. Metabolite profiling by LC-MS and GC-MS demonstrated that several metabolites related to serine, aspartate, glutamate, and branched-chain amino acid pathways were significantly elevated in OASS overexpressing nodules. Striking differences were also observed in the flavonoid levels between the OASS overexpressing and control soybean nodules. Our results suggest that OASS overexpressing plants compensate for the increase in carbon requirement for sulfur assimilation by reducing the biosynthesis of some amino acids, and by replenishing the TCA cycle through fatty acid hydrolysis. These data may indicate that in OASS overexpressing soybean nodules there is a moderate decease in the supply of energy metabolites to the nodule, which is then compensated by the degradation of cellular components to meet the needs of the nodule energy metabolism. PMID- 29402986 TI - Assessment of future climate change impacts on nonpoint source pollution in snowmelt period for a cold area using SWAT. AB - The source area of Liao River is a typical cold region in northeastern China, which experiences serious problems with agricultural nonpoint source pollution (NPS), it is important to understand future climate change impacts on NPS in the watershed. This issue has been investigated by coupling semi distributed hydrological model (SWAT), statistical downscaling model (SDSM) and global circulation model (GCMs). The results show that annual average temperature would rise by 2.1 degrees C (1.3 degrees C) in the 2080 s under scenario RCP8.5 (RCP4.5), and annual precipitation would increase by 67 mm (33 mm). The change in winter temperature and precipitation is most significant with an increase by 0.23 degrees C/10a (0.17 degrees C/10a) and 1.94 mm/10a (2.78 mm/10a). The future streamflow, TN and TP loads would decrease by 19.05% (10.59%), 12.27% (8.81%) and 10.63% (6.11%), respectively. Monthly average streamflow, TN and TP loads would decrease from March to November, and increase from December to February. This is because the increased precipitation and temperature in winter, which made the spring snowpack melting earlier. These study indicate the trends of nonpoint source pollution during the snowmelt period under climate change conditions, accordingly adaptation measures will be necessary. PMID- 29402987 TI - Matched asymptotic solution for crease nucleation in soft solids. AB - A soft solid subjected to a large compression develops sharp self-contacting folds at its free surface, known as creases. Creasing is physically different from structural elastic instabilities, like buckling or wrinkling. Indeed, it is a fully nonlinear material instability, similar to a phase-transformation. This work provides theoretical insights of the physics behind crease nucleation. Creasing is proved to occur after a global bifurcation allowing the co-existence of an outer deformation and an inner solution with localised self-contact at the free surface. The most fundamental result here is the analytic prediction of the nucleation threshold, in excellent agreement with experiments and numerical simulations. A matched asymptotic solution is given within the intermediate region between the two co-existing states. The self-contact acts like the point wise disturbance in the Oseen's correction for the Stokes flow past a circle. Analytic expressions of the matching solution and its range of validity are also derived. PMID- 29402988 TI - Reduced arctic tundra productivity linked with landform and climate change interactions. AB - Arctic tundra ecosystems have experienced unprecedented change associated with climate warming over recent decades. Across the Pan-Arctic, vegetation productivity and surface greenness have trended positively over the period of satellite observation. However, since 2011 these trends have slowed considerably, showing signs of browning in many regions. It is unclear what factors are driving this change and which regions/landforms will be most sensitive to future browning. Here we provide evidence linking decadal patterns in arctic greening and browning with regional climate change and local permafrost-driven landscape heterogeneity. We analyzed the spatial variability of decadal-scale trends in surface greenness across the Arctic Coastal Plain of northern Alaska (~60,000 km2) using the Landsat archive (1999-2014), in combination with novel 30 m classifications of polygonal tundra and regional watersheds, finding landscape heterogeneity and regional climate change to be the most important factors controlling historical greenness trends. Browning was linked to increased temperature and precipitation, with the exception of young landforms (developed following lake drainage), which will likely continue to green. Spatiotemporal model forecasting suggests carbon uptake potential to be reduced in response to warmer and/or wetter climatic conditions, potentially increasing the net loss of carbon to the atmosphere, at a greater degree than previously expected. PMID- 29402989 TI - Mesenchymal stem cells over-expressing cxcl12 enhance the radioresistance of the small intestine. AB - The chemokine C-X-C motif chemokine 12 (CXCL12) greatly impacts various biological processes in mammals, including cell survival, growth and migration. Mesenchymal stem cells (MSCs) are promising tools for carrying foreign genes to treat radiation-induced injuries in the intestinal epithelium. In this study, human adipose-derived MSCs were constructed to over-express the mouse cxcl12 gene to treat such injuries. In vitro, because of the high levels of mouse CXCL12 in conditioned medium produced by mouse cxcl12 gene-modified cells, phosphorylation of Akt at Ser473 and Erk1/2 at Thr202/Thr204 was increased within crypt cells of irradiated organoids compared with unmodified controls. Moreover, intracellular stabilization of beta-catenin was achieved after treatment of mouse cxcl12 gene modified cells with conditioned medium. As a result, survival of crypt cells was maintained and their proliferation was promoted. When delivering mouse cxcl12 gene-modified cells into irradiated BALB/c nude mice, mice were rescued despite the clearance of cells from the host within 1 week. Irradiated mice that received mouse cxcl12 gene-modified MSCs exhibited reduced serum levels of interleukin 1alpha (IL-1alpha) and IL-6 as well as elevated levels of CXCL12. Additionally, epithelial recovery from radiation stress was accelerated compared with the irradiated-alone controls. Moreover, mouse cxcl12 gene-modified MSCs were superior to unmodified cells at strengthening host repair responses to radiation stress as well as presenting increased serum CXCL12 levels and decreased serum IL 1alpha levels. Furthermore, the number of crypt cells that were positive for phosphorylated Akt at Ser473 and phosphorylated Erk1/2 at Thr202/Thr204 increased following treatment with mouse cxcl12 gene-modified MSCs. Thus, cxcl12 gene modified MSCs confer radioresistance to the intestinal epithelium. PMID- 29402991 TI - Uncovering hidden disease patterns by simulating clinical diagnostic processes. AB - Choosing a sequence of observations (often with stochastic outcomes) which maximizes the information gain from a system of interacting variables is essential for a wide range of problems in science and technology, such as clinical diagnostic problems. Here, we use a probabilistic model of diseases and signs/symptoms to simulate the effects of medical decisions on the quality of diagnosis by maximizing an appropriate objective function of the medical observations. The study provides a systematic way of proposing new medical tests, considering the significance of diseases and cost of the suggested observations. The efficacy of methods and role of the objective functions as well as initial signs/symptoms are examined by numerical simulations of the diagnostic process by exhaustive or Monte Carlo sampling algorithms. PMID- 29402990 TI - Diastolic dysfunction is more apparent in STZ-induced diabetic female mice, despite less pronounced hyperglycemia. AB - Diabetic cardiomyopathy is a distinct pathology characterized by early emergence of diastolic dysfunction. Increased cardiovascular risk associated with diabetes is more marked for women, but an understanding of the role of diastolic dysfunction in female susceptibility to diabetic cardiomyopathy is lacking. To investigate the sex-specific relationship between systemic diabetic status and in vivo occurrence of diastolic dysfunction, diabetes was induced in male and female mice by streptozotocin (5x daily i.p. 55 mg/kg). Echocardiography was performed at 7 weeks post-diabetes induction, cardiac collagen content assessed by picrosirius red staining, and gene expression measured using qPCR. The extent of diabetes-associated hyperglycemia was more marked in males than females (males: 25.8 +/- 1.2 vs 9.1 +/- 0.4 mM; females: 13.5 +/- 1.5 vs 8.4 +/- 0.4 mM, p < 0.05) yet in vivo diastolic dysfunction was evident in female (E/E' 54% increase, p < 0.05) but not male diabetic mice. Cardiac structural abnormalities (left ventricular wall thinning, collagen deposition) were similar in male and female diabetic mice. Female-specific gene expression changes in glucose metabolic and autophagy-related genes were evident. This study demonstrates that STZ-induced diabetic female mice exhibit a heightened susceptibility to diastolic dysfunction, despite exhibiting a lower extent of hyperglycemia than male mice. These findings highlight the importance of early echocardiographic screening of asymptomatic prediabetic at-risk patients. PMID- 29402992 TI - HOXD3 targeted by miR-203a suppresses cell metastasis and angiogenesis through VEGFR in human hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC), one of the most common aggressive tumors worldwide has a relatively high mortality rate among malignant tumors. MicroRNAs (miRNAs), acting as tumor suppressors, are involved in the regulation of invasion, metastasis, and angiogenesis of tumor cells. However, a potential role for miR-203a in HCC has not been described yet. In this study, we show that miR 203a markedly suppresses HCC cell migration, invasion, and angiogenesis. In addition, the transcription factor HOXD3 appears to be a direct target of miR 203a. HOXD3 knockdown substantially decreased HCC cell migration, invasion, and angiogenesis, effects similar to those seen for miR-203a expression. Rescuing the function of HOXD3 attenuated the effect of miR-203a overexpression in HCC cells. Furthermore, HOXD3 can directly target the promoter region of VEGFR and increase VEGFR expression. Taken together, our findings indicate that miR-203a inhibits HCC cell invasion, metastasis, and angiogenesis by negatively targeting HOXD3 and suppressing cell signaling through the VEGFR pathway, suggesting that miR-203a might represent a potential therapeutic target for HCC intervention. PMID- 29402993 TI - Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling. AB - Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency. PMID- 29402994 TI - Extreme plasma states in laser-governed vacuum breakdown. AB - Triggering vacuum breakdown at laser facility is expected to provide rapid electron-positron pair production for studies in laboratory astrophysics and fundamental physics. However, the density of the produced plasma may cease to increase at a relativistic critical density, when the plasma becomes opaque. Here, we identify the opportunity of breaking this limit using optimal beam configuration of petawatt-class lasers. Tightly focused laser fields allow generating plasma in a small focal volume much less than lambda3 and creating extreme plasma states in terms of density and produced currents. These states can be regarded to be a new object of nonlinear plasma physics. Using 3D QED-PIC simulations we demonstrate a possibility of reaching densities over 1025 cm-3, which is an order of magnitude higher than expected earlier. Controlling the process via initial target parameters provides an opportunity to reach the discovered plasma states at the upcoming laser facilities. PMID- 29402995 TI - Quasi-periodic concave microlens array for liquid refractive index sensing fabricated by femtosecond laser assisted with chemical etching. AB - In this study, a high-efficiency single-pulsed femtosecond laser assisted with chemical wet etching method has been proposed to obtain large-area concave microlens array (MLA). The quasi-periodic MLA consisting of about two million microlenses with tunable diameter and sag height by adjusting laser scanning speed and etching time is uniformly manufactured on fused silica and sapphire within 30 minutes. Moreover, the fabricated MLA behaves excellent optical focusing and imaging performance, which could be used to sense the change of the liquid refractive index (RI). In addition, it is demonstrated that small period and high RI of MLA could acquire high sensitivity and broad dynamic measurement range, respectively. Furthermore, the theoretical diffraction efficiency is calculated by the finite domain time difference (FDTD) method, which is in good agreement with the experimental results. PMID- 29402996 TI - DNA assay based on Nanoceria as Fluorescence Quenchers (NanoCeracQ DNA assay). AB - Functional nanomaterials with fluorescent or quenching abilities are important for the development of molecular probes for detection and studies of nucleic acids. Here, we describe a new class of molecular nanoprobes, the NanoCeracQ that uses nanoceria particles as a nanoquencher of fluorescent oligonucleotides for rapid and sensitive detection of DNA sequences and hybridization events. We show that nanoceria forms stable and reversible bionanoconjugates with oligonucleotides and can specifically recognize and detect DNA sequences in a single step. In absence of the target DNA, the nanoprobe produced minimal background fluorescence due to the high quenching efficiency of nanoceria. Competitive binding of the target induced a concentration dependent increase in the fluorescence signal due to hybridization and release of the fluorescent tag from the nanoparticle surface. The nanoprobe enabled sensitive detection of the complementary strand with a detection limit of 0.12 nM, using a single step procedure. The results show that biofunctionalized nanoceria can be used as a universal nanoquencher and nanosensing platform for fluorescent DNA detection and studies of nucleic acid interactions. This approach can find broad applications in molecular diagnostics, sensor development, gene expression profiling, imaging and forensic analysis. PMID- 29402997 TI - Two new secondary metabolites from a fungus of the genus Robillarda. AB - Two new compounds, robillafuran and (+)-robillapyrone, were isolated from the culture extract of a fungal strain of Robillarda along with (+)-monascuspyrone. The absolute configuration of (+)-robillapyrone and (+)-monascuspyrone was determined by ECD calculation. These three compounds showed preadipocyte differentiation activity at 10-40 MUM. PMID- 29402998 TI - A new macrolactam derivative from the marine actinomycete HF-11225. AB - A new macrolactam derivative, designated as nivelactam B (1), was isolated from the fermentation broth of marine-derived actinomycete HF-11225. Its structure was determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, as well as ESI-MS and comparison with data from the literature. Compound 1 showed weak cytotoxic and antifungal activities. PMID- 29402999 TI - Kanamycin and its derivative, arbekacin: significance and impact. AB - On the occasion of the 60th anniversary of the discovery (1957) of kanamycin (KM), a series of research achievements on KM and its semisynthetic derivative Arbekacin (ABK) are outlined. KM was first used clinically in 1958 and was appreciated for its remarkable curing effect on various bacterial infections, especially tuberculosis. ABK is a KM derivative rationally semisynthesized to overcome KM resistance due to enzymatic phosphorylation and acetylation. Since its approval in 1990 as an anti-MRSA drug, ABK has been and still is effectively used in chemotherapy because MRSA rarely develops high ABK-resistance. Research that illuminated the unique features of ABK enabling it to resist the development of resistance by MRSA are also described. PMID- 29403000 TI - The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. AB - Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors. PMID- 29403001 TI - Effect of Melatonin on the stability and expression of reference genes in Catharanthus roseus. AB - The role of Melatonin in influencing diverse genes in plants has gained momentum in recent years and many reports have employed qRT-PCR for their quantification. Relative quantification of gene expression relies on accurate normalization of qRT-PCR data against a stably-expressing internal reference-gene. Although researchers have been using commonly available reference-genes to assess Melatonin-induced gene expression, but to-date, there have been no attempts to validate the reference-gene stability under Melatonin-supplementation in planta. In this study, we performed stability assessment of common reference-genes under Melatonin-supplementation and abiotic stress in leaves and seedlings of Catharanthus roseus using geNorm, NormFinder, BestKeeper, DeltaCt and RefFinder algorithms. Nine candidate reference-genes were tested for stability in C. roseus (FBOX, CACS, TIP, RSP9, EXP, EXPR, SAND, F17M5, ACT) and our study inferred that while EXP and EXPR were the most-stable, F17M5 was the lowest-stable gene in the leaf-fed samples. Among seedlings of C. roseus, F17M5 and TIP were the most, while ACT was the least-stable gene. The suitability of selected stable reference gene pairs was demonstrated by assessing the transcript levels of the Melatonin biosynthesis gene SNAT under same conditions. Our study is the first to comprehensively analyze the stability of commonly-used reference-genes under Melatonin-induced conditions in C. roseus. PMID- 29403002 TI - Effect of HIV/HCV Co-Infection on the Protease Evolution of HIV-1B: A Pilot Study in a Pediatric Population. AB - This pilot study evaluates in pediatric patients the impact of HIV/HCV coinfection in the molecular evolution of the HIV-1 subtype B protease (HIV 1BPR). For this study, HIV-1B/HCV coinfected (15) and HIV-1B monoinfected (56) patients with available HIV-1B pol sequences were enrolled. Both groups of patients had comparable gender frequencies and average age, time of infection, antiretroviral treatment (ART) exposure and time under ART. Prevalence of drug resistance mutations (DRM), genetic diversity, number of synonymous (dS) and non synonymous (dN) mutations per site and selection pressures (dN - dS) in the HIV 1BPR were estimated and compared between mono- and coinfected patients. Both HIV 1B populations presented similar genetic diversity (0.050 +/- 0.02 vs. 0.045 +/- 0.01) and dS (0.074 +/- 0.03 vs. 0.078 +/- 0.04). In turn, in coinfected patients the HIV-1BPR had higher dN (0.045 +/- 0.01 vs. 0.024 +/- 0.01) and dN-dS (-0.026 +/- 0.02 vs. -0.048 +/- 0.04) values, and less amino acid sites under purifying selection (4.2% vs. 42.1%) than in monoinfected patients. Accordingly, in co infection with HCV, the HIV-1BPR sites 50, 53, 82, 84 and 88 - associated with resistance to PIs - were under neutral evolution, whereas these sites were under purifying selection in monoinfected patients. This pilot study suggests that HIV 1B may evolve differently in the presence than in the absence of HCV. PMID- 29403004 TI - A new strategy for the passive skin delivery of nanoparticulate, high molecular weight hyaluronic acid prepared by a polyion complex method. AB - Restoring hyaluronic acid (HA) content is important for maintaining the function of photo-aged skin. This study aimed to evaluate the passive delivery into skin of HA nanoparticles formed by the polyion complex method. Nanoparticles were prepared by mixing and stirring anionic HA with a cationic polymer, protamine, at the charge ratio 55:45. The permeation of fluorescently-labelled HA nanoparticles (HANP) or free HA through hairless mouse skin was characterized in vitro. HANP or free HA was applied to ultraviolet (UV)-irradiated mice in vivo, and their transepidermal water loss (TEWL) was measured after 4 days. HA that had been delivered into skin was separated and characterized by molecular sieve chromatography. HANP were able to deliver HA into the dermis both in vitro and in vivo, whereas free HA penetrated no further than the stratum corneum. Following HANP application, HA within the skin was present in the form of free HA rather than nanoparticles. When applied in vivo, HANP significantly reduced the TEWL caused by UV irradiation. Thus, although free HA does not penetrate into the skin by passive diffusion, HA can be effectively delivered by nanoparticles. HA is then released from the nanoparticles and can contribute to barrier recovery following UV irradiation. PMID- 29403003 TI - Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis. AB - Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we show that Chi3l1 expression was increased in activated T cells, especially in Th2 cells. In addition, Chi3l1-deficient T cells are hyper-responsive to TcR stimulation and are prone to differentiating into Th1 cells. Chi3l1-deficient Th1 cells show increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice show reduced melanoma lung metastasis with increased IFNgamma and TNFalpha-producing T cells in the lung. Furthermore, silencing of Chi3l1 expression in the lung using peptide-siRNA complex (dNP2-siChi3l1) efficiently inhibit lung metastasis with enhanced Th1 and CTL responses. Collectively, this study demonstrates Chi3l1 is a regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity. PMID- 29403005 TI - Nonlinear dynamics of trions under strong optical excitation in monolayer MoSe2. AB - By employing ultrafast transient reflection measurements based on two-color pump probe spectroscopy, the population and valley polarization dynamics of trions in monolayer MoSe2 were investigated at relatively high excitation densities under near-resonant excitation. Both the nonlinear dynamic photobleaching of the trion resonance and the redshift of the exciton resonance were found to be responsible for the excitation-energy- and density-dependent transient reflection change as a result of many-body interactions. Furthermore, from the polarization-resolved measurements, it was revealed that the initial fast population and polarization decay process upon strong photoexcitation observed for trions was determined by trion formation, transient phase-space filling and the short valley lifetime of excitons. The results provide a basic understanding of the nonlinear dynamics of population and valley depolarization of trions, as well as exciton-trion correlation in atomically thin MoSe2 and other transition metal dichalcogenide materials. PMID- 29403006 TI - Epidemic spreading in modular time-varying networks. AB - We investigate the effects of modular and temporal connectivity patterns on epidemic spreading. To this end, we introduce and analytically characterise a model of time-varying networks with tunable modularity. Within this framework, we study the epidemic size of Susceptible-Infected-Recovered, SIR, models and the epidemic threshold of Susceptible-Infected-Susceptible, SIS, models. Interestingly, we find that while the presence of tightly connected clusters inhibits SIR processes, it speeds up SIS phenomena. In this case, we observe that modular structures induce a reduction of the threshold with respect to time varying networks without communities. We confirm the theoretical results by means of extensive numerical simulations both on synthetic graphs as well as on a real modular and temporal network. PMID- 29403009 TI - Carbon fibers coated with graphene reinforced TiAl alloy composite with high strength and toughness. AB - To meet the more rigorous requirement in aerospace industry, recent studies on strengthening and toughening TiAl alloys mostly focus on high Nb addition, which inevitably bring in an increasing of density. In this study, a carbon fibers coated with graphene reinforced TiAl alloy composite was fabricated by powder metallurgy, melt spun and vacuum melting. This composite got remarkable mechanical properties combined with a prominent density reduction. In contrast with pure TiAl ingots, this sample exhibits an average fracture strain from 16% up to 26.27%, and an average strength from 1801 MPa up to 2312 MPa. Thus, we can achieve a new method to fabricate this low-density, good mechanical performance TiAl composite which could bring in more opportunities for application in aerospace industry. PMID- 29403007 TI - Fibroblast-associated tumour microenvironment induces vascular structure networked tumouroid. AB - In vitro three-dimensional (3D) tumour models mimic natural cancer tissue in vivo, bridging the gap between conventional 2D in vitro testing and animal models. Stromal and cancer tissues with extracellular matrix (ECM) can provide a tumour microenvironment (TME) with cell-to-cell and cell-to-ECM interactions. These interactions induce the exchange of biophysical factors, contributing to the progression, metastasis, and drug resistance of cancer. Here, we describe a 3D in vitro lung cancer model cultured in a microfluidic channel that is able to confirm the role and function of various stromal cells in tumourigenesis, thereby representing an in vivo-like TME. We founded that biophysical factors contribute to the role of fibroblast cells in tumour formation, especially, producing a nascent vessel-like tubular structure, resulting in the formation of vascularized tumour tissue. Fibroblast cells altered the gene expression of the cancer cells to enhance metastasis, survival, and angiogenesis. The device could be used for developing and screening anti-cancer drugs through the formation of the same multicellular tumour spheroids under TME interactions. We believe this microfluidic system provides interaction of TME for cancer research by culturing stromal tissue. PMID- 29403008 TI - A NIN-LIKE PROTEIN mediates nitrate-induced control of root nodule symbiosis in Lotus japonicus. AB - Legumes and rhizobia establish symbiosis in root nodules. To balance the gains and costs associated with the symbiosis, plants have developed two strategies for adapting to nitrogen availability in the soil: plants can regulate nodule number and/or stop the development or function of nodules. Although the former is accounted for by autoregulation of nodulation, a form of systemic long-range signaling, the latter strategy remains largely enigmatic. Here, we show that the Lotus japonicus NITRATE UNRESPONSIVE SYMBIOSIS 1 (NRSYM1) gene encoding a NIN LIKE PROTEIN transcription factor acts as a key regulator in the nitrate-induced pleiotropic control of root nodule symbiosis. NRSYM1 accumulates in the nucleus in response to nitrate and directly regulates the production of CLE-RS2, a root derived mobile peptide that acts as a negative regulator of nodule number. Our data provide the genetic basis for how plants respond to the nitrogen environment and control symbiosis to achieve proper plant growth. PMID- 29403010 TI - Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. AB - Clinical measurements can be viewed as useful intermediate phenotypes to promote understanding of complex human diseases. To acquire comprehensive insights into the underlying genetics, here we conducted a genome-wide association study (GWAS) of 58 quantitative traits in 162,255 Japanese individuals. Overall, we identified 1,407 trait-associated loci (P < 5.0 * 10-8), 679 of which were novel. By incorporating 32 additional GWAS results for complex diseases and traits in Japanese individuals, we further highlighted pleiotropy, genetic correlations, and cell-type specificity across quantitative traits and diseases, which substantially expands the current understanding of the associated genetics and biology. This study identified both shared polygenic effects and cell-type specificity, represented by the genetic links among clinical measurements, complex diseases, and relevant cell types. Our findings demonstrate that even without prior biological knowledge of cross-phenotype relationships, genetics corresponding to clinical measurements successfully recapture those measurements' relevance to diseases, and thus can contribute to the elucidation of unknown etiology and pathogenesis. PMID- 29403012 TI - A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. AB - Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel 1 , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl- currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'2,3, abolished the voltage- and time dependent gating of ClC-2 and strongly increased Cl- conductance at resting potentials. Expression of ClC-2Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells. PMID- 29403013 TI - The host-encoded RNase E endonuclease as the crRNA maturation enzyme in a CRISPR Cas subtype III-Bv system. AB - Specialized RNA endonucleases for the maturation of clustered regularly interspaced short palindromic repeat (CRISPR)-derived RNAs (crRNAs) are critical in CRISPR-CRISPR-associated protein (Cas) defence mechanisms. The Cas6 and Cas5d enzymes are the RNA endonucleases in many class 1 CRISPR-Cas systems. In some class 2 systems, maturation and effector functions are combined within a single enzyme or maturation proceeds through the combined actions of RNase III and trans activating CRISPR RNAs (tracrRNAs). Three separate CRISPR-Cas systems exist in the cyanobacterium Synechocystis sp. PCC 6803. Whereas Cas6-type enzymes act in two of these systems, the third, which is classified as subtype III-B variant (III-Bv), lacks cas6 homologues. Instead, the maturation of crRNAs proceeds through the activity of endoribonuclease E, leaving unusual 13- and 14-nucleotide long 5'-handles. Overexpression of RNase E leads to overaccumulation and knock down to the reduced accumulation of crRNAs in vivo, suggesting that RNase E is the limiting factor for CRISPR complex formation. Recognition by RNase E depends on a stem-loop in the CRISPR repeat, whereas base substitutions at the cleavage site trigger the appearance of secondary products, consistent with a two-step recognition and cleavage mechanism. These results suggest the adaptation of an otherwise very conserved housekeeping enzyme to accommodate new substrates and illuminate the impressive plasticity of CRISPR-Cas systems that enables them to function in particular genomic environments. PMID- 29403014 TI - Deaminase-mediated multiplex genome editing in Escherichia coli. AB - In eukaryotes, the CRISPR-Cas9 system has now been widely used as a revolutionary genome engineering tool1, 2. However, in prokaryotes, the use of nuclease mediated genome editing tools has been limited to negative selection for the already modified cells because of its lethality3, 4. Here, we report on deaminase mediated targeted nucleotide editing (Target-AID) 5 adopted in Escherichia coli. Cytidine deaminase PmCDA1 fused to the nuclease-deficient CRISPR-Cas9 system achieved specific point mutagenesis at the target sites in E. coli by introducing cytosine mutations without compromising cell growth. The cytosine-to-thymine substitutions were induced mainly within an approximately five-base window of target sequences on the protospacer adjacent motif-distal side, which can be shifted depending on the length of the single guide RNA sequence. Use of a uracil DNA glycosylase inhibitor 6 in combination with a degradation tag (LVA tag) 7 resulted in a robustly high mutation efficiency, which allowed simultaneous multiplex editing of six different genes. The major multi-copy transposase genes that consist of at least 41 loci were also simultaneously edited by using four target sequences. As this system does not rely on any additional or host dependent factors, it may be readily applicable to a wide range of bacteria. PMID- 29403011 TI - CLCN2 chloride channel mutations in familial hyperaldosteronism type II. AB - Primary aldosteronism, a common cause of severe hypertension 1 , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) 2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism. PMID- 29403015 TI - Pore-forming activity of the Pseudomonas aeruginosa type III secretion system translocon alters the host epigenome. AB - Recent studies highlight that bacterial pathogens can reprogram target cells by influencing epigenetic factors. The type III secretion system (T3SS) is a bacterial nanomachine that resembles a syringe on the bacterial surface. The T3SS 'needle' delivers translocon proteins into eukaryotic cell membranes, subsequently allowing injection of bacterial effectors into the cytosol. Here we show that Pseudomonas aeruginosa induces early T3SS-dependent dephosphorylation and deacetylation of histone H3 in eukaryotic cells. This is not triggered by any of the P. aeruginosa T3SS effectors, but results from the insertion of the PopB PopD translocon into the membrane. This suggests that the P. aeruginosa translocon is a genuine T3SS effector acting as a pore-forming toxin. We visualized the translocon plugged into the host cell membrane after the bacterium has left the site of contact, and demonstrate that subsequent ion exchange through this pore is responsible for histone H3 modifications and host cell subversion. PMID- 29403016 TI - The dramatic enhancement of ferromagnetism and band gap in Fe-doped In2O3 nanodot arrays. AB - Ordered Fe-doped In2O3 nanodot arrays with diameters between 35 nm and 80 nm are fabricated using pulsed laser deposition with the aid of ultrathin porous anodized aluminumoxide templates. The 5 at.% Fe doped In2O3 nanodot arrays are shown to consist of the cubic bixbyite structure of In2O3. The nanodot arrays are demonstrated to be doped by Fe ions with mixed valences of +2 and +3, ruling out the presence of cluster and secondary phase related to Fe. The nanodot arrays exhibit the ferromagnetism at room temperature, where the magnetic moment increases as the dot size is reduced, rising to a maximum of about 230 emu/cm3 (equivalent to an average moment on the Fe ions of 15.30 uB/Fe). This indicates an effect due to the surface of the nanodot arrays. The optical band width is also increased to 4.55 eV for the smallest dot array, thus indicating that the surface states are responsible for the magnetism and also enhance the band gap due to Burstein-Moss effect. Our results will be benefit for understanding the physical properties of oxide semiconductor nanostructures in the application of nano-spintronics devices. PMID- 29403017 TI - Conformation of methylated GGQ in the Peptidyl Transferase Center during Translation Termination. AB - The universally conserved Gly-Gly-Gln (GGQ) tripeptide in release factors or release factor-like surveillance proteins is required to catalyze the release of nascent peptide in the ribosome. The glutamine of the GGQ is methylated post translationally at the N5 position in vivo; this covalent modification is essential for optimal cell growth and efficient translation termination. However, the precise conformation of the methylated-GGQ tripeptide in the ribosome remains unknown. Using cryoEM and X-ray crystallography, we report the conformation of methylated-GGQ in the peptidyl transferase center of the ribosome during canonical translational termination and co-translation quality control. It has been suggested that the GGQ motif arose independently through convergent evolution among otherwise unrelated proteins that catalyze peptide release. The requirement for this tripeptide in the highly conserved peptidyl transferase center suggests that the conformation reported here is likely shared during termination of protein synthesis in all domains of life. PMID- 29403018 TI - Physical Limitations of Phosphor layer thickness and concentration for White LEDs. AB - Increasing phosphor layer thickness and concentration can enhance the lumen flux of white LED (W-LED). In this work, we found that increasing the phosphor layer thickness and concentration can increase its temperature, and there is also a maximum thickness and concentration beyond which their increase will not lead to lumen increase, but only temperature increase. Higher thickness and higher concentration also results in warm light instead of White light. The maximum thickness and concentration are found to be limited by the scattering of light rays with higher % decrease of blue light rays than the yellow light rays. The results obtained in this work can also be used to compute the temperature and thermo-mechanical stress distribution of an encapsulated LED, demonstrating its usefulness to the design of encapsulated LED packages. Simulation software like ANSYS and TracePro are used extensively to verify the root cause mechanisms. PMID- 29403019 TI - Bismuth Telluride nanocrystal: broadband nonlinear response and its application in ultrafast photonics. AB - We come up with a hybrid liquid exfoliation method to prepare bismuth telluride nanocrystals efficiently and cost-effectively. The nonlinear transmittance of the nanocrystals has been characterized with Z-scan technique, which can manifest its broadband saturable absorption behavior experimentally. The as-fabricated nanocrystals were integrated onto fiber end facet to form a fiber compatible nonlinear absorption device with optical deposition method, which was then used to modulate the fiber laser with different cavity configurations to deliver pulsed laser successfully. The noise-like pulse and dissipative soliton have been obtained with wavelength centered at 1562 nm and 1068 nm, respectively. These results confirm the effectiveness of the hybrid liquid exfoliation method to prepare bismuth telluride into nanocrystals, and the broadband nonlinear optical response and ultrafast photonics application potential of the nanocrystals. PMID- 29403021 TI - Use of hematopoietic cell transplantation in younger patients with acute myeloid leukemia: A National Cancer Database Study. AB - Younger patients with intermediate or high-risk acute myeloid leukemia (AML) obtain overall survival benefit from the upfront use of hematopoietic cell transplantation (HCT). We queried the National Cancer Database to study 19,897 younger patients (18-60 years) with intermediate or high-risk AML reported between 2003-2012. Multivariable logistic regression analysis was performed to identify variables associated with the utilization of HCT. Approximately 18.5% of younger patients received HCT as a part of initial therapy. A lower rate of utilization of HCT was associated with receipt of care in a non-academic hospital, African American race, male sex, age group 50-60 years, Charlson comorbidity score of >=1, uninsured status, Medicaid or Medicare insurance, and lower educational or income status. The use of HCT in younger patients varies based on non-biologic factors such as race, hospital type, insurance, educational, and income status. Socioeconomic and health system factors contribute to disparity in the uptake of HCT in the US. PMID- 29403020 TI - Updating the genomic taxonomy and epidemiology of Campylobacter hyointestinalis. AB - Campylobacter hyointestinalis is a member of an emerging group of zoonotic Campylobacter spp. that are increasingly identified in both gastric and non gastric disease in humans. Here, we discovered C. hyointestinalis in three separate classes of New Zealand ruminant livestock; cattle, sheep and deer. To investigate the relevance of these findings we performed a systematic literature review on global C. hyointestinalis epidemiology and used comparative genomics to better understand and classify members of the species. We found that C. hyointestinalis subspecies hyointestinalis has an open pangenome, with accessory gene contents involved in many essential processes such as metabolism, virulence and defence. We observed that horizontal gene transfer is likely to have played an overwhelming role in species diversification, favouring a public-goods-like mechanism of gene 'acquisition and resampling' over a tree-of-life-like vertical inheritance model of evolution. As a result, simplistic gene-based inferences of taxonomy by similarity are likely to be misleading. Such genomic plasticity will also mean that local evolutionary histories likely influence key species characteristics, such as host-association and virulence. This may help explain geographical differences in reported C. hyointestinalis epidemiology and limits what characteristics may be generalised, requiring further genomic studies of C. hyointestinalis in areas where it causes disease. PMID- 29403022 TI - Satisfaction with sexual activity and sexual dysfunction in hematopoietic stem cell transplantation survivors and their partners: a couple study. AB - Sexual dysfunction is a common long-term complication of hematopoietic stem cell transplantation (HSCT). We assessed the extent to which HSCT survivors and their partners agree on the importance of and satisfaction with sexual activity and causes of sexual dysfunction, using a cross-sectional survey. Ratings of the importance of sexual activity were significantly higher in survivors than those of partners (2.57 vs. 2.14, P < 0.01). More survivors (48.4%) tried to discuss about sexuality with their partners than partners themselves (23.1%, P < 0.01). Male survivors were more likely to be sexually active than female survivors (odds ratio [OR] 5.04, 95% CI 1.85, 13.74). While 23.3 and 38% of male survivors and partners reported "rejection of partners" as a cause of sexual dysfunction, only 13.3% and none of female partners and survivors pointed this as a cause of sexual dysfunction respectively. There was poor concordance between survivors and partners in attitudes toward sexuality, satisfaction with sexual activity, and causes of sexual dysfunction. Couples who considered adequate sexual activity important were more likely to be sexually active than those who did not (OR 5.53, 95% CI 1.18, 25.89). Our study highlights the need for providing information and counselling about sexuality both to survivors and partners. PMID- 29403023 TI - Allogenic peripheral stem cell transplantation from HLA-matched related donors for adult sickle cell disease: remarkable outcomes from a single-center trial. AB - Adult patients with sickle cell disease (SCD) are highly susceptible to stem cell transplant complications, including drug toxicity, graft versus host disease (GVHD), and graft rejection due to SCD-related tissue damage, endothelial activation, and inflammation. The scarcity of compatible stem cells for transplantation further limits treatment options, with only 43 cases of adult allogeneic peripheral blood stem cell transplantation (allo-PSCT) from human leukocyte antigen (HLA)-identical sibling donors reported in the international registry for the period 1986-2013. Herein we report remarkable outcomes in a cohort of adult SCD patients who underwent allo-PSCT using a fludarabine (Flu), busulfan (Bu), and anti-T-cell lymphocyte globulin (ATG)-based conditioning regimen in combination with very low dose total body irradiation (TBI), followed by post-transplant cyclophosphamide (Cy) and sirolimus as GVHD prophylaxis. We performed a single-center, retrospective study consisting of 20 consecutive patients (mean age 33.4 years) who underwent allo-PSCT from HLA-matched related donors with a conditioning regimen of Flu 150/Bu 3.2/Cy 29/ATG 30 (Fresenius)/TBI 200 between September 2013 and September 2017. Data were validated by an independent data audit group of the affiliated JACIE-accredited transplantation center. All patients experienced a sustained donor cell engraftment. Full donor chimerism (total cell) occurred within 180 days in all patients. Mean duration of follow-up was 13.8 months (range: 0.3-50 months), with 12 (60%) patients completing 12 months. No non-relapse mortality or graft rejection occurred. Successful treatment was achieved without the presence of graft loss, grade III IV acute GVHD, extensive chronic GVHD, or other major complications. Allo-PSCT in combination with Flu 150/Bu 3.2/Cy 29/ATG 30(Fresenius)/TBI 200- Cy/Sirolimus therapy yielded encouraging outcomes with no mortality and low incidence of GVHD. Further controlled studies will be necessary to compare transplant protocols and long-term outcomes. PMID- 29403024 TI - miR-429 suppresses tumor migration and invasion by targeting CRKL in hepatocellular carcinoma via inhibiting Raf/MEK/ERK pathway and epithelial mesenchymal transition. AB - Tumor metastasis is one of the main causes of hepatocellular carcinoma (HCC) high mortality. CRKL (v-crk sarcoma virus CT10 oncogene homologue (avian)-like) play important roles in tumor metastasis, however, the exact role and underlying mechanism of CRKL in HCC is still unknown. In our study, we demonstrated miR-429 negatively regulated CRKL expression via selectively binding to CRKL-3'-UTR at 3728-3735 bp site by post-transcriptionally mediating its functionality. Re expression and silencing of miR-429 was remarkably effective in suppressing and promoting HepG2 cell migration and invasion in vitro. Knockdown or overexpression of CRKL exhibited similar effects as the overexpression or silencing of miR-429, whereas, CRKL overexpression (without the 3'-UTR) abrogated miR-429-induced inhibition on HepG2 migration and invasion. Moreover, miR-429-CRKL axis affected HepG2 migration and invasion potentials by regulating the adhesion ability, cytoskeleton F-actin expression and arrangement of HepG2. Furthermore, interference of Raf/MEK/ERK pathway and EMT contributed to miR-429-CRKL axis mediated metastasis inhibition. Nevertheless, miR-429 could not inhibit HepG2 proliferation through CRKL/c-Jun pathway. Taken together, our data demonstrated that miR-429 might function as an antimetastatic miRNA to regulate HCC metastasis by directly targeting CRKL via modulating Raf/MEK/ERK-EMT pathway. The newly identified miR-429-CRKL axis represents a novel potential therapeutic target for HCC treatment. PMID- 29403025 TI - Genetic characteristics and phylogenetic analysis of three Chinese ethnic groups using the Huaxia Platinum System. AB - Short tandem repeats (STRs) are attractive to genetic applications like forensic, anthropological and population genetics studies. The Huaxia Platinum System was specifically developed to allow co-amplification and detection of all markers in the expanded CODIS core loci and the Chinese National Database. In this study, in continuation to our previous validation study, 568 unrelated individuals were firstly genotyped to investigate the effectiveness of this novel assay in 3 main ethnic groups of China (Han, Tibetan and Yi). The combined power of discrimination (CPD) were 0.9999999999999999999999999992, 0.999999999999999999999999992, 0.999999999999999999999999998, respectively, and the combined power of exclusion (CPE) were 0.9999999999, 0.999999995, 0.999999998, respectively. Next, genetic relationships along administrative and ethnic divisions were analyzed using pairwise genetic distances, multidimensional scaling (MDS), principal component analysis (PCA) and phylogenetic analysis. The Han ethnicity showed a high genetic homogeneity all across China, and significant genetic differences existed between Han groups and some minority groups, most prominently for the Tibetans, the Uyghurs, the Kazakhs, the Miaos, the Zhuangs and the Dais. Aforementioned results suggested that the Huaxia Platinum System is polymorphic and informative, which provides an efficient tool not only for human forensics, but also for population genetics studies. PMID- 29403027 TI - Human brain functional areas of unitary pooled activity discovered with fMRI. AB - We report the discovery of human brain functional areas of unitary pooled activity (FAUPAs) using fMRI. A FAUPA is defined as an area in which the temporal variation of the activity is the same across the entire area. This dynamically unitary activity implies a perfect temporal correlation everywhere within the FAUPA for the activity-induced BOLD response, i.e., the corresponding Pearson correlation coefficient (R) is 1 for the BOLD responses of any two locations within the FAUPA. A novel method was developed to identify the FAUPA. In this study, nine subjects had a resting-state (rs) fMRI and a task-fMRI. FAUPAs have been identified for both rs- and task-fMRI, and their determination was objective and automatic, with no a-priori knowledge. The group mean of R was 0.952 +/- 0.004 for the rs-fMRI and 0.950 +/- 0.002 for the task-fMRI, showing the dynamically unitary activity within each FAUPA. For the finger-tapping (FT) task, the group-mean BOLD signal time course of the FT-associated FAUPAs in the primary motor cortex was almost perfectly correlated with the FT-induced ideal response (R = 0.9330, P = 1.8 * 10-56), confirming the association of the FAUPA with the task. A task-associated FAUPA may play the role of a functional unit for a particular neural computation. PMID- 29403026 TI - Impaired Wnt signaling in dopamine containing neurons is associated with pathogenesis in a rotenone triggered Drosophila Parkinson's disease model. AB - Parkinson's disease, which is the one of the most common neurodegenerative movement disorder, is characterized by a progressive loss of dopamine containing neurons. The mechanisms underlying disease initiation and development are not well understood and causative therapies are currently not available. To elucidate the molecular processes during early stages of Parkinson's disease, we utilized a Drosophila model. To induce Parkinson's disease-like phenotypes, we treated flies with the pesticide rotenone and isolated dopamine producing neurons of animals that were at an early disease stage. Transcriptomic analyses revealed that gene ontologies associated with regulation of cell death and neuronal functions were significantly enriched. Moreover, the activities of the MAPK/EGFR- and TGF-beta signaling pathways were enhanced, while the Wnt pathway was dampened. In order to evaluate the role of Wnt signaling for survival of dopaminergic neurons in the disease model, we rescued the reduced Wnt signaling activity by ectopic overexpression of armadillo/beta-catenin. This intervention rescued the rotenone induced movement impairments in the Drosophila model. Taken together, this initial study showed a highly relevant role of Wnt signaling for dopamine producing neurons during pathogenesis in Parkinson's disease and it implies that interfering with this pathway might by a suitable therapeutic option for the future. PMID- 29403028 TI - Synthesis of a multifunctional hard monomer from rosin: the relationship of allyl structure in maleopimarate and UV-curing property. AB - Rosin is an important forestry resource with a specific three-membered phenanthrene ring structure, which can improve the mechanical resistance of polymer coatings. In this paper, a high purity rosin monomer, tri-allyl maleopimarate containing three allyl groups has been synthesized. The yield of the monomer product was 93.2% with the purity of 96.1%. The structure of the synthesized monomer was characterized through gas chromatography (GC), mass spectrometry (MS), hydrogen nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and elemental analysis. Additionally, we present new experimental results regarding the polymerization reaction under ultraviolet (UV) irradiation. The cured film of tri-allyl maleopimarate exhibited good mechanical properties. The films were also characterized through thermogravimetric (TG) and differential scanning calorimetry (DSC) analyses and a mechanism for polymerization was proposed. Overall, a facile catalytic process for the valorization of rosin in the field of UV polymerization is reported. PMID- 29403029 TI - Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness. AB - Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper responsiveness, is a significant public health burden. Here we report that Mas related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediates cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma. PMID- 29403030 TI - Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes. AB - In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders. PMID- 29403031 TI - Studying individual differences in human adolescent brain development. AB - Adolescence is a period of social, psychological and biological development. During adolescence, relationships with others become more complex, peer relationships are paramount and social cognition develops substantially. These psychosocial changes are paralleled by structural and functional changes in the brain. Existing research in adolescent neurocognitive development has focused largely on averages, but this obscures meaningful individual variation in development. In this Perspective, we propose that the field should now move toward studying individual differences. We start by discussing individual variation in structural and functional brain development. To illustrate the importance of considering individual differences in development, we consider three sources of variation that contribute to neurocognitive processing: socioeconomic status, culture and peer environment. To assess individual differences in neurodevelopmental trajectories, large-scale longitudinal datasets are required. Future developmental neuroimaging studies should attempt to characterize individual differences to move toward a more nuanced understanding of neurocognitive changes during adolescence. PMID- 29403032 TI - Structural tract alterations predict downstream tau accumulation in amyloid positive older individuals. AB - Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease. PMID- 29403034 TI - CRISPR interference-based specific and efficient gene inactivation in the brain. AB - CRISPR-Cas9 has been demonstrated to delete genes in postmitotic neurons. Compared to the establishment of proliferative cell lines or animal strains, it is more challenging to acquire a highly homogeneous consequence of gene editing in a stable neural network. Here we show that dCas9-based CRISPR interference (CRISPRi) can efficiently silence genes in neurons. Using a pseudotarget fishing strategy, we demonstrate that CRISPRi shows superior targeting specificity without detectable off-target activity. Furthermore, CRISPRi can achieve multiplex inactivation of genes fundamental for neurotransmitter release with high efficiency. By developing conditional CRISPRi tools targeting synaptotagmin I (Syt1), we modified the excitatory to inhibitory balance in the dentate gyrus of the mouse hippocampus and found that the dentate gyrus has distinct regulatory roles in learning and affective processes in mice. We therefore recommend CRISPRi as a useful tool for more rapid investigation of gene function in the mammalian brain. PMID- 29403035 TI - Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease. AB - During recent years, the preclinical stage of Alzheimer's disease (AD) has become a major focus of research. Continued failures in clinical trials and the realization that early intervention may offer better therapeutic outcome triggered a conceptual shift from late-stage AD pathology to early-stage pathophysiology. While much effort has been directed at understanding the factors initiating AD, little is known about the principle basis underlying the disease progression at its early stages. In this Perspective, we suggest a hypothesis to explain the transition from 'silent' signatures of aberrant neural circuit activity to clinically evident memory impairments. Namely, we propose that failures in firing homeostasis and imbalance between firing stability and synaptic plasticity in cortico-hippocampal circuits represent the driving force of early disease progression. We analyze the main types of possible homeostatic failures and provide the essential conceptual framework for examining the causal link between dysregulation of firing homeostasis, aberrant neural circuit activity and memory-related plasticity impairments associated with early AD. PMID- 29403033 TI - Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. AB - The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC >IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse. PMID- 29403036 TI - Non-invasive perturbations of intracellular flow reveal physical principles of cell organization. AB - Recent advances in cell biology enable precise molecular perturbations. The spatiotemporal organization of cells and organisms, however, also depends on physical processes such as diffusion or cytoplasmic flows, and strategies to perturb physical transport inside cells are not yet available. Here, we demonstrate focused-light-induced cytoplasmic streaming (FLUCS). FLUCS is local, directional, dynamic, probe-free, physiological, and is even applicable through rigid egg shells or cell walls. We explain FLUCS via time-dependent modelling of thermoviscous flows. Using FLUCS, we demonstrate that cytoplasmic flows drive partitioning-defective protein (PAR) polarization in Caenorhabditis elegans zygotes, and that cortical flows are sufficient to transport PAR domains and invert PAR polarity. In addition, we find that asymmetric cell division is a binary decision based on gradually varying PAR polarization states. Furthermore, the use of FLUCS for active microrheology revealed a metabolically induced fluid to-solid transition of the yeast cytoplasm. Our findings establish how a wide range of transport-dependent models of cellular organization become testable by FLUCS. PMID- 29403039 TI - Nanopillar force measurements reveal actin-cap-mediated YAP mechanotransduction. AB - A robust nanopillar platform with increased spatial resolution reveals that perinuclear forces, originating from stress fibres spanning the nucleus of fibroblasts, are significantly higher on these nanostructured substrates than the forces acting on peripheral adhesions. Many perinuclear adhesions embrace several nanopillars at once, pulling them into beta1-integrin- and zyxin-rich clusters, which are able to translocate in the direction of cell motion without losing their tensile strength. The high perinuclear forces are greatly reduced upon inhibition of cell contractility or actin polymerization and disruption of the actin cap by KASH dominant-negative mutant expression. LMNA null fibroblasts have higher peripheral versus perinuclear forces, impaired perinuclear beta1-integrin recruitment, as well as YAP nuclear translocation, functional alterations that can be rescued by lamin A expression. These highly tensed actin-cap fibres are required for YAP nuclear signalling and thus play far more important roles in sensing nanotopographies and mechanochemical signal conversion than previously thought. PMID- 29403038 TI - Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas. AB - Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-beta signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs. PMID- 29403040 TI - I will message you. PMID- 29403037 TI - The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168. AB - Growth signals, such as extracellular nutrients and growth factors, have substantial effects on genome integrity; however, the direct underlying link remains unclear. Here, we show that the mechanistic target of rapamycin (mTOR) ribosomal S6 kinase (S6K) pathway, a central regulator of growth signalling, phosphorylates RNF168 at Ser60 to inhibit its E3 ligase activity, accelerate its proteolysis and impair its function in the DNA damage response, leading to accumulated unrepaired DNA and genome instability. Moreover, loss of the tumour suppressor liver kinase B1 (LKB1; also known as STK11) hyperactivates mTOR complex 1 (mTORC1)-S6K signalling and decreases RNF168 expression, resulting in defects in the DNA damage response. Expression of a phospho-deficient RNF168-S60A mutant rescues the DNA damage repair defects and suppresses tumorigenesis caused by Lkb1 loss. These results reveal an important function of mTORC1-S6K signalling in the DNA damage response and suggest a general mechanism that connects cell growth signalling to genome stability control. PMID- 29403041 TI - Going soft. PMID- 29403042 TI - Atomic recall. PMID- 29403043 TI - A multiplexing approach. PMID- 29403044 TI - My greatest experiment. PMID- 29403045 TI - A cool paper. PMID- 29403046 TI - Publisher Correction: Nano-opto-electro-mechanical systems. AB - In the version of this Perspective originally published, in Fig. 1, in the green box labelled 'Mechanics', an erroneous grey rectangle was included; it has now been removed and the figure replaced in the online versions of the Perspective. PMID- 29403047 TI - Plastic affinity. PMID- 29403049 TI - Metabolic exhaustion in infection, cancer and autoimmunity. AB - It has become increasingly clear that changes in metabolism are not just consequences of T cell activation but instead are also essential drivers of that process that shape the extent and nature of differentiation and function. The process of T cell exhaustion has been linked to the outcome of chronic immune responses in multiple contexts, including chronic infection, cancer and autoimmunity. Factors that regulate the development and maintenance of exhaustion are of increasing interest as targets of therapeutic modulation. Studies have shown T cell immunometabolism to be integral to the control and development of T cell exhaustion. Early metabolic changes are responsible for the later emergence of exhaustion, do not simply reflect changes secondary to chronic activation and are modifiable. Increased understanding of this metabolic control promises to improve the ability to modulate T cell immunity to chronic antigen stimulation in multiple contexts. PMID- 29403048 TI - Development of a yeast internal-subunit eGFP labeling strategy and its application in subunit identification in eukaryotic group II chaperonin TRiC/CCT. AB - Unambiguous subunit assignment in a multicomponent complex is critical for thorough understanding of the machinery and its functionality. The eukaryotic group II chaperonin TRiC/CCT folds approximately 10% of cytosolic proteins and is important for the maintenance of cellular homeostasis. TRiC consists of two rings and each ring has eight homologous but distinct subunits. Unambiguous subunit identification of a macromolecular machine such as TRiC through intermediate or low-resolution cryo-EM map remains challenging. Here we present a yeast internal subunit eGFP labeling strategy termed YISEL, which can quickly introduce an eGFP tag in the internal position of a target subunit by homologous recombination, and the tag labeled protein can be expressed in endogenous level. Through this method, the labeling efficiency and tag-occupancy is ensured, and the inserted tag is usually less mobile compared to that fused to the terminus. It can also be used to bio-engineer other tag in the internal position of a protein in yeast. By applying our YISEL strategy and combined with cryo-EM 3D reconstruction, we unambiguously identified all the subunits in the cryo-EM map of TRiC, demonstrating the potential for broad application of this strategy in accurate and efficient subunit identification in other challenging complexes. PMID- 29403050 TI - Radium tracing nutrient inputs through submarine groundwater discharge in the global ocean. AB - Riverine and atmospheric inputs are often considered as the main terrestrial sources of dissolved inorganic nitrogen (DIN), phosphorus (DIP), and silicon (DSi) in the ocean. However, the fluxes of nutrients via submarine groundwater discharge (SGD) often exceed riverine inputs in different local and regional scale settings. In this study, we provide a first approximation of global nutrient fluxes to the ocean via total SGD, including pore water fluxes, by combining a global compilation of nutrient concentrations in groundwater and the SGD-derived 228Ra fluxes. In order to avoid overestimations in calculating SGD derived nutrient fluxes, the endmember value of nutrients in global groundwater was chosen from saline groundwater samples (salinity >10) which showed relatively lower values over all regions. The results show that the total SGD-derived fluxes of DIN, DIP, and DSi could be approximately 1.4-, 1.6-, and 0.7-fold of the river fluxes to the global ocean (Indo-Pacific and Atlantic Oceans), respectively. Although significant portions of these SGD-derived nutrient fluxes are thought to be recycled within sediment-aquifer systems over various timescales, SGD-derived nutrient fluxes should be included in the global ocean budget in order to better understand dynamic interactions at the land-ocean interface. PMID- 29403052 TI - Atomic scale imaging of magnetic circular dichroism by achromatic electron microscopy. AB - In order to obtain a fundamental understanding of the interplay between charge, spin, orbital and lattice degrees of freedom in magnetic materials and to predict and control their physical properties1-3, experimental techniques are required that are capable of accessing local magnetic information with atomic-scale spatial resolution. Here, we show that a combination of electron energy-loss magnetic chiral dichroism 4 and chromatic-aberration-corrected transmission electron microscopy, which reduces the focal spread of inelastically scattered electrons by orders of magnitude when compared with the use of spherical aberration correction alone, can achieve atomic-scale imaging of magnetic circular dichroism and provide element-selective orbital and spin magnetic moments atomic plane by atomic plane. This unique capability, which we demonstrate for Sr2FeMoO6, opens the door to local atomic-level studies of spin configurations in a multitude of materials that exhibit different types of magnetic coupling, thereby contributing to a detailed understanding of the physical origins of magnetic properties of materials at the highest spatial resolution. PMID- 29403051 TI - No evidence that carotenoid pigments boost either immune or antioxidant defenses in a songbird. AB - Dietary carotenoids have been proposed to boost immune system and antioxidant functions in vertebrate animals, but studies aimed at testing these physiological functions of carotenoids have often failed to find support. Here we subject yellow canaries (Serinus canaria), which possess high levels of carotenoids in their tissue, and white recessive canaries, which possess a knockdown mutation that results in very low levels of tissue carotenoids, to oxidative and pathogen challenges. Across diverse measures of physiological performance, we detect no differences between carotenoid-rich yellow and carotenoid-deficient white canaries. These results add further challenge to the assumption that carotenoids are directly involved in supporting physiological function in vertebrate animals. While some dietary carotenoids provide indirect benefits as retinoid precursors, our observations suggest that carotenoids themselves may play little to no direct role in key physiological processes in birds. PMID- 29403053 TI - Quantitative relations between interaction parameter, miscibility and function in organic solar cells. AB - Although it is known that molecular interactions govern morphology formation and purity of mixed domains of conjugated polymer donors and small-molecule acceptors, and thus largely control the achievable performance of organic solar cells, quantifying interaction-function relations has remained elusive. Here, we first determine the temperature-dependent effective amorphous-amorphous interaction parameter, chiaa(T), by mapping out the phase diagram of a model amorphous polymer:fullerene material system. We then establish a quantitative 'constant-kink-saturation' relation between chiaa and the fill factor in organic solar cells that is verified in detail in a model system and delineated across numerous high- and low-performing materials systems, including fullerene and non fullerene acceptors. Our experimental and computational data reveal that a high fill factor is obtained only when chiaa is large enough to lead to strong phase separation. Our work outlines a basis for using various miscibility tests and future simulation methods that will significantly reduce or eliminate trial-and error approaches to material synthesis and device fabrication of functional semiconducting blends and organic blends in general. PMID- 29403055 TI - 2D hole gas seen. PMID- 29403054 TI - Quantitative self-assembly prediction yields targeted nanomedicines. AB - Development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. We describe herein a targeted drug delivery system that is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules, which are the drugs themselves. The drugs assemble with the aid of sulfated indocyanines into particles with ultrahigh drug loadings of up to 90%. We devised quantitative structure nanoparticle assembly prediction (QSNAP) models to identify and validate electrotopological molecular descriptors as highly predictive indicators of nano assembly and nanoparticle size. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. This finding enables the computational design of nanomedicines based on quantitative models for drug payload selection. PMID- 29403056 TI - Direct observation of a two-dimensional hole gas at oxide interfaces. AB - The discovery of a two-dimensional electron gas (2DEG) at the LaAlO3/SrTiO3 interface 1 has resulted in the observation of many properties2-5 not present in conventional semiconductor heterostructures, and so become a focal point for device applications6-8. Its counterpart, the two-dimensional hole gas (2DHG), is expected to complement the 2DEG. However, although the 2DEG has been widely observed 9 , the 2DHG has proved elusive. Herein we demonstrate a highly mobile 2DHG in epitaxially grown SrTiO3/LaAlO3/SrTiO3 heterostructures. Using electrical transport measurements and in-line electron holography, we provide direct evidence of a 2DHG that coexists with a 2DEG at complementary heterointerfaces in the same structure. First-principles calculations, coherent Bragg rod analysis and depth-resolved cathodoluminescence spectroscopy consistently support our finding that to eliminate ionic point defects is key to realizing a 2DHG. The coexistence of a 2DEG and a 2DHG in a single oxide heterostructure provides a platform for the exciting physics of confined electron-hole systems and for developing applications. PMID- 29403057 TI - Selective layer-free blood serum ionogram based on ion-specific interactions with a nanotransistor. AB - Despite being ubiquitous in the fields of chemistry and biology, the ion-specific effects of electrolytes pose major challenges for researchers. A lack of understanding about ion-specific surface interactions has hampered the development and application of materials for (bio-)chemical sensor applications. Here, we show that scaling a silicon nanotransistor sensor down to ~25 nm provides a unique opportunity to understand and exploit ion-specific surface interactions, yielding a surface that is highly sensitive to cations and inert to pH. The unprecedented sensitivity of these devices to Na+ and divalent ions can be attributed to an overscreening effect via molecular dynamics. The surface potential of multi-ion solutions is well described by the sum of the electrochemical potentials of each cation, enabling selective measurements of a target ion concentration without requiring a selective organic layer. We use these features to construct a blood serum ionogram for Na+, K+, Ca2+ and Mg2+, in an important step towards the development of a versatile, durable and mobile chemical or blood diagnostic tool. PMID- 29403058 TI - Microplasma Jet Arrays as a Therapeutic Choice for Fungal Keratitis. AB - The clinical impact of microplasma jets on rabbit eyes infected by Candida albicans has been investigated. Arrays of such jets produce low-temperature plasma micro-columns suitable for ophthalmic therapeutics and fungal infections, in particular, and the technology is capable of being scaled to surface areas of at least 10 cm2. Keratitis was induced in the right central corneas of rabbits, whereas the left eyes served as a normal group. The rabbits were divided into the plasma non-treated group (control) and plasma treatment group. Histologic analyses of both groups showed marked reductions in the thickness, angiogenesis, and opacity of all rabbit corneas following plasma treatment. Indeed, for treatment times beyond 14 days, infected eyes exhibited no significant differences from the normal group. Healing of rabbit eyes infected by Candida albicans apparently proceeds by disrupting corneal epithelial proliferation, and by reducing fibrotic changes in the stroma. This study demonstrates that low temperature plasma jets are remarkably effective in healing Candida albicans infected corneas, thereby providing a promising medical treatment option for keratitis. PMID- 29403059 TI - Deep learning for real-time single-pixel video. AB - Single-pixel cameras capture images without the requirement for a multi-pixel sensor, enabling the use of state-of-the-art detector technologies and providing a potentially low-cost solution for sensing beyond the visible spectrum. One limitation of single-pixel cameras is the inherent trade-off between image resolution and frame rate, with current compressive (compressed) sensing techniques being unable to support real-time video. In this work we demonstrate the application of deep learning with convolutional auto-encoder networks to recover real-time 128 * 128 pixel video at 30 frames-per-second from a single pixel camera sampling at a compression ratio of 2%. In addition, by training the network on a large database of images we are able to optimise the first layer of the convolutional network, equivalent to optimising the basis used for scanning the image intensities. This work develops and implements a novel approach to solving the inverse problem for single-pixel cameras efficiently and represents a significant step towards real-time operation of computational imagers. By learning from examples in a particular context, our approach opens up the possibility of high resolution for task-specific adaptation, with importance for applications in gas sensing, 3D imaging and metrology. PMID- 29403060 TI - Effect of tube current on computed tomography radiomic features. AB - Variability in the x-ray tube current used in computed tomography may affect quantitative features extracted from the images. To investigate these effects, we scanned the Credence Cartridge Radiomics phantom 12 times, varying the tube current from 25 to 300 mA?s while keeping the other acquisition parameters constant. For each of the scans, we extracted 48 radiomic features from the categories of intensity histogram (n = 10), gray-level run length matrix (n = 11), gray-level co-occurrence matrix (n = 22), and neighborhood gray tone difference matrix (n = 5). To gauge the size of the tube current effects, we scaled the features by the coefficient of variation of the corresponding features extracted from images of non-small cell lung cancer tumors. Variations in the tube current had more effect on features extracted from homogeneous materials (acrylic, sycamore wood) than from materials with more tissue-like textures (cork, rubber particles). Thirty-eight of the 48 features extracted from acrylic were affected by current reductions compared with only 2 of the 48 features extracted from rubber particles. These results indicate that variable x-ray tube current is unlikely to have a large effect on radiomic features extracted from computed tomography images of textured objects such as tumors. PMID- 29403061 TI - Laminar Flow Attenuates Macrophage Migration Inhibitory Factor Expression in Endothelial Cells. AB - Macrophage migration inhibitory factor (MIF) is a non-canonical cytokine that is involved in multiple inflammatory diseases, including atherosclerosis. High MIF expression found in leukocytes which facilitates the initiation and progression of atherosclerosis. However, little is known about biomechanical forces in the induction of MIF in endothelial cells (ECs). Here, we show that laminar shear stress (LS) inhibits the expression of MIF in ECs. By profiling the whole transcriptome of human coronary artery ECs under different shear stress, we found that athero-protective LS attenuates the expression of MIF whereas pro atherosclerotic oscillatory shear stress (OS) significantly increased the expression of MIF. En face staining of rabbit aorta revealed high MIF immunoreactivity in lesser curvature as well as arterial bifurcation areas where OS is predominant. Mechanistically, we found that Krupple like factor 2 (KLF2) is required for inhibition of MIF expression in ECs in the context of shear stress. Knockdown of KLF2 abolishes LS-dependent MIF inhibition while overexpression of KLF2 significantly attenuated MIF expression. Overall, the present work showed that MIF is a shear stress-sensitive cytokine and is transcriptionally regulated by KLF2, suggesting that LS exerts its athero-protective effect in part by directly inhibiting pro-inflammatory MIF expression. PMID- 29403062 TI - The influence of spatial frequency content on facial expression processing: An ERP study using rapid serial visual presentation. AB - Spatial frequency (SF) contents have been shown to play an important role in emotion perception. This study employed event-related potentials (ERPs) to explore the time course of neural dynamics involved in the processing of facial expression conveying specific SF information. Participants completed a dual target rapid serial visual presentation (RSVP) task, in which SF-filtered happy, fearful, and neutral faces were presented. The face-sensitive N170 component distinguished emotional (happy and fearful) faces from neutral faces in a low spatial frequency (LSF) condition, while only happy faces were distinguished from neutral faces in a high spatial frequency (HSF) condition. The later P3 component differentiated between the three types of emotional faces in both LSF and HSF conditions. Furthermore, LSF information elicited larger P1 amplitudes than did HSF information, while HSF information elicited larger N170 and P3 amplitudes than did LSF information. Taken together, these results suggest that emotion perception is selectively tuned to distinctive SF contents at different temporal processing stages. PMID- 29403063 TI - Slow Wave Applications of Electromagnetically Induced Transparency in Microstrip Resonator. AB - We report a novel guided-wave resonator that supports multiple bands of electromagnetically induced transparency (EIT). The platform for the spatial and spectral interference is obtained by a microstrip transmission line loaded with proximity-coupled open-circuited stubs. We show experimentally that with two microstrip open stubs, a complete destructive interference takes place leading to a single EIT band with near-unity transmission efficiency. More interestingly, the addition of a third stub results in a supplementary EIT band with a Q-factor of 147 and an effective group refractive index of 530. With the open-stub configuration, the EIT phase response can be dynamically controlled by varying the capacitance between the adjacent stubs without breaking the transmission path of the underlying electromagnetic waves. Therefore, the proposed structure is well suited for buffering and tunable phase modulation applications. Since the proposed structures are compact and fully planar, we anticipate seamless integration with low-profile high frequency electronics. PMID- 29403064 TI - Phenotypic co-receptor tropism and Maraviroc sensitivity in HIV-1 subtype C from East Africa. AB - Genotypic tropism testing (GTT) for co-receptor usage is a recommended tool for clinical practice before administration of the CCR5-antagonist maraviroc. For some isolates, phenotypic tropism testing (PTT) revealed discordant results with GTT. In this study, we performed a comparative study between GTT and PTT in HIV 1C from East Africa (HIV-1CEA) and compared the data with HIV-1B and 01_AE and described the maraviroc susceptibility in the CCR5-tropic strains. Patient derived HIV-1 envgp120 region was cloned into a modified pNL4-3 plasmid expressing the luciferase gene. rPhenotyping dissected single clones from 31 HIV 1CEA infected patients and four strains with known phenotype. Additionally, 68 clones from 18 patients (HIV-1B: 5, 01_AE: 7, HIV-1CEA: 6) were used to determine the PTT in GHOST cell line. The respective V3-sequences were used for GTT. R5 tropic strains from HIV-1CEA (n = 20) and non-C (n = 12) were tested for maraviroc sensitivity in TZMbl cell line. The GTT falsely called a higher proportion of X4-tropic strains in HIV-1CET compared to PTT by both rPhenotyping and the GHOST-cell assay. When multiple clones were tested in a subset of patients' samples, both dual-tropic and R5-tropic strains were identified for HIV 1C. Relatively higher EC50 values were observed in HIV-1C strains than the non-C strains (p = 0.002). PMID- 29403065 TI - Tungsten-based Ultrathin Absorber for Visible Regime. AB - Utilizing solar energy requires perfect absorption of light by the photovoltaic cells, particularly solar thermophotovoltaics (STPVs), which can be eventually converted into useful electrical energy. Ultrathin nanostructures, named metasurfaces, provide an intriguing platform to develop the miniaturized solar energy absorbers that can find potential applications in integrated photonics, optical sensing, color imaging, thermal imaging and electromagnetic shielding. Therefore, the quest of novel materials and designs to develop highly efficient absorbers at minuscule scale is an open topic. In this paper, novel absorbers using tungsten-metasurface are developed which give ultrahigh absorbance over a wide frequency spectrum. The proposed designs are two-dimensional, polarization insensitive, broadband and are predicted to give better response under high temperatures ascribed to high melting point of tungsten i.e. 3422 degrees C. Amongst these designs, cross alignment is found optimum for tungsten, because it is impedance matched with the free space for visible spectrum. This cross arrangement is further tweaked by changing width, height and length resulting in 7 different optimized solutions giving an average absorbance greater than 98%. One, amongst these solutions, gave a maximum average absorbance of 99.3%. PMID- 29403066 TI - Insights into RNAi-based antiviral immunity in Lepidoptera: acute and persistent infections in Bombyx mori and Trichoplusia ni cell lines. AB - The control of viral infections in insects is a current issue of major concern and RNA interference (RNAi) is considered the main antiviral immune response in this group of animals. Here we demonstrate that overexpression of key RNAi factors can help to protect insect cells against viral infections. In particular, we show that overexpression of Dicer2 and Argonaute2 in lepidopteran cells leads to improved defense against the acute infection of the Cricket Paralysis Virus (CrPV). We also demonstrate an important role of RNAi in the control of persistent viral infections, as the one caused by the Macula-like Latent Virus (MLV). Specifically, a direct interaction between Argonaute2 and virus-specific small RNAs is shown. Yet, while knocking down Dicer2 and Argonaute2 resulted in higher transcript levels of the persistently infecting MLV in the lepidopteran cells under investigation, overexpression of these proteins could not further reduce these levels. Taken together, our data provide deep insight into the RNAi based interactions between insects and their viruses. In addition, our results suggest the potential use of an RNAi gain-of-function approach as an alternative strategy to obtain reduced viral-induced mortality in Lepidoptera, an insect order that encompasses multiple species of relevant economic value. PMID- 29403067 TI - Comparison between two post-dentin bond strength measurement methods. AB - The push-out (PO) test and the diametral compression (DC) test were performed to compare the merits of two post-dentin bond strength measurement methods. Compared with the push-out test, the disk in DC provided post-dentin bond strength measurements that were more precise. The load-displacement curves from the DC test were much smoother and more linear up to the point of fracture when compared to those from the PO test. Compared to the PO test, DC is easier to perform for determining the bond strength between posts and dentin. No specimen alignment is needed in the DC test, and it produces a smaller standard deviation in the measured bond strength. The main disadvantage of the DC test, however, is that finite element analysis (FEA) is required to calculate the bond strength. The shear bond strength given by the PO test based on the simple formula is not valid, though, and the peak failure load is dependent on friction at the post dentin interface. PMID- 29403068 TI - CPAP3 proteins in the mineralized cuticle of a decapod crustacean. AB - The pancrustacean theory groups crustaceans and hexapods (once thought to comprise separate clades within the Arthropoda) into a single clade. A key feature common to all pancrustaceans is their chitinous exoskeleton, with a major contribution by cuticular proteins. Among these, are the CPAP3's, a family of cuticular proteins, first identified in the hexapod Drosophila melanogaster and characterized by an N-terminal signaling peptide and three chitin-binding domains. In this study, CPAP3 proteins were mined from a transcriptomic library of a decapod crustacean, the crayfish Cherax quadricarinatus. Phylogenetic analysis of other CPAP3 proteins from hexapods and other crustaceans showed a high degree of conservation. Characterization of the crayfish proteins, designated CqCPAP3's, suggested a major role for CPAP3'sin cuticle formation. Loss-of-function experiments using RNAi supported such a notion by demonstrating crucial roles for several CqCPAP3 proteins during molting. A putative mode of action for the CqCPAP3 proteins -theoretically binding three chitin strands- was suggested by the structural data obtained from a representative recombinant CqCPAP3. The similarities between the CqCPAP3 proteins and their hexapod homologues further demonstrated common genetic and proteinaceous features of cuticle formation in pancrustaceans, thereby reinforcing the linkage between these two highly important phylogenetic groups. PMID- 29403069 TI - Genetic targeting of Purkinje fibres by Sema3a-CreERT2. AB - The maintenance of the heart rhythm and the conduction of excitatory signals require changing excitatory signals via electrical activity and coordination by communication between working and conductive cardiomyocytes. Understanding how the ventricular conduction system is established provides novel insights into the pathophysiological progress of cardiac arrhythmias. However, the major hurdle in this field is the lack of a specific genetic tool that targets the Purkinje fibres of the ventricular conduction system and no other types of cardiomyocytes or coronary vessels. Here, we generated a Sema3a-CreERT2 knock-in mouse line to test its specificity for genetically labelled Purkinje fibres. We found that Sema3a was expressed in the subendocardial layer of the trabecular myocardium in the embryonic heart and was restricted to the Purkinje fibres in the adult heart. A fate mapping study based on the Sema3a-CreERT2 line revealed that the Sema3a+ cardiomyocytes were restricted to the fate of Purkinje fibres in the perinatal but not the embryonic stage. Collectively, our study provides a new genetic tool, i.e., Sema3a-CreERT2, for studying the molecular mechanisms that regulate the function of Purkinje fibres. PMID- 29403070 TI - Results of external beam radiotherapy for diffuse choroidal hemangiomas in Sturge Weber syndrome. AB - PURPOSE: The Sturge-Weber Syndrome (SWS) is a phacomatosis which include facial nevus flammeus, glaucoma, diffuse choroidal hemangioma, and leptomeningeal hemangiomatosis. External beam radiotherapy (EBRT) using photons was used to treat retinal detachment. We investigate the anatomical and functional results in a long-term basis. METHODS: Retrospective review of SWS patients treated by EBRT (20 Gy in 10 fractions) for an exudative diffuse choroidal hemangioma. Visual acuity, B-scan tumor thickness, size of retinal detachment, intra-ocular pressure, and hypotonic treatment were collected before EBRT, 1 year after, and at the latest news. RESULTS: Twenty-five patients (26 eyes) were treated between 2001 and 2014. Retinal detachment including the macula was found among twenty-six eyes before treatment. The average follow-up time was 47 months. The mean tumor thickness was initially 4.5 mm, 2.8 mm at first year, and 2.7 mm at the last visit. The retina was reattached at the last visit for all eyes except two. The visual acuity was stable or better for 20 eyes (p = 0.02). Four patients developed mild cataract during the follow-up. CONCLUSION: EBRT using 20 Gy in 10 fractions is efficient, decreases tumor thickness, reattaches the retina, and stabilizes visual acuity. In the long term, retinal reattachment allows ocular conservation by preventing phthisis bulbi. PMID- 29403071 TI - Transconjunctival rectus muscle bridle: an adjunct in surgical exposure. PMID- 29403072 TI - Clonal genome evolution and rapid invasive spread of the marbled crayfish. AB - The marbled crayfish Procambarus virginalis is a unique freshwater crayfish characterized by very recent speciation and parthenogenetic reproduction. Marbled crayfish also represent an emerging invasive species and have formed wild populations in diverse freshwater habitats. However, our understanding of marbled crayfish biology, evolution and invasive spread has been hampered by the lack of freshwater crayfish genome sequences. We have now established a de novo draft assembly of the marbled crayfish genome. We determined the genome size at approximately 3.5 gigabase pairs and identified >21,000 genes. Further analysis confirmed the close relationship to the genome of the slough crayfish, Procambarus fallax, and also established a triploid AA'B genotype with a high level of heterozygosity. Systematic fieldwork and genotyping demonstrated the rapid expansion of marbled crayfish on Madagascar and established the marbled crayfish as a potent invader of freshwater ecosystems. Furthermore, comparative whole-genome sequencing demonstrated the clonality of the population and their genetic identity with the oldest known stock from the German aquarium trade. Our study closes an important gap in the phylogenetic analysis of animal genomes and uncovers the unique evolutionary history of an emerging invasive species. PMID- 29403073 TI - Keep ecological restoration open and flexible. PMID- 29403075 TI - Cretaceous arachnid Chimerarachne yingi gen. et sp. nov. illuminates spider origins. AB - Spiders (Araneae) are a hugely successful lineage with a long history. Details of their origins remain obscure, with little knowledge of their stem group and few insights into the sequence of character acquisition during spider evolution. Here, we describe Chimerarachne yingi gen. et sp. nov., a remarkable arachnid from the mid-Cretaceous (approximately 100 million years ago) Burmese amber of Myanmar, which documents a key transition stage in spider evolution. Like uraraneids, the two fossils available retain a segmented opisthosoma bearing a whip-like telson, but also preserve two traditional synapomorphies for Araneae: a male pedipalp modified for sperm transfer and well-defined spinnerets resembling those of modern mesothele spiders. This unique character combination resolves C. yingi within a clade including both Araneae and Uraraneida; however, its exact position relative to these orders is sensitive to different parameters of our phylogenetic analysis. Our new fossil most likely represents the earliest branch of the Araneae, and implies that there was a lineage of tailed spiders that presumably originated in the Palaeozoic and survived at least into the Cretaceous of Southeast Asia. PMID- 29403074 TI - Hemimetabolous genomes reveal molecular basis of termite eusociality. AB - Around 150 million years ago, eusocial termites evolved from within the cockroaches, 50 million years before eusocial Hymenoptera, such as bees and ants, appeared. Here, we report the 2-Gb genome of the German cockroach, Blattella germanica, and the 1.3-Gb genome of the drywood termite Cryptotermes secundus. We show evolutionary signatures of termite eusociality by comparing the genomes and transcriptomes of three termites and the cockroach against the background of 16 other eusocial and non-eusocial insects. Dramatic adaptive changes in genes underlying the production and perception of pheromones confirm the importance of chemical communication in the termites. These are accompanied by major changes in gene regulation and the molecular evolution of caste determination. Many of these results parallel molecular mechanisms of eusocial evolution in Hymenoptera. However, the specific solutions are remarkably different, thus revealing a striking case of convergence in one of the major evolutionary transitions in biological complexity. PMID- 29403076 TI - Origin of spiders and their spinning organs illuminated by mid-Cretaceous amber fossils. AB - Understanding the genealogical relationships among the arachnid orders is an onerous task, but fossils have aided in anchoring some branches of the arachnid tree of life. The discovery of Palaeozoic fossils with characters found in both extant spiders and other arachnids provided evidence for a series of extinctions of what was thought to be a grade, Uraraneida, that led to modern spiders. Here, we report two extraordinarily well-preserved Mesozoic members of Uraraneida with a segmented abdomen, multi-articulate spinnerets with well-defined spigots, modified male palps, spider-like chelicerae and a uropygid-like telson. The new fossils, belonging to the species Chimerarachne yingi, were analysed phylogenetically in a large data matrix of extant and extinct arachnids under a diverse regime of analytical conditions, most of which resulted in placing Uraraneida as the sister clade of Araneae (spiders). The phylogenetic placement of this arachnid fossil extends the presence of spinnerets and modified palps more basally in the arachnid tree than was previously thought. Ecologically, the new fossil extends the record of Uraraneida 170 million years towards the present, thus showing that uraraneids and spiders co-existed for a large fraction of their evolutionary history. PMID- 29403077 TI - Species co-occurrence analysis predicts management outcomes for multiple threats. AB - Mitigating the impacts of global anthropogenic change on species is conservation's greatest challenge. Forecasting the effects of actions to mitigate threats is hampered by incomplete information on species' responses. We develop an approach to predict community restructuring under threat management, which combines models of responses to threats with network analyses of species co occurrence. We discover that contributions by species to network co-occurrence predict their recovery under reduction of multiple threats. Highly connected species are likely to benefit more from threat management than poorly connected species. Importantly, we show that information from a few species on co occurrence and expected responses to alternative threat management actions can be used to train a response model for an entire community. We use a unique management dataset for a threatened bird community to validate our predictions and, in doing so, demonstrate positive feedbacks in occurrence and co-occurrence resulting from shared threat management responses during ecosystem recovery. PMID- 29403078 TI - Biogeography across the ages. PMID- 29403079 TI - Dinosaurs reveal the geographical signature of an evolutionary radiation. AB - Dinosaurs dominated terrestrial ecosystems across the globe for over 100 million years and provide a classic example of an evolutionary radiation. However, little is known about how these animals radiated geographically to become globally distributed. Here, we use a biogeographical model to reconstruct the dinosaurs' ancestral locations, revealing the spatial mechanisms that underpinned this 170 million-year-long radiation. We find that dinosaurs spread rapidly initially, followed by a significant continuous and gradual reduction in their speed of movement towards the Cretaceous/Tertiary boundary (66 million years ago). This suggests that the predominant mode of dinosaur speciation changed through time with speciation originally largely driven by geographical isolation-when dinosaurs speciated more, they moved further. This was gradually replaced by increasing levels of sympatric speciation (species taking advantage of ecological opportunities within their existing environment) as terrestrial space became a limiting factor. Our results uncover the geographical signature of an evolutionary radiation. PMID- 29403081 TI - Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. AB - The adverse effects of immune checkpoint inhibitors in various organs may be attributed to immune-mediated processes triggered by disrupted self-tolerance; however, it remains unclear whether they are similar or dissimilar to classic organ-specific autoimmune diseases. The present study aimed to compare clinicopathologic features between checkpoint inhibitor-induced liver injury and acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2) presented with liver dysfunction a median of 41 days (range 21-120) after the initiation of immunotherapy. All patients had elevated liver enzymes, whereas hyper-bilirubinemia was less common. None of the patients had antinuclear antibodies or IgG elevations. Stopping the immunotherapy and additional immunosuppression with corticosteroids normalized or decreased liver enzymes in all patients treated. Histologically, all biopsies showed predominantly lobular hepatitis with milder portal inflammation. Centrilobular confluent necrosis and plasmacytosis were observed in a single case, and were markedly less common and milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001, respectively). Bile duct injury, micro-abscesses, and extramedullary hematopoiesis were also found in one case each. Immunostaining revealed the presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production. PMID- 29403080 TI - Tumor suppressor CD99 is downregulated in plasma cell neoplasms lacking CCND1 translocation and distinguishes neoplastic from normal plasma cells and B-cell lymphomas with plasmacytic differentiation from primary plasma cell neoplasms. AB - CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B-cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; and (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood, and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, 8 out of 56 samples (14%) showed visibly (>10-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81, and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with cyclin D1 translocation in myeloma (p < 0.05). B-cell lymphomas with plasma cell component could be distinguished from myeloma by CD99 expression. In summary, we established that tumor suppressor CD99 is markedly downregulated in multiple myeloma. The loss is highly specific for identification of abnormal cells in primary plasma cell neoplasms, and can be exploited for diagnostic purposes. The role of CD99 in myeloma pathogenesis requires further investigation. PMID- 29403083 TI - Inflammatory and infectious manifestations of immunodeficiency in the gastrointestinal tract. AB - Immune compromise may result from genetic abnormalities, HIV/AIDS, or consequences of therapy for neoplastic and autoimmune diseases. Many immunocompromised patients develop severe gastrointestinal symptoms, particularly diarrhea, accompanied by non-specific or mild endoscopic abnormalities; mucosal biopsy with pathologic interpretation has a major role in the diagnosis and management of these patients. Immunocompromised individuals are at risk for all the diseases that affect those with a healthy immune system, but they are also prone to other illnesses that rarely affect immunocompetent patients. This review discusses the gastrointestinal manifestations of primary and acquired immunodeficiency, chemotherapy-related injury, and infections that show a predilection for immunocompromised patients. Key histologic features and relevant differential diagnoses are emphasized. PMID- 29403082 TI - A reevaluation of erythroid predominance in Acute Myeloid Leukemia using the updated WHO 2016 Criteria. AB - The 2016 WHO update changed the diagnostic criteria for myeloid neoplasms with erythroid predominance, limiting the diagnosis of acute myeloid leukemia to cases with >=20% blasts in the bone marrow or peripheral blood. Although acute myeloid leukemia with >=50% erythroid cells has historically been presumed to represent acute myeloid leukemia with myelodysplasia-related changes, this hypothesis has never been systematically examined. We sought to investigate the clinicopathologic, cytogenetic, and molecular features of acute myeloid leukemia with erythroid predominance to subclassify cases as defined by the 2016 WHO. We retrospectively identified patients with >=50% erythroid precursors and either >=20% bone marrow blasts or >=20% peripheral blood blasts at the time of initial diagnosis at seven major academic centers. Laboratory and clinical data were obtained. Patients were then reclassified according to 2016 WHO guidelines. A matched control group was also obtained. We identified 146 patients with acute myeloid leukemia with erythroid predominance (62% M, average age: 62 y, range: 5 93 y). Of these, 91 were acute myeloid leukemia with myelodysplasia-related changes, 20 (14%) were therapy-related myeloid neoplasm, 23 (16%) acute myeloid leukemia, not otherwise specified, and ten acute myeloid leukemia with recurrent cytogenetic/molecular abnormalities. The bone marrow blast count ranged from 9 41%. There was no difference in survival for patients with erythroid predominance compared to patients with acute myeloid leukemia without erythroid proliferations. In a multivariable analysis, cytogenetic risk was the only significant predictor of survival. We find a significantly lower rate of FLT3 and RAS pathway alterations in acute myeloid leukemia with erythroid predominance compared to controls. Our study is one of the first to apply the 2016 WHO guidelines for classification of acute myeloid leukemia. We find acute myeloid leukemia with erythroid predominance is a heterogeneous group and that erythroid richness has no impact on overall survival. PMID- 29403084 TI - Precise pathologic diagnosis and individualized treatment improve the outcomes of invasive micropapillary carcinoma of the breast: a 12-year prospective clinical study. AB - Invasive micropapillary carcinoma of the breast is a histologic subtype of breast cancer and associated with high incidence of lymphovascular invasion, lymph node metastasis and poor prognosis. The aim of this prospective study was to investigate the impact of precise pathologic diagnosis and individualized treatment on the outcomes of invasive micropapillary carcinoma of the breast. The study group included 2299 women with invasive micropapillary carcinoma diagnosed at Tianjin Medical University Cancer Institute and Hospital between January 2004 and December 2015. In the study group, specimens were examined with the method of whole-specimen orientation and serial sectioning, and patients received precise pathological diagnosis and individualized treatment. The control group of invasive micropapillary carcinoma consisted of 163 cases, identified through a retrospectively review of 9056 invasive carcinomas diagnosed at our institution between January 1989 and December 2003 using the standard pathology-evaluation method (i.e., not using the whole-specimen orientation and serial-sectioning method). The clinicopathological features, treatments and outcomes were compared between the two groups. The incidence of invasive micropapillary carcinoma in the study group was 6% (2299/39,714 cases), significantly higher than that of the control group (2%; 163/9056 cases). The 5-year disease-free survival in the study group was significantly higher than that in the control group (83.8 vs.45.4%; p < 0.05). The 5-year overall survival was significantly increased from 57.4% in the control group to 90.9% in the study group (p < 0.05). In the multivariate analysis, lymphovascular invasion, estrogen receptor status and lymph node metastasis were independent prognostic factors. Although invasive micropapillary carcinoma of the breast is associated with poor prognosis, precise pathologic diagnosis and individualized treatment improved the disease-free survival and overall survival of invasive micropapillary carcinoma patients. Precise pathological diagnosis is the premises for individualized treatments and for improving the outcomes of patients with invasive micropapillary carcinoma of the breast. PMID- 29403085 TI - Tumor budding as a standardized parameter in gastrointestinal carcinomas: more than just the colon. AB - Tumor budding, defined as single cells or clusters of less than five cells, is thought to be a histomorphologic marker of an aggressive tumor behavior mimicking the embryologic epithelial-mesenchymal transition, and has been well established in the past two decades as a poor prognostic factor in colorectal carcinoma. Slow uptake in routine reporting of this important pathologic prognostic feature was in part due to differing methods of assessment of budding reported in the literature, but has recently been clarified at a consensus conference on tumor budding in colorectal carcinoma. Tumor budding is also increasingly being reported as a useful pathologic prognostic feature in other gastrointestinal carcinomas, including esophageal squamous cell carcinoma and adenocarcinoma, gastric intestinal-type adenocarcinoma, pancreatic ductal adenocarcinoma, and ampullary adenocarcinoma. In this review, we will summarize the studies on tumor budding in gastrointestinal carcinomas, with a focus on the methods of assessment used and the potential clinical applications of the findings. PMID- 29403087 TI - Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations. AB - Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent. PMID- 29403088 TI - Poisson statistics-mediated particle/cell counting in microwell arrays. AB - Precise determination of particle or cell numbers is of importance for a wide array of applications in environmental studies, medical and biological applications, or manufacturing and monitoring applications in industrial production processes. A number of techniques ranging from manual counting to sophisticated equipment (e.g., flow cytometry) are available for this task. However, these methods are either labour intensive, prone to error, or require expensive equipment. Here, we present a fast, simple method for determining the number density of cells or microparticles using a microwell array. We analyze the light transmission of the microwells and categorize the microwells into two groups. As particles/cells contained in a microwell locally reduce the light transmission, these wells displayed a lower average transmission compared to unoccupied microwells. The number density of particles/cells can be calculated by Poisson statistics from the ratio of occupied to unoccupied microwells. Following this approach, the number densities of two different types of microparticles, as well as HeLa and E. Coli cells, ranging over four orders of magnitude were determined. Through the microwell array defined by microfabrication, a simple image recognition algorithm can be used with the formation of aggregates or irregular shaped samples providing no additional difficulty to the microwell recognition. Additionally, this method can be carried out using only simple equipment and data analysis automated by a computer program. PMID- 29403086 TI - Association of CDKAL1 nucleotide variants with the risk of non-syndromic cleft lip with or without cleft palate. AB - Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1 nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1 exons. A mega-analysis of the pooled individual data from the GWAS and a replication study revealed that six out of thirteen CDKAL1 variants were positively replicated and reached the threshold of statistical significance (Ptrend < 3.85E-03). They represented a single association signal and were located within the fifth intron of CDKAL1. The strongest individual variant was rs9356746 with a Ptrend value = 5.71E-06 (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.30-1.97). Sequencing analysis did not reveal any pathogenic mutations of this gene. This study provides the first evidence that chromosomal region 6p22.3 is a novel susceptibility locus for nsCL/P. The location of the risk variants within the CDKAL1 intronic sequence containing enhancer elements predicted to regulate the SOX4 transcription may suggest that SOX4, rather than CDKAL1, is a potential candidate gene for this craniofacial anomaly. PMID- 29403091 TI - Universal health coverage must include older people. PMID- 29403089 TI - Self-healing hydrogels formed by complexation between calcium ions and bisphosphonate-functionalized star-shaped polymers. AB - Star-shaped poly(ethylene glycol) (PEG) chain termini were functionalized with alendronate to create transient networks with reversible crosslinks upon addition of calcium ions. The gelation ability of alendronate-functionalized PEG was greatly dependent on the number of arms and arm molecular weight. After mixing polymer and calcium solutions, the formed hydrogels could be cut and then brought back together without any visible interface. After 2 minutes of contact, their connection was strong enough to allow for stretching without tearing through the previous fracture surface. Oscillatory rheology showed that the hydrogels recovered between 70 and 100% of the original storage and loss modulus after rupture. Frequency sweep measurements revealed a liquid-like behavior at lower frequencies and solid-like at high frequencies. Shifting frequency curves obtained at different calcium and polymer concentrations, all data collapsed in a single common master curve. This time-concentration superposition reveals a common relaxation mechanism intrinsically connected to the calcium-bisphosphonate complexation equilibrium. PMID- 29403092 TI - Space science and technologies to advance health-related sustainable development goals. PMID- 29403093 TI - Public health round-up. PMID- 29403094 TI - Removing mercury, protecting people's health. AB - Now that the Minamata Convention has come into effect, developing countries are struggling to phase out the use of mercury to protect people's health. Jan Dirk Herberman reports. PMID- 29403095 TI - Tom Frieden: strategic interventions for maximum health impact. AB - Tom Frieden tells Fiona Fleck why countries that focus on a few carefully selected public health interventions to reduce noncommunicable diseases will save the most lives. PMID- 29403096 TI - Activity-based costing of health-care delivery, Haiti. AB - Objective: To evaluate the implementation of a time-driven activity-based costing analysis at five community health facilities in Haiti. Methods: Together with stakeholders, the project team decided that health-care providers should enter start and end times of the patient encounter in every fifth patient's medical dossier. We trained one data collector per facility, who manually entered the time recordings and patient characteristics in a database and submitted the data to a cloud-based data warehouse each week. We calculated the capacity cost per minute for each resource used. An automated web-based platform multiplied reported time with capacity cost rate and provided the information to health facilities administrators. Findings: Between March 2014 and June 2015, the project tracked the clinical services for 7162 outpatients. The cost of care for specific conditions varied widely across the five facilities, due to heterogeneity in staffing and resources. For example, the average cost of a first antenatal-care visit ranged from 6.87 United States dollars (US$) at a low-level facility to US$ 25.06 at a high-level facility. Within facilities, we observed similarly variation in costs, due to factors such as patient comorbidities, patient arrival time, stocking of supplies at facilities and type of visit. Conclusion: Time-driven activity-based costing can be implemented in low-resource settings to guide resource allocation decisions. However, the extent to which this information will drive observable changes at patient, provider and institutional levels depends on several contextual factors, including budget constraints, management, policies and the political economy in which the health system is situated. PMID- 29403097 TI - Trends in catastrophic health expenditure in India: 1993 to 2014. AB - Objective: To investigate trends in out-of-pocket health-care payments and catastrophic health expenditure in India by household age composition. Methods: We obtained data from four national consumer expenditure surveys and three health care utilization surveys conducted between 1993 and 2014. Households were divided into five groups by age composition. We defined catastrophic health expenditure as out-of-pocket payments equalling or exceeding 10% of household expenditure. Factors associated with catastrophic expenditure were identified by multivariable analysis. Findings: Overall, the proportion of catastrophic health expenditure increased 1.47-fold between the 1993-1994 expenditure survey (12.4%) and the 2011 2012 expenditure survey (18.2%) and 2.24-fold between the 1995-1996 utilization survey (11.1%) and the 2014 utilization survey (24.9%). The proportion increased more in the poorest than the richest quintile: 3.00-fold versus 1.74-fold, respectively, across the utilization surveys. Catastrophic expenditure was commonest among households comprising only people aged 60 years or older: the adjusted odds ratio (aOR) was 3.26 (95% confidence interval, CI: 2.76-3.84) compared with households with no older people or children younger than 5 years. The risk was also increased among households with both older people and children (aOR: 2.58; 95% CI: 2.31-2.89), with a female head (aOR: 1.32; 95% CI: 1.19-1.47) and with a rural location (aOR: 1.27; 95% CI: 1.20-1.35). Conclusion: The proportion of households experiencing catastrophic health expenditure in India increased over the past two decades. Such expenditure was highest among households with older people. Financial protection mechanisms are needed for population groups at risk for catastrophic health expenditure. PMID- 29403098 TI - Violence motivated by perception of sexual orientation and gender identity: a systematic review. AB - Objective: To assess the prevalence of physical and sexual violence motivated by perception of sexual orientation and gender identity in sexual and gender minorities. Methods: We searched nine databases without language restrictions for peer-reviewed and grey literature published from 2000 to April 2016. We included studies with more than 50 participants that measured the prevalence of physical and sexual violence perceived as being motivated by sexual orientation and gender identity or gender expression. We excluded intimate partner violence and self harm. Due to heterogeneity and the absence of confidence intervals in most studies, we made no meta-analysis. Findings: We included 76 articles from 50 countries. These covered 74 studies conducted between 1995 and 2014, including a total of 202 607 sexual and gender minority participants. The quality of data was relatively poor due to a lack of standardized measures and sometimes small and non-randomized samples. In studies where all sexual and gender minorities were analysed as one population, the prevalence of physical and sexual violence ranged from 6% (in a study including 240 people) to 25% (49/196 people) and 5.6% (28/504) to 11.4% (55/484), respectively. For transgender people the prevalence ranged from 11.8% (of a subsample of 34 people) to 68.2% (75/110) and 7.0% (in a study including 255 people) to 49.1% (54/110). Conclusion: More data are needed on the prevalence, risk factors and consequences of physical and sexual violence motivated by sexual orientation and gender identity in different geographical and cultural settings. National violence prevention policies and interventions should include sexual and gender minorities. PMID- 29403099 TI - A life-course approach to health: synergy with sustainable development goals. AB - A life-course approach to health encompasses strategies across individuals' lives that optimize their functional ability (taking into account the interdependence of individual, social, environmental, temporal and intergenerational factors), thereby enabling well-being and the realization of rights. The approach is a perfect fit with efforts to achieve universal health coverage and meet the sustainable development goals (SDGs). Properly applied, a life-course approach can increase the effectiveness of the former and help realize the vision of the latter, especially in ensuring health and well-being for all at all ages. Its implementation requires a shared understanding by individuals and societies of how health is shaped by multiple factors throughout life and across generations. Most studies have focused on noncommunicable disease and ageing populations in high-income countries and on epidemiological, theoretical and clinical issues. The aim of this article is to show how the life-course approach to health can be extended to all age groups, health topics and countries by building on a synthesis of existing scientific evidence, experience in different countries and advances in health strategies and programmes. A conceptual framework for the approach is presented along with implications for implementation in the areas of: (i) policy and investment; (ii) health services and systems; (iii) local, multisectoral and multistakeholder action; and (iv) measurement, monitoring and research. The SDGs provide a unique context for applying a holistic, multisectoral approach to achieving transformative outcomes for people, prosperity and the environment. A life-course approach can reinforce these efforts, particularly given its emphasis on rights and equity. PMID- 29403100 TI - Controlling hepatitis C in Rwanda: a framework for a national response. AB - With the introduction of direct-acting antiviral drugs, treatment of hepatitis C is both highly effective and tolerable. Access to treatment for patients, however, remains limited in low- and middle-income countries due to the lack of supportive health infrastructure and the high cost of treatment. Poorer countries are being encouraged by international bodies to organize public health responses that would facilitate the roll-out of care and treatment on a national scale. Yet few countries have documented formal plans and policies. Here, we outline the approach taken in Rwanda to a public health framework for hepatitis C control and care within the World Health Organization hepatitis health sector strategy. This includes the development and implementation of policies and programmes, prevention efforts, screening capacity, treatment services and strategic information systems. We highlight key successes by the national programme for the control and management of hepatitis C: establishment of national governance and planning; development of diagnostic capacity; approval and introduction of direct acting antiviral treatments; training of key personnel; generation of political will and leadership; and fostering of key strategic partnerships. Existing challenges and next steps for the programme include developing a detailed monitoring and evaluation framework and tools for monitoring of viral hepatitis. The government needs to further decentralize care and integrate hepatitis C management into routine clinical services to provide better access to diagnosis and treatment for patients. Introducing rapid diagnostic tests to public health care facilities would help to increase case-finding. Increased public and private financing is essential to support care and treatment services. PMID- 29403102 TI - Policy implications of big data in the health sector. PMID- 29403101 TI - Praziquantel for the treatment of schistosomiasis during human pregnancy. AB - In 2014, an estimated 40 million women of reproductive age were infected with Schistosoma haematobium, S. japonicum and/or S. mansoni. In both 2003 and 2006, the World Health Organization (WHO) recommended that all schistosome-infected pregnant and breastfeeding women be offered treatment, with praziquantel, either individually or during treatment campaigns. In 2006, WHO also stated the need for randomized controlled trials to assess the safety and efficacy of such treatment. Some countries have yet to follow the recommendation on treatment and many programme managers and pregnant women in other countries remain reluctant to follow the recommended approach. Since 2006, two randomized controlled trials on the use of praziquantel during pregnancy have been conducted: one against S. mansoni in Uganda and the other against S. japonicum in the Philippines. In these trials, praziquantel treatment of pregnant women had no significant effect on birth weight, appeared safe and caused minimal side-effects that were similar to those seen in treated non-pregnant subjects. Having summarized the encouraging data, on efficacy, pharmacokinetics and safety, from these two trials and reviewed the safety data from non-interventional human studies, we recommend that all countries include pregnant women in praziquantel treatment campaigns. We identify the barriers to the treatment of pregnant women, in countries that already include such women in individual treatments and mass drug administration campaigns, and discuss ways to address these barriers. PMID- 29403103 TI - Involving both parents in HIV prevention during pregnancy and breastfeeding. PMID- 29403106 TI - Health, climate and small island states. PMID- 29403108 TI - Public health round-up. PMID- 29403107 TI - Qualitative evidence to improve guidelines and health decision-making. PMID- 29403109 TI - The challenges of preventing bovine tuberculosis. AB - Bovine tuberculosis destroys livelihoods and is hampering efforts to achieve the End TB Strategy goal of tuberculosis elimination by 2030. Sophie Cousins reports on efforts to stamp out this neglected infectious disease. PMID- 29403110 TI - Marion Koopmans: greater regional capacity to fight disease outbreaks. AB - Marion Koopmans tells Fiona Fleck why the world needs a publicly-funded network of hubs in all regions with local experts able to respond to infectious disease threats as they emerge. PMID- 29403111 TI - Implementation research: reactive mass vaccination with single-dose oral cholera vaccine, Zambia. AB - Objective: To describe the implementation and feasibility of an innovative mass vaccination strategy - based on single-dose oral cholera vaccine - to curb a cholera epidemic in a large urban setting. Method: In April 2016, in the early stages of a cholera outbreak in Lusaka, Zambia, the health ministry collaborated with Medecins Sans Frontieres and the World Health Organization in organizing a mass vaccination campaign, based on single-dose oral cholera vaccine. Over a period of 17 days, partners mobilized 1700 health ministry staff and community volunteers for community sensitization, social mobilization and vaccination activities in 10 townships. On each day, doses of vaccine were delivered to vaccination sites and administrative coverage was estimated. Findings: Overall, vaccination teams administered 424 100 doses of vaccine to an estimated target population of 578 043, resulting in an estimated administrative coverage of 73.4%. After the campaign, few cholera cases were reported and there was no evidence of the disease spreading within the vaccinated areas. The total cost of the campaign - 2.31 United States dollars (US$) per dose - included the relatively low cost of local delivery - US$ 0.41 per dose. Conclusion: We found that an early and large-scale targeted reactive campaign using a single-dose oral vaccine, organized in response to a cholera epidemic within a large city, to be feasible and appeared effective. While cholera vaccines remain in short supply, the maximization of the number of vaccines in response to a cholera epidemic, by the use of just one dose per member of an at-risk community, should be considered. PMID- 29403112 TI - Antibiotic use in poultry: a survey of eight farms in Thailand. AB - Objective: To investigate antibiotic use in poultry farms in Thailand and estimate the total amount of antibiotics used annually in Thai production of chicken meat. Methods: In a single province, we surveyed eight farms in which chickens were raised for meat and interviewed the farms' owners in 2016. The antibiotic use for each chicken was defined as the amount of antibiotic given to the chicken over its entire lifetime divided by the target weight of the chicken at the time of its slaughter. Assuming that the results were nationally representative, we estimated annual antibiotic use on all Thai chickens raised for meat. Findings: No use of antibiotics for growth promotion was reported. Five farms raised 1-kg chickens for company A and reportedly used no antibiotics unless the chickens were sick. The other three farms raised 3-kg chickens for company B and reported routine use of antibiotics for prophylaxis. Per kg final weight, each chicken raised for company B was reportedly routinely given a mean of 101 mg of antibiotics - that is, 33 mg of amoxicillin, 29 mg colistin, 19 mg oxytetracycline, 18 mg doxycycline and 2 mg tilmicosin. The total amount of antibiotic used on all Thai chickens raised for meat in 2016 was estimated to be 161 tonnes. Conclusion: Each year in Thailand, many tonnes of antibiotics are probably routinely used in raising chickens for meat. Labels on retail packs of meat should include data on antibiotic use in the production of the meat. PMID- 29403113 TI - Antibiotic distribution channels in Thailand: results of key-informant interviews, reviews of drug regulations and database searches. AB - Objective: To analyse how antibiotics are imported, manufactured, distributed and regulated in Thailand. Methods: We gathered information, on antibiotic distribution in Thailand, in in-depth interviews - with 43 key informants from farms, health facilities, pharmaceutical and animal feed industries, private pharmacies and regulators- and in database and literature searches. Findings: In 2016-2017, licensed antibiotic distribution in Thailand involves over 700 importers and about 24 000 distributors - e.g. retail pharmacies and wholesalers. Thailand imports antibiotics and active pharmaceutical ingredients. There is no system for monitoring the distribution of active ingredients, some of which are used directly on farms, without being processed. Most antibiotics can be bought from pharmacies, for home or farm use, without a prescription. Although the 1987 Drug Act classified most antibiotics as "dangerous drugs", it only classified a few of them as prescription-only medicines and placed no restrictions on the quantities of antibiotics that could be sold to any individual. Pharmacists working in pharmacies are covered by some of the Act's regulations, but the quality of their dispensing and prescribing appears to be largely reliant on their competences. Conclusion: In Thailand, most antibiotics are easily and widely available from retail pharmacies, without a prescription. If the inappropriate use of active pharmaceutical ingredients and antibiotics is to be reduced, we need to reclassify and restrict access to certain antibiotics and to develop systems to audit the dispensing of antibiotics in the retail sector and track the movements of active ingredients. PMID- 29403114 TI - Lessons learnt from implementation of the International Health Regulations: a systematic review. AB - Objective: To respond to the World Health Assembly call for dissemination of lessons learnt from countries that have begun implementing the International Health Regulations, 2005 revision; IHR (2005). Methods: In November 2015, we conducted a systematic search of the following online databases and sources: PubMed(r), Embase(r), Global Health, Scopus, World Health Organization (WHO) Global Index Medicus, WHO Bulletin on IHR Implementation and the International Society for Disease Surveillance. We included identified studies and reports summarizing national experience in implementing any of the IHR (2005) core capacities or their components. We excluded studies that were theoretical or referred to IHR (1969). Qualitative systematic review methodology, including meta ethnography, was used for qualitative synthesis. Findings: We analysed 51 articles from 77 countries representing all WHO Regions. The meta-syntheses identified a total of 44 lessons learnt across the eight core capacities of IHR (2005). Major themes included the need to mobilize and sustain political commitment; to adapt global requirements based on local sociocultural, epidemiological, health system and economic contexts; and to conduct baseline and follow-up assessments to monitor the status of IHR (2005) implementation. Conclusion: Although experiences of IHR (2005) implementation covered a wide global range, more documentation from Africa and Eastern Europe is needed. We did not find specific areas of weakness in monitoring IHR (2005); sustained monitoring of all core capacities is required to ensure effective systems. These lessons learnt could be adapted by countries in the process of meeting IHR (2005) requirements. PMID- 29403115 TI - Revision of clinical case definitions: influenza-like illness and severe acute respiratory infection. AB - The formulation of accurate clinical case definitions is an integral part of an effective process of public health surveillance. Although such definitions should, ideally, be based on a standardized and fixed collection of defining criteria, they often require revision to reflect new knowledge of the condition involved and improvements in diagnostic testing. Optimal case definitions also need to have a balance of sensitivity and specificity that reflects their intended use. After the 2009-2010 H1N1 influenza pandemic, the World Health Organization (WHO) initiated a technical consultation on global influenza surveillance. This prompted improvements in the sensitivity and specificity of the case definition for influenza - i.e. a respiratory disease that lacks uniquely defining symptomology. The revision process not only modified the definition of influenza-like illness, to include a simplified list of the criteria shown to be most predictive of influenza infection, but also clarified the language used for the definition, to enhance interpretability. To capture severe cases of influenza that required hospitalization, a new case definition was also developed for severe acute respiratory infection in all age groups. The new definitions have been found to capture more cases without compromising specificity. Despite the challenge still posed in the clinical separation of influenza from other respiratory infections, the global use of the new WHO case definitions should help determine global trends in the characteristics and transmission of influenza viruses and the associated disease burden. PMID- 29403117 TI - Medicines quality assurance to fight antimicrobial resistance. PMID- 29403116 TI - Pandemic risk: how large are the expected losses? AB - There is an unmet need for greater investment in preparedness against major epidemics and pandemics. The arguments in favour of such investment have been largely based on estimates of the losses in national incomes that might occur as the result of a major epidemic or pandemic. Recently, we extended the estimate to include the valuation of the lives lost as a result of pandemic-related increases in mortality. This produced markedly higher estimates of the full value of loss that might occur as the result of a future pandemic. We parametrized an exceedance probability function for a global influenza pandemic and estimated that the expected number of influenza-pandemic-related deaths is about 720 000 per year. We calculated that the expected annual losses from pandemic risk to be about 500 billion United States dollars - or 0.6% of global income - per year. This estimate falls within - but towards the lower end of - the Intergovernmental Panel on Climate Change's estimates of the value of the losses from global warming, which range from 0.2% to 2% of global income. The estimated percentage of annual national income represented by the expected value of losses varied by country income grouping: from a little over 0.3% in high-income countries to 1.6% in lower-middle-income countries. Most of the losses from influenza pandemics come from rare, severe events. PMID- 29403118 TI - A framework for stimulating economic investments to prevent emerging diseases. PMID- 29403119 TI - Complex determinants of inappropriate use of antibiotics. PMID- 29403120 TI - Estimating Morning Change in Land Surface Temperature from MODIS Day/Night Observations: Applications for Surface Energy Balance Modeling. AB - Observations of land surface temperature (LST) are crucial for the monitoring of surface energy fluxes from satellite. Methods that require high temporal resolution LST observations (e.g., from geostationary orbit) can be difficult to apply globally because several geostationary sensors are required to attain near global coverage (60 degrees N to 60 degrees S). While these LST observations are available from polar-orbiting sensors, providing global coverage at higher spatial resolutions, the temporal sampling (twice daily observations) can pose significant limitations. For example, the Atmosphere Land Exchange Inverse (ALEXI) surface energy balance model, used for monitoring evapotranspiration and drought, requires an observation of the morning change in LST - a quantity not directly observable from polar-orbiting sensors. Therefore, we have developed and evaluated a data-mining approach to estimate the mid-morning rise in LST from a single sensor (2 observations per day) of LST from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor on the Aqua platform. In general, the data-mining approach produced estimates with low relative error (5 to 10%) and statistically significant correlations when compared against geostationary observations. This approach will facilitate global, near real-time applications of ALEXI at higher spatial and temporal coverage from a single sensor than currently achievable with current geostationary datasets. PMID- 29403121 TI - Effortful control and school adjustment: The moderating role of classroom chaos. AB - Guided by the person by environment framework, the primary goal of this study was to determine whether classroom chaos moderated the relation between effortful control and kindergarteners' school adjustment. Classroom observers reported on children's (N = 301) effortful control in the fall. In the spring, teachers reported on classroom chaos and school adjustment outcomes (teacher-student relationship closeness and conflict, and school liking and avoidance). Cross level interactions between effortful control and classroom chaos predicting school adjustment outcomes were assessed. A consistent pattern of interactions between effortful control and classroom chaos indicated that the relations between effortful control and the school adjustment outcomes were strongest in high chaos classrooms. Post-hoc analyses indicated that classroom chaos was associated with poor school adjustment when effortful control was low, suggesting that the combination of high chaos and low effortful control was associated with the poorest school outcomes. PMID- 29403123 TI - Perceptions of Accredited Social Health Activists on Depression: A Qualitative Study from Karnataka, India. AB - Background: Depression is a significant public health concern in India, associated with a large treatment gap. Assessing perceptions of Accredited Social Health Activists (ASHAs) on depression can be invaluable as they are selected to work at the interface between their own communities and the health-care delivery system. Aims and Objectives: This study aimed at utilizing a qualitative approach to examine the ASHAs' understanding of depression, their mental health-care practices specific to depression, and their capacity-building needs with regard to identification and helping persons with depression. Subjects and Methods: A cross-sectional qualitative study using two focus group discussions was conducted. The sample comprised 14 ASHAs in the age range of 25-45 years from Bengaluru urban district. The data were analyzed manually by the method of directed content analysis. Results: The ASHAs were found to have inadequate knowledge of the signs and symptoms of depression, its biopsychosocial nature, and its impact on functioning. Causation of depression was narrated in terms of psychosocial stressors. The majority expressed the need for primarily psychosocial interventions for depression. All participants reported their motivation to obtain training in identifying persons with depression and providing simple psychosocial intervention for them. Conclusion: This study indicates that ASHAs have poor knowledge of depression, which could be leading to its low recognition and treatment in the communities they work in. They are therefore likely to benefit from capacity building on depression which includes familiar nomenclature, biopsychosocial elucidation of the illness, life-span approach, understanding of its impact on various domains of functioning, and the treatments available. PMID- 29403122 TI - The Clock Drawing Test versus Mini-mental Status Examination as a Screening Tool for Dementia: A Clinical Comparison. AB - There is a growing incidence of dementia patients in the community, and with this growth, there is need for rapid, valid, and easily administrable tests for the screening of dementia and mild cognitive impairment in the community. This review looks at the two most commonly used tests in dementia screening, namely, the clock drawing test (CDT) and the mini-mental status examination (MMSE). Both these tests have been used in dementia screening over the past three decades and have been the subject of scrutiny of various studies, reviews, and meta-analysis. Both these tests are analyzed on their ability to assess dementia and screen for it in the community, general practice and general hospital settings. The methods of administration and scoring of each test are discussed, and their advantages and disadvantages are explained. There is also a direct comparison made between the MMSE and CDT in dementia screening. Future research needs with these tests are also elucidated. PMID- 29403124 TI - Attitude toward Selfie Taking and its Relation to Body Image and Narcissism in Medical Students. AB - Background: The recent and rapidly popularized social phenomenon of selfie taking has been showing an increasing trend. It is thus imperative to assess the knowledge, attitude, and perception of the groups toward this phenomenon. Selfie taking is associated with younger age groups and hence, we aimed to explore the attitudes toward selfie taking and its relation toward body image and narcissism in medical college students. Methodology: This was cross-sectional study and had two groups with Group A comprising 92 first year medical students and Group B including 103 postgraduate (PG) medical students from various specialties. They were interviewed in a single session using the scale of attitude toward selfie taking questionnaire, Body Image Acceptance and Action Questionnaire (BIAAQ), and the narcissistic personality inventory. Scores obtained were computed using basic descriptive statistics and t-test where appropriate. Results: A strong positive favorable trend toward selfie taking was noticed among both groups (A = 56.5%, B = 45.6%). There was no difference in attitude between the two groups, or difference in the gender between those clicking their own selfies regularly within each group. BIAAQ reflected a significant difference among male subjects of the two groups with PG students was more concerned about body image (P = 0.001), whereas female subjects of both groups showed no such difference. The narcissism traits also showed a significant difference, only when males of both groups were compared again in favor of PG medical students (P = 0.022). Conclusion: This study revealed that selfie-taking is popular among medical students both in their undergraduate and PG period. Further research in diverse clinical and nonclinical populations is warranted to explore the relation between this phenomenon and body image acceptance or narcissistic traits. PMID- 29403125 TI - Spousal Caregiver Burden and Its Relation with Disability in Schizophrenia. AB - Background: Schizophrenia, a chronic psychiatric disorder, can affect one's productivity and psychosocial functioning. In Indian context, the responsibility of caring persons with schizophrenia is increasingly on their spouses. Spousal caregiver experience and its relation with disability in schizophrenia need to be studied. Materials and Methods: We conducted a cross-sectional study among 52 outpatients with schizophrenia and their spouses attending a tertiary psychiatric center. The objectives were: (a) to explore spousal caregiver burden in schizophrenia and (b) to assess the relation between disability and spousal caregiver burden. The study adopted recommended ethical principles. Scales such as Burden Assessment Schedule, Indian Disability Evaluation and Assessment Scale (IDEAS), and Positive and Negative Syndrome Scale were used to collect appropriate data. Descriptive analysis, bivariate analysis, and multivariate analysis were done in SPSS software version 16.0. Results: The mean spousal caregiver burden score was 73.5 (standard deviation: 14.0). In bivariate analysis, disability, duration of schizophrenia, severity of schizophrenia, place of residence, and socioeconomic status had statistically significant relation with spousal caregiver burden. Adjusted for spouses' age, gender, and other significant factors in bivariate analysis, the IDEAS global disability score (2.6, [confidence interval 0.5-3.8, P = 0.013]) retained statistically significant association with spousal caregiver burden. Conclusion: Spouses of persons with schizophrenia experience significant caregiver burden. Disability was found to be the most powerful determinant of spousal caregiver burden in the sample. Focus on disability alleviation in the management of schizophrenia may help reduce spousal caregiver burden. PMID- 29403126 TI - The Confirmatory Factor Analysis of the Original Brief Intellectual Disability Scale and Alternative Models. AB - Objective: Brief Intellectual Disability Scale (BIDS) is a measure validated for identification of children with intellectual disabilities (IDs) in countries with low disability resources. Following the publication of the exploratory factor analysis of BIDS, the authors have documented the confirmatory factor analysis (CFA) of BIDS in this study. Materials and Methods: A prospective cross-sectional study was conducted to document the CFA of the BIDS. Primary caregivers (N = 124) of children with ID were recruited and rated the BIDS. We used alternative fit indices for the evaluation of comparative fit index (CFI) and root mean square error of approximation (RMSEA) to evaluate the model fit. The 2-index fit strategy was used to select the best factor model. Results: The model fit index for the original 3-factor model and alternative 2-factor and 1-factor models with 9 items of the BIDS was under identified along with another 3-factor, 7-item model. Another 1-factor, 7-item model was identified but did not satisfy the 2 index fit strategy. A short version of the scale with a 2-factor and 7-item model of BIDS presented the best fit indices of CFI = 0.952 and RMSEA = 0.069. Conclusion: Although the original factor structure of BIDS was not confirmed in this study, another alternative a priori model for the construct validity of BIDS was confirmed. Therefore, the BIDS factor structure has been revised, refined, and trimmed to the final 2-factor, 7-item shorter version. Further documentation of the diagnostic accuracy, validity, and reliability of this shorter version of BDI is recommended. PMID- 29403127 TI - Dysfunction among Families of Children with Intellectual Disability in India Using Systems Model: Prevalence, Pattern, and Severity of Impairment. AB - Objectives: Family dysfunction is observed in families with children with intellectual disability (ID). We study the prevalence, pattern of dysfunction, and severity of impairment in these special families using Systems approach. Methods: Sixty-two special families (a child with ID) and 62 typical families (all children with typical development) were included in the present study. The presence of ID was confirmed and quantified with the Binet-Kamat Scale of intelligence or Gesell's Developmental Schedule and Vineland Social Maturity Scales among the special families. In the typical families, brief ID scale was used to rule out ID. Prevalence, pattern, and severity of family dysfunction were assessed using Family Apgar Scale, Chicago Youth Development Study Family Assessment Scale and Global Assessment of Relational Functioning Scale, respectively. Appropriate bivariate analyses were used. Results: About 53% of special families and 19% of typical families had family dysfunction. About 21% of special families and 71% of typical families had the satisfactory relational unit. Areas of adaptability, partnership, growth, affection, resolve, beliefs about family, beliefs about development, beliefs about purpose, cohesion, deviant beliefs, support, organization, and communication were significantly different between special and typical families. The functional impairment was significantly more in the special families. Conclusion: Family dysfunction is more prevalent among special families in India using systems approach. These families should be screened for dysfunction, and family therapy be prescribed when required. PMID- 29403128 TI - Add-on Aripiprazole for Atypical Antipsychotic-induced, Clinically Significant Hyperprolactinemia. AB - Background: Antipsychotic treatment-induced hyperprolactinemia is a highly distressing and disabling side effect for patients. The use of add-on aripiprazole has been identified as a possible treatment strategy in this situation. However, data on prolactin changes with add-on aripiprazole in a real world naturalistic clinical setting from India are sparse. Materials and Methods: The retrospective chart review was conducted at the specialty metabolic clinic at the National Institute of Mental Health and Neurosciences, Bengaluru, India. Sixteen patients (female: male = 13:3) who were on a stable dose of antipsychotic medications, complaining of either sexual dysfunction or menstrual irregularities, were prescribed add-on aripiprazole. The serum prolactin values were obtained before the initiation of aripiprazole and during the follow-up. Results: Patients were on treatment with risperidone, amisulpride, and olanzapine and had a prolactin level of 87.1 +/- 60.7 ng/ml. Add-on aripiprazole treatment was given with a mean dose of 13.8 +/- 7.4 mg/day. Patients had a significant reduction in prolactin level (35.6 +/- 29.1 ng/ml) following treatment with aripiprazole (P = 0.004). Conclusions: Add-on aripiprazole could be a clinically useful strategy in patients who develop antipsychotic-induced hyperprolactinemia. PMID- 29403129 TI - Psychological Dissection of Patients Having Dissociative Disorder: A Cross sectional Study. AB - Background: Patients present with dissociative disorders as a decompensation to underlying stressful situation. It is clinically important to evaluate the presence, type, and temporal relation of the stressors resulting in dissociation. Further knowing the sociodemographic and psychological profile of the dissociative patient helps in better management. Materials and Methods: The study included 55 dissociative patients aged between 5 to 45 years. Psychiatric diagnosis was made using ICD-10 DCR. Psychosocial stressors and stressful life events were assessed using presumptive stressful life events scale/life events scale for Indian children and clinical interview. Personality and temperament traits were assessed using medico psychological questionnaire and temperament measurement schedule, respectively. Intelligence quotient (IQ) was assessed using standard progressive matrices and colored progressive matrices. Statistical analysis was done using Epi Info 7 software. Results: All patients had significant psychosocial stressors preceding dissociation. Precipitating factor with temporal association was observed in only 83.64%. Family disharmony (41.82%) followed by education-related problems (29.09%) was the most common psychosocial stressors. 61.82% of the dissociative patients had psychiatric comorbidity. Mean IQ of study sample was 92.47. Dissociative children had high emotionality and energy levels but low sociability, rhythmicity, and distractibility. 50% of the adults were neurotic and had emotionally unstable personality. Conclusion: Dissociative disorders are commonly seen in females, adolescents, and in those from lower socioeconomic status and rural areas. They are always preceded by psychosocial stressors. Most of them have comorbid psychiatric disorders such as depression and anxiety. Neuroticism and emotionally unstable personality traits are common in adult patients while temperamental traits such as low sociability, low rhythmicity, low distractibility, high emotionality, and high energy levels are common in children. PMID- 29403130 TI - Suicidal Nonorganophosphate Poisoning in a Tertiary Hospital in South India: Nature, Prevalence, Risk Factors. AB - Background: People who deliberately ingest poisons commonly present to emergency departments of hospitals in India. However, there is a dearth of information on poisoning using nonorganophosphorus pesticides. Methods: This prospective, hospital-based study attempted to examine the nonorganophosphorus poisons used to attempt suicide. Data on sociodemographic characteristics of patients, site and source of poisons, co-ingested substances, premeditation, and reason for poisoning were collected. A multinomial logistic regression was performed to determine association between poison class and these exposure characteristics. Results: Three hundred and forty-one cases of attempted suicide presented during the 6-month period (1.7% of all emergency room admissions). The majority was predominantly male and was young adults. Poisoning was the most common mode (91.7%), followed by hanging (7.3%) and self-injury (3, 0.9%). Pesticides (44.3%) including organophosphates (25.5%) were the predominant poisons, followed by pharmaceuticals (27.9%), caustics/chemicals (12.0%), and plant poisons (7.0%). One hundred and nine were available for prospective interview as the others who presented were not detained for prolonged observation the emergency department. Most patients who ingested such poisons were women, from rural backgrounds and were educated. The majority sourced the poisons from home, consumed poison at home, and mixed the poison with water; these attempts were impulsive and seemed to be in response to relationship conflicts. In the multivariate analysis, education (P = 0.08) and poison source (outside the home) were significant predictors of pesticide ingestion. Conclusions: Suicidal poisoning results from a complex synthesis of socioeconomic and psychological factors; certain patterns of poisoning are likely to be more prevalent in demographic niche groups. PMID- 29403131 TI - Interepisodic Functioning in Patients with Bipolar Disorder in Remission. AB - Background and Objectives: Patients with bipolar disorder (BD), despite recovering symptomatically, suffer from several functional impairments even in remission. The actual causes of impaired functioning are less known. Materials and Methods: The study aimed to examine the clinical and psychosocial determinants of functioning in patients with BD in remission. A cross-sectional single-group design was adopted (n = 150). Participants meeting the study criteria were screened with Mini-International Neuropsychiatric Interview Scale. The selected participants were administered various tools to assess the level of functioning and the clinical, psychosocial determinants of functioning. Results: The clinical characteristics of the sample included early age of onset of illness, presence of precipitating factors, fewer episodes, minimal comorbidities, history of psychotic episodes, family history of mental illness, good medication adherence, and low depression and mania scores. Psychosocial factors included higher stress and moderate social support and self-esteem in the sample. Poor functioning patients had a history of longer hospital stay and had greater scores on depression, mania, stress, and maladaptive coping styles than better functioning patients. Conclusion: Higher depression, mania, stress, and maladaptive coping strategies were related to poor functioning, while higher medication adherence, self-esteem, and social support were related to better functioning. PMID- 29403132 TI - Can Plasticity Transform Functions in Neurodegeneration in Children as Well as Adults? An Observational Study. AB - Introduction: Creativity is a physiological need based biological function very essential for survival. However, generally in disorders of progressive cognitive dysfunction creative skills are lost. However there are situations where these potentials are temporarily enhanced. Patients and Methods: We did an observational study of children and adults, 5 adults and 2 childrens, who showed extraordinary creativity evaluated based on evidence shown by patient, peers and re produced in test situation. Discussion: Our observational study reveals spontaneous interest in new and useful creative activity in our patients with various disorders causing progressive cognitive dysfunction. This observation reveals creative gain of function does take place in the face of progressive cognitive dysfunction in the setting of several diseases and it serves as a treatment option in behaviour management. Whether it is due to disinhibition of creative areas in the brain or facilitated function in regenerating data linking circuits needs further study. Conclusion: Set goals which are survival instinct based activities are probably removed by neurodegeneration and thereby the innate creativity gets disinhibited and expressed in wonderful forms of creativity. Whether special creative circuits in the brain, which causes this extraordinary creativity also needs to be studied. These creative skills in some of our patients served as effective pharmaco sparing agents during periods of aggression and agitation by engaging them in those activities, utility of which can be considered as a therapeutic option. PMID- 29403133 TI - Unrecognized Prevalence of Macrocytosis among the Patients with First Episode of Psychosis and Depression. AB - Background: Mood disorders and psychosis has been reported among the patients with macrocytosis; however, its prevalence among the first episode of psychosis and depression is unknown. The purpose of the study was to establish the prevalence of macrocytosis among the patients with the first episode of depression and psychosis. Materials and Methods: In this cross-sectional study, three groups comprising patients with first episode of depression (n = 100), patients with the first episode of psychosis (n = 100), and healthy controls (n = 100) were included. Blood samples were collected from each participant and analyzed using the automated coulter counter. The hematological variables (e.g., macrocytosis, anemia) in the three groups were compared using the Chi-square and analysis of variance tests. Results: The prevalence of macrocytosis among patients with depression and psychosis was 2.6 (8%) and 3.3 times (11%) higher, respectively than that among the healthy controls (3%). In addition, the hemoglobin concentration, mean corpuscular volume and mean platelet volume in patients with first episodes of psychosis and depression significantly differed from those in healthy controls P < 0.001. Conclusion: This study showed that the prevalence of macrocytosis among the first episode of depression and psychosis was higher than healthy controls. Macrocytosis may have etiological and prognostic significance among these patients. Prospective studies are needed to explore the clinical significance of macrocytosis among the patients with depression and psychosis in the clinical practice. PMID- 29403134 TI - A Pilot Study of Correlation between Intelligence Quotient, Social Quotient, and Ayurveda Parameters in Children. AB - Background: Intelligence quotient (IQ) and social quotient (SQ) are comparable in predicting intelligence status. The latter is assessed whenever IQ testing is not possible. According to Ayurveda, Buddhi (intelligence) is affected by Prakriti (body constitution) which depends on the predominance of Tridosha and Triguna. There is a paucity of studies to examine their association. The study was designed to examine correlation among IQ, SQ, performance quotient (PQ) and maladaptive behaviour; and to find out their relationship with primary (Anubandhya) and secondary (Anubandha) doshas with intelligence in children with mild to moderate intellectual disability. Methodology: Children (n = 120) were recruited from outpatient department of a tertiary care hospital as part of a clinical trial of a novel Ayurveda formulation. Stanford Binet Scale, Vineland Social Maturity Scale, Seguin Form Board Test, and Maladaptive Behavior Schedule II were administered. Ayurvedic parameters were assessed clinically by Ayurveda practitioner. Separate regression analyses were carried out to look for associations. Results: IQ and SQ were positively correlated (P = 0.01). Maladaptive behavior and SQ were negatively correlated (0.05). SQ was associated with secondary dosha (P = 0.002) and stage of disease (Roga Kriyakala) (P = 0.015). IQ was also associated with secondary dosha (P = 0.008). Conclusion: SQ and IQ are positively correlated. The correlation of Anubandha (secondary) dosha was high on IQ and SQ. PMID- 29403135 TI - A 12-week Comparative Prospective Open-label Randomized Controlled Study in Depression Patients Treated with Vilazodone and Escitalopram in a Tertiary Care Hospital in North India. AB - Background: Depression is a leading cause of morbidity in modern world and introduction of selective serotonin reuptake inhibitors (SSRIs) was a revolution for treating depression. However, sexual dysfunction and weight gain always remained an issue for patients leading to discontinuation of treatment. Vilazodone is a novel SSRI and literature show better efficacy and decrease weight gain and sexual dysfunction. Aim of study: This study aims to compare the efficacy, sexual dysfunction, and weight gain caused due to vilazodone and escitalopram. Methodology: This is an open-label randomized, controlled study; 60 patients diagnosed as depression were divided into two groups of 30 each. One group was started on vilazodone and one on escitalopram randomly. The groups were compared on the basis of efficacy, weight gain, and sexual dysfunction by applying Hamilton Depression Rating Scale (HDRS) and Arizona Sexual Experience Scale (ASEX) at baseline, 4, and 12 weeks interval. Statistical analysis was done by applying Chi-square, t-test, and fisher exact test and descriptive analysis. Results: Vilazodone group shows fall in HDRS with 18.77 +/- 4.3, 14.83 +/- 3.68, and 9.63 +/- 3.06 while it was 18.8 +/- 4.09, 14.3 +/- 2.96, and 8.43 +/- 2.1 at baseline, 4, and 12 weeks, respectively. ASEX score in vilazodone was found to have 16.87 +/- 2.97, 15.37 +/- 3.1, and 11.73 +/- 3.55 while on escitalopram, 16.4 +/- 3.35, 17.13 +/- 3.48, and 18.37 +/- 4.09 at first visit, 4, and 12 weeks, respectively. Patients on vilazodone had mean weight of 69.63 +/- 7.7, 69.83 +/- 7.83, and 69.9 +/- 7.69 while on escitalopram, 72.47 +/- 7.95, 72.87 +/ 7.9, and 75.6 +/- 8.46 at baseline, 4, and 12 weeks, respectively. Conclusions: Our study shows that vilazodone has better efficacy, lesser weight gain, and lesser sexual dysfunction. PMID- 29403136 TI - A Case of Obsessive-Compulsive Disorder Comorbid with Miyoshi Myopathy. AB - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder, with predominant involvement of cortico-striato-thalamo-cortico circuitry. Although late-onset cases (>35 years) usually show an association with various neurological disorders involving basal ganglia and thalamus, it is not the case with the young-onset patients. There have been no reports of OCD comorbid with dysferlinopathy which is usually considered as a disease involving only muscles. However, recently, studies suggest involvement of brain in this disease. Here, we report a case of dysferlinopathy comorbid with OCD and discuss the related literature. PMID- 29403137 TI - A Case of Rapidly Progressing Frontotemporal Dementia. AB - Frontotemporal dementia commonly presents as a gradual change in personality, social conduct, and language ability, often sparing memory loss in early stages. We report a case of a 55-year-old female with rapid progression of memory impairment and other cognitive functions in a span of 2 years. PMID- 29403138 TI - Amisulpride Reexposure and Tardive Dyskinesia. AB - To highlight the association between amisulpride and onset of tardive dyskinesia (TD) in patient suffering with psychosis not otherwise specified (NOS), who has already been treated with amisulpride for many years. A 40-year-old female suffering with psychosis NOS since 19 years presented with recurrence of positive symptoms in the form of delusion of persecution, ideas of grandiosity since last 3 months. She was treated with amisulpride up to 400 mg/day and developed involuntary oro-buccal-lingual movement within 2 months of amisulpride therapy. Amisulpride an atypical antipsychotic can lead to the development of TD in patient who already received amisulpride for many years in the past. Reexposure with amisulpride can lead to early onset of TD due to blockade of already unregulated postsynaptic supersensitive dopamine receptors. PMID- 29403139 TI - Quetiapine-induced Diabetic Ketoacidosis. AB - Psychomotor retardation and extrapyramidal symptoms have limited the conventional antipsychotic use. Atypical antipsychotics though widely prescribed with good tolerability and efficacy, the metabolic complications associated with them are of clinical importance. Diabetic ketoacidosis (DKA) is a fatal complication of atypical antipsychotic use. We report a case of new-onset diabetes presenting as DKA with quetiapine use. PMID- 29403140 TI - Early Marked Behavioral Symptoms in Bilateral Posterior Cerebral Artery Stroke: A Disguised Presentation. AB - Clinical signs and symptoms of posterior cerebral artery (PCA) stroke are varied and can be challenging to diagnose at early stage. A case of bilateral PCA infarct presenting with marked behavioral symptoms and minimal neurological symptoms is presented here. A 34 years old female had presented with marked behavioral symptoms, blurring of vision and tingling sensation in left half of body. Though the latter complaints resolved following day, her behavioral complaints persisted. Magnetic Resonance Imaging (MRI) of brain revealed acute non-hemorrhagic infarct in bilateral PCA territory. Psychotropics were beneficial for her behavioral symptoms. Isolated behavioral symptoms in PCA stroke led to speculate anatomical substrate for those symptoms. We discussed possible anatomical substrates for behavioral symptoms. Our case adds to the existing literature on a range of disguising presentations in PCA stroke and also emphasizes those distinctions between 'neurological' or 'psychological' or 'psychiatric' disorders are often sketchy. PMID- 29403141 TI - Desvenlafaxine Overdose-induced Toxic Cardiomyopathy and Acute Left Ventricular Failure: A Case Report. PMID- 29403142 TI - Detecting T Cell Activation Using a Varying Dimension Bayesian Model. AB - The detection of T cell activation is critical in many immunological assays. However, detecting T cell activation in live tissues remains a challenge due to highly noisy data. We developed a Bayesian probabilistic model to identify T cell activation based on calcium flux, a dramatic increase in intracellular calcium concentration that occurs during T cell activation. Because a T cell has unknown number of flux events, the implementation of posterior inference requires trans dimensional posterior simulation. The model is able to detect calcium flux events at the single cell level from simulated data, as well as from noisy biological data. PMID- 29403143 TI - Rumination, Excessive Reassurance Seeking, and Stress Generation Among Early Adolescent Girls. AB - Nolen-Hoeksema proposed that rumination increases stressful events and circumstances; however, few studies have examined this question. Thus, we explored whether (a) rumination predicted increases in the generation of chronic and acute stress, (b) excessive reassurance seeking (ERS) mediated links between rumination and stress generation, (c) rumination increased exposure to acute independent (uncontrollable) stress, and (d) rumination predicted chronic stress generation in certain domains, but not others. These questions were examined in a 1-year study of 126 early adolescent girls ( M age = 12.39 years) using contextual objective stress interviews. Findings indicated that rumination predicted increases in acute dependent interpersonal stress and chronic interpersonal stress, and ERS mediated these associations. Moreover, rumination was not associated with acute independent stress. Finally, the effect of rumination on chronic stress generation was most salient in adolescents' romantic lives and in parent-adolescent relationships. These findings suggest that ruminators create stressful interpersonal environments. PMID- 29403145 TI - Water-mediated correlations in DNA-enzyme interactions. AB - In this paper we consider dipole-mediated correlations between DNA and enzymes in the context of their water environment. Such correlations emerge from electric dipole-dipole interactions between aromatic ring structures in DNA and in enzymes. We show that there are matching collective modes between DNA and enzyme dipole fields, and that a dynamic time-averaged polarization vanishes in the water dipole field only if either DNA, enzyme, or both are absent from the sample. This persistent field may serve as the electromagnetic image that, in popular colloquialisms about DNA biochemistry, allows enzymes to "scan" or "read" the double helix. Topologically nontrivial configurations in the coherent ground state requiring clamplike enzyme behavior on the DNA may stem, ultimately, from spontaneously broken gauge symmetries. PMID- 29403144 TI - Predicting the Efficacy of HER2-Targeted Therapies: A Look at the Host. AB - HER2 is overexpressed in 20% of invasive breast cancers (BCs) and correlates with a more aggressive disease. Until the advent of targeted agents, HER2 was associated with worse outcomes. Rationally designed HER2-targeted agents have been developed and introduced into clinical practice for women with HER2 amplified BC, improving disease-free and overall survival for primary and metastatic tumors. Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, combined with chemotherapy, remains the standard of care for patients with HER2-positive BCs. However, many patients do not respond to this agent, whereas newer drugs have proven to be efficacious in clinical trials. The identification of biomarkers that select sensitive tumors and patients who will benefit from these new agents would help the incorporation of these therapies, limiting the risk of side effects and overtreatment and improving the outcomes of all patients with early-stage HER2-positive BC. We review the mechanisms of action of HER2-targeting agents, focusing on the involvement of the immune system and related predictive biomarkers. PMID- 29403146 TI - Developmental Pathways of Youth Gang Membership: A Structural Test of the Social Development Model. AB - As a result of nearly 40 years of research using a risk and protective factor approach, much is known about the predictors of gang onset. Little theoretical work, however, has been done to situate this approach to studying gang membership within a more comprehensive developmental model. Using structural equation modeling techniques, the current study is the first to test the capacity of the social development model (SDM) to predict the developmental pathways that increase and decrease the likelihood of gang membership. Results suggest that the SDM provides a good accounting of the social developmental processes at age 13 that are predictive of later gang membership. These findings support the promotion of a theoretical understanding of gang membership that specifies both pro- and antisocial developmental pathways. Additionally, as the SDM is intended as a model that can guide preventive intervention, results also hold practical utility for designing strategies that can be implemented in early adolescence to address the likelihood of later gang involvement. Three key preventive intervention points to address gang membership are discussed, including promoting efforts to enhance social skills, increasing the availability of prosocial opportunities and rewarding engagement in these opportunities, and reducing antisocial socialization experiences throughout the middle- and high school years. PMID- 29403147 TI - Pain Assessment Methods and Interventions Used by Pediatric Psychologists: A Survey by the Pain Special Interest Group of the Society of Pediatric Psychology. AB - Although many valid pain-related assessment instruments and interventions exist, little is known about which are actually utilized in practice and the factors that contribute to pediatric psychologist's decisions about their use. The aim of this survey study was to present a summary of current clinical practice among pediatric psychologists in the area of pediatric pain and to identify the needs and possible resources that would enable practitioners to better implement evidence-based assessments and interventions. To accomplish this aim, the Pain Special Interest Group of the Society of Pediatric Psychology (SPP) constructed an online survey that was sent electronically to current members of the SPP list serve. Results indicated the majority of participants are guided by a theoretical model and are using evidence-based assessments and interventions, although they are not always familiar with the literature supporting their use. Providers noted evidence-based pain intervention is facilitated by assessment tools, intervention resources, and appreciation of pain interventions by multidisciplinary team members. Barriers are both logistical (clinic space and time constraints) and knowledge-based (lack of familiarity with assessments/interventions). Thus, while pediatric psychologists are progressing towards better translation of research to practice, continued educational efforts and communication among practitioners about available resources are warranted. PMID- 29403148 TI - Longitudinal associations between self-regulation and the academic and behavioral adjustment of young children born preterm. AB - Much of the research to date about the structure of self-regulation in early childhood has been conducted with low medical risk samples, with the general conclusion that self-regulation can be separated into overlapping executive function and effortful control factors that differentially predict child outcomes. We examined the factor structure of 36-month self-regulation among children born prematurely (n = 168) and the extent to which self-regulation predicted maternal ratings of children's socioemotional and academic competence when they were six years of age. Statistical analyses revealed a single self regulation factor for this high neonatal risk sample, and this self-regulation factor mediated associations between early sociodemographic risk and mothers' ratings of academic competence and externalizing problems. Our findings suggest that early intervention research with children born preterm should focus on promoting supportive early environments, particularly parental sensitivity to infant cues. PMID- 29403151 TI - New insights into the pharmacological treatment of pediatric patients with type 2 diabetes. AB - The principal treatment for children and adolescents with type 2 diabetes is dietary and exercise management. However, the blood glucose levels of some patients receiving this treatment fail to improve; thus, pharmacological treatment is eventually required. The pathophysiology of type 2 diabetes in pediatric patients appears to be similar to that in adults; thus, the range of antidiabetic drugs used in adults is likely to be effective in pediatric patients as well. However, in the majority of countries, including Japan, only metformin, glimepiride, and insulin have been approved for use in pediatric patients. Indeed, the evidence for the usefulness of antidiabetic drugs other than metformin and insulin in children and adolescents is limited at this time. Therefore, the efficacy and safety of various antidiabetic drugs, including DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, which are used in adult patients, should be evaluated in the pediatric population in a large number of centers worldwide. In addition, it is critical that researchers and clinicians establish treatment guidelines for children and adolescents with type 2 diabetes in all racial groups worldwide. PMID- 29403149 TI - Goals and Objectives to Optimize the Value of an Acute Pain Service in Perioperative Pain Management. AB - As newer pharmacologic and procedural interventions, technology, and data on outcomes in pain management are becoming available, effective acute pain management will require a dedicated Acute Pain Service (APS) to help determine the most optimal pain management plan for the patients. Goals for pain management must take into consideration the side effect profile of drugs and potential complications of procedural interventions. Multiple objective optimization is the combination of multiple different objectives for acute pain management. Simple use of opioids, for example, can reduce all pain to minimal levels, but at what cost to the patient, the medical system, and to public health as a whole? Many models for APS exist based on personnel's skills, knowledge and experience, but effective use of an APS will also require allocation of time, space, financial, and personnel resources with clear objectives and a feedback mechanism to guide changes to acute pain medicine practices to meet the constantly evolving medical field. Physician-based practices have the advantage of developing protocols for the management of low-variability, high-occurrence scenarios in addition to tailoring care to individual patients with high-variability, low-occurrence scenarios. Frequent feedback and data collection/assessment on patient outcomes is essential in evaluating the efficacy of the Acute Pain Service's intervention in improving patient outcomes in the acute and perioperative setting. PMID- 29403150 TI - Economic Considerations of Acute Pain Medicine Programs. AB - Acute pain medicine services influence many different aspects of postoperative recovery and function. Here, we discuss the various stakeholders of an acute pain medicine service, review the direct and indirect impact on said stakeholders, review the shared and competing interests between acute pain medicine programs and various payer systems, and discuss how APM services can help service lines align with the interests of the recent CMS Innovations Comprehensive Care for Joint Replacement Model. PMID- 29403153 TI - Postnatal BMI changes in children with different birthweights: A trial study for detecting early predictive factors for pediatric obesity. AB - The purpose of this study was to clarify the degree of early postnatal growth by birthweight and detect early predictive factors for pediatric obesity. Body mass index (BMI) and degree of obesity were examined in children in the fourth year of elementary school and second year of junior high school. Their BMI at birth and three years of age were also examined. Based on birthweight, participants were divided into three groups: low (< 2500 g), middle (2500-3500 g), and high (> 3500 g). Furthermore, according to the degree of obesity, they were divided into two groups: obese (20% <=) and non-obese (20% >). The change of BMI from birth to three years of age (DeltaBMI) showed a strong inverse relationship with birthweight and was significantly different among the three birthweight groups (low > middle > high). The DeltaBMI and BMI at three years of age were higher in obese than in non-obese children and showed significant positive correlations with the degree of obesity. Early postnatal growth might be determined by birthweight and was higher in obese than in non-obese children. The DeltaBMI from birth to three years of age and BMI at age of three years could be predictive factors for pediatric obesity. PMID- 29403152 TI - Adrenocortical carcinoma characterized by gynecomastia: A case report. AB - We present a 4-yr-old boy with adrenocortical carcinoma (ACC), diagnosed due to the appearance of gynecomastia as the presenting symptom. Six months prior to admission, an acute growth spurt along with the development of bilateral breast swelling was observed. He did not present any features of virilization, including enlargement of the testes, increase in testis volume, and penis size. Laboratory investigations showed gonadotropin-independent hypergonadism, with low LH/ FSH levels and elevated estradiol/testosterone levels. Abdominal computed tomography revealed a large heterogeneous mass adjacent to the right kidney and below the liver. Pathological investigations of the biopsy specimen demonstrated that the tumor was an ACC. Pre- and post-operative combination chemotherapy with mitotane was administered and surgical resection was carried out. Post-surgery, the elevated estradiol/testosterone concentrations reverted to within the reference range. Urinary steroid profile and tissue concentration analysis of estradiol and testosterone indicated the presence of estrogen in the ACC tissue. An investigation for TP53 gene aberrations revealed the presence of a germline point mutation in exon 4 (c.215C>G (p.Pro72Arg)). In ACC, the most common symptom is virilization, and feminization, characterized by gynecomastia, is very rare. However, a diagnostic possibility of ACC should be considered when we encounter patients who have developed gynecomastia without the influence of causative factors such as obesity or puberty, and do not present with the typical signs of virilization. PMID- 29403154 TI - Perinatal factors affecting growth and development at age 3 years in extremely low birth weight infants born small for gestational age. AB - Factors affecting growth and development in extremely low birth weight infants (ELBWIs) born small for gestational age (SGA) have not been precisely elucidated. We performed a retrospective analysis of ELBWIs born SGA who were treated in the neonatal intensive care unit of Kawaguchi Municipal Medical Centre, Japan. A total 244 ELBWIs were born from 2003 to 2010, and 31 were born with weight and height below the 10th percentile for their gestational age. Among the 31 ELBWIs born SGA, we excluded 9 who died before they reached 3 yr of age or who had severe developmental retardation. A total of 16 patients (weight, 510-998 g; GA, 28w0d-32w5d) who were followed until age 3 yr were eligible for our study. At age 3 yr, 94% and 88% of ELBWIs were above the -2 standard deviation (SD) for height and weight, respectively. A history of mechanical ventilation was associated with height. The average score of the full developmental quotient (DQ) was 85, and 63% (10/16) of ELBWIs scored more than 85. Lower Apgar score (<= 7) was a risk factor for lower DQ scores in motor development and full development. Our study revealed that most ELBWIs born SGA were more than -2 SD below the mean for height and body weight. PMID- 29403155 TI - Fluctuation of blood glucose levels in an infant with an ileostomy on continuous glucose monitoring: A case report. AB - Infants with an ileostomy can be at high risk of hypoglycemia because of inadequate nutritional intake; however, there are no reports investigating blood glucose (BG) in infants with ileostomy. We experienced a case of an extremely low birth weight infant who was born at 24 wk of gestation and weighted 623 g. He received an ileostomy because of an intestinal perforation. After the ileostomy, he had recurrent hypoglycemia. Continuous glucose monitoring showed fluctuation of BG levels (postprandial BG elevations and subsequent declines) and non-fasting hypoglycemia, which were undetectable with intermittent fasting BG measurement. The fluctuation of BG levels and non-fasting hypoglycemia improved after closure of the ileostomy. Patients with ileostomy may present with hypoglycemia that is undetectable with intermittent fasting BG measurement. In this case, continuous glucose monitoring was very useful for detecting fluctuation of BG levels and hypoglycemic episodes. Therefore, we recommend that continuous glucose monitoring be performed in infants with an ileostomy to confirm whether they have hypoglycemia or a fluctuation in BG levels. Further studies on the postprandial dynamics of various hormones in infants with ileostomy are required. PMID- 29403156 TI - Chiari type 1 malformation associated with central sleep apnea after high dose growth hormone (GH) therapy in a 12-year-old boy: A case report. AB - We describe the case of a short-statured 12-yr-old boy who developed a Chiari type 1 malformation associated with central sleep apnea after administration of high-dose GH therapy, which he had been receiving since the age of 10 yr and 4 mo. He responded well to GH therapy, and his height increased by 18.8 cm in 2 yr. At 12 yr and 4 mo of age, his mother reported that he had developed sleep apnea during the previous year and it had worsened over a month prior to presentation at our hospital. Otolaryngological examination did not reveal tonsillar or adenoidal hypertrophy. Polysomnography demonstrated severe central sleep apnea with an apnea-hypopnea index of 46.5/h. Sagittal T1-weighted magnetic resonance imaging (MRI) demonstrated herniation of the cerebellar tonsils 15 mm below the foramen magnum into the cervical spinal cord. Continuous positive airway pressure therapy initiated prior to performing neurosurgery was ineffective. Following uncomplicated foramen magnum decompression, his breathing pattern during sleep returned to normal. Sagittal MRI examination should be considered in patients who develop sleep apnea during/following administration of GH therapy. PMID- 29403157 TI - A follow-up during puberty in a Japanese girl with type A insulin resistance due to a novel mutation in INSR. PMID- 29403158 TI - Hybrid online sensor error detection and functional redundancy for systems with time-varying parameters. AB - Supervision and control systems rely on signals from sensors to receive information to monitor the operation of a system and adjust manipulated variables to achieve the control objective. However, sensor performance is often limited by their working conditions and sensors may also be subjected to interference by other devices. Many different types of sensor errors such as outliers, missing values, drifts and corruption with noise may occur during process operation. A hybrid online sensor error detection and functional redundancy system is developed to detect errors in online signals, and replace erroneous or missing values detected with model-based estimates. The proposed hybrid system relies on two techniques, an outlier-robust Kalman filter (ORKF) and a locally-weighted partial least squares (LW-PLS) regression model, which leverage the advantages of automatic measurement error elimination with ORKF and data-driven prediction with LW-PLS. The system includes a nominal angle analysis (NAA) method to distinguish between signal faults and large changes in sensor values caused by real dynamic changes in process operation. The performance of the system is illustrated with clinical data continuous glucose monitoring (CGM) sensors from people with type 1 diabetes. More than 50,000 CGM sensor errors were added to original CGM signals from 25 clinical experiments, then the performance of error detection and functional redundancy algorithms were analyzed. The results indicate that the proposed system can successfully detect most of the erroneous signals and substitute them with reasonable estimated values computed by functional redundancy system. PMID- 29403159 TI - Development of Preferences for Differently Aged Faces of Different Races. AB - Children's experiences with differently aged faces changes in the course of development. During infancy, most faces encountered are adult, however as children mature, exposure to child faces becomes more extensive. Does this change in experience influence preference for differently aged faces? The preferences of children for adult versus child, and adult versus infant faces were investigated. Caucasian 3- to 6-year-olds and adults were presented with adult/child and adult/infant face pairs which were either Caucasian or Asian (race consistent within pairs). Younger children (3 to 4 years) preferred adults over children, whereas older children (5 to 6 years) preferred children over adults. This preference was only detected for Caucasian faces. These data support a "here and now" model of the development of face age processing from infancy to childhood. In particular, the findings suggest that growing experience with peers influences age preferences and that race impacts on these preferences. In contrast, adults preferred infants and children over adults when the faces were Caucasian or Asian, suggesting an increasing influence of a baby schema, and a decreasing influence of race. The different preferences of younger children, older children, and adults also suggest discontinuity and the possibility of different mechanisms at work during different developmental periods. PMID- 29403160 TI - Inhibiting Interleukin 17 Can Ameliorate the Demyelination Caused by A. cantonensis via iNOS Inhibition. AB - Angiostrongylus cantonensis (A. cantonensis) is an important food-borne parasitic disease. Previous study showed that A. cantonensis infection can cause demyelination in the central nerve system, but the mechanism of action has not been understood. To explore the mechanism and to look for effective therapeutic methods, interleukin 17A (IL-17A) and iNOS expressions were detected during A. cantonensis infection. In addition, IL-17A-neutralizing antibody was applied to treat A. cantonensis-infected mice. In our results, we found that IL-17A and iNOS RNA expressions increased gradually in the process of A. cantonensis infection. When infected mice were treated with IL-17A-neutralizing antibody, the pathologic changes of demyelination alleviated obviously, followed with the elevation of myelin basic protein (MBP) in the brain. In addition, the iNOS expression of the brain in infected animals also showed a decrease in astrocytes. Our study provided evidence that IL-17A may take part in the demyelination caused by A. cantonensis and inhibiting IL-17A expression can ameliorate the pathologic changes of demyelination. Moreover, the decreasing of iNOS expression may be the key reason for the effect of IL-17A inhibition on demyelination caused by A. cantonensis. PMID- 29403162 TI - Intraoperative Cytology of Ovarian Neoplasms with an Attempt to Grade Epithelial Tumors. AB - Background: Intraoperative cytology (IOC) is a simple and quick technique with excellent preservation of cellular details. In the present study, we have evaluated the role of IOC by various methods of smear preparation and compared it with frozen section diagnosis. A scoring system was followed for epithelial tumors for characterization and grading on the basis of cellularity, pattern, nuclear, cytoplasmic features, and background details. Materials and Methods: The study was conducted during a time span of 2 years in total 48 cases of ovarian tumors. Fine-needle aspiration cytology, touch/imprint, scrape, and crush techniques were used. The smears so prepared were processed for toluidine blue and Giemsa and Papanicolaou staining. Cases were cytomorphologically categorized into four groups: Indeterminate; unequivocally benign; borderline tumor with equivocal morphology; and unequivocally malignant (graded into well, moderately, and poorly differentiated). Results: In our study, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 88.88, 96, 96, 88.88, and 92.31%, respectively, were recorded. This was comparable to frozen section diagnosis with a sensitivity, specificity, PPV, NPV, and accuracy of 85.18, 96.15, 95.83, 86.21, and 90.56%, respectively. In epithelial tumors, cytological grading correlated with histopathological grading in 85.29% cases of epithelial tumors. Conclusion: IOC gives comparable results to frozen section and can be used for intraoperative assessment of ovarian tumors. Grading of epithelial tumors on IOC can be performed and may become an important step in intraoperative decision-making for better management and outcome of the patient. PMID- 29403163 TI - Toluidine Blue with a Synergistic Effect in Morphological Assessment of Oral Cytosmears. AB - Objectives: One percent toluidine blue being the most effective adjunct is often used to detect dysplasia. Not much attention has been given to the effect of toluidine blue in enhancement of cytological smears. The present study assessed the smears before and after application of toluidine blue in smokers against non smokers using three different stains [Papanicolaou (PAP), Hematoxylin and Eosin (H and E), and Giemsa]. Study Design: Twenty-five individuals from each group participated in the study. The oral cytosmears were obtained before and after application of toluidine blue and assessed for clumping of squamous cells, cellular and nuclear pleomorphism, micronuclei, binucleation, bacterial colony units, and keratin flakes. Results: In smokers, the maximum enhancement in cytological smears post-toluidine blue application was shown by Giemsa stain than PAP and H and E stains. Among the individual parameters, nuclear pleomorphism exhibited greatest significant difference between smokers and non-smokers. Conclusion: Toluidine blue enhanced the staining characteristics both in terms of sensitivity and specificity and thereby was found to be synergistic in assessment of cytosmears. The cellular alterations noticed in the smears of smokers with clinically normal buccal mucosa can be used as a means of education tool in counselling for smoking cessation. PMID- 29403164 TI - To Evaluate the Applicability of Parameters of Cytological Grading Systems on Aspirates of Breast Carcinoma. AB - Background: Fine-needle aspiration cytology (FNAC) is still an important first line diagnostic procedure in developing countries. FNAC of breast lesions is quite specific and sensitive investigation and the results are comparable to histopathology. Aim: To evaluate applicability of parameters of different cytological grading (CG) systems, for aspirates of breast cancers, and its correlation with histopathology grading parameters. Materials and Methods: A cross-sectional observational study was carried out on 30 female patients with ductal carcinoma breast, diagnosed on FNAC and subsequently confirmed histopathologically. The cytological smears were graded using six different cytological parameters/criteria described by Robinson et al. (Robinson grading system) and modified Scarff-Bloom-Richardson (SBR) grading system considering three parameters. The results of cytological grade (CG) were compared with parameters of gold standard modified SBR histological grading (HG) system. Results: Important influential cytological parameters to predict final RBS cytological score came out to be chromatin, nucleoli, nuclear size, cell uniformity, and cell dissociation with statistically significant P value (0.0001) except for mitotic count. The important influential predictor of final SBR histological score is nuclear pleomorphism. Conclusion: SBR HG has good correlation with both RBS and SBR CG systems. The cytological nuclear grade provides important prognostic information which is very sensitive and equally specific hence should be done in breast aspirates and is now replaced by Core Needle biopsy. In developing country like India FNAC of breast aspirates still holds diagnostic value in the classification of breast lesions as compared to core guided image biopsy. PMID- 29403161 TI - Increased Abundance of Plasmacytoid Dendritic Cells and Interferon-Alpha Induces Plasma Cell Differentiation in Patients of IgA Nephropathy. AB - The roles of pDC and IFN-alpha have not been well defined in IgA nephropathy (IgAN). In this study, we investigated the abundance of pDCs and IFN-alpha in IgAN patients and the response of peripheral blood mononuclear cells (PBMCs) after stimulation of the pDC-preferred TLR9 ligand CpG2216. The effects of IFN alpha on plasma cell differentiation and leukocyte migration were also investigated. Here, we found that the percentages of pDCs were increased in PBMCs of IgAN patients, than in those of healthy controls. Plasma levels of IFN-alpha proteins and abundance of plasma cells were higher in IgAN patients than in healthy donors. Plasma IFN-alpha levels were positively associated with proteinuria, renal IgM deposition, and renal tubular atrophy/interstitial fibrosis grade in IgAN patients. Ex vivo activation of TLR9 on pDCs resulted in increased IFN-alpha production and enhanced plasma cell differentiation in IgAN patients as compared with healthy donors. IFN-alpha treatment led to increased plasma cell differentiation in vitro. IFN-alpha also significantly promoted expression of chemokines IP-10 and MCP-1 in human mesangial cells, which subsequently facilitated the transendothelial migration of human CD4+ and CD14+ cells. In conclusion, pDC and its secreted cytokine IFN-alpha may play important roles in pathological changes of IgA nephropathy. PMID- 29403165 TI - Micronucleus Study on Breast Cytology Aspirate Smears and its Diagnostic Utility. AB - Background: Micronucleus is a small fragment of nucleus present in the cells which have undergone chromosomal damage. It is used as a biomarker of genomic damage. Aims: We aim to study the presence of micronucleus on breast cytology smears and the use of scoring the micronucleus as an additional criteria for the classification of breast lesions with emphasis on borderline gray zone categories. Settings and Design: This is a cross-sectional retrospective descriptive study. Materials and Methods: Retrospective analysis of breast cytology smears received over a period of 2 years formed the basis of the study. Micronucleus scoring was done by counting the number of micronuclei in 1000 epithelial cells under oil immersion and compared in the benign, adenosis, usual/atypical ductal hyperplasia, and the three grades of infiltrating ductal carcinomas. Statistical Analysis: Descriptive analyses and one-way analysis of variance was used for statistical analysis. Results: Of the 243 cases, the average statistically significant (P < 0.05) micronuclei scores of the benign (190), adenosis (7), usual (11)/atypical (5) hyperplasia, grade 1, 2, and 3 carcinomas (30) were 0.5, 2, 2.9, 6.6, 13.2, 20.6, and 27.5, respectively (the corresponding median scores were 0.5, 2, 3, 6, and 20, respectively). Micronucleus score of <=1 had a high sensitivity (100%) and specificity (99%) in confirmation of benign cases. Micronucleus score of >=5 and <10 had a moderate sensitivity (60%) but a high specificity of 99% in detecting atypical ductal hyperplasia. Micronucleus score of >=10 had a high sensitivity (96%) and specificity (99%) of detecting carcinomas. Conclusion: Micronucleus scores showed a gradual increase across the categories proving the gradual occurrence of genomic damage. Micronucleus scoring serves as an additional criterion for the diagnosis of breast lesions. PMID- 29403166 TI - Galectin-3 and HBME-1 Expression on Agarose Cell Blocks from Fine-needle aspirates of Follicular Cell-derived Thyroid Tumors. AB - Aim: To test the expression of galectin-3 (gal-3) and Hector Battifora mesothelial antigen-1 (HBME-1) on agarose cell blocks (CBs) of fine-needle aspirates aiming to determine their diagnostic value in thyroid follicle cell derived tumors. Materials and Methods: Forty patients with thyroid nodule were enrolled. Fine-needle aspiration biopsy was done and processed to produce smears and CBs. Immune staining was done on CBs using antibodies to gal-3 and HBME-1. Diagnostic value of tests was determined in comparison to pathology. Results: Current study included 17 papillary thyroid carcinoma (PTC), 15 follicular adenoma, and 8 follicular thyroid carcinoma (FTC). In PTC diagnosis, co expression of gal-3/HBME-1 had a sensitivity of 94.1%, specificity of 73.3%, positive predictive value (PPV) of 80%, negative predictive value (NPV) 91.7%, and accuracy of 84.4%. In FTC diagnosis, combined gal-3/HBME-1 expression had a sensitivity of 75%, specificity of 78.6%, PPV of 50%, NPV of 91.7%, and accuracy of 77.8%. Co-expression of gal-3/HBME-1 raised the sensitivity of detection of differentiated thyroid carcinomas from 40% with cytomorphology to 92% and accuracy from 62.5% to 85%. Conclusion: The combined immunocytochemical expression of gal-3 and HBME-1 utilizing fine-needle aspirates can improve the sensitivity of detection and diagnostic accuracy of differentiated follicular cell-derived thyroid carcinomas. PMID- 29403167 TI - Reproducibility of "The Bethesda System for Reporting Thyroid Cytopathology:" A Retrospective Analysis of 107 Patients. AB - Objectives: Fine-needle aspiration cytology (FNAC) has emerged as an indispensable tool to discriminate thyroid lesions into benign or malignant for appropriate management. The need for simplicity of communication and standardization of terminology for thyroid FNAC reporting led to introduction of "The Bethesda system for reporting Thyroid Cytopathology" (TBSRTC) in a conference held at the National Cancer Institute in 2007. This study aims at establishing the reproducibility of TBSRTC for diagnosing thyroid lesions. Materials and Methods: The present study comprised thyroid FNAC from 107 patients retrospectively over a period of 1.5 year (June 2013 to December 2014), which were reviewed by two trained cytopathologists and re-categorized according to TBSRTC. The interobserver variation and reproducibility of the reporting system was statistically assessed using Cohen's kappa. Results: The cytopathologists were in agreement in 98 out of 107 cases (91.5%). Maximum concordance was noted in benign category (91 of 96 cases; 92.85%), followed by 2 cases each in nondiagnostic/unsatisfactory (ND/US) and follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) category (2.04% each) and 1 case each in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), suspicious for malignancy (SUS), and malignant category (1.02% each). The highest diagnostic disagreement was noted among ND/US and benign and benign and FN/SFN categories. Conclusion: The utilization of TBSRTC for reporting thyroid cytology should be promoted in our country because it provides a homogeneous, standardized, and unanimous terminology for cytological diagnosis of thyroid lesions. The present study could substantiate the diagnostic reproducibility of this system. PMID- 29403168 TI - Anaplastic Lymphoma Kinase Immunocytochemistry in Fine Needle Aspiration Diagnosis of Anaplastic Large-cell Lymphoma. AB - Background: Anaplastic large-cell lymphoma (ALCL) is a rare subtype of non Hodgkin's lymphoma (NHL) characterized by the presence of unusual giant cells. It is a CD30+lymphoma of T-cells lineage, which shows anaplastic lymphoma kinase nucleophosmin (ALK-NPM) rearrangement. ALCL on fine needle aspiration cytology (FNAC) shows unusually large and bizarre tumor cells. Materials and Methods: All aspirates seen over a 6-year period from November 2009 to November 2015 in which a diagnosis of ALCL or Hodgkin's lymphoma (HL) with bizarre giant cells were suspected on cytomorphology were prospectively selected. Twenty such aspirates were subjected to CD-30 and ALK-1 immunocytochemistry (ICC). Subsequent biopsy was available in all cases. Results: Out of 20 cases, seven cases, suspected to be ALCL on FNAC, were confirmed on biopsy. ALK-1 was positive in both cytology and biopsy of 6/7 of these. Two cases suspected to be ALCL on cytomorphology were HL (1) and diffuse large B-cell lymphoma (DLBCL) (1) on biopsy, both of which were ALK-1 negative on cytology. Eight cases of HL and three cases of large-cell NHL, which were all ALK negative on cytology, were confirmed on biopsy. Conclusion: ICC for ALK and CD30 is useful in aspiration cytodiagnosis of ALCL. One CD30 positive DLBCL and one ALK negative ALCL showed concordant results of ICC on cytology and histology. PMID- 29403169 TI - Role of Nuclear Morphometry in Breast Cancer and its Correlation with Cytomorphological Grading of Breast Cancer: A Study of 64 Cases. AB - Background: Fine needle aspiration cytology (FNAC) is a simple, rapid, inexpensive, and reliable method of diagnosis of breast mass. Cytoprognostic grading in breast cancers is important to identify high-grade tumors. Computer assisted image morphometric analysis has been developed to quantitate as well as standardize various grading systems. Aims: To apply nuclear morphometry on cytological aspirates of breast cancer and evaluate its correlation with cytomorphological grading with derivation of suitable cutoff values between various grades. Settings and Designs: Descriptive cross-sectional hospital-based study. Materials and Methods: This study included 64 breast cancer cases (29 of grade 1, 22 of grade 2, and 13 of grade 3). Image analysis was performed on Papanicolaou stained FNAC slides by NIS -Elements Advanced Research software (Ver 4.00). Nuclear morphometric parameters analyzed included 5 nuclear size, 2 shape, 4 texture, and 2 density parameters. Results: Nuclear size parameters showed an increase in values with increasing cytological grades of carcinoma. Nuclear shape parameters were not found to be significantly different between the three grades. Among nuclear texture parameters, sum intensity, and sum brightness were found to be different between the three grades. Conclusion: Nuclear morphometry can be applied to augment the cytology grading of breast cancer and thus help in classifying patients into low and high-risk groups. PMID- 29403170 TI - Comparative Assessment of Conventional Papanicolaou and Modified Ultrafast Papanicolaou Stains in Fine Needle Aspiration Samples and Body Fluids. AB - Background: Conventional Papanicolaou (Pap) stain has undergone many modifications; of these, ultrafast Pap stain is the most popular as it shortens the turnaround time of reporting. Application of modified ultrafast Pap (MUFP) stain in the evaluation of fine needle aspiration (FNA) samples and body fluids are scanty. Aim: To evaluate the utility of MUFP stain in various FNA samples and body fluids and compare the findings with those of conventional Pap stain. Materials and Methods: In this cross-sectional study, two wet-fixed and two airdried smears from each sample [301 samples (255 FNA samples and 46 body fluids)] were prepared and stained by the conventional Pap and MUFP stains, respectively. Concordant and discordant rate was calculated. Quality index (QI) of MUFP stain was assessed by background, overall staining, cell morphology, and nuclear characteristics. MUFP-stained smears were also categorized into excellent, good, and fair. Results: The concordance rate for MUFP stain was 100%. QI of MUFP stain for breast, thyroid, lymph node, soft tissue, salivary gland, and body fluids was 0.9, 0.93, 0.95, 1, 0.94, and 1, respectively. Excellent quality of stain was noted in 53.2% and good in 24.6% of the cases allowing easy diagnosis. In 22.2% of fair cases, diagnosis was possible with some difficulties. Conclusion: Our study concluded that MUFP stain could be considered as a rapid and reliable diagnostic tool and can be applied on a regular basis in FNA samples and body fluids to offer immediate diagnosis. However, caution should be taken while reporting certain MUFP-stained smears to avoid over/under diagnosis. PMID- 29403171 TI - Sputum Cytology: Curschmann's Spiral or Parasite Larva? PMID- 29403172 TI - Martian Popping Thing. PMID- 29403173 TI - Fine Needle Aspiration Cytology of Basal Cell Adenoma of Parotid Simulating Adenoid Cystic Carcinoma. AB - Basal cell adenoma is a rare type of monomorphic salivary adenoma most commonly involving the parotid gland. Cytology of basal cell adenoma closely mimics many other benign and malignant basaloid neoplasms. Cytological features of membranous basal cell adenoma simulate adenoid cystic carcinoma in fine needle aspiration cytology (FNAC) smears. Here, we are presenting a rare case of cytodiagnosis of membranous basal cell adenoma of parotid gland in an elderly lady, which mimicked adenoid cystic carcinoma on FNAC. We discuss the cytomorphology of this rare case with an emphasis on cytological difference between membranous basal cell carcinoma and adenoid cystic carcinoma as well as other basaloid neoplasms. PMID- 29403174 TI - Papillary Pattern in Acinic Cell Carcinoma of Parotid Gland: A Potential Diagnostic Pitfall on FNAC. AB - Fine needle aspiration cytology (FNAC) is often the first investigation in the work up of salivary gland lesions. However, its diagnostic accuracy is limited by the high rates of false positives and false negatives. Usually, acinic cell carcinoma is prone to be underdiagnosed because of the cytological similarity of the tumor cells to normal acinar cells, however rarely, a predominant papillary architecture on cytology may cause confusion with adenocarcinomas. We present a case of a 45-year-old male with a painful swelling of the right parotid region. FNA smears revealed a predominant papillary architecture and focal acinar pattern. A provisional diagnosis of acinic cell carcinoma was given, which was confirmed on histopathology. Familiarity with the cytomorphologic features of acinic cell carcinoma is cardinal for an accurate diagnosis and appropriate management. PMID- 29403175 TI - Cytomorphology of Skin Adnexal Tumors: A Tale of Two Scalp Swellings. AB - The primary and metastatic tumors of the skin can be effectively diagnosed by fine needle aspiration cytology (FNAC); however, the cytomorphological features of skin adnexal tumors are rarely described in the literature. We hereby describe the cytological features of two histologically confirmed cases of benign skin adnexal tumors. Case 1 is of a 46-year-old female who presented with an elevated firm nodule over the scalp. A cytological diagnosis of benign adnexal tumor possibly of sebaceous origin was given. The nodule was excised and histopathological examination confirmed the diagnosis of sebaceoma. Case 2 is of a 19-year-old male who presented with a pigmented scalp swelling. Cytomorphological features were suggestive of benign skin adnexal tumor with foci of melanin pigment. The swelling was excised and histopathological examination confirmed the diagnosis of eccrine poroma. To the best of our knowledge, only one previous report of sebaceoma and no report of eccrine poroma describing the cytological findings of these two tumors exist. We report these two cases of benign skin adnexal tumors to discuss the cytological features and the potential diagnostic dilemma that they pose to the cytologist. PMID- 29403176 TI - Cytological Diagnosis of Erythema Nodosum Leprosum in Clinically Unsuspected Cases: A Report of Two Cases. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The manifestations of this disease varies across the spectrum of tuberculoid (TT) to lepromatous (LL) leprosy. The course of this indolent disease is interrupted by acute exacerbations in the form of leprare actions. Erythema nodosum leprosum (ENL), a type 2 lepra reaction, occurs in lepromatous or borderline lepromatous cases, usually in response to multidrug therapy. Early detection and timely management of these patients is important to reduce the associated morbidity. We report two clinically unusual cases of ENL on fine-needle aspiration cytology. In one case, antileprosy treatment was completed 10 years back, whereas in the other case, ENL was the presenting feature of the disease. Cytological examination of swelling in both the cases showed neutrophils, lymphoid cells, clusters of foamy macrophages, histiocytes, and giant cells. Fite stain was positive, which confirmed the cytological diagnosis of ENL. PMID- 29403177 TI - Cytopathological Diagnosis and Differential Diagnoses of Facial Spindle Cell Lipoma. PMID- 29403178 TI - Chondromyxoid Fibroma of the Metatarsal Bone: A Diagnosis Using Fine Needle Aspiration Biopsy. PMID- 29403180 TI - JCAS: The Road Ahead. PMID- 29403179 TI - Diagnostic Role of Intraoperative Imprint Cytology in an Unusual Case of Chondrosarcoma Presenting as Acute Onset Stridor. PMID- 29403181 TI - Facial Cutaneous Sarcoid Treated Successfully with Carbon Dioxide Laser in Skin Type 6. PMID- 29403183 TI - Periorbital Biometric Measurements using ImageJ Software: Standardisation of Technique and Assessment Of Intra- and Interobserver Variability. AB - Purpose: To assess the reliability and repeatability of periorbital biometric measurements using ImageJ software and to assess if the horizontal visible iris diameter (HVID) serves as a reliable scale for facial measurements. Methods: This study was a prospective, single-blind, comparative study. Two clinicians performed 12 periorbital measurements on 100 standardised face photographs. Each individual's HVID was determined by Orbscan IIz and used as a scale for measurements using ImageJ software. All measurements were repeated using the 'average' HVID of the study population as a measurement scale. Intraclass correlation coefficient (ICC) and Pearson product-moment coefficient were used as statistical tests to analyse the data. Results: The range of ICC for intra- and interobserver variability was 0.79-0.99 and 0.86-0.99, respectively. Test-retest reliability ranged from 0.66-1.0 to 0.77-0.98, respectively. When average HVID of the study population was used as scale, ICC ranged from 0.83 to 0.99, and the test-retest reliability ranged from 0.83 to 0.96 and the measurements correlated well with recordings done with individual Orbscan HVID measurements. Conclusion: Periorbital biometric measurements using ImageJ software are reproducible and repeatable. Average HVID of the population as measured by Orbscan is a reliable scale for facial measurements. PMID- 29403182 TI - Management of stretch marks (with a focus on striae rubrae). AB - Stretch marks are one of the most common benign cutaneous lesions and encountered esthetic problems. Striae rubrae and striae albae can be differentiated on the basis of clinical appearance. Histologically, disturbances of the dermal fiber network and local expression of receptors for sexual steroids have been detected. The epidermal changes are secondary. Prevention of stretch marks using topical ointments and oils is debatable. Treatment of striae rubrae by lasers and light devices improves appearance. Microneedling and non-ablative and fractionated lasers have been used. This review provides an overview on current treatment options with a special focus on laser treatments. PMID- 29403184 TI - Fractional CO2 Laser vs Fractional CO2 with Topical Platelet-rich Plasma in the Treatment of Acne Scars: A Split-face Comparison Trial. AB - Background: It is a challenge to treat acne scars and a multimodal combination approach is necessary. While fractional CO2 lasers (FCLs) are an established treatment option, the role of platelet-rich plasma (PRP) in the treatment of acne scars is not established though it is being used extensively in other fields of medicine owing to its healing properties. We combined the two methods to assess the proposed synergistic action on acne scars. Aims and Objectives: To evaluate the effect of FCL alone vs FCL combined with PRP on the quality of acne scars. Materials and Methods: This is a left-right split-face comparison study with 30 patients with moderate-to-severe acne scars. The patients underwent three sessions of FCL and FCL + topical PRP on right and left sides of the face, respectively, at monthly intervals. Results: There was significant improvement on both sides of the face (right side, P = 0.001; left side, P = 0.0001), but the difference between the right and the left sides of the face was not statistically significant (P = 0.2891). The symptoms of redness, edema, and pain on the treated areas with laser were significantly lesser on the FCL + PRP (left) side as compared to the FCL-only (right) side. Conclusion: Both methods were effective in management of acne scars. Addition of PRP does not improve the scar quality; however, the downtime and inflammation associated with laser treatment gets significantly reduced on the PRP-treated side. PMID- 29403185 TI - Standardization of SMP Procedure and Its Impact On Outcome. AB - Background: Cosmetic deformities can result from various types of alopecia or even post hair transplantation procedures. Patients with such deformities seek aesthetically appealing longer-lasting options. Scalp concealers are commonly used by men and women to camouflage these deformities. Scalp micropigmentation (SMP) is one of the concealers recently gaining popularity. Objectives: SMP is a novel technique wherein microdot tattoos are placed in a stippling pattern to mimic hair follicles that are cut close to the scalp and various variables affecting its outcome were evaluated. Methods: Forty-five subjects were recruited for the study. The various factors affecting outcome of SMP-angle of needle against the scalp, depth of needle into the scalp, time of the needle contact in scalp, speed of the rotor, resistance of scalp, color of pigment, viscosity of dye, needle number, needle thickness, and pattern of dot placement-were systematically studied in 15 patients through clinical photographs and trichoscopy. Ideal depth of pigment deposition was assessed through histopathological examination. After using these optimum variables, standardized SMP was performed in 30 patients with hair loss (3 patients with cicatricial and 27 patients with diffuse non-cicatricial alopecia). SMP was also used to create an aesthetically denser hairline. The outcome of the procedure was evaluated using standardized global photographs. Results: The ideal parameters were established to achieve standard reproducible results. There were great patient satisfaction and acceptance of the procedure. All the patients showed moderate to great improvement after the procedure with satisfactory scalp coverage. Adverse events were transient which were seen in the form of edema and redness. Conclusion: SMP offers a non-medical, tattoo-based cosmetically appealing and effective "cover-up" that hides the unsightly conditions. The cosmetic tattoo placement creates an illusion of thicker hair. PMID- 29403186 TI - Innovative Usage of Accessory Auricles as Full-thickness Skin Graft. AB - Accessory auricles are relatively rare malformations arising from the first branchial arch which contains skin, fat and cartilage. The treatment is usually surgical removal for the cosmetic purpose. We are sharing our experience of utilising the accessory auricle skin as full thickness graft for post.burn reconstruction of the fingers contracture of a child. Even though this type of association is rare, it is an innovative idea following Sir Harold Gilles' principle 'Never throw anything away'. PMID- 29403187 TI - Use of a Hyaluronic Acid Soft-tissue Filler to Correct Congenital and Post traumatic Lip Asymmetry. AB - Background: The use of hyaluronic acid soft-tissue fillers for enhancement of lip features is a popular and minimally invasive office-based procedure used worldwide due to its relative simplicity and favorable safety profile. Materials and Methods: Hyaluronic acid was used in illustrative cases to attempt correction of congenital and acquired lip asymmetries. Results: In the cases presented, accurate and cosmetically acceptable results were attained and maintained for the duration of the product life. Conclusions: Hyaluronic acid may be used successfully when lip asymmetry is evident and is a relatively simple nonsurgical alternative. PMID- 29403188 TI - Laser Corrective Surgery with Fractional Carbon Dioxide Laser Following Full thickness Skin Grafts. AB - Full-thickness skin grafts (FTSGs) are frequently used to treat patients with burn injuries and to repair defects rendered by excisional (including Mohs) surgery. The evidence for corrective laser surgery after scar formation is well established. With regard to laser treatment of FTSG, the evidence is sparse. Laser treatment after FTSG is a novel concept, with minimal literature. We present a case series, one of the first to our knowledge, of the treatment of FTSG with fractional CO2 laser in five patients after Mohs surgery. PMID- 29403189 TI - Calculating Area of Graft Required for Vitiliginous Areas During Split-thickness Skin Grafting: A Simple, Accurate, and Cost-effective Technique. PMID- 29403190 TI - A Pilot Study to Evaluate Effectiveness of Botulinum Toxin in Treatment of Androgenetic Alopecia in Males. AB - Introduction: Androgenetic alopecia is a common form of alopecia with multifactorial etiology. Finasteride and minoxidil are approved by the FDA for the treatment of androgenetic alopecia. Balding scalp is believed to have relative microvascular insufficiency. Blood vessels in the scalp travel through the intramuscular plane. Intramuscular injection of botulinum toxin relaxes muscles and thereby increases blood flow in balding scalp. We conducted a pilot study to evaluate the efficacy of botulinum toxin in androgenetic alopecia management. Material and Methods: The study was conducted in a tertiary care center. A total of 10 male patients with androgenetic alopecia meeting inclusion criteria of the study were included. In the scalp, 30 sites were injected with 5 U of botulinum toxin in each site. Preprocedure photograph taken and evaluation was done, which was repeated after 24 weeks. Efficacy was assessed by photography and self-assessment scoring was done by patients. Results: Of 10 patients, 8 had good to excellent response on photographic assessment. At the end of 24 weeks, 1 patient showed poor and 1 showed fair response to treatment. As per self assessment, 7of 10 patients showed good to excellent response. Two patients had fair response and 1 patient showed poor response to treatment. Conclusion: Botulinum toxin was found to be safe and effective therapy for the management of androgenetic alopecia in this pilot study. Studies with larger sample size and randomized controlled trials are required to establish the role of botulinum toxin in the management of androgenetic alopecia. PMID- 29403191 TI - Easing the Excision of Earlobe Keloid. AB - Earlobe keloids are commonly encountered in this era where ear piercing is routine in various traditions. Various medical and surgical methods have been tried for its management. Surgically, fillet flap surgery has better acceptability worldwide. Various difficulties are faced during keloid excision, and we hereby describe few innovative modifications (use of needle, hydrodissection, pressure dressing, bolster button) using cost-effective and simple materials (needles, dynaplast, buttons) to ease the excision of keloids. These have easy adaptability and also reduce the recurrence rate of earlobe keloids. PMID- 29403192 TI - Use of the CONUT Index as a Predictor of Integration Of Cutaneous Grafts in Burn Patients. AB - Objective: To present the initial experience of 12 patients with burns treated with cutaneous grafts and to analyse the variables that influence their integration. Materials and Methods: We analysed data from 12 patients seen in a year in the regional hospital of high speciality of Oaxaca. Quantified variables: Age, sex, burned body surface, depth of burn, airway injury, nutritional status by CONUT index, type of graft, development of local infection and days of hospital stay. Results: We included 10 men (83%) and 2 women (17%) with median age of 28 years, median burned body surface area of 19%, depth: 75% were mixed burns and 25% were third degree; with median time between injury and application of grafts of 13 days, 1 patient presented airway injury and 50% concomitant trauma. Regarding Nutritional Status: Fifty percent had severe malnutrition, 33% moderate and 16% mild. About 67% of the grafts were meshed and 33% intact, the mean integration percentage was 80%, 25% developed local infection and the average length of hospital stay was 21 days. Conclusions: Cutaneous grafts are the definitive treatment of burns, in their integration process influence different factors, including nutritional status. The CONUT index seems to be a useful, safe and widely available tooling in the nutritional assessment of the burned patient and can be related to the percentage of integration of the grafts and the days of hospital stay. PMID- 29403193 TI - Large Unilateral Noduloplaque Over the Cheek in a Young Man. PMID- 29403194 TI - The 22nd International Pigment Cell Conference, Singapore. PMID- 29403195 TI - Vitamin D and gastrointestinal cancer. AB - Vitamin D serves as a precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Low Vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus, and cancers. Metabolite of 1, 25-dihydroxyvitamin D3 (1,25[OH]2D3) regulates numerous genes that control gut physiology and homeostasis. 1,25(OH)2D3 serves various functions such as maintaining the integrity of epithelial barrier and absorption of calcium and phosphate, and the host's defense against pathogens, and the inflammatory response by several types of secretory and immune cells. Although epidemiological data remain inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for Vitamin D, results from some correlating studies strongly suggest that Vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding Vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome. The present review highlights the role of Vitamin D in cancer of the gastrointestinal tract including esophagus, gastric (stomach), liver, pancreas, and colon. PMID- 29403196 TI - Biomedical waste management in India: Critical appraisal. AB - The safe and sustainable management of biomedical waste (BMW) is social and legal responsibility of all people supporting and financing health-care activities. Effective BMW management (BMWM) is mandatory for healthy humans and cleaner environment. This article reviews the recent 2016 BMWM rules, practical problems for its effective implementation, the major drawback of conventional techniques, and the latest eco-friendly methods for BMW disposal. The new rules are meant to improve the segregation, transportation, and disposal methods, to decrease environmental pollution so as to change the dynamic of BMW disposal and treatment in India. For effective disposal of BMWM, there should be a collective teamwork with committed government support in terms of finance and infrastructure development, dedicated health-care workers and health-care facilities, continuous monitoring of BMW practices, tough legislature, and strong regulatory bodies. The basic principle of BMWM is segregation at source and waste reduction. Besides, a lot of research and development need to be in the field of developing environmental friendly medical devices and BMW disposal systems for a greener and cleaner environment. PMID- 29403197 TI - Automated hematology analyzers: Recent trends and applications. PMID- 29403198 TI - Pattern of bone marrow involvement in non Hodgkin's lymphoma classified according to WHO classification: Report of a developing country Pakistan. AB - BACKGROUND: Limited information is available from developing countries in patients of non-Hodgkin's lymphoma (NHL). Hence, we reviewed the demographical profile along with bone marrow infiltration pattern in patients with NHL presented at Liaquat National Hospital and Medical College. MATERIALS AND METHODS: In this descriptive study, adult patients with NHL were enrolled from January 2011 to December 2015. RESULTS: One hundred and Eighty-four histopathologically confirmed cases of NHL were identified. There were 139 males and 45 females, with a male-to-female ratio of 3:1. The mean age was 48.5 +/- 16.0 years with the median age of 50 years. B-symptoms were present in 80.4% of patients. Lymph node enlargement was present in 71.1% of the cases. One hundred and sixty-eight patients had B-cell lymphoma (91.3%) and 16 patients had T-cell lymphoma (8.6%). Overall 158 (85.8%) patients had aggressive lymphoma. The frequency of bone marrow infiltration in our NHL patients was found to be 31.5%. Pattern of infiltrate was diffuse (14.6%) predominantly followed by interstitial (6.5%) and paratrabecular (5.4%) types of infiltration. The least common was nodular infiltrate accounted in 9 (4.8%) patients. CONCLUSIONS: B-cell lymphoma is more frequent than T-cell lymphoma. Younger age, aggressive lymphoma, and predominance of B-symptoms are more frequently seen. Diffuse bone marrow infiltration is more common in our set up probably because of a relatively late presentation in our patients. PMID- 29403199 TI - Need for appropriate specimen for microbiology diagnosis of chronic osteomyelitis. AB - INTRODUCTION: Chronic osteomyelitis (COM) is a common infection, especially in developing countries. An adequate bone biopsy specimen processed with appropriate microbiology culture methods for isolation and identification of the causative organisms is considered as the gold standard for the diagnosis of osteomyelitis. MATERIALS AND METHODS: The present study is a retrospective microbiology analysis of the specimen from 219 clinically diagnosed cases of COM between January 2013 and April 2016. RESULTS: The overall culture positivity was 111/219 (50. 6%), colonization was seen in 22/219 (10.5%), while the rest 86/219 (39.3%) were culture-negative specimen; culture positivity was highest from tissue specimen (71/113, 62.8%). Among the swabs, 40/106 (37.7%) were culture positive. About 28/40 (70%) culture-positive swabs showed significant growth of Gram-positive organisms. Colonization with skin flora such as diphtheroids and Coagulase negative Staphylococci was seen in 22/106 (20.7%) of the swabs. Sterile cultures (44/106, 41.6%) were high among the swab specimen. Gram-positives were most common (75/111, 67.56%). Staphylococcus aureus was the predominant organism isolated in 70/111 (63%) cases. Gram-negative bacilli showed a high level of antibiotic resistance. CONCLUSION: As per our data, the culture yield from wound swabs was low or contaminated with normal skin flora, as compared to the biopsy or tissue specimen. Hence, an appropriate sampling of the infected bone using recommended protocols is highly essential for improving microbiological yield and the outcome of COM. PMID- 29403200 TI - A search for entrustable professional activities for the 1st year pathology postgraduate trainees. AB - INTRODUCTION: During the past decade, there has been a paradigm shift in medical education from the problem-based learning to competency-based training. This has forced a rethink on the way we evaluate the residents and finally give them the right to handle patients independently. This study makes the first attempt towards designing competency-based training program for pathology residents by formulating the entrustable professional activities (EPAs) for the 1st year pathology residents. MATERIALS AND METHODS: A questionnaire comprising 18 potential EPAs in histopathology and 12 potential EPAs in cytology were circulated among the residents of Pathology Department. The respondents were asked to grade the EPAs on a scale of 0-4 based on how important they considered that activity as EPA. The cumulative score of each EPA was divided by the number of respondents to arrive at the average score. The EPAs with an average score of 3 or more qualified to be shortlisted as consensus EPAs. RESULTS: Five activities each of histopathology and cytopathology had an average score of 3 or above and were shortlisted as EPAs for the 1st year pathology postgraduates. Each of these was also mapped to their respective competencies. CONCLUSION: There is an urgent need to restructure the postgraduate pathology curriculum in line with competency based training. This study is the first step in this direction. PMID- 29403201 TI - Decreasing trend of seroprevalence of hepatic amoebiasis in tertiary care hospital of North India: 2010-2015. AB - BACKGROUND: Globally, amoebic liver abscess, a common extraintestinal complication of intestinal amoebiasis. Diagnosis of hepatic amoebiasis is based on the detection of anti-Entamoeba histolytica immunoglobulin G (IgG) antibody using enzyme-linked immunosorbent assay (ELISA), because of its technique's relatively higher sensitivity and specificity (90%). AIM: The aim of the present study was to determine the seroprevalence of hepatic amoebiasis in a referral tertiary care hospital in North India. MATERIALS AND METHODS: The blood samples were tested specifically for anti-E. histolytica IgG antibody using commercially available ELISA kit (RIDASCREEN(r)E. histolytica IgG [K1721] kit). RESULTS: A total of 879 patients (n = 879) were evaluated, of which 78.49% (690/879) were positive for anti-E. histolytica IgG antibody. The seroprevalence rates showed a declining trend from 2010 to 2015 with rates falling from 91.4% to 66.7%. He present a study showed the decreasing trend of seroprevalence of hepatic amoebiasis from 2010 to 2015. CONCLUSIONS: This decrease may be attributed to several factors such as increase in awareness, improved hygienic practices, use of safe drinking water, better socioeconomic condition, and perhaps early treatment sought for intestinal amoebiasis. PMID- 29403202 TI - Thrombocytosis in children: Clinico-hematological profile from a single centre in Eastern India. AB - BACKGROUND AND OBJECTIVE: Thrombocytosis is not an uncommon finding in hemograms of children with an incidence of 6%-15% among hospitalized children. This study aims to determine the etiology of thrombocytosis and analyze various platelet parameters in children attending our hospital. MATERIALS AND METHODS: A prospective observational study was carried out in a tertiary care center in Odisha, in eastern part of India, for 6 months from July 2016 to December 2016. All children of age group 1-14 years of age attending pediatrics and other pediatric super specialty outdoors and/or admitted to indoors and whose complete blood counts (CBC) were done were included in the study. The CBC parameters such as hemoglobin, red blood cell indices, and platelet indices (platelet distribution width [PDW], mean platelet volume [MPV], platelet large cell ratio [P-LCR]) were noted. RESULTS: Out of 2500 hemograms done in pediatrics age group, 272 (10.8%) patients showed thrombocytosis. About 99.6% of cases were of secondary thrombocytosis. Only one case of primary thrombocytosis was encountered. The most common cause of secondary thrombocytosis was infection (39.5%) alone followed by iron deficiency anemia (14.1%). With increasing platelet counts, a decrease in MPV, P-LCR, and PDW was noted which was statistically significant (P < 0.05). CONCLUSION: Thrombocytosis is not rare (10.8%) in children. Secondary thrombocytosis is common and predominatly attributed to infection. PMID- 29403203 TI - Diagnostic utility of quantitative cytomegalovirus DNA polymerase chain reaction in intestinal biopsies from patients with inflammatory bowel disease. AB - OBJECTIVES: Diagnostic utility of cytomegalovirus (CMV) DNA quantitative polymerase chain reaction (qPCR) in inflammatory bowel disease (IBD) has not been established. We aimed to compare diagnostic utility of qPCR for CMV in biopsy specimens with blood, serology, and histopathology. MATERIALS AND METHODS: A total of 132 patients were included (92 ulcerative colitis [UC], 9 Crohn's disease, and 31 unclassified IBD). Comparison between CMV IgM, CMV DNA qPCR in biopsy, in blood and histopathology was done. Positive result in any of the test was considered as CMV infection. Various risk factors for CMV association with IBD were analyzed. RESULTS: Confirmed CMV infection was seen in 41 (31.1%) patients. Diagnostic sensitivity of different assays was: DNA in biopsy seen in 37 (90.2%), DNA in blood in 19 (46.3%), CMV IgM in 15 (36.5%), and histopathology in 8 (19.5%). Thirty-two UC cases were further followed up for a median time of 14.0 (R: 3-31) months. They were grouped as group I - biopsy and blood DNA both positive (14, 43.7%), Group II - biopsy positive and blood negative (17, 53.1%), and Group III - biopsy negative but blood positive (1, 3.1%). CMV DNA viral load in Group I was significantly higher (mean: 4.2 +/- 1.0 log10 copies/mg) than Group II (mean: 3.2 +/- 0.6 copies/mg) and Group III (viral load: 2.69 log10 copies/ml), P < 0.001. Steroid refractoriness was seen more in Group I cases (n = 9) P < 0.001. A cutoff of >=2.5 log10 copies/mg of DNA in tissue was predictive for steroid refractoriness (AUROC = 0.84). CONCLUSIONS: Quantitation of CMV DNA in intestinal biopsy is a useful diagnostic tool and can predict response to steroid treatment in patients with UC. PMID- 29403204 TI - Clinical spectrum and diagnostic yields of Mycoplasma pneumoniae as a causative agent of community-acquired pneumonia. AB - INTRODUCTION: Infection with Mycoplasma pneumoniae (M. pneumonia) occurs worldwide which accounts for 15%-20% of cases of community-acquired pneumonia and indistinguishable clinically from other infectious causes of pneumonia. AIM: The aim of this study was to evaluate the real-time polymerase chain reaction (PCR) and to correlate it with other diagnostic methods such as culture, serology (ELISA), and conventional PCR along with the clinical signs and symptoms produced by M. pneumonia. MATERIALS AND METHODS: A total of 130 patients of all age groups presenting with clinical features of lower respiratory tract infections were enrolled over a period of 1 year and 2 months in a tertiary care hospital in Delhi. M. pneumoniae in throat swab samples was detected by real-time PCR, compared with culture, serology, conventional PCR, and clinical signs and symptoms. Univariate analyses were conducted to determine the association of M. pneumoniae infection among different categories of patients. RESULTS: Out of a total of 130 patients, 18 patients (14%) were positive for M. pneumoniae by any test; culture was positive in nine patients (50%), serology (IgM) in eight patients (44.4%), PCR in five patients (27.7%), and real-time PCR was positive in six patients (33.3%). Clinical signs and symptoms were higher in incidence in M. pneumoniae-positive patients. Age-matched healthy controls (30) were included in the study, and all were negative for any diagnostic test performed (P = 0.026). CONCLUSION: It was concluded that combination of M. pneumoniae-specific testing modalities is required for the diagnosis of this etiological agent rather than a single diagnostic method. PMID- 29403205 TI - Evaluation of renal function in subclinical hypothyroidism. AB - INTRODUCTION: Patients with subclinical hypothyroidism (SCH) have a few or no symptoms or signs of thyroid dysfunction and thus by its very nature, SCH is a laboratory diagnosis. Serum creatinine is elevated and glomerular filtration rate (GFR) values are reversibly reduced in overt hypothyroid patients. We hypothesize that SCH also may be associated with low GFR. AIMS AND OBJECTIVES: The objective of this study was (1) to know the effect of SCH on kidney function, (2) to find the correlation between the renal function parameter creatinine, estimated GFR (eGFR), and thyroid-stimulating hormone (TSH), and (3) to know if creatinine values can be predicted by TSH values in SCH cases. MATERIALS AND METHODS: This is a hospital-based cross-sectional study for 1 year. A total of 608 subjects of either sex were included in the study and were divided into 3 groups: (1) SCH, (2) overt hypothyroidism (OHT), and (3) euthyroidism (ET). TSH, free triiodothyronine, free thyroxine, and serum creatinine were estimated and eGFR was calculated using modification of diet in renal disease study equation and the chronic kidney disease epidemiology collaboration equations. RESULTS: Serum creatinine levels were higher and eGFR was lower significantly in the subclinical hypothyroid group when compared to the control ET group (P < 0.001). The overtly hypothyroid group had significantly higher levels of serum creatinine and lower eGFR when compared to both the groups (P < 0.001). Significant correlation between TSH, creatinine, and eGFR was found in OHT group only. Linear regression analysis showed the regression in creatinine upon TSH is attributable to 44.5% among OHT group, 48.2% in SCH group. CONCLUSION: It can be concluded that the SCH group behaves biochemically similar to OHT group and changes in serum creatinine reflect tissue hypothyroidism in SCH cases. PMID- 29403206 TI - A comparative evaluation of lithium estimation for samples collected in different tubes and its stability on storage. AB - PURPOSE: Lithium (Li) is a well-established drug for the treatment of bipolar affective disorders. Li as a drug is known to possess a narrow therapeutic index. Thus, regular monitoring of blood Li in patients receiving Li therapy is essential. Plain tubes with clot activator are known to interfere with Li estimation. The current study was planned to compare Li estimation in sera from vacutainers with clot activator, and plasma from sodium heparinized vacutainers with that of Li estimation in sera from glass vials. The time-dependant stability of Li estimation on storage at 2 degrees C-8 degrees C for 48 h in these three set of tubes was also evaluated. MATERIALS AND METHODS: Blood from the patients on Li therapy (n = 100) was collected in 3 different collection tubes: plain vacutainer with clot activator (S), Sodium heparinized vacutainer (P) and Glass vial (G) and was analyzed by ion selective electrode (ISE) analyzer for Li levels. Secondary aliquots were also taken from each type of collection tube and stored at 2 degrees C-8 degrees C. Time-dependant stability of Li estimation was checked at 12 h, 24 h, and 48 h. ANOVA followed by Tukey's posttest was performed to calculate statistical significance taking glass vial as reference collection tube. Bland-Altman plots were plotted to compare between three collection tubes at baseline. Stability on storage was defined when >95% of the samples were within allowable error limit for that time point taking baseline levels as reference. RESULTS: A mean bias of 0.18 mmol/L and mean percentage bias of 19.9% in Li levels was observed between serum from (S) than serum from (G). This difference was found to be statistically significant. However, statistically nonsignificant mean bias of 0.02 mmol/L and mean percentage bias of 3.34% in Li levels was observed between plasma from (P) and serum from (G). Time-dependant stability was observed more in glass vials as compared to vacutainers with clot activator or sodium heparin. CONCLUSION: Serum from glass vial should be the preferred method for blood collection to determine Li levels. PMID- 29403207 TI - Hematological parameters of human immunodeficiency virus positive pregnant women on antiretroviral therapy in Aminu Kano Teaching Hospital Kano, North Western Nigeria. AB - CONTEXT: Human immunodeficiency virus (HIV) scourge continues to affect young women within the reproductive age group and pregnancy is a recognized indication for the use antiretroviral (ARV) drugs among HIV-positive women. AIMS: The aim is to determine the combined effect of pregnancy, HIV and ARV drugs on the hematological parameters of the pregnant women. SETTINGS AND DESIGN: This was a comparative cross-sectional study conducted among 70 each of HIV-positive and negative pregnant women. SUBJECTS AND METHODS: Bio-demographic and clinical data were extracted from the client folder and 4 ml of blood sample was obtained from each participant. Full blood count was generated using Swelab automatic hematology analyzer while reticulocyte count and erythrocyte sedimentation rate (ESR) were conducted manually. STATISTICAL ANALYSIS USED: Data analysis was performed using SPSS version software 16 while P < 0.05 was considered statistically significant. RESULTS: Pregnant women with HIV had statistically significant lower hematocrit and white blood cell (WBC) and higher ESR than pregnant women without HIV (P < 0.000). There was no statistically significant difference between the two groups in terms of platelet and reticulocyte (P > 0.05). However, among HIV positive pregnant women, those with CD4 count <350/MUL had statistically significant lower WBC and lymphocyte count than those with CD4 count >=350/MUL (P < 0.05), whereas, those on zidovudine (AZT)-containing treatment had statistically significant lower hematocrit and higher mean cell volume than those on non-AZT-containing treatment (P < 0.05), but there was no statistically significant difference in any of the hematological parameters (P > 0.050) between women on first- and second-line ARV regimens. CONCLUSIONS: There is a significant difference in terms of hematological parameters between HIV positive and HIV-negative pregnant women in this environment. PMID- 29403208 TI - Internal quality control of blood products: An experience from a tertiary care hospital blood bank from Southern Pakistan. AB - INTRODUCTION: Internal quality control (IQC) is the backbone of quality assurance program. In blood banking, the quality control of blood products ensures the timely availability of a blood component of high quality with maximum efficacy and minimal risk to potential recipients. The main objective of this study is to analyze the IQC of blood products as an indicator of our blood bank performance. METHODS: An observational cross-sectional study was conducted at the blood bank of Liaquat National Hospital and Medical College, from January 2014 to December 2015. A total of 100 units of each blood components were arbitrarily chosen during the study. Packed red cell units were evaluated for hematocrit (HCT); random platelet concentrates were evaluated for pH, yield, and culture; fresh frozen plasma (FFP) and cryoprecipitate (CP) were evaluated for unit volume, factor VIII, and fibrinogen concentrations. RESULTS: A total of 400 units were tested for IQC. The mean HCT of packed red cells was 69.5 +/- 7.24, and in 98% units, it met the standard (<80% of HCT). The mean platelet yield was 8.8 +/- 3.40 * 109/L and pH was >=6.2 in 98% bags; cultures were negative in 97% of units tested. Mean factor VIII and fibrinogen levels were found to be 84.24 +/- 15.01 and 247.17 +/- 49.69 for FFP, respectively. For CP, mean factor VIII and fibrinogen level were found to be 178.75 +/- 86.30 and 420.7 +/- 75.32, respectively. CONCLUSION: The IQC of blood products at our blood bank is in overall compliance and met recommended international standards. Implementation of standard operating procedures, accomplishment of standard guidelines, proper documentation with regular audit, and staff competencies can improve the quality performance of the transfusion services. PMID- 29403209 TI - Development of a dry-reagent mix-based polymerase chain reaction as a novel tool for the identification of Acinetobacter species and its comparison with conventional polymerase chain reaction. AB - BACKGROUND: Nosocomial infections are often caused by multidrug-resistant bacteria and the incidence is increasing. Acinetobacter, a Gram-negative bacillus, is commonly associated with the use of intravascular catheterization and airway intubation. Polymerase chain reaction (PCR) for identification of Acinetobacter baumannii from samples has been standardized that use conventional wet-reagent mix. We have designed and optimized a dry-reagent mix for identification of Acinetobacter species by PCR. The dry-reagent mix can be stored at room temperature, has less chances of contamination, and thus can be used at point-of-care diagnosis. AIM AND OBJECTIVE: The present work was focused on comparing the sensitivity and specificity of dry-reagent PCR mix over conventional wet-reagent PCR mix for identification of Acinetobacter species. MATERIALS AND METHODS: Conventional wet-reagent mix based and dry-reagent mix based PCR were carried out for the DNA isolated from Acinetobacter species. The latter was also applied directly on bacterial growth without prior DNA extraction process. Equal numbers of bacterial isolates other than Acinetobacter species were also subjected to identification by the same protocols for determining the sensitivity and specificity of the test. RESULTS: The Acinetobacter species showed amplification of the target rpoB gene and the band was observed at 397 bp. The dry-reagent PCR mix results matched completely with the conventional wet reagent PCR mix assay. All the non-Acinetobacter isolates were negative for the PCR. This indicates that the test is highly specific. The dry-reagent mix also contained an enzyme resistant to PCR inhibitors and capable of amplifying DNA directly from cells. CONCLUSION: Performance of dry-reagent PCR mix without the need for DNA extraction and preparation of a PCR mix proved to be more sensitive and reduce the handling error, minimizes the time, manual work, and skilled labor. PMID- 29403210 TI - Prevalence of hemoglobin variants and hemoglobinopathies using cation-exchange high-performance liquid chromatography in central reference laboratory of India: A report of 65779 cases. AB - CONTEXT: Hemoglobinopathies constitute the world's most common genetically inherited red blood cell disorder. Screening and accurate identification of hemoglobin (Hb) variants have become increasingly important in antenatal diagnosis and prevention of Hb disorders. AIM: The aim of this study was to screen and identify Hb fractions prevalent in the Central Reference Laboratory of India. MATERIALS AND METHODS: A total of 65,779 cases were screened for hemoglobinopathies on the bio-rad variant high-performance liquid chromatography (HPLC) system by beta-thalassemia short program. The retention times, proportion of the hemoglobin (%) and the peak characteristics for all hemoglobin fractions were recorded. Molecular analysis of the beta-globin gene was carried out by DNA sequencing on eight cases. RESULTS: Total number of abnormal Hb fractions on cation exchange-HPLC (CE-HPLC) was seen in 12,131 (18.44%) cases. Beta thalassemia trait was the predominant genetic Hb disorder accounting for 7377 cases (11.21%) of the total cases. This was followed by sickle cell trait (2.01%), sickle cell disease (1.59%), beta-thalassemia syndrome (0.80%), HbE trait (0.79%), and borderline HbA2 (0.51%). Molecular characterization of eight rare cases of hemoglobin variants by beta-globin gene sequencing identified three cases of Hb Beth Israel, two cases of Hb Hofu trait, and one case each of Hb J Cambridge, Hb Mizunami, and Hb Sherwood Forest. CONCLUSION: Superior resolution, rapid assay time, and accurate quantification make CE-HPLC suitable for the routine investigation of hemoglobinopathies. PMID- 29403212 TI - Volume, conductance, and scatter parameters of neoplastic and nonneoplastic lymphocytes using Coulter LH780. AB - PURPOSE: Automated hematology analyzers yield a complete hematological profile including a complete blood count and a differential white blood cell count. The differential count is based on analyses of three parameters, namely, volume, conductance, and scatter (VCS). We aimed to evaluate the VCS parameters, histograms, and scatterplots of neoplastic and nonneoplastic lymphocytes. MATERIAL AND METHODS: Patients were grouped into four categories, namely, acute lymphoblastic leukemia (ALL), chronic systemic disorders, chronic lymphocytic leukemia (CLL), and acute viral disease. Lymphocytes from all four groups were compared with lymphocytes from normal participants. RESULTS AND CONCLUSIONS: The histogram for acute viral disease showed a trough at T1, which was slightly obliterated, and the F1 curve mildly extended to the right. The T1 for ALL was replaced with a peak at >40% of the preset limit. The F1 peak was shifted to left for CLL. The scatterplot for viral disease showed lymphocytes extending to the variant lymphocyte window. The lymphocytes of ALL extended to the blast window, with both increase in volume and mild increase in scatter. The lymphocytes in CLL were smaller and located below the normal lymphocyte region. Mean lymphocyte volume was significantly increased in ALL and was significantly decreased in CLL. Mean lymphocyte conductance was significantly increased in CLL and significantly decreased in both acute viral disease and ALL. Mean lymphocyte scatter was significantly decreased in acute viral disease and significantly increased in ALL. PMID- 29403211 TI - Evaluation of new indigenous "point-of-care" ABO and Rh grouping device. AB - BACKGROUND: Erycard 2.0 is a "point-of-care" device that is primarily being used for patient blood grouping before transfusion. MATERIALS AND METHODS: Erycard 2.0 was compared with conventional slide technology for accuracy and time taken for ABO and Rh forward grouping result with column agglutination technology (CAT) being the gold standard. Erycard 2.0 as a device was also evaluated for its stability under different storage conditions and stability of result till 48 h. In addition, grouping of hemolyzed samples was also tested with Erycard 2.0. Ease of use of Erycard 2.0 was evaluated with a survey among paramedical staff. RESULTS: Erycard 2.0 demonstrated 100% concordance with CAT as compared with slide technique (98.9%). Mean time taken per test by Erycard 2.0 and slide technique was 5.13 min and 1.7 min, respectively. After pretesting storage under different temperature and humidity conditions, Erycard 2.0 did not show any deviation from the result. The result did not change even after 48 h of testing and storage under room temperature. 100% concordance was recorded between pre- and post-hemolyzed blood grouping. Ease of use survey revealed that Erycard 2.0 was more acceptable to paramedical staff for its simplicity, objectivity, and performance than conventional slide technique. CONCLUSION: Erycard 2.0 can be used as "point-of-care" device for blood donor screening for ABO and Rh blood group and can possibly replace conventional slide technique. PMID- 29403213 TI - Risk factors for intestinal colonization with vancomycin resistant enterococci' A prospective study in a level III pediatric intensive care unit. AB - PURPOSE: Vancomycin-resistant enterococci (VRE) emerged as one of the major nosocomial pathogens across the globe. Gut colonization rate with VRE is higher in patients admitted to intensive care units (ICUs) due to the higher antibiotic pressure. VRE colonization increases the risk of developing infection up to 5-10 folds. The aim of this study was to determine the rates of VRE colonization among the patients admitted to pediatric ICU (PICU) and risk factors associated with it. MATERIALS AND METHODS: Rectal swabs were collected after 48 h of admission to PICU from 198 patients. The samples were inoculated onto bile esculin sodium azide agar with 6 mg/ml of vancomycin. Growth on this medium was identified by the standard biochemical test, and minimum inhibitory concentration of vancomycin and teicoplanin was detected by agar dilution method. Resistance genes for vancomycin were detected by polymerase chain reaction. Risk factors were assessed by logistic regression analysis. RESULTS: The rates of VRE colonization in patients admitted to PICU was 18.6%. The majority of the isolates were Enterococcus faecium (75.6%) followed by Enterococcus faecalis (24.4%). One patient acquired a VRE bloodstream infection (2.6%) among colonized patients, and none of the noncolonized patients acquired the infection. Consumption of vancomycin was found to be the only risk factor significantly associated with VRE colonization. CONCLUSION: Routine surveillance and isolation of patients found to be VRE colonized may not be possible in tertiary care hospitals; however, educating health-care workers, promoting handwashing with antiseptic soaps or solutions, and antibiotic Stewardship policy may help in the reduction of vancomycin resistance and VRE colonization. PMID- 29403214 TI - Utility of horizontal and vertical sections of scalp biopsies in various forms of primary alopecias. AB - BACKGROUND: This study was performed to demonstrate the usefulness of horizontal and vertical sections of scalp biopsies in diagnosing various forms of primary alopecias and to highlight the importance of error-free grossing. MATERIALS AND METHODS: A retrospective analytical review of 228 scalp biopsies was done, noting down the diagnostic histopathological features evident in horizontal and vertical sections of each cases. The idealness of the sections, especially horizontal section, was also analyzed. RESULTS: Out of the 228 cases, 44 scalp biopsies were classified histologically as cicatricial alopecias and the remaining 162 as noncicatricial alopecia. 22 cases were inconclusive owing to erroneous grossing. We found horizontal sections to be more useful in cases of noncicatricial alopecias, whereas vertical sections proved superior in cicatricial alopecias. CONCLUSION: Combining both horizontally and vertically sectioned scalp biopsies maximizes the diagnostic yield. When a single biopsy is submitted, the choice between horizontal and vertical section should depend on clinical diagnosis/suspicion. PMID- 29403215 TI - In vitro cost-effective methods to detect carbapenemases in Enterobacteriaceae. AB - The rise in carbapenemases-producing organisms has challenged the scientific community. Infections caused by these bacteria have limited treatment options. There are various types such as Klebsiella pneumoniae carbapenemase (Ambler class A), metallo-beta-lactamases of VIM-type, IMP-type, NDM-type (Ambler class B), and OXA-48-types (Ambler class D). An efficient strategy for detection of carbapenemase producers is important to determine the appropriate therapeutic modalities. In this study, four methods - Carba NP test, modified Carba NP (MCNP) test, carbapenem inactivation method (CIM) test, and Rapidec Carba NP kit test were evaluated. We evaluated an in-house MCNP test to detect carbapenemase production using a single protocol which gave reliable results. Furthermore, CIM using routine antibiotic discs gives good results. Both these tests were found to be cost-effective. PMID- 29403216 TI - Enterobius vermicularis infestation leading to Meckel's diverticulitis in an adolescent boy: An extremely rare presentation. AB - Enterobius vermicularis is an intestinal nematode commonly affecting children worldwide. Its transmission is by feco-oral route. Meckel's diverticulitis due to E. vermicularis infestation is an extremely rare presentation. An 11-year-old boy presented with acute abdomen. During surgery inflamed Meckel's diverticulum (M.D) was seen. Histopathology examination of specimen revealed E. vermicularis. Till date, only one case of E. vermicularis infestation of M.D is reported around five decades ago. This histopathological confirmation is extremely important as the required treatment (Mebendazole) of the infected case along with household contacts can prevent the spread of infection and may avoid surgery in known contacts. PMID- 29403217 TI - Cytopathological examination of bronchoalveolar lavage fluid in diagnosis of pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the deposition of extracellular lipoproteinaceous material within the air spaces. Although the diagnosis is mainly based on histopathological findings, sometimes, the diagnostic yield of transbronchial and even open lung biopsy can be unsatisfactory. The advantage with bronchoalveolar lavage (BAL) cytology is that apart from being safer for the patient, it can sample a much wider area and help in giving an early diagnosis and treatment to the patient. Herein, we present a case of PAP diagnosed on BAL fluid cytology in an elderly female. PMID- 29403218 TI - Fine-needle aspiration cytology of granulocytic sarcoma presenting as a breast lump - Report of a rare case with a comprehensive literature search. AB - Myeloid sarcoma is a neoplasm of myeloid cells that can arise before or concurrent with or may follow acute myeloid leukemia. Very rarely, it can present as an isolated breast lump. We have diagnosed a case of myeloid sarcoma by fine needle aspiration cytology (FNAC), in a 52-year-old woman who presented with the right-sided breast lump. FNAC showed hypercellular smears with immature myeloid cells few neutrophils and many large round cells with high nuclear-cytoplasmic ratio, prominent nucleoli and a moderate amount of granular cytoplasm. The blast cells were myeloperoxidase positive and complete blood count, and peripheral blood examination were normal. We report this case for its rarity and as a note of caution to a pathologist to consider myeloid sarcoma in the differential diagnosis of breast lump to provide the correct diagnosis and avoid incorrect treatment of a curable disease. PMID- 29403219 TI - External ophthalmomyiasis by Oestrus ovis: A case report from Davangere. AB - External ophthalmomyiasis is an infestation of the eye with larvae of Dermatobia hominis or Oestrus ovis (sheep bot fly). We describe a case of ophthalmomyiasis in a 38-year-old male, who presented with ocular foreign body sensation, redness, pain, and watering of the eye. The causative larvae were removed and sent to the laboratory for identification. By studying morphological features, it was identified as the first instar larvae of O. ovis. The patient was put on topical and oral antibiotics but was lost to follow-up. This is probably the first report from this part of Karnataka. PMID- 29403220 TI - Role of fine needle aspiration cytology in diagnosis of brown tumor secondary to parathyroid adenoma. AB - Brown tumor (BT) is caused by altered metabolism of calcium resulting from hyperparathyroidism (primary or secondary). The most common cause of hyperparathyroidism is isolated parathyroid adenoma (PA), and the most common symptoms are hypercalcemia related. BT is considered as a late manifestation of PA and usually diagnosed after surgical treatment of the bony lesion. Fine-needle aspiration cytology (FNAC) is a cheap, easy, and less traumatic procedure and should be performed in all lesions wherever possible as unnecessary surgeries may be avoided. We here report a rare case of PA presenting primarily as BT and diagnosed on FNAC. PMID- 29403221 TI - Granulicatella adiacens abscess: Two rare cases and review. AB - Granulicatella adiacens is a nutritionally variant streptococcus species. These bacteria are rarely isolated in the laboratory due to their fastidious growth requirements. These have been mostly reported from bloodstream infections, infective endocarditis, infections of orbit, nasolacrimal duct and breast implants. Here, we are reporting two cases of subcutaneous abscesses caused by G. adiacens. In first case, it was isolated from abscess around elbow joint and second case was a suprapatellar abscess. We have also reviewed the published data concerning diagnosis and antimicrobial susceptibility pattern of Granulicatella infections and included some Indian cases. PMID- 29403222 TI - Insulin Syringe: A Gimmick in Pediatric Dentistry. AB - Aim: The management of pain and anxiety in dentistry encompasses a number of procedural issues, including the delivery of anesthetic solution. One of the most important ways to manage the behavior of children is pain control. Trypanophobia is very common among dental patients and the most important goal of guidelines on behavior guidance for pediatric dental patient is to ease fear and anxiety in dental procedures in children. For the stated reasons, the purpose of the present study was to record child's pain sensation both objectively and subjectively while receiving dental local anesthesia using conventional syringes and diabetic needles. Materials and methods: Twenty children of age group 6 to 12 years undergoing routine dental procedures participated in the study. Every child acted as one's own control, while receiving treatment on the opposite side of the same arch. Each patient was randomly assigned to receive the injection either with conventional syringe or diabetic needle for the first visit, while the injection with the other needle was administered during the second visit. Rating scales were used for objective and subjective evaluations. Results: Statistical analysis of the measurements were made using Wilcoxon signed U test and Mann-Whitney U test which showed the mean sound, eye, motor (SEM) score difference using insulin syringe. The outcome was statistically significant when compared using the mean ranks between male and female patients with that of control group. Conclusion: It can be concluded that diabetic syringes exhibit clinical advantage and its use in pediatric dentistry for local anesthetics (LA) infiltration can prove beneficial.How to cite this article: Kour G, Masih U, Singh C, Srivastava M, Yadav P, Kushwah J. Insulin Syringe: A Gimmick in Pediatric Dentistry. Int J Clin Pediatr Dent 2017;10(4):319-323. PMID- 29403223 TI - Propolis: A Smart Supplement for an Intracanal Medicament. AB - Introduction: One of the most important factors for successful endodontic therapy is root canal cleaning. The difficulty involved in eliminating microorganisms, as well as their residual presence, warrants the use of root canal dressings after bio-mechanical preparation. Aim: The aim of the study was to compare the diffusion ability between nonalcoholic calcium hydroxide-propolis paste, calcium hydroxide-saline paste, and calcium hydroxide-propylene glycol paste. Materials and methods: For this proposed study, single-rooted extracted permanent teeth were randomly divided into three groups to fill the canals: group I: Calcium hydroxide-propylene glycol paste, group II: Calcium hydroxide-saline paste, and group III: Calcium hydroxide-propolis paste. After complete filing of the root canal, the pH values of the solutions in the flasks are measured at an interval of 3, 24, 72, 168 hours. Results: After 168-hour interval, it was noticed that the mean pH obtained by calcium hydroxide-propolis paste was 10.54 (+/- 0.38), which was greater than calcium hydroxide-propylene glycol paste 9.70 (+/- 0.45) and calcium hydroxide-saline paste 9.16 (+/- 0.30) consecutively. Conclusion: The nonalcoholic calcium hydroxide-propolis paste used during the study was able to diffuse through the dentinal tubules. Thus, it can be used as a vehicle for calcium hydroxide.How to cite this article: Baranwal R, Duggi V, Avinash A, Dubey A, Pagaria S, Munot H. Propolis: A Smart Supplement for an Intracanal Medicament. Int J Clin Pediatr Dent 2017; 10(4):324-329. PMID- 29403224 TI - Clinical Evaluation of Bond Failures and Survival of Mandibular Canine-to-canine Bonded Retainers during a 12-year Time Span. AB - Aim: The aim of this study was to assess the effectiveness of the 3-3 mandibular lingual stainless steel retainer to prevent a relapse of orthodontic treatment during the 12-year time span of the survey. Materials and methods: Fifty patients with canine-to-canine bonded retainers (placed at least 10 years earlier) were recalled. All patients had been followed up annually during this period. Patients were screened for stability of the retainer and for the condition of hard and soft oral tissues. Results: None of the patients reported a complete loss of the retainer; 14 patients reported single element partial losses and 13 reported multiple losses. Most partial failures were not perceived by patients, but noted by the orthodontist during the control visit. There was no notable variation of the gingival index occurring in these patients. In two cases patients had caries in the six teeth bonded with the retainer, but never on the lingual side; only in three teeth areas of decalcification in the proximity of bonded sites were reported. All patients showed good compliance with this kind of retention. Conclusion: The composite adhesive technique allowed a reliable positioning system for directly bonded retainers and did not influence the occurrence of carious lesions or demin-eralized spots on fixed teeth. Full teeth fixation offered the possibility of stabilizing the irregularity index highlighted in various studies without increasing any side effects on gums and hard tissues.How to cite this article: Maddalone M, Rota E, Mirabelli L, Venino PM, Porcaro G. Clinical Evaluation of Bond Failures and Survival of Mandibular Canine-to-canine Bonded Retainers during a 12-year Time Span. Int J Clin Pediatr Dent 2017;10(4):330-334. PMID- 29403225 TI - Effect of Magnetized Water Mouthrinse on Streptococcus mutans in Plaque and Saliva in Children: An in vivo Study. AB - Aim: This study was conducted to evaluate and compare the antimicrobial efficacy of magnetized water as a mouthwash on colony count of Streptococcus mutans in children. Materials and methods: Total sample size of 30 children were selected out of screened 290 children by simple random sampling between the age group of 7 and 12 years. The study was conducted over a period of 2 weeks. After selection of the children according to inclusion and exclusion criteria, children were allowed using 10 mL of 72 hours magnetized water for 3 minutes twice in a day for a period of 2 weeks, and further plaque and saliva samples were collected at 1- and 2-week intervals from baseline. Microbiological analysis of plaque and saliva samples was done by Dentocult SM strip kit (Orion Diagnostica, Finland), and the results were statistically analyzed and tabulated. Results: Statistically, there was highly significant reduction in S. mutans count in plaque as well as in saliva after 1- and 2-week intervals from baseline. Conclusion: So, finally our study showed that magnetized water is as effective a mouthwash against S. mutans and has better action in plaque as compared with saliva. It can be used as an adjunct to commercially available mouthwashes.How to cite this article: Goyal AK, Rathore AS, Garg M Mathur R, Sharma M, Khairwa A. Effect of Magnetized Watei Mouthrinse on Streptococcus mutans in Plaque and Saliva in Children: An in vivo Study. Int J Clin Pediatr Dent 2017 10(4):335-339. PMID- 29403226 TI - Comparison of Oral Health Status and Knowledge on Oral Health in Two Age Groups of Schoolchildren: A Cross-sectional Study. AB - Introduction: Oral health plays a pivotal role in the overall wellbeing of children. As children grow, there is a variation in their oral health status due to the changing trends and lifestyle. Aim: To evaluate and compare the factors related to oral health status in two age groups of school going children. Materials and methods: A total of 582 children aged 8 to 11 years from 3 schools were included. Based on their school grade, they were grouped as younger (third grade) and older (fifth grade) children. Their dental caries status, caries treatment needs, oral hygiene status were assessed. A questionnaire was given to them to assess their knowledge on oral health. Results: Both third and fifth grade children had similar caries status. The caries treatment needs was significantly higher (p = 0.02) in fifth grade children of school III. The oral hygiene status was significantly better (p = 0.004) in fifth grade children of school I and third grade children (p < 0.001) of school III. Fifth grade children were found to have more knowledge on oral health and it was statistically significant in school II (p = 0.001). In school III, as caries status increased, the oral hygiene index score significantly increased (p = 0.001). Conclusion: Age did not have any influence on the oral health status of children. The older children had better knowledge on oral health, but the oral hygiene practices were not followed effectivelyHow to cite this article: Geethapriya PR, Asokan S, Kandaswamy D. Comparison of Oral Health Status and Knowledge on Oral Health in Two Age Groups of Schoolchildren: A Cross-sectional Study. Int J Clin Pediatr Dent 2017;10(4): 340-345. PMID- 29403227 TI - Evaluation of the Relevance of Piaget's Cognitive Principles among Parented and Orphan Children in Belagavi City, Karnataka, India: A Comparative Study. AB - Aim: To determine and compare the relevance of Piaget's cognitive principles among 4- to 7-year-old parented and orphan children in Belagavi City, Karnataka, India. Materials and methods: This study was conducted on 240 children between the ages of 4 to 7 years who were equally divided into two groups of 120 parented and 120 orphan children. These were subdivided into four groups of 30 children each. Various characteristics like egocentrism, concept of cardinal numbers based on centration, lack of conservation, and reversibility were assessed, using experiments and comparison of their prevalence between two groups was carried out. Results: There is a statistically significant difference in the cognitive development among parented and orphan children age 4 to 7 years. Conclusion: There is a significantly better cognitive development among parented children as compared with orphan children in Belagavi city. Clinical significance: A child is not a miniature adult but rather can think and perceive the world differently from an adult. Understanding a child's intellectual level can enable a pedodontist to deliver improved quality care to children. According to Jean Piaget, in the preoperational period, children think symbolically and their reasoning is based more on appearance rather than logic. It is often rightly said that a child's behavior is a reflection of his parents. However, Piaget did not consider the effect of social setting and culture on the cognitive development. This study was carried out as there is not much literature available to describe the cognitive development of children in the Indian scenario and the influence of parental presence on the same.How to cite this article: Badakar CM, Thakkar PJ, Hugar SM, Kukreja P, Assudani HG, Gokhale N. Evaluation of the Relevance of Piaget's Cognitive Principles among Parented and Orphan Children in Belagavi City, Karnataka, India: A Comparative Study. Int J Clin Pediatr Dent 2017;10(4):346-350. PMID- 29403228 TI - Reinforcing Effects of Calcium Silicate-based Cement and Dual Cure Composite Resin in Simulated Immature Teeth with an Open Apex: An in vitro Study. AB - Aim: To evaluate the fracture resistance of simulated immature teeth with an apical plug of biodentine followed by composite resin vs total obturation with biodentine tested immediately and after 3 months of aging and also to find out the chemical composition of dentin in contact with these materials. Materials and methods: Extracted human maxillary central incisors with simulated immature apex with radicular dentin thickness (RDT) of 1 to 1.5 mm selected and divided into three groups of 20 each. Group I (control)-4 mm biodentine apically and thermoplasticized gutta-percha. Group II-4 mm biodentine apically and composite resin. Group III-complete obturation with biodentine. About 10 samples from each group were tested immediately and remaining 10 stored in phosphate buffered solution (PBS) and tested after 3 months for fracture resistance and chemical analysis of dentin. Results: No significant difference in fracture resistance between the groups was observed when tested immediately. After 3 months of aging, only biodentine group showed a significant reduction in fracture resistance with increased Ca/P ratio of root dentine. Conclusion: Biodentine group has shown drastic reduction in fracture resistance after 3 months of aging, and hence, cannot be recommended as a reinforcement material in immature teeth with thin dentin walls.How to cite this article: Zhabuawala MS, Nadig RR, Pai VS, Gowda Y, Aswathanarayana RM. Reinforcing Effects of Calcium Silicate-based Cement and Dual Cure Composite Resin in Simulated Immature Teeth with an Open Apex: An in vitro Study. Int J Clin Pediatr Dent 2017;10(4):351-357. PMID- 29403229 TI - In vitro Macro-qualitative Comparison of Three Enamel Stripping Procedures: What is the Best Shape We can get? AB - Aim: Interdental stripping is a common clinical procedure in orthodontic therapy, by reshaping the proximal contacts. Handheld abrasive strips have been criticized as time-consuming process. Metallic strip system, diamond disk, or segment disks have become increasingly popular. The aim of this study is to evaluate the morphological aspects of remodeled dental surfaces so as to conclude which of the different techniques (disk, bur, or strip) used to reduce the mesiodistal diameter is the best to reproduce the initial contour of the proximal surface of the tooth. Materials and methods: Seventy-nine pieces ("teeth") were prepared from permanent healthy teeth (premolars and molars) extracted for orthodontic reasons. They were mounted on a stand resembling the position of the natural teeth in a mild crowded dentition. The "teeth" are divided into three groups as follows: group S (strip): 26 "teeth," group D (disk): 25 "teeth," group B (bur): 28 "teeth." In order to study the changes, these prepared "teeth" are macro photographed in groups of 5 before and after proximal grinding. Results: The "teeth" contours have been identified using piecewise cubic Hermit polynomials. The change in the contour has been traduced in terms of the change of curvature in the "teeth" contours. We used the z-test in order to find the confidence interval for the proportion of the class "+" for each of the techniques B, S, and D. With confidence level of 95%, we obtained the following confidence intervals:B = (0.6943; 0.9057); S = (0.9093; 1.0138); D = (0.6184; 0.8616)These results can be interpreted, as the technique S is significantly much better than the other two techniques if we aim at conserving the shape of the teeth before and after treatment. Conclusion: We conclude that the use of a strip for remodeling the proximal surface of a tooth is an optimal technique to preserve the proximal shape of the tooth although it requires more time. Clinical significance: The use of abrasive strip preserves the best shape of the proximal side. Abrasive strip could be the last step of any proximal reshaping technique.How to cite this article: Nassif N, Gholmieh MN, Sfeir E, Mourad A. In vitro Macro-qualitative Comparison of Three Enamel Stripping Procedures: What is the Best Shape We can get? Int J Clin Pediatr Dent 2017;10(4):358-362. PMID- 29403230 TI - Impacted Lower Second Permanent Molars at the Ramus and Coronoid Process: A New Clinical Symptom of the WNT10A Mutation in Ectodermal Dysplasia. AB - Aim: Hidrotic ectodermal dysplasia (ED) with the WNT10A mutation produces variable dentofacial symptoms. The aim of this study was to describe a new clinical symptom, i.e., specific to the WNT10A mutation in hidrotic ED. The study investigated the migratory trend of the lower second permanent molars to the ramus or coronoid process. To the best of authors' knowledge, no data in the literature describe this trend in cases of hidrotic ED. Materials and methods: A three-generation family pedigree was established for seven families after the diagnosis of hidrotic ED in a 10-year-old boy. Thereafter, a genetic and clinical study was conducted on three families with at least one individual affected by hidrotic ED (20 individuals). We selected the children with molar germs 37 and 47. The eruption axes of these germs were then traced on the panoramic images at the initial time (T0) and 1 year later (T0 + 1 year), and the deviations between these axes were measured. Results: A significant familial consanguinity was shown. Eight subjects presented with the hidrotic ED phenotype. Among them, three individuals carried germs 37 and 47. Over time, the measured deviations between the eruption axes of the latter displayed, in the majority of the cases, a distal inclination toward the ramus. Limitations: A larger sample size is mandatory to assess the frequencies and treatment modalities. Conclusion: The presence of germs in the lower second permanent molars in patients with hidrotic ED is an important clinical symptom that should be monitored to detect and prevent ectopic migration of these teeth. Clinical significance: In hidrotic ED cases, the study of the presence of the second lower permanent germs must include clinical and radiological examinations. Establishing an inter-ceptive treatment is necessary to prevent the migration of the molars in question.How to cite this article: Sfeir E, Aboujaoude S. Impacted Lower Second Permanent Molars at the Ramus and Coronoid Process: A New Clinical Symptom of the WNT10A Mutation in Ectodermal Dysplasia. Int J Clin Pediatr Dent 2017;10(4):363-368. PMID- 29403231 TI - Is Inferior Alveolar Nerve Block Sufficient for Routine Dental Treatment in 4- to 6-year-old Children? AB - Introduction: Pain control is one of the most important aspects of behavior management in children. The most common way to achieve pain control is by using local anesthetics (LA). Many studies describe that the buccal nerve innervates the buccal gingiva and mucosa of the mandible for a variable extent from the vicinity of the lower third molar to the lower canine. Regarding the importance of appropriate and complete LA in child-behavior control, in this study, we examined the frequency of buccal gingiva anesthesia of primary mandibular molars and canine after inferior alveolar nerve block injection in 4- to 6-year-old children. Study design: In this descriptive cross-sectional study, 220 4- to 6 year-old children were randomly selected and entered into the study. Inferior alveolar nerve block was injected with the same method and standards for all children, and after ensuring the success of block injection, anesthesia of buccal mucosa of primary molars and canine was examined by stick test and reaction of child using sound, eye, motor (SEM) scale. The data from the study were analyzed using descriptive statistics and statistical software Statistical Package for the Social Sciences (SPSS) version 21. Results: The area that was the highest nonanesthetized was recorded as in the distobuccal of the second primary molars. The area of the lowest nonanesthesia was also reported in the gingiva of primary canine tooth. Conclusion: According to this study, in 15 to 30% of cases, after inferior alveolar nerve block injection, the primary mandibular molars' buccal mucosa is not anesthetized.How to cite this article: Pourkazemi M, Erfanparast L, Sheykhgermchi S, Ghanizadeh M. Is Inferior Alveolar Nerve Block Sufficient for Routine Dental Treatment in 4- to 6-year-old Children? Int J Clin Pediatr Dent 2017;10(4):369-372. PMID- 29403232 TI - Evaluation of Knowledge, Awareness, and Occurrence of Dental Injuries in Participant Children during Sports in New Delhi: A Pilot Study. AB - Aim: To evaluate the occurrence of dental injuries in children, the level of knowledge of the participants about preventive measures, and management of dental trauma during sports, in New Delhi. Materials and methods: A cross-sectional study was carried out among 450 children aged 6 to 16 years. A structured interviewer-guided questionnaire was used to determine the prevalence of oral injuries sustained during sport activities, the use of mouthguard as well as the athlete's awareness regarding use of mouthguard. The respondents consisted of 313 males (69.6%) and 137 females (30.4%) with a mean age of 12.6 years. Results: Out of the total participants, 27 (6%) had chipping or fracture of teeth, 25 (5.6%) had soft-tissue laceration, 24 (5.4%) had avulsion of teeth, and 18 (4%) had suffered fracture of jaw/bones. Out of the total participants, 263 (58.4%) knew that it was possible to replant the teeth and 187 (41.6%) did not know that it was possible to replant the teeth. Out of the total participants, 203 (45.1%) did not know what is the best time to put the teeth back in the mouth and 247 (54.9 %) answered in affirmative with variable answer. Of the total participants, 223 (49.6%) answered that they would carry avulsed tooth in water, 94 (20.8%) wrapped in cloth, 57 (12.6%) in mouth/saliva, 9 (2%) in Hanks' balanced salt solution (HBSS), and 67 (14.8%) answered others. Of the total participants, 321 (71.3%) were aware that mouthguards prevent injury and 129 (28.7%) did not know about mouthguards. Out of the total participants, 94 (20.9%) used mouthguards and 356 (79.1%) had never used mouthguards. Conclusion: Level of awareness and knowledge about sports-related orofacial injury is very poor among children in New Delhi. Education on prevention of orofacial trauma should be given to the coaches and children. Wearing of mouthguards during sport activities should be compulsory during practice and competition events.How to cite this article: Goswami M, Kumar P, Bhushan U. Evaluation of Knowledge, Awareness, and Occurrence of Dental Injuries in Participant Children during Sports in New Delhi: A Pilot Study. Int J Clin Pediatr Dent 2017;10(4):373-378. PMID- 29403233 TI - Behavior of Lebanese Pediatricians regarding Children's Oral Health. AB - Aim: The aim of the study is to evaluate the behavior of Lebanese pediatricians regarding children's oral health. Materials and methods: A cross sectional study including 100 Lebanese pediatricians was performed. They answered 11 questions. Three variables were taken into consideration: The number of years in practice, the place and the type of practice. Results: The answers were tabulated according to the latter three subdivisions. 97.7% of pediatricians who have been practicing for more than 5years reported inquiring about whether a child is taking a milk/juice bottle overnight as compared to 76.9% of pediatricians who have been practicing for less than five years. The majority of pediatricians working in cities/big villages (98.9%) and 76.9% in small villages do look for cavities during oral examination. Discussion: Independently of the years in practice, the majority of pediatricians look for cavities and check the mucosa/ tongue during the oral examination. The results regarding dental examination revealed a significant difference between the pediatricians working in cities/big villages (98.9%) and those in small villages (76.9%). Regarding the frequent diagnosis of ECC, there is also a significant difference between pediatricians working in cities/ big villages (74.7%) and those working in small villages (46.2%). Conclusion: The behavior of the Lebanese pediatricians regarding children's oral health is not satisfactory. In their daily practice, pediatricians need to have more interaction with pediatric dentists and should take into consideration the AAP and AAPD recommendations.How to cite this article: Noueiri B, Nassif N, Bacho R. Behavior of Lebanese Pediatricians regarding Children's Oral Health. Int J Clin Pediatr Dent 2017;10(4):379-383. PMID- 29403234 TI - Conscious Sedation with Nitrous Oxide to control Stress during Dental Treatment in Patients with Cerebral Palsy: An Experimental Clinical Trial. AB - Introduction: Individuals with cerebral palsy (CP) often present with oral alterations that impact oral health and require dental treatment. Aim: This study aimed to evaluate the use of conscious sedation with nitrous oxide (N2O) to control stress during dental treatment in individuals with CP using as parameters: Venham score (VS), heart rate (HR), and respiratory rate (RR). Materials and methods: A total of 77 CP patients >3 years of age with a mean age of 11.8 (+/- 6.4) years were evaluated in a rehabilitation center. Stress control was measured at the following time points: T1 (presedation), T2 (induction), T3 (sedated patient), and T4 (end). Student's t-test, the Chi-squared test, analysis of variance (ANOVA), and the McNemar test were used. The significance level was 5%. Results: Sedation ranged between 10 and 60% N2O, with an average of 35.6% (+/ 10.4). The RR did not vary among the times (p = 0.12). The HR and VS varied significantly between times (p < 0.001), as significantly higher values of HR were observed at T1. Conclusion: Conscious sedation with N2O during dental care controls stress in CP patients, as verified by a decrease in HR, and does not promote respiratory depression. Higher concentrations of N2O are recommended for CP patients with tachycardia. Clinical significance: Sedation modifies behavior during dental procedures, facilitating patient collaboration.How to cite this article: Baeder FM, Silva DF, de Albuquerque ACL, Santos MTBR. Conscious Sedation with Nitrous Oxide to control Stress during Dental Treatment in Patients with Cerebral Palsy: An Experimental Clinical Trial. Int J Clin Pediatr Dent 2017;10(4):384-390. PMID- 29403235 TI - Management of Mandibular Angle Fracture in a 9-year-old with Miniplate and Monocortical Screws: A Clinical Challenge. AB - The main characteristic feature of the pediatric mandible is that of decreased dimension, which leads to compromises in the open reduction and internal fixation (ORIF). In the dental segment, the cervically bulbous short stature primary teeth might act an obstacle during the maxillomandibular fixation conventionally. An increased osteogenic potential of bones favors rapid consolidation and remodeling in the affected region. The mixed dentition of the ugly duckling stage adds more burden while stabilizing the fractured segments. The main goal of the clinician is to achieve and restore the facial appearance and function. Hereby, we present a clinical challenge depicting a 9-year-old male with mandibular angle fracture managed by miniplate and monocortical screws fixation. How to cite this article: Shunmugavelu K, Subramaniam K. Management of Mandibular Angle Fracture in a 9 year-old with Miniplate and Monocortical Screws: A Clinical Challenge. Int J Clin Pediatr Dent 2017;10(4):391-393. PMID- 29403236 TI - Complete Overlay Denture for Pedodontic Patient with Severe Dentinogenesis Imperfecta. AB - Dentinogenesis imperfecta (DI) is a hereditary condition that may affect both primary and permanent dentition and is characterized by abnormal dentin formation. The teeth may be discolored with chipping of enamel and, in untreated cases, the entire dentition may wear off to the gingiva. This may lead to the formation of abscesses, tooth mobility, and early loss of teeth. In the Indian population, DI is found to have an incidence of 0.09%. Treatment of DI should aim to remove infection, if any, from the oral cavity; restore form, function, and esthetics; and protect posterior teeth from wear for maintaining the occlusal vertical dimension. Treatment strategies should be selected based on the presenting complaint of the patient, patient's age, and severity of the problem. This case report presents the management of severe DI with tooth worn off until gingival level in a very young patient using complete overlay denture, which has not been reported earlier. How to cite this article: Syriac G, Joseph E, Rupesh S, Mathew J. Complete Overlay Denture for Pedodontic Patient with Severe Dentinogenesis Imperfecta. Int J Clin Pediatr Dent 2017;10(4):394-398. PMID- 29403237 TI - Acrylic Planas Direct Tracks for Anterior Crossbite Correction in Primary Dentition. AB - Anterior crossbite is one of the most common forms of malocclusion in sagittal relationship of maxilla and mandible. If not corrected at the earliest, it will cause restriction of normal growth and development of both the jaws. The incidence of anterior crossbite is 4 to 5% in primary dentition. Self-correction may occur at the transient dentition or permanent dentition stage, but treating it should be the first priority. Using either removable or fixed appliances is recommended for the correction, but it depends on the patient cooperation, treatment duration, and parent approval. In this case report, we have used planas direct tracks (PDTs) which helps the forward development of mandible and corrects the malocclusion. With two modifications to PDTs, one is using acrylic instead of composite. It is advantageous to both clinicians and parents by correcting the crossbite efficiently in short duration while taking less chair-side time for fabrication and being economical. How to cite this article: Devasya A, Ramagoni NK, Taranath M, Prasad KEV, Sarpangala M. Acrylic Planas Direct Tracks for Anterior Crossbite Correction in Primary Dentition. Int J Clin Pediatr Dent 2017;10(4):399-403. PMID- 29403238 TI - Is focal spinal cord "atrophy" an evidence of chronic spinal instability? PMID- 29403239 TI - Chiari malformation: Has the dilemma ended? AB - Chiari malformation as a clinical entity has been described more than hundred years ago. The concepts regarding pathogenesis, clinical features and management options have not yet conclusively evolved. Considering that a variety of treatment methods are being adopted to treat Chiari malformation is suggestive of the fact that confusion still reigns supreme in the minds of treating clinicians. Over the years, the understanding of Chiari malformation has changed from a disease process to a natural protective phenomenon and the treatment from decompression to fixation. PMID- 29403240 TI - Only spinal fixation as treatment of prolapsed cervical intervertebral disc in patients presenting with myelopathy. AB - Aim: An alternative form of surgical treatment of prolapsed cervical intervertebral disc in patients presenting with symptoms related to myelopathy is discussed. The treatment involved fixation of the affected spinal segments and aimed at arthrodesis. No direct manipulation or handling of the disc was done. Materials and Methods: During the period August 2010 to June 2017, 16 patients presenting with symptoms attributed to myelopathy and diagnosed to have prolapsed cervical intervertebral disc were surgically treated by spinal stabilization. There were 11 males and 5 females and their ages ranged from 20 to 66 years (average: 40.6 years). Apart from clinical and radiological indicators, the number of spinal segments that were stabilized depended on direct observation of facetal morphology, alignment, and stability. Surgery involved distraction fixation of facets using Goel facet spacer (8 patients), transarticular facetal fixation (5 patients) using screws or a combination of both facetal spacer, and transarticular screws (3 patients). Results: All patients had "remarkable" clinical improvement in the immediate postoperative period as assessed by visual analog scale, Goel's clinical grading, and Japanese Orthopedic Association scores. Follow-up ranged from 3 to 84 months (average: 50 months). The herniated disc regressed or disappeared at follow-up radiological assessment that ranged from 24 h to 3 months after surgery. Conclusions: Spinal segmental fixation aiming at arthrodesis with or without distraction of facets and without any direct surgical manipulation in the disc space or removal of the prolapsed portion of the disc can be considered in the armamentarium of the surgeon. PMID- 29403241 TI - Management of acute combined fractures of the atlas and axis: A retrospective study of two trauma centers. AB - Background: Management of combination fractures of the atlas and axis varies from nonoperative immobilization to selective early surgical intervention. In this study, we present our experience in managing these injuries. Materials and Methods: Electronic databases from two level 1 trauma centers were queried to identify all patients diagnosed with C1-C2 combination fractures from 2009 to present. Patient demographics, fracture characteristics, treatment modality, complications, Frankel scores, and fusion status were collected. Patients were separated into operative and nonoperative cohorts, and comparisons were made between the two groups. Results: Forty-eight patients were included, of which 19 received operative management and 29 were treated nonoperatively. The mean age was 76.1 and 75.3 years, respectively (P = 0.877). Frankel grade distribution was similar on presentation in both groups, with most being neurologically intact. C1 fractures of both the anterior and posterior arch were present in 41.2% patients undergoing fusions compared to 27.6% of patients treated nonoperatively. No significant differences in comorbidities, neurologic deficits, or radiographic measurements were observed across the two groups. Conclusions: This study demonstrates the variety of treatment strategies used for the management of combined C1-C2 fractures. Patients managed operatively tend to have both anterior and posterior C1 arch fractures, while patients managed nonoperatively tend to have either anterior or posterior arch fractures. In general, treatments should be tailored to patients' needs depending on the stability of the fractures, neurological state, and medical comorbidities. PMID- 29403242 TI - Multilevel cervical laminectomy and fusion with posterior cervical cages. AB - Context: Cervical spondylotic myelopathy (CSM) is a progressive disease that can result in significant disability. Single-level stenosis can be effectively decompressed through either anterior or posterior techniques. However, multilevel pathology can be challenging, especially in the presence of significant spinal stenosis. Three-level anterior decompression and fusion are associated with higher nonunion rates and prolonged dysphagia. Posterior multilevel laminectomies with foraminotomies jeopardize the bone stock required for stable fixation with lateral mass screws (LMSs). Aims: This is the first case series of multilevel laminectomy and fusion for CSM instrumented with posterior cervical cages. Settings and Design: Three patients presented with a history of worsening neck pain, numbness in bilateral upper extremities and gait disturbance, and examination findings consistent with myeloradiculopathy. Cervical magnetic resonance imaging demonstrated multilevel spondylosis resulting in moderate to severe bilateral foraminal stenosis at three cervical levels. Materials and Methods: The patients underwent a multilevel posterior cervical laminectomy and instrumented fusion with intervertebral cages placed between bilateral facet joints over three levels. Oswestry disability index and visual analog scores were collected preoperatively and at each follow-up. Pre- and post-operative images were analyzed for changes in cervical alignment and presence of arthrodesis. Results: Postoperatively, all patients showed marked improvement in neurological symptoms and neck pain. They had full resolution of radicular symptoms by 6 weeks postoperatively. At 12-month follow-up, they demonstrated solid arthrodesis on X rays and computed tomography scan. Conclusions: Posterior cervical cages may be an alternative option to LMSs in multilevel cervical laminectomy and fusion for cervical spondylotic myeloradiculopathy. PMID- 29403243 TI - Outcome of conservatively treated occipital condylar fractures - A retrospective study. AB - Introduction: Occipital condyle fracture (OCF) is rare. It may, however, pose a serious threat to the patient due to destabilization of the craniocervical junction. Correct diagnosis and effective treatment are essential to prevent long term complications. The aim of this study was to retrospectively investigate our current treatment program with focus on the functional outcome. Diagnosis and classification systems were evaluated for their usefulness in the clinical practice. Materials and Methods: We retrospectively reviewed all patients treated conservatively for an occipital condylar fracture from 2010 to 2015 at our department. Fracture classifications were performed according to three established systems. The patients were followed up with clinical examination and plain radiographs at weeks 2, 6, and 12 with the addition of a dynamic flexion extension X-ray at week 14. Results: Totally 24 patients met the inclusion criteria. One was lost to follow-up and two ended treatment before completing the full treatment program due to a clinical decision. Fracture displacement was neither detected nor was any neurological deficits observed. Most patients were pain free after 6 weeks. After 14 weeks' treatment, two patients still had neck pain; the rest were pain free. Conclusions: Our data suggest that twelve weeks' conservative treatment is not necessary for unilateral OCFs without atlanto occipital dissociation (AOD). We recommend 6 weeks of conservative treatment, with clinical control and flexion-extension radiographs before ending treatment. Plain radiography is of limited value in the clinical control of this fracture type. Anderson and Montesano and Tuli et al. classification systems fulfill an academic role. We found the classification system by Mueller et al. to be more helpful in everyday clinical practice. PMID- 29403244 TI - Occipitocervical fusion - An epidemiological drift experienced in an Irish tertiary spinal referral center: Twenty-year follow-up study. AB - Background: Occipitocervical disease is common in the elderly population, and is on the rise due to an increasingly aging population. Methods: We retrospectively reviewed all patients who underwent occipitocervical fusion in our institution over a 20 year period (1996-2016) at a tertiary spinal referral centre. Patients were divided in 2 groups. Group A included all patient who underwent OCF in the first decade between 1996 and 2005. Group B was all patients who underwent OCF in the second decade between 2006 and 2016. Results: A total of 23 patients underwent occipitocervical fusion between 1996 until 2016 at our institution. Instability secondary to Rheumatoid arthritis was the leading factor in group A, responsible for 43 percent of cases. In group B, trauma was the leading burden accounting for 44 percent of the cases. In contrast to Group A however, only 19 % of OCFs occurred secondary to RA in group B. Our fusion rate was 96 percent with a survival rate of 67 percent. Conclusion: We noticed a clear epidemiological drift in the cervical spine pathologies requiring OCF during the first and second decade of study period with an increase in prevalence of pathological fractures secondary to metastatic disease. In addition, a drop in rheumatoid cervical disease requiring OCF has been noted. PMID- 29403245 TI - Machined cervical interfacet allograft spacers for the management of atlantoaxial instability. AB - Background: The use of cervical interfacet spacers (CISs) to augment stability and provide solid arthrodesis at the atlantoaxial joint has not been studied in detail. The aim of this work is to report the outcomes with the use of machined allograft CISs at C1-2. Methods: A retrospective review of 19 patients who underwent an atlantoaxial fusion with the use of CISs was performed. All patients had instability documented with flexion and extension lateral radiographs. This instability was due to trauma, degenerative stenosis, symptomatic C1-2 arthropathy, and os odontoideum. Clinical and radiological outcomes were assessed. Fusion was determined based on a lack of hardware failure, absence of motion on flexion and extension plain X-ray films, and presence of bridging trabecular bone which was most often demonstrated by a computed tomography. Results: The mean age was 69.1 +/- 12.9 years. Eight patients had traumatic fractures, six patients had degenerative stenosis, two patients had C2 neuralgia due to C1-2 arthropathy, two patients had C1-2 ligamentous subluxation, and one patient had an unstable os odontoideum. The occiput or subaxial spine was included in the arthrodesis in 10 patients. Rib autograft was utilized in most patients. No patient had postoperative neurological worsening, malposition of hardware, or vertebral artery injury and there were no mortalities. The fusion rate was 95%. The mean follow-up was 12.1 +/- 5.5 months. Conclusions: CIS is a promising adjuvant for the treatment of atlantoaxial instability. PMID- 29403246 TI - Surgical management of C-type subaxial cervical fractures using cervical traction followed by anterior cervical discectomy and fusion within 12 h after the trauma. AB - Study Design: This was a retrospective cohort study. Objective: To report our 10 year experience of closed reduction using Crutchfield traction followed by anterior cervical discectomy and fusion within 12 h from injury for C-type subaxial cervical fractures (according to the AOSpine classification system). Methods: Clinical records and neuroimaging were retrospectively reviewed. Surgical details were provided. Results: A total of 22 patients were included in the study. The cervical fracture was diagnosed after whole-body computed tomography scan on admission in all cases. Crutchfield traction was applied within 1-5 h from the diagnosis. Surgery consisting of anterior microdiscectomy and fusion with interbody cage and plating was performed 6-12 h after traction positioning. Most patients (19, 86%) had spinal cord injury: 7 were Frankel A (31%), 3 Frankel B (14%), 6 Frankel C (27%), 3 Frankel D (14%), and 3 Frankel E (14%). No neurologic deterioration was observed after the treatment. In 10 cases (45%), neurological symptoms improved 1 year after the trauma. Two patients (10%) died for complication related to spinal cord transition or other organ damage. Conclusions: Early reduction gives the best chance of recovery for patients affected by C-type subaxial cervical fracture. Rapid traction is more often successful and safer than manipulation under anesthesia. After close reduction achieving, anterior microdiscectomy, cage, and plating implant seem to be safe and effective with a low rate of complications. PMID- 29403248 TI - Functional outcome in unstable Hangman's fracture managed with anterior approach: A prospective study. AB - Aim: To study the functional outcome in unstable Hangman s fracture managed with anterior decompression and stabilization with cervical locking plate and tricortical bone graft. Materials and Methods: Between 2010 and 2016, 44 patients (range: 19-75 years) with unstable Hangman's fracture underwent anterior decompression and stabilization with cervical locking plate and tricortical bone graft in our institution. Result: According to the Levine and Edwards classification, all patients were unstable with Type IA 6 (13.6), Type IIA 35 (79.5%), Type II (0), and Type III (6.8). The mean period of follow-up was 17 months (range: 6-48 months). Neurological recovery was observed in all nine patients. All patients were relieved from axial pain. None of the patients received blood transfusion. All patients showed solid fusion with no complication related to bone graft and plate. Conclusion: The anterior C2/C3 discectomy, fusion, and stabilization with cervical locking plate and tricortical bone graft are feasible and safe method in treating HangmanEs fracture, with the benefit of high primary stability, anatomical reduction, and direct decompression of the spinal cord. PMID- 29403247 TI - Perioperative complications in patients treated with posterior cervical fusion and bilateral cages. AB - Context: Posterior cervical cages have recently become available as an alternative to lateral mass fixation in patients undergoing cervical spine surgery. Aims: The purpose of this study was to quantify the perioperative complications associated with cervical decompression and fusion in patients treated with a posterior cervical fusion (PCF) and bilateral cages. Settings and Design: A retrospective, multicenter review of prospectively collected data was performed at 11 US centers. Subjects and Methods: The charts of 89 consecutive patients with cervical radiculopathy treated surgically at one level with PCF and cages were reviewed. Three cohorts of patients were included standalone primary PCF with cages, circumferential surgery, and patients with postanterior cervical discectomy and fusion pseudarthrosis. Follow-up evaluation included clinical status and pain scale (visual analog scale). Statistical Analysis Used: The Wilcoxon test was used to test the differences for the data. The P level of 0.05 was considered significant. Results: The mean follow-up interval was 7 months (range: 62 weeks - 2 years). The overall postsurgery complication rate was 4.3%. There were two patients with neurological complications (C5 palsy, spinal cord irritation). Two patients had postoperative complications after discharge including one with atrial fibrillation and one with a parietal stroke. After accounting for relatedness to the PCF, the overall complication rate was 3.4%. The average (median) hospital stay for all three groups was 29 h. Conclusions: The results of our study show that PCF with cages can be considered a safe alternative for patients undergoing cervical spine surgery. The procedure has a favorable overall complication profile, short length of stay, and negligible blood loss. PMID- 29403249 TI - "Soft that molds the hard:" Geometric morphometry of lateral atlantoaxial joints focusing on the role of cartilage in changing the contour of bony articular surfaces. AB - Purpose: The existing literature on lateral atlantoaxial joints is predominantly on bony facets and is unable to explain various C1-2 motions observed. Geometric morphometry of facets would help us in understanding the role of cartilages in C1 2 biomechanics/kinematics. Objective: Anthropometric measurements (bone and cartilage) of the atlantoaxial joint and to assess the role of cartilages in joint biomechanics. Materials and Methods: The authors studied 10 cadaveric atlantoaxial lateral joints with the articular cartilage in situ and after removing it, using three-dimensional laser scanner. The data were compared using geometric morphometry with emphasis on surface contours of articulating surfaces. Results: The bony inferior articular facet of atlas is concave in both sagittal and coronal plane. The bony superior articular facet of axis is convex in sagittal plane and is concave (laterally) and convex medially in the coronal plane. The bony articulating surfaces were nonconcordant. The articular cartilages of both C1 and C2 are biconvex in both planes and are thicker than the concavities of bony articulating surfaces. Conclusion: The biconvex structure of cartilage converts the surface morphology of C1-C2 bony facets from concave on concavo-convex to convex on convex. This reduces the contact point making the six degrees of freedom of motion possible and also makes the joint gyroscopic. PMID- 29403250 TI - Minimally invasive surgical treatment for Kimmerle anomaly. AB - Introduction: Kimmerle anomaly is the bony ridge between the lateral mass of atlas and its posterior arch or transverse process. This bony tunnel may include the V3 segment of the vertebral artery, vertebral vein, posterior branch of the C1 spinal nerve, and the sympathetic nerves, which results in the clinical symptoms of this disease. Reports on the surgical treatment of Kimmerle anomaly are rare. There are no reports on minimally invasive surgical treatment of this pathology. Materials and Methods: Six patients with Kimmerle anomaly were treated from 2015 until 2016. Three patients underwent routine surgery through the posterior midline (posterior midline approach [PMA] group). The other three patients underwent decompression with a paravertebral transmuscular approach (PTMA group). The operation time, intraoperative blood loss, clinical symptoms before and after surgery as well as intra- and post-operative complications were compared between the PTMA and PMA groups. Results: The results of the surgical treatments were assessed at discharge and 1 year later. Blood loss, operation time, and intensity of pain at the postoperative wound area were lower in the PTMA group. There were no postoperative complications. The delayed surgical treatment outcomes did not depend on the method of artery decompression. Conclusions: Surgical treatment of vertebral artery compression in patients with Kimmerle anomaly is preferable in cases where conservative treatment is inefficient. A minimally invasive PTMA is an alternative to the routine midline posterior approach, providing direct visualization of the compressed V3 segment of the vertebral artery and minimizing postoperative pain. PMID- 29403251 TI - Transoral screw and wire fixation for unstable anterior 1/2 atlas fracture. AB - Study Design: Atlas fractures are evaluated according to the fracture type and ligamentous injury. External immobilization may result in fracture nonunion. Objective: The ideal treatment method for non-stabilized atlas fractures is limited fixation without restricting the range of motion of the atlantoaxial and atlantooccipital joints. Summary of Background Data: Such a result can be established by using either anterior fixation or posterior lateral mass fixation. However, none of these techniques can fully address anterior 1/2 atlas fractures such as in this case. Materials and Methods: A transoral technique in which bilateral screws were placed intralaminarly and connected with wire was used to reduce and stabilize an anterior 1/2 fracture of C1. Result: Radiological studies after the surgery showed good cervical alignment, no screw or wire failure and good reduction with fusion of anterior arcus of C1. Conclusions: Internal immobilization by this screw and wire osteosynthesis technique protects the mobility of the atlanto-occipital and atlantoaxial joints. The main advantage is that neither the twisted wires inserted under the anterior lamina, nor the laterally placed screw heads interfere with midline wound closure; unlike the plate/cage and rod systems used together with anterior screws. A computer navigation system with intraoperative 3D imaging facilities will be of benefit for safe placement of the screw, however we preferred a free-hand technique, as the starting point was at the fracture line along the trajectory of the routinely accessible anterior lamina. PMID- 29403252 TI - Functional and radiological outcomes of thoracolumbar traumatic spine fractures managed conservatively according to Thoracolumbar Injury Severity Score. AB - Aim: To study the functional and radiological outcomes in cases managed conservatively for single-level traumatic thoracolumbar spine fractures without neurological deficit. Materials and Methods: In this prospective study design, thirty patients who presented to tertiary care hospital and diagnosed with posttraumatic thoracolumbar vertebral fracture without any neurodeficit were recruited. All the patients were managed conservatively as per the protocol which included bed rest, spinal braces, and physiotherapy. Adequate analgesia was given wherever necessary. The patients were followed at regular intervals up to a maximum of 2 years. Clinically visual analog scale (VAS) score and Roland Morris Disability Questionnaire (RMDQ)-24 were assessed and radiologically local vertebral kyphosis, scoliosis, and loss of body height were noted at each follow up. Results: The data was statistically analyzed and the results were as follows. Thoracolumbar fractures were more in young adults (<26 years) and more so among the males (80% cases). The most common fracture type in our study was compression fracture. The most common site involved in our study was L1 vertebra (36.7%). There was a significant decrease of VAS score (pain score) in 79% cases with the maximum decrease in type A1 fracture. The mean RMDQ-4 score in our study was 5.53. The overall progression of kyphosis was 1.9 degrees . There was no relation found between the kyphotic deformity and the clinical outcomes (VAS and RMDQ-24 scores). Canal size changes were found to be insignificant at the end of 2 years compared to baseline. Conclusion: Study showed favorable outcomes in terms of return to daily activities, making it a good option in managing Type A1 dorsolumbar fractures. Though there was a progression of kyphosis but no neurological deficit was seen. PMID- 29403253 TI - The importance of the occipitocervical area in patients with ankylosing spondylitis analysis of a cohort of 86 cervical fractures in surgically treated patients. AB - Study Design: This was a retrospective analysis of prospectively collected data. Objective: The effect of C0-C1-C2 cervical ankylosis in patients with ankylosing spondylitis (AS) is not documented. The objective of this study is to describe the radiological characteristics of the occipitocervical junction in patients with AS operated for a cervical fracture and to correlate them with their clinical evolution. Materials and Methods: Analysis of patients with ankylosing spondylitis (AS) treated in a single institution of a cervical vertebral fracture between 2007 and 2014 who were prospectively followed through the SWESPINE registry. The integrity of the C0-C1-C2 joints was determined and classified into fused and nonfused joints. By determining the angle between C0-C1 and C1-C2 joints in the coronal view of the computed tomography scan (X-angle), the progressive degeneration of these joints was described. Intra- and inter-observer reliability of this test was determined. The instruments of health-related quality of life (QOL) and disability were EQ5D and Oswestry disability index (ODI), respectively. Results: A total of 86 patients with AS treated surgically for cervical fracture had complete facet ankylosis between C3 and T1 due to their pathology. Mean age 69.2 years (standard deviation [SD]: 11.7). The most common level of fracture was in C5-C6. In 24 patients, the C0-C1 joint was fused, and in 15 patients, C1-C2 joint was fused. The intra- and inter-class reliabilities for X-angle measurement were very high (intraclass correlation coefficients = 0.94; 0.92). The mean X-angle was 125 degrees (SD: 12) in nonfused patients and 136 degrees (SD: 14) in fused patients (P < 0.001). There were no differences in QOL and disability at 2 years between the two groups: EQ5D-index of 0.54 and 0.55 (P = 0.5), ODI of 26.4 and 24, (P = 0.35) respectively. Conclusions: X-angle is a reliable measure for joint integrity C0-C1-C2 in patients with AS. Total cervical ankylosis including the C0-C1-C2 segments is not related to poorer QOL and disability in these patients. PMID- 29403254 TI - Primary dorsal spine primitive neuroectodermal tumor in an adult patient: Case report and literature review. AB - Primary spinal primitive neuroectodermal tumor (psPNET) is a rare entity with few cases reported in literature. We report a case of a 50-year-old female who presented to us with paraplegia and was diagnosed with extradural dorsal spine psPNET. The diagnosis was not suspected at presentation or on radiology but was established on histopathological examination. It is important to distinguish it from central nervous system primitive neuroectodermal tumors and from other spinal tumors since it follows a different clinical course and therapeutic outcome. PMID- 29403255 TI - Unusual cause of lumbar canal stenosis in 8th decade of life - Spinal epidural lipomatosis. AB - Spinal Epidural lipomatosis (SEL) is an uncommon condition, usually presents in young and middle aged patients, with male preponderance. Idiopathic SEL is rare, particularly in 8th decade of life. SEL should also be considered as a differential diagnosis in approach of elderly patient presenting with lumbar canal stenosis. Such a case of 77 year old man is presented here. PMID- 29403256 TI - Langerhans cell histiocytosis as an unusual cause of back pain in a child: A case report and review of literature. AB - Low back pain in children and adolescents are usually attributed to mechanical causes and faulty positions. Although most of them are self-limiting, physicians should be aware of the red flag signs that warrant complete evaluation to rule out malignant causes of back pain. As delay in the diagnosis of vertebral lytic lesion may have sequelae in the growing children, pain disproportionate to the signs should have low threshold levels for evaluation. We report a case of 6-year old boy who presented with worsening back pain. Initially evaluated for tuberculosis spine, he was diagnosed to have Langerhans cell histiocytosis of spine. He improved symptomatically with chemotherapy and spine orthosis and is in complete remission now. PMID- 29403257 TI - Idiopathic hypertrophic pachymeningitis as a rare cause of cervical compressive myelopathy. AB - The spinal form of idiopathic hypertrophic pachymeningitis (IHP) is a rare condition characterized by a chronic progressive diffuse inflammatory fibrosis of the dura mater, which may evolve to the compression of the spinal cord. We present a case report about IHP focusing on its features in magnetic resonance imaging, which are determined by an intradural extramedullary mass in the cervical spine showing hypointensity on T2-weighted images and peripheral enhancement, causing compression of the spinal cord. Histological analysis showed a nonspecific chronic inflammatory process in dense fibrous tissue. The patient had a good outcome after therapy with steroids. PMID- 29403258 TI - Easy method to simplify "freehand" subaxial cervical pedicle screw insertion. AB - Study Design: Technical note. Objectives: The objective of this study is to check out safety and rationality of standardized and fast tricks to select trajectory of subaxial cervical pedicle screw (SCPS) insertion, based on simple angles to bony landmarks. Materials and Methods: Stage 1 - Computed tomography (CT) morphometric analysis of C3-C7 vertebrae of ten patients with cervical degenerative diseases. Stage 2 - SCPS insertion in 6 cadavers, according to the developed technique (59 pedicle screws). Stage 3 - SCPS insertion in 6 patients, according to the developed technique (32 pedicle screws). Results: CT morphometric analysis showed that the average length of C3-C7 pedicle channels was 32 mm, the average angle between a pedicle axis and an axis of contralateral lamina - 180 degrees , the average angle between a pedicle axis and plane of a posterior surface of a lateral mass amounted to 90 degrees and the coordinates of an optimal entry point - 2 mm from a lateral edge and 2 mm from an upper edge of the lateral mass posterior surface. During the cadaveric study, 39 screws had a satisfactory position (66.1%), 7 screws permissible (11.9%), and 13 screws unacceptable (22%). During the clinical study, 26 screws (81.25%) had satisfactory position, 4 (12.5%) had permissible position, and 2 (6.25%) unacceptable position. Conclusion: Developed and clinically approved a method for simplicity SCPS insertion is relatively safe and cheap. No doubt, it requires further investigation, but the results of primary analysis allow us to recommend it to wide practical application. PMID- 29403259 TI - Toward Unified Control of a Powered Prosthetic Leg: A Simulation Study. AB - This brief presents a novel control strategy for a powered knee-ankle prosthesis that unifies the entire gait cycle, eliminating the need to switch between controllers during different periods of gait. A reduced-order Discrete Fourier Transformation (DFT) is used to define virtual constraints that continuously parameterize periodic joint patterns as functions of a mechanical phasing variable. In order to leverage the provable stability properties of Hybrid Zero Dynamics (HZD), hybrid-invariant Bezier polynomials are converted into unified DFT virtual constraints for various walking speeds. Simulations of an amputee biped model show that the unified prosthesis controller approximates the behavior of the original HZD design under ideal scenarios and has advantages over the HZD design when hybrid invariance is violated by mismatches with the human controller. Two implementations of the unified virtual constraints, a feedback linearizing controller and a more practical joint impedance controller, produce similar results in simulation. PMID- 29403261 TI - Maximum human objectively measured pharmacologically stimulated accommodative amplitude. AB - Purpose: To measure the maximum, objectively measured, accommodative amplitude, produced by pharmacologic stimulation. Methods: Thirty-seven healthy subjects were enrolled, with a mean age of 20.2+/-1.1 years, corrected visual acuity of 20/20, and mean spherical equivalent refraction (SER) =-0.83+/-1.60 diopters. For each subject, the right pupil was dilated with phenylephrine 10%. After 30 minutes, the pupil was measured, the left eye was patched, and the right eye was autorefracted. Pilocarpine 4% was then instilled in the right eye, followed by phenylephrine. At 45 minutes after the pilocarpine, autorefraction and pupil size were again measured. Results: Mean pupil size pre- and postpilocarpine was 8.0+/ 0.8 mm and 4.4+/-1.9 mm, respectively. Pre- and postpilocarpine, the mean SER was -0.83+/-1.60 and -10.55+/-4.26 diopters, respectively. The mean pilocarpine induced accommodative amplitude was 9.73+/-3.64 diopters. Five subjects had accommodative amplitudes >=14.00 diopters. Accommodative amplitude was not significantly related to baseline SER (p-value =0.24), pre- or postpilocarpine pupil size (p-values =0.13 and 0.74), or change in pupil size (p-value =0.37). Iris color did not statistically significantly affect accommodative amplitude (p value =0.83). Conclusion: Following topically applied pilocarpine, the induced objectively measured accommodation in the young eye is greater than or equal to the reported subjectively measured voluntary maximum accommodative amplitude. PMID- 29403260 TI - Evaluation of contrast sensitivity and other visual function outcomes in diabetic macular edema patients following treatment switch to aflibercept from ranibizumab. AB - Purpose: This study aims to investigate changes in contrast sensitivity (CS), visual acuity (VA), central retinal thickness (CRT), and vision-related quality of life in subjects with recalcitrant diabetic macular edema switched from long term ranibizumab treatment to aflibercept. Patients and methods: In this prospective, investigator-masked, single-center study, 40 patients with persistent fluid, despite previous ranibizumab treatment, were switched to aflibercept with 5 consecutive monthly doses. The primary outcome was mean change from baseline to week 20 in Pelli-Robson CS. Secondary outcomes were mean change from baseline in best-corrected VA (BCVA), CRT, and National Eye Institute 25 Item Visual Function Questionnaire score. Results: Fifty eyes (baseline VA >6/30) were evaluated. A median of 21.1+/-11.9 (range 5-55) ranibizumab injections were administered prior to initiation of aflibercept. Mean CS improved from 1.40+/ 0.14 log units at baseline to 1.46+/-0.15 log units at week 20 (P<0.001). VA improved with mean logarithm of the minimum angle of resolution BCVA of 0.33+/ 0.19 at baseline compared with logarithm of the minimum angle of resolution BCVA of 0.28+/-0.16 at week 20 (P=0.0016). Mean CRT decreased from 324+/-85 to 289+/ 61 um (P<0.001). Twenty-two (55%) patients experienced an overall improvement in National Eye Institute 25-Item Visual Function Questionnaire score. Interestingly, an association was found between changes in CS and change in CRT (r2=0.385, P<0.001) and between changes in BCVA and change in CRT (r2=0.092, P=0.032). Conclusion: Switching from ranibizumab to aflibercept in patients with recalcitrant diabetic macular edema resulted in an improvement in all measured metrics, including CS, VA, and CRT. A majority of patients also indicated an improvement in vision-related quality of life. The finding of a stronger relationship between changes in CRT and CS compared with changes in CRT and BCVA suggests that the inclusion of CS as an endpoint may yield a more complete understanding of visual outcomes than that obtained by using VA alone. PMID- 29403262 TI - Optical coherence tomography angiography in choroidal melanoma and nevus. AB - Synopsis: In optical coherence tomography angiography, the choroidal vascular flow rate in choroidal melanoma is significantly lower than that in choroidal nevus. Objective: The objective of this study was to describe the choriocapillaris and retinal features imaged by optical coherence tomography angiography (OCTA) in eyes with choroidal nevus from small malignant choroidal melanoma. Methods: In this retrospective, noninvasive, observational study, 11 patients diagnosed with small choroidal mass (five with choroidal nevus and six with malignant melanoma) who underwent dilated fundus examination, ocular ultrasonography and OCTA images were compared. Results: In choroidal nevus of all patients, OCTA demonstrated a hyporeflective mass with no significant deformity of choroidal vasculature and an intact retinal pigment epithelium (RPE)-Bruch's membrane complex. The flow void mass was surrounded by an intense vascular rim named as surface microvasculature (SMV) that had an approximately similar flow rate median of 63.68 mm2 (60.42-67.62 mm2), comparable with the median of the contralateral normal eye of 61.77 mm2 (60.42-64.53 mm2; P>0.09) for nevi. OCTA showed an obscured Bruch's membrane-RPE-Bruch's membrane complex and outer retinal layer in choroidal melanomas. Choriocapillaris flow rate over the melanomas was 55.73% (41.93%-60.82%), and the corresponding normal areas had a flow area of 62.75% (61.99%-63.10%; P=0.01). A flow rate difference between choroidal melanoma and nevus was significant (P=0.006). Axial and peripheral feeding vessels were more dilated and tortuous compared with benign nevi. Conclusion: Decreased flow rate of SMV of choroidal melanoma cases compared with nevi was a significant finding. Detection of characteristic vascular features of choroidal melanoma by OCTA could make OCTA an assuring diagnostic modality to differentiate malignant lesions. PMID- 29403263 TI - Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is the most common health care-acquired infection associated with high hospital expenditures. The incidence of subsequent recurrent CDI increases with prior episodes of CDI, 15%-35% risk after primary CDI to 35%-65% risk after the first recurrent episode. Recurrent CDI is one of the most challenging and a very difficult to treat infections. Standard guidelines provide recommendations on treatment of primary CDI. However, treatment choices for recurrent CDI are limited. Recent research studies have focused on the discovery of newer alternatives for prevention of recurrent CDI targeting prime virulence factors involved in C. difficile pathogenesis. Bezlotoxumab is a human monoclonal antibody directed against C. difficile toxin B. Multiple in vitro and in vivo animal studies have demonstrated direct binding of bezlotoxumab to C. difficile toxin B preventing intestinal epithelial damage and colitis. Furthermore, this monoclonal antibody mediates early reconstitution of gut microbiota preventing risk of recurrent CDI. Randomized placebo-controlled trials showed concomitant administration of a single intravenous dose of 10 mg/kg of bezlotoxumab, in patients on standard-of-care therapy for CDI, had no substantial effect on clinical cure rates but significantly reduced the incidence of recurrent CDI (~40%). It shows efficacy against multiple strains, including the epidemic BI/NAP1/027 strain. Bezlotoxumab is a US Food and Drug administration-approved, safe and well-tolerated drug with low risk of serious adverse events and drug-drug interactions. Bezlotoxumab has emerged as a novel dynamic adjunctive therapy for prevention of recurrent CDI. Further studies on real-world experience with bezlotoxumab and its impact in reducing rates of recurrent CDI are needed. PMID- 29403264 TI - Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice. AB - The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES) induced convulsions in mice having valproic acid (VPA) as a reference antiepileptic drug (AED). Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p.) of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p.) significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R)-alpha methylhistamine (RAMH, 10 mg/kg, i.p.). Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p.) or multiple doses (15*3 mg/kg, i.p.) of H3R antagonist 2-18 on gestation day (GD) 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg) on GD 8 induced a reduced number of live embryos when compared with the i.p.-treated mice. In addition, no significant changes in the fetal body and placental weights were observed after injection of H3R antagonist 2-18 with all selected doses. However, three dose groups of i.p. and oral 15 mg/kg on GD 13 significantly affected the placental weight when compared with control group. Notably, the treatment of pregnant female with the H3R antagonist 2-18 did not produce significant malformation in the fetus in both groups. In conclusion, the novel H3R antagonist 2-18 proves to be a very safe compound and displays a low incidence of malformations, demonstrating that H3R antagonist 2-18 may have a potential future therapeutic value in epilepsy. PMID- 29403266 TI - Motivational factors for initiating, implementing, and maintaining physical activity behavior following a rehabilitation program for patients with type 2 diabetes: a longitudinal, qualitative, interview study. AB - Aim: To explore motivational factors for initiating, implementing, and maintaining physical activity following a rehabilitation program for patients with type 2 diabetes mellitus. Methods: Semi-structured, individual, qualitative interviews with five informants from the InterWalk trial were conducted at three separate occasions; at initiation of the rehabilitation program, at completion of the 12-week program, and 52 weeks after enrolment. Interviews were audio recorded, transcribed, and analyzed according to Systematic Text Condensation. The framework of Self-Determination Theory was applied to guide analysis after identification of preliminary themes. Results: Commitment and obligation were emphasized as being motivational in initiating physical activity. Toward the termination of the program, this was challenged by an expressed need for autonomy. Successful behavioral change was characterized by transfer of commitment to a new structure in everyday life, which also honored the request for autonomy. Feeling capable of participating in physical activity was facilitated through knowledge, practical experience, and progress and considered motivational, whereas lack of progress extinguished motivation. Finally, enjoyment of the activity was determining for long-term maintenance of physical activity behavior. Conclusion: Satisfaction of innate psychological needs leads to more autonomous regulation of behavior and, through this study, we investigated determining factors for extrinsically motivated behavior and factors of importance to the internalization process. PMID- 29403265 TI - Bispecific antibodies: design, therapy, perspectives. AB - Antibodies (Abs) containing two different antigen-binding sites in one molecule are called bispecific. Bispecific Abs (BsAbs) were first described in the 1960s, the first monoclonal BsAbs were generated in the 1980s by hybridoma technology, and the first article describing the therapeutic use of BsAbs was published in 1992, but the number of papers devoted to BsAbs has increased significantly in the last 10 years. Particular interest in BsAbs is due to their therapeutic use. In the last decade, two BsAbs - catumaxomab in 2009 and blinatumomab in 2014, were approved for therapeutic use. Papers published in recent years have been devoted to various methods of BsAb generation by genetic engineering and chemical conjugation, and describe preclinical and clinical trials of these drugs in a variety of diseases. This review considers diverse BsAb-production methods, describes features of therapeutic BsAbs approved for medical use, and summarizes the prospects of practical application of promising new BsAbs. PMID- 29403267 TI - Assessment of medication adherence and responsible use of isotretinoin and contraception through Belgian community pharmacies by using pharmacy refill data. AB - Purpose: The aims of the study were to evaluate medication adherence and the influencing factors for isotretinoin and contraception (oral, patches, and rings) and to evaluate the concomitant use of contraception and isotretinoin. Methods: Reimbursed prescription data from January 2012 to August 2015 of all patients in Belgium were received from Pharmanet-National Institute for Health and Disability Insurance. Medication adherence was measured according to the medication possession ratio. The influence of gender and age was analyzed using the Mann Whitney test and the Spearman coefficient correlation. The independence between adherence to contraception and adherence to isotretinoin was analyzed using the Pearson chi-square test of independence. Persistence was defined as the number of days between initiation and presumed end of treatment. The Kaplan-Meier method was used to plot the medication persistence curves, and the log-rank test was used to compare the curves. The concomitant use of contraception and isotretinoin was analyzed using descriptive statistics. Results: The medication possession ratio was >=0.8 for 46.1% of patients receiving isotretinoin and for 74.0% of women using contraception. For isotretinoin, this percentage decreased as the number of attempts increased (29.8% for the second attempt and 19.8% for more than two attempts). Men seemed more adherent than women, and a weak negative correlation between adherence and age was observed. The adherence data of isotretinoin and contraception were independent. The median persistence for isotretinoin treatment was 139 days (interquartile range 71-209) and was higher for men. Among women between 12 and 21 years old taking isotretinoin, 63.8% received at least one contraceptive prescription. However, 15.7% of women taking isotretinoin adhered to the use of contraception 1 month before, during, and 1 month after treatment. Conclusion: Medication adherence to isotretinoin and contraception and compliance with the isotretinoin safety recommendation could be improved. Health service interventions, using pharmacy refill data, should be delivered to ensure patient safety and strict adherence to contraception when under isotretinoin treatment. PMID- 29403268 TI - Different doses of steroid injection in elderly patients with carpal tunnel syndrome: a triple-blind, randomized, controlled trial. AB - Background: Carpal tunnel syndrome (CTS) is commonly seen in elderly populations, in part due to increased presence of predisposing comorbidities as well as physiological changes. We aimed at comparing the effectiveness of different doses of steroid using the ultrasound-guided hydrodissection method in elderly patients with CTS. Methods: We conducted a prospective, triple-blind, randomized, controlled trial in elderly patients with CTS. Patients were allocated to one of three groups by simplified randomization. Groups I-III received 80 mg triamcinolone (2 mL) and 1 mL of 2% lidocaine; 40 mg triamcinolone (1 mL), 1 mL of 2% lidocaine, and 1 mL normal saline; and 1 mL of 2% lidocaine and 2 mL normal saline, respectively to make up to 3 mL volume. A wrist splint was then applied for support. Outcome measures included the visual analog scale (VAS) and the Boston Carpal Tunnel Questionnaire, and median motor and sensory nerve conduction and its sonographic inlet cross-sectional area were used as objective measures. All data were recorded at baseline and 2, 12, and 24 weeks after injection. The investigators, patients, and statistician were blinded to the treatment assignment. Results: In total, 161 patients were recruited without statistically significant demographic differences between the three groups. There were no statistically significant differences between groups in any outcome, with the exception of the median distal motor latency, which was greater in Group II at all three follow-up visits, and significant baseline VAS difference between Groups I and III. Conclusion: Hydrodissection with lidocaine and normal saline is as effective as hydrodissection with low- and high-dose steroid medication in elderly patients with CTS in this study, but further studies with matched baseline measures and also a sham group are suggested for definitive recommendation. PMID- 29403269 TI - High-speed jaw-opening exercise in training suprahyoid fast-twitch muscle fibers. AB - Purpose: This study was aimed to examine the effectiveness of a high-speed jaw opening exercise, which targets the contraction of fast-twitch muscle fibers, in improving swallowing function. Subjects and methods: Twenty-one subjects (mean age 74.0+/-5.7 years) with dysphagia-related symptoms, such as coughing or choking during eating, performed the exercise. None of the included subjects had neurological symptoms or history of surgery that could cause significant dysphagia. All subjects took regular meals, and maintained independent activities of daily life. The exercise schedule consisted of 3 sets of 20 repetitions each of rapid and maximum jaw-opening movement with a 10-second interval between sets. The exercise was performed twice daily for 4 weeks. Results: Following the intervention, there was a significant increase in the vertical position of the hyoid bone at rest. Furthermore, during swallowing, the elevation of the hyoid bone and the velocity of its movement and esophageal sphincter opening increased significantly while the duration of the hyoid elevation and the pharyngeal transit time reduced significantly. Conclusions: Our results demonstrated that high-speed jaw-opening exercise resulted in increased elevation velocity of the hyoid bone during swallowing, indicating its role in effectively strengthening the fast-twitch muscle fibers of suprahyoid muscles. Furthermore, since the rest position of the hyoid bone appeared to have improved, this exercise may be especially useful in elderly individuals with a lower position of the hyoid bone at rest and those with decreased elevation of the hyoid bone during swallowing, which are known to be associated with an increased risk of aspiration. PMID- 29403270 TI - Low back pain and gastroesophageal reflux in patients with COPD: the disease in the breath. AB - COPD is a worsening condition that leads to a pathologic degeneration of the respiratory system. It represents one of the most important causes of mortality and morbidity in the world, and it is characterized by the presence of associated comorbidity. This article analyzes gastroesophageal reflux disease (GERD) and low back pain (LBP) in patients with COPD and tries to produce anatomo-clinical considerations on the reasons of the presence of these comorbidities. The considerations of the authors are based on the anatomic functions and characteristics of the respiratory diaphragm that are not always considered, from which elements useful to comprehend the symptomatic status of the patient can be deduced, finally improving the therapeutic approach. The information contained in the article can be of help to the clinician and for physiotherapy, and to all health professionals who gravitate around the patient's care, improving the approach to the diaphragm muscle. PMID- 29403271 TI - Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease. AB - COPD is a significant cause of morbidity and mortality. In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation. Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy. In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention. In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13. The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions. We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. PMID- 29403272 TI - Impact of using the new GOLD classification on the distribution of COPD severity in clinical practice. AB - Objective: The objective of this study was to examine how COPD patients were classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry-based severity system and the distribution of COPD severity using the new GOLD 2011 assessment framework. Materials and methods: This was an observational, retrospective cohort study conducted in a single tertiary center on a prospective database, which aimed to evaluate the prevalence, incidence, severity, and comorbidities of COPD. Inclusion criteria were age >=40 years and COPD diagnosis according to GOLD 2007 classification. Clinical factors were compared between the categories in GOLD 2007 and 2011 groups by using the chi2 test for categorical data and the analysis of variance for continuous data. Results: In total, 420 COPD patients were included in the analysis. The distribution of patients into GOLD 2007 categories was as follows: 6.4% (n=27) of them were classified into subgroup I, 42.1% (n=177) into subgroup II, 37.9% (n=159) into subgroup III, and 13.6% (n=57) into subgroup IV. The distribution of patients into GOLD 2011 categories was as follows: 16.4% (n=69) of them were classified into subgroup A (low risk and fewer symptoms), 32.1% (n=135) into subgroup B (low risk and more symptoms), 21.6% (n=91) into subgroup C (high risk and fewer symptoms), and 29.7% (n=125) into subgroup D (high risk and more symptoms). After the application of the new GOLD 2011 (modified Medical Research Council [mMRC] system), 22% (n=94) of patients were upgraded to a higher level than their spirometry level, and 16.2% (n=68) of them were downgraded in their severity category, meaning that almost 40% of patients changed their severity assessment category. In total, 22% of patients in stage I were allocated to group B, and 35% of patients in stage IV were allocated to group C. Patients in stage III were the most frequently upgraded to a higher risk group (D), taking into account mMRC and exacerbation history. Conclusion: Classifying patients using the new GOLD 2011 criteria reallocated a relevant proportion of patients to a different risk category and identified larger proportions of patients in the mildest and more severe groups compared with GOLD 2007 classification. PMID- 29403273 TI - The clinical implication of serum cyclophilin A in patients with chronic obstructive pulmonary disease. AB - Background: Cyclophilin A (CyPA) is a secreted molecule that is regulated by inflammatory stimuli. Although inflammation has an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), little is known regarding the relationship between serum CyPA and COPD. Methods: Ninety-three COPD patients with acute exacerbation were enrolled in the study and were reassessed during the convalescence phase. Eighty-eight controls were matched for age, gender, body mass index, smoking index and comorbidity. The basic clinical information and pulmonary function of all participants were collected. Serum levels of CyPA and other inflammation indexes were further measured. Results: Serum CyPA was significantly increased in convalescent COPD patients compared to healthy controls, and further elevated in COPD patients with acute exacerbation. Serum CyPA positively correlated with serum interleukin-6, matrix metalloproteinase-9 and high-sensitivity C-reactive protein in both the exacerbation and convalescence phases of COPD. Furthermore, it negatively correlated with percent value of forced expiratory volume in 1 second (FEV1%) predicted and FEV1/forced vital capacity in convalescent COPD patients. Conclusion: These results suggest that serum CyPA can be used as a potential inflammatory biomarker for COPD and assessment of serum CyPA may reflect the severity of inflammation in COPD. PMID- 29403274 TI - Magnetic immunoassay using CdSe/ZnS quantum dots as fluorescent probes to detect the level of DNA methyltransferase 1 in human serum sample. AB - Background: DNA methyltransferase 1 (DNMT1), a dominant enzyme responsible for the transfer of a methyl group from the universal methyl donor to the 5-position of cytosine residues in DNA, is essential for mammalian development and closely related to cancer and a variety of age-related chronic diseases. DNMT1 has become a useful biomarker in early disease diagnosis and a potential therapeutic target in cancer therapy and drug development. However, till now, most of the studies on DNA methyltransferase (MTase) detection have focused on the prokaryote MTase and its activity. Methods: A magnetic fluorescence-linked immunosorbent assay (FLISA) using CdSe/ZnS quantum dots as fluorescent probes was proposed for the rapid and sensitive detection of the DNMT1 level in this study. Key factors that affect the precision and accuracy of the determination of DNMT1 were optimized. Results: Under the optimal conditions, the limit of detection was 0.1 ng/mL, the linear range was 0.1-1,500 ng/mL, the recovery was 91.67%-106.50%, and the relative standard deviations of intra- and inter-assays were respectively 5.45%-11.29% and 7.03%-11.25%. The cross-reactivity rates with DNA methyltransferases 3a and 3b were only 4.0% and 9.4%, respectively. Furthermore, FLISA was successfully used to detect the levels of DNMT1 in human serum samples, and compared with commercial enzyme-linked immunosorbent assay (ELISA) kits. The results revealed that there was a good correlation between FLISA and commercial ELISA kits (correlation coefficient r=0.866, p=0.001). The linear scope of FLISA was broader than ELISA, and the measurement time was much shorter than ELISA kits. Conclusion: These indicated that the proposed FLISA method was sensitive and high throughput and can quickly screen the level of DNMT1 in serum samples. PMID- 29403275 TI - Development of biocompatible and VEGF-targeted paclitaxel nanodrugs on albumin and graphene oxide dual-carrier for photothermal-triggered drug delivery in vitro and in vivo. AB - In this study, we performed the characterization and synthesis of biocompatible and targeted albumin and graphene oxide (GO) dual-carrier paclitaxel (PTX) nanoparticles for photothermal-triggered tumor therapy. PTX absorbed on GO nanosheets as cores were coated with human serum albumin (HSA), following surface conjugation with monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF; denoted as mAbVEGF) via polyethylene glycol linker to form targeted nanoparticles (PTX-GHP-VEGF). The spherical nanoparticles were 191+/-5 nm in size with good stability and biocompatibility. GO functioned as the first carrier and a near infrared absorber that can generate photothermal effects under 5-minute 808-nm laser irradiation to thermal trigger the release of PTX from the second carrier HSA nanoparticles. The mechanism of thermal-triggered drug release was also investigated preliminarily, in which the heat generated by GO induced swelling of PTX-GHP-VEGF nanoparticles which released the drugs. In vitro studies found that PTX-GHP-VEGF can efficiently target human SW-13 adrenocortical carcinoma cells as evaluated by confocal fluorescence microscopy as well as transmission electron microscopy, and showed an obvious thermal-triggered antitumor effect, mediated by apoptosis. Moreover, PTX-GHP-VEGF combined with near infrared irradiation showed specific tumor suppression effects with high survival rate after 100 days of treatment. PTX-GHP-VEGF also demonstrated high biosafety with no adverse effects on normal tissues and organs. These results highlight the remarkable potential of PTX-GHP-VEGF in photothermal controllable tumor treatment. PMID- 29403276 TI - Characterization of exosomes derived from Toxoplasma gondii and their functions in modulating immune responses. AB - Introduction: Exosomes are nanograde membrane-bound vesicles secreted from most cell types through the fusion of multivesicular bodies with plasma membranes. Some of these exosomes are well defined, and are known to have immunomodulatory properties as well as play critical roles in intercellular communications. In this study, we characterized the exosomes derived from Toxoplasma gondii and their functions in aspect of immune responses. Methods: T. gondii exosomes were isolated and identified using electron microscopy, nanoparticle tracking analysis, and Western blotting. The viability of macrophage RAW264.7 cells affected by exosomes was evaluated using a Cell Counting Kit (CCK-8). Then the uptake of T. gondii exosomes by RAW264.7 cells was detected by labeling with fluorescent dye PKH67. After exosomes stimulation, in vitro the production of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and IL-10 in RAW264.7 cells were investigated using enzyme-linked immunosorbent assay (ELISA). In immunized BALB/c mice, the antibodies, cytokines as well as the percentage of CD4+ and CD8+ T cells were determined using ELISA and flow cytometric analysis. Protective efficacy was evaluated by challenging intraperitoneally with tachyzoites of T. gondii. Results: We successfully isolated and characterized the exosomes derived from T. gondii. Functionally, the viability of macrophage RAW264.7 cells was significantly affected by exosomes at a high concentration (160 MUg/mL). The production of IL-12, TNF-alpha and IFN gamma in macrophage cells were increased, and the level of IL-10 was decreased. Furthermore, BALB/c mice immunized with T. gondii exosomes showed both humoral and cellular immune responses and also exhibited a prolonged survival time. Conclusion: T. gondii exosomes could modulate macrophage activation in vitro and trigger humoral and cellular immune responses and partial protection against acute parasite infection in mice, which suggested that exosomes may serve as a potential candidate against toxoplasmosis. PMID- 29403277 TI - Understanding the translocation mechanism of PLGA nanoparticles across round window membrane into the inner ear: a guideline for inner ear drug delivery based on nanomedicine. AB - Background: The round window membrane (RWM) functions as the primary biological barrier for therapeutic agents in the inner ear via local application. Previous studies on inner ear nano-drug delivery systems mostly focused on their pharmacokinetics and distribution in the inner ear, but seldom on the interaction with the RWM. Clarifying the transport mechanism of nanoparticulate carriers across RWM will shed more light on the optimum design of nano-drug delivery systems intended for meeting demands for their clinical application. Methods: The poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) encapsulating coumarin-6 were prepared by emulsifying solvent evaporation method. We utilized confocal laser scanning microscope (CLSM) in combination with transmission electron microscope to investigate the transport pathway of PLGA NPs in the RWM. Simultaneously, the concentration and time dependence of NPs across the RWM were also determined. The endocytic mechanism of NPs through this membrane interface was classically analyzed by means of various endocytic inhibitors. The intracellular location of NPs into lysosomes was evaluated using CLSM scanning microscope colocalization analysis. The Golgi-related inhibitors were employed to probe into the function of Golgi and endoplasmic reticulum (ER) in the discharge of NPs out of cells. Results: PLGA NPs were herein transported through the RWM of a sandwich-like structure into the perilymph via the transcellular pathway. NPs were internalized predominantly via macropinocytosis and caveolin-mediated endocytic pathways. After being internalized, the endocytosed cargos were entrapped within the lysosomal compartments and/or the endoplasmic reticulum/Golgi apparatus which mediated the exocytotic release of NPs. Conclusion: For the first time, we showed the translocation itinerary of NPs in RWM, providing a guideline for the rational fabrication of inner ear nanoparticulate carriers with better therapeutic effects. PMID- 29403279 TI - Failure to improve after ovarian resection could be a marker of recurrent ovarian teratoma in anti-NMDAR encephalitis: a case report. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a type of autoimmune encephalitis that can be paraneoplastic and usually responds to tumor resection and immunotherapy. More than 75% of patients with anti-NMDAR encephalitis fully recover or have only mild sequelae, whereas the remainder experience severe disability. It remains unknown why certain cases have refractory clinical disease courses. We report a case of anti-NMDAR encephalitis with bilateral ovarian teratomas who was refractory to tumor resection and early initiation of immunotherapy. During intensive care, immunohistochemical analyses of her cerebrospinal fluid showed persistently high reactivity of NMDAR antibody over time. Six months after the operation, pelvic computed tomography detected a recurrent ovarian teratoma. After total enucleation of the bilateral ovaries, with significant pathological findings of bilateral mature cystic teratomas, her clinical condition improved rapidly, paralleled by a decrease in anti-NMDAR reactivity. This case illustrates the need to keep considering why extensive treatment fails to influence the disease when we encounter patients with refractory anti-NMDAR encephalitis. Failure to improve after ovarian resection could be a marker of recurrent ovarian teratoma in anti-NMDAR encephalitis. PMID- 29403278 TI - Reflex epilepsy: triggers and management strategies. AB - Reflex epilepsies (REs) are identified as epileptic seizures that are consistently induced by identifiable and objective-specific triggers, which may be an afferent stimulus or by the patient's own activity. RE may have different subtypes depending on the stimulus characteristic. There are significant clinical and electrophysiologic differences between different RE types. Visual stimuli sensitive or photosensitive epilepsies constitute a large proportion of the RE and are mainly related to genetic causes. Reflex epilepsies may present with focal or generalized seizures due to specific triggers, and sometimes seizures may occur spontaneously. The stimuli can be external (light flashes, hot water), internal (emotion, thinking), or both and should be distinguished from triggering precipitants, which most epileptic patients could report such as emotional stress, sleep deprivation, alcohol, and menstrual cycle. Different genetic and acquired factors may play a role in etiology of RE. This review will provide a current overview of the triggering factors and management of reflex seizures. PMID- 29403280 TI - The impact of age of onset on amygdala intrinsic connectivity in major depression. AB - Background: Early-onset major depressive disorder (EO-MDD), beginning during childhood and adolescence, is associated with more illness burden and a worse prognosis than adult-onset MDD (AO-MDD), but little is known about the neural features distinguishing these subgroup phenotypes. Functional abnormalities of the amygdala are central to major depressive disorder (MDD) neurobiology; therefore, we examined whether amygdala intrinsic connectivity (IC) can differentiate EO-MDD from AO-MDD in a cohort of adult MDD patients. Subjects and methods: Twenty-one EO-MDD (age of onset <=18 years), 31 AO-MDD patients (age of onset >=19 years), and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (7 minutes). Amygdala seed-based resting state functional connectivity was compared between groups. Results: AO-MDD patients showed loss of inverse left amygdala-left dorsolateral prefrontal cortex IC and increased inverse left amygdala-left inferior parietal IC, compared to both HCs and EO-MDD. EO-MDD showed a switch from inverse to positive IC with right dorsomedial prefrontal cortex, compared to HCs and AO-MDD. This effect was removed when we controlled for illness burden. Conclusion: Alterations in amygdala IC with the default-mode network were specifically related to EO-MDD, whereas amygdala IC with executive cognitive control regions was preferentially disrupted in AO-MDD. Increased illness burden, an important clinical marker of EO MDD, accounted for its specific effects on amygdala IC. Brain imaging has the potential for validation of clinical subtypes and can provide markers of prognostic value in MDD patients. PMID- 29403281 TI - Metastatic leiomyosarcoma presenting as a lung mass with left atrial extension: case report and anesthetic management. AB - Introduction: Lung metastasis of leiomyosarcoma that protrudes into the left atrium is an extremely rare condition. Severe complications may occur that prominently increase the mortality during the perioperative period. Currently, the anesthetic management reports are limited and there is no generally acknowledged algorithm available. Case presentation: A 67-year-old man presented with cough and dyspnea for 10 days. Workup revealed bilateral pulmonary effusion. Transthoracic echocardiography showed a large mass in the left atrium. Urgent surgical resection under cardiopulmonary bypass was performed. We focused on oxygenation improvement and cardiac function management by applying protective ventilation with low positive end expiratory pressure, low dose inotropic agents, and other methods to maintain stable homeostasis. Results of biopsy established a diagnosis of metastatic leiomyosarcoma. Conclusion: We reported a case of metastatic leiomyosarcoma presenting as a lung mass with left atrial extension and anesthetic management during surgical resection. Treating acute heart failure and refractory hypoxemia was the key focus perioperatively. PMID- 29403282 TI - Two mutations in the thiazide-sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report. AB - Background: Gitelman syndrome (GS) is considered as the most common renal tubular disorder, and we report the first Romanian patient with GS confirmed at molecular level and diagnosed according to genetic testing. Patient and methods: This paper describes the case of a 27-year-old woman admitted with severe hypokalemia, slight hypomagnesemia, hypocalcemia, hypocalciuria, metabolic alkalosis, hyperreninemia, low blood pressure, limb muscle weakness, marked fatigue and palpitations. Family history revealed a consanguineous family with autosomal recessive transmission of GS with two cases over five generations. Results: Next generation sequencing technology detected two different homozygous mutations c.1805_1806delAT and c.2660+1G>A in the SLC12A3 gene, which encodes the thiazide sensitive NaCl co-transporter, confirmed by the Sanger method. Conclusion: Clinicians should be aware of the existence of GS, manage the condition properly and consider the risk of disease recurrence to the next generations. PMID- 29403283 TI - Exploring the characteristics, global distribution and reasons for retraction of published articles involving human research participants: a literature survey. AB - Aim: Article retraction is a measure taken by journals or authors where there is evidence of research misconduct or error, redundancy, plagiarism or unethical research. Recently, the retraction of scientific publications has been on the rise. In this survey, we aimed to describe the characteristics and distribution of retracted articles and the reasons for retractions. Methods: We searched retracted articles on the PubMed database and Retraction Watch website from 1980 to February 2016. The primary outcomes were the characteristics and distribution of retracted articles and the reasons for retractions. The secondary outcomes included how article retractions were handled by journals and how to improve the journal practices toward article retractions. Results: We included 1,339 retracted articles. Most retracted articles had six authors or fewer. Article retraction was most common in the USA (26%), Japan (11%) and Germany (10%). The main reasons for article retraction were misconduct (51%, n = 685) and error (14%, n = 193). There were 66% (n = 889) of retracted articles having male senior or corresponding authors. Of the articles retracted after August 2010, 63% (n = 567) retractions were reported on Retraction Watch. Large discrepancies were observed in the ways that different journals handled article retractions. For instance, articles were completely withdrawn from some journals, while in others, articles were still available with no indication of retraction. Likewise, some retraction notices included a detailed account of the events that led to article retraction, while others only consisted of a statement indicating the article retraction. Conclusion: The characteristics, geographic distribution and reasons for retraction of published articles involving human research participants were examined in this survey. More efforts are needed to improve the consistency and transparency of journal practices toward article retractions. PMID- 29403284 TI - Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. AB - In many health care systems globally, cancer care is driven by multidisciplinary cancer teams (MDTs). A large number of studies in the past few years and across different literature have been performed to better understand how these teams work and how they manage patient care. The aim of our literature review is to synthesize current scientific and clinical understanding on cancer MDTs and their organization; this, in turn, should provide an up-to-date summary of the current knowledge that those planning or leading cancer services can use as a guide for service implementation or improvement. We describe the characteristics of an effective MDT and factors that influence how these teams work. A range of factors pertaining to teamwork, availability of patient information, leadership, team and meeting management, and workload can affect how well MDTs are implemented within patient care. We also review how to assess and improve these teams. We present a range of instruments designed to be used with cancer MDTs - including observational tools, self-assessments, and checklists. We conclude with a practical outline of what appears to be the best practices to implement (Dos) and practices to avoid (Don'ts) when setting up MDT-driven cancer care. PMID- 29403285 TI - Progranulin modulates cholangiocarcinoma cell proliferation, apoptosis, and motility via the PI3K/pAkt pathway. AB - Progranulin (PGRN) is a growth factor normally expressed in rapidly cycling epithelial cells for growth, differentiation, and motility. Several studies have shown the association of PGRN overexpression with the progression of numerous malignancies, including cholangiocarcinoma (CCA). However, the underlying mechanisms on how PGRN modulates CCA cell proliferation and motility is not clear. In this study, we investigated the prognostic significance of PGRN expression in human CCA tissue and the mechanisms of PGRN modulation of CCA cell proliferation and motility. We found that CCA tissues with high PGRN expression were correlated with poor prognosis and likelihood of metastasis. PGRN knockdown KKU-100 and KKU-213 cells demonstrated a reduced rate of proliferation and colony formation and decreased levels of phosphatidyl inositol-3-kinase (PI3K) and phosphorylated Akt (pAkt) proteins. Accumulation of cells at the G1 phase was observed and was accompanied by a reduction of cyclin D1 and CDK4 protein levels. Knockdown cells also induced apoptosis by increasing the Bax-to-Bcl-2 ratio. Increased cell apoptosis was confirmed by annexin V-FITC/PI staining. Moreover, suppression of PGRN reduced CCA cell migration and invasion in vitro. Investigating the biomarkers in epithelial-mesenchymal transition (EMT) revealed a decrease in the expression of vimentin, snail, and metalloproteinase-9. In conclusion, our findings imply that PGRN modulates cell proliferation by dysregulating the G1 phase, inhibiting apoptosis, and that it plays a role in the EMT affecting CCA cell motility, possibly via the PI3K/pAkt pathway. PMID- 29403286 TI - Biosimilar filgrastim vs filgrastim: a multicenter nationwide observational bioequivalence study in patients with chemotherapy-induced neutropenia. AB - Background: We studied the comparative effectiveness of biosimilar filgrastim vs original filgrastim in patients with chemotherapy-induced neutropenia. Patients and methods: This multicenter, observational study was conducted at 14 centers. The study included 337 patients experiencing neutropenia under chemotherapy. Patients were given either filgrastim 30 MIU or 48 MIU (Neupogen(r)) or biosimilar filgrastim 30 MIU (Leucostim(r)). Data regarding age, chemotherapeutic agents used, number of chemotherapy courses, previous diagnosis of neutropenia, neutrophil count of patients after treatment, medications used for the treatment of neutropenia, and duration of neutropenia were collected. Time to absolute neutrophil count (ANC) recovery was the primary efficacy measure. Results: Ambulatory and hospitalized patients comprised 11.3% and 45.1% of the enrolled patients, respectively, and a previous diagnosis of neutropenia was reported in 49.3% of the patients, as well. Neutropenia occurred in 13.7% (n=41), 45.5% (n=136), 27.4% (n=82), 11.4% (n=34), and 2.0% (n=6) of the patients during the first, second, third, fourth, and fifth cycles of chemotherapy, respectively. While the mean neutrophil count was 0.53+/-0.48 before treatment, a significant increase to 2.44+/-0.66 was observed after treatment (p=0.0001). While 90.3% of patients had a neutrophil count <1.49 before treatment, all patients had a neutrophil count >=1.50 after treatment. Neutropenia resolved within <=4 days of filgrastim therapy in 60.1%, 56.7%, and 52.6% of the patients receiving biosimilar filgrastim 30 MIU, original filgrastim 30 MIU, and original filgrastim 48 MIU, respectively. However, there was no significant difference between the three arms (p=0.468). Similarly, time to ANC recovery was comparable between the treatment arms (p=0.332). Conclusion: The results indicate that original filgrastim and biosimilar filgrastim have comparable efficacy in treating neutropenia. Biosimilar filgrastim provides a valuable alternative; however, there is need for further studies comparing the two products in different patient subpopulations. PMID- 29403287 TI - Long noncoding RNA H19 promotes transforming growth factor-beta-induced epithelial-mesenchymal transition by acting as a competing endogenous RNA of miR 370-3p in ovarian cancer cells. AB - Ovarian cancer is a gynecological malignant tumor with a high mortality rate among women, owing to metastatic progression and recurrence. Acquisition of invasiveness is accompanied by the loss of epithelial features and a gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). Transforming growth factor-beta (TGF-beta) has been implicated in the regulation of EMT. In the present study, we aimed to investigate the role of long noncoding RNA H19 and microRNA-370 (miR-370-3p) in TGF-beta-induced EMT. Ovarian cancer cell lines SKOV-3 and OVCAR3 were incubated with different concentrations of TGF-beta, and the results showed that TGF-beta treatment upregulated H19 and downregulated miR-370-3p. In addition, an H19 knockdown or miR-370-3p overexpression suppressed TGF-beta-induced EMT, while H19 overexpression or a miR 370-3p knockdown promoted TGF-beta-induced EMT. Mechanistically, H19 could directly bind to miR-370-3p and effectively act as its competing endogenous RNA. Furthermore, we demonstrated that this activity of H19 was involved in its promotion of TGF-beta-induced EMT. Thus, our results may provide novel insights into the process of TGF-beta-induced EMT. PMID- 29403288 TI - Overexpression of LBH is associated with poor prognosis in human hepatocellular carcinoma. AB - Purpose: Limb-bud and heart (LBH) levels are correlated with adverse survival in several malignancies; however, their significance in hepatocellular carcinoma (HCC) remains unclear. The objective of this study was to determine the association between LBH status and clinical outcomes. Methods: We selected 226 patients with HCC who were treated surgically between 2003 and 2010 at a single academic center. Immunohistochemistry (IHC) was used to detect the protein expression of LBH in HCC samples. Receiver operating characteristic (ROC) curve analysis, Spearman's rank correlation, Kaplan-Meier plots, and the Cox proportional hazards regression model were used to analyze the data. Results: A high expression of LBH was detected in 20 (8.8%) of 226 HCC samples. Correlation analysis demonstrated that LBH in HCC was significantly correlated with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels and clinical stages (P<0.05). In the Kaplan-Meier analysis, the mean survival time of patients with low levels of LBH was longer than that for those with high levels of LBH (P<0.05). The 3-year overall survival rate was 20% for patients with HCC and high levels of LBH versus 67% for patients with HCC and low levels of LBH. In the multivariate analysis, AST/ALT level, clinical stage, tumor relapse, and the level of LBH were the independent prognostic factors for overall survival (P<0.05). Conclusion: Overexpression of LBH might contribute to the development and progression of HCC. LBH could be a novel prognostic marker for HCC. PMID- 29403289 TI - Association of clinicopathologic characteristics and outcomes with EZH2 expression in patients with breast cancer in East Azerbaijan, Iran. AB - Background: Recently, it was found that the overexpression and mutation status of EZH2 affect cancer progression and patient outcome in several human tumors. We aimed to evaluate the clinicopathologic significance of EZH2 in patients with breast cancer. Methods: This was an analytical descriptive study of surgical specimens of primary breast tumors. Specimens were analyzed immunohistochemically for EZH2, estrogen receptor, progesterone receptor, Ki-67, P53, and human epidermal growth factor receptor 2 (HER2) expressions. Regression analysis was performed to calculate hazard ratios (HRs) and 95% CIs. Kaplan-Meier and Cox regression models were used to estimate the overall survival (OS) and disease free survival (DFS). Results: We included 100 patients with breast cancer (mean age 51.05+/-9.54 years). The multivariate regression analysis showed that HER2 positive patients had approximately twice the levels of EZH2 expression compared with HER2-negative patients (HR 2.16, 95% CI 0.48-11.49). The likelihood of EZH2 expression was significantly higher in patients with lymph node involvement than in those without (HR 8.44, 95% CI 3.06-23.33; P<=0.05). EZH2 expression did not have any significant effect on the OS, although the mean OS in high EZH2 expression was shorter than for those with low EZH2 expression (655 vs 787 days; log-rank P=0.336). The mean DFS was 487 days for patients with high EZH2 expression compared with 908 days for those with low EZH2 expression (log-rank P=0.188). Conclusion: There was no association found between EZH2 expression and OS and DFS in our patients. Further studies involving larger sample sizes, and conducted in different populations, are needed to validate this hypothesis. PMID- 29403290 TI - Apatinib-treated advanced medullary thyroid carcinoma: a case report. AB - Medullary thyroid carcinoma (MTC) is a rare malignancy originating from calcitonin-producing parafollicular C cells of the thyroid. Neither radiotherapy nor chemotherapy has demonstrated durable objective responses in patients with advanced MTC. Vandetanib and cabozantinib are the 2 tyrosine kinase inhibitors recently approved by the US Food and Drug Administration, which are not affordable for most Chinese patients. Herein, we report a case of an MTC patient who responded to apatinib, a Chinese homemade tyrosine kinase inhibitor-targeted vascular endothelial growth factor receptor. The patient was treated with thyroid lobectomy but developed MTC with extensive metastasis. The levels of serum calcitonin and carcino-embryonic antigen were much higher than the normal range. Apatinib was given at a dose of 500 mg daily and adjusted according to tolerance. Sixteen weeks following apatinib administration, the patient achieved a partial response, which lasted more than 9 weeks. No severe toxicity or drug-related side effect was observed during the treatment. Therefore, apatinib could be a new option for the treatment of advanced MTC. PMID- 29403291 TI - Subsequent anti-VEGF therapy after first-line anti-EGFR therapy improved overall survival of patients with metastatic colorectal cancer. AB - Colorectal cancer is one of the leading causes of cancer deaths worldwide. Due to targeted therapy, overall survival (OS) of metastatic colorectal cancer (mCRC) patients has been significantly increased over the past decade. However, the best sequencing of the therapeutic agents to be used in RAS wild-type subgroup is still under research. To determine the efficacy of targeted therapy, we collected randomized controlled trials which included patients receiving anti-epidermal growth factor receptor (EGFR) monoclonal antibody as first-line therapy in RAS/KRAS wild-type mCRC. In our study, we found that OS was significantly improved by anti-vascular endothelial growth factor (VEGF) agent after first-line anti-EGFR therapy. Our results revealed that it is a sensible treatment strategy to try anti-VEGF agent after first-line combination therapy with anti-EGFR monoclonal antibody for RAS/KRAS wild-type mCRC. PMID- 29403292 TI - Homeobox C10 knockdown suppresses cell proliferation and promotes cell apoptosis in osteosarcoma cells through regulating caspase 3. AB - Aim: Homeobox (HOX) genes and their protein products have been found to function as oncogenes in the progression of many cancers. But the role of Homeobox C10 (HOXC10) in osteosarcoma (OS) still remains less understood. In this study, we firstly determine the biologic functions of HOXC10 in OS. Materials and methods: We examined the expression of HOXC10 in OS tissues by quantitative real-time polymerase chain reaction and Western blot assays. We investigated the effects of HOXC10 on cell proliferation, apoptosis and caspase 3 activity in three OS cell lines by RNA interference, Cell Counting Kit-8, flow cytometry and colorimetric assays. Results: We found that HOXC10 was elevated in OS tissues. Silencing HOXC10 significantly inhibited cell proliferation, induced cell apoptosis and increased the expression and activity of caspase 3. The resistance assay further suggested that HOXC10 affected cell growth and apoptosis through regulating the expression and activity of caspase 3. Conclusion: HOXC10 might function as an oncogene in OS by regulating the expression and activity of caspase 3. PMID- 29403293 TI - Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. AB - Prolonged vancomycin usage may cause methicillin-resistant Staphylococcus aureus to become vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA). Mechanisms of vancomycin resistance of VISA and hVISA are still unclear. In this study, analyses of nucleotide sequence variations in 30 vancomycin sensitive S. aureus (VSSA), 41 hVISA and 16 VISA isolates revealed 29 single nucleotide variations in 12 genes (fmtC, graR, graS, htrA, mecA, pbp2, pbp4, srtA, tcaA, upps, vicK and vraR) that are related to cell wall synthesis or the two-component system. Six of these 29 single-nucleotide variations were novel and resulted in the following amino acid changes: Q692E in FmtC; T278I, P306L and I311T in HtrA; and I63V and K101E in Upps. Since P306L and I311T in HtrA and I63V in Upps were present in the majority (76.7%-86.7%) of VSSA isolates, these three amino acid variations may not be associated with vancomycin resistance. The other three amino acid variations (T278I in HtrA, K101E in Upps and Q692E in FmtC) were present in the majority (87.5%-93.8%) of hVISA and VISA isolates, but only in a small number (22.9%-25.7%) of VSSA isolates, suggesting that they are associated with vancomycin resistance. PMID- 29403294 TI - Timing of antibiotic administration and lactate measurement in septic shock patients: a comparison between hospital wards and the emergency department. AB - Background: The timing of intravenous antibiotic administration and lactate measurement is associated with survival of septic shock patients. Septic shock patients were admitted to the medical intensive care unit (MICU) from 2 major sources: hospital ward and emergency department (ED). This study aimed to compare the timing of antibiotic administration and lactate measurement between hospital wards and the ED. Patients and methods: Medical data were collected from adult patients admitted to the MICU with septic shock from January 2015 to December 2016. "Time Zero" was defined as the time of diagnosis of sepsis. The associations between the times and risk-adjusted 28-day mortality were assessed. Results: In total, 150 septic shock patients were admitted to the MICU. The median time interval (hour [h] interquartile range [IQR]) from time zero to antibiotic administration was higher in patients from the hospital wards compared to those from the ED (4.84 [3.5-8.11] vs 2.04 [1.37-3.54], P<0.01), but the lactate level measurement time interval (h [IQR]) from time zero was not different between the hospital wards and the ED (1.6 [0.2-2.7] vs 1.6 [0.9-3.0], P=0.85). In multivariate analysis, higher risk-adjusted 28-day mortality was associated with antibiotic monotherapy (odds ratio [OR]: 19.3, 95% confidence interval [CI]: 2.4-153.1, P<0.01) and admission during the weekends (OR: 24.4, 95% CI: 2.9-199.8, P<0.01). Conclusion: Antibiotic administration in septic shock patients from the hospital wards took longer, and there was also less appropriate antibiotic prescriptions seen in this group compared with those admitted from the ED. However, neither the timing of antibiotic administration nor lactate measurement was associated with mortality. PMID- 29403295 TI - Knowledge of community pharmacists about antibiotics, and their perceptions and practices regarding antimicrobial stewardship: a cross-sectional study in Punjab, Pakistan. AB - Objective: To evaluate the knowledge of community pharmacists about antibiotics, and their perceptions and practices toward antimicrobial stewardship (AMS) in Punjab, Pakistan. Materials and methods: A descriptive cross-sectional study was conducted among community pharmacists in Punjab, Pakistan from April 1, 2017 to May 31, 2017. A self-administered and pretested questionnaire was used for data collection. A simple random-sampling method was used to select community pharmacies. Independent-sample Mann-Whitney U tests, independent sample Kruskal Wallis tests, and logistic regression analysis were performed with SPSS version 21.0. Results: Of the 414 pharmacists, 400 responded to the survey (response rate 96.6%). The participants had good knowledge about antibiotics. They showed positive perceptions, but poor practices regarding AMS. All of the participants were of the view that AMS program could be beneficial for health care professionals for improvement of patient care, and 78% (n=312) of participants gave their opinion about incorporation of AMS programs in community pharmacies. Collaboration was never/rarely undertaken by pharmacists with other health care professionals over the use of antibiotics (n=311, 77.8%), and a significant proportion of participants (n=351, 87.8%) never/rarely participated in AMS awareness campaigns. Logistic regression analysis revealed that male sex (OR 0.204, 95% CI 0.104-0.4; P<0.001), age 20-29 years (OR 0.172, 95% CI 0.05-0.595; P=0.005), and <1 year of experience (OR 0.197, 95% CI 0.083-0.468; P<0.001) were the factors associated with poor practices regarding AMS. Conclusion: Pharmacists had good knowledge about antibiotics. There were some gaps in perceptions and practices of community pharmacists regarding AMS. In the current scenario, it will be critical to fill these gaps and improve perceptions and practices of community pharmacists regarding AMS by developing customized interventions. PMID- 29403296 TI - Pain associated with health and economic burden in France: results from recent National Health and Wellness Survey data. AB - Purpose: This study aimed to estimate the prevalence of pain among French adults and assess the impact of pain on health-related quality of life (HRQoL), activity impairment, and health care resource use (HRU). Patients and methods: Respondents from the 2015 France National Health and Wellness Survey (N=19,173) were categorized by self-reported pain (experienced pain in the past 12 months vs no pain) and compared on HRQoL (36-Item Short Form Health Survey version 2: Mental Component Summary, Physical Component Summary, and Short Form-6 Dimensions health utilities), activity impairment (Work Productivity and Activity Impairment questionnaire), employment status, and HRU (health care provider visits, emergency room visits, and hospitalizations). Bivariate analyses examined differences between pain groups stratified by age, sex, income, and Charlson comorbidity index (CCI) scores. Results: Pain prevalence was 20.2% (n=4007). Mean Physical Component Summary decrements with pain ranged from 3.4 to 8.1 points among those aged <35 years to those aged 45-54 years, respectively. Results for Mental Component Summary and Short Form-6 Dimensions scores followed similar patterns. Regardless of income, sex, or CCI group, pain was associated with significant decrements on all HRQoL measures (for all, p<0.05). The impact of pain on activity impairment was lowest among those <35 years; this impact was higher in middle age and then tapered off among those aged >=75 years. Pain was associated with greater activity impairment and more health care provider visits across income, sex, and CCI groups (for all, p<0.05). Generally, emergency room visits were more common among those with pain across age, sex, and CCI, but they were only significantly associated with pain in the lower income group (p<0.01). Pain was associated with significantly more hospitalizations across age and income groups. Conclusion: Results suggest pain negatively affects HRQoL, activity impairment, and HRU across demographic subgroups. These findings help underscore the considerable health and economic burden of pain in France. PMID- 29403297 TI - A cost-effectiveness analysis of varenicline for smoking cessation using data from the EAGLES trial. AB - Background: The cost-effectiveness of varenicline has been demonstrated in the US health care setting using the Benefits of Smoking Cessation on Outcomes (BENESCO) model to simulate the lifetime direct costs and consequences of a hypothetical cohort of US adult smokers who make a single attempt to quit. The aim of this study was to undertake an updated cost-effectiveness analysis, using current epidemiology inputs and recently published smoking cessation data from the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES), the largest clinical trial of smoking cessation pharmacotherapies conducted to date. Methods: BENESCO is a Markov model simulating the effect of a single attempt to quit smoking on four smoking-related diseases: coronary heart disease, stroke, chronic obstructive lung disease, and lung cancer. Inputs were updated to include efficacy from EAGLES and newer data for the epidemiology of smoking in the US, the epidemiology and direct treatment costs of the four morbidities, and the costs of the interventions. Analyses compared varenicline, bupropion, nicotine replacement therapy (NRT) patch, and placebo with regard to the incidence of smoking-related morbidity, the incidence of smoking-related mortality, and cost effectiveness at a time horizon from 2 years to lifetime. Results: The study cohort comprised of 18,394,068 US adult smokers who made a single quit attempt during the first year of the model. For varenicline, there were an estimated 319,730 fewer smoking-related morbidities at the lifetime compared with placebo. Similarly, smoking-related mortality decreased by 198,240 subjects when varenicline was compared with placebo. For the same time horizon, varenicline was more effective and less costly, ie, dominant, compared with all comparators in the cost-effectiveness analysis. Conclusion: Based on the BENESCO model, smoking cessation with varenicline results in reduced incidence of smoking-related morbidity and mortality compared with other smoking cessation interventions and remains a cost-effective strategy in the US population. PMID- 29403298 TI - The effect of oral clindamycin and rifampicin combination therapy in patients with hidradenitis suppurativa in Singapore. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory disease of follicular occlusion characterized by abscesses, draining sinuses, and scarring. The efficacy and tolerability of combination treatment with oral clindamycin and rifampicin have previously been assessed in 4 studies including groups of Caucasian patients. Overall results are promising with reported improvement rates between 71.4% and 85.7%. In this study, we propose that combination therapy is safe and efficacious in the treatment of HS, not only among Caucasians, but also in a group of Asian patients in Singapore. PMID- 29403299 TI - Ethnic/racial differences in gastrointestinal symptoms and diagnosis associated with the risk of Helicobacter pylori infection in the US. AB - Background: In the US, neither the prevalence nor the gastrointestinal (GI) diagnosis/symptoms associated with Helicobacter pylori (HP) have been examined in different racial/ethnic groups. Aim: To determine the racial/ethnic differences in HP infection associated with GI diagnoses/symptoms using the Cerner Health Facts(r) database. Methods: This cross-sectional study collected data during the period of 2000-2015 from the following ethnic/racial groups: 8,236,317 white, 2,085,389 black, 426,622 Hispanic, 293,156 Asian Pacific/Islander (APIs), and 89,179 Native American/Alaskan Native (NA/AN) patients aged 21-65 years old; the data were then analyzed. The primary dependent variable was a diagnosis of HP (ICD-9-Clinical Modification/ICD-10 classification). SAS version 9.4 was used for the statistical analysis. The statistical analysis was performed on 11,130,663 patients with GI symptoms, and of these, 152,086 patients were positive for the infection. Results: Hispanics and NA/ANs had the highest prevalence of HP associated with upper GI symptoms/diagnosis. Nevertheless, blacks and APIs presented the highest relative risk (RR) of HP associated with dyspepsia (RR [95% CI] =11.2 [10.7-11.9] and 14.2 [12.8-15.6]), peptic ulcer (RR =13.8 [13.3-14.5] and 10.7 [9.3-12.3]), and atrophic gastritis (RR =9 [8.5-9.6] and 7.4 [6.4-8.5]), respectively. In all racial/ethnic groups, HP was also associated with inflammatory bowel diseases, liver diseases, and celiac diseases. Conclusion: Black and API populations had the highest risk of HP associated with upper GI symptoms/diagnosis. Black patients also had the highest risk for HP associated with GI cancer. PMID- 29403300 TI - Association between IL-18/18R gene polymorphisms and coronary artery disease: influence of IL-18/18R genetic variants on cytokine expression. AB - Purpose: The present study investigated the influence of IL-18/18R genetic variants on cytokine expression in patients with stable coronary artery disease (CAD). Materials and methods: The polymorphisms rs1946518, rs187238, rs326, rs1169288, and rs183130 were determined in patients with and without CAD. Circulating cytokine levels were measured immunologically. Results: The rs1946518 GG genotype shows higher IL-18 concentration in the group with CAD, but still not significant. The TG genotype from rs1946518 in carriers with CAD showed a significant decrease in relation to the pro-inflammatory cytokines IL-6, IL-8, and IL-18. The decreases of IL-6 and IL-8 were also specific for rs187238 CAD carriers with the GC genotype. The CAD carriers with the AA genotype from rs326 in the IL-18R gene showed significant increase in IL-8 and IL-18 in comparison with those without CAD. Regarding rs1169288 from the IL-18R gene, IL-8 showed a T allele-dependent increase. In the last rs183130 polymorphism of the IL-18R gene, the pro-inflammatory onset showed a C allele-dependent disease-associated decrease in IL-8 CC and IL-6 CT carriers. In contrast, the CAD CT carriers in relation to IL-8 showed significant increase. Conclusions: Most of the IL-18/18R single-nucleotide polymorphisms were mainly associated with pro-inflammatory cytokines. It is surmised that these associations between some pro-inflammatory cytokines (mainly IL-8) and some IL-18R genotypes in the subjects with CAD from this study are most likely based on inflammatory-induced upregulation of IL-18R expression. PMID- 29403301 TI - Early exposure to distinct sources of lipids affects differently the development and hepatic inflammatory profiles of 21-day-old rat offspring. AB - Introduction: Maternal diet composition of fatty acids during pregnancy and lactation seems to modify the fetal programming, epigenetic pattern and offspring phenotype. Aim: Herein, we investigated the effects of maternal consumption of normal-fat diets with distinct lipid sources during pregnancy and lactation on the somatic development and proinflammatory status of 21-day-old rat offspring. Materials and Methods: On the first day of pregnancy, female Wistar rats were divided into four groups as follows: soybean oil (M-SO), lard (M-L), hydrogenated vegetable fat (M-HVF) and fish oil (M-FO). Diets were maintained during pregnancy and lactation. Male offspring constituted the SO, L, HVF and FO groups. Pups were weighed and measured weekly. Lipopolysaccharide serum concentration was determined. Tumor necrosis factor alpha, interleukin (IL)-6 and IL-10 in the liver were evaluated by enzyme-linked immunosorbent assay. Liver gene expressions were determined by real-time polymerase chain reaction. Protein expressions in the liver were analyzed by Western blotting. Results: We observed an increase in body weight and adiposity in L and HVF groups. Moreover, HVF group showed an increase in the toll-like receptor 4 mRNA levels, IL10Ralpha and phosphorylated form of IkappaB kinase (IKK; p-IKKalpha+beta) protein expression. The FO group presented a decrease in body weight, relative weight of retroperitoneal adipose tissue, ADIPOR2 gene expression, lipopolysaccharide and p-IKKalpha+beta and phosphorylated form of nuclear transcription factor kappa B (NFkappaB) p50 (p NFkappaB p50) protein expression. Conclusion: Summarily, whereas maternal intake of normal-fat diets based on L and HVF appear to affect the somatic development negatively, only early exposure to HVF impairs the pups' proinflammatory status. In contrast, maternal diets based on FO during pregnancy and lactation have been more beneficial to the adiposity and toll-like receptor 4 signaling pathway of the 21-day-old rat offspring, particularly when compared to L or HVF diets. PMID- 29403302 TI - Magnesium deficiency and increased inflammation: current perspectives. AB - Animal studies have shown that magnesium deficiency induces an inflammatory response that results in leukocyte and macrophage activation, release of inflammatory cytokines and acute-phase proteins, and excessive production of free radicals. Animal and in vitro studies indicate that the primary mechanism through which magnesium deficiency has this effect is through increasing cellular Ca2+, which is the signal that results in the priming of cells to give the inflammatory response. Primary pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin (IL)-1; the messenger cytokine IL-6; cytokine responders E selectin, intracellular adhesion molecule-1 and vascular cell adhesion molecule 1; and acute-phase reactants C-reactive protein and fibrinogen have been determined to associate magnesium deficiency with chronic low-grade inflammation (inflammatory stress). When magnesium dietary intake, supplementation, and/or serum concentration suggest/s the presence of magnesium deficiency, it often is associated with low-grade inflammation and/or with pathological conditions for which inflammatory stress is considered a risk factor. When magnesium intake, supplementation, and/or serum concentration suggest/s an adequate status, magnesium generally has not been found to significantly affect markers of chronic low-grade inflammation or chronic disease. The consistency of these findings can be modified by other nutritional and metabolic factors that affect inflammatory and oxidative stress. In spite of this, findings to date provide convincing evidence that magnesium deficiency is a significant contributor to chronic low grade inflammation that is a risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. Because magnesium deficiency commonly occurs in countries where foods rich in magnesium are not consumed in recommended amounts, magnesium should be considered an element of significant nutritional concern for health and well-being in these countries. PMID- 29403303 TI - The clinicopathological features of patients with membranous nephropathy. AB - Background: Membranous nephropathy (MN) represents a distinct glomerular disease which has been considered as a major cause of nephrotic syndrome (NS) in adults. Evidences show that the clinicopathological features of MN are various among MN cases. This study aimed to summarize and analyze the clinicopathological features of patients with MN. Methods: A total of 231 MN patients were recruited in this study. Their clinical and pathological features were collected and analyzed according to their age, gender, pathological stages, and anti-phospholipase A2 receptor (anti-PLA2R) antibodies tests. Results: Among the 231 MN cases, the ratio of male to female was 1.47 and the mean age was 47.43+/-14.32 years. Altogether, 163 (70.6%) cases were positive for NS. Their serum antiPLA2R, body mass index, total cholesterol, triglyceride, low density lipoprotein cholesterol, D2, IgA, and IgE were increased, but IgG was decreased. The majority of the patients were middle aged and old aged. In addition, the pathological stage was significantly correlated with gender (P=0.038), creatinine, (P=0.021) and IgE (P=0.003). A total of 74.9% MN patients were found to be positive for anti-PLA2R antibodies, and they were more likely to have abnormal serum indices. Conclusion: The major clinicopathological characteristics of MN patients are summarized in this study. Male and elder MN cases are likely to have rapid disease progression. Advanced pathological stages and being positive for anti-PLA2R antibodies may be potential indicators for disease activity of MN. PMID- 29403304 TI - In vitro biofilm formation by Staphylococcus aureus isolated from wounds of hospital-admitted patients and their association with antimicrobial resistance. AB - Introduction: Staphylococcus aureus including methicillin-resistant S. aureus (MRSA) has the propensity to form biofilms, and causes significant mortality and morbidity in the patients with wounds. Our aim was to study the in vitro biofilm forming ability of S. aureus isolated from wounds of hospitalized patients and their association with antimicrobial resistance. Materials and methods: Forty three clinical isolates of S. aureus were obtained from 150 pus samples using standard microbiological techniques. Biofilm formation in these isolates was detected by tissue culture plate (TCP) method and tube adherence method (TM). Antimicrobial susceptibility test was performed using the modified Kirby-Bauer disk diffusion method as per Clinical and Laboratory Standards Institute guidelines. MRSA was detected using the cefoxitin disk test. Results: Biofilm formation was observed in 30 (69.8%) and 28 (65.1%) isolates of S. aureus via TCP method and TM, respectively. Biofilm-producing S. aureus exhibited a higher incidence of antimicrobial resistance when compared with the biofilm nonproducers (P<0.05). Importantly, 86.7% of biofilm-producing S. aureus were multidrug resistant (MDR), whereas all the biofilm nonproducers were non-MDR (P<0.05). Large proportions (43.3%) of biofilm producers were identified as MRSA; however, none of the biofilm nonproducers were found to be MRSA (P<0.05). Conclusion: Both the in vitro methods showed that S. aureus isolated from wound infection of hospitalized patients have high degree of biofilm-forming ability. Biofilm producing strains have very high tendency to exhibit antimicrobial resistance, multidrug resistance and methicillin resistance. Regular surveillance of biofilm formation by S. aureus and their antimicrobial resistance profile may lead to the early treatment of the wound infection. PMID- 29403305 TI - Spotlight on topographical pressure pain sensitivity maps: a review. AB - Mechanical hyperalgesia defined as decreased pressure pain thresholds (PPTs) is commonly associated with pain. In this narrative review, we report the current state of the art within topographical pressure sensitivity maps. Such maps are based on multiple PPT assessments. The PPTs are assessed by an a priori defined grid with special focus on both spatial and temporal summation issues. The grid covers the muscle or the body region of interest using absolute or relative values determined from anatomical landmarks or anthropometric values. The collected PPTs are interpolated by Shepard or Franke and Nielson interpolation methods to create topographical pressure sensitivity maps. This new imaging technique has proven to be valuable in various disciplines including exercise physiology, neurology, physical therapy, occupational medicine, oncology, orthopedics, and sport sciences. The reviewed papers have targeted different body regions like the scalp, low back, neck-shoulder, and upper and lower extremities. The maps have delineated spatial heterogeneity in the pressure pain sensitivity underlining the different extents of pressure pain hyperalgesia in both experimentally induced and disease-associated pain conditions. Furthermore, various intervention studies have proven the utility of topographical pressure pain sensitivity maps. Topographical pressure pain sensitivity maps have contributed to revealing the efficacy of therapeutic, ergonomic, or training interventions that aim at reducing pain. PMID- 29403307 TI - The effects of black cohosh on the regulation of estrogen receptor (ERalpha) and progesterone receptor (PR) in breast cancer cells. AB - The North American plant Cimicifuga racemosa, also known as black cohosh (BC), is a herb that recently has gained attention for its hormonal effects. As the usage of hormone replacement therapy is declining due to its adverse effects in women with cancer, many are turning to herbal remedies like BC to treat menopausal symptoms. It is crucial to determine whether the effects of BC involve estrogen receptor-alpha (ERalpha). Previous studies from our laboratory have shown ERalpha to be a possible molecular target for BC. In this study, we examined the effects of BC (8% triterpene glycosides) alone and in combination with hormones and antihormones on the cellular viability, expression of ERalpha and progesterone receptor (PR)-A/B, and cytolocalization of ERalpha in ER (+) and PR-A/B (+) T-47D breast cancer cells. Cells were cultured and proteins were extracted and quantified. Western blot analysis revealed alterations in the expression of ERalpha and PR after treatment with BC (5-100 uM). BC induced a concentration dependent decrease in ERalpha and PR protein levels when compared to the control. Image cytometric analysis with propidium iodide staining was used to enumerate changes in T-47D cell number and viability. A decrease in T-47D cell viability was observed upon treatment with 5-100 uM BC. The ideal concentration of BC (100 uM) was used in combination with hormones and antihormones in an effort to further understand the possible similarities between this compound and other known effectors of ERalpha and PR. After a 24-hour concomitant treatment with and/or in combination of BC, estradiol, ICI 182, 780, and Tamoxifen, downregulation of ERalpha and PR protein levels was observed. Delineating the role of BC in the regulation of ERalpha, PR, as well as its mechanisms of action, may be important in understanding the influence of BC on hormone receptors in breast cancer. PMID- 29403306 TI - Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis. AB - In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5 fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy. PMID- 29403308 TI - The relationship between the PD-1/PD-L1 pathway and DNA mismatch repair in cervical cancer and its clinical significance. AB - Background: According to recent clinical observations, deficient DNA mismatch repair (dMMR) is capable of improving antitumor effects of the PD-1/PD-L1 pathway, suggesting that dMMR may act as a prognostic indicator of PD-1/PD-L1 antibody drugs. In this study, we examined the dMMR and PD-1/PD-L1 expression, as well as explored the correlation of dMMR status with PD-1/PD-L1 expression in cervical cancer patients, in order to optimize cervical cancer patient selection for PD-1/PD-L1 antibody drug treatment, which is helpful to avoid adverse effects and keep costs manageable. Methods: Sixty-six tissue samples from patients with squamous cell carcinoma were collected, and data of their clinical characteristics were also gathered. Based on these samples, the expression levels of MLH1, MSH2, and PD-L1 in cancer cells were tested by immunohistochemical assay (IHC). Moreover, PD-1/PD-L1 expression in tumor-invading lymphocytes (TILs) was detected by IHC as well. Six single-nucleotide-repeat markers of microsatellite instability (MSI), including NR-27, MONO-27, BAT-25, NR-24, NR-21, and BAT-26, were tested by capillary electrophoresis sequencer analysis. According to expression of MLH1, MSH2 and the MSI test, all 66 cases were divided into dMMR or proficient DNA mismatch repair (pMMR) groups. The comparisons of dMMR and PD-L1 in cancer cells and of PD-1/PD-L1 in TILs were conducted categorized by age, childbearing history, history of abortion, ethnicity, and cancer cell differentiation subgroup. Furthermore, PD-L1 levels in cancer cells and PD-1/PD L1 in TILs were analyzed and compared in both dMMR and pMMR subgroups. Results: Of the patient samples, 25.8% were associated with dMMR. PD-L1 in cancer cells, PD-L1 in TILs, and PD-1 in TILs took up 59.1%, 47.0%, and 60.6%, respectively. The data indicated that both dMMR and PD-L1 overexpression resulted from lower cancer differentiation, more incidences of childbearing, and a history of abortion. Abortion could significantly increase PD-1 expression levels in TILs. Additionally, more incidence of childbearing or older age (35-55 years) was able to upregulate PD-L1 expression in TILs. Statistical difference of PD-L1 in cancer cells could be observed between dMMR and pMMR subgroups. In the dMMR group, PD-L1 in cancer cells and PD-1 in TILs had no correlation (rs=0.161, p=0.537), but in the pMMR group, they had good correlation (rs=0.645, p<0.001). Conclusion: According to prior studies and our own experiments, PD-L1 in both cancer cells and TILs and PD-1 in TILs are widely observed in cervical cancer patients, indicating that there may be potential to apply PD-1/PD-L1 antibody drugs in cervical cancer. dMMR patients are associated with higher PD-L1 expression compared with pMMR ones, which suggested that PD-1/PD-L1 antibody drugs may work well in dMMR cervical cancer patients. Moreover, in patients with more incidences of childbearing or abortion, dMMR may be a molecular detection target for clinical application of PD-1/PD-L1 antibody drugs. PMID- 29403309 TI - A comparison of QuantStudioTM 3D Digital PCR and ARMS-PCR for measuring plasma EGFR T790M mutations of NSCLC patients. AB - Background: The AURA3 clinical trial has shown that advanced non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations in circulating tumor DNA (ctDNA) could benefit from osimertinib. Purpose: The aim of this study was to assess the usefulness of QuantStudioTM 3D Digital PCR System platform for the detection of plasma EGFR T790M mutations in NSCLC patients, and compare the performances of 3D Digital PCR and ARMS-PCR. Patients and methods: A total of 119 Chinese patients were enrolled in this study. Mutant allele frequency of plasma EGFR T790M was detected by 3D Digital PCR, then 25 selected samples were verified by ARMS-PCR and four of them were verified by next generation sequencing (NGS). Results: In total, 52.94% (69/119) had EGFR T790M mutations detected by 3D Digital PCR. In 69 positive samples, the median mutant allele frequency (AF) was 1.09% and three cases presented low concentration (AF <0.1%). Limited by the amount of plasma DNA, 17 samples (AF <2.5%) and eight samples (T790M-) were selected for verification by ARMS-PCR. Four of those samples were verified by NGS as a third verification method. Among the selected 17 positive cases, ten samples presented mutant allele frequency <0.5%, and seven samples presented intermediate mutant allele frequency (0.5% AF 2.5%). However, only three samples (3/17) were identified as positive by ARMS-PCR, namely, P6 (AF =1.09%), P7 (AF =2.09%), and P8 (AF =2.21%). It is worth mentioning that sample P9 (AF =2.05%, analyzed by 3D Digital PCR) was identified as T790M- by ARMS-PCR. Four samples were identified as T790M+ by both NGS and 3D Digital PCR, and typically three samples (3/4) presented at a low ratio (AF <0.5%). Conclusion: Our study demonstrated that 3D Digital PCR is a novel method with high sensitivity and specificity to detect EGFR T790M mutation in plasma. PMID- 29403310 TI - The role of brigatinib in crizotinib-resistant non-small cell lung cancer. AB - Despite the advances in new targeted therapies in ALK positive population, most patients progress under ALK inhibitors within first 2 years; being the brain the most frequent site of relapse. ALK mutations, in ~30% of patients, are the main known mechanism of resistance. Classically, second-generation ALK inhibitors have been the standard of care in the crizotinib-resistant population; however, each ALK inhibitor has a different spectrum of sensitivity to ALK mutations, complicating the optimal treatment strategy for the resistant population. Brigatinib (AP26113) is a novel highly selective and potent inhibitor of ALK and ROS1 with a high degree of selectivity. In vitro, brigatinib not only inhibited ALK with 12-fold higher potency compared to crizotinib, but also inhibited IGF 1R, FLT3 and EGFR mutants, with some activity against the EGFRT790M resistance mutation. In xenograft models, brigatinib overcomes resistance to ALK inhibitors, including the ALK G1202R mutation, which is resistant to first- and second generation inhibitors. The efficacy of brigatinib in crizotinib-resistant, ALK positive patients has been demonstrated in two early studies, which led to its approval in this setting, and it is currently being investigated as the first line therapy versus crizotinib in tyrosine kinase inhibitor-naive patients. Brigatinib demonstrates not only promising whole-body activity, but also an impressive improvement of intracranial outcomes in terms of both objective response rate and progression-free survival in the crizotinib-resistant population, with optimal efficacy at 180 mg (following a 90 mg run-in for 7 days) and good tolerance. These data confirm brigatinib as an excellent therapeutic strategy after crizotinib failure, particularly in the setting of central nervous system involvement. In this review, we summarize the two main clinical studies reported to date with brigatinib in ALK-positive advanced NSCLC patients, in particular, in the crizotinib-resistant population. We also address the mechanism of action for development of resistance and the challenging issues of optimal implementation for sequences of administration for ALK inhibitors. PMID- 29403311 TI - Radiation-induced secondary malignancies for nasopharyngeal carcinoma: a pilot study of patients treated via IMRT or VMAT. AB - Background: Patients treated with radiotherapy are at risk of developing a second cancer during their lifetime, which can directly impact treatment decision-making and patient management. The aim of this study was to qualify and compare the secondary cancer risk (SCR) after intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in nasopharyngeal carcinoma (NPC) patients. Patients and methods: We analyzed the treatment plans of a cohort of 10 NPC patients originally treated with IMRT or VMAT. Dose distributions in these plans were used to calculate the organ equivalent dose (OED) with Schneider's full model. Analyses were applied to the brain stem, spinal cord, oral cavity, pharynx, parotid glands, lung, mandible, healthy tissue, and planning target volume. Results: We observed that the OED-based risks of SCR were slightly higher for the oral cavity and mandible when VMAT was used. No significant difference was found in terms of the doses to other organs, including the brain stem, parotids, pharynx, submandibular gland, lung, spinal cord, and healthy tissue. In the NPC cohort, the lungs were the organs that were most sensitive to radiation induced cancer. Conclusion: VMAT afforded superior results in terms of organ-at risk-sparing compared with IMRT. Most OED-based second cancer risks for various organs were similar when VMAT and IMRT were employed, but the risks for the oral cavity and mandible were slightly higher when VMAT was used. PMID- 29403312 TI - Association between body mass index and breast cancer risk: evidence based on a dose-response meta-analysis. AB - Introduction: Breast cancer is the most common cancer in women worldwide. The association between body mass index (BMI) and breast cancer risk has been paid more attention in the past few years, but the findings are still controversial. To obtain a more reliable conclusion, we performed a dose-response meta-analysis on 12 prospective cohort studies comprising 22,728,674 participants. Methods: Linear and nonlinear trend analyses were conducted to explore the dose-response relationship between BMI and breast cancer risk. The summary relative risk (SRR) and 95% confidence intervals (CIs) were used to evaluate the cancer risk. Results: The overall results showed a weak positive association between a 5-unit increase in BMI and breast cancer risk, indicating that a 5 kg/m2 increase in BMI corresponded to a 2% increase in breast cancer risk (SRR: 1.02, 95% CI: 1.01 1.04, p<0.001). Notably, further subgroup meta-analysis found that higher BMI could be a protective factor of breast cancer risk for premenopausal women (SRR: 0.98, 95% CI: 0.96-0.99, p<0.001). In addition, the dose-response result demonstrated that there was a linear association between BMI and breast cancer risk (Pnonlinearity=0.754). Conclusion: In summary, this dose-response meta analysis of prospective cohort studies showed that every 5 kg/m2 increase in BMI corresponded to a 2% increase in breast cancer risk in women. However, higher BMI could be a protective factor in breast cancer risk for premenopausal women. Further studies are necessary to verify these findings and elucidate the pathogenic mechanisms. PMID- 29403313 TI - Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score. AB - Background and aim: Family history (FH) and genetic risk scores (GRSs) are increasingly used for risk stratification for colorectal cancer (CRC) screening. However, they were mostly considered alternatively rather than jointly. The aim of this study was to assess the potential of individual and joint risk stratification for CRC by FH and GRS. Patients and methods: A GRS was built based on the number of risk alleles in 53 previously identified single-nucleotide polymorphisms among 2,363 patients with a first diagnosis of CRC and 2,198 controls in DACHS [colorectal cancer: chances for prevention through screening], a population-based case-control study in Germany. Associations between GRS and FH with CRC risk were quantified by multiple logistic regression. Results: A total of 316 cases (13.4%) and 214 controls (9.7%) had a first-degree relative (FDR) with CRC (adjusted odds ratio [aOR] 1.86, 95% CI 1.52-2.29). A GRS in the highest decile was associated with a 3.0-fold increased risk of CRC (aOR 3.00, 95% CI 2.24-4.02) compared with the lowest decile. This association was tentatively more pronounced in older age groups. FH and GRS were essentially unrelated, and their joint consideration provided more accurate risk stratification than risk stratification based on each of the variables individually. For example, risk was 6.1-fold increased in the presence of both FH in a FDR and a GRS in the highest decile (aOR 6.14, 95% CI 3.47-10.84) compared to persons without FH and a GRS in the lowest decile. Conclusion: Both FH and the so far identified genetic variants carry essentially independent risk information and in combination provide great potential for CRC risk stratification. PMID- 29403314 TI - Guidance for using pilot studies to inform the design of intervention trials with continuous outcomes. AB - Background: A pilot study can be an important step in the assessment of an intervention by providing information to design the future definitive trial. Pilot studies can be used to estimate the recruitment and retention rates and population variance and to provide preliminary evidence of efficacy potential. However, estimation is poor because pilot studies are small, so sensitivity analyses for the main trial's sample size calculations should be undertaken. Methods: We demonstrate how to carry out easy-to-perform sensitivity analysis for designing trials based on pilot data using an example. Furthermore, we introduce rules of thumb for the size of the pilot study so that the overall sample size, for both pilot and main trials, is minimized. Results: The example illustrates how sample size estimates for the main trial can alter dramatically by plausibly varying assumptions. Required sample size for 90% power varied from 392 to 692 depending on assumptions. Some scenarios were not feasible based on the pilot study recruitment and retention rates. Conclusion: Pilot studies can be used to help design the main trial, but caution should be exercised. We recommend the use of sensitivity analyses to assess the robustness of the design assumptions for a main trial. PMID- 29403315 TI - High-potency statins but not all statins decrease the risk of new-onset osteoporotic fractures: a nationwide population-based longitudinal cohort study. AB - Background: Statins have been linked to new-onset osteoporotic fractures (NOFs), and different statins may alter the risk for the development of NOFs. Aim: In this study, we investigated the association between different statins and the development of NOFs. Patients and methods: This was a longitudinal cohort study performed using data from claim forms submitted to the Taiwan Bureau of National Health Insurance, including case patients with NOFs from January 2004 to December 2013 and non-NOF subjects. We estimated the hazard ratios (HRs) of NOFs associated with statin use. Nonuser subjects served as the reference group. Results: A total of 44,405 patients with NOFs were identified from among 170,533 patients with hyperlipidemia during the study period. The risk of developing NOFs after adjusting for age, sex, comorbidities, and concurrent medication use was lower among users of atorvastatin (HR, 0.77; 95% CI, 0.71-0.84) and rosuvastatin (HR, 0.72; 95% CI, 0.64-0.81) than among simvastatin users. Lovastatin, pravastatin, fluvastatin, and pitavastatin were not associated with the risk of developing NOFs compared with simvastatin users. Conclusion: This study supports previous reports regarding a beneficial effect of statin use and NOF risk, but not all statins. Patients taking atorvastatin or rosuvastatin were at lower risk of developing NOFs compared with simvastatin users during the 10-year follow-up. Other statins such as pravastatin, fluvastatin, lovastatin, and pitavastatin were not associated with NOFs. This study also highlighted that high-potency statin has a dose-response effect on lower NOF risk. PMID- 29403316 TI - Validation of modified World Health Organization classification for pregnant women with heart disease in a tertiary care center in southern Thailand. AB - Purpose: To validate the modified World Health Organization (WHO) classification in pregnant women with congenital and acquired heart diseases. Patients and methods: The database of pregnant women with heart disease, who delivered at Songklanagarind Hospital between January 1995 and December 2016, was retrieved from the Statistical Unit, Department of Obstetrics and Gynecology, along with the Hospital Information System of Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University. Each patient was retrospectively classified according to the modified WHO classification of maternal cardiovascular risk. Comparison of maternal and fetal outcomes among the modified WHO classes were analyzed using the chi-square test or Fisher's exact test and one-way ANOVA test. A p-value of <0.05 was considered statistically significant. Results: A total of 331 cases were studied: 157 cases with congenital heart disease and 174 cases with acquired heart disease. There were 48, 173, 32 and 78 cases in the modified WHO class I, II, III and IV, respectively. Congestive heart failure was the most common complication. The overall maternal mortality rate was 3.6%, all of which were in the modified WHO class IV. Maternal cardiovascular events occurred in 24.2% of cases, increasing rates with higher modified WHO class: 4.2%, 15.0%, 25.0% and 56.4% in class I, II, III and IV, respectively (p<0.001). Adverse fetal outcomes including preterm delivery, low birth weight, small for gestational age and neonatal intensive care unit admission were also significantly increased in class III and IV (p<0.05). Conclusion: The modified WHO classification is useful not only for obtaining a cardiovascular risk assessment in pregnant women with heart disease but also for predicting adverse fetal outcomes. It must, therefore, be implemented into routine care service at all levels of health care systems. PMID- 29403317 TI - Gender differences in dispensed analgesics in Sweden during 2006-2015 - an observational, nationwide, whole-population study. AB - Introduction: A potentially illuminating way of looking at gender differences in health and disease is to study differences in drug utilization. The aim of this study was to describe gender differences in dispensed analgesics (including nonsteroidal anti-inflammatory drugs [NSAIDs]) in Sweden during 2006-2015. Materials and Methods: The Swedish Board of Health and Welfare holds an open, Anatomical Therapeutic Chemical (ATC)-based statistical database containing aggregated data on all dispensed prescription drugs in Swedish pharmacies since 2006. The database is searchable according to sex, age (5-year intervals), and Swedish regions. Results: Nationwide, whole-population information was retrieved for all ATC codes at the second level for individuals >=20 years of age, focusing on sex-related differences. More in-depth analyses were made for analgesics, including NSAIDs. Descriptive statistics were used. Gender differences in drug prescription are pervasive in Sweden; the yearly prevalence in 2015 was higher in women for 72 out of 84 ATC groups (not adjusted for age). Analgesics, including NSAIDs, were more commonly used by women in all age groups. Gender differences were sustained over time (2006-2015) and were particularly striking for triptans. For both men and women, the yearly prevalence of opioids was stable during 2006 2015, whereas it increased for paracetamol and decreased for NSAIDs. The increase in paracetamol prescription was most noticeable for young females, and the decrease in NSAID prescription was largest in older patients (irrespective of sex). Conclusion: Gender differences in the use of analgesics probably mirror the higher prevalence of chronic pain in women. PMID- 29403318 TI - Cauliflower ear - a minimally invasive treatment method in a wrestling athlete: a case report. AB - Acute auricular hematoma can be caused by direct blunt trauma or other injury to the external ear. It is typically seen in those who practice full contact sports such as boxing, wrestling, and rugby. "Cauliflower ear" deformity, fibrocartilage formation during scarring, is a common complication of auricular hematomas. Therefore, acute drainage of the hematoma and postprocedural techniques for preventing recurrence are necessary for preventing the deformity. There are many techniques although no superior method of treatment has been found. In this case report, we describe a novel method using needle aspiration followed by the application of a magnet and an adapted disc to the affected area of the auricular. This minimally invasive, simple, and accessible method could potentially facilitate the treatment of cauliflower ear among full contact sports athletes. PMID- 29403319 TI - A review of the pharmacology and clinical efficacy of brivaracetam. AB - Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30 fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10-1,000 mg) and multiple (200-800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50-200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic-clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug-drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV. PMID- 29403320 TI - Opinions, practice patterns, and perceived barriers to lung cancer screening among attending and resident primary care physicians. AB - Introduction: The US Preventive Services Task Force recommended annual lung cancer screening with low-dose computed tomography (LDCT) for high-risk patients in December 2013. We compared lung cancer screening-related opinions and practices among attending and resident primary care physicians (PCPs). Methods: In 2015, we conducted a 23-item survey among physicians at a large academic medical center. We surveyed 100 resident PCPs (30% response rate) and 86 attending PCPs (49% response rate) in Family Medicine and Internal Medicine. The questions focused on physicians' opinions, knowledge of recommendations, self reported practice patterns, and barriers to lung cancer screening. In 2015 and 2016, we compared responses among attending versus resident PCPs using chi square/Fisher's exact tests and 2-samples t-tests. Results: Compared with resident PCPs, attending PCPs were older (mean age =47 vs 30 years) and more likely to be male (54% vs 37%). Over half of both groups concurred that inconsistent recommendations make deciding whether or not to screen difficult. A substantial proportion in both groups indicated that they were undecided about the benefit of lung cancer screening for patients (43% attending PCPs and 55% resident PCPs). The majority of attending and resident PCPs agreed that barriers to screening included limited time during patient visits (62% and 78%, respectively), cost to patients (74% and 83%, respectively), potential for complications (53% and 70%, respectively), and a high false-positive rate (67% and 73%, respectively). Conclusion: There was no evidence to suggest that attending and resident PCPs had differing opinions about lung cancer screening. For population-based implementation of lung cancer screening, physicians and trainees will need resources and time to address the benefits and harms with their patients. PMID- 29403321 TI - Actigraphy-based sleep estimation in adolescents and adults: a comparison with polysomnography using two scoring algorithms. AB - Objectives: Actigraphy is widely used to estimate sleep-wake time, despite limited information regarding the comparability of different devices and algorithms. We compared estimates of sleep-wake times determined by two wrist actigraphs (GT3X+ versus Actiwatch Spectrum [AWS]) to in-home polysomnography (PSG), using two algorithms (Sadeh and Cole-Kripke) for the GT3X+ recordings. Subjects and methods: Participants included a sample of 35 healthy volunteers (13 school children and 22 adults, 46% male) from Boston, MA, USA. Twenty-two adults wore the GT3X+ and AWS simultaneously for at least five consecutive days and nights. In addition, actigraphy and PSG were concurrently measured in 12 of these adults and another 13 children over a single night. We used intraclass correlation coefficients (ICCs), epoch-by-epoch comparisons, paired t-tests, and Bland-Altman plots to determine the level of agreement between actigraphy and PSG, and differences between devices and algorithms. Results: Each actigraph showed comparable accuracy (0.81-0.86) for sleep-wake estimation compared to PSG. When analyzing data from the GT3X+, the Cole-Kripke algorithm was more sensitive (0.88-0.96) to detect sleep, but less specific (0.35-0.64) to detect wake than the Sadeh algorithm (sensitivity: 0.82-0.91, specificity: 0.47-0.68). Total sleep time measured using the GT3X+ with both algorithms was similar to that obtained by PSG (ICC=0.64-0.88). In contrast, agreement between the GT3X+ and PSG wake after sleep onset was poor (ICC=0.00-0.10). In adults, the GT3X+ using the Cole Kripke algorithm provided data comparable to the AWS (mean bias=3.7+/-19.7 minutes for total sleep time and 8.0+/-14.2 minutes for wake after sleep onset). Conclusion: The two actigraphs provided comparable and accurate data compared to PSG, although both poorly identified wake episodes (i.e., had low specificity). Use of actigraphy scoring algorithm influenced the mean bias and level of agreement in sleep-wake times estimates. The GT3X+, when analyzed by the Cole Kripke, but not the Sadeh algorithm, provided comparable data to the AWS. PMID- 29403322 TI - Psychological treatments for the management of postsurgical pain: a systematic review of randomized controlled trials. AB - Background: Inadequately managed pain is a risk factor for chronic postsurgical pain (CPSP), a growing public health challenge. Multidisciplinary pain-management programs with psychological approaches, including cognitive behavioral therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness-based psychotherapy, have shown efficacy as treatments for chronic pain, and show promise as timely interventions in the pre/perioperative periods for the management of PSP. We reviewed the literature to identify randomized controlled trials evaluating the efficacy of these psychotherapy approaches on pain-related surgical outcomes. Materials and methods: We searched Medline, Medline-In Process, Embase and Embase Classic, and PsycInfo to identify studies meeting our search criteria. After title and abstract review, selected articles were rated for risk of bias. Results: Six papers based on five trials (four back surgery, one cardiac surgery) met our inclusion criteria. Four papers employed CBT and two CBT-physiotherapy variant; no ACT or mindfulness-based studies were identified. Considerable heterogeneity was observed in the timing and delivery of psychological interventions and length of follow-up (1 week to 2-3 years). Whereas pain-intensity reporting varied widely, pain disability was reported using consistent methods across papers. The majority of papers (four of six) reported reduced pain intensity, and all relevant papers (five of five) found improvements in pain disability. General limitations included lack of large-scale data and difficulties with blinding. Conclusion: This systematic review provides preliminary evidence that CBT-based psychological interventions reduce PSP intensity and disability. Future research should further clarify the efficacy and optimal delivery of CBT and newer psychological approaches to PSP. PMID- 29403324 TI - Pharmacokinetics-based clinical management of acquired von Willebrand syndrome: a case report. AB - von Willebrand disease (VWD) is a common bleeding disorder caused by defective or low levels of von Willebrand factor (VWF). Although most cases of VWD are caused by genetic mutations, some are acquired due to various disease states. In managing VWD, the aim is to normalize plasma levels of both VWF and factor VIII (FVIII), as this aids in hemostasis. Desmopressin usually corrects VWF level in type 1 VWD by inducing the release of endogenous VWF. In cases where desmopressin is ineffective or cannot be used, transfusion of virally inactivated, plasma derived VWF/FVIII concentrate or infusion of recombinant VWF (Vonvendi) is indicated. Treatment of acquired von Willebrand syndrome (AVWS) aims to control the underlying disease while regulating life-threatening hemorrhages with infusions of VWF/FVIII concentrate. Wide intrasubject variability in VWF and FVIII levels, particularly in AVWS, necessitates verification of response to treatment by frequent monitoring of the plasmatic VWF level. Clinical pharmacokinetics of VWF may facilitate calculation of the necessary loading and maintenance doses of VWF/FVIII concentrate in the management of AVWS patients undergoing surgery, thereby avoiding unnecessary infusion of coagulation factor concentrate. PMID- 29403323 TI - Evaluation of thrombosis-related biomarkers before and after therapy in patients with multiple myeloma. AB - Background: Thrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis. Methods: We assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of Mel-P, bortezomib, and lenalidomide on the plasma concentrations of these biomarkers were investigated. Results: The plasma concentrations of PDMP, PAI-1, HMGB1, EPCR, and sVCAM-1 were higher in MM patients than in healthy controls. Mel-P, bortezomib, and lenalidomide therapies all reduced biomarker levels after treatment. However, when only patients with higher levels of EPCR were compared, differences were seen between the three therapies in the elevation of PDMP, HMGB1, and PAI-1. Conclusion: These results suggest that both MM and therapies for MM can induce a hypercoagulable state. The elevated risk of thrombosis conferred by hypercoagulability increases patient morbidity and mortality. Attention should be paid to therapy-related thrombosis when new therapeutic regimens are selected for MM patients. PMID- 29403325 TI - TAFRO syndrome: current perspectives. AB - Multicentric Castleman's disease (MCD), a distinct subtype of Castleman's disease, is a rare, nonneoplastic, lymphoproliferative disorder. Patients with MCD present with systemic symptoms and multiple lymphadenopathy. Lymph node biopsy is necessary for the diagnosis of various histological MCD patterns including hyaline vascular, plasma cell, and mixed types. Human herpesvirus 8 (HHV8) infection was identified as an important etiology of MCD among immunocompromised patients such as those positive for human immunodeficiency virus. Although HHV8-negative MCD was reported in immunocompetent patients, the underlying etiology remains unknown. Several experts speculate that MCD in immunocompetent patients might be due to proinflammatory hypercytokinemia because of infection by a virus other than HHV8, inflammation, or neoplastic disease. In 2010, a distinct variant of HHV8-negative MCD reported in Japan was characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO). Recent case reports and a systematic review suggest that TAFRO syndrome might have a unique pathogenesis among HHV8-negative MCD variants. This review introduces TAFRO syndrome as a subtype of HHV8-negative MCD and offers an overview of the current perspectives on this syndrome. PMID- 29403326 TI - Levers of change: a review of contemporary interventions to enhance diversity in medical schools in the USA. AB - A growing body of research illustrates the importance of aligning efforts across the operational continuum to achieve diversity goals. This alignment begins with the institutional mission and the message it conveys about the priorities of the institution to potential applicants, community, staff, and faculty. The traditional themes of education, research, and service dominate most medical school mission statements. The emerging themes of physician maldistribution, overall primary-care physician shortage, diversity, and cost control are cited less frequently. The importance and salience of having administrative leaders with an explicit commitment to workforce and student diversity is a prominent and pivotal factor in the medical literature on the subject. Organizational leadership shapes the general work climate and expectations concerning diversity, recruitment, and retention. Following the Bakke decision, individual medical schools, supported by the Association of American Medical Colleges, worked to expand the frame of reference for evaluating applicants for medical school. These efforts have come together under the rubric of "holistic review", permitted by the US Supreme Court in 2003. A large diverse-applicant pool is needed to ensure the appropriate candidates can be chosen for the incoming medical school class. Understanding the optimal rationale and components for a successful recruitment program is important. Benchmarking with other schools regionally and nationally will identify what should be the relative size of a pool. Diversity is of compelling interest to us all, and should pervade all aspects of higher education, including admissions, the curriculum, student services and activities, and our faculties. The aim of medical education is to cultivate a workforce with the perspectives, aptitudes, and skills needed to fuel community-responsive health-care institutions. A commitment toward diversity needs to be made. PMID- 29403327 TI - The value of near-peer teaching in the medical curriculum. PMID- 29403329 TI - Implications of family risk pooling for individual health insurance markets. AB - While family purchase of health insurance may benefit insurance markets by pooling individual risk into family groups, the correlation across illness types in families could exacerbate adverse selection. We analyze the impact of family pooling on risk for health insurers to inform policy about family-level insurance plans. Using data on 8,927,918 enrollees in fee-for-service commercial health plans in the 2013 Truven MarketScan database, we compare the distribution of annual individual health spending across four pooling scenarios: (1) "Individual" where there is no pooling into families; (2) "real families" where costs are pooled within families; (3) "random groups" where costs are pooled within randomly generated small groups that mimic families in group size; and (4) "the Sims" where costs are pooled within random small groups which match families in demographics and size. These four simulations allow us to identify the separate contributions of group size, group composition, and family affinity in family risk pooling. Variation in individual spending under family pooling is very similar to that within "simulated families" and to that within random groups, and substantially lower than when there is no family pooling and individuals choose independently (standard deviation $12,526 vs $11,919, $12,521 and $17,890 respectively). Within-family correlations in health status and utilization do not "undo" the gains from family pooling of risks. Family pooling can mitigate selection and improve the functioning of health insurance markets. PMID- 29403328 TI - 4D printing of polymeric materials for tissue and organ regeneration. AB - Four dimensional (4D) printing is an emerging technology with great capacity for fabricating complex, stimuli-responsive 3D structures, providing great potential for tissue and organ engineering applications. Although the 4D concept was first highlighted in 2013, extensive research has rapidly developed, along with more-in depth understanding and assertions regarding the definition of 4D. In this review, we begin by establishing the criteria of 4D printing, followed by an extensive summary of state-of-the-art technological advances in the field. Both transformation-preprogrammed 4D printing and 4D printing of shape memory polymers are intensively surveyed. Afterwards we will explore and discuss the applications of 4D printing in tissue and organ regeneration, such as developing synthetic tissues and implantable scaffolds, as well as future perspectives and conclusions. PMID- 29403330 TI - Electrochemical investigation of the Eu3+/2+ redox couple in complexes with variable numbers of glycinamide and acetate pendant arms. AB - The Eu3+/2+ redox couple provides a convenient design platform for responsive pO2 sensors for magnetic resonance imaging (MRI). Specifically the Eu2+ ion provides T1w contrast enhancement under hypoxic conditions in tissues, whereas, under normoxia, the Eu3+ ion can produce contrast from chemical exchange saturation transfer in MRI. The oxidative stability of the Eu3+/2+ redox couple for a series of tetraaza macrocyclic complexes was investigated in this work using cyclic voltammetry. A series of Eu-containing cyclen-based macrocyclic complexes revealed positive shifts in the Eu3+/2+ redox potentials with each replacement of a carboxylate coordinating arm of the ligand scaffold with glycinamide pendant arms. The data obtained reveal that the complex containing four glycinamide coordinating pendant arms has the highest oxidative stability of the series investigated. PMID- 29403331 TI - WE'RE THE EYES AND THE EARS, BUT WE DON'T HAVE A VOICE: PERSPECTIVES OF HOSPICE AIDES. AB - Hospice aides are integral to the delivery of home hospice care and play an essential role in the effective communication and collaboration of the hospice interdisciplinary team. Despite their critical role, little is known about hospice aides' perceptions of their role in providing hospice services. This qualitative study explores hospice aides' perspectives of their work, their relationships with patients, families and interdisciplinary team members, and their contributions to end-of-life care. Two focus groups of hospice aides (N = 13), and 16 hours of observation of in-home caregiving were conducted. Focus group data were inductively and iteratively coded, and three themes were identified: 1) "We're the eyes and ears", 2) "We're kept out of the loop", and 3) "We have no voice." Aides described themselves as front-line providers based on the close relationships they formed with patients and family members, yet felt under-recognized by members of the hospice team. Observational field notes were reexamined with themes to confirm convergence of qualitative and observational data. Better understanding of their role could enhance integration of aides into patient- and family-centered team interactions, leading to both improved patient and family outcomes and retention and support of this critical component of the hospice workforce. PMID- 29403332 TI - The best of the best: a review of select oculoplastic case series published in 2015. AB - This review summarizes three case series published in the field of oculoplastic surgery in the year 2015. The first article describes the use of hedgehog pathway inhibitors for medical therapy of advanced periocular basal cell carcinoma and basal cell nevus syndrome. The second describes the use of c-reactive protein as a marker for starting treatment with steroids in children with orbital cellulitis. The third article presents an endoscopic medial orbital fat decompression technique for treatment of proptosis in thyroid eye disease. PMID- 29403333 TI - Aspiration of cataract in 1815 in Philadelphia, Pennsylvania. AB - We present and discuss the previously unrecognized evidence for the possible introduction of cataract extraction by aspiration into modern Western medicine on March 26, 1815, in Philadelphia, Pennsylvania, by surgeon Philip Syng Physick. On this date, he successfully extracted a cataract by suction through a tube, according to newspaper reports written by the patient, an attorney who sought a patent on the suction device. Aspects of the patient's account are confirmed by supporting evidence from the medical community and by a cataract instrument set attributed to Physick, which includes a cannula attached to a syringe. The evidence suggests that Physick was the first to reintroduce cataract aspiration to Western medicine. PMID- 29403335 TI - Takayasu arteritis-related photic and postprandial amaurosis. AB - We report the case of a 66-year-old man with Takayasu arteritis who developed photic and postprandial amaurosis occurring at a corticosteroid dose <40 mg per day, despite concurrent methotrexate. The amaurosis resolved with correction of anemia by packed red blood cell transfusion. Marginal retinal perfusion in Takayasu arteritis may precipitate symptomatic hypoxia as a result of eating a meal or exposing the eye to bright lights. Correction of anemia improves oxygen delivery to the hypoxic retina and relieves recurrent amaurosis. PMID- 29403334 TI - Surgical approach to limiting skin contracture following protractor myectomy for essential blepharospasm. AB - Purpose: To report our experience with protractor myectomy in patients with benign essential blepharospasm who did not respond to serial botulinum toxin injection, and to describe intra- and postoperative techniques that limited skin contracture while also providing excellent functional and cosmetic results. Methods: The medical records of patients with isolated, benign, essential blepharospasm who underwent protractor myectomy from 2005 to 2008 by a single surgeon were reviewed retrospectively. The technique entailed operating on a single eyelid during each procedure, using a complete en bloc resection of all orbicularis tissue, leaving all eyelid skin intact at the time of surgery, and placing the lid under stretch with Frost suture and applying a pressure dressing for 5-7 days. Results: Data from 28 eyelids in 7 patients were included. Average follow-up was 21.5 months (range, 4-76 months). Of the 28 eyelids, 20 (71.4%) showed postoperative resolution of spasm, with no further need for botulinum toxin injections. In the 8 eyelids requiring further injections, the average time to injection after surgery was 194 days (range, 78-323 days), and the average number of injections was 12 (range, 2-23 injections). All but one eyelid had excellent cosmetic results, without signs of contracture; one eyelid developed postoperative skin contracture following premature removal of the Frost suture and pressure dressing because of concerns over increased intraocular pressure. Conclusions: In our patient cohort, this modified technique resulted in excellent cosmetic and functional results and limited postoperative skin contracture. PMID- 29403336 TI - Experimental use of an extracellular matrix graft in pterygium surgery. AB - A 40-year-old man presented with a primary pterygium of the right eye and underwent pterygium excision using mitomycin C and placement of an extracellular matrix (ECM) adjuvant. As an adjuvant in pterygium surgery, ECM serves as a scaffold while promoting the growth of normal conjunctiva. Perioperatively, the ECM graft was found to be easily manipulated on the surgical field. It attached to the scleral bed with fibrin glue without complication. Postoperatively, there was no inflammation or local tissue reaction to the porcine ECM graft. At the most recent follow-up examination, 6 months postoperatively, there were no signs of recurrence of the pterygium past the limbus. This is the first report describing the use of ECM as an adjuvant to pterygium excision. PMID- 29403337 TI - Diffuse ocular and orbital inflammation after zoledronate infusion-case report and review of the literature. AB - Bisphosphonates have become a commonly used class of medications to treat osteoporosis and other bone diseases. Zoledronate (zoledronic acid) can be dosed annually via intravenous infusion, making it an appealing option for patients and physicians. We report the case of a 68-year-old woman who developed severe, unilateral, ocular inflammation, including corneal endotheliitis, anterior uveitis with hyphema, scleritis, and orbital inflammation beginning 12 hours after receiving her first zoledronate infusion. Symptoms escalated but ultimately resolved with topical steroids and high-dose systemic corticosteroids. To our knowledge, this is the first report of unilateral diffuse inflammation of the eye and orbit, including corneal inflammation developing within 12 hours of a first zoledronate infusion. PMID- 29403338 TI - Orbital leiomyosarcoma metastasis presenting prior to diagnosis of the primary tumor. AB - Leiomyosarcomas, neoplasms of smooth muscle, are rarely found within the orbit. Orbital leiomyosarcoma may be primary, metastatic, or secondary to radiation. When they are metastatic, patients almost exclusively have a history of a primary leiomyosarcoma, often occurring in the spermatic cord, skin, gastrointestinal tract, or the uterus. We present the case of 48-year-old woman who presented with a metastatic orbital leiomyosarcoma, which was identified before the primary tumor. PMID- 29403339 TI - A 60-year-old woman with an asymptomatic left lacrimal gland mass found incidentally. PMID- 29403340 TI - A 15-year-old-boy with an optic neuropathy. PMID- 29403341 TI - In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid. AB - Metabolite profiling of novel psychoactive substances (NPS) is critical for documenting drug consumption. N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4 fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA) is an emerging synthetic cannabinoid whose toxicological and metabolic data are currently unavailable. We aimed to determine optimal markers for identifying ADB-FUBINACA intake. Metabolic stability was evaluated with human liver microsome incubations. Metabolites were identified after 1 and 3 h incubation with pooled human hepatocytes, liquid chromatography- high resolution mass spectrometry in positive-ion mode (5600+ TripleTOF(r), Sciex) and several data mining approaches (MetabolitePilotTM, Sciex). Metabolite separation was achieved on an Ultra Biphenyl column (Restek(r)); full-scan TOF-MS and information-dependent acquisition MS/MS data were acquired. ADB-FUBINACA microsomal half-life was 39.7 min, with a predicted hepatic clearance of 9.0 mL/min/kg and a 0.5 extraction ratio (intermediate clearance drug). Twenty-three metabolites were identified. Major metabolic pathways were alkyl and indazole hydroxylation, terminal amide hydrolysis, subsequent glucuronide conjugations, and dehydrogenation. We recommend ADB FUBINACA hydroxyalkyl, hydroxydehydroalkyl and hydroxylindazole metabolites as ADB-FUBINACA intake markers. N-dealkylated metabolites are not specific ADB FUBINACA metabolites and should not be used as definitive markers of consumption. This is the first ADB-FUBINACA in vitro metabolism study; in vivo experiments enabling pharmacokinetic and pharmacodynamics studies or urine from authentic clinical/forensic cases are needed to confirm our results. PMID- 29403342 TI - Meet Our Regional Editor. PMID- 29403344 TI - The Influence of Study-Level Inference Models and Study Set Size on Coordinate Based fMRI Meta-Analyses. AB - Given the increasing amount of neuroimaging studies, there is a growing need to summarize published results. Coordinate-based meta-analyses use the locations of statistically significant local maxima with possibly the associated effect sizes to aggregate studies. In this paper, we investigate the influence of key characteristics of a coordinate-based meta-analysis on (1) the balance between false and true positives and (2) the activation reliability of the outcome from a coordinate-based meta-analysis. More particularly, we consider the influence of the chosen group level model at the study level [fixed effects, ordinary least squares (OLS), or mixed effects models], the type of coordinate-based meta analysis [Activation Likelihood Estimation (ALE) that only uses peak locations, fixed effects, and random effects meta-analysis that take into account both peak location and height] and the amount of studies included in the analysis (from 10 to 35). To do this, we apply a resampling scheme on a large dataset (N = 1,400) to create a test condition and compare this with an independent evaluation condition. The test condition corresponds to subsampling participants into studies and combine these using meta-analyses. The evaluation condition corresponds to a high-powered group analysis. We observe the best performance when using mixed effects models in individual studies combined with a random effects meta-analysis. Moreover the performance increases with the number of studies included in the meta-analysis. When peak height is not taken into consideration, we show that the popular ALE procedure is a good alternative in terms of the balance between type I and II errors. However, it requires more studies compared to other procedures in terms of activation reliability. Finally, we discuss the differences, interpretations, and limitations of our results. PMID- 29403343 TI - The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment. AB - Background: Antipsychotic-induced weight gain (AIWG) and other adverse metabolic effects represent serious side effects faced by many patients with psychosis that can lead to numerous comorbidities and which reduce the lifespan. While the pathophysiology of AIWG remains poorly understood, numerous studies have reported a positive association between AIWG and the therapeutic benefit of antipsychotic medications. Objectives: To review the literature to (1) determine if AIWG is consistently associated with therapeutic benefit and (2) investigate which variables may mediate such an association. Data Sources: MEDLINE, Google Scholar, Cochrane Database and PsycINFO databases were searched for articles containing all the following exploded MESH terms: schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles. Results: Our literature search uncovered 31 independent studies which investigated an AIWG-therapeutic benefit association with a total of 6063 enrolled individuals diagnosed with schizophrenia or another serious mental illness receiving antipsychotic medications. Twenty-two studies found a positive association while, 10 studies found no association and one study reported a negative association. Study variables including medication compliance, sex, ethnicity, or prior antipsychotic exposure did not appear to consistently affect the AIWG-therapeutic benefit relationship. In contrast, there was some evidence that controlling for baseline BMI/psychopathology, duration of treatment and specific agent studied [i.e., olanzapine (OLZ) or clozapine (CLZ)] strengthened the relationship between AIWG and therapeutic benefit. Limitations: There were limitations of the reviewed studies in that many had small sample sizes, and/or were retrospective. The heterogeneity of the studies also made comparisons difficult and publication bias was not controlled for. Conclusions: An AIWG therapeutic benefit association may exist and is most likely to be observed in OLZ and CLZ-treated patients. The clinical meaningfulness of this association remains unclear and weight gain and other metabolic comorbidities should be identified and treated to the same targets as the general population. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG. PMID- 29403345 TI - Nitrative Stress and Tau Accumulation in Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) in the Kii Peninsula, Japan. AB - Objective: The Kii Peninsula of Japan is known to be a high incidence area of amyotrophic lateral sclerosis/parkinsonism-dementia complex (Kii ALS/PDC) with tauopathy. Nitrative stress and oxidative stress on ALS/PDC and their relationship to tau pathology were clarified. Methods: Seven patients with Kii ALS/PDC (3 males and 4 females, average age 70.7 years, 3 with ALS, 2 with ALS with dementia, and 2 with PDC) were analyzed in this study. Five patients with Alzheimer's disease and five normal aged subjects were used as controls. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded temporal lobe sections (the hippocampal area including hippocampus, prosubiculum, subiculum, presubiculum, and parahippocampal gyri) using antibodies to detect phosphorylated tau (anti-AT-8), nitrated guanine (anti-8-NG), anti-iNOS, anti NFkappaB, and oxidized guanine (anti-8-OHdG) antibodies. Results: Most hippocampal neurons of Kii ALS/PDC patients were stained with anti-8-NG, anti iNOS, anti-NFkappaB, and anti-8-OHdG antibodies and some AT-8 positive neurons were co-stained with anti-8-NG antibody. The numbers of 8-NG positive neurons and 8-OHdG positive neurons were greater than AT-8 positive neurons and the number of 8-NG positive neurons was larger in patients with Kii ALS/PDC than in controls. Conclusion: Nitrative and oxidative stress may take priority over tau accumulation and lead to the neurodegeneration in Kii ALS/PDC. PMID- 29403346 TI - Peripheral Neuron Survival and Outgrowth on Graphene. AB - Graphene displays properties that make it appealing for neuroregenerative medicine, yet its interaction with peripheral neurons has been scarcely investigated. Here, we culture on graphene two established models for peripheral neurons: PC12 cells and DRG primary neurons. We perform a nano-resolved analysis of polymeric coatings on graphene and combine optical microscopy and viability assays to assess the material cytocompatibility and influence on differentiation. We find that differentiated PC12 cells display a remarkably increased neurite length on graphene (up to 27%) with respect to controls. Notably, DRG primary neurons survive both on bare and coated graphene. They present dense axonal networks on coated graphene, while they form cell islets characterized by dense axonal bundles on uncoated graphene. These findings indicate that graphene holds potential for nerve tissue regeneration and might pave the road to novel concepts of active nerve conduits. PMID- 29403347 TI - Brain Metabolite Diffusion from Ultra-Short to Ultra-Long Time Scales: What Do We Learn, Where Should We Go? AB - In vivo diffusion-weighted MR spectroscopy (DW-MRS) allows measuring diffusion properties of brain metabolites. Unlike water, most metabolites are confined within cells. Hence, their diffusion is expected to purely reflect intracellular properties, opening unique possibilities to use metabolites as specific probes to explore cellular organization and structure. However, interpretation and modeling of DW-MRS, and more generally of intracellular diffusion, remains difficult. In this perspective paper, we will focus on the study of the time-dependency of brain metabolite apparent diffusion coefficient (ADC). We will see how measuring ADC over several orders of magnitude of diffusion times, from less than 1 ms to more than 1 s, allows clarifying our understanding of brain metabolite diffusion, by firmly establishing that metabolites are neither massively transported by active mechanisms nor massively confined in subcellular compartments or cell bodies. Metabolites appear to be instead diffusing in long fibers typical of neurons and glial cells such as astrocytes. Furthermore, we will evoke modeling of ADC time-dependency to evaluate the effect of, and possibly quantify, some structural parameters at various spatial scales, departing from a simple model of hollow cylinders and introducing additional complexity, either short-ranged (such as dendritic spines) or long-ranged (such as cellular fibers ramification). Finally, we will discuss the experimental feasibility and expected benefits of extending the range of diffusion times toward even shorter and longer values. PMID- 29403348 TI - Training for Micrographia Alters Neural Connectivity in Parkinson's Disease. AB - Despite recent advances in clarifying the neural networks underlying rehabilitation in Parkinson's disease (PD), the impact of prolonged motor learning interventions on brain connectivity in people with PD is currently unknown. Therefore, the objective of this study was to compare cortical network changes after 6 weeks of visually cued handwriting training (= experimental) with a placebo intervention to address micrographia, a common problem in PD. Twenty seven early Parkinson's patients on dopaminergic medication performed a pre writing task in both the presence and absence of visual cues during behavioral tests and during fMRI. Subsequently, patients were randomized to the experimental (N = 13) or placebo intervention (N = 14) both lasting 6 weeks, after which they underwent the same testing procedure. We used dynamic causal modeling to compare the neural network dynamics in both groups before and after training. Most importantly, intensive writing training propagated connectivity via the left hemispheric visuomotor stream to an increased coupling with the supplementary motor area, not witnessed in the placebo group. Training enhanced communication in the left visuomotor integration system in line with the learned visually steered training. Notably, this pattern was apparent irrespective of the presence of cues, suggesting transfer from cued to uncued handwriting. We conclude that in early PD intensive motor skill learning, which led to clinical improvement, alters cortical network functioning. We showed for the first time in a placebo controlled design that it remains possible to enhance the drive to the supplementary motor area through motor learning. PMID- 29403349 TI - Group Analysis in MNE-Python of Evoked Responses from a Tactile Stimulation Paradigm: A Pipeline for Reproducibility at Every Step of Processing, Going from Individual Sensor Space Representations to an across-Group Source Space Representation. AB - An important aim of an analysis pipeline for magnetoencephalographic data is that it allows for the researcher spending maximal effort on making the statistical comparisons that will answer the questions of the researcher, while in turn spending minimal effort on the intricacies and machinery of the pipeline. I here present a set of functions and scripts that allow for setting up a clear, reproducible structure for separating raw and processed data into folders and files such that minimal effort can be spend on: (1) double-checking that the right input goes into the right functions; (2) making sure that output and intermediate steps can be accessed meaningfully; (3) applying operations efficiently across groups of subjects; (4) re-processing data if changes to any intermediate step are desirable. Applying the scripts requires only general knowledge about the Python language. The data analyses are neural responses to tactile stimulations of the right index finger in a group of 20 healthy participants acquired from an Elekta Neuromag System. Two analyses are presented: going from individual sensor space representations to, respectively, an across group sensor space representation and an across-group source space representation. The processing steps covered for the first analysis are filtering the raw data, finding events of interest in the data, epoching data, finding and removing independent components related to eye blinks and heart beats, calculating participants' individual evoked responses by averaging over epoched data and calculating a grand average sensor space representation over participants. The second analysis starts from the participants' individual evoked responses and covers: estimating noise covariance, creating a forward model, creating an inverse operator, estimating distributed source activity on the cortical surface using a minimum norm procedure, morphing those estimates onto a common cortical template and calculating the patterns of activity that are statistically different from baseline. To estimate source activity, processing of the anatomy of subjects based on magnetic resonance imaging is necessary. The necessary steps are covered here: importing magnetic resonance images, segmenting the brain, estimating boundaries between different tissue layers, making fine resolution scalp surfaces for facilitating co-registration, creating source spaces and creating volume conductors for each subject. PMID- 29403350 TI - The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports. AB - Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology ("what it feels like" to experience these states) is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception ("see," "visual," "face," "reality," "color"), emotion ("fear"), setting ("outside," "inside," "street," "front," "behind") and relatives ("mom," "dad," "brother," "parent," "family") were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non invasive measurements of brain physiology. PMID- 29403351 TI - Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases. AB - Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls. Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20), iCJD (n = 11), sCJD (n = 23), gPrD (n = 30), and AD (n = 14) patients and age-matched controls (n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis. Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level. Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)-together with specific molecular and conformational features of the pathological agent of the disease-seem to dictate the peculiar hemoglobin dysregulation found in prion and non-prion neurodegenerative disorders. In addition, these results suggest that gene expression of HBB and HBA1/2 in brain tissue is differentially affected by distinct prion and prion-like aggregating protein strains. Validation of these results in more accessible tissues could prompt the development of novel diagnostic tests for neurodegenerative disorders. PMID- 29403352 TI - New Progress on the Role of Glia in Iron Metabolism and Iron-Induced Degeneration of Dopamine Neurons in Parkinson's Disease. AB - It is now increasingly appreciated that glial cells play a critical role in the regulation of iron homeostasis. Impairment of these properties might lead to dysfunction of iron metabolism and neurodegeneration of neurons. We have previously shown that dysfunction of glia could cause iron deposit and enhance iron-induced degeneration of dopamine (DA) neurons in Parkinson's disease (PD). There also has been a substantial growth of knowledge regarding the iron metabolism of glia and their effects on iron accumulation and degeneration of DA neurons in PD in recent years. Here, we attempt to describe the role of iron metabolism of glia and the effect of glia on iron accumulation and degeneration of DA neurons in the substantia nigra of PD. This could provide evidence to reveal the mechanisms underlying nigral iron accumulation of DA neurons in PD and provide the basis for discovering new potential therapeutic targets for PD. PMID- 29403353 TI - Kv2 Ion Channels Determine the Expression and Localization of the Associated AMIGO-1 Cell Adhesion Molecule in Adult Brain Neurons. AB - Voltage-gated K+ (Kv) channels play important roles in regulating neuronal excitability. Kv channels comprise four principal alpha subunits, and transmembrane and/or cytoplasmic auxiliary subunits that modify diverse aspects of channel function. AMIGO-1, which mediates homophilic cell adhesion underlying neurite outgrowth and fasciculation during development, has recently been shown to be an auxiliary subunit of adult brain Kv2.1-containing Kv channels. We show that AMIGO-1 is extensively colocalized with both Kv2.1 and its paralog Kv2.2 in brain neurons across diverse mammals, and that in adult brain, there is no apparent population of AMIGO-1 outside of that colocalized with these Kv2 alpha subunits. AMIGO-1 is coclustered with Kv2 alpha subunits at specific plasma membrane (PM) sites associated with hypolemmal subsurface cisternae at neuronal ER:PM junctions. This distinct PM clustering of AMIGO-1 is not observed in brain neurons of mice lacking Kv2 alpha subunit expression. Moreover, in heterologous cells, coexpression of either Kv2.1 or Kv2.2 is sufficient to drive clustering of the otherwise uniformly expressed AMIGO-1. Kv2 alpha subunit coexpression also increases biosynthetic intracellular trafficking and PM expression of AMIGO-1 in heterologous cells, and analyses of Kv2.1 and Kv2.2 knockout mice show selective loss of AMIGO-1 expression and localization in neurons lacking the respective Kv2 alpha subunit. Together, these data suggest that in mammalian brain neurons, AMIGO-1 is exclusively associated with Kv2 alpha subunits, and that Kv2 alpha subunits are obligatory in determining the correct pattern of AMIGO-1 expression, PM trafficking and clustering. PMID- 29403355 TI - Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice. AB - Triclosan (TCS), a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone, and gonadotrophin-releasing hormone (GnRH) mRNA with the lack of LH surge and elevation of prolactin (PRL). TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Moreover, the estrogen (E2)-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH) and thyroid releasing hormone (TRH). In TCS mice, the treatment with Levothyroxine (L-T4) corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (>=10 mg/kg) reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function. PMID- 29403354 TI - Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism. AB - Neurodegenerative diseases (NDDs) are disorders characterized by progressive deterioration of brain structure and function. Selective neuronal populations are affected leading to symptoms which are prominently motor in amyotrophic lateral sclerosis (ALS) or Huntington's disease (HD), or cognitive in Alzheimer's disease (AD) and fronto-temporal dementia (FTD). Besides the common existence of neuronal loss, NDDs are also associated with metabolic changes such as weight gain, weight loss, loss of fat mass, as well as with altered feeding behavior. Importantly, preclinical research as well as clinical studies have demonstrated that altered energy homeostasis influences disease progression in ALS, AD and HD, suggesting that identification of the pathways leading to perturbed energy balance might provide valuable therapeutic targets Signals from both the periphery and central inputs are integrated in the hypothalamus, a major hub for the control of energy balance. Recent research identified major hypothalamic changes in multiple NDDs. Here, we review these hypothalamic alterations and seek to identify commonalities and differences in hypothalamic involvement between the different NDDs. These hypothalamic defects could be key in the development of perturbations in energy homeostasis in NDDs and further understanding of the underlying mechanisms might open up new avenues to not only treat weight loss but also to ameliorate overall neurological symptoms. PMID- 29403357 TI - Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia. AB - Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding -11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia. PMID- 29403358 TI - Novel Peptide Vaccine GV1001 Rescues Hearing in Kanamycin/Furosemide-Treated Mice. AB - The cell-penetrating peptide GV1001 has been investigated as an anticancer agent and recently demonstrated anti-oxidant and anti-inflammatory effects. It has shown a protective effect on a kanamycin (KM)-induced ototoxicity mouse model. In the present study, we administered GV1001 at different time points after inducing hair cell damage, and examined if it rescues hair cell loss and restores hearing. A deaf mouse model was created by intraperitoneal injection of KM and furosemide. First, to test the early temporal change of hearing and extent of hair cell damage after KM and furosemide injection, hearing and outer hair cells (OHCs) morphology were evaluated on day 1, day 2 and day 3 after injection. In the second experiment, following KM and furosemide injection, GV1001, dexamethasone, or saline were given for three consecutive days at different time points: D0 group (days 0, 1, and 2), D1 group (days 1, 2, and 3), D3 group (days 3, 4, and 5) and D7 group (days 7, 8, and 9). The hearing thresholds were measured at 8, 16, and 32 kHz before ototoxic insult, and 7 days and 14 days after KM and furosemide injection. After 14 days, each turn of the cochlea was imaged to evaluate OHCs damage. GV1001-treated mice showed significantly less hearing loss and OHCs damage than the saline control group in the D0, D1 and D3 groups (p < 0.0167). However, there was no hearing restoration or intact hair cell in the D7 group. GV1001 protected against cochlear hair cell damage, and furthermore, delayed administration of GV1001 up to 3 days rescued hair cell damage and hearing loss in KM/furosemide-induced deaf mouse model. PMID- 29403356 TI - Pin1 Promotes Regulated Necrosis Induced by Glutamate in Rat Retinal Neurons via CAST/Calpain2 Pathway. AB - The purpose of the current study was to investigate whether peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) can interact with calpastatin (CAST) and regulate CAST/calpain2, under excessive glutamate conditions, and subsequently regulate necrosis in rat retinal neurons. Glutamate triggered CAST/calpain2-mediated necrosis regulation in primary cultured retinal neurons, as demonstrated by propidium iodide-staining and lactate dehydrogenase assay. Co IP results and a computer simulation suggested that Pin1 could bind to CAST. Western blot, real-time quantitative polymerase chain reaction, immunofluorescence, and phosphorylation analysis results demonstrated that CAST was regulated by Pin1, as proven by the application of juglone (i.e., a Pin1 specific inhibitor). The retinal ganglion cell 5 cell line, combined with siRNA approach and flow cytometry, was then used to verify the regulatory pathway of Pin1 in CAST/calpain2-modulated neuronal necrosis that was induced by glutamate. Finally, in vivo studies further confirmed the role of Pin1 in CAST/calpain2 modulated necrosis following glutamate excitation, in the rat retinal ganglion cell and inner nuclear layers. In addition, a flash electroretinogram study provided evidence for the recovery of impaired visual function, which was induced by glutamate, with juglone treatment. Our work aims to investigate the involvement of the Pin1-CAST/calpain2 pathway in glutamate-mediated excitotoxicity. PMID- 29403359 TI - Horizontal Synchronization of Neuronal Activity in the Barrel Cortex of the Neonatal Rat by Spindle-Burst Oscillations. AB - During development, activity in the somatosensory cortex is characterized by intermittent oscillatory bursts at gamma (early gamma-oscillations, EGOs) and alpha-beta (spindle-bursts, SBs) frequencies. Here, we explored the topography of EGOs and SBs in the neighbor barrels of the whisker-related barrel cortex of neonatal rats (P4-7) during responses evoked by simultaneous activation of multiple whiskers as it occurs during natural conditions. We found that brief simultaneous deflection of all whiskers evoked complex neuronal responses comprised of EGOs and SBs. In contrast to EGOs, that specifically synchronized neuronal activity in each individual barrel, SBs efficiently synchronized activity between neighboring barrels. After plucking a single whisker, synchronous stimulation of spared whiskers evoked EGO-lacking responses in the whisker-deprived barrel, even though the remaining neuronal activity was synchronized by SBs in neighboring barrels. Thus, EGOs specifically support topographic synchronization of neuronal activity within barrels, whereas SBs support horizontal synchronization between neighboring barrels during stimulation of multiple whiskers. We suggest that these two co-existing activity patterns coordinate activity-dependent formation of topographic maps and support the emergence of integrative functions in the primary somatosensory cortex during the critical period of somatosensory maps development. PMID- 29403360 TI - Commentary: Synaptic Excitation in Spinal Motoneurons Alternates with Synaptic Inhibition and Is Balanced by Outward Rectification during Rhythmic Motor Network Activity. PMID- 29403361 TI - GABAergic Neurons in the Rat Medial Septal Complex Express Relaxin-3 Receptor (RXFP3) mRNA. AB - The medial septum (MS) complex modulates hippocampal function and related behaviors. Septohippocampal projections promote and control different forms of hippocampal synchronization. Specifically, GABAergic and cholinergic projections targeting the hippocampal formation from the MS provide bursting discharges to promote theta rhythm, or tonic activity to promote gamma oscillations. In turn, the MS is targeted by ascending projections from the hypothalamus and brainstem. One of these projections arises from the nucleus incertus in the pontine tegmentum, which contains GABA neurons that co-express the neuropeptide relaxin-3 (Rln3). Both stimulation of the nucleus incertus and septal infusion of Rln3 receptor agonist peptides promotes hippocampal theta rhythm. The Gi/o-protein coupled receptor, relaxin-family peptide receptor 3 (RXFP3), is the cognate receptor for Rln3 and identification of the transmitter phenotype of neurons expressing RXFP3 in the septohippocampal system can provide further insights into the role of Rln3 transmission in the promotion of septohippocampal theta rhythm. Therefore, we used RNAscope multiplex in situ hybridization to characterize the septal neurons expressing Rxfp3 mRNA in the rat. Our results demonstrate that Rxfp3 mRNA is abundantly expressed in vesicular GABA transporter (vGAT) mRNA- and parvalbumin (PV) mRNA-positive GABA neurons in MS, whereas ChAT mRNA-positive acetylcholine neurons lack Rxfp3 mRNA. Approximately 75% of Rxfp3 mRNA-positive neurons expressed vGAT mRNA (and 22% were PV mRNA-positive), while the remaining 25% expressed Rxfp3 mRNA only, consistent with a potential glutamatergic phenotype. Similar proportions were observed in the posterior septum. The occurrence of RXFP3 in PV-positive GABAergic neurons gives support to a role for the Rln3-RXFP3 system in septohippocampal theta rhythm. PMID- 29403363 TI - A Retrospective 2D Morphometric Analysis of Adult Female Chiari Type I Patients with Commonly Reported and Related Conditions. AB - Purpose: Researchers have sought to better understand Chiari type I malformation (CMI) through morphometric measurements beyond tonsillar position (TP). Soft tissue and bone structures within the brain and craniocervical junction have been shown to be different for CMI patients compared to healthy controls. Yet, several morphological characteristics have not been consistently associated with CMI. CMI is also associated with different prevalent conditions (PCs) such as syringomyelia, pseudotumor, Ehlers-Danlos syndrome (EDS), scoliosis, and craniocervical instability. The goal of this study was two-fold: (1) to identify unique morphological characteristics of PCs, and (2) to better explain inconsistent results from case-control comparisons of CMI. Methods: Image, demographic, and PC information was obtained through the Chiari1000, a self report web-accessed database. Twenty-eight morphometric measurements (MMs) were performed on the cranial MR images of 236 pre-surgery adult female CMI participants and 140 female healthy control participants. Custom software was used to measure 28 structures within the posterior cranial fossa (PCF) compartment, craniocervical junction, oral cavity, and intracranial area on midsagittal MR images for each participant. Results: Morphometric analysis of adult females indicated a smaller McRae line length in CMI participants with syringomyelia compared to those without syringomyelia. TP was reduced in CMI participants with EDS than those without EDS. Basion to posterior axial line was significantly longer in CMI participants with scoliosis compared to those without scoliosis. No additional MMs were found to differ between CMI participants with and without a specific PC. Four morphometric differences were found to be consistently different between CMI participants and healthy controls regardless of PC: larger TP and a smaller clivus length, fastigium, and corpus callosum height in CMI participants. Conclusion: Syringomyelia, EDS, and scoliosis were the only PCs that showed significant morphometric differences between CMI participants. Additionally, four midsagittal MR-based MMs were found to be significantly different between healthy controls and CMI participants regardless of the presence of one or more PCs. This study suggests that the prevalence of comorbid conditions are not strongly related to CMI morphology, and that inconsistent findings in the radiographic literature cannot be explained by varying prevalence of comorbid conditions in CMI study samples. PMID- 29403362 TI - Hypothalamic Projections to the Optic Tectum in Larval Zebrafish. AB - The optic tectum of larval zebrafish is an important model for understanding visual processing in vertebrates. The tectum has been traditionally viewed as dominantly visual, with a majority of studies focusing on the processes by which tectal circuits receive and process retinally-derived visual information. Recently, a handful of studies have shown a much more complex role for the optic tectum in larval zebrafish, and anatomical and functional data from these studies suggest that this role extends beyond the visual system, and beyond the processing of exclusively retinal inputs. Consistent with this evolving view of the tectum, we have used a Gal4 enhancer trap line to identify direct projections from rostral hypothalamus (RH) to the tectal neuropil of larval zebrafish. These projections ramify within the deepest laminae of the tectal neuropil, the stratum album centrale (SAC)/stratum griseum periventriculare (SPV), and also innervate strata distinct from those innervated by retinal projections. Using optogenetic stimulation of the hypothalamic projection neurons paired with calcium imaging in the tectum, we find rebound firing in tectal neurons consistent with hypothalamic inhibitory input. Our results suggest that tectal processing in larval zebrafish is modulated by hypothalamic inhibitory inputs to the deep tectal neuropil. PMID- 29403364 TI - Multisynaptic Projections from the Amygdala to the Ventral Premotor Cortex in Macaque Monkeys: Anatomical Substrate for Feeding Behavior. AB - The amygdala codes the visual-gustatory/somatosensory valence for feeding behavior. On the other hand, the ventral premotor cortex (PMv) plays a central role in reaching and grasping movements prerequisite for feeding behavior. This implies that object valence signals derived from the amygdala may be crucial for feeding-related motor actions exerted by PMv. However, since no direct connectivity between the amygdala and PMv has been reported, the structural basis of their functional interactions still remains elusive. In the present study, we employed retrograde transneuronal labeling with rabies virus to identify the amygdalar origin and possible route of multisynaptic projections to PMv in macaque monkeys. Histological analysis of the distribution pattern of labeled neurons has found that PMv receives disynaptic input primarily from the basal nucleus, especially from its intermediate subdivision. It has also been revealed that the medial (e.g., the cingulate motor areas, CMA) and lateral (e.g., the insular cortices) cortical areas, and the cholinergic cell group 4 in the basal forebrain probably mediate the projections from the amygdala to PMv. Such multisynaptic pathways might represent amygdalar influences on PMv functions for feeding behavior. PMID- 29403365 TI - A Context Dependent Interpretation of Inconsistencies in 2D:4D Findings: The Moderating Role of Status Relevance. AB - Whereas direct relationships between 2D:4D and dominance related attitudes or behavior often turn out to be weak, some literature suggests that the relation between 2D:4D and dominance is context-specific. That is, especially in status challenging situations 2D:4D may be related to dominant behavior and its correlates. Based on this perspective, we interpret inconsistencies in the literature on the relation between 2D:4D and risk taking, aggression and dominance related outcomes and investigate in our empirical study how attitudes in low 2D:4D men may change as a function of the status relevance of the context. We provide evidence for the idea that status relevance of the particular situation at hand influences the attitude towards performance-enhancing means for low 2D:4D men, but not for high 2D:4D men. We argue that 2D:4D may be related to any behavior that is functional to attain status in a specific context. Implications for (economic) decision making are discussed. PMID- 29403366 TI - Status-Dependent Vasotocin Modulation of Dominance and Subordination in the Weakly Electric Fish Gymnotus omarorum. AB - Dominant-subordinate status emerges from agonistic encounters. The weakly electric fish, Gymnotus omarorum, displays a clear-cut example of non-breeding territorial aggression. The asymmetry in the behavior of dominants and subordinates is outstanding. Dominants are highly aggressive and subordinates signal submission in a precise sequence of locomotor and electric traits: retreating, decreasing their electric organ discharge rate, and emitting transient electric signals. The hypothalamic neuropeptide arginine-vasotocin (AVT) and its mammalian homolog arginine-vasopressin, are key modulators of social behavior, known to adapt their actions to different contexts. By analyzing the effects of pharmacological manipulations of the AVT system in both dominants and subordinates, we show evidence of distinct status-dependent actions of AVT. We demonstrate an endogenous effect of AVT on dominants' aggression levels: blocking the V1a AVT receptor induced a significant decrease in dominants' attack rate. AVT administered to subordinates enhanced the expression of the electric signals of submission, without affecting subordinates' locomotor displays. This study contributes a clear example of status-dependent AVT modulation of agonistic behavior in teleosts, and reveals distinctive activation patterns of the AVT system between dominants and subordinates. PMID- 29403367 TI - Decoding Pedophilia: Increased Anterior Insula Response to Infant Animal Pictures. AB - Previous research found increased brain responses of men with sexual interest in children (i.e., pedophiles) not only to pictures of naked children but also to pictures of child faces. This opens the possibly that pedophilia is linked (in addition to or instead of an aberrant sexual system) to an over-active nurturing system. To test this hypothesis we exposed pedophiles and healthy controls to pictures of infant and adult animals during functional magnetic resonance imaging of the brain. By using pictures of infant animals (instead of human infants), we aimed to elicit nurturing processing without triggering sexual processing. We hypothesized that elevated brain responses to nurturing stimuli will be found - in addition to other brain areas - in the anterior insula of pedophiles because this area was repeatedly found to be activated when adults see pictures of babies. Behavioral ratings confirmed that pictures of infant or adult animals were not perceived as sexually arousing neither by the pedophilic participants nor by the heathy controls. Statistical analysis was applied to the whole brain as well as to the anterior insula as region of interest. Only in pedophiles did infants relative to adult animals increase brain activity in the anterior insula, supplementary motor cortex, and dorsolateral prefrontal areas. Within-group analysis revealed an increased brain response to infant animals in the left anterior insular cortex of the pedophilic participants. Currently, pedophilia is considered the consequence of disturbed sexual or executive brain processing, but details are far from known. The present findings raise the question whether there is also an over-responsive nurturing system in pedophilia. PMID- 29403368 TI - On the Efficiency of Individualized Theta/Beta Ratio Neurofeedback Combined with Forehead EMG Training in ADHD Children. AB - Background: Neurofeedback training (NFT) to decrease the theta/beta ratio (TBR) has been used for treating hyperactivity and impulsivity in attention deficit hyperactivity disorder (ADHD); however, often with low efficiency. Individual variance in EEG profile can confound NFT, because it may lead to influencing non relevant activity, if ignored. More importantly, it may lead to influencing ADHD related activities adversely, which may even result in worsening ADHD symptoms. Electromyogenic (EMG) signal resulted from forehead muscles can also explain the low efficiency of the NFT in ADHD from both practical and psychological point-of view. The first aim of this study was to determine EEG and EMG biomarkers most related to the main ADHD characteristics, such as impulsivity and hyperactivity. The second aim was to confirm our hypothesis that the efficiency of the TBR NFT can be increased by individual adjustment of the frequency bands and simultaneous training on forehead muscle tension. Methods: We recruited 94 children diagnosed with ADHD (ADHD) and 23 healthy controls (HC). All participants were male and aged between six and nine. Impulsivity and attention were assessed with Go/no-Go task and delayed gratification task, respectively; and 19-channel EEG and forehead EMG were recorded. Then, the ADHD group was randomly subdivided into (1) standard, (2) individualized, (3) individualized+EMG, and (4) sham NFT (control) groups. The groups were compared based on TBR and EEG alpha activity, as well as hyperactivity and impulsivity three times: pre-NFT, post-NFT and 6 months after the NFT (follow-up). Results: ADHD children were characterized with decreased individual alpha peak frequency, alpha bandwidth and alpha amplitude suppression magnitude, as well as with increased alpha1/alpha2 (a1/a2) ratio and scalp muscle tension when c (eta2 >= 0.212). All contingent TBR NFT groups exhibited significant NFT-related decrease in TBR not evident in the control group. Moreover, we detected a higher overall alpha activity in the individualized but not in the standard NFT group. Mixed MANOVA considering between-subject factor GROUP and within-subject factor TIME showed that the individualized+EMG group exhibited the highest level of clinical improvement, which was associated with increase in the individual alpha activity at the 6 months follow-up when comparing with the other approaches (post hoc t = 3.456, p = 0.011). Conclusions: This study identified various (adjusted) alpha activity metrics as biomarkers with close relationship with ADHD symptoms, and demonstrated that TBR NFT individually adjusted for variances in alpha activity is more successful and clinically more efficient than standard, non-individualized NFT. Moreover, these training effects of the individualized TBR NFT lasted longer when combined with EMG. PMID- 29403369 TI - Commentary: Using goal-driven deep learning models to understand sensory cortex. PMID- 29403370 TI - Reproducibility vs. Replicability: A Brief History of a Confused Terminology. PMID- 29403372 TI - Systemic Measures and Legislative and Organizational Frameworks Aimed at Preventing or Mitigating Drug Shortages in 28 European and Western Asian Countries. AB - Drug shortages have been identified as a public health problem in an increasing number of countries. This can negatively impact on the quality and efficiency of patient care, as well as contribute to increases in the cost of treatment and the workload of health care providers. Shortages also raise ethical and political issues. The scientific evidence on drug shortages is still scarce, but many lessons can be drawn from cross-country analyses. The objective of this study was to characterize, compare, and evaluate the current systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages within health care systems across a range of European and Western Asian countries. The study design was retrospective, cross-sectional, descriptive, and observational. Information was gathered through a survey distributed among senior personnel from ministries of health, state medicines agencies, local health authorities, other health or pharmaceutical pricing and reimbursement authorities, health insurance companies and academic institutions, with knowledge of the pharmaceutical markets in the 28 countries studied. Our study found that formal definitions of drug shortages currently exist in only a few countries. The characteristics of drug shortages, including their assortment, duration, frequency, and dynamics, were found to be variable and sometimes difficult to assess. Numerous information hubs were identified. Providing public access to information on drug shortages to the maximum possible extent is a prerequisite for performing more advanced studies on the problem and identifying solutions. Imposing public service obligations, providing the formal possibility to prescribe unlicensed medicines, and temporary bans on parallel exports are widespread measures. A positive finding of our study was the identification of numerous bottom-up initiatives and organizational frameworks aimed at preventing or mitigating drug shortages. The experiences and lessons drawn from these initiatives should be carefully evaluated, monitored, and presented to a wider international audience for careful appraisal. To be able to find solutions to the problem of drug shortages, there is an urgent need to develop a set of agreed definitions for drug shortages, as well as methodologies for their evaluation and monitoring. This is being progressed. PMID- 29403373 TI - Protective Effect of Klotho against Ischemic Brain Injury Is Associated with Inhibition of RIG-I/NF-kappaB Signaling. AB - Aging is the greatest independent risk factor for the occurrence of stroke and poor outcomes, at least partially through progressive increases in oxidative stress and inflammation with advanced age. Klotho is an antiaging gene, the expression of which declines with age. Klotho may protect against neuronal oxidative damage that is induced by glutamate. The present study investigated the effects of Klotho overexpression and knockdown by an intracerebroventricular injection of a lentiviral vector that encoded murine Klotho (LV-KL) or rat Klotho short-hairpin RNA (LV-KL shRNA) on cerebral ischemia injury and the underlying anti-neuroinflammatory mechanism. The overexpression of Klotho induced by LV-KL significantly improved neurobehavioral deficits and increased the number of live neurons in the hippocampal CA1 and caudate putamen subregions 72 h after cerebral hypoperfusion that was induced by transient bilateral common carotid artery occlusion (2VO) in mice. The overexpression of Klotho significantly decreased the immunoreactivity of glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1, the expression of retinoic-acid-inducible gene-I, the nuclear translocation of nuclear factor-kappaB, and the production of proinflammatory cytokines (tumor necrosis factor alpha and interleukin-6) in 2VO mice. The knockdown of Klotho mediated by LV-KL shRNA in the brain exacerbated neurological dysfunction and cerebral infarct after 22 h of reperfusion following 2 h middle cerebral artery occlusion in rats. These findings suggest that Klotho itself or enhancers of Klotho may compensate for its aging-related decline, thus providing a promising therapeutic approach for acute ischemic stroke during advanced age. PMID- 29403374 TI - Neurotrophic, Cytoprotective, and Anti-inflammatory Effects of St. John's Wort Extract on Differentiated Mouse Hippocampal HT-22 Neurons. AB - Introduction: Since ancient times Hypericum perforatum L. named St. John's wort (SJW), has been used in the management of a wide range of applications, including nervous disorders. Development of mood disorders are due to alterations in glutamate metabolism, initiation of inflammatory pathways, and changes of the neuronal plasticity. Previous studies suggest that the glutamatergic system contributes to the pathophysiology of depression. Extracts of SJW have been recommended for the treatment of depression. The aim of the present in vitro study was to evaluate the action of STW3-VI, a special SJW extract in differentiated mouse hippocampal HT-22 neurons. We evaluated the stimulation of neurogenesis, the protective effect against glutamate or N-methyl-D-aspartate receptor induced-excitotoxicity and its anti-inflammatory properties in LPS activated human macrophages. Results: After 48 h treatment, STW3-VI stimulated the neurite formation by 25% in comparison with the control and showed protective effects against glutamate- or NMDA-induced cytotoxicity by significantly increasing the viability about +25 or +50%. In conjunction with these effects, after pretreatment with STW3-VI, the intracellular reduced glutathione content was significantly 2.3-fold increased compared with the neurons incubated with glutamate alone. Additionally, pre-treatment of human macrophages with STW3-VI showed anti-inflammatory effects after 24 or 48 h concerning inhibition of LPS induced TNF release by -47.3 and -53.8% (24 h) or -25.0 to -64.8% (48 h). Conclusions: Our data provide new evidence that STW3-VI protects hippocampal cells from NMDA- or glutamate-induced cytotoxicity. Moreover, our results indicate a morphological remodeling by increasing neurite outgrowth and activation of the anti-inflammatory defense by inhibition of the cytokine production in human macrophages after STW3-VI treatment. These protective, neurotrophic and anti-inflammatory properties may be beneficial in the treatment of depressive disorders. PMID- 29403371 TI - Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects. AB - Parkinson's Disease (PD) is currently considered a systemic neurodegenerative disease manifested with not only motor but also non-motor symptoms. In particular, weight loss and malnutrition, a set of frequently neglected non-motor symptoms, are indeed negatively associated with the life quality of PD patients. Moreover, comorbidity of weight loss and malnutrition may impact disease progression, giving rise to dyskinesia, cognitive decline and orthostatic hypotension, and even resulting in disability and mortality. Nevertheless, the underlying mechanism of weight loss and malnutrition in PD remains obscure and possibly involving multitudinous, exogenous or endogenous, factors. What is more, there still does not exist any weight loss and malnutrition appraision standards and management strategies. Given this, here in this review, we elaborate the weight loss and malnutrition study status in PD and summarize potential determinants and mechanisms as well. In conclusion, we present current knowledge and future prospects of weight loss and malnutrition in the context of PD, aiming to appeal clinicians and researchers to pay a closer attention to this phenomena and enable better management and therapeutic strategies in future clinical practice. PMID- 29403375 TI - Stem Cell Metabolism in Cancer and Healthy Tissues: Pyruvate in the Limelight. AB - Normal and cancer stem cells (CSCs) share the remarkable potential to self-renew and differentiate into many distinct cell types. Although most of the stem cells remain under quiescence to maintain their undifferentiated state, they can also undergo cell divisions as required to regulate tissue homeostasis. There is now a growing evidence that cell fate determination from stem cells implies a fine tuned regulation of their energy balance and metabolic status. Stem cells can shift their metabolic substrate utilization, between glycolysis and mitochondrial oxidative metabolism, during specification and/or differentiation, as well as in order to adapt their microenvironmental niche. Pyruvate appears as a key metabolite since it is at the crossroads of cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. This Review describes how metabolic reprogramming, focusing on pyruvate utilization, drives the fate of normal and CSCs by modulating their capacity for self-renewal, clonal expansion/differentiation, as well as metastatic potential and treatment resistance in cancer. This Review also explores potential therapeutic strategies to restore or manipulate stem cell function through the use of small molecules targeting the pyruvate metabolism. PMID- 29403376 TI - Chamaejasmine B Induces the Anergy of Vascular Endothelial Cells to VEGFA Pro angiogenic Signal by Autophagic Regulation of VEGFR2 in Breast Cancer. AB - The neovascularization functions essentially for malignant upgrading and predicts poor prognosis in multiple cancers, which make it the highly effective strategy for clinical treatment. Unfortunately, the known anti-angiogenic therapies show low effectiveness against breast cancer. Recently, rebalancing the pro-angiogenic property in microenvironment shows great advantages and attracts increasing attention for breast cancer treatment. Herein, we for the first time reported that Chamaejasmine B (ICJ), extracted from Stellera chamaejasme L., possessed potent anti-angiogenic effect in breast cancer. By Transwell, tube formation and aortic-ring assays, ICJ efficiently suppressed the neovascularization potential in tumor-HUVEC co-culture model. In Matrigel plug assay, the efficacy of ICJ was further identified in vivo. Mechanistically, with little influence on HUVEC apoptosis, ICJ obviously induced autophagy as proved by the elevated LC3I/II ratio, dotted distribution of LC3 and upregulated Beclin-1. Moreover, by associating with LC3 and in turn, inhibiting the level of VEGFR2, the anti angiogenesis efficacy was closely dependent on the initiation of autophagy. Above results proved that, by attenuating the pro-angiogenic communication through VEGFR2, ICJ is a novel angiogenic inhibitor and will be a promising supplement for anti-angiogenic chemotherapy for breast cancer. PMID- 29403377 TI - Carnosic Acid Alleviates BDL-Induced Liver Fibrosis through miR-29b-3p-Mediated Inhibition of the High-Mobility Group Box 1/Toll-Like Receptor 4 Signaling Pathway in Rats. AB - Fibrosis reflects a progression to liver cancer or cirrhosis of the liver. Recent studies have shown that high-mobility group box-1 (HMGB1) plays a major role in hepatic injury and fibrosis. Carnosic acid (CA), a compound extracted from rosemary, has been reported to alleviate alcoholic and non-alcoholic fatty liver injury. CA can also alleviate renal fibrosis. We hypothesized that CA might exert anti-liver fibrosis properties through an HMGB1-related pathway, and the results of the present study showed that CA treatment significantly protected against hepatic fibrosis in a bile duct ligation (BDL) rat model. CA reduced the liver expression of alpha-smooth muscle actin (alpha-SMA) and collagen 1 (Col-1). Importantly, we found that CA ameliorated the increase in HMGB1 and Toll-like receptor 4 (TLR4) caused by BDL, and inhibited NF-kappaB p65 nuclear translocation in fibrotic livers. In vitro, CA inhibited LX2 cell activation by inhibiting HMGB1/TLR4 signaling pathway. Furthermore, miR-29b-3p decreased HMGB1 expression, and a dual-luciferase assay validated these results. Moreover, CA down-regulated HMGB1 and inhibited LX2 cell activation, and these effects were significantly counteracted by antago-miR-29b-3p, indicating that the CA-mediated inhibition of HMGB1 expression might be miR-29b-3p dependent. Collectively, the results demonstrate that a miR-29b-3p/HMGB1/TLR4/NF-kappaB signaling pathway, which can be modulated by CA, is important in liver fibrosis, and indicate that CA might be a prospective therapeutic drug for liver fibrosis. PMID- 29403379 TI - A Spontaneous Mutation in Taar1 Impacts Methamphetamine-Related Traits Exclusively in DBA/2 Mice from a Single Vendor. AB - Major gene effects on traits associated with substance use disorders are rare. Previous findings in methamphetamine drinking (MADR) lines of mice, bred for high or low voluntary MA intake, and in null mutants demonstrate a major impact of the trace amine-associated receptor 1 (Taar1) gene on a triad of MA-related traits: MA consumption, MA-induced conditioned taste aversion and MA-induced hypothermia. While inbred strains are fundamentally genetically stable, rare spontaneous mutations can become fixed and result in new or aberrant phenotypes. A single nucleotide polymorphism in Taar1 that encodes a missense proline to threonine mutation in the second transmembrane domain (Taar1m1J ) has been identified in the DBA/2J strain. MA is an agonist at this receptor, but the receptor produced by Taar1m1J does not respond to MA or endogenous ligands. In the present study, we used progeny of the C57BL/6J * DBA/2J F2 cross, the MADR lines, C57BL/6J * DBA/2J recombinant inbred strains, and DBA/2 mice sourced from four vendors to further examine Taar1-MA phenotype relations and to define the chronology of the fixation of the Taar1m1J mutation. Mice homozygous for Taar1m1J were found at high frequency early in selection for high MA intake in multiple replicates of the high MADR line, whereas Taar1m1J homozygotes were absent in the low MADR line. The homozygous Taar1m1J genotype is causally linked to increased MA intake, reduced MA-induced conditioned taste aversion, and reduced MA-induced hypothermia across models. Genotype-phenotype correlations range from 0.68 to 0.96. This Taar1 polymorphism exists in DBA/2J mice sourced directly from The Jackson Laboratory, but not DBA/2 mice sourced from Charles River (DBA/2NCrl), Envigo (formerly Harlan Sprague Dawley; DBA/2NHsd) or Taconic (DBA/2NTac). By genotyping archived samples from The Jackson Laboratory, we have determined that this mutation arose in 2001-2003. Our data strengthen the conclusion that the mutant Taar1m1J allele, which codes for a non-functional receptor protein, increases risk for multiple MA-related traits, including MA intake, in homozygous Taar1m1J individuals. PMID- 29403378 TI - Pharmacological Intervention to Modulate HDL: What Do We Target? AB - The cholesterol concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) have traditionally served as risk factors for cardiovascular disease. As such, novel therapeutic interventions aiming to raise HDL cholesterol have been tested in the clinical setting. However, most trials led to a significant increase in HDL cholesterol with no improvement in cardiovascular events. The complexity of the HDL particle, which exerts multiple physiological functions and is comprised of a number of subclasses, has raised the question as to whether there should be more focus on HDL subclass and function rather than cholesterol quantity. We review current data regarding HDL subclasses and subclass-specific functionality and highlight how current lipid modifying drugs such as statins, cholesteryl ester transfer protein inhibitors, fibrates and niacin often increase cholesterol concentrations of specific HDL subclasses. In addition this review sets out arguments suggesting that the HDL3 subclass may provide better protective effects than HDL2. PMID- 29403381 TI - Factors Contributing to Exacerbating Vulnerabilities in Global Clinical Trials. AB - Background: Although policies and guidelines make use of the concept of vulnerability, few define it. The European Union's directive for clinical trials does not include explanations for or the reasoning behind the designation of certain groups as vulnerable. Emerging economies from lower middle-income countries have, in recent years, had the largest average annual growth rate, as well as increase, in number of clinical trials registered in the US government's database. Nevertheless, careful supervision of research activities has to be ensured. Objective: To describe and analyze the features of the clinical trials involving vulnerable populations in various countries classified by development status and geographic region. Methods: Retrospective study that involved analysis of data obtained from the International Clinical Trials Registry Platform (ICTRP) database between 01/2014 and 12/2014 from countries with (i) highest trial densities during 2005 to 2012, (ii) highest average growth rate in clinical trials, and (iii) greatest trial capabilities. Results: Statistical analysis of this study showed that patients incapable of giving consent personally are 11.4 times more likely to be vulnerable patients than patients who are capable, and that patients in upper-middle-income countries are 1.7 times more likely to be vulnerable patients than patients from high-income countries when participating in global clinical trials. Malaysia (21%), Egypt (20%), Turkey (19%), Israel (18%), and Brazil (17%) had the highest percentages of vulnerable populations involving children. Conclusions: Although the inability to provide consent personally was a factor associated with vulnerability, arbitrary criteria may have been considered when classifying the populations of clinical trials as vulnerable. The EU Clinical Trials Register should provide guidance regarding exactly what aspects or factors should be taken into account to frame given populations as vulnerable, because vulnerability is not applicable to all risk situations. PMID- 29403380 TI - Recent Progress in CFTR Interactome Mapping and Its Importance for Cystic Fibrosis. AB - Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride channel found in secretory epithelia with a plethora of known interacting proteins. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease that leads to progressive respiratory illness and other complications of phenotypic variance resulting from perturbations of this protein interaction network. Studying the collection of CFTR interacting proteins and the differences between the interactomes of mutant and wild type CFTR provides insight into the molecular machinery of the disease and highlights possible therapeutic targets. This mini review focuses on functional genomics and proteomics approaches used for systematic, high-throughput identification of CFTR-interacting proteins to provide comprehensive insight into CFTR regulation and function. PMID- 29403382 TI - Menthol and Menthone Associated with Acetylsalicylic Acid and Their Relation to the Hepatic Fibrosis in Schistosoma mansoni Infected Mice. AB - Schistosomiasis is an important parasitic disease caused by Schistosoma mansoni, an intravascular trematode. Schistosomiasis treatment is limited to just one drug, Praziquantel (PZQ). Thus, studies on new antischistosomal compounds are of fundamental importance to disease control. Here we report on the effects of Mentha piperita L. compounds - menthol and menthone - in association with acetylsalicylic acid (ASA) in the regulation of hepatic fibrosis caused by schistosomiasis granulomas. Six different groups of Swiss rats were infected with 80 cercariae. Two groups received only menthol and menthol treatment at different concentrations (30 and 50 mg/kg); two groups received treatment with the same concentration of menthol and menthol, but associated the ASA. All groups received treatment for 14 consecutive days from the 35 days after the parasitic infection. In addition, three other groups were used: uninfected and untreated group, infected and untreated group and infected group treated with the commercial drug (single dose). Parasitological, cytological and histological analyses were performed. Results showed a significant reduction on the number of eosinophils found in the peritoneal cavity lavage (LPC) in all treated groups and on the number of eosinophils found in the blood of PZQ treated group, in the blood of the group treated with 30 mg/kg of Mentaliv(r) and in the blood of group treated with 50 mg/kg Mentaliv(r) + ASA when compared to the infected group. All treated groups presented a reduction in the parasite load, represented by the number of S. mansoni eggs, in the experimental group treated with 30 mg/kg of menthol and menthone a 62.80% reduction was observed and in the experimental group treated with 50 mg/kg of menthol and menthone + ASA a reduction of 64.21% was observed. In the liver histological analysis we observed that all Mentaliv(r) treated groups expressed a unique cytological profile, with diffused cells through the granuloma. In the experimental group treated with 50 mg/kg of Mentaliv(r) + ASA it was possible to observe the formation of type III collagen fibers, a typical wound healing characteristic. Our data strongly suggest that both the hepatic fibrosis and the inflammatory process were regulated through the schistosomiasis granulomatous process after treatment with menthol and menthone associated with ASA. PMID- 29403383 TI - How Realistic Are the Scientific Assumptions of the Neuroenhancement Debate? Assessing the Pharmacological Optimism and Neuroenhancement Prevalence Hypotheses. AB - Since two decades, neuroenhancement is a major topic in neuroethics and still receives much attention in the scholarly literature as well as in public media. In contrast to high hopes at the beginning of the "Decade of the Brain" in the United States and Europe that we subsume under the "pharmacological optimism hypothesis," recent evidence from clinical neuroscience suggests that developing drugs that make healthy people smarter is even more difficult than finding new treatments for patients with mental disorders. However, cognitive enhancing drugs even for patients with impaired intellectual performance have not been successfully developed yet and new drugs that might have a disruptive impact on this field are unlikely to be developed in the near future. Additionally, we discuss theoretical, empirical, and historical evidence to assess whether cognitive enhancement of the healthy is common or even epidemic and if its application will further increase in the near future, as suggested by the "neuroenhancement prevalence hypothesis." Reports, surveys, and reviews from the 1930s until today indicate that psychopharmacological neuroenhancement is a fact but less common than often stated, particularly in the public media. Non-medical use of psychostimulants for the purpose of cognitive enhancement exists since at least 80 years and it might actually have been more common in the past than today. Therefore, we conclude that the pharmacological optimism hypothesis and neuroenhancement prevalence hypotheses have to be rejected and argue that the neuroenhancement debate should take the available evidence more into account. PMID- 29403384 TI - Phenotyping of Mice with Heart Specific Overexpression of A2A-Adenosine Receptors: Evidence for Cardioprotective Effects of A2A-Adenosine Receptors. AB - Background: Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A2A-adenosine receptor (A2A-AR). Methods and Results: To better understand its role in cardiac function, we generated and characterized mice (A2A-TG) which overexpress the human A2A-AR in cardiomyocytes. In isolated atrial preparations from A2A-TG but not from WT, CGS 21680, an A2A-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A2A-TG but not WT, CGS 21680 increased the cAMP content and the phosphorylation state of phospholamban and of the inhibitory subunit of troponin in A2A-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A2A-TG compared to WT. Protein expression of the alpha subunit of the stimulatory G-protein was lower in A2A-TG than in WT but expression of the alpha-subunit of the inhibitory G-protein was higher in A2A-TG than in WT. While basal hemodynamic parameters like left intraventricular pressure and echocardiographic parameters like the systolic diameter of the interventricular septum were higher in A2A-TG than in WT, after beta-adrenergic stimulation these differences disappeared. Interestingly, A2A-TG hearts sustained global ischemia better than WT. Conclusion: We have successfully generated transgenic mice with cardiospecific overexpression of a functional A2A-AR. This receptor is able to increase cardiac function per se and after receptor stimulation. It is speculated that this receptor may be useful to sustain contractility in failing human hearts and upon ischemia and reperfusion. PMID- 29403385 TI - Differential Contribution of Constituent Metal Ions to the Cytotoxic Effects of Fast-Dissolving Metal-Oxide Nanoparticles. AB - The main mechanism of toxicity for fast-dissolving nanoparticles (NPs) is relatively simple as it originates from the intrinsic toxicity of their constituent elements rather than complicated surface reactivity. However, there is little information about the compared toxicity of fast-dissolving NP and its constituent ion, which is essential for understanding the mechanism of NP toxicity and the development of a structure-toxicity relationship (STR) model. Herein, we selected three types of fast-dissolving metal-oxide NPs (CoO, CuO, and ZnO) and constituent metal chlorides (CoCl2, CuCl2, and ZnCl2) to compare dose response curves between NP and its constituent metal. These materials were treated relevant cell lines for inhalation setting (i.e., differentiated THP-1 cells for macrophages and A549 cells for alveolar epithelial cells) and cytotoxicity as an endpoint was evaluated at 24 h post-incubation. The results showed that CoO and CuO NPs in both cell types showed similar patterns of dose response curves and cytotoxic potential compared to that of their respective metal chloride. On the other hand, ZnO NPs in both cell types showed a completely different dose-response curve compared to that of ZnCl2: ZnO NPs showed modest slope and much less potential for cytotoxicity compared to that of ZnCl2. These results imply that fast-dissolving metal-oxide NPs are not always have similar dose-response curves and toxic potentials compared to their constituent metal chlorides and this may be due to the differential mechanism of intracellular uptake of these substances and their interaction with intracellular detoxification molecules. Further investigations are needed for the use of toxic potential of metal ions as a predicting factors of fast-dissolving NPs toxicity. In addition, chelating agent specific for dissolved metal ions can be applied for the treatment of these fast-dissolving NPs. PMID- 29403386 TI - Increased Dietary Leucine Reduces Doxorubicin-Associated Cardiac Dysfunction in Rats. AB - Cardiotoxicity is one of the most significant adverse effects of the oncologic treatment with doxorubicin, which is responsible for a substantial morbid and mortality. The occurrence of heart failure with ventricular dysfunction may lead to severe cardiomyopathy and ultimately to death. Studies have focused on the effects of leucine supplementation as a strategy to minimize or revert the clinical condition of induced proteolysis by several clinical onsets. However, the impact of leucine supplementation in heart failure induced by doxorubicin is unknown. Therefore, the objective of this work is to evaluate the effects of leucine supplementation on the cardiotoxicity in the heart of rats treated with doxorubicin. Rats treated with a 7.5 mg/kg cumulative dose of doxorubicin for 14 days presented a dilatation of the left ventricle (LV), and a reduction of the ejection fraction (FE). The 5% supplementation of leucine in the rats' food prevented the malfunctioning of the LV when administered with doxorubicin. Some alterations in the extracellular matrix remodeling were confirmed by the increase of collagen fibers in the doxorubicin group, which did not increase when the treatment was associated with leucine supplementation. Leucine attenuates heart failure in this experimental model with doxorubicin. Such protection is followed by the maintenance of interstitial collagen fibers. PMID- 29403387 TI - A Hybrid Model for Safety Pharmacology on an Automated Patch Clamp Platform: Using Dynamic Clamp to Join iPSC-Derived Cardiomyocytes and Simulations of Ik1 Ion Channels in Real-Time. AB - An important aspect of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) proposal is the use of human stem cell-derived cardiomyocytes and the confirmation of their predictive power in drug safety assays. The benefits of this cell source are clear; drugs can be tested in vitro on human cardiomyocytes, with patient-specific genotypes if needed, and differentiation efficiencies are generally excellent, resulting in a virtually limitless supply of cardiomyocytes. There are, however, several challenges that will have to be surmounted before successful establishment of hSC-CMs as an all-round predictive model for drug safety assays. An important factor is the relative electrophysiological immaturity of hSC-CMs, which limits arrhythmic responses to unsafe drugs that are pro-arrhythmic in humans. Potentially, immaturity may be improved functionally by creation of hybrid models, in which the dynamic clamp technique joins simulations of lacking cardiac ion channels (e.g., IK1) with hSC-CMs in real-time during patch clamp experiments. This approach has been used successfully in manual patch clamp experiments, but throughput is low. In this study, we combined dynamic clamp with automated patch clamp of iPSC-CMs in current clamp mode, and demonstrate that IK1 conductance can be added to iPSC-CMs on an automated patch clamp platform, resulting in an improved electrophysiological maturity. PMID- 29403388 TI - Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms. AB - Characterizing the contractile function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is key for advancing their utility for cellular disease models, promoting cell based heart repair, or developing novel pharmacological interventions targeting cardiac diseases. The aim of the present study was to understand whether steady-state and kinetic force parameters of beta-myosin heavy chain (betaMyHC) isoform-expressing myofibrils within human embryonic stem cell derived cardiomyocytes (hESC-CMs) differentiated in vitro resemble those of human ventricular myofibrils (hvMFs) isolated from adult donor hearts. Contractile parameters were determined using the same micromechanical method and experimental conditions for both types of myofibrils. We identified isoforms and phosphorylation of main sarcomeric proteins involved in the modulation of force generation of both, chemically demembranated hESC-CMs (d-hESC-CMs) and hvMFs. Our results indicate that at saturating Ca2+ concentration, both human-derived contractile systems developed forces with similar rate constants (0.66 and 0.68 s 1), reaching maximum isometric force that was significantly smaller for d-hESC CMs (42 kPa) than for hvMFs (94 kPa). At submaximal Ca2+-activation, where intact cardiomyocytes normally operate, contractile parameters of d-hESC-CMs and hvMFs exhibited differences. Ca2+ sensitivity of force was higher for d-hESC-CMs (pCa50 = 6.04) than for hvMFs (pCa50 = 5.80). At half-maximum activation, the rate constant for force redevelopment was significantly faster for d-hESC-CMs (0.51 s 1) than for hvMFs (0.28 s-1). During myofibril relaxation, kinetics of the slow force decay phase were significantly faster for d-hESC-CMs (0.26 s-1) than for hvMFs (0.21 s-1), while kinetics of the fast force decay were similar and ~20x faster. Protein analysis revealed that hESC-CMs had essentially no cardiac troponin-I, and partially non-ventricular isoforms of some other sarcomeric proteins, explaining the functional discrepancies. The sarcomeric protein isoform pattern of hESC-CMs had features of human cardiomyocytes at an early developmental stage. The study indicates that morphological and ultrastructural maturation of betaMyHC isoform-expressing hESC-CMs is not necessarily accompanied by ventricular-like expression of all sarcomeric proteins. Our data suggest that hPSC-CMs could provide useful tools for investigating inherited cardiac diseases affecting contractile function during early developmental stages. PMID- 29403390 TI - Fatty Infiltration of the Myocardium and Arrhythmogenesis: Potential Cellular and Molecular Mechanisms. AB - Anatomical evidence in several species shows highly heterogeneous fat distribution in the atrial and ventricular myocardium. Atrial appendages have fat deposits, and more so on the posterior left atrium. Although such fat distributions are considered normal, fatty infiltration is regarded arrhythmogenic, and various cardiac pathophysiological conditions show excess myocardial fat deposits, especially in the epicardium. Hypotheses have been presented for the physiological and pathophysiological roles of epicardial fat, however this issue is poorly understood. Therefore, this mini-review will focus on epicardial fat distribution and the (patho)-physiological implications of this distribution. Potential molecular mechanisms that may drive structural and electrical myocardial remodeling attendant to fatty infiltration of the heart are also reviewed. PMID- 29403389 TI - Spinal Health during Unloading and Reloading Associated with Spaceflight. AB - Spinal elongation and back pain are recognized effects of exposure to microgravity, however, spinal health has received relatively little attention. This changed with the report of an increased risk of post-flight intervertebral disc (IVD) herniation and subsequent identification of spinal pathophysiology in some astronauts post-flight. Ground-based analogs, particularly bed rest, suggest that a loss of spinal curvature and IVD swelling may be factors contributing to unloading-induced spinal elongation. In flight, trunk muscle atrophy, in particular multifidus, may precipitate lumbar curvature loss and reduced spinal stability, but in-flight (ultrasound) and pre- and post-flight (MRI) imaging have yet to detect significant IVD changes. Current International Space Station missions involve short periods of moderate-to-high spinal (axial) loading during running and resistance exercise, superimposed upon a background of prolonged unloading (microgravity). Axial loading acting on a dysfunctional spine, weakened by anatomical changes and local muscle atrophy, might increase the risk of damage/injury. Alternatively, regular loading may be beneficial. Spinal pathology has been identified in-flight, but there are few contemporary reports of in flight back injury and no recent studies of post-flight back injury incidence. Accurate routine in-flight stature measurements, in- and post-flight imaging, and tracking of pain and injury (herniation) for at least 2 years post-flight is thus warranted. These should be complemented by ground-based studies, in particular hyper buoyancy floatation (HBF) a novel analog of spinal unloading, in order to elucidate the mechanisms and risk of spinal injury, and to evaluate countermeasures for exploration where injury could be mission critical. PMID- 29403391 TI - Pretreatment with AQP4 and NKCC1 Inhibitors Concurrently Attenuated Spinal Cord Edema and Tissue Damage after Spinal Cord Injury in Rats. AB - Spinal cord injury (SCI) affects more than 2.5 million people worldwide. Spinal cord edema plays critical roles in the pathological progression of SCI. This study aimed to delineate the roles of aquaporin 4 (AQP4) and Na+-K+-Cl- cotransporter 1 (NKCC1) in acute phase edema and tissue destruction after SCI and to explore whether inhibiting both AQP4 and NKCC1 could improve SCI-induced spinal edema and damage. Rat SCI model was established by modified Allen's method. Spinal cord water content, cerebrospinal fluid lactose dehydrogenase (LDH) activity, AQP4 and NKCC1 expression, and spinal cord pathology from 30 min to 7 days after SCI were monitored. Additionally, aforementioned parameters in rats treated with AQP4 and/or NKCC1 inhibitors were assessed 2 days after SCI. Spinal cord water content was significantly increased 1 h after SCI while AQP4 and NKCC1 expression and spinal fluid LDH activity elevated 6 h after SCI. Spinal cord edema and spinal cord destruction peaked around 24 h after SCI and maintained at high levels thereafter. Treating rats with AQP4 inhibitor TGN-020 and NKCC1 antagonist bumetanide significantly reduced spinal cord edema, tissue destruction, and AQP4 and NKCC1 expression after SCI in an additive manner. These results demonstrated the benefits of simultaneously inhibiting both AQP4 and NKCC1 after SCI. PMID- 29403393 TI - An Innovative Technique to Assess Spontaneous Baroreflex Sensitivity with Short Data Segments: Multiple Trigonometric Regressive Spectral Analysis. AB - Objective: As the multiple trigonometric regressive spectral (MTRS) analysis is extraordinary in its ability to analyze short local data segments down to 12 s, we wanted to evaluate the impact of the data segment settings by applying the technique of MTRS analysis for baroreflex sensitivity (BRS) estimation using a standardized data pool. Methods: Spectral and baroreflex analyses were performed on the EuroBaVar dataset (42 recordings, including lying and standing positions). For this analysis, the technique of MTRS was used. We used different global and local data segment lengths, and chose the global data segments from different positions. Three global data segments of 1 and 2 min and three local data segments of 12, 20, and 30 s were used in MTRS analysis for BRS. Results: All the BRS-values calculated on the three global data segments were highly correlated, both in the supine and standing positions; the different global data segments provided similar BRS estimations. When using different local data segments, all the BRS-values were also highly correlated. However, in the supine position, using short local data segments of 12 s overestimated BRS compared with those using 20 and 30 s. In the standing position, the BRS estimations using different local data segments were comparable. There was no proportional bias for the comparisons between different BRS estimations. Conclusion: We demonstrate that BRS estimation by the MTRS technique is stable when using different global data segments, and MTRS is extraordinary in its ability to evaluate BRS in even short local data segments (20 and 30 s). Because of the non-stationary character of most biosignals, the MTRS technique would be preferable for BRS analysis especially in conditions when only short stationary data segments are available or when dynamic changes of BRS should be monitored. PMID- 29403394 TI - Editorial: Vision in Cephalopods. PMID- 29403392 TI - Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease. AB - Background: Ischemic heart disease (IHD) has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS) as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated. Materials and Methods: Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI) topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses) for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures. Results: The total of 1,056 high-quality IHD associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD) were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules). These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620) and Renin-angiotensin system (hsa04614), with the molecular functions of angiotensin maturation (GO:0002003) and response to bacterium (GO:0009617), which had been validated by classical Chinese herbal formulas related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO) and published biomedical literatures. Conclusion: A network medicine-based approach was proposed to identify the underlying molecular modules of PSCS complicated with IHD, which could be used for interpreting the pharmacological mechanisms of well-established Chinese herbal formulas (e.g., Tao Hong Si Wu Tang, Dan Shen Yin, Hunag Lian Wen Dan Tang and Gua Lou Xie Bai Ban Xia Tang). In addition, these results delivered novel understandings of the molecular network mechanisms of IHD phenotype subtypes with PSCS complications, which would be both insightful for IHD precision medicine and the integration of disease and TCM syndrome diagnoses. PMID- 29403395 TI - Efficacy of Internet-Based Guided Treatment for Genito-Pelvic Pain/Penetration Disorder: Rationale, Treatment Protocol, and Design of a Randomized Controlled Trial. AB - Introduction: Genito-pelvic pain/penetration disorder (GPPPD) not only adversely affects women's sexuality and sexual satisfaction but is also associated with a wide range of psychosocial consequences such as reduced quality of life and well being, mental health comorbidities, and relationship distress. Evidence for effective treatment options is scarce. Aim: This article describes the rationale, treatment protocol, and study design for a randomized controlled trial examining the efficacy of an Internet-based guided intervention for GPPPD. Method: Two hundred women who meet the criteria for GPPPD and have not been able to experience sexual intercourse for at least the last 6 months will be recruited and randomly assigned either to the intervention group (IG) or a 6-month waitlist control group. Assessments take place at baseline (T1), peritreatment after completion of Session 5 in IG (T2), after completion of Session 8 or 12 weeks after randomization (T3), and after 6 months (T4). Data will be analyzed on an intention-to-treat and a completer basis. Main outcome measures: The primary outcome will be sexual intercourse involving the insertion of the partner's penis at posttreatment. Secondary outcomes include, e.g., improved non-intercourse penetration, sexual functioning, dyadic stress coping, reduced fear of sexuality and negative penetration-related cognitions. Fear of sexuality, penetration related cognitions, and exercise intensity will be assessed as mediators of intercourse in the IG. Sexual dysfunctions of partners will be measured at baseline (T1) and investigated as a potential moderator of the primary treatment outcome. Discussion: Given the burden associated with GPPPD and the need for specialized treatment, there is a surprising lack of evidence-based treatment options. This study aims to assess whether Internet-based interventions could contribute to closing this treatment gap. Clinical Trial Registration: German Register of Clinical Studies (DRKS): DRKS00010228. PMID- 29403396 TI - Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response. AB - Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty two lean volunteers underwent a functional magnetic resonance imaging (fMRI) scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD) response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen) and ventral striatum (nucleus accumbens). The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman's correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption. Added sugar intake was negatively associated with GLP-1 response to glucose. Post hoc analysis revealed a negative correlation between GLP-1 response to glucose and BOLD response to food cues in the dorsal striatum. Our findings suggest that habitual added sugar intake is related to increased striatal response to food cues and decreased GLP-1 release following glucose intake, which could contribute to susceptibility to overeating. PMID- 29403398 TI - Commercial Video Games As Therapy: A New Research Agenda to Unlock the Potential of a Global Pastime. AB - Emerging research suggests that commercial, off-the-shelf video games have potential applications in preventive and therapeutic medicine. Despite these promising findings, systematic efforts to characterize and better understand this potential have not been undertaken. Serious academic study of the therapeutic potential of commercial video games faces several challenges, including a lack of standard terminology, rapidly changing technology, societal attitudes toward video games, and understanding and accounting for complex interactions between individual, social, and cultural health determinants. As a vehicle to launch a new interdisciplinary research agenda, the present paper provides background information on the use of commercial video games for the prevention, treatment, and rehabilitation of mental and other health conditions, and discusses ongoing grassroots efforts by online communities to use video games for healing and recovery. PMID- 29403397 TI - Deficits in Response Inhibition in Patients with Attention-Deficit/Hyperactivity Disorder: The Impaired Self-Protection System Hypothesis. AB - Problems in inhibitory control are regarded in Psychology as a key problem associated with attention-deficit/hyperactivity disorder (ADHD). They, however, might not be primary deficits, but instead a consequence of inattention. At least two components have been identified and dissociated in studies in regards to inhibitory control: interference suppression, responsible for controlling interference by resisting irrelevant or misleading information, and response inhibition, referring to withholding a response or overriding an ongoing behavior. Poor error awareness and self-monitoring undermine an individual's ability to inhibit inadequate responses and change course of action. In non social contexts, an individual depends on his own cognition to regulate his mistakes. In social contexts, however, there are many social cues that should help that individual to perceive his mistakes and inhibit inadequate responses. The processes involved in perceiving and interpreting those social cues are arguably part of a self-protection system (SPS). Individuals with ADHD not only present impulsive behaviors in social contexts, but also have difficulty perceiving their inadequate responses and overriding ongoing actions toward more appropriate ones. In this paper, we discuss that those difficulties are arguably a consequence of an impaired SPS, due to visual attention deficits and subsequent failure in perceiving and recognizing accurately negative emotions in facial expressions, especially anger. We discuss evidence that children with ADHD exhibit problems in a series of components involved in the activation of that system and advocate that the inability to identify the anger expressed by others, and thus, not experiencing the fear response that should follow, is, ultimately, what prevents them from inhibiting the ongoing inappropriate behavior, since a potential threat is not registered. Getting involved in high-risk situations, such as reckless driving, could also be a consequence of not registering a threat and thus, not experiencing fear. PMID- 29403399 TI - Effects of Endurance Exercise Modalities on Arterial Stiffness in Patients Suffering from Unipolar Depression: A Randomized Controlled Trial. AB - Background: Psychiatric disorders are associated with a higher prevalence of cardiovascular disease and mortality. Regular exercise has been shown to reduce depressive symptoms and improve arterial stiffness as a biomarker of cardiovascular risk. We aimed to investigate the effects of different exercise modalities on depression severity index and arterial stiffness in patients suffering from unipolar depression. Methods: 34 patients suffering from unipolar depression [female: 25, male: 9, age: 37.8, Beck-Depression-Inventory-II (BDI-II) score: 31.0] were enrolled in this two-armed randomized controlled trial. Central hemodynamics, augmentation index at heart rate 75/min (AIx@75) and aortic pulse wave velocity (PWV) were obtained by an oscillometric monitoring device. Maximal bicycle ergometer exercise testing yielded maximal fitness parameters. Patients were assigned to either high-intensity low volume (HILV) or moderate continuous aerobic training (MCT). Both intervention groups trained three times a week during a 4-week intervention period. BDI-II were filled out by the patients before and after the intervention period. Results: We found moderate interaction effects on depression severity reduction [Formula: see text]. HILV showed a 85% beneficial effect in lowering BDI-II scores compared to MCT (HILV: pre: 28.8 (9.5), post: 15.5 (8.5), SMD = 1.48), MCT: (pre: 33.8 (8.5), post: 22.6 (7.5), SMD = 1.40). Reduction of AIx@75 was more pronounced after MCT (SMD = 0.61) compared to HILV (SMD = 0.08), showing 37% possibly beneficial effects of MCT over HILV. PWV remained unchanged in both training groups. Conclusion: Both training regimes showed large effects on the reduction of depressive symptoms. While HILV was more effective in lowering depression severity, MCT was more effective in additionally lowering peripheral arterial stiffness. Exercise should be considered an important strategy for preventive as well as rehabilitative treatment in depression. PMID- 29403400 TI - No Laughing Matter: Presence, Consumption Trends, Drug Awareness, and Perceptions of "Hippy Crack" (Nitrous Oxide) among Young Adults in England. AB - In clinical settings, nitrous oxide gas is a safe anesthetic used during childbirth, in dentistry, and to relieve anxiety in emergencies. Colloquially known as "hippy crack"' or "laughing gas," it is increasingly taken recreationally for its euphoric and relaxing effects and hallucinogenic properties. Using a self-reported survey, we gathered quantitative and qualitative information on users and non-users of hippy crack among a young population regarding: consumption patterns, knowledge, risk awareness and intentions toward future abuse. Quantitative responses from a total of 140 participants were analyzed for frequencies and relationships, whereas qualitative data were evaluated via identifying the reoccurring themes. Overall, 77.1% (n = 108) had heard of hippy crack and 27.9% (n = 39) admitted to past-year use. Prior users mostly indicated intended future use, had an average low number of past year uses but some with > 20 occasions, had a varied number of inhalations per occasion (often 1-10) with an effect lasting up to 5 min, and a majority preferred social rather than lone use. For non-users, 79.2% said they would take hippy crack with the vast majority (94%) preferring a social setting. The results show a concerning gap between available evidence and awareness of side effects. Despite serious reported side effects, including psychosis and myeloneuropathy especially on the young developing brain-only a minority (29.3%) was aware of any side effects. In contrast, in a hypothetical scenario depicting a first social encounter with hippy crack, the qualitative responses were in contrast to qualitative outcomes revealing that participants would try (n = 30)/not try (n = 25) it, would feel under pressure to try it (n = 6) with only 11 opting to exit the situation. In summary, this first report of trends and perceptions of the use of hippy crack among young adults in the England highlights a lack of concern with side effects, coupled to a willingness to partake. Because typical users are young with risks to the still developing brain, education about the nitrous oxide abuse is warranted to prevent impaired brain development. Further studies to investigate the possible effects of nitrous oxide on the developing brain in young adults would advance meaningful prevention. PMID- 29403401 TI - An Integrated Model of Emotional Problems, Beta Power of Electroencephalography, and Low Frequency of Heart Rate Variability after Childhood Trauma in a Non Clinical Sample: A Path Analysis Study. AB - Childhood trauma is known to be related to emotional problems, quantitative electroencephalography (EEG) indices, and heart rate variability (HRV) indices in adulthood, whereas directions among these factors have not been reported yet. This study aimed to evaluate pathway models in young and healthy adults: (1) one with physiological factors first and emotional problems later in adulthood as results of childhood trauma and (2) one with emotional problems first and physiological factors later. A total of 103 non-clinical volunteers were included. Self-reported psychological scales, including the Childhood Trauma Questionnaire (CTQ), State-Trait Anxiety Inventory, Beck Depression Inventory, and Affective Lability Scale were administered. For physiological evaluation, EEG record was performed during resting eyes closed condition in addition to the resting-state HRV, and the quantitative power analyses of eight EEG bands and three HRV components were calculated in the frequency domain. After a normality test, Pearson's correlation analysis to make path models and path analyses to examine them were conducted. The CTQ score was significantly correlated with depression, state and trait anxiety, affective lability, and HRV low-frequency (LF) power. LF power was associated with beta2 (18-22 Hz) power that was related to affective lability. Affective lability was associated with state anxiety, trait anxiety, and depression. Based on the correlation and the hypothesis, two models were composed: a model with pathways from CTQ score to affective lability, and a model with pathways from CTQ score to LF power. The second model showed significantly better fit than the first model (AICmodel1 = 63.403 > AICmodel2 = 46.003), which revealed that child trauma could affect emotion, and then physiology. The specific directions of relationships among emotions, the EEG, and HRV in adulthood after childhood trauma was discussed. PMID- 29403402 TI - A Thematic Inquiry into the Burnout Experience of Australian Solo-Practicing Clinical Psychologists. AB - Objective: Burnout is conceptualized as a syndrome that consists of emotional exhaustion, depersonalization, and decreased personal accomplishment. Despite the increased frequency and severity of burnout in the Western world, there is limited published research regarding the experiences of clinical psychologists who have had burnout. The present study examines clinical psychologists' different experiences of burnout in Australia. Design and Methods: In the year 2015, six privately practicing and solo-employed clinical psychologists provided rich qualitative data by participating in semi-structured interviews. Thematic analysis was the method used to analyze clinical psychologists' natural accounts of their burnout experiences. Using NVivo, emerging themes were identified through coding 'first order constructs' and then axial code 'second order constructs.' Findings: Clinical psychologists indicated that their roles are demanding and a diverse range of symptoms, including the enduring effects of burnout, mental stress, fatigue, decreased personal accomplishment, negative affect, depersonalization, reduced productivity and motivation, and insomnia. They identified precursors of burnout, including excessive workload and hours of work, life stresses, mismanaged workload, and transference. Clinical psychologists suggested that protective factors of burnout include knowledge and years worked in direct care, and trusting and long-term relationships. They indicated that the barriers to overcoming burnout include the fallacy that their clients' expectations and needs are more important than their own, the financial cost of working in private practice, contemporary knowledge and inadequate education regarding self-care, and time constraints. Discussion and Conclusion: The findings presented in this study provide psychologists and other health professionals with an insight about the burnout experience and inform professionals of the mental shortcomings of working as a solo-practicing clinical psychologist. Findings from this study should lead to an increased understanding of the complexities of burnout, and ultimately reduced cases of burnout, absenteeism, and staff disengagement. PMID- 29403403 TI - Work Engagement among Rescue Workers: Psychometric Properties of the Portuguese UWES. AB - Rescue workers have a stressful and risky occupation where being engaged is crucial to face physical and emotional risks in order to help other persons. This study aims to estimate work engagement levels of rescue workers (namely comparing nurses, firefighters, and police officers) and to assess the validity evidence related to the internal structure of the Portuguese versions of the UWES-17 and UWES-9, namely, dimensionality, measurement invariance between occupational groups, and reliability of the scores. To evaluate the dimensionality, we compared the fit of the three-factor model with the fit of a second-order model. A Portuguese version of the instrument was applied to a convenience sample of 3,887 rescue workers (50% nurses, 39% firefighters, and 11% police officers). Work engagement levels were moderate to high, with firefighters being the highest and nurses being the lowest engaged. Psychometric properties were evaluated in the three-factor original structure revealing acceptable fit to the data in the UWES-17, although the UWES-9 had better psychometric properties. Given the observed statistically significant correlations between the three original factors, we proposed a 2nd hierarchal structure that we named work engagement. The UWES-9 first-order model obtained full uniqueness measurement invariance, and the second-order model obtained partial (metric) second-order invariance. PMID- 29403404 TI - Word Naming in the L1 and L2: A Dynamic Perspective on Automatization and the Degree of Semantic Involvement in Naming. AB - Reaction time data have long been collected in order to gain insight into the underlying mechanisms involved in language processing. Means analyses often attempt to break down what factors relate to what portion of the total reaction time. From a dynamic systems theory perspective or an interaction dominant view of language processing, it is impossible to isolate discrete factors contributing to language processing, since these continually and interactively play a role. Non-linear analyses offer the tools to investigate the underlying process of language use in time, without having to isolate discrete factors. Patterns of variability in reaction time data may disclose the relative contribution of automatic (grapheme-to-phoneme conversion) processing and attention-demanding (semantic) processing. The presence of a fractal structure in the variability of a reaction time series indicates automaticity in the mental structures contributing to a task. A decorrelated pattern of variability will indicate a higher degree of attention-demanding processing. A focus on variability patterns allows us to examine the relative contribution of automatic and attention demanding processing when a speaker is using the mother tongue (L1) or a second language (L2). A word naming task conducted in the L1 (Dutch) and L2 (English) shows L1 word processing to rely more on automatic spelling-to-sound conversion than L2 word processing. A word naming task with a semantic categorization subtask showed more reliance on attention-demanding semantic processing when using the L2. A comparison to L1 English data shows this was not only due to the amount of language use or language dominance, but also to the difference in orthographic depth between Dutch and English. An important implication of this finding is that when the same task is used to test and compare different languages, one cannot straightforwardly assume the same cognitive sub processes are involved to an equal degree using the same task in different languages. PMID- 29403405 TI - The Relationship between Teacher Support and Students' Academic Emotions: A Meta Analysis. AB - This meta-analysis examines the association between teacher support and students' academic emotions [both positive academic emotions (PAEs) and negative academic emotions (NAEs)] and explores how student characteristics moderate these relationships. We identified 65 primary studies with 58,368 students. The results provided strong evidence linking teacher support and students' academic emotions. Furthermore, students' culture, age, and gender moderated these links. The correlation between teacher support and PAEs was stronger for Western European and American students than for East Asian students, while the correlation between teacher support and NAEs was stronger for East Asian students than for Western European and American students. Also, the correlation between teacher support and PAEs was strong among university students and weaker among middle school students, compared to other students. The correlation between teacher support and NAEs was stronger for middle school students and for female students, compared to other students. PMID- 29403406 TI - Mindfully Green and Healthy: An Indirect Path from Mindfulness to Ecological Behavior. AB - This paper examines the nature of the link between mindfulness and ecological behavior. Based on the notion that mindfulness incorporates heightened awareness of bodily sensations, we suggest an indirect path from mindfulness to ecological behavior that is mediated through individual health behavior, such as improved nutrition and increased exercise. This indirect path is corroborated with two online studies (n = 147/n = 239) where mindfulness, personal health behavior and ecological behavior were assessed. We conclude that increased mindful awareness of momentary experience indeed favors more healthy lifestyles, which in turn relate to increased ecological behavior beyond personal health benefits. The findings support an agreeableness of personal and planetary health behavior and open up a path for environmental educational interventions based on mindfulness practices and personal health gains. PMID- 29403407 TI - Auditory Feedback Assists Post hoc Error Correction of Temporal Reproduction, and Perception of Self-Produced Time Intervals in Subsecond Range. AB - We examined whether auditory feedback assists the post hoc error correction of temporal reproduction, and the perception of self-produced time intervals in the subsecond and suprasecond ranges. Here, we employed a temporal reproduction task with a single motor response at a point in time with and without auditory feedback. This task limits participants to reducing errors by employing auditory feedback in a post hoc manner. Additionally, the participants were asked to judge the self-produced timing in this task. The results showed that, in the presence of auditory feedback, the participants exhibited smaller variability and bias in terms of temporal reproduction and the perception of self-produced time intervals in the subsecond range but not in the suprasecond range. Furthermore, in the presence of auditory feedback, the positive serial dependency of temporal reproduction, which is the tendency of reproduced intervals to be similar to those in adjacent trials, was reduced in the subsecond range but not in the suprasecond range. These results suggest that auditory feedback assists the post hoc error correction of temporal reproduction, and the perception of self produced time intervals in the subsecond range. PMID- 29403408 TI - The Emotional Modulation of Facial Mimicry: A Kinematic Study. AB - It is well-established that the observation of emotional facial expression induces facial mimicry responses in the observers. However, how the interaction between emotional and motor components of facial expressions can modulate the motor behavior of the perceiver is still unknown. We have developed a kinematic experiment to evaluate the effect of different oro-facial expressions on perceiver's face movements. Participants were asked to perform two movements, i.e., lip stretching and lip protrusion, in response to the observation of four meaningful (i.e., smile, angry-mouth, kiss, and spit) and two meaningless mouth gestures. All the stimuli were characterized by different motor patterns (mouth aperture or mouth closure). Response Times and kinematics parameters of the movements (amplitude, duration, and mean velocity) were recorded and analyzed. Results evidenced a dissociated effect on reaction times and movement kinematics. We found shorter reaction time when a mouth movement was preceded by the observation of a meaningful and motorically congruent oro-facial gesture, in line with facial mimicry effect. On the contrary, during execution, the perception of smile was associated with the facilitation, in terms of shorter duration and higher velocity of the incongruent movement, i.e., lip protrusion. The same effect resulted in response to kiss and spit that significantly facilitated the execution of lip stretching. We called this phenomenon facial mimicry reversal effect, intended as the overturning of the effect normally observed during facial mimicry. In general, the findings show that both motor features and types of emotional oro-facial gestures (conveying positive or negative valence) affect the kinematics of subsequent mouth movements at different levels: while congruent motor features facilitate a general motor response, motor execution could be speeded by gestures that are motorically incongruent with the observed one. Moreover, valence effect depends on the specific movement required. Results are discussed in relation to the Basic Emotion Theory and embodied cognition framework. PMID- 29403409 TI - Designing Awe in Virtual Reality: An Experimental Study. AB - Awe is a little-studied emotion with a great transformative potential. Therefore, the interest toward the study of awe's underlying mechanisms has been increased. Specifically, researchers have been interested in how to reproduce intense feelings of awe within laboratory conditions. It has been proposed that the use of virtual reality (VR) could be an effective way to induce awe in controlled experimental settings, thanks to its ability of providing participants with a sense of "presence," that is, the subjective feeling of being displaced in another physical or imaginary place. However, the potential of VR as awe-inducing medium has not been fully tested yet. In the present study, we provided an evidence-based design and a validation of four immersive virtual environments (VEs) involving 36 participants in a within-subject design. Of these, three VEs were designed to induce awe, whereas the fourth VE was targeted as an emotionally neutral stimulus. Participants self-reported the extent to which they felt awe, general affect and sense of presence related to each environment. As expected, results showed that awe-VEs could induce significantly higher levels of awe and presence as compared to the neutral VE. Furthermore, these VEs induced significantly more positive than negative affect. These findings supported the potential of immersive VR for inducing awe and provide useful indications for the design of awe-inspiring virtual environments. PMID- 29403410 TI - Editorial: Underrepresentation of Women in Science: International and Cross Disciplinary Evidence and Debate. PMID- 29403411 TI - A Cluster Randomized-Controlled Trial of the Impact of the Tools of the Mind Curriculum on Self-Regulation in Canadian Preschoolers. AB - Early self-regulation predicts school readiness, academic success, and quality of life in adulthood. Its development in the preschool years is rapid and also malleable. Thus, preschool curricula that promote the development of self regulation may help set children on a more positive developmental trajectory. We conducted a cluster-randomized controlled trial of the Tools of the Mind preschool curriculum, a program that targets self-regulation through imaginative play and self-regulatory language (Tools; clinical trials identifier NCT02462733). Previous research with Tools is limited, with mixed evidence of its effectiveness. Moreover, it is unclear whether it would benefit all preschoolers or primarily those with poorly developed cognitive capacities (e.g., language, executive function, attention). The study goals were to ascertain whether the Tools program leads to greater gains in self-regulation compared to Playing to Learn (YMCA PTL), another play based program that does not target self-regulation specifically, and whether the effects were moderated by children's initial language and hyperactivity/inattention. Two hundred and sixty 3- to 4-year-olds attending 20 largely urban daycares were randomly assigned, at the site level, to receive either Tools or YMCA PTL (the business-as-usual curriculum) for 15 months. We assessed self-regulation at pre-, mid and post intervention, using two executive function tasks, and two questionnaires regarding behavior at home and at school, to capture development in cognitive as well as socio-emotional aspects of self-regulation. Fidelity data showed that only the teachers at the Tools sites implemented Tools, and did so with reasonable success. We found that children who received Tools made greater gains on a behavioral measure of executive function than their YMCA PTL peers, but the difference was significant only for those children whose parents rated them high in hyperactivity/inattention initially. The effect of Tools did not vary with children's initial language skills. We suggest that, as both programs promote quality play and that the two groups fared similarly well overall, Tools and YMCA PTL may be effective curricula choices for a diverse preschool classroom. However, Tools may be advantageous in classrooms with children experiencing greater challenges with self-regulation, at no apparent cost to those less challenged in this regard. PMID- 29403412 TI - Visual Complexity and Affect: Ratings Reflect More Than Meets the Eye. AB - Pictorial stimuli can vary on many dimensions, several aspects of which are captured by the term 'visual complexity.' Visual complexity can be described as, "a picture of a few objects, colors, or structures would be less complex than a very colorful picture of many objects that is composed of several components." Prior studies have reported a relationship between affect and visual complexity, where complex pictures are rated as more pleasant and arousing. However, a relationship in the opposite direction, an effect of affect on visual complexity, is also possible; emotional arousal and valence are known to influence selective attention and visual processing. In a series of experiments, we found that ratings of visual complexity correlated with affective ratings, and independently also with computational measures of visual complexity. These computational measures did not correlate with affect, suggesting that complexity ratings are separately related to distinct factors. We investigated the relationship between affect and ratings of visual complexity, finding an 'arousal-complexity bias' to be a robust phenomenon. Moreover, we found this bias could be attenuated when explicitly indicated but did not correlate with inter-individual difference measures of affective processing, and was largely unrelated to cognitive and eyetracking measures. Taken together, the arousal-complexity bias seems to be caused by a relationship between arousal and visual processing as it has been described for the greater vividness of arousing pictures. The described arousal complexity bias is also of relevance from an experimental perspective because visual complexity is often considered a variable to control for when using pictorial stimuli. PMID- 29403413 TI - Orthographic Transparency Enhances Morphological Segmentation in Children Reading Hebrew Words. AB - Morphological processing of derived words develops simultaneously with reading acquisition. However, the reader's engagement in morphological segmentation may depend on the language morphological richness and orthographic transparency, and the readers' reading skills. The current study tested the common idea that morphological segmentation is enhanced in non-transparent orthographies to compensate for the absence of phonological information. Hebrew's rich morphology and the dual version of the Hebrew script (with and without diacritic marks) provides an opportunity to study the interaction of orthographic transparency and morphological segmentation on the development of reading skills in a within language design. Hebrew speaking 2nd (N = 27) and 5th (N = 29) grade children read aloud 96 noun words. Half of the words were simple mono-morphemic words and half were bi-morphemic derivations composed of a productive root and a morphemic pattern. In each list half of the words were presented in the transparent version of the script (with diacritic marks), and half in the non-transparent version (without diacritic marks). Our results show that in both groups, derived bi morphemic words were identified more accurately than mono-morphemic words, but only for the transparent, pointed, script. For the un-pointed script the reverse was found, namely, that bi-morphemic words were read less accurately than mono morphemic words, especially in second grade. Second grade children also read mono morphemic words faster than bi-morphemic words. Finally, correlations with a standardized measure of morphological awareness were found only for second grade children, and only in bi-morphemic words. These results, showing greater morphological effects in second grade compared to fifth grade children suggest that for children raised in a language with a rich morphology, common and easily segmented morphemic units may be more beneficial for younger compared to older readers. Moreover, in contrast to the common hypothesis, our results show that morphemic segmentation does not compensate for the missing phonological information in a non-transparent orthography, but rather that morphological segmentation is most beneficial in the highly transparent script. These results are consistent with the idea that morphological and phonological segmentation processes occur simultaneously and do not constitute alternative pathways to visual word recognition. PMID- 29403414 TI - Encoding and Retrieval Interference in Sentence Comprehension: Evidence from Agreement. AB - Long-distance verb-argument dependencies generally require the integration of a fronted argument when the verb is encountered for sentence interpretation. Under a parsing model that handles long-distance dependencies through a cue-based retrieval mechanism, retrieval is hampered when retrieval cues also resonate with non-target elements (retrieval interference). However, similarity-based interference may also stem from interference arising during the encoding of elements in memory (encoding interference), an effect that is not directly accountable for by a cue-based retrieval mechanism. Although encoding and retrieval interference are clearly distinct at the theoretical level, it is difficult to disentangle the two on empirical grounds, since encoding interference may also manifest at the retrieval region. We report two self-paced reading experiments aimed at teasing apart the role of each component in gender and number subject-verb agreement in Italian and English object relative clauses. In Italian, the verb does not agree in gender with the subject, thus providing no cue for retrieval. In English, although present tense verbs agree in number with the subject, past tense verbs do not, allowing us to test the role of number as a retrieval cue within the same language. Results from both experiments converge, showing similarity-based interference at encoding, and some evidence for an effect at retrieval. After having pointed out the non-negligible role of encoding in sentence comprehension, and noting that Lewis and Vasishth's (2005) ACT-R model of sentence processing, the most fully developed cue-based retrieval approach to sentence processing does not predict encoding effects, we propose an augmentation of this model that predicts these effects. We then also propose a self-organizing sentence processing model (SOSP), which has the advantage of accounting for retrieval and encoding interference with a single mechanism. PMID- 29403415 TI - Social Relatedness and Physical Health Are More Strongly Related in Older Than Younger Adults: Findings from the Korean Adult Longitudinal Study. AB - Previous research indicates that social relatedness is beneficial to physical health; however, findings on the relative strength of the relationship between these variables have been inconsistent. The present study employed cross sectional survey (Study 1) and a daily diary survey (Study 2) to examine the link between social relatedness and physical health by age. Using a representative sample of Korean adults (N = 371) aged from 20 to 69, Study 1 examines the link between social relatedness (loneliness, perceived social support) and physical health (physical symptoms, chronic health conditions) using age as a moderator. The results show that participants' age moderates the association between social relatedness and physical health. Study 2 (N = 384) further corroborated the findings from Study 1 by showing that when controlling for the physical symptoms experienced prior to the daily diary reports, the level of loneliness experienced over a 13-day period exacerbates the age differences in the physical symptoms. The present study thus provides converging evidence that social relatedness plays a significant role in physical health, particularly in the older population. PMID- 29403416 TI - Broadening Humor: Comic Styles Differentially Tap into Temperament, Character, and Ability. AB - The present study introduces eight comic styles (i.e., fun, humor, nonsense, wit, irony, satire, sarcasm, and cynicism) and examines the validity of a set of 48 marker items for their assessment, the Comic Style Markers (CSM). These styles were originally developed to describe literary work and are used here to describe individual differences. Study 1 examines whether the eight styles can be distinguished empirically, in self- and other-reports, and in two languages. In different samples of altogether more than 1500 adult participants, the CSM was developed and evaluated with respect to internal consistency, homogeneity, test retest reliability, factorial validity, and construct and criterion validity. Internal consistency was sufficiently high, and the median test-retest reliability over a period of 1-2 weeks was 0.86 (N = 148). Exploratory and confirmatory factor analyses showed that the eight styles could be distinguished in both English- (N = 303) and German-speaking samples (N = 1018 and 368). Comparing self- and other-reports (N = 210) supported both convergent and discriminant validity. The intercorrelations among the eight scales ranged from close to zero (between humor and sarcasm/cynicism) to large and positive (between sarcasm and cynicism). Consequently, second-order factor analyses revealed either two bipolar factors (based on ipsative data) or three unipolar factors (based on normative data). Study 2 related the CSM to instruments measuring personality (N = 999), intelligence (N = 214), and character strengths (N = 252), showing that (a) wit was the only style correlated with (verbal) intelligence, (b) fun was related to indicators of vitality and extraversion, (c) humor was related to character strengths of the heart, and (d) comic styles related to mock/ridicule (i.e., sarcasm, cynicism, but also irony) correlated negatively with character strengths of the virtues temperance, transcendence, and humanity. By contrast, satire had a moral goodness that was lacking in sarcasm and cynicism. Most importantly, the two studies revealed that humor might be related to a variety of character strengths depending on the comic style utilized, and that more styles may be distinguished than has been done in the past. The CSM is recommended for future explorations and refinements of comic styles. PMID- 29403417 TI - Development of a Work Climate Scale in Emergency Health Services. AB - An adequate work climate fosters productivity in organizations and increases employee satisfaction. Workers in emergency health services (EHS) have an extremely high degree of responsibility and consequent stress. Therefore, it is essential to foster a good work climate in this context. Despite this, scales with a full study of their psychometric properties (i.e., validity evidence based on test content, internal structure and relations to other variables, and reliability) are not available to measure work climate in EHS specifically. For this reason, our objective was to develop a scale to measure the quality of work climates in EHS. We carried out three studies. In Study 1, we used a mixed-method approach to identify the latent conceptual structure of the construct work climate. Thus, we integrated the results found in (a) a previous study, where a content analysis of seven in-depth interviews obtained from EHS professionals in two hospitals in Gibraltar Countryside County was carried out; and (b) the factor analysis of the responses given by 113 EHS professionals from these same centers to 18 items that measured the work climate in health organizations. As a result, we obtained 56 items grouped into four factors (work satisfaction, productivity/achievement of aims, interpersonal relationships, and performance at work). In Study 2, we presented validity evidence based on test content through experts' judgment. Fourteen experts from the methodology and health fields evaluated the representativeness, utility, and feasibility of each of the 56 items with respect to their factor (theoretical dimension). Forty items met the inclusion criterion, which was to obtain an Osterlind index value greater than or equal to 0.5 in the three aspects assessed. In Study 3, 201 EHS professionals from the same centers completed the resulting 40-item scale. This new instrument produced validity evidence based on the internal structure in a second-order factor model with four components (RMSEA = 0.079, GFI = 0.97, AGFI = 0.97, CFI = 0.97; NFI = 0.95, and NNFI = 0.97); absence of Differential Item Functioning (DIF) in 80% of the items; reliability (alpha = 0.96); and validity evidence based on relations to other variables, specifically the test-criterion relationship (rho = 0.680). Finally, we discuss further developments of the instrument and its possible implications for EHS workers. PMID- 29403418 TI - Binge Drinking and the Young Brain: A Mini Review of the Neurobiological Underpinnings of Alcohol-Induced Blackout. AB - Binge drinking has significant effects on memory, particularly with regards to the transfer of information to long-term storage. Partial or complete blocking of memory formation is known as blackout. Youth represents a critical period in brain development that is particularly vulnerable to alcohol misuse. Animal models show that the adolescent brain is more vulnerable to the acute and chronic effects of alcohol compared with the adult brain. This mini-review addresses the neurobiological underpinnings of binge drinking and associated memory loss (blackout) in the adolescent and young adult period. Although the extent to which there are pre-existing versus alcohol-induced neurobiological changes remains unclear, it is likely that repetitive binge drinking in youth has detrimental effects on cognitive and social functioning. Given its role in learning and memory, the hippocampus is a critical region with neuroimaging research showing notable changes in this structure associated with alcohol misuse in young people. There is a great need for earlier identification of biological markers associated with alcohol-related brain damage. As a means to assess in vivo neurochemistry, magnetic resonance spectroscopy (MRS) has emerged as a particularly promising technique since changes in neurometabolites often precede gross structural changes. Thus, the current paper addresses how MRS biomarkers of neurotransmission (glutamate, GABA) and oxidative stress (indexed by depleted glutathione) in the hippocampal region of young binge drinkers may underlie propensity for blackouts and other memory impairments. MRS biomarkers may have particular utility in determining the acute versus longer-term effects of binge drinking in young people. PMID- 29403419 TI - Corrigendum: Exhausted Parents: Development and Preliminary Validation of the Parental Burnout Inventory. AB - [This corrects the article on p. 163 in vol. 8, PMID: 28232811.]. PMID- 29403420 TI - Diffusion Weighted/Tensor Imaging, Functional MRI and Perfusion Weighted Imaging in Glioblastoma-Foundations and Future. AB - In this article, we review the basics of diffusion tensor imaging and functional MRI, their current utility in preoperative neurosurgical mapping, and their limitations. We also discuss potential future applications, including implementation of resting state functional MRI. We then discuss perfusion and diffusion-weighted imaging and their application in advanced neuro-oncologic practice. We explain how these modalities can be helpful in guiding surgical biopsies and differentiating recurrent tumor from treatment related changes. PMID- 29403421 TI - Endovascular Treatment of Anterior Circulation Large Vessel Occlusion in the Elderly. AB - Endovascular treatment of anterior circulation large vessel occlusion in the elderly population presents special challenges and opportunities. In this review, we discuss the published literature regarding thrombectomy in elderly patients and also discuss specific issues related to treatment in this patient population. In summary, while the overall outcomes following thrombectomy in elderly patients are worse than following thrombectomy in younger patients, there appears to be a similar benefit as in young patients. While there are challenges with successfully delivering thrombectomy in older patients, age alone should not be an independent exclusion from thrombectomy. PMID- 29403422 TI - Short-term Efficacy of Hand-Arm Bimanual Intensive Training on Upper Arm Function in Acute Stroke Patients: A Randomized Controlled Trial. AB - Background: Rehabilitation training during the acute phase of stroke (<48 h) markedly improves impaired upper-limb movement. Hand-arm bimanual intensive training (HABIT) represents an intervention that promotes improvements in upper extremity function in children with cerebral palsy. This study repurposed HABIT in acute stroke patients and assessed recovery of upper extremity function when compared with a conventional rehabilitation program (CRP). Methods: In a randomized trial, 128 patients with acute stroke were assigned to the HABIT or the CRP groups. The primary endpoint was clinical motor functional assessment that was guided by the Fugl-Meyer motor assessment (FMA) and outcomes of the action research arm test (ARAT). The secondary endpoint was an improved neurophysiological evaluation according to the motor-evoked potential amplitude (AMP), resting motion threshold (RMT), and central motor conduction time (CMCT) scores over the 2-week course of therapy. In both groups, scores were evaluated at baseline, 1 week from commencing therapy, and post-therapy. Results: After 2 weeks, the HABIT group showed improved scores as compared the CRP group for FMA (51.7 +/- 6.44 vs. 43.5 +/- 5.6, P < 0.001), ARAT (34.5 +/- 6.2 vs. 33.3 +/- 6.3, P = 0.022), and AMP (1.1 +/- 0.1 vs. 1.0 +/- 0.1, P < 0.001). However, CMCT (8.6 +/- 1.0 vs. 9.1 +/- 0.6, P = 0.054) and RMT (55.3 +/- 4.2 vs. 57.5 +/- 4.1, P = 0.088) were similar when comparing between groups. Conclusion: HABIT significantly improved motor functional and neuro-physiological outcomes in patients with acute stroke, which suggested that HABIT might represent an improved therapeutic strategy as compared CRP. PMID- 29403424 TI - Parenting Stress and Emotional/Behavioral Problems in Adolescents with Primary Headache. AB - Primary headache is a frequent and disabling disorder, common among children and adolescents, and it is a painful syndrome often accompanied by functional impairment and associated with emotional and behavior problems. The aim of this study was to investigate parenting stress and emotional/behavioral problems in adolescents affected by primary headache compared with healthy adolescents. The study population consisted of 35 adolescents and a control group of 23 healthy subjects. The assessment included the administration of clinical standardized scales such as Parent Stress Index-Short Form, Pediatric Migraine Disability Assessment Score Questionnaire, and Child Behavior Checklist (CBCL). Headache group and control group did not differ in terms of parenting stress (p = 0.29). On the contrary, headache group showed more internalizing problems (p = 0.023), affective problems (p = 0.01), anxious (p = 0.001), and somatic complaints (p < 0.001) compared with control group. In addition, we found a significant correlation between PSI domains and specific CBCL subscales in the headache group. The findings emphasize the need for expanded intervention in the clinical treatment of pediatric headache, a treatment that may also include the family members. Further research is needed. PMID- 29403423 TI - Postural Stabilization Differences in Idiopathic Parkinson's Disease and Progressive Supranuclear Palsy during Self-Triggered Fast Forward Weight Lifting. AB - Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Self-triggered, weighted movements appear to provoke falls in IPD, but not in PSP. Repeated self-triggered lifting of a 0.5-1 kg weight (<2% of body weight) with the dominant hand was performed in 17 PSP, 15 IPD with falling history, and 16 controls on a posturography platform. PSP showed excessive force scaling of weight and body motion with high-frequency multiaxial body sway, whereas IPD presented a delayed-onset forward body displacement. Differences in center of mass displacement apparent at very small weights indicate that both syndromes decompensate postural control already within stability limits. PSP may be subject to specific postural system devolution. IPD are susceptible to delayed forward falling. Differential physiotherapy strategies are suggested. PMID- 29403425 TI - Maternal Alexithymia and Attachment Style: Which Relationship with Their Children's Headache Features and Psychological Profile? AB - Introduction: A growing body of literature has shown an association between somatic symptoms and insecure "attachment style." In a recent study, we found a relationship between migraine severity, ambivalent attachment style, and psychological symptoms in children/adolescents. There is evidence that caregivers' attachment styles and their way of management/expression of emotions can influence children's psychological profile and pain expression. To date, data dealing with headache are scarce. Our aim was to study the role of maternal alexithymia and attachment style on their children's migraine severity, attachment style, and psychological profile. Materials and methods: We enrolled 84 consecutive patients suffering from migraine without aura (female: 45, male: 39; mean age 11.8 +/- 2.4 years). According to headache frequency, children/adolescents were divided into two groups: (1) high frequency (patients reporting from weekly to daily attacks), and (2) low frequency (patients having <=3 episodes per month). We divided headache attacks intensity into two groups (mild and severe pain). SAFA "Anxiety," "Depression," and "Somatization" scales were used to explore children's psychological profile. To evaluate attachment style, the semi-projective test SAT for patients and ASQ Questionnaire for mothers were employed. Maternal alexithymia traits were assessed by TAS-20. Results: We found a significant higher score in maternal alexithymia levels in children classified as "ambivalent," compared to those classified as "avoiding" (Total scale: p = 0.011). A positive correlation has been identified between mother's TAS-20 Total score and the children's SAFA-A Total score (p = 0.026). In particular, positive correlations were found between maternal alexithymia and children's "Separation anxiety" (p = 0.009) and "School anxiety" (p = 0.015) subscales. Maternal "Externally-oriented thinking" subscale correlated with children's school anxiety (p = 0.050). Moreover, we found a correlation between TAS-20 Total score and SAFA-D "Feeling of guilt" subscale (p = 0.014). Our data showed no relationship between TAS-20 and ASQ questionnaires and children's migraine intensity and frequency. Conclusion: Maternal alexithymia and attachment style have no impact on children's migraine severity. However, our results suggest that, although maternal alexithymic traits have no causative roles on children's migraine severity, they show a relationship with patients' attachment style and psychological symptoms, which in turn may impact on migraine severity. PMID- 29403426 TI - Heart Rate Variability in Healthy Non-Concussed Youth Athletes: Exploring the Effect of Age, Sex, and Concussion-Like Symptoms. AB - Background: Heart rate variability (HRV) is a non-invasive neurophysiological measure of autonomic nervous system regulation emerging in concussion research. To date, most concussion studies have focused on the university-aged athlete with no research examining healthy active youths. Corroborating changes in HRV alongside traditional subjective self-report measures (concussion symptoms) in the non-concussed state provides a foundation for interpreting change following concussion. The objectives were to (1) explore the influence of age and sex on HRV and (2) examine the relationship between HRV and baseline/pre-injury concussion symptom domains (physical, cognitive, emotional, and fatigue) in healthy youth athletes. Method: Healthy, youth athletes 13-18 years of age [N = 294, female = 166 (56.5%), male = 128 (43.5%)] participated in this cross sectional study. Age, sex, and concussion-like symptoms were collected as part of a baseline/pre-injury assessment. The Post-Concussion Symptom Inventory-SR13 (PCSI-SR13) was used to collect domain scores for physical, cognitive, emotional, and fatigue symptoms. HRV was collected for 24 h. HRV measures included time (SDNN, RMSSD, and pNN50) and frequency (HF, HFnu, LF, LFnu, and total power) domain HRV measures. Variables were logarithmically transformed to increase robustness of linear regression models. Results: Older youth participants displayed significantly higher HRV compared to younger participants (p < 0.05). Females displayed significantly lower HRV compared to males (p < 0.05). A significant interaction effect between concussion-like symptoms and HRV indicated differential patterns as a function of sex (p < 0.05). Youth athletes who reported more cognitive symptoms had lower HRV (p < 0.05). Conclusion: HRV was found to have a significant relationship with a traditional clinical measure (subjective self-report of concussion-like symptoms) utilized in concussion assessment and management. Baseline/pre-concussion trends in HRV were significantly associated with age and sex, highlighting the value in understanding key demographic factors within the context of concussion-like symptoms. PMID- 29403427 TI - Blood Glutamate Levels Are Closely Related to Acute Lung Injury and Prognosis after Stroke. AB - Background: Acute lung injury (ALI) is a serious complication of stroke that occurs with a high incidence. Our preclinical results indicated that ALI might be related to blood glutamate levels after brain injury. The purpose of this study was to assess dynamic changes in blood glutamate levels in patients with stroke and to determine the correlation between blood glutamate levels, ALI, and long term prognosis after stroke. Methods: Venous blood samples were collected from controls and patients with stroke at admission and on the third and seventh day after the onset of stroke. Patients were followed for 3 months. The correlations among blood glutamate levels, severities of stroke and ALI, and long-term outcomes were analyzed, and the predictive values of blood glutamate levels and severity scores for ALI were assessed. Results: In this study, a total of 384 patients with stroke were enrolled, with a median age of 59 years. Patients showed significantly increased blood glutamate levels within 7 days of stroke onset (p < 0.05), and patients with more severe injuries showed higher blood glutamate levels. Moreover, blood glutamate levels were closely related to the occurrence (adjusted odds ratio, 3.022, p = 0.003) and severity (p < 0.001) of ALI and the long-term prognosis after stroke (p < 0.05), and they were a more accurate predictor of ALI than the more commonly used severity scores (p < 0.01). Conclusion: These results indicated that an increased blood glutamate level was closely related to the development of ALI and a poor prognosis after stroke. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR-RPC 15006770. PMID- 29403428 TI - Relationship between Glioblastoma Dose Volume Parameters Measured by Dual Time Point Fluoroethylthyrosine-PET and Clinical Outcomes. AB - Glioblastoma multiforme (GBM) is highly invasive. Despite irradiation with wide margins, GBM usually recurs in-field. Recent in vitro data have suggested that progression might be promoted by sublethal irradiation. Fluoroethylthyrosine-PET (FET-PET) can be used to detect glioblastoma invasion not apparent on MRI. We therefore performed a retrospective analysis of a prospective clinical study to examine whether glioblastoma outcomes depend on dose volume parameters measured by MRI and FET-PET. Twenty-three patients were prospectively recruited to a study examining the role of dual time point FET-PET in the treatment planning of GBM radiotherapy. The dose delivered to the site of recurrence was subdivided into suboptimal-dose (SOD) and high-dose (HD) areas. Types of progression were defined for correlation with dosimetric parameters including V100% of gross tumor volume (GTV)PET, GTVPETMRI, and GTVMRI. The HD area did not cover the entire GTVPETMRI in any case. Recurrences were significantly more frequent in the SubD area (chi squared test, p = 0.004). There was no relationship between increasing dose volume and progression. The V100% for GTVPET and progression-free survival (PFS) was positively correlated (Spearman's rho 0.417; p = 0.038). Progression is more common in areas with suboptimal dosing. Dose heterogeneity within GTVPET may be responsible for shorter PFS. PMID- 29403429 TI - Alzheimer's Disease Mutant Mice Exhibit Reduced Brain Tissue Stiffness Compared to Wild-type Mice in both Normoxia and following Intermittent Hypoxia Mimicking Sleep Apnea. AB - Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness. Aim: To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA. Methods: Six-eight month old (B6C3 Tg(APPswe,PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O2 40 s to 5% O2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-MUm brain cortex slices was measured by atomic force microscopy. Results: Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice. Conclusion: AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD. PMID- 29403430 TI - Altered Regional Brain Cortical Thickness in Pediatric Obstructive Sleep Apnea. AB - Rationale: Obstructive sleep apnea (OSA) affects 2-5% of all children and is associated with cognitive and behavioral deficits, resulting in poor school performance. These psychological deficits may arise from brain injury, as seen in preliminary findings of lower gray matter volume among pediatric OSA patients. However, the psychological deficits in OSA are closely related to functions in the cortex, and such brain areas have not been specifically assessed. The objective was to determine whether cortical thickness, a marker of possible brain injury, is altered in children with OSA. Methods: We examined regional brain cortical thicknesses using high-resolution T1-weighted magnetic resonance images in 16 pediatric OSA patients (8 males; mean age +/- SD = 8.4 +/- 1.2 years; mean apnea/hypopnea index +/- SD = 11 +/- 6 events/h) and 138 controls (8.3 +/- 1.1 years; 62 male; 138 subjects from the NIH Pediatric MRI database) to identify cortical thickness differences in pediatric OSA subjects. Results: Cortical thinning occurred in multiple regions including the superior frontal, ventral medial prefrontal, and superior parietal cortices. The left side showed greater thinning in the superior frontal cortex. Cortical thickening was observed in bilateral precentral gyrus, mid-to-posterior insular cortices, and left central gyrus, as well as right anterior insula cortex. Conclusion: Changes in cortical thickness are present in children with OSA and likely indicate disruption to neural developmental processes, including maturational patterns of cortical volume increases and synaptic pruning. Regions with thicker cortices may reflect inflammation or astrocyte activation. Both the thinning and thickening associated with OSA in children may contribute to the cognitive and behavioral dysfunction frequently found in the condition. PMID- 29403431 TI - Acquired Sleep-Related Hypermotor Epilepsy with Disrupted White Matter Tracts Assessed by Multishell Diffusion Magnetic Resonance Imaging. AB - Sleep-related hypermotor epilepsy (SHE) (previously frontal lobe epilepsy) is a rare seizure disorder commonly misdiagnosed or unrecognized, causing negative patient sequelae. While usually reported in familial studies, it is more commonly acquired. Diagnosis is a challenge due to its low incidence in comparison with the more common sleep disorders or psychogenic etiologies in the differential diagnosis. Diagnosis is scaled on degree of certainty based on described or clinically documented semiology, with video EEG as a helpful, but not necessary, adjunct. Current treatment is similar to other focal epilepsies. We studied a 36 year-old active duty male soldier who presented with 2 years of predominantly sleep related, abrupt, short, and anamnestic hyperkinetic movements with unstructured vocalizations. Prior workup included non-contributory video electroencephalograph (EEG) and polysomnography as well as normal brain magnetic resonance imaging (MRI). Treatments for presumed psychiatric and parasomnia disturbances were not effective in establishing diagnosis or relief. Evaluation at our tertiary, multidisciplinary care institution recorded events consistent with the diagnosis of clinical SHE. He was enrolled in an advanced multishell diffusion-weighted imaging MRI research study to evaluate white matter tracts, given his history of mild, repetitive, non-penetrating traumatic brain injury, not otherwise requiring hospitalization. Multishell diffusion MRI tractography found changes not previously described in the right frontal lobe white matter tracts. These changes were consistent with neurological localization and serve as a potential nidus for this patient's seizure disorder. Misdiagnosis of SHE can result in detrimental biopsychosocial sequelae of untreated epilepsy, unnecessary or harmful intervention, or the stigmata of a behavioral disorder. Further investigation into diagnosis and etiology of acquired SHE is needed. Assessment for white matter abnormalities can potentially provide information into pathogenesis of epilepsy disorders. PMID- 29403432 TI - The Pollutant Organotins Leads to Respiratory Disease by Inflammation: A Mini Review. AB - Organotins (OTs) are organometallic pollutants. The OTs are organometallic pollutants that are used in many industrial, agricultural, and domestic products, and it works as powerful biocidal compound against large types of microorganisms such as fungi and bacteria. In addition, OTs are well known to be endocrine disrupting chemicals, leading abnormalities an "imposex" phenomenon in the female mollusks. There are some studies showing that OTs' exposure is responsible for neural, endocrine, and reproductive dysfunctions in vitro and in vivo models. However, OTs' effects over the mammalian immune system are poorly understood, particularly in respiratory diseases. The immune system, as well as their cellular components, performs a pivotal role in the control of the several physiologic functions, and in the maintenance and recovery of homeostasis. Thus, it is becoming important to better understand the association between environmental contaminants, as OTs, and the physiological function of immune system. There are no many scientific works studying the relationship between OTs and respiratory disease, especially about immune system activation. Herein, we reported studies in animal, humans, and in vitro models. We searched studies in PUBMED, LILACS, and Scielo platforms. Studies have reported that OTs exposure was able to suppress T helper 1 (Th1) and exacerbate T helper 2 (Th2) response in the immune system. In addition, OTs' contact could elevate in the airway inflammatory response, throughout a mechanism associated with the apoptosis of T-regulatory cells and increased oxidative stress response. In addition, OTs induce macrophage recruitment to the tissue, leading to the increased necrosis, which stimulates an inflammatory cytokines secretion exacerbating the local inflammation and tissue function loss. Thus, the main intention of this mini-review is to up to date the main findings involving the inflammatory profile (especially Th1 and Th2 response) in the respiratory tract as a result of OTs' exposure. PMID- 29403433 TI - Prepubertal Ovariectomy Exaggerates Adult Affective Behaviors and Alters the Hippocampal Transcriptome in a Genetic Rat Model of Depression. AB - Major depressive disorder (MDD) is a debilitating illness that affects twice as many women than men postpuberty. This female bias is thought to be caused by greater heritability of MDD in women and increased vulnerability induced by female sex hormones. We tested this hypothesis by removing the ovaries from prepubertal Wistar Kyoto (WKY) more immobile (WMI) females, a genetic animal model of depression, and its genetically close control, the WKY less immobile (WLI). In adulthood, prepubertally ovariectomized (PrePubOVX) animals and their Sham-operated controls were tested for depression- and anxiety-like behaviors, using the routinely employed forced swim and open field tests, respectively, and RNA-sequencing was performed on their hippocampal RNA. Our results confirmed that the behavioral and hippocampal expression changes that occur after prepubertal ovariectomy are the consequences of an interaction between genetic predisposition to depressive behavior and ovarian hormone-regulated processes. Lack of ovarian hormones during and after puberty in the WLIs led to increased depression-like behavior. In WMIs, both depression- and anxiety-like behaviors worsened by prepubertal ovariectomy. The unbiased exploration of the hippocampal transcriptome identified sets of differentially expressed genes (DEGs) between the strains and treatment groups. The relatively small number of hippocampal DEGs resulting from the genetic differences between the strains confirmed the genetic relatedness of these strains. Nevertheless, the differences in DEGs between the strains in response to prepubertal ovariectomy identified different molecular processes, including the importance of glucocorticoid receptor-mediated mechanisms, that may be causative of the increased depression-like behavior in the presence or absence of genetic predisposition. This study contributes to the understanding of hormonal maturation-induced changes in affective behaviors and the hippocampal transcriptome as it relates to genetic predisposition to depression. PMID- 29403434 TI - Endocrine Regulation in the Ovary by MicroRNA during the Estrous Cycle. AB - Hormonal control of the estrous cycle that occurs in therian mammals is essential for the production of a functional egg. Supporting somatic cell types found within the ovary, such as granulosa and theca cells, respond to endocrine signals to support oocyte maturation and ovulation. Following the release of the egg, now available for fertilization, coordinated hormonal signaling between the mother and putative embryo are required for the establishment of pregnancy. If no conception occurs, both the ovary and uterus are "reset" in preparation for another cycle. The complex molecular changes that occur within cells in response to hormone signaling include a network of non-coding microRNAs (miRNAs) that posttranscriptionally regulate gene expression. They are thus able to fine-tune cellular responses to hormones and confer robustness in gene regulation. In this review, we outline the important roles established for miRNAs in regulating female reproductive hormone signaling during estrus, with a particular focus on signaling pathways in the ovary. Understanding this miRNA network can provide important insights to improving assisted reproductive technologies and may be useful in the diagnosis of female reproductive disorders. PMID- 29403435 TI - The Significance of 18F-Fluorocholine-PET/CT as Localizing Imaging Technique in Patients with Primary Hyperparathyroidism and Negative Conventional Imaging. AB - Objective: The essential prerequisite for focused parathyroidectomy in patients with primary hyperparathyroidism (pHPT) is proper localization of all autonomic tissue. Sensitivity of conventional imaging modalities (ultrasound, 99mTc sestamibi scintigraphy/SPECT/CT) is influenced by different factors (i.e., size/weight and position of autonomic tissue) and decreases in the presence of a multinodular goiter. Therefore, a considerable percentage of pHPT patients have negative or equivocal localization studies before surgery. The aim of this study is to evaluate the utility of FCH-PET/CT for preoperative localization in patients with pHPT and negative/equivocal 99mTc-sestamibi scintigraphy/SPECT/CT and/or ultrasound. Methods and measurements: Between 2014 and 2017, a total of 39 patients with pHPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In the analysis, we included those (n = 23) who had surgery and a histopathologic workup of the lesions. Results: 19 of 23 patients demonstrated no tracer uptake with 99mTc-sestamibi scintigraphy/SPECT/CT, 6 patients had an equivocal sonographic lesion, and multinodular goiter was present in 43% (10/23). In 21 of 23 patients, hyperfunctioning parathyroid tissue was identified correctly by FCH-PET/CT [21 true positive, 1 false negative, and 1 false positive; per-patient sensitivity 95.5% (95% confidence interval {CI}, 77.2 99.9)]. 29 lesions were resected [21 true positives, 3 false negatives, 1 false positive, and 4 true negatives; per-lesion sensitivity 87.5% (95% CI, 67.6 97.3)]. All patients were classified as having surgical success according to a decrease of intraoperative parathyroid hormone of >=50% and normalization of postoperative serum calcium levels. Conclusion: Despite a high prevalence of multinodular goiter, diagnostic accuracy of FCH-PET/CT in our patient group was excellent. Therefore, FCH-PET/CT is a promising new imaging tool in patients with pHPT and negative/equivocal results by conventional imaging techniques. PMID- 29403437 TI - In Vivo Imaging of Transplanted Pancreatic Islets. AB - The beta-cells in the islets of Langerhans in the pancreas secrete insulin and play an important role in glucose homeostasis. Diabetes, characterized by hyperglycemia, results from an absolute or a relative deficiency of the pancreatic beta-cell mass. Islet transplantation has been considered to be a useful therapeutic approach, but it is largely unsuccessful because most of the transplanted islets are lost in the early stage of transplantation. To evaluate the efficacy of intervention methods for the improvement of islet survival, monitoring of the functional islet mass is needed. Various techniques to image and track transplanted islets have been investigated to assess islets after transplantation. In this review, recent progresses in imaging methods to visualize islets are discussed. PMID- 29403436 TI - From Diabetes Care to Diabetes Cure-The Integration of Systems Biology, eHealth, and Behavioral Change. AB - From a biological view, most of the processes involved in insulin resistance, which drives the pathobiology of type 2 diabetes, are reversible. This theoretically makes the disease reversible and curable by changing dietary habits and physical activity, particularly when adopted early in the disease process. Yet, this is not fully implemented and exploited in health care due to numerous obstacles. This article reviews the state of the art in all areas involved in a diabetes cure-focused therapy and discusses the scientific and technological advancements that need to be integrated into a systems approach sustainable lifestyle-based healthcare system and economy. The implementation of lifestyle as cure necessitates personalized and sustained lifestyle adaptations, which can only be established by a systems approach, including all relevant aspects (personalized diagnosis and diet, physical activity and stress management, self empowerment, motivation, participation and health literacy, all facilitated by blended care and ehealth). Introduction of such a systems approach in type 2 diabetes therapy not only requires a concerted action of many stakeholders but also a change in healthcare economy, with new winners and losers. A "call for action" is put forward to actually initiate this transition. The solution provided for type 2 diabetes is translatable to other lifestyle-related disorders. PMID- 29403439 TI - Oncocytic Adrenocortical Neoplasm with Concomitant Papillary Thyroid Cancer. AB - Adrenal oncocytoma (AO) is an extremely rare adrenocortical neoplasm and little is known about its malignant potential, secretory properties, and hereditary origin. We present the case of a benign AO with concomitant incidentally found papillary thyroid cancer (PTC) and review similar cases in the literature. Immunohistochemistry and next-generation sequencing (NGS) were performed. A 66 year-old women was incidentally found to have a large, androgen-secreting right adrenal mass. 18F-Fluorodeoxyglucose positron emission tomography showed intense uptake (SUVmax 88.7) of this mass and found a hypermetabolic right thyroid mass. Open adrenalectomy was performed for this highly suspicious adrenal mass. Histopathology revealed benign AO that was BRAFV600E negative, with low Ki-67, and no somatic mutation found on NGS. Thyroidectomy revealed invasive, BRAFV600E positive PTC. At 6 months follow-up, androgen levels returned to normal, and no recurrence was seen on imaging. To our knowledge, this is the first report of an androgen-secreting AO with concomitant PTC. Possibly the simultaneous discovery of two independent neoplasms was observed. In conclusion, this case highlights that care should be given to exclude concomitant neoplasms. Long-term and regular imaging with biochemical follow-up is warranted, since the outcome and clinical behavior of AO remains uncertain. PMID- 29403438 TI - The Metabolic Syndrome and Its Components in African-American Women: Emerging Trends and Implications. AB - The Metabolic Syndrome (MetS) is recognized as a predictor of cardiovascular outcomes and type 2 diabetes (T2DM). The MetS is a constellation of clinical and metabolic risk factors that include abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. There are ethnic and racial differences in the prevalence of MetS and its components. In general, African-Americans have lower prevalence of MetS when compared to whites, but suffer disproportionately from higher cardiovascular mortality and T2DM. Specifically, African-American women (AAW) have higher rates of T2DM and cardiovascular mortality despite a more favorable lipid and lipoprotein profile. This is paradoxical. However, there is a general upward trend in the prevalence of MetS in the US. The reasons are debatable, but could be multifactorial, including genetics and environmental factors. Thus, there is a need to understand the increasing trend in the MetS, its components, and the associated outcomes for AAW. Therefore, the purpose of this mini review is to (1) understand the increasing prevalence of MetS and its components in AAW and (2) provide suggestions for future prevention of cardiovascular disease and T2DM in AAW. PMID- 29403440 TI - Editorial: Obesity, Smoking, and Fatty Liver Disease. PMID- 29403441 TI - A Pathogen Secreted Protein as a Detection Marker for Citrus Huanglongbing. AB - The citrus industry is facing an unprecedented crisis due to Huanglongbing (HLB, aka citrus greening disease), a bacterial disease associated with the pathogen Candidatus Liberibacter asiaticus (CLas) that affects all commercial varieties. Transmitted by the Asian citrus psyllid (ACP), CLas colonizes citrus phloem, leading to reduced yield and fruit quality, and eventually tree decline and death. Since adequate curative measures are not available, a key step in HLB management is to restrict the spread of the disease by identifying infected trees and removing them in a timely manner. However, uneven distribution of CLas cells in infected trees and the long latency for disease symptom development makes sampling of trees for CLas detection challenging. Here, we report that a CLas secreted protein can be used as a biomarker for detecting HLB infected citrus. Proteins secreted from CLas cells can presumably move along the phloem, beyond the site of ACP inoculation and CLas colonized plant cells, thereby increasing the chance of detecting infected trees. We generated a polyclonal antibody that effectively binds to the secreted protein and developed serological assays that can successfully detect CLas infection. This work demonstrates that antibody based diagnosis using a CLas secreted protein as the detection marker for infected trees offers a high-throughput and economic approach that complements the approved quantitative polymerase chain reaction-based methods to enhance HLB management programs. PMID- 29403442 TI - Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice. AB - We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms. PMID- 29403443 TI - Dicer-like Proteins Regulate the Growth, Conidiation, and Pathogenicity of Colletotrichum gloeosporioides from Hevea brasiliensis. AB - Colletotrichum gloeosporioides from Hevea brasiliensis is the hemibiotrophic fungi which could cause anthracnose in rubber trees. Dicer like proteins (DCL) were the core enzymes for generation of small RNAs. In the present study, the knocking-out mutants of two dicer like proteins encoding genes of C. gloeosporioides were constructed; and functions of two proteins were investigated. The results showed that DCL play important roles in regulating the growth, conidiation and pathogenicity of C. gloeosporioides; and there is a functional redundancy between DCL1 and DCL2. Microscopy analysis and DAB staining revealed that loss of penetration ability into the host cells, instead of the decreased growth rate, was the main cause for the impaired pathogenicity of the DeltaDcl1DeltaDcl2 double mutant. Proteomics analysis suggested that DCL proteins affected the expression of functional proteins to regulating multiple biological processes of C. gloeosporioides. These data lead to a better understanding of the functions of DCL proteins in regulating the development and pathogenesis of C. gloeosporioides. PMID- 29403444 TI - Orpheovirus IHUMI-LCC2: A New Virus among the Giant Viruses. AB - Giant viruses continue to invade the world of virology, in gigantic genome sizes and various particles shapes. Strains discoveries and metagenomic studies make it possible to reveal the complexity of these microorganisms, their origins, ecosystems and putative roles. We isolated from a rat stool sample a new giant virus "Orpheovirus IHUMI-LCC2," using Vermamoeba vermiformis as host cell. In this paper, we describe the main genomic features and replicative cycle of Orpheovirus IHUMI-LCC2. It possesses a circular genome exceeding 1.4 Megabases with 25% G+C content and ovoidal-shaped particles ranging from 900 to 1300 nm. Particles are closed by at least one thick membrane in a single ostiole-like shape in their apex. Phylogenetic analysis and the reciprocal best hit for Orpheovirus show a connection to the proposed Pithoviridae family. However, some genomic characteristics bear witness to a completely divergent evolution for Orpheovirus IHUMI-LCC2 when compared to Cedratviruses or Pithoviruses. PMID- 29403445 TI - Interaction of the Morphogenic Protein RodZ with the Bacillus subtilis Min System. AB - Vegetative cell division in Bacillus subtilis takes place precisely at the middle of the cell to ensure that two viable daughter cells are formed. The first event in cell division is the positioning of the FtsZ Z-ring at the correct site. This is controlled by the coordinated action of both negative and positive regulators. The existence of positive regulators has been inferred, but none have presently been identified in B. subtilis. Noc and the Min system belong to negative regulators; Noc prevents division from occurring over the chromosomes, and the Min system inhibits cell division at the poles. Here we report that the morphogenic protein, RodZ, an essential cell shape determinant, is also required for proper septum positioning during vegetative growth. In rodZ mutant cells, the vegetative septum is positioned off center, giving rise to small, round, DNA containing cells. Searching for the molecular mechanism giving rise to this phenotype led us to discover that RodZ directly interacts with MinJ. We hypothesize that RodZ may aid the Min system in preventing non-medial vegetative division. PMID- 29403446 TI - Mycobacterium Biofilms. AB - The genus Mycobacterium includes human pathogens (Mycobacterium tuberculosis and Mycobacterium leprae) and environmental organisms known as non-tuberculous mycobacteria (NTM) that, when associated with biomaterials and chronic disease, can cause human infections. A common pathogenic factor of mycobacteria is the formation of biofilms. Various molecules are involved in this process, including glycopeptidolipids, shorter-chain mycolic acids, and GroEL1 chaperone. Nutrients, ions, and carbon sources influence bacterial behavior and have a regulatory role in biofilm formation. The ultrastructure of mycobacterial biofilms can be studied by confocal laser scanning microscopy, a technique that reveals different phenotypic characteristics. Cording is associated with NTM pathogenicity, and is also considered an important property of M. tuberculosis strains. Mycobacterial biofilms are more resistant to environmental aggressions and disinfectants than the planktonic form. Biofilm-forming mycobacteria have been reported in many environmental studies, especially in water systems. NTM cause respiratory disease in patients with underlying diseases, such as old tuberculosis scars, bronchiectasis, and cystic fibrosis. Pathogens can be either slowly growing mycobacteria, such as Mycobacterium avium complex, or rapidly growing species, such as Mycobacterium abscessus. Another important biofilm-related group of infections are those associated with biomaterials, and in this setting the most frequently isolated organisms are rapidly growing mycobacteria. M. tuberculosis can develop a biofilm which plays a role in the process of casseous necrosis and cavity formation in lung tissue. M. tuberculosis also develops biofilms on clinical biomaterials. Biofilm development is an important factor for antimicrobial resistance, as it affords protection against antibiotics that are normally active against the same bacteria in the planktonic state. This antibiotic resistance of biofilm-forming microorganisms may result in treatment failure, and biofilms have to be physically eradicated to resolve the infection. New strategies with potential antibiofilm molecules that improve treatment efficacy have been developed. A novel antibiofilm approach focuses on Methylobacterium sp. An understanding of biofilm is essential for the appropriate management of patients with many NTM diseases, while the recent discovery of M. tuberculosis biofilms opens a new research field. PMID- 29403447 TI - Mycobacterium tuberculosis Acquires Limited Genetic Diversity in Prolonged Infections, Reactivations and Transmissions Involving Multiple Hosts. AB - Background:Mycobacterium tuberculosis (MTB) has limited ability to acquire variability. Analysis of its microevolution might help us to evaluate the pathways followed to acquire greater infective success. Whole-genome sequencing (WGS) in the analysis of the transmission of MTB has elucidated the magnitude of variability in MTB. Analysis of transmission currently depends on the identification of clusters, according to the threshold of variability (<5 SNPs) between isolates. Objective: We evaluated whether the acquisition of variability in MTB, was more frequent in situations which could favor it, namely intrapatient, prolonged infections or reactivations and interpatient transmissions involving multiple sequential hosts. Methods: We used WGS to analyze the accumulation of variability in sequential isolates from prolonged infections or translations from latency to reactivation. We then measured microevolution in transmission clusters with prolonged transmission time, high number of involved cases, simultaneous involvement of latency and active transmission. Results: Intrapatient and interpatient acquisition of variability was limited, within the ranges expected according to the thresholds of variability proposed, even though bursts of variability were observed. Conclusions: The thresholds of variability proposed for MTB seem to be valid in most circumstances, including those theoretically favoring acquisition of variability. Our data point to multifactorial modulation of microevolution, although further studies are necessary to elucidate the factors underlying this modulation. PMID- 29403449 TI - Endophyte Chaetomium globosum D38 Promotes Bioactive Constituents Accumulation and Root Production in Salvia miltiorrhiza. AB - Salvia miltiorrhiza is known for tanshinones and salvianolic acids, which have been shown to have a protective effect against ROS, especially for cardiovascular diseases and other various ailments of human organs. Due to the low yield of tanshinones and their analogs in S. miltiorrhiza, multiple stimulation strategies have been developed to improve tanshinones production in plant tissue cultures. Endophytic fungi have been reported to form different relationships with their host plants, including symbiotic, mutualistic, commensalistic, and parasitic interactions. Thus we take the assumption that endophytic fungi may be a potential microbial tool for secondary metabolism promotion in medicinal plants. We recently isolated Chaetomium globosum D38 from the roots of S. miltiorrhiza and our study aimed to examine the effects of this live endophytic fungus D38 and its elicitor on the accumulation of tanshinones in the hairy root cultures of S. miltiorrhiza. Our results revealed that C. globosum D38 mainly colonized in the intercellular gap of xylem parenchyma cells of S. miltiorrhiza hairy roots during the long term co-existence without any toxicity. Moreover, both of the live fungus and its mycelia extract could increase the production of tanshinones, especially for dihydrotanshinone I and cryptotanshinone. The effect of the mycelia extract was much stronger than that of the live fungus on tanshinones synthesis, which significantly increased the transcriptional activity of those key genes in tanshinone biosynthetic pathway. Furthermore, the live C. globosum D38 could also be made into biotic fertilizer used for S. miltiorrhiza seedlings culture, which not only significantly promoted the growth of the host plant, but also notably enhanced the accumulation of tanshinones and salvianolic acids. We thus speculated that, in the soil environment D38 could form bitrophic and mutual beneficial interactions with the host and enhance the plant growth and its secondary metabolism on the whole so as to have facilitative effects on both tanshinones and salvianolic acids accumulation. In conclusion, Chaetomium globosum D38 was a highly beneficial endophytic fungus for the growth and metabolism of S. miltiorrhiza. PMID- 29403448 TI - Advances in Diagnosis, Surveillance, and Monitoring of Zika Virus: An Update. AB - Zika virus (ZIKV) is associated with numerous human health-related disorders, including fetal microcephaly, neurological signs, and autoimmune disorders such as Guillain-Barre syndrome (GBS). Perceiving the ZIKA associated losses, in 2016, the World Health Organization (WHO) declared it as a global public health emergency. In consequence, an upsurge in the research on ZIKV was seen around the globe, with significant attainments over developing several effective diagnostics, drugs, therapies, and vaccines countering this life-threatening virus at an early step. State-of-art tools developed led the researchers to explore virus at the molecular level, and in-depth epidemiological investigations to understand the reason for increased pathogenicity and different clinical manifestations. These days, ZIKV infection is diagnosed based on clinical manifestations, along with serological and molecular detection tools. As, isolation of ZIKV is a tedious task; molecular assays such as reverse transcription-polymerase chain reaction (RT-PCR), real-time qRT-PCR, loop mediated isothermal amplification (LAMP), lateral flow assays (LFAs), biosensors, nucleic acid sequence-based amplification (NASBA) tests, strand invasion-based amplification tests and immune assays like enzyme-linked immunosorbent assay (ELISA) are in-use to ascertain the ZIKV infection or Zika fever. Herein, this review highlights the recent advances in the diagnosis, surveillance, and monitoring of ZIKV. These new insights gained from the recent advances can aid in the rapid and definitive detection of this virus and/or Zika fever. The summarized information will aid the strategies to design and adopt effective prevention and control strategies to counter this viral pathogen of great public health concern. PMID- 29403450 TI - The Outer Membrane Protein OmpW Enhanced V. cholerae Growth in Hypersaline Conditions by Transporting Carnitine. AB - Pathogenic marine bacteria are found in environments and food sources with high salt concentrations, which the bacteria must effectively manage for their survival. Several mechanisms, such as the transport of ions and compatible solutes as well as changes in aerobic and anaerobic respiration, confer salt tolerance to bacteria. In this study, we found that the outer membrane protein OmpW was related to salt stress in Vibrio cholerae and that ompW gene transcription and expression were up-regulated in cultures containing high NaCl concentrations. Deletion of ompW resulted in reduced V. cholerae growth in hypersaline culture conditions. Supplements of the compatible solutes betaine, L carnitine, or L-lysine enhanced the growth of V. cholerae in hypersaline media. Supplements of betaine or L-lysine had the same growth enhancement effect on the ompW-deletion mutant cultured in hypersaline media, whereas L-carnitine supplementation did not restore mutant growth. In addition, the uptake of L carnitine was decreased in the ompW-deletion mutant. Our study showed that among the multiplex factors that enhance the hypersaline tolerance of V. cholerae, OmpW also plays a role by transporting L-carnitine. PMID- 29403451 TI - Lactobacillus rhamnosus GG Affects Microbiota and Suppresses Autophagy in the Intestines of Pigs Challenged with Salmonella Infantis. AB - Salmonella enterica serovar Infantis (S. Infantis) is a common source of foodborne gastroenteritis worldwide. Here, Lactobacillus rhamnosus GG (LGG) was administrated to weaned piglets for 1 week before S. Infantis challenge. S. Infantis caused decreased ileal mucosal microbiota diversity, a dramatic Lactobacillus amylovorus bloom, and decreased abundance of Arsenicicoccus, Janibacter, Kocuria, Nocardioides, Devosia, Paracoccus, Psychrobacter, and Weissella. The beneficial effect of LGG correlated with the moderate expansion of L. amylovorus, L. agilis, and several members of the phyla Proteobacteria, Firmicutes, and Bacteroidetes. S. Infantis translocation to the liver was decreased in the LGG-pretreated piglets. An in vitro model of LGG and S. Infantis co-incubation (involving the porcine intestinal epithelial cell line IPEC-J2) was established, and nalidixic acid was used to kill the extracellular S. Infantis. LGG suppressed the initial S. Infantis invasion in the IPEC-J2 cells and deceased the rate of cell death. LGG inhibited S. Infantis-induced autophagy and promoted epidermal growth factor receptor (EGFR) and Akt phosphorylation in both the ileum and IPEC-J2 cells. Our findings suggest that LGG inhibited S. Infantis-induced autophagy by promoting EGFR-mediated activation of the negative mediator Akt, which, in turn, suppressed intestinal epithelial cell death and thus restricted systemic S. Infantis infection. LGG can restore the gut microbiota balance and preserve the autophagy-related intestinal epithelial barrier, thereby controlling infections. PMID- 29403452 TI - The Aspergillus fumigatus Sialidase (Kdnase) Contributes to Cell Wall Integrity and Virulence in Amphotericin B-Treated Mice. AB - Aspergillus fumigatus is a filamentous fungus that can cause a life-threatening invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. We previously characterized an exo-sialidase from A. fumigatus that prefers the sialic acid substrate, 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (Kdn); hence it is a Kdnase. Sialidases are known virulence factors in other pathogens; therefore, the goal of our study was to evaluate the importance of Kdnase in A. fumigatus. A kdnase knockout strain (Deltakdnase) was unable to grow on medium containing Kdn and displayed reduced growth and abnormal morphology. Deltakdnase was more sensitive than wild type to hyperosmotic conditions and the antifungal agent, amphotericin B. In contrast, Deltakdnase had increased resistance to nikkomycin, Congo Red and Calcofluor White indicating activation of compensatory cell wall chitin deposition. Increased cell wall thickness and chitin content in Deltakdnase were confirmed by electron and immunofluorescence microscopy. In a neutropenic mouse model of invasive aspergillosis, the Deltakdnase strain had attenuated virulence and a significantly lower lung fungal burden but only in animals that received liposomal amphotericin B after spore exposure. Macrophage numbers were almost twofold higher in lung sections from mice that received the Deltakdnase strain, possibly related to higher survival of macrophages that internalized the Deltakdnase conidia. Thus, A. fumigatus Kdnase is important for fungal cell wall integrity and virulence, and because Kdnase is not present in the host, it may represent a potential target for the development of novel antifungal agents. PMID- 29403453 TI - Multi-Platform Sequencing Approach Reveals a Novel Transcriptome Profile in Pseudorabies Virus. AB - Third-generation sequencing is an emerging technology that is capable of solving several problems that earlier approaches were not able to, including the identification of transcripts isoforms and overlapping transcripts. In this study, we used long-read sequencing for the analysis of pseudorabies virus (PRV) transcriptome, including Oxford Nanopore Technologies MinION, PacBio RS-II, and Illumina HiScanSQ platforms. We also used data from our previous short-read and long-read sequencing studies for the comparison of the results and in order to confirm the obtained data. Our investigations identified 19 formerly unknown putative protein-coding genes, all of which are 5' truncated forms of earlier annotated longer PRV genes. Additionally, we detected 19 non-coding RNAs, including 5' and 3' truncated transcripts without in-frame ORFs, antisense RNAs, as well as RNA molecules encoded by those parts of the viral genome where no transcription had been detected before. This study has also led to the identification of three complex transcripts and 50 distinct length isoforms, including transcription start and end variants. We also detected 121 novel transcript overlaps, and two transcripts that overlap the replication origins of PRV. Furthermore, in silico analysis revealed 145 upstream ORFs, many of which are located on the longer 5' isoforms of the transcripts. PMID- 29403454 TI - Environmental Factors Support the Formation of Specific Bacterial Assemblages on Microplastics. AB - While the global distribution of microplastics (MP) in the marine environment is currently being critically evaluated, the potential role of MP as a vector for distinct microbial assemblages or even pathogenic bacteria is hardly understood. To gain a deeper understanding, we investigated how different in situ conditions contribute to the composition and specificity of MP-associated bacterial communities in relation to communities on natural particles. Polystyrene (PS), polyethylene (PE), and wooden pellets were incubated for 2 weeks along an environmental gradient, ranging from marine (coastal Baltic Sea) to freshwater (waste water treatment plant, WWTP) conditions. The associated assemblages as well as the water communities were investigated applying high-throughput 16S rRNA gene sequencing. Our setup allowed for the first time to determine MP-dependent and -independent assemblage factors as subject to different environmental conditions in one system. Most importantly, plastic-specific assemblages were found to develop solely under certain conditions, such as lower nutrient concentration and higher salinity, while the bacterial genus Erythrobacter, known for the ability to utilize polycyclic aromatic hydrocarbons (PAH), was found specifically on MP across a broader section of the gradient. We discovered no enrichment of potential pathogens on PE or PS; however, the abundant colonization of MP in a WWTP by certain bacteria commonly associated with antibiotic resistance suggests MP as a possible hotspot for horizontal gene transfer. Taken together, our study clarifies that the surrounding environment prevailingly shapes the biofilm communities, but that MP-specific assemblage factors exist. These findings point to the ecological significance of specific MP-promoted bacterial populations in aquatic environments and particularly in plastic accumulation zones. PMID- 29403455 TI - Antagonistic and Detoxification Potentials of Trichoderma Isolates for Control of Zearalenone (ZEN) Producing Fusarium graminearum. AB - Fungi belonging to Fusarium genus can infect crops in the field and cause subsequent mycotoxin contamination, which leads to yield and quality losses of agricultural commodities. The mycotoxin zearalenone (ZEN) produced by several Fusarium species (such as F. graminearum and F. culmorum) is a commonly-detected contaminant in foodstuffs, posing a tremendous risk to food safety. Thus, different strategies have been studied to manage toxigenic pathogens and mycotoxin contamination. In recent years, biological control of toxigenic fungi is emerging as an environment-friendly strategy, while Trichoderma is a fungal genus with great antagonistic potentials for controlling mycotoxin producing pathogens. The primary objective of this study was to explore the potentials of selected Trichoderma isolates on ZEN-producing F. graminearum, and the second aim was to investigate the metabolic activity of different Trichoderma isolates on ZEN. Three tested Trichoderma isolates were proved to be potential candidates for control of ZEN producers. In addition, we reported the capacity of Trichoderma to convert ZEN into its reduced and sulfated forms for the first time, and provided evidences that the tested Trichoderma could not detoxify ZEN via glycosylation. This provides more insight in the interaction between ZEN-producing fungi and Trichoderma isolates. PMID- 29403456 TI - Genetic Analysis of Human Norovirus Strains in Japan in 2016-2017. AB - In the 2016/2017 winter season in Japan, HuNoV GII.P16-GII.2 strains (2016 strains) emerged and caused large outbreaks of acute gastroenteritis. To better understand the outbreaks, we examined the molecular evolution of the VP1 gene and RdRp region in 2016 strains from patients by studying their time-scale evolutionary phylogeny, positive/negative selection, conformational epitopes, and phylodynamics. The time-scale phylogeny suggested that the common ancestors of the 2016 strains VP1 gene and RdRp region diverged in 2006 and 1999, respectively, and that the 2016 strain was the progeny of a pre-2016 GII.2. The evolutionary rates of the VP1 gene and RdRp region were around 10-3 substitutions/site/year. Amino acid substitutions (position 341) in an epitope in the P2 domain of 2016 strains were not found in pre-2016 GII.2 strains. Bayesian skyline plot analyses showed that the effective population size of the VP1 gene in GII.2 strains was almost constant for those 50 years, although the number of patients with NoV GII.2 increased in 2016. The 2016 strain may be involved in future outbreaks in Japan and elsewhere. PMID- 29403457 TI - Transcriptome Analysis of a Bloom-Forming Cyanobacterium Microcystis aeruginosa during Ma-LMM01 Phage Infection. AB - Microcystis aeruginosa forms massive blooms in eutrophic freshwaters, where it is constantly exposed to lytic cyanophages. Unlike other marine cyanobacteria, M. aeruginosa possess remarkably abundant and diverse potential antiviral defense genes. Interestingly, T4-like cyanophage Ma-LMM01, which is the sole cultured lytic cyanophage infecting M. aeruginosa, lacks the host-derived genes involved in maintaining host photosynthesis and directing host metabolism that are abundant in other marine cyanophages. Based on genomic comparisons with closely related cyanobacteria and their phages, Ma-LMM01 is predicted to employ a novel infection program that differs from that of other marine cyanophages. Here, we used RNA-seq technology and in silico analysis to examine transcriptional dynamics during Ma-LMM01 infection to reveal host transcriptional responses to phage infection, and to elucidate the infection program used by Ma-LMM01 to avoid the highly abundant host defense systems. Phage-derived reads increased only slightly at 1 h post-infection, but significantly increased from 16% of total cellular reads at 3 h post-infection to 33% of all reads by 6 h post-infection. Strikingly, almost none of the host genes (0.17%) showed a significant change in expression during infection. However, like other lytic dsDNA phages, including marine cyanophages, phage gene dynamics revealed three expression classes: early (host-takeover), middle (replication), and late (virion morphogenesis). The early genes were concentrated in a single ~5.8-kb window spanning 10 open reading frames (gp054-gp063) on the phage genome. None of the early genes showed homology to the early genes of other T4-like phages, including known marine cyanophages. Bacterial RNA polymerase (sigma70) recognition sequences were also found in the upstream region of middle and late genes, whereas phage-specific motifs were not found. Our findings suggest that unlike other known T4-like phages, Ma-LMM01 achieves three sequential gene expression patterns with no change in host promoter activity. This type of infection that does not cause significant change in host transcriptional levels may be advantageous in allowing Ma-LMM01 to escape host defense systems while maintaining host photosynthesis. PMID- 29403458 TI - Contribution of Bicarbonate Assimilation to Carbon Pool Dynamics in the Deep Mediterranean Sea and Cultivation of Actively Nitrifying and CO2-Fixing Bathypelagic Prokaryotic Consortia. AB - Covering two-thirds of our planet, the global deep ocean plays a central role in supporting life on Earth. Among other processes, this biggest ecosystem buffers the rise of atmospheric CO2. Despite carbon sequestration in the deep ocean has been known for a long time, microbial activity in the meso- and bathypelagic realm via the "assimilation of bicarbonate in the dark" (ABD) has only recently been described in more details. Based on recent findings, this process seems primarily the result of chemosynthetic and anaplerotic reactions driven by different groups of deep-sea prokaryoplankton. We quantified bicarbonate assimilation in relation to total prokaryotic abundance, prokaryotic heterotrophic production and respiration in the meso- and bathypelagic Mediterranean Sea. The measured ABD values, ranging from 133 to 370 MUg C m-3 d 1, were among the highest ones reported worldwide for similar depths, likely due to the elevated temperature of the deep Mediterranean Sea (13-14 degrees C also at abyssal depths). Integrated over the dark water column (>=200 m depth), bicarbonate assimilation in the deep-sea ranged from 396 to 873 mg C m-2 d-1. This quantity of produced de novo organic carbon amounts to about 85-424% of the phytoplankton primary production and covers up to 62% of deep-sea prokaryotic total carbon demand. Hence, the ABD process in the meso- and bathypelagic Mediterranean Sea might substantially contribute to the inorganic and organic pool and significantly sustain the deep-sea microbial food web. To elucidate the ABD key-players, we established three actively nitrifying and CO2-fixing prokaryotic enrichments. Consortia were characterized by the co-occurrence of chemolithoautotrophic Thaumarchaeota and chemoheterotrophic proteobacteria. One of the enrichments, originated from Ionian bathypelagic waters (3,000 m depth) and supplemented with low concentrations of ammonia, was dominated by the Thaumarchaeota "low-ammonia-concentration" deep-sea ecotype, an enigmatic and ecologically important group of organisms, uncultured until this study. PMID- 29403460 TI - Editorial: Molecular Biology of Bamboo mosaic Virus-A Type Member of the Potexvirus Genus. PMID- 29403459 TI - Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression. AB - Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer. PMID- 29403461 TI - Stripping Away the Soil: Plant Growth Promoting Microbiology Opportunities in Aquaponics. AB - As the processes facilitated by plant growth promoting microorganisms (PGPMs) become better characterized, it is evident that PGPMs may be critical for successful sustainable agricultural practices. Microbes enrich plant growth through various mechanisms, such as enhancing resistance to disease and drought, producing beneficial molecules, and supplying nutrients and trace metals to the plant rhizosphere. Previous studies of PGPMs have focused primarily on soil-based crops. In contrast, aquaponics is a water-based agricultural system, in which production relies upon internal nutrient recycling to co-cultivate plants with fish. This arrangement has management benefits compared to soil-based agriculture, as system components may be designed to directly harness microbial processes that make nutrients bioavailable to plants in downstream components. However, aquaponic systems also present unique management challenges. Microbes may compete with plants for certain micronutrients, such as iron, which makes exogenous supplementation necessary, adding production cost and process complexity, and limiting profitability and system sustainability. Research on PGPMs in aquaponic systems currently lags behind traditional agricultural systems, however, it is clear that certain parallels in nutrient use and plant microbe interactions are retained from soil-based agricultural systems. PMID- 29403462 TI - High-Temperature Induced Changes of Extracellular Metabolites in Pleurotus ostreatus and Their Positive Effects on the Growth of Trichoderma asperellum. AB - Pleurotus ostreatus is a widely cultivated edible fungus in China. Green mold disease of P. ostreatus which can seriously affect yield is a common disease during cultivation. It occurs mostly after P. ostreatus mycelia have been subjected to high temperatures. However, little information is available on the relationship between high temperature and green mold disease. The aim of this study is to prove that extracellular metabolites of P. ostreatus affected by high temperature can promote the growth of Trichoderma asperellum. After P. ostreatus mycelia was subjected to high temperature, the extracellular fluid of P. ostreatus showed a higher promoting effect on mycelial growth and conidial germination of T. asperellum. The thiobarbituric acid reactive substance (TBARS) content reached the maximum after 48 h at 36 degrees C. A comprehensive metabolite profiling strategy involving gas chromatography-mass spectrometry (GC/MS) combined with liquid chromatography-mass spectrometry (LC/MS) was used to analyze the changes of extracellular metabolites in response to high temperature. A total of 141 differential metabolites were identified, including 84.4% up regulated and 15.6% down-regulated. Exogenous metabolites whose concentrations were increased after high temperature were randomly selected, and nearly all of them were able to promote the mycelial growth and conidial germination of T. asperellum. The combination of all selected exogenous metabolites also has the promotion effects on the mycelial growth and conidial germination of T. asperellum in a given concentration range in vitro. Overall, these results provide a first view that high temperature affects the extracellular metabolites of P. ostreatus, and the extensive change in metabolites promotes T. asperellum growth. PMID- 29403463 TI - A P7 Phage-Like Plasmid Carrying mcr-1 in an ST15 Klebsiella pneumoniae Clinical Isolate. AB - A Klebsiella pneumoniae clinical strain, named SCKP83, was isolated and found to be resistant to colistin thanks to the presence plasmid-borne colistin resistant gene mcr-1. The strain was subjected to whole genome sequencing and conjugation experiments. The subsequent analysis indicated that the strain belongs to ST15 and the capsular type K41. In SCKP83, mcr-1 was carried by a 97.4-kb non-self transmissible plasmid, a 90.9-kb region of which was predicted as an intact phage. This phage was 47.79% GC content, encoded 105 proteins and contained three tRNAs. mcr-1 was located downstream of two copies of the insertion sequence ISApl1 (one complete and one truncated) and was inserted in the ant1 gene, which encodes a putative antirepressor for antagonizing C1 repression, in this phage. The phage is highly similar to phage P7 (77% coverage and 98% identity) from Escherichia coli. Several similar mcr-1-carrying plasmids have been found in E. coli at various locations in China, suggesting that these phage-like plasmids have circulated in China. The findings in this study suggest that the P7 phage like plasmids are not restricted to E. coli and may represent new vehicles to mediate the inter-species spread of mcr-1. PMID- 29403464 TI - Morpho-Molecular Characterization of Two Ampelomyces spp. (Pleosporales) Strains Mycoparasites of Powdery Mildew of Hevea brasiliensis. AB - Powdery mildew disease of rubber affects immature green leaves, buds, inflorescences, and other immature tissues of rubber trees, resulting in up to 45% losses in rubber latex yield worldwide. The disease is often controlled by dusting the diseased plants with powdered sulfur, which can have long-term negative effects on the environment. Therefore, it is necessary to search for alternative and environmentally friendly control methods for this disease. This study aimed to identify mycoparasites associated with rubber powdery mildew species, and characterize them on the basis of morpho-molecular characteristics and phylogenetic analyses of ITS rDNA regions. We observed that the Ampelomyces fungus parasitizes rubber powdery mildew, and eventually destroys it. Furthermore, on the basis of phylogenetic analyses and morphological characteristics we confirmed that the Ampelomyces mycoparasite isolated from rubber powdery mildew is closely related to other mycohost taxa in the Erysiphe genus. A total of 73 (71 retrieved from GenBank and two obtained from fresh collections of rubber powdery mildew fungi) Ampelomyces spp. were analyzed using ITS rDNA sequences and 153 polymorphic sites were identified through haplotypic analyses. A total of 28 haplotypes (H1-H28) were identified to have a complex network of mutation events. The results from phylogenetic tree constructed on the basis of maximum likelihood analyses, and the haplotype network tree revealed similar relationships of clustering pattern. This work presents the first report on morpho-molecular characterization of Ampelomyces species that are mycoparasites of powdery mildew of Hevea brasiliensis. PMID- 29403465 TI - Deletion of Lytic Transglycosylases Increases Beta-Lactam Resistance in Shewanella oneidensis. AB - Production of chromosome-encoded beta-lactamases confers resistance to beta lactams in many Gram-negative bacteria. Some inducible beta-lactamases, especially the class C beta-lactamase AmpC in Enterobacteriaceae, share a common regulatory mechanism, the ampR-ampC paradigm. Induction of ampC is intimately linked to peptidoglycan recycling, and the LysR-type transcriptional regulator AmpR plays a central role in the process. However, our previous studies have demonstrated that the expression of class D beta-lactamase gene blaA in Shewanella oneidensis is distinct from the established paradigm since an AmpR homolog is absent and major peptidoglycan recycling enzymes play opposite roles in beta-lactamase expression. Given that lytic transglycosylases (LTs), a class of peptidoglycan hydrolases cleaving the beta-1,4 glycosidic linkage in glycan strands of peptidoglycan, can disturb peptidoglycan recycling, and thus may affect induction of blaA. In this study, we investigated impacts of such enzymes on susceptibility to beta-lactams. Deletion of three LTs (SltY, MltB and MltB2) increased beta-lactam resistance, while four other LTs (MltD, MltD2, MltF, and Slt2) seemed dispensable to beta-lactam resistance. The double LT mutants DeltamltBDeltamltB2 and DeltasltYDeltamltB2 had beta-lactam resistance stronger than any of the single mutants. Deletion of ampG (encoding permease AmpG) and mrcA (encoding penicillin binding protein 1a, PBP1a) from both double LT mutants further increased the resistance to beta-lactams. Notably, all increased beta lactam resistance phenotypes were in accordance with enhanced blaA expression. Although significant, the increase in beta-lactamase activity after inactivating LTs is much lower than that produced by PBP1a inactivation. Our data implicate that LTs play important roles in blaA expression in S. oneidensis. PMID- 29403466 TI - The Novel Phages phiCD5763 and phiCD2955 Represent Two Groups of Big Plasmidial Siphoviridae Phages of Clostridium difficile. AB - Until recently, Clostridium difficile phages were limited to Myoviruses and Siphoviruses of medium genome length (32-57 kb). Here we report the finding of phiCD5763, a Siphovirus with a large extrachromosomal circular genome (132.5 kb, 172 ORFs) and a large capsid (205.6 +/- 25.6 nm in diameter) infecting MLST Clade 1 strains of C. difficile. Two subgroups of big phage genomes similar to phiCD5763 were identified in 32 NAPCR1/RT012/ST-54 C. difficile isolates from Costa Rica and in whole genome sequences (WGS) of 41 C. difficile isolates of Clades 1, 2, 3, and 4 from Canada, USA, UK, Belgium, Iraq, and China. Through comparative genomics we discovered another putative big phage genome in a non NAPCR1 isolate from Costa Rica, phiCD2955, which represents other big phage genomes found in 130 WGS of MLST Clade 1 and 2 isolates from Canada, USA, Hungary, France, Austria, and UK. phiCD2955 (131.6 kb, 172 ORFs) is related to a previously reported C. difficile phage genome, phiCD211/phiCDIF1296T. Detailed genome analyses of phiCD5763, phiCD2955, phiCD211/phiCDIF1296T, and seven other putative C. difficile big phage genome sequences of 131-136 kb reconstructed from publicly available WGS revealed a modular gene organization and high levels of sequence heterogeneity at several hotspots, suggesting that these genomes correspond to biological entities undergoing recombination. Compared to other C. difficile phages, these big phages have unique predicted terminase, capsid, portal, neck and tail proteins, receptor binding proteins (RBPs), recombinases, resolvases, primases, helicases, ligases, and hypothetical proteins. Moreover, their predicted gene load suggests a complex regulation of both phage and host functions. Overall, our results indicate that the prevalence of C. difficile big bacteriophages is more widespread than realized and open new avenues of research aiming to decipher how these viral elements influence the biology of this emerging pathogen. PMID- 29403467 TI - Collection and Curation of Transcriptional Regulatory Interactions in Aspergillus nidulans and Neurospora crassa Reveal Structural and Evolutionary Features of the Regulatory Networks. AB - Transcriptional regulation has important roles in various biological processes (e.g., development and metabolism) in filamentous fungi. However, regulatory interactions between transcription factors (TFs) and their target genes in these species have only been described in different forms by primary scientific literature, which limits the integrated analysis of these data. Here, we extensively curated the reported transcriptional regulatory interactions in Aspergillus nidulans and Neurospora crassa. For each interaction, the identifiers of involved proteins or genes were unified, and the types of supporting experiments were recorded. Then, transcriptional regulatory networks were reconstructed from the interactions supported by classical low-throughput experiments. Analysis of the networks revealed the presence of hub targets regulated by multiple TFs and network motifs of other structures (e.g., regulatory loops). Comparison of the regulatory interactions between the two species identified 33 conserved interactions supported by classical experiments in both species, most of which are involved in the regulation of metabolic genes. We anticipate the curated data would serve as a catalog for the studies of transcriptional regulation in filamentous fungi. PMID- 29403468 TI - Computational Pipeline for the PGV-001 Neoantigen Vaccine Trial. AB - This paper describes the sequencing protocol and computational pipeline for the PGV-001 personalized vaccine trial. PGV-001 is a therapeutic peptide vaccine targeting neoantigens identified from patient tumor samples. Peptides are selected by a computational pipeline that identifies mutations from tumor/normal exome sequencing and ranks mutant sequences by a combination of predicted Class I MHC affinity and abundance estimated from tumor RNA. The personalized genomic vaccine (PGV) pipeline is modular and consists of independently usable tools and software libraries. We hope that the functionality of these tools may extend beyond the specifics of the PGV-001 trial and enable other research groups in their own neoantigen investigations. PMID- 29403470 TI - Expression of Tumor Necrosis Factor Receptor 2 Characterizes TLR9-Driven Formation of Interleukin-10-Producing B Cells. AB - B cell-derived interleukin-10 (IL-10) production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2) expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2- fractions correspond to IL-10+ and IL-10- fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset. PMID- 29403471 TI - Immune Tolerance to Apoptotic Self Is Mediated Primarily by Regulatory B1a Cells. AB - The chronic autoimmune inflammatory diseases, systemic lupus erythematosus and Sjogren's syndrome, develop when tolerance to apoptotic cells (ACs) is lost. We have previously reported that this tolerance is maintained by innate-like, IL-10 secreting regulatory B cells. Two questions remained. First, do these regulatory B cells belong predominantly to a single subset of steady-state B cells and second, what is their specificity? We report here that innate-like B cells with markers characteristic for B1a cells (CD43+veCD19hiCD5+veIgMhiIgDlo) constitute 80% of splenic and 96% of peritoneal B cells that respond to ACs by secreting IL 10. AC responsive B1a cells secrete self-reactive natural antibodies (NAbs) and IL-10, which is augmented by toll-like receptor (TLR) 7 or TLR9 stimulation. In so doing, they both accelerate the clearance of dying cells by macrophages and inhibit their potential to mount proinflammatory immune responses. While B1a cells make prolonged contact with ACs, they do not require TIM1 or complement to mediate their regulatory function. In an animal model of neural inflammation (experimental autoimmune encephalomyelitis), just 105 activated B1a B cells was sufficient to restrain inflammation. Activated B1a B cells also induced antigen specific T cells to secrete IL-10. Hence, regulatory B1a cells specifically recognize and augment tolerance to apoptotic self via IL-10 and NAbs; but once activated, can also prevent autoimmune mediated inflammation. PMID- 29403469 TI - E-Selectin Ligands in the Human Mononuclear Phagocyte System: Implications for Infection, Inflammation, and Immunotherapy. AB - The mononuclear phagocyte system comprises a network of circulating monocytes and dendritic cells (DCs), and "histiocytes" (tissue-resident macrophages and DCs) that are derived in part from blood-borne monocytes and DCs. The capacity of circulating monocytes and DCs to function as the body's first-line defense against offending pathogens greatly depends on their ability to egress the bloodstream and infiltrate inflammatory sites. Extravasation involves a sequence of coordinated molecular events and is initiated by E-selectin-mediated deceleration of the circulating leukocytes onto microvascular endothelial cells of the target tissue. E-selectin is inducibly expressed by cytokines (tumor necrosis factor-alpha and IL-1beta) on inflamed endothelium, and binds to sialofucosylated glycan determinants displayed on protein and lipid scaffolds of blood cells. Efficient extravasation of circulating monocytes and DCs to inflamed tissues is crucial in facilitating an effective immune response, but also fuels the immunopathology of several inflammatory disorders. Thus, insights into the structural and functional properties of the E-selectin ligands expressed by different monocyte and DC populations is key to understanding the biology of protective immunity and the pathobiology of several acute and chronic inflammatory diseases. This review will address the role of E-selectin in recruitment of human circulating monocytes and DCs to sites of tissue injury/inflammation, the structural biology of the E-selectin ligands expressed by these cells, and the molecular effectors that shape E-selectin ligand cell specific display. In addition, therapeutic approaches targeting E-selectin receptor/ligand interactions, which can be used to boost host defense or, conversely, to dampen pathological inflammatory conditions, will also be discussed. PMID- 29403472 TI - Interleukin (IL)-23 Stimulates IFN-gamma Secretion by CD56bright Natural Killer Cells and Enhances IL-18-Driven Dendritic Cells Activation. AB - Interleukin (IL)-23 is a member of the IL-12 family of cytokines that, as the other members of this family, is secreted by monocytes, macrophages, and dendritic cells (DC) upon recognition of bacterial, viral, and fungal components. IL-23 is critical during immunity against acute infections, and it is also involved in the development of autoimmune diseases. Although immunoregulatory effects of IL-23 on mouse natural killer (NK) cells have been described, the effect of IL-23 on human NK cells remains ill-defined. In this study, we observed that monocytes stimulated with LPS secreted IL-23 and that blockade of this cytokine during monocyte and NK cell coculture led to a diminished production of IFN-gamma by NK cells. Accordingly, rIL-23-induced NK cell activation and stimulated IFN-gamma production by CD56bright NK cells. This effect involved MEK1/MEK2, JNK, PI3K, mammalian target of rapamycin, and NF-kappaB, but not STAT 1, STAT-3, nor p38 MAPK pathways. Moreover, while NK cell-mediated cytotoxicity remained unaltered, antibody-dependent cellular cytotoxicity (ADCC) was enhanced after IL-23 stimulation. In addition, IL-23 displayed a synergistic effect with IL-18 for IFN-gamma production by both CD56bright and CD56dim NK cells, and this effect was due to a priming effect of IL-23 for IL-18 responsiveness. Furthermore, NK cells pre-stimulated with IL-18 promoted an increase in CD86 expression and IL-12 secretion by DC treated with LPS, and IL-23 potentiated these effects. Moreover, IL-23-driven enhancement of NK cell "helper" function was dependent on NK cell-derived IFN-gamma. Therefore, our results suggest that IL-23 may trigger NK cell-mediated "helper" effects on adaptive immunity, shaping T cell responses during different pathological situations through the regulation of DC maturation. PMID- 29403473 TI - Shuttling Tolerogenic Dendritic Cells across the Blood-Brain Barrier In Vitro via the Introduction of De Novo C-C Chemokine Receptor 5 Expression Using Messenger RNA Electroporation. AB - The use of tolerance-inducing dendritic cells (tolDCs) has been proven to be safe and well tolerated in the treatment of autoimmune diseases. Nevertheless, several challenges remain, including finding ways to facilitate the migration of cell therapeutic products to lymph nodes, and the site of inflammation. In the treatment of neuroinflammatory diseases, such as multiple sclerosis (MS), the blood-brain barrier (BBB) represents a major obstacle to the delivery of therapeutic agents to the inflamed central nervous system (CNS). As it was previously demonstrated that C-C chemokine receptor 5 (CCR5) may be involved in inflammatory migration of DCs, the aim of this study was to investigate CCR5 driven migration of tolDCs. Only a minority of in vitro generated vitamin D3 (vitD3)-treated tolDCs expressed the inflammatory chemokine receptor CCR5. Thus, messenger RNA (mRNA) encoding CCR5 was introduced by means of electroporation (EP). After mRNA EP, tolDCs transiently displayed increased levels of CCR5 protein expression. Accordingly, the capacity of mRNA electroporated tolDCs to transmigrate toward a chemokine gradient in an in vitro model of the BBB improved significantly. Neither the tolerogenic phenotype nor the T cell-stimulatory function of tolDCs was affected by mRNA EP. EP of tolDCs with mRNA encoding CCR5 enabled these cells to migrate to inflammatory sites. The approach used herein has important implications for the treatment of MS. Using this approach, tolDCs actively shuttle across the BBB, allowing in situ down-modulation of autoimmune responses in the CNS. PMID- 29403474 TI - Human NF-kappaB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease Molecular Mechanisms and Consequences. AB - Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-kappaB1) related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-kappaB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein-Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-kappaB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease. PMID- 29403475 TI - Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid-containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton's tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end-organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE. PMID- 29403476 TI - Contribution of IL-1RI Signaling to Protection against Cryptococcus neoformans 52D in a Mouse Model of Infection. AB - Interleukin-1 alpha (IL-1alpha) and interleukin-1 beta (IL-1beta) are pro inflammatory cytokines that are induced after Cryptococcus neoformans infection and activate the interleukin-1 receptor type I (IL-1RI). To establish the role of IL-1RI signaling in protection against cryptococcal infection, we analyzed wild type (WT) and IL-1RI-deficient (IL-1RI-/-) mice on the BALB/c background. IL-1RI /- mice had significantly reduced survival compared to WT mice after intratracheal challenge with C. neoformans 52D. Microbiological analysis showed a significant increase in the lung and brain fungal burden of IL-1RI-/- compared to WT mice beginning at weeks 1 and 4 postinfection, respectively. Histopathology showed that IL-1RI-/- mice exhibit greater airway epithelial mucus secretion and prominent eosinophilic crystals that were absent in WT mice. Susceptibility of IL 1RI-/- mice was associated with significant induction of a Th2-biased immune response characterized by pulmonary eosinophilia, M2 macrophage polarization, and recruitment of CD4+ IL-13+ T cells. Expression of pro-inflammatory [IL-1alpha, IL 1beta, TNFalpha, and monocyte chemoattractant protein 1 (MCP-1)], Th1-associated (IFNgamma), and Th17-associated (IL-17A) cytokines was significantly reduced in IL-1RI-/- lungs compared to WT. WT mice also had higher expression of KC/CXCL1 and sustained neutrophil recruitment to the lung; however, antibody-mediated depletion of these cells showed that they were dispensable for lung fungal clearance. In conclusion, our data indicate that IL-1RI signaling is required to activate a complex series of innate and adaptive immune responses that collectively enhance host defense and survival after C. neoformans 52D infection in BALB/c mice. PMID- 29403477 TI - A Multifaceted Role of Tryptophan Metabolism and Indoleamine 2,3-Dioxygenase Activity in Aspergillus fumigatus-Host Interactions. AB - Aspergillus fumigatus is the most prevalent filamentous fungal pathogen of humans, causing either severe allergic bronchopulmonary aspergillosis or often fatal invasive pulmonary aspergillosis (IPA) in individuals with hyper- or hypo immune deficiencies, respectively. Disease is primarily initiated upon the inhalation of the ubiquitous airborne conidia-the initial inoculum produced by A. fumigatus-which are complete developmental units with an ability to exploit diverse environments, ranging from agricultural composts to animal lungs. Upon infection, conidia initially rely on their own metabolic processes for survival in the host's lungs, a nutritionally limiting environment. One such nutritional limitation is the availability of aromatic amino acids (AAAs) as animals lack the enzymes to synthesize tryptophan (Trp) and phenylalanine and only produce tyrosine from dietary phenylalanine. However, A. fumigatus produces all three AAAs through the shikimate-chorismate pathway, where they play a critical role in fungal growth and development and in yielding many downstream metabolites. The downstream metabolites of Trp in A. fumigatus include the immunomodulatory kynurenine derived from indoleamine 2,3-dioxygenase (IDO) and toxins such as fumiquinazolines, gliotoxin, and fumitremorgins. Host IDO activity and/or host/microbe-derived kynurenines are increasingly correlated with many Aspergillus diseases including IPA and infections of chronic granulomatous disease patients. In this review, we will describe the potential metabolic cross talk between the host and the pathogen, specifically focusing on Trp metabolism, the implications for therapeutics, and the recent studies on the coevolution of host and microbe IDO activation in regulating inflammation, while controlling infection. PMID- 29403479 TI - Assessment of Antibodies Induced by Multivalent Transmission-Blocking Malaria Vaccines. AB - A malaria transmission-blocking vaccine would be a critical tool in achieving malaria elimination and eradication. By using chimpanzee adenovirus serotype 63 and modified vaccinia virus Ankara viral vectored vaccines, we investigated whether incorporating two antigens into one vaccine would result in higher transmission-reducing activity than one antigen. We demonstrated that when Pfs25 was administered with other antigens Pfs28 or Pfs230C, either concurrently as a mixed vaccine or co-expressed as a dual-antigen vaccine, the antibody response in mice to each antigen was comparable to a monoantigen vaccine, without immunological interference. However, we found that the transmission-reducing activity (functional activity) of dual-antigen vaccines was not additive. Dual antigen vaccines generally only elicited similar transmission-reducing activity to monoantigen vaccines and in one instance had lower transmission-reducing activity. We found that despite the lack of immunological interference of dual antigen vaccines, they are still not as effective at blocking malaria transmission as Pfs25-IMX313, the current leading candidate for viral vectored vaccines. Pfs25-IMX313 elicited similar quality antibodies to dual-antigen vaccines, but higher antibody titers. PMID- 29403478 TI - Genomic and Phenotypic Variation in Morphogenetic Networks of Two Candida albicans Isolates Subtends Their Different Pathogenic Potential. AB - The transition from commensalism to pathogenicity of Candida albicans reflects both the host inability to mount specific immune responses and the microorganism's dimorphic switch efficiency. In this study, we used whole genome sequencing and microarray analysis to investigate the genomic determinants of the phenotypic changes observed in two C. albicans clinical isolates (YL1 and YQ2). In vitro experiments employing epithelial, microglial, and peripheral blood mononuclear cells were thus used to evaluate C. albicans isolates interaction with first line host defenses, measuring adhesion, susceptibility to phagocytosis, and induction of secretory responses. Moreover, a murine model of peritoneal infection was used to compare the in vivo pathogenic potential of the two isolates. Genome sequence and gene expression analysis of C. albicans YL1 and YQ2 showed significant changes in cellular pathways involved in environmental stress response, adhesion, filamentous growth, invasiveness, and dimorphic transition. This was in accordance with the observed marked phenotypic differences in biofilm production, dimorphic switch efficiency, cell adhesion, invasion, and survival to phagocyte-mediated host defenses. The mutations in key regulators of the hyphal growth pathway in the more virulent strain corresponded to an overall greater number of budding yeast cells released. Compared to YQ2, YL1 consistently showed enhanced pathogenic potential, since in vitro, it was less susceptible to ingestion by phagocytic cells and more efficient in invading epithelial cells, while in vivo YL1 was more effective than YQ2 in recruiting inflammatory cells, eliciting IL-1beta response and eluding phagocytic cells. Overall, these results indicate an unexpected isolate-specific variation in pathways important for host invasion and colonization, showing how the genetic background of C. albicans may greatly affect its behavior both in vitro and in vivo. Based on this approach, we propose that the co-occurrence of changes in sequence and expression in genes and pathways driving dimorphic transition and pathogenicity reflects a selective balance between traits favoring dissemination of the pathogen and traits involved in host defense evasion. This study highlights the importance of investigating strain-level, rather than species level, differences, when determining fungal-host interactions and defining commensal or pathogen behavior. PMID- 29403480 TI - Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages. AB - Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO2) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1beta. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufriere Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufriere Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1beta in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1beta in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1beta secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro. Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles. PMID- 29403481 TI - CD4+ T Helper Cells Play a Key Role in Maintaining Diabetogenic CD8+ T Cell Function in the Pancreas. AB - Autoreactive CD8+ and CD4+ T cells have been assigned independent key roles in the destruction of insulin-producing beta cells resulting in type 1 diabetes. Although CD4 help for the generation of efficient CD8+ T cell responses in lymphoid tissue has been extensively described, whether these two cell populations cooperate in islet destruction in situ remains unclear. By using intravital 2-photon microscopy in a mouse model of diabetes, we visualized both effector T cell populations in the pancreas during disease onset. CD4+ T helper cells displayed a much higher arrest in the exocrine tissue than islet-specific CD8+ T cells. This increased arrest was major histocompatibility complex (MHC) class II-dependent and locally correlated with antigen-presenting cell recruitment. CD8+ T cells deprived of continued CD4 help specifically in the pancreas, through blocking MHC class II recognition, failed to maintain optimal effector functions, which contributed to hamper diabetes progression. Thus, we provide novel insight in the cellular mechanisms regulating effector T cell functionality in peripheral tissues with important implications for immunotherapies. PMID- 29403482 TI - B and T Cell Phenotypic Profiles of African HIV-Infected and HIV-Exposed Uninfected Infants: Associations with Antibody Responses to the Pentavalent Rotavirus Vaccine. AB - We examined associations between B and T cell phenotypic profiles and antibody responses to the pentavalent rotavirus vaccine (RV5) in perinatally HIV-infected (PHIV) infants on antiretroviral therapy and in HIV-exposed uninfected (PHEU) infants enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials P1072 study (NCT00880698). Of 17 B and T cell subsets analyzed, PHIV and PHEU differed only in the number of CD4+ T cells and frequency of naive B cells, which were higher in PHEU than in PHIV. In contrast, the B and T cell phenotypic profiles of PHIV and PHEU markedly differed from those of geographically matched contemporary HIV-unexposed infants. The frequency of regulatory T and B cells (Treg, Breg) of PHIV and PHEU displayed two patterns of associations: FOXP3+ CD25+ Treg positively correlated with CD4+ T cell numbers; while TGFbeta+ Treg and IL10+ Treg and Breg positively correlated with the frequencies of inflammatory and activated T cells. Moreover, the frequencies of activated and inflammatory T cells of PHIV and PHEU positively correlated with the frequency of immature B cells. Correlations were not affected by HIV status and persisted over time. PHIV and PHEU antibody responses to RV5 positively correlated with CD4+ T cell counts and negatively with the proportion of immature B cells, similarly to what has been previously described in chronic HIV infection. Unique to PHIV and PHEU, anti-RV5 antibodies positively correlated with CD4+/CD8+FOXP3+CD25+% and negatively with CD4+IL10+% Tregs. In conclusion, PHEU shared with PHIV abnormal B and T cell phenotypic profiles. PHIV and PHEU antibody responses to RV5 were modulated by typical HIV-associated immune response modifiers except for the association between CD4+/CD8+FOXP3+CD25+Treg and increased antibody production. PMID- 29403484 TI - Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation. AB - Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation (n = 26) and to investigate whether this differs from pretransplantation (n = 9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls (p = 0.002) and pretransplantation (p < 0.0001). Moreover, the CD59 expression diminishes posttransplantation on all distinct lymphocyte subsets (p < 0.02). This effect appeared to be specific for CD59 since the expression of other surface markers remained stable or inclined following transplantation. The highest antigen expression posttransplantation was observed on CD4+ T cells and monocytes (p <= 0.002). These findings show that CD59 expression on leukocytes diminishes posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation. If such reduction in CD59 expression also occurs on endothelial cells from the transplanted organ, this could lead to a change into a prothrombotic and proinflammatory phenotype. PMID- 29403483 TI - Protein Palmitoylation and Its Role in Bacterial and Viral Infections. AB - S-palmitoylation is a reversible, enzymatic posttranslational modification of proteins in which palmitoyl chain is attached to a cysteine residue via a thioester linkage. S-palmitoylation determines the functioning of proteins by affecting their association with membranes, compartmentalization in membrane domains, trafficking, and stability. In this review, we focus on S-palmitoylation of proteins, which are crucial for the interactions of pathogenic bacteria and viruses with the host. We discuss the role of palmitoylated proteins in the invasion of host cells by bacteria and viruses, and those involved in the host responses to the infection. We highlight recent data on protein S-palmitoylation in pathogens and their hosts obtained owing to the development of methods based on click chemistry and acyl-biotin exchange allowing proteomic analysis of protein lipidation. The role of the palmitoyl moiety present in bacterial lipopolysaccharide and lipoproteins, contributing to infectivity and affecting recognition of bacteria by innate immune receptors, is also discussed. PMID- 29403485 TI - Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway. AB - Rabies is an ancient disease but remains endemic in most parts of the world and causes approximately 59,000 deaths annually. The mechanism through which the causative agent, rabies virus (RABV), evades the host immune response and infects the host central nervous system (CNS) has not been completely elucidated thus far. Our previous studies have shown that lab-attenuated, but not wild-type (wt), RABV activates the innate immune response in the mouse and dog models. In this present study, we demonstrate that lab-attenuated RABV causes abortive infection in astrocytes, the most abundant glial cells in the CNS. Furthermore, we found that lab-attenuated RABV produces more double-stranded RNA (dsRNA) than wt RABV, which is recognized by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5). Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Notably, lab-attenuated RABV replicates in a manner identical to that of wt RABV in MAVS-/- astrocytes. It was also found that lab-attenuated, but not wt, RABV induces the expression of inflammatory cytokines via the MAVS- p38/NF kappaB signaling pathway. These inflammatory cytokines increase the blood-brain barrier permeability and thus enable immune cells and antibodies infiltrate the CNS parenchyma, resulting in RABV control and elimination. In contrast, wt RABV restricts dsRNA production and thus evades innate recognition by RIG-I/MDA5 in astrocytes, which could be one of the mechanisms by which wt RABV evades the host immune response in resident CNS cells. Our findings suggest that astrocytes play a critical role in limiting the replication of lab-attenuated RABV in the CNS. PMID- 29403487 TI - Caprine Monocytes Release Extracellular Traps against Neospora caninum In Vitro. AB - Neospora caninum is an obligate intracellular apicomplexan parasite that causes reproductive loss and severe economic losses in dairy and goat industry. In the present study, we aim to investigate the effects of N. caninum tachyzoites on the release of extracellular traps (ETs) in caprine monocytes and furthermore elucidated parts of its molecular mechanisms. N. caninum tachyzoite-induced monocytes-derived ETs formation was detected by scanning electron microscopy. H3 and myeloperoxidase (MPO) within monocyte-ETs structures were examined using laser scanning confocal microscopy analyses. The results showed that N. caninum tachyzoites were not only able to trigger ETs formation in caprine monocytes, but also that monocyte-released ETs were capable of entrapping viable tachyzoites. Histones and MPO were found to be decorating the DNA within the monocytes derived ETs structures thus proving the classical components of ETs. Furthermore, inhibitors of NADPH oxidase-, MPO-, ERK 1/2-, or p38 MAPK-signaling pathway significantly decreased N. caninum tachyzoite-triggered caprine monocyte-derived ETosis. This is the first report of ETs release extruded from caprine monocytes after N. caninum exposure and thus showing that this early innate immune effector mechanism might be relevant during the acute phase of caprine neosporosis. PMID- 29403488 TI - Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major. AB - The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF-/-) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF-/- mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45+F4/80+CD11bhiLy6Clow) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF. PMID- 29403489 TI - Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages. AB - Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-beta (TRIF) protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-beta and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4. PMID- 29403486 TI - NLR-Dependent Regulation of Inflammation in Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) associated with inappropriate activation of lymphocytes, hyperinflammatory responses, demyelination, and neuronal damage. In the past decade, a number of biological immunomodulators have been developed that suppress the peripheral immune responses and slow down the progression of the disease. However, once the inflammation of the CNS has commenced, it can cause serious permanent neuronal damage. Therefore, there is a need for developing novel therapeutic approaches that control and regulate inflammatory responses within the CNS. Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular regulators of inflammation expressed by many cell types within the CNS. They redirect multiple signaling pathways initiated by pathogens and molecules released by injured tissues. NLR family members include positive regulators of inflammation, such as NLRP3 and NLRC4 and anti-inflammatory NLRs, such as NLRX1 and NLRP12. They exert immunomodulatory effect at the level of peripheral immune responses, including antigen recognition and lymphocyte activation and differentiation. Also, NLRs regulate tissue inflammatory responses. Understanding the molecular mechanisms that are placed at the crossroad of innate and adaptive immune responses, such as NLR-dependent pathways, could lead to the discovery of new therapeutic targets. In this review, we provide a summary of the role of NLRs in the pathogenesis of MS. We also summarize how anti-inflammatory NLRs regulate the immune response within the CNS. Finally, we speculate the therapeutic potential of targeting NLRs in MS. PMID- 29403490 TI - Corticosterone Preexposure Increases NF-kappaB Translocation and Sensitizes IL 1beta Responses in BV2 Microglia-Like Cells. AB - Corticosterone (CORT), a critical mediator of the hypothalamus pituitary adrenal axis in rodents, is a stress hormone that is classically viewed as possessing immune-suppressive properties. CORT is now appreciated to also mediate the neuroimmune-priming effect of stress to innate-immune stimulation, and hence serves as a mechanistic link to the neuroimmune involvement in stress-related disorders. However, these dichotomous actions of CORT remain poorly defined. This study investigated the conditions and concentration dependency of CORT's actions required to prime the innate-immune system. Here, we measured the effect of CORT pretreatment on the downstream pro-inflammatory responses of BV2 mouse microglia like cells stimulated by lipopolysaccharide (LPS). We quantified the concentration-dependent CORT-mediated attenuation and enhancement of LPS stimulated inflammatory response. A high physiological concentration (500 nM) of CORT attenuated LPS-induced inflammatory IL-1beta cytokine production in a glucocorticoid receptor-dependent manner. However, a low concentration (50 nM) of CORT increased expression and release of IL-1beta in a mineralocorticoid receptor dependent manner, with accompanied increases in NF-kappaB translocation and changes to related gene transcription. These results suggest that a mild elevation in CORT may cause selective adaptations in microglia-like cells to overrespond to a second immune challenge in a non-classical manner, thus partially explaining both pro- and anti-inflammatory effects of CORT reported in the literature. PMID- 29403491 TI - Epigenetic Maintenance of Acquired Gene Expression Programs during Memory CD8 T Cell Homeostasis. AB - Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens containing their cognate epitope. Because of their ability to provide lifelong protection, the generation of memory T cells is now a major focus for current vaccination or adoptive cell therapy approaches to treat chronic viral infections and cancer. It is now clear that maintenance of memory CD8 T cells occurs through a process of antigen-independent homeostatic proliferation, which is regulated in part by the gamma chain cytokines IL-7 and IL-15. Here, we will describe the role of these cytokines in the survival and self-renewal of memory CD8 T cells. Further, we will describe the role of epigenetics in the maintenance of acquired functions among memory CD8 T cells during homeostatic proliferation. PMID- 29403492 TI - Flow Cytometric Clinical Immunomonitoring Using Peptide-MHC Class II Tetramers: Optimization of Methods and Protocol Development. AB - With the advent of novel strategies to induce tolerance in autoimmune and autoimmune-like conditions, clinical trials of antigen-specific tolerizing immunotherapy have become a reality. Besides safety, it will be essential to gather mechanistic data on responding CD4+ T cells to assess the effects of various immunomodulatory approaches in early-phase trials. Peptide-MHC class II (pMHCII) multimers are an ideal tool for monitoring antigen-specific CD4+ T cell responses in unmanipulated cells directly ex vivo. Various protocols have been published but there are reagent and assay limitations across laboratories that could hinder their global application to immune monitoring. In this methodological analysis, we compare protocols and test available reagents to identify sources of variability and to determine the limitations of the tetramer binding assay. We describe a robust pMHCII flow cytometry-based assay to quantify and phenotype antigen-specific CD4+ T cells directly ex vivo from frozen peripheral blood mononuclear cell samples, which we suggest should be tested across various laboratories to standardize immune-monitoring results. PMID- 29403494 TI - Simple, Reproducible, and Efficient Clinical Grading System for Murine Models of Acute Graft-versus-Host Disease. AB - Acute graft-versus-host disease (aGVHD) represents a challenging complication after allogeneic hematopoietic stem cell transplantation. Despite the intensive preclinical research in the field of prevention and treatment of aGVHD, and the presence of a well-established clinical grading system to evaluate human aGVHD, such a valid tool is still lacking for the evaluation of murine aGVHD. Indeed, several scoring systems have been reported, but none of them has been properly evaluated and they all share some limitations: they incompletely reflect the disease, rely on severity stages that are distinguished by subjective assessment of clinical criteria and are not easy to discriminate, which could render evaluation more time consuming, and their reproducibility among different experimenters is uncertain. Consequently, clinical murine aGVHD description is often based merely on animal weight loss and mortality. Here, we propose a simple scoring system of aGVHD relying on the binary (yes or no) evaluation of five important visual parameters that reflect the complexity of the disease without the need to sacrifice the mice. We show that this scoring system is consistent with the gold standard histological staging of aGVHD across several donor/recipient mice combinations. This system is also a strong predictor of survival of recipient mice when used early after transplant and is highly reproducible between experimenters. PMID- 29403493 TI - The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy. AB - Non-coding RNAs (ncRNAs) can be divided into circular non-coding RNAs (circRNAs) and linear ncRNAs. ncRNAs exist in different cell types, including normal cells, tumor cells and immunocytes. Linear ncRNAs, such as long ncRNAs and microRNAs, have been found to play important roles in the regulation of tumor immunity and immunotherapy; however, the functions of circRNAs in tumor immunity and immunotherapy are less known. Here, we review the current status of ncRNAs in the regulation of tumor immunity and immunotherapy and emphatically discuss the potential roles of circRNAs as tumor antigens in the regulation of tumor immunity and immunotherapy. PMID- 29403495 TI - Differing House Finch Cytokine Expression Responses to Original and Evolved Isolates of Mycoplasma gallisepticum. AB - The recent emergence of the poultry bacterial pathogen Mycoplasma gallisepticum (MG) in free-living house finches (Haemorhous mexicanus), which causes mycoplasmal conjunctivitis in this passerine bird species, resulted in a rapid coevolutionary arms-race between MG and its novel avian host. Despite extensive research on the ecological and evolutionary dynamics of this host-pathogen system over the past two decades, the immunological responses of house finches to MG infection remain poorly understood. We developed seven new probe-based one-step quantitative reverse transcription polymerase chain reaction assays to investigate mRNA expression of house finch cytokine genes (IL1B, IL6, IL10, IL18, TGFB2, TNFSF15, and CXCLi2, syn. IL8L). These assays were then used to describe cytokine transcription profiles in a panel of 15 house finch tissues collected at three distinct time points during MG infection. Based on initial screening that indicated strong pro-inflammatory cytokine expression during MG infection at the periorbital sites in particular, we selected two key house finch tissues for further characterization: the nictitating membrane, i.e., the internal eyelid in direct contact with MG, and the Harderian gland, the secondary lymphoid tissue responsible for regulation of periorbital immunity. We characterized cytokine responses in these two tissues for 60 house finches experimentally inoculated either with media alone (sham) or one of two MG isolates: the earliest known pathogen isolate from house finches (VA1994) or an evolutionarily more derived isolate collected in 2006 (NC2006), which is known to be more virulent. We show that the more derived and virulent isolate NC2006, relative to VA1994, triggers stronger local inflammatory cytokine signaling, with peak cytokine expression generally occurring 3-6 days following MG inoculation. We also found that the extent of pro-inflammatory interleukin 1 beta signaling was correlated with conjunctival MG loads and the extent of clinical signs of conjunctivitis, the main pathological effect of MG in house finches. These results suggest that the pathogenicity caused by MG infection in house finches is largely mediated by host pro-inflammatory immune responses, with important implications for the dynamics of host-pathogen coevolution. PMID- 29403497 TI - TRAIL-Mediated Suppression of T Cell Receptor Signaling Inhibits T Cell Activation and Inflammation in Experimental Autoimmune Encephalomyelitis. AB - Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses. PMID- 29403498 TI - Two Distinct Pathways in Mice Generate Antinuclear Antigen-Reactive B Cell Repertoires. AB - The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline sequences and somatic mutations contribute to autospecificity of B cell clones. For this issue, we investigated the development of antinuclear autoantibodies (ANAs) and their repertoire in two different mouse models. First, in aging mice that were shown to gain several autoimmune features over time including ANAs. Second, in mice undergoing a chronic graft-versus-host disease (GVHD), thereby developing systemic lupus erythematosus-like symptoms. Detailed repertoire analysis revealed that somatic hypermutations (SHM) were present in all Vh and practically all Vl regions of ANAs generated in these two models. The ANA B cell repertoire in aging mice was restricted, dominated by clonally related Vh1-26/Vk4-74 antibodies. In the collection of GVHD-derived ANAs, the repertoire was less restricted, but the usage of the Vh1-26/Vk4-74 combination was still apparent. Germline conversion showed that the SHM in the 4-74 light chain are deterministic for autoreactivity. Detailed analysis revealed that antinuclear reactivity of these antibodies could be induced by a single amino acid substitution in the CDR1 of the Vk4-74. In both aging B6 and young GVHD mice, conversion of the somatic mutations in the Vh and Vl regions of non Vh1-26/Vk4-74 using antibodies showed that B cells with a germline-encoded V gene could also contribute to the ANA-reactive B cell repertoire. These findings indicate that two distinct pathways generate ANA-producing B cells in both model systems. In one pathway, they are generated by Vh1-26/Vk4-74 expressing B cells in the course of immune responses to an antigen that is neither a nuclear antigen nor any other self-antigen. In the other pathway, ANA-producing B cells are derived from progenitors in the bone marrow that express B cell receptors (BCRs), which bind to nuclear antigens and that escape tolerance induction, possibly as a result of crosslinking of their BCRs by multivalent determinants of nuclear antigens. PMID- 29403496 TI - Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy. AB - Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B. T-cell adhesion molecules and, in particular, lymphocyte-function-associated antigen-1 and CD103 integrins, and their cognate ligands, respectively, intercellular adhesion molecule 1 and E-cadherin, on target cells, are involved in strengthening the interaction between CTL and tumor cells. Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied cancers. TCRbeta chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate human leukocyte antigen class I-restricted cytotoxic activity toward autologous tumor cells. Several of them recognize truly tumor-specific antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward tumor neoantigens is associated with patient response to immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based vaccines. These tumor specific mutation-derived antigens open up new perspectives for development of effective second-generation therapeutic cancer vaccines. PMID- 29403499 TI - Incomplete Memories: The Natural Suppression of Tissue-Resident Memory CD8 T Cells in the Lung. AB - The yearly, cyclic impact of viruses like influenza on human health and the economy is due to the high rates of mutation of traditional antibody targets, which negate any preexisting humoral immunity. However, the seasonality of influenza infections can equally be attributed to an absent or defective memory CD8 T cell response since the epitopes recognized by these cells are derived from essential virus proteins that mutate infrequently. Experiments in mouse models show that protection from heterologous influenza infection is temporally limited and conferred by a population of tissue-resident memory (TRM) cells residing in the lung and lung airways. TRM are elicited by a diverse set of pathogens penetrating mucosal barriers and broadly identified by extravascular staining and expression of the activation and adhesion molecules CD69 and CD103. Interestingly, lung TRM fail to express these molecules, which could limit tissue retention, resulting in airway expulsion or death with concomitant loss of heterologous protection. Here, we make the case that respiratory infections uniquely evoke a form of natural immunosuppression whereby specific cytokines and cell-cell interactions negatively impact memory cell programming and differentiation. Respiratory memory is not only short-lived but most of the memory cells in the lung parenchyma may not be bona fide TRM. Given the quantity of microbes humans inhale over a lifetime, limiting cellular residence could be a mechanism employed by the respiratory tract to preserve organismal vitality. Therefore, successful efforts to improve respiratory immunity must carefully and selectively breach these inherent tissue barriers. PMID- 29403500 TI - Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells. AB - Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART treated subjects. Our findings suggest that ELCs harbor a "healthy" state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status. PMID- 29403501 TI - High-Resolution Mapping and Dynamics of the Transcriptome, Transcription Factors, and Transcription Co-Factor Networks in Classically and Alternatively Activated Macrophages. AB - Macrophages are the prime innate immune cells of the inflammatory response, and the combination of multiple signaling inputs derived from the recognition of host factors [e.g., interferon-g (IFN-gamma)] and invading pathogen products (e.g., toll-like receptors (TLRs) agonists) are required to maintain essential macrophage function. The profound effects on biological outcomes of inflammation associated with IFN-gamma pretreatment ("priming") and TLR4 ligand bacterial lipopolysaccharide (LPS)-induced macrophage activation (M1 or classical activation) have long been recognized, but the underlying mechanisms are not well defined. Therefore, we analyzed gene expression profiles of macrophages and identified genes, transcription factors (TFs), and transcription co-factors (TcoFs) that are uniquely or highly expressed in IFN-gamma-mediated TLR4 ligand LPS-inducible versus only TLR4 ligand LPS-inducible primary macrophages. This macrophage gene expression has not been observed in macrophage cell lines. We also showed that interleukin (IL)-4 and IL-13 (M2 or alternative activation) elicited the induction of a distinct subset of genes related to M2 macrophage polarization. Importantly, this macrophage gene expression was also associated with promoter conservation. In particular, our approach revealed novel roles for the TFs and TcoFs in response to inflammation. We believe that the systematic approach presented herein is an important framework to better understand the transcriptional machinery of different macrophage subtypes. PMID- 29403502 TI - Integrins Modulate T Cell Receptor Signaling by Constraining Actin Flow at the Immunological Synapse. AB - Full T cell activation requires coordination of signals from multiple receptor ligand pairs that interact in parallel at a specialized cell-cell contact site termed the immunological synapse (IS). Signaling at the IS is intimately associated with actin dynamics; T cell receptor (TCR) engagement induces centripetal flow of the T cell actin network, which in turn enhances the function of ligand-bound integrins by promoting conformational change. Here, we have investigated the effects of integrin engagement on actin flow, and on associated signaling events downstream of the TCR. We show that integrin engagement significantly decelerates centripetal flow of the actin network. In primary CD4+ T cells, engagement of either LFA-1 or VLA-4 by their respective ligands ICAM-1 and VCAM-1 slows actin flow. Slowing is greatest when T cells interact with low mobility integrin ligands, supporting a predominately drag-based mechanism. Using integrin ligands presented on patterned surfaces, we demonstrate that the effects of localized integrin engagement are distributed across the actin network, and that focal adhesion proteins, such as talin, vinculin, and paxillin, are recruited to sites of integrin engagement. Further analysis shows that talin and vinculin are interdependent upon one another for recruitment, and that ongoing actin flow is required. Suppression of vinculin or talin partially relieves integrin-dependent slowing of actin flow, indicating that these proteins serve as molecular clutches that couple engaged integrins to the dynamic actin network. Finally, we found that integrin-dependent slowing of actin flow is associated with reduction in tyrosine phosphorylation downstream of the TCR, and that this modulation of TCR signaling depends on expression of talin and vinculin. More generally, we found that integrin-dependent effects on actin retrograde flow were strongly correlated with effects on TCR signaling. Taken together, these studies support a model in which ligand-bound integrins engage the actin cytoskeletal network via talin and vinculin, and tune TCR signaling events by modulating actin dynamics at the IS. PMID- 29403503 TI - Assessing the Importance of Domestic Vaccine Manufacturing Centers: An Overview of Immunization Programs, Vaccine Manufacture, and Distribution. AB - Vaccines have significantly reduced the detrimental effects of numerous human infectious diseases worldwide, helped to reduce drastically child mortality rates and even achieved eradication of major pathogens, such as smallpox. These achievements have been possible due to a dedicated effort for vaccine research and development, as well as an effective transfer of these vaccines to public health care systems globally. Either public or private institutions have committed to developing and manufacturing vaccines for local or international population supply. However, current vaccine manufacturers worldwide might not be able to guarantee sufficient vaccine supplies for all nations when epidemics or pandemics events could take place. Currently, different countries produce their own vaccine supplies under Good Manufacturing Practices, which include the USA, Canada, China, India, some nations in Europe and South America, such as Germany, the Netherlands, Italy, France, Argentina, and Brazil, respectively. Here, we discuss some of the vaccine programs and manufacturing capacities, comparing the current models of vaccine management between industrialized and developing countries. Because local vaccine production undoubtedly provides significant benefits for the respective population, the manufacture capacity of these prophylactic products should be included in every country as a matter of national safety. PMID- 29403504 TI - Perspective on Protein Arginine Deiminase Activity-Bicarbonate Is a pH Independent Regulator of Citrullination. AB - Protein citrullination catalyzed by peptidyl arginine deiminase (PADs) is involved in autoimmune disease pathogenesis, especially in rheumatoid arthritis. Calcium is a key regulator of PAD activity, but under normal physiological conditions it remains uncertain how intracellular calcium levels can be raised to sufficiently high levels to activate these enzymes. In pursuit of trying to identify other factors that influence PAD activity, we identified bicarbonate as a potential regulator of PAD activity. We demonstrate that physiological levels of bicarbonate upregulate citrullination by recombinant PAD2/4 and endogenous PADs in neutrophils. The impact of bicarbonate is independent of calcium and pH. Adding bicarbonate to commercial PAD activity kits could increase assay performance and biological relevance. These results suggest that citrullination activity is regulated by multiple factors including calcium and bicarbonate. We also provide commentary on the current understanding of PAD regulation and future perspective of research in this area. PMID- 29403505 TI - Proteomic Analysis of Differentially Accumulated Proteins in Cucumber (Cucumis sativus) Fruit Peel in Response to Pre-storage Cold Acclimation. AB - Harvested fruits are still living organs and respond to environmental stimuli. Low temperature storage is effective in extending life of harvested fruit, but it may also cause chilling injury. Cold acclimation has been shown to induce chilling tolerance in plants, but what proteomic changes caused by cold acclimation are related to defense against chilling stress remains largely unclear. Here, 3 d of pre-storage cold acclimation (PsCA) at 10 degrees C reduced chilling injury and secondary disease severity in cucumber stored at 5 degrees C by 51 and 94%, respectively, compared with the control which was directly stored at 5 degrees C. Proteomic analysis of cucumber peel identified 21 significant differentially-accumulated proteins (SDAPs) right after PsCA treatment and 23 after the following cold storage (PsCA+CS). These proteins are mainly related to stress response and defense (SRD), energy metabolism, protein metabolism, signal transduction, primary metabolism, and transcription. The SRD proteins, which made up 37% of the 21 and 47% of the 23, respectively, represented the largest class of SDAPs, and all but one protein were up-regulated, suggesting accumulation of proteins involved in defense response is central feature of proteomic profile changes brought about by PsCA. In fruit just after PsCA treatment, the identified SDAPs are related to responses to various stresses, including chilling, salt stress, dehydration, fungi, bacteria, insects, and DNA damage. However, after prolonged cold storage, the targeted proteins in acclimated fruit were narrowed down in scope to those involved in defense against chilling and pathogens. The change patterns at the transcription level of the majority of the up-regulated differentially-accumulated proteins were highly consistent with those at protein level. Taken all, the results suggest that the short-time cold acclimation initiated comprehensive defense responses in cucumber fruit at first, while the long term storage thereafter altered the responses more specifically to chilling. These findings add to the understanding of plants' molecular responses to cold acclimation. PMID- 29403506 TI - Dissection of Insertion-Deletion Variants within Differentially Expressed Genes Involved in Wood Formation in Populus. AB - Short insertions and deletions (InDels) are one of the major genetic variants and are distributed widely across the genome; however, few investigations of InDels have been conducted in long-lived perennial plants. Here, we employed a combination of RNA-seq and population resequencing to identify InDels within differentially expressed (DE) genes underlying wood formation in a natural population of Populus tomentosa (435 individuals) and utilized InDel-based association mapping to detect the causal variants under additive, dominance, and epistasis underlying growth and wood properties. In the present paper, 5,482 InDels detected from 629 DE genes showed uneven distributions throughout all 19 chromosomes, and 95.9% of these loci were diallelic InDels. Seventy-four InDels (positive false discovery rate q <= 0.10) from 68 genes exhibited significant additive/dominant effects on 10 growth and wood-properties, with an average of 14.7% phenotypic variance explained. Potential pleiotropy was observed in one third of the InDels (representing 24 genes). Seven genes exhibited significantly differential expression among the genotypic classes of associated InDels, indicating possible important roles for these InDels. Epistasis analysis showed that overlapping interacting genes formed unique interconnected networks for each trait, supporting the putative biochemical links that control quantitative traits. Therefore, the identification and utilization of InDels in trees will be recognized as an effective marker system for molecular marker-assisted breeding applications, and further facilitate our understanding of quantitative genomics. PMID- 29403507 TI - Phosphorylation of Ribosomal Protein RPS6 Integrates Light Signals and Circadian Clock Signals. AB - The translation of mRNA into protein is tightly regulated by the light environment as well as by the circadian clock. Although changes in translational efficiency have been well documented at the level of mRNA-ribosome loading, the underlying mechanisms are unclear. The reversible phosphorylation of RIBOSOMAL PROTEIN OF THE SMALL SUBUNIT 6 (RPS6) has been known for 40 years, but the biochemical significance of this event remains unclear to this day. Here, we confirm using a clock-deficient strain of Arabidopsis thaliana that RPS6 phosphorylation (RPS6-P) is controlled by the diel light-dark cycle with a peak during the day. Strikingly, when wild-type, clock-enabled, seedlings that have been entrained to a light-dark cycle are placed under free-running conditions, the circadian clock drives a cycle of RPS6-P with an opposite phase, peaking during the subjective night. We show that in wild-type seedlings under a light dark cycle, the incoherent light and clock signals are integrated by the plant to cause an oscillation in RPS6-P with a reduced amplitude with a peak during the day. Sucrose can stimulate RPS6-P, as seen when sucrose in the medium masks the light response of etiolated seedlings. However, the diel cycles of RPS6-P are observed in the presence of 1% sucrose and in its absence. Sucrose at a high concentration of 3% appears to interfere with the robust integration of light and clock signals at the level of RPS6-P. Finally, we addressed whether RPS6-P occurs uniformly in polysomes, non-polysomal ribosomes and their subunits, and non ribosomal protein. It is the polysomal RPS6 whose phosphorylation is most highly stimulated by light and repressed by darkness. These data exemplify a striking case of contrasting biochemical regulation between clock signals and light signals. Although the physiological significance of RPS6-P remains unknown, our data provide a mechanistic basis for the future understanding of this enigmatic event. PMID- 29403509 TI - Loss of the Arabidopsis Protein Kinases ANPs Affects Root Cell Wall Composition, and Triggers the Cell Wall Damage Syndrome. AB - The Arabidopsis NPK1-related Protein kinases ANP1, ANP2 and ANP3 belong to the MAP kinase kinase kinase (MAPKKK) superfamily and were previously described to be crucial for cytokinesis, elicitor-induced immunity and development. Here we investigate the basis of their role in development by using conditional beta estradiol-inducible triple mutants to overcome lethality. In seedlings, lack of ANPs causes root cell bulging, with the transition zone being the most sensitive region. We uncover a role of ANPs in the regulation of cell wall composition and suggest that developmental defects of the triple mutants, observed at the cellular level, might be a consequence of the alterations of the pectic and cellulosic cell wall components. Lack of ANPs also induced a typical cell wall damage syndrome (CWDS) similar to that observed in plants treated with the cellulose biosynthesis inhibitor isoxaben (ISX). Moreover, anp double mutants and plants overexpressing single ANPs (ANP1 or ANP3) respectively showed increased and reduced accumulation of jasmonic acid and PDF1.2 transcripts upon ISX treatment, suggesting that ANPs are part of the pathway targeted by this inhibitor and play a role in cell wall integrity surveillance. Highlights: The loss of ANP function affects cell wall composition and leads to typical cell wall damage-induced phenotypes, such as ectopic lignification and jasmonic acid accumulation. PMID- 29403510 TI - Inflorescence Development and the Role of LsFT in Regulating Bolting in Lettuce (Lactuca sativa L.). AB - Lettuce (Lactuca sativa L.) is one of the most important leafy vegetable that is consumed during its vegetative growth. The transition from vegetative to reproductive growth is induced by high temperature, which has significant economic effect on lettuce production. However, the progression of floral transition and the molecular regulation of bolting are largely unknown. Here we morphologically characterized the inflorescence development and functionally analyzed the FLOWERING LOCUS T (LsFT) gene during bolting regulation in lettuce. We described the eight developmental stages during floral transition process. The expression of LsFT was negatively correlated with bolting in different lettuce varieties, and was promoted by heat treatment. Overexpression of LsFT could recover the late-flowering phenotype of ft-2 mutant. Knockdown of LsFT by RNA interference dramatically delayed bolting in lettuce, and failed to respond to high temperature. Therefore, this study dissects the process of inflorescence development and characterizes the role of LsFT in bolting regulation in lettuce. PMID- 29403508 TI - The Symbiosome: Legume and Rhizobia Co-evolution toward a Nitrogen-Fixing Organelle? AB - In legume nodules, symbiosomes containing endosymbiotic rhizobial bacteria act as temporary plant organelles that are responsible for nitrogen fixation, these bacteria develop mutual metabolic dependence with the host legume. In most legumes, the rhizobia infect post-mitotic cells that have lost their ability to divide, although in some nodules cells do maintain their mitotic capacity after infection. Here, we review what is currently known about legume symbiosomes from an evolutionary and developmental perspective, and in the context of the different interactions between diazotroph bacteria and eukaryotes. As a result, it can be concluded that the symbiosome possesses organelle-like characteristics due to its metabolic behavior, the composite origin and differentiation of its membrane, the retargeting of host cell proteins, the control of microsymbiont proliferation and differentiation by the host legume, and the cytoskeletal dynamics and symbiosome segregation during the division of rhizobia-infected cells. Different degrees of symbiosome evolution can be defined, specifically in relation to rhizobial infection and to the different types of nodule. Thus, our current understanding of the symbiosome suggests that it might be considered a nitrogen-fixing link in organelle evolution and that the distinct types of legume symbiosomes could represent different evolutionary stages toward the generation of a nitrogen-fixing organelle. PMID- 29403512 TI - Cover Crops and Fertilization Alter Nitrogen Loss in Organic and Conventional Conservation Agriculture Systems. AB - Agroecosystem nitrogen (N) loss produces greenhouse gases, induces eutrophication, and is costly for farmers; therefore, conservation agricultural management practices aimed at reducing N loss are increasingly adopted. However, the ecosystem consequences of these practices have not been well-studied. We quantified N loss via leaching, NH3 volatilization, N2O emissions, and N retention in plant and soil pools of corn conservation agroecosystems in Kentucky, USA. Three systems were evaluated: (1) an unfertilized, organic system with cover crops hairy vetch (Vicia villosa), winter wheat (Triticum aestivum), or a mix of the two (bi-culture); (2) an organic system with a hairy vetch cover crop employing three fertilization schemes (0 N, organic N, or a fertilizer N credit approach); and (3) a conventional system with a winter wheat cover crop and three fertilization schemes (0 N, urea N, or organic N). In the unfertilized organic system, cover crop species affected NO3-N leaching (vetch > bi-culture > wheat) and N2O-N emissions and yield during corn growth (vetch, bi-culture > wheat). Fertilization increased soil inorganic N, gaseous N loss, N leaching, and yield in the organic vetch and conventional wheat systems. Fertilizer scheme affected the magnitude of growing season N2O-N loss in the organic vetch system (organic N > fertilizer N-credit) and the timing of loss (organic N delayed N2O-N loss vs. urea) and NO3-N leaching (urea >> organic N) in the conventional wheat system, but had no effect on yield. Cover crop selection and N fertilization techniques can reduce N leaching and greenhouse gas emissions without sacrificing yield, thereby enhancing N conservation in both organic and conventional conservation agriculture systems. PMID- 29403511 TI - Auxin-BR Interaction Regulates Plant Growth and Development. AB - Plants develop a high flexibility to alter growth, development, and metabolism to adapt to the ever-changing environments. Multiple signaling pathways are involved in these processes and the molecular pathways to transduce various developmental signals are not linear but are interconnected by a complex network and even feedback mutually to achieve the final outcome. This review will focus on two important plant hormones, auxin and brassinosteroid (BR), based on the most recent progresses about these two hormone regulated plant growth and development in Arabidopsis, and highlight the cross-talks between these two phytohormones. PMID- 29403513 TI - Evaluation of a Biostimulant (Pepton) Based in Enzymatic Hydrolyzed Animal Protein in Comparison to Seaweed Extracts on Root Development, Vegetative Growth, Flowering, and Yield of Gold Cherry Tomatoes Grown under Low Stress Ambient Field Conditions. AB - The objectives of this experiment were to determine the effects of different application rates of an enzyme hydrolyzed animal protein biostimulant (Pepton) compared to a standard application rate of a biostimulant derived from seaweed extract (Acadian) on plant growth parameters and yield of gold cherry tomatoes (Solanum lycopersicum L.). Biostimulant treatments were applied starting at 15 days after transplant and every 2 weeks thereafter for a total of 5 applications. One treatment group received no biostimulant (Control). Three treatment groups (Pepton-2, Pepton-3, Pepton-4) received Pepton at different application rates equivalent to 2, 3, or 4 kg/ha applied by foliar (first 2 applications) and by irrigation (last 3 applications). Another treatment group (Acadian) received Acadian at 1.5 L/ha by irrigation for all five applications. All groups received the regular fertilizer application for this crop at transplantation, flowering, and fruiting periods. There were four plots per treatment group. Each plot had a surface area of 21 m2 that consisted of two rows that were 7 m long and 1.5 m wide. Plant height, stem diameter, distance from head to bouquet flowering, fruit set distance between the entire cluster and cluster flowering fruit set, leaf length, and number of leaves per plant was recorded for 20 plants (5 plants per plot) at 56 and 61 days after the first application. Root length and diameter of cherry tomatoes were determined at harvest from 20 randomly selected plants. Harvesting yield per plot was registered and production per hectare was calculated. Both biostimulants improved (P < 0.05) all vegetative parameters compared with the control group. There was a positive linear (P < 0.001) effect of Pepton application rate for all parameters. The calculated yield was 7.8 and 1 Ton/ha greater that represent 27 and 2.9% higher production for Pepton applied at 4 kg/ha compared to the control and to Acadian, respectively. In conclusion, Pepton was effective improving yield of gold cherry tomatoes under the low stress ambient growing conditions of this experiment. Probably short-chain peptides present in Pepton are involved in endogenous hormones and metabolic mediators that could explain the results obtained in this study. PMID- 29403514 TI - Host Delivered RNAi of Two Cuticle Collagen Genes, Mi-col-1 and Lemmi-5 Hampers Structure and Fecundity in Meloidogyne incognita. AB - Root-knot nematodes have emerged as devastating parasites causing substantial losses to agricultural economy worldwide. Tomato is the most favored host for major species of root-knot nematodes. Control strategies like use of nematicides have proved to be harmful to the environment. Other control methods like development of resistant cultivars and crop rotation have serious limitations. This study deals with the application of host generated RNA interference toward development of resistance against root-knot nematode Meloidogyne incognita in tomato. Two cuticle collagen genes viz. Mi-col-1 and Lemmi-5 involved in the synthesis and maintenance of the cuticle in M. incognita were targeted through host generated RNA interference. Expression of both Mi-col-1 and Lemmi-5 was found to be higher in adult females followed by egg masses and J2s. Tomato var. Pusa Ruby was transformed with the RNAi constructs of these genes to develop transgenic lines expressing the target dsRNAs. 30.80-35.00% reduction in the number of adult females, 50.06-65.73% reduction in the number of egg mass per plant and 76.47-82.59% reduction in the number of eggs per egg mass were observed for the T1 events expressing Mi-col-1 dsRNA. Similarly, 34.14-38.54% reduction in the number of adult females, 62.34-66.71% reduction in number of egg mass per plant and 67.13-79.76% reduction in the number of eggs per egg mass were observed for the T1 generation expressing Lemmi-5 dsRNA. The multiplication factor of M. incognita reduced significantly in both the cases and the structure of adult females isolated from transgenic plants were heavily distorted. This study demonstrates the role of the cuticle collagen genes Mi-col-1 and Lemmi-5 in the structure and development of M. incognita cuticle inside the host and reinforces the potential of host generated RNA interference for management of plant parasitic nematodes (PPNs). PMID- 29403515 TI - Functional Characterization of the Maize Phytochrome-Interacting Factors PIF4 and PIF5. AB - : Phytochrome-interacting factors (PIFs) play important roles in photomorphogenesis, the shade avoidance response, and other aspects of plant growth and development. PIF family proteins have been well-studied in Arabidopsis thaliana, but little is known about their physiological functions and molecular mechanisms in maize (Zea mays). In this study, we investigated the physiological functions of ZmPIF4 and ZmPIF5, two highly conserved members of the PIF gene family. RT-qPCR and western blot analyses revealed that ZmPIF4 and ZmPIF5 expression and ZmPIF4 and ZmPIF5 levels peak at night and remain low during the day. Overexpression of ZmPIF4 and ZmPIF5 in Arabidopsis partially rescued the reduced hypocotyl elongation and defective response to gravity in pif1 pif3 pif4 pif5 quadruple mutants (pifq). In addition, under high red: far-red light conditions, Arabidopsis lines overexpressing ZmPIF4 exhibited a constitutive shade avoidance response, including early flowering, slender leaves and inflorescences, plant lodging and precocious leaf senescence. Furthermore, ZmPIF4 physically interacted with the Arabidopsis DELLA protein REPRESSOR OF GA1-3 (RGA), indicating a potential interaction between ZmPIF4 and gibberellin signaling pathway on plant growth. Taken together, our results revealed that ZmPIF4 and ZmPIF5 are functionally conserved proteins that may play conserved roles in the response to phytochrome signaling in plants. HIGHLIGHTS: In this study, the functions of ZmPIF4 and ZmPIF5 were characterized by expression in Arabidopsis, revealing conserved roles of PIF family proteins in photomorphogenesis and the shade avoidance response in land plants. PMID- 29403516 TI - Metagenomic and Metatranscriptomic Analyses of Diverse Watermelon Cultivars Reveal the Role of Fruit Associated Microbiome in Carbohydrate Metabolism and Ripening of Mature Fruits. AB - The plant microbiome is a key determinant of plant health and productivity, and changes in the plant microbiome can alter the tolerance to biotic and abiotic stresses and the quality of end produce. Little is known about the microbial diversity and its effect on carbohydrate metabolism in ripe fruits. In this study, we aimed to understand the diversity and function of microorganisms in relation to carbohydrate metabolism of ripe watermelon fruits. We used 16S metagenomics and RNAseq metatranscriptomics for analysis of red (PI459074, Congo, and SDRose) and yellow fruit-flesh cultivars (PI227202, PI435990, and JBush) of geographically and metabolically diverse watermelon cultivars. Metagenomics data showed that Proteobacteria were abundant in SDRose and PI227202, whereas Cyanobacteria were most abundant in Congo and PI4559074. In the case of metatranscriptome data, Proteobacteria was the most abundant in all cultivars. High expression of genes linked to infectious diseases and the expression of peptidoglycan hydrolases associated to pathogenicity of eukaryotic hosts was observed in SDRose, which could have resulted in low microbial diversity in this cultivar. The presence of GH28, associated with polygalacturonase activity in JBush and SDRose could be related to cell wall modifications including de esterification and depolymerization, and consequent loss of galacturonic acid and neutral sugars. Moreover, based on the KEGG annotation of the expressed genes, nine alpha-galactosidase genes involved in key processes of galactosyl oligosaccharide metabolism, such as raffinose family were identified and galactose metabolism pathway was reconstructed. Results of this study underline the links between the host and fruit-associated microbiome in carbohydrate metabolism of the ripe fruits. The cultivar difference in watermelon reflects the quantum and diversity of the microbiome, which would benefit watermelon and other plant breeders aiming at the holobiont concept to incorporate associated microbiomes in breeding programs. PMID- 29403517 TI - Transcriptomic and Physiological Evidence for the Relationship between Unsaturated Fatty Acid and Salt Stress in Peanut. AB - Peanut (Arachis hypogaea L.) is one of the five major oilseed crops cultivated worldwide. Salt stress is a common adverse condition for the growth of this crop in many countries and regions. In this study, physiological parameters and transcriptome profiles of peanut seedlings exposed to salt stress (250 mM NaCl for 4 days, S4) and recovery for 3 days (when transferred to standard conditions for 3 days, R3) were analyzed to detect genes associated with salt stress and recovery in peanut. We observed that the quantum yield of PSII electron transport (PhiPSII) and the maximal photochemical efficiency of PSII (Fv/Fm) decreased in S4 compared with the control, and increased in R3 compared with those in S4. Seedling fresh weight, dry weight and PSI oxidoreductive activity (DeltaI/Io) were inhibited in S4 and did not recover in R3. Superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities decreased in S4 and increased in R3, whereas superoxide anion ([Formula: see text]) and hydrogen peroxide (H2O2) contents increased in S4 and decreased in R3. Transcriptome analysis revealed 1,742 differentially expressed genes (DEGs) under salt stress and 390 DEGs under recovery. Among these DEGs, two DEGs encoding omega-3 fatty acid desaturase that synthesized linolenic acid (18:3) from linoleic acid (18:2) were down-regulated in S4 and up-regulated in R3. Furthermore, omega-3 fatty acid desaturase activity decreased under salt stress and increased under recovery. Consistent with this result, 18:3 content decreased under salt stress and increased under recovery compared with that under salt treatment. In conclusion, salt stress markedly changed the activity of omega-3 fatty acid desaturase and fatty acid composition. The findings provide novel insights for the improvement of salt tolerance in peanut. PMID- 29403518 TI - Environmental and Genetic Variation for Yield-Related Traits of Durum Wheat as Affected by Development. AB - Phenology has a profound effect on adaptation and productivity of crops. The impact of phenology on tillering and fertility traits of durum wheat (Triticum turgidum L. subsp. durum Desf.) was evaluated with the aim of specifying which group of flowering genes (Vrn, Ppd, or eps) was involved in their control. A recombinant inbred line population was grown under four contrasting conditions of vernalization and daylength. Phenotyping was carried out according to robust phenological models dissecting both phenological and yield related traits. Whole genome profiling was performed using the DArT-Seq technology. The genetic variability for tillering was mainly related to the genetic variability for vernalization sensitivity, as shown by the many quantitative trait loci (QTLs) identified in non-vernalized plants associated to both tillering and phenological traits. No effects of photoperiod sensitivity on spikelet number were detected in short-day-grown plants, apparently because of limited genetic variability in photoperiod sensitivity of the population. Earliness per se was involved in control of spikelet number via final leaf number, with these traits genetically correlated and sharing some QTLs. Chaff weight and number of kernels per g chaff were negatively associated and related to anthesis date under most conditions. QTL mapping uncovered novel loci involved in phenological control of tillering and fertility traits, and confirmed the presence of several well-established loci. Phenotyping of both phenology and kernel number according to a robust physiological model amplified the possibility of identifying genetic factors underlying their variations. Also, isolating known flowering gene cues by manipulation of environmental conditions provided the opportunity for each group of genes to be expressed without confounding effects of the others. This information helps to predict the consequences of either genetic manipulation of flowering genes and changes in environmental conditions on the potential yield of durum wheat. PMID- 29403519 TI - The Effect of Poplar PsnGS1.2 Overexpression on Growth, Secondary Cell Wall, and Fiber Characteristics in Tobacco. AB - The glutamine synthetase (GS1) is a key enzyme that catalyzes the reaction of glutamate and ammonia to produce glutamine in the nitrogen (N) metabolism. Previous studies on GS1s in several plant species suggest that overexpression of GS1s can enhance N utilization, accelerate plant vegetative growth, and change wood formation. In this study, we isolated a GS1 gene, termed PsnGS1.2, from Populus simonii * Populus nigra. This gene was expressed at a higher level in roots, and relatively lower but detectable levels in xylem, leaves and phloem of P. simonii * P. nigra. The protein encoded by PsnGS1.2 is primarily located in the cytoplasm. Overexpression of PsnGS1.2 in tobacco led to the increased GS1 activity and IAA content, the augmented N assimilation, and the enlarged leaves with altered anatomical structures. These changes presumably promoted photosynthetic, growth, and biomass productivity. It was noteworthy that the secondary cell walls and fiber characteristics changed remarkably in PsnGS1.2 transgenic tobacco. These changes aligned well with the altered expression levels of the genes involved in fiber development, secondary cell wall component biosynthesis, IAA biosynthesis, amino acid transport, and starch breakdown. Taken together, the results from our study suggest that catalytic functions of PsnGS1.2 on N assimilation and metabolism in transgenic tobacco had significant effects on vegetative growth, leaf development, and secondary cell wall formation and properties through acceleration of photosynthesis and IAA biosynthesis, and redirection of carbon flux to synthesis of more cellulose and hemicellulose. PMID- 29403520 TI - Gene Expression Profiling of Iron Deficiency Chlorosis Sensitive and Tolerant Soybean Indicates Key Roles for Phenylpropanoids under Alkalinity Stress. AB - Alkaline soils comprise 30% of the earth and have low plant-available iron (Fe) concentration, and can cause iron deficiency chlorosis (IDC). IDC causes soybean yield losses of $260 million annually. However, it is not known whether molecular responses to IDC are equivalent to responses to low iron supply. IDC tolerant and sensitive soybean lines provide a contrast to identify specific factors associated with IDC. We used RNA-seq to compare gene expression under combinations of normal pH (5.7) or alkaline pH (7.7, imposed by 2.5 mM bicarbonate, or pH 8.2 imposed by 5 mM bicarbonate) and normal (25 MUM) or low (1 MUM) iron conditions from roots of these lines. Thus, we were able to treat pH and Fe supply as separate variables. We also noted differential gene expression between IDC sensitive and tolerant genotypes in each condition. Classical iron uptake genes, including ferric-chelate reductase (FCR) and ferrous transporters, were upregulated by both Fe deficiency and alkaline stress, however, their gene products did not function well at alkaline pH. In addition, genes in the phenylpropanoid synthesis pathway were upregulated in both alkaline and low Fe conditions. These genes lead to the production of fluorescent root exudate (FluRE) compounds, such as coumarins. Fluorescence of nutrient solution increased with alkaline treatment, and was higher in the IDC tolerant line. Some of these genes also localized to previously identified QTL regions associated with IDC. We hypothesize that FluRE become essential at alkaline pH where the classical iron uptake system does not function well. This work could result in new strategies to screen for IDC tolerance, and provide breeding targets to improve crop alkaline stress tolerance. PMID- 29403521 TI - Simple Assessment of Nitrogen Nutrition Index in Summer Maize by Using Chlorophyll Meter Readings. AB - Rapid and non-destructive diagnostic tools to accurately assess crop nitrogen nutrition index (NNI) are imperative for improving crop nitrogen (N) diagnosis and sustaining crop production. This study was aimed to develop the relationships among NNI, leaf N gradient, chlorophyll meter (CM) readings gradient, and positional differences chlorophyll meter index [PDCMI, the ratio of CM readings between different leaf layers (LLs) of crop canopy] and to validate the accuracy and stability of these relationships across the different LLs, years, sites, and cultivars. Six multi-N rates (0-320 kg ha-1) field experiments were conducted with four summer maize cultivars (Zhengdan958, Denghai605, Xundan20, and Denghai661) at two different sites located in China. Six summer maize plants per plot were harvested at each sampling stage to assess NNI, leaf N concentration and CM readings of different LLs during the vegetative growth period. The results showed that the leaf N gradient, CM readings gradient and PDCMI of different LLs decreased, while the NNI values increased with increasing N supply. The leaf N gradient and CM readings gradient increased gradually from top to bottom of the canopy and CM readings of the bottom LL were more sensitive to changes in plant N concentration. The significantly positive relationship between NNI and CM readings of different LLs (LL1 to LL3) was observed, yet these relationships varied across the years. In contrast, the relationships between NNI and PDCMI of different LLs (LL1 to LL3) were significantly negative. The strongest relationship between PDCMI and NNI which was stable across the cultivars and years was observed for PDCMI1-3 (NNI = -5.74 * PDCMI1-3+1.5, R2 = 0.76**). Additionally, the models developed in this study were validated with the data acquired from two independent experiments to assess their accuracy of prediction. The root mean square error value of 0.1 indicated that the most accurate and robust relationship was observed between PDCMI1-3 and NNI. The projected results would help to develop a simple, non-destructive and reliable approach to accurately assess the crop N status for precisely managing N application during the growth period of summer maize crop. PMID- 29403522 TI - In-field High Throughput Phenotyping and Cotton Plant Growth Analysis Using LiDAR. AB - Plant breeding programs and a wide range of plant science applications would greatly benefit from the development of in-field high throughput phenotyping technologies. In this study, a terrestrial LiDAR-based high throughput phenotyping system was developed. A 2D LiDAR was applied to scan plants from overhead in the field, and an RTK-GPS was used to provide spatial coordinates. Precise 3D models of scanned plants were reconstructed based on the LiDAR and RTK GPS data. The ground plane of the 3D model was separated by RANSAC algorithm and a Euclidean clustering algorithm was applied to remove noise generated by weeds. After that, clean 3D surface models of cotton plants were obtained, from which three plot-level morphologic traits including canopy height, projected canopy area, and plant volume were derived. Canopy height ranging from 85th percentile to the maximum height were computed based on the histogram of the z coordinate for all measured points; projected canopy area was derived by projecting all points on a ground plane; and a Trapezoidal rule based algorithm was proposed to estimate plant volume. Results of validation experiments showed good agreement between LiDAR measurements and manual measurements for maximum canopy height, projected canopy area, and plant volume, with R2-values of 0.97, 0.97, and 0.98, respectively. The developed system was used to scan the whole field repeatedly over the period from 43 to 109 days after planting. Growth trends and growth rate curves for all three derived morphologic traits were established over the monitoring period for each cultivar. Overall, four different cultivars showed similar growth trends and growth rate patterns. Each cultivar continued to grow until ~88 days after planting, and from then on varied little. However, the actual values were cultivar specific. Correlation analysis between morphologic traits and final yield was conducted over the monitoring period. When considering each cultivar individually, the three traits showed the best correlations with final yield during the period between around 67 and 109 days after planting, with maximum R2-values of up to 0.84, 0.88, and 0.85, respectively. The developed system demonstrated relatively high throughput data collection and analysis. PMID- 29403523 TI - Genome-Wide Identification of Cyclic Nucleotide-Gated Ion Channel Gene Family in Wheat and Functional Analyses of TaCNGC14 and TaCNGC16. AB - Cyclic nucleotide gated channels (CNGCs) play multifaceted roles in plants, particularly with respect to signaling processes associated with abiotic stress signaling and during host-pathogen interactions. Despite key roles during plant survival and response to environment, little is known about the activity and function of CNGC family in common wheat (Triticum aestivum L.), a key stable food around the globe. In this study, we performed a genome-wide identification of CNGC family in wheat and identified a total 47 TaCNGCs in wheat, classifying these genes into four major groups (I-IV) with two sub-groups (IVa and IVb). Sequence analysis revealed the presence of several conserved motifs, including a phosphate binding cassette (PBC) and a "hinge" region, both of which have been hypothesized to be critical for the function of wheat CNGCs. During wheat infection with Pst, the transcript levels of TaCNGC14 and TaCNGC16, both members of group IVb, showed significant induction during a compatible interaction, while a reduction in gene expression was observed in incompatible interactions. In addition, TaCNGC14 and TaCNGC16 mRNA accumulation was significantly influenced by exogenously applied hormones, including abscisic acid (ABA), methyl jasmonate (MeJA), and salicylic acid (SA), suggesting a role in hormone signaling and/or perception. Silencing of TaCNGC14 and TaCNGC16 limited Pst growth and increased wheat resistance against Pst. The results presented herein contribute to our understanding of the wheat CNGC gene family and the mechanism of TaCNGCs signaling during wheat-Pst interaction. PMID- 29403524 TI - The Arabidopsis thaliana Knockout Mutant for Phytochelatin Synthase1 (cad1-3) Is Defective in Callose Deposition, Bacterial Pathogen Defense and Auxin Content, But Shows an Increased Stem Lignification. AB - The enzyme phytochelatin synthase (PCS) has long been studied with regard to its role in metal(loid) detoxification in several organisms, i.e., plants, yeasts, and nematodes. It is in fact widely recognized that PCS detoxifies a number of heavy metals by catalyzing the formation of thiol-rich oligomers, namely phytochelatins, from glutathione and related peptides. However, recent investigations have highlighted other possible roles played by the PCS enzyme in the plant cell, e.g., the control of pathogen-triggered callose deposition. In order to examine novel aspects of Arabidopsis thaliana PCS1 (AtPCS1) functions and to elucidate its possible roles in the secondary metabolism, metabolomic data of A. thaliana wild-type and cad1-3 mutant were compared, the latter lacking AtPCS1. HPLC-ESI-MS analysis showed differences in the relative levels of metabolites from the glucosinolate and phenylpropanoid pathways between cad1-3 and wild-type plants. Specifically, in control (Cd-untreated) plants, higher levels of 4-methoxy-indol-3-ylmethylglucosinolate were found in cad1-3 plants vs. wild-type. Moreover, the cad1-3 mutant showed to be impaired in the deposit of callose after Cd exposure, suggesting that AtPCS1 protects the plant against the toxicity of heavy metals not only by synthesizing PCs, but also by contributing to callose deposition. In line with the contribution of callose in counteracting Cd toxicity, we found that another callose-defective mutant, pen2-1, was more sensitive to high concentrations of Cd than wild-type plants. Moreover, cad1-3 plants were more susceptible than wild-type to the hemibiotrophic bacterial pathogen Pseudomonas syringae. The metabolome also revealed differences in the relative levels of hydroxycinnamic acids and flavonols, with consequences on cell wall properties and auxin content, respectively. First, increased lignification in the cad1-3 stems was found, probably aimed at counteracting the entry of Cd into the inner tissues. Second, in cad1-3 shoots, increased relative levels of kaempferol 3,7 dirhamnoside and quercetin hexoside rhamnoside were detected. These flavonols are endogenous inhibitors of auxin transport in planta; auxin levels in both roots and shoots of the cad1-3 mutant were in fact lower than those of the wild-type. Overall, our data highlight novel aspects of AtPCS1 functions in A. thaliana. PMID- 29403525 TI - The Wheat Bax Inhibitor-1 Protein Interacts with an Aquaporin TaPIP1 and Enhances Disease Resistance in Arabidopsis. AB - Bax inhibitor-1 (BI-1) is an endoplasmic reticulum (ER)-resident cell death suppressor evolutionarily conserved in eukaryotes. The ability of BI-1 to inhibit the biotic and abiotic stresses have been well-studied in Arabidopsis, while the functions of wheat BI-1 are largely unknown. In this study, the wheat BI-1 gene TaBI-1.1 was isolated by an RNA-seq analysis of Fusarium graminearum (Fg)-treated wheat. TaBI-1.1 expression was induced by a salicylic acid (SA) treatment and down-regulated by an abscisic acid (ABA) treatment. Based on beta-glucuronidase (GUS) staining, TaBI-1.1 was expressed in mature leaves and roots but not in the hypocotyl or young leaves. Constitutive expression of TaBI-1.1 in Arabidopsis enhanced its resistance to Pseudomonas syringae pv. Tomato (Pst) DC3000 infection and induced SA-related gene expression. Additionally, TaBI-1.1 transgenic Arabidopsis exhibited an alleviation of damage caused by high concentrations of SA and decreased the sensitivity to ABA. Consistent with the phenotype, the RNA seq analysis of 35S::TaBI-1.1 and Col-0 plants showed that TaBI-1.1 was involved in biotic stresses. These results suggested that TaBI-1.1 positively regulates SA signals and plays important roles in the response to biotic stresses. In addition, TaBI-1.1 interacted with the aquaporin TaPIP1, and both them were localized to ER membrane. Furthermore, we demonstrated that TaPIP1 was up regulated by SA treatment and TaPIP1 transgenic Arabidopsis enhanced the resistance to Pst DC3000 infection. Thus, the interaction between TaBI-1.1 and TaPIP1 on the ER membrane probably occurs in response to SA signals and defense response. PMID- 29403527 TI - Microsatellites Associated with Growth Performance and Analysis of Resistance to Aeromonas hydrophila in Tambaqui Colossoma macropomum. AB - Tambaqui, Colossoma macropomum, is the main native fish species produced in Brazil, and is an important species for genetic improvement in aquaculture. In addition, breeding studies on this species can be optimized with the use of molecular markers associated with productive phenotypes. The objective of the present study was to test the performance of growth traits and resistance to the bacteria, Aeromonas hydrophila, in association with microsatellite markers in C. macropomum. In this study, three full-sib families were subjected to bacterial challenge and morphometric growth assessments. Tambaqui families subjected to the bacterial challenge differed significantly in death time and mortality rate. There was, however, no association between resistance to bacteria and microsatellite markers. In relation to growth traits, we observed a marker/phenotype association in two microsatellites. The marker in the 6b isoform x5 gene (TNCRC6b) was associated with length, whereas an anonymous marker was associated with height. The present study highlighted the evaluation of molecular markers associated with growth traits, and can serve as the basis for future marker-assisted selection (MAS) of tambaqui. PMID- 29403528 TI - Eye Tracking Based Control System for Natural Human-Computer Interaction. AB - Eye movement can be regarded as a pivotal real-time input medium for human computer communication, which is especially important for people with physical disability. In order to improve the reliability, mobility, and usability of eye tracking technique in user-computer dialogue, a novel eye control system with integrating both mouse and keyboard functions is proposed in this paper. The proposed system focuses on providing a simple and convenient interactive mode by only using user's eye. The usage flow of the proposed system is designed to perfectly follow human natural habits. Additionally, a magnifier module is proposed to allow the accurate operation. In the experiment, two interactive tasks with different difficulty (searching article and browsing multimedia web) were done to compare the proposed eye control tool with an existing system. The Technology Acceptance Model (TAM) measures are used to evaluate the perceived effectiveness of our system. It is demonstrated that the proposed system is very effective with regard to usability and interface design. PMID- 29403526 TI - Using RNA Sequence and Structure for the Prediction of Riboswitch Aptamer: A Comprehensive Review of Available Software and Tools. AB - RNA molecules are essential players in many fundamental biological processes. Prokaryotes and eukaryotes have distinct RNA classes with specific structural features and functional roles. Computational prediction of protein structures is a research field in which high confidence three-dimensional protein models can be proposed based on the sequence alignment between target and templates. However, to date, only a few approaches have been developed for the computational prediction of RNA structures. Similar to proteins, RNA structures may be altered due to the interaction with various ligands, including proteins, other RNAs, and metabolites. A riboswitch is a molecular mechanism, found in the three kingdoms of life, in which the RNA structure is modified by the binding of a metabolite. It can regulate multiple gene expression mechanisms, such as transcription, translation initiation, and mRNA splicing and processing. Due to their nature, these entities also act on the regulation of gene expression and detection of small metabolites and have the potential to helping in the discovery of new classes of antimicrobial agents. In this review, we describe software and web servers currently available for riboswitch aptamer identification and secondary and tertiary structure prediction, including applications. PMID- 29403529 TI - Image Enhancement via Subimage Histogram Equalization Based on Mean and Variance. AB - This paper puts forward a novel image enhancement method via Mean and Variance based Subimage Histogram Equalization (MVSIHE), which effectively increases the contrast of the input image with brightness and details well preserved compared with some other methods based on histogram equalization (HE). Firstly, the histogram of input image is divided into four segments based on the mean and variance of luminance component, and the histogram bins of each segment are modified and equalized, respectively. Secondly, the result is obtained via the concatenation of the processed subhistograms. Lastly, the normalization method is deployed on intensity levels, and the integration of the processed image with the input image is performed. 100 benchmark images from a public image database named CVG-UGR-Database are used for comparison with other state-of-the-art methods. The experiment results show that the algorithm can not only enhance image information effectively but also well preserve brightness and details of the original image. PMID- 29403530 TI - Proximal Sessile Serrated Adenomas Are More Prevalent in Caucasians, and Gastroenterologists Are Better Than Nongastroenterologists at Their Detection. AB - Background and Aim: Proximal sessile serrated adenomas (PSSA) leading to colorectal cancer (CRC) represent an alternate pathway for CRC development. In this study, we aim to determine the prevalence of PSSAs and the impact of patient, colonoscopy, and endoscopist-related factors on PSSA detection. Methods: Patients >= 50 years of age undergoing a screening colonoscopy between 2012 and 2014 were included. Detection rates based on patient gender, race, colonoscopy timing, fellow participation, bowel preparation quality, and specialty of the endoscopist were calculated. t-tests were used to compare detection rates and a multivariate-adjusted analysis was performed. Results: 140 PSSAs were detected from 4151 colonoscopies, with a prevalence of 3.4%. Detection rate was higher in Caucasians compared to African-Americans (AA) (3.7 +/- 4.1 versus 0.96 +/- 3.5; p < 0.001). Gastroenterologists detected more PSSAs compared to nongastroenterologists (3.9 +/- 3.5 versus 2.2 +/- 3.0; p = 0.028). These findings were still significant after adjusted multivariate analysis. The rest of the factors did not make significant difference in PSSA detection rate. Conclusions: PSSAs are more prevalent in Caucasians compared to AAs. Racial difference in prevalence of PSSAs is intriguing and warrants further investigation. Gastroenterologists have a significantly higher PSSADR compared to nongastroenterologists. Educational measures should be implemented in nongastroenterologists to improve their PSSA detection rates. PMID- 29403531 TI - Granulocyte-Monocyte Apheresis in Steroid-Dependent, Azathioprine Intolerant/Resistant Moderate Ulcerative Colitis: A Prospective Multicenter Study. AB - Background: Granulocyte-monocyte apheresis has been proposed for the treatment of ulcerative colitis, although it is limited by costs and variability of results. Aim: To assess effectiveness of granulocyte-monocyte apheresis in patients with steroid-dependent, azathioprine-intolerant/resistant moderate ulcerative colitis. Methods: Consecutive patients fulfilling inclusion criteria were prospectively enrolled, treated by apheresis, and followed up for 12 months. The primary end point of the study was steroid-free clinical remission at 12 months, with no need for biologic therapy or surgery. Results: From January to December 2013, 33 patients were enrolled. After one year of follow-up, 12 (36%) patients had clinical remission, were steroid-free, and had no need for biological therapy or surgery; 3 (9%) cases showed a clinical response (but not clinical remission). Moreover, 12 (36%) patients required biologic therapy, 4 (12%) underwent colectomy, and in the other 2 (6%) a reduction, but not withdrawal, of steroid dose was achieved. Conclusions: Our study shows that a standard course of granulocyte-monocyte apheresis is associated with a 36% steroid-free clinical remission in patients with steroid-dependent, azathioprine-intolerant or resistant moderate ulcerative colitis. Apheresis might represent an alternative to biologic therapy or surgery in this specific subgroup of patients. This trial is registered with Clinicaltrial.gov NCT03189888. PMID- 29403532 TI - Efficacy of Once Daily versus Divided Daily Administration of Low Daily Dosage (15 mg/Day) of Methimazole in the Induction of Euthyroidism in Graves' Hyperthyroidism: A Randomized Controlled Study. AB - Background: Previous studies used unequal or high daily dosages of methimazole (MMI) to compare the efficacy of once daily dose regimen (OD-MMI) with that of divided daily doses regimen (DD-MMI) in inducing euthyroidism. Objectives: To compare the efficacy of OD-MMI to that of DD-MMI using low daily dosage of MMI in inducing euthyroidism. Methods: Fifty patients with clinically nonsevere Graves' hyperthyroidism were randomized to be treated with 15 mg/day OD-MMI or 15 mg/day DD-MMI. Results: 21 cases (84%) in OD-MMI and 23 cases (92%) in DD-MMI were eligible for analyses. During the treatment, there was no difference in baseline characteristics, serum FT3 and FT4 reductions, and cumulative rate of achieving euthyroidism (4.8% versus 4.3%, 28.6% versus 34.8%, 71.4% versus 82.6%, and 85.7% versus 87.0% at 2, 4, 8, and 12 weeks, resp.) between both regimens. Hypothyroidism developed in DD-MMI significantly more than in OD-MMI (17.4% versus 0%, p < 0.05). Conclusions: Treatment with MMI at a low daily dosage of 15 mg/day OD-MMI is as effective as DD-MMI in the reduction of serum thyroid hormone levels and induction of euthyroidism. The OD-MMI regimen is preferable to the DD MMI regimen in the treatment of clinically nonsevere Graves' hyperthyroidism. This trial is registered with Thai Clinical Trials Registry: TCTR20170529001. PMID- 29403533 TI - Associated Factors and Outcome of Uterine Rupture at Suhul General Hospital, Shire Town, North West Tigray, Ethiopia 2016: A Case-Control Study. AB - Background: Uterine rupture is tearing of the uterine wall during pregnancy or delivery. It may extend to partial or whole thickness of the uterine wall. It is usually a case where obstetric care is poor. In extensive damage, death of the baby and sometimes even maternal death are evident. Objective: This study assesses associated factors and outcome of uterine rupture at Suhul General Hospital, Tigray Region, Ethiopia, 2016. Methodology: A case-control study was conducted by review of data from September 2012 to August 2016. A total of 336 samples were studied after calculating by EPI-INFO using proportion of multiparity (53%) and ratio of 1 : 2 for cases and controls, respectively. Analysis was done using SPSS version 20. Bivariate and multivariate logistic regression was applied with p < 0.05. Result: ANC, grand multiparity, malpresentation, and obstructed labor had association, but previous cesarean delivery was not significant. Perinatal mortality was 105 (93%) versus 13 (5.8%) in cases and controls, respectively. Anemia was highest for both groups (53.7% versus 32.1%). Conclusion: Majority of uterine rupture is attributed to prolonged or obstructed labor. Cases of uterine rupture had prompt management preventing maternal mortality, but burden of perinatal death is still high. PMID- 29403534 TI - Soft Tissue Repair with Easy-Accessible Autologous Newborn Placenta or Umbilical Cord Blood in Severe Malformations: A Primary Evaluation. AB - Disrupted organogenesis leads to permanent malformations that may require surgical correction. Autologous tissue grafts may be needed in severe lack of orthotopic tissue but include donor site morbidity. The placenta is commonly discarded after birth and has a therapeutic potential. The aim of this study was to determine if the amnion from placenta or plasma rich of growth factors (PRGF) with mononuclear cells (MNC) from umbilical cord blood (UCB), collected noninvasively, could be used as bio-constructs for autologous transplantation as an easy-accessible no cell culture-required method. Human amnion and PRGF gel were isolated and kept in culture for up to 21 days with or without small intestine submucosa (SIS). The cells in the constructs showed a robust phenotype without induced increased proliferation (Ki67) or apoptosis (caspase 3), but the constructs showed decreased integrity of the amnion-epithelial layer at the end of culture. Amnion-residing cells in the SIS constructs expressed CD73 or pan cytokeratin, and cells in the PRGF-SIS constructs expressed CD45 and CD34. This study shows that amnion and UCB are potential sources for production of autologous grafts in the correction of congenital soft tissue defects. The constructs can be made promptly after birth with minimal handling or cell expansion needed. PMID- 29403535 TI - Surface Electromyography Analysis of the Lower Extremities of Subjects Participating in Baduanjin Exercises. AB - Purpose: The purpose of this study was to assess the effects of practicing Baduanjin exercises on the lower extremities of subjects using electromyography analysis. Subjects: 110 healthy adults were randomly assigned as subjects to two groups: SG group who received sixteen weeks of Baduanjin training and CG group who received no training. Methods: The methods used in this study included the use of a sixteen-channel sEMG system to record and measure activity changes in vastus medialis and vastus lateralis. Results: After 16 weeks of Baduanjin training, the results of this study showed that the SG group had significant increases in RMS (root mean square) (in vastus lateralis, p > 0.05; in vastus medialis, p < 0.05), in AEMG (average electromyographic activity) (in vastus lateralis, p > 0.05; in vastus medialis, p < 0.05), and in IEMG (integrated electromyogram) (in vastus lateralis, p > 0.05; in vastus medialis, p < 0.05). No adverse events from treatment were reported during the whole period of this study. Conclusion: This study concludes that performing 16 weeks of Baduanjin training can significantly improve strength and the physical function of the lower extremities among healthy adults. PMID- 29403536 TI - Yangyin Runchang Decoction Improves Intestinal Motility in Mice with Atropine/Diphenoxylate-Induced Slow-Transit Constipation. AB - This study assessed the efficacy and mechanism of action of Yangyin Runchang decoction (YRD) in the treatment of slow-transit constipation (STC). ICR mice were randomly divided into four groups (n = 10/group) and treated with saline (normal control; NC), atropine/diphenoxylate (model control; MC; 20 mg/kg), or atropine/diphenoxylate plus low-dose YRD (L-YRD; 29.6 g/kg) or high-dose YRD (H YRD; 59.2 g/kg). Intestinal motility was assessed by evaluating feces and the intestinal transit rate (ITR). The serum level of stem cell factor (SCF) and changes in interstitial cells of Cajal (ICCs) were also evaluated. Additionally, the expression of SCF and c-kit and the intracellular Ca2+ concentration [Ca2+] I were investigated. Fecal volume and ITR were greater in the L-YRD and H-YRD groups than in the MC group. The serum SCF level was lower in the MC group than in the NC group; this effect was ameliorated in the YRD-treated mice. Additionally, YRD-treated mice had more ICCs and elevated expression of c-kit and membrane-bound SCF, and YRD also increased [Ca2+] Iin vitro in isolated ICCs. YRD treatment in this STC mouse model was effective, possibly via the restoration of the SCF/c-kit pathway, increase in the ICC count, and enhancement of ICC function by increasing [Ca2+] i . PMID- 29403537 TI - Dai-Huang-Fu-Zi-Tang Alleviates Intestinal Injury Associated with Severe Acute Pancreatitis by Regulating Mitochondrial Permeability Transition Pore of Intestinal Mucosa Epithelial Cells. AB - Objective: The aim of the present study was to examine whether Dai-Huang-Fu-Zi Tang (DHFZT) could regulate mitochondrial permeability transition pore (MPTP) of intestinal mucosa epithelial cells for alleviating intestinal injury associated with severe acute pancreatitis (SAP). Methods: A total of 72 Sprague-Dawley rats were randomly divided into 3 groups (sham group, SAP group, and DHFZT group, n = 24 per group). The rats in each group were divided into 4 subgroups (n = 6 per subgroup) accordingly at 1, 3, 6, and 12 h after the operation. The contents of serum amylase, D-lactic acid, diamine oxidase activity, and degree of MPTP were measured by dry chemical method and enzyme-linked immunosorbent assay. The change of mitochondria of intestinal epithelial cells was observed by transmission electron microscopy. Results: The present study showed that DHFZT inhibited the openness of MPTP at 3, 6, and 12 h after the operation. Meanwhile, it reduced the contents of serum D-lactic acid and activity of diamine oxidase activity and also drastically relieved histopathological manifestations and epithelial cells injury of intestine. Conclusion: DHFZT alleviates intestinal injury associated SAP via reducing the openness of MPTP. In addition, DHFZT could also decrease the content of serum diamine oxidase activity and D-lactic acid after SAP. PMID- 29403538 TI - Tripterygium wilfordii Glycosides Upregulate the New Anti-Inflammatory Cytokine IL-37 through ERK1/2 and p38 MAPK Signal Pathways. AB - As a Chinese traditional patent medicine, Tripterygium wilfordii glycosides (TWG) have been approved by the China State Food and Drug Administration (Z32021007) for autoimmune and inflammatory diseases. Application of TWG leads to significant decrease of the inflammatory cytokines, such as IL-6, IL-1beta, and TNF-alpha. However, little is known whether TWG could regulate the anti-inflammatory cytokines and what the mechanism is. Here, we found that TWG could induce the upregulation of IL-37 which is a new anti-inflammatory cytokine. Furthermore, the inhibitors of ERK1/2 and/or p38 MAPK pathways suppressed IL-37 expression induced by TWG, indicating that the two pathways took part in this process. In conclusion, TWG could upregulate the anti-inflammatory cytokine IL-37 and ERK1/2 and p38 MAPK signal pathways were involved in the upregulation of IL-37 induced by TWG. The results showed that TWG had a potent activity on promoting the expression of IL-37, a new anti-inflammatory cytokine, which help further understanding the anti-inflammatory mechanism for the clinical application of TWG in therapy of diseases. PMID- 29403539 TI - Defining the Optimal Time of Adaptive Replanning in Prostate Cancer Patients with Weight Change during Volumetric Arc Radiotherapy: A Dosimetric and Mathematical Analysis Using the Gamma Index. AB - We evaluated the changes in the dose distribution of radiation during volumetric arc radiotherapy (VMAT), to determine the right time for adaptive replanning in prostate cancer patients with progressive weight (WT) changes. Five prostate cancer patients treated with VMAT were selected for dosimetric analysis. On the original computed tomography images, nine artificial body contours were created to reflect progressive WT changes. Combined with three different photon energies (6, 10, and 15-MV), 27 comparable virtual VMAT plans were created per patient. The dosimetric analysis included evaluation of target coverage (D95%, Dmax), conformity index, homogeneity index, and organs at risk doses. The dose differences among the plans were determined using the gamma index analysis and were compared with the dosimetric analysis. Mean D95% became lower than 98% when body contour expanded by 2.0 cm or more and Dmax became higher than 107% when body contour contracted by 1.5 cm or more in 10-MV plans. This cut-off values correlated well with gamma index analysis results. Adaptive replanning should, therefore, be considered if the depth of body contour becomes 1.5 cm smaller (WT loss) or 2.0 cm larger (WT gain) in patients treated by VMAT with 10-MV photons. PMID- 29403540 TI - Intent to sustain use of a mental health innovation by school providers: What matters most? AB - Despite innovations being routinely introduced in schools to support the mental health of students, few are successfully maintained over time. This study explores the role of innovation characteristics, individual attitudes and skills, and organizational factors in school providers' decisions to continue use of Centervention, a technology-based tool that supports implementation of evidence based mental health interventions (EBIs). Data were collected from 44 providers through online surveys following use of Centervention over a one-year period. When considered with individual and organizational factors, experience with Centervention (usability, usefulness, and satisfaction) was found to be the most influential predictor of intent to sustain use. Results reinforce the importance of (1) differentiating between factors that predict initial adoption vs. those that enable sustainability and (2) tailoring sustainability decision models to the nature of the innovation. They also support the need to incorporate strategies to enhance provider experience during implementation of an innovation. PMID- 29403541 TI - IVIg for apparently autoimmune small-fiber polyneuropathy: first analysis of efficacy and safety. AB - Objectives: Small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. We have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barre and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this 'apparently autoimmune SFPN' (aaSFPN), but intravenous immunoglobulin (IVIg), first-line for Guillain-Barre and CIDP, is prescribed off label for aaSFPN despite very high cost. This project aimed to conduct the first systematic evaluation of IVIg's effectiveness for aaSFPN. Methods: With IRB approval, we extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution and other potential causes excluded. IVIg needed to have been dosed at ?1 g/kg/4 weeks for ?3 months. We chose two primary outcomes - changes in composite autonomic function testing (AFT) reports of SFPN and in ratings of pain severity - to capture objective as well as patient-prioritized outcomes. Results: Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62% of skin biopsies, and 89% of composite AFT. Evidence of autoimmunity included 27% of patients having systemic autoimmune disorders, 20% having prior organ-specific autoimmune illnesses and 80% having ?1/5 abnormal blood-test markers associated with autoimmunity. A total of 73% had apparent small-fiber-restricted autoimmunity. IVIg treatment duration averaged 28 +/- 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89% at baseline to 55% (p ? 0.001). Sweat production normalized (p = 0.039) and the other four domains all trended toward improvement. Among patients with pre treatment pain ?3/10, severity averaging 6.3 +/- 1.7 dropped to 5.2 +/- 2.1 (p = 0.007). Overall, 74% of patients rated themselves 'improved' and their neurologists labeled 77% as 'IVIg responders'; 16% entered remissions that were sustained after IVIg withdrawal. All adverse events were expected; most were typical infusion reactions. The two moderate complications (3.6%) were vein thromboses not requiring discontinuation. The one severe event (1.8%), hemolytic anemia, remitted after IVIg discontinuation. Conclusion: These results provide Class IV, real-world, proof-of-concept evidence suggesting that IVIg is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provide rationale for prospective trials, inform trial design and indirectly support the discovery of small-fiber-targeting autoimmune/inflammatory illnesses. PMID- 29403542 TI - Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies. AB - Polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy is the most common paraproteinemic neuropathy, comprising a clinicopathologically and immunologically distinct entity. The clinical spectrum spans from distal paresthesias and mild gait imbalance to more severe sensory ataxia, with falls and a varying degree of distal sensorimotor deficits. In approximately 75% of patients, the monoclonal IgM immunoreacts with myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), or other peripheral nerve glycolipids that serve as antigens. These antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, splitting the myelin lamellae, while adoptive transfer of patients' IgM into susceptible host animals causes sensory ataxia and reproduces the human pathology. In spite of the apparently convincing pathogenicity of these antibodies, the response to immunotherapies remains suboptimal. Clorambuscil, cladibrine, cyclophospamide and intravenous immunoglobulin may help some patients but the benefits are minimal and transient. Open-label studies in >200 patients indicate that rituximab is helpful in 30-50% of these patients, even with long-term benefits, probably by suppressing IgM anti-MAG antibodies or inducing immunoregulatory T cells. Two controlled studies with rituximab did not however meet the primary endpoint, mostly because of the poor sensitivity of the scales used; they did however show statistical improvement in secondary endpoints and improved clinical functions in several patients. This review provides an overview of the clinical phenotypes and immunoreactivity of IgM to glycolipids or glycoproteins of peripheral nerve myelin, summarizes the progress on treatment with rituximab as a promising therapy, discusses the pitfalls of scales used, identifies possible biomarkers of response to therapy and highlights the promising new anti-B cell or target specific immunotherapies. PMID- 29403543 TI - When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. AB - The prognosis for patients with myasthenia gravis (MG) has improved significantly over the past half century, including substantial reductions in mortality and morbidity. However, approximately 10% of patients fails to respond adequately to current therapies and are considered treatment refractory, or treatment intolerant, and up to 80% have disease that fails to achieve complete stable remission. Although patients with autoantibodies to muscle-specific tyrosine kinase (anti-MuSK positive) are more likely to become treatment refractory than those with autoantibodies to the acetylcholine receptor (anti-AChR positive), each of these serotypes is substantially represented in the refractory MG population. Other risk factors for becoming treatment refractory include history of thymoma or thymectomy and female sex. A modified treatment algorithm for MG is proposed: patients who have disease that fails to respond to the stepwise approach to therapy, are treatment intolerant, or who require chronic rescue measures despite ongoing therapy, should be considered treatment refractory and emerging therapies should be considered. Three emerging monoclonal antibody-based therapies are discussed: the anti-B-cell agent rituximab; the terminal complement activation inhibitor eculizumab; and belimumab, which targets B-cell activating factor. Increased understanding of molecular pathophysiology and accurate antibody subtyping in MG should lead to the use of new therapeutic agents and successful management of treatment-refractory patients. PMID- 29403545 TI - Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature. AB - Background: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. Methods: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. Results: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. Conclusions: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV. PMID- 29403544 TI - Current therapeutic approaches to diffuse grade II and III gliomas. AB - The 2016 WHO classification of Tumors of the Central Nervous System brought major conceptual and practical changes in the classification of diffuse gliomas, by combining molecular features and histology into 'integrated' diagnoses. In diffuse gliomas, molecular profiling has thus become essential for nosological purposes, as well as to plan adequate treatment strategies and identify patients susceptible of target therapy. WHO grade II (low grade) and grade III (anaplastic) diffuse gliomas form a heterogeneous group of neoplasms, also known as 'lower-grade gliomas', characterized by a wide range of malignant potential. Molecular profile accounts for this biological diversity, and provides an accurate prognostic stratification of tumors in this group. Treatment strategies in lower-grade gliomas are ultimately based on molecular profile and WHO grade, as well as on patient characteristics such as age and Karnofsky performance status. The purpose of this review is to summarize recent advances in the classification of grade II and III gliomas, synthesize current treatment schemes according to molecular profile and describe ongoing research and future perspectives for the use of target therapies. PMID- 29403547 TI - Transfection of neurotrophin-3 into neural stem cells using ultrasound with microbubbles to treat denervated muscle atrophy. AB - Neurotrophin-3 (NT-3) has potential as a therapeutic agent for the treatment of patients with denervated muscle atrophy. However, the endogenous secretion of NT 3 is low and exogenous NT-3 lacks sufficient time to accumulate due to its short half-life. The transfection of NT-3 has been demonstrated to have a beneficial effect on denervated muscle and motor endplates. Neural stem cells (NSCs) differentiate into neurons and form motor endplate nerve-muscle connections. It has been previously demonstrated that local and noninvasive transfection can be performed using ultrasound with microbubbles (MBs). In the current study, hematoxylin and eosin, acetylcholinesterase and gold chloride staining, as well as transmission electron microscopy, were performed to verify the effects of this treatment strategy. The results demonstrated that using ultrasound with MBs for the transfection of NT-3 into NSCs, and their subsequent transplantation in vivo, attenuated the atrophy of denervated muscle and reduced motor endplate degeneration. This noninvasive, efficient and targeted treatment strategy may therefore be a potential treatment for patients with denervated muscle atrophy. PMID- 29403546 TI - Rheumatic heart disease across the Western Pacific: not just a Pacific Island problem. AB - Some of the highest recorded rheumatic heart disease (RHD) prevalence and mortality rates are from the World Health Organization's Western Pacific Region (WPR). RHD burden has been well documented in much of the WPR subregion of Oceania, but less is known about RHD outside the Pacific Islands and Australasia. We aimed to review RHD burden in WPR outside Oceania to identify countries with high RHD burden and those with contemporary data gaps. We searched the peer reviewed literature for English-language primary studies published between 1980 and April 2017 that reported RHD prevalence or mortality in the 13 WPR countries/areas outside Oceania, and Taiwan. We also searched for official government reports and health indicator documents. Results were synthesised narratively and reported stratified by 2015 Human Development Index (HDI) level. 30 peer-reviewed publications fulfilling inclusion criteria were identified, representing nine countries/areas. RHD prevalence and mortality have fallen in association with economic development, particularly in very high HDI countries. In several countries that have undergone recent economic development, RHD persists particularly among older populations. In poorer WPR countries there is a persistent RHD burden, including in young populations. Some countries had no available data. Although RHD burden has declined in many high-resource settings across the WPR, in several poorer countries, the impact of RHD appears to continue. Elsewhere, insufficient contemporary data make it difficult to gauge the current status of RHD burden and control. Concerted efforts are needed to fill information gaps and implement action to address this avoidable disease. PMID- 29403548 TI - MicroRNA-31 promotes arterial smooth muscle cell proliferation and migration by targeting mitofusin-2 in arteriosclerosis obliterans of the lower extremitie. AB - MicroRNA (miR)-31 serves a key role in various biological processes, including tumor development, angiogenesis and inflammation. Whether miR-31 is involved in the pathological processes of arteriosclerosis obliterans (ASO) remains to be elucidated, as does the mechanism of miR-31 regulation of arterial smooth muscle cells (ASMCs). In the present study, miR-31 expression was detected by reverse transcription-quantitative polymerase chain reaction and in situ hybridization, and was significantly upregulated in human ASO arterial walls compared with normal arterial walls (P<0.001). In addition, miR-31 proliferation was detected by Cell Counting Kit-8 and EdU assays; proliferation was significantly promoted in platelet-derived growth factor (PDGF)-BB-induced human ASMCs (HASMCs) (P<0.001). miR-31 migration was detected by transwell and wound closure assays, and was revealed to be promoted in PDGF-BB-induced HASMCs (P<0.001). Lastly, HASMCs were transfected with miR-31 mimics and inhibitors, and negative controls. A dual-luciferase reporter assay was performed to verify that mitofusin-2 (MFN2) was a direct target of miR-31 and that MFN2 expression was significantly downregulated by miR-31 at a post-transcriptional level in HASMCs as detected by western blotting (P<0.01). These findings suggest that miR-31 is able to promote the proliferation and migration of HASMCs, at least in part, by targeting MFN2. The results of the present study provide novel insight into the underlying mechanisms and roles of miR-31/MFN2 in the pathology of ASO, which may offer a potential therapeutic target for the treatment of ASO. PMID- 29403549 TI - Observational analysis on inflammatory reaction to talc pleurodesis: Small and large animal model series review. AB - Talc pleurodesis has been associated with pleuropulmonary damage, particularly long-term damage due to its inert nature. The present model series review aimed to assess the safety of this procedure by examining inflammatory stimulus, biocompatibility and tissue reaction following talc pleurodesis. Talc slurry was performed in rabbits: 200 mg/kg checked at postoperative day 14 (five models), 200 mg/kg checked at postoperative day 28 (five models), 40 mg/kg, checked at postoperative day 14 (five models), 40 mg/kg checked at postoperative day 28 (five models). Talc poudrage was performed in pigs: 55 mg/kg checked at postoperative day 60 (18 models). Tissue inspection and data collection followed the surgical pathology approach currently used in clinical practice. As this was an observational study, no statistical analysis was performed. Regarding the rabbit model (Oryctolagus cunicoli), the extent of adhesions ranged between 0 and 30%, and between 0 and 10% following 14 and 28 days, respectively. No intraparenchymal granuloma was observed whereas, pleural granulomas were extensively encountered following both talc dosages, with more evidence of visceral pleura granulomas following 200 mg/kg compared with 40 mg/kg. Severe florid inflammation was observed in 2/10 cases following 40 mg/kg. Parathymic, pericardium granulomas and mediastinal lymphadenopathy were evidenced at 28 days. At 60 days, from rare adhesions to extended pleurodesis were observed in the pig model (Sus Scrofa domesticus). Pleural granulomas were ubiquitous on visceral and parietal pleurae. Severe spotted inflammation among the adhesions were recorded in 15/18 pigs. Intraparenchymal granulomas were observed in 9/18 lungs. Talc produced unpredictable pleurodesis in both animal models with enduring pleural inflammation whether it was performed via slurry or poudrage. Furthermore, talc appeared to have triggered extended pleural damage, intraparenchymal nodules (porcine poudrage) and mediastinal migration (rabbit slurry). PMID- 29403550 TI - Morphological and molecular variations induce mitochondrial dysfunction as a possible underlying mechanism of athletic amenorrhea. AB - Female athletes may experience difficulties in achieving pregnancy due to athletic amenorrhea (AA); however, the underlying mechanisms of AA remain unknown. The present study focuses on the mitochondrial alteration and its function in detecting the possible mechanism of AA. An AA rat model was established by excessive swimming. Hematoxylin and eosin staining, and transmission electron microscopic methods were performed to evaluate the morphological changes of the ovary, immunohistochemical examinations and radioimmunoassays were used to detect the reproductive hormones and corresponding receptors. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to test the mtDNA copy number. PCR and western blot analysis were used to test the expression of ND2. The change of morphological features of the rat ovaries revealed evident abnormalities. Particularly, the features of the mitochondria were markedly altered. In addition, reproductive hormones in the serum and tissues of AA rats were also detected to evaluate the function of the ovaries, and the levels of these hormones were significantly decreased. Furthermore, the mitochondrial DNA copy number (mtDNA) and expression of NADH dehydrogenase subunit 2 (ND2) were quantitated by qPCR or western blot analysis. Accordingly, the mtDNA copy number and expression of ND2 expression were markedly reduced in the AA rats. In conclusion, mitochondrial dysfunction in AA may affect the cellular energy supply and, therefore, result in dysfunction of the ovary. Thus, mitochondrial dysfunction may be considered as a possible underlying mechanism for the occurrence of AA. PMID- 29403551 TI - Pterostilbene protects against acute renal ischemia reperfusion injury and inhibits oxidative stress, inducible nitric oxide synthase expression and inflammation in rats via the Toll-like receptor 4/nuclear factor-kappaB signaling pathway. AB - Previous studies have demonstrated that pterostilbene (Pter) prevents oxidative stress, suppresses cell growth and exhibits anti-fungal and anti-inflammatory effects. Pter is used to treat a number of clinical diseases, including Alzheimer's disease, various malignancies and hypercholesteremia. The aim of the present study was to investigate whether Pter protects against acute renal ischemia reperfusion injury (IRI) and inhibits oxidative stress, inducible nitric oxide synthase (iNOS) expression and inflammation in rats. A total of 40 adult male Sprague Dawley rats were divided into the following 5 groups at random: Control group, where rats were not subjected to renal IRI; IRI group, where rats were subjected to renal IRI; Pter 10 group, where rats underwent renal IRI and were treated with 10 mg/kg Pter; Pter 20 group, where rats underwent renal IRI and were treated with 20 mg/kg Pter; Pter 30 group, where rats underwent renal IRI and were treated with 30 mg/kg Pter. The results demonstrated that Pter treatment improved renal function following acute renal IRI. Compared with the untreated renal IRI group, myeloperoxidase, iNOS, interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha expression levels were significantly decreased (P<0.01), whereas IL-10 expression levels were significantly increased (P<0.01) following treatment with Pter in acute renal IRI rats. In addition, Pter significantly attenuated caspase-3 activity and the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-kappaB signaling pathway induced by acute renal IRI (P<0.01). These results provide evidence to suggest that administration of Pter may protect against acute renal IRI and inhibit oxidative stress, iNOS expression and inflammation in rats via the TLR4/NF-kappaB signaling pathway. PMID- 29403552 TI - Downregulation of YAP inhibits proliferation and induces apoptosis in Eca-109 cells. AB - A previous study reported that Yes-associated protein (YAP) gene was overexpressed in esophageal squamous cell carcinoma (ESCC); however, the exact role of YAP in ESCC remains largely unclear. The present study aimed to investigate the effects of YAP inhibition on ESCC. In order to investigate the exact role of YAP in ESCC cells, a stable YAP low-expression ESCC cell line was established using YAP-small interfering RNA. MTT assay was performed to examine the cell proliferation ability, while flow cytometry were used to detect the cell apoptosis and cell cycle distribution. In addition, reverse transcription quantitative polymerase chain reaction and western blot analysis were applied for mRNA and protein level detection, respectively. The results suggested that YAP gene inhibition significantly repressed the ECA-109 cell proliferation and induced cell apoptosis, whereas this inhibition had no significant effects on cell cycle. Furthermore, the expression levels of cell apoptosis-associated proteins were determined in the current study, and the data demonstrated that the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein ratio and phosphorylated extracellular signal-regulated kinase expression were significantly reduced, while the p53 and caspase 3 levels were notably increased in YAP gene-inhibited ECA-109 cells. In conclusion, the current study revealed that YAP gene inhibition suppresses the proliferation and induces apoptosis in ECA-109 cells, indicating that the YAP gene serves as an oncogene in ESCC. PMID- 29403553 TI - Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO-cGMP pathway. AB - Oxidative stress is closely associated with the onset of diabetes mellitus (DM). Diabetic urethropathy is one of the most common complications of DM, but few studies have been conducted to investigate the role of oxidative stress in diabetic urethropathy. Grape seed proanthocyanidin extract (GSPE) has been previously reported to reduce oxidative injury. The present study aimed to investigate the role of oxidative stress and the protective effects of GSPE on urethral dysfunction using a streptozotocin-induced DM rat model. Female Wistar rats were divided into a control group (n=36), a DM group (n=36) and a DM + GSPE group (n=36). Urodynamic testing was performed using a PowerLab data acquisition device. The expression of neuronal nitric oxide synthase (nNOS), 3-nitrotyrosine and nuclear factor erythroid 2-related factor 2 (Nrf2) was determined using western blot analysis. The expression of 3-nitrotyrosine was also determined using immunohistochemistry. Nitric oxide (NO), cyclic guanosine monophosphate (cGMP), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial ELISA kits. A significant increase was observed in the intravesical pressure thresholds for inducing urethral relaxation and the urethral perfusion pressure nadir in DM rats compared with the control group. GSPE was observed to reverse the increase of these parameters compared with the DM group. In addition, GSPE could reverse the downregulation of nNOS, NO and cGMP expression, and the decreased activities of antioxidant enzymes (SOD and GSH-Px). GSPE reversed the upregulation of 3 nitrotyrosine and MDA in DM rats. GSPE also activated Nrf2, which is a key antioxidative transcription factor. The findings of the present study demonstrated that GSPE protects urethra function in DM rats through modulating the NO-cGMP signaling pathway. The protective roles of GSPE may be associated with activation of the Nrf2 defense pathway. PMID- 29403554 TI - Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase and nuclear factor-kappaB signaling pathways. AB - Myocardial ischemia-reperfusion injury is one of the most common cardiovascular diseases, and can lead to serious damage and dysfunction of the myocardial tissue. Previous studies have demonstrated that berberine exhibits ameliorative effects on cardiovascular disease. The present study further investigated the efficacy and potential mechanism underlying the effects of berberine on ischemia reperfusion injury in a mouse model. Inflammatory markers were measured in the serum and levels of inflammatory proteins in myocardial cells were investigated after treatment with berberine. In addition, the apoptosis of myocardial cells was investigated after berberine treatment. Apoptosis-associated gene expression levels and apoptotic signaling pathways were analyzed in myocardial cells after treatment with berberine. The phosphoinositide 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) and nuclear factor (NF)-kappaB signaling pathways were also analyzed in myocardial cells after treatment with berberine. Histological analysis was used to analyze the potential benefits of berberine in ischemia-reperfusion injury. The present study identified that inflammatory responses and inflammatory factors were decreased in the myocardial cells of the mouse model of ischemia-reperfusion injury. Mechanism analysis demonstrated that berberine inhibited apoptotic protease-activating factor 1, caspase-3 and caspase 9 expression in myocardial cells. The expression of Bcl2-associated agonist of cell death, Bcl-2-like protein 1 and cellular tumor antigen p53 was upregulated. Expression of NF-kappaB p65, inhibitor of NF-kappaB kinase subunit beta (IKK beta), NF-kappaB inhibitor alpha (IkappaBalpha), and NF-kappaB activity, were inhibited in myocardial cells in the mouse model of ischemia-reperfusion injury. In conclusion, the results of the present study indicate that berberine inhibits inflammatory responses through the NF-kappaB signaling pathway and suppresses the apoptosis of myocardial cells via the PI3K/AKT signaling pathway in a mouse model of ischemia-reperfusion injury. These results suggest that berberine is a potential drug for the treatment of patients with ischemia-reperfusion injury. PMID- 29403555 TI - Effects of miR-21 on proliferation and apoptosis in human gastric adenocarcinoma cells. AB - The present study investigated the expression of miR-21 in MGC803 gastric cancer cells and its effects on Bcl-2 expression and cell proliferation, apoptosis, and invasion. In total 50 patients were recruited with gastric cancer who were admitted to the Henan Province People's Hospital. The samples of gastric cancer and the adjacent normal tissues were collected after surgery. We found that mRNA levels of miR-21 and Bcl-2 were significantly elevated in tumor tissues compared to control tissue. The expression of Bcl-2 protein was also elevated in cancerous tissue. This high expression of Bcl-2 was associated with clinical stage, lymph node metastasis, and tumor differentiation degree. Inhibition of miR-21 reduced the levels of miR-21 and Bcl-2 in MGC803 cells, and lowered cell proliferation and invasiveness. These results indicate that miR-21 and Bcl-2 may participate in the occurrence and development of gastric adenocarcinoma, suggesting their potential role as biomarkers and therapeutic targets. PMID- 29403556 TI - Pyrroline-5-carboxylate reductase 1 promotes proliferation and inhibits apoptosis in non-small cell lung cancer. AB - Disordered tumor cell metabolism is involved in the process of tumorigenesis. Proline metabolism is of critical importance for tumor cells, and pyrroline-5 carboxylate reductase 1 (PYCR1), a key proline biosynthesis enzyme, has been reported to be overexpressed in prostate cancer and to promote tumor cell growth in breast cancer. The present study investigated the relationship between PYCR1 and non-small cell lung cancer (NSCLC). The results revealed that PYCR1 was overexpressed in NSCLC tumor tissues compared with adjacent normal tissues. High PYCR1 expression was associated with poor prognosis in patients with NSCLC. Following knockdown of PYCR1 by small interfering RNA, cell proliferation was revealed to be significantly inhibited and the cell cycle was arrested, while apoptosis was increased in SPC-A1 and H1703 NSCLC cells. Furthermore, the silencing of PYCR1 resulted in the downregulation of expression of the cell cycle regulator cyclin D1, the regulator of the mitochondrial apoptotic pathway B-cell lymphoma-2, and B-cell lymphoma-extra large. The results of the present study indicated the involvement of PYCR1 in the proliferation and apoptosis of NSCLC. Therefore, PYCR1 may be a novel therapeutic target for inhibiting cell proliferation in lung cancer. PMID- 29403557 TI - High secreted protein acidic and rich in cysteine expression in peritumoral fibroblasts predicts better prognosis in patients with resectable gastric cancer. AB - Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein that may serve an important role in epithelial-mesenchymal transition. Recent studies have demonstrated that SPARC status is a prognostic indicator in various cancer types; however, its value remains unclear in gastric cancer (GC). In the present study, the localization and prognostic impact of SPARC expression were evaluated in patients with GC. Immunohistochemical analysis of SPARC expression was performed in 117 surgically resected GC specimens, and the localization of SPARC positive cells, as well as the rassociation between SPARC expression and clinicopathological characteristics were evaluated. High SPARC expression was observed in 47 cases; the glycoprotein was localized in the peritumoral fibroblasts, but was rarely observed in the cytoplasm of cancer cells. Heterogeneity of SPARC expression was observed in 52 cases. High stromal SPARC expression was identified to be an independent predictor of more favorable prognosis (overall survival and recurrence free survival) in all patients (P<0.001). On subgroup analysis, this association remained significant in patients who received adjuvant chemotherapy, but not in patients who did not (P<0.001). Stromal SPARC expression predicts better prognosis in GC patients who underwent curative resection; this appears to be associated with improved response to chemotherapy. PMID- 29403558 TI - Potential biological process of X-linked inhibitor of apoptosis protein in renal cell carcinoma based upon differential protein expression analysis. AB - The X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the IAP family and is a potent inhibitor of the caspase/apoptosis pathway. It has also been revealed that XIAP has additional biological functions that rely on its direct inhibition of apoptosis. In the present study, stably transfected Caki-1 cells with XIAP-knockdown were generated, and an isobaric tag for relative and absolute quantitation-based proteomics approach was employed to investigate the regulatory mechanism of XIAP in renal cell carcinoma (RCC). The results demonstrate that the sensitivity of the RCC cell line to apoptotic stimulation increased markedly with XIAP-knockdown. A number of differentially expressed proteins were detected between the original Caki-1 cell line and the XIAP-knockdown Caki-1 cell line; 87 at 0 h (prior to etoposide treatment), 178 at 0.5 h and 169 at 3 h, while no differentially expressed proteins were detected (ratio >1.5 or <0.5; P<0.05) at 12 h after etoposide treatment. Through analysis of the differentially expressed proteins, it was revealed that XIAP may participate in the tumor protein p53 pathway, the Wnt signaling pathway, glucose metabolism, endoplasmic reticulum stress, cytoskeletal regulation and DNA repair. These results indicate that XIAP may have a number of biological functions and may provide an insight into the biomedical significance of XIAP overexpression in RCC. PMID- 29403559 TI - Synergistic effect of targeting dishevelled-3 and the epidermal growth factor receptor-tyrosine kinase inhibitor on mesothelioma cells in vitro. AB - It was previously revealed that Wnt signaling is activated in mesothelioma cells. Although epidermal growth factor receptor (EGFR) is expressed in mesothelioma cells, EGFR-tyrosine kinase inhibitors (TKIs) are not effective for mesothelioma treatment. However, in non-small cell lung cancer, the blocking of Wnt signaling has been identified to enhance the anticancer effect of EGFR-TKIs. To confirm the anticancer effect of blocking Wnt signaling in combination with EGFR-TKI treatment in mesothelioma, the present study evaluated the effect of simultaneous suppression of human dishevelled-3 (Dvl-3) expression with Dvl-3 small interfering RNA (siRNA) and of EGFR inhibition with gefitinib on mesothelioma cell viability. Mesothelioma cell lines with and without beta-catenin gene expression were transfected with Dvl-3 siRNA and were cultured with gefitinib, and cell viability, colony formation and cell cycle analyses were performed. Dvl 3 siRNA downregulated the expression of Dvl-3 in mesothelioma cells. The combination of Dvl-3 siRNA with gefitinib acted synergistically to induce concomitant suppression of cell viability and colony formation, suggesting that inhibition of Wnt signaling by downregulating Dvl-3 with siRNA and inhibiting EGFR with gefitinib leads to significant antitumor effects. PMID- 29403560 TI - Thrombopoietin protects H9C2 cells from excessive autophagy and apoptosis in doxorubicin-induced cardiotoxicity. AB - Cardiac toxicity has been the major concern when using doxorubicin (DOX) in cancer therapy. Thrombopoietin (TPO) protects cardiac cells from DOX-induced cell damage; however, its molecular mechanism remains exclusive. The anti-autophagic and anti-apoptotic effects of TPO upon DOX treatment were studied in the cardiac H9C2 cell line, with bafilomycin A1 treatment as a positive control for autophagy inhibition. Cell viability was measured by Cell Counting Kit-8 assay in different treatment groups. The mRNA and/or protein levels of apoptotic markers and autophagy-associated factors were detected. The mean number of microtubule associated protein 1A/1B-light chain 3 (LC3) puncta per cell was quantified to indicate autophagosomes and autolysosomes, of which the ones co-stained with lysosomal-associated membrane protein 1 were considered as autolysosomes. DOX treatment (5 ug/ml, 24 h) significantly impaired H9C2 cell viability compared with the control, while TPO pretreatment (10 ng/ml, 36 h) improved cell viability upon DOX treatment. DOX exposure markedly increased LC3 puncta in H9C2 cells, and TPO pretreatment reduced the number of autophagosomes, but showed no significant inhibitory effect on autolysosome formation. The autophagy inhibition by TPO upon DOX treatment was confirmed according to protein quantification of LC3-II and nucleoporin 62. TPO also suppressed autophagy-promoting protein Beclin-1, and elevated the anti-autophagic factors GATA-binding protein-4 and B cell lymphoma 2. Furthermore, TPO reduced DOX-induced apoptosis in H9C2 cells, as reflected by the amount changes of caspase-3. Taken together, these results revealed that TPO has a protective role in H9C2 cells from DOX-induced autophagy as well as apoptosis, and indicated that TPO may act as a cardioprotective drug in DOX treated patients. PMID- 29403561 TI - Comparison of five staging systems in predicting the survival rate of patients with hepatocellular carcinoma undergoing trans-arterial chemoembolization therapy. AB - The majority of patients with unresectable hepatocellular carcinoma (HCC) undergo trans-arterial chemoembolization (TACE). However, the prognosis of HCC remains poor. In the present study, five staging systems were compared to predict the survival rate of patients with HCC undergoing TACE treatment. A total of 220 patients with HCC were examined according to the model to estimate survival for hepatocellular carcinoma (MESH), hepatoma arterial embolization prognostic score (HAP), modified HAP (mHAP), performance status combined Japan Integrated Staging system (PSJIS) and tumor-node-metastasis (TNM) staging systems. The endpoints of the study were 3-month survival, 6-month survival, 1-year survival and overall survival (OS) rates. Receiver operating characteristic curve analysis indicated that the area under the curve of MESH, HAP, mHAP, PSJIS and TNM was 0.858, 0.728, 0.690, 0.688 and 0.699, respectively, in predicting 3-month survival rates; 0.822, 0.747, 0.720, 0.722 and 0.715, respectively, in predicting 6-month survival rates and 0.725, 0.664, 0.672, 0.645 and 0.654, respectively, in predicting 1-year survival rates. Discriminatory ability, homogeneity, monotonicity and prognostic stratification ability was evaluated using a likelihood ratio test and Akaike information criterion values among the five staging systems, and revealed that the MESH system was the optimal prognostic staging system for HCC. In conclusion, the results of the present study suggest that the MESH system is the most accurate prognostic staging system of 3-month survival, 6-month survival, 1-year survival and OS rates among the five systems analyzed in patients with HCC who have received TACE treatment. PMID- 29403562 TI - PDCD5 regulates cell proliferation, cell cycle progression and apoptosis. AB - Programmed cell death (PDCD)5 is cloned from human leukemia cell line TF-1. PDCD5 is one of the members of the programmed cell death protein family that is frequently involved in tumor growth and apoptosis. To investigate the molecular and cellular functions of PDCD5, the present study established a PDCD5 stably overexpressing A431 cell line and examined the role of PDCD5 in cell proliferation, cell cycle progression and apoptosis. The data demonstrated that overexpression of PDCD5 significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and apoptosis in A431 cells. The expression profiles of certain key regulators of these cellular events were further investigated, including P53, B cell lymphoma (BCL)-2, BCL-2 associated X protein (BAX) and caspase (CASP)3. The data demonstrated that at the transcript and protein levels, P53, BAX and CASP3 were all upregulated in the PDCD5 stably overexpressing A431 cells whereas BCL-2 was downregulated, indicating that PDCD5 acts as an important upstream regulator of P53, BCL-2, BAX and CASP3. The data suggest that PDCD5 regulates cell proliferation, cell cycle progression and apoptosis in A431 cells. PDCD5 may be a novel tumor suppressor gene, and may be potentially used for cancer treatment in the future. PMID- 29403563 TI - High frequency and prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma with R-CHOP treatment. AB - The aim of this study was to analyze the prevalence and prognostic value of myeloid differentiation factor 88 (MYD88) L265P in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We assessed the MYD88 L265P mutation using an allele-specific semi-nested polymerase chain reaction method in 53 DLBCL patients treated with R-CHOP. The MYD88 L265P mutation was detected in 16 of 53 DLBCL (30.19%) samples from patients treated with R-CHOP. Age and location were statistically significantly associated with MYD88 L265P (P=0.025, 0.033, respectively), while treatment response and tumor recurrence were not. Univariate analysis showed that B symptoms (P=0.004) and Ki-67 (P=0.03) were significantly associated with progression-free survival (PFS), while MYD88 L265P showed no significant association with overall survival and PFS. Multivariate analysis showed that B symptoms were significantly associated with PFS. Our study suggests that the prognostic value of MYD88 L265P in DLBCL patients with R-CHOP requires further research. PMID- 29403564 TI - The hepatoprotective role of reduced glutathione and its underlying mechanism in oxaliplatin-induced acute liver injury. AB - Currently, the underlying mechanism of oxaliplatin (OXA) induced live injury is unclear. In addition, there is no standard clinical treatment for OXA-induced acute liver injury (ALI). In this study, we established an animal model of OXA induced ALI, and studied the role of oxidative stress in OXA-induced ALI and the impacts of reduced glutathione (GSH) treatment on OXA-induced ALI. To establish an OXA-induced ALI model, KM mice received intraperitoneal injection of OXA (8 mg/kg) for 4 days. Serum alanine aminotransferase (ALT), aspartate aminotransferase levels (AST), hepatic pathology and oxidative stress indicators in liver tissues were analyzed. To study the impact of GSH treatment on OXA induced ALI, mice were treated with GSH (400 mg/kg, i.p). In this ALI mouse model, ALT and AST levels were significantly increased (P<0.01). Liver pathological examination revealed varying degrees of liver cell turbidity and degeneration, even balloon-like changes and focal necrosis, and sinusoidal hemorrhage in some cells. Compared with control group, the malondialdehyde (MDA) and GSH levels were significantly increased in OXA-treated group (P<0.01), while the superoxide dismutase SOD and GSH-peroxidase levels were decreased after OXA withdrawal (P<0.01). When GSH was used to treat OXA-induced ALI mice, the pathological injury of liver tissues was alleviated, and serum ALT and AST were significantly decreased. In addition, GSH treatment could reduce the OXA-induced increase of MDA level (P<0.05) in liver tissues, but had no impact on SOD level (P>0.05). We have successfully established an OXA-induced ALI model. Using this model, we discover that oxidative stress plays an important role in OXA-induced ALI. GSH-based hepatoprotective therapy can partially inhibit oxidative stress and alleviate OXA-induced ALI. PMID- 29403565 TI - Cell Migration in Microfabricated 3D Collagen Microtracks is Mediated through the Prometastatic Protein Girdin. AB - Introduction: In vivo, cancer cells can utilize tube-like microtracks formed within the extracellular matrix (ECM) of the stroma as 'highways' to escape the primary tumor, however very little is known about the molecular mechanisms that govern cell migration through these microtracks. Cell polarization and actin organization are both essential for efficient cell migration and cells are known to migrate very unidirectionally in confined spaces. In this study, we focused on understanding the role of Girdin during unidirectional migration. Girdin is a prometastatic protein known to be involved in cell polarity by directly interacting with the cell polarity protein Par-3 (Partitioning defective-3) and also known as an actin binding protein. Methods: We utilized a microfabricated platform to recreate these microtracks in vitro using collagen and used siRNA to knockdown Girdin in MDA-MB-231 cells. Results: Our data indicate that knockdown of Girdin results in decreased cell speed during 3D collagen microtrack migration. Loss of Girdin also results in altered cell morphology and cell orientation. Moreover, Girdin-depletion impairs actin organization and stress fiber formation, which can be restored by upregulating the GTPase RhoA. Activation of RhoA induces actin stress fiber formation, restores elongated migratory cell shape and partial cell migration in 3D collagen microtracks in the absence of Girdin. Conclusions: Our data suggest that Girdin helps directional migration in collagen microtracks by promoting actin cytoskeletal organization and maintaining morphological cell polarity. PMID- 29403566 TI - Management of Glenoid Defects in Anterior Shoulder Instability: A Review of Current Concepts. AB - Background: Bone defects of the glenoid are often found in patients with traumatic anterior glenohumeral instability. There is no consensus regarding which glenoid defects need to be treated surgically. The aim of this review is to describe the management of glenoid defects in anterior shoulder instability in patients with traumatic anterior glenohumeral instability. Methods: We conducted a review of the literature through a Pubmed search. Results: The management of glenoid defects in anterior shoulder instability consists of conservative or operative treatment. There is a wide variety in the treatment options. Also, the diagnostics of the presence and size of a glenoid bone defect is still debated on in literature. Conclusion: Based on the current available literature, we advise to begin management of traumatic anterior shoulder instability combined with glenoid defects with conservative treatment. Operative treatment can be used when the bone fragment consists of a large glenoid surface and the patient is active, or in the case of a chronic defect or recurrent instability. PMID- 29403567 TI - Random Forest Missing Data Algorithms. AB - Random forest (RF) missing data algorithms are an attractive approach for imputing missing data. They have the desirable properties of being able to handle mixed types of missing data, they are adaptive to interactions and nonlinearity, and they have the potential to scale to big data settings. Currently there are many different RF imputation algorithms, but relatively little guidance about their efficacy. Using a large, diverse collection of data sets, imputation performance of various RF algorithms was assessed under different missing data mechanisms. Algorithms included proximity imputation, on the fly imputation, and imputation utilizing multivariate unsupervised and supervised splitting-the latter class representing a generalization of a new promising imputation algorithm called missForest. Our findings reveal RF imputation to be generally robust with performance improving with increasing correlation. Performance was good under moderate to high missingness, and even (in certain cases) when data was missing not at random. PMID- 29403569 TI - "Alexa, Refill My Omeprazole". PMID- 29403568 TI - Tree based weighted learning for estimating individualized treatment rules with censored data. AB - Estimating individualized treatment rules is a central task for personalized medicine. [23] and [22] proposed outcome weighted learning to estimate individualized treatment rules directly through maximizing the expected outcome without modeling the response directly. In this paper, we extend the outcome weighted learning to right censored survival data without requiring either inverse probability of censoring weighting or semiparametric modeling of the censoring and failure times as done in [26]. To accomplish this, we take advantage of the tree based approach proposed in [28] to nonparametrically impute the survival time in two different ways. The first approach replaces the reward of each individual by the expected survival time, while in the second approach only the censored observations are imputed by their conditional expected failure times. We establish consistency and convergence rates for both estimators. In simulation studies, our estimators demonstrate improved performance compared to existing methods. We also illustrate the proposed method on a phase III clinical trial of non-small cell lung cancer. PMID- 29403570 TI - Prospective Bundled Payments in a Changing Environment: The Experience of a Self Funded, State-Sponsored Plan. AB - Background: Healthcare reimbursement, which has traditionally been based on the quantity of services delivered, is currently moving toward value-based reimbursement-a system that addresses the quantity, quality, and cost of services. One such arrangement has been the evolution of bundled payments for a specific procedure or for an episode of care, paid prospectively or through post hoc reconciliation. Objective: To evaluate the impact of instituting bundled payments that incorporate facility charges, physician fees, and all ancillary charges by the State of Oklahoma HealthChoice public employee insurance plan. Method: From January 1 through December 31, 2016, HealthChoice, a large, government-sponsored Oklahoma health plan, implemented a voluntary, prospective, bundled payment system with network facilities, called Select. The Select program allows members at the time of certification of the services to opt to use participating facilities for specified services at a bundled rate, with deductible and coinsurance covered by the health plan. That is, the program allows any plan member to choose either a participating Select facility with no out-of-pocket costs or standard benefits at a participating network facility. Results: During 2016, more than 7900 procedures were performed for 5907 patients who chose the Select arrangement (also designated as the intervention group). The most common outpatient Select procedures were for cardiology, colonoscopy, and magnetic resonance imaging scans. The most common inpatient procedures for Select covered patients were in 6 diagnosis-related groups covering spinal fusions, joint replacement surgeries, and percutaneous coronary artery stenting. The allowable costs were similar for bundled procedures at ambulatory surgery centers and at outpatient hospital facilities; the allowable costs for patients not in the Select program (mean, $813) were lower at ambulatory surgery centers than at outpatient hospital departments (mean, $3086) because of differences in case mix. Patients in the Select system who had outpatient procedures had significantly fewer subsequent claims than those who were not in Select for hospitalization (1.7% vs 2.5%, respectively) and emergency department visits (4.4% vs 11.5%, respectively) in the 30 days postprocedure. Quality measures (eg, wound infection and reoperation) were similar for patients who were and were not in the Select group and had procedures. Surgical complication (ie, return to surgery) rates were higher for the Select group. Conclusion: The Select program demonstrated promising results during its first year of operation, suggesting that prospective bundled payment arrangements can be implemented successfully. Further research on reimbursement mechanisms, that is, how to pay physicians and facilities, and quality of outcomes is needed, especially with respect to which procedures are most suitable for this payment arrangement. PMID- 29403572 TI - AMCP Nexus 2017 Highlights. AB - The following summaries represent a small sample of real-world, evidence-based information presented at AMCP Nexus 2017, October 16-19, 2017, in Dallas, TX. PMID- 29403571 TI - The Effects of a Sitagliptin Formulary Restriction Program on Diabetes Medication Use. AB - Background: Health plans have responded to the many treatment options for type 2 diabetes mellitus by implementing formulary restriction policies, including step therapy, to control costs. Little is known about the impact of step therapy programs on antidiabetes medication use. Objective: To assess the impact of a sitagliptin step therapy program on antidiabetes medication use among sitagliptin users. Methods: Using pharmacy claims from the Symphony Health Solutions' Integrated Dataverse, we compared the use of sitagliptin and other antidiabetes medications by patients enrolled in a health plan (Plan A) that implemented a sitagliptin step therapy program on July 1, 2013, with the use by patients who were contemporaneously enrolled in 2 comparison plans-Plans B and C-without step therapy programs. Sitagliptin-a dipeptidyl peptidase (DPP)-4 inhibitor-was in tier 3 in Plans A and B and in tier 2 in Plan C during the study period. We assessed the use of antidiabetes medications during the pre-step therapy period (January-June 2013) and the post-step therapy period (October 2013-March 2014). Results: We identified 2995 patients enrolled in Plan A, 751 enrolled in Plan B, and 394 enrolled in Plan C who received sitagliptin during the pre-step therapy period. Patient characteristics and pre-step therapy sitagliptin use were similar across plans. During the post-step therapy period, more patients in Plan A (approximately 70%) discontinued sitagliptin than patients in Plan B (approximately 51%) and Plan C (approximately 25%). Approximately 30% of patients in Plan A switched to another DPP-4 inhibitor compared with approximately 15% and 2% of patients in Plans B and C, respectively. Seventeen percent of patients in Plan A discontinued sitagliptin without replacement but continued using other antidiabetes medications compared with approximately 13% and 8% of patients in Plans B and C, respectively. In all, 17% of patients in Plans A and B and 11% of patients in Plan C discontinued using all antidiabetes medications. Conclusion: The step therapy program changed patients' use of sitagliptin, which was the target of the step therapy program, as well as of other antidiabetes medications. Most patients stopped sitagliptin treatment after the step therapy program started. Some patients discontinued sitagliptin treatment without replacement, but others discontinued using all antidiabetes medications. PMID- 29403573 TI - Comparing the Medicaid Retrospective Drug Utilization Review Program Cost-Savings Methods Used by State Agencies. AB - Background: The Medicaid Drug Utilization Review (DUR) program is a 2-phase process conducted by Medicaid state agencies. The first phase is a prospective DUR and involves electronically monitoring prescription drug claims to identify prescription-related problems, such as therapeutic duplication, contraindications, incorrect dosage, or duration of treatment. The second phase is a retrospective DUR and involves ongoing and periodic examinations of claims data to identify patterns of fraud, abuse, underutilization, drug-drug interaction, or medically unnecessary care, implementing corrective actions when needed. The Centers for Medicare & Medicaid Services requires each state to measure prescription drug cost-savings generated from its DUR programs on an annual basis, but it provides no guidance or unified methodology for doing so. Objectives: To describe and synthesize the methodologies used by states to measure cost-savings using their Medicaid retrospective DUR program in federal fiscal years 2014 and 2015. Method: For each state, the cost-savings methodologies included in the Medicaid DUR 2014 and 2015 reports were downloaded from Medicaid's website. The reports were then reviewed and synthesized. Methods described by the states were classified according to research designs often described in evaluation textbooks. Discussion: In 2014, the most often used prescription drugs cost-savings estimation methodology for the Medicaid retrospective DUR program was a simple pre-post intervention method, without a comparison group (ie, 12 states). In 2015, the most common methodology used was a pre-post intervention method, with a comparison group (ie, 14 states). Comparisons of savings attributed to the program among states are still unreliable, because of a lack of a common methodology available for measuring cost-savings. Conclusion: There is great variation among states in the methods used to measure prescription drug utilization cost-savings. This analysis suggests that there is still room for improvement in terms of methodology transparency, which is important, because lack of transparency hinders states from learning from each other. Ultimately, the federal government needs to evaluate and improve its DUR program. PMID- 29403574 TI - A State-wide Health IT Infrastructure for Population Health: Building a Community wide Electronic Platform for Maryland's All-Payer Global Budget. AB - Maryland Department of Health (MDH) has been preparing for alignment of its population health initiatives with Maryland's unique All-Payer hospital global budget program. In order to operationalize population health initiatives, it is required to identify a starter set of measures addressing community level health interventions and to collect interoperable data for those measures. The broad adoption of electronic health records (EHRs) with ongoing data collection on almost all patients in the state, combined with hospital participation in health information exchange (HIE) initiatives, provides an unprecedented opportunity for near real-time assessment of the health of the communities. MDH's EHR-based monitoring complements, and perhaps replaces, ad-hoc assessments based on limited surveys, billing, and other administrative data. This article explores the potential expansion of health IT capacity as a method to improve population health across Maryland. First, we propose a progression plan for four selected community-wide population health measures: body mass index, blood pressure, smoking status, and falls-related injuries. We then present an assessment of the current and near real-time availability of digital data in Maryland including the geographic granularity on which each measure can be assessed statewide. Finally, we provide general recommendations to improve interoperable data collection for selected measures over time via the Maryland HIE. This paper is intended to serve as a high level guiding framework for communities across the US that are undergoing healthcare transformation toward integrated models of care using universal interoperable EHRs. PMID- 29403575 TI - Meaningful Use and Electronic Laboratory Reporting: Challenges Health Information Technology Vendors Face in Kentucky. AB - Objectives: To explore the challenges Health Information Technology (HIT) vendors face to satisfy the requirements for Meaningful Use (MU) and Electronic Laboratory Reporting (ELR) of reportable diseases to the public health departments in Kentucky. Methodology: A survey was conducted of Health Information Exchange (HIE) vendors in Kentucky through the Kentucky Health Information Exchange (KHIE). The survey was cross-sectional. Data were collected between February and March 2014. Participants were recruited from KHIE vendors. Participants received online survey link and by email and asked to submit their responses. Vendors' feedback were summarized and analyzed to identify their challenges. Out of the 55 vendors who received the survey, 35(63.64%) responded. Results: Of the seven transport protocol options for ELR, vendors selected virtual private network (VPN) as the most difficult to implement (31.7%). Secure File Transfer Protocol (SFTP) was selected as preferred ELR transport protocol (31.4%). Most of the respondents, 80% responded that they do not have any challenge with the Health Level 7 (HL7) standard implementation guide required by MU for 2014 ELR certification. Conclusion: The study found that the most difficult transport protocol to implement for ELR is VPN and if vendors have preference, they would use SFTP for ELR over KHIE choice of VPN and Simple Object Access Protocol (SOAP). KHIE vendors do not see any variability in what is reportable by different jurisdiction and also it is not difficult for them to detect what is reportable from one jurisdiction verse the other. PMID- 29403576 TI - Estimated and Interactively Visualized Female Breast Cancer Incidence Rates in Missouri Senate Districts: 2008-2012. AB - Objectives: To measure and interactively visualize female breast cancer (FBC) incidence rates in Missouri by age, race, stage and grade, and senate district of residence at diagnosis from 2008 to 2012. Methods: An observational epidemiological study. The FBC cases in counties split by senate districts were geocoded. Population database was created. A database was created within SEER*Stat. The incidence rates and the 95% Confidence Interval (CI) were age standardized using US 2000 Standard Population. The Census Bureau's Cartographic Boundary Files were used to create maps showing Missouri senate districts. Incidence results were loaded along with the maps into InstantAtlasTM software to produce interactive reports. Results: Cancer profiles were created for all 34 Missouri senate districts. An area profile and a double map that included interactive maps, graphs, and tables for the 34 Missouri senate districts were built. Conclusion: The results may provide an estimation of social inequality within the state and could provide clues about the impact of level of coverage and accessibility to screening and health care services on disease prevention and early diagnosis. PMID- 29403577 TI - Case Study: Converting Paper-based Case Report Forms to an Electronic Format (e CRF) with ACASI Self-Report Integration. AB - This paper will discuss the integration of electronic Case Report Forms (e-CRFs) into an already existing Android-based Audio Computer-Assisted Self-Interview (ACASI) software solution that was developed for a public health project in Kampala, Uganda, the technical outcome results, and lessons learned that may be useful to other projects requiring or considering such a technology solution. The developed product can function without a connection to the Internet and allows for synchronizing collected data once connectivity is possible. Previously, only paper-based CRFs were utilized at the Uganda project site. A subset or select group of CRFs were targeted for integration with ACASI in order to test feasibility and success. Survey volume, error rate, and acceptance of the system, as well as the operational and technical design of the solution, will be discussed. PMID- 29403578 TI - The Use of Electronic Medical Record Data to Analyze the Association Between Atrial Fibrillation and Birth Month. AB - Objectives: Cardiovascular disease is a condition of enormous public health concern. Recently, a population study newly revealed associations between cardiovascular diseases and birth month. Here, we investigated the association between atrial fibrillation in cardiovascular disease and birth month. Methods: We retrospectively extracted birth date data from 6,016 patients with atrial fibrillation (3,876 males; 2,140 females) from our electronic medical records. The number of live births in Japan fluctuates seasonally. Therefore, we corrected the number of patients for each birth month based on a Japanese population survey report. Then, a test of the significance of the association between atrial fibrillation and birth month was performed using a chi-square test. In addition, we compared the results of an analysis of patient data with that of simulated data that showed no association with birth month. Results: The deviations of birth month were not significant (overall: p = 0.631, males: p = 0.842, females: p = 0.333). The number of female patients born in the first quarter of the year was slightly higher than those born in the other quarters of the year (p = 0.030). However, by comparing the magnitudes of dispersion in the simulated data, it seems that this finding was mere coincidence. Conclusion: An association between atrial fibrillation and birth month could not be confirmed in our Japanese study. However, this might be due to differences in ethnicity. Further epidemiologic studies on this topic may result in reduction of disease risk in the general population and contribute to public health. PMID- 29403579 TI - Computed tomography as primary postoperative follow-up after laparoscopic Roux-en Y gastric bypass. AB - AIM: To evaluate upper abdominal computed tomography (CT) scan as primary follow up after laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: This prospective study was approved by the Ethical Committee of the State of Zurich, and informed consent was obtained from all patients. Sixty-one patients who underwent LRYGB received upper abdominal CT on postoperative day 1, with the following scan parameters: 0.6 mm collimation, 1.2 mm pitch, CareKV with reference 120 mAs and 120 kV, and 0.5 s rotation time. Diluted water-soluble radiographic contrast medium (50 mL) was administered to achieve gastric pouch distension without movement of the patient. 3D images were evaluated to assess postoperative complications and the radiation dose received was analysed. RESULTS: From the 70 patients initially enrolled in the study, 9 were excluded from analysis upon the intraoperative decision to perform a sleeve gastrectomy and not a LRYGB. In all of the 61 patients who were included in the analysis, CT was feasible and there were no instances of aspiration or vomiting. In 7 patients, two upper abdominal scans were necessary as the pouch was not distended by contrast medium in the first acquisition. Radiologically, no leak and no relevant stenosis were found on the first postoperative day. These early postoperative CT findings were consistent with the findings at clinical follow-up 6 wk postoperatively, with no leaks, stenosis or obstructions being diagnosed. The average total dose length product in CT was 536.6 mGycm resulting in an average effective dose of 7.8 mSv. The most common surgical complication, superficial surgical site infections (n = 4), always occurred at the upper left trocar site, where the circular stapler had been introduced. CONCLUSION: Early LRYGB postoperative multislice spiral CT scan is feasible, with low morbidity, and provides more accurate anatomical information than standard upper gastrointestinal contrast study. PMID- 29403581 TI - Importance of Posterior Corneal Astigmatism in Eyes with Keratoconus. PMID- 29403580 TI - Correction to "Asymmetrically hypointense veins on T2*w imaging and susceptibility-weighted imaging in ischemic stroke" [World J Radiol 2013; 5(4): 156-165]. AB - [This corrects the article on p. 4 in vol. 5, PMID: 23671751.]. PMID- 29403582 TI - Characteristics of Posterior Corneal Astigmatism in Different Stages of Keratoconus. AB - Purpose: To evaluate the magnitudes and axis orientation of anterior corneal astigmatism (ACA) and posterior corneal astigmatism (PCA), the ratio of ACA to PCA, and the correlation between ACA and PCA in the different stages of keratoconus (KCN). Methods: This retrospective case series comprised 161 eyes of 161 patients with KCN (104 men, 57 women; mean age, 22.35 +/- 6.10 years). The participants were divided into four subgroups according to the Amsler-Krumeich classification. A Scheimpflug imaging system was used to measure the magnitude and axis orientation of ACA and PCA. The posterior-anterior corneal astigmatism ratio was also calculated. The results were compared among different subgroups. Results: The average amounts of anterior, posterior, and total corneal astigmatism were 4.08 +/- 2.21 diopters (D), 0.86 +/- 0.46 D, and 3.50 +/- 1.94 D, respectively. With-the-rule, against-the-rule, and oblique astigmatisms of the posterior surface of the cornea were found in 61 eyes (37.9%), 67 eyes (41.6%), and 33 eyes (20.5%), respectively; corresponding figures in the anterior corneal surface were 55 eyes (32.4%), 56 eyes (34.8%), and 50 eyes (31.1%), respectively. A strong correlation (P <= 0.001, r = 0.839) was found between ACA and PCA in the different stages of KCN; the correlation was weaker in eyes with grade 3 (P <= 0.001, r = 0.711) and grade 4 (P <= 0.001, r = 0.717) KCN. The maximum posterior anterior corneal astigmatism ratio (PCA/ACA, 0.246) was found in patients with stage 1 KCN. Conclusion: Corneal astigmatism in anterior surface was more affected than posterior surface by increasing in the KCN severity, although PCA was more affected than ACA in an early stage of KCN. PMID- 29403583 TI - Factors Influencing Graft Endothelial Cell Density after Descemet Stripping Automated Endothelial Keratoplasty. AB - Purpose: To determine the factors that influence the endothelial cell density (ECD) of donor grafts after Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: This retrospective, interventional case series comprised 77 eyes of 64 patients who underwent DSAEK. Confocal microscopy was performed at the final follow-up examination to evaluate the endothelial cell count, cell morphology, and graft thickness. Univariate and multiple linear regression analyses were used to investigate recipient-, donor-, surgical-, and postoperative related variables capable of influencing graft endothelial cell counts after DSAEK. Results: The mean patient age was 62.3 +/- 15.6 years; patients were followed-up for 26.2 +/- 20.9 months postoperatively. Forty-six eyes (59.7%) underwent stand-alone DSAEK; 31 eyes (40.3%) underwent DSAEK combined with cataract surgery. The donor trephination size was 8.0 +/- 0.21 mm. The mean donor age was 30.4 +/- 11.2 years, and the mean preoperative endothelial cell density was 3127.4 +/- 315.1 cells/mm2, which decreased to 1788.6 +/- 716.5 cells/mm2 postoperatively (P < 0.001). The mean postoperative central graft thickness was 102.4 +/- 31.6 MUm. Univariate analysis revealed that postoperative ECD was significantly associated with death to preservation time (P = 0.046), graft thickness (P = 0.016), follow-up duration (P = 0.005), and graft non attachment (P = 0.049). Multiple regression analyses identified graft thickness (beta = 10.62, P = 0.003) and follow-up duration (beta = -22.09, P = 0.001) as the significant characteristics influencing postoperative ECD. Conclusion: The primary predictors of ECD after DSAEK were graft thickness and duration of follow up. Surgeons' requests for ultrathin DSAEK donor grafts to improve visual outcomes might not have the desired postoperative outcome with respect to ECD. PMID- 29403584 TI - Visual Outcomes and Refractive Status after Combined Silicone Oil Removal/Cataract Surgery with Intraocular Lens Implantation. AB - Purpose: To evaluate refractive status and identify predictors of surgical success following a combined silicone oil removal/cataract surgery with intraocular lens (IOL) implantation procedure. Methods: In this single-armed, retrospective study, we reviewed patients who underwent vitreoretinal surgery followed by a combined silicone oil removal/cataract surgery procedure between 2009 and 2013. Preoperative data included patient demographics, refractive status, IOL power, and axial length (measured with the IOL Master). Postoperative data were obtained from the 8-week follow-up visit and from the last follow-up visit attended that included refractive error (RE) evaluation (e.g., myopic, hyperopic, and astigmatic). Associations between variables and refractive status were examined. Blindness was defined as a best-corrected visual acuity (BCVA) worse than 3/60. Results: Nighty-eight eyes were ultimately included in analyses. Following surgery, 37.0% of eyes achieved BCVA better than 6/18. The incidence of blindness (BCVA worse than 3/60) was reduced from 47.0% before surgery to 17.3% after surgery. Additionally, 33.7% of eyes did not require refractive correction. Forty-two percent of eyes were under-corrected (>0.5 D hyperopia) following surgery. Age, gender, silicone oil viscosity, axial length, IOL type, initial vitreoretinal pathology, surgeon, and IOL calculation formula were not significantly associated with surgical outcomes (all P > 0.05). Conclusion: A combined silicone oil removal/cataract surgery with IOL implantation procedure restored functional vision in approximately one-third of cases. However, nearly half of patients were under-corrected. Unfortunately, we did not identify any factors that predicted surgical success. PMID- 29403585 TI - Effects of Dexamethasone Implant on Multifocal Electroretinography in Central Retinal Vein Occlusion. AB - Purpose: To investigate the effect of Ozurdex (dexamethasone intravitreal implant) on multifocal electroretinography (mfERG) findings during the treatment of macular edema secondary to the central retinal vein occlusion (CRVO). Methods: Fifteen eyes of 15 patients who were treated with Ozurdex implant due to CRVO related macular edema were included in this study. Best corrected visual acuity (BCVA), central macular thickness (CMT), and mfERG evaluations were performed for all patients before injection of Ozurdex. After the injection, BCVA and CMT were measured at months 3 and 6 and mfERG test was performed at month 6 for all patients. Results: Pre-implantation mfERG P wave amplitude values of r1, r2, r3, r4 and r5 were 57.8 +/- 14.8, 25.1 +/- 10.6, 17.2 +/- 7.3, 12.0 +/- 5.0 and 7.1 +/- 3.6 nV/deg2, respectively. They increased to 72.9 +/- 33.2, 31.2 +/- 9.3, 22.6 +/- 7.6, 15.6 +/- 7.1 and 10.9 +/- 5.7 nV/deg2, respectively, at month 6. However, these increases were not statistically significant (all P > 0.05). Pre implantation mfERG r1, r2, r3, r4 and r5 P wave implicit times were 40.1 +/- 10.9, 39.4 +/- 3, 38.4 +/- 3.4, 38.2 +/- 3.1 and 39.3 +/- 2.2 ms, respectively and these values were measured as 38.9 +/- 8.2, 38.4 +/- 4.7, 37 +/- 3.8, 37.5 +/ 4.6 and 37.7 +/- 4.7 ms at 6 months. Although there were reductions in P wave implicit times in all rings, they were not statistically significant (all P > 0.05). Conclusion: In this prospective study, we found that the Ozurdex implant had no effect on mfERG findings 6 months after insertion for treatment of CRVO related macular edema. PMID- 29403586 TI - Efficacy of Intravitreal Bevacizumab for the Treatment of Zone I Type 1 Retinopathy of Prematurity. AB - Purpose: To describe the efficacy of intravitreal bevacizumab for the treatment of type 1 retinopathy of prematurity (ROP) in zone I. Methods: Preterm infants with type 1 ROP in zone I (zone I ROP, any stage with plus disease or zone I ROP, stage 3 without plus disease) were enrolled in this prospective study. Intravitreal bevacizumab (0.625 mg/0.025 ml) was injected under topical anesthesia. Patients were followed weekly for 4 weeks and then biweekly till 90 weeks gestational age. Results: Seventy eyes of 35 patients with type 1 ROP in zone I were enrolled. At a gestational age of 90 weeks, ROP regressed with complete or near-complete peripheral retinal vascularization, in 82.9% of eyes after a single injection and in 92.9% of eyes after up to two injections. In five eyes (7.1%), ROP progressed to stage 4B or 5, so surgical management was required. There were no major complications such as endophthalmitis, cataract, or vitreous hemorrhage after injection. Conclusion: Intravitreal bevacizumab injection is an effective method for the management of patients with Zone I ROP requiring treatment; however, some cases may progress to more advanced stages and require surgical management. Close monitoring for recurrence or progression is necessary. Eyes with persistent zone I ROP may progress to advanced stages when treated with intravitreal bevacizumab injection and re-treatment may be needed. PMID- 29403587 TI - Ophthalmologic Findings in Patients with Neuro-metabolic Disorders. AB - Purpose: We aimed to present the ophthalmic manifestations of neuro-metabolic disorders. Methods: Patients who were diagnosed with neuro-metabolic disorders in the Neurology Department of Mofid Pediatric Hospital in Tehran, Iran, between 2004 and 2014 were included in this study. Disorders were confirmed using clinical findings, neuroimaging, laboratory data, and genomic analyses. All enrolled patients were assessed for ophthalmological abnormalities. Results: A total of 213 patients with 34 different neuro-metabolic disorders were included. Ophthalmological abnormalities were observed in 33.5% of patients. Abnormal findings in the anterior segment included Kayser-Fleischer rings, congenital or secondary cataracts, and lens dislocation into the anterior chamber. Posterior segment (i.e., retina, vitreous body, and optic nerve) evaluation revealed retinitis pigmentosa, cherry-red spots, and optic atrophy. In addition, strabismus, nystagmus, and lack of fixation were noted during external examination. Conclusion: Ophthalmological examination and assessment is essential in patients that may exhibit neuro-metabolic disorders. PMID- 29403588 TI - Choroidal Thickness in Healthy Subjects. AB - Purpose: To measure the choroidal thickness by enhanced depth imaging optical coherence tomography (EDI-OCT) in normal eyes. Methods: In a prospective case series, 208 eyes of 104 normal Iranian subjects were enrolled. Complete ophthalmic examination was performed. Inclusion criteria were best corrected visual acuity (BCVA) >=20/20, <= +/-1 diopter of refractive error in either spherical or cylindrical components, normal intraocular pressure (IOP) and no systemic or ocular diseases. The choroidal thickness was measured by EDI-OCT subfoveally, and 1500 MUm and 3000 MUm nasal and temporal to the fovea. Results: Mean age was 34.6 +/- 9.8 years (range, 18-57 years). Mean subfoveal choroidal thickness was 363 +/- 84 MUm. Choroidal thickness was 292 +/- 76 and 194 +/- 58 MUm at 1500 and 3000 MUm nasal to the fovea, respectively, and 314 +/- 77 and 268 +/- 66 MUm at 1500 and 3000 MUm temporal to the fovea, respectively. There was no statistically significant difference in the choroidal thickness between sexes and laterality of the eyes. Choroidal thickness at fovea (P < 0.001) and at all extrafoveal locations decreased significantly for every 10 years increase in age. Conclusion: In normal Iranian subjects participating in this study, mean choroidal thickness was comparable with other reports. PMID- 29403589 TI - Effect of Different Illumination Sources on Reading and Visual Performance. AB - Purpose: To investigate visual performance during reading under different illumination sources. Methods: This experimental quantitative study included 40 (20 females and 20 males) emmetropic participants with no history of ocular pathology. The participants were randomly assigned to read a near visual task under four different illuminations (400-lux constant): compact fluorescent light (CFL), tungsten light (TUNG), fluorescent tube light (FLUO), and light emitting diode (LED). Subsequently, we evaluated the participants' experiences of eight symptoms of visual comfort. Results: The mean age of the participants was 19.86 +/- 1.09 (range: 18-21) years. There was no statistically significant difference between the reading rates of males and females under the different illuminations (P = 0.99); however, the reading rate was fastest among males under CFL, and among females under FLUO. One way analysis of variance (ANOVA) revealed a strong significant difference (P = 0.001) between males and females (P = 0.002) regarding the visual performance and illuminations. Conclusion: This study demonstrates the influence of illumination on reading rate; there were no significant differences between males and females under different illuminations, however, males preferred CFL and females preferred FLUO for faster reading and visual comfort. Interestingly, neither preferred LED or TUNG. Although energy efficient, visual performance under LED is poor; it is uncomfortable for prolonged reading and causes early symptoms of fatigue. PMID- 29403590 TI - Visual Impairment Registry of Patients from North Kolkata, Eastern India: A Hospital-based Study. AB - Purpose: To study the demographic profile, severity and causes of visual impairment among registered patients in a tertiary care hospital in north Kolkata, eastern India, and to assess the magnitude of under-registration in that population. Methods: This is a retrospective analytical study. A review of all visually impaired patients registered at our tertiary care hospital during a ten year period from January 2005 to December 2014, which is entitled for certification of people of north Kolkata, eastern India (with a population denominator of 1.1 million), was performed. Overall, 2472 eyes of 1236 patients were analyzed in terms of demographic characteristics, cause of visual impairment, and percentage of visual disability as per the guidelines established by the government of India. Results: Male patients (844, 68.28%; 95% confidence interval [CI], 65.69-70.87) registered more often than female patients (392; 31.72%, P = 0.0004). The registration rate for visual impairment was 11.24 per 100,000 per annum; this is not the true incidence rate, as both new patients and those visiting for renewal of certification were included in the study. Optic atrophy was the most common cause of visual impairment (384 eyes, 15.53%; 95% CI, 14.1-16.96). Conclusion: Commonest cause of visual impairment was optic atrophy followed by microphthalmos. Under-registration is a prevalent problem as the registration system is voluntary rather than mandatory, and female patients are more likely to be unregistered in this area. PMID- 29403592 TI - Management of Retinal Diseases in Pregnant Patients. AB - Pregnancy leads to significant changes in the body, which potentially affect the retina. Pregnancy can induce disease, such as that seen in hypertensive retinopathy and choroidopathy. It can cause exudative retinal detachments in the HELLP syndrome (hemolysis, elevated liver enzymes and low platelets), disseminated intravascular coagulation (DIC), and thrombotic thrombocytopenic purpura (TTP), and provoke arterial and venous retinal occlusive disease. Pregnancy may also exacerbate pre-existing retinal disease, such as idiopathic central serous chorioretinopathy (ICSC) and diabetic retinopathy. Special consideration needs to be exercised when treating pregnant patients in choosing medications, as well as in selecting diagnostic modalities and surgical methods. PMID- 29403591 TI - Evolution of Cyclophotocoagulation. AB - Cyclodestructive techniques have been a treatment option for refractory glaucoma since its first use in the 1930s. Over the past nine decades, cyclodestruction has advanced from the initial cyclodiathermy to micropulse transscleral cyclophotocoagulation (MP-TSCPC) which is the current treatment available. Complications associated with cyclodestruction including pain, hyphema, vision loss, hypotony and phthisis have led ophthalmologists to shy away from these techniques when other glaucoma treatment options are available. Recent studies have shown encouraging clinical results with fewer complications following cyclophotocoagulation, contributing greatly to the current increase in the use of cyclophotocoagulation as primary treatment for glaucoma. We performed our literature search on Google Scholar Database, Pubmed, Web of Sciences and Cochrane Library databases published prior to September 2017 using keywords relevant to cyclodestruction, cyclophotocoagulation and treatment of refractory glaucoma. PMID- 29403593 TI - Upcoming Methods and Specifications of Continuous Intraocular Pressure Monitoring Systems for Glaucoma. AB - Glaucoma is the leading cause of irreversible blindness and vision loss in the world. Although intraocular pressure (IOP) is no longer considered the only risk factor for glaucoma, it is still the most important one. In most cases, high IOP is secondary to trabecular meshwork dysfunction. High IOP leads to compaction of the lamina cribrosa and subsequent damage to retinal ganglion cell axons. Damage to the optic nerve head is evident on funduscopy as posterior bowing of the lamina cribrosa and increased cupping. Currently, the only documented method to slow or halt the progression of this disease is to decrease the IOP; hence, accurate IOP measurement is crucial not only for diagnosis, but also for the management. Due to the dynamic nature and fluctuation of the IOP, a single clinical measurement is not a reliable indicator of diurnal IOP; it requires 24 hour monitoring methods. Technological advances in microelectromechanical systems and microfluidics provide a promising solution for the effective measurement of IOP. This paper provides a broad overview of the upcoming technologies to be used for continuous IOP monitoring. PMID- 29403594 TI - Possible Role of Descemet-Stroma Interface for Descemet's Membrane Detachment after Penetrating Keratoplasty. AB - Purpose: To report two cases of spontaneous Descemet's membrane detachment (DMD) and dehiscence following penetrating keratoplasty (PK). Case Reports: Spontaneous DMD or Descemet's membrane (DM) dehiscence following PK is a rare occurrence. Here, we describe two cases of such an occurrence following PK arising from the graft-host interface. A possible causative relation between DMD/dehiscence and DM stromal interface attachment is suggested. Conclusion: DMD and dehiscence after PK can be explained by the peripheral thinning of DM and possible changes to the recently characterized anchoring zone of interwoven collagen fibers and proteoglycans at the Descemet-stroma interface. PMID- 29403595 TI - Visibility of Blood Flow on Optical Coherence Tomography Angiography in a Case of Branch Retinal Artery Occlusion. AB - Purpose: We report the variability in flow angiogram during the course of branch retinal artery occlusion (BRAO) in a case imaged by optical coherence tomography angiography (OCTA). Case Report: OCTA was performed in a patient with BRAO at initial examination and 6 hours later. Initially, the occluded retinal artery and its branches were not detected on OCTA whereas a slow perfusion was present on fluorescein angiography. Six hours after initial examination, flow was detected on OCTA image in the previously occluded artery. Conclusion: This case confirmed the relevance of using OCTA in monitoring BRAO and showed that capillaries with a very slow flow are not visible on OCTA angiograms. It emphasizes that non perfusion on OCTA should be interpreted with caution. PMID- 29403597 TI - Compound Nevus Simulating a Conjunctival Melanoma. PMID- 29403596 TI - Primary Atypical Lipomatous Tumor of the Orbit: A Case Report. AB - Purpose: To describe a case of primary atypical orbital lipomatous tumor (ALT). Case Report: A 35-year-old man presented with a two-month history of left eye proptosis and vertical diplopia. His visual acuity was 20/30 OD and 20/60 OS. External examination showed proptosis and downward displacement of the left eye with mild lid erythema. Extraocular movements were reduced in the left eye, with 10% and 70% motility in upgaze and abduction/adduction, respectively. Imaging showed a mass (22 * 16 * 46 mm) in the superior left orbit that infiltrated the orbital fat and the superior rectus muscle. A biopsy of the mass showed mature adipose tissue intermingled with fibrous zones of hyperchromatic stromal cells with nuclear atypia. Fluorescence in situ hybridization analysis demonstrated positive amplification for MDM2/CEP12. The MDM2 to CEP12 ratio was 5:7. A diagnosis of ALT was confirmed. An orbital exenteration was recommended, which the patient declined. Conclusion: Although rare, the differential for unilateral proptosis with or without diplopia should include orbital liposarcomas including the ALT subtype. Imaging, biopsy, staining, and/or FISH analysis for proto oncogenes can assist with diagnosis and staging, while the standard treatment is exenteration. PMID- 29403598 TI - Sub-internal Limiting Membrane Cavity Following Valsalva Retinopathy Resembling Central Serous Chorioretinopathy. PMID- 29403599 TI - Conjunctival Rhinosporidiosis with Lateral Rectus Muscle Involvement. PMID- 29403600 TI - Unilateral Myelinated Retinal Nerve Fibers. PMID- 29403601 TI - Author's Reply. PMID- 29403602 TI - Comparative effectiveness of intra-articular prolotherapy versus peri-articular prolotherapy on pain reduction and improving function in patients with knee osteoarthritis: A randomized clinical trial. AB - Background: Osteoarthritis is a common degenerative disease. Prolotherapy is an alternative therapy used in multiple musculoskeletal disorders. Objective: To compare the effectiveness of intra-articular dextrose injection versus peri articular prolotherapy in patients with knee osteoarthritis (KOA). Methods: Fifty two adults with painful primary knee osteoarthritis for at least three months were randomized to intra- and peri-articular injection groups. Prolotherapy was done twice with two week intervals. The outcome measures included the Oxford Knee Scale (OKS), Western Ontario McMaster University Osteoarthritis Index (WOMAC), and Visual Analogue Scale (VAS), which were obtained from patients before the first injection at the base line and after the second injection at the fourth and eighth weeks. Results: There were no statistically significant differences between demographic characteristics; before the injection, pain intensity, OKS, and WOMAC scores were approximately equal between the two groups. After dextrose prolotherapy, VAS, OKS, and WOMAC scores improved from baseline through the fourth and eighth weeks in both groups without any superiority between the two methods of injections (p<0.001). Conclusion: Dextrose prolotherapy either intra- or peri-articular injection resulted in significant improvement, so it could be an inexpensive and effective management of knee osteoarthritis. Trial registration: The study protocol was registered as a clinical trial under registration ID of IRCT2016091229795N1 at the Iranian Registry of Clinical Trials (http://www.irct.ir). Funding: The authors received no financial support for the research, authorship, or publication of this article. PMID- 29403604 TI - Factors affecting public dissatisfaction with urban family physician plan: A general population based study in Fars Province. AB - Background: Understanding the level of public satisfaction with a family physician plan as well as the relevant factors in this respect, can be employed as valuable tools in identifying quality of services. Objective: To determine the factors affecting public dissatisfaction with an urban family physician plan in Iran. Methods: This cross-sectional study was conducted from January 2014 through June 2015 on Fars Province residents in Iran, selected based on cluster sampling method. The data collection instrument was comprised of a two-part checklist including demographic information and items related to dissatisfaction with the family physician plan, specialists, para-clinic services, pharmacy, physicians on shift work, emergency services, and family physician assistants. Data were described by SPSS 20. Results: In this study, 1,020 individuals (524 males, 496 females) were investigated. Based on the results, the most frequent factor affecting dissatisfaction with physicians was their single work shifts and unavailability (53%). In terms of dissatisfaction with family physicians' specialist colleagues and para-clinic services, the most common factors were related to difficulty in obtaining a referral form (41.5%) and making appointments (21.6%), respectively. Given the level of dissatisfaction with pharmacies, the significant factor was reported to be excessive delay in medication delivery (31.6%); and in terms of physicians on shift work and emergency services, the most important factor was lower work hours for family physicians (9.2%). Conclusion: It seems that, the most common causes of dissatisfaction with the urban family physician plan are due to the short duration of services, obtaining a referral form and making appointments, and providing prescribed medications. PMID- 29403603 TI - The effect of consumption of garlic tablet on proteins oxidation biomarkers in postmenopausal osteoporotic women: A randomized clinical trial. AB - Background: Osteoporosis (OP) is one of the most prevalent metabolic bone diseases at higher ages, especially in postmenopausal women. Objective: To determine the effect of consumption of garlic tablet on proteins oxidation biomarkers in postmenopausal osteoporotic women. Methods: The present study was a double-blind randomized controlled clinical trial that included 42 postmenopausal women in Yazd during 2014-2015. Osteoporotic women were randomly assigned into two groups: the garlic group (GG) and the placebo group (PG). Participants in GG took two garlic tablets daily for 1 month and the participants in PG took placebo tablets in the same manner. After 30 days, the plasma level of carbonyl groups (PCO), total antioxidant capacity (TAC), and advanced oxidation protein products (AOPPs) were assessed by spectrophotometric assays. Also, Malondialdehyde (MDA) content was measured according to the procedure of Thiobarbituric Acid (TBA). Data were analyzed by SPSS version 18, using paired-samples t-test, independent samples t-test, Wilcoxon, and Mann-Whitney U test. Results: This study showed that garlic tablets had decreased PCO plasma levels (47.37+/-5.98 vs. 19.62+/ 3.40 nM, p<=0.001, before and after the study, respectively), AOPPs (738.95+/ 151.86 vs. 585.12+/-209.99 MUM, p<=0.008, before and after the study, respectively), and increased TAC (11.34+/-10.80 vs. 47.93+/-17.80, p<=0.001, before and after the study, respectively). The parameters in placebo groups showed no significant differences before and after the study, respectively. The levels of MDA before taking the drug in comparison to before Garlic group was also reduced (1.30+/-1.04 vs. 0.92+/-0.81 MUM, p=0.01, before and after the study, respectively). Conclusion: The role of oxidative stress in the pathophysiology of many diseases such as osteoporosis has been demonstrated. The present study showed that garlic consumption can reduce the oxidative stress. Trial registration: The protocol of trial was registered at the Iranian clinical trial register (www.irct.ir) with ID: IRCT138811183273N1. Funding: This study funded by Shahid Sadoughi University of Medical Sciences (Yazd, Iran). PMID- 29403605 TI - Disaster risk assessment in educational hospitals. AB - This is a letter to editor and does not have abstract. PMID- 29403606 TI - Outcomes of photorefractive keratectomy in patients with atypical topography. AB - Background: Photorefractive keratectomy (PRK) is at risk of serious complications such as corneal ectasia, which can reduce corrected distance visual acuity. The rate of complications of PRK is higher in patients with atypical topography. Objective: To determine the outcomes of photorefractive keratectomy in patients with atypical topography. Methods: This cross-sectional study was done in 2015 in Shiraz in Iran. We included 85 eyes in this study. The samples were selected using a simple random sampling method. All patients were under evaluation for uncorrected distance visual acuity, corrected distance visual acuity, manifest refraction, corneal topography, central corneal thickness using pentacam, slit lamp microscopy, and detailed fondus evaluation. The postoperative examination was done 1-7 years after surgery. Data were analyzed using IBM SPSS 21.0 version. To analyze the data, descriptive statistics (frequency, percentage, mean, and standard deviation), chi-square, and independent samples t-test were used. Results: We studied 85 eyes. Among the patients, 23 (27.1%) were male and 62 (72.9%) were female. Mean age of the participants was 28.25+/-5.55 years. Mean postoperative refraction was - 0.37+/-0.55 diopters. Keratoconus or corneal ectasia was not reported in any patient in this study. There was no statistically significant difference between SI index before and after operation (p=0.736). Mean preoperative refraction was -3.84 +/- 1.46 diopters in males and -4.20+/ 1.96 diopters in females; thus there was not statistically significant difference (p = 0.435). Conclusion: PRK is a safe and efficient photorefractive surgery and is associated with low complication rate in patients with atypical topography. PMID- 29403607 TI - Obstacles facing evidence based medicine in physical medicine and rehabilitation: from opinion and knowledge to practice. AB - Background: Evidence-based medicine (EBM) is a new approach to medicine which can guide clinical services toward effective and beneficial results with the least side effects or errors. Up to now, there have been few available articles about specialists' EBM status, specifically the status of physiatrists in the area of EBM. Objective: To determine the present status of physiatrists' attitudes, knowledge and skill in the area of EBM and the existing obstacles. Methods: The cross-sectional study was performed in 2014 among physiatrists in Iran. The valid and reliable questionnaire contained 25 questions in 8 fields including demographic and professional information, point of view regarding EBM, familiarity with databases, educational history and information about EBM, use of scientific resources, scientific evidence usage, and the amount of access to resources. Final analysis of the questionnaires was done using SPSS version 16. Results: One hundred twenty-eight questionnaires were completed (response percentage 52.2%). In total, 48.4% specialists had attended EBM workshops and 89.6% of people were familiar with medical search engines. The amount of familiarity with databases was mostly with MEDLINE/PubMed (52.3%). Respondents mainly had a positive point of view towards EBM. Those who had access to databases at work or somewhere out of home had a more positive attitude (p=0.002). Those who had attended EBM workshops and members of faculty also had more positive attitudes (p=0.003 and p=0.01, respectively). Around 70% of responders had adequate knowledge regarding EBM. Physicians, members of faculty and participants who had spent more time on research, reviewed articles and attended workshops had more knowledge (p=0.001). There were three major obstacles recognized: An insufficient amount of knowledge regarding the principles, advantages and applications of EBM, difficulty with gaining access to associated databases and an insufficient amount of activity in judging and analyzing the related articles. Conclusion: Results from our study revealed that although there is a significant number of physiatrists who are familiar with the practicality of EBM, they are still not familiar enough with its concepts and applications. PMID- 29403608 TI - Risk factors associated with metabolic syndrome and cardiovascular disease among women with polycystic ovary syndrome in Tabuk, Saudi Arabia. AB - Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder at a reproductive age. It is associated with a high risk of metabolic syndrome (MS) and cardiovascular diseases (CVD). Objective: To measure the prevalence of MS in women with PCOS and to assess the global cardiovascular risk (CVR) among them. Methods: This cross-sectional study was conducted at King Khalid Hospital, Tabuk, Saudi Arabia during the period from February through December 2014. A total of 404 infertile women were randomly selected, and checked for diagnosing PCOS, MS and estimated CVD probability. Data were analyzed by IBM-SPSS version 22, using independent-samples t-test, Chi-square, and conditional logistic regression. A p-value of <0.05 was considered significant. Results: MS was diagnosed in 58% and 32% of women with and without PCOS respectively (p<0.00). Results showed a statistically significant association between the two syndromes. Patients with the two syndromes showed high averages of clinical and biochemical values (p<0.00), high rate of predicted CVR, a high percentage of clustering of MS factors, and that weight-waist circumference - HDL are predictive for the occurrence of MS. Conclusion: PCOS is associated with the risk of development of MS, and CVD. Screening for early detection of PCOS and MS and the application of cohort studies are recommended to better explore the role of PCOS in the development of CVD and to assess the significance of interventions. PMID- 29403609 TI - The comparison of spiritual health and self-esteem in women with and without sexual violence. AB - Background and aim: Sexual violence is a serious public health problem which is common around the world. The aim of this study was to evaluate spiritual health and self-esteem in sexual violence victims. Methods: This cross-sectional study was performed on 66 subjects in the group of sexual violence women and 147 subjects in the group of women with no experience of sexual violence who referred to Tehran Forensic Medical Center and the health centers of Shahid Beheshti University of Medical Sciences respectively, in 2015, in Tehran, Iran. Sexual violence was considered as vaginal or anal penetration. Paloutzian & Ellison spiritual health questionnaire and Rosenberg self-esteem scale were used for data collecting. Data were analyzed using IBM-SPSS version 21. The Kolmogorov Simonov test was used for normality distribution of variables. Descriptive and the Mann Whitney tests were used to analyze the data. Statistical significance was set to p<0.05. Results: Sexual activity in both groups was started at 20 years old. Most of the abused subjects were single (48.8%), with education level below diploma (55.2%), unemployed (67%) and with an average annual income of 200 million Rials ($7,000). Familiarity with the offender was mostly as friendship (42.4%), and the offence had occurred through deception (37.8%). No significant difference was found between the total mean scores of self-esteem in the two groups (M1: 21.89, M2: 21.02; p=0.76) while a significant difference was seen between the mean scores of spiritual health, which indicates a lower level of spiritual health in women with sexual violence (M1: 74.59 (2.03), M2: 86.39 (3.12); p<0.001). Conclusion: The results of the present study highlight the importance of spirituality in sexual violence so policies to promote spiritual health are recommended to protect women. PMID- 29403610 TI - Correlation between health literacy and health-related quality of life in patients with hypertension, in Tehran, Iran, 2015-2016. AB - Background and Objective: Hypertension is considered an important public health problem in developed and developing countries. This disease is closely associated with the quality of life of patients, and it seems that health literacy plays a role in this regard. Due to lack of information on the role of health literacy on the quality of life in patients with hypertension, this study has aimed to determine the correlation between health literacy and health-related quality of life in patients with hypertension. Methods: This study is cross-sectional. The sample consisted of 400 patients with hypertension who were enrolled if available. To collect data, a demographic questionnaire (SF-36), Short Form Health Survey, and Health Literacy for Iranian Adults (HELIA) Inventory were used. Data were analyzed using SPSS software version 21 for descriptive and inferential statistics (e.g., mean, standard deviation, t-test, and Pearson correlation coefficient). Results: The mean and standard deviation scores of health literacy and health-related quality of life were, respectively, 68.66 (+/ 13.56) and 52.94 (+/-15.20). There was positive and significant correlation between health literacy and health-related quality of life (p<0.01, r=0.30). Conclusion: According to research findings, there was a significant positive correlation between health literacy and health-related quality of life. Given the importance of health literacy in the quality of life in patients with hypertension, it seems essential that nursing officials and policymakers take steps to promote patients' health and quality of life by using training programs appropriate for the patients' health literacy level. PMID- 29403611 TI - Nurses' perspective on spiritual leadership: A qualitative study based on Fry's spiritual leadership model. AB - Background: Spiritual leadership and spirituality in organizations have the capacity to develop individual and organizational outcomes. This concept, as a newly established paradigm, has many ambiguities and definitions highly affected by cultural contexts. Objective: This study aimed at determining the concept of spiritual leadership from nurses' perspective and recognizing aspects of spiritual leadership model in the Iranian nurses' sociocultural context, to achieve a common and comprehensive understanding of the concept under study. Methods: This qualitative study used a directed content analysis method. The participants of this study were 14 managers and nurses employed at different wards of hospitals affiliated to medical universities of Tehran, and were selected using purposive sampling method on the basis of inclusion criteria. The data were collected via individual, deep, and semi-structured interviews from October 2015 to March 2016. Results: In this study, 14 participants were interviewed, 11 females and three males aged between 26 and 52 years old with a mean working experience of 13 years. After data analysis, 33 subcategories were distilled which fell into nine categories and three main categories including "spiritual leadership", "spiritual well-being", and "organizational consequences". The findings indicated that spiritual leadership can, through application of intrinsic motivation, help develop individual and organizational outcomes by the use of elements of extrinsic motivation in organizational learning. Conclusion: Nursing managers and nurses expunged upon various dimensions of spiritual leadership. The elements of extrinsic motivation and organizational learning have the potential to develop spiritual leadership. The nursing leaders can use this potential to foster the outcomes of nursing services. PMID- 29403612 TI - Evaluation of cardiac functions in children with Duchenne Muscular Dystrophy: A prospective case-control study. AB - Background: Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. The incidence of cardiomyopathy in DMD increases with age, so its early detection is important because institution of cardioprotective medical therapies may slow adverse remodeling and attenuate heart failure symptoms in these patients. Objective: To assess the cardiac functions in children clinically suspected to have DMD. Methods: Over a one-year period, 28 male children aged from 3 to 18 years old, who met the criteria for diagnosis of DMD compared to 47 healthy controls children, were approached to participate in the study. The included children were subjected to full clinical examination, and blood samples were collected to determine creatinine phosphokinase (CPK), troponin I enzyme, myoglobin and lactate dehydrogenase (LDH) enzyme level. Echocardiography and 12-leads electrocardiogram (ECG) were also done for children in both groups. Data were analyzed using Independent-samples t-test, Mann-Whitney U, Chi square, and Fisher's exact test. Results: The mean age of the cases group was 7.29+/-3.24 years versus 8.06+/-2.86 years for controls. In DMD group, 25% had positive family history of DMD while 35.7% of them had positive consanguinity. All cases had elevated CPK level while CPK level in controls was normal (p<0.0001). LDH level was elevated in 19 cases (67.86%) of DMD while all controls children had normal LDH level (p<0.0001). Furthermore, the mean serum myoglobin level of DMD patients was higher relative to that of healthy controls (39.39+/-7.25 versus 33.68 +/-12.38 ng/ml respectively) (p=0.01). Echocardiography of our patients revealed that seven cases (25%) had low ejection fraction (EF) and fraction shortening (FS). In addition, all controls children had normal EF (p<0.0001) and normal FS (p<0.0001). Interestingly, ECG showed that 28.57% of cases had sinus tachycardia vs. 6.88% for controls (p=0.0001). Prolonged QTc interval was present in 39.29% of cases (mean 431.39+/-43.60) while all controls had normal QTc duration for age (mean of 415.17+/-25.2) (p<0.0001). Conclusion: ECG manifestations in children with DMD in the form of sinus tachycardia and prolonged QTc interval are an early alarm for developing cardiomyopathy before overt echocardiographic findings appear. PMID- 29403614 TI - The prevalence of violence against women and some related factors in Sanandaj city (Iran) in 2015. AB - Background and aim: Violence against women is considered as one of the social problems of all countries in the world. The aim of this study was to determine the prevalence of violence against married women referring to health centers, and determining its related factors in Sanandaj, Iran, in 2015. Methods: This cross sectional study was conducted on 700 married women referred to health centers in Sanandaj, Iran in 2015. A researcher made questionnaire was used to collect data. To perform sampling, the city was divided into 5 regions and from each region, one health center was selected randomly. Data were analyzed by SPSS 18 and using descriptive statistics, independent-samples t-test, chi-square test and ANOVA. Significance level of .05 was considered. Results: The results of this study showed that all women in the study had been subjected to violence at least once. In 11.7% of cases, the violence was moderate and severe. A total of 9.6% had been subjected to physical violence, 42.2% to verbal and psychological violence, 52.4% to sexual violence and 53.4% to economic violence. It was a statistically significant correlation between violence and following variables; education (p=0.0001), occupation (p=0.0001), history of domestic violence in family (p=0.0001), and having a boy in the family (p=0.0001). There was no statistically significant relationship between the number of girls in the family and violence against women (p=0.19). Conclusion: Although Physical violence against women has decreased, other forms of violence including; verbal, sexual and economic were used against women. It seems that the problem of violence against women would not be solved without improving women's socio-economic status. PMID- 29403613 TI - Profile of peptic ulcer disease and its risk factors in Arar, Northern Saudi Arabia. AB - Background: Peptic ulcer disease is a multifactorial health problem, and its prevalence and risk factors have changed considerably within the past century. Objective: To determine the prevalence of peptic ulcer among the population of Arar city and to identify risk factors for peptic ulcer and to estimate their relative impact on ulcer incidence. Methods: A cross-sectional study was carried out on the population of Arar city, Northern Saudi Arabia from November 01, 2016 to April 30, 2017. Data were analyzed by SPSS version 16, using descriptive statistics, prevalence, and Chi-square test. Results: Total prevalence of peptic ulcer among the studied respondents was thus: 21.9% had peptic ulcer; 16.2% gastric ulcer and 5.6% duodenal ulcer. In 19.7% of the cases, the pain was severe, 92.4% reported that pain was precipitated by certain food. In addition to heartburn, 78.8% reported loss of appetite, 71.2% indigestion, 66.7% regurgitation, 59.1% nausea and vomiting and 42.4% with chest pain. Regarding the risk factors, coffee drinking came in first place (81.8%) followed by physical stress in 77.3%, spicy food in 57.6%, prolonged use of Non-steroidal anti inflammatory drugs (NSAIDs) in 33.3% and Helicobacter pylori (H. pylori) infection in 24.2%. A further 22.7% reported melena as a complication while only 10.6% reported hematemesis. Conclusion: This is the first population-based study in Arar, Northern Saudi Arabia reporting point prevalence of peptic ulcer disease. The rate of 16.2% for gastric ulcer and 5.6% for duodenal ulcers are substantially high. Coffee drinking, physical stress, spicy food, prolonged use of NSAID and H. pylori infection were the reported risk factors. Population-based endoscopic studies are recommended. PMID- 29403615 TI - Deep venous thrombosis in elderly patients as a surgical emergency at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. AB - Background: Deep venous thrombosis (DVT) is a condition that occurs frequently among surgical, as well as acutely ill hospitalized medical patients, and is responsible for significant morbidity and mortality in hospitalized patients. Risk factors include older age, surgery and immobilization (as with bed rest, orthopedic casts, and sitting on long flights. Objective: This study was conducted to identify the frequency and factors associated with occurrence of DVT among elderly patients referred to King Abdulaziz University (KAU) Hospital, Jeddah, Kingdom of Saudi Arabia. Methods: The current study is a hospital based cross sectional study. The emergency, inpatients and outpatients' departments at KAU hospital were reviewed. We studied all the referred elderly subjects during the study period. All elderly patients (540) referred to or admitted to the hospital departments and who were clinically suspected to have DVT and subjected to Doppler examination were included in the study. Data were analyzed using descriptive statistics and Chi square test. Results: Based on the results of Doppler examination, DVT was detected in 97 (18.0%) of the studied elderly population. There were no significant differences in gender between patients who developed DVT and those who were negative by Doppler examination (p=0.018). Other comorbidities as diabetes, IHD and hypertension were significantly associated with the occurrence of DVT among the participants (p=0.05, 0.05 and 0.04 respectively). Furthermore, the other investigated factors such as being bed ridden, cancer, orthopedic cast and previous DVT were not significantly associated with the development of DVT among the studied elderly patients (p=0.42, 0.16, 0.45 and 0.75 respectively). Conclusion: DVT has high prevalence in Jeddah; KSA. Thrombophilia screening should be regular for elderly patients with diabetes, hypertension and bed-ridden patients with recurrent DVT or patients with other risk factors. Knowing the most common risk factors and their significance in developing DVT is essential for early detection of DVT to prevent unwanted complications for elderlies. PMID- 29403616 TI - Asymptomatic bacteriuria in pregnant women attending Boo-Ali Hospital Tehran Iran: Urine analysis vs. urine culture. AB - Background: Asymptomatic bacteriuria is one of the common problems in pregnancy. Asymptomatic bacteriuria is associated with pyelonephritis, preterm labor and low birth weight infants. The physiological and anatomical changes in pregnancy facilitate urinary tract infection (UTI) during pregnancy. Several tests are available for diagnosis of asymptomatic bacteriuria. The urine culture is a gold standard diagnostic test for asymptomatic bacteriuria but it is expensive and time-consuming. Screening methods may be useful in detecting high-risk pregnant women for asymptomatic bacteriuria. Objective: The aim of the present study was to compare urine analysis as a rapid screening test to urine culture in diagnosis of asymptomatic bacteriuria. Methods: A total of 123 pregnant women attending the obstetrics clinic of Boo-Ali hospital in Tehran, Iran from March 2013 to September 2014 were included in the present diagnostic cross-sectional study. One hundred twenty three mid-stream urine samples were inoculated into cultures and were processed by dipstick (nitrite test and leucocyte esterase test) and microscopic pus cell count. The sensitivity, specificity, positive predictive value and negative predictive value of nitrite test, leucocyte esterase test and microscopic pus cell count were compared with urine culture in diagnosis of asymptomatic bacteriuria by using SPSS version 19. Results: Of 123 urine samples, significant asymptomatic bacteriuria (>=104 cfu/Ml) was detected in 8 (6.5%) subjects. The sensitivity and specificity of nitrite test were 37% and 100% respectively. The sensitivity of pus cell count alone and leucocyte esterase test alone were 100% but the specificity of them were 64% and 65% respectively. We found high negative predictive value by Pus cell count and the leucocyte esterase test (100%) and low positive predictive value by them (16% and 17% respectively). Conclusion: Urine culture is the most useful test for diagnosis of asymptomatic bacteriuria. None of our screening tests had a sensitivity and specificity of 100%, whereas we can only refer the pregnant women with positive leucocyte esterase test and significant pyuria to the urine culture. PMID- 29403617 TI - General health literacy assessment of Iranian women in Mashhad. AB - Background: In women's health, literacy determines their participation in self and family health promotion. Low health literacy is as barrier for understanding medical recommendations, disease prevention and health care. Aim: To assess women's health literacy and relative factors in Mashhad (Iran). Methods: Women referring to healthcare centers in Mashhad in 2012 and 2013, participated in this cross-sectional study by stratified sampling method. The validated Persian version of Rapid Estimate of Adult Literacy in Medicine-revised questionnaire was used. Vocabulary comprehension and reading scores of health literacy was assessed. Comparisons were done in demographic subgroups by ANOVA, Mann-Whitney U, Kruskal-Wallis, Pearson correlation coefficient, and Chi-Square tests. Results: In total, 250 women with a mean age of 32.1+/-10.23 years and the mean education level of 10.58+/-3.67 years were studied. The mean reading score was 11.58+/-2.51 and the mean vocabulary comprehension score was 17.24+/-4.73. Participants' health literacy score had positive correlation with age and education, and significant difference in health literacy scores between occupational groups was seen. Housewives' health literacy scores were lower than others (p<0.05). Conclusion: Low health literacy was a common problem amongst younger women, especially among women who had less education. These women are at risk of early marriage and child bearing and require more health care. Health care professionals should use effective methods for easier transfer recommendation, also, producing medical information booklets, texts, and videos for different community subgroups through public media or even in cyberspace with clear and common words consisting of essential information. PMID- 29403618 TI - The effects of combined sertraline and aspirin therapy on depression severity among patients with major depressive disorder: A randomized clinical trial. AB - Background: Different studies have been conducted to find the best adjuvant therapies for depression management. There are controversies over the effects of aspirin as an adjuvant therapy for depression. Objective: To determine the effects of combined sertraline and aspirin therapy on depression severity among patients with major depressive disorder. Methods: This randomized clinical trial was conducted at Kargarnejad Psychiatric Hospital in Kashan, Isfahan, Iran, from September 1, 2016 to November 1, 2016. The study participants included 100 patients with major depressive disorder who were assigned to aspirin and placebo groups by the use of computer-generated random numbers. Patients in these groups respectively received sertraline-aspirin and sertraline-placebo for eight consecutive weeks. Patients were prescribed 80 milligrams of aspirin twice a day. Also, sertraline was administered at a dose of 50-200 milligrams daily. Beck Depression Inventory was employed for depression severity assessment at four time points, namely before, two, four, and eight weeks after the beginning of the intervention. Medication side effects were also assessed eight weeks after the beginning of the intervention. Data were analyzed by SPSS version 12.0, using Chi square and the Independent-samples t-test (alpha=0.05). Results: Both groups were matched in terms of age (p=0.46), gender (p=0.539), and depression severity (p=0.509, with mean score 33.5+/-4.1 vs. 32.8+/-5.9) at baseline. However, depression scores were reduced significantly four and eight weeks after initiation of therapy just in the sertraline-aspirin group (p<0.05). Conclusion: As an adjuvant therapy, aspirin can reduce depression severity among patients with major depressive disorder. Yet, further studies are needed to prove the effectiveness of aspirin and other anti-inflammatory agents in reducing depression severity. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT2016082829556N1. Funding: The authors received financial support from Research Deputy of Kashan University of Medical Sciences, Kashan, Isfahan, Iran. PMID- 29403619 TI - National survey of availability of physical rehabilitation services in Iran: A mixed methods study. AB - Background: The prevalence of disability in Iran has increased due to ageing of the population and the presence of chronic diseases. However, little is known about the availability of rehabilitation services in Iran. Objective: To study the availability of physical rehabilitation services in Iran. Methods: This was a mixed method study. In the first phase, a qualitative design was conducted for designing an instrument with focus groups based on Service Availability and Readiness Assessment (SARA) instrument (developed by World Health Organization). Content analysis was used for data analysis. Then, in the second phase, a cross sectional study was performed to collect the data with census method in Iran. This study was formed from June to October 2015, and samples consisted of all governmental, public non-governmental and private facilities established for rehabilitation centers affiliated with the Ministry of Health and Medical Education, Ministry of Labor, Cooperative and Social Welfare and the Iranian Red Crescent Society. Data analyses were performed using SPSS software (version 16). Descriptive statistical analysis (percentage and frequency) were calculated for quantitative data. Results: In the first phase, the content analysis of qualitative data identified a Master Facilities List (MFL) of rehabilitation services and service providers in Iran. Results of the second phase showed that the rate of inpatient, outpatient, community-based and long-term care centers per 1,000,000 populations in Iran were 1.68, 89.24, 66.21 and 3.6, respectively. Also, that the rate of rehabilitation professionals including physical medicine and rehabilitation specialists, physiotherapists, occupational therapists, speech therapists, and audiologists were 3.90, 64.65, 22.09, 22.83 and 24.18 per 1,000,000 populations, respectively. Conclusion: There is a need to increase the availability of rehabilitation services and to promote rehabilitation referrals by using an interdisciplinary team approach. PMID- 29403620 TI - Psychometric properties of the Persian version of the Intensive and Critical Care Nursing Competence Scale version-1 (ICCN-CS-1). AB - Background: Nursing competence is highly related to patient outcomes and patient safety issues, especially in intensive care units. Competence assessment tools are needed specifically for intensive care nursing. Objective: This study was performed to determine psychometric properties of the Intensive and Critical Care Nursing Competence Scale version-1 between Iranian Nurses. Methods: The present study was a methodological research in which 289 nurses of Intensive Care Units from nine hospitals in Shahid Beheshti University of Medical Sciences in Tehran were selected between 2015 and 2016. The original version of the scale was translated into Persian and back-translated into English, and the comments of the developer were applied. The validity of the scale was the determined quality (content validity and face validity) and quantity (confirmatory factor analysis). Reliability of the scale was reported by Cronbach's alpha coefficient and Intra class Correlation Coefficient. SPSS-PC (v.21) and LISREL (v.8.5) were used to analyze the data. Results: The intensive and critical care nursing competence scale version-1 is a self-assessment test that consists of 144 items and four domains which are the knowledge base, the skill base, the attitudes and values base and the experience base, which are divided into clinical competence and professional competence. Content and face validity was confirmed by 10 experts and 10 practitioner nurses in the intensive care units. In confirmatory factor analysis, all fitness indexes, except goodness of fit index (0.64), confirmed the four-factor structure of the ICCN-CS-1. The results of the factor analysis, load factor between 0.304 and 0.727 items was estimated; only 4 items out of 144 items, that were loaded were less than 0.3 due to high Cronbach's alpha coefficient (0.984-0.986), all items were preserved, no item was removed and 4 subscales of the original scale were confirmed. Conclusion: The results of this study indicated that the Persian version of "The Intensive and Critical Care Nursing Competence Scale version-1" is a valid and reliable scale for the assessment of competency among Iranian nurses, and it can be used as a reliable scale in nursing management, education and research. PMID- 29403621 TI - The prevalence of cardiovascular diseases risk factors associated with psoriasis in Saudi Arabia. AB - Background: Extensive studies have revealed an increased risk of major adverse cardiac outcomes in patients with severe psoriasis. However, some studies show conflicting results. Objective: This study was conducted to assess the CV risk factors in psoriasis patients, and compare it with non-psoriatic patients. In addition, we evaluated if psoriasis is an independent CV risk factor, if its severity can predict CV risk, and if systemic psoriasis treatments modify CV risk. Methods: This was a case-control study in 200 participants -100 with psoriasis, and 100 with dermatitis who served as the control. The study was carried out from September 2015 to September 2016. Data was collected using self administered questionnaires, one each for both groups. Questions include body surface area, current psoriasis/dermatitis therapies, presence of diabetes mellitus, hypertension, smoking history, weight, height, body mass index (BMI), elevated cholesterol, Coronary Artery Disease (CAD) history. Results: Analyses of the associations between psoriasis and CV symptoms has demonstrated that psoriasis was associated with CAD (p<0.001) and hospitalizations (p<0.001) due to CAD. We found that the psoriasis group have the following association: Angina (p=0.005), hypertension (p=0.001), diabetes mellitus (p=0.016), hypercholesterolemia (p=0.015), and "CAD succeeding psoriasis (p=0.001)" (it assesses how many patients with psoriasis had CAD after they are diagnosed with psoriasis). Our study showed that there was no statistically significant risk of CVD in dermatitis patients (p=0.16). There was no association between severity of psoriasis and CV risk (p=0.07). Conclusions: There is a higher CV risk prevalence among Saudi psoriatic patients and this confirms that psoriasis is an independent CV risk factor in this population. PMID- 29403622 TI - Identifying self-care behaviors in middle-aged women: A qualitative study. AB - Background: Women in their middle-age enjoy abilities that affect their health promotion and improvement. Throughout their entire lifetime, women strive to maintain and improve their health through benefiting from behaviors that come from experience. Objective: This study was carried out with the aim of identifying self-care behaviors that middle-aged women consider as far as maintaining and promoting their health are concerned. Methods: The study was conducted using a qualitative approach in conventional content analysis. Participants comprised of 20 middle-aged women from Zahedan, Iran in 2016 that were invited to enter the study using purposive sampling, and were given semi structured interviews. After data collection, all interviews were transcribed, reviewed and then the subcategories were extracted. Results: The findings of this study include a main category "preventive self-care behaviors" and three subcategories of "understanding health and disease", "health knowledge" and "awareness of the health threats". Conclusion: The findings suggest that preventive self-care behaviors of women are associated with features such as understanding health and disease, health knowledge and awareness of the associated health risks. As a matter of fact, preventive behaviors encompass strategies that women apply to improve their physical and mental health. PMID- 29403623 TI - Explaining the role of organizational culture on succession-planning at the Ministry of Health and Medical Education: A qualitative study. AB - Background: Developing and guiding new knowledge are futile unless the organizational culture can also be transformed. Future leaders cannot emerge out of an organizational environment that is not conducive to the accumulation of experiences. Objective: The aim of this study was to explore the role of organizational culture in creating a succession-planning system at the Ministry of Health and Medical Education in 2014. Methods: The present qualitative framework analysis held interviews with 23 director generals, administrative directors and deputies from the headquarters of the Iranian Ministry of Health and Medical Education in 2014 who were selected through snowball sampling. The data obtained were analyzed in MAXQDA-10. Codes were extracted using inductive techniques. Results: The cultural factors affecting succession-planning at the Ministry of Health and Medical Education were identified and classified under three main areas, including the cultural factors related to the directors with four themes (Directors' job security, Constructive competition, Transparency and trust development, Creating opportunities), to the personnel with four themes (Organizational identity and loyalty, Trust in the organization, Talent and merit, Peer envy) and to the system with two themes (Values and beliefs, Politicization). Conclusion: Findings of the study show that establishment and institutionalization of the succession planning to the Ministry of Health and Medical Education is deeply affected by the components of organizational culture. Accordingly, unprofessional organization culture can deprive the organization of numerous advantages in multiple-succession planning. PMID- 29403624 TI - The effect of xerostomia and hyposalivation on the quality of life of patients with type II diabetes mellitus. AB - Background: Diabetes mellitus is a chronic metabolic disease which can have numerous physical effects for patient. Xerostomia is one of these complications. Compared to healthy people, patients with diabetes mellitus, have a worse quality of life, and complications of diabetes are the main determinants of quality of life in these patients. Objective: The aim of this study was to determine the effects of xerostomia and hyposalivation on quality of life of patients with type 2 diabetes mellitus. Methods: This descriptive-analytical epidemiological study was conducted on 200 patients with type 2 diabetes mellitus referred to the diabetes clinic of Shahid Mostafavi in Sari city from October 2015 to January in 2016. A questionnaire containing personal characteristics and medical situation was completed by each person. Then, the Persian Oral Health Impact Profile-14 (OHIP-14-PER) questionnaire was completed by the patients. Eventually, with the use of chewable paraffin for 1.5 min by the patient, stimulated salivary flow rate (SSFR) test was performed, and in order to determine hyposalivation, their saliva amount underwent a gravimetric test. Finally, using statistical software SPSS16, the information was statistically analyzed by independent-samples t-test, Mann-Whitney U, Chi-squared and fisher exact tests. Results: The average age of patient was 56.41 years old (43% male and 57% female). Mean SSFR was 0.7 ml/min in patients and xerostomia were confirmed in 112 patients. Difference between age, gender, drug use, years affecting to diabetes and FBS amount in patient with hyposalivation were not statistically meaningful in proportion to patients without it. But difference between HbA1C and SSFR in patients with hyposalivation were statistically meaningful than to patients without it (p=0.03, p=0.001 respectively). The mean patient score to OHIP-14 were obtained as 38.17. The questionnaire score difference in patients with hyposalivation in proportion to patients without it were not statistically meaningful. Conclusion: Hyposalivation possibility increases in diabetic patients with low metabolic control which can cause more severe side effects in relation to oral health. Xerostomia in diabetic patients has negative effects on oral health related quality of life. Diabetic control and patients' oral problem improvement is effective in their quality of life promotion. PMID- 29403625 TI - Association between severity of depression and clinico-biochemical markers of polycystic ovary syndrome. AB - Background: Polycystic ovary syndrome (PCOS), as the most common endocrine disorder among reproductive-aged women may lead to psychological morbidity. Objectives: The present study set out to evaluate the severity of depression in PCOS and non-PCOS women and to evaluate correlation between depression score with body mass index, HOMA-IR, and testosterone level in every group (PCOS and non PCOS women) in Yazd province. Methods: In this cross-sectional study, 62 women with PCOS and 61 non- PCOS subjects (20 to 40 years) who were attending Imam-Ali Clinic in Yazd, Iran from September 2014 through March 2015 participated. These persons completed the Beck Depression Short Inventory (BDI-S) Questionnaire. Frequency of depression in PCOD and healthy persons and correlation between depression severity with body mass index, HOMA-IR, testosterone level in PCOS and non- PCOS women were evaluated by ANOVA test and independent-samples t-test and Pearson correlation. P-value of less than 0.05 was considered as statistically significant. Data analyses were performed using SPSS version 16. Results: Of 62 PCOS subjects, 40 (64.5%) were verified positive for depression, determined by the BDI-S Questionnaire. In the control group, 60.7% had depression. Mean+/-SE score of depression for PCOS and non-PCOS women were 7.47+/-5.54 and 7.57+/-5.77 respectively. There was no statistically significant correlation between body mass index, HOMA-IR, testosterone level with depression score in either group separately or together. Conclusions: We found considerable amounts of depression in our population. There is no correlation between body mass index, HOMA-IR, and testosterone level with depression score in our study. PMID- 29403626 TI - A review of effective herbal medicines in controlling menopausal symptoms. AB - Background: Acute menopausal syndrome especially hot flashes, is one of the most common gynecological problems during menopause. Due to the side effects of hormone therapy, herbal and complementary medicines are always of immense interest to people in the treatment and management of the symptoms and complications of menopause. Objective: The aim of this study was to investigate the mechanisms and effects of medicinal plants employed in the treatment of menopausal symptoms. Methods: This review article was carried out by examining clinical trial studies between the period of 1994 and 2016. The keywords, which include menopause, climacteric, hot flushes, flashes, herb and phytoestrogens were used to search for herbal medicines used in clinical trials for the treatment of menopausal symptoms using databases such as PubMed, Medline, Scopus, Google scholar, SID and Magiran. Results: The results of the study showed that the medicinal plants, which include Sage herb (Salvia officinalis), Lemon balm (Melissa officinalis), Valerina officinalis, Black cohosh (Cimicifuga racemosa), Fenugreek (Trigonella foenum-graecum), Black cumin (Nigella sativa), Vitex (Vitex agnus-castus), Fennel (Foeniculum vulgare), Evening primrose (Oenothera biennis), Ginkgo biloba, Alfalfa (Medicago sativa), Hypericum perforatum, Panax ginseng, Pimpinella anisum, Licorice (Glycyrrhiza glabra), Passiflora incarnata, Red clover (Trifolium pratense), and Glycine soja were effective in the treatment of acute menopausal syndrome with different mechanisms. Conclusion: Medicinal plants can play an imperative role in the treatment of acute menopausal syndrome; however, further studies are required to buttress their efficacy in the treatment of acute menopausal syndrome. PMID- 29403627 TI - Related factors of violence against women with infertility: A systematic review study based on an ecological approach. AB - Background and aim: Infertility as a global problem, affects the different aspects of women's health. Also, violence against infertile women affects their psychological wellbeing and treatment consequence. This study aimed at reviewing related factors to violence against infertile women, based on an ecological approach. Methods: In this systematic review, the researchers conducted their search in electronic databases such as Google Scholar, and then in more specialized ones such as Medline via PubMed, Science Direct, Up-to-date, Springer, SID, Magiran, Iranmedex and Irandoc with the key words violence, infertility, women, risk factors, social environment, and individuality, from 1988 to 2016. The selection of papers was undertaken from 20-27 January 2017. The articles were selected based on the following criteria: 1), the articles focused on the research question 2), infertility and violence were included in the title of the articles, and 3) articles were published in online journals. Exclusion criteria were articles which focused on violence against the general population, pregnant women and female sex workers and articles that were not available in full text form or written in other languages (Not Persian or English). The quality of selected studies was appraised using a 16-item checklist adapted from Tao. This checklist consisted of 16 items which used a 0 or 1 scoring system (not eligible or eligible). If an article received a score of 75% (12-16 points), it was of high quality. A score of 50% to 74% (8-12 points) indicated moderate quality, and less than 50% (8 points) indicated low quality. The process of titles, abstracts and full-texts' appraisal led to the selection of 16 articles, which were used to write this article. Results: Two of the articles based on 16 items of the check list had high quality score, 8 of them had moderate and the remaining articles had low quality score. Our findings were classified under three categories corresponding with the ecological approach: (1) Microsystem level "individual sociodemographic and infertility characteristics", (2) Mesosystem level "interpersonal' and husband sociodemographic characteristics" and (3) Macro system level considered ethnicity and cultural factors. Conclusion: Violence against infertile women and the stress caused by it, would affect the consequences of infertility treatment. It is noted that various cultural contextual factors cause violence in different societies. There is a need for the development of screening tools and applying counselors to identify infertile women at the risk of violence, and provide clinical services, counseling and social support. PMID- 29403628 TI - Epidemiology of work-related injuries among insured construction workers in Iran. AB - Background and aim: Work-related injuries are among the most important health problems in developing countries, such as Iran. The purpose of this study was to determine the epidemiology of work-related injuries among construction workers who had been insured by the Iranian Social Security Organization (ISSO). Methods: This is a cross-sectional study. The population included all construction workers who had a work- related accident during 2012 in Iran, which were recorded in the ISSO database after inspection. The effects of independent variables on injuries were estimated by logistic regression. SPSS software version 18 was used for analyzing the data. Results: Overall, 5352 work-related injuries were investigated. The incidence rate of fatal and nonfatal injuries was 0.07 in 1000 and 11.18 in 1000 workers, respectively. More than half of these accidents were due to careless activities. A younger age at the time of the accident (OR=0.98, CI: 0.97-0.99, p=0.001), being married (OR=1.37, CI: 1.04-1.79, p=0.02), place of accident (OR=1.86, CI: 1.18-2.92, p=0.007), lack of information (OR=5.28, CI: 1.57-17.75, p=0.007), disrespect of safety regulations (OR=3.11, CI: 1.87-5.17, p=0.001), non-use of protective equipment (OR=2.98, CI: 1.62-5.50, p=0.001), and defective equipment (OR=2.22, CI: 1.18-4.20, p=0.01) had a significant effect on the incidence of work-related injury. Conclusions: The pattern of work-related injury in Iran was almost similar in regard to age, gender, cause and type of the accident, with other parts of the world. PMID- 29403629 TI - The comparison of frequency of the upper limb musculoskeletal disorders among patients with diabetes type II with normal cases. AB - Background and aim: Musculoskeletal disease, that is recognized in diabetes and diabetes mellitus (DM) has shown a higher prevalence of chronic musculoskeletal complications. This study aimed at assessing the frequency of upper limb musculoskeletal disorders among patients with diabetes type II with normal cases in Mashhad, Iran. Methods: A cross-section of 100 patients with upper limb musculoskeletal disorders were enrolled in this study. The patients were examined by a unique physician considering carpal tunnel syndrome disorder, trigger finger, adhesive capsulitis, and Dupuytren's contracture at Ghaem hospital, Mashhad, Iran in 2015. All collected data were recorded by using SPSS version 21 and were analyzed through independent-samples t-test for comparing changes, and Chi-square. Results: In this study, the mean age was 51.7+/-8.7 years old. Gender frequency was 114 (57%) male, and 86 (43%) female. There was no significant difference between groups in cases of gender frequency and mean of age (p>0.05). In evaluation of association between the two groups, there was significant difference for adhesive capsulitis, (p=0.04). Chi-square test showed significant association for age and adhesive capsulitis between the two groups, (p=0.040); but no other diabetes-related disorders, (p<0.05). Conclusion: The results of this study showed that in patients with diabetes mellitus and musculoskeletal complications such as upper limb musculoskeletal abnormalities, it will lead to an increase in skeletal muscle effects in DM patients. It is recommended that musculoskeletal examination is done periodically in DM patients for identification of these disorders and necessary actions are carried out for prevention of the disorders as soon as possible. PMID- 29403630 TI - An overview of skin lesions adapted to Cutaneous Leishmaniasis in Persian Medicine. AB - Background: Cutaneous Leishmaniasis (CL) which is prevalent in all continents and is classified by the WHO as one of the neglected tropical diseases, existed in the past also, and discovered ancient works confirm this issue. The lack of adaptation of diseases between Persian Medicine (PM) and Modern medicine, led to no usage of effective therapeutic experiences of prior physicians. Objective: The purpose of this study is finding skin lesions adapted to CL in PM for usage of same disease treatment in the next clinical trials, and the use of approved therapies in CL. Methods: In a narrative review, without time limitation, documentary study was conducted for different names and clinical aspects of CL in printed and electronic resources of modern medicine such as: Rook's Textbook of Dermatology, Harper's Textbook of Pediatric Dermatology, PubMed, and Embase. Then, found names were searched in printed and electronic resources of PM such as: Al-Qanun fi al-tibb, Al-Tasrif leman ajeza an-e-Taliff, JamiTib 1.5 published by Noorsoft.org. Then, skin lesions which were similar to CL with these aspects were searched: clinical manifestation and forms, chronicity, curability, mosquito bite, were studied in references of PM. Finally, matching, syllogism and logical inference were performed and conclusion was made. Results: Forty-five names for CL were found in the searched resources. However, only Balkhieh, Kheyroonieh and Baghdadi button were names found in PM resources. Also, from 61 studied skin lesions in PM resources, only 6 cases had similarities to CL. Conclusion: In spite of the existence of CL's similarity with Balkhieh, Kheyroonieh and the Baghdadi button, there are serious differentiations. Zat-ol-asl rashes and reddish solb rashes, kinds of stranger rashes, probably adapted with CL. PMID- 29403631 TI - Self-care behavior of type 2 diabetes mellitus patients in Bandar Abbas in 2015. AB - Background: Diabetes self-care helps to control the blood sugar which, in turn, results in a better state of health. However, more than 50% of diabetic patients do not have self-care capabilities. Objective: To determine type 2 diabetes self care capabilities among patients visiting a Bandar Abbas diabetes clinic in 2016. Methods: The present descriptive-analytical research was of a cross-sectional type. The sample was comprised of 120 patients afflicted with type 2 diabetes, who had been selected through the simple randomized sampling method. The data collection instrument was a questionnaire comprised of two sections: demographic information, and a summary of patients' diabetes self-care activities. A 7-point Likert scale was used for the rating. The final score would be interpreted as any of the three levels: good (acceptable) (75-100), moderate (50-74) and poor (below 50). The data entered SPSS version 18.0 for the required statistical analyses. Results: The mean age of the sample was 51.88+/-10.12 years. Of the 120 subjects, 86 were female (71.7%) and 34 were male (28.3%). The findings revealed that the self-care capability of 83 subjects (69.2%) was poor; capability of 28 subjects was moderate (23.3%) and the same score of good/acceptable in 9 subjects (7.5%). Conclusion: The results of the present research indicate that a large number of diabetic patients have a poor self-care capability. Due to the key role of such activities in a diabetic patient's life, it is suggested to include educational programs to increase the level of self-care capabilities among these patients. PMID- 29403632 TI - Et3B-mediated two- and three-component coupling reactions via radical decarbonylation of alpha-alkoxyacyl tellurides: single-step construction of densely oxygenated carboskeletons. AB - The single-step construction of various densely oxygenated carboskeletons was achieved by radical-based two- and three-component coupling reactions of sugar derivatives, without the need for light or heat. Et3B/O2-mediated decarbonylation readily converted alpha-alkoxyacyl tellurides to alpha-alkoxy carbon radicals, which intermolecularly added to glyoxylic oxime ether or enones to provide the two-component adducts. Furthermore, the three-component adducts were produced by an intermolecular aldol reaction between the aldehyde and the boron enolates generated by capture of the two-component radical intermediates by Et3B. This powerful coupling method serves as a novel strategy for the convergent synthesis of polyol natural products. PMID- 29403633 TI - Electrode initiated proton-coupled electron transfer to promote degradation of a nickel(ii) coordination complex. AB - A Ni(ii) bisphosphine dithiolate compound degrades into an electrode-adsorbed film that can evolve hydrogen under reducing and protic conditions. An electrochemical study suggests that the degradation mechanism involves an initial concerted proton-electron transfer. The potential susceptibility of Ni-S bonds in molecular hydrogen evolution catalysts to degradation via C-S bond cleavage is discussed. PMID- 29403634 TI - gamma-Al2O3 supported Pd@CeO2 core@shell nanospheres: salting-out assisted growth and self-assembly, and their catalytic performance in CO oxidation. AB - In this paper, we have successfully demonstrated the clean synthesis of high quality Pd@CeO2 core@shell nanospheres with tunable Pd core sizes in water, and furthermore loaded the as-obtained Pd@CeO2 products on commercial gamma-Al2O3via electrostatic interaction. KBr here plays two key roles in inducing the growth and self-assembly of Pd@CeO2 core@shell nanospheres. First, Br- ions can retard the reduction of Pd2+ ions via the formation of the more stable complex of [PdBr4]2- so as to tune the size of Pd cores. Second, it greatly decreases the colloidal stability, and hence the surface polarity-weakened Pd and CeO2 NPs have to spontaneously self-assemble into more stable and ordered structures. Among different-sized Pd samples, the as-obtained 8 nm-Pd@CeO2/Al2O3 one exhibits the best performance in catalytic CO oxidation, which can catalyze 100% CO conversion into CO2 at 95 degrees C, which is much lower than the previously reported CeO2 encapsulated Pd samples. PMID- 29403635 TI - Site-specific bioalkylation of rapamycin by the RapM 16-O-methyltransferase. AB - The methylation of natural products by S-adenosyl methionine (AdoMet, also known as SAM)-dependent methyltransferase enzymes is a common tailoring step in many biosynthetic pathways. The introduction of methyl substituents can affect the biological and physicochemical properties of the secondary metabolites produced. Recently it has become apparent that some AdoMet-dependent methyltransferases exhibit promiscuity and will accept AdoMet analogues enabling the transfer of alternative alkyl groups. In this study we have characterised a methyltransferase, RapM, which is involved in the biosynthesis of the potent immunosuppressive agent rapamycin. We have shown that recombinant RapM regioselectively methylates the C16 hydroxyl group of desmethyl rapamycin precursors in vitro and is promiscuous in accepting alternative co-factors in addition to AdoMet. A coupled enzyme system was developed, including a mutant human enzyme methionine adenosyl transferase (MAT), along with RapM, which was used to prepare alkylated rapamycin derivatives (rapalogs) with alternative ethyl and allyl ether groups, derived from simple S-ethyl or S-allyl methionine analogues. There are two other methyltransferases RapI and RapQ which provide methyl substituents of rapamycin. Consequently, using the enzymatic approach described here, it should be possible to generate a diverse array of alkylated rapalogs, with altered properties, that would be difficult to obtain by traditional synthetic approaches. PMID- 29403636 TI - Side-on coordination of boryl and borylene complexes to cationic coinage metal fragments. AB - The M-(eta2-BMn) complex [(eta5-C5H5)(OC)2Mn{MU-B(Cl)(tBu)Au(PPh3)}] (2) can be functionalized via halide substitution reactions to afford isostructural complexes [(eta5-C5H5)(OC)2Mn{MU-B(R)(tBu)Au(PPh3)}] (R = Ph, CCPh and NCS). It also reacts with coinage metal complexes [MCl(PPh3)] (M = Au, Ag and Cu) in the presence of halide abstraction reagents to afford borylene-bridged heteromultinuclear complexes [{(eta5-C5H5)(OC)2Mn}2{MU2-B(tBu)}2M][BArx4] (M = Au, Ag and Cu; Arx = 3,5-C6H3Cl2, 3,5-C6H3(CF3)2). Experimental characterization as well as computational studies revealed that these complexes are best viewed as transition metal borylene complexes side-on coordinated to monovalent coinage metal cations, thus representing the first boron analogs of Stone's alkylidyne bridged multinuclear complexes. PMID- 29403637 TI - Total synthesis and biochemical characterization of mirror image barnase. AB - In this study we synthesized and characterized mirror image barnase (B. amyloliquefaciens ribonuclease). d-Barnase was identical to l-barnase, when analyzed by liquid chromatography and mass-spectrometry. Proteolysis of the mirror image enzyme revealed that in contrast to its native counterpart, d barnase was completely stable to digestive proteases. In enzymatic assays, d barnase had the reciprocal chiral specificity and was fully active towards mirror image substrates. Interestingly, d-barnase also hydrolyzed the substrate of the native chirality, albeit 4000 times less efficiently. This effect was further confirmed by digesting a native 112-mer RNA with the enzyme. Additional studies revealed that barnase accommodates a range of substrates with various chiralities, but the prime requirement for guanosine remains. These studies point toward using mirror image enzymes as modern agents in biotechnology. PMID- 29403638 TI - Ru(ii)-Re(i) binuclear photocatalysts connected by -CH2XCH2- (X = O, S, CH2) for CO2 reduction. AB - We developed Ru(ii)-Re(i) supramolecular photocatalysts in which each metal complex unit is connected by a -CH2XCH2- (X = O, S, CH2) chain. The photocatalyst with X = O exhibited the best photocatalytic efficiency for CO2 reduction in the reported systems using a NAD(P)H model compound as an electron donor because the introduced oxygen atom strengthened the oxidation power of the Ru photosensitizer unit in the excited state and accelerated electron transfer from the one-electron reduced Ru photosensitizer unit to the Re catalyst unit. In contrast, the catalytic ability of the photocatalyst with X = S rapidly decreased during irradiation because the supramolecular structure split into mononuclear complexes. A detailed mechanism for the efficient photocatalytic reaction involving these supramolecular photocatalysts was investigated for the first time. PMID- 29403639 TI - Theoretical studies on the photophysical properties of luminescent pincer gold(iii) arylacetylide complexes: the role of pi-conjugation at the C deprotonated [C^N^C] ligand. AB - We have performed theoretical analyses of the photophysical properties of a series of cyclometalated gold(iii) arylacetylide complexes, [(C^N^C)AuIIIC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 CPh-4-OMe], with different extents of pi-conjugation at the doubly C-deprotonated [C^N^C] ligand via replacement of one of the phenyl moieties in the non-conjugated CH^N^C ligand (1) by a naphthalenyl (2) or a fluorenyl moiety (3-exo and 3-endo; HCH^N^CH = 2,6-diphenylpyridine). Conforming to the conventional wisdom that extended pi-conjugation imposes rigidity on the structure of the 3IL(pipi*(C^N^C)) excited state (IL = intraligand), the calculated Huang-Rhys factors for the 3IL -> S0 transition follow the order: 1 > 2 > 3-exo ~ 3-endo, which corroborates qualitatively the experimental non-radiative decay rate constants, knr: 1 ? 2 > 3-exo, but not 3-endo. Density Functional Theory (DFT) calculations revealed that there is an additional triplet excited state minimum of 3LLCT character (LLCT = ligand-to-ligand charge transfer; 3[pi(C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 CPh-4-OMe) > pi*(C^N^C)]) for complexes 1 and 3-endo. This 3LLCT excited state, possessing a large out-of-plane torsional motion between the planes of the C^N^C and arylacetylide ligands, has a double minimum anharmonic potential energy surface along this torsional coordinate which leads to enhanced Franck-Condon overlap between the 3LLCT excited state and the ground state. Together with the larger spin-orbit coupling (SOC) and solvent reorganization energy for the 3LLCT -> S0 transition compared with those for the 3IL -> S0 transition, the calculated knr values for the 3LLCT -> S0 transition are more than 690- and 1500-fold greater than the corresponding 3IL -> S0 transition for complexes 1 and 3-endo respectively. Importantly, when this 3LLCT -> S0 decay channel is taken into consideration, the non-radiative decay rate constant knr could be reproduced quantitatively and in the order of: 1 ? 3-endo, 2 > 3-exo. This challenges the common view that the facile non-radiative decay rate of transition metal complexes is due to the presence of a low-lying metal-centred 3dd or 3LMCT excited state (LMCT = ligand-to-metal charge transfer). By analysis of the relative order of MOs of the chromophoric [C^N^C] cyclometalated and arylacetylide ligands, one may discern why complexes 1 and 3-endo have a low lying 3LLCT excited state while 3-exo does not. PMID- 29403640 TI - Using IR vibrations to quantitatively describe and predict site-selectivity in multivariate Rh-catalyzed C-H functionalization. AB - Achieving selective C-H functionalization is a significant challenge that requires discrimination between many similar C-H bonds. Yet, reaction systems employing Rh2(DOSP)4 and Rh2(BPCP)4 were recently demonstrated to afford high levels of selectivity in the C-H insertion of carbenes into toluene-derived substrates. Herein, we explore the origin of this selectivity through a systematic analysis of substrate and reagent features that alter levels of selectivity from 20 : 1 to 1 : 610 for secondary (or tertiary)-to-primary benzylic C-H functionalization of toluene derivatives. Describing this variation using infrared vibrations and point charges, we have developed a mathematical model from which are identified features of the systems that determine levels of site-selectivity and are applied as predictive factors to describe the selectivity behavior of new substrate/reagent combinations. PMID- 29403641 TI - Nanoarmoring: strategies for preparation of multi-catalytic enzyme polymer conjugates and enhancement of high temperature biocatalysis. AB - We report a general and modular approach for the synthesis of multi enzyme polymer conjugates (MECs) consisting of five different enzymes of diverse isoelectric points and distinct catalytic properties conjugated within a single universal polymer scaffold. The five model enzymes chosen include glucose oxidase (GOx), acid phosphatase (AP), lactate dehydrogenase (LDH), horseradish peroxidase (HRP) and lipase (Lip). Poly(acrylic acid) (PAA) is used as the model synthetic polymer scaffold that will covalently conjugate and stabilize multiple enzymes concurrently. Parallel and sequential synthetic protocols are used to synthesise MECs, 5-P and 5-S, respectively. Also, five different single enzyme-PAA conjugates (SECs) including GOx-PAA, AP-PAA, LDH-PAA, HRP-PAA and Lip-PAA are synthesized. The composition, structure and morphology of MECs and SECs are confirmed by agarose gel electrophoresis, dynamic light scattering, circular dichroism spectroscopy and transmission electron microscopy. The bioreactor comprising MEC functions as a single biocatalyst can carry out at least five different or orthogonal catalytic reactions by virtue of the five stabilized enzymes, which has never been achieved to-date. Using activity assays relevant for each of the enzymes, for example AP, the specific activity of AP at room temperature and 7.4 pH in PB is determined and set at 100%. Interestingly, MECs 5 P and 5-S show specific activities of 1800% and 600%, respectively, compared to 100% specific activity of AP at room temperature (RT). The catalytic efficiencies of 5-P and 5-S are 1.55 * 10-3 and 1.68 * 10-3, respectively, compared to 9.11 * 10-5 for AP under similar RT conditions. Similarly, AP relevant catalytic activities of 5-P and 5-S at 65 degrees C show 100 and 300%, respectively, relative to native AP activity at RT as the native AP is catalytically inactive at 65 degrees C The catalytic activity trends suggest: (1) MECs show enhanced catalytic activities compared to native enzymes under similar assay conditions and (2) 5-S is better suited for high temperature biocatalysis, while both 5-S and 5-P are suitable for room temperature biocatalysis. Initial cytotoxicity results show that these MECs are non-lethal to human cells including human embryonic kidney [HEK] cells when treated with doses of 0.01 mg mL-1 for 72 h. This cytotoxicity data is relevant for future biological applications. PMID- 29403642 TI - Characterisation of the French ferret population, husbandry, reported medical care and feeding habits. AB - Ferrets have become a common companion animal. But no data are available on the French population of ferrets. The goal of the survey was to characterise this population, including demographic characteristics, husbandry, reported medical care and feeding habits. Complete data were available for 1205 pet ferrets in 709 households. Most ferrets (86.1 %) lived indoors, 1 % received only artificial lighting, and 47 % chewed their cage. For 60 % of the ferrets, body weight was higher in winter and lower in summer. Neutered ferrets (58.5 % of males and 62.9 % of females) appeared lighter than intact ferrets of comparable age. A majority (52.4 %) of ferrets received a mix of commercial foods and fresh foods, but 28.6 % were offered no commercial foods. Data were analysed using several multivariable logistic regression models including age, sex, castration, food type and artificial lighting developed for four clinical outcome (lethargy and/or insulinoma, dental problems, diarrhoea and/or bird-seed stools and alopecia). Predictors of four clinical outcomes (lethargy, dental disease, diarrhoea and alopecia) were examined using multivariable logistic regression, with age, sex, neuter status, food type and artificial lighting as the exposure variables. Aged ferrets were more likely to have lethargy, insulinoma, dental problems and alopecia. Ferrets with artificial lighting were more likely to show alopecia. Additionally, ferrets fed commercial food only or a mixed diet (both commercial food and fresh food) were more likely to have lethargy, insulinoma, dental problems, diarrhoea and/or bird-seed stools compared with ferrets fed fresh food only. We also found a significant association between neutering and alopecia. It is to our knowledge the first description of the French population of the ferret as a companion animal. PMID- 29403644 TI - Optically Reconfigurable Chiral Microspheres of Self-Organized Helical Superstructures with Handedness Inversion. AB - Optically reconfigurable monodisperse chiral microspheres of self-organized helical superstructures with dynamic chirality were fabricated via a capillary based microfluidic technique. Light-driven handedness-invertible transformations between different configurations of microspheres were vividly observed and optically tunable RGB photonic cross-communications among the microspheres were demonstrated. PMID- 29403643 TI - Down syndrome and microRNAs. AB - In recent years numerous studies have indicated the importance of microRNAs (miRNA/miRs) in human pathology. Down syndrome (DS) is the most prevalent survivable chromosomal disorder and is attributed to trisomy 21 and the subsequent alteration of the dosage of genes located on this chromosome. A number of miRNAs are overexpressed in down syndrome, including miR-155, miR-802, miR- 125b-2, let-7c and miR-99a. This overexpression may contribute to the neuropathology, congenital heart defects, leukemia and low rate of solid tumor development observed in patients with DS. MiRNAs located on other chromosomes and with associated target genes on or off chromosome 21 may also be involved in the DS phenotype. In the present review, an overview of miRNAs and the haploinsufficiency and protein translation of specific miRNA targets in DS are discussed. This aimed to aid understanding of the pathogenesis of DS, and may contribute to the development of novel strategies for the prevention and treatment of the pathologies of DS. PMID- 29403645 TI - Impact of prenatal stress on mother-infant dyadic behavior during the still-face paradigm. AB - Background: Mother-infant interaction provides important training for the infant's ability to cope with stress and the development of resilience. Prenatal stress (PS) and its impact on the offspring's development have long been a focus of stress research, with studies highlighting both harmful and beneficial effects. The aim of the current study was to examine the possible influence of both psychological stress and hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy with mother-child dyadic behavior following stress exposure. Methods: The behavior of 164 mother-infant dyads during the still-face situation was filmed at six months postpartum and coded into three dyadic patterns: 1) both positive, 2) infant protesting-mother positive, and 3) infant protesting-mother negative. PS exposure was assessed prenatally according to psychological measures (i.e., psychopathological, perceived and psychosocial PS; n = 164) and HPA axis activity measures (maternal salivary cortisol, i.e., cortisol decline and area under the curve with respect to ground (AUCg); n = 134). Results: Mother-infant dyads in both the high- and low-stress groups showed decreasing positive and increasing negative dyadic behavior in the reunion episode, which is associated with the well-known "still-face" and "carry-over" effect. Furthermore, mother infant dyads with higher psychosocial PS exhibited significantly more positive dyadic behavior than the low psychosocial PS group in the first play episode, but not in the reunion episode. Similarly, mother-infant dyads with high HPA axis activity (i.e. high AUCg) but steeper diurnal cortisol decline (i.e. cortisol decline) displayed significantly less negative behavior in the reunion episode than dyads with low HPA axis activity. No significant results were found for psychopathological stress and perceived stress. Conclusions: The results suggest a beneficial effect of higher psychosocial PS and higher prenatal maternal HPA axis activity in late gestation, which is in line with "stress inoculation" theories. PMID- 29403647 TI - Assessing the relative importance of health and conformation traits in the cavalier king Charles spaniel. AB - Background: The selection of a future breeding dog is a complicated task, in which disease characteristics and different traits have to be combined and weighed against one another. Truncation selection, that is the exclusion of affected animals, may be very inefficient when selecting on a large number of traits, and may result in a reduction of the genetic diversity in a population or breed. Selection could be facilitated by the use of a selection index that combines multiple traits or breeding values into one score. This however requires a consideration of their relative value according to their economic weight, which is difficult to express in monetary units for health traits. The use of a choice experiment to derive non-market values might be a solution to this problem. This is a pilot study to assess the potential use of choice experiments to ascertain the public preference and relative importance attached to health- and conformation traits in the selection of a Cavalier King Charles spaniel. The focus was on two prevalent disorders, mitral valve disease and syringomyelia, and on several important conformation traits such as muzzle length and eye shape. Based on available prior information, a Bayesian D-optimal design approach was used to develop a choice experiment and the resulting choice sets. Results: Every participant (breeder or owner) in the choice experiment was presented with a total of 17 choice sets, in which at most four traits could vary to reduce the cognitive burden. A total of 114 respondents participated in the choice experiment and results showed that respondents (breeders/owners) current attitudes were directed towards health (syringomyelia and mitral valve disease), followed by eye shape and level of inbreeding. Conclusions: This approach identifies the value breeders and owners attach to certain traits in the breeding objective. The resulting relative weights, represented as the logworths obtained from the choice experiment, could be an alternative to economic weights. They could be implemented as a weight when breeding values are available, but more study on this topic will be necessary. A challenge in this approach is to scale up the experiment with additional traits. Moreover, for other traits, the genetic parameters and correlations should be known first, in order to include them in the health selection index as well. PMID- 29403646 TI - Barriers and facilitators to early rehabilitation in mechanically ventilated patients-a theory-driven interview study. AB - Background: Despite a supportive evidence base and a push to implement, the uptake of early rehabilitation in critical care has been inconsistent. The objective of this study was to explore barriers and facilitators to early rehabilitation for critically ill patients receiving invasive mechanical ventilation. Methods: Using the Theoretical Domains Framework (TDF) of behavior change, we conducted semi-structured interviews exploring barriers and facilitators to early rehabilitation among four purposively sampled ICU clinician groups (nurses, rehabilitation professionals, respiratory therapists, and physicians). The TDF is a comprehensive framework of 14 "construct domains," synthesized from 33 theories of behavior that was developed to study determinants of behavior and to design interventions to improve evidence-based healthcare practice. A topic guide was developed and piloted based on the TDF and expert knowledge. Interviews were audio-recorded and transcribed verbatim. Transcripts were content analyzed by coding items into domains and then synthesized into more specific, over-arching themes or "beliefs." An expert consensus group used structured decision rules to classify beliefs as high, moderate, or low in importance. Results: We interviewed 40 stakeholders from the four clinician groups and identified 135 separate beliefs. Of these, 19 were classified as high, 40 as moderate, and 76 of low importance as barriers or facilitators. All beliefs classified as highly important fell within one of seven TDF domains: skills, social/professional role and identity, beliefs about capabilities, beliefs about consequences, environmental context/resources, social influences, and behavioral regulation. Beliefs of lower importance fell under the following seven domains: knowledge; optimism; reinforcement; intention; goals; memory, attention, and decision processes; and emotion. Quantitative differences in stated beliefs about early rehabilitation between professional groups were not common. Conclusions: This study identified important barriers and facilitators to early rehabilitation in critical care patients. Domains identified as important should be considered when designing interventions to increase uptake of early rehabilitation. PMID- 29403648 TI - Bacteriological profile and antibiotic susceptibility pattern of common isolates of neonatal sepsis, Ho Municipality, Ghana-2016. AB - Background: Globally, 4 million neonates die annually, with one-third of such deaths occurring as a result of infections. In 2011, there were 7.2million deaths in children below 5 years globally, and a proportion of 40% of these deaths occurred in neonates. Sepsis was reported to account for one-third of these deaths. Presently, multidrug antibiotic resistance is rapidly increasing in Neonatal Intensive Care Units (NICUs), particularly in developing countries and poses a threat to public health. The change in these organisms has been reported to vary across regions, between health facilities and even within the same facility. Continuous surveillance is required to inform antibiotic choice for neonatal sepsis management. We identified the common causative organisms of neonatal sepsis and their antibiotic susceptibility pattern in the Ho municipality. Method: A cross sectional study was conducted in the Ho municipality from January to May, 2016. A semi-structured questionnaire was used to collect socio-demographic data from mothers of neonates with clinically suspected of sepsis. Clinical data of both mothers and neonates were extracted from case notes. A 2 ml volume of blood was also taken from neonates and dispensed into a 20 ml mixture of thioglycollate fluid broth and tryptone soy broth for culture and antibiotic susceptibility pattern determined. Results: Out of the 150 clinically suspected neonatal sepsis cases, 91 (60.7%) were males. The Median gestational week was 38 (IQR: 36-39) and Median birthweight was 3.0 kg (IQR 2.5-3.4). The prevalence of culture positive sepsis was 17.3% of the 150 suspected cases. A total of 26 different pathogens were isolated, of which gram positive organisms had a preponderance of 18 (69%) over gram negative organisms 8 (31%). Staphylococcus epidermidis was the most common 14 (53.8%) isolate identified. There was a single isolate (4%) each of Proteus mirabilis and Escherichia coli identified. All the isolates identified showed 100% resistance to ampicillin. Conclusion: The prevalence of culture proven sepsis was 17.3% and Staphylococcus epidermidis was the most common isolate identified. Pathogens isolated were resistant to the first line drugs for management of neonatal sepsis. Hence, the need for a review of first line drug for empirical treatment in neonatal sepsis. PMID- 29403649 TI - A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS). AB - Background: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis. Methods: Using a randomised (1:1) double-blind placebo-controlled feasibility study, 40 men and women (20 in each trial arm) with a recent diagnosis (< 10 years) of relapsing and remitting MS (RRMS) and who are over 18 years of age will be recruited from neurology clinics and throughout the Thames Valley community. During a 6-week nutrition intervention period, participants will consume the cocoa beverage, high flavonoid or low flavonoid content, at breakfast daily. At baseline, demographic factors and disease-related factors will be assessed. Fatigue, activity and quality of life, in addition to other measures, will be taken at three visits (baseline, week 3 and week 6) in a university setting by a researcher blinded to group membership. Feasibility and fidelity will be assessed through recruitment and retention, adherence and a quantitative process evaluation at the end of the trial.We will describe demographic factors (age, gender, level of education) as well as disease-related factors (disease burden scores, length of time diagnosed with MS) and cognitive assessment, depression and quality of life and general physical activity in order to characterise participants and determine possible mediators to identify the processes by which the intervention may bring about change. Feasibility (recruitment, safety, feasibility of implementation of the intervention and evaluation, protocol adherence and data completion) and potential for benefit (estimates of effect size and variability) will be determined to inform future planned studies. Results will be presented using point estimates, 95% confidence intervals and p values. Primary statistical analysis will be on an intention-to-treat basis and will use the complete case data set. Discussion: We propose that a flavonoid enriched cocoa beverage for the management of fatigue will be well received by participants. Further, if it is implemented early in the disease course of people diagnosed with RRMS, it will improve mobility and functioning by modifying fatigue. Trial registration: Registered with ISRCTN Registry. Trial registration No: ISRCTN69897291; Date April 2016. PMID- 29403651 TI - The influence of phylodynamic model specifications on parameter estimates of the Zika virus epidemic. AB - Each new virus introduced into the human population could potentially spread and cause a worldwide epidemic. Thus, early quantification of epidemic spread is crucial. Real-time sequencing followed by Bayesian phylodynamic analysis has proven to be extremely informative in this respect. Bayesian phylodynamic analyses require a model to be chosen and prior distributions on model parameters to be specified. We study here how choices regarding the tree prior influence quantification of epidemic spread in an emerging epidemic by focusing on estimates of the parameters clock rate, tree height, and reproductive number in the currently ongoing Zika virus epidemic in the Americas. While parameter estimates are quite robust to reasonable variations in the model settings when studying the complete data set, it is impossible to obtain unequivocal estimates when reducing the data to local Zika epidemics in Brazil and Florida, USA. Beyond the empirical insights, this study highlights the conceptual differences between the so-called birth-death and coalescent tree priors: while sequence sampling times alone can strongly inform the tree height and reproductive number under a birth-death model, the coalescent tree height prior is typically only slightly influenced by this information. Such conceptual differences together with non trivial interactions of different priors complicate proper interpretation of empirical results. Overall, our findings indicate that phylodynamic analyses of early viral spread data must be carried out with care as data sets may not necessarily be informative enough yet to provide estimates robust to prior settings. It is necessary to do a robustness check of these data sets by scanning several models and prior distributions. Only if the posterior distributions are robust to reasonable changes of the prior distribution, the parameter estimates can be trusted. Such robustness tests will help making real-time phylodynamic analyses of spreading epidemic more reliable in the future. PMID- 29403650 TI - Reducing stigma among healthcare providers to improve mental health services (RESHAPE): protocol for a pilot cluster randomized controlled trial of a stigma reduction intervention for training primary healthcare workers in Nepal. AB - Background: Non-specialist healthcare providers, including primary and community healthcare workers, in low- and middle-income countries can effectively treat mental illness. However, scaling-up mental health services within existing health systems has been limited by barriers such as stigma against people with mental illness. Therefore, interventions are needed to address attitudes and behaviors among non-specialists. Aimed at addressing this gap, REducing Stigma among HealthcAre Providers to ImprovE mental health services (RESHAPE) is an intervention in which social contact with mental health service users is added to training for non-specialist healthcare workers integrating mental health services into primary healthcare. Methods: This protocol describes a mixed methods pilot and feasibility study in primary care centers in Chitwan, Nepal. The qualitative component will include key informant interviews and focus group discussions. The quantitative component consists of a pilot cluster randomized controlled trial (c RCT), which will establish parameters for a future effectiveness study of RESHAPE compared to training as usual (TAU). Primary healthcare facilities (the cluster unit, k = 34) will be randomized to TAU or RESHAPE. The direct beneficiaries of the intervention are the primary healthcare workers in the facilities (n = 150); indirect beneficiaries are their patients (n = 100). The TAU condition is existing mental health training and supervision for primary healthcare workers delivered through the Programme for Improving Mental healthcarE (PRIME) implementing the mental health Gap Action Programme (mhGAP). The primary objective is to evaluate acceptability and feasibility through qualitative interviews with primary healthcare workers, trainers, and mental health service users. The secondary objective is to collect quantitative information on health worker outcomes including mental health stigma (Social Distance Scale), clinical knowledge (mhGAP), clinical competency (ENhancing Assessment of Common Therapeutic factors, ENACT), and implicit attitudes (Implicit Association Test, IAT), and patient outcomes including stigma-related barriers to care, daily functioning, and symptoms. Discussion: The pilot and feasibility study will contribute to refining recommendations for implementation of mhGAP and other mental health services in primary healthcare settings in low-resource health systems. The pilot c-RCT findings will inform an effectiveness trial of RESHAPE to advance the evidence-base for optimal approaches to training and supervision for non-specialist providers. Trial registration: ClinicalTrials.gov identifier, NCT02793271. PMID- 29403653 TI - Prevalence of Gram-Negative Bacilli Isolated from the Equipment and Surfaces in Hospital Wards of Golestan Province, North of Iran. AB - Nosocomial infections are one of the most common causes of death in hospitals. This study aimed to determine the prevalence of gram-negative bacilli isolated from the equipment in hospital wards of the Golestan province, in the year 2015. In this cross-sectional study in 2015, 1980 samples from medical and nonmedical equipment and surfaces were collected from the wards of 13 teaching hospitals, in the Golestan province. Samples were inoculated into eosin methylene blue agar and blood agar culture media and isolated colonies were identified by standard biochemical tests. The obtained results were then analyzed using SPSS 22 software and chi2 test. Among 1980 isolated samples, 601 samples (30.35%) were infected with gram-negative bacilli while Enterobacter aerogenes (37.27%) was responsible for most of the contaminations. The highest rate of infection was observed in the intensive care unit (33.1%), and the highest level of contamination in the medical equipment was associated with laryngoscope and its blade (10.48%), as well as ECG sensor and its monitoring connector (6.65%). Meanwhile, phone (6.32%) and patients' beds and linen (5.15%) had the highest level of contamination in the nonmedical equipment. Considering the high rates of gram-negative bacilli contamination in the hospital wards of the Golestan province, thorough hand washing as the main action for disinfection and sterilizing the equipment, as well as performing periodic cultivation alongside the use of standard guidelines for prevention and control of nosocomial infections, are recommended to reduce the level of contamination. PMID- 29403652 TI - High Level of Specific Anti-Plasmodium Falciparum Merozoite IgG1 Antibodies in Rural Asymptomatic Individuals of Dienga, South-Eastern Gabon. AB - Plasmodium falciparum merozoite antigens (PfMAgs) play an essential role in the development of immunity to malaria. Currently, P. falciparum: protein 113 (Pf 113), apical membrane antigen 1 (AMA1), erythrocyte binding antigens (EBA175), and reticulocyte binding protein homologue 5 (RH5) are among the most PfMAgs studied. A comparative analysis of naturally acquired antibodies against these antigens in children would increase our knowledge about the development of protective immunity. Analysis of antibodies to Pf113, PfAMA1, PfEBA175, and PfRH5 was conducted in rural population during 2013 and 2014. Both prevalence and levels of total IgG anti-PfAMA1 were higher than that of IgG anti-PfEBA175, anti PfRH5, and anti-Pf113. Seroconversion to PfAMA1 and PfEBA175 occurred moderately in young children and reached to the maximum in adolescent and in adults. High prevalence of IgG anti-Pf113 was observed in young children of 3 to 6 years old in 2013. The four antigens were recognized by IgG 1, 2, 3, and 4 antibodies from a large proportion of the subjects, and all of them induced high levels of specific IgG1 against PfAMA1, PfEBA175, fewer by Pf113 and PfRH5. Many asymptomatic children had specific IgG1 recognizing multiple antigens, and these IgG1 antibodies could be associated with a reduced risk of developing malaria symptoms. PMID- 29403654 TI - Seroprevalence of Chlamydophila Psittaci among Employees of Two German Duck Farms. AB - Psittacosis is a zoonotic infectious disease that is caused by Chlamydophila psittaci. To determine the occupational risk of getting the infection, we investigated the seroprevalence of C. psittaci among employees of two German duck farms and two slaughterhouses according to their level of exposure to the pathogen during the years 2010, 2007, and 2004. In summary, we found low seroprevalence (~ 8%) throughout the study population almost irrespective of the duty of a given worker. Surprisingly, in 2010, the anti-C. psittaci-specific antibody prevalence in the group of slaughterer (38.9%) was significantly increased in comparison to the non-exposed employees (p = 0.00578). This indicates that individuals in the surrounding of slaughterhouses exposed especially to aerosols containing C. psittaci elementary bodies bear a greater occupational risk of getting infected. PMID- 29403655 TI - Influence of Broth Enrichment as well as Storage and Transport Time on the Sensitivity of MRSA Surveillance in the Tropics. AB - Direct growth on blood and screening agar for methicillin-resistant Staphylococcus aureus (MRSA) at a tropical surveillance site was compared with broth enrichment and subsequent growth on selective MRSA agar after international sample transport. In Madagascar, 1548 swabs from an MRSA surveillance study were assessed for growth on Columbia blood agar enriched with 5% sheep blood and MRSA screening agar at the surveillance site with subsequent cold storage of the samples and shipment to Germany. In Germany, 1541 shipped samples were analyzed by non-selective broth enrichment with subsequent culture on MRSA selective agar. A total of 28 MRSA isolates were detected. Of these, 20 strains were isolated from direct culture on blood and MRSA screening agars at the surveillance site, 24 MRSA strains were isolated using the broth enrichment method in Germany, and 16 MRSA strains were identified by both approaches. In spite of the observed die off of individual strains due to long-term storage and transport, broth enrichment with subsequent screening on MRSA selective agar after international sample shipment led to comparable sensitivity of MRSA detection like streaking on blood and MRSA agar at the tropical surveillance site. PMID- 29403656 TI - Seroepidemiology of Infection with Neospora Caninum, Leptospira, and Bovine Herpesvirus Type 1 in Water Buffaloes (Bubalus Bubalis) in Veracruz, Mexico. AB - We aimed to determine the seroprevalence of infection with Neospora caninum, Leptospira, and bovine herpesvirus type 1 and risk factors associated with these infections in water buffaloes in Veracruz State, Mexico. Through a cross sectional study, 144 water buffaloes (Bubalus bubalis) raised in 5 ranches of Veracruz were examined for anti-N. caninum and anti-bovine herpesvirus type 1 antibodies by enzyme immunoassays, and anti-Leptospira interrogans antibodies by microscopic agglutination test. Of the 144 buffaloes studied, 35 (24.3%) were positive for N. caninum, 50 (34.7%) for Leptospira, and 83 (57.6%) for bovine herpes virus. The frequencies of leptospiral serovars in buffaloes were as follows: 18.7% for Muenchen (n = 27), 10.4% for Hardjo LT (n = 15), 9.0% for Pyrogenes (n = 13), and 4.8% for Icterohaemorrhagiae (n = 7). Seropositive buffaloes were found in all 5 ranches studied. Logistic regression showed that cohabitation of buffaloes with cows was associated with infection with Leptospira (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.04-4.5; P = 0.03) and bovine herpesvirus (OR, 12.0; 95% CI, 4.0-36.2; P < 0.01). This is the first study that provides serological evidence of N. caninum, Leptospira, and bovine herpesvirus type 1 infections in water buffaloes in Mexico. Our findings could be used to enhance preventive measures against these infections. PMID- 29403657 TI - On the Role of Enterococci in the Bloodstream: Results of a Single-Center, Retrospective, Observational Study at a German University Hospital. AB - This study assesses the clinical relevance of vancomycin-susceptible enterococci in bacteremic patients and compares it with bacteremia due to Staphylococcus aureus and Escherichia coli. During a 5-year-study interval, clinical and diagnostic features of patients with enterococcal bacteremia were compared to those of patients with E. coli or S. aureus bacteremia. Each patient was only counted once per hospital stay. During the 5-year study interval, data from 267 patients with enterococcal bacteremia and from 661 patients with bacteremia due to E. coli or S. aureus were evaluated. In spite of a comparable risk of death, patients with enterococci more frequently needed catecholamines and invasive ventilation. Furthermore, enterococci were more frequently associated with a mixed bacterial flora in bloodstream infections. While fatal sepsis due to E. coli and S. aureus was associated with typical shock symptoms, this association was not confirmed for enterococci. Although enterococcal bacteremia is associated with a risk of dying comparable to that with bacteremia due to E. coli and S. aureus, a lower pathogenic potential of enterococci in bloodstream has to be acknowledged. Enterococci in the bloodstream are more likely to be an epiphenomenon of impending death than its major cause. PMID- 29403658 TI - Antimicrobial Resistance-Transducing Bacteriophages Isolated from Surfaces of Equine Surgery Clinics - A Pilot Study. AB - In the past, the horizontal transfer of antimicrobial resistance genes was mainly associated with conjugative plasmids or transposons, whereas transduction by bacteriophages was thought to be a rare event. In order to analyze the likelihood of transduction of antimicrobial resistance in the field of clinical veterinary medicine, we isolated phages from Escherichia coli from a surgery suite of an equine clinic. In a pilot study, the surgery suite of a horse clinic was sampled directly after surgery and subsequently sampled after cleaning and disinfection following a sampling plan based on hygiene, surgery, and anesthesia. In total, 31 surface sampling sites were defined and sampled. At 24 of these 31 surface sampling sites, coliphages were isolated. At 12 sites, coliphages were found after cleaning and disinfection. Randomly selected phages were tested for their ability of antimicrobial resistance transduction. Ten of 31 phages were detected to transfer antimicrobial resistance. These phages most often transduced resistance to streptomycin, encoded by the addA1 gene (n = 9), followed by resistance to chloramphenicol by cmlA (n = 3) and ampicillin (n = 1). This is, to the best of our knowledge, the first report on antimicrobial resistance transferring bacteriophages that have been isolated at equine veterinary clinics. PMID- 29403659 TI - Toxoplasma Gondii Exposure and Neurological Disorders: An Age- and Gender-Matched Case-Control Pilot Study. AB - Little is known about the association of Toxoplasma gondii infection and neurological disorders. We performed a case-control study with 344 patients with neurological diseases and 344 neurologically healthy age- and gender-matched subjects. Sera of participants were analyzed for anti-T. gondii IgG and IgM antibodies using commercially available immunoassays. Anti-T. gondii IgG antibodies were detected in 25 (7.3%) cases and in 35 (10.2%) controls (odds ratio [OR] = 0.69; 95% confidence interval [CI]: 0.40-1.18; P = 0.17). Anti-T. gondii IgM antibodies were found in 5 (14.3%) of the 25 IgG seropositive cases and in 13 (37.1 degrees %) of the 35 IgG seropositive controls (P = 0.15). Anti T. gondii IgG antibodies were found in 8 (3.8%) of 213 female cases and in 23 (10.8%) of 213 female controls (OR = 0.32; 95% CI: 0.14-0.73; P = 0.005); and in 17 (13.0%) of 131 male cases and in 12 (9.2%) of 131 male controls (P = 0.32). No direct association between IgG seropositivity and specific neurological disorders was detected. We found no support for a role of latent T. gondii infection in the risk for neurological disorders in this setting. With respect to specific neurological disorders, further studies using larger patient cohorts will be required. PMID- 29403660 TI - Equivalent Performance of the Cobas(r) Cdiff Test for Use on the Cobas(r) Liat(r) System and the Cobas(r) 4800 System. AB - Clostridium difficile infection is a significant health burden, and innovative solutions are needed to shorten time to diagnosis and improve infection control. We evaluated the performance of the cobas(r) Cdiff test for use on the cobas(r) Liat(r) System (cobas(r) Liat(r) Cdiff), a single-sample, on-demand, and automated molecular solution with a 20-min turnaround time. The limit of detection was 45-90 colony-forming units (CFUs)/swab for toxigenic strains that covered the most prevalent toxinotypes, including the hyper-virulent epidemic 027/BI/NAP1 strain. Using 442 prospectively collected clinical stool specimens, we compared the performance of the cobas(r) Liat(r) Cdiff to direct culture and to the cobas(r) Cdiff test on the cobas(r) 4800 System (cobas(r) 4800 Cdiff) - a medium-throughput molecular platform. The sensitivity and specificity of the cobas(r) Liat(r) Cdiff compared to direct culture were 93.1% and 95.1%, respectively, and this performance did not statistically differ from the cobas(r) 4800 Cdiff (P < 0.05). Direct correlation of the cobas(r) Liat(r) and cobas(r) 4800 Cdiff tests yielded overall percent agreement of 98.6%. The test performance, automation, and turnaround time of the cobas(r) Liat(r) Cdiff enable its use for on-demand and out-of-hours testing as a complement to existing batch testing solutions like the cobas(r) 4800 Cdiff. PMID- 29403661 TI - The EFPA Test-Review Model: When Good Intentions Meet a Methodological Thought Disorder. AB - The European Federation of Psychologists' Associations (EFPA) has issued sets of test standards and guidelines for psychometric test reviews without any attempt to address the critical content of many substantive publications by measurement experts such as Joel Michell. For example, he has argued that the psychometric test-theory which underpins classical and modern IRT psychometrics is "pathological", with the entire profession of psychometricians suffering from a methodological thought disorder. With the advent of new kinds of assessment now being created by the "Next Generation" of psychologists which no longer conform to the item-based, statistical test theory generated last century, a new framework is set out for constructing evidence-bases suitable for these "Next Generation" of assessments, which avoids the illusory beliefs of equal-interval or quantitatively structured psychological attributes. Finally, with no systematic or substantive refutations of the logic, axioms, and evidence set out by Michell and others; it is concluded psychologists and their professional associations remain in denial. As with the eventual demise of a similar attempt to maintain the status quo of professional beliefs within forensic clinical psychology and psychiatry during the last century, those following certain EFPA guidelines might now find themselves required to justify their professional beliefs in legal rather than academic environments. PMID- 29403663 TI - Cancer in ANCA-Associated Glomerulonephritis: A Registry-Based Cohort Study. AB - Background: Immunosuppressive therapy for antineutrophil cytoplasmic antibody associated vasculitis has been associated with increased malignancy risk. Objectives: To quantify the cancer risk associated with contemporary cyclophosphamide-sparing protocols. Methods: Patients from the Norwegian Kidney Biopsy Registry between 1988 and 2012 who had biopsy-verified pauci-immune glomerulonephritis and positive antineutrophil cytoplasmic antibody (ANCA) serology were included. Standardised incidence ratios (SIRs) were calculated to compare the study cohort with the general population. Results: The study cohort included 419 patients. During 3010 person-years, cancer developed in 41 patients (9.79%); the expected number of cancer cases was 37.5 (8.95%). The cohort had SIRs as follows: 1.09, all cancer types (95% CI, 0.81 to 1.49); 0.96, all types except nonmelanoma skin cancer (95% CI, 0.69 to 1.34); 3.40, nonmelanoma skin cancer (95% CI, 1.62 to 7.14); 3.52, hematologic cancer (95% CI, 1.32 to 9.37); 2.12, posttransplant cancer (95% CI, 1.01 to 4.44); and 1.53, during the 1-5-year follow-up after diagnosis (95% CI, 1.01 to 2.32). Conclusions: Cancer risk did not increase significantly in this cohort with ANCA-associated glomerulonephritis. However, increased risk of nonmelanoma skin cancer, posttransplant cancer, and hematologic cancer indicates an association between immunosuppression and malignancy. PMID- 29403664 TI - Cost-Effectiveness Analysis of Total Hip Arthroplasty Performed by a Canadian Short-Stay Surgical Team in Ecuador. AB - Background: Few charitable overseas surgical missions produce cost-effectiveness analyses of their work. Methods: We compared the pre- and postoperative health status for 157 total hip arthroplasty (THA) patients operated on from 2007 to 2011 attended by an annual Canadian orthopedic mission to Ecuador to determine the quality-adjusted life years (QALYs) gained. The costs of each mission are known. The cost per surgery was divided by the average lifetime QALYs gained to estimate an incremental cost-effectiveness ratio (ICER) in Canadian dollars per QALY. Results: The average lifetime QALYs (95% CI) gained were 1.46 (1.4-1.5), 2.5 (2.4-2.6), and 2.9 (2.7-3.1) for unilateral, bilateral, and staged (two THAs in different years) operations, respectively. The ICERs were $4,442 for unilateral, $2,939 for bilateral, and $4392 for staged procedures. Seventy percent of the mission budget was spent on the transport and accommodation of volunteers. Conclusion: THA by a Canadian short-stay surgical team was highly cost-effective, according to criteria from the National Institute for Health and Care Excellence and the World Health Organization. We encourage other international missions to provide similar cost-effectiveness data to enable better comparison between mission types and between mission and nonmission care. PMID- 29403662 TI - Surgical Options for the Refractive Correction of Keratoconus: Myth or Reality. AB - Keratoconus provides a decrease of quality of life to the patients who suffer from it. The treatment used as well as the method to correct the refractive error of these patients may influence on the impact of the disease on their quality of life. The purpose of this review is to describe the evidence about the conservative surgical treatment for keratoconus aiming to therapeutic and refractive effect. The visual rehabilitation for keratoconic corneas requires addressing three concerns: halting the ectatic process, improving corneal shape, and minimizing the residual refractive error. Cross-linking can halt the disease progression, intrastromal corneal ring segments can improve the corneal shape and hence the visual quality and reduce the refractive error, PRK can correct mild moderate refractive error, and intraocular lenses can correct from low to high refractive error associated with keratoconus. Any of these surgical options can be performed alone or combined with the other techniques depending on what the case requires. Although it could be considered that the surgical option for the refracto-therapeutic treatment of the keratoconus is a reality, controlled, randomized studies with larger cohorts and longer follow-up periods are needed to determine which refractive procedure and/or sequence are most suitable for each case. PMID- 29403665 TI - Sinus Floor Elevation with Modified Crestal Approach and Single Loaded Short Implants: A Case Report with 4 Years of Follow-Up. AB - Tooth extraction is usually followed by bone reduction. In the maxillary posterior region, this remodelling combined with sinus pneumatisation and periodontal defects may lead to a reduced basal bone height available for implant placement. Sinus floor elevation can be performed with different surgical techniques. Crestal approach has demonstrated to be effective, less invasive, and associated with a reduced morbidity. This article reports a modified sinus floor elevation by means of rotary, noncutting instruments, addition of xenograft, and 2 short-threaded implant placements. The aim of the study was to evaluate the implant's success and intrasinus radiographical bone gain after 4 years of functional loading. The premolar implant site presented a starting basal bone height of 6 mm, while the molar site was of 2 mm. In the first surgical step, sinus floor elevation was performed mesially and the implant was inserted, and distally only sinus floor elevation was performed. After 6 months, the mesial implant was uncovered and the second implant was inserted; 4 months later, the second fixture was uncovered, and both fixtures were loaded with single provisional screw-retained crowns and later with single screw-retained porcelain fused to metal crowns. Implants integrated successfully, and crestal bone remodelling did not exceed the smooth collar. Bone gain was 3 mm for the mesial implant and more than 5 mm for the distal one. PMID- 29403666 TI - Fatal Mesenteric Ischemia Induced by Synthetic Cannabinoids: A Case Report and Literature Review. AB - Worldwide use of synthetic cannabinoids (SCs) is rapidly increasing, in part due to the generation of numerous new compounds, sidestepping legal restrictions. Their detection using standard toxicology panels is difficult, due to their vast heterogeneity and lack of structural resemblance to cannabinoids. Sympathetic overactivity and arterial spasm play a role in some of the life-threatening reactions to SCs, such as coronary or cerebral vasoconstriction. Here we report a patient with repeated consumption of SCs that led to mesenteric ischemia and death. A 29-year-old man was frequently evaluated in the Emergency Medicine Department for recurrent transient crampy abdominal pain, associated with the use of the SCs colloquially known as "Mr. Nice Guy." He was finally hospitalized with a protracted attack, associated with diarrhea and leukocytosis. Initial evaluation including computed tomography was unremarkable. Diarrhea and leukocytosis gradually resolved, but bouts of hypertension and abdominal pain occurred in association with repeated consumption of the SCs. On the fifth hospital day, the patient developed abrupt abdominal pain, associated with profound shock and signs of peritoneal irritation and succumbed within an hour. Postmortem CT scan was consistent with intestinal perforation most probably due to a nonobstructive mesenteric infarction. There was no evidence of a single vessel infarction. PMID- 29403667 TI - Localized Subcutaneous Insulin-Derived Amyloidosis Excised after Evaluation Using Ultrasonography in a Patient with Type 2 Diabetes Mellitus. AB - A 62-year-old man with type 2 diabetes mellitus, who had been on insulin therapy for the past 20 years, was found to have subcutaneous mass formation in the abdomen during a workup of worsened glycemic control. Because of suspected amyloid deposition, he was advised to avoid injections to the mass, which led to improvement of glycemic control. However, he strongly requested mass excision and was hospitalized. After evaluation using ultrasonography and computed tomography, a total mass excision was performed, and a diagnosis of insulin-derived amyloidosis was made. Comparison of the ultrasonographic and histopathological findings demonstrated that the location of the amyloid deposition nearly corresponded to the hypoechoic region. This case highlights that ultrasonography, which is a noninvasive imaging modality, can be useful for detection of insulin derived amyloidosis. PMID- 29403668 TI - Asynchronous Bilateral Ovarian Torsion: Three Cases, Three Lessons. AB - Background: Ovarian torsion (OT) is a serious condition, and delay in surgical intervention may result in loss of the ovary. Children and adolescents who have suffered from ovarian torsion may be at risk for asynchronous torsion of the contralateral ovary. Study objective: Three cases of asynchronous bilateral ovarian torsion were reported to analyse clinical history of three patients, to review the current literature, and to draw a conclusion for future treatment. Design: Case reports and review of the literature. Result: When a prepubertal girl presents with an ovarian torsion, several considerations have to be taken in account in order to preserve her future fertility; in particular, the pediatric surgeon/gynecologist has to preserve as much as possible the twisted ovary in addition to considering the fate of the contralateral ovary. Summary and Conclusions: Pelvic pain in a young girl has always raised the clinical suspect of an ovarian torsion; the possibility of asynchronous bilateral ovarian torsion is rare, but it is described in the literature and has catastrophic consequences; this condition has to be known and treated in the proper way by pediatric surgeons as well as by gynecologists in order to maximize the future fertility of the young patients. PMID- 29403669 TI - Right Internal Jugular Vein Phlebectasia: A Rare Cause of Neck Swelling. AB - Internal jugular vein (IJV) phlebectasia is a rare condition presenting as a self reducible soft tissue swelling of the neck due to fusiform dilation of the venous wall. We report the case of a 7-year-old boy who presented with painless soft mass in the side of the neck which appears during coughing and straining and reduces spontaneously. Diagnosis was confirmed by Doppler ultrasonography and magnetic resonance imaging of the neck. Conservative management and regular follow-up were considered. In this case report, we highlight this rare benign condition as an uncommon differential of neck swellings in order to avoid unnecessary diagnostic workup and interventions. PMID- 29403670 TI - Recurrent Enlarging Mesenteric Desmoid Tumor following Remote Surgical Resection. AB - Intra-abdominal desmoid tumors are commonly associated with genetic syndromes such as familial polyposis coli. Radiological cross imaging studies such as CT and MRI are used in the preoperative work-up of such tumors. Postoperatively, CT and MRI are useful in the assessment of recurrent desmoid tumors. MRI is more accurate in tissue characterization. Where possible, surgical resection remains the standard first-line treatment. For patients where surgery is not possible, or the resection margins are not clear, other forms of treatment are possible. These include hormonal and nonhormonal options. We present a case of a recurrent sporadic intra-abdominal (mesenteric) desmoid tumor. Such an entity is rare with few cases reported in the literature. Treatment options regarding intra-abdominal desmoid tumors will be discussed. PMID- 29403671 TI - A Rare Finding of Falciform Ligament Thrombosis as a Sequel of Acute Pancreatitis. AB - Falciform ligament (remnant of umbilical vein) is an anatomical structure that connects the liver to the anterior abdominal wall. This case reports a rare clinical presentation of falciform ligament thrombosis as a consequence of acute gallstone pancreatitis, in a patient with noncirrhotic liver. A 55-year-old female with a history of cholelithiasis was admitted with abdominal pain. Biochemistry profile showed hyperamylasemia and deranged liver function tests. Computerized Tomography (CT) revealed a 3 cm attenuated structure that can be traced up to the left portal vein, which represents an acute thrombosis of the falciform ligament. The patient was treated with Tinzaparin and subsequently anticoagulated. She subsequently had a laparoscopic cholecystectomy and made an uneventful recovery. We suspect that pancreatitis caused thrombophlebitis subsequently leading to recanalization and thrombosis of the umbilical vein. Falciform ligament thrombosis is a rare and poorly described complication following pancreatitis which clinicians and radiologists should be aware of. PMID- 29403672 TI - Improving Upper Extremity Function and Quality of Life with a Tongue Driven Exoskeleton: A Pilot Study Quantifying Stroke Rehabilitation. AB - Stroke is a leading cause of long-term disability around the world. Many survivors experience upper extremity (UE) impairment with few rehabilitation opportunities, secondary to a lack of voluntary muscle control. We developed a novel rehabilitation paradigm (TDS-HM) that uses a Tongue Drive System (TDS) to control a UE robotic device (Hand Mentor: HM) while engaging with an interactive user interface. In this study, six stroke survivors with moderate to severe UE impairment completed 15 two-hour sessions of TDS-HM training over five weeks. Participants were instructed to move their paretic arm, with synchronized tongue commands to track a target waveform while using visual feedback to make accurate movements. Following TDS-HM training, significant improvements in tracking performance translated into improvements in the UE portion of the Fugl-Meyer Motor Assessment, range of motion, and all subscores for the Stroke Impact Scale. Regression modeling found daily training time to be a significant predictor of decreases in tracking error, indicating the presence of a potential dose-response relationship. The results of this pilot study indicate that the TDS-HM system can elicit significant improvements in moderate to severely impaired stroke survivors. This pilot study gives preliminary insight into the volume of treatment time required to improve outcomes. PMID- 29403673 TI - Enzyme-Instructed Self-Assembly of Peptides Containing Phosphoserine to Form Supramolecular Hydrogels as Potential Soft Biomaterials. AB - Enzyme-instructed self-assembly (EISA) offers a facile approach to explore the supramolecular assemblies of small molecules in cellular milieu for a variety of biomedical applications. One of the commonly used enzymes is phosphatase, but the study of the substrates of phosphatases mainly focuses on the phosphotyrosine containing peptides. In this work, we examine the EISA of phosphoserine containing small peptides for the first time by designing and synthesizing a series of precursors containing only phosphoserine or both phosphoserine and phosphotyrosine. Conjugating a phosphoserine to the C-terminal of a well established self-assembling peptide backbone, (naphthalene-2-ly)-acetyl diphenylalanine (NapFF), affords a novel hydrogelation precursor for EISA. The incorporation of phosphotyrosine, another substrate of phosphatase, into the resulting precursor, provides one more enzymatic trigger on a single molecule, and meanwhile increases the precursors' propensity to aggregate after being fully dephosphorylated. Exchanging the positions of phosphorylated serine and tyrosine in the peptide backbone provides insights on how the specific molecular structures influence self-assembling behaviors of small peptides and the subsequent cellular responses. Moreover, the utilization of D-amino acids largely enhances the biostability of the peptides, thus providing a unique soft material for potential biomedical applications. PMID- 29403674 TI - Identification and determination of the major constituents in traditional Chinese medicine Longdan Xiegan Pill by HPLC-DAD-ESI-MS. AB - A novel and sensitive HPLC-UV method has been developed for the simultaneous determination of twelve major compounds in Longdan Xiegan Pill. The chemical profile of the twelve compounds, including geniposidic acid (1), geniposide(2), gentiopicroside(3), liquiritin(4), crocin(5), baicalin(6), wogonoside(7), baicalein(8), glycyrrhizic acid (9), wogonin (10), oroxylin A (11) and aristolochic acid A (12), was acquired using high-performance liquid chromatography-diode array detector coupled with an electrospray tandem mass spectrometer (HPLC-DAD-ESI-MS). The analysis was performed on a Dikma Platisil ODS C18 column (250 mm * 4. 6 mm, 5 MUm) with a gradient solvent system of acetonitrile-0. 1% aqueous formic acid. The validation was carried out and the linearities (r > 0. 9996), repeatability (RSD<1. 8%), intra- and inter-day precision (RSD< 1. 3%), and recoveries (ranging from 96. 6% to 103. 4%) were acceptable. The limits of detection (LOD) of these compounds ranged from 0.29 to 4. 17 ng. Aristolochic acid A, which is the toxic ingredient, was not detected in all the batches of Longdan Xiegan Pill. Furthermore, hierarchical cluster analysis was used to evaluate the variation of the herbal prescription. The proposed method is simple, effective and suitable for the quality control of this traditional Chinese medicine (TCM). PMID- 29403675 TI - LC-MS determination and pharmacokinetic study of salidroside in rat plasma after oral administration of suspensions of traditional Chinese medicine Erzhi Wan and Fructus Ligustri lucidi. AB - A simple, rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed for the determination of salidroside in rat plasma and study of its pharmacokinetics after oral administration of suspension of Erzhi Wan and Fructus Ligustri lucidi into Wistar rats. Plasma sample of 200 MUL was extracted with acetic ether-isopropanol (2:1) and the extraction was performed on a Kromasil C18 column (150 mm * 4. 6 mm, 5 MUm) with the mobile phase of methanol water (41:59, v/v) within a run time of 6.0 min. The analyte was monitored with positive electrospray ionization (ESI) by selected ion monitoring (SIM) mode. The target ions were m/z 323.05 for salidroside and m/z 411.05 for internal Standard (IS) geniposide. A good linear relationship was obtained over the range of 5.0 500.0 ng/mL and the lower limit of quantification was 5.0 ng/mL. The validated method was successfully applied to the pharmacokinetic study of salidroside in rat plasma after oral administration of suspension of Erzhi Wan and Fructus Ligustri lucidi. PMID- 29403677 TI - Quantification of six bioactive compounds in Zhenqi Fuzheng preparation by high performance liquid chromatography coupled with diode array detector and evaporative light scattering detector. AB - A simple and accurate high-performance liquid chromatography (HPLC) coupled with diode array detector (DAD) and evaporative light scattering detector (ELSD) was established for the determination of six bioactive compounds in Zhenqi Fuzheng preparation (ZFP). The monitoring wavelengths were 254, 275 and 328 nm. Under the optimum conditions, good separation was achieved, and the assay was fully validated in respect of precision, repeatability and accuracy. The proposed method was successfully applied to quantify the six ingredients in 31 batches of ZFP samples and evaluate the variation by hierarchical cluster analysis (HCA), which demonstrated significant variations on the content of these compounds in the samples from different manufacturers with different preparation procedures. The developed HPLC method can be used as a valid analytical method to evaluate the intrinsic quality of this preparation. PMID- 29403676 TI - Response surface optimization of microwave-assisted extraction for HPLC fluorescence determination of puerarin and daidzein in Radix Puerariae thomsonii. AB - Microwave-assisted extraction was optimized with response surface methodology for HPLC-fluorescence determination of puerarin and daidzein in Radix Puerariae thomsonii. The optimized extraction procedure was achieved by soaking the sample with 70% methanol (1:15, v/v) for 30 min, and then microwave irradiation for 11 min at a power of 600 W. Coupling the extraction process with HPLC-fluorescence presented good recovery, satisfactory precision, and good linear relation. Compared with a method from the Chinese Pharmacopoeia, the proposed method enables higher extraction efficiency and more aecurate analytical results. It can be of Potential value in quality assessment of Radix Puerariae thomsonii medicinal materials. PMID- 29403678 TI - Preparation and evaluation of monolithic molecularly imprinted stationary phase for S-naproxen. AB - An S-naproxen (S-NAP) molecularly imprinted monolithic stationary phase (MIMSP) with specific recognition for S-NAP and naproxen (NAP) was prepared by in situ technique, utilizing 4-vinylpridine (4-VP) as a function monomer, ethylene glycol dimethacrylate (EDMA) as a cross-linking agent, and low-polar solvents (toluene and dodecanol) as porogenic solvents. The selectivity of the polymers for S-NAP and NAP was evaluated by high performance liquid chromatography (HPLC). The binding characteristics were tested by Scatchard analysis. Racemic NAP could be specifically separated to some extent. At the same time, NAP could be separated from ibuprofen under optimized conditions. Scatchard analysis showed that two classes of binding sites existed in the S-NAP-imprinted polymers, with their dissociation constants estimated to be 1.045 and 5.496 MUM, respectively. The results demonstrate that S-NAP and NAP can be recognized specifically on the obtained MIMSP. PMID- 29403679 TI - Simultaneous determination of captopril and hydrochlorothiazide by time-resolved chemiluminescence with artificial neural network calibration. AB - The combined use of chemometrics and chemiluminescence (CL) measurements, with the aid of the stopped-flow mixing technique, developed a simple time-resolved CL method for the simultaneous determination of captopril (CPL) and hydrochlorothiazide (HCT). The stopped-flow technique in a continuous-flow system was employed in this work in order to emphasize the kinetic differences between the two analytes in cerium (IV)-rhodamine 6G CL system. After the flow was stopped, an initial rise of CL signal was observed for HCT standards, while a direct decay of CL signal was obtained for CPL standards. The mixed CL signal was monitored and recorded on the whole process of continuousflow/stopped-flow, and the obtained data were processed by the chemometric approach of artificial neural network. The relative prediction error (RPE) of CPL and HCT was 5.9% and 8.7%, respectively. The recoveries of CPL and HCT in tablets were found to fall in the range between 95% and 106%. The proposed method was successfully applied to the simultaneous determination of CPL and HCT in a compound pharmaceutical formulation. PMID- 29403680 TI - Synthesis of a new chitosan derivative and assay of Escherichia coli adsorption. AB - A new chitosan derivative is prepared using chitosan. Ethyl cholorocarbonate was first introduced to the hydroxyl group of phthaloylchitosan through a nucleophilic reaction. Hydrazine was then added to recover the amino groups of chitosan, and promote cross-linking. The structure of this new chitosan derivative was characterized by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopy, and its physical properties were determined by X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The thermal and chemical stabilities of the new derivative were improved compared with those of native chitosan. Assay of Escherichia coli adhesion on a film based on this chitosan derivative showed good adsorption and biofilm formation. PMID- 29403681 TI - Rapid europium-sensitized fluorescent determination of ulifloxacin, the active metabolite of prulifloxacin, in human serum and urine. AB - A new fluorescent method was developed based on the ulifloxacin-europium (III) sodium dodecylbenzene sulfonate system for the determination of ulifloxacin, the active metabolite of prulifloxacin. Sodium dodecylbenzene sulfonate formed a ternary complex with ulifloxacin-europium (III) and significantly enhaneed the characteristic fluorescence of europium (III). The enhanced fluorescence intensity showed a good linear relationship with the concentration of ulifloxacin in the range of 5.0 * 10-8 - 2.0 * 10-6M with a detection limit of 2.0 * 10-10 M (3sigma). This method is rapid and sensitive, and has been successfully applied to the determination of ulifloxacin in human urine and serum samples. PMID- 29403682 TI - Flow injection chemiluminescence determination of loxoprofen and naproxen with the acidic permanganate-sulfite system. AB - A novel flow injection chemiluminescence (CL) method for the determination of loxoprofen and naproxen was proposed based on the CL system of KMnO4, and Na2SO3 in acid media. The CL intensity of KMnO4-Na2SO3 was greatly enhaneed in the presence of loxoprofen and naproxen. The mechanism of the CL reaction was studied by the kinetic proecss and UV-vis absorption and the conditions were optimized. Under optimized conditions, the CL intensity was linear with loxoprofen and naproxen concentration in the range of 7.0 * 10-8 - 1.0 * 10-5 g/mL and 2.0 * 10 7 - 4.0 * 10-6 g/mL with the detection limit of 2.0 * 10-8 g/mL and 3.0 * 10-8 g/mL (S/N = 3), respectively. Thc relative standard deviations were 2.39% and 1.37% for 5.0 * 10-7 g/mL naproxen and 5.0 * 10-7 g/mL loxoprofen (n = 10), respectively. The proposed method was satisfactorily applied to thc determination of loxoprofen and naproxen in pharmaceutical preparations. PMID- 29403683 TI - Diterpenoid alkaloids from a Tibetan medicinal plant Aconitum richardsonianum var. pseudosessiliflorum and their cytotoxic activity. AB - The chemical constituents from Aconitum richardsonianum var. pseudosessiliflorum were investigated. The roots of this plant were extracted three times with 90% EtOH at the room temperature. The ethanol extracts were combined and concentrated under reduced pressure to yield residue, which was suspended in water and successively partitioned with chloroform. The chloroform extraction was isolated and purified by silica gel and Sephadex LH-20 column chromatography. Six compounds were isolated and elucidated as delelatine (1), isodelpheline (2), 3 acetylaconitine (3), isoatisine (4), nordhagenine A (5) and yunaconitine (6). Compounds 1-5 were obtained from Aconitum Brunneum for the first time. Compound (1) showed significant cytotoxic activities (IC50= 4.36 MUM) against the human tumor cell line P388. PMID- 29403685 TI - Determination of phthalate esters in physiological saline solution by monolithic silica spin column extraction method. AB - Monolithic silica spin column extraction (MonoSpin-SPE) was developed as a simple, sensitive, and eco-friendly pretreatment method which combined with ultra fast liquid chromatography-mass spectrometry (UFLC-MS) to determine the levels of six phthalate esters, dimethyl-(DMP), diethyl-(DEP), dipropyl- [DPrP], butyl benzyl-(BBP), dicyclohexyl(DcHP), and di- n-octyl-(DOP) phthalate in physiological saline samples. Under optimized experimental conditions, the method was linear in the following ranges: 0.2- 50 MU/L for DMP, DEP, DPrP, DcHP and DOP; 5 - 100 MU/L for BBP. The correlation coefficients (R2) were in the range of O. 9951 - O. 9995 for all the analytes and the limits of detection (LODs) and limits of quantification (LOQs) were in the ranges of 0.02 - 0.9 MU/L and 0.08 - 2.7 MU/L, respectively. The pretreatment process showed good reproducibility with inter-day and intra-day relative standard deviations (RSDs) below 8.5% and 11.2%, respectively. This method was used to determine the levels of six phthalate esters in physiological saline samples and the recoveries ranged from 71.2% to 107. 3%. DMP and DEP were found in actual physical saline samples (brand A and brand B). PMID- 29403684 TI - Applications of HPLC/MS in the analysis of traditional Chinese medicines. AB - In China, traditional Chinese medicines (TCMs) have been used in clinical applications for thousands of years. The successful hyphenation of high Performance liquid chromatography (HPLC) and mass spectrometry (MS) has been applied widely in TCMs and biological samples analysis. Undoubtedly, HPLC/MS technique has facilitated the understanding of the treatment mechanism of TCMs. We reviewed more than 350 published papers within the last 5 years on HPLC/MS in the analysis of TCMs. The present review focused on the applications of HPLC/MS in the component analysis, metabolites analysis, and pharmacokinetics of TCMs etc. 50% of the literature is related to the component analysis of TCMs, which show that this field is the most popular type of research. In the metabolites analysis, HPLC coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry has been demonstrated to be the powerful tool for the characterization of structural features and fragmentation behavior patterns. This paper presented a brief overview of the applications of HPLC/MS in the analysis of TCMs. HPLC/MS in the fingerprint analysis is reviewed elsewhere. PMID- 29403686 TI - Determination of wholesome elements and heavy metals in safflower (Carthamus tinctorius L.) from Xinjiang and Henan by ICP-MS/ICP-AES. AB - An inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma atomic emission spectrometry (ICP-AES) was developed to determine 19 elements in safflower, a traditional Chinese medicinal herb from Xinjiang Autonomous Region and Henan Province of China. Totally 19 elements in safflower included heavy metals, i. e. As, Cd, Cu, Hg and Pb, and wholesome elements, i. e. Al, Ca, Co, Cr, Fe, Mg, Mn, Mo, Ni, P, Se, Sr, V and Zn. The results showed that the concentrations of heavy metals in safflower samples were both low, all of which met the national hygiene standards except for Pb in Xinjiang sample. Meanwhile, the distribution tendency of elements in the two samples was similar, which indicated that the plant might absorb given elements in a proportional way. The method can be used for the quality control of elements in safflower, and it provides a way for the determination of the contents of safflower from Xinjiang and Henan. PMID- 29403687 TI - Chemiluminescence determination of melamine with Luminol-K3Fe(CN)6 system. AB - A sensitive chemiluminescence (CL) method was developed for determining melamine in urine and plasma samples based on the fact that melamine can remarkably enhance the chemiluminescence of Luminol-K3 Fe(CN)6 system in alkaline medium. The determination conditions were optimized. Under optimum conditions, the chemiluminescence intensity had a good linear relationship with melamine in the range of 9.0 * 10-9 - 7.0 * 10-6 g/mL with a correlation coefficient of 0.9992. The detection limits (3sigma) were 3.54 ng/mL for urine sample and 6.58 ng/mL for plasma sample. The average recoveries of melamine were 102.6% for urine sample and 95.1% for plasma sample. Melamine in samples was extracted with liquid-liquid extraction procedures and the assay results coincided very well with that determined with flow injection chemiluminescence method. The method provides a reproducible and stable approach for sensitive detection and quantification of melamine in urine and plasma samples. PMID- 29403688 TI - Sensitive determination of 4-O-methylhonokiol in rabbit plasma by high performance liquid chromatography and application to its pharmacokinetic investigation. AB - A novel high Performance liquid Chromatographie method was developed for the determination of 4-O-methylhonokiol in rabbit plasma and was applied to its pharmacokinetic investigation. Plasma samples were treated by one-fold volume of methanol and acetonitrile to remove the interference proteins. A reverse phase column of SHIM-PACK VP-ODS (150 mm * 4.6 mm, 5.0 Mm) was used to separate 4-O methylhonokiol in the plasma samples. The detection limit of 4-O-methylhonokiol was 0.2 MUg/L and the linear range was 0.012 - 1.536 MUg/L. The good extraction recoveries were obtained for the spiked samples (84.7%, 89.3% and 87.7% for low, middle and high concentrations of added Standards, respectively). The relative standard deviation of intra-day and inter-day precisions was in the range from 0.6% to 13.5%. The pharmacokinetic study of 4-O-methylhonokiol was made and the results from the plasma-concentration curve of 4-O-methylhonokiol showed a two apartment open model. This work developed a sensitive, stable and rapid HPLC method for the determination of 4-O-methylhonokiol and the developed method has been successfully applied to a pharmacokinetic study of 4-O-methylhonokiol. PMID- 29403689 TI - Development of the fingerprints for the quality evaluation of Viscum coloratum by high Performance liquid chromatography. AB - A high-Performance liquid chromatography coupled ultraviolet (HPLC-UV) method was developed for a chemical fingerprint analysis of Viscum coloratum. Eighteen peaks were selected as the common peaks and Homoeriodictyol-7-0-beta-D-apiosiyl-(1->2) beta-D-glucoside was used as a reference. The relative areas of common peaks were used for hierarchical clustering analysis and similarity calculation. Thirty seven samples collected from different sources were classified into five groups. The similarities of 21 batches Viscum coloratum samples were beyond 0.90. The results obtained suggest that the Chromatographie fingerprint can efficiently identify Viscum coloratum. Additionally, the fingerprints can then be used to evaluate the correlation between Viscum coloratum and hosts. PMID- 29403690 TI - Evaluation preparation technology of Xiaochaihu granules using fingerprint-peak pattern matching. AB - An approach was proposed to evaluate preparation technology by means of fingerprint-peak matching technology of high Performance liquid chromatography with diode array detector (HPLC-DAD). Similarity and hierarchical clustering analysis (HCA) were applied to identify the 15 batches of Xiaochaihu granules from different manufacturers and our laboratory, and peak pattern matching between the composite formulae and Radix Bupleuri Chinensis, which was one of the main ingredients of Xiaochaihu granules, was utilized to evaluate the preparation technology of Xiaochaihu granules via the indexes of the relative deviation of retention time (RT) and UV spectrum feature similarity of their corresponding peaks. Eleven matching peaks were found between Xiaochaihu granules and Radix Bupleuri Chinensis. However, the saikosaponin A and saikosaponin D, which are the important active components in Radix Bupleuri Chinensis, were not found in Xiaochaihu granules from any manufacturers. The peak areas of 11 characteristic peaks of Xiaochaihu granules samples formed a matrix of 11 * 15. The result of HCA showed that Xiaochaihu granules samples were divided into four kinds of category. Xiaochaihu granules samples from the same manufacturer were basically clustered of the same category. The results suggested that the saikosaponin A and saikosaponin D are prone to structural transformation under the condition of decoction and in the presence of the organic acidic components. These active components, existing in raw herb, might transform to a series of non-active secondary saikosaponin due to unfavourable preparation technology. So the conventional decoction-based preparation technology of Xiaochaihu granules might greatly affect its quality and therapeutic effectiveness. This study demonstrates that fingerprint-peak matching technology can not only be used for quality control of this composite formulae, but also provide some guidance for preparation technology of Xiaochaihu granules. PMID- 29403691 TI - Using cell membrane chromatography and HPLC-TOF/MS method for in vivo study of active components from roots of Aconitum carmichaeli. AB - An offline two-dimensional system combining a rat cardiac muscle cell membrane chromatography time-of-flight mass spectrometry (CMC-TOF/MS) with a high Performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF/MS) was established for investigating the parent components and metabolites in rat urine samples after administration of the roots of Aconitum carmichaeli. On the basis ofthe analysis of the first dimension, retention components of the urine sample were collected into 30 fractions (one fraction per minute). Then offline analysis of the second dimension was carried out. 34 compounds including 24 parent alkaloids and 10 potential metabolites were identified from the dosed rat urine, and then binding affinities of different compounds on cell membranes were compared and influences of some functional groups on activity were estimated with the semi-quantification and curve fitting method. As a result, binding affinities decreased along with the process of deacylation, debenzoylation and demethylation, which may be related to the alleviation of toxicity in the procedure of herb processing or metabolism. Moreover, some minor components in rat urine (Songorine, 14-benzoylneoline, Deoxyaconitine, etc.) exerted relatively strong affinity on cell membranes are worth exploring. The results delivered by the System suggest that the CMC can be applied to in vivo study. PMID- 29403692 TI - Pharmacokinetic behavior of 16-dehydropregnenolone after intramuscular administration in rats. AB - The pharmacokinetics of 16-dehydropregnenolone (16-DHP), a sterols compound isolated from Solanum lyratum Thunb., was investigated in rats following a Single intramuscular administration (40 mg/kg). The concentration of 16-DHP in rat plasma was determined by a high Performance liquid chromatography (HPLC) method with UV detection. Levonorgestrel was used as the internal Standard (IS). The pharmacokinetic parameters of 16-DHP were derived by non-compartmental method. After a Single intramuscular administration, the maximum plasma concentration (Cmax) was (289 +/- 25) ng/mL, time to reach Cmax(tmax) was (0.38 +/- 0.14) h, the elimination half-life (t1/2) was (2.5 +/- 1.1) h, the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(0-t)) was (544 +/- 73)ng . h/mL. The results indicated that 16 DHP was absorbed quickly and eliminated rapidly in rats after the intramuscular injection. PMID- 29403693 TI - The clinical value of enzyme-multiplied immunoassay technique monitoring the plasma concentrations of cyclosporine A after renal transplantation. AB - The feasibility and the clinical value of the enzyme-multiplied immunoassay technique (EMIT) monitoring of blood concentrations of cyclosporine A (CsA) in patients treated with CsA were investigated after kidney transplantation. The validation method was performed to the EMIT determination of CsA blood concentration, the CsA whole blood 'trough concentrations (C0) of patients in different time periods after renal transplantation were monitored, and combined with the clinical complications, the statistical results were analyzed and compared. EMIT was precise, accurate and stable, also with a high quality control. The mean postoperative blood concentration of CsA was as follows: <1 month, (281.4 +/- 57.9)ng/mL; 2 - 3 months, (264.5 +/- 41. 2)ng/mL; 4 - 5 months, (236.4 +/- 38. 9)ng/mL; 6 - 12 months, (206.5 +/- 32.6)ng/mL; >12 months, (185.6 +/- 28.1)ng/mL. The toxic reaction rate of CsA blood concentration within the recommended therapeutic concentration was 14. 1%, significantly lower than that of the none-recommended dose group (37.2%) (P < 0.05); the transplantation rejection rate was 4.4%, significantly lower than that of the none-recommended dose group (22.5%) (P < 0.05). Using EMIT to monitor the blood concentration of CsA as the routine laboratory method is feasible, and is able to reduce the CsA toxicity and rejection significantly, leading to achieving the desired therapeutic effect. PMID- 29403694 TI - Highly sensitive chemiluminescence technology for protein detection using aptamer based rolling circle amplification platform. AB - A robust, selective and highly sensitive chemiluminescent (CL) platform for protein assay was presented in this paper. This novel CL approach utilized rolling circle amplification (RCA) as a signal enhancement technique and the 96 well plate as the immobilization and separation carrier. Typically, the antibody immobilized on the surface of 96-well plate was sandwiched with the protein target and the aptamer-primer sequence. This aptamer-primer sequence was then employed as the primer of RCA. Based on this design, a number of the biotinylated probes and streptavidin-horseradish peroxidase (SA-HRP) were captured on the plate, and the CL signal was amplified. In summary, our results demonstrated a robust biosensor with a detection limit of 10 fM that is easy to be established and utilized, and devoid of light source. Therefore, this new technique will broaden the perspective for future development of DNA-based biosensors for the detection of other protein biomarkers related to clinical diseases, by taking advantages of high sensitivity and selectivity. PMID- 29403695 TI - Chemiluminescence enzyme immunoassay based on magnetic nanoparticles for detection of hepatocellular carcinoma marker glypican-3. AB - Glypican-3 (GPC3) is reported as a great promising tumor marker for hepatocellular carcinoma (HCC) diagnosis. Highly sensitive and accurate analysis of serum GPC3 (sGPC3), in combination with or instead of traditional HCC marker alpha-fetoprotein (AFP), is essential for early diagnosis of HCC. Biomaterial functionalized magnetic particles have been utilized as solid supports with good biological compatibility for sensitive immunoassay. Here, the magnetic nanoparticles (MnPs) and magnetic microparticles (MmPs) with carboxyl groups were further modified with streptavidin, and applied for the development of chemiluminescence enzyme immunoassay (CLEIA). After comparing between MnPs- and MmPs-based CLEIA, MnPs-based CLEIA was proved to be a better method with less assay time, greater sensitivity, better linearity and longer chemiluminescence platform. MnPs-based CLEIA was applied for detection of sGPC3 in normal liver, hepatocirrhosis, secondary liver cancer and HCC serum samples. The results indicated that sGPC3 was effective in diagnosis of HCC with high performance. PMID- 29403696 TI - Microfluidics-based assay on the effects of microenvironmental geometry and aqueous flow on bacterial adhesion behaviors. AB - A new microfluidic system with four different microchambers (a circle and three equilateral concave polygons) was designed and fabricated using poly(dimethylsiloxane) (PDMS) and the soft lithography method. Using this microfluidic device at six flow rates (5, 10, 20, 30, 40, and 50 MUL/h), the effects of microenvironmental geometry and aqueous flow on bacterial adhesion behaviors were investigated. Escherichia coli HB101 pGLO, which could produce a green fluorescent protein induced by l-arabinose, was utilized as the model bacteria. The results demonstrated that bacterial adhesion was significantly related to culture time, microenvironment geometry, and aqueous flow rates. Adhered bacterial density increased with the culture time. Initially, the adhesion occurred at the microchamber sides, and then the entire chamber was gradually covered with increased culture time. Adhesion densities in the side zones were larger than those in the center zones because of the lower shearing force in the side zone. Also, the adhesion densities in the complex chambers were larger than those in the simple chambers. At low flow rates, the orientation of adhered bacteria was random and disorderly. At high flow rates, bacterial orientation became close to the streamline and oriented toward the flow direction. All these results implied that bacterial adhesion tended to occur in complicated aqueous flow areas. The present study provided an on-chip flow system for physiological behavior of biological cells, as well as provided a strategic cue for the prevention of bacterial infection and biofilm formation. PMID- 29403697 TI - Analysis of chiral non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac binding with HSA. AB - The protein binding of non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac with human serum albumin (HSA) was investigated using indirect chiral high performance liquid chromatography (HPLC) and ultrafiltration techniques. S-(-)-1-(1-naphthyl)-ethylamine (S-NEA) was utilized as chiral derivatization reagent and pre-column derivatization RP-HPLC method was established for the separation and assay of the three pairs of enantiomer. The method had good linear relationship over the investigated concentration range without interference. The average extraction efficiency was higher than 85% in different systems, and the intra-day and inter-day precisions were less than 15%. In serum albumin, the protein binding of etodolac enantiomers showed significant stereoselectivity that the affinity of S-enantiomer was stronger than R enantiomer, and the stereoselectivity ratio reached 6.06; Flurbiprofen had only weak stereoselectivity in HSA, and ketoprofen had no stereoselectivity at all. Scatchard curves showed that all the three chiral drugs had two types of binding sites in HSA. PMID- 29403698 TI - Quantitative analysis of a novel antimicrobial peptide in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry. AB - We described the first results of a quantitative ultra performance liquid chromatography-tandem mass spectrometry method for a novel antimicrobial peptide (phylloseptin, PSN-1). Chromatographic separation was accomplished on a Waters bridged ethyl hybrid (BEH) C18 (50 mm*2.1 mm, 1.7 MUm) column with acetonitrile water (25:75, v/v) as isocratic mobile phase. Mass spectrometry detection was performed in the positive electrospray ionization mode and by monitoring of the transitions at m/z 679.6/120, 509.6/120 (PSN-1) and m/z 340.7/165 (Thymopentin, IS). Protein precipitation was investigated and the recovery was satisfactory (above 82%). The method was shown to be reproducible and reliable with intra-day precision below 5.3%, inter-day precision below 14.2%, and linear range from 0.02 to 2 MUg/mL with r>0.994. The method was successfully applied to a pharmacokinetic study of PSN-1 in rats after intravenous administration. PMID- 29403699 TI - Analysis and determination of diterpenoids in unprocessed and processed Euphorbia lathyris seeds by HPLC-ESI-MS. AB - Euphorbia lathyris (Caper spurge) is a toxic and potent Chinese materia medica (T/PCMM). This study sought a method for identifying five diterpenoids (Euphorbia factors L1-L3, L7a and L8) with the spectra of UV and mass, quantifying three diterpenoids L1, L2, and L8 in crude extracts of unprocessed and processed E. lathyris seeds by liquid chromatography/electrospray ionization mass spectrometry (LC-ESI-MS). The analysis was achieved on an Agilent Eclipse XDB-C18 column (4.6 mm*150 mm i.d., 5 MUm) with an isocratic elution with a mobile phase consisting of water and acetonitrile at a flow rate of 0.25 mL/min at column temperature of 30 degrees C and UV detection was set at 272 nm. An ESI source was used with a positive ionization mode. The calibration curve was linear in the ranges of 9.9 79 MUg/mL for Euphorbia factor L1, 3.8-30.5 MUg/mL for Euphorbia factor L2, and 1.0-20.6 MUg/mL for Euphorbia factor L8. The average recoveries (n=6) of three diterpenoids were 98.39%, 91.10% and 96.94%, respectively, with RSD of 2.5%, 2.4% and 2.1%, respectively. The contents of the three diterpenoids in processed E. lathyris seeds were 3.435, 1.367 and 0.286 mg/g, respectively, which decreased more sharply than those in unprocessed E. lathyris seeds which were 4.915, 1.944 and 0.425 mg/g, respectively. The method is simple, accurate, reliable and reproducible, and it can be applied to control the quality of unprocessed and processed E. lathyris seeds. PMID- 29403700 TI - Comparative analysis of essential oils found in Rhizomes Curcumae and Radix Curcumae by gas chromatography-mass spectrometry. AB - A comparison of the volatile compounds in Rhizomes Curcumae (Ezhu) and Radix Curcumae (Yujin) was undertaken using gas chromatography-mass spectrometry (GC MS). Ultrasonic extraction and GC-MS methods were developed for the simultaneous determination of five sesquiterpenes, namely, alpha-pinene, beta-elemene, curcumol, germacrone and curdione, in Ezhu and Yunjin. Good linearity (r>0.999) and high inter-day precision were observed over the investigated concentration ranges. The validated method was successfully used for the simultaneous determination of five sesquiterpenes in Ezhu and Yujin. The quantitative method can be effectively used to evaluate and monitor the quality of Chinese curcuma in clinical use. PMID- 29403701 TI - A rapid method for the determination of dopamine in porcine muscle by pre-column derivatization and HPLC with fluorescence detection. AB - A rapid method has been developed based on the sample preparation procedure named as QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe), combined with reversed-phase high performance liquid chromatography with fluorescence detector and C18 column after pre-column derivatization using o-phthalaldehyde and 2 mercaptoethanol to determine dopamine in porcine muscle. Methanol and deionized water (0.1% acetic acid, v/v) with a ratio of 60:40 was used as mobile phase. The flow rate was 0.8 mL/min and dopamine was eluted within 15 min. The linearity range was 0.003-8 MUg/mL with r=0.9992. The detection limit for dopamine was 4 MUg/kg and the quantification limit was 9 MUg/kg. Recovery studies were carried out at 0.1, 0.5 and 1.0 mg/kg fortification levels and the average recoveries obtained ranged from 90.4% to 98.2% with relative standard deviations between 3.5% and 8.1%. The method was found to be suitable for detection of dopamine in animal product tissues at the maximum residue level. PMID- 29403702 TI - Rapid determination of volatile constituents in safflower from Xinjiang and Henan by ultrasonic-assisted solvent extraction and GC-MS. AB - The total volatile components were extracted from safflower by ultrasonic assisted solvent extraction (USE) and their chemical constituents were analyzed by gas chromatography-mass spectrometry (GC-MS) to provide scientific basis for the quality control of safflower. Five different solvents (diethyl ether, ethanol, ethyl acetate, dichloromethane and acetone) were used and compared in terms of number of volatile components extracted and the peak areas of these components in TIC. The results showed that USE could be used as an efficient and rapid method for extracting the volatile components from safflower. It also could be found that the number of components in the TIC of ethyl acetate extract was more than that in the TIC of other solvent ones. Meanwhile, the volatile components of safflower from Xinjiang Autonomous Region and Henan Province of China were different in chemical components and relative contents. It could be concluded that both the extraction solvents and geographical origin of safflower are responsible for these differences. The experimental results also indicated that USE/GC-MS is a simple, rapid and effective method to analyze the volatile oil components of safflower. PMID- 29403703 TI - Simultaneous determination of 12, 13-dihydroxyeuparin and glycyrrhizic acid in Yanyanfang mixture by high performance liquid chromatography. AB - A reversed phase high performance liquid chromatography (HPLC) method was established for the simultaneous determination of 12, 13-dihydroxyeuparin and glycyrrhizic acid in Yanyanfang mixture. A Grace Apollo C18 column (250 mm*4.6 mm, 5 MUm) was used as the stationary phase and the mobile phase was composed of acetonitrile and aqueous phosphoric acid (0.2%, v/v). Gradient elution was carried out at the flow rate of 1.0 mL/min and the column temperature was 30 degrees C. An ultraviolet (UV) detector was used with a selected wavelength of 240 nm. Calibration curves were linear within the concentration range of 4.6 45.75 MUg/mL for 12, 13-dihydroxyeuparin (r>0.9999) and 106.9-1068.9 MUg/mL for glycyrrhizic acid (r>0.9999), respectively. Recoveries were 102.18% for 12, 13 dihydroxyeuparin and 101.17% for glycyrrhizic acid. The method developed could be applied to the simultaneous determination of 12, 13-dihydroxyeuparin and glycyrrhizic acid in Yanyanfang mixture. PMID- 29403705 TI - Sensing of chlorpheniramine in pharmaceutical applications by sequential injector coupled with potentiometer. AB - This paper reports on development of a system consisting of a portable sequential injector coupled with potentiometric unit for sensing of chlorpheniramine (CPA), based on the reaction of CPA with potassium permanganate in acidic media. Various experimental conditions affecting the potential intensity were studied and incorporated into the procedure. Under the optimum conditions, linear relationship between the CPA concentration and peak area was obtained for the concentration range of 0.1-50 ppm. The method reflects good recovery with relative standard deviation (RSD)<3%. The detection limit was 0.05 ppm. The developed method was successfully applied for determination of CPA in pure form and in pharmaceutical dosage forms. The results, obtained using the method, are in accord with the results of the British pharmacopoeia method. In addition to its accuracy and precision, the method has the advantages of being simple, inexpensive and rapid. PMID- 29403704 TI - Liquid chromatography coupled with time-of-flight and ion trap mass spectrometry for qualitative analysis of herbal medicines. AB - With the expansion of herbal medicine (HM) market, the issue on how to apply up to-date analytical tools on qualitative analysis of HMs to assure their quality, safety and efficacy has been arousing great attention. Due to its inherent characteristics of accurate mass measurements and multiple stages analysis, the integrated strategy of liquid chromatography (LC) coupled with time-of-flight mass spectrometry (TOF-MS) and ion trap mass spectrometry (IT-MS) is well-suited to be performed as qualitative analysis tool in this field. The purpose of this review is to provide an overview on the potential of this integrated strategy, including the review of general features of LC-IT-MS and LC-TOF-MS, the advantages of their combination, the common procedures for structure elucidation, the potential of LC-hybrid-IT-TOF/MS and also the summary and discussion of the applications of the integrated strategy for HM qualitative analysis (2006-2011). The advantages and future developments of LC coupled with IT and TOF-MS are highlighted. PMID- 29403706 TI - Development and validation of analytical method for the estimation of lamivudine in rabbit plasma. AB - Lamivudine has been widely used in the treatment of HIV disease. A reliable, sensitive reversed phase high performance liquid chromatography (RP-HPLC) method was developed and validated for lamivudine in rabbit plasma. The method was developed on Hypersil BDS C-18 column (250 mm*4.6 mm, 5 MUm) using a mobile phase of 0.25% Triethylamine buffer (pH 3.0): acetonitrile (70:30, v/v). The efficient was monitored by UV detector at 256 nm. The total run time was 15 min with a flow rate of 1.0 mL/min. Calibration curve was linear over the concentration range of 25-2000 ng/mL. The retention times of lamivudine and internal standard (Nelfinavir) were 8.78 min and 10.86 min, respectively. The developed RP-HPLC method can be successfully applied for the quantitative pharmacokinetic parameters determination of lamivudine in rabbit model. PMID- 29403707 TI - An ionic liquid supported CeO2 nanoparticles-carbon nanotubes composite-enhanced electrochemical DNA-based sensor for the detection of Pb2. AB - An electrochemical sensor incorporating a signal enhancement for the determination of lead (II) ions (Pb2+) was designed on the basis of the thrombin binding aptamer (TBA) as a molecular recognition element and ionic liquid supported cerium oxide (CeO2) nanoparticles-carbon nanotubes composite modification. The composite comprises nanoparticles CeO2, multi-wall carbon nanotubes (MWNTs) and hydrophobic room temperature ionic liquid (RTIL) 1-ethyl-3 methylimidazolium tetrafluoroborate (EMIMBF4). The electrochemical sensors were fabricated by immersing the CeO2-MWNTs-EMIMBF4 modified glassy carbon electrode (GCE) into the solution of TBA probe. In the presence of Pb2+, the TBA probe could form stable G-quartet structure by the specific binding interactions between Pb2+ and TBA. The TBA-bound Pb2+ can be electrochemically reduced, which provides a readout signal for quantitative detection of Pb2+. The reduction peak current is linearly related to the concentration of Pb2+ from 1.0*10-8 M to 1.0*10-5 M with a detection limit of 5*10-9 M. This work demonstrates that the CeO2-MWNTs-EMIMBF4 nanocomposite modified GCE provides a promising platform for immobilizing the TBA probe and enhancing the sensitivity of the DNA-based sensors. PMID- 29403708 TI - Screening of chemokine receptor CCR4 antagonists by capillary zone electrophoresis. AB - CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptor, which plays a pivotal role in allergic inflammation. The interaction between 2-(2-(4 chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamoyl]-methyl}-4-oxo-thiazolidin-3 yl)-N-(3-morpholin-4-yl-propyl)-acetamide (S009) and the N-terminal extracellular tail (ML40) of CCR4 has been validated to be high affinity by capillary zone electrophoresis (CZE). The S009 is a known CCR4 antagonist. Now, a series of new thiourea derivatives have been synthesized. Compared with positive control S009, they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases. The synthesized compounds XJH-5, XJH-4, XJH-17 and XJH-1 displayed the interaction with ML40, but XJH-9, XJH-10, XJH-11, XJH-12, XJH-13, XJH-14, XJH-3, XJH-8, XJH-6, XJH-7, XJH-15, XJH-16 and XJH-2 did not bind to ML40. Both qualification and quantification characterizations of the binding were determined. The affinity of the four compounds was valued by the binding constant, which was similar with the results of chemotactic experiments. The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases. PMID- 29403709 TI - Comparative pharmacokinetics of chlorogenic acid after oral administration in rats. AB - The present study was aimed at the comparison of the pharmacokinetics of pure chlorogenic acid and extract of Solanum lyratum Thunb. The animals were allocated to two groups, and were administered chlorogenic acid or extract of S. lyratum Thunb. at a dose of 50.0 mg/kg orally. Blood samples were collected up to 8 h post-dosing. Plasma chlorogenic acid analyses were performed using an HPLC method with UV detector. The pharmacokinetic parameters were evaluated using non compartmental assessment. Significant differences existed in the two groups for AUC0-t , AUC0-infinity and CLz/F. The reliable HPLC method was successfully applied to the determination of chlorogenic acid in rat plasma at dosage of 50.0 mg/kg. PMID- 29403710 TI - Stability indicating high performance thin-layer chromatographic method for simultaneous estimation of pantoprazole sodium and itopride hydrochloride in combined dosage form. AB - A specific, precise and stability indicating high-performance thin-layer chromatographic method for simultaneous estimation of pantoprazole sodium and itopride hydrochloride in pharmaceutical formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F254 as the stationary phase. The solvent system consisted of methanol:water:ammonium acetate; 4.0:1.0:0.5 (v/v/v). This system was found to give compact and dense spots for both itopride hydrochloride (Rf value of 0.55+/ 0.02) and pantoprazole sodium (Rf value of 0.85+/-0.04). Densitometric analysis of both drugs was carried out in the reflectance-absorbance mode at 289 nm. The linear regression analysis data for the calibration plots showed a good linear relationship with R2=0.9988+/-0.0012 in the concentration range of 100-400 ng for pantoprazole sodium. Also, the linear regression analysis data for the calibration plots showed a good linear relationship with R2=0.9990+/-0.0008 in the concentration range of 200-1200 ng for itopride hydrochloride. The method was validated for specificity, precision, robustness and recovery. Statistical analysis proves that the method is repeatable and selective for the estimation of both the said drugs. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating method. PMID- 29403711 TI - Simultaneous quantification of five major active components in capsules of the traditional Chinese medicine 'Shu-Jin-Zhi-Tong' by high performance liquid chromatography. AB - A simple and reliable high performance liquid chromatography (HPLC) method has been developed for the simultaneous quantification of five major bioactive components in 'Shu-Jin-Zhi-Tong' capsules (SJZTC), for the purposes of quality control of this commonly prescribed traditional Chinese medicine. Under the optimum conditions, excellent separation was achieved, and the assay was fully validated in terms of linearity, precision, repeatability, stability and accuracy. The validated method was applied successfully to the determination of the five compounds in SJZTC samples from different production batches. The HPLC method can be used as a valid analytical method to evaluate the intrinsic quality of SJZTC. PMID- 29403712 TI - Validation and application by HPLC for simultaneous determination of vitexin-2"-O glucoside, vitexin-2"-O-rhamnoside, rutin, vitexin, and hyperoside. AB - A simple, precise, and rapid high-performance liquid chromatographic method was developed and validated for the simultaneous determination of vitexin-2"-O glucoside, vitexin-2"-O-rhamnoside, rutin, vitexin, and hyperoside. The HPLC separation was performed using a Shim-pack VP-ODS C18 column (250 mm*4.6 mm i.d., 5 MUm) with the isocratic mobile phase consisting of tetrahydrofuran/ acetonitrile/0.05% phosphoric acid solution (20:3:77, v/v/v), and the flow rate was set at 1.0 mL/min. UV detection was carried out at a wavelength of 360 nm and the whole analysis took 25 min. The method was linear in the range of 4.12-206.00 MUg/mL for vitexin-2"-O-glucoside, 4.05-202.50 MUg/mL for vitexin-2"-O rhamnoside, 1.64-82.00 MUg/mL for rutin, 1.74-87.00 MUg/mL for vitexin, and 1.41 70.60 MUg/mL for hyperoside with the correlation coefficient for each analyte more than 0.998. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.6 and 2 ng for vitexin-2"-O-glucoside, 0.6 and 2 ng for vitexin-2"-O rhamnoside, 0.3 and 1 ng for rutin, 1 and 3 ng for vitexin, and 0.5 and 2 ng for hyperoside, respectively. Intra- and inter-day precision and accuracy (RSD) were less than 3%. The developed HPLC method was successfully applied to the analysis of five flavonoids in hawthorn leaves, hawthorn fruits, and the preparations containing hawthorn leaves or fruits. PMID- 29403713 TI - Determination and pharmacokinetic study of catechin in rat plasma by HPLC. AB - A high performance liquid chromatographic method was developed and validated for the quantitative determination of catechin in rat plasma and its pharmacokinetic study after intragastric administration of Catechu and Xiongdanjiangre Wan into SD rats. Plasma samples were prepared by protein precipitation using methanol-5% aqueous zinc sulfate (70:30, v/v) as precipitant. Chromatographic separation was achieved on Hypersil C18 column (250 mm*4.6 mm, 10 MUm) with acetonitrile-water triethylamine (6:94:0.3, v/v/v, pH 4.0+/-0.1, adjusted with phosphoric acid) as mobile phase, followed by a UV detection at 207 nm. Good linearity was obtained over the range of 0.143-7.15 mg/L of catechin, with correlation coefficient of 0.9992. The method was simple, sensitive, accurate and reproducible and has been successfully applied to the pharmacokinetic study of catechin in rat plasma. PMID- 29403714 TI - Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples. AB - A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid-liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti estrogenic drug administration. PMID- 29403715 TI - Spectrofluorimetric method for determination of some angiotensin II receptor antagonists. AB - A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA's), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9982-0.9991) were obtained over the concentration range from 0.006 MUg/mL to 1.7 MUg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets. PMID- 29403716 TI - Precolumn derivatization LC-MS/MS method for the determination and pharmacokinetic study of glucosamine in human plasma and urine. AB - A selective precolumn derivatization liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of glucosamine in human plasma and urine has been developed and validated. Glucosamine was derivatized by o-phthalaldehyde/3-mercaptopropionic acid. Chromatographic separation was performed on a Phenomenex ODS column (150 mm*4.6 mm, 5 MUm) using linear gradient elution by a mobile phase consisting of methanol (A), and an aqueous solution containing 0.2% ammonium acetate and 0.1% formic acid (B) at a flow rate of 1 mL/min. Tolterodine tartrate was used as the internal standard (IS). With protein precipitation by acetonitrile and then the simple one-step derivatization, a sensitive bio-assay was achieved with the lower limit of quantitation (LLOQ) as low as 12 ng/mL for plasma. The standard addition calibration curves suitable for clinical sample analysis showed good linearity over the range of 0.012-8.27 MUg/mL in plasma and 1.80-84.1 MUg/mL in urine. The fully validated method has been successfully applied to a pharmacokinetic study of compound glucosamine sulfate dispersible tablets in health Chinese volunteers receiving single oral doses at 500, 1000 and 1500 mg of glucosamine sulfate, as well as multiple oral doses of 500 mg t.i.d. for 7 consecutive days. PMID- 29403717 TI - Analysis of in vivo absorption of didanosine tablets in male adult dogs by HPLC. AB - Didanosine is an effective antiviral drug in untreated and antiretroviral therapy experienced patients with Human Immunodeficiency Virus (HIV). An automated system using on-line solid extraction and High Performance Liquid Chromatography (HPLC) with ultraviolet (UV) detection was developed and validated for pharmacokinetic analysis of didanosine in dog plasma. Modifications were introduced on a previous methodology for simultaneous analysis of antiretroviral drugs in human plasma. Extraction was carried out on C18 cartridges, with high extraction yield as stationary phase, whereas mobile phase consisted of a mixture of 0.02 M potassium phosphate buffer, acetonitrile (KH2PO4: acetonitrile: 96:4, v/v) and 0.5% (w/v) of heptane sulphonic acid. The pH was adjusted to 6.5 with triethylamine. All samples and standard solutions were chromatographed at 28 degrees C. For an isocratic run, the flux was 1.0 mL/min, detection was at 250 nm and injected volume was 20 MUL. The method was selective and linear for concentrations between 50 and 5000 ng/mL. Drug stability data ranged from 96% to 98%, and limit of quantification was 25 ng/mL. Extraction yield was up to 95%. Drug stability in dog plasma was kept frozen at -20 degrees C for one month after three freeze thaw cycles, and for 24 h after processing in the auto sampler. Assay was successfully applied to measure didanosine concentrations in plasma dogs. PMID- 29403719 TI - Spectrophotometric method for the determination of ketoconazole based on amplification reactions. AB - This paper describes a sensitive spectrophotometric method developed for determination of Ketoconazole (KC) in tablets based on amplification reactions. Ketoconazole was oxidized with periodate, resulting in formation of KC2+ and iodate ions. After masking the excess periodate with molybdate, the iodate was treated with iodide to release iodine. The liberated iodine was transformed to [Formula: see text] species and extracted as ion-pair with rhodamine 6G into toluene for spectrophotometric measurement at 535 nm. A linear calibration graph was obtained between 0.2136 MUg/mL and 1.7088 MUg/mL of Ketoconazole with a molar absorptivity of 5*105 mol.L-1 cm-1. The procedure was successfully applied for the determination of ketoconazole in tablet formulation. PMID- 29403718 TI - Characterization of flavonoids in Millettia nitida var. hirsutissima by HPLC/DAD/ESI-MS n. AB - Millettia nitida var. hirsutissima is a Chinese herbal medicine used for the treatment of gynecological diseases. An HPLC/DAD/ESI-MS n method was established for the rapid separation and characterization of bioactive flavonoids in M. nitida var. hirsutissima. A total of 32 flavonoids were detected, of which 14 compounds were unambiguously characterized by comparing their retention time, UV, and MS spectra with those of the reference standards, and the others were tentatively identified based on their tandem mass spectrometry fragmentation data obtained in the negative ionization mode on line. Nineteen of these compounds characterized were reported from this plant for the first time. PMID- 29403720 TI - High performance liquid chromatographic separation of thirteen drugs collected in Chinese Pharmacopoeia 2010(Ch.P2010) on cellulose ramification chiral stationary phase. AB - The enantiomers separation of thirteen drugs collected in Ch.P2010 was performed on chiral stationary phase of cellulose ramification (chiralpak OD and chiralpak OJ) by high performance liquid chromatographic (HPLC) methods, which included ibuprofen (C1), ketoprofen (C2), nitrendipine (C3), nimodipine (C4), felodipine (C5), omeprazole (C6), praziquantel (C7), propranolol hydrochloride (C8), atenolol (C9), sulpiride (C10), clenbuterol hydrochloride (C11), verapamil hydrochloride (C12), and chlorphenamine maleate (C13). The mobile phase consisted of isopropanol and n-hexane. The detection wavelength was set at 254 nm and the flow rate was 0.7 mL/min. The enantiomers separation of these thirteen racemates on chiralpak OD column and chiralpak OJ column was studied, while the effects of proportion of organic additives, alcohol displacer and temperature on the separation were studied. And the mechanism of some of racemates was discussed. The results indicated that thirteen chiral drugs could be separated on chiral stationary phase of cellulose ramification in normal phase chromatographic system. The chromatographic retention and resolution of enantiomers could be adjusted by factors including column temperature and the concentration of alcohol displacer and organic alkaline modifier in mobile phase. It was shown that the resolution was improved with reducing concentration of alcohol displacer. When concentration of organic alkaline modifier was 0.2% (v/v), the resolution and the peak shape were fairly good. Most racemates mentioned above had better resolution at column temperature of 25 degrees C. When racemates were separated, the temperature should be kept so as to obtain stable separation results. PMID- 29403721 TI - Glassy carbon electrode modified with multi-walled carbon nanotubes sensor for the quantification of antihistamine drug pheniramine in solubilized systems. AB - A sensitive electroanalytical method for quantification of pheniramine in pharmaceutical formulation has been investigated on the basis of the enhanced electrochemical response at glassy carbon electrode modified with multi-walled carbon nanotubes in the presence of sodium lauryl sulfate. The experimental results suggest that the pheniramine in anionic surfactant solution exhibits electrocatalytic effect resulting in a marked enhancement of the peak current response. Peak current response is linearly dependent on the concentration of pheniramine in the range 200-1500 MUg/mL with correlation coefficient 0.9987. The limit of detection is 58.31 MUg/mL. The modified electrode shows good sensitivity and repeatability. PMID- 29403722 TI - Determination of metabolite of nicergoline in human plasma by high-performance liquid chromatography and its application in pharmacokinetic studies. AB - A fast, simple and sensitive high performance liquid chromatographic (HPLC) method has been developed for determination of 10alpha-methoxy-6-methyl ergoline 8beta-methanol (MDL, a main metabolite of nicergoline) in human plasma. One-step liquid-liquid extraction (LLE) with diethyl ether was employed as the sample preparation method. Tizanidine hydrochloride was selected as the internal standard (IS). Analysis was carried out on a Diamonsil ODS column (150 mm*4.6 mm, 5 MUm) using acetonitrile-ammonium acetate (0.1 mol/L) (15/85, v/v) as mobile phase at detection wavelength of 224 nm. The calibration curves were linear over the range of 2.288-73.2 ng/mL with a lower limit of quantitation (LLOQ) of 2.288 ng/mL. The intra- and inter-day precision values were below 13% and the recoveries were from 74.47% to 83.20% at three quality control levels. The method herein described was successfully applied in a randomized crossover bioequivalence study of two different nicergoline preparations after administration of 30 mg in 20 healthy volunteers. PMID- 29403723 TI - Development and validation of a reversed-phase HPLC method for analysis of tetrahydrozoline hydrochloride in eye drop formulations. AB - A simple, precise, accurate, and stability-indicating method is developed and validated for analysis of tetrahydrozoline hydrochloride in eye drop formulations. Separation was achieved on a reversed-phase C8 column (125 mm*4.6 mm i.d., 5 MUm) using a mobile phase consisting of acetonitrile/phosphate buffer of pH 3.0 (20:80, v/v) at a flow rate of 1.0 mL/min and UV detection at 240 nm. This method is validated according to United States Pharmacopeia requirements for new methods, which include accuracy, precision, selectivity, robustness, and linearity and range. This method shows enough selectivity, accuracy, precision, and linearity and range to satisfy Federal Drug Administration/International Conference on Harmonization regulatory requirements. The current method demonstrates good linearity over the range of 0.025-0.075 mg/mL of tetrahydrozoline with r2 0.999. The average recovery of the method is 100.8% with a relative standard deviation of 0.47%. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operators has proven that the method is robust and rugged. PMID- 29403724 TI - Fingerprint analysis of placenta polypeptide injection by high performance liquid chromatography. AB - : Objective: To develop the representative fingerprint for the quality control of placenta polypeptide injection. Methods: The chromatographic separation was performed using a Phenomenex Gemini C18 column (250 mm*4.6 mm, 5 MUm) maintained at 30 degrees C. 0.1% aqueous trifluoroacetic acid (Solvent A) and acetonitrile contained 0.1% TFA (Solvent B) were used as mobile phase with a gradient elution. Detection wavelength was 280 nm with the sample injection volume of 50 MUL; the flow rate was 1.0 mL/min. The fingerprints of different samples were investigated by similarity analysis. Results: Nine peaks were identified as the characteristic common peaks. The similarities of the fingerprints of the 10 batches of samples were above 0.992. Conclusion: This method showed high precision and good repeatability, and provided the basis for the improvement of the quality control of placenta polypeptide injection. PMID- 29403725 TI - Determination of fluoroquinolones, sulfonamides, and tetracyclines multiresidues simultaneously in porcine tissue by MSPD and HPLC-DAD. AB - An efficient method is provided to detect simultaneously some important veterinary drugs from different classes in highly complex animal tissue matrix. This method using matrix solid-phase dispersion (MSPD) and high performance liquid chromatography (HPLC) with diode array detection (DAD) is developed to effectively determine two fluoroquinolones (enoxacin and lomefloxacin), two sulfonamides (sulfanilamide and sulfamethoxazole) and one tetracycline (tetracycline) simultaneously in porcine tissues. In the process, MSPD methodology was used to treat samples, washed by n-hexane to remove lipid, eluted the analytes with acetonitrile-dichloromethane (1:1, v/v). Solvent acetonitrile and solvent acetic acid (0.1%) were combined in a gradient. HPLC-DAD analysis of the tissue samples was performed within 15 min at a flow rate of 1.0 mL/min. The results showed that a recovery at 0.1, 0.5 and 1.0 MUg/g fortification levels ranged from 80.6% to 99.2% with satisfactory relative standard deviations (RSDs) (below 6.1%, n=3) and the limits of quantitation (LOQ) ranged from 7 MUg/kg to 34 MUg/kg in porcine tissues. Utilization of the method in successfully simultaneous analysis of porcine tissue incurred with veterinary drug multiresidues is described. PMID- 29403726 TI - Immobilized enzyme reactors in HPLC and its application in inhibitor screening: A review. AB - This paper sets out to summarize the literatures based on immobilized enzyme bio chromatography and its application in inhibitors screening in the last decade. In order to screen enzyme inhibitors from a mass of compounds in preliminary screening, multi-pore materials with good biocompatibility are used for the supports of immobilizing enzymes, and then the immobilized enzyme reactor applied as the immobilized enzyme stationary phase in HPLC. Therefore, a technology platform of high throughput screening is gradually established to screen the enzyme inhibitors as new anti-tumor drugs. Here, we briefly summarize the selective methods of supports, immobilization techniques, co-immobilized enzymes system and the screening model. PMID- 29403727 TI - Determination of drug, excipients and coating distribution in pharmaceutical tablets using NIR-CI. AB - The growing interest of the pharmaceutical industry in Near Infrared-Chemical Imaging (NIR-CI) is a result of its high usefulness for quality control analyses of drugs throughout their production process (particularly of its non-destructive nature and expeditious data acquisition). In this work, the concentration and distribution of the major and minor components of pharmaceutical tablets are determined and the spatial distribution from the internal and external sides has been obtained. In addition, the same NIR-CI allowed the coating thickness and its surface distribution to be quantified. Images were processed to extract the target data and calibration models constructed using the Partial Least Squares (PLS) algorithms. The concentrations of Active Pharmaceutical Ingredient (API) and excipients obtained for uncoated cores were essentially identical to the nominal values of the pharmaceutical formulation. But the predictive ability of the calibration models applied to the coated tablets decreased as the coating thickness increased. PMID- 29403728 TI - Voltammetric quantification of anti-hepatitis drug Adefovir in biological matrix and pharmaceutical formulation. AB - Electrochemical reduction behavior of Adefovir was studied using Hanging Mercury Drop Electrode (HMDE) in Britton-Robinson (BR) buffer solution. Voltammetric study showed one well-defined reduction peak in the potential range -1.2 to -1.4 V (vs. Ag/AgCl) due to reduction of C=N bond of the imidazole ring. Solid-phase extraction and protein-precipitation techniques were employed for extraction of Adefovir from human plasma. The proposed method allows quantification of Adefovir in human plasma over the concentration range 0.50-5.00 MUg/mL with the detection limit 0.17 MUg/mL, whereas in pharmaceutical formulation 0.25-2.25 MUg/mL with the detection limit 0.08 MUg/mL. PMID- 29403729 TI - Validated stability indicating methods for determination of nitazoxanide in presence of its degradation products. AB - Three sensitive, selective and reproducible stability-indicating methods are presented for determination of nitazoxanide (NTZ), a new anti-protozoal drug, in presence of its degradation products. Method A utilizes the first derivative of ratio spectra spectrophotometry by measurement of the amplitude at 364.4 nm using one of the degradation products as a divisor. Method B is a chemometric-assisted spectrophotometry, where principal component regression (PCR) and partial least squares (PLS) were applied. These two approaches were successfully applied to quantify NTZ in presence of degradation products using the information included in the absorption spectra in the range 260-360 nm. Method C is based on the separation of NTZ from its degradation products followed by densitometric measurement of the bands at 254 nm. The separation was carried out on silica gel 60F254, using chloroform-methanol-ammonia solution-glacial acetic acid (95:5:1:1 by volume, pH=5.80) as a developing system. These methods are suitable as stability-indicating methods for the determination of NTZ in presence of its degradation products either in bulk powder or in pharmaceutical formulations. Statistical analysis of the results has been carried out revealing high accuracy and good precision. PMID- 29403730 TI - The expert system of genotype discrimination for D5S818 locus based on near infrared spectroscopy-principal discriminant variate. AB - This paper studied the expert system of genotype discrimination for the STR locus D5S818 based on near-infrared spectroscopy-principal discriminant variate (PDV). Six genotypes, i.e. genotypes 10-10, 10-11, 11-11, 11-12, 11-13 and 13-13, were selected as research subjects. Based on the optimum polymerase chain reaction (PCR) conditions, about 54 measuring samples for each genotype were obtained; these samples were tested by near-infrared spectroscopy directly. With differences between homozygote genotypes and heterozygote ones, and differences of the total number of core repeat units between the six genotypes, two types of genotyping-tree structure were constructed and their respective PDV models were studied using the near-infrared spectra of the samples as recognition variables. Finally, based on the classification ability of these two genotyping-tree structures, an optimum expert system of genotype discrimination was built using the PDV models. The result demonstrated that the built expert system had good discriminability and robustness; without any preprocessing for PCR products, the six genotypes studied could be discriminated rapidly and correctly. It provided a methodological support for establishing an expert system of genotype discrimination for all genotypes of locus D5S818 and other STR loci. PMID- 29403731 TI - Voltammetric behavior of sedative drug midazolam at glassy carbon electrode in solubilized systems. AB - Redox behavior of midazolam was studied at a glassy carbon electrode in various buffer systems, supporting electrolytes and pH using differential pulse, square wave and cyclic voltammetry. Based on its reduction behavior, a direct differential pulse voltammetric method has been developed and validated for the determination of midazolam in parenteral dosage. Three well-defined peaks were observed in 0.1% SLS, Britton-Robinson (BR) buffer of pH 2.5. The effect of surfactants like sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB) and Tween 20 was studied. Among these surfactants SLS showed significant enhancement in reduction peak. The cathodic peak currents were directly proportional to the concentration of midazolam with correlation coefficient of 0.99. PMID- 29403732 TI - Comparison of chemiluminescence enzyme immunoassay based on magnetic microparticles with traditional colorimetric ELISA for the detection of serum alpha-fetoprotein. AB - A chemiluminescence enzyme immunoassay based on magnetic microparticles (MmPs CLEIA) was developed to evaluate serum alpha-fetoprotein (AFP) in parallel with traditional colorimetric enzyme-linked immunosorbent assay (ELISA). A systematic comparison between the MmPs-CLEIA and colorimetric ELISA concluded that the MPs CLEIA exhibited fewer dosages of immunoreagents, less total assay time, and better linearity, recovery, precision, sensitivity and validity. AFP was detected in forty human serum samples by the proposed MPs-CLEIA and ELISA, and the results were compared with commercial electrochemiluminescence immunoassay (ECLIA) kit. The correlation coefficient between MPs-CLEIA and ELISA was obtained with R2=0.6703; however, the correlation between MPs-CLEIA and ECLIA (R2=0.9582) was obviously better than that between colorimetric ELISA and ECLIA (R2=0.6866). PMID- 29403733 TI - Development and validation of RP-HPLC and RP-UPLC methods for quantification of parathyroid hormones (1-34) in medicinal product formulated with meta-cresol. AB - Rapid and sensitive reversed phase high performance liquid chromatography (RP HPLC) and ultra performance liquid chromatography (RP-UPLC) method with UV detection has been developed and validated for quantification of parathyroid hormone (PTH) in presence of meta-cresol as a stabilizer in a pharmaceutical formulation. Chromatography was performed with mobile phase containing 0.1% Trifluoroacetic acid (TFA) in MilliQ water and 0.1% TFA in acetonitrile with gradient program and flow rate at 0.3 mL/min for HPLC and 0.4 mL/min for UPLC. Quantification was accomplished with internal reference standard (qualified against innovator product and National Institute for Biological Standards and Control (NIBSC) standard). The methods were validated for linearity (correlation coefficient=0.99), range, accuracy, precision and robustness. Robustness was confirmed by considering three factors; mobile phase composition, column temperature and flow rate/age of mobile phase. Intermediate precision was confirmed on different equipments, different columns and on different days. The relative standard deviation (RSD) (<2% for RP-HPLC and <1% for UPLC, n=30) indicated a good precision. Retention time was found about 17 min and 2 min by HPLC and UPLC methods, respectively. Both methods are simple, highly sensitive, precise and accurate and have the potential of being useful for routine quality control. PMID- 29403734 TI - Separation, identification, and quantification of active constituents in Fructus Psoraleae by high-performance liquid chromatography with UV, ion trap mass spectrometry, and electrochemical detection. AB - The qualitative and quantitative analysis of active constituents in Fructus Psoraleae is presented by high-performance liquid chromatography (HPLC) coupled with different detections. Extracts of Fructus Psoraleae were examined by HPLC with ion trap mass spectrometry (IT-MS) and 18 major compounds of coumarins, benzofuran glycosides, flavonoids, and meroterpene were identified. The determination of four major constituents including bavachin, isobavachalcone, bavachinin, and bakuchiol was accomplished by HPLC with UV, MS, and electrochemical detection (ECD). These methods were evaluated for a number of validation characteristics (repeatability, LOD, calibration range, and recovery). ECD obtained a high sensitivity for analysis of the four components; MS provided a high selectivity and sensitivity for determination of bavachin, isobavachalcone, and bavachinin in negative-ion mode. After optimization of the methods, separation, identification. and quantification of the four components in Fructus Psoraleae were comprehensively tested by HPLC with UV, MS, and ECD. PMID- 29403735 TI - Development and validation of a normal-phase HPTLC method for the simultaneous analysis of Lamivudine and Zidovudine in fixed-dose combination tablets. AB - Simultaneous quantification of Lamivudine and Zidovudine in tablets by HPTLC method was developed and validated. The chromatograms were developed using a mobile phase of toluene:ethyl acetate:methanol (4:4:2, v/v/v) on pre-coated plate of silica gel GF aluminum TLC plate and quantified by densitometric absorbance mode at 276 nm. The Rf values were 0.41+/-0.03 and 0.60+/-0.04 for Lamivudine and Zidovudine, respectively. The linearity of the method was found to be within the concentration range of 50-250 ng/spot for Lamivudine and for Zidovudine, it was 100-500 ng/spot. The lower limits of detection and quantification were 2.23 ng/spot and 7.90 ng/spot for Lamivudine and 2.90 ng/spot and 8.85 ng/spot for Zidovudine. The method was also validated for precision, specificity and recovery. This developed method was used to analyze fixed-dose tablets (Duovir, Cipla Ltd) samples of Lamivudine and Zidovudine. PMID- 29403736 TI - New fluorimetric assay of horseradish peroxidase using sesamol as substrate and its application to EIA. AB - Horseradish peroxidase (HRP) is generally used as a label enzyme in enzyme immunoassay (EIA). The procedure used for HRP detection in EIA is critical for sensitivity and precision. This paper describes a novel fluorimetric assay for horseradish peroxidase (HRP) using sesamol as substrate. The principle of the assay is as follow: sesamol (3,4-methylenedioxy phenol) is reacted enzymatically in the presence of hydrogen peroxide to produce dimeric sesamol. The dimer is fluorescent and can be detected sensitively at ex. 347 nm, em. 427 nm. The measurable range of HRP was 1.0*10-18 to 1.0*10-15 mol/assay, with a detection limit of 1.0*10-18 mol/assay. The coefficient of variation (CV, n=8) was examined at each point on the standard curve, with a mean CV percentage of 3.8%. This assay system was applied to thyroid stimulating hormone (TSH) EIA using HRP as the label enzyme. PMID- 29403737 TI - Development and validation of RP-HPLC and RP-UPLC methods for quantification of erythropoietin formulated with human serum albumin. AB - Rapid and sensitive reverse phase high performance liquid chromatography (RP HPLC) and ultra performance liquid chromatography (UPLC) methods with UV detection for quantification of erythropoietin (EPO) in presence of human serum albumin (HSA) as a stabilizer in a pharmaceutical formulation of EPO have been developed and validated. Chromatography was performed with mobile phase containing 0.1% Trifluoroacetic acid (TFA) in MilliQ water and 0.1% TFA in acetonitrile with gradient program and a flow rate of 1.5 mL/min for HPLC and 0.35 mL/min for UPLC. Quantification was accomplished with internal reference standard (qualified using EP reference standard). The methods were validated for linearity (correlation coefficient=0.99), accuracy, precision and robustness. Robustness was confirmed by considering three factors; percentages of TFA in mobile phase, age of test sample and mobile phase and column temperature. Intermediate precision was confirmed by different analysts, different equipments and on different days. The relative standard deviation (RSD) value (<2%, n=30) indicated good precision of the developed method. The proposed RP-HPLC method had retention time less than 20 min while the developed UPLC method had retention time less than 4 min. Both the RP-HPLC and UPLC methods were simple, highly sensitive, precise and accurate, suggesting that the developed methods are useful for routine quality control. PMID- 29403738 TI - Simultaneous determination of pioglitazone and candesartan in human plasma by LC MS/MS and its application to a human pharmacokinetic study. AB - A simple and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method has been developed and fully validated for simultaneous quantification of pioglitazone and candesartan in human plasma. Irbesartan was used as an internal standard. The analytes were extracted from human plasma samples by solid-phase extraction technique using a Strata-X 33 MUm polymeric sorbent. The reconstituted samples were chromatographed on a C18 column by using a 80:20 (v/v) mixture of acetonitrile and 0.1% formic acid as the mobile phase at a flow rate of 0.8 mL/min. The calibration curves obtained were linear (r>=0.99) over the concentration range of 15-3000 ng/mL for pioglitazone and 5-608 ng/mL for candesartan. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. A run time of 2.7 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies. PMID- 29403739 TI - Capture of cervical exfoliative cells on a glass slide coated by 3 glycidyloxypropyl trimethoxysilane and poly-L-lysine. AB - A new modification method for glass slides was developed and applied to make ThinPrep Pap smears, in order to increase the adhesion ability of cervical exfoliative cells. 3-glycidyloxypropyl trimethoxysilane (GOPS) was coated on the glass slides firstly on the slides, then poly-L-lysine (PLL) was covalently modified onto the above epoxy-terminated slides to form GOPS-PLL double decorated slides. The modified slides were characterized using X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The cell adhesion ability effect was tested and compared with traditional PLL coated slides by fixing the cervical exfoliative cells on the double adorned slides. The control test was conducted by the bare glass slides unmodified. The cell morphology of cervical exfoliative cells adhered on different slides was observed under the microscope after Papanicolaou staining. The number of cervical exfoliative cells on the unmodified slides, PLL coated slides and GOPS-PLL coated slides was 1030+/-300, 3283+/-226 and 4119+/-280 (n=12), respectively. The data among the three different modification methods showed significant differences (one-way analysis of variance, ANOVA test, P<0.05). The cell capturing effect of the GOPS-PLL slide was the best among the three different modified slides. In addition, the GOPS-PLL slide could enhance the uniformity of the adhered cells and be widely applied to the ThinPrep system for cervical carcinoma screening to increase the accuracy rate of diagnosis. PMID- 29403740 TI - Quantification of desloratadine in human plasma by LC-ESI-MS/MS and application to a pharmacokinetic study. AB - A simple, sensitive, and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of desloratadine (DL) in human plasma using desloratadine-d5 (DLD5) as an internal standard (IS). Chromatographic separation was performed using an Xbridge C18 column (50 mm*4.6 mm, 5 MUm) with an isocratic mobile phase composed of 10 mM ammonium formate: methanol (20:80, v/v), at a flow rate of 0.7 mL/min. DL and DLD5 were detected with proton adducts at m/z 311.2->259.2 and 316.2->264.3 in multiple reaction monitoring (MRM) positive modes, respectively. Liquid-liquid extraction (LLE) method was used to extract the drug and the IS. The method was validated over a linear concentration range of 5.0-5000.0 pg/mL with a correlation coefficient of (r2)>=0.9994. This method demonstrated intra- and inter-day precision within 0.7 2.0% and 0.7-2.7%, and an accuracy within 101.4-102.4%, and 99.5-104.8%. DL was found to be stable throughout the freeze-thaw cycles, bench-top, and postoperative stability studies. This method was successfully applied in the analysis of plasma samples following oral administration of DL (5 mg) in 35 healthy Indian male human volunteers under fasting conditions. PMID- 29403742 TI - Adsorptive stripping voltammetric methods for determination of aripiprazole. AB - Anodic behavior of aripiprazole (ARP) was studied using electrochemical methods. Charge transfer, diffusion and surface coverage coefficients of adsorbed molecules and the number of electrons transferred in electrode mechanisms were calculated for quasi-reversible and adsorption-controlled electrochemical oxidation of ARP at 1.15 V versus Ag/AgCl at pH 4.0 in Britton-Robinson buffer (BR) on glassy carbon electrode. Voltammetric methods for direct determination of ARP in pharmaceutical dosage forms and biological samples were developed. Linearity range is found as from 11.4 MUM (5.11 mg/L) to 157 MUM (70.41 mg/L) without stripping mode and it is found as from 0.221 MUM (0.10 mg/L) to 13.6 MUM (6.10 mg/L) with stripping mode. Limit of detection (LOD) was found to be 0.11 MUM (0.05 mg/L) in stripping voltammetry. Methods were successfully applied to assay the drug in tablets, human serum and human urine with good recoveries between 95.0% and 104.6% with relative standard deviation less than 10%. PMID- 29403741 TI - Preparation of gastro-resistant pellets containing chitosan microspheres for improvement of oral didanosine bioavailability. AB - The purpose of this work was to introduce a new concept of coated pellets containing chitosan microspheres loaded with didadosine for oral administration, aiming at reducing the frequency of administration and improving the bioavailability by a suitable release profile. Chitosan microspheres were produced under fluidized bed, followed by extrusion and spheronization to obtain pellets with a mean diameter of about 1 mm. The pellets were then coated with Kollidon(r) VA64 and Kollicoat(r) MAE100P in water dispersion to depict a sustained release profile. Conventional hard gelatine capsules were loaded with these pellets and tested in vitro for their release profile of didadosine. Dissolution testing confirmed that chitosan microsphere pellets provides appropriate sustained release up to 2 h behavior for didanosine. PMID- 29403744 TI - High performance liquid chromatography mass spectrometric method for the simultaneous quantification of pravastatin and aspirin in human plasma: Pharmacokinetic application. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method has been developed and fully validated for the simultaneous quantification of pravastatin and aspirin in human plasma. Furosemide was used as an internal standard. Analytes and the internal standard were extracted from human plasma by liquid-liquid extraction technique using methyl tertiary butyl ether. The reconstituted samples were chromatographed on a Zorbax SB-C18 column by using a mixture of 5 mM ammonium acetate buffer and acetonitrile (20:80, v/v) as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r>=0.99) over the concentration range of 0.50-600.29 ng/mL for pravastatin and 20.07-2012.00 ng/mL for aspirin. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.0 min for each sample made it possible to analyze more than 400 human plasma samples per day. The proposed method was found to be applicable to clinical studies. PMID- 29403743 TI - Validated spectrofluorimetric method for the determination of atorvastatin in pharmaceutical preparations. AB - A rapid, sensitive and simple spectrofluorimetric method was developed for the estimation of atorvastatin. In this method, the native fluorescence characteristics of atorvastatin have been studied in both acidic and basic media. High sensitivity was obtained with 5% acetic acid at 389 nm using 276 nm for excitation. Regression analysis showed a good correlation coefficient (r=0.9995) between fluorescence intensity and concentration over the range of 1.5-4 MUg/mL with detection limit of 0.012 MUg/mL. The proposed method was successfully applied to the analysis of atorvastatin in pure and pharmaceutical dosage forms with average recovery of 100.29+/-0.47%. The results were compared favorably with those of the reported method. PMID- 29403745 TI - Simple and sensitive determination of sparfloxacin in pharmaceuticals and biological samples by immunoassay. AB - Plasma quinolone concentrations are not routinely measured in clinical practice. However, in order to optimize quinolone treatment, monitoring of plasma concentrations could sometimes be useful particularly in critically ill patients. In this study, anti-sparfloxacin antibody was obtained by immunizing rabbits with sparfloxacin conjugated with bovine serum albumin using isobutyl chloroformate method. After the assay procedure was optimized, the standard curve of sparfloxacin was established. The practical measuring range of the competitive ELISA extended from 5 ng/mL to 2 MUg/mL. The recovery rates and coefficients of variation for rat plasma, urine and tissues were 87.7-106.2% and 4.8-15.3%, respectively. To demonstrate the potential of the ELISA, a preliminary pharmacokinetics and tissue distribution study of sparfloxacin in rats and quantitative analysis of sparfloxacin in several pharmaceuticals were performed and compared with high-performance liquid chromatography (HPLC). The experimental data indicated that the proposed method would be a valuable tool in therapeutic drug monitoring (TDM) for sparfloxacin. PMID- 29403746 TI - Analysis of species-dependent hydrolysis and protein binding of esmolol enantiomers. AB - The stereoselective hydrolysis of esmolol in whole blood and in its separated components from rat, rabbit and human was investigated. Blood esterase activities were variable in different species in the order of rat>rabbit>human. Rat plasma showed the high esterase activity and had no stereoselectivity to enantiomers. Rabbit red blood cell (RBC) membrane, RBC cytosol and plasma all hydrolyzed esmolol but with different esterase activity, whereas the hydrolysis in RBC membrane and cytosol showed significant stereoselectivity towards R-(+)-esmolol. Esterase in RBC cytosol from human blood mainly contributed to the esmolol hydrolysis, which was demonstrated with no stereoselctivity. Esterase in human plasma showed a low activity, but a remarkable stereoselectivity with R-(+) esmolol. In addition, the protein concentration affected the hydrolysis behavior of esmolol in RBC suspension. Protein binding of esmolol enantiomers in human plasma, human serum albumin (HSA) and alpha1-acid glycoprotein (AGP) revealed that there was a significant difference in bound fractions between two enantiomers, especially for AGP. Our results indicated that the stereoselective protein binding might play a role in the different hydrolysis rates of esmolol enantiomers in human plasma. PMID- 29403747 TI - Validated gradient stability indicating HPLC method for determining Diltiazem Hydrochloride and related substances in bulk drug and novel tablet formulation. AB - A stability-indicating liquid chromatographic method has been developed and validated for the determination of Diltiazem Hydrochloride (DTZ) together with its six related substances (Diltiazem sulphoxide, Imp-A, Imp-B, Imp-D, Imp-E, and Imp-F) in a laboratory mixture as well as in a novel tablet formulation developed in-house. Efficient chromatographic separation was achieved on a Hypersil BDS C18 (150 mm*4.6 mm, 5.0 MUm) with mobile phase containing 0.2% Triethylamine (TEA) in gradient combination with acetonitrile (ACN) at a flow rate of 1.0 mL/min and the eluent was monitored at 240 nm. In the developed method, the resolution of DTZ from any pair of impurities was found to be greater than 2.0. The test solution and related substances were found to be stable in the diluent for 24 h. The developed method resolved the drug from its known impurities, stated above, and also from additional impurities generated when the formulation was subjected to forced degradation; the mass balance was found close to 99.9%. Regression analyses indicate correlation coefficient value greater than 0.997 for DTZ and its six known impurities. The LOD for DTZ and the known impurities was at a level below 0.02%. The method has shown good, consistent recoveries for DTZ (99.8 101.2%) and also for its six known impurities (97.2-101.3%). The method was found to be accurate, precise, linear, specific, sensitive, rugged, robust, and stability-indicating. PMID- 29403748 TI - Simultaneous determination of oleanolic acid and ursolic acid by RP-HPLC in the leaves of Eriobotrya japonica Lindl. AB - Oleanolic acid (OA) and ursolic acid (UA) are isomeric triterpenic acids and only one methyl's position is different between them. OA and UA always exist in the same plant, so it is difficult to separate them when determining contents by RP HPLC. In this study, a very simple mobile phase for HPLC was developed to simultaneously determine UA and OA, and the factors affecting separation were also discussed. The mobile phase is methanol: water (95:5) with flow rate 0.4 mL/min. The retention time for OA and UA was 20.58 and 21.57 min, respectively, the resolution was 1.61. The average contents of OA and UA of three Loquat leaves sets were 1.4 mg/g and 5.6 mg/g, respectively. Regarding the HPLC, we found that changing mobile phase, adjusting the pH value or adding ion-pairing agent could not affect the separation between UA and OA greatly. While adjustment of the flow rate and column temperature could improve the resolution greatly. PMID- 29403749 TI - Second-order calibration applied to quantification of two active components of Schisandra chinensis in complex matrix. AB - The effectiveness of traditional Chinese medicine (TCM) against various diseases urges more low cost, speed and sensitive analytical methods for investigating the phamacology of TCM and providing a theoretical basis for clinical use. The potential of second-order calibration method was validated for the quantification of two effective ingredients of Schisandra chinensis in human plasma using spectrofluorimetry. The results obtained in the present study demonstrate the advantages of this strategy for multi-target determination in complex matrices. Although the spectra of the analytes are similar and a large number of interferences also exist, second-order calibration method could predict the accurate concentrations together with reasonable resolution of spectral profiles for analytes of interest owing to its 'second-order advantage'. Moreover, the method presented in this work allows one to simply experimental procedure as well as reduces the use of harmful chemical solvents. PMID- 29403750 TI - Quantification of sibutramine and its two metabolites in human plasma by LC-ESI MS/MS and its application in a bioequivalence study. AB - Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years. The use of anti-obesity drugs such as sibutramine is somewhat helpful. There is a need to quantify such drugs in biological samples, which is generally quite difficult. In this report, we developed and validated a simple, sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of sibutramine (SB) and its two metabolites N-des methyl sibutramine (DSB) and N-di desmethyl sibutramine (DDSB) in human plasma. Zorbax SB-C18 (4.6 mm*75 mm, 3.5 MUm, 80 A) analytical column and 5 mM ammonium formate:acetonitrile (10:90, v/v) mobile phase were used for chromatographic separation of SB, DSB and DDSB. Multiple reaction monitoring (MRM) in the positive mode was used to detect SB, DSB and DDSB at m/z 280.3/124.9, 266.3/125.3 and 252.2/124.9, respectively. Liquid-liquid extraction was used for the extraction of analytes and internal standard from human plasma. This method was validated over a linear concentration range of 10.0 10,000.0 pg/mL for SB, DSB and DDSB with correlation coefficients (r) of >=0.9997. The drug and the two metabolites were stable in plasma samples. The validated method was successfully applied in a bioequivalence and pharmacokinetic study with human volunteers under fasting condition. PMID- 29403751 TI - Preparative isolation and purification of 12,13-dihydroxyeuparin from Radix Eupatorii Chinensis by high-speed counter-current chromatography. AB - An efficient method for the isolation and purification of 12,13-dihydroxyeuparin from Radix Eupatorii Chinensis by high speed counter-current chromatography (HSCCC) was established in this paper. The ether extracts of Radix Eupatorii Chinensis were purified by HSCCC with a solvent system of hexyl hydride-ethyl acetate-methanol-water (1:2:1:2, v/v/v/v). The upper phase was used as the stationary phase and the lower phase as the mobile phase. About 8.4 mg of 12,13 dihydroxyeuparin was obtained from 200 mg of ether extracts from Radix Eupatorii Chinensis in one-step HSCCC separation, with the purity of 96.71%, as determined by HPLC. After methanol-water recrystallization, the purity of 12,13 dihydroxyeuparin reached 99.83%. Such a simple and effective method was fairly useful to prepare pure compound as reference substances for related study on Radix Eupatorii Chinensis. PMID- 29403752 TI - LC-UV and LC-MS evaluation of stress degradation behavior of desvenlafaxine. AB - The objective of current study was to develop a validated specific stability indicating reversed-phase liquid chromatographic method for the quantitative determination of desvenlafaxine in bulk sample and pharmaceutical dosage form in the presence of degradation products. Forced degradation studies were performed on bulk sample of desvenlafaxine as per ICH prescribed stress conditions using acid, base, oxidative and photolytic degradation to show the stability indicating power of the method. Significant degradation was observed under acidic stress condition and the degradation product formed was identified by LC-MS and a degradation pathway for drug has been proposed. Successful separation of drug from degradation products formed under stress conditions was achieved on a SymmetryShield column C18 (5 MUm, 250 mm*4.6 mm, i.d.) using the mobile phase consisting of a mixture of 0.2% (v/v) triethylamine in ammonium acetate (0.05 M; pH 6.5) and methanol using isocratic gradient. PMID- 29403753 TI - A validated stability-indicating LC method for the separation of enantiomer and potential impurities of Linezolid using polar organic mode. AB - Although a number of methods are available for evaluating Linezolid and its possible impurities, a common method for separation if its potential impurities, degradants and enantiomer in a single method with good efficiency remain unavailable. With the objective of developing an advanced method with shorter runtimes, a simple, precise, accurate stability-indicating LC method was developed for the determination of purity of Linezolid drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of Linezolid along with the chiral impurity. This method can also be used for the estimation of assay of Linezolid in drug substance as well as in drug product. The method was developed using Chiralpak IA (250 mm*4.6 mm, 5 MUm) column. A mixture of acetonitrile, ethanol, n-butyl amine and trifluoro acetic acid in 96:4:0.10:0.16 (v/v/v/v) ratio was used as a mobile phase. The eluted compounds were monitored at 254 nm. Linezolid was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability. PMID- 29403754 TI - Two spectrophotometric methods for simultaneous determination of some antihyperlipidemic drugs. AB - Two simple, accurate, precise and economic spectrophotometric methods have been developed for simultaneous determination of Atorvastatin calcium (ATR) and Ezetimibe (EZ) in their bulk powder and pharmaceutical dosage form. Method (I) is based on dual wavelength analysis while method (II) is the mean centering of ratio spectra spectrophotometric (MCR) method. In method (I), two wavelengths were selected for each drug in such a way that the difference in absorbance was zero for the second drug. At wavelengths 226.6 and 244 nm EZ had equal absorbance values; therefore, these two wavelengths have been used to determine ATR; on a similar basis 228.6 and 262.8 nm were selected to determine EZ in their binary mixtures. In method II, the absorption spectra of both ATR and EZ with different concentrations were recorded over the range 200-350, divided by the spectrum of suitable divisor of both ATR and EZ and then the obtained ratio spectra were mean centered. The concentrations of active components were then determined from the calibration graphs obtained by measuring the amplitudes at 215-260 nm (peak to peak) for both ATR and EZ. Accuracy and precision of the developed methods have been tested; in addition recovery studies have been carried out in order to confirm their accuracy. On the other hand, selectivities of the methods were tested by application for determination of different synthetic mixtures containing different ratios of the studied drugs. The developed methods have been successfully used for determination of ATR and EZ in their combined dosage form and statistical comparison of the developed methods with the reported spectrophotometric one using F and Student's t-tests showed no significant difference regarding both accuracy and precision. PMID- 29403755 TI - Synchronized separation of atorvastatin-an antihyperlipidemic drug with antihypertensive, antidiabetic, antithrombotic drugs by RP-LC for determination in combined formulations. AB - A new rapid and sensitive high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of atorvastatin-an antihyperlipidemic drug along with most commonly prescribed drugs (antihyperlipidemic, antihypertensive, antidiabetic, antithrombotic) in bulk and marketed combined formulations. The chromatographic separation was carried out by gradient elution mode with acetonitrile as organic modifier and 0.1% triethylamine acetate (TEAA) buffer pH 5 at a flow rate of 1 mL/min and a diode array detector at wavelength 230 nm was employed for detection of the analytes. Calibration curves were linear in the range of 5-150 MUg/mL for all the drugs with correlation coefficients of determination (r2 values)>=0.999. Limits of detection (LODs) and Limits of quantification (LOQs) ranged from 0.1 to 0.27 MUg/mL and 0.3 to 0.89 MUg/mL respectively. Intra-day and inter-day precision was studied at three concentration levels (20, 60 and 100 MUg/mL). The intra-day and inter-day RSD for all compounds was less than 2.0%. The accuracy for all compounds was found to be between 98% and 102%. Thus, the performance of the method described allows its use in quantification of atorvastatin along with 9 most commonly prescribed drugs available in market as atorvastatin combined dosage forms. PMID- 29403756 TI - Cytotoxicity and cellular imaging of quantum dots protected by polyelectrolyte. AB - The nanocomposites of poly-diallyldimethylammonium chloride (PDADMAC) and CdTe quantum dots (QDs) (i.e. QDs-PDADMAC nanocomposites) have been prepared based on electrostatic interaction and their fluorescence stability in aqueous solution has been investigated. MTT method (3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide method) was used to study their cytotoxicity and A549 lung cancer cell as a model cell was also used to evaluate their cellular imaging. It was shown that the fluorescence stability of QDs-PDADMAC nanocomposites was much better than that of bare QDs both in aqueous solution and cell. Meanwhile, QDs-PDADMAC nanocomposites display very low cytotoxicity in the low concentrations and better staining ability compared with QDs. QDs-PDADMAC nanocomposites will have great advantage on the cell analysis detection and imaging. PMID- 29403757 TI - Stability-indicating liquid chromatographic method for the determination of Letrozole in pharmaceutical formulations. AB - A stability-indicating high-performance liquid chromatographic method was developed and validated for the determination of Letrozole in tablet dosage forms. Reversed-phase chromatography was performed on Shimadzu Model LC-Class-Vp with Lichrocart/Lichrosphere 100 C-18 (250 mm*4.6 mm, 5 MUm particle size) column with methanol: tetra butyl ammonium hydrogen sulfate (80:20V/V) as mobile phase at a flow rate of 1 mL/min with UV detection at 240 nm. Linearity was observed in the concentration range of 0.5-150 MUg/mL (R2=0.9998) with regression equation y=102582x+43185. The limit of quantitation (LOQ) and limit of detection (LOD) were found to be 0.043 and 0.012 MUg/mL respectively. The forced degradation studies were performed by using HCl, NaOH, H2O2, thermal and UV radiation. Letrozole is more sensitive towards alkaline conditions and very much resistant towards acidic, oxidative and photolytic degradations. The method was validated as per ICH guidelines. The RSD for intra-day (0.78-0.97) and inter-day (0.86 0.96) precision were found to be lesser than 1%. The percentage recovery was in good agreement with the labeled amount in the pharmaceutical formulations and the method is simple, specific, precise and accurate for the determination of Letrozole in pharmaceutical formulations. PMID- 29403758 TI - Azeotropic mixture used for development and validation of Lornoxicam in bulk and its tablet dosage form by spectrophotometric method. AB - A novel, safe, economic and sensitive method of spectrophotometric estimation has been developed using Azeoptropic mixture (water:methanol: 60:40, v/v) for the quantitative determination of Lornoxicam, a practically water-insoluble drug. Hence, Lornoxicam stock solution was prepared in Azeoptropic mixture. Lornoxicam showed maximum absorbance at 383 nm. Beer's law was obeyed in the concentration range 4-24 MUg/mL with regression coefficient of 0.999. The method was validated in terms of linearity (R2=0.999), precision (CV for intra-day and inter-day was 0.28-0.68 and 0.12-0.92, respectively), accuracy (98.03-100.59% w/w) and specificity. This method is simple, precise, accurate, sensitive and reproducible and can be used for the routine quality control testing of the marketed formulations. PMID- 29403759 TI - Rapid analysis of piperazine ferulate tablets by optic-fiber sensing technology and the similarity of ultraviolet spectra. AB - A rapid analysis method of piperazine ferulate tablets by optic-fiber sensing technology with UV-vis absorption spectrum was established. Qualitative and quantitative data were obtained and compared by maximum and minimum wavelength, absorbance and contrast spectra. Similarity method was used to identify authenticity of drugs. The difference of contents measured by this method and UV determination method in China Pharmacopoeia showed no statistical significance (P>0.05), while the similarity can be used as a parameter to identify the authenticity of drugs. PMID- 29403760 TI - Determination of genotoxic alkyl methane sulfonates and alkyl paratoluene sulfonates in lamivudine using hyphenated techniques. AB - Two highly sensitive methods for the determination of genotoxic alkyl methane sulfonates (AMSs) and alkyl paratoluene sulfonates (APTSs) in lamivudine using hyphenated techniques have been presented. AMSs were determined by GC-MS method using GSBP-INOWAX (30 m*0.25 mm*0.25 MUm) column. Temperature program was set by maintaining at 100 degrees C initially for 3 min, then rised to 220 degrees C at the rate of 15 degrees C/min and maintained at 220 degrees C for 16 min. N,N dimethyl formamide was used as diluent. APTSs were determined by LC-MS using Zorbax, Rx C8, 250 mm*4.6 mm, 5 MUm column as stationary phase. 0.01 M ammonium acetate is used as buffer. The mixture of buffer and methanol in 75:25 (v/v) ratio was used as mobile phase A and mixture of buffer and methanol in 5:95 (v/v) ratio was used as mobile phase B. The gradient program (T/%B) was set as 0/28, 16/50, 17/100, 23/100, 27/28 and 40/28. Both the methods were validated as per International Conference on Harmonization guidelines. Limit of quantitation was found 1.5 MUg/mL for AMSs and was in the range of 1.0-1.5 MUg/mL for APTSs. PMID- 29403761 TI - Simultaneous determination of telmisartan and amlodipine in human plasma by LC MS/MS and its application in a human pharmacokinetic study. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method has been developed and fully validated for the simultaneous quantification of telmisartan and amlodipine in human plasma. Carbamazepine was used as an internal standard. Analytes and the internal standard were extracted from human plasma by solid-phase extraction technique using Waters Oasis(r) HLB 1 cm3 (30 mg) extraction cartridge. The reconstituted samples were chromatographed on a Hypurity advance C18 column (50 mm*4.6 mm, 5 MUm) using a mixture of acetonitrile-5 mM ammonium acetate buffer (pH-4.0) (50:50, v/v) as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r>=0.99) over the concentration range of 2.01-400.06 ng/mL for telmisartan and 0.05-10.01 ng/mL for amlodipine. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The proposed method was found to be applicable to clinical studies. PMID- 29403762 TI - Authentication and distinction of Shenmai injection with HPLC fingerprint analysis assisted by pattern recognition techniques. AB - In this paper, the feasibility and advantages of employing high performance liquid chromatographic (HPLC) fingerprints combined with pattern recognition techniques for quality control of Shenmai injection were investigated and demonstrated. The Similarity Evaluation System was employed to evaluate the similarities of samples of Shenmai injection, and the HPLC generated chromatographic data were analyzed using hierarchical clustering analysis (HCA) and soft independent modeling of class analogy (SIMCA). Consistent results were obtained to show that the authentic samples and the blended samples were successfully classified by SIMCA, which could be applied to accurate discrimination and quality control of Shenmai injection. Furthermore, samples could also be grouped in accordance with manufacturers. Our results revealed that the developed method has potential perspective for the original discrimination and quality control of Shenmai injection. PMID- 29403763 TI - Kinetic spectrophotometric method for determination of amlodipine besylate in its pharmaceutical tablets. AB - A simple and sensitive kinetic spectrophotometric method has been developed and validated for determination of amlodipine besylate (AML). The method was based on the condensation reaction of AML with 7-chloro-4-nitro-2,1,3-benzoxadiazole in an alkaline buffer (pH 8.6) producing a highly colored product. The color development was monitored spectrophometrically at the maximum absorption lambdamax 470 nm. The factors affecting the reaction were studied and the conditions were optimized. The stoichiometry of the reaction was determined, and the reaction pathway was postulated. Moreover, both the activation energy and the specific rate constant (at 70 degrees C) of the reaction were found to be 6.74 kcal mole-1 and 3.58 s-1, respectively. The initial rate and fixed time methods were utilized for constructing the calibration graphs for the determination of AML concentration. Under the optimum reaction conditions, the limits of detection and quantification were 0.35 and 1.05 MUg/mL, respectively. The precision of the method was satisfactory; the relative standard deviations were 0.85-1.76%. The proposed method was successfully applied to the analysis of AML in its pure form and tablets with good accuracy; the recovery percentages ranged from 99.55+/ 1.69% to 100.65+/-1.48%. The results were compared with that of the reported method. PMID- 29403764 TI - Bio-analytical method development and validation of Rasagiline by high performance liquid chromatography tandem mass spectrometry detection and its application to pharmacokinetic study. AB - The most suitable bio-analytical method based on liquid-liquid extraction has been developed and validated for quantification of Rasagiline in human plasma. Rasagiline-13C3 mesylate was used as an internal standard for Rasagiline. Zorbax Eclipse Plus C18 (2.1 mm*50 mm, 3.5 MUm) column provided chromatographic separation of analyte followed by detection with mass spectrometry. The method involved simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-4000 system. The total run time was 3.0 min. The proposed method has been validated with the linear range of 5-12000 pg/mL for Rasagiline. The intra-run and inter-run precision values were within 1.3%-2.9% and 1.6%-2.2% respectively for Rasagiline. The overall recovery for Rasagiline and Rasagiline-13C3 mesylate analog was 96.9% and 96.7% respectively. This validated method was successfully applied to the bioequivalence and pharmacokinetic study of human volunteers under fasting condition. PMID- 29403765 TI - Normal and reverse flow injection-spectrophotometric determination of thiamine hydrochloride in pharmaceutical preparations using diazotized metoclopramide. AB - Simple and sensitive normal and reverse flow injection methods for spectrophotometric determination of thiamine hydrochloride (THC) at the microgram level were proposed and optimized. Both methods are based on the reaction between THC and diazotized metoclopramide in alkaline medium. Beer's law was obeyed over the range of 10-300 and 2-90 MUg/mL, the limits of detection were 2.118 and 0.839 MUg/mL and the sampling rates were 80 and 95 injections per hour for normal and reverse flow injection methods respectively. The application of both methods to commercially available pharmaceuticals produced acceptable results. The flow system is suitable for application in quality control processes. PMID- 29403766 TI - Analysis of arecoline in Semen Arecae decoction pieces by microchip capillary electrophoresis with contactless conductivity detection. AB - A new method for the determination of arecoline in Semen Arecae decoction pieces by microchip capillary electrophoresis with contactless conductivity detection (MCE-CCD) was proposed. The effects of various electrophoretic operating parameters on the analysis of arecoline were studied. Under the optimal conditions, arecoline was rapidly separated and detected in 1 min with good linearity over the concentration range of 20-1500 MUM (r2=0.9991) and the detection limit of 5 MUM (S/N=3). The method was used for the analysis of arecoline satisfactorily with a recovery of 96.8-104%. PMID- 29403767 TI - Pre-concentration and determination of amitriptyline residues in waste water by ionic liquid based immersed droplet microextraction and HPLC. AB - This paper describes a new approach for the determination of amitriptyline in wastewater by ionic liquid based immersed droplet microextraction (IL-IDME) prior to high-performance liquid chromatography with ultraviolet detection. 1-Hexyl-3 methylimidazolium hexafluorophosphate ([C6MIM][PF6]) was used as an ionic liquid. Various factors that affect extraction, such as volume of ionic liquid, stirring rate, extraction time, pH of the aqueous solution and salting effect, were optimized. The optimal conditions were as follows: microextraction time, 10 min; stirring rate, 720 rpm; pH, 11; ionic drop volume, 100 MUL; and no sodium chloride addition. In quantitative experiments the method showed linearity in a range from 0.01 to 10 MUg/mL, a limit of detection of 0.004 MUg/mL and an excellent pre-concentration factor (PF) of 1100. Finally, the method was successfully applied to the determination of amitriptyline in the hospital wastewater samples. PMID- 29403768 TI - Development and validation of a RP-HPLC method for the simultaneous determination of Embelin, Rottlerin and Ellagic acid in Vidangadi churna. AB - Vidangadi churna is a popular Ayurvedic formulation described in the chapter Krimicikitsa of the Ayurvedic literature Cakradatta for the treatment of Krimiroga. The preparation is a composite mixture of the fine powder of fruits of Vidang (Embelia ribs), glandular trichomes of the fruits of Kamala (Mallotus philippensis), mature fruits of Harde (Terminalia chebula), Saindhava and Yavakshara. The use of reversed phase C18 column eluted with gradient mobile phase of acetonitrile and water enabled the efficient separation of the chemical markers in 22 min. Validation of the method was performed in order to demonstrate its selectivity, accuracy, precision, repeatability and recovery. All calibration curves showed good linear correlation coefficients (r2>0.995) within the tested ranges. Three markers in Vidangadi churna were quantified with respect to Embelin (0.647%, w/w), Rottlerin (4.419%, w/w), and Ellagic acid (0.459%, w/w). Intra-and inter-day RSDs of retention times and peak areas were less than 3.12%. The recoveries were between 99.66% and 102.33%. In conclusion, a method has been developed for the simultaneous quantification of three markers in Vidangadi churna. The RP-HPLC method was simple, precise and accurate and can be used for the quality control of the raw materials as well as formulations. PMID- 29403769 TI - Impurity profiling and in-process testing of drugs for injection by fast liquid chromatography. AB - Liquid chromatography (LC) is considered by many as a mature technique. Nonetheless, LC technology continues to evolve driven by the need for high throughput and high-resolution analyses. Over the past several years, small particle size packing materials have been introduced by several column manufacturers to enable fast and efficient LC separations. Several examples of pharmaceutical analyses, including impurity profiling of taxanes and atracurium besylate, in-process testing of peptides in injectable dosage form, using sub-2 MUm column technology are presented in this paper, demonstrating some of the capabilities and limitations of the technology. PMID- 29403770 TI - Determination of metronidazole in a rat stomach by HPLC for obtaining basic data of the eradication therapy of Helicobacter pylori. AB - In the eradication therapy of Helicobacter pylori changes of antibiotics as these concentrations or amount in the stomach after oral administration were not clear. A simple and accurate method for determining the concentration of metronidazole (MTZ) in homogenate of rat stomach was developed in order to obtain basic data to design a pharmaceutical preparation having targeting ability to the surface of gastric-mucosa. This method included a deproteinization process by methanol, separation with reversed-phase high-performance liquid chromatography, and detection with an ultraviolet wavelength of 370 nm. Regression analysis showed that the method was linear over a standard curve range from 5 MUg/mL to 2000 MUg/mL. The inter-day precision and accuracy values between the ranges were 5.0% or better and -7.5 to 5.2%, respectively. The newly developed method was applied to an analysis of gastric samples after oral administration of MTZ at a dose of 5 mg/kg. It was found that the residual MTZ in the stomach was determined within 5 h after dosing. This method is useful for monitoring MTZ in stomach after its oral administration to rats. PMID- 29403771 TI - A smart simple spectrophotometric method for simultaneous determination of binary mixtures. AB - A new simple spectrophotometric method was developed for the simultaneous determination of drugs with interfering spectra in binary mixtures without previous separation. The new method is based on a simple modification for the ratio subtraction method. This modification enabled wider range of application. The proposed ratio difference method was applied for the determination of brimonidine and timolol in laboratory prepared mixtures with mean percentage recoveries 100.40+/-2.29 and 101.23+/-1.30 respectively, and in their pharmaceutical formulation with mean percentage recoveries 101.08+/-0.44 and 100.66+/-0.52 respectively. The suggested ratio difference method was validated according to USP guidelines and can be applied for routine quality control testing. PMID- 29403772 TI - Monitoring the hydrolyzation of aspirin during the dissolution testing for aspirin delayed-release tablets with a fiber-optic dissolution system. AB - The purpose of this study was to investigate the hydrolyzation of aspirin during the process of dissolution testing for aspirin delayed-release tablets. Hydrolysis product of salicylic acid can result in adverse effects and affect the determination of dissolution rate assaying. In this study, the technique of differential spectra was employed, which made it possible to monitor the dissolution testing in situ. The results showed that the hydrolyzation of aspirin made the percentage of salicylic acid exceed the limit of free salicylic acid (4.0), and the hydrolyzation may affect the quality detection of aspirin delayed release tablets. PMID- 29403773 TI - Development and validation of RP-HPLC method for estimation of eplerenone in spiked human plasma. AB - A rapid and simple high performance liquid chromatography (HPLC) method with a UV detection (241 nm) was developed and validated for estimation of eplerenone from spiked human plasma. The analyte and the internal standard (valdecoxib) were extracted with a mixture of dichloromethane and diethyl ether. The chromatographic separation was performed on a HiQSil C-18HS column (250 mm*4.6 mm, 5 MUm) with a mobile phase consisting of acetonitrile:water (50:50, v/v) at flow rate of 1 mL/min. The calibration curve was linear in the range 100-3200 ng/mL and the heteroscedasticity was minimized by using weighted least squares regression with weighting factor 1/X. PMID- 29403774 TI - Separation and enrichment of trace ractopamine in biological samples by uniformly sized molecularly imprinted polymers. AB - In order to prepare a high capacity packing material for solid-phase extraction with specific recognition ability of trace ractopamine in biological samples, uniformly-sized, molecularly imprinted polymers (MIPs) were prepared by a multi step swelling and polymerization method using methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, and toluene as a porogen respectively. Scanning electron microscope and specific surface area were employed to identify the characteristics of MIPs. Ultraviolet spectroscopy, Fourier transform infrared spectroscopy, Scatchard analysis and kinetic study were performed to interpret the specific recognition ability and the binding process of MIPs. The results showed that, compared with other reports, MIPs synthetized in this study showed high adsorption capacity besides specific recognition ability. The adsorption capacity of MIPs was 0.063 mmol/g at 1 mmol/L ractopamine concentration with the distribution coefficient 1.70. The resulting MIPs could be used as solid-phase extraction materials for separation and enrichment of trace ractopamine in biological samples. PMID- 29403775 TI - Validated LC-MS/MS method for simultaneous determination of SIM and its acid form in human plasma and cell lysate: Pharmacokinetic application. AB - Simvastatin (SIM) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC-MS/MS method was developed to measure SIM and its acid form (SIMA) in plasma and peripheral blood mononuclear cells (PBMCs) obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75:25 (% v/v) acetonitrile:ammonium acetate (0.1 M, pH 5.0) mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5-500 ng/mL for SIM and 5 500 ng/mL for SIMA in plasma and 2.5-250 ng/mL for SIM and 5-250 ng/mL for SIMA in cell lysate. Recovery was >58% for SIM and >75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients. PMID- 29403776 TI - Solid-state characterization and impurities determination of fluconazol generic products marketed in Morocco. AB - In this paper, we report the results of quality control based in physicochemical characterization and impurities determination of three samples of fluconazole drug substances marketed in Morocco. These samples were supplied by different pharmaceuticals companies. The sample A, as the discovered product, was supplied by Pfizer, while samples B and C (generics), were manufactured by two different Indian industries. Solid-state characterization of the three samples was realized with different physicochemical methods as: X-ray powder diffraction, Fourier transformation infrared spectroscopy, differential scanning calorimetry. High performance liquid chromatography was used to quantify the impurities in the different samples. The results from the physicochemical methods cited above, showed difference in polymorph structure of the three drug substances. Sample A consisted in pure polymorph III, sample B consisted in pure polymorph II, sample C consisted in a mixture of fluconazole Form III, form II and the monohydrate. This result was confirmed by differential scanning calorimetry. Also it was demonstrated that solvents used during the re-crystallization step were among the origins of these differences in the structure form. On the other hand, the result of the stability study under humidity and temperature showed that fluconazole polymorphic transformation could be owed to the no compliance with the conditions of storage. The HPLC analysis of these compounds showed the presence of specific impurities for each polymorphic form, and a possible relationship could be exist between impurities and crystalline form of fluconazole. PMID- 29403777 TI - Chromatographic fingerprinting and quantitative analysis for the quality evaluation of Xinkeshu tablet. AB - A simple, sensitive and accurate method based on high performance liquid chromatography (HPLC) with diode array detector (DAD) was developed and validated for systematic quality evaluation of one type of traditional Chinese medicine preparations named Xinkeshu (XKS) tablet. In this study, the chromatographic fingerprints of XKS tablet were developed first, 23 peaks were selected as the common peaks to evaluate the similarities among different batches of XKS samples, which were manufactured in a long time span of three years. Additionally, simultaneous quantification of six markers in XKS tablet, including Danshensu, Protocatechuic aldehyde, Puerarin, Daidzin, Salvianolic acid B and Daidzein, was performed. The validation results showed that the developed method was specific, accurate, precise and robust. The preliminary explanation on why a close similarity between fingerprints did not exactly mean similar contents of chemical components in samples was given. The contribution of each chromatographic peak to similarity was also evaluated. The developed method offers an efficient, reliable and practical approach for systematic quality evaluation of XKS tablet. PMID- 29403778 TI - Kinetics study of metaxalone degradation under hydrolytic, oxidative and thermal stress conditions using stability-indicating HPLC method. AB - An isocratic stability indicating RP-HPLC-UV method is presented for the determination of metaxalone (MET) in the presence of its degradation products. The method uses Dr. Maisch C18 column (250 mm*4.6 mm, 5 MUm) with mobile phase consisting of acetonitrile-potassium dihydrogen orthophosphate buffer with 4 mL of 0.4% triethyl amine (pH 3.0; 10 mM) (58:42, v/v) at a flow rate of 1.0 mL/min. pH of the buffer was adjusted with o-phosphoric acid. UV detection was performed at 225 nm. The method was validated for specificity, linearity, precision, accuracy, limit of detection, limit of quantification and robustness. The calibration plot was linear over the concentration range of 1-100 MUg/mL having a correlation coefficient (r2) of 0.999. Limits of detection and quantification were 0.3 and 1 MUg/mL, respectively. Intra-day and inter-day precision (% RSD) was 0.65 and 0.79 respectively. The proposed method was used to investigate the degradation kinetics of MET under different stress conditions employed. Degradation of MET followed a pseudo-first-order kinetics, and rate constant (K), time left for 50% potency (t1/2), and time left for 90% potency (t90) were calculated. PMID- 29403779 TI - Simultaneous determination of nortriptyline hydrochloride and fluphenazine hydrochloride in microgram quantities from low dosage forms by liquid chromatography-UV detection. AB - A novel method for the simultaneous high-performance liquid chromatographic determination of nortriptyline hydrochloride and fluphenazine hydrochloride was developed and validated. Fluvastatin sodium was used as internal standard. The determination was performed on a Hypersil Gold C8 column (250 mm * 4.6 mm i.d., 5 MUm particle size) at 25 degrees C; the mobile phase, consisting of a mixture of formic acid (0.1 M, pH 2.16)-methanol (33:67, v/v), was delivered at a flow rate of 1.1 mL/min and detector wavelength at 251 nm. The retention time of nortriptyline, fluphenazine and fluvastatin was found to be 5.11, 8.05 and 11.38 min, respectively. Linearity ranges were 5.0-1350.0 and 10.0-1350.0 MUg/mL with limit of detection values of 0.72 and 0.31 MUg/mL, for nortriptyline and fluphenazine, respectively. Results of assay and recovery studies were statistically evaluated for its accuracy and precision. Correlation coefficients (r2) of the regression equations were greater than 0.999 in all cases. According to the validation results, the proposed method was found to be specific, accurate, precise and could be applied to the simultaneous quantitative analysis of nortriptyline and fluphenazine. PMID- 29403780 TI - Cathodic adsorptive stripping voltammetry of an anti-emetic agent Granisetron in pharmaceutical formulation and biological matrix. AB - Granisetron showed one well-defined reduction peak at Hanging Mercury Drop Electrode (HMDE) in the potential range from -1.3 to -1.5 V due to reduction of C=N bond. Solid-phase extraction technique was employed for extraction of Granisetron from spiked human plasma. Granisetron showed peak current enhancement of 4.45% at square-wave voltammetry and 5.33% at cyclic voltammetry as compared with the non stripping techniques. The proposed voltammetric method allowed quantification of Granisetron in pharmaceutical formulation over the target concentration range of 50-200 ng/mL with detection limit 13.63 ng/mL, whereas in human plasma 50-225 ng/mL with detection limit 11.75 ng/mL. PMID- 29403781 TI - An analytical method for Fe(II) and Fe(III) determination in pharmaceutical grade iron sucrose complex and sodium ferric gluconate complex. AB - A robust voltammetric method has been developed and validated for the determination of Fe(II) and Fe(III) in pharmaceutical iron polysaccharidic complexes. Undesirable low molecular weight iron complexes, at concentration about 3% in the pharmaceutical formulation, can be easily determined with good accuracy and precision. This methodology can be proposed as a viable, environmentally sustainable substitute for the conventional Normal Pulse Polarographic method in US Pharmacopeia, with better analytical figures of merit, and reduced Hg consumption. A deeper insight in Fe(II) and Fe(III) composition can be gained by the combined use of a new potentiometric technique after chemical decomposition of the complex. PMID- 29403782 TI - Development and validation of a simple UV spectrophotometric method for the determination of levofloxacin both in bulk and marketed dosage formulations. AB - A rapid, specific and economic UV spectrophotometric method has been developed using a solvent composed of water:methanol:acetonitrile (9:0.5:0.5) to determine the levofloxacin content in bulk and pharmaceutical dosage formulations. At a pre determined lambdamax of 292 nm, it was proved linear in the range of 1.0-12.0 MUg/mL, and exhibited good correlation coefficient (R2=0.9998) and excellent mean recovery (99.00-100.07%). This method was successfully applied to the determination of levofloxacin content in five marketed brands from Bangladesh and the results were in good agreement with the label claims. The method was validated statistically and by recovery studies for linearity, precision, repeatability, and reproducibility. The obtained results proved that the method can be employed for the routine analysis of levofloxacin in bulks as well as in the commercial formulations. PMID- 29403783 TI - Sensitive determination of buformin using poly-aminobenzoic acid modified glassy carbon electrode. AB - Glassy carbon electrode, which is used to electrochemically determine the content of buformin, is modified with an electropolymerized film of p-aminobenzoic acid in pH 7.0 acetate buffer solution (ABS). The polymer showed an excellent electrocatalytic activity for the reduction of buformin. In pH 7.0 ABS, the cathodic peak current increased linearly over three concentration intervals of buformin, and the detection limit (S/N=3) was 2.0*10-9 g/mL. The method was successfully applied to directly determine buformin in tablets with standard addition recoveries of 95.8-102.5%. The proposed method is simple, cheap and highly efficient. PMID- 29403784 TI - New chiral reverse phase HPLC method for enantioselective analysis of ketorolac using chiral AGP column. AB - A simple, specific, precise, sensitive and rapid reverse phase-HPLC method was developed for determination of ketorolac enantiomers, a potent nonnarcotic analgesic in pharmaceutical formulations. The method was developed on a chiral AGP column. Mobile phase was 0.1 M sodium phosphate buffer (pH 4.5): Isopropanol (98:2, v/v), at a flow rate of 1 mL/min with run time of 15 min. Ultraviolet detection was made at 322 nm. The linearity range was 0.02-10 MUg/mL for each of the enantiomers. The mobile phase composition was systematically studied to find the optimum chromatographic conditions. Validation of the method under the conditions selected showed that it was selective and precise and that the detector response was linear function of ketorolac. PMID- 29403785 TI - Development and validation of the stability-indicating LC-UV method for the determination of Cefditoren pivoxil. AB - An isocratic RP-HPLC method was developed for the determination of Cefditoren pivoxil in pharmaceutical formulations using a C-18 column with water acetonitrile (50:50, v/v) as mobile phase and flow rate 1.2 mL/min (UV detection at 218 nm). Linearity was observed in the concentration range 1.0-250 MUg/mL (R2=0.999) with regression equation y=24194x+10749. The forced degradation studies were performed by using HCl, NaOH, and H2O2, and thermal and UV radiation. Cefditoren pivoxil is more sensitive towards oxidation and alkaline conditions and resistant towards acidic and photolytic degradations. The method was validated as per ICH guidelines. PMID- 29403786 TI - Novel and validated titrimetric method for determination of selected angiotensin II-receptor antagonists in pharmaceutical preparations and its comparison with UV spectrophotometric determination. AB - A novel and simple titrimetric method for determination of commonly used angiotensin-II-receptor antagonists (ARA-IIs) is developed and validated. The direct acid base titration of four ARA-IIs, namely eprosartan mesylate, irbesartan, telmisartan and valsartan, was carried out in the mixture of ethanol:water (1:1) as solvent using standardized sodium hydroxide aqueous solution as titrant, either visually using phenolphthalein as an indicator or potentiometrically using combined pH electrode. The method was found to be accurate and precise, having relative standard deviation of less than 2% for all ARA-IIs studied. Also, it was shown that the method could be successfully applied to the assay of commercial pharmaceuticals containing the above-mentioned ARA IIs. The validity of the method was tested by the recovery studies of standard addition to pharmaceuticals and the results were found to be satisfactory. Results obtained by this method were found to be in good agreement with those obtained by UV spectrophotometric method. For UV spectrophotometric analysis ethanol was used as a solvent and wavelength of 233 nm, 246 nm, 296 nm, and 250 nm was selected for determination of eprosartan mesylate, irbesartan, telmisartan, and valsartan respectively. The proposed titrimetric method is simple, rapid, convenient and sufficiently precise for quality control purposes. PMID- 29403787 TI - Cleaning level acceptance criteria and HPLC-DAD method validation for the determination of Nabumetone residues on manufacturing equipment using swab sampling. AB - Prevention of cross contamination with active pharmaceutical ingredients is crucial and requires special attention in pharmaceutical industries. Current method validation describes the determination of Nabumetone (NAB) residue on a stainless steel surface using swab sampling with a sensitive HPLC-DAD analysis. The acceptance limit was decided as 2 MUg swab per 100 cm2. Cotton swabs impregnated with extraction solution were used to determine residual drug content. Recoveries were 90.88%, 91.42%, and 92. 21% with RSD ranging from 2.2% to 3.88% at three concentration levels. Residual concentration was found to be linear in the range of 0.1-4.56 MUg/mL, when estimated using a Phenomenex Luna C18 (25 cm*5 MUm*4.6 mm i.d.) column at 1.0 mL/min flow rate and 230 nm. The mobile phase consisted of a mixture of methanol:acetonitrile:water (55:30:15, v/v/v). The LOD and LOQ for NAB were found to be 0.05 and 0.16 MUg/mL, respectively. The validated method was found to be simple, selective and sensitive for demonstration of cleaning validation of NAB residues on a stainless steel surface. PMID- 29403788 TI - Development of a validated HPLC method for the separation and analysis of a Bromazepam, Medazepam and Midazolam mixture. AB - The purpose of this work was to develop a rapid, sensitive and validated HPLC method for the separation and analysis of a Bromazepam, Medazepam and Midazolam mixture. The three benzodiazepine compounds were separated on a reversed-phase C18 column at 50 degrees C using a mobile phase containing 25% acetonitrile, 45% methanol and 30% ammonium acetate (0.05 M). The pH was adjusted to pH=9 by the addition of ammonia solution (35%, w/w). The samples were detected using a UV detector at 240 nm. The validation study of the method included the effect of temperature, flow rate, ratio of the components of the mobile phase and the pH of the mobile phase on the efficiency of separation. The linear range of Bromazepam and Midazolam was between 0.12 and 0.18 mg/mL, while that of Medazepam was between 0.08 and 0.12 mg/mL. The relative standard deviation for precision was less than 2%. The linearity, selectivity, accuracy and robustness of the developed method showed acceptable values. The method was applied to the analysis of the samples of raw material of the three compounds under study, and the percentage of recoveries was 99.89%+/-1.06. It was also applied to the analysis of samples of pharmaceutical preparations of those compounds and spiked serum samples. Recoveries from serum samples ranged between 91.5% and 99.0%. The developed method is suitable for quality control of Bromazepam, Medazepam and Midazolam in their mixtures and in pharmaceutical preparations (tablets, capsules, ampoules). It can also be used to determine their concentrations in serum. PMID- 29403789 TI - Development and validation of analytical method for the estimation of nateglinide in rabbit plasma. AB - Nateglinide has been widely used in the treatment of type-2 diabetics as an insulin secretogoga. A reliable, rapid, simple and sensitive reversed-phase high performance liquid chromatography (RP-HPLC) method was developed and validated for determination of nateglinide in rabbit plasma. The method was developed on Hypersil BDSC-18 column (250 mm*4.6 mm, 5 mm) using a mobile phase of 10 mM phosphate buffer (pH 2.5) and acetonitrile (35:65, v/v). The elute was monitored with the UV-vis detector at 210 nm with a flow rate of 1 mL/min. Calibration curve was linear over the concentration range of 25-2000 ng/mL. The retention times of nateglinide and internal standard (gliclazide) were 9.608 min and 11.821 min respectively. The developed RP-HPLC method can be successfully applied to the quantitative pharmacokinetic parameters determination of nateglinide in rabbit model. PMID- 29403790 TI - Quantitation of bivalirudin, a novel anticoagulant peptide, in human plasma by LC MS/MS: Method development, validation and application to pharmacokinetics. AB - A rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of a novel anticoagulant peptide bivalirudin in human plasma has been developed and validated. Plasma samples were precipitated protein with acetonitrile and re-extracted with dichloromethane, after which the analyte and triptorelin as an internal standard (IS) were separated on a 300SB-C18 column (150 mm*4.6 mm i.d., 5 MUm particle size) using 0.1% formic acid:methanol (45:55, v/v) as mobile phase. The triple-quadrupole mass spectrometer, equipped with electrospray ionization (ESI) interface, was operated in the positive ion mode, and the multiple-reaction monitoring (MRM) transitions of bivalirudin and IS were at m/z 1091.0->650.4 and m/z 656.5->249.3, respectively. The lower limit of quantification (LLOQ) was 1 ng/mL for 100 MUL plasma sample and the assay was linear over the concentration range 1-1000 ng/mL. The accuracy was within a range from -0.4% to 0.5% in terms of relative error (RE) and the intra- and inter-day precisions in terms of relative standard deviation (RSD) were <=2.92 and <=3.36, respectively. The method was successfully applied to a pharmacokinetic study involving intravenous administration of bivalirudin (0.5 mg/kg) to Chinese volunteers. PMID- 29403791 TI - Simultaneous determination of atorvastatin, metformin and glimepiride in human plasma by LC-MS/MS and its application to a human pharmacokinetic study. AB - A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) assay method has been developed and fully validated for the simultaneous quantification of atorvastatin, metformin and glimepiride in human plasma. Carbamazepine was used as internal standard (IS). The analytes were extracted from 200 MUL aliquots of human plasma via protein precipitation using acetonitrile. The reconstituted samples were chromatographed on a Alltima HP C18 column by using a 60:40 (v/v) mixture of acetonitrile and 10 mM ammonium acetate (pH 3.0) as the mobile phase at a flow rate of 1.1 mL/min. The calibration curves obtained were linear (r2 >=0.99) over the concentration range of 0.50-150.03 ng/mL for atorvastatin, 12.14-1207.50 ng/mL for metformin and 4.98-494.29 ng/mL for glimepiride. The API-4000 LC-MS/MS in multiple reaction monitoring (MRM) mode was used for detection. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. All the analytes were found to be stable in a battery of stability studies. The method is precise and sensitive enough for its intended purpose. A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The developed assay method was successfully applied to a pharmacokinetic study in human male volunteers. PMID- 29403792 TI - Study on changes of polyamine levels in mice with the development of U14 cervical cancer. AB - This study was performed to investigate the possible involvement of polyamines in the development of cervical cancer. The objective of the present study was therefore to find the specific polyamine indicators, which could be used as useful markers for the early determination of cervical cancer. A simple method for the simultaneous determination of plasma concentrations of five polyamines in normal and U14 model mice was developed by using HPLC-MS. The samples were derivatized by benzoyl chloride. The derived polyamines were separated on a C18 column by a gradient elution with methanol-water, and then detected with HPLC-MS. The results showed that all polyamine levels in the U14 model mice were higher than those in normal ones. The cadaverine, putrescine and 1, 3-diaminopropane levels were significantly higher in U14 model mice plasma than those in normal mice plasma, especially the putrescine and 1, 3-diaminopropane (P<0.01). The cadaverine, putrescine and 1, 3-diaminopropane levels were significantly higher in U14 mice model urine than those in normal mice urine, especially the cadaverine and 1, 3-diaminopropane (P<0.01). Putrescine, cadaverine and 1, 3 diaminopropane might be the indicators of the cervical cancer. PMID- 29403793 TI - On-line coupling of derivatization with pre-concentration to determine trace levels of methotrexate. AB - A new simple, sensitive and precise green analytical procedure using an automated packed-reactor derivatization technique coupled with on-line solid-phase enrichment (SPEn) has been developed and evaluated to determine trace levels of methotrexate (MTX). The method was based on injection of MTX into a flowing stream of phosphate buffer (0.04 M, pH 3.4), carried through the packed oxidant reactor of Cerium (IV) trihydroxyhydroperoxide for oxidative cleavage of the drug into highly fluorescent product, 2,4-diaminopteridine-6-carboxylic acid, followed by SPEn on a head of short ODS column (10 mm*4.6 mm i.d., 5 MUm particle size). The flow rate was 0.25 mL/min and packed reactor temperature was 40 degrees C. The trapped product was back-flush eluted from the ODS column to the detector by column-switching with an environmentally friendly mobile phase consisting of ethanol and phosphate buffer (0.04 M, pH 3.4) in the ratio of 5:95 (v/v). The eluent was monitored at emission and excitation wavelengths of 460 and 360 nm, respectively. The calibration curve was linear over the concentration range of 1.25-50 ng/mL with a detection limit of 0.08 ng/mL. The method was successfully applied to determine MTX in pharmaceutical formulations with mean percentage recovery ranging from 99.48 to 99.60. PMID- 29403794 TI - A rapid and sensitive liquid chromatography-tandem mass spectrometric assay for duloxetine in human plasma: Its pharmacokinetic application. AB - This paper describes a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry assay for the determination of duloxetine in human plasma. A duloxetine stable labeled isotope (duloxetine d5) was used as an internal standard. Analyte and the internal standard were extracted from 100 MUL of human plasma via solid phase extraction technique using Oasis HLB cartridges. The chromatographic separation was achieved on a C18 column by using a mixture of acetonitrile-5 mM ammonium acetate buffer (83:17, v/v) as the mobile phase at a flow rate of 0.9 mL/min. The calibration curve obtained was linear (r2>=0.99) over the concentration range of 0.05-101 ng/mL. Multiple-reaction monitoring mode (MRM) was used for quantification of ion transitions at m/z 298.3/154.1 and 303.3/159.1 for the drug and the internal standard, respectively. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies. PMID- 29403795 TI - Systematical approach in evaluation of LC method for determination of raloxifene hydrochloride and its impurities employing experimental design. AB - Method validation presents a detailed investigation of analytical method and provision of the evidence that the method, when correctly applied, produces results that fit to the purpose. In order to achieve the method validation scope efficiently, experimental design presents a very useful tool. The greatest benefits of such approach could be seen in robustness testing through the provision of very useful data about the control of the chromatographic system during the routine application. In this paper, robustness testing of the LC method proposed for the determination of raloxifene hydrochloride and its four impurities was done employing Plackett-Burman design. Applying this design, the effect of five real factors (acetonitrile content, sodium dodecyl sulfate content, column temperature, pH of the mobile phase and flow rate) on the corresponding resolution factors was investigated through twelve experiments. Furthermore, the insignificance intervals for significant factors were calculated and the parameters for system suitability tests were defined. Eventually, the other validation parameters were tested and the effectiveness of the proposed analytical method with a high degree of accuracy was confirmed. PMID- 29403796 TI - Selective micellar electrokinetic chromatographic method for simultaneous determination of some pharmaceutical binary mixtures containing non-steroidal anti-inflammatory drugs. AB - A simple and selective micellar electrokinetic chromatographic (MEKC) method has been developed for the analysis of five pharmaceutical binary mixtures containing three non-steroidal anti-inflammatory drugs (NSAIDs). The investigated mixtures were Ibuprofen (IP)-Paracetamol (PC), Ibuprofen (IP)-Chlorzoxazone (CZ), Ibuprofen (IP)-Methocarbamol (MC), Ketoprofen (KP)-Chlorzoxazone (CZ) and Diclofenac sodium (DS)-Lidocaine hydrochloride (LC). The separation was run for all mixtures using borate buffer (20 mM, pH 9) containing 15% (v/v) methanol and 100 mM sodium dodecyl sulphate (SDS) at 15 kV and the components were detected at 214 nm. Different factors affecting the electrophoretic mobility of the seven investigated drugs were studied and optimized. The method was validated according to international conference of harmonization (ICH) guidelines and United States pharmacopoeia (USP). The method was applied to the analysis of five pharmaceutical binary mixtures in their dosage forms. The results were compared with other reported high performance liquid chromatographic methods and no significant differences were observed. PMID- 29403798 TI - Development and validation of a stability indicating RP-HPLC method for the determination of Rufinamide. AB - A stability-indicating RP-HPLC method was developed and validated for the determination of Rufinamide in tablet dosage forms using C 18 column (250 mm*4.6 mm, 5 MUm) with mobile phase consisting of water-acetonitrile (40:60, v/v) with a flow rate of 0.8 mL/min (UV detection 215 nm). Linearity was observed over the concentration range 1.0-200 MUg/mL (R2=0.9997) with regression equation y=113190 x+63053. Rufinamide was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation. Rufinamide is more sensitive towards acidic degradation. The method was validated as per ICH guidelines. PMID- 29403797 TI - Investigation of the interaction between two phenylethanoid glycosides and bovine serum albumin by spectroscopic methods. AB - Two phenylethanoid glycosides, acteoside and forsythoside B, were first isolated from the traditional Chinese herb Callicarpa peii H.T. Chang. The interaction between the two phenylethanoid glycosides and bovine serum albumin (BSA) was investigated by fluorescence, UV-vis absorbance and circular dichroism (CD). The results showed that the quenching mechanism in the drug-BSA binary systems was a combination of static quenching and non-radiative energy transfer. Displacement experiments confirmed that the drug bound to the site I of BSA. UV-vis and CD measurements indicated that the binding of the drug to BSA induced conformational changes in BSA. PMID- 29403799 TI - Effects of temperature and wavelength choice on in-situ dissolution test of Cimetidine tablets. AB - The effects of temperature and wavelength choice on in-situ dissolution test instrument of Cimetidine were studied. Absorbance (A)<1.0 is required when using a fiber-optic dissolution test system. The detection wavelength of lambdamax (218 nm) was replaced by 244 nm to carry out this test. The absorbance of Cimetidine solution at different temperature showed an obvious change. Calibration of Cimetidine solution should be tested at the same temperature (37 degrees C) with the test solution. A suitable wavelength with smaller tangent slope could be chosen for in-situ dissolution test of Cimetidine tablets. PMID- 29403800 TI - Liquid chromatography tandem mass spectrometry method for the estimation of lamotrigine in human plasma: Application to a pharmacokinetic study. AB - A reliable, selective and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of lamotrigine in human plasma using lamotrigine-13C3, d3 as an internal standard. Analyte and internal standard were extracted from human plasma by solid-phase extraction and detected in positive ion mode by tandem mass spectrometry with electrospray ionization (ESI) interface. Chromatographic separation was performed on a Chromolith(r) SpeedROD; RP-18e column (50-4.6 mm i.d.) using acetonitrile: 5+/-0.1 mM ammonium formate solution (90:10, v/v) as the mobile phase at a flow rate of 0.500 mL/min. The calibration curves were linear over the range of 5.02 1226.47 ng/mL with the lower limit of quantitation validated at 5.02 ng/mL. The analytes were found stable in human plasma through three freeze (-20 degrees C) thaw (ice-cold water bath) cycles and under storage on bench-top in ice-cold water bath for at least 6.8 h, and also in the mobile phase at 10 degrees C for at least 57 h. The method has shown good reproducibility, as the intra- and inter day precisions were within 3.0%, while the accuracies were within +/-6.0% of nominal values. The validated LC-MS/MS method was applied for the evaluation of pharmacokinetic and bioequivalence parameters of lamotrigine after an oral administration of 50 mg lamotrigine tablet to thirty-two healthy adult male volunteers. PMID- 29403801 TI - Determination of cefcapene acid by LC-MS and their application to a pharmacokinetic study in healthy Chinese volunteers. AB - Simple, rapid and specific liquid chromatography-mass spectrometry (LC-MS) methods have been developed and validated for the quantification of cefcapene acid in human plasma and urine. Plasma samples were simply pretreated with methanol for deproteinization. Urine samples were briefly diluted with methanol water (50:50, v/v), and centrifuged to remove large particles. Chromatographic separation was performed on a Hedera ODS-2 column. For the plasma assay, the isocratic mobile phase consisted of 35% solvent A (Methanol) and 65% solvent B (10 mM ammonium acetate buffer solution containing 0.2% folic acid) with a flow rate of 0.3 mL/min. For the urine assay, the isocratic mobile phase consisted of 30% solvent A (Methanol) and 70% solvent B (10 mM ammonium acetate buffer solution containing 0.2% folic acid) with a flow rate of 0.3 mL/min. The assays were linear over the concentration ranges of 0.03-5 MUg/mL in plasma and 0.1-400 MUg/mL in urine, and were successfully applied to a pharmacokinetic study after single and multiple oral administrations of cefcapene pivoxil hydrochloride tablets in healthy Chinese volunteers. PMID- 29403804 TI - Establishment of inherent stability of pramipexole and development of validated stability indicating LC-UV and LC-MS method. AB - Pramipexole belongs to a class of nonergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease. A validated specific stability indicating reversed-phase liquid chromatographic method has been developed for the quantitative determination of pramipexole in bulk as well as in pharmaceutical dosage forms in the presence of degradation products. Forced degradation studies were performed by exposition of drug to hydrolytic (acidic and basic), oxidative and photolytic stress conditions, as defined under ICH guideline Q1A (R2). Significant degradation was observed under hydrolytic, oxidative and photolytic conditions and the degradation products formed were identified by LC-MS. PMID- 29403803 TI - Electrochemical study and application on rutin at chitosan/graphene films modified glassy carbon electrode. AB - Graphene (G) was dispersed into 0.5% chitosan (Chit) solution, then the composite films were coated on glassy carbon electrode (GCE), the electrochemical behavior of rutin on a Chit/G modified GCE was investigated and the electrochemical parameters of rutin were calculated. Rutin effectively accumulated on the Chit/G/GCE and caused a pair of redox peaks at around 408 mV and 482 mV (vs. SCE) in 0.1 M phosphate buffer solution (pH 4.0). Under optimized conditions, the anodic peak current was linear to the rutin concentration in the range of 5*10-7 1.04*10-5 M. The regression equation was: y=9.9219x-0.0025, r= 0.9958. The proposed method was successfully used for the determination of rutin content in tablet samples with satisfactory results. PMID- 29403802 TI - Reversed-phase fused-core HPLC modeling of peptides. AB - Different fused-core stationary phase chemistries (C18, Amide, Phenyl-hexyl and Peptide ES-C18) were used for the analysis of 21 structurally representative model peptides. In addition, the effects of the mobile phase composition (ACN or MeOH as organic modifier; formic acid or acetic acid, as acidifying component) on the column selectivity, peak shape and overall chromatographic performance were evaluated. The RP-amide column, combined with a formic acid-acetonitrile based gradient system, performed as best. A peptide reversed-phase retention model is proposed, consisting of 5 variables: log SumAA, log Sv, clog P, log nHDon and log nHAcc. Quantitative structure-retention relationship (QSRR) models were constructed for 16 different chromatographic systems. The accuracy of this peptide retention model was demonstrated by the comparison between predicted and experimentally obtained retention times, explaining on average 86% of the variability. Moreover, using an external set of 5 validation peptides, the predictive power of the model was also demonstrated. This peptide retention model includes the novel in-silico calculated amino acid descriptor, AA, which was calculated from log P, 3D-MoRSE, RDF and WHIM descriptors. PMID- 29403805 TI - New simple spectrophotometric method for determination of the binary mixtures (atorvastatin calcium and ezetimibe; candesartan cilexetil and hydrochlorothiazide) in tablets. AB - A new simple spectrophotometric method was developed for the determination of binary mixtures without prior separation. The method is based on the generation of ratio spectra of compound X by using a standard spectrum of compound Y as a divisor. The peak to trough amplitudes between two selected wavelengths in the ratio spectra are proportional to concentration of X without interference from Y. The method was demonstrated by determination of two drug combinations. The first consists of the two antihyperlipidemics: atorvastatin calcium (ATV) and ezetimibe (EZE), and the second comprises the antihypertensives: candesartan cilexetil (CAN) and hydrochlorothiazide (HCT). For mixture 1, ATV was determined using 10 MUg/mL EZE as the divisor to generate the ratio spectra, and the peak to trough amplitudes between 231 and 276 nm were plotted against ATV concentration. Similarly, by using 10 MUg/mL ATV as divisor, the peak to trough amplitudes between 231 and 276 nm were found proportional to EZE concentration. Calibration curves were linear in the range 2.5-40 MUg/mL for both drugs. For mixture 2, divisor concentration was 7.5 MUg/mL for both drugs. CAN was determined using its peak to trough amplitudes at 251 and 277 nm, while HCT was estimated using the amplitudes between 251 and 276 nm. The measured amplitudes were linearly correlated to concentration in the ranges 2.5-50 and 1-30 MUg/mL for CAN and HCT, respectively. The proposed spectrophotometric method was validated and successfully applied for the assay of both drug combinations in several laboratory-prepared mixtures and commercial tablets. PMID- 29403806 TI - Luminol-K3Fe(CN)6 chemiluminescence system for the determination of glipizide. AB - A rapid and sensitive flow-injection chemiluminescence (CL) method for the determination of glipizide was developed on the basis of finding that glipizide can enhance the CL intensity of the luminol-K3Fe(CN)6 system. In optimum condition, the increased CL intensity was directly proportional to the concentration of glipizide in the range from 4.0*10-8 g/mL to 1.0*10-6 g/mL and the detection limit was 1.0*10-8 g/mL glipizide. The relative standard deviation (RSD) of the developed method was 2.1% with 11 repeated measurements of 1.0*10-7 g/mL glipizide. The developed method has been successfully applied to the analysis of glipizide in its pharmaceutical preparations. PMID- 29403807 TI - Anodic Voltammetric determination of gemifloxacin using screen-printed carbon electrode. AB - The electrochemical oxidation behavior and voltammetric assay of gemifloxacin were investigated using differential-pulse and cyclic voltammetry on a screen printed carbon electrode. The effects of pH, scan rates, and concentration of the drug on the anodic peak current were studied. Voltammograms of gemifloxacin in Tris-HCl buffer (pH 7.0) exhibited a well-defined single oxidation peak. A differential-pulse voltammetric procedure for the quantitation of gemifloxacin has been developed and suitably validated with respect to linearity, limits of detection and quantification, accuracy, precision, specificity, and robustness. The calibration was linear from 0.5 to 10.0 MUM, and the limits of detection and quantification were 0.15 and 5.0 MUM. Recoveries ranging from 96.26% to 103.64% were obtained. The method was successfully applied to the determination of gemifloxacin in pharmaceutical tablets without any pre-treatment. Excipients present in the tablets did not interfere in the assay. PMID- 29403808 TI - Analysis of spironolactone residues in industrial wastewater and in drug formulations by cathodic stripping voltammetry. AB - The redox behavior of spironolactone (SP) drug in Britton-Robinson (BR) buffer of pH 2-11 was investigated by differential pulse cathodic stripping voltammetry (DPCSV) and cyclic voltammetry (CV) at hanging mercury dropping electrode (HMDE). At pH 9-10.5, the DPCSV of SP drug showed two cathodic peaks at -1.15 and -1.38 V at the HMDE vs. Ag/AgCl reference electrode. In the CV, at pH 9-10, the dependence of the cathodic peak current, Ip , c and peak potential, Ep,c of the second peak (Ep,c2) on the scan rate (nu) and on the depolizer (SP) concentrations was typical of an electrode coupled (EC) chemical reaction type mechanism. The plot of Ip , c at -1.380 V of the DPCSV vs. SP concentration at pH 9 was linear over the concentration range of 1.2*10-10-9.6*10-7 M. The lower limit of detection (LLOD) and limit of quantification (LOQ) of the drug were 1.1*10-11 and 4.14*10-11 M, respectively. The method was successfully applied for the analysis of SP residues in industrial wastewater, in pure form (98.2+/-3.1%) and in drug formulations e.g. Aldactone(r) tablet (98.35+/-2.9%).The method was validated by comparison with HPLC and the official data methods. PMID- 29403809 TI - LC-MS/MS assay for the determination of natamycin in rabbit and human plasma: Application to a pharmacokinetics and protein binding study. AB - To enable reliable quantification of natamycin in rabbit and human plasma, a validated, sensitive and selective liquid chromatography-tandem mass spectrometry assay was developed. The chromatographic separation was achieved isocratically on a Cyano column using methanol: aqueous 3.5 mM ammonium acetate (pH 4) (90:10 v/v). The assay was validated over a concentration range of 6.25-400 ng/mL with lower limit of detection of 3.12 ng/mL. Quantification was performed using the transitions 664.5->137.2m/z for natamycin and 923.5->183.4m/z for the IS. The method was validated with respect to linearity, accuracy, precision, recovery and stability. This assay has been successfully applied to a pharmacokinetic study of natamycin in NZ rabbit and plasma protein binding in human plasma. PMID- 29403810 TI - Simultaneous quantification of prodrug oseltamivir and its metabolite oseltamivir carboxylate in human plasma by LC-MS/MS to support a bioequivalence study. AB - A simple, precise and rapid liquid chromatography-tandem mass spectrometry (LC MS/MS) method has been developed and validated for the simultaneous determination of oseltamivir and oseltamivir carboxylate, a neuraminidase inhibitor, using their deuterated analogs as internal standards (ISs). The method involved solid phase extraction of the analytes and ISs from 200 MUL human plasma with no reconstitution and drying steps. The chromatographic separation was achieved on a Symmetry C18 (100 mm*4.6 mm, 5 MUm) column using 10 mM ammonium formate and acetonitrile (30:70, v/v) as the mobile phase in a run time of 2.0 min. Quantitation of analytes and ISs were done by multiple reaction monitoring on a triple quadrupole mass spectrometer in the positive ionization mode. The linearity of the method was established in the concentration range of 0.5-200 ng/mL and 2.0-800 ng/mL for oseltamivir and oseltamivir carboxylate respectively. The mean extraction recovery for oseltamivir (94.4%) and oseltamivir carboxylate (92.7%) from spiked plasma samples was consistent and reproducible. The application of this method was demonstrated by a bioequivalence study in 42 healthy Indian subjects with 75 mg oseltamivir phosphate capsules. The assay reproducibility was established by reanalysis of 151 incurred subject samples. PMID- 29403811 TI - Improved reversed phase liquid chromatographic method with pulsed electrochemical detection for tobramycin in bulk and pharmaceutical formulation. AB - Tobramycin is one of the aminoglycoside antibiotics that lack a UV absorbing chromophore. However, the application of pulsed electrochemical detection (PED) has been used successfully for the analysis of this and similar antibiotics. This work describes an improved liquid chromatographic (LC) method combined with PED, which is able to separate much more impurities than before. Using a Discovery C 18 RP column (250 mm*4.6 mm i.d., 5 MUm), isocratic elution was carried out with a mobile phase, containing sodium sulfate (35 g/L), sodium octanesulphonic acid (1 g/L), tetrahydrofuran (14 mL/L) and 0.2 M phosphate buffer pH 3.0 (50 mL/L). Using these experimental conditions, the limit of quantification (LOQ, S/N=10) was 5 ng. The linearity was examined in the range LOQ-60 MUg/mL and the coefficient of determination was 0.998. The method also proved to be repeatable and the recovery was close to 100%. The influence of the different chromatographic parameters on the separation was investigated by means of an experimental design. The proposed method is useful in quality control of tobramycin drug substances and drug products. PMID- 29403812 TI - Determination and stress studies on YK-1101, a potential histone deacetylase, by HPLC-UV and HPLC-TOF/MS methods. AB - YK-1101, with its structure as S-((E)-4-((7S,10S,Z)-4-ethylidene-7-isopropyl 2,5,8,12-tetraoxo -9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca 1(17),15(18)-dien-10-yl)but-3-en-1-yl) ethanethioate, is synthesized as a potential histone deacetylase inhibitor. Its quality and stability under various stress conditions are not fully understood. In this study, a high performance liquid chromatographic (HPLC) method was established and validated for the analysis of YK-1101 bulk drug samples. The chromatographic separation was performed on a C18 column with acetonitrile and water as mobile phase in a gradient elution. Based on the established method, the stability studies of YK 1101 under various stress conditions were carried out. YK-1101 was shown to undergo degradation under basic and acidic stress conditions, while it was stable under oxidative, photolytic and thermal conditions. In addition, a time of flight mass spectrometer (TOF/MS) was coupled to HPLC for the characterization of major degradation products produced under basic and acidic stress conditions. Their degradation pathways were also discussed. PMID- 29403813 TI - Determination of sildenafil by preconcentration on surfactant coated polymeric resin followed by spectrofluorimetry. AB - The illicit addition of phosphodiesterase type-5 (PDE-5) inhibitors like sildenafil (Viagra) in product offered as herbal medicine or dietary supplement for male erectile dysfunction has concerned authorities in recent times. In this paper, we proposed a sensitive surfactant-coated Amberlite XADTM resin for sildenafil preconcentration method with spectrofluorimetric detection. Retention capacity of micellar coated XAD resin for sildenafil was studied and the obtained eluate was measured by spectrofluorometer at excitation and emission wavelengths of 350 and 430 nm, respectively. This method allowed the detection of sildenafil at 0.15 ng/mL with linear range of 0.0003-7.0 MUg/mL. The method has been successfully applied to the analysis of some local commercially available herbal medicines and urine. PMID- 29403814 TI - Accurate quantitation standards of glutathione via traceable sulfur measurement by inductively coupled plasma optical emission spectrometry and ion chromatography. AB - The quantitative analysis of glutathione (GSH) is important in different fields like medicine, biology, and biotechnology. Accurate quantitative measurements of this analyte have been hampered by the lack of well characterized reference standards. The proposed procedure is intended to provide an accurate and definitive method for the quantitation of GSH for reference measurements. Measurement of the stoichiometrically existing sulfur content in purified GSH offers an approach for its quantitation and calibration through an appropriate characterized reference material (CRM) for sulfur would provide a methodology for the certification of GSH quantity, that is traceable to SI (International system of units). The inductively coupled plasma optical emission spectrometry (ICP-OES) approach negates the need for any sample digestion. The sulfur content of the purified GSH is quantitatively converted into sulfate ions by microwave-assisted UV digestion in the presence of hydrogen peroxide prior to ion chromatography (IC) measurements. The measurement of sulfur by ICP-OES and IC (as sulfate) using the "high performance" methodology could be useful for characterizing primary calibration standards and certified reference materials with low uncertainties. The relative expanded uncertainties (% U) expressed at 95% confidence interval for ICP-OES analyses varied from 0.1% to 0.3%, while in the case of IC, they were between 0.2% and 1.2%. The described methods are more suitable for characterizing primary calibration standards and certifying reference materials of GSH, than for routine measurements. PMID- 29403815 TI - Release test of alliin/alliinase double-layer tablet by HPLC-Allicin determination. AB - A simple, precise and accurate method was developed and validated for the determination of allicin release from alliin/alliinase double-layer tablets. According to Appendix XC II of Chinese Pharmacopoeia 2010 edition Volume II, a small glass-method was adopted at the rotational speed of 100 r/min using 100 mL phosphate buffer (pH 6.8) as release medium. The release amount was determined by HPLC with a C18 column (250 mm*4.6 mm, 5 MUm) using the mobile phase consisting of methanol -0.4% carboxylic acid (65:35) at a flow rate of 1 mL/min and UV detection at 242 nm. The current method demonstrates good linearity over the range 4.052-405.2 MUg/mL (r2=0.9999) with an average recovery of 105.5%(RSD=1.25%). The accumulative release of alliin/alliinase double-layer tablets had good homogeneity for within- and between-batches. The method established is simple, accurate and repeatable for the determination of allicin release from alliin/alliinase double-layer tablets. PMID- 29403816 TI - Thermally decarboxylated sodium bicarbonate: Interactions with water vapour, calorimetric study. AB - Isothermal titration calorimetry (ITC) was used to study interactions between water vapour and the surface of thermally converted sodium bicarbonate (NaHCO3). The decarboxylation degree of the samples was varied from 3% to 35% and the humidity range was 54-100%. The obtained enthalpy values were all exothermic and showed a positive linear correlation with decarboxylation degrees for each humidity studied. The critical humidity, 75% (RHo), was determined as the inflection point on a plot of the mean-DeltaH kJ/mole Na2CO3 against RH. Humidities above the critical humidity lead to complete surface dissolution. The water uptake (m) was determined after each calorimetric experiment, complementing the enthalpy data. A mechanism of water vapour interaction with decarboxylated samples, including the formation of trona and Wegscheider's salt on the bicarbonate surface is proposed for humidities below RHo. PMID- 29403817 TI - Fluorescence spectroscopy of osthole binding to human serum albumin. AB - The interaction of human serum albumin (HSA) with osthole was investigated by fluorescence spectroscopy. Osthole can quench the fluorescence of HSA and the quenching mechanism is a static process. The binding site number n and apparent binding constant K were measured at different temperatures. The thermodynamic parameters DeltaH0, DeltaG0 and DeltaS0 were calculated at different temperatures. The results indicated that electrostatic forces played a major role in the interaction of osthole with HSA. Results of osthole synchronous fluorescence and UV absorption spectra showed that the microenvironment and conformation of HSA were changed. PMID- 29403818 TI - Development of a validated UPLC-qTOF-MS/MS method for determination of bioactive constituent from Glycyrrhiza glabra. AB - An ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-qTOF-MS/MS) method was developed and validated for the simultaneous determination of glycyrrhizin and glycyrrhetic acid. These analytes were separated on a reverse phase C18 column using a mobile phase of acetonitrile:2% acetic acid in water (75:25, v/v) with a flow rate of 200 MUL/min. The qTOF-MS was operated under multiple reaction monitoring (MRM) mode using the electrospray ionization (ESI) technique with positive ion polarity. A comparison of three different extraction techniques i.e. accelerated solvent extraction (ASE), extraction under ultrasonic waves (USW) and the classical extraction by percolation (CE) method was done and quantification of these extracts was also carried out by the proposed method. PMID- 29403819 TI - Development and validation of a rapid chromatographic method for the analysis of flunarizine and its main production impurities. AB - A rapid selective method for the analysis of flunarizine and its associated impurities was developed and validated according to ICH guidelines. The separation was carried out using a Thermo Scientific Hypersil Gold C18 column (50 mm*4.6 mm i.d., 1.9 MUm particle size) with a gradient mobile phase of acetonitrile-ammonium acetate-tetrabutylammoniumhydrogen sulfate buffer, at a flow rate of 1.8 mL/min and UV detection at 230 nm. Naturally aged samples were also tested to determine sample stability. A profile of sample and impurity breakdown was also presented. PMID- 29403820 TI - Volatile components of Rhizoma Alpiniae Officinarum using three different extraction methods combined with gas chromatography-mass spectrometry. AB - Volatile components from Rhizoma Alpiniae Officinarum were respectively extracted by three methods including hydrodistillation, headspace solid-phase microextraction (HS-SPME) and diethyl ether extraction. A total of 40 (hydrodistillation), 32 (HS-SPME) and 37 (diethyl ether extraction) compounds were respectively identified by gas chromatography-mass spectrometry (GC/MS) and 22 compounds were overlapped, including alpha-farnesene, gamma-muurolene, 2,6 dimethyl-6-(4-methyl-3-pentenyl)bicyclo[3.1.1]hept-2-ene, eucalyptol and cadina 1(10), 4-diene and so forth, varying in relative contents. HS-SPME is fast, sample saving and solvent-free and it also can achieve similar profiles as those from hydrodistillation and solvent extraction. Therefore, it can be the priority for extracting volatile components from medicinal plants. PMID- 29403821 TI - A sensitive, simple and rapid HPLC-MS/MS method for simultaneous quantification of buprenorpine and its N-dealkylated metabolite norbuprenorphine in human plasma. AB - A sensitive, simple and rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and fully validated for the simultaneous quantification of buprenorphine (BUP) and its N-dealkylated metabolite norbuprenorphine (NBUP) in 200 MUL human plasma. Human plasma samples were prepared using liquid-liquid extraction, and then separated on a Shiseido MG C18 (5 MUm, 2.0 mm*50 mm) via 4.1 min gradient elution. Following electrospray ionization, the analytes were quantified on a triple-quadrupole mass spectrometer in multiple-reaction-monitoring (MRM) positive ion mode. Linearity was achieved from 25.0 to 10000 pg/mL for buprenorphine, from 20.0 to 8000 pg/mL for norbuprenorphine with r2>0.99. The method was demonstrated with acceptable accuracy, precision and specificity for the detection of buprenorphine and norbuprenorphine. Recovery was 81.8-88.8% for buprenorphine and 77.0-84.6% for norbuprenorphine, and the matrix effect was 95.6-97.4% for buprenorphine and 94.0 96.9% for norbuprenorphine; all were not concentration dependent. With validated matrix and autosampler stability data, this method was successfully applied in a bioequivalence study to support abbreviated new drug application. PMID- 29403822 TI - LC-MS/MS determination and pharmacokinetic study of bergenin, the main bioactive component of Bergenia purpurascens after oral administration in rats. AB - Bergenin, a C-glucoside of 4-O-methyl gallic acid from Bergenia purpurascens, is a naturally antitussive and expectorant agent. A rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of the active component-bergenin, in rat plasma after oral administration of aqueous B. purpurascens extract. The plasma samples were pretreated by protein precipitation with acetonitrile and chromatographic separation was achieved on a Diamonsil(r) C18 column (150 mm*4.6 mm, 5 MUm) with isocratic elution using a mobile phase consisting of water-methanol (30:70, v/v) at a flow rate of 0.6 mL/min. The detection was accomplished by a triple quadrupole tandem mass spectrometer in multiple-reaction monitoring (MRM) scanning via an electrospray ionization (ESI) source operating in the negative mode. The optimized mass transition ion-pairs (m/z) for quantitation were 327.3/192.0 for bergenin, and 431.1/311.1 for IS. The time for each analysis run was only 3.5 min between injections. The calibration curve exhibited good linearity (r2>0.99) over a range of 1.00-2000 ng/mL for bergenin. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. The intra- and inter-day precisions were no more than 11.8%, and relative errors (RE) were within the range of 0.0-4.4%. The validated method was successfully applied to investigate the pharmacokinetics of bergenin after oral administration of B. purpurascens extract in rats. PMID- 29403823 TI - Ultra-high-performance liquid chromatography for the determination of exenatide in monkey plasma by tandem quadrupole mass spectrometry. AB - A highly sensitive ultra-high-performance liquid chromatographic-tandem mass spectrometry (UPLC/MS/MS) method was developed for the quantification of the synthetic peptide drug of exenatide in monkey plasma. Sample preparation was carried out by solid-phase extraction (SPE), and bivalirudin was used as the internal standard (IS). An excellent chromatographic separation was obtained on a reversed-phase C18 column with a gradient elution. Detection utilized a Qtrap 5500 system operated in the positive ion mode with multiple reaction monitoring (MRM). The proposed method was validated by assessing the specificity, linearity, intra- and inter-day precision and accuracy, recovery, and stability. The method resulted in a linear calibration range of 0.10-30 ng/mL, extracting with only 50 MUL monkey plasma aliquots. The intra- and inter-day precisions (as relative standard deviation) were less than 7.5% and 9.6%, respectively. The method could be successfully utilized for the pharmacokinetic study of exenatide in monkeys following a single subcutaneous injection of Byetta. PMID- 29403824 TI - A simple method for the isolation and purification of resveratrol from Polygonum cuspidatum. AB - Resveratrol, a polyphenol compound with strong biological activity, has been widely used in medicine, health products and cosmetic industries. It is also the main active component of Polygonum cuspidatum, a well-known traditional Chinese medicine. We developed a simple and effective method for the preparation of resveratrol from P. cuspidatum. The whole preparative process consisted of reflux extraction, filtering, hydrolyzing, liquid-liquid extraction and eluting. Filtering is to remove non polar or less polar compounds and debris fragments from the extract. Hydrolyzing is to transform polydatin to resveratrol to improve the yield of resveratrol. Eluting is to remove impurities including strong acidic and water-soluble compounds. By acid hydrolysis of glycoside (polydatin), the yield of resveratrol increased about 4-fold. The extraction recovery in different stages was high, and the content of resveratrol in the final product was over 73.8%. Compared with other methods reported, this technology is eco-friendly, easier to perform, and also has a lower cost. PMID- 29403825 TI - Quantitative analysis of cefixime via complexation with palladium(II) in pharmaceutical formulations by spectrophotometry. AB - An optimized and validated spectrophotometric method has been developed for the determination of cefixime in pharmaceutical formulations. The method is based on the complexation reaction between cefixime and palladium ion in the presence of acidic buffer solution (pH 3) in ethanol-distilled water medium at room temperature. The complex absorbed maximally at 352 nm. Beer's law is obeyed in the working concentration range of 2.5-35 MUg/mL with apparent molar absorptivity of 1.015*104 L/mol cm and Sandell's sensitivity of 0.001 MUg/cm2/0.001 absorbance unit. The limits of detection and quantitation for the proposed method are 0.175 and 0.583 MUg/mL, respectively. The effect of common excipients used as additives has been studied in the determination of cefixime. The proposed method has been successfully applied for the determination of cefixime in pharmaceutical formulations. The results obtained by the proposed method were statistically compared with the reference method using t and F values and found no significant difference between the two methods. PMID- 29403826 TI - Investigation of the interaction between indigotin and two serum albumins by spectroscopic approaches. AB - The binding characteristics of indigotin with human serum albumin (HSA) and bovine serum albumin (BSA) have been investigated by various spectroscopic techniques. Spectroscopic analysis revealed that the quenching mechanism between indigotin and HSA/BSA belonged to the static quenching. The displacement experiments suggested that indigotin primarily bound to tryptophan residues on proteins within site I. The thermodynamic parameters indicated that the binding of indigotin-HSA/BSA mainly depended on the hydrophobic interaction. The binding distance of indigotin to HSA/BSA was evaluated. The results by synchronous fluorescence, three-dimensional fluorescence, Fourier Transform Infrared spectroscopy (FT-IR) and circular dichroism (CD) spectra showed that the conformation of proteins altered in the presence of indigotin. PMID- 29403827 TI - Application of UPLC-MS/MS for separation and quantification of 3alpha-Hydroxy Tibolone and comparative bioavailability of two Tibolone formulations in healthy volunteers. AB - A novel, fast, sensitive and robust method based on ultra-performance liquid chromatography coupled to atmospheric pressure electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) has been developed to separate two Tibolone stereoisomers i.e., 3alpha-Hydroxy Tibolone and 3beta-Hydroxy Tibolone and to quantify 3alpha-Hydroxy Tibolone using p-toulenesulfonyl isocyanate (PTSI) as a derivatizing reagent in human plasma. 3alpha-Hydroxy Tibolone-13CD3 was used as an internal standard (IS). The analyte and IS were extracted from human plasma by liquid-liquid extraction using ethyl acetate. Extracted samples were analyzed by UPLC-ESI-MS/MS. Chromatography was performed using binary gradient on UPLC analytical column. A linear calibration curve over the range of 0.100-35.000 ng/mL was obtained and lower limit of quantification (LLOQ) was 0.100 ng/mL demonstrating acceptable accuracy and precision. This method was successfully applied to a pharmacokinetic study in order to compare a test Tibolone 2.5 mg formulation vs. a reference 2.5 mg Tibolone tablet formulation in 50 post menopausal/surgical menopause female human volunteers under fasting conditions. It is concluded that test formulation of Tibolone is bioequivalent to reference formulation of Tibolone. PMID- 29403828 TI - Fingerprint analysis of Cirsium japonicum DC. using high performance liquid chromatography. AB - In many areas of China Cirsium setosum is used as Cirsium japonicum DC. Although the two herbs have similar appearance and many similar compounds, they are totally different medicinal material, and have different pharmacodynamic actions. The fingerprint spectrum can be a good tool to distinguish the two herbs and control the quality of Cirsium japonicum DC. In this paper, the chemical fingerprint of Cirsium japonicum DC was established using raw materials from 15 origins in China. The chromatographic separations were obtained by a SHIM-PACK VP ODS column (150 mm*4.6 mm i.d., 5 MUm) using gradient elution, and run time of 80 min. The peak of linarin was considered as the control peak. The experimental data were analyzed with the software of Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (Version 2004A) and the quality control system of both the overall qualitative similarities and the overall quantitative similarities of traditional Chinese medicine chromatographic fingerprints. PMID- 29403829 TI - Simultaneous pharmacokinetic assessment of cefadroxil and clavulanic acid in human plasma by LC-MS and its application to bioequivalence studies. AB - A simple, rapid and selective liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) assay method has been developed and fully validated for the simultaneous quantification of cefadroxil (CF) and clavulanic acid (CA) in human plasma. Analytes and internal standard (IS) were extracted from human plasma by solid-phase extraction (SPE) technique using Sam prep (3 mL, 100 mg) extraction cartridge. The extracted samples were chromatographed on a reverse phase C18 column using a mixture of methanol: acetonitrile: 2 mM ammonium acetate (pH 3.5) (25:25:50, v/v/v) as the mobile phase at a flow rate of 0.8 mL/min. Quantification of the analytes and IS were carried out using single quadrupole LC-APCI-MS through selected-ion monitoring (SIM) at m/z 362 and m/z 198, for CF and CA, respectively. Method validation was performed as per the FDA guidelines and the results met the acceptance criteria. Plasma concentration of CF and CA followed by the oral administration of CF/CA (500/125 mg) pill to healthy male volunteers (n=12) was measured. Area under plasma concentration-time curve from 0 to 12 h (AUC0-12 h) and 0 h extrapolated to infinity (AUC0-infinity) were calculated. The ratio of AUC0-12 h/AUC0-infinity was found to be >85% for all the subjects, as recommended by the FDA guidelines. PMID- 29403830 TI - Characterization of phloroglucinol derivatives and diterpenes in Euphorbia ebracteolata Hayata by utilizing ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Euphorbia ebracteolata Hayata (E. ebracteolata) is a Chinese herbal medicine used for the treatment of tumor diseases. An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) based chemical profiling approach was established for the rapid separation and characterization on phloroglucinol derivatives and diterpenes in E. ebracteolata. Three phloroglucinol derivatives and nine diterpenes were identified by exact mass measurement and were further confirmed by Ms2 data. In addition, the chemical profiles of six compounds were acquired by reference standards. Furthermore, the fragmentation rules of phloroglucinol derivatives and diterpenes of E. ebracteolata were analyzed, and each chromatographic peak was classified. PMID- 29403831 TI - In vitro antibacterial and free radical scavenging activity of green hull of Juglans regia. AB - Antioxidant supplements from plants are vital to count the oxidative damage in cells. We assessed the antioxidants and antibacterial activity of green hull of Juglans regia in this study. According to our results the maximum antibacterial activity was observed in ethanolic extract when compared to other extract. So, the ethanolic extract was studied for antioxidant activity which exhibited high antiradical activity against DPPH, hydroxyl, and nitric oxide radicals. In conclusion, green hull of J. regia showed strong reducing power activity and total antioxidant capacity. The results justify the therapeutic application of plant in the indigenous system of medicine. PMID- 29403832 TI - Fused-core particle technology in high-performance liquid chromatography: An overview. AB - The advent of superficially porous particles (SPPs) for packed HPLC columns has changed the way that many practitioners have approached the problem of developing needed separations. The very high efficiency of such columns, combined with convenient operating conditions, modest back pressures and the ability to use conventional HPLC instruments has resulted in intense basic studies of SPP technology, and widespread applications in many sciences. This report contains an overview of the SPP technology first developed in 2006 by Advanced Materials Technology, Inc., for sub-3-MUm particles, then expanded into a family of SPP products with different particle sizes, pore sizes and other physical parameters. This approach was designed so that each particle of the family could be optimized for separating a particular group of compounds, usually based on solute size. PMID- 29403833 TI - Kinetic performance comparison of fully and superficially porous particles with sizes ranging between 2.7 MUm and 5 MUm: Intrinsic evaluation and application to a pharmaceutical test compound. AB - The reintroduction of superficially porous particles has resulted in a leap forward for the separation performance in liquid chromatography. The underlying reasons for the higher efficiency of columns packed with these particles are discussed. The performance of the newly introduced 5 MUm superficially porous particles is evaluated and compared to 2.7 MUm superficially porous and 3.5 and 5 MUm fully porous columns using typical test compounds (alkylphenones) and a relevant pharmaceutical compound (impurity of amoxicillin). The 5 MUm superficially porous particles provide a superior kinetic performance compared to both the 3.5 and 5 MUm fully porous particles over the entire relevant range of separation conditions. The performance of the superficially porous particles, however, appears to depend strongly on retention and analyte properties, emphasizing the importance of comparing different columns under realistic conditions (high enough k) and using the compound of interest. PMID- 29403834 TI - Determination of sodium hyaluronate in pharmaceutical formulations by HPLC-UV. AB - A liquid chromatography (HPLC) method with UV detection was developed for determination of sodium hyaluronate in pharmaceutical formulation. Sodium hyaluronate is a polymer of disaccharides, composed of d-glucuronic acid and d-N acetylglucosamine, linked via alternating beta-1, 4 and beta-1, 3 glycosidic bonds. Being a polymer compound it lacks a UV absorbing chromophore. In the absence of a UV absorbing chromophore and highly polar nature of compound, the analysis becomes a major challenge. To overcome these problems a novel method for the determination of sodium hyaluronate was developed and validated based on size exclusion liquid chromatography (SEC) with UV detection. An isocratic mobile phase consisting of buffer 0.05 M potassium dihydrogen phosphate, pH adjusted to 7.0 using potassium hydroxide (10%) was used. Chromatography was carried out at 25 degrees C on a BioSep SEC S2000, 300 mm*7.8 mm column. The detection was carried out using variable wavelength UV-vis detector set at 205 nm. The compounds were eluted isocratically at a steady flow rate of 1.0 mL/min. Sodium hyaluronate retention time was about 4.9 min with an asymmetry factor of 1.93. A calibration curve was obtained from 1 to 38 g/mL (r>0.9998). Within-day % RSD was 1.0 and between-day % RSD was 1.10. Specificity/selectivity experiments revealed the absence of interference from excipients, recovery from spiked samples for sodium hyaluronate was 99-102. The developed method was applied to the determination of sodium hyaluronate in pharmaceutical drug substance and product. PMID- 29403835 TI - A critical quality parameter in quantitative fused-core chromatography: The injection volume. AB - As part of the method development, the injection volume as a critical quality attribute in fast fused-core chromatography was evaluated. Spilanthol, a pharmaceutically interesting N-alkylamide currently under investigation in our laboratory, was chosen as the model compound. Spilanthol was dissolved in both PBS and MeOH/H2O (70/30, v/v) and subsequently analyzed using a fused-core system hereby selecting five chromatographic characteristics (retention time, area, height, theoretical plates and symmetry factor) as responses. We demonstrated that the injection volume significantly influenced both the qualitative and quantitative performance of fused-core chromatography, a phenomenon which is confounded with the nature of the used sample solvent. From 2 MUL up to 100 MUL injection volume with PBS as solvent, the symmetry factor decreased favorably by 20%. Moreover, the theoretical plates and the quantitative parameters (area and height) increased up to 30%. On the contrary, in this injection volume range, the theoretical plates for the methanol-based samples decreased by more than 60%, while the symmetry factor increased and the height decreased, both by 30%. The injection volume is thus a critical and often overlooked parameter in fused-core method description and validation. PMID- 29403836 TI - Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411). AB - CDRI compound no. 99/411 is a potent 1,2,4-trioxane antimalarial candidate drug under development at our Institute. An HPLC method for determination of CDRI 99/411 with its starting material and intermediates has been developed and validated for in process quality control and stability studies. The analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and lower limit of quantification (LLOQ) were determined according to International Conference on Harmonization ICH Q2(R1) guidelines. HPLC separation was achieved on a RP-select B Lichrosphere(r) column (250 mm*4 mm, 5 MUm, Merck) using water containing 0.1% glacial acetic acid and acetonitrile as the mobile phase in a gradient elution. The eluents were monitored by a photo diode array detector at 245 and 275 nm. Based on signal to noise ratio of 3 and 10 the LOD of CDRI 99/411 was 0.55 ug/mL, while the LLOQ was 1.05 ug/mL. The calibration curves were linear in the range of 1.05-68 ug/mL. Precision of the method was determined by inter- and intra-assay variations within the acceptable range. PMID- 29403837 TI - Application of LC-MS/MS for quantitative analysis of glucocorticoids and stimulants in biological fluids. AB - Liquid chromatography tandem mass chromatography (LC-MS/MS) is an important hyphenated technique for quantitative analysis of drugs in biological fluids. Because of high sensitivity and selectivity, LC-MS/MS has been used for pharmacokinetic studies, metabolites identification in the plasma and urine. This manuscript gives comprehensive analytical review, focusing on chromatographic separation approaches (column packing materials, column length and mobile phase) as well as different acquisition modes (SIM, MRM) for quantitative analysis of glucocorticoids and stimulants. This review is not meant to be exhaustive but rather to provide a general overview for detection and confirmation of target drugs using LC-MS/MS and thus useful in the doping analysis, toxicological studies as well as in pharmaceutical analysis. PMID- 29403838 TI - Chiral separation of bavachinin in Fructus Psoraleae and rat plasma by liquid chromatography using permethylated-beta-CD as a chiral selector. AB - A simple, sensitive and selective method of high-performance liquid chromatography (HPLC) has been successfully developed for separation of bavachinin enantiomers in Fructus Psoraleae and rat plasma. The separation and detection conditions of HPLC were optimized. Chiral bavachinin were separated with the mobile phase of methanol and water (70:30, v/v) at a flow rate of 1.0 mL/min. The linear ranges were in the range of 20-1000 MUg/mL. The detection limits were tested as 4 ng/mL and 6 ng/mL for (+)-bavachinin and (-)-bavachinin, respectively. The method has been applied to analyze chiral bavachinin in rat plasma. HPLC-MS method was used to test the accuracy. PMID- 29403839 TI - Copper interactions with DNA of chromatin and its role in neurodegenerative disorders. AB - In this study, we have demonstrated the conformational changes to DNA induced by abnormal interactions of copper using circular dichroism, in combination with UV absorbance and fluorescence spectroscopy. Results confirm that binding of copper to bases of DNA in chromatin is concentration dependent. Binding efficiency of Cu2+ ions to DNA is increased in proportion to the degree of unwinding of the double helix induced by denaturation. Altered B-DNA conformation will alter the integrity of DNA which may affect the normal process of DNA replication and transcription. Copper induced DNA damage in the brain may cause neurotoxicity and the neuronal cell death and is implicated in Alzheimer's disease and other neurological disorders. PMID- 29403840 TI - A novel luminol-based chemiluminescence method for the determination of amikacin sulfate in serum by using trivalent copper-periodate complex. AB - A novel chemiluminescence (CL) reaction was based on the oxidizing reaction of luminol by the trivalent copper-periodate complex (K5[Cu(HIO6)2], DPC) in alkaline medium. The CL intensity could be enhanced in the presence of amikacin sulfate (AKS). A new CL method was developed for the determination of AKS by coupling with flow injection (FI) technology. Because of the distinctive oxidative effect of DPC, the luminol-based CL reaction could occur at a low concentration of 10-7 M. The relative CL intensity was proportional to the concentration of AKS in the range of 4.0*10-9-4.0*10-6 g/mL with the detection limit of 1.2*10-9 g/mL. The relative standard deviation was 2.1% for 8.0*10-9 g/mL AKS (n=9). The proposed method was successfully applied to the direct determination of AKS at the level of ng/mL in serum samples. The recovery varied from 97.0% to 106.3%. A possible mechanism of the CL reaction was discussed in detail by relating to the CL kinetic characteristics and electrochemical activities of the oxidant DPC. PMID- 29403841 TI - In situ modified screen printed and carbon paste ion selective electrodes for potentiometric determination of naphazoline hydrochloride in its formulation. AB - The construction and performance characteristics of new sensitive and selective in situ modified screen printed (ISPE) and carbon paste (ICPE) electrodes for determination of naphazoline hydrochloride (NPZ-HCl) have been developed. The electrodes under investigation show potentiometric response for NPZ-HCl in the concentration range from 7.0*10-7 to 1.0*10-2 M at 25 degrees C and the electrode response is independent of pH in the range of 3.1-7.9. These sensors have slope values of 59.7+/-0.6 and 59.2+/-0.2 mV decade-1 with detection limit values of 5.6*10-7 and 5.9*10-7 M NPZ-HCl using ISPE and ICPE, respectively. These electrodes show fast response time of 4-7 s and 5-8 s and exhibits lifetimes of 28 and 30 days for ISPE and ICPE, respectively. Selectivity for NPZ HCl with respect to a number of interfering materials was also investigated. It was found that there is no interference from the investigated inorganic cations, anions, sugars and other pharmaceutical excipients. The proposed sensors were applied for the determination of NPZ-HCl in pharmaceutical formulation using the direct potentiometric method. It showed a mean average recovery of 100.2% and 102.6% for ISPE and ICPE, respectively. The obtained results using the proposed sensors were in good agreement with those obtained using the official method. The proposed sensors show significantly high selectivity, response time, accuracy, precision, limit of detection (LOD) and limit of quantification (LOQ) compared with other proposed methods. PMID- 29403842 TI - Simultaneous determination of human plasma protein binding of bioactive flavonoids in Polygonum orientale by equilibrium dialysis combined with UPLC MS/MS. AB - A simple and selective ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) assay was developed for the determination of the human plasma protein binding of four bioactive flavonoids (such as orientin and vitexin) in Polygonum orientale. Protein precipitation was used for sample preparation. Equilibrium dialysis technique was applied to determine the plasma protein binding under physiological conditions. The separation was achieved through a Waters C18 column with a mobile phase composed of 0.1% formic acid in acetonitrile and 0.1% aqueous formic acid using step gradient elution at a flow rate of 0.35 mL/min. A Waters ACQUITYTM TQD system was operated under the multiple reaction monitoring (MRM) mode of positive electrospray ionization. All of the recovery, precision, accuracy and stability of the method met the requirements. Good correlations (r>0.99) of the four compounds were found, which suggested that these compounds can be simultaneously determined with acceptable accuracy. Results showed that the plasma protein bindings of the four bioactive flavonoids were in the range of 74-89% over the six concentrations studied. The binding parameters containing protein binding affinity, protein binding dissociation constant, and protein binding site were studied. The maximum ability to bind with protein was also determined in the assay in order to understand the drug-protein binding of each compound better. PMID- 29403843 TI - A novel and rapid microbiological assay for ciprofloxacin hydrochloride. AB - The present work reports a simple, fast and sensitive microbiological assay applying the turbidimetric method for the determination of ciprofloxacin hydrochloride (CIPRO HCl) in ophthalmic solutions. The validation method yielded good results and included excellent linearity, precision, accuracy and specificity. The bioassay is based on the inhibitory effect of CIPRO HCl upon the strain of Staphylococcus epidermidis ATCC 12228 used as the test microorganism. The results were treated statistically by analysis of variance (ANOVA) and were found to be linear (r=0.9994, in the range of 14.0-56.0 ug/mL), precise (intraday RSD%=2.06; interday RSD%=2.30) and accurate (recovery=99.71%). The turbidimetric assay was compared to the UV spectrophotometric and HPLC methods for the same drug. The turbidimetric bioassay described on this paper for determination of ciprofloxacin hydrochloride in ophthalmic solution is an alternative to the physicochemical methods disclosed in the literature and can be used in quality control routine. PMID- 29403844 TI - Pharmacokinetic study of inosiplex tablets in healthy Chinese volunteers by hyphenated HPLC and tandem MS techniques. AB - Inosiplex is a compound formulation composed of inosine and p-acetaminobenzoic acid (PABA) salt of N,N-dimethylamino-2-propanol (DIP). This study was to investigate the clinical plasma pharmacokinetic properties of DIP and PABA after single and multiple oral doses of inosiplex tablets in healthy Chinese volunteers. The established LC/MS/MS method for plasma DIP determination had a linear range of 0.02-10 ug/mL, and the HPLC method for plasma PABA determination had a linear range of 0.05-40 ug/mL. Linear pharmacokinetic characteristics were found with single oral doses of 0.5, 1.0 and 2.0 g. No obvious accumulation effects were observed for DIP and PABA. PMID- 29403845 TI - Simultaneous determination of asenapine and valproic acid in human plasma using LC-MS/MS: Application of the method to support pharmacokinetic study. AB - Combination of asenapine with valproic acid received regulatory approval for acute treatment of schizophrenia and maniac episodes of bipolar disorders. A simple LC-MS/MS method was developed and validated for simultaneous quantification of asenapine and valproic acid in human plasma. Internal standards were added to 300 MUL of plasma sample prior to liquid-liquid extraction using methyl tertiary butyl ether (MTBE). Chromatographic separation was achieved on Phenomenex C18 column (50 mm*4.6 mm, 5 MUm) in isocratic mode at 40 degrees C. The mobile phase used was 10 mM ammonium formate-acetonitrile (5:95, v/v) at a constant flow rate of 0.8 mL/min monitored on triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) mode. The injection volume used for LC-MS/MS analysis was 15 MUL and the run time was 2.5 min. These low run time and small injection volume suggest the high efficiency of the proposed method. The method was validated over the concentration range of 0.1 10.02 ng/mL and 10-20,000 ng/mL for asenapine and valproic acid respectively. The method recoveries of asenapine (81.33%), valproic acid (81.70%), gliclazide (78.45%) and benzoic acid (79.73) from spiked plasma samples were consistent and reproducible. The application of this method was demonstrated by a pharmacokinetic study in 8 healthy male volunteers with 5 mg asenapine and 250 mg valproic acid administration. PMID- 29403846 TI - Analysis on fat-soluble components of sinapis semina from different habitats by GC-MS. AB - A simple and rapid gas chromatography/mass spectrometry (GC/MS) analysis method was developed for the determination of fat-soluble parts of sinapis semina. Four major compounds were chosen as marker compounds to evaluate the method. Various extraction techniques were evaluated and the greatest efficiency was observed with sonication extraction using diethyl ether. The method was valuated as follows: acceptable apparatus suitability was obtained by testing the resolutions, tailing factors and theoretical plate number of the marker compounds; the precision and reproducibility, expressed as relative standard deviation (RSD), fell within the prescribed limits. Eight samples of sinapis semina collected from markets in Xi'an were monitored by using the method. The fingerprints of those samples were analyzed by hierarchical cluster analysis (HCA) similarity analysis. The result indicated that the combination of fingerprint and HCA could be used to analyze sinapis semina from different habitats. PMID- 29403847 TI - Rapid, simple and stability-indicating determination of polyhexamethylene biguanide in liquid and gel-like dosage forms by liquid chromatography with diode array detection. AB - A rapid and simple method for the determination of polyhexamethylene biguanide (polyhexanide, PHMB) in liquid and gel-like pharmaceutical formulations by means of high performance liquid chromatography coupled to diode-array detection (HPLC DAD) was developed. Best separation was achieved using a cyanopropyl bonded phase (Agilent Zorbax Eclipse XDB-CN column 4.6 mm*75 mm with particle size of 3.5 MUm) as well as gradient elution consisting of acetonitrile/deionized water at a flow rate of 1.0 mL/min. The optimized and applied chromatographic conditions permitted separation of polyhexanide from interacting matrix with subsequent detection at a wavelength of 235 nm with good sensitivity. The method validation was carried out with regard to the guidelines for analytical procedures demanded by the International Conference on Harmonisation (ICH). Mean recoveries of 102% and 101% for gel-like as well as liquid preparations were obtained. Suitable repeatability as well as intermediate precision could be achieved with limits of detection <=0.004 mg/mL for both formulations, equivalent to <=0.004% PHMB concerning sample preparation. Determination of PHMB was accomplished without tedious sample preparation. Interacting matrix could be eliminated by the chromatographic procedure with excellent performance of system suitability. All analytical requirements were fulfilled permitting a reliable and precise determination of PHMB in pharmaceuticals. Furthermore, the developed method was applied to stability testing of pharmaceutical preparations containing PHMB. PMID- 29403848 TI - Determination of epristeride by its quenching effect on the fluorescence of L tryptophan. AB - A rapid, novel spectrofluorimetric method to determine epristeride (EP) in biological fluids and a pharmaceutical formulation was developed, based on the fact that fluorescence intensity of l-tryptophan could be quenched by EP in the medium of pH=9.0. The various factors influencing fluorescence quenching were discussed. The quenching mechanism was investigated with the quenching type, synchronous fluorescence spectra and quantum efficiency. Under the optimized conditions, fluorescence quenching value (DeltaF=Fl-tryptophan-FEP-l-tryptophan) showed a good linear relationship with the EP concentration ranging from 0.4 to 12.0 MUg/mL. The linearity, recovery and limit of detection demonstrated that the proposed method was suitable for EP determination in biological fluids and EP tablets. The method was successfully applied to the analysis of EP in real samples and the obtained results were in good agreement with the results of the official method. PMID- 29403849 TI - Quantitative analysis of catechins in Saraca asoca and correlation with antimicrobial activity. AB - Herbal medicines are highly complex and have unknown mechanisms in diseases treatment. Saraca asoca (Roxb.), De. Wild has been recommended to treat gynecological disorders and used in several commercial polyherbal formulations. In present study, efforts have been made to explore antimicrobial activity and its co-relation with the distributions of catechins in the organs of S. asoca using targeted MS/MS. Eight extracts (cold and hot water) from four different organs of S. asoca and two drugs were prepared and antimicrobial activity was assessed by microbroth dilution assay. Quantitative and qualitative analysis of catechins in crude extracts was done by using targeted and auto-MS/MS and correlated with antimicrobial activity. (+)-Catechin and (+)-epicatechin and their biosynthesis related compound were found to be up-regulated in regenerated bark and leaves extracts. (-)-Epigallocatechin was found to be significantly higher in bark water extract as compared to others but showed low antimicrobial activity. Result showed down-regulation of (-)-epigallocatechin and up-regulation of (+)-catechin and (+)-epicatechin in the regenerated bark and leaves of S. asoca. It might be the contributing factor in the antimicrobial activity of regenerated bark and leaves of the plant. The concentration of (+)-epicatechin in processed drugs (Ashokarishta) from Baidyanath was found to be seven times higher than that of Dabur Pvt. Ltd., but no antimicrobial activity was observed, indicating the variations among the plant based drugs. This will be helpful in rational use of S. asoca parts. Furthermore, the analytical method developed is sensitive, repeatable and reliable; therefore, it is suitable for quality control of herbal drugs. PMID- 29403850 TI - Preparative separation and purification of deoxyschizandrin from Schisandrae Sphenantherae Fructus by high-speed counter-current chromatography. AB - A high-speed counter-current chromatography (HSCCC) method was successfully developed for the preparative separation and purification of deoxyschizandrin from Schisandrae Sphenantherae Fructus in one step. The purity of deoxyschizandrin was 98.5%, and the structure was identified by MS, UV and NMR. This method was simple, fast, convenient and appropriate to prepare pure compound as reference substances for related research on Schisandrae Sphenantherae Fructus. PMID- 29403851 TI - Optimization and validation of a fast RP-HPLC method for the determination of dobutamine in rat plasma: Pharmacokinetic studies in healthy rat subjects. AB - A novel isocratic reverse phase high performance liquid chromatography (RP-HPLC) with photo diode array (PDA) detection method for the determination of dobutamine (DBT) in rat plasma was developed and validated after optimization of various chromatographic conditions and other experimental parameters. Homoveratrylamine was used as an internal standard. Methanol was used as the extracting solvent for the preparation of plasma samples. Samples were separated on a Symmetry C18 (250 mm*4.6 mm i.d., 5 MUm) analytical column. Acetonitrile and 15 mM potassium dihydrogen phosphate (pH 5.0 with 0.3% TEA) (20:80, v/v) was used. The column oven temperature was optimized at 35 degrees C and the flow rate was 0.8 mL/min. The detection wavelength was fixed at 230 nm for entire analysis. The calibration curve was found to be linear over the concentration range of 50-2000 ng/mL (r2=0.9992). The limit of quantification (LOQ) of the method was 50 ng/mL. The % RSD values of accuracy and precision values for intra and inter days were <15% at quality control (QC) concentrations. Recovery, stability and robustness were studied within the acceptable range according to ICH guidelines. The method was efficiently applied to a pharmacokinetic study in healthy Wistar rats. PMID- 29403852 TI - Development and validation of an rp-hplc method for simultaneous determination of Ramipril and Amlodipine in tablets. AB - An rp-hplc method for the simultaneous determination of Ramipril (RP) and Amlodipine (AL) in tablets was developed and validated by Chinese Pharmacopoeia 2010. The linearity of the proposed method was investigated in the range of 0.01 0.25 mg/mL (r2=0.9998) for RP and 0.014-0.36 mg/mL (r2=0.9997) for AL. The limits of detection (LOD) were 0.06 MUg/mL and 0.02 MUg/mL for RP and AL, and the limits of quantitation (LOQ) were 0.2 MUg/mL and 0.07 MUg/mL, respectively. Some major impurities and degradation products did not disturb the detection of RP and AL and the assay can thus be considered stability-indicating. PMID- 29403853 TI - Simultaneous determination of five diterpenoid alkaloids in Herba Delphinii by HPLC/ELSD. AB - A HPLC-ELSD method was developed and validated for simultaneous determination of five Hetisane-type diterpenoid alkaloids in a Tibetan traditional herbal medicine, "Gebu Dilu" (Herba Delphinii), using a Kromasil C18 column (250 mm*4.6 mm, 5 MUm) with the mobile phase consisting of acetonitrile and 0.1% triethylamine in gradient (detected by evaporative light scattering detector). The linear ranges of five compounds were determined and method validation was evaluated completely. The established method is rapid and accurate with high repeatability, and can be applied for the quality control of Herba Delphinii. PMID- 29403854 TI - Voltammetric quantitation of nitazoxanide by glassy carbon electrode. AB - The present study reports voltammetric reduction of nitazoxanide in Britton Robinson (B-R) buffer by cyclic and square-wave voltammetry at glassy carbon electrode. A versatile fully validated voltammetric method for quantitative determination of nitazoxanide in pharmaceutical formulation has been proposed. A squrewave peak current was linear over the nitazoxanide concentration in the range of 20-140 ug/mL. The limit of detection (LOD) and limit of quantification (LOQ) was calculated to be 5.23 MUg/mL and 17.45 MUg/mL, respectively. PMID- 29403855 TI - Preparative isolation of Heteroclitin D from Kadsurae Caulis using normal-phase flash chromatography. AB - Heteroclitin D (H.D) was successfully isolated from Kadsurae Caulis by using flash chromatography and recrystallized by methanol, 10.2 mg of H.D was obtained from 4.86 g of crude extract, and the purity determined by HPLC was 99.4%. The structure was identified by UV, IR, MS, and NMR analysis. The fast, simple and efficient method can be applied to the preparation of reference substance of H. D. PMID- 29403856 TI - Screening of wild plant species for antibacterial activity and phytochemical analysis of Tragia involucrata L. AB - Eight wild plant species namely Tragia involucrata L., Cleistanthus collinus (Roxb.)Benth. Ex Hook.f., Sphaeranthus indicus L., Vicoa indica (L.) Dc., Allmania nodiflora (L.) R.Br. ex wight., Habenaria elliptica Wight., Eriocaulon thwaitesii Koern. and Evolvulus alsinoides L. were used for phytochemical extraction with four different solvents. Antibacterial activity of these plants was studied against Escherichia coli NCIM 2065 using Kirby Bauer agar disc diffusion assay. Effective antibacterial activity was shown by T. involucrata acetone extract (27.3 mm), compared to standard medicinal drug amoxicillin (28.3 mm). Minimum inhibitory concentration (MIC) of T. involucrata extract was 15 mg/mL and hence, it could be pursued further for obtaining phytomedicine. Biochemical constituents of T. involucrata fresh leaf were: sugars (55 mg/g), starch (0.7182 mg/g), proteins (0.0166 mg/g) and lipids (170 mg/g). Alkaloids, tannins, phenolic compounds, flavonoids and steroids were also observed qualitatively. PMID- 29403857 TI - Rapid sensitive validated UPLC-MS method for determination of venlafaxine and its metabolite in rat plasma: Application to pharmacokinetic study. AB - A new ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-MS/ESI) method for simultaneous determination of venlafaxine (VEN) and its metabolite O-desmethylvenlafaxine (ODV) in rat plasma has been developed and validated using Venlafaxine d6 as the internal standard. The compounds and internal standard were extracted from plasma by solid phase extraction. The UPLC separation of the analytes was performed on ACQUITY UPLC(r) BEH Shield RP18 (1.7 um, 100 mm*2.1 mm) column, using isocratic elution with mobile phase constituted of water (containing 2 mM ammonium acetate): acetonitrile (20:80, v/v) at a flow rate of 0.3 mL/min. All of the analytes were eluted within 1.5 min. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer, operating in multiple reaction monitoring (MRM) and positive ion mode. The precursor to product ion transitions monitored for VEN, ODV and Venlafaxine d6 were m/z 278.3->121.08, 264.2->107.1 and 284.4->121.0, respectively. The developed and validated method was used for the pharmacokinetic study of VEN in rats. PMID- 29403858 TI - Method development and validation of Guanfacine in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study. AB - A selective, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method has been developed and validated for the quantitation of Guanfacine in rat plasma. Sample clean-up involved liquid-liquid extraction (LLE) and 100 MUL of rat plasma was used. YMC BASIC column (50 mm*2.0 mm, 3.5 um) was used. Mobile phase used was 10 mM ammonium formate (pH 4.0):acetonitrile (70:30, v/v) at a flow rate of 0.3 mL/min. The parent->product ion transitions for the drug (m/z 246.0->159.0) and IS (m/z 252.0->161.1) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The method was validated over the concentration range of 50.00-10,000.00 pg/mL for Guanfacine. The method was successfully applied into a pharmacokinetic study in rat plasma. PMID- 29403859 TI - Bioanalytical method development and validation of milnacipran in rat plasma by LC-MS/MS detection and its application to a pharmacokinetic study. AB - A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of milnacipran (MC) in rat plasma by using the liquid-liquid extraction method. Milnacipran-d10 (MCD10) was used as an internal standard (IS). Chromatographic separation was achieved on Zorbax SB-CN (4.6 mm*75 mm, 3.5 um) column with an isocratic mobile phase composed of 10 mM ammonium acetate (pH 4.0) and methanol in the ratio of 25:75(v/v), at a flow-rate of 0.7 mL/min. MC and MCD10 were detected with proton adducts at m/z 247.2->230.3 and m/z 257.2->240.4 in multiple reaction monitoring (MRM) positive mode respectively. The method was validated over a linear concentration range of 1.00-400.00 ng/mL with a correlation coefficient (r2)>=0.9850. This method demonstrated intra- and inter-day precision within 5.40 10.85% and 4.40-8.29% and accuracy within 97.00-104.20% and 101.64-106.23%. MC was found to be stable throughout three freeze-thaw cycles, bench top and postoperative stability studies. This method was successfully applied to a pharmacokinetic study of rats through i.v. administration. PMID- 29403860 TI - A validated LC-MS/MS method for the determination of tolterodine and its metabolite in rat plasma and application to pharmacokinetic study. AB - Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used for simultaneous quantification of tolterodine and its metabolite 5-hydroxy methyl tolterodine in rat plasma. Tolterodine-d6 and 5-hydroxy methyl tolterodine-d14 were used as internal standards (IS). Chromatographic separation was performed on Ascentis Express RP amide (50 mm*4.6 mm, 2.7 MUm) column with an isocratic mobile phase composed of 10 mM ammonium acetate and acetonitrile in the ratio of 20:80 (v/v), at a flow-rate of 0.5 mL/min. Tolterodine, tolterodine-d6, 5-hydroxy methyl tolterodine and 5-hydroxy methyl tolterodine-d14 were detected with proton adducts at m/z 326.1->147.1, 332.3->153.1, 342.2->223.1 and 356.2->223.1 in multiple reaction monitoring (MRM) positive mode respectively. The drug, metabolite and internal standards were extracted by liquid-liquid extraction method. The method was validated over a linear concentration range of 20.00 5000.00 pg/mL for tolterodine and 20.00-5000.00 pg/mL for 5-hydroxy methyl tolterodine. This method demonstrated intra- and inter-day precision of 0.62 6.36% and 1.73-4.84% for tolterodine, 1.38-4.22% and 1.62-4.25% for 5-hydroxy methyl tolterodine respectively. This method also demonstrated intra- and inter day accuracy of 98.75-103.56% and 99.20-104.40% for tolterodine, 98.08-104.67% and 98.73-103.06% for 5-hydroxy methyl tolterodine respectively. Both analytes were found to be stable throughout freeze-thaw cycles, bench top and postoperative stability studies. This method was successfully applied for the pharmacokinetic analysis of rat plasma samples following i.v. administration. PMID- 29403861 TI - Validated HPLC method for identification and quantification of p-hydroxy benzoic acid and agnuside in Vitex negundo and Vitex trifolia. AB - A high performance liquid chromatography coupled with photodiode array detection method was developed for the identification and quantification of p-hydroxy benzoic acid and agnuside in the extracts of Vitex negundo and Vitex trifolia. The separation was achieved using acetonitrile and O-phosphoric acid-water (0.5%, v/v) as the mobile phase in an isocratic elution mode. Mean retention times of standard p-hydroxy benzoic acid and agnuside were 6.14 and 11.90 min respectively. The developed method was validated as per the ICH guidelines for limit of detection, limit of quantification, linearity, accuracy and precision. Good linearity (r2>=0.999) was observed for both the compounds in wide concentration range. Relative standard deviation values for intra-day and inter day precision studies were less than 2%. The analytical recoveries of p-hydroxy benzoic acid and agnuside by the developed HPLC method were 93.07% and 106.11% respectively. Two compounds were identified and quantified in leaves and bar extracts of V. negundo and V. trifolia using the developed HPLC method. PMID- 29403862 TI - QuEChERS extraction of benzodiazepines in biological matrices. AB - Two common analytical chemical problems often encountered when using chromatographic techniques in drug analysis are matrix interferences and ion suppression. Common sample preparation often involves the dilution of the sample prior to injection onto an instrument, especially for liquid chromatography-mass spectrometry (LC-MS) analyses. This practice frequently does not minimize or eliminate conditions that may cause ion-suppression and therefore, suffer more from reduced method robustness. In order to achieve higher quality results and minimize possible interferences, various sample preparation techniques may be considered. Through the use of QuEChERS ("catchers"), a novel sample preparation technique used for high aqueous content samples, benzodiazepines can be extracted from biological fluids, such as blood and urine. This approach has shown increased recoveries of target compounds when using quantification by both external and internal standard. This increase in the recoveries has been attributed to a matrix enhancement and was determined through the use of the method of standard addition. While improving the overall analytical method for gas chromatography-mass spectrometry (GC-MS) analysis, it is not clear if this approach represents an overall benefit for laboratories that have both GC-MS and high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) capability. Demonstrating evidence of variable ionization (enhancement, ion source inertness, etc.), the method of quantification should be focused on in future studies. PMID- 29403863 TI - Measurement uncertainty in pharmaceutical analysis and its application. AB - The measurement uncertainty provides complete information about an analytical result. This is very important because several decisions of compliance or non compliance are based on analytical results in pharmaceutical industries. The aim of this work was to evaluate and discuss the estimation of uncertainty in pharmaceutical analysis. The uncertainty is a useful tool in the assessment of compliance or non-compliance of in-process and final pharmaceutical products as well as in the assessment of pharmaceutical equivalence and stability study of drug products. PMID- 29403864 TI - Metabolic profiling of plasma from cardiac surgical patients concurrently administered with tranexamic acid: DI-SPME-LC-MS analysis. AB - A metabolic profile of plasma samples from patients undergoing heart surgery with the use of cardiopulmonary bypass (CPB) and concurrent administration of tranexamic acid was determined. Direct immersion solid phase microextraction (DI SPME), a new sampling and sample preparation tool for metabolomics, was used in this study for the first time to investigate clinical samples. The results showed alteration of diverse compounds involved in different biochemical pathways. The most significant contribution in changes induced by surgery and applied pharmacotherapy was noticed in metabolic profile of lysophospholipids, triacylglycerols, mediators of platelet aggregation, and linoleic acid metabolites. Two cases of individual response to treatment were also reported. PMID- 29403865 TI - Identification of metabolites of Radix Paeoniae Alba extract in rat bile, plasma and urine by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. AB - Ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was developed to identify the absorbed parent components and metabolites in rat bile, plasma and urine after oral administration of Radix Paeoniae Alba extract (RPAE). A total of 65 compounds were detected in rat bile, plasma and urine samples, including 11 parent compounds and 54 metabolites. The results indicated that glucuronidation, hydroxylation and methylation were the major metabolic pathways of the components of RPAE. Furthermore, the results of this work demonstrated that UPLC-Q-TOF/MS combined with MetaboLynxTM software and mass defect filtering (MDF) could provide unique high throughput capabilities for drug metabolism study, with excellent MS mass accuracy and enhanced MSE data acquisition. With the MSE technique, both precursor and fragment mass spectra can be simultaneously acquired by alternating between high and low collision energy during a single chromatographic run. PMID- 29403866 TI - Simultaneous quantitation of atorvastatin and its two active metabolites in human plasma by liquid chromatography/(-) electrospray tandem mass spectrometry. AB - A sensitive, accurate and selective liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed and validated for the simultaneous quantitation of atorvastatin (AT) and its equipotent hydroxyl metabolites, 2 hydroxy atorvastatin (2-AT) and 4-hydroxy atorvastatin (4-AT), in human plasma. Electrospray ionization (ESI) interface in negative ion mode was selected to improve the selectivity and the sensitivity required for this application. Additionally, a solid phase extraction (SPE) step was performed to reduce any ion suppression and/or enhancement effects. The separation of all compounds was achieved in less than 6 min using a C18 reverse-phase fused-core(r) column and a mobile phase, composed of a mixture of 0.005% formic acid in water:acetonitrile:methanol (35:25:40, v/v/v), in isocratic mode at a flow rate of 0.6 mL/min. The method has lower limit of quantitation (LLOQ) of 0.050 ng/mL for all analytes. The method has shown tremendous reproducibility, with intra- and inter-day precision less than 6.6%, and intra- and inter-day accuracy within +/-4.3% of nominal values, for all analytes, and has proved to be highly reliable for the analysis of clinical samples. PMID- 29403867 TI - LC-UV/MS quality analytics of paediatric artemether formulations. AB - A highly selective and stability-indicating HPLC-method, combined with appropriate sample preparation steps, is developed for beta-artemether assay and profiling of related impurities, including possible degradants, in a complex powder for oral suspension. Following HPLC conditions allowed the required selectivity: a Prevail organic acid (OA) column (250 mm*4.6 mm, 5 MUm), flow rate set at 1.5 mL/min combined with a linear gradient (where A=25 mM phosphate buffer (pH 2.5), and B=acetonitrile) from 30% to 75% B in a runtime of 60 min. Quantitative UV-detection was performed at 210 nm. Acetonitrile was applied as extraction solvent for sample preparation. Using acetonitrile-water mixtures as extraction solvent, a compartmental behaviour by a non-solving excipient-bound fraction and an artemether-solubilising free fraction of solvent was demonstrated, making a mobile phase based extraction not a good choice. Method validation showed that the developed HPLC-method is considered to be suitable for its intended regulatory stability-quality characterisation of beta-artemether paediatric formulations. Furthermore, LC-MS on references as well as on stability samples was performed allowing identity confirmation of the beta-artemether related impurities. MS-fragmentation scheme of beta-artemether and its related substances is proposed, explaining the m/z values of the in-source fragments obtained. PMID- 29403868 TI - Comparative pharmacokinetics of five saponins after intravenous administration of TSFS injection and TSFS injection plus TFFG in rats under different physiological states. AB - Sanqi is a popular traditional Chinese medicine and commonly used for promoting blood circulation and removing blood stasis. Notoginsenoside R1, ginsenoside Rg1, Re, Rb1 and Rd are the major active constituents of Sanqi. The purpose of the study was to investigate the pharmacokinetic behavior of the five active constituents from total saponin from Sanqi when it was used in the blood stasis animals or in combination with Gegen. The concentrations of the five active constituents in rat plasma were determined by an ultra-HPLC-ESI-MS/MS method. The main pharmacokinetic parameters were calculated and statistically analyzed using the unpaired student's t-test. It was found that the pharmacokinetic parameters of notoginsenoside R1, ginsenoside Rg1 and Rb1 represented a statistically significant difference (P<0.05) between the normal rats and the blood stasis rats after administration of total saponin from Sanqi (TSFS). And there were statistically significant differences (P<0.05) in the pharmacokinetic parameters of all the five constituents between administration of TSFS alone and combined with total flavonoid from Gegen (TFFG) in blood stasis rats. It suggested that the pharmacokinetic behavior of the active constituents from TSFS could be changed when it was used in blood stasis animals or in combination with TFFG. PMID- 29403869 TI - Development of a sensitive and rapid method for quantitation of (S)-(-)- and (R) (+)-metoprolol in human plasma by chiral LC-ESI-MS/MS. AB - A selective, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method has been developed for separation and quantification of metoprolol enantiomers on a chiral Lux Amylose-2 (250 mm*4.6 mm, 5 MUm) column. Solid phase extraction of (S)-(-)- and (R)-(+)-metoprolol and rac-metoprolol-d6 as an internal standard (IS) was achieved on Lichrosep DVB HL cartridges employing 200 MUL human plasma. Both the analytes were chromatographically separated with a resolution factor of 2.24 using 15 mM ammonium acetate in water, pH 5.0 and 0.1% (v/v) diethyl amine in acetonitrile (50:50, v/v) as the mobile phase within 7.0 min. The precursor->product ion transitions for the enantiomers and IS were monitored in the multiple reaction monitoring and positive ionization mode. The method was validated over the concentration range of 0.500-500 ng/mL for both the enantiomers. Matrix effect was assessed by post-column analyte infusion experiment and the mean extraction recovery was greater than 94.0% for both the enantiomers at all quality control levels. The stability of analytes was evaluated in plasma and whole blood under different storage conditions. The method was successfully applied to a clinical study in 14 healthy volunteers after oral administration of 200 mg metoprolol tablet under fasting conditions. The assay reproducibility is shown by reanalysis of 68 incurred samples. The suitability of the developed method was assessed in comparison with different chromatographic methods developed for stereoselective analysis of metoprolol in biological matrices. PMID- 29403870 TI - Charge-transfer interaction of drug quinidine with quinol, picric acid and DDQ: Spectroscopic characterization and biological activity studies towards understanding the drug-receptor mechanism. AB - Investigation of charge-transfer (CT) complexes of drugs has been recognized as an important phenomenon in understanding of the drug-receptor binding mechanism. Structural, thermal, morphological and biological behavior of CT complexes formed between drug quinidine (Qui) as a donor and quinol (QL), picric acid (PA) or dichlorodicyanobenzoquinone (DDQ) as acceptors were reported. The newly synthesized CT complexes have been spectroscopically characterized via elemental analysis; infrared (IR), Raman, 1H NMR and electronic absorption spectroscopy; powder X-ray diffraction (PXRD); thermogravimetric (TG) analysis and scanning electron microscopy (SEM). It was found that the obtained complexes are nanoscale, semi-crystalline particles, thermally stable and spontaneous. The molecular composition of the obtained complexes was determined using spectrophotometric titration method and was found to be 1:1 ratios (donor:acceptor). Finally, the biological activities of the obtained CT complexes were tested for their antibacterial activities. The results obtained herein are satisfactory for estimation of drug Qui in the pharmaceutical form. PMID- 29403871 TI - Quantitative and qualitative analysis of common peaks in chemical fingerprint of Yuanhu Zhitong tablet by HPLC-DAD-MS/MS. AB - A quality control (QC) strategy for quantitative and qualitative analysis of "common peaks" in chemical fingerprint was proposed to analyze Yuanhu Zhitong tablet (YZT), using high performance liquid chromatography with diode array detector and tandem mass spectrometry (HPLC-DAD-MS/MS). The chromatographic separation was achieved on an Agilent Eclipse plus C18 column with a gradient elution using a mixture of 0.40/00 ammonium acetate aqueous (pH 6.0 adjusted with glacial acetic acid) and acetonitrile. In chemical fingerprint, 40 peaks were assigned as the "common peaks". For quantification of "common peaks", the detection wavelength was set at 254 nm, 270 nm, 280 nm and 345 nm, respectively. The method was validated and good results were obtained to simultaneously determine 10 analytes (protopine, jatrorrhizine, coptisine, palmatine, berberine, xanthotoxin, bergapten, tetrahydropalmatine, imperatorin and isoimperatorin). For qualification of "common peaks", 33 compounds including 10 quantitative analytes were identified or tentatively characterized using LC-MS/MS. These results demonstrated that the present approach may be a powerful and useful tool to tackle the complex quality issue of YZT. PMID- 29403872 TI - Selective separation, detection of zotepine and mass spectral characterization of degradants by LC-MS/MS/QTOF. AB - A simple, precise, accurate stability-indicating gradient reversed-phase high performance liquid chromatographic (RP-HPLC) method was developed for the quantitative determination of zotepine (ZTP) in bulk and pharmaceutical dosage forms in the presence of its degradation products (DPs). The method was developed using Phenomenex C18 column (250 mm*4.6 mm i.d., 5 um) with a mobile phase containing a gradient mixture of solvents, A (0.05% trifluoroacetic acid (TFA), pH=3.0) and B (acetonitrile). The eluted compounds were monitored at 254 nm; the run time was within 20.0 min, in which ZTP and its DPs were well separated, with a resolution of >1.5. The stress testing of ZTP was carried out under acidic, alkaline, neutral hydrolysis, oxidative, photolytic and thermal stress conditions. ZTP was found to degrade significantly in acidic, photolytic, thermal and oxidative stress conditions and remain stable in basic and neutral conditions. The developed method was validated with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness as per ICH guidelines. This method was also suitable for the assay determination of ZTP in pharmaceutical dosage forms. The DPs were characterized by LC-MS/MS and their fragmentation pathways were proposed. PMID- 29403873 TI - A solid-phase extraction approach for the identification of pharmaceutical-sludge adsorption mechanisms. AB - It is important to understand the adsorption mechanism of chemicals and active pharmaceutical ingredients (API) on sewage sludge since wastewater treatment plants are the last barrier before the release of these compounds to the environment. Adsorption models were developed considering mostly hydrophobic API sludge interaction. They have poor predictive ability, especially with ionisable compounds. This work proposes a solid-phase extraction (SPE) approach to estimate rapidly the API-sludge interaction. Sludge-filled SPE cartridges could not be percolated with API spiked mobile phases so different powders were tested as SPE sludge supports. Polytetrafluoroethylene (PTFE) was selected and tested at different PTFE/sludge ratios under eight different adsorption conditions with three API ionisable compounds. The PTFE/sludge mixtures with 50% or less sludge could be used in SPE mode for API sorption studies with methanol/water liquid phases. The results gave insights into API-sludge interactions. It was found that pi-pi, hydrogen-bonding and charge-charge interactions were as important as hydrophobicity in the adsorption mechanism of charged APIs on sludge. PMID- 29403874 TI - Reagent-free determination of amikacin content in amikacin sulfate injections by FTIR derivative spectroscopy in a continuous flow system. AB - The quantitative estimation of amikacin (AMK) in AMK sulfate injection samples is reported using FTIR-derivative spectrometric method in a continuous flow system. Fourier transform of mid-IR spectra were recorded without any sample pretreatment. A good linear calibration (r>0.999, %RSD<2.0) in the range of 7.7 77.0 mg/mL was found. The results showed a good correlation with the manufacturer's and overall they all fell within acceptable limits of most pharmacopoeial monographs on AMK sulfate. PMID- 29403875 TI - Determination of a novel ACE inhibitor in the presence of alkaline and oxidative degradation products using smart spectrophotometric and chemometric methods. AB - Simple, accurate, sensitive and validated UV spectrophotometric and chemometric methods were developed for the determination of imidapril hydrochloride (IMD) in the presence of both its alkaline (AKN) and oxidative (OXI) degradation products and in its pharmaceutical formulation. Method A is the fourth derivative spectra (D4) which allows the determination of IMD in the presence of both AKN and OXD, in pure form and in tablets by measuring the peak amplitude at 243.0 nm. Methods B, C and D, manipulating ratio spectra, were also developed. Method B is the double divisor-ratio difference spectrophotometric one (DD-RD) by computing the difference between the amplitudes of IMD ratio spectra at 232 and 256.3 nm. Method C is the double divisor-first derivative of ratio spectra method (DD-DR1) at 243.2 nm, while method D is the mean centering of ratio spectra (MCR) at 288.0 nm. Methods A, B, C and D could successfully determine IMD in a concentration range of 4.0-32.0 ug/mL. Methods E and F are principal component regression (PCR) and partial least-squares (PLS), respectively, for the simultaneous determination of IMD in the presence of both AKN and OXI, in pure form and in its tablets. The developed methods have the advantage of simultaneous determination of the cited components without any pre-treatment. The accuracy, precision and linearity ranges of the developed methods were determined. The results obtained were statistically compared with those of a reported HPLC method, and there was no significant difference between the proposed methods and the reported method regarding both accuracy and precision. PMID- 29403876 TI - Improved simultaneous quantitation of candesartan and hydrochlorthiazide in human plasma by UPLC-MS/MS and its application in bioequivalence studies. AB - A validated ultra-performance liquid chromatography mass spectrometric method (UPLC-MS/MS) was used for the simultaneous quantitation of candesartan (CN) and hydrochlorothiazide (HCT) in human plasma. The analysis was performed on UPLC MS/MS system using turbo ion spray interface. Negative ions were measured in multiple reaction monitoring (MRM) mode. The analytes were extracted using a liquid-liquid extraction (LLE) method by using 0.1 mL of plasma volume. The lower limit of quantitation for CN and HCT was 1.00 ng/mL whereas the upper limit of quantitation was 499.15 ng/mL and 601.61 ng/mL for CN and HCT respectively. CN d4 and HCT-13Cd2 were used as the internal standards for CN and HCT respectively. The chromatography was achieved within 2.0 min run time using a C18 Phenomenex, Gemini NX (100 mm*4.6 mm, 5 um) column with organic mixture:buffer solution (80:20, v/v) at a flow rate of 0.800 mL/min. The method has been successfully applied to establish the bioequivalence of candesartan cilexetil (CNC) and HCT immediate release tablets with reference product in human subjects. PMID- 29403877 TI - Determination of gouty arthritis' biomarkers in human urine using reversed-phase high-performance liquid chromatography. AB - Creatinine, uric acid, hypoxanthine and xanthine are important diagnostic biomarkers in human urine for gouty arthritis or renal disease diacrisis. A simple method for simultaneous determination of these biomarkers in urine based on reversed-phase high-performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detector was proposed. After pretreatment by dilution, centrifugation and filtration, the biomarkers in urine samples were separated by ODS-BP column by elution with methanol/50 mM NaH2PO4 buffer solution at pH 5.26 (5:95). Good linearity between peak areas and concentrations of standards was obtained for the biomarkers with correlation coefficients in the range of 0.9957 0.9993. The proposed analytical method has satisfactory repeatability (the recovery of data in a range of creatinine, uric acid, hypoxanthine and xanthine was 93.49-97.90%, 95.38-96.45%, 112.46-115.78% and 90.82-97.13% with standard deviation of <5%, respectively) and the limits of detection (LODs, S/N>=3) for creatinine, uric acid, hypoxanthine, and xanthine were 0.010, 0.025, 0.050 and 0.025 mg/L, respectively. The established method was proved to be simple, accurate, sensitive and reliable for the quantitation of gouty arthritis' biomarkers in human urine samples. The ratio of creatinine to uric acid was found to be a possible factor for assessment of gouty arthritis. PMID- 29403878 TI - Development of forced degradation and stability indicating studies of drugs-A review. AB - Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method. PMID- 29403879 TI - Direct detection and identification of active pharmaceutical ingredients in intact tablets by helium plasma ionization (HePI) mass spectrometry. AB - A simple modification converts an electrospray ion source to an ambient-pressure helium plasma ionization source without the need of additional expensive hardware. Peaks for active ingredients were observed in the spectra recorded from intact pharmaceutical tablets placed in this source. A flow of heated nitrogen was used to thermally desorb analytes to gas phase. The desorption temperatures were sometimes as low as 50 degrees C. For example, negative-ion spectra recorded from an aspirin tablet showed peaks at m/z 137 (salicylate anion) and 179 (acetylsalicylate anion) which were absent in the background spectra. The overall ion intensity increased as the desorption gas temperature was elevated. Within the same acquisition experiment, both positive- and negative-ion signals for acetaminophen were recorded from volatiles emanating from Tylenol tablets by switching the polarity of the capillary back and forth. Moreover, different preparations of acetaminophen tablets could be distinguished by their ion intensity thermograms. PMID- 29403880 TI - Derringer desirability and kinetic plot LC-column comparison approach for MS compatible lipopeptide analysis. AB - Lipopeptides are currently re-emerging as an interesting subgroup in the peptide research field, having historical applications as antibacterial and antifungal agents and new potential applications as antiviral, antitumor, immune-modulating and cell-penetrating compounds. However, due to their specific structure, chromatographic analysis often requires special buffer systems or the use of trifluoroacetic acid, limiting mass spectrometry detection. Therefore, we used a traditional aqueous/acetonitrile based gradient system, containing 0.1% (m/v) formic acid, to separate four pharmaceutically relevant lipopeptides (polymyxin B1, caspofungin, daptomycin and gramicidin A1), which were selected based upon hierarchical cluster analysis (HCA) and principal component analysis (PCA). In total, the performance of four different C18 columns, including one UPLC column, were evaluated using two parallel approaches. First, a Derringer desirability function was used, whereby six single and multiple chromatographic response values were rescaled into one overall D-value per column. Using this approach, the YMC Pack Pro C18 column was ranked as the best column for general MS compatible lipopeptide separation. Secondly, the kinetic plot approach was used to compare the different columns at different flow rate ranges. As the optimal kinetic column performance is obtained at its maximal pressure, the length elongation factor lambda (Pmax/Pexp) was used to transform the obtained experimental data (retention times and peak capacities) and construct kinetic performance limit (KPL) curves, allowing a direct visual and unbiased comparison of the selected columns, whereby the YMC Triart C18 UPLC and ACE C18 columns performed as best. Finally, differences in column performance and the (dis)advantages of both approaches are discussed. PMID- 29403881 TI - Combined collision-induced dissociation and photo-selected reaction monitoring mass spectrometry modes for simultaneous analysis of coagulation factors and estrogens. AB - Oral estrogens are directly associated with changes in plasma levels of coagulation proteins. Thus, the detection of any variation in protein concentrations due to estrogen contraceptives, by a simultaneous analysis of both coagulation proteins and estrogens, would be a very informative tool. In the present study, the merit of photo-selected reaction monitoring (SRM), a new analytical tool, was evaluated towards estrogens detection in plasma. Then, SRM and photo-SRM detection modes were combined for the simultaneous analysis of estrogen molecules together with heparin co-factor and factor XIIa, two proteins involved in the coagulation cascade. This study shows that photo-SRM could open new multiplexed analytical routes. PMID- 29403882 TI - Profiling the dynamics of abscisic acid and ABA-glucose ester after using the glucosyltransferase UGT71C5 to mediate abscisic acid homeostasis in Arabidopsis thaliana by HPLC-ESI-MS/MS. AB - The HPLC-MS/MS method was developed to profile the dynamics of abscisic acid (ABA) and ABA-glucose ester (ABA-GE) after cloning glycosyltransferase enzyme family gene AtUGT71C5 into Arabidopsis thaliana. By constructing over-expression lines (OE) and down-expression lines (DN), we acquired mutant strains to analyze the function of AtUGT71C5. The multiple-reaction monitoring (MRM) was used for quantitative determination in negative mode. The transition was m/z 263.1->153.0 for ABA ([M-H]+), m/z 425.1->263.0 for ABA-GE ([M-H]+), and m/z 321.0->152.0 for chloramphenicol. The linear range was 0.8684-217.1 ng/mL for ABA and 0.3920-196.0 ng/mL for ABA-GE. The accuracy was 88.0-109.0% for ABA and 86.6-113.0% for ABA GE; the inter-day and intra-day precisions were less than 5.4% for ABA and 8.9% for ABA-GE, respectively. This method is simple and sensitive enough for determination of ABA and ABA-GE in A. thaliana leaves. All the evidence confirmed the speculation that AtUGT71C5 can mediate abscisic acid homeostasis. PMID- 29403883 TI - Enantiomeric characterization and structure elucidation of Otamixaban. AB - Otamixaban is a potent (Ki=0.5 nM) fXa inhibitor currently in late-stage clinical development at Sanofi for the management of acute coronary syndrome. Being unproductive in obtaining a suitable crystal of Otamixaban, the required enantiomeric characterization has been accomplished using vibrational circular dichroism (VCD) spectroscopy. Selected by a spectrum similarity index, the calculated spectra of several higher energy conformers were found to match well with the observed spectra. The characteristic IR bands of these conformers were also identified and attributed to the solvation effect. Combined with both the single crystal x-ray diffraction results for an intermediate and the proton NMR study, the absolute configuration of Otamixaban is unambiguously determined to be (R,R). PMID- 29403884 TI - Determination of mycophenolic acid in human plasma by ultra performance liquid chromatography tandem mass spectrometry. AB - A simple, sensitive and high throughput ultra performance liquid chromatography tandem mass spectrometry method has been developed for the determination of mycophenolic acid in human plasma. The method involved simple protein precipitation of MPA along with its deuterated analog as an internal standard (IS) from 50 uL of human plasma. The chromatographic analysis was done on Acquity UPLC C18 (100 mm*2.1 mm, 1.7 um) column under isocratic conditions using acetonitrile and 10 mM ammonium formate, pH 3.00 (75:25, v/v) as the mobile phase. A triple quadrupole mass spectrometer operating in the positive ionization mode was used for quantitation. In-source conversion of mycophenolic glucuronide metabolite to the parent drug was selectively controlled by suitable optimization of cone voltage, cone gas flow and desolvation temperature. The method was validated over a wide concentration range of 15-15000 ng/mL. The mean extraction recovery for the analyte and IS was >95%. Matrix effect expressed as matrix factors ranged from 0.97 to 1.02. The method was successfully applied to support a bioequivalence study of 500 mg mycophenolate mofetil tablet in 72 healthy subjects. PMID- 29403885 TI - Quality analysis of commercial samples of Ziziphi spinosae semen (suanzaoren) by means of chromatographic fingerprinting assisted by principal component analysis. AB - Due to the scarcity of resources of Ziziphi spinosae semen (ZSS), many inferior goods and even adulterants are generally found in medicine markets. To strengthen the quality control, HPLC fingerprint common pattern established in this paper showed three main bioactive compounds in one chromatogram simultaneously. Principal component analysis based on DAD signals could discriminate adulterants and inferiorities. Principal component analysis indicated that all samples could be mainly regrouped into two main clusters according to the first principal component (PC1, redefined as Vicenin II) and the second principal component (PC2, redefined as zizyphusine). PC1 and PC2 could explain 91.42% of the variance. Content of zizyphusine fluctuated more greatly than that of spinosin, and this result was also confirmed by the HPTLC result. Samples with low content of jujubosides and two common adulterants could not be used equivalently with authenticated ones in clinic, while one reference standard extract could substitute the crude drug in pharmaceutical production. Giving special consideration to the well-known bioactive saponins but with low response by end absorption, a fast and cheap HPTLC method for quality control of ZSS was developed and the result obtained was commensurate well with that of HPLC analysis. Samples having similar fingerprints to HPTLC common pattern targeting at saponins could be regarded as authenticated ones. This work provided a faster and cheaper way for quality control of ZSS and laid foundation for establishing a more effective quality control method for ZSS. PMID- 29403887 TI - Ionic liquids functionalized beta-cyclodextrin polymer for separation/analysis of magnolol. AB - Ionic liquids functionalized beta-cyclodextrin polymer, a mono-6-deoxy-6-(1,2 dimethylimidazolium)-beta-cyclodextrin iodide polymer (ILs-beta-CDCP), was synthesized as a solid-phase adsorbent coupled with high-performance liquid chromatography for separating or analyzing magnolol in drug samples. The results showed that magnolol was adsorbed rapidly on ILs-beta-CDCP and eluted with methanol. Under the optimum conditions, preconcentration factor of the proposed method was 12. The linear range, limit of detection (LOD), correlation coefficient (R) and relative standard deviation (RSD) were found to be 0.02-8.00 MUg/mL, 1.9 ng/mL, 0.9992 and 2.76% (n=3, c=2.00 MUg/mL), respectively. The interaction between ILs-beta-CDCP and magnolol was studied through the inclusion constant, FTIR and TGA analysis. This proposed method has been successfully applied to the determination of magnolol in real samples. PMID- 29403888 TI - Comparative dissolution study on counterfeit medicines of PDE-5 inhibitors. AB - Counterfeit medicines are a growing problem in both developing and industrialised countries. In general the evaluation of these medicines is limited to the identification and the dosage of the active ingredients. In this study in vitro dissolution tests were conducted on two sets of counterfeit medicines containing PDE-5 inhibitors (sildenafil citrate and tadalafil). The dissolution profiles were statistically compared to the ones of the genuine products using the f2 method and a comparison at each time point using the Cochran test. The results showed low equivalences between counterfeit and genuine products as well as higher variations around the mean dissolution value at the different time points for the counterfeit products. PMID- 29403886 TI - Chemometrics: A new scenario in herbal drug standardization. AB - Chromatography and spectroscopy techniques are the most commonly used methods in standardization of herbal medicines but the herbal system is not easy to analyze because of their complexity of chemical composition. Many cutting-edge analytical technologies have been introduced to evaluate the quality of medicinal plants and significant amount of measurement data has been produced. Chemometric techniques provide a good opportunity for mining more useful chemical information from the original data. Then, the application of chemometrics in the field of medicinal plants is spontaneous and necessary. Comprehensive methods and hyphenated techniques associated with chemometrics used for extracting useful information and supplying various methods of data processing are now more and more widely used in medicinal plants, among which chemometrics resolution methods and principal component analysis (PCA) are most commonly used techniques. This review focuses on the recent various important analytical techniques, important chemometrics tools and interpretation of results by PCA, and applications of chemometrics in quality evaluation of medicinal plants in the authenticity, efficacy and consistency. PMID- 29403889 TI - Stability-indicating HPLC-DAD methods for determination of two binary mixtures: Rabeprazole sodium-mosapride citrate and rabeprazole sodium-itopride hydrochloride. AB - Two selective stability-indicating HPLC methods are described for determination of rabeprazole sodium (RZ)-mosapride citrate (MR) and RZ-itopride hydrochloride (IO) mixtures in the presence of their ICH-stress formed degradation products. Separations were achieved on X-Bridge C18 column using two mobile phases: the first for RZ-MR mixture consisted of acetonitrile: 0.025 M KH2PO4 solution: TEA (30:69:1 v/v; pH 7.0); the second for RZ-IO mixture was at ratio of 25:74:1 (v/v; pH 9.25). The detection wavelength was 283 nm. The two methods were validated and validation acceptance criteria were met in all cases. Peak purity testing using contrast angle theory, relative absorbance and log A versus the wavelengths plots were presented. The % recoveries of the intact drugs were between 99.1% and 102.2% with RSD% values less than 1.6%. Application of the proposed HPLC methods indicated that the methods could be adopted to follow the stability of their formulations. PMID- 29403890 TI - An in-vitro cocktail assay for assessing compound-mediated inhibition of six major cytochrome P450 enzymes. AB - An efficient screening assay was developed and validated for simultaneous assessment of compound-mediated inhibition of six major human cytochrome P450 (CYP) enzymes. This method employed a cocktail of six probe substrates (i.e., phenacetin, amodiaquine, diclofenac, S-mephenytoin, dextromethorphan and midazolam for CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4, respectively) as well as individual prototypical inhibitors of the six CYP enzymes in human liver microsomes under optimized incubation conditions. The corresponding marker metabolites (i.e., acetaminophen, N-desethylamodiaquine, 4-OH-diclofenac, 4-OH-S mephenytoin, dextrorphan and 1-OH-midazolam) in the incubates were quantified using LC-MS/MS methods either by an internal standard (IS) calibration curve or a simplified analyte-to-IS peak area ratio approach. The results showed that the IC50 values determined by the cocktail approach were in good agreement with those obtained by the individual substrate approach as well as those reported in the literature. Besides, no remarkable difference was observed between the two quantification approaches. In conclusion, this new cocktail assay can be used for reliable screening of compound-mediated CYP inhibition. PMID- 29403891 TI - Extraction and determination of trace amounts of chlorpromazine in biological fluids using magnetic solid phase extraction followed by HPLC. AB - A simple, rapid and sensitive method termed as magnetic solid phase extraction (MSPE) combined with high-performance liquid chromatography-ultraviolet detector (HPLC-UV) has been proposed for the determination of trace amounts of chlorpromazine (CPZ) in water, urine and plasma samples. The separation and determination was performed on a C18 column under the optimal chromatographic conditions. Several factors influencing the extraction efficiency of CPZ, such as pH, surfactant and adsorbent amounts, ionic strength, extraction time, sample volume and desorption conditions, were studied and optimized. Under the optimal MSPE conditions, the extraction percentage of CPZ was 74%, 27% and 16% in water, urine and plasma samples, respectively. The limits of detection (LODs) of the proposed approach were 0.1, 5.0 and 10 ng/mL in water, urine and plasma samples, respectively. The relative standard deviations (RSDs) based on five replicate determinations at 10 ng/mL level of CPZ was 1.2%. Good linear behaviors over the investigated concentration ranges (0.25-300 ng/mL) with good coefficient of determination, R2>0.9998, were obtained. Good spike recoveries with relative errors less than 9.0% were obtained when applying the proposed method to water, urine and plasma samples. PMID- 29403892 TI - Simultaneous determination of ezetimibe and simvastatin in rat plasma by stable isotope dilution LC-ESI-MS/MS and its application to a pharmacokinetic study. AB - A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes: ezetimibe d4 and simvastatin d6 were used as internal standards for ezetimibe and simvastatin, respectively. MS/MS detection involved a switch of electron spray ionization mode from negative to positive at retention time 3.01 min. Samples were extracted from plasma by liquid liquid extraction using tertiary butyl methyl ether. Chromatographic separation was achieved with Agilent Eclipse XBD-C18 column using mobile phase that consisted of a mixture of ammonium acetate (pH4.5; 10 mM)-acetonitrile (25:75 v/v). The method was linear and validated over the concentration range of 0.2 40.0 ng/mL for simvastatin and 0.05-15.0 ng/mL for ezetimibe. The transitions selected were m/z 408.3->271.1 and m/z 412.0->275.10 for ezetimibe and ezetimibe d4, and m/z 419.30->285.20 and m/z 425.40->199.20 for simvastatin and simvastatin d6. Intra- and inter-batch precisions for ezetimibe were 1.6-14.8% and 2.1-13.4%; and for simvastatin 0.94-9.56% and 0.79-12%, respectively. The proposed method was sensitive, selective, precise and accurate for the quantification of ezetimibe and simvastatin simultaneously in rat plasma. The method was successfully applied to a pharmacokinetic study by oral co-administration of ezetimibe and simvastatin in SD rats. PMID- 29403893 TI - Pioglitazone: A review of analytical methods. AB - Pioglitazone is an oral anti-hyperglycemic agent. It is used for the treatment of diabetes mellitus type 2. It selectively stimulates nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma). It was the tenth-best-selling drug in the U.S. in 2008. This article examines published analytical methods reported so far in the literature for the determination of pioglitazone in biological samples and pharmaceutical formulations. They include various techniques like electrochemical methods, spectrophotometry, capillary electrophoresis, high-performance liquid chromatography, liquid chromatography electrospray ionization-tandem mass spectrometry and high-performance thin layer chromatography. PMID- 29403894 TI - Risk evaluation of impurities in topical excipients: The acetol case. AB - Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82*10-3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 ug/(day?person), the toxicity qualified specification limits of acetol in topical excipients were calculated to be 90 ug/mL and 180 ug/mL for propylene glycol and glycerol, respectively. It is concluded that setting specification limits for impurities within a quality-by design approach requires a case-by-case evaluation as demonstrated here with acetol. PMID- 29403895 TI - Ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry method for the simultaneous determination of itraconazole and hydroxy itraconazole in human plasma. AB - A highly sensitive, selective, and precise ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous quantification of itraconazole and hydroxy itraconazole in human plasma by a single liquid-liquid extraction step. The precursor to product ion transitions of m/z 705.3/392.3, m/z 721.2/408.3 and m/z 708.2/435.4 were used to detect and quantify itraconazole, hydroxy itraconazole and itraconazole-d3 respectively. The lower limit of quantitation was found to be 0.500 ng/mL for itraconazole and 1.00 ng/mL for hydroxy itraconazole. The mean recoveries for itraconazole and hydroxy itraconazole were found to be 100.045% and 100.021%, respectively. This developed method with a chromatographic run time of 2.0 min was successfully applied to a bioequivalence study of 100 mg itraconazole capsule. PMID- 29403896 TI - Simultaneous determination of three curcuminoids in Curcuma longa L. by high performance liquid chromatography coupled with electrochemical detection. AB - A novel method for analysis of three active components curcumin, demethoxycurcumin and bisdemethoxycurcumin in Curcuma longa L. was developed by HPLC coupled with electrochemical detection. Three curcuminoids were well separated on a C18 column and detected with high sensitivity. A mobile phase containing acetonitrile and 10 mM Na2HPO4-H3PO4 (pH 5.0) (50:50, v/v) was used. Good linearity was obtained in the range of 0.208-41.6, 0.197-39.4, and 0.227-114 MUM for curcumin, demethoxycurcumin and bisdemethoxycurcumin respectively. The limit of detection reached up to 10-8 M, which was lower than that by UV detection. The relative standard deviations (RSDs) ranged from 1.06% to 1.88% for intra-day precision and from 4.30% to 5.79% for inter-day precision, respectively. The proposed method has been applied in real herb sample and recoveries ranging from 86.3% to 111% were obtained. PMID- 29403897 TI - Trace analysis of mefenamic acid in human serum and pharmaceutical wastewater samples after pre-concentration with Ni-Al layered double hydroxide nano particles. AB - In this work, the nickel-aluminum layered double hydroxide (Ni-Al LDH) with nitrate interlayer anion was synthesized and used as a solid phase extraction sorbent for the selective separation and pre-concentration of mefenamic acid prior to quantification by UV detection at lambdamax=286 nm. Extraction procedure is based on the adsorption of mefenamate anions on the Ni-Al(NO3-) LDH and/or their exchange with LDH interlayer NO3- anions. The effects of several parameters such as cations and interlayer anions type in LDH structure, pH, sample flow rate, elution conditions, amount of nano-sorbent and co-existing ions on the extraction were investigated and optimized. Under the optimum conditions, the calibration graph was linear within the range of 2-1000 ug/L with a correlation coefficient of 0.9995. The limit of detection and relative standard deviation were 0.6 ug/L and 0.84% (30 ug/L, n=6), respectively. The presented method was successfully applied to determine of mefenamic acid in human serum and pharmaceutical wastewater samples. PMID- 29403898 TI - Identification, synthesis and characterization of an unknown process related impurity in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI IT/MS, 1H, 13C and 1H-1H COSY NMR. AB - A new impurity was detected during high performance liquid chromatographic (HPLC) analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liquid chromatography mass spectrometry using electrospray ionization and ion trap analyzer (LC/ESI-IT/MS) analysis. Proposed structure of impurity was unambiguously confirmed by synthesis followed by characterization using 1H, 13C nuclear magnetic resonance spectrometry (NMR), 1H-1H correlation spectroscopy (COSY) and infrared spectroscopy (IR). Based on the spectroscopic and spectrometric data, unknown impurity was characterized as 5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10 yl propionate. PMID- 29403899 TI - Simultaneous determination of borneol and its metabolite in rat plasma by GC-MS and its application to pharmacokinetic study. AB - A gas chromatography mass spectrometry (GC-MS) method has been developed and fully validated for the simultaneous determination of natural borneol (NB) and its metabolite, camphor, in rat plasma. Following a single liquid-liquid extraction, the analytes were separated using an HP-5MS capillary column (0.25 mm*30 m*0.25 MUm) and analyzed by MS in the selected ion monitoring mode. Selected ion monitor (m/z) of borneol, camphor and internal standard was 95, 95 and 128, respectively. Linearity, accuracy, precision and extraction recovery of the analytes were all satisfactory. The method was successfully applied to pharmacokinetic studies of NB after oral administration to Wistar rats. PMID- 29403900 TI - Synthesis of carbon nanosheet from barley and its use as non-enzymatic glucose biosensor. AB - In this work, carbon nanosheet (CNS) based electrode was designed for electrochemical biosensing of glucose. CNS has been obtained by the pyrolysis of barley at 600-750 degrees C in a muffle furnace; it was then purified and functionalized. The CNS has been characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and Raman spectroscopic techniques. The electrochemical activity of CNS-based electrode was investigated by linear sweep voltammetry (LSV) and square wave voltammetry (SWV), for the oxidation of glucose in 0.001 M H2SO4 (pH 6.0). The linear range of the sensor was found to be 10-4-10 6 M (1-100 uM) within the response time of 4 s. Interestingly, its sensitivity reached as high as ~26.002+/-0.01 MUA/MUM cm2. Electrochemical experiments revealed that the proposed electrode offered an excellent electrochemical activity towards the oxidation of glucose and could be applied for the construction of non-enzymatic glucose biosensors. PMID- 29403901 TI - UPLC-Q-TOF/MS based metabolomic profiling of serum and urine of hyperlipidemic rats induced by high fat diet. AB - Hyperlipidemia is considered to be a high lipid level in blood, can induce metabolic disorders and dysfunctions of the body, and results in some severe complications. Therefore, hunting for some metabolite markers and clarifying the metabolic pathways in vivo will be an important strategy in the treatment and prevention of hyperlipidemia. In this study, a rat model of hyperlipidemia was constructed according to histopathological data and biochemical parameters, and the metabolites of serum and urine were analyzed by UPLC-Q-TOF/MS. Combining pattern recognition and statistical analysis, 19 candidate biomarkers were screened and identified. These changed metabolites indicated that during the development and progression of hyperlipidemia, energy metabolism, lipid metabolism, amino acid metabolism and nucleotide metabolism were mainly disturbed, which are reported to be closely related to diabetes, cardiovascular diseases, etc. This study demonstrated that a UPLC-Q-TOF/MS based metabolomic approach is useful to profile the alternation of endogenous metabolites of hyperlipidemia. PMID- 29403902 TI - O-(beta-hydroxyethyl)rutosides determination by micellar flow injection (FI) spectrofluorimetry. AB - A simple, eco-friendly, sensitive and economic flow injection spectrofluorimetric method was developed for the determination of O-(beta-hydroxyethyl)rutosides. The procedure was based on the use of an anionic surfactant such as sodium dodecyl sulfate to provide an appreciable O-(beta-hydroxyethyl)rutosides fluorescence enhancement, increasing considerably the sensitivity of detection. All the variables affecting the fluorescence intensity were studied and optimized. The flow rate was 5 mL/min with detection at 450 nm (after excitation at 346 nm). A linear correlation between drug amount and peak area was established for O-(beta hydroxyethyl)rutosides in the range of 0.01-200 ug/mL with a detection limit of 0.001 ug/mL (s/n=3). Validation processes were performed by recovering studies with satisfactory results. The new methodology can be employed for the routine analysis of O-(beta-hydroxyethyl)rutosides in bulks as well as in commercial formulations. PMID- 29403903 TI - Stability-indicating assay method for determination of actarit, its process related impurities and degradation products: Insight into stability profile and degradation pathways?. AB - The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC-PDA-MS). A specific and sensitive stability indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated. PMID- 29403904 TI - Chromatographic behavior of co-eluted plasma compounds and effect on screening of drugs by APCI-LC-MS(/MS): Applications to selected cardiovascular drugs. AB - Chromatographic behavior of co-eluted compounds from un-extracted drug-free plasma samples was studied by LC-MS and LC-MS/MS with positive APCI. Under soft gradient, total ion chromatogram (TIC) consisted of two major peaks separated by a constant lower intensity region. Early peak (0.15-0.4 min) belongs to polar plasma compounds and consisted of smaller mass ions (m/z<250); late peak (3.6-4.6 min) belongs to thermally unstable phospholipids and consisted of fragments with m/z<300. Late peak is more sensitive to variations in chromatographic and MS parameters. Screening of most targeted cardiovascular drugs at levels lower than 50 ng/mL has been possible by LC-MS for drugs with retention factors larger than three. Matrix effects and recovery, at 20 and 200 ng/mL, were evaluated for spiked plasma samples with 15 cardiovascular drugs, by MRM-LC-MS/MS. Average recoveries were above 90% and matrix effects expressed as percent matrix factor (% MF) were above 100%, indicating enhancement character for APCI. Large uncertainties were significant for drugs with smaller masses (m/z<250) and retention factors lower than two. PMID- 29403905 TI - Investigation on the differences of four flavonoids with similar structure binding to human serum albumin. AB - Flavonoids are structurally diverse and the most ubiquitous groups of polyphenols distributed in the various plants, which possess intensive biological activities. In this study, the interaction mechanisms between four flavonoids containing one glucose unit with similar molecular weight isolated from the Tibetan medicinal herb Pyrethrum tatsienense, namely, apigenin-7-O-beta-D-glucoside(1), luteolin-7 O-beta-D-glucoside(2), quercetin-7-O-beta-D-glucoside(3), quercetin-3-O-beta-D glycoside(4), and human serum albumin(HSA), were investigated by fluorescence, UV vis absorbance, circular dichroism, and molecular modeling. The effects of biological metal ions Mg2+, Zn2+, and Cu2+ on the binding affinity between flavonoids and HSA were further examined. Structure-activity relationships of four flavonoids binding to HSA were discussed in depth and some meaningful conclusions have been drawn by the experiment data and theoretical simulation. In addition, an interesting phenomenon was observed that the microenvironment of the binding site I in HSA has hardly changed in the presence of 4 differentiating from the other three flavonoids on the basis of conformation investigations. PMID- 29403906 TI - Simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by LC ESI-MS/MS and its application to pharmacokinetics in rats. AB - Polypill is a fixed-dose combination that contains three or more active ingredients used as a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. A novel and accurate liquid chromatography tandem mass spectrometry method using electrospray ionization mode has been developed and validated for the simultaneous determination of amlodipine (AMD), valsartan (VAL) using losartan (LOS) as an internal standard (IS), and hydrochlorothiazide (HCT) using furosemide (FSD) as an IS. The separation was carried on Aquasil C18 (50 mm*2.1 mm, 5 um) reversed phase column using acetonitrile and water containing 0.1% formic acid (50:50, v/v) as the mobile phase. The method was validated in terms of linearity, accuracy and precision over the concentration range of 1-1000 ng/mL. The intra and inter-day precision and accuracy, stability and extraction recoveries of all the analytes were in the acceptable range. This method can be successfully applied to the pharmacokinetic study of AMD, VAL and HCT when given as a polypill. PMID- 29403907 TI - Isolation and evaluation of antiglycation potential of polyalthic acid (furano terpene) from Daniella oliveri. AB - A furano-diterpene (polyalthic acid) was isolated as a major stable compound for the first time from the oleoresin of the Daniella oliveri of the family Caesalpiniacea through column chromatography fractionation. Polyalthic acid was characterized using data obtained from EIMS, HREIMS, ESI-MS, MALDI-MS as well as 1D and 2D NMR and it was evaluated for its potential to inhibit the formation of advanced glycation end-products (AGEs) using a standard in vitro antiglycation procedure. Polyalthic acid indicated a negative antiglycation potential compared to standard inhibitor that has 85% inhibition, which is an indication that polyalthic acid may not contribute to the antiglycation activity of the plant as acclaimed in folkloric medicine. The negative antiglycation observed could indicate that the polyalthic acid could trigger glycation, thereby subjecting users to various degrees of complications. The bioactivity evaluation on molinspiration evaluator indicated that polyalthic acid could be a potential drug candidate. The biological and chemical insights gained on polyalthic acid provide a good basis for future research. PMID- 29403908 TI - Highly sensitive trivalent copper chelate-luminol chemiluminescence system for capillary electrophoresis chiral separation and determination of ofloxacin enantiomers in urine samples. AB - A simple, fast and sensitive capillary electrophoresis (CE) strategy combined with chemiluminescence (CL) detection for analysis of ofloxacin (OF) enantiomers was established in the present work. Sulfonated beta-cyclodextrin (beta-CD) was used as the chiral additive being added into the running buffer of luminol diperiodatocuprate (III) (K5[Cu(HIO6)2], DPC) chemiluminescence system. Under the optimum conditions, the proposed method was successfully applied to separation and analysis of OF enantiomers with the detection limits (S/N=3) of 8.0 nM and 7.0 nM for levofloxacin and dextrofloxacin, respectively. The linear ranges were both 0.010-100 MUM. The method was utilized for analyzing OF in urine; the results obtained were satisfactory and recoveries were 89.5-110.8%, which demonstrated the reliability of this method. This approach can also be further extended to analyze different commercial OF medicines. PMID- 29403909 TI - Determination of cilostazol and its active metabolite 3,4-dehydro cilostazol from small plasma volume by UPLC-MS/MS. AB - A simple, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of cilostazol and its pharmacologically active metabolite 3,4 dehydro cilostazol in human plasma using deuterated analogs as internal standards (ISs). Plasma samples were prepared using solid phase extraction and chromatographic separation was performed on UPLC BEH C18 (50 mm*2.1 mm, 1.7 um) column. The method was established over a concentration range of 0.5-1000 ng/mL for cilostazol and 0.5-500 ng/mL for 3,4-dehydro cilostazol. Intra- and inter batch precision (% CV) and accuracy for the analytes were found within 0.93-1.88 and 98.8-101.7% for cilostazol and 0.91-2.79 and 98.0-102.7% for the metabolite respectively. The assay recovery was within 95-97% for both the analytes and internal standards. The method was successfully applied to support a bioequivalence study of 100 mg cilostazol in 30 healthy subjects. PMID- 29403910 TI - Development of an LC-MS/MS method for determination of 2-oxo-clopidogrel in human plasma. AB - A sensitive and selective liquid chromatography-tandem mass spectrometric (LC MS/MS) method was established to determine 2-oxo-clopidogrel, a crucial intermediate metabolite in human plasma. A chromatographic separation was performed on a Sapphire C18 column following a liquid-liquid extraction sample preparation with methyl t-butyl ether. Detection was carried out on a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) with an electrospray ionization (ESI) mode. The method was validated in terms of specificity, accuracy, precision and limit of quantification. The calibration curves ranged from 0.50 to 50.0 ng/mL with good linearity. The stability was fully validated with addition of 1,4-dithio-DL-threitol (DTT) into the plasma sample prior to and in the preparation procedure. The validated method was proved to be suitable for use in pharmacokinetic study after single oral administration of 75 mg clopidogrel tablets in human subjects, which could make contribution to intensive study of the clinical drug-drug interactions of clopidogrel and individual treatment. PMID- 29403911 TI - Development and validation of microbial bioassay for quantification of Levofloxacin in pharmaceutical preparations. AB - The aim of this study was to develop and validate a simple, sensitive, precise and cost-effective one-level agar diffusion (5+1) bioassay for estimation of potency and bioactivity of Levofloxacin in pharmaceutical preparation which has not yet been reported in any pharmacopoeia. Among 16 microbial strains, Bacillus pumilus ATCC-14884 was selected as the most significant strain against Levofloxacin. Bioassay was optimized by investigating several factors such as buffer pH, inoculums concentration and reference standard concentration. Identification of Levofloxacin in commercial sample Levoflox tablet was done by FTIR spectroscopy. Mean potency recovery value for Levofloxacin in Levoflox tablet was estimated as 100.90%. A validated bioassay method showed linearity (r2=0.988), precision (Interday RSD=1.05%, between analyst RSD=1.02%) and accuracy (101.23%, RSD=0.72%). Bioassay was correlated with HPLC using same sample and estimated potencies were 100.90% and 99.37%, respectively. Results show that bioassay is a suitable method for estimation of potency and bioactivity of Levofloxacin pharmaceutical preparations. PMID- 29403912 TI - Analytical quality-by-design approach for sample treatment of BSA-containing solutions. AB - The sample preparation of samples containing bovine serum albumin (BSA), e.g., as used in transdermal Franz diffusion cell (FDC) solutions, was evaluated using an analytical quality-by-design (QbD) approach. Traditional precipitation of BSA by adding an equal volume of organic solvent, often successfully used with conventional HPLC-PDA, was found insufficiently robust when novel fused-core HPLC and/or UPLC-MS methods were used. In this study, three factors (acetonitrile (%), formic acid (%) and boiling time (min)) were included in the experimental design to determine an optimal and more suitable sample treatment of BSA-containing FDC solutions. Using a QbD and Derringer desirability (D) approach, combining BSA loss, dilution factor and variability, we constructed an optimal working space with the edge of failure defined as D<0.9. The design space is modelled and is confirmed to have an ACN range of 83+/-3% and FA content of 1+/-0.25%. PMID- 29403913 TI - LC, MS n and LC-MS/MS studies for the characterization of degradation products of amlodipine. AB - In the present study, comprehensive stress testing of amlodipine (AM) was carried out according to International Conference on Harmonization (ICH) Q1A(R2) guideline. AM was subjected to acidic, neutral and alkaline hydrolysis, oxidation, photolysis and thermal stress conditions. The drug showed instability in acidic and alkaline conditions, while it remained stable to neutral, oxidative, light and thermal stress. A total of nine degradation products (DPs) were formed from AM, which could be separated by the developed gradient LC method on a C18 column. The products formed under various stress conditions were investigated by LC-MS/MS analysis. The previously developed LC method was suitably modified for LC-MS/MS studies by replacing phosphate buffer with ammonium acetate buffer of the same concentration (pH 5.0). A complete fragmentation pathway of the drug was first established to characterize all the degradation products using LC-MS/MS and multi-stage mass (MS n ) fragmentation studies. The obtained mass values were used to study elemental compositions, and the total information helped with the identification of DPs, along with its degradation pathway. PMID- 29403914 TI - Direct injection HILIC-MS/MS analysis of darunavir in rat plasma applying supported liquid extraction. AB - A novel bioanalytical method was developed and validated for the quantitative determination of darunavir (DRV) in rat plasma by employing hydrophilic interaction chromatography and tandem mass spectrometry (HILIC-MS/MS) with supported liquid extraction (SLE). Irbesartan (IRB) was used as an internal standard (IS). The analyte in rat plasma (200 uL) was isolated through SLE using ethyl acetate as the eluting solvent. The chromatographic separation was achieved on Luna-HILIC (250 mm*4.6 mm, 5 MUm) column with a mobile phase of 0.1% of formic acid in water:acetonitrile (5: 95, v/v), at a constant flow rate of 1.0 mL/min. The MS/MS ion transitions for DRV (548.1->392.0) and IS (429.2->207.1) were monitored on an ion trap mass spectrometer, operating in the multiple reaction monitoring (MRM) mode. The lower limit of quantitation (LLOQ) was 0.2 ng/mL and quantitation range was 0.2-5000 ng/mL. The method was validated for its selectivity, sensitivity, carryover, linearity, precision, accuracy, recovery, matrix effect and stability. The method was successfully applied to pharmacokinetic study in rats. PMID- 29403915 TI - Protective effect of Genistein against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in Swiss albino rats. AB - In the present study, we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine (NDEA). NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen. The male rats were exposed to NDEA (0.1 mg/mL) dissolved in drinking water separately and along with 25, 50, 100 mg/mL of Genistein for 21 days. The activities of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were measured in blood serum. Lipid peroxidation, protein carbonyl content, micronucleus frequency and DNA damage (Comet assay) were performed on rat hepatocytes. The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e., SGOT, SGPT, ALP and LDH (P<0.05). The HE staining of histological sections of the liver also revealed a protective effect of Genistein. A significant dose dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1 mg/mL) along with Genistein (P<0.05). The results obtained for the comet assay in rat hepatocytes showed a significant dose dependent decrease in the mean tail length (P<0.05). Thus the present study supports the hepatoprotective role of Genistein. PMID- 29403916 TI - A newfangled study using risk silhouette and uncertainty approximation for quantification of acyclovir in diverse formulation. AB - Risk assessment and uncertainty approximation are two major and important parameters that need to be adopted for the development of pharmaceutical process to ensure reliable results. Additionally, there is a need to switch from the traditional method validation checklist to provide a high level of assurance of method reliability to measure quality attribute of a drug product. In the present work, evaluation of risk profile, combined standard uncertainty and expanded uncertainty in the analysis of acyclovir were studied. Uncertainty was calculated using cause-effect approach, and to make it more accurately applicable a method was validated in our laboratory as per the ICH guidelines. While assessing the results of validation, the calibration model was justified by the lack of fit and Levene's test. Risk profile represents the future applications of this method. In uncertainty the major contribution is due to sample concentration and mass. This work demonstrates the application of theoretical concepts of calibration model tests, relative bias, risk profile and uncertainty in routine methods used for analysis in pharmaceutical field. PMID- 29403917 TI - Capillary electrophoresis to determine entrapment efficiency of a nanostructured lipid carrier loaded with piroxicam. AB - A simple and fast capillary electrophoresis method has been developed to determine the amount of piroxicam loaded in a drug delivery system based on nanostructured lipid carriers (NLCs). The entrapment efficiency of the nanostructured lipid carrier was estimated by measuring the concentration of drug not entrapped in a suspension of NLC. The influence of different parameters on migration times, peak symmetry, efficiency and resolution was studied; these parameters included the pH of the electrophoretic buffer solution and the applied voltage. The piroxicam peak was obtained with a satisfactory resolution. The separation was carried out using a running buffer composed of 50 mM ammonium acetate and 13.75 mM ammonia at pH 9. The optimal voltage was 20 kV and the cartridge temperature was 20 degrees C. The corresponding calibration curve was linear over the range of 2.7-5.4 ug/mL of NLC suspension. The reproducibility of migration time and peak area were investigated, and the obtained RSD% values (n=5) were 0.99 and 2.13, respectively. PMID- 29403918 TI - Bioautography and its scope in the field of natural product chemistry. AB - Medicinal plants, vegetables and fruits are the sources of huge number of bioactive lead/scaffolds with therapeutic and nutraceutical importance. Bioautography is a means of target-directed isolation of active molecules on chromatogram. Organic solvents employed in chromatographic separation process can be completely removed before biological detection because these solvents cause inactivation of enzymes and/or death of living organisms. They offer a rapid and easy identification of bioactive lead/scaffolds in complex matrices of plant extracts. Bioautography is a technique to isolate hit(s)/lead(s) by employing a suitable chromatographic process followed by a biological detection system. This review critically describes the methodologies to identify antimicrobial, antioxidant, enzyme inhibitor lead/scaffolds by employing bioautography. A significant number of examples have been incorporated to authenticate the methodologies. PMID- 29403919 TI - Simultaneous determination of four active components in Alisma orientale (Sam.) Juz. by HPLC-DAD using a single reference standard. AB - A rapid, simple and practical high-performance liquid chromatography method coupled with diode array detector (HPLC-DAD) was developed to evaluate the quality of Alisma orientale (Sam.) Juz. through a simultaneous determination of four major active triterpenes using a single standard to determine the multi components (SSDMCs). Alisol B 23-acetate was selected as the reference compound for calculating the relative response factors. All calibration curves showed good linearity (R2>0.9998) within test ranges. RSDs for intra- and inter-day of four analytes were less than 3.6% and 2.3%; the overall recovery was 92.1-110.2% (SSDMC). The proposed method was successfully applied to quantify the four components in 20 samples from different localities in China. Moreover, significant variations were demonstrated in the content of these compounds. In addition, hierarchical clustering analysis (HCA) and principal components analysis (PCA) were performed to differentiate and classify the samples based on the contents of Alisol C 23-acetate, Alisol A, Alisol A 24-acetate and Alisol B 23-acetate. This simple, rapid, low-cost and reliable HPLC-DAD method using SSDMC is suitable for routine quantitative analysis and quality control of A. orientale (Sam.) Juz. PMID- 29403920 TI - Quantification of 17-desacetyl norgestimate in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to bioequivalence study. AB - A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the estimation of 17-desacetyl norgestimate in human plasma using solid-phase extraction technique. 17-desacetyl norgestimate D6 was used as the internal standard. Simple gradient chromatographic conditions and mass spectrometric detection enabled accurate and precise measurement of 17-desacetyl norgestimate at sub-picogram levels. The proposed method was validated for a linear range of 20-5000 pg/mL with a correlation coefficient >=0.9988. The intra-run and inter-run precision and accuracy were within 10%. The overall recoveries for 17-desacetyl norgestimate and 17-desacetyl norgestimate D6 were 96.30% and 93.90%, respectively. The total run time was 4.5 min. The developed method was applied for the determination of the pharmacokinetic parameters of 17-desacetyl norgestimate following a single oral administration of a norgestimate and ethinyl estradiol 0.250 mg/0.035 mg tablets in 35 healthy female volunteers. PMID- 29403921 TI - Selective and rapid determination of raltegravir in human plasma by liquid chromatography-tandem mass spectrometry in the negative ionization mode. AB - A selective and rapid high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of raltegravir using raltegravir-d3 as an internal standard (IS). The analyte and IS were extracted with methylene chloride and n-hexane solvent mixture from 100 uL human plasma. The chromatographic separation was achieved on a Chromolith RP-18e endcapped C18 (100 mm*4.6 mm) column in a run time of 2.0 min. Quantitation was performed in the negative ionization mode using the transitions of m/z 443.1 >316.1 for raltegravir and m/z 446.1->319.0 for IS. The linearity of the method was established in the concentration range of 2.0-6000 ng/mL. The mean extraction recovery for raltegravir and IS was 92.6% and 91.8%, respectively, and the IS normalized matrix factors for raltegravir ranged from 0.992 to 0.999. The application of this method was demonstrated by a bioequivalence study on 18 healthy subjects. PMID- 29403923 TI - Liquid chromatography/tandem mass spectrometry method for quantitative estimation of solutol HS15 and its applications. AB - A rapid, sensitive and selective pseudoMRM (pMRM)-based method for the determination of solutol HS15 (SHS15) in rat plasma was developed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). The most abundant ions corresponding to SHS15 free polyethyleneglycol (PEG) oligomers at m/z 481, 525, 569, 613, 657, 701, 745, 789, 833, 877, 921 and 965 were selected for pMRM in electrospray mode of ionization. Purity of the lipophilic and hydrophilic components of SHS15 was estimated using evaporative light scattering detector (ELSD). Plasma concentrations of SHS15 were measured after oral administration at 2.50 g/kg dose and intravenous administration at 1.00 g/kg dose in male Sprague Dawley rats. SHS15 has poor oral bioavailability of 13.74% in rats. Differences in pharmacokinetics of oligomers were studied. A novel proposal was conveyed to the scientific community, where formulation excipient could be analyzed as a qualifier in the analysis of new chemical entities (NCEs) to address the spiky plasma concentration profiles. PMID- 29403922 TI - Optimization of high pressure machine decocting process for Dachengqi Tang using HPLC fingerprints combined with the Box-Behnken experimental design. AB - Using Dachengqi Tang (DCQT) as a model, high performance liquid chromatography (HPLC) fingerprints were applied to optimize machine extracting process with the Box-Behnken experimental design. HPLC fingerprints were carried out to investigate the chemical ingredients of DCQT; synthetic weighing method based on analytic hierarchy process (AHP) and criteria importance through intercriteria correlation (CRITIC) was performed to calculate synthetic scores of fingerprints; using the mark ingredients contents and synthetic scores as indicators, the Box Behnken design was carried out to optimize the process parameters of machine decocting process under high pressure for DCQT. Results of optimal process showed that the herb materials were soaked for 45 min and extracted with 9 folds volume of water in the decocting machine under the temperature of 140 degrees C till the pressure arrived at 0.25 MPa; then hot decoction was excreted to soak Dahuang and Mangxiao for 5 min. Finally, obtained solutions were mixed, filtrated and packed. It concluded that HPLC fingerprints combined with the Box-Behnken experimental design could be used to optimize extracting process of traditional Chinese medicine (TCM). PMID- 29403924 TI - Quantitative estimation of (-)-hinokinin, a trypanosomicidal marker in Piper cubeba, and some of its commercial formulations using HPLC-PDA. AB - The fruits of Piper cubeba have been used in Ayurvedic system of medicine for pain, tastelessness, painful urination and mouth diseases. Among its various chemical constituents, (-)-hinokinin, a trypanosomicidal dibenzylbutyrolactone lignan, is found in significant quantities. For quality evaluation of P. cubeba fruit and its commercial formulations, there is an urgent need to develop an analytical method based on (-)-hinokinin. For this purpose, an HPLC method was developed using photo diode array detector and Waters HR C18 column with gradient elution consisting of water and acetonitrile. The developed method was validated as per ICH-Q2B guidelines and found to be accurate, precise and linear over a wide range of concentrations (5-300 ug/mL). (-)-Hinokinin contents were found to be in the range of 0.005-0.109% (m/m) in various P. cubeba samples. The developed method was extended to LC-MS for further identification and characterization of ( )-hinokinin in samples. The developed method is simple, rapid and specific, and can be used as a tool for quality control of P. cubeba fruits and its commercial formulations. PMID- 29403925 TI - Monolithic LC method applied to fesoterodine fumarate low dose extended-release tablets: Dissolution and release kinetics. AB - A dissolution test for fesoterodine low dose extended-release tablets using liquid chromatographic (LC) method equipped with a C18 monolithic column was developed and validated. LC system was operated isocratically at controlled temperature (40 degrees C) using a mobile phase of acetonitrile:methanol:0.03 M ammonium acetate (pH 3.8) (30:15:55, v/v/v), run at a flow rate of 1.5 mL/min and detected at 208 nm. The best dissolution conditions for this formulation were achieved using a USP apparatus 2 (paddle) at 100 rpm and 900 mL of phosphate buffer at pH 6.8 as the dissolution medium. Validation parameters such as the specificity, linearity, accuracy, precision, and robustness were evaluated according to international guidelines, giving results within the acceptable range. The kinetic parameters of drug release were also investigated using model dependent methods and the dissolution profiles were best described by the Higuchi model. The validated dissolution test can be applied for quality control of this formulation. PMID- 29403926 TI - Non-covalent binding analysis of sulfamethoxazole to human serum albumin: Fluorescence spectroscopy, UV-vis, FT-IR, voltammetric and molecular modeling. AB - This study was designed to examine the interaction of sulfamethoxazole (SMZ) with human serum albumin(HSA). Spectroscopic analysis of the emission quenching at different temperatures revealed that the quenching mechanism of human serum albumin by SMZ was static mechanism. The binding constant values for the SMZ-HSA system were obtained to be 22,500 L/mol at 288 K, 15,600 L/mol at 298 K, and 8500 L/mol at 308 K. The distance r between donor and acceptor was evaluated according to the theory of Foster energy transfer. The results of spectroscopic analysis and molecular modeling techniques showed that the conformation of human serum albumin had been changed in the presence of SMZ. The thermodynamic parameters, namely enthalpy change (?H0) -36.0 kJ/mol, entropy change (?S0) -41.3 J/mol K and free energy change (?G0) -23.7 kJ/mol, were calculated by using van't Hoff equation. The effect of common ions on the binding of SMZ to HSA was tested. PMID- 29403927 TI - Determination of diclofenac in pharmaceutical preparations by voltammetry and gas chromatography methods. AB - Rapid, sensitive and specific methods were developed for the determination of diclofenac in pharmaceutical preparations by linear sweep voltammetry (LSV) and gas chromatography (GC) with mass spectrometry (MS) detection. The linearity was established over the concentration range of 5-35 MUg/mL for LSV and 0.25-5 MUg/mL for GC-MS method. The intra- and inter-day relative standard deviation (RSD) was less than 4.39% and 4.62% for LSV and GC-MS, respectively. Limits of quantification (LOQ) were determined as 4.8 and 0.15 MUg/mL for LSV and GC-MS, respectively. No interference was found from tablet excipients at the selected assay conditions. The methods were applied for the quality control of commercial diclofenac dosage forms to quantify the drug and to check the formulation content uniformity. PMID- 29403928 TI - Comparison of conventional and supported liquid extraction methods for the determination of sitagliptin and simvastatin in rat plasma by LC-ESI-MS/MS. AB - Three extraction methods were compared for their efficiency to analyze sitagliptin and simvastatin in rat plasma by LC-MS/MS, including (1) liquid liquid extraction (LLE), (2) solid phase extraction (SPE) and (3) supported liquid extraction (SLE). Comparison of recoveries of analytes with different extraction methods revealed that SLE was the best extraction method. The detection was facilitated with ion trap-mass spectrometer by multiple reactions monitoring (MRM) in a positive ion mode with ESI. The transitions monitored were m/z 441.1->325.2 for simvastatin, 408.2->235.1 for sitagliptin and 278.1->260.1 for the IS. The lower limit of quantification (LLOQ) was 0.2 ng/mL for sitagliptin and 0.1 ng/mL for simvastatin. The effective SLE offers enhanced chromatographic selectivity, thus facilitating the potential utility of the method for routine analysis of biological samples along with pharmacokinetic studies. PMID- 29403929 TI - Quality evaluation of synthetic quorum sensing peptides used in R&D. AB - Peptides are becoming an important class of molecules in the pharmaceutical field. Closely related peptide-impurities in peptides are inherent to the synthesis approach and have demonstrated to potentially mask biomedical experimental results. Quorum sensing peptides are attracting high interest in R&D and therefore a representative set of quorum sensing peptides, with a requested purity of at least 95.0%, was evaluated for their purity and nature of related impurities. In-house quality control (QC) revealed a large discrepancy between the purity levels as stated on the supplier's certificate of analysis and our QC results. By using our QC analysis flowchart, we demonstrated that only 44.0% of the peptides met the required purity. The main compound of one sample was even found to have a different structure compared to the desired peptide. We also found that the majority of the related impurities were lacking amino acid(s) in the desired peptide sequence. Relying on the certificates of analysis as provided by the supplier might have serious consequences for peptide research, and peptide researchers should implement and maintain a thorough in-house QC. PMID- 29403930 TI - Extraction, characterization and biological studies of phytochemicals from Mammea suriga. AB - The present work involves extraction of phytochemicals from the root bark of a well-known Indian traditional medicinal plant, viz. Mammea suriga, with various solvents and evaluation of their in vitro antimicrobial and antioxidant activities using standard methods. The phytochemical analysis indicates the presence of some interesting secondary metabolites like flavonoids, cardiac glycosides, alkaloids, saponins and tannins in the extracts. Also, the solvent extracts displayed promising antimicrobial activity against Staphylococcus aureus, Bacillus subtilis and Cryptococcus neoformans with inhibition zone in a range of 20-33 mm. Further, results of their antioxidant screening revealed that aqueous extract (with IC50 values of 111.51+/-1.03 and 31.05+/-0.92 MUg/mL in total reducing power assay and DPHH radical scavenging assay, respectively) and ethanolic extract (with IC50 values of 128.00+/-1.01 and 33.25+/-0.89 MUg/mL in total reducing power assay and DPHH radical scavenging assay, respectively) were better antioxidants than standard ascorbic acid. Interestingly, FT-IR analysis of each extract established the presence of various biologically active functional groups in it. PMID- 29403931 TI - Liquid chromatography-tandem mass spectrometry method for the estimation of adefovir in human plasma: Application to a pharmacokinetic study. AB - An analytical method based on solid phase extraction was developed and validated for analysis of adefovir in human plasma. Adefovir-d4 was used as an internal standard and Synergi MAX RP80A (150 mm*4.6 mm, 4 um) column provided the desired chromatographic separation of compounds followed by detection with mass spectrometry. The method used simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode. The calibration curves were linear over the range of 0.50-42.47 ng/mL with the lower limit of quantitation validated at 0.50 ng/mL. Matrix effect was assessed by post-column infusion experiment to monitor phospholipids and post-extraction addition experiment was performed. The degree of matrix effect for adefovir was determined as 7.5% and ion-enhancement in five different lots of human plasma was 7.1% and had no impact on study samples analysis with 4.5 min run time. The intra- and inter-day precision values were within 7.7% and 7.8%, respectively, for adefovir at the lower limit of quantification level. Validated bioanalytical method was successfully applied to clinical sample analysis. PMID- 29403932 TI - Selective extraction of dimethoate from cucumber samples by use of molecularly imprinted microspheres. AB - Molecularly imprinted polymers for dimethoate recognition were synthesized by the precipitation polymerization technique using methyl methacrylate (MMA) as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the cross linker. The morphology, adsorption and recognition properties were investigated by scanning electron microscopy (SEM), static adsorption test, and competitive adsorption test. To obtain the best selectivity and binding performance, the synthesis and adsorption conditions of MIPs were optimized through single factor experiments. Under the optimized conditions, the resultant polymers exhibited uniform size, satisfactory binding capacity and significant selectivity. Furthermore, the imprinted polymers were successfully applied as a specific solid phase extractants combined with high performance liquid chromatography (HPLC) for determination of dimethoate residues in the cucumber samples. The average recoveries of three spiked samples ranged from 78.5% to 87.9% with the relative standard deviations (RSDs) less than 4.4% and the limit of detection (LOD) obtained for dimethoate as low as 2.3 MUg/mL. PMID- 29403933 TI - Isolation and characterization of a degradation product in leflunomide and a validated selective stability-indicating HPLC-UV method for their quantification. AB - Leflunomide (LLM) is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, and photolysis as recommended by International Conference on Harmonization guideline Q1A(R2). In total, four degradation products (I-IV) were formed under different conditions. Products I, II and IV were formed in alkaline hydrolytic, acidic hydrolytic and alkaline photolytic conditions. LLM and all degradation products were optimally resolved by gradient elution over a C18 column. The major degradation product (IV) formed in hydrolytic alkaline conditions was isolated through column chromatography. Based on its 1H NMR, IR and mass spectral data, it was characterized as a British Pharmacopoeial impurity B. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged and robust for quantification of LLM as well as product IV. Finally, the method was applied to stability testing of the commercially available LLM tablets. PMID- 29403935 TI - Development and validation of a GC-FID method for quantitative analysis of oleic acid and related fatty acids. AB - Oleic acid is a common pharmaceutical excipient that has been widely used in various dosage forms. Gas chromatography (GC) has often been used as the quantitation method for fatty acids normally requiring a derivatization step. The aim of this study was to develop a simple, robust, and derivatization-free GC method that is suitable for routine analysis of all the major components in oleic acid USP-NF (United States Pharmacopeia-National Formulary) material. A gas chromatography-flame ionization detection (GC-FID) method was developed for direct quantitative analysis of oleic acid and related fatty acids in oleic acid USP-NF material. Fifteen fatty acids were separated using a DB-FFAP (nitroterephthalic acid modified polyethylene glycol) capillary GC column (30 m*0.32 mm i.d.) with a total run time of 20 min. The method was validated in terms of specificity, linearity, precision, accuracy, sensitivity, and robustness. The method can be routinely used for the purpose of oleic acid USP-NF material analysis. PMID- 29403934 TI - Quantitative bioanalytical and analytical method development of dibenzazepine derivative, carbamazepine: A review. AB - Bioanalytical methods are widely used for quantitative estimation of drugs and their metabolites in physiological matrices. These methods could be applied to studies in areas of human clinical pharmacology and toxicology. The major bioanalytical services are method development, method validation and sample analysis (method application). Various methods such as GC, LC-MS/MS, HPLC, HPTLC, micellar electrokinetic chromatography, and UFLC have been used in laboratories for the qualitative and quantitative analysis of carbamazepine in biological samples throughout all phases of clinical research and quality control. The article incorporates various reported methods developed to help analysts in choosing crucial parameters for new method development of carbamazepine and its derivatives and also enumerates metabolites, and impurities reported so far. PMID- 29403936 TI - Fabrication of multiwalled carbon nanotube-surfactant modified sensor for the direct determination of toxic drug 4-aminoantipyrine. AB - A multi-walled carbon nanotube (MWCNT)-cetyltrimethylammonium bromide (CTAB) surfactant composite modified glassy carbon electrode (GCE) was developed as a novel system for the determination of 4-aminoantipyrine(AAP). The oxidation process was irreversible over the pH range studied and exhibited a diffusion controlled behavior. All experimental parameters were optimized. The combination of MWCNT-CTAB endows the biosensor with large surface area, good biological compatibility, electricity and stability, high selectivity and sensitivity. MWCNT CTAB/GCE electrode gave a linear response for AAP from 5.0*10-9 to 4.0*10-8 M with a detection limit of 1.63*10-10 M. The modified electrode showed good selectivity against interfering species and also exhibited good reproducibility. The present electrochemical sensor based on the MWCNT-CTAB/GCE electrode was applied to the determination of AAP in real samples. PMID- 29403937 TI - Simultaneous determination of four Sudan dyes in rat blood by UFLC-MS/MS and its application to a pharmacokinetic study in rats. AB - A rapid and sensitive method based on ultrafast liquid chromatography-tandem mass spectrometry was developed and validated for simultaneous determination of Sudan I, Sudan II, Sudan III, and Sudan IV levels in rat whole blood. Cleanert C18 mixed-mode polymeric sorbent was used for effective solid-phase extraction cleanup. Separation was carried out on a reversed-phase C18 column (100 mm*2.1 mm, 1.8 MUm) using 0.1% (v/v) formic acid in water/0.1% (v/v) formic acid in acetonitrile as the mobile phase in gradient elution. Quantification was performed by an electrospray ionization source in the positive multiple reaction monitoring mode using D5-Sudan I as the internal standard. Calibration curves showed good linearity between 0.2 and 20.0 MUg/L, with correlation coefficients higher than 0.9990. The average recovery rates were between 93.05% and 114.98%. The intra- and inter-day relative standard deviations were within 6.2%. The lower limit of quantification was 0.2 MUg/L. All the analytes were found to be stable in a series of stability studies. The proposed method was successfully applied to a pharmacokinetic study of four Sudan dyes after oral administration to rats. PMID- 29403938 TI - Multi-spectroscopic investigation of the binding interaction of fosfomycin with bovine serum albumin. AB - The interaction between fosfomycin (FOS) and bovine serum albumin (BSA) has been investigated effectively by multi-spectroscopic techniques under physiological pH 7.4. FOS quenched the intrinsic fluorescence of BSA via static quenching. The number of binding sites n and observed binding constant KA were measured by the fluorescence quenching method. The thermodynamic parameters DeltaG0, DeltaH0 and DeltaS0 were calculated at different temperatures according to the van't Hoff equation. The site of binding of FOS in the protein was proposed to be Sudlow's site I based on displacement experiments using site markers viz. warfarin, ibuprofen and digitoxin. The distance r between the donor (BSA) and acceptor (FOS) molecules was obtained according to the Forster theory. The effect of FOS on the conformation of BSA was analyzed using synchronous fluorescence spectra (SFS), circular dichroism (CD) and 3D fluorescence spectra. A molecular modeling study further confirmed the binding mode obtained by the experimental studies. PMID- 29403939 TI - Identification, synthesis and characterization of process related impurities of benidipine hydrochloride, stress-testing/stability studies and HPLC/UPLC method validations. AB - Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpiperidin-3-ol (Ben-2), which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine. PMID- 29403940 TI - Simultaneous quantitation of folic acid and 5-methyltetrahydrofolic acid in human plasma by HPLC-MS/MS and its application to a pharmacokinetic study. AB - A sensitive method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the simultaneous determination of folic acid (FA) and its active metabolite, 5-methyltetrahydrofolic acid (5-M THF), in human plasma. The analytes were extracted from plasma with methanol solution containing 10 mg/mL of 2-mercaptoethanol and 0.025% (v/v) ammonium hydroxide. FA and 5-M-THF were more stable after the addition of 2 mercaptoethanol and ammonium hydroxide in the sample preparation procedures of this study than they were in the previously published methods. Chromatographic separation was performed on a Hedera ODS-2 column using a gradient elution system of acetonitrile and 1 mM ammonium acetate buffer solution containing 0.6% formic acid as mobile phase. LC-MS/MS was carried out with an ESI ion-source and operated in the multiple reaction monitoring (MRM) mode. The assay was linear over the concentration ranges of 0.249-19.9 ng/mL for FA, and 5.05-50.5 ng/mL for 5-M-THF. The developed LC-MS/MS method offers increased sensitivity for quantification of FA and 5-M-THF in human plasma and was applicable to a pharmacokinetic study of FA and 5-M-THF. PMID- 29403941 TI - Species authentication and geographical origin discrimination of herbal medicines by near infrared spectroscopy: A review. AB - Near infrared (NIR) spectroscopy as a rapid and nondestructive analytical technique, integrated with chemometrics, is a powerful process analytical tool for the pharmaceutical industry and is becoming an attractive complementary technique for herbal medicine analysis. This review mainly focuses on the recent applications of NIR spectroscopy in species authentication of herbal medicines and their geographical origin discrimination. PMID- 29403942 TI - Four new degradation products of doxorubicin: An application of forced degradation study and hyphenated chromatographic techniques. AB - Forced degradation study on doxorubicin (DOX) was carried out under hydrolytic condition in acidic, alkaline and neutral media at varied temperatures, as well as under peroxide, thermal and photolytic conditions in accordance with International Conference on Harmonization (ICH) guidelines Q1(R2). It was found extremely unstable to alkaline hydrolysis even at room temperature, unstable to acid hydrolysis at 80 degrees C, and to oxidation at room temperature. It degraded to four products (O-I-O-IV) in oxidative condition, and to single product (A-I) in acid hydrolytic condition. These products were resolved on a C8 (150 mm*4.6 mm, 5 um) column with isocratic elution using mobile phase consisting of HCOONH4 (10 mM, pH 2.5), acetonitrile and methanol (65:15:20, v/v/v). Liquid chromatography-photodiode array (LC-PDA) technique was used to ascertain the purity of the products noted in LC-UV chromatogram. For their characterization, a six stage mass fragmentation (MS6) pattern of DOX was outlined through mass spectral studies in positive mode of electrospray ionization (+ESI) as well as through accurate mass spectral data of DOX and the products generated through liquid chromatography-time of flight mass spectrometry (LC-MS-TOF) on degraded drug solutions. Based on it, O-I-O-IV were characterized as 3-hydroxy-9 desacetyldoxorubicin-9-hydroperoxide, 1-hydroxy-9-desacetyldoxorubicin-9 hydroperoxide, 9-desacetyldoxorubicin-9-hydroperoxide and 9-desacetyldoxorubicin, respectively, whereas A-I was characterized as deglucosaminyl doxorubicin. While A-I was found to be a pharmacopoeial impurity, all oxidative products were found to be new degradation impurities. The mechanisms and pathways of degradation of doxorubicin were outlined and discussed. PMID- 29403943 TI - Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals. AB - An efficient generic static headspace gas chromatography (HSGC) method was developed, optimized and validated for the routine determination of several residual solvents (RS) in drug substance, using a strategy with two sets of calibration. Dimethylsulfoxide (DMSO) was selected as the sample diluent and internal standards were used to minimize signal variations due to the preparative step. A gas chromatograph from Agilent Model 6890 equipped with flame ionization detector (FID) and a DB-624 (30 m*0.53 mm i.d., 3.00 um film thickness) column was used. The inlet split ratio was 5:1. The influencing factors in the chromatographic separation of the analytes were determined through a fractional factorial experimental design. Significant variables: the initial temperature (IT), the final temperature (FT) of the oven and the carrier gas flow rate (F) were optimized using a central composite design. Response transformation and desirability function were applied to find out the optimal combination of the chromatographic variables to achieve an adequate resolution of the analytes and short analysis time. These conditions were 30 degrees C for IT, 158 degrees C for FT and 1.90 mL/min for F. The method was proven to be accurate, linear in a wide range and very sensitive for the analyzed solvents through a comprehensive validation according to the ICH guidelines. PMID- 29403944 TI - Application of RP-HPLC method in dissolution testing and statistical evaluation by NASSAM for simultaneous estimation of tertiary combined dosages forms. AB - A dissolution method with robust high performance liquid chromatographic (HPLC) analysis for immediate release tablet formulation was developed and validated to meet the requirement as per International Conference on Harmonization (ICH) and United States Food and Drug Administration (USFDA) guidelines. The method involved the use of Agilent ZORBAX Eclipse XDB C18 column, and temperature was maintained at 30 degrees C. After optimization, the mobile phase was selected as phosphate buffer (KH2PO4, 30 mM) : ACN (60:40, v/v) with pH 3.0, and retention time Rt was found as 3.24, 4.16, and 2.55 min for paracetamol (PCM), chlorpheniramine maleate (CPM) and phenylephrine hydrochloride (PH) respectively at 265 nm and at a flow rate of 1 mL/min. The relative standard deviation (%RSD) for 6 replicate measurements was found to be less than 2%. Furthermore net analyte signal standard addition method (NASSAM) with spectrophotometer was performed for standard and liquid oral suspension. On the basis of selectivity, sensitivity and accuracy analysis, it was confirmed that this novel method could be useful for simultaneous estimation of the given drug combinations. Two-way analysis of variance (ANOVA) was applied for evaluating the statistical difference between the assay results obtained via both NASSAM and RP-HPLC methods and ultimately no significant difference was found between both the methods. All the methods and results were acceptable and confirmed that the method was suitable for intended use. PMID- 29403945 TI - High-sensitivity simultaneous liquid chromatography-tandem mass spectrometry assay of ethinyl estradiol and levonorgestrel in human plasma. AB - A sensitive and simultaneous liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of ethinyl estradiol and levonorgestrel. The analytes were extracted with methyl-tert-butyl ether: n hexane (50:50, v/v) solvent mixture, followed by dansyl derivatization. The chromatographic separation was performed on a Kinetex C18 (50 mm*4.6 mm, 2.6 um) column with a mobile phase of 0.1% (v/v) formic acid in water and acetonitrile in gradient composition. The mass transitions were monitored in electrospray positive ionization mode. The assay exhibited a linear range of 0.100-20.0 ng/mL for levonorgestrel and 4.00-500 pg/mL for ethinyl estradiol in human plasma. A run time of 9.0 min for each sample made it possible to analyze a throughput of more than 100 samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic and bioequivalence studies. PMID- 29403946 TI - Determination of atractylon in rat plasma by a GC-MS method and its application to a pharmacokinetic study. AB - A sensitive and selective method based on gas chromatography hyphenated to mass spectrometry (GC-MS) was developed and validated for the determination of atractylon in rat plasma. Plasma samples were processed by liquid-liquid extraction with ethyl acetate-n-hexane (1:1, v/v) using acetophenone as an internal standard (IS). Analytes were determined in selective ion monitoring (SIM) mode using target ions at m/z 108.1 for atractylon and m/z 105.1 for acetophenone. The calibration curve was linear over the concentration range of 10 1000 ng/mL with lower limit of quantification of 10 ng/mL. The intra- and inter day precision variations were not more than 10.4% and 9.6%, respectively, whilst accuracy values ranged from -6.5% to 4.9%. Extraction recovery of the assay was satisfactory. This method was successfully applied to quantification and pharmacokinetic study of atractylon in rat plasma after intragastric administration of Atractylodis extract. PMID- 29403947 TI - Rapid screening and distribution of bioactive compounds in different parts of Berberis petiolaris using direct analysis in real time mass spectrometry. AB - Berberis petiolaris Wall. ex G. Don, an unexplored medicinal plant belonging to the family Berberidaceae, is a large deciduous shrub found in Western Himalaya between 1800-3000 m. Chemical profiling of fruit, leaf, root and stem was done by direct analysis in real time mass spectrometry followed by multivariate analysis for discrimination among the plant parts. The bioactive compounds, including magnoflorine, berberine, jatrorrhizine, thalifendine/berberrubine, demethyleneberberine, reticuline, 8-oxoberberine, N-methyltetrahydroberberine, tetrahydropalmatine, tetrahydroberberine and palmatine, were identified by their exact mass measurement and the corresponding molecular formula of each compound. A comparative study of distribution pattern for all these bioactive alkaloids showed qualitative and quantitative variations in different parts of B. petiolaris. Principal component analysis clearly discriminated each part of B. petiolaris plant. PMID- 29403948 TI - Development of cell metabolite analysis on microfluidic platform. AB - Cell metabolite analysis is of great interest to analytical chemists and physiologists, with some metabolites having been identified as important indicators of major diseases such as cancer. A high-throughput and sensitive method for drug metabolite analysis will largely promote the drug discovery industry. The basic barrier of metabolite analysis comes from the interference of complex components in cell biological system and low abundance of target substances. As a powerful tool in biosample analysis, microfluidic chip enhances the sensitivity and throughput by integrating multiple functional units into one chip. In this review, we discussed three critical steps of establishing functional microfluidic platform for cellular metabolism study. Cell in vitro culture model, on chip sample pretreatment, and microchip combined detectors were described in details and demonstrated by works in five years. And a brief summary was given to discuss the advantages as well as challenges of applying microchip method in cell metabolite and biosample analysis. PMID- 29403949 TI - Thermal stability and hydration behavior of ritonavir sulfate: A vibrational spectroscopic approach. AB - Ritonavir sulfate is a protease inhibitor widely used in the treatment of acquired immunodeficiency syndrome. In order to elucidate the inherent stability and sensitivity characteristics of ritonavir sulfate, it was investigated under forced thermal and hydration stress conditions as recommended by the International Conference on Harmonization guidelines. In addition, competency of vibrational (infrared and Raman) spectroscopy was assessed to identify structural changes of the drug symbolizing its stress degradation. High performance liquid chromatography was used as a confirmatory technique for both thermal and hydration stress study, while thermogravimetric analysis/differential thermal analysis and atomic force microscopy substantiated the implementation of vibrational spectroscopy in this framework. The results exhibited high thermal stability of the drug as significant variations were observed in the diffuse reflectance infrared Fourier transform spectra only after the drug exposure to thermal radiations at 100 degrees C. Hydration behavior of ritonavir sulfate was evaluated using Raman spectroscopy and the value of critical relative humidity was found to be >67%. An important aspect of this study was to utilize vibrational spectroscopic technique to address stability issues of pharmacological molecules, not only for their processing in pharmaceutical industry, but also for predicting their shelf lives and suitable storage conditions. PMID- 29403950 TI - Identification, synthesis and characterization of process related desfluoro impurity of ezetimibe and HPLC method validations. AB - Ezetimibe, which selectively inhibits cholesterol absorption across the intestinal wall and is used as an antihyperlipidemic agent, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of ezetimibe, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in reverse phase gradient high performance liquid chromatography (HPLC) method and its molecular weight was determined by LC-MS analysis. The impurity was identified as (3R,4S)-3-((S)-3-(4 fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-1-phenylazetidin-2-one which is called desfluoro ezetimibe (lactam-related) impurity, synthesized and characterized, the mechanism of its formation was discussed in detail. After all standardization procedures, it was used as a reference standard during validation of HPLC method and routine analyses. In addition, content of Eze-1 desfluoro impurity in Eze-1 intermediates was specified as 0.10% to keep the formation of desfluoro ezetimibe impurity under control and the related substances HPLC method was validated accordingly. PMID- 29403951 TI - Quantification of tolvaptan in rabbit plasma by LC-MS/MS: Application to a pharmacokinetic study. AB - A sensitive, selective and high-throughput liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the quantitation of tolvaptan in rabbit plasma. Sample clean-up involved liquid liquid extraction (LLE) and chromatography was performed on Zorbax SB C18 analytical column (50 mm*2.1 mm, 3.5 um) using 0.1% formic acid:methanol (20:80, v/v) as the mobile phase. The parent->product ion transitions for the drug (m/z 449.2->252.1) and IS (m/z 456.2->259.2) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The method was validated over the concentration range of 0.10 1000.00 ng/mL and successfully applied to a pharmacokinetic study of healthy rabbits. PMID- 29403952 TI - Antimicrobial and antiproliferative prospective of kosinostatin - a secondary metabolite isolated from Streptomyces sp. AB - Cancer is a communal health hazard worldwide. The present investigation attempts to evaluate antimicrobial and anticancer potential of kosinostatin on mammary carcinoma cell line (MCF-7). The anticancer and antiproliferative activities of kosinostatin were analyzed on MCF cell line by MTT assay and cytotoxicity assays like lactate dehydrogenase (LDH) and glutathione (GSH). The secondary metabolite kosinostatin exhibited its apoptotic nature by expressing p53 protein. Collectively, the results acquired from this study promise that kosinostatin shows the potent anticancer activity. PMID- 29403953 TI - Optimization, validation and application of an assay for the activity of HMG-CoA reductase in vitro by LC-MS/MS. AB - A stable HMG-CoA reductase (HMGR) reaction in vitro was developed by a sensitive, selective and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The optimized enzyme reaction condition contained 1.5 MUg of HMGR, 20 nM of NADPH with 50 min of reaction time. The method was validated by several intra- and inter-day assays. The production transitions of m/z 147.0/59.1 and m/z 154.0/59.1 were used to detect and quantify mevalonolactone (MVAL) and MVAL-D7, respectively. The accuracy and precision of the method were evaluated over the concentration range of 0.005-1.000 MUg/mL for MVAL and 0.010-0.500 MUg/mL for lovastatin acid in three validation batch runs. The lower limit of quantitation was found to be 0.005 MUg/mL for MVAL and 0.010 MUg/mL for lovastatin acid. Intra day and inter-day precision ranged from 0.95% to 2.39% and 2.26% to 3.38% for MVAL, 1.46% to 3.89% and 0.57% to 5.10% for lovastatin acid, respectively. The results showed that the active ingredients in Xuezhikang capsules were 12.2 and 14.5 mg/g, respectively. This assay method could be successfully applied to the quality control study of Xuezhikang capsule for the first time. PMID- 29403954 TI - In vitro-in vivo studies of the quantitative effect of calcium, multivitamins and milk on single dose ciprofloxacin bioavailability. AB - Ciprofloxacin, commonly used in India as an anti-microbial for prolonged use in chronic and non-specific indications, may affect the bioavailability of the drug. The drug prescribed is commonly taken with multivitamins, calcium and milk. A simple and reliable analytical methodology obtaining a correlation with in vivo urinary excretion studies using UV and HPLC and in vitro dissolution studies (IVIVC) has shown a significant increase in elimination rate of ciprofloxacin co administered with multivitamins, calcium and milk. Appreciable IVIVC results proved that dissolution studies could serve as an alternative to in vivo bioavailability and also support bio-waivers. PMID- 29403955 TI - Comparative study of adsorptive role of carbonaceous materials in removal of UV active impurities of paclitaxel extracts. AB - Graphite oxide (GO) and reduced graphene oxide (rGO) nanosheets were synthesized with a low-cost manufacturing method. The morphology and structures of the synthesized samples were studied using X-ray diffraction (XRD), atomic force microscopy (AFM), Fourier-transform infrared (FTIR) and Raman spectroscopy. The efficiencies of GO and rGO as novel candidate adsorbents in the pre-purification of paclitaxel were compared and contrasted with those of commercial graphite (Gt), graphene (G) and multi-wall carbon nanotube (MWCNT). According to UV-vis and HPLC analyses, rGO was evaluated as the best absorbent for the removal of impurities in pre-purification of paclitaxel from plant cell cultures. In contrast, the GO had the poorest proficiency for paclitaxel pre-purification in comparison with the other carbonaceous adsorbents. This is attributed to the existence of many localized defects in the pi-structure of GO that is related to weakness of pi-pi stacking interactions between crude extract impurities and GO. PMID- 29403957 TI - Simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation by ultra-high performance liquid chromatography coupled with nano quantity analyte detector. AB - A novel method for simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation was developed using ultra-high performance liquid chromatography coupled with a nano quantitation analytical detector (UHPLC-NQAD). All components in kolliphor HS15 and miglyol 812 were well separated on an Acquity BEH C18 column. Mobile phase A was 0.1% trifluoroacetic acid (TFA) in water and mobile phase B was acetonitrile. A gradient elution sequence was programed initially with 60% organic solvent, slowly increased to 100% within 8 min. The flow rate was 0.7 mL/min. Good linearity (r>0.95) was obtained in the range of 27.6-1381.1 MUg/mL for polyoxyl 15 hydroxystearate in kolliphor HS15, 0.8-202.0 MUg/mL for caprylic acid triglyceride and 2.7-221.9 MUg/mL for capric acid triglyceride in miglyol 812. The relative standard deviations (RSD) ranged from 0.6% to 1.7% for intra-day precision and from 0.4% to 2.7% for inter-day precision. The overall recoveries (accuracy) were 99.7%-101.4% for polyoxyl 15 hydroxystearate in kolliphor HS15, 96.7%-99.6% for caprylic acid triglyceride, and 94.1%-103.3% for capric acid triglyceride in miglyol 812. Quantification limits (QL) were determined as 27.6 MUg/mL for polyoxyl 15 hydroxystearate in kolliphor HS15, 0.8 MUg/mL for caprylic acid triglyceride, and 2.7 MUg/mL for capric acid triglyceride in miglyol 812. No interferences were observed in the retention time ranges of kolliphor HS15 and miglyol 812. The method was validated in terms of specificity, linearity, precision, accuracy, QL, and robustness. The proposed method has been applied to microemulsion formulation analyses with good recoveries (82.2%-103.4%). PMID- 29403956 TI - Significance and challenges of stereoselectivity assessing methods in drug metabolism. AB - Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug-drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D) and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs) is expensive. As a detector of chromatographic methods, mass spectrometry (MS) is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR) and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism. PMID- 29403958 TI - LC-HRMS determination of piperine on rat dried blood spots: A pharmacokinetic study. AB - A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed and validated for the determination of piperine (PPR) on dried blood spots (DBS). DBS samples were prepared by spiking the whole blood with analyte to produce 30 uL of blood spots on specimen collection cards. Chromatographic separation was achieved on an Atlantis dC18 column using acetonitrile and water (0.1% formic acid) (85:15, v/v) as mobile phase in an isocratic mode of elution at a flow rate of 0.75 mL/min. MS detection was carried out in electrospray positive ion mode for the target ions and monitored at m/z 286.1465 for PPR and 272.1303 for the internal standard (IS). The developed method exhibited a linear dynamic range over 0.01-2000 ng/mL for PPR on DBS. The overall extraction recovery of PPR from DBS was 92.5%. Influence of hematocrit and spot volume on DBS was also evaluated and found to be well within the acceptable limits. The method was successfully applied to pharmacokinetic studies of PPR in rats. PMID- 29403959 TI - Implementation of a single quad MS detector in routine QC analysis of peptide drugs. AB - A newly developed single quad mass spectrometry (MS) detector was coupled to a ultra-high performance liquid chromatography (UPLC) system and implemented in the routine quality control (QC) and impurity analysis of four therapeutic peptides, namely bleomycin sulfate, tyrothricin, vancomycin HCl and bacitracin, which were selected given their multi-component drug nature and their closely structurally related impurity profiles. The QC and impurity profiling results obtained using the ultra-high performance liquid chromatography ultraviolet/mass spectrometry (UPLC-UV/MS) detection system were analyzed against the results obtained using traditional high performance liquid chromatography-ultraviolet detection (HPLC UV) methods derived from pharmacopoeial methods. In general, the used stationary phases of sub-2 um particle (UPLC) technology resulted in lower limits of detection and higher resolution separations, which resulted in more detected impurities and shorter overall run times contrasting the traditional HPLC columns. Moreover, online coupling with a single quad MS detector allowed direct peak identification of the main compounds as well as small impurities, hereby increasing the information content without the need of reference standards. PMID- 29403960 TI - Application of a UPLC-MS/MS method to the protein binding study of TM-2 in rat, human and beagle dog plasma. AB - TM-2 known as a potential antitumor drug is a novel semi-synthetic taxane derivative. As drug-protein interactions contribute to insights into pharmacokinetic and pharmacodynamic properties, we elucidated the binding of TM-2 to plasma protein. In this study, a simple, rapid and reliable method was developed and validated employing equilibrium dialysis for the separation of bound and unbound drugs and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the quantitation. Protein binding reached equilibrium within 24 h of incubation at 37 degrees C. After liquid-liquid extraction with methyl tert-butyl ether, the samples were separated on Thermo Syncronis UPLC(r) C18 (2.1 mm*50 mm, 1.7 um), and acquisition of mass spectrometric data was performed in multiple reaction monitoring (MRM) mode via positive electrospray ionization. The assay was linear over the concentration rang of 5-2000 ng/mL. The intra- and inter-day precisions were 0.1%-14.8%, and the accuracy was from -6.4% to 7.0%. This assay has been successfully applied to a protein binding study of TM-2 in rat, human and beagle dog plasma. TM-2 showed high protein binding of 81.4%+/-6.5% (rat), 87.9%+/-3.6% (human) and 79.4%+/-4.0% (beagle dog). The results revealed that there was an insignificant difference among the three species. PMID- 29403961 TI - The synthesis of boronic-imine structured compounds and identification of their anticancer, antimicrobial and antioxidant activities. AB - Boronic acid compounds with different substituted groups were handled to synthesize various ligands encoded as B1, B2, B3, B4, B5, B6, B7 and B8. B5 and B7 were tested for the cytotoxic activity against the prostate cancer cells and it was found that the cell viability of cancer cells was decreased while most of the healthy cells could still be viable. 5 uM solutions of B5 and B7 decreased the cell viability to 33% and 44% whereas healthy cells were 71% and 95%, respectively, after treatment. Antimicrobial properties were explored against the bacterial and fungal microorganisms with B1, B5 and B7. The inhibition zones were evaluated for all boronic structures, and the growth inhibition zones were determined in a range of 7-13 mm diameter for different microorganism species. Staphylococcus aureus was the common microorganism that three boronic compounds with imine ligands showed the activity. Antioxidant features of B2, B3, B4, B5, B6, B7 and B8 were investigated by different processes such as Beta-carotene bleaching (BCB), 2,2-diphenyl picryl hydrazyl (DPPH), 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS) and CUPric reducing antioxidant capacity (CUPRAC) methods. Significant antioxidant activity was achieved by the phenyl boronic based ligands and these compounds demonstrated as much activity as standards (alpha-Toc and BHT). In addition, all structures were applied properly without any decomposition during the experiments. They were rather stable both in aqueous media and solid state. PMID- 29403962 TI - Dissolution method for delapril and manidipine combination tablets based on an absorption profile of manidipine. AB - The present study describes the development and validation of a dissolution method for delapril (DEL) and manidipine (MAN) combination tablets, using a simulated absorption profile based on in vivo data for MAN. The suitable in vitro dissolution profile for this formulation was obtained using 900 mL of citrate buffer pH 3.2 at 37 degrees C+/-0.5 degrees C as dissolution medium and USP apparatus 2 (paddle) at 75 rpm. All samples were analyzed by a liquid chromatography (LC) method. Under these conditions, a significant linear relationship between the absorbed (calculated by deconvolution approach) and dissolved fractions of MAN was obtained (R=0.997) and an in vivo-in vitro (IVIV) correlation for this particular formulation containing MAN can be established. Validation parameters for dissolution methodology such as the specificity, linearity, accuracy and precision were also evaluated according to the international guidelines, giving results within the acceptable range. Therefore, the proposed dissolution conditions can be applied for the simultaneous release analysis of DEL and MAN from the solid dosage form, contributing to the improvement of the quality control of pharmaceutics and minimizing the number of bioavailability studies. PMID- 29403963 TI - Spectroscopic analysis on the binding interaction of biologically active pyrimidine derivative with bovine serum albumin. AB - A biologically active antibacterial reagent, 2-amino-6-hydroxy-4-(4-N, N dimethylaminophenyl)-pyrimidine-5-carbonitrile (AHDMAPPC), was synthesized. It was employed to investigate the binding interaction with the bovine serum albumin (BSA) in detail using different spectroscopic methods. It exhibited antibacterial activity against Escherichia coli and Staphylococcus aureus which are common food poisoning bacteria. The experimental results showed that the fluorescence quenching of model carrier protein BSA by AHDMAPPC was due to static quenching. The site binding constants and number of binding sites (n~1) were determined at three different temperatures based on fluorescence quenching results. The thermodynamic parameters, enthalpy change (DeltaH), free energy (DeltaG) and entropy change (DeltaS) for the reaction were calculated to be 15.15 kJ/mol, 36.11 kJ/mol and 51.26 J/mol K according to van't Hoff equation, respectively. The results indicated that the reaction was an endothermic and spontaneous process, and hydrophobic interactions played a major role in the binding between drug and BSA. The distance between donor and acceptor is 2.79 nm according to Forster's theory. The alterations of the BSA secondary structure in the presence of AHDMAPPC were confirmed by UV-visible, synchronous fluorescence, circular dichroism (CD) and three-dimensional fluorescence spectra. All these results indicated that AHDMAPPC can bind to BSA and be effectively transported and eliminated in the body. It can be a useful guideline for further drug design. PMID- 29403964 TI - Optimization of wavelength range and data interval in chemometric analysis of complex pharmaceutical mixtures. AB - The performance of different chemometric approaches was evaluated in the spectrophotometric determination of pharmaceutical mixtures characterized by having the amount of components with a very high ratio. Principal component regression (PCR), partial least squares with one dependent variable (PLS1) or multi-dependent variables (PLS2), and multivariate curve resolution (MCR) were applied to the spectral data of a ternary mixture containing paracetamol, sodium ascorbate and chlorpheniramine (150:140:1, m/m/m), and a quaternary mixture containing paracetamol, caffeine, phenylephrine and chlorpheniramine (125:6. 25:1.25:1, m/m/m/m). The UV spectra of the calibration samples in the range of 200-320 nm were pre-treated by removing noise and useless data, and the wavelength regions having the most useful analytical information were selected using the regression coefficients calculated in the multivariate modeling. All the defined chemometric models were validated on external sample sets and then applied to commercial pharmaceutical formulations. Different data intervals, fixed at 0.5, 1.0, and 2.0 point/nm, were tested to optimize the prediction ability of the models. The best results were obtained using the PLS1calibration models and the quantification of the species of a lower amount was significantly improved by adopting 0.5 data interval, which showed accuracy between 94.24% and 107.76%. PMID- 29403966 TI - The pharmacokinetic study of rutin in rat plasma based on an electrochemically reduced graphene oxide modified sensor. AB - An electrochemical method based on a directly electrochemically reduced graphene oxide (ERGO) film coated on a glassy carbon electrode (GCE) was developed for the rapid and convenient determination of rutin in plasma. ERGO was modified on the surface of GCE by one-step electro-deposition method. Electrochemical behavior of rutin on ERGO/GCE indicated that rutin underwent a surface-controlled quasi reversible process and the electrochemical parameters such as charge transfer coefficient (alpha), electron transfer number (n) and electrode reaction standard rate constant (ks ) were 0.53, 2 and 3.4 s-1, respectively. The electrochemical sensor for rutin in plasma provided a wide linear response range of 4.70*10-7 1.25*10-5 M with the detection limit (s/n=3) of 1.84*10-8 M. The assay was successfully used to the pharmacokinetic study of rutin. The pharmacokinetic parameters such as elimination rate half-life (t1/2), area under curve (AUC), and plasma clearance (CL) were calculated to be 3.345+/-0.647 min, 5750+/-656.0 ug min/mL, and 5.891+/-0.458 mL/min/kg, respectively. The proposed method utilized a small sample volume of 10 MUL and had no complicated sample pretreatment (without deproteinization), which was simple, eco-friendly, and time- and cost-efficient for rutin pharmacokinetic studies. PMID- 29403965 TI - Methods for in vitro evaluating antimicrobial activity: A review. AB - In recent years, there has been a growing interest in researching and developing new antimicrobial agents from various sources to combat microbial resistance. Therefore, a greater attention has been paid to antimicrobial activity screening and evaluating methods. Several bioassays such as disk-diffusion, well diffusion and broth or agar dilution are well known and commonly used, but others such as flow cytofluorometric and bioluminescent methods are not widely used because they require specified equipment and further evaluation for reproducibility and standardization, even if they can provide rapid results of the antimicrobial agent's effects and a better understanding of their impact on the viability and cell damage inflicted to the tested microorganism. In this review article, an exhaustive list of in vitro antimicrobial susceptibility testing methods and detailed information on their advantages and limitations are reported. PMID- 29403967 TI - Determination of lercanidipine in human plasma by an improved UPLC-MS/MS method for a bioequivalence study. AB - An improved and reliable ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the determination of lercanidipine in human plasma. Plasma samples with lercanidipine d3 as an internal standard (IS) were prepared by solid phase extraction on Phenomenex Strata-X cartridges using 100 uL of human plasma. Chromatographic analysis was performed on UPLC BEH C18 (50 mm*2.1 mm, 1.7 um) column under isocratic conditions. Linear calibration curves were obtained over a wide dynamic concentration range of 0.010-20.0 ng/mL. Matrix effect was assessed by post column infusion, post-extraction spiking and standard-line slope methods. The mean extraction recovery was >94% for the analyte and IS. Inter-batch and intra batch precision (% CV) across five quality controls was <5.8%. Bioequivalence study was performed with 36 healthy subjects after oral administration of 10 mg of lercanidipine and the assay reproducibility was evaluated by reanalysis of 133 incurred samples. PMID- 29403968 TI - Determination of torasemide in human plasma and its bioequivalence study by high performance liquid chromatography with electrospray ionization tandem mass spectrometry. AB - A sensitive and selective method using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS) to determine the concentration of torasemide in human plasma samples was developed and validated. Tolbutamide was chosen as the internal standard (IS). The chromatography was performed on a Gl Sciences Inertsil ODS-3 column (100 mm*2.1 mm i.d., 5.0 um) within 5 min, using methanol with 10 mM ammonium formate (60:40, v/v) as mobile phase at a flow rate of 0.2 mL/min. The targeted compound was detected in negative ionization at m/z 347.00 for torasemide and 269.00 for IS. The linearity range of this method was found to be within the concentration range of 1-2500 ng/mL (r=0.9984) for torasemide in human plasma. The accuracy of this measurement was between 94.05% and 103.86%. The extracted recovery efficiency was from 84.20% to 86.47% at three concentration levels. This method was also successfully applied in pharmacokinetics and bioequivalence studies in Chinese volunteers. PMID- 29403969 TI - Optimized high performance liquid chromatography-ultraviolet detection method using core-shell particles for the therapeutic monitoring of methotrexate. AB - Methotrexate (MTX) is an antineoplastic drug, and due to its high toxicity, the therapeutic drug monitoring is strictly conducted in the clinical practice. The chemometric optimization and validation of a high performance liquid chromatography (HPLC) method using core-shell particles is presented for the determination of MTX in plasma during therapeutic monitoring. Experimental design and response surface methodology (RSM) were applied for the optimization of the chromatographic system and the analyte extraction step. A Poroshell 120 EC-C18 (3.0 mm*75 mm, 2.7 MUm) column was used to obtain a fast and efficient separation in a complete run time of 4 min. The optimum conditions for the chromatographic system resulted in a mobile phase consisting of acetic acid/sodium acetate buffer solution (85.0 mM, pH=4.00) and 11.2% of acetonitrile at a flow rate of 0.4 mL/min. Selectivity, linearity, accuracy and precision were demonstrated in a range of 0.10-6.0 uM of MTX. The application of the optimized method required only 150 uL of patient plasma and a low consumption of solvent to provide rapid results. PMID- 29403970 TI - Liquid chromatography-tandem mass spectrometry method for simultaneous determination of valproic acid and its ene-metabolites in epilepsy patient plasma. AB - A simple and high throughput method was developed and validated for simultaneous determination of valproic acid and its two toxicant ene-metabolites, 2 enevalproic acid and 4-enevalproic acid in epilepsy patient plasma using liquid chromatography-tandem mass spectrometry. Probenecid was used as internal standard and solid-phase extraction was selected for sample preparation. A chromatographic separation was performed on an Agilent Poroshell SB-C18 column (50 mm*4.6 mm i.d., 2.7 MUm) by an optimized gradient elution at a flow rate of 0.9 mL/min. The total run time was 7 min. Electrospray ionization was used in negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 143.0->143.0 for valproic acid, m/z 140.9->140.9 for 2-enevalproic acid and 4 enevalproic acid for their poor fragments, and m/z 283.9->239.9 for probenecid. The results showed good linearity of valproic acid, 2-enevalproic acid and 4 enevalproic acid in their respective linear ranges. The correlation coefficients were more than 0.998. The intra- and inter-day precision of the assay was less than 11.0% and the accuracy ranged from 2% to 12%. This analytical method was successfully applied to assay plasma concentrations of valproic acid and its two ene-metabolites in epilepsy patient plasma and used for therapeutic drug monitoring. PMID- 29403971 TI - Study and ICH validation of a reverse-phase liquid chromatographic method for the quantification of the intact monoclonal antibody cetuximab. AB - Cetuximab (CTX) is a potent chimeric mouse/human monoclonal antibody (mAb) approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses performed for full study on this biopharmaceutic, the determination of the concentration preparations throughout manufacturing and subsequent handling in hospital is particularly relevant. In the present work, the study and validation of a method for quantifying intact CTX by reverse-phase high-performance liquid chromatography with diode array detection ((RP)HPLC/DAD) is presented. With that end, we checked the performance of a chromatographic method for quantifying CTX and conducted a study to validate the method as stability-indicating in accordance with the International Conference on Harmonization guidelines (ICH) for biotechnological drugs; therefore, we evaluated linearity, accuracy, precision, detection and quantification limits, robustness and system suitability. The specificity of the method and the robustness of the mAb formulation against external stress factors were estimated by comprehensive chromatographic analysis by subjecting CTX to several informative stress conditions. As demonstrated, the method is rapid, accurate, and reproducible for CTX quantification. It was also successfully used to quantify CTX in a long-term stability study performed under hospital conditions. PMID- 29403972 TI - Free radical scavenging potential and HPTLC analysis of Indigofera tinctoria linn (Fabaceae). AB - The objective of this study was to evaluate the free radical scavenging potential and high performance thin layer chromatography (HPTLC) fingerprinting of Indigofera tinctoria (I. tinctoria). Phytochemical analysis was carried out using standard methods, and free radical scavenging activity of the plant was determined using 2,2-diphenyl-1-picrylhydrazy (DPPH), nitric oxide (NO) and superoxide anion ([Formula: see text]) radical scavenging capacities. HPTLC plate was kept in CAMAG TLC Scanner 3 and the Rf values at fingerprint data were recorded by WINCATS software. Aqueous extract of I. tinctoria reliably showed the total phenolics (267.2+/-2.42 mg/g), flavonoids (75.43+/-3.36 mg/g) and antioxidants (349.11+/-8.04 mg/g). The extract was found to have DPPH (52.08%), NO (23.12%) and [Formula: see text] (26.79%) scavenging activities at the concentration of 250 MUg/mL and the results were statistically significant compared with ascorbic acid standard (p<0.05). HPTLC results confirmed that the extract contained several potential active components such as phenols, flavonoids, saponins and terpenoids as the slides revealed multi-colored bands of varying intensities. This study confirmed that the plant had multipotential antioxidant and free radicals scavenging activities. PMID- 29403973 TI - Comparison of reversed-phase enantioselective HPLC methods for determining the enantiomeric purity of (S)-omeprazole in the presence of its related substances. AB - A simple analytical high-performance liquid chromatography (HPLC) method was applied for the enantiomeric excess determination of esomeprazole ((S)-OME), the enantiopure active ingredient contained in drug products, in the presence of its potential organic impurities A-E. The enantioselective separation was accomplished on the immobilized-type Chiralpak ID-3 chiral stationary phase (CSP) under reversed-phase conditions. The results were evaluated and compared with those obtained by the official enantioselective method of European Pharmacopoeia used as the reference for checking the enantiomeric excess of (S)-OME. It has been established that the use of the Chiralpak ID-3 CSP allows the determination of the enantiomeric purity of (S)-OME without any interference coming from its chiral and achiral related substances. The analytical procedure of the drug regulatory agencies based on the AGP CSP suffered instead from poor specificity due to overlap of the peaks pertinent to the achiral impurity A and the chiral impurity (R)-OME (impurity F). PMID- 29403974 TI - Analytical methods for determination of terbinafine hydrochloride in pharmaceuticals and biological materials. AB - Terbinafine is a new powerful antifungal agent indicated for both oral and topical treatment of mycosessince. It is highly effective in the treatment of determatomycoses. The chemical and pharmaceutical analysis of the drug requires effective analytical methods for quality control and pharmacodynamic and pharmacokinetic studies. Ever since it was introduced as an effective antifungal agent, many methods have been developed and validated for its assay in pharmaceuticals and biological materials. This article reviews the various methods reported during the last 25 years. PMID- 29403975 TI - Ion-pairing HPLC methods to determine EDTA and DTPA in small molecule and biological pharmaceutical formulations. AB - Ion-pairing high-performance liquid chromatography-ultraviolet (HPLC-UV) methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid (EDTA) in Abilify(r) (a small molecule drug with aripiprazole as the active pharmaceutical ingredient) oral solution and diethylenetriaminepentaacetic acid (DTPA) in Yervoy(r) (a monoclonal antibody drug with ipilimumab as the active pharmaceutical ingredient) intravenous formulation. Since the analytes, EDTA and DTPA, do not contain chromophores, transition metal ions (Cu2+, Fe3+) which generate highly stable metallocomplexes with the chelating agents were added into the sample preparation to enhance UV detection. The use of metallocomplexes with ion-pairing chromatography provides the ability to achieve the desired sensitivity and selectivity in the development of the method. Specifically, the sample preparation involving metallocomplex formation allowed sensitive UV detection. Copper was utilized for the determination of EDTA and iron was utilized for the determination of DTPA. In the case of EDTA, a gradient mobile phase separated the components of the formulation from the analyte. In the method for DTPA, the active drug substance, ipilimumab, was eluted in the void. In addition, the optimization of the concentration of the ion-pairing reagent was discussed as a means of enhancing the retention of the aminopolycarboxylic acids (APCAs) including EDTA and DTPA and the specificity of the method. The analytical method development was designed based on the chromatographic properties of the analytes, the nature of the sample matrix and the intended purpose of the method. Validation data were presented for the two methods. Finally, both methods were successfully utilized in determining the fate of the chelates. PMID- 29403976 TI - A novel surface molecularly imprinted polymer as the solid-phase extraction adsorbent for the selective determination of ampicillin sodium in milk and blood samples. AB - Surface molecularly imprinted polymers (SMIPs) for selective adsorption of ampicillin sodium were synthesized using surface molecular imprinting technique with silica gel as a support. The physical and morphological characteristics of the polymers were investigated by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), elemental analysis and nitrogen adsorption-desorption test. The obtained results showed that the SMIPs displayed great adsorption capacity (13.5 MUg/mg), high recognition ability (the imprinted factor is 3.2) and good binding kinetics for ampicillin sodium. Finally, as solid phase extraction adsorbents, the SMIPs coupled with HPLC method were validated and applied for the enrichment, purification and determination of ampicillin sodium in real milk and blood samples. The averages of spiked accuracy ranged from 92.1% to 107.6%. The relative standard deviations of intra- and inter-day precisions were less than 4.6%. This study provides a new and promising method for enriching, extracting and determining ampicillin sodium in complex biological samples. PMID- 29403977 TI - Molecular dynamics of amorphous pharmaceutical fenofibrate studied by broadband dielectric spectroscopy. AB - Fenofibrate is mainly used to reduce cholesterol level in patients at risk of cardiovascular disease. Thermal transition study with the help of differential scanning calorimetry (DSC) shows that the aforesaid active pharmaceutical ingredient (API) is a good glass former. Based on our DSC study, the molecular dynamics of this API has been carried out by broadband dielectric spectroscopy (BDS) covering wide temperature and frequency ranges. Dielectric measurements of amorphous fenofibrate were performed after its vitrification by fast cooling from a few degrees above the melting point (Tm=354.11 K) to deep glassy state. The sample does not show any crystallization tendency during cooling and reaches the glassy state. The temperature dependence of the structural relaxation has been fitted by single Vogel-Fulcher-Tamman (VFT) equation. From VFT fit, glass transition temperature (Tg) was estimated as 250.56 K and fragility (m) was determined as 94.02. This drug is classified as a fragile glass former. Deviations of experimental data from Kohlrausch-Williams-Watts (KWW) fits on high frequency flank of alpha-peak indicate the presence of an excess wing in fenofibrate. Based on Ngai's coupling model, we identified the excess wing as true Johari-Goldstein (JG) process. Below the glass transition temperature one can clearly see a secondary relaxation (gamma) with an activation energy of 32.67 kJ/mol. PMID- 29403978 TI - On-line near-infrared spectroscopy optimizing and monitoring biotransformation process of gamma-aminobutyric acid. AB - Near-infrared spectroscopy (NIRS) with its fast and nondestructive advantages can be qualified for the real-time quantitative analysis. This paper demonstrates that NIRS combined with partial least squares (PLS) regression can be used as a rapid analytical method to simultaneously quantify l-glutamic acid (l-Glu) and gamma-aminobutyric acid (GABA) in a biotransformation process and to guide the optimization of production conditions when the merits of NIRS are combined with response surface methodology. The high performance liquid chromatography (HPLC) reference analysis was performed by the o-phthaldialdehyde pre-column derivatization. NIRS measurements of two batches of 141 samples were firstly analyzed by PLS with several spectral pre-processing methods. Compared with those of the HPLC reference analysis, the resulting determination coefficients (R2), root mean square error of prediction (RMSEP) and residual predictive deviation (RPD) of the external validation for the l-Glu concentration were 99.5%, 1.62 g/L, and 11.3, respectively. For the GABA concentration, R2, RMSEP, and RPD were 99.8%, 4.00 g/L, and 16.4, respectively. This NIRS model was then used to optimize the biotransformation process through a Box-Behnken experimental design. Under the optimal conditions without pH adjustment, 200 g/L l-Glu could be catalyzed by 7148 U/L glutamate decarboxylase (GAD) to GABA, reaching 99% conversion at the fifth hour. NIRS analysis provided timely information on the conversion from l-Glu to GABA. The results suggest that the NIRS model can not only be used for the routine profiling of enzymatic conversion, providing a simple and effective method of monitoring the biotransformation process of GABA, but also be considered to be an optimal tool to guide the optimization of production conditions. PMID- 29403979 TI - Monitoring real time polymorphic transformation of sulfanilamide by diffuse reflectance visible spectroscopy. AB - This study investigated the development of a novel approach to surface characterization of drug polymorphism and the extension of the capabilities of this method to perform 'real time' in situ measurements. This was achieved using diffuse reflectance visible (DRV) spectroscopy and dye deposition, using the pH sensitive dye, thymol blue (TB). Two polymorphs, SFN-beta and SFN-gamma, of the drug substance sulfanilamide (SFN) were examined. The interaction of adsorbed dye with polymorphs showed different behavior, and thus reported different DRV spectra. Consideration of the acid/base properties of the morphological forms of the drug molecule provided a rationalization of the mechanism of differential coloration by indicator dyes. The kinetics of the polymorphic transformation of SFN polymorphs was monitored using treatment with TB dye and DRV spectroscopy. The thermally-induced transformation fitted a first-order solid-state kinetic model (R2=0.992), giving a rate constant of 2.43*10-2 s-1. PMID- 29403980 TI - Development of an LC-MS/MS method for the quantitation of deoxyglycychloxazol in rat plasma and its application in pharmacokinetic study. AB - Deoxyglycychloxazol (TY501) is a glycyrrhetinic acid derivative which exhibits high anti-inflammatory activity and reduced pseudoaldosteronism compared to glycyrrhetinic acid. In this study, a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the quantitation of TY501 in rat plasma. Plasma samples were treated by precipitating protein with methanol and supernatants were separated by a Symmetry C8 column with the mobile phase consisting of methanol and 10 mM ammonium formate (containing 0.1% of formic acid) (90:10, v/v). The selected reaction monitoring (SRM) transitions were performed at m/z 647.4->191.2 for TY501 and m/z 473.3->143.3 for astragaloside aglycone (IS) in the positive ion mode with atmospheric pressure chemical ionization (APCI) source. Calibration curve was linear over the concentration range of 5-5000 ng/mL. The lower limit of quantification was 5 ng/mL. The mean recovery was over 88%. The intra- and inter-day precisions were lower than 6.0% and 12.8%, respectively, and the accuracy was within +/-1.3%. TY501 was stable under usual storage conditions and handling procedure. The validated method has been successfully applied to a pharmacokinetic study after oral administration of TY501 to rats at a dosage of 10 mg/kg. PMID- 29403981 TI - Development and validation of a high throughput UPLC-MS/MS method for simultaneous quantification of esomeprazole, rabeprazole and levosulpiride in human plasma. AB - A high throughput ultra pressure liquid chromatography-mass spectrometry (UPLC MS/MS) method with good sensitivity and selectivity has been developed and validated for simultaneous quantification of esomeprazole, rabeprazole and levosulpiride in human plasma using lansoprazole as internal standard (IS). The extraction method based on liquid-liquid extraction technique was used to extract the analytes and IS from of 50 uL of human plasma using methyl tert-butyl ether:ethyl acetate (80:20, v/v), which offers a high recovery. Chromatographic separation of analytes and IS was achieved on a Hypersil gold C18 column using gradient mobile phase consisting of 2 mM ammonium formate/acetonitrile. The flow rate was set at 0.5 mL/min to elute all the analytes and IS within 1.00 min runtime. Detection of target compounds was performed on a triple quadruple mass spectrometer by multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). Method validation results demonstrated that the developed method has good precision and accuracy over the concentration ranges of 0.1-2000 ng/mL for each analyte. Stability of compounds was established in a battery of stability studies, i.e., bench top, autosampler, dry extract and long-term storage stability as well as freeze-thaw cycles. The validated method has been successfully applied to analyze human plasma samples for application in pharmacokinetic studies. PMID- 29403982 TI - Simultaneous determination of doxorubicin and its dipeptide prodrug in mice plasma by HPLC with fluorescence detection. AB - A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC-FD) has been developed for simultaneous quantification of doxorubicin (DOX) and its dipeptide conjugate prodrug (PDOX) in mice plasma. The chromatographic separation was carried out on an Amethyst C18-H column with gradient mobile phase of 0.1% formic acid and 0.1% formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity (R2>0.999) over the concentration ranges. The extraction recoveries ranged from 84.0% to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC-FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX. PMID- 29403983 TI - Preliminary assessment of two non-destructive instrumental techniques for quality evaluation of Lobelia chinensis Lour. AB - Two non-destructive instrumental methods, infrared spectroscopy (IR) and X-ray diffraction (XRD), were studied for quality evaluation of Lobelia chinensis Lour. (L. chinensis). We obtained the IR spectra and XRD patterns of L. chinensis collected from different sources. The similarity of samples was analyzed by calculating the cosine coefficient. The cosine values were in the range of 0.83 0.90, indicating that the main components of L. chinensis samples are similar. Sample L1 and L6 showed a slightly lower similarity than that of L2, L3, L4, L5 detected by the two methods, which revealed that IR and XRD methods exhibited analogous detection ability for quality evaluation of L. chinensis. The two methods could be highly recommended as simple and rapid detection means for quality evaluation of L. chinensis. PMID- 29403984 TI - Selection of appropriate analytical tools to determine the potency and bioactivity of antibiotics and antibiotic resistance. AB - Antibiotics are the chemotherapeutic agents that kill or inhibit the pathogenic microorganisms. Resistance of microorganism to antibiotics is a growing problem around the world due to indiscriminate and irrational use of antibiotics. In order to overcome the resistance problem and to safely use antibiotics, the correct measurement of potency and bioactivity of antibiotics is essential. Microbiological assay and high performance liquid chromatography (HPLC) method are used to quantify the potency of antibiotics. HPLC method is commonly used for the quantification of potency of antibiotics, but unable to determine the bioactivity; whereas microbiological assay estimates both potency and bioactivity of antibiotics. Additionally, bioassay is used to estimate the effective dose against antibiotic resistant microbes. Simultaneously, microbiological assay addresses the several parameters such as minimal inhibitory concentration (MIC), minimum bactericidal concentration (MBC), mutation prevention concentration (MPC) and critical concentration (Ccr) which are used to describe the potency in a more informative way. Microbiological assay is a simple, sensitive, precise and cost effective method which gives reproducible results similar to HPLC. However, the HPLC cannot be a complete substitute for microbiological assay and both methods have their own significance to obtain more realistic and precise results. PMID- 29403985 TI - Determination of reactive oxygen generated from natural medicines and their antibacterial activity. AB - Extracts of 16 natural medicine powders (Galla chinensis, Malloti cortex, Cassiae semen, Sophorae radix, Myricae cortex, Crataegi fructus, Gambir, Mume fructus, Geranii herba, Phellodendri cortex, Coptidis rhizoma, Swertiae herba, and Cinnamomi cortex) were assayed for reactive oxygen concentrations using the peroxyoxalate chemiluminescent detection system. High luminescence intensity was observed in Galla chinensis, Geranii herba, Malloti cortex, Myricae cortex, and Cinnamomi cortex. Additional experiments identified the reactive oxygen species as hydrogen peroxide. Galla chinensis generated 2.4*10-4 mol/L hydrogen peroxide from a 1 mg/mL solution. In bacterial growth tests, Galla chinensis extract had antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacteroides thetaiotaomicron, Campylobacter sputorum biovar sputorum, Streptococcus salivarius thermophilus, Lactobacillus casei, and Bifidobacterium longum infantis. This antibacterial activity was decreased by the addition of catalase. It revealed that hydrogen peroxide which Galla chinensis produced participated in antibacterial activity. PMID- 29403986 TI - Determination of 6258-70, a new semi-synthetic taxane, in rat plasma and tissues: Application to the pharmacokinetics and tissue distribution study. AB - Cancer is the leading cause of death all over the world. Among the chemotherapy drugs, taxanes play an important role in cancer treatment. 6258-70 is a new semi synthetic taxane which has a broad spectrum of antitumor activity. A fast and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) method was developed for quantification of 6258-70 in rat plasma and tissues in this paper. After extraction by liquid-liquid extraction method with methyl tert-butyl ether, the samples were separated on a Kinetex C18 column (50 mm*2.1 mm, 2.6 um, Phenomenex, USA) within 3 min. The method was fully validated with the matrix effect between 87.7% and 99.5% and the recovery ranging from 80.3% to 90.1%. The intra- and inter-day precisions were less than 9.5% and the accuracy ranged from -3.8% to 6.5%. The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats. The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg, and there was no significant difference between the two genders. The tissue distribution study showed that 6258-70 had an effective penetration, spread widely and rapidly and could cross blood-brain barrier. The results of pharmacokinetics and tissue distribution may provide a guide for future study. PMID- 29403987 TI - Liquid chromatography--tandem mass spectrometry method for simultaneous determination of albendazole and albendazole sulfoxide in human plasma for bioequivalence studies. AB - An improved high performance liquid chromatography--tandem mass spectrometry (LC MS/MS) method has been developed for sensitive and rapid determination of albendazole (ABZ) and its active metabolite, albendazole sulfoxide (ABZSO), in the positive ionization mode. The method utilized solid phase extraction (SPE) for sample preparation of the analytes and their deuterated internal standards (ISs) from 100 uL human plasma. The chromatography was carried out on Hypurity C18 column using acetonitrile-2.0 mM ammonium acetate, pH 5.0 (80:20, v/v) as the mobile phase. The assay exhibited a linear response over the concentration range of 0.200-50.0 ng/mL for ABZ and 3.00-600 ng/mL for ABZSO. The recoveries of the analytes and ISs ranged from 86.03%-89.66% and 89.85%-98.94%, respectively. Matrix effect, expressed as IS-normalized matrix factors, ranged from 0.985 to 1.042 for the both analytes. The method was successfully applied for two separate studies in healthy subjects using single dose of 400 mg conventional tablets and 400 mg chewable ABZ tablets, respectively. PMID- 29403988 TI - Graphene quantum dot modified glassy carbon electrode for the determination of doxorubicin hydrochloride in human plasma. AB - Low toxic graphene quantum dot (GQD) was synthesized by pyrolyzing citric acid in alkaline solution and characterized by ultraviolet--visible (UV-vis) spectroscopy, X-ray diffraction (XRD), atomic force microscopy (AFM), spectrofluorimetery and dynamic light scattering (DLS) techniques. GQD was used for electrode modification and electro-oxidation of doxorubicin (DOX) at low potential. A substantial decrease in the overvoltage (-0.56 V) of the DOX oxidation reaction (compared to ordinary electrodes) was observed using GQD as coating of glassy carbon electrode (GCE). Differential pulse voltammetry was used to evaluate the analytical performance of DOX in the presence of phosphate buffer solution (pH 4.0) and good limit of detection was obtained by the proposed sensor. Such ability of GQD to promote the DOX electron-transfer reaction suggests great promise for its application as an electrochemical sensor. PMID- 29403989 TI - The thermal and storage stability of bovine haemoglobin by ultraviolet-visible and circular dichroism spectroscopies. AB - The effects of temperature, pH and long-term storage on the secondary structure and conformation changes of bovine haemoglobin (bHb) were studied using circular dichroism (CD) and ultraviolet--visible (UV-vis) spectroscopies. Neural network software was used to deconvolute the CD data to obtain the fractional content of the five secondary structures. The storage stability of bHb solutions in pH 6, 7 and 8 buffers was significantly higher at 4 degrees C than at 23 degrees C for the first 3 days. A complete denaturation of bHb was observed after 40 days irrespective of storage temperature or pH. The bHb solutions were also exposed to heating and cooling cycles between 25 and 65 degrees C and structural changes were followed by UV-vis and CD spectroscopies. These experiments demonstrated that alpha-helix content of bHb decreased steadily with the increasing temperature above 35 degrees C at all pH values. The loss in alpha-helicity and gain in random coil conformations was pH-dependent and the greatest under alkaline conditions. Furthermore, there was minimal recovery of the secondary structure content upon cooling to 25 degrees C. The use of bHb as a model drug is very common and this study elucidates the significance of storage and processing conditions on its stability. PMID- 29403990 TI - Quality evaluation of Huaijiao pill by chromatographic fingerprint and simultaneous determination of its major bioactive components. AB - For quality control purpose, an approach of combining chromatographic fingerprint of Huaijiao pill (HP) and simultaneous determination of its major bioactive components was developed using high performance liquid chromatography coupled with diode array detector (HPLC--DAD). For fingerprint analysis, 16 peaks were selected as the characteristic peaks to evaluate the similarities of different samples collected from different batches of three manufacturers. The similarities of 17 Huaijiao pill samples were beyond 0.966, indicating that samples from different batches and manufacturers were, to some extent, consistent. Additionally, simultaneous quantification of seven bioactive markers, namely sophoricoside, baicalin, naringin, genistein, rutin, quercetin and 5-O methylvisammioside, in HP was performed to interpret the quality consistency. The validation of the proposed approach was acceptable, with the accuracy of 90.2% 106.9% in recovery test. The intra-day and inter-day precisions of the method were evaluated and the RSD values were less than 2.81%. The results from the quantitative data showed that the contents of six marker compounds (except for 5 O-methylvisammioside) were quite consistent between batches produced by one manufacturer and significantly distinctive among different manufacturers. The proposed approach was expected to be developed as a powerful tool for the quality control of HP. PMID- 29403991 TI - Effects of urea, metal ions and surfactants on the binding of baicalein with bovine serum albumin. AB - The interaction of baicalein with bovine serum albumin (BSA) was investigated with the help of spectroscopic and molecular docking studies. The binding affinity of baicalein towards BSA was estimated to be in order of 105 M-1 from fluorescence quenching studies. Negative DeltaH degrees (-5.66+/-0.14 kJ/mol) and positive (DeltaS degrees ) (+79.96+/-0.65 J/mol K) indicate the presence of electrostatic interactions along with the hydrophobic forces that result in a positive DeltaS degrees . The hydrophobic association of baicalein with BSA diminishes in the presence of sodium dodecyl sulfate (SDS) due to probable hydrophobic association of baicalein with SDS, resulting in a negative DeltaS degrees (-40.65+/-0.87 J/mol K). Matrix-assisted laser desorption ionization/time of flight (MALDI--TOF) experiments indicate a 1:1 complexation between baicalein and BSA. The unfolding and refolding phenomena of BSA were investigated in the absence and presence of baicalein using steady-state and fluorescence lifetime measurements. It was observed that the presence of urea ruptured the non-covalent interaction between baicalein and BSA. The presence of metal ions (Ag+, Mg2+, Ni2+, Mn2+, Co2+and Zn2+) increased the binding affinity of ligand towards BSA. The changes in conformational aspects of BSA after ligand binding were also investigated using circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopic techniques. Site selectivity studies following molecular docking analyses indicated the binding of baicalein to site 1 (subdomain IIA) of BSA. PMID- 29403992 TI - Validation of a liquid chromatographic method for the pharmaceutical quality control of products containing elacridar. AB - Many anticancer drugs have an impaired bioavailability and poor brain penetration because they are substrates to drug efflux pumps such as P-glycoprotein and Breast Cancer Resistance Protein. Elacridar is a strong inhibitor of these two drug efflux pumps and therefore has great potential to improve oral absorption and brain penetration of many anticancer drugs. Currently, a clinical formulation of elacridar is unavailable and therefore the pharmaceutical development of a drug product is highly warranted. This also necessitates the availability of an analytical method for its quality control. A reverse-phase high-performance liquid chromatographic method with ultraviolet detection was developed for the pharmaceutical quality control of products containing elacridar as the active pharmaceutical ingredient. The analytical method was validated for linearity, accuracy, precision, selectivity, carry-over, stability of stock and reference solutions, stability of the final extract, stability-indicating capability and impurity testing. We found that elacridar is unstable in aqueous solutions that are exposed to light because a hydroxylation product of elacridar is formed. Therefore, sample solutions with elacridar must be protected from light. PMID- 29403993 TI - SPE-UPLC-MS/MS assay for determination of letrozole in human plasma and its application to bioequivalence study in healthy postmenopausal Indian women. AB - A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method is described for determination of letrozole in human plasma. Following solid phase extraction (SPE) of letrozole and letrozole d4 on Orochem DVB-LP cartridges, chromatography was performed on Acquity UPLC BEH C18 (50 mm*2.1 mm, 1.7 um) column using methanol-0.1% formic acid in water (85:15, v/v) as the mobile phase. Detection was carried out on a triple quadrupole mass spectrometer with an electrospray source, operated under positive ionization mode. Quantitation of letrozole and letrozole-d4 was done using multiple reaction monitoring (MRM) following the transitions at m/z 286.2->217.0 and m/z 290.2->221.0, respectively. The calibration plots were linear through the concentration range of 0.10-100 ng/mL (r2>=0.9990) using 100 uL human plasma. The extraction recovery of letrozole ranged from 94.3% to 96.2% and the intra-batch and inter-batch precision was <=5.2%. The method was successfully applied to a bioequivalence study of letrozole after oral administration of 2.5 mg tablet formulation to 16 healthy postmenopausal Indian women. The assay reproducibility was also established through incurred sample reanalysis (ISR) of 74 subject samples. PMID- 29403994 TI - Development of a physiologically relevant dripping analytical method using simulated nasal mucus for nasal spray formulation analysis. AB - Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography (TLC) substrate. The dripping behavior of nasal formulations containing a range of 1% Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray. PMID- 29403995 TI - Detection of phthalates migration from disposable tablewares to drinking water using hexafluoroisopropanol-induced catanionic surfactant coacervate extraction. AB - Hexafluoroisopropanol (HFIP)-induced sodium dodecyl sulfate/dodecyltrimethylammonium bromide (SDS/DTAB) catanionic surfactant coacervate extraction method coupled with high performance liquid chromatography (HPLC) was used to detect the migration of phthalates from disposable tablewares to drinking water. The concentration factors are larger than 82 and extraction recoveries over 53% for water samples spiked with 100 or 200 ng/mL phthalates. Limit of detection is in the range of 1.0-2.6 ng/mL. Good linearity with correlation coefficients larger than 0.9985 is obtained in the concentration of 20-1500 or 40-3000 ng/mL. Relative recoveries are from 82.4% to 123.6% for water samples spiked with 30/60, 250/500, and 1500/3000 ng/mL phthalates, respectively. Relative standard deviations (RSDs) are 0.4%-7.4% for intraday precision (n=5) and 0.6%-7.8% for interday precision (n=3). Four of studied phthalates are found in the drinking water samples prepared from four kinds of tablewares. PMID- 29403996 TI - Inclusion complexes of cefuroxime axetil with beta-cyclodextrin: Physicochemical characterization, molecular modeling and effect of l-arginine on complexation. AB - The inclusion complexes of poorly water-soluble cephalosporin, cefuroxime axetil (CFA), were prepared with beta-cyclodextrin (betaCD) with or without addition of l-arginine (ARG) to improve its physicochemical properties. We also investigated the effect of ARG on complexation efficiency (CE) of betaCD towards CFA in an aqueous medium through phase solubility behaviour according to Higuchi and Connors. Although phase solubility studies showed AL (linear) type of solubility curve in presence and absence of ARG, the CE and association constant (Ks) of betaCD towards CFA were significantly promoted in presence of ARG, justifying its use as a ternary component. The solid systems of CFA with betaCD were obtained by spray drying technique with or without incorporation of ARG and characterized by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM), and saturation solubility and dissolution studies. The molecular modeling studies provided a better insight into geometry and inclusion mode of CFA inside betaCD cavity. The solubility and dissolution rate of CFA were significantly improved upon complexation with betaCD as compared to CFA alone. However, ternary system incorporated with ARG performed better than binary system in physicochemical evaluation. In conclusion, ARG could be exploited as a ternary component to improve the physicochemical properties of CFA via betaCD complexation. PMID- 29403997 TI - Analysis of residual crosslinking agent content in UV cross-linked poly(ethylene oxide) hydrogels for dermatological application by gas chromatography. AB - Acrylates have been widely used in the synthesis of pharmaceutical polymers. The quantitation of residual acrylate monomers is vital as they are strong irritants and allergens, but after polymerization, are relatively inert, causing no irritation and allergies. Poly(ethylene oxide) (PEO) hydrogels were prepared using pentaerythritol tetra-acrylate (PETRA) as UV crosslinking agent. A simple, accurate, and robust quantitation method was developed based on gas chromatographic techniques (GC), which is suitable for routine analysis of residual PETRA monomers in these hydrogels. Unreacted PETRA was initially identified using gas chromatography-mass spectrometry (GC-MS). The quantitation of analyte was performed and validated using gas chromatography equipped with a flame ionization detector (GC-FID). A linear relationship was obtained over the range of 0.0002%-0.0450% (m/m) with a correlation coefficient (r2) greater than 0.99. The recovery (>90%), intra-day precision (%RSD <0.67), inter-day precision (%RSD <2.5%), and robustness (%RSD <1.62%) of the method were within the acceptable values. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.0001% (m/m) and 0.0002% (m/m), respectively. This assay provides a simple and quick way of screening for residual acrylate monomer in hydrogels. PMID- 29403998 TI - Pharmacokinetics of gene recombined angiogenesis inhibitor Kringle 5 in vivo using 131I specific markers and SPECT/CT. AB - The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokinetics, the determination of metabolic principles, and evaluation of treatment effect. The objective of the study was to investigate the pharmacokinetic characteristics of gene recombination angiogenesis inhibitor Kringle 5 in vivo. The SPECT/CT and specific 131I-Kringle 5 marked by Iodogen method were both applied to explore the pharmacokinetic characteristics of 131I-Kringle 5 in vivo, and to investigate the dynamic distributions of 131I-Kringle 5 in target organs. Labeling recombinant angiogenesis inhibitor Kringle 5 using 131I with longer half-life and imaging in vivo using SPECT instead of PET, could overcome the limitations of previous methods. When the doses of 131I-Kringle 5 were 10.0, 7.5 and 5.0 g/kg, respectively, the two-compartment open models can be determined within all the metabolic process in vivo. There were no significant differences in t1/2alpha, t1/2beta, apparent volume of distribution and CL between those three levels. The ratio of AUC(0~infinity) among three different groups of 10.0, 7.5 and 5.0 g/kg was 2.56:1.44:1.0, which was close to the ratio (2:1.5:1.0). It could be clear that in the range of 5.0-10.0 g/kg, Kringle 5 was characterized by the first order pharmacokinetics. Approximately 30 min after 131I-Kringle 5 was injected, 131I-Kringle 5 could be observed to concentrate in the heart, kidneys, liver and other organs by means of planar imaging and tomography. After 1 h of being injected, more radionuclide retained in the bladder, but not in intestinal. It could be concluded that 131I-Kringle 5 is mainly excreted through the kidneys. About 2 h after the injection of 131I-Kringle 5, the radionuclide in the heart, kidneys, liver and other organs was gradually reduced, while more radionuclide was concentrated in the bladder. The radionuclide was completely metabolized within 24 h, and the distribution of radioactivity in rats was similar to normal levels. In our study, the specific marker 131I-Kringle 5 and SPECT/CT were successfully used to explore pharmacokinetic characteristics of Kringle 5 in rats. The study could provide a new evaluation platform of the specific, in vivo and real-time functional imaging and pharmacokinetics for the clinical application of 131I-Kringle 5. PMID- 29403999 TI - Isocoreopsin: An active constituent of n-butanol extract of Butea monosperma flowers against colorectal cancer (CRC). AB - The herb Butea monosperma constitutes several human health beneficial components, which are mostly studied for their anticancer effects. In this study, the activity of n-butanol fractions of B. monosperma floral extract was examined on inhibiting aberrant crypt foci (ACF) formation in azoxymethane induced Wistar albino rats. The n-butanol extracts (150 mg/kg) decreased the ACF formation (per rat) by 92% and 78% in short- and long-term in vivo treatments, respectively. All the compounds in the n-butanol extract were isolated and purified using column and reverse-phase high pressure liquid chromatography (HPLC). Their structures were characterized using UV-visible spectroscopy, nuclear magnetic resonance (NMR) and electrospray-ionisation mass spectrometry (ESI-MS) to determine important flavonoids, namely isocoreopsin, butrin and isobutrin. These compounds were studied for their free radical scavenging and anticancer activities. The compound isocoreopsin showed significantly greater efficacy in cell death on human colon and liver cancer cell lines (50 MUg/mL in HT-29 and 100 MUg/mL in HepG2) than butrin (100 MUg/mL in HT-29 and 500 MUg/mL in HepG2) and isobutrin (80 MUg/mL in HT-29 and 150 MUg/mL in HepG2). These results suggest that isocoreopsin, butrin and isobutrin are the important key compounds for the chemoprevention of colon cancer and isocoreopsin can be considered as a promising novel drug. PMID- 29404000 TI - A simple dilute and shoot methodology for the identification and quantification of illegal insulin. AB - The occurrence of illegal medicines is a well-established global problem and concerns mostly small molecules. However, due to the advances in genomics and recombinant expression technologies there is an increased development of polypeptide therapeutics. Insulin is one of the best known polypeptide drug, and illegal versions of this medicine led to lethal incidents in the past. Therefore, it is crucial for the public health sector to develop reliable, efficient, cheap, unbiased and easily applicable active pharmaceutical ingredient (API) identification and quantification strategies for routine analysis of suspected illegal insulins. Here we demonstrate that our combined label-free full scan approach is not only able to distinguish between all those different versions of insulin and the insulins originating from different species, but also able to chromatographically separate human insulin and insulin lispro in conditions that are compatible with mass spectrometry (MS). Additionally, we were also able to selectively quantify the different insulins, including human insulin and insulin lispro according to the validation criteria, put forward by the United Nations (UN), for the analysis of seized illicit drugs. The proposed identification and quantification method is currently being used in our official medicines control laboratory to analyze insulins retrieved from the illegal market. PMID- 29404001 TI - Quantification of neomangiferin in rat plasma by liquid chromatography-tandem mass spectrometry and its application to bioavailability study. AB - Neomangiferin, a natural C-glucosyl xanthone, has recently received a great deal of attention due to its multiple biological activities. In this study, a rapid and sensitive ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the quantification of neomangiferin in rat plasma was developed. Using chloramphenicol as an internal standard (IS), plasma samples were subjected to a direct protein precipitation process using methanol (containing 0.05% formic acid). Quantification was performed by multiple reactions monitoring (MRM) method, with the transitions of the parent ions to the product ions of m/z 583.1->330.9 for NG and m/z 321.1->151.9 for IS. The assay was shown to be linear over the range of 0.2-400 ng/mL, with a lower limit of quantification of 0.2 ng/mL. Mean recovery of neomangiferin in plasma was in the range of 97.76%-101.94%. Relative standard deviations (RSDs) of intra-day and inter-day precision were both <10%. The accuracy of the method ranged from 94.20% to 108.72%. This method was successfully applied to pharmacokinetic study of neomangiferin after intravenous (2 mg/kg) and intragastric (10 mg/kg) administration for the first time. The oral absolute bioavailability of neomangiferin was estimated to be 0.53%+/-0.08% with an elimination half-life (t1/2) value of 2.74+/-0.92 h, indicating its poor absorption and/or strong metabolism in vivo. PMID- 29404002 TI - Development and characterization of ethylcellulose based microsphere for sustained release of nifedipine. AB - This article introduced the work of ethylcellulose based polymeric microsphere loaded with nifedipine for reduction in frequency of administration with low solubility in aqueous medium and high rate of absorption in the stomach. The non aqueous polymeric suspension was put dropwise into an aqueous medium containing polyvinyl alcohol as a surfactant for the synthesis of microsphere by solvent evaporation. The microspheres were characterized by different techniques, namely, XRD, SEM, and NMR. The formation of microspheres was confirmed by SEM. XRD analysis revealed the semi-crystallinity nature of microspheres. The NMR study indicated the presence of hetero-aromatic nucleus in the microsphere. PMID- 29404003 TI - Screening primary racemic amines for enantioseparation by derivatized polysaccharide and cyclofructan columns. AB - It is a challenge to separate the enantiomers of native chiral amines prone to deleterious silanol interactions. A set of 39 underivatized chiral primary amines was screened for enantiomeric separation. Seven recently introduced commercial chiral columns were tested. They included six polysaccharide based chiral stationary phases (CSP) with bonded derivatives, ChiralPak(r) IA, IB, IC, ID, IE and IF columns and a cyclofructan derivatized CSP, Larihc(r) CF6-P column. Both the normal phase (NP) mode with heptane/alcohol mobile phases and the polar organic (PO) mode with acetonitrile/alcohol were evaluated. It was found that the cyclofructan based CSP demonstrated the highest success rate in separating primary amines in the PO mode with only one chiral amine not resolved. It is shown that, when screening the columns, there is no standard optimal condition; an excellent mobile phase composition for one column may be poorly suited to another one. Although butylamine was a good mobile phase additive for the polysaccharide columns in both PO and NP modes, it was detrimental to the enantio recognition capability of the cyclofructan column. Triethylamine was the appropriate silanol screening agent for this latter column. PMID- 29404004 TI - Comparison of ESI- and APCI-LC-MS/MS methods: A case study of levonorgestrel in human plasma. AB - Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) techniques for liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination of levonorgestrel were evaluated. In consideration of difference in ionization mechanism, the two ionization sources were compared in terms of LC conditions, MS parameters and performance of method. The sensitivity for detection of levonorgestrel with ESI was 0.25 ng/mL which was lower than 1 ng/mL with APCI. Matrix effects were evaluated for levonorgestrel and canrenone (internal standard, IS) in human plasma, and the results showed that APCI source appeared to be slightly less liable to matrix effect than ESI source. With an overall consideration, ESI was chosen as a better ionization technique for rapid and sensitive quantification of levonorgestrel. The optimized LC-ESI-MS/MS method was validated for a linear range of 0.25-50 ng/mL with a correlation coefficient >=0.99. The intra- and inter-batch precision and accuracy were within 11.72% and 6.58%, respectively. The application of this method was demonstrated by a bioequivalence study following a single oral administration of 1.5 mg levonorgestrel tablets in 21 Chinese healthy female volunteers. PMID- 29404005 TI - Structural characterization of monoterpene indole alkaloids in ethanolic extracts of Rauwolfia species by liquid chromatography with quadrupole time-of-flight mass spectrometry. AB - Rauwolfia species (Apocynaceae) are medicinal plants well known worldwide due to its potent bioactive monoterpene indole alkaloids (MIAs) such as reserpine, ajmalicine, ajmaline, serpentine and yohimbine. Reserpine, ajmalicine and ajmaline are powerful antihypertensive, tranquilizing agents used in hypertension. Yohimbine is an aphrodisiac used in dietary supplements. As there is no report on the comparative and comprehensive phytochemical investigation of the roots of Rauwolfia species, we have developed an efficient and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for ethanolic root extract of Rauwolfia species to elucidate the fragmentation pathways for dereplication of bioactive MIAs using high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-QTOF-MS/MS) in positive ion mode. We identified and established diagnostic fragment ions and fragmentation pathways using reserpine, ajmalicine, ajmaline, serpentine and yohimbine. The MS/MS spectra of reserpine, ajmalicine, and ajmaline showed C-ring-cleavage whereas E-ring cleavage was observed in serpentine via Retro Diels Alder (RDA). A total of 47 bioactive MIAs were identified and characterized on the basis of their molecular formula, exact mass measurements and MS/MS analysis. Reserpine, ajmalicine, ajmaline, serpentine and yohimbine were unambiguously identified by comparison with their authentic standards and other 42 MIAs were tentatively identified and characterized from the roots of Rauwolfia hookeri, Rauwolfia micrantha, Rauwolfia serpentina, Rauwolfia verticillata, Rauwolfia tetraphylla and Rauwolfia vomitoria. Application of LC-MS followed by principal component analysis (PCA) has been successfully used to discriminate among six Rauwolfia species. PMID- 29404006 TI - The impact of storage conditions upon gentamicin coated antimicrobial implants. AB - A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 degrees C, 75% relative humidity or exposure to light. The effect of gamma-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography-mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities. PMID- 29404007 TI - Optimization of microwave-assisted extraction of bioactive alkaloids from lotus plumule using response surface methodology. AB - In this work, a fast and efficient microwave-assisted extraction (MAE) method was developed to extract main bioactive alkaloids from lotus plumue. To optimize MAE conditions, three main factors were selected using univariate approach experiments, and then central composite design (CCD). The optimal extraction conditions were as follows: methanol concentration of 65%, microwave power of 200 W, and extraction time of 260 s. An high performance liquid chromatography-diode array detector (HPLC-DAD) method was established to quantitatively analyze these phytochemicals in different lotus plumule samples and in different part of lotus. Chromatographic separation was carried out on an Agilent Zorbax Extend-C18 column (4.6 mm*150 mm, 3.5 um). Gradient elution was applied with the mobile phase constituted with 0.1% triethylamine in water (A) and acetonitrile (B): 40%-70% B at 0-8 min, 70%-100% B at 8-9 min, 100% B for 2 min, and then equilibrated with 40% B for 2 min. PMID- 29404008 TI - Wound healing activity of Delonix elata stem bark extract and its isolated constituent quercetin-3-rhamnopyranosyl-(1-6) glucopyranoside in rats. AB - Delonix elata L. is a Ceasalpinaceae species and is traditionally used in India for treatment of skin diseases, liver diseases and rheumatic problems. However, systematic evaluation of its wound healing activity is lacking. Thus, in the present study, we aimed to assess the wound healing activity of D. elata stem bark extract (DSE) and its isolated constituent quercetin-3-rhamnopyranosyl-(1-6) glucopyranoside (QRPG) in rats. The formulations effects on wound healing were assessed by the wound contraction rate, epithelialization period, tensile strength, content of the hydroxyproline, hexosamine and uronic acid in granulation tissue, histopathological studies and Col 1 alpha (I) expression level in wound tissue by reverse transcription polymerase chain reaction (RT-PCR) study. The topical application of DSE ointment caused faster epithelialization, significant wound contraction (100%), and better tensile strength (710.5+/-10.5 g/cm2), while QRPG showed wound epithelialization with 98.2% contraction, better than that of the control group (78.18%). The biochemical analysis of granulation tissue revealed that DSE and QRPG significantly increased hydroxyproline, hexosamine and uronic acid content. A significant increase in the expression of Col 1 alpha (I) was observed in the wound tissue of DSE and QRPG treated rats. DSE and QRPG were shown to enhance wound healing by increasing collagen synthesis through up-regulation of Col 1 alpha (I), thus validating ethnomedicinal uses. PMID- 29404009 TI - Development of an HPLC-UV assay method for the simultaneous quantification of nine antiretroviral agents in the plasma of HIV-infected patients. AB - A new method using high-performance liquid chromatography coupled with ultra violet detection (HPLC-UV) was developed and validated for the simultaneous quantification of atazanavir, dolutegravir, darunavir, efavirenz, etravirine lopinavir, raltegravir, rilpivirine and tipranavir in human plasma. For the first time we reported here the development and validation of an HPLC-UV assay to quantify the frequently administered 9 antiretroviral compounds including dolutegravir and rilpivirine. A simple solid phase extraction procedure was applied to 500 uL aliquots of plasma. The chromatographic separation of the drugs and internal standard (quinoxaline) was achieved with a gradient of acetonitrile and sodium acetate buffer on a C18 reverse-phase analytical column with a 25 min analytical run time. Calibration curves were optimised according to the therapeutic range of drug concentrations in patients, and the coefficient of determination (r2) was higher than 0.99 for all analytes. Mean intraday and interday precisions (RSD) for all compounds were less than 15.0%, and the mean accuracy (% deviation from nominal concentration) was also found to be less than 15.0%. Extraction recovery range was between 80% and 120% for all drugs analysed. The solid phase extraction and HPLC-UV method enable a specific, sensitive, and reliable simultaneous determination of nine antiretroviral agents in plasma. Good extraction efficiency and low limit of HPLC-UV quantification make this method suitable for use in clinical trials and therapeutic drug monitoring. PMID- 29404010 TI - Determination of pKa values of alendronate sodium in aqueous solution by piecewise linear regression based on acid-base potentiometric titration. AB - As a mono-sodium salt form of alendronic acid, alendronate sodium presents multi level ionization for the dissociation of its four hydroxyl groups. The dissociation constants of alendronate sodium were determined in this work by studying the piecewise linear relationship between volume of titrant and pH value based on acid-base potentiometric titration reaction. The distribution curves of alendronate sodium were drawn according to the determined pKa values. There were 4 dissociation constants (pKa1=2.43, pKa2=7.55, pKa3=10.80, pKa4=11.99, respectively) of alendronate sodium, and 12 existing forms, of which 4 could be ignored, existing in different pH environments. PMID- 29404011 TI - CdS nanocrystals as fluorescent probe for detection of dolasetron mesylate in aqueous solution: Application to biomedical analysis. AB - A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3 Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2-40 ug/mL with detection limit (LOD) 1.512 ug/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results. PMID- 29404012 TI - Stability study on an anti-cancer drug 4-(3,5-bis(2-chlorobenzylidene)-4-oxo piperidine-1-yl)-4-oxo-2-butenoic acid (CLEFMA) using a stability-indicating HPLC method. AB - CLEFMA, 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid, is a new chemical entity with anti-cancer and anti-inflammatory activities. Here, we report its stability in solution against stress conditions of exposure to acid/base, light, oxidant, high temperature, and plasma. The identity of the degradation products was ascertained by mass and proton nuclear magnetic resonance spectroscopy. To facilitate this study, we developed and validated a reverse phase high performance liquid chromatography method for detection of CLEFMA and its degradation. The method was linear over a range of 1-100 ug/mL; the accuracy and precision were within acceptable limits; it was stability indicating as it successfully separated cis-/trans-isomers of CLEFMA as well as its degradation product. The major degradation product was produced from amide hydrolysis at maleic acid functionality caused by an acidic buffer, oxidant (3% hydrogen peroxide), or temperature stress (40-60 degrees C). The log k-pH profile showed that CLEFMA was most stable at neutral pH. In accelerated stability study we found that the shelf-life (T90% ) of CLEFMA at 25 degrees C and 4 degrees C was 45 days and 220 days, respectively. Upon exposure to UV light (365 nm), the normally prevalent trans-CLEFMA attained cis-configuration. This isomerization also involved the maleic acid moiety. CLEFMA was stable in plasma from which it could be efficiently extracted by an acetonitrile precipitation method. These results indicate that CLEFMA is sensitive to hydrolytic cleavage at its maleic acid moiety, and it is recommended that its samples should be stored under refrigerated and light-free conditions, and under inert environment. PMID- 29404014 TI - Binding interaction of phosphorus heterocycles with bovine serum albumin: A biochemical study. AB - Interaction between bovine serum albumin (BSA) and phosphorus heterocycles (PHs) was studied using multi-spectroscopic techniques. The results indicated the high binding affinity of PHs to BSA as it quenches the intrinsic fluorescence of BSA. The experimental data suggested the fluorescence quenching mechanism between PHs and BSA as a dynamic quenching. From the UV-vis studies, the apparent association constant (Kapp) was found to be 9.25*102, 1.27*104 and 9.01*102 L/mol for the interaction of BSA with PH-1, PH-2 and PH-3 respectively. According to the Forster's non-radiation energy transfer (FRET) theory, the binding distances between BSA and PHs were calculated. The binding distances (r) of PH-1, PH-2 and PH-3 were found to be 2.86, 3.03, and 5.12 nm, respectively, indicating energy transfer occurs between BSA and PHs. The binding constants of the PHs obtained from the fluorescence quenching data were found to be decreased with increase of temperature. The negative values of the thermodynamic parameters DeltaH, DeltaS and DeltaG at different temperatures revealed that the binding process is spontaneous; hydrogen bonds and van der Waals interaction were the main force to stabilize the complex. The microenvironment of the protein-binding site was studied by synchronous fluorescence and circular dichroism (CD) techniques and data indicated that the conformation of BSA changed in the presence of PHs. Finally, we studied the BSA-PHs docking using Autodock and results suggest that PHs is located in the cleft between the domains of BSA. PMID- 29404013 TI - Bioinformatic prediction and functional characterization of human KIAA0100 gene. AB - Our previous study demonstrated that human KIAA0100 gene was a novel acute monocytic leukemia-associated antigen (MLAA) gene. But the functional characterization of human KIAA0100 gene has remained unknown to date. Here, firstly, bioinformatic prediction of human KIAA0100 gene was carried out using online softwares; Secondly, Human KIAA0100 gene expression was downregulated by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) 9 system in U937 cells. Cell proliferation and apoptosis were next evaluated in KIAA0100-knockdown U937 cells. The bioinformatic prediction showed that human KIAA0100 gene was located on 17q11.2, and human KIAA0100 protein was located in the secretory pathway. Besides, human KIAA0100 protein contained a signalpeptide, a transmembrane region, three types of secondary structures (alpha helix, extended strand, and random coil) , and four domains from mitochondrial protein 27 (FMP27). The observation on functional characterization of human KIAA0100 gene revealed that its downregulation inhibited cell proliferation, and promoted cell apoptosis in U937 cells. To summarize, these results suggest human KIAA0100 gene possibly comes within mitochondrial genome; moreover, it is a novel anti-apoptotic factor related to carcinogenesis or progression in acute monocytic leukemia, and may be a potential target for immunotherapy against acute monocytic leukemia. PMID- 29404015 TI - Fabrication of an electrochemical sensor for determination of doxorubicin in human plasma and its interaction with DNA. AB - In this work, an electrochemical sensor was fabricated for determination of an anthracycline, doxorubicin (DOX) as a chemotherapy drug in plasma based on multi walled carbon nanotubes modified platinum electrode (Pt/MWCNTs). DOX was effectively accumulated on the surface of modified electrode and generated a pair of redox peaks at around 0.522 and 0.647 V (vs. Ag/AgCl) in Britton Robinson (B R) buffer (pH 4.0, 0.1 M). The electrochemical parameters including pH, type of buffer, accumulation time, amount of modifier and scan rate were optimized. Under the optimized conditions, there was a linear correlation between cathodic peak current and concentration of DOX in the range of 0.05-4.0 ug/mL with the detection limit of 0.002 ug/mL. The number of electron transfers (n) and electron transfer-coefficient (alpha) were estimated as 2.0 and 0.25, respectively. The constructed sensor displayed excellent precision, sensitivity, repeatability and selectivity in the determination of doxorubicin in plasma. Moreover, cyclic voltammetry studies of DOX in the presence of DNA showed an intercalation mechanism with binding constant (Kb) of 1.12*105 L/mol. PMID- 29404017 TI - Analysis of bacitracin and its related substances by liquid chromatography tandem mass spectrometry. AB - A suitable liquid chromatography quadrupole time-of-flight mass spectrometric (LC Q-TOF-MS) method was developed for separation and characterization of related substances in bacitracin test drug. The separation was performed on LiChrospher RP-18 column using methanol as mobile phase A and 0.2% ammonium acetate buffer solution as mobile phase B in gradient elution. A total of 12 related substances were detected through high resolution mass spectrometric determination in a positive electrospray ionization mode. They were identified as co-existing active components and degradation products of bacitracin through the analysis and elucidation of both the protonated parents and the product ions of all the related substances and their fragmentation pathways were also proposed. PMID- 29404016 TI - N-alkylamide profiling of Achillea ptarmica and Achillea millefolium extracts by liquid and gas chromatography-mass spectrometry. AB - Achillea millefolium and Achillea ptarmica are both plants belonging to the Asteracea family and are traditionally used for their medicinal properties. It has already been shown that some N-alkylamides (NAAs) are responsible for these pharmacological actions. Therefore, in the present study, the NAA content of the two plants was analytically characterised. Different extracts were prepared from the roots, the leaves, the stems and the flowers. The structures of NAAs have been assigned in ethanolic extracts of Achillea millefolium and Achillea ptarmica using high performance liquid chromatography - electrospray ionisation - mass spectrometry (HPLC-ESI-MS) and gas chromatography - electron impact - mass spectrometry (GC-EI-MS). Using both analytical techniques, the structures of 14 and 15 NAAs have been assigned in Achillea ptarmica and Achillea millefolium, respectively. Structures of two new NAAs, previously never observed in Achillea ptarmica, were assigned: deca-2E,6Z,8E-trienoic acid 2-methylbutylamide (homospilanthol) or a related isomeric compound and deca-2E,4E-dienoic acid N methyl isobutylamide. The structure of homospilanthol or a related isomeric compound was also assigned in Achillea millefolium for the first time. PMID- 29404018 TI - Simultaneous analysis of allopurinol and oxypurinol using a validated liquid chromatography-tandem mass spectrometry method in human plasma. AB - The present study describes a simple, reliable and reproducible liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for the simultaneous determination of allopurinol and its active metabolite, oxypurinol in human plasma for a pharmacokinetic/bioequivalence study. After protein precipitation (PPT) of 100 uL plasma sample with 1.0% formic acid in acetonitrile, the recovery of the analytes and allopurinol-d2 as an internal standard ranged from 85.36% to 91.20%. The analytes were separated on Hypersil Gold (150 mm*4.6 mm, 5 um) column using 0.1% formic acid-acetonitrile (98:2, v/v) as the mobile phase. Quantification was done using electrospray ionization in the positive mode. The calibration concentration range was established from 60.0 to 6000 ng/mL for allopurinol and 80.0-8000 ng/mL for oxypurinol. Matrix effect in human plasma, expressed as IS-normalized matrix factors ranged from 1.003 to 1.030 for both the analytes. The developed method was found suitable for a clinical study with 300 mg allopurinol tablet formulation in healthy subjects. PMID- 29404019 TI - Determination of fenticonazole in human plasma by HPLC-MS/MS and its application to pharmacokinetic studies. AB - Two simple and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed and validated for the determination of fenticonazole in human plasma after percutaneous and intravaginal administration. Mifepristone was used as an internal standard (IS), and simple protein precipitation by acetonitrile containing 2% acetic acid was utilized for extracting the analytes from the plasma samples. Chromatographic separation was performed on a Kinetex XB-C18 column. The quantitation was performed by a mass spectrometer equipped with an electrospray ionization source in multiple reactions monitoring (MRM) positive ion mode using precursor-to product ion transitions of m/z 455.2-199.1 for fenticonazole and m/z 430.2-372.3 for mifepristone. The validated linear ranges were 5-1000 pg/mL and 0.1-20 ng/mL fenticonazole in plasma for the methods A and B, respectively. For the two methods, the accuracy data ranged from 85% to 115%, the intra- and inter-batch precision data were less than 15%, the recovery data were more than 90%, and no matrix interference was observed. The methods A and B were successfully validated and applied to the pharmacokinetic studies of fenticonazole gel in Chinese healthy volunteers after percutaneous and intravaginal administration, respectively. PMID- 29404020 TI - Bile salt induced solubilization of methylene blue: Study on methylene blue fluorescence properties and molecular mechanics calculation. AB - Methylene blue (MB) is a hydrophobic drug molecule, having importance both as a staining reagent and pharmaceutical agent. MB is strongly fluorescent, with an emission peak at 686 nm (lambdaex 665 nm). In the study, the possibility of MB as an extrinsic fluorophore to study the micellization behavior of bile salts (BSs) was carried out. Since BSs are drug delivery systems, the solubilization of hydrophobic MB drug molecule by BSs was achieved and the nature of association of MB with BS media, namely sodium cholate (NaC) and sodium deoxycholate (NaDC) was evaluated. Change in the photophysical properties of MB is monitored through fluorescence intensity and fluorescence anisotropy at emission peak, 686 nm of MB. Molecular mechanics calculations were carried out to evaluate the MB-BS association. The estimated heat of formation, DeltaHf values are -625.19 kcal/mol for MB-NaC and -757.48 kcal/mol for MB-NaDC. The photophysical study also revealed that MB reports the step-wise aggregation pattern of BSs media, as an extrinsic fluorescence probe. PMID- 29404021 TI - Analysis of isoquinoline alkaloids from Mahonia leschenaultia and Mahonia napaulensis roots using UHPLC-Orbitrap-MSn and UHPLC-QqQLIT-MS/MS. AB - Mahonia leschenaultia (ML) and Mahonia napaulensis (MN) are less known and unexplored medicinal plants of the family Berberidaceae. They are used by the Todas of Nilgiris in their religious and medical practices but chemically less identified. Hence, we decided to do extensive phytochemical analysis to explore the potential of these plant extracts. An ultrahigh performance electrospray tandem mass spectrometry (UHPLC-ESI-MS/MS) method was successfully developed for qualitative analysis of the bioactive components in Mahonia species using Orbitrap Velos Pro mass spectrometer. Sixteen compounds were identified by comparison of their retention times and mass spectra (MS) with authentic standards and reported literature. Multi-stage mass spectra (MS2-8) for the identification of protoberberine and aporphine alkaloids showed the sequential expulsion of all the substituents attached with their basic skeleton followed by CO loss. Eight of the identified compounds (berberine, jatrorrhizine, palmatine, magnoflorine, isocorydine, glaucine, tetrahydropalmatine and tetrahydroberberine) were simultaneously determined by another UHPLC-ESI-MS/MS method under the multiple reactions monitoring (MRM) mode quantitatively using triple quadrupole linear ion trap mass spectrometer. The analytical method was validated for 8 bioactive compounds with overall recovery in the range 98.5%-103.6% (RSD<=2.2%), precise (RSD<=2.07%) and linear (r>=0.9995) over the concentration range of 0.5 1000 ng/mL and successfully applied in ML and MN roots, which suggests the suitability of the proposed approach for the routine analysis of Mahonia species and their quality control. PMID- 29404023 TI - An improved LC-MS/MS method for the quantification of alverine and para hydroxy alverine in human plasma for a bioequivalence study?. AB - A highly sensitive and selective high performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of alverine (ALV) and its active metabolite, para hydroxy alverine (PHA), in human plasma. For sample preparation, solid phase extraction of analytes was performed on Phenomenex Strata-X cartridges using alverine-d5 as the internal standard. The analytes were separated on Symmetry Shield RP18 (150 mm*3.9 mm, 5 um) column with a mobile phase consisting of acetonitrile and 10 mM ammonium formate (65:35, v/v). Detection and quantitation was done by electrospray ionization mass spectrometry in the positive mode using multiple reaction monitoring. The assay method was fully validated over the concentration range of 15.0-15,000 pg/mL for ALV and 30.0-15,000 pg/mL for PHA. The intra-day and inter-day accuracy and precision (% CV) ranged from 94.00% to 96.00% and 0.48% to 4.15% for both the analytes. The mean recovery obtained for ALV and PHA was 80.59% and 81.26%, respectively. Matrix effect, expressed as IS-normalized matrix factor ranged from 0.982 to 1.009 for both the analytes. The application of the method was demonstrated for the specific analysis of ALV and PHA for a bioequivalence study in 52 healthy subjects using 120 mg ALV capsules. The assay reproducibility was also verified by reanalysis of 175 incurred subject samples. PMID- 29404022 TI - N-glycans released from glycoproteins using a commercial kit and comprehensively analyzed with a hypothetical database. AB - The glycosylation of proteins is responsible for their structural and functional roles in many cellular activities. This work describes a strategy that combines an efficient release, labeling and liquid chromatography-mass spectral analysis with the use of a comprehensive database to analyze N-glycans. The analytical method described relies on a recently commercialized kit in which quick deglycosylation is followed by rapid labeling and cleanup of labeled glycans. This greatly improves the separation, mass spectrometry (MS) analysis and fluorescence detection of N-glycans. A hypothetical database, constructed using GlycResoft, provides all compositional possibilities of N-glycans based on the common sugar residues found in N-glycans. In the initial version this database contains >8,700 N-glycans, and is compatible with MS instrument software and expandable. N-glycans from four different well-studied glycoproteins were analyzed by this strategy. The results provided much more accurate and comprehensive data than had been previously reported. This strategy was then used to analyze the N-glycans present on the membrane glycoproteins of gastric carcinoma cells with different degrees of differentiation. Accurate and comprehensive N-glycan data from those cells was obtained efficiently and their differences compared corresponding to their differentiation states. Thus, the novel strategy developed greatly improves accuracy, efficiency and comprehensiveness of N-glycan analysis. PMID- 29404024 TI - Investigation of binding behaviour of procainamide hydrochloride with human serum albumin using synchronous, 3D fluorescence and circular dichroism. AB - Interaction of procainamide hydrochloride (PAH) with human serum albumin (HSA) is of great significance in understanding the pharmacokinetic and pharmacodynamic mechanisms of the drug. Multi-spectroscopic techniques were used to investigate the binding mode of PAH to HSA and results revealed the presence of static type of quenching mechanism. The number of binding sites, binding constants and thermodynamic parameters were calculated. The results showed a spontaneous binding of PAH to HSA and hydrophobic interactions played a major role. In addition, the distance between PAH and the Trp-214 was estimated employing the Forster's theory. Site marker competitive experiments indicated that the binding of PAH to HSA primarily took place in subdomain IIA (Sudlow's site I). The influence of interference of some common metal ions on the binding of PAH to HSA was studied. Synchronous fluorescence spectra (SFS), 3D fluorescence spectra and circular dichroism (CD) results indicated the conformational changes in the structure of HSA. PMID- 29404025 TI - Square wave voltammetric quantification of folic acid, uric acid and ascorbic acid in biological matrix. AB - Nowadays, modified electrodes with metal nanoparticles have appeared as an alternative for the electroanalysis of various compounds. In this study, gold nanoparticles (GNPs) were chosen as interesting metal nanoparticles for modifying of carbon paste electrode (CPE). GNPs and the gold nanoparticles-modified carbon paste electrode (GNPs/CPE) were characterized by UV-Vis spectroscopy, transmission electron microscopy (TEM) and scanning electron microscopy (SEM). GNPs/CPE as a simple and sensitive electrode was used to study three important biological molecules: folic acid (FA), uric acid (UA) and ascorbic acid (AA). Square wave voltammetry (SWV) was used as an accurate technique for quantitative measurements. A good linear relation was observed between anodic peak current (ipa) and FA (5.2 * 10-6 - 2.5 * 10-5 M), UA (1.2 * 10-6 - 2.1 * 10-5 M) and AA (1.2 * 10-6 - 2.5 * 10-5 M) concentrations in simultaneous determination of these molecules. PMID- 29404026 TI - Degradation kinetics of larotaxel and identification of its degradation products in alkaline condition. AB - Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC-MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH (1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0) and temperature (0, 25, 37 and 45 degrees C). The linear range was 0.5-25 MUg/mL, the intra- and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4-104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 kJ/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 degrees C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q-TOF-MS. The three degradation products were confirmed as 10 deacetyl larotaxel, 7, 8-cyclopropyl baccatin III and 10-deacetyl-7, 8 cyclopropyl baccatin III. PMID- 29404027 TI - Anti-atherosclerotic activity of root bark of Premna integrifolia Linn. in high fat diet induced atherosclerosis model rats. AB - Premna integrifolia Linn. is a medicinal plant used in "Dhasamula" drug preparation of Ayurvedic systems of medicine in the treatment of various ailments like bronchitis, dyspepsia, liver disorders, piles, constipation, hyperlipidemia and fever. The anti-atherosclerotic activity of hydroalcoholic extract (HAE) of root bark of P. integrifolia was evaluated in high fat diet induced atherosclerosis rats. Sixty Wistar rats were divided into six groups: the first group served as control, the second group was fed with high fat diet and the other three groups were fed with high fat diet along with various concentrations of HAE and the last group was treated with atorvastatin for 30 days. Lipid and lipoprotein profile, atherogenic index, and cardiac markers and histopathological evaluation of aorta were determined in high fat diet induced atherosclerosis rats. HAE of P. integrifolia produced a significant and dose-dependent anti atherosclerotic activity in terms of reduction in lipids and lipoprotein profile, atherogenic index, HMG-CoA reductase activity, marker enzymes such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), alteration in collagen and calcium contents, mild mineralization and focal rupture of intima and media of aorta was noticed in treated groups as compared to the control. The results suggested that anti-atherosclerotic activity of HAE of P. integrifolia Linn. was due to its modulatory activity on metabolic pathway of lipid. The results contribute to the validation of the traditional use of Agnimantha in high fat diet induced atherosclerosis rats. PMID- 29404028 TI - A stability-indicating high performance liquid chromatography method to determine apocynin in nanoparticles. AB - In this study, we developed and validated a fast, specific, sensitive, precise and stability-indicating high performance liquid chromatography (HPLC) method to determine the drug apocynin in bovine serum albumin (BSA) nanoparticles. Chromatographic analyses were performed on an RP C18 column and using a photodiode array detector at a wavelength of 276 nm. Mobile phase consisted of a mixture of acetonitrile and 1% acetic acid (60:40, v/v), and it was eluted isocratically at a flow rate of 0.8 mL/min. The retention time of apocynin chromatographic peak was 1.65 min. The method was linear, precise, accurate and specific in the range of 5-100 MUg/mL. The intra- and inter-day precisions presented relative standard deviation (RSD) values lower than 2%. The method was robust regarding changes in mobile phase proportion, but not for flow rate. Limits of detection and quantitation were 78 ng/mL and 238 ng/mL, respectively. Apocynin was exposed to acid and alkali hydrolysis, oxidation and visible light. The drug suffered mild degradation under acid and oxidation conditions and great degradation under alkali conditions. Light exposure did not degrade the drug. The method was successfully applied to determine the encapsulation efficiency of apocynin in BSA nanoparticles. PMID- 29404029 TI - Development and validation of a stability-indicating RP-HPLC method for estimation of atazanavir sulfate in bulk. AB - A stability-indicating reverse phase-high performance liquid chromatography (RP HPLC) method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C18 column Phenomenix (250 mm*4.6 mm, 5 MUm) with a mobile phase consisting of 900 mL of HPLC grade methanol and 100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45 MUm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90 MUg/mL (coefficient of determination R2 was 0.999) with equation, y=23.427x+37.732. Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines. PMID- 29404030 TI - Electromembrane extraction-Recent trends and where to go. AB - Electromembrane extraction (EME) is an analytical microextraction technique, where charged analytes (such as drug substances) are extracted from an aqueous sample (such as a biological fluid), through a supported liquid membrane (SLM) comprising a water immiscible organic solvent, and into an aqueous acceptor solution. The driving force for the extraction is an electrical potential (dc) applied across the SLM. In this paper, EME is reviewed. First, the principle for EME is explained with focus on extraction of cationic and anionic analytes, and typical performance data are presented. Second, papers published in 2016 are reviewed and discussed with focus on (a) new SLMs, (b) new support materials for the SLM, (c) new sample additives improving extraction, (d) new technical configurations, (e) improved theoretical understanding, and (f) pharmaceutical new applications. Finally, important future research objectives and directions are defined for further development of EME, with the aim of establishing EME in the toolbox of future analytical laboratories. PMID- 29404031 TI - Multi-spectroscopic characterization of bovine serum albumin upon interaction with atomoxetine. AB - The quenching interaction of atomoxetine (ATX) with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH=7.4) by multi spectroscopic techniques. The mechanism of ATX-BSA system was a dynamic quenching process and was confirmed by the fluorescence spectra and lifetime measurements. The number of binding sites, binding constants and other binding characteristics were computed. Thermodynamic parameters ?H degrees and ?S degrees indicated that intermolecular hydrophobic forces predominantly stabilized the drug-protein system. The average binding distance between BSA and ATX was studied by Forsters theory. UV-absorption, Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), synchronous spectra and three-dimensional (3D) fluorescence spectral results revealed the changes in micro-environment of secondary structure of protein upon the interaction with ATX. Displacement of site probes and the effects of some common metal ions on the binding of ATX with BSA interaction were also studied. PMID- 29404033 TI - Fast and sensitive LC-MS/MS method for the simultaneous determination of lisinopril and hydrochlorothiazide in human plasma. AB - A sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of lisinopril (LIS) and hydrochlorothiazide (HCTZ) in human plasma using their labeled internal standards (ISs). Sample pre-treatment involved solid phase extraction on Waters Oasis HLB cartridges using 100 uL of plasma, followed by liquid chromatography on Hypersil Gold C18 (50 mm*3.0 mm, 5 um) column. The analytes were eluted within 2.0 min using acetonitrile-5.0 mM ammonium formate, pH 4.5 (85:15, v/v) as the mobile phase. The analytes and ISs were analyzed in the negative ionization mode and quantified using multiple reaction monitoring. The method showed excellent linearity over the concentration range of 0.50-250.0 ng/mL for both the analytes. The intra-batch and inter-batch precision (% CV) was <=5.26% and their extraction recoveries were in the range of 96.6%-103.1%. Matrix effect evaluated in terms of IS-normalized matrix factors ranged from 0.97 to 1.03 for both the analytes. The validated method was successfully applied to determine the plasma concentration of the drugs using 10 mg lisinopril and 12.5 mg hydrochlorothiazide fixed dose formulation in 18 healthy Indian volunteers. PMID- 29404032 TI - Separation of atropisomers by chiral liquid chromatography and thermodynamic analysis of separation mechanism. AB - In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from a scientific and regulatory perspective. The compound of interest contains two stereogenic axes due to the hindered rotation around the single bonds connecting the aryl groups, which results in four potential configurational isomers (atropisomers). The separation of the four atropisomers is achieved on a derivatized beta-cyclodextrin bonded stationary phase. Further investigation shows that low temperature conditions, including sample preparation (-70 degrees C), sample storage (-70 degrees C), and chromatographic separation (6 degrees C), were critical to preventing interconversion. LC-UV-Laser Polarimetric analysis identified peak 1/2 as a pair of enantiomers and peak 3/4 as another. Thermodynamic analysis of the retention data indicated that the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positive slope of the van't Huff plot. The difference in absolute Delta (Delta H), ranged from 2.20 kJ/mol to 2.42 kJ/mol. PMID- 29404034 TI - Effect of processing on the alkaloids in Aconitum tubers by HPLC-TOF/MS. AB - According to the Chinese Pharmacopoeia 2015, only processed Aconitum tubers can be clinically applied, and the effect of processing is unclear. This research aimed to explore the effect of processing on cardiac efficacy of alkaloids in Aconitum tubers. First, the chemical ingredients in unprocessed and processed Aconitum tubers were identified and compared by using high performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF/MS) and multivariate pattern recognition methods. Then the representative alkaloids in Aconitum tubers, aconitine, benzoylaconine, and aconine, which belong to diester diterpenoid alkaloids, monoester-diterpenoid alkaloids, and amine-diterpenoid alkaloids, respectively, were selected for further validation of attenuated mechanism. Subsequent pharmacological experiments with aconitine, benzoylaconine, and aconine in SD rats were used for validate the effect of processing on cardiac functions. After processing the Aconitum tubers, it was found that the contents of diester-diterpenoid alkaloids were reduced, and those of monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids were increased, suggesting that diester diterpenoid alkaloids were transformed into monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids. Through further decocting the aconitine in boiling water, it was confirmed that the three alkaloids could be progressively transformed. Pharmacological experiments with aconitine, benzoylaconine, and aconine in SD rats showed that aconitine at a dose of 0.01 mg/kg and aconine at a dose of 10 mg/kg enhanced the cardiac function, while benzoylaconine at a dose of 2 mg/kg weakened the cardiac function. The effect of processing is attributed to the transformation of the most toxic diester-diterpenoid alkaloids into less toxic monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids. PMID- 29404035 TI - DNA-binding studies of valrubicin as a chemotherapy drug using spectroscopy and electrochemical techniques. AB - In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4) using UV-Vis spectrophotometry and cyclic voltammetry techniques. Valrubicin intercalated into double stranded DNA under a weak displacement reaction with methylene blue (MB) molecule in a competitive reaction. The binding constant (kb) of valrubicin-DNA was determined as 1.75*103 L/mol by spectrophotometric titration. The value of non-electrostatic binding constant ([Formula: see text]) was almost constant at different ionic strengths while the ratio of [Formula: see text]/kb increased from 4.51% to 23.77%. These results indicate that valrubicin binds to ds-DNA via electrostatic and intercalation modes. Thermodynamic parameters including DeltaH0, DeltaS0 and DeltaG0 for valrubicin-DNA interaction were determined as -25.21*103 kJ/mol, 1.55*102 kJ/mol K and -22.03 kJ/mol, respectively. Cyclic voltammetry study shows a pair of redox peaks for valrubicin at 0.45 V and 0.36 V (vs. Ag/AgCl). The peak currents decreased and peak positions shifted to positive direction in the presence of DNA, showing intercalation mechanism due to the variation in formal potential. PMID- 29404036 TI - Hepatoprotective activity of Macrothelypteris torresiana (Gaudich.) aerial parts against CCl4-induced hepatotoxicity in rodents and analysis of polyphenolic compounds by HPTLC. AB - Macrothelypteris torresiana is a fern species belonging to family Thelypteridaceae. The present study was conducted to evaluate hepatoprotective potential of ethanol extract from M. torresiana aerial parts (EEMTAP) and detect the polyphenolic compounds present in the extract using high performance thin layer chromatography (HPTLC). Hepatoprotective potential of EEMTAP were tested at doses of 300 and 600 mg/kg, per os (p.o.), on Wistar albino rats. The extract and silymarin treated animal groups showed significant decrease in activities of different biochemical parameters like serum glutamic oxaloacetic transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), alkaline phosphatase (ALP), which were elevated by carbon tetrachloride (CCl4) intoxication. The levels of total bilirubin and total protein alongwith the liver weight were also restored to normalcy by EEMTAP and silymarin treatment. After CCl4 administration the level of hepatic antioxidant enzymes such as Glutathione (GSH) and Catalase (CAT) were decreased whereas the level of hepatic lipid peroxidation (LPO) was elevated. The level of these hepatic antioxidant enzymes were also brought to normalcy by EEMTAP and silymarin treatment. Histological studies supported the biochemical findings and treatment with EEMTAP at doses 300 and 600 mg/kg, p.o. was found to be effective in restoring CCl4-induced hepatotoxicity in rats. A simple HPTLC analysis was conducted for the detection of polyphenolic compounds in EEMTAP, and the result revealed the presence of caffeic acid as phenolic acid and quercetin as flavonoid. The proposed HPTLC method is simple, concise and provides a good resolution of caffeic acid and quercetin from other constituents present in EEMTAP. PMID- 29404037 TI - Preparation of monoclonal antibody against human KIAA0100 protein and Northern blot analysis of human KIAA0100 gene. AB - Monoclonal antibodies (MAbs) are important tools for the study of proteins' function and structure. But there has been no report on the preparation of MAbs against human KIAA0100 protein up to date. Here, first, we generated the mouse MAb against human KIAA0100 protein using purified recombinant 6*Histidinc (6*His) tagged human KIAA0100 protein segment (1557-2234) as an antigen; then, the mRNA expression of human KIAA0100 gene was detected in U937 cells using Northern blot analysis. The results showed that the mouse MAb against human KIAA0100 protein could sensitively recognize the human KIAA0100 protein using Western blot analysis and immunocytochemistry analysis. Besides, Western blot analysis revealed that human KIAA0100 gene possibly encoded two different protein products (254 kDa and <250 kDa) in U937 cells. Moreover, Northern blot analysis confirmed that human KIAA0100 gene might produced two different mRNA products (6000-10000 bp and 5000-6000 bp) in U937 cells. The results provide a basis for large-scale production of the MAb against human KIAA0100 protein, which will be useful for the study of human KIAA0100 protein's function/structure and MAb-targeted drugs in the future. PMID- 29404038 TI - Highly sensitive assay for the determination of therapeutic peptide desmopressin in human plasma by UPLC-MS/MS. AB - An analytical method based on ultra-performance liquid chromatography with positive ion electrospray ionization (ESI) coupled with tandem mass spectrometry detection (UPLC-MS/MS) was developed and validated for the determination of therapeutic peptide desmopressin in human plasma. A desmopressin stable labeled isotope (desmopressin d8) was used as an internal standard. Analyte and the internal standard were extracted from 200 uL of human plasma via solid-phase extraction technique using Oasis WCX cartridges. The chromatographic separation was achieved on an Aquity UPLC HSS T3 column by using a gradient mixture of methanol and 1 mM ammonium formate buffer as the mobile phase. The calibration curve obtained was linear (r2 >=0.99) over the concentration range of 1.01-200 pg/mL. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. The proposed method was successfully applied to pharmacokinetic studies in humans. PMID- 29404039 TI - Analytical techniques for serratiopeptidase: A review. AB - A review is presented on different analytical techniques used for qualitative and quantitative analysis of serratiopeptidase, a proteolytic enzyme, which has recently gained importance as an anti-inflammatory agent. Efforts have been made to collate all the relevant references to the extent possible. The review discusses the advantages and disadvantages of the cited analytical techniques, which will help to give insights into the methods used for estimation of serratiopeptidase as such, from clinical isolates and from its dosage forms. The review highlights the basic as well as advanced techniques performed for estimating serratiopeptidase. The techniques illustrated here have been demonstrated to be useful for qualitative and quantitative determination of serratiopeptidase and may find application in analyzing other related proteases. PMID- 29404040 TI - Potential of RP-UHPLC-DAD-MS for the qualitative and quantitative analysis of sofosbuvir in film coated tablets and profiling degradants. AB - Sofosbuvir is one of the new direct-acting antiviral drugs against hepatitis C virus (HCV) infection. This drug has recently been launched into the market, and generic versions of the medication are expected to be produced by local drug producers in some countries. Therefore, new methods are required to control sofosbuvir in pharmaceuticals. In the present study, a new method based on reversed phase (RP)-ultra-high performance liquid chromatography (UHPLC) coupled to diode array detection (DAD) and mass spectrometry (MS) was developed to facilitate the qualitative and quantitative analysis of sofosbuvir in film coated tablets. A wavelength of 260 nm was selected to perform a cost-effective quantification and the method showed adequate linearity, with an R2 value of 0.9998, and acceptable values of accuracy (75%-102%) and precision (residual standard deviation <5%). The detection and quantification limits were 0.07 MUg/mL and 0.36 MUg/mL, respectively. Furthermore, the use of high-resolution MS enabled us to ensure the specificity, check impurities and better sensitivity. Therefore, this methodology promises to be suitable not only for the routine analysis of sofosbuvir in pharmaceutical dosage forms, but also for potential degradants. PMID- 29404042 TI - Identification and characterization of related substances in EVT-401 by hyphenated LC-MS techniques. AB - A sensitive and selective method was developed for the separation and characterization of related substances (RSs) in EVT-401 by hyphenated LC-MS techniques. Complete separation of the RSs was achieved with an Inertsil ODS-SP column (250 mm*4.6 mm, 5 um) by linear gradient elution using a mobile phase consisting of 0.2% formic acid solution, methanol and acetonitrile. EVT-401 was found to be susceptible to acid, alkaline and oxidative stresses, while relatively stable under photolytic and thermal dry stress conditions. Fourteen RSs including six process-related substances and eight degradation products were detected and identified in EVT-401 with positive ESI high-resolution TOF-MS analysis of their parent ions and the corresponding product mass spectra elucidation, and some of them were further verified by chemical synthesis and NMR spectroscopy. The specific LC-MS method developed for separation, identification and characterization of RSs is valuable for EVT-401 manufacturing process optimization and quality control. PMID- 29404041 TI - Identification and characterization of phenolics and terpenoids from ethanolic extracts of Phyllanthus species by HPLC-ESI-QTOF-MS/MS. AB - Phyllanthus species plants are a rich source of phenolics and widely used due to their medicinal properties. A liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed using high-pressure liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-QTOF-MS/MS) for the identification and characterization of quercetin, kaempferol, ellagic acid and their derivatives in ethanolic extracts of Phyllanthus species. The chromatographic separation was carried out on Thermo Betasil C8 column (250 mm*4.5 mm, 5 um) using 0.1% formic acid in water and 0.1% formic acid in methanol as the mobile phase. The identification of diagnostic fragment ions and optimization of collision energies were carried out using 21 reference standards. Totally 51 compounds were identified which include 21 compounds identified and characterized unambiguously by comparison with their authentic standards and the remaining 30 were tentatively identified and characterized in ethanolic extracts of P. emblica, P. fraternus, P. amarus and P. niruri. PMID- 29404043 TI - A stability-indicating LC-MS/MS method for zidovudine: Identification, characterization and toxicity prediction of two major acid degradation products. AB - Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guideline. Successful separation of AZT and its degradation products was achieved by gradient elution mode on reverse phase C18 column using 10 mM ammonium acetate: acetonitrile as the mobile phase at 0.8 mL/min flow rate, 25 uL injection volume, 30 degrees C column temperature and 285 nm detection wavelength. Two major acid degradation products were identified and characterized by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS/MS) and accurate mass measurements. The probable mechanisms for the formation of degradation products were identified based on a comparison of the fragmentation pattern of the [M + H] + ions of AZT and its degradation products. One of the degradation products, DP-1, was isolated by semi preparative high performance liquid chromatography (HPLC) using Waters XBridge Prep C18 (250 mm*10 mm, 5 um). Degradation products showed higher toxicity compared to the drug in some models assessed by TOPKAT software. The method validation was performed with respect to robustness, specificity, linearity, precision and accuracy as per ICH guideline Q2 (R1). PMID- 29404044 TI - Formulation, stability testing, and analytical characterization of melatonin based preparation for clinical trial. AB - A new institutional clinical trial assessed the improvement of sleep disorders in 40 children with autism treated by immediate-release melatonin formulation in different regimens (0.5 mg, 2 mg, and 6 mg daily) for one month. The objectives of present study were to (i) prepare low-dose melatonin hard capsules for pediatric use controlled by two complementary methods and (ii) carry out a stability study in order to determine a use-by-date. Validation of preparation process was claimed as ascertained by mass uniformity of hard capsules. Multicomponent analysis by attenuated total reflectance Fourier transformed infrared (ATR-FTIR) of melatonin/microcrystalline cellulose mixture allowed to identify and quantify relative content of active pharmaceutical ingredients and excipients. Absolute melatonin content analysis by high performance liquid chromatography in 0.5 mg and 6 mg melatonin capsules was 93.6%+/-4.1% and 98.7%+/ 6.9% of theoretical value, respectively. Forced degradation study showed a good separation of melatonin and its degradation products. The capability of the method was 15, confirming a risk of false negative <0.01%. Stability test and dissolution test were compliant over 18 months of storage with European Pharmacopoeia. Preparation of melatonin hard capsules was completed manually and melatonin in hard capsules was stable for 18 months, in spite of low doses of active ingredient. ATR-FTIR offers a real alternative to HPLC for quality control of high-dose melatonin hard capsules before the release of clinical batches. PMID- 29404045 TI - Taste masking of ofloxacin and formation of interpenetrating polymer network beads for sustained release. AB - The objective of this study was to carry out taste masking of ofloxacin (Ofl) by ion exchange resins (IERs) followed by sustained release of Ofl by forming interpenetrating polymer network (IPN) beads. Drug-resin complexes (DRCs) with three different ratios of Ofl to IERs (1:1, 1:2, 1:4) were prepared by batch method and investigated for in vivo and in vitro taste masking. DRC of methacrylic acid-divinyl benzene (MD) resin and Ofl prepared at a ratio of 1:4 was used to form IPN beads. IPN beads of MD 1:4 were prepared by following the ionic cross-linking method using sodium carboxymethyl xanthan gum (SCMXG) and SCMXG-sodium carboxymethyl cellulose (SCMXG-SCMC). IPN beads were characterized with FT-IR and further studied on sustained release of Ofl at different pH. In vivo taste masking carried out by human volunteers showed that MD 1:4 significantly reduced the bitterness of Ofl. Characterization studies such as FT IR, DSC, P-XRD and taste masking showed that complex formation took place between drug and resin. In vitro study at gastric pH showed complete release of drug from MD 1:4 within 30 min whereas IPN beads took 5 h at gastric pH and 10 h at salivary pH for the complete release of drug. As the crosslinking increased the release kinetics changed into non-Fickian diffusion to zero-order release mechanism. MD 1:4 showed better performance for the taste masking of Ofl and IPNs beads prepared from it were found useful for the sustained release of Ofl at both the pH, indicating a versatile drug delivery system. PMID- 29404046 TI - A chemiluminescence reagent free method for the determination of captopril in medicine and urine samples by using trivalent silver. AB - A novel flow-injection chemiluminescence (FI-CL) method free of CL reagent was developed for the determination of captopril based on its enhancing effect on the CL derived from diperiodatoargentate(III)-sulfuric acid system. Compared with the conventional CL system, the CL system based on trivalent silver was characterized of good selectivity for the absence of CL reagent. The CL mechanism was discussed through CL spectra and UV-vis absorption spectra. The conditions of the FI-CL system were investigated and optimized. Under the optimal conditions, the relative CL intensity was linear with the captopril concentration in the range of 0.3-15.0 MUg/mL. The detection limit for captopril was 0.05 MUg/mL, and the relative standard deviation (n=11) was 2.0% for 5.0 MUg/mL captopril. The proposed method was applied to the analysis of captopril in tablet and human urine with the recoveries of 83.1%-112.5%, and the relative standard deviations of 0.5%-4.4%. The results obtained by the proposed method agreed well with those obtained from HPLC method. The proposed method is fast, convenient, and cost effective for the determination of captopril in medicine and biological samples. PMID- 29404047 TI - Electrochemical determination of an anti-hyperlipidimic drug pitavastatin at electrochemical sensor based on electrochemically pre-treated polymer film modified GCE. AB - An electrochemically pretreated silver macroporous (Ag MP) multiwalled carbon nanotube modified glassy carbon electrode (PAN-Ag MP-MWCNT-GCE) was fabricated for the selective determination of an anti-hyperlipidimic drug, pitavastatin (PST). The fabricated electrochemical sensor was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The fabricated electrode was employed in quantifying and determining PST through differential pulse adsorptive stripping voltammetry (DPAdSV) and CV. The electrode fabrication proceeded with remarkable sensitivity to the determination of PST. The effect of various optimized parameters such as pH, scan rate (nu), accumulation time (tacc), accumulation potential (Uacc) and loading volumes of Ag MP-MWCNT suspension were investigated to evaluate the performance of synthesized electrochemical sensor and to propose a simple, accurate, rapid and economical procedure for the quantification of PST in pharmaceutical formulations and biological fluids. A linear response of PST concentration in the range 2.0*10-7 1.6*10-6 M with low detection (LOD) and quantification (LOQ) limits of 9.66+/ 0.04 nM and 32.25+/-0.07 nM, respectively, were obtained under these optimized conditions. PMID- 29404048 TI - Chromatoprobe as a sample-sparing technique for residual solvent analysis of drug discovery candidates by gas chromatography. AB - In drug discovery research, residual solvent measurement is an integral part of purity analysis for synthesis of a drug candidate before it is used for toxicity testing. This is usually carried out using gas chromatography (GC) with direct injection sample introduction. This method requires testing compounds to be soluble at high concentrations (>50 mg/mL, usually in DMSO) to achieve acceptable sensitivity, a hurdle which is not always achievable for some samples such as cyclic peptides and oligonucleotides. To overcome the limitation associated with the direct injection approach, a new method using the Chromatoprobe thermal extraction device was developed for quantifying residual solvents of drug discovery compounds. This method not only consumes significantly less material (less than 1 mg), but also shows higher sensitivity than the direct injection approach. In addition, because no diluent is required with the Chromatoprobe thermal extraction, all residual solvents can be detected and measured without further method optimization. In our study, we compared data from GC residual solvent analysis using the Chromatoprobe solid sample introduction to those of the direct injection method for seven in-house samples. Our results showed a good agreement between the data from these two sample introduction methods. Thus, the Chromatoprobe sample introduction method provided a sample-sparing alternative to the direct injection method for the measurement of residual solvents in drug discovery. This method can be particularly useful for residual solvent analysis in samples that are available only in limited amounts, poorly soluble, and/or unstable in the diluents used for the direct injection method. PMID- 29404049 TI - A holistic strategy for quality and safety control of traditional Chinese medicines by the "iVarious" standard system. AB - An effective quality control system is the key to ensuring the quality, safety and efficacy of traditional Chinese medicines (TCMs). However, the current quality standard research lacks the top-design and systematic design, mostly based on specific technologies or evaluation methods. To resolve the challenges and questions of quality control of TCMs, a brand-new quality standard system, named "iVarious", was proposed. The system comprises eight elements in a modular format. Meaning of every element was specifically illustrated via corresponding research instances. Furthermore, frankincense study was taken as an example for demonstrating standards and research process, based on the "iVarious" system. This system highlighted a holistic strategy for effectiveness, security, integrity and systematization of quality and safety control standards of TCMs. The establishment of "iVarious" integrates multi-disciplinary technologies and progressive methods, basis elements and key points of standard construction. The system provides a novel idea and technological demonstration for regulation establishment of TCMs quality standards. PMID- 29404050 TI - Chemical and microbiological characterization of tinctures and microcapsules loaded with Brazilian red propolis extract. AB - The aim of this study was to characterize tinctures and microcapsules loaded with an ethanol extract of red propolis through chemical, physicochemical and microbiological assays in order to establish quality control tools for nutraceutical preparations of red propolis. The markers (isoflavonoids, chalcones, pterocarpans, flavones, phenolic acids, terpenes and guttiferones) present in the tinctures A and B were identified and confirmed using LC/ESI/FTMS/Orbitrap. Four compositions (A, B, C and D) were prepared to contain B tincture of the red propolis with some pharmaceutical excipients and submitted to two drying processes, i. e. spray-drying and freeze-drying to obtain microcapsules loaded with the red propolis extract. The tinctures and microcapsules of the red propolis were submitted to the total flavonoid content and antioxidant activity tests. The antibacterial activity and minimum inhibitory concentration (MIC) were tested using Staphylococcus aureus ATCC 25293 and Pseudomonas aeruginosa ATCC 27853 strains. The tinctures and microcapsules presented high flavonoid quantities from 20.50 to 40.79 mg/100 mg of the microcapsules. The antioxidant activity and IC50 were determined for the tinctures A and B (IC50: 6.95 ug/mL and 7.48 ug/mL), the spray-dried microcapsules (IC50: 8.89-15.63 ug/mL) and the freeze-dried microcapsules (IC50: 11.83-23.36 ug/mL). The tinctures and microcapsules were proved to be bioactive against gram-positive and gram-negative bacteria with inhibition halos superior to 10 mm at concentration of 200 ug/mL and MIC values of 135.87-271.74 ug/mL using gram-positive strain and 271.74-543.48 ug/mL using gram-negative strain. The tinctures and microcapsules of the red propolis have a potential application for nutraceutical products. PMID- 29404051 TI - Simultaneous quantification of amiloride and hydrochlorothiazide in human plasma by liquid chromatography-tandem mass spectrometry. AB - A selective, sensitive and precise assay based on solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous determination of amiloride (AMI) and hydrochlorothiazide (HCTZ) in human plasma. Sample clean-up with 250 uL of plasma was done on Phenomenex StrataTM-X extraction cartridges using their labeled internal standards (AMI-15N3 and HCTZ-13C,d2). Chromatography was performed on Hypersil Gold C18 (50 mm*3.0 mm, 5 um) column using acetonitrile with 4.0 mM ammonium formate (pH 4.0, adjusted with 0.1% formic acid) (80:20, v/v) as the mobile phase. Detection was carried out on a triple quadrupole API 5500 mass spectrometer utilizing an electrospray ionization interface and operating in the positive ionization mode for AMI and negative ionization mode for HCTZ. Multiple reaction monitoring was used following the transitions at m/z 230.6/116.0, m/z 233.6/116.0, m/z 296.0/204.9 and m/z 299.0/205.9 for AMI, AMI-15N3, HCTZ and HCTZ-13C,d2, respectively. Calibration curves were linear (r2>=0.9997) over the concentration range of 0.050-50.0 and 0.50-500 ng/mL for AMI and HCTZ, respectively, with acceptable accuracy and precision. The signal-to-noise ratio at the limit of quantitation was >=14 for both the analytes. The mean recovery of AMI and HCTZ from plasma was 89.0% and 98.7%, respectively. The IS-normalized matrix factors determined for matrix effect ranged from 0.971 to 1.024 for both the analytes. The validated LC-MS/MS method was successfully applied to a bioequivalence study using 5 mg AMI and 50 mg HCTZ fixed dose tablet formulation in 18 healthy Indian volunteers with good reproducibility. PMID- 29404052 TI - Degradation rates and products of fluticasone propionate in alkaline solutions. AB - The apparent degradation rate constant of fluticasone propionate (FLT) in 0.1 M NaOH:methanol=1:1 at 37 degrees C was previously reported to be 0.169+/-0.003 h 1, and four degradation products (products 1-4) were observed in the solution. The aims of the present study were to assess the degradation rates of FLT in other alkaline solutions and clarify the chemical structures of the four degradation products in order to obtain basic data for designing an enema for inflammatory bowel disease. The apparent degradation rate constants in 0.05 M NaOH and 0.1 M NaOH:CH3CN=1:1 were 0.472+/-0.013 h-1 and 0.154+/-0.000 h-1 (n=3), respectively. The chemical structures of products 1-4 in 0.1 M NaOH:methanol=1:1 were revealed by nuclear magnetic resonance (NMR) and mass spectrometry data. The chemical structure of products 2 was that the 17-position of the thioester moiety of FLT was substituted by a carboxylic acid. The degradation product in 0.1 M NaOH:CH3CN=1:1 was found to be product 2 based on 1H NMR data. The degradation product in 0.05 M NaOH was considered to be product 2 based on the retention time of HPLC. These results are useful for detecting the degradation products of FLT by enzymes of the intestinal bacterial flora in the large intestine after dosing FLT as an enema. PMID- 29404053 TI - Separation and determination of acetyl-glutamine enantiomers by HPLC-MS and its application in pharmacokinetic study. AB - A high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) method was established for the separation and determination of acetyl-glutamine enantiomers (acetyl-L-glutamine and acetyl-D-glutamine) simultaneously. Baseline separation was achieved on Chiralpak AD-H column (250 mm * 4.6 mm, 5 um). n Hexane (containing 0.1% acetic acid) and ethanol (75:25, v/v) were used as mobile phase at a flow rate of 0.6 mL/min. The detection was operated in the negative ion mode with an ESI source. [M-H]-m/z 187.0540 for enantiomers and [M-H]-m/z 179.0240 for aspirin (IS) were selected as detecting ions. The linear range of the calibration curve for each enantiomer was 0.05-40 ug/mL. The precision of this method at concentrations of 0.5-20 ug/mL was within 7.23%, and the accuracy was 99.81%-107.81%. The precision at LOQ (0.05 ug/mL) was between 16.28% and 17.56%, which was poor than that at QC levels. The average extraction recovery was higher than 85% for both enantiomers at QC levels. The pharmacokinetics of enantiomers was found to be stereoselective. There was not chiral inversion in vivo or in vitro between enantiomers. PMID- 29404054 TI - Application of an LC-MS/MS method for the analysis of amlodipine, valsartan and hydrochlorothiazide in polypill for a bioequivalence study. AB - A sensitive and selective method has been proposed for the simultaneous determination of amlodipine (AML), valsartan (VAL) and hydrochlorothiazide (HCTZ) in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analytes and their deuterated analogs were quantitatively extracted from 100 uL human plasma by solid phase extraction on Oasis HLB cartridges. The chromatographic separation of the analytes was achieved on a Chromolith RP18e (100 mm * 4.6 mm) analytical column within 2.5 min. The resolution factor between AML and VAL, AML and HCTZ, and VAL and HCTZ was 2.9, 1.5 and 1.4, respectively, under isocratic conditions. The method was validated over a dynamic concentration range of 0.02-20.0 ng/mL for AML, 5.00-10,000 ng/mL for VAL and 0.20-200 ng/mL for HCTZ. Ion-suppression/enhancement effects were investigated by post-column infusion technique. The mean IS-normalized matrix factors for AML, VAL and HCTZ were 0.992, 0.994 and 0.998, respectively. The intra-batch and inter-batch precision (% CV) across quality control levels was <= 5.56% and the recovery was in the range of 93.4%-99.6% for all the analytes. The method was successfully applied to a bioequivalence study of 5 mg AML + 160 mg VAL + 12.5 mg HCTZ tablet formulation (test and reference) in 18 healthy Indian males under fasting. The mean log-transformed ratios of Cmax, AUC0-120h and AUC0-inf and their 90% CIs were within 90.2%-102.1%. The assay reproducibility was demonstrated by reanalysis of 90 incurred samples. PMID- 29404055 TI - Identification of botanical origin of Chinese unifloral honeys by free amino acid profiles and chemometric methods. AB - The amino acid contents of five floral sources Chinese honeys (jujube, rape, chaste, acacia, and lungan) were measured using reversed phase high-performance liquid chromatography (RP-HPLC). The results showed that proline was the main amino acid in most of the analyzed samples. Phenylalanine presents at the highest content in chaste honey samples, and the total amino acid contents of chaste honeys were also significantly higher than those of other honey samples. Based on the amino acid contents, honey samples were classified using chemometric methods (cluster analysis (CA), principal component analysis (PCA), and discriminant analysis (DA)). According to the CA results, chaste honeys could be separated from other honeys, while the remaining samples were correctly grouped together when the chaste honey data were excluded. By using DA, the overall correct classification rate reached 100%. The results revealed that amino acid contents could potentially be used as indicators to identify the botanical origin of unifloral honeys. PMID- 29404056 TI - Analysis of penicillamine using Cu-modified graphene quantum dots synthesized from uric acid as single precursor. AB - A simple methodology was developed to quantify penicillamine (PA) in pharmaceutical samples, using the selective interaction of the drug with Cu modified graphene quantum dots (Cu-GQDs). The proposed strategy combines the advantages of carbon dots (over other nanoparticles) with the high affinity of PA for the proposed Cu-GQDs, resulting in a significant and selective quenching effect. Under the optimum conditions for the interaction, a linear response (in the 0.10-7.50 umol/L PA concentration range) was observed. The highly fluorescent GQDs used were synthesized using uric acid as single precursor and then characterized by high resolution transmission electron microscopy, Raman spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, fluorescence, and absorption spectroscopy. The proposed methodology could also be extended to other compounds, further expanding the applicability of GQDs. PMID- 29404057 TI - In-depth investigation on physicochemical and thermal properties of magnesium (II) gluconate using spectroscopic and thermoanalytical techniques. AB - Magnesium gluconate is a classical organometallic pharmaceutical compound used for the prevention and treatment of hypomagnesemia as a source of magnesium ion. The present research described the in-depth study on solid state properties viz. physicochemical and thermal properties of magnesium gluconate using sophisticated analytical techniques like PXRD, PSA, FT-IR, UV-Vis spectroscopy, TGA/DTG, and DSC. Magnesium gluconate was found to be crystalline in nature along with the crystallite size ranging from 14.10 to 47.35 nm. The particle size distribution was at d(0.1)=6.552 um, d(0.5)=38.299 um, d(0.9)=173.712 um and D(4,3)=67.122 um along with the specific surface area of 0.372 m2/g. The wavelength for the maximum absorbance was at 198.0 nm. Magnesium gluconate exhibited 88.51% weight loss with three stages of thermal degradation process up to 895.18 degrees C from room temperature. The TGA/DTG thermograms of the analyte indicated that magnesium gluconate was thermally stable up to around 165 degrees C. Consequently, the melting temperature of magnesium gluconate was found to be 169.90 degrees C along with the enthalpy of fusion of 308.7 J/g. Thus, the authors conclude that the achieved results from this study are very useful in pharmaceutical and nutraceutical industries for the identification, characterization and qualitative analysis of magnesium gluconate for preformulation studies and also for developing magnesium gluconate based novel formulation. PMID- 29404058 TI - Effect of plasma surface treatment of poly(dimethylsiloxane) on the permeation of pharmaceutical compounds. AB - This paper addresses the modification of poly(dimethylsiloxane), i.e. PDMS, using plasma surface treatment and a novel application of the membrane created. A set of model compounds were analysed to determine their permeation through PDMS, both with and without plasma treatment. It was found that plasma treatment reduced permeation for the majority of compounds but had little effect on some compounds, such as caffeine, with results indicating that polarity plays an important role in permeation, as is seen in human skin. Most importantly, a direct correlation was observed between plasma-modified permeation data and literature data through calculation of membrane permeability (Kp) values suggesting plasma-modified silicone membrane (PMSM) could be considered as a suitable in vivo replacement to predict clinical skin permeation. PMID- 29404059 TI - Isolation, characterization and chromatography based purification of antibacterial compound isolated from rare endophytic actinomycetes Micrococcus yunnanensis. AB - Endophytic actinomycetes are considered as one of the relatively unexplored potential sources in search of antibiotic producer against antibiotic resistant pathogens. A potent strain isolated from Catharanthus roseus that displays antibacterial potential against antibiotic resistant human pathogen Staphylococcus aureus was characterized and designated as Micrococcus yunnanensis strain rsk5. Rsk5 is capable of producing optimum antibacterial metabolites on starch casein medium at 30 degrees C, pH 5 and 2% NaCl condition. The crude antibacterial agent was extracted from fermentation broth by ethyl acetate and separated by TLC using chloroform-methanol (24:1, v/v) solvent system with Rf value of 0.26. It was partially purified by flash chromatography, followed by HPLC and analyzed by ultraviolet visible spectrophotometer to get absorption maxima at 208.4 nm. The ESI-MS spectra showed molecular ion peaks at m/z 472.4 [M H], which does not match with any known antibacterial compound. PMID- 29404060 TI - Application of HPLC and ESI-MS techniques in the analysis of phenolic acids and flavonoids from green leafy vegetables (GLVs). AB - Diets containing high proportions of fruits and vegetables reduce the risk of onset of chronic diseases. The role of herbal medicines in improving human health is gaining popularity over the years, which also increases the need for safety and efficiency of these products. Green leafy vegetables (GLVs) are the richest source of phenolic compounds with excellent antioxidant properties. Increased consumption of diets containing phenolic compounds may give positive and better results to human health and significantly improves the immune system. Highly selective, susceptible and versatile analytical techniques are necessary for extraction, identification, and quantification of phenolic compounds from plant extracts, which helps to utilize their important biological properties. Recent advances in the pre-treatment procedures, separation techniques and spectrometry methods are used for qualitative and quantitative analysis of phenolic compounds. The online coupling of liquid chromatography with mass spectrometry (LC-MS) has become a useful tool in the metabolic profiling of plant samples. In this review, the separation and identification of phenolic acids and flavonoids from GLVs by LC-MS have been discussed along with the general extraction procedures and other sources of mass spectrometer used. The review is devoted to the understanding of the structural configuration, nature and accumulation pattern of phenolic acids and flavonoids in plants and to highlighting the recent developments in the chemical investigation of these compounds by chromatographic and spectroscopic techniques. It concludes with the advantages of the combination of these two methods and prospects. PMID- 29404061 TI - Development of a novel stability indicating RP-HPLC method for quantification of Connexin43 mimetic peptide and determination of its degradation kinetics in biological fluids. AB - Connexin43 mimetic peptide (Cx43MP) has been intensively investigated for its therapeutic effect in the management of inflammatory eye conditions, spinal cord injury, wound healing and ischemia-induced brain damage. Here, we report on a validated stability-indicating reversed-phase high performance liquid chromatography (RP-HPLC) method for the quantification of Cx43MP under stress conditions. These included exposure to acid/base, light, oxidation and high temperature. In addition, the degradation kinetics of the peptide were evaluated in bovine vitreous and drug-free human plasma at 37 degrees C. Detection of Cx43MP was carried out at 214 nm with a retention time of 7.5 min. The method showed excellent linearity over the concentration range of 0.9-250 ug/mL (R2 >= 0.998), and the limits of detection (LOD) and quantification (LOQ) were found to be 0.90 and 2.98 MUg/mL, respectively. The accuracy of the method determined by the mean percentage recovery at 7.8, 62.5 and 250 ug/mL was 96.79%, 98.25% and 99.06% with a RSD of < 2.2%. Accelerated stability studies revealed that Cx43MP was more sensitive to basic conditions and completely degraded within 24 h at 37 degrees C (0% recovery) and within 12 h at 80 degrees C (0.34% recovery). Cx43MP was found to be more stable in bovine vitreous (t1/2slow= 171.8 min) compared to human plasma (t1/2slow = 39.3 min) at 37 degrees C according to the two phase degradation kinetic model. These findings are important for further pre-clinical development of Cx43MP. PMID- 29404062 TI - A validated UPLC-MS/MS method for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma. AB - A sensitive, rapid, simple and economical ultra-performance liquid chromatography tandem mass spectrometric method (UPLC-MS/MS) was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard (IS). Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A (aqueous phase: 0.15% formic acid and 0.05% ammonium acetate) and B (organic phase: acetonitrile) (A:B=40:60, v/v). The flow rate was 0.25 mL/min and the total run time was 6 min. The multiple reaction monitoring (MRM) transitions, m/z 494.5 >394.5 for imatinib, 488.7->401.5 for dasatinib, 530.7->289.5 for nilotinib and 528.5->403.4 for IS, were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 2.6-5250.0 ng/mL for imatinib, 2.0 490.0 ng/mL for dasatinib, and 2.4-4700.0 ng/mL for nilotinib. The method showed acceptable results on sensitivity, specificity, recovery, precision, accuracy and stability tests. This UPLC-MS/MS assay was successfully used for human plasma samples analysis and no significant differences were found in imatinib steady state trough concentrations among the SLC22A5 -1889T>C or SLCO1B3 699G>A genotypes (P>0.05). This validated method can provide support for clinical therapeutic drug monitoring and pharmacokinetic investigations of these three tyrosine kinase inhibitors (TKIs). PMID- 29404063 TI - Development and validation of a high throughput LC-MS/MS method for simultaneous quantitation of pioglitazone and telmisartan in rat plasma and its application to a pharmacokinetic study. AB - Management of cardiovascular risk factors in diabetes demands special attention due to their co-existence. Pioglitazone (PIO) and telmisartan (TLM) combination can be beneficial in effective control of cardiovascular complication in diabetes. In this research, we developed and validated a high throughput LC-MS/MS method for simultaneous quantitation of PIO and TLM in rat plasma. This developed method is more sensitive and can quantitate the analytes in relatively shorter period of time compared to the previously reported methods for their individual quantification. Moreover, till date, there is no bioanalytical method available to simultaneously quantitate PIO and TLM in a single run. The method was validated according to the USFDA guidelines for bioanalytical method validation. A linear response of the analytes was observed over the range of 0.005-10 ug/mL with satisfactory precision and accuracy. Accuracy at four quality control levels was within 94.27%-106.10%. The intra- and inter-day precision ranged from 2.32% 10.14 and 5.02%-8.12%, respectively. The method was reproducible and sensitive enough to quantitate PIO and TLM in rat plasma samples of a preclinical pharmacokinetic study. Due to the potential of PIO-TLM combination to be therapeutically explored, this method is expected to have significant usefulness in future. PMID- 29404064 TI - Application of a validated HPLC-PDA method for the determination of melatonin content and its release from poly(lactic acid) nanoparticles. AB - Melatonin is a natural hormone and with the advancement of age its production declines and thereby may result in some neurological disorders. Exogenous administration of melatonin has been suggested as a neuroprotective agent. Due to its low oral bioavailability, the loading of melatonin in polymeric nanoparticles could be an important tool to effectively use exogenous melatonin. The quantification of the incorporated drug within polymeric nanoparticles is an important step in nanoparticles characterization. An analytical method using high performance liquid chromatography equipped with photodiode array detector (HPLC PDA) was developed and validated for melatonin determination in poly (lactic acid) nanoparticles obtained by a single emulsion-solvent evaporation technique. The melatonin in vitro release profile also was determined by the HPLC method. Mobile phase consisted of acetonitrile: water (65:35, v/v) pumped at a flow rate of 0.9 mL/min, in the isocratic mode and PDA detector was set at 220 nm. The method was validated in terms of the selectivity, linearity, precision, accuracy, robustness, limits of detection and quantification. Analytical curve was linear over the concentration range of 10-100 MUg/mL, and limits of detection and quantification were 25.9 ng/mL and 78.7 ng/mL, respectively. The mean recovery for melatonin was 100.47% (RSD = 1.25%, n = 9). In the intra- and inter-assay, the coefficient of variation was less than 2%. Robustness was proved performing changes in mobile phase, column temperature and flow rate. The method was suitable for the determination of melatonin encapsulation efficiency in poly(lactic acid) nanoparticles and for the evaluation of melatonin in vitro release profile. PMID- 29404065 TI - Synthesis, isolation, identification and characterization of new process-related impurity in isoproterenol hydrochloride by HPLC, LC/ESI-MS and NMR. AB - One unknown impurity (Imp-II) during the analysis of laboratory batches of isoproterenol hydrochloride was detected in the level ranging from 0.04% to 0.12% by high performance liquid chromatography with UV detection. The unknown impurity structure was proposed as 4-[2-(propan-2-ylamino)ethyl]benzene-1,2-diol (Imp-II) using the liquid chromatography--mass spectrophotometry (LC--MS) analysis. Imp-II was isolated by semi-preparative liquid chromatography from the impurity-enriched reaction crude sample. Its proposed structure was confirmed by nuclear magnetic spectroscopy such as 1H, 13C, DEPT (1D NMR), HSQC (2D NMR) and infrared spectroscopy (IR), and retention time and purity with HPLC followed by the chemical synthesis. Due to less removable nature of Imp-II during the purification, the synthetic process was optimized proficiently to control the formation of Imp-II below to the limit<0.12% in the course of reaction. The new chemical route was developed for the preparation of this impurity in required quantity with purity to use as reference standard. The most probable mechanism for the formation of Imp-II was discussed in details. PMID- 29404066 TI - Quantification of theophylline or paracetamol in milk matrices by high performance liquid chromatography. AB - A simple, accurate and sensitive high-performance liquid chromatography (HPLC) method was developed, validated and applied to the determination of either theophylline or paracetamol in milk-based samples. The method allowed drug quantification in fresh and powdered milk with a relatively short run time of analysis and it was also successfully applied to the quantification of the drugs in solid dosage forms intended for pediatric use. Moreover, the main significant advantages over other published works are the simplicity of the sample preparation, reduced assay time and sample loss. The method meets the International Conference on Harmonization guideline for analytical methods validation regarding specificity, linearity, accuracy, precision, specificity and robustness as required by health authorities and applied by industry while designing and marketing new drug products. The technique encompasses the separation of the analytes with a reverse phase C18 column under isocratic conditions and UV detection at 272 nm and 243 nm, respectively, for theophylline and paracetamol. The lower limit of quantification for both drugs was determined as 0.2 ug/mL and the between-batch accuracy was approximately 99.7%. This HPLC method allows quantification of theophylline and paracetamol in milk matrices and it can be applied in the design, development and production of milk-based pediatric dosage forms. PMID- 29404068 TI - Simultaneous colorimetric determination of morphine and ibuprofen based on the aggregation of gold nanoparticles using partial least square. AB - In this work a new method is presented for simultaneous colorimetric determination of morphine(MOR) and ibuprofen(IBU) based on the aggregation of citrate-capped gold nanoparticles (AuNPs). Citrate-capped gold nanoparticles were aggregated in the presence of morphine and ibuprofen. The difference in kinetics of AuNPs aggregation in the presence of morphine / ibuprofen was used for simultaneous analysis of morphine and ibuprofen. The formation and size of synthesized Au NPs and the aggregated forms were monitored by infra-Red (IR) spectroscopy and transmission electron microscopy (TEM) respectively.. By adding morphine or ibuprofen the absorbance was decreased at 520 nm and increased at 620 nm. The difference in kinetic profiles of aggregation was applied for simultaneous analysis of MOR and IBU using partial least square regression as an efficient multivariate calibration method. The number of PLS latent variables was optimized by leave-one-out cross-validation method using predicted residual error sum of square. The proposed model exhibited a high capability in simultaneous prediction of MOR and IBU concentrations in real samples. Our results showed linear ranges of 1.33-33.29 ug/mL (R2=0.9904) and 0.28-6.9 ug/mL (R2=0.9902) for MOR and IBU respectively with low detection limits of 0.15 and 0.03 ug/mL(S/N=5). PMID- 29404067 TI - Development of a UPLC-MS/MS method for determination of pimavanserin tartrate in rat plasma: Application to a pharmacokinetic study. AB - A simple, rapid and sensitive method based on an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for the determination of pimavanserin in rat plasma. The analyte was extracted by protein precipitation with methanol and separated on an ACQUITY BEH C18 column (100 * 2.1 mm, 1.7 um; Waters, USA), with an isocratic elution of acetonitrile-water containing 10 mM ammonium acetate (70:30, v/v), at a flow rate of 0.2 mL/min for 2.5 min. The analyte and clarithromycin (the internal standard) were detected and quantified in positive ion mode using multiple reaction monitoring transitions at m/z 428.2 -> 223.0 for pimavanserin and m/z 748.5 -> 589.5 for clarithromycin. Relative coefficient (r) for the calibration curve was more than 0.9980. The intra-day and inter-day precisions (relative standard deviation, RSD%) were less than 13.3% and 10.5%, respectively, and the accuracy (relative error, RE%) was within +/- 11.5%. The analytical method was successfully applied to a routine pharmacokinetic study of pimavanserin in rats after oral administration at the dose of 10 mg/kg. PMID- 29404069 TI - Determination of ergocalciferol in human plasma after Diels-Alder derivatization by LC-MS/MS and its application to a bioequivalence study. AB - An accurate, sensitive and selective method is developed for determination of ergocalciferol (vitamin D2) in human plasma using LC-MS/MS. After liquid-liquid extraction with n-hexane, ergocalciferol was derivatized by reacting with 4 phenyl-1,2,4-triazoline-3,5-dione (PTAD), a strong dienophile based on Diels Alder reaction. Ergocalciferol and its deuterated internal standard, ergocalciferol-d6, were analyzed on X Select CSH C18 (100 mm*4.6 mm, 2.5 um) column using acetonitrile and 0.1% (v/v) formic acid in water containing 0.14% methylamine within 6.0 min under gradient elution mode. Tandem mass spectrometry in positive ionization mode was used to quantify ergocalciferol by multiple reaction monitoring (MRM). Entire data processing was done using Watson LIMSTM software which provided excellent data integrity and high throughput with improved operational efficiency. The major advantage of this method includes higher sensitivity (0.10 ng/mL), superior extraction efficiency (>=83%) and small sample volume (100 uL) for processing. The method was linear in the concentration range of 0.10-100 ng/mL for ergocalciferol. The intra-batch and inter-batch accuracy and precision (% CV) values varied from 97.3% to 109.0% and 1.01% to 5.16%, respectively. The method was successfully applied to support a bioequivalence study of 1.25 mg ergocalciferol capsules in 12 healthy subjects. PMID- 29404070 TI - Tuberculous Pleural Effusion. AB - When a patient presents with new pleural effusion, the diagnosis of tuberculous (TB) pleuritis should be considered. The patient is at risk for developing pulmonary or extrapulmonary TB if the diagnosis is not made. Between 3% and 25% of patients with TB will have TB pleuritis. The incidence of TB pleuritis is higher in patients who are human immunodeficiency virus (HIV)-positive. Pleural fluid is an exudate that usually has a predominance of lymphocytes. The easiest way to diagnose TB pleuritis in a patient with lymphocytic pleural effusion is to demonstrate a pleural fluid adenosine deaminase level above 40 IU/L. The treatment for TB pleuritis is the same as that for pulmonary TB. Tuberculous empyema is a rare occurrence, and the treatment is difficult. PMID- 29404071 TI - Overnight Transcutaneous Carbon Dioxide Monitoring in Eucapnic Patients with Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: We monitored increases in CO2 levels during sleep by measuring transcutaneous pCO2 (PtcCO2) to determine its relationship with polysomnographic data in normocapnic patients with obstructive sleep apnea syndrome (OSAS). MATERIAL AND METHODS: Between October 2011 and December 2012, 139 patients underwent PtcCO2 monitoring with polysomnography. All patients were evaluated with arterial blood gas (ABG) measurements and pulmonary function tests (PFTs). We excluded 13 patients with COPD and/or daytime hypercapnia and 29 patients whose PtcCO2 records could not be evaluated. RESULTS: The patients' mean age was 46.8+/-10.3 years. Fifty-nine patients (60.8%) were male, and 38 (39.2%) patients were female. The mean overnight PtcCO2 was <=45 mm Hg in 84 (86.6%) patients and >45 mm Hg in 13 (13.4%) patients. In the group with PtcCO2>45 mm Hg, 10 patients had an apnea-hypopnea index (AHI) >15, and 3 patients had an AHI<15, without a statistically significant difference (p=0.078). The mean apnea and apnea/interapnea periods were similar. The mean PtcCO2 values correlated with time spent when the SpO2 was <90% (r=0.220, p<0.031). When we grouped the patients by AHI, 60 (61.8%) patients had an AHI>15 (moderate to severe OSAS), and 37 (37.2%) had an AHI<15 (mild OSAS). Of the former group, 16.7% had a mean PtcCO2 >45 mm Hg, whereas this ratio was 8.1% in the latter group. The difference was not statistically significant (p=0.359). In the group with an AHI>15, the highest PtcCO2 levels were significantly higher (p<0.05). CONCLUSION: We conclude that seemingly eucapnic OSAS patients may experience hypercapnia when sleeping, and PtcCO2 monitoring may be useful in the early diagnosis of hypercapnia. PMID- 29404072 TI - Status of Exposure to Second-Hand Smoke at Home in Children under Five Years of Age: An Example from Ankara Province. AB - OBJECTIVES: The present study aimed to investigate smoking status of households having children under 5 years of age and any changes in their smoking habits after the enforcement of the anti-tobacco Law Nb. 4207 and after the birth of the child based on the records of two Family Health Centres in Ankara. MATERIAL AND METHODS: Within the scope of this cross-sectional study, 192 houses, in which 228 children under five years of age were living, were evaluated. Data were collected via face-to-face interview. Data collection form included information regarding socio-demographic characteristics, health status, smoking habits, status of exposure to second-hand smoke. Data transfer to the computer and data analyses were performed using the SPSS 15.0 statistical package program. RESULTS: According to the statements of the study participants, the rate of smoking in the balcony, kitchen, toilet-bathroom, and rooms of the house decreased after the enforcement of the anti-tobacco Law Nb. 4207. Similar decrease was valid also for working environment. The decrease in the rate of smoking was the least in "Balconies" at both home and working environments. Birth of a child was also a factor that decreased the rate of smoking. A decrease was observed in almost all parts (bedroom, kitchen, balcony, and toilet-bathroom) of the houses after birth of a child. CONCLUSION: Exposure to second-hand smoke at homes, where children under the age of five years were living, could not be completely (100%) prevented. Health care workers' persistent study on this issue may contribute to the awareness of parents in preventing exposure to second-hand smoke. PMID- 29404073 TI - Video-Assisted Thoracoscopic Pleurectomy in Spontaneous Pneumothorax Surgery. AB - OBJECTIVES: Published experiences with thoracoscopic apical or total pleurectomy for patients with a pneumothorax are limited. We aimed to evaluate the long-term results and effectiveness of pleurectomy in our patients, that vast majority of whom underwent thoracoscopic apical or total pleurectomy. MATERIAL AND METHODS: Between January 2001 and December 2010, in the Istanbul University Medical School Department of Thoracic Surgery, 67 patients, consisting of 52 patients with a primary spontaneous pneumothorax and 15 with a secondary spontaneous pneumothorax who underwent 72 processes of thoracoscopic resection of blebs or bullae and pleural symphysis, consisting of 43% total pleurectomy, 42% apical pleurectomy plus pleural abrasion, and 15% non-pleurectomy pleurodesis procedures due to prolonged air leak or recurrent spontaneous pneumothorax, were analyzed retrospectively. The applied pleural procedures were: 1. total pleurectomy 2. apical pleurectomy and pleural abrasion for the remaining parts and 3. non pleurectomy pleurodesis procedures. The long-term outcomes of patients undergoing the three different pleural procedures were compared. RESULTS: Total pleurectomy process, apical pleurectomy and abrasion process for remaining parietal pleura, and non-pleurectomy pleurodesis procedures were performed 31, 30, and 11 times, respectively. No recurrence was observed in the total pleurectomy group, 1 recurrence was observed for the apical pleurectomy plus pleural abrasion group, and 2 recurrences were observed for the non-pleurectomy group. CONCLUSION: Video assisted thoracoscopic pleurectomy is a safe and effective method in spontaneous pneumothorax surgery. Especially, total pleurectomy has efficient results in the prevention of recurrences. PMID- 29404074 TI - Full-Time ICU Staff in the Intensive Care Unit: Does It Improve the Outcome? AB - OBJECTIVES: Patients with various severities are cared for in the intensive care unit (ICU) by an experienced ICU physician. We aimed to assess whether there is any difference in intubated ICU patient management when undertaken by a 24-hour intensivist versus a periodic experienced specialist in the ICU. MATERIAL AND METHODS: A retrospective, cross-sectional, observational study was done in a tertiary teaching hospital ICU. Patients receiving invasive mechanical ventilation (IMV) were classified into: group 1, managed by an experienced ICU pulmonary specialist during night shifts in 2006-2007, and group 2, managed by an intensivist around the clock in 2011. Patients were excluded if they were <18 years old, tracheostomized, or transferred from another ICU. Patient demographics and ICU data (IMV duration, sedation doses and duration, weekend extubation, ICU severity score [APACHE II], length of ICU stay, and mortality) were recorded, and groups were compared. RESULTS: In group 1, 131 of 215 IMV patients were included in the study, and in group 2, 294 of 374 patients were included. The sedation infusion rate, duration of IMV, self-extubation rate, and lenght of stay (LOS) of ICU were significantly increased in group 1 compared with group 2 (72.5% vs. 40.8%, p<0.0001; 152 vs. 68 hours, p<0.001; 24.4% vs. 13.9%, p<0.006; 13 vs. 8 days, p<0.0001, respectively). The weekend extubation rate and APACHE II scores were significantly lower in group 1 compared with group 2 (7.1% vs. 25.3%, p<0.0001; 22 vs. 25, p<0.017, respectively). Mortality rates were similar in the two groups (35.9% vs. 37.4%, p=0.76). CONCLUSION: A 24-hour intensivist appears to be better for decreasing IMV duration and LOS in the ICU. These results may be useful to address decreasing morbidity and, as a result, cost of ICU stays by 24 hour intensivist coverage, especially for patients with IMV. PMID- 29404075 TI - A Rare Cause of Chylothorax: Hennekam Syndrome. AB - Hennekam syndrome was defined as a syndrome characterized by a new autosomal recessive, severe lymphedema in legs, face and genitalia with intestinal lymphangiectasia, various face anomalies and severe mental retardation. A 21 years old male patient was examined due to bilateral pleural effusion. There were edema in both legs and eyelids, swelling in the scrotum and operation scar, broad forehead and face, depressed nasal bridge, epicanthal folds and micrognathia in the physical examination. Chylothorax was diagnosed due to level of pleural triglyceride (650 mg/dL). Lymphatic flow delayed in both lower extremities in lymphoscintigraphy. The patient was diagnosed as Hennekam syndrome due to face anomalies, lymphedema, epilepsy, chylothorax and mild mental retardation. PMID- 29404076 TI - Cases Diagnosed with Swyer James Macleod Syndrome in Adulthood. AB - Swyer-James-MacLeod syndrome or unilateral hyperlucent lung syndrome is a rare disease characterised by hypoplasia of the pulmonary artery, unilateral hyperlucent lung and usually bronchiectasis. The syndrome was first described by Swyer and James in 1953 in a child case, and in the following year 9 adult cases were reported by MacLeod. We retrospectively reviewed 6 adult cases, five female and one male, who were followed-up with the diagnosis of Swyer-James-MacLeod syndrome between 2005 and 2012 in our clinic. The clinical and radiological features of these 6 cases are presented in the light of the literature. PMID- 29404077 TI - Summary of Consensus Report on Preoperative Evaluation. PMID- 29404079 TI - Thoracic Traumas: A Single-Center Experience. AB - OBJECTIVES: Trauma is currently among the most important health problems resulting in mortality. Approximately 25% of trauma-related deaths are associated with thoracic trauma. In the present study, morbidity and mortality rates and interventions performed in patients who had been treated as inpatients in Dr. Siyami Ersek Thoracic and Cardiovascular Surgery hospital after trauma were aimed to be evaluated. MATERIAL AND METHODS: In our study, 404 patients who were treated as inpatients because of thoracic trauma between January 2005 and December 2008 were retrospectively evaluated. RESULTS: The rates of blunt and penetrating trauma were 39.6% and 60.4%, respectively. In the study, 115 (28.4%) patients were noted to have pneumothorax, 99 (24.5%) had hemothorax, and 57 (14.1%) had hemopneumothorax. While tube thoracostomy was sufficient for treatment in approximately 80% of the patients, major surgical interventions were performed in 12.6% of the patients. Mortality rate was found to be 2.2%. CONCLUSION: In patients with chest trauma, necessary interventions should be started at the time of the event, and the time from trauma to arriving at the emergency department should be made the best of. Mortality and morbidity rates in thoracic trauma cases may be reduced by timely interventions and effective intensive care monitoring. PMID- 29404080 TI - Comparison of Patients with Community-Acquired Pneumonia Who Did and Did not Receive Treatment in Accordance with the 2009 Pneumonia Guideline of Turkish Thoracic Society. AB - OBJECTIVES: The purpose of our study was to compare community-acquired pneumonia (CAP) patients who were and were not administered treatment in accordance with the Turkish Thoracic Society (TTS) 2009 pneumonia guideline in terms of hospital stay length, treatment cost, and treatment efficacy. MATERIAL AND METHODS: Patients who were admitted to our hospital and who were diagnosed with CAP were included in the study. Demographic characteristics of the patients, symptoms at the time of diagnosis, physical examination, laboratory and radiological findings, treatments, response to treatment at follow-up, length of hospital stay, and direct cost of treatment were recorded in the TTS pneumonia database (TURCAP: TURKEY Community Acquired Pneumonia). Taking into consideration the "Turkish Thoracic Society Consensus Report on the Diagnosis and Treatment of Community-acquired pneumonia in Adults (2009)," the patients recorded in the database were evaluated in terms of conformity to the guideline. RESULTS: This present study included 156 patients diagnosed with CAP. Sixty-six patients (42.3%) were females, and 96 (57.7%) were males, and the mean age of the patients was 70.4 years. The most common symptoms on admission were cough (94.9%), expectoration of purulent sputum (77.6%), and fever (58%). Comorbid diseases were chronic obstructive pulmonary disease (COPD; 29.5%), asthma (3.2%), lung cancer (8.3%), cardiovascular diseases (32.7%), and diabetes mellitus (12.8%). It was observed that 67.3% of the patients received treatment in accordance with the guideline. No significant difference was found in terms of gender and symptoms between the groups that received and did not receive treatment in accordance with the guideline. The mean age of the patients who received treatment according to the guideline was higher than that of the patients who did not receive treatment according to the guideline; COPD was more frequent in the group of patients who received treatment according to the guideline. Pneumonia Severity Index and Confusion, Urea, Respiratory rate, Blood pressure-Age>65 scores of the patients who were treated according to the guideline was higher and treatment resulted in death in 8% of these patients. CONCLUSION: Hospital stay length, treatment cost, and treatment efficacy were similar in patients who were and were not administered treatment in accordance with the guideline. PMID- 29404078 TI - Does Total Parenteral Nutrition Increase the Mortality of Patients with Severe Sepsis in the ICU? AB - OBJECTIVES: We aimed to evaluate the independent association between total parenteral nutrition (TPN) and nosocomial infection and intensive care unit (ICU) mortality in patients with severe pulmonary sepsis. MATERIAL AND METHODS: The present study was designed as a retrospective observational cohort study. We enrolled all patients with severe sepsis due to pulmonary infections who stayed more than 24 h in the respiratory ICU between January 2009 and December 2010. We recorded demographic characteristics, ICU severity scores, Acute Physiologic and Chronic Health Evaluation II (APACHE II) and first day Sequential Organ Failure Assessment (SOFA) score in the ICU, TPN because of intolerance to enteral feeding, ICU data, and mortality. To evaluate the risk factors for mortality, we performed adjusted logistic regression test for TPN, nosocomial infection, and SOFA in the model. RESULTS: Five hundred and fifty patients (males=375, females=175) with severe sepsis were involved in the study during the study period. The median and interquartile range (IQR) of age, APACHE II, and SOFA score at the time of admission to the ICU were 65 years (53-73), 20 (16-25), and 4 (3-6), respectively. Mortality rate was 18% (n=99). Adjusted odds ratio (OR), confidence intervals (CI) 95%, and p values of TPN, nosocomial infection, and first day SOFA score for mortality were as follows: OR:3.8, CI:2.3-6.1, p<0.001; OR:2.4, CI: 1.4-3.9, p<0.001; and OR: 1.3, CI:1.2-1.4, p<0.001, respectively. CONCLUSION: Nosocomial infection and the need for TPN because of intolerance of enteral nutrition (EN) is associated with a higher mortality rate in patients with severe sepsis in the ICU. Rational use of antibiotics and application of hospital acquired infection control program will further reduce mortality. PMID- 29404081 TI - The Prevalence of Allergic Diseases and Associated Risk Factors in School-Age Children and Adults in Erzurum, Turkey. AB - OBJECTIVES: Allergic diseases are a major public health problem, owing to their socioeconomic burden and high frequency. The aim of this study was to assess the prevalence and risk factors of allergic diseases in adults and children in the province of Erzurum. MATERIAL AND METHODS: Primary school students aged 11-12 years old filled out the International Study of Asthma and Allergies in Childhood (ISAAC) phase II questionnaire, and their parents filled out the European Community Respiratory Health Survey (ECRHS) questionnaire by themselves. We enrolled 494 questionnaires for ISAAC and 946 for ECRHS. RESULTS: The survey response rates were 91.8% for ISAAC and 87% for ECRHS. The frequencies of doctor diagnosed asthma, allergic rhinitis, conjunctivitis, atopic dermatitis, and food allergy in children were 11.9%, 8.9%, 27.3%, 3.6%, and 6.5%, respectively. In adults, the rates of wheezing in the chest, accompanying shortness of breath, and wheezing in the absence of flu within the last 12 months were 8%, 8%, and 5.5%, respectively, whereas the rate of asthma attack in the last 12 months was 2.9%, the rate of asthma medication usage was 2.6%, and the frequency of allergic rhinitis was 1.6%. The determined risk factors for childhood were "duration of attending a nursery" for asthma (p=0.02, OR=2.51, 95% CI=1.14-5.53), "having ever been to a nursery" for atopic dermatitis (p=0.02, OR=3.83, 95% CI=1.24-11.8), and "a family history of rhinitis" for food allergy (p=0.01, OR=2.94, 95% CI=1.13-6 57). CONCLUSION: The prevalence of allergic diseases in children and adults in Erzurum was found to be lower than in studies conducted throughout Turkey and in western regions of the Country. Going to a nursery, the length of nursery education, and a family history of rhinitis were identified as the risk factors for allergic diseases in children. The identification of regional risk factors and taking preventive measures in this regard may provide a reduction in the incidence of allergic diseases. PMID- 29404082 TI - Ethical Issues in Tuberculosis Control. AB - Tuberculosis (TB) remains a major global public health problem as also defined by the World Health Organization (WHO). On the other hand, the incidence of TB worldwide decreases at a lower rate than the intended targets, and it is seen that the targets set for 2015 will not be achieved at the global level. According to the WHO, failure to achieve the targets in TB control results from "resource constraints", "conflict and instability" and "generalized human immunodeficiency virus epidemics". This article is aimed to maintain an ethical debate in TB control and to investigate the WHO's TB control policy and question the reasons for failure of this policy. Within the scope of this article; the TB of TB control was problematized at macro political level within the context of philosophy, while the approach of health care staff to TB patients was analysed at micro level within the context of professional ethics. PMID- 29404084 TI - Chilaiditi Syndrome in Two Cases Presented with Respiratory Distress Symptoms. AB - Chilaiditi syndrome is a rare syndrome known hepatodiaphramatic interposition of as colon or small intestine. As this pathology is usually asymptomatic, it is incidentally identified in adults and rarely reported in children. Herein, two children cases are presented with respiratory distress, who were diagnosed as Chilaiditi syndrome by chest radiography. PMID- 29404083 TI - Updates in Chronic Obstructive Pulmonary Disease for the Year 2014. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the world. Research conducted over the past decade has contributed much to our current knowledge of the pathogenesis and treatment of COPD. Additionally, an evolving literature has recently accumulated information about the management of COPD and also about exacerbations. This article reviews a concise summary on the updates in COPD including 1) new pathogenic mechanisms and therapeutic targets, 2) management of patients in Group B, C and D according to GOLD 2014 report; 3) prevention and management of exacerbation; 4) monitoring of natural history; and 5) essential but usually forgotten parts of the management. PMID- 29404085 TI - Mediastinal Teratoma with Coexisting Adenocarcinoma and Carcinoid Tumor (Somatic Type Malignancy): A Case Report with a Review of the Literature. AB - Germ cell tumors constitute 10% to 15% of anterior mediastinal neoplasms. Of these, mature teratoma is the most common. Somatic malignant transformation in mature teratoma is a very rare phenomenon. In the anterior mediastinum, few cases of malignant transformation in the form of carcinoma, sarcoma, or neuroendocrine tumors have been described. We present the case of a mature mediastinal teratoma in a 24-year-old female, diagnosed on computed tomography, where both carcinoid tumor and adenocarcinoma were seen. To the best of our knowledge, this is the first report of such a case. Malignant transformation in a mature teratoma confers a significantly worse prognosis and is difficult to diagnose only on clinical and radiological evaluation. As these lesions are so rare, the treatment options for these lesions are also not clearly defined. Extensive sampling and careful microscopic examination are needed when teratomas are submitted for pathological evaluation. PMID- 29404086 TI - Elimination of Asbestos-Related Diseases in Turkey Still Has a Long Way to Go. PMID- 29404087 TI - Hospital Treatment Costs and Factors Affecting These Costs in Community-Acquired Pneumonia. AB - OBJECTIVES: Community-acquired pneumonia (CAP) accounts for an important part of hospital admissions and health expenses worldwide. The cost increases when treated in a hospital, and reports on this issue are limited in Turkey. This study aimed to investigate direct hospital costs and factors affecting these costs for patients who were hospitalized in our clinic because of the diagnosis of CAP. MATERIAL AND METHODS: The records of patients who had been hospitalized for the diagnosis of CAP were retrospectively reviewed. Demographic features, radiological features, pneumonia severity index (PSI), CURB-65 scorings, duration of hospitalization, treatments, and the results of treatments were examined. Total hospitalization costs and the expenses for intervention, medication, examinations, and additional services were recorded. The effect of data on the cost was evaluated. RESULTS: The study was conducted with 87 patients with CAP. The mean duration of hospitalization was 15.6 days and nine patients (10.3%) were exitus. The median total hospital cost was 2062 (451-11690) TL [952 euros (?), 1305 dollars ($)], and the median hospitalization expense per day was 148 Turkish Lira (TL) (68.3 ?, 93.7 $). Medication expenses and total cost were higher in male patients than in female patients. Abscess/necrotizing pneumonia increased the cost depending on the infiltration that occurred either alone or with parapneumonic pleurisy. Whereas an increase in the PSI stage increased the total cost and expenses for intervention and medication, medication expenses increased in patients with CURB-65 score of 3 and 4 (p<0.05). Age, smoking, and low oxygen saturation level did not affect the cost. No statistically significant difference was found between the expenses of exitus patients and the expenses of patients who recovered. CONCLUSION: CAP can lead to high costs and result in death. In our study, it was concluded that the cost increased in male patients, patients with abscess/necrotizing pneumonia, and patients with high PSI scores. PMID- 29404088 TI - Idiopathic Pulmonary Fibrosis: A Study of 46 Patients from Western India: Clinical Presentations and Survival. AB - OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease (ILD) diagnosed all over the world as well as in India. The objective was to study the clinical presentations, treatment options, and survival of patients diagnosed with IPF. MATERIALS AND METHODS: This was a 6-year retrospective observational study. All patients diagnosed with ILD underwent a comprehensive evaluation to confirm the diagnosis of IPF and were subsequently included in the study. Clinical data and laboratory data were recorded. Patients were treated as per current guidelines. RESULTS: Out of the total number of patients (n=123) diagnosed with ILD, 46 (37.4%) patients were included in the study [Males, n=19 (41%) and females, n=27 (59%)]. Sixty-seven percent (n=31) of the patients were in the age group of 61-80 years. The mean age of males and females was 68.36 and 66.25 years, respectively. Clubbing was observed in 67% (n=29) of the patients. The mean forced vital capacity (FVC) was 52%. High resolution computed tomography (HRCT) of the chest showed a definite usual interstitial pneumonia (UIP) pattern of honeycombing in 60% (n=28) of the patients. Desaturation on a 6 min walk distance was noted in 60% (n=28) of the patients. Ten patients wrongly received-anti tuberculosis treatment (21%) before they were diagnosed with IPF. The median delay in diagnosis was 20 months. The 5 year survival rate was 25%; the average survival was 39 months. Patients receiving pirfenidone showed a survival benefit compared with those having received triple therapy. Survival in IPF was significantly low compared with that in other ILDs. Twenty-four (52%) patients died during the study. CONCLUSION: IPF is a disease which affects the fourth to seventh decade of the Indian population with low survival. PMID- 29404089 TI - Factors Affecting Smoking Status of Nursing Students and Their Addiction Levels. AB - OBJECTIVES: This study was conducted to determine the smoking habits of students of Ataturk Health College of Dicle University and the factors affecting them. MATERIAL AND METHODS: This cross-sectional study was performed between April 15 and 19, 2013. The selection of sampling was not conducted, since the whole study population included. Of 400 registered students, 326 (81.5%) were included. For collecting data, a questionnaire form designed by the researcher and Fagerstrom test for nicotine dependence for determining the addiction level were applied. Percentage calculation was used for analyzing data, and chi-square test was employed for evaluating the relationship between the variables. RESULTS: The mean age of students was 21.4+/-2.3 years. Of them, 12.3% still smoked and 4% had quit. Of the smokers, 21.9% were males and 3.5% were females. Of the smokers, 67.5% stated that they tried to quit smoking and 72.5% replied that they thought of quitting smoking in the future. It was found that 47.5% of the students smoked 11-20 cigarettes a day. Of the students who still smoked and who had quitted, 47.2% had begun to smoke at the age of 10-15 years. As the cause for smoking initiation, 50.9% of the students revealed stress, difficulties, and sadness and 35.8% revealed the effect of a friend. A statistically significant difference was found between smoking habit and age, gender, class, and the presence of smokers among close friends (p<0.05). Moreover, it was detected that 35% of the students were over dependent. CONCLUSION: The prevalence of smoking among the youth is high. To decrease smoking prevalence, the reasons for smoking initiation should be investigated and some precautions should be taken before the university age, and they should be continued during the university education. PMID- 29404090 TI - Determination of Factors Affecting Mortality of Patients with Sepsis in a Tertiary Intensive Care Unit. AB - OBJECTIVES: Sepsis is a disease with high mortality that is frequently observed in intensive care units. This study aimed to determine the risk factors affecting mortality of patients with sepsis who were followed up in the intensive care unit (ICU). We aimed to contribute to literature by evaluating the relationship between mortality and pro-brain natriuretic peptide (pro-BNP9), C-reactive protein (CRP), thrombocyte count, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, duration of hospitalization in the intensive care unit, and the presence of multidrug resistant microorganism. MATERIAL AND METHODS: Patients hospitalized in ICU because of the diagnosis of sepsis and septic shock between December 2010 and June 2012 were included in this retrospective study. RESULTS: A total of 141 patients, including 74 male (52.5%) and 67 female (47.5%) patients, were involved in the study, and the median age was 66.8+/-17.9 years. Sixty-nine patients (48.9%) were discharged from the ICU; however, 72 patients (51.1%) were exitus. Multidrug-resistant microorganism was detected in 34 patients (24.1%). The patients' median SOFA score was 9.16+/-3.16, median APACHE-II score was 24.9+/ 7.83, and median duration of hospitalization in the ICU was 8.44+/-11.61 days. It was found that mortality rate significantly increased in patients with the APACHE II score of 24.5 and over, SOFA score of 8.5 and over, pro BNP value of 7241 ng/L and over, and CRP value of 96.5 mg/dL and over. Mortality rate was detected to be higher in patients undergoing invasive mechanical ventilation than in patients undergoing non-invasive mechanical ventilation. When thrombocyte count and mortality were associated with each other, it was found that the median value was 86000 mg/dL in exitus patients, whereas it was 185000 mg/dL in patients discharged from the ICU. CONCLUSION: It was revealed that increased APACHE-II score, increased SOFA score, increased pro BNP score, increased CRP, the presence of multidrug-resistant microorganism, and decreased thrombocyte count elevated the rate of mortality. However, no relationship was observed between the duration of hospitalization in the ICU and mortality. PMID- 29404092 TI - Erratum. AB - [This corrects the article on p. 86 in vol. 16.]. PMID- 29404093 TI - Tobacco Control in Turkey. PMID- 29404091 TI - Allergic Respiratory Inflammation and Remodeling. AB - Asthma and rhinitis are inflammatory diseases of the respiratory tract. Respiratory inflammation of the adaptive and innate immune system is the focus of this review, and chronic inflammation is not limited to the respiratory tissue. The inflammatory response, which consists of phagocytes, eosinophils, mast cells, and lymphocytes, spreads along the respiratory tract, leading to tissue damage. Mast cells and eosinophils are commonly recognized for their detrimental role in allergic reactions on activation through the high- and low-affinity receptors for IgE FcERI. These cells rapidly produce and secrete many of the mediators responsible for the typical symptoms of asthma and rhinitis. However, increasing amount of evidence demonstrate that mast cells and leukocytes have vital roles in host defense against pathogenesis. Histological methods are used to study leukocytes and receptor expression pattern in different respiratory tract compartments. The overall aim of this review was to understand the relationship between upper and lower respiratory tract inflammation and remodeling in patients with allergic and non-allergic asthma and rhinitis. In conclusion, this review discusses the relationship between the upper and lower airway in respiratory disease and focuses on the effect of respiratory processes on laryngeal inflammation, remodeling, function, and symptoms; however, they also have a central role in the initiation of the allergic immune response. Our findings suggest that there are differences that contribute to the development of immunopathological mechanisms of these clinically distinct forms of asthma, rhinitis, and chronic obstructive pulmonary disease. PMID- 29404094 TI - Cow's Milk Allergy in Preterm Infant with Bronchopulmonary Dysplasia. AB - Cow's milk allergy is frequent in the first year of life. The symptoms may start during the first weeks of life, and may be cutaneous (50-60%), gastrointestinal (50-60%) or respiratory (20-30%), often involving more than one organ system. In this report, we describe a case of cow's milk allergy in a preterm infant in whom rectal bleeding and respiratory symptoms resolved with the introduction of an extensively hydrolyzed formula. Occurrence of the respiratory symptoms of this disorder in a preterm infant with bronchopulmonary dysplasia may cause re hospitalization after discharge. PMID- 29404095 TI - A Case of Langerhans Cell Histiocytosis with Atypical Radiological Presentation. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by the accumulation of histiocytes within the airspaces or parenchyma of the lung. It almost always occurs in smokers between the ages of 20 and 40. Bronchoscopic interventions, such as transbronchial biopsy (TBB) and bronchoalveolar lavage (BAL), should be performed before other more invasive procedures, but their diagnostic yield is lower. TBB is frequently non-diagnostic due to inadequate sampling. BAL cellular analysis may show alveolar macrophage predominance, and the detection of >5% of CD1a-positive cells in BAL fluid is highly suggestive and specific for the disease; however, this increase is not observed frequently. Surgical lung biopsy is the most definite modality for diagnosis. Smoking cessation must be recommended for all patients. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Here, we presented a 48-year-old smoker with an unusual and unexpected radiological presentation. PMID- 29404096 TI - The Environment Policy Statement of Turkish Thoracic Society. PMID- 29404097 TI - Effects of an Asthma Training and Monitoring Program on Children's Disease Management and Quality of Life. AB - OBJECTIVES: To determine the effects of an asthma training and monitoring program on children's disease management and quality of life. MATERIAL AND METHODS: The sample consisted of 120 children and their parents. Data were collected during, at the beginning, and at the end of the 3-month monitoring period using four forms and a quality of life scale. After an initial evaluation, approaches to control symptoms and asthma triggers and measures that might be taken for them were taught to the children and parents. The children recorded the conditions of trigger exposure, experience of disease symptoms, their effects on daily activities, and therapeutic implementations on a daily basis. RESULTS: During the 3-month monitoring period, the number of days when the children were exposed to triggers (p=0.000) and experienced disease symptoms decreased to a statistically significant level (p=0.006). Majority of domestic triggers disappeared, but those stemming from the structure of the house and non-domestic triggers indicated no change (p>0.05). Moreover, 30.8% of the children applied to a physician/hospital/emergency service, 4.2% of the children were hospitalized, and 30% of them could not go to school. The number of times when the children applied to a physician/hospital/emergency (p=0.013), the number of times they used medicines (p=0.050), and the number of days they could not go to school (p=0.002) decreased at a statistically significant level, and their quality of life increased (p=0.001). CONCLUSION: Asthma training and monitoring program decreased children's rate of experiencing asthma symptoms and implementations of therapeutic purposes and increased their life quality. PMID- 29404098 TI - Knowledge Level of Family Physicians about Tuberculosis and their Attitudes and Views Regarding their Willingness to Work at a Tuberculosis Dispensary. AB - OBJECTIVES: Upon transitioning to the family medicine system in Turkey, the number of tuberculosis dispensaries (TDs) was reduced, and important responsibilities have been given to family physicians in tuberculosis (TB) control. Furthermore, with the new system, the incomes of doctors working at TDs remained quite lower than those of family physicians. The primary aim of this study was to examine whether family physicians possess the necessary level of knowledge regarding TB, and the secondary aim was to evaluate the attitudes and views of primary care physicians regarding working at TDs because of this economic inequality. MATERIAL AND METHODS: A questionnaire consisting of 15 questions that measures the basic knowledge regarding TB and that evaluates the role of family health centers in TB control and the willingness of doctors to work at TDs was presented to family physicians in the city of Sakarya. RESULTS: Of the 84 family physicians that participated in the study, 43% did not have sufficient knowledge about diagnosis, 56% about medicine information, and 77% about transmission and duration of treatment. In addition, 74% of family physicians stated that TD workers run the risk of infection and that their chances of contracting TB are higher, 90% stated that TD workers should be provided with the same economic conditions as family physicians, and 68% stated that TD workers should be positively discriminated. Half of the participants stated, as it stands, that they do not want to work at a TD, and 31% stated that they would definitely not work at a TD even if TD workers are provided with the same economic conditions as family physicians or they are positively discriminated. CONCLUSION: To take the national fight against TB to a higher level, we reached the conclusion that it is important that the lack of knowledge of family physicians should be remedied, that TB should be included in their job descriptions, and that TD workers should be provided with the same economic conditions as family physicians. PMID- 29404099 TI - Eosinophilic Lung Disease: Accompanied with 12 Cases. AB - OBJECTIVES: Eosinophilic lung diseases are a rare group of heterogeneous diseases characterized by the increase of the eosinophil ratio in airways and lung parenchyma. In our clinic, patients diagnosed with eosinophilic lung disease were evaluated with their clinical features and prognoses. MATERIAL AND METHODS: In our clinic, 12 cases that were diagnosed and followed up for eosinophilic lung disease [eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) (n=4), chronic eosinophilic pneumonia (CEP) (n=7), and simple pulmonary eosinophilia (Loffler's syndrome) (n=1)] were retrospectively evaluated. RESULTS: Of the 12 cases, 8 were females, and the average age was 43 (28-72) years. All cases were undergoing bronchodilator therapy with asthma diagnosis (2 months-40 years). Additionally, 4 of the cases had sinusitis, and 1 had allergic rhinitis. The most common complaints of the patients were difficulty in breathing and coughing, and the duration of complaints was a median of 2 months. Peripheral eosinophilia and total IgE elevation were present during the admission of all cases; additionally, leucocyte elevation was recorded in 10 of them, anemia in 4 of them, and thrombocytosis in 4 of them. Moreover, 43% of the recorded DLCO values were lower than normal. Of the 10 cases that underwent bronchoalveolar lavage (BAL), the eosinophil ratio was above 25% in 7 subjects. Of the 8 cases that underwent transbronchial biopsy, eosinophil-involving infiltration was detected in 6 subjects. Additional findings in cases diagnosed with EGPA were nasal polyposis (n=1), sinusitis (n=2), polyneuropathy (n=1), cardiac involvement (n=2), and skin involvement in biopsy (n=1). Spontaneous recovery was observed in the patient diagnosed with simple pulmonary eosinophilia during the follow-up that was performed based on the history and laboratory and BAL results of the patient. Prednisolone treatment was started for all cases, except for simple pulmonary eosinophilia, and their controls were performed. Relapse was observed in eight cases (EGPA: 4, CEP: 4); during the relapse treatment of one case diagnosed with EGPA, exitus occurred. One case rejected treatment despite the presence of peripheral eosinophilia, and the other cases are being followed-up without medication. CONCLUSION: Given that the clinical pictures in pulmonary eosinophilia syndromes are on a wide spectrum, a specific diagnosis is important. Progression may differ in each patient, and a close follow-up is necessary during and after the treatment. PMID- 29404100 TI - Diagnostic Dilemma in Hydatid Cysts: Tumor-Mimicking Hydatid Cysts. AB - OBJECTIVES: Hydatid cysts are sometimes confused with different pathologies, and problems arise in their diagnosis and treatment. In this study, cases that are followed up with a diagnosis of lung malignancy and that are detected to have hydatid cysts were retrospectively examined. MATERIAL AND METHODS: Seven patients with hydatid cysts whose clinical and radiological features were consistent with lung malignancy were retrospectively examined between 2010 and 2014 regarding sex, age, symptoms, diagnostic methods, surgical procedures performed, and postoperative complications. In the diagnosis of the patients, radiological diagnostic methods such as chest radiography, thoracic computed tomography (TCT), and positron emission tomography+computed tomography (PET-CT) as well as invasive diagnostic methods such as bronchoscopy, fine-needle aspiration biopsy, thoracentesis, and video-assisted thoracoscopic surgery were used. RESULTS: The average diameter of the lesions was determined as 4.14+/-1.57 cm in TCT. Maximum standardized uptake value (SUV max) was measured as 8.77+/-3.41 (5.4-15.1) in the PET-CT analysis. Bronchoscopy, fine-needle aspiration biopsy, and thoracentesis yielded no results. Definitive diagnosis was established by performing thoracotomy and video-assisted thoracoscopic surgery. CONCLUSION: Pulmonary hydatid cysts can appear as malignant diseases such as lung cancer as well as infectious pathologies such as tuberculosis or benign pathologies. Radiologically, it should be kept in mind that pulmonary hydatid cysts can mimic many pulmonary pathologies, particularly malignancies. Necessary examinations towards its differential diagnosis must be performed in the preoperative period. PMID- 29404101 TI - Lung Function Tests in Preschool Children. AB - The measurement of lung function by spirometry is routinely used to monitor and adequately treat children with asthma. The assessment and evaluation of lung function in children aged 3-5 years has been neglected for a long time because of the difficulty to perform forced expiratory maneuvers. However, the use of techniques such as the interrupter technique and the forced oscillation technique, which only require passive collaboration and where the only request to the child is to breathe at tidal volume, has overcome this limitation. Other techniques such as the measurement of specific airway resistance by plethysmography or the measurement of the lung clearance index using the multiple breath washout might be helpful in this regard, although these techniques are less standardized in preschool children. PMID- 29404102 TI - An Exemplary Case of Promotion Activities and Taste Panels from the Perspective of Tobacco Control. AB - The Framework Convention on Tobacco Control is a multilateral international agreement which has been generated to protect the health of nationals and nations against the hazards/risks of tobacco and its products. All high contracting parties to the Convention undertake the international responsibility to fulfill all the requirements of the Convention's articles in national legal systems. The Framework Convention on Tobacco Control has a considerable place among other international conventions on health. Within the self-executing desing/system of the Convention, a vital regulation focuses on banning the advertisement, promotion, and sponsorship of tobacco products. Because they are one of the various components of tobacco advertisement, promotion, and sponsorship, taste panels should be assessed within the content of the Convention. Thus, banning taste panel activities is an important step in tobacco control and it is one of the basic areas where medical and law sciences should collaborate. In this article, a comprehensive frame has been drawn to the issue and recommendations have been developed for the future. PMID- 29404103 TI - A Rare Cause of Spontaneous Pneumomediastinum: Ecstasy Ingestion. AB - Ecstasy ingestion has life-threatening effects such as hyperpyrexia, rhabdomyolysis, disseminated intravascular coagulation, coma, and death. In the present report, we aimed to highlight ecstasy as a rare cause of spontaneous pneumomediastinum and its potential life-threatening effects. A 16-year-old female with dyspnea and chest pain presented to the emergency department. Chest computed tomography demonstrated pneumomediastinum at the level of the thoracic inlet and upper and posterior mediastinum. The patient was admitted to the thoracic surgery department with a preliminary diagnosis of spontaneous pneumomediastinum. She refused to answer any questions during the first visit, an a psychiatric consultation was requested. The most important finding of psychiatric consultation was ecstasy abuse, which could not be identified in the emergency department evaluation. Four days later, the symptoms resolved completely and control chest X-rays showed no complications; therefore, the patient was discharged. While investigating the etiology of spontaneous mediastinum, particularly in a young, healthy patient, ecstasy abuse should always be considered. Because the fatal complications that may develop due to ecstasy ingestion may be overlooked. PMID- 29404104 TI - Diagnosis and Management of Parathyroid Cysts: Description with Two Cases. AB - Parathyroid cysts are unilocular, thin-walled cysts, and they are seen very rarely. Their formation mechanisms are not clear. They are usually localized in the cervical region, and mediastinal settlements are rare. They are usually asymptomatic, but cysts that have settled in the neck may be symptomatic, such as tracheal pressure symptoms. There are two types-namely, functional cysts and non functional cysts-depending on their hormonal characteristics. There are still difficulties in the diagnosis, and they can be mistaken by thyroid pathology. Treatment is surgery. We discussed two cases of parathyroid cysts that we surgically excised. PMID- 29404105 TI - Coal Mine Accidents. AB - The underground coal mining, in terms of fatal and injury accidents, has the first place among all businesses due to "spontaneous combustion of coal" and "presence of methane gas" in coalmines. In May 2014, the most casualties (301 people) of recent years occurred in the Soma Eynez mining quarry that accounts for almost half of the death of the last 30 years. The Turkish Thoracic Society Environmental and Occupational Lung Disease assembly, aimed to determine the causes of coal mine accidents and analyze what should be done to prevent occurrence of accidents and casualties. PMID- 29404106 TI - Coal Mining in Turkey: State and Private Sector Interactions Subcontracting and Redevance. AB - In this introductory report, coal mining accidents in Turkey, the historical perspective of the subcontracting and redevance system, and its effects on coal mining accidents are briefly reviewed. PMID- 29404107 TI - The History of the Coal Mining Industry and Mining Accidents in the World and Turkey. AB - Three per thousand of the world's coal reserves and 2% of lignite reserves exist in Turkey. Coal mining is the highest ranking industry for accidents and deaths per capita. For this reason, continuous monitoring and more attention should be given to the mining industry. In this review, the basic statistical data related to Turkey's mining and mining disasters are summarized. PMID- 29404108 TI - Causes of Coal Mine Accidents in the World and Turkey. AB - Occupational accidents and occupational diseases are common in the mining sector in Turkey and throughout the world. The most common causes of accidents in coal mining are firedamp and dust explosions, landslips, mine fires, and technical failures related to transport and mechanization. An analysis of occupational accidents in the consideration of social and economic factors will let understand the real causes behind these accidents, which are said to happen inevitably due to technical deficiencies or failures. Irregular working conditions, based on profit maximization and cost minimization, are related to strategic operational preferences and public policies. Proving that accidents in mines, where occupational health and safety measures are not implemented and inspections are not done properly or at all, are caused by the fact that production is imposed to be carried out in the fastest, cheapest, and most profitable way will allow us to take steps to prevent further mine accidents. PMID- 29404109 TI - Search and Rescue in Mine Disasters: Dos and Don'ts. AB - Mining is a very hard and risky sector that includes domino effect risks in any adverse event and requires knowledge, experience, proficiency and continuous auditing, and it is very hard and risky. Turkey has not signed International Labour Organization (ILO) contract number 176 yet. This contract is named the 1995 Safety and Health in Mines Convention, and the safe and healthy working conditions are set, and obligations are listed. The most important mistakes are made because these national and international rules and regulations are not carried out. In this chapter, these mistakes are elaborated, and suggestions are made. PMID- 29404110 TI - Respiratory Emergencies and Management of Mining Accidents. AB - The rapid detection of the reasons for mining accidents that lead to emergency situations is vital for search and rescue work. The control of fire and gas leakage provides an immediate approach for rescue works for deaths or injuries and the detection of who needs resuscitation outside of the mine. The evacuation and recovery operations should be directed by continuous monitoring of the mine environment due to fire and explosion risks. The main toxic gases in mines are carbon monoxide (CO) and carbon dioxide (CO2); the flammable gases are methane (CH4), CO, and hydrogen (H2); the suffocating gases are CO2, nitrogen (N20), and CH4; and the toxic gases are CO, nitrogen oxides (NOx), and hydrogen sulfide (H2S). PMID- 29404111 TI - Role of Occupational Physician in Mining Accidents. AB - As in all work areas, the activity of protecting worker health must be done together with monitoring of the workplace and health surveillance at the mine. Health surveillance must configure with the correct recruitment examination and periodic examinations on time. It is necessary if we aim for occupational safety at mines, where the industrial accident frequency is very high. A true and real first aid schedule is very important for helping decrease the severity after accidents. These facts must create the basic rules of an occupational physician's work at a mine. PMID- 29404112 TI - Precautions for the Prevention of Mine Accidents and Related Respiratory Emergencies. AB - Mine accidents and related respiratory emergencies can be prevented. Employers and governments have responsibilities to protect employees from mine accident associated respiratory emergencies. Effective ventilation in the mines, usage of new mining technologies, and education of employees are the primary routes. Use of the personal protective equipment is valid when general precautions are not adequate. PMID- 29404113 TI - Turkey Asbestos Control Strategic Plan Final Report. PMID- 29404114 TI - Effect of Nasal Continuous Positive Airway Pressure Therapy on the Functional Respiratory Parameters and Cardiopulmonary Exercise Test in Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: Nasal continuous positive airway pressure (nCPAP) treatment is the gold standard treatment for obstructive sleep apnea syndrome (OSAS). In this study, we aimed to show that the pulmonary functions, exercise limitation on the cardiopulmonary exercise test (CPET), and the health-related quality of life can be improved after a short treatment period by nCPAP. MATERIALS AND METHODS: Our case group with severe obstructive sleep apnea (OSA) performed incremental CPET before and after 8 weeks of nCPAP treatment. All the subjects also underwent physical examination, body composition analysis, simple spirometric measurements, maximal inspiratory pressure (PImax)-maximal expiratory pressure (PEmax), and lung volume tests before and after nCPAP treatment. RESULTS: Thirty-one patients (4 female, 27 male) completed the study. The mean age of the patients was 53.41 +/- 1.46 years. Sixteen had at least one comorbidity. In addition, 17 of the subjects were ex-smokers. After nCPAP treatment for 8 weeks, higher PImax-PEmax (p< 0.05), peak oxygen uptake (p= 0.001), workpeak (p= 0.000), maximal heart rates (p= 0.000), and short form-36 scores (p< 0.05) were observed. nCPAP treatment helped control the blood pressure (p= 0.005). There was no significant change in body composition analysis, spirometric parameters, and lung volumes. CONCLUSION: In a short time period, nCPAP can improve exercise capacity, respiratory muscle strength, and the health-related quality of life scores and help control blood pressure. PMID- 29404115 TI - Thrombocytopenia: A Risk Factor of Mortality for Patients with Sepsis in the Intensive Care Unit. AB - OBJECTIVES: The objective of this study was to evaluate the intensive care unit (ICU) and long-term mortality in sepsis patients with/without thrombocytopenia on the fifth day of ICU admission. MATERIALS AND METHODS: The retrospective observational cohort study was performed in a teaching hospital, and patients with sepsis who stayed more than 4 days in the ICU between January 2012 and December 2012 were included. Patients were divided into two groups according to thier platelet count at fifth day of ICU stay: Group 1, < 150.000/MUL; Group 2, >150.000/MUL. Patients having thrombocytopenia on admission were excluded. The patients' characteristics, comorbid diseases, body mass index, arterial blood gas analysis and blood biochemistry results, SIRS criteria, Acute Physiological and Chronic Health Evaluation Score II (APACHE II), implication of invasive and non invasive mechanical ventilation, use of sedation, nutrition information, and culture results of microbiological samples were recorded. The groups were compared according to the recorded data. Logistic regression analysis was performed for ICU mortality; the Kaplan-Meier test was used to evaluate 12-month survival after ICU discharge. RESULTS: During the period, 1003 patients were admitted to the ICU; 307 sepsis patients were included in the study. Group 1 (n= 67) and Group 2 (n=240) had similar patient characteristics and sepsis findings. The groups had similar ICU and hospital stays; mortality was higher in Group 1 than in Group 2 (40.3% vs. 17.5%, respectively, p< 0.001). Fifth day thrombocytopenia, septic shock, male gender, and low albumin levels were found to be risk factors of ICU mortality; the respective odds ratios, 95% confidence intervals, and p values for these factors were 3.03, [1.15-7.45], p= 0.025; 4.97, [1.79-13.86], p= 0.002; 3.61, [1.27-10.23], p= 0.001; and 0.19, [0.07-0.52], p= 0.001. Follow-up after a year indicated that 124 out of 238 (52.1%) patients died, and 50% of the deaths occurred in the first 2 months. Kaplan-Meier analysis revealed no statistically significant effects of thrombocytopenia at ICU day 5 on 12-month mortality after ICU discharge. CONCLUSION: Higher rates of septic shock and mortality were seen in sepsis patients with thrombocytopenia in the ICU. The measurement of thrombocytopenia in the ICU, which is easy and low-cost, may help to predict mortality. Thus, precautions can be taken early in patient treatment and follow-up. As we know, early intervention is crucial in the approach to sepsis. PMID- 29404116 TI - Can a Computer-Based Prescription of Free Medication Increase Smoking Cessation Rates Efficiently? AB - OBJECTIVES: In 2011, in the context of a research project, bupropion and varenicline were distributed to smoking cessation clinics by the Ministry of Health of Turkey to be prescribed free of charge by a computer-based system. In the present study, we compared smoking cessation rates between patients who were prescribed free medications during the period of the project and those who had to pay for their medication. MATERIAL AND METHODS: Six hundred four patients who applied during the project period were given either bupropion or varenicline, which were prescribed using an algorithm-based computer system. Three hundred sixteen patients who applied after that period were prescribed medicines deemed appropriate by the attending physician but had to pay for the medication on their own. Follow-up visits were arranged for one year. Carbon monoxide (CO) levels in the expired air were used as indicators of cessation. RESULTS: A total of 537 patients began treatment, of which 438 (81.6%) applied during the first period (group 1) and 99 (18.4%) applied during the second period (group 2). The mean age and concomitant disease presence were higher in the second-period patients (p< 0.05). Advanced age, comorbidities, pathological findings in spirometry, and chest X-ray were also higher in those who paid for the cost of their treatment (p= 0.009, 0.001, 0.006, 0.001, respectively). Smoking cessation rates were found to be 14.8% and 27.3% after six months (p= 0.008) and 10.7% and 18.2% after one year (p= 0.059), respectively, for group 1 and group 2. Age, dependence score, cigarettes smoked (as pack-years), and percentage of patients who paid for the treatment were found to be significantly higher (p< 0.001, 0.021, 0.018, 0.001, respectively) for those who quit smoking at the end of six months. For the patients who quit smoking at the end of one year, age was found to be significantly higher (p= 0.008), and the number of males was higher, although the difference was not statistically significant (p= 0.05). When logistic regression analysis was applied, age, dependence score, and paid treatment were found to be independent variables (p= 0.002, 0.008, 0.012, respectively) for those who quit smoking at the end of six months. Only age was found to be an independent variable for those who quit smoking at the end of one year (p= 0.029). CONCLUSION: More smokers could receive treatment by the distribution of free drugs. However, quitting rates at the end of six months were higher when patients had to pay for their treatment. On the other hand, quitting rates at the end of one year were not affected by whether the treatment was paid for or free of charge. The most important factor increasing quitting rates at the end of six months and one year was found to be advanced age. PMID- 29404117 TI - The Role of Endobronchial Biopsy in the Diagnosis of Pulmonary Sarcoidosis. AB - OBJECTIVES: This study aimed to investigate the additional diagnostic value of endobronchial biopsy (EBB) in the diagnosis of pulmonary sarcoidosis. MATERIALS AND METHODS: This retrospective cross-sectional study included 59 patients with a preliminary diagnosis of sarcoidosis who were admitted to the Pulmonary Diseases Outpatient Clinic of a tertiary healthcare center between January 2005 and October 2012. The socio-demographic characteristics of the patients as well as clinical and radiological findings were recorded. All patients, irrespective of the presence of an endobronchial lesion (EBL), underwent fiberoptic bronchoscopy (FOB); two to four specimens were taken using EBB from the carina of the right middle lobe in the patients with EBL. RESULTS: Of the patients, 39 (66.1%) had normal bronchoscopic findings, while 5 had EBL. Diagnosis was based on EBB in 11 patients (18.6%). Six patients (15.3%) with normal bronchial mucosae were pathologically diagnosed by EBB. There was no statistically significant relationship between the diagnostic ratio of EBB and disease stage, extrapulmonary involvement, FOB findings, elevated lymphocyte rate in bronchoalveolar lavage (>= 13%), a CD4/CD8 ratio of >= 3.5, and serum angiotensin converting enzyme (ACE) level (p> 0.05). CONCLUSION: EBB not only offers the advantage of a high diagnostic ratio in patients with mucosal abnormalities but also contributes to pathological diagnosis in patients with normal mucosa. We recommend using EBB to support diagnosis with a low complication rate for patients undergoing FOB with a preliminary diagnosis of sarcoidosis in healthcare centers, where endobronchial ultrasound (EBUS) is unavailable. PMID- 29404118 TI - A Case of Idiopathic Subglottic and Bilateral Bronchial Stenosis. AB - Subglottic stenosis is rarely idiopathic. In this case report, a 40-year-old female patient presented with subglottic stenosis with an unidentified etiology along with bilateral bronchial stenosis. Hoarseness arose in the last 4 years in this patient, who was undergoing treatment because of asthma for 13 years. Her physical examination revealed the presence of bilateral rhonci. Her tomography analysis revealed tracheal stenosis in a 2-cm segment at the C6-7 level. Her bronchoscopy analysis revealed subglottic stenosis. White plaques were observed in the entire tracheobronchial tree; biopsy was performed and lavage was taken. Samples were sent for pathological and microbiological examinations. Stenosis in the bronchial system was clear in the left main bronchus entry and at the right intermediate bronchus level. Dilatation was performed. Chronic active inflammation and squamous hyperplasia were observed in the pathology of the biopsies. Growth did not occur in tuberculosis and nonspecific cultures. Reflux was not present in the gastrointestinal system examination. All serological and rheumatologic examinations performed were normal. Idiopathic subglottic stenosis is exceedingly rare. Bronchial system stenosis accompanying idiopathic tracheal stenosis is even rarer, and its treatment is difficult. PMID- 29404119 TI - Flexible Fiberoptic Bronchoscopy Through the Laryngeal Mask Airway in a Small Premature Infant. AB - Flexible bronchoscopy (FB) can be used safely for wider indications in children. Ultra-thin bronchoscopes are used for premature or newborn infants and are of limited diagnostic value. Bronchoscopes with a suction channel, may lead to problems when the nasal passage is narrow, particularly in patients under 2.5 kg. In addition, it may cause bronchospasm and hypoxia in small infants during the procedure because of an almost complete obstruction of the airway. A laryngeal mask airway (LMA) may prevent both bronchospasm and hypoxia because it does not need a nasal route. In addition, the LMA allows positive pressure ventilation during the procedure. We performed FB with a 3.7 mm bronchoscope through the LMA in a 75-day-old and 1910 g premature baby with atelectasis. This is the first and successful FB experience in such a small premature infant reported in the literature using a 3.7 mm bronchoscope through the LMA. PMID- 29404120 TI - New-Onset Sarcoidosis After Remission of Cushing's Syndrome. AB - Exposure to high levels of endogenous or exogenous glucocorticoids suppresses the inflammatory response genes. Excessive endogenous hypercortisolism may mask the active inflammatory diseases. Rebound immune modulation may occur after Cushing's syndrome (CS) remission, leading to the new onset of autoimmune diseases. Here, we report a 27-year-old female patient who was recently diagnosed with sarcoidosis after remission of CS. Normal thorax imaging showed that the patient was free of disease during the course of CS and without any symptoms of sarcoidosis. After complete remission of CS, she was diagnosed with sarcoidosis based on clinical and radiological evidence. Excessive hypercortisolism may suppress the active inflammatory stage of sarcoidosis. However, the disease became apparent after the reduction of cortisol levels following the treatment of CS. PMID- 29404121 TI - Spontaneous Mediastinal Emphysema Associated with the Use of Synthetic Cannabinoid (Bonsai). AB - Spontaneous Mediastinal Emphysema (SME), which is a rarely seen case is defined as the detection of free air in the mediastinum without any trauma. Although rare, some cases secondary to drug use have been reported. In this study, two SME cases that developed due to the use of a synthetic cannabinoid known as "bonzai", which has recently become widespread in Turkey, are presented. We would like to emphasize that SME should also be considered in the differential diagnosis of patients who present with the symptoms of chest pain and dyspnea and have a history of drug use. PMID- 29404122 TI - The Importance of Neutrophil-to-Lymphocyte Ratio in Chronic Obstructive Pulmonary Disease. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, neutrophil-to-lymphocyte ratio (NLR) has gathered increasing interest in the detection of inflammation in inflammatory diseases. This study aimed to investigate the role of NLR in COPD for identifying the detection of inflammation and recognition of acute exacerbation. MATERIAL AND METHODS: The laboratory results of 103 COPD patients were included into the study, of which 47 patients were in acute exacerbation and 56 patients were at stable period, and there were 40 gender and age-matched healthy controls. Complete blood count (CBC), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were evaluated. NLR was calculated from CBC. RESULTS: NLR values of patients with COPD (both acutely exacerbated and stable) were found significantly higher than those of the controls (p< 0.001, p< 0.05; respectively). In all patients with COPD, NLR values positively correlated with serum CRP (r= 0.641, p< 0.001) and ESR (r= 0.276, p= 0.005) levels and negatively correlated with forced vital capacity (r= -0.20, p= 0.043) and forced expiratory volume in the 1st second (r= -0.288, p= 0.003). For an NLR cutoff of 3.34, sensitivity for detecting exacerbation of COPD was 78.7% and specificity was 73.2% (AUC 0.863, p< 0.001). CONCLUSION: Our results suggest that NLR may be considered as a reliable and simple indicator in the determination of increased inflammation in patients with COPD. Furthermore, NLR could be useful for the early detection of possible acute exacerbations in patients with COPD. PMID- 29404123 TI - The Prevelance of Tobacco Use and the Factors Influencing in Students Studying at Two Dentistry Faculties in Turkey. AB - OBJECTIVES: The objective of this study was to determine the pattern and effects of tobacco and tobacco products use among students of dentistry. MATERIAL AND METHODS: A cross sectional study was performed in the Dentistry Faculty of Ege and Dicle Universities between April and May 2013. All freshmen and senior year students receiving education in both universities were included into the study (n= 321). A questionnaire consisting of 26 questions was used to determine the smoking habits of the students and the influencing factors regarding this habit. Students replied the questions under supervision. RESULTS: A survey was conducted among 298 students out of 321 who were attending both universities. 46.6% of the participants were female and 53.4% were male. Smoking prevelance of the students was 29.9%. It was 19.9% in freshmen students and 45.8% in senior students. According to the first class of students in the fifth grade students in the prevalence of smoking in was found to be highly statistically significant (p< 0.001). Among other tobacco products the following was identified as mostly used: waterpipe, also known as narghile (27.4%), cigarwraps (9.7%), cigar (9.4%) and smoking pipe (2.0%). While 22.5% of the students stated that they started smoking after the age of 15, 36.0% started between the ages of 15 and 18 and 41.5% after the age of 19. The rate of smoking in the house was significantly higher (p< 0.001) among smokers than non-smokers. While 78.7% of the students stated that they would like to quit, 64.3% tried once or more to quit. CONCLUSION: Smoking habit was found to be higher among medical students than the social average. Smoking is more frequent in higher classes. From early years onwards, students of dentistry should be intensively educated regarding the harmful effects of tobacco on health, and efforts should be made to prevent and control of tobacco epidemic. PMID- 29404124 TI - The Incidence and Related Risk Factors of Chronic Thromboembolic Pulmonary Hypertension after Acute Pulmonary Embolism. AB - OBJECTIVES: More than half of (> 50%) the patients with choronic thromboembolic pulmonary hypertension (CTEPH) have no acute pulmonary embolism history with clinical signs, so determining the actual incidence and prevalence of CTEPH is difficult. This study aimed to investigate the incidence of CTEPH and the risk factors that may be associated with CTEPH in patients with acute pulmonary thromboembolism (PTE). MATERIAL AND METHODS: Three hundred and eighteen patients with acute pulmonary embolism diagnosed by thorax CT or ventilation/perfussion scintigraphy in our clinic were included into this study. Patients with risk factors for pulmonary hypertension other than thromboembolic disease were excluded from the study. Patients with pulmonary hypertension (PHT) (systolic PAB > 35 mmHg) determined by echocardiography performed in the 6th month were enrolled into the study. RESULTS: Fifty-seven of the 112 patients were female, and the mean age was 57.09 +/- 17.30 (16-86) years. Presence of PHT was determined in the 6th month in 45 of the 112 patients (8 of them were symptomatic) and CTEPH incidence (symptomatic + asymptomatic) was identified as 40.16%. Symptomatic CTEPH incidence was calculated as 7.14%. When we searched about the risk factors that may have a role in the development of CTEPH; we determined that CTEPH risk was increased 4.59 times by only being male (95% CI 1.071-19.683, p= 0.040), 218 times by previous history of DVT (95% CI 1.235 38543.073, p= 0.041), and 56.903 times by PaO2 < 80 mmHg (95% CI 2.656-1219.228, p= 0.010). CONCLUSION: CTEPH development after PTE is a situation that can occur in many patients. If probable risk factors are known, patients can be closely monitorized for CTEPH development. PMID- 29404125 TI - Use of High-Resolution Computed Tomography (HRCT) in Diagnosis of Sputum Negative Pulmonary Tuberculosis. AB - OBJECTIVES: To study the role of high-resolution computed tomography (HRCT) in the diagnosis of pulmonary tuberculosis (PTB) in sputum smear negative patients and to design HRCT criterion to forecast the threat of pulmonary tuberculosis. MATERIAL AND METHODS: We studied 69 patients having sputum smear negative for acid-fast bacilli (AFB) but still with clinical suspicion of PTB after taking written informed consent. We studied their medical characteristics, numerous separate HRCT-results and combination of HRCT findings to foresee the danger for PTB by utilizing univariate and multivariate investigation. Temporary HRCT diagnostic criteria were planned in view of these outcomes to find out the risk of PTB and tested these criteria on our patients. RESULTS: Chronic cough and night sweats were highly linked to a greater risk of PTB among clinical features. On HRCT chest presence of cavity, centrilobular nodules, consolidation, ground glass opacity (GGO), lymphadenopathy, main lesion in S1, S2, S6, lobular consolidation, other minute nodules and tree in bud appearance was significantly linked to an elevated risk of PTB in linear regression analysis. While cavity, centrilobular nodules, interlobular septal thickening, pleural effusion and tree in-bud appearance was significantly linked to a greater threat of PTB in multivariate regression analysis. Positioning of the patients utilizing our HRCT indicative criteria uncovered reliable sensitivity and specificity for PTB patients determining that HRCT is a useful tool in sputum negative PTB patients. CONCLUSION: HRCT is useful in selecting individuals with greater chances of PTB in the sputum smear-negative setting. PMID- 29404126 TI - Respiratory Disability in The Van Region Based on the Medical Board Reports. AB - OBJECTIVES: Respiratory system disorders have an impact on daily living activities of subjects, resulting in disability. Data should be gathered on disability for health services. The present study aimed to review the records of patients with a respiratory disability report from our medical board, and contribute to the national and regional statistics on disability. MATERIAL AND METHODS: We retrospectively reviewed sociodemographic characteristics, respiratory diseases and disability rates of the patients who were examined by the Chest Diseases Department during the Medical Board evaluations in our hospital between January 1st and July 1st, 2014. RESULTS: Among 4285 patients whose applications were submitted to the medical board for evaluation, 401 (9.3%) had a respiratory disease. Of these patients, 163 were male, and 238 were female, with a mean age of 64.2 years. The most common diseases associated with disability were chronic obstructive pulmonary disease, asthma and sequelae tuberculosis. The disability rating for respiratory system was 80% in 24.9% of patients, 40% in 34.7% of patients, and 20% in 40.4% of patients. Patients with a respiratory disability report were also considered disabled by the departments of Physical Therapy and Rehabilitation, Cardiology and Eye diseases. There was a positive correlation between disability rating and age, and a negative correlation between forced expiratory volume in first second (FEV1) and oxigen saturation measured by pulse oximeter (SpO2) values (p= 0.002; p< 0.001; p< 0.001, respectively). Furthermore, smokers had a higher disability rating compared to non-smokers (p= 0.02). CONCLUSION: In Turkey, we have limited number of studies about respiratory disability. We believe that the present study will help determination of the etiology of respiratory disability and contribute to any action on prevention of these disorders in our region. PMID- 29404127 TI - History of Lung Transplantation. AB - History of lung transplantation in the world can be traced back to the early years of the 20th century when experimental vascular anastomotic techniques were developed by Carrel and Guthrie, followed by transplantation of thoracic organs on animal models by Demikhov and finally it was James Hardy who did the first lung transplantation attempt on human. But it was not until the discovery of cyclosporine and development of better surgical techniques that success could be achieved in that field by the Toronto Lung Transplant Group led by Joel Cooper. Up to the present day, over 51.000 lung transplants were performed in the world at different centers. The start of lung transplantation in Turkey has been delayed for various reasons. From 1998 on, there were several attempts but the first successful lung transplant was performed at Sureyyapasa Hospital in 2009. Today there are four lung transplant centers in Turkey; two in Istanbul, one in Ankara and another one in Izmir. Three lung transplant centers from Istanbul which belong to private sector have newly applied for licence from the Ministry of Health. PMID- 29404128 TI - Pneumomediastinum After Difficult Vaginal Delivery. AB - 17-year-old primigravida patient presented with chest pain, dyspnea, sore throat and a sensation of swelling in the neck and throat approximately 3 hours after difficult vaginal delivery at home. Breath sounds were equal bilaterally. Physical examination revealed subcutaneous emphysema that expanded from the anterior thorax to the neck. Posteroanterior (PA) chest X-ray showed air in the neck and thoracic computed tomography showed pneumomediastinum. The patient was admitted to our clinic and was started on ampicillin-sulbactam 3 * 1 grams iv, paracetamol 2 * 1000 mg and 3 L/min of oxygen therapy. C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR), which were monitored on a daily basis, showed decline. Repeated chest X-rays did not show any progression. The patient was clinically stable and was discharged from the hospital on the third day. Currently in her third month of follow-up, the patient is stable. PMID- 29404129 TI - Unusual Radiological Sign in Bronchial Atresia. AB - Bronchial atresia is usually diagnosed by incidentally detecting opacitiy at hilar ragion and hyperinflation around this opacity on chest X-ray. It may rarely be detected as air sac like atresic bronchus. The breath sounds in the right hemithorax were heard less when compared to the left hemithorax in the auscultation of a 16-year-old male patient with allergic rhinitis. The patient had no pulmonary complaints, and this finding was not recorded in his previous follow-up. In order to determine the etiology of hyperinflation seen on chest X ray, computed tomography was performed. Hyperinflation was identified in the lower lobe superior segment of the right lung, which could be secondary to bronchial atresia. It was confirmed that in the evaluation of computed tomography with three-dimensional reconstruction, lower lobe superior segment bronchus of the right lung was atresic and contrary to expected mucus opacity in the distal of atresia, dilated bronchus was filled with air. This case was especially presented to lay emphasis on careful auscultation and share its unusual radiological presentation which had been reported twice before. PMID- 29404130 TI - Nebulized Lidocaine as an Alternative Therapy for Reactive Airway Dysfunction Syndrome. AB - Reactive airway dysfunction syndrome (RADS) is a variant of irritant-induced asthma that develops in subjects without prior bronchoobstructive disease, following high-level exposure to nonimmunogenic irritants. Recommended maintenance treatment for RADS is not different from asthma. But in some cases, severe symptoms may persist despite the bronchodilators and corticosteroids. We describe the first case of a patient with RADS, unresponsive to all medical agents, who was successfully treated with lidocaine. PMID- 29404131 TI - Severe Pneumonia Treated Succesfully with Levofloxacin and Oseltamivir During Flu Epidemic. AB - Viral pneumonia is an important cause of community acquired pneumonias (CAP). It's not only specific to childhood period. Although immunocompromised adults are susceptible; all young and healthy adults are at risk. Viral pneumonias are usually underestimated due to lack of diagnostic modalities so a clinician must be aware of. Co-infection of viruses and bacteria is not uncommon and can be mortal especially in a flu epidemic, therefore, in the absence of diagnostic tools initiating to anti-viral treatment without delay is important. PMID- 29404132 TI - Do Meteorological Changes Have an Effect on The Occurence of Spontaneous Pneumothorax? AB - OBJECTIVES: Spontaneous pneumothorax refers to the leakage of air into the space between the parietal and the visceral layers of the pleura. It occurs with or without a known lung disease. We aimed to investigate the effects of atmospheric pressure, humidity, and temperature changes on the incidence of spontaneous pneumothorax (SP). MATERIAL AND METHODS: This study included 551 patients with spontaneous pneumothorax retrospectively screened between January 2009 and December 2013. The medical data of the patients were accessed via their medical records on the hospital automation system. The atmospheric pressure, temperature, humidity rate, amount of precipitation, and wind velocity on the day of spontaneous pneumothorax were obtained from the data provided by the general directorate of meteorology. The three consecutive days on which at least 2 cases of SP presented were collectively considered as a cluster. The study data were analyzed with the SPSS version 15 software package, using the Chi-square and the Student's t tests. A p value less than 0.05 was considered statistically significant. RESULTS: Of the 552 patients included in the study, 89.3% had primary spontaneous pneumothorax and 10.7% had secondary spontaneous pneumothorax. Ninety-two percent of the patients were male and 8% were female. The mean age was 24 years. Clustering was observed in 71.7% of the study population. No significant differences were observed between yearly and monthly SP incidences. There were, however, differences between the days with SP and the days without SP with respect to atmospheric pressure, ambient temperature, wind velocity, and humidity rate. The differences between the atmospheric pressures were not statistically significant, although the differences between the ambient temperature and the humidity rate were statistically significant (p<= 0.05). CONCLUSION: We determined that the changes in the ambient temperature and the humidity rate affected the rate of spontaneous pneumothorax by altering the meteorological conditions. PMID- 29404133 TI - Arterial Blood Gas Analysis in Chronic Obstructive Pulmonary Disease Patients Undergoing Coronary Artery Bypass Surgery. AB - OBJECTIVES: We aimed to investigate the impact of arterial blood gas (ABG) on morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients undergoing CABG surgery. MATERIAL AND METHODS: The records for 75 COPD patients who underwent elective CABG surgery our institution clinic between November 2008 to 2011 and had a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <= 70% value in the pulmonary function tests (PFT) performed prior to the surgery were evaluated retrospectively. COPD patients were divided into two groups; Group 1; FEV1 >= 60% and Group 2; FEV1 <= 59%. Groups were compared for mortality and adverse events after identification of other preoperative and postoperative factors that could affect mortality and adverse events. An ABG was obtained immediately before and 3 to 6 hours after surgery to study the predictive value of ABG in seperate COPD groups. RESULTS: There were no significant differences in patients with high partial pressure carbondioxide (PaCO2) preoperative values compared to patients with normal values. Also there were no significant differences in patients with lower partial pressure of oxygen (PaO2) preoperative values compared to patients with normal values in terms of mortality. Postoperative myocardial infarction (MI) was significantly higher in patients with low PaO2 values (p< 0.05). CONCLUSION: In conclusion, in our study, there could not be found a relation between the degree of preoperative obstruction and mortality for COPD patients who underwent CABG surgery. ABG was not found useful for predicting mortality in COPD patients undergoing CABG surgery, but could be useful to predict postoperative MI in patients with COPD. PMID- 29404134 TI - The Effect of Flexible Bronchoscopy on Anxiety in Children. AB - OBJECTIVES: Flexible bronchoscopy (FB) is a semi-invasive diagnostic tool that allows direct visualization of the airways. The use for diagnostic and therapeutic purposes in children is incrasing with the developments in modern anesthesia. Irrespective of the type of the invasive diagnostic procedure, these interventions are known to cause anxiety in patients. The aim of our study was to evaluate the anxiety and depression status in children hospitalized for bronchoscopy and to investigate the effects of FB. MATERIAL AND METHODS: Thirty children hospitalized for FB and 30 controls, aged 7 to 16 years, were enrolled in this study. Anxiety was evaluated with the "Hospital anxiety and depression scale" (HADS)" besides other parameters recorded. RESULTS: The mean HADS anxiety scores in the patient and control groups were respectively 10.1 (3.5) and 2.7 (1.3) (p= 0.001). The mean HADS depression scores were respectively 8.8 (3.7) and 2.2 (1.1) (p= 0.001). Among the patients, 50% had anxiety and 53.3% had findings while none in the control group showed signs of anxiety and depression. A positive correlation was found between the age and, anxiety and depression scores in patients' groups (respectively r1= 0.257; p= 0.05 and r2= 0.288; p= 0.02). CONCLUSION: Anxiety was demonstrated in nearly half of the children hospitalized for bronchoscopy. It has been observed that behavioral and physical problems may be encountered in approximately 40-60% of children who feel generalized anxiety before anesthesia, during the preoperative, postoperative period, and subsequent periods. These results suggest that the detection of children with increased anxiety and indicate the individual requirements can be assisted pharmacological and psychological supports. PMID- 29404135 TI - Analysis of Patients with Spontaneous Pneumomediastinum. AB - OBJECTIVES: Spontaneous pneumomediastinum is characterized by the presence of air in the mediastinum without any reason. The objective of this study is to report our experience in the diagnosis and treatment of this clinical condition. MATERIAL AND METHODS: 21 patients with spontaneous pneumomediastinum who were referred to our clinic between January 2010 and May 2015 were evaluated retrospectively. The presence of radiological pneumomediastinum and the absence a traumatic cause were taken as the basic criterion. RESULTS: The mean age of the patients was 24.78 +/- 4.37 years. Thirteen patients were male, eight patients were female. The main complaints of the patients were chest pain, dyspnea, neck pain, sore throat and cough. Thirteen patients were smokers. Seven patients had a prior history of asthma, five patient had chronic bronchitis and one patient had cronic obstructive lung diseases. No precipitating factor was identified in 9 patients. While initial complaints was associated with physical effort in 7 patients, three patients cough and two patients had a history of severe crying. Pneumomediastinum was diagnosed by chest radiography in 8 patients, and with chest CT in 13 patients. All the patients were performed bronchoscopy and radiograph of esophagus. Electrocardiogram was taken for all patients. Arrhythmia was detected in 4 of the patients. Treatment included analgesia, rest and oxygen therapy. Mortalitiy and morbidity were not seen. The mean length of hospital stay was 4.4 +/- 2.17 days. CONCLUSION: Spontaneous pneumomediastinum is a benign process. Despite its low incidence, it should be considered in the differential diagnosis of acute chest pain. PMID- 29404136 TI - Depressive Symptoms in Patients with Obstructive Sleep Apnea. AB - OBJECTIVES: Different studies have investigate depressive symptom degree within sleep disordered patients with obstructive sleep apnea (OSA). However, little is known and unclear about OSA in patients with depression symptom in the literature. The purpose of this study was to investigate patients with OSA would have a higher prevalence of depression symptom relative to control patients. MATERIAL AND METHODS: 72 patients with OSA (AHI >= 5) and 24 control subjects (AHI < 5) were assessed for depression symptom using the Beck Depression Inventory. Participants were underwent an overnight polysomnography assessment. An apnea-hypopnea index >= 5 events per hour was used as diagnosis for OSA. The associations between each total score on the Beck Depressive Inventory (BDI) and polysomnographic parameters were examined by correlation analysis. RESULTS: We demonstrated that BDI scores has statistically significant correlation with the OSA in our present study according to similar previous studies (p= 0.008). Oxygen Desaturation Index (ODI) has correlated with BDI (r= 0.31). CONCLUSION: These findings show that the frequency depression symptom is higher among individuals with OSA. Patients with OSA should be screened cautiously for depressive disorders. PMID- 29404137 TI - How to Conduct a Pleural Research: Master's Advice. PMID- 29404138 TI - Response of Complex Undefined Hypereosinophilic Syndrome to Treatment with Imatinib. AB - Hypereosinophilic syndomes (HESs) include potentially lethal multisystem disorders characterized by eosinophilic infiltration of a variable spectrum of target organs, predominantly the skin, heart, lungs, gastrointestinal tract, and nervous system. Based on recent advances in molecular and genetic diagnostic techniques and increasing experience with differences in clinical features and prognosis, subtypes have been defined, including "myeloproliferative-HES ", "lymphocytic-HES", "familial eosinophilia", "overlap HES", "undefined HES" ("complex undefined HES", "simple undefined HES", "episodic undefined HES") and "eosinophil associated diseases" (such as Churg-Strauss syndrome). HES should be kept in mind in the differential diagnosis of eosinophilic lung diseases especially in patients with peripheral eosinophilia and pulmonary infiltrates. Corticosteroids represent an effective firstline approach to decreasing eosinophil counts in the majority of cases. Imatinib might be used for corticosteroid nonresponders. We herein report a patient with "complex undefined HES" who had disease resistant to corticosteroids, but who had a significant response after treatment with imatinib. PMID- 29404139 TI - A Pulmonary Tuberculosis Case Presented with Tonsillar Involvement. AB - Tonsillar tuberculosis is a rare form of extra pulmonary tuberculosis. We reported a case with tonsillar tuberculosis secondary to pulmonary tuberculosis in this paper. A 26 year old, unimmunocompromised man admitted to head and neck surgery clinic with complaints of fever, throat ache and difficulty swallowing. The patient was consulted by infectious diseases clinic because of examination findings and his history. Asid fast basili was determined in tonsillar lesion smear, sputum and the patient was diagnosed as tonsillar and pulmonary tuberculosis. Antituberculous agents were started. Complaints of the patient were decreased and any adverse effect was developed. Treatment was completed in 9 months. In patients with long-term difficulty swallowing and fever, countries in which tuberculosis is prevalent, tonsillar tuberculosis should be considered, even if the patients were unimmunocompromised. PMID- 29404140 TI - Squamous Cell Cancer of The Lung with Synchronous Renal Cell Carcinoma. AB - Coexistence of two or more primary cancers is a relatively rare case. Not with standing that the coexistence of multiple primary cancers is often discussed in the literature, there is a small number of publications concerning the coexistence of squamous cell lung carcinoma and renal cancer. In this case report, detection of both squamous cell lung carcinoma and primary renal cancer in one male patient is going to be discussed. PMID- 29404141 TI - The Right Inferior Pulmonary Vein Related Inflammatory Myofibroblastic Tumor in an Adult Case. AB - Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm, which is derived of mesenchymal origin. Here we present an adult case with IMT, the origin of which was considered to be right inferior pulmonary vein. A male patient who was 52 years old, admitted to our outpatient clinic with the complaint of shortness of breath. He had cigarette smoking history for 30 years. On direct posterior - anterior X-Ray of the chest, a well-circumscribed mass with calcification in right hilum of the lung was observed. There was a mass which was extending to the inferior inferior pulmonary vein from right hilum of the lung, was measured 70 * 60 mm on computed tomography of the chest. Hamartoma, teratoma and Castleman Disease were among the possible diagnoses. On diagnostic bronchoscopy, signs of pressure from outside to the bronchi of the right middle and lower lobe was observed. Surgical excision is decided and the mass was totally excised through a muscle-sparing thoracotomy. The mass thought to arise from the inferior pulmonary vein on intraoperative inspection and right inferior lobe excision is undertaken by intrapericardial approach. No postoperative complication is encountered. Histological examination of the mass indicated inflammatory myofibroblastic tumor. Main treatment of IMT is surgical excision with negative surgical margin. Here in we present an IMT which is encountered at an unexpected location is excised completely with right lower lobe excision by an intrapericardial approach. PMID- 29404142 TI - The Future Plans of Turkish Thoracic Journal. PMID- 29404143 TI - Investigation of Sleep Quality and Sleep Disorders in Students of Medicine. AB - OBJECTIVES: This study was performed on Suleyman Demirel University medical students to determine the quality of sleep and to investigate factors that affect of sleep quality. MATERIAL AND METHODS: Suleyman Demirel University Medical students at 1, 2, 3, 4, 5 and 6 classes included to this cross-sectional analytical study (n= 720). Refused to fill to the survey (188), and students were not come to faculty (195), applied survey to 337 students (46.8%). Epworth sleepiness scale (ESS), Pittsburgh (PSQI) and Berlin sleep questionnaires, and 13 pieces closed and open-ended socio-demographic questions were conduct a questionnare under observation. The collected data were analyzed by using descriptive statistics, chi-square, two independent groups t test, Pearson and Spearman's correlation, Mann-Whitney U, Kruskal-Wallis and ANOVA tests. RESULTS: 337 students participated in the study, 42.1% were male, 57.9% were female, mean age was 21.3 +/- 2.1 years. Depending on Body mass index (BMI) 31 were poor, 212 normal, 53 overweight, and 4 obese students. In 118 students (35.3%), and these students have a chronic disease associated with 15.6% used the drug because of illness and 38 percent of students (11.6%) were smokers. 18.1 +/- 16.1 min for pupils in times of falling asleep, sleep duration per night. 6.6 +/- 1.3h, the mean departure time was 7.7 +/- 1.8. Scale with a total score of Pittsburgh class (p= 0.000), age (p= 0.003), BMI (p= 0.015) had a significant correlation between. Pittsburgh PUKI scores and without a significant difference in gender (p= 0.054), the use of stimulant substances (p= 0.032), weight (p= 0.021) and snoring (p= 0.002) with no significant difference were found. ESS total score and gender (p= 0.025), drug use (p= 0.035) and sports activities (p= 0.038). Ten students had snoring (3.0%), 5 students (1.5%) had witnessed apnea. Snoring 17.2% to in ESS > 10 points on it. Pittsburgh, the mean scores of those who witnessed apnea (14.0 +/- 5.3), witnessed apnea, according to non-students (10.2 +/- 6.4) were higher (p= 0.191).The effects PSQI and ESS results on the term were statistically significant by the multivariate regression analysis [F(10.602)= 4.56; p< 0.05; Wilkis Lamda 0.864, partial n2= 0.07]. To estimate of the value of PSQI by the stepwise regression analysis was performed; age and fall asleep properties has been included of the model (R2= 89%, p< 0.05). To estimate of the value of PSQI by the stepwise regression analysis was performed; fall asleep property has been included of the model in the the male gender (R2= 80%, p< 0.05). To estimate of the value of ESS by the stepwise regression analysis was performed; term property has been included of the model (R2= 65%, p< 0.05). CONCLUSION: Medical school students participating in our study, although female-male ratio close to each other, we found that higher ESS and Pittsburgh scores in female more than male. In this case may be related to physiological, genetic, environmental, cultural and psychological differences. PMID- 29404144 TI - Analysis of Chromosome 3, 7 and 8 Centromeric Regions in Bronchial Lavage Specimens by FISH. AB - OBJECTIVES: Multiple genetic changes are observed in malignant tumors but are rare or absent in benign conditions. Aneuploidy is the most common feature of solid tumors including lung cancer and diagnosis of malignant tumors is possible through detection of aneuploidy. The aim of this study was to investigate chromosomal abnormalities in cells from non-small cell lung cancer patients obtained bronchoscopically and to evaluate the suitability of fluorescence in situ hybridization (FISH). MATERIAL AND METHODS: Bronchial lavage samples of 17 non-small cell lung cancer (NSCLC) patients were evaluated with four-color FISH using deoxyribonucleic acid (DNA) probes specific for the centromere regions of chromosomes 3, 7 and 8. tested specimens were first hybridized with probes, then visualized under fluorescence microscobe and captured with device's camera. RESULTS: High number of aneuploidic cells were detected in all the samples. Increased or decreased abnormal copies or chromosomes 3, 7 and 8 were obserced in all the 17 patients. Aneuploidy of chromosome 3 (21.35%) was higher than those of chromosome 7 (9.06%) and chromosome 8 (15.47%). Moreover, our results were significant for monosomy and trisomy of chromosome 3, trisomy of chromosome 7, nullisomy, monosomy and trisomy of, chromosome 8 (p< 0.05). CONCLUSION: It has been observed that FISH is a useful technique for detection of aneuploidy in bronchial lavage samples obtained by bronchoscopy. Interphase cells were evaluated without cell culturing with this method and high number of tumor cells were enumerated rapidly. Our study has demonstrated that, FISH technique may be used successfully in detection of chromosome number abnormalities in NSCLC patients and may facilitate evaluation of genetic abnormalities. PMID- 29404145 TI - Management of Massive Hemoptysis: Analyses of 58 Patients. AB - OBJECTIVES: The objective was to describe changing patterns of etiological factors and treatment modalities for massive hemoptysis. MATERIAL AND METHODS: From January 2008-December 2012, the medical records of 58 massive hemoptysis patients were reviewed. RESULTS: Fifty-eight patients, 44 were men (75.9%) and 14 were women (24.1%), with a mean age of 51.4 years (range= 19-84 years), were divided into three groups; surgical management (n= 37, 63.8%), conservative management (n= 14, 24.1%) and bronchial artery embolization (n= 6, 10.4%). One case (1.7%) had combined treatment modality; bronchial artery embolization was followed by surgical resection. Anatomical lung resections were the most preferred resection type in the surgical management group (n= 34, 91.9%). The most common etiological factor was bronchiectasis (n= 19, 32.8%); followed by bronchial cancer (n= 14, 24.1%). The duration of hospitalization in the surgical management group was 11.4 days (range= 4-24); whereas in the bronchial artery embolization group, hospitalization was only four days (range= 2-7) (p< 0.01). Prolonged air leak (n= 7; 18.9%) was the most common complication in the surgical management group. CONCLUSION: We emphasize that bronchiectasis was leading cause of massive hemoptysis. Surgical treatment remains the definitive therapy in the management of massive hemoptysis with decreased mortality rates over decades; whereas bronchial artery embolization is an effective therapeutic tool. PMID- 29404146 TI - Serum Heat Shock Protein Levels and the Relationship of Heat Shock Proteins with Various Parameters in Chronic Obstructive Pulmonary Disease Patients. AB - OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is accompanied by increased cellular stress and inflammation. Most of the Heat Shock Proteins (HSPs) have strong cytoprotective effects. The role of HSPs in COPD pathogenesis has not determined completely. We investigated the serum level of HSPs in COPD patients, smokers without COPD and healthy non-smoking controls. Also, we evaluated the relationship of HSPs with various parameters (inflammatory, oxidative, functional status, quality of life) in COPD patients. MATERIAL AND METHODS: The levels of stress protein (HSP27, HSP70, HSP60, HSP90, CyPA), interleukin-6, C-reactive protein and malondialdehyde were measured in 16 healthy non-smoker, 14 smokers without COPD and 50 patients with stable COPD. Pulmonary function tests (PFT) and arterial blood gases parameters were measured. Health Related Quality of Life was evaluated and exercise capacity was measured with 6 minute walking test. RESULTS: Only HSP27 levels was significantly higher in COPD patients when compared with both healthy non-smoker and smokers without COPD (for both, p< 0.001). There was a weak-moderate negative correlation between serum levels of HSP27 and PFT parameters and between HSP27 levels and PaO2. Serum levels of HSP27 showed a weak-moderate positive correlation with symptom, activity and total scores. Subjects evaluated only smokers without COPD and patients with COPD; HSP27 had an area under the curve (AUC) in the receiver operating characteristic (ROC) curve of 0.819 (0.702-0.935; 95% CI; p= 0.000). CONCLUSION: Increased serum levels of HSP27 was found in COPD patients and our results showed sensitivity and specificity of serum HSP27 as diagnostic markers for COPD. PMID- 29404147 TI - Right Sided Aortic Arch Resembling Asthma. AB - Exertional dyspnoea and shortness of breath at rest are common complaints in asthmatic patients. However, symptoms sometimes do not resolve under optimal medical treatment. In such cases infrequent causes of dyspnoea may be the underlying basis. We present a 38-year-old patient who suffered from shortness of breath not amenable to medical treatment for asthma for five years. In her medical history, the patient was on salbutamol inhalation as well as budesonide/formoterol inhalation for 5 years and the symptoms did not ameliorate. We diagnosed a right sided aortic arch after investigations. In this rare anomaly, both trachea and oesophagus might be encircled and compressed by large vessels as well as the aortic arch. Although some signs of right sided aortic arch can be recognized in chest radiograph and spirometry, accurate diagnosis is made by contrast enhanced computed tomography or angiography. Delay in diagnosis of right sided aortic arch may result in unnecessary investigations and prolonged periods of ineffective treatment. Diagnosis of right sided aortic arch leads to improvement in symptoms and withdrawal of unnecessary treatment. PMID- 29404148 TI - Two Chronic Granulomatous Disease Diagnosed in Adult Age. AB - Chronic granulomatous disease (CGD) is a rare, inherited primary immunodeficiency that is usually diagnosed at adulthood and is presented with recurrent bacterial and fungal infections. In this case report, two adult cases of CGD have been presented. A 29-year-old woman was referred to our clinic with hypoxic respiratory failure, with a pre-diagnosis of multidrug resistant tuberculosis (TB). Her lung biopsy had been reported as granulomatous inflammation, she had not responded to a 5 month anti-TB treatment. A complete medical history consisted of 4 occasions of treatment with anti-TB drugs and that her sister and brother had undergone TB therapy. However, since childhood, a TB bacilli had never been isolated microbiologically in the siblings. Patient's parents were third degree consanguineous. The patient still had a purulent drainage around the operation site. Microbiological studies of the wound drainage and respiratory tract have not encountered any specific microorganism. Investigation of an immunodeficiency has proved CGD through nitroblue tetrazolium test. Her siblings has been diagnosed as CGD as well. Second case, a 19-year-old male, has been admitted to our clinic with complaints of fever, chest pain and an abscess lesion in the anterior chest wall. His medical history comprised 3 recurrences of pneumonia within last 2 years. In physical examination, a 3 * 5 cm fluctuant swelling lesion on the anterior chest wall. Radiologically, new pneumonic consolidations were detected. Sputum specimens did not provide any specific microorganism, cultures of the chest-wall abscess fluid grew aspergillus. His parents had been living in the same village but no consanguinity was known. Due to recurrent infections, immunodeficiency tests had been investigated. He was diagnosed as CGD due to dihydrorhodamin test. These two cases signify that, in our country where consanguinity is common, etiology of recurrent unexplained infections, abscesses and granulomas should be investigated and CGD should be in differantial diagnosis list. PMID- 29404149 TI - Pulmonary Mucormycosis Over 130 Years: A Case Report and Literature Review. AB - Mucor is a ubiquitous fungus that belongs to the family of Zygomycetes, though a noninvasive saprophyte in the normal host, it can cause life threatening infections in immunocompromised patients, including angioinvasive pulmonary mucormycosis; a disease notorious for its high mortality. This article tracks the ever-changing management of pulmonary mucormycosis over the last 130 years, and how this affected mortality. PMID- 29404150 TI - Diffusely Increased Splenic Fluorodeoxyglucose Uptake in Lung Cancer Patients. AB - OBJECTIVES: This study aimed to investigate the association of diffuse splenic F 18 fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) with tumor maximum standardized uptake value (SUVmax), presence of distant metastases, and hematological and inflammatory parameters. MATERIAL AND METHODS: Initial FDG PET/CT of 15 lung cancer patients with diffuse splenic FDG uptake were retrospectively analyzed (Group 1). Twelve patients who recently underwent FDG PET/CT for histopathologically proven lung cancer were enrolled as the control group (Group 2). All 27 patients had hematological data, including C-reactive protein (CRP) level, within 5 days before or after PET/CT. To determine SUVmax, the region of interests included the tumor, liver, spleen, and iliac crest. The possible associations between the spleen/liver (S/L) and bone marrow/liver (BM/L) ratios and tumor SUVmax, presence of metastasis, and hematological parameters were evaluated. RESULTS: The S/L ratio and hemoglobin (Hb) levels were different between the two groups (p=0.000 and 0.05, respectively). The number of patients with anemia were significantly higher in Group 1 than in Group 2 (p=0.02). Although mean Hb levels were different between the two groups, there was no correlation between Hb levels and S/L ratios. There was no significant difference between the two groups with respect to the numbers of patients who had an accompanying infection site. Only CRP levels were correlated with S/L ratios in Group 1 among various other parameters (r=0.559, p=0.05). CONCLUSION: Our results suggested that inflammation degree correlated with increased splenic FDG uptake in lung cancer patients and was enhanced by anemia. Systemic inflammation and anemia could be important causes of diffusely increased splenic FDG accumulation on PET/CT examinations of lung cancer patients. PMID- 29404151 TI - Frequency of Silent Brain Metastasis Before Prophylactic Cranial Irradiation in Small Cell Lung Cancer. AB - OBJECTIVES: Prophylactic cranial irradiation (PCI) decreases incidence of brain metastasis and improves survival in patients with limited disease-small cell lung cancer (LD-SCLC) who achieved complete response (CR) after treatment. There is no satisfactory evidence about the necessity of new brain imaging for asymptomatic metastasis immediately prior to PCI. The present study aimed to evaluate the frequency of brain metastasis in SCLC patients without neurological symptoms who are candidates for PCI. MATERIAL AND METHODS: The data files of 243 patients with SCLC referred for cranial irradiation were retrospectively reviewed. The patients with following characteristics were enrolled to the study; 1) LD-SCLC patients with CR after chemoradiotherapy who are candidates for PCI. 2) No neurological signs or symptoms of brain metastasis after chemoradiotherapy. 3) Having brain imaging at initial diagnosis and before PCI. RESULTS: Ninety-nine patients (83 male, 83.3%) were included in this study. Median age was 60 years. Time interval between initial and reevaluation for brain metastasis was median 5.5 months (range; 4.7-7.1). Asymptomatic brain metastasis rate was 20.2% (18/99). CONCLUSION: Even if local disease is under control, asymptomatic brain metastasis is not rare. Therefore, patients who are candidates for PCI after completion of chemoradiotherapy should be reimaged for brain metastasis before PCI. PMID- 29404152 TI - The Effect of Working in a Smoke-Free Workplace on use of Smoking and Smokeless Tobacco. AB - OBJECTIVES: The aim of this study was to evaluate whether smokeless tobacco (Maras powder) use increased among smokers working at smoke-free workplaces or not. MATERIAL AND METHODS: In Kahramanmaras city, 242 male workers who were current or former smokers, working at strictly smoke-free workplaces were included in this study. A total of 21 questions, including the Fagerstrom Test for Nicotine Dependence, were asked. RESULTS: All the participants were male with a mean age of 29.33+/-6.66 years, and the age range was 17-55 years. Current smokers were 90 (37.2%) and former smokers were 152 (62.8%). Former smokers were asked the reason why they quit smoking; the predominant reasons were the health hazards of smoking and the financial burden of cigarettes. The quitting rate was significantly higher among married participants (p=0.023). Maras powder users were 184 (76%), users who never smoked were 54 (22.3%), and former users were 4 (1.7%). We asked the Maras powder users if they had been using it before the smoking bans, and 96 workers (51.1%) answered "no." The question "Did the use of Maras powder increase with smoking bans"? was asked, and 118 workers (62.8%) answered "yes." The level of education among Maras powder users was significantly lower than non-users (p=0.001). CONCLUSION: Working in smoke-free workplaces is associated with increased rates of quitting smoking and also with increased use of Maras powder, a local form of oral smokeless tobacco. PMID- 29404153 TI - Quality of Life Questionnaire for Turkish Patients with Primary Ciliary Dyskinesia. AB - OBJECTIVES: Primary ciliary dyskinesia (PCD) is a major cause of progressive lung disease, and physiological measures do not reflect the impact of the disease on patients' daily symptoms or physical and social functions. We need valid and reliable health-related quality-of-life (HRQOL) measures in PCD to assess the symptoms and daily functions from the patient's perspective. Our aim was to develop a Turkish translation of PCD-specific HRQOL questionnairre to be used as outcomes in clinical trials. MATERIAL AND METHODS: This study was conducted at the Division of Pediatric Pulmonology, Hacettepe University Faculty of Medicine and the Division of Pediatric Pulmonology, Marmara University Faculty of Medicine. Forward and back translations were performed by three different translators. We recruited participants with PCD from different age groups of both sexes, with an aim to represent a wide spectrum of disease severity and performed the prototype of the translation in these participants. RESULTS: Five participants from each age group [children (6-12 years), teenagers (13-17 years), adults (18+ years) and parents of children aged from 6 to 12 years] responded to the HRQOL questionnaire. Content analysis of the questions included the following domains depending on age: Respiratory Symptoms, Physical Functioning, Emotional Functioning, Treatment Burden, Ears and Hearing, Sinus Symptoms, Social Functioning, Role Functioning, Vitality, Health Perceptions, School Functioning, Eating and Weight. After the participants have completed the questionnaire, a cognitive debriefing interview was conducted with them, and the results of the interviews were used to form a final version of PCD-specific HRQOL, ready for formal validation. CONCLUSION: A Turkish translation of PCD-specific HRQOL questionnaire was developed to meet the standards set by international guidelines. This questionnaire is expected to be useful as end points in clinical trials for monitoring health outcomes and for improving clinical decisions. PMID- 29404154 TI - Mycobacterium Tuberculosis and Nontuberculous Mycobacteria Coinfection of the Lungs. AB - Tuberculosis is highly prevalent in our country and nontuberculous mycobacteria (NTM) are frequently found in respiratory specimens recently. A 65-year-old woman was admitted with complaints of fever, cough, weight loss, and hemoptysis. On the patient's chest radiography an upper lobe cavity in both lungs and consolidation was detected. Acid-fast bacilli 4+ were observed in smear of sputum and culture results M. intracellulare and M. tuberculosis were observed together. The patient's treatment was arranged. Through this case, we want to emphasize that tuberculosis and nontuberculous mycobacterial disease can coexist. PMID- 29404155 TI - Primary Ciliary Dyskinesia: Ready for Quality of Life Assessment. PMID- 29404156 TI - Influence of Statin Therapy on Exacerbation Frequency in Patients with Chronic Obstructive Pulmonary Disease. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease, in which chronic and systemic inflammation plays an important role. By decreasing neutrophil infiltration and cytokine production, statins have anti inflammatory mechanisms. MATERIALS AND METHODS: Fifty-seven patients who had diagnosis of chronic obstructive pulmonary disease according to GOLD guideline were included in the study; 20 of them were statin users. Statin users group were patients being under medication with regular simvastatin, atorvastatin or rosuvastatin 20 mg per day for at least the past 1 year. RESULTS: There was statistically no significant difference between patients with or without statin treatment with respect to; age, female-male ratio, COPD severity level, medication used for COPD, pulmonary function tests results and smoking habits. COPD exacerbation frequency in patients using statins was significantly less than patients not using statins (p<0.05). Patient number with COPD exacerbation, antibiotic treatment and outpatient clinic administration and outpatient clinic administration frequency was significantly lower in statin using patients (p<0.05). CONCLUSION: COPD patients receiving statins have a lower frequency of COPD exacarbations, hospital administration and antibiotic treatment compared to patients not receiving statins. PMID- 29404157 TI - To Investigate the Effects of Air Pollution (PM10 and SO2) on the Respiratory Diseases Asthma and Chronic Obstructive Pulmonary Disease. AB - OBJECTIVES: Effects of air pollution parameters of sulfur dioxide (SO2) and particulate matter (PM10) values on the respiratory system were investigated. MATERIAL AND METHODS: Data of SO2 and PM10 were obtained daily for air pollution and classified into two groups: Group I (2006-2007), coal burning years and Group II (2008-2009), natural gas+ coal burning. Groups I and II were divided into two subgroups according to the months of combustion as combustible (November-April) and noncombustible (May-October). The number of patients with asthma and chronic obstructive pulmonary disorder (COPD) was recorded between 2006 and 2009. RESULTS: There was no statistically significant difference between Groups I and II for PM10 and SO2 (p>0.05). Within the years, the values of SO2 and PM10 were statistically different between the groups defined by month (p<0.01). The number of patients in the combustible and noncombustible subgroups were found to be different for every 4 years, and the numbers of patients with COPD or asthma were not changed through the years. There was a strong correlation between PM10 and COPD (r=0.59, p<0.01) and a weak correlation between PM10 and asthma (r=0.25, p>0.05). A correlation was found between SO2 and COPD (p<0.01) but not between SO2 and asthma (p>0.05). The number of visits for COPD and asthma was statistically different between combustible and noncombustible subgroups (X2:58.61, p=0.000; X2:34.55, p=0.000, respectively). The r2 values for SO2 and PM10 for COPD patients were 17% and 24%, respectively, in contrast to 8% and 5%, respectivley for asthma patients. CONCLUSION: Air pollution is known to increase respiratory disease occurrences. With decrease in the usage of solid fuel, air pollution could be reduced and may be effective in preventing respiratory diseases. PMID- 29404158 TI - Is There a Link Between Obstructive Sleep Apnea Syndrome and Fibromyalgia Syndrome? AB - OBJECTIVES: Fibromyalgia syndrome (FMS) is characterized by complaints of chronic musculoskeletal pain, fatigue, and difficulty in falling asleep. Obstructive sleep apnea syndrome (OSAS) is associated with symptoms, such as morning fatigueness and unrefreshing sleep. We aimed to investigate the presence of OSAS and objectively demonstrate changes in sleep pattern in patients with FMS. MATERIAL AND METHODS: Polysomnographic investigations were performed on 24 patients with FMS. Patients were divided into two groups: patients with and without OSAS (Group 1 and Group 2, respectively). A total of 40 patients without FMS who presented to the sleep disorders polyclinic with an initial diagnosis of OSAS were included in Group 3. Based on their apnea hypopnea index (AHI), OSAS in the patients were categorized as mild (AHI, 5-15), moderate (30), or severe (>30). RESULTS: OSAS was detected in 50% of patients with FMS. The most prominent clinical findings were morning fatigue and sleep disorder, which were similar in three groups. In polysomnography (PSG) evaluation, patients with FMS had mild (33%), moderate (25%), and severe (42%) OSAS. In correlation analyses, negative correlations were observed between fibromyalgia impact questionnaire (FIQ) and mean oxygen saturation, visual analogue scale (VAS), and minimum oxygen saturation, whereas a positive correlation was found between FIQ and desaturation times in patients with FMS. CONCLUSION: Detection of OSAS in 50% of the patients with FMS, and similar rates of complaints of sleep disorder and morning fatigue of OSAS and FMS cases are important results. Detection of correlation between the severity of hypoxemia and FIQ and VAS scores are significant because it signifies the contribution of increased tissue hypoxemia to the deterioration of clinical status. Diagnosis and treatment of OSAS associated with FMS are important because of their favorable contributions to the improvement of the clinical picture of FMS. PMID- 29404159 TI - Presence of Headache and Migraine in Asthma Patients. AB - OBJECTIVES: Migraine is a diseases characterized with severe headaches, with neurological and systemic findings. The purpose of this study is to investigate the prevalence of migraine and to examine whether there is a relationship between atopic disorders, parental history and migraine in asthma patients. MATERIAL AND METHODS: A total of 288 asthma outpatients, who had the diagnosis by an early or late test of reversibility showing a reversible airway obstruction according to hospital database were included. The presence of headache, atopic symptoms and parental history about asthma, atopic disorders and migraine were asked. The patients with headache were consultated by neurology department and investigated about the presence of migraine. The diagnosis of migraine headache was made if patients fulfilled the International Headache Society (IHS) criteria. RESULTS: 60.4% of patients described a headache. There were 94 patients (32.6%) with headaches meeting the IHS criteria for migraine. Only 12 patients had migraine with aura. There were atopic symptoms in 86.8% of patients. According to parental history, there were asthma in 47.9%, atopic symptoms in 39.6% and migraine in 22.2% of parents. Patients with atopic symptoms were found to have significantly high rate of headaches (65.3%) "p=0.007". The prevalence of migraine was significantly high in patients with parental atopic symptoms (54%) "p=0.002". Multiple logistic regression analysis identified that gender, parental history of asthma, allergia and migraine, and smoking were independent risk factors for presence of migraine in asthmatics. CONCLUSION: There is a high prevalence of migraine headaches in patients with asthma. The coexistence of asthma and headaches may be related with a similar pathophysiological mechanism; parental history, common genetic compounds and smoking may play role in this mechanism. The headaches in asthma patients, atopic symptoms and family history should be questioned, and clinicians should be careful about the presence of migraine. PMID- 29404160 TI - Spontaneous Splenic Rupture in the Early Postoperative Period to After Lobectomy. AB - Spontaneous splenic rupture is a quite rare entity that may develop secondary to some special situations (lymphoma, post-abdominal surgey etc). In the literature, the case of a patient has been reported following thoracic surgery. In a patient who had undergone right upper lobectomy for pulmonary carcinoma, signs of acute abdomen and low levels in the hemogram were detected on the fifth postoperative day; therefore, the patient underwent further investigations. A radiological evaluation revealed splenic rupture, and the patient was operated on. A case is presented that may be fatal and requires emergency response and that has to be kept in mind, although it is extremely rare. A case of spontaneous splenic rupture has been presented that may be fatal and requires emergency response; this should be kept in mind, although it is extremely rare. PMID- 29404161 TI - Primary Pulmonary Malignant Fibrous Histiocytoma. AB - Malignant fibrous histiocytoma (MFH) cases are classified within the group of nonclassified sarcomas. The etiopathogenesis is unclear; however, MFH commonly develops in scar tissue and in areas exposed to radiation. MFH is the most common soft tissue sarcoma in adults and may be borne in the lungs, chest wall, mediastinum, or other tissues. Primary MFH of the lung constitutes less than 0.2% of all pulmonary neoplasms; thus, an optimal treatment strategy has not yet been elucidated. We aimed to report a case of MFH of the lung with subsequent treatment administration. PMID- 29404163 TI - Can we Protect the Society from Passive Smoking? PMID- 29404162 TI - The View of the Turkish Thoracic Society on the Report of the GOLD 2017 Global Strategy for the Diagnosis, Management, and Prevention of COPD. AB - Since the Global Initiative for Obstructive Lung Disease (GOLD) published its first guidelines on chronic obstructive pulmonary disease (COPD) in 2001, much has changed till 2017. Previous versions of GOLD guidelines mentioned the forced expiratory volume in one second (FEV1)-based approach for staging and treatment modalities. Since 2011, a composite multi-dimensional approach has been introduced to cover various aspects of the disease. Unfortunately, this approach was not found to be correlated with mortality as well as the FEV1-based approach, despite the fact that it was better for estimating exacerbation rates. Although this assessment tool has been considered as a big step in personalized medicine, the system was rather complex to use in daily practice. In 2017, GOLD introduced a major revision in many aspects of the disease. This mainly includes a revised assessment tool and treatment algorithm. This new ABCD algorithm has excluded spirometry for guiding pharmacological therapy. Treatment recommendations are mainly based on symptoms and exacerbation rates. Escalation and de-escalation strategies have been proposed for the first time. The spirometric measurement has only been retained to confirm the diagnosis and lead to nonpharmacological therapies. In this report, the Turkish Thoracic Society COPD assembly aimed to summarize and give an insight to the Turkish interpretation of GOLD 2017. PMID- 29404164 TI - Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small-Cell Lung Cancer. AB - Systemic treatment is the basic treatment approach to advanced-stage non-small cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future. PMID- 29404165 TI - Clinical and Serological Features of Eosinophilic and Vasculitic Phases of Eosinophilic Granulomatosis with Poliangiitis: a Case Series of 15 Patients. AB - OBJECTIVES: Eosinophilic granulomatosis with poliangiitis (EGPA) which was previously called Churg-Strauss Syndrome, is classified into eosinophilic and vasculitic phases. To characterize the eosinophilic and vasculitic phases of the disease in terms of clinical findings, serology, and treatment. MATERIALS AND METHODS: We included 15 EGPA patients in the study. The clinical, serological, and therapeutic characteristics and the treatment responses of the patients were recorded. RESULTS: Thirteen patients were classified as being in the eosinophilic phase and two were classified as being in the vasculitic phase of EGPA. Initial symptoms were worsening asthma in all patients (n=15; 100%). All patients had rhinosinusitis, and 66.6% had hypersensitivity to nonsteroidal anti-inflammatory drugs. The two patients in the vasculitic phase did not have nasal polyposis. Pulmonary and nervous system involvement were the most common symptoms. The erythrocyte sedimentation rates (ESRs) of the two patients in the vasculitic phase were 65 mm/h and 55 mm/h, while ESR was normal in eosinophilic-phase patients. Antineutrophil cytoplasmic antibodies (ANCA) was detected in one patient (6.6%) who was in the vasculitic phase (Case 15). The disease was under control with higher doses of methylprednisolone in the vasculitic phase (Case 14: 12 mg/day, Case 15: 10 mg/day) than in the eosinophilic phase. Relapse was detected in the two patients in the vasculitic phase. Oral corticosteroid was not discontinued in any case, and no mortality was reported. CONCLUSION: Patients with eosinophilic phase or vasculitic phase EGPA had similar clinical onset. However, higher ESR, ANCA positivity, and extrapulmonary organ involvement were only found in patients in the vasculitic phase. Corticosteroid responsiveness was very good in all patients in the eosinophilic phase, and the disease could be controlled with a very low maintenance dose of a corticosteroid. PMID- 29404166 TI - Does the Incidence and Mortality of Pulmonary Thromboembolism Change Over the Years? AB - OBJECTIVES: In the last 20 years, with the use of computed tomography (CT) angiography, the number of patients diagnosed with pulmonary thromboembolism (PTE) has increased. At the same time, data show that pulmonary embolism mortality has also reduced in this duration. MATERIAL AND METHODS: In this study, we analyzed records of patients with PTE (using ICD's) in the hospital automation system from 2001 to 2013. Data regarding age, sex, date of diagnosis, diagnosis of cancer, hemodynamic status, initial and maintenance treatment, hospital length of stay, and hospital mortality were recorded. Primary endpoints of the study were hospital length of stay and all-cause hospital mortality. RESULTS: The total number of patients included in the study was 1185. The median age was 61 years in 2001 and 71 years in 2013. The number of patients who were diagnosed using CT increased from 10% to 92.8%. Between 2001 and 2013, the number of patients diagnosed with PTE increased, and of all patients with PTE, 13.7% was diagnosed in 2009. The hospital length of stay of 13 days declined to 9 days. The use of a vena cava filter in 2007 was 1.1% and that in 2013 was 4.6%. Mortality rate was 15%, however hospital mortality did not significantly differ over the years but varied between 9.4% and 18.8%. Increased use of thrombolytics in patients with massive PTE has been observed over the years. Massive PTE ratio in 2006 was 8.5% and thrombolytic use was 5.8%, however in 2013, these ratios were 2.6%, 6% respectively (p=0.017). CONCLUSION: Finally, despite the increased number of patients diagnosed with PTE over the years, the mortality rate was not observed to have changed from 2001 to 2013. PMID- 29404167 TI - Organizing Pneumonia as a Histopathological Term. AB - OBJECTIVES: Organizing pneumonia (OP) is an interstitial lung disease characterized by granulation tissue buds in alveoli and alveolar ductus, possibly accompanied by bronchiolar involvement. Histopathologically, OP may signify a primary disease and be observed as a contiguous disease or as a minor component of other diseases. In this study, the clinical significance of histopathological OP lesions and clinical and radiological features of patients with primary OP were examined. MATERIAL AND METHODS: Between January 2011 and January 2015, of 6,346 lung pathology reports, 138 patients with OP lesions were retrospectively evaluated. According to the final diagnoses, patients were grouped as reactive OP (those with final diagnosis other than OP) and primary OP (those with OP). Patients with primary OP were classified according to etiology as cryptogenic and secondary OP. Radiological evaluation was conducted within a categorization of "typical," "focal," and "infiltrative." RESULTS: Of 138 patients, 25% were males and the mean age was 54+/-14 years. Pathologically, 61% of patients had reactive OP and 39% had primary OP. All reactive OP lesions were reported using surgical specimens, and the most frequent primary diagnoses were malignancy (65%), infection (15%), interstitial lung diseases other than OP (7%), and bronchiectasis (5%). Other diagnoses included bullae, foreign body, hamartoma, bronchogenic cyst, and bronchopleural fistula. Of all the primary OP patients, 48 had cryptogenic OP and six had secondary OP. Radiological involvement was consistent with typical OP in 30%, focal OP in 63%, and infiltrative OP in 7% of the patients. All focal OP lesions were defined using surgical resections. Positron emission computed tomography (PET-CT) was recorded in 28 patients. In 11 patients, lymphadenomegaly was comorbid. The mean widest diameter of focal opacity was 2.7+/-1.2 (1.2-4.9) cm, and the mean the maximum standardized uptake value (SUVmax was 6.1+/-3.9 (1.7-16.7). CONCLUSION: OP lesions generally present as a minor component of other diseases. In patients with OP, cryptogenic OP and radiological focal OP is more frequently observed. Most focal OP lesions are detected using surgical resections because of malignant prediagnosis owing to elevated SUVmax. PMID- 29404168 TI - A Study Examining Compliance with the Anti-Tobacco Law Nb. 4207 Inside Taxis. AB - OBJECTIVES: This observational study assessed compliance with the anti-tobacco Law Nb 4207 with regard to taxis in Cankaya district, Ankara. MATERIAL AND METHODS: This descriptive study was conducted in Kizilay, Kugulu, and Tandogan intersections on January 18-23, 2016 between 9.00-11.00 and 14.00-16.00 hours in Ankara. Data regarding the status of the taxi (either cruising or not), smoking inside taxis, smoking status of the taxi drivers and/or clients, location of the clients in the taxi, presence of a child in the taxi, and status of the windows (open or not) were recorded using a data-gathering form. RESULTS: Three thousand six hundred fifty-six taxis were evaluated, of which 79 (2.2%) taxi drivers were observed smoking. Clients were observed smoking in 17 taxis (1.3%). Ninety-four taxi drivers and/or clients (2.6%) were observed smoking. Taxi drivers smoked more frequently in the absence of a client. In addition, a smoking client influenced the taxi driver's smoking status (p<0.001). CONCLUSION: Violation of the anti-tobacco Law Nb 4207 was observed. In this regard, the number of inspections needs to be increased. Systematic training programs for the taxi drivers regarding the risks of tobacco should be a priority. Preventive studies concerning the hazards of passive smoking should be also conducted at a community level. PMID- 29404169 TI - Ranitidine-Induced Anaphylaxis in a Patient with Acute COPD Exacerbation. AB - Ranitidine is a well-tolerated H2-receptor antagonist commonly used in peptic ulcer treatment and stress ulcer prophylaxis. Anaphylaxis is rarely observed with ranitidine. We report the case of a patient who developed anaphylaxis after intravenous injection of ranitidine for acute COPD exacerbation. This article underlines the importance of awareness that in COPD acute exacerbation treatment, ranitidine, which is usually administered with methylprednisolone, also has anaphylaxis potential. PMID- 29404170 TI - A Rare Case of Progressive Dyspnea and Bilateral Lung Infiltration in a Young Male. AB - Pulmonary lymphangitic carcinomatosis (PLC) is defined as infiltration of the lymphatic vessels and perilymphatic connective tissue with tumor cells, which is secondary to malignancy. Therefore, it rarely appears as an initial finding preceding a diagnosis of malignancy. A 30-year-old male patient was hospitalized in our clinic with a pre-diagnosis of interstitial lung disease owing to the complaints of dry cough, progressive dyspnea, and acute respiratory insufficiency. He was diagnosed with signet ring cell carcinoma, which is a histologic subtype of adenocarcinoma, via gastroscopy, and lung involvement was consistent with PLC. Regardless of the patient age, PLC should be considered in differential diagnoses of progressive dyspnea, acute respiratory failure, and widespread interstitial lung involvement. PMID- 29404171 TI - If You Know the Enemy and Your Weapons, You Need not Fear the Management of Chronic Obstructive Pulmonary Disease. PMID- 29404173 TI - Results of Polysomnographies and Treatment Strategies in Elderly Patients with Symptoms of Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: In this study, we evaluated data regarding the management of geriatric patients with symptoms of obstructive sleep apnea syndrome (age, >65 years) who were admitted to our sleep clinic. MATERIAL AND METHODS: Symptoms and sleep data of the patients were retrospectively evaluated, and the patients were reevaluated after treatment. RESULTS: A total of 85 patients with a median age of 69 years were included. Snoring and fatigue were the most common symptoms. Cardiovascular diseases were the most frequently listed comorbidity. The median Epworth sleepiness scale was 10, and based on Berlin sleep questionnaire findings, 63.5% of the participants were in the high-risk group. Eighty-seven percent were diagnosed with obstructive sleep apnea (2/3 of them were positional), and moderate-to-severe obstructive sleep apnea was observed more in women than in men. Only one patient was diagnosed with central sleep apnea. There were positive and linear correlations between increased age and the apnea hypopnea index, arousal index, Epworth sleepiness scale, and being in a high-risk group according to the Berlin sleep scale; however, there was no correlation between increased age and the number of hypopnea and apnea events. There were also positive and linear correlations between the apnea-hypopnea index and the Epworth sleepiness scale, being in a high-risk group according to the Berlin sleep questionnaire, an increased number of known medical conditions, and increased body mass index. We were able to contact 72 of the 85 patients via phone calls. Patients who adjusted to treatment had positive feedbacks. CONCLUSION: Sleep disorders are observed more in the elderly, and an increasing age is an independent factor for sleep disorders. Besides the usual signs and symptoms of sleep disorders, it should be considered in elderly who have cognitive dysfunction and dementia. PMID- 29404172 TI - Immune Checkpoint Inhibitors in Advanced-Stage Non-small Cell Lung Cancer. AB - More than half of non-small cell lung cancer (NSCLC) patients are at an advanced stage at the time of diagnosis, and they have a poor prognosis. Systemic treatment is the basic treatment approach for advanced-stage NSCLC, and chemotherapy and targeted treatments are commonly used based on the molecular characteristics. Although targeted therapies have led to a significant level of improvement in terms of survival, the results are still unsatisfactory. However, considerable attention has been focused to the immunotherapy with recent positive results reported by studies on this field. In this context, a certain portion of clinical studies have shown dramatic results, and these have involved inhibitors developed particularly against the immune checkpoint protein programmed death receptor-1 and its ligand (programmed death ligand-1). This review aims to present the significance of immune checkpoint inhibitors in NSCLC and to summarize the findings of relevant contemporary clinical studies. PMID- 29404174 TI - A Basic Question: Are Patients with Chronic Obstructive Pulmonary Disease Aware of Their Disease? AB - OBJECTIVES: Increased awareness and understanding of chronic obstructive pulmonary disease (COPD) is important for its management, but there are limited data regarding the basic knowledge among patients with COPD. This study aimed to evaluate the basic information and knowledge of patients who were specifically provided with a medical exemption certificate for COPD. MATERIAL AND METHODS: This cross-sectional, observational, single-center study was conducted at an outpatient clinic of our hospital and included 201 consecutive ambulatory patients who visited the outpatient clinic between January 01, 2015 and June 30, 2015. Data regarding sex, age, educational level, symptoms, smoking history, years since diagnosis, years since obtaining the exemption certificate, and COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease-GOLD) stage were obtained. A questionnaire comprising 15 questions was used. RESULTS: The question regarding the organ primarily affected by COPD was correctly answered as "lung" by 145 (72%) of patients. In addition, 152 (76%) patients declared that they knew the localization of the affected organ; only 44 (22%) patients correctly located the organ on an image. Only seven (3.5% of the total) patients could correctly write "chronic obstructive pulmonary disease." CONCLUSION: The lack of awareness among patients with COPD emphasizes the lack in the field of patient education. Simple questionnaires can be used to determine and also to improve the awareness and basic knowledge among patients with chronic diseases. PMID- 29404175 TI - Characterization of Chronic Obstructive Pulmonary Disease Patients with a Long Length of Stay: A Retrospective Observational Cohort Study. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) exacerbation is one of the most common reasons for hospital admission. Patients with COPD with a long length of stay (LoS) occupy a disproportionately high fraction of hospital bed days. The objective of this study was to identify associations of long LoS in patients admitted with COPD exacerbation. MATERIAL AND METHODS: From December 2012 until June 2013, 499 patients were admitted to Queens Hospital, Romford, UK, with COPD exacerbation. Mean LoS was 7 days, with a median of 5 days, and a 90th percentile of 14 days. In this retrospective observational cohort study, 64 patients with a short LoS were compared with 62 patients with a long LoS. RESULTS: Relative to the short LoS, patients with long LoS had significantly lower arterial blood pH, higher arterial PaCO2 and HCO3, higher white cell count, higher globulin and more frequent chest X-ray changes, lower albumin levels, and lower Barthel and Braden scores. They were less likely to have seen the hospital COPD specialist nurse, more likely to require escalation of social care on discharge, and more likely to die during admission. Nearly 66% of the long LoS patients remained in hospital beyond the time of being medically fit for discharge. Commonly cited reasons for delayed discharge were the wait for therapy and social services assessments and the wait for commencement of community social care. CONCLUSION: Meticulous targeting of features peculiar to long LoS patients has the potential to reduce future hospital bed-days for patients with COPD in our and other hospitals. PMID- 29404176 TI - The Reliability and Validation of the Turkish Version of the Asthma Self Management Knowledge Questionnaire. AB - OBJECTIVES: There is no validated questionnaire in Turkish to assess asthma knowledge. In this study, we aimed to evaluate the reliability and validity of the Turkish version of the Asthma Self-Management Knowledge Questionnaire (AKQ) among asthmatic adults. MATERIAL AND METHODS: The AKQ was translated into Turkish by two medical-text translators, followed by back translation and final review by two clinicians with experience in asthma management. The Turkish Asthma Self Management Questionnaire was then applied to 202 adult asthma patients, and additional demographic and clinical features of the patients were collected for analysis. RESULTS: The internal reliability of the 24-item AKQ was not high (Cronbach's alpha=0.55). Tukey's test of additivity was significant (p<0.001). This result revealed that all questions are consistent and measure the same concepts. Factor analysis demonstrated a probable structure of 10 factors that together explained 63.7% of total variance in results. Intra-class reliability of the AKQ was quite high. CONCLUSION: This study shows that AKQ seems to be a suitable instrument to evaluate the effect of different components of asthma knowledge - such as triggers, medications, asthma exacerbations, and avoidance measures - in adult asthmatics. PMID- 29404177 TI - A Rare Cause of Hemoptysis in Childhood: Tracheal Capillary Hemangioma. AB - Hemangiomas are benign tumors most frequently seen in childhood and are mostly associated with cutaneous and mucosal surfaces. Tracheal capillary hemangiomas are extremely rare. The most common presenting symptom is hemoptysis, ranging from minor to major and chronic cough. We present the case of a 12-year-old boy with recurrent hemoptysis due to tracheal capillary hemangioma, who was treated with interventional bronchoscopy. PMID- 29404178 TI - A Case of Pulmonary Alveolar Microlithiasis Diagnosed by Transbronchial Biopsy. AB - Pulmonary alveolar microlithiasis is a rare infiltrative pulmonary disease, in which intraalveolar accumulation of small stones (microliths) consisting of calcium phosphatite occurs. It is an autosomal recessive disorder. The disease occurs as a result of the disruption of type IIb sodium phosphate cotransporter in type II alveolar cells after the mutation of SLC34A2. Majority of patients are diagnosed between age 20 and 40. Here, we present a case of alveolar microlithiasis that was diagnosed with transbronchial biopsy. PMID- 29404179 TI - A Prospective Review of the Results of Patients Treated and Followed up for a Diagnosis of Sarcoidosis. AB - OBJECTIVES: The present study reports the treatment and follow-up results of patients prospectively diagnosed and treated in a public hospital. MATERIAL AND METHODS: The present study reports the prospective follow-up data of 21 sarcoidosis cases followed up and treated in the Department of Chest Diseases of Dortyol State Hospital from January 2010 to December 2014. RESULTS: The 21 cases had a mean age of 44+/-10 years and a mean follow-up period of 38+/-13 months. While 10 cases were given steroid treatment, 11 cases were radiologically followed up. Besides pulmonary involvement, skin findings were detected in 7 cases and ophthalmologic findings were detected in 3 cases. In the treatment group, regression was observed in the radiographic findings of 6 cases, while no radiologically significant changes were seen in 4 cases. In the follow-up group, regression was observed in the radiographic findings of 9 cases, while no significant changes were seen in mediastinal LAPs of 2 cases. At the end of the treatment, it was found that 1 case developed steroid-induced myopathy, 1 case developed fungus ball of the sequelae, 1 case had loss of vision secondary to posterior uveitis, and 1 case had a risk of steroid-induced osteoporosis. CONCLUSION: Choice of treatment procedure based on the stage and clinical results of the patient is still the most effective method in sarcoidosis treatment. PMID- 29404180 TI - Evaluation of Treatment Indications, Tuberculin Skin Test, and Bacillus Calmette Guerin Vaccination Scars in the Cases of Latent Tuberculosis Infection Treatment. AB - OBJECTIVES: The aim of our study was to evaluate the latent tuberculosis infection (LTBI) treatment application and to investigate if there is change between tuberculin skin test (TST) results according to bacillus Calmette-Guerin (BCG) scar numbers after LTBI treatment with isoniazid (INH). MATERIAL AND METHODS: Data were collected from the LTBI treatment files from the dispensary of 2006. The results were statistically evaluated. RESULTS: Latent tuberculosis infection was administered to 253 cases in 2006. The male/female case rate was 51/49. The age of most patients was under 15 years out of 14 cases. The mean age was 8.92+/-6.87 years (range, 0-84 years). One case had liver function test abnormality and INH was stopped in the first month of treatment. The completion rate of LTBI treatment was 95%. BCG vaccination rate was 93%. Active tuberculosis did not develop during the LTBI treatment in our study. Of all the cases, 221 scar numbers and TST were full. Of all cases 221 the scar numbers and TST value were full.TST of the 221 cases according to BCG vaccine scar numbers and indications were compared pre- and post-treatment with INH. Indications for LTBI treatment in these cases were close contact with smear-positive active pulmonary tuberculosis cases (n=77, 35%), TST-positive children aged <15 years (n=138, 62%), and the other (n=6, 3%) immunosuppressed patient cases. After treatment with INH, TST values decreased in the TST-positive children aged <15 years with one and 2 scars, with a statistically significant this result were found statistically significant (p<0.05). CONCLUSION: The age of patients in most cases with LTBI treatment was under 15 years. The treatment completion rate and BCG vaccination rate were high. One case had liver function test abnormality. Active tuberculosis did not develop during the LTBI treatment. In the group with TST positive children aged <15 years with one and 2 BCG vaccine scars, the decrease between pre- and post-treatment TST results showed a statistically significant difference. PMID- 29404181 TI - Association between the Serum Metabolic Profile and Lung Function in Chronic Obstructive Pulmonary Disease. AB - OBJECTIVES: Although dietary patterns are known to modulate disease severity in patients with chronic obstructive pulmonary disease (COPD), the relationship between the circulating lipid profile and lung function in COPD has not been studied extensively. MATERIAL AND METHODS: There were 43 COPD patients with a history of smoking and 39 patients with a history of biomass fuel exposure recruited in this study, along with 43 age-matched healthy controls. All participants underwent complete lung function profiling, and their glucose and lipid profiles were measured. The association between the metabolic profile and lung function was assessed using the Spearman's rank-order correlation coefficient. RESULTS: 52.4% of the COPD patients were smokers compared to the healthy group (46.5%). We found an inverse correlation between triglyceride and functional residual capacity (p=-0.21, p=0.05) and a positive association between serum cholesterol and overall airway resistance (R5) (p=0.24, p=0.04) and central airway resistance (R20) (p=0.32, p=0.004). Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) ratio and LDL/HDL ratio were also found to correlate with R5 (p=0.25, 0.23, and 0.22, respectively) and R20 (p=0.31, 0.24, and 0.24, respectively). No significant association was observed between other metabolites and either spirometric or plethysmographic lung function indices. CONCLUSION: High serum triglyceride and cholesterol may increase the resistance in the airways, which may lead to increased airway obstruction. Therefore, monitoring of lipid profile should be considered in the diagnosis and management of COPD. PMID- 29404182 TI - A Prospective Study of Bacteriological Etiology in Hospitalized Acute Exacerbation of COPD Patients: Relationship with Lung Function and Respiratory Failure. AB - OBJECTIVES: Bacterial infections are the major cause of acute exacerbation of COPD (AE-COPD). The relationship between lung functions and respiratory failure (arterial blood gas parameters) with the etiology of AE-COPD has not been clearly understood. We conducted this study to determine the bacterial profile in AE-COPD and to identify the associated risk factors and drug sensitivity pattern. MATERIAL AND METHODS: Seventy-two patients hospitalized for AE-COPD were prospectively evaluated. Quantitative sputum culture, blood gas analysis, and drug sensitivity testing were performed at the time of admission, and pulmonary function testing was performed 6 weeks after discharge as per standard guidelines. RESULTS: Bacterial pathogens were isolated in 34 (47.22%) cases. Pathogens isolated were Pseudomonas aeruginosa (38.23%), Klebsiella pneumoniae (29.41%), Staphylococcus aureus (23.53%), Streptococcus pneumoniae (5.88%), and Acinetobacter spp. (2.94%). Isolation of bacterial pathogen was observed in patients with advancing age (p=0.02), frequent exacerbations (p<0.001), systemic steroid use (p=0.005), and deranged lung function (p=0.02). Binary logistic regression analysis revealed that higher partial pressure of carbon dioxide (PaCO2) was independently associated with isolation of K. pneumoniae (p=0.025) and P. aeruginosa (p=0.001). Additional independent factors that favor isolation of K. pneumoniae were age >55 years (p=0.017) and systemic steroid use (p=0.017). Antibiotic sensitivity testing showed that ciprofloxacin and piperacillin/tazobactum were effective in 27/34 (79.41%) of isolates followed by gentamycin in 26/34 (76%). CONCLUSION: Hypercapnic respiratory failure is an independent risk factor for isolation of K. pneumoniae and P. aeruginosa in addition to advanced age and systemic steroid use. These findings may be an important adjunct in deciding the initial antibiotic therapy. PMID- 29404183 TI - Effects of Modes, Obesity, and Body Position on Non-invasive Positive Pressure Ventilation Success in the Intensive Care Unit: A Randomized Controlled Study. AB - OBJECTIVES: Different outcomes and success rates of non-invasive positive pressure ventilation (NPPV) in patients with acute hypercapnic respiratory failure (AHRF) still pose a significant problem in intensive care units. Previous studies investigating different modes, body positioning, and obesity-associated hypoventilation in patients with chronic respiratory failure showed that these factors may affect ventilator mechanics to achieve a better minute ventilation. This study tried to compare pressure support (BiPAP-S) and average volume targeted pressure support (AVAPS-S) modes in patients with acute or acute-on chronic hypercapnic respiratory failure. In addition, short-term effects of body position and obesity within both modes were analyzed. MATERIAL and METHODS: We conducted a randomized controlled study in a 7-bed intensive care unit. The course of blood gas analysis and differences in ventilation variables were compared between BiPAP-S (n=33) and AVAPS-S (n=29), and between semi-recumbent and lateral positions in both modes. RESULTS: No difference was found in the length of hospital stay and the course of PaCO2, pH, and HCO3 levels between the modes. There was a mean reduction of 5.7+/-4.1 mmHg in the PaCO2 levels in the AVAPS-S mode, and 2.7+/-2.3 mmHg in the BiPAP-S mode per session (p<0.05). Obesity didn't have any effect on the course of PaCO2 in both the modes. Body positioning had no notable effect in both modes. CONCLUSION: Although the decrease in the PaCO2 levels in the AVAPS-S mode per session was remarkably high, the course was similar in both modes. Furthermore, obesity and body positioning had no prominent effect on the PaCO2 response and ventilator mechanics. Post hoc power analysis showed that the sample size was not adequate to detect a significant difference between the modes. PMID- 29404184 TI - Cross-cultural Adaptation and Validation of Beliefs about Medicines Questionnaire on Asthma and Chronic Obstructive Pulmonary Disease Patients. AB - OBJECTIVES: Inadequate adaptation to long-term treatment of chronic illnesses is the most common reason for the inability to obtain the benefits medications can provide. Treatment compliance is influenced by several factors. Beliefs about Medicines Questionnaire (BMQ) developed by Horne et al. in 1999 to evaluate the cognitive representation of medicines have many validation studies, which resulted in good psychometric properties. The aim of the present study was to evaluate the reliability and validity of the BMQ Turkish translation in patients with asthma and chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: Fifty asthma and 50 COPD patients participated in this methodological study. The scale was adapted to Turkish through translation, comparison with other language versions, back translation, and a pre-test. The structural validity was assessed using factor analysis. RESULTS: Similar to the original scale, factor analysis confirmed that BMQ had a four-factor structure that accounts for 58.23% of the total variance. The BMQ showed an acceptable internal consistency (Cronbach's alpha coefficient: specific-necessity, 0.832: specific concerns, 0.722; general-harm, 0.792; and general-overuse, 0.682). The factor analysis revealed the same patterns for all questions between the Turkish and original scales. CONCLUSION: The psychometric properties of the BMQ were consistent with those reported in the original study. We found that the Turkish translation of BMQ is a valid and reliable tool for assessing medicine-related beliefs in patients with asthma and COPD. PMID- 29404186 TI - A Rare Vascular Anomaly during Central Venous Catheterization: A Persistent Left Sided Superior Vena Cava. AB - A persistent left-sided superior vena cava (PLSVC) is the most frequent abnormality of the venous system; however, it is not a very well-known variation among physicians. Herein we report the case of a patient with a PLSVC who was diagnosed after central venous catheterization (CVC). An 80-year-old man was admitted to the emergency room with cardiopulmonary arrest. After the return of spontaneous circulation, CVC was blindly performed from the left jugular vein without any complications. However, routine chest X-ray after catheterization revealed that the catheter was moving down directly to the left heart. Thoracic computed tomography showed the right brachiocephalic vein draining into the left brachiocephalic vein and forming the left superior vena cava in front of the aortic arch. The left superior vena cava merged into the right atrium after crossing the left pulmonary artery. CVC is widely used in clinical practice, and therefore clinicians should be aware of possible variations in central veins, particularly during blind catheterization. PMID- 29404185 TI - Non-astmatic Eosinophilic Bronchitis. AB - Non-asthmatic eosinophilic bronchitis (NAEB) is eosinophilic inflammation of the respiratory tract, without any bronchospasm. In this article, we want to draw attention to the NAEB. It should also be considered in differential diagnosis of chronic cough. Eosinophilia is present in all induced or spontaneous sputum samples of NAEB patients. NAEB patients and asthmatic patients have similar airway inflammation. Remarkably, NAEB mainly occurs in the lower airways. Unlike asthma, mast cells in NAEB are active in the bronchial epithelium. Diagnosis is based on the clinical, radiological, and spirometric measurements of other causes of chronic cough (Post-nasal discharge syndrome, asthma, gastroesophageal reflux etc.) and the assessment of inflammation in the lower respiratory tract. Airway inflammation can be assessed by sputum induction. The main treatment is anti inflammatory therapy with inhaled corticosteroids and taking protective measures if inflammation is due to occupational exposure or allergen inhalation. If NAEB is untreated, it may be transient, episodic, or persistent; rarely, long-term oral steroid treatment may be required in patients. There is a requirement for studies that investigate the role of non-invasive markers of chronic inflammation associated with NAEB and the effectiveness of other treatments. PMID- 29404188 TI - Erratum. AB - [This corrects the article on p. S27 in vol. 16.]. PMID- 29404187 TI - A Case Report of Secondary Simultaneous Bilateral Pneumothorax Due to Pazopanib Treatment. AB - Secondary spontaneous pneumothorax almost always develops secondary to an underlying lung disease. A pneumothorax secondary to a malignancy is very rare, and is observed most frequently in soft tissue sarcomas. Pazopanib, a tyrosine kinase inhibitor, is used in metastatic soft tissue sarcomas treatment. The rate of pneumothorax that is caused by pazopanib is about 14% in the literature. The patient being presented in this article underwent surgery for soft tissue sarcoma, postoperatively received pazopanib (Votrient(r) 400 mg, oral, Glaxo Group Ltd, Brentford, UK) treatment due to widespread bilateral lung metastases, and developed synchronous spontaneous pneumothorax. PMID- 29404190 TI - A proposed classification for assessing rupture risk in patients with intracranial arteriovenous malformations. AB - Background: Whether cerebral arteriovenous malformations (AVMs) should be treated remains an ongoing debate. Nevertheless, there is a need for predictive factors that assist in labelling lesions as low or high risk for future rupture. Our aim was to design a new classification that would consider hemodynamic and anatomic factors in the rapid assessment of rupture risk in patients with AVMs. Methods: This was a retrospective study that included 639 patients with ruptured and unruptured AVMs. We proposed a new classification score (1-4 points) for AVM rupture risk using three factors: feeding artery mean velocity (Vm), nidus size, and type of venous drainage. We employed descriptive statistics and logistic regression analysis. Results: A total of 639 patients with cerebral AVMs, 388 (60%) had unruptured AVMs and 251 (40%) had ruptured AVMs. Logistic regression analysis revealed a significant effect of Vm, nidus size, and venous drainage type in accounting for the variability of rupture odds (P = 0.0001, R2 = 0.437) for patients with AVMs. Based in the odds ratios, grades 1 and 2 of the proposed classification were corresponded to low risk of hemorrhage, while grades 3 and 4 were associated with hemorrhage: 1 point OR = (0.107 95% CI; 0.061-0.188), 2 point OR = (0.227 95% CI; 0.153-0.338), 3 point OR = (3.292 95% CI; 2.325-4.661), and 4 point OR = (23.304 95% CI; 11.077-49.027). Conclusion: This classification is useful and easy to use, and it may allow for the individualisation of each cerebral AVM and the assessment of rupture risk based on a model of categorisation. PMID- 29404192 TI - Spinal cord herniation after brachial plexus injury. AB - Background: Spinal cord herniation (SCH) is an uncommon cause of myelopathy. Documented trauma is a rare cause, and most cases are idiopathic. One special type of trauma that may lead to SCH is a brachial plexus injury. We report a case of SCH with delayed neurological symptoms after a brachial plexus injury. We reviewed the literature and illustrated the closing technique as described by Batzdorf. Case Description: Following a motor vehicle accident, a 27-year-old male sustained a brachial plexus injury and multiple left-sided nerve root avulsions (C6, C7, and C8) resulting into a full paralysis of the left arm. There was also a loss of pain and temperature sensation on the right side of the body. He underwent reconstructive surgery without any functional improvement. After 6 to 7 years his condition worsened. Magnetic resonance imaging revealed a left sided SCH at the level of C7. He underwent a C6-C7 laminectomy which revealed a pseudomeningocele at C6-C7 accompanied by focal SCH at the location of the C7 root. The SCH was reduced intradurally and the dural defect of the meningocele was covered with a Neuropatch membrane wrapped around the spinal cord (between the spinal cord and the dura) according to the technique described by Batzdorf. Postoperatively, the neurological symptoms improved. Conclusion: SCH should be surgically repaired utilizing the technique described by Batzdorf if further neurological deficits develop. PMID- 29404193 TI - Descent of the anterior communicating artery after removal of pituitary macroadenoma using transsphenoidal surgery. AB - Background: After removal of pituitary macroadenoma, the anterior communicating artery (AComA) descends toward the original position. However, the process and contributing factors of this descent are not elucidated. Methods: This retrospective study included 102 patients who underwent transsphenoidal surgery (TSS) for macroadenomas with maximum diameters of >2 cm. Sequential T2-weighted magnetic resonance images were used to assess the AComA flow void and its distance from the planum sphenoidale before and after TSS. The AComA position in relation to the adenoma was divided into four groups as follows: anterior, anterosuperior, superior, and posterior. The descent was compared to the presence of intratumoral hemorrhage or adenoma extension into the sphenoid sinus. Results: One week after TSS, the AComA descent was more pronounced than when originally in the superior position (6.5 +/- 3.7 mm vs 4.4 +/- 3.5 mm, P < 0.0001). The postoperative descents of the AComA were well correlated with those of residual adenomas only when in the superior position (P = 0.030). The AComA descent was more significant at 1 week (4.4 +/- 3.5 mm) than at 1 week to 3 months (0.7 +/- 1.0 mm) in all the groups. Both intratumoral hemorrhage and sphenoid sinus extension of adenoma did not affect the AComA descent in each group. Conclusion: AComA descent was most influenced when it was superior to the macroadenoma and progressed mostly within 1 week after TSS, probably initiating during TSS. The position of the AComA in relation to a macroadenoma should be considered preoperatively to avoid vascular injury. PMID- 29404194 TI - Perioperative malnutrition and its relationship to length of stay and complications in patients undergoing surgery for cervical myelopathy. AB - Background: Surgical treatment of cervical myelopathy is common, and the impact of perioperative malnutrition in these patients is unclear; yet, malnutrition pre and postoperatively has been associated with higher rates of wound infection in spine patients. We evaluated the association of low prealbumin level, a marker for poor nutrition, with length of hospitalization and complication rates after surgery for cervical myelopathy. Methods: We retrospectively identified patients with cervical myelopathy who underwent anterior cervical discectomy and fusion, anterior cervical corpectomy and fusion, or posterior cervical decompression and fusion over a 5-year period. Patients' prealbumin levels were measured within 4 days of surgery; they were divided into low and normal groups (threshold 15 mg/dL). Demographic, clinical, operative, and postoperative parameters were correlated with prealbumin levels by utilizing univariate and multivariable analyses. Results: Eighteen patients were in the "low prealbumin" group and 37 were in the "normal prealbumin" group. Patients with low prealbumin were significantly more likely to have an extended length of hospitalization/stay (LOS) (median 6 days, interquartile range 7.5 days vs. median 3 days, interquartile range 2 days, P < 0.001) and more postoperative complications (33% versus 0%, P < 0.001). Multivariable analysis revealed that only the low prealbumin category (P < 0.001) was associated with a prolonged LOS. Conclusions: Low prealbumin levels were associated with prolonged LOS after surgery for cervical myelopathy. We need to better define the effects of malnutrition in patients with cervical myelopathy in the future. PMID- 29404191 TI - Long-chain omega-3 fatty acids in aneurysmal subarachnoid hemorrhage: A randomized pilot trial of pharmaconutrition. AB - Background: Functional recovery after aneurysmal subarachnoid hemorrhage (SAH) remains a significant problem. We tested a novel therapeutic approach with long chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) to assess the safety and feasibility of an effectiveness trial. Methods: We conducted a multicentre, parallel, randomized, open-label pilot trial. Patients admitted within 72 hours after SAH with modified Fisher scale scores of 3 or 4 who were selected for scheduled aneurysm clipping were allocated to receive either n-3 PUFA treatment (parenteral perioperative: 5 days; oral: 8 weeks) plus usual care or usual care alone. Exploratory outcome measures included major postoperative intracranial bleeding complications (PIBCs), cerebral infarction caused by delayed cerebral ischemia, shunt-dependent hydrocephalus, and consent rate. The computed tomography evaluator was blinded to the group assignment. Results: Forty-one patients were randomized, but one patient had to be excluded after allocation. Twenty patients remained for intention to treat analysis in each trial arm. No PIBs (95% confidence interval [CI]: 0.00 to 0.16) or other unexpected harm were observed in the intervention group (IG). No patient suspended the intervention due to side effects. There was a trend towards improvements in all benefit related outcomes in the IG. The overall consent rate was 0.91 (95% CI: 0.78 to 0.96), and there was no consent withdrawal. Conclusions: Although the balance between the benefit and harm of the intervention appears highly favourable, further testing on SAH patients is required. We recommend proceeding with amendments in a dose-finding trial to determine the optimal duration of parenteral treatment. PMID- 29404195 TI - Language and style: A barrier to neurosurgical research and advancement in Latin America. AB - Background: The neurosurgical burden in Latin America is understudied and likely underestimated, thus it is imperative to improve quality, training, and delivery of neurosurgical care. A significant aspect of this endeavor is for Latin America to become an integral aspect of the global neurosurgical community, however, there is a paucity of ideology and literature coming from Central and South America. We sought to explore neurosurgical dialogue originating from Latin America as well as barriers to the advancement of neurosurgery in this region. Methods: We conducted a systematic literature review exploring research originating in Latin America in three international neurosurgical journals - Journal of Neurosurgery, Surgical Neurology International, and World Neurosurgery. We utilized PubMed search algorithms to identify articles. Inclusion criteria included publication within the three aforementioned journals, author affiliation with Latin American institutions, and publication within the specified time frame of January 2014 to July 2017. Results: There were 7469 articles identified that met the search criteria. Of these 7469 articles, 326 (4.4%) were from Latin American nations. Conclusion: Our data suggests a relatively low percentage of neurosurgical research originating from Latin America, suggesting a significant lack of participation in the global neurosurgical community. Barriers to global scientific communication include language, rhetorical style, culture, history, biases, funding, and governmental support. Despite challenges, Latin America is making strides towards improvement including the development of neurosurgical societies, as well as international collaborative training and research programs. We consider our report to be a valid initiation of discussion of the broader issue of neurosurgical communication. PMID- 29404196 TI - Masseter Muscle Thickness in Unilateral Partial Edentulism: An Ultrasonographic Study. AB - Introduction: Teeth and facial muscles play a very important role in occlusal equilibrium and function. Occlusal derangement, seen in unilateral partially edentulous individuals, has an effect on masseter muscle anatomy and function. The present study aims to evaluate masseter muscle thickness in unilateral partial edentulism. Patients and Methods: Institutional ethics committee approval was obtained before the commencement of the study. The study involved patients who routinely visited the Department of Oral Medicine and Radiology, Sri Ramachandra University. The study sample included 27 unilateral edentulous patients (Group E) and 30 controls (Group C). The masseter muscle thickness was evaluated using high-resolution ultrasound real-time scanner (linear transducer - 7.5-10 MHz) at both relaxed and contracted states. Statistical Analysis Used: The results were analyzed using paired t-test and independent t-test. Duration of edentulism and muscle thickness was assessed using Pearson's correlation coefficient. Results: The study patients' age ranged between 25 and 48 years (mean - 36 years). The comparative evaluation of masseter muscle thickness between the dentulous and edentulous sides of experimental group was statistically significant (P < 0.05). However, no statistically significant difference in masseter muscle thickness was found between the dentulous side of control and experimental groups. The correlation between the duration of partial edentulism and muscle thickness was statistically insignificant. Conclusion: The study proves masseter atrophy in the edentulous side. However, since the difference is found to be marginal with the present sample, a greater sample is necessary to establish and prove the present findings as well as to correlate with the duration of edentulism. Further studies are aimed to assess the muscle morphology after prosthetic rehabilitation. PMID- 29404197 TI - Superb Microvascular Imaging: Added Value and Novel Applications. AB - Determining the presence and characteristics of vascular flow is an essential part of sonography interrogation. However, small vessels and low velocities are not always possible to depict with conventional color and power Doppler ultrasound. This can be frustrating, especially when the diagnosis depends mainly on the existence of vascular flow, the sonographic examination will be inconclusive, further imaging examinations will be required and diagnosis delayed. Superb microvascular imaging (SMI) is a novel vascular imaging mode, which provides visualization of low velocity and microvascular flow. SMI uses a clutter suppression algorithm to extract flow signals and depicts this information as a color overlay image or as a monochrome or color map of flow. By using SMI, high frame rates and high-resolution images remain maintained. With SMI, it is possible to visualize small vessels including their branches that, until now, it is possible to demonstrate only using contrast-enhanced ultrasound. Availability of this additional technology on all ultrasound machines may make some of the computed tomography scans unnecessary. In our paper, we describe six patients, aged 16-73 years, in which final diagnosis was achieved only with SMI and where conventional color and power Doppler failed. All these examinations were performed using Aplio 500 Platinum ultrasound unit (Toshiba Medical Systems, Tokyo, Japan). PMID- 29404199 TI - Correction: Largest global shark biomass found in the northern Galapagos Islands of Darwin and Wolf. AB - [This corrects the article DOI: 10.7717/peerj.1911.]. PMID- 29404198 TI - Sleep Quality, Perceived Stress, and Caffeinated Drinks Intake in Psychiatry Residents: A Cross-Sectional Study. AB - Background: Medical residencies are highly demanding and stressful and have been associated with mental and emotional problems. Studies that evaluated this relationship in Italian psychiatry residents are scarce. In this study, we examined sleep quality and its association with perceived stress and caffeinated beverages consumption in Italian psychiatry residents. Methods: Seventy-two PGY1 5 psychiatry residents at two University Hospitals in Italy were asked to complete an anonymous questionnaire. The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale were used to determine the sleep quality and the level of daytime sleepiness (EDS). In addition, we investigated perceived stress and caffeinated drinks consumption (coffee, tea, soda, energy drinks). Results: Seventy psychiatry residents responded to the survey (97.2% response rate) (M = 34.3%, F = 65.7%; mean age = 30.5 +/- 4.2 SD years). 44.3% had poor sleep quality and 15.7% had abnormal EDS. 64.3% reported significant perceived stress. Perceived stress score and coffee consumption were associated with greater likelihood of poor sleep quality. Conclusions: Psychiatry residents have high prevalence of poor sleep quality. Future longitudinal studies are needed to investigate causality and identify appropriate coping strategies and lifestyle changes aimed to improve mental health in psychiatry trainees. PMID- 29404200 TI - Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, downregulates the expression of proteins associated with dengue virus infection. AB - Dengue is endemic throughout tropical and subtropical regions of the world. Currently, there is no clinically approved therapeutic drug available for this acute viral infection. Although the first dengue vaccine Dengvaxia has been approved for use in certain countries, it is limited to those without a previous dengue infection while the safety and efficacy of the vaccine in those elderly and younger children still need to be identified. Therefore, it is becoming increasingly important to develop therapeutics/drugs to combat dengue virus (DENV) infection. YK51 is a synthetic analogue of 4-Hydroxypandurantin A (a compound found in the crude extract of the rhizomes of Boesenbergia rotunda) that has been extensively studied by our research group. It has been shown to possess outstanding antiviral activity due to its inhibitory activity against NS2B/NS3 DENV2 protease. However, it is not known how YK51 affects the proteome of DENV infected cells. Therefore, we performed a comparative proteomics analysis to identify changes in protein expression in DENV infected HepG2 cells treated with YK51. Classical two-dimensional gel electrophoresis followed by protein identification using tandem mass spectrometry was employed in this study. Thirty proteins were found to be down-regulated with YK51 treatment. In silico analysis predicted that the down-regulation of eight of these proteins may inhibit viral infection. Our results suggested that apart from inhibiting the NS2B/NS3 DENV2 protease, YK51 may also be causing the down-regulation of a number of proteins that may be responsible in, and/or essential to virus infection. However, functional characterization of these proteins will be necessary before we can conclusively determine their roles in DENV infection. PMID- 29404201 TI - Genetic analysis of the Hungarian draft horse population using partial mitochondrial DNA D-loop sequencing. AB - Background: The Hungarian draft is a horse breed with a recent mixed ancestry created in the 1920s by crossing local mares with draught horses imported from France and Belgium. The interest in its conservation and characterization has increased over the last few years. The aim of this work is to contribute to the characterization of the endangered Hungarian heavy draft horse populations in order to obtain useful information to implement conservation strategies for these genetic stocks. Methods: To genetically characterize the breed and to set up the basis for a conservation program, in the present study a hypervariable region of the mitochrondial DNA (D-loop) was used to assess genetic diversity in Hungarian draft horses. Two hundred and eighty five sequences obtained in our laboratory and 419 downloaded sequences available from Genbank were analyzed. Results: One hundred and sixty-four haplotypes and thirty-six polymorphic sites were observed. High haplotype and nucleotide diversity values (Hd = 0.954 +/- 0.004; pi = 0.028 +/- 0.0004) were identified in Hungarian population, although they were higher within than among the different populations (Hd = 0.972 +/- 0.002; pi = 0.03097 +/- 0.002). Fourteen of the previously observed seventeen haplogroups were detected. Discussion: Our samples showed a large intra- and interbreed variation. There was no clear clustering on the median joining network figure. The overall information collected in this work led us to consider that the genetic scenario observed for Hungarian draft breed is more likely the result of contributions from 'ancestrally' different genetic backgrounds. This study could contribute to the development of a breeding plan for Hungarian draft horses and help to formulate a genetic conservation plan, avoiding inbreeding while. PMID- 29404202 TI - Positive end expiratory pressure in acute hypoxemic respiratory failure due to community acquired pneumonia: do we need a personalized approach? AB - Background: Acute respiratory failure (ARF) is a life-threatening complication in patients with community acquired pneumonia (CAP). The use of non-invasive ventilation is controversial. With this prospective, observational study we aimed to describe a protocol to assess whether a patient with moderate-to-severe hypoxemic ARF secondary to CAP benefits, in clinical and laboratoristic terms, from the application of a positive end expiratory pressure (PEEP) + oxygen vs oxygen alone. Methods: Patients who benefit from PEEP application (PEEP responders) were defined as those with partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) increase >20% and/or reduction of respiratory distress during PEEP + oxygen therapy compared to oxygen therapy alone. Clinical characteristics and outcomes were compared between PEEP responders and PEEP-non responders. Results: Out of 41 patients, 27 (66%) benefit from PEEP application (PEEP-responders), the best response was obtained with a PEEP of 10 cmH2O in 13 patients, 7.5 cmH2O in eight and 5 cmH2O in six. PEEP responders were less likely to present comorbidities compared to PEEP-non responders. No differences between groups were found in regards to endotracheal intubation criteria fullfillment, intensive care unit admission and in-hospital mortality, while PEEP-responders had a shorter length of hospital stay. Discussion: The application of a protocol to evaluate PEEP responsiveness might be useful in patients with moderate-to-severe hypoxemic ARF due to CAP in order to personalize and maximize the effectiveness of therapy, and prevent the inappropriate PEEP use. PEEP responsiveness does not seem to be associated with better outcomes, with the exception of a shorter length of hospital stay. PMID- 29404203 TI - Signals of forest degradation in the demography of common Asian amphibians. AB - Background: Lowland areas in tropical East and Southeast Asia have a long history of conversion from forestland to agricultural land, with many remaining forests being chronically degraded by wood cutting, livestock grazing, and burning. Wetland-breeding amphibians that have evolved in lowland forests in the region have adjusted to changes in habitat composition caused by humans' activities, and populations continue to persist. However, we have little understanding of the impacts of forest disturbance on these species beyond assessments of abundance and distribution, and species considered to be common and widespread have been largely neglected. Methods: We examined body condition and sex ratios of toads (Duttaphrynus melanostictus), predation risk in treefrogs (2 Polypedates spp.), and growth and survival of leaf litter frogs (2 Microhyla spp.) in agricultural land, degraded forest, and intact forest in two study areas, Thailand and Hong Kong. Results: Toad populations exhibited higher body condition and female-biased sex ratios in intact forest. Predation of treefrog embryos by flies was lower in intact and degraded forests than in agricultural land. Embryonic survival and larval growth and survival in leaf litter frogs were lower in intact forests than in agricultural land. Results for each study were similar between study areas. Discussion: For three of five of these common amphibian species, we documented signals of forest loss and disturbance in their populations. Although these species occur in disturbed habitats, loss of forest cover continues to degrade aspects of their population demography. We urge conservation biologists to consider that populations of species appearing to be common, widespread, and tolerant of human disturbance may be eroding over time. PMID- 29404204 TI - Intra-colonial diversity in the scleractinian coral, Acropora millepora: identifying the nutritional gradients underlying physiological integration and compartmentalised functioning. AB - Scleractinian corals are colonial organisms comprising multiple physiologically integrated polyps and branches. Colonialism in corals is highly beneficial, and allows a single colony to undergo several life processes at once through physiological integration and compartmentalised functioning. Elucidating differences in the biochemical composition of intra-colonial branch positions will provide valuable insight into the nutritional reserves underlying different regions in individual coral colonies. This will also ascertain prudent harvesting strategies of wild donor-colonies to generate coral stock with high survival and vigour prospects for reef-rehabilitation efforts and captive husbandry. This study examined the effects of colony branch position on the nutritional profile of two different colony sizes of the common scleractinian, Acropora millepora. For smaller colonies, branches were sampled at three locations: the colony centre (S-centre), 50% of the longitudinal radius length (LRL) (S-50), and the colony edge (S-edge). For larger colonies, four locations were sampled: the colony centre (L-centre), 33.3% of the LRL (L-33), 66.6% of the LRL (L-66), and the edge (L-edge). Results demonstrate significant branch position effects, with the edge regions containing higher protein, likely due to increased tissue synthesis and calcification. Meanwhile, storage lipid and total fatty acid concentrations were lower at the edges, possibly reflecting catabolism of high-energy nutrients to support proliferating cells. Results also showed a significant effect of colony size in the two classes examined. While the major protein and structural lipid sink was exhibited at the edge for both sizes, the major sink for high-energy lipids and fatty acids appeared to be the L-66 position of the larger colonies and the S-centre and S-50 positions for the smaller colonies. These results confirm that the scleractinian coral colony is not nutritionally homogeneous, and while different regions of the coral colony are functionally specialised, so too are their nutritional profiles geared toward meeting specific energetic demands. PMID- 29404205 TI - The first report of the prevalence of Nosema ceranae in Bulgaria. AB - Nosema apis and Nosema ceranae are the two main microsporidian parasites causing nosematosis in the honey bee Apis mellifera. The aim of the present study is to investigate the presence of Nosema apis and Nosema ceranae in the area of Bulgaria. The 16S (SSU) rDNA gene region was chosen for analysis. A duplex PCR assay was performed on 108 honey bee samples from three different parts of the country (South, North and West Bulgaria). The results showed that the samples from the northern part of the country were with the highest prevalence (77.2%) for Nosema ceranae while those from the mountainous parts (the Rodopa Mountains, South Bulgaria) were with the lowest rate (13.9%). Infection with Nosema apis alone and co-infection N. apis/N. ceranae were not detected in any samples. These findings suggest that Nosema ceranae is the dominant species in the Bulgarian honey bee. It is not known when the introduction of Nosema ceranae in Bulgaria has occurred, but as in the rest of the world, this species has become the dominant one in Bulgarian Apis mellifera. In conclusion, this is the first report for molecular detection of Nosema infection of honey bee in Bulgaria. The results showed that N. ceranae is the main Nosema species in Bulgaria. PMID- 29404206 TI - Spatial and temporal patterns of human Puumala virus (PUUV) infections in Germany. AB - Background: Worldwide, the number of recorded human hantavirus infections as well as the number of affected countries is on the rise. In Europe, most human hantavirus infections are caused by the Puumala virus (PUUV), with bank voles (Myodes glareolus) as reservoir hosts. Generally, infection outbreaks have been related to environmental conditions, particularly climatic conditions, food supply for the reservoir species and land use. However, although attempts have been made, the insufficient availability of environmental data is often hampering accurate temporal and spatially explicit models of human hantavirus infections. Methods: In the present study, dynamics of human PUUV infections between 2001 and 2015 were explored using ArcGIS in order to identify spatio-temporal patterns. Results: Percentage cover of forest area was identified as an important factor for the spatial pattern, whereas beech mast was found explaining temporal patterns of human PUUV infections in Germany. High numbers of infections were recorded in 2007, 2010 and 2012 and areas with highest records were located in Baden-Wuerttemberg (southwest Germany) and North Rhine-Westphalia (western Germany). Conclusion: More reliable data on reservoir host distribution, pathogen verification as well as an increased awareness of physicians are some of the factors that should improve future human infection risk assessments in Germany. PMID- 29404207 TI - Novel NAC-loaded poly(lactide-co-glycolide acid) nanoparticles for cataract treatment: preparation, characterization, evaluation of structure, cytotoxicity, and molecular docking studies. AB - Background: N-acetylcarnosine (NAC), a dipeptide with powerful antioxidant properties that is extensively used as a pharmaceutical prodrug for the treatment of cataract and acute gastric disease, was investigated by molecular dynamics with the GROMACS program in order to understand the solvent effect on peptide conformation of the peptide molecule used as a component of a drug and which presents substantial information on where drug molecules bind and how they exert their effects. Besides, molecular docking simulation was performed by using the AutoDock Vina program which identify the kind of interaction between the drug and proteins. A delivery system based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with NAC (NAC-PLGA-NPs) for the treatment of cataract was prepared for the first time in this study in order to enhance drug bioavailability and biocompatibility. The objective of this work was to prepare and evaluate the structural formulation, characterization, and cytotoxicity studies of NAC-loaded NPs based on PLGA for cataract treatment. Methods: PLGA and NAC-loaded PLGA NPs were prepared using the double emulsion (w/o/w) method, and characterizations of the NPs were carried out with UV-Vis spectrometer to determine drug concentration, the Zeta-sizer system to analyze size and zeta potential, FTIR spectrometer to determine the incorporation of drug and PLGA, and TEM analysis for morphological evaluation. Results: NAC-loaded PLGA NPs were successfully obtained according to UV-Vis and FTIR spectroscopy, Zeta-sizer system. And it was clearly observed from the TEM analysis that the peptide-loaded NPs had spherical and non-aggregated morphology. Also, the NPs had low toxicity at lower concentrations, and toxicity was augmented by increasing the concentration of the drug. Discussion: The NAC molecule, which has been investigated as a drug molecule due to its antioxidant and oxidative stress reducing properties, especially in cataract treatment, was encapsulated with a PLGA polymer in order to increase drug bioavailability. This study may contribute to the design of drugs for cataract treatment with better reactivity and stability. PMID- 29404208 TI - Distribution of bacterial communities along the spatial and environmental gradients from Bohai Sea to northern Yellow Sea. AB - The eutrophic Bohai Sea receives large amount of suspended material, nutrients and contaminant from terrestrial runoff, and exchanges waters with the northern Yellow Sea through a narrow strait. This coastal region provides an ideal model system to study microbial biogeography. We performed high-throughput sequencing to investigate the distribution of bacterial taxa along spatial and environmental gradients. The results showed bacterial communities presented remarkable horizontal and vertical distribution under coastal gradients of spatial and environmental factors. Fourteen abundant taxa clustered the samples into three distinctive groups, reflecting typical habitats in shallow coastal water (seafloor depth <= 20 m), sunlit surface layer (at water surface with seafloor depth >20 m) and bottom water (at 2-3 m above sediment with seafloor depth >20 m). The most significant taxa of each cluster were determined by the least discriminant analysis effect size, and strongly correlated with spatial and environmental variables. Environmental factors (especially turbidity and nitrite) exhibited significant influences on bacterial beta-diversity in surface water (at 0 m sampling depth), while community similarity in bottom water (at 2-3 m above sediment) was mainly determined by depth. In both surface and bottom water, we found bacterial community similarity and the number of OTUs shared between every two sites decreased with increasing geographic distance. Bacterial dispersal was also affected by phosphate, which was possible due to the high ratios of IN/IP in this coastal sea area. PMID- 29404210 TI - Ants of the Monomorium monomorium species-group (Hymenoptera: Formicidae) in the Arabian Peninsula with description of a new species from southwestern Saudi Arabia. AB - We revise the taxonomy of the myrmicine ants of the Monomorium monomorium species group for the Arabian Peninsula. Six species are recognized: Monomorium aeyade Collingwood & Agosti, 1996, M. clavicorne Andre, 1881, M. exiguum Forel, 1894, M. holothir Bolton, 1987, M. mohammedi sp. n., and M. sarawatense Sharaf & Aldawood, 2013. On the basis of the worker caste, we describe Monomorium mohammedi sp. n. from the southwestern region of the Kingdom of Saudi Arabia (KSA). We designate a neotype for Monomorium aeyade Collingwood & Agosti and redescribe and illustrate the worker caste. Furthermore, we provide a worker-based species identification key, distribution maps for the treated species, and ecological and biological notes, if available. Monomorium holothir is recorded for the first time from the KSA. Also, we propose M. clavicorne var. punica Santschi, 1915a as a junior synonym of M. clavicorne, as well as M. dryhimi Aldawood & Sharaf, 2011 and M. montanum Collingwood & Agosti, 1996 to be treated as junior synonyms of Monomorium exiguum. PMID- 29404209 TI - Development of an RNA interference (RNAi) gene knockdown protocol in the anaerobic gut fungus Pecoramyces ruminantium strain C1A. AB - Members of the anaerobic gut fungi (AGF) reside in rumen, hindgut, and feces of ruminant and non-ruminant herbivorous mammals and reptilian herbivores. No protocols for gene insertion, deletion, silencing, or mutation are currently available for the AGF, rendering gene-targeted molecular biological manipulations unfeasible. Here, we developed and optimized an RNA interference (RNAi)-based protocol for targeted gene silencing in the anaerobic gut fungus Pecoramyces ruminantium strain C1A. Analysis of the C1A genome identified genes encoding enzymes required for RNA silencing in fungi (Dicer, Argonaute, Neurospora crassa QDE-3 homolog DNA helicase, Argonaute-interacting protein, and Neurospora crassa QIP homolog exonuclease); and the competency of C1A germinating spores for RNA uptake was confirmed using fluorescently labeled small interfering RNAs (siRNA). Addition of chemically-synthesized siRNAs targeting D-lactate dehydrogenase (ldhD) gene to C1A germinating spores resulted in marked target gene silencing; as evident by significantly lower ldhD transcriptional levels, a marked reduction in the D-LDH specific enzymatic activity in intracellular protein extracts, and a reduction in D-lactate levels accumulating in the culture supernatant. Comparative transcriptomic analysis of untreated versus siRNA-treated cultures identified a few off-target siRNA-mediated gene silencing effects. As well, significant differential up-regulation of the gene encoding NAD-dependent 2 hydroxyacid dehydrogenase (Pfam00389) in siRNA-treated C1A cultures was observed, which could possibly compensate for loss of D-LDH as an electron sink mechanism in C1A. The results demonstrate the feasibility of RNAi in anaerobic fungi, and opens the door for gene silencing-based studies in this fungal clade. PMID- 29404211 TI - Cost-benefit analysis for invasive species control: the case of greater Canada goose Branta canadensis in Flanders (northern Belgium). AB - Background: Sound decisions on control actions for established invasive alien species (IAS) require information on ecological as well as socio-economic impact of the species and of its management. Cost-benefit analysis provides part of this information, yet has received relatively little attention in the scientific literature on IAS. Methods: We apply a bio-economic model in a cost-benefit analysis framework to greater Canada goose Branta canadensis, an IAS with documented social, economic and ecological impacts in Flanders (northern Belgium). We compared a business as usual (BAU) scenario which involved non coordinated hunting and egg destruction with an enhanced scenario based on a continuation of these activities but supplemented with coordinated capture of moulting birds. To assess population growth under the BAU scenario we fitted a logistic growth model to the observed pre-moult capture population. Projected damage costs included water eutrophication and damage to cultivated grasslands and were calculated for all scenarios. Management costs of the moult captures were based on a representative average of the actual cost of planning and executing moult captures. Results: Comparing the scenarios with different capture rates, different costs for eutrophication and various discount rates, showed avoided damage costs were in the range of 21.15 M? to 45.82 M? under the moult capture scenario. The lowest value for the avoided costs applied to the scenario where we lowered the capture rate by 10%. The highest value occurred in the scenario where we lowered the real discount rate from 4% to 2.5%. Discussion: The reduction in damage costs always outweighed the additional management costs of moult captures. Therefore, additional coordinated moult captures could be applied to limit the negative economic impact of greater Canada goose at a regional scale. We further discuss the strengths and weaknesses of our approach and its potential application to other IAS. PMID- 29404212 TI - A quasi-randomised, controlled, feasibility trial of GLITtER (Green Light Imaging Interpretation to Enhance Recovery)-a psychoeducational intervention for adults with low back pain attending secondary care. AB - Background: Although it is broadly accepted that clinicians should endeavour to reassure patients with low back pain, to do so can present a significant clinical challenge. Guidance for how to provide effective reassurance is scarce and there may be a need to counter patient concerns arising from misinterpretation of spinal imaging findings. 'GLITtER' (Green Light Imaging Intervention to Enhance Recovery) was developed as a standardised method of communicating imaging findings in a manner that is reassuring and promotes engagement in an active recovery. This feasibility study is an important step towards definitive testing of its effect. Methods: This feasibility study was a prospective, quasi randomised, parallel trial with longitudinal follow-up, involving sampling of patients attending a spinal outpatient clinic at a metropolitan hospital. English speaking adults (18-75 years) presenting to the clinic with low back pain and prior spinal imaging were considered for inclusion. Eligible patients were allocated to receive a GLITtER consultation or a standard consultation (as determined by appointment scheduling and clinician availability), and were blinded to their allocation. Full details of the GLITtER intervention are described in accordance with the Tidier template.Follow-up data were collected after 1 and 3 months. The primary outcome of this study was the fulfillment of specific feasibility criteria which were established a priori. Determination of a sample size for a definitive randomised controlled trial was a secondary objective. Results: Two hundred seventy-six patients underwent preliminary screening and 31 patients met the final eligibility criteria for study inclusion. Seventeen participants were allocated to the intervention group and 14 were allocated to the control group. Three month follow-up data were available from 42% of the 31 enrolled participants (N = 13, six intervention, seven control). Feasibility indicators for consent, resource burden and acceptability of the GLITtER intervention were met, however participant recruitment was slower than anticipated and an acceptable follow-up rate was not achieved. Conclusions: Failure to achieve pre-specified recruitment and follow-up rates were important outcomes of this feasibility study. We attribute failure to issues that are likely to be relevant for other clinical trials with this population. It is realistic to consider that these challenges can be overcome through careful strategy, ample funding and continued partnership with health care providers. Trial registration: The trial was registered on the Australian and New Zealand Clinical Trials Registry on 28/2/2017 (ACTRN12617000317392). PMID- 29404213 TI - Detours in long-distance migration across the Qinghai-Tibetan Plateau: individual consistency and habitat associations. AB - Migratory birds often follow detours when confronted with ecological barriers, and understanding the extent and the underlying drivers of such detours can provide important insights into the associated cost to the annual energy budget and the migration strategies. The Qinghai-Tibetan Plateau is the most daunting geographical barrier for migratory birds because the partial pressure of oxygen is dramatically reduced and flight costs greatly increase. We analyzed the repeated migration detours and habitat associations of four Pallas's Gulls Larus ichthyaetus across the Qinghai-Tibetan Plateau over 22 migration seasons. Gulls exhibited notable detours, with the maximum distance being more than double that of the expected shortest route, that extended rather than reduced the passage across the plateau. The extent of longitudinal detours significantly increased with latitude, and detours were longer in autumn than in spring. Compared with the expected shortest routes, proximity to water bodies increased along autumn migration routes, but detour-habitat associations were weak along spring migration routes. Thus, habitat availability was likely one, but not the only, factor shaping the extent of detours, and migration routes were determined by different mechanisms between seasons. Significant between-individual variation but high individual consistency in migration timing and routes were revealed in both seasons, indicating a stronger influence of endogenous schedules than local environmental conditions. Gulls may benefit from repeated use of familiar routes and stopover sites, which may be particularly significant in the challenging environment of the Qinghai-Tibetan Plateau. PMID- 29404214 TI - Gene-based association study for lipid traits in diverse cohorts implicates BACE1 and SIDT2 regulation in triglyceride levels. AB - Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted on lipid genetics, they mainly focus on Europeans and thus their transferability to diverse populations is unclear. We performed SNP- and gene-level genome-wide association studies (GWAS) of four lipid traits in cohorts from Nigeria and the Philippines and compared them to the results of larger, predominantly European meta-analyses. Two previously implicated loci met genome-wide significance in our SNP-level GWAS in the Nigerian cohort, rs34065661 in CETP associated with HDL cholesterol (P = 9.0 * 10-10) and rs1065853 upstream of APOE associated with LDL cholesterol (P = 6.6 * 10-9). The top SNP in the Filipino cohort associated with triglyceride levels (rs662799; P = 2.7 * 10-16) and has been previously implicated in other East Asian studies. While this SNP is located directly upstream of well known APOA5, we show it may also be involved in the regulation of BACE1 and SIDT2. Our gene-based association analysis, PrediXcan, revealed decreased expression of BACE1 and decreased expression of SIDT2 in several tissues, all driven by rs662799, significantly associate with increased triglyceride levels in Filipinos (FDR <0.1). In addition, our PrediXcan analysis implicated gene regulation as the mechanism underlying the associations of many other previously discovered lipid loci. Our novel BACE1 and SIDT2 findings were confirmed using summary statistics from the Global Lipids Genetic Consortium (GLGC) meta-GWAS. PMID- 29404215 TI - Equine glucagon-like peptide-1 receptor physiology. AB - Background: Equine metabolic syndrome (EMS) is associated with insulin dysregulation, which often manifests as post-prandial hyperinsulinemia. Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP 1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. However, little is known about the equine GLP-1 receptor (eGLP-1R), or whether GLP-1 concentrations can be manipulated. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated. Methods: Archived and abattoir-sourced tissues from healthy horses were used. Reverse transcriptase PCR was used to determine the tissue distribution of the eGLP-1R gene, with immunohistochemical confirmation of its pancreatic location. The GLP-1 secretion from intestinal explants in response to 4 and 12 mM glucose was quantified in vitro. Pancreatic islets were freshly isolated to assess the insulin secretory response to GLP-1 agonism and antagonism in vitro, using concentration-response experiments. Results: The eGLP-1R gene is widely distributed in horses (pancreas, heart, liver, kidney, duodenum, digital lamellae, tongue and gluteal skeletal muscle). Within the pancreas the eGLP-1R was immunolocalised to the pancreatic islets. Insulin secretion from pancreatic islets was concentration-dependent with human GLP-1, but not the synthetic analogue exendin-4. The GLP-1R antagonist exendin 9-39 (1 nM) reduced (P = 0.08) insulin secretion by 27%. Discussion: The distribution of the eGLP-1R across a range of tissues indicates that it may have functions beyond insulin release. The ability to reduce insulin secretion, and therefore hyperinsulinemia, through eGLP-1R antagonism is a promising and novel approach to managing equine insulin dysregulation. PMID- 29404216 TI - Evaluating outcomes of management targeting the recovery of a migratory songbird of conservation concern. AB - Background: Assessing outcomes of habitat management is critical for informing and adapting conservation plans. From 2013-2019, a multi-stage management initiative, led by the American Bird Conservancy (ABC), aims to create >25,000 ha of shrubland and early-successional vegetation to benefit Golden-winged Warblers (Vermivora chrysoptera) in managed forested landscapes of the western Great Lakes region. We studied a dense breeding population of Golden-winged Warblers at Rice Lake National Wildlife Refuge (NWR) in Minnesota, USA, where ABC initiative management was implemented to benefit the species. Methods: We monitored abundance before (2011-2014) and after (2015-2016) management, and we estimated full-season productivity (i.e., young recruited into the fall population) from predictive, spatially explicit models, informed by nest and fledgling survival data collected at sites in the western Great Lakes region, including Rice Lake NWR, during 2011 and 2012. Then, using biologically informed models of bird response to observed and predicted vegetation succession, we estimated the cumulative change in population recruitment over various scenarios of vegetation succession and demographic response. Results: We observed an 32% decline in abundance of breeding pairs and estimated a 27% decline in per-pair full-season productivity following management, compared to no change in a nearby control site. In models that ranged from highly optimistic to progressively more realistic scenarios, we estimated a net loss of 72-460 juvenile Golden-winged Warblers produced from the managed site in the 10-20 years following management. Even if our well-informed and locally validated productivity models produced erroneous estimates and the management resulted in only a temporary reduction in abundance (i.e., no change in productivity), our forecast models still predicted a net loss of 137-260 juvenile Golden-winged Warblers from the managed area over the same time frame. Conclusions: Our study site represents only a small portion of a massive management initiative; however, the management at our site was conducted in accordance with the initiative's management plans, the resulting vegetation structure is consistent with that of other areas managed under the initiative, and those responsible for the initiative have described the management at our study site as successful Golden-winged Warbler management. Our assessment demonstrates that, at least for the only site for which pre- and post management data on Golden-winged Warblers exist, the ABC management initiative is having a substantial and likely enduring negative impact on the species it purports to benefit. We suggest that incorporating region-specific, empirical information about Golden-winged Warbler-habitat relations into habitat management efforts would increase the likelihood of a positive response by Golden-winged Warblers. PMID- 29404217 TI - Evaluating the adaptive evolutionary convergence of carnivorous plant taxa through functional genomics. AB - Carnivorous plants are striking examples of evolutionary convergence, displaying complex and often highly similar adaptations despite lack of shared ancestry. Using available carnivorous plant genomes along with non-carnivorous reference taxa, this study examines the convergence of functional overrepresentation of genes previously implicated in plant carnivory. Gene Ontology (GO) coding was used to quantitatively score functional representation in these taxa, in terms of proportion of carnivory-associated functions relative to all functional sequence. Statistical analysis revealed that, in carnivorous plants as a group, only two of the 24 functions tested showed a signal of substantial overrepresentation. However, when the four carnivorous taxa were analyzed individually, 11 functions were found to be significant in at least one taxon. Though carnivorous plants collectively may show overrepresentation in functions from the predicted set, the specific functions that are overrepresented vary substantially from taxon to taxon. While it is possible that some functions serve a similar practical purpose such that one taxon does not need to utilize both to achieve the same result, it appears that there are multiple approaches for the evolution of carnivorous function in plant genomes. Our approach could be applied to tests of functional convergence in other systems provided on the availability of genomes and annotation data for a group. PMID- 29404218 TI - Assessing the difference of tolerance and phytoremediation potential in mercury contaminated soil of a non-food energy crop, Helianthus tuberosus L. (Jerusalem artichoke). AB - This study was conducted to evaluate the effects of mercury stress on growth, photosynthesis and mercury accumulation in different cultivars of a non-food energy crop, Jerusalem artichoke, and to screen appropriate cultivars for their efficacy in the phytoremediation of mercury (Hg2+) contaminated soil. Cultivars LZJ033 (high above-ground biomass and nutrient content, and strongly sexual reproduction) and LZJ119 (a long period of vegetative growth) exhibited more tolerance to mercury stress than LZJ047 (the highest tuber yield and total sugar content). The lines LZJ119 and LZJ047 showed delays in emergence time of about four weeks, and LZJ047 exhibited the highest mortality rate, 85.19%, under treatment with 10 mg kg-1 mercury. The MDA (malondialdehyde) content increased whereas and the Pn (net photosynthetic rate), Fv /Fm (the maximum quantum yield of PSII photochemistry) and chlorophyll content decreased in response to mercury stress. The stem diameter, stem biomass and photosynthetic rate of Jerusalem artichoke showed some modest increases in response to mercury stress and exhibited hormesis at least 1 mg kg-1 mercury treatment. Overall, LZJ119 produced more biomass under mercury stress, whereas LZJ033 exhibited a greater capacity for mercury bioaccumulation. Accordingly, LZJ119 may be a good candidate cultivar for use in cases of moderate-low mercury contamination, whereas LZJ033 may be a better candidate under conditions of high mercury contamination. When Jerusalem artichoke was cultivated in mercury contaminated soil, it not only removed the mercury from soil but also produced large amounts of tubers and shoots which could be used as feedstock for the production of bioethanol. PMID- 29404220 TI - The role of awareness of repetition during the development of automaticity in a dot-counting task. AB - This study examined whether being aware of the repetition of stimuli in a simple numerosity task could aid the development of automaticity. The numerosity task used in this study was a simple counting task. Thirty-four participants were divided into two groups. One group was instructed that the stimuli would repeat many times throughout the experiment. The results showed no significant differences in the way automatic processing developed between the groups. Similarly, there was no correlation between the point at which automatic processing developed and the point at which participants felt they benefitted from the repetition of stimuli. These results suggest that extra-trial features of a task may have no effect on the development of automaticity, a finding consistent with the instance theory of automatisation. PMID- 29404219 TI - Evidence for widespread dysregulation of circadian clock progression in human cancer. AB - The ubiquitous daily rhythms in mammalian physiology are guided by progression of the circadian clock. In mice, systemic disruption of the clock can promote tumor growth. In vitro, multiple oncogenes can disrupt the clock. However, due to the difficulties of studying circadian rhythms in solid tissues in humans, whether the clock is disrupted within human tumors has remained unknown. We sought to determine the state of the circadian clock in human cancer using publicly available transcriptome data. We developed a method, called the clock correlation distance (CCD), to infer circadian clock progression in a group of samples based on the co-expression of 12 clock genes. Our method can be applied to modestly sized datasets in which samples are not labeled with time of day and coverage of the circadian cycle is incomplete. We used the method to define a signature of clock gene co-expression in healthy mouse organs, then validated the signature in healthy human tissues. By then comparing human tumor and non-tumor samples from twenty datasets of a range of cancer types, we discovered that clock gene co expression in tumors is consistently perturbed. Subsequent analysis of data from clock gene knockouts in mice suggested that perturbed clock gene co-expression in human cancer is not caused solely by the inactivation of clock genes. Furthermore, focusing on lung cancer, we found that human lung tumors showed systematic changes in expression in a large set of genes previously inferred to be rhythmic in healthy lung. Our findings suggest that clock progression is dysregulated in many solid human cancers and that this dysregulation could have broad effects on circadian physiology within tumors. In addition, our approach opens the door to using publicly available data to infer circadian clock progression in a multitude of human phenotypes. PMID- 29404221 TI - The association between chronic bullying victimization with weight status and body self-image: a cross-national study in 39 countries. AB - Background: Childhood obesity and school bullying are pervasive public health issues and known to co-occur in adolescents. However, the association between underweight or thinness and chronic bullying victimization is unclear. The current study examined whether chronic bullying victimization is associated with weight status and body self-image. Methods: A school-based, cross-sectional study in 39 North American and European countries and regions was conducted. A total of 213,595 adolescents aged 11, 13, and 15 years were surveyed in 2009/10. Chronic bullying victimization was identified using the Revised Olweus Bully/Victim Questionnaire. Weight status was determined using self-reported height and weight and the body mass index (BMI), and body self-image was based on perceived weight. We tested associations between underweight and bullying victimization using three level logistic regression models. Results: Of the 213,595 adolescents investigated, 11.28% adolescents reported chronic bullying victimization, 14.80% were classified as overweight/obese according to age- and sex-specific BMI criteria, 12.97% were underweight, and 28.36% considered themselves a little bit fat or too fat, 14.57% were too thin. Bullying victimization was less common in older adolescent boys and girls. Weight status was associated with chronic bullying victimization (adjusted ORunderweight = 1.10, 95% CI = 1.05-1.16, p = 0.002; adjusted ORoverweight = 1.40, 95% CI = 1.32-1.49, p < 0.0001; adjusted ORobese = 1.91, 95% CI = 1.71-2.14, p < 0.0001). Body self-image also related to chronic bullying victimization (adjusted ORtoo thin = 1.42, 95% CI = 1.36-1.49, p < 0.0001; adjusted ORa little bit fat = 1.54, 95% CI = 1.48-1.61, p < 0.0001; adjusted ORtoo fat = 3.30, 95% CI = 2.96-3.68, p < 0.0001). Conclusion: Both perceived weight and self-rated overweight are associated with chronic bullying victimization. Both overweight and underweight children are at risk of being chronically bullied. PMID- 29404222 TI - Evolutionary dynamics of GII.17 norovirus. AB - Background: During the winter of 2014-2015, a rarely reported norovirus (NoV) genotype GII.17 was found to have increased its frequency in norovirus outbreaks in East Asia, surpassing the GII.4 NoV infections. GII.17 genotype has been detected for over three decades in the world. The aim of this study is to examine the evolutionary dynamics of GII.17 over the last four decades. Methods: NoV GII.17 sequences with complete or nearly complete VP1 were downloaded from GenBank and the phylogenetic analyses were then conducted. Results: The maximum likelihood analysis showed that GII.17 genotype could be divided into four different clades (Clades A-D). The strains detected after 2012, which could be the cause of the outbreaks, were separated into Clades C-D with their mean amino acid distance being 4.5%. Bayesian Markov chain Monte Carlo analyses indicated that the rate of nucleotide substitution per sites was 1.68 * 10-3 nucleotide substitutions/site/year and the time of the most recent common ancestor was 1840. The P2 subdomain of GII.17 was highly variable with 44% (56/128) amino acids variations including two insertions at positions 295-296 and one deletion at position 385 (Clades C and D) and one insertion at position 375 (Clade D). Variations existed in Epitopes A, B and D corresponding to GII.4 and human histo blood group antigens binding site I in P2 subdomain. Conclusion: The novel GII.17 strains that caused outbreaks in 2013-2015 may have two new variants. The evolvement of HBGAs binding site and epitopes in P2 subdomain might contribute to the novel GII.17 strains predominance in some regions. PMID- 29404223 TI - Incidence of and social-demographic and obstetric factors associated with postpartum depression: differences among ethnic Han and Kazak women of Northwestern China. AB - Background: Studies on postpartum depression (PPD) in China have focused primarily on women of Han ethnicity, whereas work on other ethnic groups has proven limited. This study explored the ethnic differences of associated social demographic and obstetric factors for PPD between Han-majority and Kazak-minority women in northwestern China. Methods: Han and Kazak women who received routine examinations at four hospitals in a multi-ethnic area of China six weeks after childbirth between March 2016 and December 2016 were included in the study. Data on the women's socio-demographic characteristics, obstetric factors, and possible depression at six weeks after childbirth were collected. We examined the associated factors of PPD using multivariable logistic regression analyses by ethnic group. Results: The overall incidence of PPD was 14.6% (184/1,263) at six weeks after childbirth. PPD was detected more frequently among Kazak (16.1%) than Han women (13.1%). Kazak women exhibited a higher risk of PPD (adjusted OR = 1.561, 95% CI [1.108-2.198], P = 0.011). Urinary incontinence (UI) represented a significant risk factor of PPD for Kazak compared with Han women (OR = 1.720, 95% CI [1.056-2.804], P = 0.003). In contrast, the presence of the mother-in-law as a caregiver after childbirth demonstrated a positive association with PPD among Han (OR = 2.600, 95% CI [1.499-4.512], P = 0.001), but not with Kazak women. Conclusions: Kazak women were more likely to develop PPD than Han women, even after controlling for confounders. Moreover, distinct risk factors for PPD existed for Han and Kazak women. Future research that explores the relationships between Han women and their mothers-in-law as well as Kazak women's attitudes toward UI could help us further understand PPD in these populations. PMID- 29404224 TI - A review of bottom-up vs. top-down control of sponges on Caribbean fore-reefs: what's old, what's new, and future directions. AB - Interest in the ecology of sponges on coral reefs has grown in recent years with mounting evidence that sponges are becoming dominant members of reef communities, particularly in the Caribbean. New estimates of water column processing by sponge pumping activities combined with discoveries related to carbon and nutrient cycling have led to novel hypotheses about the role of sponges in reef ecosystem function. Among these developments, a debate has emerged about the relative effects of bottom-up (food availability) and top-down (predation) control on the community of sponges on Caribbean fore-reefs. In this review, we evaluate the impact of the latest findings on the debate, as well as provide new insights based on older citations. Recent studies that employed different research methods have demonstrated that dissolved organic carbon (DOC) and detritus are the principal sources of food for a growing list of sponge species, challenging the idea that the relative availability of living picoplankton is the sole proxy for sponge growth or abundance. New reports have confirmed earlier findings that reef macroalgae release labile DOC available for sponge nutrition. Evidence for top down control of sponge community structure by fish predation is further supported by gut content studies and historical population estimates of hawksbill turtles, which likely had a much greater impact on relative sponge abundances on Caribbean reefs of the past. Implicit to investigations designed to address the bottom-up vs. top-down debate are appropriate studies of Caribbean fore-reef environments, where benthic communities are relatively homogeneous and terrestrial influences and abiotic effects are minimized. One recent study designed to test both aspects of the debate did so using experiments conducted entirely in shallow lagoonal habitats dominated by mangroves and seagrass beds. The top-down results from this study are reinterpreted as supporting past research demonstrating predator preferences for sponge species that are abundant in these lagoonal habitats, but grazed away in fore-reef habitats. We conclude that sponge communities on Caribbean fore-reefs of the past and present are largely structured by predation, and offer new directions for research, such as determining the environmental conditions under which sponges may be food-limited (e.g., deep sea, lagoonal habitats) and monitoring changes in sponge community structure as populations of hawksbill turtles rebound. PMID- 29404225 TI - On the morphological variability of Ichniotherium tracks and evolution of locomotion in the sistergroup of amniotes. AB - Ichniotherium tracks with a relatively short pedal digit V (digit length ratio V/IV < 0.6) form the majority of yet described Late Carboniferous to Early Permian diadectomorph tracks and can be related to a certain diadectid clade with corresponding phalangeal reduction that includes Diadectes and its close relatives. Here we document the variation of digit proportions and trackway parameters in 25 trackways (69 step cycles) from nine localities and seven further specimens with incomplete step cycles from the type locality of Ichniotherium cottae (Gottlob quarry) in order to find out whether this type of Ichniotherium tracks represents a homogeneous group or an assemblage of distinct morphotypes and includes variability indicative for evolutionary change in trackmaker locomotion. According to our results, the largest sample of tracks from three Lower Permian sites of the Thuringian Forest, commonly referred to I. cottae, is not homogeneous but shows a clear distinction in pace length, pace angulation, apparent trunk length and toe proportions between tracks from Bromacker quarry and those from the stratigraphically older sites Birkheide and Gottlob quarry. Three Late Carboniferous trackways of Ichniotherium with relatively short pedal digit V from Haine's Farm, Ohio, and Alveley near Birmingham, United Kingdom, that have been referred to the ichnotaxa "Baropus hainesi," "Megabaropus hainesi" and "Ichniotherium willsi," respectively, share a marked outward rotation of foot imprints with respect to walking direction. Apart from this feature they are in many aspects similar to the Birkheide and Gottlob records of I. cottae. With the possible exception of the Maroon Formation (Early Permian, Colorado) sample, Early Permian Ichniotherium trackways with a relatively short pedal digit V fall into the morphological spectrum of the three well defined "Hainesi-Willsi," "Birkheide-Gottlob" and "Bromacker" morphotypes. With their more obtuse pace angulations and higher body-size-normalized pace and stride lengths the Bromacker type tracks imply higher walking speeds of their trackmakers compared to all other Ichniotherium tracks. More generally, a trend towards higher locomotion capability from the last common ancestor of all Ichniotherium producers to the last common ancestor of all "Ichniotherium with relatively short pedal digit V" and from the latter to the trackmakers of the mid Early Permian Bromacker type can be deduced-with the reservation that overall sample size is relatively small, making this scenario a preliminary assessment. Whether the presumed advancements represent a more general pattern within diadectomorphs remains open until the non-European Ichniotherium trackway record improves. Ichnotaxonomic implications are discussed. PMID- 29404226 TI - Automatic Detection of Compensation During Robotic Stroke Rehabilitation Therapy. AB - Robotic stroke rehabilitation therapy can greatly increase the efficiency of therapy delivery. However, when left unsupervised, users often compensate for limitations in affected muscles and joints by recruiting unaffected muscles and joints, leading to undesirable rehabilitation outcomes. This paper aims to develop a computer vision system that augments robotic stroke rehabilitation therapy by automatically detecting such compensatory motions. Nine stroke survivors and ten healthy adults participated in this study. All participants completed scripted motions using a table-top rehabilitation robot. The healthy participants also simulated three types of compensatory motions. The 3-D trajectories of upper body joint positions tracked over time were used for multiclass classification of postures. A support vector machine (SVM) classifier detected lean-forward compensation from healthy participants with excellent accuracy (AUC = 0.98, F1 = 0.82), followed by trunk-rotation compensation (AUC = 0.77, F1 = 0.57). Shoulder-elevation compensation was not well detected (AUC = 0.66, F1 = 0.07). A recurrent neural network (RNN) classifier, which encodes the temporal dependency of video frames, obtained similar results. In contrast, F1 scores in stroke survivors were low for all three compensations while using RNN: lean-forward compensation (AUC = 0.77, F1 = 0.17), trunk-rotation compensation (AUC = 0.81, F1 = 0.27), and shoulder-elevation compensation (AUC = 0.27, F1 = 0.07). The result was similar while using SVM. To improve detection accuracy for stroke survivors, future work should focus on predefining the range of motion, direct camera placement, delivering exercise intensity tantamount to that of real stroke therapies, adjusting seat height, and recording full therapy sessions. PMID- 29404227 TI - A Knowledge-Based Approach to Automatic Detection of Equipment Alarm Sounds in a Neonatal Intensive Care Unit Environment. AB - A large number of alarm sounds triggered by biomedical equipment occur frequently in the noisy environment of a neonatal intensive care unit (NICU) and play a key role in providing healthcare. In this paper, our work on the development of an automatic system for detection of acoustic alarms in that difficult environment is presented. Such automatic detection system is needed for the investigation of how a preterm infant reacts to auditory stimuli of the NICU environment and for an improved real-time patient monitoring. The approach presented in this paper consists of using the available knowledge about each alarm class in the design of the detection system. The information about the frequency structure is used in the feature extraction stage, and the time structure knowledge is incorporated at the post-processing stage. Several alternative methods are compared for feature extraction, modeling, and post-processing. The detection performance is evaluated with real data recorded in the NICU of the hospital, and by using both frame level and period-level metrics. The experimental results show that the inclusion of both spectral and temporal information allows to improve the baseline detection performance by more than 60%. PMID- 29404228 TI - Separating Visuospatial from Visuomotor Coordination in Skill Estimation in Learning Disabled Children: The Eta-Mu Model. AB - Purpose A model aimed at detecting the proportion of visuoperceptive and visuomotor coordination impairment in children with ascertained or suspected learning disability is described. The final purpose is to provide customized rehabilitation programs. Methods In this pilot study, four children (8-9 years) were administered a set of standardized tests to evaluate their ability to perform visuoperceptive and visuomotor tasks. Depending on the individual outcomes, two indexes have been computed from the resulting z-scores: eta (Eta) that quantifies the visuoperceptive impairment, and MU (Mu) that expresses the alteration in visuomotor coordination. Results A condition of abnormality was evident in each patient: Subjects 1 and 3 suffered mainly from a visuoperceptive alteration (eta higher than expected), while Subject 4 had reduced visuomotor coordination (MU higher than expected). Subject 2 showed balanced visuoperceptive and visuomotor impairment. Based on the obtained eta and MU values, each child underwent a customized rehabilitation treatment, then they were examined again. At re-test, eta or MU turned balanced and z-scores improved in the four patients. Conclusions The Eta/Mu model is effective in detecting the type of damage by quantifying the share of visuoperceptive and visuomotor coordination involvement in dyslexic children, allowing a customized rehabilitative approach. Such an approach, focused on treating the function found to be defective, appears to be effective in rebalancing individual visuomotor and visuoperceptive skills; it should, therefore, be taken into consideration when updating the rehabilitation plans of learning disabled children. PMID- 29404229 TI - Clinical Implications of a Novel, Iron-containing Fiducial Marker in Radiotherapy for Liver Tumors: An Initial Experience. AB - A 0.5%-iron-containing fiducial marker, Gold AnchorTM (Naslund Medical AB, Huddinge, Sweden), has been recently developed. Herein, we report our initial experiences with the clinical use of the Gold AnchorTM (GA) in radiotherapy for liver tumors. Data of four consecutive patients with liver tumors, including two liver metastases and two hepatocellular carcinomas, were retrospectively analyzed. The GA was percutaneously placed under local anesthesia, close to the tumor. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI) was performed after the placement of the GA. Radiotherapy was designed using the volumetric modulated arc therapy technique. All procedures for placement of the GA were successfully performed with no complications. The GA exhibited various forms in the liver in the four patients. All of the GAs were well-detected on MRI, planned computed tomography (CT), and cone-beam CT. Additionally, the tadpole-like shape of the GA showed better detectability than the uptake of lipiodol emulsion and could be used for three dimensional correlation during setup in daily image-guided radiotherapy. GA was a useful tool in image registration of radiotherapy with a high applicability. Additionally, the tadpole-like shape can be recommended for liver radiotherapy. Our findings suggest that the GA will indeed be useful in clinical practice. PMID- 29404230 TI - Process parametric study for COD removal of electroplating industry effluent. AB - This paper investigated the effects of parameters, like inoculum size (15, 10 and 5% of the working volume of the reactor), gas velocities (0.0027, 0.00342 and 0.0068 m/s), bed heights (0.3, 0.6 and 0.9 m), static bed heights (4.85 and 2.43 cm), sizes of solid media particles (12, 4 mm), and the height to diameter ratio (H/D: 0.25 and 0.5) onto COD reduction process for electroplating effluent (initial COD values: 1140 ppm) using Pseudomonas aeruginosa and Pseudomonas putida. The authors derived simple mathematical correlations representing the entire COD reduction process. The correlation between the inoculum volume and gas velocities was in the form of an equation Y = ax2 + bx + c, as deduced from nonlinear regressions. The correlations were validated, and percentage errors were found out to infer the effects of all parameters in the COD reduction process. The maximum COD reduction was achieved to 28.30 ppm (97.52%), in a batch mode, at 10% inoculum size, 0.0027 m/s low gas velocity and a static bed height of 2.43 cm. PMID- 29404231 TI - Draft genome sequence of Paenibacillus strain LK1, a phytohormone producing bacterium. AB - A high-quality draft genome sequence of a multi-antibiotic resistant strain, Paenibacillus strain LK1 isolated from the rhizosphere of Auricularia auricular is described. Strain LK1 produced several types of phytohormones, which included Indole-3-acetic acid (IAA) and Zeatin. Phylogenetic analysis of the 16S rRNA gene of strain LK1 showed a close relationship to P. taichungensis and P. pabuli (99% gene sequence similarity). The genome size of strain LK1 was estimated to be 7.16 Mb that consisted of 82 contigs contained in 49 scaffolds. The G + C content of the genome was 45.63% and it encoded 6499 genes, 115 pseudo genes, 8 rRNAs, 33 tRNAs, and 4 ncRNAs, based on the Prokaryotic Genome Annotation Pipeline (PGAP). Further analysis of the genome of strain LK1 identified 16 genes encoding monooxygenase and six genes encoding cytochrome P450, which may be potentially involved in zeatin biosynthesis. The draft whole genome sequence and annotation of strain LK1 has been deposited at DDBJ/EMBL/GenBank under the accession number (PEII00000000). PMID- 29404232 TI - Characterization of detergent compatible protease from halophilic Virgibacillus sp. CD6. AB - A halophilic bacterium, Virgibacillus sp. strain CD6, was isolated from salted fish and its extracellular protease was characterized. Protease production was found to be highest when yeast extract was used as nitrogen source for growth. The protease exhibited stability at wide range of salt concentration (0-12.5%, w/v), temperatures (20-60 degrees C), and pH (4-10) with maximum activity at 10.0% (w/v) NaCl, 60 degrees C, pH 7 and 10, indicating its polyextremophilicity. The protease activity was enhanced in the presence of Mg2+, Mn2+, Cd2+, and Al3+ (107-122% relative activity), and with retention of activity > 80% for all of other metal ions examined (K+, Ca2+, Cu2+, Co2+, Ni2+, Zn2+, and Fe3+). Both PMSF and EDTA inhibited protease activity, denoting serine protease and metalloprotease properties, respectively. High stability (> 70%) was demonstrated in the presence of organic solvents and detergent constituents, and the extracellular protease from strain CD6 was also found to be compatible in commercial detergents. Proteinaceous stain removal efficacy revealed that crude protease of strain CD6 could significantly enhance the performance of commercial detergent. The protease from Virgibacillus sp. strain CD6 could serve as a promising alternative for various applications, especially in detergent industry. PMID- 29404234 TI - Recent Advances in Pediatric Skull Base Surgery. PMID- 29404235 TI - Developmental Considerations in Pediatric Skull Base Surgery. AB - Objectives To review developmental surgical anatomy and technical nuances related to pediatric skull base surgery. Design Retrospective, single-center case series with literature review. Setting MD Anderson Cancer Center. Participants Patients undergoing pediatric skull base surgery. Main Outcome Measures Review developmental anatomy of the pediatric skull base as it relates to technical nuance of various surgical approaches and insight gained from a 25 year institutional experience with this unique patient population. Results Thirty-nine patients meeting these criteria were identified over a 13-year period from 2003 to 2016 and compared to a previously reported earlier cohort from 1992 to 2002. The most common benign pathologies included nerve sheath tumors (11%), juvenile nasopharyngeal angiofibromas (9.5%), and craniopharyngiomas (4.8%). The most common malignancies were chondrosarcoma (11%), chordoma (11%), and rabdomyosarcoma (11%). Varied surgical approaches were utilized and were similar between the two cohorts save for the increased use of endoscopic surgical techniques in the most recent cohort. The most common sites of tumor origin were the infratemporal fossa, sinonasal cavities, clivus, temporal bone, and parasellar region. Gross total resection and postoperative complication rates were similar between the two patient cohorts. Conclusions Pediatric skull base tumors, while rare, often are treated surgically, necessitating an in depth understanding of the anatomy of the developing skull base. PMID- 29404236 TI - Endoscopic Management of Developmental Anomalies of the Skull Base. AB - Developmental anomalies of the skull base may present in childhood or as an adult. The most common pathologies include dermoid, encephalocele, and glioma. Encephaloceles may present as part of a syndrome. Other entities include infantile hemangiomas and teratoma. Endoscopic techniques provide a less invasive and morbid option for treatment. Proper evaluation and treatment is necessary to prevent complications such as meningitis. PMID- 29404237 TI - Juvenile Angiofibroma: Current Management Strategies. AB - Juvenile angiofibroma (JA) is a benign, highly vascular tumor which is diagnosed on the basis of clinical and imaging features. It has a characteristic pattern of spread commonly involving the pterygopalatine fossa and pterygoid base. The mainstay of treatment is surgery, while radiotherapy is rarely used for the treatment of recurrent lesion. Endoscopic endonasal surgery is currently the treatment of choice for small to intermediate size JAs, and is feasible even for advanced lesions; however, this should only be practiced in well-experienced centers. PMID- 29404233 TI - Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications. AB - Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications. PMID- 29404239 TI - Nasoseptal Flap for Skull Base Reconstruction in Children. AB - Objective The endoscopic endonasal approach is being increasingly used for the resection and reconstruction of anterior skull base (ASB) lesions. Vascularized nasoseptal flaps (NSF) have become the workhorse for the reconstruction of ASB defects, resulting in a significant decrease in the incidence of cerebrospinal fluid (CSF) leaks. The objective of this study was to investigate the efficacy and safety of NSF in children. Methods This is a retrospective analysis of the medical records of all patients under the age of 18 years who underwent endoscopic repair of ASB lesions with the use of NSF at our tertiary medical center between 1/2011 and 8/2016. Results Twelve children underwent ASB defect repair for both benign and malignant neoplasms using the endoscopic endonasal NSF technique. Four children had previously undergone ASB surgery. The male-to-female ratio was 1:1, the average age was 12.3 years, the average hospitalization time was 8.3 days, and the maximum follow-up period was 24 months, during which craniofacial growth appeared to be unimpaired. A lumbar drain was used postoperatively in six cases. Crust formation and synechia were observed in two cases. There was one case of a major long-term complication (a CSF leak followed by meningitis). Conclusions Endoscopic endonasal NSF was both an effective and a safe technique for ASB defect reconstruction in 12 children for both benign and malignant neoplasms. It had a high success rate and a low complication rate. No apparent negative influence on craniofacial growth was observed in our series. PMID- 29404238 TI - Fibro-Osseous Lesions of the Skull Base in the Pediatric Population. AB - Fibro-osseous lesions of the skull base include a variety of lesions with different biologic behavior. The most common lesions include fibrous dysplasia, osteoma, aneurysmal bone cyst, and juvenile ossifying fibroma. The diagnosis can usually be established with radiographic imaging. In the absence of symptoms, slow-growing lesions can often be observed. When surgery is indicated for relief of symptoms, endoscopic endonasal techniques are well suited for all age groups. PMID- 29404240 TI - Open Approaches to the Anterior Skull Base in Children: Review of the Literature. AB - Introduction Skull base lesions in children and adolescents are rare, and comprise only 5.6% of all skull base surgery. Anterior skull base lesions dominate, averaging slightly more than 50% of the cases. Until recently, surgery of the anterior skull base was dominated by open procedures and endoscopic skull base surgery was reserved for benign pathologies. Endoscopic skull base surgery is gradually gaining popularity. In spite of that, open skull base surgery is still considered the "gold standard" for the treatment of anterior skull base lesions, and it is the preferred approach in selected cases. Objective This article reviews current concepts and open approaches to the anterior skull base in children in the era of endoscopic surgery. Materials and Methods Comprehensive literature review. Results Extensive intracranial-intradural invasion, extensive orbital invasion, encasement of the optic nerve or the internal carotid artery, lateral supraorbital dural involvement and involvement of the anterior table of the frontal sinus or lateral portion of the frontal sinus precludes endoscopic surgery, and mandates open skull base surgery. The open approaches which are used most frequently for surgical resection of anterior skull base tumors are the transfacial/transmaxillary, subcranial, and subfrontal approaches. Reconstruction of anterior skull base defects is discussed in a separate article in this supplement. Discussion Although endoscopic skull base surgery in children is gaining popularity in developed countries, in many cases open surgery is still required. In addition, in developing countries, which accounts for more than 80% of the world's population, limited access to expensive equipment precludes the use of endoscopic surgery. Several open surgical approaches are still employed to resect anterior skull base lesions in the pediatric population. With this large armamentarium of surgical approaches, tailoring the most suitable approach to a specific lesion in regard to its nature, location, and extent is of utmost importance. PMID- 29404241 TI - Lateral Skull Base Approaches in Pediatric Skull Base Surgery. AB - Lateral skull base pathology is rare in children. Awareness of the potential for lateral skull base lesions in children is imperative for timely identification and appropriate management. Some of the common presentations and pathologies shall be presented, as well as a variety of approaches that may be utilized to access the lateral skull base in the pediatric patient. Although the lateral skull base approaches utilized in adults may also be considered for management of pediatric lesions, some special considerations given the small developing anatomy need to be kept in mind. PMID- 29404242 TI - Rhabdomyosarcoma of the Head and Neck: A Multimodal Approach. AB - Head and neck rhabdomyosarcoma (HNRMS) is a uniquely challenging site to treat given the young patient age and critical anatomy of the head and neck region. We review the characteristics, management, and future directions in the treatment of HNRMS. Most patients who present with HNRMS have unresectable disease due to functional and/or cosmetic constraints. However, surgical resection and brachytherapy serve a critical role in select patients. The treatment paradigm for the majority of patients with HNRMS consists of definitive chemotherapy and radiation therapy. As the incidence of late toxicities increases with improved survival, modern efforts must focus on ways to decrease long-term morbidity. We recommend a multimodal approach emphasizing the preservation of form and function for the treatment of HNRMS. PMID- 29404244 TI - Skull Base Reconstruction in the Pediatric Patient. AB - Introduction Pediatric skull base and craniofacial reconstruction presents a unique challenge since the potential benefits of therapy must be balanced against the cumulative impact of multimodality treatment on craniofacial growth, donor site morbidity, and the potential for serious psychosocial issues. Objectives To suggest an algorithm for skull base reconstruction in children and adolescents after tumor resection. Materials and Methods Comprehensive literature review and summary of our experience. Results We advocate soft-tissue reconstruction as the primary technique, reserving bony flaps for definitive procedures in survivors who have reached skeletal maturity. Free soft-tissue transfer in microvascular technique is the mainstay for reconstruction of large, three-dimensional defects, involving more than one anatomic region of the skull base, as well as defects involving an irradiated field. However, to reduce total operative time, intraoperative blood loss, postoperative hospital stay, and donor-site morbidity, locoregional flaps are better be considered the flap of first choice for skull base reconstruction in children and adolescents, as long as the flap is large enough to cover the defect. Our "workhorse" for dural reconstruction is the double-layer fascia lata. Advances in endoscopic surgery, image guidance, alloplastic grafts, and biomaterials have increased the armamentarium for reconstruction of small and mid-sized defects. Conclusions Skull base reconstruction using locoregional flaps or free flaps may be safely performed in pediatrics. Although the general principles of skull base reconstruction are applicable to nearly all patients, the unique demands of skull base surgery in pediatrics merit special attention. Multidisciplinary care in experienced centers is of utmost importance. PMID- 29404246 TI - Suprasellar Tumors (Part 1). PMID- 29404247 TI - Endoscopic Endonasal Resection of Retrochiasmatic Craniopharyngioma with Fascia Lata Button and Nasoseptal Flap Reconstruction. AB - Surgery for craniopharyngiomas can be challenging due to the involvement of multiple critical neurovascular structures. The expanded endoscopic endonasal approach can provide superior access to suprasellar craniopharyngiomas, particularly with retrochiasmatic extension and significant hypothalamic involvement. We describe the surgical technique used to treat a 30-year-old patient who presented with 4 weeks of worsening vision, fatigue, and memory loss. His vision was counting fingers at 1 feet on the right and 20/800 on the left with a temporal hemianopsia. Laboratory evaluation demonstrated central hypoadrenalism, hypothyroidism, and hypogonadism. Imaging showed a large solid and cystic suprasellar mass. The transtubercular approach with removal of the lateral tubercular strut can provide wide bilateral access to the opticocarotid region. The superior intercavernous sinus must be coagulated and ligated. Initial arachnoid dissection is centered at the midline, mobilizing the superior hypophyseal branches to the optic apparatus laterally. The cyst capsule is opened and care is taken to minimize spillage of cyst fluid into the subarachnoid space. Central debulking and then extracapsular dissection is performed under direct visualization using sharp dissection. Reconstruction of the dura is performed with an inlay/onlay fascia lata button that is held together with four sutures that hold the graft edges against the native dural edges. This is followed by vascularized nasoseptal flap reconstruction. No lumbar drain or nonabsorbable packing is required. The patient's vision had dramatic improvement and by 1 week postoperatively was 20/20 with full visual fields. Postoperative diabetes insipidus was managed with nasal desmopressin. Postoperative MRI demonstrated complete removal. The link to the video can be found at: https://youtu.be/QQxCNUcq1qg . PMID- 29404243 TI - Pediatric Craniopharyngiomas: A Primer for the Skull Base Surgeon. AB - Pediatric craniopharyngioma is a rare sellar-region epithelial tumor that, in spite of its typically benign pathology, has the potential to be clinically devastating, and presents a host of formidable management challenges for the skull base surgeon. Strategies in craniopharyngioma care have been the cause of considerable controversy, with respect to both philosophical and technical issues. Key questions remain unresolved, and include optimizing extent-of resection goals; the ideal radiation modality and its role as an alternative, adjuvant, or salvage treatment; appropriate indications for expanded endoscopic endonasal surgery as an alternative to transcranial microsurgery; risks and benefits of skull base techniques in a pediatric population; benefits of and indications for intracavitary therapies; and the preferred management of common treatment complications. Correspondingly, we sought to review the preceding basic science and clinical outcomes literature on pediatric craniopharyngioma, so as to synthesize overarching recommendations, highlight major points of evidence and their conflicts, and assemble a general algorithm for skull base surgeons to use in tailoring treatment plans to the individual patient, tumor, and clinical course. In general terms, we concluded that safe, maximal, hypothalamic-sparing resection provides very good tumor control while minimizing severe deficits. Endoscopic endonasal, intraventricular, and transcranial skull base technique all have clear roles in the armamentarium, alongside standard craniotomies; these roles frequently overlap, and may be further optimized by using the approaches in adaptive combinations. Where aggressive subtotal resection is achieved, patients should be closely followed, with radiation initiated at the time of progression or recurrence-ideally via proton beam therapy, although three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic radiosurgery are very appropriate in a range of circumstances, governed by access, patient age, disease architecture, and character of the recurrence. Perhaps most importantly, outcomes appear to be optimized by consolidated, multidisciplinary care. As such, we recommend treatment in highly experienced centers wherever possible, and emphasize the importance of longitudinal follow-up particularly given the high incidence of recurrences and complications in a benign disease that effects a young patient population at risk of severe morbidity from hypothalamic or pituitary injury in childhood. PMID- 29404248 TI - Expanded Endoscopic Endonasal Resection of Retrochiasmatic Craniopharyngioma. AB - This video abstract demonstrates the use of the expanded endoscopic endonasal approach for the resection of a retrochiasmatic craniopharyngioma. These tumors are notoriously difficult to treat, and many approaches have been tried to facilitate safe and effective resection. The endoscopic endonasal approach has been increasingly utilized for selected sellar/suprasellar pathology. We present the case of a 39-year-old man who was found to have a cystic, partially calcified suprasellar mass consistent with a craniopharyngioma. To facilitate robust skull base repair, a vascularized nasoseptal flap was harvested. A wide sphenoidotomy was performed and the sella and tuberculum were exposed. After the dural opening and arachnoid dissection, the stalk was identified, merging seamlessly with the tumor capsule. The lesion was then internally debulked with the use of an ultrasonic aspirator. The capsule was then dissected off of the optic chiasm, thalamus, and hypothalamus. The cavity was inspected with an angled endoscope to ensure complete resection. A multilayered reconstruction was performed using autologous fascia lata, the previously harvested nasoseptal flap, and dural sealant. Postoperatively, the patient did have expected panhypopituitarism but remained neurologically intact and had improvement in his vision. In conclusion, this video demonstrates how an expanded endonasal approach can be used to safely resect a craniopharyngioma, even when in close proximity to delicate structures such as the optic chiasm. The link to the video can be found at: https://youtu.be/tahjHmrXhc4 . PMID- 29404249 TI - Extended Endoscopic Endonasal Approach for Suprasellar Craniopharyngioma. AB - Objectives We illustrate a suprasellar craniopharyngiomas treated with an extended endoscopic endonasal approach (EEEA). Design Case report of a 43-year old male affected by cerebral lesion located in suprasellar region involving the third ventricle and compressing the neurovascular structures, causing an anterosuperior dislocation of the chiasma. There is a complete disruption of the pituitary stalk that can explain the clinical finding of partial anterior hypopituitarism and hyperprolactinemia. The lesion is characterized by a solid and cystic component. Considering the absence of lateral extension and the suprasellar location of the lesion, an EEEA is preferred. Setting University Hospital "Ospedale di Circolo," Department of Neurosurgery, Varese, Italy. Participants Neurosurgical and ENT Skull Base Team. Main Outcome Measures A bilateral parasagittal approach is performed using a four-hand technique. The first step of the surgery is the preparation of the Hadad's flap. The approach is extended to the planum sphenoidalis to expose the suprasellar region. The lesion is completely removed employing also an ultrasound aspirator. Skull base reconstruction is performed with three-layer technique: graft of fat tissue, fascia lata, and nasoseptal flap. Results No postoperative complications occurred. In the post-op, the patient presents a panhypopituitarism and an improvement in neurological status. The visual deficit remains stable. Post-op magnetic resonance imaging at 1 year documents the complete absence of pathological contrast enhancement. Conclusions EEEA is a feasible approach in treating craniopharyngioma with suprasellar extension. The advantages include optimal visualization, good resection rate, and absence of brain retraction. The link to the video can be found at: https://youtu.be/IYm-8P1jbBo . PMID- 29404250 TI - Extended Endoscopic Endonasal Approach for Craniopharyngioma Removal. AB - Objective Endoscopic transsphenoidal extended endoscopic approach (EEA) represents a valid alternative to microsurgery for craniopharyngiomas removal, especially for retrochiasmatic lesions without large parasellar extension. The present video illustrates the salient surgical steps of the EEA for craniopahryngioma removal. Patient A 52-year-old man presented with a bitemporal hemianopia and a bilateral decreased visual acuity. MRI showed a Kassam type III cystic craniopharyngioma with a solid component ( Fig. 1 , panels A and B). Surgical Procedure The head is rotated 10 degrees toward the surgeons. The nasal step is started through the left nostril with a middle turbinectomy. A nasoseptal flap is harvested and positioned in the left choana. The binostril approach allows a large sphenoidotomy to expose the key anatomic landmarks. The craniotomy boundaries are the planum sphenoidale superiorly, the median opticocarotid recesses, the internal carotid artery laterally and the clival recess inferiorly. After dural opening and superior intercavernous sinus coagulation, the tumor is entirely removed ( Fig. 2 , panels A and B). Skull base reconstruction is ensured by fascia lata grafting and nasoseptal flap positioning. Results Postoperative MRI showed the complete tumor resection ( Fig. 1 , panels C and D). At 3 months postoperatively, the bitemporal hemianopia regressed and the visual acuity improved. A novel left homonymous hemianopia developed secondary to optic tract manipulation. Conclusions The extended EEA is a valid surgical approach for craniopharyngioma resection. A comprehensive knowledge of the sellar and parasellar anatomy is mandatory for safe tumor removal with decreased morbidity and satisfactory oncologic results. The link to the video can be found at: https://youtu.be/NrCPPnVK2qA . PMID- 29404245 TI - Pediatric Pituitary Adenoma: Case Series, Review of the Literature, and a Skull Base Treatment Paradigm. AB - Background Pediatric pituitary adenoma is a rare skull base neoplasm, accounting for 3% of all intracranial neoplasms in children and 5% of pituitary adenomas. Compared with pituitary tumors in adults, secreting tumors predominate and longer disease trajectories are expected due to the patient age resulting in a natural history and treatment paradigm that is complex and controversial. Objectives The aims of this study were to describe a large, single-institution series of pediatric pituitary adenomas with extensive long-term follow-up and to conduct a systematic review examining outcomes after pituitary adenoma surgery in the pediatric population. Methods The study cohort was compiled by searching institutional pathology and operative reports using diagnosis and site codes for pituitary and sellar pathology, from 1956 to 2016. Systematic review of the English language literature since 1970 was conducted using PubMed, MEDLINE, Embase, and Google Scholar. Results Thirty-nine surgically managed pediatric pituitary adenomas were identified, including 15 prolactinomas, 14 corticotrophs, 7 somatotrophs, and 4 non-secreting adenomas. All patients underwent transsphenoidal resection (TSR) as the initial surgical treatment. Surgical cure was achieved in 18 (46%); 21 experienced recurrent/persistent disease, with secondary treatments including repeat surgery in 10, radiation in 14, adjuvant pharmacotherapy in 11, and bilateral adrenalectomy in 3. At the last follow-up (median 87 months, range 3-581), nine remained with recurrent/persistent disease (23%). Thirty-seven publications reporting surgical series of pediatric pituitary adenomas were included, containing 1,284 patients. Adrenocorticotropic hormone (ACTH)-secreting tumors were most prevalent (43%), followed by prolactin (PRL) secreting (37%), growth hormone (GH)-secreting (12%), and nonsecreting (7%). Surgical cure was reported in 65%. Complications included pituitary insufficiency (23%), permanent visual dysfunction (6%), chronic diabetes insipidus (DI) (3%), and postoperative cerebrospinal fluid (CSF) leak (4%). Mean follow-up was 63 months (range 0-240), with recurrent/persistent disease reported in 18% at the time of last follow-up. Conclusion Pediatric pituitary adenomas are diverse and challenging tumors with complexities far beyond those encountered in the management of routine adult pituitary disease, including nuanced decision-making, a technically demanding operative environment, high propensity for recurrence, and the potentially serious consequences of hypopituitarism with respect to fertility and growth potential in a pediatric population. Optimal treatment requires a high degree of individualization, and patients are most likely to benefit from consolidated, multidisciplinary care in highly experienced centers. PMID- 29404251 TI - Extended Endoscopic Approach for Resection of Craniopharyngiomas. AB - Objectives Extended endoscopic approaches are useful for resection of selected craniopharyngiomas. Midline, extraventricular, and predominantly cystic lesions are good candidates for endoscopic resection. In this video, we demonstrate the endoscopic endonasal resection of a large suprasellar craniopharyngioma and discuss the nuances of the surgical technique. Design/Setting Surgical video of an extended endoscopic approach for resection of a suprasellar craniopharyngioma. Results We report the case of a 56-year-old woman who presented with bitemporal hemianopsia and visual acuity deterioration secondary to a large suprasellar solid-cystic lesion. The patient underwent an extended endoscopic transtuberculum approach for resection of the lesion, which was diagnosed as a papillary craniopharyngioma. This video discusses the anatomy and surgical technique applied for endoscopic resection of such lesions. Conclusion Endoscopic endonasal surgery is a useful technique for management of craniopharyngiomas. It is associated with good clinical outcomes in selected cases. Complications, such as postoperative CSF leak, may occur and should be carefully managed. The link to the video can be found at: https://youtu.be/EneOCiQE7yo . PMID- 29404252 TI - Endoscopic Transsphenoidal Resection of Craniopharyngioma. AB - Objectives To demonstrate, step-by-step, the technique and efficacy of endoscopic transsphenoidal approach in resection of a suprasellar craniopharyngioma. Design The video shows a step-by-step approach to the resection, covering the exposure, access, resection, and confirmation of resection and reconstruction. Setting The surgery was performed in the University of Malaya Medical Centre, a tertiary referral center in the capital of Malaysia. Participants Surgery was performed jointly by Professor Prepageran from the department of otorhinolaryngology and Professor Vicknes Waran from the division of neurosurgery. Both surgeons are from the University of Malaya. Video compilation, editing, and voice narration was done by Dr. Kong Yew Liew. Main Outcome Measures Completeness of resection and avoidance of intra- and postoperative complications. Results Based on intraoperative views and MRI findings, the tumor was completely resected with the patient suffering only transient diabetes insipidus. Conclusion Central suprasellar tumors can be removed completely via an endoscopic transsphenoidal approach with minimal morbidity to the patient. The link to the video can be found at: https://youtu.be/ZNIHfk12cYg . PMID- 29404253 TI - The Posterior Transpetrosal Approach in a Case of Large Retrochiasmatic Craniopharyngioma: Operative Video and Technical Nuances. AB - Objectives To discuss the use of the posterior petrosal approach for the resection of a retrochiasmatic craniopharyngioma. Design Operative video. Results In this case video, the authors discuss the surgical management of a large craniopharyngioma, presenting with mass effect on the third ventricle and optic apparatus. A first surgical stage, through an endoscopic endonasal transtubercular approach, allowed satisfactory decompression of the optic chiasma and nerves in preparation for adjuvant therapy. However, accelerated growth of the tumor, with renewed visual deficits and mass effect on the hypothalamus and third ventricle, warranted a supplementary resection. A posterior transpetrosal 1 2 (also called "retrolabyrinthine transtentorial") was performed to obtain a better exposure of the tumor and the surrounding anatomy (floor and walls of the third ventricle, perforating vessels, optic nerves, etc.) 3 . Nuances of technique and surgical pearls related to the posterior transpetrosal are discussed and illustrated in this operative video, including the posterior mobilization of the transverse-sigmoid sinuses junction, preservation of the venous anatomy during the tentorial incision, identification and preservation of the floor of the third ventricle during tumor resection, and a careful multilayer closure. Conclusion Retrochiasmatic craniopharyngiomas are difficult to reach tumors that often require skull base approaches, either endoscopic endonasal or transcranial. The posterior transpetrosal approach is an important part of the surgical armamentarium to safely resect these complex tumors. The link to the video can be found at: https://youtu.be/2MyGLJ_v1kI . PMID- 29404254 TI - Contralateral Minimum Anterior and Posterior Combined Petrosal Approach for Retrochiasmatic Craniopharyngiomas: An Alternative Technique. AB - Retrochiasmatic craniopharyngiomas (RC) are a challenge for the neurosurgeon to treat surgically, restrained by their location in the interpeduncular fossa, surrounded by vital neurovascular structures, narrow corridor and poor visibility. Many approaches are possible and elucidated in the literature, which the surgeon chooses, based on multiple factors, such as the size of tumor, calcification, laterality, preoperative neurological deficits and the endocrine function status, recurrence, postradiotherapy status, or significant superior and/or posterior extension. 1 2 We describe a contralateral minimum anterior and posterior (CL-MAPC) petrosal approach for a case of recurrent RC, in a 37-year old female patient operated before using a pterional approach, now presented with left homonymous hemianopia and panhypopituitarism ( Fig. 1 ). We preferred a contralateral approach to protect the ipsilateral optic tract (OT) from retraction injury, which formed an obstacle to the tumor from ipsilateral side. Apart from various benefits described by the author previously for RC, using MAPC petrosal approach, the CL-MAPC offers a safe corridor, protecting the ipsilateral OT, visualization of tumor origin usually posterior to chiasm, wider corridor if PCoM could be sacrificed, as it was done in this case, and pituitary stalk identification, with a probability of its functional preservation, unlike a necessity of pituitary transposition in EEA, though the endocrine outcome is poor after a radical resection irrespective of the approach chosen. 1 3 4 There was complete excision of the tumor with preservation of visual function postoperatively. We recommend the use of CL-MAPC as an alternative to EEA in some specific indications when the tumor is large, calcified, obscuring OT on the ipsilateral side and with significant lateral extension, which may be limiting factors in EEA ( Fig. 2 ). The link to the video can be found at: https://youtu.be/gWCJmh4_evs . PMID- 29404255 TI - One-piece Orbitozygomatic Craniotomy for Resection of Rathke's Cleft Cyst: Operative Video. AB - Objective The video stars orbitozygomatic resection of Rathke's cleft cyst with suprasellar extension in a 37-year-old male patient presenting with severe headaches and bitemporal hemianopia. Clinical and radiological characteristics along with surgical technique (positioning, bony opening, surgical dissection and debulking, closure), histopathology, and postoperative course are described. Methods Preoperative MRI demonstrated a noncontrast-enhancing cystic lesion in the sella with suprasellar extension causing compression of both optic nerves. A one-piece orbitozygomatic craniotomy was performed. The tumor was encountered in the interoptic space. First, the cyst was decompressed and fluid appearing like motor oil was aspirated. Both optic nerves were decompressed and dissected free from the cyst wall. Intraoperatively, the most challenging aspect was separating the tumor from surrounding vascular structures, including bilateral A1 arteries and the left carotid bifurcation. A combination of sharp and blunt dissection was utilized to free the tumor from adhesions to critical neurovascular structures. Once freed, the suprasellar aspect of the tumor was mobilized into the operative cavity and debulked. Finally, the sellar component of the tumor was removed all the way down to the sellar floor. Postoperative MRI demonstrated decompressed bilateral optic nerves with an intact pituitary stalk with preservation of normal pituitary gland. Histopathology identified pathognomonic features consistent with diagnosis of Rathke's cleft cyst, including flattened ciliated epithelium and presence of Rathke's cleft remnants. Results Postoperatively, bilateral improvement in vision was noted with transient diabetes insipidus. Patient was discharged home on postoperative day 4. Conclusion A one-piece orbitozygomatic craniotomy is an effective and safe strategy for resection of Rathke's cleft cysts with suprasellar extension. The link to the video can be found at: https://youtu.be/-Yqtcd2gLSs . PMID- 29404256 TI - Modified One-Piece Extended Transbasal Approach for Endoscopic-Assisted Microsurgical Resection of Tuberculum Sellae Meningioma: Operative Video and Technical Nuances. AB - The optimal approach for surgical resection of tuberculum sellae meningiomas remains controversial. Approach selection is largely based on a variety of factors, such as tumor size, extent and location relative to the optic canal and internal carotid artery, the presence of vascular encasement, and surgeon's preference. In this operative video manuscript, the authors demonstrate the importance of an open transcranial approach when the tumor extends lateral to the optic nerve over the internal carotid artery into the opticocarotid triangle, which is a difficult region to safely access with a purely endoscopic endonasal approach. We present a case of an endoscopic-assisted microsurgical resection of a tuberculum sellae meningioma using a modified one-piece extended transbasal approach in a patient with unilateral visual loss. The approach allows both interhemispheric and subfrontal routes to the suprasellar region. Early optic nerve decompression and division of the falciform ligament is critical to optimize visual outcomes. This video atlas demonstrates the operative technique and surgical nuances of the skull base approach, optic nerve decompression, tumor arachnoid dissection, and safe handling of the neurovascular structures. A gross total resection was achieved and the patient had restoration of normal vision with normal pituitary function. In summary, the modified one-piece extended transbasal approach with endoscopic assistance is an important strategy in the armamentarium for surgical management of tuberculum sellae meningiomas. The link to the video can be found at: https://www.youtube.com/watch?v=jKNtRzMSFVE . PMID- 29404257 TI - Contralateral Eyebrow Approach for Unilateral Suprasellar Meningioma. AB - Unilateral suprasellar meningiomas have distinct features compared to other midline tumors, as they may produce severe visual symptoms even if small due to an early involvement of the optic canal. Surgical treatment of these tumors from an ipsilateral approach is challenging, as the tumor is covered by the optic nerve that needs to be mobilized to access the optic canal extension. A contralateral approach allows a direct line of sight to the tumor despite a longer working distance. We report the case of a 49-year-old patient presenting with unilateral visual loss related to a left suprasellar meningioma extending to the left optic canal and displacing the optic nerve laterally. Through a right eyebrow approach, a 2.5/2 cm supraorbital bone flap was raised and the orbital floor was thoroughly flattened. After dural opening, the carotid cistern was opened and CSF evacuated allowing a surgery without fixed retractors. The intracranial part of the tumor was removed, but the optic nerve seemed to be still displaced by the intracanalicular part. Under copious irrigation, the medial part of the optic canal was drilled, the dura incised, and the tumor removed. Postoperative course was favorable and the patient made a complete visual recovery. Postoperative MRI showed complete removal of the tumor. We present different surgical steps and discuss the nuances of the procedure. The contralateral eyebrow approach is an interesting addition to the surgical armamentarium and should be discussed for unilateral suprasellar tumors. The link to the video can be found at: https://youtu.be/2LTEOaGoKzo . PMID- 29404258 TI - Microsurgical Resection of Tuberculum Sellae Meningioma via Pterional Craniotomy with Extradural Anterior Clinoidectomy and Optic Unroofing. AB - Microsurgical treatment of suprasellar tumors, in particular tuberculum sellae meningiomas, poses significant challenge. These tumors are surrounded by vital neurovascular structures, such as optic apparatus, pituitary stalk, internal carotid artery and its branches, and anterior cerebral arteries. In large and complex cases, early identification and decompression of these structures may facilitate safer dissection and resection. Therefore, extradural anterior clinoidectomy with optic unroofing facilitates the internal carotid artery exposure and optic nerve decompression. In this video, we describe a 37-year-old female patient who presented with new onset of severe headaches. On visual examination, she was found to have bitemporal visual defects. MRI scan of the head showed a large, approximately 3 cm suprasellar tumor consistent with tuberculum sellae meningioma. She underwent surgical resection via pterional craniotomy with extradural anterior clinoidectomy and optic unroofing. Microsurgical gross total resection was achieved and histopathology was WHO grade II meningioma. She had an uneventful postoperative course and visual field examination improved significantly. In this video, surgical technique in performing extradural anterior clinoidectomy and optic unroofing and steps of microsurgical resection are demonstrated. The link to the video can be found at: https://youtu.be/oPZ8NTyvxJc . PMID- 29404259 TI - Tuberculum Meningioma: Orbitopterional Approach. AB - This is a case of an extensive tuberculum sella meningioma involving the circle of Willis down to the basilar artery that presented with bilateral visual loss worse on the right than left side. A one-piece right orbitopterional approach along the worse eye was used to gain access to the three cranial fossae. The orbitotomy facilitates access to the midline structures and contralateral base of the tumor with minimal brain retraction. Tumor resection is initiated by first identifying the tumor capsule, followed by piecemeal debulking via ultrasonic aspiration. Early decompression of the ipsilateral optic nerve was performed. Gross total resection of the tumor was achieved through multiple windows as follows: prechiasmatic, opticocarotid, and carotid oculomotor. Sharp dissection is performed around critical neurovascular structures to reduce strain and vascular injury. The circle of Willis including the small perforators was completely preserved. Postoperative examination at follow-up demonstrated improvement in vision less on the right side and resolution of postoperative partial third nerve palsy. The link to the video can be found at: https://youtu.be/XfEh8CjkvA0 . PMID- 29404260 TI - Microsurgical Resection of Lateral Tuberculum Sellae Meningioma: Operative Video. AB - Tuberculum Sellae Meningiomas (TSMs) are lesions dramatically related to the optic apparatus once the principal clinical complain remains on visual alterations. This is the main picture on decision making to evaluate the best time, risk-benefit, and surgical approaches to the patient treatment. In this video, we present a 65 years old female with 30 days complaint of unilateral (right) complete blindness and complete impaired right eye field test. On physical examination, there were normal pupillary function to light tests. The scans demonstrated the presence of a TSM mostly related to the right optic nerve and encasing it altogether with the right internal carotid artery. Promptly, surgery was addressed using a modified one piece cranio-orbital-zygomatic approach with extra-dural anterior clinoidectomy, as this is the procedure of choice of the senior author (LB), with easy access to decompression of the optic canal and nerve. As demonstrated on the video, the optic nerve was encased by the tumor and pushed upwards against the falciform ligament. Complete resection and decompression was established with step by step dissection, starting unroofing the optic canal, opening the ligament and finally with carefully tumor debulking. Pathology demonstrated a grade one meningioma. The patient improved remarkably her visual acuity and visual field tests on the postoperative period, emphasizing the importance of early treatment for nerve function outcome. The link to the video can be found at: https://youtu.be/pALZqDUkltQ . PMID- 29404261 TI - Microsurgical Resection of Tuberculum Sellae Meningioma through Left Cranio orbital Approach. AB - In this video clip, the authors present the resection of a tuberculum sellae meningioma with compression of the left optic nerve and a chiasm ( Fig. 1 ) through a standard cranial orbital (CO) skull base approach. 1 2 3 The key step in the tumor resection was microsurgical dissection of left and right A1 segments of the anterior cerebral artery and the anterior communicating artery and the separation of the tumor from these vascular structures. This was followed by careful separation of the meningioma from both optic nerves, the chiasm and the pituitary stalk. The final step was coagulation and resection of the tumor origin on the dura of the tuberculum sellae, devascularizing the tumor. Once this was achieved, the tumor was removed. Using this approach, an optimal surgical corridor to the sellar area was provided while minimizing the retraction of frontal and temporal lobes. The link to the video can be found at: https://youtu.be/O59Fj2dNXB0 . PMID- 29404262 TI - Tuberculum Sellae Meningioma Resection: Technical Nuances on the Frontopterional Approach. AB - Tuberculum sellae meningioma remains a surgical challenge. Deep location of tumor, vascular and nerve encasement, and pituitary stalk involvement are the main technical issues. The frontopterional approach represents a natural, simple, and elegant approach to this area enabling surgeon to have a direct control on all anatomical structures. A 42-year-old woman was referred with a delayed diagnosis of tuberculum sellae meningioma due to the presence of HLA-B27 associated uveitis. She presented with 1/10 visual acuity in the left eye and no right visual function. A left frontopterional craniotomy was performed. Visual function improved postoperatively. The video illustrates the cisternal anatomy via pterional approach. The link to the video can be found at: https://youtu.be/Hmbf5bt7A64 . PMID- 29404263 TI - Endoscope-Assisted Microsurgical Removal of an Optic Foramen Meningioma through a Frontolateral Minicraniotomy. AB - A 72-year-old male patient with visual disturbance of the right eye was diagnosed with a small meningioma of the right optic foramen extending to the carotid cistern. The operation was performed through an individually tailored frontolateral minicraniotomy via a curvilinear skin incision behind the hairline. Endoscope-assisted microsurgical technique was used to resect the lesion. The roof of the optic canal was partly removed to get access to the intraforaminal tumor parts. The lesion could be completely removed and the patient showed a satisfactory visual recovery in the follow-up examinations. The link to the video can be found at: https://youtu.be/p8EZx7aryeQ . PMID- 29404264 TI - Exercise as a Sex-Specific Treatment for Substance Use Disorder. AB - Purpose of Review: Exercise is a promising treatment for substance use disorder that may reduce withdrawal symptoms and prevent relapse. In this review, we discuss recent evidence from clinical and preclinical studies for its efficacy, from a behavioral to a molecular level, in order to understand the exercise conditions that lead to beneficial effects. We also highlight the few recent findings of sex-specific differences. Recent Findings: Clinical and preclinical findings show that exercise decreases withdrawal symptoms, including craving, in both males and females. Evidence from clinical studies support the efficacy of exercise to prevent relapse to smoking, although further research is needed to examine sex differences, establish long-term efficacy, and to determine if effects extend to other substance use disorders. Preclinical findings also support the potential utility of exercise to prevent relapse with evidence suggesting that its efficacy is enhanced in males, and mediated by blocking drug induced adaptations that occur during early abstinence. Summary: Sex differences and timing of exercise availability during abstinence should be considered in future studies examining exercise as an intervention for relapse. A better understanding of the neurobiological mechanisms underlying the efficacy of exercise to reduce withdrawal symptoms and prevent relapse is needed to guide its development as a sex-specific treatment. PMID- 29404266 TI - Necrotizing fungal gingivitis in a patient with Acute Myelogenous Leukemia: visible yet obscure. AB - Oral fungal infections present with atypical and varied manifestations, and distinguishing them from other entities including leukemic infiltration can be diagnostically challenging. In this report, we describe a 62 year old female with acute myeloid leukemia who presented, towards the end of her second treatment cycle of decitabine in a prolonged neutropenic state, with a month of painful, necrotic-appearing marginal gingival lesions. She was duly initiated on empiric broad spectrum antifungal treatment but did not show a clinical response with the appearance of new skin lesions concerning for progressive fungemia. Concurrent gingival and cutaneous biopsy showed fungal invasion with Fusarium. Despite changing antifungal treatment the lesions progressed, and white blood cell (WBC) transfusions were instituted. The patient had an impressive response with gradual resolution of the skin lesions and regression in gingival lesions over a week of therapy. This case illustrates the highly atypical, confounding appearance of oral fungal infections in immunocompromised hematological malignancy patients. Maxillary and mandibular marginal gingival involvement, although extremely rare, should be recognized as potential sites of fungal involvement. Accurate diagnosis entails a biopsy especially in ambiguous clinical scenarios, as presented here. The role of WBC transfusions in the management of these rare fungal pathogenic infections needs to re-established. PMID- 29404267 TI - The Islamic tradition and health inequities: A preliminary conceptual model based on a systematic literature review of Muslim health-care disparities. AB - Objective: The objective of this study was to identify mechanisms by which Islamic beliefs, values, and Muslim identity might contribute to health inequities among Muslim populations. Methods: A systematic literature review of empirical studies in Medline from 1980 to 2009 was conducted. The search strategy used three terms covering health-care disparities, ethnicity, and location to uncover relevant papers. Results: A total of 171 articles were relevant based on titles and abstracts. Upon subsequent full-text review, most studies did not include religious identity or religiosity as explanatory variables for observed health disparities. Of 29 studies mentioning Islam within the text, 19 implicated Muslim identity or practices as potential explanations for health differences between Muslim and non-Muslim groups. These 19 studies generated six mechanisms that related the Islamic tradition, Muslim practices, and health inequities: (1) Interpretations of health and/or lack of health based on Islamic theology; (2) Ethical and/or cultural challenges within the clinical realm stemming from Islamic values or practices; (3) Perceived discrimination due to, or a lack of cultural accommodation of, religious values or practices in the clinical realm; (4) Health practices rooted within the Islamic tradition; (5) Patterns of health care seeking based on Islamic values; and (6) Adverse health exposures due to having a Muslim identity. Conclusion: While there is scant empirical research on Muslim health-care disparities, a preliminary conceptual model relating Islam to health inequities can be built from the extant literature. This model can serve to organize research on Muslim health and distinguish different ways in which a Muslim identity might contribute to the patterning of health disparities. PMID- 29404268 TI - Pilot study: Comparing efficacy of 14-day triple therapy Clarithromycin versus levofloxacin on eradication of Helicobacter pylori infection in Syrian population single-center experience. AB - Context: Goals: To compare the efficacy of standard triple therapy with clarithromycin versus triple therapy with levofloxacin for treatment of Helicobacter pylori-positive infection in a referral hospital in Damascus, Syria. Design: pilot prospective open-label randomized controlled trial. Subjects and Methods: Eighty treatment-naive patients who tested positive for H. pylori gastric infection were randomly assigned to one of two treatment groups with randomization ratio of 50/50. Group (A) was treated with clarithromycin (500 mg), amoxicillin (1000 mg), and esomeprazole (20 mg), each twice/day for 14 days, while Group (B) was treated with levofloxacin (500 mg), amoxicillin (1000 mg), and esomeprazole (20 mg), each twice/day for 14 days.[1] After 6 weeks of treatment, all patients underwent endoscopy and biopsy to evaluate H. pylori infection eradication. Results: Forty patients were allocated in each group; 37 patients completed the follow-up in each group. Thirteen patients in Group (A) were cured, with an eradication rate of 35.1% according to per-protocol analysis (PPA) and 32.5% according to intention-to-treat analysis (ITT), while in Group (B), 11 patients were cured, with an eradication rate of 29.7% according to PPA and 27.5% according to ITT with P = 0.80. No serious adverse events reported in both the groups. Conclusions: Clarithromycin is slightly better than levofloxacin in treatment of H. pylori gastric infection, but both regimens show low effectiveness with suboptimal eradication rates in our selected population. PMID- 29404265 TI - Pancreatic cancer: Current status and Challenges. AB - Purpose of the review: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance. The purpose of this review is to summarize current understanding of etiological factors including emerging evidence on the role of infectious agents, factors associated with therapeutic resistance and therapeutic options. Recent findings: The unique aspect of PanCA is "desmoplasia", a process that involves proliferation of stromal fibroblasts and collagen deposition in and around the filtrating cancer. Recent studies have identified pancreatic stellate cells (PSCs) as a potential source of such desmoplasia. Biphasic interactions between PSCs and cancer cells, endothelial cells, and/or myeloid derived suppressor cells in the tumor microenvironment contribute to pancreatic carcinogenesis. Summary: We summarize limitations of current therapeutic approaches and potential strategies to overcome these limitations using natural products including botanicals as adjuvant/neo-adjuvant for effective management of PanCA. PMID- 29404269 TI - The prevalence of restless leg syndrome among pregnant Saudi women. AB - Objectives: Restless legs syndrome (RLS) is common among pregnant women, but it has not been documented in pregnant Saudi Arabian women. The main purpose of this study was to estimate the extent of the prevalence of RLS and identify both the associated factors and the associated risk factors among pregnant Saudi women. Methods: A cross-sectional study was conducted among pregnant women visiting obstetric clinics at King Abdulaziz Medical City in Riyadh (KAMC-Riyadh) over the period from June 1 to November 1, 2014. We interviewed the participants and collected demographic data, number of pregnancies, duration of pregnancy, comorbidities, and symptoms of RLS. The diagnosis of RLS is based on the four criteria designated by the International RLS Study Group. Results: The total number of participants enrolled was 517, and the mean age was 30.11 +/- 5.42 years. The prevalence of RLS was 21.3% (110/517) (95% confidence interval [CI]: 17.83%-25.06%). RLS symptoms were more common among women in the third trimester (24.1%) compared to the second trimester (14.3%) and first trimester (13.6%), P = 0.043. The stepwise multivariate logistic model identified insomnia (odds ratio [OR]: 3.6, 95% CI: 2.167-6.017, P = 0.001), and poor sleep quality (OR: 4.9, 95% CI: 1.473-16.454, P = 0.010) were associated with RLS. Conclusion: RLS occurs in two of ten pregnant women visiting obstetric clinics at KAMC-Riyadh and is strongly associated with insomnia and poor sleep quality. Studies are needed to explore the causality of these associations. PMID- 29404270 TI - Attitudes, barriers, and practices toward research and publication among medical students at the University of Damascus, Syria. AB - Introduction: Research is crucial for health-care delivery. However, medical students may not participate in research during their training, which might negatively affect their understanding of the importance of research and their future ability to conduct research projects. This is more prominent in developing countries. We aim to assess the attitudes of a sample of Syrian medical students toward research and suggest plausible solutions to reduce their self-reported barriers. Methods: A cross-sectional study was conducted using a self administered, pretested questionnaire. Results: Three hundred and twenty-three responses were included. Most students demonstrated positive attitudes toward research. However, most of the responses indicated that they did not receive any training in academic writing or research and therefore did not have the opportunity to participate in formal research projects or scholarly writing. Students reported various types of barriers that challenged their progress in the field of research. Students who reported being encouraged by their professors to participate in research and writing/publishing scientific papers or reported receiving training about these activities were more likely to participate in research projects or writing scientific articles. Conclusion: Students have positive attitudes toward research and publication while they reported poor education, limited participation, and presence of many barriers that impede their participation in such activities. PMID- 29404272 TI - Type I Kounis syndrome variant: A case report and literature review. AB - Kounis syndrome defined as the occurrence of acute coronary syndrome in the setting of allergic reaction due to mast cells activation and inflammatory mediators release that induces coronary vasospasm, plaque erosion, or even stent thrombosis. A 25-year-old postpartum female with asthma and recurrent episodes of chest pain was admitted with ST-segment elevation myocardial infarction in the setting of coronary artery spasms. The patient was started on calcium channel blockers and nitrite-based medication with no improvement. She was noted to have eosinophilia and initiation of corticosteroid-based regimen lead to resolution of chest pain episodes and normalization of eosinophilia. Kounis syndrome should be considered in young patients with chest pain. Coronary vasodilators are considered as the first-line of treatment. The use of corticosteroids has been described in the literature in severe or refractory cases. PMID- 29404271 TI - Nivolumab-induced new-onset seronegative rheumatoid arthritis in a patient with advanced metastatic melanoma: A case report and literature review. AB - Immune-related adverse events have been reported in patients treated with anti programmed death-1 receptor drugs such as nivolumab. We present a case of a new onset seronegative rheumatoid arthritis in a patient with metastatic melanoma treated with nivolumab. PMID- 29404273 TI - Heterogeneity of Phosphatidylinositol-3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin Activation in Cancer: Is PI3K Isoform Specificity Important? PMID- 29404274 TI - Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer via Regulation of the Extracelluar Matrix. AB - Human epididymis protein 4 (HE4) has received much attention recently due to its diagnostic and prognostic abilities for epithelial ovarian cancer. Since its inclusion in the Risk of Ovarian Malignancy Algorithm (ROMA), studies have focused on its functional effects in ovarian cancer. Here, we aimed to investigate the role of HE4 in invasion, haptotaxis, and adhesion of ovarian cancer cells. Furthermore, we sought to gain an understanding of relevant transcriptional profiles and protein kinase signaling pathways mediated by this multifunctional protein. Exposure of OVCAR8 ovarian cancer cells to recombinant HE4 (rHE4) promoted invasion, haptotaxis toward a fibronectin substrate, and adhesion onto fibronectin. Overexpression of HE4 or treatment with rHE4 led to upregulation of several transcripts coding for extracellular matrix proteins, including SERPINB2, GREM1, LAMC2, and LAMB3. Gene ontology indicated an enrichment of terms related to extracellular matrix, cell migration, adhesion, growth, and kinase phosphorylation. LAMC2 and LAMB3 protein levels were constitutively elevated in cells overexpressing HE4 and were upregulated in a time-dependent manner in cells exposed to rHE4 in the media. Deposition of laminin-332, the heterotrimer comprising LAMC2 and LAMB3 proteins, was increased in OVCAR8 cells treated with rHE4 or conditioned media from HE4-overexpressing cells. Enzymatic activity of matriptase, a serine protease that cleaves laminin 332 and contributes to its pro-migratory functional activity, was enhanced by rHE4 treatment in vitro. Proteomic analysis revealed activation of focal adhesion kinase signaling in OVCAR8 cells treated with conditioned media from HE4 overexpressing cells. Focal adhesions were increased in cells treated with rHE4 in the presence of fibronectin. These results indicate a direct role for HE4 in mediating malignant properties of ovarian cancer cells and validate the need for HE4-targeted therapies that will suppress activation of oncogenic transcriptional activation and signaling cascades. PMID- 29404276 TI - Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications. AB - A major challenge in clinical management of prostate cancer (PC) is to limit tumor growth and prevent metastatic spreading. Considerable efforts have been made to discover new compounds for PC therapy and recent years have seen promising progress in this field. Pharmacological approaches have been designed to achieve benefits in PC treatment and avoid the negative side effects resulting from administration of antagonists or agonists or new drugs. Nonetheless, the currently available therapies frequently induce resistance and PC progresses toward castration-resistant forms that can be caused by the androgen receptor reactivation and/or mutations, or derangement of signaling pathways. Preclinical and clinical findings have also shown that other nuclear receptors are frequently altered in PC. In this review, we focus on the role of estradiol/estradiol receptor (ER) axis, which controls PC growth and progression. Selective targeting of ER subtypes (alpha or beta) may be an attractive way to limit the growth and spreading of prostatic cancer cells. PMID- 29404277 TI - Biofilm Formation and Motility Are Promoted by Cj0588-Directed Methylation of rRNA in Campylobacter jejuni. AB - Numerous bacterial pathogens express an ortholog of the enzyme TlyA, which is an rRNA 2'-O-methyltransferase associated with resistance to cyclic peptide antibiotics such as capreomycin. Several other virulence traits have also been attributed to TlyA, and these appear to be unrelated to its methyltransferase activity. The bacterial pathogen Campylobacter jejuni possesses the TlyA homolog Cj0588, which has been shown to contribute to virulence. Here, we investigate the mechanism of Cj0588 action and demonstrate that it is a type I homolog of TlyA that 2'-O-methylates 23S rRNA nucleotide C1920. This same specific function is retained by Cj0588 both in vitro and also when expressed in Escherichia coli. Deletion of the cj0588 gene in C. jejuni or substitution with alanine of K80, D162, or K188 in the catalytic center of the enzyme cause complete loss of 2'-O methylation activity. Cofactor interactions remain unchanged and binding affinity to the ribosomal substrate is only slightly reduced, indicating that the inactivated proteins are folded correctly. The substitution mutations thus dissociate the 2'-O-methylation function of Cj0588/TlyA from any other putative roles that the protein might play. C. jejuni strains expressing catalytically inactive versions of Cj0588 have the same phenotype as cj0588-null mutants, and show altered tolerance to capreomycin due to perturbed ribosomal subunit association, reduced motility and impaired ability to form biofilms. These functions are reestablished when methyltransferase activity is restored and we conclude that the contribution of Cj0588 to virulence in C. jejuni is a consequence of the enzyme's ability to methylate its rRNA. PMID- 29404275 TI - Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein-Barr Virus (EBV). AB - Background: Although the risk factors for breast cancer are well established, namely female gender, early menarche and late menopause plus the protective influence of early pregnancy, the underlying causes of breast cancer remain unknown. The development of substantial recent evidence indicates that a handful of viruses may have a role in breast cancer. These viruses are mouse mammary tumor virus (MMTV), bovine leukemia virus (BLV), human papilloma viruses (HPVs), and Epstein-Barr virus (EBV-also known as human herpes virus type 4). Each of these viruses has documented oncogenic potential. The aim of this review is to inform the scientific and general community about this recent evidence. The evidence: MMTV and human breast cancer-the evidence is detailed and comprehensive but cannot be regarded as conclusive. BLV and human breast cancer-the evidence is limited. However, in view of the emerging information about BLV in human breast cancer, it is prudent to encourage the elimination of BLV in cattle, particularly in the dairy industry. HPVs and breast cancer-the evidence is substantial but not conclusive. The availability of effective preventive vaccines is a major advantage and their use should be encouraged. EBV and breast cancer-the evidence is also substantial but not conclusive. Currently, there are no practical means of either prevention or treatment. Although there is evidence of genetic predisposition, and cancer in general is a culmination of events, there is no evidence that inherited genetic traits are causal. Conclusion: The influence of oncogenic viruses is currently the major plausible hypothesis for a direct cause of human breast cancer. PMID- 29404278 TI - Iron Starvation Conditions Upregulate Ehrlichia ruminantium Type IV Secretion System, tr1 Transcription Factor and map1 Genes Family through the Master Regulatory Protein ErxR. AB - Ehrlichia ruminantium is an obligatory intracellular bacterium that causes heartwater, a fatal disease in ruminants. Due to its intracellular nature, E. ruminantium requires a set of specific virulence factors, such as the type IV secretion system (T4SS), and outer membrane proteins (Map proteins) in order to avoid and subvert the host's immune response. Several studies have been conducted to understand the regulation of the T4SS or outer membrane proteins, in Ehrlichia, but no integrated approach has been used to understand the regulation of Ehrlichia pathogenicity determinants in response to environmental cues. Iron is known to be a key nutrient for bacterial growth both in the environment and within hosts. In this study, we experimentally demonstrated the regulation of virB, map1, and tr1 genes by the newly identified master regulator ErxR (for Ehrlichia ruminantium expression regulator). We also analyzed the effect of iron depletion on the expression of erxR gene, tr1 transcription factor, T4SS and map1 genes clusters in E. ruminantium. We show that exposure of E. ruminantium to iron starvation induces erxR and subsequently tr1, virB, and map1 genes. Our results reveal tight co-regulation of T4SS and map1 genes via the ErxR regulatory protein at the transcriptional level, and, for the first time link map genes to the virulence function sensu stricto, thereby advancing our understanding of Ehrlichia's infection process. These results suggest that Ehrlichia is able to sense changes in iron concentrations in the environment and to regulate the expression of virulence factors accordingly. PMID- 29404279 TI - Dysbiosis of the Vaginal Microbiota and Higher Vaginal Kynurenine/Tryptophan Ratio Reveals an Association with Chlamydia trachomatis Genital Infections. AB - The natural course of Chlamydia trachomatis urogenital tract infections varies between individuals. While protective immunity can occur, some women can become reinfected, contributing to the development of severe pathology. While the reasons for these differences are unknown, an individual's response to induced interferon-gamma (IFN-gamma) is suggested to be critical. IFN-gamma induction of the enzyme indoleamine 2,3-dioxygenase, which depletes tryptophan, may be the key. One hypothesis suggests that indole-producing bacteria in the vaginal microbiota can provide a substrate for the Chlamydia to synthesize tryptophan, rescuing the Chlamydia from host IFN-gamma attack. We studied a cohort of 25 women who were either, Chlamydia negative, Chlamydia positive with a single infection, or Chlamydia positive with repeated infection, to test our hypothesis. We characterized their vaginal microbiota, cytokine response, as well as their tryptophan, kynurenine and indole concentrations directly in vaginal secretions. We found that C. trachomatis urogenital tract infections either initial or repeat infections, were associated with elevated vaginal kynurenine/tryptophan ratios, primarily as a result of elevated kynurenine levels. In addition, vaginal microbiota of community state type (CST) IV showed significantly lower vaginal tryptophan levels compared to CST I and III, which might be related to a higher abundance of indole producers found within this group. Furthermore, we found a higher abundance of indole producers in women who cleared their Chlamydia infection post antibiotic treatment. This study demonstrates for the first time in vivo, the association between high vaginal kynurenine/tryptophan ratios and C. trachomatis infections. In addition, tryptophan depletion was associated with vaginal microbiota of CST IV. PMID- 29404280 TI - Innate Immune Interactions between Bacillus anthracis and Host Neutrophils. AB - Bacillus anthracis, the causative agent of anthrax, has been a focus of study in host-pathogen dynamics since the nineteenth century. While the interaction between anthrax and host macrophages has been extensively modeled, comparatively little is known about the effect of anthrax on the immune function of neutrophils, a key frontline effector of innate immune defense. Here we showed that depletion of neutrophils significantly enhanced mortality in a systemic model of anthrax infection in mice. Ex vivo, we found that freshly isolated human neutrophils can rapidly kill anthrax, with specific inhibitor studies showing that phagocytosis and reactive oxygen species (ROS) generation contribute to this efficient bacterial clearance. Anthrax toxins, comprising lethal toxin (LT) and edema toxin (ET), are known to have major roles in B. anthracis macrophage resistance and systemic toxicity. Employing isogenic wild-type and mutant toxin deficient B. anthracis strains, we show that despite previous studies that reported inhibition of neutrophil function by purified LT or ET, endogenous production of these toxins by live vegetative B. anthracis failed to alter key neutrophil functions. The lack of alteration in neutrophil function is accompanied by rapid killing of B. anthracis by neutrophils, regardless of the bacteria's expression of anthrax toxins. Lastly, our study demonstrates for the first time that anthrax induced neutrophil extracellular trap (NET) formation. PMID- 29404281 TI - The Life Cycle of L. pneumophila: Cellular Differentiation Is Linked to Virulence and Metabolism. AB - Legionella pneumophila is a gram-negative bacterium that inhabits freshwater ecosystems, where it is present in biofilm or as planktonic form. L. pneumophila is mainly found associated with protozoa, which serve as protection from hostile environments and as replication niche. If inhaled within aerosols, L. pneumophila is also able to infect and replicate in human alveolar macrophages, eventually causing the Legionnaires' disease. The transition between intracellular and extracellular environments triggers a differentiation program in which metabolic as well as morphogenetic changes occur. We here describe the current knowledge on how the different developmental states of this bacterium are regulated, with a particular emphasis on the stringent response activated during the transition from the replicative phase to the infectious phase and the metabolic features going in hand. We propose that the cellular differentiation of this intracellular pathogen is closely associated to key metabolic changes in the bacterium and the host cell, which together have a crucial role in the regulation of L. pneumophila virulence. PMID- 29404283 TI - Genetic diversity analysis of cultivated Korarima [Aframomum corrorima (Braun) P.C.M. Jansen] populations from southwestern Ethiopia using inter simple sequence repeats (ISSR) marker. AB - Background: Korarima (Aframomum corrorima) is a perennial and aromatic herb native and widely distributed in southwestern Ethiopia. It is known for its fine flavor as a spice in various Ethiopian traditional dishes. Few molecular studies have been performed on this species so far. In the present paper, the ISSR technique was employed to study the genetic diversity in populations of cultivated A. corrorima. Results: Seven ISSR primers produced a total of 86 clearly scorable DNA bands. High levels of genetic diversity were detected in cultivated A. corrorima (percentage of polymorphic bands = 97.67%, gene diversity = 0.35, Shannon's information index = 0.52). Analysis of molecular variance (AMOVA) showed that 27.47% of the variation is attributed to the variation among populations and 72.53% to the variation within populations. The Fst (0.28) value showed a significant (p < 0.0001) genetic differentiation among populations. This was supported by the high coefficient of gene differentiation (Gst = 0.32) and low estimated gene flow (Nm = 1.08). A neighbor-joining dendrogram showed that the thirteen cultivated populations were separated into three clusters, which was in good accordance with the results provided by the two dimensional and three dimensional coordinate analyses. However, the clusters did not reveal clear pattern of populations clustering according to their geographic origin. This could be due to human mediated transfer of genetic material among different localities. Conclusion: The genetic diversity in populations of A. corrorima from the southwestern part of Ethiopia was relatively high. This finding should be taken into account when conservation actions, management policies for the species and site identification for in situ and ex situ conservation strategies are developed. Mizan Teferi II population displayed the highest genetic diversity; this population should be considered as the key site in designing conservation strategies for this crop. In addition, Jimma I and Jimma II populations with lowest genetic diversity, should also be considered due to the putative risk of extinction that they face because of the low genetic diversity. PMID- 29404284 TI - Pretreatment neutrophil-lymphocyte ratio: useful prognostic biomarker in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common liver malignancy and the third most common cause of cancer-related deaths. Liver resection (LR) and liver transplantation (LT) are the only curative modalities for HCC. Despite recent advances and the adoption of the Milan and University of California, San Francisco, criteria, HCC recurrence after LR and LT remains a challenge. Several markers and prognostic scores have been proposed to predict tumor aggressiveness and supplement radiological data; among them, neutrophil-lymphocyte ratio (NLR) has recently gained significant interest. An elevated NLR is thought to predispose to HCC recurrence by creating a protumorigenic microenvironment through both relative neutrophilia and lymphocytopenia. In the present review, we attempted to summarize the published work on the role of pretreatment NLR as a prognostic marker for HCC following LR and LT. A total of 13 LT and 18 LR studies were included from 2008 to 2015. Pretransplant NLR was most often predictive of HCC recurrence, recurrence-free survival, and overall survival. NLR was, however, more variably and less clearly associated with worse outcomes following LR. PMID- 29404285 TI - Role of percutaneous computed tomography-guided radiofrequency ablation in treatment of osteoid osteoma. AB - Aim: The aim of the study was to evaluate efficacy of percutaneous computed tomography (CT)-guided radiofrequency ablation (RFA) of nidus in osteoid osteoma (OO). Materials and Methods: RFA was performed on fifty patients with clinically and radiologically diagnosed OO. RFA was done in the department of radio diagnosis in our institute (a tertiary care providing institute in Ahmedabad, Western India). Ablation was performed by putting at an electrode tip (3-5 mm) into nidus under CT guidance with targeted temperature of 90 degrees C for 3 min. Results: All procedures were technically successful. No immediate major or minor complications were observed. Complete clinical success was achieved in 46 patients. Only four patients required second intervention. Conclusion: Our experience indicates a 98% success rate. No major complications were noted. PMID- 29404282 TI - Colonization, Infection, and the Accessory Genome of Klebsiella pneumoniae. AB - Klebsiella pneumoniae is a Gram-negative pathogen that has a large accessory genome of plasmids and chromosomal gene loci. This accessory genome divides K. pneumoniae strains into opportunistic, hypervirulent, and multidrug-resistant groups and separates K. pneumoniae from two closely related species, Klebsiella variicola and Klebsiella quasipneumoniae. Some strains of K. pneumoniae act as opportunistic pathogens, infecting critically ill and immunocompromised patients. These K. pneumoniae are a common cause of health-care associated infections including pneumonia, urinary tract infections (UTIs), and bloodstream infections. K. variicola and K. quasipneumoniae are often clinically indistinguishable from opportunistic K. pneumoniae. Other strains of K. pneumoniae are hypervirulent, infecting healthy people in community settings and causing severe infections including pyogenic liver abscess, endophthalmitis, and meningitis. A third group of K. pneumoniae encode carbapenemases, making them highly antibiotic-resistant. These strains act as opportunists but are exceedingly difficult to treat. All of these groups of K. pneumoniae and related species can colonize the gastrointestinal tract, and the accessory genome may determine if a colonizing strain remains asymptomatic or progresses to cause disease. This review will explore the associations between colonization and infection with opportunistic, antibiotic-resistant, and hypervirulent K. pneumoniae strains and the role of the accessory genome in distinguishing these groups and related species. As K. pneumoniae infections become progressively more difficult to treat in the face of antibiotic resistance and hypervirulent strains, an increased understanding of the epidemiology and pathogenesis of these bacteria is vital. PMID- 29404286 TI - Male breast cancer: A retrospective review of clinical profile from a tertiary cancer care center of India. AB - Aim: Present study was done with an aim to analyse the clinicopathological and survival characteristics of male breast cancer patients. Methods: We did a retrospective review of our database and analysed total 27 patients who presented to breast oncology unit of Rajiv Gandhi cancer centre and research institute from January 2010 to April 2016. Results: Most common stage at presentation in our study was in stage II. The median follow up was 32.75 months. The actuarial 5 year survival was 92.30% and DFS was 76.30%. Only hormone receptor status was found as a significant prognostic variable among the prognostic factors studied for disease free survival. Conclusions: Carcinoma breast in male is a relatively rare disease and management principles are translated from our understanding of breast cancer in women. A relatively early stage at presentation is a contrasting finding of our series which may be responsible for a significantly better actuarial 5 year survival rates. PMID- 29404287 TI - Osimertinib in Indian patients with T790M-positive advanced nonsmall cell lung cancer. PMID- 29404288 TI - Tolerance and adverse event profile with sorafenib in Indian patients with advanced hepatocellular carcinoma. AB - Background: The current standard of treatment for advanced hepatocellular cancer Hepatocellular carcinoma (HCC) is Sorafenib. Data regarding its tolerance and adverse event profile in Indian patients is scarce. Materials and Methods: The primary aim of this analysis was to assess the adverse events (Grade 3 and Grade 4 as per CTCAE v4.0) and requirements for dose reduction with sorafenib in advanced HCC. Details of consecutive patients started on 800 mg/day dosing were obtained from a prospectively maintained database (over a period of 6 months) and analyzed. Results: Thirty-nine patients were available for inclusion in the study. Median age was 58 years (range: 20-75). All patients were classified as Barcelona clinic liver cancer C. Common side effects seen were liver dysfunction (38.5%), hand-foot-syndrome-rash (HFSR) (Grade 2 and 3-25.6%), fatigue (Grade 2 and Grade 3-10.3%), and diarrhea (7.7%). Dose reduction was required in 43.6% of patients. Drug interruptions/cessation was required in 38.5% of patients within the first four months of treatment. Nearly 41% of patients required cessation of sorafenib due to intolerable side-effects while 28.2% stopped sorafenib due to progressive disease. At a median follow-up of 4.9 months, median event-free survival (EFS) was 4.20 months (95% confidence interval: 3.343-5.068). Conclusion: A higher incidence of liver dysfunction and HFSR is seen in Indian patients as compared to published data. A significant proportion of patients required cessation of sorafenib due to adverse events in our series. However, EFS remains on par with that seen in larger studies with sorafenib in advanced HCC. PMID- 29404289 TI - Metastatic anorectal melanomas - An exploratory retrospective analysis on the benefits of systemic therapy versus best supportive care in a resource-limited setting from India. AB - Aim: Data regarding the optimal management of metastatic anorectal melanoma (mARM) is scarce. The primary aim was to evaluate the potential benefits of systemic therapy in mARM. Materials and Methods: This is a retrospective analysis of all mARM who presented between July 2013 and June 2015 at the Department of GI Medical Oncology, Tata Memorial Hospital. Results: Of a total of 37 patients, twelve patients were planned for best supportive care (BSC) only while the remaining 25 patients received systemic therapy. The median overall survival (OS) for the whole cohort was 27 weeks. The OS was significantly better in patients who received first-line therapy as compared to those who were offered BSC (median OS: 14 vs. 33 weeks; P = 0.04). Patients with PS of 1 did significantly better than PS of 2 more (OS 70 vs. 17 weeks; P = 0.015). Conclusion: mARM should be offered chemotherapy, especially in good performance patients. Paclitaxel/Platinum or Capecitabine/Temozolomide regimens can be considered as the preferred regime in the resource-limited setting where immunotherapy may not be a feasible option. PMID- 29404290 TI - Musculoskeletal chronic graft versus host disease - A rare complication of allogeneic hematopoietic stem cell transplantation: A case report and review of its literature. PMID- 29404291 TI - Prognostic significance of bone only metastasis compared to visceral metastasis in patients with carcinoma cervix treated with platinum-based chemotherapy. AB - Context: Carcinoma cervix is a leading cause of cancer in Indian females where 15%-60% of the cases eventually metastasize. Bone only metastasis is rare, and data on its response and survival with systemic therapy as compared to other visceral metastasis are limited. Settings and Design: The study design was a retrospective analysis. Materials and Methods: We retrospectively analyzed our data between May 2013 and April 2015 to identify the cases of bone only metastasis and visceral metastasis and tried to analyze their outcomes with paclitaxel- and carboplatin-based chemotherapy and bisphosphonates (for bone metastasis only). Results: Totally, 12 cases with bone only metastasis (Group 1) and 43 cases with visceral metastasis (Group 2) were identified. Most common sites of bone metastasis were vertebrae (66.67%) and pelvis (25%) while that of visceral metastasis was liver (44.18%) and lung (34.88%). Only 33.33% and 34.88% of cases in Group 1 and Group 2, respectively, could complete all six cycles of chemotherapy. Overall, response rates were 41.67% and 30.32% in Group 1 and Group 2, respectively. Median progression-free survival and overall survival (OS) were 10 months and 14 months, respectively, in Group 1 as compared to 4 months and 9 months, respectively, in Group 2. The difference in survival was statistically significant. Statistical Analysis Used: It was carried out by SPSS software version 20. Conclusion: Bone only metastasis is a rare and distinct entity with favorable outcomes as compared to visceral metastasis. However, disease remains aggressive and poor OS emphasizing the need of further research. PMID- 29404292 TI - Retraction: Recurrent Glioblastoma: Where we stand. AB - [This retracts the article on p. 163 in vol. 4, PMID: 26981507.]. PMID- 29404294 TI - Short message service prompted mouth self-examination in oral cancer patients as an alternative to frequent hospital-based surveillance. AB - Introduction: Oral squamous cell carcinoma (OSCC) are amongst commonest cancer in the Indian sub-continent. After treatment, these patients require frequent followup to look for recurrences/second primary. Mouth Self Examination (MSE) has a great potential in all levels of prevention of oral cancer. However, the compliance to self-examination has been reported as poor. Mobile phone is a cheap and effective way to reach out to people. Short Message Service (SMS) is extremely popular can be a very effective motivational and interactive tool in health care setting. Methodology: We aimed to identify in adequately treated OSCC patients, the influence of health provider initiated SMS on the compliance to the MSE and to establish the efficacy of MSE by comparing patients' MSE interpretation via replies to the SMS with that of the experts' opinion on clinical examination status during follow up. Conclusion: We conclude that MSE can be very useful in adequately treated OSCC patients for evaluating disease status. All treated OSCC patients must be adequately educated for MSE as an integral part of treatment & follow-up protocol by the health provider facility. Health provider generated SMS reminders do improve motivation and compliance towards MSE but don't seem to reduce dropouts in follow up for large and diverse population like that in India. PMID- 29404293 TI - Oncology Gold Standard(r) practical consensus recommendations for the use of monoclonal antibodies in the management of squamous cell carcinoma of head and neck. AB - We present the 2017 Oncology Gold Standard Practical Consensus Recommendation for use of monoclonal antibodies in the management of advanced squamous cell carcinoma of head neck region. PMID- 29404296 TI - Regional reporting of the incidence of Anaplastic Lymphoma Kinase mutation in 379 non-small-cell lung cancer patients from Kolkata: Using immunohistochemistry as the diagnostic modality in a significant subset. AB - Context: Regional epidemiology of anaplastic lymphoma kinase (ALK) mutation in non-small-cell lung cancer (NSCLC) is an unmet need in India, and so is the knowledge of its incidence based on immunohistochemistry (IHC). Aims: Reporting the incidence of ALK mutation in NSCLC from Kolkata, incorporating IHC as the diagnostic modality in a considerable subset of patients. Subjects and Methods: It is a retrospective observational study done on NSCLC patients with adenocarcinoma histology, unselected by epidermal growth factor receptor, whose samples were tested for ALK mutation status between March 1, 2013, and March 15, 2017. The study involved all cancer facilities in Kolkata, except Tata Medical Centre. Up to June 2015, the tests were done by fluorescence in situ hybridization (FISH) and from July 2015 to the end, tests were done using IHC, as per the standard testing guidelines existing during the respective time periods. Results were documented in a de-identified manner to analyze the incidence of ALK mutations. Results: A total of 379 patients was tested for ALK mutations. March 2013 to June 2015, 200 (52.77%) patients were tested by FISH, 17 (8.5%) samples were unreportable and 4 patients [(2.19%) 4/183] tested positive for ALK mutations. From July 2015 to March 2017, 179 (47.22%) patients were tested by IHC, 9 (5.02%) samples were unreportable, and 10 patients [(5.88%) 10/170] tested positive for ALK mutations. Overall, 26 (6.8%) samples were unreportable and 14 [(3.9%) 14/353] patients tested positive for ALK mutations. Conclusions: The overall incidence of ALK mutation positive NSCLC in Kolkata is 3.9%. The incidence by IHC is 5.88% and by FISH is 2.19%, in the subset of patients tested by these two modalities respectively. PMID- 29404295 TI - Primary central nervous system lymphoma in immunocompetent patients: A regional cancer center experience. AB - Background: Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive extranodal non-Hodgkin's lymphoma which occurs in both immunocompromised and immunocompetent patients. It has an overall poor prognosis in spite of a multimodality treatment approach including chemotherapy and radiotherapy. This study attempts to further delineate the clinicopathological, immunohistochemical, and radiological profile of PCNSL at Kidwai Memorial Institute of Oncology, Karnataka, India. Materials and Methods: All the pathologically confirmed PCNSL cases between January 2010 and June 2016, at our center, were analyzed retrospectively. The influence of potential prognostic parameters on overall survival (OS) was investigated by log-rank test and Cox regression analysis. Results: Of the 26 PCNSL patients, 17 (65.3%) were males. Median age at diagnosis was 42.5 years. None of the patients had HIV or Epstein Barr virus positivity and only four patients (15.4%) had B-symptoms. The most common location in the brain was cerebral hemispheres in 15 patients (57%) and 10 patients (38.5%) had multiple intracranial lesions. Histologically, all were diffuse large B-cell lymphomas, except one case of anaplastic large cell lymphoma. Immunohistochemically, 18 patients (69%) had MUM 1 positivity and 20 cases (77%) belonged to nongerminal center subtype. DeAngelis protocol was followed in 24 patients (92%), and among this cohort, Memorial Sloan Kettering Cancer Center Class 1 (n = 17) and Class 2 (n = 7) patients had a median OS of 25 months and 11 months, respectively. Conclusion: None of the potential prognostic factors had a statistically significant influence on OS in our patients. High dose methotrexate combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify more effective primary chemotherapy regimens to further improve the treatment outcome. PMID- 29404297 TI - Cutaneous Hodgkin's lymphoma. PMID- 29404298 TI - Clinicopathological and molecular epidemiological study of lung cancer patients seen at a tertiary care hospital in Northern India. AB - Aims: The primary objective of this study was to estimate the clinicopathological and molecular profile of lung cancer patients along with the evaluation of their clinical characteristics at a tertiary care hospital in Northern India. Subjects and Methods: A total of 421 patients with lung cancer histology who were treated at Max Super Speciality Hospitals were included in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and permission was obtained from the Ethics Committee before the start of the study. Clinical characteristics and molecular profiling data were collected from the patient's medical records. Results: There were 330 (78.4%) men and 91 (21.6%) women with a median age of 62 years (range: 30-93 years). Of the 421 patients, 388 (92.2%) patients had the nonsmall cell lung cancer (NSCLC) histology whereas 33 (7.8%) patients were of SCLC histology. Histology and gender had a significant association with NSCLC and SCLC (P < 0.05). Epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene testing was done in 120 and 93 patients, respectively. Of the 120 patients, 24 (20%) cases were positive for EGFR mutations whereas EML4-ALK fusion gene was present in 8 (8.6%) out of 93 patients. Conclusions: Our study confirms the importance of molecular testing in the NSCLC patient subgroup with an aim to identify the exact molecular targets that can benefit from the newer generation of targeted therapies. PMID- 29404299 TI - Long-term follow-up of retinoblastoma survivors: Experience from India. AB - Background: Retinoblastoma (Rb) is the most common primary intraocular tumor of infancy and childhood. Survivors' ocular and visual problems and increased risk for subsequent malignancy are well documented, but data on long-term health status of Rb survivors are limited, this being particularly true for India. Methodology: Children who had completed treatment for Rb at least 2 years ago before and were under follow-up at the after cancer treatment clinic were evaluated. Results: In our series of 213 patients, the median age was 29 months, there was a male preponderance, and majority had unilateral disease. Enucleation was done in almost three-fourth and 3% underwent bilateral enucleation. Majority of the patients received chemotherapy, and few received radiation. Growth was affected in about one-third and majority were those who had received radiation. Diminished vision was noticed in about one-sixth. Orbital hypoplasia and contracted socket were seen in 14.1% cases. 2.7% were hearing impaired. About one sixth had a global intelligence delay. Second neoplasms were seen in 0.01%. No other abnormalities were seen. Conclusions: Common late effects in our Rb survivors include diminished vision in the salvage eye, intellectual disability, and contracted socket; there is a need for timely institution of prosthesis to avoid late effects such as hypoplasia, contracted sockets, and better cosmesis and enhanced self-esteem. Second neoplasm is a concern. Lifelong follow-up and counseling of a healthy lifestyle are needed for Rb survivors. PMID- 29404300 TI - Good response to erlotinib in a patient after progression on osimertinib: A rare case of spatiotemporal T790M heterogeneity in a patient with epidermal growth factor receptor-mutant nonsmall cell lung cancer. PMID- 29404301 TI - Adolescents and young adults: A study of distribution of cancer at ages 15-39 years in a tertiary care hospital from North India: Epidemiological considerations. AB - Purpose: This study aimed to analyze cancer pattern among adolescents and young adults (AYA) in a tertiary care center in North India. Materials and Methods: A retrospective study from January 2011 to December 2014 was undertaken on AYA cancer patients (aged 15-39 years). Results: Totally 1077 cases of AYA cancers were identified for analyzing the frequency and pattern of cancer distribution. The most common cancer was head and neck (32%) followed by breast (14.2%). The distribution pattern was observed to be varying in different age groups with lymphoma, leukemia, bone tumors, and sarcomas in adolescents while carcinomas being more frequent in young adults. Conclusion: Cancer distribution patterns are distinct among AYA in terms of epidemiology and biology. PMID- 29404302 TI - Epidemiology of cancer in young in central India: An analysis of rural cancer hospital data. AB - Background: Cancers in teenage and young adults (TYAs), though an increasing cause of mortality in our country, have been scarcely studied. The lack of studies of TYAs can significantly affect the outcomes of the youth in the prime of their lives. Aims: The aim of this study was to study the type of cancers in the TYA at a rural cancer center in central India. Design and Methods: A prospective study in the department of medical oncology, from the period of January 2013 till March 2016, was done. Data regarding socioepidemiological factors were collected for new cancer patients between the age group of 15-30 years in semi-structured questionnaire and from the hospital records. Cancers were classified according to the Birch classification. The cases were analyzed according to the epidemiological profile, classification of cancer, and age-wise distribution using descriptive analysis. Results: In this study, out of 5221 cancer patients, TYAs accounted for 327 (6.26%) with 189 males and 138 females (M: F- 1.37:1). The maximum cases were seen in 25-30 years' age group. Carcinoma was the most common malignancy (54.74%) with an increase from 19.56% in the 15-19 years' age group to 64.82% in the 25-30-year-old patients. Conclusion: The present study gives a glimpse of the TYA cancers in the central India. More than half of the young cancer patients suffer from carcinomas with about half of these being head and neck cancers. PMID- 29404303 TI - Myoepithelial carcinoma of the breast: Case report of a rare entity and its response to chemotherapy. PMID- 29404305 TI - Profile of patients undergoing palliative radiotherapy: A single-institute study from a tertiary care oncology center. AB - Background: Palliative radiotherapy (PRT) plays a significant role in the palliation of symptoms in patients with cancer and constitutes nearly 50% of the workload in different settings. Aims: The aim is to study patient-, disease-, and treatment-related characteristics in locoregionally advanced and metastatic malignancies meriting palliative management. Setting and Design: This was a retrospective observational study in a tertiary care government institute with academic and research potential. Methodology: The electronic medical records, medical documents, and radiotherapy (RT) treatment charts were retrieved and studied. Observations: A total of 460 patients were included in the study over 2 years, forming 30% of the total number of patients treated during the study period. Three hundred and ninety-six patients received PRT to the metastatic sites, while 64 patients received extremely hypofractionated PRT to the primary for symptomatic relief. Totally 442 patients showed good symptomatic response to PRT. One hundred and thirty-eight patients underwent re-irradiation. Lung was the most common primary site seen in 155 cases. The most common indication for PRT was palliation of pain from painful metastases as seen in 240 cases, and the next common indication was palliative whole-brain RT for brain metastases as seen in 159 cases. Conclusion: PRT forms an integral and important aspect of palliative care to the vast number of patients harboring metastatic disease that warrants some form of treatment for symptomatic relief. Short course of PRT in outdoor setting is a preferred mode of treatment to improve the quality of life of these distressed patients. PMID- 29404304 TI - EMERALD: Emergency visit audit of patients treated under medical oncology in a tertiary cancer center: Logical steps to decrease the burden. AB - Background: We are a tertiary care cancer center and have approximately 1000-1500 emergency visits by cancer patients undergoing treatment under the adult medical oncology unit each month. However, due to the lack of a systematic audit, we are unable to plan steps toward the improvement in quality of emergency services, and hence the audit was planned. Methods: All emergency visits under the adult medical oncology department in the month of July 2015 were audited. The cause of visit, the demographic details, cancer details, and chemotherapy status were obtained from the electronic medical records. The emergency visits were classified as avoidable or unavoidable. Descriptive statistics were performed. Reasons for avoidable emergency visits were sought. Results: Out of 1199 visits, 1168 visits were classifiable. Six hundred and ninety-six visits were classified as unavoidable (59.6%, 95% CI: 56.7-62.4), 386 visits were classified as probably avoidable visit (33.0%, 95% CI: 30.4-35.8) whereas the remaining 86 (7.4%, 95% CI: 6.0-9.01) were classified as absolutely avoidable. Two hundred and ninety seven visits happened on weekends (25.6%) and 138 visits converted into an inpatient admission (11.9%). The factors associated with avoidable visits were curative intention of treatment (odds ratio - 2.49), discontinued chemotherapy status (risk ratio [RR] - 8.28), and private category file status (RR - 1.89). Conclusion: A proportion of visits to emergency services can be curtailed. Approximately one-fourth of patients are seen on weekends, and only about one tenth of patients get admitted. PMID- 29404306 TI - Triple primary malignancies in head-and-neck region: A report of four cases. PMID- 29404307 TI - EGCG Maintains Th1/Th2 Balance and Mitigates Ulcerative Colitis Induced by Dextran Sulfate Sodium through TLR4/MyD88/NF-kappaB Signaling Pathway in Rats. AB - Objective: To observe the protective effect of epigallocatechin gallate (EGCG) on dextran sulfate sodium- (DSS-) induced ulcerative colitis in rats and to explore the roles of TLR4/MyD88/NF-kappaB signaling pathway. Methods: Rat models of ulcerative colitis were established by giving DSS. EGCG (50 mg/kg/d) was given to assess disease activity index. HE staining was applied to observe histological changes. ELISA and qPCR detected the expression of inflammatory factors. Flow cytometry was used to measure the percentage of CD4+IFN-gamma+ and CD4+IL-4+ in the spleen and colon. TLR4 antagonist E5564 was given in each group. Flow cytometry was utilized to detect CD4+IFN-gamma+ and CD4+IL-4+ cells. Immunohistochemistry, qPCR, and western blot assay were applied to measure the expression of TLR4, MyD88, and NF-kappaB. Results: EGCG improved the intestinal mucosal injury in rats, inhibited production of inflammatory factors, maintained the balance of Th1/Th2, and reduced the expression of TLR4, MyD88, and NF-kappaB. After TLR4 antagonism, the protective effect of EGCG on intestinal mucosal injury was weakened in rats with ulcerative colitis, and the expressions of inflammatory factors were upregulated. Conclusion: EGCG can inhibit the intestinal inflammatory response by reducing the severity of ulcerative colitis and maintaining the Th1/Th2 balance through the TLR4/MyD88/NF-kappaB signaling pathway. PMID- 29404308 TI - Current Status of Tissue Engineering in the Management of Severe Hypospadias. AB - Hypospadias, characterized by misplacement of the urinary meatus in the lower side of the penis, is a frequent birth defect in male children. Because of the huge variation in the anatomic presentation of hypospadias, no single urethroplasty procedure is suitable for all situations. Hence, many surgical techniques have emerged to address the shortage of tissues required to bridge the gap in the urethra particularly in the severe forms of hypospadias. However, the rate of postoperative complications of currently available surgical procedures reaches up to one-fourth of the patients having severe hypospadias. Moreover, these urethroplasty techniques are technically demanding and require considerable surgical experience. These limitations have fueled the development of novel tissue engineering techniques that aim to simplify the surgical procedures and to reduce the rate of complications. Several types of biomaterials have been considered for urethral repair, including synthetic and natural polymers, which in some cases have been seeded with cells prior to implantation. These methods have been tested in preclinical and clinical studies, with variable degrees of success. This review describes the different urethral tissue engineering methodologies, with focus on the approaches used for the treatment of hypospadias. At present, despite many significant advances, the search for a suitable tissue engineering approach for use in routine clinical applications continues. PMID- 29404310 TI - Is It Ethical to Test Apparently "Healthy" Children for Autosomal Dominant Polycystic Kidney Disease and Risk Medicalizing Thousands? PMID- 29404309 TI - Genetic Programming of Hypertension. AB - The heritability of hypertension (HTN) is widely recognized and as a result, extensive studies ranging from genetic linkage analyses to genome-wide association studies are actively ongoing to elucidate the etiology of both monogenic and polygenic forms of HTN. Due to the complex nature of essential HTN, however, single genes affecting blood pressure (BP) variability remain difficult to isolate and identify and have rendered the development of single-gene targeted therapies challenging. The roles of other causative factors in modulating BP, such as gene-environment interactions and epigenetic factors, are increasingly being brought to the forefront. In this review, we discuss the various monogenic HTN syndromes and corresponding pathophysiologic mechanisms, the different methodologies employed in genetic studies of essential HTN, the mechanisms for epigenetic modulation of essential HTN, pharmacogenomics and HTN, and finally, recent advances in genetic studies of essential HTN in the pediatric population. PMID- 29404311 TI - The Value of Fecal Markers in Predicting Relapse in Inflammatory Bowel Diseases. AB - The inflammatory bowel diseases (IBDs) are lifelong chronic illnesses that place an immense burden on patients. The primary aim of therapy is to reduce disease burden and prevent relapse. However, the occurrence of relapses is often unpredictable. Current disease monitoring is primarily by way of clinical indices, with relapses often only recognized once the inflammatory episode is established with subsequent symptoms and gut damage. The window between initial upregulation of the inflammatory response and the recognition of symptoms may provide an opportunity to prevent the relapse and associated morbidity. This review will describe the existing literature surrounding predictive indicators of relapse of IBD with a specific focus on fecal biomarkers. Fecal biomarkers offer promise as a convenient, non-invasive, low cost option for disease monitoring that is predictive of subsequent relapse. To exploit the potential of fecal biomarkers in this role, further research is now required. This research needs to assess multiple fecal markers in context with demographics, disease phenotype, genetics, and intestinal microbiome composition, to build disease behavior models that can provide the clinician with sufficient confidence to intervene and change the long-term disease course. PMID- 29404313 TI - C-Reactive Protein Correlates with Negative Symptoms in Patients with Schizophrenia. AB - Peripheral and CNS-localized inflammatory processes are hypothesized to contribute to the complex pathophysiology of schizophrenia. Elevated levels of the acute phase reactant C-reactive protein (CRP) have been observed in schizophrenia, yet relatively few studies have investigated the association between this inflammatory biomarker and psychotic symptoms in schizophrenia. This study is a pilot cross-sectional analysis investigating the relation of plasma CRP levels and the positive and negative symptoms of schizophrenia (the primary aim), assessed by the Positive and Negative Syndrome Scale (PANSS). A secondary analysis was also performed evaluating the potential association of CRP with cognitive function using the NIH Toolbox Cognitive Test Battery. After adjusting for age, sex, race, and body mass index, a positive correlation was observed between CRP and PANSS negative symptoms (rho = 0.37, p = 0.05). There was no correlation between plasma CRP and any of the NIH Toolbox measures of cognitive function in the unadjusted or adjusted analyses. Though limited by a relatively small sample size and the unavailability of longitudinal data, the correlation between CRP and psychopathology in this sample of patients supports a role for inflammation in the pathophysiology of schizophrenia. PMID- 29404312 TI - Advances in Diagnosis and Management of Hemodynamic Instability in Neonatal Shock. AB - Shock in newborn infants has unique etiopathologic origins that require careful assessment to direct specific interventions. Early diagnosis is key to successful management. Unlike adults and pediatric patients, shock in newborn infants is often recognized in the uncompensated phase by the presence of hypotension, which may be too late. The routine methods of evaluation used in the adult and pediatric population are often invasive and less feasible. We aim to discuss the pathophysiology in shock in newborn infants, including the transitional changes at birth and unique features that contribute to the challenges in early identification. Special emphasis has been placed on bedside focused echocardiography/focused cardiac ultrasound, which can be used as an additional tool for early, neonatologist driven, ongoing evaluation and management. An approach to goal oriented management of shock has been described and how bed side functional echocardiography can help in making a logical choice of intervention (fluid therapy, inotropic therapy or vasopressor therapy) in infants with shock. PMID- 29404314 TI - Ignoring Adjuvant Toxicity Falsifies the Safety Profile of Commercial Pesticides. AB - Commercial formulations of pesticides are invariably not single ingredients. Instead they are cocktails of chemicals, composed of a designated pesticidal "active principle" and "other ingredients," with the latter collectively also known as "adjuvants." These include surfactants, antifoaming agents, dyes, etc. Some adjuvants are added to influence the absorption and stability of the active principle and thus promote its pesticidal action. Currently, the health risk assessment of pesticides in the European Union and in the United States focuses almost exclusively on the stated active principle. Nonetheless, adjuvants can also be toxic in their own right with numerous negative health effects having been reported in humans and on the environment. Despite the known toxicity of adjuvants, they are regulated differently from active principles, with their toxic effects being generally ignored. Adjuvants are not subject to an acceptable daily intake, and they are not included in the health risk assessment of dietary exposures to pesticide residues. Here, we illustrate this gap in risk assessment by reference to glyphosate, the most used pesticide active ingredient. We also investigate the case of neonicotinoid insecticides, which are strongly suspected to be involved in bee and bumblebee colony collapse disorder. Authors of studies sometimes use the name of the active principle (for example glyphosate) when they are testing a commercial formulation containing multiple (active principle plus adjuvant) ingredients. This results in confusion in the scientific literature and within regulatory circles and leads to a misrepresentation of the safety profile of commercial pesticides. Urgent action is needed to lift the veil on the presence of adjuvants in food and human bodily fluids, as well as in the environment (such as in air, water, and soil) and to characterize their toxicological properties. This must be accompanied by regulatory precautionary measures to protect the environment and general human population from some toxic adjuvants that are currently missing from risk assessments. PMID- 29404315 TI - Editorial: Educating the Global Workforce for Public Health. PMID- 29404316 TI - Control of a Mycoplasma pneumoniae Outbreak in an Institutional Setting Using Azithromycin Prophylaxis. AB - Background: Mycoplasma pneumoniae is a major cause of respiratory infection of varying severity. Outbreaks of M. pneumoniae infection commonly occur in closed or semi-closed communities and settings. The control of such outbreaks is challenging, owing to delayed detection, long incubation period, and paucity of infection control guidelines. Methods: Between May and July 2015, a residential facility for adults with developmental disabilities in Southern Israel witnessed an outbreak of acute respiratory infection, subsequently diagnosed as associated with M. pneumoniae. All relevant data were collected as a part of a formal outbreak investigation. Strict infection control procedures were implemented, and azithromycin prophylaxis was provided to all residents. Results: Out of 215 residents, there were 29 suspected cases, 23 of which were confirmed as M. pneumoniae infection by serology or nucleic acid testing, for an attack rate of 11%. There were no cases of severe or fatal illness. An infection control strategy, including implementation of strict case isolation, enforcement of hygiene measures, a high index of suspicion for case detection, and use of azithromycin prophylaxis for all residents, led to rapid cessation of the outbreak. Discussion: The use of azithromycin prophylaxis may be worthwhile in closed institutional settings in which M. pneumoniae infections are documented. The dynamics of this outbreak suggest that if spread between wards is anticipated, expanding prophylaxis beyond immediate contacts of affected individuals should be considered. PMID- 29404317 TI - Hair As a Barrier to Physical Activity among African American Women: A Qualitative Exploration. AB - Background: African American (AA) women face unique sociocultural barriers to physical activity (PA) engagement. Such barriers may contribute to their low PA levels and high cardiometabolic disease burden. One particular barrier reported among AA women in recent research is that being physically active can have an undesirable effect on the hairstyles and hair maintenance of many AA women. However, the underlying mechanisms contributing to this barrier have not been fully elucidated. The purpose of this study is to explore hairstyle maintenance as a barrier to PA among AA women and to identify effective strategies to overcome this barrier in the design of a culturally relevant PA intervention. Methods: A qualitative study design was used. Data were collected from the focus groups comprising 23 sedentary and obese AA women (median age = 38.1 years, median body mass index = 39.8 kg/m2). Content analysis was used to analyze these focus group data. Results: Three key themes emerged from the qualitative narratives of participants: (1) impact of perspiration on hair and hairstyle maintenance, (2) image and social comparisons, and (3) solutions to overcome hair related barriers to PA. For impact of perspiration and hairstyle maintenance, participants described how perspiring while engaging in PA negatively impacts many of their hairstyles. Participants further discussed how time and monetary burdens associated with PA-related hairstyle maintenance further contributed to this issue. Findings for the theme of image and social comparison focused on how an AA woman's hairstyle is an important part of the image and the social comparisons made by non-AAs regarding the hairstyles and maintenance practices of AA women. For solutions to hairstyle maintenance barriers, participant described a variety of potential styling techniques that may help alleviate PA-related maintenance concerns, including braids, locks, and natural hairstyles. However, no styling technique was uniformly endorsed by all study participants. Conclusion: Findings highlight the significance of hair in the AA community and provide further insight on appropriate intervention design strategies to overcome this sociocultural barrier to PA. Future research is needed to corroborate and further expand on our findings. PMID- 29404318 TI - The Border Health Consortium of the Californias-Forming a Binational (California Baja California) Entity to Address the Health of a Border Region: A Case Study. AB - The California-Baja California border region is one of the most frequently traversed areas in the world with a shared population, environment, and health concerns. The Border Health Consortium of the Californias (the "Consortium") was formed in 2013 to bring together leadership working in the areas of public health, health care, academia, government, and the non-profit sector, with the goal of aligning efforts to improve health outcomes in the region. The Consortium utilizes a Collective Impact framework which supports a shared vision for a healthy border region, mutually reinforcing activities among member organizations and work groups, and a binational executive committee that ensures continuous communication and progress toward meeting its goals. The Consortium is comprised of four binational work groups which address human immunodeficiency virus, tuberculosis, obesity, and mental health, all mutual priorities in the border region. The Consortium holds two general binational meetings each year alternating between California and Baja California. The work groups meet regularly to share information, resources and provide binational training opportunities. Since inception, the Consortium has been successful in strengthening binational communication, coordination, and collaboration by providing an opportunity for individuals to meet one another, learn about each other systems, and foster meaningful relationships. With binational leadership support and commitment, the Consortium could certainly be replicated in other border jurisdictions both nationally and internationally. The present article describes the background, methodology, accomplishments, challenges, and lessons learned in forming the Consortium. PMID- 29404319 TI - Intervention among Suicidal Men: Future Directions for Telephone Crisis Support Research. AB - Telephone crisis support is a confidential, accessible, and immediate service that is uniquely set up to reduce male suicide deaths through crisis intervention. However, research focusing on telephone crisis support with suicidal men is currently limited. To highlight the need to address service delivery for men experiencing suicidal crisis, this perspective article identifies key challenges facing current telephone crisis support research and proposes that understanding of the role of telephone crisis helplines in supporting suicidal men may be strengthened by careful examination of the context of telephone crisis support, together with the impact this has on help-provision for male suicidal callers. In particular, the impact of the time- and information poor context of telephone crisis support on crisis-line staff's identification of, and response to, male callers with thoughts of suicide is examined. Future directions for research in the provision of telephone crisis support for suicidal men are discussed. PMID- 29404320 TI - An Online Respiratory Quotient-Feedback Strategy of Feeding Yeast Extract for Efficient Arachidonic Acid Production by Mortierella alpina. AB - Mortierella alpina (M. alpina) is well known for arachidonic acid (ARA) production. However, low efficiency and unstableness are long existed problems for industrial production of ARA by M. alpina due to the lack of online regulations. The aim of the present work is to develop an online-regulation strategy for efficient and stable ARA production in industry. The strategy was developed in 50 L fermenters and then applied in a 200 m3 fermenter. Results indicated that yeast extract (YE) highly increased cell growth in shake flask, it was then used in bioreactor fermentation by various feeding strategies. Feeding YE to control respiratory quotient (RQ) at 1.1 during 0-48 h and at 1.5 during 48 160 h, dry cell weight, and ARA titer reached 53.1 and 11.49 g/L in 50 L fermenter, which were increased by 79.4 and 36.9% as compared to that without YE feeding, respectively. Then, the online RQ-feedback strategy was applied in 200 m3 bioreactor fermentation and an average ARA titer of 16.82 g/L was obtained from 12 batches, which was 41.0% higher than the control batches. This is the first report on successful application of online RQ-feedback control of YE in ARA production, especially in an industrial scale of 200 m3 fermentation. It could be applied to other industrial production of microbial oil by oleaginous microorganisms. PMID- 29404321 TI - Logistic Regression of Ligands of Chemotaxis Receptors Offers Clues about Their Recognition by Bacteria. AB - Because of relative simplicity of signal transduction pathway, bacterial chemotaxis sensory systems have been expected to be applied to biosensor. Tar and Tsr receptors mediate chemotaxis of Escherichia coli and have been studied extensively as models of chemoreception by bacterial two-transmembrane receptors. Such studies are typically conducted using two canonical ligands: l-aspartate for Tar and l-serine for Tsr. However, Tar and Tsr also recognize various analogs of aspartate and serine; it remains unknown whether the mechanism by which the canonical ligands are recognized is also common to the analogs. Moreover, in terms of engineering, it is important to know a single species of receptor can recognize various ligands to utilize bacterial receptor as the sensor for wide range of substances. To answer these questions, we tried to extract the features that are common to the recognition of the different analogs by constructing classification models based on machine-learning. We computed 20 physicochemical parameters for each of 38 well-known attractants that act as chemoreception ligands, and 15 known non-attractants. The classification models were generated by utilizing one or more of the seven physicochemical properties as descriptors. From the classification models, we identified the most effective physicochemical parameter for classification: the minimum electron potential. This descriptor that occurred repeatedly in classification models with the highest accuracies, This descriptor used alone could accurately classify 42/53 of compounds. Among the 11 misclassified compounds, eight contained two carboxyl groups, which is analogous to the structure of characteristic of aspartate analog. When considered separately, 16 of the 17 aspartate analogs could be classified accurately based on the distance between their two carboxyl groups. As shown in these results, we succeed to predict the ligands for bacterial chemoreceptors using only a few descriptors; single descriptor for single receptor. This result might be due to the relatively simple topology of bacterial two-transmembrane receptors compared to the G-protein-coupled receptors of seven-transmembrane receptors. Moreover, this distance between carboxyl groups correlated with the receptor binding affinity of the aspartate analogs. In view of this correlation, we propose a common mechanism underlying ligand recognition by Tar of compounds with two carboxyl groups. PMID- 29404322 TI - Application of a omega-3 Desaturase with an Arachidonic Acid Preference to Eicosapentaenoic Acid Production in Mortierella alpina. AB - In the industrial oleaginous fungus Mortierella alpina, the arachidonic acid (AA; C20:4; omega-6) fraction can reach 50% of the total fatty acids (TFAs) in vivo. However, the eicosapentaenoic acid (EPA; C20:5; omega-3) fraction is less than 3% when this fungus is cultivated at a low temperature (12 degrees C). Omega-3 fatty acid desaturase is a key enzyme in omega-3 long-chain polyunsaturated fatty acids biosynthesis pathways. To enhance EPA production, we transformed the omega-3 fatty acid desaturase (PaD17), which exhibits strong Delta-17 desaturase activity, into M. alpina, thus increasing the AA to EPA conversion rate to 49.8%. This PaD17-harboring M. alpina reconstruction strain produced 617 mg L-1 of EPA at room temperature in broth medium, this yield was increased to 1.73 g L-1 after culture medium optimization (i.e., about threefold higher than that under original culture conditions), with concomitant respective increases in dry cell weight and TFA content to 16.55 and 6.46 g L-1. These findings suggest a new platform for the future industrial production of EPA. PMID- 29404324 TI - Localization of Engineered Vasculature within 3D Tissue Constructs. AB - Today, in vitro vessel network systems frequently serve as models for investigating cellular and functional mechanisms underlying angiogenesis and vasculogenesis. Understanding the cues triggering the observed cell migration, organization, and differentiation, as well as the time frame of these processes, can improve the design of engineered microvasculature. Here, we present first evidence of the migration of endothelial cells into the depths of the scaffold, where they formed blood vessels surrounded by extracellular matrix and supporting cells. The supporting cells presented localization-dependent phenotypes, where cells adjacent to blood vessels displayed a more mature phenotype, with smooth muscle cell characteristics, whereas cells on the scaffold surface showed a pericyte-like phenotype. Yes-associated protein (YAP), a transcription activator of genes involved in cell proliferation and tissue growth, displayed spatially dependent expression, with cells on the surface showing more nuclear YAP than cells situated deeper within the scaffold. PMID- 29404323 TI - MicroRNA-146a Regulates Perfusion Recovery in Response to Arterial Occlusion via Arteriogenesis. AB - The growth of endogenous collateral arteries that bypass arterial occlusion(s), or arteriogenesis, is a fundamental shear stress-induced adaptation with implications for treating peripheral arterial disease. MicroRNAs (miRs) are key regulators of gene expression in response to injury and have strong therapeutic potential. In a previous study, we identified miR-146a as a candidate regulator of vascular remodeling. Here, we tested whether miR-146a regulates in vitro angiogenic endothelial cell (EC) behaviors, as well as perfusion recovery, arteriogenesis, and angiogenesis in response to femoral arterial ligation (FAL) in vivo. We found miR-146a inhibition impaired EC tube formation and migration in vitro. Following FAL, Balb/c mice were treated with a single, intramuscular injection of anti-miR-146a or scramble locked nucleic acid (LNA) oligonucleotides directly into the non-ischemic gracilis muscles. Serial laser Doppler imaging demonstrated that anti-miR-146a treated mice exhibited significantly greater perfusion recovery (a 16% increase) compared mice treated with scramble LNA. Moreover, anti-miR-146a treated mice exhibited a 22% increase in collateral artery diameter compared to controls, while there was no significant effect on in vivo angiogenesis or muscle regeneration. Despite exerting no beneficial effects on angiogenesis, the inhibition of mechanosensitive miR-146a enhances perfusion recovery after FAL via enhanced arteriogenesis. PMID- 29404326 TI - Interaction between Mitochondrial Reactive Oxygen Species, Heme Oxygenase, and Nitric Oxide Synthase Stimulates Phagocytosis in Macrophages. AB - Background: Macrophages are cells of the innate immune system that populate every organ. They are required not only for defense against invading pathogens and tissue repair but also for maintenance of tissue homeostasis and iron homeostasis. Aim: The aim of this study is to understand whether heme oxygenase (HO) and nitric oxide synthase (NOS) contribute to the regulation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and phagocytosis, two key components of macrophage function. Methods: This study was carried out using resting J774A.1 macrophages treated with hemin or vehicle. Activity of NOS, HO, or NOX was inhibited using specific inhibitors. Reactive oxygen species (ROS) formation was determined by Amplex(r) red assay, and phagocytosis was measured using fluorescein isothiocyanate-labeled bacteria. In addition, we analyzed the fate of the intracellular heme by using electron spin resonance. Results: We show that both enzymes NOS and HO are essential for phagocytic activity of macrophages. NOS does not directly affect phagocytosis, but stimulates NOX activity via nitric oxide-triggered ROS production of mitochondria. Treatment of macrophages with hemin results in intracellular accumulation of ferrous heme and an inhibition of phagocytosis. In contrast to NOS, HO products, including carbon monoxide, neither clearly affect NOX activity nor clearly affect phagocytosis, but phagocytosis is accelerated by HO-mediated degradation of heme. Conclusion: Both enzymes contribute to the bactericidal activity of macrophages independently, by controlling different pathways. PMID- 29404325 TI - Metabolic Disorders in Chronic Lung Diseases. AB - Chronic lung diseases represent complex diseases with gradually increasing incidence, characterized by significant medical and financial burden for both patients and relatives. Their increasing incidence and complexity render a comprehensive, multidisciplinary, and personalized approach critically important. This approach includes the assessment of comorbid conditions including metabolic dysfunctions. Several lines of evidence show that metabolic comorbidities, including diabetes mellitus, dyslipidemia, osteoporosis, vitamin D deficiency, and thyroid dysfunction have a significant impact on symptoms, quality of life, management, economic burden, and disease mortality. Most recently, novel pathogenetic pathways and potential therapeutic targets have been identified through large-scale studies of metabolites, called metabolomics. This review article aims to summarize the current state of knowledge on the prevalence of metabolic comorbidities in chronic lung diseases, highlight their impact on disease clinical course, delineate mechanistic links, and report future perspectives on the role of metabolites as disease modifiers and therapeutic targets. PMID- 29404327 TI - Fluid Redistribution in Sleep Apnea: Therapeutic Implications in Edematous States. AB - Sleep apnea (SA), a condition associated with increased cardiovascular risk, has been traditionally associated with obesity and aging. However, in patients with fluid-retaining states, such as congestive heart failure and end-stage renal disease, both prevalence and severity of SA are increased. Recently, fluid shift has been recognized to play an important role in the pathophysiology of SA, since the fluid retained in the legs during the day shifts rostrally while recumbent, leading to edema of upper airways. Such simple physics, observed even in healthy individuals, has great impact in patients with fluid overload. Correction of the excess fluid volume has risen as a potential target therapy to improve SA, by attenuation of nocturnal fluid shift. Such strategy has gained special attention, since the standard treatment for SA, the positive airway pressure, has low compliance rates among its users and has failed to reduce cardiovascular outcomes. This review focuses on the pathophysiology of edema and fluid shift, and summarizes the most relevant findings of studies that investigated the impact of treating volume overload on SA. We aim to expand horizons in the treatment of SA by calling attention to a potentially reversible condition, which is commonly underestimated in clinical practice. PMID- 29404328 TI - Hypoxia Induced Factor in Chronic Kidney Disease: Friend or Foe? AB - Many studies have shown evidence that erythropoiesis-stimulating agents (ESAs), as a classic treatment for chronic kidney disease (CKD)-related anemia, have several disadvantages and may trigger various adverse events with long-term use. The hypoxia-induced factor (HIF) pathway has been intensively investigated in kidney disease, especially in CKD, as research has shown that HIF-mediated erythropoiesis might work as a potential therapeutic strategy for managing CKD related anemia. Development of prolyl hydroxylase domain inhibitors (PHIs), as an effective HIF activator, is a valuable step toward finding a replacement for ESAs, which showed an effective erythropoiesis through a comprehensive and physiological approach by promoting erythropoietin production, increasing iron bioavailability and improving chronic inflammatory status. Heretofore no adverse events or obvious off-target effects have been reported in clinical trials of PHIs. Nevertheless, a cautious inspection with extended follow-up period is warranted to validate the safety of prolonged HIF elevation, especially considering its ambiguous role in fibrogenesis and inflammation responses and possible risks in accelerating vascular calcification and tumorigenesis. A weighed dosing strategy might be the key to circumvent the unexpected side-effect brought by pleotropic effects of HIF elevation and achieve a selective augmentation of HIF-mediated signaling pathway. New studies with longer follow-up period and adequate analysis about the risks for proinflammation, vascular calcification and tumorigenesis are needed to ensure the drugs are safe for long term use before being widely accepted in daily clinical practice. PMID- 29404329 TI - Enhanced Recovery after Vascular Surgery. AB - The beginnings of the enhanced recovery after surgery (ERAS) program were first developed for patients in colorectal surgery, and after it was established as the standard of care in this surgical field, it began to be applied in many others surgical areas. This is multimodal, evidence-based approach program and includes simultaneous optimization of preoperative status of patients, adequate selection of surgical procedure and postoperative management. The aim of this program is to reduce complications, the length of hospital stay and to improve the patients outcome. Over the past decades, special attention was directed to the postoperative management in vascular surgery, especially after major vascular surgery because of the great risk of multiorgan failure, such as: respiratory failure, myocardial infarction, hemodynamic instability, coagulopathy, renal failure, neurological disorders, and intra-abdominal complications. Although a lot of effort was put into it, there is no unique acceptable program for ERAS in this surgical field, and there is still a need to point out the factors responsible for postoperative outcomes of these patients. So far, it is known that special attention should be paid to already existing diseases, type and the duration of the surgical intervention, hemodynamic and fluid management, nutrition, pain management, and early mobilization of patients. PMID- 29404330 TI - Analysis of Dietary Intake during Consecutive-Day Chemotherapy for Bone and Soft Tissue Sarcomas. AB - Background: Bone and soft tissue sarcomas are commonly treated with consecutive day chemotherapy regimens consisting of multiple anticancer agents. Chemotherapy induced nausea and vomiting (CINV) is a serious adverse effect of these regimens and may result in decreased energy intake during chemotherapy. Decreased energy intake may lead to undernutrition and may cause adverse effects on patient quality of life and survival. Methods: Patients with bone and soft tissue sarcomas who received consecutive-day chemotherapy were retrospectively evaluated. CINV and dietary energy intake were assessed, as well as the occurrences of hiccups and constipation during chemotherapy. Results: A total of 13 patients, 10 males and 3 females, with a total 16 chemotherapy courses were included in the study. All patients received antiemetic prophylaxis. The CINV control rate, defined as no emesis and no rescue therapy, gradually decreased from chemotherapy day 1 (94%) to day 5 (75%). Four patients experienced emesis, two of whom had been treated with a cisplatin-containing regimen. Decreased dietary energy intake was possibly associated with CINV during chemotherapy. Anorexia was grade 2 except for one case of grade 3. The incidences of hiccups and constipation were high on days 3-5. Conclusion: Antiemetic prophylaxis treatment did not prevent emesis due to consecutive-day chemotherapy, especially with cisplatin-containing regimens, in patients with bone and soft-tissue tumors. Dietary energy intake decreased during chemotherapy, and this appeared to be associated with CINV. In addition, the incidence of hiccups and constipation increased during the course of consecutive-day chemotherapy regimens. Although these results are based on a small number of patients, it may be important to observe nutritional status during chemotherapy, as this may reflect a patient's general condition. Nutritional counseling might be useful in supporting nutritional status in patients undergoing chemotherapy. PMID- 29404331 TI - Navy Bean and Rice Bran Intake Alters the Plasma Metabolome of Children at Risk for Cardiovascular Disease. AB - : Abnormal cholesterol in childhood predicts cardiovascular disease (CVD) risk in adulthood. Navy beans and rice bran have demonstrated efficacy in regulating blood lipids in adults and children; however, their effects on modulating the child plasma metabolome has not been investigated and warrants investigation. A pilot, randomized-controlled, clinical trial was conducted in 38 children (10 +/- 0.8 years old) with abnormal cholesterol. Participants consumed a snack for 4 weeks containing either: no navy bean or rice bran (control); 17.5 g/day cooked navy bean powder; 15 g/day heat-stabilized rice bran; or 9 g/day navy beans and 8 g/day rice bran. Plasma metabolites were extracted using 80% methanol for global, non-targeted metabolic profiling via ultra-high performance liquid-chromatography tandem mass spectrometry. Differences in plasma metabolite levels after 4 weeks of dietary intervention compared to control and baseline were analyzed using analysis of variance and Welch's t-tests (p <= 0.05). Navy bean and/or rice bran consumption influenced 71 plasma compounds compared to control (p <= 0.05), with lipids representing 46% of the total plasma metabolome. Significant changes were determined for 18 plasma lipids in the navy bean group and 10 plasma lipids for the rice bran group compared to control, and 48 lipids in the navy bean group and 40 in the rice bran group compared to baseline. These results support the hypothesis that consumption of these foods impact blood lipid metabolism with implications for reducing CVD risk in children. Complementary and distinct lipid pathways were affected by the diet groups, including acylcarnitines and lysolipids (navy bean), sphingolipids (rice bran), and phospholipids (navy bean + rice bran). Navy bean consumption decreased free fatty acids associated with metabolic diseases (palmitate and arachidonate) and increased the relative abundance of endogenous anti-inflammatory lipids (endocannabinoids, N linoleoylglycine, 12,13-diHOME). Several diet-derived amino acids, phytochemicals, and cofactors/vitamins with cardioprotective properties were increased compared to control and/or baseline, including 6-oxopiperidine-2 carboxylate (1.87-fold), N-methylpipecolate (1.89-fold), trigonelline (4.44- to 7.75-fold), S-methylcysteine (2.12-fold) (navy bean), salicylate (2.74-fold), and pyridoxal (3.35- to 3.96-fold) (rice bran). Findings from this pilot study support the need for investigating the effects of these foods for longer durations to reduce CVD risk. TRIAL REGISTRATION: clinicaltrials.gov (identifier NCT01911390). PMID- 29404332 TI - Household Food Insecurity along an Agro-Ecological Gradient Influences Children's Nutritional Status in South Africa. AB - The burden of food insecurity and malnutrition is a severe problem experienced by many poor households and children under the age of five are at high risk. The objective of the study was to examine household food insecurity, dietary diversity, and child nutritional status in relation to local context which influences access to and ability to grow food in South Africa and explore the links and associations between these and household socio-economic status. Using a 48-h dietary recall method, we interviewed 554 women from randomly selected households along a rural-urban continuum in three towns situated along an agro ecological gradient. The Household Dietary Diversity Scores (HDDS) and the Household Food Insecurity Access Scale (HFIAS) tools were used to measure household dietary diversity and food insecurity, respectively. Anthropometric measurements with 216 children (2-5 years) from the sampled households were conducted using height-for-age and mid-upper arm circumference (MUAC) as indicators of stunting and wasting, respectively. The key findings were that mean HDDS declined with decreasing agro-ecological potential from the wettest site (8.44 +/- 1.72) to the other two drier sites (7.83 +/- 1.59 and 7.76 +/- 1.63). The mean HFIAS followed the opposite trend. Stunted growth was the dominant form of malnutrition detected in 35% of children and 18% of children were wasted. Child wasting was greatest at the site with lowest agro-ecological potential. Children from households with low HDDS had large MUAC which showed an inverse association among HDDS and obesity. Areas with agro-ecological potential had lower prevalence of food insecurity and wasting in children. Agro-ecological potential has significant influence on children's nutritional status, which is also related to household food security and socio-economic status. Dependence on food purchasing and any limitations in households' income, access to land and food, can result in different forms of malnutrition in children. Responses to address malnutrition in South Africa need to be prioritized and move beyond relying on food security and nutritional-specific interventions, but rather on nutrition-specific and sensitive programs and approaches; and building an enabling environment. Land availability, agriculture (including climate-smart agriculture especially in drier areas), and wild foods usage should be promoted. PMID- 29404333 TI - Food for an Urban Planet: Challenges and Research Opportunities. PMID- 29404334 TI - Astaxanthin in Exercise Metabolism, Performance and Recovery: A Review. AB - During periods of heavy exercise training and competition, lipid, protein, and nucleic molecules can become damaged due to an overproduction of reactive oxygen and nitrogen species (RONS) within the exercising organism. As antioxidants can prevent and delay cellular oxidative damage through removing, deactivating, and preventing the formation of RONS, supplementation with exogenous antioxidant compounds has become a commercialized nutritional strategy commonly adopted by recreationally active individuals and athletes. The following review is written as a critical appraisal of the current literature surrounding astaxanthin and its potential application as a dietary supplement in exercising humans. Astaxanthin is a lipid-soluble antioxidant carotenoid available to supplement through the intake of Haematococcus pluvialis-derived antioxidant products. Based upon in vitro and in vivo research conducted in mice exercise models, evidence would suggest that astaxanthin supplementation could potentially improve indices of exercise metabolism, performance, and recovery because of its potent antioxidant capacity. In exercising humans, however, these observations have yet to be consistently realized, with equivocal data reported. Implicated, in part, by the scarcity of well-controlled, scientifically rigorous research, future investigation is necessary to enable a more robust conclusion in regard to the efficacy of astaxanthin supplementation and its potential role in substrate utilization, endurance performance, and acute recovery in exercising humans. PMID- 29404335 TI - Characterization of Cancer Stem Cells in Colon Adenocarcinoma Metastasis to the Liver. AB - Background: Fifty percent of colorectal cancer (CRC) patients develop liver metastasis. This study identified and characterized cancer stem cells (CSCs) within colon adenocarcinoma metastasis to the liver (CAML). Methods: 3,3 Diaminobenzidine immunohistochemical (IHC) staining was performed on nine CAML samples for embryonic stem cell (ESC) markers OCT4, SOX2, NANOG, c-Myc, and KLF4. Immunofluorescence (IF) IHC staining was performed to investigate coexpression of two markers. NanoString mRNA expression analysis and colorimetric in situ hybridization (CISH) were performed on four snap-frozen CAML tissue samples for transcript expression of these ESC markers. Cells stained positively and negatively for each marker by IHC and CISH staining were counted and analyzed. Results: 3,3-Diaminobenzidine IHC staining, and NanoString and CISH mRNA analyses demonstrated the expression of OCT4, SOX2, NANOG, c-Myc, and KLF4 within in all nine CAML samples, except for SOX2 which was below detectable levels on NanoString mRNA analysis. IF IHC staining showed the presence of a SOX2+/NANOG+/KLF4+/c-Myc+/OCT- CSC subpopulation within the tumor nests, and a SOX2+/NANOG+/KLF4+/c-Myc+/OCT4- CSC subpopulation and a SOX2+/NANOG+/KLF4+/c Myc+/OCT4+ CSC subpopulation within the peritumoral stroma. Conclusion: The novel finding of three CSC subpopulations within CAML provides insights into the biology of CRC. PMID- 29404336 TI - Assessing the GRIP of Ventral Hernia Repair: How to Securely Fasten DIS Classified Meshes. AB - Recurrences are frequently observed after ventral hernia repair. Based on clinical data, the mesh-defect area ratio (MDAR) can lead to lower recurrence rates. Using dynamic intermittent strain (DIS) in a pig tissue model, MDAR can be modified to give a measure called grip to better assess the mechanical stability of ventral hernia repair. The focus of this experimental study is to assess the different aspects of mesh overlap (OL) and fixation only in bridging repair of ventral hernias. DIS mimics coughing actions in an ex vivo model with the repetition of submaximal impacts delivered via a hydraulically driven plastic containment. Tissue derived from pig bellies simulates a ventral hernia with varying defect sizes. MDAR is calculated from the hernia orifice and the mesh OL. Commercially available meshes were strengthened with glue, tacks, and sutures to bridge the defects. The reconstructions are strained with up to 425 dynamic impacts. The grip of each repair is assessed using MDAR modified by the strength of the fixation. The DIS classification is based on bridging of a 5 cm ventral hernia orifice with an OL of 5 cm in a sublay position. The classification discriminates meshes properties upon DIS strain. MDAR is calculated to be 9 under these conditions. Decreasing the OL or increasing the hernia orifice reduces MDAR to numbers below 9. MDAR is modified to reach GRIP. Closure of the peritoneum adds about 4 to the grip given by MDAR. The multiplying factor of a transmural suture or one tack of Securestrap(r) or Protack(r) is 0.5 times the number of tacks applied. The multiplier given by a bonding spot of Glubran(r) is similar to that of an Absorbatack(r) being 0.33. Plotting the likelihood of a bridging repair to survive more than 400 DIS impacts versus the grip estimated from the factors given above, the grip to be passed for a durable repair is 10 for Parietex Progrip(r), and Dynamesh Cicat(r) and 25 for Dynamesh IPOM(r). Clinical data previously published can be reculculated to assess MDAR and permit an estimation of the grip of the reconstruction. In these recalculations, a correlation between MDAR and long-term recurrence rates is found. A dimensionless number called grip can be calculated. The grip can be modified by fixation in a reproducible way. A higher grip can improve the durability of ventral hernia repair. We believe that a higher grip leads to lower recurrence rates in the clinical setting. PMID- 29404337 TI - Preoperative Radiotherapy and Wide Resection for Soft Tissue Sarcomas: Achieving a Low Rate of Major Wound Complications with the Use of Flaps. Results of a Single Surgical Team. AB - Background: Surgery in combination with radiotherapy (RT) has become the standard of care for most soft tissue sarcomas. The choice between pre- and postoperative RT is controversial. Preoperative RT is associated with a 32-35% rate of major wound complications (MWC) and 16-25% rate of reoperation. The role of vascularized soft tissue "flaps" in reducing complications is unclear. We report the outcomes of patients treated with preoperative RT, resection, and flap reconstruction. Patients and methods: 122 treatment episodes involving 117 patients were retrospectively reviewed. All patients were treated with 50.4 Gy of external beam radiation. Surgery was performed at 4-8 weeks after completion of RT by the same combination of orthopedic oncology and plastic reconstructive surgeon. Defects were reconstructed with 64 free and 59 pedicled/local flaps. Results: 30 (25%) patients experienced a MWC and 17 (14%) required further surgery. 20% of complications were exclusively related to the donor site. There was complete or partial loss of three flaps. There was no difference in the rate of MWC or reoperation for complications with respect to age, sex, tumor site, previous unplanned excision, tumor grade, depth, and type of flap. Tumor size >=8 cm was associated with a higher rate of reoperation (11/44 vs 6/78; P = 0.008) but the rate of MWC was not significant (16/44 vs 14/78; P = 0.066). Conclusion: The use of soft tissue flaps is associated with a low rate of MWC and reoperation. Our results suggest that a high rate of flap usage may be required to observe a reduction in complication rates. PMID- 29404338 TI - Insight into Two ABC Transporter Families Involved in Lantibiotic Resistance. AB - Antimicrobial peptides, which contain (methyl)-lanthionine-rings are called lantibiotics. They are produced by several Gram-positive bacteria and are mainly active against these bacteria. Although these are highly potent antimicrobials, some human pathogenic bacteria express specific ABC transporters that confer resistance and counteract their antimicrobial activity. Two distinct ABC transporter families are known to be involved in this process. These are the Cpr- and Bce-type ABC transporter families, named after their involvement in cationic peptide resistance in Clostridium difficile, and bacitracin efflux in Bacillus subtilis, respectively. Both resistance systems differentiate to each other in terms of the proteins involved. Here, we summarize the current knowledge and describe the divergence as well as the common features present in both the systems to confer lantibiotic resistance. PMID- 29404339 TI - Chloroplast Chaperonin: An Intricate Protein Folding Machine for Photosynthesis. AB - Group I chaperonins are large cylindrical-shaped nano-machines that function as a central hub in the protein quality control system in the bacterial cytosol, mitochondria and chloroplasts. In chloroplasts, proteins newly synthesized by chloroplast ribosomes, unfolded by diverse stresses, or translocated from the cytosol run the risk of aberrant folding and aggregation. The chloroplast chaperonin system assists these proteins in folding into their native states. A widely known protein folded by chloroplast chaperonin is the large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), an enzyme responsible for the fixation of inorganic CO2 into organic carbohydrates during photosynthesis. Chloroplast chaperonin was initially identified as a Rubisco binding protein. All photosynthetic eucaryotes genomes encode multiple chaperonin genes which can be divided into alpha and beta subtypes. Unlike the homo oligomeric chaperonins from bacteria and mitochondria, chloroplast chaperonins are more complex and exists as intricate hetero-oligomers containing both subtypes. The Group I chaperonin requires proper interaction with a detachable lid-like co-chaperonin in the presence of ATP and Mg2+ for substrate encapsulation and conformational transition. Besides the typical Cpn10-like co chaperonin, a unique co-chaperonin consisting of two tandem Cpn10-like domains joined head-to-tail exists in chloroplasts. Since chloroplasts were proposed as sensors to various environmental stresses, this diversified chloroplast chaperonin system has the potential to adapt to complex conditions by accommodating specific substrates or through regulation at both the transcriptional and post-translational levels. In this review, we discuss recent progress on the unique structure and function of the chloroplast chaperonin system based on model organisms Chlamydomonas reinhardtii and Arabidopsis thaliana. Knowledge of the chloroplast chaperonin system may ultimately lead to successful reconstitution of eukaryotic Rubisco in vitro. PMID- 29404340 TI - Assays of D-Amino Acid Oxidase Activity. AB - D-amino acid oxidase (DAAO) is a well-known flavoenzyme that catalyzes the oxidative FAD-dependent deamination of D-amino acids. As a result of the absolute stereoselectivity and broad substrate specificity, microbial DAAOs have been employed as industrial biocatalysts in the production of semi-synthetic cephalosporins and enantiomerically pure amino acids. Moreover, in mammals, DAAO is present in specific brain areas and degrades D-serine, an endogenous coagonist of the N-methyl-D-aspartate receptors (NMDARs). Dysregulation of D-serine metabolism due to an altered DAAO functionality is related to pathological NMDARs dysfunctions such as in amyotrophic lateral sclerosis and schizophrenia. In this protocol paper, we describe a variety of direct assays based on the determination of molecular oxygen consumption, reduction of alternative electron acceptors, or alpha-keto acid production, of coupled assays to detect the hydrogen peroxide or the ammonium production, and an indirect assay of the alpha-keto acid production based on a chemical derivatization. These analytical assays allow the determination of DAAO activity both on recombinant enzyme preparations, in cells, and in tissue samples. PMID- 29404341 TI - Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets. AB - Cardiovascular disease remains the main cause of morbidity and mortality in patients with diabetes. The risk of vascular ischemia is increased in this population and outcome following an event is inferior compared to individuals with normal glucose metabolism. The reasons for the adverse vascular profile in diabetes are related to a combination of more extensive atherosclerotic disease coupled with an enhanced thrombotic environment. Long-term measures to halt the accelerated atherosclerotic process in diabetes have only partially addressed vascular pathology, while long-term antithrombotic management remains largely similar to individuals without diabetes. We address in this review the pathophysiological mechanisms responsible for atherosclerosis with special emphasis on diabetes-related pathways. We also cover the enhanced thrombotic milieu, characterized by increased platelet activation, raised activity of procoagulant proteins together with compromised function of the fibrinolytic system. Potential new therapeutic targets to reduce the risk of atherothrombosis in diabetes are explored, including alternative use of existing therapies. Special emphasis is placed on diabetes-specific therapeutic targets that have the potential to reduce vascular risk while keeping an acceptable clinical side effect profile. It is now generally acknowledged that diabetes is not a single clinical entity but a continuum of various stages of the condition with each having a different vascular risk. Therefore, we propose that future therapies aiming to reduce vascular risk in diabetes require a stratified approach with each group having a "stage-specific" vascular management strategy. This "individualized care" in diabetes may prove to be essential to improve vascular outcome in this high risk population. PMID- 29404342 TI - Message in a Microbottle: Modulation of Vascular Inflammation and Atherosclerosis by Extracellular Vesicles. AB - Extracellular vesicles (EVs) have emerged as a novel intercellular communication system. By carrying bioactive lipids, miRNAs and proteins they can modulate target cell functions and phenotype. Circulating levels of EVs are increased in inflammatory conditions, e.g., cardiovascular disease patients, and their functional contribution to atherosclerotic disease development is currently heavily studied. This review will describe how EVs can modulate vascular cell functions relevant to vascular inflammation and atherosclerosis, particularly highlighting the role of EV-associated proteolytic activity and effector proteins involved. Furthermore, we will discuss key questions and challenges, especially for EV-based therapeutics. PMID- 29404343 TI - Caudal Fossa Ratio in Normal Dogs and Eurasier Dogs with VLDLR-Associated Genetic Cerebellar Hypoplasia. AB - Cerebellar and hindbrain malformations, such as cerebellar hypoplasia (CH), vermis hypoplasia, and Dandy-Walker malformation, occur in dogs as well as in humans. Neuroimaging is essential for a precise description of these malformations and defining translational animal models. Neuroimaging is increasingly performed in puppies, but there is a lack of data on developmental changes in the caudal fossa, which can impair assessment of caudal fossa size in this age group. The purpose of this study was to validate caudal fossa ratio (CFR) in dogs and to explore CFR in Eurasier dogs with genetic CH. CFR was calculated from midsagittal brain images of 130 dogs as caudal fossa area/total cranial cavity area. In addition, the volume of the caudal fossa was measured in 64 randomly selected dogs from this group. Repeated measurements were used to investigate inter- and intra-rater variability and influence of imaging modality. Furthermore, the influence of age, weight, and breed was explored. The CFR was a reliable parameter with negligible influence from the examiners, imaging modality, and weight of the dog. The midsagittal area of the caudal fossa and the volume of the caudal fossa correlated closely with each other. In this study, we observed a smaller CFR in puppies. The CFR in adult dogs lies within 0.255 and 0.330, while CFR is smaller in puppies up to 4 months of age. Besides age, there was also an effect of breed, which should be explored in larger data sets. Measurements of CFR in Eurasier dogs with genetic CH caused by a mutation in the very-low-density-lipoprotein-receptor gene revealed the presence of two variants, one with an enlarged caudal fossa and one with a normal to small caudal fossa. This observation indicates that there is phenotypic heterogeneity and interaction between the developing cerebellum and the surrounding mesenchyme in this animal model. PMID- 29404344 TI - Real-Time Quaking-Induced Conversion Detection of Bovine Spongiform Encephalopathy Prions in a Subclinical Steer. AB - Bovine spongiform encephalopathy (BSE) belongs to a group of fatal prion diseases that result from the misfolding of the cellular prion protein (PrPC) into a pathogenic form (PrPSc) that accumulates in the brain. In vitro assays such as serial protein misfolding amplification and real-time quaking-induced conversion (RT-QuIC) allow assessment of the conversion of PrPC to PrPSc. RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. However, there is no such comparison of RT-QuIC data between BSE positive and presymptomatic cattle. Further, the current study assesses prion distribution in multiple brain regions of clinically ill or subclinical animals. Here, we compare RT-QuIC reactions seeded with brain samples collected from experimentally inoculated cattle that were clinically ill or subclinically affected with BSE. The results demonstrate RT-QuIC seeding in various brain regions of an animal with subclinical BSE despite being determined negative by immunohistochemistry. Bioassay of the subclinical animal and RT-QuIC of brainstem from inoculated knockout (PRNP-/-) cattle were used to confirm infectivity in the subclinical animal and determine that RT-QuIC reactions were not the result of residual inoculum, respectively. These results confirm that RT-QuIC is a highly sensitive prion detection assay that can detect prions in a steer prior to the onset of clinical signs of BSE. PMID- 29404346 TI - Priorities and Future Actions for an Effective Use of Phytotherapy in Livestock Outputs from an Expert Workshop. AB - This study reflects on the recognised need for more joined-up, high-quality research on phytotherapy that addresses the current societal challenges in finding alternatives to the use of antibiotics. The study applied a multidisciplinary participatory approach in an expert workshop exercise within the FP7 EU IMPRO project. Prior to this study, a literature review was elaborated on research in the field of phytotherapy as applied to farm animals, cooperation between research bodies and initiatives to reduce the use of antibiotics by using phytotherapeutic remedies. The review was delivered to the participants of the workshop so as to receive feedback on it and enrich the discussion. Different expertise, background in research or veterinary practice, and varying positions regarding phytotherapy were the criteria in targeting participants. A structured workshop was subsequently organised, with questions to experts addressing scientific validation of phytotherapy, effective treatment under farm conditions and necessary developments for the future. Challenges identified by the experts were as follows: poor study designs, lack of reproducibility of studies, poor standardisation of products, cost-benefit concerns, lack of veterinarian training and poor data availability. To overcome obstacles, the need for improved study designs for clinical trials was given priority in order to prove the efficacy of remedies and to implement a monitoring system which enables the assessment of the effectiveness of treatments in farm practice. Reflections in this report are intended to be a resource for scientists, policy makers and end users for an effective use of phytotherapy at farm level. PMID- 29404347 TI - Advances in Cardiology, Interventional Cardiology, Electrophysiology, and Structural Heart Disease: A Moving Target. PMID- 29404345 TI - Fecal Nutrients Suggest Diets of Higher Fiber Levels in Free-Ranging than in Captive Proboscis Monkeys (Nasalis larvatus). AB - Understanding the natural diet of species may provide useful information that can contribute to successful captive maintenance. A common problem experienced with captive foregut-fermenting primate (colobine) diets is that they are deficient in fiber and therefore highly digestible. This may contribute to gastrointestinal disorders often observed in zoos. An approach to obtain information relevant for the improvement of diets is to compare the nutrient composition of feces from free-ranging and captive individuals. In theory, fecal material can be considered a proxy for diet intake integrated over a certain period of time. We collected fecal samples from eight free-ranging proboscis monkey (Nasalis larvatus, a highly endangered colobine species) groups from a secondary forest along the Kinabatangan River and four from a mixed mangrove-riverine forest along the Garama River, Sabah, Borneo, Malaysia. We also collected fecal samples from 12 individual captive adult/sub-adult proboscis monkeys from three different zoos. We confirmed that feces from free-ranging monkeys contained more fiber and less metabolic fecal nitrogen than those from captive specimens, indicating a less digestible diet in the wild. Modifying the diets of captive colobines to include more fiber, comparable to those of free-ranging ones, may contribute to their health and survival. PMID- 29404348 TI - Impact of smoking in patients undergoing transcatheter aortic valve replacement. AB - Background: The paradox that smokers have better clinical outcomes in cardiovascular diseases remains controversial. No literature exists studying impact of smoking on outcomes following transcatheter aortic valve replacement (TAVR). Methods: We performed an electronic search of the 2011-2012 National Inpatient Sample (NIS) database to identify all TAVR hospitalizations. Outcomes were measured comparing smokers to non-smokers. Results: A total of 8,345 TAVR hospitalizations were identified with 24% being smokers. Compared to non-smokers, smokers were younger (80.4+/-8.8 vs. 81.4+/-9.2 years, P<0.001), were more often men (63.6% vs. 47.8%, P<0.001), and had a higher disease burden. Despite a higher disease burden, smokers had lower post procedure stroke (2.8% vs. 3.1%), hemorrhage events (28.2% vs. 32.0%, P<0.05) and lower all cause in-hospital mortality (1.2% vs. 5.7%, adjusted odds ratio 0.21, 95% CI: 0.13-0.32, P<0.001) compared to non-smokers. Conclusions: Despite having a higher cardiovascular disease burden, smokers had better outcomes compared to non-smokers. Therefore the smoker's paradox is applicable in the TAVR cohort. PMID- 29404349 TI - Impact of family history of coronary artery disease on in-hospital clinical outcomes in ST-segment myocardial infarction. AB - Background: Patients with a family history of coronary artery disease (FHxCAD) are at increased risk for development of myocardial infarction (MI). However, the data on the influence of FHxCAD on in-hospital clinical outcomes post ST-segment myocardial infarction (STEMI) is limited. Hence, we evaluated the impact of FHxCAD on in-hospital clinical outcomes post STEMI in an unselected nationwide cohort. Methods: Nationwide Inpatient Sample (NIS) database [2003-2011] was used to compare differences in all-cause in-hospital mortality and adverse clinical events (cardiogenic shock, acute cerebrovascular events and use of intra-aortic balloon pump) between patients with and without FHxCAD. Results: A total of 2,123,492 STEMI admissions were identified, of which 7.4% (n=158,079) patients were with FHxCAD and 92.6% (n=1,965,413) were without FHxCAD. The FHxCAD group had lower in-hospital mortality [1.4% vs. 8.1%; adjusted odds ratio (OR): 0.42, 95% confidence interval (CI): 0.41-0.44; P<0.001] when compared with no-FHxCAD group. They underwent a significantly higher number of coronary interventions, and were less likely to develop cardiogenic shock, acute cerebrovascular events and to require intra-aortic balloon pump during hospitalization. Conclusions: This large sample size study demonstrates that STEMI patients with FHxCAD had lower in-hospital mortality and adverse clinical events in comparison to patients with no-FHxCAD. Further research is warranted to determine whether the superior outcomes in FHxCAD patients with STEMI are related to differences in strategies related to diet, exercise, use of medications or coronary interventions. PMID- 29404350 TI - Stress-induced thrombus: prevalence of thromboembolic events and the role of anticoagulation in Takotsubo cardiomyopathy. AB - Background: Takotsubo cardiomyopathy (TCM), also known as stress-induced cardiomyopathy has a favorable prognosis with expected recovery in weeks. Left ventricular (LV) thrombus is a known complication of TCM, which can lead to embolization and potentially a stroke. The prevalence of LV thrombus and the role of anticoagulation have yet to be fully defined in this condition. Methods: We performed a search of published literature through PubMed and Scopus, which identified 282 patients with TCM in whom the incidence of LV thrombus and/or thromboembolic event was reported. In order to contrast this to the current anticoagulation strategy of atrial fibrillation, the occurrence of LV thrombus was compared to the adjusted stroke rate using the CHADS2 score. Results: Of the 282 patients identified through a literature search, 26 (9.2%) were noted to have a thromboembolic event in the setting of TCM. The incidence of thromboembolic event ranged from 5.3% to as high as 14.3%. When compared to the CH2sDS2-VASc score, the average incidence of LV thrombus in our study equated to a score between 4 and 5. Conclusions: While the occurrence of LV thrombus in TCM is variable among studies, the average incidence remains relatively high. Thus, making LV thrombus a significant complication of stress-induced cardiomyopathy. Prophylactic anticoagulation until recovery may have a role in reducing the rate of LV thrombus. Further studies will be needed to determine the rate of embolization and utility of anticoagulation in TCM. PMID- 29404351 TI - Trends, predictors and outcomes of ischemic stroke and intracranial hemorrhage in patients with a left ventricular assist device. AB - Background: Patients with a left ventricular assist device (LVAD) are at a higher risk of ischemic stroke (IS) and intracranial hemorrhage (ICH). There is limited data available on risk factors and outcomes associated with IS and ICH in LVAD patients. Methods: All patients >18 years of age with an LVAD were identified based on the U.S. Nationwide Inpatient Sample (NIS) database from the year 2007 to 2011. Patients with a discharge diagnosis of IS were compared to those without IS. In a separate analysis, patients with a discharge diagnosis of ICH were compared to patients without ICH. Trends, predictors and outcomes of IS and ICH were analyzed using a multivariate regression model. Results: Out of 17,323 discharges with a primary diagnosis of heart failure with LVAD, 624 (3.6%) patients had a co-diagnosis of IS and 387 (2.2%) had a co-diagnosis of ICH. From 2007 to 2011, the discharge diagnosis of heart failure with LVAD increased from 946 to 5,540, but the proportion of patients with IS remained about 3.4%, while the incidence of ICH decreased from 3.8% in 2007 to a plateau of around 2.2% in the following years. After adjusting for potential confounders, increasing Charlson Comorbidity Index (CCI) score was an independent predictor of IS and ICH. In-hospital mortality was four-fold higher in the IS group (odds ratio: 4.2; 95% CI: 2.3-7.6; P<0.0001) and 18-fold higher in the ICH group (OR: 18; 95% CI: 9 34, P<0.0001). Renal disease (OR: 5.3; CI: 1.3-22.1; P=0.02), liver disease (OR: 4.9; CI: 1.1-21.2; P=0.03) and abnormal coagulation profile (OR: 4.8; CI: 1.6 14.4; P=0.01) were independent predictors of mortality in LVAD patients with IS. Presence of diabetes mellitus (OR 4.3, P=0.1) and liver disease (or 2.8, P=0.2) showed trends towards predicting mortality in LVAD patients with ICH but did not reach statistical significance. Conclusions: Increasing comorbidity burden significantly increases the risk of both IS and ICH with LVAD. In our cohort, the incidence of IS and ICH increases the mortality 4- and 18-fold, respectively. Renal disease, liver disease and abnormal coagulation profile were independent predictors of mortality in LVAD patients with IS. PMID- 29404352 TI - Severe sepsis and cardiac arrhythmias. AB - Background: Although sepsis is a known risk factor for cardiac arrhythmias, data on incidence and outcomes of atrial and ventricular arrhythmias in severe sepsis is limited. The purpose of this study is to examine the association of severe sepsis with cardiac arrhythmias and their impact on outcome in this patient population. Methods: We used hospital discharge data from the Nationwide Inpatient Sample (NIS) during the year 2012. All patients 18 years or older were included in the study. The International Classification of Diseases-Clinical Modification, 9th revision (ICD-9-CM) code was used to identify patients with discharge diagnosis of severe sepsis, atrial fibrillation (A Fib), atrial flutter (AFL), ventricular fibrillation (VF) arrest and non-ventricular fibrillation (non VF) arrest. In order to study the association of arrhythmias with severe sepsis, two groups were defined: group a-with severe sepsis was compared to group b without severe sepsis. Univariate and multivariate logistic regression methods were used to adjust for potential confounding factors and variables associated with cardiac arrhythmias were determined. Results: A total of 30,712,524 NIS hospital discharges (weighted for national estimate) were included in our study, of which 1,756,965 (5.7%) had severe sepsis. On multivariate analysis, after adjusting for potential confounders, severe sepsis was associated with higher risk of A Fib (OR, 1.23; 95% CI, 1.21-1.24), AFL (OR, 1.34; 95% CI, 1.30-1.40), VF arrest (OR, 2.58; 95% CI, 2.38-2.79) (OR, 3.31; 95% CI, 3.07-3.57) and non-VF arrest (OR, 4.91; 95% CI, 4.74-5.07). In the severe sepsis group, cardiac arrhythmia was associated with higher in-hospital mortality (OR, 1.41; 95% CI, 1.37-1.45), length of stay (LOS) >75% quartile (OR, 1.50; 95% CI, 1.46-1.53) and total hospital charges >75% quartile (OR, 1.37; 95% CI, 1.34-1.41). Advanced age, male sex, ischemic heart disease, diabetes mellitus (DM), congestive heart failure (CHF), valvular heart disease, respiratory failure, mechanical ventilation and use of vasopressors were independently associated with cardiac arrhythmias. Conclusions: Patients with severe sepsis are at high risk of atrial and life threatening ventricular arrhythmias. Despite adjustment for potential confounding factors, patients hospitalized with severe sepsis carry a significantly higher risk for cardiac arrest and increased mortality. PMID- 29404353 TI - Simultaneous acute cardio-cerebral infarction: is there a consensus for management? AB - Acute ischemic stroke (AIS) and acute myocardial infarction (AMI) are both life threatening medical conditions with narrow therapeutic time-window that carry grave prognosis if not addressed promptly. The acute management of both condition is well documented in the literature, however the management of a simultaneous presentation of both AIS and AMI is unclear. A delayed intervention of one infarcted territory for the other may result in permanent irreversible morbidity or disability, and even death. In addition, the use of antiplatelet and anticoagulants that are inherently part of an AMI management may increase the risk for hemorrhagic conversion associated with intravenous thrombolysis used in AIS, and the use of a thrombolytic in AIS increases the risk of cardiac wall rupture in the setting of an AMI. Despite this ambiguity, there is no clear evidence-based guideline or clinical studies that have addressed the optimal management of this rare co-occurrence. This review paper examines the existing literature on the management of simultaneous acute cardio-cerebral infarction (CCI) and highlights the existing challenge to management. PMID- 29404355 TI - When more is not better-appropriately excluding patients from mechanical circulatory support therapy. AB - Mechanical circulatory support (MCS) devices are continually evolving and are providing greater hemodynamic support. This review was conducted to evaluate the prophylactic use of MCS in hemodynamically stable patients who were awaiting future coronary artery revascularization. A thorough review of published literature was conducted to evaluate for patients and clinical scenarios that are indicated for MCS, including hemodynamically stable and unstable patients awaiting revascularization. Although there have been several studies demonstrating the benefit of MCS use in hemodynamically unstable patients, there was limited trials in patients that were hemodynamically stable. The use of prophylactic MCS was limited to intra-aortic balloon pump (IABP) in "high risk" patients awaiting coronary artery bypass grafting (CABG). This review article was conducted to evaluate for possible prophylactic MCS in patients awaiting revascularization. In hemodynamically stable patients, literature is limited to the use of IABP for "high-risk" patients awaiting CABG. A thorough review of literature suggest that hemodynamically stable patients likely would not benefit from prophylactic placement MCS while awaiting revascularization although further clinical trials are needed to identify the ideal patients and clinical scenarios for the use of MCS. PMID- 29404354 TI - Outcomes following transcatheter aortic valve replacement in patients with native aortic valve regurgitation. AB - Due to the absence of annular calcification for device anchoring, it is presumed that transcatheter aortic valve replacement (TAVR) is not suitable for the treatment of native aortic valve regurgitation (NAVR) resulting in very limited data and experience concerning its safety and efficacy. We sought to review published data on the safety and efficacy of TAVR in high-risk patients with NAVR. Studies including case reports, case series and original articles published between 2002 and 2016 on TAVR in patients with NAVR were identified with a systematic electronic search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Only studies reporting data on demographic and procedural characteristics, management and follow up outcomes were analyzed. A total of 30 publications describing 182 patients were identified. Most patients (54%) were men, with a mean age of 70.1+/-2.6 years, mean logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE) of 21.8%+/-4.5% and mean Society of Thoracic Surgeons (STS) score of 8%+/-1.8% for mortality. The majority (87%) of patients had severe NAVR with no valvular calcification. TAVR was mostly performed through the femoral (58.8%) and apical (33.1%) approach. Device success, defined by VARC-2, was achieved in 86.3% of our study population. A second valve was required in 17 patients (9.3%) during the index procedure for residual aortic regurgitation or malposition. Post procedure aortic regurgitation of grade 1 or less was present in 80 patients (81%). Pacemaker implantation was required post procedure in 17 patients (9.3%). The 30-day and 1-year mortality was 11.9% and 16.2%, respectively. TAVR is associated with favorable pacemaker implantation and 1-year mortality rates with a high 30-day mortality among selected patients with NAVR. PMID- 29404356 TI - A review of racial disparities in transcatheter aortic valve replacement (TAVR): accessibility, referrals and implantation. AB - Racial disparities in transcatheter aortic valve replacement (TAVR) implantation results from several factors, including socioeconomic disparities, inherent biases in healthcare provision, fewer referrals to specialists and language barriers in some minority populations. In this review article, we discuss the current data on the racial disparities in TAVR, explore the prevalence of aortic stenosis in different demographics in the United States and we proffer practical solutions to these problems. PMID- 29404357 TI - Permanent pacemaker insertion in patients with conduction abnormalities post transcatheter aortic valve replacement: a review and proposed guidelines. AB - Conduction abnormalities are a common and serious complication of transcatheter aortic valve replacement (TAVR) with well-established predictive factors. Current guidelines are not concrete, leaving several questions unanswered about indications, timing and risks of pacemaker implantation post-TAVR. In this review article, we discuss current guidelines, predictors of pacemaker implantation, clinical implications of this procedure and our recommendations for reducing the pacemaker implantation rate post-TAVR. PMID- 29404358 TI - Asian-Indians: a review of coronary artery disease in this understudied cohort in the United States. AB - Coronary artery disease (CAD) is a major cause of cardiovascular death worldwide. Prevalence of CAD is highly variable among different races. Asian Indians have been noted to have the highest CAD rates and the conventional risk factors fail to explain this difference completely. Asian Indians constitute a fifth of the global population, and the higher rates of CAD in this population constitute a major health challenge. There have been studies in the early 2000s that investigate the risk factors in this population; however, very few studies have been done since then that explore the higher CAD rates in Asian Indians. This is a comprehensive and current review of the known risk factors for CAD in Asian Indians and strategies physicians should consider relieving this burden. PMID- 29404359 TI - Incidence and predictors of acute coronary syndrome within a year following a negative stress test-a false sense of security: is routine screening any useful? AB - One of the major issues in management of the acute coronary syndrome (ACS) is classification of patients with atypical presentation who have low risk of having a coronary episode at presentation. There have been multiple studies on the stratification of high risk patients and medical management of such cases, however, there is a sub-class of patients who do not fit any category. In this paper, we have looked at the current literature on stratification of patients based on the study tools available and the risk of having a coronary episode during the following year. In our overview, we have found that the current methods in place namely, cardiac stress test and stress echocardiogram have a good prognostic factor in terms of mortality in the next one year and can safely stratify the patients at low risk when correlated with clinical presentation and laboratory studies. However, such data are limited for computerized tomography or magnetic resonant imaging and their application might be limited due to accessibility and cost of studies. Current guidelines for classification of high risk patient do an excellent job and we believe that proper application of stress tests together with other imaging modalities together with laboratory, clinical judgment, and proper use of medical management can help with safe discharge of patients from the emergency department (ED) and reduction of burden from healthcare. PMID- 29404360 TI - Access site complications in transcutaneous aortic valve replacement: frequency, outcomes, prevention, and treatment. AB - Aortic stenosis (AS) is a common cause of valvular heart disease with heavy disease burden in elderly patients. It is present in almost 7% of patients older than 65. The mortality rate increases significantly once it becomes symptomatic with average life expectancy of around 1-year. Symptoms include angina, syncope, or heart failure. This requires either surgical or transcutaneous replacement. Transcutaneous aortic valve replacement (TAVR) use has increased in recent years from high risk patients to now even including intermediate risk patients. With the increased number of procedures performed, one of the consequences is access site complications. These complications can lead to increased hospitalization, cost, infections, and eventually worse outcomes. In this manuscript, we provide a comprehensive review discussing the consequences, outcomes, frequency, predictors and some possible solutions to these complications set forth in these studies. PMID- 29404361 TI - Double conduction through the atrioventricular node following acute medullary infarction: a case report. AB - Lateral medullary syndrome (LMS), also known as Wallenberg's syndrome, PICA syndrome, results from occlusion of the posterior inferior cerebellar artery, with associated infarction of parts of medulla oblongata, and cerebellum on the ipsilateral side. It often manifests as various patterns of sensory, motor, and autonomic deficits. While sensorimotor dysfunction presents as a predicted pattern of clinical signs and symptoms, autonomic dysfunction is usually less clinically apparent, and can be easily mistaken as a concomitant pathology in the end organ it affects. In this case, we present a case of an unusual pattern of cardiac arrhythmia as the first objective finding of LMS, caused by autonomic instability following infarction of vagus nerve nuclei in the medulla. PMID- 29404362 TI - The potential detrimental effects of calcium channel blockers' overdose and current available management. AB - Calcium channel blockers (CCBs) are prescribed in a wide variety of cardiovascular conditions. Overdose of this commonly used drug can result in negative physiologic consequences including severe hypotension and even death due to metabolic and hemodynamic compromise. We report the fatal case of an amlodipine overdose, which caused intractable acidosis and cardiovascular failure in a 51-year-old male. PMID- 29404363 TI - Electrocardiographic artifact potentially misleading to the wrong management. AB - Atrial flutter (AF) is the second most common supraventricular tachyarrhythmia following atrial fibrillation. We present an interesting case of a diagnostic challenge manifested as an electrocardiogram (ECG) recording mimicking AF in a patient with Parkinson's disease (PD). A 72-year-old African-American female with history of PD presented to our Emergency Department with a one day history of chest pain. Her vital signs were within normal limits. Physical exam was remarkable for bilateral resting hand tremors at a frequency of 6-8 hertz and mild cogwheel rigidity in both upper extremities. Initial ECG was interpreted as AF prompting admission. After careful review of her ECG by a cardiologist, several features such as, sharply contoured upright p waves in all leads, different flutter wave morphologies in the same leads, more prominence of "pseudo flutter" waves in the limb leads compared to the precordial leads, and return to isoelectric baseline after sharp peaked p waves, questioned the diagnosis of AF. A repeat 12 lead ECG clearly demonstrated normal sinus rhythm, and the patient remained completely asymptomatic throughout the stay. A 48-hour Holter monitoring in the clinic later confirmed consistent sinus rhythm with no evidence of any arrhythmias Tremor induced artifacts can be mistaken for arrhythmias. Correct and accurate diagnosis is critically important, in order to avoid wrong treatment and unnecessary interventions. Our case illustrates the importance of recognizing artifact related ECG changes to prevent unnecessary treatment and hospital admissions. PMID- 29404364 TI - Peri-procedural antibiotic prophylaxis in ventricular septal defect: a case study to re-visit guidelines. AB - The current American Heart Association (AHA)/American College of Cardiology (ACC) guidelines do not recommend antibiotic prophylaxis for infective endocarditis (IE) in patients with acyanotic congenital valvular heart disease due to lack of any proven benefit and potential harm associated with antibiotics. As recognized by the guidelines, some acyanotic congenital heart disease, such as ventricular septal defects (VSDs), are associated with a high velocity jet and pose a greater risk of peri-procedural endocarditis. We suggest that an acyanotic congenital heart disease with high velocity jet should be considered for antibiotic prophylaxis for IE. PMID- 29404365 TI - Acute right ventricular failure after orthotopic liver transplantation. AB - The interdependence between the heart and liver in maintaining hemodynamic stability during the perioperative period of either orthotopic heart (OHT) or liver (OLT) transplantation is important. The pre-transplant hemodynamic changes that occur in patients with end-stage liver disease (ESLD) can include decreased systemic vascular resistance, poor ventricular response to stress and increased cardiac output (CO). Concomitant pulmonary disorders are often present in ESLD. Portopulmonary hypertension (PoPHTN) is an important marker for increased mortality in liver transplant patients. The pathophysiologic mechanisms specific to PoPHTN have been compared with other known forms of pulmonary hypertension, including primary pulmonary hypertension, and has been found to fall within a spectrum of disorders related to factors both due to intrinsic liver failure [with resultant portal hypertension and hepatopulmonary syndrome (HPS)] as well as pulmonary vascular remodeling. We present a 47-year-old Caucasian female with ESLD secondary to non-alcoholic steatohepatitis and HPS. Our current case demonstrates the difficulty in managing patients with acute pulmonary hypertension after OLT. Review of the contemporary literature demonstrated a total of eight case reports of post-transplant severe pulmonary hypertension thought to be due to a combination of either HPS or PoPHTN. This case highlights the complexities of patient management in the acute setting after OLT. Furthermore, it demonstrates the intricate role of careful preoperative evaluation and screening in patients undergoing workup for solid organ transplantation. PMID- 29404366 TI - Occlusion of right coronary artery by microembolization caused by excessive diagnostic catheter manipulation. AB - With advancing technology and newer therapeutic and diagnostic techniques, physicians are now encountering new complications or increasing frequency of known complications than before. left cardiac catheterization and coronary angiography is not an exception. As transradial cardiac catheterization is now becoming more popular, operators should be more aware of related challenges and limitations associated. Tortuous right bracheocephalic artery is an anatomical variance that makes radial catheterization more difficult, and may indeed add additional time and risk to the procedure and patient, respectively. Hence, we present this case report. PMID- 29404367 TI - Paradoxical emboli following a pulmonary embolus in the presence of a patent foramen ovale. AB - A paradoxical embolism is defined as a systemic arterial embolus due to passage of a venous thrombus through a right to left shunt. We describe a case of acute cerebral vascular accident (CVA), right subclavian arterial embolus, and pulmonary emboli in the setting of a large patent foramen ovale (PFO). A 74-year old woman with multiple comorbidities presented to the emergency department with acute onset of shortness of breath, weakness, and right arm pain. She was found to have bilateral pulmonary emboli, left CVA, and a right subclavian arterial embolus on computed tomography (CT). She emergently underwent embolectomy of her right upper extremity along with a fasciotomy. On chest CT, a PFO was visualized. Transesophageal echocardiogram (TEE) revealed a large PFO with at least a 3-mm primum/secundum separation and evidence of right to left shunting. Multidisciplinary consensus was that she would benefit from closure of her PFO in order to reduce her risk of further emboli. The patient was agreeable and taken to the catheterization lab where a sizing balloon over a stiff wire was advanced to measure the size of the defect. A 25-mm Cardioform device was successfully delivered across the defect. The patient was started on oral anticoagulation and antiplatelets. In summary, increase in right-sided pressures from pulmonary emboli can cause right to left shunting and lead to a paradoxical embolus. Assessment of patients who present with acute CVA or arterial embolus in the setting of pulmonary emboli with elevated right atrial pressures should include an evaluation for a PFO. Closure of PFO in these patients is of potential additive benefit. PMID- 29404369 TI - Pattern and Appropriateness of Medicines Prescribed to Outpatients at a University Hospital in Northwestern Ethiopia. AB - The study assessed the pattern and appropriateness of medicines prescribed to outpatients at Gondar University Referral Hospital in northwestern Ethiopia. An institution-based cross-sectional study was employed, through interviews and prescription reviews, among 346 patients at the outpatient pharmacy, from 2nd to 20th of May 2016. Data on sociodemographic profile of patients and medicines prescribed to them were collected. A mean of 1.72 medicines per encounter was prescribed, over a third of the total being anti-infectives. Patients were able to get about 85% of these medicines. An unskilled government employee would be required to work more than one and a half day to be able to afford the average priced medicine. Among prescriptions with two or more medicines, more than a third had at least one potential drug-drug interaction (PDDI), the commonest pair containing amoxicillin and doxycycline. Being male, being older (50-59 years), and increased number of medicines were associated with higher likelihood of PDDIs. In conclusion, the number of medicines prescribed per encounter was up to accepted standard. However, their availability fell short, together with considerable cost. Regarding appropriateness, a significant proportion of potential drug-drug interactions is identified and associated with patient's sex, age, and number of medicines prescribed. PMID- 29404368 TI - Crystalloid Coload Reduced the Incidence of Hypotension in Spinal Anesthesia for Cesarean Delivery, When Compared to Crystalloid Preload: A Meta-Analysis. AB - Objective: To determine whether crystalloid infusion just after intrathecal injection (coload) would be better than infusion before anesthesia (preload) for hypotension prophylaxis in spinal anesthesia for cesarean delivery. Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and other databases for randomized controlled trials comparing coload of crystalloid with preload in parturients receiving spinal anesthesia for cesarean delivery. Primary outcome was intraoperative incidence of hypotension. Other outcomes were intraoperative need for vasopressors, hemodynamic variables, neonatal outcomes (umbilical artery pH and Apgar scores), and the incidence of maternal nausea and vomiting. We used RevMan 5.2 and STATA 12.0 for the data analyses. Results: Ten studies with 824 cases were included. The incidence of hypotension was significantly higher in the preload group compared with the coload group (57.8% versus 47.1%, odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.11-2.37, and P = 0.01). More patients needed intraoperative vasopressors (OR = 1.71, 95% CI = 1.07-2.04, and P = 0.02) when receiving crystalloid preload. In addition, the incidence of nausea and vomiting was higher in the preload group (OR = 3.40, 95% CI = 1.88-6.16, and P < 0.0001). There were no differences in neonatal outcomes between the groups. Conclusions: For parturients receiving crystalloid loading in spinal anesthesia for cesarean delivery, coload strategy is superior to preload for the prevention of maternal hypotension. PMID- 29404370 TI - Prevalence of Cam and Pincer Deformities in the X-Rays of Asymptomatic Individuals. AB - Objective: The presence of radiological signs of femoroacetabular impingement (FAI) is not necessarily associated with symptoms. Hence, the prevalence of cam and pincer deformities in the overall population may be underestimated. The purpose of this study was to screen an unselected cohort of people without hip symptoms for native radiological signs of cam and pincer deformities to determine their actual prevalence. Materials and Methods: 110 asymptomatic patients had AP pelvis X-rays and cross-table hip X-rays performed. We evaluated the images for the presence of cross-over signs and measured lateral center edge (LCE) angles, alpha angles (alpha-angles), and femoral offset ratios. Results: Positive cross over signs were seen in 34%; LCE angles > 40 degrees in 13%; and femoral offset ratios < 0.18 in 43%. In 41% of the patients, alpha-angles were >50 degrees . Male patients showed significantly higher alpha-angles, lower offset ratios, and a higher prevalence of cross-over signs. In contrast, female patients had significantly higher LCE angles. Conclusion: According to our data, radiological signs of cam and pincer deformities are common in asymptomatic people. In clinical practice, patients presenting with hip pain and radiological signs of FAI should undergo further diagnostic evaluation. However, in asymptomatic patients, no further evaluation is recommended. PMID- 29404371 TI - miR-503 Is Involved in the Protective Effect of Phase II Enzyme Inducer (CPDT) in Diabetic Cardiomyopathy via Nrf2/ARE Signaling Pathway. AB - Diabetic cardiomyopathy (DCM) is a common heart disease. The Phase II enzyme inducer (CPDT) is a complex enzyme that promotes the expression of antioxidant enzymes through activating nuclear factor erythroid 2-related factor 2 (Nrf2); these compounds have been shown to protect against oxidative stress. However, whether these compounds have similar protective effects in DCM still remains unclear. The purpose of this study is to investigate the protective effects and potential mechanism of CPDT in diabetic cardiomyopathy. In the results, firstly, compared with control rats, myocardial cell size, left ventricular mass index, and myocardial apoptosis index were increased, miR-503 was increased, and Nrf2, malondialdehyde (MDA), and heme oxygenase 1 (HO-1) were decreased in diabetic cardiomyopathy rats. Furthermore, compared with diabetic cardiomyopathy rats, these above parameters show the opposite change in CPDT treatment rats. In addition, the bioinformatics and luciferase reporter assay demonstrated that Nrf2 is a direct target of miR-503. Finally, the miR-503 could also regulate Nrf2 in the myocardial cells. Therefore, miR-503 is involved in the protective effect of CPDT in diabetic cardiomyopathy via Nrf2/ARE signaling pathway; miR-503 and Nrf2 may be a promising therapeutic target for the management of diabetic cardiomyopathy. PMID- 29404373 TI - New Biomarkers of Innate and Adaptive Immunity in Infectious Diseases. PMID- 29404372 TI - Quantitative Proteomic Analysis of Hepatic Tissue of T2DM Rhesus Macaque. AB - Type 2 diabetes mellitus (T2DM) is a metabolic disorder that severely affects human health, but the pathogenesis of the disease remains unknown. The high fat/high-sucrose diets combined with streptozotocin- (STZ-) induced nonhuman primate animal model of diabetes are a valuable research source of T2DM. Here, we present a study of a STZ rhesus macaque model of T2DM that utilizes quantitative iTRAQ-based proteomic method. We compared the protein profiles in the liver of STZ-treated macaques as well as age-matched healthy controls. We identified 171 proteins differentially expressed in the STZ-treated groups, about 70 of which were documented as diabetes-related gene in previous studies. Pathway analyses indicated that the biological functions of differentially expressed proteins were related to glycolysis/gluconeogenesis, fatty acid metabolism, complements, and coagulation cascades. Expression change in tryptophan metabolism pathway was also found in this study which may be associations with diabetes. This study is the first to explore genome-wide protein expression in hepatic tissue of diabetes macaque model using HPLC-Q-TOF/MS technology. In addition to providing potential T2DM biomarkers, this quantitative proteomic study may also shed insights regarding the molecular pathogenesis of T2DM. PMID- 29404375 TI - Use of Selective Serotonin Reuptake Inhibitor and Midodrine in a Patient With Autonomic Instability 2/2 Compressive Squamous Cell Carcinoma and Pain. AB - A rare cause of reflex syncope is metastatic cancers involving the head and neck. These can irritate the glossopharyngeal nerve and lead to glossopharyngeal neuralgia with associated syncope. This type of syncope is difficult to treat since it commonly involves both a vasodepressor and cardioinhibitory response, and typically requires removal of the irritative focus. We report a case of a 52 year-old male who presented from home with syncope. He endorsed a 5-week history of progressively worsened positional headaches and dramatic 40-pound weight loss with night sweats over 6 months. In the emergency department, his heart rate was noted to drop into the 20s with associated hypotension 60/31 mm Hg. Heart rate and blood pressure increased with intravenous atropine. Physical examination revealed a large ulcerative lesion in the left tonsillar area. After biopsy of the lesion, a diagnosis of stage IV squamous cell carcinoma of the neck was made; computed tomography angiogram and positron emission tomography/computed tomography confirmed involvement in the posterior tongue extending to the left palatine tonsil in addition to the left jugular chain. The patient was started on cisplatin and radiation therapy, but continued to have episodes of syncope associated with bradycardia and hypotension. After a failed trial of benztropine, the patient was started on sertraline and midodrine with resolution of syncope. This could be a potential treatment option in those with compressive mixed syncope who are not candidates for surgery or chemotherapy or are awaiting definitive treatment. PMID- 29404374 TI - Bioprinting of skin constructs for wound healing. AB - Extensive burns and full-thickness skin wounds are difficult to repair. Autologous split-thickness skin graft (ASSG) is still used as the gold standard in the clinic. However, the shortage of donor skin tissues is a serious problem. A potential solution to this problem is to fabricate skin constructs using biomaterial scaffolds with or without cells. Bioprinting is being applied to address the need for skin tissues suitable for transplantation, and can lead to the development of skin equivalents for wound healing therapy. Here, we summarize strategies of bioprinting and review current advances of bioprinting of skin constructs. There will be challenges on the way of 3D bioprinting for skin regeneration, but we still believe bioprinting will be potential skills for wounds healing in the foreseeable future. PMID- 29404376 TI - Successful Use of Intravenous Immunoglobulin G to Treat Refractory Heparin Induced Thrombocytopenia With Thrombosis Complicating Peripheral Blood Stem Cell Harvest. AB - Heparin-induced thrombocytopenia is a well-known, life-threatening complication that occurs in 5% of patients exposed to heparin. It causes thrombocytopenia in roughly 85% to 90% of affected individuals, with expected recovery in approximately 4 to 10 days following heparin withdrawal. However, there is an entity known as refractory heparin-induced thrombocytopenia with thrombosis in which patients have prolonged thrombocytopenia, refractory to the current standard of care. We present one such case of a 48-year-old male with R-ISS (Revised International Staging System) stage II kappa light chain multiple myeloma in stringent complete response status postinduction therapy. He developed heparin-induced thrombocytopenia with thrombosis during peripheral blood stem cell harvesting, manifesting as acute right coronary artery thrombus and severe thrombocytopenia. Although his clinical course was prolonged, he was ultimately successfully treated with intravenous immunoglobulin G 500 mg/kg/day over 4 days. PMID- 29404377 TI - Nonspecific Chronic Anteromedial Knee Pain Neuroma as a Cause of Infrapatellar Pain Syndrome: Case Study and Literature Review. PMID- 29404379 TI - Erratum. AB - [This corrects the article DOI: 10.1093/ofid/ofx073.][This corrects the article DOI: 10.1093/ofid/ofx073.]. PMID- 29404378 TI - Modeling Individual Differences in the Go/No-go Task with a Diffusion Model. AB - The go/no-go task is one in which there are two choices, but the subject responds only to one of them, waiting out a time-out for the other choice. The task has a long history in psychology and modern applications in the clinical/neuropsychological domain. In this article we fit a diffusion model to both experimental and simulated data. The model is the same as the two-choice model and assumes that there are two decision boundaries and termination at one of them produces a response and at the other, the subject waits out the trial. In prior modeling, both two-choice and go/no-go data were fit simultaneously and only group data were fit. Here the model is fit to just go/no-go data for individual subjects. This allows analyses of individual differences which is important for clinical applications. First, we fit the standard two-choice model to two-choice data and fit the go/no-go model to RTs from one of the choices and accuracy from the two-choice data. Parameter values were similar between the models and had high correlations. The go/no-go model was also fit to data from a go/no-go version of the task with the same subjects as the two-choice task. A simulation study with ranges of parameter values that are obtained in practice showed similar parameter recovery between the two-choice and go/no-go models. Results show that a diffusion model with an implicit (no response) boundary can be fit to data with almost the same accuracy as fitting the two-choice model to two-choice data. PMID- 29404380 TI - Erratum. AB - [This corrects the article DOI: 10.1093/ofid/ofx156.][This corrects the article DOI: 10.1093/ofid/ofx156.]. PMID- 29404381 TI - Tobacco Regulation and Cost-Benefit Analysis: How Should We Value Foregone Consumer Surplus? AB - Recent tobacco regulations proposed by the Food and Drug Administration have raised a thorny question: how should the cost-benefit analysis accompanying such policies value foregone consumer surplus associated with regulation-induced reductions in smoking? In a model with rational and fully informed consumers, this question is straightforward. There is disagreement, however, about whether consumers are rational and fully informed, and the literature offers little practical guidance about what approach the FDA should use if they are not. In this paper, we outline the history of the FDA's recent attempts to regulate cigarettes and other tobacco products and how they have valued foregone consumer surplus in cost-benefit analyses. We advocate replacing the approach used in most of this literature, which first calculates health gains associated with regulation and then "offsets" them by some factor reflecting consumer surplus losses, with a more general behavioral public finance framework for welfare analysis. This framework applies standard tools of welfare analysis to consumer demand that may be "biased" (that is, not necessarily rational and fully informed) without requiring specific assumptions about the reason for the bias. This framework would require estimates of both biased and unbiased consumer demand; we sketch an agenda to help develop these in the context of smoking. The use of this framework would substantially reduce the confusion currently surrounding welfare analysis of tobacco regulation. PMID- 29404382 TI - When Foreign Domestic Helpers Care for and About Older People in Their Homes: I Am a Maid or a Friend. AB - We examine the lived experiences of foreign domestic helpers (FDH) working with community-dwelling older people in Hong Kong. Unstructured interviews were conducted with 11 female FDHs, and thematically analyzed. The theme inescapable functioning commodity represented the embodied commodification of FDHs to be functional for older people in home care. Another theme, destined reciprocity of companionship, highlighted the FDHs' capacity to commit to home care and be concerned about older people. The waxing and waning of the possibilities of commodified companionship indicated the intermittent capacity of FDHs to find meaning in their care, in which performative nature for functional purposes and emotional engagement took turns to be the foci in migrant home care. This study addresses the transition of FDHs from task-oriented relation to companions of older people through care work. Discussion draws on the development of a kin-like relationship between FDHs and older people with emotional reciprocity grounded in moral values. PMID- 29404383 TI - Efficacy of endoscopic treatment using double-balloon enteroscopy for postoperative bile leakage in patients with hepaticojejunostomy. AB - Background and study aims Endoscopic treatment for post-operative bile is technically challenging in patients with altered gastrointestinal anatomy. This study evaluated the effectiveness of using a short-type double-balloon enteroscope to treat postoperative bile leakage after hepaticojejunostomy. PMID- 29404385 TI - Never tear us a-PARP: Dealing with DNA lesions during mitosis. AB - Tumors defective in homologous recombination (HR) are highly sensitive to poly ADP-ribose polymerase (PARP) inhibition, however the cell biological mechanisms underlying this synthetic lethality remain elusive. We recently identified that PARP inhibitor-induced DNA lesions persist until mitosis, subsequently causing mitotic chromatin bridges, multinucleation and apoptosis. Here, we discuss the implications of these findings. PMID- 29404384 TI - Fully-covered metal stents with endoscopic suturing vs. partially-covered metal stents for benign upper gastrointestinal diseases: a comparative study. AB - Background and study aims : Self-expandable metallic stents (SEMS) have been increasingly used in benign conditions (e. g. strictures, fistulas, leaks, and perforations). Fully covered SEMS (FSEMS) were introduced to avoid undesirable consequences of partially covered SEMS (PSEMS), but come with higher risk of stent migration. Endoscopic suturing (ES) for stent fixation has been shown to reduce migration of FSEMS. Our aim was to compare the outcomes of FSEMS with ES (FS/ES) versus PSEMS in patients with benign upper gastrointestinal conditions. Patients and methods : We retrospectively identified all patients who underwent stent placement for benign gastrointestinal conditions at seven US tertiary-care centers. Patients were divided into two groups: FSEMS with ES (FS/ES group) and PSEMS (PSEMS group). Clinical outcomes between the two groups were compared. Results : A total of 74 (FS/ES 46, PSEMS 28) patients were included. On multivariable analysis, there was no significant difference in rate of stent migration between FS/ES (43 %) and PSEMS (15 %) (adjusted odds ratio 0.56; 95 % CI 0.15 - 2.00). Clinical success was similar [68 % vs. 64 %; P = 0.81]. Rate of adverse events (AEs) was higher in PSEMS group [13 (46 %) vs. 10 (21 %); P = 0.03). Difficult stent removal was higher in the PSEMS group (n = 5;17 %) vs. 0 % in the FS/ES group; P = 0.005. Conclusions : The proportion of stent migration of FS/ES and PSEMS are similar. Rates of other stent-related AEs were higher in the PSEMS group. PSEMS was associated with tissue ingrowth or overgrowth leading to difficult stent removal, and secondary stricture formation. Thus, FSEMS with ES for stent fixation may be the preferred modality over PSEMS for the treatment of benign upper gastrointestinal conditions. PMID- 29404386 TI - Bcl-2 proteins: Unraveling the details of a complex and dynamic network. AB - Apoptosis regulation by Bcl-2 proteins is pivotal for mammalians, not only because it is key for development but also because aberrant apoptosis is prerequisite to severe diseases, like cancer. Recently, we quantified interactions within the Bcl-2 protein network in solution and membranes, and addressed membrane recruitment, preference of interaction partners and the consequences for Bax activation and inhibition. PMID- 29404387 TI - MICAL redox enzymes and actin remodeling: New links to classical tumorigenic and cancer pathways. AB - MICAL Redox enzymes have recently emerged as direct regulators of cell shape and motility - working through specific reversible post-translational oxidation of actin to disassemble and remodel the cytoskeleton. Links are also now emerging between MICALs and cancer, including our recent results that regulation of MICAL sensitizes cancer cells to the cancer drug Gleevec. Targeting this new actin regulatory enzyme system may thus provide new therapeutic options for cancer treatment. PMID- 29404388 TI - Mechanistic understanding of the role of ATRX in senescence provides new insight for combinatorial therapies with CDK4 inhibitors. AB - Senescence is an irreversible form of growth arrest and is generally considered a favorable outcome of cancer therapies, yet little is known about the molecular events that distinguish this state from readily reversible growth arrest (i.e. quiescence). Recently, we discovered that during therapy induced senescence the chromatin remodeling protein alpha-thalassemia, mental retardation, X-linked (ATRX) represses Harvey rat sarcoma viral oncogene homolog (HRAS), and repression of HRAS is necessary to establish senescence, suggesting how new clinical combinations might be used to achieve durable senescence. PMID- 29404389 TI - COBRA methods and metabolic drug targets in cancer. AB - The identification of therapeutic strategies exploiting the metabolic alterations of malignant cells is a relevant area in cancer research. Here, we discuss a novel computational method, based on the COBRA (COnstraint-Based Reconstruction and Analysis) framework for metabolic networks, to perform this task. Current and future steps are presented. PMID- 29404390 TI - Switching from TNF-induced inflammation to death signaling. AB - TNFR1-mediated cell signaling involves complex molecular pathways leading to inflammation and death. Cytosolic RARgamma plays a pivotal role in converting TNF induced inflammatory responses to RIP1 initiated cell death and this finely regulated function of RARgamma serves as a checkpoint to engage death pathways in response to TNF. PMID- 29404391 TI - RAD6 promotes chemoresistance in ovarian cancer. AB - Mortality in ovarian cancer is predominantly due to acquired chemoresistance and tumor recurrence. UBIQUITIN CONJUGATING ENZYME E2 or RAD6 expression increases in cell lines and patient tumors in response to platinum-based chemotherapy and promotes both activation of DNA damage response pathways and expression of stemness genes and a stem cell-like phenotype driving ovarian cancer chemoresistance. PMID- 29404392 TI - Utilizing panels of patient derived xenografts to aid the development of antibody drug conjugates. AB - Despite numerous endeavors in clinical trials there are few clinically approved Antibody Drug Conjugate (ADC) therapies. Here we comment on our recent publication demonstrating the power of using panels of patient-derived xenografts (PDX) prior to Phase 1, to assess the potential heterogeneity of response a clinical candidate may show across a population. Furthermore we discuss how the same approach has been used in an additional ADC program. PMID- 29404393 TI - Dimeric quinacrines as chemical tools to identify PPT1, a new regulator of autophagy in cancer cells. AB - DQ661 is a novel dimeric quinacrine that affects multiple lysosomal functions (autophagy and macropinocytosis) and mTORC1 (mechanistic target of rapamycin) activity by specifically targeting protein-palmitoyl thioesterase 1 (PPT1). DQ661 has in vivo activity in immunocompetent mouse models of cancer, and constitutes a new tool compound for the study of lysosomal function in cancer and therapeutic resistance. PMID- 29404394 TI - To die or not to die: Regulatory feedback phosphorylation circuits determine receptor-interacting protein kinase-1 (RIPK1) function. AB - Complex posttranslational modifications determine the effects of receptor interacting protein kinase-1 (RIPK1) on cell survival and death. Studies from us and others have revealed a p38MAPK/MK2-dependent checkpoint in RIPK1 signaling. MAPKAP kinase 2 (MK2) phosphorylates RIPK1 to suppress RIPK1-mediated apoptosis and necroptosis in response to diverse stimuli relevant to inflammation, infection, genotoxic stress and chemotherapy. PMID- 29404395 TI - Crack the state of silence: Tune the depth of cellular quiescence for cancer therapy. AB - The regulation of cellular quiescence underlies numerous physiopathological phenomena. We recently found that quiescence depth can be tuned as to adjust a dimmer switch, by altering the expression of genes in the Retinoblastoma (Rb)-E2f pathway. Reducing quiescence depth may wake dormant cancer cells and make them susceptible to treatment. PMID- 29404396 TI - Auto-Commentary on: "Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells". AB - We have recently uncovered an abnormal increase in mitochondrial oxidative metabolism in therapy-resistant chronic myeloid leukaemia stem cells (LSCs). By simultaneously disrupting mitochondrial respiration and inhibiting BCR-ABL kinase activity using the antibiotic tigecycline and imatinib respectively, we effectively eradicated LSCs and prevented disease relapse in pre-clinical animal models. PMID- 29404397 TI - Intratumoral bacteria may elicit chemoresistance by metabolizing anticancer agents. AB - We recently reported that bacteria can be found within pancreatic ductal adenocarcinoma (PDAC) tumors. Some of these bacteria can metabolize and thereby inactivate the nucleoside analog gemcitabine. We demonstrated that the long isoform of the bacterial enzyme cytidine deaminase (CDD) mediates the metabolism of gemcitabine. The clinical effect of overcoming this potential mechanism of drug resistance has yet to be studied. PMID- 29404398 TI - Gene gating at nuclear pores prevents the formation of R loops. AB - Transcription is an important source of genetic variability. A large amount of transcription-associated genome variation arises from the unscheduled formation of R loops. We have recently found that physical proximity of chromatin to nuclear pores prevents the formation of pathological R loops during transcription. Our study opens new perspectives to understand genome stability as a function of nuclear location. PMID- 29404399 TI - The turtle and the rabbit story in a modern (PI3)key. AB - Mitosis is a complex process controlling proper distribution of chromosomes and preventing genomic instability, a typical hallmark of cancer. We recently reported that that a class II isoform of Phosphoinositide 3-kinase (PI3K), PI3K C2alpha, is involved in the organization of the mitotic spindle. Our study demonstrate that, differently to all other PI3K isoforms, PI3K-C2alpha shows an unexpected tumor suppressor function independent of its catalytic activity. PMID- 29404400 TI - miRNA displacement as a promising approach for cancer therapy. AB - microRNA (miRNA) are critical post-transcriptional regulators and key players in diseases development. We demonstrated that non-canonical microRNA Responsive Elements (here MRE-16) could sequester miR-16, dampening miR-16 tumor suppressor function. We developed small oligonucleotides, masking specifically these unusual miR-16 binding sites, that restored miR-16 function. This constitutes a promising targeted approach. PMID- 29404401 TI - miRNA-convergent gene fusions. AB - In a recent study published in Nature Communications, we showed that intron encoded microRNA genes (miRNA) are frequent partners of fusion genes in the cancer genome. Analyzed from a functional rather than structural perspective, these rearrangements represent a new class of fusions we called "miRNA-convergent fusions". PMID- 29404402 TI - An Essential Postdevelopmental Role for Lis1 in Mice. AB - LIS1 mutations cause lissencephaly (LIS), a severe developmental brain malformation. Much less is known about its role in the mature nervous system. LIS1 regulates the microtubule motor cytoplasmic dynein 1 (dynein), and as LIS1 and dynein are both expressed in the adult nervous system, Lis1 could potentially regulate dynein-dependent processes such as axonal transport. We therefore knocked out Lis1 in adult mice using tamoxifen-induced, Cre-ER-mediated recombination. When an actin promoter was used to drive Cre-ER expression (Act Cre-ER), heterozygous Lis1 knockout (KO) caused no obvious change in viability or behavior, despite evidence of widespread recombination by a Cre reporter three weeks after tamoxifen exposure. In contrast, homozygous Lis1 KO caused the rapid onset of neurological symptoms in both male and female mice. One tamoxifen-dosing regimen caused prominent recombination in the midbrain/hindbrain, PNS, and cardiac/skeletal muscle within a week; these mice developed severe symptoms in that time frame and were killed. A different tamoxifen regimen resulted in delayed recombination in midbrain/hindbrain, but not in other tissues, and also delayed the onset of symptoms. This indicates that Lis1 loss in the midbrain/hindbrain causes the severe phenotype. In support of this, brainstem regions known to house cardiorespiratory centers showed signs of axonal dysfunction in KO animals. Transport defects, neurofilament (NF) alterations, and varicosities were observed in axons in cultured DRG neurons from KO animals. Because no symptoms were observed when a cardiac specific Cre-ER promoter was used, we propose a vital role for Lis1 in autonomic neurons and implicate defective axonal transport in the KO phenotype. PMID- 29404404 TI - Areas prone to slow slip events impede earthquake rupture propagation and promote afterslip. AB - At subduction zones, transient aseismic slip occurs either as afterslip following a large earthquake or as episodic slow slip events during the interseismic period. Afterslip and slow slip events are usually considered as distinct processes occurring on separate fault areas governed by different frictional properties. Continuous GPS (Global Positioning System) measurements following the 2016 Mw (moment magnitude) 7.8 Ecuador earthquake reveal that large and rapid afterslip developed at discrete areas of the megathrust that had previously hosted slow slip events. Regardless of whether they were locked or not before the earthquake, these areas appear to persistently release stress by aseismic slip throughout the earthquake cycle and outline the seismic rupture, an observation potentially leading to a better anticipation of future large earthquakes. PMID- 29404403 TI - Electrical Stimulation Modulates High gamma Activity and Human Memory Performance. AB - Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high gamma (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with "poor" memory encoding. The high gamma modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high gamma activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high gamma activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation. PMID- 29404405 TI - Drought will not leave your glass empty: Low risk of hydraulic failure revealed by long-term drought observations in world's top wine regions. AB - Grapevines are crops of global economic importance that will face increasing drought stress because many varieties are described as highly sensitive to hydraulic failure as frequency and intensity of summer drought increase. We developed and used novel approaches to define water stress thresholds for preventing hydraulic failure, which were compared to the drought stress experienced over a decade in two of the world's top wine regions, Napa and Bordeaux. We identified the physiological thresholds for drought-induced mortality in stems and leaves and found small intervarietal differences. Long term observations in Napa and Bordeaux revealed that grapevines never reach their lethal water-potential thresholds under seasonal droughts, owing to a vulnerability segmentation promoting petiole embolism and leaf mortality. Our findings will aid farmers in reducing water use without risking grapevine hydraulic integrity. PMID- 29404406 TI - An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells. AB - Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is required for ESC to exit the naive pluripotent state; however, its intrinsic catalytic activity is dispensable for this process. The depletion of the H3K4 demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition from naive to primed pluripotency. Thus, we define an opposing regulatory axis, wherein Lsd1 and associated co-repressors directly repress Mll4 activated gene targets. This finding has broad reaching implications for human developmental syndromes and the treatment of tumors carrying Mll4 mutations. PMID- 29404407 TI - Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. AB - Genome editing with CRISPR/Cas9 is a promising new approach for correcting or mitigating disease-causing mutations. Duchenne muscular dystrophy (DMD) is associated with lethal degeneration of cardiac and skeletal muscle caused by more than 3000 different mutations in the X-linked dystrophin gene (DMD). Most of these mutations are clustered in "hotspots." There is a fortuitous correspondence between the eukaryotic splice acceptor and splice donor sequences and the protospacer adjacent motif sequences that govern prokaryotic CRISPR/Cas9 target gene recognition and cleavage. Taking advantage of this correspondence, we screened for optimal guide RNAs capable of introducing insertion/deletion (indel) mutations by nonhomologous end joining that abolish conserved RNA splice sites in 12 exons that potentially allow skipping of the most common mutant or out-of frame DMD exons within or nearby mutational hotspots. We refer to the correction of DMD mutations by exon skipping as myoediting. In proof-of-concept studies, we performed myoediting in representative induced pluripotent stem cells from multiple patients with large deletions, point mutations, or duplications within the DMD gene and efficiently restored dystrophin protein expression in derivative cardiomyocytes. In three-dimensional engineered heart muscle (EHM), myoediting of DMD mutations restored dystrophin expression and the corresponding mechanical force of contraction. Correcting only a subset of cardiomyocytes (30 to 50%) was sufficient to rescue the mutant EHM phenotype to near-normal control levels. We conclude that abolishing conserved RNA splicing acceptor/donor sites and directing the splicing machinery to skip mutant or out-of-frame exons through myoediting allow correction of the cardiac abnormalities associated with DMD by eliminating the underlying genetic basis of the disease. PMID- 29404408 TI - Depressive symptoms and sickle cell pain: The moderating role of internalized stigma. AB - Recent studies describe the clinical implications of sickle cell disease (SCD) stigma. However, little is known about its link to depressive symptoms or its relative influence on the association between depressive symptoms and SCD pain. We examined whether internalized stigma about SCD moderated the relation between depressive symptoms and pain among 69 adults attending a SCD clinic who reported pain episodes and healthcare use over the past three months. Unadjusted bivariate analyses showed a marginal association between depressive symptoms and SCD pain frequency (r = .21, p < .10). Further analyses adjusting for health care use indicated a moderating effect of internalized stigma (b = -.10, p < .05): a significant association between depressive symptoms and pain was observed among participants low in internalized stigma, but this relationship was attenuated at moderate and high stigma levels. These results denote counterintuitive consequences of internalized attitudes about SCD and suggest a need for further study of the psychosocial and clinical implications of SCD stigma. PMID- 29404409 TI - The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users. AB - Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18-30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls. Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis*DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability. Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected. PMID- 29404410 TI - Ectopic Expression of O Antigen in Bordetella pertussis by a Novel Genomic Integration System. AB - We describe a novel genome integration system that enables the introduction of DNA fragments as large as 50 kbp into the chromosomes of recipient bacteria. This system, named BPI, comprises a bacterial artificial chromosome vector and phage derived gene integration machinery. We introduced the wbm locus of Bordetella bronchiseptica, which is required for O antigen biosynthesis, into the chromosome of B. pertussis, which intrinsically lacks O antigen, using the BPI system. After the introduction of the wbm locus, B. pertussis presented an additional substance in the lipooligosaccharide fraction that was specifically recognized by the anti B. bronchiseptica antibody but not the anti-B. pertussis antibody, indicating that B. pertussis expressed O antigen corresponding to that of B. bronchiseptica. O antigen-expressing B. pertussis was less sensitive to the bactericidal effects of serum and polymyxin B than the isogenic parental strain. In addition, an in vivo competitive infection assay showed that O antigen-expressing B. pertussis dominantly colonized the mouse respiratory tract over the parental strain. These results indicate that the BPI system provides a means to alter the phenotypes of bacteria by introducing large exogenous DNA fragments. IMPORTANCE Some bacterial phenotypes emerge through the cooperative functions of a number of genes residing within a large genetic locus. To transfer the phenotype of one bacterium to another, a means to introduce the large genetic locus into the recipient bacterium is needed. Therefore, we developed a novel system by combining the advantages of a bacterial artificial chromosome vector and phage-derived gene integration machinery. In this study, we succeeded for the first time in introducing a gene locus involved in O antigen biosynthesis of Bordetella bronchiseptica into the chromosome of B. pertussis, which intrinsically lacks O antigen, and using this system we analyzed phenotypic alterations in the resultant mutant strain of B. pertussis. The present results demonstrate that this system successfully accomplished the above-described purpose. We consider this system to be applicable to a number of bacteria other than Bordetella. PMID- 29404411 TI - Lanthanide-Dependent Regulation of Methylotrophy in Methylobacteriumaquaticum Strain 22A. AB - Methylobacterium species are representative of methylotrophic bacteria. Their genomes usually encode two types of methanol dehydrogenases (MDHs): MxaF and XoxF. The former is a Ca2+-dependent enzyme, and the latter was recently determined to be a lanthanide-dependent enzyme that is necessary for the expression of mxaF. This finding revealed the unexpected and important roles of lanthanides in bacterial methylotrophy. In this study, we performed transcriptome sequencing (RNA-seq) analysis using M. aquaticum strain 22A grown in the presence of different lanthanides. Expression of mxaF and xoxF1 genes showed a clear inverse correlation in response to La3+. We observed downregulation of formaldehyde oxidation pathways, high formaldehyde dehydrogenase activity, and low accumulation of formaldehyde in the reaction with cells grown in the presence of La3+; this might be due to the direct oxidation of methanol to formate by XoxF1. Lanthanides induced the transcription of AT-rich genes, the function of most of which was unknown, and genes possibly related to cellular survival, as well as other MDH homologues. These results revealed not only the metabolic response toward altered primary methanol oxidation, but also the possible targets to be investigated further in order to better understand methylotrophy in the presence of lanthanides. IMPORTANCE Lanthanides have been considered unimportant for biological processes. In methylotrophic bacteria, however, a methanol dehydrogenase (MDH) encoded by xoxF was recently found to be lanthanide dependent, while the classic-type mxaFI is calcium dependent. XoxF-type MDHs are more widespread in diverse bacterial genera, suggesting their importance for methylotrophy. Methylobacterium species, representative methylotrophic and predominating alphaproteobacteria in the phyllosphere, contain both types and regulate their expression depending on the availability of lanthanides. RNA-seq analysis showed that the regulation takes place not only for MDH genes but also the subsequent formaldehyde oxidation pathways and respiratory chain, which might be due to the direct oxidation of methanol to formate by XoxF. In addition, a considerable number of genes of unknown function, including AT-rich genes, were found to be upregulated in the presence of lanthanides. This study provides first insights into the specific reaction of methylotrophic bacteria to the presence of lanthanides, emphasizing the biological relevance of this trace metal. PMID- 29404412 TI - In Situ Analyses Directly in Diarrheal Stool Reveal Large Variations in Bacterial Load and Active Toxin Expression of Enterotoxigenic Escherichiacoli and Vibrio cholerae. AB - The bacterial pathogens enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae are major causes of diarrhea. ETEC causes diarrhea by production of the heat-labile toxin (LT) and heat-stable toxins (STh and STp), while V. cholerae produces cholera toxin (CT). In this study, we determined the occurrence and bacterial doses of the two pathogens and their respective toxin expression levels directly in liquid diarrheal stools of patients in Dhaka, Bangladesh. By quantitative culture and real-time quantitative PCR (qPCR) detection of the toxin genes, the two pathogens were found to coexist in several of the patients, at concentrations between 102 and 108 bacterial gene copies per ml. Even in culture negative samples, gene copy numbers of 102 to 104 of either ETEC or V. cholerae toxin genes were detected by qPCR. RNA was extracted directly from stool, and gene expression levels, quantified by reverse transcriptase qPCR (RT-qPCR), of the genes encoding CT, LT, STh, and STp showed expression of toxin genes. Toxin enzyme-linked immunosorbent assay (ELISA) confirmed active toxin secretion directly in the liquid diarrhea. Analysis of ETEC isolates by multiplex PCR, dot blot analysis, and genome sequencing suggested that there are genetic ETEC profiles that are more commonly found as dominating single pathogens and others that are coinfectants with lower bacterial loads. The ETEC genomes, including assembled genomes of dominating ETEC isolates expressing LT/STh/CS5/CS6 and LT/CS7, are provided. In addition, this study highlights an emerging important ETEC strain expressing LT/STp and the novel colonization factor CS27b. These findings have implications for investigations of pathogenesis as well as for vaccine development. IMPORTANCE The cause of diarrheal disease is usually determined by screening for several microorganisms by various methods, and sole detection is used to assign the agent as the cause of disease. However, it has become increasingly clear that many infections are caused by coinfections with several pathogens and that the dose of the infecting pathogen is important. We quantified the absolute numbers of enterotoxigenic E. coli (ETEC) and Vibrio cholerae directly in diarrheal fluid. We noted several events where both pathogens were found but also a large dose dependency. In three samples, we found ETEC as the only pathogen sought for. These isolates belonged to globally distributed ETEC clones and were the dominating species in stool with active toxin expression. This suggests that certain superior virulent ETEC lineages are able to outcompete the gut microbiota and be the sole cause of disease and hence need to be specifically monitored. PMID- 29404413 TI - BioID Reveals Novel Proteins of the Plasmodium Parasitophorous Vacuole Membrane. AB - During their development within the vertebrate host, Plasmodium parasites infect hepatocytes and red blood cells. Within these cells, parasites are surrounded by a parasitophorous vacuole membrane (PVM). The PVM plays an essential role for the interaction of parasites with their host cells; however, only a limited number of proteins of this membrane have been identified so far. This is partially because systematic proteomic analysis of the protein content of the PVM has been difficult in the past, due to difficulties encountered in attempts to separate the PVM from other membranes such as the parasite plasma membrane. In this study, we adapted the BioID technique to in vitro-cultivated Plasmodium berghei blood stage parasites and utilized the promiscuous biotin ligase BirA* fused to PVM resident exported protein 1 to biotinylate proteins of the PVM. These we further processed by affinity purification, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and label-free quantitation, leading to a list of 61 known and candidate PVM proteins. Seven proteins were analyzed further during blood and liver stage development. This resulted in the identification of three novel PVM proteins, which were the serine/threonine protein phosphatase UIS2 (PlasmoDB accession no. PBANKA_1328000) and two conserved Plasmodium proteins with unknown functions (PBANKA_0519300 and PBANKA_0509000). In conclusion, our report expands the number of known PVM proteins and experimentally validates BioID as a powerful method to screen for novel constituents of specific cellular compartments in P. berghei. IMPORTANCE Intracellular pathogens are often surrounded by a host-cell derived membrane. This membrane is modified by the pathogens to their own needs and is crucial for their intracellular lifestyle. In Plasmodium parasites, this membrane is referred to as the PVM and only a limited number of its proteins are known so far. Here, we applied in rodent P. berghei parasites a method called BioID, which is based on biotinylation of proximal and interacting proteins by the promiscuous biotin ligase BirA*, and demonstrated its usefulness in identification of novel PVM proteins. PMID- 29404414 TI - An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant Acinetobacter baumannii-Infected Wounds. AB - The antibiotic paenimucillin A was originally identified using a culture independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR A. baumannii wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents. IMPORTANCE Natural product-inspired antibiotics have saved millions of lives and played a critical role in modern medicine. However, the emergence of drug-resistant pathogens is outpacing the rate at which new clinically useful antibiotics are being discovered. The lack of a means to combat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii is of particular concern. The sharp increase in cases of MDR A. baumannii infections in recent years prompted the CDC (https://www.cdc.gov/drugresistance/biggest_threats.html) and WHO (http://www.who.int/medicines/publications/global-priority-list-antibiotic resistant-bacteria/en/) to list this pathogen as a "serious threat" and "critical pathogen," respectively. Here we report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR A. baumannii strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR A. baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen. PMID- 29404415 TI - Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug Resistant Staphylococcus aureus. AB - Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but the clinical relevance is unknown. Here, by analyzing 7,099 S. aureus genomes, we demonstrate that the most prevalent RpoB mutations promote clinically relevant phenotypic plasticity resulting in the emergence of stable S. aureus lineages, associated with increased risk of therapeutic failure through generation of small-colony variants (SCVs) and coresistance to last-line antimicrobial agents. We found eight RpoB mutations that accounted for 93% (469/505) of the total number of Rifr mutations. The most frequently selected amino acid substitutions affecting residue 481 (H481N/Y) were associated with worldwide expansions of Rifr clones spanning decades. Recreating the H481N/Y mutations confirmed no impact on S. aureus growth, but the H481N mutation promoted the emergence of a subpopulation of stable Rifr SCVs with reduced susceptibility to vancomycin and daptomycin. Recreating the other frequent RpoB mutations showed similar impacts on resistance to these last-line agents. We found that 86% of all Rifr isolates in our global sample carried the mutations promoting cross-resistance to vancomycin and 52% to both vancomycin and daptomycin. As four of the most frequent RpoB mutations confer only low-level Rifr, equal to or below some international breakpoints, we recommend decreasing these breakpoints and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these clinically deleterious mutations. IMPORTANCE Increasing antibiotic resistance in the major human pathogen Staphylococcus aureus is threatening the ability to treat patients with these infections. Recent laboratory studies suggest that mutations in the gene commonly associated with rifampin resistance may also impact susceptibility to other last-line antibiotics in S. aureus; however, the overall frequency and clinical impact of these mutations are unknown. By mining a global collection of clinical S. aureus genomes and by mutagenesis experiments, this work reveals that common rifampin-induced rpoB mutations promote phenotypic plasticity that has led to the global emergence of stable, multidrug-resistant S. aureus lineages that are associated with increased risk of therapeutic failure through coresistance to other last-line antimicrobials. We recommend decreasing susceptibility breakpoints for rifampin to allow phenotypic detection of critical rpoB mutations conferring low resistance to rifampin and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these deleterious mutations globally. PMID- 29404416 TI - RcaE-Dependent Regulation of Carboxysome Structural Proteins Has a Central Role in Environmental Determination of Carboxysome Morphology and Abundance in Fremyella diplosiphon. AB - Carboxysomes are central to the carbon dioxide-concentrating mechanism (CCM) and carbon fixation in cyanobacteria. Although the structure is well understood, roles of environmental cues in the synthesis, positioning, and functional tuning of carboxysomes have not been systematically studied. Fremyella diplosiphon is a model cyanobacterium for assessing impacts of environmental light cues on photosynthetic pigmentation and tuning of photosynthetic efficiency during complementary chromatic acclimation (CCA), which is controlled by the photoreceptor RcaE. Given the central role of carboxysomes in photosynthesis, we investigated roles of light-dependent RcaE signaling in carboxysome structure and function. A DeltarcaE mutant exhibits altered carboxysome size and number, ccm gene expression, and carboxysome protein accumulation relative to the wild-type (WT) strain. Several Ccm proteins, including carboxysome shell proteins and core nucleating factors, overaccumulate in DeltarcaE cells relative to WT cells. Additionally, levels of carboxysome cargo RuBisCO in the DeltarcaE mutant are lower than or unchanged from those in the WT strain. This shift in the ratios of carboxysome shell and nucleating components to the carboxysome cargo appears to drive carboxysome morphology and abundance dynamics. Carboxysomes are also occasionally mislocalized spatially to the periphery of spherical mutants within thylakoid membranes, suggesting that carboxysome positioning is impacted by cell shape. The RcaE photoreceptor links perception of external light cues to regulating carboxysome structure and function and, thus, to the cellular capacity for carbon fixation. IMPORTANCE Carboxysomes are proteinaceous subcellular compartments, or bacterial organelles, found in cyanobacteria that consist of a protein shell surrounding a core primarily composed of the enzyme ribulose-1,5 biphosphate carboxylase/oxygenase (RuBisCO) that is central to the carbon dioxide concentrating mechanism (CCM) and carbon fixation. Whereas significant insights have been gained regarding the structure and synthesis of carboxysomes, limited attention has been given to how their size, abundance, and protein composition are regulated to ensure optimal carbon fixation in dynamic environments. Given the centrality of carboxysomes in photosynthesis, we provide an analysis of the role of a photoreceptor, RcaE, which functions in matching photosynthetic pigmentation to the external environment during complementary chromatic acclimation and thereby optimizing photosynthetic efficiency, in regulating carboxysome dynamics. Our data highlight a role for RcaE in perceiving external light cues and regulating carboxysome structure and function and, thus, in the cellular capacity for carbon fixation and organismal fitness. PMID- 29404417 TI - Air-Dried Brown Seaweed, Ascophyllum nodosum, Alters the Rumen Microbiome in a Manner That Changes Rumen Fermentation Profiles and Lowers the Prevalence of Foodborne Pathogens. AB - The use of Tasco (air-dried Ascophyllum nodosum) as a feed supplement for ruminants has been reported to affect rumen fermentation and reduce Escherichia coli O157:H7 shedding in feces, but the mode of action behind this phenomenon is unclear. In this study, the effects of four Tasco levels (0, 1, 3, and 5%) on rumen microbiota and rumen/fecal E. coli O serogroups in rams were investigated. Rumen total bacteria and archaea were linearly reduced (P < 0.001) and protozoa were linearly increased (P < 0.001) by increasing levels of Tasco. The relative abundances of seven bacterial species and one protozoal species differed among Tasco levels. With Tasco, 14 predicted metabolic pathways were enriched while only 3 were suppressed. A lower ruminal butyrate concentration is possibly associated with enrichment of the "butanoate metabolism" pathway in Tasco-fed rams. The ruminal total E. coli population was linearly reduced (P < 0.001) by Tasco. Supplementation with Tasco only completely eliminated O121 in the rumen and feces, and higher levels of Tasco (3 and 5%) reduced fecal shedding of serogroups O45, O103, and O111 even though these serogroups were present in the rumen. Our results suggest that Tasco effectively reduced pathogenic E. coli but had only minimal impacts on rumen fermentation in rams. IMPORTANCE Maintaining product safety and reducing the carbon footprint of production are two sustainability goals of the livestock industry. The objective of this study was to study the impact of Tasco, a product derived from the brown macroalga Ascophyllum nodosum, on the rumen microbiome and its function. The inclusion of Tasco altered both rumen and fecal microbiota levels without affecting rumen fermentation. Tasco reduced fecal Escherichia coli populations and specifically reduced the prevalence of Shiga toxin-producing E. coli O45, O103, O111, and O121 in feces. The findings of this study highlight the application of Tasco as a potential feed additive to reduce pathogen shedding in rams without interfering with ruminal metabolism. PMID- 29404418 TI - Intravaginal Administration of Interleukin 12 during Genital Gonococcal Infection in Mice Induces Immunity to Heterologous Strains of Neisseria gonorrhoeae. AB - It has previously been shown that genital tract infection with Neisseria gonorrhoeae in mice does not induce a state of protective immunity against reinfection but instead suppresses the development of adaptive immune responses against N. gonorrhoeae dependent on transforming growth factor beta (TGF-beta) and interleukin 10 (IL-10). Intravaginal administration during gonococcal infection of IL-12 encapsulated in biodegradable microspheres (IL-12/ms) reverses the immunosuppression and promotes the production of gamma interferon (IFN-gamma) and of specific antibodies in serum and genital secretions and accelerates clearance of the infection. In this study, microspheres were shown to remain largely within the genital tract lumen and to release IL-12 over the course of 4 days. Antigonococcal IgA and IgG antibodies induced by IL-12/ms treatment reacted with antigenically different strains of N. gonorrhoeae and led to resistance to reinfection with heterologous and homologous strains. Immune resistance to reinfection persisted for at least 6 months after clearance of the primary infection. Experiments performed with immunodeficient strains of mice lacking either IFN-gamma or B cells demonstrated that both IFN-gamma and B cells were necessary for the IL-12-induced generation of immune responses to N. gonorrhoeae and the resulting accelerated clearance of the infection. It is therefore concluded that intravaginally administered IL-12/ms achieves its effect by the sustained release of IL-12 that promotes Th1-driven adaptive immune responses, including the production of specific antigonococcal antibodies that cross-react with multiple strains of N. gonorrhoeae. IL-12-enhanced immunity to N. gonorrhoeae can be recalled against reinfection after prolonged intervals and is dependent upon both IFN-gamma and antibody production by B cells. IMPORTANCE Genital infection with Neisseria gonorrhoeae (gonorrhea) is a significant cause of reproductive tract morbidity in women, leading to pelvic inflammatory disease, tubal factor infertility, and increased risk for ectopic pregnancy. WHO estimates that 78 million new infections occur annually worldwide. In the United States, >350,000 cases are reported annually, but the true incidence is probably >800,000 cases/year. Increasing resistance to currently available antibiotics raises concern that gonorrhea might become untreatable. Infection does not induce a state of immune protection against reinfection. Previous studies have shown that N. gonorrhoeae suppresses the development of adaptive immune responses by mechanisms dependent on the regulatory cytokines TGF-beta and IL-10. This study shows that intravaginal treatment of gonococcal infection in female mice with microencapsulated IL-12 induces persisting anamnestic immunity against reinfection with N. gonorrhoeae, even of antigenically diverse strains, dependent on T-cell production of IFN-gamma and B-cell production of antibodies. PMID- 29404419 TI - Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection. AB - Dengue virus (DENV) is among the most important human arboviruses and is clinically and experimentally associated with lipid metabolism disorders. Using high-resolution respirometry, we analyzed the metabolic switches induced by DENV in a human hepatic cell line. This experimental approach allowed us to determine the contribution of fatty acids, glutamine, glucose, and pyruvate to mitochondrial bioenergetics, shedding light on the mechanisms involved in DENV induced metabolic alterations. We found that while infection strongly inhibits glutamine oxidation, it increases the cellular capacity of metabolizing glucose; remarkably, though, this substrate, instead being used as an energy source, performs an anaplerotic role in the oxidation of endogenous lipids. Fatty acids become the main energetic substrate in infected cell, and through the pharmacological modulation of beta-oxidation we demonstrated that this pathway is essential for virus replication. Interestingly, infected cells were much less susceptible to the Crabtree effect, i.e., the glucose-mediated inhibition of mitochondrial oxygen consumption, suggesting that infection favors cellular respiration by increasing ADP availability. IMPORTANCE Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology. PMID- 29404420 TI - Limited Evidence for Infection of Urban and Peri-urban Nonhuman Primates with Zika and Chikungunya Viruses in Brazil. AB - Chikungunya virus (CHIKV) and Zika virus (ZIKV) emerged in the Americas in 2013. Limited antigenic variability of CHIKV and ZIKV may restrict urban transmission cycles due to population protective immunity. In Africa, sylvatic transmission cycles involving nonhuman primates (NHP) are known for CHIKV and ZIKV, causing cyclic reemergence in humans. To evaluate whether sylvatic cycles can be expected in Latin America, we tested 207 NHP collected between 2012 and 2017 in urban and peri-urban settings in Brazil for infection with ZIKV and CHIKV. No animal tested positive for viral RNA in genus-specific and species-specific reverse transcription-PCR (RT-PCR) assays. In contrast, six animals (2.9%) from the families Atelidae, Callitrichidae, and Cebidae showed ZIKV-specific antibodies and 11 (5.3%) showed CHIKV-specific antibodies in plaque reduction neutralization tests (PRNT). Reactivity was monotypic against either ZIKV or CHIKV in all cases, opposing unspecific virucidal activity of sera. PRNT endpoint titers were low at 1:40 in all NHP, and positive specimens did not correspond to the likely dispersal route and time of introduction of both arboviruses. All antibody positive samples were therefore tested against the NHP-associated yellow fever virus (YFV) and Mayaro virus (MAYV) and against the human-associated dengue virus (DENV) by PRNT. Two ZIKV-positive samples were simultaneously DENV positive and two CHIKV-positive samples were simultaneously MAYV positive, at titers of 1:40 to 1:160. This suggested cross-reactive antibodies against heterologous alphaviruses and flaviviruses in 24% of ZIKV-positive/CHIKV-positive sera. In sum, low seroprevalence, invariably low antibody titers, and the distribution of positive specimens call into question the capability of ZIKV and CHIKV to infect New World NHP and establish sylvatic transmission cycles. IMPORTANCE Since 2013, Zika virus (ZIKV) and chikungunya virus (CHIKV) have infected millions of people in the Americas via urban transmission cycles. Nonhuman primates (NHP) are involved in sylvatic transmission cycles maintaining ZIKV and CHIKV in the Old World. We tested NHP sampled during 2012 to 2017 in urban and peri-urban areas severely affected by ZIKV and CHIKV in Brazil. Seroprevalence and antibody titers were low for both viruses. Additionally, we found evidence for infection by heterologous viruses eliciting cross-reactive antibodies. Our data suggest that urban or peri-urban NHP are not easily infected by ZIKV and CHIKV despite intense local transmission. These data may imply that the ZIKV and CHIKV outbreaks in the Americas cannot be sustained in urban or peri-urban NHP once human population immunity limits urban transmission cycles. Investigation of diverse animals is urgently required to determine the fate of the ZIKV and CHIKV outbreaks in the Americas. PMID- 29404421 TI - The Odyssey of the Ancestral Escherich Strain through Culture Collections: an Example of Allopatric Diversification. AB - More than a century ago, Theodor Escherich isolated the bacterium that was to become Escherichia coli, one of the most studied organisms. Not long after, the strain began an odyssey and landed in many laboratories across the world. As laboratory culture conditions could be responsible for major changes in bacterial strains, we conducted a genome analysis of isolates of this emblematic strain from different culture collections (England, France, the United States, Germany). Strikingly, many discrepancies between the isolates were observed, as revealed by multilocus sequence typing (MLST), the presence of virulence-associated genes, core genome MLST, and single nucleotide polymorphism/indel analyses. These differences are correlated with the phylogeographic history of the strain and were due to an unprecedented number of mutations in coding DNA repair functions such as mismatch repair (MutL) and oxidized guanine nucleotide pool cleaning (MutT), conferring a specific mutational spectrum and leading to a mutator phenotype. The mutator phenotype was probably acquired during subculturing and corresponded to second-order selection. Furthermore, all of the isolates exhibited hypersusceptibility to antibiotics due to mutations in efflux pump- and porin-encoding genes, as well as a specific mutation in the sigma factor-encoding gene rpoS. These defects reflect a self-preservation and nutritional competence tradeoff allowing survival under the starvation conditions imposed by storage. From a clinical point of view, dealing with such mutator strains can lead microbiologists to draw false conclusions about isolate relatedness and may impact therapeutic effectiveness. IMPORTANCE Mutator phenotypes have been described in laboratory-evolved bacteria, as well as in natural isolates. Several genes can be impacted, each of them being associated with a typical mutational spectrum. By studying one of the oldest strains available, the ancestral Escherich strain, we were able to identify its mutator status leading to tremendous genetic diversity among the isolates from various collections and allowing us to reconstruct the phylogeographic history of the strain. This mutator phenotype was probably acquired during the storage of the strain, promoting adaptation to a specific environment. Other mutations in rpoS and efflux pump- and porin-encoding genes highlight the acclimatization of the strain through self-preservation and nutritional competence regulation. This strain history can be viewed as unintentional experimental evolution in culture collections all over the word since 1885, mimicking the long-term experimental evolution of E. coli of Lenski et al. (O. Tenaillon, J. E. Barrick, N. Ribeck, D. E. Deatherage, J. L. Blanchard, A. Dasgupta, G. C. Wu, S. Wielgoss, S. Cruveiller, C. Medigue, D. Schneider, and R. E. Lenski, Nature 536:165-170, 2016, https://doi.org/10.1038/nature18959) that shares numerous molecular features. PMID- 29404422 TI - Abiotic Stresses Shift Belowground Populus-Associated Bacteria Toward a Core Stress Microbiome. AB - Adverse growth conditions can lead to decreased plant growth, productivity, and survival, resulting in poor yields or failure of crops and biofeedstocks. In some cases, the microbial community associated with plants has been shown to alleviate plant stress and increase plant growth under suboptimal growing conditions. A systematic understanding of how the microbial community changes under these conditions is required to understand the contribution of the microbiome to water utilization, nutrient uptake, and ultimately yield. Using a microbiome inoculation strategy, we studied how the belowground microbiome of Populus deltoides changes in response to diverse environmental conditions, including water limitation, light limitation (shading), and metal toxicity. While plant responses to treatments in terms of growth, photosynthesis, gene expression and metabolite profiles were varied, we identified a core set of bacterial genera that change in abundance in response to host stress. The results of this study indicate substantial structure in the plant microbiome community and identify potential drivers of the phytobiome response to stress. IMPORTANCE The identification of a common "stress microbiome" indicates tightly controlled relationships between the plant host and bacterial associates and a conserved structure in bacterial communities associated with poplar trees under different growth conditions. The ability of the microbiome to buffer the plant from extreme environmental conditions coupled with the conserved stress microbiome observed in this study suggests an opportunity for future efforts aimed at predictably modulating the microbiome to optimize plant growth. PMID- 29404423 TI - Host-Virus Protein Interaction Network Reveals the Involvement of Multiple Host Processes in the Life Cycle of Hepatitis E Virus. AB - Comprehensive knowledge of host-pathogen interactions is central to understand the life cycle of a pathogen and devise specific therapeutic strategies. Protein protein interactions (PPIs) are key mediators of host-pathogen interactions. Hepatitis E virus (HEV) is a major cause of viral hepatitis in humans. Recent reports also demonstrate its extrahepatic manifestations in the brain. Toward understanding the molecular details of HEV life cycle, we screened human liver and fetal brain cDNA libraries to identify the host interaction partners of proteins encoded by genotype 1 HEV and constructed the virus-host PPI network. Analysis of the network indicated a role of HEV proteins in modulating multiple host biological processes such as stress and immune responses, the ubiquitin proteasome system, energy and iron metabolism, and protein translation. Further investigations revealed the presence of multiple host translation regulatory factors in the viral translation/replication complex. Depletion of host translation factors such as eIF4A2, eIF3A, and RACK1 significantly reduced the viral replication, whereas eIF2AK4 depletion had no effect. These findings highlight the ingenuity of the pathogen in manipulating the host machinery to its own benefit, a clear understanding of which is essential for the identification of strategic targets and development of specific antivirals against HEV. IMPORTANCE Hepatitis E virus (HEV) is a pathogen that is transmitted by the fecal oral route. Owing to the lack of an efficient laboratory model, the life cycle of the virus is poorly understood. During the course of infection, interactions between the viral and host proteins play essential roles, a clear understanding of which is essential to decode the life cycle of the virus. In this study, we identified the direct host interaction partners of all HEV proteins and generated a PPI network. Our functional analysis of the HEV-human PPI network reveals a role of HEV proteins in modulating multiple host biological processes such as stress and immune responses, the ubiquitin-proteasome system, energy and iron metabolism, and protein translation. Further investigations revealed an essential role of several host factors in HEV replication. Collectively, the results from our study provide a vast resource of PPI data from HEV and its human host and identify the molecular components of the viral translation/replication machinery. PMID- 29404424 TI - Signatures of Selection at Drug Resistance Loci in Mycobacterium tuberculosis. AB - Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis. Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tuberculosis arises solely by de novo chromosomal mutation. Using whole-genome sequencing data from two natural populations of M. tuberculosis, we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant subpopulations to be less diverse than susceptible subpopulations, consistent with ongoing transmission of resistant M. tuberculosis. A subset of resistance genes ("sloppy targets") were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For "tight targets" of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times in the phylogeny and segregated at markedly different frequencies in resistant and susceptible subpopulations. These results suggest that diverse genetic architectures underlie drug resistance in M. tuberculosis and that combined approaches are needed to identify causal mutations. Extrapolating from patterns observed for well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria. IMPORTANCEMycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tuberculosis populations. Identifying the mutations that cause drug resistance in M. tuberculosis is important for guiding TB treatment and halting the spread of drug resistance. Whole-genome sequencing (WGS) of M. tuberculosis isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug-resistant M. tuberculosis to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tuberculosis and other clonal pathogens. PMID- 29404425 TI - Gut Microbiota Offers Universal Biomarkers across Ethnicity in Inflammatory Bowel Disease Diagnosis and Infliximab Response Prediction. AB - Gut microbiota dysbiosis contributes to the onset and perpetuation of inflammatory bowel disease (IBD). Given that gut microbiotas vary across geography and ethnicity, it remains obscure whether any universal microbial signatures for IBD diagnosis and prognosis evaluation exist irrespective of populations. Here we profiled the fecal microbiota of a series of Chinese IBD patients and combined them with two Western IBD cohorts, PRISM and RISK, for meta analyses. We found that the gut microbial alteration patterns in IBD are similar among Chinese and Westerners. Our prediction model based on gut microbiome for IBD diagnosis is robust across the cohorts, which showed 87.5% and 79.1% prediction accuracy in Crohn's disease (CD) and ulcerative colitis (UC) patients, respectively. A relative increase in the levels of Actinobacteria and Proteobacteria (Enterobacteriaceae) and a relative decrease in the levels of Firmicutes (Clostridiales) were strongly correlated with IBD severity (P < 0.05). Additionally, restoration of gut microbiota diversity and a significant increase in Clostridiales relative abundance were found in patients responding to infliximab (IFX [Remicade]) treatment compared to those in relapse. Moreover, certain microbes, mainly Clostridiales, predicted the treatment effectiveness with 86.5% accuracy alone and 93.8% accuracy in combination with calprotectin levels and Crohn's disease activity index (CDAI). Taking the results together, we conclude that gut microbiota can offer a set of universal biomarkers for diagnosis, disease activity evaluation, and infliximab treatment response prediction in IBD. IMPORTANCE In the present report, we show that the human fecal microbiota contains promising and universal biomarkers for the noninvasive evaluation of inflammatory bowel disease severity and IFX treatment efficacy, emphasizing the potential ability to mine the gut microbiota as a modality to stratify IBD patients and apply personalized therapy for optimal outcomes. PMID- 29404426 TI - Omics-Based Insights into Flavor Development and Microbial Succession within Surface-Ripened Cheese. AB - In this study, a young Cheddar curd was used to produce two types of surface ripened cheese, using two commercial smear-culture mixes of yeasts and bacteria. Whole-metagenome shotgun sequencing was used to screen the microbial population within the smear-culture mixes and on the cheese surface, with comparisons of microorganisms at both the species and the strain level. The use of two smear mixes resulted in the development of distinct microbiotas on the surfaces of the two test cheeses. In one case, most of the species inoculated on the cheese established themselves successfully on the surface during ripening, while in the other, some of the species inoculated were not detected during ripening and the most dominant bacterial species, Glutamicibacter arilaitensis, was not a constituent of the culture mix. Generally, yeast species, such as Debaryomyces hansenii and Geotrichum candidum, were dominant during the first stage of ripening but were overtaken by bacterial species, such as Brevibacterium linens and G. arilaitensis, in the later stages. Using correlation analysis, it was possible to associate individual microorganisms with volatile compounds detected by gas chromatography-mass spectrometry in the cheese surface. Specifically, D. hansenii correlated with the production of alcohols and carboxylic acids, G. arilaitensis with alcohols, carboxylic acids and ketones, and B. linens and G. candidum with sulfur compounds. In addition, metagenomic sequencing was used to analyze the metabolic potential of the microbial populations on the surfaces of the test cheeses, revealing a high relative abundance of metagenomic clusters associated with the modification of color, variation of pH, and flavor development. IMPORTANCE Fermented foods, in particular, surface-ripened cheese, represent a model to explain the metabolic interactions which regulate microbial succession in complex environments. This study explains the role of individual species in a heterogeneous microbial environment, i.e., the exterior of surface ripened cheese. Through whole-metagenome shotgun sequencing, it was possible to investigate the metabolic potential of the resident microorganisms and show how variations in the microbial populations influence important aspects of cheese ripening, especially flavor development. Overall, in addition to providing fundamental insights, this research has considerable industrial relevance relating to the production of fermented food with specific qualities. PMID- 29404428 TI - Introducing Hepatology Communications. PMID- 29404427 TI - Linking Nitrogen Load to the Structure and Function of Wetland Soil and Rhizosphere Microbial Communities. AB - Wetland ecosystems are important reservoirs of biodiversity and significantly contribute to emissions of the greenhouse gases CO2, N2O, and CH4. High anthropogenic nitrogen (N) inputs from agriculture and fossil fuel combustion have been recognized as a severe threat to biodiversity and ecosystem functioning, such as control of greenhouse gas emissions. Therefore, it is important to understand how increased N input into pristine wetlands affects the composition and activity of microorganisms, especially in interaction with dominant wetland plants. In a series of incubations analyzed over 90 days, we disentangled the effects of N fertilization on the microbial community in bulk soil and the rhizosphere of Juncus acutiflorus, a common and abundant graminoid wetland plant. We observed an increase in greenhouse gas emissions when N is increased in incubations with J. acutiflorus, changing the system from a greenhouse gas sink to a source. Using 16S rRNA gene amplicon sequencing, we determined that the bacterial orders Opitutales, subgroup 6 Acidobacteria, and Sphingobacteriales significantly responded to high N availability. Based on metagenomic data, we hypothesize that these groups are contributing to the increased greenhouse gas emissions. These results indicated that increased N input leads to shifts in microbial activity within the rhizosphere, altering N cycling dynamics. Our study provides a framework for connecting environmental conditions of wetland bulk and rhizosphere soil to the structure and metabolic output of microbial communities. IMPORTANCE Microorganisms living within the rhizospheres of wetland plants significantly contribute to greenhouse gas emissions. Understanding how microbes produce these gases under conditions that have been imposed by human activities (i.e., nitrogen pollution) is important to the development of future management strategies. Our results illustrate that within the rhizosphere of the wetland plant Juncus acutiflorus, physiological differences associated with nitrogen availability can influence microbial activity linked to greenhouse gas production. By pairing taxonomic information and environmental conditions like nitrogen availability with functional outputs of a system such as greenhouse gas fluxes, we present a framework to link certain taxa to both nitrogen load and greenhouse gas production. We view this type of combined information as essential in moving forward in our understanding of complex systems such as rhizosphere microbial communities. PMID- 29404430 TI - Screening for hepatocellular carcinoma: What is missing? AB - While there are guidelines from all major liver societies for the screening and management of hepatocellular carcinoma (HCC), many issues remain surrounding the actual practice of screening. This review discusses how to diagnose and screen HCC and more importantly, how well we diagnose and screen for HCC. Improved survival and outcomes after HCC diagnosis depend upon accurate diagnosis of cirrhosis and the timeliness of screening. With all oral direct-acting antivirals now widely available for hepatitis C, there are increasing numbers of patients who may be cured but are still at risk of HCC. Some uncontrolled studies suggest that direct-acting antiviral therapy may even increase the risk of HCC. Before we discuss expansion of who should be screened, we need physicians to realize how poorly we screen those patients who are already recommended for screening by guidelines. (Hepatology Communications 2017;1:18-22). PMID- 29404429 TI - Update on pharmacotherapies for cholestatic liver disease. AB - Cholestatic liver diseases are conditions with impaired bile formation and/or flow due to genetic, immunologic, environmental, or other causes. Unless successfully treated, this can lead to chronic liver injury and end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) embody the most prominent adult cholestatic liver diseases with regard to incidence, morbidity, and mortality. A considerable proportion of patients with PBC and PSC experience progressive liver disease and ultimately liver-related death due to a paucity of effective pharmacotherapy; however, novel pharmacologic developments offer substantial promise in this regard. Here, we provide a brief review and update on current and emerging pharmacotherapies for PBC and PSC. (Hepatology Communications 2017;1:7-17). PMID- 29404431 TI - microRNA-200a: A stage-dependent biomarker and predictor of steatosis and liver cell injury in human immunodeficiency virus patients. AB - Nonalcoholic fatty liver disease contributes to liver-related mortality and has a high prevalence among patients with human immunodeficiency virus (HIV). The early detection of steatosis could prevent disease progression through life-style changes. However, as the common serum markers are nonspecific and the gold standard for the detection of nonalcoholic fatty liver disease remains the invasive liver biopsy, its verification is limited. Therefore, the search for novel biomarkers is essential. Several studies have emphasized the role of microRNAs (miRNAs) as biomarkers for certain liver diseases. With our study, we aimed to investigate the potential of miR-200a as a biomarker for liver injury, fibrosis, and steatosis in HIV patients. The study cohort consisted of 89 HIV patients. Clinical and laboratory parameters were assessed twice, within a median follow-up period of 12 months. miR-200a serum levels were determined by real-time polymerase chain reaction and normalized to spiked-in RNA (SV40). miR-200a serum levels showed a significant correlation with the patients' controlled attenuation parameter scores and their body weight at baseline and with alanine aminotransferase serum levels at follow-up. At baseline, we observed a stage dependent increase in miR-200a serum levels according to the degree of steatosis. More importantly, patients with higher baseline levels of miR-200a recorded a progression of steatosis at follow-up. Remarkably, miR-200a not only reveals a prognostic value for steatosis but possibly also for liver damage and metabolic adaptions as patients with an increase in alanine aminotransferase/aspartate aminotransferase serum levels over time also recorded higher baseline miR-200a levels. Conclusion : Our study reveals miR-200a not only to be a stage-dependent biomarker of steatosis but also to be a predictor of steatosis progression and probably liver cell injury in HIV patients. (Hepatology Communications 2017;1:36 45). PMID- 29404432 TI - Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: Preliminary prospective study based on serial liver biopsies. AB - A prospective study based on serial liver biopsies was performed to investigate the efficacy of sodium-glucose cotransporter 2 inhibitor for nonalcoholic fatty liver disease complicated with type 2 diabetes mellitus. Conclusion: Treatment for 24 weeks resulted in improvement in histopathologic features in all 5 patients. (Hepatology Communications 2017;1:46-52). PMID- 29404433 TI - Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma. AB - Determination of cirrhosis in nonalcoholic fatty liver disease (NAFLD) is important as it alters prognosis and management. We aimed to examine whether cirrhosis was diagnosed incidentally or intentionally in patients with NAFLD. We reviewed 100 patients with NAFLD cirrhosis to determine mode of cirrhosis diagnosis (incidental or by intent), severity of liver disease at diagnosis, diagnostician, and previous clinical imaging or laboratory evidence of unrecognized cirrhosis. The majority (66/100) of patients with NAFLD cirrhosis were diagnosed incidentally, with the majority of these (74%) diagnosed with NAFLD simultaneously. Those with incidental cirrhosis diagnoses had more deranged platelet and international normalized ratio levels (P < 0.05) and were more likely to have concomitant hepatocellular carcinoma (HCC) (12% versus 0%, P < 0.05). Incidental cirrhosis was diagnosed following imaging (32%) or liver tests (26%) performed for reasons unrelated to liver disease, following unexpected endoscopic finding of varices (21%) or an unexpected surgical finding (14%). Diagnoses by intent were predominantly made by gastroenterologists/hepatologists, whereas general practitioners, surgeons, and physicians tended to diagnose cirrhosis incidentally (P < 0.001). The majority of patients diagnosed incidentally (n = 48/66, 73%) had previous thrombocytopenia, splenomegaly, or high noninvasive fibrosis scores. Following diagnosis, patients diagnosed incidentally were less likely to undergo HCC screening. Conclusion: The majority of patients with NAFLD cirrhosis are diagnosed incidentally. These patients are more likely to have advanced liver disease and HCC. Increased awareness of screening for cirrhosis is needed in patients with NAFLD. (Hepatology Communications 2017;1:53-60). PMID- 29404435 TI - Some Recollections of the American Association for the Study of Liver Diseases Transformative Decade 1970-1979. PMID- 29404434 TI - Gut microbial composition can differentially regulate bile acid synthesis in humanized mice. AB - We previously reported that alcohol drinkers with and without cirrhosis showed a significant increase in fecal bile acid secretion compared to nondrinkers. We hypothesized this may be due to activation by alcohol of hepatic cyclic adenosine monophosphate responsive element-binding protein 3-like protein 3 (CREBH), which induces cholesterol 7alpha-hydroxylase (Cyp7a1). Alternatively, the gut microbiota composition in the absence of alcohol might increase bile acid synthesis by up-regulating Cyp7a1. To test this hypothesis, we humanized germ free (GF) mice with stool from healthy human subjects (Ctrl-Hum), human subjects with cirrhosis (Cirr-Hum), and human subjects with cirrhosis and active alcoholism (Alc-Hum). All animals were fed a normal chow diet, and none demonstrated cirrhosis. Both hepatic Cyp7a1 and sterol 12alpha-hydroxylase (Cyp8b1) messenger RNA (mRNA) levels were significantly induced in the Alc-Hum and Ctrl-Hum mice but not in the Cirr-Hum mice or GF mice. Liver bile acid concentration was correspondingly increased in the Alc-Hum mice despite fibroblast growth factor 15, fibroblast growth receptor 4, and small heterodimer partner mRNA levels being significantly induced in the large bowel and liver of the Ctrl-Hum mice and Alc-Hum mice but not in the Cirr-Hum mice or GF mice. This suggests that the normal pathways of Cyp7a1 repression were activated in the Alc Hum mice and Ctrl-Hum mice. CREBH mRNA was significantly induced only in the Ctrl Hum mice and Alc-Hum mice, possibly indicating that the gut microbiota up regulate CREBH and induce bile acid synthesis genes. Analysis of stool bile acids showed that the microbiota of the Cirr-Hum and Alc-Hum mice had a greater ability to deconjugate and 7alpha-dehydroxylate primary bile acids compared to the microbiota of the Cirr-Hum mice. 16S ribosomal RNA gene sequencing of the gut microbiota showed that the relative abundance of taxa that 7-alpha dehydroxylate primary bile acids was higher in the Ctrl-Hum and Alc-Hum groups. Conclusion: The composition of gut microbiota influences the regulation of the rate-limiting enzymes in bile acid synthesis in the liver. (Hepatology Communications 2017;1:61 70). PMID- 29404436 TI - Latin American Association for the Study of the Liver. PMID- 29404437 TI - Targeting bile acids and lipotoxicity for NASH treatment. PMID- 29404438 TI - A global perspective on hepatitis B-related single nucleotide polymorphisms and evolution during human migration. AB - Genome-wide association studies have indicated that human leukocyte antigen (HLA) DP and HLA-DQ play roles in persistent hepatitis B virus (HBV) infection in Asia. To understand the evolution of HBV-related single nucleotide polymorphisms (SNPs) and to correlate these SNPs with chronic HBV infection among different populations, we conducted a global perspective study on hepatitis-related SNPs. We selected 12 HBV-related SNPs on the HLA locus and two HBV and three hepatitis C virus immune-related SNPs for analysis. Five nasopharyngeal carcinoma-related SNPs served as controls. All SNP data worldwide from 26 populations were downloaded from 1,000 genomes. We found a dramatic difference in the allele frequency in most of the HBV- and HLA-related SNPs in East Asia compared to the other continents. A sharp change in allele frequency in 8 of 12 SNPs was found between Bengali populations in Bangladesh and Chinese Dai populations in Xishuangbanna, China (P < 0.001); these areas represent the junction of South and East Asia. For the immune-related SNPs, significant changes were found after leaving Africa. Most of these genes shifted from higher expression genotypes in Africa to lower expression genotypes in either Europe or South Asia (P < 0.001). During this two-stage adaptation, immunity adjusted toward a weak immune response, which could have been a survival strategy during human migration to East Asia. The prevalence of chronic HBV infection in Africa is as high as in Asia; however, the HBV-related SNP genotypes are not present in Africa, and so the genetic mechanism of chronic HBV infection in Africa needs further exploration. Conclusion: Two stages of genetic changes toward a weak immune response occurred when humans migrated out of Africa. These changes could be a survival strategy for avoiding cytokine storms and surviving in new environments. (Hepatology Communications 2017;1:1005-1013). PMID- 29404439 TI - HBV reactivation in allogeneic stem cell transplant recipients: Risk factors, outcome, and role of hepatitis B virus mutations. AB - Hepatitis B virus (HBV) reactivation (HBVr) in recipients of allogeneic hematopoetic stem cells (aHSCs) appears heterogeneously with respect to its frequency, manifestation, and outcome. The aim of this study was to present data from a large German cohort of recipients of aHSC transplantation (aHSCT), focusing on the incidence of HBVr in antibody to hepatitis B core antigen (anti HBc)-positive aHSCT recipients, its clinical outcome, and the role of mutations in HBV. Between 2005 and 2015, 1,871 patients received aHSCT at University Hospital Essen. A follow-up of at least 6 months after transplant was available in 55 patients who were anti-HBc-positive; clinical and virologic data were analyzed. The HBV genome was sequenced with next generation technology from serum samples of 8 patients with HBVr. Thirteen out of 55 (23.6%) patients developed HBVr at a median of 26 months after aHSCT. After initiation of antiviral treatment, complete HBV DNA suppression was achieved in 7/10 (70%) patients 1 to 40 months after HBVr. Nine of 13 patients had increased alanine aminotransferase; 3 patients had compromised coagulation and model for end-stage liver disease scores of 18-27, and 1 of these patients died due to liver failure 5 weeks after HBVr. As a risk factor for HBVr, we identified anti-HBc signal to cut-off ration (S/CO) >=7.5 before transplantation. Complete HBV DNA suppression was achieved in 7/10 patients; therapy-relevant mutations were found in 1 patient. In 4/8 patients, immune escape mutations were detected either as majority or minority variants. Conclusion: HBVr is common in anti-HBc-positive aHRCT recipients and can lead to severe hepatitis with compromised coagulation. The level of anti-HBc S/CO before transplantation is a risk factor for HBVr. Complete virologic response under adequate antiviral treatment could not be achieved in all patients. (Hepatology Communications 2017;1:1014-1023). PMID- 29404440 TI - Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis. Notably, NAFLD patients exhibit a deficiency in fibroblast growth factor 19 (FGF19), an endocrine hormone in the gut-liver axis that controls de novo bile acid synthesis, lipogenesis, and energy homeostasis. Using a mouse model that reproduces the clinical progression of human NAFLD, including the development of simple steatosis, nonalcoholic steatohepatitis (NASH), and advanced "burnt-out" NASH with hepatocellular carcinoma, we demonstrate that FGF19 as well as an engineered nontumorigenic FGF19 analogue, M70, ameliorate bile acid toxicity and lipotoxicity to restore liver health. Mass spectrometry-based lipidomics analysis of livers from mice treated with FGF19 or M70 revealed significant reductions in the levels of toxic lipid species (i.e., diacylglycerols, ceramides and free cholesterol) and an increase in levels of unoxidized cardiolipins, an important component of the inner mitochondrial membrane. Furthermore, treatment with FGF19 or M70 rapidly and profoundly reduced levels of liver enzymes, resolved the histologic features of NASH, and enhanced insulin sensitivity, energy homeostasis, and lipid metabolism. Whereas FGF19 induced hepatocellular carcinoma formation following prolonged exposure in these mice, animals expressing M70 showed no evidence of liver tumorigenesis in this model. Conclusion: We have engineered an FGF19 hormone that is capable of regulating multiple pathways to deliver antisteatotic, anti-inflammatory, and antifibrotic activities and that represents a potentially promising therapeutic for patients with NASH. (Hepatology Communications 2017;1:1024-1042). PMID- 29404441 TI - The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. AB - Cytochrome P450 2E1 (CYP2E1) plays an important role in alcohol and toxin metabolism by catalyzing the conversion of substrates into more polar metabolites and producing reactive oxygen species. Reactive oxygen species-induced oxidative stress promotes hepatocyte injury and death, which in turn induces inflammation, activation of hepatic stellate cells, and liver fibrosis. Here, we analyzed mice expressing only the human CYP2E1 gene (hCYP2E1) to determine differences in hCYP2E1 versus endogenous mouse Cyp2e1 function with different liver injuries. After intragastric alcohol feeding, CYP2E1 expression was induced in both hCYP2E1 and wild-type (Wt) mice. hCYP2E1 mice had greater inflammation, fibrosis, and lipid peroxidation but less hepatic steatosis. In addition, hCYP2E1 mice demonstrated increased expression of fibrogenic and proinflammatory genes but decreased expression of de novo lipogenic genes compared to Wt mice. Lipidomics of free fatty acid, triacylglycerol, diacylglycerol, and cholesterol ester species and proinflammatory prostaglandins support these conclusions. Carbon tetrachloride-induced injury suppressed expression of both mouse and human CYP2E1, but again hCYP2E1 mice exhibited greater hepatic stellate cell activation and fibrosis than Wt controls with comparable expression of proinflammatory genes. By contrast, 14-day bile duct ligation induced comparable cholestatic injury and fibrosis in both genotypes. Conclusion: Alcohol-induced liver fibrosis but not hepatic steatosis is more severe in the hCYP2E1 mouse than in the Wt mouse, demonstrating the use of this model to provide insight into the pathogenesis of alcoholic liver disease. (Hepatology Communications 2017;1:1043 1057). PMID- 29404442 TI - Generation of safe and therapeutically effective human induced pluripotent stem cell-derived hepatocyte-like cells for regenerative medicine. AB - Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells are expected to be applied for regenerative medicine. In this study, we attempted to generate safe and therapeutically effective human iPS-HLCs for hepatocyte transplantation. First, human iPS-HLCs were generated from a human leukocyte antigen-homozygous donor on the assumption that the allogenic transplantation might be carried out. Highly efficient hepatocyte differentiation was performed under a feeder-free condition using human recombinant laminin 111, laminin 511, and type IV collagen. The percentage of asialoglycoprotein receptor 1-positive cells was greater than 80%, while the percentage of residual undifferentiated cells was approximately 0.003%. In addition, no teratoma formation was observed even at 16 weeks after human iPS-HLC transplantation. Furthermore, harmful genetic somatic single-nucleotide substitutions were not observed during the hepatocyte differentiation process. We also developed a cryopreservation protocol for hepatoblast-like cells without negatively affecting their hepatocyte differentiation potential by programming the freezing temperature. To evaluate the therapeutic potential of human iPS-HLCs, these cells (1 * 106 cells/mouse) were intrasplenically transplanted into acute liver injury mice treated with 3 mL/kg CCl4 only once and chronic liver injury mice treated with 0.6 mL/kg CCl4 twice weekly for 8 weeks. By human iPS-HLC transplantation, the survival rate of the acute liver injury mice was significantly increased and the liver fibrosis level of chronic liver injury mice was significantly decreased. Conclusion: We were able to generate safe and therapeutically effective human iPS-HLCs for hepatocyte transplantation. (Hepatology Communications 2017;1:1058-1069). PMID- 29404443 TI - Prediction of histologic alcoholic hepatitis based on clinical presentation limits the need for liver biopsy. AB - The clinical presentation of alcoholic hepatitis (AH) can be mimicked by other alcoholic liver diseases. The aim of this study was to identify clinical features that predict AH on liver biopsy. Biopsies from patients hospitalized for presumed severe AH were used to identify a derivation cohort (101 patients) and validation cohort (71 patients). Using histologic scores for hepatocyte ballooning, Mallory Denk bodies, and lobular inflammation, 95 patient biopsies (55%) were classified as definite AH, 55 (32%) as possible AH, and 22 (13%) as no AH. Survival was similar among the groups, but mortality was significantly increased for patients with fatty change <=50% on initial liver biopsy. An analysis limited to uninfected patients with definite AH or no AH in the derivation cohort identified a greater leukocyte count at admission and radiographic evidence of liver surface nodularity as independent predictors of definite AH on biopsy (P < 0.05). In the derivation cohort, the leukocyte count thresholds for ensuring 100% specificity for diagnosing definite AH were 10 * 109/L if the liver surface was nodular and 14 * 109/L if the liver surface was smooth, with a sensitivity of 76% and an area under the receiver operator characteristic curve of 0.88. In the validation cohort, these thresholds had a specificity of 86%, a sensitivity of 59%, and an area under the receiver operator characteristic curve of 0.72. Conclusion: The combination of an elevated leukocyte count and a nodular liver surface in the absence of active infection retrospectively identified patients with a high likelihood of histologic AH for whom liver biopsy may not be necessary. For patients with suspected severe AH who do not fulfill these criteria, liver biopsy is important to exclude other variants of alcoholic liver disease. (Hepatology Communications 2017;1:1070-1084). PMID- 29404444 TI - Hairy and enhancer of split 6 prevents hepatic lipid accumulation through inhibition of Pparg2 expression. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPARgamma2 isoform reprograms liver for lipid storage and causes abnormal fat accumulation in certain pathophysiologic conditions. The current study aimed to investigate a role of transcriptional repressor hairy and enhancer of split 6 (HES6) in the regulation of Pparg2 expression and hepatic steatosis induced by diet. Liver-specific overexpression of Hes6 using adenovirus reduced Pparg2 messenger RNA levels by 90% and hepatic triglyceride accumulation by 22% compared to the levels in mice injected with an adenoviral empty vector with Western diet feeding. In sharp contrast, silencing Hes6 gene expression using short hairpin RNA increased hepatic lipid accumulation and Pparg2 messenger RNA levels by 70% and 4-fold, respectively. To locate hepatocyte nuclear factor 4 alpha (HNF4alpha) binding site(s), through which repressional activity of HES6 is mediated, a 2.5-kb Pparg2 promoter-driven luciferase reporter was constructed for transient transfection assays. Subsequently, chromatin immunoprecipitation and electrophoretic mobility shift assays were performed. An HNF4alpha binding consensus sequence was identified at 903 base pairs upstream from the transcription start site of Pparg2. Deletion or point mutation of the sequence in a luciferase reporter containing the Pparg2 promoter abolished HNF4alpha-mediated activation in HeLa cells. Chromatin immunoprecipitation and electrophoretic mobility shift assays further confirmed direct recruitment and binding of HNF4alpha to the site. Gene expression analysis with liver samples from subjects with nonalcoholic steatohepatitis suggested that the axis of the Hes6-Hnf4a Pparg2 transcriptional cascade is also responsible for hepatic fat accumulation in humans. Conclusion: HES6 represses Pparg2 gene expression, thereby preventing hepatic lipid accumulation induced by chronic Western diet feeding or pathophysiologic conditions. (Hepatology Communications 2017;1:1085-1098). PMID- 29404446 TI - Advancing hepatology research: Excellence in open access. PMID- 29404445 TI - Periostin promotes malignant potential by induction of epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. AB - Periostin, a secreted matricellular protein, has been reported to induce epithelial-mesenchymal transition (EMT), which increases motility and invasiveness in various epithelial cancer cells. Periostin is also overexpressed in intrahepatic cholangiocarcinoma (ICC) and suggested to be a biomarker for tumor progression and poor prognosis; however, its functional role in ICC is not fully understood. Here, we investigated whether periostin influences malignant potential through the induction of EMT in ICC. Analyses of surgical resected ICC specimens revealed that the gene expression of periostin was significantly higher in ICC tumors than in adjacent nontumor liver tissues and was closely correlated with the expression of mesenchymal markers, including N-cadherin, vimentin, and fibronectin. However, the expression level of periostin varied in each case. Consistently, the expression of periostin in HuH28 (an undifferentiated ICC cell) was markedly higher than in HuCCT-1 (a moderately differentiated ICC cell). In addition, high-level secretion of periostin into culture media was observed in HuH28 but not in HuCCT-1. To identify the biological significance of periostin in EMT, gene silencing of periostin by small interfering RNA was performed in HuH28 cells. Periostin knockdown in HuH28 cells significantly down-regulated mesenchymal markers and up-regulated epithelial markers, suggesting the reversal of EMT, namely mesenchymal-epithelial transition. Along with these changes, cell proliferation was significantly suppressed by 52%. In addition, cell migration and invasion were significantly suppressed by 62% and 61%, respectively, with reduced gene expression of matrix metalloproteinase 2. Interestingly, chemosensitivity to gemcitabine was also significantly improved by periostin depletion. Conclusion: Periostin plays an important role in the regulation of malignant potential through EMT and is suggested to be a novel target for the treatment of ICC. (Hepatology Communications 2017;1:1099-1109). PMID- 29404448 TI - Potential epidemiologic, economic, and budgetary impacts of current rates of hepatitis C treatment in medicare and non-medicare populations. AB - We forecast the health and budgetary impact of hepatitis C (HCV) treatment on the Medicare program based on currently observed rates of treatment among Medicare and non-Medicare patients and identify the impact of higher rates of treatment among non-Medicare populations. We developed a computer microsimulation model to conduct an epidemiologic forecast, a budgetary impact analysis, and a cost effectiveness analysis of the treatment of HCV based on three scenarios: 1) no treatment, 2) continuation of current-treatment rates, and 3) treatment rates among non-Medicare patients increased to match that of Medicare patients. The simulated population is based on National Health and Nutrition Examination Survey data. HCV progression rates and costs were calculated in Surveillance, Epidemiology, and End Results Program Medicare 5% claims data from the Chronic Hepatitis Cohort Study and published literature. We estimate that 13.6% of patients with HCV in the United States are enrolled in Medicare, but 75% will enter Medicare in the next 20 years. Medicare patients were over 5 times as likely to be treated in 2014-2015 as other patients. Medicare paid over $9 billion in treatment costs in both 2015 and 2016 and will total $28.4 billion from 2017-2026. Increasing treatment rates among non-Medicare patients would lead to 234,000 more patients being treated, reduce HCV mortality by 19%, and decrease Medicare costs by $18.6 billion from 2017-2026. We find that treatment remains cost-effective under most assumptions, costing $31,718 per quality adjusted life year gained. Conclusion: Medicare treats a disproportionately large share of HCV patients. Continued low rates of treatment among non-Medicare HCV patients will result in both reduced and deferred treatment, shifting future treatment costs to Medicare while increasing overall medical management costs, morbidity, and mortality. (Hepatology Communications 2017;1:99-109). PMID- 29404449 TI - Resistance mutations of hepatitis B virus in entecavir-refractory patients. AB - The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti-HBV reagents; it has a very low resistance rate and is used as the first-line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV-refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare-up) and assessed ETV resistance using replication-competent 1.38-fold HBV genome-length molecular clones. The full genome sequences of infected HBVs in ETV-refractory patients were determined. The HBV molecular clones were generated with the patient-derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core-particle-associated HBV DNA using Southern blotting and real time polymerase chain reaction. Among these cases, ETV-resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV-resistant mutation was detected in the other cases. The identified ETV-resistant mutations did not confer resistance to tenofovir disoproxil fumarate. Conclusion: The HBV replication model with patient-derived sequences is useful for assessing replication efficiency, susceptibility to anti HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment-failure cases of chronic hepatitis B. (Hepatology Communications 2017;1:110-121). PMID- 29404447 TI - Hepatitis C virus infection in children and adolescents. PMID- 29404450 TI - Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. AB - Alcohol consumption is a well-established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol-induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7-mediated lipophagic pathway. Rats chronically fed an ethanol-containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol-fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7-depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation-induced Rab7 activation in primary hepatocytes isolated from chronic ethanol-fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140-152). PMID- 29404452 TI - Interview with American Association for the Study of Liver Diseases president Dr. Anna Lok. PMID- 29404453 TI - Treating fatty liver disease by modulating mitochondrial pyruvate metabolism. AB - Modifying the entry of pyruvate into mitochondria may provide a unique approach to treat metabolic disease. The pharmacology of a new class of insulin sensitizers directed against a newly identified mitochondrial target may treat many aspects of nonalcoholic steatohepatitis, including fibrosis. This commentary suggests treating nonalcoholic steatohepatitis through a newly identified mechanism consistent with pathophysiology. (Hepatology Communications 2017;1:193 197). PMID- 29404451 TI - MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting beta-catenin and Wnt signaling. AB - Hepatoblastoma (HBL) is the most common pediatric liver cancer. In this malignant neoplasm, beta-catenin protein accumulates and increases Wnt signaling due to recurrent activating mutations in the catenin-beta 1 (CTNNB1) gene. Therefore, beta-catenin is a key therapeutic target in HBL. However, controlling beta catenin production with therapeutic molecules has been challenging. New biological studies could provide alternative therapeutic solutions for the treatment of HBL, especially for advanced tumors and metastatic disease. In this study, we identified microRNAs (miRNAs) that target beta-catenin and block HBL cell proliferation in vitro and tumor growth in vivo. Using our dual-fluorescence FunREG system, we screened a library of 1,712 miRNA mimics and selected candidates inhibiting CTNNB1 expression through interaction with its untranslated regions. After validating the regulatory effect of nine miRNAs on beta-catenin in HBL cells, we measured their expression in patient samples. Let-7i-3p, miR-449b 3p, miR-624-5p, and miR-885-5p were decreased in tumors compared to normal livers. Moreover, they inhibited HBL cell growth and Wnt signaling activity in vitro partly through beta-catenin down-regulation. Additionally, miR-624-5p induced cell senescence in vitro, blocked experimental HBL growth in vivo, and directly targeted the beta-catenin 3'-untranslated region. Conclusion: Our results shed light on how beta-catenin-regulating miRNAs control HBL progression through Wnt signaling inactivation. In particular, miR-624-5p may constitute a promising candidate for miRNA replacement therapy for HBL patients. (Hepatology Communications 2017;1:168-183). PMID- 29404454 TI - Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury. AB - Liver fibrosis, a condition that is characterized by excessive production and accumulation of extracellular matrix, including collagen, is the most common outcome of chronic liver injuries of different etiologies. Vitamin A-storing hepatic stellate cells (HSCs) are considered to be the main source of this collagen production, with activation in response to liver injury. In contrast, the contribution of other cell types to this fibrogenic response remains largely elusive due to the lack of specific surface markers to identify and isolate these cells for detailed analysis. Here, we identify a mesenchymal population of thymus cell antigen 1 (Thy1)+ CD45- cells (Thy1 MCs) in the mouse liver; these cells reside near the portal vein in vivo and indicate profibrogenic characteristics in vitro, shown by their expression of collagen and alpha-smooth muscle actin. Flow cytometric analysis of mouse liver nonparenchymal cells revealed that vitamin A storage and Thy1 expression were mutually exclusive, indicating that Thy1 MCs are distinct from HSCs. Importantly, Thy1 MCs reacted and contributed to the development of liver fibrosis specifically in mouse models of cholestatic liver injury. With the occurrence of cholestatic liver injury, collagen-producing Thy1 MCs expanded in cell number and inhibited collagen degradation through up regulation of matrix metalloproteinase inhibitor Timp1 expression, thereby promoting the accumulation of extracellular matrix in the periportal area. Conclusion: This study establishes Thy1 as a useful cell surface marker to prospectively identify and isolate periportal fibroblasts and further highlights a significant contribution of these cells to the pathogenesis of liver fibrosis caused by cholestatic liver injuries. We suggest that Thy1 MCs may be an interesting therapeutic target for treating liver fibrosis in addition to the well-characterized HSCs. (Hepatology Communications 2017;1:198-214). PMID- 29404455 TI - Identification of a novel alpha-fetoprotein-expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver. AB - The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self-proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP-producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP-positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP-positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte-lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up-regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP-positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1-conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215-229). PMID- 29404457 TI - Sofosbuvir-based regimens for the treatment of chronic hepatitis C in severe renal dysfunction. AB - Sofosbuvir (SOF) is a nonstructural 5B polymerase inhibitor with activity in all hepatitis C virus (HCV) genotypes and is the backbone of many anti-HCV drug regimens. SOF is converted into inactive metabolites that undergo renal excretion. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m2 may experience increased drug exposure and thus potential toxicities along with decreased efficacy due to dose reduction or drug discontinuation. This is a single-center study evaluating safety and effectiveness of SOF-based regimens in patients with severe renal dysfunction, defined as eGFR <30 mL/minute/1.73 m2, including those receiving concurrent hemodialysis. Data were collected from patients with HCV and severe renal dysfunction who started full-dose (400 mg) SOF-based antiviral therapy +/- ribavirin between April 2014 and February 2016. Medical records were reviewed for demographics, medical history, laboratory, radiologic imaging, echocardiography, transplant status, and liver pathologic findings. Twenty-nine patients were identified; 12 had cirrhosis and 4 of those had decompensated cirrhosis. Fourteen patients had undergone transplantation of liver and/or kidney and were on calcineurin inhibitors, with 42% requiring dose increases or decreases while on therapy. All patients attained viral suppression on treatment, and 97% had a sustained viral response at 12 weeks posttreatment. There were no early treatment discontinuations. One death occurred posttreatment from a non-ST elevation myocardial infarction in a patient with a history of coronary artery disease and ischemic cardiomyopathy. Conclusion: SOF-based regimens appear safe in a broad range of patients with severe renal dysfunction, including those with decompensated cirrhosis and liver transplant. To confirm these retrospective findings, prospective studies that include SOF and SOF metabolite measurements coupled with prospective serial monitoring of electrocardiograms and echocardiograms are needed. (Hepatology Communications 2017;1:248-255). PMID- 29404456 TI - Up-regulation of golgi alpha-mannosidase IA and down-regulation of golgi alpha mannosidase IC activates unfolded protein response during hepatocarcinogenesis. AB - alpha-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of alpha-1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of alpha-1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, alpha fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1-overexpressing cells but decreased in MAN1C1-overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1 activated genes. Using the MAN1A1 liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up-regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230-247). PMID- 29404458 TI - Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals. AB - The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER) stress response. In this study, we examined whether HCV clearance by interferon alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone-mediated autophagy (CMA) in infected primary human hepatocytes and Huh-7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin-3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome-dependent mechanism because lysosome-associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon-alpha-based antiviral therapies normalizes the ER stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV-infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV-induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER-stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256-269). PMID- 29404459 TI - Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection. AB - The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF-PK model predicted average steady-state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate ka = 0.43/hour and elimination rate ke = 0.045/hour. The PK/PD model identified an average delay of 0.56 hours and an LNF concentration that decreases HDV production by 50%, EC50 = 227 ng/mL, with a Hill factor h = 1.48. The HDV half life in blood was 1.87 days, and the average steady-state LNF efficacy in blocking HDV production was E = 87.7% for group 1 and E = 95.2% for group 2. A biphasic HDV decline with an average phase 1 decline (0.9 log10 IU/mL and 1.32 log10 IU/mL) was observed in groups 1 and 2, respectively. Phase 2 was not significantly (P = 0.94) different between the two groups, with an average slope of -0.06 log IU/mL/day. The model suggests an LNF dose of ~610 mg bid would achieve E = 99%. Conclusion: The first PK/PD modeling study in patients with chronic HDV indicates that a ~3-fold increase in LNF dose (~610 mg bid) would achieve 99% antiviral efficacy. A ritonavir-boosted LNF combination may provide a means to increase LNF efficacy with minimal side effects. The modeling findings provide an important advance in understanding HDV dynamics and the basis to optimize LNF therapy for hepatitis D. (Hepatology Communications 2017;1:288-292). PMID- 29404460 TI - Atovaquone/proguanil-induced autoimmune-like hepatitis. AB - We report a novel association between the commonly used antimalarial medication atovaquone/proguanil and drug-induced autoimmune-like hepatitis. The patient developed severe liver disease fulfilling biochemical, immunologic, and histologic criteria for the diagnosis of autoimmune hepatitis after the inadvertent rechallenge with the offending drug, which had caused self-limited hepatitic symptoms a year previously. Over a period of 18 months, the patient underwent two follow-up liver biopsies showing progressive resolution of the liver inflammation and achieved complete biochemical and immunologic remission on steroids. This remission persisted for 20 months following treatment withdrawal. Conclusion: This well documented case raises awareness of the potential hepatotoxicity of atovaquone/proguanil. (Hepatology Communications 2017;1:293 298). PMID- 29404461 TI - CAT-2003: A novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3 Leiden mice. AB - CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3 Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325). PMID- 29404462 TI - Intermittent hypoxia is a proinflammatory stimulus resulting in IL-6 expression and M1 macrophage polarization. AB - The biological factors that promote inflammation or nonalcoholic steatohepatitis (NASH) in the setting of nonalcoholic fatty liver disease remain incompletely understood. Clinical studies have demonstrated an association between obstructive sleep apnea (OSA) and both inflammation and fibrosis in NASH, but the mechanism has not been identified. In this study, we use in vitro modeling to examine the impact of intermittent hypoxia on the liver. Hepatocyte, stellate cell, and macrophage cell lines were exposed to intermittent or sustained hypoxia. Candidate genes associated with inflammation, fibrosis, and lipogenesis were analyzed. Circulating cytokines were assessed in human serum of patients with nonalcoholic fatty liver disease. Intermittent hypoxia results in significant induction of interleukin (IL)-6 expression in both hepatocytes and macrophages. The increase in IL-6 expression was independent of hypoxia inducible factor 1 induction but appeared to be in part related to antioxidant response element and nuclear factor kappa B activation. Mature microRNA 365 (miR-365) has been demonstrated to regulate IL-6 expression, and we found that miR-365 expression was decreased in the setting of intermittent hypoxia. Furthermore, macrophage cell lines showed polarization to an M1 but not M2 phenotype. Finally, we found a trend toward higher circulating levels of IL-6 in patients with OSA and NASH. Conclusion: Intermittent hypoxia acts as a potent proinflammatory stimulus, resulting in IL-6 induction and M1 macrophage polarization. Increased IL-6 expression may be due to both induction of antioxidant response element and nuclear factor kappa B as well as inhibition of miR-365 expression. Higher levels of IL-6 were observed in human samples of patients with OSA and NASH. These findings provide biological insight into mechanisms by which obstructive sleep apnea potentiates inflammation and fibrosis in patients with fatty liver disease. (Hepatology Communications 2017;1:326-337). PMID- 29404463 TI - Current guidelines for chemoembolization for hepatocellular carcinoma: Room for improvement? AB - Transarterial chemoembolization (TACE) is the most common oncologic therapy used according to the American Association for the Study of Liver Diseases (AASLD) guidelines established in 2005, revised in 2011. The purpose of this study was to determine how AASLD criteria for the management of hepatocellular carcinoma (HCC) have impacted TACE practice in the community. Clinical, demographic, and cause of death information were collected for patients diagnosed with HCC in the 2012 linkage of the Surveillance, Epidemiology, and End Results Medicare database. Propensity score survival analysis was used to compare survival outcomes in patients whose HCC tumor characteristics were less than, met, or were beyond AASLD criteria. The proportion of patients with HCC receiving TACE who met the AASLD-recommended criteria increased after the 2005 guidelines were published. Up to 17% of patients treated with TACE had tumor characteristics less than the AASLD criteria and were not offered potentially curative therapies. Propensity score matching demonstrated the largest survival advantage in patients with HCC whose tumor characteristics met the AASLD criteria (hazard ratio, 0.42; 95% confidence interval, 0.38-0.47). A significant survival advantage was also observed in patients with HCC whose tumor characteristics exceeded the AASLD criteria. Conclusion: The AASLD criteria successfully identify a population of patients with HCC that maximally benefit from TACE therapy. However, patients with HCC with tumor characteristics beyond the AASLD criteria also appear to receive a significant survival advantage with TACE. Further studies are necessary to improve referral patterns and appropriate use of chemoembolization in the management of unresectable HCC. (Hepatology Communications 2017;1:338-346). PMID- 29404464 TI - Factors influencing decisions about a career in hepatology: A survey of gastroenterology fellows. AB - Despite an unmet need for hepatologists in the United States, every year transplant hepatology (TH) fellowship positions remain unfilled. To address this, we investigated factors that influence trainee decisions about pursuing a career in hepatology. We invited current gastroenterology (GI) and TH fellows from all Accreditation Council for Graduate Medical Education-accredited programs for the academic year 2014-2015 to participate in an online survey about factors influencing decisions to train in hepatology. The same paper-based survey was distributed at a nationally recognized GI board review course. The survey was completed by 180 participants of which 91% were current GI or TH fellows and 24% were not aware of the pilot 3-year combined GI and TH training program. A majority of respondents (57%) reported that a shorter time (3 versus 4 years) to become board certification eligible would influence their decisions to pursue TH. The most common reasons for not pursuing hepatology were less endoscopy time (67%), additional length of training (64%), and lack of financial compensation (44%). Personal satisfaction (66%), management of complex multisystem disease (60%), and long-term relationships with patients (57%) were the most attractive factors. Sixty-one percent of participants reported having a mentor, and 94% of those with mentors reported that their mentors influenced their career decisions. Conclusion: We have identified several factors that affect fellows' decision to pursue TH. Shorter training, increased financial compensation, and increased endoscopy time are potentially modifiable factors that may increase the number of trainees seeking careers in hepatology and help alleviate the deficit of hepatologists. (Hepatology Communications 2017;1:347-353). PMID- 29404465 TI - Nonalcoholic fatty liver disease and the ongoing role of liver biopsy evaluation. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the most common underlying causes of chronically elevated liver tests and liver disease in adults and children worldwide and may be strongly suspected if not diagnosed by ever evolving and available serologic and imaging-based noninvasive tests. However, the definitive diagnosis of the most progressive form of NAFLD, nonalcoholic steatohepatitis, and the identification of fibrosis stage still require liver biopsy evaluation as noninvasive testing has not replaced some of the specifics or the totality of information obtainable from liver biopsy. In this review, both the role and value of a liver biopsy evaluation in NAFLD/ nonalcoholic steatohepatitis are examined from publications related to a selected variety of settings. Details of the most commonly used semiquantitative methods of analysis are discussed, and some useful potential pitfalls for differential diagnostic consideration in liver biopsy interpretation are given. (Hepatology Communications 2017;1:370-378). PMID- 29404467 TI - Recurrence of primary biliary cholangitis after liver transplantation: A Japanese perspective. PMID- 29404466 TI - Sequencing of hepatitis C virus for detection of resistance to direct-acting antiviral therapy: A systematic review. AB - The significance of the clinical impact of direct-acting antiviral (DAA) resistance-associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype- and subtype-specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority. (Hepatology Communications 2017;1:379-390). PMID- 29404468 TI - Risk factors for recurrence of primary biliary cholangitis after liver transplantation in female patients: A Japanese multicenter retrospective study. AB - Primary biliary cholangitis (PBC) is diagnosed mainly in female individuals, and risk factors for PBC recurrence (rPBC) after liver transplantation (LT) from cadaveric donors have been reported. We conducted a retrospective multicenter study of rPBC in female patients after living-donor LT (LDLT). A total of 388 female patients undergoing LDLT for end-stage PBC were enrolled, and the effects of preoperative and operative factors were evaluated. Postoperative factors were evaluated in 312 patients who survived for more than 1 year post-LDLT. rPBC was defined as abnormal hepatic enzyme levels with typical histological findings in liver biopsies. Fifty-eight patients (14.9%) developed rPBC with a median of 4.6 (0.8-14.5) years post-LT. Cox hazard analysis (P < 0.05) showed that younger recipient age (hazard ratio, 0.95; 95% confidence interval, 0.920-0.982), shorter operative time (1.00; 0.995-0.999), higher serum immunoglobulin M level (1.00; 1.001-1.002), donor sex mismatch (2.45; 1.268-4.736), human leukocyte antigen B60 (2.56; 1.336-4.921) and DR8 (1.98; 1.134-3.448), and initial treatment with cyclosporine A (3.14; 1.602-6.138) were significantly associated with rPBC. The frequencies of Child-Turcotte-Pugh class C (0.46; 0.274-0.775), the model of end stage liver disease score (0.96; 0.914-0.998), and updated Mayo risk score (1.02; 1.005-1.033) were significantly lower in rPBC. Posttransplantation use of steroids decreased and that of antimetabolites increased the frequency of rPBC. Conclusion: The timing of LT, recipient conditions, donor characteristics, and immunosuppressive medications may be associated with rPBC in LT recipients. (Hepatology Communications 2017;1:394-405). PMID- 29404469 TI - Significant association between FOXP3 gene polymorphism and steroid-resistant acute rejection in living donor liver transplantation. AB - Previous studies have found that preferential accumulation of regulatory T (Treg) cells in liver allografts during acute cellular rejection (ACR) is associated with less severe rejection, suggesting a role of Treg cells in preventing excessive progress of ACR. We investigated the impact of single nucleotide polymorphisms (SNPs) in the Forkhead box P3 (FOXP3) gene, a master regulator gene of Treg cells, on ACR severity in liver transplant (LT) recipients. In total, 102 living donor LT patients were enrolled in this study and categorized into no rejection (n = 86), steroid-sensitive acute rejection (SSAR; n = 11), and steroid resistant acute rejection (SRAR; n = 5). FOXP3 SNPs -3499 A/G (rs3761547), -3279 A/C (rs3761548), and -924 A/G (rs2232365) were genotyped using the polymerase chain reaction restriction fragment length polymorphism technique. T-cell responses to allostimulation were evaluated by the mixed lymphocyte reaction assay. We found no statistical association between the FOXP3 SNP genotype frequencies and ACR incidence. However, significantly higher incidence of SRAR was observed in LT patients with the FOXP3 rs3761548 A/C+A/A genotype than in those with the C/C genotype (A/C+A/A versus C/C; no rejection, SSAR, SRAR, 85.71%, 0%, 14.29% versus 83.58%, 16.42%, 0%, respectively; P = 0.0005). The mixed lymphocyte reaction assay performed at the time of ACR diagnosis showed higher anti-donor CD4+ T-cell responses in patients carrying rs3761548 A/C+A/A than in those with the C/C genotype (P = 0.019). No significant association was observed between the incidence of SRAR and either rs3761547A/G or rs2232365 A/G. Infectious complications and overall survival were not related to FOXP3 SNPs. Conclusion: Our findings indicate that FOXP3 SNP rs3761548 A/C might be a predisposing factor for SRAR after liver transplantation. (Hepatology Communications 2017;1:406-420). PMID- 29404470 TI - Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. AB - Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD). The minimal pathologic criteria for NASH include hepatic steatosis, ballooning degeneration, and lobular inflammation. The resolution of NASH, which relies on the loss of ballooning degeneration, is subject to sampling and observer variability in pathologic interpretation. Ballooning is associated with advanced hepatic fibrosis in cross-sectional studies but is not a predictor of mortality in NAFLD. Fibrosis staging, while still subject to some sampling variability, has less observer variability and is a robust predictor of liver related mortality in NAFLD. In this study, we hypothesize that, regardless of the diagnosis of NASH, the presence of steatofibrosis (steatosis accompanied by fibrosis) regardless of other pathologic features can also be a robust predictor of mortality in NAFLD. We used our previously reported cohort of patients with NAFLD with liver biopsies and long-term mortality follow-up. Cox proportional hazard models were used to determine the predictors of overall and liver-related mortality. Of 209 enrolled NAFLD subjects, 97 can be classified as having steatofibrosis. During follow-up (median 150 months), 64 (30.6%) patients died, with 18 (8.6%) from liver-related causes. Adjusted for age, both diagnostic categories of NASH and steatofibrosis were significantly and similarly associated with liver-related mortality (adjusted hazard ratio [aHR], 9.9; 95% confidence interval (CI), 1.3-74.9; P = 0.027; aHR, 6.7; 95% CI, 1.5-29.8; P = 0.013, respectively). However, only steatofibrosis showed independent association with overall mortality (aHR, 1.76; 95% CI, 1.02-3.05; P = 0.043). Conclusion: Steatofibrosis and NASH are similarly associated with liver-related mortality, but only steatofibrosis is associated with overall mortality in patients with NAFLD. Given the inherent observer variability in ballooning degeneration, a key diagnostic component of NASH, we suggest that steatofibrosis should be considered a viable diagnostic classification for NAFLD subjects at risk or adverse outcomes and provides a simpler endpoint for clinical trials of therapeutic agents. (Hepatology Communications 2017;1:421-428). PMID- 29404471 TI - Prevalence and economic burden of extrahepatic manifestations of hepatitis C virus are underestimated but can be improved with therapy. AB - Despite guideline recommendations, access to hepatitis C virus (HCV) treatment is frequently restricted, with some payers approving therapy for only those with advanced disease or cirrhosis. However, delaying potentially curative treatment until the development of advanced liver disease may have costly consequences in terms of both hepatic complications and extrahepatic manifestations (EHMs) of HCV. Using a large claims database from the United States, we measured the risks and medical costs of 20 EHMs and investigated the role of treatment in different stages of liver fibrosis for mitigating the clinical and economic burden of these EHMs. After adjusting for potential confounders, including comorbid liver disease, patients with HCV had a significantly higher risk for any EHM (adjusted odds ratio, 2.23; P < 0.05) and higher EHM-related annual medical costs (adjusted medical cost difference, $6,458; P < 0.05) compared to matched patients without HCV. HCV treatment can offset the higher medical costs in patients with HCV by saving ~$25,000 in all-cause medical costs per patient per year, with a large proportion attributable to savings in EHM-related medical costs (adjusted cost difference $12,773, P < 0.05). Finally, additional EHM-related medical costs could be saved by initiating HCV therapy in early stage fibrosis as opposed to late-stage fibrosis (adjusted medical cost difference, $10,409; P < 0.05). Conclusion: The clinical and economic burden of EHMs is substantial and can be reduced through viral eradication, especially if treatment is initiated early and not delayed until fibrosis advances. Considering that the wholesale acquisition cost of a 12-week course of therapy ranges from $55,000 to $147,000, the results of the current study suggest the cost of these treatments could be offset within 3 to 6 years by savings in all-cause medical costs. (Hepatology Communications 2017;1:439-452). PMID- 29404472 TI - Clinical burden of liver disease from hemochromatosis at an academic medical center. AB - Hereditary hemochromatosis (HH) can cause cirrhosis and hepatocellular carcinoma (HCC), but the frequency of these complications is controversial. To address this question, we reviewed the experience with HH at an academic medical center that is the sole liver transplantation center in a state with a population that is >90% Caucasian. The records of all subjects with International Classification of Diseases, Ninth Revision, code 275, "disorders of iron metabolism" seen at the University of Iowa Hospitals and Clinics between January 1, 2004 and December 31, 2014 were reviewed, and HFE C282Y homozygotes and C282Y/H63D compound heterozygotes were identified. Clinical, pathologic, and laboratory data from these subjects were examined in detail. We identified 118 C282Y homozygotes and 44 compound heterozygotes; 22 of the former and 3 of the latter had advanced hepatic fibrosis (bridging or cirrhosis). Male patients predominated in both groups. Most of the C282Y homozygotes and all compound heterozygotes had causes of chronic liver disease in addition to iron overload. Together, these accounted for 0.42% of cases of cirrhosis seen at the University of Iowa Hospitals and Clinics during this period. Two male patients with cirrhosis attributable solely to iron overload presented with cardiac dysfunction and atrial fibrillation; this classical presentation was rare, representing approximately one per 3,000 cases of cirrhosis. Eight homozygotes were diagnosed with HCC, representing 1.8% of patients with HCC. Conclusion: Despite the expected high prevalence of HH mutations in our state and the referral bias inherent in our study, serious hepatic manifestations of HH were uncommon. These data support claims that the penetrance of frank clinical hemochromatosis is low. (Hepatology Communications 2017;1:453-459). PMID- 29404473 TI - Transjugular intrahepatic portosystemic shunt does not independently increase risk of death in high model for end stage liver disease patients. AB - Physicians often exclude patients with a model for end-stage liver disease (MELD) score >= 18 from a transjugular intrahepatic portosystemic shunt (TIPS) procedure due to the concern for higher risk of death. We aimed to determine if TIPS increased the risk of death in these patients. We analyzed the interaction between TIPS and MELD in 106 patients with TIPS and 79 with intractable ascites without TIPS. We performed Cox proportional hazard regression, including both TIPS and MELD as time-dependent covariates together with their interaction, to calculate the impact of TIPS on the risk of death associated with a high MELD score. We found a negative interaction between a high MELD score and a history of TIPS, with potentially important effect sizes. Patients with MELD scores >=18 had a 51% lower incremental risk of death (lower risk than would be expected from the combined independent risks of MELD and needing/receiving TIPS) associated with TIPS than patients with MELD scores <18 (hazard ratio for TIPS, 0.49; 95% confidence interval, 0.10-2.45) in the first 6 months following TIPS. There was an 80% lower incremental risk of death among patients with a MELD score >=18 (hazard ratio for TIPS, 0.20; 95% confidence interval, 0.03-1.23) 6 months after the TIPS procedure. Conclusion: Risk of death is associated with underlying disease severity as shown by the MELD score and the need for TIPS, and both history of TIPS and high MELD score independently increased the risk of mortality. However, the risk of death after TIPS was progressively lower than expected as the MELD score increased. (Hepatology Communications 2017;1:460-468). PMID- 29404475 TI - Idiosyncratic drug-induced liver injury: A short review. AB - Idiosyncratic drug-induced liver injury (iDILI) is a rare adverse drug reaction that occasionally leads to acute liver failure or even death. An aging population that uses more drugs, a constant influx of newly developed drugs, and a growing risk from herbal and dietary supplements of uncertain quality can lead to an increase in iDILI. Antimicrobials, central nervous system agents, and herbal and dietary supplements are the most common causes of iDILI in developed countries. iDILI is still a diagnosis of exclusion, and thus careful history taking and thorough work-ups for competing etiologies, such as acute viral hepatitis, autoimmune hepatitis, and others, are essential. The pathogenesis of iDILI is not clear and includes a mix of host reactions, drug metabolites, and environmental factors. Immediate cessation of the suspected offending drug is key to preventing or minimizing progressive damage. No definitive therapies for iDILI are available, and the treatments remain largely supportive. (Hepatology Communications 2017;1:494-500). PMID- 29404474 TI - Transforming growth factor-beta in liver cancer stem cells and regeneration. AB - Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem-like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor beta (TGF-beta) pathway, loss of p53 and/or activation of beta-catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF-beta signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF-beta in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477-493). PMID- 29404476 TI - The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. AB - IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (alpha, gamma, delta). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet; the foz/foz model; the CCl4-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of beta-oxidation-related and fatty acid desaturation related genes in both the methionine- and choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARalpha, PPARdelta, or PPARgamma agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524-537). PMID- 29404477 TI - The emergence of NS5B resistance associated substitution S282T after sofosbuvir based treatment. AB - S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF-based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff). To date, over 12,000 patients have been treated in SOF or LDV/SOF phase 2 and 3 studies. Of these, deep sequencing was available at baseline in 8598 patients (62.4% genotype [GT] 1, 10.7% GT2, 20.9% GT3, and 6.0% GT4-6) and at virologic failure in 901 patients. In the 8598 patients, no S282T substitution was detected at baseline; at virologic failure, 10 of the 901 (1%) patients had S282T detected. The SOF-based regimen associated with treatment-emergent S282T was SOF monotherapy in two patients, retreatment with LDV/SOF in prior LDV/SOF failures in three patients, LDV/SOF for 8 weeks in 1 GT1 patient, LDV/SOF for 12 weeks in 1 patient each with GT3, GT4, and GT5, and LDV/SOF + ribavirin for 12 weeks in 1 GT6 patient. Nine of 10 patients with emergent S282T received an SOF based retreatment regimen, eight of whom achieved sustained virologic response 12 weeks after treatment and one of whom failed retreatment. Conclusion: The emergence of S282T substitution was rare in patients who fail SOF-based regimens. Successful retreatment of prior SOF failure patients is possible in the presence of S282T substitution with SOF in combination with various direct-acting antiviral agents. (Hepatology Communications 2017;1:538-549). PMID- 29404478 TI - Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor alpha. AB - Ribavirin (RBV) has been widely used as an antiviral reagent, specifically for patients with chronic hepatitis C. We previously demonstrated that adenosine kinase, which monophosphorylates RBV into the metabolically active form, is a key determinant for RBV sensitivity against hepatitis C virus RNA replication. However, the precise mechanism of RBV action and whether RBV affects cellular metabolism remain unclear. Analysis of liver gene expression profiles obtained from patients with advanced chronic hepatitis C treated with the combination of pegylated interferon and RBV showed that the adenosine kinase expression level tends to be lower in patients who are overweight and significantly decreases with progression to advanced fibrosis stages. In our effort to investigate whether RBV affects cellular metabolism, we found that RBV treatment under clinically achievable concentrations suppressed lipogenesis in hepatic cells. In this process, guanosine triphosphate depletion through inosine monophosphate dehydrogenase inhibition by RBV and adenosine monophosphate-activated protein kinase-related kinases, especially microtubule affinity regulating kinase 4, were required. In addition, RBV treatment led to the down-regulation of retinoid X receptor alpha (RXRalpha), a key nuclear receptor in various metabolic processes, including lipogenesis. Moreover, we found that guanosine triphosphate depletion in cells induced the down-regulation of RXRalpha, which was mediated by microtubule affinity regulating kinase 4. Overexpression of RXRalpha attenuated the RBV action for suppression of lipogenic genes and intracellular neutral lipids, suggesting that down-regulation of RXRalpha was required for the suppression of lipogenesis in RBV action. Conclusion: We provide novel insights about RBV action in lipogenesis and its mechanisms involving inosine monophosphate dehydrogenase inhibition, adenosine monophosphate-activated protein kinase-related kinases, and down-regulation of RXRalpha. RBV may be a potential reagent for anticancer therapy against the active lipogenesis involved in hepatocarcinogenesis. (Hepatology Communications 2017;1:550-563). PMID- 29404479 TI - Deciphering the epidemiology of hepatocellular carcinoma through the passage of time: A study of 1,401 patients across 3 decades. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers globally. With advances in therapy for chronic viral hepatitis, changing social circumstances, and increasing practice of HCC surveillance, the epidemiology of HCC is expected to change over time. We explored the temporal trends in HCC in Singapore, a multiethnic Asian country, over the last 3 decades. Patients with HCC were prospectively enrolled and stratified into two cohorts (C1, 1988-2002; C2, 2003-2016). Patient and tumor characteristics, management, and survival were compared between the two cohorts, and a survival census was performed on October 31, 2015. There were 1,401 patients, and the mean age at diagnosis of HCC for C1 and C2 was 60.1 and 63.5 years, respectively. Male patient preponderance decreased significantly, with the male to female ratio falling from 5.2:1 to 3.9:1 between C1 and C2. Hepatitis B, although still the predominant risk factor for HCC, showed a significant decline from C1 to C2 (76.5% to 68.2%), while the nonviral etiology increased significantly over the same period (14.4% versus 25.0%, respectively). Significantly more patients in C2 than C1 were diagnosed through surveillance (39.2% versus 11.3%, respectively) and had better physical performance (Eastern Cooperative Oncology Group 0, 62.1% versus 20.4%, respectively). While Child-Pugh status was comparable, significantly more patients in C2 than C1 had early stage disease (Barcelona Clinic Liver Cancer 0 A, 39.5% versus 7.4%, respectively), which translated into significantly higher median survival (18.6 months versus 3.8 months, respectively). Conclusion: Over the past 3 decades, hepatitis B-related HCC has been decreasing while HCC due to nonviral etiology has been increasing significantly. Surveillance to diagnose early stage HCC is important in improving the outcome of HCC. (Hepatology Communications 2017;1:564-571). PMID- 29404480 TI - Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: Facilitating development approaches for an emerging epidemic. AB - Due to the increasing prevalence of nonalcoholic steatohepatitis (NASH) and its associated health burden, there is a high need to develop therapeutic strategies for patients with this disease. Unfortunately, its long and asymptomatic natural history, the uncertainties about disease progression, the fact that most patients are undiagnosed, and the requirement for sequential liver biopsies create substantial challenges for clinical development. Adaptive design methods are increasingly used in clinical research as they provide the flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation and make prompt preplanned adaptations without undermining the validity or integrity of the trial. Given the high unmet medical need and the lack of validated surrogate endpoints in NASH, the use of adaptive design methods appears reasonable. Furthermore, due to the limited number of patients willing to have multiple liver biopsies and the need for long-term exposure to assess an impact in outcomes, a continuous seamless adaptive design may reduce the overall sample size while allowing patients to continue after each one of the phases. Here, we review strategic frameworks that include potential surrogate endpoints as well as statistical and logistical approaches that could be considered for applying adaptive designs to clinical trials in NASH with the goal of facilitating drug development for this growing medical need. (Hepatology Communications 2017;1:577-585). PMID- 29404481 TI - Long-term survival after surveillance and treatment in patients with chronic viral hepatitis and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the main cause of mortality in patients with chronic viral hepatitis (CVH). We determined the impact of surveillance and treatments on long-term outcomes in patients with CVH who developed HCC. Between 1984 and 2014, 333 patients with HCC and with hepatitis B or hepatitis C virus infection were evaluated. An adjusted lead time bias interval was added to patients with HCC who presented with HCC (no surveillance), and their survival was compared to patients whose HCC was detected by surveillance. After HCC treatments, survival rates within and beyond 3 years of follow-up were compared. In 175 (53%) patients, HCC was detected through surveillance using alpha fetoprotein and abdominal ultrasound examinations. Compared to 158 (47%) patients with HCC who had no surveillance, more patients with HCC detected by surveillance received surgical and locoregional treatments (P < 0.0001 to P < 0.001), and their 1-, 3-, and 5-year overall and disease-free survival rates were significantly higher (P < 0.001 for both). During the first 3 years of follow up, patients with HCC receiving liver transplantation had similar survival rates as those with liver resection or radiofrequency ablation (RFA); however, due to HCC recurrence, survival in resection and RFA patients became significantly less when followed beyond 3 years (P = 0.001 to P = 0.04). Factors associated with mortality included tumors beyond University of California at San Francisco criteria (hazard ratio [HR] 2.02; P < 0.0001), Child-Pugh class B and C (HR, 1.58-2.26; P = 0.043 to P = 0.015, respectively), alpha-fetoprotein per log ng/mL increase (HR, 1.30; P < 0.0001), previous antiviral therapy in hepatitis B virus patients (HR, 0.62; P = 0.032), and treatments other than liver transplantation (HR, 2.38-6.45; P < 0.0001 to P < 0.003). Conclusion. Patients with HCC detected by surveillance had prolonged survival. Due to HCC recurrence, survival rates after liver resection and RFA were lower when followed beyond 3 years after treatments. (Hepatology Communications 2017;1:595-608). PMID- 29404482 TI - Nonalcoholic fatty liver with a hepatic arterial buffer response strongly associated with future metabolic disease. AB - A change in hepatic blood flow caused by the hepatic arterial buffer response (HABR) occurs as fatty liver disease progress. The aim of this longitudinal cohort study was to investigate whether fatty liver with the HABR induces metabolic disorders. In 2009 and 2010, 494 (89.5%) participants were enrolled. The median follow-up duration was 5.0 (interquartile range, 3.9-6.0) years. The hazard ratios of fatty liver with the HABR for incident metabolic disorders were assessed by Cox proportional hazard models. A non-fatty liver group (non-FL group, hepatorenal echo intensity ratio <1.12), a fatty liver without portal hypertension (FL group, hepatorenal echo intensity ratio >=1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein <3.1) group, and a fatty liver with portal hypertension (FL HABR group, hepatorenal echo intensity ratio >=1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein >=3.1) group were defined based on echo intensity and Doppler ultrasonography. Fatty liver with and without the HABR was significantly associated with the incidence of diabetes on multivariate analysis (non-FL versus FL group, hazard ratio, 3.36; 95% confidence interval, 1.05-12.85; FL versus FL with the HABR group, HR, 2.68; 95% confidence interval, 1.28-6.04). With respect to the incidence of hypertension and dyslipidemia, only FL with the HABR was a significant factor (hypertension, non-FL versus FL, P = 0.874, FL versus FL-HABR, P = 0.016, non-FL versus FL-HABR, P = 0.023; dyslipidemia, non-FL versus FL, P = 0.311, FL versus FL-HABR, P = 0.194, non-FL versus FL-HABR, P = 0.038). Conclusion: Fatty liver with the HABR is a high-risk condition for metabolic diseases. (Hepatology Communications 2017;1:623-633). PMID- 29404483 TI - Characteristics of hepatic insulin-sensitive nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% +/- 5.2% versus 91.0% +/- 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% +/- 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% +/- 16.1% versus 20.4% +/- 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634 647). PMID- 29404484 TI - The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. AB - Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator-activated receptor-alpha/delta (PPAR-alpha/delta) agonists show some efficacy. Seladelpar (MBX-8025), a selective PPAR-delta agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR-delta activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild-type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8-12) were then randomized to receive MBX-8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX-8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300-600 U/L in vehicle-treated foz/foz mice; MBX-8025 reduced alanine aminotransferase by 50%. In addition, MBX-8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle-treated foz/foz versus wild-type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle-treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX-8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet-fed obese diabetic mice. Selective PPAR-delta agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017;1:663-674). PMID- 29404485 TI - Increased ethanol-inducible cytochrome P450-2E1 and cytochrome P450 isoforms in exosomes of alcohol-exposed rodents and patients with alcoholism through oxidative and endoplasmic reticulum stress. AB - This study investigated the role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in enhancing CYP2E1 and other P450 proteins in extracellular vesicles (EVs) from alcohol-exposed rodents and human patients with alcoholism and their effects on oxidative hepatocyte injury. Female Fischer rats and wild-type or Cyp2e1-null mice were exposed to three oral doses of binge ethanol or dextrose control at 12-hour intervals. Plasma EV and hepatic proteins from alcohol-exposed rodents, patients with alcoholism, and their respective controls were isolated and characterized. The number of EVs and the amounts of EV CYP2E1, CYP2A, CYP1A1/2, and CYP4B proteins were markedly elevated in both patients with alcoholism and alcohol-exposed rats and mice. The number of EVs and EV P450 proteins were significantly reduced in ethanol-exposed rats fed a diet containing polyunsaturated fatty acids. The increased number of EVs and EV CYP2E1 and other P450 isoforms in alcohol-exposed wild types were significantly reduced in the corresponding Cyp2e1-null mice. EV CYP2E1 amounts depended on increased oxidative and endoplasmic reticulum (ER) stress because their levels were decreased by cotreatment with the antioxidant N-acetylcysteine or the CYP2E1 inhibitor chlormethiazole but increased by ER stress-inducer thapsigargin, which was blocked by 4-phenylbutyric acid. Furthermore, cell death rates were elevated when primary hepatocytes or human hepatoma cells were exposed to EVs from alcohol exposed rodents and patients with alcoholism, demonstrating that EVs from alcohol exposed rats and patients with alcoholism are functional and can promote cell death by activating the apoptosis signaling pathway, including phospho-c-Jun N terminal kinase, proapoptotic Bax, and activated caspase-3. Conclusion: CYP2E1 has an important role in elevating EV CYP2E1 and other P450 isoforms through increased oxidative and ER stress. Elevated EV-CYP2E1 detected after withdrawal from alcohol or exposure to the CYP2E1 inducer pyrazole can be a potential biomarker for liver injury. (Hepatology Communications 2017;1:675-690). PMID- 29404486 TI - A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells. AB - We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half-life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691-703). PMID- 29404487 TI - Profiling of the circadian metabolome in thioacetamide-induced liver cirrhosis in mice. AB - Liver cirrhosis can disturb circadian rhythms, decreasing patient quality of life. Changes in metabolic products in cirrhosis are poorly understood. We evaluated changes in liver metabolism products using a thioacetamide-induced mouse model of liver cirrhosis exhibiting circadian rhythm disturbance. Principal component analysis indicated that the circular progression found in the control group was disrupted in the thioacetamide group, and Jonckheere-Terpstra-Kendall analysis showed an imbalanced pattern of oscillating metabolic products. In addition to changes in serotonin and other vitamin A-related metabolites, differences in metabolic products associated with energetics, redox homeostasis, bile acid production, inflammation, and other processes were identified. Carbohydrate metabolism showed a reduction in metabolic products associated with the tricarboxylic acid cycle, suggesting up-regulation of glycolysis and reduced mitochondrial activity. Lipid metabolism showed an increase in omega-oxidation products, suggesting decreased beta-oxidation. Conclusion: These data will be useful for chronotherapy and modulation of circadian rhythms in patients with liver damage. (Hepatology Communications 2017;1:704-718). PMID- 29404488 TI - Adding to the evidence base: Effectiveness of hepatocellular carcinoma surveillance in clinical practice. PMID- 29404490 TI - Survival following hospitalization with hepatocellular carcinoma among people notified with hepatitis B or C virus in Australia (2000-2014). AB - We assessed trends in HCC survival in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in New South Wales, Australia. Data on HBV (n = 54,399) and HCV (n = 96,908) notifications (1993-2012) were linked to a hospitalization database (July 2000-June 2014), the New South Wales Cancer Registry, and the New South Wales Death Registry. A total of 725 (1.3%) first HBV hepatocellular carcinoma (HCC) and 1,309 (1.4%) first HCV-HCC hospitalizations were included. Death occurred in 60.4% of HBV-HCC and 69.6% of HCV-HCC patients. Median survival following first HBV-HCC hospitalization improved from 0.6 years (95% confidence interval [CI] 0.39-1.28) in 2000-2004 to 2.8 years (1.54-5.54) in 2010-2014. Median survival following first HCV-HCC hospitalization was 0.8 years (0.45-1.33) in 2000-2004 and 0.9 (0.67-1.18) in 2010-2014. One-year HBV-HCC survival in 2010-2014 compared to 2000-2004 improved for those with (94% versus 81%) and without (42% versus 33%) potentially curative procedures (liver resection, liver transplantation, and radiofrequency ablation). Factors associated with improved survival following HBV-HCC were later study period (hazard ratio [HR] = 0.74; 95% CI, 0.57-0.97) and potentially curative procedures (liver resection, liver transplantation, and radiofrequency ablation) (HR = 0.23; 95% CI, 0.17-0.29), while male gender (HR = 1.37; 95% CI, 1.03-1.82), human immunodeficiency virus coinfection (HR = 3.06; 95% CI, 1.36-6.88), and Charlson Comorbidity Index >=3 (HR = 1.81; 95% CI, 1.35-2.40) were associated with reduced survival. Factors associated with improved survival following HCC-HCV were Asia Pacific country of birth (HR = 0.68; 95% CI, 0.55-0.84) and potentially curative procedures (HR = 0.21; 95% CI, 0.17-0.25), while age (HR = 1.01; 95% CI, 1.01 1.02), rural place of residence (HR = 1.46; 95% CI, 1.22-1.74), and human immunodeficiency virus coinfection (HR = 2.71; 95% CI, 1.19-6.15) were associated with reduced survival. Conclusion: All-cause survival following HBV-HCC has improved considerably, suggesting an impact of more effective antiviral therapy and earlier HCC diagnosis; in contrast, all-cause survival for HCV-HCC is unchanged. (Hepatology Communications 2017;1:736-747). PMID- 29404489 TI - Drug-induced cholestasis. AB - Cholestatic drug-induced liver injury (DILI) can be a diagnostic challenge due to a large differential diagnosis, variability in clinical presentation, and lack of serologic biomarkers associated with this condition. The clinical presentation of drug-induced cholestasis includes bland cholestasis, cholestatic hepatitis, secondary sclerosing cholangitis, and vanishing bile duct syndrome. The associate mortality of cholestatic DILI can be as high as 10%, and thus prompt recognition and removal of the offending agent is of critical importance. Several risk factors have been identified for drug-induced cholestasis, including older age, genetic determinants, and properties of certain medications. Antibiotics, particularly amoxicillin/clavulanate, remain the predominant cause of cholestatic DILI, although a variety of other medications associated with this condition have been identified. In this review, we summarize the presentation, clinical approach, risk factors, implicated medications, and management of drug-induced cholestatic liver injury. (Hepatology Communications 2017;1:726-735). PMID- 29404491 TI - Remodeling the model for end-stage liver disease for predicting mortality risk in critically ill patients with cirrhosis and acute kidney injury. AB - Serum creatinine measurement demonstrates a poor specificity and sensitivity for the early diagnosis of acute kidney injury (AKI) in patients with cirrhosis. The existing model for end-stage liver disease (MELD) score reveals multiple pitfalls in critically ill patients with cirrhosis and acute kidney injury (CAKI). The aim of this study was to re-evaluate the role of creatinine values in the existing MELD score and to develop a novel score for CAKI, named the "acute kidney injury model for end-stage liver disease score" (AKI-MELD score). We extracted 651 CAKI from the Multiparameter Intelligent Monitoring in Intensive Care database. A time dependent Cox regression analysis was performed for developing remodeled MELD scores (Reweight-MELD score, Del-Cr-MELD score, and AKI-MELD score). The area under the receiver operating characteristic curve provided the discriminative power of scoring models related to outcome. The hazard ratio of creatinine was 1.104 (95% confidence interval [CI], 0.945-1.290; P = 0.211). Reweight-MELD score and Del-Cr-MELD score (decreasing the weight of creatinine) were superior to the original MELD score (all P < 0.001). The new AKI-MELD score consists of bilirubin, the international normalized ratio, and the ratio of creatinine in 48 hours to creatinine at admission. It had competitive discriminative ability for predicting mortality (area under the receiver operating characteristic curve, 0.720 [95% CI, 0.653-0.762] at 30 days, 0.688 [95% CI, 0.630-0.742] at 90 days, and 0.671 [95% CI, 0.612-0.725] at 1 year). Further, AKI-MELD score had significantly higher predictive ability in comparison with MELD score, MELD-Na score, and Updated MELD score (all P < 0.001). Conclusion: The predictive value of creatinine for CAKI should be re-evaluated. AKI-MELD score is a potentially reliable tool to determine the prognosis for mortality of CAKI. (Hepatology Communications 2017;1:748-756). PMID- 29404492 TI - Concomitant proton pump inhibitor use does not reduce the efficacy of elbasvir/grazoprevir: A pooled analysis of 1,322 patients with hepatitis C infection. AB - Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance-associated substitutions. This post-hoc analysis assessed 12-week sustained viral response (SVR12) and pharmacokinetics of fixed-dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self-reported PPI use. Data were derived from six phase 3 EBR/GZR trials with treatment-naive or treatment-experienced genotype 1- or 4-infected patients, with or without compensated cirrhosis. Baseline PPI use was defined as >=7 consecutive days of use between study days -7 and 7. Bivariate analyses assessed PPI use and factors associated with SVR12 with sex, age (continuous and dichotomous), cirrhosis status, prior treatment status, baseline HCV RNA (continuous and dichotomous), HCV genotype, and baseline resistance-associated substitutions as variables in the models. Overall, 12% (162/1,322) of EBR/GZR-treated patients reported baseline PPI use. Of those, 96% achieved SVR12. In patients without PPI use, 97% achieved SVR12. PPI use was not a predictive factor in achieving SVR12 based on a univariate analysis (P = 0.188). In the bivariate models, none of the interaction terms involving PPI use were statistically significant. There was no significant effect of PPI usage, regardless of adjustment for considered factors. The estimated area under the curve and maximum concentration values for EBR were comparable among patients with and without reported PPI use. Conclusion: These results demonstrate that PPI use with EBR/GZR had no clinically significant effect on SVR12 rates in genotype 1/4-infected patients with or without compensated cirrhosis. (clinicaltrials.gov identifiers: NCT02092350, NCT02105467, NCT02105662, NCT02105688, NCT02105701, NCT02358044) (Hepatology Communications 2017;1:757-764). PMID- 29404493 TI - Role of gp91phox in hepatic macrophage programming and alcoholic liver disease. AB - Hepatic macrophages (MPhis) are important in the development and progression of alcoholic liver disease (ALD). This study investigates the role of gp91phox (nicotinamide adenine dinucleotide phosphate oxidase 2) in the severity of ALD and specifically in regulating hepatic MPhi efferocytic capability and the subsequent reprogramming associated with resolution of inflammation. After 4 weeks of ethanol feeding, more severe ALD developed in gp91phox-/- mice than in wild-type (WT) C57Bl/6J mice, evidenced by increased liver injury and inflammation. This phenomenon was not sex dependent, and thus the majority of experiments were performed with female mice. While total hepatic MPhi numbers did not differ between genotypes, hepatic infiltrating MPhis (IMs) were slightly more numerous in gp91phox-/- mice, and both IMs and resident Kupffer cells displayed enhanced proinflammatory and reduced tissue-restorative programming compared with these cells from WT mice. The ratio of proinflammatory IMs with higher expression of Ly6C (Ly6Chi) to anti-inflammatory IMs with lower expression of Ly6C (Ly6Clow) was significantly higher in gp91phox-/- mice compared to WT mice. Greater numbers of apoptotic cells accumulated in the liver of gp91phox-/- mice compared to WT mice, and receptors for binding and engulfing apoptotic cells were expressed at much lower levels on both Kupffer cells and IMs of gp91phox-/- mice. Interactions with apoptotic cells (binding and engulfment) in vitro were significantly fewer for gp91phox-/- MPhis than for WT MPhis, resulting in diminished expression of tissue restorative mediators by hepatic MPhis of gp91phox-/- mice. Conclusion: gp91phox plays a critical role in the differentiation of proinflammatory hepatic MPhis to a tissue-restorative phenotype, likely through programming for efferocytosis, and thereby lessens the severity of ALD. These findings enhance our understanding of the tissue environmental cues that regulate MPhi phenotypes. This knowledge could help in designing MPhi-targeting strategies to prevent and treat ALD. (Hepatology Communications 2017;1:765-779). PMID- 29404494 TI - Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis. AB - In contrast to patients with viral hepatitis, patients with nonalcoholic fatty liver disease (NAFLD) can progress to hepatocellular carcinoma during the initial stages of liver fibrosis. Development and implementation of noninvasive methods for diagnosis and progression prediction are important for effective NAFLD surveillance. Mac-2 binding protein (Mac-2bp) is a useful nonalcoholic steatohepatitis (NASH) diagnosis biomarker and a powerful prediction biomarker for NAFLD fibrosis stage. Wisteria floribunda agglutinin (WFA)-positive Mac-2bp (WFA+-M2BP) is a novel serum fibrosis biomarker for chronic hepatitis C that has clinical validity. Mac-2bp and WFA+-M2BP are also clinical NAFLD biomarker candidates. We examined the efficacy of Mac-2bp and WFA+-M2BP for NAFLD assessment using patients with biopsy-proven NAFLD (n = 510; NAFLD cohort) and subjects who received a health check-up (n = 2,122; check-up cohort). In the NAFLD cohort, we set the fibrosis predicting cutoff values as 1.80 (F1), 2.21 (F2), and 2.24 MUg/mL (F3). In the subjects with fatty liver from the check-up cohort (n = 1,291), the serum Mac-2bp levels were >1.80 MUg/mL in 38.6% of the subjects (n = 498), and >2.24 MUg/mL in 24.6% of the subjects (n = 318). The NAFLD cohort results indicated that Mac-2bp and WFA+-M2BP were equally useful for NASH diagnosis. During the early stages of fibrosis (F1, F2), the increase in Mac 2bp was statistically significant but WFA+-M2BP did not increase. Logistic regression analysis revealed that Mac-2bp was an independent determinant for the prediction of advanced fibrosis stage (>=F2), even when adjusted for WFA+-M2BP. Immunohistochemical staining of Mac-2bp revealed that hepatocytes strongly expressed Mac-2bp in patients with NAFLD. Conclusion: Our results indicated that hepatocyte-derived Mac-2bp would be a useful single biomarker for NASH diagnosis and fibrosis stage prediction in patients with NAFLD. (Hepatology Communications 2017;1:780-791). PMID- 29404496 TI - Megatrends in bile acid receptor research. PMID- 29404495 TI - Nicotinamide N-methyltransferase expression decreases in iron overload, exacerbating toxicity in mouse hepatocytes. AB - Iron overload causes the generation of reactive oxygen species that can lead to lasting damage to the liver and other organs. The goal of this study was to identify genes that modify the toxicity of iron overload. We studied the effect of iron overload on the hepatic transcriptional and metabolomic profile in mouse models using a dietary model of iron overload and a genetic model, the hemojuvelin knockout mouse. We then evaluated the correlation of nicotinamide N methyltransferase (NNMT) expression with body iron stores in human patients and the effect of NNMT knockdown on gene expression and viability in primary mouse hepatocytes. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism and that NNMT, an enzyme that methylates nicotinamide and regulates hepatic glucose and cholesterol metabolism, is one of the most strongly down regulated genes in the liver in both genetic and dietary iron overload. We found that hepatic NNMT expression is inversely correlated with serum ferritin levels and serum transferrin saturation in patients who are obese, suggesting that body iron stores regulate human liver NNMT expression. Furthermore, we demonstrated that adenoviral knockdown of NNMT in primary mouse hepatocytes exacerbates iron induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of NNMT partially reversed these effects. Conclusion: Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases NNMT expression, while NNMT deficiency worsens the toxic effect of iron overload. For these reasons, NNMT may be a drug target for the prevention of iron induced hepatotoxicity. (Hepatology Communications 2017;1:803-815). PMID- 29404497 TI - Rate of seeding with biopsies and ablations of hepatocellular carcinoma: A retrospective cohort study. AB - Biopsies of liver masses that prove to be hepatocellular carcinomas (HCCs) are associated with a risk of seeding the abdominal or chest wall with tumor cells. The reported frequency of seeding varies greatly in the literature. We performed a retrospective cohort study in a large integrated health care system to examine rates of seeding in patients with HCC who had targeted liver biopsies, ablations, or both performed by community radiologists. We reviewed pathology and radiology records to determine the occurrence of wall seeding, defined as a chest or abdominal wall lesion along a definite or probable needle tract. A total of 1,015 patients had targeted liver biopsies (795), ablations (72), or both (148). Multiple procedures were done in 284 patients (28%). Six cases of seeding were identified. The rate of wall seeding was 2/795 patients (0.13%; 95% confidence interval [CI], 0.00%-0.60%) if only biopsies were done versus 4/220 (1.82%; 95% CI, 0.05%-3.58%) if ablations were performed (P = 0.01). The rate was 0/72 (0.00%; 95% CI, 0.00%-0.04%) with ablations alone and 4/148 (2.70%; 95% CI, 0.74% 6.78%) if both procedures were done (P = 0.31). Of those with 1 year follow-up (n = 441), the rate of seeding was 2/269 (0.74%; 95% CI, 0.00%-1.77%) if biopsies alone were done and 4/172 (2.33%; 95% CI, 0.07%-4.58%) if ablations were done. In none of the cases was the seeding a proximate cause of death. Conclusion: Biopsies of liver masses are associated with a low rate of wall seeding when performed in a community setting and when they are the sole procedures. Ablations may have a higher rate of seeding, particularly if done with biopsies, but are still rare. (Hepatology Communications 2017;1:841-851). PMID- 29404498 TI - Activin A is a prominent autocrine regulator of hepatocyte growth arrest. AB - Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A stimulated effects, hepatocytes were cocultured with engineered activin A secreting cell lines (RF1, TL8) or transduced with an adeno-associated virus vector encoding activin betaA, which led to strikingly altered expression of cell cycle-related genes (Ki-67, E2F transcription factor 1 [E2F1], minichromosome maintenance complex component 2 [Mcm2], forkhead box M1 [FoxM1]) and senescence related genes (cyclin-dependent kinase inhibitor 2B [p15INK4b/CDKN2B], differentiated embryo-chondrocyte expressed gene 1 [DEC1]) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [Adam12], semaphorin 7A [Sema7a], LIM and cysteine-rich domains-1 [Lmcd1], DAB2, clathrin adaptor protein [Dab2]). Among the main activin A-mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down-regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (Cyp2C11), sulfotransferase family 1A, member 1 (Sult1a1), glycine-N-acyltransferase (Glyat), and bile acid-CoA:amino acid N acyltransferase (Baat). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)-4alpha and peroxisome proliferator-activated receptor gamma (PPARgamma) as key targets of activin A signaling. Conclusion: Our in vitro models demonstrated that activin A stimulated growth inhibition and cellular senescence is mediated through p15INK4b/CDKN2B and is associated with up- and down-regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. (Hepatology Communications 2017;1:852-870). PMID- 29404499 TI - Segregated hepatocyte proliferation and metabolic states within the regenerating mouse liver. AB - Mammalian partial hepatectomy (PH) induces an orchestrated compensatory hyperplasia, or regeneration, in remaining tissue to restore liver mass; during this process, liver functions are maintained. We probed this process in mice with feeding- and light/dark-entrained animals subjected to sham or PH surgery. Early on (i.e., 10 hours), irrespective of sham or PH surgery, hepatocytes equidistant from the portal and central veins (i.e., midlobular) accumulated the G1-phase cell-division-cycle marker cyclin D1. By 24 hours, however, cyclin D1 disappeared absent PH but was reinforced in midlobular hepatocytes after PH. At 48 hours after PH and 2 hours fasting, synchronously mitotic hepatocytes possessed less glycogen than surrounding nonproliferating hepatocytes. The differential glycogen content generated a conspicuous entangled pattern of proliferating midlobular and nonproliferating periportal and pericentral hepatocytes. The nonproliferating hepatocytes maintained aspects of normal liver properties. Conclusion: In the post-PH regenerating mouse liver, a binary switch segregates midlobular cells to proliferate side-by-side with nonproliferating periportal and pericentral cells, which maintain metabolic functions. Our results also indicate that mechanisms of liver regeneration display evolutionary flexibility. (Hepatology Communications 2017;1:871-885). PMID- 29404500 TI - Progression of liver fibrosis is associated with non-liver-related mortality in patients with nonalcoholic fatty liver disease. AB - In patients with nonalcoholic fatty liver disease (NAFLD), prognosis and outcome, especially non-liver-related mortality, remain incompletely elucidated. We clarified the mortality from all causes in patients with NAFLD. A total of 4,073 patients with NAFLD diagnosed by ultrasonography were enrolled. We investigated the causes of death and analyzed the mortality from non-liver-related diseases according to the degrees of steatosis and fibrosis using the competing risk method. We used the NAFLD fibrosis score (NFS) to assess fibrosis severity and the ultrasonography fatty liver score to evaluate steatosis severity. The numbers of patients with NFS indicating low, intermediate, and high probabilities of advanced fibrosis were 2,451 (60.2%), 1,462 (35.9%), and 160 (3.9%), respectively. Of the 4,073 patients, 179 died during follow-up, but only nine deaths were due to liver-related diseases. Of the remaining 170 patients who died due to non-liver-related diseases, 83 (48.8%), 42 (24.7%), and 45 (26.5%) patients died due to malignancies, cerebrovascular and cardiovascular diseases, and benign diseases (excluding cerebrovascular and cardiovascular diseases), respectively. Multivariate analysis showed that the intermediate and high NFS groups were independently associated with each disease category: hazard ratio (HR) 2.163 (95% confidence interval [CI], 1.354-3.457) and HR 4.814 (95% CI, 2.323-9.977) for malignancies; HR 2.265 (95% CI, 1.141-4.497) and HR 8.482 (95% CI, 3.558-20.220) for cerebrovascular and cardiovascular diseases; and HR 3.216 (95% CI, 1.641-6.303) and HR 5.558 (95% CI, 1.923-16.070) for benign diseases, respectively. Conversely, the status of steatosis was not associated with risk of mortality in multivariate analysis. Conclusion: Progression of liver fibrosis severity was associated with mortality from various non-liver-related causes in patients with NAFLD. (Hepatology Communications 2017;1:928-945). PMID- 29404501 TI - Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis. AB - The farnesoid X receptor (FXR) agonist, a bile acid-activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer-344 rats were fed a choline-deficient, L-amino acid-defined diet (CDAA). The in vitro and in vivo effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor beta1 and toll-like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 disruption, whereas losartan directly suppressed activated-HSC (Ac-HSC) regulation. The in vitro inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor beta1, toll like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor-kappaB and mothers against decapentaplegic homolog 3 in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS-administered OLETF and CDAA-treated rats. Conclusion: INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac-HSC proliferation. Combined therapy may represent a promising novel approach for NASH. (Hepatology Communications 2017;1:928-945). PMID- 29404502 TI - Neutrophil gelatinase-associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases. AB - Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end-stage liver disease and Child-Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase-associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real-time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll-like receptor 4, and interleukin-6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow-up period of 9.9 months. The patients with blood NGAL <=119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946-956). PMID- 29404503 TI - The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis. AB - The pathogenesis of primary sclerosing cholangitis (PSC) and the mechanistic link to inflammatory bowel disease remain ill-defined. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1)/clusters of differentiation (CD) 39, the dominant purinergic ecto-enzyme, modulates intestinal inflammation. Here, we have explored the role of CD39 in biliary injury and fibrosis. The impact of CD39 deletion on disease severity was studied in multidrug resistance protein 2 (Mdr2)-/- and 3,5 diethoxycarbonyl-1,4-dihydrocollidine mouse models of sclerosing cholangitis and biliary fibrosis. Antibody-mediated CD8+ T-cell depletion, selective gut decontamination, experimental colitis, and administration of stable adenosine triphosphate (ATP) agonist were performed. Retinoic acid-induced gut imprinting on T cells was studied in vitro. Over half of Mdr2-/-;CD39-/- double mutants, expected by Mendelian genetics, died in utero. Compared to Mdr2-/-;CD39+/+, surviving Mdr2-/-;CD39-/- mice demonstrated exacerbated liver injury, fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and integrin alpha4beta7, a T-cell gut-tropism receptor. CD8+ cell depletion in Mdr2-/-;CD39-/- mice diminished hepatobiliary injury and fibrosis. Treatment with antibiotics attenuated, whereas dextran sulfate sodium-induced colitis exacerbated, liver fibrosis in Mdr2-/- mice. Colonic administration of alphabeta-ATP into CD39-sufficient Mdr2-/- mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2-/-;CD39-/- mice. In vitro, addition of ATP promoted the retinoic acid-induced imprinting of gut homing integrin alpha4beta7 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up-regulated in samples of patients with inflammatory bowel disease. Conclusion: CD39 deletion promotes biliary injury and fibrosis through gut-imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (Hepatology Communications 2017;1:957-972). PMID- 29404505 TI - Lean NAFLD: A not so benign condition? PMID- 29404504 TI - Three variants in the nicotinamide adenine dinucleotide phosphate oxidase complex are associated with HCV-related liver damage. AB - Approximately 71 million people are chronically infected with the hepatitis C virus (HCV), a potentially lethal pathogen. HCV generates oxidative stress correlating with disease severity. HCV proteins increase reactive oxygen species production by stimulating nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity. Reactive oxygen species are necessary for host defense and cell signaling; however, elevated NOX activity contributes to cancer, and NOX overexpression is associated with hepatic fibrosis. Our aim was to investigate whether single nucleotide polymorphisms (SNPs) in NOX family members are associated with HCV-related liver damage. Three hundred and thirty-one individuals of European ancestry and 90 individuals of African ancestry, all diagnosed with HCV, were genotyped for 243 tagSNPs in NOX enzymes and their regulatory factors. Pathology scores were available for 288 Caucasians and 71 Africans, and mortality status was determined for all subjects. SNPs were tested for association with pathology scores and as predictors of mortality. In Africans, homozygosity for the A allele of rs12753665 (neutrophil cytosolic factor 2) and homozygosity for the T allele of rs760519 (neutrophil cytosolic factor 4) were associated with and predictive of higher rates of advanced fibrosis and cirrhosis compared to other genotypes after controlling for age and sex. In Caucasians, homozygosity for the T allele of rs2292464 (dual oxidase 1) was associated with and predictive of decreased periportal inflammation after controlling for age and sex. No SNPs were significant predictors of mortality. Conclusion: In this exploratory study, three NOX-related polymorphisms in two ethnic groups were significantly associated with hepatic inflammation and fibrosis. Future studies investigating these SNPs in larger cohorts of patients with HCV are warranted. (Hepatology Communications 2017;1:973-982). PMID- 29404506 TI - A new mechanism of action of glucagon-like peptide-1 agonist in hepatic steatosis: Promotion of hepatic insulin clearance through induction of carcinoembryonic antigen-related cell adhesion molecule 1. PMID- 29404507 TI - Sex-specific analysis post-liver transplantation in hemochromatosis with aplastic anemia and hepatocellular carcinoma. AB - A 42-year-old man with hemochromatosis and cirrhosis developed aplastic anemia. He underwent liver transplantation from a female donor and splenectomy, and his aplastic anemia spontaneously resolved. A bone marrow examination 6 months after the liver transplant showed 17.5% female cells. He did well for 13 years without the need for any blood product support but then developed bone pain and was found to have metastatic hepatocellular carcinoma in the vertebral bodies. Molecular analysis demonstrated that the tumor cells were from his original liver. No primary liver tumor was identified in the explant. The case demonstrates the application of fluorescent in situ hybridization with X and Y chromosome-specific probes to study chimerism and tumor origin after liver transplantation between individuals of different sex. (Hepatology Communications 2018;2:13-15). PMID- 29404508 TI - Sofosbuvir induced steven Johnson Syndrome in a patient with hepatitis C virus related cirrhosis. AB - Sofosbuvir is an imperative drug used in treatment regimens for hepatitis C virus (HCV). It is considered relatively safe with fewer adverse effects than other treatments. Here, we report a rare and potentially serious, dermatologic, adverse effect following the use of sofosbuvir. A 35-year-old man with genotype 3-related HCV cirrhosis presented with decompensated ascites and jaundice following 7 weeks of therapy with peginterferon alpha-2a and oral ribavirin. After peginterferon withdrawal and stabilization, oral sofosbuvir and ribavirin were started; 10 days later, he developed itching over the trunk and legs, followed by multiple papules and vesicles over an erythematous base. Over the next 15 days, the rash progressed with the formation of blisters and peeling skin. Simultaneously, the oral mucosa and lips developed crusting and painful erosions. Considering drug induced Steven John Syndrome (SJS), sofosbuvir and ribavirin were withdrawn and the patient was treated with topical emollients, steroids, and supportive care. The lesions improved over the next 4 weeks, with some residual hyperpigmentation. Rechallenge with sofosbuvir alone at one eighth the dose resulted in similar skin and mucosal lesions after 2 months; these lesions also improved after sofosbuvir withdrawal. The Algorithm of Drug Causality for Epidermal Necrolysis score was 7, which suggested sofosbuvir as the very probable drug resulting in SJS in our patient. Conclusion: The appearance of SJS following sofosbuvir use is an important and potentially fatal complication from a drug that serves as the backbone of several HCV treatment regimens. Treating physicians must use sofosbuvir with caution and consider withholding or discontinuing this drug in patients with such severe dermatologic manifestations. (Hepatology Communications 2018;2:16-20). PMID- 29404509 TI - Newly discovered hepatitis C virus minicores circulate in human blood. AB - Hepatitis C virus (HCV) is one of the most prevalent causes of chronic blood borne infections worldwide. Despite developments of highly effective treatments, most infected individuals are unaware of their infection. Approximately 75% of infections are in low- and middle-income countries; therefore, continuing research in HCV molecular virology and the development of vaccines and affordable diagnostics is required to reduce the global burden. Various intracellular forms of the HCV nucleocapsid (core) protein are produced in cell culture; these comprise the conventional p21 core and the newly discovered shorter isoforms (minicores). Minicores lack the N-terminus of p21 core. This study was conducted to determine if minicores are secreted in cell culture and more importantly if they circulate in the blood of individuals infected with HCV. We also developed a new monoclonal antibody that detects minicores targeting a C-terminal region common to p21 core and minicores. Direct evidence of minicores requires western blot analysis to distinguish the detection of p21 core from minicores. However, the sensitivity for western blot detection of HCV proteins from blood is nil without their prior purification/enrichment from blood. Therefore, we developed a purification method based on a heparin/Mn+2 precipitation of apolipoprotein B containing lipoproteins because HCV is thought to circulate as a hybrid lipoviral particle. Minicores are secreted in culture when cells are grown in the presence of human serum. The heparin/Mn+2 precipitate from HCV-infected cell culture supernatants and from the blood of 4 patients with high-titer genotype-1 HCV contained minicores. Conclusion: Minicores are major newly discovered HCV proteins that are secreted and circulate in blood during natural infections. Minicore proteins have translational potential as targets in diagnostic assays and in vaccine development. (Hepatology Communications 2018;2:21-28). PMID- 29404510 TI - Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis. AB - Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well-characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation. (Hepatology Communications 2018;2:29-34). PMID- 29404511 TI - Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis. AB - Exenatide, a glucagon-like peptide-1 receptor agonist, induces insulin secretion. Its role in insulin clearance has not been adequately examined. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance to maintain insulin sensitivity. Feeding C57BL/6J mice a high-fat diet down-regulates hepatic Ceacam1 transcription to cause hyperinsulinemia, insulin resistance, and hepatic steatosis, as in Ceacam1 null mice (Cc1-/- ). Thus, we tested whether exenatide regulates Ceacam1 expression in high-fat diet-fed mice and whether this contributes to its insulin sensitizing effect. Exenatide (100 nM) induced the transcriptional activity of wild-type Ceacam1 promoter but not the constructs harboring block mutations of peroxisome proliferator-activated receptor response element and retinoid X receptor alpha, individually or collectively, in HepG2 human hepatoma cells. Chromatin immunoprecipitation analysis demonstrated binding of peroxisome proliferator-activated receptor gamma to Ceacam1 promoter in response to rosiglitazone and exenatide. Consistently, exenatide induced Ceacam1 messenger RNA expression within 12 hours in the absence but not in the presence of the glucagon-like peptide-1 receptor antagonist exendin 9-39. Exenatide (20 ng/g body weight once daily intraperitoneal injection in the last 30 days of feeding) restored hepatic Ceacam1 expression and insulin clearance to curb diet-induced metabolic abnormalities and steatohepatitis in wild-type but not Cc1-/- mice fed a high-fat diet for 2 months. Conclusion: Exenatide promotes insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the resulting hepatic steatosis, and this contributes to its insulin sensitizing effect. Our data further highlight the relevance of physiologic insulin metabolism in maintaining insulin sensitivity and normal lipid metabolism. (Hepatology Communications 2018;2:35-47). PMID- 29404512 TI - Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. AB - Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI >= 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P = 0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P = 0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48-57). PMID- 29404513 TI - Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease. AB - Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68). PMID- 29404514 TI - Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice. AB - Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high-fat diet-induced systemic hyperglycemia and hyperinsulinemia, improved whole-body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl-coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single-nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69-83). PMID- 29404516 TI - Deficiency of cholesterol 7alpha-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice. AB - Alcoholic fatty liver disease (AFLD) is a major risk factor for cirrhosis associated liver diseases. Studies demonstrate that alcohol increases serum bile acids in humans and rodents. AFLD has been linked to cholestasis, although the physiologic relevance of increased bile acids in AFLD and the underlying mechanism of increasing the bile acid pool by alcohol feeding are still unclear. In this study, we used mouse models either deficient of or overexpressing cholesterol 7alpha-hydroxylase (Cyp7a1), the rate-limiting and key regulatory enzyme in bile acid synthesis, to study the effect of alcohol drinking in liver metabolism and inflammation. Mice were challenged with chronic ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight). Alcohol feeding reduced bile acid synthesis gene expression but increased the bile acid pool size, hepatic triglycerides and cholesterol, and inflammation and injury in wild-type mice and aggravated liver inflammation and injury in Cyp7a1 deficient mice. Interestingly, alcohol-induced hepatic inflammation and injury were ameliorated in Cyp7a1 transgenic mice. Conclusion: Alcohol feeding alters hepatic bile acid and cholesterol metabolism to cause liver inflammation and injury, while maintenance of bile acid and cholesterol homeostasis protect against alcohol-induced hepatic inflammation and injury. Our findings indicate that CYP7A1 plays a key role in protection against alcohol-induced steatohepatitis. (Hepatology Communications 2018;2:99-112). PMID- 29404515 TI - Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease. AB - The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14-16 weeks) and old (>1.5 years) wild-type (WT) littermates and global Opn knockout (Opn-/- ) mice for HPSC mobilization to the liver. In addition, WT and Opn-/- mice were chronically fed the Lieber-DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS-D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn /- mice. Granulocyte colony-stimulating factor and macrophage colony-stimulating factor were increased in Opn-/- mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol-fed Opn-/- mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn-/- compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD. (Hepatology Communications 2018;2:84-98). PMID- 29404517 TI - Hepatology mentorship: A bold idea: Data from the emerging liver scholars program. PMID- 29404518 TI - Hepatology Communications: Now in pubmed central and applying for other indices. PMID- 29404519 TI - Elucidating the differences in pathogenicity between hepatitis E virus genotypes: The quest continues. PMID- 29404520 TI - Liver tissue engineering: From implantable tissue to whole organ engineering. AB - The term "liver tissue engineering" summarizes one of the ultimate goals of modern biotechnology: the possibility of reproducing in total or in part the functions of the liver in order to treat acute or chronic liver disorders and, ultimately, create a fully functional organ to be transplanted or used as an extracorporeal device. All the technical approaches in the area of liver tissue engineering are based on allocating adult hepatocytes or stem cell-derived hepatocyte-like cells within a three-dimensional structure able to ensure their survival and to maintain their functional phenotype. The hosting structure can be a construct in which hepatocytes are embedded in alginate and/or gelatin or are seeded in a pre-arranged scaffold made with different types of biomaterials. According to a more advanced methodology termed three-dimensional bioprinting, hepatocytes are mixed with a bio-ink and the mixture is printed in different forms, such as tissue-like layers or spheroids. In the last decade, efforts to engineer a cell microenvironment recapitulating the dynamic native extracellular matrix have become increasingly successful, leading to the hope of satisfying the clinical demand for tissue (or organ) repair and replacement within a reasonable timeframe. Indeed, the preclinical work performed in recent years has shown promising results, and the advancement in the biotechnology of bioreactors, ex vivo perfusion machines, and cell expansion systems associated with a better understanding of liver development and the extracellular matrix microenvironment will facilitate and expedite the translation to technical applications. (Hepatology Communications 2018;2:131-141). PMID- 29404521 TI - Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature. AB - Idiosyncratic drug-induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant-free survival. Pirfenidone is an anti-inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini-review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77-year-old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long-term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI-ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI-ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone-related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142-147). PMID- 29404522 TI - Distinct clinical and magnetic resonance features of metastatic hepatocellular carcinoma treated with pembrolizumab: A case report of late response after pseudoprogression. AB - There are few effective therapies for unresectable or metastatic hepatocellular carcinoma. Recent data have demonstrated efficacy of immune checkpoint blockade in this difficult to treat disease; however, clinical experience is limited. We report a case of hepatocellular carcinoma displaying pseudoprogression followed by a late response with novel magnetic resonance imaging features following treatment with the anti-programmed cell death protein 1 agent pembrolizumab. (Hepatology Communications 2018;2:148-151). PMID- 29404523 TI - Can genetic testing guide the therapy of cholestatic pruritus? A case of benign recurrent intrahepatic cholestasis type 2 with severe nasobiliary drainage refractory itch. AB - Benign recurrent intrahepatic cholestasis (BRIC) is a peculiar familial disease caused by mutations of the genes encoding hepatocanalicular flippase for phosphatidylserine (ATP8B1; BRIC type 1) or the bile salt export pump (ABCB11; BRIC type 2). Here, we report on a patient with nasobiliary drainage-refractory BRIC type 2 who improved under plasma separation and anion absorption therapy. We also suggest that nasobiliary drainage might be an ineffective approach in carriers of severe loss-of-function mutations of the bile salt export pump ABCB11. (Hepatology Communications 2018;2:152-154). PMID- 29404524 TI - Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model. AB - Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three-dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ~40 kDa and the other, a more heavily glycosylated form, at ~50 kDa. Increased expression of the 40-kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three-dimensional culture. Moreover, coculturing of cancer associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40-kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155-172). PMID- 29404526 TI - Incidence and cost analysis of hospital admission and 30-day readmission among patients with cirrhosis. AB - We examined risks for first hospitalization and the rate, risk factors, costs, and 1-year outcome of 30-day readmission among patients admitted for complications of cirrhosis. Data were retrospectively analyzed for adult patients with cirrhosis residing in Minnesota, Iowa, or Wisconsin and admitted from 2010 through 2013 at both campuses of the Mayo Clinic Hospital in Rochester, MN. Readmission was captured at the two hospitals as well as at community hospitals in the tristate area within the Mayo Clinic Health System. The incidence of hospitalization for complications of cirrhosis was 100/100,000 population, with increasing age and male sex being the strongest risks for hospitalization. For the 2,048 hospitalized study patients, the overall 30-day readmission rate was 32%; 498 (24.3%) patients were readmitted to Mayo Clinic hospitals and 157 (7.7%) to community hospitals, mainly for complications of portal hypertension (52%) and infections (30%). Readmission could not be predicted accurately. There were 146 deaths during readmission and an additional 105 deaths up to 1 year of follow-up (50.4% total mortality). Annual postindex hospitalization costs for those with a 30-day readmission were substantially higher ($73,252) than those readmitted beyond 30 days ($62,053) or those not readmitted ($5,719). At 1-year follow-up, only 20.4% of patients readmitted within 30 days were at home. In conclusion, patients with cirrhosis have high rates of hospitalization, especially among men over 65 years, and of unscheduled 30-day readmission. Readmission cannot be accurately predicted. Postindex hospitalization costs are high; nationally, the annual costs are estimated to be more than $4.45 billion. Only 20% of patients readmitted within 30 days are home at 1 year. (Hepatology Communications 2018;2:188-198). PMID- 29404525 TI - Hepatitis E virus replication and interferon responses in human placental cells. AB - Hepatitis E virus (HEV) is a member of the genus Orthohepevirus in the family Hepeviridae and the causative agent of hepatitis E in humans. HEV is a major health problem in developing countries, causing mortality rates up to 25% in pregnant women. However, these cases are mainly reported for HEV genotype (gt)1, while gt3 infections are usually associated with subclinical courses of disease. The pathogenic mechanisms of adverse maternal and fetal outcome during pregnancy in HEV-infected pregnant women remain elusive. In this study, we observed that HEV is capable of completing the full viral life cycle in placental-derived cells (JEG-3). Following transfection of JEG-3 cells, HEV replication of both HEV gts could be observed. Furthermore, determination of extracellular and intracellular viral capsid levels, infectivity, and biophysical properties revealed production of HEV infectious particles with similar characteristics as in liver-derived cells. Viral entry was analyzed by infection of target cells and detection of either viral RNA or staining for viral capsid protein by immunofluorescence. HEV gt1 and gt3 were efficiently inhibited by ribavirin in placental as well as in human hepatoma cells. In contrast, interferon-alpha sensitivity was lower in the placental cells compared to liver cells for gt1 but not gt3 HEV. Simultaneous determination of interferon-stimulated gene expression levels demonstrated an efficient HEV-dependent restriction in JEG-3. Conclusion: We showed differential tissue-specific host responses to HEV genotypes, adding to our understanding of the mechanisms contributing to fatal outcomes of HEV infections during pregnancy. Using this cell-culture system, new therapeutic options for HEV during pregnancy can be identified and evaluated. (Hepatology Communications 2018;2:173-187). PMID- 29404527 TI - Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high-quality follow-up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow-up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow-up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (+/-1.7) and 9.3 (+/-1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end-stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty-six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy-proven fibrosis stage F3-F4 and 2 patients with end-stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end-stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end stage liver disease. (Hepatology Communications 2018;2:199-210). PMID- 29404528 TI - Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis. AB - Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro-C3) and degradation (matrix metalloproteinase-degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, alpha-smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro-C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro-C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1-3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro-C3 levels were associated with injury, disease severity scores (Model for End-Stage Liver Disease, Child-Pugh, chronic liver failure-C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure-C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211-222). PMID- 29404529 TI - Prevalence of premenstrual syndrome in Iran: A systematic review and meta analysis. AB - Background: Premenstrual syndrome (PMS) is a common disorder characterized by physical, mental and behavioral changes in the luteal phase of the menstrual cycle in the reproductive age women. Objective: The present study aimed to determine the overall prevalence of PMS in Iran by a systematic review and meta analysis study. Materials and Methods: In this systematic review and meta analysis, we searched international databases included ISI Web of Knowledge, PubMed/Medline, Scopus, Google Scholar, and also local databases including Iranmedex, Scientific Information Database, and Magiran for articles in English and Persian language published up to September 2016. We carried out data analysis with Stata version 11. We examined heterogeneity in the results of studies through I2 statistics and Chi-square based Q test. Also, we investigated the effects of potential heterogeneity factors in the prevalence of PMS by meta regression. Results: We studied a total of 9147 reproductive-age women from 24 articles which entered to meta-analysis. Based on the result of random effect model, we estimated the overall prevalence of PMS 70.8% [95% CI: 63.8-77.7]. The results of subgroup analysis revealed that prevalence of PMS was 80.4% (95% CI; 66.9-93.9) among high school students, 68.9% (95% CI; 59.2-78.6) among university students, and 54.9% (95% CI; 51.6-58.2) in general population. Univariate meta regression model showed that prevalence of PMS was decreased by increasing the age of subjects but this was not statistically significant (p=0.155). Conclusion: Our finding showed that PMS was prevalent in Iranian reproductive age women especially among high school students. More epidemiological research for determining factors that affect PMS prevalence seems essential. PMID- 29404530 TI - The effect of a positive reappraisal coping intervention and problem-solving skills training on coping strategies during waiting period of IUI treatment: An RCT. AB - Background: Waiting period of fertility treatment is stressful, therefore it is necessary to use effective coping strategies to cope with waiting period of intrauterine insemination (IUI) treatment. Objective: The aim of this study was comparing the effect of the positive reappraisal coping intervention (PRCI) with the problem-solving skills training (PSS) on the coping strategies of IUI waiting period, in infertile women referred to Milad Infertility Center in Mashhad. Materials and Methods: In this randomized clinical trial, 108 women were evaluated into three groups. The control group received the routine care, but in PRCI group, two training sessions were held and they were asked to review the coping thoughts cards and fill out the daily monitoring forms during the waiting period, and in PSS group problem-solving skill were taught during 3 sessions. The coping strategies were compared between three groups on the 10th day of IUI waiting period. Results: Results showed that the mean score for problem-focused were significantly different between the control (28.54+/-9.70), PSS (33.71+/ 9.31), and PRCI (30.74+/-10.96) (p=0.025) groups. There were significant differences between the PSS group and others groups, and mean emotion-focused were significantly different between the control (32.09+/-11.65), PSS (29.20+/ 9.88), and PRCI (28.74+/-7.96) (p=0.036) groups. There were significant differences between the PRCI and the control group (p=0.047). Conclusion: PSS was more effective to increase problem-focused coping strategies than PRCI, therefore it is recommended that this intervention should be used in infertility treatment centers. PMID- 29404531 TI - Triage by cervical length sonographic measurements for targeted therapy in threatened preterm labor: A double blind randomized clinical trial. AB - Background: Preterm labor and birth are associated with several neonatal complications including respiratory distress syndrome and intraventricular hemorrhage. Differentiating true and false labor pain is a dilemma to obstetricians. Objective: To elucidate the role of cervical length measurement in prediction of birth in pregnant women with threatened preterm labor. Materials and Methods: In this double blind randomized clinical trial, 120 women with gestational age <34 wk who presented painful uterine contractions randomly assigned to undergo measurement of cervical length. Patients were registered in the hospital and a unit number was given. Based on the unit numbers, patients were randomly assigned to two groups using a computerized random digit generator. All participants were managed accordingly (n=65) or to receive tocolysis as planned (n=55). Tocolysis was prescribed when cervical length was <15 mm while those with cervical length >=15 mm were managed expectantly. Delivery within 7 days of the presentation was the primary outcome. Results: This RCT showed in case group, 78.9% of patient with cervical length <15 mm were delivered within 7 days and only 21.1% of them maintained their pregnancy. Of those with cervical length >=15 mm, only 15.2% were delivered within the study period and the rest (84.8%) maintained their pregnancy (p<0.001). Conclusion: "Our results indicate that in women who presented preterm labor symptoms, cervical length measurement will result in decreased unnecessary tocolytic treatment. Women with cervical length >=15mm should not receive tocolysis, however, withholding corticosteroid therapy in these patients needs further evidence. PMID- 29404532 TI - Y chromosome microdeletions frequency in idiopathic azoospermia, oligoasthenozoospermia, and oligospermia. AB - Background: Genetic factors are candidates for about 30% of male infertility with sperm production-related abnormalities. Y chromosome microdeletions are responsible for around 10% of male infertility. These microdeletions generally occur in azoospermia factor on the Yq. That is often associated with the quantitative reduction of sperm. Objective: The aim of this cross-sectional study was to determine the frequency of Yq microdeletions among idiopathic azoospermic, oligoasthenozoospermic, and oligospermic men in Shohada infertility center, Chaharmahal va Bakhtiari province. Materials and Methods: A total of 81 idiopathic azoospermic, oligoasthenozoospermic, and oligospermic infertile men were selected as cases and 81 fertile men assigned to control group. For molecular investigations, 13 sequence-tagged site markers were chosen from azoospermia factor (AZF) region for detection of Y chromosome microdeletions and amplified by two separate multiplex-polymerase chain reaction. The relationship between the AZF microdeletions and incidence of male infertility in the family, consanguineous parents, smoking, and the levels of reproductive hormones among infertile men were investigated. Results: The total frequency of the microdeletions was 6.17% (2 cases in azoospermic, 3 cases in oligoasthenozoospermic subgroups, and none in the oligospermic participants and the control group). Most deletions (3.7%) were seen in the AZFb followed by the AZFc (2.46%) and none in AZFa. No significant association was seen between the microdeletions and clinical characteristics. Conclusion: Although the frequency of Yq chromosome microdeletions in Chaharmahal va Bakhtiari province is lower than the mean frequency of Iran, the frequency is comparable to those reported by some studies in Iran. PMID- 29404533 TI - Comparison of Chlamydia trachomatis infection among infertile and fertile women in Ahvaz, Iran: A case-control study. AB - Background: Chlamydia trachomatis (C. trachomatis) is the main cause of bacterial sexually transmitted infections. In women, this infection can lead to tubal infertility. Objective: In this study we investigated C. trachomatis among infertile and fertile women with both polymerase chain reaction (PCR) and ELISA methods in Ahvaz, Iran. Materials and Methods: This case-control study was conducted at the Infertility Clinic of University Jahad, Ahvaz, Iran from January to August 2017. A total of 225 vaginal swabs and blood samples (100 infertile and 125 fertile women) were collected. Detection of C. trachomatis DNA was performed from vaginal swabs by amplification of MOMP gene. Also, anti C. trachomatis immunoglobulin M (IgM) and immunoglobulin G antibodies in the serum samples were recognized by enzyme-linked immunosorbent assay (ELISA). Results: Results showed that, 6 (6%) infertile and 2 (1.6%) fertile women were positive for IgM (p=0.21). Also, PCR was positive for C. trachomatis infection in 5 infertile (5%) and 2 fertile women (1.6%) (p=0.35). We did not find any seropositive immunoglobulin G in both groups. Conclusion: In this study, no significant difference was found between fertile and infertile groups for C. trachomatis infection. Also, the correlation between IgM and PCR results revealed a relatively strong agreement and seems both PCR and IgM assays are appropriate for the accurate diagnosis of C. trachomatis infections. PMID- 29404534 TI - Bibliometric and thematic analysis of articles in the field of infertility (2011 2015). AB - Background: Infertility is a disease that results in the abnormal functioning of the male or female reproductive system. Systematic research planning on any subject, including infertility is in need of solid data regarding previous efforts in this field and to identify the gaps in the research. Objective: The aim of this research is to study the thematic structure of articles related to infertility. Materials and Methods: In this descriptive-analytical study with a scientometric approach, the PubMed database was searched for research publications indexed under "Infertility" over the period 2011-2015. Specific parameters were retrieved from the PubMed. Articles about infertility were analyzed regarding the journal of publication, topics, and countries using Net draw, Ucinet and RavarPreMap software. Also, the most influential topics were analyzed by indicators in the analysis of the network: closeness centrality, and between centrality. Results: The growth in scientific productions the area of infertility over the mentioned period shows an upward trend with the highest growths seen in countries like the United States, the UK, Netherlands, China, and Germany. Moreover, the contents such as fertilization in vitro, adverse effects, spermatozoa, pregnancy rate, and treatment outcome were among the most frequently used topics in the sphere. Conclusion: Thematic analysis can provide us the research topics, important expressions, and the relationships between them. Users and policymakers can also have a better understanding of the research status in the sphere and consequently, they can plan to increase the quantity and quality of scientific productions in a more efficient way. PMID- 29404535 TI - Cervical gland area as an ultrasound marker for prediction of preterm delivery: A cohort study. AB - Background: Preterm labor is a major cause of perinatal morbidity and mortality and it might be predicted by assessing the cervical change. Objective: To assess the association between absence of cervical gland area (CGA) and spontaneous preterm labor (SPTL). Materials and Methods: This prospective cohort study was performed on 200 singleton pregnant women with a history of SPTL, second trimester abortion in the previous pregnancy or lower abdominal pain in current pregnancy. Each patient underwent one transvaginal ultrasound examination between 14-28 wk of gestation. Cervical length was measured and CGA was identified and their relationship with SPTL before 35 and 37 wk gestation was evaluated using STATA software version 10. Results: The mean of cervical length was 36.5 mm (SD=8.4), the shortest measurement was 9 mm, and the longest one was 61 mm. Short cervical length (<=18mm) was significantly associated with SPTL before 35 and 37 wk gestation.Cervical gland area (the hypoechogenic or echogenic area around the cervical canal) was present in 189 (94.5%) patients. Absent of CGA had a significant relationship with SPTL before 35 and 37 wk gestation (p=0.01 and p<0.001, respectively). Cervical length was shorter in women with absent CGA in comparison with subjects with present CGA: 37+/-10 mm in CGA present group and 23+/-9 mm in CGA absent group (p<0.001). Conclusion: Our study showed that cervical gland area might be an important predictor of SPTL which should be confirmed with further researches. PMID- 29404536 TI - Low-dose hCG as trigger day and 35 hr later have different ovarian hyperstimulation syndrome occurrence in females undergoing In vitro fertilization: An RCT. AB - Background: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication, which can cause high morbidity and mortality. Use of gonadotropin releasing hormone (GnRH) agonist instead of human chorionic gonadotropin (hCG) in GnRH antagonist cycles causes luteinizing hormone surge by GnRH stimulation which reduces the risk of OHSS by reducing the total amount of gonadotropin; however, there is no possibility of transferring fresh embryos. Objective: The current study aimed to evaluate the effect of hCG along with GnRH agonist administration in the occurrence of OHSS and pregnancy rate in females undergoing in vitro fertilization. Materials and Methods: The current randomized clinical trial was conducted on 80 cases in 2 groups. Gonal-F was used to stimulate the oocyte from the second day of menstruation. When follicle size was 12-14 mm, GnRH antagonist was added to the protocol till the detection of more than two follicles greater than 18 mm. Then, GnRH agonist was added to the protocol as a trigger. In group A, 35 hr after the administration of GnRH agonist, the low-dose human hCG, 1500 IU, was used. In group B, low-dose hCG, 1500 IU, was used at the same time by GnRH agonist administration. The rate of pregnancy, OHSS, and its severity were compared between 2 groups within 2 wk. Results: There was no significant difference regarding chemical and clinical pregnancies between the 2 groups. Severe OHSS was significantly higher in group B (p= 0.03). Conclusion: Administration of hCG 35 hr after GnRH agonist administration results in lower rate of severe OHSS. PMID- 29404537 TI - General rules of fragmentation evidencing lasso structures in CID and ETD. AB - Lasso peptides constitute a structurally unique class of ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked structure in which the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Tandem mass spectrometry using collision induced dissociation (CID) and electron capture dissociation (ECD) have shown previously different fragmentation patterns for capistruin, microcin J25 and their corresponding branched-cyclic forms in which the C-terminal tail is unthreaded. In order to develop general rules that unambiguously discriminate the lasso and branched-cyclic topologies, this report presents experimental evidence for a set of twenty-one lasso peptides analyzed by CID and electron transfer dissociation (ETD). CID experiments on lasso peptides specifically yielded mechanically interlocked species with associated bi and yj fragments. For class II lasso peptides, these lasso-specific fragments were observed only for peptides in which the loop, located above the macrolactam ring, was strictly longer than four amino acid residues. For class I and III lasso peptides, part of the C-terminal tail remains covalently linked to the macrolactam ring by disulfide bonds; associated bi and yj fragments therefore do not clearly constitute a signature of the lasso topology. ETD experiments of lasso peptides showed a significant increase of hydrogen migration events in the loop region when compared to their branched-cyclic topoisomers, leading to the formation of specific ci/z'j fragments for all lasso peptides, regardless of their class and loop size. Our experiments enabled us to establish general rules for obtaining structural details from CID and ETD fragmentation patterns, obviating the need for structure determination by NMR or X-ray crystallography. PMID- 29404538 TI - 15N isotopic labelling for in-cell protein studies by NMR spectroscopy and single cell IR synchrotron radiation FTIR microscopy: a correlative study. AB - The ultimate goal of modern structural biology is to probe protein structures and dynamics in their physiological microenvironment. In-cell NMR spectroscopy is an ideal technique for achieving this goal, being able to investigate proteins at atomic-resolution in living cells. The reliability of the results provided by in cell NMR relies on the selectivity of the labelling methodology coupled with the filtering capabilities offered by heteronuclear NMR experiments. However, solution NMR is not well-suited either for measuring to what extent the non specific labelling occurs, or to evaluate how it is affected by cell-to-cell variability and, eventually, whether the labelling procedure affects the cellular macromolecular content in general. To answer these questions, we correlated in cell 1D 1H and 2D 1H-15N NMR experiments on HEK293T cells overexpressing superoxide dismutase 1 (SOD1) with single-cell Synchrotron Radiation FTIR Microscopy (FTIRM) experiments on the same samples. We verified that SOD1 overexpression in 15N-enriched media does not induce modifications in the overall cellular profile, and that the cell-to-cell labelling variability is independent of SOD1 overexpression and is likely cell cycle-related. We concluded that the non-specific incorporation of 15N into cellular components other than the protein of interest is one of the main factors that hinder the possibility of in-cell conformational studies by FTIRM at the single-cell level. Improving labelling selectivity by employing protein insertion approaches, and increasing FTIRM sensitivity by plasmonic enhancement, would open new perspectives for in-cell ultra-sensitive single-protein conformational studies complementing NMR and vibrational analyses. PMID- 29404545 TI - On the thermotropic and magnetotropic phase behavior of lipid liquid crystals containing magnetic nanoparticles. AB - The inclusion of superparamagnetic iron oxide nanoparticles (SPIONs) in lipid mesophases is a promising strategy for drug-delivery applications, combining the innate biocompatibility of lipid architectures with SPIONs' response to external magnetic fields. Moreover, the organization of SPIONs within the lipid scaffold can lead to locally enhanced SPIONs concentration and improved magnetic response, which is key to overcome the current limitations of hyperthermic treatments. Here we present a Small-Angle X-ray Scattering (SAXS) structural investigation of the thermotropic and magnetotropic behavior of glyceryl monooleate (GMO)/water mesophases, loaded with hydrophobic SPIONs. We prove that even very low amounts of SPIONs deeply alter the phase behavior and thermotropic properties of the mesophases, promoting a cubic to hexagonal phase transition, which is similarly induced upon application of an Alternating Magnetic Field (AMF). Moreover, in the hexagonal phase SPIONs spontaneously self-assemble within the lipid scaffold into a linear supraparticle. This phase behavior is interpreted in the framework of the Helfrich's theory, which shows that SPIONs affect the mesophase both from a viscoelastic and from a structural standpoint. Finally, the dispersion of these cubic phases into stable magnetic colloidal particles, which retain their liquid crystalline internal structure, is addressed as a promising route towards magneto responsive drug-delivery systems (DDS). PMID- 29404544 TI - Selecting optimal features from Fourier transform infrared spectroscopy for discrete-frequency imaging. AB - Tissue histology utilizing chemical and immunohistochemical labels plays an important role in biomedicine and disease diagnosis. Recent research suggests that mid-infrared (IR) spectroscopic imaging may augment histology by providing quantitative molecular information. One of the major barriers to this approach is long acquisition time using Fourier-transform infrared (FTIR) spectroscopy. Recent advances in discrete frequency sources, particularly quantum cascade lasers (QCLs), may mitigate this problem by allowing selective sampling of the absorption spectrum. However, DFIR imaging only provides a significant advantage when the number of spectral samples is minimized, requiring a priori knowledge of important spectral features. In this paper, we demonstrate the use of a GPU-based genetic algorithm (GA) using linear discriminant analysis (LDA) for DFIR feature selection. Our proposed method relies on pre-acquired broadband FTIR images for feature selection. Based on user-selected criteria for classification accuracy, our algorithm provides a minimal set of features that can be used with DFIR in a time-frame more practical for clinical diagnosis. PMID- 29404546 TI - Chiral triazolylidene-Pd-PEPPSI: synthesis, characterization, and application in asymmetric Suzuki-Miyaura cross-coupling. AB - A chiral triazolylidene-Pd-PEPPSI (PEPPSI = pyridine, enhanced, precatalyst, preparation, stabilization, initiation) complex with ferrocene-based planar chirality has been synthesized and characterized. Investigation of the electronic and steric nature of this complex revealed its powerful electron-donating ability (TEP 2044 cm-1) and high steric bulk (%Vbur = 42.2). These unique properties allow the complex to exhibit very high catalytic activity (TON = 420) for asymmetric Suzuki-Miyaura cross-coupling, providing the coupling product with good enantioselectivity (75% ee). PMID- 29404547 TI - Mechanistic understanding of tungsten oxide in-plane nanostructure growth via sequential infiltration synthesis. AB - Tungsten oxide (WO3-x) nanostructures with hexagonal in-plane arrangements were fabricated by sequential infiltration synthesis (SIS), using the selective interaction of gas phase precursors with functional groups in one domain of a block copolymer (BCP) self-assembled template. Such structures are highly desirable for various practical applications and as model systems for fundamental studies. The nanostructures were characterized by cross-sectional scanning electron microscopy, grazing-incidence small/wide-angle X-ray scattering (GISAXS/GIWAXS), and X-ray absorption near edge structure (XANES) measurements at each stage during the SIS process and subsequent thermal treatments, to provide a comprehensive picture of their evolution in morphology, crystallography and electronic structure. In particular, we discuss the critical role of SIS Al2O3 seeds toward modifying the chemical affinity and free volume in a polymer for subsequent infiltration of gas phase precursors. The insights into SIS growth obtained from this study are valuable to the design and fabrication of a wide range of targeted nanostructures. PMID- 29404548 TI - A copper-catalyzed carbonylative four-component reaction of ethene and aliphatic olefins. AB - To have a balance between reactivity and selectivity has been a long-standing challenge in multicomponent reactions. In this communication, a carbonylative four-component reaction has been developed. With copper as the catalyst, using ethene including other aliphatic alkenes, alcohols and acetonitrile as the substrates under CO pressure, various desired products were produced in moderate to good yields. The obtained products can be applied in the synthesis of delta valerolactams. Good functional group tolerance and reaction efficiency can be observed here. PMID- 29404549 TI - A mineralized cell-based functional platform: construction of yeast cells with biogenetic intracellular hydroxyapatite nanoscaffolds. AB - A unique mineralized cell-based functional platform with biogenic intracellular hydroxyapatite nanoscaffolds (nHAP@yeasts) has been intelligently constructed using a biomimetic mineralization approach. Such a platform not only preserves the nature and functions of cells but also possesses intracellular nanoscaffolds, which endow the mineralized cells with novel functions in biological and nanotechnological applications. Benefiting from their unique organism shell and inorganic core, the nHAP@yeasts are biocompatible and have a large loading capacity for drugs. Such anaerobic microorganisms could be beneficial as drug carriers for the effective delivery and release of loaded drugs in tumors because they prefer to locate and grow in reduced oxygen surroundings. A functional investigation indicated that the nHAP@yeasts, functionalized with folic acid (nHAP@yeasts-FA) as cell-based carriers, showed dual responsive release profiles based on the FA dependency of tumors and the pH-sensitivity of the HAP nanoparticles, and they significantly inhibited tumor growth while displaying low toxicity. This study for the first time provides a bio-friendly strategy to biosynthesize a mineralized cell-based functional platform with biogenic intracellular nanominerals (carbonate, sulfides, selenides, metals, etc.) for biological and nanotechnological application. PMID- 29404550 TI - Frequent detection of a human fecal indicator in the urban ocean: environmental drivers and covariation with enterococci. AB - Fecal pollution of surface waters presents a global human health threat. New molecular indicators of fecal pollution have been developed to address shortcomings of traditional culturable fecal indicators. However, there is still little information on their fate and transport in the environment. The present study uses spatially and temporally extensive data on traditional (culturable enterococci, cENT) and molecular (qPCR-enterococci, qENT and human-associated marker, HF183/BacR287) indicator concentrations in marine water surrounding highly-urbanized San Francisco, California, USA to investigate environmental and anthropogenic processes that impact fecal pollution. We constructed multivariable regression models for fecal indicator bacteria at 14 sampling stations. The human marker was detected more frequently in our study than in many other published studies, with detection frequency at some stations as high as 97%. The odds of cENT, qENT, and HF183/BacR287 exceeding health-relevant thresholds were statistically elevated immediately following discharges of partially treated combined sewage, and cENT levels dissipated after approximately 1 day. However, combined sewer discharges were not important predictors of indicator levels typically measured in weekly monitoring samples. Instead, precipitation and solar insolation were important predictors of cENT in weekly samples, while precipitation and water temperature were important predictors of HF183/BacR287 and qENT. The importance of precipitation highlights the significance of untreated storm water as a source of fecal pollution to the urban ocean, even for a city served by a combined sewage system. Sunlight and water temperature likely control persistence of the indicators via photoinactivation and dark decay processes, respectively. PMID- 29404551 TI - Blue light filtered white light induces depression-like responses and temporary spatial learning deficits in rats. AB - OBJECTIVES: Ambient light has a vital impact on mood and cognitive functions. Blue light has been previously reported to play a salient role in the antidepressant effect via melanopsin. Whether blue light filtered white light (BFW) affects mood and cognitive functions remains unclear. The present study aimed to investigate whether BFW led to depression-like symptoms and cognitive deficits including spatial learning and memory abilities in rats, and whether they were associated with the light-responsive function in retinal explants. METHODS: Male Sprague-Dawley albino rats were randomly divided into 2 groups (n = 10) and treated with a white light-emitting diode (LED) light source and BFW light source, respectively, under a standard 12 : 12 h L/D condition over 30 days. The sucrose consumption test, forced swim test (FST) and the level of plasma corticosterone (CORT) were employed to evaluate depression-like symptoms in rats. Cognitive functions were assessed by the Morris water maze (MWM) test. A multi-electrode array (MEA) system was utilized to measure electro-retinogram (ERG) responses induced by white or BFW flashes. RESULTS: The effect of BFW over 30 days on depression-like responses in rats was indicated by decreased sucrose consumption in the sucrose consumption test, an increased immobility time in the FST and an elevated level of plasma CORT. BFW led to temporary spatial learning deficits in rats, which was evidenced by prolonged escape latency and swimming distances in the spatial navigation test. However, no changes were observed in the short memory ability of rats treated with BFW. The micro-ERG results showed a delayed implicit time and reduced amplitudes evoked by BFW flashes compared to the white flash group. CONCLUSIONS: BFW induces depression-like symptoms and temporary spatial learning deficits in rats, which might be closely related to the impairment of light-evoked output signals in the retina. PMID- 29404552 TI - Passive diffusive flux chambers - a new method to quantify vapour intrusion into indoor air. AB - A new instrumental method (a passive flux chamber) to quantify emission rates of volatile organic compounds (VOCs) from natural ground surfaces and floors or pavements was developed and tested against the traditional emission isolation flux chamber (the dynamic flux chamber). Dynamic flux chambers have been used for some decades to measure diffusive mass flux of VOCs at contaminated sites thereby providing quantitative estimates of the contribution of contaminant vapour fluxes to indoor air concentrations for human health risk assessments. The new method described here measures diffusive mass flux from surfaces utilising a high uptake rate passive absorptive sampling tube placed within a chamber to capture the mass molecular flux. The passive flux chamber was developed to provide a technically simpler and more cost effective means of quantifying vapour intrusion rates into buildings where the dominant pathway for VOC intrusion through floors is molecular diffusion rather than pressure driven advective flows through floor gaps and cracks. The passive flux chamber operation is based on the principal of molecular diffusion and the random movement of molecules in the gaseous phase. The efficiency of the passive chamber in capturing the total mass flux was tested by measuring comparative concentrations in adjacent identical chambers, one fitted with and the other without an absorptive sampling tube. For chambers fitted with sampling tubes the internal chamber concentrations of VOCs were on average 85% lower than for co-located chambers not fitted with the absorption tubes, demonstrating a high rate of capture of VOC flux into the chamber and a close and satisfactory approximation of mass flux. Eighteen field comparisons of surface fluxes measured by the passive and dynamic flux chamber methods showed that on average the passive chambers produced flux rates a factor of two greater than the dynamic flux chambers. PMID- 29404553 TI - Nonsolvent-induced morphological changes and nanoporosity in poly(l-lactide) films. AB - The role of a nonsolvent in controlling the crystallization and morphology of solvent-crystallized poly(l-lactide) (PLLA) films was investigated using various microscopy techniques and small- and wide-angle X-ray scattering (SAXS/WAXS). PLLA films crystallized in THF and acetone had 40-80 MUm spherulites. When water was present in the solvent, a completely different morphology was observed with nanosized voids and the surfaces of the films were smooth. In contrast, SEM studies revealed that the films crystallized in acetone and THF which had macroporous structures, had larger voids and film surfaces were rough because of the presence of globular structures. Voids appeared within the spherulites in the THF/water treated film, whereas crystals nucleated at the surface of the nanosized voids in acetone/water treated PLLA films. The formation of such voids is attributed to the interface-enhanced crystal nucleation in a solvent/nonsolvent system where the nonsolvent increases the polymer crystal nucleation and the subsequent evaporation of the nonsolvent. The method described in this work can be extended to other polymers to control the morphologies of polymer films during solvent-induced crystallization. PMID- 29404554 TI - A hemiaminal-ether structure stabilized by lanthanide complexes with an imidazole based Schiff base ligand. AB - Imidazole-based lanthanide complexes bearing a hemiaminal-ether pendant, [Ln(L' OR)(NO3)2](NO3).solvent (Ln = Tb and Gd; L'-OR = hemiaminal-ether ligand, 1,9 bis(1H-imidazole-4-yl)-5-[(R-1H-imidazole-4-yl)alkyl]-2,5,8-triazanon-1,8-dien; R = Me and Et; solvent = MeOH, EtOH, and H2O; abbreviated as LnL'-OR), were unexpectedly obtained from the reaction of diethylenetriamine with 4 imidazolecarbaldehyde in the presence of lanthanide nitrate in alcohol. These LnL'-OR structures were also obtained by treating dipodal imidazole-based lanthanide complexes [Ln(HL)(NO3)2(MeOH)](NO3).MeOH (HL = bis{[2-{(imidazole-4 yl)methylidene}amino]ethyl}amine; abbreviated as LnHL) independently with (i) 4 imidazolecarbaldehyde, (ii) HNO3, or (iii) NO in alcohol. The results indicate that the hemiaminal-ether structure is stabilized by the lanthanide complex. The LnL'-OR structures were confirmed by X-ray analysis and cold electrospray ionization mass spectrometry in solution. The photophysical properties indicate that the L'-OR ligands can sensitize the Tb3+ luminescence. A significant spectral change was observed by the ligand component exchange. The exchange of the ligand component of the non-luminescent imidazole-based Tb complex, [Tb(MeL)(NO3)2](NO3) (MeL = bis{[2-{(1-methylimidazole-2 yl)methylidene}amino]ethyl}amine; abbreviated as TbMeL), results in a significant spectral change. PMID- 29404555 TI - Goodbye to S2- in aqueous solution. AB - New Raman spectra of Na2S dissolved in hyper-concentrated NaOH(aq) and CsOH(aq) cast serious doubt on the widely-assumed existence of S2-(aq). To avoid conceptual and practical problems with sulfide equilibria in numerous applications, S2-(aq) should be expunged from the chemical literature. Thermodynamic databases involving sulfide minerals also need careful revision. PMID- 29404556 TI - Mechanical and thermal properties of grain boundary in a planar heterostructure of graphene and hexagonal boron nitride. AB - In this study, the mechanical properties of grain boundaries (GBs) in planar heterostructures of graphene and hexagonal boron nitride (h-BN) were studied using the molecular dynamics method in combination with the density functional theory and classical disclination theory. The hybrid interface between graphene and h-BN grains was optimally matched by a non-bisector GB composed of pentagon heptagon defects arranged in a periodic manner. GB was found to be a vulnerable spot to initiate failure under uniaxial tension; moreover, the tensile strength was found to anomalously increase with an increase in the mismatch angle between graphene and h-BN grains, i.e., the density of pentagon-heptagon defects along the GBs. The disclination theory was successfully adopted to predict the stress field caused by lattice mismatch at the GB. Comparison between stress contours of GBs with different mismatch angles demonstrates that the arrangement of 5-7 disclinations along the GB is crucial to the strength, and the stress concentration at the GB decreases with an increase in disclination density; this results in an anomalous increase of strength with an increase in the mismatch angle of grains. Moreover, the thermal transfer efficiency of the hybrid GB was revealed to be dependent not only on the mismatch angle of grains but also on the direction of the thermal flux. Thermal transfer efficiency from graphene to h-BN is higher than that from h-BN to graphene. Detailed analyses for the phonon density of states (PDOS) of GB atoms were carried out for the mismatch angle dependence of interfacial conductance. Our results provide useful insights for the application of two-dimensional polycrystalline heterostructures in next generation electronic nanodevices. PMID- 29404557 TI - Total synthesis and structural elucidation of spongosoritin A. AB - Two putative structures of spongosoritin A, with syn (6R,8R) and anti (6S,8R) configurations, were each synthesised in a total of 11 linear steps with only 8 purification procedures. The key steps in our strategy included Evans alkylation and olefin dihydroxylation to install the C8 and C6 stereocentres, a transacetalisation/dehydration cascade to construct the furanylidene core, and chromatographic separation of 9E- and 9Z-isomers of the final compounds with silver nitrate impregnated silica. Comparison of the 1H and 13C NMR data for the synthetic syn- and anti-isomers to that reported for the natural product revealed that the relative configuration of spongosoritin A is syn. The absolute stereochemistry was also confirmed as 6R,8R based on optical rotation measurements where the synthetic syn (6R,8R) and natural product had the same sign of optical rotation (negative). PMID- 29404560 TI - Tissue Markers for Acute Multiple Sclerosis Treatment Response-A Step Toward Personalized Medicine. PMID- 29404561 TI - Typographic Error in Figure. PMID- 29404562 TI - Tau in Chronic Traumatic Encephalopathy-Reply. PMID- 29404559 TI - Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1. AB - Importance: Life expectancy is greatly shortened in patients presenting with myotonic dystrophy type 1 (DM1), the most common neuromuscular disease. A reliable prediction of survival in patients with DM1 is critically important to plan personalized health supervision. Objective: To develop and validate a prognostic score to predict 10-year survival in patients with DM1. Design, Setting, and Participants: In this longitudinal cohort study, between January 2000 and November 2014, we enrolled 1296 adults referred to 4 tertiary neuromuscular centers in France for management of genetically proven DM1, including 1066 patients in the derivation cohort and 230 in the validation cohort. Data were analyzed from December 2016 to March 2017. Main Outcomes and Measures: Factors associated with survival by multiple variable Cox modeling, including 95% confidence intervals, and development of a predictive score validated internally and externally. Mean values are reported with their standard deviations. Results: Of the 1296 included patients, 670 (51.7%) were women, and the mean (SD) age was 39.8 (13.7) years. Among the 1066 patients (82.3%) in the derivation cohort, 241 (22.6%) died over a median (interquartile range) follow-up of 11.7 (7.7-14.3) years. Age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. Simplified score points were attributed to each predictor, and adding these points yielded scores between 0 and 20, with 0 indicating the lowest and 20 the highest risk of death. The 10-year survival rate was 96.6% (95% CI, 94.4-98.9) in the group with 0 to 4 points, 92.2% (95% CI, 88.8-95.6) in the group with 5 to 7 points, 80.7% (95% CI, 75.4-86.1) in the group with 8 to 10 points, 57.9% (95% CI, 49.2-66.6) in the group with 11 to 13 points, and 19.4% (95% CI, 8.6-30.1) in the group with 14 points or more. In 230 patients (17.7%) included in the validation cohort, the 10 year survival rates for the groups with 0 to 4, 5 to 7, 8 to 10, 11 to 13, and 14 points or more were 99.3% (95% CI, 95.0-100), 80.6% (95% CI, 67.1-96.7), 79.3% (95% CI, 66.2-95.1), 43.2% (95% CI, 28.2-66.1), and 21.6% (95% CI, 10.0-46.8), respectively. The calibration curves did not deviate from the reference line. The C index was 0.753 (95% CI, 0.722-0.785) in the derivation cohort and 0.806 (95% CI, 0.758-0.855) in the validation cohort. Conclusions and Relevance: The DM1 prognostic score is associated with long-term survival. PMID- 29404563 TI - Tau in Chronic Traumatic Encephalopathy. PMID- 29404565 TI - Keeping Faith With Patients After Stroke or Transient Ischemic Attack. PMID- 29404564 TI - Statistical Code to Support the Scientific Story. PMID- 29404566 TI - Hot Tea Consumption and the Risk for Esophageal Cancer. PMID- 29404567 TI - The Personal Care Products Safety Act. PMID- 29404558 TI - Environmental effects of ozone depletion, UV radiation and interactions with climate change: UNEP Environmental Effects Assessment Panel, update 2017. AB - The Environmental Effects Assessment Panel (EEAP) is one of three Panels of experts that inform the Parties to the Montreal Protocol. The EEAP focuses on the effects of UV radiation on human health, terrestrial and aquatic ecosystems, air quality, and materials, as well as on the interactive effects of UV radiation and global climate change. When considering the effects of climate change, it has become clear that processes resulting in changes in stratospheric ozone are more complex than previously held. Because of the Montreal Protocol, there are now indications of the beginnings of a recovery of stratospheric ozone, although the time required to reach levels like those before the 1960s is still uncertain, particularly as the effects of stratospheric ozone on climate change and vice versa, are not yet fully understood. Some regions will likely receive enhanced levels of UV radiation, while other areas will likely experience a reduction in UV radiation as ozone- and climate-driven changes affect the amounts of UV radiation reaching the Earth's surface. Like the other Panels, the EEAP produces detailed Quadrennial Reports every four years; the most recent was published as a series of seven papers in 2015 (Photochem. Photobiol. Sci., 2015, 14, 1-184). In the years in between, the EEAP produces less detailed and shorter Update Reports of recent and relevant scientific findings. The most recent of these was for 2016 (Photochem. Photobiol. Sci., 2017, 16, 107-145). The present 2017 Update Report assesses some of the highlights and new insights about the interactive nature of the direct and indirect effects of UV radiation, atmospheric processes, and climate change. A full 2018 Quadrennial Assessment, will be made available in 2018/2019. PMID- 29404568 TI - Vitamin and Mineral Supplements: What Clinicians Need to Know. PMID- 29404569 TI - Statistical Code for Clinical Research Papers in a High-Impact Specialist Medical Journal. PMID- 29404571 TI - Hope, Optimism, and Compassionate Communication. PMID- 29404570 TI - Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease. AB - Importance: Chronic kidney disease (CKD) is common in adults with heart failure and is associated with an increased risk of sudden cardiac death. Randomized trials of participants without CKD have demonstrated that implantable cardioverter defibrillators (ICDs) decrease the risk of arrhythmic death in selected patients with reduced left ventricular ejection fraction (LVEF) heart failure. However, whether ICDs improve clinical outcomes in patients with CKD is not well elucidated. Objective: To examine the association of primary prevention ICDs with risk of death and hospitalization in a community-based population of potentially ICD-eligible patients who had heart failure with reduced LVEF and CKD. Design, Settings, and Participants: This noninterventional cohort study included adults with heart failure and an LVEF of 40% or less and measures of serum creatinine levels available from January 1, 2005, through December 31, 2012, who were enrolled in 4 Kaiser Permanente health care delivery systems. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2. Patients who received and did not receive an ICD were matched (1:3) on CKD status, age, and high-dimensional propensity score to receive an ICD. Follow-up was completed on December 31, 2013. Data were analyzed from 2015 to 2017. Exposures: Placement of an ICD. Main Outcomes and Measures: All-cause death, hospitalizations due to heart failure, and any-cause hospitalizations. Results: A total of 5877 matched eligible adults with CKD (1556 with an ICD and 4321 without an ICD) were identified (4049 men [68.9%] and 1828 women [31.1%]; mean [SD] age, 72.9 [8.2] years). In models adjusted for demographics, comorbidity, and cardiovascular medication use, no difference was found in all-cause mortality between patients with CKD in the ICD vs non-ICD groups (adjusted hazard ratio, 0.96; 95% CI, 0.87-1.06). However, ICD placement was associated with increased risk of subsequent hospitalization due to heart failure (adjusted relative risk, 1.49; 95% CI, 1.33-1.60) and any-cause hospitalization (adjusted relative risk, 1.25; 95% CI, 1.20-1.30) among patients with CKD. Conclusions and Relevance: In a large, contemporary, noninterventional study of community-based patients with heart failure and CKD, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization. The potential risks and benefits of ICDs should be carefully considered in patients with heart failure and CKD. PMID- 29404572 TI - Association of Rideshare-Based Transportation Services and Missed Primary Care Appointments: A Clinical Trial. AB - Importance: Transportation barriers contribute to missed primary care appointments for patients with Medicaid. Rideshare services have been proposed as alternatives to nonemergency medical transportation programs because of convenience and lower costs. Objective: To evaluate the association between rideshare-based medical transportation and missed primary care appointments among Medicaid patients. Design, Setting, and Participants: In a prospective clinical trial, 786 Medicaid beneficiaries who resided in West Philadelphia and were established primary care patients at 1 of 2 academic internal medicine practices located within the same building were included. Participants were allocated to being offered complimentary ride-sharing services (intervention arm) or usual care (control arm) based on the prescheduled day of their primary care appointment reminder. Those scheduled on even-numbered weekdays were in the intervention arm and on odd-numbered weekdays, the control arm. The primary study outcome was the rate of missed appointments, estimated using an intent-to-treat approach. All individuals receiving a phone call reminder were included in the study sample, regardless of whether they answered their phone. The study was conducted between October 24, 2016, and April 20, 2017. Interventions: A model of providing rideshare-based transportation was designed. As part of usual care, patients assigned to both arms received automated appointment phone call reminders. As part of the study protocol, patients assigned to both arms received up to 3 additional appointment reminder phone calls from research staff 2 days before their scheduled appointment. During these calls, patients in the intervention arm were offered a complimentary ridesharing service. Research staff prescheduled rides for those interested in the service. After their appointment, patients phoned research staff to initiate a return trip home. Main Outcomes and Measures: Missed appointment rate (no shows and same-day cancellations) in the intervention compared with control arm. Results: Of the 786 patients allocated to the intervention or control arm, 566 (72.0%) were women; mean (SD) age was 46.0. (12.5) years. Within the intervention arm, 85 among 288 (26.0%) participants who answered the phone call used ridesharing. The missed appointment rate was 36.5% (144 of 394) for the intervention arm and 36.7% (144 of 392) for the control arm (P = .96). Conclusions and Relevance: The uptake of ridesharing was low and did not decrease missed primary care appointments. Future studies trying to reduce missed appointments should explore alternative delivery models or targeting populations with stronger transportation needs. Trial Registration: clinicaltrials.gov Identifier: NCT02955433. PMID- 29404573 TI - Putting the "She" in Doctor. PMID- 29404574 TI - Use of Oxyhemoglobin Saturation or Oxygen Tension-An Unsolved Question. PMID- 29404575 TI - Factors Associated With Variation in Long-term Acute Care Hospital vs Skilled Nursing Facility Use Among Hospitalized Older Adults. AB - Importance: Despite providing an overlapping level of care, it is unknown why hospitalized older adults are transferred to long-term acute care hospitals (LTACs) vs less costly skilled nursing facilities (SNFs) for postacute care. Objective: To examine factors associated with variation in LTAC vs SNF transfer among hospitalized older adults. Design, Setting, and Participants: We conducted this retrospective observational cohort study of hospitalized older adults (>=65 years) transferred to an LTAC vs SNF during fiscal year 2012 using national 5% Medicare data. Main Outcomes and Measures: Predictors of LTAC transfer were assessed using a multilevel mixed-effects model adjusting for patient-, hospital , and region-level factors. We estimated variation partition coefficients and adjusted hospital- and region-specific LTAC transfer rates using sequential models. Results: Among 65 525 hospitalized older adults (42 461 [64.8%] women; 39 908 [60.9%] >=85 years) transferred to an LTAC or SNF, 3093 (4.7%) were transferred to an LTAC. We identified 29 patient-, 3 hospital-, and 5 region level independent predictors. The strongest predictors of LTAC transfer were receiving a tracheostomy (adjusted odds ration [aOR], 23.8; 95% CI, 15.8-35.9) and being hospitalized in close proximity to an LTAC (0-2 vs >42 miles; aOR, 8.4, 95% CI, 6.1-11.5). After adjusting for case-mix, differences between patients explained 52.1% (95% CI, 47.7%-56.5%) of the variation in LTAC use. The remainder was attributable to hospital (15.0%; 95% CI, 12.3%-17.6%), and regional differences (32.9%; 95% CI, 27.6%-38.3%). Case-mix adjusted LTAC use was very high in the South (17%-37%) compared with the Pacific Northwest, North, and Northeast (<2.2%). From the full multilevel model, the median adjusted hospital LTAC transfer rate was 2.1% (10th-90th percentile, 0.24%-10.8%). Even within a region, adjusted hospital LTAC transfer rates varied substantially (intraclass correlation coefficient [ICC], 0.26; 95% CI, 0.23-0.30). Conclusions and Relevance: Although many patient-level factors were associated with LTAC use, half of the variation in LTAC vs SNF transfer is independent of patients' illness severity or clinical complexity, and is explained by where the patient was hospitalized and in what region, with far greater use in the South. Even among hospitals in regions with similar LTAC access, there was considerable variation in LTAC use. Given the higher expense associated with LTACs vs SNFs, greater attention is needed to define the optimal role of LTACs in the postacute care of older adults. PMID- 29404576 TI - Hot Tea Consumption and Its Interactions With Alcohol and Tobacco Use on the Risk for Esophageal Cancer: A Population-Based Cohort Study. AB - : This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Although consumption of tea at high temperatures has been suggested as a risk factor for esophageal cancer, an association has not been observed consistently, and whether any relationship is independent of alcohol and tobacco exposure has not been evaluated. Objective: To examine whether high-temperature tea drinking, along with the established risk factors of alcohol consumption and smoking, is associated with esophageal cancer risk. Design: China Kadoorie Biobank, a prospective cohort study established during 2004 to 2008. Setting: 10 areas across China. Participants: 456 155 persons aged 30 to 79 years. Those who had cancer at baseline or who reduced consumption of tea, alcohol, or tobacco before baseline were excluded. Measurements: The usual temperature at which tea was consumed, other tea consumption metrics, and lifestyle behaviors were self-reported once, at baseline. Outcome was esophageal cancer incidence up to 2015. Results: During a median follow-up of 9.2 years, 1731 incident esophageal cancer cases were documented. High-temperature tea drinking combined with either alcohol consumption or smoking was associated with a greater risk for esophageal cancer than hot tea drinking alone. Compared with participants who drank tea less than weekly and consumed fewer than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol daily had the greatest risk for esophageal cancer (hazard ratio [HR], 5.00 [95% CI, 3.64 to 6.88]). Likewise, the HR for current smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67). Limitation: Tea consumption was self-reported once, at baseline, leading to potential nondifferential misclassification and attenuation of the association. Conclusion: Drinking tea at high temperatures is associated with an increased risk for esophageal cancer when combined with excessive alcohol or tobacco use. Primary Funding Source: National Natural Science Foundation of China and National Key Research and Development Program. PMID- 29404577 TI - Persistence of Sexual Harassment and Gender Bias in Medicine Across Generations Us Too. PMID- 29404579 TI - What Parents of Children With Complex Medical Conditions Want Their Child's Physicians to Understand. PMID- 29404580 TI - qSOFA, Cue Confusion. PMID- 29404578 TI - Quality of Care for Veterans With Transient Ischemic Attack and Minor Stroke. AB - Importance: The timely delivery of guideline-concordant care may reduce the risk of recurrent vascular events for patients with transient ischemic attack (TIA) and minor stroke. Although many health care organizations measure stroke care quality, few evaluate performance for patients with TIA or minor stroke, and most include only a limited subset of guideline-recommended processes. Objective: To assess the quality of guideline-recommended TIA and minor stroke care across the Veterans Health Administration (VHA) system nationwide. Design, Setting, and Participants: This cohort study included 8201 patients with TIA or minor stroke cared for in any VHA emergency department (ED) or inpatient setting during federal fiscal year 2014 (October 1, 2013, through September 31, 2014). Patients with length of stay longer than 6 days, ventilator use, feeding tube use, coma, intensive care unit stay, inpatient rehabilitation stay before discharge, or receipt of thrombolysis were excluded. Outlier facilities for each process of care were identified by constructing 95% CIs around the facility pass rate and national pass rate sites when the 95% CIs did not overlap. Data analysis occurred from January 16, 2016, through June 30, 2017. Main Outcomes and Measures: Ten elements of care were assessed using validated electronic quality measures. Results: In the 8201 patients included in the study (mean [SD] age, 68.8 [11.4] years; 7877 [96.0%] male; 4856 [59.2%] white), performance varied across elements of care: brain imaging by day 2 (6720/7563 [88.9%]; 95% CI, 88.2%-89.6%), antithrombotic use by day 2 (6265/7477 [83.8%]; 95% CI, 83.0%-84.6%), hemoglobin A1c measurement by discharge or within the preceding 120 days (2859/3464 [82.5%]; 95% CI, 81.2%-83.8%), anticoagulation for atrial fibrillation by day 7 after discharge (1003/1222 [82.1%]; 95% CI, 80.0%-84.2%), deep vein thrombosis prophylaxis by day 2 (3253/4346 [74.9%]; 95% CI, 73.6%-76.2%), hypertension control by day 90 after discharge (4292/5979 [71.8%]; 95% CI, 70.7%-72.9%), neurology consultation by day 1 (5521/7823 [70.6%]; 95% CI, 69.6%-71.6%), electrocardiography by day 2 or within 1 day prior (5073/7570 [67.0%]; 95% CI, 65.9%-68.1%), carotid artery imaging by day 2 or within 6 months prior (4923/7685 [64.1%]; 95% CI, 63.0%-65.2%), and moderate- to high-potency statin prescription by day 7 after discharge (3329/7054 [47.2%]; 95% CI, 46.0%-48.4%). Performance varied substantially across facilities (eg, neurology consultation had a facility outlier rate of 53.0%). Performance was higher for admitted patients than for patients cared for only in EDs with the greatest disparity for carotid artery imaging (4478/5927 [75.6%] vs 445/1758 [25.3%]; P < .001). Conclusions and Relevance: This national study of VHA system quality of care for patients with TIA or minor stroke identified opportunities to improve care quality, particularly for patients who were discharged from the ED. Health care systems should engage in ongoing TIA care performance assessment to complement existing stroke performance measurement. PMID- 29404581 TI - Evolution of Unilateral Basal Ganglia Lesion Over 16 Months. PMID- 29404582 TI - Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta analysis. AB - Background: The quick Sequential Organ Failure Assessment (qSOFA) has been proposed for prediction of mortality in patients with suspected infection. Purpose: To summarize and compare the prognostic accuracy of qSOFA and the systemic inflammatory response syndrome (SIRS) criteria for prediction of mortality in adult patients with suspected infection. Data Sources: Four databases from inception through November 2017. Study Selection: English-language studies using qSOFA for prediction of mortality (in-hospital, 28-day, or 30-day) in adult patients with suspected infection in the intensive care unit (ICU), emergency department (ED), or hospital wards. Data Extraction: Two investigators independently extracted data and assessed study quality using standard criteria. Data Synthesis: Thirty-eight studies were included (n = 385 333). qSOFA was associated with a pooled sensitivity of 60.8% (95% CI, 51.4% to 69.4%) and a pooled specificity of 72.0% (CI, 63.4% to 79.2%) for mortality. The SIRS criteria were associated with a pooled sensitivity of 88.1% (CI, 82.3% to 92.1%) and a pooled specificity of 25.8% (CI, 17.1% to 36.9%). The pooled sensitivity of qSOFA was higher in the ICU population (87.2% [CI, 75.8% to 93.7%]) than the non-ICU population (51.2% [CI, 43.6% to 58.7%]). The pooled specificity of qSOFA was higher in the non-ICU population (79.6% [CI, 73.3% to 84.7%]) than the ICU population (33.3% [CI, 23.8% to 44.4%]). Limitation: Potential risk of bias in included studies due to qSOFA interpretation and patient selection. Conclusion: qSOFA had poor sensitivity and moderate specificity for short-term mortality. The SIRS criteria had sensitivity superior to that of qSOFA, supporting their use for screening of patients and as a prompt for treatment initiation. Primary Funding Source: Canadian Association of Emergency Physicians. (PROSPERO: CRD42017075964). PMID- 29404584 TI - Web Exclusives. Annals Graphic Medicine - Memento Mori. PMID- 29404583 TI - Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis. AB - Importance: Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell- and macrophage associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response. Objective: To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis. Design, Setting and Participants: This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded. Main Outcomes and Measures: The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters. Results: The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], -1.43; 95% CI, -3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01). Conclusions and Relevance: This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions. PMID- 29404585 TI - Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels. PMID- 29404586 TI - Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels. PMID- 29404587 TI - MACRA: Big Fix or Big Problem? PMID- 29404588 TI - MACRA: Big Fix or Big Problem? PMID- 29404589 TI - Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy. PMID- 29404590 TI - Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy. PMID- 29404591 TI - Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy. PMID- 29404592 TI - Correction: On the Communicability of Chronic Diseases. PMID- 29404593 TI - Ezekiel. PMID- 29404594 TI - Long Coat Doctor. PMID- 29404595 TI - Should This Patient Receive Hormone Therapy for Her Menopausal Symptoms?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. AB - Hormone therapy (HT) was widely prescribed in the 1980s and 1990s and has been controversial since the initial results of the Women's Health Initiative (WHI) trial in the early 2000s suggested that it increased risk for breast cancer and coronary heart disease and did not prolong life. However, more recent data and reexamination of the WHI results suggest that HT is safe and effective for many women when used around the time of menopause. Two experts debate the 2017 Hormone Therapy Position Statement of The North American Menopause Society, which recommends HT as first-line treatment of vasomotor symptoms, and apply it to the care of Ms. R, a 52-year-old woman with severe hot flashes, sleep disturbance, and irritability. PMID- 29404596 TI - Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2018. PMID- 29404598 TI - Annals for Educators - 6 February 2018. PMID- 29404597 TI - Cellulitis and Soft Tissue Infections. AB - Cellulitis and soft tissue infections are a diverse group of diseases that range from uncomplicated cellulitis to necrotizing fasciitis. Management of predisposing conditions is the primary means of prevention. Cellulitis is a clinical diagnosis and thus is made on the basis of history and physical examination. Imaging may be helpful for characterizing purulent soft tissue infections and associated osteomyelitis. Treatment varies according to the type of infection. The foundations of treatment are drainage of purulence and antibiotics, the latter targeted at the infection's most likely cause. PMID- 29404600 TI - Hot Tea and Esophageal Cancer. PMID- 29404599 TI - Association of Rooming-in With Outcomes for Neonatal Abstinence Syndrome: A Systematic Review and Meta-analysis. AB - Importance: Rising incidence of neonatal abstinence syndrome (NAS) is straining perinatal care systems. Newborns with NAS traditionally receive care in neonatal intensive care units (NICUs), but rooming-in with mother and family has been proposed to reduce the use of pharmacotherapy, length of stay (LOS), and cost. Objective: To systematically review and meta-analyze if rooming-in is associated with improved outcomes for newborns with NAS. Data Sources: MEDLINE, CINAHL, The Cochrane Library, and clinicaltrials.gov were searched from inception through June 25, 2017. Study Selection: This investigation included randomized clinical trials, cohort studies, quasi-experimental studies, and before-and-after quality improvement investigations comparing rooming-in vs standard NICU care for newborns with NAS. Data Extraction and Synthesis: Two independent investigators reviewed studies for inclusion. A random-effects model was used to pool dichotomous outcomes using risk ratio (RR) and 95% CI. The study evaluated continuous outcomes using weighted mean difference (WMD) and 95% CI. Main Outcomes and Measures: The primary outcome was newborn treatment with pharmacotherapy. Secondary outcomes included LOS, inpatient cost, and harms from treatment, including in-hospital adverse events and readmission rates. Results: Of 413 publications, 6 studies (n = 549 [number of patients]) met inclusion criteria. In meta-analysis of 6 studies, there was consistent evidence that rooming-in is preferable to NICU care for reducing both the use of pharmacotherapy (RR, 0.37; 95% CI, 0.19-0.71; I2 = 85%) and LOS (WMD, -10.41 days; 95% CI, -16.84 to -3.98 days; I2 = 91%). Sensitivity analysis resolved the heterogeneity for the use of pharmacotherapy, significantly favoring rooming-in (RR, 0.32; 95% CI, 0.18-0.57; I2 = 13%). Three studies reported that inpatient costs were lower with rooming-in; however, significant heterogeneity precluded quantitative analysis. Qualitative analysis favored rooming-in over NICU care for increasing breastfeeding rates and discharge home in familial custody, but few studies reported on these outcomes. Rooming-in was not associated with higher rates of readmission or in-hospital adverse events. Conclusions and Relevance: Opioid-exposed newborns rooming-in with mother or other family members appear to be significantly less likely to be treated with pharmacotherapy and have substantial reductions in LOS compared with those cared for in NICUs. Rooming-in should be recommended as a preferred inpatient care model for NAS. PMID- 29404601 TI - New Strategies Are Needed to Stop Overdose Fatalities: The Case for Supervised Injection Facilities. PMID- 29404604 TI - Misspelled Name and Data Error in Text. PMID- 29404606 TI - Hudson River, Manhattan. PMID- 29404607 TI - False Information About Breast Cancer Screening. PMID- 29404608 TI - False Information About Breast Cancer Screening. PMID- 29404609 TI - False Information About Breast Cancer Screening. PMID- 29404610 TI - Further Limitations of a Model-Based Study of People Living With HIV and Lung Cancer Mortality. PMID- 29404612 TI - Services Provided by Internal Medicine Physicians Compared With Emergency Physicians: Flawed Data. PMID- 29404611 TI - Immortal Time Bias in Assessing Evidence-Based Care Processes for Staphylococcus aureus Bacteremia. PMID- 29404613 TI - Inconsistent Hypertension Guidelines: We Need a Little Help Here. PMID- 29404614 TI - False Information About Breast Cancer Screening-Reply. PMID- 29404615 TI - Further Limitations of a Model-Based Study of People Living With HIV and Lung Cancer Mortality-Reply. PMID- 29404616 TI - Immortal Time Bias in Assessing Evidence-Based Care Processes for Staphylococcus aureus Bacteremia-Reply. PMID- 29404617 TI - Services Provided By Internal Medicine Physicians Compared With Emergency Physicians: Flawed Data-Reply. PMID- 29404619 TI - Draining Papule on the Lateral Neck of an Infant. PMID- 29404620 TI - Use of Oxyhemoglobin Saturation or Oxygen Tension-an Unsolved Question-Reply. PMID- 29404621 TI - Endovascular Treatment of Dural Arteriovenous Fistulas of the Anterior or Posterior Condylar Vein : A Cadaveric and Clinical Study and Literature Review. AB - Dural arteriovenous fistulas (DAVF) involving the anterior and posterior condylar vein at the skull base are rare but important to recognize. Due to the highly variable anatomy of the venous system of the skull base, detailed anatomical knowledge is essential for correct diagnosis and appropriate treatment of these lesions. In this report we review the normal anatomy of the condylar veins and describe rare and, to our knowledge, not previously reported anatomical variants. We also highlight the treatment modalities for these lesions with focus on the endovascular transvenous occlusion based on four consecutive cases from our center. PMID- 29404623 TI - Erratum to: World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2016): Poster Abstracts. AB - An error occurred in the authorship of abstract P818 (Awareness of Osteoporosis Among Iranian Female Head of Household) of the article "World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2016). PMID- 29404622 TI - [Pathogenesis of atopic dermatitis]. AB - Atopic dermatitis (AD) is one of the most common chronic inflammatory diseases and is also one of the most frequent reasons to consult a dermatologist. Over the past few years there has been a rapidly growing understanding of the cellular, molecular and immunological relationships as well as genetic variations, which leads to a better comprehension of the disease. Consequently, there are innovative targeted therapies in clinical studies or already approved for therapy. To make reasonable use of the new targeted therapies a good understanding of the pathogenesis is very important. In the future, stratification of patients with AD and the resulting personalized therapies will gain in importance. This review depicts the up to date state of knowledge on the complex pathogenesis of AD. PMID- 29404625 TI - Performance of FRAX in clinical practice according to sex and osteoporosis definitions: the Manitoba BMD registry. AB - : Among 62,275 women and 6455 men, FRAX stratified risk for incident major osteoporotic fracture (MOF) and incident hip fracture (HF) without sex interaction. Performance was good in those with osteoporosis regardless of how this was defined. INTRODUCTION: Some studies have reported that FRAX performance differs according to sex and/or osteoporosis definitions. We evaluated whether the performance of FRAX to predict incident MOF and HF in women and men was affected by the presence or absence of osteoporosis defined by World Health Organization (WHO) or National Osteoporosis Foundation (NOF) criteria. METHODS: We studied women and men age >= 40 years with baseline hip and spine DXA scans (1996-2013). Individuals were classified into four non-overlapping subgroups: osteoporosis by WHO criteria, osteoporosis exclusively by NOF criteria, high fracture risk by FRAX (MOF >= 20% or HF >= 3%, without osteoporosis), and low fracture risk (MOF < 20% and HF < 3% without osteoporosis). In each subgroup, we evaluated stratification (hazard ratios [HR]) and calibration (observed vs predicted 10-year fracture probability) for incident fracture. RESULTS: The population included 62,275 women (5345 MOF and 1471 HF) and 6455 men (405 MOF and 108 HF). FRAX scores were strongly predictive of MOF (HR per SD: women 2.12, 95% CI 2.06-2.18; men 1.89, 95% CI 1.73-2.08; sex interaction p value = 0.97) and HF (women 4.78, 95% CI 4.44-5.14; men 4.20, 95% CI 3.22-5.49; sex interaction p value = 0.71). FRAX scores gave similar HRs for MOF among the four subgroups (subgroup interaction p value 0.34 for women, 0.22 for men). Observed versus predicted 10-year MOF and HF probability for the defined subgroups demonstrated a high level of concordance for women and men (all r2 >= 0.9). CONCLUSIONS: FRAX was a strong and consistent predictor of MOF and HF in both women and men and performed well in those with osteoporosis whether defined by WHO or NOF criteria. PMID- 29404627 TI - [Combination of percutaneous radiotherapy, brachytherapy, and androgen deprivation equivalent alternatives to radical prostatectomy for prostate cancer]. PMID- 29404626 TI - Direct dose correlation of MRI morphologic alterations of healthy liver tissue after robotic liver SBRT. AB - PURPOSE: For assessing healthy liver reactions after robotic SBRT (stereotactic body radiotherapy), we investigated early morphologic alterations on MRI (magnetic resonance imaging) with respect to patient and treatment plan parameters. PATIENTS AND METHODS: MRI data at 6-17 weeks post-treatment from 22 patients with 42 liver metastases were analyzed retrospectively. Median prescription dose was 40 Gy delivered in 3-5 fractions. T2- and T1-weighted MRI were registered to the treatment plan. Absolute doses were converted to EQD2 (Equivalent dose in 2Gy fractions) with alpha/beta-ratios of 2 and 3 Gy for healthy, and 8 Gy for modelling pre-damaged liver tissue. RESULTS: Sharply defined, centroid-shaped morphologic alterations were observed outside the high dose volume surrounding the GTV. On T2-w MRI, hyperintensity at EQD2 isodoses of 113.3 +/- 66.1 Gy2, 97.5 +/- 54.7 Gy3, and 66.5 +/- 32.0 Gy8 significantly depended on PTV dimension (p = 0.02) and healthy liver EQD2 (p = 0.05). On T1-w non-contrast MRI, hypointensity at EQD2 isodoses of 113.3 +/- 49.3 Gy2, 97.4 +/- 41.0 Gy3, and 65.7 +/- 24.2 Gy8 significantly depended on prior chemotherapy (p = 0.01) and total liver volume (p = 0.05). On T1-w gadolinium-contrast delayed MRI, hypointensity at EQD2 isodoses of 90.6 +/- 42.5 Gy2, 79.3 +/- 35.3 Gy3, and 56.6 +/- 20.9 Gy8 significantly depended on total (p = 0.04) and healthy (p = 0.01) liver EQD2. CONCLUSIONS: Early post-treatment changes in healthy liver tissue after robotic SBRT could spatially be correlated to respective isodoses. Median nominal doses of 10.1-11.3 Gy per fraction (EQD2 79-97 Gy3) induce characteristic morphologic alterations surrounding the lesions, potentially allowing for dosimetric in-vivo accuracy assessments. Comparison to other techniques and investigations of the short- and long-term clinical impact require further research. PMID- 29404628 TI - Meta-analysis of percutaneous transforaminal endoscopic discectomy vs. fenestration discectomy in the treatment of lumbar disc herniation. AB - OBJECTIVE: The aim of this study was to systematically review the efficacy of percutaneous transforaminal endoscopic discectomy (PTED) and fenestration discectomy (FD) in the treatment of lumbar disc herniation (LDH). MATERIAL AND METHODS: We performed a systematic search in MEDLINE, EMBASE, PubMed, Web of Science, Cochrane databases, Chinese Biomedical Literature Database, CNKI, and Wanfang Data for all relevant studies. All statistical analyses wer performed using Review Manager version 5.3. Dichotomous data were calculated by odds ratio (OR) and continuous data were calculated by mean difference (MD) with 95% confidence intervals (CI). RESULTS: A total of 17 articles with 1390 study subjects were included, with 733 patients in the PTED group and 657 patients in the FD group. The results of the meta-analysis showed that postoperative the visual analog scale (VAS) score (mean difference [MD] -0.13; 95% confidence interval [CI] -0.22 to -0.03; P = 0.009) and postoperative complications (MD 0.52; 95% CI 0.26 to 1.04; P = 0.06) showed no significant differences between the PTED group and the FD group, while the PTED group had significantly better results in operation time (MD 0.47; 95% CI -11.34 to 12.28; P = 0.94), length of incision (MD -3.74; 95% CI -4.28 to -3.19; P < 0.00001), amount of bleeding (MD 63.66, 95% CI -77.65 to -49.67; P < 0.00001), time of postoperative bed rest (MD 90.19; 95% CI -106.82 to -73.56; P < 0.00001), hospitalization time (MD -5.90; 95% CI -7.21 to -4.59; P < 0.00001), and postoperative Oswestry disability index (ODI) score (MD -0.59; 95% CI -1.11 to -0.08; P = 0.02) compared with the FD group. CONCLUSION: The Percutaneous transforaminal endoscopic discectomy is associated with better postoperative ODI score, better results in length of incision, lower blood loss, shorter operation time, postoperative bed time and hospitalization time. The complications did not differ significantly between PTED and FD in the treatment of lumbar disc herniation. These findings provide evidence to support PTED is efficacious for LDH; however, scar repair of a ruptured anulus fibrosus needs a long time and the patients undergoing PTED should be advised to stay in bed for a long time even if the symptoms are markedly relieved. These results are not limited to randomized controlled trials and lack data about the long-term outcome. PMID- 29404629 TI - [Rare cause of right-sided lower abdominal pain]. PMID- 29404630 TI - [In search of a travel guide-results from a survey of E-health startup companies]. AB - As is the case in other sectors, innovative digital products have started to enter the health market, too. If digital products like apps are considered medical devices, startups are often confronted with regulatory procedures that they deem to be slow and with which they are not familiar. This applies to both the certification procedures and the requirements and procedures for reimbursement, where problems could occur. The aim of this article is to better understand the startups' experience in navigating through these procedures, the hurdles they encounter, and their need for support. Therefore, the digital association Bitkom e. V. and the Federal Institute for Drugs and Medical Devices (BfArM) conducted a web-based survey on five themes with a total of 23 questions. These questions focused inter alia on the composition of the team, product planning, familiarity with regulatory requirements, experience with institutions and different sources of information, the assessment of challenges in the process, and the resulting need for support.The analysis on the basis of 18 complete replies has shown that startups work on products with documentation and communications functions, but also integrate diagnostic and therapeutic features. The latter are characteristics of medical devices. Startups consider themselves to be relatively familiar with regulatory requirements regarding medical devices. The largest hurdles are associated with reimbursement: long and costly processes until the startups' products could be reimbursed.Both with regard to reimbursement and certification, startups see a need for low-threshold, cost efficient advisory services and a simplification and acceleration of existing procedures with regard to medical devices. PMID- 29404631 TI - New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways. AB - Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. We determined the expression of JAK2, p-JAK2, STAT3, p-STAT3, SOCS3, IRS-1, p-IRS-1, AKT, p-AKT, GSK3beta, p-GSK3beta, and apoE in the liver, as well as hepatic mRNA levels of pon1, pon2, and pon3. CPF markedly disrupted both leptin and insulin homeostasis, particularly in apoE3 mice. Indeed, only CPF fed apoE3 mice exhibited an increased phosphorylation ratio of STAT3, as well as increased total SOCS3 protein levels. Similarly, the exposure to CPF drastically reduced the phosphorylation ratio of both AKT and GSK3beta, especially in apoE3 mice. Overall, CPF reduced the expression of the three pon genes, principally in C57BL/6 and apoE3 mice. These results provide notable mechanistic insights on the metabolic effects of the pesticide CPF, and attest the increased vulnerability of apoE3 carriers to its metabolic-disruptor role. PMID- 29404632 TI - Correction to: Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel. AB - The correct Author names are shown in this paper. PMID- 29404633 TI - [Bonzai, lead and bath salt-poisoning with new and old drugs : Synthetic amphetamines, cathinones, cannabinoids and opioids-an overview]. AB - BACKGROUND: There has been an increase in the number of serious poisonings and deaths after the use of new psychoactive substances (NPS). These are usually bought online: sometimes legally, often illegally or "in the grey area". OBJECTIVES: Characteristics of different NPS. Legal status concerning the New Psychoactive Substances Act (NpSG). Risk assessment of several substance groups, possible complications of acute poisonings, therapeutic recommendations. MATERIALS AND METHODS: Literature search and evaluation of own case data. Discussion of official statistics, literature and expert recommendations. RESULTS: There has been an increase in the number of poisonings with NPS and associated deaths: in Germany in 2016 there were 98 deaths compared to 39 deaths in 2015. Serious acute poisonings require intensive care therapy. Therapy is usually symptomatic. Referring to the drugs discussed in this article an antidote is only available for the synthetic opioid: naloxone. CONCLUSIONS: With the NpSG being in force since the end of 2016, the number of severe intoxications with NPS will probably (not immediately) decrease. It remains to be seen if the increasing number of fatalities will decrease again. Consultation with a poison centre is recommended in cases of suspected intoxication with NPS. Diagnosis and therapy can then be discussed. Toxicological screening may be false negative because many synthetic drugs are not detected in standard analysis. The NPS often require a special analysis. PMID- 29404634 TI - Neural changes associated with cerebellar tDCS studied using MR spectroscopy. AB - Anodal cerebellar transcranial direct current stimulation (tDCS) is known to enhance motor learning, and therefore, has been suggested to hold promise as a therapeutic intervention. However, the neural mechanisms underpinning the effects of cerebellar tDCS are currently unknown. We investigated the neural changes associated with cerebellar tDCS using magnetic resonance spectroscopy (MRS). 34 healthy participants were divided into two groups which received either concurrent anodal or sham cerebellar tDCS during a visuomotor adaptation task. The anodal group underwent an additional session involving MRS in which the main inhibitory and excitatory neurotransmitters: GABA and glutamate (Glu) were measured pre-, during, and post anodal cerebellar tDCS, but without the behavioural task. We found no significant group-level changes in GABA or glutamate during- or post-tDCS compared to pre-tDCS levels, however, there was large degree of variability across participants. Although cerebellar tDCS did not affect visuomotor adaptation, surprisingly cerebellar tDCS increased motor memory retention with this being strongly correlated with a decrease in cerebellar glutamate levels during tDCS across participants. This work provides novel insights regarding the neural mechanisms which may underlie cerebellar tDCS, but also reveals limitations in the ability to produce robust effects across participants and between studies. PMID- 29404635 TI - EEG-like signals can be synthesized from surface representations of single motor units of facial muscles. AB - Electrodes for recording electroencephalogram (EEG) are placed on or around cranial muscles; hence, their electrical activity may contaminate the EEG signal even at rest conditions. Due to its role in maintaining mandibular posture, tonic activity of temporalis muscle interferes with the EEG signal particularly at fronto-temporal locations at single motor unit (SMU) level. By obtaining surface representation of a motor unit, we can evaluate its interference in EEG and if we could sum surface representations of several tonically active motor units, we could estimate the overall myogenic contamination in EEG. Therefore, in this study, we followed re-composition (RC) approach and generated EEG-like artefact model using surface representations of single motor units (RC). Furthermore, we compared signal characteristics of RC signals with simultaneously recorded EEG signal at different locations in terms of power spectral density and coherence. First, we found that RC signal represented the power spectral distribution of an EMG signal. Second, RC signal reflected the discharge rate of a SMU giving the greatest surface representation amplitude and strongest interference appeared as distinguishable frequency peak on RC power spectra. Moreover, for strong interferences, RC also contaminated the EEG at F7 and other EEG electrodes. These findings are important to illustrate the susceptibility of EEG signal to myogenic artefacts even at rest and the research using EEG coherence comparisons should consider muscle activity while drawing conclusions about neuronal interactions and oscillations. PMID- 29404636 TI - [Frequency and age distribution of combined sternovertebral injuries : Analysis of routine data from German hospitals 2005-2012]. AB - BACKGROUND: Combinations of sternal and spinal fractures often occur due to high velocity accidents and are associated with a high incidence of concomitant injuries. The anterior thoracic wall is described as the fourth column of torso stability, which is why sternovertebral injuries (SVI) present a high risk of sagittal deformation of the trunk, in particular injuries of the thoracic spine. To date, no studies have been published on the frequency distribution of the involved vertebral bodies in large patient groups. OBJECTIVES: This study was intended to elaborate a frequency distribution of vertebral fractures accompanying sternal fractures (SF) and examine the risk of a vertebral fracture accompanying a SF. MATERIAL AND METHODS: A total of 48,193 cases with the main or secondary diagnosis of a SF and 897,963 cases with vertebral fractures based on routine data of German hospitals from the years 2005-2012 were evaluated. A concomitant injury to the spinal column was examined for each vertebral body and then evaluated statistically. RESULTS AND CONCLUSIONS: Of all patients with a SF 30.96% also suffered from a vertebral fracture. Of these 3.11% were SF as the main diagnosis and 60.89% the secondary diagnosis. While vertebral fractures generally occurred most frequently in the region of the thoracolumbar transition and the second cervical vertebral body, the SVI showed a further frequency peak in the range from the lower cervical spine to the middle thoracic spine. The present study was able to show a frequency distribution of accompanying vertebral body injuries in a large and representative collective in the case of SF for the first time. PMID- 29404637 TI - Introduction to the special section on pancreatic cancer. PMID- 29404638 TI - Current concepts in molecular genetics and management guidelines for pancreatic cystic neoplasms: an essential update for radiologists. AB - Cystic neoplasms in the pancreas are encountered frequently on imaging, often detected incidentally during evaluation for other conditions. They can have a variety of clinical and imaging presentations, and similarly, wide-ranging prognostic and treatment implications. In the majority, imaging helps in diagnosis of pancreatic cystic neoplasms (PCNs) and guides management decisions. But, a significant minority of the PCNs remain indeterminate. There have been multiple recent advances in biomarkers and molecular genetics which will likely prove helpful in risk stratification of PCNs. Several prominent national and international societies, as well as consensus groups have put forth recommendations to help guide management of PCNs. The purpose of this article is to discuss the role of imaging in evaluation of PCNs, review the recent advances in molecular genetics and pancreatic cyst fluid analysis, and analyze the pros and cons of major evidence-based and consensus guidelines for management of PCNs. PMID- 29404639 TI - CT colonography interpretation: how to maximize polyp detection and minimize overcalling. AB - This article outlines how to achieve maximum accuracy in interpreting CT colonography (CTC) regarding colonic findings. Interpreting extracolonic findings seen on CTC is a separate diagnostic task and will not be addressed in this article. While many interpretive pitfalls are in fact related to CTC techniques, this article focuses on issues that are related to interpretive knowledge and skills, avoiding in-depth discussions on CTC techniques. Principal methods and further tips for detecting possible polyp candidates and for confirming true soft tissue polyps will be discussed. Specific points about optimizing interpretation strategies for difficult flat polyps including sessile serrated polyp will be raised. There are numerous interpretive pitfalls regarding the colonic interpretation of CTC. Knowledge of these pitfalls will shorten the learning curve and help achieve accurate reads. PMID- 29404640 TI - [Oxytocin: From a Hormone for Birth to a Social Hormone : The Hormonal Governance of Sociability aka Society]. AB - In the mass media, the hormone Oxytocin is currently being debated as the biochemical basis of sociability and a powerful neuropharmacological solution for (re-)establishing societal cohesion. Given its beginning as a 'bodyhormone' early in the 20th century, this article will trace the extraordinary career of Oxytocin from a regulator of birth to a regulator of society. What makes so strong a claim intelligible and acceptable? Our analysis of the scientific discourse on Oxytocin (1906-1990), the mass media discourse since the 1990s, and its repercussions for the scientific discourse during the same period, suggest a series of re configurations of scientific theories and practices, as well as of the conception of the substance itself. Oxytocin became established in the first half of the 20th century, and as a neurohormone as early as the 1950s, yet during the following decades attracted little scientific attention. Only following the mass media's focus on the suggested effects of Oxytocin on love and bonding did the substance increasingly become the focus of empirical research. This work argues that the reception of Oxytocin as a potential neurohormonal basis for individual sociability strongly relies on the mass media discourses, biopolitical linkages that had already been made in the first half of the 20th century aiming at the regulation of life, and a technoscientific mode of research on Oxytocin. At their intersection Oxytocin emerged as a social hormone. PMID- 29404641 TI - LCL: (Locked Cheek Lift) Three-Dimensional Cheek Lift and Inferior Palpebral Rejuvenation. AB - BACKGROUND: Many recent advances in face lift techniques have been made to reverse the aging process of the mid-face. In this study, we present a new technique by which mid-face rejuvenation can be achieved in double-angle vectors and allows adaption to the underlying bony structure. The locked cheek lift (LCL) allows effective, simple and rapid lifting of the malar fat pad in two planes. Correction of the curvature of the face and reduction of the height of lid cheek junction distance can be achieved without an incision at the lower eyelid. METHODS: In total, 115 patients (77 females and 38 males) have been operated on using the LCL technique by a single surgeon; patient ages ranged between 37 and 71 years old (average = 51). Follow-up was performed by the same team for a year postoperatively. The facial expression and lid cheek distance have been evaluated during this period. RESULTS: After a year from the operation, the lid cheek distance correction was maintained in 95.7% of the cases, with stable position of the ascended malar fat pad. Postoperative edema and ecchymosis were limited. CONCLUSION: LCL is an effective, simple and rapid surgical technique, which is capable of correcting the cheek gravitational migration, reducing the lid cheek distance (LCD), maintaining the ascended stable malar fat pad for a long time with a short recovery period and minimal risk of complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29404642 TI - Inefficient Ventriculoarterial Coupling in Fontan Patients: A Cardiac Magnetic Resonance Study. AB - The ventriculoarterial coupling (VAC) ratio, the ratio of arterial elastance (Ea) to ventricular end-systolic elastance (Ees), reflects cardiovascular efficiency. Little is known about this ratio in patients who have undergone the Fontan procedure. Our aim was to assess the VAC ratio in a cohort of Fontan patients using a cardiac magnetic resonance (CMR) method, and to examine its relation to outcomes. We retrospectively assessed VAC from CMR data on 195 Fontan patients (age 19.6 +/- 10.7 years) and 42 controls (age 15.2 +/- 2.2 years). The VAC ratio was calculated as Ea/Ees (Ea = mean arterial blood pressure (MBP)/ventricular stroke volume; Ees = MBP/end-systolic volume). Compared with controls, Fontan patients had lower body surface area-adjusted median Ees (1.54 vs. 2.4, p < 0.001) and Ea (1.35 vs. 1.48, p = 0.01), and a higher median VAC ratio (0.88 vs. 0.62, p < 0.001). After a median follow-up of 4 years (range 1-10), 20 patients reached a composite endpoint of death or heart transplant listing. On multivariable modeling, being in the lowest tertile of the VAC ratio was independently associated with the composite endpoint (odds ratio 11.39, p = 0.02), and inclusion of the VAC ratio in the model improved prediction compared to traditional risk factors. In patients without ventricular dilation, the VAC ratio was the only factor predictive of the composite endpoint (p = 0.02). In conclusion, we found evidence for inefficient ventriculoarterial coupling in Fontan patients. The VAC ratio improved prediction of outcomes and was especially useful in patients without ventricular dilation. Further investigation into the clinical significance of ventriculoarterial coupling in this patient population is warranted. PMID- 29404644 TI - A novel biological recovery approach for PHA employing selective digestion of bacterial biomass in animals. AB - Polyhydroxyalkanoate (PHA) is a family of microbial polyesters that is completely biodegradable and possesses the mechanical and thermal properties of some commonly used petrochemical-based plastics. Therefore, PHA is attractive as a biodegradable thermoplastic. It has always been a challenge to commercialize PHA due to the high cost involved in the biosynthesis of PHA via bacterial fermentation and the subsequent purification of the synthesized PHA from bacterial cells. Innovative enterprise by researchers from various disciplines over several decades successfully reduced the cost of PHA production through the efficient use of cheap and renewable feedstock, precisely controlled fermentation process, and customized bacterial strains. Despite the fact that PHA yields have been improved tremendously, the recovery and purification processes of PHA from bacterial cells remain exhaustive and require large amounts of water and high energy input besides some chemicals. In addition, the residual cell biomass ends up as waste that needs to be treated. We have found that some animals can readily feed on the dried bacterial cells that contain PHA granules. The digestive system of the animals is able to assimilate the bacterial cells but not the PHA granules which are excreted in the form of fecal pellets, thus resulting in partial recovery and purification of PHA. In this mini-review, we will discuss this new concept of biological recovery, the selection of the animal model for biological recovery, and the properties and possible applications of the biologically recovered PHA. PMID- 29404645 TI - [From stiff man syndrome to stiff person spectrum disorders]. AB - The identification of new variants of the stiff man syndrome (SMS) and of new, probably pathogenic neuronal autoantibodies has led to the concept of stiff man (or person) spectrum disorders (SPSD). This is an expanding group of rare chronic autoimmune inflammatory diseases of the central nervous system (CNS) that have in common the main symptoms of fluctuating rigidity and spasms with pronounced stimulus sensitivity. These core symptoms are mandatory and can be accompanied by a wide variety of other neurological signs. The SPSDs are associated with autoantibodies directed against neuronal proteins that attenuate excitability. Neither clinical phenotypes nor the course of SPSD correlate closely with the antibody status. The treatment of these diseases aims at maintaining mobility and is pragmatically oriented to the degree of impediment and comprises antispastic, anticonvulsant and immunomodulating or immunosuppressive medication strategies. PMID- 29404643 TI - Baicalin reverses the impairment of synaptogenesis induced by dopamine burden via the stimulation of GABAAR-TrkB interaction in minimal hepatic encephalopathy. AB - BACKGROUND: It has been reported that D1 receptor (D1R) activation reduces GABAA receptor (GABAAR) current, and baicalin (BAI) displays therapeutic efficacy in diseases involving cognitive impairment. METHODS: We investigated the mechanisms by which BAI could improve DA-induced minimal hepatic encephalopathy (MHE) using immunoblotting, immunofluorescence, and co-immunoprecipitation. RESULTS: BAI did not induce toxicity on the primary cultured neurons. And no obvious toxicity of BAI to the brain was found in rats. DA activated D1R/dopamine and adenosine 3'5' monophosphate-regulated phospho-protein (DARPP32) to reduce the GABAAR current; BAI treatment did not change the D1R/DARPP32 levels but blocked DA-induced reduction of GABAAR levels in primary cultured neurons. DA decreased the interaction of GABAAR with TrkB and the expression of downstream AKT, which was blocked by BAI treatment. Moreover, BAI reversed the decrease in the expression of GABAAR/TrkB/AKT and prevented the impairment of synaptogenesis and memory deficits in MHE rats. CONCLUSIONS: These results suggest that BAI has neuroprotective and synaptoprotective effects on MHE which are not related to upstream D1R/DARPP32 signaling, but to the targeting of downstream GABAAR signaling to TrkB. PMID- 29404646 TI - [Pathophysiology of tremor]. AB - Tremor is clinically defined as a rhythmic, oscillating movement of parts of the body, which functionally leads to impairment of the coordination and execution of targeted movements. It can be a symptom of a primary disease, such as resting tremor in Parkinson's disease or occur as an independent disease, such as essential or orthostatic tremor. For the development of tremor, cerebral components as well as mechanisms at the spinal and muscular level play an important role. This review presents the results of new imaging and electrophysiological studies that have led to important advances in our understanding of the pathophysiology of tremor. We discuss pathophysiological models for the development of resting tremor in Parkinson's disease, essential and orthostatic tremor. We describe recent developments starting from the classical generator model, with an onset of pathological oscillations in distinct cerebral regions, to a network perspective in which tremor arises and spreads through existing anatomical or newly emerged pathological brain networks. In particular translational approaches are presented and discussed. These could serve in the future as a basis for the development of new therapeutic strategies. PMID- 29404647 TI - [Essential tremor: state of the art]. AB - Essential tremor (ET) is currently classified as a syndrome rather than a unique disease, primarily involving monosymptomatic action tremor in both hands. Different etiologies are presumed to underlie this condition. Currently only a few monogenetic conditions are known to present with this syndrome. If accompanied by additional symptoms that do not in themselves constitute a new syndrome, such as abnormal tandem gait or postures, the syndrome should be diagnosed as "ET plus". ET is associated with abnormal rhythmic activation of the cerebello-thalamo-cortical tremor circuit. Despite its strong heritability, the genetics of ET have not been elucidated as yet. Age-correlated tremor is one of the presumed subgroups of ET. Late onset is associated with a shortened life expectancy. From a treatment perspective, propranolol and primidone represent the drugs of first choice, followed by topiramate. Deep brain stimulation of the Vim nucleus of the thalamus is a proven treatment option in severely affected patients. PMID- 29404649 TI - [Tremor]. PMID- 29404648 TI - [Psychotherapy of depressive disorders: Evidence in chronic depression and comorbidities]. AB - BACKGROUND: Psychotherapy has been shown to be an effective treatment option for depressive disorders; however, its effectiveness varies depending on patient and therapist characteristics and the individual form of the depressive disorder. OBJECTIVES: The aim of this article is to present the current evidence for psychotherapeutic antidepressive treatments for patients with chronic and treatment-resistant depression as well as for patients with mental and somatic comorbidities. MATERIAL AND METHODS: During the revision of the currently valid German S3- and National Disease Management Guideline (NDMG) on unipolar depression published in 2015, a comprehensive and systematic evidence search including psychotherapy for specific patient groups was conducted. The results of this search along with a systematic update are summarized. RESULTS: Psychotherapy has been shown to be effective in reducing depressive symptoms in patients suffering from chronic and treatment-resistant depression and in patients with mental and somatic comorbidities. The evidence is insufficient particularly for patients with mental comorbidities. CONCLUSION: Based on the current evidence and clinical expertise the NDMG recommends psychotherapy alone or in combination with pharmacotherapy to treat most of these depressive patient groups. Evidence gaps were identified, which highlight the need for further research. PMID- 29404650 TI - [Coagulation factors and multiple sclerosis : Key factors in the pathogenesis?] AB - Environmental factors and genetic predisposition influence the individual risk to develop multiple sclerosis (MS). Preclinical results in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), prove a significant contribution of the corpuscular and plasmatic coagulation system for the severity of MS. It was recently shown that key molecules of the coagulation cascade, such as fibrinogen, thrombin and factor XII can influence neuroinflammatory disorders such as MS. The inhibition of both fibrinogen and factor XII led to a significantly improved disease course in animal models. Furthermore, in patients suffering from MS a dysregulation of diverse coagulation factors was demonstrated. The precise role of these changes for the pathogenesis of MS remains to be clarified. Nonetheless, the identification of molecular mechanisms between inflammation and the coagulation cascade might provide completely new perspectives for the therapy of MS; however, as most of the currently available data were obtained from animal models, this knowledge must be interpreted with an adequate degree of caution. PMID- 29404651 TI - [Multiple sclerosis and hepatitis B vaccination : What does the verdict of the European Court of Justice on liability after vaccination mean?] AB - In June 2017 the European Court of Justice (ECJ) issued a verdict on the legal assessment of the association between hepatitis B immunization and the subsequent manifestation of multiple sclerosis (MS). This led to a high level of insecurity in the medical field as well as the normal population, especially in MS patients. The aim of this article is to briefly present the evidence-based medical facts and in particular to clearly highlight the legal aspects of the abovenamed ECJ verdict. PMID- 29404652 TI - Increased injury rates after the restructure of Germany's national second league of team handball. AB - PURPOSE: Scientific injury data in men's professional team handball injuries are rare and even less scientific information exists on injury prevention. In 2011, Germany's national second team handball league was restructured by merging the existing two regional leagues into one league. This study evaluates the injury patterns in professional team handball and compares the injury rates between the first and second league before and after the restructure. METHODS: All players of Germany's national first and second men's team handball leagues have mandatory trauma insurance with the same insurance company. This retrospective cohort study analysed the injury data of three consecutive seasons 2010-2013 using standardized injury definitions. RESULTS: 1194 professional team handball players were included in this study. The majority of severe injuries affected the lower extremities, shoulders, and hands. The average injury incidence significantly differed between the first (4.9 injuries per 1000 h) and the second league (3.9 per 1000 h, p < 0.01). The injury incidence in the restructured second league had increased from 3.7 to 4.1 per 1000 h (p < 0.01) and prevalence from 67.1 to 79.3% (p < 0.001), thus almost to the same levels of the first league. The second league showed more time-loss injuries at all severity levels. CONCLUSION: This study yielded a high injury incidence after the restructure of the national second team handball league and presents details on prevalence, incidence, and patterns of injury in professional men's team handball. This study is an important basis for developing injury prevention strategies that should focus on the shoulders, hands, and lower extremities and on reducing the number of matches and travel burden. LEVEL OF EVIDENCE: III. PMID- 29404653 TI - Surgeon experience with dynamic intraligamentary stabilization does not influence risk of failure. AB - PURPOSE: Studies on dynamic intraligamentary stabilization (DIS) of acute anterior cruciate ligament (ACL) ruptures reported failure rates similar to those of conventional ACL reconstruction. This study aimed to determine whether surgeon experience with DIS is associated with revision rates or patient-reported outcomes. The hypothesis was that more experienced surgeons achieved better outcomes following DIS due to substantial learning curve. METHODS: The authors prospectively enrolled 110 consecutive patients that underwent DIS and evaluated them at a minimum of 2 years. The effects of independent variables (surgeon experience, gender, age, adjuvant procedures, tear location, preinjury Tegner score, time from injury to surgery, and follow-up) on four principal outcomes (revision ACL surgery, any re-operation, IKDC and Lysholm score) were analyzed using univariable and multivariable regressions. RESULTS: From the 110 patients enrolled, 14 patients (13%) were lost to follow-up. Of the remaining 96 patients, 11 underwent revision ACL surgery, leaving 85 patients for clinical assessment at a mean of 2.2 +/- 0.4 years (range 2.0-3.8). Arthroscopic reoperations were performed in 26 (27%) patients, including 11 (11%) revision ACL surgeries. Multivariable regressions revealed: (1) no associations between the reoperation rate and the independent variables, (2) better IKDC scores for 'designer surgeons' (b = 10.7; CI 4.9-16.5; p < 0.001), higher preinjury Tegner scores (b = 2.5, CI 0.8-4.2; p = 0.005), and younger patients (b = 0.3, CI 0.0-0.6; p = 0.039), and (3) better Lysholm scores for 'designer surgeons' (b = 7.8, CI 2.8 12.8; p = 0.005) and preinjury Tegner score (b = 1.9, CI 0.5-3.4; p = 0.010). CONCLUSION: Surgeon experience with DIS was not associated with rates of revision ACL surgery or general re-operations. Future, larger-scaled studies are needed to confirm these findings. Patients operated by 'designer surgeons' had slightly better IKDC and Lysholm scores, which could be due to better patient selection and/or positively biased attitudes of both surgeons and patients. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 29404654 TI - Translation and validation of the simplified Chinese version of the anterior cruciate ligament-return to sport after injury (ACL-RSI). AB - PURPOSE: The aim of this study is to obtain a translation and adaptation of the anterior cruciate ligament-return to sport after injury (ACL-RSI) into simplified Chinese and validate the simplified Chinese version. METHODS: Translation and adaptation were performed according to the guidelines of the American Academy of Orthopaedic Surgeons Outcome Committee. A total of 122 patients who were diagnosed with an ACL injury and underwent primary arthroscopic anterior cruciate ligament reconstruction (ACLR) between 2015 and 2016 were included in this study. The simplified Chinese version of the ACL-RSI (SC-ACL-RSI), Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm score and International Knee Documentation Committee (IKDC) subjective knee form were completed. Psychometric evaluations included score distribution, internal consistency, test-retest reliability, and construct and discriminant validity. RESULTS: SC-ACL-RSI scores exhibited a normal distribution without ceiling and floor effects. Internal consistency was high (Cronbach's alpha = 0.94). The intraclass correlation coefficient was 0.98, indicating excellent test-retest reliability. SC-ACL-RSI scores were correlated with all KOOS subscales (r = 0.30 to 0.69, p < 0.001), the IKDC subjective knee form (r = 0.46, p < 0.001) and the Lysholm score (r = 0.56, p < 0.001). The mean scores between patients who returned to the same preinjury level of sport (65.1 +/- 14.3) and those who could not return to the same level (51.0 +/- 15.0) were significantly different (p < 0.001). CONCLUSIONS: The SC-ACL RSI is a reliable and valid instrument to evaluate the psychological impact of a patient returning to sport after ACLR. It is important to evaluate patients' ability to return to sport after an ACL injury. The information provided by the SC-ACL-RSI will affect decisions regarding treatment and rehabilitation plans, which are more likely to influence clinical outcomes. LEVEL OF EVIDENCE: II. PMID- 29404655 TI - Concomitant injuries may not reduce the likelihood of achieving symmetrical muscle function one year after anterior cruciate ligament reconstruction: a prospective observational study based on 263 patients. AB - PURPOSE: A better understanding of patient characteristics and the way common concomitant injuries affect the recovery of muscle function after surgery should help providers to treat patients with anterior cruciate ligament (ACL) injuries. The aim of this study was to determine whether patient characteristics, concomitant injuries and graft choice at ACL reconstruction were associated with symmetrical knee muscle function at one year. The hypothesis was that the presence of concomitant injuries would negatively influence the opportunity to achieve symmetrical knee function at the one-year follow-up. METHODS: Data was extracted from the Swedish National Knee Ligament Register and a rehabilitation outcome register between August 2012 and December 2016. The patients had been evaluated with a battery of tests comprising knee extension and flexion strength, vertical jump, hop for distance and the side-hop test one year after ACL reconstruction. Univariable and multivariable logistic regression analyses were performed with achieving a limb symmetry index (LSI) of >= 90% in all tests of muscle function as primary outcome. RESULTS: A total of 263 patients with a mean age of 26.7 +/- 10.3 years were included in the study (47% females). No patient demographic or intra-operative predictors were found to be significant when attempting to predict the achievement of a symmetrical muscle function. Lateral meniscus injury and a patellar tendon autograft reduced the odds of achieving an LSI of >= 90% in knee extension strength, OR = 0.49 [(95% CI 0.25-0.97), p = 0.039] and OR = 0.30 [(95% CI 0.14-0.67), p = 0.0033] respectively. In addition, reduced odds of recovering knee extension strength were found in older patients, OR = 0.76 [(95% CI 0.60-0.98), p = 0.034]. A higher pre-injury level of physical activity increased the odds of recovering knee flexion strength, OR = 1.14 [(95% CI 1.01-1.29), p = 0.037]. CONCLUSION: Intra-operatively identified concomitant injuries or graft choice did not affect the likelihood of recovering symmetrical performance in five different tests of muscle function one year after ACL reconstruction. However, fewer than one in four patients achieved an LSI of >= 90% in all tests. LEVEL OF EVIDENCE: Prospective observational study: Level 2. PMID- 29404657 TI - Catecholamine crisis during induction of general anesthesia : A case report. AB - Catecholamine crises associated with pheochromocytoma may cause life-threatening cardiovascular conditions. We report the case of a 75-year-old male who developed a hypertensive crisis during induction of general anesthesia for elective resection of a cervical neuroma due to an undiagnosed pheochromocytoma. Hemodynamic instability occurred immediately after the injection of fentanyl, propofol and rocuronium, prior to laryngoscopy and in the absence of any manipulation of the abdomen. In this case report, we present the management of this incident and discuss the underlying pathophysiology triggering a catecholamine crisis. PMID- 29404656 TI - [Hypovolemic and hemorrhagic shock]. AB - The term "shock" refers to a life-threatening circulatory failure caused by an imbalance between the supply and demand of cellular oxygen. Hypovolemic shock is characterized by a reduction of intravascular volume and a subsequent reduction in preload. The body compensates the loss of volume by increasing the stroke volume, heart frequency, oxygen extraction rate, and later by an increased concentration of 2,3-diphosphoglycerate with a rightward shift of the oxygen dissociation curve. Hypovolemic hemorrhagic shock impairs the macrocirculation and microcirculation and therefore affects many organ systems (e.g. kidneys, endocrine system and endothelium). For further identification of a state of shock caused by bleeding, vital functions, coagulation tests and hematopoietic procedures are implemented. Every hospital should be in possession of a specific protocol for massive transfusions. The differentiated systemic treatment of bleeding consists of maintenance of an adequate homeostasis and the administration of blood products and coagulation factors. PMID- 29404658 TI - [Miscommunication as a risk focus in patient safety : Work process analysis in prehospital emergency care]. AB - BACKGROUND: In an analysis of a critical incident reporting system (CIRS) in out of-hospital emergency medicine, it was demonstrated that in 30% of cases deficient communication led to a threat to patients; however, the analysis did not show what exactly the most dangerous work processes are. Current research shows the impact of poor communication on patient safety. OBJECTIVES: An out-of hospital workflow analysis collects data about key work processes and risk areas. The analysis points out confounding factors for a sufficient communication. Almost 70% of critical incidents are based on human factors. Factors, such as communication and teamwork have an impact but fatigue, noise levels and illness also have a major influence. MATERIAL AND METHODS: (I) CIRS database analysis The workflow analysis was based on 247 CIRS cases. This was completed by participant observation and interviews with emergency doctors and paramedics. The 247 CIRS cases displayed 282 communication incidents, which are categorized into 6 subcategories of miscommunication. One CIRS case can be classified into different categories if more communication incidents were validated by the reviewers and four experienced emergency physicians sorted these cases into six subcategories. (II) Workflow analysis The workflow analysis was carried out between 2015 and 2016 in Jena and Berlin, Germany. The focal point of research was to find accumulation of communication risks in different parts of prehospital patient care. During 30 h driving with emergency ambulances, the author interviewed 12 members of the emergency medical service of which 5 were emergency physicians and 7 paramedics. A total of 11 internal medicine cases and one automobile accident were monitored. After patient care the author asked in a 15-min interview if miscommunication or communication incidents occurred. RESULTS: (I) CIRS analysis Between 2005 and 2015, 845 reports were reported to the database. The experts identified 247 incident reports with communication failure. All communication aspects were analyzed and classified. We identified 282 communication incidents. (II) Workflow analysis The analysis showed three phases of prehospital patient care: 1. incoming emergency call and dispatch of ambulance service, 2. prehospital treatment, 3. transportation to a hospital. Overall, the number of incidences is increasing as a consequence of parallel workflows. Category 1 was particularly significant and predominantly, paramedics criticized that emergency physicians did not acknowledge their advice (n = 73 vs. n = 9). Category 3 with n = 63, category 4 with n = 20 and category 2 with n = 13 were the major reasons for incidents. CONCLUSION: A better interface communication helps to coordinate patient transfer and is an option for optimizing resources. Frequent training in communication is an option to avoid incidents. PMID- 29404659 TI - The Phenomenon of Neutrophil Extracellular Traps in Vascular Diseases. AB - Vascular diseases constitute a global health issue due to the increasing number of cases of patients with these diseases. The pathogenesis of the majority of these diseases, including atherosclerosis and thrombosis, is complex and not yet fully understood. One of the major causes for their occurrence can be immune disorders resulting in the development of a chronic inflammation within the vessels. In recent years, studies have placed emphasis on the role of neutrophils in the development of these diseases, i.e., the discovery of neutrophil extracellular traps (NETs) demonstrated that the structures released by the cells may contribute to the enhancement of inflammatory reactions and cell damage. This article summarizes current knowledge on the role of NETs during atherosclerosis, thrombosis and small-vessel vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV). PMID- 29404660 TI - Peripheral DXA measurement around ankle joint to diagnose osteoporosis as assessed by central DXA measurement. AB - OBJECTIVE: This study evaluated the correlation between central and peripheral bone mineral density (BMD) of the ankle joint, using dual-energy X-ray absorptiometry (DXA). We also investigated whether peripheral ankle BMD could be used to identify individuals who were diagnosed with osteoporosis, using central DXA. METHODS: We recruited 134 volunteers aged 20-90 years who agreed to participate in this study. Central BMD of the lumbar spine and left femur, and peripheral BMD of the medial malleolus, distal tibia, lateral malleolus, and talus were measured with DXA. RESULTS: Among the peripheral sites of the ankle, the highest and lowest BMD were observed in the talus and lateral malleolus, respectively. All peripheral DXA measurements of the ankle joint were significantly correlated with central DXA measurements. There was a good correlation (r: 0.656-0.725) between peripheral and central BMD for the older age group (> 50 years), but fair-to-good correlation (r: 0.263-0.654) for the younger age group (< 50 years). The cut-off values for peripheral BMD of the ankle joint between osteoporosis and non-osteoporosis were 0.548 g/cm2 (sensitivity, 89.0%; specificity, 69.0%) for the medial malleolus, 0.626 g/cm2 (sensitivity, 83.3%; specificity, 82.8%) for the distal tibia, 0.47 g/cm2 (sensitivity, 100.0%; specificity, 65.5%) for the lateral malleolus, and 0.973 g/cm2 (sensitivity, 72.2%; specificity, 83.6%) for the talus (p < 0.001). CONCLUSIONS: This study showed good correlation between peripheral BMD around ankle joint and central BMD for older age group. Further study is required to use the ankle DXA as a valid clinical tool for the diagnosis of osteoporosis and fracture risk assessment. PMID- 29404662 TI - ? PMID- 29404661 TI - Kinetics of the B-A transition of DNA: analysis of potential contributions to a reaction barrier. AB - Because of open problems in the relation between results obtained by relaxation experiments and molecular dynamics simulations on the B-A transition of DNA, relaxation measurements of the B-A dynamics have been extended to a wider range of conditions. Field-induced reaction effects are measured selectively by the magic angle technique using a novel cell construction preventing perturbations from cell window anisotropy. The kinetics was recorded for the case of poly[d(AT)] up to the salt concentration limit of 4.4 mM, where aggregation does not yet interfere. Now experimental data on the B-A dynamics are available for poly[d(AT)] at salt concentrations of 0.18, 0.73, 2.44 and 4.4 mM. In all cases, a spectrum of time constants is found, ranging from ~ 10 MUs up to components approaching ~ 1 ms. The relatively small dependence of these data on the salt concentration indicates that electrostatic effects on the kinetics are not as strong as may be expected. The ethanol content at the transition center is a linear function of the logarithm of the salt concentration, and the slope is close to that expected from polyelectrolyte theory. The B-A transition dynamics was also measured in D2O at a salt concentration of 2.4 mM: the center of the transition is found at 20.0 mol/l H2O and at 20.1 mol/l D2O with an estimated accuracy of +/- 0.1 mol/l; the spectrum of time constants at the respective transition centers is very similar. The experimental results are discussed regarding the data obtained by molecular dynamics simulations. PMID- 29404663 TI - What is novel about certified reference materials? PMID- 29404664 TI - Cu isotope fractionation response to oxidative stress in a hepatic cell line studied using multi-collector ICP-mass spectrometry. AB - Reactive oxygen species (ROS) are generated in biological processes involving electron transfer reactions and can act in a beneficial or deleterious way. When intracellular ROS levels exceed the cell's anti-oxidant capacity, oxidative stress occurs. In this work, Cu isotope fractionation was evaluated in HepG2 cells under oxidative stress conditions attained in various ways. HepG2 is a well characterised human hepatoblastoma cell line adapted to grow under high oxidative stress conditions. During a pre-incubation stage, cells were exposed to a non toxic concentration of Cu for 24 h. Subsequently, the medium was replaced and cells were exposed to one of three different external stressors: H2O2, tumour necrosis factor alpha (TNFalpha) or UV radiation. The isotopic composition of the intracellular Cu was determined by multi-collector ICP-mass spectrometry to evaluate the isotope fractionation accompanying Cu fluxes between cells and culture medium. For half of these setups, the pre-incubation solution also contained N-acetyl-cysteine (NAC) as an anti-oxidant to evaluate its protective effect against oxidative stress via its influence on the extent of Cu isotope fractionation. Oxidative stress caused the intracellular Cu isotopic composition to be heavier compared to that in untreated control cells. The H2O2 and TNFalpha exposures rendered similar results, comparable to those obtained after mild UV exposure. The heaviest Cu isotopic composition was observed under the strongest oxidative conditions tested, i.e., when the cell surfaces were directly exposed to UV radiation without apical medium and in absence of NAC. NAC mitigated the extent of isotope fractionation in all cases. PMID- 29404665 TI - Target screening of 105 veterinary drug residues in milk using UHPLC/ESI Q Orbitrap multiplexing data independent acquisition. AB - This paper presents a multi-class target screening method for the detection of 105 veterinary drug residues from 11 classes in milk using ultra-high performance liquid chromatography electrospray ionization quadrupole Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap). The method is based on a non-target approach of full mass scan and multiplexing data-independent acquisition (Full MS/mDIA). The veterinary drugs include endectocides, fluoroquinolones, ionophores, macrolides, nitroimidazole, NSAIDs, beta-lactams, penicillins, phenicols, sulfonamides, and tetracyclines. Veterinary drug residues were extracted from milk using a salting-out and solid-phase extraction (SOSPE) procedure, which entailed the precipitation of milk proteins by an extraction buffer (oxalic acid and EDTA, pH 3) and acetonitrile, a salting-out acetonitrile/water phase separation using ammonium sulfate, and solid-phase extraction for clean-up using polymeric reversed-phase sorbent cartridges. The Q-Orbitrap Full MS/dd-MS2 (data dependent acquisition) was used to acquire product-ion spectra of individual veterinary drugs to build a compound database and a mass spectral library, whereas its Full MS/mDIA was utilized to acquire sample data from milk for target screening of veterinary drugs fortified at 1.0 or 10.0 MUg/kg. The in-spectrum mass correction or solvent background lock-mass correction was used to minimize mass error when building the compound database from experimental dd-MS2 accurate mass data. Retention time alignment and response threshold adjustment were used to eliminate or reduce false negatives and/or false positive rates. The validated method was capable of screening 58% and 96% of 105 veterinary drugs at 1.0 and 10.0 MUg/kg, respectively, without manually evaluating every compound during data processing, which will reduce the workload in routine practice. PMID- 29404666 TI - Intra-articular fractures of the distal humerus-a review of the current practice. AB - Intra-articular fractures of the distal humerus are complex injuries that can considerably limit elbow function if not treated appropriately. Surgical management is indicated for most intra-articular distal humerus fractures with the goal of restoring elbow range of motion and function. Open reduction and internal fixation (ORIF) with plates and screws has been the preferred surgical option. Double plating is recommended for bicolumnar fractures and plates can be applied either parallel or orthogonal to each other. Surgical approach for ORIF of the distal humerus can be performed through an olecranon osteotomy, but other approaches that preserve the olecranon are also in use, such as the triceps reflecting, triceps-splitting, paratricipital, and triceps-reflecting anconeus pedicle approach. The ulnar nerve is identified during the approach, followed by either in situ decompression or anterior transposition. Elbow arthroplasty has also emerged as a viable alternative to ORIF for fixation of these fractures in elderly patients with poor bone quality. PMID- 29404667 TI - Extra-articular resection is a limb-salvage option for sarcoma involving the hip joint. AB - INTRODUCTION: With the development of surgical techniques and improvements in hemi-pelvic prosthesis systems, extra-articular resection can be performed as a limb-salvage procedure in selected patients whose hip joint is invaded by a sarcoma. The aim of this study was to describe the indications for and the technical details, post-operative complications, and oncologic and functional outcomes of this procedure. METHODS: Eighteen patients with Enneking IIB or IB sarcoma who underwent extra-articular resection of the hip joint were enrolled. A modular pelvic endoprosthesis combined with a femoral endoprosthesis was used to reconstruct the bone and joint defect. Pathological diagnoses included osteosarcoma (7 patients), chondrosarcoma (7), undifferentiated high-grade pleomorphic sarcoma (3), and malignant peripheral nerve-sheath tumour (1). RESULTS: Wide, marginal and intralesional surgical margin was achieved in 13, four and one patients, respectively. There was one peri-operative death and the other 17 patients were followed up for 35.0 months (range, 10-75 months). Three patients had early-stage dislocations. One had a traumatic dislocation three years later. Two patients had wound complications. The average MSTS 93 score was 63.5% +/- 10.8%. Four patients had local recurrence. The estimated three-year disease-free survival and overall survival for the 18 patients were both 50.0%. CONCLUSION: Although technically demanding, extra-articular resection of hip is a limb-salvage procedure that is worth considering for carefully selected patients. PMID- 29404668 TI - Demographic and socioeconomic factors influencing the incidence of clavicle fractures, a national population-based survey of five hundred and twelve thousand, one hundred and eighty seven individuals. AB - BACKGROUND: This study aims to investigate the population-based incidence of clavicle fracture and the related risk factors in China. METHODS: All the data on clavicle fractures were available from the China National Fracture Survey (CNFS) database performed in 2015. In the CNFS, all eligible household members were sampled from eight provinces, 24 urban cities, and 24 rural counties in China, using stratified random sampling and the probability proportional to size method. Questionnaires were sent to every participant for data collection. Information on age, gender, height, weight, ethnic group, education, professional, smoking, alcohol consumption, sleeping time per day, dietary habits, and others was collected. Fracture case was identified by patients' self report and further confirmation by medical data. RESULTS: A total of 512,187 valid questionnaires were collected, and relevant data were extracted and analyzed. There were 89 patients with 89 clavicle fractures in 2014, indicating that the incidence was 17.4 (95%CI, 13.8-21.0) per 100,000 person-years. Traffic accidents and falls were the most predominant cause for clavicle factures, leading to 91.0% of all the injuries. Over 85% of them occurred on the road and at home. Age of 45-64, average sleep time < seven hours/day, smoking, alcohol consumption and history of previous fracture were identified as independent risk factors for clavicle fracture. Overweight (BMI, 24.0-27.9) was a significant protective factor, which was estimated to reduce 72% of the clavicle fractures, compared to normal BMI (18.5-23.9). CONCLUSIONS: Public health policies focusing on decreasing alcohol consumption, smoking cessation, and encouraging individuals to obtain sufficient sleep should be implemented. Middle-aged individuals with previous history of fracture should strengthen the awareness of prevention and health care and decrease risky activities to reduce the clavicle fractures. PMID- 29404669 TI - Clinical and magnetic resonance imaging assessment of anatomical lateral ankle ligament reconstruction: comparison of tendon allograft and autograft. AB - PURPOSE: To compare the results of anatomical lateral ankle ligament (LAL) reconstruction with tendon allograft and autograft using clinical scores and ultrashort echo time (UTE) sequence of MRI. METHODS: A total of 26 patients with LAL reconstruction were recruited in this study, including 16 using semitendinosus allografts and 10 using semitendinosus autograft. All of them were diagnosed as chronic ankle instability and accepted anatomic reconstruction. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson score, and radiological evaluation using MRI UTE scanning were extracted from each patient. The comparative analysis of the clinical assessments and UTE-T2* values were performed between the patients using autografts and allografts. RESULTS: For the allograft group, the mean AOFAS score improved from 69.9 +/- 13.3 to 94.8 +/- 5.4 (P = 0.000), and the mean Karlsson score improved from 70.3 +/- 12.2 to 93.8 +/- 5.6 (P = 0.000). For the autograft group, the mean AOFAS score improved from 68.4 +/- 10.0 to 94.7 +/- 5.0 (P = 0.000), and the mean Karlsson score improved from 64.5 +/- 14.4 to 95.0 +/- 5.8 (P = 0.000). No significant differences were found between the allograft and autograft neither before (AOFAS P = 0.756, Karlsson P = 0.285) nor after (AOFAS P = 0.957, Karlsson P = 0.574) surgery. While the UTE T2* values in allograft were higher than those of autograft group both in anterior talofibular ligament (8.3 +/- 1.0 vs 7.6 +/- 1.1 P = 0.027) and intra-tunnel graft (7.8 +/- 0.6 vs 7.2 +/- 0.8 P = 0.045). CONCLUSION: Both allograft and autograft reconstructions could get an ideal patient satisfaction and clinical functional outcomes at the follow-up. Higher T2* values were found in allograft group which indicated that autograft had some superiorities in respect of revascularization process, collagen structure, water content, and tendon properties. PMID- 29404670 TI - Single-stage multi-level construct design incorporating ribs and chest wall reconstruction after en bloc resection of spinal tumour. AB - PURPOSE: Multi-level reconstruction incorporating the chest wall and ribs is technically demanding after multi-segmental total en bloc spondylectomy (TES) of thoracic spinal tumours. Few surgical techniques are reported for effective reconstruction. A novel and straightforward technical reconstruction through posterior-lateral approach was presented to solve the extensive chest wall defect and prevent occurrences of severe respiratory dysfunctions after performing TES. The preliminary outcomes of surgery were reviewed. METHODS: Multi-level TES was performed for five patients with primary or recurrent thoracic spinal malignancies through posterior-lateral approach. The involved ribs and chest wall were removed to achieve tumour-free margin. Then titanium mesh with allograft bone and pedicle screw-rod system were adopted for the circumferential spinal reconstruction routinely. Titanium rods were modified accordingly to attach to the screw-rod system proximally, and the distal end of rods was dynamically inserted into the ribs. RESULTS: The mean surgery time was 6.7 hours (range 5-8), with the average blood loss of 3260 ml (range 2300-4500). No severe neurological complications were reported while three patients had complaints of slight numbness of chest skin (no. 1, 3, and 5). No severe respiratory complications occurred during peri-operative period. No implant failure and no local recurrence or distant metastases were observed with an average follow-up of 12.5 months. CONCLUSIONS: The single-stage reconstructions incorporating spine and chest wall are straightforward and easy to perform. The preliminary outcomes of co reconstructions are promising and favourable. More studies and longer follow-up are required to validate this technique. PMID- 29404672 TI - Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C peptide levels, through meta-genome-wide association studies (meta-GWAS). METHODS: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. RESULTS: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 * 10-8), meeting the genome-wide significance threshold (p < 5 * 10-8). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07 0.10, p = 8.43 * 10-8). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (beta [SE] = - 0.39 [0.07], p = 9.72 * 10-8). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 * 10-8). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. CONCLUSIONS/INTERPRETATION: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function. PMID- 29404674 TI - Chronic urinary tract infection and bladder carcinoma risk: a meta-analysis of case-control and cohort studies. AB - OBJECTIVE: This meta-analysis of published case-control and cohort studies sought to quantify the magnitude and direction of association between chronic UTI (defined as the infection of the urinary tract that either does not respond to treatment or keeps recurring) and risk of bladder carcinoma (BCa) (i.e., including mainly urothelial carcinoma, squamous cell carcinoma or adenocarcinoma). METHODS: A literature search was conducted using Medline, Embase, Ovid, Web of Science, Science Direct and Cochrane Library, which was supplemented with manual search of reference lists of the identified articles. Case-control and cohort studies examining UTI as a predictor of BCa risk published through June 2016 were eligible. Using random-effects models, odds ratios (OR) or relative risks (RR) from eligible studies were combined to synthesize summary effect estimates. The included studies were assessed for methodological quality and potential publication bias. Heterogeneity by study characteristics was examined by sub-group and meta-regression analyses. RESULTS: Eighteen case-control and three cohort studies published between 1963 and 2016 were eligible. Random-effects models showed that UTI was significantly associated with an increased BCa risk both in case-control studies (summary ORRE = 2.33; 95% CI 1.86, 2.92) and cohort studies (summary RRRE = 2.88; 95% CI 1.20, 6.89). The observed relationship of UTI with an increased BCa risk was independent of the study characteristics considered. No significant publication bias was detected. CONCLUSIONS: Chronic UTI was significantly and independently associated with an increased BCa risk. However, due to the presence of high between-study heterogeneity and inconsistent patterns of adjusted confounding effects, more data are needed to clarify the role of chronic UTI in causation of BCa and if established, prompt and effective treatment of UTI may minimize a substantial proportion of BCa risk. PMID- 29404673 TI - Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes. AB - AIMS/HYPOTHESIS: Islet autoimmunity usually starts with the appearance of autoantibodies against either insulin (IAA) or GAD65 (GADA). This categorises children with preclinical type 1 diabetes into two immune phenotypes, which differ in their genetic background and may have different aetiology. The aim was to study whether Coxsackievirus group B (CVB) infections, which have been linked to the initiation of islet autoimmunity, are associated with either of these two phenotypes in children with HLA-conferred susceptibility to type 1 diabetes. METHODS: All samples were from children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Individuals are recruited to the DIPP study from the general population of new-born infants who carry defined HLA genotypes associated with susceptibility to type 1 diabetes. Our study cohort included 91 children who developed IAA and 78 children who developed GADA as their first appearing single autoantibody and remained persistently seropositive for islet autoantibodies, along with 181 and 151 individually matched autoantibody negative control children, respectively. Seroconversion to positivity for neutralising antibodies was detected as the surrogate marker of CVB infections in serial follow-up serum samples collected before and at the appearance of islet autoantibodies in each individual. RESULTS: CVB1 infections were associated with the appearance of IAA as the first autoantibody (OR 2.4 [95% CI 1.4, 4.2], corrected p = 0.018). CVB5 infection also tended to be associated with the appearance of IAA, however, this did not reach statistical significance (OR 2.3, [0.7, 7.5], p = 0.163); no other CVB types were associated with increased risk of IAA. Children who had signs of a CVB1 infection either alone or prior to infections by other CVBs were at the highest risk for developing IAA (OR 5.3 [95% CI 2.4, 11.7], p < 0.001). None of the CVBs were associated with the appearance of GADA. CONCLUSIONS/INTERPRETATION: CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process. PMID- 29404676 TI - Medulloblastoma in association with sacral agenesis; a case report. AB - Medulloblastoma is a congenital brain tumor which can be associated with different congenital anomalies. However, coincidence of cerebellar medulloblastoma with sacral agenesis has not been reported so far. A variety of genetic and/or environmental predisposing factors have been proposed for both diseases. Herein, an unprecedented coincidence of these two conditions is presented. A neonate was born with lumbosacral agenesis, paraplegia, and atrophic legs, and he developed medulloblastoma with three ventricular hydrocephalus 3 years later. Different aspects regarding the embryology and etiology of both ailments are discussed, assuming the possibility that the same genetic and/or environmental risk factors may have played a part in both conditions. PMID- 29404675 TI - Detection of Shigella spp. nucleic acids in the synovial tissue of Tunisian rheumatoid arthritis patients and other forms of arthritis by quantitative real time polymerase chain reaction. AB - Enterobacterial components in the joints of patients are believed to contribute to a perpetuating inflammation leading to a reactive arthritis (ReA), a condition in which microbial agents cannot be recovered from the joint. At present, it is unclear whether nucleic acids from Shigella spp. are playing a pathogenic role in causing not only ReA but also other forms of arthritis. Quantitative real-time polymerase chain reaction assay (qPCR) is the method of choice for the identification of bacteria within the synovium. The aim of our study was to detect the presence of Shigella spp. nucleic acids in the synovial tissue (ST) of Tunisian arthritis patients. We investigated 57 ST samples from rheumatoid arthritis (RA) n = 38, undifferentiated oligoarthritis (UOA) n = 12, and spondyloarthritis (SpA) n = 7 patients; 5 ST samples from healthy individuals were used as controls. Shigella spp. DNA and mRNA transcripts encoding the virulence gene A (VirA) were examined using an optimized qPCR with newly designed primers and probes. Using qPCR, Shigella spp. DNA was found in 37/57 (65%) ST samples (24/38, i.e., 63.2% of RA, 8/12, i.e., 67% of UOA, and 5/7, i.e., 71.4% of SpA patients). Paired DNA and mRNA were extracted from 39 ST samples, whose VirA cDNA was found in 29/39 (74.4%) patients. qPCR did not yield any nucleic acids in the five healthy control ST samples. The qPCR assay was sensitive and showed a good intra- and inter-run reproducibility. These preliminary findings generated by an optimized, highly sensitive PCR assay underline a potential role of past gastrointestinal infections. In Tunisian patients, a bacterial etiology involving Shigella spp. in the manifestation of arthritic disorders including RA might be more common than expected. PMID- 29404677 TI - [Marginal protection of retinal cells by bisperoxovanadium : Appropriate therapy in the model of retinal ischemia?] AB - BACKGROUND: Ischemic processes usually lead to the destruction of retinal cells and therefore play a key role in a multitude of eye diseases. OBJECTIVE: The aim of this study was to investigate whether bisperoxovanadium has a potential neuroprotective effect in an ischemia/reperfusion animal model. MATERIAL AND METHODS: Initially, ischemia was induced in one eye of an ischemia/reperfusion model and 3 days later, a 14-day medication-based treatment was initiated. Bisperoxovanadium was administered intraperitoneally every 3 days. Subsequently, the number of ganglion cells, the rate of apoptosis, amacrine cells, macroglia, microglia, and their activation state, as well as photoreceptors were determined by histological and immunohistochemical analyses. RESULTS: In comparison to the control group, a significant retinal ganglion cell loss, a significant reduction of the inner layers as well as a decrease in photoreceptor and amacrine cell numbers could be determined in the ischemic eyes. In addition, there was an increase in the number of microglia in these animals. The rats treated with bisperoxovanadium did not exhibit a significant neuroprotective effect regarding the number of ganglion cells, the rate of apoptosis, macroglia, amacrine cells, or photoreceptors; however, a low structural degeneration of photoreceptors could be observed as an effect of the treatment. Additionally, fewer microglia and activated microglia were observed after bisperoxovanadium treatment. CONCLUSION: Bisperoxovanadium seems to have only a marginal neuroprotective effect on ischemic retinae. It needs to be examined whether earlier therapy onset, higher dose or different route of administration would significantly improve the results or whether this therapeutic approach is unsuitable. PMID- 29404678 TI - [Biomechanical investigations on accommodation of the eye]. AB - BACKGROUND: The biomechanics of accommodation are of particular interest in terms of the causes of presbyopia and the function of intraocular lenses. OBJECTIVE: The aim of the present article is to model the mechanism of accommodation in detail. MATERIALS AND METHODS: The state of the art of applying biomechanical models to accommodation is presented, which enables the accommodation process to be understood. RESULTS AND CONCLUSION: The established models, which are based on the Helmholtz theory, can explain the accommodation process in a plausible manner. These models thereby also enable further investigations on the genesis of presbyopia as well as on the development of accommodative intraocular lenses and implants. However, measurements are always necessary to compare the simulation results with reality, and to provide input and material data as well as geometric dimensions of components of the eye. PMID- 29404679 TI - [Conjunctival pseudomelanoma]. PMID- 29404680 TI - The contribution of comorbidities to mortality in hospitalized patients with heart failure. AB - BACKGROUND: Heart failure (HF) with reduced ejection fraction (HFrEF) has a worse prognosis than HF with preserved EF (HFpEF). The study aimed to evaluate whether different comorbidity profiles of HFrEF- and HFpEF-patients or HF-specific mechanisms contribute to a greater extent to this difference. METHODS: We linked data from two health insurances to data from a cardiology clinic hospital information system. Patients with a hospitalization with HF in 2005-2011, categorized as HFrEF (EF < 45%) or HFpEF (EF >= 45%), were propensity score (PS) matched to controls without HF on comorbidites and medication to assure similar comorbidity profiles of patients and their respective controls. The balance of the covariates in patients and controls was compared via the standardized difference (SDiff). Age-standardized 1-year mortality rates (MR) with 95% confidence intervals (CI) were calculated. RESULTS: 777 HFrEF-patients (1135 HFpEF-patients) were PS-matched to 3446 (4832) controls. Balance between patients and controls was largely achieved with a SDiff < 0.1 on most variables considered. The age-standardized 1-year MRs per 1000 persons in HFrEF-patients and controls were 267.8 (95% CI 175.9-359.8) and 86.1 (95% CI 70.0-102.3). MRs in HFpEF-patients and controls were 166.2 (95% CI 101.5-230.9) and 61.5 (95% CI 52.9 70.1). Thus, differences in MRs between patients and their controls were higher for HFrEF (181.7) than for HFpEF (104.7). CONCLUSIONS: Given the similar comorbidity profiles between HF-patients and controls, the higher difference in mortality rates between HFrEF-patients and controls points more to HF-specific mechanisms for these patients, whereas for HFpEF-patients a higher contribution of comorbidity is suggested by our results. PMID- 29404681 TI - O-acetylserine(thio)lyase (OAS-TL) molecular expression in Pancratium maritimum L. (Amaryllidaceae) under salt stress. AB - MAIN CONCLUSION: Different levels of salt stress affected the OAS-TL expression levels in Pancratium maritimum organs (bulb, leaf and root). A detailed method has been described for the identification of the conserved domain of the OAS-TL cDNA in sea daffodil given the scarce data available for the Amaryllidaceae family. Pancratium maritimum or sea daffodil (Amaryllidaceae) is a bulbous geophyte growing on coastal sands. In this study, we investigated the involvement of cysteine synthesis for salt tolerance through the expression of the enzyme O acetylserine(thio)lyase (OAS-TL) during the stress response to NaCl treatments in P. maritimum. Quantitative real-time PCR was used in different organs (bulb, leaf and root). PMID- 29404682 TI - A note on improved statistical approaches to account for pseudoprogression. AB - Responses to immuno-oncology agents are often subject to misinterpretation as apparent tumor growth due to immune infiltration leads to the appearance of progressive disease and can result in the discontinuation of effective therapeutic agents. Better statistical strategies to determine experimental outcomes are needed to distinguish between true and pseudoprogression. We applied time-to-event statistical analyses methods that account for study design features and capture the longitudinal and panoramic aspects of pseudoprogression to test superiority of a combination of RRx-001, a novel tumor-associated macrophage polarizing agent in Phase 2, and an anti-PD-L1 antibody in a myeloma preclinical model, comparing to traditional, mean-based mixed effects modeling approaches that did not show statistical significance. Nonparametric p values for the difference of cumulative incidence rates of time to >= 50% tumor growth reduction and its associated restricted mean survival times are computed and found to be statistically significant. Kaplan-Meier description of time-to-volume reduction (>= 50%) coupled with Cox's proportional hazards model follows the data longitudinally and therefore permits an analysis of immune infiltration resolution, making it an improved method for analysis of preclinical experiments with immuno-oncology agents. PMID- 29404684 TI - [A new rubric in Der Schmerz: "PAIN CLINICAL UPDATES"]. PMID- 29404683 TI - An enhanced genome-scale metabolic reconstruction of Streptomyces clavuligerus identifies novel strain improvement strategies. AB - In this work, we expanded and updated a genome-scale metabolic model of Streptomyces clavuligerus. The model includes 1021 genes and 1494 biochemical reactions; genome-reaction information was curated and new features related to clavam metabolism and to the biomass synthesis equation were incorporated. The model was validated using experimental data from the literature and simulations were performed to predict cellular growth and clavulanic acid biosynthesis. Flux balance analysis (FBA) showed that limiting concentrations of phosphate and an excess of ammonia accumulation are unfavorable for growth and clavulanic acid biosynthesis. The evaluation of different objective functions for FBA showed that maximization of ATP yields the best predictions for cellular behavior in continuous cultures, while the maximization of growth rate provides better predictions for batch cultures. Through gene essentiality analysis, 130 essential genes were found using a limited in silico media, while 100 essential genes were identified in amino acid-supplemented media. Finally, a strain design was carried out to identify candidate genes to be overexpressed or knocked out so as to maximize antibiotic biosynthesis. Interestingly, potential metabolic engineering targets, identified in this study, have not been tested experimentally. PMID- 29404685 TI - [Persisting pain and cortical reorganization after macroreplantation of the upper extremity]. PMID- 29404686 TI - Effects of haloperidol and clozapine on synapse-related gene expression in specific brain regions of male rats. AB - We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded. PMID- 29404687 TI - The leaf phenophase of deciduous species altered by land pavements. AB - It has been widely reported that the urban environment alters leaf and flowering phenophases; however, it remains unclear if land pavement is correlated with these alterations. In this paper, two popular deciduous urban trees in northern China, ash (Fraxinus chinensis) and maple (Acer truncatum), were planted in pervious and impervious pavements at three spacings (0.5 m * 0.5 m, 1.0 m * 1.0 m, and 2.0 m * 2.0 m apart). The beginning and end dates of the processes of leaf budburst and senescence were recorded in spring and fall of 2015, respectively. The results show that leaf budburst and senescence were significantly advanced in pavement compared to non-pavement lands. The date of full leaf budburst was earlier by 0.7-9.3 days for ash and by 0.3-2.3 days for maple under pavements than non-pavements, respectively. As tree spacing increases, the advanced days of leaf budburst became longer. Our results clearly indicate that alteration of leaf phenophases is attributed to land pavement, which should be taken into consideration in urban planning and urban plant management. PMID- 29404688 TI - Correction to: Comments on Chavent et al.: Renovascular hypertension: results in adulthood of renal autotransplantation performed in children. AB - In the name of the first author, the element "Della" was misinterpreted as a second given name. In fact, it is part of her surname. PMID- 29404689 TI - Hyperchloremia is independently associated with mortality in critically ill children who ultimately require continuous renal replacement therapy. AB - BACKGROUND: The optimal fluid management in critically ill children is currently under investigation with several studies suggesting that hyperchloremia, chloride load, and the use of chloride-rich fluids contribute to worse outcomes. METHODS: This is a single-center retrospective cohort study of Pediatric Intensive Care Unit patients from 2008 to 2016 requiring continuous renal replacement therapy (CRRT). Patients were excluded if they had end-stage renal disease, a disorder of chloride transport, or concurrent provision of extracorporeal membrane oxygenation therapy. RESULTS: Patients (n = 66) were dichotomized into two groups (peak chloride (Cl) >= 110 mmol/L vs. peak Cl < 110 mmol/L prior to CRRT initiation). Hyperchloremia was present in 39 (59%) children. Baseline characteristics were similar between groups. Fluid overload at CRRT initiation was more common in patients with hyperchloremia (11.5% IQR 3.8-22.4) compared to those without (5.5% IQR 0.9-13.9) (p = 0.04). Mortality was significantly higher in patients with hyperchloremia (n = 26, 67%) compared to those without (n = 8, 29%) (p = 0.006). Patients with hyperchloremia had 10.9 times greater odds of death compared to those without hyperchloremia, after adjusting for percent fluid overload, PRISM III score, time to initiation of CRRT, height, and weight (95% CI 2.4 to 49.5, p = 0.002). CONCLUSIONS: Hyperchloremia is common among critically ill children prior to CRRT initiation. In this population, hyperchloremia is independently associated with mortality. Further studies are needed to determine the impact of hyperchloremia on all critically ill children and the impact of chloride load on outcomes. PMID- 29404690 TI - Temperature effects on a marine herbivore depend strongly on diet across multiple generations. AB - Increasing sea surface temperatures are predicted to alter marine plant-herbivore interactions and, thus, the structure and function of algal and seagrass communities. Given the fundamental role of host plant quality in determining herbivore fitness, predicting the effects of increased temperatures requires an understanding of how temperature may interact with diet quality. We used an herbivorous marine amphipod, Sunamphitoe parmerong, to test how temperature and diet interact to alter herbivore growth, feeding rates, survival, and fecundity in short- and long-term assays. In short-term thermal stress assays, S. parmerong was tolerant to the range of temperatures that it currently experiences in nature (20-26 degrees C), with mortality at temperatures > 27 degrees C. In longer term experiments, two generations of S. parmerong were reared in nine combinations of temperature (ambient, + 2, + 4 degrees C) and diet (two high- and one low-quality algal species) treatments. Temperature and diet interacted to determine total numbers of amphipods in the F1 generation and the potential F2 population size (sum of brooded eggs and newly hatched juveniles). The size and development rate of F1 individuals were affected by diet, but not temperature. Consumption rates per capita were highest at intermediate temperatures but could not explain the observed differences in survival. Our results show that predicting the effects of increasing temperature on marine herbivores will be complicated by variation in host plant quality, and that climate-driven changes to plant availability will affect herbivore performance, and thus the strength of plant-herbivore interactions. PMID- 29404691 TI - Interdisciplinary Telemedicine in the Management of Dysphagia in Head and Neck. AB - The study considered the feasibility and impact of interdisciplinary telemedicine discussions in the management of post-treatment dysphagia in patients with head and neck tumors. This is a retrospective analysis of patients with persistent dysphagia after treatment for head and neck pathology, at an institute in India. The cases were discussed in the telemedicine meeting conducted between host institute and a second unit in the United States. A monthly meeting was organized, using an internet-based video conference system. The ongoing swallowing problems and management were presented, and through discussions, a plan for further management was formulated and carried out. The Functional Oral Intake Scale (FOIS) was measured before and after the implementation of the plan. Twenty-six patients were discussed, out of which, 22 were head and neck malignancies. The recommendations concurred with that of the host unit in 18, differed for three and additive in five patients. The pre-treatment mean FOIS was 1.46 with a standard deviation of 0.989 and post-treatment mean improved to 3.92 with a standard deviation of 1.809 (p < 0.0001). The present study supports the success of an interdisciplinary telemedicine meeting to manage difficult cases of dysphagia in head and neck. The outcome in terms of the FOIS score improved significantly after implementing them. In addition to the direct patient benefits, the meeting helped to facilitate interdepartmental collaboration between two units treating similar sets of patients across the globe, in specialized clinical areas like dysphagia management. PMID- 29404692 TI - Utilising the Intel RealSense Camera for Measuring Health Outcomes in Clinical Research. AB - Applications utilising 3D Camera technologies for the measurement of health outcomes in the health and wellness sector continues to expand. The Intel(r) RealSenseTM is one of the leading 3D depth sensing cameras currently available on the market and aligns itself for use in many applications, including robotics, automation, and medical systems. One of the most prominent areas is the production of interactive solutions for rehabilitation which includes gait analysis and facial tracking. Advancements in depth camera technology has resulted in a noticeable increase in the integration of these technologies into portable platforms, suggesting significant future potential for pervasive in clinic and field based health assessment solutions. This paper reviews the Intel RealSense technology's technical capabilities and discusses its application to clinical research and includes examples where the Intel RealSense camera range has been used for the measurement of health outcomes. This review supports the use of the technology to develop robust, objective movement and mobility-based endpoints to enable accurate tracking of the effects of treatment interventions in clinical trials. PMID- 29404694 TI - Letter to the Editor concerning "Robot-assisted and conventional freehand pedicle screw placement: a systematic review and meta-analysis of randomized controlled trials" by Gao ST et al. (Eur Spine J; 2017. DOI 10.1007/s00586-017-5333-y). PMID- 29404693 TI - Decompression with or without concomitant fusion in lumbar stenosis due to degenerative spondylolisthesis: a systematic review. AB - PURPOSE: The primary objective of this systematic review is to compare the outcome after decompression with and without concomitant instrumented fusion in patients with lumbar stenosis and degenerative spondylolisthesis. Does adding fusion to simple decompression lead to better results? METHODS: PubMed, Embase, CENTRAL, Cochrane, Web of Science, CINAHL and Academic Search Premier were searched. All studies comparing outcome of decompression alone to decompression with concomitant-instrumented fusion in patients suffering from symptomatic lumbar stenosis with degenerative spondylolisthesis were included. Risk of bias was assessed using an adapted version of the Cowley checklist. RESULTS: Eleven studies were included in the analysis involving 3119 patients in total. In the majority of studies, including two RCTs, clinical outcome of both patient groups was comparable regarding most clinical outcome measures. CONCLUSION: Currently there is not enough evidence that adding instrumented fusion to a decompression leads to superior outcomes compared to decompression only in patients with lumbar stenosis and degenerative spondylolisthesis. The most important clinical outcome measures, including the ODI, show comparable results. Therefore, the least invasive and least costly procedure, being decompression alone, is preferred in patients with low-grade spondylolisthesis with predominant leg pain. These slides can be retrieved under Electronic Supplementary Material. PMID- 29404695 TI - Expert's comment concerning Grand Rounds Case entitled "pancreatic fracture: a rare complication following scoliosis surgery" by Melodie Juricic Jr. et al. (Eur Spine J; [2017]: doi: 10.1007/s00586-017-5318-x). PMID- 29404696 TI - Nectar trichome structure of aquatic bladderworts from the section Utricularia (Lentibulariaceae) with observation of flower visitors and pollinators. AB - In Utricularia, the flower spur is a nectary and in this organ, nectar is produced and stored. This study aimed to examine the structure of the nectary trichomes in four Utricularia species (Utricularia vulgaris L., U. australis R.Br., U. bremii Heer and U. foliosa L.) from the generic section Utricularia. We have investigated whether species with different spur morphology had similar spur anatomy and nectary trichome structure. In Utricularia flowers, nectar is produced by spur capitate trichomes (sessile or stalked). Our results showed that regardless of the various spur morphology, trichomes have similar architecture and ultrastructure. Head cells of these trichomes are transfer cells with an eccrine nectar secretion. Examined species differed in the micromorphology of papillae in spurs. The fly Eristalis tenax was found to be a pollinator of U. vulgaris. Small Halictidae bees seem to be pollinators of U. foliosa. PMID- 29404697 TI - Cold, antioxidant and osmotic pre-treatments maintain the structural integrity of meristematic cells and improve plant regeneration in cryopreserved kiwifruit shoot tips. AB - Cryopreservation is a reliable and cost-effective method for the long-term preservation of clonally propagated species. The number of vegetatively propagated species conserved by cryopreservation is increasing through development of vitrification-based methods; droplet vitrification in particular is becoming the preferred method for many species, as it ensures fast freezing and thawing rates. This research investigated if cold, antioxidant and osmotic pre-treatments could maintain the structural integrity of cells, thence aid in developing a droplet vitrification protocol for kiwifruit using Actinidia chinensis var. chinensis 'Hort16A' as a model. Cold acclimation of donor plantlets at 4 degrees C for 2 weeks followed by sucrose pre-culture of shoot tips and supplementation of ascorbic acid (0.4 mM) in all media throughout the procedure registered 40% regeneration after cryopreservation. Transmission electron microscope imaging of meristematic cells confirmed sucrose and ascorbic acid pre-treatment of shoot tips from cold acclimated plantlets following treatment in vitrification solution exhibited severe plasmolysis and some disruption of membrane and vacuoles. In contrast cells without cold acclimation or sucrose and ascorbic acid pre-treatments exhibited minimal change after exposure to vitrification solution. After cryopreservation and recovery, all cells of untreated shoot tips showed rupture of the plasma membrane, loss of cytoplasmic contents and organelle distortions. By comparison, most pre-treated shoot-tip cells from cold acclimated plantlets retained their structural integrity, showing that only those cells that have been dehydrated and plasmolysed can withstand cryopreservation by vitrification. PMID- 29404698 TI - Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice. AB - Cannabinoid-1 (CB1) receptors are broadly distributed in the central and peripheral nervous systems; among others, they are located in the enteric nervous system. In the gastrointestinal (GI) system, they participate in regulation of intestinal motility or ion transport. The aim of our study was to assess the effect of 1,2,3-triazole derivatives (compound 1: 2-[4,5-bis(2,4-dichlorophenyl) 2H-1,2,3-triazol-2-yl]-N-(2-fluorobenzyl)acetamide, compound 2: 2-[4,5-bis(2,4 dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(4-fluorobenzyl)acetamide, compound 3: N benzyl-2-[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2H-1,2,3-triazol-2 yl]acetamide]), characterized in vitro as CB1 antagonists with high CB1 over CB2 selectivity, in the mouse GI tract. The action of compounds 1-3 was assessed in vitro (electrical field stimulated smooth muscle contractility of the mouse ileum and colon) and in vivo (whole GI transit time). Compound 1 decreased ileal (10-6 M) and colonic (10-7-10-6 M) smooth muscles contractility. Moreover, it prolonged whole GI transit. Compound 2 (10-10-10-8 M) slightly increased the amplitude of muscle contractions in the ileum, but at a higher concentration (10-6 M), the amplitude was decreased. Compound 2 reduced colonic contractility but accelerated GI transit. Compound 3 decreased the amplitude of intestinal muscle contractions in the ileum (10-6 M) and colon (10-10-10-6 M). Moreover, it increased the GI transit time in vivo. Triazole derivatives possess easily modifiable structure and interesting pharmacological action in the GI tract; further, alterations may enhance their efficacy at CB receptors and provide low side effect profile in clinical conditions. PMID- 29404700 TI - Abstracts of the 84th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) and the 20th Annual Meeting of the Association of the Clinical Pharmacology Germany (VKliPha) With contribution of the Arbeitsgemeinschaft fur Angewandte Humanpharmakologie e. V. (AGAH). PMID- 29404702 TI - On government-regulated access to diagnostic imaging in neurosurgery. PMID- 29404701 TI - Colour change in a structural ornament is related to individual quality, parasites and mating patterns in the blue tit. AB - Carry-over effects refer to processes that occur in one season and influence fitness in the following. In birds, two costly activities, namely reproduction and moult, are restricted to a small time window, and sometimes overlap. Thus, colour in newly moulted feathers is likely to be affected by the costs of reproduction. Using models of bird vision we investigated male colour change in a free-living population of blue tits (Cyanistes caeruleus) in three sampling occasions: spring 1, winter and spring 2. We related crown, tail, breast and cheek feather colouration after the moult (winter) to the intensity of infections by blood parasites during reproduction (spring 1). In the following spring (spring 2), we explored mating patterns with respect to changes in feather colour (springs 1 vs. 2). Males that were less intensely infected by the malaria parasite Plasmodium while breeding showed purer white cheek feathers in winter, which may indicate higher feather quality. Increased brightness in the white cheek was associated with better body condition during reproduction. In the following season, males with brighter cheeks paired with females that had noticeably brighter cheek patches compared to the male's previous mate. These results suggest that the conditions experienced during reproduction are likely to affect moult and thus feather colouration, at least in the white patch. High quality individuals may allocate resources efficiently during reproduction increasing future reproductive success through variation in mating patterns. Carry-over effects from reproduction might extend not only to the non-breeding phase, but also to the following breeding season. PMID- 29404699 TI - Paraoxonases: metabolic role and pharmacological projection. AB - Atherosclerosis is one of the leading causes of death in Western countries, with high-density lipoproteins (HDL) playing an important protective role due to their ability to inhibit oxidation of low-density lipoproteins (LDL), thus relieving vascular subendothelial damage. One of the proteins constituting HDL particles is paraoxonase-1 (PON1), an enzyme able to hydrolyze aryl esters, lactones, and organophosphates. Other closely related paraoxonases are designated as PON2, which is a protein localized inside many different kinds of cells, and PON3, not only present in HDL but also in mitochondria and endoplasmic reticulum, as well. Given that the amount and the activity of PON1 in human serum are significantly lower in people suffering from cardiovascular diseases, enhancing both parameters might contribute to their treatment and prevention. One of the physiologically interesting substrates for the abovementioned hydrolytic cleavage is homocysteine thiolactone (HTL), an atherothrombotic active form of homocysteine. Although it was therefore postulated that PON1 would participate in preventing the HTL mediated lipid peroxidation, some attention is recently paid to other enzymes, like biphenyl hydrolase-like protein, that seem to more selectively involved in lowering this risk factor. The aim of this paper is to elucidate the role of paraoxonases, especially PON1, by reviewing the latest studies in order to understand both its physiological role and modulation by drugs, nutrients, and plant extracts. PMID- 29404703 TI - The role of computed tomography in the screening of patients presenting with symptoms of an intracranial tumour. AB - BACKGROUND: To improve the quality of care for brain cancer patients, the Danish Ministry of Health has set standards for the diagnosis and treatment. When a patient is suspected of having a malignant tumour involving the brain, it is required that a magnetic resonance imaging of the cerebrum (MRI-C) be obtained within seven calendar days of referral from a primary care provider. This standard has the potential to consume MR imaging time that might otherwise be used for evaluation or treatment monitoring of other patients. This study primarily aims to assess the sensitivity of computed tomography of the brain (CT C) for the detection of intracranial tumour as the initial diagnostic imaging. METHODS: This is a single-center retrospective study of patients referred to the IBCP with brain cancer suspicion. The average follow-up was 37 months. All included patients underwent a CT-C scan and subsequently a MRI-C if deemed necessary. The study population was divided into two groups based on the findings: tumour versus non-tumour. Sensitivity and specificity of the CT-C was calculated. RESULTS: Eight hundred seventeen patients were included. Median age was 55 years and 50% were male. CT-C had a sensitivity of 98.5% and a specificity of 98.4%. The overall mortality rate was 7% in the non-tumour group and 58% in the tumour group over the course of the study period. The tumour group was on average older compared to the non-tumour group (65 years [55-75 years] vs 52 years [38-65 years]) p < .001). The only symptom associated with brain tumour was the presence of a focal deficit (p = .002). CONCLUSION: This study shows that CT C scans are highly sensitive and specific and can be used as the primary screening tool for patients referred with a suspicion for brain cancer. PMID- 29404704 TI - A Visual Decision Support Tool for Appendectomy Care. AB - Appendectomy is the most common abdominal surgical procedure performed in children in the United States. In order to assist care providers in creating treatment plans for the postoperative management of pediatric appendicitis, we have developed a predictive statistical model of outcomes on which we have built a prototype decision aid application. The model, trained on 3724 anonymized care records and evaluated on a separate set of 2205 cases from a tertiary care center, achieves 97.0% specificity, 25.1% true sensitivity, and 58.8% precision. We have also built an interactive decision support tool augmented with simple visualization techniques designed for clinicians to use in the course of making care decisions (e.g., discharge) and in patient/stakeholder communication. Its focus is on end-user ease of use and integration into existing clinician workflows, and is designed to evolve its predictions as more and better data become available. PMID- 29404705 TI - Computer simulations of drug release from a liposome into the bloodstream. AB - I propose two-dimensional simulations of drug release from a liposome into the bloodstream. I perform the fluid-structure coupling, between the particles deformation (the liposome and the red blood cells) and the plasma flow, using the immersed boundary method. I compute both the flow and the drug mass transport using the lattice Boltzmann method. The simulations allow computing the instantaneous amount of the released drug, its distribution and its accumulation in the blood vessel wall. These quantities are sensitive to multiple factors and parameters. Here, I briefly explore the impact of having surrounding red blood cells, which are found to enhance slightly the drug release at large Schmidt numbers. In the limit of extremely large permeability of the particles, the drug transport is mainly affected by the complex flow induced by the interplay between the applied flow and the collective motion of the particles. PMID- 29404706 TI - Notable mixed substrate fermentation by native Kodamaea ohmeri strains isolated from Lagenaria siceraria flowers and ethanol production on paddy straw hydrolysates. AB - BACKGROUND: Bioethanol obtained by fermenting cellulosic fraction of biomass holds promise for blending in petroleum. Cellulose hydrolysis yields glucose while hemicellulose hydrolysis predominantly yields xylose. Economic feasibility of bioethanol depends on complete utilization of biomass carbohydrates and an efficient co-fermenting organism is a prerequisite. While hexose fermentation capability of Saccharomyces cerevisiae is a boon, however, its inability to ferment pentose is a setback. RESULTS: Two xylose fermenting Kodamaea ohmeri strains were isolated from Lagenaria siceraria flowers through enrichment on xylose. They showed 61% glucose fermentation efficiency in fortified medium. Medium engineering with 0.1% yeast extract and peptone, stimulated co fermentation potential of both strains yielding maximum ethanol 0.25 g g-1 on mixed sugars with ~ 50% fermentation efficiency. Strains were tolerant to inhibitors like 5-hydroxymethyl furfural, furfural and acetic acid. Both K. ohmeri strains grew well on biologically pretreated rice straw hydrolysates and produced ethanol. CONCLUSIONS: This is the first report of native Kodamaea sp. exhibiting notable mixed substrate utilization and ethanol fermentation. K. ohmeri strains showed relevant traits like utilizing and co-fermenting mixed sugars, exhibiting excellent growth, inhibitor tolerance, and ethanol production on rice straw hydrolysates. PMID- 29404707 TI - A Comparison of Two Methods for the Preparation Cefquinome-Loaded Gelatin Microspheres for Lung Targeting. AB - PURPOSE: The aim of this study was to prepare CEQ-loaded gelatin microspheres and compare two preparation methods, evaluate targeting to the lungs. METHODS: Gelatin microspheres containing CEQ were prepared by an emulsion cross-linking method (ECLM) and a spray-drying method (SDM) and were characterized in terms of morphology, size, drug-loading coefficient, encapsulation ratio and in vitro release. RESULTS: The microspheres prepared by ECLM gave a drug loading (DL) of 19.4 +/- 2.4% and an entrapment efficiency (EE) of 80.8 +/- 3.2%. The microspheres prepared by SDM resulted in a DL value of 20.8 +/- 2.7% and an EE of 95.3 +/- 3.8%. The average particle size of microspheres was 7-30 MUm by both methods and both preparations sustained CEQ release for 36 h in the target tissue (lungs). The in vitro release profile of the microspheres matched the Korsmeyer Peppas release pattern. In vivo studies identified the lung as the target tissue and the region of maximum CEQ release. Histopathological examination showed a partial lung inflammation that disappeared spontaneously as the microspheres were biodegraded. In general, the formulations were safe. CONCLUSION: The well sustained CEQ release from the microspheres revealed its suitability as a drug delivery vehicle that minimized injury to healthy tissues while achieving the accumulation of therapeutic drug for lung targeting. The intravenous administration of CEQ gelatin microspheres prepared by SDM is of potential value in treating lung diseases in animals. PMID- 29404708 TI - Feasibility of 15O-water PET studies of auditory system activation during general anesthesia in children. AB - BACKGROUND: 15O-Water positron emission tomography (PET) enables functional imaging of the auditory system during stimulation via a promontory electrode or cochlear implant, which is not possible using functional magnetic resonance imaging (fMRI). Although PET has been introduced in this context decades ago, its feasibility when performed during general anesthesia has not yet been explored. However, due to a shift to earlier (and bilateral) auditory implantation, the need to study children during general anesthesia appeared, since they are not able to cooperate during scanning. Therefore, we evaluated retrospectively results of individual SPM (statistical parametric mapping) analysis of 15O-water PET in 17 children studied during general anesthesia and compared them to those in 9 adults studied while awake. Specifically, the influence of scan duration, smoothing filter kernel employed during preprocessing, and cut-off value used for statistical inferences were evaluated. Frequencies, peak heights, and extents of activations in auditory and extra-auditory brain regions (AR and eAR) were registered. RESULTS: It was possible to demonstrate activations in auditory brain regions during general anesthesia; however, the frequency and markedness of positive findings were dependent on some of the abovementioned influence factors. Scan duration (60 vs. 90 s) had no significant influence on peak height of auditory cortex activations. To achieve a similar frequency and extent of AR activations during general anesthesia compared to waking state, a lower cut-off for statistical inferences (p < 0.05 or p < 0.01 vs. p < 0.001) had to be applied. However, this lower cut-off was frequently associated with unexpected, "artificial" activations in eAR. These activations in eAR could be slightly reduced by the use of a stronger smoothing filter kernel during preprocessing of the data (e.g., [30 mm]3). CONCLUSIONS: Our data indicate that it is feasible to detect auditory cortex activations in 15O-water PET during general anesthesia. Combined with the improved signal to noise ratios of modern PET scanners, this suggests reasonable prospects for further evaluation of the method for clinical use in auditory implant users. Adapted parameters for data analysis seem to be helpful to improve the proportion of signals in AR versus eAR. PMID- 29404709 TI - The pattern is the issue: recent advances in adenocarcinoma of the uterine cervix. AB - In this article, we review a novel risk stratification system for endocervical adenocarcinoma, developed by an international consortium of pathologists after reviewing over 350 such tumors. Their analysis culminated in a three-tiered histopathologic system based on morphologic examination of the tumor, independent of clinical features and stage (depth of invasion). It resulted in better determination of patients' tumors and likelihood of lymph node metastasis as well as aggressive behavior. A non-destructive pattern (that in some cases was in the histologic differential diagnosis with adenocarcinoma in situ) had an indolent behavior and was labeled pattern A. The other two patterns had destructive invasion, one only focally (pattern B) while pattern C showed diffuse destructive invasion. This system can help select appropriate treatment modalities avoiding unnecessary complications. We comment on specifics of this system as well as issues in differentiation of the tumor patterns, its clinical utility and recent advances in the molecular arena. PMID- 29404710 TI - The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors. AB - PURPOSE: To measure aggregate and particle formation in tumor necrosis factor alpha (TNF-alpha) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes. METHODS: TNF-alpha inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10 degrees C for 120min/5 degrees C for 60 min) or continuous low storage temperature (-20 degrees C for 96 h) before thawing at 2-8 degrees C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy. RESULTS: Ten out of twenty one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products. CONCLUSION: TNF-alpha inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients' homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range. PMID- 29404711 TI - The Emerging Threat of Antifungal Resistance in Transplant Infectious Diseases. AB - PURPOSE OF REVIEW: The global emergence of antifungal resistance among Candida spp. and Aspergillus spp. will disproportionately affect transplantation recipients, who are prone to invasive fungal disease. RECENT FINDINGS: Invasive candidiasis is increasingly caused by non-albicans Candida species with reduced susceptibility to first-line antifungals. Echinocandin resistance in Candida glabrata is increasing in some settings. Candida auris has rapidly emerged as a global concern due to multidrug resistance and efficient nosocomial spread in healthcare settings. Azole-resistant Aspergillus fumigatus is already an important concern in some European countries and is increasingly reported elsewhere, possibly driven by agricultural use of triazole fungicides. Antifungal resistance is anticipated to expand among these and other common fungal pathogens. Culture-independent detection methods will become more important for rapid diagnosis and to guide empiric therapy. Antifungal stewardship is of critical importance to conserve our limited antifungal armamentarium for transplantation recipients and other vulnerable patients. PMID- 29404712 TI - Brownian motion near an elastic cell membrane: A theoretical study. AB - Elastic confinements are an important component of many biological systems and dictate the transport properties of suspended particles under flow. In this paper, we review the Brownian motion of a particle moving in the vicinity of a living cell whose membrane is endowed with a resistance towards shear and bending. The analytical calculations proceed through the computation of the frequency-dependent mobility functions and the application of the fluctuation dissipation theorem. Elastic interfaces endow the system with memory effects that lead to a long-lived anomalous subdiffusive regime of nearby particles. In the steady limit, the diffusional behavior approaches that near a no-slip hard wall. The analytical predictions are validated and supplemented with boundary-integral simulations. PMID- 29404713 TI - Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. AB - BACKGROUND: OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is desirable. METHODS: The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) Study ( ClinicalTrials.gov , NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (+/-7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline. RESULTS: Enrolled patients (N = 716) were 18-73 years old and most were female (n = 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (n = 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (- 9.2 days and - 10.7 days, respectively, P < 0.0001) was observed. Significant improvements (P < 0.0001) in HIT-6 scores (- 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported >=1 treatment-emergent adverse events; most frequently reported was neck pain (n = 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported. CONCLUSIONS: The COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm. TRIAL REGISTRATION: Trial registration number: NCT01516892 . Name of registry: clinicaltrials.gov . Date of registration: January 20 2012. Date of enrollment of first patient: December 2011. PMID- 29404714 TI - Migraine and the Hippocampus. AB - PURPOSE OF REVIEW: The hippocampus is involved in pain processing, pain-related attention and anxiety, and stress response. The present review compiles the present knowledge of hippocampal volume, activity, and connectivity regarding migraine. RECENT FINDINGS: For hippocampal volume, a longitudinal study discovered decreased volume in newly diagnosed migraine patients after 1 year. Two cross-sectional studies suggested an adaptive increase of volume at low headache frequency and a maladaptive decrease of volume at higher headache frequency. Patients who carried a COMT Val homozygous were found to have larger hippocampi on both sides compared with healthy controls with the same polymorphism. For hippocampal activation, one study showed greater nociceptive activation in patients with migraine compared to healthy controls, with the activity correlated to headache frequency. Another study showed greater deactivation and higher functional connectivity linked to other pain-processing regions in low frequency compared to high-frequency migraineurs. At resting state, intraregional functional connectivity of hippocampus was demonstrated to be lower, and connectivity of the hippocampus with other brain regions was different in patients carrying specific genetic variants. For structural connectivity, two studies suggest a stronger connectivity between the hippocampus and other corticolimbic regions, and the altered connectivities are responsible for migraine-associated allodynia or placebo effect of migraine. Factors including headache frequency, accumulative number of migraine attacks, anxiety score, depression score, and genetic variants are related to hippocampal morphology and functional changes in people with migraine. Future studies should select participants precisely and appropriately control for genetic variants to investigate the complex relationship between the hippocampus and migraine. PMID- 29404715 TI - The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. AB - PURPOSE OF REVIEW: Complex regional pain syndrome (CRPS) is a painful debilitating neurological condition that accounts for approximately 1.2% of adult chronic pain population. Ketamine, an NMDA receptor antagonist, is an anesthetic agent that has been used by some pain specialists for CRPS. There is a growing body of clinical evidence to support the use of ketamine in the treatment of neuropathic pain, especially CRPS. This meta-analysis study was aimed to examine the efficacy of ketamine in the treatment of CRPS. RECENT FINDINGS: A search of Embase, Pubmed, Web of Knowledge, Cochrane, Clinical Trial.gov , and FDA.gov between Jan 1, 1950, and August 1, 2017, was conducted to evaluate ketamine infusion therapy in the treatment of CRPS. We selected randomized clinical trials or cohort studies for meta-analyses. I 2 index estimates were calculated to test for variability and heterogeneity across the included studies. The primary outcome is pain relief. The effect of ketamine treatment for complex regional pain syndrome was assessed by 0-10 scale numerical rating pain score. The secondary outcome is the pain relief event rate, which is defined as the percentage of participants who achieved 30% or higher pain relief in each of the qualified studies. Our meta-analysis results showed that the Ketamine treatment led to a decreased mean of pain score in comparison to the self-controlled baseline (p < 0.000001). However, there is a statistical significance of between study heterogeneity. The immediate pain relief event rate was 69% (95% confidence interval (CI) 53%, 84%). The pain relief event rate at the 1-3 months follow-ups was 58% (95% CI 41%, 75%). The current available studies regarding ketamine infusion for CRPS were reviewed, and meta-analyses were conducted to evaluate the efficacy of ketamine infusion in the treatment of CRPS. Our findings suggested that ketamine infusion can provide clinically effective pain relief in short term for less than 3 months. However, because of the high heterogeneity of the included studies and publication bias, additional random controlled trials and standardized multicenter studies are needed to confirm this conclusion. Furthermore, studies are needed to prove long-term efficacy of ketamine infusion in the treatment of CRPS. PMID- 29404716 TI - Oral health training, knowledge, attitudes and practices of primary care paediatricians: a European survey. AB - : Oral health is an essential component of children's general health. The aim of this study is to evaluate the training, knowledge, attitudes and practices of primary care paediatricians in oral health in Europe. Paediatricians were invited to complete a survey on the web. There was a 54.3% response rate. The oral health education of the responders was received mainly through continuing medical education and practical experience (51%) rather than in medical school or during paediatric residency training (33%). Twenty-four percent of the responders did not know that the first signs of caries were white spots on the surfaces of teeth. Although 98.8% of paediatricians check the oral health status of children, only 52% feel confident enough to identify dental caries. A large proportion of the paediatricians (43%) recommended a first dental visit for children above the age of 3 years and only 7% under 1 year of age. CONCLUSIONS: Paediatricians are familiar with some aspects of the oral health but are not confident in identifying the risk factors. The current postgraduate curriculum in Paediatrics should incorporate training on basic oral healthcare. In addition, continuous educational programmes are needed to keep the knowledge of the paediatrician up to date. What is Known: * Oral health is an essential component of general health that influences the functional, psychological and social dimensions of a child's well-being. * Paediatricians are the leading providers of primary healthcare for children. What is New: * Paediatricians are familiar with some aspects of the oral health of children but are not confident in identifying the risk factors responsible for oral disease. * The current postgraduate curriculum in Paediatrics should incorporate training on basic oral healthcare in children. PMID- 29404717 TI - Pulse oximetry findings in newborns with antenatally diagnosed congenital heart disease. AB - : A retrospective review of admission preductal oxygen saturations of neonates with antenatally diagnosed critical congenital heart disease (CCHD) was performed to investigate the differences in newborn pulse oximetry (Pulsox) by specific CCHD diagnosis. Saturations were recorded at median of < 1 h (range < 1-9 h) after delivery. Data was stratified by CCHD diagnosis and analysed according to the three different admission Pulsox thresholds, <= 90, <= 92 and <= 95%. Of the 276 neonates studied, 208 were clinically well at admission, with no co morbidities, gestation > 34 weeks and birth weight > 1.8 kg. A statistically significant increase in the proportion with low admission saturations was seen using <= 95% saturation threshold (72% (95% CI 66-78)) compared to <= 92% (52% (95% CI 46-59)) and <= 90% (46% (95% CI 39-52)). Sub-group analysis found the proportion of neonates with low saturations varied according to the specific CCHD diagnosis with only 20-42% of neonates with aortic stenosis, coarctation of the aorta and pulmonary stenosis having saturations <= 95%. CONCLUSION: The proportion of neonates with low admission oxygen saturation varied by CCHD diagnosis with those without critically reduced pulmonary blood flow not having low admission saturations, in general, even using the <= 95% threshold which had the highest proportions of abnormal saturations. This data may assist developing Pulsox screening policies. What is Known: * The addition of pulse oximetry (Pulsox) screening to the routine newborn examination increases the sensitivity of CCHD detection. Pulsox screening is also highly specific for CCHD in asymptomatic neonates, with low false-positive rates. * Early diagnosis of CCHD improves patient outcomes in relation to both morbidity and mortality. What is New: * The proportion of affected infants with an abnormal Pulsox result varies by CCHD diagnosis and screening threshold. In our study using the <= 95% threshold gave the highest proportion of neonates with abnormal saturations at admission. * In general, Pulsox yield of abnormal results is low for CCHD diagnoses not associated with critically reduced pulmonary blood flow; however, increasing the Pulsox threshold increased the proportion of infants with an abnormal result. PMID- 29404718 TI - Sociocultural risk factors for developmental delay in children aged 3-60 months: a nested case-control study. AB - : Identifying children at risk for developmental delay (DD) is important for improving prognosis. In this sense, we estimated sociocultural factors that may be associated with DD in early childhood. In our nested case-control study, 95 were included in the case group and 190 were randomly selected to control group. To identify the risk factors, we conducted a backward conditional logistic regression and a final multivariable model was developed. Maternal age of >=35 years, low maternal and paternal education level, low socioeconomic level, consanguineous marriage, and delivery by cesarean section increased the risk of DD. After adjustment, the risk of DD was significantly increased by maternal age >= 35 years (odds ratio (OR) 3.04, 95%CI 1.38-6.70), maternal education level of primary school or lower (OR 14.56, 95%CI 5.40-39.24), consanguineous marriage (OR 3.99, 95%CI 1.69-9.40), and delivery by cesarean section (OR 3.34, 95%CI 1.80 6.18). CONCLUSION: DD can be identified early during well-child visits. In such cases, it is critical for the health of the child and community to screen for possible risk factors, eliminate the causes, and refer families to rehabilitation services. What is known: * The causes of DD may be classified into prenatal, perinatal, and postnatal factors. * Early identification may improve later outcomes of DD. Most studies conducted on this topic have focused on prematurity. What is new: * This study focused on maternal, paternal, and sociocultural factors that may be associated with DD in early childhood in this study that was conducted on a community-based sample. * The risk of DD was increased by maternal age >= 35 years, maternal education level of primary school or lower, consanguineous marriage and delivery by cesarean section. PMID- 29404719 TI - Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants. AB - The aims of this study were to describe hepcidin levels and to assess their associations with iron status and the main variants in the HFE gene in healthy and full-term newborns during the first year of life, as a longitudinal study conducted on 140 infants. Anthropometric and biochemical parameters, hepcidin, hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), mean corpuscular volume (MCV), and C-reactive protein (CRP), were assessed in 6- and 12-month-olds. Infants were genotyped for the three main HFE variants: C282Y, H63D, and S65C. Hepcidin levels increased from 6 to 12 months of age (43.7 +/- 1.5 to 52.0 +/- 1.5 ng/mL; p < 0.001), showing higher levels in infants with better iron status compared to those with iron deficiency (ID) (44.8 +/- 1.5 vs 37.9 +/- 1.3 ng/mL, p < 0.018, and 54.3 +/- 1.5 vs 44.0 +/- 1.4 ng/mL, p < 0.038, in 6- and 12-month-olds, respectively). In multivariate linear regression models, iron status was found to be associated with hepcidin levels in infants with wild type HFE gene (p = 0.046 and p = 0.048 in 6- and 12-month-olds, respectively). However, this association was not found in HFE-alteration-carrying infants. Hepcidin levels increased in healthy infants during the first year of life and were positively associated with iron levels only in infants with wild-type HFE gene, a situation that requires further investigation. PMID- 29404720 TI - Extramedullary involvement of the stomach presenting as multiple white elevations in the initial diagnosis of chronic myeloid leukemia treated with dasatinib. PMID- 29404721 TI - Philadelphia chromosome-negative acute promyelocytic leukemia manifesting after long-term imatinib treatment for chronic myeloid leukemia: a case report and literature review. PMID- 29404722 TI - Crisis Communication in Public Health Emergencies: The Limits of 'Legal Control' and the Risks for Harmful Outcomes in a Digital Age. AB - Communication by public authorities during a crisis situation is an essential and indispensable part of any response to a situation that may threaten both life and property. In the online connected world possibilities for such communication have grown further, in particular with the opportunity that social media presents. As a consequence, communication strategies have become a key plank of responses to crises ranging from epidemics to terrorism to natural disaster. Such strategies involve a range of innovative practices on social media. Whilst being able to bring about positive effects, they can also bring about a range of harmful unintended side effects. This include economic harms produced by incorrect information and a range of social harms that can be fuelled by myths and rumours, worsening negative phenomena such as stigmatisation and discrimination. Given the potential for such harms, one might expect that affected or potentially affected individuals would be able to challenge such measures before courts or administrative tribunals. As this paper demonstrates however this is not the case. More often than not seemingly applicable legal approaches are unlikely to be able to engage such methods. This is often because such measures represent activities that are purely expressive in nature and therefore not capable of imposing any binding legal or corporeal changes on individuals. Whilst some forms of soft law may pose requirements for public officials involved in such activities (e.g. codes of conduct or of professional ethics), they are not likely to offer potentially harmed individuals the chance to to challenge particular communication strategies before courts or legal tribunals. The result is that public authorities largely have a free reign to communicate how they wish and do not have to have to comply with a range of requirements (e.g. relating to form and substantive) content) that would in general apply to most forms of official administrative act. PMID- 29404724 TI - Eigenstrain as a mechanical set-point of cells. AB - Cell contraction regulates how cells sense their mechanical environment. We sought to identify the set-point of cell contraction, also referred to as tensional homeostasis. In this work, bovine aortic endothelial cells (BAECs), cultured on substrates with different stiffness, were characterized using traction force microscopy (TFM). Numerical models were developed to provide insights into the mechanics of cell-substrate interactions. Cell contraction was modeled as eigenstrain which could induce isometric cell contraction without external forces. The predicted traction stresses matched well with TFM measurements. Furthermore, our numerical model provided cell stress and displacement maps for inspecting the fundamental regulating mechanism of cell mechanosensing. We showed that cell spread area, traction force on a substrate, as well as the average stress of a cell were increased in response to a stiffer substrate. However, the cell average strain, which is cell type-specific, was kept at the same level regardless of the substrate stiffness. This indicated that the cell average strain is the tensional homeostasis that each type of cell tries to maintain. Furthermore, cell contraction in terms of eigenstrain was found to be the same for both BAECs and fibroblast cells in different mechanical environments. This implied a potential mechanical set-point across different cell types. Our results suggest that additional measurements of contractility might be useful for monitoring cell mechanosensing as well as dynamic remodeling of the extracellular matrix (ECM). This work could help to advance the understanding of the cell-ECM relationship, leading to better regenerative strategies. PMID- 29404723 TI - Physiological predictors of respiratory and cough assistance needs after extubation. AB - BACKGROUND: Identifying patients at high risk of post-extubation acute respiratory failure requiring respiratory or mechanical cough assistance remains challenging. Here, our primary aim was to evaluate the accuracy of easily collected parameters obtained before or just after extubation in predicting the risk of post-extubation acute respiratory failure requiring, at best, noninvasive mechanical ventilation (NIV) and/or mechanical cough assistance and, at worst, reintubation after extubation. METHODS: We conducted a multicenter prospective, open-label, observational study from April 2012 through April 2015. Patients who passed a weaning test after at least 72 h of endotracheal mechanical ventilation (MV) were included. Just before extubation, spirometry and maximal pressures were measured by a technician. The results were not disclosed to the bedside physicians. Patients were followed until discharge or death. RESULTS: Among 3458 patients admitted to the ICU, 730 received endotracheal MV for longer than 72 h and were then extubated; among these, 130 were included. At inclusion, the 130 patients had mean ICU stay and endotracheal MV durations both equal to 11 +/- 4.2 days. After extubation, 36 patients required curative NIV, 7 both curative NIV and mechanical cough assistance, and 8 only mechanical cough assistance; 6 patients, all of whom first received NIV, required reintubation within 48 h. The group that required NIV after extubation had a significantly higher proportion of patients with chronic respiratory disease (P = 0.015), longer endotracheal MV duration at inclusion, and lower Medical Research Council (MRC) score (P = 0.02, P = 0.01, and P = 0.004, respectively). By multivariate analysis, forced vital capacity (FVC) and peak cough expiratory flow (PCEF) were independently associated with (NIV) and/or mechanical cough assistance and/or reintubation after extubation. Areas under the ROC curves for pre-extubation PCEF and FVC were 0.71 and 0.76, respectively. CONCLUSION: In conclusion, FVC measured before extubation correlates closely with FVC after extubation and may serve as an objective predictor of post-extubation respiratory failure requiring NIV and/or mechanical cough assistance and/or reintubation in heterogeneous populations of medical ICU patients. ClinicalTrials.gov as #NCT01564745. PMID- 29404725 TI - Comparison of the efficacy and tolerability of tocilizumab, sarilumab, and sirukumab in patients with active rheumatoid arthritis: a Bayesian network meta analysis of randomized controlled trials. AB - The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab were assessed in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab in RA patients and an inadequate MTX or TNF inhibitor response. Fourteen RCTs, comprising 9753 patients, met the inclusion criteria. Tocilizumab 8 mg combined with MTX or as monotherapy was the most effective treatment for active RA with an inadequate MTX or TNF antagonist response, followed by sarilumab and sirukumab, regardless of MTX combination. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg + MTX had the highest probability of being the best treatment to achieve the ACR50 response rate, followed by tocilizumab 8 mg, sarilumab 200 mg, sarilumab 200 mg + MTX, sirukumab 100 mg, tocilizumab 4 mg + MTX, sirukumab 100 mg + MTX, sirukumab 50 mg + MTX, sarilumab 150 mg + MTX, adalimumab 40 mg, and sirukumab 50 mg, and placebo + MTX. No significant differences were observed in withdrawals owing to adverse events after treatment with tocilizumab 8 mg + MTX, sirukumab 100 mg + MTX, or sarilumab 200 mg + MTX. In RA patients with an inadequate MTX or anti-TNF therapy response, tocilizumab 8 mg as monotherapy and combined with MTX showed acceptable tolerability and the highest performance based on the ACR50 response rate, followed by sarilumab and sirukumab. PMID- 29404726 TI - The enigmatic neutrophil: what we do not know. AB - The neutrophil appears to be undergoing a renaissance of sorts. While it was for many years thought to be a killing machine brought into tissues to eradicate pathogens, it is now being implicated in many other processes, ranging from acute injury and repair, chronic inflammatory processes, cancer and auto-immunity. Not only is it an effector of the innate immune response, it appears to also potentially contribute to adaptive immunity, implicated in either contributing to the development of specific adaptive immune responses or perhaps even instructing and directing certain adaptive immune responses. With this renewed interest in the neutrophil and its numerous new functions, it is worth examining not what we know but rather what we do not know and what still needs to be more thoroughly examined. In this review, consideration is given to such topics as neutrophil subtypes, neutrophil differentiation, neutrophil as a director of immunity, neutrophil residency and ultimately death of the neutrophil. PMID- 29404727 TI - Combined use of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and platelet rich plasma (PRP) stimulates proliferation and differentiation of myoblasts in vitro: new therapeutic perspectives for skeletal muscle repair/regeneration. AB - Satellite cell-mediated skeletal muscle repair/regeneration is compromised in cases of extended damage. Bone marrow mesenchymal stromal cells (BM-MSCs) hold promise for muscle healing but some criticisms hamper their clinical application, including the need to avoid animal serum contamination for expansion and the scarce survival after transplant. In this context, platelet-rich plasma (PRP) could offer advantages. Here, we compare the effects of PRP or standard culture media on C2C12 myoblast, satellite cell and BM-MSC viability, survival, proliferation and myogenic differentiation and evaluate PRP/BM-MSC combination effects in promoting myogenic differentiation. PRP induced an increase of mitochondrial activity and Ki67 expression comparable or even greater than that elicited by standard media and promoted AKT signaling activation in myoblasts and BM-MSCs and Notch-1 pathway activation in BM-MSCs. It stimulated MyoD, myogenin, alpha-sarcomeric actin and MMP-2 expression in myoblasts and satellite cell activation. Notably, PRP/BM-MSC combination was more effective than PRP alone. We found that BM-MSCs influenced myoblast responses through a paracrine activation of AKT signaling, contributing to shed light on BM-MSC action mechanisms. Our results suggest that PRP represents a good serum substitute for BM-MSC manipulation in vitro and could be beneficial towards transplanted cells in vivo. Moreover, it might influence muscle resident progenitors' fate, thus favoring the endogenous repair/regeneration mechanisms. Finally, within the limitations of an in vitro experimentation, this study provides an experimental background for considering the PRP/BM-MSC combination as a potential therapeutic tool for skeletal muscle damage, combining the beneficial effects of BM-MSCs and PRP on muscle tissue, while potentiating BM-MSC functionality. PMID- 29404728 TI - Earthworm coelomocyte extracellular traps: structural and functional similarities with neutrophil NETs. AB - Invertebrate immunity is associated with natural mechanisms that include cellular and humoral elements, similar to those that play a role in vertebrate innate immune responses. Formation of extracellular traps (ETs) is a newly discovered mechanism to combat pathogens, operating not only in vertebrate leucocytes but also in invertebrate immune cells. The ET components include extracellular DNA (exDNA), antimicrobial proteins and histones. Formation of mammalian ETs depends on enzymes such as neutrophil elastase, myeloperoxidase, the citrullination of histones and protease activity. It was confirmed that coelomocytes immunocompetent cells of the earthworm Eisenia andrei-are also able to release ETs in a protease-dependent manner, dependent or independent of the formation of reactive oxygen species and rearrangement of the cell cytoskeleton. Similar to vertebrate leukocytes (e.g., neutrophil), coelomocytes are responsible for many immune functions like phagocytosis, cytotoxicity and secretion of humoral factors. ETs formed by coelomocyte analogues to neutrophil ETs consist of exDNA, histone H3 and attached to these structures proteins, e.g., heat shock proteins HSP27. The latter fact confirms that mechanisms of ET release are conserved in evolution. The study on Annelida adds this animal group to the list of invertebrates capable of ET release, but most importantly provides insides into innate mechanisms of ET formation in lower animal taxa. PMID- 29404729 TI - Evaluation of 22G fine-needle aspiration (FNA) versus fine-needle biopsy (FNB) for endoscopic ultrasound-guided sampling of pancreatic lesions: a prospective comparison study. AB - BACKGROUND: To compare the diagnostic yield and safety of 22G endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic ultrasound guided fine-needle biopsy (EUS-FNB) in the diagnosis of pancreatic solid lesions. METHODS: Between April 2014 and September 2015, 36 patients with pancreatic solid lesions were included for endoscopic ultrasound test. Patients were randomly divided into two groups: EUS-FNA (n = 18) and EUS-FNB (n = 18). Each nidus was punctured three times (15 ~ 20 insertions for each puncture) with a 22G needle. The core specimens were analyzed, and the diagnostic yields of FNA and FNB were evaluated. RESULTS: The procedure success rate was 100% with no complications. Cytological and histological examinations found that the diagnostic yield of FNB and FNA were both 83.3%. To get a definitive diagnosis, FNB needed fewer punctures than FNA (1.11 vs. 1.83; P < 0.05). CONCLUSIONS: 22G EUS-FNB is a safe and effective way to diagnose pancreatic solid lesions. FNB required a lower number of needle passes to achieve a diagnosis compared with FNA. PMID- 29404730 TI - Laparoscopic total extraperitoneal hernia repair under regional anesthesia: a systematic review of the literature. AB - BACKGROUND: General anesthesia has been used as a standard for laparoscopic inguinal hernia repair including both techniques (Trans-Abdominal Pre-Peritoneal repair and the Total Extra-Peritoneal repair), while regional anesthesia has been occasionally applied in high risk patients where general anesthesia is contraindicated. In case of the total extraperitoneal repair (TEP), several authors have attempted to perform TEP repair under regional anesthesia and reported on the safety and feasibility of this procedure. METHODS: The present review was conducted according to the PRISMA guidelines. Outcome parameters where patients and hernia characteristics, characteristics of anesthesia and surgery procedure, perioperative complications, length of hospital stay, follow up duration. RESULTS: Eight studies on 1287 male and 24 female patients underwent laparoscopic TEP under spinal anesthesia were systematically analyzed. The most common anesthetic agent used, was bupivacaine 0,5%. The conversion rate to general anesthesia, due to anesthesia failure was 0.76% and the rate of conversion to open procedure was 0.2%. The most common intraoperative incidence was hypotension which was successfully managed with the appropriate medical intervention. Seroma was the most common postoperative complication regarding the procedure. The estimation of overall mean length of stay was 1.56 days. CONCLUSIONS: Spinal anesthesia for total extraperitoneal inguinal hernia repair seems safe and feasible. However, more well-designed randomized clinical studies are required to determine the safety as well as the advantages and disadvantages of regional anesthesia in TEP hernia repair in different population groups before this method can be adopted into routine daily clinical practice. PMID- 29404731 TI - Meta-analysis of outcomes of endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for the management of acute cholecystitis. AB - BACKGROUND: Endoscopic ultrasound-guided gallbladder drainage is a novel method of treating acute cholecystitis in patients deemed too high risk for surgery. It involves endoscopic stent placement between the gallbladder and the alimentary tract to internally drain the infection and is an alternative to percutaneous cholecystostomy (PC). This meta-analysis assesses the clinical outcomes of high risk patients undergoing endoscopic drainage with an acute cholecystoenterostomy (ACE) compared with PC in acute cholecystitis. METHODS: A literature search was performed using the preferred reporting items for systematic reviews and meta analyses guidelines. Databases were searched for studies reporting outcomes of patients undergoing ACE or PC. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: A total of 1593 citations were reviewed; five studies comprising 495 patients were ultimately selected for analysis. There were no differences in technical or clinical success rates between the two groups on pooled meta-analysis. ACE had significantly lower post-procedural pain scores (mean difference - 3.0, 95% CI - 2.3 to - 3.6, p < 0.001, on a 10-point pain scale). There were no statistically significant differences in procedure complications between groups. Re intervention rates were significantly higher in the PC group (OR 4.3, 95% CI 2.0 9.3, p < 0.001). CONCLUSION: ACE is a promising alternative to PC in high-risk patients with acute cholecystitis, with equivalent success rates, improved pain scores and lower re-intervention rates, without the morbidities associated with external drainage. PMID- 29404732 TI - Endoloop versus endostapler: what is the best option for appendiceal stump closure in children with complicated appendicitis? Results of a multicentric international survey. AB - BACKGROUND: There is a limited and conflicting evidence about the most appropriate method for appendiceal stump closure during laparoscopic appendectomy (LA). We aimed to compare endoloop (EL) versus endostapler (ES) for stump closure during LA for complicated perforated appendicitis in children. METHODS: We retrospectively reviewed the records of 708 patients (463 boys and 245 girls with an average age of 9.8 years) who underwent LA for complicated appendicitis in 5 international centers of Pediatric Surgery over a 5-years period (January 2011 December 2016). The appendix was perforated with localized peritonitis in 470 cases and diffuse peritonitis in 238 patients. EL was used in 374 cases (G1), whereas ES was adopted in 334 cases (G2). RESULTS: No intra-operative complication occurred in both groups but 5 conversions to open surgery were reported in G1 (1.3%) and 4 in G2 (1.1%) (OR 1.1; 95% CI 0.30-4.19). Use of EL was significantly associated with higher incidence of intra-abdominal abscess (OR 1.36; 95% CI 0.84-2.18), postoperative ileus (OR 3.61; 95% CI 0.76-17.11), and re operations/readmissions (OR 6.46; 95% CI 1.46-28.62) compared to ES. The average cost of supplies for LA was significantly higher in G2 (? 915.60) compared to G1 (? 578.36) (p = 0.0001). The average cost of re-operations/readmissions was significantly higher in G1 (? 4.091,39) compared to G2 (? 2.127,88) (p = 0.0001) (OR 1.72; 95% CI 1.47-2.01). CONCLUSIONS: Our study is the first in the pediatric population to demonstrate that the method used for appendiceal stump closure may influence the outcome of LA in complicated appendicitis. Although ES is more expensive compared to EL, our results demonstrated that appendix stump closure should be performed using ES rather than EL in complicated perforated appendicitis since its use was associated with a lower incidence of postoperative intra-abdominal abscess and postoperative ileus and lower re-operations and readmissions rates and costs. PMID- 29404733 TI - A model for predicting the GEARS score from virtual reality surgical simulator metrics. AB - BACKGROUND: Surgical education relies heavily upon simulation. Assessment tools include robotic simulator assessments and Global Evaluative Assessment of Robotic Skills (GEARS) metrics, which have been validated. Training programs use GEARS for proficiency testing; however, it requires a trained human evaluator. Due to limited time, learners are reliant on surgical simulator feedback to improve their skills. GEARS and simulator scores have been shown to be correlated but in what capacity is unknown. Our goal is to develop a model for predicting GEARS score using simulator metrics. METHODS: Linear and multivariate logistic regressions were used on previously reported data by this group. Subjects performed simple (Ring and Rail 1) and complex (Suture Sponge 1) tasks on simulators, the dV-Trainer (dVT) and the da Vinci Skills Simulator (dVSS). They were scored via simulator metrics and GEARS. RESULTS: A linear model for each simulator and exercise showed a positive linear correlation. Equations were developed for predicting GEARS Total Score from simulator Overall Score. Next, the effects of each individual simulator metric on the GEARS Total Score for each simulator and exercise were examined. On the dVSS, Excessive Instrument Force was significant for Ring and Rail 1 and Instrument Collision was significant for Suture Sponge 1. On the dVT, Time to Complete was significant for both exercises. Once the significant variables were identified, multivariate models were generated. Comparing the predicted GEARS Total Score from the linear model (using only simulator Overall Score) to that using the multivariate model (using the significant variables for each simulator and exercise), the results were similar. CONCLUSIONS: Our results suggest that trainees can use simulator Overall Score to predict GEARS Total Score using our linear regression equations. This can improve the training process for those preparing for high-stakes assessments. PMID- 29404734 TI - Hospital variation in rates of concurrent fundoplication during gastrostomy enteral access procedures. AB - BACKGROUND: This study aimed to determine whether (1) the propensity for concurrent fundoplication during gastrostomy varies among hospitals, and (2) postoperative morbidity differs among institutions performing fundoplication more or less frequently. METHODS: Children who underwent gastrostomy with or without concurrent fundoplication were identified in the American College of Surgeons National Surgical Quality Improvement Program Pediatric (ACS-NSQIP-P). A hierarchical multivariate regression modeled the excess effects that hospitals exerted over propensity for concurrent fundoplication adjusting for preoperative clinical variables. Hospitals were designated as low outliers (significantly lower-adjusted odds of concurrent fundoplication than the average hospital with similar patient mix), average hospitals, and high outliers based on their risk adjusted concurrent fundoplication practice. The postoperative morbidity rates were compared among low-outlier, average, and high-outlier hospitals. RESULTS: Between 2011 and 2013, 3775 children underwent gastrostomy at one of 54 ACS-NSQIP P participating hospitals. The mean hospital concurrent fundoplication rate was 11.7% (range 0-64%). There was no significant difference in unadjusted morbidity rate in children with concurrent fundoplication, 11.0% compared to 9.7% in children without concurrent fundoplication. After controlling for clinical variables, 8 hospitals were identified as low outliers (fundoplication rate of 0.4%) and 16 hospitals were identified as high outliers (fundoplication rate of 34.6%). The average unadjusted morbidity rate among hospitals with low, average, and high odds of concurrent fundoplication were 9.6, 10.6, and 8.4%, respectively. CONCLUSION: Hospitals vary significantly in propensity for concurrent fundoplication during gastrostomy yet postoperative morbidity does not differ significantly among institutions performing fundoplication more or less frequently. PMID- 29404736 TI - Identifying neuropathic pain in patients with multiple sclerosis: a cross sectional multicenter study using highly specific criteria. AB - BACKGROUND: Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. MATERIALS AND METHODS: After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. RESULTS: We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. CONCLUSIONS: Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication. PMID- 29404737 TI - Post-traumatic taste disorders: a case series. AB - Since 1800s there are reports of post-traumatic anosmia, but few studies investigated post-traumatic gustatory deficit and adopted validated evaluation tests. Peripheral and/or central mechanisms may be involved in the genesis of post-traumatic gustatory dysfunction. Beyond a reduction/loss (hypogeusia/ageusia) of gustatory function following a trauma, qualitative taste changes (dysgeusia) may occur. Especially when persistent, taste deficits might be particularly relevant for patient's quality of life and activities of daily life, but knowledge on this topic is limited. Fifty-three consecutive patients with previous head trauma were recruited. Every patient underwent a careful history taking and thorough olfactory and gustatory chemosensory testing by Sniffin'Sticks Extended test, Whole Mouth Test and Taste Strips Test. All patients had olfactory abnormalities (hyposmia: n = 10, functional anosmia: n = 43), while 10 of them (19%) showed taste deficits (dysgeusia: n = 3, dysgeusia with hypogeusia: n = 1, hypogeusia: n = 5, ageusia: n = 1). Here, we report clinical and neuroimaging data and detailed description of four meaningful cases representing central and peripheral injury patterns. Chemosensory evaluation might be useful to explore taste disorder, a still neglected and underestimated sequela of head trauma. PMID- 29404735 TI - Riluzole and other prognostic factors in ALS: a population-based registry study in Italy. AB - OBJECTIVE: In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy. METHODS: A registry for ALS has been collecting all incident cases in ERR since 2009. Detailed clinical data from all patients diagnosed with ALS between 1.1.2009 and 31.12.2014 have been analyzed for this study, with last follow up date set at 31.12.2015. RESULTS: During the 6 years of the study, there were 681 incident cases with a median tracheostomy-free survival of 40 months (95% CI 36 44) from onset and of 26 months (95% CI 24-30) from diagnosis; 573 patients (84.14%) were treated with riluzole, 207 (30.39%) patients underwent gastrostomy, 246 (36.12%) non invasive ventilation, and 103 (15.15%) invasive ventilation. Patients who took treatment for >= 75% of disease duration from diagnosis had a median survival of 29 months compared to 18 months in patients with < 75% treatment duration. In multivariable analysis, factors independently influencing survival were age at onset (HR 1.04, 95% CI 1.02-1.05, p < 0.001), dementia (HR 1.56, 95% CI 1.05-2.32, p = 0.027), degree of diagnostic certainty (HR 0.88, 95% CI 0.78-0.98, p = 0.021), gastrostomy (HR 1.46, 95% CI 1.14-1.88, p = 0.003), NIV (HR 1.43, 95% CI 1.12-1.82, p = 0.004), and weight loss at diagnosis (HR 1.05, 95% CI 1.03-1.07, p < 0.001), diagnostic delay (HR 0.98, 95% CI 0.97-0.99, p = 0.004), and % treatment duration (HR 0.98, 95% CI 0.98-0.99, p < 0.001). CONCLUSIONS: Independently from other prognostic factors, patients who received riluzole for a longer period of time survived longer, but further population based studies are needed to verify if long-tem use of riluzole prolongs survival. PMID- 29404738 TI - Correction to: Effects of multi-component mixtures from sewage treatment plant effluent on common carp (Cyprinus carpio) under fully realistic condition. AB - The original version of this Article unfortunately contained an error. The authors' given and family names were transposed erroneously. It has been corrected now in this Erratum. PMID- 29404739 TI - Multi-scale Homogenization of Caddisfly Metacomminities in Human-modified Landscapes. AB - The multiple scale of stream networks spatial organization reflects the hierarchical arrangement of streams habitats with increasingly levels of complexity from sub-catchments until entire hydrographic basins. Through these multiple spatial scales, local stream habitats form nested subsets of increasingly landscape scale and habitat size with varying contributions of both alpha and beta diversity for the regional diversity. Here, we aimed to test the relative importance of multiple nested hierarchical levels of spatial scales while determining alpha and beta diversity of caddisflies in regions with different levels of landscape degradation in a core Cerrado area in Brazil. We used quantitative environmental variables to test the hypothesis that landscape homogenization affects the contribution of alpha and beta diversity of caddisflies to regional diversity. We found that the contribution of alpha and beta diversity for gamma diversity varied according to landscape degradation. Sub catchments with more intense agriculture had lower diversity at multiple levels, markedly alpha and beta diversities. We have also found that environmental predictors mainly associated with water quality, channel size, and habitat integrity (lower scores indicate stream degradation) were related to community dissimilarity at the catchment scale. For an effective management of the headwater biodiversity of caddisfly, towards the conservation of these catchments, heterogeneous streams with more pristine riparian vegetation found within the river basin need to be preserved in protected areas. Additionally, in the most degraded areas the restoration of riparian vegetation and size increase of protected areas will be needed to accomplish such effort. PMID- 29404740 TI - Early and late pregnancy outcomes in women treated with cold-coagulation versus LLETZ cervical treatment for cervical intraepithelial neoplasia; a retrospective cohort study. AB - PURPOSE: To compare the pregnancy outcomes between women who were treated with cold-coagulation versus large loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia. METHODS: This was a retrospective cohort study of women who had a single cervical treatment between 2010 and 2011. We identified those women who had a singleton pregnancy subsequent to their cervical treatment until September 2017. Women with previous cervical treatment, previous miscarriage or preterm delivery were excluded. RESULTS: We identified 86 women with a pregnancy after LLETZ treatment and 75 women after cold coagulation. Those who had LLETZ when compared to cold coagulation miscarried more often in the first trimester (33.7 vs 17.3%; p = 0.01) than in the second trimester. In women with LLETZ this effect of increased early miscarriage was shown to be prolonged and to persist up to 17 months after excision. Women with LLETZ when compared to cold coagulation had higher spontaneous preterm birth rates (8.9 vs 6.7%) even though the difference was non significant, with the earliest spontaneous preterm birth occurring at 32 weeks and 34 weeks, respectively. CONCLUSION: We found that women who received LLETZ treatment when compared to cold coagulation had higher spontaneous preterm birth rates in their subsequent pregnancy and miscarried more frequently in the first trimester, and demonstrated an increased early miscarriage risk that persisted for more than a year after excisional treatment. PMID- 29404741 TI - The risk of placenta accreta following primary cesarean delivery. AB - OBJECTIVE: To (a) evaluate the risk for placenta accreta following primary cesarean section (CS), in regard to the stage of labor, the cesarean section was taken (elective prelabor vs. unplanned during labor); and (b) investigate whether the association between placenta accreta and maternal and neonatal complications is modified by the type of the primary CS. STUDY DESIGN: In a population-based retrospective cohort study, we included all singleton deliveries occurred in Soroka University Medical Center between 1991 and 2015, of women who had a history of a single CS. The deliveries were divided into three groups according to the delivery stage the primary CS was carried out: 'Unplanned 1' (first stage up to 10 cm), 'Unplanned 2' (second stage-10 cm) and 'Elective' prelabor CS. We assessed the association between the study group and placenta accreta using logistic generalized estimation equation (GEE) models. We additionally assessed maternal and neonatal complications associated with placenta accreta among women who had elective and unplanned CS separately. RESULTS: We included 22,036 deliveries to 13,727 women with a history of one CS, of which 0.9% (n = 207) had placenta accreta in the following pregnancies: 12% (n = 25) in the 'Unplanned 1' group, 7.2% (n = 15) in the ' Unplanned 2' group and 80.8% (n = 167) in the 'elective' group. We found no difference in the risk for subsequent placenta accreta between the groups. In a stratified analysis by the timing of the primary cesarean delivery, the risk for maternal complications, associated with placenta accreta, was more pronounced among women who had an unplanned CS (OR 27.96, P < 0.01) compared to women who had an elective cesarean delivery (OR 13.72, P < 0.01). CONCLUSIONS: The stage in which CS is performed has no influence on the risk for placenta accreta in the following pregnancies, women who had an unplanned CS are in a higher risk for placenta accrete-associated maternal complications. This should be taken into consideration while counselling women about their risk while considering trial of labor after cesarean section. PMID- 29404742 TI - Reliability and validity of the German version of the Maternal-Fetal Attachment Scale. AB - OBJECTIVES: In understanding early disturbances in the mother-child relationship, maternal-fetal attachment has become an important concept. To date no study has investigated the reliability and validity of the German version of the Maternal Fetal Attachment Scale (MFAS). The present study aimed to close this gap. METHODS: Questionnaires were completed in a sample of 324 women [third trimester (T1), first week postpartum (T2), and 4 months postpartum (T3)]. In addition to the MFAS (T1), the following measures were assessed: the questionnaire of partnership (T1), the postpartum bonding questionnaire (T2), the Edinburgh Postnatal Depression Scale (T1-T3), the State Trait Anxiety Inventory (T1-T3), and the pregnancy related anxiety questionnaire (T1-T3). Factor structure was analyzed using a principal component analysis (PCA) with varimax rotation. Internal and convergent validities were calculated. RESULTS: In contrast to the original version with five subscales, PCA yielded a three-factor solution, consisting of the three independent dimensions "anticipation", "empathy", and "caring", explaining 34.9% of the variance together. Good internal reliabilities were found for the total MFAS scale. Maternal-fetal attachment showed a significant negative correlation with postpartum bonding impairment. While no correlations were found with depression, general anxiety and pregnancy-related anxiety during pregnancy, maternal-fetal attachment was significantly related to aspects of partnership quality. In the postpartum period, maternal attachment showed a strong negative correlation with maternal anxiety. CONCLUSIONS: Our results suggest that the German version of the MFAS is a reliable and valid questionnaire to measure the emotional relationship of the mother to the unborn child during pregnancy. PMID- 29404743 TI - No evidence of obstetrical adverse events after hyperimmune globulin application for primary cytomegalovirus infection in pregnancy: experience from a single centre. AB - PURPOSE: To determine the frequency of obstetrical adverse events and clinical outcome in infants following antenatal hyperimmune globulin (HIG) treatment for primary cytomegalovirus (CMV) infection in pregnancy. METHODS: Data from 50 women including three twin pregnancies were retrospectively evaluated. Primary infection was defined by seroconversion or the presence of CMV-specific IgM and low IgG avidity. All women received two or more infusions of HIG (200 U/kg). Congenital CMV (cCMV) infection was diagnosed by detection of CMV in amniotic fluid and/or neonatal urine. We compared gestational age (GA) at birth, head circumference (HC) and birth weight (BW) of infants in our study cohort with those of live-born infants delivered in our clinic between 2015 and 2016. RESULTS: Median gestational age at time of maternal CMV diagnosis was 13 weeks. One-hundred-forty-one maternal HIG doses were given. No HIG-related severe adverse reactions occurred. Preterm birth rate was 4.2% (2/47) in singleton pregnancies. None of the neonates had birth weight or head circumference < 3rd percentile (< 3P) for gestational age. There was no statistically significant difference regarding GA, BW and HC between our study cohort and the total population of live-born infants. The frequency of CMV-related sequelae in infants with cCMV infection was 10.5% (2/19) (one with bilateral hearing loss and one with mild motoric delay), both cases following first trimester maternal infection. CONCLUSION: Antenatal HIG treatment was well tolerated and not associated with prematurity or decreased birth weight. HIG application might have a favorable effect on the clinical course of congenital CMV infection. PMID- 29404744 TI - Preoperative elevated platelet count and thrombocytosis in gynecologic malignancies. PMID- 29404745 TI - In silico analysis of the EF-hand proteins in the genome of Giardia intestinalis assembly A. AB - Giardia intestinalis is a parasite that inhabits the small intestine of humans and other mammals, causing a disease that can manifest itself with acute diarrhea. This parasite is an early divergent eukaryote with a compact genome and a life cycle composed of two distinct cell types: the trophozoite, the replicative form, and the cyst, the infectious form. Signal transduction pathways implicated in differentiation processes of G. intestinalis are largely unknown. Calcium, considered an essential messenger in cell signaling, has been shown to regulate a myriad of key cell processes including metabolism, motility, and exocytosis, among other important functions, through calcium-binding proteins (CaBPs). The most important and largest family of CaBPs is the EF-hand protein family. To investigate the nature of calcium signaling pathways present in this protozoan, an in silico analysis of the genome to identify genes encoding EF-hand proteins was undertaken. Twenty-eight sequences containing EF-hand domains were found; most of which have only a pair of domains, and half of the sequences were divergent or unique to Giardia. In addition, the transcription pattern for eight genes encoding EF-hand proteins was assessed during encystation. It was found that all the genes were differentially transcribed suggesting a different function in this process. The in silico results suggest that in G. intestinalis, calcium is involved in the regulation of protein phosphorylation through kinases and phosphatases. PMID- 29404746 TI - Full mitochondrial and nuclear genome comparison confirms that Onchocerca sp. "Siisa" is Onchocerca ochengi. AB - Onchocerca ochengi is a nodule-forming filarial nematode parasite of cattle. It is the closest known relative of the human parasite Onchocerca volvulus, with which it shares the black fly vector Simulium damnosum. Onchocerca sp. "Siisa" was described in black flies and in cattle and, based on limited mitochondrial sequence information, appeared to be about equally phylogenetically distant from O. ochengi and O. volvulus. Based on molecular genetic markers and apparent interbreeding, we later proposed that O. sp. "Siisa" belongs to the species O. ochengi. However, we did not demonstrate directly that the hybrids were fertile, and we were still unable to resolve the phylogenetic relationship of O. ochengi, O. sp. "Siisa," and O. volvulus, leaving some concerns with the conclusion mentioned above. Here, we present fully assembled, manually curated mitochondrial genomes of O. ochengi and O. sp. "Siisa," and we compare multiple individuals of these two taxa with respect to their whole mitochondrial and nuclear genomes. Based on the mitochondrial genomes, O. ochengi and O. sp. "Siisa" are phylogenetically much closer to each other than to O. volvulus. The differences between them are well within the range of what is expected for within-species variation. The nuclear genome comparison provided no indication of genetic separation of O. ochengi and O. sp. "Siisa." From this, in combination with the earlier literature, we conclude that O. ochengi and O. sp. "Siisa" should be considered one species. PMID- 29404747 TI - Does Dientamoeba fragilis cause diarrhea? A systematic review. AB - It remains controversial whether Dientamoeba fragilis is a commensal parasite or a pathogen. The objective of this systematic review was to establish the strength of the evidence that Dientamoeba fragilis would cause diarrhea. A search was performed for studies that reported either the association between D. fragilis detection in stools and diarrhea or diarrhea outcomes with D. fragilis therapy or challenge. Data from seven studies of specific populations reported that 22% had D. fragilis in stools of which only 23% had diarrhea. Eleven studies of stool samples submitted to laboratories reported that 4.3% of individuals had D. fragilis of which 54% had diarrhea. Twelve studies reported that D. fragilis was detected from 1.6% of individuals with diarrhea and 9.6% of diarrheal stools. Five studies analyzed the prevalence of D. fragilis in individuals with and without diarrhea; the two with a statistically significant difference between groups had discordant results. The only cohort study with an appropriate control group reported diarrhea in a higher proportion of children with D. fragilis than in controls. No D. fragilis treatment studies included diarrhea as an outcome. There were only two challenge studies involving one person each. In conclusion, the evidence that D. fragilis would cause diarrhea or that treatment would hasten diarrhea resolution is inconclusive. PMID- 29404748 TI - Phlebotomus langeroni Nitzulescu (Diptera, Psychodidae) a new vector for Leishmania infantum in Europe. AB - Burrows of the wild rabbit, Oryctolagus cuniculus, a lagomorph that has been recently suggested as a Leishmania infantum reservoir, constitute an unspoilt biotope in phlebotomine studies in Europe. We hypothesize that Phlebotomus langeroni, a proven vector of L. infantum in North Africa, is associated with rabbits and may have been overlooked in Europe. Sandfly captures were carried out with CDC light traps in an L. infantum endemic area of southern Spain with a high density of lagomorphs and a large numbers of burrows. The stable, permanent, and highly abundant presence of P. langeroni was assessed. After morphological identification, this sandfly species was characterized by comparing it with P. perniciosus and other P. langeroni populations from North Africa through molecular techniques. P. langeroni had not been found in southern Spain to date, despite being a highly investigated area, except for this particular biotope. Its activity period turned out to begin in mid-July, ending in late October, accounting for a maximum activity during this month. This study shows that P. langeroni is associated with the existence of rabbit burrows and has been overlooked in Europe. L. infantum DNA was found in almost half of the female specimens (47.6%) captured inside a biotope where wild rabbits are infected as well. PMID- 29404749 TI - Protective vaccination alters gene expression of the liver of Balb/c mice in response to early prepatent blood-stage malaria of Plasmodium chabaudi. AB - Current knowledge about liver responses to blood-stage malaria and their modulation by vaccination is still unclear. This study investigated effects of protective vaccination on liver gene and lincRNA expression of Balb/c mice at early prepatency of Plasmodium chabaudi blood-stage malaria. When a blood-stage vaccine was used to induce > 80% survival of otherwise lethal malaria, significant differences (p < 0.01) were detectable in global liver gene expression between vaccination-protected (potentially surviving) and non protected non-vaccinated mice on day 1 p.i.. In the livers of protected mice, gene expression microarrays identified 224 and 419 genes, whose expression was up and downregulated by > 3-fold, respectively. There were 24 genes upregulated by > 10-fold, including 10 IFN-inducible genes encompassing GTPases Irgm1, 2, and 3, and guanylate-binding protein Gbp11, the IL-1 decoy receptors Il1f9 and Il1ra1, the Il6 gene, and the gene for facilitated glucose transportation. Moreover, the IL-18 decoy receptor gene Il18bp, Gzmb, the genes Lif and Osmr encoding proteins of the IL-6 family, and the taurine transporter gene Slc6a6 were expressed > 3 fold in vaccinated mice. The genes Gbp10, 6, 4 were expressed by > 50% in vaccination-protected than in non-vaccinated mice. In addition, 43 lincRNA species were up- and 36 downregulated. Our data suggested novel regulatory elements of potential anti-malaria activity activated by protective vaccination in the liver, evidenced in response to early prepatent infections in vaccination protected mice of otherwise lethal blood-stage malaria of P. chabaudi. PMID- 29404750 TI - Acute Limb Ischemia Secondary to Native Artery Occlusion: Results of a Contemporary Case Series. AB - BACKGROUND: The treatment of acute limb ischemia (ALI) has barely changed over the last years. However, the progressive implementation of anticoagulants, antiplatelet agents or statins within the population might have modified the profile and prognosis of patients suffering an ALI. The aim of this study was to evaluate the current results of the management of ALI secondary to a native artery occlusion. METHODS: Retrospective study of 220 consecutive patients (mean age 78 years; 49% male) was conducted between 2007 and 2015. ALI secondary to trauma or grafts/stents occlusions were excluded. Statistical analysis was performed with logistic regression. RESULTS: A total of 141 cases (64.1%) were attributed to embolism and 79 (35.9%) to acute arterial thrombosis. Peripheral neuro-ischemic impairment occurred in 135 patients (61.4%), being severe in 42 (19.1%). ALI treatment included anticoagulation (n = 27; 12.3%), regional fibrinolysis (n = 2; 1%), embolectomy/thrombectomy (n = 129; 58.6%), angioplasty/stenting (n = 8; 3.6%), bypass (n = 47; 21.3%) or direct major limb amputation (n = 7; 3.2%). Limb salvage and survival rates at 30/90 days were 95%/95% and 82.3%/74.1%, respectively. Independent risk factors for major amputation were diabetes, severe neuro-ischemic impairment, acute arterial thrombosis and treatment delay >1 day after vascular consultation. In addition, age, chronic peripheral arterial disease, any neuro-ischemic impairment and a hospitalization for any other reason simultaneous to the ALI were independently associated with mortality. CONCLUSIONS: Regardless of excellent limb salvage rates, patients currently suffering from an ALI are, when compared to previous studies, older than before and with an increased rate of mortality. Risk factors do not appear to be modifiable once the ALI appears so prevention strategies should be aimed to avoid the episode. PMID- 29404751 TI - Commentary on Burke TF et al. "Safety and Feasibility of a Ketamine Package to Support Emergency and Essential Surgery in Kenya when No Anesthetist is Available: An Analysis of 1216 Consecutive Operative Procedures". PMID- 29404752 TI - Welcome New Associate Editor Anthony Kim to the World Journal of Surgery. PMID- 29404754 TI - Data Improvement Through Simplification: Implications for Low-Resource Settings. AB - BACKGROUND: The focus of many data collection efforts centers on creation of more granular data. The assumption is that more complex data are better able to predict outcomes. We hypothesized that data are often needlessly complex. We sought to demonstrate this concept by examination of the American Society of Anesthesiologists (ASA) scoring system. METHODS: First, we created every possible consecutive two, three and four category combinations of the current five category ASA score. This resulted in 14 combinations of simplified ASA. We compared the predictive ability of these simplified scores for postoperative outcomes for 2.3 million patients in the NSQIP database. Individual model performance was assessed by comparing receiver operator characteristic (ROC) curves for each model with the standard ASA. RESULTS: Two of our 4-category models and one of our 3-category models had ability to predict all outcomes equivalent to standard ASA. These results held for all outcomes and on all subgroups tested. The performance of the three best performing simplified ASA scores were also equivalent to the standard ASA score in the univariate analysis and when included in a multivariate model. CONCLUSIONS: It is assumed that the most granular data and use of the largest number of variables for risk-adjusted predictions will increase accuracy. This complexity is often at the expense of utility. Using the single best predictor in surgical outcomes research, we have shown this is not the case. In this example, we demonstrate that one can simplify ASA into a 3-category variable without losing any ability to predict outcomes. PMID- 29404753 TI - Defining Early Recurrence of Hilar Cholangiocarcinoma After Curative-intent Surgery: A Multi-institutional Study from the US Extrahepatic Biliary Malignancy Consortium. AB - BACKGROUND: Time to tumor recurrence may be associated with outcomes following resection of hepatobiliary cancers. The objective of the current study was to investigate risk factors and prognosis among patients with early versus late recurrence of hilar cholangiocarcinoma (HCCA) after curative-intent resection. METHODS: A total of 225 patients who underwent curative-intent resection for HCCA were identified from 10 academic centers in the USA. Data on clinicopathologic characteristics, pre-, intra-, and postoperative details and overall survival (OS) were analyzed. The slope of the curves identified by linear regression was used to categorize recurrences as early versus late. RESULTS: With a median follow-up of 18.0 months, 99 (44.0%) patients experienced a tumor recurrence. According to the slope of the curves identified by linear regression, the functions of the two straight lines were y = -0.465x + 16.99 and y = -0.12x + 7.16. The intercept value of the two lines was 28.5 months, and therefore, 30 months (2.5 years) was defined as the cutoff to differentiate early from late recurrence. Among 99 patients who experienced recurrence, the majority (n = 80, 80.8%) occurred within the first 2.5 years (early recurrence), while 19.2% of recurrences occurred beyond 2.5 years (late recurrence). Early recurrence was more likely present as distant disease (75.1% vs. 31.6%, p = 0.001) and was associated with a worse OS (Median OS, early 21.5 vs. late 50.4 months, p < 0.001). On multivariable analysis, poor tumor differentiation (HR 10.3, p = 0.021), microvascular invasion (HR 3.3, p = 0.037), perineural invasion (HR 3.9, p = 0.029), lymph node metastases (HR 5.0, p = 0.004), and microscopic positive margin (HR 3.5, p = 0.046) were independent risk factors associated with early recurrence. CONCLUSIONS: Early recurrence of HCCA after curative resection was common (~35.6%). Early recurrence was strongly associated with aggressive tumor characteristics, increased risk of distant metastatic recurrence and a worse long term survival. PMID- 29404755 TI - A Novel Indocyanine Green Fluorescence-Guided Video-Assisted Technique for Sentinel Node Biopsy in Breast Cancer. AB - BACKGROUND: The equipment to detect indocyanine green (ICG) fluorescence for sentinel lymph node (SLN) biopsy in breast cancer is not widely accessible nor optimal. The fluorescence appears as a poorly defined white shine on a black background, and dimmed lighting is required. The aim of this study was to assess the feasibility, accuracy and healthcare costs of a novel approach for SLN biopsy by a video-assisted ICG-guided technique. METHODS: The technique for detecting SLN was radioisotope (RI) in 194 cases, video-assisted ICG-guided in 70 cases and a combined method in 71 cases. In the video-assisted ICG group, a full HD laparoscopic system equipped with xenon lamps was used for a laser-free detection of ICG within a colored and magnified high-resolution image. RESULTS: Detection of ICG fluorescence using a laparoscope with a near-infrared filter provided a highly defined and colored image during SLN biopsy. SLN was identified in 100% of patients in all groups. Multiple SLNs were identified in 0.5% of RI patients, in 12.9% of ICG patients and in 14.1% of ICG + RI patients (p < 0.0001). In ICG + RI group, 95.1% of lymph nodes were radioactive and 92.7% were fluorescent. Operative times and healthcare costs were equivalent between groups. CONCLUSIONS: Video-assisted ICG-guided technique is a feasible and surgeon-friendly method for SLN biopsy, with equivalent efficacy compared to RI, providing an accurate staging of the axilla. PMID- 29404756 TI - Why I Quit Pre-Exposure Prophylaxis (PrEP)? A Mixed-Method Study Exploring Reasons for PrEP Discontinuation and Potential Re-initiation Among Gay and Bisexual Men. AB - Literature concerning pre-exposure prophylaxis (PrEP) among gay and bisexual identifying men (GBM) has explored facilitators and barriers to uptake and adherence. Far less reported are the reasons why GBM discontinue PrEP use. A national sample of 1071 GBM completed surveys about PrEP use and discontinuation. Participants who were still taking PrEP the 24-month follow up were compared to those that had stopped. Eighteen percent (n = 31) of GBM who reported ever using PrEP discontinued use. Younger (AOR = 0.96; 95% CI 0.92-1.00), and unemployed (AOR = 4.58; 95% CI 1.43-14.70) GBM were more likely to discontinue PrEP than their counterparts. Those that discontinued provided details on why via a free response question. The most common reasons for discontinuation were lower perceived HIV risk (50%) and cost/insurance (30%). Reasons for potential re initiation included higher-risk sexual activities and changes to structural related barriers. More research is needed to inform interventions on how GBM can continue taking PrEP during changes to employment that effect insurance coverage and cost. PMID- 29404758 TI - On publishing in Mycorrhiza. PMID- 29404757 TI - Motivated Reasoning and HIV Risk? Views on Relationships, Trust, and Risk from Young Women in Cape Town, South Africa, and Implications for Oral PrEP. AB - In high prevalence environments relationship characteristics are likely to be associated with HIV risk, yet evidence indicates general underestimation of risk. Furthermore uncertainty about partner's risk may challenge PrEP demand among young African women. We conducted quantitative and qualitative interviews with women before and after HIV discussions with partners, to explore how partner's behavior affected risk perceptions and interest in PrEP. Twenty-three women were interviewed once; twelve had a follow-up interview after speaking to their partners. Fourteen women were willing to have their partner contacted; yet two men participated. Several themes related to relationships and risk were identified. These highlighted that young women's romantic feelings and expectations influenced their perceptions of risk within their relationships, consistent with the concept of motivated reasoning. Findings emphasize challenges in using risk to promote HIV prevention among young women. Framing PrEP in a positive empowering way that avoids linking it to relationship risk may ultimately encourage greater uptake. PMID- 29404759 TI - Shifts in renin-angiotensin system components, angiogenesis, and oxidative stress related protein expression in the lamina cribrosa region of streptozotocin induced diabetic mice. AB - PURPOSE: This study aimed to analyse shifts in renin-angiotensin system (RAS) components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa (LC) region in streptozotocin (STZ)-induced diabetic mice. METHODS: Six months after diabetes induction, the retinal vessels of male C57BL/6 J mice were observed by colour photography, fundus fluorescein angiography (FFA), and immunofluorescent staining following incubation with CD31. Immunofluorescence for glial fibrillary acidic protein (GFAP), alpha-smooth muscle actin (alpha SMA),and NG2 was also performed. Angiotensin-converting enzyme 1 (ACE1), angiotensin II type I receptor (AT1R), renin, hypoxia-inducible factor 1-alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and haeme oxygenase 1 (HO-1) expression levels were confirmed by immunohistochemical and western blotting analyses. RESULTS: Compared with control mice, diabetic mice had significantly higher blood glucose concentrations (p < 0.001) and significantly lower body weights (p < 0.001). Colour photography and FFA did not reveal any vessel abnormalities in the diabetic mice; however, immunostaining of whole-mount retinas revealed an increased number of retinal vessels. Furthermore, histopathological staining showed significant reduction in the whole retinal thickness. GFAP expression was slightly higher, whereas fewer NG2+ pericytes were observed in diabetic mice than in control mice. ACE1, AT1R, renin, HIF-1alpha, VEGF, VEGFR2, and HO-1 expression were up-regulated in the LC of the STZ-induced diabetic mice. CONCLUSIONS: Collectively, ACE 1, AT1R, HIF-1alpha, VEGF, VEGFR2, and HO-1 activation in the LC region in diabetic mice may be involved in diabetes via the RAS and induction of angiogenesis and oxidative stress. PMID- 29404760 TI - Colour discrimination ellipses in choroideremia. AB - PURPOSE: The purpose of this study was to characterise alterations in colour discrimination in a cohort of patients with choroideremia prior to gene therapy, using a test previously validated for use in patients with retinal dystrophies. METHODS: We tested 20 eyes of 10 patients with a diagnosis of choroideremia and an age-matched cohort of 10 eyes of 10 normal controls using the "Cambridge Colour Test" (CCT), in which subjects are required to distinguish the gap in a C presented in one of 4 orientations in a Stilling-type array. Colour discrimination was probed along eight axes in the CIE L*u*v* colour space, and the resulting data were plotted in the CIE 1976 chromaticity diagram and fitted with least-squares ellipses. Subsequently, we estimated the achromatic area for each subject by calculating the area of the resultant discrimination ellipse and calculated sensitivity thresholds along relevant colour confusion axes. RESULTS: Colour discrimination-as quantified by log10 of the ellipse area expressed in square 1/1000th2 units in CIE 1976-was 2.26 (range 1.82 to 2.67) for normal subjects and 3.85 (range 2.35 to 5.41) for choroideremia patients. There was a statistically significant correlation between both achromatic area and red-green colour discrimination at the CCT and BCVA, and to a lesser degree between blue colour discrimination at the CCT and BCVA. The majority of ellipses in choroideremia were aligned close to the tritan axis, and loss of sensitivity was significantly larger in the tritan direction than in the red-green. CONCLUSIONS: The majority of our patients demonstrated greater loss in tritan discrimination than in red-green colour discrimination using the CCT. There was a significant correlation between achromatic area and BCVA. In keeping with our current understanding of the machinery of colour vision, there was a significant correlation between BCVA and colour discrimination thresholds, which was stronger for red-green colour discrimination, than for tritan colour discrimination. We propose that this and similar tests of colour discrimination may prove to be suitable tools for assessing functional outcomes in gene therapy trials for choroideremia. PMID- 29404761 TI - [Off to on: treatment of systemic immunological diseases with biologics]. PMID- 29404765 TI - The identification and characterization of novel rat hepatitis E virus strains in Bali and Sumbawa, Indonesia. AB - All three genetic groups of ratHEV have been found in Indonesia, suggesting the presence of additional variants of ratHEV in unexamined areas of Indonesia. A total of 242 wild rats were captured in Bali and Sumbawa, Indonesia, during 2014 2016. Among them, 4.1% were seropositive for anti-ratHEV IgG and two (0.8%) had detectable ratHEV RNA: ratESUMBAWA-140L and ratEBali2016D-047L, sharing 84.9 85.4% and 86.9-92.1% nucleotide identity with the reported G2 strains, respectively. The provisional criteria supported the notion that the ratEBali2016D-047L and ratESUMBAWA-140L strains were novel G2 variants. These results suggested the spatial distribution of further divergent ratHEV strains in Indonesia. PMID- 29404766 TI - Pre-treatment magnetic resonance-based texture features as potential imaging biomarkers for predicting event free survival in anal cancer treated by chemoradiotherapy. AB - AIM: To assess regular MRI findings and tumour texture features on pre-CRT imaging as potential predictive factors of event-free survival (disease progression or death) after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) without metastasis. MATERIALS AND METHODS: We retrospectively included 28 patients treated by CRT for pathologically proven ASCC with a pre-CRT MRI. Texture analysis was carried out with axial T2W images by delineating a 3D region of interest around the entire tumour volume. First-order analysis by quantification of the histogram was carried out. Second-order statistical texture features were derived from the calculation of the grey-level co-occurrence matrix using a distance of 1 (d1), 2 (d2) and 5 (d5) pixels. Prognostic factors were assessed by Cox regression and performance of the model by the Harrell C-index. RESULTS: Eight tumour progressions led to six tumour-specific deaths. After adjusting for age, gender and tumour grade, skewness (HR = 0.131, 95% CI = 0 0.447, p = 0.005) and cluster shade_d1 (HR = 0.601, 95% CI = 0-0.861, p = 0.027) were associated with event occurrence. The corresponding Harrell C-indices were 0.846, 95% CI = 0.697-0.993, and 0.851, 95% CI = 0.708-0.994. CONCLUSION: ASCC MR texture analysis provides prognostic factors of event occurrence and requires additional studies to assess its potential in an "individual dose" strategy for ASCC chemoradiation therapy. KEY POINTS: * MR texture features help to identify tumours with high progression risk. * Texture feature maps help to identify intra tumoral heterogeneity. * Texture features are a better prognostic factor than regular MR findings. PMID- 29404768 TI - Intravoxel incoherent motion magnetic resonance imaging for differentiating metastatic and non-metastatic lymph nodes in pancreatic ductal adenocarcinoma. AB - OBJECTIVES: To evaluate the diagnostic potential of intravoxel incoherent motion (IVIM) DWI for differentiating metastatic and non-metastatic lymph node stations (LNS) in pancreatic ductal adenocarcinoma (PDAC). METHODS: 59 LNS histologically diagnosed following surgical resection from 15 patients were included. IVIM DWI with 12 b values was added to the standard MRI protocol. Evaluation of parameters was performed pre-operatively and included the apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*) and perfusion fraction (f). Diagnostic performance of ADC, D, D* and f for differentiating between metastatic and non-metastatic LNS was evaluated using ROC analysis. RESULTS: Metastatic LNS had significantly lower D, D*, f and ADC values than the non-metastatic LNS (p< 0.01). The best diagnostic performance was found in D, with an area under the ROC curve of 0.979, while the area under the ROC curve values of D*, f and ADC were 0.867, 0.855 and 0.940, respectively. The optimal cut-off values for distinguishing metastatic and non-metastatic lymph nodes were D = 1.180 * 10-3 mm2/s; D* = 14.750 * 10-3 mm2/s, f = 20.65 %, and ADC = 1.390 * 10-3 mm2/s. CONCLUSION: IVIM DWI is useful for differentiating between metastatic and non-metastatic LNS in PDAC. KEY POINTS: * IVIM DWI is feasible for diagnosing LN metastasis in PDAC. * Metastatic LNS has lower D, D*, f, ADC values than non-metastatic LNS. * D-value from IVIM model has best diagnostic performance, followed by ADC value. * D* has the lowest AUC value. PMID- 29404767 TI - Shear-wave elastography can evaluate annulus fibrosus alteration in adolescent scoliosis. AB - OBJECTIVES: In vitro studies showed that annulus fibrosus lose its integrity in idiopathic scoliosis. Shear-wave ultrasound elastography can be used for non invasive measurement of shear-wave speed (SWS) in vivo in the annulus fibrosus, a parameter related to its mechanical properties. The main aim was to assess SWS in lumbar annulus fibrosus of scoliotic adolescents and compare it to healthy subjects. METHODS: SWS was measured in 180 lumbar IVDs (L3L4, L4L5, L5S1) of 30 healthy adolescents (13 +/- 1.9 years old) and 30 adolescent idiopathic scoliosis patients (13 +/- 2 years old, Cobb angle: 28.8 degrees +/- 10.4 degrees ). SWS was compared between the scoliosis and healthy control groups. RESULTS: In healthy subjects, average SWS (all disc levels pooled) was 3.0 +/- 0.3 m/s, whereas in scoliotic patients it was significantly higher at 3.5 +/- 0.3 m/s (p = 0.0004; Mann-Whitney test). Differences were also significant at all disc levels. No difference was observed between males and females. No correlation was found with age, weight and height. CONCLUSION: Non-invasive shear-wave ultrasound is a novel method of assessment to quantitative alteration of annulus fibrosus. These preliminary results are promising for considering shear-wave elastography as a biomechanical marker for assessment of idiopathic scoliosis. KEY POINTS: * Adolescent idiopathic scoliosis may have an altered lumbar annulus fibrosus. * Shear-wave elastography can quantify lumbar annulus fibrosus mechanical properties. * Shear-wave speed was higher in scoliotic annulus than in healthy subjects. * Elastography showed potential as a biomechanical marker for characterizing disc alteration. PMID- 29404769 TI - Genotype prediction of ATRX mutation in lower-grade gliomas using an MRI radiomics signature. AB - OBJECTIVES: To predict ATRX mutation status in patients with lower-grade gliomas using radiomic analysis. METHODS: Cancer Genome Atlas (TCGA) patients with lower grade gliomas were randomly allocated into training (n = 63) and validation (n = 32) sets. An independent external-validation set (n = 91) was built based on the Chinese Genome Atlas (CGGA) database. After feature extraction, an ATRX-related signature was constructed. Subsequently, the radiomic signature was combined with a support vector machine to predict ATRX mutation status in training, validation and external-validation sets. Predictive performance was assessed by receiver operating characteristic curve analysis. Correlations between the selected features were also evaluated. RESULTS: Nine radiomic features were screened as an ATRX-associated radiomic signature of lower-grade gliomas based on the LASSO regression model. All nine radiomic features were texture-associated (e.g. sum average and variance). The predictive efficiencies measured by the area under the curve were 94.0 %, 92.5 % and 72.5 % in the training, validation and external validation sets, respectively. The overall correlations between the nine radiomic features were low in both TCGA and CGGA databases. CONCLUSIONS: Using radiomic analysis, we achieved efficient prediction of ATRX genotype in lower-grade gliomas, and our model was effective in two independent databases. KEY POINTS: * ATRX in lower-grade gliomas could be predicted using radiomic analysis. * The LASSO regression algorithm and SVM performed well in radiomic analysis. * Nine radiomic features were screened as an ATRX-predictive radiomic signature. * The machine-learning model for ATRX-prediction was validated by an independent database. PMID- 29404771 TI - Liver fibrosis: stretched exponential model outperforms mono-exponential and bi exponential models of diffusion-weighted MRI. AB - OBJECTIVES: To compare the ability of diffusion-weighted imaging (DWI) parameters acquired from three different models for the diagnosis of hepatic fibrosis (HF). METHODS: Ninety-five patients underwent DWI using nine b values at 3 T magnetic resonance. The hepatic apparent diffusion coefficient (ADC) from a mono exponential model, the true diffusion coefficient (D t ), pseudo-diffusion coefficient (D p ) and perfusion fraction (f) from a biexponential model, and the distributed diffusion coefficient (DDC) and intravoxel heterogeneity index (alpha) from a stretched exponential model were compared with the pathological HF stage. For the stretched exponential model, parameters were also obtained using a dataset of six b values (DDC#, alpha#). The diagnostic performances of the parameters for HF staging were evaluated with Obuchowski measures and receiver operating characteristics (ROC) analysis. The measurement variability of DWI parameters was evaluated using the coefficient of variation (CoV). RESULTS: Diagnostic accuracy for HF staging was highest for DDC# (Obuchowski measures, 0.770 +/- 0.03), and it was significantly higher than that of ADC (0.597 +/- 0.05, p < 0.001), D t (0.575 +/- 0.05, p < 0.001) and f (0.669 +/- 0.04, p = 0.035). The parameters from stretched exponential DWI and D p showed higher areas under the ROC curve (AUCs) for determining significant fibrosis (>=F2) and cirrhosis (F = 4) than other parameters. However, D p showed significantly higher measurement variability (CoV, 74.6%) than DDC# (16.1%, p < 0.001) and alpha# (15.1%, p < 0.001). CONCLUSIONS: Stretched exponential DWI is a promising method for HF staging with good diagnostic performance and fewer b-value acquisitions, allowing shorter acquisition time. KEY POINTS: * Stretched exponential DWI provides a precise and accurate model for HF staging. * Stretched exponential DWI parameters are more reliable than D p from bi-exponential DWI model * Acquisition of six b values is sufficient to obtain accurate DDC and alpha. PMID- 29404770 TI - High-pitch low-voltage CT coronary artery calcium scoring with tin filtration: accuracy and radiation dose reduction. AB - OBJECTIVES: To investigate diagnostic accuracy and radiation dose of high-pitch CT coronary artery calcium scoring (CACS) with tin filtration (Sn100kVp) versus standard 120kVp high-pitch acquisition. METHODS: 78 patients (58% male, 61.5+/ 9.1 years) were prospectively enrolled. Subjects underwent clinical 120kVp high pitch CACS using third-generation dual-source CT followed by additional high pitch Sn100kVp acquisition. Agatston scores, calcium volume scores, Agatston score categories, percentile-based risk categorization and radiation metrics were compared. RESULTS: 61/78 patients showed coronary calcifications. Median Agatston scores were 34.9 [0.7-197.1] and 41.7 [0.7-207.2] and calcium volume scores were 34.1 [0.7-218.0] for Sn100kVp and 35.7 [1.1-221.0] for 120kVp acquisitions, respectively (both p<0.0001). Bland-Altman analysis revealed underestimated Agatston scores and calcium volume scores with Sn100kVp versus 120kVp acquisitions (mean difference: 16.4 and 11.5). However, Agatston score categories and percentile-based risk categories showed excellent agreement (K=0.98 and K=0.99). Image noise was 25.8+/-4.4HU and 16.6+/-2.9HU in Sn100kVp and 120kVp scans, respectively (p<0.0001). Dose-length-product was 9.9+/-4.8mGy*cm and 40.9+/-14.4mGy*cm with Sn100kVp and 120kVp scans, respectively (p<0.0001). This resulted in significant effective radiation dose reduction (0.13+/-0.07mSv vs. 0.57+/-0.2mSv, p<0.0001) for Sn100kVp acquisitions. CONCLUSION: CACS using high pitch low-voltage tin-filtered acquisitions demonstrates excellent agreement in Agatston score and percentile-based cardiac risk categorization with standard 120kVp high-pitch acquisitions. Furthermore, radiation dose was significantly reduced by 78% while maintaining accurate risk prediction. KEY POINTS: * Coronary artery calcium scoring with tin filtration reduces radiation dose by 78%. * There is excellent correlation between high-pitch Sn100kVp and standard 120kVp acquisitions. * Excellent agreement regarding Agatston score categories and percentile-based risk categorization was achieved. * No cardiac risk reclassifications were observed using Sn100kVp coronary artery calcium scoring. PMID- 29404772 TI - Imaging prediction of nonalcoholic steatohepatitis using computed tomography texture analysis. AB - OBJECTIVES: To determine if texture analysis of non-contrast-enhanced CT (NECT) images is able to predict nonalcoholic steatohepatitis (NASH). METHODS: NECT images from 88 patients who underwent a liver biopsy for the diagnosis of suspected NASH were assessed and texture feature parameters were obtained without and with filtration. The patient population was divided into a predictive learning dataset and a validation dataset, and further divided into groups according to the prediction of liver fibrosis as assessed by hyaluronic acid levels. The reference standard was the histological result of a liver biopsy. A predictive model for NASH was developed using parameters derived from the learning dataset that demonstrated areas under the receiver operating characteristic curve (AUC) of >0.65. The resulting model was then applied to the validation dataset. RESULTS: In patients without suspected fibrosis, the texture parameter mean without filter and skewness with a 2-mm filter were selected for the NASH prediction model. The AUC of the predictive model for the validation dataset was 0.94 and the accuracy was 94%. In patients with suspicion of fibrosis, the mean without filtration and kurtosis with a 4-mm filter were selected for the NASH prediction model. The AUC for the validation dataset was 0.60 and the accuracy was 42%. CONCLUSIONS: In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH. KEY POINTS: * In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH. * The mean without filtration and skewness with a 2-mm filter were modest predictors of NASH in patients without suspicion of liver fibrosis. * Hepatic fibrosis masks the characteristic texture features of NASH. PMID- 29404773 TI - Dual-energy CT: a phantom comparison of different platforms for abdominal imaging. AB - OBJECTIVES: Evaluation of imaging performance across dual-energy CT (DECT) platforms, including dual-layer CT (DLCT), rapid-kVp-switching CT (KVSCT) and dual-source CT (DSCT). METHODS: A semi-anthropomorphic abdomen phantom was imaged on these DECT systems. Scans were repeated three times for CTDIvol levels of 10 mGy, 20 mGy, 30 mGy and different fat-simulating extension rings. Over the available range of virtual-monoenergetic images (VMI), noise as well as quantitative accuracy of hounsfield units (HU) and iodine concentrations were evaluated. RESULTS: For all VMI levels, HU values could be determined with high accuracy compared to theoretical values. For KVSCT and DSCT, a noise increase was observed towards lower VMI levels. A patient-size dependent increase in the uncertainty of quantitative iodine concentrations is observed for all platforms. For a medium patient size the iodine concentration root-mean-square deviation at 20 mGy is 0.17 mg/ml (DLCT), 0.30 mg/ml (KVSCT) and 0.77mg/ml (DSCT). CONCLUSION: Noticeable performance differences are observed between investigated DECT systems. Iodine concentrations and VMI HUs are accurately determined across all DECT systems. KVSCT and DLCT deliver slightly more accurate iodine concentration values than DSCT for investigated scenarios. In DLCT, low-noise and high-image contrast at low VMI levels may help to increase diagnostic information in abdominal CT. KEY POINTS: * Current dual-energy CT platforms provide accurate, reliable quantitative information. * Dual-energy CT cross-platform evaluation revealed noticeable performance differences between different systems. * Dual layer CT offers constant noise levels over the complete energy range. PMID- 29404774 TI - Are pancreatic IPMN volumes measured on MRI images more reproducible than diameters? An assessment in a large single-institution cohort. AB - OBJECTIVES: To assess reproducibility of volume and diameter measurement of intraductal papillary mucinous neoplasms (IPMNs) on MRI images. METHODS: Three readers measured the diameters and volumes of 164 IPMNs on axial T2-weighted images and coronal thin-slice navigator heavily T2-weighted images using manual and semiautomatic techniques. Interobserver reproducibility and variability were assessed. RESULTS: Interobserver intraclass correlation coefficients (ICCs) for the largest diameter measured using manual and semiautomatic techniques were 0.979 and 0.909 in the axial plane, and 0.969 and 0.961 in the coronal plane, respectively. Interobserver ICCs for the volume measurements were 0.973 and 0.970 in axial and coronal planes, respectively. The highest intraobserver reproducibility was noted for coronal manual measurements (ICC 0.981) followed by axial manual measurements (ICC 0.969). For the diameter measurements, Bland Altman analysis revealed the lowest interobserver variability for manual axial measurements with an average range of 95% limits of agreement (LOA) of 0.68 cm. Axial and coronal volume measurements showed similar 95% LOA ranges (8.9 cm3 and 9.4 cm3, respectively). CONCLUSIONS: Volume and diameter measurements on axial and coronal images show good interobserver and intraobserver reproducibility. The single largest diameter measured manually on axial images showed the highest reproducibility and lowest variability. The 95% LOA may help define reproducible size changes in these lesions using measurements from different readers. KEY POINTS: * MRI measurements by different radiologists can be used for IPMN follow up. * Both diameter and volume measurements demonstrate excellent interobserver and intraobserver reproducibility. * Manual axial measurements show the highest interobserver reproducibility in determining size. * Axial and coronal volume measurements show similar limits of agreement. * Manual axial measurements show the lowest variability in agreement range. PMID- 29404776 TI - Magnitude of cyantraniliprole residues in tomato following open field application: pre-harvest interval determination and risk assessment. AB - Cyantraniliprole is an anthranilic diamide insecticide, belonging to the ryanoid class, with a broad range of applications against several pests. In the presented work, a reliable analytical technique employing high-performance liquid chromatography coupled with photodiode array detector (HPLC-DAD) for analyzing cyantraniliprole residues in tomato was developed. The method was then applied to field-incurred tomato samples collected after applications under open field conditions. The latter aimed to ensure the safe application of cyantraniliprole to tomato and contribute the derived residue data to the risk assessment under field conditions. Sample preparation involved a single step extraction with acetonitrile and sodium chloride for partitioning. The extract was purified utilizing florisil as cleanup reagent. The developed method was further evaluated by comparing the analytical results with those obtained using the QuEChERS technique. The novel method outbalanced QuEChERS regarding matrix interferences in the analysis, while it met all guideline criteria. Hence, it showed excellent linearity over the assayed concentration and yielded satisfactory recovery rate in the range of 88.9 to 96.5%. The half-life of degradation of cyantraniliprole was determined at 2.6 days. Based on the Codex MRL, the pre-harvest interval (PHI) for cyantraniliprole on tomato was 3 days, after treatment at the recommended dose. To our knowledge, the present work provides the first record on PHI determination of cyantraniliprole in tomato under open field conditions in Egypt and the broad Mediterranean region. PMID- 29404775 TI - Endovascular interventional modalities for haemorrhage control in abnormal placental implantation deliveries: a systematic review and meta-analysis. AB - OBJECTIVES: To examine the evidence regarding the effectiveness and safety of endovascular interventional modalities for haemorrhage control in abnormal placentation deliveries. METHODS: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to July 2017. Blood loss volume was regarded as the primary endpoint. Other important results are described. Random and fixed effects models were used for the meta analysis. RESULTS: Of 385 studies identified, 69 (1,811 patients, mean age 32.9 years, range 23-39 years) were included. Mean gestational age at delivery was 35.1 weeks (range 27-38 weeks). Of 1,395 patients who underwent endovascular intervention, 587 (42%) had placenta accreta, 254 (18%) placenta increta and 313 (22%) placenta percreta. Prophylactic balloon occlusion of the internal iliac arteries (PBOIIA) was performed in 470 patients (33.6%), of the abdominal aorta (PBOAA) in 460 patients (33%), of the uterine artery (PBOUA) in 181 patients (13%), and of the common iliac arteries (PBOCIA) in 21 patients (1.5%). Primary embolization of the UA was performed in 246 patients (18%), of the pelvic collateral arteries in 12 patients (0.9%), and of the anterior division of the IIA in 5 patients (0.3%). Follow-up ranged from 0.5 to 42 months. Endovascular intervention was associated with less blood loss than no endovascular intervention (p < 0.001) with the lowest blood loss volume in patients who underwent PBOAA (p < 0.001). PBOAA was associated with a lower rate of hysterectomy (p = 0.030). Endovascular intervention did not result in increases in operative time or hospital stay. CONCLUSIONS: Endovascular intervention is effective in controlling haemorrhage in abnormal placentation deliveries. PBOAA was associated with a lower rate of hysterectomy and less blood loss than other modalities. KEY POINTS: * Endovascular intervention in abnormal placentation deliveries is effective in reducing blood loss. * Endovascular intervention did not result in longer operative time or hospital stay. * Prophylactic balloon occlusion of the abdominal aorta is superior to other modalities. PMID- 29404777 TI - Verapamil Inhibits Ser202/Thr205 Phosphorylation of Tau by Blocking TXNIP/ROS/p38 MAPK Pathway. AB - PURPOSE: Oxidative stress is a hallmark of Alzheimer's Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects. METHODS: We analyzed TXNIP expression and tau phosphorylation in the hippocampus of the 5xFAD mice in the absence and presence of a pharmacological treatment with Verapamil. Using SH-SY5Y cells, we verified the causative role of TXNIP in promoting tau phosphorylation at Ser202/Thr205, by inducing TXNIP silencing. RESULTS: The amyloid beta peptide (Abeta1-42) leads to TXNIP over-expression in SH-SY5Y cells, which in turns induces oxidative stress and the activation of p38 MAPK, promoting tau phosphorylation at Ser202/Thr205. Silencing of TXNIP abolishes Abeta1-42-induced tau phosphorylation, p38 MAPK phosphorylation and subsequent tau phosphorylation. Verapamil prevents TXNIP expression as well as p38 MAPK and tau phosphorylation at Ser202/Thr205 in the hippocampus of the 5xFAD mice. CONCLUSIONS: Our study unveil a novel pathway involved in AD progression that is inhibited by Verapamil, shedding new light on the understanding of the therapeutic potential of Verapamil in AD. PMID- 29404779 TI - Physician turnover effect for in-hospital cardiopulmonary resuscitation: a 10 year experience in a tertiary academic hospital. AB - PURPOSE: Controversy exists as to whether the physician turnover affects patient outcome in academic hospitals. In-hospital cardiopulmonary resuscitation (CPR) is an important indicator of in-hospital mortality. This study aimed to investigate whether the physician turnover is associated with the in-hospital CPR rate. METHODS: This retrospective cohort study was conducted at a single center; all in hospital CPR cases among in-patients from 1 January 2007 to 31 December 2016 were analyzed. The turnover period was defined as the changeover of the trainee workforce in March, May, and November. The primary outcome was any variation in the monthly in-hospital CPR events (per 1000 admissions). The secondary outcomes were return of spontaneous circulation (ROSC), CPR in intensive care unit (ICU), monthly in-hospital deaths per 1000 admissions, and average length of hospital stay. RESULTS: A total of 2182 in-hospital CPR cases were included in the analysis. Monthly in-hospital CPR rates were greater during the turnover period when compared to the non-turnover period (4.66 +/- 1.02 vs. 4.18 +/- 1.56, P = 0.027). There was no significant difference in ROSC rate, CPR in ICU rate, monthly in-hospital deaths per 1000 admissions, or average length of hospital stay between the two periods. CONCLUSION: Our findings indicate that physician turnover may be associated with in-hospital CPR rate. However, physician turnover was not associated with ROSC rate, rate of CPR in the ICU, in-hospital death, or length of hospital stay. PMID- 29404778 TI - Waste anesthetic gas exposure and strategies for solution. AB - As inhaled anesthetics are widely used, medical staff have inevitably suffered from exposure to anesthetic waste gases (WAGs). Whether chronic exposure to WAGs has an impact on the health of medical staff has long been a common concern, but conclusions are not consistent. Many measures and equipment have been proposed to reduce the concentration of WAGs as far as possible. This review aims to dissect the current exposure to WAGs and its influence on medical staff in the workplace and the environment, and summarize strategies to reduce WAGs. PMID- 29404780 TI - Pharmaceutical interventions on prescribed medicines in community pharmacies: focus on patient-reported problems. AB - Background While dispensing prescribed medicines, pharmacists frequently encounter technical and clinical problems that require a pharmaceutical intervention. Objective To describe the pharmaceutical interventions performed by community pharmacists while dispensing prescribed medicines and to investigate, in-depth, the patient-reported problems with the prescribed medicines that triggered pharmaceutical interventions. Method Twenty-one pharmacists each collected 30 prescriptions requiring a pharmaceutical intervention on five selected days within a five-week period. All pharmaceutical interventions were classified using the PharmDISC system. Results Of all 430 pharmaceutical interventions, 286 (66.5%) pharmaceutical interventions had a clinical cause and 144 (33.5%) pharmaceutical interventions a technical cause. Pharmacists mainly intervened to substitute a drug (n = 132, 30.7%), adjust a dose (n = 57, 13.3%), and clarify/complete information (n = 48, 11.2%). A total of 243 (56.5%) pharmaceutical interventions resulted in a change of the prescription. The implementation rate of pharmaceutical interventions reached 88.6%. Altogether, patient-reported problems triggered 99 (23.0%) pharmaceutical interventions. In 15 (15.2%) of these PIs, contact with the prescriber was necessary, whereas 61 (84.8%) PIs only involved the pharmacist. Conclusion While dispensing prescribed medicines, pharmacists performed individualised pharmaceutical interventions to solve or prevent drug-related problems. That almost a quarter of all pharmaceutical interventions triggered by patient-reported problems highlights the importance of direct patient-pharmacist interaction when dispensing prescribed medicines. PMID- 29404781 TI - Effect of nutrient management on soil organic carbon sequestration, fertility, and productivity under rice-wheat cropping system in semi-reclaimed sodic soils of North India. AB - The ever shrinking agricultural land availability and the swelling demand of food for the growing population fetch our attention towards utilizing partially reclaimed sodic soils for cultivation. In the present investigation, we compared six treatments, like control (T1), existing farmers' practice (T2), balanced inorganic fertilization (T3) and combined application of green gram (Vigna radiate) with inorganic NPK (T4), green manure (Sesbania aculeate) with inorganic NPK (T5), and farmyard manure with inorganic NPK (T6), to study the influence of nutrient management on soil organic carbon sequestration and soil fertility under long-term rice-wheat cropping system along with its productivity in gypsum amended partially reclaimed sodic soils of semi-arid sub-tropical Indian climate. On an average, combined application of organics along with fertilizer NPK (T4, T5, and T6) decreased soil pH, ESP, and BD by 3.5, 13.0, and 6.7% than FP (T2) and 3.7, 12.5, and 6.7%, than balanced inorganic fertilizer application (T3), respectively, in surface (0-20 cm). These treatments (T4, T5, and T6) also increased 14.1% N and 19.5% P availability in soil over the usual farmers' practice (FP) with an additional saving of 44.4 and 27.3% fertilizer N and P, respectively. Long-term (6 years) incorporation of organics (T4, T5, and T6) sequestered 1.5 and 2.0 times higher soil organic carbon as compared to the balanced inorganic (T3) and FP (T2) treatments, respectively. The allocation of soil organic carbon into active and passive pools determines its relative susceptibility towards oxidation. The lower active to passive ratio (1.63) in FYM treated plots along with its potentiality of higher soil organic carbon (SOC) sequestration compared to the initial stock proved its acceptability for long term sustenance under intensive cropping even in partially reclaimed sodic soils. Among all the treatments, T4 yielded the maximum from second year onwards. Moreover, after 6 years of continuous cultivation, the observed EWY (2011-2012) was found to be 41.9 and 33.1% higher in T4 as compared to FP (T2) and T3, respectively. Thus, for maintaining higher yield coupled with improved SOC sequestration and nutrient availability, T4 followed by T6 treatments would be the suitable options for long-term intensive rice-wheat system in partially reclaimed sodic soils of northern India. PMID- 29404782 TI - An alternative method to implement contact angle boundary condition and its application in hybrid lattice-Boltzmann finite-difference simulations of two phase flows with immersed surfaces. AB - We propose an alternative method to implement the contact angle boundary condition on a solid wall and apply it in hybrid lattice-Boltzmann finite difference simulations of two-phase flows with immersed surfaces in which the flow equations are solved by the lattice-Boltzmann method and the interface equations are solved by the finite-difference method. Using the hyperbolic tangent profile of the order parameter across an interface in phase-field theory, we were able to obtain its unknown value at a ghost point from the information at only one point in the fluid domain. This is in contrast with existing approaches relying on interpolations involving several points. The special feature allows it to be more easily implemented on immersed surfaces cutting through the grid lines. It was properly incorporated into the framework of the hybrid lattice Boltzmann finite-difference simulation, and applied successfully for several problems with different levels of complexity. First, the equilibrium shapes of a droplet on a sphere with different contact angles and radii were studied under cylindrical geometry and a good agreement with theoretical predictions was found. Preliminary studies on a three-dimensional droplet spreading on a sphere were also performed and the results agreed well with the corresponding axisymmetric results. Second, the spreading of a two-dimensional drop on an embedded inclined wall with a given contact angle was investigated and the results matched those on a flat wall at the domain boundary under the same condition. Third, capillary filling in a cylindrical tube was studied and the speed of the interface in the tube was found to follow Washburn's law. Fourth, a droplet impacting on a sphere was investigated and several different outcomes were captured depending on the Reynolds number, the viscosity ratio, and the wettability and radius of the sphere. Finally, the proposed method was shown to be capable of studying even more complicated problems involving the interaction between a droplet and multiple objects of different sizes and contact angles. PMID- 29404783 TI - Neuropathology and biochemistry of early onset familial Alzheimer's disease caused by presenilin-1 missense mutation Thr116Asn. AB - The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances. Neuropathological assessment revealed widespread beta-amyloid (Thal phase 5) and tau (Braak stage 6) pathology. Abundant deposition of diffuse and cored plaques was distributed in cortical and subcortical areas, as well as in the cerebellum, while cotton wool plaques were observed mainly in the occipital cortex. Cerebral amyloid angiopathy was present throughout the brain. In the neocortex, tau pathology, especially neuropil threads, was more abundant in the frontal and occipital cortex and in the hippocampus. Proteomic analyses revealed that the pattern of sarkosyl insoluble tau was similar to the one seen in sporadic AD. No alpha-synuclein or TDP-43 pathology was found either in cortical nor in subcortical areas. Here, we present the first comprehensive neuropathological and biochemical study of early onset FAD with a missense mutation Thr116Asn in the presenilin 1 gene. In contrast to other PS1-linked AD patients, the present subject developed cotton wool plaques which were not associated with spastic paraparesis. PMID- 29404784 TI - Stimulation of Cysteine-Coated CdSe/ZnS Quantum Dot Luminescence by meso-Tetrakis (p-sulfonato-phenyl) Porphyrin. AB - Interaction between porphyrins and quantum dots (QD) via energy and/or charge transfer is usually accompanied by reduction of the QD luminescence intensity and lifetime. However, for CdSe/ZnS-Cys QD water solutions, kept at 276 K during 3 months (aged QD), the significant increase in the luminescence intensity at the addition of meso-tetrakis (p-sulfonato-phenyl) porphyrin (TPPS4) has been observed in this study. Aggregation of QD during the storage provokes reduction in the quantum yield and lifetime of their luminescence. Using steady-state and time-resolved fluorescence techniques, we demonstrated that TPPS4 stimulated disaggregation of aged CdSe/ZnS-Cys QD in aqueous solutions, increasing the quantum yield of their luminescence, which finally reached that of the fresh prepared QD. Disaggregation takes place due to increase in electrostatic repulsion between QD at their binding with negatively charged porphyrin molecules. Binding of just four porphyrin molecules per single QD was sufficient for total QD disaggregation. The analysis of QD luminescence decay curves demonstrated that disaggregation stronger affected the luminescence related with the electron-hole annihilation in the QD shell. The obtained results demonstrate the way to repair aged QD by adding of some molecules or ions to the solutions, stimulating QD disaggregation and restoring their luminescence characteristics, which could be important for QD biomedical applications, such as bioimaging and fluorescence diagnostics. On the other hand, the disaggregation is important for QD applications in biology and medicine since it reduces the size of the particles facilitating their internalization into living cells across the cell membrane. PMID- 29404785 TI - Implementing ABPM into Clinical Practice. AB - PURPOSE OF REVIEW: To review the data supporting the use of ambulatory blood pressure monitoring (ABPM), and to provide practical guidance for practitioners who are establishing an ambulatory monitoring service. RECENT FINDINGS: ABPM results more accurately reflect the risk of cardiovascular events than do office measurements of blood pressure. Moreover, many patients with high blood pressure in the office have normal blood pressure on ABPM-a pattern known as white coat hypertension-and have a prognosis similar to individuals who are normotensive in both settings. For these reasons, ABPM is recommended by the US Preventive Services Task Force to confirm the diagnosis of hypertension in patients with high office blood pressure before medical therapy is initiated. Similarly, the 2017 ACC/AHA High Blood Pressure Clinical Practice Guideline advocates the use of out-of-office blood pressure measurements to confirm hypertension and evaluate the efficacy of blood pressure-lowering medications. In addition to white coat hypertension, blood pressure phenotypes that are associated with increased cardiovascular risk and that can be recognized by ABPM include masked hypertension-characterized by normal office blood pressure but high values on ABPM-and high nocturnal blood pressure. In this review, best practices for starting a clinical ABPM service, performing an ABPM monitoring session, and interpreting and reporting ABPM data are described. ABPM is a valuable adjunct to careful office blood pressure measurement in diagnosing hypertension and in guiding antihypertensive therapy. Following recommended best practices can facilitate implementation of ABPM into clinical practice. PMID- 29404786 TI - Multiple scattering of an ultrasonic shock wave in bubbly media. AB - This experimental study deals with the propagation of an ultrasonic shock wave in a random heterogeneous medium, constituted of identical 75MUm radius bubbles, trapped in a yield-stress fluid. The fundamental frequency of the incident wave (in the MHz range) was much larger than the resonance frequency of bubbles (38kHz). A well-expanded coda, resulting from the multiple scattering of the incident shock wave through the heterogeneous medium, was experimentally measured in transmission. Despite the significant amplitude of the shock wave (90kPa), no sign of nonlinear response of the bubbles was detected. Both the coherent and incoherent fields were successfully described by linear theories. Using a shock wave presents the advantage of characterizing the medium over a large frequency range (1.5-15MHz). PMID- 29404787 TI - Complex Regional Pain Syndrome, Current Concepts and Treatment Options. AB - PURPOSE OF REVIEW: Complex regional pain syndrome (CRPS) refers to a chronic pain condition that is characterized by progressively worsening spontaneous regional pain without dermatomal distribution. The symptomatology includes pain out of proportion in time and severity to the inciting event. The purpose of this review is to present the most current information concerning epidemiology, diagnosis, pathophysiology, and therapy for CRPS. RECENT FINDINGS: In recent years, discovery of pathophysiologic mechanisms of CRPS has led to significant strides in the understanding of the disease process. Continued elucidation of the underlying pathophysiological mechanisms will allow for the development of more targeted and effective evidence-based therapy protocols. Further large clinical trials are needed to investigate mechanisms and treatment of the disorder. PMID- 29404789 TI - Proceedings of Reanimation 2018, the French Intensive Care Society International Congress. PMID- 29404788 TI - Surgical Treatment of Valvular Heart Disease: Overview of Mechanical and Tissue Prostheses, Advantages, Disadvantages, and Implications for Clinical Use. AB - Valvular heart disease (VHD) affects a large number of patients annually. From a surgical standpoint, there are two primary options for valve replacement: mechanical or bioprosthetic. While there are clear advantages and disadvantages to either option, and recent literature does challenge some of the prior dictums of valve choice, a handful of absolutes remain true. Mechanical valves provide superior durability and freedom from re-operation when compared to their bioprosthetic counterparts, at the expense of bleeding or thrombotic complications associated with the need for lifelong oral anticoagulation. Unless a clear contraindication to oral anticoagulation exists, we recommend implanting mechanical valves for patients less than 60 years old and those who are older than 65 but maintained on anticoagulation for reasons other than their valvular disease. Bioprosthetic valves should be placed in patients who are greater than 65 years old or those patients who have a postoperative life expectancy of less than 10 years. Valve choice in patients between the ages of 60 to 70 is not dictated by guidelines and is less clear, with patient preference playing a larger role than their age range. PMID- 29404790 TI - MicroRNA Expression Levels and Histopathological Features of Colorectal Cancer. AB - INTRODUCTION: Non-coding RNAs have opened a new window in cancer biology. MicroRNAs (miRNAs), as a family of non-coding RNAs, play an important role in the gene regulation. The aberrant expression of these small molecules has been documented to involve in colorectal cancer (CRC) pathogenesis. This study aimed to examine the expression of miRNAs in CRC and to correlate their expression levels with histological markers (Ki-67 and CD34). MATERIALS AND METHODS: Tumor tissues and matched normal adjacent tissues were collected from 36 patients with newly diagnosed CRC. Immunohistochemical (IHC) staining of tumor tissues was performed for Ki-67 (proliferation) and CD34 (angiogenesis) markers, and the immunoexpression staining scores were obtained. A polyadenylation SYBER Green quantitative real-time PCR technique was used to quantify the expression of a panel of five CRC-related miRNAs (hsa-miR-21, 31, 20a, 133b, and 145). Histopathological (H) scores and miRNA expression levels were correlated with clinicopathological features including the degree of differentiation, staging, and lymphovascular invasion. RESULTS: Our results showed the significant difference between the two groups for the expression level of hsa-miR-21, hsa-miR 31, hsa-miR-145, and miR-20a (P < 0.001), but not for hsa-miR-133b (P = 0.57). Further analysis revealed an inverse significant correlation between hsa-miR-145 and Ki-67 (r = - 0.942, P < 0.001). While a positive correlation was observed between hsa-miR-21 and Ki-67 (r = 0.920, P < 0.001), and hsa-miR-21 and CD34 (r = 0.981, P < 0.001). Also, a positive correlation between hsa-miR-31 and Ki-67 (r = 0.913, P < 0.001), hsa-miR-31 and CD34 (r = 0.798, P < 0.05), hsa-miR-20a and Ki 67 (r = 0.871, P < 0.001), and hsa-miR-20a and CD34 (r = 0.890, P < 0.001) was found. CONCLUSION: Dysregulation of miRNAs and correlation with molecular histopathology indicate a biological role for miRNAs in various cellular processes including cell proliferation and angiogenesis in CRC development. On the other hand, the pattern of miRNA expression and its correlation with histological markers are potentially valuable to apply as diagnostic biomarkers for CRC. PMID- 29404791 TI - Chronification of Pain: Mechanisms, Current Understanding, and Clinical Implications. AB - PURPOSE OF REVIEW: The development of acute to chronic pain involves distinct pathophysiological changes in the peripheral and central nervous systems. This article reviews the mechanisms, etiologies, and management of chronic pain syndromes with updates from recent findings in the literature. RECENT FINDINGS: Chronic post-surgical pain (CPSP) is not limited to major surgeries and can develop after smaller procedures such as hernia repairs. While nerve injury has traditionally been thought to be the culprit for CPSP, it is evident that nerve sparing surgical techniques are not completely preventative. Regional analgesia and agents such as ketamine, gabapentinoids, and COX-2 inhibitors have also been found to decrease the risks of developing chronic pain to varying degrees. Yet, given the correlation of central sensitization with the development of chronic pain, it is reasonable to utilize aggressive multimodal analgesia whenever possible. Development of chronic pain is typically a result of peripheral and central sensitization, with CPSP being one of the most common presentations. Using minimally invasive surgical techniques may reduce the risk of CPSP. Regional anesthetic techniques and preemptive analgesia should also be utilized when appropriate to reduce the intensity and duration of acute post-operative pain, which has been correlated with higher incidences of chronic pain. PMID- 29404792 TI - Intrathecal Drug Delivery and Spinal Cord Stimulation for the Treatment of Cancer Pain. AB - PURPOSE OF REVIEW: The purpose of the present investigation is to summarize the body and quality of evidence including the most recent studies in support of intrathecal drug delivery systems and spinal cord stimulation for the treatment of cancer-related pain. RECENT FINDINGS: In the past 3 years, a number of prospective studies have been published supporting intrathecal drug delivery systems for cancer pain. Additional investigation with adjuvants to morphine based analgesia including dexmedetomidine and ziconotide support drug-induced benefits of patient-controlled intrathecal analgesia. A study has also been recently published regarding cost-savings for intrathecal drug delivery system compared to pharmacologic management, but an analysis in the Ontario, Canada healthcare system projects additional financial costs. Finally, the Polyanalgesic Consensus Committee has updated its recommendations regarding clinical guidelines for intrathecal drug delivery systems to include new information on dosing, trialing, safety, and systemic opioid reduction. There is still a paucity of clinical evidence for spinal cord stimulation in the treatment of cancer pain. There are new intrathecal drugs under investigation including various conopeptides and AYX1. Large, prospective, modern, randomized controlled studies are still needed to support the use of both intrathecal drug delivery systems as well as spinal cord stimulation for cancer pain populations. There are multiple prospective and small randomized controlled studies that highlight a potential promising future for these interventional modalities. Related to the challenge and urgency of cancer pain, the pain practitioner community is moving toward a multimodal approach that includes discussions regarding the role of intrathecal therapies and spinal cord stimulation to the individualized treatment of patients. PMID- 29404793 TI - Design of an Orthopedic Product by Using Additive Manufacturing Technology: The Arm Splint. AB - The traditional fabrication process of custom-made splints has hardly undergone any progress since the beginning of its use at the end of the eighteenth century. New manufacturing techniques and the new materials can help to modernize this treatment method of fractures. The use of Additive Manufacturing has been proposed in recent years as an alternative process for the manufacture of splints and there has been an increase in public awareness and exploration. For this reason, in this study a splint model printed in 3D, that replaces the deficiencies of the cast maintaining its virtues, has been proposed. The proposed methodology is based on three-dimensional digitalization techniques and 3D modeling with reverse engineering software. The work integrates different scientific disciplines to achieve its main goal: to improve life quality of the patient. In addition, the splint has been designed based on the principles of sustainable development. The design of splint is made of Polycarbonate by technique of Additive Manufacturing with fused deposition manufacturing, and conceived with organic shapes, customizing openings and closing buttons with rubber. In this preliminary study the final result is a prototype of the 3D printed arm splint in a reduced scale by using PLA as material. PMID- 29404794 TI - Computational Assessment of Pharmacokinetics and Biological Effects of Some Anabolic and Androgen Steroids. AB - PURPOSE: The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. METHODS: The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism. RESULTS: Investigated steroids usually reveal a high gastrointestinal absorption and a good oral bioavailability, may inhibit someof the human cytochromes involved in the metabolism of xenobiotics (CYP2C9 being the most affected) and reflect a good capacity for skin penetration. There are predicted numerous side effects of investigated steroids in humans: genotoxic carcinogenicity, hepatotoxicity, cardiovascular, hematotoxic and genitourinary effects, dermal irritations, endocrine disruption and reproductive dysfunction. CONCLUSIONS: These results are important to be known as an occupational exposure to anabolic and androgenic steroids at workplaces may occur and because there also is a deliberate human exposure to steroids for their performance enhancement and anti-aging properties. PMID- 29404795 TI - Prolonged extracorporeal membrane oxygenation for pediatric necrotizing pneumonia due to Streptococcus pneumonia and influenza H1N1 co-infection: how long should we wait for native lung recovery? AB - Most children with severe respiratory failure require extracorporeal membrane oxygenation (ECMO) for 7-10 days. However, some may need prolonged duration ECMO (> 14 days). To date, no consensus exists on how long to wait for native lung recovery. Here we report the case of a 3-year-old boy who developed severe necrotizing pneumonia requiring venovenous (VV) ECMO after 19 days of mechanical ventilation. In the first 4 weeks of his ECMO run, he showed no lung aeration, requiring total extracorporeal support. However, after we started strategies for promoting lung recovery such as daily prone positioning and regular use of toilet bronchoscopy and inhalative DNAse to clear secretions, by week five his tidal volumes gradually increased and he was successfully decannulated after 43 days. Moreover, we decided not to proceed to a surgical removal of the necrotic lung area. At present, he is 1-year post discharge and has fully recovered. This report shows that unexpected native lung recovery is possible even after prolonged loss of lung function and that a previous healthy lung can recover from apparent irreversible lung injury. PMID- 29404796 TI - Continuous renal replacement therapy with a polymethyl methacrylate membrane hemofilter suppresses inflammation in patients after open-heart surgery with cardiopulmonary bypass. AB - Cardiopulmonary bypass (CPB) induces a complex inflammatory response involving an increase in inflammatory cytokines, called postperfusion syndrome. Previous studies demonstrated that adsorption of the serum cytokines can reduce acute inflammation and improve clinical outcomes. In this study, patients were placed on continuous renal replacement therapy (CRRT) with a polymethyl methacrylate (PMMA) membrane hemofilter immediately after the start of an open-heart surgery with CPB and throughout the postoperative course to prevent postperfusion syndrome. The aim of this study was to assess whether continuous CRRT using a PMMA filter (PMMA-CRRT) could affect cytokine expression and improve perioperative outcomes. We designed a randomized controlled trial, which included 19 consecutive adult patients on maintenance dialysis and 7 consecutive adult patients who were not on maintenance dialysis (NHD group). Patients on maintenance dialysis were randomly divided into two groups: Ten patients who received CRRT with a polysulfone membrane hemofilter (PS group) and nine patients who received CRRT with a PMMA membrane (PMMA group). Blood samples were collected from the radial or brachial artery at five different time points. Comparisons between the PS, PMMA, and NHD groups revealed a significant main effect of time on changes in serum IL-6 and IL-8 concentrations (p < 0.01) and an interaction (p < 0.05) between time and group. Plasma IL-6 and IL-8 levels after surgery were significantly lower in the PMMA group than in the PS group, while other cytokines measured in this study were not significantly different. In addition, clinical outcomes were not significantly different between the groups. The continuous use of PMMA-CRRT throughout the perioperative period suppressed serum IL-6 and IL-8 concentrations, although there were no differences in clinical outcomes. PMID- 29404798 TI - Category learning in the color-word contingency learning paradigm. AB - In the typical color-word contingency learning paradigm, participants respond to the print color of words where each word is presented most often in one color. Learning is indicated by faster and more accurate responses when a word is presented in its usual color, relative to another color. To eliminate the possibility that this effect is driven exclusively by the familiarity of item specific word-color pairings, we examine whether contingency learning effects can be observed also when colors are related to categories of words rather than to individual words. To this end, the reported experiments used three categories of words (animals, verbs, and professions) that were each predictive of one color. Importantly, each individual word was presented only once, thus eliminating individual color-word contingencies. Nevertheless, for the first time, a category based contingency effect was observed, with faster and more accurate responses when a category item was presented in the color in which most of the other items of that category were presented. This finding helps to constrain episodic learning models and sets the stage for new research on category-based contingency learning. PMID- 29404797 TI - Nasoseptal Perforation: from Etiology to Treatment. AB - PURPOSE OF REVIEW: Nasal septum perforation (NSP) is a communication between the two nasal cavities. This review contributes to the better knowledge of NSP causes, diagnosis, and treatment. RECENT FINDINGS: NSP prevalence is about 1%. Clinical presentation may range from absence of symptoms to the presence of bothersome sinonasal symptoms. NSP is more frequently caused by trauma or post surgery, inflammatory diseases, and abuse substances. Conservative management (nasal irrigation, topical use of antibiotic or lubricant ointments, or placement of prosthesis) is considered the first-line treatment. Symptomatic NSP not improving with local therapies usually requires surgical approach. Selection of the technique for the endoscopic septal repair depends on perforation characteristics and surgeon experience. When NSP is diagnosed, its cause has to be promptly determined. Most of them can be controlled with conservative measures. Surgical/endoscopic approaches are usually needed in refractory cases, and new repair techniques have to be considered. PMID- 29404799 TI - Low-level orientation information for social evaluation in face images. AB - Observers make a range of social evaluations based on facial appearance, including judgments of trustworthiness, warmth, competence, and other aspects of personality. What visual information do people use to make these judgments? While links have been made between perceived social characteristics and other high level properties of facial appearance (e.g., attractiveness, masculinity), there has been comparatively little effort to link social evaluations to low-level visual features, like spatial frequency and orientation sub-bands, known to be critically important for face processing. We explored the extent to which different social evaluations depended critically on horizontal orientation energy vs. vertical orientation energy, as is the case for face identification and emotion recognition. We found that while trustworthiness judgments exhibited this bias for horizontal orientations, competence and dominance did not, suggesting that social evaluations may depend on a multi-channel representation of facial appearance at early stages of visual processing. PMID- 29404801 TI - Correction to: Association of adiposity with hemoglobin levels in patients with chronic kidney disease not on dialysis. AB - The article Association of adiposity with hemoglobin levels in patients with chronic kidney disease not on dialysis, written by Hirokazu Honda, Kota Ono, Tadao Akizawa, Kosaku Nitta and Akira Hishida, was originally published electronically on the publisher's internet portal (currently springerlink) on November 4, 2017 without open access. With the author(s)' decision to opt for Open Choice, the copyright of the article changed on February 6, 2018 to (c) The Author(s) [2017] and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article was corrected. PMID- 29404800 TI - The effect of the position of atypical character-to-sound correspondences on reading kanji words aloud: Evidence for a sublexical serially operating kanji reading process. AB - In English, the size of the regularity effect on word reading-aloud latency decreases across position of irregularity. This has been explained by a sublexical serially operating reading mechanism. It is unclear whether sublexical serial processing occurs in reading two-character kanji words aloud. To investigate this issue, we studied how the position of atypical character-to sound correspondences influenced reading performance. When participants read inconsistent-atypical words aloud mixed randomly with nonwords, reading latencies of words with an inconsistent-atypical correspondence in the initial position were significantly longer than words with an inconsistent-atypical correspondence in the second position. The significant difference of reading latencies for inconsistent-atypical words disappeared when inconsistent-atypical words were presented without nonwords. Moreover, reading latencies for words with an inconsistent-atypical correspondence in the first position were shorter than for words with a typical correspondence in the first position. This typicality effect was absent when the atypicality was in the second position. These position-of atypicality effects suggest that sublexical processing of kanji occurs serially and that the phonology of two-character kanji words is generated from both a lexical parallel process and a sublexical serial process. PMID- 29404802 TI - Antiaflatoxigenic effect of fullerene C60 nanoparticles at environmentally plausible concentrations. AB - Increased interest in fullerene C60 and derivatives in recent years implies an intensification of their environmental spread. Yet, the potential risks for living organisms are largely unknown, including the interaction of C60 with fungal organisms. This may be especially relevant for mycotoxigenic fungi since C60 may both scavenge and produce reactive oxygen species (ROS), and oxidative stress induces mycotoxin production in fungi. Therefore, this study examined effects of environmentally plausible concentrations of C60 (0, 10, 50, and 100 ng/mL) on Aspergillus flavus growth and aflatoxin production in culture media. In addition, ROS-dependent oxidative stress biomarkers-thiobarbituric acid reactive substances (TBARS), reduced and oxidised glutathione ratio, superoxide dismutase isoenzymes, catalase, glutathione peroxidase, and glutathione reductase were determined in mycelia. Nanoparticles of fullerene C60 (nC60) did not exhibit strong antifungal activity against A. flavus. At the same time, nC60 caused an antiaflatoxigenic effect at 10-100 ng/mL, and 50 ng/mL unexpectedly enhanced aflatoxin production. The TBARS content, reduced and oxidised glutathione ratio, and copper, zinc superoxide dismutase activity suggest that 10 ng/mL nC60 exerted antioxidative action and reduced aflatoxin B1 production within fungal cells. Detected prooxidative effects of 50 ng/mL fullerene exceeded cellular defenses and consequently enhanced aflatoxin B1 production. Finally, the results obtained with 100 ng/mL nC60 point to prooxidative effects, but the absence of increase in aflatoxin output may indicate additional, presumably cytotoxic effects of nC60. Thus, a range of rather low levels of nC60 in the environment has a potential to modify aflatoxin production in A. flavus. Due to possible implications, further studies should test these results in environmental conditions. PMID- 29404803 TI - The use of ocular ultrasound to diagnose retinal detachment: a case demonstrating the sonographic findings. AB - Retinal detachment is an ophthalmologic emergency that requires immediate medical attention as it can potentially lead to permanent vision loss. The gold standard for diagnosing retinal detachment is dilated funduscopic exam. However, when this exam is not feasible such as in an emergency room setting or if visualization of the posterior portion of the eye is not possible due to vitreous hemorrhage or dense cataracts, ocular ultrasound provides a readily available and effective alternative. We present the sonographic appearance of chronic retinal detachment in a 24-year-old female with a longstanding history of poorly controlled type 1 diabetes who could not undergo dilated funduscopic exam due to intra-ocular hemorrhage. While retinal detachment is more likely to be detected by radiologists on computed tomography (CT) or magnetic resonance imaging (MRI), radiologists should be aware of the ultrasound findings as well, especially as it becomes a more frequently utilized method for diagnosing retinal detachment in an emergency room setting. PMID- 29404804 TI - Variation in emergency department use of computed tomography for investigation of acute aortic dissection. AB - INTRODUCTION: Acute aortic dissection (AAD) is a life-threatening condition making early diagnosis critical. Although 90% present with acute pain, the myriad of associated symptoms can make diagnosis a challenge. Our objective was to assess how we are using computed tomography to rule out acute aortic dissection specifically rate of ordering, diagnostic yield, and variation in practice. METHODS: We included consecutive adult patients presenting to two tertiary academic care emergency departments over one calendar year presenting with non traumatic chest, back, abdominal, or flank pain. Primary outcome was rate of CT thorax/abdomen ordered to rule out AAD. Secondary outcome was variation in CT ordering, measured comparing number of CTs ordered per physician. Sample size of 12 per group was calculated based on an expected delta in mean CT ordered of 5 and a within group SD of 3. RESULTS: Thirty-one thousand two hundred one patients presented with truncal pain during the study period, 22,729 were included (mean 47 years, SD 18.5 years, 56.2% female); prevalence of AAD (N = 4) was 0.02%. CT was ordered to rule out AAD in 175 (0.7%) patients (mean 62 years, SD 16.5, 50.6% female). Significant variation between physicians ordering was found, with individual physicians ordering varying from 0.6 to 12%. CONCLUSIONS: Current rate of imaging for acute aortic dissection is low and potentially inefficient, with a large variation in practice. These findings suggest potential for more standardized and efficient use of CT for the diagnosis of acute aortic dissection. PMID- 29404805 TI - Inborn errors of metabolism and the human interactome: a systems medicine approach. AB - The group of inborn errors of metabolism (IEM) displays a marked heterogeneity and IEM can affect virtually all functions and organs of the human organism; however, IEM share that their associated proteins function in metabolism. Most proteins carry out cellular functions by interacting with other proteins, and thus are organized in biological networks. Therefore, diseases are rarely the consequence of single gene mutations but of the perturbations caused in the related cellular network. Systematic approaches that integrate multi-omics and database information into biological networks have successfully expanded our knowledge of complex disorders but network-based strategies have been rarely applied to study IEM. We analyzed IEM on a proteome scale and found that IEM associated proteins are organized as a network of linked modules within the human interactome of protein interactions, the IEM interactome. Certain IEM disease groups formed self-contained disease modules, which were highly interlinked. On the other hand, we observed disease modules consisting of proteins from many different disease groups in the IEM interactome. Moreover, we explored the overlap between IEM and non-IEM disease genes and applied network medicine approaches to investigate shared biological pathways, clinical signs and symptoms, and links to drug targets. The provided resources may help to elucidate the molecular mechanisms underlying new IEM, to uncover the significance of disease-associated mutations, to identify new biomarkers, and to develop novel therapeutic strategies. PMID- 29404806 TI - First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial. AB - PURPOSE: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL). METHODS: Postmenopausal women (N = 668) with HR+ , HER2- ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis. RESULTS: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8 23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change >= 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI. CONCLUSION: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2- ABC. PMID- 29404807 TI - Physical activity during adolescence and young adulthood and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. AB - BACKGROUND: Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer. METHODS: We conducted a case-control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12-13, ages 14-17, ages 18-22, ages 23-29 and ages 30-34 were determined using the Nurses' Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12 34), during adolescence (ages 12-17) and during early adulthood (ages 18-34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status. RESULTS: Overall, there was no significant association between total physical activity and subsequent breast cancer risk (ORQ4 vs. Q1 = 1.01, 95% CI 0.69-1.47; P-trend = 0.72). Moderate physical activity between ages 12-17 was associated with a 38% decreased risk of premenopausal breast cancer (ORQ4 vs. Q1 = 0.62; 95% CI 0.40-0.96; P trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause. CONCLUSIONS: These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers. IMPACT: Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population. PMID- 29404809 TI - Tetsuo Hida, M.D. (1948-2008). PMID- 29404808 TI - Effects of different growth temperatures on growth, development, and plastid pigments metabolism of tobacco (Nicotiana tabacum L.) plants. AB - BACKGROUND: Temperature remarkably affects the growth and metabolism of plants. Tobacco is an important cash crop, and the long-term effects of different growth temperatures (18.5, 23.5 and 28.5 degrees C, daily average) on growth, development and plastid pigments metabolism of tobacco plants were investigated in this study. RESULTS: Compared with tobacco plants grown under 23.5 degrees C, treatments with 18.5 and 28.5 degrees C inhibited the expansion of leaves. The contents of superoxide anion (O 2.- ), hydrogen peroxide (H2O2) and malonaldehyde (MDA) in the leaves were significantly increased under 28.5 degrees C from 0 to 60 days, which in turn accelerated the flowering and senescence of tobacco plants. By contrast, the treatment with 18.5 degrees C remarkably decreased O 2. , H2O2 and MDA, and delayed the flowering and senescence. Furthermore, treatment with 18.5 degrees C significantly up-regulated the expression of glutamyl-tRNA reductase (Glu-TR) and magnesium chelatase (MgCH), and down-regulated the ferri chelatase (FeCH), protochlorophyllide oxidoreductase, chlorophyllase (CHLase), phaeophorbide a monooxygenase (PaO) and phytoene synthase (PSY), which further promoted the accumulation of chlorophyll (Chls) and reduced the carotenoids (Cars) in leaves. On the contrary, exposing to 28.5 degrees C remarkably down regulated the Glu-TR and MgCH, and up-regulated the FeCH, CHLase, PaO and PSY, which in turn decreased the Chls and increased the Cars in tobacco leaves. CONCLUSION: As compared with the plants grown under 23.5 degrees C, lower (18.5 degrees C) and higher (28.5 degrees C) growth temperature inhibited the growth of tobacco plants. In general, treatment with 28.5 degrees C accelerated the flowering and senescence of tobacco plants by enhancing the accumulation of O 2.- and H2O2 in leaves, while exposing to 18.5 degrees C had the opposite effects. Treatment with 18.5 degrees C increased the content of Chls and reduced the Cars in leaves. In contrast, Treatment with 28.5 degrees C decreased the Chls and increased the Cars. Moreover, both O 2.- and H2O2 took part in the breakdown of Chls in tobacco leaves to some extent. The results suggest that growth temperature could regulate growth, development, and plastid pigments metabolism, and 23.5 degrees C could be an optimal temperature for growth, development and metabolism of plastid pigments of tobacco plants under the experimental conditions. PMID- 29404810 TI - Roughness, surface energy, and superficial damages of CAD/CAM materials after surface treatment. AB - OBJECTIVES: The aim of this study was to examine the effects of surface pre treatment on CAD/CAM materials including ceramics, zirconia, resin-infiltrated ceramic, and resin-based composite. MATERIALS AND METHODS: Specimens were made of ten CAD/CAM materials (Celtra Duo, Degudent, D; Vita Suprinity, Vita, D; E.max CAD, Ivoclar-Vivadent, FL; E.max ZirCAD, Ivoclar-Vivadent, FL; Vita Enamic, Vita, D; Cerasmart, GC, B; LAVA Ultimate, 3M, D; SHOFU Block HC, SHOFU, US; Grandio Blocs, VOCO, D; BRILLIANT Crios, Coltene, CH) and pretreated to represent clinical procedures (Hf 20 s/5%; phosphoric acid 20 s/37%; Monobond etch and prime (Ivoclar-Vivadent, FL); water-cooled diamond bur (80 MUm; 4 MUm); Al2O3 blasting (50 MUm/1 bar, 50 MUm/2 bar, 120 MUm/1 bar, 120 MUm/2 bar); untreated; manufacturer's instructions). SEM-analysis (Phenom, FEI, NL) of the surfaces was performed (magnifications <= 10,000*). Roughness values Ra, Rz (KJ 3D, Keyence, J), and surface energy SE (OCA15 plus, SCA20, DataPhysics, D) were determined (statistics: non-parametric Mann-Whitney U test/Kruskal-Wallis test for independent specimen, alpha = 0.05). RESULTS: Kruskal-Wallis revealed significant (p < 0.001) differences for all materials with different surface treatments. Roughness ranged from Ra = 0.05 MUm (VS; D4)/Rz = 0.41 MUm (VS; D4) to Ra = 1.82 MUm (EMA; SB120/2)/Rz = 12.05 MUm (CS; SB 120/2), SE from 22.7 mN/m (VE; M) to 52.8 mN/m (CD; M). SEM analysis showed material-dependent damages after pre treatment. CONCLUSION: Different CAD/CAM materials require individual pre treatment for optimized and protective surface activation. CLINICAL RELEVANCE: Cementation is a key factor for clinical success. Given the variety of available CAD/CAM materials, specific procedures are needed. PMID- 29404811 TI - Zinc and silica are active components to efficiently treat in vitro simulated eroded dentin. AB - OBJECTIVES: Biomaterials for treating dentin hypersensitivity and dentin wear were evaluated to efficiently occlude the dentinal tubules and to increase dentin resistance to abrasion. MATERIALS AND METHODS: Twenty-four dentin surfaces were treated with EDTA to expose dentinal tubules and were (1) non-brushed, (2) brushed with distilled water, or with pastes containing (3) monetite, (4) brushite, (5) Zn-monetite, (6) Zn-brushite, (7) Silica-brushite, and (8) NovaMin(r). Topographical, nanomechanical, and chemical analysis were assessed on dentin surfaces (n = 3) after artificial saliva immersion for 24 h, and after citric acid challenge. Twenty-one further dentin specimens were created to evaluate dentin permeability after brushing, saliva storage, and acid application (n = 3). ANOVA, Student-Newman-Keuls (p < 0.05), and Student t test (p < 0.001) were used. RESULTS: Particles containing major proportion of silica attained intratubular occlusion by carbonate crystals (Raman carbonate peak heights 15.17 and 19.24 au; complex modulus 110 and 140 GPa, at intratubular dentin). When brushing with pastes containing higher proportion of silica or zinc, phosphate calcium compounds were encountered into tubules and over dentin surfaces (Raman intratubular phosphate peak heights 49 to 70 au, and at the intertubular dentin 78 to 92). The formed carbonated apatite and calcium phosphate layer were resistant to citric acid application. Zinc compounds drastically increased tubule occlusion, decreased dentin permeability (up to 30%), and augmented mechanical properties at the intertubular dentin (90-130 GPa); it was maintained after acid challenging. CONCLUSIONS: Zinc-containing pastes occluded dentinal tubules and improved dentin mechanical properties. CLINICAL RELEVANCE: Using zinc as an active component to treat eroded dentin is encouraged. PMID- 29404812 TI - Evaluation of the genotoxic effects of formocresol application in vital pulp therapy of primary teeth: a clinical study and meta-analysis. AB - OBJECTIVES: This in vivo research investigated whether pulp treatments using formocresol for 7 days would cause mutagenic changes in children's lymphocytes. MATERIALS AND METHODS: The mutagenicity was tested in lymphocyte cultures established from the peripheral blood of children living in Brazil. The samples consisted of 2000 cells from teeth undergoing formocresol pulpotomies in which the formocresol pellet was sealed in the primary tooth for 7 days. It was removed on the seventh day, the base was placed, and the tooth was restored. Two venous blood samples (6-8 ml) were collected from each child; the first was prior to pulp therapy, and the second was 7 days later. Two thousand metaphases were analyzed. The level of significance adopted for the statistics was P < 0.05, and a random effects meta-analysis was performed combining this and two previous studies. RESULTS: There was no significant difference found in the metaphase analysis between the blood samples taken before and after the pulpotomy treatment (Wilcoxon signed rank test); however, the meta-analysis showed a significant difference between the combined studies. CONCLUSIONS: This study did not reveal any mutagenic effects, but based on the combined meta-analysis, we recommend the careful use of formocresol. CLINICAL RELEVANCE: This research helps to bring scientific evidence of the safe use of formocresol in deciduous pulpotomy treatments. PMID- 29404813 TI - Impact of simulated reduced alveolar bone support, increased tooth mobility, and distal post-supported, root-treated abutment tooth on load capability of all ceramic zirconia-supported cantilever FDP. AB - OBJECTIVES: The aim of this in vitro study was an analysis of the impact of simulated reduced alveolar bone support and post-restored, endodontically treated distal abutment tooth on load capability of all-ceramic zirconia-based cantilever fixed dental prosthesis (CFDP). MATERIAL AND METHODS: The roots of human lower sound premolars (n = 80) were divided into five experimental groups to be restored with all-ceramic zirconia-supported three-unit CFDP regarding bone loss (BL) relative to the cement-enamel junction (CEJ): 2 mm below CEJ = 0% BL (control group), group 25% distal BL, group 50% distal BL, group 50% mesial and distal BL, and group 50% distal BL and adhesive post-supported restoration. Specimens were exposed to simulated clinical function by thermo-mechanical loading (6.000 cycles 5 degrees -55 degrees ; 1.2 * 106 cycles 0-50 N) and subsequent linear loading until failure. RESULTS: Tooth mobility increased significantly for groups with simulated bone loss (p < 0.001). Four specimens failed during thermal cycling and mechanical loading (TCML). The maximum load capability ranged from 350 to 569 N, and did not differ significantly between experimental groups (p = 0.095). Groups with simulated bone loss revealed more tooth fractures at distal abutment teeth, whereas technical failures were more frequent in the control group (p = 0.024). CONCLUSIONS: Differences of alveolar bone support and respectively increased tooth mobility between mesial and distal abutments did not influence load capability. A distal adhesively post-and-core supported, root-treated abutment tooth did not increase risk of three-unit CFDP failure. CLINICAL RELEVANCE: CFDPs are a treatment option used with caution when reduced alveolar bone support, increased tooth mobility, and distal post supported, root-treated abutment teeth are involved. PMID- 29404814 TI - The Dynamics of Networks of Identical Theta Neurons. AB - We consider finite and infinite all-to-all coupled networks of identical theta neurons. Two types of synaptic interactions are investigated: instantaneous and delayed (via first-order synaptic processing). Extensive use is made of the Watanabe/Strogatz (WS) ansatz for reducing the dimension of networks of identical sinusoidally-coupled oscillators. As well as the degeneracy associated with the constants of motion of the WS ansatz, we also find continuous families of solutions for instantaneously coupled neurons, resulting from the reversibility of the reduced model and the form of the synaptic input. We also investigate a number of similar related models. We conclude that the dynamics of networks of all-to-all coupled identical neurons can be surprisingly complicated. PMID- 29404815 TI - Intra-cellular lactate concentration in T lymphocytes from septic shock patients a pilot study. AB - BACKGROUND: Sepsis-associated hyperlactatemia is a widely used biomarker, associated with initial severity and poor outcomes. This increased circulating lactate concentration has been proposed to result in part from a mismatch between oxygen delivery and demand in organs. However, other mechanisms may participate. In particular, a metabolic reprogramming similar to the Warburg effect initially described in cancer cells could lead to increased lactate production by immune cells such as T lymphocytes after sepsis. The objective of this study was to set up a protocol for lactate measurement in T lymphocytes, and to evaluate whether lactate production by T lymphocytes was increased in septic shock patients. METHODS: We first optimized protocols for lactate and pyruvate measurements in T lymphocytes purified from healthy volunteers' blood, either stimulated with phytohaemagglutinine (PHA) or left untreated. We then conducted a pilot study to confirm the feasibility of this protocol in samples from septic shock patients. RESULTS: PHA stimulation induced aerobic glycolysis in human lymphocytes ex vivo, with increased lactate and pyruvate productions. To correctly measure this phenomenon, minimal cell number was 250,000 and optimal culture duration was 40 h. We also observed a significant correlation between lactate concentration in T lymphocytes and in their culture supernatants. We were able to measure lactate concentration in T lymphocytes from septic shock patients. Our preliminary results showed that intra-lymphocyte lactate concentration was not different between patients and healthy volunteers. CONCLUSION: This protocol should now be tested in a larger cohort of patients. The association between immune cell metabolic reprogramming as measured by lactate concentration in T cells and functionality represents an exciting field for research. PMID- 29404816 TI - Experimental and theoretical studies of Schiff bases as corrosion inhibitors. AB - BACKGROUND: Relatively inexpensive, stable Schiff bases, namely 3-((4 hydroxybenzylidene)amino)-2-methylquinazolin-4(3H)-one (BZ3) and 3-((4 (dimethylamino)benzylidene)amino)-2-methylquinazolin-4(3H)-one (BZ4), were employed as highly efficient inhibitors of mild steel corrosion by corrosive acid. FINDINGS: The inhibition efficiencies were estimated based on weight loss method. Moreover, scanning electron microscopy was used to investigate the inhibition mechanism. The synthesized Schiff bases were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy and micro-elemental analysis. The inhibition efficiency depends on three factors: the amount of nitrogen in the inhibitor, the inhibitor concentration and the inhibitor molecular weight. CONCLUSIONS: Inhibition efficiencies of 96 and 92% were achieved with BZ4 and BZ3, respectively, at the maximum tested concentration. Density functional theory calculations of BZ3 and BZ4 were performed to compare the effects of hydroxyl and N,N-dimethylamino substituents on the inhibition efficiency, providing insight for designing new molecular structures that exhibit enhanced inhibition efficiencies. PMID- 29404817 TI - Dissociation of beta-Sheet Stacking of Amyloid beta Fibrils by Irradiation of Intense, Short-Pulsed Mid-infrared Laser. AB - Structure of amyloid beta (Abeta) fibrils is rigidly stacked by beta-sheet conformation, and the fibril state of Abeta is profoundly related to pathogenesis of Alzheimer's disease (AD). Although mid-infrared light has been used for various biological researches, it has not yet been known whether the infrared light changes the fibril structure of Abeta. In this study, we tested the effect of irradiation of intense mid-infrared light from a free-electron laser (FEL) targeting the amide bond on the reduction of beta-sheet content in Abeta fibrils. The FEL reduced entire contents of proteins exhibiting beta-sheet structure in brain sections from AD model mice, as shown by synchrotron-radiation infrared microscopy analysis. Since Abeta1-42 fibril absorbed a considerable FEL energy at amide I band (6.17 MUm), we irradiated the FEL at 6.17 MUm and found that beta sheet content of naked Abeta1-42 fibril was decreased using infrared microscopic analysis. Consistent with the decrease in the beta-sheet content, Congo-red signal is decreased after the irradiation to Abeta1-42 fibril. Furthermore, electron microscopy analysis revealed that morphologies of the fibril and proto fibril were largely changed after the irradiation. Thus, mid-infrared light dissociates beta-sheet structure of Abeta fibrils, which justifies exploration of possible laser-based therapy for AD. PMID- 29404818 TI - Electrophysiological and Oviposition Responses of Tuta absoluta Females to Herbivore-Induced Volatiles in Tomato Plants. AB - In response to attack by herbivorous insects, plants produce semiochemicals for intra- and interspecific communication. The perception of these semiochemicals by conspecifics of the herbivore defines their choice for oviposition and feeding. We aimed to investigate the role of herbivore-induced plant volatiles (HIPVs) by Tuta absoluta larvae on the oviposition choice of conspecific females on tomato plants. We performed two- choice and non-choice bioassays with plants damaged by larvae feeding and intact control plants. We also collected headspace volatiles of those plants and tested the response of female antennae on those blends with Gas Chromatography- Electro-Antennographical Detection (GC-EAD). In total 55 compounds were collected from the headspace of T. absoluta larvae-infested plants. Our results show that female moths preferred to oviposit on intact control plants instead of damaged ones. Herbivory induced the emission of hexanal, (Zeta)-3-hexen-1-ol, (E)-beta-ocimene, linalool, (Z)-3-hexenyl butanoate, methyl salicylate, indole, nerolidol, guaidiene-6,9, beta-pinene, beta myrcene, alpha-terpinene, hexenyl hexanoate, beta-elemene, beta-caryophyllene and (Epsilon-Epsilon)- 4,8,12-trimethyl-1,3,7,11-tridecatetraene (TMTT), one unidentified sesquiterpene and three unknown compounds. In Electroantennographic (EAG) assays, the antennae of T. absoluta females responded to hexanal, (Zeta)-3 hexen-1-ol, methyl salicylate and indole. The antennae of T. absoluta females exhibited a dose-response in EAG studies with authentic samples. Strong EAG responses were obtained for compounds induced on damaged tomato plants, as well as in nonanal, a compound emitted by both infested and control plants. These compounds could be utilized in integrated pest management of T. absoluta. PMID- 29404819 TI - Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment. RESULTS: This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment. CONCLUSIONS: Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT. PMID- 29404820 TI - Sarcopenia and Comorbidity in Gastric Cancer Surgery as a Useful Combined Factor to Predict Eventual Death from Other Causes. AB - BACKGROUND: Sarcopenia is recognized as an important prognostic factor in various types of cancer, including gastric cancer. While long-term survival analyses typically focus on overall and disease-specific survival, death from other causes has received far less attention. METHODS: We reviewed medical records of 491 gastric cancer patients who underwent gastrectomy from January 2005 to March 2014 and whose preoperative computed tomography (CT) images were available for evaluation of sarcopenia. Sarcopenia was defined as the SMA/BSA index (skeletal muscle area divided by body surface area) below the sex-specific lowest quartile. RESULTS: Sarcopenia was significantly associated with age, high body mass index (BMI), presence of comorbidity, high American Society of Anesthesiologists physical status (ASA-PS), high T score, advanced stage, large blood loss, and long hospital stay, but was not significantly associated with postoperative complications. Univariate and multivariate analyses of prognostic factors for overall survival revealed that sarcopenia is an independent predictor of poor prognosis [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.01-2.09, p = 0.0454]. Our analysis of death due to other causes found that non-gastric cancer related deaths were more frequent among sarcopenia patients with comorbidities than in the rest of our study population (p = 0.0001), while univariate and multivariate analyses revealed that sarcopenia with comorbidity was an independent risk factor for non-gastric cancer-related death (HR 1.84, 95% CI 1.31-3.61, p = 0.0308), as was age. CONCLUSION: For gastric cancer patients, sarcopenia increases the risk of death from other causes following surgery, which reveals the importance of developing treatment strategies based not only on cancer status but also on other clinical factors, including sarcopenia and comorbidity. PMID- 29404821 TI - Spexin in the half-smooth tongue sole (Cynoglossus semilaevis): molecular cloning, expression profiles, and physiological effects. AB - Spexin (SPX), a novel neuropeptide discovered by the bioinformatics approach, has been shown to exert pleiotropic functions in mammals. However, little information regarding the physiological role of SPX is available in teleosts. As a first step, we cloned the spexin gene from a flatfish, the half-smooth tongue sole. The open reading frame (ORF) of tongue sole spexin contained 363 nucleotides encoding a 120 amino acid (aa) preprohormone with a calculated molecular mass and isoelectric point of 14.06 kDa and 5.86, respectively. The tongue sole SPX precursor contained a 27 aa signal peptide and a 14 aa mature peptide flanked by two dibasic protein cleavage sites (RR and GRR). Tissue distribution analysis showed that spexin mRNA could be detected in various tissues, notably in the brain. In addition, fasting stimulated the hypothalamic expression of spexin mRNA. Intraperitoneal injection of SPX increased gnih and gnrh3 mRNA levels in the hypothalamus; however, SPX inhibited the pituitary expression of gh, fshbeta, and gthalpha mRNAs. Overall, our results reveal the existence of a functional SPX in the tongue sole, which could represent an important factor in the neuroendocrine control of flatfish reproduction and growth, and the spexin mRNA expression is regulated by feeding status. PMID- 29404822 TI - Effects of temperature and melatonin on day-night expression patterns of arginine vasotocin and isotocin mRNA in the diencephalon of a temperate wrasse Halichoeres tenuispinis. AB - Most wrasses are protogynous species that swim to feed, reproduce during the daytime, and bury themselves under the sandy bottom at night. In temperate and subtropical wrasses, low temperature influences emergence from the sandy bottom in the morning, and induces a hibernation-like state in winter. We cloned and characterized the prohormone complementary DNAs (cDNAs) of arginine vasotocin (AVT) and isotocin (IT) in a temperate wrasse (Halichoeres tenuispinis) and examined the effects of day/night and temperature on their expression in the diencephalon, because these neurohypophysial peptides are related to the sex behavior of wrasses. The full-length cDNAs of pro-AVT and pro-IT were 938 base pairs (154 amino acids) and 759 base pairs (156 amino acids) in length, respectively. Both pro-peptides contained a signal sequence followed by the respective hormones and neurophysin connected by a Gly-Lys-Arg bridge. Reverse transcription polymerase chain reaction (RT-PCR) revealed that pro-AVT mRNA expression was specifically observed in the diencephalon, whereas pro-IT mRNA expression was seen in the whole brain. Quantitative RT-PCR revealed that the mRNA abundance of pro-AVT and pro-IT was higher at midday (zeitgeber time 6; ZT6) than at midnight (ZT18) under 12 h light and 12 h darkness (LD 12:12) conditions, but not under constant light. Intraperitoneal injection of melatonin decreased the mRNA abundance of pro-AVT, but not of pro-IT. When fish were reared under LD 12:12 conditions at 25, 20, and 15 degrees C, day high and night low mRNA expressions of pro-AVT and pro-IT were maintained. A field survey revealed seasonal variation in the number of swimming fish at observatory sites; many fish emerged from the sandy bottom in summer, but not in winter, suggesting a hibernation-like state under the sandy bottom under low temperature conditions. We conclude that the day-night fluctuation of pro-AVT and pro-IT mRNA abundance in the brain is not affected by temperature and repeated under the sandy bottom in winter. PMID- 29404823 TI - "Second-Class Status?" Insight into Communication Patterns and Common Concerns Among Men with Hereditary Breast and Ovarian Cancer Syndrome. AB - Hereditary breast and ovarian cancer syndrome (HBOC) is a cancer predisposition syndrome that affects both men and women, with more significant cancer risk elevations in women. Dissemination patterns regarding familial genetic risk information among females with HBOC are fairly well defined, but knowledge about how males share this information is limited. We interviewed 21 people primarily Ashkenazi Jewish men who were accrued via listserv email through Facing Our Risk of Cancer Empowered (FORCE). Interviews focused on family cancer history, experiences with cancer and genetic testing, motivations to pursue genetic testing and subsequently disclose genetic test results, information-sharing patterns, health care provider response, and participants' emotional support systems. The interviews were transcribed in their entirety, coded, and analyzed based on recurring themes. Eighteen transcripts were used for the analysis. Results were classified into five main themes. Participants (n = 8) were most concerned about cancer risk for their children and female family members, and most (n = 11) mentioned that HBOC provides them increased personal awareness, but has a negligible impact on their life overall (n = 9). Men (n = 11) were interested in a male-focused support group to discuss HBOC and gain knowledge and information. Participants (n = 9) took on active and open communication roles with family members and health care providers. The majority of participants (n = 14) discussed the need for knowledge and awareness among the health care community and general population regarding male HBOC risks. This study serves as a pilot study and provides important and novel insights into psychosocial impacts, communication patterns, encounters with health care professionals, and expressed needs of males with HBOC. PMID- 29404824 TI - Formal description of Mycobacterium neglectum sp. nov. and Mycobacterium palauense sp. nov., rapidly growing actinobacteria. AB - The taxonomic positions of two fast growing mycobacteria (CECT 8778T and CECT 8779T) were established using a polyphasic approach. The strains were shown to have chemotaxonomic, cultural and morphological properties consistent with their classification in the genus Mycobacterium. Multi-locus sequence analyses (MLSA) show that strain CECT 8778T forms a well-supported clade together with the type strains of Mycobacterium aurum, Mycobacterium austroafricanum and Mycobacterium vanbaalenii while strain CECT 8779T presents as a distinct branch that is well separated from its near phylogenetic neighbours; it is also apparent from the MLSA genetic distances that these strains are most closely related to the type strains of Mycobacterium mageritense and M. vanbaalenii, respectively. Digital DNA:DNA hybridization and average nucleotide identity values between each of the strains and its close phylogenetic neighbour are below the 70 and 96% threshold values for definition of prokaryotic species; these results are underpinned by corresponding phenotypic data. Based upon the consensus of the phenotypic and phylogenetic analyses, it can be concluded that the two strains represent novel species within the genus Mycobacterium for which the following names are proposed: Mycobacterium neglectum sp. nov., with the type strain CECT 8778T (BN 3150T = DSM 44756T) and Mycobacterium palauense sp. nov., with the type strain CECT 8779T (= DSM 44914T). PMID- 29404825 TI - Correction to: Photosystem I-LHCII megacomplexes respond to high light and aging in plants. AB - The funding statement in the last sentence of the Acknowledgements section in the original publication is incorrect. The corrected Acknowledgements section is printed below. PMID- 29404826 TI - Neurological Complications of Acute and Chronic Sinusitis. AB - PURPOSE OF REVIEW: Acute and chronic sinusitis can give rise to a wide array of intracranial and orbital complications. These complications include brain abscess, subdural empyema, epidural abscess, meningitis, venous sinus thrombosis, frontal bone osteomyelitis, and orbital cellulitis and abscess. Despite numerous medical advances, these complications carry a risk of mortality and significant morbidity. RECENT FINDINGS: Recent studies have shown improvement in both the mortality and the morbidity associated with the neurologic complications of acute and chronic sinusitis. However, there are still a large portion of patients with long-term sequelae, and the literature reports a morbidity rate of approximately 30%. The most common post-treatment morbidities include permanent changes in vision, seizures, and hemiparesis. Although the overall incidence of neurologic complications from a sinogenic source are rare, the potential long-term complications can be devastating making prompt diagnosis and treatment vital to improving outcomes. PMID- 29404827 TI - From Futile to Fruitful: Diesel Soot as White Light Emitter. AB - The present work describes a solution for the effective use of the hazardous particulate matter (diesel soot) from the internal combustion engines (ICEs) as a potential material emitting white light for white light emitting diodes (WLEDs). The washed soot samples are subjected to Field Emission Scanning Electron Microscopy (FESEM), High- Resolution Transmission Electron Microscopy (HR-TEM), Energy Dispersive Spectroscopy (EDS), UV-Visible, Photoluminescent (PL) Spectroscopy and quantum yield measurements. The CIE plot and Correlated Color Temperature (CCT) reveals the white fluorescence on photoexcitation. The sample on ultraviolet (UV) laser excitation, provides a visual confirmation of white light emission from the sample. The diesel soot collected from public transport buses of different years of manufacture invariably exhibit white fluorescence at an excitation of 350 nm. The sample show a quantum yield of 47.09%. The study is significant in the context of pollution and search for low-cost, rare-earth phosphor free material for white light emission and thereby turning the hazardous, futile material into a fruitful material that can be used for potential applications in photonics and electronics. PMID- 29404828 TI - Tumor necrosis factor (TNF) and TNFR1 polymorphisms are not risk factors for rheumatoid arthritis in a Mexican population. AB - Tumor necrosis factor (TNF) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Different genetic variants including the TNF -308G/A polymorphism are associated with RA susceptibility. However, these findings have not been replicated in all populations. The aim of this study was to determine whether the TNF -1031T/C (rs1799964), -376G/A (rs1800750), -308G/A (rs1800629) 238G/A (rs361525), and TNFR1 -609G/T polymorphisms are associated with RA susceptibility in a sample of Mexican patients. Our study included 499 patients with RA and 492 healthy controls. The genotypes of the TNF polymorphisms were obtained using TaqMan assay. The genotype and allele frequencies of the TNF 1031T/C, -376G/A, -308G/A, -238G/A, and TNFR1 -609G/T polymorphisms were similar among RA cases versus healthy controls, and no association with RA susceptibility was identified. Our results suggest that the TNF -1031T/C, -376G/A, -308G/A, 238G/A, and TNFR1 -609G/T polymorphisms are not associated with RA susceptibility in a sample of Mexican patients. PMID- 29404829 TI - Polymorphic nuclear markers for coastal plant species with dynamic geographic distributions, the rock samphire (Crithmum maritimum) and the vulnerable dune pansy (Viola tricolor subsp. curtisii). AB - Identifying spatial patterns of genetic differentiation across a species range is critical to set up conservation and restoration decision-making. This is especially timely, since global change triggers shifts in species' geographic distribution and in the geographical variation of mating system and patterns of genetic differentiation, with varying consequences at the trailing and leading edges of a species' distribution. Using 454 pyrosequencing, we developed nuclear microsatellite loci for two plant species showing a strictly coastal geographical distribution and contrasting range dynamics: the expanding rock samphire (Crithmum maritimum, 21 loci) and the highly endangered and receding dune pansy (Viola tricolor subsp. curtisii, 12 loci). Population genetic structure was then assessed by genotyping more than 100 individuals from four populations of each of the two target species. Rock samphire displayed high levels of genetic differentiation (FST = 0.38), and a genetic structure typical of a mostly selfing species (FIS ranging from 0.16 to 0.58). Populations of dune pansy showed a less pronounced level of population structuring (FST = 0.25) and a genotypic structure more suggestive of a mixed-mating system when excluding two loci with heterozygote excess. These results demonstrate that the genetic markers developed here are useful to assess the mating system of populations of these two species. They will be tools of choice to investigate phylogeographical patterns and variation in mating system over the geographical distribution ranges for two coastal plant species that are subject to dynamic evolution due to rapid contemporary global change. PMID- 29404830 TI - Genetic and Environmental Influences on Self-Control: Assessing Self-Control with the ASEBA Self-Control Scale. AB - This study used a theoretically-derived set of items of the Achenbach System of Empirically Based Assessment to develop the Achenbach Self-Control Scale (ASCS) for 7-16 year olds. Using a large dataset of over 20,000 children, who are enrolled in the Netherlands Twin Register, we demonstrated the psychometric properties of the ASCS for parent-, self- and teacher-report by examining internal and criterion validity, and inter-rater and test-retest reliability. We found associations between the ASCS and measures of well-being, educational achievement, and substance use. Next, we applied the classical twin design to estimate the genetic and environmental contributions to self-control. Genetic influences accounted for 64-75% of the variance in self-control based on parent- and teacher-report (age 7-12), and for 47-49% of the variance in self-control based on self-report (age 12-16), with the remaining variance accounted by non shared environmental influences. In conclusion, we developed a validated and accessible self-control scale, and show that genetic influences explain a majority of the individual differences in self-control across youth aged 7-16 years. PMID- 29404831 TI - Confirmatory Factor Analysis of the Nepean Dysphoria Scale in a Clinical Sample. AB - The construct of dysphoria has been described inconsistently across a broad range of psychopathology. The term has been used to refer to an irritable state of discontent, but is also thought to incorporate anger, resentment and nonspecific symptoms associated with anxiety and depression, such as tension and unhappiness. The Nepean Dysphoria Scale has been developed to allow assessment of dysphoria, but its factor structure has not yet been investigated in clinical samples. We aimed to determine the latent structure of dysphoria as reflected by the Nepean Dysphoria Scale, using a clinical sample. Adults (N = 206) seeking treatment at a range of mental health services were administered the Nepean Dysphoria Scale. Four putative factor structures were investigated using confirmatory factor analysis: a single-factor model, a hierarchical model, a bifactor model and a four-factor model as identified in previous studies. No model fit the data except for a four-factor model when a revised 22-item version of the original 24-item scale was investigated. A four-factor structure similar to that identified in non clinical samples was supported, albeit following the removal of two items. The Nepean Dysphoria Scale appears to have utility for the assessment of dysphoria in routine clinical settings. PMID- 29404832 TI - Redescription of the kiwi tick Ixodes anatis (Acari: Ixodidae) from New Zealand, with notes on its biology. AB - Ixodes anatis Chilton is of veterinary and conservation importance in New Zealand due to its association with the threatened kiwi (Aves: Apterygidae: Apteryx spp.). Since the tick's description in 1904, there has been debate regarding its correct taxonomic position and nomenclature. Herein all life stages of this species are redescribed and accompanied by electron micrographs and drawings. The systematics, host preferences, distribution, disease relationships and conservation biology of the species are also discussed. PMID- 29404833 TI - Domestic Violence Victims in Shelters: What Do We Know About Their Mental Health? AB - In this study, the relationship between mental disorders, childhood trauma and sociodemographic characteristics was evaulated in women staying in shelters due to domestic violence. The study comprised 59 volunteers, staying in women's shelters in Istanbul due to domestic violence. The structured clinical interview for DSM-IV TR axis 1 disorders (SCID-I), Domestic Violence Data Form, Hamilton Rating Scale for Depression, Beck Anxiety Inventory and Childhood Trauma Questionnaire were applied by a psychiatric expert in face-to-face interviews. Of the cases 76.3% were diagnosed with at least one psychiatric disorder. Post traumatic stress disorder was the most common diagnosis (50.8%). In our study 59% of women had attempted suicide at least once, and 66% of these were found to have attempted suicide after violence started. Previous psychiatric diagnosis and exposure to childhood abuse were observed to be risk factors for suicide attempts. Psychiatric disease comorbidities and suicide attempt were identified at high rates in women exposed to domestic violence. PMID- 29404834 TI - Managing the Mental Distress of the Hematopoietic Stem Cell Transplant (HSCT) Patient: a Focus on Delirium. AB - PURPOSE OF REVIEW: To highlight the breadth and types of mental distress experienced by hematopoietic stem cell transplant (HSCT) patients and highlight the need for better prevention and management of delirium. RECENT FINDINGS: Recent publications highlight additional risks factors which predict for mental distress during the HSCT process. Despite new medications and additional psychological reports, there is little progress in non-pharmacologic or medication therapy in the prevention and treatment of delirium. Mental distress, especially delirium, is common during the HSCT process. The morbidity associated with delirium and other mental distress can still be significant at 6-12 months after the completion of the procedure affecting patient functioning and quality of life (QOL). Medication interventions may be helpful but should be used sparingly for targeted patients during HSCT. Additional interventions are needed to prevent and treat delirium in HSCT patients. PMID- 29404835 TI - Fatigue and depressive symptoms improve but remain negatively related to work functioning over 18 months after return to work in cancer patients. AB - PURPOSE: The aims of this study are to investigate the course of work functioning, health status, and work-related factors among cancer patients during 18 months after return to work (RTW) and to examine the associations between these variables and work functioning over time. METHODS: Data were used from the 18-month longitudinal "Work Life after Cancer" (WOLICA) cohort, among 384 cancer patients who resumed work. Linear mixed models were performed to examine the different courses during 18-month follow-up. Linear regression analyses with generalized estimating equations (GEE) were used to examine the associations and interactions. RESULTS: Cancer patients reported an increase of work functioning and a decrease of fatigue and depressive symptoms in the first 12 months, followed by a stable course between 12 and 18 months. Cognitive symptoms were stable during the first 18 months. Working hours increased and social support decreased during the first 6 months; both remained stable between 6 and 18 months. Fatigue, depressive, and cognitive symptoms were negatively associated with work functioning over time; working hours and supervisor social support were positively associated. CONCLUSIONS: Interventions to improve cancer patients' work functioning over time might be promising if they are aimed at reducing fatigue, depressive symptoms, cognitive symptoms, and encouraging supervisor social support. IMPLICATIONS FOR CANCER SURVIVORS: It is important to monitor cancer patients not only in the period directly after RTW but up to 18 months after RTW, allowing for timely interventions when needed. PMID- 29404837 TI - Correction to: Development of a sensitive PCR-dot blot assay to supplement serological tests for diagnosing Lyme disease. AB - In the original version of this article, the word "flagellin" is not correct. The correct word should be "P66" throughout the body of the article. PMID- 29404836 TI - Characterization of the nasopharyngeal and middle ear microbiota in gastroesophageal reflux-prone versus gastroesophageal reflux non-prone children. AB - Otitis media (OM) is one of the most common pediatric infections worldwide, but the complex microbiology associated with OM is poorly understood. Previous studies have shown an association between OM and gastroesophageal reflux (GER) in children. Therefore, in order to bridge the gap in our current understanding of the interaction between GER and OM, we investigated the nasopharyngeal and middle ear microbiota of children suffering from GER-associated OM and OM only, using culture-independent 16S rRNA gene sequencing. Middle ear fluid, nasopharyngeal swabs, and clinical data were collected as part of a prospective pilot study conducted at the Department of Otorhinolaryngology of the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. A total of 30 children up to 12 years of age who suffered from recurrent acute otitis media (AOM) (5), chronic otitis media with effusion (OME) (23), or both (2), and who were listed for tympanostomy tube placement, were included in the study. Nine children were included in the GER-associated OM cohort and 21 in the OM-only cohort. We found no obvious effect of GER on the nasopharyngeal and middle ear microbiota between the two groups of children. However, our results highlight the need to assess the true role of Alloiococcus spp. and Turicella spp. in children presenting with a high prevalence of recurrent AOM and chronic OME. PMID- 29404838 TI - Germline promoter hypermethylation in BRCA1 and BRCA2 genes is not present in hereditary breast cancer patients. AB - PURPOSE: Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome. METHODS: We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. RESULTS: Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed. CONCLUSIONS: Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assay for the detection of germline hypermethylation as an effective pre screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA. PMID- 29404839 TI - Coupled Imaging with [18F]FBB and [18F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain. AB - PURPOSE: The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2 [18F]fluoro -D-glucose ([18F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2 {2-[2-[18F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [18F]FBB) in a group of patients affected by Alzheimer's disease (AD). PROCEDURES: We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [18F]FDG and [18F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [18F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [18F]FDG PET/CT scans. RESULTS: SPM analysis in AD patients showed a significant negative correlation between [18F] FBB and [18F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group. CONCLUSIONS: Combined imaging with [18F]FBB and [18FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD. PMID- 29404840 TI - Lithium Inhibits GSK3beta Activity via Two Different Signaling Pathways in Neurons After Spinal Cord Injury. AB - Spinal cord injury (SCI) is a type of long-term disability with a high morbidity rate in clinical settings for which there is no effective clinical treatment to date. Usually, lithium is used as a popular mood stabilizer. Recently, growing evidence has shown that lithium has clear neuroprotective effects after SCI, and the administration of lithium can effectively improve locomotor recovery. However, the exact neuroprotective mechanism of lithium is still not understood. Glycogen synthase kinase-3 beta (GSK3beta) is a serine/threonine kinase that plays an important role in the neuroprotective effects of lithium both in vivo and in vitro. In this study, we discovered that lithium inhibits GSK3beta activity through two different signaling pathways in spinal cord neurons. In the acute phase, lithium inhibited GSK3beta activity by stimulating phosphorylation of AKT; in the chronic phase, we first discovered that lithium additionally upregulated the expression of Na+, K+-ATPase alpha1 (NKA alpha1), which had an inhibitory effect on GSK3beta activity by inducing the expression of glucocorticoid inducible kinase 1 (SGK1). SGK1 is well known as a regulator of the GSK3beta/beta-catenin signaling pathway. Moreover, the suppressed activity of GSK3beta increased the level of beta-catenin in the cytoplasm, which gave rise to the translocation of the freely stabilized beta-catenin to the nucleus. In addition, the accumulation of beta-catenin in the nucleus had the benefits of neuronal survival. Hopefully our findings from this study are beneficial in revealing the neuroprotective mechanism of lithium and in offering novel targets for the development of new SCI therapeutic drugs. PMID- 29404841 TI - A multi-center survey on dietary knowledge and behavior among inpatients in oncology department. AB - OBJECTIVE: To investigate the current associated factors of dietary knowledge and behavior, the intake and nutritional status in malignancy Chinese inpatients, and the malnutrition causes involved in dietary nutrition knowledge level and behavior, providing recommendations to patients for nutrition education and intervention. METHOD: Five hundred and thirty-five participants from 18 hospitals were investigated by a questionnaire related to dietary knowledge and behavior. Physicians asked and recorded the level of dietary intake and appetite scoring of the participants. The nutritional risk screening with the Nutritional Risk Screening 2002 (NRS-2002) and the dietary survey by 24 h dietary recalls were completed by a dietitian. Besides, the target energy intake and the target protein intake were calculated by the "rule of thumb" recommended by ESPEN guideline, comparing the difference between the actual intake and target intake. RESULTS: According to the questionnaire, 95.2% of participants thought it was important to have a good dietetic habit, and nearly half of them have searched for guides on how to diet; 70% of the patients had no clear idea of what was a scientific diet; 82% of patients had contradictory dietary knowledge; 64.2% of patients would listen to the opinion of the attending physician when a contradiction happened. The main three ways of learning about healthy diet were attending physician, network, and TV, respectively, with the values 26.0, 18.5, and 16.1%. Importantly, 99.6% of patients have made mistakes about dietary knowledge, for example, crab, chicken, lamb, fish, and prawns should not be eaten in their concept. In addition, more than 90% of participants have taken Ganoderma lucidum spore powder, sea cucumber, ginseng, Cordyceps sinensis, and so on. Ninety-three percent of the patients never reached a qualified nutrition education. Besides, 15.6% of the participants had nutritional risk (NRS-2002 >= 3). The actual daily energy intake was 1169.20 +/- 465.97 kcal, which was significantly less than target energy intake (P < 0.01), amounting to 65.3% of the target requirements. The actual daily protein intake was 46.55 +/- 21.40 g, which was significantly less than target protein intake (P < 0.01), amounting to 74.44%. On the other hand, 69% of the participants were "Not too bad, Ok, Good, or Very good" according to the records of physicians, while 34% of them did not reach 60%of the target requirements through dietary survey. CONCLUSION: The survey indicated that cancer patients had poor understanding of the scientific dietary nutrition and were in low level of normative nutritional education among Chinese malignancy inpatients. Dietary intake of most cancer patients decreased, and the actual intake cannot be revealed by NRS-2002 score or the physicians' inquiry. It is necessary to enhance the cooperation between dietitians and physicians and develop nutrition education to improve the level of dietary knowledge. PMID- 29404842 TI - Cardiorespiratory fitness and adiposity in breast cancer survivors: is meeting current physical activity recommendations really enough? AB - PURPOSE: Breast cancer (BC) survivors are becoming increasingly predisposed to cardiovascular disease (CVD) mortality. Low cardiorespiratory fitness and physical activity (PA) levels, as well as high values of adiposity indices, contribute to CVD risk. We evaluated adiposity, cardiorespiratory profile, and PA levels in two independent cohorts of BC survivors. METHODS: Data were collected from two groups (99% women) from different areas of Madrid (Spain): group 1, n = 110, age 51.4 +/- 9.7 years, median time from diagnosis 365 days (95% confidence interval [CI], 354-401), and group 2, n = 93, age 54.7 +/- 8.9 years, 1714 days (95% CI, 1502-1938). We estimated peak oxygen uptake (VO2peak) and measured body mass index (BMI), waist circumference (WC), waist-to-hip index, and accelerometry determined PA. RESULTS: Both groups had values of BMI in the overweight range (25.3 +/- 4.3 and 27.1 +/- 5.1 kg/m2, p = 0.003). Estimated VO2peak levels were lower in group 2 than in group 1 (28.1 +/- 9.1 and 23.7 +/- 8.8 ml/kg/min, p < 0.001), although levels in both groups were low. Yet, the majority of participants in both groups (81 and 88%, p = 0.234) met international PA recommendations (235 +/- 196 and 351 +/- 173 min/week of moderate-vigorous PA, p < 0.001). Both groups had very low levels of vigorous PA. These results were essentially independent of type of treatment (anthracycline/radiotherapy). CONCLUSIONS: We found a poor cardiorespiratory profile in two independent BC cohorts that differed in median time from diagnosis (as well in socioeconomic status), supporting the notion that implementation of PA (possibly focusing on vigorous PA) and dietary intervention is urgently needed in this patient population. PMID- 29404843 TI - Perceived stress and its associated demographic-clinical characteristics and positive expectations among Chinese cervical, kidney, and bladder cancer patients. AB - PURPOSE: Positive expectations about personal abilities and future outcomes are important in shaping human behavior and emotion, which may influence the psychological adjustment in cancer patients. We aimed to assess two basic kinds of perceived stress in Chinese cancer patients and to investigate their associations with demographic-clinical characteristics and positive expectations. METHODS: A multi-center, cross-sectional study was conducted in consecutive cervical, kidney, and bladder cancer inpatients from three general hospitals in Liaoning province from February 2013 to August 2014. A total of 790 patients eligible for this study completed questionnaires on demographic-clinical variables, optimism, general self-efficacy, perceived global, and cancer-related stress anonymously. Hierarchical regression analyses were conducted to examine the relationships between optimism, general self-efficacy, and perceived stress, after controlling for possible covariates. RESULTS: Mean score of perceived global stress was 17.85 (SD 4.43). Mean score of perceived cancer-related stress was 37.15 (SD 12.66); 38.1% of the sample scored 44 and above, 20.1% scored 50 and above. Education, physical activity, cancer stage, and time since diagnosis were significantly associated with perceived stress. Optimism and general self efficacy accounted for an additional variance in perceived global (14.9%) and cancer-related stress (16.9%), and both of them were independent and protective variables of perceived stress. CONCLUSIONS: This study recognized cancer patients at risk for high levels of perceived stress and extended the understanding of the association between positive expectations and perceived global and cancer-related stress. Enhancing or maintaining optimism and general self-efficacy might be potential targets for future psychosocial interventions aimed at relieving perceived stress in cancer patients. PMID- 29404844 TI - Breast cancer and chronic pain: a mixed methods review. AB - BACKGROUND: More patients are surviving breast cancer; however, many complain of persistent pain, which significantly impacts on their lives. Studies have predominantly examined risk factors alone. This mixed methods study will systematically compare prospective and retrospective studies of chronic pain following breast cancer treatment. A wider scope than risk factors alone is included in a narrative review element. RESULTS: Common risk factors and themes were identified, and these were compared with some of the retrospective literature available. Several common themes arose in the literature such as common patient demographics, perioperative and postoperative management, treatment modalities and psychological factors. The variation in disease severity, treatment mode and symptom progression between participants in the studies made it difficult to draw conclusions from both the prospective and retrospective literature. CONCLUSION: Chronic pain is common after breast cancer. The literature has focused predominantly on risk factors for the development of chronic pain. It may be more beneficial to focus on chronic pain mechanisms and to consider the patient's narrative and experience of their illness and how this has impacted on the perception and intensity of persistent pain. A shared understanding between the patient and professional is likely to have more beneficial outcomes. PMID- 29404845 TI - Environmental Health of Children: Time to Translate Knowledge into Action. PMID- 29404846 TI - Correction to: Mesenchymal Stem Cell Deformability and Implications for Microvascular Sequestration. AB - This article was updated to correct the spelling of author Brittany L. Banik's name. PMID- 29404847 TI - Human Brain Modeling with Its Anatomical Structure and Realistic Material Properties for Brain Injury Prediction. AB - Impairments of executive brain function after traumatic brain injury (TBI) due to head impacts in traffic accidents need to be obviated. Finite element (FE) analyses with a human brain model facilitate understanding of the TBI mechanisms. However, conventional brain FE models do not suitably describe the anatomical structure in the deep brain, which is a critical region for executive brain function, and the material properties of brain parenchyma. In this study, for better TBI prediction, a novel brain FE model with anatomical structure in the deep brain was developed. The developed model comprises a constitutive model of brain parenchyma considering anisotropy and strain rate dependency. Validation was performed against postmortem human subject test data associated with brain deformation during head impact. Brain injury analyses were performed using head acceleration curves obtained from reconstruction analysis of rear-end collision with a human whole-body FE model. The difference in structure was found to affect the regions of strain concentration, while the difference in material model contributed to the peak strain value. The injury prediction result by the proposed model was consistent with the characteristics in the neuroimaging data of TBI patients due to traffic accidents. PMID- 29404848 TI - Eliminating Regurgitation Reduces Fibrotic Remodeling of Functional Mitral Regurgitation Conditioned Valves. AB - Functional mitral regurgitation (FMR) is an insidious and poorly understood condition affecting patients with myocardial disease. While current treatments reduce regurgitation, their ability to reverse mitral valve pathology is unclear. We utilized a pseudo-physiological flow loop to study how repair impacted valve composition. Porcine mitral valves were cultured in control geometry (native papillary muscle position and annular area) or high-tension FMR geometry (5 mm apical and 5 mm lateral displacement of papillary muscles, 65% increased annular area) for 2 weeks. To mimic repair, a reversal condition was created by returning one-week FMR conditioned valves to a non-regurgitant geometry and culturing for 1 week. Valve composition and material properties were analyzed. After two-week culture, FMR conditioned tissues were stiffer and stronger than control and underwent extensive fibrotic remodeling, with increased prolyl-4-hydroxylase, lysyl oxidase, matrix metalloproteinase-1, and decorin. The reversal condition displayed a heterogeneous, leaflet- and orientation-dependent response. Reversal conditioned anterior leaflets and circumferential tissue sections continued to have significant fibrotic remodeling compared to control, whereas reversal conditioned posterior leaflets, chordae tendineae, and radial tissue sections had significantly decreased remodeling compared to FMR-conditioned tissues. These findings suggest current repairs only partially reverse pathology, underscoring the need for innovation in the treatment of FMR. PMID- 29404849 TI - Evaluation of physiological response and performance by supplementation of Curcuma longa in broiler feed under hot humid tropical climate. AB - Dietary manipulation has been seen as one of the practical ways to ameliorate the adverse effects of thermal stress in the hot humid tropical climate. In order to investigate the influence of Curcuma longa (turmeric) rhizome powder on physiological responses and performance under hot humid tropical climate, 240 broiler chicks were randomly assigned to four dietary treatments having four replicates of 15 birds each in a complete randomized design. Broiler birds were fed basal diets and supplemented with 0 (CT), 4 (TG), 8 (FT), and 12 g (SG) of turmeric powder/kg of diet for 8 weeks. Data were collected weekly on feed intake and body weights. Blood samples were collected from eight birds per treatment at week 4 (starter phase) and week 8 (finisher phase) of the experiment for the determination of plasma 3,5,3'-triiodothyronine (T3), superoxide dismutase (SOD), malondialdehyde (MDA). Rectal temperature of the birds was also taken. At 56 days of age, eight birds from each treatment were slaughtered for the determination of relative organ weights. Results showed that the final weights of the birds in FT were significantly higher than those of the birds in TG, SG, and CT. The weight gain of the birds in FT was higher than those of the birds in SG while those of SG were higher than those of TG whose values were higher than that of CT. The feed conversion ratio of the broiler chickens in CT was higher (P < 0.05) than those of other treatment groups while the birds in FT and SG had similar feed conversion ratios. SOD of birds fed turmeric rhizome powder was higher than the birds in the control group at both starter and finisher phases. Furthermore, MDA of the birds in FT was lower than those of the birds in the other treatment groups at the finisher phase. Plasma T3 was higher in the birds fed turmeric at the finisher phase than chickens in the control group. There was no difference in the rectal temperatures of the birds. To conclude, turmeric rhizome powder improved the physiological response and performance of broiler chicken under hot humid tropical climate in a dose-dependent characteristic and the optimum supplementation rate of 8 g/kg of diet was recorded. PMID- 29404850 TI - MABAL: a Novel Deep-Learning Architecture for Machine-Assisted Bone Age Labeling. AB - Bone age assessment (BAA) is a commonly performed diagnostic study in pediatric radiology to assess skeletal maturity. The most commonly utilized method for assessment of BAA is the Greulich and Pyle method (Pediatr Radiol 46.9:1269-1274, 2016; Arch Dis Child 81.2:172-173, 1999) atlas. The evaluation of BAA can be a tedious and time-consuming process for the radiologist. As such, several computer assisted detection/diagnosis (CAD) methods have been proposed for automation of BAA. Classical CAD tools have traditionally relied on hard-coded algorithmic features for BAA which suffer from a variety of drawbacks. Recently, the advent and proliferation of convolutional neural networks (CNNs) has shown promise in a variety of medical imaging applications. There have been at least two published applications of using deep learning for evaluation of bone age (Med Image Anal 36:41-51, 2017; JDI 1-5, 2017). However, current implementations are limited by a combination of both architecture design and relatively small datasets. The purpose of this study is to demonstrate the benefits of a customized neural network algorithm carefully calibrated to the evaluation of bone age utilizing a relatively large institutional dataset. In doing so, this study will aim to show that advanced architectures can be successfully trained from scratch in the medical imaging domain and can generate results that outperform any existing proposed algorithm. The training data consisted of 10,289 images of different skeletal age examinations, 8909 from the hospital Picture Archiving and Communication System at our institution and 1383 from the public Digital Hand Atlas Database. The data was separated into four cohorts, one each for male and female children above the age of 8, and one each for male and female children below the age of 10. The testing set consisted of 20 radiographs of each 1-year age cohort from 0 to 1 years to 14-15+ years, half male and half female. The testing set included left-hand radiographs done for bone age assessment, trauma evaluation without significant findings, and skeletal surveys. A 14 hidden layer customized neural network was designed for this study. The network included several state of the art techniques including residual-style connections, inception layers, and spatial transformer layers. Data augmentation was applied to the network inputs to prevent overfitting. A linear regression output was utilized. Mean square error was used as the network loss function and mean absolute error (MAE) was utilized as the primary performance metric. MAE accuracies on the validation and test sets for young females were 0.654 and 0.561 respectively. For older females, validation and test accuracies were 0.662 and 0.497 respectively. For young males, validation and test accuracies were 0.649 and 0.585 respectively. Finally, for older males, validation and test set accuracies were 0.581 and 0.501 respectively. The female cohorts were trained for 900 epochs each and the male cohorts were trained for 600 epochs. An eightfold cross-validation set was employed for hyperparameter tuning. Test error was obtained after training on a full data set with the selected hyperparameters. Using our proposed customized neural network architecture on our large available data, we achieved an aggregate validation and test set mean absolute errors of 0.637 and 0.536 respectively. To date, this is the best published performance on utilizing deep learning for bone age assessment. Our results support our initial hypothesis that customized, purpose-built neural networks provide improved performance over networks derived from pre-trained imaging data sets. We build on that initial work by showing that the addition of state-of-the-art techniques such as residual connections and inception architecture further improves prediction accuracy. This is important because the current assumption for use of residual and/or inception architectures is that a large pre-trained network is required for successful implementation given the relatively small datasets in medical imaging. Instead we show that a small, customized architecture incorporating advanced CNN strategies can indeed be trained from scratch, yielding significant improvements in algorithm accuracy. It should be noted that for all four cohorts, testing error outperformed validation error. One reason for this is that our ground truth for our test set was obtained by averaging two pediatric radiologist reads compared to our training data for which only a single read was used. This suggests that despite relatively noisy training data, the algorithm could successfully model the variation between observers and generate estimates that are close to the expected ground truth. PMID- 29404852 TI - Efficient algorithm for baseline wander and powerline noise removal from ECG signals based on discrete Fourier series. AB - Electrocardiogram (ECG) signals are often contaminated with artefacts and noises which can lead to incorrect diagnosis when they are visually inspected by cardiologists. In this paper, the well-known discrete Fourier series (DFS) is re explored and an efficient DFS-based method is proposed to reduce contribution of both baseline wander (BW) and powerline interference (PLI) noises in ECG records. In the first step, the determination of the exact number of low frequency harmonics contributing in BW is achieved. Next, the baseline drift is estimated by the sum of all associated Fourier sinusoids components. Then, the baseline shift is discarded efficiently by a subtraction of its approximated version from the original biased ECG signal. Concerning the PLI, the subtraction of the contributing harmonics calculated in the same manner reduces efficiently such type of noise. In addition of visual quality results, the proposed algorithm shows superior performance in terms of higher signal-to-noise ratio and smaller mean square error when faced to the DCT-based algorithm. PMID- 29404851 TI - A General Framework for Monitoring Image Acquisition Workflow in the Radiology Environment: Timeliness for Acute Stroke CT Imaging. AB - Many facets of an image acquisition workflow leave a digital footprint, making workflow analysis amenable to an informatics-based solution. This paper describes a detailed framework for analyzing workflow and uses acute stroke response timeliness in CT as a practical demonstration. We review methods for accessing the digital footprints resulting from common technologist/device interactions. This overview lays a foundation for obtaining data for workflow analysis. We demonstrate the method by analyzing CT imaging efficiency in the setting of acute stroke. We successfully used digital footprints of CT technologists to analyze their workflow. We presented an overview of other digital footprints including but not limited to contrast administration, patient positioning, billing, reformat creation, and scheduling. A framework for analyzing image acquisition workflow was presented. This framework is transferable to any modality, as the key steps of image acquisition, image reconstruction, image post processing, and image transfer to PACS are common to any imaging modality in diagnostic radiology. PMID- 29404853 TI - Implantation of multiple polytetrafluoroethylene covered stent inside drug eluting stent to rescue purulent coronary artery ectasia with giant saccular aneurysm. AB - A 79-year-old male with diabetes mellitus and old cerebral infarction was admitted to hospital due to fever and palpitation. Diagnosis of purulent pericarditis was established by pericardial effusion examination. The patient's general condition improved temporarily after drainage of the pericardial effusion. However, computed tomography demonstrated a saccular aneurysm arising from RCA have rapidly grown even larger, up to 63 * 51 mm on 7th hospital day. This indicated that the risk of rupture of the aneurysm was high. Percutaneous coronary intervention was applied to prevent rupture of the aneurysm. Several polytetrafluoroethylene (PTFE)-covered stents were required to cover the extended aneurysm lesion. A long drug-eluting stent (DES), which was initially implanted through the aneurysm, was itself implanted with 3 PTFE-covered stents located inside the DES. This procedure provided protection against endoleak of the aneurysm. To our knowledge, the present case shows for the first time that PTFE covered stents located within DES are useful in treatment of a giant coronary aneurysm. PMID- 29404854 TI - Erratum to: Relapsing Uveitis in Association with Presumed Sinus Histiocytosis. PMID- 29404856 TI - Analysis and Fem Simulation Methodology of Dynamic Behavior of Human Rotator Cuff in Repetitive Routines: Musician Case Study. AB - The majority of musculoskeletal injuries located in the shoulder are often due to repetitive or sustained movements that occur in work routines in different areas. In the case of musicians, such as violinists, who have long and daily training routines, the repetitive movements they perform are forced and sometimes the postures are not natural. Therefore, this article aims to study and simulate the dynamic behavior of the glenohumeral joint under repetitive conditions that represent the different postures assumed by a violinist during his daily training. For this purpose, the criteria provided by the RULA (rapid upper limb assessment) method have been used. Subsequently, by using as a reference geometry that of the articulation under study generated and modeled in CATIA(r)[VERSION 5R21], a FEM analysis has been proposed with the software ANSYS(r)[VERSION 17.1] simulating the short and cyclic movements of the Humerus of the violinists. With the analysis carried out, thanks to linear and isotropic approximations of the joint, it has been possible to know the approximate dynamic behavior of tissues, muscles and tendons, and the response of the joint in terms of fatigue. PMID- 29404855 TI - An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats. AB - At elevated levels, fluoride (F-) exposure has been associated with adverse human health effects. In rodents, F- exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.5 ppm F-) or a low F- diet (3.24 ppm F-) with drinking water exposure to 0, 10, or 20 ppm F- from gestational day 6 through adulthood. At postnatal day 25, brain F- levels were 0.048 or 0.081 MUg/g and femur 235 or 379.8 MUg/g for 10 and 20 ppm F-, respectively. Levels increase with age and in adults, levels for plasma were 0.036 or 0.025 MUg/ml; for the brain 0.266 or 0.850 MUg/g; and for the femur, 681.2 or 993.4 MUg/g. At these exposure levels, we observed no exposure-related differences in motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze. Serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were not altered as a function of 10 or 20 ppm F- in the drinking water. No exposure related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides. Mild inflammation in the prostate gland was observed at 20 ppm F-. No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F-. PMID- 29404857 TI - Erratum to: Effects of Reference Axes Used During Measurements of Ocular and Corneal Higher-Order Aberrations in Patients Following LASIK. PMID- 29404859 TI - Serum Exosomes Attenuate H2O2-Induced Apoptosis in Rat H9C2 Cardiomyocytes via ERK1/2. AB - Exosomes are small-sized vesicles that can be released from cells into the serum. Exosomes play important roles in regulating many biological processes including cell proliferation, apoptosis, cell cycle, and metabolism. However, the roles and mechanisms of plasma exosomes in the apoptosis of rat H9C2 cardiomyocytes are largely unknown. In this study, we isolated plasma exosomes as confirmed by the marker protein CD63. Using flow cytometry and western blot analysis, we found that exosomes attenuated hydrogen peroxide (H2O2)-induced apoptosis and improved survival of rat H9C2 cardiomyocytes. Furthermore, the anti-apoptosis effects of serum exosomes in rat H9C2 cardiomyocytes were mediated by the activation of ERK1/2 signaling pathway. These data indicated that plasma exosomes had the protective effects against cardiomyocyte apoptosis and might be a novel therapy strategy for myocardial injury. PMID- 29404858 TI - Bayesian Networks: A New Approach to Predict Therapeutic Range Achievement of Initial Cyclosporine Blood Concentration After Pediatric Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Pediatric hematopoietic stem cell transplantation (HSCT) allows the treatment of numerous diseases, both malignant and non-malignant. Cyclosporine, a narrow therapeutic index drug, is the major immunosuppressant used to prevent graft-versus-host disease (GVHD), but may also cause severe adverse effects in case of overdosing. OBJECTIVE: The objective of this study is to predict the initial cyclosporine residual blood concentration value after pediatric HSCT, and consequently the dose necessary to reach the therapeutic range, using a mathematical individual predictive model. METHODS: Clinical and biological data collected from the graft infusion for 2 months after transplantation in 155 pediatric patients undergoing HSCT between 2008 and 2016 were used to generate synthetic data for 1000 subjects which were used to build a Bayesian network model. We compared the characteristics and sensitivity to clinical or biological missing data of this model with four other methods. RESULTS: The tree-augmented Naive Bayesian network showed the best characteristics, with no missing data (area under the curve of the receiving operator characteristics curve [AUC-ROC] of 0.89 +/- 0.02), 18.9 +/- 2.6% of patients misclassified, and positive and negative predictive values of 85.9 +/- 3.4% and 74.2 +/- 5.1%, respectively, and this trend is found in the synthetic dataset from no to 10% missing data. The most relevant variables that could influence whether the initial residual cyclosporine concentration is in the therapeutic range are the last dose before measurement and the mean dose before measurement. CONCLUSIONS: We developed and cross-validated an online Bayesian network to predict the first cyclosporine concentration after pediatric HSCT. This model allows simulation of different dosing regimens, and enables the best dosing regimen to reach the therapeutic range immediately after transplantation to be found, minimizing the risk of adverse effects and GVHD occurrence. PMID- 29404860 TI - Ranibizumab versus aflibercept for the treatment of vascularized pigment epithelium detachment due to age-related macular degeneration. AB - PURPOSE: To compare the efficacy and safety of two intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, ranibizumab and aflibercept, for the treatment of vascularized pigment epithelium detachment (vPED) due to age related macular degeneration (AMD) in a follow-up time of 12 months. METHODS: Participants in this study were 71 patients (71 eyes) with vPED due to AMD, who were treated with intravitreal 0.5 mg ranibizumab (n = 38) or 2.0 mg aflibercept (n = 33) and had at least 12-month follow-up. All patients underwent best corrected visual acuity (BCVA) measurement and optical coherence tomography at baseline and at every visit. The PED height, the presence of subretinal fluid (SRF), intraretinal fluid and diffuse macular edema (DME) were recorded at each visit. RESULTS: There was a statistically significant difference in BCVA between the two groups at month 12 in favor of aflibercept. However, both agents were found to improve or stabilize BCVA in the majority of patients at the end of the follow-up. The change in PED height did not differ significantly between the two groups at the end of the follow-up with similar number of injections. At month 12, there was a significant improvement in SRF presence in both groups compared to baseline. CONCLUSIONS: Although aflibercept was found to be superior to ranibizumab regarding BCVA improvement, both agents showed anatomical effectiveness with significant reduction in PED height and SRF absorption in patients with vPED due to AMD. PMID- 29404861 TI - Therapeutic potential of curcumin in major retinal pathologies. AB - PURPOSE: The retina is continually exposed to free radicals from its rich blood supply, numerous mitochondria, and photons of light which strike its surface. Most pathological processes that take place in the retina, such as inflammation, cell apoptosis, or angiogenesis, can hence involve free radicals directly or indirectly. Since inflammatory and oxidative stress pathways underlie retinal pathology, compounds that address these factors are therefore natural choices for treatment. This review article summarizes and provides commentary on curcumin's therapeutic potential use in ophthalmology with principal focus on retinal dosorders. METHODS: Curcumin (diferuloylmethane) is a compound of the Indian spice turmeric (Curcuma longa) that has been found to be efficacious in preventing and treating a number of inflammatory diseases and neoplastic processes. Curcumin exerts anti-inflammatory, anti-tumor, antioxidant, and VEGF inhibition properties through modulation of numerous biochemical mediators. This makes curcumin particularly effective in retinal disorders. RESULTS: Curcumin has found a role in slowing, and in some cases even reversing, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, proliferative vitreoretinopathy, and retinal cancers. CONCLUSIONS: However, studies on curcumin's efficacy have been limited mostly to animal studies. Moreover, the biomedical potential of curcumin is not easy to use, given its low solubility and oral bioavailability-more attention therefore has been given to nanoparticles and liposomes. PMID- 29404862 TI - Choices Behind Numbers: a Review of the Major Air Pollution Health Impact Assessments in Europe. AB - PURPOSE OF REVIEW: The aim of this review is to identify the key contextual and methodological differences in health impact assessments (HIA) of ambient air pollution performed for Europe. We limited our review to multi-country reviews. An additional aim is to quantify some of these differences by applying them in a HIA template in three European cities. RECENT FINDINGS: Several HIAs of ambient air pollution have been performed for Europe, and their key results have been largely disseminated. Different studies have, however, come up with substantial differences in attributed health effects. It is of importance to review the background contributing to these differences and to quantify their importance for decision makers who will use them. We identified several methodological differences that could explain the discrepancy behind the number of attributable deaths or years of life lost. The main differences are due to the exposure response functions chosen, the ways of assessing air pollution levels, the air pollution scenarios and the study population. In the quantification part, we found that using risk estimates from the European Study of Cohorts for Air Pollution Effects (ESCAPE) instead of the American Cancer Society (ACS) study could nearly double the attributable burden of ambient air pollution. This study provides some insights into the differential results in previously published HIAs on air pollution in Europe. These results are important for stakeholders in order to make informed decisions. PMID- 29404864 TI - Effects of glyphosate formulations on the population dynamics of two freshwater cladoceran species. AB - The general objective of this work is to experimentally assess the effects of acute glyphosate pollution on two freshwater cladoceran species (Daphnia magna and Ceriodaphnia dubia) and to use this information to predict the population dynamics and the potential for recovery of exposed organisms. Five to six concentrations of four formulations of glyphosate (4-Gly) (Eskoba(r), Panzer Gold(r), Roundup Ultramax(r) and Sulfosato Touchdown(r)) were evaluated in both cladoceran species through acute tests and 15-day recovery tests in order to estimate the population dynamics of microcrustaceans. The endpoints of the recovery test were: survival, growth (number of molts), fecundity, and the intrinsic population growth rate (r). A matrix population model (MPM) was applied to r of the survivor individuals of the acute tests, followed by a Monte Carlo simulation study. Among the 4-Gly tested, Sulfosato Touchdown(r) was the one that showed higher toxicity, and C. dubia was the most sensitive species. The Monte Carlo simulation study showed an average value of lambda always <1 for D. magna, indicating that its populations would not be able to survive under natural environmental conditions after an acute Gly exposure between 0.25 and 35 a.e. mg L-1. The average value of lambda for C. dubia was also <1 after exposure to Roundup Ultramax(r): 1.30 and 1.20 for 1.21 and 2.5 mg a.e. L-1,respectively. The combined methodology-recovery tests and the later analysis through MPM with a Monte Carlo simulation study-is proposed to integrate key demographic parameters and predict the possible fate of microcrustacean populations after being exposed to acute 4-Gly contamination events. PMID- 29404863 TI - In vitro evidence that platelet-rich plasma stimulates cellular processes involved in endometrial regeneration. AB - PURPOSE: The study aims to test the hypothesis that platelet-rich plasma (PRP) stimulates cellular processes involved in endometrial regeneration relevant to clinical management of poor endometrial growth or intrauterine scarring. METHODS: Human endometrial stromal fibroblasts (eSF), endometrial mesenchymal stem cells (eMSC), bone marrow-derived mesenchymal stem cells (BM-MSC), and Ishikawa endometrial adenocarcinoma cells (IC) were cultured with/without 5% activated (a) PRP, non-activated (na) PRP, aPPP (platelet-poor-plasma), and naPPP. Treatment effects were evaluated with cell proliferation (WST-1), wound healing, and chemotaxis Transwell migration assays. Mesenchymal-to-epithelial transition (MET) was evaluated by cytokeratin and vimentin expression. Differential gene expression of various markers was analyzed by multiplex Q-PCR. RESULTS: Activated PRP enhanced migration of all cell types, compared to naPRP, aPPP, naPPP, and vehicle controls, in a time-dependent manner (p < 0.05). The WST-1 assay showed increased stromal and mesenchymal cell proliferation by aPRP vs. naPRP, aPPP, and naPPP (p < 0.05), while IC proliferation was enhanced by aPRP and aPPP (p < 0.05). There was no evidence of MET. Expressions of MMP1, MMP3, MMP7, and MMP26 were increased by aPRP (p < 0.05) in eMSC and eSF. Transcripts for inflammation markers/chemokines were upregulated by aPRP vs. aPPP (p < 0.05) in eMSC and eSF. No difference in estrogen or progesterone receptor mRNAs was observed. CONCLUSIONS: This is the first study evaluating the effect of PRP on different human endometrial cells involved in tissue regeneration. These data provide an initial ex vivo proof of principle for autologous PRP to promote endometrial regeneration in clinical situations with compromised endometrial growth and scarring. PMID- 29404865 TI - Polycyclic aromatic hydrocarbons (PAHs) in sediments from a typical urban impacted river: application of a comprehensive risk assessment. AB - Soweto and Lenasia, the most densely populated area of South Africa, is simultaneously a thriving metropolis, with a fair share of people still living in squalor conditions directly dependant on the natural resources. Because of industrialisation the populace and environment in this urban area are exposed to various pollutants. The aquatic environment was selected as a proxy to study the effect of industrial pollution in this area. The concentrations, source identification, and various environmental risks of polycyclic aromatic hydrocarbons (PAHs) were determined in sediments of the upper reaches of the Klip River. Composite sediment samples collected in low-flow conditions in 2013 and 2014 ranged from 270-5400 ng/g. The PAHs in this aquatic ecosystem were dominated by 4-ring congeners and could be attributed to combustion of organic fuels by chemical mass balance. Heavy traffic and industrial complexes in the northern part of the study area were responsible for the PAH fingerprints. Probable adverse effects such as toxicity to benthic biota were proven after comparison with international sediment quality guidelines (SQG) both survey years. Toxic equivalence quotients (TEQs) calculated for the sediments using fish potency factors (FPFs) were up to 30 times greater than the Canadian guideline for dioxin like compounds, indicating high probability of carcinogenic effect to fish mediated through the aryl-hydrocarbon receptor. Finally, sediments in the area posed moderate to high ecological risk, which corroborates the other toxicity assessments. The advantage of investigating multiple risk endpoints, is the comprehensive results obtained that allows for a more realistic representation of the study area. Consequently more aspects are kept into account that results in better conclusions. PMID- 29404866 TI - Differential expression of the PAL gene family in rice seedlings exposed to chromium by microarray analysis. AB - Phenylalanine ammonia-lyase (PAL) is one of the principle enzymes involved in plant's secondary metabolism. Expression of individual isogene from the PAL gene family is variable with species of plants in responses to different stresses. In this study, transcriptome analysis of the PAL gene family in rice seedlings exposed to potassium chromate Cr(VI) or chromium nitrate Cr(III) was conducted using Agilent 44K rice microarray and real-time quantitative RT-PCR. Uptake and accumulation of both Cr species by rice seedlings and their effect on PAL activity were also determined. Three days of Cr exposure led to significant accumulation of Cr in plant tissues, but majority being in roots rather than shoots. Changes of PAL activities in rice tissues were evident from both Cr treatments. Individual isogene from the rice PAL gene family was expressed differentially in response to both Cr variants. Comparing gene expression between two Cr treatments, only osPAL2 and osPAL4 genes were expressed in similar patterns. Also, gene expression pattern was inconsistent in both plant tissues. Results indicated that expression of individual isoform from the rice PAL gene family is tissue, and stimulus specific under different Cr exposure, suggesting their different detoxification strategies for decreasing or eliminating Cr stresses. PMID- 29404867 TI - Short-term effects of two fungicides on enchytraeid and earthworm communities under field conditions. AB - Because of the wide use of pesticides in agriculture, there is still a need of higher-tier field studies to assess ecotoxicological effects of commercial formulations on a wider variety of non-target soil organisms such as soil annelids. We here tested the effects of different concentrations of two fungicide formulations, i.e., Cuprafor Micro(r) (composed of 500 g kg-1 copper oxychloride) and Swing Gold(r) (composed of 50 g l-1 epoxiconazole and 133 g l-1 dimoxystrobin) on two families of terrestrial oligochaetes (Lumbricidae and Enchytraeidae) after 1 month of exposure. We also assessed the feeding activity of soil organisms using the bait lamina method. Along with the feeding activity, the enchytraeid density, diversity and communities were not different in the control and the contaminated plots. By contrast, epigeic earthworms were absent and earthworm diversity and densities of anecic species decreased significantly in the plots contaminated at ten times the recommended dose of the Swing Gold(r) formulation. The copper fungicide (at 0.75 and 7.5 kg Cu ha-1) and the treatment with the pesticide mixture (Cuprafor Micro(r) at 0.75 kg Cu ha-1 and Swing Gold(r) at the recommended dose) did not affect Oligochaeta communities compared with the control, except the Shannon index for earthworms in the mixture of both fungicides. Responses of the two annelid families to the tested pesticides were different with higher effects observed on the diversity and the community structure of earthworms compared with enchytraeids. This study allowed detecting early changes on oligochaete populations after pesticide application. PMID- 29404868 TI - Selective toxicity of the mesoionic insecticide, triflumezopyrim, to rice planthoppers and beneficial arthropods. AB - The novel mesoionic insecticide triflumezopyrim was highly effective in controlling both imidacloprid-susceptible and resistant planthopper populations in Malaysia. However, the toxicity of triflumezopyrim to planthopper populations and their natural enemies has been under-investigated in China. In this study, the median lethal concentrations (LC50) of triflumezopyrim were determined in eight field populations of Nilaparvata lugens and one population of Sogatella furcifera from China under laboratory conditions. Triflumezopyrim showed higher toxicity to planthopper populations than the commonly-used insecticide, imidacloprid. Furthermore, the lethal effect of triflumezopyrim on eight beneficial arthropods of planthoppers was investigated in the laboratory and compared with three commonly-used insecticides, thiamethoxam, chlorpyrifos and abamectin. Triflumezopyrim was harmless to Anagrus nilaparvatae, Cyrtorhinus lividipennis and Paederus fuscipes, while thiamethoxam, chlorpyrifos and abamectin were moderately harmful or harmful to the insect parasitoid and predators. Triflumezopyrim and thiamethoxam were harmless to the predatory spiders Pirata subpiraticus, Ummeliata insecticeps, Hylyphantes graminicola and Pardosa pseudoannulata, and slightly harmful to Theridion octomaculatum. Chlorpyrifos caused slight to high toxicity to four spider species except U. insecticeps. Abamectin was moderately to highly toxic to all five spider species. Our results indicate that triflumezopyrim has high efficacy for rice planthoppers populations and is compatibile with their natural enemies in China. PMID- 29404869 TI - Bioconcentration and effects of hexabromocyclododecane exposure in crucian carp (Carassius auratus). AB - As a cycloaliphatic brominated flame retardant, hexabromocyclododecane (HBCD) has been widely used in building thermal insulation and fireproof materials. However, there is little information on the bioconcentration as well as effects with respect to HBCD exposure in the aquatic environment. To investigate the bioconcentration of HBCD in tissues (muscle and liver) and its biochemical and behavioural effects, juvenile crucian carp (Carassius auratus) were exposed to different concentrations of technical HBCD (nominal concentrations, 2, 20, 200 MUg/L) for 7 days, using a flow-through exposure system. HBCD was found to concentrate in the liver and muscle with a terminal concentration of 0.60 +/- 0.22 MUg/g lw (lipid weight) and 0.18 +/- 0.02 MUg/g lw, respectively, at an environmentally-relevant concentration (2 MUg/L). The total thyroxine and total triiodothyronine in the fish plasma were lowered as a result of exposure to the HBCD. Acetylcholinesterase activity in the brain was increased, while swimming activity was inhibited and shoaling inclination was enhanced after exposure to 200 MUg/L HBCD. Feeding rate was suppressed in the 20 and 200 MUg/L treatment groups. In summary, HBCD concentrations 10-100* higher than the current environmentally-relevant exposures induced adverse effects in the fish species tested in this study. These results suggest that increasing environmental concentrations and/or species with higher sensitivity than carp might be adversely affected by HBCD. PMID- 29404870 TI - Genetic effects in Helix aspersa near a coal plant revealed by the micronucleus test. AB - Coal plants can be a major source of mutagenic pollutants. In this study we used the common land snail Helix aspersa, to detect the mutagenic effect of pollution from a coal plant in central Italy applying the micronucleus test (MN) on snail's haemocytes and evaluating trace elements concentration (As Cd, Pb, Hg, and Zn) in soil and snails. Snails from a biological farm were exposed for 13 days in five locations at different distances from the plant. Wild snails collected in the same locations were also analysed. MN frequency in exposed snails was significantly higher in four locations within 10 km from to the plant, with respect to the control and the farthest location. Comparing the MN frequency between farmed and wild snails, a significantly higher frequency emerged for the exposed snails in all locations except the farthest, likely indicating adaptation or selection of the wild organisms due to chronic exposure to pollutants. In natural snails significantly higher MN frequencies with near the plant emerged as well. Trace elements analysis showed significant correlations between MN frequencies and both Zn and As concentrations in soil, for both exposed and wild snails, and Zn and Pb concentrations in exposed snails. Our results were consistent with those previously obtained when evaluating primary DNA damage in natural snails from the same area and show that the snails near the plant were affected by a permanent cytogenetic damage. Moreover, they confirm the suitability of snails for biomonitoring the presence of pollutants with mutagenic effect. PMID- 29404871 TI - Involvement of the Negative Feedback of IL-33 Signaling in the Anti-Inflammatory Effect of Electro-acupuncture on Allergic Contact Dermatitis via Targeting MicroRNA-155 in Mast Cells. AB - In this study, we aimed to investigate the effect of electro-acupuncture (EA) at the Zusanli acupoint (ST36) on interleukin (IL)-33-mediated mast cell activation. Firstly, 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in rats was developed with or without EA treatment. Then, rat peritoneal mast cells (RPMCs) were obtained and cultured in the presence of IL-33. EA treatment relieved ear swelling and reduced mast cell infiltration in the local inflammation area with DNFB challenge, accompanying the decrement of IL-33 production. RPMCs isolated from ACD rats with EA treatment showed significant downregulation of IL-6, TNF-alpha, IL-13, and MCP-1 production following IL-33 stimulation. However, there was no obvious difference in surface ST2 receptor expression among different groups. In addition, EA selectively altered IL-33 signaling, suppressing p38 phosphorylation as well as NF-kappaB- and AP-1 mediated transcription but not Akt phosphorylation. Importantly, EA lowered microRNA (miR)-155 expression in the RPMCs, which presented a positive correlation with IL-33-induced IL-6 production. Furthermore, overexpression of miR-155 in the RPMCs was established following miR-155 mimic transfection. RPMCs with the overexpressed miR-155 displayed an obvious increment of inflammatory cytokine and abrogated the inhibitive effect of EA on NF-kappaB- and AP-1 regulated transcription in response to IL-33 compared with those without transfected-miR-155. These findings demonstrate EA treatment inhibits NF-kappaB and AP-1 activation as well as promotes the negative feedback regulation of IL-33 signaling via targeting miR-155 in mast cells, which contribute to the anti inflammatory effect of EA on DNFB-induced ACD in rats. PMID- 29404873 TI - Correction to: Comparison of the gut microbiota composition between wild and captive sika deer (Cervus nippon hortulorum) from feces by high-throughput sequencing. AB - The authors regret the following errors occurred in the original publication of the article (Guan et al. 2017). The corrected texts have been presented with this erratum. PMID- 29404872 TI - Acute Inflammation and Metabolism. AB - Inflammation is an adaptive process to the noxious stimuli that the human body is constantly exposed to. From the local inflammatory response to a full-blown systemic inflammation, a wide complex sequence of events occurs. Persistent immunosuppression and catabolism may ensue, until multiple organ failure finally sets in. And since clinically useful and specific biomarkers are lacking, diagnosis may come late. A thorough understanding of these events (how they begin, how they evolve, and how to modulate them) is imperative, but as yet poorly studied. This review aims to consolidate current knowledge of these events so that the management of these patients is not only evidence-based, but also built on an understanding of the inner workings of the human body in health and in disease. PMID- 29404874 TI - Direct oral anti-coagulants compared to vitamin-K antagonists in cardioversion of atrial fibrillation: an updated meta-analysis. AB - Pharmacological or electrical cardioversion allows immediate symptoms improvement in the setting of paroxysmal or persistent atrial fibrillation (AF), although the periprocedural risk of systemic embolism should be considered. Recently, there was a great interest on the safety and efficacy of direct oral anticoagulants (DOACs) when used for the cardioversion of non-valvular AF. We performed a random effects meta-analysis of patients undergoing both electrical and pharmacologic cardioversion for non-valvular AF in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF TIMI 48, X-VeRT, ENSURE-AF, and EMANATE trials. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for stroke/systemic embolism (SSE) and major bleeding (MB) at follow-up. A total of 8564 patients have been included in the analysis. When compared with patients receiving vitamin-K antagonists (VKAs), patients receiving DOACs had a lower risk of SSE (RR 0.70, 95% CI 0.33-1.546, P = 0.34), as well as of MB (RR 0.86;,95% CI 0.47-1.58, P = 0.62), although both were non-significant. Funnel plot analysis showed, however, lower RRs with more recent ad hoc studies in comparison with registrational studies, even though statistical significance was not reached. DOACs are as effective and as safe as VKAs for thromboembolic prevention in non valvular AF in the setting of cardioversion. There are differences, although non significant, between registrational studies and studies enrolling exclusively patients undergoing cardioversion of AF. PMID- 29404875 TI - Acute agranulocytosis after oral administration of dabigatran: a rare case report and a short review of literature. AB - This case report describes agranulocytosis immediately after oral administration of dabigatran in a 68 years old man with atrial fibrillation (AF). Dabigatran is an oral, reversible and competitive thrombin inhibitor that has shown promising results. In patients with atrial fibrillation of RE-LY study (Randomized Evaluation of Long-Term Anticoagulant Therapy), dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Dabigatran is administered as a prodrug and the peak of the plasma concentrations occurs within 2 h of ingestion. Agranulocytosis is characterized by a severe decrease or lack of circulating granulocytes. This rare event can be found among people taking dabigratan, especially for people who are female, over the age of 60, who took the drug for < 1 month. Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. The patient's white blood cell count increased abruptly after discontinuation of the drug, suggesting an immune response caused by dabigatran. Although anticoagulant drugs are commonly used to treat atrial fibrillation, attention should be paid to this aspect and possible drug interactions. PMID- 29404877 TI - O-GlcNAc: a novel regulator of immunometabolism. AB - The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4+ T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4+ T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked beta-N acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4+ T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4+ T cells and uncover new potential therapeutic targets. PMID- 29404876 TI - Thrombosis in Philadelphia negative classical myeloproliferative neoplasms: a narrative review on epidemiology, risk assessment, and pathophysiologic mechanisms. AB - Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis. PMID- 29404878 TI - Models of Disease Vector Control: When Can Aggressive Initial Intervention Lower Long-Term Cost? AB - Insecticide spraying of housing units is an important control measure for vector borne infections such as Chagas disease. As vectors may invade both from other infested houses and sylvatic areas and as the effectiveness of insecticide wears off over time, the dynamics of (re)infestations can be approximated by [Formula: see text]-type models with a reservoir, where housing units are treated as hosts, and insecticide spraying corresponds to removal of hosts. Here, we investigate three ODE-based models of this type. We describe a dual-rate effect where an initially very high spraying rate can push the system into a region of the state space with low endemic levels of infestation that can be maintained in the long run at relatively moderate cost, while in the absence of an aggressive initial intervention the same average cost would only allow a much less significant reduction in long-term infestation levels. We determine some sufficient and some necessary conditions under which this effect occurs and show that it is robust in models that incorporate some heterogeneity in the relevant properties of housing units. PMID- 29404879 TI - Mathematical Analysis of the Escherichia coli Chemotaxis Signalling Pathway. AB - We undertake a detailed mathematical analysis of a recent nonlinear ordinary differential equation (ODE) model describing the chemotactic signalling cascade within an Escherichia coli cell. The model includes a detailed description of the cell signalling cascade and an average approximation of the receptor activity. A steady-state stability analysis reveals the system exhibits one positive real steady state which is shown to be asymptotically stable. Given the occurrence of a negative feedback between phosphorylated CheB (CheB-P) and the receptor state, we ask under what conditions the system may exhibit oscillatory-type behaviour. A detailed analysis of parameter space reveals that whilst variation in kinetic rate parameters within known biological limits is unlikely to lead to such behaviour, changes in the total concentration of the signalling proteins do. We postulate that experimentally observed overshoot behaviour can actually be described by damped oscillatory dynamics and consider the relationship between overshoot amplitude, total cell protein concentration and the magnitude of the external ligand stimulus. Model reductions in the full ODE model allow us to understand the link between phosphorylation events and the negative feedback between CheB-P and receptor methylation, as well as elucidate why some mathematical models exhibit overshoot and others do not. Our paper closes by discussing intercell variability of total protein concentration as a means of ensuring the overall survival of a population as cells are subjected to different environments. PMID- 29404881 TI - Appointment scheduling in multi-stage outpatient clinics. AB - Healthcare providers can benefit from adding less costly capacity to their existing resources in order to satisfy demand while maintaining the quality of patient care. The addition of mid-level service providers (MLSPs) such as physician assistants or nurse practitioners that carry out portions of patient care provides a viable alternative for adding physician capacity. This research considers the circumstances under which adding an MLSP to a single-physician outpatient office becomes the best strategy for the clinic, and determines how scheduling policies from the widely-researched single-stage environment should be adjusted for a multi-stage environment. Compared to a single-stage system where a physician completes all portions of the service, we show that adding an MLSP can reduce patient waiting time, patient flow time, and physician service time with patients. This, in turn, can enable the clinic to see more patients and/or free up physician time for other tasks. Appointment scheduling rules are developed for a multi-stage outpatient service system using a simulation optimization approach. Performance measures focus on the patient experience and clinic operation before and during each stage of service. PMID- 29404880 TI - Residues and sources of organochlorine pesticides in soils of elementary schools and communities in Wenchuan 5.12 Earthquake-affected areas. AB - The disinfectants and pesticides extensively used after Wenchuan 5.12 Earthquake on May 12, 2008 (so-called Wenchuan 5.12 Earthquake), for epidemic prevention purpose can raise great concerns of environmental pollution and potential personal exposure. To investigate the soil pollution caused by the intensive application in earthquake-affected areas, surface soil samples from two elementary schools, two communities and two background areas were collected in Beichuan County and Dujiangyan City once per location in spring and in autumn in 2011 and then analyzed by gas chromatography/mass spectrometry for organochlorine pesticides (OCPs). The results showed serious soil pollution of hexachlorocyclohexanes (HCHs, 0.05-60.05 ng/g) and dichloro-diphenyl trichloroethane (DDTs, 0.06-35.79 ng/g) in the study areas compared with Wolong Nature Reserve (0.03-0.81 ng/g for HCHs and 0.02-0.40 ng/g for DDTs). The concentrations of most OCPs in soil of Beichuan County (e.g., 0.10-60.05 ng/g for HCHs and 0.17-35.79 ng/g for DDTs) were much higher than those of Dujiangyan City (e.g., 0.05-20.58 ng/g for HCHs and 0.06-10.69 ng/g for DDTs). In Beichuan County, the highest concentrations of HCHs and DDTs were found in the elementary school. In Dujiangyan City, the highest concentrations of HCHs and DDTs were found in the elementary school and the community, respectively. The concentrations of HCHs and DDTs were generally higher in spring than those in autumn. The predominant species (gamma-HCH in ?HCHs and 4,4'-DDT in ?DDTs) and specific ratios suggested new inputs of lindane and technical DDT in the study areas. Therefore, continuous soil monitoring and possible intervention would be recommended to minimize local residents' exposure to these toxic chemicals. PMID- 29404884 TI - UKCPA News. PMID- 29404882 TI - The peripheral corticotropin-releasing factor (CRF)-induced analgesic effect on somatic pain sensitivity in conscious rats: involving CRF, opioid and glucocorticoid receptors. AB - The corticotropin-releasing factor (CRF) is involved in somatic pain regulation and may produce an analgesic effect in humans and animals, although the mechanisms of the CRF-induced analgesia remain unclear. CRF action is mediated by the CRF receptors of subtypes 1 and 2 (CRF-R1 and CRF-R2, respectively). Activation of the hypothalamic -pituitary -adrenocortical axis (HPA) is provided by CRF-R1; but CRF-R2 are also involved in the regulation of the HPA axis, and, respectively, glucocorticoids, the end hormones of the HPA axis, also participate in somatic pain regulation. Additionally, opioids may contribute to the CRF induced analgesia. This article serves as an overview of the role of CRF-R1 and CRF-R2, as well as glucocorticoid and opioid receptors in peripheral CRF-induced analgesia in conscious rats, while we focused on the data obtained under normal (non-pathological) conditions including results of our studies in rats. The involvement of CRF-R1 and CRF-R2, glucocorticoids and opioid receptors was studied under the same experimental conditions following pretreatment with appropriate antagonists: NBI 27914, astressin2-B, naltrexone and RU 38486, respectively. Somatic pain sensitivity was measured by the tail flick latencies induced by thermal stimulus (tail flick test). Peripheral administration of the CRF caused both an increase in the tail flick latencies (analgesic effect) and plasma corticosterone levels. Pretreatment with NBI 27914, astressin2-B, naltrexone or RU 38486 attenuated the peripheral CRF-induced analgesia. The results obtained suggest that the peripheral CRF-induced analgesic effect may be mediated through the involvement of CRF-R1 and CRF-R2 as well as opioid and glucocorticoid receptors, including CRF-R2 and opioid receptors within periaqueductal gray matter of the midbrain. PMID- 29404885 TI - In Memoriam. PMID- 29404883 TI - Anti-inflammatory activity of nanoemulsions of essential oil from Rosmarinus officinalis L.: in vitro and in zebrafish studies. AB - The essential oil from Rosmarinus officinalis L. (OERO) has bioactive compounds with anti-inflammatory activity. The objective of this study was to evaluate the anti-inflammatory potency of nanoemulsions containing essential oil of Rosmarinus officinalis L. (NOERO, NECHA, NECULT, and NECOM) in vitro and in vivo. This study was accomplished in a quantitative format through tests with diphenyl picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), cellular antioxidant activity (CCA), determination of nitric oxide production, cellular viability and anti-inflammatory activity in zebrafish. OERO's were submitted to the analysis-coupled gas chromatography-mass spectrometry (GC-MS), which highlighted 1,8-cineol and camphor as major compounds. NOEROs were obtained by a low-energy method and presenting the medium size smaller than 200 nm. The efficiency of encapsulation by spectrometry and gas chromatographic analysis was 67.61 and 75.38%, respectively. In the CCA assay, all of the samples presented percentage values of inhibition similar to the quercetin pattern, indicating antioxidant activity. In the test for determination of NO., all of the samples inhibited the production of NO. when compared to LPS, and NOEROS were more effective than OEROS to 5 ug/mL. In the cell viability assay, the cells remained viable after contact with the samples, demonstrating an absence of cytotoxicity. This study showed that all nanoemulsions (NECHA, NECULT, and NECOM) showed no toxicity to macrophages, besides demonstrating antioxidant activity and potentiation of the essential oil effect in the proliferation of viable fibroblasts. Nanoemulsions has also shown the ability to potentiate the anti-inflammatory action of essential oils by exerting immunomodulatory activity by inhibiting the production of the pro-inflammatory mediator nitric oxide. The results obtained with NECHA in zebrafish confirm the hypothesis that prominent terpenic compounds, alpha-pinene, 1,8-cineole, and camphor, became more available at the target sites, inhibiting the inflammatory process in this animal species. PMID- 29404886 TI - Nucleotide and nucleoside involvement in immunomodulation in experimental Chagas disease. AB - The aim of this study was to evaluate whether Trypanosma cruzi infections cause alterations in the levels of seric purines, which could contribute to host immunomodulation. Twelve mice were divided into two groups identified as control (uninfected) and infected (T. cruzi) groups. The influence of the disease on seric purine levels was verified on day 20 post-infection (PI) by HPLC. Infected mice had circulating trypomastigotes during the experiment, as well as amastigote forms in the heart associated with inflammatory infiltrates. Increases on adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine (ADO), inosine (INO), and uric acid (URIC) levels were observed in the infected animals, while the adenosine monophosphate (AMP) and xanthine (XAN) levels were reduced compared with mice of the control group, indicating a possible impairment on the purinergic system, and consequently, on the immune system during the clinical course of the disease. In summary, the T. cruzi infection alters the seric purine levels, and consequently, modulates the immune system. PMID- 29404887 TI - MicroRNA-101 inhibits angiogenesis via COX-2 in endometrial carcinoma. AB - Abnormal angiogenesis is critically involved in tumor progression and metastasis including endometrial cancer and is regulated by microRNAs such as microRNA-101 (miR-101). We hypothesize that miR-101 expression is disrupted in endometrial cancer and modulation of miR-101 levels is sufficient to regulate tumor growth through angiogenesis. We examined the expression levels of miR-101 and factors involved in angiogenesis in the patients with endometrial cancer. We also overexpressed or inhibited miR-101 in RL-95-2 cells and examined their effects on cell toxicity and tumor growth. Finally, we determined if miR-101 regulated tumorigenesis through cyclooxygenase-2 (COX-2). We found that miR-101 levels were significantly reduced. Factors involved in angiogenesis included vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and aromatase (P450arom), which were increased in endometrial carcinoma. Modulation of miR-101 level was sufficient to affect tumor growth. Finally, we found that the effects of miR-101 inhibition on tumor growth were suppressed by COX-2 inhibition. Our results suggest that modulating miR-101 and COX-2 levels or their activity may be a potential therapeutic strategy for endometrial cancer. PMID- 29404889 TI - Cloning non-HUMAN primates by somatic cell nuclear transfer. PMID- 29404888 TI - HIV-1 Nef CAWLEAQ motif: a regulator of monocytes invasion through ENO1 modulation. AB - HIV-1 transmission and spread involves significant host-virus interaction. Possible targets for obstacle of HIV-1 lie at the site of mucosal barriers. Thus a better understanding of how HIV-1 infects target cells at such sites and leads their invasion is required, with prime focus on the host determinants regulating HIV-1 spread. For the viral infectivity and pathogenicity, HIV-1 Nef facilitates immune evasion through protein-protein interactions within host cell. HIV-1 Nef is significant for viral infectivity and pathogenicity. It enhances HIV-1 replication, facilitating immune evasion by interacting with various host factors and altering cellular pathways via multiple protein-protein interactions. In this study, HIV-1 Nef forms with specific mutations, revealing sequence variability, were studied for their effects in human SupT1 T cell line and (THP-1) monocyte macrophage cell line. Proteins being downregulated by Nef in SupT1 were further observed in THP-1, and interestingly two host proteins' (ENO-1 and VDAC1) expression was found to be cell lineage specific, being stimulatory in macrophages/monocytes and inhibitory in T cells. Cell migration, invasion and ADP release studies were employed to determine the biological function affected by Nef-mediated regulation of these two host proteins. ENO1-regulated function: cell invasion was enhanced in THP-1 cells, but was inhibited in SupT1 cells by Nef RP01. In addition, the modulation of proteins and cell invasion remained unaffected by a Nef RP14. These results indicated that regulation of host protein expression and invasive property of host cells by Nef was sequence specific, suggesting involvement of a particular motif of Nef. To precisely determine this site, we designed a heptapeptide including the CAWLEAQ-regulating sequence of Nef. Macrophages/monocytes being the major cells affected by HIV-1 at mucosal barriers were particularly investigated by the peptide. The peptide led to reversal of differential expressions of ENO1 in both SupT1 and THP-1 and inhibition of enhanced invasiveness in THP-1 cells. Further AP-1 was identified as a factor involved in this Nef-mediated regulation of host proteins. Together these findings suggest a possible mechanism of host invasion by HIV-1 through the CAWLEAQ motif of Nef-mediated regulation of ENO1 and identify a potential therapeutic target for HIV-1 entry at mucosal barriers. PMID- 29404890 TI - Comparison of clinical performance of size 1.5 SupremeTM LMA and ProsealTM LMA among Asian children: a randomized controlled trial. AB - To date, most of the studies on safety and efficacy of supraglottic airway devices were done in Caucasian patients, and the results may not be extrapolated to Asian patients due to the different airway anatomy. We conducted this study to compare SupremeTM LMA (SLMA) and ProsealTM LMA (PLMA) size 1.5 in anaesthetized children among an Asian population. This prospective randomized clinical trial was conducted in a tertiary teaching hospital from September 2013 until May 2016. Sixty children, weighing 5-10 kg, who were scheduled for elective surgery under general anaesthesia were recruited and completed the study. Patients were randomly assigned to have either SLMA or PLMA as the airway device for general anaesthesia, and standard anaesthesia protocol was followed. The primary outcome measured was the oropharyngeal leak pressure (OLP). The rate of successful insertion, insertion time, fibreoptic view of larynx and airway complications for each device were also assessed. There were no statistically significant differences between SLMA and PLMA size 1.5 in oropharyngeal leak pressure [19.1 (+/- 5.5) cmH2O vs. 19.8 (+/- 4.5) cmH2O, p = 0.68]. Secondary outcomes including time to insertion [20.8 (+/- 8.3) vs. 22.1 (+/- 8.3) s, p = 0.57], first attempt success rate for device insertion, fibreoptic view of larynx, and airway complications were also comparable between the two devices. We found that all the patients who had a failed device insertion (either PLMA or SLMA) were of a smaller size (5-6.2 kg). The oropharyngeal leak pressure of the SLMA 1.5 was comparable with the PLMA 1.5, and both devices were able to maintain an airway effectively without significant clinical complications in anaesthetized children from an Asian population. PMID- 29404891 TI - Assessment of changes in blood glucose concentration with intravascular microdialysis. AB - Blood glucose and its variability of is a major prognostic factor associated with morbidity. We hypothesized that intravenous microdialysis incorporated in a central venous catheter (CVC) would be interchangeable with changes in blood glucose measured by the reference method using a blood gas analyzer. Microdialysis and central venous blood glucose measurements were simultaneously recorded in high-risk cardiac surgical patients. The correlation between absolute values was determined by linear regression and the Bland-Altman test for repeated measurements was used to compare bias, precision, and limits of agreement. Changes in blood glucose measurement were evaluated by four-quadrant plot and trend interchangeability methods (TIM). In the 23 patients analyzed, the CVC was used as part of standard care with no complications. The correlation coefficient for absolute values (N = 99) was R = 0.91 (P < 0.001). The bias, precision and limits of agreement were - 9.1, 17.4 and - 43.2 to 24.9 mg/dL, respectively. The concordance rate for changes in blood glucose measurements (N = 77) was 85% with the four-quadrant plot. The TIM showed that 14 (18%) changes of blood glucose measurements were uninterpretable. Among the remaining 63 (82%) interpretable changes, 23 (37%) were interchangeable, 13 (20%) were in the gray zone, and 27 (43%) were not interchangeable. Microdialysis using a CVC appears to provide imprecise absolute blood glucose values with risk of insulin misuse. Moreover, only one third of changes in blood glucose measurements were interchangeable with the reference method using the TIM. PMID- 29404892 TI - Cerebral oximetry during preoperative resuscitation in elderly patients with hip fracture: a prospective observational study. AB - This study explores the association between postadmission and intraoperative cerebral oxygenation (ScO2), reflecting systemic perfusion, and postoperative mortality and delirium. Forty elderly (age > 65 years) patients with hip fractures were included in this prospective observational study. The ScO2 was determined using near-infrared spectroscopy at initial resuscitation after patients were admitted to the hospital and during surgery. Postoperative delirium was assessed up to seven days after surgery using the memorial delirium assessment scale and the confusion assessment method. Ten patients (25%) developed postoperative delirium within the first seven postoperative days. At initial resuscitation ScO2 was lower in patients that later developed delirium, but the difference was not significant (p = 0.331). Intraoperative ScO2 values remained similar in the two groups. Mortality regardless of cause was 10% (4 out of 40 patients) after 30 days. At initial resuscitation ScO2 was significant lower in the mortality group than in the surviving group (p = 0.042), and the ScO2 nadir values were also significant lower (p = 0.047). Low ScO2 during initial resuscitation (defined as ScO2 < 55 for a minimum of two consecutive minutes) was also significantly associated with 30-day mortality (p = 0.015). There were no associations between low blood pressure and postoperative delirium or 30-day mortality. We found that low preoperative ScO2 was better associated with 30-day all-cause mortality in elderly patients undergoing surgery for hip fracture than blood pressure measurements. Future studies in preoperative resuscitation of hip fracture patients should focus on perfusion measures as opposed to conventional haemodynamic. PMID- 29404893 TI - Pathogenesis of non-functioning pituitary adenomas. AB - The pathogenesis of non functioning pituitary adenomas (NFPA) is a complex process involving several factors, from molecular to genetic and epigenetic modifications, where tumor suppressor genes, oncogenes, cell cycle derangements have been demonstrated to play an important role. MicroRNAs (miRNAs) have also been identified as possible players in NFPA tumorigenesis and pituitary stem cells have been investigated for their potential role in pituitary tumor initiation. However, a critical role for paracrine signalling has also been highlighted. This review focuses on the current knowledge on the involvement of these factors in NFPA pathogenesis. PMID- 29404896 TI - Refining risk in diabetes and CAD with SPECT MPI: New insights and future challenges. PMID- 29404894 TI - Corticotrophic pituitary carcinoma with cervical metastases: case series and literature review. AB - PURPOSE: Pituitary tumors are the second most common intracranial tumors, however, pituitary carcinoma is a rare clinical entity which represents only 0.1 0.2% of all pituitary tumors. Diagnosis of pituitary carcinoma requires the presence of metastasis. Early identification of pituitary carcinoma is difficult, and only recently have guidelines been published for the treatment of aggressive pituitary tumors. We present two cases from our institution, with a review of other cases available in literature in order to better characterize this rare disease. METHODS: A retrospective review of two patients with pituitary carcinoma treated at a tertiary medical center was performed. The MEDLINE database was searched for all cases of pituitary carcinoma. Information for age at diagnosis, sex, pituitary tumor type, latency period from pituitary tumor to presentation of carcinoma, sites of metastasis, number of surgical therapies, radiation and chemotherapy, and survival after diagnosis were collected. RESULTS: A total of 69 studies were available for review for a total of 72 unique cases. The average age at diagnosis was 46.3 years. The most common tumors were ACTH-secreting (34.7%), Prolactin-secreting (23.6%), and Null Cell (15.3%). The average latency period from pituitary tumor diagnosis to metastasis was 9 years. All patients underwent surgical therapy during their treatment, with an average of 2.76 procedures. The mortality rate was 54.8% with average time to death after diagnosis of approximately 10 months. CONCLUSIONS: Pituitary carcinoma is a rare disease with high mortality rate and is a diagnostic and treatment challenge. Further study is required but is difficult due to its low incidence. PMID- 29404895 TI - Molecular AFM imaging of Hsp70-1A association with dipalmitoyl phosphatidylserine reveals membrane blebbing in the presence of cholesterol. AB - Hsp70-1A-the major stress-inducible member of the HSP70 chaperone family-is being implicated in cancer diseases with the development of resistances to standard therapies. In normal cells, the protein is purely cytosolic, but in a growing number of tumor cells, a significant fraction can be identified on to the cell surface. The anchoring mechanism is still under debate, as Hsp70-1A lacks conventional signaling sequences for translocation from the cytosol to exoplasmic leaflet of the plasma membrane and common membrane binding domains. Recent reports propose a lipid-mediated anchoring mechanism based on a specific interaction with charged, saturated lipids such as dipalmitoyl phosphatidylserine (DPPS). Here, we prepared planar supported lipid bilayers (SLBs) to visualize the association of Hsp70-1A directly and on the single molecule level by atomic force microscopy (AFM). The single molecule sensitivity of our approach allowed us to explore the low concentration range of 0.05 to 1.0 MUg/ml of Hsp70-1A which was not studied before. We compared the binding of the protein to bilayers with 20% DPPS lipid content both in the absence and presence of cholesterol. Hsp70-1A inserted exclusively into DPPS domains and assembled in clusters with increasing protein density. A critical density was reached for incubation with 0.5 MUg/ml (7 nM); at higher concentrations, membrane defects were observed that originated from cluster centers. In the presence of cholesterol, this critical concentration leads to the formation of membrane blebs, which burst at higher concentrations supporting a previously proposed non-classical pathway for the export of Hsp70-1A by tumor cells. In the discussion of our data, we attempt to link the lipid mediated plasma membrane localization of Hsp70-1A to its potential involvement in the development of resistances to radiation and chemotherapy based on our own findings and the current literature. PMID- 29404897 TI - Epidemiological and genetic characteristics of the fifth avian influenza A(H7N9) wave in Suzhou, China, from October 2016 to April 2017. AB - Human infections with H7N9 viruses can cause severe pneumonia and even death. To characterize the epidemiology and genetics of the H7N9 viruses circulating during from October 2016 to April 2017 in Suzhou, China, all pharyngeal swab samples were collected from severe acute respiratory infections (SARI) cases during this fifth wave of infection, and we amplified the H7N9 H7 and N9 genes using a real time polymerase chain reaction (PCR). Positive samples were subjected to virus isolation and gene sequencing to analyze the evolution and variation of the H7N9 strains. The epidemiological features of H7N9 patients have not changed and there were no significant mutations in the key sites of the hemagglutinin (HA) gene sequence, but we identified the K526R and E627 K substitutions in the PB2 protein. In the neuraminidase (NA) protein, drug-resistant mutations (R294 K and H276Y) occurred in a few strains. Most of the H7N9 viruses isolated from Suzhou had no drug resistance mutations, but it is necessary to closely monitor and analyze the probable emergence of mutations and the spread of resistant strains. The reduction of the N-glycosylation site at position 42 of NA was observed in some strains. PMID- 29404898 TI - Induction chemotherapy with the EXTREME regimen in frail patients with locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: Induction chemotherapy (IC) with TPF (docetaxel, cisplatin, 5FU) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is limited to fit patients. OBJECTIVE: We conducted a retrospective cohort study to assess the use of the EXTREME regimen (platinum-based therapy, 5FU, cetuximab) as IC in frail patients with LAHNSCC. PATIENTS AND METHODS: Retrospective analysis of all consecutive patients with unresectable LAHNSCC treated with the EXTREME regimen, with or without 5FU as IC, from two French centers from 2008 to 2015. We assessed the rate of completed sequence defined as at least two cycles of IC and definitive radiation therapy. RESULTS: We included 34 patients with a median age of 56 years [44-70]. The primary site of tumor development was the oropharynx (67%, n=23, all HPV negative), hypopharynx (21%, n=7) and the oral cavity (12%, n=4). At inclusion, patients presented: T4 76, 5% (n=26), N2c 41% (n=14), N3 26% (n=9), stage disease IVa 62% (n=21), IVb 38% (n=13), ECOG PS2 38% (n=13), decreased weight (10% in one month or 15% in 6 months) 74% (n=25). The sequence was achieved for 76% (n=26) of patients and 80% (n=27) presented a clinical response after the chemotherapy course with notably increased weight (40%, n=11) or general status (75%, n=26). Median PFS and OS were 5.7 and 15.5 months, respectively. Disease progression at 3 months was significantly associated with decreased median overall survival (13.6 versus 21.9 months, p=0.01). CONCLUSION: This is the first study to report the use of the EXTREME regimen as induction chemotherapy, and although this IC was used in a very frail population, the majority completed the sequence with significant clinical benefit. PMID- 29404899 TI - TOX3 Variants Are Involved in Restless Legs Syndrome and Parkinson's Disease with Opposite Effects. AB - Parkinson's disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p = 0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p = 0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05-2.54, p = 0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD. PMID- 29404900 TI - Body composition and sarcopenia in patients with chronic obstructive pulmonary disease. AB - PURPOSE: Changes in body composition are commonly present in chronic obstructive pulmonary disease (COPD). The main aim of this study were to evaluate changes in body composition and the prevalence of pre-sarcopenia and sarcopenia in patients with COPD, compared with two control groups and correlate these parameters with indices of COPD severity (VEF1 and GOLD) and prognosis (BODE). METHODS: This was a cross-sectional study in COPD patients (DG) that undergone body composition assessment by DXA. Two control groups were used, smokers individuals without COPD (smokers group, SG), and healthy never smokers individuals (never smokers group, NSG). RESULTS: DG comprised 121 patients (65 women, mean age 67.9 +/- 8.6 years). The percentage of total body fat mass (TFM) was significantly lower in DG in both genders, despite no difference in BMI. Both BMI and relative skeletal muscle mass index (RSMI) decreased according to the worsening of GOLD in men and women, as well as the TFM and total lean mass (TLM) in men. As BODE get worse, BMI and RSMI decreased in both sexes, as well as TLM in men. The prevalence of pre-sarcopenia in the DG was 46.3% and no different with controls. In DG 12.4% were sarcopenic. Patients with sarcopenia were older and had worse prognosis. Higher BODE prognostic index, higher the prevalence of sarcopenia (OR 3.5, 95% CI 1.06-11.56, p = 0.035). CONCLUSIONS: This study showed alterations in body composition parameters in patients with COPD. A high prevalence of sarcopenia and the association with worse prognostic index. PMID- 29404901 TI - Female gonadal functions and ovarian reserve in patients with acromegaly: experience from a single tertiary center. AB - PURPOSE: To evaluate the gonadal functions and related factors in female patients with acromegaly at the time of diagnosis, the course of gonadal dysfunctions and pregnancies during the follow-up period, and the investigation of ovarian reserve with serum anti-Mullerian hormone (AMH) levels in patients with reproductive age. METHODS: Patients who were not menopausal at the time of acromegaly diagnosis (n = 47) were included in this study. Baseline gonadal status was evaluated retrospectively. Patients were divided into three groups: normal gonadal function (group 1), gonadal dysfunction without central hypogonadism (group 2), and central hypogonadism (group 3). Group 1 and group 2 were compared in terms of clinical and laboratory findings. AMH levels were studied in patients who were <= 45 years old (n = 14) at the time of the study. Data related to pregnancies (n = 13) were evaluated retrospectively. RESULTS: Group 1 included 18 patients (38%), group 2 included 18 patients (38%), and group 3 included 11 patients (24%). The estimated duration of acromegaly was longer, and baseline PRL levels were higher, in group 2 than group 1 (p = 0.002 and p = 0.015, respectively). Gonadal functions recovered in 66% of patients. AMH levels were low in 64% of patients. The frequency of maternal diabetes and hypertension was 7.7%, and there was no tumoral growth in any of the pregnancies. CONCLUSION: The most important factors affecting gonadal functions, excluding central hypogonadism, are hyperprolactinemia and the duration of the indolent period before diagnosis of acromegaly. AMH levels in the majority of patients were found to be lower than the expected age. Despite the decreased ovarian reserve, fertilization and normal birth can be achieved with careful surveillance. PMID- 29404902 TI - Comment on "The pros and cons of continuous glucose monitoring for patients with type 1 diabetes on multiple daily injections of insulin". Authors' reply. PMID- 29404904 TI - Surgical strategy for refractory aortitis. AB - In some instances, we encounter cases suffered from inflammatory aortic diseases (aortitis) in Japan, some of which are at the active stages with systemic inflammation. Most of them are refractory with some technical difficulties of surgical treatment. The aortic wall, particularly, at the active stage, is too fragile to hold the surgical sutures. Consequently, the suture reinforcement with Teflon felt is required. In the late stage after surgery, false aneurysms on the suture line, that is, suture detachment potentially occur. To prevent such sequelae in the early and late phases, continuous (life-long) as well as perioperative inflammation control using corticosteroid as an initial drug and/or other immunosuppression agents. This decade, instead of the conventional open surgical repairs, endovascular treatments have widely spread, predominantly for stenotic aortic/arterial lesions. In particular, for more difficult patients suffered from more troublesome Behcet disease, endovascular treatments would have greater advantages to avoid more occasionally occurred pseudo-aneurysm on the other parts as well as the surgical suture lines. The key issues on surgical treatment for refractory aortitis are perioperative inflammation control including the long term with corticosteroid and/or immunosuppressive agents, appropriate open surgical or endovascular treatment approaches, and sufficient reinforcement of surgical suture lines. PMID- 29404903 TI - Pre-operative localization of abnormal parathyroid tissue by 99mTc-sestamibi in primary hyperparathyroidism using four-quadrant site analysis: an evaluation of the predictive value of vitamin D deficiency. AB - CONTEXT: Accurate preoperative localization of abnormal parathyroid tissue aids importantly in minimally invasive parathyroidectomy in patients with primary hyperparathyroidism. Vitamin D deficiency may possibly influence the success and characteristics of pre-operative localization because it is associated with more active disease and possibly larger adenomas. This could increase the sensitivity of the sestamibi to identify abnormal parathyroid tissue, but earlier reports are conflicting. Vitamin D deficiency could also influence the nature of preoperative localization because it could lead to multi-gland stimulation of parathyroid tissue giving an appearance of multi-gland disease, which may lower accuracy of preoperative localization with sestamibi. OBJECTIVE: To examine the relationship between vitamin D deficiency and correct parathyroid tissue localization by four pole thyroid quadrant analysis. DESIGN: Retrospective study. SETTING: Referral center. PARTICIPANTS: A total of 138 patients were divided into three groups according to the level of 25OHD; <20 ng/mL (vitamin D deficient), >=20 to <30 ng/mL (vitamin D insufficient) and >=30 ng/mL (vitamin D replete). MAIN OUTCOMES: Quadrant localization using 99mTc-sestamibi/SPECT. RESULTS: Among those with single-gland disease, the proportion of patients with correct quadrant localization were 60.0, 68.3 and 63.5% (p = 0.778), and the accuracy of sestamibi was 89.3, 90.6 and 89.9% for the deficient, insufficiency and replete groups, respectively. Among those with multi-gland disease, the proportion of patients with correct quadrant localization were 50.0, 25.0 and 18.2% (p = 0.619) while the accuracy was 50.0, 50.0 and 45.5%, respectively. Multi-gland disease did not occur more frequently in any of the three groups (p = 0.296). CONCLUSIONS: Vitamin D levels do not affect the accuracy of preoperative localization with sestamibi. PMID- 29404905 TI - Sir Jeffrey Hudson, the midget of the Queen Henrietta Marie. PMID- 29404906 TI - A Tuscan general with morbid obesity. PMID- 29404907 TI - Biochemical Characterization of the Engineered Soluble Photoactivated Guanylate Cyclases from Microbes Expands Optogenetic Tools. AB - Cyclic nucleotide, such as cyclic GMP, is a secondary messenger that regulates a wide range of biological process via the diverse signaling cascades. Photoactivated adenylyl cyclases (PACs), constituted of blue light utilizing flavin (BLUF) and cyclase homology domain (CHD), are used as an optogenetic tool to modulate the cyclic AMP (cAMP) level and to study cAMP-mediated signal transduction mechanisms. Here, we have engineered photoactivated adenylyl cyclases (PACs) from microbes to photoactivated guanylyl cyclases (PGCs) via mutagenesis of the substrate binding-specific residues in cyclase homology domain. We demonstrate purification, photodynamic, and detailed biochemical characterization of the engineered PGCs that can serve as optogenetic tool for manipulation of cGMP level in the cells. Engineered PGCs show typical BLUF photoreceptor properties with different recovery kinetics and varying light regulated guanylyl cyclase activities. PMID- 29404908 TI - Immobilization of Carboxypeptidase A into Modified Chitosan Matrixes by Covalent Attachment. AB - Carboxypeptidase A (CPA) is a metalloexopeptidase that catalyzes the hydrolysis of the peptide bonds that are adjacent to the C-terminal end of a polypeptide chain. The enzyme preferentially cleaves over C-terminal L-amino acids with aromatic or branched side chains. This is of main importance for food industry because it can be employed for manufacturing functional foods from different protein sources with reduced hydrophobic amino acid content for patients with deficiencies in the absorption or digestion of the corresponding amino acids. In that way, strategies for effective multipoint covalent immobilization of CPA metalloenzyme on chitosan beads have been developed. The study of the ability to produce several chemical modifications on chitosan molecules before, during and after its coagulation to form carrier beads lead in a protective effect of the polymer matrix. The chemical modification of chitosan through the use of an N alkylation strategy produced the best derivatives. N-alkyl chitosan derivative beads with D-fructose presented values of 0.86 for immobilization yield, 314.6 IU g-1 bead for initial activity of biocatalyst and were 5675.64-fold more stable than the free enzyme at 55 degrees C. Results have shown that these derivatives would present a potential technological application in hydrolytic processes due to both their physical properties, such as low swelling capacity, reduced metal chelation ability and bulk mesoporosity, and increased operational stability when compared with soluble enzyme. PMID- 29404909 TI - Substituting Both the N-Terminal and "Cord" Regions of a Xylanase from Aspergillus oryzae to Improve Its Temperature Characteristics. AB - To improve the temperature characteristics of AoXyn11A, a mesophilic glycoside hydrolase family (GHF) 11 xylanase from Aspergillus oryzae CICC40186, its N terminal and "cord" regions were selected to be substituted by means of the computer-aided analysis and calculation. In brief, one mutant, named ATX11A41, possessing the lowest root-mean-square deviation (RMSD) value was designed based on the molecular dynamics (MD) simulation by substituting the N-terminal 41 amino acids of AoXyn11A with the corresponding 42 ones of pXYL11, a thermophilic GHF11 xylanase from Thermobifida fusca. On the basis of the primary structure alignment of pXYL11 with ATX11A41 (or AoXyn11A), another mutant, named ATX11A41/cord, was designed by substituting the cord region (93GTYNPGSGG101) of ATX11A41 with the corresponding one (93GTYRPTG99) of pXYL11. Both mutant-encoding genes, ATx11A41 and ATx11A41/cord, were constructed as designed theoretically by a megaprimer PCR technique and were expressed in Pichia pastoris GS115. The specific activities of recombinant (re) AoXyn11A, ATX11A41, and ATX11A41/cord were 2916.7, 2667.6, and 2457.0 U/mg, respectively. The analysis of temperature characteristics displayed that the temperature optimum (Topt) of reATX11A41 or reATX11A41/cord was 65 degrees C, which was 15 degrees C higher than that of reAoXyn11A. The thermal inactivation half-life (t1/2) values of reATX11A41 and reATX11A41/cord at 60 degrees C were 55 and 83 min, respectively, whereas that of reAoXyn11A was only 18 min at 50 degrees C. The melting temperature (Tm) values of reAoXyn11A, reATX11A41, and reATX11A41/cord were 54.2, 66.7, and 71.9 degrees C, respectively. In conclusion, the above findings indicated that the substitution of both the N-terminal and cord regions of a mesophilic AoXyn11A greatly contributed to its improved temperature characteristics. PMID- 29404910 TI - Long-Term Risks and Possible Benefits Associated with Late Adolescent Romantic Relationship Quality. AB - Adolescent romantic relationships have the potential to affect psychological functioning well into adulthood. This study assessed adolescent romantic relationship qualities as long-term predictors of psychological functioning utilizing a longitudinal multi-method, multi-informant study of 80 participants (59% female; 54% Caucasian, 35% African American, 11% mixed or other race) assessed at age 17 along with their romantic partners and at ages 25-27. Controlling for gender, family income, and baseline mental health, partner reported hostile conflict at age 17 predicted relative increases in internalizing behaviors from age 17 to 27. In contrast, observed teen support with their partner during a help-seeking task at age 17 predicted relative decreases in externalizing behaviors over time. The results are interpreted as suggesting qualities that may help determine whether adolescent romances have positive vs. negative long-term psychological health implications. PMID- 29404912 TI - Differences in Scope Assignments for Child and Adult Speakers of Mandarin. AB - The present study used a Truth Value Judgment Task to investigate whether changes in sentence structure lead to corresponding changes in the assignment of scope relations by Mandarin-speaking children and adults. In one condition, participants were presented with ordinary negative sentences containing disjunction; this condition was designed to verify the existing claim that disjunction is a positive polarity item for adult speakers of Mandarin, but not for child speakers. In a second condition, participants were presented with negative sentences where the disjunction phrase was preposed from object position; this condition was designed to examine the extent to which changes in sentence structure can result in changes in scope assignments to negated disjunctions. The results indicate that the preposed disjunction phrase undergoes reconstruction for children, whereas reconstruction is blocked for adults. This finding also suggests that Mandarin-speaking children and adults exhibit different scope preferences for negated disjunctions, regardless of where the disjunction phrase appears in the surface syntax. PMID- 29404911 TI - Social Costs for Wannabes: Moderating Effects of Popularity and Gender on the Links between Popularity Goals and Negative Peer Experiences. AB - Youth in early adolescence are highly concerned with being popular in the peer group, but the desire to be popular can have maladaptive consequences for individuals. In fact, qualitative work suggests that youth with high popularity goals who are nonetheless unpopular have negative experiences with their peers. However, little quantitative work has examined this possibility. The purpose of the current study was to examine if popularity goals were linked with physical (e.g., being hit) and relational (e.g., being excluded) victimization and peer rejection, particularly for individuals who strived for popularity but were viewed by their peers as unpopular. Late elementary and early middle school participants (N = 205; 54% female) completed self-reports of popularity goals and peer nominations of popularity and peer rejection. Teachers reported on students' experiences of relational and physical victimization. Peer nominated popularity and gender were moderators of the association between popularity goals and negative peer experiences. Consistent with hypotheses, girls who were unpopular but wanted to be popular were more likely to experience peer rejection and relational victimization. Unexpectedly, boys who were unpopular but did not desire to be popular were more likely to be rejected and relationally victimized. The findings suggest that intervention and prevention programs may benefit from addressing the social status goals of low status youth in a gender-specific manner. PMID- 29404913 TI - Technique Feature Analysis or Involvement Load Hypothesis: Estimating Their Predictive Power in Vocabulary Learning. AB - Vocabulary learning has always been a great concern and has attracted the attention of many researchers. Among the vocabulary learning hypotheses, involvement load hypothesis and technique feature analysis have been proposed which attempt to bring some concepts like noticing, motivation, and generation into focus. In the current study, 90 high proficiency EFL students were assigned into three vocabulary tasks of sentence making, composition, and reading comprehension in order to examine the power of involvement load hypothesis and technique feature analysis frameworks in predicting vocabulary learning. It was unraveled that involvement load hypothesis cannot be a good predictor, and technique feature analysis was a good predictor in pretest to posttest score change and not in during-task activity. The implications of the results will be discussed in the light of preparing vocabulary tasks. PMID- 29404914 TI - From Corpora to Experiments: Methodological Triangulation in the Study of Word Order at the Interfaces in Adult Late Bilinguals (L2 learners). AB - This paper shows the need to triangulate different approaches in Bilingualism and Second Language Acquisition (SLA) research to fully understand late bilinguals' interlanguage grammars. Methodologically, we show how experimental and corpus data can be (and should be) triangulated by reporting on a corpus study (Lozano and Mendikoetxea in Biling Lang Cognit 13(4):475-497, 2010) and a new follow-up offline experiment investigating Subject-Verb inversion (Subject-Verb/Verb Subject order) in L1 Spanish-L2 English (n = 417). Theoretically, we follow a recent line in psycholinguistic approaches to Bilingualism and SLA research (Interface Hypothesis, Sorace in Linguist Approaches Biling 1(1):1-33, 2011). It focuses on the interface between syntax and language-external modules of the mind/brain (syntax-discourse [end-focus principle] and syntax-phonology [end weight principle]) as well as a language-internal interface (lexicon-syntax [unaccusative hypothesis]). We argue that it is precisely this multi-faceted interface approach (corpus and experimental data, core syntax and the interfaces, representational and processing models) that provides a deeper understanding of (i) the factors that favour inversion in L2 acquisition in particular and (ii) interlanguage grammars in general. PMID- 29404915 TI - Clinical features of solitary functioning kidney. PMID- 29404916 TI - A case of pancreatic AV malformation in an elderly man. AB - A 60-year-old man presented with recurrent abdominal pain and weight loss for 6 months. Abdominal imaging showed a large vascular lesion in the head and neck of pancreas suggestive of arteriovenous malformation (AV malformation). Endoscopic ultrasound was done which showed features of AV malformation with no evidence of pancreatic malignancy. Surgery was planned for definitive treatment of malformation. Digital subtraction angiography with angioembolization was done prior to surgery to reduce vascularity of the lesion. He recovered after a pylorus preserving pancreaticoduodenectomy. Histopathology of the resected specimen confirmed the pancreatic AV malformation. There has been no recurrence at 2 years of follow-up. PMID- 29404918 TI - The agreement between venous and arterial blood gases in critical care and ward patients: is there a need to stratify for shock? PMID- 29404917 TI - EEG captures affective touch: CT-optimal touch and neural oscillations. AB - Tactile interactions are of developmental importance to social and emotional interactions across species. In beginning to understand the affective component of tactile stimulation, research has begun to elucidate the neural mechanisms that underscore slow, affective touch. Here, we extended this emerging body of work and examined whether affective touch (C tactile [CT]-optimal speed), as compared to nonaffective touch (non-CT-optimal speed) and no touch conditions, modulated EEG oscillations. We report an attenuation in alpha and beta activity to affective and nonaffective touch relative to the no touch condition. Further, we found an attenuation in theta activity specific to the affective, as compared to the nonaffective touch and no touch conditions. Similar to theta, we also observed an attenuation of beta oscillations during the affective touch condition, although only in parietal scalp sites. Decreased activity in theta and parietal-beta ranges may reflect attentional-emotional regulatory mechanisms; however, future work is needed to provide insight into the potential neural coupling between theta and beta and their specific role in encoding slow, tactile stimulation. PMID- 29404919 TI - In reply: the agreement between venous and arterial blood gas in critical care and ward patients: is there a need to stratify for shock? PMID- 29404921 TI - Update on Bowel Preparation for Colonoscopy. AB - PURPOSE OF REVIEW: Colonoscopy is the gold standard for visualization and diagnosis of conditions involving the colon and terminal ileum. It also facilitates screening and prevention of colorectal cancer, which is the second leading cause of cancer death in the USA. Adequate cleansing is essential for thorough visualization of the colon with successful detection of colon polyps. RECENT FINDINGS: While the original large-volume polyethylene glycol preparations are still commonly used, several lower volume regimens are widely available and selected based on provider and patient preferences. There remains a strong urge from patients for an even lower volume and more palatable regimen. Split-dose preparation is strongly recommended and additional data has come to support same day preparation regimens as well. Despite extensive research and comparison of various preparation regimens, between 10 and 25% of patients continue to have inadequate colon cleansing on the day of colonoscopy. Several patient factors have been associated with poor preparation and this chapter will touch on scoring systems, which may be used to predict colon cleansing. Documentation of preparation quality is essential to guide the practitioner in timing of follow-up examination. We recommend the use of the Boston Bowel Preparation Scale (BBPS) which is a validated and reliable scale for evaluation of cleansing. In patients with an inadequate preparation, we emphasize the importance of repeat examinations with consideration of a more aggressive preparation regimen. We predict that dietary liberalization prior to colonoscopy will be more commonly practiced in the future as it improves both patient satisfaction and adherence. Thorough bowel cleansing is essential for visualization of the colon with successful detection of colon polyps. While polyethylene glycol regimens are still the most commonly used for preparation, recommendations regarding dose timing and volume continue to evolve to optimize patient satisfaction and success of bowel cleanse. As the patients presenting for colonoscopy are evermore complex with medical comorbidities and extensive medication lists, a patient-centered approach to colonoscopy preparation will likely yield the highest rates of success. PMID- 29404922 TI - Conflict and well-being: a comparative study of health-related quality of life, stress, and insecurity of university students in the West Bank and Jordan. AB - PURPOSE: A significant body of research indicates that the conflict environment is detrimental to the quality of life and well-being of civilians. This study assesses the health-related quality of life, stress, and insecurity of the West Bank, which has been engaged in conflict for seven decades, in comparison to a demographically and culturally similar population in Jordan, a neighboring nation with no conflict. We expect the Jordanian sample to report better functioning. METHODS: We collected 793 surveys from university students (mean age = 20.2) in Nablus, West Bank (398 [50.2%]) and Irbid, Jordan (395 [49.8%]). The survey instrument consisted of the SF-36 to measure HRQoL, the PSS-4 to measure stress, and an insecurity scale, along with demographic characteristics. RESULTS: Our findings indicate that outcomes in the West Bank were not significantly worse than in Jordan, and in some cases represented better functioning, especially in the SF-36 measures. CONCLUSIONS: Our counterintuitive results suggest that health and well-being outcomes are dependent on many factors in addition to conflict. For one, it may be that the better perceived health and well-being of the Palestinians is because they have developed a culture of resilience. Additionally, Jordanians are undergoing a period of instability due to internal struggles and surrounding conflicts. PMID- 29404920 TI - Management of Anemia in Patients with Inflammatory Bowel Disease (IBD). AB - PURPOSE OF REVIEW: Anemia is the most common complication as well as an extra intestinal manifestation of inflammatory bowel disease (IBD). It is associated with a significant impact on patient's quality of life (QoL); as well it represents a common cause of frequent hospitalization, delay of hospital inpatient discharge and overall increased healthcare burden. In spite of all these, anemia is still often underdiagnosed and undertreated. Our aim in this review is to provide a pathway for physicians to help them achieve early diagnosis as well as timely and appropriate treatment of anemia which in turn would hopefully reduce the prevalence and subsequent complications of this condition among IBD patients. RECENT FINDINGS: The etiology of anemia among IBD patients is most commonly due to iron deficiency anemia (IDA) followed by anemia of chronic disease. Despite this, more than a third of anemic ulcerative colitis (UC) patients are not tested for IDA and among those tested and diagnosed with IDA, a quarter are not treated with iron replacement therapy. A new algorithm has been validated to predict who will develop moderate to severe anemia at the time of UC diagnosis. While oral iron is effective for the treatment of mild iron deficiency-related anemia, the absorption of iron is influenced by chronic inflammatory states as a consequence of the presence of elevated levels of hepcidin. Also, it is important to recognize that ferritin is elevated in chronic inflammatory states and among patients with active IBD, ferritin levels less than 100 are considered to be diagnostic of iron deficiency. Newer formulations of intra-venous (IV) iron have a good safety profile and can be used for replenishment of iron stores and prevention of iron deficiency in the future. Routine screening for anemia is important among patients with IBD. The cornerstone for the accurate management of anemia in IBD patients lies in accurately diagnosing the type of anemia. All IBD patients with IDA should be considered appropriate for therapy with iron supplementation whereas IV administration of iron is recommended in patients with clinically active IBD, or for patients who are previously intolerant to oral iron, with hemoglobin levels below 10 g/dL, and in patients who need erythropoiesis-stimulating agents (ESAs). As the recurrence of anemia is common after resolution, the monitoring for recurrent anemia is equally important during the course of therapy. PMID- 29404923 TI - Manual lymphatic drainage and quality of life in patients with lymphoedema and mixed oedema: a systematic review of randomised controlled trials. AB - PURPOSE: To assess the impact of manual lymphatic drainage (MLD) on the health related quality of life (HRQoL) of adults with lymphoedema or mixed oedema, through a systematic review of randomised controlled trials (RCTs). METHODS: MEDLINE, EMBASE, PsycINFO, CENTRAL, the Cochrane Database of Systematic Reviews and ClinicalTrials.gov were searched to identify RCTs evaluating HRQoL after a MLD intervention compared to non-MLD interventions (PROSPERO 2016:CRD42016042255). We extracted the effect of the interventions on the HRQoL (primary outcome) as well as data on volume and functional changes, and adverse events when available (secondary outcomes). RESULTS: Eight studies were eligible. The studies were heterogeneous in the aetiology of oedema, schemes of MLD applied, additional treatments offered with MLD, length of follow-up, instruments used to assess HRQoL and interventions offered to the control group. Five studies included patients with breast cancer-related arm lymphoedema; one study reported increased HRQoL among patients randomised to the MLD group. The two RCTs that involved patients with leg mixed oedema due to chronic venous insufficiency did not find between-group differences in the overall HRQoL. One trial included patients with hand oedema from systemic sclerosis and showed higher HRQoL in the group that received MLD. No studies reported reductions in HRQoL, or severe adverse events after MLD. The small numbers of patients analysed in all studies may have resulted in lack of power to detect between-group differences in HRQoL. CONCLUSIONS: The effect of MLD on the HRQoL of patients with chronic oedema is unclear. PMID- 29404924 TI - Quality of life in older adults with sensory impairments: a systematic review. AB - PURPOSE: Sensory impairments are common in older adults. Hearing and visual impairments affect their physical and mental health and quality of life adversely. However, systematic reviews of the relationship between hearing impairment, visual impairment, dual sensory impairment, and quality of life are scarce. The purpose of this systematic review was to determine the relationship between hearing impairment, visual impairment, dual sensory impairment, and quality of life. METHODS: Searches of EMBASE, PubMed, CINAHL, MEDLINE, Cochrane Library, and Airiti Library were conducted between January 2006 and December 2017 using the keywords "quality of life," "life satisfaction," "well-being," "hearing impairment," and "visual impairment." Two authors independently assessed methodologic quality using a modified Downs and Black tool. Data were extracted by the first author and then cross-checked by the second author. RESULTS: Twenty three studies consisting mostly of community-dwelling older adults were included in our review. Sensory impairment was found to be in significant association with quality of life, with an increase in hearing impairment or visual impairment severity resulting in a lower quality of life. Quality of life for dual sensory impairment was worse than for hearing impairment or visual impairment individually. CONCLUSIONS: A significant association was confirmed between hearing impairment, visual impairment, dual sensory impairment, and quality of life. Our review can be used to enhance health care personnel's understanding of sensory impairment in older adults and enable health care personnel to actively assess older adults' sensory functions, so that they can help alleviate the negative impact of sensory impairments on QOL in older adults. PMID- 29404925 TI - How does age affect the relationship between weight and health utility during the middle years of childhood? AB - PURPOSE: The limited literature examining weight status and preference-based health-related quality of life (HRQL) in young children is equivocal. This study aims to examine how the association between weight status and preference-based HRQL changes as children develop between the ages of 6 and 10 years old. METHODS: The Child Health Utility 9D (CHU-9D) was used to determine preference-based HRQL. Height and weight data were also collected and used to calculate z-BMI adjusted for age and gender. 1467 children were recruited from 54 schools across the West Midlands. Data were collected at four time points over 5 years. Impact of weight on dimensions of HRQL was assessed via the distribution of responses to CHU-9D dimensions by weight status. Multi-level regression analysis controlling for ethnicity, deprivation and other relevant co-variates was conducted to examine the relationship between weight and HRQL. RESULTS: There was no evidence to suggest that the weight status impacted upon the distribution of responses to CHU 9D dimensions. Correspondingly, the multi-level regression analysis found no statistically significant differences in CHU-9D scores between underweight, healthy weight, overweight and obese children. CONCLUSIONS: The evidence surrounding the link between preference-based HRQL and weight status in children is limited. This study found no association between weight status and HRQL as measured by the CHU-9D in children between the ages of 5 and 10 years in the UK. Given this, it is recommended that future studies aiming to prevent obesity in children in their middle years do not rely solely on preference-based measures for economic evaluation, and instead focus on capturing clinical or wellbeing outcomes. PMID- 29404926 TI - Synergistical action of the beta2 adrenoceptor and fatty acid binding protein 2 polymorphisms on the loss of glomerular filtration rate in Chinese patients with type 2 diabetic nephropathy. AB - PURPOSE: Since altered sympathetic nerve activity and insulin resistance are implicated in the pathogenesis of type 2 diabetic nephropathy, we investigated the effect of polymorphic Arg16Gly and Gln27Glu in the beta2 adrenoceptor gene and Ala54Thr in the fatty acid binding protein 2 gene on the estimated glomerular filtration rate (eGFR) in Chinese patients with the above disease. METHODS: A total of 552 diabetic subjects recruited from annual health examinations were studied. The eGFR was calculated from the Modification of Diet in Renal Disease equation for the Chinese. Plasma norepinephrine level and genotype were determined by high-performance liquid chromatography-tandem mass spectrometry and TaqMan method, respectively. Holter-derived heart rate viability (HRV) and the MRI-generated renal apparent diffusion coefficient (ADC) were evaluated. RESULTS: The Gly16Gly and Thr54Thr homozygotes had significantly higher microalbuminuria and lower eGFR against other genotypes in their individual polymorphism. Besides, the Gly16Gly variant exhibited markedly elevated norepinephrine level, whereas indicative of insulin resistance was increased in the Thr54Thr one. Multiple linear regression analysis further confirmed the independent genetic effect on the eGFR. Moreover, multifactor dimensionality reduction method detected a gene gene synergistic action that subjects with the Gly16Gly/Thr54Thr genotype were exposed to higher risk of eGFR loss. Finally, these findings were accompanied by lower HRV and ADC, indicating sympathetically mediated hemodynamic changes. CONCLUSIONS: By uncovering the genetic component of the coherent interplay between the elevated sympathetic nerve activity and metabolic disorders, our observations might promote the development of novel personalized prevention and management strategies against the diabetic nephropathy, especially in the genetically susceptible individuals. PMID- 29404927 TI - Fast GFR decline and progression to CKD among primary care patients with preserved GFR. AB - BACKGROUND: Fast glomerular filtration rate (GFR) decline is associated with adverse outcomes, but the associated risk factors among patients without chronic kidney disease (CKD) are not well defined. METHODS: From a primary care registry of 37,796, we identified 2219 (6%) adults with at least three estimated (e)GFR values and a baseline eGFR between 60 and 119 ml/min/1.73 m2 during an observation period of 8 years. We defined fast GFR decline as > 5 ml/min/1.73 m2 per year. The outcome measure was incident CKD (eGFR < 60 ml/min/1.73 m2). Clinical and demographic characteristics were compared using Chi-square and independent-samples t tests. RESULTS: Older age, African-American race, unmarried status, hypertension and type 2 diabetes were more common in both fast decliners and those who developed incident CKD (p < 0.0001 to < 0.05). Lower neighborhood socioeconomic status, current smoking and baseline eGFR 90-119 ml/min/1.73 m2 were associated with fast decline (p < 0.01), while baseline eGFR 60-74 ml/min/1.73 m2 with incident CKD (p < 0.05). In multivariate regression models, among fast decliners with mildly reduced baseline eGFR (60-89 ml/min/1.73 m2), older age was significantly associated with incident CKD [odds ratio (OR) 1.04; 95% CI 1.01-1.08], and among those with normal baseline eGFR (>= 90-119 ml/min/1.73 m2), type 2 diabetes was significantly associated with incident CKD (OR 3.83; 95% CI 1.35-10.89). CONCLUSIONS: Among primary care patients without CKD, GFR is checked infrequently. We have identified patients at high risk of progressive CKD, in whom we suggest a closer monitoring of renal function. PMID- 29404928 TI - Evaluation of quality of life, physical, and mental aspects in longevous patients with chronic kidney disease. AB - PURPOSE: The diagnosis of chronic kidney disease (CKD) in elderly individuals has been increasing. The objective of this study was to evaluate physical, mental and social aspects in longevous elderly patients with CKD. METHODS: Eighty patients with CKD (stage 4 and 5, not on dialysis) and 60 longevous elderly (>= 80 years) paired by gender and age living in the community were evaluated. Physical, cognitive, social and quality of life aspects were analyzed according to the following scales: Charlson comorbidity index, Medical Outcomes Study Short Form 36-Item (SF-36), Medical Outcomes Study, Boston Naming Test, verbal fluency test (animal naming), sit-to-stand test, gait speed, and the Mini-Mental state examination. RESULTS: Compared to the control group, the CKD group had a higher mean in the comorbidities index (3.5 +/- 1.2 vs. 1.0 +/- 1, respectively, p < 0.001). In the multivariate analysis, the CKD group presented worse performance in the SF-36 dimensions: 'physical functioning,' 'general health,' 'emotional functioning,' 'vitality,' and physical component summary. On the other hand, they presented better results for the 'mental health' dimension, in addition to lower social support, worse verbal fluency and worse results on the sit-to-stand test. CONCLUSIONS: Longevous patients with stage 4 or 5 CKD presented worse evaluation in several domains of physical and emotional functioning, lower social support and evidence of worse cognitive performance. These aspects should be taken into account in order to improve the care provided to these patients, improve their quality of life and prevent their morbidity. PMID- 29404929 TI - Nutritional status in short daily hemodialysis versus conventional hemodialysis patients in China. AB - PURPOSE: Malnutrition is the main determinant of mortality and morbidity in maintenance hemodialysis patients. In many countries except for China, it has been reported that short daily hemodialysis (SDHD) could improve nutritional status. We will report here the nutritional results obtained in the SDHD therapy period compared with conventional hemodialysis (cHD) therapy period in Chinese patients. METHODS: This study compared 29 SDHD patients (SDHD group), each patient served as his own control, with 30 cHD patients (cHD group) serving as the parallel controls. The hematologic parameters, anthropometric measurements, modified quantitative subjective global assessment (MQSGA) score, weekly standard Kt/V (std Kt/V) and average daily intake of protein were measured at baseline (SDHD0 or cHD0 period), at 3 months (SDHD1 or cHD1 period) and at 6 months (SDHD2 or cHD2 period). RESULTS: The average daily intake of protein, dry weight, body mass index, mid-arm circumference, mid-arm muscle circumference, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at SDHD0 (p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively). Meanwhile, the average daily intake of protein, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at cHD2 (p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively), whereas the MQSGA score at SDHD2 was lower than the score at SDHD0 and cHD0 (p < 0.05, respectively). CONCLUSIONS: SDHD may improve the nutritional status compared with cHD in Chinese patients undergoing maintenance hemodialysis. PMID- 29404930 TI - Comparative efficacy of pharmacological interventions for contrast-induced nephropathy prevention after coronary angiography: a network meta-analysis from randomized trials. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is the major complication related to contrast media administration in patients after coronary angiography (CAG). However, inconsistent results have been published in the literature regarding the effects of pharmacological drugs on CIN prevention. We conducted a network meta analysis to evaluate the relative efficacy of pharmacological interventions for the prevention of CIN. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to July 2017. We included any randomized controlled trials of eleven pharmacological interventions that reported the prevention of CIN. RESULTS: We identified 3850 records through database searches, of which 107 studies comprising 21,450 participants were finally identified. Compared with intravenous saline, intravenous saline plus pharmacological drugs including statin [relative risk (RR) 0.57; 95% credibility interval (CrI) 0.39 to 0.83], N-acetylcysteine (NAC) (RR 0.84; 95% CrI, 0.71 to 0.98), vitamin and its analogues (RR 0.66; 95% CrI 0.45 to 0.97), brain natriuretic peptide (BNP) and its analogues (RR 0.46; 95% CrI 0.30 to 0.70), prostaglandin analogues (RR 0.37; 95% CrI 0.18 to 0.76), NAC plus sodium bicarbonate (SB) (RR 0.60; 95% CrI 0.39 to 0.90), and statin plus NAC (RR 0.39; 95% CrI 0.21 to 0.70), have helped to reduce the incidence of CIN in patients after CAG. The top four ranked treatments were statin plus NAC, BNP and its analogues, statin, and vitamin and its analogues, respectively. NAC plus intravenous saline was associated with lower incidence of short-term all-cause mortality than intravenous saline alone (RR 0.62; 95% CI, 0.40 to 0.96; P = 0.03). However, no evidence indicated that any of the pharmacological drugs were associated with a reduced requirement for dialysis and major adverse cardiac and cerebrovascular events (MACCE). CONCLUSIONS: Statin plus NAC plus intravenous saline seems to be the most effective treatment for the prevention of CIN in patients after CAG. NAC plus intravenous saline may have a protective role against short-term all-cause mortality. However, none of these drugs has effectively decreased the requirement for dialysis and MACCE. PMID- 29404931 TI - Genotyping as a Key Element of Sample Size Optimization in Bioequivalence of Risperidone Tablets. AB - BACKGROUND AND OBJECTIVES: Risperidone is a derivative of benzisoxazole and is widely used for schizophrenia and other psychiatric illnesses in both adults and children. Previous studies have confirmed that it is a highly variable drug (within-subject variability >= 30%). To reduce the large sample size required for bioequivalence researches on highly variable drugs, a role for genotyping in the design of the bioequivalence study was employed. METHODS: A randomized, open label, two-period crossover study was adopted: 20 subjects with specific genotypes carrying cytochrome P450 (CYP) 2D6*10 were randomized to two groups to receive a single oral dose of trial formulation or reference formulation with a 2 week washout period. Blood concentrations of risperidone (parent drug) and 9 hydroxy risperidone (active metabolite) were measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Eighteen out of the 20 subjects completed the study (two did not finish the test in the second period). The pharmacokinetic parameters of AUClast, AUCinfinity and Cmax for the 18 subjects after a single oral dose of the trial or reference preparation were 216.1 +/- 88.7 and 220.5 +/- 96.8 ng.h/mL; 221.6 +/- 93.1 and 226.4 +/- 103.5 ng.h/mL; 36.7 +/- 10.3 and 36.0 +/- 10.2 ng/mL, respectively. The CVw of risperidone in natural logarithm-transformed Cmax was 22.4 and 25.38% for 9-hydroxy risperidone. CONCLUSIONS: The test formulation met the Food and Drug Administration guidelines and regulation criteria for bioequivalence. By controlling the genotype, it could actually help reduce the CVw, which may be a feasible method to decrease the sample size for the bioequivalence study of highly variable drugs. PMID- 29404932 TI - Neuronal Activities in the Mouse Visual Cortex Predict Patterns of Sensory Stimuli. AB - Visual cortex forms the basis of visual processing and plays important roles in visual encoding. By using the recently published Allen Brain Observatory dataset consisting of large-scale calcium imaging of mouse V1 activities under visual stimuli, we were able to obtain high-quality data capturing simultaneous neuronal activities at multiple sub-areas and cortical depths of V1. Using prediction models, we analyzed the activity profiles related to static and drifting grating stimuli. We conducted a comprehensive survey of the coding ability of multiple cortical locations toward different stimulus attributes. Specifically, we focused on orientations and spatial frequencies (for static stimuli), as well as moving directions and speed (for drifting stimuli). By using results produced from a prediction model, we quantified the decoding performance profile at different sub areas and layers of V1. In addition, we analyzed the interactions and interference between different stimulus attributes. The insights obtained from these discoveries would contribute to more precise and quantitative understanding of V1 coding mechanisms. PMID- 29404933 TI - Learning Efficient Spatial-Temporal Gait Features with Deep Learning for Human Identification. AB - The integration of the latest breakthroughs in bioinformatics technology from one side and artificial intelligence from another side, enables remarkable advances in the fields of intelligent security guard computational biology, healthcare, and so on. Among them, biometrics based automatic human identification is one of the most fundamental and significant research topic. Human gait, which is a biometric features with the unique capability, has gained significant attentions as the remarkable characteristics of remote accessed, robust and security in the biometrics based human identification. However, the existed methods cannot well handle the indistinctive inter-class differences and large intra-class variations of human gait in real-world situation. In this paper, we have developed an efficient spatial-temporal gait features with deep learning for human identification. First of all, we proposed a gait energy image (GEI) based Siamese neural network to automatically extract robust and discriminative spatial gait features for human identification. Furthermore, we exploit the deep 3-dimensional convolutional networks to learn the human gait convolutional 3D (C3D) as the temporal gait features. Finally, the GEI and C3D gait features are embedded into the null space by the Null Foley-Sammon Transform (NFST). In the new space, the spatial-temporal features are sufficiently combined with distance metric learning to drive the similarity metric to be small for pairs of gait from the same person, and large for pairs from different persons. Consequently, the experiments on the world's largest gait database show our framework impressively outperforms state-of-the-art methods. PMID- 29404934 TI - Biochemical and pathologic factors affecting technetium-99m methoxyisobutylisonitrile imaging results in patients with primary hyperparathyroidism. AB - OBJECTIVE: Technetium 99 m methoxyisobutylisonitrile (Tc-99m MIBI) scintigraphy represents the most commonly utilized imaging modality for the detection of the diseased gland in patients with primary hyperparathyroidism (PHPT). In this study, we aimed to identify potential biological factors with an impact on MIBI sensitivity. METHODS: A total of 147 patients with surgically confirmed parathyroid adenomas were assessed retrospectively. Data including medical history, biochemical and hormonal measurements, cervical US, Tc-99m MIBI scans as well as pathology reports were retrieved and recorded. RESULTS: Of the 147 patients, there were a total of 77, 39, and 31 cases with a positive, negative, and suspicious parathyroid adenoma on Tc-99m MIBI scan, respectively. Serum calcium (Ca), parathyroid hormone (PTH) and 25 (OH) D levels were comparable among MIBI positive and negative patients [Ca: 11.5 +/- 0.9 vs 11.3 +/- 0.9 mg/dL (P = 0.42); PTH: 216 (146-347) vs 194 (140-317) pg/mL (P = 0.45); 25(OH)D: 8.4 (5.7-18.2) vs 10.0 (4.7-23.3) ng/mL (P = 0.64), respectively]. P-glycoprotein (P gp) staining was negative in both groups. Also, pathological examination of tissue preparations revealed no difference in terms of the volume of the adenomas, incidence of cystic adenomas, cell-type dominance (oxyphilic cell), percent fat, and Ki-67 ratio in MIBI positive and negative groups. The rate of hyalinization was 13% in MIBI positive and 28% in MIBI negative subjects, the difference being statistically significant (P = 0.04). CONCLUSION: Presence of hyalinization in parathyroid adenomas was found to be negatively correlated with MIBI scan results. PMID- 29404935 TI - The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients. AB - BACKGROUND: Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. OBJECTIVES: First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. SETTING: This study was performed in a general hospital specialized in bariatric surgery. METHODS: Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of >= 140 kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700 IU of nadroparin for 4 weeks. Anti-Xa activity was determined 4 h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850 IU nadroparin in another 50 patients (52%). RESULTS: TBW of the complete group was 148.5 +/- 12.6 kg. Mean anti-Xa activity following 5700 IU nadroparin was 0.19 +/ 0.07 IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW >= 80 kg had insufficient anti-Xa activity concentrations. No VTE events occurred. CONCLUSIONS: In morbidly obese patients, a postoperative dose of 5700 IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW >= 80 kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels. PMID- 29404936 TI - The Impact of Bariatric Surgery on Short Term Risk of Clostridium Difficile Admissions. AB - BACKGROUND AND AIMS: Clostridium difficile infection (CDI) is major health care concern with reports linking it to obesity. Our aim was to investigate the little known impact of the two most common bariatric surgeries, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), on risk of CDI admissions. METHODS: This is a retrospective cohort study using the 2013 Nationwide Readmission Database. We examined inpatient CDI rates within 120 days after RYGB (n = 40,059) and VSG (n = 45,394). In a time to event analysis we also evaluated inpatient CDI rates up to 11 months post-surgery. We chose morbidly obese patients that underwent non-emergent ventral hernia repair (VHR) as additional surgical controls (n = 9673). RESULT: CDI rates were higher after RYGB than VSG in the first 30 days (odds ratio [OR] = 2.10; 95% confidence interval [CI], 1.05-4.20) with a similar but nonsignificant trend within 31-120 days. CDI rates were also higher after RYGB compared to VHR controls within 31-120 days after surgery (OR = 3.22, 95%CI: 1.31, 7.88, p = 0.01). In a time to event analysis with up to 11 months follow up, RYGB led to higher CDI compared to VSG (hazard ratio [HR] = 1.87; 95% CI, 1.12-3.13) with a trend towards higher CDI compared to VHR (HR = 1.95; 95% CI, 0.94-4.06). Similar CDI rates occurred after VSG vs VHR. CONCLUSIONS: RYGB may increase the risk of CDI hospitalization when compared to VSG and VHR controls. This data suggest VSG may be a better bariatric choice when post-surgical CDI risk is a concern. PMID- 29404937 TI - Perioperative Short-Term Outcome in Super-Super-Obese Patients Undergoing Bariatric Surgery. AB - BACKGROUND: Prevalence of obesity is increasing with a pandemic magnitude worldwide. Incidence of super-super-obesity (> 60 kg/m2) is expanding by the same means. While bariatric surgery is the only approach with proven long-term results, surgical outcome in super-super-obesity is still discussed controversially. OBJECTIVE: This retrospective study examined bariatric surgery patients' short-term outcome in relation to their degree of obesity. SETTING: Data collection was performed in a German university medical center between March 2010 and November 2013. METHODS: This study analyzes a cohort of 715 patients in a single institution. Patients were subdivided into three groups, obese (<= 49.9 kg/m2), super-obese (>= 50 kg/m2), and super-super-obese (>= 60 kg/m2), and evaluated regarding perioperative outcome. RESULTS: Three hundred eighty-one patients were included into obese (O); 225 patients, into super-obese (SO); and 109 patients, into super-super-obese (SSO) cohort. There were no significant differences regarding patient characteristics including quantity of comorbidities and perioperative outcome. BMI was significantly lower in patients with complications, compared to patients without complications (p < 0.05), whereas patients' age was significantly higher (p < 0.05) in complication cohort. One SSO patient died of a septic multiorgan failure. Thus, the 30-day overall mortality was 0.14%. The BMI showed an inverse correlation to the patients' age at surgery (p < 0.05). CONCLUSION: Super-super-obesity should not be considered as a limiting factor for bariatric surgery outcome; however, the patients' age, surgeries prior to the bariatric procedure, and comorbidities must be considered prior to bariatric surgical treatment. PMID- 29404938 TI - Safety of Mini/One Anastomosis Gastric Bypass (MGB/OAGB)-Reply to Musella et al. PMID- 29404939 TI - Diagnosing Internal Herniation After Roux-en-Y Gastric Bypass Surgery: Literature Overview, Cadaver Study and the Added Value of 3D CT Angiography. AB - PURPOSE: The purposes of the study are to outline the complexity of diagnosing internal herniation after Roux-en-Y gastric bypass (RYGB) surgery and to investigate the added value of computed tomography angiography (CTA) for diagnosing internal herniation. MATERIALS AND METHODS: A cadaver study was performed to investigate the manifestations of internal hernias and mesenteric vascularization. Furthermore, a prospective, ethics approved study with retrospective interpretation was conducted. Ten patients, clinically suspected for internal herniation, were prospectively included. After informed consent was obtained, these subjects underwent abdominal CT examination, including additional arterial phase CTA. All subjects underwent diagnostic laparoscopy for suspected internal herniation. The CTA was used to create a 3D reconstruction of the mesenteric arteries and surgical staples (3D CTA). The 3D CTA was interpreted, taking into account the presence and type of internal hernia that was found upon laparoscopy. RESULTS: Cadaveric analysis demonstrated the complexity of internal herniation. It also confirmed the expected changes in vascular structure and surgical staple arrangement in the presence of internal herniation. 3D CTA studies of the subjects with active internal hernias demonstrated remarkable differences when compared to control 3D CTA studies. The blood supply of herniated intestinal limbs in particular showed abnormal trajectories. Additionally, enteroenterostomy staple lines had migrated or altered orientation. CONCLUSION: 3D CTA is a promising technique for diagnosing active internal hernias. Our findings suggest that for diagnosing internal hernias, focus should probably shift from routine abdominal CT examination towards the 3D assessment of the mesenteric vasculature and surgical staples. PMID- 29404941 TI - A Randomized Trial to Improve Communication between Patients and Providers in a Primary Care Walk-In Clinic. PMID- 29404940 TI - Impact of Procalcitonin Guidance on Management of Adults Hospitalized with Chronic Obstructive Pulmonary Disease Exacerbations. AB - BACKGROUND: Antibiotics are often prescribed for hospitalized patients with chronic obstructive pulmonary disease (COPD) exacerbations. The use of procalcitonin (PCT) in the management of pneumonia has safely reduced antibiotic durations, but limited data on the impact of PCT guidance on the management of COPD exacerbations remain. OBJECTIVE: To determine the impact of PCT guidance on antibiotic utilization for hospitalized adults with exacerbations of COPD. DESIGN: A retrospective, pre-/post-intervention cohort study was conducted to compare the management of patients admitted with COPD exacerbations before and after implementation of PCT guidance. The pre-intervention period was March 1, 2014, through October 31, 2014, and the post-intervention period was March 1, 2015, through October 31, 2015. PARTICIPANTS: All patients with hospital admissions during the pre- and post-intervention period with COPD exacerbations were included. Patients with concomitant pneumonia were excluded. INTERVENTION: Availability of PCT laboratory values in tandem with a PCT guidance algorithm and education. MAIN MEASURES: The primary outcome was duration of antibiotic therapy for COPD. Secondary objectives included duration of inpatient length of stay (LOS) and 30-day readmission rates. KEY RESULTS: There were a total of 166 and 139 patients in the pre- and post-intervention cohorts, respectively. There were no differences in mean age (66.2 vs. 65.9; P = 0.82) or use of home oxygenation (34% vs. 39%; P = 0.42) in the pre- and post-intervention groups, respectively. PCT guidance was associated with a reduced number of antibiotic days (5.3 vs. 3.0; p = 0.01) and inpatient LOS (4.1 days vs. 2.9 days; P = 0.01). Respiratory related 30-day readmission rates were unaffected (10.8% vs. 9.4%; P = 0.25). CONCLUSIONS: Utilizing PCT guidance in the management of COPD exacerbations was associated with a decreased total duration of antibiotic therapy and hospital LOS without negatively impacting hospital readmissions. PMID- 29404942 TI - Adequacy of Depression Treatment in Spouses of Cancer Survivors: Findings From a Nationally Representative US Survey. AB - BACKGROUND: Recent research suggests that mental health problems in spouses of cancer survivors are associated with worse mental health in the survivors themselves. Adequately treating spousal mental health problems therefore represents an opportunity to improve outcomes for both cancer survivors and their co-surviving family members. OBJECTIVE: Using nationally representative data, this study sought to determine how depression treatment differs between spouses of cancer survivors with depression compared to the general married population and assess rural/urban disparities in treatment. DESIGN: The design of the study is cross sectional. PARTICIPANTS: Data are from the Medical Expenditures Panel Survey, a household-based survey of US adults; we concatenated data from 2004 to 2013. We identified spouses of cancer survivors (n = 225) and a comparison group of married adults (n = 3678). MAIN MEASURES: Key measures included depression, guideline concordance of depression treatment (at least four prescriptions related to depression treatment, or at least eight psychotherapy or counseling visits), and sociodemographic characteristics. Logistic regressions evaluated the association between whether their spouse had cancer and receipt of guideline concordant treatment, controlling for sociodemographic characteristics; secondary analyses included rurality as a moderator. Analyses were weighted to account for the complex sampling design. KEY RESULTS: Spouses of cancer survivors were 33% less likely to receive guideline-concordant depression treatment than comparison spouses (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.45-0.99), controlling for covariates. Rural-urban disparities were observed: rural spouses of cancer survivors were 72% less likely to receive guideline-concordant treatment (OR 0.28, 95% CI 0.11-0.68) than rural comparison spouses. Spouses of cancer survivors and comparison spouses were no different in their receipt of any treatment versus no treatment. CONCLUSIONS: Spouses of cancer survivors with depression may be at increased risk of non-guideline-concordant depression treatment, particularly in rural areas. The findings have implications for identifying and educating individuals with depression in primary care and other clinical areas. PMID- 29404943 TI - Prediction of Future Chronic Opioid Use Among Hospitalized Patients. AB - BACKGROUND: Opioids are commonly prescribed in the hospital; yet, little is known about which patients will progress to chronic opioid therapy (COT) following discharge. We defined COT as receipt of >= 90-day supply of opioids with < 30-day gap in supply over a 180-day period or receipt of >= 10 opioid prescriptions over 1 year. Predictive tools to identify hospitalized patients at risk for future chronic opioid use could have clinical utility to improve pain management strategies and patient education during hospitalization and discharge. OBJECTIVE: The objective of this study was to identify a parsimonious statistical model for predicting future COT among hospitalized patients not on COT before hospitalization. DESIGN: Retrospective analysis electronic health record (EHR) data from 2008 to 2014 using logistic regression. PATIENTS: Hospitalized patients at an urban, safety net hospital. MAIN MEASUREMENTS: Independent variables included medical and mental health diagnoses, substance and tobacco use disorder, chronic or acute pain, surgical intervention during hospitalization, past year receipt of opioid or non-opioid analgesics or benzodiazepines, opioid receipt at hospital discharge, milligrams of morphine equivalents prescribed per hospital day, and others. KEY RESULTS: Model prediction performance was estimated using area under the receiver operator curve, accuracy, sensitivity, and specificity. A model with 13 covariates was chosen using stepwise logistic regression on a randomly down-sampled subset of the data. Sensitivity and specificity were optimized using the Youden's index. This model predicted correctly COT in 79% of the patients and no COT correctly in 78% of the patients. CONCLUSIONS: Our model accessed EHR data to predict 79% of the future COT among hospitalized patients. Application of such a predictive model within the EHR could identify patients at high risk for future chronic opioid use to allow clinicians to provide early patient education about pain management strategies and, when able, to wean opioids prior to discharge while incorporating alternative therapies for pain into discharge planning. PMID- 29404944 TI - Balancing the Rights to Protection and Participation: A Call for Expanded Access to Ethically Conducted Correctional Health Research. AB - Incarcerated individuals, over 95% of whom are eventually released, experience high burdens of chronic disease and behavioral health and social risk factors. Understanding the health needs of this population is critical to ensuring that general medicine physicians in prisons and in the community are adequately prepared to meet those needs. However, people in prison are significantly underrepresented in health research. In response to historical exploitation of prisoners in medical experimentation, federal guidelines appropriately require additional oversight for, and limit the scope of, research in prisons. Yet, according to a 2006 Institute of Medicine report, these requirements have produced inconsistent local regulations that often limit opportunities for incarcerated individuals to participate in research, and can slow the development of innovative medical interventions to improve their health. In this article, we describe the historical context surrounding regulations on research involving individuals in prison, the harms that can arise from excessive limitations to research in such settings, and the benefits of greater access to ethically conducted research in prison. We conclude with recommended actions that can be taken by general medicine researchers, correctional leaders, and policymakers to achieve consistent access to health research for incarcerated populations. PMID- 29404945 TI - Electronic Health Records: a "Quadruple Win," a "Quadruple Failure," or Simply Time for a Reboot? PMID- 29404946 TI - Capsule Commentary on Murray et al. Antihypertensive Medication and Dementia Risk in Older Adult African-Americans with Hypertension: a Prospective Cohort Study. PMID- 29404947 TI - Characteristics of Patient-Centered Medical Home Initiatives that Generated Savings for Medicare: a Qualitative Multi-Case Analysis. AB - BACKGROUND: Through the Multi-Payer Advanced Primary Care Practice (MAPCP) Demonstration, Medicare, Medicaid, and private payers offered supplemental payments to 849 primary care practices that became patient-centered medical homes (PCMHs) in eight states; practices also received technical assistance and data reports. Average Medicare payments were capped at $10 per beneficiary per month in each state. OBJECTIVE: Since there was variation in the eight participating states' demonstration designs, experiences, and outcomes, we conducted a qualitative multi-case analysis to identify the key factors that differentiated states that were estimated to have generated net savings for Medicare from states that did not. PARTICIPANTS: States' MAPCP Demonstration initiatives were comprehensively profiled in case studies based on secondary document review, three rounds of annual interviews with state staff, payers, practices, and other stakeholders, and other data sources. APPROACH: Case study findings were summarized in a case-ordered predictor-outcome matrix, which identified the presence or absence of key demonstration design features and experiences and arrayed states based on the amount of net savings or losses they generated for Medicare. We then used this matrix to identify initiative features that were present in at least three of the four states that generated net savings and absent from at least three of the four states that did not generate savings. RESULTS: A majority of the states that generated net savings: required practices to be recognized PCMHs to enter the demonstration, did not allow late entrants into the demonstration, used a consistent demonstration payment model across participating payers, and offered practices opportunities to earn performance bonuses. Practices in states that generated net savings also tended to report receiving the demonstration payments and bonuses they expected to receive, without any issues. CONCLUSIONS: Designers of future PCMH initiatives may increase their likelihood of generating net savings by incorporating the demonstration features we identified. PMID- 29404948 TI - A Randomized Trial on the Efficacy of Mastery Learning for Primary Care Provider Melanoma Opportunistic Screening Skills and Practice. AB - BACKGROUND: Early detection of melanoma represents an opportunity to reduce the burden of disease among people at increased risk for melanoma. OBJECTIVE: To develop and demonstrate the efficacy of online training. DESIGN: Randomized educational trial. PARTICIPANTS: Primary care providers (PCPs). INTERVENTION: Mastery learning course with visual and dermoscopic assessment, diagnosis and management, and deliberate practice with feedback to reach a minimum passing standard. MAIN MEASURES: Pre-test/post-test diagnostic accuracy. Referral of concerning lesions for 3 months before and after the educational intervention. KEY RESULTS: Among the 89 PCPs, 89.8% were internal medicine physicians, and the remainder were physician assistants embedded in internists' practices. There were no differences between control and intervention groups regarding gender, age, race, or percentage of full-time PCPs. The control group had more PCPs who reported less than 5 years of practice (n = 18) than the intervention group (n = 6) (chi2 [6, n = 89] = 14.34, p = 0.03). PCPs in the intervention group answered more melanoma detection questions correctly on the post-test (M = 10.05, SE = 1.24) compared to control group PCPs (M = 7.11, SE = 0.24), and had fewer false positive and no false-negative melanoma diagnoses (intervention, M = 1.09, SE = 0. 20; control, M = 3.1, SE = 0.23; ANCOVA, F[1,378] =27.86, p < 0.001; etap2 = 0.26). PCPs who underwent training referred fewer benign lesions, including nevi, seborrheic keratoses, and dermatofibromas, than control PCPs (F[1,79] = 72.89, p < 0.001; etap2 = 0.489; F[1,79] = 25.82, p < 0.001; etap2 = 0.246; F[1,79] = 34.25, p < 0.001; etap2 = 0.302; respectively). Those receiving training referred significantly more melanomas than controls (F[1,79] = 24.38, p < 0.001; etap2 = 0.236). Referred melanomas (0.8 +/- 0.07 per month for intervention, 0.17 +/- 0.06 for control) were mostly located on the head and neck. CONCLUSIONS: Mastery learning improved PCPs' ability to detect melanoma on a standardized post-test and may improve referral of patients with suspected melanoma. Further studies are needed to confirm this finding. ClinicalTrials.gov NCT02385253. PMID- 29404951 TI - Geochemistry of rare earth elements within waste rocks from the Montviel carbonatite deposit, Quebec, Canada. AB - Several rare earth element (REE) mine projects around the world are currently at the feasibility stage. Unfortunately, few studies have evaluated the contamination potential of REE and their effects on the environment. In this project, the waste rocks from the carbonatites within the Montviel proterozoic alkaline intrusion (near Lebel-sur-Quevillon, Quebec, Canada) are assessed in this research. The mineralization is mainly constituted by light REE (LREE) fluorocarbonates (qaqarssukite-Ce, kukharenkoite-Ce), LREE carbonates (burbankite, Sr-Ba-Ca-REE, barytocalcite, strontianite, Ba-REE-carbonates), and phosphates (apatite, monazite). The gangue minerals are biotites, chlorite, albite, ankerite, siderite, and calcite. The SEM-EDS analyses show that (i) the majority of REE are associated with the fine fraction (< 106 MUm), (ii) REE are mainly associated with carbonates, (iii) all analyzed minerals preferably contain LREE (La, Ce, Pr, Nd, Sm, Eu), (iv) the sum of LREE in each analyzed mineral varies between ~ 3 and 10 wt%, (v) the heavy REE (HREE) identified are Gd and Yb at < 0.4 wt%, and (vi) three groups of carbonate minerals were observed containing variable concentrations of Ca, Na, and F. Furthermore, the mineralogical composition of REE-bearing minerals, REE mobility, and REE speciation was investigated. The leachability and geochemical behavior of these REE-bearing mine wastes were tested using normalized kinetic testing (humidity cells). Leachate results displayed higher LREE concentrations, with decreasing shale-normalized patterns. Thermodynamical equilibrium calculations suggest that the precipitation of secondary REE minerals may control the REE mobility. PMID- 29404949 TI - Molecular detection and genotypic characterization of enteric adenoviruses in a hospital wastewater. AB - Hospital wastewater (HWW) represents a major source of the diffusion of many antibiotics and some toxic pathogenic microorganisms in the aquatic environment. Sanitation services play a critical role in controlling transmission of numerous waterborne pathogens, especially enteric human adenoviruses (HAdVs) that can cause acute gastroenteritis. This study intended to evaluate the human adenoviruses (HAdVs) detection rates, to determine the genotype of these viruses and to assess the efficiency of HAdVs removal in hospital pilot wastewater treatment plant (PWWTP) in Tunis City, Tunisia. Therefore, hospital wastewater samples (n = 102) were collected during the study year from the two biological wastewater treatment techniques: natural oxidizing ponds and the rotating biological disks or biodisks. Nested polymerase chain reaction (Nested PCR) was used to evaluate the HAdVs detection rates. The genotype of HAdVs positive samples was achieved by the sequencing of the PCR products. HAdVs were detected in 64% (65/102) of positive wastewater samples. A substantial increase in the frequencies of HAdVs was observed at the exit of the two wastewater treatment techniques studied. The typing of HAdVs species F showed the occurrence of only HAdVs type 41. This data acquired for the first time in Tunisia showed high persistence and survival of HAdVs in the two biological wastewater treatment techniques experienced, and mainly highlighted the poor virological quality of the treated wastewater intended for recycling, agriculture reuse, and discharges into the natural receiving environments. Consequently, tertiary wastewater treatment appeared necessary in this case to decrease the load of enteric viruses flowing in the water environment. PMID- 29404950 TI - Effect of dewatering and composting on helminth eggs removal from lagooning sludge under semi-arid climate. AB - In this work, we assessed the drying and composting effectiveness of helminth eggs removal from sewage sludge of a lagoon wastewater treatment plant located in Chichaoua city. The composting was run after mixing sludge with green waste in different proportions: M1 (1/2 sludge + 1/2 green waste), M2 ([Formula: see text] sludge + [Formula: see text] green waste), and M3 ([Formula: see text] sludge + [Formula: see text] green waste) for 105 days. The analysis of the dewatered sewage sludge showed a load of 8-24 helminth eggs/g of fresh matter identified as Ascaris spp. eggs (5-19 eggs/g) followed by Toxocara spp. (0.2 to 2.4 eggs/g); Hookworm spp. and Capillaria spp. (0.4-1 egg/g); Trichuris spp., Taenia spp., and Shistosoma spp. (< 1 egg/g) in the untreated sludge. After 105 days of treatment by composting, we noted a total reduction of helminth eggs in the order of 97.5, 97.83, and 98.37% for mixtures M1, M2, and M3, respectively. The Ascaris spp. eggs were reduced by 98% for M1 and M3 treatments and by 97% for M2 Treatment. Toxocara spp., Hookworm spp., Trichuris spp., Capillaria spp., and Shistosoma spp. eggs were totally eliminated (100% decrease) and the Taenia spp. was absent from the first stage of composting. These results confirm the effectiveness of both dehydrating and composting processes on the removal of helminth eggs. PMID- 29404952 TI - In situ investigation of heavy metals at trace concentrations in greenhouse soils via portable X-ray fluorescence spectroscopy. AB - Soil pollution by heavy metals (HMs) has rapidly become a major threat to vegetable security. Nearly all cultivated soils are at risk of metal accumulation, and greenhouse soils are among the most heavily impacted soils. In this study, a rapid assessment of HMs at trace concentrations was conducted via portable X-ray fluorescence (PXRF) spectroscopy in Shouguang, China. Measurements were made via PXRF under in situ, ex situ and sieved conditions and by inductively coupled plasma mass spectrometry (ICP-MS) after acid digestion. The performance of each PXRF measure relative to the ICP-MS method was assessed by linear regression. Redundancy analysis was performed to quantify the proportion of explained variability between the PXRF and ICP-MS data. Evaluation of the possible sources of HMs and their potential risks was then conducted by multivariate analysis. The results showed that the PXRF data were closely correlated with ICP-MS quantification for Cu, Mn and Zn, whereas no significant correlations were found for As, Ni and Pb. The uncertainties of PXRF measurement derived from soil heterogeneity accounted for 20.02% of total variability and those from moisture and particle size accounted for 20.15%. The geo-accumulation index (Igeo) indicated that the greenhouse soils were potentially contaminated by Cu and Zn (Igeo > 0), which can be attributed to anthropogenic activities. Overall, PXRF spectroscopy is promising as a rapid and nondestructive in situ technique for assessing the potential risks of HMs at trace concentrations in greenhouse soils. PMID- 29404953 TI - The effect of dietary selenium addition on the concentrations of heavy metals in the tissues of fallow deer (Dama dama L.) in Croatia. AB - The aim of this research was to determine the concentrations of cadmium, lead, mercury, and arsenic and the essential elements iron and selenium in the tissues (muscle, kidney, liver, spleen, and fat) of fallow deer (Dama dama L.) without and with supplemental selenium addition. Another aim was to determine the effect of selenium addition on the indicators of oxidative stress, namely, the levels of superoxide dismutase, glutathione peroxidase, glutathione, and vitamin E. The research was carried out with 40 fallow deer during two research periods. Supplemental feed without selenium addition was provided during the first research period, and supplemental feed with added selenium (3 mg/kg) was provided for 60 days during the second research period. The concentration of selenium in tissues was higher in the second research period than in the first research period (in kidney tissue, 0.957 vs. 0.688 mg/kg, P < 0.05). The dietary addition of selenium decreased (P < 0.05) the concentrations of some heavy metals (lead in the spleen = 0.06 vs. 0.27 mg/kg and in the fatty tissue = 0.17 vs. 0.69 mg/kg; arsenic in the muscle tissue = 0.005 vs. 0.014 mg/kg, liver = 0.003 vs. 0.009 mg/kg, spleen = 0.004 vs. 0.013 mg/kg, and fat = 0.008 vs. 0.016 mg/kg). The activity of glutathione peroxidase was significantly higher (P < 0.05) in the second research period than in the first research period (1375.36 vs. 933.23 U/L). PMID- 29404954 TI - Tools, techniques, and technologies for pollution prevention, control, and resource recovery. PMID- 29404955 TI - Comparative Study of Glyceryl Behenate or Polyoxyethylene 40 Stearate-Based Lipid Carriers for Trans-Resveratrol Delivery: Development, Characterization and Evaluation of the In Vitro Tyrosinase Inhibition. AB - Trans-resveratrol (RSV) is a natural compound with several properties, such as the ability to inhibit the tyrosinase enzyme, with potential application as a skin-lightning agent and for the treatment of skin disorders associated with hyperpigmentation and melanogenesis. However, the drug faces several drawbacks which altogether limit its therapeutic application. Thus, drug loading into nanocarriers emerge as an alternative to circumvent these problems. Herein, nanostructured lipid carriers (NLCs) have been employed for RSV encapsulation, with comparison of two different lipids, glyceryl behenate (more hydrophobic), and polyoxyethylene 40 (PEG 40) stearate. PEG 40 stearate-containing NLCs presented smaller particle size and polydispersity compared with glyceryl behenate, attributed to better emulsification and nanoparticle formation, resulting in higher RSV encapsulation efficiency. Drug was loaded in both carriers as a molecular dispersion. Furthermore, the formulations had very low RSV release, which occurred due to the crystallinity degree of lipid matrix, in accordance with the DSC data. Moreover, RSV cytotoxicity against L-929 cells was not increased when loaded into nanocarriers. Interestingly, RSV-loaded formulation prepared with PEG-40 stearate resulted on greater tyrosinase inhibition than RSV solution and formulation containing glyceryl behenate, equivalent to 1.31 and 1.83 times higher, respectively, demonstrating that the incorporation of RSV into NLC allowed an enhanced tyrosinase inhibitory activity. Overall, the results obtained herein evidence potential for future in vivo evaluation of RSV-loaded NLCs. PMID- 29404956 TI - Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson's Disease Models. AB - The exact mechanism of gut dysfunction in Parkinson's disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1 week) or subchronic (3 weeks) gut inflammation did not show a significant increase in colonic alpha-synuclein and phosphorylated alpha synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gut disturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation. PMID- 29404957 TI - Neurofascin Knock Down in the Basolateral Amygdala Mediates Resilience of Memory and Plasticity in the Dorsal Dentate Gyrus Under Stress. AB - Activation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of rats. Metaplastic effects of such a BLA modulation on hippocampal synaptic function were assessed using BLA priming prior to the induction of long-term potentiation (LTP) on dentate gyrus synapses in anesthetized rats in vivo. The knock down of neurofascin in the BLA prevented a priming-induced impairment on LTP maintenance in the dentate gyrus. At the behavioral level, a similar effect was observable, with neurofascin knock down preventing the detrimental impact of acute traumatic stress on hippocampus-dependent spatial memory retrieval in a water maze task. These findings suggest that reducing GABAergic inhibition specifically at the AIS synapses of the BLA alters amygdalo-hippocampal interactions such that it attenuates the adverse impact of acute stress exposure on cognition-related hippocampal functions. PMID- 29404960 TI - Associations and hallucinations in mice and men. AB - Powers et al. (2017, Science, 357(6351), 596-600) report that Pavlovian conditioning can result in the perception of a stimulus in its absence, and that this effect is related to hallucinations outside the laboratory. Considered alongside similar studies in animals, this suggests that associatively produced perceptual processing offers a means to study hallucination-like behaviour in the animal laboratory. PMID- 29404958 TI - Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer's Disease. AB - There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with beta amyloid (Abeta) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Abeta. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Abeta plays a key role, as is the case of T2DM. PMID- 29404959 TI - Conserved Upstream Regulatory Regions in Mammalian Tyrosine Hydroxylase. AB - Tyrosine hydroxylase (Th) encodes the rate-limiting enzyme in catecholamine biosynthesis, and the regulation of its transcription is critical for the specification and maintenance of catecholaminergic neuron phenotypes. For many genes, regulatory genomic DNA sequences that are upstream of the proximal promoter control expression levels as well as region-specific expression patterns. The regulatory architecture of the genomic DNA upstream of the Th proximal promoter, however, is poorly understood. In this study, we examined the 11 kb upstream nucleotide sequence of Th from nine mammalian species and identified five highly conserved regions. Using cultured human cells and mouse olfactory bulb tissue, chromatin immunoprecipitation (ChIP) assays show that these conserved regions recruit transcription factors that are established regulators of Th transcription (such as NURR1, PITX3, FOXA2, MEIS2, and PAX6). This analysis also identified a conserved binding site for CTCF, and functional studies in cultured human cells and ChIP assays with mouse tissue show that CTCF is a novel regulator of Th transcription in the forebrain. Together, the findings in this study provide key insights into the upstream regulatory genomic architecture and regulatory mechanisms controlling mammalian Th gene transcription. PMID- 29404961 TI - Rotational stress influences sensitized, but not habituated, exploratory behaviors in the woodlouse, Porcellio scaber. AB - Terrestrial isopods (or woodlice), like the members of the other arthropod taxa, have a sophisticated nervous system that makes them sensitive to specific environmental factors. They can search for survival-related opportunities (e.g., approaching food sources or avoiding sunny areas). Two experiments examined how rotational stress could influence the propensity of common woodlice, Porcellio scaber to exhibit survival-related behaviors such as traveling and rearing up in a hostile environment. Experiment 1 assessed the behaviors of stressed and nonstressed woodlice exposed to a familiar or a novel environment without rewards. Experiment 2 assessed the effects of stress in woodlice given a free choice between a familiar and a novel environment without rewards. In the nonstressed individuals, the results showed a decrease in locomotor activity (habituation) and an increase in the time spent rearing up (sensitization) on the arena's walls over time. In the stressed individuals, repeated rotation had a detrimental effect on the time spent rearing up, but locomotion was decreased only in the stressed individuals that were not preexposed to the test environment beforehand. In addition, immobilization periods-as a plausible indicator of stress-were longer in the absence of preexposure. It is suggested that preexposure had some antistress protective effects on habituated but not on sensitized, exploratory behaviors in woodlice. PMID- 29404962 TI - Recovery of Immunoglobulin VJ Recombinations from Pancreatic Cancer Exome Files Strongly Correlates with Reduced Survival. AB - We assessed pancreatic cancer, lymphocyte infiltrates with a computational genomics approach. We took advantage of tumor-specimen exome files available from the cancer genome atlas to mine T- and B-cell immune receptor recombinations, using highly efficient, scripted algorithms established in several previous reports. Surprisingly, the results indicated that pancreatic cancer exomes represent one of the highest level yields for immune receptor recombinations, significantly higher than two comparison cancers used in this study, head and neck and bladder cancer. In particular, pancreatic cancer exomes have very large numbers of immunoglobulin light chain recombinations, both with regard to number of samples characterized by recovery of such recombinations and with regard to numbers of recombination reads per sample. These results were consistent with B cell biomarkers, which emphasized the Th2 nature of the pancreatic lymphocyte infiltrate. The tumor specimen exomes with B-cell immune receptor recombination reads represented a dramatically poor outcome, a result not detected with either the head and neck or bladder cancer datasets. The results presented here support the potential value of immunotherapies designed to engineer a Th2 to Th1 shift in treating certain forms of pancreatic cancer. PMID- 29404963 TI - The Love Song of the Pimped Student. PMID- 29404964 TI - Are contemporary femoral components sizing and design likely to affect functional results in TKA? A mathematical model of an implanted knee to predict knee forces. AB - PURPOSE: This study is aimed to investigate the effects of the choice of femoral and tibial components on several mechanical outputs that might be associated with total knee replacement surgery outcomes using a validated computational model: the Kansas knee simulator. METHODS: Two models from the same range of implants were taken into account: Model 1, the femoral component fitted the femoral epiphysis, with physiological positioning of the articulating surface using a 10 mm-thick tibial component, and in Model 2, the femoral component was 4 mm smaller than in Model 1, and a 14-mm-thick tibial component was used with a similar tibial resection and the tibio-femoral joint line was 4 mm more proximal to compensate the increased posterior bone resection and maintain proper soft-tissue tension in flexion. Changes in reaction forces and contact pressures between the components, changes in extensor muscle forces and changes in patello-femoral joint kinematics during walking gait have been studied. RESULTS: While the computational model predicted that most kinematic and kinetic outputs, including tibio-femoral and patello-femoral joint motions, contact forces, pressures and areas, were similar for Model 1 and Model 2, and a dramatic difference has been found in the extensor muscle forces necessary to flex and extend the knee. To reproduce the same knee motion with a knee reconstructed as in Model 2, a patient would need to generate approximately 40% greater extensor muscle force throughout the gait cycle in order to do so. CONCLUSION: As a consequence of such a large increase in the extensor muscle force, the knee motions would probably be compromised and, subsequently, a patient with a knee reconstructed as in Model 2 would be less likely to be able to reproduce normal knee function and therefore more likely to report poor outcome. PMID- 29404965 TI - Medication Profiles of Patients with Cognitive Impairment and High Anticholinergic Burden. AB - BACKGROUND: Drugs with anticholinergic properties are considered potentially inappropriate in patients with cognitive impairment because harms-including delirium, falls, and fractures-may outweigh benefits. OBJECTIVE: To highlight opportunities to improve clinical decision making and care for patients with cognitive impairment and multiple chronic conditions, we identified distinct subgroups of patients with mild cognitive impairment (MCI) and dementia who had high cumulative anticholinergic burden and specific patterns of anticholinergic use. PATIENTS AND METHODS: We conducted a retrospective cohort study in a not-for profit, integrated delivery system. Participants included community-dwelling adults aged 65 years and older (n = 13,627) with MCI or dementia and at least two other chronic diseases. We calculated the Anticholinergic Cognitive Burden (ACB) score for each participant from pharmacy and electronic health record (EHR) data. Among individuals with a mean 12-month ACB score >= 2, we used agglomerative hierarchical clustering to identify groups or clusters of individuals with similar anticholinergic prescription patterns. RESULTS: Twenty-four percent (3257 participants) had high anticholinergic burden, defined as an ACB score >= 2. Clinically meaningful clusters based upon anchoring medications or drug classes included a cluster of cardiovascular medications (n = 1497; 46%); two clusters of antidepressant medications (n = 633; 20%); and a cluster based on use of bladder antimuscarinics (n = 431; 13%). Several clusters comprised multiple central nervous system (CNS)-active drugs. CONCLUSIONS: Cardiovascular and CNS-active medications comprise a substantial portion of anticholinergic burden in people with cognitive impairment and multiple chronic conditions. Antidepressants were highly prevalent. Clinical profiles elucidated by these clusters of anticholinergic medications can inform targeted approaches to care. PMID- 29404966 TI - Efficacy and Safety of Secukinumab in Elderly Subjects with Moderate to Severe Plaque Psoriasis: A Pooled Analysis of Phase III Studies. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease, affecting patients of a wide age range, including elderly patients. Elderly patients can respond differently to drug treatments and can be more vulnerable to adverse reactions. There are limited data on biologic therapies for psoriasis in elderly subjects. Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL 17A, has proven significant efficacy in the treatment of moderate to severe psoriasis. AIMS: A post-hoc analysis of three phase III trials (ERASURE, FIXTURE and CLEAR) was performed to evaluate the efficacy and safety of secukinumab in elderly subjects. METHODS: Studies were multicentre, randomized, parallel-group, double-blind, 52-week phase III trials in subjects with moderate to severe plaque psoriasis. For efficacy analyses, 67 elderly subjects (>= 65 years) treated with secukinumab 300 mg were compared with 841 younger subjects (18-64 years). Psoriasis Area and Severity Index (PASI), Dermatological Life Quality Index (DLQI) and safety were analysed. RESULTS: Elderly subjects had higher baseline frequencies of cardiovascular and metabolic disorders. Secukinumab efficacy in elderly subjects was comparable to that in younger subjects throughout 52 weeks of treatment. PASI 75 response was reached by 81.8% of elderly subjects and 79.4% of younger subjects at Week 52. Similar rates of DLQI 0/1 response were observed. The total rate of adverse events was similar between elderly and younger subjects. CONCLUSIONS: Secukinumab at the recommended dose (300 mg) is effective and acceptably safe in subjects aged >= 65 years with moderate to severe psoriasis, with quality-of-life benefits, despite an increased prevalence of cardiovascular and metabolic comorbidities in this population. PMID- 29404967 TI - Behavioral Health Risk Factors: the Interaction of Personal and Country Effects. AB - PURPOSE: This study investigated the relationship between the individual's self assessed health status (SAHS) and health-risk factors (smoking, alcohol consumption and obesity), in 16 European countries. The associations were studied for the individual and for the country measures-and in particular, for the unexplored aspect of interaction between individual and country levels of the three risk factors. METHOD: Data for 47,114 adults, who participated in the Survey of Health Aging and Retirement Europe (SHARE), were analyzed using Multilevel Regression Analysis. The individual data were complemented by OECD data that provided country-specific risk measures: percentage of daily smokers, annual per-capita consumption of alcohol (liters), and percentage of obese individuals. RESULTS: We found that the individual's SAHS is negatively associated with smoking and with weight-risk factors and is positively associated with her/his alcohol consumption. The most pronounced associations relate to the weight variables, albeit they are attenuated in countries with higher percentages of obese individuals. Significant differences across countries were evidenced in the association between SAHS and smoking and between SAHS and alcohol consumption. CONCLUSION: Individual health levels are associated with individual risk factors and also with the behaviors in the country. Significant interactions might indicate that psychological factors are at work. PMID- 29404968 TI - Aerosol Vacuum-Assisted Plasma Ionization (Aero-VaPI) Coupled to Ion Mobility Mass Spectrometry. AB - In this communication, we report on the real-time analysis of organic aerosol particles by Vacuum-assisted Plasma Ionization-Mass Spectrometry (Aero-VaPI-MS) using a home-built VaPI ion source coupled to a Synapt G2-S HDMS ion mobility mass spectrometry (IM-MS) system. Standards of organic molecules of interest in prebiotic chemistry were used to generate aerosols. Monocaprin and decanoic acid aerosol particles were successfully detected in both the positive and negative ion modes, respectively. A complex aerosol mixture of different sizes of polymers of L-malic acid was also examined through ion mobility (IM) separations, resulting in the detection of polymers of up to eight monomeric units. This noncommercial plasma ion source is proposed as a low cost alternative to other plasma ionization platforms used for aerosol analysis, and a higher-performance alternative to more traditional aerosol mass spectrometers. VaPI provides robust online ionization of organics in aerosols without extensive ion activation, with the coupling to IM-MS providing higher peak capacity and excellent mass accuracy. Graphical Abstract ?. PMID- 29404969 TI - Neutral Loss Scan - Based Strategy for Integrated Identification of Amorfrutin Derivatives, New Peroxisome Proliferator-Activated Receptor Gamma Agonists, from Amorpha Fruticosa by UPLC-QqQ-MS/MS and UPLC-Q-TOF-MS. AB - Amorfrutins with a 2-hydroxybenzoic acid core structure are promising natural PPARgamma agonists with potent antidiabetic activity. Owing to the complex matrix and low concentration in botanical material, the identification of unknown amorfrutins remains a challenge. In the present study, a combined application of UPLC-Q-TOF-MS and UPLC-QqQ-MS was developed to discover unknown amorfrutins from fruits of Amorpha fruticosa. First, reference compounds of amorfrutin A (AA), amorfrutin B (AB), and 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (AC) were analyzed using UPLC-Q-TOF-MS to reveal the characteristic fragment ions and the possible neutral loss. Second, the extract of A. fruticosa was separated and screened by UPLC-QqQ-MS using neutral loss scan to find out suspect compounds associated with the specified neutral fragment Deltam/z 44. Third, the extract was re-analyzed by UPLC-Q-TOF-MS to obtain the exact mass of quasi-molecular ion and fragment ions of each suspect compound, and to subsequently calculate their corresponding molecular formulas. Finally, according to the molecular formula of suspect compound and its fragment ions and comparing with literature data, structure elucidation of four unidentified amorfrutins was achieved. The results indicated that the combination of QqQ-MS neutral loss scan and Q-TOF-MS molecular formula calculation was proven to be a powerful tool for unknown natural product identification, and this strategy provides an effective solution to discover natural products or metabolites of trace content. Graphical Abstract ?. PMID- 29404970 TI - Fungal Secretome Analysis via PepSAVI-MS: Identification of the Bioactive Peptide KP4 from Ustilago maydis. AB - Fungal secondary metabolites represent a rich and largely untapped source for bioactive molecules, including peptides with substantial structural diversity and pharmacological potential. As methods proceed to take a deep dive into fungal genomes, complimentary methods to identify bioactive components are required to keep pace with the expanding fungal repertoire. We developed PepSAVI-MS to expedite the search for natural product bioactive peptides and herein demonstrate proof-of-principle applicability of the pipeline for the discovery of bioactive peptides from fungal secretomes via identification of the antifungal killer toxin KP4 from Ustilago maydis P4. This work opens the door to investigating microbial secretomes with a new lens, and could have broad applications across human health, agriculture, and food safety. Graphical Abstract. PMID- 29404972 TI - Journals Can Persuade Authors to Learn Publishing's Ethics. AB - Some researchers, even professors in universities, sometimes do unethical actions unintentionally due to lack of a mentor in their academic life. In this opinion piece, we aim to show that journals and publishers can play the role of a mentor for authors of scientific articles, especially young M.Sc. and Ph.D. students, to teach them the ethics in research and publishing. In this way, both journals and researchers will benefit from such a plan. PMID- 29404971 TI - Detection of Single Quantum Dots in Model Systems with Sheet Illumination Microscopy. AB - Single molecule detection and tracking provides at times the only possible method to observe the interactions of low numbers of biomolecules, inlcuding DNA, receptors and signal mediating proteins in living systems. However, most existing imaging methods do not enable both high sensitivity and non-invasive imaging of large specimens. In this study we report a new setup for selective plane illumination microscopy (SPIM), which enables fast imaging and single molecule tracking with the resolution of confocal microscopy and the optical penetration beyond 300 MUm. We detect and report our instrumental figures of merit, control values of fluorescence properties of single nano crystals in comparison to both standard widefield configurations, and also values of nanocrystals in multicellular "fruiting bodies" of Dictyostelium, an excellent control as a model developmental system. In the Dictyostelium , we also report some of our first tracking of single nanocrystals with SPIM. The new SPIM setup represents a new technique, which enables fast single molecule imaging and tracking in living systems. PMID- 29404973 TI - Correctable Myths About Research Misconduct in the Biomedical Sciences. AB - A recent National Academy report on research integrity noted that policies are not evidence-based, with no formal entity responsible to attend to this deficit. Here we describe four areas of research misconduct (RM) regulations governing Public Health Service funded research that are empirically and/or ethically questionable. Policies for human subject protection, RM and conflict of interest are not harmonized, making it extremely difficult to deal with complex cases which often contain allegations in all of these areas. Second, detection of RM has depended entirely on whistleblowers in spite of evidence of significant under reporting. Third, the scientific record is far from cleansed of the effects of falsified/fabricated work through current mechanisms of retraction. Finally, lack of fairness in the regulations may reflect lack of a Belmont Report-like document to guide ethics of RM policy. These issues are likely common in other countries. RM regulations should be harmonized with related regulations and their effectiveness tracked, open access to data for independent replication and improved statistical tests are an essential supplement to whistleblowers, correction of the scientific record will require a major effort, and further ethical analysis and guidance are as important as is empirical study for the improvement of RM regulations. Further consideration should be given to assigning current regulations for human subjects protection, RM and conflict of interest to a single authority and to the further development of a Belmont-like report of essential principles, for RM. PMID- 29404974 TI - Productivity of CNPq Researchers from Different Fields in Biomedical Sciences: The Need for Objective Bibliometric Parameters-A Report from Brazil. AB - In Brazil, the CNPq (National Council for Scientific and Technological Development) provides grants, funds and fellowships to productive scientists to support their investigations. They are ranked and categorized into four hierarchical levels ranging from PQ 1A (the highest) to PQ 1D (the lowest). Few studies, however, report and analyse scientific productivity in different sub fields of Biomedical Sciences (BS), e.g., Biochemistry, Pharmacology, Biophysics and Physiology. In fact, systematic comparisons of productivity among the PQ 1 categories within the above sub-fields are lacking in the literature. Here, the scientific productivity of 323 investigators receiving PQ 1 fellowships (A to D levels) in these sub-fields of BS was investigated. The Scopus database was used to compile the total number of articles, citations, h-index values and authorship positions (first-, co- or last-listed author) in the most cited papers by researchers granted CNPq fellowships. We found that researchers from Pharmacology had the best performance for all of the parameters analysed, followed by those in Biochemistry. There was great variability in scientific productivity within the PQ 1A level in all of the sub-fields of BS, but not within the other levels (1B, 1C and 1D). Analysis of the most cited papers of PQ 1(A-D) researchers in Pharmacology revealed that the citations of researchers in the 1C and 1D levels were associated with publications with their senior supervisors, whereas those in the 1B level were less connected with their supervisors in comparison to those in 1A. Taken together, these findings suggest that the scientific performance of PQ 1A researchers in BS is not homogenous. In our opinion, parameters such as the most cited papers without the involvement of Ph.D. and/or post-doctoral supervisors should be used to make decisions regarding any given researcher's fellowship award level. PMID- 29404975 TI - The Emerging Role of Cardiac Magnetic Resonance Imaging in the Evaluation of Patients with HFpEF. AB - PURPOSE OF REVIEW: To give an update on the emerging role of cardiac magnetic resonance imaging in the evaluation of patients with heart failure with preserved ejection fraction (HFpEF). This is important as the diagnosis of HFpEF remains challenging and cardiac imaging is pivotal in establishing the function of the heart and whether there is evidence of structural heart disease or diastolic dysfunction. Echocardiography is widely available, although the gold standard in quantifying heart function is cardiac magnetic resonance (CMR) imaging. RECENT FINDINGS: This review includes the recently updated 2016 European Society of Cardiology guidelines on diagnosing HFpEF that define the central role of imaging in identifying patients with HFpEF. Moreover, it includes the pathophysiology in HFpEF, how CMR works, and details current CMR techniques used to assess structural heart disease and diastolic function. Furthermore, it highlights promising research techniques that over the next few years may become more used in identifying these patients. CMR has an emerging role in establishing the diagnosis of HFpEF by measuring the left ventricular ejection fraction (LVEF) and evidence of structural heart disease and diastolic dysfunction. PMID- 29404976 TI - An Appraisal of Biomarker-Based Risk-Scoring Models in Chronic Heart Failure: Which One Is Best? AB - PURPOSE OF REVIEW: While prediction models incorporating biomarkers are used in heart failure, these have shown wide-ranging discrimination and calibration. This review will discuss externally validated biomarker-based risk models in chronic heart failure patients assessing their quality and relevance to clinical practice. RECENT FINDINGS: Biomarkers may help in determining prognosis in chronic heart failure patients as they reflect early pathologic processes, even before symptoms or worsening disease. We present the characteristics and describe the performance of 10 externally validated prediction models including at least one biomarker among their predictive factors. Very few models report adequate discrimination and calibration. Some studies evaluated the additional predictive value of adding a biomarker to a model. However, these have not been routinely assessed in subsequent validation studies. New and existing prediction models should include biomarkers, which improve model performance. Ongoing research is needed to assess the performance of models in contemporary patients. PMID- 29404978 TI - High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma. AB - Epileptic seizures are an important cause of morbidity in glioma patients. Substantial lines of evidence support the concept of the excitatory neurotransmitter glutamate being a crucial mediator of glioma-associated seizures. In gliomas, non-vesicular secretion of glutamate via the cystine glutamate exchanger (SLC7A11, xCT) constitutes the main mechanism contributing to high extracellular glutamate concentrations. However, a convincing "proof-of relevance" of this mechanism in patient material is lacking. A cohort of 229 consecutive patients with newly diagnosed glioma was analyzed with respect to presence, time course, and severity of epileptic seizures. 14 patients were excluded due to previous epileptic seizures, insufficient clinical data or insufficient tumor material. The maximal immunohistochemical expression of xCT was determined in 1-3 independent samples from central tumor areas of each tumor using tissue microarrays. In addition to histological grading of the tumors, isocitrate dehydrogenase 1 (IDH1) R132H mutational status was determined by immunohistochemistry. 215 consecutive glioma patients were included in the study (7.4% grade II, 7.0% grade III, 85.6% grade IV). High xCT expression was significantly associated with seizures at onset (p = 0.05) but not with development of seizures or with refractory seizures. Low-grade gliomas (WHO II/III) had lower xCT expression than glioblastoma (p = 0.001), and tumors without IDH1 R132H mutation tended to have higher xCT levels (p = 0.07). In a multivariate analysis, high xCT expression and WHO tumor grade but not IDH1 R132H mutation, were significantly associated with epileptic seizures at diagnosis (odds ratio 2.2, p = 0.02). Further, xCT expression did not correlate with survival (p = 0.27, log-rank test). Thus, high xCT expression is an independent marker for glioma-associated seizures at diagnosis especially in high-grade glioma, but is not associated with worse survival in our cohort. PMID- 29404977 TI - Drug-Induced Ototoxicity: Diagnosis and Monitoring. AB - Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials. PMID- 29404979 TI - NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients. AB - From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients. PMID- 29404980 TI - Granulomatous diseases of the breast and axilla: radiological findings with pathological correlation. AB - OBJECTIVES: This article reviews our experience and describes the literature findings of granulomatous diseases of the breast and axilla. METHODS: After approval of the Institutional Review Board was obtained, the surgical pathological records from January 2000 to January 2017 were searched for the keyword granulomatous. Clinical, imaging and histology findings were reviewed by both a fellowship-trained radiologist and a breast-imaging consultant radiologist, reviewing 127 patients (age range, 32-86 years; 126 women and 1 man). RESULTS: Most common causes of granulomatous lesions of the breast and axilla included silicone granulomas 33% (n = 42), fat necrosis 29% (n = 37) and suture granulomas 11% (n = 14). In 16% (n = 20), no cause could be found and clinical history was consistent with idiopathic granulomatous mastitis. Other granulomatous aetiologies included granulomatous infections, sarcoidosis and Sjogren's syndrome. Causes of axillary granulomatous disease were similar to the breast; however, a case of cat-scratch disease was found that only involved the axillary lymph nodes. They can have a variable appearance on imaging and may mimic malignancy with irregular masses seen on mammography, ultrasound and magnetic resonance imaging. Fistulas to the skin and nipple retraction can suggest chronicity and a granulomatous aetiology. Combination of clinical history, laboratory and imaging findings can be diagnostic. CONCLUSIONS: Granulomatous processes of the breast are rare. The diagnosis can, however, be made if there is relevant history (prior trauma, silicone breast implants, lactation), laboratory (systemic or infectious processes) and imaging findings (fistula, nipple retraction). Recognising these entities is important for establishing pathological concordance after biopsy and for preventing unnecessary treatment. TEACHING POINTS: Breast granulomatous are rare but can mimic breast carcinoma on imaging Imaging with clinical and laboratory findings can correctly diagnosis specific granulomatous breast diseases Recognition of the imaging findings allows appropriate pathological concordance and treatment. PMID- 29404981 TI - Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD). AB - The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development. PMID- 29404982 TI - Effects of Copper and Zinc Supplementation on Weight Gain and Hematological Parameters in Pre-weaning Calves. AB - Cow-calf operations may be affected by trace mineral deficiencies, particularly copper (Cu) and zinc (Zn) deficiency, which may decrease the calf daily weight gain and alter hematological parameters. We evaluated the effect of Cu and Zn supplementation on pre-weaning calves (n = 40; 92 +/- 6 kg initial body weight) from the Salado River basin, Buenos Aires, Argentina. Calves were divided into four groups (n = 10 each) and subcutaneously administered 0.3 mg/kg Cu (Cu group), 1 mg/kg Zn (Zn group), Cu and Zn together (Cu + Zn group), and sterile saline solution (control group) every 40 days for 120 days. Plasma Cu and Zn concentrations, hematological parameters, and weight were recorded every 40 days. A completely randomized 2 * 2 factorial treatment design was used and data were analyzed with a mixed model for repeated measures over time. Cu and Zn were detected in plasma after the second sampling. Cu * Zn interaction was significant (p = 0.09), being Cu concentration higher in the Cu + Zn than in the Cu group. Differences in weight gain (Zn * time interaction; p < 0.01) were observed in the Zn but not in the Cu group (p > 0.1). On the other hand, none of the treatments altered any of the hematological parameters assessed (p > 0.1). Our results show the risk of lower weight gain due to Zn deficiency in pre-weaning calves raised in the Salado River basin. PMID- 29404984 TI - Intrapancreatic Accessory Spleen Masquerading as a Pancreatic Neuroendocrine Tumor. PMID- 29404983 TI - Underutilization of Treatment for Regional Gastric Cancer Among the Elderly in the USA. AB - BACKGROUND: In the USA, a quarter of elderly patients do not receive any treatment for regional gastric cancer, which results in poorer outcomes. We sought to identify factors associated with undertreatment of regional gastric cancer in this population, as well as to assess overall survival in the undertreated population. METHODS: Elderly patients (aged >= 65 years) diagnosed with regional gastric cancer between 2001 and 2009 were identified from the Surveillance Epidemiology and End Results (SEER)-Medicare linked databases. Treatment was defined as receiving any medical or surgical therapy for gastric cancer. Logistic regression analysis was used to identify factors associated with failure to receive treatment. Overall survival was analyzed using the Kaplan Meier method and Cox proportional hazard model. RESULTS: Of 5972 patients with regional gastric cancer, 1586 (26.5%) received no treatment. Median age was 78 years; 56.1% of patients were men. On multivariable analysis, the factors strongly associated with lack of therapy were age >= 80 years, black race, lower education level, and diagnosis before 2007. As expected, patients who received therapy had better overall survival (log-rank test, p < 0.001). Specifically, median survival and 5-year survival were 16.5 months and 20.5% for treated patients, compared with 9.1 months and 19.0% for untreated patients. CONCLUSIONS: Elderly patients with gastric cancer have better overall 5-year survival after receiving treatment for their cancer. Disparities in the use of treatment for curable cancers are associated with older age, black race, lower educational level, and diagnosis before 2007. PMID- 29404985 TI - Propensity Score-Matched Analysis of Clinical and Financial Outcomes After Robotic and Laparoscopic Colorectal Resection. AB - PURPOSE: The study aims to evaluate the clinical and financial outcomes of the use of robotic when compared to laparoscopic colorectal surgery and any changes in these over time. METHODS: From the Premier Perspective database, patients who underwent elective laparoscopic and robotic colorectal resections from 2012 to 2014 were included. Laparoscopic colorectal resections were propensity score matched to robotic cases for patient, disease, procedure, surgeon specialty, and hospital type and volume. The two groups were compared for conversion, hospital stay, 30-day post-discharge readmission, mortality, and complications. Direct, cumulative, and total (including 30-day post-discharge) costs were evaluated. Clinical and financial outcomes were also separately assessed for each of the included years. RESULTS: Of 36,701 patients, 32,783 (89.3%) had laparoscopic colorectal resection and 3918 (10.7%) had robotic colorectal resection; 4438 procedures (2219 in each group) were propensity score matched. For the entire period, conversion to open approach (4.7 vs. 3.7%, p = 0.1) and hospital stay (mean days [SD] 6 [5.3] vs. 5 [4.6], p = 0.2) were comparable between robotic and laparoscopic procedures. Surgical and medical complications were also the same for the two groups. However, the robotic approach was associated with lower readmission (6.3 vs. 4.8%, p = 0.04). Wound or abdominal infection (4.7 vs. 2.3%, p = 0.01) and respiratory complications (7.4 vs. 4.7%, p = 0.02) were significantly lower for the robotic group in the final year of inclusion, 2014. Direct, cumulative, and total (including 30-day post-discharge) costs were significantly higher for robotic surgery. The difference in costs between the two approaches reduced over time (direct cost difference: 2012, $2698 vs. 2013, $2235 vs. 2014, $1402). CONCLUSION: Robotic colorectal surgery can be performed with comparable clinical outcomes to laparoscopy. With greater use of the technology, some further recovery benefits may be evident. The robotic approach is more expensive but cost differences have been diminishing over time. PMID- 29404986 TI - Predictors of Short-Term Readmission After Pancreaticoduodenectomy. AB - BACKGROUND: Readmissions are a common complication after pancreaticoduodenectomy and are increasingly being used as a performance metric affecting quality assessment, public reporting, and reimbursement. This study aims to identify general and pancreatectomy-specific factors contributing to 30-day readmission after pancreaticoduodenectomy, and determine the additive value of incorporating pancreatectomy-specific factors into a large national dataset. METHODS: Prospective American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) data were retrospectively analyzed for patients who underwent pancreaticoduodenectomy (PD) between 2011 and 2015. Additionally, a subset of patients with pancreatectomy-targeted data between 2014 and 2015 were analyzed. RESULTS: Outcomes of 18,440 pancreaticoduodenectomies were analyzed, and found to have an 18.7% overall readmission rate. Multivariable modeling with pancreatectomy-specific variables increased the predictive value of the model (area under receiver operator characteristic 0.66 to 0.73). Statistically significant independent contributors to readmission included renal insufficiency, sepsis, septic shock, organ space infection, dehiscence, venous thromboembolism, pancreatic fistula, delayed gastric emptying, need for percutaneous drainage, and reoperation. CONCLUSIONS: Large registry analyses of pancreatectomy outcomes are markedly improved by the incorporation of granular procedure-specific data. These data emphasize the need for prevention and careful management of perioperative infectious complications, fluid management, thromboprophylaxis, and pancreatic fistulae. PMID- 29404988 TI - Leveraging Formylglycine-Generating Enzyme for Production of Site-Specifically Modified Bioconjugates. AB - Enzymatic modification of proteins can generate uniquely reactive chemical functionality, enabling site-specific reactions on the protein surface. Formylglycine-generating enzyme (FGE) is one enzyme that can be exploited in this fashion. FGE binds its consensus sequence (CXPXR, known as the "aldehyde-tag") and converts the cysteine to a formylglycine (fGly). fGly-containing proteins contain a bioorthogonal aldehyde on their surface that can be modified selectively in the presence of the 20 canonical amino acids. Here, we describe protocols for the generation of a site-specifically modified protein, an antibody drug conjugate (ADC), using aldehyde-tagging protocols and aldehyde-reactive conjugation chemistry. PMID- 29404987 TI - Enhanced Recovery via Peripheral Nerve Block for Open Hepatectomy. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are now commonplace in many fields of surgery, but only limited data exists for their use in hepatobiliary surgery. We implemented standardized ERAS protocols for all open hepatectomies and replaced thoracic epidurals with a transversus abdominis plane (TAP) block. METHODS: We performed a retrospective cohort study of all patients undergoing open hepatectomy during the 14 months before and 19 months after implementation of an ERAS protocol at our institution (January 2014-September 2016). Trained abstractors reviewed charts for patient demographics, perioperative details, and healthcare utilization. All nursing-reported visual analog scale pain scores were sampled to identify patients with uncontrolled pain (daily mean score > 5). Outcomes included length of stay (LOS), costs, and 30-day readmission. RESULTS: A total of 127 patients (mean age 54.6 +/- 13.0 years, 44% female) underwent open liver resection (69 [54%] after ERAS implementation). ERAS protocols were associated with significantly lower rates of ICU admission (47 vs. 13%, p < 0.001), shorter LOS (median 5.3 vs. 4.3 days, p = 0.007), and lower median costs ($3566 less, p = 0.03). Readmission remained low throughout the study period (5% pre-ERAS, 4% during ERAS, p = 0.83). Rates of uncontrolled pain were either the same or better after ERAS implementation through post-operative day #3 (41% pre-ERAS, 23% during ERAS, p = 0.03). DISCUSSION: The use of TAP block for hepatectomy as part of an ERAS protocol is associated with improved quality and cost of care. Surgeons performing liver resections should consider standardization of evidence-based best practices in all patients. PMID- 29404989 TI - Artificial Division of Codon Boxes for Expansion of the Amino Acid Repertoire of Ribosomal Polypeptide Synthesis. AB - In ribosomal polypeptide synthesis, the 61 sense codons redundantly code for the 20 proteinogenic amino acids. The genetic code contains eight family codon boxes consisting of synonymous codons that redundantly code for the same amino acid. Here, we describe the protocol of a recently published method to artificially divide such family codon boxes and encode multiple nonproteinogenic amino acids in addition to the 20 proteinogenic ones in a reprogrammed genetic code. To achieve this, an in vitro translation system reconstituted with 32 in vitro transcribed tRNASNN's (S = C or G; N = U, C, A or G) was first developed, where the 32 tRNA transcripts can be charged with 20 proteinogenic amino acids by aminoacyl-tRNA synthetases in situ and orthogonally decode the corresponding 31 NNS sense codons as well as the AUG initiation codon. When some redundant tRNAGNN's are replaced with tRNAGNN's precharged with nonproteinogenic amino acids by means of flexizymes, the nonproteinogenic and proteinogenic aminoacyl tRNAs can decode the NNC and NNG codons in the same family codon box independently. In this protocol, we describe expression of model peptides, including a macrocyclic peptide containing three kinds of N-methyl-amino acids reassigned to the vacant codons generated by the method of artificial division of codon boxes. PMID- 29404990 TI - Cell-Free Protein Synthesis for Multiple Site-Specific Incorporation of Noncanonical Amino Acids Using Cell Extracts from RF-1 Deletion E. coli Strains. AB - Cell-free protein synthesis (CFPS) is an effective method for the site-specific incorporations of noncanonical amino acids (ncAAs) into proteins. The nature of in vitro synthesis enables the use of experimental conditions that are toxic or reduce cellular uptake during in vivo site-specific incorporations of ncAAs. Using the Escherichia coli cell extract (S30) from the highly reproductive RF-1 deletion strains, B-60.?A::Z and B-95.?A, with orthogonal tRNA and aminoacyl-tRNA synthetase (aaRS) pairs from Methanosarcina mazei, we have developed CFPS methods for the highly productive and efficient multiple incorporation of ncAAs. In this chapter, we describe our methods for the preparation of the S30 and the orthogonal tRNAPyl and PylRS pair, and two CFPS protocols for ncAA incorporation. PMID- 29404991 TI - Tub-Tag Labeling; Chemoenzymatic Incorporation of Unnatural Amino Acids. AB - Tub-tag labeling is a chemoenzymatic method that enables the site-specific labeling of proteins. Here, the natural enzyme tubulin tyrosine ligase incorporates noncanonical tyrosine derivatives to the terminal carboxylic acid of proteins containing a 14-amino acid recognition sequence called Tub-tag. The tyrosine derivative carries a unique chemical reporter allowing for a subsequent bioorthogonal modification of proteins with a great variety of probes. Here, we describe the Tub-tag protein modification protocol in detail and explain its utilization to generate labeled proteins for advanced applications in cell biology, imaging, and diagnostics. PMID- 29404992 TI - Directed Evolution of Orthogonal Pyrrolysyl-tRNA Synthetases in Escherichia coli for the Genetic Encoding of Noncanonical Amino Acids. AB - The directed evolution of orthogonal aminoacyl-tRNA synthetases (aaRS) for the genetic encoding of noncanonical amino acids (ncAA) has paved the way for the site-specific incorporation of >170 functionally diverse ncAAs into proteins in a large number of organisms [1, 2]. Here, we describe the directed evolution of orthogonal pyrrolysyl-tRNA synthetase (PylRS) mutants with new amino acid selectivities from libraries using a two-step selection protocol based on chloramphenicol and barnase reporter systems. Although this protocol focuses on the evolution of PylRS variants, this procedure can be universally employed to evolve orthogonal aaRS. PMID- 29404993 TI - Genetic Code Expansion in Enteric Bacterial Pathogens. AB - The genetic code expansion strategy has become an elegant method for site specific incorporation of noncanonical amino acids with diverse functionalities into proteins of interest in bacteria, yeast, mammalian cells, and even animals. This technique allows precise labeling as well as manipulation of a given protein to dissect its physiological and/or pathological roles under living conditions. Here, we demonstrate the extension of a recently emerged pyrrolysine-based genetic code expansion strategy for encoding noncanonical amino acids into enteric bacterial pathogens. PMID- 29404994 TI - Self-Directed in Cell Production of Methionine Analogue Azidohomoalanine by Synthetic Metabolism and Its Incorporation into Model Proteins. AB - Common protocols for the incorporation of noncanonical amino acids (ncAAs) into proteins require addition of the desired ncAA to the growth medium, its cellular uptake, and subsequent intracellular accumulation. This feeding scheme is generally suitable for small-scale proof-of-concept incorporation experiments. However, it is no general solution for orthogonal translation of ncAAs, as their chemical synthesis is generally tedious and expensive. Here, we describe a simple protocol that efficiently couples in situ semi-synthetic biosynthesis of L azidohomoalanine and its incorporation into proteins at L-methionine (Met) positions. In our metabolically engineered Met-auxotrophic Escherichia coli strain, Aha is biosynthesized from externally added sodium azide and O-acetyl-L homoserine as inexpensive precursors. This represents an efficient platform for expression of azide-containing proteins suitable for site-selective bioorthogonal strategies aimed at noninvasive protein modifications (Tornoe et al., J Org Chem 67:3057-3064, 2002; Kiick et al., Angew Chem Int Ed 39:2148-2152, 2000; Budisa, Angew Chem Int Ed Engl 47:6426-6463, 2004; van Hest, J Am Chem Soc 122:1282-1288, 2000). PMID- 29404995 TI - Residue-Specific Incorporation of Noncanonical Amino Acids for Protein Engineering. AB - The incorporation of noncanonical amino acids has given protein chemists access to an expanded repertoire of amino acids. This methodology has significantly broadened the scope of protein engineering allowing introduction of amino acids with non-native functionalities, such as bioorthogonal reactive handles (azides and alkynes) and hydrophobic fluorinated side chains. Here, we describe the efficient residue-specific replacement of methionine by azidonorleucine in an engineered green fluorescent protein using a bacterial expression system to introduce a single reactive site for the strain-promoted azide-alkyne cycloaddition. PMID- 29404996 TI - Using Amber and Ochre Nonsense Codons to Code Two Different Noncanonical Amino Acids in One Protein Gene. AB - In Escherichia coli, conventional amber and ochre stop codons can be separately targeted by engineered amber-suppressing Methanocaldococcus jannaschii tyrosyl tRNA synthetase-tRNAPyl and ochre-suppressing Methanosarcina maezi pyrrolysyl tRNA synthetase-tRNAPyl pairs for coding two different noncanonical amino acids in one protein gene. Here, we describe the application of this approach to produce a protein with two distinct chemical functionalites which can be selectively labeled with two fluorescent dyes. PMID- 29404997 TI - Genetic Incorporation of Unnatural Amino Acids into Proteins of Interest in Streptomyces venezuelae ATCC 15439. AB - Site-specific, genetic incorporation of unnatural amino acids (UAAs) into proteins in living cells using engineered orthogonal aminoacyl-tRNA synthetase (aaRS)/tRNA pairs is a powerful tool for studying and manipulating protein structure and function. To date, UAA incorporation systems have been developed for several bacterial and eukaryotic model hosts. Due to the importance of Streptomyces as prolific producers of bioactive natural products and as model hosts for natural product biosynthesis and bioengineering studies, we have developed systems for the incorporation of the UAAs p-iodo-L-phenylalanine (pIPhe) and p-azido-L-phenylalanine (pAzPhe) into green fluorescent protein (GFP) in Streptomyces venezuelae ATCC 15439. Here, we describe the procedure for using this system to site-specifically incorporate pIPhe or pAzPhe into proteins of interest in S. venezuelae. The modular design of plasmids harboring UAA incorporation systems enables use of other aaRS or aaRS/tRNA pairs for the incorporation of other UAAs; and the vector backbone used allows the system to be transferred to diverse Streptomyces species via both protoplast transformation and conjugation. PMID- 29404998 TI - Expression and Purification of Site-Specifically Lysine-Acetylated and Natively Folded Proteins for Biophysical Investigations. AB - N-(epsilon)-lysine-acetylation (short: lysine-acetylation) is a dynamic and powerful posttranslational modification to regulate protein function. Mutational approaches are often poor to access the real mechanistic impact of lysine acetylation at the molecular level. Therefore, the ability to site-specifically incorporate N-(epsilon)-acetyl-L-lysine (short: AcK) into proteins dramatically increased our understanding how lysine-acetylation regulates protein function by using diverse molecular mechanisms going far beyond neutralizing a positive charge at the lysine-side chain. Genetically encoding AcK is a powerful way to introduce AcK into proteins, resulting in homogenously, quantitatively, and site specifically lysine-acetylated proteins. Thereby, lysine-acetylated proteins can be produced in their natively-folded state in a high quality and in a yield sufficient to perform biophysical studies, including X-ray crystallography. This protocol describes the expression and purification of site-specifically lysine acetylated proteins in Escherichia coli using the genetic-code expansion concept (GCEC) and subsequent steps to assess the successful incorporation of AcK by immunoblotting and mass-spectrometry. PMID- 29404999 TI - Site-Specific Incorporation of Sulfotyrosine Using an Expanded Genetic Code. AB - Tyrosine sulfation is an important posttranslational modification found in bacteria and higher eukaryotes. However, the chemical synthesis or expression of homogenously sulfated proteins is particularly difficult, limiting our study and application of tyrosine-sulfated proteins. With the recent development of genomically recoded organisms and orthogonal translation components, we can often treat otherwise posttranslationally-modified amino acids as noncanonical amino acids (ncAAs) encoded by an expanded genetic code. Here, we describe methods for the co-translational incorporation of one or multiple sulfotyrosines into proteins using standard or genomically recoded Escherichia coli stains, thereby achieving the direct expression of site-specifically tyrosine sulfated proteins in vivo. PMID- 29405000 TI - Site-Specific Protein Labeling with Tetrazine Amino Acids. AB - Genetic code expansion is commonly used to introduce bioorthogonal reactive functional groups onto proteins for labeling. In recent years, the inverse electron demand Diels-Alder reaction between tetrazines and strained trans cyclooctenes has increased in popularity as a bioorthogonal ligation for protein labeling due to its fast reaction rate and high in vivo stability. We provide methods for the facile synthesis of a tetrazine containing amino acid, Tet-v2.0, and the site-specific incorporation of Tet-v2.0 into proteins via genetic code expansion. Furthermore, we demonstrate that proteins containing Tet-v2.0 can be quickly and efficiently reacted with strained alkene labels at low concentrations. This chemistry has enabled the labeling of protein surfaces with fluorophores, inhibitors, or common posttranslational modifications such as glycosylation or lipidation. PMID- 29405001 TI - Mapping of Protein Interfaces in Live Cells Using Genetically Encoded Crosslinkers. AB - Understanding the topology of protein-protein interactions is a matter of fundamental importance in the biomedical field. Biophysical approaches such as X ray crystallography and nuclear magnetic resonance can investigate in detail only isolated protein complexes that are reconstituted in an artificial environment. Alternative methods are needed to investigate protein interactions in a physiological context, as well as to characterize protein complexes that elude the direct structural characterization. We describe here a general strategy to investigate protein interactions at the molecular level directly in the live mammalian cell, which is based on the genetic incorporation of photo- and chemical crosslinking noncanonical amino acids. First a photo-crosslinking amino acid is used to map putative interaction surfaces and determine which positions of a protein come into proximity of an associated partner. In a second step, the subset of residues that belong to the binding interface are substituted with a chemical crosslinker that reacts selectively with proximal cysteines strategically placed in the interaction partner. This allows determining inter molecular spatial constraints that provide the basis for building accurate molecular models. In this chapter, we illustrate the detailed application of this experimental strategy to unravel the binding modus of the 40-mer neuropeptide hormone Urocortin1 to its class B G-protein coupled receptor, the corticotropin releasing factor receptor type 1. The approach is in principle applicable to any protein complex independent of protein type and size, employs established techniques of noncanonical amino acid mutagenesis, and is feasible in any molecular biology laboratory. PMID- 29405002 TI - Generation of Stable Amber Suppression Cell Lines. AB - Noncanonical amino acid mutagenesis via amber suppression provides the means to tailor proteins inside living cells. A wide range of noncanonical amino acids have been incorporated using the Methanococcus pyrrolysyl-tRNA synthetase/tRNACUA (PylRS/PylT) in mammalian cell systems in proof of principle experiments, for (1) minimal genetically encoded fluorescence or affinity tagging, (2) photo-control of enzymes, (3) genetically encoded posttranslational protein modifications. We have developed a general and efficient method to genomically integrate the PylRS/PylT amber suppression machinery using PiggyBac-mediated transposition. A general protocol for the generation of stable amber suppression cell lines is described here. Using the modular plasmid system, homogenous and highly efficient amber suppression in a wide range of cell lines can be achieved. PMID- 29405003 TI - Trapping Chromatin Interacting Proteins with Genetically Encoded, UV-Activatable Crosslinkers In Vivo. AB - The installation of unnatural amino acids into proteins of living cells is an enabling technology that facilitates an enormous number of applications. UV activatable crosslinker amino acids allow the formation of a covalent bond between interaction partners in living cells with nearly perfect spatial and temporal control. Here, we describe how this method can be employed to map chromatin interactions and to follow these interactions across the cell cycle in synchronized yeast populations. This method thereby provides unprecedented insights into the molecular events controlling chromatin reorganization in mitosis. As similar tools are available for other organisms, it should be possible to derive similar strategies for these and for other synchronizable processes. PMID- 29405004 TI - Genetically Encoding Unnatural Amino Acids in Neurons In Vitro and in the Embryonic Mouse Brain for Optical Control of Neuronal Proteins. AB - Deciphering neuronal networks governing specific brain functions is a longstanding mission in neuroscience, yet global manipulation of protein functions pharmacologically or genetically lacks sufficient specificity to reveal a neuronal protein's function in a particular neuron or a circuitry. Photostimulation presents a great venue for researchers to control neuronal proteins with high temporal and spatial resolution. Recently, an approach to optically control the function of a neuronal protein directly in neurons has been demonstrated using genetically encoded light-sensitive Unnatural amino acids (Uaas). Here, we describe procedures for genetically incorporating Uaas into target neuronal proteins in neurons in vitro and in embryonic mouse brain. As an example, a photocaged Uaa was incorporated into an inwardly rectifying potassium channel Kir2.1 to render Kir2.1 photo-activatable. This method has the potential to be generally applied to many neuronal proteins to achieve optical regulation of different processes in brains. Uaas with other properties can be similarly incorporated into neuronal proteins in neurons for various applications. PMID- 29405005 TI - Genetic Code Expansion- and Click Chemistry-Based Site-Specific Protein Labeling for Intracellular DNA-PAINT Imaging. AB - Super-resolution microscopy allows imaging of cellular structures at nanometer resolution. This comes with a demand for small labels which can be attached directly to the structures of interest. In the context of protein labeling, one way to achieve this is by using genetic code expansion (GCE) and click chemistry. With GCE, small labeling handles in the form of noncanonical amino acids (ncAAs) are site-specifically introduced into a target protein. In a subsequent step, these amino acids can be directly labeled with small organic dyes by click chemistry reactions. Click chemistry labeling can also be combined with other methods, such as DNA-PAINT in which a "clickable" oligonucleotide is first attached to the ncAA-bearing target protein and then labeled with complementary fluorescent oligonucleotides. This protocol will cover both aspects: I describe (1) how to encode ncAAs and perform intracellular click chemistry-based labeling with an improved GCE system for eukaryotic cells and (2) how to combine click chemistry-based labeling with DNA-PAINT super-resolution imaging. As an example, I show click-PAINT imaging of vimentin and low-abundance nuclear protein, nucleoporin 153. PMID- 29405006 TI - MultiBacTAG-Genetic Code Expansion Using the Baculovirus Expression System in Sf21 Cells. AB - The combination of genetic code expansion (GCE) and baculovirus-based protein expression in Spodoptera frugiperda cells is a powerful tool to express multiprotein complexes with site-specifically introduced noncanonical amino acids. This protocol describes the integration of synthetase and tRNA gene indispensable for GCE into the backbone of the Bacmid, the Tn7-mediated transposition of various genes of interest, as well as the final expression of protein using the MultiBacTAG system with different noncanonical amino acids. PMID- 29405007 TI - Production and Chemoselective Modification of Adeno-Associated Virus Site Specifically Incorporating an Unnatural Amino Acid Residue into Its Capsid. AB - The ability to modify the capsid proteins of human viruses is desirable both for installing probes to study their structure and function, and to attach retargeting agents to engineer viral infectivity. However, the installation of such capsid modifications currently faces two major challenges: (1) The complex and delicate capsid proteins often do not tolerate large modifications, and (2) capsid proteins are composed of the 20 canonical amino acids, precluding site specific chemical modification of the virus. Here, we describe a technology for generating adeno-associated virus (AAV) while incorporating an unnatural amino acid (UAA) into specific sites of the virus capsid. Incorporation of this UAA is generally tolerated well, presumably due to its small structural footprint. The resulting virus can be precisely functionalized at the site of UAA incorporation using chemoselective conjugation strategies targeted toward the azido side chain of this UAA. This technology provides a powerful way to modify AAV with unprecedented precision to both probe and engineer its entry process. PMID- 29405008 TI - Generation of Intramolecular FRET Probes via Noncanonical Amino Acid Mutagenesis. AB - Forster resonance energy transfer (FRET) probes are powerful tools to monitor protein-protein interactions and enzyme activities in a spatiotemporal manner in live cells. Using a combination of noncanonical amino acid (ncAA) mutagenesis and bioorthogonal labeling, we have developed intramolecular FRET probes consisting of a fluorescent protein and an organic dye within an individual protein. Herein we present a general approach to establish intramolecular FRET probes for imaging of protein activity in live cells. PMID- 29405009 TI - Fluorogenic Tetrazine-Siliconrhodamine Probe for the Labeling of Noncanonical Amino Acid Tagged Proteins. AB - Tetrazine-bearing fluorescent labels enable site-specific tagging of proteins that are genetically manipulated with dienophile modified noncanonical amino acids. The inverse electron demand Diels-Alder reaction between the tetrazine and the dienophile fulfills the criteria of bioorthogonality allowing fluorescent labeling schemes of live cells. Here, we describe the detailed synthetic and labeling protocols of a near infrared emitting siliconrhodamine-tetrazine probe suitable for super-resolution imaging of residue-specifically engineered proteins in mammalian cells. PMID- 29405010 TI - Site-Specific Protein Labeling Utilizing Lipoic Acid Ligase (LplA) and Bioorthogonal Inverse Electron Demand Diels-Alder Reaction. AB - Here, we describe a two-step protocol for selective protein labeling based on enzyme-mediated peptide labeling utilizing lipoic acid ligase (LplA) and bioorthogonal chemistry. The method can be applied to purified proteins, protein in cell lysates, as well as living cells. In a first step a W37V mutant of the lipoic acid ligase (LplAW37V) from Escherichia coli is utilized to ligate a synthetic chemical handle site-specifically to a lysine residue in a 13 amino acid peptide motif-a short sequence that can be genetically expressed as a fusion with any protein of interest. In a second step, a molecular probe can be attached to the chemical handle in a bioorthogonal Diels-Alder reaction with inverse electron demand (DAinv). This method is a complementary approach to protein labeling using genetic code expansion and circumvents larger protein tags while maintaining label specificity, providing experimental flexibility and straightforwardness. PMID- 29405011 TI - Genetic Encoding of Unnatural Amino Acids in C. elegans. AB - Site-specific incorporation of unnatural amino acids (UAAs) has greatly expanded the toolkit available to study biological phenomena in single cells. However, to address questions involving complex cellular interactions such as development, ageing, and the functions of the nervous system it is often necessary to use multicellular model organisms. The nematode Caenorhabditis elegans was the first organism to have its genetic code expanded. Due to its small size, ease of cultivation, and excellent UAA incorporation efficiency, C. elegans makes an ideal model organism to apply UAAs as tools to investigate the functioning of multicellular systems.Here, we describe methods to generate transgenic C. elegans capable of UAA incorporation, as well as how to deliver unnatural amino acids and test incorporation. Furthermore, we describe methods to uncage photosensitive unnatural amino acid derivatives. PMID- 29405012 TI - Whether sports participation is healthy or detrimental for the individual is a matter of dosage. PMID- 29405013 TI - Region-Specific Methylation Profiling in Acute Myeloid Leukemia. AB - Alteration of DNA methylation level in cancer diseases leads to deregulation of gene expression-silencing of tumor suppressor genes and enhancing of protooncogenes. There are several tools devoted to the problem of identification of CpG sites' demethylation but majority of them focuses on single site level and does not allow for quantification of region methylation changes. The aim was to create an adaptive algorithm supporting detection of differentially methylated CpG sites and genomic regions specific for acute myeloid leukemia. Knowledge on AML methylation fingerprint helps in better understanding the epigenetics of leukemogenesis. Proposed algorithm is data driven and does not use predefined quantification thresholds. Gaussian mixture modeling supports classification of CpG sites to several levels of demethylation. p value integration allows for translation from single site demethylation to the demethylation of gene promoter and body regions. Methylation profiles of healthy controls and AML patients were examined (GEO:GSE63409). The differences in whole genome methylation profiles were observed. The methylation profile differs significantly among genomic regions. The lowest methylation level was observed for promoter regions, while sites from intergenic regions were by average higher methylated. The observed number of AML related down methylated sites has not substantially exceeded the expected number by chance. Intergenic regions were characterized by the highest percentage of AML up methylated sites. Methylation enhancement/diminution is the most frequent for intergenic region while methylation compensation (positive or negative) is specific for promoter regions. Functional analysis performed for AML down methylated or extreme high up methylated genes showed strong connection to the leukemic processes. PMID- 29405014 TI - [Sharing Perspectives on Home Healthcare]. AB - The baby boom after World War II, coupled with the rapid advances in medical technology and public health, has led to the current rapid aging in the world's population. Countries in Asia are experiencing a faster rate of aging than most other countries around the world. Taiwan is expected to advance from an aged society to a super-aged society in the next 7~10 years. Consequently, the demand for long-term care is increasing. The focus of healthcare has changed from acute to chronic, from disease-oriented to function-oriented and from cure to care. Families, once the cornerstone of care, have become overwhelmed by the effects of the declining birthrate and aging. Encountering the public demand for a balance between healthcare and quality of life has led to the increasing role of home based care in the medical system. The elderly-care profession is diverse and growing. The trend of transdisciplinary team which integrating care professions, nursing professions, family medicine, geriatric medicine, rehabilitation medicine, telemedicine, and medical aids with the resource of social welfare enables home health care services to better provide well-rounded medical care. Before end of life, hospice home care services increase the likelihood of dying at home in accordance with the patient's preference, easing the symptoms of terminal illness and reducing the sorrow experienced by family members. The single insurer model used by the National Health Insurance system will inevitably replace some hospital and institutional services with home health care services that more effectively and flexibly use medical resources and attenuate the increase in medical costs. PMID- 29405015 TI - [Role of Visiting Nursing Care in Japanese Home Healthcare]. AB - Taiwan's rapidly aging society is expected to make it a super-aged society in 2026. By 2060, people aged 65 or older will account for 40% of the population, a ratio that will approximate that in Japan. In Japan, the elderly population was 27.3% in 2016. By 2025, when the baby-boomers become 75 years old in Japan, issues of long-term care and end-of-life care will be more important and challenging. Since 1976, more Japanese have died in hospital settings than in home settings. Although the percentage of people dying at home increased slightly to 12.7% in 2016, after the recent introduction and promotion of home healthcare, Japan will face a significant challenge to deal with the healthcare 'tsunami' of high natural death rates, which is expected to impose a heavy death burdened on society by 2040, when the death rate is expected to reach 1,670,000/year. Therefore, the Japanese authorities have begun to promote the Community-based Integrated Care System, in which home healthcare and visiting nursing play crucial roles. This article summarizes the historical trend and current situation of visiting nursing in Japan. Japan uses a hybrid payment system for visiting nursing that is financially supported both through private medical insurance policies and Kaigo insurance (Japanese long-term care insurance). The total of 8613 visiting nursing stations that were active in community settings in 2016 cooperated with 14,000 support clinics for home healthcare and cared for 570,000 patients in home settings. We believe that visiting nursing will play an important role in home healthcare in Taiwan in the future. PMID- 29405016 TI - [An Occupational Therapy Intervention for People With Dementia]. AB - The percentage of individuals with dementia worldwide is increasing with the continued trend toward global trend overall. As options for the medical treatment of dementia remain limited, combined, non-pharmacological interventions are necessary to maintain and slow the degeneration of functional capabilities. Additionally, there is a need to help caregivers develop better patterns of care and methods to reduce the burden of care. Therefore, occupational therapists play an important role in the dementia care team. This article introduces how occupational therapists help dementia patient maintain their functional capabilities and delay degeneration and help caregivers reduce their burden of care. Both activities are based on the concept of occupational therapy, which includes three important components: people, activities, and the environment. PMID- 29405017 TI - [The Promotion of Resources Integration in Long-Term Care Service: The Experience of Taipei City Hospital]. AB - The home-based medical care integrated plan under Taiwan National Health Insurance has changed from paying for home-based medical care, home-based nursing, home-based respiratory treatment, and palliative care to paying for a single, continuous home-based care service package. Formerly, physician-visit regulations limited home visits for home-based nursing to providing medical related assessments only. This limitation not only did not provide practical assistance to the public but also caused additional problems for those with mobility problems or who faced difficulties in making visits hospital. This 2016 change in regulations opens the door for doctors to step out their 'ivory tower', while offering the public more options to seek medical assistance in the hope that patients may change their health-seeking behavior. The home-based concept that underlies the medical service system is rooted deeply in the community in order to set up a sound, integrated model of community medical care. It is a critical issue to proceed with timely job handover confirmation with the connecting team and to provide patients with continuous-care services prior to discharge through the discharge-planning service and the connection with the connecting team. This is currently believed to be the only continuous home-based medical care integrated service model in the world. This model not only connects services such as health literacy, rehabilitation, home-based medical care, home based nursing, community palliative care, and death but also integrates community resources, builds community resources networks, and provides high quality community care services. PMID- 29405018 TI - [Preoperative Disability and Its Influencing Factors in Patients With Lumbar Spondylolisthesis]. AB - BACKGROUND: Patients with lumbar spondylolisthesis typically suffer from symptom discomfort and various degrees of disability for months or years prior to receiving surgical treatments. Knowing the factors that influence the disability status of these patients will help healthcare providers develop effective preventive measures. PURPOSE: To explore preoperative disability and its important predictive factors in patients with lumbar spondylolisthesis. METHODS: A predictive correlational design was used and a convenience sample of eighty-six lumbar spondylolisthesis preoperative patients were recruited from a medical center in northern Taiwan. Data were collected using a study questionnaire, which included the Oswestry disability index, the revised geriatric depression scale short form, and a pain numeric rating scale. RESULTS: The average disability index of the participants was 48.52 (SD = 16.14). The multiple linear regression analyses identified lower back pain, depression, age, and gender as significant predictors of preoperative disability, collectively explaining 40.9% of the variation in disability severity. Being female, being older, having a higher degree of lower back pain, and having depression were significantly associated with preoperative disability. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results of the present study indicate that lumbar spondylolisthesis patients who are older in age, female, currently experiencing lower back pain, and suffering from depression face a higher risk of preoperative disability. Patients in these at-risk categories should be assessed actively and provided with appropriate patient education in order to enhance their quality of life. PMID- 29405019 TI - [The Influence of Breastfeeding Self-Efficacy and Breastfeeding Intention on Breastfeeding Behavior in Postpartum Women]. AB - BACKGROUND: World Health Organization (WHO) guidelines recommend that infants should be breastfed for six month after childbirth. The average duration of breastfeeding in Taiwan still falls short of this sixth-month timeline. In order to improve the duration of breastfeeding, it is crucial to understand the factors that affect related behavior. PURPOSE: To explore the effects of breastfeeding self-efficacy and breastfeeding intention among exclusive-breastfeeding women during the initial six months after childbirth and to verify the reliability and validity of the infant feeding intentions scale (Chinese version). METHODS: Purposive sampling was used to select and enroll a total of 167 breastfeeding women from a southern metropolitan medical-teaching hospital. Data were collected using a structured questionnaire and phone interviews. Data were analyzed using SPSS 18.0, LISREL8.7, and S-Plus package software to obtain scores for the independent-sample t test, Pearson's product-moment correlation coefficient, one way analysis of variance, survival analysis, and reliability and validity. RESULTS: Breastfeeding self-efficacy scores ranged from 14 to 70, with a mean score of 44.80 (+/-11.56). Infant feeding intention scores ranged from 14 to 70, with a mean score of 12.20 (+/-3.14). Additionally, 29.9% of the participants breastfed exclusively for the entire six months after childbirth. Breastfeeding self-efficacy and breastfeeding intention were positively correlated (r = .45, p < .001). Education level, occupation, and breastfeeding intention were each identified as factors that significantly influenced the success of exclusive breastfeeding during the initial six months after childbirth. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Breastfeeding self-efficacy and breastfeeding intention are correlated with breastfeeding behavior. Based on findings, medical staff should target promotion and education regarding the importance of breastfeeding particularly toward women who have lower levels of education, who are employed, and who express low initial intention to breastfeed. PMID- 29405020 TI - [Exploration of the Association Between Workplace Bullying and Attitudes Toward Patient Safety in Female Nurses]. AB - BACKGROUND: Workplace bullying is known to have a significant and detrimental effect on the physical and psychological outcomes of its victims. The reactions of victims to bullying may decrease clinical care outcomes and patient safety. PURPOSE: To explore the relationship between workplace bullying and the attitudes of female nurses toward the safety of their patients. METHODS: This cross sectional survey study used convenience sampling. Participants included female nurses from a regional teaching hospital. The research tool was a three-part, structured questionnaire that included a basic personal information datasheet, negative behavior scale, and patient safety attitude scale. The researcher distributed 420 questionnaires and collected 329 valid samples (valid return rate: 78.3%). Data were analyzed using SPSS software version 22.0. RESULTS: The analysis found that 29.8% of the participants had suffered from various degrees of workplace bullying. The mean score for patient safety attitudes was 3.58 (standard deviation = 0.55). Workplace bullying and patient safety attitudes were negatively correlated (p < .1), and being a recipient of workplace bullying was identified as a significant predictor of attitudes toward patient safety. CONCLUSIONS: Based on the results, we suggest that supervisors should take the initiative to care for their nursing staffs and to provide them with training in conflict-oriented skills. Organization managers should set up relevant committee notification mechanisms that construct the safe working environment necessary to reduce workplace bullying and to enhance the patient safety attitudes of nurses, which will indirectly improve the quality of patient care. PMID- 29405021 TI - [Effect of Oral Glutamine on Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: An Evidence-Based Appraisal]. AB - BACKGROUND: Chemotherapy may induce peripheral neuropathy, which often results in the chemotherapy dose being reduced or the chemotherapy regimen being stopped. At present, there are no treatment guidelines for chemotherapy-induced peripheral neuropathy. Glutamine is one of the treatment strategies currently applied in practice. This strategy is expensive and lacks clear evidence as to its efficacy. PURPOSE: To evaluate the effect of oral glutamine on CIPN in cancer patients. METHODS: PICO (population- intervention- comparison- outcome) was used to focus the problem: P: cancer patient; I: glutamine, L-glutamine; C: usual care; O: alleviate, reduce, improve, and prevent. Databases searched included Airiti Library, Cochrane Library, CINAHL, and PubMed. Three randomized clinical trials and two quasi-experimental designs were evaluated using evidence-based appraisal. RESULTS: Four studies used 30 g/day of glutamine either at the beginning of chemotherapy or at 24 hours after the beginning of chemotherapy. The shortest duration for taking glutamine was four days and longest duration was two months. The incidences of CIPN-induced pain were significantly different (risk ratio = 0.26; 95% CI [0.09, 0.70], Z = 2.65, p = .008) between the intervention and control groups. The incidences of CIPN grading, numbness, and muscle weakness were not significantly different between the intervention and control groups. From an economic point of view, the clinical efficacy of taking glutamine does not justify the additional daily cost to the patient of NT 500 (about US 17). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Because of the small sample size, minimal effects of glutamine, and no significant decrease in risk, we do not suggest routinely using oral glutamine to prevent or reduce CIPN symptoms in cancer patients. PMID- 29405022 TI - [The Pain-Relief Efficacy of Passive Music-Based Interventions in Cancer Patients Undergoing Diagnostic Biopsies and Surgery: A Systematic Review and Meta Analysis]. AB - BACKGROUND: Music-based intervention is commonly used as a non-pharmacological strategy to reduce pain in hospitalized patients. PURPOSE: To conduct a systematic review and meta-analysis to examine the effects of passive music-based interventions on pain relief in cancer patients undergoing diagnostic biopsies and surgeries and to identify the moderating variables in order to identify clinically validated interventional strategies and related suggestions. METHODS: Studies using an RCT (randomized clinical trial) design that were published before 2016 were collected from the following databases: Cochrane Library/Trials, PubMed, PsycINFO, CINHAL, and Index to Taiwan Periodical Literature System. The high-quality studies, defined as those earning a modified Jadad scale score >3, were then analyzed using comprehensive meta-analysis software. RESULTS: The passive music-based interventions had a small-to-moderate overall effect (g = .42, p = .02) on pain relief in the subjects undergoing diagnostic biopsies and surgery in the analyzed studies (n = 12). Subgroup analysis identified the moderating variables affecting pain reduction as the type of anesthesia administered and the settings, frequency, and music therapist that were used in the intervention. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Passive music-based interventions have a significant pain reduction effect and may be used as an effective, non-pharmacologic intervention for cancer patients undergoing diagnostic biopsies and surgery. Delivering 2-3 intervention sessions daily, using a certificated music therapist to deliver/guide the sessions, holding the sessions in waiting-room or ward settings, and administering a general anesthesia were identified as the crucial factors impacting the effectiveness of music intervention on pain relief. PMID- 29405023 TI - [A Survey of the Factors of Influence and Interventional Strategies for Breast Cancer Survivors' Transition Care Across Multiple Theoretical Perspectives]. AB - Breast cancer significantly threatens the life of women, while the adverse effects of cancer treatment degrade quality of life and psychological well-being. The quality of transitional care following the completion of treatment significantly affects the ability of breast cancer patients to transition successfully into survivorship. This paper introduces multiple theoretical perspectives and provides an overview of the tenets of each in order to identify the positions of breast cancer survivors and to highlight the factors and strategies that influence their transitional care. The theoretical perspectives that are introduced include the social-ecological model, transition theory, and the strengths perspective. In order to improve the holistic care of women with breast cancer, factors relevant to transition are categorized into the individual, interpersonal, organizational, community, and policy levels. Furthermore, empirical interventions, which are based on the respective advantages of the various levels of the social-ecological model, are proposed in order to conform to the sociocultural context and clinical practices. Healthcare providers should leverage the strengths and resources at each level to develop feasible strategies and to provide quality of care in order to assist breast cancer patients to transition successfully from treatment to survivorship and to holistically improve their subsequent quality of life and function. PMID- 29405024 TI - [Travel Preparations for Patients Receiving Peritoneal Dialysis]. AB - People who receive peritoneal dialysis (PD) have more freedom than those who are on hemodialysis. However, some PD patients have difficulty adapting to their new environment and thus remain largely homebound. When they work or travel abord, who cannot rely wholly on others, these patients must handle certain life problems alone. It is essential for nursing staff to help PD patients to prepare for overcoming typical inconveniences, improving quality of life, and handling unfamiliar environments. The present study assists patients to arrange domestic and foreign tourism and to participate in various activities. The intervention teaches the pre-assessment of tourism, the assessment and selection of the sterile environment for exchange, the arrangements for dialysate, planning for handling complications, the travel matters attention, and other tourist information using group or individual instruction. It is expected that patients with peritoneal dialysis will be more willing to leave their houses and be better prepared to travel, which should lead to their having more fun and to their greater enjoyment of life. PMID- 29405025 TI - [Applying Game-Based Learning in Nursing Education: Empathy Board Game Learning]. AB - Attending lectures and reading are two common approaches to acquiring knowledge, while repetitive practice is a common approach to acquiring skills. Nurturing proper attitudes in students is one of the greatest challenges for educators. Health professionals must incorporate empathy into their practice. Creative teaching strategies may offer a feasible approach to enhancing empathy-related competence. The present article focuses on analyzing current, empathy-related curriculums in nursing education in Taiwan, exploring the concepts of empathy and game-based learning, presenting the development of an empathy board game as a teaching aid, and, finally, evaluating the developed education application. Based on the learner-centered principle, this aid was designed with peer learning, allowing learners to influence the learning process, to simulate the various roles of clients, and to develop diverse interpersonal dialogues. The continuous learning loops were formed using the gamification mechanism and transformation, enabling students to connect and practice the three elements of empathy ability: emotion, cognition and expression. Via the game elements of competition, interaction, storytelling, real-time responses, concretizing feedback, integrated peer learning, and equality between teachers and students, students who play patient roles are able to perceive different levels of comfort, which encourages the development of insight into the meaning of empathy. Thereby, the goals of the empathy lesson is achievable within a creative game-based learning environment. PMID- 29405026 TI - [Care Plan for Resuming the Physical Activity of Patients With Pancreatic Cancer and Diabetes After Surgery]. AB - Many barriers influence the ability of postoperative cancer patients to reengage in normal physical activities. Training programs have been shown to be effective in helping restore physical activity in patients and in reducing the care burdens of family members. Nurses cannot use physical activity guidelines in their care plan to assess individual needs. The clinical practice guidelines for physical activity in survivorship were published by the National Comprehensive Cancer Network (NCCN) in 2016. These guidelines are used to assess patients' physical status, curable factors, physical barriers, and risk of postoperative pancreatic cancer and diabetes. In line with this assessment tool, the physical activity guidelines, and the recommendations for cancer patients, the authors planned a physical activity training program that addressed the actual needs of patients under their care. Further, the authors provided special notes for a diabetic diet that helped reduce the barriers to resuming physical activity and enhanced independent care efficacy. Meanwhile, the authors encouraged family members to participate in patient-care activities and family mental-health support and to promote patient participation in the training program in order to increase quality of life. The present project demonstrates that this care plan may provide an effective guide for nurses to help other cancer patients resume physical activity. PMID- 29405027 TI - The emerging picture of ALS: a multisystem, not only a "motor neuron disease. AB - Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons: compelling evidence points now towards additional involvement of extramotor functions. Beside the cognitive-behavioural disturbances, many ALS patients express extrapyramidal deficits: neuropathological findings fully support the multisystem brain degeneration. The therapeutical option to treat the multisystemic character of ALS represents an additional difficult task in absence of sensitive biomarkers or better understanding of the pathophysiological mechanisms of the disease. Future clinical trials need to identify subgroups of patients, representing the post-hoc analysis after a trial the extreme effort to define sensitive ALS patients to new treatments, as the edaravone story seems to demonstrate. PMID- 29405028 TI - Next Generation Sequencing and ALS: known genes, different phenotyphes. AB - Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease clinically characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. Most cases appear to be sporadic, but 5-10 % of cases have a family history of the disease, and over the last decade, identification of mutations in about 20 genes predisposing to these disorders has provided the means to better understand their pathogenesis. Next Generation sequencing (NGS) is an advanced high-throughput DNA sequencing technology which have rapidly contributed to an acceleration in the discovery of genetic risk factors for both familial and sporadic neurological and neurodegenerative diseases. These strategies allowed to rapidly identify disease associated variants and genetic risk factors for both familial (fALS) and sporadic ALS (sALS), strongly contributing to the knowledge of the genetic architecture of ALS. Moreover, as the number of ALS genes grows, many of the proteins they encode are in intracellular processes shared with other known diseases, suggesting an overlapping of clinical and phatological features between different diseases. To emphasize this concept, the review focuses on genes coding for Valosin-containing protein (VPC) and two Heterogeneous nuclear RNA-binding proteins (HNRNPA1 and hnRNPA2B1), recently idefied through NGS, where different mutations have been associated in both ALS and other neurological and neurodegenerative diseases. PMID- 29405029 TI - Are there endogenous stem cells in the spinal cord? AB - Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche. PMID- 29405030 TI - Cross-talk between pathogenic mechanisms in neurodegeneration: the role of oxidative stress in Amyotrophic Lateral Sclerosis. AB - The mechanisms underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that affects the motor system with progressive paralysis, are complex and not yet fully understood. It is generally agreed that ALS is a multifactorial and multisystem disease due not only possibly to genetic causes but also to other factors like oxidative stress, mitochondrial dysfunction, protein aggregation, RNA dysmetabolism, autophagy, and excitotoxicity glutamate-mediate. Altered oxidative stress biomarker profile has been repeatedly reported in ALS patients, which may suggest that abnormal free radical production is relevant in the ALS pathogenesis. This review aims to investigate how oxidative stress can affect other proposed mechanisms of neurodegeneration in ALS. PMID- 29405031 TI - Imaging techniques in ALS. AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of both upper and lower motor neuron located in the spinal cord and brainstem. Diagnosis of ALS is predominantly clinical, nevertheless, electromyography and Magnetic Resonance Imaging (MRI) may provide support. Several advanced MRI techniques have been proven useful for ALS diagnosis and, indeed, the combination of different MRI techniques demonstrated an improvement in sensitivity and specificity as far as 90%. This review focus on the imaging techniques currently used in the diagnosis and management of ALS with brief considerations on future applications. PMID- 29405032 TI - The multisystem degeneration amyotrophic lateral sclerosis - neuropathological staging and clinical translation. AB - Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP 43 pathology in sporadic ALS (sALS) has been recently proposed. According to it, 4 stages can be recognized, where pTDP-43 inclusions are found in the agranular motor cortex and alpha-motor neurons of the brain stem and spinal cord (stage 1), in prefrontal neocortex (middle frontal gyrus), reticular formation, and precerebellar nuclei (stage 2), in further areas of the prefrontal neocortex (gyrus rectus and orbitofrontal gyri), postcentrally located sensory cortex, and basal ganglia (stage 3), and in the anteromedial temporal lobe including the hippocampus (stage 4). Based on this staging effort, a corticofugal axonal model for spreading of pathology can be hypothesized, whereby pathology starts in the primary motor cortex and spreads from there via axonal projections to lower motor neurons and to subcortical structures. Recent neuroradiological evidence seems to support the proposed staging system. From the clinical standpoint, a proportion of ALS patients display extramotor deficits (namely cognitive-behavioural disturbances, impaired ocular movements, and extrapyramidal alterations), which seem to correspond to the pathological involvement of the relevant cerebral structures. This review describes neuropathological sALS staging and addresses clinical evidence corresponding to this staging, pointing towards the concept of ALS as a multisystem brain degeneration disorder instead of a disease confined to motor neurons. PMID- 29405033 TI - Therapy in Amyotrophic Lateral Sclerosis (ALS): an unexpected evolving scenario. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease resulting in increasing disability, being uniformly fatal. Since its approval in the 1990s, riluzole remained for long time the unique treatment, offering modest survival benefit. Most recently a second drug has been approved by the US Food and Drug Administration for treatment of ALS: edaravone. Significant advances have been made in the symptomatic management of the disease but more effective drug therapy targeting disease progression is still dreadfully needed, the success appearing almost a miracle. Recent discoveries related to genetics indicate divergent mechanisms of disease encouraging precision medicine leading to molecularly tailored interventions. The search for effective therapy still faces important challenges in the areas of both basic science and animal research, adequate translation of results into human clinical trials, inherent bias in human studies, and issues related to delays in clinical diagnosis. It is interesting to point out that ALS research may speed up drug development not only for this disease, but also for other more prevalent neurodegenerative diseases: the reverse is also conceivable. PMID- 29405034 TI - Revisiting the gamma loop in ALS. AB - Amyotrophic Lateral Sclerosis (ALS) is a fast progressive neurodegenerative disease characterized by muscle denervation, weakening and atrophy, which eventually culminates into death, mainly due to respiratory failure. The traditional view of ALS as a disorder affecting selectively motor neurons throughout the central nervous system has been progressively dispelled by innumerous lines of evidence indicating that other cells but motor neurons may be affected as well. Remarkably, this disorder is not limited to the motor system but rather configures as a systemic disease yielding a plethora of clinical signs. Among this broad clinical spectrum, sensory neuropathy occurring parallel to motor dysfunction is a quite frequent feature within ALS patients, which has spurred the interest of many investigators during the years. In line with this, morphological studies have confirmed that sensory neurons and axons' degeneration may occur in both ALS- experimental models and -patients. Noteworthy, this may have a nonetheless negligible role in ALS -related motor decline, as highlighted by recent studies showing that, degeneration of type I/II proprioceptive fibers is a primary source of alpha-motor neurons' death. These latter in fact, differently from gamma motor neurons, are a direct monosynaptic target of proprioceptive fibers. The present findings contribute to define a novel scenario of sensorimotor ALS pathophysiology where the gamma loop's fine connectivity may play a key role. In support to this view, in the present manuscript we provide a reappraisal on the role of single gamma loop's components in ALS. PMID- 29405035 TI - Protective effects of long-term lithium administration in a slowly progressive SMA mouse model. AB - In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long term treatment of spinal muscle atrophy. PMID- 29405036 TI - Structural modeling of altered CLCN1 conformation following a novel mutation in a patient affected by autosomal dominant myotonia congenita (Thomsen disease). PMID- 29405037 TI - Osmotic therapies added to antibiotics for acute bacterial meningitis. AB - BACKGROUND: Every day children and adults die from acute community-acquired bacterial meningitis, particularly in low-income countries, and survivors risk deafness, epilepsy and neurological disabilities. Osmotic therapies may attract extra-vascular fluid and reduce cerebral oedema, and thus reduce death and improve neurological outcomes.This is an update of a Cochrane Review first published in 2013. OBJECTIVES: To evaluate the effects of osmotic therapies added to antibiotics for acute bacterial meningitis in children and adults on mortality, deafness and neurological disability. SEARCH METHODS: We searched CENTRAL (2017, Issue 1), MEDLINE (1950 to 17 February 2017), Embase (1974 to 17 February 2017), CINAHL (1981 to 17 February 2017), LILACS (1982 to 17 February 2017) and registers of ongoing clinical trials (ClinicalTrials.com, WHO ICTRP) (21 February 2017). We also searched conference abstracts and contacted researchers in the field (up to 12 December 2015). SELECTION CRITERIA: Randomised controlled trials testing any osmotic therapy in adults or children with acute bacterial meningitis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and selected trials for inclusion. Results are presented using risk ratios (RR) and 95% confidence intervals (CI) and grouped according to whether the participants received steroids or not. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included five trials with 1451 participants. Four trials evaluated glycerol against placebo, and one evaluated glycerol against 50% dextrose; in addition three trials evaluated dexamethasone and one trial evaluated acetaminophen (paracetamol) in a factorial design. Stratified analysis shows no effect modification with steroids; we present aggregate effect estimates.Compared to placebo, glycerol probably has little or no effect on death in people with bacterial meningitis (RR 1.08, 95% CI 0.90 to 1.30; 5 studies, 1272 participants; moderate-certainty evidence), but may reduce neurological disability (RR 0.73, 95% CI 0.53 to 1.00; 5 studies, 1270 participants; low-certainty evidence).Glycerol may have little or no effect on seizures during treatment for meningitis (RR 1.08, 95% CI 0.90 to 1.30; 4 studies, 1090 participants; low certainty evidence).Glycerol may reduce the risk of subsequent deafness (RR 0.64, 95% CI 0.44 to 0.93; 5 studies, 922 participants; low to moderate-certainty evidence).Glycerol probably has little or no effect on gastrointestinal bleeding (RR 0.93, 95% CI 0.39 to 2.19; 3 studies, 607 participants; moderate-certainty evidence). The evidence on nausea, vomiting and diarrhoea is uncertain (RR 1.09, 95% CI 0.81 to 1.47; 2 studies, 851 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Glycerol was the only osmotic therapy evaluated, and data from trials to date have not demonstrated an effect on death. Glycerol may reduce neurological deficiency and deafness. PMID- 29405038 TI - Systemic treatments for metastatic cutaneous melanoma. AB - BACKGROUND: The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000. OBJECTIVES: To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma. SEARCH METHODS: We searched the following databases up to October 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers and the ASCO database in February 2017, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We considered RCTs of systemic therapies for people with unresectable lymph node metastasis and distant metastatic cutaneous melanoma compared to any other treatment. We checked the reference lists of selected articles to identify further references to relevant trials. DATA COLLECTION AND ANALYSIS: Two review authors extracted data, and a third review author independently verified extracted data. We implemented a network meta-analysis approach to make indirect comparisons and rank treatments according to their effectiveness (as measured by the impact on survival) and harm (as measured by occurrence of high-grade toxicity). The same two review authors independently assessed the risk of bias of eligible studies according to Cochrane standards and assessed evidence quality based on the GRADE criteria. MAIN RESULTS: We included 122 RCTs (28,561 participants). Of these, 83 RCTs, encompassing 21 different comparisons, were included in meta-analyses. Included participants were men and women with a mean age of 57.5 years who were recruited from hospital settings. Twenty-nine studies included people whose cancer had spread to their brains. Interventions were categorised into five groups: conventional chemotherapy (including single agent and polychemotherapy), biochemotherapy (combining chemotherapy with cytokines such as interleukin-2 and interferon-alpha), immune checkpoint inhibitors (such as anti-CTLA4 and anti-PD1 monoclonal antibodies), small-molecule targeted drugs used for melanomas with specific gene changes (such as BRAF inhibitors and MEK inhibitors), and other agents (such as anti-angiogenic drugs). Most interventions were compared with chemotherapy. In many cases, trials were sponsored by pharmaceutical companies producing the tested drug: this was especially true for new classes of drugs, such as immune checkpoint inhibitors and small-molecule targeted drugs.When compared to single agent chemotherapy, the combination of multiple chemotherapeutic agents (polychemotherapy) did not translate into significantly better survival (overall survival: HR 0.99, 95% CI 0.85 to 1.16, 6 studies, 594 participants; high-quality evidence; progression free survival: HR 1.07, 95% CI 0.91 to 1.25, 5 studies, 398 participants; high quality evidence. Those who received combined treatment are probably burdened by higher toxicity rates (RR 1.97, 95% CI 1.44 to 2.71, 3 studies, 390 participants; moderate-quality evidence). (We defined toxicity as the occurrence of grade 3 (G3) or higher adverse events according to the World Health Organization scale.)Compared to chemotherapy, biochemotherapy (chemotherapy combined with both interferon-alpha and interleukin-2) improved progression-free survival (HR 0.90, 95% CI 0.83 to 0.99, 6 studies, 964 participants; high-quality evidence), but did not significantly improve overall survival (HR 0.94, 95% CI 0.84 to 1.06, 7 studies, 1317 participants; high-quality evidence). Biochemotherapy had higher toxicity rates (RR 1.35, 95% CI 1.14 to 1.61, 2 studies, 631 participants; high quality evidence).With regard to immune checkpoint inhibitors, anti-CTLA4 monoclonal antibodies plus chemotherapy probably increased the chance of progression-free survival compared to chemotherapy alone (HR 0.76, 95% CI 0.63 to 0.92, 1 study, 502 participants; moderate-quality evidence), but may not significantly improve overall survival (HR 0.81, 95% CI 0.65 to 1.01, 2 studies, 1157 participants; low-quality evidence). Compared to chemotherapy alone, anti CTLA4 monoclonal antibodies is likely to be associated with higher toxicity rates (RR 1.69, 95% CI 1.19 to 2.42, 2 studies, 1142 participants; moderate-quality evidence).Compared to chemotherapy, anti-PD1 monoclonal antibodies (immune checkpoint inhibitors) improved overall survival (HR 0.42, 95% CI 0.37 to 0.48, 1 study, 418 participants; high-quality evidence) and probably improved progression free survival (HR 0.49, 95% CI 0.39 to 0.61, 2 studies, 957 participants; moderate-quality evidence). Anti-PD1 monoclonal antibodies may also result in less toxicity than chemotherapy (RR 0.55, 95% CI 0.31 to 0.97, 3 studies, 1360 participants; low-quality evidence).Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival (HR 0.63, 95% CI 0.60 to 0.66, 1 study, 764 participants; high-quality evidence) and progression-free survival (HR 0.54, 95% CI 0.50 to 0.60, 2 studies, 1465 participants; high-quality evidence). Anti-PD1 monoclonal antibodies may result in better toxicity outcomes than anti-CTLA4 monoclonal antibodies (RR 0.70, 95% CI 0.54 to 0.91, 2 studies, 1465 participants; low-quality evidence).Compared to anti-CTLA4 monoclonal antibodies alone, the combination of anti-CTLA4 plus anti PD1 monoclonal antibodies was associated with better progression-free survival (HR 0.40, 95% CI 0.35 to 0.46, 2 studies, 738 participants; high-quality evidence). There may be no significant difference in toxicity outcomes (RR 1.57, 95% CI 0.85 to 2.92, 2 studies, 764 participants; low-quality evidence) (no data for overall survival were available).The class of small-molecule targeted drugs, BRAF inhibitors (which are active exclusively against BRAF-mutated melanoma), performed better than chemotherapy in terms of overall survival (HR 0.40, 95% CI 0.28 to 0.57, 2 studies, 925 participants; high-quality evidence) and progression free survival (HR 0.27, 95% CI 0.21 to 0.34, 2 studies, 925 participants; high quality evidence), and there may be no significant difference in toxicity (RR 1.27, 95% CI 0.48 to 3.33, 2 studies, 408 participants; low-quality evidence).Compared to chemotherapy, MEK inhibitors (which are active exclusively against BRAF-mutated melanoma) may not significantly improve overall survival (HR 0.85, 95% CI 0.58 to 1.25, 3 studies, 496 participants; low-quality evidence), but they probably lead to better progression-free survival (HR 0.58, 95% CI 0.42 to 0.80, 3 studies, 496 participants; moderate-quality evidence). However, MEK inhibitors probably have higher toxicity rates (RR 1.61, 95% CI 1.08 to 2.41, 1 study, 91 participants; moderate-quality evidence).Compared to BRAF inhibitors, the combination of BRAF plus MEK inhibitors was associated with better overall survival (HR 0.70, 95% CI 0.59 to 0.82, 4 studies, 1784 participants; high quality evidence). BRAF plus MEK inhibitors was also probably better in terms of progression-free survival (HR 0.56, 95% CI 0.44 to 0.71, 4 studies, 1784 participants; moderate-quality evidence), and there appears likely to be no significant difference in toxicity (RR 1.01, 95% CI 0.85 to 1.20, 4 studies, 1774 participants; moderate-quality evidence).Compared to chemotherapy, the combination of chemotherapy plus anti-angiogenic drugs was probably associated with better overall survival (HR 0.60, 95% CI 0.45 to 0.81; moderate-quality evidence) and progression-free survival (HR 0.69, 95% CI 0.52 to 0.92; moderate quality evidence). There may be no difference in terms of toxicity (RR 0.68, 95% CI 0.09 to 5.32; low-quality evidence). All results for this comparison were based on 324 participants from 2 studies.Network meta-analysis focused on chemotherapy as the common comparator and currently approved treatments for which high- to moderate-quality evidence of efficacy (as represented by treatment effect on progression-free survival) was available (based on the above results) for: biochemotherapy (with both interferon-alpha and interleukin-2); anti-CTLA4 monoclonal antibodies; anti-PD1 monoclonal antibodies; anti-CTLA4 plus anti-PD1 monoclonal antibodies; BRAF inhibitors; MEK inhibitors, and BRAF plus MEK inhibitors. Analysis (which included 19 RCTs and 7632 participants) generated 21 indirect comparisons.The best evidence (moderate-quality evidence) for progression-free survival was found for the following indirect comparisons:* both combinations of immune checkpoint inhibitors (HR 0.30, 95% CI 0.17 to 0.51) and small-molecule targeted drugs (HR 0.17, 95% CI 0.11 to 0.26) probably improved progression-free survival compared to chemotherapy;* both BRAF inhibitors (HR 0.40, 95% CI 0.23 to 0.68) and combinations of small-molecule targeted drugs (HR 0.22, 95% CI 0.12 to 0.39) were probably associated with better progression-free survival compared to anti-CTLA4 monoclonal antibodies;* biochemotherapy (HR 2.81, 95% CI 1.76 to 4.51) probably lead to worse progression-free survival compared to BRAF inhibitors;* the combination of small-molecule targeted drugs probably improved progression-free survival (HR 0.38, 95% CI 0.21 to 0.68) compared to anti-PD1 monoclonal antibodies;* both biochemotherapy (HR 5.05, 95% CI 3.01 to 8.45) and MEK inhibitors (HR 3.16, 95% CI 1.77 to 5.65) were probably associated with worse progression-free survival compared to the combination of small molecule targeted drugs; and* biochemotherapy was probably associated with worse progression-free survival (HR 2.81, 95% CI 1.54 to 5.11) compared to the combination of immune checkpoint inhibitors.The best evidence (moderate-quality evidence) for toxicity was found for the following indirect comparisons:* combination of immune checkpoint inhibitors (RR 3.49, 95% CI 2.12 to 5.77) probably increased toxicity compared to chemotherapy;* combination of immune checkpoint inhibitors probably increased toxicity (RR 2.50, 95% CI 1.20 to 5.20) compared to BRAF inhibitors;* the combination of immune checkpoint inhibitors probably increased toxicity (RR 3.83, 95% CI 2.59 to 5.68) compared to anti-PD1 monoclonal antibodies; and* biochemotherapy was probably associated with lower toxicity (RR 0.41, 95% CI 0.24 to 0.71) compared to the combination of immune checkpoint inhibitors.Network meta-analysis-based ranking suggested that the combination of BRAF plus MEK inhibitors is the most effective strategy in terms of progression-free survival, whereas anti-PD1 monoclonal antibodies are associated with the lowest toxicity.Overall, the risk of bias of the included trials can be considered as limited. When considering the 122 trials included in this review and the seven types of bias we assessed, we performed 854 evaluations only seven of which (< 1%) assigned high risk to six trials. AUTHORS' CONCLUSIONS: We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.Evidence quality was reduced due to imprecision, between study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers. PMID- 29405040 TI - Phytochemical composition, biological potential and enzyme inhibition activity of Scandix pecten-veneris L. AB - OBJECTIVE: Scandix pecten-veneris L. is a less studied wild edible herb and is considered an extinct plant species in many parts of the world. This study was designed to evaluate its phytochemical composition and biological potential of S. pecten-veneris L. METHODS: Phytochemicals including alkaloids, flavonoids, polyphenols, and tannins were determined in extracts of S. pecten-veneris. Antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), while reducing power was tested by ferric reducing/antioxidant power (FRAP) assay. Antimicrobial activity against seven bacterial and four fungal strains was evaluated using agar well diffusion assay. Enzymes inhibition study was performed for urease, phosphodiesterase-I, and catalase-II. RESULTS: S. pecten-veneris showed moderate antiradical activity and reducing potential of hydroxyl radicals to about 20% of the initial value. The antioxidant activity of various extracts of S. pecten-veneris showed a linear correlation with total phenolic contents in the order of water>n-butanol>chloroform>ethyl acetate>methanol extracts. S. pecten-veneris leaves showed the highest inhibitory activity against Staphylococcus aureus while the highest antifungal activity was observed against Candida albicans. The plant extract was most potent against urease enzymes but showed moderate activity against phosphodiestrase-I and carbonic anhydrase-II. CONCLUSIONS: Our data demonstrate that in addition to its culinary uses, S. pecten-veneris has good medicinal potential and hence could be used for treating some specific health ailments. PMID- 29405041 TI - Role of jasmonic acid in improving tolerance of rapeseed (Brassica napus L.) to Cd toxicity. AB - The well-known detrimental effects of cadmium (Cd) on plants are chloroplast destruction, photosynthetic pigment inhibition, imbalance of essential plant nutrients, and membrane damage. Jasmonic acid (JA) is an alleviator against different stresses such as salinity and drought. However, the functional attributes of JA in plants such as the interactive effects of JA application and Cd on rapeseed in response to heavy metal stress remain unclear. JA at 50 umol/L was observed in literature to have senescence effects in plants. In the present study, 25 umol/L JA is observed to be a "stress ameliorating molecule" by improving the tolerance of rapeseed plants to Cd toxicity. JA reduces the Cd uptake in the leaves, thereby reducing membrane damage and malondialdehyde content and increasing the essential nutrient uptake. Furthermore, JA shields the chloroplast against the damaging effects of Cd, thereby increasing gas exchange and photosynthetic pigments. Moreover, JA modulates the antioxidant enzyme activity to strengthen the internal defense system. Our results demonstrate the function of JA in alleviating Cd toxicity and its underlying mechanism. Moreover, JA attenuates the damage of Cd to plants. This study enriches our knowledge regarding the use of and protection provided by JA in Cd stress. PMID- 29405039 TI - A review of the use of pteridophytes for treating human ailments. AB - The aim of this review was to explore the pharmacological activity of early tracheophytes (pteridophytes) as an alternative medicine for treating human ailments. As the first vascular plants, pteridophytes (aka, ferns and fern allies) are an ancient lineage, and human beings have been exploring and using taxa from this lineage for over 2000 years because of their beneficial properties. We have documented the medicinal uses of pteridophytes belonging to thirty different families. The lycophyte Selaginella sp. was shown in earlier studies to have multiple pharmacological activity, such as antioxidant, anti inflammatory, anti-cancer, antidiabetic, antiviral, antimicrobial, and anti Alzheimer properties. Among all the pteridophytes examined, taxa from the Pteridaceae, Polypodiaceae, and Adiantaceae exhibited significant medicinal activity. Based on our review, many pteridophytes have properties that could be used in alternative medicine for treatment of various human illnesses. Biotechnological tools can be used to preserve and even improve their bioactive molecules for the preparation of medicines against illness. Even though several studies have reported medicinal uses of ferns, the possible bioactive compounds of several pteridophytes have not been identified. Furthermore, their optimal dosage level and treatment strategies still need to be determined. Finally, the future direction of pteridophyte research is discussed. PMID- 29405042 TI - Variations in cadmium and nitrate co-accumulation among water spinach genotypes and implications for screening safe genotypes for human consumption. AB - Vegetables are important constituents of the human diet. Heavy metals and nitrate are among the major contaminants of vegetables. Consumption of vegetables and fruits with accumulated heavy metals and nitrate has the potential to damage different body organs leading to unwanted effects. Breeding vegetables with low heavy metal and nitrate contaminants is a cost-effective approach. We investigated 38 water spinach genotypes for low Cd and nitrate co-accumulation. Four genotypes, i.e. JXDY, GZQL, XGDB, and B888, were found to have low co accumulation of Cd (<0.71 mg/kg dry weight) and nitrate (<3100 mg/kg fresh weight) in the edible parts when grown in soils with moderate contamination of both Cd (1.10 mg/kg) and nitrate (235.2 mg/kg). These genotypes should be appropriate with minimized risk to humans who consume them. The Cd levels in the edible parts of water spinach were positively correlated with the concentration of Pb or Zn, but Cd, Pb, or Zn was negatively correlated with P concentration. These results indicate that these three heavy metals may be absorbed into the plant in similar proportions or in combination, minimizing the influx to aerial parts. Increasing P fertilizer application rates appears to prevent heavy metal and nitrate translocation to shoot tissues and the edible parts of water spinach on co-contaminated soils. PMID- 29405043 TI - Toxicity testing of four silver nanoparticle-coated dental castings in 3-D LO2 cell cultures. AB - To address the controversial issue of the toxicity of dental alloys and silver nanoparticles in medical applications, an in vivo-like LO2 3-D model was constructed within polyvinylidene fluoride hollow fiber materials to mimic the microenvironment of liver tissue. The use of microscopy methods and the measurement of liver-specific functions optimized the model for best cell performances and also proved the superiority of the 3-D LO2 model when compared with the traditional monolayer model. Toxicity tests were conducted using the newly constructed model, finding that four dental castings coated with silver nanoparticles were toxic to human hepatocytes after cell viability assays. In general, the toxicity of both the castings and the coated silver nanoparticles aggravated as time increased, yet the nanoparticles attenuated the general toxicity by preventing metal ion release, especially at high concentrations. PMID- 29405044 TI - HIV and paraquat poisoning: fighting fire with fire? AB - Though the cases of HIV patients with paraquat (PQ) poisoning are rare, we still found the common features. These recovered HIV patients tended to result in much less lung injury, and had low CD4+ T lymphocyte levels due to HIV infection, which meant they were under the immunosuppressive condition during treatment. This may be conducive to relieve the acute inflammation and lung fibrosis induced by PQ. Thus, we consider the immunosuppressive therapy for PQ poisoning to be appropriate. However, the drugs used currently may be not optimal for toxic patient. As next step, we will add the CD4+ T lymphocyte-targeted immunosuppressive drug to treat PQ poisoning patients. PMID- 29405045 TI - Telemedicine for ROP. AB - With the increasing survival of preterm babies in the Asia-Pacific region, there has been an increase in the incidence of retinopathy of prematurity (ROP). There is also a lack of trained ophthalmologists to screen for this disease. New strategies for screening of ROP are required, wherein the load on the ophthalmologist can be reduced. Telemedicine is an excellent tool to address this need. This paper reviews the initial studies comparing digital imaging with indirect ophthalmoscopy, the current active ROP telescreening programs in the world, and ends with studies dealing with automated diagnosis of ROP. PMID- 29405047 TI - Linear-array photoacoustic imaging using minimum variance-based delay multiply and sum adaptive beamforming algorithm. AB - In photoacoustic imaging, delay-and-sum (DAS) beamformer is a common beamforming algorithm having a simple implementation. However, it results in a poor resolution and high sidelobes. To address these challenges, a new algorithm namely delay-multiply-and-sum (DMAS) was introduced having lower sidelobes compared to DAS. To improve the resolution of DMAS, a beamformer is introduced using minimum variance (MV) adaptive beamforming combined with DMAS, so-called minimum variance-based DMAS (MVB-DMAS). It is shown that expanding the DMAS equation results in multiple terms representing a DAS algebra. It is proposed to use the MV adaptive beamformer instead of the existing DAS. MVB-DMAS is evaluated numerically and experimentally. In particular, at the depth of 45 mm MVB-DMAS results in about 31, 18, and 8 dB sidelobes reduction compared to DAS, MV, and DMAS, respectively. The quantitative results of the simulations show that MVB DMAS leads to improvement in full-width-half-maximum about 96%, 94%, and 45% and signal-to-noise ratio about 89%, 15%, and 35% compared to DAS, DMAS, MV, respectively. In particular, at the depth of 33 mm of the experimental images, MVB-DMAS results in about 20 dB sidelobes reduction in comparison with other beamformers. PMID- 29405046 TI - Anti-VEGF Agents and the Risk of Arteriothrombotic Events. AB - Blockade of vascular endothelial growth factor (VEGF) signaling, whether via sequestration of free VEGF or via inhibition of the tyrosine kinases activated by VEGF, is associated with decreased nitric oxide (NO) and prostaglandin-I 2 (PG-I 2) production along with vascular endothelial cell death. Systemic administration of drugs that block VEGF signaling (eg, for cancer treatment) is associated with systemic complications such as hypertension and thrombosis. Evidence regarding the risk of systemic serious adverse events after intravitreal injection of anti VEGF agents in patients with diabetic macular edema or neovascular age-related macular degeneration is inconsistent, in part because of study design limitations (eg, bias of ascertainment through strict enrollment criteria and/or inadequate power to identify the risk of low frequency events). Studies involving patients at high risk of arteriothrombotic events (eg, patients with diabetic macular edema) who have high exposure to intravitreal anti-VEGF therapy (eg, monthly aflibercept or ranibizumab injection) demonstrate an increased risk of all-cause mortality compared with randomized controls. The pharmacokinetics of anti-VEGF drug clearance from the systemic circulation and the documented sustained reduction in free plasma VEGF levels after intravitreal aflibercept and bevacizumab injection are consistent with these findings. Although the frequency of systemic serious adverse events after intravitreal anti-VEGF therapy is low, some patients may be at higher risk (eg, those with recent stroke or multiple strokes), and physicians may wish to take special measures with these patients to minimize the risk of systemic complications. PMID- 29405048 TI - Elucidating the contribution of Rayleigh scattering to the bluish appearance of veins. AB - The bluish appearance of veins located immediately beneath the skin has long been a topic of interest for biomedical optics researchers. Despite this interest, a thorough identification of the specific optical processes responsible for this phenomenon remains to be achieved. We employ controlled in silico experiments to address this enduring open problem. Our experiments, which are supported by measured data available in the scientific literature, are performed using first principles models of light interaction with human skin and blood. Using this investigation approach, we quantitatively demonstrate that Rayleigh scattering caused by collagen fibrils present in the papillary dermis, a sublayer of the skin, can play a pivotal role in the bluish appearance of veins as suggested by previous works in this area. Moreover, also taking color perception aspects into account, we systematically assess the effects of variations in fibril radius and papillary dermis thickness on the coloration of veins under different illuminants. Notably, this assessment indicates that Rayleigh scattering elicited by reticulin fibrils, another type of fibril found in the papillary dermis, is unlikely to significantly contribute to the bluish appearance of veins. By strengthening the current understanding of light attenuation mechanisms affecting the appearance of skin and blood, our investigation contributes to the development of more effective technologies aimed at the noninvasive measurement of the physiological properties of these tissues. PMID- 29405049 TI - Delivery and reveal of localization of upconversion luminescent microparticles and quantum dots in the skin in vivo by fractional laser microablation, multimodal imaging, and optical clearing. AB - Delivery and spatial localization of upconversion luminescent microparticles [Y2O3:Yb, Er] (mean size ~1.6 MUm) and quantum dots (QDs) (CuInS2/ZnS nanoparticles coated with polyethylene glycol-based amphiphilic polymer, mean size ~20 nm) inside rat skin was studied in vivo using a multimodal optical imaging approach. The particles were embedded into the skin dermis to the depth from 300 to 500 MUm through microchannels performed by fractional laser microablation. Low-frequency ultrasound was applied to enhance penetration of the particles into the skin. Visualization of the particles was revealed using a combination of luminescent spectroscopy, optical coherence tomography, confocal microscopy, and histochemical analysis. Optical clearing was used to enhance the image contrast of the luminescent signal from the particles. It was demonstrated that the penetration depth of particles depends on their size, resulting in a different detection time interval (days) of the luminescent signal from microparticles and QDs inside the rat skin in vivo. We show that luminescent signal from the upconversion microparticles and QDs was detected after the particle delivery into the rat skin in vivo during eighth and fourth days, respectively. We hypothesize that the upconversion microparticles have created a long-time depot localized in the laser-created channels, as the QDs spread over the surrounding tissues. PMID- 29405050 TI - Vector extrapolation methods for accelerating iterative reconstruction methods in limited-data photoacoustic tomography. AB - As limited data photoacoustic tomographic image reconstruction problem is known to be ill-posed, the iterative reconstruction methods were proven to be effective in terms of providing good quality initial pressure distribution. Often, these iterative methods require a large number of iterations to converge to a solution, in turn making the image reconstruction procedure computationally inefficient. In this work, two variants of vector polynomial extrapolation techniques were deployed to accelerate two standard iterative photoacoustic image reconstruction algorithms, including regularized steepest descent and total variation regularization methods. It is shown using numerical and experimental phantom cases that these extrapolation methods that are proposed in this work can provide significant acceleration (as high as 4.7 times) along with added advantage of improving reconstructed image quality. PMID- 29405051 TI - Plasmonic Resonance Energy Transfer Enhanced Photodynamic Therapy with Au@SiO2@Cu2O/Perfluorohexane Nanocomposites. AB - Reactive oxygen species generation efficiency of photosensitizers and hypoxia microenvironment in solid tumor hamper photodynamic therapy (PDT) efficacy. Here, we introduce an efficient inorganic photosensitizer by incorporating plasmonic gold metal nanostructures into Cu2O semiconductors for PDT. By utilizing the plasmon-induced resonance energy transfer (PIRET) process from Au to Cu2O, Au@SiO2@Cu2O (ASC) demonstrates a high singlet oxygen quantum yield of 0.71 under a 670 nm laser irradiation. The ASC is loaded into oxygen self-enriched perfluorohexane (PFH) droplets and coated with liposome (Lip) to form Lip(ASC/PFH) nanocomposites. The achieved Lip(ASC/PFH) shows considerable anticancer efficacy for in vitro cancer cells and in vivo tumor growth. The proposed oxygen self-enriched PIRET-PDT concept has significant implication in PDT design. PMID- 29405052 TI - Efficient Planar-Heterojunction Perovskite Solar Cells Fabricated by High Throughput Sheath-Gas-Assisted Electrospray. AB - When a perovskite precursor solution is electrosprayed using the conventional method where the nebulization of the solution is primarily governed by electrostatics, its high electrical conductivity tends to cause electrospray instabilities and thus makes high-quality perovskite films very difficult to obtain. Here, we report high-throughput fabrication of efficient perovskite solar cells (PSCs) whose CH3NH3PbI3-xClx films are deposited using a sheath-gas assisted electrospray system. Our system, based on strong pneumatic nebulization as well as high-voltage electrostatic charging of droplets, enables very stable high-flow electrospray of small charged droplets, even for the highly conductive perovskite precursor solution. Consequently, with the control of the drying rate of the droplets deposited on substrates by adjusting the substrate temperature during deposition, crystalline, void-free CH3NH3PbI3-xClx films with nearly 100% surface coverage and high thickness uniformity are obtained. Inverted planar heterojunction PSCs employing these films have a maximum power conversion efficiency of 14.2% with a small standard deviation of 0.9%, comparable to that of the spin-coated device. PMID- 29405053 TI - Evidence on Enhanced Exciton Polarizability in Donor/Acceptor Bulk Heterojunction Organic Photovoltaics. AB - Using electroabsorption spectroscopy, we explore the polarizability of Frenkel excitons in both pristine donor and D/A blend films. We observe for the first time that the polarizability of excitonic states in pristine donors can be dramatically increased by adding an n-type acceptor. By investigating the dielectric effect in different organic semiconductor systems, we find that the polarizability of Frenkel excitons has direct correlation with the measured dielectric constant of the bulk heterojunction thin films. Our results disclose the difference in the nature of Frenkel excitons in pristine donor and D/A blend systems, revealing an important role of excitonic states in charge separation process of organic photovoltaic devices. PMID- 29405054 TI - Near-Infrared-Light-Induced Morphology Transition of Poly(ether amine) Nanoparticles for Supersensitive Drug Release. AB - Near-infrared (NIR)-light-controlled drug release has aroused great interest because of its advantages in spatiotemporal control. Herein, a photothermally induced morphology transition of the nanoparticles (NPs) for supersensitive drug release has been demonstrated. Doxorubicin (DOX)- and cyanine (Cy)-coloaded thermosensitive poly(ether amine) NPs (DOX&Cy@PEA81) were developed. Because of the photothermal activity of Cy upon irradiation, increase in temperature at the tumor site results, which would be used not only for photothermal therapy but also to spur the release of DOX from the NPs for tunable chemotherapy. The NIR laser-driven DOX release was validated by a series of intracellular and in vivo experiments on animals. Meanwhile, the chemo-photothermal combinatorial therapy results in optimal cytotoxicity and tumor inhibition. This article provides a promising approach to realizing supersensitive drug release and synergistic chemo photothermal therapy for cancer. PMID- 29405055 TI - Culture-Free Detection of Bacterial Pathogens on Plasmonic Nanopillar Arrays Using Rapid Raman Mapping. AB - We utilized a fast Raman spectral mapping technique for fast detection of bacterial pathogens. Three-dimensional (3D) plasmonic nanopillar arrays were fabricated using the nanolithography-free process consisting of maskless Ar plasma treatment of a polyethylene terephthalate substrate and subsequent metal deposition. Bacterial pathogens were immobilized on the positively charged poly(l lysine)-coated 3D plasmonic substrate through electrostatic interactions. Then, the bacterial surfaces were selectively labeled with antibody-conjugated surface enhanced Raman scattering (SERS) nanotags, and Raman mapping images were collected and statistically analyzed for quantitative analysis of bacteria. Salmonella typhimurium was selected as a model pathogen bacterium to confirm the efficacy of our SERS imaging technique. Minimum number of Raman mapping points with statistical reliability was determined to reduce assay time. It was possible to get a statistically reliable standard calibration curve for 529 pixels (laser spot with 60 MUm interval), which required a total mapping time of 45 min to get a standard calibration curve for five different concentrations of bacteria in the 0 to 106 CFU/mL range. No amplification step was necessary for quantification because low-abundance target bacteria could be measured using the Raman spectral mapping technique. Therefore, this approach allows accurate quantification of bacterial pathogens without any culturing or enrichment process. PMID- 29405056 TI - Ultrathin Alumina Mask-Assisted Nanopore Patterning on Monolayer MoS2 for Highly Catalytic Efficiency in Hydrogen Evolution Reaction. AB - Nanostructured molybdenum disulfide (MoS2) has been considered as one of the most promising catalysts in the hydrogen evolution reaction (HER), for its approximately intermediate hydrogen binding free energy to noble metals and much lower cost. The catalytically active sites of MoS2 are along the edges, whereas thermodynamically MoS2 favors the presence of a two-dimensional (2-D) basal plane and the catalytically active atoms only constitute a small portion of the material. The lack of catalytically active sites and low catalytic efficiency impede its massive application. To address the issue, we have activated the basal plane of monolayer 2H MoS2 through an ultrathin alumina mask (UTAM)-assisted nanopore arrays patterning, creating a high edge density. The introduced catalytically active sites are identified by Cu electrochemical deposition, and the hydrogen generation properties are assessed in detail. We demonstrate a remarkably improved HER performance as well as the identical catalysis of the artificial edges and the pristine metallic edges of monolayer MoS2. Such a porous monolayer nanostructure can achieve a much higher edge atom ratio than the pristine monolayer MoS2 flakes, which can lead to a much improved catalytic efficiency. This controllable edge engineering can also be extended to the basal plane modifications of other 2-D materials, for improving their edge-related properties. PMID- 29405057 TI - Nanoliter Sensing for Infrared Bioanalytics. AB - Nondestructive label-free bioanalytics of microliter to nanoliter sample volumes with low analyte concentrations requires novel analytic approaches. For this purpose, we present an optofluidic platform that combines surface-enhanced in situ infrared spectroscopy with microfluidics for sensing of surface-immobilized ultrathin biomolecular films in liquid analytes. Submonolayer sensitivity down to surface densities of few ng/cm2 is demonstrated for the adsorption of the thiolate tripeptide glutathione and for the recognition of streptavidin on a biotinylated enhancement substrate. Nonfunctionalized and functionalized metal island films on planar oxidized silicon substrates are used for signal enhancement with quantifiable enhancement properties. A single-reflection geometry at an incidence angle below the attenuated-total-reflection (ATR) regime is used with ordinary planar, IR-transparent windows. The geometry circumvents the strong IR absorption of common polymer materials and of aqueous environments in the IR fingerprint region. This practice enables straightforward quantitative analyses of, e.g., adsorption kinetics as well as chemical and structural properties in dependence of external stimuli. PMID- 29405059 TI - 3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-linking Strategy. AB - Methacrylated gelatin (GelMA) has been widely used as a tissue-engineered scaffold material, but only low-concentration GelMA hydrogels were found to be promising cell-laden bioinks with excellent cell viability. In this work, we reported a strategy for precise deposition of 5% (w/v) cell-laden GelMA bioinks into controlled microarchitectures with high cell viability using extrusion-based three-dimensional (3D) bioprinting. By adding gelatin into GelMA bioinks, a two step cross-linking combining the rapid and reversible thermo-cross-linking of gelatin with irreversible photo-cross-linking of GelMA was achieved. The GelMA/gelatin bioinks showed significant advantages in processability because the tunable rheology and the rapid thermo-cross-linking of bioinks improved the shape fidelity after bioprinting. Here, the rheology, mechanical properties, and swelling of GelMA/gelatin bioinks with different concentration ratios were carefully characterized to obtain the optimized bioprinting setup. We successfully printed the 5% (w/v) GelMA with 8% (w/v) gelatin into 3D structures, which had the similar geometrical resolution as that of the structures printed by 30% (w/v) GelMA bioinks. Moreover, the cell viability of 5/8% (w/v) GelMA/gelatin bioinks was demonstrated by in vitro culture and cell printing of bone marrow stem cells (BMSCs). Larger BMSC spreading area was found on 5/8% (w/v) GelMA/gelatin scaffolds, and the BMSC viability after the printing of 5/8% (w/v) GelMA/gelatin cell-laden bioinks was more than 90%, which was very close to the viability of printing pure 5% (w/v) GelMA cell-laden bioinks. Therefore, this printing strategy of GelMA/gelatin bioinks may extensively extend the applications of GelMA hydrogels for tissue engineering, organ printing, or drug delivery. PMID- 29405058 TI - Suspect Screening Analysis of Chemicals in Consumer Products. AB - A two-dimensional gas chromatography-time-of-flight/mass spectrometry (GC*GC TOF/MS) suspect screening analysis method was used to rapidly characterize chemicals in 100 consumer products-which included formulations (e.g., shampoos, paints), articles (e.g., upholsteries, shower curtains), and foods (cereals)-and therefore supports broader efforts to prioritize chemicals based on potential human health risks. Analyses yielded 4270 unique chemical signatures across the products, with 1602 signatures tentatively identified using the National Institute of Standards and Technology 2008 spectral database. Chemical standards confirmed the presence of 119 compounds. Of the 1602 tentatively identified chemicals, 1404 were not present in a public database of known consumer product chemicals. Reported data and model predictions of chemical functional use were applied to evaluate the tentative chemical identifications. Estimated chemical concentrations were compared to manufacturer-reported values and other measured data. Chemical presence and concentration data can now be used to improve estimates of chemical exposure, and refine estimates of risk posed to human health and the environment. PMID- 29405060 TI - A Highly Sensitive Strategy for Fluorescence Imaging of MicroRNA in Living Cells and in Vivo Based on Graphene Oxide-Enhanced Signal Molecules Quenching of Molecular Beacon. AB - In situ imaging of microRNA (miRNA) in living cells and in vivo is beneficial for promoting the studies on miRNA-related physiological and pathological processes. However, the current strategies usually have a low signal-to-background ratio, which greatly affects the sensitivity and imaging performance. To solve this problem, we developed a highly sensitive strategy for fluorescence imaging of miRNA in living cells and in vivo based on graphene oxide (GO)-enhanced signal molecule quenching of a molecular beacon (MB). 2Cy5-MB was designed by coupling two Cy5 molecules onto the opposite ends of MB. The fluorescence intensities of two Cy5 molecules were reduced because of the self-quenching effect. After adsorbing on the GO surface, the fluorescence quenching of the molecules was enhanced by fluorescence resonance energy transfer. This double-quenching effect significantly reduced the fluorescence background. In the presence of one miRNA molecule, the fluorescence signals of two Cy5 molecules were simultaneously recovered. Therefore, a significantly enhanced signal-to-background ratio was obtained, which greatly improved the detection sensitivity. In the presence of miRNA, the fluorescence intensity of 2Cy5-MB-GO recovered about 156 times and the detection limit was 30 pM. Compared with 1Cy5-MB-GO, the elevated fluorescence intensity was enhanced 8 times and the detection limit was reduced by an order of magnitude. Furthermore, fluorescence imaging experiments demonstrated that 2Cy5 MB-GO could visually detect microRNA-21 in various cancer cells and tumor tissues. This simple and effective strategy provides a new sensing platform for highly sensitive detection and simultaneous imaging analysis of multiple low level biomarkers in living cells and in vivo. PMID- 29405061 TI - Simple Hydrogen Plasma Doping Process of Amorphous Indium Gallium Zinc Oxide Based Phototransistors for Visible Light Detection. AB - A homojunction-structured amorphous indium gallium zinc oxide (a-IGZO) phototransistor that can detect visible light is reported. The key element of this technology is an absorption layer composed of hydrogen-doped a-IGZO. This absorption layer is fabricated by simple hydrogen plasma doping, and subgap states are induced by increasing the amount of hydrogen impurities. These subgap states, which lead to a higher number of photoexcited carriers and aggravate the instability under negative bias illumination stress, enabled the detection of a wide range of visible light (400-700 nm). The optimal condition of the hydrogen doped absorption layer (HAL) is fabricated at a hydrogen partial pressure ratio of 2%. As a result, the optimized a-IGZO phototransistor with the HAL exhibits a high photoresponsivity of 1932.6 A/W, a photosensitivity of 3.85 * 106, and a detectivity of 6.93 * 1011 Jones under 635 nm light illumination. PMID- 29405062 TI - Cerasomal Lovastatin Nanohybrids for Efficient Inhibition of Triple-Negative Breast Cancer Stem Cells To Improve Therapeutic Efficacy. AB - Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a higher risk in younger women and a poorer prognosis and without targeted therapies available currently. Cancer stem cells (CSCs) are increasingly recognized as the main cause of treatment failure and tumor recurrence. The present paper reports the encapsulation of lovastatin (LV) into cerasomes. Compared with free LV, cerasome-encapsulated LV (C-LV) nanohybrids showed cytotoxicity to MDA-MB-231 CSCs in a dose- and time-dependent manner. Furthermore, intravenous injection of C-LV nanohybrids resulted in a significant tumor size reduction in a dose dependent manner in xenograft tumors derived from subcutaneous inoculation of MDA MB-231 cells. Furthermore, histopathological and/or immunohistochemical analysis revealed that C-LV nanohybrids significantly induced mammary gland formation and apoptosis and inhibited angiogenesis, the CSC phenotype, and the epithelial-to mesenchymal transition in xenograft tumors. Most importantly, C-LV nanohybrids were found to be more effective than free LV in inhibiting the growth of breast cancer xenografts and the stemness properties in vivo. To the best of our knowledge, ours is the first demonstration of nanohybrids for efficient inhibition of CSCs derived from TNBC, offering a new option for the TNBC treatment. PMID- 29405063 TI - Coordinated Responsive Arrays of Surface-Linked Polymer Islands-CORALs. AB - The concept of co-ordinated responsive arrays of surface-linked islands (polymer CORALs) is introduced. This study targets a responsive system capable of revealing or covering the substrate surface in response to environmental changes in a reversible way. A convenient method of fabrication of polymer CORALs is proposed. It is based on microphase separation that occurs in thin films of supramolecular assemblies of block copolymers with reactive blocks. Such blocks form nanometer-size domains that may serve as anchors for surface-linked polymer islands. Two characteristics of the islands are critically important for the switching function: high grafting density within the islands and small lateral separation that allows interactions between polymer chains grafted to the neighboring islands. This combination permits complete coverage of the substrate surface upon exposure to a good solvent (relaxed state). In a weak solvent, the chains collapse within the islands, thus revealing the substrate (compact state). The morphology of the CORALs in both states and some details of the switching process were studied with atomic force microscopy, grazing incidence small-angle scattering, and coarse-grained molecular dynamic simulations. PMID- 29405065 TI - Solvent-Minimized, Chromatography-Free, Diastereoselective Synthesis of Oxazolidine-Dispirooxindoles via oxa-1,3-Dipolar Cycloaddition of 3-Oxindole. AB - An efficient and diastereoselective decarboxylative oxa-1,3-dipolar cycloaddition between 3-oxindoles and diverse amino acids is developed to access novel oxazolidine-dispirooxindole skeletons bearing vicinal quaternary carbon centers. This protocol features operational simplicity, a broad substrate scope, and good to excellent chemical yields and diastereoselectivities. In particular, minimal solvent (1 mL/10 mmol) and chromatography-free purification render this synthetic process more efficient and environmentally benign in the context of green chemistry. PMID- 29405064 TI - Fundamental Insights into the Reductive Covalent Cross-Linking of Single-Walled Carbon Nanotubes. AB - Single-walled carbon nanotubes (SWCNT) have been covalently cross-linked via a reductive functionalization pathway, utilizing negatively charged carbon nanotubides (KC4). We have compared the use of difunctional linkers acting as molecular pillars between the nanotubes, namely, p-diiodobenzene, p diiodobiphenyl, benzene-4,4'-bis(diazonium), and 1,1'-biphenyl-4,4' bis(diazonium) salts as electrophiles. We have employed statistical Raman spectroscopy (SRS), a forefront characterization tool consisting of thermogravimetric analysis coupled with gas chromatography and mass spectrometry (TG-GC-MS) and aberration-corrected high-resolution transmission electron microscopy imaging series at 80 kV to unambiguously demonstrate the covalent binding of the molecular linkers. The present study shows that the SWCNT functionalization using iodide derivatives leads to the best results in terms of bulk functionalization homogeneity ( Hbulk) and degree of addition. Phenylene linkers yield the highest degree of functionalization, whereas biphenylene units induce a higher surface area with an increase in the thermal stability and an improved electrochemical performance in the oxygen reduction reaction (ORR). This work illustrates the importance of molecular engineering in the design of novel functional materials and provides important insights into the understanding of basic principles of reductive cross-linking of carbon nanotubes. PMID- 29405066 TI - The Role of Defects in Fe(II)-Goethite Electron Transfer. AB - Despite substantial experimental evidence for Fe(II)-Fe(III) oxide electron transfer, computational chemistry calculations suggest that oxidation of sorbed Fe(II) by goethite is kinetically inhibited on structurally perfect surfaces. We used a combination of 57Fe Mossbauer spectroscopy, synchrotron X-ray absorption and magnetic circular dichroism (XAS/XMCD) spectroscopies to investigate whether Fe(II)-goethite electron transfer is influenced by defects. Specifically, Fe L edge and O K-edge XAS indicates that the outermost few Angstroms of goethite synthesized by low temperature Fe(III) hydrolysis is iron deficient relative to oxygen, suggesting the presence of defects from Fe vacancies. This nonstoichiometric goethite undergoes facile Fe(II)-Fe(III) oxide electron transfer, depositing additional goethite consistent with experimental precedent. Hydrothermal treatment of this goethite, however, appears to remove defects, decrease the amount of Fe(II) oxidation, and change the composition of the oxidation product. When hydrothermally treated goethite was ground, surface defect characteristics as well as the extent of electron transfer were largely restored. Our findings suggest that surface defects play a commanding role in Fe(II)-goethite redox interaction, as predicted by computational chemistry. Moreover, it suggests that, in the environment, the extent of this interaction will vary depending on diagenetic history, local redox conditions, as well as being subject to regeneration via seasonal fluctuations. PMID- 29405067 TI - Amino-Functionalized Luminescent Metal-Organic Framework Test Paper for Rapid and Selective Sensing of SO2 Gas and Its Derivatives by Luminescence Turn-On Effect. AB - Rapid and selective sensing of sulfur dioxide (SO2) gas has attracted more and more attention because SO2 not only causes environmental pollution but also severely affects the health of human beings. Here we report an amino functionalized luminescent metal-organic framework (MOF) material (i.e., MOF-5 NH2) and further investigate its sensing property for SO2 gas and its derivatives as a luminescent probe. The results indicate that the MOF-5-NH2 probe can selectively and sensitively sense SO2 derivatives (i.e., SO32-) in real time by a luminescence turn-on effect with a lower detection limit of 0.168 ppm and a response time of less than 15 s. Importantly, the luminescence turn-on phenomenon can be observed by the naked eye. We also assembled MOF-5-NH2 into a test paper to achieve the aim of portable detection, and the lower-limit concentration of the test paper for sensing SO2 in real time was found to be about 0.05 ppm. Moreover, MOF-5-NH2 also shows good anti-interference ability, strong luminescence stability, and reusability, which means that this material is an excellent sensing candidate. The amino functionalization may also provide a modification strategy to design luminescent sensors for other atmospheric pollutants. PMID- 29405068 TI - The Myth of Visible Light Photocatalysis Using Lanthanide Upconversion Materials. AB - Upconversion luminescence is a nonlinear optical process achieved by certain engineered materials, which allows conversion of low energy photons into higher energy photons. Of particular relevance to environmental technology, lanthanide based upconversion phosphors have appeared in dozens of publications as a tool for achieving visible light activation of wide-band gap semiconductor photocatalysts, such as TiO2, for degradation of water contaminants. Supposedly, the phosphor particles act to convert sub-band gap energy photons (e.g., solar visible light) into higher energy ultraviolet photons, thus driving catalytic aqueous contaminant degradation. Herein, however, we reexamined the photophysical properties of the popular visible-to-UV converters Y2SiO5:Pr3+ and Y3Al5O12:Er3+, and found that their efficiencies are not nearly high enough to induce catalytic degradations under the reported excitation conditions. Furthermore, our experiments indicate that the false narrative of visible-to-UV upconversion sensitized photocatalysis likely arose due to coincidental enhancements of dye degradation via direct electron injection that occur in the presence of dielectric-semiconductor (phosphor-catalyst) interfaces. These effects were unrelated to upconversion and only occurred for dye solutions illuminated within the chromophore absorption bands. We conclude that upconversion using Pr3+ or Er3+-activated systems is not a technologically appealing mechanism for visible light photocatalysis, and provide experimental guidelines for avoiding future misinterpretation of these phenomena. PMID- 29405069 TI - Work support, psychological well-being and safety performance among nurses in Hong Kong. AB - This study investigated the mediating role of psychological well-being between work support and safety performance of 314 Hong Kong nurses, using self-reported questionnaires. Results showed that psychological well-being mediated the effects of work support on safety performance. The findings illustrate that work support was an important element to improve psychological well-being. This could generate better safety performance of the nurses. Implications and limitations are discussed. PMID- 29405070 TI - Bayesian adaptive trials for rare cardiovascular conditions. AB - Escalating costs of cardiovascular trials are limiting medical innovations, prompting the development of more efficient and flexible study designs. The Bayesian paradigm offers a framework conducive to adaptive trial methodologies and is well suited for the study of small populations. Bayesian adaptive trials provide a statistical structure for combining prior information with accumulating data to compute probabilities of unknown quantities of interest. Adaptive design features are useful in modifying randomization schemes, adjusting sample sizes and providing continuous surveillance to guide decisions on dropping study arms or premature trial interruption. Advantages include greater efficiency, minimization of risks, inclusion of knowledge as it is generated, cost savings and more intuitive interpretability. Extensive high-level computations are facilitated by an expanding armamentarium of available tools. PMID- 29405071 TI - Subcutaneous rituximab with recombinant human hyaluronidase in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia. AB - The anti-CD20 monoclonal antibody rituximab (MabThera(r)/Rituxan(r)) has been proven to improve outcomes in a range of B-cell malignancies. Initially developed as a formulation for intravenous infusion, administration times for rituximab can be prolonged and associated with infusion-related reactions, prompting a combined clinical development program investigating subcutaneous delivery in combination with recombinant human hyaluronidase. As this program comes to fruition, this article reviews the evidence demonstrating subcutaneous rituximab to have noninferior pharmacokinetics when delivered at a fixed-dose as well as equivalent clinical outcomes in the treatment of follicular lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma. This mode of delivery is more preferable to patients and healthcare professionals and is associated with time and cost savings. PMID- 29405072 TI - Current status of stem cells in cardiac repair. AB - One out of every two men and one out of every three women greater than the age of 40 will experience an acute myocardial infarction (AMI) at some time during their lifetime. As more patients survive their AMIs, the incidence of congestive heart failure (CHF) is increasing. 6 million people in the USA have ischemic cardiomyopathies and CHF. The search for new and innovative treatments for patients with AMI and CHF has led to investigations and use of human embryonic stem cells, cardiac stem/progenitor cells, bone marrow-derived mononuclear cells and mesenchymal stem cells for treatment of these heart conditions. This paper reviews current investigations with human embryonic, cardiac, bone marrow and mesenchymal stem cells, and also stem cell paracrine factors and exosomes. PMID- 29405073 TI - The use of neo adjuvant single-agent vinblastine for tumour shrinkage in a highly vascular paediatric low-grade glioma. AB - Vinblastine has shown activity as second line treatment in Low Grade Glioma (LGG) in children as well as anti-angiogenic activity in vitro. A 5 year old girl presented with 6 week history of headaches. MRI demonstrated a right temporo parietal mass with abnormal pathological vasculature including aneurysmal vessels. Biopsy showed a pilocytic astrocytoma. Due to increased risk from surgery, first line treatment with vinblastine was given. Over 10 months, progressive reduction of tumour vascularity was demonstrated. The tumour was then surgically removed after 14 months of therapy. To our knowledge, this is the first report in which vinblastine has been successfully used in LGG to obtain tumour shrinkage prior to total tumor resection in a high vascularized LGG. PMID- 29405074 TI - Assessment of acetamiprid-induced genotoxic effects in bone marrow cells of Swiss albino male mice. AB - Acetamiprid (ACE), a neonicotinoid insecticide, is widely used in agriculture either alone or in combination with other insecticides. A combined approach employing micronucleus test (MNT) and chromosomal aberrations (CA) assay was utilized to assess the genotoxic effects of ACE in bone marrow of Swiss albino male mice. Acetamiprid was administered i.p. daily at 4.6 and 2.3 mg/kg/day along with 3% gum acacia as negative control for 60 and 90 days and cyclophosphamide (50 mg/kg b.wt.) as positive control. ACE treatment resulted in a dose-dependent increase in the frequencies of micronuclei per cell and chromosomal aberrations in bone marrow cells. The increased micronuclei formation in total erythrocyte cells (immature PCEs and mature NCEs) was observed only at higher dose level (4.6 mg/kg b.wt.) administered for 90 days. The test also indicated the cytotoxic effect of higher dose level of pesticide by PCE/NCE ratio. The number of chromosomal aberrations were increased in the pesticide treated group compared to the negative control group, although significant increase was observed only in the group exposed to higher dose level of pesticide for both 60 and 90 days. Thus, daily exposure of ACE at a dose level of 4.6 mg/kg body weight for 60 and 90 days caused genotoxic and cytotoxic effects on the somatic cells of Swiss albino male mice. PMID- 29405076 TI - Tools to investigate and avoid drug-hypersensitivity in drug development. AB - INTRODUCTION: Drug hypersensitivity reactions (DHRs) are common adverse effects of pharmaceuticals that clinically resemble allergies, and which are becoming an important burden to healthcare systems. Alongside accurate diagnostic techniques, tools which can predict potential drug-inducing hypersensitivity reactions in the pre-clinical phase are critical. Despite the important adverse reactions linked to immune-mediated hypersensitivity, at present, there are no validated or required in vivo or in vitro methods to screen the sensitizing potential of drugs and their metabolites in the pre-clinical phase. Areas covered: Enhanced prediction in preclinical safety evaluation is extremely important. The purpose of this review is to assess the state of the art of tools available to assess the allergenic potential of drugs and to highlight our current understanding of the molecular mechanisms underlying inappropriate immune activation. Expert opinion: The knowledge that allergenic drugs share common mechanisms of immune cell activation with chemical allergens, and of the definition of the mechanistic pathway to adverse outcomes, can enhance targeting toxicity testing in drug development and hazard assessment of hypersensitivity. Additional efforts and extensive resources are necessary to improve preclinical testing methodologies, including optimization, better design and interpretation of data. PMID- 29405077 TI - Barriers to implementation of a pelvic examination among family doctors in primary care clinics. AB - OBJECTIVE: although the pelvic examination of female patients should be an integral part of the physical examination in family medicine there are many barriers to the conduct of this intimate examination by family doctors. THE OBJECTIVE: an assessment of the attitudes and barriers reported by family doctors on conducting a pelvic examination. METHODS: An anonymous, self-administered questionnaire. RESULTS: Two hundred thirty doctors participated in the study, of who 157 were males (68.9%). The mean age was 42.2 +/- 9.6 years. 179 family doctors (77.8%) thought that the pelvic examination should be an important part of their work as a family doctor, 100 (43.9%) said that they had conducted a pelvic examination in the past, but the majority (85.2%) had not done a pelvic examination over the previous year. Senior doctors did more pelvic examinations than younger doctors (P = 0.007). Graduates of Israeli medical schools were more likely than those who graduated elsewhere to state that family doctors should do pelvic examinations (P = 0.032). Graduates of non-Israeli medical schools cited less experience (P = 0.002) and less motivation (P = 0.006) as reasons for not doing pelvic examinations. CONCLUSIONS: Although most family doctors believe that pelvic examinations are an important part of their work, only a small percentage actually do a pelvic examination. Among the reasons for not doing the examination are lack of knowledge, lack of experience, and work burden. PMID- 29405075 TI - Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. AB - The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid beta-protein self-aggregation by 65.49% at 25 MUM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD. PMID- 29405078 TI - Non-indicated use of prophylactic antibiotics in gynaecological surgery at an academic tertiary medical centre. AB - Surgical site infections (SSI) are the most common surgical complication. Perioperative antibiotics can reduce SSI when used properly. Despite guidelines from The American College of Obstetrics and Gynecology, non-indicated antibiotic use is widespread which exposes women to unnecessary risks. This study represents a quality improvement analysis assessing surgeon compliance with established guidelines regarding antibiotic use in gynaecological surgery. This is a single centre, retrospective study examining gynaecological procedures over two years. Cases were identified using Current Procedure Terminology codes. Perioperative antibiotics were used contrary to published guidelines in 199 of 1046 cases. Three variables were independently associated with inappropriate administration of perioperative antibiotics: entrance into abdominal cavity, higher EBL, and longer procedures. Impact statement Overuse of antibiotics has unintended consequences including allergic sequelae, extended length of hospital stay, increased healthcare costs, and the formation of antibiotic-resistant organisms. Antibiotic stewardship programmes have been shown to reduce the number of resistant pathogens, decrease incidence of Clostridium difficile colitis, and decrease length of hospital stay without increasing infection rates. Further outcomes-based research is needed regarding the use of antibiotic stewardship programmes in gynaecological surgery. PMID- 29405079 TI - Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation. AB - Oestrogens with no or reduced oestrogen receptor (ER) binding properties are reported to have neuroprotective functions. However, we have previously shown that the hormonally inactive isomer of 17beta-estradiol (17beta-E), 17alpha estradiol (17alpha-E), down-regulates glutathione (GSH) synthesis, and fails to rescue serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in micromolar concentration. The present study examined cellular protective effects of new 17beta-E analogs and 2-methoxyestradiol (2-ME) analogs with no or little oestrogen activity. 17beta-E, 17alpha-E, 2-ME, and an antagonist of the G protein-coupled oestrogen receptor (GPER), G36, were also included. Both 17alpha E and 2-ME protected against deprivation-induced cell death in PC12 cells at 1 nM, but they enhanced the deprivation-induced cell death accompanied by caspase 3 activity and decreased intracellular GSH levels during deprivation at 10 uM. In addition, 10 MUM 17alpha-E activated the p38 mitogen activated protein kinase pathway, which was linked to the enhanced death and reduced GSH levels. Analogs of 2-ME modified with a 6-isoquinoline moiety (6iq) protected against deprivation induced cell death at 1 nM and did not interfere with the GSH levels nor increase p38 protein levels at 10 uM. The promoter activity of the catalytic subunit of the rate-limiting enzyme, glutamate cysteine ligase (GCLC) in GSH synthesis as well as protein levels of GCLC and Nrf2, increased with the 2-ME analogs at 10 uM. In conclusion, the steroids have differential protective effects, and modifying 2-ME may give the steroid more favourable properties than 17alpha-E, 2 ME, and G36 in regard to GSH regulation. PMID- 29405080 TI - Artesunate enhances gammadelta T-cell-mediated antitumor activity through augmenting gammadelta T-cell function and reversing immune escape of HepG2 cells. AB - OBJECTIVE: To explore the effect and mechanism of artesunate on gammadelta T cell mediated antitumor immune responses against hepatoma carcinoma cells (HepG2) in vitro. METHODS: Human gammadelta T cells or HepG2 were respectively treated with artesunate, subjected to co-culture as appropriate, and the following assays were subsequently conducted: CCK8 to examine cell viability; LDH release assay to detect the killing effect of gammadelta T cells on HepG2 cells; flow cytometry to examine the expression of perforin (PFP) and granzyme B (GraB) of gammadelta T cells; ELISA to evaluate the levels of TGF-beta1 and IL-10 in the collected supernatant of HepG2 cells pretreated with artesunate; and Western blot analysis to examine Fas, FasL, STAT3, p-STAT3 expression of HepG2 cells induced by artesunate. Results: The results showed that the cytotoxicity effect of gammadelta T cells pretreated with artesunate on HepG2 cells was augmented via elevating the expression of GraB in gammadelta T cells. Furthermore, treatment with artesunate reversed the inhibition of HepG2 cells on gammadelta T cells by reducing the secretion of TGF-beta1 in HepG2 cells supernatant and enhanced the antitumor effect of gammadelta T cells against HepG2 cells through increasing the expression of Fas on HepG2 cells, which may be attributed to the inhibition of STAT3 signaling protein. CONCLUSION: Artesunate has several mechanisms for augmenting the antitumor immune responses mediated by gammadelta T cells. These results suggested artesunate may be an efficacious agent in the treatment of hepatocellular carcinoma. PMID- 29405081 TI - Acute inhalation of combustion smoke triggers neuroinflammation and persistent anxiety-like behavior in the mouse. AB - CONTEXT: Acute inhalation of combustion smoke triggers neurologic sequelae in survivors. Due to the challenges posed by heterogeneity of smoke exposures in humans, mechanistic links between acute smoke inhalation and neuropathologic sequelae have not been systematically investigated. METHODS: Here, using mouse model of acute inhalation of combustion smoke, we studied longitudinal neurobehavioral manifestations of smoke exposures and molecular/cellular changes in the mouse brain. RESULTS: Immunohistochemical analyses at eight months post smoke, revealed hippocampal astrogliosis and microgliosis accompanied by reduced myelination. Elevated expression of proinflammatory cytokines was also detected. Longitudinal testing in different neurobehavioral paradigms in the course of post smoke recovery, revealed lasting anxiety-like behavior. The examined paradigms included the open field exploration/anxiety testing at two, four and six months post-smoke, which detected decreases in total distance traveled and time spent in the central arena in the smoke-exposed compared to sham-control mice, suggestive of dampened exploratory activity and increased anxiety-like behavior. In agreement with reduced open field activity, cued fear conditioning test revealed increased freezing in response to conditioned auditory stimulus in mice after acute smoke inhalation. Similarly, elevated plus maze testing demonstrated lesser presence in open arms of the maze, consistent with anxiety-like behavior, for the post-smoke exposure mice. CONCLUSIONS: Taken together, our data demonstrate for the first time persistent neurobehavioral manifestations of acute inhalation of combustion smoke and provide new insights into long-term progression of events initiated by disrupted brain oxygenation that might contribute to lasting adverse sequelae in survivors of smoke inhalation injuries. PMID- 29405083 TI - Cervical cancer - does the morphological subtype affect survival rates? AB - A retrospective population-based observational study using cancer registration data of women diagnosed with invasive cervical cancer between 2006 and 2010, in England, was carried out to explore how different morphological subtypes affect survival rates. Age-standardised net survival rates by morphological subtype are presented alongside with excess mortality modelling accounting for the impact of demographic, diagnostic and tumour factors. The three main morphological subtypes (squamous cell carcinoma (SCC), adenocarcinoma and adenosquamous carcinoma) have similar one-year net survival rates of approximately 85%. After adjusting for other important determinants of survival, there were no differences at five-years amongst the three main morphological subtypes, with unadjusted survival rates of 55-65%. As expected, women presenting with neuroendocrine tumours had a much poorer outcome than other epithelial cervical malignancies, with 1-year survival of up to 55%, five-year survival of 34% and excess mortality rates compared to SCC varying between 1.9 and 5.9. Impact Statement What is already known on this subject: This is the first study on survival by cervical cancer morphological subtype using national cancer data. What the results of this study add: This study uses excess mortality modelling to investigate the effects of the morphological subtypes whilst adjusting the other factors that affect cervical cancer survival such as stage, age and grade. What the implications are of these findings for clinical practice and/or further research: It is known that cervical neuroendocrine tumours have a poor prognosis and this is confirmed by this study. Squamous cell carcinomas (SCC), adenocarcinomas (AC) and adenosquamous carcinomas (ASC) have the highest net survival and when accounting for other factors there are no differences amongst these morphological subtypes in terms of survival. PMID- 29405084 TI - An updated analysis of respiratory tract cells at risk for formaldehyde carcinogenesis. AB - Study of the mode of action (MOA) relating exposure to a given chemical with an associated adverse outcome is an iterative process with each iteration driven by new understandings of the relevant biology. Here, we revisit a previously described, MOA-based clonal growth model of the human respiratory tract cancer risk associated with formaldehyde inhalation. Changes reflect a better understanding of populations of cells at risk of carcinogenic transformation in the pharynx, larynx and respiratory bronchiolar portions of the human respiratory tract and inclusion of basal cells in the pool of cells at risk. The focus of this report is not on cancer risk per se, but rather on the sensitivity of model parameters and predicted risks to alternative descriptions of the fraction of cells at risk for carcinogenic transformation. For a population of formaldehyde exposed nonsmokers, revised specification of cells at risk resulted in changes in both parameter estimates and in predicted risks. Compared to our previous assessment, predicted additional risks were up to 87% greater at exposure levels <=1 ppm, but up to about 130% lower at high exposure levels (2-5 ppm). While this work should not be considered an update to MOA-based risk assessments for formaldehyde described previously, it illustrates the sensitivity of parameter estimates and risk predictions to the quantitative specification of cells at risk of carcinogenic transformation and, therefore, the motivation for describing the relevant biology as accurately as possible. PMID- 29405085 TI - The potential impact of using a surfactant and an alcoholic co-surfactant on SRB activity during EOR. AB - Surfactants and co-surfactants play an important role in enhanced oil recovery for they improve petroleum solubility and reduce interfacial tensions between oil, water and the rock formation. Ethanol is receiving renewed attention as potential co-surfactant because of the negative results obtained with the use of salts and alkaline substances. Sulphate-reducing bacteria (SRB) can use surfactants and co-surfactants as carbon sources and, consequently, this can increase the biological accumulation of sulphide (souring). The aim of this research is to correlate SRB activity with different concentrations of co surfactant (ethanol) as an attempt to quantifying in which concentration such compound can potentially increase or inhibit souring. The results show that the combination of surfactant (lauryl glucoside) and co-surfactant (ethanol) can increase SRB activity to about 2.3-fold. The highest sulphate consumption rate of 591 MUg l-1 h-1 was observed in experiments with 0.03% and 1.5% (v/v) of surfactant and ethanol, respectively. The experiments indicated that SRB activity is only controlled by ethanol concentrations above 6.5% (v/v). Ethanol can potentially decrease costs with the use of biocides and significantly increase oil recovery ratios. Tests with the model Desulfovibrio vulgaris were not comparable with the results obtained with the SRB consortium. PMID- 29405082 TI - Genotyping comparison of Mycobacterium leprae isolates by VNTR analysis from nasal samples in a Brazilian endemic region. AB - This study analyzed the genetic diversity by MIRU-VNTR of Mycobacterium leprae isolates from nasal cavities and related to epidemiological and clinical data. The sample consisted of 48 newly diagnosed leprosy cases that tested positive for M. leprae PCR in nasal secretion (NS) attending to the National Reference Center of Dermatology Dona Libania (CDERM), Fortaleza, Brazil. Total DNA was extracted from NS of each patient and used for amplification of four M. leprae VNTR loci. Four clusters of M. leprae isolates were formed with identical genotypes. In the spatial analysis, 12 leprosy cases presented similar genotypes organized into 4 clusters. The most common genotypes in the current study was AC8b: 8, AC9: 7, AC8a: 8, GTA9: 10, which may represent a genotype of circulating strains most often in Ceara. A minimum set of four MIRU-VNTR loci was demonstrated to study the genetic diversity of M. leprae isolates from NS. PMID- 29405086 TI - Enhancement of CO2 biofixation and lipid production by Chlorella vulgaris using coloured polypropylene film. AB - Chlorella vulgaris was cultivated with light at different wavelengths (lambdamax) and irradiation intensities (I) by applying a coloured tape (CT) as a simple, inexpensive light filter. C. vulgaris was cultivated in a standard medium using blue (CTB), green (CTG), red (CTR), yellow (CTY) and white (CTW) CT to filter the light, as well the unfiltered light (U). The influence of lambdamax and I on specific growth rate (MU), nutrient removal efficiency (% RE of total nitrogen, TN, and phosphorus, TP), CO2 fixation rate (RC) and lipid productivity (Plipid) were evaluated. The highest biomass concentration Xmax of 2.26 g L-1 was measured for CTW with corresponding MU, TN and TP RE, RC and Plipid values of 0.95 d-1, 92% and 100%, 0.67 g L-1 d-1 and 83.6 mg L-1 d-1, respectively. The normalised MU and Plipid for U were significantly lower than in CTW of 33-50% and 75%, respectively. The corresponding non-normalised parameter values for CTB were significantly lower at 0.45 d-1, 0.18 g L-1, 15% and 37%, 0.03 g L-1 d-1 and 1.2 mg L-1 d-1. Results suggest a significant impact of I and lambdamax, with up to a 50% increase in growth and nutrient RE from optimising these parameters. PMID- 29405087 TI - A previous caesarean section is not a risk factor for tubal abnormalities in the infertile population. AB - In this retrospective cohort study of 1716 cases of women undergoing infertility treatment between the years 1999-2012, we aimed to identify whether parturients with a previous surgical history are at a higher risk for tubal abnormalities as determined by hysterosalpingography (HSG) in this infertile population. Amongst the study population, tubal obstruction was identified on HSG in 15.8% of patients with no past history of an abdominal surgery and 16.3% of patients with a previous caesarean section (CS) delivery. These rates were significantly lower than those for women with a previous gynaecological surgery (34.7%) or abdominal surgery (27%) (p < .001 for all comparisons). Our results suggest that past history of CS poses no additional risk for tubal abnormality within the infertile population, whereas a history of other abdominal or gynaecological surgical procedures doubles this risk. Impact Statement What is already known on this subject? While numerous risk factors for tubal factor infertility have been established, to date, the relation between previous abdominal surgeries and the risk for tubal factor infertility remains inconclusive. What the results of this study add? In this study, we aimed to evaluate the correlation between previous CS history and the risk for having tubal factor infertility. Our results demonstrated that previous caesarean section delivery does not increase the risk for tubal factor infertility in the infertile population, whereas history of other abdominal or gynaecological surgical procedures doubles this risk. What the implications are of these findings for clinical practice and/or further research? Further research is needed for further evaluation of this association and its clinical implications. PMID- 29405088 TI - Central microinjection of phytohormone abscisic acid changes feeding behavior, decreases body weight, and reduces brain oxidative stress in rats. AB - OBJECTIVES: Natural products have a potential role on food intake in mammals. It has been reported that phytohormone abscisic acid (ABA) has a regulatory role on metabolic processes. Here, the effects of ABA on feeding behavior and brain oxidative stress were investigated in male Wistar rats. METHODS: ABA was injected intracerebroventricularly. Experimental groups were included (n = 9): control (received no injection), ABA vehicle (received normal saline), and ABA-treated groups were injected with different doses of ABA (2.5, 5, and 10 MUg/rat for 7 days). Daily cumulative daytime and nighttime food consumption, meal frequency, meal duration, and alteration in body weight were recorded. At the end of behavioral experiment, catalase and peroxidase activity and malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels were assayed. RESULTS: The results showed that ABA (5 and 10 MUg) increased the meal frequency. Moreover, ABA could decrease body weight and MDA and H2O2 levels and increased the catalase and peroxidase activities in diencephalon. It also decreased the MDA concentration in the brain stem. DISCUSSION: Taken together, ABA has an important effect on feeding behavior and body weight in rats likely via increasing antioxidant capacity. However, further studies are still required to determine the underlying mechanisms of ABA on the feeding behavior. PMID- 29405089 TI - Correction to: Cassidy et al., Disposition and metabolism of [14C]-galunisertib, a TGF-bRI kinase/ALK5 inhibitor, following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics. PMID- 29405090 TI - Systematic review of proposed definitions of nocturnal polyuria and population based evidence of their diagnostic accuracy. AB - Background Evidence of diagnostic accuracy for proposed definitions of nocturnal polyuria is currently unclear. Purpose Systematic review to determine population based evidence of the diagnostic accuracy of proposed definitions of nocturnal polyuria based on data from frequency-volume charts. Methods Seventeen pre specified search terms identified 351 unique investigations published from 1990 to 2016 in BIOSIS, Embase, Embase Alerts, International Pharmaceutical Abstract, Medline, and Cochrane. Thirteen original communications were included in this review based on pre-specified exclusion criteria. Data were extracted from each paper regarding subject age, sex, ethnicity, health status, sample size, data collection methods, and diagnostic discrimination of proposed definitions including sensitivity, specificity, positive and negative predictive value. Results The sample size of study cohorts, participant age, sex, ethnicity, and health status varied considerably in 13 studies reporting on the diagnostic performance of seven different definitions of nocturnal polyuria using frequency volume chart data from 4968 participants. Most study cohorts were small, mono ethnic, including only Caucasian males aged 50 or higher with primary or secondary polyuria that were compared to a control group of healthy men without nocturia in prospective or retrospective settings. Proposed definitions had poor discriminatory accuracy in evaluations based on data from subjects independent from the original study cohorts with findings being similar regarding the most widely evaluated definition endorsed by ICS. Conclusions Diagnostic performance characteristics for proposed definitions of nocturnal polyuria show poor to modest discrimination and are not based on sufficient level of evidence from representative, multi-ethnic population-based data from both females and males of all adult ages. PMID- 29405091 TI - Linking biofilm spatial structure to real-time microscopic oxygen decay imaging. AB - Two non-destructive techniques, confocal laser scanning microscopy (CLSM) and planar optode (VisiSens imaging), were combined to relate the fine-scale spatial structure of biofilm components to real-time images of oxygen decay in aquatic biofilms. Both techniques were applied to biofilms grown for seven days at contrasting light and temperature (10/20 degrees C) conditions. The geo statistical analyses of CLSM images indicated that biofilm structures consisted of small (~100 MUm) and middle sized (~101 MUm) irregular aggregates. Cyanobacteria and EPS (extracellular polymeric substances) showed larger aggregate sizes in dark grown biofilms while, for algae, aggregates were larger in light-20 degrees C conditions. Light-20 degrees C biofilms were most dense while 10 degrees C biofilms showed a sparser structure and lower respiration rates. There was a positive relationship between the number of pixels occupied and the oxygen decay rate. The combination of optodes and CLMS, taking advantage of geo-statistics, is a promising way to relate biofilm architecture and metabolism at the micrometric scale. PMID- 29405093 TI - Corrigendum. PMID- 29405092 TI - A porcine model of skin wound infected with a polybacterial biofilm. AB - A clinically relevant porcine model of a biofilm-infected wound was established in 10 minipigs. The wounds of six experimental animals were infected with a modified polymicrobial Lubbock chronic wound biofilm consisting of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Bacillus subtilis. Four animals served as uninfected controls. The wounds were monitored until they had healed for 24 days. The biofilm persisted in the wounds up to day 14 and significantly affected healing. The control to infected healed wound area ratios were: 45%/21%, 66%/37%, and 90%/57% on days 7, 10 and 14, respectively. The implanted biofilm prolonged inflammation, increased necrosis, delayed granulation and impaired development of the extracellular matrix as seen in histological and gene expression analyses. This model provides a therapeutic one-week window for testing of anti-biofilm treatments and for research on the pathogenesis of wound infections in pig that is clinically the most relevant animal wound healing model. PMID- 29405094 TI - HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency. AB - BCL2-associated athanogene (BAG)-3 is viewed as a platform that would physically and functionally link distinct classes of molecular chaperones of the heat shock protein (HSP) family for the stabilization and clearance of damaged proteins. In this study, we show that HSPB8, a member of the small heat shock protein subfamily, cooperates with BAG3 to coordinate the sequestration of harmful proteins and the cellular adaptive response upon proteasome inhibition. Silencing of HSPB8, like depletion of BAG3, inhibited targeting of ubiquitinated proteins to the juxtanuclear aggresome, a mammalian system of spatial quality control. However, aggresome targeting was restored in BAG3-depleted cells by a mutant BAG3 defective in HSPB8 binding, uncoupling HSPB8 function from its binding to BAG3. Depletion of HSPB8 impaired formation of ubiquitinated microaggregates in an early phase and interfered with accurate modifications of the stress sensor p62/sequestosome (SQSTM)-1. This impairment correlated with decreased coupling of BAG3 to p62/SQSTM1 in response to stress, hindering Kelch-like ECH-associated protein (KEAP)-1 sequestration and stabilization of nuclear factor E2-related factor (Nrf)-2, an important arm of the antioxidant defense. Notably, the myopathy-associated mutation of BAG3 (P209L), which lies within the HSPB8-binding motif, deregulated the association between BAG3 and p62/SQSTM1 and the KEAP1-Nrf2 signaling axis. Together, our findings support a so-far-unrecognized role for the HSPB8-BAG3 connection in mounting of an efficient stress response, which may be involved in BAG3-related human diseases.-Guilbert, S. M., Lambert, H., Rodrigue, M.-A., Fuchs, M., Landry, J., Lavoie, J. N. HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency. PMID- 29405095 TI - Shift work cycle-induced alterations of circadian rhythms potentiate the effects of high-fat diet on inflammation and metabolism. AB - Based on genetic models with mutation or deletion of core clock genes, circadian disruption has been implicated in the pathophysiology of metabolic disorders. Thus, we examined whether circadian desynchronization in response to shift work type schedules is sufficient to compromise metabolic homeostasis and whether inflammatory mediators provide a key link in the mechanism by which alterations of circadian timekeeping contribute to diet-induced metabolic dysregulation. In high-fat diet (HFD)-fed mice, exposure to chronic shifts of the light-dark cycle (12 h advance every 5 d): 1) disrupts photoentrainment of circadian behavior and modulates the period of spleen and macrophage clock gene rhythms; 2) potentiates HFD-induced adipose tissue infiltration and activation of proinflammatory M1 macrophages; 3) amplifies macrophage proinflammatory cytokine expression in adipose tissue and bone marrow-derived macrophages; and 4) exacerbates diet induced increases in body weight, insulin resistance, and glucose intolerance in the absence of changes in total daily food intake. Thus, complete disruption of circadian rhythmicity or clock gene function as transcription factors is not requisite to the link between circadian and metabolic phenotypes. These findings suggest that macrophage proinflammatory activation and inflammatory signaling are key processes in the physiologic cascade by which dysregulation of circadian rhythmicity exacerbates diet-induced systemic insulin resistance and glucose intolerance.-Kim, S.-M., Neuendorff, N., Alaniz, R. C., Sun, Y., Chapkin, R. S., Earnest, D. J. Shift work cycle-induced alterations of circadian rhythms potentiate the effects of high-fat diet on inflammation and metabolism. PMID- 29405097 TI - Relevant patient characteristics for guiding tailored integrated diabetes primary care: a systematic review. AB - : AimTo identify which patient-related effect modifiers influence the outcomes of integrated care programs for type 2 diabetes in primary care. BACKGROUND: Integrated care is a widespread management strategy for the treatment of type 2 diabetes. However, most integrated care programs are not tailored to patients' needs, preferences and abilities. There is increasing consensus that such a patient-centered approach could improve the management of type 2 diabetes. Thus far, it remains unclear which patient-related effect modifiers should guide such an approach. METHODS: PubMed, CINAHL and EMBASE were searched for empirical studies published after 1998. A systematic literature review was conducted according to the PRISMA guidelines.FindingsIn total, 23 out of 1015 studies were included. A total of 21 studies measured the effects of integrated diabetes care programs on hemoglobin A1c (HbA1c) and three on low-density lipoprotein cholesterol, systolic blood pressure and health-care utilization. In total, 49 patient characteristics were assessed as potential effect modifiers with HbA1c as an outcome, of which 46 were person or health-related and only three were context related. Younger age, insulin therapy and longer disease duration were associated with higher HbA1c levels in cross-sectional and longitudinal studies. Higher baseline HbA1c was associated with higher HbA1c at follow-up in longitudinal studies. Information on context- and person-related characteristics was limited, but is necessary to help identify the care needs of individual patients and implement an effective integrated type 2 diabetes tailored care program. PMID- 29405096 TI - A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression. AB - Hypercapnia, elevated levels of CO2 in the blood, is a known marker for poor clinical prognosis and is associated with increased mortality in patients hospitalized with both bacterial and viral pneumonias. Although studies have established a connection between elevated CO2 levels and poor pneumonia outcomes, a mechanistic basis of this association has not yet been established. We previously reported that hypercapnia inhibits expression of key NF-kappaB regulated, innate immune cytokines, TNF-alpha, and IL-6, in LPS-stimulated macrophages in vitro and in mice during Pseudomonas pneumonia. The transcription factor heat shock factor 1 (HSF1) is important in maintaining proteostasis during stress and has been shown to negatively regulate NF-kappaB activity. In this study, we tested the hypothesis that HSF1 activation in response to hypercapnia results in attenuated NF-kappaB-regulated gene expression. We found that hypercapnia induced the protein expression and nuclear accumulation of HSF1 in primary murine alveolar macrophages and in an alveolar macrophage cell line (MH S). In MH-S cells treated with short interfering RNA targeting Hsf1, LPS-induced IL-6 and TNF-alpha release were elevated during exposure to hypercapnia. Pseudomonas-infected Hsf1+/+ (wild-type) mice, maintained in a hypercapnic environment, showed lower levels of IL-6 and TNF-alpha in bronchoalveolar lavage fluid and IL-1beta in lung tissue than did infected mice maintained in room air. In contrast, infected Hsf1+/- mice exposed to either hypercapnia or room air had similarly elevated levels of those cytokines. These results suggest that hypercapnia-mediated inhibition of NF-kappaB cytokine production is dependent on HSF1 expression and/or activation.-Lu, Z., Casalino-Matsuda, S. M., Nair, A., Buchbinder, A., Budinger, G. R. S., Sporn, P. H. S., Gates, K. L. A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression. PMID- 29405098 TI - INTEGRATED CARE PATHWAYS IN LUNG CANCER: A QUALITY IMPROVEMENT PROJECT. AB - BACKGROUND: Non small cell lung cancer (NSCLC) diagnosis and treatment is a highly complex process, requiring managerial skills merged with clinical knowledge and experience. Integrated care pathways (ICPs) might be a good strategy to overview and improve patient's management. The aim of this study was to review the ICPs of NSCLC patients in a University Hospital and to identify areas of quality improvement. MATERIALS AND METHODS: The electronic medical records of 169 NSCLC patients visited at the University Hospital were retrospectively reviewed. Quality of care (QoC) has been measured trough fifteen indicators, selected according main international Guidelines and approved by the multi-disciplinary team for thoracic malignancies. Results have been compared with those of a similar retrospective study conducted at the same hospital in 2008. RESULTS: A total of 146 patients were considered eligible. Eight of fifteen indicators were not in line with the benchmarks. We compared the results obtained in the two separate periods. Moreover, we process some proposal to be discussed with the general management of the hospital, aimed to redesign NSCLC care pathways. CONCLUSIONS: ICPs confirm to be feasible and to be an effective tool in real life. The periodic measurement of QoC indicators is necessary to ensure clinical governance of patients pathways. PMID- 29405099 TI - Trypanosoma cruzi Detection in Colombian Patients with a Diagnosis of Esophageal Achalasia. AB - Achalasia is a motility disorder of the esophagus that might be secondary to a chronic Trypanosoma cruzi infection. Several studies have investigated esophageal achalasia in patients with Chagas disease (CD) in Latin America, but no related studies have been performed in Colombia. The goals of the present study were to determine the presence of anti-T. cruzi antibodies in patients with esophageal achalasia who visited a referral hospital in Bogota, Colombia, and to detect the presence of the parasite and its discrete typing units (DTUs). This cross sectional study was conducted in adult patients (18-65 years old) who were previously diagnosed with esophageal achalasia and from whom blood was drawn to assess antibodies against T. cruzi using four different serological tests. Trypanosoma cruzi DNA was detected by conventional polymerase chain reaction (cPCR) and quantitative polymerase chain reaction (qPCR). In total, 38 patients, with an average age of 46.6 years (standard deviation of +/-16.2) and comprising 16 men and 22 women, were enrolled. Five (13.15%) patients were found to be positive for anti-T. cruzi antibodies by indirect immunofluorescence assay (IFA), and two patients who were negative according to IFA were reactive by both enzyme linked immunosorbent assay and immunoblot (5.3%). Parasite DNA was detected in two of these seven patients by cPCR and in one of these by qPCR. The parasite DTU obtained was TcI. In summary, this study identified T. cruzi in Colombian patients with esophageal achalasia, indicating that digestive compromise could also be present in patients with chronic CD. PMID- 29405100 TI - The Impact of a Fogarty International Center-Supported Tuberculosis Research Training Program in the Country of Georgia. AB - In 2004, there existed limited tuberculosis (TB) research capacity in the country of Georgia. In response, a collaborative research training program (RTP) supported by a National Institutes of Health Fogarty International Center Global Infectious Diseases grant was formed between a U.S. academic institution and the National Center for Tuberculosis and Lung Disease (NCTLD) and other institutions in Georgia. We sought to assess outcomes of this RTP. The TB RTP combined didactic and mentored research training for Georgian trainees. Long-term trainees were supported for a 2-year period and with posttrainee career development mentoring. Metrics used to measure program performance included publications, grants received, and career advancement. From 2004 to 2015, 20 trainees participated in the program with 15 (75%) authoring a total of 65 publications in PubMed-listed journals. The median number of publications per trainee was six (interquartile range 2-14). A total of 16 (80%) trainees remain working in the area of TB; nine were promoted to leadership positions and three to lead research units at Georgian institutions. Ten (50%) trainees were the principal investigator (PI) of a peer-reviewed external grant after Fogarty-supported training, and 40% served as research mentors. Annual TB-related research funding at the NCTLD increased from $5,000 in 2005 to ~$1.5 million in 2017. A Georgian Fogarty trainee was either PI, site PI, or coinvestigator on > 90% of all research funding. We believe that the NIH Fogarty-funded TB research training grant has made critical contributions to increasing the TB-related research infrastructure and capacity in Georgia, particularly at the NCTLD. PMID- 29405101 TI - Island-Wide Surveillance of Gastrointestinal Protozoan Infection on Fiji by Expanding Lymphatic Filariasis Transmission Assessment Surveys as an Access Platform. AB - As part of lymphatic filariasis (LF) transmission assessment surveys (TAS) on Fiji, an island-wide assessment of gastrointestinal protozoan infection was performed by inspection of a concomitant stool sample collection to investigate the distribution of parasitic protozoa. All grade 1 and 2 students of 69 schools on the two main islands were targeted in two phases (one in the Western Division and the other in the Central and Northern Divisions, except Taveuni sub-Division of Northern), where fecal samples of 1,800 students were available for coproscopy using formalin-ether-acetate concentration. The overall prevalence of Giardia infection was 1.6%, having 2.2% in Western and 0.8% in Central/Northern Divisions (P = 0.094). The school-level prevalence of giardiasis ranged from 0% to 15.4%, and hotspot analysis using the Getis-Ord Gi* method detected spatial heterogeneity of giardiasis prevalence in schools around Lautoka (Z-score = 3.36, P value < 0.05), an area affected by Cyclone Kofi in February 2014. Any protozoan infection prevalence was 4.9% in Western and 4.4% in Central/Northern Divisions (P = 0.825). Real-time polymerase chain reaction analysis to confirm the findings from a parasitological examination of a 10% stool archive in 95% ethanol from Western Division revealed an elevated prevalence of giardiasis up to 22.4%, the presence of Entamoeba histolytica, and the absence of Cryptosporidium parvum. Obtaining stool samples alongside LF TAS is a convenient access platform for cosurveillance of gastrointestinal protozoan infection and has pinpointed hitherto unknown hotspots of giardiasis in urban city centers of Fiji. This calls for greater attention to apply tailored water, sanitation and hygiene measures for the control of these parasites. PMID- 29405102 TI - Prevalence of Chagas Disease among Solid Organ-Transplanted Patients in a Nonendemic Country. AB - Reactivation of Chagas disease in the chronic phase may occur after solid organ transplantation, which may result in high parasitemia and severe clinical manifestations such as myocarditis and meningoencephalitis. The aim of the present study is to describe the prevalence of Chagas disease among solid organ transplanted patients in a tertiary hospital from a nonendemic country. A cross sectional study was performed at Vall d'Hebron University Hospital (Barcelona, Spain) from April to September 2016. Chagas disease screening was performed through serological tests in adult patients coming from endemic areas that had received solid organ transplantation and were being controlled in our hospital during the study period. Overall, 42 patients were included, 20 (47.6%) were male and median age was 50.5 (23-73) years. Transplanted organs were as follows: 18 kidneys, 17 lungs, and 7 livers. Three patients had Chagas disease, corresponding to a prevalence among this group of solid organ-transplanted patients of 7.1%. All three patients were born in Bolivia, had been diagnosed with Chagas disease and received specific treatment before the organ transplantation. We highly recommend providing screening tests for Chagas disease in patients with or candidates for solid organ transplantation coming from endemic areas, early treatment with benznidazole, and close follow-up to prevent clinical reactivations. PMID- 29405103 TI - Case Report: A Case of Severe Cerebral Malaria Managed with Therapeutic Hypothermia and Other Modalities for Brain Edema. AB - Malarial infections are uncommon in the United States and almost all reported cases stem from recent travelers coming from endemic countries. Cerebral malaria (CM) is a severe form of the disease usually affecting children and individuals with limited immunity. Despite proper management, mortality from CM can reach up to 25%, especially when it is associated with brain edema. Inefficient management of the edema may result in brain herniation and death. Uniform guidelines for management of CM-associated brain edema are lacking. In this report, we present a case of CM with associated severe brain edema that was successfully managed using a unique combination of therapeutic hypothermia, hypertonic saline, mannitol, and hyperventilation along with the antimalarial drugs quinidine and doxycycline. Our use of hypothermia was based on its proven benefit for improving neurological outcomes in post-cardiac arrest patients and previous in vitro research, suggesting its potential inhibitory role on malaria growth. PMID- 29405104 TI - Expectoration of Cryptosporidium Parasites in Sputum of Human Immunodeficiency Virus-Positive and -Negative Adults. AB - Respiratory cryptosporidiosis is thought to be a rare, end-stage complication of HIV. Few studies have systematically examined the frequency of such infection in adults. Sputum specimens submitted for tuberculosis (TB) testing at Mulago Hospital, Uganda, were anonymously retested for Cryptosporidium using real-time polymerase chain reaction (PCR). Visual confirmation using immunofluorescence confocal microscopy was performed for a subset of PCR-positive samples. Of 824 sputum samples tested, 24 (2.9%) were Cryptosporidium positive. Prevalence in sputum ranged between 0% and 10% in each month of the study and exceeded TB prevalence in some months. In this referral population, respiratory Cryptosporidium prevalence was lower in people with HIV (1.3% versus 4.4% without HIV, P = 0.028) and higher in those with TB (6.8% versus 2.6% without TB, P = 0.086). The weak association between respiratory Cryptosporidium infection and TB persisted after controlling for HIV (odds ratio = 3.2, 95% confidence interval: 0.9, 11.8; P = 0.080). This is the first study to document adult respiratory tract cryptosporidiosis in a referral population with presumed TB. These findings 1) confirm that Cryptosporidium respiratory infection occurs in HIV-negative and positive adults; 2) suggest there is potential for Cryptosporidium to be disseminated or transmitted by coughing or expectoration; and 3) identify possible synergy between Cryptosporidium and TB in the respiratory tract. PMID- 29405105 TI - An Assessment of Household and Individual-Level Mosquito Prevention Methods during the Chikungunya Virus Outbreak in the United States Virgin Islands, 2014 2015. AB - Recent large-scale chikungunya virus (CHIKV) and Zika virus epidemics in the Americas pose a growing public health threat. Given that mosquito bite prevention and vector control are the main prevention methods available to reduce transmission of these viruses, we assessed adherence to these methods in the United States Virgin Islands (USVI). We interviewed 334 USVI residents between December 2014 and February 2015 to measure differences in mosquito prevention practices by gender, income, presence of CHIKV symptoms, and age. Only 27% (91/334) of participants reported having an air conditioner, and of the 91 with air-conditioners, 18 (20%) reported never using it. Annual household income > $50,000 was associated with owning and using an air conditioner (41%; 95% confidence interval [CI]: 28-53% compared with annual household income <= $50,000: 17%; 95% CI: 12-22%). The majority of participants reported the presence of vegetation in their yard or near their home (79%; 265) and a cistern on their property (78%; 259). Only 52 (16%) participants reported wearing mosquito repellent more than once per week. Although the majority (80%; 268) of participants reported having screens on all of their windows and doors, most (82%; 273) of those interviewed still reported seeing mosquitoes in their homes. Given the uniformly low adherence to individual- and household-level mosquito bite prevention measures in the USVI, these findings emphasize the need for improved public health messaging and investment in therapeutic and vaccine research to mitigate vector-borne disease outbreaks. PMID- 29405106 TI - A Cluster-Randomized Trial to Evaluate the Impact of an Inclusive, Community-Led Total Sanitation Intervention on Sanitation Access for People with Disabilities in Malawi. AB - Community-led total sanitation (CLTS) is a common method for promoting sanitation in low-income settings. This cluster-randomized trial evaluated an intervention to improve inclusion of people with disability in CLTS through training facilitators. A qualitative study examined intervention acceptability. The trial included 171 people with disabilities (78 control and 93 intervention) living in 15 intervention and 15 control communities. In the intervention arm, respondents were more likely to participate in a community meeting about sanitation (+18.7%, 95% confidence interval [CI]: 3.2, 34.2) and to have been visited to discuss sanitation (+19.7, 95% CI: 0.6, 37.8). More intervention households improved latrine access for the disabled member (+9%, CI: -3.1, 21.0). Inclusive CLTS could improve sanitation access for people with disability but requires support to households beyond that provided in this trial. PMID- 29405107 TI - Zika Virus Infection in Syrian Golden Hamsters and Strain 13 Guinea Pigs. AB - To evaluate potential immunocompetent small animal models of Zika virus (ZIKV) infection, we inoculated Syrian golden hamsters (subcutaneously or intraperitoneally) and strain 13 guinea pigs (intraperitoneally) with Senegalese ZIKV strain ArD 41525 or Philippines ZIKV strain CPC-0740. We did not detect viremia in hamsters inoculated subcutaneously with either virus strain, although some hamsters developed virus neutralizing antibodies. However, we detected statistically significant higher viremias (P = 0.0285) and a higher median neutralization titer (P = 0.0163) in hamsters inoculated intraperitoneally with strain ArD 41525 compared with strain CPC-0740. Furthermore, some hamsters inoculated with strain ArD 41525 displayed mild signs of disease. By contrast, strain 13 guinea pigs inoculated intraperitoneally with either strain did not have detectable viremias and less than half developed virus neutralizing antibodies. Our results support the use of the Syrian golden hamster intraperitoneal model to explore phenotypic variation between ZIKV strains. PMID- 29405108 TI - Regulatory T-Cell Dynamics in Cutaneous and Mucocutaneous Leishmaniasis due to Leishmania braziliensis. AB - To evaluate the dynamics of regulatory T cells (Tregs) during tegumentary leishmaniasis, we assessed peripheral blood and biopsies from 54 patients. Patients with cutaneous leishmaniasis (CL) had a decreased proportion of Tregs in the peripheral blood, but the proportion was higher in the biopsies of lesions. During treatment of CL, circulating Tregs increased reaching normal proportions, whereas antigen-specific interferon-gamma responses diminished. By contrast, circulating Tregs from mucosal leishmaniasis patients failed to normalize during treatment. C-C chemokine receptor type 5 was expressed on a large proportion of Tregs at the site of infection. These results demonstrate increased Tregs at the site of infection, possibly homing from the peripheral circulation. PMID- 29405109 TI - Characterizing Potential Risks of Fecal-Oral Microbial Transmission for Infants and Young Children in Rural Zambia. AB - Undernourished children in low-income contexts often suffer from environmental enteric disorder-damage to the intestines probably caused by chronic exposure to bacterial pathogens from feces. We aimed to identify strategies for reducing infants and young children's (IYC) exposure to human and animal feces in rural farming families by conducting direct observation of 30 caregiver-infant dyads for 143 hours and recording water, sanitation, and hygiene (WASH)-related behaviors to identify possible pathways of fecal-oral transmission of bacteria among IYC in rural Zambia. In addition to mouthing visibly dirty hands, toys, sibling's body parts, and food, 14 IYC actively ingested 6.1 +/- 2.5 (mean +/- standard deviation [SD]) pieces of soil and stones and one ingested animal feces 6.0 +/- 0 times in the span of 5 hours. Ninety-three percent (21 of 30) of mothers reported observing the index-child eating soil and 17% (5 of 30) of mothers reported observing the index-child eating chicken feces. Adult and child handwashing was uncommon, and even though 70% (28 of 30) of households had access to a latrine, human feces were found in 67% of homestead yards. Most animals present in the household were un-corralled, and the highest observable counts of feces came from chickens, pigs, and cattle. To protect IYC in low-income communities from the exploratory ingestion of feces and soil, Baby WASH interventions will need to interrupt fecal-oral microbial transmission vectors specific to IYC with a focus on feasibility, caregiver practices, and local perceptions of risk. PMID- 29405110 TI - Mapping Out the under-Recognized Burden of Human Infertility Linked to Schistosoma haematobium Infection. PMID- 29405111 TI - Case Report: Misleading Serological Diagnosis of Paracoccidioidomycosis in a Young Patient with the Acute Form Disease: Paracoccidioides brasiliensis or Paracoccidioides lutzii? AB - Negative results in serological routine screening of patients with microbiologically proven Paracoccidioidomycosis (PCM) are occasionally reported. Failure in detecting anti-Paracoccidioides antibodies has been ascribed to factors either related to serological techniques or to the status of the host immune reactivity. Recently, this issue has been renewed by the recognition that the Paracoccidioides genera comprises two species, lutzii and brasiliensis, which have distinct antigenic profiles and, therefore, may elicit different host antibody responses. We describe a patient with the acute form PCM due to Paracoccidioides brasiliensis with negative results on two reference centers' routine screening for P. brasiliensis antibodies, but positive results with Paracoccidioides lutzii antigens. The present case report suggests that antibodies elicited during P. brasiliensis infection recognize antigenic fractions shared by both species, highlighting the difficulties in distinguishing the two infections by means of the currently available routine serological assays. PMID- 29405112 TI - Brexit and What It Means for Global Health. PMID- 29405113 TI - Point Mutations at gyrA and gyrB Genes of Levofloxacin-Resistant Helicobacter pylori Isolates in the Esophageal Mucosa from a Venezuelan Population. AB - The treatment of Helicobacter pylori infection is complicated by antibiotic resistance. A high levofloxacin (LVX) resistance rate was previously demonstrated in H. pylori isolates from gastric mucosa (40%) and esophagus (19%) in individual hosts of a Venezuelan population. We aimed to assess the molecular mechanisms of LVX resistance and susceptibility in isolates from the gastroesophageal mucosa, by studying point mutations in the quinolone resistance-determining region of gyrA and gyrB genes. Sequencing of gyrA and gyrB genes (N = 120) helped to identify point mutations in 60 isolates (30 from antrum and 30 from esophagus) of five dyspeptic patients. Double (Asn87Thr and Asp91Asn) and single (Asn87Ile or Asn87Thr) mutations in the gyrA gene were identified in the esophageal mucosa. These mutations have been commonly found in the stomach. Occurrence of a single (Asn87Ile) mutation was associated with high resistance (minimum inhibitory concentration >= 32 MUg/mL) to LVX. Only a single (Ser479Gly) mutation was found in the gyrB gene in both mucosae. One patient presented isolates with no mutations in the two genes studied. Isolates with the same mutation pattern in individual hosts revealed identical genetic profiles for these genes, confirming that isolates identified in the esophageal mucosa come from isolates colonizing the stomach. Helicobacter pylori resistance to LVX in the esophagus is related to double- and single-point mutations in gyrA and gyrB genes, such as those found in the stomach. Levofloxacin should be applied with caution, because its antibiotic effect on H. pylori is decreasing in Latin America, perhaps owing to high prescription rates. PMID- 29405114 TI - Decreased Sensitivity of Schistosoma sp. Egg Microscopy in Women and HIV-Infected Individuals. AB - It has been postulated that impaired host immunity due to HIV infection reduces parasite egg excretion. Schistosoma/HIV interactions have also been shown to differ by sex. We hypothesized that egg excretion would vary based on both HIV status and sex. We examined data from more than 1,700 participants in eight studies conducted in northwest Tanzania between 2010 and 2016. Schistosoma infection was defined by circulating anodic antigen (CAA) serum levels >= 30 pg/mL and/or egg positivity in either stool by Kato Katz method or urine by filtration. We used multivariable analyses to determine the impact of confounding factors such as sex, age, previous praziquantel treatment, and worm burden as measured by serum CAA level, on the relationship between egg excretion and HIV status. HIV-infected individuals were significantly less likely to excrete schistosome eggs than HIV-uninfected individuals, even after controlling for worm burden and sex (OR = 0.6 [0.4, 0.9], P = 0.005). Furthermore, after controlling for worm burden and HIV status, women had lower odds of egg excretion than men (OR = 0.4 [0.3, 0.5], P < 0.001). Sensitivity of egg microscopy was lower in HIV infected women than HIV-uninfected men (41% versus 61%, P < 0.001), whereas sensitivity in women remained low in both groups (33% versus 37%, P = 0.664). Our study is the first to report that women with Schistosoma infection excrete fewer eggs than men for a given worm burden, regardless of HIV the status. These findings suggest that guidelines for use of microscopy to diagnose Schistosoma infections in HIV-infected individuals and in women merit reconsideration. PMID- 29405115 TI - Clinical Manifestations and Modes of Death among Patients with Ebola Virus Disease, Monrovia, Liberia, 2014. AB - Although the high case fatality rate (CFR) associated with Ebola virus disease (EVD) is well documented, there are limited data on the actual modes of death. We conducted a retrospective, observational cohort study among patients with laboratory-confirmed EVD. The patients were all seen at the Eternal Love Winning Africa Ebola Treatment Unit in Monrovia, Liberia, from June to August 2014. Our primary objective was to describe the modes of death of our patients and to determine predictors of mortality. Data were available for 53 patients with laboratory-confirmed EVD, with a median age of 35 years. The most frequent presenting symptoms were weakness (91%), fever (81%), and diarrhea (78%). Visible hemorrhage was noted in 25% of the cases. The CFR was 79%. Odds of death were higher in patients with diarrhea (odds ratio = 26.1, P < 0.01). All patients with hemorrhagic signs died (P < 0.01). Among the 18 fatal cases for which clinical information was available, three distinct modes of death were observed: sudden death after a moderate disease process (44%), profuse hemorrhage (33%), and encephalopathy (22%). We found that these modes of death varied by age (P = 0.04), maximum temperature (P = 0.43), heart rate on admission (P = 0.04), time to death from symptom onset (P = 0.13), and duration of hospitalization (P = 0.04). Although further study is required, our findings provide a foundation for developing treatment strategies that factor in patients with specific disease phenotypes (which often require the use of aggressive hydration). These findings provide insights into underlying pathogenic mechanisms resulting in severe EVD and suggest direction for future research and development of effective treatment options. PMID- 29405116 TI - Developmental evolution of the forebrain in cavefish, from natural variations in neuropeptides to behavior. AB - The fish Astyanax mexicanus comes in two forms: the normal surface-dwelling and the blind depigmented cave-adapted morphs. Comparing the development of their basal forebrain, we found quantitative differences in numbers of cells in specific clusters for six out of nine studied neuropeptidergic cell types. Investigating the origins of these differences, we showed that early Shh and Fgf signaling impact on the development of NPY and Hypocretin clusters, via effect on Lhx7 and Lhx9 transcription factors, respectively. Finally, we demonstrated that such neurodevelopmental evolution underlies behavioral evolution, linking a higher number of Hypocretin cells with hyperactivity in cavefish. Early embryonic modifications in signaling/patterning at neural plate stage therefore impact neuronal development and later larval behavior, bridging developmental evolution of a neuronal system and the adaptive behavior it governs. This work uncovers novel variations underlying the evolution and adaptation of cavefish to their extreme environment. PMID- 29405117 TI - Hypocretin underlies the evolution of sleep loss in the Mexican cavefish. AB - The duration of sleep varies dramatically between species, yet little is known about the genetic basis or evolutionary factors driving this variation in behavior. The Mexican cavefish, Astyanax mexicanus, exists as surface populations that inhabit rivers, and multiple cave populations with convergent evolution on sleep loss. The number of Hypocretin/Orexin (HCRT)-positive hypothalamic neurons is increased significantly in cavefish, and HCRT is upregulated at both the transcript and protein levels. Pharmacological or genetic inhibition of HCRT signaling increases sleep in cavefish, suggesting enhanced HCRT signaling underlies the evolution of sleep loss. Ablation of the lateral line or starvation, manipulations that selectively promote sleep in cavefish, inhibit hcrt expression in cavefish while having little effect on surface fish. These findings provide the first evidence of genetic and neuronal changes that contribute to the evolution of sleep loss, and support a conserved role for HCRT in sleep regulation. PMID- 29405118 TI - R-spondins can potentiate WNT signaling without LGRs. AB - The WNT signaling pathway regulates patterning and morphogenesis during development and promotes tissue renewal and regeneration in adults. The R-spondin (RSPO) family of four secreted proteins, RSPO1-4, amplifies target cell sensitivity to WNT ligands by increasing WNT receptor levels. Leucine-rich repeat containing G-protein coupled receptors (LGRs) 4-6 are considered obligate high affinity receptors for RSPOs. We discovered that RSPO2 and RSPO3, but not RSPO1 or RSPO4, can potentiate WNT/beta-catenin signaling in the absence of all three LGRs. By mapping the domains on RSPO3 that are necessary and sufficient for this activity, we show that the requirement for LGRs is dictated by the interaction between RSPOs and the ZNRF3/RNF43 E3 ubiquitin ligases and that LGR-independent signaling depends on heparan sulfate proteoglycans (HSPGs). We propose that RSPOs can potentiate WNT signals through distinct mechanisms that differ in their use of either LGRs or HSPGs, with implications for understanding their biological functions. PMID- 29405119 TI - Thalamocortical and corticothalamic pathways differentially contribute to goal directed behaviors in the rat. AB - Highly distributed neural circuits are thought to support adaptive decision making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat. Using a chemogenetic approach to inhibit projection-defined dmPFC and MD neurons during an instrumental learning task, we show that thalamocortical and corticothalamic pathways differentially support goal attributes. Both pathways participate in adaptation to the current goal value, but only thalamocortical neurons are required to integrate current causal relationships. These data indicate that antiparallel flow of information within thalamocortical circuits may convey qualitatively distinct aspects of adaptive decision-making and highlight the importance of the direction of information flow within neural circuits. PMID- 29405120 TI - Pleomorphic Multinucleated Plasma Cells Simulating Megakaryocytes in an Anaplastic Variant of Myeloma. PMID- 29405121 TI - Accuracy and precision of patient positioning for pelvic MR-only radiation therapy using digitally reconstructed radiographs. AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) has in recent years emerged as an imaging modality to drive precise contouring of targets and organs at risk in external beam radiation therapy. Moreover, recent advances in MRI enable treatment of cancer without computed tomography (CT) simulation. A commercially available MR-only solution, MRCAT, offers a single-modality approach that provides density information for dose calculation and generation of positioning reference images. We evaluated the accuracy of patient positioning based on MRCAT digitally reconstructed radiographs (DRRs) by comparing to standard CT based workflow. MATERIALS AND METHODS: Twenty consecutive prostate cancer patients being treated with external beam radiation therapy were included in the study. DRRs were generated for each patient based on the planning CT and MRCAT. The accuracy assessment was performed by manually registering the DRR images to planar kV setup images using bony landmarks. A Bayesian linear mixed effects model was used to separate systematic and random components (inter- and intra-observer variation) in the assessment. In addition, method agreement was assessed using a Bland-Altman analysis. RESULTS: The systematic difference between MRCAT and CT based patient positioning, averaged over the study population, were found to be (mean [95% CI]) -0.49 [-0.85 to -0.13] mm, 0.11 [ 0.33 to +0.57] mm and -0.05 [-0.23 to +0.36] mm in vertical, longitudinal and lateral directions, respectively. The increases in total random uncertainty were estimated to be below 0.5 mm for all directions, when using MR-only workflow instead of CT. CONCLUSIONS: The MRCAT pseudo-CT method provides clinically acceptable accuracy and precision for patient positioning for pelvic radiation therapy based on planar DRR images. Furthermore, due to the reduction of geometric uncertainty, compared to dual-modality workflow, the approach is likely to improve the total geometric accuracy of pelvic radiation therapy. PMID- 29405122 TI - Experimental validation of a deforming grid 4D dose calculation for PBS proton therapy. AB - The aim of this study was to verify the temporal accuracy of the estimated dose distribution by a 4D dose calculation (4DDC) in comparison to measurements. A single-field plan (0.6 Gy), optimised for a liver patient case (CTV volume: 403cc), was delivered to a homogeneous PMMA phantom and measured by a high resolution scintillating-CCD system at two water equivalent depths. Various motion scenarios (no motion and motions with amplitude of 10 mm and two periods: 3.7 s and 4.4 s) were simulated using a 4D Quasar phantom and logged by an optical tracking system in real-time. Three motion mitigation approaches (single delivery, 6[Formula: see text] layered and volumetric rescanning) were applied, resulting in 10 individual measurements. 4D dose distributions were retrospectively calculated in water by taking into account the delivery log files (retrospective) containing information on the actually delivered spot positions, fluences, and time stamps. Moreover, in order to evaluate the sensitivity of the 4DDC inputs, the corresponding prospective 4DDCs were performed as a comparison, using the estimated time stamps of the spot delivery and repeated periodical motion patterns. 2D gamma analyses and dose-difference-histograms were used to quantify the agreement between measurements and calculations for all pixels with [Formula: see text]5% of the maximum calculated dose. The results show that a mean gamma score of 99.2% with standard deviation 1.0% can be achieved for 3%/3 mm criteria and all scenarios can reach a score of more than 95%. The average area with more than 5% dose difference was 6.2%. Deviations due to input uncertainties were obvious for single scan deliveries but could be smeared out once rescanning was applied. Thus, the deforming grid 4DDC has been demonstrated to be able to predict the complex patterns of 4D dose distributions for PBS proton therapy with high dosimetric and geometric accuracy, and it can be used as a valid clinical tool for 4D treatment planning, motion mitigation selection, and eventually 4D optimisation applications if the correct temporal information is available. PMID- 29405123 TI - Prototype volumetric ultrasound tomography image guidance system for prone stereotactic partial breast irradiation: proof-of-concept. AB - Accurate dose delivery in stereotactic partial breast irradiation (S-PBI) is challenging because of the target position uncertainty caused by breast deformation, the target volume changes caused by lumpectomy cavity shrinkage, and the target delineation uncertainty on simulation computed tomography (CT) images caused by poor soft tissue contrast. We have developed a volumetric ultrasound tomography (UST) image guidance system for prone position S-PBI. The system is composed of a novel 3D printed rotation water tank, a patient-specific resin breast immobilization cup, and a 1D array ultrasound transducer. Coronal 2D US images were acquired in 5 degrees increments over a 360 degrees range, and planes were acquired every 2 mm in elevation. A super-compounding technique was used to reconstruct the image volume. The image quality of UST was evaluated with a BB-1 breast phantom and BioZorb surgical marker, and the results revealed that UST offered better soft tissue contrast than CT and similar image quality to MR. In the evaluated plane, the size and location of five embedded objects were measured and compared to MR, which is considered as the ground truth. Objects' diameters and the distances between objects in UST differ by approximately 1 to 2 mm from those in MR, which showed that UST offers the image quality required for S-PBI. In future work we will develop a robotic system that will be ultimately implemented in the clinic. PMID- 29405124 TI - Performance of a new accelerating-electrode-equipped fast-time-response PMT coupled with fast LGSO. AB - In this study, we measured the performance of a newly developed Hamamatsu Photonics R13478 photomultiplier tube (PMT) and compared the results with those of an existing R9800 PMT. In R13478, an accelerating electrode is placed between the focusing electrode and first dynode for time resolution improvement through reduced transit time jitter. We investigated the time resolution dependence on the supply voltage and time pickoff method for R13478 and R9800 PMTs, each coupled with a 2.9 * 2.9 * 20 mm3 fast LGSO:Ce (0.025 mol%) crystal. In addition, we measured the PMT time resolutions coupled with the crystals in edge and laid positions to determine the effects of the reduced position dependence of transit time in R13478. R13478 exhibited a better time performance than R9800 in various ways. The rise time of R13478 for our experimental setup was 1.54 ns, 100 ps shorter than that of R9800 because of the reduced transit time. Further, R13478 achieved a 169 ps single time resolution at the recommended supply voltage, while this value was 187 ps for R9800. The time resolution of R13478 was also significantly better for a low time pickoff threshold level and a high supplied voltage, which are conditions vulnerable to transit time jitter and noise, respectively. A considerable difference in time resolution was observed for the laid position (R13478: 144 ps; R9800: 167 ps), indicating that the accelerating electrode reduced spatial transit time difference. Overall, we showed the effects of the differentiated characteristics of R13478 PMT compared with R9800 and confirmed its excellent time performance. We suggest use of this device as a photodetector effective for fast timing applications such as time-of flight positron emission tomography. PMID- 29405125 TI - Phase transition studies of Na3Bi system under uniaxial strain. AB - We investigated the electronic properties and phase transitions of Na3Bi in four structural phases (space groups P63/mmc, P3(_)c1, Fm3(_)m and Cmcm) under constant-volume uniaxial strain using first-principles method. For P63/mmc and P3(_)c1-Na3Bi, an important phase transition from a topological Dirac semimetal (TDS) to a topological insulator (TI) appears under compression strain around 4.5%. The insulating gap increases with the increasing compressive strain and up to around 0.1eV at strain 10%. However, both P63/mmc and P3(_)c1-Na3Bi still keep the properties of TDS within tensile strain 0~10%, although the Dirac points move away from the ? point along ?-A in reciprocal space as tensile strain increases. The Na3Bi with space group Fm3(_)m is identified as a topological semimetal (TS) with the inverted bands between Na-3s and Bi-6p and parabolic dispersion in the vicinity of ? point. Interestingly, for Fm3(_)m-Na3Bi, both compression and tensile strain leads to a TDS which are identified by calculating surface Fermi arcs and topological invariants at time-reversal planes (kz=0 and kz=?/c) in reciprocal space. Additionally, we confirmed the high pressure phase Cmcm-Na3Bi is an ordinary insulator with a gap about 0.62eV. It is noteworthy that its gap almost keeps a constant around 0.60eV within compression strain 0~10%. In contrast, a remarkable phase transition from an insulator to a metal phase appears under tensile strain. Moreover, this phase transition is highly sensitive to tensile strain and takes place only strain 1.0%. These strain-induced electronic structures and phase transitions of Na3Bi system in various phase are important due to their possible applications under high pressure in future electronic devices. PMID- 29405126 TI - Evaluation of the UF/NCI hybrid computational phantoms for use in organ dosimetry of pediatric patients undergoing fluoroscopically guided cardiac procedures. AB - Epidemiologic data demonstrate that pediatric patients face a higher relative risk of radiation induced cancers than their adult counterparts at equivalent exposures. Infants and children with congenital heart defects are a critical patient population exposed to ionizing radiation during life-saving procedures. These patients will likely incur numerous procedures throughout their lifespan, each time increasing their cumulative radiation absorbed dose. As continued improvements in long-term prognosis of congenital heart defect patients is achieved, a better understanding of organ radiation dose following treatment becomes increasingly vital. Dosimetry of these patients can be accomplished using Monte Carlo radiation transport simulations, coupled with modern anatomical patient models. The aim of this study was to evaluate the performance of the University of Florida/National Cancer Institute (UF/NCI) pediatric hybrid computational phantom library for organ dose assessment of patients that have undergone fluoroscopically guided cardiac catheterizations. In this study, two types of simulations were modeled. A dose assessment was performed on 29 patient specific voxel phantoms (taken as representing the patient's true anatomy), height/weight-matched hybrid library phantoms, and age-matched reference phantoms. Two exposure studies were conducted for each phantom type. First, a parametric study was constructed by the attending pediatric interventional cardiologist at the University of Florida to model the range of parameters seen clinically. Second, four clinical cardiac procedures were simulated based upon internal logfiles captured by a Toshiba Infinix-i Cardiac Bi-Plane fluoroscopic unit. Performance of the phantom library was quantified by computing both the percent difference in individual organ doses, as well as the organ dose root mean square values for overall phantom assessment between the matched phantoms (UF/NCI library or reference) and the patient-specific phantoms. The UF/NCI hybrid phantoms performed at percent differences of between 15% and 30% for the parametric set of irradiation events. Among internal logfile reconstructed procedures, the UF/NCI hybrid phantoms performed with RMS organ dose values between 7% and 29%. Percent improvement in organ dosimetry via the use of hybrid library phantoms over the reference phantoms ranged from 6.6% to 93%. The use of a hybrid phantom library, Monte Carlo radiation transport methods, and clinical information on irradiation events provide a means for tracking organ dose in these radiosensitive patients undergoing fluoroscopically guided cardiac procedures. PMID- 29405127 TI - First principles study of LiAlO2: new dense monoclinic phase under high pressure. AB - In this work, we have systematically explored the crystal structures of LiAlO2 at high pressures using crystal structure prediction method in combination with the density functional theory calculations. Besides the reported alpha, beta, gamma, delta and epsilon-phases, here we propose a new monoclinic zeta-LiAlO2 (C2/m) structure, which becomes thermodynamically and dynamically stable above 27 GPa. It is found that the cation coordination number increases from 4 to 6 under compression. Consisting of the compact {LiO6} and {AlO6} octahedrons, the newly discovered zeta-phase possesses a very high density. Further electronic calculations show that LiAlO2 is still an insulator up to 60 GPa, and its bandgap increases upon compression. The present study advances our understanding on the crystal structures and high-pressure phase transitions of LiAlO2 that may trigger applications in multiple areas of industry and provoke more related basic science research. PMID- 29405128 TI - Designing polymer gels and composites that undergo bio-inspired phototactic reconfiguration and motion. AB - Inspired by the adaptive behavior of photo-responsive biological organisms, we develop analytical and computational models to design polymer gels and composites that can be dynamically reconfigured and driven to move with the application of light. We focus on gels formed from poly(N-isopropylacrylamide) and functionalized with spirobenzopyran (SP) chromophores, which become hydrophobic under blue light in acidic aqueous solution. Using our modeling approaches, we irradiate the gels through photomasks and demonstrate that the shapes of the samples can be reversibly and remotely 'remolded' by varying the apertures in the masks. By simulating the effect of repeatedly moving the light across the sample, we also show that the gel can undergo directed motion. We then examine gels that contain both SP chromophores and the ruthenium catalysts that drive the oscillatory Belousov-Zhabotinsky reaction. These dual-functionalized gels undergo spontaneous, self-sustained motion even when the lights are held stationary. We also simulate the behavior of composites formed from SP-functionalized fibers embedded in the poly(N-isopropylacrylamide) gel. With the SP-functionalization confined to the fibers, light and heat act as orthogonal stimuli and thus the composites display distinctly different modes of movement when the different cues are applied to the samples. Overall, our findings provide guidelines for using light to controllably reconfigure the shape and drive the movement of gel-based materials and thus, tailor the material to display different functionalities. PMID- 29405129 TI - Nicotinamide: Mechanism of action and indications in dermatology. PMID- 29405130 TI - Penile Mycobacterium avium complex spindle cell pseudotumor. PMID- 29405131 TI - Madelung's disease: A benign symmetric lipomatosis. PMID- 29405132 TI - Linear orofacial lichen sclerosus. PMID- 29405133 TI - Antihypertensives in dermatology Part II - Cutaneous adverse reactions to antihypertensives. AB - Antihypertensive drugs are prescribed frequently and can cause cutaneous adverse reactions. The exact incidence and frequency of these reactions are unknown. Multiple antihypertensive drug consumption has contributed to a substantial increase in the number of cutaneous adverse reactions to them. Thus, there is a need for dermatologists and physicians to be aware of the wide range of available antihypertensives and the type of reactions that can be expected. This review article focuses on the various clinical presentations that have been implicated or associated with them. The diagnosis and management have been discussed in brief. PMID- 29405134 TI - Our microbial signatures. PMID- 29405135 TI - An update on technical, interpretative and clinical relevance of antimicrobial synergy testing methodologies. AB - Testing for antimicrobial interactions has gained popularity in the last decade due to the increasing prevalence of drug-resistant organisms and limited options for the treatment of these infections. In vitro combination testing provides information, on which two or more antimicrobials can be combined for a good clinical outcome. Amongst the various in vitro methods of drug interactions, time kill assay (TKA), checkerboard (CB) assay and E-test-based methods are most commonly used. Comparative performance of these methods reveals the TKA as the most promising method to detect synergistic combinations followed by CB assay and E-test. Various combinations of antimicrobials have been tested to demonstrate synergistic activity. Promising results were obtained for the combinations of meropenem plus colistin and rifampicin plus colistin against Acinetobacter baumannii, colistin plus carbapenem and carbapenem plus fluoroquinolones against Pseudomonas aeruginosa and colistin/polymyxin B plus rifampicin/meropenem against Klebsiella pneumoniae. Antagonism was detected in only few instances. The presence of synergy or antagonism with a combination seems to correlate with minimum inhibitory concentration of the agent and molecular mechanism involved in the resistance. Further studies need to be conducted to assess the utility of in vitro testing to predict clinical outcome and direct therapy for drug-resistant organisms. PMID- 29405136 TI - Stenotrophomonas maltophilia: From trivial to grievous. AB - Stenotrophomonas maltophilia, once regarded as an organism of low virulence, has evolved as a significant opportunistic pathogen causing severe human infections in both hospital and community settings, especially amongst highly debilitated patients. Globally, S. maltophilia ranks third amongst the four most common pathogenic non-fermenting Gram-negative bacilli (NFGNBs), others being Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia cepacia complex (Bcc). The worth of accurate identification of S. maltophilia comes to the forefront as it needs to be differentiated from other NFGNBs such as Acinetobacter, P. aeruginosa and Bcc due to its inherently contrasting antibiotic susceptibility pattern. Consequently, its correct identification is essential as no single drug is amply effective against all NFGNBs, which hinders initiation of appropriate empirical treatment resulting in increased morbidity and mortality. PMID- 29405137 TI - Spectrum of infections in acute febrile illness in central India. AB - INTRODUCTION: Infectious agent when enters in the host results in febrile illness. This may lead to increase in morbidity or even mortality in undiagnosed/untreated cases. There are many aetiological agents which lead to acute febrile illness. Among these aetiological agents, important is bacterial or viral aetiology. OBJECTIVE: The objective of this study is: (i) To know the aetiological agents responsible for acute undifferentiated febrile illness (AUFI) by serological test or by bacterial culture and (ii) To know the clinical profile of AUFI. METHODOLOGY: A total of 270 patients were enroled in the study with a history of AUFI admitted in medicine and paediatric department from January 2015 to November 2016 of tertiary care hospital of central India. Blood sample was collected for blood culture, clot culture and serological tests for immunochromatographic tests (ICTs) and ICT-positive results were confirmed by respective enzyme-linked immunosorbent assay (ELISA). All negative serum samples by immunochromatography were retested for disease-specific ELISA as scrub typhus, dengue and leptospirosis. RESULTS: Out of 270 patients, 127 (47%) were of scrub typhus, 33 (12%) were malaria cases, 47 (17.40%) were dengue, 12 (4%) were enteric fever, 5 (2%) were leptospirosis, undiagnosed were 18 (6.66%) and other infections (viz viral, urinary tract infection, upper and lower respiratory tract infection and acute gastroenteritis) accounts for 28 (10.37%) cases. We have also noticed that there was co-infection of scrub typhus and dengue, leptospirosis and scrub typhus. CONCLUSION: It is important to know the cause and clinical profile of AUFIs for their proper management also it will help to prevent morbidity and mortality in AUFI cases. PMID- 29405138 TI - Correlation of in vitro sensitivity of chloroquine and other antimalarials with the partner drug resistance to Plasmodium falciparum malaria in selected sites of India. AB - BACKGROUND: Antimalarial drug resistance is a potential threat for control and elimination of malaria. To ascertain the status of antimalarial drug resistance at the study sites, correlation between in vitro drug sensitivity pattern and drug resistance molecular markers in Plasmodium falciparum malaria was undertaken. MATERIALS AND METHODS: Polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt) K76T and pfmdr1 N86Y were studied in relation to the in vitro susceptibility of P. falciparum in culture (n = 10) and field isolates (n = 40) to chloroquine (CQ), amodiaquine (AQ), quinine (QN), mefloquine (MQ) and artemisinin (ART). The prevalence of drug resistance molecular markers, pfdhfr (codon S108N, C59R, N51I, I164 L and A16V), pfdhps (codon S436F and A437G), pfATPase6 (codon D639G and E431K) and mutation in the propeller domain of pfK13 gene were also analysed. Chi-square test and parametric Pearson correlation test were performed using SPSS version 17. RESULTS: In vitro assay showed 18% resistance to CQ, 8% to AQ and 4% to QN. However, no resistance was observed towards MQ and ART. The mutations in pfcrt and pfmdr1 were statistically not significantly associated with susceptibility responses for antimalarials; however, increased IC50values of drugs were reflected as mutant and/or mixed isolates for both gene polymorphisms. CQ was found as independent predictor for other antimalarials, i.e., AQ, QN and ART, with r2 score 0.241, 0.241 and 0.091, respectively. Mutation in the pfATPase6 gene at codon E431K was observed in only one sample from Tripura which also had increased IC50value of 6.28 nM. However, moderate numbers of mutations at codon S108N, C59R and I164 L for pfdhfr gene and S436F and A437G for pfdhps gene were also observed. None of the samples showed mutation in propeller domain of pfK13 gene. CONCLUSION: The correlation between IC50and molecular markers for antimalarial drug resistance is reported for the first time through this study. A positive correlation between in vitro drug resistance with molecular markers for antimalarial drug resistance could make in vitro assay a reliable tool to predict drug efficacy which is needed for detection of emerging resistance in the country. PMID- 29405139 TI - Microbiology, clinical spectrum and outcome of peritonitis in patients undergoing peritoneal dialysis in India: Results from a multicentric, observational study. AB - BACKGROUND: Peritoneal dialysis (PD)-related peritonitis is a major risk factor for drop out of patients on continuous ambulatory PD (CAPD) and automated PD (APD). Factors affecting PD-related peritonitis and centre-specific microbiological data are lacking in India. A multicentric prospective observational study was designed to overcome the gaps in the existing data regarding causative organism and outcome. METHODOLOGY: The present study was a prospective, uncontrolled, open-label; observational study conducted in 21 centres representing all the four geographical regions (North, South, East and West) of India between April 2010 and December 2011. RESULTS: A total of 244 patients on chronic PD with peritonitis were enrolled in the study (CAPD and APD), who met the inclusion criteria, from 21 centres covering the different geographical areas of India. Amongst the 85 samples that were culture positive, 38 (44.7%) were in the monsoon season followed by 23 (27.1%) in the post-monsoon, 18 (21.2%) during winter and 11 (12.9%) during summer. Maximum culture positivity (72.7%) was observed with automated culture technique. Microorganisms could be isolated in only 85 cases (35.3%) while the remaining samples were culture negative (156/241, 64.7% of samples). Organisms isolated were Gram-negative in 47.8%, Gram-positive in 36.7%, fungal in 13.3% and Mycobacterium tuberculosis in 2.2%. CONCLUSION: This large multicentre study of peritonitis offers insights into the aetiology and outcomes of infectious complications of chronic PD in India that are germane to clinical decision-making. PMID- 29405140 TI - Pre-transplant cytomegalovirus immunoglobulin G antibody levels could prevent severe cytomegalovirus infections post-transplant in liver transplant recipients: Experience from a tertiary care liver centre. AB - BACKGROUND: Humoral immune responses in cytomegalovirus (CMV) are not studied well. Pre-transplant CMV immunoglobulin G (IgG) antibody levels (Pre-Tx IgG) could influence the occurrence of post-transplant CMV infections. OBJECTIVE: Correlation between pre-Tx IgG and post-Tx risk of acquiring CMV infection was investigated. MATERIALS AND METHODS: A total of 146 liver Tx recipients, not on CMV prophylaxis, were included. Pre-Tx IgG in donor (D) and recipient (R) were estimated and all the recipients were followed up for 1 year for CMV infections. RESULTS: D+ R+ serostatus was seen in 142 (97.3%) and D- R+ in 4 (2.7%). A total of 113 (77.4%) recipients had pre-Tx IgG of >=250 AU/ml. Overall, post-Tx CMV infections were seen in 54 (36.9%) recipients. In 32 (59.2%) patients, CMV infection was seen during the 1st month after TX. Incidences of post-Tx CMV infection in recipients with pre-Tx IgG <250 AU/mL and >=250 AU/mL were 42.4% and 34.5%, respectively (P = 0.99). Median viral load was significantly higher in patients with pre-Tx IgG <250 AU/ml: 4log10 (R: 2.8-6.6 log 10) copies/ml than those with >=250 AU/ml: 2.2 log10 (R: 1.6-3.8 log10) copies/ml, P = 0.04. There was no difference in the time of occurrence of CMV infection in both the groups. Concurrent occurrence of rejection and CMV infection was seen in significantly more patients 18/54 (32.7%) than in patients without CMV infection (12/99, 12%, P = 0.002). CONCLUSIONS: Higher pre-Tx CMV IgG levels might prevent severe CMV infections post-Tx. Recipients with low pre-Tx CMV titre might be benefitted by CMV prophylaxis or aggressive pre-emptive treatment. PMID- 29405141 TI - Incidence of ventilator-associated pneumonia and impact of multidrug-resistant infections on patient's outcome: Experience at an Apex Trauma Centre in North India. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) remains one of the most common nosocomial infections in the Intensive Care Unit. In the face of extremely high rates of antimicrobial resistance, it is essential to gauge the clinical significance of isolation of multidrug-resistant (MDR) pathogens from clinical samples. This study details the trend of VAP and the clinical significance of isolation of MDR pathogens from respiratory samples at an Indian tertiary care hospital. METHODS: The study was conducted over a 5-year period. VAP was diagnosed on the basis of centres for disease control and prevention criteria. The trend in the rates was compared with preventive measures. Phenotypic and genotypic resistance to beta-lactamases was determined using standard methods. The correlation of isolation of a multi-resistant pathogen with the clinical outcome, length of stay and cost of antimicrobial was ascertained. A clone of Acinetobacter baumannii identified through multilocus sequence typing was used to answer the question of whether resistant bugs always have a fatal outcome. RESULTS: The total ventilator days (VDs) for these patients amounted to 36,278. A total of 433 episodes of VAP occurred during the study, amounting to an overall VAP rate of 11.9/1000 VDs. There was a decline in the rates of VAP over the 5 year period, due to intensive surveillance and preventive activities. A. baumannii (54%) was the most common pathogen, followed by Pseudomonas aeruginosa (21%). A high rate of MDR was seen, with the presence of extended-spectrum beta lactamases, AmpC and carbapenemase genes. The presence of MDR was not always associated with a fatal outcome. CONCLUSIONS: Isolation of MDR pathogens from bronchoalveolar lavage does not always adversely affect the outcome of patients. It requires an interdisciplinary team of clinical microbiologists, physicians and hospital infection control nurses, to collectively manage these patients. PMID- 29405142 TI - Distribution of different genes responsible for invasive characteristics, detection of point mutations in capsular gene wchA and biofilm production among the invasive and non-invasive isolates of Streptococcus pneumoniae. AB - BACKGROUND: Streptococcus pneumoniae continues to cause morbidity and mortality across the globe, with developing countries bearing the brunt of the disease. It is mainly responsible for meningitis, pneumonia and septicaemia primarily in children, elderly and immunocompromised persons. Colonisation and persistence in the human nasopharynx occur during early childhood, and it appears to be prerequisite for invasive pneumococcal disease (IPD). Factors that help in persistent colonisation and subsequent invasion are ill understood. Several virulence factors have been incriminated for nasopharyngeal carriage (NC) as well as for the manifestation of the pathogenesis of IPD. MATERIALS AND METHODS: This study attempts to characterise the S. pneumoniae isolates through analysing the distribution of different virulence markers such as lytA, ply, pbpA, eno, psaA, amiA, ciaR and wchA among the isolates obtained from disease and NC. A total of 37 isolates which include 14 invasive and 23 non-invasive isolates were investigated by polymerase chain reaction to detect the genes. Eight representative isolates were investigated for mutations in wchA by DNA sequencing that may responsible for capsular variation. RESULTS: Ply, pbpA, amiA and eno were observed in a greater percentage of invasive isolates than non-invasive isolates though these differences are not statistically significant. Other two genes ciaH and psaA did not show any significant difference between two groups of isolates. Biofilm production was significantly higher in than non-invasive isolates when compared to invasive isolates. Sequence analysis of wchA revealed three significant point mutations or single-nucleotide polymorphisms (SNPs) among the isolates of one particular cluster (cluster III). These SNPs are responsible for a non-synonymous mutation in wchA bringing in an amino acid change in WchA protein, which is a part of the capsule of S. pneumoniae. Notably, all the three isolates present in cluster III had these SNPs and all of them were isolated from ocular infections. CONCLUSION: The results of our study implies a possible capsular variations among the isolates and this may have an impact on capsular typing. PMID- 29405143 TI - Hypertonic xylose agar medium: A novel medium for differentiation of Candida dubliniensis from Candida albicans. AB - BACKGROUND: Candida dubliniensis is a pathogenic Candida species which shares many phenotypic features with Candida albicans. These similarities have caused significant problems in the identification of C. dubliniensis in an average clinical mycology laboratory. Several phenotypic-based tests have been developed to distinguish C. albicans from C. dubliniensis but none has been demonstrated being sufficient alone for accurate differentiation of the two species. AIM: To facilitate the differentiation of these species, we evaluated the utility of a novel medium 'Hypertonic Xylose Agar Medium' (HXAM). MATERIALS AND METHODS: A total of 200 Candida spp. were tested in this study which included 186 stock strains of C. albicans and 14 strains of C. dubliniensis. Identification of all these strains was confirmed by polymerase chain reaction-restriction fragment length polymorphism using Bln I (Avr II) enzyme. All isolates were inoculated on HXAM, incubated at 28 degrees C and examined for visible growth every day up to 7 days. RESULTS: On this medium at 28 degrees C, all 186 C. albicans isolates showed visible growth at 48 h of incubation whereas none of the 14 C. dubliniensis isolates did so even on extending the incubation period up to 7 days. CONCLUSION: Hence, we propose HXAM as a sole phenotypic method for identifying C. dubliniensis from germ-tube-positive isolates or from stock collections of known C. albicans. PMID- 29405144 TI - The bioinformatics analyses reveal novel antigen epitopes in major outer membrane protein of Chlamydia trachomatis. AB - PURPOSE: The aim of this study was to predict the T-cell and B-cell epitopes in major outer membrane protein (MOMP) of Chlamydia trachomatis (CT) by using online software and also to analyse the secondary structure of MOMP through bioinformatics tools. MATERIALS AND METHODS: The predictions of secondary structure of MOMP protein were carried out using SOPMA software, and the prediction of B-cell epitopes in MOMP protein was carried out using IEDB and LEPS software, while the T-cell epitopes were predicted by the software of IEBD and SYFPEITHI. The predictions from the software were combined with MOMP protein characteristics, including surface features, hydrophilicity, flexibility, accessibility and plasticity, to analyse the common epitope areas' response by T cells and B-cells. RESULTS: In the secondary structure of CT MOMP, the alpha helices accounted for 41.62% of total amino acid, while the beta sheets and random coil accounted for 19.80% and 32.49%, respectively. Predictions combined with MOMP protein surface features, hydrophilicity, flexibility, accessibility and plasticity were further characterised, and three high-score B-cell epitope areas were found as located in 24-31, 307-311 and 318-327 amino acids of MOMP protein, respectively; in the meanwhile, three high-score T-cell epitope areas were found in 234-236, 323-329 and 338-343 amino acids of MOMP using major histocompatibility complex (MHC) class I HLA-A 0201 restrictive T-cell epitope analyser. CONCLUSION: We established the methods by using the biological information network technologies for looking the T-cell antigen epitopes and B cell antigen epitopes in MOMP of CT, and three novel T-cell epitopes as well as three novel B-cell epitopes were identified in the current study. It provides important information for further studying the antigenicity of CT MOMP protein and also provides useful information for developing highly efficient subunit vaccines for CT. PMID- 29405145 TI - Aetiological study of viruses causing acute encephalitis syndrome in North West India. AB - CONTEXT: Acute encephalitis syndrome (AES) is a serious public health problem, caused mainly by viruses. However, the profile of viruses causing AES in Rajasthan is not well characterised. AIMS: The present study was undertaken to identify the viruses causing AES and develop diagnostic algorithm so as to help in improved diagnosis, treatment, prevention and control. SETTINGS AND DESIGN: The present study is a hospital-based descriptive, observational study. Samples were processed at Grade-1 DHR/ICMR Viral Research and Diagnostic Laboratory at SMS, Jaipur. SUBJECTS AND METHODS: Cerebrospinal fluid (CSF) samples were processed for IgM antibody detection by enzyme-linked immunosorbent assay (ELISA) for mumps virus (MPV), measles virus (MV), Rubella virus (RV), Japanese encephalitis virus (JEV), West Nile virus (WNV) and Dengue virus using commercial kits. Nucleic acid was extracted from CSF using automated extraction system. Real time polymerase chain reaction was done using specific primers and probes for Herpes simplex virus (HSV), Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and enterovirus (EV). STATISTICAL ANALYSIS USED: Statistical analysis was done using ANOVA. RESULTS: Among 3088 patients, 702 (22.7%) patients were positive for one or more viruses. HSV (261;8.45%) was the most common followed by EBV (173;5.6%), VZV (97;3.1%), CMV (68;2.2%), EV (32;1.03%), MPV (27;0.9%), DV (28;0.9%), MV (19;0.6%) and RV (6;0.2%). CONCLUSIONS: AES occurred sporadically in Rajasthan, samples should be tested first for herpes group of viruses followed by EV or/and for arboviruses depending on season or measles, mumps and RVs in children. PMID- 29405146 TI - Identification of medically important Candida species by polymerase chain reaction-restriction fragment length polymorphism analysis of the rDNA ITS1 and ITS2 regions. AB - AIM: We aimed to identify the distribution of species in candidal strains isolated from clinical samples and restriction fragment length polymorphism (RFLP) method based on Msp I and Bln I restrictive enzyme cuts of polymerase chain reaction (PCR) products after the amplification of ITS1 and ITS2 regions of rDNA genotypically. MATERIALS AND METHODS: One hundred and fifty candidal strains isolated from various clinical samples were studies/ included. Phenotypic species assessment was performed using automated VITEK-2 system and kit used with the biochemical tests. Common genomic region amplification peculiar to candidal strains was carried out using ITS1 and ITS2 primer pairs. After the amplification, PCR products were cut with Msp I and Bln I restriction enzymes for species identification. RESULTS: The majority of Candida isolates were isolated from urine (78.6%) while other isolates were composed of strains isolated from swab, wound, blood and other samples by 11.3%, 3.3%, 2% and 4.7%, respectively. The result of RFLP analysis carried out with Msp I and Bln I restriction enzymes showed that candidal strains were Candida albicans by 45.3%, Candida glabrata by 19.3%, Candida tropicalis by 14.6%, Candida parapsilosis by 5.3%, Candida krusei by 5.3%, Candida lusitaniae by 0.6% and other candidal strains by 9.3%. CONCLUSION: When the ability to identify Candida to species level of phenotypic and PCR-RFLP methods was assessed, a great difference was found between these two methods. It may be argued that Msp I and Bln I restriction enzyme fragments can be used in the identification of medically important Candida species. Further studies are needed to develop this kind of restriction profile to be used in the identification of candidal strains. PMID- 29405147 TI - Profiling of Aggregatibacter actinomycetemcomitans Serotypes B and C and the genotypes in periodontal health and disease. AB - BACKGROUND: A. actinomycetemcomitans is prevalent in periodontitis but is found in some periodontally healthy individuals as well. Certain serotypes of the organism have shown to determine severity of the disease. The distribution of serotype and genotype is affected by geographic and ethnic variation. Therefore, the present study was aimed to detect serotypes b & c of A. actinomycetemcomitans and the genotypes and find its correlation with periodontal status. MATERIALS AND METHODS: A total of 75 subjects (25 aggressive periodontitis, 25 chronic periodontitis and 25 periodontally healthy) in age range of 14-55 yrs were included. Subgingival plaque samples were collected and checked for the presence of A. actinomycetemcomitans. Following isolation of the organism, detection of the serotype b or c was done by multiplex PCR. Genotyping of A. actinomycetemcomitans was done by arbitrarily primed PCR(polymerase chain reaction). RESULTS: Out of 75 plaque samples, 35(46.66%) tested positive for A. actinomycetemcomitans. Serotype c was detected in 19/35 (54.28%), whereas serotype b alone was not detected in any of the samples. Two samples were positive for both the serotypes (b and c) (5.71%) and 14 (40%) were untypeable. 14 different arbitrarily primed PCR genotypes were obtained among 35 A. actinomycetemcomitans isolates. CONCLUSION: Serotype c was predominant in periodontally diseased as well as periodontally healthy individuals. An association could be present between genotype - serotype and genotype - periodontal status. PMID- 29405148 TI - Fasciolopsiasis in children: Clinical, sociodemographic profile and outcome. AB - PURPOSE: To describe the clinical and sociodemographic profile of fasciolopsiasis in children. MATERIALS AND METHODS: A chart review of 56 children presenting with the passage of adult Fasciolopsis buski per stool from February 2015 to January 2016 was done for their clinical profile and risk factors for acquiring fasciolopsiasis in the Paediatric Unit of a medical college of Northern India. RESULTS: The mean age of presentation was 8.2 years (2-14 years age group). Persistent diarrhoea (85.71%) was the most common presentation, whereas anaemia (71.42%) was the most common sign. Protein-energy malnutrition (PEM) and tuberculosis were well-associated comorbid conditions in this study. Polyparasitism was an important finding, Hymenolepis nana being the most common associated parasite. Patients were treated either with praziquantel or nitazoxanide. CONCLUSION: All patients recovered well except one who died due to severe PEM and disseminated tuberculosis and two cases presented with relapse. Most of the cases of polyparasitism were associated with tuberculosis. PMID- 29405149 TI - Fecal carriage of carbapenem-resistant Enterobacteriaceae and risk factor analysis in hospitalised patients: A single centre study from India. AB - PURPOSE: Carbapenem-resistant Enterobacteriaceae (CRE) have emerged and disseminated widely causing a variety of infections. In India, the carriage of CRE in hospitalised patients has not been well-studied. Therefore, we conducted the present study to observe gut carriage rate of CRE in patients admitted to our tertiary care hospital. METHODS: A total of 232 faecal swabs collected from consecutive stool samples from admitted patients were inoculated on ChromID extended spectrum beta-lactamase plates and members of Enterobacteriaceae family were subjected to antibiotic susceptibility as per the Clinical Laboratory Standards Institute guidelines. Polymerase chain reaction for blaVIM, blaKPC, blaIMPand blaNDM-1 genes was performed. CRE was identified if the isolates showed resistance to either imipenem or meropenem or showed the presence of resistant genes. Risk factors of patients with or without CRE colonisation were also analysed. RESULTS: A total of 232 faecal swabs yielded 252 Enterobacteriaceae isolates, of which 49 isolates from 42 patients showed the presence of CRE (occurrence 42/232; 18.1%); 27 isolates from 22 patients carried blaNDM-1, whereas 20 isolates from 17 patients possessed blaVIMgene. No isolate was positive for blaKPCand blaIMPgenes. The CRE was common in both intensive care units (38.4%) and wards (46%) which may reflect the excessive use of broad spectrum antibiotics in both these settings. The CRE was also found to have a significantly higher antimicrobial resistance as compared to non-CRE isolates. The logistic regression analysis of significance showed the presence of any indwelling device (P = 0.049) and nasogastric tube (P = 0.043) as independent risk factors for acquiring gut colonisation. CONCLUSIONS: The study is the first from India to show high CRE carriage in patients admitted to a tertiary care centre and emphasises the need of strict antimicrobial stewardship implementation in hospitals to prevent dissemination of multidrug-resistant CRE. PMID- 29405150 TI - Seroprevalence, risk factors and genotype distribution for Hepatitis C infection: A study from rural hospital in Maharashtra. AB - BACKGROUND AND OBJECTIVES: Hepatitis C is global health problem affecting a significant portion of the world's population. Available data in Western Maharashtra on seroprevalence, risk factors and genotype distribution are very limited. OBJECTIVES: The present study was carried out to estimate the seroprevalence, factors influencing transmission and distribution of genotype of hepatitis C virus (HCV) in a hospital-based population. MATERIALS AND METHODS: This was a cross-sectional, hospital-based study. A total of 25193 serum samples were tested for HCV and HBV infection. All samples from HCV antibody-positive patients were subjected for HCV RNA detection and genotype. Chi-square, unpaired t-test, logistic regression analysis was used for statistical analysis. RESULTS: The seroprevalence for anti-HCV-Ab was 0.46%. Backward multivariate logistic regression analysis revealed increasing age; alcoholic, blood transfusion and dialysis were significant risk factors. Of 116 patients with HCV, 8 (6.89%) patients had HCV-HBV co-infection. The most common genotype (61.90%) was 3 followed by Genotype 1 (38.09%). CONCLUSIONS: In the present study, significant risk factors were a history of blood transfusion, habit of alcohol, dialysis. The prevention of HCV infection can be achieved by screening of blood and blood products and creating awareness about risk factors. Since the efficacy of current and new therapies differ by genotype, genotype study is essential. PMID- 29405151 TI - Evaluation of genotype MTBDRplus line probe assay in detection of rifampicin and isoniazid resistance in comparison to solid culture drug susceptibility testing in a tertiary care centre of western Uttar Pradesh. AB - BACKGROUND: Isoniazid (INH) and rifampicin (Rif) are the key first-line antituberculosis drugs, and resistance to these drugs i.e., multi-drug-resistant tuberculosis (MDR-TB), is likely to result in treatment failure and poor clinical outcomes. India has the highest burden of TB and MDR-TB in the world, disproportionately high even for India's population. The GenoType(r) MTBDRplus molecular method allows rapid detection of Rif and INH resistance. AIM: The present study was done to compare the performance of line probe assay test (GenoType(r) MTBDRplus) with solid culture method for an early diagnosis of MDR TB. METHODS: Totally 1503 sputum samples of MDR-TB suspects were subjected to fluorescent microscopy. Decontamination was done by N-acetyl-L-cysteine and sodium hydroxide method. Fluorescent microscopy-positive samples were subjected to GenoType(r) MTBDRplus (HAIN Lifescience) assay. Sixty-two random samples were compared with phenotypic drug susceptibility testing (DST) (1% proportion method) using solid culture method by Lowenstein-Jensen media. RESULTS: The sensitivity, specificity, positive predictive value and negative predictive value for detection of resistance to Rif were 94.74%, 95.35%, 90% and 97.62% and to INH were 92.00%, 91.89%, 88.46% and 94.44%, respectively, in comparison with the phenotypic DST. CONCLUSION: GenoType(r) MTBDRplus has good sensitivity and specificity in detecting MDR-TB cases with a significantly lesser turnaround time as compared to conventional DST method and simultaneous detection of Rif and INH resistance. This technique saves several weeks of time required for culture and DST. PMID- 29405152 TI - Genetic diversity and allelic variation in south Indian isolates of Group A streptococci causing invasive disease. AB - BACKGROUND: Reported literature on invasive group A streptococcal isolates in India is very scanty. This study was undertaken to determine the molecular heterogeneity of such isolates as seen in a tertiary care center. MATERIALS AND METHODS: Thirty two blood culture isolates and 18 from other sterile body fluids were characterized by emm gene sequencing and multilocus sequence typing. RESULTS: Forty two emm types were identified including 25 from 32 blood isolates and 17 from 18 other body fluid isolates. Types 110, 74, 63, 85, 102, 105, 124 and st854.1 were common to both groups and accounted for 40% of the isolates. Two types namely, stKNB6 and stKNB9 were newly identified types. MLST identified forty eight sequence types (MLST - ST) of which 31 were from 32 blood isolates and 17 from 18 body fluid isolates; thirty three of them were hitherto unrecognized at the time of identification. Two blood isolates of emm 85 had the same MLST - ST 484 while three blood isolates of emm 110 had three different STs namely, ST 493, 494 and 497. Two types, ST 493 and ST497 had single locus variation while ST 497 had a double locus variation. CONCLUSIONS: Our study shows that subtle allelic variations in the house keeping genes results in the development of new strains in a given emm type and contribute significantly to the existing high diversity of strains circulating in the community. PMID- 29405153 TI - Effect of Interleukin-28B polymorphism on Interleukin-28 expression and immunological recovery amongst HIV-1-infected individuals following antiretroviral therapy. AB - PURPOSE: Type III interferon is well known to have diverse antiviral and immunomodulatory activities. Studies describing the association of interleukin (IL)-28 polymorphisms in treatment-experienced HIV participants are limited. This study was aimed to determine the association of IL-28B gene polymorphisms with immunological recovery in HIV patients on 6-9 months of antiretroviral therapy (ART). METHODS: Eighty treatment-naive HIV patients were recruited, of which 48 patients were followed up after 6-9 months of ART. Whole blood samples were collected before and after 6-9 months of ART. CD4, CD8 and CD3 counts were enumerated flow cytometry. IL-28B polymorphisms (rs12979860 and rs8099917) were profiled by polymerase chain reaction (PCR)-restriction fragment length polymorphism. The IL-28 mRNA and plasma HIV-1 viral load were estimated using real-time PCR and plasma IL-28 level by ELISA. RESULTS: The CD4, CD4/CD3%, IL-28 mRNA and reversal of CD4/CD8 ratio were significantly increased following 6-9 months of ART (P < 0.01). The rs12979860 CC genotype and rs12979860:rs8099917 (CC: TT) haplotype showed significant association with higher CD4+ T-cell count amongst treatment-naive HIV-infected individuals (P < 0.05). In addition, there was a significant association of rs12979860 CC genotype with increase in CD4/CD3% following 6-9 months of ART. IL-28 mRNA showed correlation with the HIV-1 viral load, and there was a significant increase in the IL-28 mRNA expression following 6-9 months of ART. CONCLUSION: Our preliminary findings suggest that IL-28 polymorphisms could influence both immunological recovery and therapeutic response in HIV infection. Hence, functional studies are warranted to understand the mechanistic basis of IL-28-mediated host genetic influence on HIV therapeutic response. PMID- 29405154 TI - Dosing strategy based on prevailing aminoglycoside minimum inhibitory concentration in India: Evidence and issues. AB - Aminoglycosides are important agents used for treating drug-resistant infections. The current dosing regimen of aminoglycosides does not achieve sufficient serum level concentration for the infected bacterial pathogen interpreted as susceptible based on laboratory testing. Minimum inhibitory concentration was determined for nearly 2000 isolates of Enterobacteriaceae and Pseudomonas aeruginosa by broth microdilution method. Results were interpreted based on CLSI and EUCAST interpretative criteria and the inconsistencies in the susceptibility profile were noted. This study provides insights into the inconsistencies existing in the laboratory interpretation and the corresponding clinical success rates. This urges the need for revising clinical breakpoints for amikacin, to resolve under dosing leading to clinical failure. PMID- 29405155 TI - Clinically relevant yeast species identified by sequencing the internal transcribed spacer region of r-RNA gene and Vitek 2 compact (YST card) commercial identification system: Experience in a Tertiary Care Hospital in Assam, Northeast India. AB - In this retrospective study from 2012 to 2015, 333 clinical isolates of yeasts were identified using Vitek 2 Compact System YST ID card (Biomerieux, France) and internal transcribed spacer (ITS) sequencing. Eighteen species were identified by ITS sequencing. Candida albicans was the most common species (46.5%), followed by Candida tropicalis (27%). The total species supported by Vitek System was 11 (61.11%). The sensitivity of the system in identifying these 11 species was 66.66%-100%; specificity 98.37%-100%; positive predictive value 70%-100%, negative predictive value 96.05%-100%, and diagnostic accuracy 96.99%-100%. Diagnostic accuracy of ITS1 and ITS2 sequences individually was 98.49% and 100% using NCBI Genbank database. PMID- 29405156 TI - Melioidosis: Reinfection going incognito as relapse. AB - Melioidosis has recently gained importance as an emerging disease in India. Recurrent melioidosis has been reported from different parts of the world and can be due to relapse or reinfection. Distinction between relapse and reinfection is important for epidemiology, investigation and management. Here, we present the data regarding rate of recurrence and utility of multilocus sequence typing (MLST) in differentiating relapse form reinfection amongst melioidosis patients from a tertiary care hospital in South India. Amongst the 31 patients who survived and underwent follow-up, 4 (13%) presented with recurrence. Three cases (75%) were identified as reinfection and one (25%) as relapse based on MLST. Re exposure to environmental Burkholderia pseudomallei amongst patients with melioidosis in endemic areas is likely. In such a scenario, more often than not, recurrence of melioidosis can be attributed to reinfection. PMID- 29405157 TI - An improvised medium for axenic cultivation of Acanthamoeba spp. AB - Acanthamoebae can be easily grown in bacterised cultures, but their growth in axenic media is tedious and many times unsuccessful. We thus experimented with some additives in the conventional axenic medium for growth of various isolates of Acanthamoeba. Addition of Torula yeast RNA was found to significantly enhance the growth of Acanthamoebae in the axenic culture medium. PMID- 29405158 TI - Molecular identification and detection of virulent factors in Helicobacter pylori from gastric biopsy samples of patients attended at Assam Medical College and Hospital, Dibrugarh, Assam, India. AB - The present study aimed to detect the major virulence determinants of Helicobacter pylori, the gastric bacteria by polymerase chain reaction from genomic DNA of 314 gastric biopsies from dyspeptic patients in 2015-2016 through upper gastrointestinal endoscopy. In 153 cases out of 314, the high prevalence of oipA gene followed by cagA-vacA s1 m1 combined genotypes was found in mostly gastritis/duodenitis patients followed by the peptic ulcer and normal patients. Therefore, the clinical significance of the virulence markers of H. pylori associated with the severe forms of gastroduodenal diseases is still a matter of controversy since the endoscopically normal patients were found to harbour the virulent genes. PMID- 29405159 TI - Infections in live donor liver transplant recipients: A study of timeline, aetiology and antimicrobial resistance of bacterial and fungal infections from the developing world. AB - Infections are the leading cause of morbidity and mortality in liver transplant (LT) recipients. We studied timeline, spectrum of infection, system involved, and antimicrobial resistance in 64 patients undergoing live donor LT with 6-month follow-up. Of 64 patients, 38 (59.5%) patients had 103 infectious episodes, 10 patients had single infectious episode and 28 patients had two or more infectious episodes. 96 (93.2%) were bacterial and Candida infections were in 7 (6.8%). Early phase had 30 (29.1%) episodes; intermediate phase 25 (24.2%) and late phase 48 (46.6%). Mortality was 11/64 (17.1%). Knowledge of timeline, aetiological agent and antimicrobial resistance is useful to guide empirical therapy and infection prevention. PMID- 29405160 TI - Demographic profile of healthy children with nasopharyngeal colonisation of Streptococcus pneumoniae: A research paper. AB - BACKGROUND: Pneumonia is a preventable cause of mortality in children. Streptococcus pneumoniae colonising the nasopharynx of healthy children can cause invasive diseases and the serotype distribution of colonisation isolates should be an indicator of invasive disease, antibiotic resistance profiles, and potential vaccine coverage. Identifying factors influencing nasopharyngeal colonisation, the serotypes and antimicrobial resistance pattern can improve rational preventive strategies. OBJECTIVES: Identify risk factors associated with nasopharyngeal colonisation of S.pneumoniae in healthy children between 6 months to 5 years of age. Determine the serotype and antibiotic sensitivity of S. pneumoniae isolated from nasopharynx of healthy children. METHODS: This prospective observational included 500 healthy children, 6months to 5 years of age. Demographic features of the study population, the serotypes and antimicrobial sensitivity pattern of S.Pneumoniae isolated from cultures of nasopharyngeal swabs were subjected to statistical analysis. RESULTS: S. pneumoniae was isolated in 9% of 450 children. Increased nasopharyngeal carriage rate was associated with overcrowding 48.8% and poor ventilation 35.5%. 6B (n=16) was the most common serotype isolated. 69% were serogroups known to cause invasive disease All S. pneumoniae isolates were susceptible to vancomycin and linezolid. Antimicrobial susceptibility of PCV 7 serotypes were greater than non PCV 7 serotypes for almost all antimicrobials tested. Penicillin resistance was 11 % and MDR 51. PMID- 29405161 TI - Increased recognition of Chryseobacterium species as an emerging cause of nosocomial urinary tract infection following introduction of matrix-assisted laser desorption/ionisation-time of flight for bacterial identification. AB - Chryseobacterium species are rarely reported as aetiological agents of nosocomial urinary tract infection. Here, we evaluated the clinical significance of 19 isolates of Chryseobacterium species (15 Chryseobacterium indologenes and 4 Chryseobacterium gleum; identified by matrix-assisted laser desorption/ionisation time of flight [MALDI-TOF]) obtained from urine or percutaneous nephrostomy drainage of 16 patients with urological complaints. The strains possessed drug resistance to multiple antibiotics. 14 isolates showed the presence of carbapenemases. Both MALDI-TOF and repetitive sequence-based-polymerase chain reaction grouped them into three clusters (Kappa 1.000). They may colonise the urinary tract acting as a reservoir for dissemination of drug resistance within hospital environment. PMID- 29405162 TI - Diagnosis and treatment of diffusible Penicillium marneffei in human immunodeficiency virus-negative patients: A challenge for the physician. AB - Penicillium marneffei infection in human immunodeficiency virus (HIV)-negative patients is addressed far less often. In this article, a small cohort of HIV negative patients who disseminated P. marneffei infection was included. Sites of infection were found from blood culture, as subcutaneous nodules, or from lymph node biopsy. Fever, rash, swollen lymph nodes, anaemia and weight loss were common characteristics in most infected patients. The signs and symptoms are diverse and create challenges for accurate diagnosis. This paper will assist our understanding of this disease and contribute to an appropriate regime of therapy, thus improving the health of P. marneffei-positive patients. PMID- 29405163 TI - Cladophialophora bantiana brain abscess: A report of two cases treated with voriconazole. AB - Cerebral phaeohyphomycosis is an infection caused by a number of dematiaceous fungi, characterised by the presence of melanised hyphae in the invaded tissue. Cladophialophora bantiana is the most common species affecting the humans, which has a predilection for causing the central nervous system infections resulting in high mortality. We hereby report a success story of two cases of brain abscess caused by C. bantiana who were treated with surgical source reduction and voriconazole therapy. PMID- 29405164 TI - Implementation challenges in bio-medical waste management rules, 2016. PMID- 29405165 TI - The expression of the new epididymal luminal protein of PDZ domain containing 1 is decreased in asthenozoospermia. AB - Spermatozoa are not mature until they transit the epididymis where they acquire motility and the ability to fertilize an egg through sequential modifications. The epididymis has three functional regions, caput, corpus, and cauda, and the luminal proteins of the epididymis play important roles in the above modifications. However, the proteins with differential enrichment between the caput and cauda are still largely unknown. To reveal the functions of the caput and cauda during sperm maturation, luminal proteins from caput and cauda of mice were analyzed by isobaric tag for relative and absolute quantitation (iTRAQ). Overall, 128 differentially enriched proteins were found, of which 46 were caput enriched and 82 were cauda enriched. Bioinformatic analysis showed that lipid metabolism was active in the caput; while anion- and cation-binding activity and phosphorus and organophosphate metabolism were active in the cauda. A new epididymal luminal protein, the caput-enriched PDZ domain containing 1 (Pdzk1), also named Na+/H+ exchange regulatory cofactor 3 (NHERF3), which plays a critical role in cholesterol metabolism and carnitine transport, was found in the lipid metabolism. Western blotting and immunofluorescence analyses showed that Pdzk1 was expressed in the epididymis but not in the testis, and localized at the middle piece of the sperm tail. Pdzk1 protein level was also reduced in the spermatozoa in case of asthenozoospermic patients compared with that in normozoospermic men, suggesting that Pdzk1 may participate in sperm maturation regulation and may be associated with male infertility. These results may provide new insights into the mechanisms of sperm maturation and male infertility. PMID- 29405166 TI - Testosterone replacement therapy: Dilemmas and challenges in China and Asia. PMID- 29405167 TI - Current status of sperm banking for young cancer patients in Japanese nationwide survey. AB - This study aimed to ascertain the current status of Japanese sperm banking for young cancer patients. During 2015, we mailed the directors of 695 institutes where sperm cryopreservation might be performed with questionnaires requesting information on the number of patients, age, precryopreservation chemotherapy, semen analyses results and diagnoses, cryopreservation success rate, and causes of unsuccessful cryopreservation. Of these 695 institutes, 92 had cryopreserved sperm before chemotherapy within the study period. In all, 820 cancer patients (237 testicular, 383 hematological, 46 bone and soft tissue, 20 brain, and 134 other malignancy) consulted the responding institutes for sperm cryopreservation. Except for testicular tumor, the number of patients whose sperm was preserved before cancer treatment was low compared to that of young cancer patients. Approximately 20% of patients with malignancies other than testicular tumor underwent chemotherapy before cryopreservation. The success rate of cryopreservation in hematological malignancy was 82.5%, significantly lower than that of both the testicular cancer (93.6%) and other malignancy groups (95.6%) (P < 0.05). The primary reasons for preservation failure were azoospermia and poor semen quality. Patients with hematological malignancies had a higher rate of unsuccessful cryopreservation compared to those in other groups, possibly due to the large number of patients requesting sperm cryopreservation after chemotherapy induction. In Japan, information regarding sperm banking prior to cancer treatment appears to be lacking. Information regarding sperm preservation before chemotherapy should be provided to all Japanese oncologists. PMID- 29405168 TI - Penile sensory thresholds in subtypes of premature ejaculation: implications of comorbid erectile dysfunction. AB - Penile hypersensitivity plays an important role in premature ejaculation (PE), but differences in penile sensitivity among subtypes of PE are unknown. Therefore, we compared penile sensory thresholds in PE subtypes of lifelong and acquired PE, PE with and without erectile dysfunction (ED), PE with an intravaginal ejaculation latency time <=1 min and >1 min, and PE with and without orgasmic pleasure perceptual dysfunction. During August 2014 to January 2016, 136 patients with PE were included. Penile warm, cold, and vibratory thresholds were measured. Data of clinical characteristics, sexual life, Premature Ejaculation Diagnostic Tool (PEDT) score, and the 5-item version of the International Index of Erectile Function (IIEF-5) score were collected. Vibratory thresholds of the PE with ED group were higher in the right coronal sulcus (median amplitude: 4.92 vs 3.65 MU m, P = 0.02) and the right penile shaft (median amplitude: 3.87 vs 3.30 MU m, P = 0.03), while differences in penile sensory thresholds between other subtypes were not significant. The median PEDT score was lower in the PE without ED group (12 vs 14, P < 0.001). The IIEF-5 and PEDT scores were negatively correlated (r = -0.29, P < 0.001). Patients with orgasmic pleasure perceptual dysfunction had a lower median IIEF-5 score (20 vs 21, P = 0.02). Patients with PE and ED had lower penile sensitivity, and ED was associated with more severe symptoms and weaker orgasmic pleasure perception. In men with PE, management of comorbid ED is necessary. In case of side effects in erectile function, topical anesthetics should be cautiously used in men with PE and ED. PMID- 29405169 TI - An association study of the single-nucleotide polymorphism c190C>T (Arg64Cys) in the human testis-specific histone variant, H3t, of Japanese patients with Sertoli cell-only syndrome. PMID- 29405170 TI - Why is understanding the relationship of testosterone to cardiovascular risk so important? PMID- 29405171 TI - Production of germline chimeric quails following spermatogonial cell transplantation in busulfan-treated testis. PMID- 29405172 TI - Evaluation of PSA-age volume score in predicting prostate cancer in Chinese population. AB - This study was performed to evaluate prostate-specific antigen-age volume (PSA AV) scores in predicting prostate cancer (PCa) in a Chinese biopsy population. A total of 2355 men who underwent initial prostate biopsy from January 2006 to November 2015 in Huashan Hospital were recruited in the current study. The PSA-AV scores were calculated and assessed together with PSA and PSA density (PSAD) retrospectively. Among 2133 patients included in the analysis, 947 (44.4%) were diagnosed with PCa. The mean age, PSA, and positive rates of digital rectal examination result and transrectal ultrasound result were statistically higher in men diagnosed with PCa (all P < 0.05). The values of area under the receiver operating characteristic curves (AUCs) of PSAD and PSA-AV were 0.864 and 0.851, respectively, in predicting PCa in the entire population, both performed better than PSA (AUC = 0.805; P < 0.05). The superiority of PSAD and PSA-AV was more obvious in subgroup with PSA ranging from 2.0 ng ml-1 to 20.0 ng ml-1. A PSA-AV score of 400 had a sensitivity and specificity of 93.7% and 40.0%, respectively. In conclusion, the PSA-AV score performed equally with PSAD and was better than PSA in predicting PCa. This indicated that PSA-AV score could be a useful tool for predicting PCa in Chinese population. PMID- 29405173 TI - Prevalence of musculoskeletal disorders in subjects not exposed to biomechanical overload. AB - BACKGROUND: Data on the prevalence of work-related musculoskeletal disorders (WMSDs) in groups of unexposed subjects may serve for comparison in studies on risk/damage in groups of exposed subjects and for the planning of preventive interventions. OBJECTIVES: To assess the musculoskeletal health status in a group of working subjects not exposed to biomechanical overload. METHODS: Medical histories were collected by occupational health physicians as part of an active health surveillance program. An ad hoc questionnaire was administered to the subjects to detect musculoskeletal disorders. RESULTS: The sample consisted of 1023 subjects (605 females and 418 males) with a mean age of 40 years. The prevalence of acute low back pain and disc hernia was 4% and 5.6% respectively; 4.3% of subjects were affected by at least one disorder of the upper limbs while the prevalence of knee disorders was 1.7%. Standardized data proved to be in line with previous studies with the exception of a greater prevalence of shoulder disorders and disc hernia. CONCLUSIONS: WMSDs occur ubiquitously across the general working population unexposed to biomechanical overload. Such findings represent a valid reference for groups of exposed working subjects, in that any excess of such disorders/pathology may be due to specific work conditions. PMID- 29405174 TI - Global Postural Reeducation in patients with chronic nonspecific neck pain: cross over analysis of a randomized controlled trial. AB - OBJECTIVE: To compare the effects of Global Postural Reeducation (GPR) with Manual Therapy (MT) in participants with chronic nonspecific neck pain (NP). METHODS: Pre- and post-treatment analysis of cross-over data from an RCT was done. Seventy-eight subjects with chronic nonspecific NP aged 18 to 80 years completed the trial. The group who had received GPR crossed-over to MT and the previous MT group received GPR for 9 sessions once or twice a week. Measures were assessed at pre-treatment and post-treatment. Outcome measures included pain intensity [Visual Analogue Scale (VAS)], disability (Neck Disability Index), cervical Range of Motion (ROM), and kinesiophobia [Tampa Scale of Kinesiophobia (TSK)]. RESULTS: GPR targeted to crossed-over participants produced greater improvements in pain [Diff=-8.6; 95%CI=(-13.3; -3.8)], disability [Diff=-1.5; 95%CI=-2.8; -0.1], kinesiophobia [Diff=-1.8; 95%CI=(-3.2; -0.3)], and flexion/extension neck ROM [Diff=5.6; 95%CI=(1.8; 9.3)] at post-treatment compared to the MT group. When evaluating clinical improvement, by means of Minimal Clinically Important Differences, we found that GPR relevantly reduced neck disability with respect to MT [OR=2.13; 95% CI=(1.05; 4.35)], whereas the improvement of pain did not differ between groups [OR=1.84; 95%CI=0.85; 3.99)]. CONCLUSIONS: These results within the crossed-over group confirm previous findings from an RCT with the same sample. Sequence of treatment (GPR-to-MT vs MT to-GPR) does not seem to weaken the greater effects of GPR compared to MT approach for chronic NP. Our findings suggest that GPR can induce hypoalgesic effects, reduce disability and kinesiophobia, and improve flexion/extension in neck ROM. PMID- 29405175 TI - Assessment of dexterity and diagnostic accuracy of the Functional Dexterity Test in patients with carpal tunnel syndrome. AB - BACKGROUND: The diagnosis of carpal tunnel syndrome (STC) is centered on the symptoms. However, patients also show an impairment of sensorimotor functions, but the relationship between STC and manual dexterity has never been investigated. OBJECTIVES: To analyze the correlation between manual dexterity and severity of the STC. Another objective was the diagnostic accuracy of the clinical battery including provocative tests (Phalen, Tinel) and Functional Dexterity Test (FDT). METHODS: A sample of 80 subjects with suspected STC was subdivided into 4 groups based on EMG (severe/extreme-GrA, moderate-GrB, mild/minimal-GrC, negative-GrD) and evaluated in blind by Phalen, Tinel and FDT. The relationship between the FDT and the allocation of subjects was investigated by Spearman's rho, while the groups were compared with univariate ANOVA and Tukey's post hoc analysis. Diagnostic accuracy of the clinical battery was expressed by sensitivity, specificity, and likelihood ratios (LR). RESULTS: A moderate (r=0.48, p minor of 0.001) correlation was found between FDT and the 4 groups. ANOVA has returned a significant difference between GrA vs. all others and between GrB vs. GrD. The battery showed a sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) of 70%, 94%, 11.98 and 0.31 respectively. CONCLUSIONS: The results of this study supported the hypothesis that STC patients also have a dexterity impairment. The FDT was able to discriminate between three levels of severity (negative, mild to moderate, severe to extreme), maintaining a good level of diagnostic accuracy in addition to provocative tests. PMID- 29405176 TI - Gender and Country of birth inequalities in occupational diseases compensation rate in Italy: INAIL data base analysis (2010-2013). AB - BACKGROUND: In Italy and in Europe occupational diseases (OD) claims are growing among women, and international studies show women's lower compensation rate. OBJECTIVES: Analysis of occupational diseases compensation rate among "Italian" women (country of birth: Italy) and "immigrant" women (country of birth: not Italy) focusing on biomechanical overload of the upper limb, the most common OD in Italy. METHODS: INAIL (Italian National Institute for Insurance against Accidents at Work) statistical data (2010-2013) on ascertained OD in Industry Services (I-S) were analyzed by gender and country of birth with particular attention to biomechanical overload of the upper limb and to occupational diseases not included in the official OD list. RESULTS: A significantly lower compensation rate was found among women (Italy: 39% females vs 43% males; not Italy: 32.5% females vs 36% males). Women's lower success rate was also found for biomechanical overload of the upper limb (Italy: 73% females vs 76% males; not Italy: 64% females vs 70% males), including carpal tunnel syndrome (Italy: 72% females vs 74% males; not Italy: 62% females vs 64% males) and supraspinatus muscle tendinitis (Italy: 71% females vs 79% males; not Italy: 62.5% females vs 72.5% males). Women's claims were more frequent for OD not in the official list (Italy: 53% females vs 51% males; not Italy: 54% females vs 53% males) and had a lower rate of recognition and compensation (Italy: 13% females vs 19% males; not Italy 10% females vs 14% males). Since 2010 women compensation rate has shown a reduction after the initial amelioration in 2008 when biomechanical overload of the upper limb was included in the official list of OD. CONCLUSIONS: An overall lower compensation rate among "Italian" and "immigrant" women was found for biomechanical overload disorders of the upper limb and for not officially recognized occupational diseases. Good gender-oriented preventive practices should be promoted. PMID- 29405177 TI - Study of congenital malformations among the progeny of the personnel of an interforce military shooting range in Sardinia, Italy. AB - BACKGROUND: Claims of an excess of congenital malformations in a village nearby the military shooting range of Salto di Quirra (PISQ), Sardinia have attracted media attention. OBJECTIVE: To verify such reports with a retrospective study of the reproductive history of the PISQ personnel. METHODS: In 2011, we interviewed 390 soldiers employed at the PISQ shooting range (86.7% of the total workforce) about their reproductive history, including age at first conception, number of live births and spontaneous abortions, and cases of malformations among their progeny, as well as work history and lifestyle habits. We used a job-exposure matrix to assess occupational exposure to radiofrequency, extremely low frequency electromagnetic fields, solvents and nanoparticles, and whether holding an operative job in the shooting range areas. RESULTS: The rate of congenital malformations among the progeny of the study subjects was close to the expectation (20.2x10^-3 live births, 95% CI 6.3-34.0; 8 cases observed versus 8.6 expected based on the 2005 rate of the Emilia Romagna region), it was lower in the years subsequent to the onset of service at PISQ (11.0x10^-3, 95% CI 0.0 26.1; two cases observed versus 3.9 expected), and it did not vary by residence in the surrounding villages or elsewhere. None of the exposures we assessed was associated with an increase in the rate of congenital malformations. CONCLUSIONS: The limited statistical power of our study allows to exclude that a strong excess of congenital malformations occurred among the progeny of the PISQ shooting range personnel. PMID- 29405178 TI - Assessment of occupational radiation dose in interventional settings. AB - INTRODUCTION: In light of both current Italian radioprotection law and the new European Directive, radiation dose monitoring was carried out on the interventional staff, of the new Papa Giovanni XXIII Hospital in Bergamo, Italy, potentially exposed to high radiation levels. METHODS: Interventional activities were mapped and personal dose data were collected for three years using thermo luminescent dosimeters. Effective dose (ED) to whole body and equivalent dose (HT) to hands and eye lenses were estimated from Hp(10) and Hp(0.07) measurements. RESULTS: During the monitoring period, individual annual cumulative ED ranged from 0.2 to 9.3 mSv for radiologists (N=4), from 0.1 to 4.6 mSv for neuroradiologists (N=4), from 0.1 to 2.0 mSv for nurses (N=11), and from less than 0.1 to 1.2 mSv for radiographers (N=14). Individual annual HTs to hands ranged from 1.5 to 282.0 mSv for radiologists, from 0.5 to 99.7 mSv for neuroradiologists, from 1.9 to 12.8 mSv for nurses and from 0.7 to 12 mSv for radiographers. Individual annual HTs to eye lenses ranged from 1.1 to 110.9 mSv, from 0.6 to 58.3 mSv, from 0.1 to 8.6 mSv, from less than 0.1 to 11.7 mSv for radiologists, neuroradiologists, nurses and radiographers respectively. CONCLUSIONS: The doses received by medical doctors were higher than those for the other two groups. The Italian dose limits have been respected for all operator categories. The eye lens dose limit of the new European Directive (BSS 2013) was exceeded in 2013 by three medical doctors, prompting prescription of protective glasses. Since 2015 also this new limit has been observed. PMID- 29405179 TI - Dopa-Responsive Dystonia in Han Chinese Patients: One Novel Heterozygous Mutation in GTP Cyclohydrolase 1 (GCH1) and Three Known Mutations in TH. AB - BACKGROUND This study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD). MATERIAL AND METHODS Relevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted. RESULTS One novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site. CONCLUSIONS Patients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD. PMID- 29405180 TI - [On the occasion of the 200th birthday anniversary of D.E. Min]. AB - This article is dedicated to the memory of the outstanding Russian forensic doctor and literary figure professor D.E. Min on the occasion of his 200th birthday anniversary. The assignment of D.E. Min to the position of the head of Department of the State Medical Practice at the Emperor's Moscow University coincided with the large-scale judiciary reform carried out in the country at that time which envisaged, among other innovations, the practice of questioning of an expert in the court room. The new developments in the practical expert activities required the revision of the former approaches to the education and training of forensic medical experts. D.E. Min was the first to introduce the practice of public defense of expert judgements by the students of the Department as an indispensable component of their routine learning activities. He founded the museum of forensic medicine and pioneered the method for teaching the intravital forensic examination. D.E. Min initiated and supervised original research on mechanical asphyxia, forensic-medical toxicology, and traumatology. D.E. Min and his co-workers were frequently engaged by the agencies in charge of preliminary investigation to participate in forensic medical expertise associated with the inquiries into the most lurid criminal cases of those times. The scientist made the essential contribution to the development of forensic medicine in this country and the modernization of the academic process at the Department of the State Medical Practice that greatly promoted satisfaction of the basic requirements of practical forensic medical activities. PMID- 29405181 TI - [The synopsis of results of the 20 year activities of the Department of Forensic Medicine, I.M. Sechenov First Moscow State Medical University (Sechenovsky University)]. AB - The present article was designed to summarize the results of the 20 year scientific, practical, and educational activities of the Department of Forensic Medicine, I.M. Sechenov First Moscow State Medical University (Sechenovsky University). The main directions of the research work and achievements of the Department's staff are described, and the prospects for its further development are highlighted. The new approaches to and technologies for the teaching and training specialists in forensic medicine are introduced to meet the novel requirements imposed in the framework of the ongoing reform of higher medical education in accordance with the main principles of the Bologna declaration. PMID- 29405182 TI - [The characteristic features of vertebral lesions in the victims of a road traffic accident with intrusion into the passenger car compartment]. AB - The objective of the present study was to develop the diagnostic criteria for determining the positions of the participants of a road traffic accident inside the passenger car compartment based on the analysis of the characteristic features of vertebral lesions in the victims. The archival documents of forensic medical expertises were used to analyze the specific characteristics of fractured cervical vertebra in the victims of the accident inside the passenger car compartments including the drivers (n=92), the occupants of the forward (n=43) and rear (n=37) seats of the car. Localization and mechanisms behind the formation of vertebral lesions in the cervical part of the spinal column associated with the intra-compartment injury is of primary importance for the diagnostic purposes. The character of an injury to the cervical region gives evidence of the position of the driver and the occupants of the car inside the passenger compartment at the moment of the accident. Injuries to the cervical, thoracic, and/or sacral vertebrae may be indicative of the seat (either driver's, forward or rear) occupied by the victim(s). The fractures of the sacral part of the vertebral column are of negligible value for the differential diagnostics between the positions of the driver and/or other victims because they equally frequently occur in the drivers and occupants of both the forward and rear seats. Nevertheless, the proposed criteria made it possible to construct the mathematical model in the form of the logistic regression equations and to use them for making the probabilistic predictions as regards the positions of the participants of a road traffic accident inside the passenger car compartment based on the selected combination of pathomorphological characteristics in the victims. PMID- 29405183 TI - [The forensic medical evaluation of the injuries inflicted inside the passenger compartment of a moving car equipped with the modern personal safety systems]. AB - The objective of the present study was to elucidate the characteristic features of the injuries inflicted to the victims of a road traffic accident inside the passenger compartment of a moving car equipped with the modern personal safety systems. The materials available for the present work included the lesions documented in 210 drivers and 150 occupants of the car passenger compartments. Both comparative, morphometric and statistical methods were used to analyze the data obtained. The morphometric analysis included identification of the form of the injury, such as extravasation, wounds, fractures, and lesions of the internal organs (e.g. hemorrhages, ruptures, etc.), their number and localization. Special attention was given to the specific features of the injuries to the occupants of the cars equipped with the modern personal safety systems. The study has demonstrated that the form, frequency, and localization of the injuries inflicted to the victims of a road traffic accident inside the passenger car compartment (including the drivers and other occupants) can be used for determining the positions of the victims at the moment of the accident. PMID- 29405184 TI - [Forensic medical determination of the age based on the analysis of CT-scanograms of the skull and the craniovertebral region in the sagittal projection]. AB - The objective of the present study was to determine the biological age of the unrecognized individuals based on the analysis of CT-scanograms of the skull and the craniovertebral region in the sagittal projection. We investigated the structure of the spongy substance of the clinoid plate of the sella turcica and the clivus of the cranium, involution of the vertebrae configuration in the medial atlantoaxial articulation, frontal and sphenoidal sinuses. A total of 80 skulls of Caucasoid individuals at the age ranging from 4 to 84 years belonging to an Eastern Slavonic population (free from the pathological lesions in the above cranial structures) were available for the examination. The results of the multifactorial analysis gave evidence of the possibility to estimate the age of individual subjects based on the comprehensive aggregate qualitative and quantitative characteristic in the framework of the linear regression model by making use of the age-related changes in the frontal and sphenoidal sinuses, the sella turcica and the clivus of the cranium, the first and the second cervical vertebrae with an accuracy to within 6 years. It is concluded that the application of the systems for the automated statistical analysis of the images for the purposes of forensic medical expertise would allow to obtain the results of great practical and scientific value. PMID- 29405185 TI - [The peculiar morphological features of the surface relief of the major local ruptures of the liver in the case of a blunt injury]. AB - The objective of the present study was the comprehensive investigation of morphogenesis of the surface relief of the major local ruptures of the liver in the case of a blunt injury and the obtaining of an additional information on the possibility to use these data for the purposes of forensic medical expertise. We explored the reliefs of the major local ruptures of the liver in the cases of a single fatal blunt injury inflicted in a traffic accident, by kicking or a powerful stroke with the fist. In addition, the threshold hepatic lesions depending on their severity were determined experimentally. The model allowing to describe the qualitative relief alterations of the rupture surface associated with a blunt injury has been developed. The main elements of the surface relief of the major ruptures include avulsion and shear ridges, folds as well as 'extension zones'. Three types of possible rupture surface reliefs have been identified, viz. relatively uniform, stratified and fragmented non-uniform ones. Such reliefs are formed in the case of a threshold injury, powerful stroke with the leg or the fist, and road traffic accident, respectively. The location of the shear ridges at the ruptured surface makes it possible to determine the direction of growth of the local major rupture and of the stroke vector. The presence of multiple 'extension zones' at the surface of the local major rupture may serve as an indicator either of the influence of the unlimited traumatic surface or of the very strong stroke. The above features of the relief of the rupture surface provide the conditions for the application of the statistical approach to the elucidation of the mechanisms underlying the deformation and the destruction of the parenchymatous organs suffering a blunt injury. PMID- 29405187 TI - [The peculiar morphological features of the imprints of straight and wavy head hair dirtied with blood]. AB - The objective of the present study was to elucidate the specific morphological features of the imprints of blood-soaked straight and wavy head hair. The contact imprints of straight and wavy head hair dirtied with blood were obtained experimentally. The imprints of straight hair were shown to exhibit the elements in the form of the rectilinear and bow-shaped slightly bent stripes. The imprints of wavy hair were shaped as the arches, waves, circles, and a large number of various small elements, such as dashes and commas. PMID- 29405186 TI - [The forensic medical characteristic of the age based on the results of the comprehensive examination of the thyroid cartilage]. AB - The objective of the present study was the development of the diagnostic model for determining the human age based on the results of the comprehensive examination of the 230 thyroid cartilages (TC) obtained from the corpses of men and women of different age. TC were examined with the use of the anthropometric, X-ray, and histological methods. The anthropometric investigations confirmed the gender-related differences in the structure of human TC. Various characteristics of TC were shown to correlate with the age but these relationships were rather weak even if formally significant. The X-ray studies of TC have revealed the significant correlation of the relative amount of the bone tissue on the images with the age (r=0.8). Of the 27 parameters subjected to the morphometric evaluation, the following ones were shown to significantly correlates with the age: percentage of the bony (r=0,82) and cartilaginous (r=-0.8) tissue areas, average density of the adipose (r=0.76) and reticular (r=0.7) tissues, the maximum length of trabeculae (r=0.67), the width of the mature cartilage zone (r=0.54), the cortical plate thickness (r=0.5), and the mean number of immature chondrocytes in the field of vision (r=0.5). The comprehensive investigation into the structure of the human thyroid cartilage provided a basis for the development of the method for determining the human age with the use of the linear regression equations. It is concluded that the proposed method can be employed as an additional diagnostic tool for determining the human age for the purposes of forensic medical expertise and personality identification. PMID- 29405188 TI - [The peculiar morphological features of the blood stains on the snow over of different density]. AB - The objective of the present study was to elucidate the peculiar morphological features of the blood stains on the snow over of different density. We have undertaken the modeling and investigation of the blood stains on the loose snow cover (rho=0.35+/-0.03 g/cm3) and at the areas of snow compacted by a motor vehicle wheel (rho=0.96+/-0.03 g/cm3) with the use of the visual, metric, descriptive, and statistical methods. The analysis of the blood stain patterns on the loose snow showed that a blood drop tends to form a depressed cylindrical canal at the bottom of which an irregularly shaped spherical element can be seen; it is composed of small snow crystals soaked with blood. The upper end of the canal has the fine-scalloped edge tending to shed unevenly. The morphological picture of the blood stains at the compacted snow cover is similar to that on the hard wettable rough surfaces; they have the oval shape and the unevenly serrated edge with the well apparent signs of sputtering.at the periphery. PMID- 29405189 TI - [The construction of the three-dimensional model of the damaged bone tissue based on its roentgenogram]. AB - The objective of the present work was to develop the method for the visualization of the shape of the bone surface in the region of its traumatic damage based on the results of the analysis of a single X-ray image for the solution of the problems facing forensic medical expertise and traumatology. The three dimensional models of the fractures of the long tubular bones constructed with the use of the visualization technique were shown to adequately reproduce the morphological picture of the injury. It allowed to enhance the potential of the forensic medical analysis and the accuracy of the diagnostic methods employed for the purposes of forensic medical expertise. PMID- 29405190 TI - [The characteristic of protein biosynthesis in brain neurons with chronic alcohol intoxication]. AB - The objective of the present study was to evaluate the possibilities for the use of the changes in the AgNOR staining patterns in the neurons of the dorsal raphe nucleus (DRN) for the purposes of the medical differential diagnostics of the cases of death from chronic alcohol intoxication. We elucidated the characteristics of the activity of protein biosynthesis including the number and the area of the nucleoli in the nuclei of the neurons of the individuals who had died from chronic alcohol intoxication (n=20) in comparison with the subjects of the control group (n=13). To reveal the morphological structures associated with protein biosynthesis in the nucleoli of the serotoninergic neurons of the dorsal raphe nucleus in the brain, the histological preparations were stained with the use of the silver-staining technique for nucleolar organizer regions (AgNOR). The comparative statistical analysis of the results thus obtained with the calculated confidence coefficients was carried out. The aggregated analysis of all the dorsal raphe subnuclei revealed the impairment of the AgNOR staining characteristics in the neurons of the subjects who had died from chronic alcohol intoxication in comparison with those of the subjects comprising the control group. It is concluded that the results of the study can be used for differential diagnostics of deaths from chronic alcohol intoxication and other causes. PMID- 29405191 TI - [Visualization of the reconstruction of a criminal event by means of 3D modeling]. AB - Forensic medical expertise carried out with a view to reconstruction of an event is a time-consuming procedure because it requires collection of a large amounts of various materials for the institution of a criminal investigation including physical evidence, photoboards of the site of an occurrence, etc. A forensic medical expert may encounter difficulties when reconstructing and scrutinizing the scene of action at a single computer monitor in order to analyze the behaviour of each participant of the event. Of great help in such situations are modern software programs allowing to visualize the site of an occurrence with a maximum approximation to reality, simulate the actions of the victim(s) and alleged offender(s), perform a large number of other forensic studies. The present article provides the practical examples illustrating the possibilities of reconstruction of various events with the use of the three-dimensional modeling based on the MicroSmith Poser and Agisoft PhotoScan software packages for clarifying various circumstances, facts, and conditions of special interest for the preliminary investigation and inquiries. PMID- 29405192 TI - [Changes in the brain vascular bed associated with sudden death of young subjects]. AB - This article presents an overview of the literature publications concerning pathological changes in the cerebral blood vessels and the factors underlying the development of hemorrhagic complications leading to sudden death of young people. The special emphasis is placed on the most important causes behind the changes in the vascular wall (including the congenital ones) responsible for the high risk of rupture of the intracerebral vessels associated with the development of hemorrhagic complications. PMID- 29405193 TI - [The forensic medical characteristic of sudden death associated with metabolic syndrome]. AB - The detection of grade II-III central obesity on a corpse in conjunction with the identification of two additional criteria (such as arterial hypertension and impaired glucose tolerance) provides, if combined with the autopsy data (including the visual reduction of muscular mass, the increased total amount of the adipose tissue, gynecomastia in men together with hypertrophied abdominal adipose tissue accumulation, decreased face and body pilosis), a basis for diagnostics of metabolic syndrome (MS). The objective parameters for this purpose are waist circumference measurements, corpse weight and height, the degree of visceral obesity, narrowing of the renal arteries as a result of their compression by the surrounding adipose tissue, and accumulation of epicardial fat confirmed by the results of the biochemical analysis. The signs of plasmorrhagia combined with fibrinoid degeneration of the vascular walls in the microcirculatory bed make it possible to suspect, with a high degree of probability, the development of hypertensive crisis that may result in a sudden death of the patients presenting with metabolic syndrome. PMID- 29405194 TI - [The significance of student competitions for the development of motivation for education and the acquisition of professional competences in the students the Department of Forensic Medical Expertise of the Sechenovsky University]. AB - Russia joined the Bologna process in 2003 and since that time has become integrated into the unified European educational space. The key element of the new form of the higher education process is the self-guided unsupervised work of the students. Motivation is needed to promote the involvement of the students in the educational process which implies the necessity of the goal-oriented initiative for the acquisition of professional knowledge and practical experience in the field of forensic medicine. To achieve this goal, the Department of Forensic Medicine of I.M. Sechenov First Moscow State Medical University places special emphasis on the experience with carrying out student competitions. Each such competition consists of several contests focused on the solution of a specific problem, e.g. the inspection of the place of occurrence under investigation with a gunshot or punctured-and-incised wound, forensic medical autopsy, problem studies, and intelligence tests. All the contests and problem studies are held in the form of an interactive game. The experience gained in the course of the student competitions gives practical evidence that the interdepartmental intelligence contests contribute to raising the interest of students in forensic medicine. The open competition provides a highly efficient tool for the popularization of scientific knowledge and the promotion of interest in the participation in the forensic medical research activities. Moreover, the student competitions facilitate formation of the earlier professional skills indispensable for team working and the development of abilities for making decisions under the extreme conditions. In addition, the contests teach the participants the art of public appearance. They improve the quality of vocational training in forensic medicine and help to establish the first professional contacts at the interinstitutional (including international) level. PMID- 29405195 TI - Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. AB - This corrects the article DOI: 10.1038/ncomms15132. PMID- 29405196 TI - Haematological cancer: Dasatinib regulates immune cell function. PMID- 29405198 TI - Haematological cancer: Blinatumomab facilitates complete responses. PMID- 29405197 TI - Bridging the gap: are animal models consistent with clinical cancer cachexia? PMID- 29405199 TI - Melanoma: Neo/adjuvant BRAF/MEKi improves outcomes. PMID- 29405200 TI - Immunotherapy: Local chemotherapy synergizes with CTLA-4 inhibition. PMID- 29405202 TI - Breast cancer: Recurrent fusions in endocrine-resistant disease. PMID- 29405203 TI - Diagnosis: CancerSEEK and destroy - a blood test for early cancer detection. PMID- 29405205 TI - Bladder cancer: Improving NMIBC risk stratification. PMID- 29405204 TI - Labiaplasty: motivation, techniques, and ethics. AB - Labiaplasty (also known as labia minora reduction) is attracting increasing attention in the media and in online forums. Controversy exists among health-care professionals on how to manage a request for this surgery. Furthermore, the indications for and outcomes of labiaplasty have not yet been systematically assessed, and long-term outcomes have not yet been reported. Labia minora hypertrophy is defined as enlargement of the labia minora; however, the natural variation of labia minora size has scarcely been studied, with only one study suggesting objective criteria. Perception of the 'normal' appearance of labia minora is influenced by culture, exposure to idealized photographs in media, health-care professionals' opinions, and family, friends, and sexual partners (although this influence has not been substantiated by research). The desire for labiaplasty is predominantly based on dissatisfaction with genital appearance and not on functional complaints. Most health-care professionals believe that women seeking labiaplasty should be referred to a psychiatrist or psychologist for consultation before surgery, although whether counselling and education are effective at alleviating dissatisfaction or a low genital self-esteem is not clear. As the nature of patient motivation for this type of surgery is often psychological, counselling and education could be useful in reducing the demand for labiaplasty. However, current studies on surgical technique and outcomes include few patients, therefore, evidence on the results of different labiaplasty techniques and patient satisfaction is inconclusive. Further research is required to assess the value of this treatment and the appropriate indications for it. Improved understanding as to why women seek this treatment is needed and whether conservative treatments (such as counselling) are effective. Furthermore, systematic assessment of the surgical and patient-reported outcomes of labiaplasty is needed to assess whether it is safe and effective. Moreover, understanding the effect of cultural trends, for example, the way in which many women in Western society see any exception to the ideal body as a problem, will be insightful. PMID- 29405201 TI - Targeting the IL-6/JAK/STAT3 signalling axis in cancer. AB - The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors. PMID- 29405207 TI - High-pressure and temperature dependence of the spontaneous resolution of 1,1' binaphthyl enantiomers. AB - High pressure increases the temperature of the spontaneous resolution of 1,1' binaphthyl conformational enantiomers in the crystalline state, which confirms that the enantiomers and racemates are stabilized in the molecular environments in compressed structures. The established pressure-temperature (p-T) preference diagram for the racemate-enantiomer spontaneous crystallization corresponds to a boundary between solid phases, as it is consistent with the Clausius-Clapeyron equation, however, the hysteresis of such a solid-state transformation extends to very high pressure, to 3 GPa, at least according to this study. High-pressure X ray diffraction study on single crystals of 1,1'-binaphthyl racemate and enantiomer reveals their monotonic compression and structural changes up to 3 GPa. It also reveals the increasing role of intermolecular interactions for stabilizing the structures, despite the exceptionally large density difference between the racemate (1.277 g cm-1) and enantiomers (1.183 g cm-1). PMID- 29405206 TI - The potential of 3D printing in urological research and patient care. AB - 3D printing is an evolving technology that enables the creation of unique organic and inorganic structures with high precision. In urology, the technology has demonstrated potential uses in both patient and clinician education as well as in clinical practice. The four major techniques used for 3D printing are inkjet printing, extrusion printing, laser sintering, and stereolithography. Each of these techniques can be applied to the production of models for education and surgical planning, prosthetic construction, and tissue bioengineering. Bioengineering is potentially the most important application of 3D printing, as the ability to produce functional organic constructs might, in the future, enable urologists to replicate and replace abnormal tissues with neo-organs, improving patient survival and quality of life. PMID- 29405208 TI - Supramolecular protein cages constructed from a crystalline protein matrix. AB - Protein crystals are formed via ordered arrangements of proteins, which assemble to form supramolecular structures. Here, we show a method for the assembly of supramolecular protein cages within a crystalline environment. The cages are stabilized by covalent cross-linking allowing their release via dissolution of the crystal. The high stability of the desiccated protein crystals allows cages to be constructed. PMID- 29405209 TI - Simple preparation of magnetic field-responsive structural colored Janus particles. AB - We established a simple method for preparing Janus particles displaying different structural colors using submicron-sized fine silica particles and magnetic nanoparticles composed of Fe3O4. A w/o emulsion is prepared by vortex-stirring a mixed aqueous solution of suspended fine silica particles and magnetic nanoparticles and of hexadecane containing an emulsifier. Subsequent drying of the emulsion on a hot plate using a magnetic stirrer provides a polydisperse particle aggregate displaying two different structural colors according to the ratio of the amount of fine silica particles to the amount of magnetic nanoparticles. This polydisperse particle aggregate can be converted into monodisperse particles simply by using a sieve made of stainless steel. In the presence of a magnet, the monodisperse Janus particles can change their orientation and can switch between two different structural colors. PMID- 29405210 TI - Synergism of fictitious forces on nickel cobaltite nanofibers: electrospinning forces revisited. AB - Randomly oriented nanofibers of nickel cobaltite (NCO) were fabricated using sol gel electrospinning followed by calcination. The precursor fibers were collected on rotating disc (RDI) and rotating drum (RDR) collectors. Variable fictitious forces produce continuous deflection at each fiber landing position on the RDI collector, which subjects the nanofibers to non-bundling. On the other hand, in the case of the RDR collector, the fictitious forces act just at the surface, and these forces merely cause slip of the fibers along the rotational axis of the RDR. This slip along with the retained Columbic charges on the surface of the fibers produces fiber bundling, which affects the morphological and structural properties of the NCO nanofibers obtained by calcining the precursor fibers. The use of the RDI collector in sol-gel electrospinning is a simple and optimal method of fabricating precursor nanofibers, which yields non-agglomerated and impurity-free inorganic nanofibers. PMID- 29405211 TI - Stimuli-responsive protection of optically excited triplet ensembles against deactivation by molecular oxygen. AB - Herein we demonstrate temperature-dependent sacrificial singlet oxygen scavenging properties of N-butyl-2-pyridone, ensuring efficient stimuli-responsive protection of densely populated excited triplet state ensembles against deactivation by molecular oxygen. As an acting external stimulus the temperature was chosen: it will be shown that at low temperature the concentration of singlet oxygen will be substantially lowered; in contrast, at elevated temperatures singlet oxygen will not be captured, and thus the optically excited densely populated triplet ensembles will be effectively depopulated. The singlet oxygen scavenging ability of N-butyl-2-pyridone demonstrates long-term protection of a triplet-triplet annihilation upconversion process against photooxidation. PMID- 29405212 TI - Revisiting absorption and electronic circular dichroism spectra of cholesterol in solution: a joint experimental and theoretical study. AB - Cholesterol is doubtless one of the most studied bio-molecules, which unfortunately features low emitting properties, precluding its in vivo study by fluorescence experiments. The design of fluorescent analogues of cholesterol is thus an appealing challenge in biochemistry, which simultaneously requires minor changes in its chemical structure (to retain main biological properties) and considerable enhancement of light emission. To this aim, the photochemical behaviour of the native molecule has to be deeply understood. In this work, we focused our attention on the electronic absorption of cholesterol in several common organic solutions, combining experimental (through ultraviolet-visible and electronic circular dichroism spectroscopy) and theoretical approaches (at the time-dependent density functional theory level) in order to solve the important discrepancies previously reported in the literature on the maximum absorption wavelengths and on the nature (Rydberg and/or pi -> pi*) of the associated electronic transition. PMID- 29405213 TI - Highly sensitive colorimetric detection of allergies based on an immunoassay using peroxidase-mimicking nanozymes. AB - Nanomaterials that exhibit enzyme-like characteristics, which are called nanozymes, have recently attracted significant attention due to their potential to overcome the intrinsic limitations of natural enzymes, such as low stability and relatively high cost for preparation and purification. In this study, we report a highly efficient colorimetric allergy detection system based on an immunoassay utilizing the peroxidase-mimicking activity of hierarchically structured platinum nanoparticles (H-Pt NPs). The H-Pt NPs had a diameter of 30 nm, and were synthesized by a seed-mediated growth method, which led to a significant amount of peroxidase-like activity. This activity mainly occurs because of the high catalytic power of the Pt element, and the fact that the H-Pt NPs have a large surface area available for catalytic events. The H-Pt NPs were conjugated to an antibody for the detection of immunoglobulin E (IgE) in the analytes; IgE is a representative marker for the diagnosis of allergies. They were then successfully integrated into a conventionally used allergy diagnostic test, the ImmunoCAP diagnostic test, as a replacement for natural signaling enzymes. Using this strategy, total and specific IgE levels were detected within 5 min at room temperature, with high specificity and sensitivity. The practical utility of the immunoassay was also successfully verified by correctly determining the levels of both total and specific IgE in real human serum samples with high precision and reproducibility. The present H-Pt NP-based immunoassay system would serve as a platform for rapid, robust, and convenient analysis of IgE, and can be extended to the construction of diagnostic systems for a variety of clinically important target molecules. PMID- 29405214 TI - Liquid crystals of hard rectangles on flat and cylindrical manifolds. AB - Using the classical density functional theory of freezing and Monte Carlo computer simulations, we explore the liquid-crystalline phase behavior of hard rectangles on flat and cylindrical manifolds. Moreover, we study the effect of a static external field which couples to the rectangles' orientations, aligning them towards a preferred direction. In the flat and field-free case, the bulk phase diagram involves stable isotropic, nematic, tetratic, and smectic phases depending on the aspect ratio and number density of the particles. The external field shifts the transition curves significantly and generates a binematic phase at the expense of the tetratic phase. On a cylindrical manifold, we observe tilted smectic-like order, as obtained by wrapping a smectic layer around a cylinder. We find in general good agreement between our density functional calculations and particle-resolved computer simulations and mention possible setups to verify our predictions in experiments. PMID- 29405215 TI - Candida albicans zincophore and zinc transporter interactions with Zn(ii) and Ni(ii). AB - The interaction between the Pra1 zincophore and the Zrt1 zinc(ii) transporter is crucial for adequate Zn(ii) acquisition in Candida albicans, the most common cause of fungal infections in humans. Pointing out the precise Zn(ii) binding site on Zrt1 and describing the thermodynamics of such binding are important steps, which allow one to understand the interactions between Pra1, Zn(ii) and Zrt1. Zrt1 coordinates Zn(ii) via the side chains of 156His, 161His, 162Cys and 168His, and this binding is stronger than the binding of Zn(ii) to Pra1, allowing efficient zinc transfer from the zincophore to the zinc transporter. Additional analysis of Pra1 and Zrt1 complexes with Ni(ii), another metal ion necessary for fungal survival, shows the specificity of the studied system - Ni(ii) does not interfere with the Zn(ii) binding to Pra1, though it might form a comparably stable complex with Zrt1. PMID- 29405216 TI - Exploring the optical properties of Vernier phase yttrium oxyfluoride thin films grown by pulsed liquid injection MOCVD. AB - In this work, we report on the first successful deposition of Vernier phase yttrium oxyfluoride (V-YOF) thin films on Si (100) wafers using pulsed liquid injection metal organic chemical vapor deposition (PLI-MOCVD). The formation of V YOF has been confirmed by X-ray diffraction measurements and electron probe microanalysis. The infrared phonon modes of V-YOF thin films and their corresponding optical constants as inferred from spectroscopic ellipsometry are reported here for the first time. The V-YOF thin films are featured by a broad absorption band centering around 370-373 cm-1; their refractive index is located between those of YF3 and Y2O3, and which shows an intimate relationship with the oxygen content in the film. The luminescence properties of Er3+ doped V-YOF thin films are finally examined and compared with that of YF3. Our results highlight that the as-deposited V-YOF thin films by PLI-MOCVD serve as promising candidates as efficient host material for spectral conversion for photovoltaic applications. PMID- 29405221 TI - Cylindrical micelles of a POSS amphiphilic dendrimer as nano-reactors for polymerization. AB - A low generation amphiphilic dendrimer, POSS-AD, which has a POSS core and eight amphiphilic arms, was synthesized and used as a nano-reactor to produce well defined polymer nano-cylinders. Confirmed by small-angle X-ray scattering (SAXS), Raman and NMR spectrometry, monodispersed cylindrical micelles that contain a hydrophilic cavity with a diameter of 2.09 nm and a length of 4.26 nm were produced via co-assembling POSS-AD with hydrophilic liquids, such as H2O and HEMA in hydrophobic solvents. Taking the HEMA/POSS-AD cylindrical micelles as nano reactors, polymerization of HEMA within the micelles results in polymer nano cylinders (POSS-ADNPs) with a diameter of 2.24 nm and a length of 5.02 nm. The study confirmed that despite the inability to maintain specific shape in solution, low generation dendrimers form well-defined nano-containers or nano reactors, which relies on co-assembling with hydrophilic guest molecules. These nano-reactors are robust enough to maintain their shape during the polymerization of the guest molecules. Polymer nano-cylinders with dimensions less than 10 nm can thus be produced from the HEMA/POSS-AD micelles. Since the chemical structure of low-generation dendrimers and the contents of the co-assembled nano-reactors can be easily adjusted, the concept holds the potential for the further developments of low-generation amphiphilic dendrimers. PMID- 29405222 TI - Formation of UV-induced DNA damage contributing to skin cancer development. AB - UV-induced DNA damage plays a key role in the initiation phase of skin cancer. When left unrepaired or when damaged cells are not eliminated by apoptosis, DNA lesions express their mutagneic properties, leading to the activation of proto oncogene or the inactivation of tumor suppression genes. The chemical nature and the amount of DNA damage strongly depend on the wavelength of the incident photons. The most energetic part of the solar spectrum at the Earth's surface (UVB, 280-320 nm) leads to the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (64PPs). Less energetic but 20 times more intense UVA (320-400 nm) also induces the formation of CPDs together with a wide variety of oxidatively generated lesions such as single strand breaks and oxidized bases. Among those, 8-oxo-7,8-dihydroguanine (8-oxoGua) is the most frequent since it can be produced by several mechanisms. Data available on the respective yield of DNA photoproducts in cells and skin show that exposure to sunlight mostly induces pyrimidine dimers, which explains the mutational signature found in skin tumors, with lower amounts of 8-oxoGua and strand breaks. The present review aims at describing the basic photochemistry of DNA and discussing the quantitative formation of the different UV-induced DNA lesions reported in the literature. Additional information on mutagenesis, repair and photoprotection is briefly provided. PMID- 29405224 TI - Oversimplification of Dementia Risk Reduction Messaging Is a Threat to Knowledge Translation in Dementia Prevention Research. PMID- 29405223 TI - Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones. AB - Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work has been performed on the optimisation of their synthesis and subsequent reaction with immunoglobulins. Herein we present a novel synthetic route towards functionalised dibromopyridazinediones, proceeding via an isolatable dibromopyridazinedione-NHS ester. Reaction of this activated intermediate with a variety of amines produces functional dibromopyridazinediones in good to excellent yields. The disulfide rebridging capacity of these reagents was optimised on the clinically relevant IgG1 trastuzumab, resulting in a general method which allows for the generation of site-selectively modified native trastuzumab with over 90% homogeneity (no disulfide scrambling) without the need for protein engineering or enzymatic conjugation. PMID- 29405225 TI - Primary Prevention of Dementia: The Future of Population-Based Multidomain Lifestyle Interventions. PMID- 29405226 TI - Delayed-Start Analyses in the Phase 3 Solanezumab EXPEDITION3 Study in Mild Alzheimer's Disease. AB - OBJECTIVE: A delayed-start design has been proposed to assess a potential disease modifying effect in investigational drugs for Alzheimer's disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer's Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer's Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect. PMID- 29405227 TI - Detecting Treatment Group Differences in Alzheimer's Disease Clinical Trials: A Comparison of Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB). AB - The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer's Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of >= 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences. PMID- 29405228 TI - Associations of Long-Term Tea Consumption with Depressive and Anxiety Symptoms in Community-Living Elderly: Findings from the Diet and Healthy Aging Study. AB - OBJECTIVE: To examine the association between long-term tea consumption and depressive and anxiety symptoms in community-living elderly. DESIGN: Community based cross-sectional study. SETTING: The Diet and Healthy Aging Study (DaHA), a prospective cohort study in Singapore. PARTICIPANTS: 614 elderly aged 60 years and above, who were free of dementia and cognitive impairment. MEASUREMENTS: Information on tea consumption was obtained through interviewer-administered questionnaire. Long-term tea drinking was defined as regular consumption for at least 15 years. Depressive and anxiety symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15) and the 20-item Geriatric Anxiety Inventory (GAI), respectively. A generalized structural equation model (gSEM) was applied to ascertain the association between long-term tea consumption and depressive and anxiety symptoms. RESULTS: About 59% of the subjects had consumed tea for over 15 years. Long term tea consumption was significantly associated with a reduced odds of having depressive and anxiety symptoms, after adjusting for demographics (i.e., age, gender, education and ethnicity), comorbid conditions (i.e., heart disease, diabetes, stroke, hypertension and hyperlipidaemia) and long-term coffee consumption. CONCLUSION: There was evidence suggesting that long-term tea consumption was associated with reduced depressive and anxiety symptoms among community-living elderly. This suggests that it is worthwhile to further investigate the role of tea's bioactive compounds in promoting mental health in aging. PMID- 29405229 TI - Effects of Omega-3 Fatty Acids on Resting Cerebral Perfusion in Patients with Mild Cognitive Impairment: A Randomized Controlled Trial. AB - Alteration of cerebral perfusion can be considered as a possible therapeutic target in mild cognitive impairment. This randomized, placebo-controlled, double blind proof-of-concept study assessed effects of omega-3 fatty acids on cerebral perfusion in patients with mild cognitive impairment. In thirteen patients (omega:n=5; placebo:n=8) cerebral perfusion was measured before and after 26 weeks intervention within posterior cortical regions using magnetic resonance imaging. There was a medium effect of intervention on cerebral blood flow (eta2=0.122) and blood volume (eta2=0.098). The omega group showed an increase in blood flow (mean difference: 0.02 [corresponds to 26.1%], 95% confidence interval:0.00-0.05) and blood volume (mean difference: 0.08 [corresponds to 18.5%], 95% confidence interval:0.01-0.15), which was not observed in the placebo group. These preliminary findings suggest that omega-3 fatty acids supplementation may improve perfusion in cerebral regions typically affected in mild cognitive impairment.Regulation of perfusion may help to maintain brain structure and function and potentially delay conversion to dementia. PMID- 29405230 TI - Trajectory of the MAPT-PACC-Preclinical Alzheimer Cognitive Composite in the Placebo Group of a Randomized Control Trial: Results from the MAPT Study: Lessons for Further Trials. AB - Defining the primary cognitive endpoint is a major decision for Alzheimer's disease preventive trials. As an example for further trials we present in detail the three-year cognitive decline in the placebo group of MAPT trial, a randomized controlled trial (RCT) using a cognitive composite score (MAPT-PACC). Participants were dementia-free adults 70 years or older, with subjective memory complaints. Our findings as expected showed subjects with older age (>75), higher beta amyloid brain deposition, APOE-epsilon4 allele carriers, with low RBC DHA+EPA levels and higher CDR level are at higher risk of cognitive decline. The data presented in this paper can be useful for future preventive trials to choose the primary cognitive end point, assess the clinical relevance of cognitive changes and perform sample size calculation for several targeted population eg. ApoE4, amyloid +, oldest old, lower n3-PUFA. We believe that the trial group with CDR 0.5, without being selected by a memory test endpoint is a good target population for AD preventive trials. PMID- 29405232 TI - Cognitive Frailty and Incidence of Dementia in Older Persons. AB - BACKGROUND: Cognitive frailty may be a preventive or therapeutic target for preventing dementia and functional decline with age. OBJECTIVES: To examine the relationship between physical and cognitive frailty and the incidence of dementia in community-living older persons. DESIGN: A prospective cohort study. SETTING: General community in Japan. PARTICIPANTS: A total of 4072 persons aged >= 65 years. SETTING: A community in Japan. PARTICIPANTS: A total of 4072 community dwelling older persons aged >= 65 years participated in the study. MEASUREMENTS: We characterized physical frailty as >= 3 of the following criteria: slow walking speed, muscle weakness, exhaustion, low physical activity, and weight loss. We used the National Center for Geriatrics and Gerontology-Functional Assessment Tool, which includes tests of word list memory, attention, and executive function, and processing speed to screen for cognitive frailty. The presence of >= 2 cognitive impairments, indicated by an age-adjusted score of at least 1.5 standard deviations below the reference threshold, was defined as cognitive frailty. The incidence of dementia was determined using data collected by the Japanese Health Insurance System over 24 months. RESULTS: The overall prevalence rates of physical frailty, cognitive impairment, and cognitive frailty (i.e., coexistence of frailty and cognitive impairment) were 5.1%, 5.5%, and 1.1%, respectively. During the follow-up period, 81 participants (2.0%) developed dementia. We found significant relationships between the incidence of dementia and cognitive impairment (hazard ratio (HR): 3.85, 95% confidence interval (95% CI): 2.09-7.10) and cognitive frailty (HR: 6.19, 95% CI: 2.7-13.99). However, the association between dementia and physical frailty did not reach significance (HR: 1.95, 95% CI: 0.97-3.91). CONCLUSIONS: Individuals with cognitive frailty had the highest risk of dementia. Future research should implement dementia prevention strategies among older persons with cognitive frailty. PMID- 29405231 TI - Care Management to Promote Treatment Adherence in Patients with Cognitive Impairment and Vascular Risk Factors: A Demonstration Project. AB - Dementia prevention is highly important. Improved control of vascular risk factors has the potential to decrease dementia risk, but may be difficult. Therefore, we developed and piloted a care management protocol for Veterans at risk for dementia. We enrolled 32 Veterans with diabetes and hypertension, at least one of which was poorly controlled, and cognitive impairment. Participants were randomly assigned to a 6-month care management intervention or to usual care. At enrollment, 6-months and 12-months, we assessed cognitive performance, mood, and diabetes and hypertension control. At follow-up, diastolic blood pressure was lower in intervention participants at 6 months (p=.041) and 12 months (p=.022); hemoglobin A1c, global mental status and mood did not differ between groups. Recall of a distractor list (p=.006) and logical memory long delay recall (p=.036) were better at 6 months in the intervention group (p=.006). Care management may contribute to improved control of dementia risk factors. PMID- 29405233 TI - The Value of Pre-Screening in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease Trial. AB - The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial evaluates the anti-amyloid-beta antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD. PMID- 29405234 TI - Costs and Resource Use Associated with Alzheimer's Disease in Italy: Results from an Observational Study. AB - BACKGROUND: The GERAS II study aimed to assess societal costs and resource use associated with Alzheimer's disease (AD) for patients and their primary caregivers in Italy and Spain, stratified for different severity stages of AD at baseline. This report presents baseline results for Italy. DESIGN: GERAS II was a prospective, multicentre, observational study of routine care in AD. SETTING: Community-dwelling patients attending specialist secondary care centres (memory clinics/Alzheimer's Evaluation Units) and their primary informal caregivers were recruited into the study. PARTICIPANTS: Patients were aged >=55 years, presented within the normal course of care, had a diagnosis of probable AD and a Mini Mental State Examination (MMSE) score of <=26. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild, MMSE score 21-26; moderate, MMSE score 15-20; or moderately severe/severe, MMSE score <15. MEASUREMENTS: Data collected for patients and caregivers included demographics/clinical characteristics; current medication; patient cognitive, functional and behavioural assessments; patient and caregiver health-related quality of life (HRQoL); and patient and caregiver resource use. The costs associated with the resources used were calculated. Costs were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs. RESULTS: Of 198 patients enrolled from Italy, 29 (15%) had mild AD dementia, 80 (40%) had moderate AD dementia, and 89 (45%) had moderately severe/severe AD dementia. Patient and caregiver characteristics showed some differences between AD dementia severity groups; for example, a numerically higher proportion of patients with mild and moderately severe/severe AD dementia were taking memantine compared with those with moderate AD dementia. Patient functioning and behavioural and psychological symptoms worsened with increasing AD dementia severity (p<0.05 between groups for all measures). No significant difference between the disease severity groups was observed in patient HRQoL, and there was no clear pattern in resource use. However, all measures of caregiver time spent helping the patient differed significantly between groups (p<0.05) and were highest in patients with moderately severe/severe AD dementia. Mean (standard deviation) total monthly societal costs per patient (2013 values) were ?1850 (1901), ?1552 (1322) and ?2728 (2184) for patients with mild, moderate and moderately severe/severe AD dementia, respectively (p<0.001 between groups). Caregiver informal care costs were the greatest contributor to total societal costs and amounted to ?1370, ?1223 and ?2223 per patient per month for mild, moderate and moderately severe/severe AD dementia groups, respectively (p<0.001 between groups). CONCLUSION: Total Italian societal costs generally increased with increasing AD dementia severity. However, costs were slightly lower for moderate than for mild AD dementia, possibly reflecting the observed unusual trend of greater caregiver time and higher memantine use in patients with mild versus moderate AD dementia. PMID- 29405235 TI - Neuroprotective Effects of Guarana (Paullinia cupana Mart.) against Vincristine in Vitro Exposure. AB - BACKGROUND: Vincristine (VCR) is not a specific chemotherapeutic drug, responsible for cause several side effects. In this sense, many natural products have been studied to reduce this problem. Objetives: To examine the guarana neuroprotective effect in mice brain and cerebellum cells against vincristine (VCR) exposition. DESIGN: An in vitro study was performed using mice brain and cerebellum mice in monolayer culture. First, cells were exposed to VCR (0.009 uM for 24 hours and 0.0007 uM for 72 hours) to measure the cytotoxicity effect. Also, the cellular effect of hydroalcoholic extract of guarana (10; 30; 100 and 300 MUg/mL) was evaluated in the same cells in 24 and 72 hours. After that, cells were exposed to VCR and guarana extract to evaluate the neuroprotective effect of guarana. MEASUREMENTS: Cell viability was analyzed by MTT, Free dsDNA and LHD Assays. Moreover, metabolism oxidative profile was evaluated by reactive oxygen species (ROS), lipoperoxidation (LPO) and catalase (CAT) levels through DCFH-DA, TBARS and Catalase Activity Assays, respectively. RESULTS: Our findings revealed that VCR caused neuronal cytotoxicity by reducing cell viability and increasing ROS and LPO levels. On the other hand, guarana did not cause cell damage in none of tested concentrations. In addition, guarana exhibited a notable protective effect on brain and cerebellum cells exposed to VCR by increasing cell viability, stimulating CAT activity, reducing levels of ROS and LPO. CONCLUSIONS: In this sense, guarana is a remarkable antioxidant fruit that could be a target in new therapies development to reduce VCR neurotoxicity. . PMID- 29405236 TI - Combining Geospatial Analysis with Dementia Risk Utilising General Practice Data: A Systematic Review. AB - Geographical information systems (GIS) and geospatial analysis techniques will help to identify significant dementia risk clusters (hotspots) across communities and will enable policy makers to target prevention interventions to the right place. This review synthesises the published literature on geospatial analysis techniques for quantifying and mapping dementia risk, and reviews available dementia risk assessment tools. A systematic literature review was undertaken in four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Sciences) from their inception to March 2017 for all articles relating to dementia. The search terms included: 'dementia', 'Alzheimer's disease', 'general practice database', 'family physician', 'AD risk assessment tools', 'Geographical Information Systems' and 'geospatial analysis', 'geographical variation' and 'spatial variation'. To date, most geospatial studies on dementia have been carried out retrospectively using population based data. An alternative approach is utilisation of a rich source of general practice (family physician) databases to predict dementia risk based on available dementia risk assessment tools. In conclusion, the estimated risks of dementia can thus be geo-attributed and mapped at a small scale using geographical information systems and geospatial analysis techniques to identify dementia risk clusters across the communities and refine our understanding of the interaction between socio-demographic and environmental factors, and dementia risk clusters. . PMID- 29405237 TI - The Relationship of Omega 3 Polyunsaturated Fatty Acids in Red Blood Cell Membranes with Cognitive Function and Brain Structure: A Review Focussed on Alzheimer's Disease. AB - Significant research attention has focussed on the identification of nutraceutical agents for the prevention of cognitive decline as a natural means of cognitive preservation in the elderly. There is some evidence for a reduction of brain omega 3 polyunsaturated fatty acids (n-3 PUFAs) in normal aging and in Alzheimer's disease. n-3 PUFAs exhibit anti-inflammatory and anti-amyloidogenic properties as well as being able to reduce tau phosphorylation. Many observational studies have demonstrated a link between n-3 PUFAs and cognitive aging, and some, but not all, randomized controlled trials have demonstrated a benefit of n-3 PUFA supplementation on cognition, particularly in those subjects with mild cognitive impairment. The identification of a biomarker that reflects n 3 PUFA intake over time and consequent tissue levels is required. In this narrative review we discuss the evidence associating red blood cell membrane n-3 PUFAs with cognitive function and structural brain changes associated with Alzheimer's disease. PMID- 29405238 TI - Letter to the editor: Dementia: Creating a Knowledge-Based Healthcare Profession. PMID- 29405239 TI - Letter to the editor: Long-Term Tea Consumption and Depressive and Anxiety Symptoms in Elderly. PMID- 29405240 TI - Letter to the editor: Responses. Long-Term Tea Consumption and Depressive and Anxiety Symptoms in Elderly. PMID- 29405241 TI - Productivity estimation in economic evaluations of occupational health and safety interventions: a systematic review. AB - Objectives Occupational health and safety (OHS) interventions' effect on worker productivity is an essential, but complex element of the value of these programs. The trustworthiness of economic evaluation studies, aiming to provide guidance to decision-makers in the field of OHS, depends at least partly on how accurately productivity changes are measured. We aim to review the methods used to estimate productivity changes in recently published economic evaluations of OHS interventions. Methods We performed systematic searches of economic evaluations of OHS programs published between 2007 and 2017 and reviewed these studies' methods to quantify the programs' impact on worker productivity Results Of the 90 identified studies, 44 used a human capital approach, 17 a friction cost approach, 13 stated productivity in natural units (eg, a cost-per-absence-day avoided), 7 made use of compensation expenses, 4 used output-based methods, 4 an "ad hoc" approach, and 1 study did not state its method. Different approaches were combined in 19 studies. Within these methods, we observed a wide diversity in their precise implementation, especially regarding the measurement and valuation of absenteeism and presenteeism. Conclusions Productivity is a key element of the economic attractiveness of investing in OHS. Economic evaluation studies of OHS would benefit from more methodological standardization in their approach to quantifying productivity change. Future research should better account for the methodological uncertainty that occurs in estimating it in order to demonstrate the impact that particular choices and approaches to productivity estimation can have on cost-effectiveness results. PMID- 29405242 TI - Occupational exposure to organic solvents and risk of male breast cancer: a European multicenter case-control study. AB - Objectives The etiology of male breast cancer (MBC) is largely unknown but a causal role of exposure to organic solvents has been suggested. Previous studies on occupational risk factors of breast cancer were often restricted to women who are frequently exposed to lower levels and at a lower frequency than men. We investigated the association between MBC and occupational exposure to petroleum and oxygenated and chlorinated solvents in a multicenter case-control study of rare cancers in Europe. Methods The study included 104 MBC cases and 1901 controls. Detailed lifetime work history was obtained during interviews, together with sociodemographic characteristics, medical history and lifestyle factors. Occupational exposures to solvents were estimated from a job-exposure matrix. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated using unconditional logistic regression models. Results Lifetime cumulative exposure to trichloroethylene >23.9 ppm years was associated with an increased MBC risk, compared to non-exposure [OR (95% CI): 2.1 (1.2-4.0); P trend <0.01). This increase in risk persisted when only exposures that occurred >=10 years before diagnosis were considered. In addition, a possible role for benzene and ethylene glycol in MBC risk was suggested, but no exposure-response trend was observed. Conclusions These findings add to the evidence of an increased risk of breast cancer among men professionally exposed to trichloroethylene and possibly to benzene or ethylene glycol. Further studies should be conducted in populations with high level of exposure to confirm our results. PMID- 29405244 TI - Isolated Adrenocorticotropic Hormone Deficiency in Melanoma Patients Treated with Nivolumab. PMID- 29405243 TI - Characteristics of Familial Melanoma in Valencia, Spain, Based on the Presence of CDKN2A Mutations and MC1R Variants. AB - Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families (17% CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma (SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area. PMID- 29405245 TI - Initial Results of Secukinumab Drug Survival in Patients with Psoriasis: A Multicentre Daily Practice Cohort Study. AB - Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials. However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan-Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least one episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practice. PMID- 29405246 TI - Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients. AB - Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388 1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis. PMID- 29405247 TI - Brownish Plaque with Progressive Growth on the Breast: A Quiz. PMID- 29405248 TI - RASA1 Variants in Capillary Malformations of Children: A Comment to Maruani A et al. PMID- 29405249 TI - Distinctive peri-luminal presence of agrin in murine and human carotid atherosclerotic plaques. AB - The clinical consequences of arterial atherosclerotic lesions depend, apart from their size, on their composition of cellular and extracellular components. While an intact endothelium at the interface of atherosclerotic plaques towards the blood can prevent its erosion, underlying smooth muscle cells within the plaque can reduce the risk of plaque ruptures, due to the deposition of stabilizing extracellular matrix. Basement membranes underlay and support the function of endothelial cells, and embed smooth muscle cells in the media, the source of most smooth muscle cells within atherosclerotic plaques. In the present study mouse atherosclerotic plaques were comparatively analyzed for the basement membrane components laminin, type IV collagen, perlecan, and agrin. Distinct agrin immunofluorescence was found in the peri-luminal area in mouse carotid atherosclerotic plaques. Agrin was also clearly present in the media, with a significant increase in regions directly associated with plaque tissue. In addition, ten human endarterectomy specimens were investigated for this heparan sulfate proteoglycan. No statistically significant differences in agrin immunofluorescence were noticed between five specimens from symptomatic and five from asymptomatic patients. In all these plaques agrin was present in a distinctive manner in a narrow zone partially or almost completely surrounding the lumen. Additionally it was also present around the small lumina of the CD31 positive neovessels. The presence of agrin at locations with particular importance for the growth and stability of atherosclerotic plaques renders this molecule strategically positioned to influence plaque development and vulnerability. PMID- 29405250 TI - Botulinum toxin: A review of the mode of action in migraine. AB - Botulinum toxin serotype A (BoNT/A) was originally used in neurology for the treatment of dystonia and blepharospasms, but is now clinically used worldwide for the treatment of chronic migraine. Still, the possible mode of action of BoNT/A in migraine is not fully known. However, the mode of action of BoNT/A has been investigated in experimental pain as well as migraine models, which may elucidate the underlying mechanisms in migraine. The aim of this study was to review studies on the possible mode of action of BoNT/A in relation to chronic migraine treatment. Observations suggest that the mode of action of BoNT/A may not be limited to the injection site, but also includes anatomically connected sites due to axonal transport. The mechanisms behind the effect of BoNT/A in chronic migraine may also include modulation of neurotransmitter release, changes in surface expression of receptors and cytokines as well as enhancement of opioidergic transmission. Clinical and experimental studies with botulinum toxin in the last decade have advanced our understanding of headache and other pain states. More research into botulinum toxin as treatment for headache is warranted as it can be an attractive alternative for patients who do not respond positively to other drugs. PMID- 29405251 TI - Impact of specialist management on survival from radiation-associated angiosarcoma of the breast. AB - BACKGROUND: Radiation-associated angiosarcoma of the breast (RAAS) is a rare complication of adjuvant radiotherapy associated with poor survival. The British Sarcoma Group guidelines recommend that all angiosarcomas are referred to a sarcoma multidisciplinary team, although there is no recommendation that patients are managed within a sarcoma service. The aims of this study were to compare survival, complete excision rates and local recurrence rates of patients managed within a sarcoma service and those managed within local hospitals. METHODS: All patients with RAAS referred to a regional sarcoma service between 1998 and 2015 were identified from prospective databases. Patient records, and radiology, pathology and operation notes were reviewed retrospectively. RESULTS: Thirty-six patients were operated on with curative intent; 26 were managed by the sarcoma service (of whom 21 underwent radical excision of the irradiated field followed by chest wall reconstruction) and ten were managed locally. Median age was 69.5 (range 43-85) years. Disease-specific survival was significantly longer in patients managed by the sarcoma service than in those managed locally: median 91.1 (range 69.2-113.0) versus 48.8 (18.6-79.1) months respectively (P = 0.012). Overall survival rates were similar (P = 0.112). There was no difference in complete excision rate (18 of 26 in sarcoma service versus 5 of 10 in local services; P = 0.456), although the local recurrence rate was significantly lower among patients managed by the sarcoma service (9 of 26 versus 8 of 10; P = 0.015). CONCLUSION: Specialist management of RAAS leads to fewer local recurrences and improved disease-specific survival. Early referral and management within specialist units is recommended. PMID- 29405252 TI - Randomized clinical trial of intraoperative parathyroid gland angiography with indocyanine green fluorescence predicting parathyroid function after thyroid surgery. AB - BACKGROUND: Hypoparathyroidism, the most common complication after thyroid surgery, leads to hypocalcaemia and significant medical problems. An RCT was undertaken to determine whether intraoperative parathyroid gland angiography with indocyanine green (ICG) could predict postoperative hypoparathyroidism, and obviate the need for systematic blood tests and oral calcium supplementation. METHODS: Between September 2014 and February 2016, patients who had at least one well perfused parathyroid gland on ICG angiography were randomized to receive standard follow-up (measurement of calcium and parathyroid hormone (PTH) on postoperative day (POD) 1 and systematic supplementation with calcium and vitamin D; control group) or no supplementation and no blood test on POD 1 (intervention group). In all patients, calcium and PTH levels were measured 10-15 days after thyroidectomy. The primary endpoint was hypocalcaemia on POD 10-15. RESULTS: A total of 196 patients underwent ICG angiography during thyroid surgery, of whom 146 had at least one well perfused parathyroid gland on ICG angiography and were randomized. None of these patients presented with hypoparathyroidism, including those who did not receive calcium supplementation. The intervention group was statistically non-inferior to the control group (exact 95 per cent c.i. of the difference in proportion of patients with hypocalcaemia -0.053 to 0.053; P = 0.012). Eleven of the 50 excluded patients, in whom no well perfused parathyroid gland could be identified by angiography, presented with hypoparathyroidism on POD 1, and six on POD 10-15, which was significantly different from the findings in randomized patients (P = 0.007). CONCLUSION: ICG angiography reliably predicts the vascularization of the parathyroid glands and obviates the need for postoperative measurement of calcium and PTH, and supplementation with calcium in patients with at least one well perfused parathyroid gland. Registration number: NCT02249780 (http://www.clinicaltrials.gov). PMID- 29405253 TI - Meta-analysis of mortality in patients with high-risk intraductal papillary mucinous neoplasms under observation. AB - BACKGROUND: Although consensus guidelines suggest that patients with high-risk intraductal papillary mucinous neoplasms (IPMNs) should have surgery, a non operative strategy is often selected in patients who are poor surgical candidates. The aim was to determine the risk of disease-related death from IPMN in patients with worrisome features or high-risk stigmata who were kept under observation. METHODS: A PubMed literature search was undertaken of articles published from August 1992 to June 2016 (updated October 2017). The methodology was developed from PRISMA and MOOSE checklists. Incidence proportions and rates of overall and IPMN-related deaths were calculated, with subgroup analyses for main-duct/mixed-type and branch-duct IPMNs. Quality of the studies, publication bias and heterogeneity were explored. RESULTS: Six studies reported data on overall mortality and eight described disease-specific mortality for 556 patients during follow-up ranging from 24.9 to 60.0 months. Pooled rates of overall and IPMN-related mortality were 30.9 (95 per cent c.i. 19.6 to 45.1) and 11.6 (6.0 to 21.2) per cent respectively. The pooled incidence rate for overall mortality was substantially higher than that for IPMN-related mortality: 78 (95 per cent c.i. 44 to 111) and 23 (9 to 37) per 1000 patient-years respectively. The pooled incidence rate for disease-specific mortality was considerably lower for branch duct than for main-duct or mixed-type IPMNs: 5 (0 to 10) and 32 (12 to 52) per 1000 patient-years respectively. CONCLUSION: In patients unfit for surgery, IPMN related mortality among patients with worrisome features and high-risk stigmata is low, and the risk of death from other causes much higher. PMID- 29405255 TI - Efficacy and safety of continuous every-2-week dosing of ixekizumab over 52 weeks in patients with moderate-to-severe plaque psoriasis in a randomized phase III trial (IXORA-P). AB - BACKGROUND: Ixekizumab is an interleukin-17A antagonist approved for treatment of moderate-to-severe plaque psoriasis with a recommended 160-mg starting dose, then 80 mg every 2 weeks (Q2W) to week 12, and every 4 weeks (Q4W) thereafter. OBJECTIVE: To evaluate continuous Q2W dosing over 52 weeks. METHODS: In this phase III, multicentre, double-blinded, parallel-group trial, three ixekizumab dosing regimens were assessed for efficacy and safety at week 52 in patients with moderate-to-severe plaque psoriasis randomized at a 2 : 1 : 1 ratio to continuous Q2W (n = 611), continuous Q4W (n = 310) or dose adjustment per protocol (Q4W/Q2W, n = 306), each with a 160-mg starting dose. Dose adjustment was determined by predefined criteria to which investigators were blinded; 72 (23?5%) patients in the Q4W/Q2W group adjusted dose. Efficacy outcomes were evaluated using logistic regression. RESULTS: Co-primary end points were met at week 52: Psoriasis Area and Severity Index 75 responses for Q2W and Q4W dose groups were 85.9% and 79.0%, respectively (P = 0.006), and static patient global assessment 0/1 responses for Q2W and Q4W dose groups were 78.6% and 70.6%, respectively (P = 0.005). Treatment emergent and serious adverse events were comparable across dose groups. CONCLUSIONS: Ixekizumab Q2W had higher efficacy at week 52 than ixekizumab Q4W, with no increase in safety events. PMID- 29405254 TI - Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population. PMID- 29405256 TI - Oral retinoids and depression: reply from the authors. PMID- 29405257 TI - Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis? AB - BACKGROUND: Despite the heavy purulence observed in hidradenitis suppurativa (HS), the kinetics of complement anaphylatoxins acting to prime chemotaxis of neutrophils has not been studied. OBJECTIVES: To explore complement activation in HS. METHODS: Circulating concentrations of complement factor C5a, as well as of membrane attack complex C5b-9, were determined in the plasma of 54 treatment naive patients and of 14 healthy controls, as well as in the pus of seven patients. Results were correlated with Hurley stage and International Hidradenitis Suppurativa Severity Score. Peripheral blood mononuclear cells (PBMCs) were isolated from seven patients with Hurley stage III HS and seven healthy volunteers and stimulated in the presence of 25% of plasma for the production of tumour necrosis factor-alpha (TNF-alpha). RESULTS: Circulating C5a and C5b-9 were significantly greater in patient than in control plasma; however, concentrations in pus were very low. Circulating C5a levels exceeding 28 ng mL-1 were associated with a specificity > 90% with the occurrence of HS. Circulating levels of C5a and C5b-9 were greater in patients with more severe HS. PBMCs of patients produced high concentrations of TNF-alpha only when growth medium was enriched with patient plasma; this was reversed with the addition of the C5a blocker IFX-1. CONCLUSIONS: Systemic complement activation occurs in HS and may be used as a surrogate biomarker of HS. C5a stimulates overproduction of TNF alpha and may be a future therapeutic target. PMID- 29405258 TI - Videolaryngoscopy vs. Macintosh laryngoscopy for double-lumen tube intubation in thoracic surgery: a systematic review and meta-analysis. AB - Double-lumen intubation is more difficult than single-lumen tracheal intubation. Videolaryngoscopes have many advantages in airway management. However, the advantages of videolaryngoscopy for intubation with a double-lumen tube remain controversial compared with traditional Macintosh laryngoscopy. In this study, we searched MEDLINE, Embase, Cochrane Library and the Web of Science for randomised controlled trials comparing videolaryngoscopy with Macintosh laryngoscopy for double-lumen tube intubation. We found that videolaryngoscopy provided a higher success rate at first attempt for double-lumen tube intubation, with an odds ratio (95%CI) of 2.77 (1.92-4.00) (12 studies, 1215 patients, moderate-quality evidence, p < 0.00001), as well as a lower incidence of oral, mucosal or dental injuries during double-lumen tube intubation, odds ratio (95%CI) 0.36 (0.15-0.85) (11 studies, 1145 patients, low-quality evidence, p = 0.02), and for postoperative sore throat, odds ratio (95%CI) 0.54 (0.36-0.81) (7 studies, 561 patients, moderate-quality evidence, p = 0.003), compared with Macintosh laryngoscopy. There were no significant differences in intubation time, with a standardised mean difference (95%CI) of -0.10 (-0.62 to 0.42) (14 studies, 1310 patients, very low-quality evidence, p = 0.71); and the incidence of postoperative voice change, odds ratio (95%CI) 0.53 (0.21-1.31) (7 studies, 535 patients, low-quality evidence, p = 0.17). Videolaryngoscopy led to a higher incidence of malpositioned double-lumen tube, with an odds ratio (95%CI) of 2.23 (1.10-4.52) (six studies, 487 patients, moderate-quality evidence, p = 0.03). PMID- 29405259 TI - Application of in vivo reflectance confocal microscopy and ex vivo fluorescence confocal microscopy in the most common subtypes of basal cell carcinoma and correlation with histopathology. PMID- 29405260 TI - Hyaluronan metabolism enhanced during epidermal differentiation is suppressed by vitamin C. AB - BACKGROUND: Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases and catabolized by hyaluronidases, reactive oxygen species and KIAA1199. OBJECTIVES: To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C on these events. METHODS: Hyaluronan synthesis and expression of the hyaluronan-related genes were analysed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes using quantitative reverse transcriptase polymerase chain reaction, immunostaining and Western blotting, in the presence and absence of vitamin C. RESULTS: With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2 and Hyal2 showed a transient upregulation during stratification, Hyal1 transcription remained permanently increased and transcription of the hyaluronan receptor, Cd44, decreased. At maturation, vitamin C downregulated Has2, Hyal2 and Cd44, whereas it increased high-molecular-mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan. CONCLUSIONS: Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan. PMID- 29405262 TI - Wide skin markings pattern: melanoma descriptor or patient-related factor? PMID- 29405263 TI - Mosquito repellents for malaria prevention. AB - BACKGROUND: Malaria is an important cause of illness and death across endemic regions. Considerable success against malaria has been achieved within the past decade mainly through long-lasting insecticide-treated nets (LLINs). However, elimination of the disease is proving difficult as current control methods do not protect against mosquitoes biting outdoors and when people are active. Repellents may provide a personal protection solution during these times. OBJECTIVES: To assess the impact of topical repellents, insecticide-treated clothing, and spatial repellents on malaria transmission. SEARCH METHODS: We searched the following databases up to 26 June 2017: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; US AFPMB; CAB Abstracts; and LILACS. We also searched trial registration platforms and conference proceedings; and contacted organizations and companies for ongoing and unpublished trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and cluster randomized controlled trials of topical repellents proven to repel mosquitoes; permethrin-treated clothing; and spatial repellents such as mosquito coils. We included trials that investigated the use of repellents with or without LLINs, referred to as insecticide-treated nets. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed trials for inclusion, extracted the data, and assessed the risk of bias. A third review author resolved any discrepancies. We analysed data by conducting meta-analysis and stratified by whether the trials had included LLINs. We combined results from cRCTs with individually RCTs by adjusting for clustering and presented results using forest plots. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: Eight cRCTs and two RCTs met the inclusion criteria. Six trials investigated topical repellents, two trials investigated insecticide-treated clothing, and two trials investigated spatial repellents.Topical repellentsSix RCTS, five of them cluster-randomized, investigated topical repellents involving residents of malaria-endemic regions. Four trials used topical repellents in combination with nets, but two trials undertaken in displaced populations used topical repellents alone. It is unclear if topical repellents can prevent clinical malaria (RR 0.65, 95% CI 0.4 to 1.07, very low certainty evidence) or malaria infection (RR 0.84, 95% CI 0.64 to 1.12, low-certainty evidence) caused by P. falciparum. It is also unclear if there is any protection against clinical cases of P. vivax (RR 1.32, 95% CI 0.99 to 1.76, low-certainty evidence) or incidence of infections (RR 1.07, 95% CI 0.80 to 1.41, low-certainty evidence). Subgroup analysis of trials including insecticide treated nets did not show a protective effect of topical repellents against malaria. Only two studies did not include insecticide-treated nets, and they measured different outcomes; one reported a protective effect against clinical cases of P. falciparum (RR 0.40, 95% CI 0.23 to 0.71); but the other study measured no protective effect against malaria infection incidence caused by either P. falciparum or P. vivax.Insecticide-treated clothingInsecticide-treated clothing were investigated in trials conducted in refugee camps in Pakistan and amongst military based in the Colombian Amazon. Neither study provided participants with insecticide-treated nets. In the absence of nets, treated clothing may reduce the incidence of clinical malaria caused by P. falciparum by approximately 50% (RR 0.49, 95% CI 0.29 to 0.83, low-certainty evidence) and P. vivax (RR 0.64, 95% CI 0.40 to 1.01, low-certainty evidence).Spatial repellentsTwo cluster-randomized RCTs investigated mosquito coils for malaria prevention. We do not know the effect of spatial repellents on malaria prevention (RR 0.24, 95% CI 0.03 to 1.72, very low certainty evidence). There was large heterogeneity between studies and one study had high risk of bias. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude topical or spatial repellents can prevent malaria. There is a need for better designed trials to generate higher certainty of evidence before well-informed recommendations can be made. Adherence to daily compliance remains a major limitation. Insecticide treated clothing may reduce risk of malaria infection in the absence of insecticide-treated nets; further studies on insecticide-treated clothing in the general population should be done to broaden the applicability of the results. PMID- 29405264 TI - Agminated Spitz naevi or metastatic spitzoid melanoma? PMID- 29405261 TI - Dual oxidase: a novel therapeutic target in allergic disease. AB - NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. PMID- 29405265 TI - Muscle tone assessments for children aged 0 to 12 years: a systematic review. AB - AIM: The aim of this study was to identify and examine the psychometric properties of muscle tone assessments for children aged 0 to 12 years. METHOD: Four electronic databases were searched to identify studies that included assessments of resting and/or active muscle tone. Methodological quality and overall psychometric evidence of studies were rated using the COnsensus-based Standards for the selection of health Measurement INstruments checklist. RESULTS: Twenty-one assessments were identified from 97 included studies. All assessments were broad developmental assessments that included muscle tone items or subscales. Most assessments (16/21) were designed for young children (<2y). Four assessments measured resting and active tone and demonstrated at least moderate validity or reliability: the Amiel-Tison Neurological Assessment (ATNA) at term, Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS), Premie-Neuro for newborn infants, and the Hammersmith Infant Neurological Examination (HINE) for infants aged 2 months to 2 years. For children over 2 years, the Neurological Sensory Motor Developmental Assessment (NSMDA) assesses resting and active tone but has limited validity. INTERPRETATION: The ATNA at term, NNNS, Premie-Neuro, HINE, and NSMDA can assess resting and active tone in infants and/or children. Further psychometric research is required to extend reliability, validity, and responsiveness data, particularly for older children. WHAT THIS PAPER ADDS: This is the first review of muscle tone assessments for children aged 0 to 12 years. Twenty-one assessments contain muscle tone items and 16 are for children under 2 years. Four assessments are reliable or valid to measure both resting and active tone. PMID- 29405266 TI - Nanos3 of the frog Rana rugosa: Molecular cloning and characterization. AB - Nanos is expressed in the primordial germ cells (PGCs) and also the germ cells of a variety of organisms as diverse as Drosophila, medaka fish, Xenopus and mouse. In Nanos3-deficient mice, PGCs fail to incorporate into the gonad and the size of the testis and ovary is thereby dramatically reduced. To elucidate the role of Nanos in an amphibian species, we cloned Nanos3 cDNA from the testis of the R. rugosa frog. RT-PCR analysis showed strong expression of Nanos3 mRNA in the testis of adult R. rugosa frogs, but expression was not sexually dimorphic during gonadal differentiation. In Nanos3-knockdown tadpoles produced by the CRISPR/Cas9 system, the number of germ cells decreased dramatically in the gonads of both male and female tadpoles before sex determination and thereafter. This was confirmed by three dimensional imaging of wild-type and Nanos3 knockdown gonads using serial sections immunostained for Vasa, a marker specific to germ cells. Taken together, these results suggest that Nanos3 protein function is conserved between R. rugosa and mouse. PMID- 29405268 TI - Effectiveness of shrinkage and variable selection methods for the prediction of complex human traits using data from distantly related individuals. PMID- 29405269 TI - Outcomes for women without conventional treatment for stage 1A (microinvasive) carcinoma of the cervix. AB - BACKGROUND: An unethical clinical study that entailed withholding treatment from women diagnosed with cervical intraepithelial neoplasia 3 (CIN3) was conducted at National Women's Hospital, Auckland, New Zealand. Women with microinvasive carcinoma of the cervix also had treatment withheld. AIMS: To describe the management and outcomes for women with microinvasive carcinoma for many of whom conventional treatment was withheld. MATERIALS AND METHODS: Retrospective cohort study of women with a diagnosis of stage 1A cervical carcinoma at National Women's Hospital. Medical records, cytology and histopathology were reviewed and data linked with cancer and death registries up to December 2000. RESULTS: Between 1955 and 1976, 62 women were initially diagnosed with stage 1A cervical cancer and 20 were diagnosed during follow up (to 1995). Sixty of the 82 women had initial management characterised as 'probably non-curative'; 20 of these received only a small diagnostic excision. Women in the latter group were more likely to: (i) subsequently have positive cytology (P < 0.0005), (ii) have untreated positive cytology (P = 0.02), and (iii) undergo multiple biopsies after initial management (P = 0.001). Of the women who received only a small diagnostic excision, eight of 20 developed invasive carcinoma of the cervix (>= stage 1B) or vaginal vault, compared to two of 22 women who received initial treatment characterised as 'probably curative'. CONCLUSIONS: Women with microinvasive carcinoma were included in a natural history study of CIN3; they underwent numerous procedures designed to observe rather than treat their condition, and had a substantial risk of invasive cancer. PMID- 29405267 TI - Pharmacological and neurosurgical interventions for managing dystonia in cerebral palsy: a systematic review. AB - AIM: To systematically review evidence for pharmacological/neurosurgical interventions for managing dystonia in individuals with cerebral palsy (CP) to inform a care pathway. METHOD: Searches included studies with a minimum of five participants with dystonia in CP receiving oral baclofen, benzodiazepines (clonazepam, diazepam, lorazepam), clonidine, gabapentin, levodopa, trihexyphenidyl, botulinum toxin, intrathecal baclofen (ITB), or deep brain stimulation (DBS). Evidence was classified according to American Academy of Neurology guidelines. RESULTS: Twenty-eight articles underwent data extraction: one levodopa, five trihexyphenidyl, three botulinum toxin, six ITB, and 13 DBS studies. No articles for oral baclofen, benzodiazepines, clonidine, or gabapentin met the inclusion criteria. Evidence for reducing dystonia was level C (possibly effective) for ITB and DBS; level C (possibly ineffective) for trihexyphenidyl; and level U (inadequate data) for botulinum toxin. INTERPRETATION: For dystonia reduction, ITB and DBS are possibly effective, whereas trihexyphenidyl was possibly ineffective. There is insufficient evidence to support oral medications or botulinum toxin to reduce dystonia. There is insufficient evidence for pharmacological and neurosurgical interventions to improve motor function, decrease pain, and ease caregiving. The majority of the pharmacological and neurosurgical management of dystonia in CP is based on clinical expert opinion. WHAT THIS PAPER ADDS: Intrathecal baclofen and deep brain stimulation are possibly effective in reducing dystonia. Current evidence does not support effectiveness of oral medications or botulinum toxin to reduce dystonia. Evidence is inadequate for pharmacological/neurosurgical interventions impact on improving motor function, pain/comfort, and easing caregiving. The majority of the care pathway rests on expert opinion. PMID- 29405272 TI - Quality of life and patient-reported outcomes. PMID- 29405270 TI - A triglyceride-rich lipoprotein environment exacerbates renal injury in the accelerated nephrotoxic nephritis model. AB - Hyperlipidaemia accompanies chronic renal disease either as a consequence of the renal dysfunction or as part of generalized metabolic derangements. Under both situations, the lipid profile is characterized by accumulation of triglyceride rich lipoproteins (TGRLs). This lipid profile is recognized as a risk factor for cardiovascular complications. Whether it may pose a risk for renal injury as well remains unclear. A hyper-TGRL state was generated in C57BL/6 mice using poloxamer 407 (P-407) and immune complex-mediated renal injury was triggered using the accelerated nephrotoxic nephritis (ANTN) model. The hyper-TGRL animals were hypersensitive to ANTN demonstrated by greater haematuria and glomerular cellularity. These changes were accompanied by increased glomerular accumulation of CD68+ macrophages. The hypersensitive response to ANTN was not seen in low density lipoprotein receptor knock-out mice fed with a high fat diet, where triglyceride levels were lower but cholesterol levels comparable to those obtained using P-407. These data indicate that a hyper-TGRL state might be more detrimental to the kidneys than low-density lipoprotein-driven hypercholesterolaemia during immune complex-mediated nephritis. We speculate that the hyper-TGRL environment primes the kidney to exacerbated renal damage following an inflammatory insult with increased accumulation of macrophages that may play a key role in mediating the injurious effects. PMID- 29405273 TI - Impact of abdominal aortic aneurysm screening on quality of life. AB - BACKGROUND: Screening for abdominal aortic aneurysm (AAA) is known to reduce AAA related mortality; however, the psychological impact of population AAA screening is unclear. The aim was to assess the impact of AAA diagnosis on quality of life (QoL) using data from an established AAA screening programme. METHODS: Mental and physical QoL scores for men diagnosed with AAA through participation in the English and Welsh AAA screening programmes were compared with no-AAA controls. Participants were identified through the United Kingdom Aneurysm Growth Study (UKAGS), a nationwide prospective cohort study of men with an AAA of less than 55 mm diagnosed through voluntary participation in screening. The UKAGS participants completed QoL questionnaires at the time of screening and annually thereafter. RESULTS: A transient reduction in mental QoL scores was observed following the diagnosis of AAA, returning to baseline levels after 12 months. Physical QoL remained consistently lower in the AAA cohort. Participants thought about their AAA and the AAA growth progressively less 12 months after the initial screening diagnosis. AAA growth rate had no influence over QoL parameters. DISCUSSION: This study suggests that screening for AAA does reduce mental QoL; however, this effect is transient (less than 12 months). Men diagnosed with AAA have a consistently worse physical QoL compared with controls. PMID- 29405275 TI - Surgeon volume and prognosis of patients with advanced papillary thyroid cancer and lateral nodal metastasis. AB - BACKGROUND: Surgery is the most important treatment modality for papillary thyroid cancer (PTC). However, the relationship between surgeon volume and long term oncological outcomes has not been explored. METHODS: Patients diagnosed with N1b PTC after initial thyroid surgery between 1 July 1994 and 31 December 2011 were eligible for inclusion in the study. Surgeons were categorized into high (at least 100 operations per year) and low (fewer than 100 operations per year) volume groups. Kaplan-Meier survival analysis according to surgeon volume was performed, and Cox proportional hazard modelling was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals according to patient, tumour and surgeon factors. RESULTS: A total of 1103 patients with a median follow-up of 81 (i.q.r. 62-108) months were included in the study. During follow-up, 200 patients (18.1 per cent) developed structural recurrence. A high surgeon volume was associated with low structural recurrence (P = 0.006). After adjustment for age, sex and conventional risk factors for recurrence (histology, tumour size, gross extrathyroidal extension, margin status, more than 5 positive lymph nodes, radioactive iodine therapy), the adjusted HR for structural recurrence for low volume surgeons was 1.46 (95 per cent c.i. 1.08 to 1.96), compared with high volume surgeons. Distant metastasis (P = 0.242) and disease-specific mortality (P = 0.288) were not affected by surgeon volume. CONCLUSION: Surgeon volume is associated with structural recurrence, but not distant metastasis or cancer specific death in patients with N1b PTC. Surgeon volume is important in initial surgery for advanced PTC with extensive nodal metastasis in order to ensure curative outcome and reduce treatment-related morbidity. PMID- 29405274 TI - Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. AB - BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62.3 versus 63.8 months respectively; hazard ratio 1.01, 95 per cent c.i. 0.70 to 1.45; P = 0.964) and relapse-free survival (median 36.0 versus 39.9 months; hazard ratio 0.93, 0.66 to 1.32; P = 0.693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/). PMID- 29405276 TI - Meta-analysis of metabolic surgery versus medical treatment for microvascular complications in patients with type 2 diabetes mellitus. AB - BACKGROUND: This study aimed to examine the effect of metabolic surgery on pre existing and future microvascular complications in patients with type 2 diabetes mellitus (T2DM) in comparison with medical treatment. Although metabolic surgery is the most effective treatment for obese patients with T2DM regarding glycaemic control, it is unclear whether the incidence or severity of microvascular complications is reduced. METHODS: A systematic literature search was performed in MEDLINE, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) with no language restrictions, looking for RCTs, case control trials and cohort studies that assessed the effect of metabolic surgery on the incidence of microvascular diabetic complications compared with medical treatment as control. The study was registered in the International prospective register of systematic reviews (CRD42016042994). RESULTS: The literature search yielded 1559 articles. Ten studies (3 RCTs, 7 controlled clinical trials) investigating 17 532 patients were included. Metabolic surgery reduced the incidence of microvascular complications (odds ratio 0.26, 95 per cent c.i. 0.16 to 0.42; P < 0.001) compared with medical treatment. Pre-existing diabetic nephropathy was strongly improved by metabolic surgery versus medical treatment (odds ratio 15.41, 1.28 to 185.46; P = 0.03). CONCLUSION: In patients with T2DM, metabolic surgery prevented the development of microvascular complications better than medical treatment . Metabolic surgery improved pre-existing diabetic nephropathy compared with medical treatment. PMID- 29405277 TI - Quality of life after hepatic resection. AB - BACKGROUND: Long-term quality of life (QoL) after liver resection is becoming increasingly important, as improvements in operative methods and perioperative care have decreased morbidity and mortality rates. In this study, postoperative QoL after resection of benign or malignant liver tumours was evaluated. METHODS: In this single-centre study, QoL was evaluated prospectively using the European Organisation for Research and Treatment of Cancer QLQ-C30 and the liver-specific QLQ-LMC21 module before, and 1, 3, 6 and 12 months after open or laparoscopic liver surgery. RESULTS: Between June 2007 and January 2013, 188 patients (130 with malignant and 58 with benign tumours) requiring major liver resection were included. Global health status was no different between the two groups before and 1 month after liver resection. All patients showed an improvement in global health status at 3, 6 and 12 months after surgery. Patients with benign tumours had better global health status than those with malignant tumours at these time points (P < 0.001, P = 0.002 and P = 0.006 respectively). Patients with benign disease had better physical function scores (P = 0.011, P = 0.025 and P = 0.041) and lower fatigue scores (P = 0.001, P = 0.002 and P = 0.002) at 3, 6 and 12 months than those with malignant disease. CONCLUSION: This study confirmed overall good QoL in patients undergoing liver resection for benign or malignant tumours, which improved after surgery. Benign diseases were associated with better short- and long-term QoL scores. PMID- 29405278 TI - Effect of parathyroidectomy on quality of life and non-specific symptoms in normocalcaemic primary hyperparathyroidism. AB - BACKGROUND: Normocalcaemic primary hyperparathyroidism (NcPHPT) is a new clinical entity being diagnosed increasingly among patients with mild primary hyperparathyroidism (PHPT). The aim of this study was to evaluate quality of life and non-specific symptoms before and after parathyroidectomy in patients with NcPHPT compared with those with hypercalcaemic mild PHPT (Hc-m-PHPT). METHODS: This was a prospective multicentre study of patients with mild PHPT from four university hospitals. Patients were evaluated before operation, and 3, 6 and 12 months after surgery for quality of life using the SF-36-v2(r) questionnaire, as well as for 25 non-specific symptoms. RESULTS: Before operation, the only statistically significant difference between the NcPHPT and Hc-m-PHPT groups was in the mean(s.d.) blood calcium level (2.54 versus 2.73 mmol; P < 0.001). At 1 year after surgery, the blood calcium level had improved significantly in both groups, with no significant difference between them. Quality of life improved significantly in each group compared with its preoperative score, with regard to the physical component summary (P = 0.040 and P = 0.016 respectively), whereas the mental component summary improved significantly in the Hc-m-PHPT group only (P = 0.043). Only two non-specific symptoms improved significantly in the NcPHPT group compared with nine in the Hc-m-PHPT group. CONCLUSION: Parathyroidectomy mildly improves quality of life and some non-specific symptoms in patients with NcPHPT. PMID- 29405280 TI - Systematic review and simulation study of ignoring clustered data in surgical trials. AB - BACKGROUND: Multiple surgical procedures in a single patient are relatively common and lead to dependent (clustered) data. This dependency needs to be accounted for in study design and data analysis. A systematic review was performed to assess how clustered data were handled in inguinal hernia trials. The impact of ignoring clustered data was estimated using simulations. METHODS: PubMed, Embase and the Cochrane Library were reviewed systematically for RCTs published between 2004 and 2013, including patients undergoing unilateral or bilateral inguinal hernia repair. Study characteristics determining the appropriateness of handling clustered data were extracted. Using simulations, various statistical methods accounting for clustered data were compared with an analysis ignoring clustering by assuming 100 hernias, with a varying percentage of patients having bilateral hernias. RESULTS: Of the 50 eligible trials including patients with bilateral hernias, 20 (40 per cent) did not provide information on how they dealt with clustered data and 18 (36 per cent) avoided clustering by assessing the outcome by patient and not by hernia. None of the remaining 12 trials (24 per cent) considered clustering in the design or analysis. In the simulations, ignoring clustering led to an increased type I error rate of up to 12 per cent and to a loss in power of up to 15 per cent, depending on whether the patient or the hernia was the randomization unit. CONCLUSION: Clustering was rarely considered in inguinal hernia trials. The simulations underline the importance of considering clustering as part of the statistical analysis to avoid false-positive and false-negative results, and hence inappropriate study conclusions. PMID- 29405281 TI - Health-related quality of life after open transhiatal and transthoracic oesophagectomy for cancer. AB - BACKGROUND: Transhiatal and transthoracic oesophagectomy in patients with oesophageal cancer have similar survival rates. Whether these approaches differ in health-related quality of life (HRQoL) is uncertain and was examined in this study. METHODS: Patients undergoing transhiatal or transthoracic surgery for lower-third oesophageal or gastro-oesophageal junctional cancer between 2011 and 2015 were selected from an institutional database. HRQoL outcomes were measured at 6 and 12 months after surgery using validated written questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25). Linear mixed models provided mean score differences (MSDs) with 95 per cent confidence intervals, adjusted for preoperative HRQoL, age, physical status (ASA fitness grade), tumour location, tumour stage, neoadjuvant therapy, adjuvant therapy and postoperative complications. MSD values of 10 or more were regarded as clinically relevant. RESULTS: Some 146 patients underwent transhiatal (86, 58.9 per cent) or transthoracic (60, 41.1 per cent) oesophagectomy. The HRQoL questionnaires were returned by 111 patients at 6 months and 74 at 12 months. At 6 months, transthoracic oesophagectomy was associated with worse role function (MSD -12, 95 per cent c.i. -23 to 0; P = 0.046). At 12 months, patients in the transthoracic group had more nausea and vomiting (MSD 11, 0 to 22; P = 0.045), dyspnoea (MSD 13, 1 to 25; P = 0.029) and constipation (MSD 20, 7 to 33; P = 0.003) than those in the transhiatal group. CONCLUSION: Transhiatal oesophagectomy seems to offer better HRQoL than transthoracic oesophagectomy 6 and 12 months after surgery. PMID- 29405282 TI - The effectiveness of the Pathways and Resources for Engagement and Participation (PREP) intervention: improving participation of adolescents with physical disabilities. AB - AIM: This study examined the effectiveness of the Pathways and Resources for Engagement and Participation (PREP) intervention in improving the participation of adolescents in community-based activities. METHOD: Twenty-eight adolescents (14 males, 14 females), aged 12 to 18 years (mean 14y 6mo, SD 21.6mo) with moderate physical disabilities participated in a 12-week PREP intervention. An interrupted time series design with multiple baselines was employed, replicating the intervention effect across three chosen activities and all participants. An occupational therapist worked individually with adolescents and parents to identify and implement strategies to remove environmental barriers that impede participation in selected activities. Activity performance was repeatedly measured using the Canadian Occupational Performance Measure (COPM) at baseline, intervention, and follow-up (20wks). For each activity, the trajectory representing change in performance was analyzed descriptively. Segmented regression combined with a mixed-effects modeling approach was used to statistically estimate the overall effectiveness of the intervention within and across 79 activities. RESULTS: A statistically significant improvement (B=2.08, p<0.001) was observed across all activities, 59 per cent of which also indicated a clinically significant change of more than 2 points on the COPM scale. Levels of performance were maintained during follow-up with an additional increase of 0.66 points on the COPM scale (t=3.04, p=0.004). Intervention was most effective for males and those with a higher number of functional issues. INTERPRETATION: Findings illustrate that participation can be improved by changing the environment only. Such evidence further supports emerging therapeutic approaches that are activity-based, goal-oriented, and ecological in nature. WHAT THIS PAPER ADDS: Environment-based intervention strategies, guided by the Pathways and Resources for Engagement and Participation, are effective in improving and maintaining adolescent participation. Intervention was most effective for males and those with a higher number of functional issues. The study design serves as an example for future pragmatic studies accounting for individual-based changes and contexts. PMID- 29405283 TI - The effect of statin use on the incidence of prostate cancer: A population-based nested case-control study. AB - Preclinical studies suggest statins may help prevent prostate cancer (PC), but epidemiologic results are mixed. Many epidemiological studies have relatively short prediagnosis drug exposure data, which may miss some statin use. We completed a nested case-control study investigating the impact of statin use on PC diagnosis and clinically significant PC using data from men aged >=40 years in the Canadian province of Saskatchewan between 1990 and 2010. Drug exposure histories were derived from a population-based prescription drug database. We used conditional logistic regression to model use of statins as a class and stratified analyses for groups defined by lipophilicity. Clinically significant PC was defined as Gleason score 8-10 OR stage C or D or III or IV at diagnosis. 12,745 cases of PC were risk-set matched on age and geographic location to 50,979 controls. Greater than 90% of subjects had prediagnosis drug exposure histories >15 years. 2,064 (16.2%) cases and 7,956 (15.6%) controls were dispensed one or more statin prescriptions. In multivariable models, ever prescription of statins was not associated with PC diagnosis (OR 0.97; 95% CI 0.90-1.05). Neither lipophilic statins (OR 0.96, 95% CI 0.88-1.04) nor hydrophilic statins (OR 1.06, 95% CI 0.95-1.20) impacted PC diagnosis. There was no effect of the dose or duration of statin use. Diagnosis of clinically significant PC decreased with statin use (OR 0.84, 95% CI 0.73-0.97). Statin use is not associated with overall PC risk, regardless of duration or dose of statin exposure. Statin use is associated with a decreased risk of clinically significant PC. PMID- 29405284 TI - Sports and Headaches. AB - In the United States, up to 3.8 million people per year have sports-related mild traumatic brain injury frequently followed by a variety of headaches. Headaches associated with sports (exertional, weightlifter's, and external compression headache) are also reviewed. PMID- 29405285 TI - Children with myelin oligodendrocyte glycoprotein antibodies-associated disease: relation of phenotypes to central nervous system myelin maturation. PMID- 29405286 TI - Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment. AB - Nervous system development is a precisely orchestrated series of events requiring a multitude of intrinsic and extrinsic cues. Sortilin and SorCS2 are members of the Vps10p receptor family with complementary influence on some of these cues including the neurotrophins (NTs). However, the developmental time points where sortilin and SorCS2 exert their activities in conjunction or independently still remain unclear. In this study we present the characterization of the spatiotemporal expression pattern of sortilin and SorCS2 in the developing murine nervous system. Sortilin is highly expressed in the fetal nervous system with expression localized to distinct cell populations. Expression was high in neurons of the cortical plate and developing allocortex, as well as subpallial structures. Furthermore, the neuroepithelium lining the ventricles and the choroid plexus showed high expression of sortilin, together with the developing retina, spinal ganglia, and sympathetic ganglia. In contrast, SorCS2 was confined in a marked degree to the thalamus and, at E13.5, the floor plate from midbrain rostrally to spinal cord caudally. SorCS2 was also found in the ventricular zones of the ventral hippocampus and nucleus accumbens areas, in the meninges and in Schwann cells. Hence, sortilin and SorCS2 are extensively present in several distinct anatomical areas in the developing nervous system and are rarely co expressed. Possible functions of sortilin and SorCS2 pertain to NT signaling, axon guidance and beyond. The present data will form the basis for hypotheses and study designs for unravelling the functions of sortilin and SorCS2 during the establishment of neuronal structures and connections. PMID- 29405287 TI - Gray matter volume of the anterior insular cortex and social networking. AB - In human life, social context requires the engagement in complex interactions among individuals as the dynamics of social networks. The evolution of the brain as the neurological basis of the mind must be crucial in supporting social networking. Although the relationship between social networking and the amygdala, a small but core region for emotion processing, has been reported, other structures supporting sophisticated social interactions must be involved and need to be identified. In this study, we examined the relationship between morphology of the anterior insular cortex (AIC), a structure involved in basic and high level cognition, and social networking. Two independent cohorts of individuals (New York group n = 50, Beijing group n = 100) were recruited. Structural magnetic resonance images were acquired and the social network index (SNI), a composite measure summarizing an individual's network diversity, size, and complexity, was measured. The association between morphological features of the AIC, in addition to amygdala, and the SNI was examined. Positive correlations between the measures of the volume as well as sulcal depth of the AIC and the SNI were found in both groups, while a significant positive correlation between the volume of the amygdala and the SNI was only found in the New York group. The converging results from the two groups suggest that the AIC supports network level social interactions. PMID- 29405288 TI - Interactive media versus human activities to reduce waiting room anxiety: what is the best option for children with disabilities? PMID- 29405289 TI - Role of artificial intelligence in the care of patients with nonsmall cell lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. In up to 57% of patients, it is diagnosed at an advanced stage and the 5-year survival rate ranges between 10%-16%. There has been a significant amount of research using machine learning to generate tools using patient data to improve outcomes. METHODS: This narrative review is based on research material obtained from PubMed up to Nov 2017. The search terms include "artificial intelligence," "machine learning," "lung cancer," "Nonsmall Cell Lung Cancer (NSCLC)," "diagnosis" and "treatment." RESULTS: Recent studies support the use of computer-aided systems and the use of radiomic features to help diagnose lung cancer earlier. Other studies have looked at machine learning (ML) methods that offer prognostic tools to doctors and help them in choosing personalized treatment options for their patients based on molecular, genetics and histological features. Combining artificial intelligence approaches into health care may serve as a beneficial tool for patients with NSCLC, and this review outlines these benefits and current shortcomings throughout the continuum of care. CONCLUSION: We present a review of the various applications of ML methods in NSCLC as it relates to improving diagnosis, treatment and outcomes. PMID- 29405290 TI - Degradation of L-Ascorbic Acid in the Amorphous Solid State. AB - : Ascorbic acid degradation in amorphous solid dispersions was compared to its degradation in the crystalline state. Physical blends and lyophiles of ascorbic acid and polymers (pectins and polyvinylpyrrolidone [PVP]) were prepared initially at 50:50 (w/w), with further studies using the polymer that best inhibited ascorbic acid crystallization in the lyophiles in 14 vitamin : PVP ratios. Samples were stored in controlled environments (25 to 60 degrees C, 0% to 23% RH) for 1 mo and analyzed periodically to track the physical appearance, change in moisture content, physical state (powder x-ray diffraction and polarized light microscopy), and vitamin loss (high performance liquid chromatography) over time. The glass transition temperatures of select samples were determined using differential scanning calorimetry, and moisture sorption profiles were generated. Ascorbic acid in the amorphous form, even in the glassy amorphous state, was more labile than in the crystalline form in some formulations at the highest storage temperature. Lyophiles stored at 25 and 40 degrees C and those in which ascorbic acid had crystallized at 60 degrees C (>=70% ascorbic acid : PVP) had no significant difference in vitamin loss (P > 0.05) relative to physical blend controls, and the length of storage had little effect. At 60 degrees C, amorphous ascorbic acid lyophiles (<=60% ascorbic acid : PVP) lost significantly more vitamin (P < 0.05) relative to physical blend controls after 1 wk, and vitamin loss significantly increased over time. In these lyophiles, vitamin degradation also significantly increased (P < 0.05) at lower proportions of ascorbic acid, a scenario likely encountered in foods wherein vitamins are naturally present or added at low concentrations and production practices may promote amorphization of the vitamin. PRACTICAL APPLICATION: Vitamin C is one of the most unstable vitamins in foods. This study documents that amorphous ascorbic acid is less stable than crystalline ascorbic acid in some environments (for example, higher temperatures within 1 wk), especially when the vitamin is present at low concentrations in a product. These findings increase the understanding of how material science properties influence the stability of vitamin C. PMID- 29405292 TI - Health-related quality of life of children and adolescents with cerebral palsy in low- and middle-income countries: a systematic review. AB - AIM: To systematically review literature on health-related quality of life (HRQoL) of children and adolescents (<=18yo) with cerebral palsy (CP) from low- and middle-income countries (LMICs) to identify trends in HRQoL and areas for future research. METHOD: We systematically reviewed six key bibliographic databases and two reviewers independently screened results. Peer-reviewed original articles examining HRQoL of children from LMICs were eligible. RESULTS: A total of 22 524 papers were identified, of which 16, from eight LMICs, were included. Four measures of HRQoL were used; Child Health Questionnaire Parent Form 50 (n=5); Paediatric Quality of Life Inventory 3.0 and 4.0 (n=4); CP Quality of Life Questionnaire for Children (n=4); Lifestyle Assessment Questionnaire CP (n=3). Children with CP from LMICs (n=1579; 2-18y) had significantly poorer HRQoL on all instrument dimensions when compared to age-matched controls (p<0.003) and on all except two dimensions when compared to peers in high-income countries (p<0.001). Physical well-being dimensions of HRQoL were poorest overall and associated with impaired motor function. INTERPRETATION: Research to improve HRQoL in LMICs is required and should address all aspects of HRQoL. Future research is recommended to incorporate multi-respondent assessment, utilize both general and CP-specific measures of HRQoL, and delineate adolescents as a unique cohort. What this paper adds Children with cerebral palsy from low- and middle income countries are at high risk of poor health-related quality of life (HRQoL). Physical well-being was poorest dimension of HRQoL and associated with impaired motor function. PMID- 29405291 TI - Upregulated N-cadherin expression is associated with poor prognosis in epithelial derived solid tumours: A meta-analysis. AB - BACKGROUND: N-cadherin is an important molecular in epithelial-mesenchymal transition (EMT) and has been reported to be associated with aggressive behaviours of tumours. However, prognostic value of N-cadherin in solid malignancies remains controversially. MATERIALS AND METHODS: The Pubmed/MELINE and EMBASE databases were used for a comprehensive literature searching. Pooled risk ratio (RR) and hazard ratio (HR) with their corresponding 95% confidence intervals (CIs) were employed to quantify the prognostic role. RESULTS: Involving 36 studies with 5705 patients were performed to investigate relationships between N-cadherin upregulation and clinicopathological features, survival. Results suggested upregulated N-cadherin was associated with lymph node metastasis (RR = 1.16, 95% CI [1.00, 1.35]), higher histological grade (RR = 1.36, 95%CI [1.14, 1.62]), angiolymphatic invasion (RR = 1.19, 95% CI [1.06, 1.34]) and advanced clinical stage (RR = 1.32, 95% CI [1.06, 1.64]), while upregulated N-cadherin was apt to be associated with distant metastasis (RR = 1.43, 95% CI [0.99, 2.05]). Moreover, N-cadherin was correlated with poor prognosis of 3-year survival (HR = 1.78, 95% CI [1.51, 2.10]), 5-year survival (HR = 1.57, 95% CI [1.17, 2.10]) and overall survival (OS) (HR = 1.32, 95% CI [1.20, 1.44]). Subgroup analyses according to cancer types were also conducted for applying these conclusions to some tumours more properly. No publication bias was found except subgroup analysis of distant metastasis (P = .652 for Begg's test and 0.023 for Egger's test). CONCLUSIONS: Taken together, upregulation of N-cadherin is associated with more aggressive behaviours of epithelial-derived solid malignancies and can be regarded as a predictor of poor survival. PMID- 29405293 TI - Frying of the Dispersion Droplets with Varying Contents of Chickpea Flour and Gum Arabic: Product Characterization and Modeling. AB - : Dispersions having chickpea (37%, 40%, and 43%, w/w) and gum arabic (0%, 1%, 2%, 3%, 4%, and 5%, w/w) solids were prepared. These dispersion droplets were fried, and the physical, sensory, and microstructural characteristics of the fried products were determined. The oil content in the fried snack decreased up to 20.3% when the level of chickpea and/or gum in the dispersions was increased. The compression curve for fried snack showed 5 major zones and exhibited the failure phenomenon. Failure force (6.5 to 11.4 N) increased with chickpea flour in the dispersions. Fracture strain (12.0% to 19.5%) indicated that all the fried samples were soft-crisp products. An increase in chickpea flour concentration offered an ovoid/oblong shape of dispersion droplets while falling to oil, and changed the spherical shape of the fried snack. The near-spherical product could be obtained by using 37% chickpea flour containing 0 to 2% of gum arabic, or with the 40% and 0 to 1% combinations. The hue or dominant wavelength increased from 578.5 nm (flour) to 581.0 to 582.7 nm (product) indicating a shift toward red coloration. A porous microstructure with scattered small cavities and large vacuoles of the fried snack were observed; big vacuoles were located in the inner portion of the fried product. The cells were divided into closed and open cells and were characterized by image analysis. The air cells usually had an elliptical shape with varying sizes; the cell wall thickness was between 12 and 80 MUm. An artificial neural network (ANN) structure of 2-9-2 was developed for the prediction of sensory overall acceptability and oil content of the fried snack. PRACTICAL APPLICATION: Chickpea flour is used in several food preparations. The addition of gum arabic affects the textural and structural characteristics, and the sensory acceptance; the fried dispersion droplets have a lower fat content when gum arabic is used compared to samples fried without the addition of gum arabic. The fried dispersion droplets change their shape with the level of the ingredients used in the dispersion. PMID- 29405295 TI - A new clinical tool for measuring limited selective voluntary motor control in cerebral palsy. PMID- 29405294 TI - Development of ON and OFF cholinergic amacrine cells in the human fetal retina. AB - Choline acetyltransferase (ChAT) expressing retinal amacrine cells are present across vertebrates. These interneurons play important roles in the development of retinal projections to the brain and in motion detection, specifically in generating direction-selective responses to moving stimuli. ChAT amacrine cells typically comprise two spatially segregated populations that form circuits in the 'ON' or 'OFF' synaptic layers of the inner retina. This stereotypic arrangement is also found across the adult human retina, with the notable exception that ChAT expression is evident in the ON but not OFF layer of the fovea, a region specialized for high-acuity vision. We thus investigated whether the human fovea exhibits a developmental path for ON and OFF ChAT cells that is retinal location specific. Our analysis shows that at each retinal location, human ON and OFF ChAT cells differentiate, form their separate synaptic layers, and establish non random mosaics at about the same time. However, unlike in the adult fovea, ChAT immunostaining is initially robust in both ON and OFF populations, up until at least mid-gestation. ChAT expression in the OFF layer in the fovea is therefore significantly reduced after mid-gestation. OFF ChAT cells in the human fovea and in the retinal periphery thus follow distinct maturational paths. PMID- 29405296 TI - Comparative analysis of the transcriptome of injured nerve segments reveals spatiotemporal responses to neural damage in mice. AB - Nerves are particularly vulnerable to damage due to their unique structure with meter-long axons. In the peripheral nervous system neurons and Schwann cells can activate the injury-response program that directs axons to either regenerate or degenerate after traumatic nerve injury. However, the differences between the genetic programs driving nerve regeneration and degeneration have not yet been described extensively. To understand these differences, in this study we have compared the injury-induced transcriptomic changes between the regenerating proximal segment and the degenerating distal segment of a transected nerve, at different post-injury time points. We analyzed the spatiotemporal dynamics of the mouse transcriptome using a sciatic nerve-injury model by means of RNA sequencing. The results of the differentially regulated genes (DEGs) analysis show that some DEG groups are similarly regulated in both proximal and distal segments, and primarily display a positive correlation. However, some DEG groups are exclusively regulated in either the proximal or the distal segment, suggesting that these DEG groups constitute a genetic network for distinguishing the regenerative and degenerative responses. In addition, our gene ontology analysis revealed an enrichment of particular biological processes in different phases and locations. Thus, our data provide a spatiotemporal profile of the transcriptomes that are differentially regulated in either regenerating or degenerating nerves, in vivo. The specific biological processes enriched in the DEG groups might delineate the injury-responsive program that induces contrasting regenerative and degenerative responses in different nerve segments. PMID- 29405297 TI - The influence of smoking, age and stage at diagnosis on the survival after larynx, hypopharynx and oral cavity cancers in Europe: The ARCAGE study. AB - Head and neck cancer (HNC) is a preventable malignancy that continues to cause substantial morbidity and mortality worldwide. Using data from the ARCAGE and Rome studies, we investigated the main predictors of survival after larynx, hypopharynx and oral cavity (OC) cancers. We used the Kaplan-Meier method to estimate overall survival, and Cox proportional models to examine the relationship between survival and sociodemographic and clinical characteristics. 604 larynx, 146 hypopharynx and 460 OC cancer cases were included in this study. Over a median follow-up time of 4.6 years, nearly 50% (n = 586) of patients died. Five-year survival was 65% for larynx, 55% for OC and 35% for hypopharynx cancers. In a multivariable analysis, we observed an increased mortality risk among older (>=71 years) versus younger (<=50 years) patients with larynx/hypopharynx combined (LH) and OC cancers [HR = 1.61, 95% CI 1.09-2.38 (LH) and HR = 2.12, 95% CI 1.35-3.33 (OC)], current versus never smokers [HR = 2.67, 95% CI 1.40-5.08 (LH) and HR = 2.16, 95% CI 1.32-3.54 (OC)] and advanced versus early stage disease at diagnosis [IV versus I, HR = 2.60, 95% CI 1.78-3.79 (LH) and HR = 3.17, 95% CI 2.05-4.89 (OC)]. Survival was not associated with sex, alcohol consumption, education, oral health, p16 expression, presence of HPV infection or body mass index 2 years before cancer diagnosis. Despite advances in diagnosis and therapeutic modalities, survival after HNC remains low in Europe. In addition to the recognized prognostic effect of stage at diagnosis, smoking history and older age at diagnosis are important prognostic indicators for HNC. PMID- 29405298 TI - Medical imaging data in the digital innovation age. AB - As we reflect on decades of exponential advancements in electronic innovation, we can see the field of medical imaging eclipsed by a new digital landscape - one that is inexpensive, fast, and powerful. This new paradigm presents new opportunities to innovate in both research and clinical settings. In this article, we review the current role of data: the common perceptions around its valuation and the infrastructure currently in place for data-driven innovation. Looking forward, we consider what has already been achieved using modern data capacities, the opportunities we have for further expansion in this area, and the obstacles we will need to transcend. PMID- 29405299 TI - Adult-onset primary cyclic autoimmune neutropenia: a case report. AB - BACKGROUND: A few cases of primary autoimmune neutropenia (AIN) have been reported in adults, but cyclic primary AIN, which is characterized by the periodic oscillation of neutrophils, is uncommon in adults. STUDY DESIGN AND METHODS: Herein, we report a 70-year-old man referred to our hospital with severe neutropenia and thrombocytopenia. He had experienced intermittent episodes of low extremity purpura for the past 3 months, with cellulitis on the skin of the scalp 1 month previously. RESULTS: The patient presented with severely low neutrophil and platelet (PLT) counts. Myeloid progenitors and megakaryocytes were increased in the marrow, but mature neutrophils were remarkably decreased. Anti-neutrophil antibodies to specific epitopes were detected at neutropenia. Based on these findings, AIN accompanied by autoimmune thrombocytopenia was diagnosed. The patient experienced synchronous fluctuations of neutrophil and PLT counts three times. Despite no treatment, the neutrophil count fluctuated within the range of 0.06 * 109 to 1.65 * 109 /L, and the PLT count fluctuated from 0.7 * 1010 to 20.5 * 1010 /L. We identified an inverse relationship between neutrophil count and anti-neutrophil antibody titers, establishing the conclusive diagnosis of cyclic AIN. After prednisolone treatment, the neutrophil and PLT counts normalized, and the patient has maintained long-term remission. CONCLUSION: We report a rare case of cyclic AIN diagnosed from the inverse association between periodic oscillation of anti-neutrophil antibody titers and neutrophil counts. This clinical course suggests that in AIN patients, laboratory data and recurrent signs of infection should be monitored regularly, including shortly after neutrophil recovery. PMID- 29405300 TI - Evidence of effectiveness of preventive dental care in reducing dental treatment use and related expenditures. AB - OBJECTIVES: Preventive dental health services are intended to reduce the likelihood of development of tooth decay and the need for more intensive treatment overtime. The evidence on the effectiveness of preventive dental care in reducing treatment services and expenditures is lagging for adults, particularly those with lower incomes and chronic conditions. We assessed the impact of preventive dental services on dental treatment service use and expenditures overall and by category of service. METHODS: We calculated the annual numbers of preventive (periodic diagnostic and prophylactic procedures) and treatment (restorative, surgery, prosthodontic, endodontic, and periodontic) services per beneficiary using Medicaid enrollment and claims data for beneficiaries with three categories of conditions (diabetes, heart disease, and respiratory disease) from 10 largest California counties. We used Cragg hurdle exponential regression models controlling for past service use, demographics, length of enrollment, and county. RESULTS: We found that using preventive services in 2005-2007 was associated with higher likelihood and number of treatment dental services used, but associated with lower treatment expenditures in 2008. The reduction in expenditures was noted only in restorative, prosthodontics, and periodontic services. CONCLUSIONS: The findings provide much needed evidence of the contribution of preventive dental care in maintaining oral health of low-income adults with chronic conditions and potential for savings to the Medicaid program. Providing lower cost preventive dental care to the individuals with chronic conditions would achieve better oral health and lower treatment expenditures. PMID- 29405301 TI - Monte Carlo simulations of elemental imaging using the neutron-associated particle technique. AB - PURPOSE: The purpose of this study is to develop and employ a Monte Carlo (MC) simulation model of associated particle neutron elemental imaging (APNEI) in order to determine the three-dimensional (3D) imaging resolution of such a system by examining relevant physical and technological parameters and to thereby begin to explore the range of clinical applicability of APNEI to fields such as medical diagnostics, intervention, and etiological research. METHODS: The presented APNEI model was defined in MCNP by a Gaussian-distributed and isotropic surface source emitting deuterium + deuterium (DD) neutrons, iron as the target element, nine iron-containing voxels (1 cm3 volume each) arranged in a 3-by-3 array as the interrogated volume of interest, and finally, by high-purity germanium (HPGe) gamma-ray detectors anterior and posterior to the 9-voxel array. The MCNP f8 pulse height tally was employed in conjunction with the PTRAC particle tracking function to not only determine the signal acquired from iron inelastic scatter gamma-rays but also to quantitate each of the nine target voxels' contribution to the overall iron signal - each detected iron inelastic scatter gamma-ray being traced to the source neutron which incited its emission. RESULTS: With the spatial, vector, and timing information of the series of events for each relevant neutron history as collected by PTRAC, realistic grayscale images of the distribution of iron concentration in the 9-voxel array were simulated in both the projective and depth dimensions. With an overall 225 ps timing resolution, 6.25 mm2 imaging plate pixels assumed to have well localized scintillation, and a DD neutron, Gaussian-distributed source spot with a diameter of 2 mm, projective and depth resolutions of < 1 cm and <3 cm are achievable, respectively, for iron containing voxels on the order of 1,000 ppm Fe. CONCLUSIONS: The imaging resolution offered by APNEI of target elements such as iron lends itself to potential applications in disease diagnosis and treatment planning (high resolution) as well as to ordnance and contraband detection (low resolution). However, experimental study beyond simulation is required to optimize the layout and electronic configuration of APNEI system components - including realistic shielding and phantom materials - for background signal reduction in order to accurately determine the detection limits and spatial resolution of iron and other elements of interest on a case-by-case basis. PMID- 29405302 TI - Changes in plasma unit distributions to hospitals over a 10-year period. AB - BACKGROUND: There are many influences on a hospital's demand for plasma. Pharmaceuticals are now being administered for many indications instead of plasma, although trauma resuscitation now emphasizes increased and early intervention with plasma. This multinational study evaluated changes in blood center plasma unit distributions over a 10-year period. STUDY DESIGN AND METHODS: Data on the total number and the ABO groups of plasma unit distributions were obtained from nine American blood collectors (ABCs) and nine national or provincial blood services (NPBS) from 2007 through 2016. Plasma distributions to trauma hospitals by five ABCs and four NPBS were also analyzed. RESULTS: The overall number of plasma unit distributions from ABCs decreased by 23.1% from 2007 to 2016, but the relative proportion of distributed AB plasma units increased during the same period. The NPBS (excluding the Japanese Red Cross [JRC]) also had a 35.4% decrease in the overall number of plasma unit distributions with an increase in the relative proportion of AB plasma distributions between 2007 and 2016. The JRC, however, reported an increase in the overall number of plasma distributions by 13.5% in 2016 compared to 2007. The proportion of low-titer A plasma distributions increased to 1.6% of total plasma distributions by ABCs in 2016. There was a trend of distributing increasing proportions of group AB plasma units to trauma hospitals over the 10-year period. CONCLUSION: Although the number of plasma unit distributions has decreased at many blood collectors over time, the proportion of AB units has increased at both ABCs and NPBS. PMID- 29405303 TI - Iron deficiency and preoperative anaemia in patients scheduled for elective hip- and knee arthroplasty - an observational study. AB - BACKGROUND AND OBJECTIVES: Preoperative anaemia is prevalent in elderly patients scheduled for major orthopaedic surgery and is associated with increased transfusion risk and postoperative morbidity. New guidelines recommend preoperative correction of anaemia and iron deficiency in all patients with a Hb < 13 g/dl. However, iron deficiency and other causes of preoperative anaemia in hip- (THA) and knee (TKA) arthroplasty are only sparsely studied. MATERIALS AND METHODS: Preoperative Hb and iron status were prospectively collected from 882 unselected elective fast-track THA/TKA patients and analysed according to both WHO anaemia criteria (Hb < 12 g/dl females, <13 g/dl males) and Hb < 13 g/dl for both genders. Iron deficiency (ID) and other possible anaemia causes were classified by ferritin, transferrin saturation, P-cobalamin, P-folate, C-reactive protein and creatinine. RESULTS: Ninety-five (10.8%) and 243 (27.6%) of the study population were WHO anaemic or had a Hb < 13 g/dl, respectively. Transfusion was more common in anaemic vs. non-anaemic patients 43 vs. 13%; (P < 0.001), and in patients with Hb < 13 g/dl vs. Hb > 13 g/dl 28 vs. 11% (P < 0.001). 154 (17.5%) of all patients had ID, and ID was the most common cause of anaemia with a prevalence of 41% in WHO anaemic patients and 33% in patients with Hb < 13 g/dl. A further 19 (20%) and 46 (19%) patients, respectively, had evidence of iron sequestration. CONCLUSION: Anaemia is prevalent prior to THA and TKA with iron deficiency as the most common and reversible cause. PMID- 29405304 TI - Transfusion reactions after transfusion of platelets stored in PAS-B, PAS-C, or plasma: a nationwide comparison. AB - BACKGROUND: Platelets (PLTs) stored in PLT additive solution (PAS) are associated with fewer allergic reactions than plasma-stored PLTs. However, earlier studies could not provide conclusive evidence on febrile reactions and did not analyze other transfusion reactions separately due to limited sample size. We therefore compared incidences of all transfusion reactions of PAS-B-PLTs, PAS-C-PLTs, and plasma-PLTs. STUDY DESIGN AND METHODS: In this observational study, all transfusion reactions reported to the national hemovigilance office of the Netherlands from 2006 to 2015 were included. RESULTS: During the study period, a total of 2407 transfusion reactions after PLT transfusions were reported. In that period 553,267 pooled buffy coat-derived PLT units were issued, of which 83,884 were stored in PAS-B, 45,728 in PAS-C, and 423,655 in plasma. Regarding transfusion-related circulatory overload, transfusion-related acute lung injury, and "other reactions" no significant differences were observed between the PLT products. When PAS-B-PLT transfusions were compared to plasma-PLT transfusions, the overall relative risk (RR; 95% confidence interval [CI]) of transfusion reactions was 0.99 (0.88-1.11); for allergic and febrile nonhemolytic transfusion reactions (FNHTRs) it was 0.66 (0.55-0.80) and 1.54 (1.27-1.86), respectively. When PAS-C-PLTs were compared to plasma-PLTs, the RR (95% CI) was 0.56 (0.46 0.68) for all transfusion reactions, 0.38 (0.28-0.52) for allergic reactions, and 0.82 (0.59-1.13) for FNHTRs. When PAS-C-PLTs were compared to PAS-B-PLTs, for all reactions the RR (95% CI) was 0.56 (0.45-0.70) for allergic reactions 0.58 (0.40 0.82), and for FNHTRs 0.53 (0.37-0.75). CONCLUSIONS: PAS-C-PLTs are associated with fewer transfusion reactions compared to plasma-PLTs and compared to PAS-B PLTs. PMID- 29405305 TI - Becoming a nurse faculty leader: Taking risks by being willing to fail. AB - BACKGROUND: Higher education is undergoing rapid transformation requiring nurse faculty leaders to engage in risk taking. Consequently, what is known about the experience of taking risks? How do leaders decide what constitutes a risk worth taking? How do leaders who take risks tolerate failure? The purpose of this study was to explicate the leadership practices of risk taking in nurse faculty leaders. METHOD: Interpretive phenomenology was used to explore the experience of risk taking among 15 self-identified nurse faculty leaders. Unstructured audio recorded interviews were conducted in which participants described their experiences of taking risks. Transcribed interviews were analyzed by a research team to uncover themes in the narrative data. RESULTS: A theme, willingness to fail, and three subthemes, enacting a culture of experimentation, working hard for success, and learning from failure are reported. CONCLUSION: This study provides practical know-how and an evidence-base to support nurse academic leaders in the practice of risk taking during these challenging times in higher education. PMID- 29405306 TI - Pathogen reduction combined with rapid diagnostic tests to reduce the risk of transfusion-transmitted infections in Uganda. AB - BACKGROUND: Blood safety and transfusion-transmitted infections (TTIs) are a major concern in low-resource areas. Laboratory screening of donors, a key contributor to blood safety, is usually done by enzyme-linked immunosorbent assay (ELISA) methods, which use expensive reagents and necessitate complex instruments and sophisticated laboratory staff. Rapid diagnostic tests (RDTs) are less expensive and easier to perform but have less sensitivity. Pathogen reduction technology (PRT) reduces transfusion transmission of malaria and may be effective in decreasing other TTIs. We explored the potential to improve blood safety by combining PRT and RDTs in comparison with current ELISA testing. STUDY DESIGN AND METHODS: We identified the sensitivity of RDTs available in Uganda and the sensitivity of currently used ELISA. Data from a riboflavin-and-UV-based photochemical treatment PRT were used. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and malaria were studied. Probability models were developed for estimation of the number of infectious units of blood for each of these four infections using either current ELISA or the combination of RDT and PRT. RESULTS: Compared to currently used ELISA, the combination of RDTs and PRT could reduce the rate of infectious units by 100, 20, 98, and 83% for HIV, HBV, HCV, and malaria, respectively, and would prevent use of 758 units of infectious blood per 10,000 units transfused. CONCLUSION: The combination of RDTs and PRT may improve blood safety in low-resource areas. PMID- 29405307 TI - Feasibility of real-time motion management with helical tomotherapy. AB - PURPOSE: This study investigates the potential application of image-based motion tracking and real-time motion correction to a helical tomotherapy system. METHODS: A kV x-ray imaging system was added to a helical tomotherapy system, mounted 90 degrees offset from the MV treatment beam, and an optical camera system was mounted above the foot of the couch. This experimental system tracks target motion by acquiring an x-ray image every few seconds during gantry rotation. For respiratory (periodic) motion, software correlates internal target positions visible in the x-ray images with marker positions detected continuously by the camera, and generates an internal-external correlation model to continuously determine the target position in three-dimensions (3D). Motion correction is performed by continuously updating jaw positions and MLC leaf patterns to reshape (effectively re-pointing) the treatment beam to follow the 3D target motion. For motion due to processes other than respiration (e.g., digestion), no correlation model is used - instead, target tracking is achieved with the periodically acquired x-ray images, without correlating with a continuous camera signal. RESULTS: The system's ability to correct for respiratory motion was demonstrated using a helical treatment plan delivered to a small (10 mm diameter) target. The phantom was moved following a breathing trace with an amplitude of 15 mm. Film measurements of delivered dose without motion, with motion, and with motion correction were acquired. Without motion correction, dose differences within the target of up to 30% were observed. With motion correction enabled, dose differences in the moving target were less than 2%. Nonrespiratory system performance was demonstrated using a helical treatment plan for a 55 mm diameter target following a prostate motion trace with up to 14 mm of motion. Without motion correction, dose differences up to 16% and shifts of greater than 5 mm were observed. Motion correction reduced these to less than a 6% dose difference and shifts of less than 2 mm. CONCLUSIONS: Real-time motion tracking and correction is technically feasible on a helical tomotherapy system. In one experiment, dose differences due to respiratory motion were greatly reduced. Dose differences due to nonrespiratory motion were also reduced, although not as much as in the respiratory case due to less frequent tracking updates. In both cases, beam-on time was not increased by motion correction, since the system tracks and corrects for motion simultaneously with treatment delivery. PMID- 29405308 TI - Ecodesign of cosmetic formulae: methodology and application. AB - OBJECTIVE: This article describes an easy-to-use ecodesign methodology developed and applied since 2014 by the L'Oreal Group to improve the sustainable performance of its new products without any compromise on their cosmetic efficacy. METHODS: Cosmetic products, after being used, are often discharged into the sewers and the aquatic compartment. This discharge is considered as dispersive and continuous. A consistent progress in reducing the environmental impact of cosmetic products can be achieved through focusing upon three strategic indicators: biodegradability, grey water footprint adapted for ecodesign (GWFE) and a global indicator, complementary to these two endpoints. Biodegradability represents the key process in the removal of organic ingredients from the environment. GWFE is defined herein as the theoretical volume of natural freshwater required to dilute a cosmetic formula after being used by the consumer, down to a concentration without any foreseeable toxic effects upon aquatic species. Finally, the complementary indicator highlights a possible alert on formula ingredients due to an unfavourable environmental profile based on hazard properties: for example Global Harmonization System/Classification, Labelling and Packaging (GHS/CLP) H410 classification or potential very persistent and very bioaccumulative (vPvB) classification. RESULTS: The ecodesign of a new cosmetic product can be a challenge as the cosmetic properties and quality of this new product should at least match the benchmark reference. As shown in the case studies described herein, new methodologies have been developed to maximize the biodegradability of cosmetic formulae, to minimize their GWFE and to limit the use of ingredients that present an unfavourable environmental profile, while reaching the highest standards in terms of cosmetic efficacy. CONCLUSION: By applying these methodologies, highly biodegradable products (>= 95% based on ingredient composition) have been developed and marketed, with a low GWFE. This new ecodesign approach shows that embedding sustainability in developing new cosmetic products can also open up new innovative opportunities. PMID- 29405309 TI - Aspirin does not prevent growth of vestibular schwannomas: A case-control study. AB - OBJECTIVES/HYPOTHESIS: To determine if aspirin intake is associated with reduced growth of vestibular schwannomas (VS). To determine the prevalence of contraindications to regular aspirin in patients with VS. STUDY DESIGN: Retrospective, observational case-control study. METHODS: The study utilized a postal questionnaire and telephone interviews to determine aspirin exposure. Propensity score matching was used to control for age, sex, and tumor size. Cases were defined as patients with VS proven to have grown on serial magnetic resonance imaging (MRI). Controls were defined as patient with VS stable on serial MRI. Prevalence of regular aspirin use was compared in patients with growing VS versus stable VS. Absolute and relative contraindications to aspirin intake were recorded. RESULTS: Six hundred fifty-three patients with VS were contacted, and responses were received by 67% (220 cases and 217 controls). The mean tumor size was 11.3 mm (9.0 mm and 13.3 mm in controls and cases, respectively). Aspirin exposure was more common in stable VS than growing VS (22.1% vs. 17.3%). However, following matching to control for covariates, aspirin was not found to be associated with VS stability (P = .475). Multiple logistic regression (analysis of variance) found tumor size to be the only factor strongly associated with tumor growth (P < .0001). Ninety-two percent of patients were able to take aspirin, with the majority being at low risk of complications from regular use. CONCLUSIONS: This study aimed to examine the relationship between aspirin intake and VS stability. In contrast to previous reports, after controlling for covariates, the findings do not demonstrate an association. Only tumor size at diagnosis appears predictive of risk of VS growth. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:2139-2144, 2018. PMID- 29405310 TI - Development and validation of the mastocytosis activity score. AB - BACKGROUND: Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific and validated instrument to measure and monitor signs and symptoms in patients with mastocytosis. OBJECTIVE: To develop and validate a disease-specific tool to measure and monitor the activity of signs and symptoms in patients with mastocytosis, the Mastocytosis Activity Score (MAS). METHODS: Nineteen potential MAS items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients followed by a review for face validity. The resulting MAS was tested for validity, reliability and influence factors. In parallel, a US American English version of the MAS was developed. RESULTS: A total of 68 mastocytosis patients took part in the MAS validation study. The final 9-item MAS was found to have a three-domain structure ("skin," "gastrointestinal tract" and "other"), a valid total score and an excellent test retest reliability. Multiple regression analysis revealed that disease duration, age or gender is not a significant determinant of the MAS results. CONCLUSIONS: The MAS is a disease-specific, valid and reliable patient-reported outcome measure for adult patients with cutaneous and indolent systemic mastocytosis. It may serve as a valuable tool to measure and monitor mastocytosis activity, both, in clinical trials and in routine care. PMID- 29405311 TI - Internal breast dosimetry in mammography: Experimental methods and Monte Carlo validation with a monoenergetic x-ray beam. AB - PURPOSE: To investigate the performance, such as energy dependence and sensitivity, of thermoluminescent dosimeters (TLD), metal oxide semiconductor field-effect transistor dosimeters (MOSFET), and GafChromicTM films, and to validate the estimates of local dose deposition of a Monte Carlo (MC) simulation for breast dosimetry applications. METHODS: Experimental measurements were performed using a monoenergetic beam at the ELETTRA synchrotron radiation light source (Trieste, Italy). The three types of dosimeters were irradiated in a plane transversal to the beam axis and calibrated in terms of air kerma. The sensitivity of MOSFET dosimeters and GafChromicTM films was evaluated in the range of 18-28 keV. Three different calibration curves for the GafChromicTM films were tested (logarithmic, rational, and exponential functions) to evaluate the best-fit curve in the dose range of 1-20 mGy. Internal phantom dose measurements were performed at 20 keV for four different depths (range 0-3 cm, with 1 cm steps) using a homogeneous 50% glandular breast phantom. A GEANT4 MC simulation was modified to match the experimental setup. Thirty sensitive volumes, on the axial-phantom plane were included at each depth in the simulation to characterize the internal dose variation and compare it to the experimental TLD and MOSFET measurements. Experimental 2D dose maps were obtained with the GafChromicTM films and compared to the simulated 2D dose distributions estimated with the MC simulations. RESULTS: The sensitivity of the MOSFET dosimeters and GafChromicTM films increased with x-ray energy, by up to 37% and 48%, respectively. Dose response curves for the GafChromicTM film result in an uncertainty lower than 5% above 6 mGy, when a logarithmic relationship is used in the dose range of 1-10 mGy. All experimental values fall within the experimental uncertainty and a good agreement (within 5%) is found against the MC simulation. The dose decreased with increasing phantom depth, with the reduction being ~80% after 3 cm. The uncertainty of the empirical measurements makes the experimental values compatible with a flat behavior across the phantom slab for all the investigated depths, while the MC points to a dose profile with a maximum toward the center of the phantom. CONCLUSIONS: The calibration procedures and the experimental methodologies proposed lead to good accuracy for internal breast dose estimation. In addition, these procedures can be successfully applied to validate MC codes for breast dosimetry at the local dose level. The agreement among the experimental and MC results not only shows the correctness of the empirical procedures used but also of the simulation parameters. PMID- 29405312 TI - Microscale isolation of native forms of lysozyme from chicken egg white by gel isoelectric focusing. AB - To separate and extract the native states of lysozyme from chicken egg white, a hybrid method for the mobilization of proteins after non-denaturing gel isoelectric focusing (IEF) combined with detection of lysozyme activity was developed. When the proteins in the chicken egg white were first separated using non-denaturing gel IEF, a lysozyme was obtained at the top of the gel column at the cathode end of the IEF. And, when the IEF-separated proteins of the egg white were mobilized by replacing the cathodic sodium hydroxide solution with phosphoric acid solution, an additional active state of the lysozyme that could be bound to proteins, such as ovotransferrin, was extracted from the solution. Furthermore, it was shown that the addition of lysozyme, obtained via IEF, to pure ovotransferrin generated a complex manifesting lysozyme activity, clearly indicating a successful reconstruction of the lysozyme-ovotransferrin complex in vitro. Therefore, the obtained results demonstrated that the native states of lysozymes, such as lysozyme and the lysozyme-ovotransferrin complex, can be effectively separated and extracted using non-denaturing gel IEF. Thus, this method can be applied to separate and extract different charge states of native proteins that retain their biological activities. PMID- 29405313 TI - Dual respiratory and cardiac motion estimation in PET imaging: Methods design and quantitative evaluation. AB - PURPOSE: The goal of this study was to develop and evaluate four post reconstruction respiratory and cardiac (R&C) motion vector field (MVF) estimation methods for cardiac 4D PET data. METHOD: In Method 1, the dual R&C motions were estimated directly from the dual R&C gated images. In Method 2, respiratory motion (RM) and cardiac motion (CM) were separately estimated from the respiratory gated only and cardiac gated only images. The effects of RM on CM estimation were modeled in Method 3 by applying an image-based RM correction on the cardiac gated images before CM estimation, the effects of CM on RM estimation were neglected. Method 4 iteratively models the mutual effects of RM and CM during dual R&C motion estimations. Realistic simulation data were generated for quantitative evaluation of four methods. Almost noise-free PET projection data were generated from the 4D XCAT phantom with realistic R&C MVF using Monte Carlo simulation. Poisson noise was added to the scaled projection data to generate additional datasets of two more different noise levels. All the projection data were reconstructed using a 4D image reconstruction method to obtain dual R&C gated images. The four dual R&C MVF estimation methods were applied to the dual R&C gated images and the accuracy of motion estimation was quantitatively evaluated using the root mean square error (RMSE) of the estimated MVFs. RESULTS: Results show that among the four estimation methods, Methods 2 performed the worst for noise-free case while Method 1 performed the worst for noisy cases in terms of quantitative accuracy of the estimated MVF. Methods 4 and 3 showed comparable results and achieved RMSE lower by up to 35% than that in Method 1 for noisy cases. CONCLUSION: In conclusion, we have developed and evaluated 4 different post-reconstruction R&C MVF estimation methods for use in 4D PET imaging. Comparison of the performance of four methods on simulated data indicates separate R&C estimation with modeling of RM before CM estimation (Method 3) to be the best option for accurate estimation of dual R&C motion in clinical situation. PMID- 29405314 TI - A comparison of contact force and remote magnetic navigation on lesion formation for the ablation of atrial fibrillation. AB - RATIONALE: Pulmonary vein isolation (PVI) is the method of choice for the treatment of drug-resistant atrial fibrillation (AF). However, arrhythmia recurrences are frequent due to suboptimal lesions formation and pulmonary vein reconnection. Contact force (CF)- and remote magnetic navigation (RMN)-guided catheters are both capable of improving contact and energy transfer to the tissue, possibly improving PVI outcome. OBJECTIVE: The objective of our study was to compare CF- and RMN-guided PVI in patients with paroxysmal AF in terms of surrogate parameters of the dimension and quality of the lesions. METHODS AND RESULTS: Between March 2014 and March 2016, 44 patients affected by paroxysmal AF underwent a circumferential PVI procedure, 22 with a CF catheter and 22 with a RMN catheter. Signals were recorded before and after 30 seconds of radiofrequency point-by-point delivery. For each location, signal energy attenuation and impedance drop were evaluated as lesion dimension surrogates and signal fragmentation and shrinkage were estimated as lesion quality surrogates. Statistical analysis shows that CF catheter achieves higher attenuation and impedance drop than RMN-guided catheter, which instead performs better in terms of shrinkage and fragmentation. There were no differences in terms of PVI rate and sinus rhythm maintenance 1 year after the procedure (77.2% in both groups). CONCLUSIONS: CF-guided catheters produce lesions that are larger but less homogeneous than those produced by RMN-guided catheters in terms of surrogate parameters. These two features could possibly offset each other, resulting in identical acute and long-term outcomes. PMID- 29405315 TI - Comparative study of cyto- and genotoxic potential with mechanistic insights of tungsten oxide nano- and microparticles in lung carcinoma cells. AB - The exigency of semiconductor and super capacitor tungsten oxide nanoparticles (WO3 NPs) is increasing in various sectors. However, limited information on their toxicity and biological interactions are available. Hence, we explored the underlying mechanisms of toxicity induced by WO3 NPs and their microparticles (MPs) using different concentrations (0-300 MUg ml-1 ) in human lung carcinoma (A549) cells. The mean size of WO3 NPs and MPs by transmission electron microscopy was 53.84 nm and 3.88 MUm, respectively. WO3 NPs induced reduction in cell viability, membrane damage and the degree of induction was size- and dose dependent. There was a significant increase in the percentage tail DNA and micronuclei formation at 200 and 300 MUg ml-1 after 24 hours of exposure. The DNA damage induced by WO3 NPs could be attributed to increased oxidative stress and inflammation through reactive oxygen species generation, which correlated with the depletion of reduced glutathione content, catalase and an increase in malondialdehyde levels. Cellular uptake studies unveiled that both the particles were attached/surrounded to the cell membrane according to their size. In addition, NP inhibited the progression of the cell cycle in the G2 /M phase. Other studies such as caspase-9 and -3 and Annexin-V-fluorescein isothiocyanate revealed that NPs induced intrinsic apoptotic cell death at 200 and 300 MUg ml-1 concentrations. However, in comparison to NPs, WO3 MPs did not incite any toxic effects at the tested concentrations. Under these experimental conditions, the no observed-significant-effect level of WO3 NPs was determined to be <=200 MUg ml-1 in A549 cells. PMID- 29405316 TI - Acquired long QT syndrome and torsade de pointes. AB - Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug-induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and torsade de pointes, electrocardiographic characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field. PMID- 29405318 TI - The new world of placenta accreta spectrum disorders. PMID- 29405317 TI - FIGO consensus guidelines on placenta accreta spectrum disorders: Nonconservative surgical management. PMID- 29405319 TI - FIGO consensus guidelines on placenta accreta spectrum disorders: Prenatal diagnosis and screening. PMID- 29405320 TI - FIGO consensus guidelines on placenta accreta spectrum disorders: Conservative management. PMID- 29405321 TI - FIGO consensus guidelines on placenta accreta spectrum disorders: Epidemiology. PMID- 29405323 TI - Remote magnetic navigation versus contact force technology: The two faces of the ablation lesion. PMID- 29405322 TI - FIGO consensus guidelines on placenta accreta spectrum disorders: Introduction. PMID- 29405324 TI - Combination of the best pacing configuration and atrioventricular and interventricular delays optimization in cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy optimization can be pursued by left ventricular pacing vector selection and atrioventricular (AV) and interventricular (VV) delays optimization. The combination of these methods and its comparison with multipoint pacing (MPP) is scarcely studied. METHODS: Using noninvasive cardiac output (CO) measurement, the best of five left ventricular pacing vectors was determined, then AV and VV delays optimization was applied on top of the best vector. Response to the optimization protocol was defined as a >5% CO increase compared to the standard biventricular configuration. RESULTS: Twenty-two patients (18 men, age 71 +/- 9 years) were included. Standard biventricular configuration increased CO compared to baseline (4.65 +/- 1.55 L/min vs 4.27 +/- 1.53 L/min, respectively, P = 0.02). The best quadripolar configuration increased CO to 4.85 +/- 1.67 L/min (P = 0.03 compared to the standard biventricular configuration). AV then VV delay optimization both provided additional benefit (final CO 5.56 +/- 2.03 L/min, P = 0.001 compared to the best quadripolar configuration). Fifteen (68%) patients responded to the optimization protocol. Anatomical MPP (based on maximal anatomical separation between electrodes) and electrical MPP (based on maximal electrical activation difference between electrodes) were evaluated in 16 patients and yielded a CO similar to that of the optimization procedure. CONCLUSIONS: The combination of choosing the best quadripolar pacing configuration and optimizing atrioventricular and interventricular delays resulted in an improvement of cardiac output compared to standard biventricular stimulation in 68% of patients. The final cardiac output was comparable to multipoint pacing. PMID- 29405325 TI - Are There Really Too Many Eukaryote LGTs? A Reply To William Martin. PMID- 29405326 TI - Hemodynamic Effects of Connection to Continuous Renal Replacement Therapy in a Pediatric Animal Model. AB - To assess the hemodynamic effects of connection to continuous renal replacement therapy (CRRT) in a pediatric experimental animal model. Prospective experimental study was performed using piglets between 2 and 3 months of age and 9-11 kg. CRRT with a PrismaflexR monitor and HF20 filter (surface of 0.2 m2 ) was started after monitoring and anesthetic induction with an initial blood flow at 20 mL/min with 10 mL/min increases every minute until the goal flow of 5 mL/kg/min was achieved. Heart rate, blood pressure, central venous pressure, cardiac index, and renal blood flow were registered at baseline, 5, 15, 30, 60, 120, 180, 240, and 360 min. IBM SPSS Statistics 20.0 package was used for analysis. A P value of <0.05 was considered statistically significant. Thirty-four piglets were studied. Blood pressure, cardiac output, and systemic vascular resistance significantly decreased 5-min after CRRT connection (mean arterial pressure from 85.5 to 70.8 mm Hg, P < 0.001, cardiac index from 3.6 to 3.3 L/min/m2 P = 0.024, and systemic vascular resistance index from 1759 to 1607 dyn.s/cm5 P = 0.012). No significant changes were found in renal blood flow or central venous pressure. All parameters gradually increased at 15 and 30 min after connection but complete recovery was never achieved. Connection to CRRT produces a significant decrease in arterial pressure, cardiac index, and peripheral vascular resistances in hemodynamically stable piglets. PMID- 29405327 TI - Quality indicators in a community optometrist led cataract shared care scheme. AB - PURPOSE: Cataract shared care schemes involving community optometrists show wide variation in practice. We report on defined key performance indicators (KPIs) which improve accountability between stakeholders. METHODS: In this prospective study over nine months at a UK public hospital, we evaluated the outcomes of consecutive direct cataract referrals from community optometrists against two KPIs agreed under a service-level agreement between the Hospital Eye Service and community optometrists: (1) 85% of patients listed for cataract listing at first consultation; and (2) 90% postoperative feedback return rate on patients discharged to community optometrists. A detailed analysis on referral triage, surgical listing and postoperative form return rate is reported in this study. RESULTS: A total of 733 direct cataract referrals were received using a designated referral form of which 86% were listed for cataract surgery. The predominant reason for not listing was a failure to reach the visual threshold set by the local clinical commissioning guidelines. Out of 569 cataract surgical episodes, 402 (71%) patients were discharged on the same day of surgery to community optometrist follow up. Completed postoperative feedback was returned from 374 patients (93%). CONCLUSION: Direct cataract referrals from accredited community optometrists led to a majority of patients receiving a definitive clinical decision during first consultation. Postoperative community follow up reduced hospital visits and allowed for convenient consultation closer to home following uncomplicated cataract surgery. A service-level agreement with an accreditation scheme measured against KPIs enhances the accountability of stakeholders involved in the cataract shared care scheme. PMID- 29405328 TI - Orchestrating liver repair: A newly discovered function of hepatic iNKT cells. PMID- 29405330 TI - Parentage complexity in socially monogamous lemurs (Eulemur rubriventer): Integrating genetic and observational data. AB - Genetic analyses of parentage sometimes reveal that "socially monogamous" (pair living) species do not reside in strict family groups. Circumstances such as adult turnovers and extra-pair copulations, among others, may result in non nuclear families. These genetic relationships within groups have implications for interpreting social behaviors. Red-bellied lemurs (Eulemur rubriventer) live in groups generally comprising an adult male-female pair plus immatures, and early genetic analyses of parentage in a relatively small sample suggested they mate monogamously. However, previous research on this taxon has also identified scenarios in which non-nuclear families might result, such as adult turnovers. To assess the potential occurrence of non-nuclear families in this "socially monogamous" taxon, as well as the social conditions under which they might occur, we combined behavioral observations of wild red-bellied lemurs in Ranomafana National Park with genetic parentage analysis of immatures from 17 groups. We found that the majority of groups (75%) represented nuclear family groups. However, 25% of groups represented non-nuclear families at some point during the study. The social factors that resulted in non-nuclear families were varied and included at least one adult turnover, and potentially delayed female dispersals and extra-pair copulations. Our results suggest that red-bellied lemurs are generally reproductively monogamous, with only limited evidence that non-nuclear families result from non-monogamous reproduction. However, similar to other pair living primates, red-bellied lemurs appear to exhibit flexibility in their social organization and mating strategies. Multiple lines of evidence should be considered when inferring parent-offspring relationships within pair-living groups. PMID- 29405331 TI - The analysis of alpha-1-antitrypsin glycosylation with direct LC-MS/MS. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based methodology has been developed to differentiate core- and antennary-fucosylated glycosylation of glycopeptides. Both the glycosylation sites (heterogeneity) and multiple possible glycan occupancy at each site (microheterogeneity) can be resolved via intact glycopeptide analysis. The serum glycoprotein alpha-1-antitrypsin (A1AT) which contains both core- and antennary-fucosylated glycosites was used in this study. Sialidase was used to remove the sialic acids in order to simplify the glycosylation microheterogeneity and to enhance the MS signal of glycopeptides with similar glycan structures. beta1-3,4 galactosidase was used to differentiate core- and antennary-fucosylation. In-source dissociation was found to severely affect the identification and quantification of glycopeptides with low abundance glycan modification. The settings of the mass spectrometer were therefore optimized to minimize the in-source dissociation. A three-step mass spectrometry fragmentation strategy was used for glycopeptide identification, facilitated by pGlyco software annotation and manual checking. The collision energy used for initial glycopeptide fragmentation was found to be crucial for improved detection of oxonium ions and better selection of Y1 ion (peptide+GlcNAc). Structural assignments revealed that all three glycosylation sites of A1AT glycopeptides contain complex N-glycan structures: site Asn70 contains biantennary glycans without fucosylation; site Asn107 contains bi-, tri- and tetra-antennary glycans with both core- and antennary-fucosylation; site Asn271 contains bi- and tri antennary glycans with both core- and antennary-fucosylation. The relative intensity of core- and antennary-fucosylation on Asn107 was similar to that of the A1AT protein indicating that the glycosylation level of Asn107 is much larger than the other two sites. PMID- 29405333 TI - Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro. AB - : Early detection and clear delineation of microscopic lesions during surgery are critical to the prognosis and survival of patients with hepatocellular carcinoma (HCC), a devastating malignancy without effective treatments except for resection. Tools to specifically identify and differentiate micronodules from normal tissue in HCC patients can have a positive impact on survival. Here, we discovered a peptide that preferentially binds to HCC cells through phage display. Significant accumulation of the fluorescence-labeled peptide in tumor from ectopic and orthotopic HCC mice was observed within 2 hours of systemic injection. Contrast between tumor and surrounding liver is up to 6.5-fold, and useful contrast lasts for 30 hours. Micronodules (0.03 cm in diameter) in liver and lung can clearly be distinguished from normal tissue with this fluorescence labeled peptide in orthotopic HCC mice and HCC patients. Compared to indocyanine green, a Food and Drug Administration-approved imaging contrast agent, an up to 8.7-fold higher differentiation ratio of tumor to fibrosis is achieved with this fluorescence-labeled peptide. Importantly, this peptide enables up to 10-fold differentiation between HCC and peritumoral tissue in human tissues and the complete removal of tumor in HCC mice with surgical navigation. No abnormalities in behavior or activity are observed after systemic treatment, indicating the absence of overt toxicity. The peptide is metabolized with a half-life of approximately 4 hours in serum. CONCLUSION: Our findings demonstrate that micronodules can be specifically differentiated with high sensitivity from surrounding tissue with this molecule, opening clinical possibilities for early detection and precise surgery of HCC. (Hepatology 2018). PMID- 29405334 TI - Mitonuclear Mate Choice: A Missing Component of Sexual Selection Theory? AB - The fitness of a eukaryote hinges on the coordinated function of the products of its nuclear and mitochondrial genomes in achieving oxidative phosphorylation (OXPHOS). I propose that sexual selection plays a key role in the maintenance of mitonuclear coadaptation across generations because it enables pre-zygotic sorting for coadapted mitonuclear genotypes. At each new generation, sexual reproduction creates new combinations of nuclear and mitochondrial genes, and the potential arises for mitonuclear incompatibilities and reduced fitness. In reviewing the literature, I hypothesize that individuals engaged in mate choice select partners with correct species-typical mitochondrial and nuclear genotypes as well as individuals with highly functional cellular respiration. The implication is that mate choice for compatible nuclear and mitochondrial genes can play a significant role in generating the patterns of ornamentation and preferences observed in animals. A number of testable predictions emerge from this mitonuclear compatibility hypothesis of sexual selection. PMID- 29405335 TI - Dielectrophoretic analysis of treated cancer cells for rapid assessment of treatment efficacy. AB - Whilst personalized medicine (where interventions are precisely tailored to a patient's genotype and phenotype, as well as the nature and state of the disease) is regarded as an optimal form of treatment, the time and cost associated with it means it remains inaccessible to the greater public. A simpler alternative, stratified medicine, identifies groups of patients who are likely to respond to a given treatment. This allows appropriate treatments to be selected at the start of therapy, avoiding the common "trial and error" approach of replacing a therapy only once it is demonstrated to be ineffective in the patient. For stratification to be effective, tests are required that rapidly predict treatment effectiveness. Most tests use genetic analysis to identify drug targets, but these can be expensive and may not detect changes in the phenotype that affect drug sensitivity. An alternative method is to assess the whole-cell phenotype by evaluating drug response using cells from a biopsy. We assessed dielectrophoresis to assess drug efficacy on short timescales and at low cost. To explore the principle of assessing drug efficacy we examined two cell lines (one expressing EGFR, one not) with the drug Iressa. We then further explored the sensitive cells using combinations of chemotherapeutic and radiotherapeutic therapies. Our results compare with known effects of these cell/treatment combination, and offer the additional benefit over methods such as TUNEL of detecting drug effects such as cell cycle arrest, which do not cause cell death. PMID- 29405336 TI - Ruthenium counterstaining for imaging mass cytometry. AB - Imaging mass cytometry is a novel imaging modality that enables simultaneous antibody-based detection of >40 epitopes and molecules in tissue sections at subcellular resolution by the use of isotopically pure metal tags. Essential for any imaging approach in which antigen detection is performed is counterstaining, which reveals the overall structure of the tissue. Counterstaining is necessary because antigens of interest are often present in only a small subset of cells, and the rest of the tissue structures are not visible. As most biological tissues are nearly transparent or non-fluorescent, chromogenic reagents such as haematoxylin (for immunohistochemistry) or fluorescent dyes such as 4',6 diamidino-2-phenylindole (which stains nuclei for epifluorescence and confocal microscopy) are utilized. Here, we describe a metal-based counterstain for imaging mass cytometry based on simple oxidation and subsequent covalent binding of the tissue components to ruthenium tetroxide (RuO4 ). RuO4 counterstaining reveals general tissue structure both in areas with high cell content and in stromal areas with low cellularity and fibrous or hyaline material in a manner analogous to haematoxylin in immunohistochemical counterstaining or eosin or other anionic dyes in conventional histology. Our new counterstain approach is applicable to any metal-based imaging technique, and will facilitate the adaptation of imaging mass cytometry for routine applications in clinical and research laboratories. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29405332 TI - The Eukaryotic CMG Helicase at the Replication Fork: Emerging Architecture Reveals an Unexpected Mechanism. AB - The eukaryotic helicase is an 11-subunit machine containing an Mcm2-7 motor ring that encircles DNA, Cdc45 and the GINS tetramer, referred to as CMG (Cdc45, Mcm2 7, GINS). CMG is "built" on DNA at origins in two steps. First, two Mcm2-7 rings are assembled around duplex DNA at origins in G1 phase, forming the Mcm2-7 "double hexamer." In a second step, in S phase Cdc45 and GINS are assembled onto each Mcm2-7 ring, hence producing two CMGs that ultimately form two replication forks that travel in opposite directions. Here, we review recent findings about CMG structure and function. The CMG unwinds the parental duplex and is also the organizing center of the replisome: it binds DNA polymerases and other factors. EM studies reveal a 20-subunit core replisome with the leading Pol epsilon and lagging Pol alpha-primase on opposite faces of CMG, forming a fundamentally asymmetric architecture. Structural studies of CMG at a replication fork reveal unexpected details of how CMG engages the DNA fork. The structures of CMG and the Mcm2-7 double hexamer on DNA suggest a completely unanticipated process for formation of bidirectional replication forks at origins. PMID- 29405337 TI - Altered expression of glutamate transporter-1 and water channel protein aquaporin 4 in human temporal cortex with Alzheimer's disease. AB - AIMS: Glutamate neurotoxicity plays an important role in the pathogenesis of various neurodegenerative disorders. Many studies have demonstrated that glutamate transporter-1 (GLT-1), the dominant astrocytic glutamate transporter, is significantly reduced in the cerebral cortex of patients with Alzheimer's disease (AD), suggesting that glutamate-mediated excitotoxicity might contribute to the pathogenesis of AD. In a previous study, we have demonstrated marked alterations in the expression of the astrocytic water channel protein aquaporin-4 (AQP4) in relation to amyloid beta deposition in human AD brains. As a functional complex, GLT-1 and AQP4 in astrocytes may play a neuroprotective role in the progression of AD pathology. However, few studies have examined the correlation between the expression of GLT-1 and that of AQP4 in human AD brain. METHODS: Here, using immunohistochemistry with antibodies against GLT-1 and AQP4, we studied the expression levels and distribution patterns of GLT-1 in areas showing various patterns of AQP4 expression in autopsied temporal lobes from eight patients with AD and five controls without neurological disorders. RESULTS: GLT-1 staining in the control group was present throughout the neocortex as uniform neuropil staining with co-localized AQP4. The AD group showed a significant reduction in GLT-1 expression, whereas cortical AQP4 immunoreactivity was more intense in the AD group than in the control group. There were two different patterns of GLT-1 and AQP4 expression in the AD group: (i) uneven GLT-1 expression in the neuropil where diffuse but intense AQP4 expression was evident, and (ii) senile plaque-like co-expression of GLT-1 and AQP4. CONCLUSIONS: These findings suggest disruption of glutamate/water homoeostasis in the AD brain. PMID- 29405329 TI - Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. PMID- 29405339 TI - Exploring the perspectives of 10-, 11-, and 12-year-old primary school students on physical activity engagement-"'Cause you can't just be sitting at a desk all the time!" AB - BACKGROUND: Research indicates that 91% of Canadian children are not engaging in enough physical activity (PA) to achieve health benefits. Physical education (PE) classes have been identified as a way to improve child health by facilitating engagement in movement-based activities. The daily physical activity (DPA) initiative was created with similar intentions and requires that students participate in at least 20 min of PA daily via PE classes and/or during instructional time for other subjects. Despite recommendations that 150 min of exercise/play be incurred weekly through either avenue, nearly half of Canadian schools fail to achieve this goal. The disconnect between PA-related school policies and low reported participation rates suggests that additional research is warranted. The purpose of this study was to explore the perspectives of primary students regarding the facilitators, barriers, and recommendations for PA engagement at their schools. METHODS: Researchers conducted nine group interviews with 53 children aged 10-12, representing six primary schools in Northwestern Ontario using a semi-structured interview format. Sessions were analysed using inductive content analysis. RESULTS: Participants discussed several facilitators of PA including enjoying activities (alleviating boredom and participating with others), accomplishment (skill building and enhanced self-image), and benefits in the classroom (thinking clearly and enhanced readiness to learn). Barriers to PA participation included school rules and culture (PA/PE restrictions, heavy workload, and "no work, no PA"), personal struggles (physical challenges and varied skill levels), and technology (being addictive and a replacement for being active). Recommendations for enhancing engagement that were outlined by the children centred around PE and daily physical activity (increase opportunities and involve students in planning/delivery) and recess-based themes (decrease focus on safety and make equipment more available). CONCLUSION: These student perspectives and related recommendations may be beneficial for administrators and teachers in similar contexts who are seeking to enhance PA engagement among students with the goal of improving child health. PMID- 29405338 TI - Toward valid and reliable brain imaging results in eating disorders. AB - Human brain imaging can help improve our understanding of mechanisms underlying brain function and how they drive behavior in health and disease. Such knowledge may eventually help us to devise better treatments for psychiatric disorders. However, the brain imaging literature in psychiatry and especially eating disorders has been inconsistent, and studies are often difficult to replicate. The extent or severity of extremes of eating and state of illness, which are often associated with differences in, for instance hormonal status, comorbidity, and medication use, commonly differ between studies and likely add to variation across study results. Those effects are in addition to the well-described problems arising from differences in task designs, data quality control procedures, image data preprocessing and analysis or statistical thresholds applied across studies. Which of those factors are most relevant to improve reproducibility is still a question for debate and further research. Here we propose guidelines for brain imaging research in eating disorders to acquire valid results that are more reliable and clinically useful. PMID- 29405341 TI - Metastatic melanoma with dedifferentiation and extensive rhabdomyosarcomatous heterologous component. AB - Melanoma may undergo dedifferentiation and sarcomatous transformation with loss of melanocytic markers. Dedifferentiated melanoma rarely forms true rhabdomyoblasts with skeletal muscle immunophenotype (rhabdomyosarcomatous heterologous component). A 52-year-old woman was diagnosed with invasive melanoma (Breslow thickness 0.83 mm) of the upper back in 2012, treated by wide local excision only. In 2013, an axillary mass was excised to show metastatic melanoma with 2 morphologies: an epithelioid morphology expressing S100 and MART-1 and a spindled morphology with loss of melanocytic markers but strong expression of desmin. This metastasis was found to have BRAF V600E mutation. In 2015, a thoracic epidural mass biopsy showed atypical spindle cells with focal HMB-45 but essentially no S100 expression. Numerous rhabdomyoblasts, some with striations that were strongly positive for desmin and myogenin, were present. In 2016, a right nephrectomy was performed for metastasis to the kidney, and showed sheets of spindle cells and rhabdomyoblasts expressing desmin and myogenin but not S100. Only focal areas demonstrated expression of HMB-45 and SOX-10, supporting the melanocytic origin of the tumor. The numerous rhabdomyoblasts and the loss of S100 expression in the metastatic lesions in this case could have easily led to misdiagnosis if the clinical history was not known. PMID- 29405340 TI - Material elemental decomposition in dual and multi-energy CT via a sparsity dictionary approach for proton stopping power ratio calculation. AB - PURPOSE: Accurate calculation of proton stopping power ratio (SPR) relative to water is crucial to proton therapy treatment planning, since SPR affects prediction of beam range. Current standard practice derives SPR using a single CT scan. Recent studies showed that dual-energy CT (DECT) offers advantages to accurately determine SPR. One method to further improve accuracy is to incorporate prior knowledge on human tissue composition through a dictionary approach. In addition, it is also suggested that using CT images with multiple (more than two) energy channels, i.e., multi-energy CT (MECT), can further improve accuracy. In this paper, we proposed a sparse dictionary-based method to convert CT numbers of DECT or MECT to elemental composition (EC) and relative electron density (rED) for SPR computation. METHOD: A dictionary was constructed to include materials generated based on human tissues of known compositions. For a voxel with CT numbers of different energy channels, its EC and rED are determined subject to a constraint that the resulting EC is a linear non-negative combination of only a few tissues in the dictionary. We formulated this as a non convex optimization problem. A novel algorithm was designed to solve the problem. The proposed method has a unified structure to handle both DECT and MECT with different number of channels. We tested our method in both simulation and experimental studies. RESULTS: Average errors of SPR in experimental studies were 0.70% in DECT, 0.53% in MECT with three energy channels, and 0.45% in MECT with four channels. We also studied the impact of parameter values and established appropriate parameter values for our method. CONCLUSION: The proposed method can accurately calculate SPR using DECT and MECT. The results suggest that using more energy channels may improve the SPR estimation accuracy. PMID- 29405343 TI - There is moderate evidence for the effectiveness of occupation and activity-based interventions for people with traumatic brain injury although more evidence is needed for interventions provided specifically by occupational therapists. PMID- 29405342 TI - Melanoma mimicking Rosai-Dorfman disease. AB - Despite well-defined clinical and histopathological features of melanoma, atypical presentations mimicking other skin disorders can result in a delayed diagnosis or misdiagnosis and subsequent inappropriate treatment. Rosai-Dorfman disease (RDD) is a rare histiocytic disorder with unique clinical and histopathological features. We report a case of melanoma treated with cryotherapy that mimicked RDD both clinically and histopathologically. We compare this RDD like melanoma to classic RDD, outlining the importance of clinicopathological correlation prior to treatment, as well as the potential pitfalls in diagnosis after cryotherapy of pigmented lesions. PMID- 29405344 TI - Life stories support staff and relatives to see, hear and understand people with dementia living in a nursing home as a whole person. PMID- 29405346 TI - Health apps and knowledge translation. PMID- 29405347 TI - Cutaneous meningeal heterotopia on the thigh. PMID- 29405348 TI - The free androgen index is inaccurate in women when the SHBG concentration is low. AB - OBJECTIVE/CONTEXT: The free androgen index (FAI) is known to give erroneous results in men, but it is still a commonly used test for the investigation of hyperandrogenism in women. This study aimed to compare the results of the FAI with the gold standard equilibrium dialysis method for free testosterone in women. DESIGN/PATIENTS: Free serum testosterone T (ED-T) and total serum T (T) were measured by equilibrium dialysis and LC-MS/MS in patients with polycystic ovarian syndrome (n = 130), normal female controls (n = 53) and normal males (n = 120). Calculated free T (cFT) and free androgen index (FAI) were also measured in these patients. In addition, cFT was retrospectively calculated in 4223 female patients with a normal T (<1.6 nmol/L) routinely investigated for hyperandrogenism. RESULTS: The cFT showed good agreement with measured ED-T, and the ratio cFT/ED-T was stable across all SHBG concentrations. In contrast, the FAI/ED-T ratio and the FAI/cFT ratio increased when the concentration of SHBG fell below 30 nmol/L. CONCLUSIONS: The FAI is not a reliable indicator of free T when the SHBG concentration is low and would give misleading information in a large number of women being investigated for hyperandrogenism. PMID- 29405349 TI - Paraneoplastic plaque-like cutaneous mucinosis in a patient with lung adenocarcinoma. PMID- 29405350 TI - Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. AB - OBJECTIVE: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 +/- 25 vs -21 +/- 14 mmHg [mean +/- standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 +/- 8 vs 25 +/- 11 beats per minute [bpm], p < 0.0001). A DeltaHR/DeltaSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION: A blunted HR increase during hypotension suggests a neurogenic cause. A DeltaHR/DeltaSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522-531. PMID- 29405351 TI - Predicting clinical diagnosis in Huntington's disease: An imaging polymarker. AB - OBJECTIVE: Huntington's disease (HD) gene carriers can be identified before clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real-life clinical diagnosis in HD. METHOD: A multivariate machine learning approach was applied to resting-state and structural magnetic resonance imaging scans from 19 premanifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years postscanning) and 21 healthy controls. A classification model was developed using cross-group comparisons between preHD and controls, and within the preHD group in relation to "estimated" and "actual" proximity to disease onset. Imaging measures were modeled individually, and combined, and permutation modeling robustly tested classification accuracy. RESULTS: Classification performance for preHDs versus controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy, including those who were not expected to manifest in that time scale based on the currently adopted statistical models. INTERPRETATION: We propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of HD, with implications for prognostication and preclinical trials. Ann Neurol 2018;83:532-543. PMID- 29405352 TI - An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor-positive myasthenia gravis patients. AB - A chronic autoimmune disease, myasthenia gravis (MG) is characterized in 85% of patients by antibodies directed against the acetylcholine receptor (AChR) located at the neuromuscular junction. The functional and effective balance between regulatory T cells (Treg cells) and effector T cells (Teff cells) is lost in the hyperplastic thymus of MG patients with antibodies specific for the AChR (AChR+ MG patients). The objective of this review is to describe how Treg cells and inflammatory T cells participate in this imbalance and contribute to induce a chronic inflammatory state in the MG thymus. We discuss the origins and characteristics of Treg cells and their reported dysfunctions in AChR+ MG patients. We also review the inflammatory condition observed in MG thymus, including overexpression of interleukin (IL)-1beta, IL-6, and IL-23, cytokines that promote the differentiation of T helper 17 (TH 17) cells and the expression of IL-17. We summarize the preclinical models used to determine the implication of expression of cytokines, such as IL-6, IL-12 (IL-23 subunit), IL-17, and interferon gamma to the development of experimental autoimmune MG. Finally, we suggest that biological agents, such as humanized monoclonal antibodies that target the IL-23/TH 17 pathway, should be investigated in the context of MG, as they have proven efficiency in other autoimmune diseases. PMID- 29405353 TI - Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms. AB - The neuromuscular junction (NMJ) is a cholinergic synapse in vertebrates. This synapse connects motoneurons to muscles and is responsible for muscle contraction, a physiological process that is essential for survival. A key factor for the normal functioning of this synapse is the regulation of acetylcholine (ACh) levels in the synaptic cleft. This is ensured by acetylcholinesterase (AChE), which degrades ACh. A number of mutations in synaptic genes expressed in motoneurons or muscle cells have been identified and are causative for a class of neuromuscular diseases called congenital myasthenic syndromes (CMSs). One of these CMSs is due to deficiency in AChE, which is absent or diffuse in the synaptic cleft. Here, I focus on the origins of the syndrome. The role of ColQ, a collagen that anchors AChE in the synaptic cleft, is discussed in this context. Studies performed on patient biopsies, transgenic mice, and muscle cultures have provided a more comprehensive view of the connectome at the NMJ that should be useful for understanding the differences in the symptoms observed in specific CMSs due to mutated proteins in the synaptic cleft. PMID- 29405354 TI - Role of IL-13Ralpha2 in modulating IL-13-induced MUC5AC and ciliary changes in healthy and CRSwNP mucosa. AB - BACKGROUND: The IL-13 receptor alpha2 (IL-13Ralpha2) is a receptor for IL-13 which has conflicting roles in mediating IL-13 responses in the lower airway, with little known about its impact on upper airway diseases. We sought to investigate the expression of IL-13 receptors, IL-13Ralpha1 and IL-13Ralpha2, in chronically inflamed nasal epithelium, and explore IL-13-induced signaling pathways in an in vitro model of human nasal epithelial cells (hNECs). METHODS: The protein and mRNA expression levels of IL-13 and its receptors in nasal biopsies of patients with nasal polyps (NP) and healthy controls were evaluated. We investigated goblet cell stimulation with mucus hypersecretion induced by IL 13 (10 ng/mL, 72 hours) treatment in hNECs using a pseudostratified epithelium in air-liquid interface (ALI) culture. RESULTS: There were significant increases in IL-13, IL-13Ralpha1, and IL-13Ralpha2 mRNA and protein levels in NP epithelium with healthy controls as baseline. MUC5AC mRNA positively correlated with IL 13Ralpha2 (r = .5886, P = .002) but not with IL-13Ralpha1 in primary hNECs. IL-13 treatment resulted in a significant increase in mRNA and protein levels of IL 13Ralpha2 only in hNECs. IL-13 treatment induced an activation of extracellular signal-regulated kinases (ERK)1/2 and an upregulation of C-JUN, where the IL-13 induced effects on hNECs could be attenuated by ERK1/2 inhibitor (50 MUmol/L) or dexamethasone (10-4 -10-7 mol/L) treatment. CONCLUSIONS: IL-13Ralpha2 has a potential role in IL-13-induced MUC5AC and ciliary changes through ERK1/2 signal pathway in the nasal epithelium. IL-13Ralpha2 may contribute to airway inflammation and aberrant remodeling which are the main pathological features of CRSwNP. PMID- 29405355 TI - Cortisol evaluation during the acute phase of traumatic brain injury-A prospective study. AB - BACKGROUND: Biochemical diagnosis of adrenal insufficiency (AI) is difficult in the context of traumatic brain injury (TBI). AIM: To assess the frequency and predictive factors of AI in victims of TBI from Algiers. METHODS: Between November 2009 and December 2013, TBI victims had a single 8-9 am serum cortisol measurement during the acute postinjury period (0-7 days). AI was defined according to basal cortisol levels of 83, 276 and 414 nmol/L. Variables studied were TBI severity according to Glasgow coma scale, duration of intubation and coma, pupillary status, hypotension, anaemia, brain imaging findings, diabetes insipidus and medication. Insulin tolerance test was performed during the recovery phase, defining AI as peak cortisol <500 nmol/L. RESULTS: Cortisol samples were obtained at median 3 (1-7) days from 277 patients (257M: 20F) aged 32 (18-65) years. Acute AI frequency was 8 (2.8%), 20 (21%) and 35 (37%), respectively using the three cortisol cut-offs. Factors predicting AI were diastolic hypotension, sedative medication, diabetes insipidus, skull base fracture and intraparenchymal haematoma. Mortality was highest in patients with acute cortisol <276 nmol/L (44.6% with OR for death 1.64, 95% CI 0.92-3.0, P = .12). During the recovery phase, AI was present in 3 of 3, 12 of 24, 4 of 16 and 20 of 66 patients with week 1 cortisol <83, 83-276, 277-414 and >414 nmol/L. CONCLUSION: Hydrocortisone replacement is advised in TBI patients with morning cortisol <276 nmol/L or those <414 nmol/L with additional risk factors for AI. As acute and subsequent AI are poorly correlated, patients with moderate/severe TBI require adrenal re-evaluation during the recovery phase. PMID- 29405356 TI - Evaluation of diffusive gradients in thin films for prediction of copper bioaccumulation by yellow lampmussel (Lampsilis cariosa) and fathead minnow (Pimephales promelas). AB - Using a coupled method of diffusive gradients in thin films (DGT) exposure with aquatic organism bioassays, we assessed the use of DGT as a tool for estimating copper (Cu) bioavailability in contaminated waters. The DGT-accumulated Cu fraction could possibly be used as a surrogate for other assessments of metal bioavailability. The Cu concentrations in fathead minnow (Pimephales promelas) and yellow lampmussel (Lampsilis cariosa) soft tissue were compared with DGT accumulated Cu after 2, 4, and 6 d of exposure to a Cu concentration series in static, water-only assays. The DGT-accumulated Cu was found to include free Cu ions, labile inorganic Cu complexes, and labile dissolved organic matter Cu complexes, compared with Cu speciation output from the biotic ligand model. Regressions of Cu concentrations between DGT and fathead minnow at 4 and 6 d of exposure demonstrated linear relationships. The Cu bioaccumulated in yellow lampmussel was overpredicted by DGT at Cu concentrations greater than 10 ug L-1 , which may be caused by internal regulation of Cu. The speciation component of the biotic ligand model predicted relationships between inorganic Cu and animal accumulated Cu that were similar to predicted relationships between DGT-indicated Cu and animal-accumulated Cu at all deployment durations. Environ Toxicol Chem 2018;37:1535-1544. (c) 2018 SETAC. PMID- 29405357 TI - Flow MRI simulation in complex 3D geometries: Application to the cerebral venous network. AB - PURPOSE: Develop and evaluate a complete tool to include 3D fluid flows in MRI simulation, leveraging from existing software. Simulation of MR spin flow motion is of high interest in the study of flow artifacts and angiography. However, at present, only a few simulators include this option and most are restricted to static tissue imaging. THEORY AND METHODS: An extension of JEMRIS, one of the most advanced high performance open-source simulation platforms to date, was developed. The implementation of a Lagrangian description of the flow allows simulating any MR experiment, including both static tissues and complex flow data from computational fluid dynamics. Simulations of simple flow models are compared with real experiments on a physical flow phantom. A realistic simulation of 3D flow MRI on the cerebral venous network is also carried out. RESULTS: Simulations and real experiments are in good agreement. The generality of the framework is illustrated in 2D and 3D with some common flow artifacts (misregistration and inflow enhancement) and with the three main angiographic techniques: phase contrast velocimetry (PC), time-of-flight, and contrast-enhanced imaging MRA. CONCLUSION: The framework provides a versatile and reusable tool for the simulation of any MRI experiment including physiological fluids and arbitrarily complex flow motion. PMID- 29405358 TI - Corrigendum: Potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 labeled with carbon-13 and carbon-14. PMID- 29405359 TI - Intermittent fasting in Type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial. AB - AIMS: To establish whether the risk of hypoglycaemia is greater with 2 consecutive days of very-low-calorie diet compared with 2 non-consecutive days of very-low-calorie diet in people with Type 2 diabetes. METHODS: This was a non blinded randomized parallel group interventional trial of intermittent fasting in adults. The participants had a BMI of 30-45 kg/m2 , Type 2 diabetes treated with metformin and/or hypoglycaemic medications and an HbA1c concentration of 50-86 mmol/mol (6.7-10%). The participants followed a 2092-2510-kJ diet on 2 days per week for 12 weeks. A total of 41 participants were randomized 1:1 to consecutive (n=19) or non-consecutive (n=22) day fasts, of whom 37 (n=18 and n=19, respectively) were included in the final analysis. The primary outcome was difference in the rate of hypoglycaemia between the two study arms. Secondary outcomes included change in diet, quality of life, weight, lipid, glucose and HbA1c levels, and liver function. RESULTS: The mean hypoglycaemia rate was 1.4 events over 12 weeks. Fasting increased the rate of hypoglycaemia despite medication reduction (RR 2.05, 95% CI 1.17 to 3.52). There was no difference between fasting on consecutive days and fasting on non-consecutive days (RR 1.54, 95% CI 0.35 to 6.11). Improvements in weight, HbA1c , fasting glucose and quality of life were experienced by participants in both arms. CONCLUSIONS: In individuals with Type 2 diabetes on hypoglycaemic medications, fasting of any type increased the rate of hypoglycaemia. With education and medication reduction, fewer than expected hypoglycaemic events occurred. Although it was not possible to determine whether fasting on consecutive days increased the risk of hypoglycaemia, an acceptable rate was observed in both arms. PMID- 29405360 TI - Calcium signaling: decoding mechanism of calcium signatures. PMID- 29405361 TI - Xylem dysfunction in fires: towards a hydraulic theory of plant responses to multiple disturbance stressors. PMID- 29405362 TI - Confronting the wildlife trade through public education at zoological institutions in Chengdu, P.R. China. AB - The wildlife trade poses substantial threats to global biodiversity. China is a significant source of threatened species and also a market for wildlife products. Zoological parks (zoos), which are a popular leisure attraction in China as elsewhere, are increasingly conceptualized as places to educate visitors about both animals and environmental threats more generally. This paper reports on an attempt to inform Chinese zoo visitors about the threats presented by the wildlife trade, and about the opportunity to take personal actions to help protect wildlife. Results from a baseline survey of attitudes among 524 adult visitors to animal exhibits in Chengdu, China showed a high degree of concern about wildlife paired with a lack of confidence about what could be done. A sense of connection to nature, along with a perception of personal efficacy, were the strongest predictors of concern about the wildlife trade. Based in part on these results, an informational exhibit was designed and implemented in two locations in Chengdu. A survey of 533 visitors to assess the impact of the new exhibit showed that connection and perceived efficacy continued to predict concern, and that talking about the exhibit was associated with increased knowledge and concern. Though causality cannot be definitively concluded, results suggest that zoos have the potential to influence attitudes and perceived norms regarding the wildlife trade. By affirming the importance of a feeling of connection, the findings indicate that animal facilities may have an important role in fostering the human relationship to the natural world. PMID- 29405363 TI - Evaluating Scholarship Productivity in COAMFTE-Accredited Doctoral Programs: An Update. AB - Scholarly productivity continues to be used as a significant factor when universities make decisions about granting tenure to faculty, allocating resources, and supporting program goals. In 2009, DuPree, White, Meredith, Ruddick, and Anderson reviewed research productivity in faculty from COAMFTE accredited PhD programs. As an update, the purpose of this article is to re examine scholarly productivity trends among COAMFTE-accredited doctoral programs through the use of several evaluation methods. Specifically, productivity was examined in the following areas: (a) family therapy journal publications; (b) publications in any type of peer-reviewed journal; (c) h-factor index scores; and (d) historic and recent journal publication trends. PMID- 29405364 TI - Synergy between bio-based industry and the feed industry through biorefinery. PMID- 29405365 TI - Immunotoxicity in green mussels under perfluoroalkyl substance (PFAS) exposure: Reversible response and response model development. AB - The immunotoxicity of 4 commonly detected perfluoroalkyl substances (PFASs), namely, perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) was investigated by measuring biomarkers of the immune profile of green mussels, Perna viridis. The biomarkers included neutral red retention, phagocytosis, and spontaneous cytotoxicity, all of which were tested on mussel hemocytes. Hemocytes are an important component of the invertebrate immune system. We found that exposure to PFASs could lead to reduced hemocyte cell viability and suppress immune function by up to 50% of normal performance within the experimental exposure range. The results indicate that PFASs have an immunotoxic potential and thus could pose severe health risks to aquatic organisms. The reported immunotoxicity is likely to result from the compounds' direct and indirect interactions with the hemocyte membrane, and therefore likely to affect the functionality of these cells. The immunotoxic response was found to be related to the organism's burden of PFASs, and was reversible when the compounds were removed from the test organisms. Based on this relationship, models using an organism's PFAS concentration and bioaccumulation factor (BAF) as the independent variables were established to quantify PFAS-induced immunotoxicity. The models help us to gain a better understanding of the toxic mechanism of PFASs, and provide a tool to evaluate adverse effects for the whole group of compounds with one mathematical equation. Environ Toxicol Chem 2018;37:1138-1145. (c) 2018 SETAC. PMID- 29405366 TI - Correlation of right ventricular multielectrode endocardial unipolar mapping and epicardial scar. AB - AIMS: Prior studies identified a relationship between epicardial bipolar and endocardial unipolar voltage. Whether the relationship is valid with smaller multielectrode mapping catheters has not been reported. We explored the association of right ventricular (RV) endocardial unipolar voltage mapping with epicardial bipolar voltage mapping using a multielectrode mapping catheter. METHODS: Electrograms from patients who underwent multielectrode endocardial and epicardial RV electroanatomical mapping during ablation procedures were analyzed. Each endocardial mapping point was matched to the corresponding nearest epicardial point. The correlation between unipolar endocardial voltage and epicardial bipolar voltage was determined. The optimal unipolar threshold to detect epicardial low voltage (< 1.0 mV) and dense scar (0.5 mV) was calculated. RESULTS: A total of 4,895 points were analyzed. There was a significant correlation between endocardial unipolar and epicardial bipolar voltage (Spearman rho = 0.499, P = < 0.001). The extent of the correlation was inversely associated with wall thickness. The receiver operator characteristic analysis of endocardial unipolar voltage predicting epicardial bipolar voltage of < 1.0 mV and < 0.5 showed an area under the curve of 0.769 and 0.812, respectively. The endocardial unipolar voltage that had the highest sensitivity and specificity in detecting epicardial bipolar voltage of < 1.0 mV and < 0.5 mV was 3.3 mV (70.3% sensitivity, 70.3% specificity), and 2.8 mV (sensitivity 73.8%, specificity 73.3%), respectively. CONCLUSION: Epicardial low voltage of the RV can be assessed by unipolar endocardial voltage using small multielectrode catheters. The strength of the association was inversely correlated with the wall thickness. PMID- 29405367 TI - Influence of evolution on cam deformity and its impact on biomechanics of the human hip joint. AB - Anatomy and biomechanics of the human hip joint are a consequence of the evolution of permanent bipedal gait. Habitat and behaviour have an impact on hip morphology and significant differences are present even within the same biological family. The forces acting upon the hip joint are mainly a function of gravitation and strength of the muscles. Acetabular and femoral anatomy ensure an inherently stable hip with a wide range of motion. The femoral head in first human ancestors with upright gait was spherical (coxa rotunda). Coxa rotunda is also seen in close human relatives (great apes) and remains the predominant anatomy of present-day humans. High impact sport during adolescence with open physis however can activate an underlying genetic predisposition for reinforcement of the femoral neck, causing an epiphyseal extension and the formation of an osseous asphericity at the antero-superior femoral neck (cam deformity). The morphology of cam deformity is similar to the aspherical hips of quadrupeds (coxa recta), with the difference that in quadrupeds the asphericity is posterior. It has been postulated that this is due to the fact that humans bear weight on the extended leg, while quadrupeds bear weight at 90-100 degrees flexion. The asphericity alters the biomechanical properties of the joint and as it is forced into the acetabulum leading to secondary cartilage damage. It is considered a risk factor for later development of osteoarthritis of the hip. Clinically this presents as reduced range of motion, which can be an indicator for the structural deformity of the hip. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX-XX, 2018. PMID- 29405368 TI - Proactive telephone support provided to breastfeeding mothers of preterm infants after discharge: a randomised controlled trial. AB - AIM: The aim was to evaluate the effectiveness of proactive telephone support provided to breastfeeding mothers of preterm infants after discharge from neonatal intensive care units (NICU). METHODS: Between March 2013 and December 2015, a randomised controlled trial was conducted at six NICUs across Sweden. At each NICU, a breastfeeding support team recruited, randomised and delivered the support to participating mothers. The intervention group received a daily proactive telephone call up to 14 days after discharge from the support team. The control group could initiate telephone contact themselves. Primary outcome was exclusive breastfeeding eight weeks after discharge. Secondary outcomes were maternal satisfaction with breastfeeding, attachment, quality of life and parental stress. RESULTS: In total, 493 mothers were randomised, 231 to intervention group and 262 to control group. There were no differences between the groups for exclusive breastfeeding, odds ratio 0.96, 95% CI 0.66-1.38, nor for maternal satisfaction with breastfeeding, attachment or quality of life. The intervention group reported significantly less parental stress than the controls, t = 2.44, 95% CI 0.03-0.23, effect size d = 0.26. CONCLUSION: In this trial, proactive telephone support was not associated with increased exclusive breastfeeding prevalence eight weeks following discharge. However, intervention group mothers showed significantly lower parental stress. PMID- 29405369 TI - Do substantial BMI reduction episodes among Swedish schoolchildren have any impact on their final height? AB - AIM: This study investigated whether substantial body mass index (BMI) reductions in Swedish schoolchildren aged seven years to 19 years, caused by disease, healthy or unhealthy behaviour, had any impact on their final height. METHODS: We used height and weight data on 6572 subjects from two nationally representative longitudinal samples of Swedish children born in 1973 and 1981. These provided information on their final height and any BMI reduction episodes. RESULTS: Of the 6572 subjects (50.9% boys), among individuals with information on final height, 1118 had a BMI reduction of 5% and <10%, and 346 had at least one substantial BMI reduction of 10% or more. On a group level, there was no statistically significant difference in the final height of individuals with BMI reductions of 10% or more and those without. The findings were independent of age and the subject's BMI at the start of the reduction episode. However, there were a number of cases where a substantial BMI reduction probably had an impact on the subject's final height. CONCLUSION: Our study found no evidence that a substantial BMI reduction had any impact on final height on a group level, but further analyses of specific case studies are necessary to determine whether substantial BMI reduction might have an impact on final height. PMID- 29405370 TI - Diabetic retinopathy in a remote Indigenous primary healthcare population: a Central Australian diabetic retinopathy screening study in the Telehealth Eye and Associated Medical Services Network project. AB - AIM: To determine diabetic retinopathy prevalence and severity among remote Indigenous Australians. METHODS: A cross-sectional diabetic retinopathy screening study of Indigenous adults with Type 2 diabetes was conducted by locally trained non-ophthalmic retinal imagers in a remote Aboriginal community-controlled primary healthcare clinic in Central Australia and certified non-ophthalmic graders in a retinal grading centre in Melbourne, Australia. The main outcome measure was prevalence of any diabetic retinopathy and sight-threatening diabetic retinopathy. RESULTS: Among 301 participants (33% male), gradable image rates were 78.7% (n = 237) for diabetic retinopathy and 83.1% (n = 250) for diabetic macular oedema, and 77.7% (n = 234) were gradable for both diabetic retinopathy and diabetic macular oedema. For the gradable subset, the median (range) age was 48 (19-86) years and known diabetes duration 9.0 (0-24) years. The prevalence of diabetic retinopathy was 47% (n = 110) and for diabetic macular oedema it was 14.4% (n = 36). In the fully gradable imaging studies, sight-threatening diabetic retinopathy prevalence was 16.2% (n = 38): 14.1% (n = 33) for clinically significant macular oedema, 1.3% (n = 3) for proliferative diabetic retinopathy and 0.9% (n = 2) for both. Sight-threatening diabetic retinopathy had been treated in 78% of detected cases. CONCLUSIONS: A novel telemedicine diabetic retinopathy screening service detected a higher prevalence of 'any' diabetic retinopathy and sight-threatening diabetic retinopathy in a remote primary care setting than reported in earlier surveys among Indigenous and non-Indigenous populations. Whether the observed high prevalence of diabetic retinopathy was attributable to greater detection, increasing diabetic retinopathy prevalence, local factors, or a combination of these requires further investigation and, potentially, specific primary care guidelines for diabetic retinopathy management in remote Australia. Clinical Trials registration number: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN 12616000370404. PMID- 29405371 TI - Disclosing the physiology of pulp tissue for vital pulp therapy. AB - The discovery that dentine is a reservoir of bioactive molecules that can be recruited on demand has attracted efforts to develop new protocols and materials for vital pulp therapy (VPT). The noncollagenous proteins (NCPs) present in the dentine extracellular matrix (ECM) include growth factors (TGF-beta1, BMP-7, FGF 2, IGF-1 and IGF-2, NGF and GDNF), extracellular matrix molecules (DSP, DPP, BSP, DMP-1 and DSPP) and both anti-inflammatory and pro-inflammatory chemokines and cytokines (TNF-alpha, IL-1, IL-6 and IL-10). Molecules such as DSP and DPP are mainly expressed by odontoblasts, and they are cleaved products from dentine sialophosphoprotein (DSPP). Some molecules, such as TGF-beta1, specifically interact with decorin/biglycan in dentine. Although TGF-beta1 increases the expression and secretion of NGF in human pulp cells, NGF induces mineralization and increases the expression of DSPP and DMP-1. Furthermore, GDNF may act as a cell survival factor and mitogen during tooth injury and repair. Pulp capping materials, such as MTA and calcium hydroxide, can solubilize bioactive dentine molecules (TGF-beta1, NGF and GDNF) that stimulate tertiary dentinogenesis. The binding of these signalling molecules leads to activation of several signalling transduction pathways involved in dentinogenesis, odontoblast differentiation and inflammatory responses, such as the p38 MAPK, NF-kbeta and Wnt/beta-catenin signalling pathways. Understanding the cascade of cellular and molecular events underlying the repair and regeneration processes provides a reasonable new approach to VPT through a targeted interaction between tooth tissue and bioactive molecules. PMID- 29405373 TI - Hepatocellular carcinoma: Liver biopsy in the balance. PMID- 29405372 TI - Melatonin increases brown adipose tissue mass and function in Zucker diabetic fatty rats: implications for obesity control. AB - Melatonin limits obesity in rodents without affecting food intake and activity, suggesting a thermogenic effect. Previously we demonstrated that melatonin browns subcutaneous fat in Zucker diabetic fatty (ZDF) rats. Other works pointed to melatonin as a signal that increases brown adipose tissue (BAT) mass and function in rodents. However, direct proof of thermogenic properties (uncoupled mitochondria) of the newly recruited BAT in response to melatonin is still lacking. Therefore, in this work, we investigated if melatonin recruits thermogenic BAT in ZDF rats. Zucker lean (ZL) and ZDF animals were subdivided into two groups, control (C) and treated with oral melatonin (M) for 6 weeks. Mitochondrial mass, activity of citrate synthase (CS), and respiratory chain complexes I and IV were lower in C-ZDF than in C-ZL animals (P < .001). Melatonin treatment increased BAT weight in ZDF rats (P < .001). Also, it rose mitochondrial mass (P < .01) and activities of CS and complexes I and IV (P < .001) in both, ZDF and ZL rats. Uncoupling protein 1 (UCP1) mRNA and protein were 50% lower in BAT from obese rats. Also, guanosine diphosphate (GDP) binding was lower in ZDF than in lean rats (P < .01). Melatonin treatment of obese rats restored the expression of UCP1 and GDP binding to levels of lean rats and sensitized the thermogenic response to cold exposure. These data demonstrated that melatonin recruits thermogenic BAT in ZDF rats. This may contribute to melatonin's control of body weight and its metabolic benefits. PMID- 29405374 TI - Separating fast and slow exchange transfer and magnetization transfer using off resonance variable-delay multiple-pulse (VDMP) MRI. AB - PURPOSE: To develop a method that can separate and quantify the fast (>1 kHz) and slow exchange transfer and magnetization transfer components in Z-spectra. METHODS: Z-spectra were recorded as a function of mixing time using a train of selective pulses providing variable-delay multipulse build-up curves. Fast and slow transfer components in the Z-spectra were separated and quantified on a voxel-by-voxel basis by fitting the mixing time-dependent CEST signal using a 3 pool model. RESULTS: Phantom studies of glutamate solution, bovine serum albumin solution, and hair conditioner showed the capability of the proposed method to separate fast and slow transfer components. In vivo mouse brain studies showed a strong contrast between white matter and gray matter in the slow-transferring map, corresponding to an asymmetric component of the conventional semisolid magnetization transfer contrast. In addition, a fast-transferring proton map was found that was homogeneous across the brain and attributed to the total contributions of the fast-exchanging protons from proteins, metabolites, and a symmetric magnetization transfer contrast component. CONCLUSIONS: This new method provides a simple way to extract fast and slow transfer components from the Z spectrum, leading to novel MRI contrasts, and providing insight into the different magnetization transfer contrast contributions. PMID- 29405375 TI - Herpes zoster at the vaccination site in immunized healthy children. AB - In this case series, we report seven immunized healthy children without underlying immunodeficiency who presented with herpes zoster that correlated with varicella-zoster vaccination site. The morphology of the lesions included erythematous papules, pseudovesicles, and plaques, with associated pain in two and pruritus in three patients; systemic symptoms ranged from none to low-grade fevers, upper respiratory symptoms, and joint pain. These cases highlight the clinical, diagnostic, and therapeutic implications of herpes zoster in vaccinated children. PMID- 29405376 TI - Using anaerobic blood cultures for infants younger than 90 days rarely showed anaerobic infections but increased yields of bacterial growth. AB - AIM: The use of anaerobic blood cultures in infants suspected of bacteraemia is controversial. Our children's hospital uses both aerobic and anaerobic media, regardless of the risk of anaerobic infection, and the aim of this study was to re-evaluate the use of anaerobic cultures in infants. METHODS: We collected retrospective data from 2002 to 2016 on all blood cultures taken from infants younger than 90 days in the Hadassah-Hebrew University Medical Centre, Jerusalem, Israel. The incidence and characteristics of infants with positive anaerobic blood cultures were assessed. RESULTS: During the study period, 51 035 blood cultures were drawn from 44 304 infants. Of these, 1496 (2.9%) were clinically significant positive cultures. Pathogenic obligatory anaerobic bacteraemia was extremely rare, with only 37 positive cultures (0.07%) from all of the cultures drawn. No specific risk factors for obligatory anaerobic bacteraemia could be defined, but as many as 174 (11.6%) clinically significant isolates were only detected in the anaerobic culture bottle. CONCLUSION: True anaerobic bacteraemia was extremely rare in neonates. Nevertheless, using anaerobic culture media may increase the overall yield of bacterial culture growth by isolating anaerobic facultative bacteria. This should be weighed up against increasing the volume of blood used for the aerobic culture. PMID- 29405377 TI - Broadening Our Horizons: JBMR and JBMR Plus Embrace Preprints. PMID- 29405379 TI - Mucosal-associated invariant T cells in autoimmune and immune-mediated diseases. AB - Autoimmune and inflammatory diseases have complex etiologies not fully understood. Both innate and adaptive immune cells are involved in the pathogenesis of these diseases. Mucosal-associated invariant T (MAIT) cells express an invariant TCRalpha chain (Valpha7.2-Jalpha33 in humans and Valpha19 Jalpha33 in mice) and recognize the conserved MHC-I-related molecule MR1 presenting bacterial metabolites derived from the synthesis of vitamin B. MAIT cells harbor tissue homing properties and produce inflammatory cytokines, suggesting that MAIT cells may play a key role in autoimmune and inflammatory diseases. In this review, we described the current knowledge on MAIT cells in these pathologies, based on patients analyses as well as mouse models. While most of the studies support a deleterious role of MAIT cells in tissue inflammation and destruction, a few reports suggest a protective role of MAIT cells. MAIT cells could represent a new biomarker of disease progression, and a better knowledge of their function might open new avenues for therapeutic strategies based on their manipulation. PMID- 29405378 TI - Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population Based and Clinically Ascertained Samples. AB - BACKGROUND: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. METHODS: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. RESULTS: Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. CONCLUSIONS: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder. PMID- 29405380 TI - Effects of temperature and precipitation on grassland bird nesting success as mediated by patch size. AB - Grassland birds are declining faster than any other bird guild across North America. Shrinking ranges and population declines are attributed to widespread habitat loss and increasingly fragmented landscapes of agriculture and other land uses that are misaligned with grassland bird conservation. Concurrent with habitat loss and degradation, temperate grasslands have been disproportionally affected by climate change relative to most other terrestrial biomes. Distributions of grassland birds often correlate with gradients in climate, but few researchers have explored the consequences of weather on the demography of grassland birds inhabiting a range of grassland fragments. To do so, we modeled the effects of temperature and precipitation on nesting success rates of 12 grassland bird species inhabiting a range of grassland patches across North America (21,000 nests from 81 individual studies). Higher amounts of precipitation in the preceding year were associated with higher nesting success, but wetter conditions during the active breeding season reduced nesting success. Extremely cold or hot conditions during the early breeding season were associated with lower rates of nesting success. The direct and indirect influence of temperature and precipitation on nesting success was moderated by grassland patch size. The positive effects of precipitation in the preceding year on nesting success were strongest in relatively small grassland patches and had little effect in large patches. Conversely, warm temperatures reduced nesting success in small grassland patches but increased nesting success in large patches. Mechanisms underlying these differences may be patch-size-induced variation in microclimates and predator activity. Although the exact cause is unclear, large grassland patches, the most common metric of grassland conservation, appears to moderate the effects of weather on grassland-bird demography and could be an effective component of climate-change adaptation. PMID- 29405381 TI - Intracerebroventricular administration of growth hormone induces morphological changes in pyramidal neurons of the hippocampus and prefrontal cortex in adult rats. AB - A growing body of evidence suggests that growth hormone (GH) affects synaptic plasticity at both the molecular and electrophysiological levels. However, unclear is whether plasticity that is stimulated by GH is associated with changes in neuron structure. This study investigated the effect of intracerebroventricular (ICV) administration of GH on the morphology of pyramidal neurons of the CA1 region of the dorsal hippocampus and layer III of the prefrontal cortex. Male Wistar rats received daily ICV injections of GH (120 ng) for 7 days, and they were euthanized 21 days later. Changes in neuronal morphology were evaluated using Golgi-Cox staining and subsequent Sholl analysis. GH administration increased total dendritic length in the CA1 region of the dorsal hippocampus and prefrontal cortex. The Sholl analysis revealed an increase in dendritic length of the third to eighth branch orders in the hippocampus and from the third to sixth branch orders in the prefrontal cortex. Interestingly, GH treatment increased the density of dendritic spines in both brain regions, favoring the presence of mushroom-like spines only in the CA1 hippocampal region. Our results indicated that GH induces changes in the length of dendritic trees and the density of dendritic spines in two high-plasticity brain regions, suggesting that GH-induced synaptic plasticity at the molecular and electrophysiological levels may be associated with these structural changes in neurons. PMID- 29405382 TI - Spontaneous rupture of the ascending aorta. AB - BACKGROUND: Nontraumatic, spontaneous rupture of the ascending aorta is rare and the etiology is largely unknown. METHODS: We reviewed seven patients from our institution, with no known aortic disease or hereditary connective tissue disorder that presented with spontaneous ascending aortic rupture from 2012 to 2017. RESULTS: Most patients presented with non-radiating chest pain along with hypertension (71.4%). The mean ascending aortic diameter at rupture was 4.60 +/- 0.62 cm. The median door-to-operating room time was 2.58 h, resulting from effective implementation of an aortic emergency protocol. There were no operative mortalities. CONCLUSIONS: In patients with ascending aortic rupture, aortic diameter may not always correlate with the risk of rupture. Rapid diagnosis combined with a multidisciplinary approach is vital for the successful management of these high-risk patients. PMID- 29405383 TI - The Quest for Osteoporosis Mechanisms and Rational Therapies: How Far We've Come, How Much Further We Need to Go. AB - During the last 40 years, understanding of bone biology and the pathogenesis of osteoporosis, the most common and impactful bone disease of old age, has improved dramatically thanks to basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies. Culprits of osteoporosis are no longer a matter of speculation based on in vitro observations. Instead, they can be identified and dissected at the cellular and molecular level using genetic approaches; and their effect on distinct bone envelopes and anatomic regions can be functionally assessed in vivo. The landscape of pharmacotherapies for osteoporosis has also changed profoundly with the emergence of several potent antiresorptive drugs as well as anabolic agents, displacing estrogen replacement as the treatment of choice. In spite of these major positive developments, the optimal duration of the available therapies and their long-term safety remain matters of conjecture and some concern. Moreover, antiresorptive therapies are used indiscriminately for patients of all ages on the assumption that suppressing remodeling is always beneficial for bone, but rebound remodeling upon their discontinuation suggests otherwise. In this invited perspective, I highlight the latest state of knowledge of bone-intrinsic and extrinsic mechanisms responsible for the development of osteoporosis in both sexes; differences between the mechanisms responsible for the effects of aging and estrogen deficiency; and the role of old osteocytes in the development of cortical porosity. In addition, I highlight advances toward the goal of developing drugs for several degenerative diseases of old age at once, including osteoporosis, by targeting shared mechanisms of aging. (c) 2018 American Society for Bone and Mineral Research. PMID- 29405384 TI - In vitro antibiofilm and anti-adhesion effects of magnesium oxide nanoparticles against antibiotic resistant bacteria. AB - The aim of the current investigation was to determine the antibacterial and antibiofilm potential of MgO nanoparticles (NPs) against antibiotic-resistant clinical strains of bacteria. MgO NPs were synthesized by a wet chemical method and further characterized by scanning electron microscopy and energy dispersive X ray. Antibacterial activity was determined by broth microdilution and agar diffusion methods. The Bradford method was used to assess cellular protein leakage as a result of loss of membrane integrity. Microtiter plate assay following crystal violet staining was employed to determine the effect of MgO NPs on biofilm formation and removal of established biofilms. MIC values ranged between 125 and 500 MUg/mL. Moreover, treatment with MgO NPs accelerated rate of membrane disruption, measured as a function of leakage of cellular proteins. Leakage of cellular protein content was greater among gram-negative bacteria. Cell adherence assay indicated 25.3-49.8% inhibition of bacterial attachment to plastic surfaces. According to a static biofilm method, MgO NPs reduced biofilm formation potential from 31% to 82.9% in a time-dependent manner. Moreover, NPs also significantly reduced the biomass of 48, 72, 96 and 120 hr old biofilms (P < 0.05). Cytotoxicity experiments using a neutral red assay revealed that MgO NPs are non-toxic to HeLa cells at concentrations of 15-120 MUg/mL. These data provide in vitro scientific evidence that MgO NPs are effective and safe antibiofilm agents that inhibit adhesion, biofilm formation and removal of established biofilms of multidrug-resistant bacteria. PMID- 29405386 TI - Plasma exeresis for active acne vulgaris: Clinical and in vivo microscopic documentation of treatment efficacy by means of reflectance confocal microscopy. PMID- 29405385 TI - Specificity Protein 7 Is Required for Proliferation and Differentiation of Ameloblasts and Odontoblasts. AB - The Sp7/Osterix transcription factor is essential for bone development. Mutations of the Sp7 gene in humans are associated with craniofacial anomalies and osteogenesis imperfecta. However, the role of Sp7 in embryonic tooth development remains unknown. Here we identified the functional requirement of Sp7 for dentin synthesis and tooth development. Sp7-null mice exhibit craniofacial dysmorphogenesis and are completely void of alveolar bone. Surprisingly, initial tooth morphogenesis progressed normally in Sp7-null mice. Thus the formation of alveolar bone is not a prerequisite for tooth morphogenesis. Sp7 is required for mineralization of palatal tissue but is not essential for palatal fusion. The reduced proliferative capacity of Sp7-deficient ectomesenchyme results in small and misshapen teeth with randomly arranged cuboidal preodontoblasts and preameloblasts. Sp7 promotes functional maturation and polarization of odontoblasts. Markers of mature odontoblast (Col1a, Oc, Dspp, Dmp1) and ameloblast (Enam, Amelx, Mmp20, Amtn, Klk4) are barely expressed in incisors and molar tissues of Sp7-null mice. Consequently, dentin and enamel matrix are absent in the Sp7-null littermates. Interestingly, the Sp7 expression is restricted to cells of the dental mesenchyme indicating the effect on oral epithelium-derived ameloblasts is cell-nonautonomous. Abundant expression of Fgf3 and Fgf8 ligand was noted in the developing tooth of wild-type mice. Both ligands were remarkably absent in the Sp7-null incisor and molar, suggesting cross-signaling between mesenchyme and epithelium is disrupted. Finally, promoter-reporter assays revealed that Sp7 directly controls the expression of Fgf-ligands. Together, our data demonstrate that Sp7 is obligatory for the differentiation of both ameloblasts and odontoblasts but not for the initial tooth morphogenesis. (c) 2018 American Society for Bone and Mineral Research. PMID- 29405426 TI - Overcoming a treatment barrier in treating hepatitis C in dialysis patients. PMID- 29405427 TI - A Bayesian confirmatory factor model for multivariate observations in the form of two-way tables of data. AB - Researchers collected multiple measurements on patients with schizophrenia and their relatives, as well as control subjects and their relatives, to study vulnerability factors for schizophrenics and their near relatives. Observations across individuals from the same family are correlated, and also the multiple outcome measures on the same individuals are correlated. Traditional data analyses model outcomes separately and thus do not provide information about the interrelationships among outcomes. We propose a novel Bayesian family factor model (BFFM), which extends the classical confirmatory factor analysis model to explain the correlations among observed variables using a combination of family member and outcome factors. Traditional methods for fitting confirmatory factor analysis models, such as full-information maximum likelihood (FIML) estimation using quasi-Newton optimization (QNO), can have convergence problems and Heywood cases (lack of convergence) caused by empirical underidentification. In contrast, modern Bayesian Markov chain Monte Carlo handles these inference problems easily. Simulations compare the BFFM to FIML-QNO in settings where the true covariance matrix is identified, close to not identified, and not identified. For these settings, FIML-QNO fails to fit the data in 13%, 57%, and 85% of the cases, respectively, while MCMC provides stable estimates. When both methods successfully fit the data, estimates from the BFFM have smaller variances and comparable mean-squared errors. We illustrate the BFFM by analyzing data on data from schizophrenics and their family members. PMID- 29405428 TI - The 2014 BCSH criteria and the 2016 WHO criteria for essential thrombocythemia: A comparison in a large-scale cohort. AB - OBJECTIVE: There are currently 2 representative diagnostic criteria for essential thrombocythemia (ET), the 2014 British Committee for Standards in Hematology Guidelines (BCSH) criteria and the 2016 World Health Organization (WHO) criteria. We compare and discuss the advantages and disadvantages of the 2 criteria. METHOD: We applied the 2 criteria to 403 patients with thrombocytosis and suspected myeloproliferative neoplasms (MPN) and compared patient populations. RESULTS: The BCSH criteria diagnosed ET in 279 patients (BCSH-ET) whereas the WHO criteria diagnosed ET in 203 patients (WHO-ET). There were 83 patients diagnosable only by the BCSH criteria (BCSH-only-ET), of which under the WHO classification, 69 patients fell under the category of MPN, unclassifiable (MPN u), 12 patients were PMF, prefibrotic/early stage (pre-PMF), and 2 patients were polycythemia vera. Patient characteristics such as age, hemoglobin, hematocrit, platelet counts, lactate dehydrogenase levels, JAK2V617F allele burdens, prevalence of myelofibrosis and splenomegaly, and frequencies of thrombotic events and treatment did not differ between WHO-ET and BCSH-only-ET, but BCSH only-ET patients showed higher WBC counts and higher JAK2V617F mutation frequencies. CONCLUSION: The BCSH criteria diagnosed ET in a broader range of patients encompassing a significant number of patients who would otherwise be diagnosed as pre-PMF or MPN-u. PMID- 29405429 TI - Age-related differences in the functional properties of lips compared with skin. AB - BACKGROUND/AIMS: Lips can easily become dry and rough and their biggest problems are drying and chapping. The cause of those problems is considered to be that the stratum corneum (SC) moisture is small and its barrier function is low. However, those problems decrease in subjects as they approach 40 years of age, after which problems due to their shape and color increase. The purpose of this study was to investigate relationships between SC properties of the lips during aging and to clarify the cause(s) of lip problems. METHODS: One hundred and 38 Japanese female subjects with normal skin ranging in age from 16 to 78 years were enrolled in the study. The capacitance and transepidermal water loss (TEWL) values, viscoelasticity, and color of their lips were measured and compared with their cheeks. RESULTS: The capacitance values for the lip and the cheek increased and TEWL values for both areas decreased with age. TEWL values for the lip decreased until ~30 years of age and this is considered to be related to the problem of drying. Although the maximum amplitude Uf of the lip increased with age, the Ur /Uf had no correlation with age. As for color, the L* and a* values decreased with age. CONCLUSION: Age-related changes with regard to SC functions, viscoelasticity and color of the lips have been clarified for the first time, and it is clear that these changes are related to problems of the lips. Compared with the cheeks, differences with the lips are more apparent. PMID- 29405430 TI - TFM classification and staging of oral submucous fibrosis: A new proposal. AB - BACKGROUND: We have evaluated the rationale of existing grading and staging schemes of oral submucous fibrosis (OSMF) based on how they are categorized. A novel classification and staging scheme is proposed. METHODS: A total of 300 OSMF patients were evaluated for agreement between functional, clinical, and histopathological staging. Bilateral biopsies were assessed in 25 patients to evaluate for any differences in histopathological staging of OSMF in the same mouth. Extent of clinician agreement for categorized staging data was evaluated using Cohen's weighted kappa analysis. Cross-tabulation was performed on categorical grading data to understand the intercorrelation, and the unweighted kappa analysis was used to assess the bilateral grade agreement. Probabilities of less than 0.05 were considered significant. Data were analyzed using SPSS Statistics (version 25.0, IBM, USA). RESULTS: A low agreement was found between all the stages depicting the independent nature of trismus, clinical features, and histopathological components (K = 0.312, 0.167, 0.152) in OSMF. Following analysis, a three-component classification scheme (TFM classification) was developed that describes the severity of each independently, grouping them using a novel three-tier staging scheme as a guide to the treatment plan. CONCLUSION: The proposed classification and staging could be useful for effective communication, categorization, and for recording data and prognosis, and for guiding treatment plans. Furthermore, the classification considers OSMF malignant transformation in detail. PMID- 29405431 TI - Pre-close technique of percutaneous closure for delayed hemostasis of large-bore femoral sheaths. AB - Advancement of coronary interventions and portable hemodynamic device requires placement of large bore sheaths. Access for large caliber sheaths, its placement, maintenance, and hemostasis is very challenging and one of the key ailments for successful procedures. Traditional hemostasis method is manual compression, which is unattractive due to its own limitations and subsequent complications. Single closure device for sheath size larger than 8 French (Fr) is not available. We performed retrospective analysis of large cohort of patients with 13, 14 Fr sheaths (Impella device [ABIOMED]) percutaneous closure with the use of two Perclose devices. Two perclose devices were placed in a "Preclose" fashion and hemostasis was obtained few days later once hemodynamic support was weaned off by deployment of perclose sutures. PMID- 29405432 TI - Use of medical photography among dermatologists: a nationwide online survey study. AB - BACKGROUND: Medical photography enhances patient care, medical education and research. Despite medical photography's widespread use, little is known about how dermatologists choose to implement photography in routine clinical practice, and how they approach issues of image storage, image security and patient consent. OBJECTIVE: To characterize dermatologists' medical photography habits and opinions. METHODS: A 32-item anonymous, multiple-choice SurveyMonkey questionnaire about medical photography practices was emailed to programme directors of the 117 United States (US) dermatology residency programmes between May and August 2015, with a request to forward to faculty and affiliated dermatologists. Only board-certified dermatologists practicing in the United States were eligible. The Institutional Review Board exempted our study from full review. RESULTS: Our survey included 153 board-certified dermatologists, primarily representing the north-east (43.1%) and identifying as academic dermatologists (75.5%). Medical photography is prevalent: 61.8% report everyday use and 21.7% photograph every patient. Those reporting rare use (3.3%) were, on average, 20 years older. Dermatologists most commonly use photography to mark biopsy sites (87.5%), track disease (82.9%) and for education/teaching (72.4%). Nearly half (46%) use smartphone cameras. Emailing and texting photographs with patients or colleagues are common (69.1%). Most dermatologists (75.7%) always request patient consent for photographs. Only 23.7% adhere to a photography protocol and 73.9% desire more training opportunities. CONCLUSION: Dermatologists value medical photography. While patterns of image acquisition, storage and consent are noted, a variety of methods and preferences exist. Clearer photography guidelines and increased educational resources are likely to improve image quality, exchangeability and confidentiality. PMID- 29405433 TI - The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine. AB - In autosomal dominant skin disorders, the well-known type 1 segmental mosaicism reflects heterozygosity for a postzygotic new mutation. By contrast, type 2 segmental mosaicism originates in a heterozygous embryo from an early postzygotic mutational event giving rise to loss of the corresponding wild-type allele, which results in a pronounced segmental involvement being superimposed on the ordinary, non-segmental phenotype. Today, this concept has been proven by molecular analysis in many cutaneous traits. The purpose of this review was to seek publications of cases suggesting an extracutaneous manifestation of type 2 segmental mosaicism. Case reports documenting a pronounced extracutaneous segmental involvement were collected from the literature available in PubMed and from personal communications to the author. Pertinent cases are compared to the description of cutaneous segmental mosaicism of type 1 or type 2 as reported in a given trait. In total, reports suggesting extracutaneous type 2 segmental mosaicism were found in 14 different autosomal dominant skin disorders. In this way, clinical evidence is accumulated that extracutaneous type 2 segmental mosaicism does likewise occur in many autosomal dominant skin disorders. So far, however, molecular proof of this particular form of mosaicism is lacking. The present review may stimulate readers to inform colleagues of other specialties on this new concept, in order to initiate further research in this particular field of knowledge that has important implications for diagnosis, treatment and genetic counselling. PMID- 29405434 TI - Fifty years of colic surgery. AB - Colic surgery is one of few treatments in which a veterinarian can use a skill to save an animal's life from a deadly disease within a short timeframe. Unfortunately, such success is not achieved without considerable risk for surgical failure, which is responsible for most complications in the immediate post-operative period. The last 50 years have witnessed considerable improvements in colic surgery, although a ranking of the most important ones might not meet with universal agreement. Teamwork plays a critical role in the final outcome, starting and finishing with the referring veterinarian and owner. These individuals are responsible for promptly transferring the horse to a surgical facility and then dealing with aftercare and delayed complications. The surgeon is responsible for the intervening steps, including the decision on the need for surgery, and works with the anaesthesiologist to help a metabolically challenged patient to tolerate surgery and anaesthesia. Although early referral and improved diagnostic procedures can have a positive influence on survival, perceived improvements in surgery and anaesthesia need to be reviewed with some circumspection. Although more rigorous definitions and statistical analyses used in recent studies can invalidate comparisons with older studies, complication rates appear to be on the rise, despite putative improvements in dealing with them. This trend tends to diminish the value of colic surgery through increasing costs, overreliance on post-operative pharmacological management, growing pessimism, high rates of intraoperative euthanasia, and possibly reduced long term survival. Future efforts should address these concerns, mostly through emphasis on prompt referral, good surgical technique and reducing the cost of colic surgery to an affordable level that saves more lives. PMID- 29405435 TI - Immediate post-operative broncho-alveolar lavage IL-6 and IL-8 are associated with early outcomes after lung transplantation. AB - INTRODUCTION: Previous studies demonstrated that increased cytokine and chemokine levels, either shortly before or after lung transplantation, were associated with post-transplant outcome. However, small patient cohorts were mostly used, focusing on 1 molecule and 1 outcome. In a large single-center cohort, we investigated the predictive value of immediate post-operative broncho-alveolar lavage (BAL) expression of IL-6 and IL-8 on multiple key outcomes, including PGD, CLAD, graft survival, as well as several secondary outcomes. MATERIAL AND METHODS: All patients undergoing a first lung transplant in whom routine bronchoscopy with BAL was performed during the first 48 hours post transplantation were included. IL-6 and IL-8 protein levels were measured in BAL via ELISA. RESULTS: A total of 336 patients were included. High IL-6 levels measured within 24 hours of transplantation were associated with longer time on ICU and time to hospital discharge; and increased prevalence of PGD grade 3. Increased IL-8 levels, measured within 24 hours, were associated with PGD3, more ECMO use, higher donor paO2 , younger donor age, but not with other short-or long term outcome. IL-6 and IL-8 measured between 24 and 48 hours of transplantation were not associated with any outcome parameters. CONCLUSION: Recipient BAL IL-6 and IL-8 within 24 hours post-transplant were associated with an increased incidence of PGD3. PMID- 29405436 TI - The role of breastfeeding in the association between maternal and infant cortisol attunement in the first postpartum year. AB - AIM: To explore the role of breastfeeding as a possible link between maternal and infant cortisol attunement across the first postpartum year. METHODS: Mothers (n = 93) provided salivary samples for cortisol levels over a two-day period during mid-pregnancy and at three, six and 12 months and infants at six and 12 months postpartum. Breastfeeding status was established at these same time points. RESULTS: Among breastfeeding mothers, positive correlations were found between maternal cortisol levels during pregnancy and at three months postpartum and infant cortisol at six or 12 months postpartum. Among nonbreastfeeding mothers, these same maternal and infant cortisol relations were inverse and less pronounced. Further, in breastfeeding mothers, the relationship between maternal prenatal cortisol and infant cortisol at 12 months was mediated through maternal cortisol at three months postpartum. CONCLUSION: These results suggest that maternal cortisol levels are positively associated with cortisol levels of the infant, among mothers who breastfeed. This relationship persists over a one-year period. PMID- 29405437 TI - Studying the effect of systemic and biological drugs on intima-media thickness in patients suffering from moderate and severe psoriasis. AB - BACKGROUND: Psoriasis has been related to a large number of cardiovascular risk factors such as hypertension, diabetes mellitus and arteriosclerosis. The increased carotid intima-media thickness (IMT) could be considered to be a marker of generalized arteriosclerosis. OBJECTIVE: To assess the effect of systemic and biological drugs on psoriatic patients' carotid IMT. METHODS: A prospective study was performed. We studied 53 patients with moderate and severe psoriasis from our psoriasis dermatological unit, analysing lipid and glucose metabolism and performing a carotid IMT sonography before introduction of systemic and biological drugs. After that, we performed an 8-month closely analytic and sonographic follow-up. RESULTS: The IMT of the patients with psoriasis treated with biological drugs tended to decrease, although this occurrence was not statistically significant (P = 0.086). The subgroup analysis revealed that patients treated with methotrexate (P = 0.045) and anti-IL-12/23 (P = 0.010) presented a decrease in their IMT levels. This analysis also showed a decrease in glycaemia and insulin levels in patients treated with TNF-alpha inhibitors and ustekinumab. CONCLUSIONS: Our study suggests that the carotid IMT may benefit from treatment with biological drugs, particularly anti-IL-12/23 and methotrexate in patients suffering from moderate and severe psoriasis. However, larger longitudinal studies should be performed to fully confirm these results. PMID- 29405439 TI - Non-invasive evaluation of human mucosal structures by multiphoton laser scanning tomography in vitro. AB - BACKGROUND: Mucous membranes may be affected by various diseases and the diagnostic accessibility is limited. Multiphoton laser tomography (MPT) is a useful tool for in vivo evaluation of superficial skin structures and might also be useful for the imaging of mucosa. OBJECTIVES: In order to investigate the suitability of MPT for the evaluation of mucous membranes, tissue samples of different donors and anatomical localizations have been imaged. METHODS: Human mucosa samples from the urinary bladder, palatine tonsil and ocular conjunctiva were investigated by MPT and subsequently compared with conventional histology. RESULTS: Horizontal images of the epithelium and the underlying connective tissue were obtained using the autofluorescence and second harmonics generation signals by MPT. The stratification of multilayered epithelium was consistently reproduced. Also inflammatory changes like lymphocytic infiltrates and widened intercellular spaces were imaged in some cases. CONCLUSION: Mucous tissue samples were obtained and MPT imaging was successfully performed. In the direct comparison with histology of the same tissue samples, the characteristic morphology of the epithelia was found. Further studies are necessary in order to compare images of healthy and diseased mucosal epithelium and the use of MPT for its evaluation in vivo. PMID- 29405438 TI - Mixed Valence Perovskite Cs2 Au2 I6 : A Potential Material for Thin-Film Pb-Free Photovoltaic Cells with Ultrahigh Efficiency. AB - New light is shed on the previously known perovskite material, Cs2 Au2 I6 , as a potential active material for high-efficiency thin-film Pb-free photovoltaic cells. First-principles calculations demonstrate that Cs2 Au2 I6 has an optimal band gap that is close to the Shockley-Queisser value. The band gap size is governed by intermediate band formation. Charge disproportionation on Au makes Cs2 Au2 I6 a double-perovskite material, although it is stoichiometrically a single perovskite. In contrast to most previously discussed double perovskites, Cs2 Au2 I6 has a direct-band-gap feature, and optical simulation predicts that a very thin layer of active material is sufficient to achieve a high photoconversion efficiency using a polycrystalline film layer. The already confirmed synthesizability of this material, coupled with the state-of-the-art multiscale simulations connecting from the material to the device, strongly suggests that Cs2 Au2 I6 will serve as the active material in highly efficient, nontoxic, and thin-film perovskite solar cells in the very near future. PMID- 29405440 TI - Ebselen inhibits the activity of acetylcholinesterase globular isoform G4 in vitro and attenuates scopolamine-induced amnesia in mice. AB - There is a well-known relationship between the cholinergic system and learning, memory, and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro, ebselen at concentrations equal or higher than 10 MUM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform. Treatment of mice with ebselen (50 mg/kg, i.p.) was effective against impairment of spatial recognition memory in both Y-maze and novel object recognition tests induced by scopolamine (1 mg/kg, i.p.). Ebselen (50 mg/kg) inhibited hippocampal AChE activity in mice. The present study demonstrates that ebselen inhibited the G4/AChE isoform in vitro and elicited an anti-amnesic effect in a mouse model induced by scopolamine. These findings reveal ebselen as a potential compound in terms of opening up valid therapeutic avenues for the treatment of memory impairment diseases. PMID- 29405441 TI - Interfacial Coupling Effect in Organic/Inorganic Nanocomposites with High Energy Density. AB - Organic/inorganic nanocomposites (OINs) can be potentially used as high performance capacitors due to their rapid charge-discharge capability along with respectable power density. The coupling effect of the filler/matrix interface plays a prominent role in the dielectric and electric properties of OINs. Along with a review of contemporary theoretical models, recent advances in interfacial optimization to improve energy density through careful interface control and design are also presented. Possible mechanisms that may improve energy density and potential applications for high-energy-density capacitors are also highlighted. PMID- 29405442 TI - Visually Imperceptible Liquid-Metal Circuits for Transparent, Stretchable Electronics with Direct Laser Writing. AB - A material architecture and laser-based microfabrication technique is introduced to produce electrically conductive films (sheet resistance = 2.95 Omega sq-1 ; resistivity = 1.77 * 10-6 Omega m) that are soft, elastic (strain limit >100%), and optically transparent. The films are composed of a grid-like array of visually imperceptible liquid-metal (LM) lines on a clear elastomer. Unlike previous efforts in transparent LM circuitry, the current approach enables fully imperceptible electronics that have not only high optical transmittance (>85% at 550 nm) but are also invisible under typical lighting conditions and reading distances. This unique combination of properties is enabled with a laser writing technique that results in LM grid patterns with a line width and pitch as small as 4.5 and 100 um, respectively-yielding grid-like wiring that has adequate conductivity for digital functionality but is also well below the threshold for visual perception. The electrical, mechanical, electromechanical, and optomechanical properties of the films are characterized and it is found that high conductivity and transparency are preserved at tensile strains of ~100%. To demonstrate their effectiveness for emerging applications in transparent displays and sensing electronics, the material architecture is incorporated into a couple of illustrative use cases related to chemical hazard warning. PMID- 29405443 TI - Levocarnitine for vismodegib-associated muscle spasms: a pilot randomized, double blind, placebo-controlled, investigator-initiated trial. PMID- 29405444 TI - A Plasmonic Sensor Array with Ultrahigh Figures of Merit and Resonance Linewidths down to 3 nm. AB - Surface plasmon polaritons (SPPs) are extremely sensitive to the surrounding refractive index and have found important applications in ultrasensitive label free sensing. Reducing the linewidth of an SPP mode is an effective way to improve the figure of merit (FOM) and hence the sensitivity of the plasmonic mode. Many efforts have been devoted to achieving a narrow linewidth by mode coupling, which inevitably results in an asymmetrical lineshape compromising the performance. Instead, the SPP modes are directly narrowed by elaborately engineering periodic plasmonic structures with minimized feature sizes to effectively reduce the radiative losses. A narrow linewidth smaller than 8 nm is achieved over a wide wavelength ranging from 600 to 960 nm and a minimum full width at half maximum of 3 nm at 960 nm. Benefiting from the almost perfect Lorentzian lineshape and the extremely narrow linewidth, a record FOM value of 730 is obtained. The sensor is capable of detecting bovine serum albumin with an ultralow concentration of 10-10 m. The sensor has great potential for practical application for its ultrahigh FOM, broad working wavelength, and ease of high throughput fabrication. PMID- 29405445 TI - The possible critical role of T-cell help in DSA-mediated graft loss. AB - In this review, we discuss a possible central role of T-cell help in severe forms of graft damage mediated by donor-specific HLA antibodies (DSA). Some kidney transplant recipients with pretransplant DSA show a high graft failure rate, whereas in other patients DSA do not harm the transplanted kidney and in most cases, disappear shortly after transplantation. Analyzing 80 desensitized highly immunized kidney transplant recipients and another multicenter cohort of 385 patients with pretransplant HLA antibodies, we reported recently that an ongoing T-cell help from an activated immune system, as measured by an increased level of soluble CD30 in serum, might be necessary for the DSA to exert a deleterious effect. Patients positive for both pretransplant DSA and sCD30 appear to require special measures, such as the elimination of DSA from the circulation, potent immunosuppression, good HLA-matching, and intense post-transplant monitoring, whereas exclusion of DSA-positive patients from transplantation in the absence of high sCD30 may not be justified in all cases, even if the pretransplant DSA are strong and complement-activating. PMID- 29405446 TI - Role of hemostatic powders in the management of lower gastrointestinal bleeding: A review. AB - Despite the recent advances in endoscopic hemostatic techniques, the management of lower gastrointestinal bleeding could be sometimes challenging. Hemostatic powders such as Hemospray, EndoClot, and Ankaferd Blood Stopper have found their way into digestive endoscopy and are licenced in many countries especially for use in upper gastrointestinal bleeding. We reviewed the literature on the use of these hemostatic powders in different situations in lower gastrointestinal bleeding and looked at the success rate and rebleeding rate. Most of the data are derived from case reports, retrospective and prospective case series with absence of any randomized controlled trials. Hemostatic powders were used as primary or salvage therapy to control bleeding from polypectomy site, colonic tumors, diverticula, arteriovenous malformations, radiation proctitis, ischemic colitis, and surgical intestinal anastomosis. The rate of immediate control of bleeding is in the range of 88-100% with a recurrence rate of 3-13% except for radiation proctitis bleeding where rebleeding rate can be as high as 77%. Although there are many advantages for the use of local hemostatic agents in lower gastrointestinal bleeding, future randomized controlled trials comparing them with conventional methods are needed. PMID- 29405447 TI - Nutritional therapy complications in children with ultra-short bowel syndrome include growth deficiency but not cholestasis. AB - AIM: Children with ultra-short bowel syndrome (USBS) have not been extensively studied to date because the condition is rare. The aim of the study was to assess the nutritional status of children with USBS receiving home parenteral nutrition, using citrulline serum concentration and cholestasis. METHODS: We studied 17 patients with USBS, with a median age of 6.6 years and median duration of parenteral nutrition of 6.6 years. The study was carried out at The Children's Memorial Health Institute, Warsaw, from January 2014 to January 2015. RESULTS: The median standard deviation score (SDS) was -1.2 for body mass according to chronological age, -1.72 according to height and -0.59 according to height for age. Patients requiring seven days per week parenteral nutrition had a citrulline concentration below 10 MUmol/L. Decreased bone-mineral density was observed in 87% of the patients. Low values of 25-hydroxyvitamin D were found in 53% of the children. None of the patients had elevated conjugated bilirubin levels above 34.2 MUmol/L. CONCLUSION: Children with USBS were growth deficient according to their chronological age, with frequent abnormal bone mineralisation and vitamin D deficiency. Children requiring parenteral nutrition seven days a week had citrulline concentrations below 10 MUmol/L. Cholestasis was not seen. PMID- 29405448 TI - Correlation of Structural and Magnetic Properties in a Set of Mononuclear Lanthanide Complexes. AB - The electronic and magnetic properties of a set of mononuclear terbium(III) and dysprosium(III) complexes with two tetradentate 1-hydroxy-pyridin-2-one (1,2 HOPO) ligands are reported. Two primary coordination geometries are observed, depending on the length of the linker between the 1,2-HOPO donor moieties and the resulting arrangements of the linker. Fine details of the magnetic circular dichroism (MCD) spectra of the dysprosium(III) complexes illustrate differences in the splitting of the J multiplets and allow for a thorough ligand field analysis. High frequency electron paramagnetic resonance (HF-EPR) studies of the terbium(III) complexes give insight into the composition of the ground states. Ab initio calculations are utilized to rationalize the experimental results and further illustrate the effect of the structural features on the electronic and magnetic properties of the different complexes. PMID- 29405449 TI - Covalent Immobilization of (-)-Riboflavin on Polymer Functionalized Silica Particles: Application in the Photocatalytic E->Z Isomerization of Polarized Alkenes. AB - The covalent immobilization of the biomimetic, photo-organocatalyst (-) riboflavin on silica micro- and nanoparticles via atom transfer radical polymerization (ATRP) is disclosed. Given the effectiveness of (-)-riboflavin as a versatile, environmentally benign photocatalyst, an immobilization strategy based on acrylate-linker modification of the catalyst core and controlled polymerization on initiator pre-functionalized silica particles has been developed. Validation of this approach is demonstrated in the E->Z isomerization of a benchmark cinnamonitrile (Z/E up to 88:12) with 0.97 mol % catalyst loading. Characterization of the immobilized photocatalyst supports covalent embedding of the catalyst in the polymeric brushes on the silica particle surface. PMID- 29405450 TI - Use of SkinFibrometer(r) to measure skin elasticity and its correlation with Cutometer(r) and DUB(r) Skinscanner. AB - BACKGROUND: Skin elasticity is an important indicator of skin aging. The aim of this study was to demonstrate that the SkinFibrometer(r) is appropriate for measuring skin biomechanical properties, and to correlate it with elasticity parameters measured using the Cutometer(r) and with dermis structural properties measured using DUB(r) Skinscanner. MATERIALS AND METHODS: Twenty-one individuals participated in this study. The skin of the cheek, around the eye, and the volar forearm were evaluated. To analyze correlations of elasticity parameters, the induration value against the indenter pressure of SkinFibrometer(r) and R, Q parameters of Cutometer(r) were compared. Dermal echogenicity using DUB(r) Skinscanner was compared with the induration value of SkinFibrometer(r) . RESULTS: The younger age group showed more firm and elastic skin properties compared to the older age group, and the elasticity values of the volar forearm were significantly higher than those of the cheek and around the eye region. Even though the measuring principle is different, both SkinFibrometer(r) and Cutometer(r) demonstrated the same trends of skin elasticity differences according to age and anatomical regions. There were significant correlations between the induration value of SkinFibrometer(r) , representing skin firmness, and R0, Q0 and R2, R5, R7, Q1, Q2 of Cutometer(r) , which represent skin firmness and resilience, respectively (P < .01). In addition, dermal echogenicity positively correlated with skin firmness determined by SkinFibrometer(r) (P < .01). CONCLUSION: We identified correlations between skin elasticity parameters evaluated by two different methods of suction and indentation, and demonstrated that the SkinFibrometer(r) is an objective, non-invasive evaluation tool for skin stiffness and elasticity. PMID- 29405451 TI - Nicotinic activity layer specifically modulates synaptic potentiation in the mouse insular cortex. AB - Nicotinic acetylcholine receptors (nAChRs) in the insular cortex play an important role in nicotine addiction, but its cellular and synaptic mechanisms underlying nicotine addiction still remain unresolved. In layer 5 pyramidal neurons of the mouse insular cortex, activation of nAChRs suppresses synaptic potentiation through enhancing GABAergic synaptic transmission via activation of beta2-containing nAChRs in non-fast-spiking (non-FS) interneurons. However, it has not been addressed whether and how activation of nAChRs modulates synaptic plasticity in layers 3 and 6 pyramidal neurons of the insular cortex. In this study, I demonstrate that activation of nAChRs oppositely modulates synaptic potentiation in layers 3 and 6 pyramidal neurons of the insular cortex. In layer 3 pyramidal neurons, activation of nAChRs depressed synaptic potentiation induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training) through enhancing GABAergic synaptic transmission via activation of beta2-containing nAChRs in non-FS interneurons. By contrast, in layer 6 pyramidal neurons, activation of nAChRs enhanced synaptic potentiation through activating postsynaptic beta2-containing nAChRs. These results indicate, in different layers of the mouse insular cortex, paired training-induced synaptic potentiation is oppositely regulated by activation of nAChRs which are located on GABAergic interneurons (layer 3) and on pyramidal neurons (layer 6). Thus, layer specific modulation of synaptic potentiation may be involved in cellular and synaptic mechanisms of insular cortical changes in nicotine addiction. PMID- 29405452 TI - Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1 stage exchange model of MRSA implant-associated osteomyelitis. AB - Methicillin-resistant Staphylococcus aureus (MRSA) reinfection following revision surgery remains a major orthopaedic problem. Toward the development of immunotherapy with anti-glucosaminidase monoclonal antibodies (anti-Gmd), we aimed to: (i) develop a murine 1-stage exchange model of bioluminescent MRSA (USA300LAC::lux) contaminated femoral implants; and (ii) utilize this model to demonstrate the synergistic effects of combination vancomycin and anti-Gmd therapy on reinfection and bone healing. Following an infection surgery, the original plate and two screws were removed on day 7, and exchanged with sterile implants. Mice were randomized to five groups: (i) no infection control; (ii) infected placebo; (iii) anti-Gmd; (iv) vancomycin; and (v) combination therapy. Bioluminescent imaging (BLI) was performed on days 0, 1, 3, 5, 7, 8, 10, 12, and 14. Mice were euthanized on day 14 (day 7 post-revision), and efficacy was assessed via colony forming units (CFU) on explanted hardware, micro-CT, and histology. As monotherapies, anti-Gmd inhibited Staphylococcus abscess communities, and vancomycin reduced CFU on the implants. However, only combination therapy prevented increased BLI post-revision surgery, with a significant 6.5-fold reduction on day 10 (p < 0.05 vs. placebo), and achieved sterile implant levels by day 12. Synergistic effects were also apparent from reduced osteolysis and increased new bone formation around the screws only observed following combination therapy. Taken together, we find that: (i) this murine femoral plate 1-stage revision model can efficiently evaluate therapies to prevent reinfection; and (ii) immunotherapy plays a distinct role from antibiotics to reduce reinfection following revision surgery, such that synergy to achieve osseointegration is possible. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1590-1598, 2018. PMID- 29405453 TI - Electrogenic N-methyl-D-aspartate receptor signaling enhances binaural responses in the adult brainstem. AB - In sensory systems, the neuronal representation of external stimuli is enhanced along the sensory pathway. In the auditory system, strong enhancement of binaural information takes place between the brainstem and the midbrain; however, the underlying cellular mechanisms are unknown. Here we investigated the transformation of binaural information in the dorsal nucleus of the lateral lemniscus (DNLL), a nucleus that connects the binaural nuclei in the brainstem and the inferior colliculus in the midbrain. We used in vitro and in vivo electrophysiology in adult Mongolian gerbils to show that N-methyl-D-aspartate receptor (NMDARs) play a critical role in neuronal encoding of stimulus properties in the DNLL. While NMDARs increase firing rates, the timing and the accuracy of the neuronal responses remain unchanged. NMDAR-mediated excitation increases the information about the acoustic stimulus. Taken together, our results show that NMDARs in the DNLL enhance the auditory information content in adult mammal brainstem. PMID- 29405454 TI - The radial artery: Results and technical considerations. AB - BACKGROUND: The radial artery (RA) is a frequently used conduit for coronary artery bypass graft (CABG). We review the results of the use of the RA in CABG patients and discuss the unique technical considerations when using this conduit. METHODS: A literature search was performed in PubMed through December 2017 on the comparative efficacy of the RA to other conduits and technical considerations for the use of the RA in CABG surgery. RESULTS: When compared to the saphenous vein graft, the RA proved to be superior in graft patency in multiple randomized clinical trials. The RA was associated with better clinical outcomes in observational studies. The debate over the second best arterial conduit remains unresolved between the RA and the right internal thoracic artery. Preoperative evaluation of the patient's coronary anatomy and the quality of the RA is imperative to achieve the best clinical outcome with RA grafting. CONCLUSION: With careful preoperative planning and attention to technical details, the RA is an excellent choice as the second conduit for CABG surgery. PMID- 29405455 TI - Proton-Dependent Switching of a Novel Amino Chlorin Derivative as a Fluorescent Probe and Photosensitizer for Acidic Media. AB - A novel chlorin derivative (TPCF20 -NMe2 ) has been synthesized as a syn adduct of a pyrrolidine-fused chlorin bearing a C-linked N,N-dimethylaminophenyl residue. The absorption spectrum of TPCF20 -NMe2 is essentially identical to that of TPCF20 in N,N-dimethylformamide, indicating a very weak interaction between the chlorin macrocycle and the amine group in the ground state. However, the fluorescence emission of the chlorin moiety in TPCF20 -NMe2 is effectively quenched by the attached amine unit. Moreover, TPCF20 -NMe2 is unable to attain a triplet excited state or to photosensitize singlet molecular oxygen. Spectroscopic and redox properties indicate that intramolecular photoinduced electron transfer can take place from the N,N-dimethylaminophenyl group to the chlorin macrocycle. Thus, in an acid medium, protonation of the amino group leads to a considerable increase in the fluorescence emission, triplet excited-state formation, and singlet molecular oxygen production. Photodynamic inactivation of Escherichia coli sensitized by TPCF20 -NMe2 is negligible at neutral pH. However, this chlorin becomes highly effective in inactivating E. coli cells under acidic conditions. Therefore, these results indicate that TPCF20 -NMe2 is an interesting molecular structure, in which protonation of the amino group can be used as an off/on molecular switch activating red fluorescence emission and photodynamic activity capable of eradicating bacteria. PMID- 29405456 TI - A Capillary Flow Dynamics-Based Sensing Modality for Direct Environmental Pathogen Monitoring. AB - Toward ultra-simple and field-ready biosensors, we demonstrate a novel assay transducer mechanism based on interfacial property changes and capillary flow dynamics in antibody-conjugated submicron particle suspensions. Differential capillary flow is tunable, allowing pathogen quantification as a function of flow rate through a paper-based microfluidic device. Flow models based on interfacial and rheological properties indicate a significant relationship between the flow rate and the interfacial effects caused by target-particle aggregation. This mechanism is demonstrated for assays of Escherichia coli K12 in water samples and Zika virus (ZIKV) in blood serum. These assays achieved very low limits of detection compared with other demonstrated methods (1 log CFU/mL E. coli and 20 pg/mL ZIKV whole virus) with an operating time of 30 s, showing promise for environmental and health monitoring. PMID- 29405457 TI - Aqueous Red-Emissive Probe for the Selective Fluorescent Detection of Cysteine by Deprotection/Cyclization Cascade Resulting in Large Stokes' Shift. AB - Cysteine plays a crucial role in cellular functions and in human pathologies. However, the development of cysteine probes with extremely accurate detection is still a key challenge for the field. Herein, we have fully characterized and developed a novel selective fluorescent probe: red emission, aqueous detection and large Stokes' shift for cysteine (Reals-C). Key in the probe synthesis is a Michael addition onto an acroylate group and subsequent intramolecular cyclization. The probe exhibits analyte detection via an intricate role set up by the leaving groups so to discriminate and form the red-emissive analyte sensing platform (lambdaex =471 nm, lambdaem =637 nm) through a chemical cascade pathway. Furthermore, the sensing ability of the probe was demonstrated by both in vitro and in vivo assays. This probe enables for successfully endogenous cysteine sensing in HaCaT human keratinocytes through comparison with a commercial thiol sensitive probe; Reals-C shows excellent in vivo cysteine detection in a drug induced animal liver injury model. PMID- 29405459 TI - Activation of organum vasculosum neurons and water intake in mice by vasopressin neurons in the suprachiasmatic nucleus. AB - Previous studies have shown that mice housed under 12:12 h light-dark conditions display a pronounced increase in water intake during a 2-hour anticipatory period (AP) near the end of their active period (Zeitgeber Time ZT; ZT21.5-ZT23.5) compared to the preceding basal period (BP, ZT19.5-ZT21.5). This increased water intake during the AP is not associated with physiological stimuli for thirst, such as food intake, hyperosmolality, hyperthermia, or hypovolemia. Denying mice the water intake supplement during the AP causes them to be dehydrated at wake time. These observations suggest that this form of thirst may be driven by the circadian clock and serve to mitigate the dehydrating effect of absence of water intake during sleep. Here we review recent findings showing that this behavior is mediated by vasopressin (VP) containing neurons in the suprachiasmatic nucleus (SCN). SCN VP neurons project to the organum vasculosum lamina terminalis (OVLT) where the activity dependent release of VP causes excitation of thirst-promoting neurons. SCN VP neurons increase their electrical activity during the AP and the resultant release of VP causes an increase in the action potential firing rate of OVLT neurons. Experiments involving optogenetic control of VP release from the axon terminals of SCN neurons indicate that this network mechanism is necessary and sufficient to mediate pre-sleep water intake in mice. These findings provide insight into the output mechanisms that are used by the central clock to generate circadian rhythms, and reveal that the regulation of water intake contributes to osmoregulatory homeostasis during sleep. This article is protected by copyright. All rights reserved. PMID- 29405458 TI - Controlling Photoconductivity in PBI Films by Supramolecular Assembly. AB - Perylene bisimides (PBIs) self-assemble in solution. The solubility of the PBIs is commonly changed through the choice of substituents at the imide positions. It is generally assumed this substitution does not affect the electronic properties of the PBI, and that the properties of the self-assembled aggregate are essentially that of the isolated molecule. However, substituents do affect the self-assembly, resulting in potentially different packing in the formed aggregates. Here, we show that the photoconductivity of films formed from a library of substituted PBIs varies strongly with the substituent and demonstrate that this is due to the different ways in which they pack. Our results open the possibility for tuning the optoelectronic properties of self-assembled PBIs by controlling the aggregate structure through careful choice of substituent, as demonstrated by us here optimising the photoconductivity of PBI films in this way. PMID- 29405460 TI - One explanation to rule them all? Identifying sub-groups of non-drinking Swedish ninth graders. AB - INTRODUCTION AND AIMS: Researchers in a number of countries have recently identified major changes in adolescent alcohol consumption since the early 2000s, with the prevalence of teenage drinking more than halving in some countries. The major aims of the current study are to examine if there are sub-groups among non drinking Swedish ninth graders and to describe how the prevalence of these groups has changed during the period 1999 to 2015. DESIGN AND METHODS: Data from five waves of the Swedish European School Survey Project on Alcohol and other Drugs study was used. The data covered 16 years and the total sample comprised 14 976 students. Latent class analysis was used to identify sub-groups of non-drinkers (n = 4267) based on parental approval towards drinking, parental monitoring, leisure time activities, school performance and use of other substances. RESULTS: Five latent classes were found: computer gamers (8.3%), strict parents (36.5%), liberal parents (27.0%), controlling but liberal parents (16.6%) and sports (11.6%). In the non-drinking sub-group the strict parents group increased most between 1999 and 2015. DISCUSSION AND CONCLUSIONS: The results imply that there is notable within-group diversity in non-drinking youth. Several mechanisms and explanations are thus likely to be behind the decline in drinking participation among Swedish adolescents. PMID- 29405461 TI - Tranquilizer misuse among active cocaine users: Predictors of initiation. AB - INTRODUCTION AND AIMS: Tranquilizer use is associated with negative health outcomes among people who use drugs. This paper aims to estimate the incidence rate (initiation) and identify predictors of tranquilizer misuse (TM) among cocaine users. DESIGN AND METHODS: A prospective cohort study was conducted in Montreal, Canada. Interviewer-administered questionnaires were carried out at 3 month intervals. Initiation was defined as misusing a tranquilizer for the first time during follow-up. 'Lasting-initiation', defined as reporting TM at the next visit following first use, was also examined. Cox proportional hazard regression analyses were carried out to assess predictors of initiation to TM. RESULTS: Among the 245 participants who were eligible for the initiation analyses, 123 started TM during follow-up for an incidence rate of 40.49 per 100 person-years (95% confidence interval, CI: 33.80-48.15). Of the 123 initiates, 35.7% were still using at the interview following initiation for an incidence rate of 14.70 per 100 person-years (95% CI: 10.82-19.56). Multivariate models showed that independent predictors of initiation and 'lasting initiation' were identical as having had a criminal activity as the main source of income, having been recently in treatment for a substance use disorder (SUD) and reporting non-medical use of prescription opioids. DISCUSSION AND CONCLUSIONS: The incidence rate of TM initiation was high among a sample of cocaine users. Initiation was predicted by a problematic drug use pattern involving polydrug use, involvement in the street economy and having been in treatment for a SUD. These findings have implications for prevention and harm reduction strategies. PMID- 29405462 TI - Environmental peanut exposure increases the risk of peanut sensitization in high risk children. AB - BACKGROUND: High household peanut consumption is associated with the development of peanut allergy, especially when peanut allergic cases are compared against atopic controls; thus, environmental peanut exposure (EPE) may be a risk factor for peanut sensitization and allergy. In this study, we explored the relationship between EPE and school-age peanut sensitization in a population-based cohort. METHODS: Maternal bed dust was collected postnatally, and EPE was quantified using a polyclonal peanut ELISA. Peanut sensitization was assessed by specific IgE to peanut extract and sIgE to peanut protein component allergens Ara h 1, 2 or 3 >= 0.35kU/L (primary peanut sensitization). Initial nested case-control analysis was performed comparing peanut-sensitized cases against high-risk controls (matched for parental atopy) (n = 411) using a conditional regression analysis. This was followed by whole cohort analysis (n = 1878) comparing EPE against peanut sIgE sensitization at ages 4 and 8 years using generalized estimating equations and against primary peanut sensitization at age 8 years using a logistic regression model. Finally, a subgroup analysis was performed comparing the impact of EPE in peanut-sensitized vs egg-sensitized, peanut tolerant individuals using logistic regression analysis. Levels of EPE were compared between groups using the Mann-Whitney U test. RESULTS: In the nested case-control analysis, a higher level of EPE around birth was associated with peanut-specific IgE sensitization at age 4 years (OR=1.41, 95% CI:1.05-1.90) and primary peanut sensitization at age 8 years (OR=2.11, 95% CI:1.38-3.22) compared against high-risk controls. When the whole BAMSE cohort was assessed, EPE was no longer associated with peanut sensitization; however, on subgroup analysis, EPE was associated with primary peanut sensitization when compared against egg sensitized peanut-tolerant controls with an adjusted odds ratio of 1.44 per unit EPE (95% CI:1.06-1.94). There was no significant interaction between EPE and FLG loss-of-function mutations, egg sensitization at age 4 years, infantile eczema or parental atopy on peanut sensitization. CONCLUSIONS: Higher levels of environmental exposure to peanut in the first few months of life appear to increase the probability of developing school-age peanut sensitization in atopic children (based on egg sensitization and parental atopy). PMID- 29405463 TI - Ethers as Oxygen Donor and Carbon Source in Non-hydrolytic Sol-Gel: One-Pot, Atom Economic Synthesis of Mesoporous TiO2 -Carbon Nanocomposites. AB - Mesoporous TiO2 -carbon nanocomposites were synthesized using an original non hydrolytic sol-gel (NHSG) route, based on the reaction of simple ethers (diisopropyl ether or tetrahydrofuran) with titanium tetrachloride. In this atom economic, solvent-free process, the ether acts not only as an oxygen donor but also as the sole carbon source. Increasing the reaction temperature to 180 degrees C leads to the decomposition of the alkyl chloride by-product and to the formation of hydrocarbon polymers, which are converted to carbon by pyrolysis under argon. The carbon-TiO2 nanocomposites and their TiO2 counterparts (obtained by calcination) were characterized by nitrogen physisorption, XRD, solid state 13 C NMR and Raman spectroscopies, SEM, and TEM. The nanocomposites are mesoporous with surface areas of up to 75 m2 g-1 and pore sizes around 10 nm. They are composed of aggregated anatase nanocrystals coated by an amorphous carbon film. Playing on the nature of the ether and on the reaction temperature allows control over the carbon content in the nanocomposites. The nature of the ether also influences the size of the TiO2 crystallites and the morphology of the nanocomposite. To further characterize the carbon coating, the behavior of the carbon-TiO2 nanocomposites and bare TiO2 samples toward lithium insertion deinsertion was investigated in half-cells. This simple NHSG approach should provide a general method for the synthesis of a wide range of carbon-metal oxide nanocomposites. PMID- 29405464 TI - Tris(1-methyl-imidazol-2-yl)phosphane Complexes of Pnictogen, Tetrel, and Triel Cations. AB - cations gallium indium nitrogen ligands pnictogens tetrelThe synthesis and characterization of salts with the generic formula [P(Im)3 M][OTf]x (Im=1-methyl imidazol-2-yl; M=P, As or Sb and x=3; M=Ge or Sn and x=2) are reported. In all cases, the cations adopt a cage structure with two chemically and energetically distinct apical lone pairs. In contrast, complexes of gallium and indium engage two P(Im)3 ligands resulting in a distorted octahedral geometry for the triel center in compounds of the generic formula [{P(Im)3 }2 M][OTf]3 (M=Ga or In). An assessment of the acidity and basicity of the new compounds is presented. PMID- 29405465 TI - Intravenous fentanyl use among people who inject drugs in Australia. AB - INTRODUCTION AND AIMS: There is a current epidemic of pharmaceutical opioid (PO) misuse, particularly fentanyl and fentanyl analogues, globally. Fentanyl is a highly potent synthetic opioid with rapid onset and significantly higher risk of overdose compared with other opioids. Contexts and correlates of fentanyl use among people who inject drugs (PWID) in Australia are under-researched. DESIGN AND METHODS: The Australian Needle Syringe Program Survey is conducted annually. Consenting PWID complete a self-administered questionnaire and provide a capillary dried blood spot for human immunodeficiency virus and hepatitis C virus antibody testing. Bivariate and multivariate logistic regressions determined correlates of recent (last 6 months) fentanyl injection in 2014. RESULTS: Recent fentanyl injection was reported by 8% (n = 193) of the total sample. Among the 848 PWID who recently injected POs, 23% injected fentanyl. Compared with PO injectors who had not injected fentanyl, those who had injected fentanyl were significantly more likely to identify as Indigenous Australian [adjusted odds ratio (AOR) 1.61; 95% confidence interval (CI) 1.04, 2.51; P = 0.034], inject daily or more frequently (AOR 1.92; 95% CI 1.30, 2.83; P = 0.005), inject in public (AOR 1.43; 95% CI 1.01, 2.02; P = 0.042) and to have overdosed in the past year (AOR 2.16; 95% CI 1.48, 3.13; P < 0.001), but were significantly less likely to receptively share syringes (AOR 0.56; 95% CI 0.36, 0.87; P = 0.010). DISCUSSION AND CONCLUSIONS: Fentanyl injectors in Australia are significantly more likely to identify as Indigenous, report frequent injection, inject in public and experience overdose. Increased access to harm reduction interventions, including naloxone distribution, wheel filters and supervised injection facilities, are likely to benefit this population. PMID- 29405466 TI - Prediction of carotid intima-media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability. AB - BACKGROUND AND AIM: Western societies, with growing prevalence, suffer from various metabolic diseases like obesity and hepatic steatosis, better defined as non-alcoholic fatty liver disease, or cardiovascular (CV) diseases that are strictly linked to each other. The association of their occurrence with the altered homeostasis of metals is an intriguing issue. Copper in particular was identified as key player in various metabolic derangements. On these bases, we aimed at investigating the possible association of serum copper levels with an indicator of early CV risk as the intima-media thickness (IMT) of carotid artery and its predictive value in a selected population of obese patients. METHODS: We performed a cross-sectional study recruiting 100 obese patients characterized by a low prevalence of comorbidities. Ultrasound investigation for hepatic steatosis and IMT evaluation were performed. Serum samples were collected and then analyzed through atomic absorption spectrometry to evaluate their copper content. Possible correlations between copper bioavailability and biochemical, clinical, and anthropometric characteristics of patients were sought. RESULTS: Age negatively predicted copper serum levels of patients (P = 0.009). However, the most interesting finding is the negative prediction of IMT by the copper serum levels (t = -2.23, P = 0.028, least absolute deviations regression). Factor analysis confirmed the aforementioned inverse correlation and highlighted the strong inverse correlation between smoking and copper serum levels. CONCLUSION: Our data show that an altered copper bioavailability predicts early atherosclerosis as main CV risk in obese patients with hepatic steatosis detected by ultrasound, shedding some light in this pathological scenario. PMID- 29405467 TI - Parent Discrepancies in Ratings of Child Behaviors Following Wartime Deployment. AB - Researchers have shown that parents often disagree in their ratings of their children's behavior, and that these discrepancies are typically related to child and family characteristics (e.g., child's age, parent psychopathology). Few studies, however, have examined discrepancies in how mothers and fathers rate child behavior during a stressful family context such as a parent's wartime deployment. The present study of 174 military families (children aged 6 to 11 years; 54.0% female) examined whether family factors (parental sense of control, marital satisfaction) and contextual risk factors related to a parent's wartime deployment (number and length of deployments, battle experiences, and posttraumatic stress disorder [PTSD] symptoms) were associated with discrepancies in how mothers and fathers rated internalizing and externalizing behaviors in their children. Using a latent congruency model, our results showed that when parents self-reported higher levels of PTSD symptoms, both mothers, beta = -.33, p = .021, and fathers, beta = .41, p = .026, tended to also report higher levels of internalizing symptoms in their child, relative to what their spouse reported. In comparison to mothers, fathers also tended to report higher levels of child externalizing symptoms, beta = .44, p = .019. Our findings may help clinicians understand how parent mental health within a stressful family context relates and/or informs a parent's ratings on assessments of his or her child's internalizing and externalizing symptoms. PMID- 29405468 TI - Prevention of hypophosphatemia during continuous renal replacement therapy-An overlooked problem. AB - Hypophosphatemia is a common and potentially serious complication occurring during continuous renal replacement therapy (CRRT). Phosphate supplementation is required in the vast majority of patients undergoing CRRT, particularly beyond the first 48 hours. Supplementation can be provided either as a standalone oral or parenteral treatment or as an additive to CRRT solutions. Each approach has advantages and disadvantages, and clinicians must weigh the individual factors most relevant in their practice setting. Currently there are no consensus protocols for phosphate replacement in CRRT, and many centers replete phosphate in response to hypophosphatemia as opposed to pre-emptively. Repletion protocols have also been challenged in recent years by shortages in injectable phosphate solutions. More recently a commercially available phosphate-containing CRRT solution was approved in the United States, but there has been limited clinical experience with this product. In this review, we present recommendations for phosphate repletion in CRRT to prevent hypophosphatemia, and describe our experience using phosphate-containing CRRT solutions. PMID- 29405469 TI - Immunoassay interference secondary to therapeutic high-dose biotin: A paediatric case report. PMID- 29405470 TI - Neural mechanisms of mental schema: a triplet of delta, low beta/spindle and ripple oscillations. AB - Schemas are higher-level knowledge structures that integrate and organise lower level representations. As internal templates, schemas are formed according to how events are perceived, interpreted and remembered. Although these higher-level units are assumed to play a fundamental role in our daily life from an early age, the neuronal basis and mechanisms of schema formation and use remain largely unknown. It is important to elucidate how the brain constructs and maintains these higher-level units. In order to examine the possible neural underpinnings of schema, we recapitulate previous work and discuss their findings related to schemas as the brain template. We specifically focused on low beta/spindle oscillations, which are assumed to be the key components of schemas, and propose that the brain template is implemented with a triplet of neural oscillations, that is delta, low beta/spindle and ripple oscillations. PMID- 29405471 TI - Quantitative MRI in murine radiation-induced rectocolitis: comparison with histopathological inflammation score. AB - Murine radiation-induced rectocolitis is considered to be a relevant animal model of gastrointestinal inflammation. The purpose of our study was to compare quantitative MRI and histopathological features in this gastrointestinal inflammation model. Radiation rectocolitis was induced by localized single-dose radiation (27 Gy) in Sprague-Dawley rats. T2 -weighted, T1 -weighted and diffusion-weighted MRI was performed at 7 T in 16 rats between 2 and 4 weeks after irradiation and in 10 control rats. Rats were sacrificed and the histopathological inflammation score of the colorectal samples was assessed. The irradiated rats showed significant increase in colorectal wall thickness (2.1 +/- 0.3 mm versus 0.8 +/- 0.3 mm in control rats, P < 0.0001), normalized T2 signal intensity (4 +/- 0.8 versus 2 +/- 0.4 AU, P < 0.0001), normalized T1 signal intensity (1.4 +/- 0.1 versus 1.1 +/- 0.2 AU, P = 0.0009) and apparent and pure diffusion coefficients (ADC and D) (2.06 * 10-3 +/- 0.34 versus 1.51 * 10-3 +/- 0.23 mm2 /s, P = 0.0004, and 1.97 * 10-3 +/- 0.43 mm2 /s versus 1.48 * 10-3 +/- 0.29 mm2 /s, P = 0.008, respectively). Colorectal wall thickness (r = 0.84, P < 0.0001), normalized T2 signal intensity (r = 0.85, P < 0.0001) and ADC (r = 0.80, P < 0.0001) were strongly correlated with the histopathological inflammation score, whereas normalized T1 signal intensity and D were moderately correlated (r = 0.64, P = 0.0006, and r = 0.65, P = 0.0003, respectively). High-field MRI features of single-dose radiation-induced rectocolitis in rats differ significantly from those of control rats. Quantitative MRI characteristics, especially wall thickness, normalized T2 signal intensity, ADC and D, are potential markers of the histopathological inflammation score. PMID- 29405473 TI - Inhibition of Dr-dut gene causes DNA damage in planarian. AB - The DUT gene encodes Deoxyuridine triphosphatase (dUTPase), which is involved in nucleotide metabolism. dUTPase prevents uracil misincorporation in DNA by balancing the intracellular ratio between dUTP and dTTP. This study aimed to investigate the role of Dr-dut gene in the planarian Dugesia ryukyuensis by assessing the consequences of Dr-dut silencing on known phenomena, including regeneration following amputation and radiation damage. We functionally disrupted planarian Dr-dut mRNA by feeding RNAi-containing food to animals. Dr-dut RNAi resulted in the death of planarians in 28 days, and elevated double-stranded DNA breakage. Expression of the DNA damage response gene Dr-atm and the DNA repair genes Dr-rad51 and Dr-rad51c temporarily increased, and then decreased following the onset of feeding. When RNAi-treated planarians were amputated, both head and tail parts failed to regenerate, and the animals died in 25 and 29 days, respectively. Administration of 5-fluorouracil (5-FU) also resulted in death and DNA damage, and synergistically caused higher genotoxicity in planarian fed Dr dut RNAi-containing food. PMID- 29405472 TI - Supplemented stallion seminal plasma can improve impaired motility due to the dilution effect in chilled Asian elephant sperm. AB - The dilution effect and effect of restoring seminal plasma (SP) proportion in diluted semen were determined in chilled Asian elephant sperm. Semen was collected from eight males, and samples with >=30% motile sperm were used in the study. Tris-glucose-egg yolk extender (TE) was used for cooled storage at 4 degrees C for 48 hr. In experiment 1 (n = 18), semen was diluted to 1:1, 1:3, 1:7 and 1:15 with TE (volume per volume). There were no significant changes in sperm viability and sperm with normal acrosome integrity among dilutions, but sperm motility and motility velocities were greater (p < .05) in the 1:1 dilution than those of the 1:7 and 1:15 dilutions at 48 hr of storage. In experiment 2, supplemented SP was derived from elephants and stallions. In experiment 2.1, diluted semen (1:7 dilution) was restored with SP to obtain a 1:2 proportion (n = 8). Sperm motility, viability and sperm with normal acrosome integrity were similar among treatments, but motility velocities were greater (p < .05) with stallion SP at 48 hr of storage. In experiment 2.2, diluted semen (1:15 dilution) was restored with SP to obtain a 1:3 proportion (n = 10). Sperm viability and sperm with normal acrosome integrity were similar among treatments at 48 hr of storage. However, sperm motility and motility velocities were greater (p < .05) with stallion SP than those of others. In conclusion, elephant sperm motility was affected by a dilution effect and restoration of SP proportion with stallion SP, but not with elephant SP, could improve motility in chilled highly diluted sperm. PMID- 29405474 TI - Position matters: Validation of medicare hospital claims for myocardial infarction against medical record review in the atherosclerosis risk in communities study. AB - PURPOSE: The objectives of this study were to investigate sensitivity and specificity of myocardial infarction (MI) case definitions using multiple discharge code positions and multiple diagnosis codes when comparing administrative data to hospital surveillance data. METHODS: Hospital surveillance data for ARIC Study cohort participants with matching participant ID and service dates to Centers for Medicare and Medicaid Services (CMS) hospitalization records for hospitalizations occurring between 2001 and 2013 were included in this study. Classification of Definite or Probable MI from ARIC medical record review defined "gold standard" comparison for validation measures. In primary analyses, an MI was defined with ICD9 code 410 from CMS records. Secondary analyses defined MI using code 410 in combination with additional codes. RESULTS: A total of 25 549 hospitalization records met study criteria. In primary analysis, specificity was at least 0.98 for all CMS definitions by discharge code position. Sensitivity ranged from 0.48 for primary position only to 0.63 when definition included any discharge code position. The sensitivity of definitions including codes 410 and 411.1 were higher than sensitivity observed when using code 410 alone. Specificity of these alternate definitions was higher for women (0.98) than for men (0.96). CONCLUSION: Algorithms that rely exclusively on primary discharge code position will miss approximately 50% of all MI cases due to low sensitivity of this definition. We recommend defining MI by code 410 in any of first 5 discharge code positions overall and by codes 410 and 411.1 in any of first 3 positions for sensitivity analyses of women. PMID- 29405476 TI - Endoscope-assisted conservative resection and reconstruction in recurrent subglottic carcinoma. AB - BACKGROUND: Very few cases of conservative laryngectomy in recurrent carcinoma of subglottis postradiotherapy have been reported. Technical aspects of conservative resection and reconstruction in subglottic carcinoma have not been well described. METHODS: Herein, we present a case of recurrent carcinoma of subglottis for which conservative resection with adequate margins was done with endoscope assistance and defect reconstructed by buccal mucosa, conchal cartilage, and temporoparietal free flap. The technique of resection, reconstruction, complications, postoperative outcome, and our suggestions are described. RESULTS: The lesion could be removed with wide margins. Reconstruction could preserve the voice, and deglutition was unaffected. There was no donor site related complication. Complications were a result of the choice of the stent, which included infection and difficulty in removal. CONCLUSION: Selected cases of recurrent carcinoma of the subglottis can be managed by conservative resection with adequate margins and appropriate reconstruction with good functional outcomes. PMID- 29405475 TI - Estimating abundance of an open population with an N-mixture model using auxiliary data on animal movements. AB - Accurate assessment of abundance forms a central challenge in population ecology and wildlife management. Many statistical techniques have been developed to estimate population sizes because populations change over time and space and to correct for the bias resulting from animals that are present in a study area but not observed. The mobility of individuals makes it difficult to design sampling procedures that account for movement into and out of areas with fixed jurisdictional boundaries. Aerial surveys are the gold standard used to obtain data of large mobile species in geographic regions with harsh terrain, but these surveys can be prohibitively expensive and dangerous. Estimating abundance with ground-based census methods have practical advantages, but it can be difficult to simultaneously account for temporary emigration and observer error to avoid biased results. Contemporary research in population ecology increasingly relies on telemetry observations of the states and locations of individuals to gain insight on vital rates, animal movements, and population abundance. Analytical models that use observations of movements to improve estimates of abundance have not been developed. Here we build upon existing multi-state mark-recapture methods using a hierarchical N-mixture model with multiple sources of data, including telemetry data on locations of individuals, to improve estimates of population sizes. We used a state-space approach to model animal movements to approximate the number of marked animals present within the study area at any observation period, thereby accounting for a frequently changing number of marked individuals. We illustrate the approach using data on a population of elk (Cervus elaphus nelsoni) in Northern Colorado, USA. We demonstrate substantial improvement compared to existing abundance estimation methods and corroborate our results from the ground based surveys with estimates from aerial surveys during the same seasons. We develop a hierarchical Bayesian N-mixture model using multiple sources of data on abundance, movement and survival to estimate the population size of a mobile species that uses remote conservation areas. The model improves accuracy of inference relative to previous methods for estimating abundance of open populations. PMID- 29405477 TI - Factors associated with delayed referral for infantile hemangioma necessitating propranolol. AB - BACKGROUND: Oral propranolol is the gold standard to treat infantile hemangiomas. There is better efficacy and a lower risk of sequelae if therapy is started before the end of the growth phase, but most children are referred too late. Herein, we report the first study to investigate the delay and its associated factors when referring infants with infantile hemangiomas that need propranolol therapy. OBJECTIVES: The primary objective was to determine the delay in referral (time between age at referral [first phone contact] and the optimal age for referral (fixed at 75 days). The second objective was to determine the impact of weighted factors associated with delayed referral assessed by logistic regression performed on two subgroups (referral <=75 vs. >75 days). METHODS: Monocentric, retrospective, observational study included infants with infantile hemangiomas treated with oral propranolol between August 2014 and May 2017. RESULTS: Eighty two children (83% females) were included. Before referral, 81 (99%) children had seen another physician (a paediatrician in 67% of cases). Median age at referral was 99 days [2-478] and 63% phoned after 75 days. Median age at the first visit was 111 days [2-515], and median age when propranolol was started was 128 days [32-541]. After adjustment, in multivariate analyses, location on the lips (OR (CI 95%): 4.21[1.19-14.89]) and superficial hemangioma (OR (CI 95%): 4.19 [1.55 11.34]) emerged as the most significant factors to influence referral before 75 days. CONCLUSIONS: This study adds to our understanding regarding delayed referral and has identified targets for future information campaigns. PMID- 29405478 TI - Extracting functional groups of ALLINI to design derivatives of FDA-approved drugs: Inhibition of HIV-1 integrase. AB - HIV-1 integrase (IN) is crucial for integration of viral DNA into the host genome and a promising target in development of antiretroviral inhibitors. In this work, six new compounds were designed by linking the structures of two different class of HIV-1 IN inhibitors (active site binders and allosteric IN inhibitors (ALLINIs)). Among newly designed compounds, INRAT10b was found most potent HIV-1 IN inhibitor considering different docking results. To further validate protein ligand interactions obtained from dockings, molecular dynamics simulations were performed for inhibitor raltegravir and INRAT10b placed either at active site or allosteric site of HIV-1 IN (monomer or dimer). Results suggest that both raltegravir and INRAT10b were interacting with residue Gln62, Gly140, Ile141, and Ser147. However, INRAT10b interacts better with high H-bond occupancy, which can explain the strong binding affinity of INRAT10b than raltegravir with the HIV-1 IN protein. Subdomains rearrangements in HIV-1 IN suggest that the C-terminal and catalytic core domains develop their closeness in the presence of ligand. More significantly, the newly designed derivatives represent novel compounds targeting catalytic site and C-terminal (protein-protein interaction) domains simultaneously. And we also propose INRAT10b as a promising lead compound for the development of potent HIV-1 IN inhibitors. PMID- 29405479 TI - Persistent Extreme Hyperextension of the Fetal Neck: Clinical and Neuroimaging Findings. AB - BACKGROUND AND PURPOSE: Persistent hyperextension of the fetal craniocervical junction or neck is one of several fetal positions commonly observed on prenatal imaging. Underlying fetal structural etiologies such as fetal neck masses and iniencephaly can be detected as causes of hyperextension. Caesarean delivery is considered in cases of vaginal delivery or obstructed labor for fear of cervical spinal cord injury. In this case series, we describe the prenatal magnetic resonance imaging (MRI) findings and their potential role in obstetric management and discuss postnatal outcomes in fetuses demonstrating prenatal imaging findings of persistent extreme hyperextension of the neck. METHODS: A retrospective cohort of fetuses with extreme fetal neck hyperextension on prenatal ultrasound and subsequent MRI is described. RESULTS: Persistent extreme neck hyperextension was demonstrated in four pregnancies. One patient showed resolution of head positioning prior to labor. In the other 3 patients, neck hyperextension persisted until labor. In these three pregnancies, caesarean section with early intubation was performed due to concern for airway compromise and cervical cord injury. An underlying structural neck abnormality with airway compromise was noted only in 1 patient (large venolymphatic malformation). No airway compromise, cervical spine, or spinal cord anomaly was identified in the remaining 3 patients. Noncervical fetal anomalies were detected only in 1 patient (arthogryposis multiplex and clubfoot deformities). In patients with no structural neck abnormality, early extubation was performed shortly following labor. CONCLUSIONS: Detailed, high-resolution fetal MRI may serve as a valuable secondary imaging modality for clinical decision making regarding management of pregnancy, in utero therapy, mode of delivery, and postnatal care. PMID- 29405482 TI - Molecular genetic analyses of human endogenous retroviral elements belonging to the HERV-P and HERV-R family in primary cutaneous T-cell lymphomas. PMID- 29405480 TI - Diverse actions of the modulatory peptide neurotensin on central synaptic transmission. AB - Neurotensin (NT) is a 13 amino acid neuropeptide that is expressed throughout the central nervous system and is implicated in the etiology of multiple diseases and disorders. Many primary investigations of NT-induced modulation of neuronal excitability at the level of the synapse have been conducted, but they have not been summarized in review form in nearly 30 years. Therefore, the goal of this review is to discuss the many actions of NT on neuronal excitability across brain regions as well as NT circuit architecture. In the basal ganglia as well as other brain nuclei, NT can act through diverse intracellular signaling cascades to enhance or depress neuronal activity by modulating activity of ion channels, ionotropic and metabotropic neurotransmitter receptors, and presynaptic release of neurotransmitters. Further, NT can produce indirect effects by evoking endocannabinoid release, and recently has itself been identified as a putative retrograde messenger. In the basal ganglia, the diverse actions and circuit architecture of NT signaling allow for input-specific control of reward-related behaviors. PMID- 29405481 TI - Comparison of fungal fluorescent staining and ITS rDNA PCR-based sequencing with conventional methods for the diagnosis of onychomycosis. AB - BACKGROUND: The current gold standard for diagnosing onychomycosis is direct microscopic examination and culturing. Fungal culture is a time-consuming procedure, while direct microscopy of potassium hydroxide (KOH) mounts suffers from low sensitivity. More rapid and sensitive methods for the diagnosis of onychomycosis are in high demand. OBJECTIVE: To establish an effective method for the diagnosis of onychomycosis by assessing the efficacies of fungal fluorescent staining and internal transcribed spacer (ITS) ribosomal DNA (rDNA) polymerase chain reaction (PCR)-based sequencing. METHODS: A total of 204 clinical specimens from patients with suspected onychomycosis were analysed. The gold standard for a true positive sample was positive by KOH, culturing or both methods. All specimens were also tested by fungal fluorescent staining and ITS rDNA PCR-based sequencing. We compared the detection, sensitivity and specificity for these two methods with conventional methods. RESULTS: In total, 126 (62%) and 102 (50%) were detected by fluorescent staining and PCR-based sequencing, respectively. According to the conventional diagnostic standard, the sensitivity of fluorescent staining and PCR-based sequencing was 97% and 78%, respectively, and specificities of 89% and 90%, respectively. Use of fluorescence enhanced the sensitivity of direct examination by 12% compared with KOH. PCR-based sequencing increased the sensitivity by 6% compared with culturing. CONCLUSIONS: Fluorescence microscopy has a higher sensitivity for the detection of fungi in nail specimens compared with KOH and can be used as a rapid screening tool. PCR based sequencing was faster and more sensitive compared with culture and when used in conjunction with fluorescence microscopy resulted in higher efficiency. PMID- 29405483 TI - Serum prolactin levels are associated with prefrontal hemodynamic responses using near-infrared spectroscopy in male psychotic patients treated with antipsychotics. PMID- 29405484 TI - Report of four novel variants in ASNS causing asparagine synthetase deficiency and review of literature. PMID- 29405485 TI - Video didactic at the point of care impacts hand hygiene compliance in the neonatal intensive care unit (NICU). AB - OBJECTIVE: To increase the hand-washing (HW) duration of staff and visitors in the NICU to a minimum of 20 seconds as recommended by the CDC. METHODS: Intervention included video didactic triggered by motion sensor to play above wash basin. Video enacted Centers for Disease Control and Prevention (CDC) HW technique in real time and displayed timer of 20 seconds. HW was reviewed from surveillance video. Swabs of hands plated and observed for qualitative growth (QG) of bacterial colonies. RESULTS: In visitors, the mean HW duration at baseline was 16.3 seconds and increased to 23.4 seconds at the 2-week interval (p = .003) and 22.9 seconds at the 9-month interval (p < .0005). In staff, the mean HW duration at baseline was 18.4 seconds and increased to 29.0 seconds at 2-week interval (p = .001) and 25.7 seconds at the 9-month interval (p < .0005). In visitors, HW compliance at baseline was 33% and increased to 52% at the 2-week interval (p = .076) and 69% at the 9-month interval (p = .001). In staff, HW compliance at baseline was 42% and increased to 64% at the 2-week interval (p = .025) and 72% at the 9-month interval (p = .001). Increasing HW was significantly associated with linear decrease in bacterial QG. CONCLUSIONS: The intervention significantly increased mean HW time, compliance with a 20-econd wash time and decreased bacterial QG of hands and these results were sustained over a 9-month period. PMID- 29405486 TI - Stress and marital adjustment in families of children with cancer. AB - OBJECTIVE: Pediatric cancer is highly stressful for parents. The current prospective study examines the impact of several stressors (financial strain, life threat, treatment intensity, treatment-related events, and negative life events) on the trajectory of marital adjustment across the first year following diagnosis. We examined whether average level of stressors across the year was related to (1) levels of marital adjustment at the end of the first year of treatment and () the rate of change in marital adjustment. METHOD: One hundred and thirty families of children newly diagnosed with cancer (M age = 6.33 years, SD = 3.61) participated. Primary caregivers provided 12 monthly reports on marital adjustment and stressors. RESULTS: Multilevel models indicated that although marital adjustment was stable across the first year on average, random effect estimates suggested that this was the result of differing trajectories between families (eg, some increasing and others decreasing). Five individual stress constructs and a cumulative stress composite were then used to predict this variability. Higher average economic strain was related to consistently poorer marital adjustment across time. Higher average frequency of treatment related events and negative life events were associated with decreasing adjustment over time and lower adjustment at the end of the first year of treatment. Perception of life threat and treatment intensity were not associated with final levels or trajectory of adjustment. Finally, higher cumulative stress was associated with consistently poorer marital adjustment across time. CONCLUSION: Implications for identification of at-risk families are discussed, and importance of delivering tailored interventions for this population. PMID- 29405488 TI - Plant biotic interactions: from conflict to collaboration. PMID- 29405489 TI - Post-Treatment-Free Main Chain Donor and Side Chain Acceptor (D-s-A) Copolymer for Efficient Nonfullerene Solar Cells with a Small Voltage Loss. AB - Main chain donor and side chain acceptor (D-s-A) copolymers are an important branch of the D-A copolymer family. However, the development of D-s-A copolymers significantly falls behind the alternative D-A copolymers, especially for organic solar cells, because a breakthrough in device performance is not yet obtained with a reported power conversion efficiency (PCE) of 2%-4%. Herein, a newly developed D-s-A copolymer PDRCNBDT, bearing 2-(1, 1-dicyanomethylene) rhodanine pendant group as the donor material, delivers a high PCE of 5.3% for nonfullerene solar cells. To the best of our knowledge, this is the best value reported for D s-A copolymers to date. The improved PCE is observed to be associated with a very small energy loss (Eloss ) of 0.57 eV, accompanied by a high open-circuit voltage (Voc ) of 1.015 eV. It is important to note that this efficient D-s-A copolymer is employed in organic solar cells (OSCs), free of additive and annealing treatments. PMID- 29405490 TI - Macrocycle-Enabled Counteranion Trapping for Improved Catalytic Efficiency. AB - The tight host-guest binding enabled by functional macrocycles can be utilized to tune catalysis. While the strong crown ether-cation complexation has been widely applied on enhancing the reactivity of the paired anion, the complementary strategy by applying a macrocyclic anion receptor to trap a counteranion to improve the cation catalytic activity remains unexplored. To realize this strategy, a macrocycle incorporating multiple cooperative H-bonding sites was synthesized and shown to tightly trap ethanedisulfonate anion in crystals and in acetonitrile solution (K>106 m-1 ). With the strong binding tendency, the presence of as low as 0.25 mol % of the macrocycle can significantly improve the ethanedisulfonic acid-catalyzed Povarov reaction efficiency, while the acyclic analogues had diminished effect. Catalysis outcomes and binding studies taken together suggested the macrocycle promotion was through favoring the substrate protonation by trapping the counteranion of the acid catalyst. PMID- 29405487 TI - History of psychosis and mania, and outcomes after kidney transplantation - a retrospective study. AB - History of psychosis or mania, if uncontrolled, both represent relative contraindications for kidney transplantation. We examined 3680 US veterans who underwent kidney transplantation. The diagnosis of history of psychosis/mania was based on a validated algorithm. Measured confounders were used to create a propensity score-matched cohort (n = 442). Associations between pretransplantation psychosis/mania and death with functioning graft, all-cause death, graft loss, and rejection were examined in survival models and logistic regression models. Post-transplant medication nonadherence was assessed using proportion of days covered (PDC) for tacrolimus and mycophenolic acid in both groups. The mean +/- SD age of the cohort at baseline was 61 +/- 11 years, 92% were male, and 66% and 27% of patients were white and African-American, respectively. Compared to patients without history of psychosis/mania, patients with a history of psychosis/mania had similar risk of death with functioning graft [subhazard ratio (SHR) (95% confidence interval (CI)): 0.94(0.42-2.09)], all-cause death [hazard ratio (95% CI): 1.04 (0.51-2.14)], graft loss [SHR (95% CI): 1.07 (0.45-2.57)], and rejection [odds ratio(95% CI): 1.23(0.60-2.53)]. Moreover, there was no difference in immunosuppressive drug PDC in patients with and without history of psychosis/mania (PDC: 76 +/- 21% vs. 78 +/- 19%, P = 0.529 for tacrolimus; PDC: 78 +/- 17% vs. 79 +/- 18%, P = 0.666 for mycophenolic acid). After careful selection, pretransplantation psychosis/mania is not associated with adverse outcomes in kidney transplant recipients. PMID- 29405491 TI - Analysis of influencing factors of boar claw lesion and lameness. AB - This study aimed to investigate the factors affecting boar claw lesions and lameness. A total of 1299 boars were examined for claw lesions and lameness, including 788 boars reared in individual pens with solid concreted floor (IPS) and 511 boars raised in individual stalls with slatted floor (ISS). Flooring type showed significant impacts on all claw lesion types (P < 0.01). Except for swelling ankle, boar age had significant effects on all other claw lesion types (P < 0.01). In addition, only heel overgrowth and erosion, cracked wall horizontal, heel-sole crack, dew claws, and toes were significantly related to boar breeds (P < 0.05). Furthermore, IPS lame boars had higher prevalence of lameness in the hind limb (P < 0.05), whereas in ISS lame boars, there were no significant differences in prevalence of lameness between the fore and hind limbs (P > 0.05). Boar lameness was moderately correlated with swelling ankle (Phi = 0.5571). In conclusion, claw lesions can be influenced by flooring type, boar age and breed, and could serve as a predictor for boar lameness. PMID- 29405492 TI - Effects of naloxegol on whole gut transit in opioid-naive healthy subjects receiving codeine: A randomized, controlled trial. AB - BACKGROUND: Nausea, vomiting, and constipation (OIC) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu-opiate opioid receptor antagonist. AIM: To compare the effects on pan gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. METHODS: We conducted a randomized, double-blind, placebo-controlled, single-center, parallel-group study in 72 healthy opioid-naive adults, randomized to: codeine (30 mg q.i.d.), naloxegol (25 mg daily), codeine and naloxegol, or matching placebo. During 3 days of treatment, we measured gastric emptying (GE) T1/2 , colonic filling at 6 hours (CF6), colonic geometric center at 24 and 48 hours, and ascending colon emptying (ACE) T1/2 . KEY RESULTS: Participants were 59.7% women, median BMI 25.0 kg/m2 , and median age 33.8 years. Codeine significantly retarded GE T1/2, CF6, overall colonic transit, and ACE T1/2 . There was significant difference (P = .026) in GE T1/2 between codeine (144.0 min [IQR 110.5-238.6]) and naloxegol (95.5 min [89.1-135.4]). There was a significant overall group difference in CF6 (P = .023), with significant difference (P = .019) between codeine (11.0% [0.0-45.0]) and naloxegol (51% [18.8-76.2]). However, no significant differences were found between codeine-treated participants concomitantly receiving placebo or naloxegol. CONCLUSIONS AND INFERENCES: Short-term administration of naloxegol (25 mg) in healthy, opioid naive volunteers does not reverse the retardation of gastric, small bowel, or colonic transit induced by acute administration of codeine. Further studies with naloxegol at higher dose are warranted to assess the ability to reverse the retardation of transit caused by acute administration of codeine in opioid-naive subjects. PMID- 29405493 TI - A novel missense mutation, p.Phe360Cys, in FIX gene results in haemophilia B in a female patient with skewed X-inactivation. PMID- 29405494 TI - Ternary Mixed-Valence Organotin Copper Selenide Clusters. AB - Reactions of the organotin selenide chloride clusters [(R1 SnIV )3 Se4 Cl] (A, R1 =CMe2 CH2 C(O)Me) or [(R1 SnIV )4 Se6 ] (B) with [Cu(PPh3 )3-x Clx ] yield cluster compounds with different inorganic, mixed-valence core structures: [Cu4 SnII SnIV6 Se12 ], [Cu2 SnII2 SnIV4 Se8 Cl2 ], [Cu2 SnII SnIV4 Se8 ], [Cu2 SnII2 SnIV2 Se4 Cl4 ], and [Cu2 SnIV2 Se4 ]. Five of the compounds, namely [(CuPPh3 )2 {(R1 SnIV )2 Se4 }] (1), [(CuPPh3 )2 SnII {(R2 SnIV )2 Se4 }2 ] (2), [(CuPPh3 )2 (SnII Cl)2 {(RSnIV )2 Se4 }2 ] (3) [(CuPPh3 )2 (SnII Cu2 ){(R1 SnIV )2 Se4 }3 ] (4), and [Cu(CuPPh3 )(SnII Cu2 ){(R1 SnIV )2 Se4 }3 ] (5) are structurally closely related. They are based on [(CuPPh3 )2 {(RSnIV )2 Se4 }n ] aggregates comprising [(RSnIV )2 Se4 ] and [CuPPh3 ] building units, which are linked by further metal atoms. A sixth compound, [(CuPPh3 )2 (SnII Cl)2 {(R1 SnIV Cl)Se2 }2 ] (6), differs from the others by containing [(RSnIV Cl)Se2 ] units instead, which affects the absorption properties. The compounds were analyzed by single crystal X-ray diffraction, NMR and 119 Sn Mossbauer spectroscopy, DFT calculations as well as optical absorption experiments. PMID- 29405495 TI - To brand or not to brand a product placement? Evidence from a field study of two influence mechanisms of positive portrayals of alcohol in film. AB - INTRODUCTION AND AIMS: We propose that branded and non-branded product placements in movies are interpreted differently and that a movie with unbranded alcohol portrayals influences audiences' alcohol-related beliefs and choices indirectly, through the process of narrative transportation, whereas a movie with branded alcohol placements impacts audiences' alcohol beliefs and choices via a more basic social-cognitive process of influence. DESIGN AND METHODS: Ordinary moviegoers (N = 758) attended a showing of The Snows of Kilimanjaro (2011) in a popular theatre in Tacna, Peru. Subjects were randomly assigned to watch the original movie, with branded alcohol portrayals, or a brand-free, control version. Reactions to the movie and alcohol-related beliefs were collected in a survey immediately after the film exposure and real beverage choices were measured. RESULTS: The findings reveal that exposure to unbranded positive portrayals of alcohol produces story-consistent beliefs and alcohol choices through the process of narrative transportation and that exposure to branded positive alcohol portrayals produces direct effects in terms of alcohol expectancies and brand choice, despite lowering narrative transportation. Although viewers disengage more from the characters, and experience lesser enjoyment and perceived realism when exposed to actual brands in a movie, they still hold positive alcohol expectancies and are more likely to select the placed brand, a process consistent with social cognitive theory. DISCUSSION AND CONCLUSIONS: The findings suggest caution about the recommended policy of removing branding from alcohol placements, such as in the case with plain packaging in tobacco, and instead call for effective policies to constrain alcohol product placement, as was done with tobacco placements. PMID- 29405496 TI - Clinical use of recombinant factor VIII Fc and recombinant factor IX Fc in patients with haemophilia A and B. AB - INTRODUCTION: Although clinical trials have demonstrated extended half-life (EHL) VIII and IX fusion proteins to be safe and efficacious in patients with haemophilia A and B, studies on real-world clinical application have not been performed. AIM: To retrospectively examine the real-world experience of rFVIII Fc and rFIX Fc in patients. METHODS: A retrospective review of existing medical records of patients with haemophilia A or haemophilia B who had been prescribed rFVIII Fc or rFIX Fc was conducted from the Children's Hospital Los Angeles Haemostasis and Thrombosis Centre database. RESULTS: A total of 36 male subjects enroled in the study (17 patients with haemophilia A and 19 patients with haemophilia B; 0-18 years of age, N = 27; >18 years of age, N = 9). Patients had a reduction of their ABR and AJBR following initiation of EHL factors. For patients with haemophilia A, the ABR and ABJR fell from 2.3 and 1.8 to 1.3 and 0.71, respectively. For patients with haemophilia B, the ABR and ABJR fell from 2.5 and 2.1 to 0.82 and 0.37, respectively. Five of 36 patients reverted from EHL back to standard half-life (SHL) factor treatment. Overall, treatment with EHL factors reduced factor consumption by nearly half compared to treatment with SHL factors in patients with haemophilia B. CONCLUSION: This study demonstrates the largely successful transition of 36 patients from SHL to EHL factor products. PMID- 29405497 TI - Structural insights into the binding and catalytic mechanisms of the Listeria monocytogenes bacteriophage glycosyl hydrolase PlyP40. AB - Endolysins are bacteriophage-encoded peptidoglycan hydrolases that specifically degrade the bacterial cell wall at the end of the phage lytic cycle. They feature a distinct modular architecture, consisting of enzymatically active domains (EADs) and cell wall-binding domains (CBDs). Structural analysis of the complete enzymes or individual domains is required for better understanding the mechanisms of peptidoglycan degradation and provides guidelines for the rational design of chimeric enzymes. We here report the crystal structure of the EAD of PlyP40, a member of the GH-25 family of glycosyl hydrolases, and the first muramidase reported for Listeria phages. Site-directed mutagenesis confirmed key amino acids (Glu98 and Trp10) involved in catalysis and substrate stabilization. In addition, we found that PlyP40 contains two heterogeneous CBD modules with homology to SH3 and LysM domains. Truncation analysis revealed that both domains are required for full activity but contribute to cell wall recognition and lysis differently. Replacement of CBDP40 with a corresponding domain from a different Listeria phage endolysin yielded an enzyme with a significant shift in pH optimum. Finally, domain swapping between PlyP40 and the streptococcal endolysin Cpl-1 produced an intergeneric chimera with activity against Listeria cells, indicating that structural similarity of individual domains determines enzyme function. PMID- 29405498 TI - Sensitive and Selective Detection of Phosgene, Diphosgene, and Triphosgene by a 3,4-Diaminonaphthalimide in Solutions and the Gas Phase. AB - Phosgene and its substitutes, diphosgene and triphosgene, are highly toxic and widely used chemicals, so it is necessary to investigate their reactivity and develop facile, sensitive, and specific methods for detecting them. In this work, we have developed a new 1,8-naphthalimide-based fluorescent chemosensor, Phos-2, which exhibits high sensitivity (detection limits: 0.2-0.7 nm), high selectivity to phosgene and its substitutes over nitric oxide (NO), various acyl chlorides, and nerve agent mimics in solutions. Based on investigation of the reaction kinetics of Phos-2 with phosgene and its substitutes, a two-step sensing mechanism was clarified. The second-order rate constants (k2 ) of Phos-2 reveal that the relative rate constants of phosgene, diphosgene, and triphosgene are 40:4:1. Moreover, a Phos-2 test paper has been fabricated as a low-cost, sensitive (~5 ppm from observation by the naked eye or 0.1 ppm from a measurement), and efficient method for visual detection of a low concentration of phosgene in the gas phase. PMID- 29405499 TI - Azoliniums, Adducts, NHCs and Azomethine Ylides: Divergence in Wanzlick Equilibrium and Olefin Metathesis Catalyst Formation. AB - The dimerization of a saturated N-heterocyclic carbene (NHC) to tricyclic piperazine in preference to the commonly observed Wanzlick dimerization is presented. Mechanistic investigations revealed that the N-fluorene substituent of the heterocycle is implicated in both ring opening of corresponding carbene dimer and tautomerization of NHC to an azomethine ylide. This has consequences for the fate of the NHC when generated from either an azolinium salt or a pentafluorophenyl adduct. The insights gained permitted the synthesis of a new indenylidene metathesis precatalyst, which exhibits exceptional selectivity and high TONS in self-metathesis of 1-octene. PMID- 29405500 TI - Isolation of a laccase-coding gene from the lignin-degrading fungus Phlebia brevispora BAFC 633 and heterologous expression in Pichia pastoris. AB - AIMS: Isolate and characterize a laccase-encoding gene (lac I) of Phlebia brevispora BAFC 633, as well as cloning and expressing cDNA of lac I in Pichia pastoris. And to obtain a purified and characterized recombinant laccase to analyse the biotechnological application potential. METHODS AND RESULTS: Lac I was cloned and sequenced, it contains 2447 pb obtained by PCR and long-distance inverse PCR. Upstream of the structural region of the laccase gene, response elements such as metals, antioxidants, copper, nitrogen and heat shock were found. The coding region consisted of a 1563-pb ORF encoding 521 amino acids. Lac I was functionally expressed in P. pastoris and it was shown that the gene cloned using the alpha-factor signal peptide was more efficient than the native signal sequence, in directing the secretion of the recombinant protein. Km and highest kcat /Km values towards ABTS, followed by 2,6-dimethylphenol, were similar to other laccases. Lac I showed tolerance to NaCl and solvents, and nine synthetic dyes could be degraded to different degrees. CONCLUSIONS: Lac I-encoding gene could be successfully sequenced having cis-acting elements located at the regulatory region. It was found that lac I cDNA expressed in P. pastoris using the alpha-factor signal peptide was more efficient than the native signal sequence. The purified Lac I exhibited high tolerance towards NaCl and various solvents and degraded some recalcitrant synthetic dyes. SIGNIFICANCE AND IMPACT OF THE STUDY: The cis-acting elements may be involved in the transcriptional regulation of laccase gene expression. These results may provide a further insight into potential ways of optimizing fermentation process and also open new frontiers for engineering strong promoters for laccase production. The Lac I stability in chloride and solvents and broad decolorization of synthetic dyes are important for its use in organic synthesis work and degradation of dyes from textile effluents respectively. PMID- 29405502 TI - The impact of staffing model in a 6-day rehabilitation physiotherapy service. AB - BACKGROUND AND PURPOSE: The impact of staffing model providing weekend physiotherapy rehabilitation has not been evaluated. This study aims to determine the impact of staffing a weekend rehabilitation service with physiotherapists currently working in rehabilitation compared to acute hospital physiotherapists, on length of stay (LOS), functional independence and gait and balance, and to determine the impact on neurological, orthopaedic, and reconditioning diagnostic groups. METHODS: A prospective cohort study with historical control was completed in a private, metropolitan Australian rehabilitation unit. All participants admitted to the rehabilitation unit over two, 20-week periods in 2011 and 2012 were included. Weekend physiotherapy was provided by physiotherapists working in rehabilitation in 2012 (intervention) and physiotherapists working in the acute wards in 2011 (control). Outcomes included LOS, Functional Independence Measure (FIM), and gait and balance measures. RESULTS: Overall, there were 504 participants; 234 in 2012 and 270 in 2011. No difference was found in LOS between staffing models (mean difference-1.5 days, 95%CI -4.4 to 1.3). Greater FIM change (mean difference 3.5, 95%CI 0.3 to 6.7) and efficiency (FIM change/LOS: mean difference 0.3, 95%CI 0.1 to 0.5) were found with rehabilitation compared to acute staffing. There was no between-group difference in gait or balance performance. When diagnostic groups were compared, no difference in LOS was found between staffing models. Participants with an orthopaedic diagnosis had a significantly greater FIM change (mean difference 3.8, 95%CI 0.4 to 7.1), whereas FIM efficiency was improved in neurological (mean difference 0.4, 95%CI 0.1 to 0.7) and orthopaedic populations (mean difference 0.3, 95%CI 0.03 to 0.5) with rehabilitation staffing. DISCUSSION: Staffing a weekend rehabilitation service with physiotherapists currently working in rehabilitation influences functional independence. Different diagnostic groups appear to respond differently. PMID- 29405501 TI - Importance of the lipid-related pathways in the association between statins, mortality, and cardiovascular disease risk: The Multi-Ethnic Study of Atherosclerosis. AB - PURPOSE: Estimating how much of the impact of statins on coronary heart diseases (CHD), cardiovascular disease (CVD), and mortality risk is attributable to their effect on low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides. METHODS: A semi-parametric g-formula estimator together with data from the Multi-Ethnic Study of Atherosclerosis (a prospective multi-center cohort study) was utilized to perform a mediation analysis. A total of 5280 participants, men and women of various race/ethnicities from multiple sites across the United States, were considered in the current study. RESULTS: The adherence adjusted total relative risk reduction (RRR) estimate (95% confidence interval) of statins on CHD was 14% (-16%, 37%), and the indirect component through LDL was 23% (-4%, 58%). For CVD, the total RRR was 23% (2%, 40%), and the indirect component through LDL was 5% (-13%, 25%). The total RRR of mortality was 18% (-1%, 35%), and the indirect component through LDL was 4% (-17%, 12%). The estimated indirect components through HDL and triglycerides were close to zero with narrow confidence intervals for all 3 outcomes. CONCLUSIONS: The estimated effect of statins on mortality, CVD, and CHD appeared to be independent of their estimated effect on HDL and triglycerides. Our study provides evidence that the preventive effect of statins on CHD could be attributed in large part to their effect on LDL. Our g-formula estimator is a promising approach to elucidate pathways, even if it is hard to make firm conclusions for the LDL pathway on mortality and CVD. PMID- 29405503 TI - Review: An Australian model of care for co-morbid diabetes and chronic kidney disease. AB - Diabetes and chronic kidney disease (CKD) are two of the most prevalent co-morbid chronic diseases in Australia. The increasing complexity of multi-morbidity, and current gaps in health-care delivery for people with co-morbid diabetes and CKD, emphasise the need for better models of care for this population. Previously, proposed published models of care for co-morbid diabetes and CKD have not been co designed with stake-holders or formally evaluated. Particular components of health-care shown to be effective in this population are interventions that: are structured, intensive and multifaceted (treating diabetes and multiple cardiovascular risk factors); involve multiple medical disciplines; improve self management by the patient; and upskill primary health-care. Here we present an integrated patient-centred model of health-care delivery incorporating these components and co-designed with key stake-holders including specialist health professionals, general practitioners and Diabetes and Kidney Health Australia. The development of the model of care was informed by focus groups of patients and health-professionals; and semi-structured interviews of care-givers and health professionals. Other distinctives of this model of care are routine screening for psychological morbidity; patient-support through a phone advice line; and focused primary health-care support in the management of diabetes and CKD. Additionally, the model of care integrates with the patient-centred health-care home currently being rolled out by the Australian Department of Health. This model of care will be evaluated after implementation across two tertiary health services and their primary care catchment areas. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29405504 TI - Sleep and dream habits in a sample of French college students who report no sleep disorders. AB - There is a lack of up-to-date data on sleep and dream habits of college students. To fill in this gap, we used an online questionnaire sent to the student mailing lists of two major universities of Lyon (Lyon 1 and Lyon 2) for the recruitment of an functional magnetic resonance imaging study with sleep disorders as exclusion criteria. In the sample (1,137 French college students, 411 males, mean age = 22.2 +/- 2.4 years, body mass index = 22.0 +/- 3.2 kg m-2 ), on average, the participants reported spending about 8 hr in bed during weekdays, 9 hr during the weekends, and 90.9% of them reported no difficulty falling asleep. Less than 0.4% of students reported to have sleep-walking episodes regularly, but nearly 7% reported regular sleep-talking episodes. The average dream recall frequency was about 3 mornings per week with a dream in mind. Dream recall frequency was positively correlated with the clarity of dream content and the frequency of lucid dreaming, and was negatively correlated with age. Fourteen percent of the students reported frequent lucid dreams, and 6% reported frequent recurrent dreams. We found a gender effect for several sleep and dream parameters, including dream recall frequency and time in bed, both of which were higher in women than in men. We have also observed differences between academic disciplines, namely humanities students (Lyon 2) reported spending more time in bed than sciences students (Lyon 1). These results confirm a gender difference for several sleep and dream parameters, and suggest a link between academic disciplines and sleep duration. PMID- 29405505 TI - Sympathetic vasomotor activity during dynamic exercise with resistive breathing: Sex differences and the nerve to show it! PMID- 29405506 TI - Perovskite Solar Cells: From the Atomic Level to Film Quality and Device Performance. AB - Organic-inorganic perovskites have made tremendous progress in recent years due to exceptional material properties such as high panchromatic absorption, charge carrier diffusion lengths, and a sharp optical band edge. The combination of high quality semiconductor performance with low-cost deposition techniques seems to be a match made in heaven, creating great excitement far beyond academic ivory towers. This is particularly true for perovskite solar cells (PSCs) that have shown unprecedented gains in efficiency and stability over a time span of just five years. Now there are serious efforts for commercialization with the hope that PSCs can make a major impact in generating inexpensive, sustainable solar electricity. In this Review, we will focus on perovskite material properties as well as on devices from the atomic to the thin film level to highlight the remaining challenges and to anticipate the future developments of PSCs. PMID- 29405507 TI - Medicine-related beliefs predict attribution of symptoms to a sham medicine: A prospective study. AB - OBJECTIVES: To investigate a range of possible predictors of nocebo responses to medicines. DESIGN: Prospective cohort study. METHODS: In total, 203 healthy adult volunteers completed measures concerning demographics, psychological factors, medicine-related beliefs, baseline symptoms, and symptom expectations before taking a sham pill, described as 'a well-known tablet available without prescription' that was known to be associated with several side effects. Associations between these measures and subsequent attribution of symptoms to the tablet were assessed using a hurdle model consisting of a joint logistic and truncated negative binomial regression. RESULTS: Men had an increased odds of attributing symptoms to the tablet OR = 1.52, and older participants had decreased odds, OR = 0.97. Medicine-related beliefs were important, with modern health worries, belief that medicines cause harm and perceived sensitivity to medicines associated with increased odds of symptom attribution, OR = 1.02, 1.10, 1.09, respectively. Trust in medicines and pharmaceutical companies decreased the odds of symptom attribution, OR = 0.91, 0.88, respectively. The number of symptoms at baseline and the expected likelihood of symptoms were associated with an increased odds of attributing symptoms to the tablet, OR = 1.07, 1.06, respectively. Anxiety, previous symptom experience, symptom expectations, and modern health worries were also important in predicting the number of symptoms participants attributed to the tablet. CONCLUSION: It is hard to predict who is at risk of developing nocebo responses to medicines from demographic or personality characteristics. Context-specific factors such as beliefs about and trust in medicines, current symptoms and symptom expectations are more useful as predictors. More work is needed to investigate this in a patient sample. Statement of contribution What is already known on this subject? Many patients report non-specific side effects to their medication which may arise through a nocebo effect. Whether some people are particularly predisposed to experience nocebo effects remains unclear. What does this study add? Demographic and personality characteristics are poor predictors of symptom attribution to a sham medicine. Instead, context-specific factors that concern people's beliefs surrounding medicines, their current symptoms, and symptom expectations are more useful as predictors of symptom attribution. PMID- 29405508 TI - Reduced prefrontal hemodynamic response in adult attention-deficit hyperactivity disorder as measured by near-infrared spectroscopy. AB - AIM: Recent developments in near-infrared spectroscopy (NIRS) have enabled non invasive clarification of brain functions in psychiatric disorders. In pediatric attention-deficit hyperactivity disorder (ADHD), reduced prefrontal hemodynamic responses have been observed with NIRS repeatedly. However, there are few studies of adult ADHD by multi-channel NIRS. Therefore, in this study, we used multi channel NIRS to examine the characteristics of prefrontal hemodynamic responses during the Stroop Color-Word Task (SCWT) in adult ADHD patients and in age- and sex-matched control subjects. METHODS: Twelve treatment-naive adults with ADHD and 12 age- and sex-matched healthy control subjects participated in the present study after giving consent. We used 24-channel NIRS to measure the oxygenated hemoglobin (oxy-Hb) changes at the frontal lobes of participants during the SCWT. We compared the oxy-Hb changes between adults with ADHD and control subjects by t tests with Bonferroni correction. RESULTS: During the SCWT, the oxy-Hb changes observed in the ADHD group were significantly smaller than those in the control group in channels 11, 16, 18, 21, 22, 23, and 24, corresponding to the prefrontal cortex. At channels 16, 21, 23, and 24 of the ADHD group, there were negative correlations between the symptomatic severity and the oxy-Hb changes. CONCLUSION: The present study suggests that adults with ADHD have reduced prefrontal hemodynamic response as measured by NIRS. PMID- 29405510 TI - Effect of deferred or no treatment with ursodeoxycholic acid in patients with early primary biliary cholangitis. AB - AIM: As primary biliary cholangitis (PBC) is a heterogeneous disease, we hypothesized that there is a population of patients with early PBC who do not require prompt treatment with ursodeoxycholic acid (UDCA). In this study, we analyzed data from a large-scale PBC cohort in Japan, and retrospectively investigated whether outcomes of early PBC patients were affected with prompt or deferred/no UDCA treatment. METHODS: We defined early PBC as asymptomatic, serum alkaline phosphatase <1.67-fold the upper limit of normal, normal bilirubin, and histological stages I-II at presentation. We compared the outcomes of early PBC patients between the treatment regimens; prompt treatment group (UDCA was initiated within 1 year after diagnosis) and deferred/no treatment group (UDCA initiated >1 year after diagnosis or never initiated). Furthermore, we examined the outcomes of early PBC patients alternatively defined only with symptomatology and biochemistry. RESULTS: We identified 562 early PBC patients (prompt: n = 509; deferred/no treatment: n = 53). Incidence rates (per 1000 patient-years) for liver-related mortality or liver transplantation and decompensating events were 0.5 and 5.4, respectively, in the prompt treatment group, and 0 and 8.7, respectively, in the deferred/no treatment group. Multivariate analyses showed that age and bilirubin were significantly associated with developing decompensating events, whereas the prompt and deferred/no treatments were not. We obtained similar results in early PBC patients defined without histological examination. CONCLUSIONS: We showed that deferred/no treatment for early PBC patients did not affect the outcomes. This study provides a rationale for a future prospective, randomized study. PMID- 29405509 TI - Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. AB - AIMS: In exocrine pancreatic insufficiency (EPI), the quantity and/or activity of pancreatic digestive enzymes are below the levels required for normal digestion, leading to maldigestion and malabsorption. Diagnosis of EPI is often challenging because the characteristic signs and symptoms overlap with those of other gastrointestinal conditions. Additionally, there is no single convenient, or specific diagnostic test for EPI. The aim of this review is to provide a framework for differential diagnosis of EPI vs other malabsorptive conditions. METHODS: This is a non-systematic narrative review summarising information pertaining to the aetiology, diagnosis and management of EPI. RESULTS: Exocrine pancreatic insufficiency may be caused by pancreatic disorders, including chronic pancreatitis, cystic fibrosis, pancreatic resection and pancreatic cancer. EPI may also result from extra-pancreatic conditions, including coeliac disease, Zollinger-Ellison syndrome and gastric surgery. Timely and accurate diagnosis of EPI is important, as delays in treatment prolong maldigestion and malabsorption, with potentially serious consequences for malnutrition, overall health and quality of life. Symptoms of EPI are non-specific; therefore, a high index of clinical suspicion is required to make a correct diagnosis. PMID- 29405511 TI - A flattening oxygen consumption trajectory phenotypes disease severity and poor prognosis in patients with heart failure with reduced, mid-range, and preserved ejection fraction. AB - BACKGROUND: In heart failure (HF), a flattening oxygen consumption (VO2 ) trajectory during cardiopulmonary exercise test (CPET) reflects an acutely compromised cardiac output. We hypothesized that a flattening VO2 trajectory is helpful in phenotyping disease severity and prognosis in HF with either reduced (HFrEF), mid-range (HFmrEF), or preserved (HFpEF) ejection fraction. METHODS AND RESULTS: Overall, 319 HF patients (198 HFrEF, 80 HFmrEF, and 41 HFpEF) underwent CPET. A flattening VO2 trajectory was tracked and defined as an inflection of VO2 linearity as a function of work rate with a second slope downward inflection >35% extent of the first one. Peak VO2 , the minute ventilation/carbon dioxide production (VE/VCO2 ) slope, and the presence of exercise oscillatory ventilation (EOV) were also determined. Pulmonary artery systolic pressure (PASP) and tricuspid annular plane systolic excursion (TAPSE) were measured by echocardiography. A flattening VO2 occurred in 92 patients (28.8%). PASP and TAPSE at rest were significantly higher and lower (P < 0.001), respectively. The primary outcome was the combination of all-cause death, heart transplantation and left ventricular assist device implantation. The secondary outcome was the primary outcome plus hospitalization for cardiac reasons. In the multivariate model including peak VO2 , VE/VCO2 slope, EOV and VO2 trajectory, a flattening VO2 trajectory and EOV were retained in the regression for primary (X2 = 35.78, and 36.36, respectively; P < 0.001) and secondary (X2 = 12.45 and 47.91, respectively; P < 0.001) outcomes. CONCLUSIONS: Results point to a flattening VO2 trajectory as a likely new and strong predictor of events in HF with any ejection fraction. Given the relation of right-sided cardiac dysfunction to pulmonary hypertension, this oxygen pattern might suggest a real-time decrease in pulmonary blood flow to the left heart. PMID- 29405512 TI - Ready-made versus custom-made mandibular advancement appliances in obstructive sleep apnea: A systematic review and meta-analysis. AB - Mandibular advancement appliances (MAAs) are an increasingly accepted treatment choice in obstructive sleep apnea management. The ready-made MAAs has questioned the need for a customised MAAs, given the former is more accessible and considerably cheaper. We conducted a systematic review and meta-analysis to evaluate both objective and patient-centred outcomes in relation to ready-made and custom-made MAAs s. Biomedical electronic databases, clinical trials registers and Grey literature were searched to January 2017, for randomised controlled trials. Meta-analyses of clinical trials were conducted for a range of objective (apnea-hypopnea index, treatment response) and subjective scales (daytime sleepiness; quality of life; patient preference and adherence). The review included three randomised controlled trials, which revealed low risk of bias. Custom-made MAAs s achieved a significant mean difference in the apnea hypopnea index (-3.2; 95% confidence interval -5.18, -1.22; p = .004), daytime sleepiness (-0.98; 95% confidence interval -1.97, 0.01; p = .05), observed mean difference in Functional Outcomes of Sleep Questionnaire scores (0.76; 95% confidence interval 0.14, 1.38; p = .02), self-reported adherence (6.4-7 nights per week and 5-6.3 hr per night) and expressed preference (p <= .001) when compared with the ready-made MAAs s. Custom-made MAAs s offer clear definable advantages, demonstrating significant clinical effectiveness, patient preference and adherence. PMID- 29405513 TI - Renin-angiotensin system inhibition-it's been a long but fruitful journey. PMID- 29405514 TI - Structural basis for substrate recognition and inhibition of prephenate aminotransferase from Arabidopsis. AB - Aromatic amino acids are protein building blocks and precursors to a number of plant natural products, such as the structural polymer lignin and a variety of medicinally relevant compounds. Plants make tyrosine and phenylalanine by a different pathway from many microbes; this pathway requires prephenate aminotransferase (PAT) as the key enzyme. Prephenate aminotransferase produces arogenate, the unique and immediate precursor for both tyrosine and phenylalanine in plants, and also has aspartate aminotransferase (AAT) activity. The molecular mechanisms governing the substrate specificity and activation or inhibition of PAT are currently unknown. Here we present the X-ray crystal structures of the wild-type and various mutants of PAT from Arabidopsis thaliana (AtPAT). Steady state kinetic and ligand-binding analyses identified key residues, such as Glu108, that are involved in both keto acid and amino acid substrate specificities and probably contributed to the evolution of PAT activity among class Ib AAT enzymes. Structures of AtPAT mutants co-crystallized with either alpha-ketoglutarate or pyridoxamine 5'-phosphate and glutamate further define the molecular mechanisms underlying recognition of keto acid and amino acid substrates. Furthermore, cysteine was identified as an inhibitor of PAT from A. thaliana and Antirrhinum majus plants as well as the bacterium Chlorobium tepidum, uncovering a potential new effector of PAT. PMID- 29405515 TI - Bacillus Calmette-Guerin, polysaccharide nucleic acid in the treatment of cutaneous and oral lichen planus. AB - The aim of this study was to evaluate the safety and efficacy of Bacillus Calmette-Guerin, polysaccharide nucleic acid (BCG-PSN) therapy in the treatment of oral and cutaneous LP. Twenty-four LP patients were included in this study and classified randomly into; Oral LP group (OLP), 11 patients and Cutaneous LP group (CLP), 13 patients. All patients received intradermal injections of BCG-PSN, twice weekly for three weeks. Patients with complete response were followed up for 3 months. The assessment in OLP was based on the reduction in the treated area, (Reticulation/Erythema/Ulceration) REU scoring system and numerical rating scale (NRS). CLP evaluated by the response to treatment as (complete, partial and no response) and visual analogue scale (VAS). There were highly significant differences in the diminution of lesion areas (p < .006), NRS scores (p < .001), REU score (p < .011), and VAS (p < .001) after treatment. The majority of patients achieved complete response after 3-week management. The BCG-PNS is safe and effective in the treatment of oral and cutaneous LP. PMID- 29405516 TI - Assessment of Risk Evaluation and Mitigation Strategies (REMS) for varenicline (Chantix): A multistage patient survey. AB - PURPOSE: To evaluate the Risk Evaluation and Mitigation Strategies (REMS) for varenicline by assessing patients' understanding of the varenicline medication guide (MG) at pre-specified time points: 18 months, 3 years, and 7 years after the REMS approval. METHODS: Self-administered surveys were mailed to people who received varenicline based on a pharmacy dispensing. Survey questions assessed understanding of potential risks outlined in the MG: neuropsychiatric symptoms, skin reactions, allergic reactions, and cardiovascular risks. Crude and weighted analyses were conducted. RESULTS: The response to the survey overall was between 18% and 19%. Among responders, approximately 90% recalled receiving the MG, and at least 80% read all or part of it. At least 88% correctly identified neuropsychiatric symptoms as potential medication effects, while 41% did so for skin reactions, 53% for allergic reactions, and 82% for cardiovascular risks. Patients who read the MG had a high proportion of correct responses to the risk comprehension questions. CONCLUSIONS: A large majority of patients who were dispensed varenicline recalled receiving the MG and were able to correctly recall neuropsychiatric and cardiovascular risks in all 3 surveys. The varenicline MG may be an effective tool for patient education. PMID- 29405517 TI - Activation of amylin receptors attenuates alcohol-mediated behaviours in rodents. AB - Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans. PMID- 29405518 TI - Contractile injection systems of bacteriophages and related systems. AB - Contractile tail bacteriophages, or myobacteriophages, use a sophisticated biomolecular structure to inject their genome into the bacterial host cell. This structure consists of a contractile sheath enveloping a rigid tube that is sharpened by a spike-shaped protein complex at its tip. The spike complex forms the centerpiece of a baseplate complex that terminates the sheath and the tube. The baseplate anchors the tail to the target cell membrane with the help of fibrous proteins emanating from it and triggers contraction of the sheath. The contracting sheath drives the tube with its spiky tip through the target cell membrane. Subsequently, the bacteriophage genome is injected through the tube. The structural transformation of the bacteriophage T4 baseplate upon binding to the host cell has been recently described in near-atomic detail. In this review we discuss structural elements and features of this mechanism that are likely to be conserved in all contractile injection systems (systems evolutionary and structurally related to contractile bacteriophage tails). These include the type VI secretion system (T6SS), which is used by bacteria to transfer effectors into other bacteria and into eukaryotic cells, and tailocins, a large family of contractile bacteriophage tail-like compounds that includes the P. aeruginosa R type pyocins. PMID- 29405519 TI - Patient preference study for different characteristics of systemic psoriasis treatments (Protimisis). AB - "The Protimisis" study was a multicenter, cross-sectional study investigating the relative importance and economic value that patients assign to different characteristics of systemic psoriasis treatments. Treatment preferences were investigated with the DCE methodology and patients had to decide over the most important aspects of different psoriasis treatments. A questionnaire regarding demographic data/medical history and the DLQI and EQ-5D-3L questionnaires were also completed. A total of 310 patients were included. Out of those, 37.4% reported using oral medications for psoriasis as their most recent treatment, while the remaining patients reported treatment with injections once per week (14.8%), injections twice per week (7.4%), injections once every three months (29.4%) and intravenous injections every two months (8.4%) as their most recent treatment. Mean DLQI score was 6.6 (SD 6.5), and in the EQ-5D-3L index, 71.0% of patients reported having problems with anxiety or depression. DCE analysis showed a clear preference for treatments with longer dosing intervals, rapid onset of action, lasting clinical response, low risk of SAEs and lower cost. The risk of SAEs was the most important treatment characteristic (54% of patients). Older patients showed less concern for safety matters than younger patients. The highest willingness-to-pay was recorded for treatments with longer dosing intervals and for safer treatment options. PMID- 29405520 TI - Do predictors of smoking relapse change as a function of duration of abstinence? Findings from the United States, Canada, United Kingdom and Australia. AB - AIMS: To estimate predictors of time to smoking relapse and test if prediction varied by quit duration. DESIGN: Longitudinal cohort data from the International Tobacco Control Four-Country survey with annual follow up collected between 2002 and 2015. SETTING: Canada, United States, United Kingdom and Australia. PARTICIPANTS: A total of 9171 eligible adult smokers who had made at least one quit attempt during the study period. MEASUREMENTS: Time to relapse was the main outcome. Predictor variables included pre-quit baseline measures of nicotine dependence, smoking and quitting-related motivations, quitting capacity and social influence, and also two post-quit measures, use of stop-smoking medications and quit duration (1-7 days, 8-14 days, 15-31 days, 1-3 months, 3-6 months, 6-12 months, 1-2 years and 2+ years), along with socio-demographics. FINDINGS: All factors were predictive of relapse within the first 6 months of quitting but only wanting to quit, quit intentions and number of friends who smoke were still predictive of relapse in the 6-12-month period of quitting [hazard ratios (HR) = 1.20, P < 0.05; 1.13, P < 0.05; and 1.21, P < 0.001, respectively]. Number of friends smoking was the only remaining predictor of relapse in the 1-2 years quit period (HR = 1.19, P = 0.001) with none predictive beyond the 2-year quit period. Use of stop-smoking medications during quit attempts was related negatively to relapse during the first 2 weeks of quitting (HR = 0.71-0.84), but related positively to relapse in the 1-6-month quit period (HR = 1.29-1.54). Predictive effects of all factors showed significant interaction with quit duration except for perceiving smoking as an important part of life, prematurely stubbing out a cigarette and wanting to quit. CONCLUSIONS: Among adult smokers in the United States, Canada, United Kingdom and Australia, factors associated with smoking relapse differ between the early and later stages of a quit attempt, suggesting that the determinants of relapse change as a function of abstinence duration. PMID- 29405522 TI - FNA of peri-implant seroma of the breast. PMID- 29405521 TI - Greenhouse gas fluxes over managed grasslands in Central Europe. AB - Central European grasslands are characterized by a wide range of different management practices in close geographical proximity. Site-specific management strategies strongly affect the biosphere-atmosphere exchange of the three greenhouse gases (GHG) carbon dioxide (CO2 ), nitrous oxide (N2 O), and methane (CH4 ). The evaluation of environmental impacts at site level is challenging, because most in situ measurements focus on the quantification of CO2 exchange, while long-term N2 O and CH4 flux measurements at ecosystem scale remain scarce. Here, we synthesized ecosystem CO2 , N2 O, and CH4 fluxes from 14 managed grassland sites, quantified by eddy covariance or chamber techniques. We found that grasslands were on average a CO2 sink (-1,783 to -91 g CO2 m-2 year-1 ), but a N2 O source (18-638 g CO2 -eq. m-2 year-1 ), and either a CH4 sink or source (-9 to 488 g CO2 -eq. m-2 year-1 ). The net GHG balance (NGB) of nine sites where measurements of all three GHGs were available was found between 2,761 and -58 g CO2 -eq. m-2 year-1 , with N2 O and CH4 emissions offsetting concurrent CO2 uptake by on average 21 +/- 6% across sites. The only positive NGB was found for one site during a restoration year with ploughing. The predictive power of soil parameters for N2 O and CH4 fluxes was generally low and varied considerably within years. However, after site-specific data normalization, we identified environmental conditions that indicated enhanced GHG source/sink activity ("sweet spots") and gave a good prediction of normalized overall fluxes across sites. The application of animal slurry to grasslands increased N2 O and CH4 emissions. The N2 O-N emission factor across sites was 1.8 +/- 0.5%, but varied considerably at site level among the years (0.1%-8.6%). Although grassland management led to increased N2 O and CH4 emissions, the CO2 sink strength was generally the most dominant component of the annual GHG budget. PMID- 29405523 TI - CRNDE: An important oncogenic long non-coding RNA in human cancers. AB - Aberrant overexpression of long non-coding RNA CRNDE (Colorectal Neoplasia Differentially Expressed) is confirmed in various human cancers, which is correlated with advanced clinicopathological features and poor prognosis. CRNDE promotes cancer cell proliferation, migration and invasion, and suppresses apoptosis in complicated mechanisms, which result in the initialization and development of human cancers. In this review, we provide an overview of the oncogenic role and potential clinical applications of CRNDE. PMID- 29405524 TI - Genome sequence of M6, a diploid inbred clone of the high-glycoalkaloid-producing tuber-bearing potato species Solanum chacoense, reveals residual heterozygosity. AB - Cultivated potato (Solanum tuberosum L.) is a highly heterozygous autotetraploid that presents challenges in genome analyses and breeding. Wild potato species serve as a resource for the introgression of important agronomic traits into cultivated potato. One key species is Solanum chacoense and the diploid, inbred clone M6, which is self-compatible and has desirable tuber market quality and disease resistance traits. Sequencing and assembly of the genome of the M6 clone of S. chacoense generated an assembly of 825 767 562 bp in 8260 scaffolds with an N50 scaffold size of 713 602 bp. Pseudomolecule construction anchored 508 Mb of the genome assembly into 12 chromosomes. Genome annotation yielded 49 124 high confidence gene models representing 37 740 genes. Comparative analyses of the M6 genome with six other Solanaceae species revealed a core set of 158 367 Solanaceae genes and 1897 genes unique to three potato species. Analysis of single nucleotide polymorphisms across the M6 genome revealed enhanced residual heterozygosity on chromosomes 4, 8 and 9 relative to the other chromosomes. Access to the M6 genome provides a resource for identification of key genes for important agronomic traits and aids in genome-enabled development of inbred diploid potatoes with the potential to accelerate potato breeding. PMID- 29405525 TI - Inhibition and kinetic studies of cellulose- and hemicellulose-degrading enzymes of Ganoderma boninense by naturally occurring phenolic compounds. AB - AIM: Ganoderma sp, the causal pathogen of the basal stem rot (BSR) disease of oil palm, secretes extracellular hydrolytic enzymes. These play an important role in the pathogenesis of BSR by nourishing the pathogen through the digestion of cellulose and hemicellulose of the host tissue. Active suppression of hydrolytic enzymes secreted by Ganoderma boninense by various naturally occurring phenolic compounds and estimation of their efficacy on pathogen suppression is focused in this study. METHODS AND RESULTS: Ten naturally occurring phenolic compounds were assessed for their inhibitory effect on the hydrolytic enzymes of G. boninense. The enzyme kinetics (Vmax and Km ) and the stability of the hydrolytic enzymes were also characterized. The selected compounds had shown inhibitory effect at various concentrations. Two types of inhibitions namely uncompetitive and noncompetitive were observed in the presence of phenolic compounds. Among all the phenolic compounds tested, benzoic acid was the most effective compound suppressive to the growth and production of hydrolytic enzymes secreted by G. boninense. The phenolic compounds as inhibitory agents can be a better replacement for the metal ions which are known as conventional inhibitors till date. The three hydrolytic enzymes were stable in a wide range of pH and temperature. CONCLUSION: These findings highlight the efficacy of the applications of phenolic compounds to control Ganoderma. SIGNIFICANCE AND IMPACT OF THE STUDY: The study has proved a replacement for chemical controls of G. boninense with naturally occurring phenolic compounds. PMID- 29405526 TI - A systematic review and meta-analysis of genotypic methods for detecting antibiotic resistance in Helicobacter pylori. AB - BACKGROUND: Antibiotic susceptibility testing is essential for tailored treatments to cure Helicobacter pylori (H. pylori) infection. However, phenotypic methods have some limitations. OBJECTIVES: To evaluate the feasibility of genotypic detection methods compared with phenotypic detection methods using samples taken from H. pylori-infected patients. METHODS: Literature searches were conducted in the following databases (from January 2000 to November 2016): PubMed, Embase, the Cochrane Library, and Web of Science. A meta-analysis and systematic review was performed for studies that compared genotypic methods with phenotypic methods for the detection of H. pylori antibiotic susceptibility. RESULTS: This meta-analysis showed that the pooled sensitivity, specificity, and diagnostic odds ratio (DOR) for the A2142G/C and/or A2143G combination for the detection of clarithromycin resistance in the strain samples were 0.97 (95% CI: 0.94-0.99), 1.00 (95% CI: 0.99-1.00), and 13 742 (95% CI: 1708-110 554), respectively. The pooled sensitivity, specificity, and DOR for the A2142G/C and/or A2143G combination for the detection of clarithromycin resistance in biopsy samples were 0.96 (95% CI: 0.90-0.99), 0.96 (95% CI: 0.91-0.99), and 722 (95% CI: 117-4443), respectively. The summarized sensitivity, specificity, and DOR value for the ability of the genotypic methods to detect quinolone resistance in biopsy specimens were 0.97 (95% CI: 0.87-0.99), 0.99 (95% CI: 0.92-1.00), and 6042 (95% CI: 486-75 143), respectively. CONCLUSION: The genotypic detection methods were reliable for the diagnosis of clarithromycin and quinolone resistance in the strain and biopsy specimens. The A2142G/C and/or A2143G combination had the best sensitivity and specificity for the detection of clarithromycin resistance. PMID- 29405527 TI - Pre-outbreak forest conditions mediate the effects of spruce beetle outbreaks on fuels in subalpine forests of Colorado. AB - Over the past 30 years, forest disturbances have increased in size, intensity, and frequency globally, and are predicted to continue increasing due to climate change, potentially relaxing the constraints of vegetation properties on disturbance regimes. However, the consequences of the potentially declining importance of vegetation in determining future disturbance regimes are not well understood. Historically, bark beetles preferentially attack older trees and stands in later stages of development. However, as climate warming intensifies outbreaks by promoting growth of beetle populations and compromising tree defenses, smaller diameter trees and stands in early stages of development now are being affected by outbreaks. To date, no study has considered how stand age and other pre-outbreak forest conditions mediate the effects of outbreaks on surface and aerial fuel arrangements. We collected fuels data across a chronosequence of post-outbreak sites affected by spruce beetle (SB) between the 1940s and the 2010s, stratified by young (<130 yr) and old (>130 yr) post-fire stands. Canopy and surface fuel loads were calculated for each tree and stand, and available crown fuel load, crown bulk density, and canopy bulk densities were estimated. Canopy bulk density and density of live canopy individuals were reduced in all stands affected by SB, though foliage loss was proportionally greater in old stands as compared to young stands. Fine surface fuel loads in young stands were three times greater shortly (<30 yr) following outbreak as compared to young stands not affected by outbreak, after which the abundance of fine surface fuels decreased to below endemic (i.e., non-outbreak) levels. In both young and old stands, the net effect of SB outbreaks during the 20th and 21st centuries reduced total canopy fuels and increased stand-scale spatial heterogeneity of canopy fuels following outbreak. Importantly, the decrease in canopy fuels following outbreaks was greater in young post-fire stands than in older stands, suggesting that SB outbreaks may more substantially reduce risk of active crown fire when they affect stands in earlier stages of development. The current study shows that the effects of SB outbreaks on forest structure and on fuel profiles are strongly contingent on pre-outbreak conditions as determined by pre-outbreak disturbance history. PMID- 29405528 TI - Discovery and Enumeration of Organic-Chemical and Biomimetic Reaction Cycles within the Network of Chemistry. AB - Analysis of the chemical-organic knowledge represented as a giant network reveals that it contains millions of reaction sequences closing into cycles. Without realizing it, independent chemists working at different times have jointly created examples of cyclic sequences that allow for the recovery of useful reagents and for the autoamplification of synthetically important molecules, those that mimic biological cycles, and those that can be operated one-pot. PMID- 29405529 TI - High-Flux Membranes Based on the Covalent Organic Framework COF-LZU1 for Selective Dye Separation by Nanofiltration. AB - Covalent organic frameworks (COFs) are attractive candidates for advanced water treatment membranes owing to their high porosity and well-organized channel structures. Herein, the continuous two-dimensional imine-linked COF-LZU1 membrane with a thickness of only 400 nm was prepared on alumina tubes by in situ solvothermal synthesis. The membrane shows excellent water permeance (ca. 760 L m 2 h-1 MPa-1 ) and favorable rejection rates exceeding 90 % for water-soluble dyes larger than 1.2 nm. The water permeance through the COF-LZU1 membrane is much higher than that of most membranes with similar rejection rates. Long-time operation demonstrates the outstanding stability of the COF-LZU1 membrane. As the membrane has no selectivity for hydrated salt ions (selectivity <12 %), it is also suitable for the purification of dye products from saline solutions. The excellent performance and the outstanding water stability render the COF-LZU1 membrane an interesting system for water purification. PMID- 29405530 TI - Survival of Escherichia coli O157:H7 and Salmonella enterica in animal waste based composts as influenced by compost type, storage condition and inoculum level. AB - AIM: Survival of Escherichia coli O157:H7 and Salmonella enterica in animal waste based composts was studied with different compost types, storage conditions and inoculum levels. METHODS AND RESULTS: A cocktail of three E. coli O157:H7 or S. enterica strains was inoculated into dairy manure-based composts (A and B) or poultry litter-based composts (C and D), respectively, at final concentrations of c. 5 or 2 log CFU per gram. Composts were then stored at 5 and 22 degrees C, and under greenhouse condition. Both pathogens survived better at 5 than 22 degrees C and under greenhouse conditions. Escherichia coli O157:H7 at both inoculation levels survived for >168 days in composts A and B under at 5 degrees C, whereas the longest survival of S. enterica at both inoculation levels was observed to be >168 days in compost C at 5 degrees C. Overall, composts A and C provided better survival conditions for E. coli O157:H7 and S. enterica, respectively, and both pathogens at the high inoculum level survived better as compared to the low inoculum level. CONCLUSIONS: Escherichia coli O157:H7 and S. enterica could potentially survive for long periods of time in dairy and poultry composts. Some factors influencing the pathogen survival included compost type, storage condition and inoculum level. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results have provided scientific data on the pathogen survival in dairy and poultry composts, which could be used for the risk assessment of using animal waste-based composts as biological soil amendments. PMID- 29405531 TI - Universality of the Sodium Ion Binding Mechanism in Class A G-Protein-Coupled Receptors. AB - The allosteric modulation of G-protein-coupled receptors (GPCRs) by sodium ions has received significant attention as crystal structures of several receptors show Na+ ions bound to the inactive conformations at the conserved Asp2.50 . To date, structures from 24 families of GPCRs have been determined, though mechanistic insights into Na+ binding to the allosteric site are limited. We performed hundreds-of-microsecond long simulations of 18 GPCRs and elucidated their Na+ binding mechanism. In class A GPCRs, the Na+ ion binds to the conserved residue 2.50 whereas in class B receptors, it binds at 3.43b, 6.53b, and 7.49b. Using Markov state models, we obtained the free energy profiles and kinetics of Na+ binding to the allosteric site, which reveal a conserved mechanism of Na+ binding for GPCRs and show the residues that act as major barriers for ion diffusion. Furthermore, we also show that the Na+ ion can bind to GPCRs from the intracellular side when the allosteric site is inaccessible from the extracellular side. PMID- 29405532 TI - Water-Assisted Size and Shape Control of CsPbBr3 Perovskite Nanocrystals. AB - Lead-halide perovskites are well known to decompose rapidly when exposed to polar solvents, such as water. Contrary to this common-place observation, we have found that through introducing a suitable minor amount of water into the reaction mixture, we can synthesize stable CsPbBr3 nanocrystals. The size and the crystallinity, and as a result the band gap tunability of the strongly emitting CsPbBr3 nanocrystals correlate with the water content. Suitable amounts of water change the crystallization environment, inducing the formation of differently shaped perovskites, namely spherical NCs, rectangular nanoplatelets, or nanowires. Bright CsPbBr3 nanocrystals with the photoluminescence quantum yield reaching 90 % were employed for fabrication of inverted hybrid inorganic/organic light-emitting devices, with the peak luminance of 4428 cd m-2 and external quantum yield of 1.7 %. PMID- 29405533 TI - The role of sleep in aesthetic perception and empathy: A mediation analysis. AB - The ability to experience aesthetics plays a fundamental role in human social interactions, as well as the capacity to feel empathy. Some studies have shown that beauty perception shares part of the neural network underlying emotional and empathic abilities, which are also known to affect sleep quality and duration. In this study, we evaluated for the first time the effects of sleep on the relation between aesthetic perception and empathic abilities in healthy subjects using a mediation analysis approach. One-hundred and twenty-six subjects participated in this study. One-hundred and one subjects slept at home (Sleep Group). The remaining 25 subjects were tested as controls after 1 night of sleep deprivation to assess the effects of lack of sleep on aesthetic perception and empathy (Sleep Deprived Group). All participants underwent one testing session in which they performed a battery of empathy tests and an aesthetic perception task (Golden Beauty). The results showed that sleep duration mediates the relationship between empathy and aesthetic perception in the sleep group. The mediation effect of sleep was more evident on the emotional empathy measures. Conversely, in the sleep deprivation group the lack of correlations among empathy, aesthetic perception and sleep variables did not allow to perform the mediation analysis. These results suggest that adequate sleep duration may play a significant role in improving cognitive and emotional empathic abilities as well as the capability to give accurate aesthetic judgements. PMID- 29405534 TI - Dura to spinal cord distance at different vertebral levels in children and its implications on epidural analgesia: A retrospective MRI-based study. AB - BACKGROUND: The distance from the dura to spinal cord is not uniform at different vertebral levels. The dura to spinal cord distance may be a critical factor in avoiding the potential for neurological injury caused by needle trauma after a dural puncture. Typically, the greater the dura to spinal cord distance, the larger the potential safety margin. The objective of our study is to measure dura to spinal cord distance at two thoracic levels T6 -7 , T9 -10 , and one lumbar level L1 -2 using MRI images. METHODS: Eighty-eight children under the age of 8 years old qualified for the study. The distance from dural side of ligamentum flavum to the posterior margin of the spinal cord was defined as dura to spinal cord distance. Sagittal T2 -weighted images of the thoracic and lumbar spine were used to measure the dura to spinal cord distance at the T6-7 , T9-10 , and L1-2 interspaces. Measurements were taken perpendicular to long axis of the vertebral body at each level. RESULTS: The dura to spinal cord distance was 5.9 +/- 1.6 mm at T6-7 (range: 1.4-9.9 mm), 5.0 +/- 1.6 mm at T9-10 (1.2-8.1 mm), and 3.6 +/- 1.2 mm at L1-2 (1.2-6.8 mm). There were no evident differences in dura to spinal cord distance by gender, age, height, or weight. CONCLUSION: The present study reports that the largest dura to spinal cord distance is found at the T5-6 level, and the shortest dura to spinal cord distance at the L1-2 level. There appears to be substantially more room in the dorsal subarachnoid space at the thoracic level. The risk of spinal cord damage resulting from accidental epidural needle advancement may be greater in the lumbar region due to a more dorsal location of the spinal cord in the vertebral canal compared to the thoracic region. PMID- 29405535 TI - Directing Aluminum Atoms into Energetically Favorable Tetrahedral Sites in a Zeolite Framework by Using Organic Structure-Directing Agents. AB - The Al location in zeolites can have massive influences on the zeolite properties because it directly correlates with the cationic active sites. Herein, the synthesis of IFR zeolites with controlled Al distribution at different tetrahedral sites (T sites) is reported. The computational calculations suggest that organic structure-directing agents (OSDAs) used for zeolite synthesis can alter the energetically favorable T sites for Al. Zeolite products synthesized under identical conditions but with different OSDAs are found to have altered fractions of Al at different T sites in accordance with the energies derived from the zeolite-OSDA complexes. Our finding thus provides evidence for the ability of OSDAs to direct Al into more energetically favorable T sites, thereby offering rational synthetic guidelines for the selective placement of Al into specific crystallographic sites. PMID- 29405536 TI - Sacrifice and extracranial reconstruction of the common or internal carotid artery in advanced head and neck carcinoma: Review and meta-analysis. AB - BACKGROUND: Sacrifice and reconstruction of the carotid artery in cases of head and neck carcinoma with invasion of the common or internal carotid artery is debated. METHODS: We conducted a systematic search of electronic databases and provide a review and meta-analysis. RESULTS: Of the 72 articles identified, 24 met the inclusion criteria resulting in the inclusion of 357 patients. The overall perioperative 30-day mortality was 3.6% (13/357). Permanent cerebrovascular complications occurred in 3.6% (13/357). Carotid blowout episodes were encountered in 1.4% (5/357). The meta-regression analysis showed a significant difference in 1-year overall survival between reports published from 1981-1999 (37.0%) and 2001-2016 (65.4%; P = .02). CONCLUSION: This review provides evidence that sacrifice with extracranial reconstruction of common or internal carotid artery in selected patients with head and neck carcinoma may improve survival with acceptable complication rates. However, all of the published literature is retrospective involving selected series and, therefore, precludes determining the absolute effectiveness of the surgery. PMID- 29405537 TI - Tooth loss, swallowing dysfunction and mortality in Japanese older adults receiving home care services. AB - AIM: Severe tooth loss and swallowing dysfunction occur more frequently in dependent older adult populations. Poor oral health and functional status are expected to have a negative impact on general health. We examined whether mortality is related to the number of teeth and swallowing function in dependent older Japanese individuals receiving home care services. METHODS: Older adults aged >=65 years who were receiving home care were included. The planned follow-up period was 3 years. Baseline data on the number of teeth, swallowing function, nutritional status, cognitive ability and activities of daily living were collected. RESULTS: A total of 259 participants (mean age 85.0 +/- 7.7 years) were enrolled. The mean length of follow up was 26.2 months. Severe tooth loss (<=9 present teeth) and swallowing dysfunction were observed in 68.0% and 32.0% of the participants, respectively. Cox's proportional hazards regression model showed that participants with both <=9 teeth and swallowing dysfunction were at a higher risk of mortality compared with those with both >=10 teeth and normal swallowing function (hazard ratio 2.89, 95% confidence interval 1.22-6.83). A significant interaction among severe tooth loss, swallowing dysfunction and mortality risk was observed. CONCLUSIONS: Severe tooth loss and swallowing dysfunction were associated with increased mortality. The present study suggests that the maintenance of oral health and swallowing function has a positive effect on general health. Therefore, attention should be given to both tooth loss and swallowing function in dependent older adult populations. Geriatr Gerontol Int 2018; 18: 873-880. PMID- 29405538 TI - Assessing the feasibility of an electronic patient-reported outcome (ePRO) collection system in caregivers of cancer patients. PMID- 29405539 TI - Very short DNA segments can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly. AB - Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0.7 and 2.5 Mb at two of the breakpoints in 1q24.3 and 6q24.1-q24.2, respectively, which could explain most symptoms of the patient. Subsequent whole genome mate-pair sequencing confirmed the chromothriptic nature of the rearrangement. The four participating chromosomes were broken into 29 segments longer than 1 kb. Sanger sequencing of all breakpoint junctions revealed additional complexity compatible with the involvement of different repair pathways. We observed translocation of a 33 bp long DNA fragment, which may have implications for the definition of the lower size limit of structural variants. Our observations and literature review indicate that even very small fragments from shattered chromosomes can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly. PMID- 29405540 TI - Effect of race on the glycaemic response to sitagliptin: Insights from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). AB - AIM: Pooled efficacy studies suggest that glycaemic responses to dipeptidyl peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha-glucosidase inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy. MATERIALS AND METHODS: TECOS enrolled 14 671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48-64 mmol/mol (6.5%-8.0%), and randomized them, double-blind, to sitagliptin or placebo. There were 3265 patients (22.3%) from Asian countries. Background glucose-lowering therapies were unaltered for the first 4 months post randomization unless clinically essential, facilitating comparison of sitagliptin-associated effects in self-identified East Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups. RESULTS: Median baseline HbA1c by race was 54 to 57 mmol/mol (7.1%-7.4%). Mean 4-month reduction in placebo-adjusted HbA1c was greatest in East Asians ( 6.6 mmol/mol [-0.60%] vs <=6.0 mmol/mol [<=0.55%] in other groups), with significantly greater reduction vs the 2 largest groups (White Caucasians, Other Asians; P < .0001) after adjustment for covariates. After the first 4 months, East and Other Asians were more likely to initiate additional oral therapy (metformin and/or sulfonylureas) than insulin vs White Caucasians (P < .0001). Acarbose use increased in the Asian patients, but no glycaemic interaction with allocated study medication was observed (adjusted P = .12). CONCLUSIONS: The greatest initial reduction in HbA1c with sitagliptin in the TECOS population was in East Asians. No enhanced glycaemic effect was seen when sitagliptin was given with acarbose. PMID- 29405541 TI - Structural Diversity and Anticancer Activity of Marine-Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer. AB - Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides, named loggerpeptins A-C (1-3), along with molassamide (4), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFkappaB activation, we assessed the effects of 4 on the expression of target genes, including ICAM-1. ICAM-1 is also a direct target of elastase and, in our studies, compound 4 attenuated both elastase-induced ICAM-1 gene expression and ICAM-1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase-mediated migration of highly invasive triple-negative breast cancer cells. PMID- 29405542 TI - Re: A comparison of the cost-utility of ultrasound-guided high-intensity focused ultrasound and hysterectomy for adenomyosis: a retrospective study: Is the cost effectiveness of HIFU for adenomyosis and fibroids feasible? PMID- 29405543 TI - Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: Time to overcome multifactorial therapeutic inertia? AB - Cardiovascular disease is a major cause of morbidity and mortality globally and the largest contributor to healthcare costs. There is good evidence that management of risk factors such as blood pressure, dyslipidaemia and glucose can lead to improved microvascular and macrovascular complications in individuals with type 2 diabetes mellitus. Legacy effect is a phenomenon used to describe the prolonged benefits of glucose, blood pressure or lipid control in individuals with cardiovascular disease, diabetes or in primary prevention of cardiovascular disease by early risk factor control. There is now also good quality evidence on the legacy benefits of multifactorial risk factor interventions on renal, cardiovascular and mortality outcomes. Despite this robust evidence, therapeutic inertia is widespread in the management of these risk factors in clinical practice. PMID- 29405544 TI - Highly Enantioselective [3+2] Annulation of Indoles with Quinones to Access Structurally Diverse Benzofuroindolines. AB - A facile and efficient method to produce optically pure benzofuroindolines, especially those without 3-substituents that are susceptible to rearomatization, through [3+2] annulation of indoles with quinones is described. The suitable combination of a BOX ligand CuII hydrate complex and freshly activated molecular sieves functions to give controllably dynamic release of water, which enables the success of this reaction. This reaction can be performed on a gram scale with only 0.5 mol % catalyst loading. PMID- 29405545 TI - The chaperone Chs7 forms a stable complex with Chs3 and promotes its activity at the cell surface. AB - The polytopic yeast protein Chs3 (chitin synthase III) relies on a dedicated membrane-localized chaperone, Chs7, for its folding and expression at the cell surface. In the absence of Chs7, Chs3 forms high molecular weight aggregates and is retained in the endoplasmic reticulum (ER). Chs7 was reported to be an ER resident protein, but its role in Chs3 folding and transport was not well characterized. Here, we show that Chs7 itself exits the ER and localizes with Chs3 at the bud neck and intracellular compartments. We identified mutations in the Chs7 C-terminal cytosolic domain that do not affect its chaperone function, but cause it to dissociate from Chs3 at a post-ER transport step. Mutations that prevent the continued association of Chs7 with Chs3 do not block delivery of Chs3 to the cell surface, but dramatically reduce its catalytic activity. This suggests that Chs7 engages in functionally distinct interactions with Chs3 to first promote its folding and ER exit, and subsequently to regulate its activity at the plasma membrane. PMID- 29405547 TI - Abdominal aortic calcification score predicts the occurrence of coronary artery disease in middle-aged peritoneal dialysis patients. AB - BACKGROUND: Abdominal aortic calcification (AAC) score in dialysis patients was associated with coronary artery disease (CAD) in cross-sectional study, but the use of AAC score in the CAD occurrence prediction was not clear. We aimed to use AAC score in the estimation of CAD occurrence in middle-aged peritoneal dialysis (PD) patients. METHODS: Middle-aged (45-65 years old) PD patients were recruited and followed up until CAD occurrence, patient mortality, or PD failure. We quantified AAC score by lateral lumbar radiography, and used Receiver operation curve (ROC) analysis to find the cutoff value for CAD prediction. CAD free survival was analysis by Kaplan-Meier study. RESULTS: There were 187 patients recruited for study with a mean follow-up of 1027+/-427 days. AAC score in patients with CAD during follow-up period (9.7+/-7.6, n=41) was higher than in patients without CAD occurrence (5.5+/-6.1, n=146) (p<0.001). Multivariate hazard ratio of AAC score for CAD was 1.07 (p=0.044). ROC study showed that an AAC score of 5.5 had a sensitivity of 0.667 and a specificity of 0.581 in the prediction of CAD occurrence. Patients with AAC score above 5.5 had significantly higher cumulative incidence of CAD than patients with AAC score below 5.5 (Log-rank test, p=0.003). Age (p=0.002), diabetes (p=0.002), hypertension (p=0.032), longer dialysis vintage (p<0.001) and lower serum potassium (p=0.012) were main parameters significantly associated with higher AAC score CONCLUSIONS: AAC score can predict CAD occurrence in PD patients. Age, diabetes, hypertension, dialysis vintage and low serum potassium level are main factors associated with higher AAC score. PMID- 29405546 TI - Detection of exogenous double-stranded RNA movement in in vitro peanut plants. AB - New technologies are needed to eliminate mycotoxins and/or fungal pathogens from agricultural products. RNA interference (RNAi) has shown potential to control fungi associated with crops. In RNAi, double-stranded RNA (dsRNA) targets homologous mRNA for cleavage, and can reach the mRNA of pathogens in contact with the plant. The key element in this process is the movement of RNA signals cell-to cell and over long distances within the plant, and between host plants and parasites. In this study, we selected a regulatory gene in the aflatoxin biosynthesis pathway, aflS/aflR, necessary for the production of aflatoxins in Aspergillus spp. We designed a Dicer-substrate RNA (DsiRNA) to study the movement and stability of the duplex over time in in vitro peanut plants using stem-loop primers and RT-PCR for DsiRNA detection. The preliminary results demonstrated that DsiRNA was absorbed and moved away from the point of application, spread systemically and was transported rapidly, most likely through the phloem of the shoot, to the sink tissues, such as new auxiliary shoots, flowers and newly formed pegs. The DsiRNA remained detectable for at least 30 days after treatment. This is the first time that movement of exogenous DsiRNA in in vitro peanut plants has been described. Since DsiRNA was detectable in the pegs 15 days after treatment, aflatoxin reduction may be possible if the duplexes containing part of the aflatoxin biosynthesis pathogen gene induce silencing in the peanut seeds colonised by Aspergillus spp. The application of small RNAs could be a non transformative option for mycotoxin contamination control. PMID- 29405548 TI - Efficacy of Alternating Conventional Stimulation and High Frequency Stimulation in Improving Spinal Cord Stimulation Outcomes: A Pilot Study. AB - INTRODUCTION: Spinal cord stimulation (SCS) is an established, effective method of treating chronic pain. High frequency stimulation (HFS) is an alternative SCS waveform that has been shown to alleviate pain but also necessitates more frequent recharging. The purpose of this pilot study is to evaluate efficacy of alternating conventional stimulation and HFS (termed "shuffle" stimulation) in improving SCS outcomes. METHODS: Shuffle stimulation was designed to deliver conventional stimulation in upright positions with relative HFS in lying positions, automated through accelerometer technology. In this 13-week cross-over study, patients were randomized to receiving conventional and shuffle stimulation in four-week blocks. Pain outcomes and sensory testing were compared from preoperative baseline and at the conclusion of each study period. RESULTS: Twelve patients completed this study. Two patients showed no change from baseline visual analogue scale (VAS) with either type of stimulation and were excluded from statistical analysis of pain outcomes. Mean numerical rating scale (NRS) scores assessing current pain were significantly lower in shuffle stimulation (4.0 +/- 1.6) compared to conventional stimulation (5.8 +/- 2.3) (p = 0.024). In the total cohort, 7 of 11 patients preferred shuffle over conventional stimulation. CONCLUSIONS: This study generated preliminary evidence showing improved NRS current pain scores in shuffle stimulation compared to conventional stimulation. More patients preferred shuffle stimulation compared to conventional stimulation. Optimizing stimulation when patients are recumbent may increase patient satisfaction and pain control. The potential advantages of shuffle stimulation may warrant further investigation. PMID- 29405549 TI - Solvent-Induced Crystal Polymorphism as Studied by Pyroelectric Measurements and Impedance Spectroscopy: Alcohols as Tailor-Made Inhibitors of alpha-Glycine. AB - Metastable polymorphs commonly emerge when the formation of the stable analogues is inhibited by using different solvents or auxiliaries. Herein, we report that when glycine is grown in aqueous solutions in the presence of low concentrations of different co-solvents, only alcohols and acetone, unlike water and acetic acid, are selectively incorporated in minute amounts within the bulk of the alpha polymorph. These findings demonstrate that although water binds more strongly to the growing face of the crystal, alcohols and acetone are exclusively incorporated, and thus serve as efficient inhibitors of this polymorph, leading to the precipitation of the beta-form. These solvents then create polar domains detectable by pyroelectric measurements and impedance spectroscopy. These results suggest that in the control of crystal polymorphism with co-solvents, one should consider also the different desolvation rates in addition to the energy of binding to the growing faces of the crystal. PMID- 29405552 TI - Dr. Stanley Henshaw: Reflections on Four Decades Of Abortion Research. PMID- 29405550 TI - Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. AB - Moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age-related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age-related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24-month-old C57BL/6 mice were treated with a cell-permeable, mitochondria-targeted antioxidant peptide (SS 31; 10 mg kg-1 day-1 , i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS-31 significantly improved neurovascular coupling responses by increasing NO-mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS-31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age-related vascular cognitive impairment (VCI). PMID- 29405551 TI - Effect of a clockwise-locked deletion in FliG on the FliG ring structure of the bacterial flagellar motor. AB - FliG is a rotor protein of the bacterial flagellar motor. FliG consists of FliGN , FliGM and FliGC domains. Intermolecular FliGM -FliGC interactions promote FliG ring formation on the cytoplasmic face of the MS ring. A conformational change in HelixMC connecting FliGM and FliGC is responsible for the switching between the counterclockwise (CCW) and clockwise (CW) rotational states of the FliG ring. However, it remains unknown how it occurs. Here, we carried out in vivo disulfide cross-linking experiments to see the effect of a CW-locked deletion (?PAA) in FliG on the FliG ring structure in Salmonella enterica. Higher-order oligomers were observed in the membrane fraction of the fliG(?PAA + G166C/G194C) strain upon oxidation with iodine in a way similar to FliG(G166C/G194C), indicating that the PAA deletion does not inhibit domain-swap polymerization of FliG. FliG(?PAA + E174C) formed a cross-linked homodimer whereas FliG(E174C) did not, indicating that Glu174 in HelixMC of one FliG protomer is located much closer to that of its neighboring subunit in the CW motor than in the CCW motor. We will discuss possible helical rearrangements of HelixMC that induce a structural remodeling of the FliG ring upon flagellar motor switching. PMID- 29405553 TI - Fractional flow reserve guided percutaneous coronary intervention results in reduced ischemic myocardium and improved outcomes. AB - OBJECTIVES: To determine if fractional flow reserve guided percutaneous coronary intervention (FFR-guided PCI) is associated with reduced ischemic myocardium compared with angiography-guided PCI. BACKGROUND: Although FFR-guided PCI has been shown to improve outcomes, it remains unclear if it reduces the extent of ischemic myocardium at risk compared with angiography-guided PCI. METHODS: We evaluated 380 patients (190 FFR-guided PCI cases and 190 propensity-matched controls) who underwent PCI from 2009 to 2014. Clinical, laboratory, angiographic, stress testing, and major adverse cardiac events [MACE] (all-cause mortality, recurrence of MI requiring PCI, stroke) data were collected. RESULTS: Mean age was 63 +/- 11 years; the majority of patients were males (76%) and Caucasian (77%). Median duration of follow up was 3.4 [Range: 1.9, 5.0] years. Procedural complications including coronary dissection (2% vs. 0%, P = .12) and perforation (0% vs. 0%, P = 1.00) were similar between FFR-guided and angiography guided PCI patients. FFR-guided PCI patients had lower unadjusted (14.7% vs. 23.2%, P = .04) and adjusted [OR = 0.58 (95% CI: 0.34-0.98)] risk of repeat revascularization at one year. FFR-guided PCI patients were less likely (23% vs. 32%, P = .02) to have ischemia and had lower (5.9% vs. 21.1%, P < .001) ischemic burden (moderate-severe ischemia) on post-PCI stress testing. Presence of ischemia post-PCI remained a strong predictor of MACE [OR = 2.14 (95%CI: 1.28 3.60)] with worse survival compared to those without ischemia (HR = 1.63 (95% CI: 1.06-2.51). CONCLUSION: Compared with angiography-guided PCI, FFR-guided PCI results in less repeat revascularization and a lower incidence of post PCI ischemia translating into improved survival, without an increase in complications. PMID- 29405554 TI - Six-month outcome after transcatheter edge-to-edge repair of severe tricuspid regurgitation in patients with heart failure. AB - AIMS: Severe tricuspid regurgitation (TR) is common in patients with right-sided heart failure (HF) and causes substantial morbidity and mortality. Treatment options beyond medical therapy are limited for high-risk patients. Transcatheter edge-to-edge tricuspid valve (TV) repair showed procedural safety and short-term efficacy. Impact on mid-term outcome is unclear. This dual-centre observational study evaluates the mid-term safety, efficacy and clinical outcome after edge-to edge TV repair for severe TR in patients with HF. METHODS AND RESULTS: Overall, 50 patients with right-sided HF and severe TR were treated with the transcatheter edge-to-edge repair technique; 14 patients were treated for isolated TR and 36 patients for combined mitral regurgitation (MR) and TR. At 6-month follow-up (available for 98% of patients), a persistent reduction of at least one echocardiographic TR grade was achieved in 90% of patients and New York Heart Association class improved in 79% of patients. The 6-minute walk distance increased by 44% (+84 m, P < 0.001), the median N-terminal pro-B-type natriuretic peptide decreased by 30% (from 3625 to 2526 pg/mL, P = 0.002), and the quality of life score improved by 16% (decrease of 6 points in the Minnesota Living with Heart Failure Questionnaire score, P = 0.056). The improvements were comparable in patients undergoing isolated TR or combined MR and TR treatment. During follow up, 8 patients died, 14 were hospitalized for worsening of HF, 2 underwent TV surgery, and 2 received a second TV clip procedure. CONCLUSIONS: Transcatheter edge-to-edge TV repair for severe TR is safe and effective in reducing TR. It appears to be associated with improved clinical outcome in the majority of patients. PMID- 29405555 TI - Solid pseudopapillary tumor of pancreas: A case report and review of genetic features. PMID- 29405556 TI - Heparin use for diagnostic cardiac catheterization with a radial artery approach: An international survey of practice patterns. AB - OBJECTIVES: We aimed to describe global practice patterns of unfractionated heparin (UFH) use for diagnostic transradial cardiac catheterization. BACKGROUND: The use of the radial artery approach for cardiac catheterization is increasing globally. Limited contemporary data exist to support the use or optimal dosing of UFH to prevent radial artery occlusion (RAO) and other thromboembolic complications. METHODS: We performed a web-based international survey of 450 interventional cardiologists from 34 countries. We collected information regarding the experience and use of UFH for diagnostic transradial cardiac catheterization. RESULTS: The survey was conducted between June and July 2016 and was completed by 227 (50.4%) interventional cardiologists. Overall, 83.3% performed >75% of their coronary angiograms via a radial approach, with the plurality (41.9%) having 10-20 years of clinical experience. Of all respondents, 7.5% did not use UFH for routine diagnostic transradial heart catheterization. Of the 92.5% who did use UFH, it was preferentially administered intra-arterially by 60% and intravenously by 40%. The majority (62.6%) of interventionalists used a fixed UFH dose with 5,000 IU being the most common dose (used in 48%). For those using a weight-based UFH (50 IU/kg) dosing regimen for diagnostic procedures (36.1%), the administered UFH dose ranged from 2,000 up to 10,000 IU. CONCLUSIONS: Despite the lack of firm evidence, the majority of interventional cardiologists who participated in the survey use UFH to prevent RAO for diagnostic transradial coronary angiography. However, there exist large practice disparities with regards to dose and route of administration. Given this knowledge gap, a dedicated randomized trial is warranted. PMID- 29405557 TI - Tricuspid regurgitation as a complication of Edwards Sapien XT valve implantation in pulmonary position a problem to deal with. AB - Nowadays, percutaneous pulmonary valve implantation (PPVI) is a suitable alternative to surgical procedure in patients with right ventricle outflow tract dysfunction. Two valves are currently available for PPVI: the Melody valve and the Edwards Sapien valve. The following complications may occur: coronary artery compression, deformation of the aortic root, stent or valve embolization, damage of distal pulmonary arteries, access site injuries. Here, we report on three cases of severe tricuspid regurgitation due to valvular and subvalvular apparatus damage during Edwards Sapien XT valve implantation. PMID- 29405558 TI - Biocompatible porous titanium scaffolds produced using a novel space holder technique. AB - We describe a new fabrication strategy for production of porous titanium scaffolds for skeletal implants which provides a promising new approach to repair and remodel damaged bone tissue. The new strategy involves powder sintering of titanium powder, employing pharmaceutical sugar pellets as temporary space holders, to facilitate production of porous scaffolds with structures optimized for mechanical performance and osseointegration of implants. The spherical sugar pellets, with controlled size fractions and excellent biocompatibility, are easily removed by dissolution prior to sintering providing an ideal space holder material for controlled synthesis of titanium scaffolds with desired porosities and pore sizes. The scaffolds contain pores with high degrees of sphericity and interconnectivity which impart excellent mechanical properties and superior biocompatibility to the structures. Scaffolds with 40% porosity and a pore size range of 300-425 um exhibited an effective Young's modulus of 16.4 +/- 3.5 GPa and strength of 176 +/- 6 MPa, which closely mimics the properties of human bone, and were also able to support cell adhesion, viability and spreading in cell culture tests. Porous titanium scaffolds manufactured by this approach have excellent potential for hard tissue engineering applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2796-2806, 2018. PMID- 29405559 TI - Classifying Degraded Modern Polymeric Museum Artefacts by Their Smell. AB - The use of VOC analysis to diagnose degradation in modern polymeric museum artefacts is reported. Volatile organic compound (VOC) analysis is a successful method for diagnosing medical conditions but to date has found little application in museums. Modern polymers are increasingly found in museum collections but pose serious conservation difficulties owing to unstable and widely varying formulations. Solid-phase microextraction gas chromatography/mass spectrometry and linear discriminant analysis were used to classify samples according to the length of time they had been artificially degraded. Accuracies in classification of 50-83 % were obtained after validation with separate test sets. The method was applied to three artefacts from collections at Tate to detect evidence of degradation. This approach could be used for any material in heritage collections and more widely in the field of polymer degradation. PMID- 29405560 TI - Osteostimulative calcium phosphosilicate biomaterials partially restore the cytocompatibility of decontaminated titanium surfaces in a peri-implantitis model. AB - Bacterial peri-implant biofilms, and the chemotherapeutics for their removal alter titanium surface cytocompatibility. In this study we aimed to assess the adjunctive use of an osteostimulative biomaterial utilizing a peri-implantitis model under the hypothesis that it will increase cell migration towards treated titanium surfaces. Acid-etched titanium surfaces were inoculated with a multi species biofilm model and treated with 1.5% NaOCl in a previously characterized in vitro peri-implantitis model. Cell migration of MG63 cells towards the treated titanium surface (CTRL) was significantly reduced following inoculation with biofilm and chemotherapeutic treatment as compared to sterile controls. Addition of a tricalcium phosphate biomaterial (TCP) as a control for Ca+2 had a small non significant effect, while BG significantly increased MG63 chemotaxis to titanium to levels comparable to sterile (STE). Similarly, cell viability at 5 days was increased in BG and TCP as compared to CTRL. SEM imaging confirmed the improved cytocompatibility of BG and TCP surfaces as compared to CTRL. Osteostimulative BG exhibited a strong chemotactic effect to osteoblasts, which was stronger than what was expected due to the chemotactic effect of Ca+2 alone (TCP). In addition, substantially increased cell attachment and viability was found on treated implant surfaces as compared to CTRL. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2645-2652, 2018. PMID- 29405561 TI - Immune response to human telomerase reverse transcriptase-derived helper T cell epitopes in hepatocellular carcinoma patients. AB - BACKGROUND AND AIMS: Human telomerase reverse transcriptase is a catalytic enzyme involved in telomere elongation. It is expressed in many tumours, including hepatocellular carcinoma. The purpose of the present study was to identify major histocompatibility complex class II-restricted helper T cell epitopes derived from human telomerase reverse transcriptase in patients with hepatocellular carcinoma. METHODS: TEPITOPE software was used to predict helper T cell epitopes based on the entire amino acid sequence of human telomerase reverse transcriptase, and peptides were synthesized based on the predicted sequence. Interferon (IFN)-gamma enzyme linked immunospot assay was performed to examine the T cell response to each of the synthesized peptides in peripheral blood mononuclear cells. Furthermore, the peptides were labelled with fluorescein isothiocyanate to test their binding affinity for major histocompatibility complex class II molecules. Lastly, the association between patient characteristics and the level of immune response to these epitopes was examined. RESULTS: Positive T cell response (>10% enzyme linked immunospot positivity) was detected against 4 of 10 peptides. Among all peptides, positive T cell response to the hTERT68 peptide was detected most frequently. While hTERT68 was HLA DRB1*0405-restricted, it also bound to other MCH class II molecules. Positive helper T cell response was detected most frequently in hepatocellular carcinoma patients with a low serum alpha-foetoprotein level. Several treatments for hepatocellular carcinoma enhanced the immune response against the peptides. CONCLUSION: Our findings indicate that helper T cell epitopes identified in the present study may be useful to investigate immune responses and for immunotherapy in hepatocellular carcinoma patients. PMID- 29405562 TI - Low BMI is correlated with increased TGF-beta and IL-10 mRNA levels in the peripheral blood of breast cancer patients. AB - Transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and forkhead box P3 (Foxp3) have important roles in breast cancer development. Previous studies confirmed a correlation between these immune molecules and tumor characteristics, but their association with nutritional status in breast cancer is largely unknown. We aimed to investigate the association between body mass index (BMI), hemoglobin, total protein, albumin, globulin (GLB), albumin/GLB ratio (AGR), pre-albumin, prognostic nutritional index, and TGF-beta, IL-10, and Foxp3 mRNA expression in patients with breast cancer. Quantitative real-time PCR was used to detect the mRNA expression of TGF-beta, IL-10, and Foxp3 in the peripheral blood of 107 patients with breast cancer and 21 healthy controls. We found that TGF-beta mRNA levels were 2.6-fold, 3.2-fold, and 2.3-fold higher in patients with low BMI (<23), low AGR, and high GLB, respectively, than in their counterparts (P < 0.05). In addition, IL-10 mRNA expression levels in patients with normal BMI (<23) were 2.8-fold and 3.5-fold higher than in those who were overweight (23<= BMI <25) and obese (BMI >= 25), respectively (P < 0.05). In addition, TGF-beta, IL-10, and Foxp3 mRNA levels were significantly higher in patients with breast cancer than in healthy controls (P < 0.05). In summary, our results suggest that nutritional status, especially BMI, may strongly affect systematic immune function in patients with breast cancer. (c) 2018 IUBMB Life, 70(3):237-245, 2018. PMID- 29405563 TI - Early involvement of the emergency department pharmacist in severe trauma. PMID- 29405564 TI - Transcatheter pledget-assisted suture tricuspid annuloplasty (PASTA) to create a double-orifice valve. AB - OBJECTIVES: Pledget-assisted suture tricuspid valve annuloplasty (PASTA) is a novel technique using marketed equipment to deliver percutaneous trans-annular sutures to create a double-orifice tricuspid valve. BACKGROUND: Tricuspid regurgitation is a malignant disease with high surgical mortality and no commercially available transcatheter solution in the US. METHODS: Two iterations of PASTA were tested using trans-apical or trans-jugular access in swine. Catheters directed paired coronary guidewires to septal and lateral targets on the tricuspid annulus under fluoroscopic and echocardiographic guidance. Guidewires were electrified to traverse the annular targets and exchanged for pledgeted sutures. The sutures were drawn together and knotted, apposing septal and lateral targets, creating a double orifice tricuspid valve. RESULTS: Twenty two pigs underwent PASTA. Annular and chamber dimensions were reduced (annular area, 10.1 +/- 0.8 cm2 to 3.8 +/- 1.5 cm2 (naive) and 13.1 +/- 1.5 cm2 to 6.2 +/- 1.0 cm2 (diseased); septal-lateral diameter, 3.9 +/- 0.3 mm to 1.4 +/- 0.6 mm (naive) and 4.4 +/- 0.4 mm to 1.7 +/- 1.0 mm (diseased); and right ventricular end-diastolic volume, 94 +/- 13 ml to 85 +/- 14 ml (naive) and 157 +/- 25 ml to 143 +/- 20 ml (diseased)). MRI derived tricuspid regurgitation fraction fell from 32 +/- 12% to 4 +/- 5%. Results were sustained at 30 days. Pledget pull-through force was five-fold higher (40.6 +/- 11.7N vs 8.0 +/- 2.6N, P < .01) using this strategy compared to single puncture techniques used to anchor current investigational devices. Serious complications were related to apical access. CONCLUSIONS: PASTA reduces annular dimensions and tricuspid regurgitation in pigs. It may be cautiously applied to selected patients with severe tricuspid regurgitation and no options. This is the first transcatheter procedure, to our knowledge, to deliver standard pledgeted sutures to repair cardiac pathology. PMID- 29405565 TI - Atomic Layers of MoO2 with Exposed High-Energy (010) Facets for Efficient Oxygen Reduction. AB - Although 2D nanocrystals with exposed high-energy facets are highly desired in the field of catalysts due to their anticipant high catalytic activities, they are difficult to be gained. Here, atomic layers of metallic molybdenum dioxide (MoO2 ) with primarily exposed high-energy (010) facet are achieved via a facile carbothermic reduction approach. The resultant MoO2 exhibits single-crystalline, monoclinic, and ultrathin features with nearly 100% exposed (010) facet, which can significantly reduce reaction barriers toward the oxygen reduction reaction. As a consequence, the atomic layers of MoO2 exhibit high electrocatalytic activity, excellent tolerance to methanol, and good stability for the oxygen reduction reaction in alkaline electrolyte, superior to commercial Pt/C catalysts. It is believed that such new transition metal oxide catalysts with exposed high-energy facets have broad applications in the areas of energy storage and conversions. PMID- 29405567 TI - The development of CotA mediator cocktail system for dyes decolorization. AB - AIMS: The increasing use of dyes leads to serious environmental concerns, it is significant to explore eco-friendly and economic approaches for dye decolorization. This study aimed to develop mediator cocktail (AS and ABTS) for enhancing the capability of laccase-mediator system in the removal of dyes. METHODS AND RESULTS: By mediator screening, the mediators of ABTS and AS (ABTS, 2, 2'-azino-bis-(3-ethylbenzothiazo-thiazoline-6-sulphonic acid); AS, acetosyringone) were combined for dyes decolorization. The Box-Behnken Design and response surface analysis was performed to optimize experiment conditions. Comparing the CotA-ABTS-AS cocktail system with CotA-single mediator system showed that the coupling of ABTS and AS could increase the decolorization rate 15 times higher, save a third of the cost and shorten the reaction time by 50%. In addition, our studies revealed that sequential oxidation may occur in CotA-ABTS AS system. CONCLUSIONS: Compared with CotA laccase-single mediator system, the CotA-ABTS-AS cocktail system showed advantages including higher efficiency, lower cost and shorter reaction time. SIGNIFICANCE AND IMPACT OF THE STUDY: This was the first report on the dyes decolorization by laccase mediator cocktail system. These results paved the curb for the application of laccase mediator system in various industrial processes. PMID- 29405568 TI - Microfabricated Probes for Studying Brain Chemistry: A Review. AB - Probe techniques for monitoring in vivo chemistry (e.g., electrochemical sensors and microdialysis sampling probes) have significantly contributed to a better understanding of neurotransmission in correlation to behaviors and neurological disorders. Microfabrication allows construction of neural probes with high reproducibility, scalability, design flexibility, and multiplexed features. This technology has translated well into fabricating miniaturized neurochemical probes for electrochemical detection and sampling. Microfabricated electrochemical probes provide a better control of spatial resolution with multisite detection on a single compact platform. This development allows the observation of heterogeneity of neurochemical activity precisely within the brain region. Microfabricated sampling probes are starting to emerge that enable chemical measurements at high spatial resolution and potential for reducing tissue damage. Recent advancement in analytical methods also facilitates neurochemical monitoring at high temporal resolution. Furthermore, a positive feature of microfabricated probes is that they can be feasibly built with other sensing and stimulating platforms including optogenetics. Such integrated probes will empower researchers to precisely elucidate brain function and develop novel treatments for neurological disorders. PMID- 29405566 TI - Nomenclature for factors of the HLA system, update December 2017. PMID- 29405570 TI - Functionalized Graphdiyne Nanowires: On-Surface Synthesis and Assessment of Band Structure, Flexibility, and Information Storage Potential. AB - Carbon nanomaterials exhibit extraordinary mechanical and electronic properties desirable for future technologies. Beyond the popular sp2 -scaffolds, there is growing interest in their graphdiyne-related counterparts incorporating both sp2 and sp bonding in a regular scheme. Herein, we introduce carbonitrile functionalized graphdiyne nanowires, as a novel conjugated, one-dimensional (1D) carbon nanomaterial systematically combining the virtues of covalent coupling and supramolecular concepts that are fabricated by on-surface synthesis. Specifically, a terphenylene backbone is extended with reactive terminal alkyne and polar carbonitrile (CN) moieties providing the required functionalities. It is demonstrated that the CN functionalization enables highly selective alkyne homocoupling forming polymer strands and gives rise to mutual lateral attraction entailing room-temperature stable double-stranded assemblies. By exploiting the templating effect of the vicinal Ag(455) surface, 40 nm long semiconducting nanowires are obtained and the first experimental assessment of their electronic band structure is achieved by angle-resolved photoemission spectroscopy indicating an effective mass below 0.1m0 for the top of the highest occupied band. Via molecular manipulation it is showcased that the novel oligomer exhibits extreme mechanical flexibility and opens unexplored ways of information encoding in clearly distinguishable CN-phenyl trans-cis species. Thus, conformational data storage with density of 0.36 bit nm-2 and temperature stability beyond 150 K comes in reach. PMID- 29405571 TI - Characterization of Candida spp. interference on the Sysmex XN-1000 body fluid mode. PMID- 29405572 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 7/2018. PMID- 29405569 TI - Nomenclature for factors of the HLA system, update October 2017. PMID- 29405573 TI - From Symmetry Breaking to Unraveling the Origin of the Chirality of Ligated Au13 Cu2 Nanoclusters. AB - A general method, using mixed ligands (here diphosphines and thiolates) is devised to turn an achiral metal cluster, Au13 Cu2 , into an enantiomeric pair by breaking (lowering) the overall molecular symmetry with the ligands. Using an achiral diphosphine, a racemic [Au13 Cu2 (DPPP)3 (SPy)6 ]+ was prepared which crystallizes in centrosymmetric space groups. Using chiral diphosphines, enantioselective synthesis of an optically pure, enantiomeric pair of [Au13 Cu2 ((2r,4r)/(2s,4s)-BDPP)3 (SPy)6 ]+ was achieved in one pot. Their circular dichroism (CD) spectra give perfect mirror images in the range of 250-500 nm with maximum anisotropy factors of 1.2*10-3 . DFT calculations provided good correlations with the observed CD spectra of the enantiomers and, more importantly, revealed the origin of the chirality. Racemization studies show high stability (no racemization at 70 degrees C) of these chiral nanoclusters, which hold great promise in applications such as asymmetry catalysis. PMID- 29405574 TI - She is in science to stay! PMID- 29405575 TI - Epidemiology of seasonal influenza in the Middle East and North Africa regions, 2010-2016: Circulating influenza A and B viruses and spatial timing of epidemics. AB - BACKGROUND: There is a limited knowledge regarding the epidemiology of influenza in Middle East and North Africa. OBJECTIVES: We described the patterns of influenza circulation and the timing of seasonal epidemics in countries of Middle East and North Africa. METHODS: We used virological surveillance data for 2010 2016 from the WHO FluNet database. In each country, we calculated the median proportion of cases that were caused by each virus type and subtype; determined the timing and amplitude of the primary and secondary peaks; and used linear regression models to test for spatial trends in the timing of epidemics. RESULTS: We included 70 532 influenza cases from seventeen countries. Influenza A and B accounted for a median 76.5% and 23.5% of cases in a season and were the dominant type in 86.8% and 13.2% of seasons. The proportion of influenza A cases that were subtyped was 85.9%, while only 4.4% of influenza B cases were characterized. For most countries, influenza seasonality was similar to the Northern Hemisphere, with a single large peak between January and March; exceptions were the countries in the Arabian Peninsula and Jordan, all of which showed clear secondary peaks, and some countries had an earlier primary peak (in November-December in Bahrain and Qatar). The direction of the timing of influenza activity was east to west and south to north in 2012-2013 and 2015-2016, and west to east in 2014-2015. CONCLUSIONS: The epidemiology of influenza is generally uniform in countries of Middle East and North Africa, with influenza B playing an important role in the seasonal disease burden. PMID- 29405576 TI - Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor. AB - SCOPE: Aberrant vascular smooth muscle cell (VSMC) proliferation is involved in atherosclerotic plaque formation and restenosis. Mediterranean spices have been reported to confer cardioprotection, but their direct influence on VSMCs has largely not been investigated. This study aims at examining rosmarinic acid (RA) and 11 related constituents for inhibition of VSMC proliferation in vitro, and at characterizing the most promising compound for their mode of action and influence on neointima formation in vivo. METHODS AND RESULTS: RA, rosmarinic acid methyl ester (RAME), and caffeic acid methyl ester inhibit VSMC proliferation in a resazurin conversion assay with IC50 s of 5.79, 3.12, and 6.78 um, respectively. RAME significantly reduced neointima formation in vivo in a mouse femoral artery cuff model. Accordingly, RAME leads to an accumulation of VSMCs in the G0 /G1 cell-cycle phase, as indicated by blunted retinoblastoma protein phosphorylation upon mitogen stimulation and inhibition of cyclin-dependent kinase 2 in vitro. CONCLUSION: RAME represses PDGF-induced VSMC proliferation in vitro and reduces neointima formation in vivo. These results recommend RAME as an interesting compound with VSMC-inhibiting potential. Future metabolism and pharmacokinetics studies might help to further evaluate the potential relevance of RAME and other spice-derived polyphenolics for vasoprotection. PMID- 29405577 TI - Impacts of Dietary Pleurotus eryngii Polysaccharide on Nutrient Digestion, Metabolism, and Immune Response of the Small Intestine and Colon-An iTRAQ-Based Proteomic Analysis. AB - Pleurotus eryngii polysaccharides have been shown to exert significant biological activities to the host. However, few studies have been conducted on its effects on gastrointestinal tract (GIT) health alteration. In the present study, small intestinal and colonic proteome alterations generated by dietary supplementation with a novel homogeneous P. eryngii polysaccharide (PEP) in C57BL/6 mice, based on the isobaric tag for relative and absolute quantification (iTRAQ) proteomics, are investigated. Compared to the control group, PEP supplementation result in a total of 113 and 194 significant differential proteins (DPs) in the small intestine and colon, respectively. Interestingly, DPs in small intestine are mainly related to the transport and biosynthetic process, along with the digestion and absorption pathway of nutrients, whereas the colonic DPs are significantly found participating in numerous metabolic processes. Moreover, the alterations of some DPs in small intestine and colon are speculated to correlate with the colonic microbiota structure and are involved in the regulation of host immune response. Subsequently, some critical DPs of small intestine and colon are selected and validated by Western blotting. The current research facilitated the generation of potential insights into the health benefit activities and functional mechanisms of polysaccharides from P. eryngii. PMID- 29405578 TI - Pre-analytical stability of coagulation parameters in plasma stored at room temperature. AB - INTRODUCTION: Haemostasis testing is influenced by many pre-analytical variables, such as storage time and temperature, which can affect the stability of coagulation factors and influence the results of coagulation assays. We investigated the stability of haemostasis tests after storage of aliquoted plasma at RT, including the variability of measurement principle and reagent used for determination. METHODS: Blood samples from 20 healthy volunteers were obtained, processed to PPP and aliquoted. Aliquots were stored at RT for 0 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours. PT, aPTT, fibrinogen, D Dimers and coagulation factors (FII, FV, FVII, FX, FVIII, FIX, FXI, FXII) were determined by STA-R Max(r) and ACL-TOP(r) . VWF:Ag and vWF:RCo were determined by AcuStar(r) . Clinically relevant changes, compared to the initial measurement, were denoted as a percentage change of > 10% according to the 99% CI. RESULTS: For both analysers, a clinically relevant change of > 10% was observed for FV after 2 hours, FVIII after 4 hours and for aPTT, FII, FVII, FX and FXII after 48 hours of storage at RT. Statistically significant, but no clinically relevant differences were observed after 48-hours storage for PT, fibrinogen and FIX. D Dimers, FXI, vWF:Ag and vWF:RCo were found stable up to 48 hours at RT. CONCLUSION: Overall, compared to the limits given by the current CLSI guidelines, for most coagulation parameters investigated in this study a longer storage period could be accepted. Time intervals for FVIII and FV dosage were shorter than recommended by the CLSI guidelines. For PT determination, our findings were consistent. PMID- 29405579 TI - A Cisplatin-Loaded Immunochemotherapeutic Nanohybrid Bearing Immune Checkpoint Inhibitors for Enhanced Cervical Cancer Therapy. AB - The efficacy of conventional chemotherapy is hindered by cancer cell escape from the immune system. A multifunctional nanohybrid system is reported for effective immunochemotherapy against cervical cancer. This nanohybrid contains both immune checkpoint inhibitor and cisplatin anticancer prodrug, showing improved cellular accumulation and increased binding of Pt to DNA and resulting in elevated apoptosis than using cisplatin alone when tested in cervical cancer cells. The immune checkpoint inhibitor enables the inhibition of indoleamine-2,3-dioxygenase and reverses immunosuppressive T cells to recognize cancer cells, leading to T cell proliferation and activation, cancer cell cycle arrest, and ultimately increased cancer cell death. The nanohybrid is also active in vivo against the growth of human cervical tumors. Overall, a strategy is provided using a multifunctional nanohybrid system to boost the antitumor activity of cisplatin. PMID- 29405580 TI - In vitro and in vivo characterization of modulation of the vacuolar cation channel TRPY1 from Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae possesses a transient receptor potential (TRP) channel homolog TRPY1 in its vacuolar membrane, considered to be an ancestral TRP channel. So far, studies have focused on the channel properties of TRPY1, but its regulation and physiologic role remained to be elucidated. Here, we investigated TRPY1 channel function in vitro and in vivo. Patch-clamp recording of TRPY1 in yeast vacuolar membranes showed that Ca2+ on the lumen side inhibited TRPY1 mediated channel activity, whereas luminal Zn2+ increased the currents. TRPY1 was activated in the presence of a reducing agent, 2-mercaptoethanol. The cysteine at position 624 was identified as the target for this activating action. This activation was independent of the presence of cytosolic Ca2+ . The amplitude of TRPY1-mediated current was reduced by addition of phosphatidylinositol 3 phosphate on the cytosolic side but not by phosphatidylinositol (PI) or phosphatidylinositol 3,5-phosphate. Measurement of the transient Ca2+ increase in response to hyper-osmotic shock in several yeast mutants defective in different steps of the PI phosphate biogenesis pathway supported this interpretation. Addition of a microtubule inhibitor strongly decreased the transient cytosolic Ca2+ increase upon hyper-osmotic shock. Taken together, the data indicate that the vacuolar TRPY1 Ca2+ channel mediates the perception of cytosolic signals that were induced by external changes in osmolarity, and participates in the modulation of cytosolic calcium signaling through Ca2+ release from the vacuole to maintain intracellular Ca2+ homeostasis in yeast. PMID- 29405581 TI - Predicting the Helical Sense of Poly(phenylacetylene)s from their Electron Circular Dichroism Spectra. AB - The calculated ECD spectrum (time-dependent density functional theory TD-DFT) for small oligomers of polyphenylacetylenes (PPAs) show a very good match with the experimental spectra of the PPA polymers, particularly with the first Cotton band associated to the helical sense of the internal polyenic backbone. This has been proven with a series of PPAs representative of cis-cisoidal, cis-transoidal, compressed and stretched polyene backbones, with identical or opposite internal/external rotational senses and allows the prediction of the helical sense of the internal helix of a PPA directly from its CD spectra. PMID- 29405582 TI - Long-term visual outcome in a Danish population of patients with idiopathic intracranial hypertension. AB - PURPOSE: Idiopathic intracranial hypertension (IIH) is characterized by raised intracranial pressure (ICP), normal cerebrospinal composition and exclusion of alternative causes to increased ICP. The aim of this study was to evaluate long term visual outcome in a Danish population of IIH patients. METHODS: Retrospective chart review of 41 women diagnosed with IIH between June 2007 and March 2013. Best-corrected visual acuity (BCVA), colour vision, grade and type of visual field (VF) defects and grade of papilloedema according to the Modified Frisen Score were recorded at baseline visit (V0), 2-6 months (V1) and 13 months follow-up visit (V2) from time of diagnosis. RESULTS: Best-corrected visual acuity (BCVA) was reduced in 25% of eyes at V0, in 10% at V1 and in 15% at V2. Colour vision was barely affected. Visual field (VF) was affected (>grade 0) in 87% of eyes at V0 and VF defect grade significantly improved by 0.58 at V1 (p value <0.0001) and by 0.55 at V2 (p-value <0.001). The most common type of VF defect at V0 was a nerve fibre layer defect (56.4%), and the second most common type was an enlarged blind spot (20.5%). There was no correlation between BCVA and VF defect type. Mean grade of papilloedema decreased from 2.2 at V0 to 0.5 at V2. The grade of papilloedema at V2 was not significantly related to the severity of papilloedema at V0 (p-values 0.65 and 0.48). CONCLUSION: Idiopathic intracranial hypertension (IIH) is associated with long-term loss of visual function, and relevant treatment strategies need to be improved. PMID- 29405583 TI - Label-free quantification of the effects of lithium niobate polarization on cell adhesion via holographic microscopy. AB - The surface of a c- cut ferroelectric crystal at room temperature is characterized by the so-called screening surface charges, able to compensate the charge due to the spontaneous polarization. Recently, these charges inspired the investigation of the interaction affinity of live cells with lithium niobate and lithium tantalate crystals. However, different knowledge gaps still remain that prevent a reasonable application of these materials for biological applications. Here, a label-free holographic total internal reflection microscopy is shown; the technique is able to evaluate quantitatively the contact area of live fibroblast cells adhering onto the surface of a ferroelectric lithium niobate crystal. The results show values of contact area significantly different between cells adhering onto the positive or negative face of the crystal. This reinforces the reasons for using the polarization charge of these materials to study and/or control cellular processes and, thus, to develop an innovative platform based on polar dielectric functional substrates. PMID- 29405584 TI - A red-emitting indolium fluorescence probe for membranes - flavonoids interactions. AB - The red-emitting indolium derivative compound (E)-2-(4-(diphenylamino)styryl) 1,3,3-trimethyl-3H-indol-1-ium iodide (H3) was demonstrated as a sensitive membrane fluorescence probe. The probe located at the interface of liposomes when mixed showed much fluorescence enhancement by inhibiting the twisted intramolecular charge transfer state. After ultrasonic treatment, it penetrated into lipid bilayers with the emissions leveling off and a rather large encapsulation efficiency (71.4%) in liposomes. The zeta-potential and particle size measurement confirmed that the charged indolium group was embedded deeply into lipid bilayers. The probe was then used to monitor the affinities of antioxidant flavonoids for membranes. It was verified that quercetin easily interacted with liposomes and dissociated the probe from the internal lipid within 60 s under the condition of simply mixing. The assessment of binding affinities of six flavonoids and the coincident results with their antioxidation activities indicated that it was a promising membrane probe for the study of drug bio-affinities. PMID- 29405585 TI - Mindfulness meditation improves metabolic profiles in healthy and depressive participants. PMID- 29405586 TI - Nutrient sensing, growth and senescence. AB - Cell growth is dictated by a wide range of mitogenic signals, the amplitude and relative contribution of which vary throughout development, differentiation and in a tissue-specific manner. The ability to sense and appropriately respond to changes in mitogens is fundamental to control cell growth, and reduced responsiveness of nutrient sensing pathways is widely associated with human disease and ageing. Cellular senescence is an important tumour suppressor mechanism that is characterised by an irreversible exit from the cell cycle in response to replicative exhaustion or excessive DNA damage. Despite the fact that senescent cells can no longer divide, they remain metabolically active and display a range of pro-growth phenotypes that are supported in part by the mTORC1 autophagy signalling axis. As our understanding of the basic mechanisms of controlling mTORC1-autophagy activity and cell growth continues to expand, we are able to explore how changes in nutrient sensing contribute to the acquisition and maintenance of cellular senescence. Furthermore, while the protective effect of senescence to limit cellular transformation is clear, more recently, the age related accumulation of these pro-inflammatory senescent cells has been shown to contribute to a decline in organismal fitness. We will further discuss whether dysregulation of nutrient sensing pathways can be targeted to promote senescent cell death which would have important implications for healthy ageing. PMID- 29405588 TI - Radical Alkyne peri-Annulation Reactions for the Synthesis of Functionalized Phenalenes, Benzanthrenes, and Olympicene. AB - Radical cyclization reactions at a peri position were used for the synthesis of polyaromatic compounds. Depending on the choice of reaction conditions and substrate, this flexible approach led to Bu3 Sn-substituted phenalene, benzanthrene, and olympicene derivatives. Subsequent reactions with electrophiles provided synthetic access to previously inaccessible functionalized polyaromatic compounds. PMID- 29405589 TI - Development of Clay-Based Films. AB - Phyllosilicate (clay) is used as a filler to improve the thermal stability and gas barrier properties of plastic films. However, few film preparation trials used clays as the main component. Many researchers have studied clay-based films (CBFs) that are heat-resistant and have high gas barrier properties against various gases (such as oxygen, water vapor, and hydrogen) over a wide range of temperatures. An organic binder improves the film toughness, but increases gas permeation. CBFs are obtained by solution casting and show excellent incombustibility and electrical insulation. Moreover, transparent films, e. g. for optoelectronic applications, can be prepared using synthetic clay, which does not contain colored impurities. The water vapor barrier properties of CBFs were achieved using reduced-charge smectite. Applications of CBF materials include food packaging, solar cell back sheets, hydrogen tanks, gaskets, water vapor barrier display films, substrates for printed electronics, thermal insulation, and electric insulation. Recent achievements in the field and future prospects are discussed. PMID- 29405587 TI - Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin. AB - A-lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A-lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease associated mutant form progerin (LADelta50), whose expression underlies the development of Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose- and E3 ligase-dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic-lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A-lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2 lamin A axis in age-related diseases such as cancer. PMID- 29405590 TI - From Conventional Lewis Acids to Heterogeneous Montmorillonite K10: Eco-Friendly Plant-Based Catalysts Used as Green Lewis Acids. AB - The concept of green chemistry began in the USA in the 1990s. Since the publication of the 12 principles of this concept, many reactions in organic chemistry have been developed, and chemical products have been synthesized under environmentally friendly conditions. Lewis acid mediated synthetic transformations are by far the most numerous and best studied. However, the use of certain Lewis acids may cause risks to environmental and human health. This Review discusses the evolution of Lewis acid catalyzed reactions from a homogeneous liquid phase to the solid phase to yield the expected organic molecules under green, safe conditions. In particular, recent developments and applications of biosourced catalysts from plants are highlighted. PMID- 29405591 TI - Cultural factors influencing Japanese nurses' assertive communication. Part 1: Collectivism. AB - Culture influences the way health-care professionals communicate with each other and their ability to relate to colleagues in an assertive manner. Cultural barriers can also make it difficult for nurses to speak up even when they have concerns about patient safety. An understanding of the potential impact of cultural factors is therefore needed when developing assertiveness communication training programs. This paper presents the findings from a study that explored Japanese nurses' perceptions of how culture and values impact assertive communication in health care. Semistructured interviews with 23 registered nurses were undertaken, and data were analyzed using directed content analysis. Two major themes were identified: collectivism and hierarchy/power. In the present study, we discuss the cultural values related to collectivism that included four categories of "wa" (harmony), "uchi to soto" (inside and outside), implicit communication/ambiguity, and "nemawashi" (groundwork). The findings highlight the impact of culture on nurses' assertive communication behaviors and can be used to inform the design of culturally-appropriate assertiveness communication training programs for Japanese nurses working both within their own country or internationally. PMID- 29405592 TI - Increased mortality in octogenarians treated for lifestyle limiting claudication. AB - OBJECTIVE: Treatment for lifestyle limiting claudication (LLC) that is due to infra-inguinal peripheral artery disease relies on either bypass, angioplasty, and/or stenting. Given the enthusiasm and shift toward more endovascular therapy for treatment of LLC, we sought to analyze whether octogenarians benefit from infra-inguinal interventions in the same manner as their younger counterparts. METHODS: We identified all patients admitted for elective treatment of LLC from the Nationwide Inpatient Sample from 2003 to 2012, who received open surgical or endovascular intervention for infra-inguinal peripheral arterial disease. These patients were divided into two groups including those between the ages 60-80 years (younger cohort) and those older than 80 years (octogenarians). Primary end points included morbidity and mortality and the secondary end-points were length of hospital stay (LOS) and disposition after dismissal. RESULTS: Among 59,323 discharges identified in the dataset, 34,658 (58%) were males. There were 50,323 (85%) patients in the younger cohort and 9,000 (15%) octogenarians. The mean age was 69.9 +/- 5.7 years and 84.2 +/- 3.0 years for the younger cohort and octogenarians, respectively. The mean Charlson comorbidity index (CCI) was higher in our younger cohort (2.1 +/- 1.1, P < 0.001). Octogenarians mainly treated with open surgery prior to 2004 are now treated endovascularly and this trend has remained stable. The younger cohort's treatment modality has fluctuated through the study period and most recently is treated mainly with open surgery. The rate of acute kidney injury, exacerbation of congestive heart failure and mortality was higher in octogenarians (P < 0.001). The rate of infectious wound complications was higher in the younger cohort (P < 0.05). Octogenarians have longer LOS and are dismissed in higher percentage to a skilled nursing facility (P < 0.001). On binary logistic regression analysis, age over 80 years, female sex, higher CCI and having an open as opposed to an endovascular procedure are independent predictors of in-hospital mortality. CONCLUSIONS: Although endovascular techniques seem to dominate the care for octogenarians with LLC, the overall morbidity and mortality rates are significantly higher in this patient population. Other options such as medical management and/or supervised exercise therapy should be explored in this patient group. PMID- 29405593 TI - Severe prostate enlargement with severe lower urinary tract symptoms in poorly controlled acromegaly successfully treated with 5alpha-reductase inhibitors: A 15 year longitudinal case report. AB - Acromegaly is a rare disease associated with an increased risk of prostate enlargement. Severe prostate enlargement with severe lower urinary tract symptoms (LUTS) in an acromegalic patient is even more uncommon. Herein we report on a 55 year-old man who was diagnosed with acromegaly and prostate enlargement at 40 years of age. Transsphenoidal surgery, postoperative radiotherapy, and octreotide medical therapy failed to control the acromegaly, and growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels remained elevated. When the patient was 53 years of age, severe LUTS and prostate enlargement (prostate volume = 128 mL) were noted. However, LUTS improved and prostate volume decreased markedly after 5alpha-reductase inhibitors were used, despite the poorly controlled acromegaly (elevated GH and IGF-1 levels). This is the first long-term observation of LUTS and prostate enlargement in a poorly controlled acromegalic patient. Although the GH-IGF-1 axis was a factor contributing to prostate enlargement, the present case suggests that androgens may still play an essential role in prostate enlargement and symptoms in active acromegalic patients >50 years of age. Indeed, we should be aware that suppressing the GH-IGF-1 axis is not the only treatment choice for prostate enlargement in acromegalic patients, and even in poorly controlled acromegalic patients in whom suppression of the GH IGF-1 axis is difficult. Symptomatic prostate enlargement in cases of active acromegaly can be treated with 5alpha-reductase inhibitors, as in general benign prostate hyperplasia populations. PMID- 29405594 TI - Maximal efficiency is required to minimize complications and hospital stay after TAVR. AB - When TAVR is performed with transfemoral percutaneous approach, local anesthesia, no routine post-procedural intensive care admission, an early discharge (<3 days) can be adopted in most TAVR patients Avoiding peri-procedural complications and minimizing pace-maker implantation rate are key to allow early patient discharge When properly selected, patients discharged early have low discharge have low risk of adverse events and readmissions in the first 30 days. PMID- 29405595 TI - Intra-cardiac echo for left atrial appendage occlusion. AB - Left atrial appendage occlusion using the Amulet device can be accomplished with fluoroscopic and intra-cardiac echo (ICE) imaging for guidance, obviating the need for general anesthesia and trans-esophageal echo. The ICE device can be placed directly into the left atrium, parallel to the occluder delivery system, using a single transseptal puncture, rather than via double transseptal puncture. The ideal methods for left atrial appendage imaging and procedure guidance have yet to be defined. The utility of CT evaluation is increasingly recognized. The emergence of three-dimensional ICE is likely to further our progress along the path of simplifying the LAAO procedure. PMID- 29405596 TI - Hybrid coronary revascularization: Time for a new comparator? AB - The present meta-analysis found no significant difference between hybrid coronary revascularization (HCR) and bypass surgery (CABG) regarding intermediate-term major adverse cardiac and cerebrovascular events. HCR is feasible, historically with higher revascularization rates but less perioperative morbidity With a comparable frequency of repeat revascularization between current-generation drug eluting stents and CABG, future trials of HCR are considering multi-vessel PCI as the new comparator. PMID- 29405597 TI - If not now, why are you waiting? AB - There is some surrogate outcome data supporting deferring PCI in STEMI No hard data to support deferring PCI in STEMI No hard data to refute deferring PCI in STEMI Current national quality measures do not offer a method to adequately document appropriateness of deferring PCI. PMID- 29405598 TI - Cardiac enzyme elevation after coronary revascularization. AB - CK-MB elevation post-PCI correlates with procedural complications, diffuse atherosclerosis, and adverse long-term prognosis. Troponin elevation has an earlier pattern of rise than CK-MB and can be used as a surrogate. High sensitivity troponin can enable ruling out enzymatic elevation very early after PCI and facilitate discharge timing. PMID- 29405599 TI - Wanted: Expert operators for coronary chronic total occlusion interventions. AB - Coronary chronic total occlusions can be recanalized by expert operators with high success and acceptable complication rates. Developing a procedural plan (using the hybrid or another algorithm) is critical for success. Live case demonstrations appear safe and can be of high educational value. The key factor for achieving good outcomes in chronic total occlusion interventions remains operator expertise. Development of more expert operators will improve the treatment options for this challenging group of lesions and patients. PMID- 29405600 TI - Conscious sedation for TAVR: A wave of the future? AB - As indications for TAVR continue to grow, experienced centers strive to adopt further minimally invasive techniques and continue to improve outcomes. Meta analysis of the available data demonstrate that conscious sedation is associated with decreased ICU and hospitalization time, and is not associated with decreased procedural efficacy or safety. Randomized Controlled clinical Trial data will be needed to confirm observational findings suggesting decreased mortality with conscious sedation versus general anesthesia. PMID- 29405601 TI - The promise of effective P2Y12 platelet receptor pretreatment: Not crushed yet. AB - Pre-treatment with intact oral clopidogrel and prasugrel tablets in a representative observational study is not associated with altered ischemic or bleeding outcomes in acute coronary syndrome (ACS) patients. Limited by cost, cangrelor, a rapidly acting intravenous P2Y12 platelet receptor inhibitor, achieved meaningful reductions in major adverse cardiovascular events (MACE) and stent thrombosis (ST) compared to oral clopidogrel pretreatment. Crushed prasugrel and ticagrelor (CP&T) administered orally achieve accepted thresholds of therapeutic platelet inhibition in one hour in approximately 2/3rds of patients compared to 1/3rd with intact oral tablets. A large, simple randomized trial should test whether CP&T pre-treatment could capture some of the potential outcome benefit of rapid P2Y12 inhibition at no incremental risk and cost. PMID- 29405602 TI - Perforations and how to manage: The coronary interventionalist and peripheral interventionalist working together for a solution. AB - Perforations can occur in both peripheral and coronary interventional procedures potentially resulting in severe morbidity A readily available therapeutic option to treat perforations should be present in every cath lab that does coronary and peripheral procedures The use of a coagulated thrombus injection can be an effective treatment option, but if a major vessel is affected that must remain patent, one viable option is to administer the patients' own clotted blood to recanalize the vessel without permanent sequelae. PMID- 29405603 TI - Safety and Observations from a Placebo-Controlled, Crossover Study to Assess Use of Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism. AB - The aim of this exploratory study was to assess the safety and clinical effects of autologous umbilical cord blood (AUCB) infusion in children with idiopathic autism spectrum disorder (ASD). Twenty-nine children 2 to 6 years of age with a confirmed diagnosis of ASD participated in this randomized, blinded, placebo controlled, crossover trial. Participants were randomized to receive AUCB or placebo, evaluated at baseline, 12, and 24 weeks, received the opposite infusion, then re-evaluated at the same time points. Evaluations included assessments of safety, Expressive One Word Picture Vocabulary Test, 4th edition, Receptive One Word Picture Vocabulary Test, 4th edition, Clinical Global Impression, Stanford Binet Fluid Reasoning and Knowledge, and the Vineland Adaptive Behavior and Socialization Subscales. Generalized linear models were used to assess the effects of the response variables at the 12- and 24-week time periods under each condition (AUCB, placebo). There were no serious adverse events. There were trends toward improvement, particularly in socialization, but there were no statistically significant differences for any endpoints. The results of this study suggest that autologous umbilical cord infusions are safe for children with ASD. Tightly controlled trials are necessary to further progress the study of AUCB for autism. Stem Cells Translational Medicine 2018;7:333-341. PMID- 29405604 TI - Associations of the trunk skeletal musculature and dietary intake to biomarkers of cardiometabolic health after spinal cord injury. AB - PURPOSE: Skeletal muscle atrophy and poor dietary habits may contribute to increased adiposity and impaired metabolic health after spinal cord injury (SCI). The relative association of trunk muscle cross-sectional areas (CSA) versus dietary habits to central adiposity and impaired metabolic health after SCI remains unclear. METHODS: Twenty-two men with motor complete SCI completed five day dietary recalls for 4 weeks. Trunk muscle CSAs as well as visceral and subcutaneous adipose tissue (VAT and SAT, respectively) were quantified using magnetic resonance imaging. Basal metabolic rate (BMR), glucose effectiveness, insulin sensitivity and lipid profile were measured after overnight fast. RESULTS: Antero-lateral trunk muscle (r = -0.79, P < 0.001) and posterior trunk muscle (r = -0.56, P = 0.008) CSAs normalized to total trunk CSA were negatively related to VAT. Antero-lateral trunk muscle ratio (TMR) was positively related to BMR (r = 0.54, P = 0.01), and posterior TMR was positively related to peak oxygen uptake (VO2 peak; r = 0.71, P = 0.003). After accounting for total TMR as a co variate, total fat (r = 0.47, P = 0.04) and protein (r = 0.61, P = 0.004) intakes were positively related to fasting insulin levels. CONCLUSION: Trunk muscle CSAs normalized to total trunk CSA were negatively associated with central adiposity. Both trunk muscles and dietary macro-nutrients are related to markers of metabolic health. The study highlights the significance of developing an exercise intervention with a healthy dietary regimen to attenuate the development of central adiposity associated metabolic disorders after SCI. PMID- 29405605 TI - 13 C Flux Analysis Reveals that Rebalancing Medium Amino Acid Composition can Reduce Ammonia Production while Preserving Central Carbon Metabolism of CHO Cell Cultures. AB - 13 C metabolic flux analysis (MFA) provides a rigorous approach to quantify intracellular metabolism of industrial cell lines. In this study, 13 C MFA was used to characterize the metabolic response of Chinese hamster ovary (CHO) cells to a novel medium variant designed to reduce ammonia production. Ammonia inhibits growth and viability of CHO cell cultures, alters glycosylation of recombinant proteins, and enhances product degradation. Ammonia production was reduced by manipulating the amino acid composition of the culture medium; specifically, glutamine, glutamate, asparagine, aspartate, and serine levels were adjusted. Parallel 13 C flux analysis experiments determined that, while ammonia production decreased by roughly 40%, CHO cell metabolic phenotype, growth, viability, and monoclonal antibody (mAb) titer were not significantly altered by the changes in media composition. This study illustrates how 13 C flux analysis can be applied to assess the metabolic effects of media manipulations on mammalian cell cultures. The analysis revealed that adjusting the amino acid composition of CHO cell culture media can effectively reduce ammonia production while preserving fluxes throughout central carbon metabolism. PMID- 29405606 TI - Re: Safety and effectiveness of female tubal sterilisation by hysteroscopy, laparoscopy or laparotomy: a register-based study. PMID- 29405607 TI - A Novel, Well-Resolved Direct Laser Bioprinting System for Rapid Cell Encapsulation and Microwell Fabrication. AB - A direct laser bioprinting (DLBP) system is introduced in this work. The DLBP system applies visible-laser-induced photo-crosslinking at a wavelength of 405 nm using the photoinitiator VA-086. It is shown that such a system can fabricate vertical structures with fine features (less than 50 um) and high cell viability (greater than 95%). Experimental characterizations and theoretical simulations are presented, and good agreement is seen between the experiments and theory. The DLBP system is applied to the fabrication of (1) cell-laden hydrogel microgrids, (2) hydrogel microwells, as well as a test of (3) cell encapsulation, and (4) cell seeding. The DLBP system is found to be a promising tool for bioprinting. PMID- 29405608 TI - Role of prophylactic azithromycin to reduce airway inflammation and mortality in a RSV mouse infection model. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of morbidity and mortality in vulnerable populations. Macrolides have received considerable attention for their anti-inflammatory actions beyond their antibacterial effect. We hypothesize that prophylactic azithromycin will be effective in reducing the severity of RSV infection in a mouse model. METHODS: Four groups of BALB/c mice were studied for 8 days: Control (C), RSV-infected (R), early prophylaxis with daily azithromycin from days 1 to 8, (E), and late prophylaxis with daily azithromycin from days 4 to 8 (L). Mice were infected with RSV on day 4, except for the control group. All groups were followed for a total of 8 days when bronchoalveolar lavage cell count and cytokines levels were measured. Mouse weight, histopathology, and mortality data were obtained. RESULTS: Prophylactic azithromycin significantly attenuated post-viral weight loss between group R and both groups E and L (P = 0.0236, 0.0179, respectively). IL-6, IL-5, and Interferon-Gamma were significantly lower in group L (P = 0.0294, 0.0131, and 0.0056, respectively) compared with group R. The total cell count was significantly lower for group L as compared with group R (P < 0.05). Mortality was only observed in group R (8%). Lung histology in the prophylactic groups showed diminished inflammatory infiltrates and cellularity when compared with group R. CONCLUSION: Prophylactic azithromycin effectively reduced weight loss, airway inflammation, cytokine levels and mortality in RSV-infected mice. These results support the rationale for future clinical trials to evaluate the effects of prophylactic azithromycin for RSV infection. PMID- 29405610 TI - Progress of Multicompartmental Particles for Medical Applications. AB - Particulate materials are becoming increasingly used in the literature for medical applications, but translation to the clinical setting has remained challenging as many particle systems face challenges from in vivo barriers. Multicompartmental particles that can incorporate several materials in an individual particle may allow for more intricate control and addressing of issues that otherwise standard particles are unable to. Here, some of the advances made in the use of multicompartmental particles for medical applications are briefly described. PMID- 29405609 TI - L-Cysteine Production in Escherichia coli Based on Rational Metabolic Engineering and Modular Strategy. AB - L-cysteine is an amino acid with important physiological functions and has a wide range of applications in medicine, food, animal feed, and cosmetics industry. In this study, the L-cysteine synthesis in Escherichia coliEscherichia coli is divided into four modules: the transport module, sulfur module, precursor module, and degradation module. The engineered strain LH03 (overexpression of the feedback-insensitive cysE and the exporter ydeD in JM109) accumulated 45.8 mg L-1 of L-cysteine in 48 hr with yield of 0.4% g/g glucose. Further modifications of strains and culture conditions which based on the rational metabolic engineering and modular strategy improved the L-cysteine biosynthesis significantly. The engineered strain LH06 (with additional overexpression of serA, serC, and serB and double mutant of tnaA and sdaA in LH03) produced 620.9 mg L-1 of L-cysteine with yield of 6.0% g/g glucose, which increased the production by 12 times and the yield by 14 times more than those of LH03 in the original condition. In fed batch fermentation performed in a 5-L reactor, the concentration of L-cysteine achieved 5.1 g L-1 in 32 hr. This work demonstrates that the combination of rational metabolic engineering and module strategy is a promising approach for increasing the L-cysteine production in E. coli. PMID- 29405611 TI - Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial. AB - AIMS: The LION-HEART study was a multicentre, double-blind, randomised, parallel group, placebo-controlled trial evaluating the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. METHODS AND RESULTS: Sixty-nine patients from 12 centres were randomly assigned at a 2:1 ratio to levosimendan or placebo groups, receiving treatment by a 6-hour intravenous infusion (0.2 MUg/kg/min without bolus) every 2 weeks for 12 weeks. The primary endpoint was the effect on serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) throughout the treatment period in comparison with placebo. Secondary endpoints included evaluation of safety, clinical events and health-related quality of life (HRQoL). The area under the curve (AUC, pg.day/mL) of the levels of NT-proBNP over time for patients who received levosimendan was significantly lower than for the placebo group (344 * 103 [95% Confidence Interval (CI) 283 * 103 -404 * 103 ] vs. 535 * 103 [443 * 103 -626 * 103 ], p = 0.003). In comparison with the placebo group, the patients on levosimendan experienced a reduction in the rate of heart failure hospitalisation (hazard ratio 0.25; 95% CI 0.11-0.56; P = 0.001). Patients on levosimendan were less likely to experience a clinically significant decline in HRQoL over time (P = 0.022). Adverse event rates were similar in the two treatment groups. CONCLUSIONS: In this small pilot study, intermittent administration of levosimendan to ambulatory patients with advanced systolic heart failure reduced plasma concentrations of NT-proBNP, worsening of HRQoL and hospitalisation for heart failure. The efficacy and safety of this intervention should be confirmed in larger trials. PMID- 29405613 TI - Re: Pregnancy outcomes in patients with uterine fibroids treated with ultrasound guided high-intensity focused ultrasound: Is the noninvasive nature of HIFU ablation for uterine fibroids and adenomyosis setting patients up for future operative delivery? PMID- 29405612 TI - Risk scoring tool to predict respiratory syncytial virus hospitalisation in premature infants. AB - BACKGROUND: The objective was to develop a risk scoring tool which predicts respiratory syncytial virus hospitalisation (RSVH) in moderate-late preterm infants (32-35 weeks' gestational age) in the Northern Hemisphere. METHODS: Risk factors for RSVH were pooled from six observational studies of infants born 32 weeks and 0 days to 35 weeks and 6 days without comorbidity from 2000 to 2014. Of 13 475 infants, 484 had RSVH in the first year of life. Logistic regression was used to identify the most predictive risk factors, based on area under the receiver operating characteristic curve (AUROC). The model was validated internally by 100-fold bootstrapping and externally with data from a seventh observational study. The model coefficients were converted into rounded multipliers, stratified into risk groups, and number needed to treat (NNT) calculated. RESULTS: The risk factors identified in the model included (i) proximity of birth to the RSV season; (ii) second-hand smoke exposure; and (iii) siblings and/or daycare. The AUROC was 0.773 (sensitivity: 68.9%; specificity: 73.0%). The mean AUROC from internal bootstrapping was 0.773. For external validation with data from Ireland, the AUROC was 0.707 using Irish coefficients and 0.681 using source model coefficients. Cut-off scores for RSVH were <=19 for low- (1.0%), 20-45 for moderate- (3.3%), and 50-56 (9.5%) for high-risk infants. The high-risk group captured 62.0% of RSVHs within 23.6% of the total population (NNT 15.3). CONCLUSIONS: This risk scoring tool has good predictive accuracy and can improve targeting for RSVH prevention in moderate-late preterm infants. PMID- 29405614 TI - Common bile duct obstruction secondary to gastroduodenal pseudoaneurysm. PMID- 29405615 TI - Pancreatic cyst biopsy: Improvement in diagnosis with micro forceps biopsy. PMID- 29405616 TI - Flow-volume loops measured with electrical impedance tomography in pediatric patients with asthma. AB - BACKGROUND: Electrical impedance tomography (EIT) provides information on global and regional ventilation during tidal breathing and mechanical ventilation. During forced expiration maneuvers, the linearity of EIT and spirometric data has been documented in healthy persons. The present study investigates the potential diagnostic use of EIT in pediatric patients with asthma. METHODS: EIT and spirometry were performed in 58 children with asthma (average age +/- SD: 11.86 +/- 3.13 years), and 58 healthy controls (average age +/- SD: 12.12 +/- 2.9 years). The correlation between EIT data and simultaneously acquired spirometric data were tested for FEV1, FEV0.5 , MEF75 , MEF50 , and MEF25 . Binary classification tests were performed for the EIT-derived Tiffeneau index FEV1 /FVC and the bronchodilator test index DeltaFEV1 . Average flow-volume (FV) loops were generated for patients with pathologic spirometry to demonstrate the feasibility of EIT for graphic diagnosis of asthma. RESULTS: Spirometry and global EIT-based FV loops showed a strong correlation (P < 0.001, r > 0.9 in FEV1 and FEV0.5 ). In all criteria, the binary classification tests yielded high specificity (>93%), a high positive predictive value (>=75%) and a high negative predictive value (>80%), while sensitivity was higher in DeltaFEV1 (86.67%) and lower in FEV1 /FVC (25% and 35.29%). A typical concave shape of the EIT-derived average FV loops was observed for asthmatic children with improvement after bronchospasmolysis. CONCLUSIONS: Global FV loops derived from EIT correlate well with spirometry. Positive bronchospasmolysis can be observed in EIT-derived FV loops. Flow-volume loops originated from EIT have a potential to visualize pulmonary function. PMID- 29405617 TI - Structuring of Amide Cross-Linked Non-Bridged and Bridged Alkyl-Based Silsesquioxanes. AB - The development of sophisticated organized materials exhibiting enhanced properties is a challenging topic of the domain of organic/inorganic hybrid materials. This review, composed of four sections, reports the work we have carried out over the last 10 years on the synthesis of amide cross-linked alkyl/siloxane hybrids by means of sol-gel chemistry and self-directed assembly/self-organization routes relying on weak interactions (hydrophobic interactions and hydrogen bonding). The various as-produced lamellar structures displaying a myriad of morphologies, often closely resembling those found in natural materials, are discussed. The major role played by the synthetic conditions (pH, water content, co-solvent(s) nature/concentration and dopant presence/concentration), the alkyl chains (length and presence of ramification or not) and the number of the amide cross-links present in the precursor, is evidenced. Examples of highly organized hybrids structures incorporating ionic species (alkali and alkaline earth metal salts) and optically-active centers (organic dyes and lanthanide ions) are described. A useful qualitative relationship deduced between the emission quantum yield of the ordered hybrid materials and the degree of order of the hydrogen-bonded network is highlighted. PMID- 29405618 TI - Photosensitive Nanoparticles Combining Vascular-Independent Intratumor Distribution and On-Demand Oxygen-Depot Delivery for Enhanced Cancer Photodynamic Therapy. AB - In drug delivery, the poor tumor perfusion results in disappointing therapeutic efficacy. Nanomedicines for photodynamic therapy (PDT) greatly need deep tumor penetration due to short lifespan and weak diffusion of the cytotoxic reactive oxygen species (ROS). The damage of only shallow cells can easily cause invasiveness and metastasis. Moreover, even if the nanomedicines enter into deeper lesion, the effectiveness of PDT is limited due to the hypoxic microenvironment. Here, a deep penetrating and oxygen self-sufficient PDT nanoparticle is developed for balanced ROS distribution within tumor and efficient cancer therapy. The designed nanoparticles (CNPs/IP) are doubly emulsified (W/O/W) from poly(ethylene glycol)-poly(epsilon-caprolactone) copolymers doped with photosensitizer IR780 in the O layer and oxygen depot perfluorooctyl bromide (PFOB) inside the core, and functionalized with the tumor penetrating peptide Cys-Arg-Gly-Asp-Lys (CRGDK). The CRGDK modification significantly improves penetration depth of CNPs/IP and makes the CNPs/IP arrive at both the periphery and hypoxic interior of tumors where the PFOB releases oxygen, effectively alleviating hypoxia and guaranteeing efficient PDT performance. The improved intratumoral distribution of photosensitizer and adequate oxygen supply augment the sensitivity of tumor cells to PDT and significantly improve PDT efficiency. Such a nanosystem provides a potential platform for improved therapeutic index in anticancer therapy. PMID- 29405619 TI - Upcoming Meetings Therapeutic Apheresis and Dialysis February 2018. PMID- 29405620 TI - Therapeutic Plasma Exchange Strategy in Complement-Mediated Diseases: An Overview. PMID- 29405621 TI - The ISFA wishes to acknowledge the following 2018 Corporate Sponsors. PMID- 29405622 TI - Can Lipoprotein Apheresis Offer a Therapeutic Role in the Management of Patients With Refractory Angina and Raised Lipoprotein(a)? PMID- 29405623 TI - Cucurbitane Triterpenoids from the Fruits of Momordica Charantia Improve Insulin Sensitivity and Glucose Homeostasis in Streptozotocin-Induced Diabetic Mice. AB - SCOPE: Momordica charantia (M. charantia) has antidiabetic effects, and cucurbitane-type triterpenoid is one of the compounds of M. charantia. This study aims to investigate whether the new cucurbitane-type triterpenoids affect insulin sensitivity both in vitro and in vivo, and the underlying mechanisms. METHODS AND RESULTS: Four compounds (C1-C4) isolated from the ethanol extract of M. charantia enhance glucose uptake in C2C12 myotubes via insulin receptor substrate-1 (IRS-1) rather than via adenosine monophosphate-activated protein kinase. The most potent, compound 2 (C2), significantly increases the activation of IRS-1 and downstream signaling pathways, resulting in glucose transporter 4 translocation. Furthermore, these C2-induced in vitro effects are blocked by specific signal inhibitors. We further evaluate the antidiabetic effect of C2 using a streptozotocin (STZ)-induced diabetic mouse model. Consistent with in vitro data, treatment with C2 (1.68 mg kg-1 ) significantly decreases blood glucose level and enhances glycogen storage in STZ-injected mice. These effects appear to be mediated by the IRS-1 signaling pathway in skeletal muscle, not in adipose and liver tissues, suggesting that C2 improves hyperglycemia by increasing glucose uptake into skeletal muscle. CONCLUSION: Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis. PMID- 29405624 TI - The HLA-A*30:02~C*18:02~B*57:03 African haplotype identified with the deletion of the HLA-DRB1 gene in individuals from La Reunion Island. AB - We found a haplotype with the deletion of the HLA-DRB1 gene in two unrelated individuals originated from La Reunion Island, probably resulting from a deletion in the African haplotype A*30:02~C*18:02~B*57:03~DRB1*13:01. PMID- 29405625 TI - Digit Tip Regeneration: Merging Regeneration Biology with Regenerative Medicine. AB - Regeneration Biology is the study of organisms with endogenous regenerative abilities, whereas Regenerative Medicine focuses on engineering solutions for human injuries that do not regenerate. While the two fields are fundamentally different in their approach, there is an obvious interface involving mammalian regeneration models. The fingertip is the only part of the human limb that is regeneration-competent and the regenerating mouse digit tip has emerged as a model to study a clinically relevant regenerative response. In this article, we discuss how studies of digit tip regeneration have identified critical components of the regenerative response, and how an understanding of endogenous regeneration can lead to expanding the regenerative capabilities of nonregenerative amputation wounds. Such studies demonstrate that regeneration-incompetent wounds can respond to treatment with individual morphogenetic agents by initiating a multi-tissue response that culminates in structural regeneration. In addition, the healing process of nonregenerative wounds are found to cycle through nonresponsive, responsive and nonresponsive phases, and we call the responsive phase the Regeneration Window. We also find the responsiveness of mature healed amputation wounds can be reactivated by reinjury, thus nonregenerated wounds retain a potential for regeneration. We propose that regeneration-incompetent injuries possess dormant regenerative potential that can be activated by targeted treatment with specific morphogenetic agents. We believe that future Regenerative Medicine-based-therapies should be designed to promote, not replace, regenerative responses. Stem Cells Translational Medicine 2018;7:262-270. PMID- 29405627 TI - The effect of antiseptic oral sprays on dental plaque and gingival inflammation: A systematic review and meta-analysis. AB - AIM: To review the effectiveness of antiseptic oral sprays on oral health. METHODS AND MATERIALS: Three electronic databases (PubMed, Cochrane Library and Web of Science) were systematically searched to identify relevant studies. Only randomized controlled trials (RCTs) comparing the effect of oral sprays to placebo/control spray or mouthrinse on dental plaque and gingival inflammation were included. RESULTS: Among a total of 996 papers, 20 effective studies fulfilled the selection criteria, and 8 studies were suitable for inclusion in meta-analyses. A meta-analysis of three studies using a 0.2% chlorhexidine (CHX) spray intervention, without prophylaxis at baseline, showed reductions in Plaque Index (PI) (Silness and Loe) and Gingival Index (GI) (Silness and Loe) scores of 0.74 (95% CI: -1.03 to -0.45) and 0.22 (95% CI: -0.38 to -0.06), respectively. Five studies provided a prophylaxis for subjects before study initiation. Three of these five studies used 0.2% CHX spray. A meta-analysis demonstrated an increase of 0.18 (95% CI: -0.01 to 0.37) in PI (Silness and Loe) scores. Two RCTs compared 0.12% and 0.2% CHX spray, and a meta-analysis showed increases of 1.71 (95% CI: 1.27 to 2.14) and 1.58 (95% CI: 1.23 to 1.93), respectively, in PI (Quigley and Hein) scores. Of the RCTs not amenable to meta-analysis, eight studies reported significant improvements in PI and GI scores. CONCLUSIONS: Available evidence suggests that oral sprays are an acceptable delivery method for antiseptic agents. Further high-quality studies are warranted to determine the effectiveness of alternative chemotherapeutic agents delivered via oral sprays on oral health. PMID- 29405626 TI - Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy. AB - AIMS: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS: SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with >=30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION: SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease. PMID- 29405628 TI - Death-specific rate due to asthma and chronic obstructive pulmonary disease in Iran. AB - BACKGROUND AND OBJECTIVE: Asthma and chronic obstructive pulmonary disease (COPD) could be considered as a major health problem in industrialized and developing countries. This study was designed to analyze the trends of mortality from asthma and COPD at national and subnational levels in Iran based on National Death Registry, from 2001 to 2015. MATERIALS AND METHODS: We used Death Registration System (DRS) as the basic source of data. Death Registration System data were available from 1995 to 2010 in Iran's Ministry of Health. Although, Tehran and Isfahan, 2 most populated cities in Iran, had independent death registry systems in their cemeteries, by combining their data we achieved more comprehensive and representative data on death among Iranian people. We addressed incompleteness and misclassification of death registry system using demographic and statistical methods. We also employed spatio-temporal and Gaussian process regression to extrapolate and interpolate mortality rates for the missing data. RESULTS: Age standardized asthma mortality rate was 7.2 (5.6-9.2) in females and 8.8 (6.9 11.1) in males at the national level in 2015. Age-standardized COPD mortality rates in females and males, respectively, were 8.46 (6.6-10.9) and 12.38 (9.8 15.6) during the studied years. A reduction in age-standardized asthma mortality was observed during the period of study. In addition, the trend of COPD mortality was increasing. CONCLUSIONS: It seems that mortality rate attributable to COPD has risen during the past 15 years in Iran. It could have increased because of increased exposure of people to related risk factors such as air pollution which is a common problem in larger cities and border provinces. PMID- 29405629 TI - Topological analysis of DPY19L3, a human C-mannosyltransferase. AB - C-mannosylation is a rare type of protein glycosylation, the functions and mechanisms of which remain unclear. Recently, we identified DPY19L3 as a C mannosyltransferase of R-spondin1 in human cells. DPY19L3 is predicted to be a multipass transmembrane protein that localizes to the endoplasmic reticulum (ER); however, its structure is undetermined. In this study, we propose a topological structure of DPY19L3 by in silico analysis and experimental methods such as redox sensitive luciferase assay and introduction of N-glycosylation sites, suggesting that DPY19L3 comprises 11 transmembrane regions and two re-entrant loops with the N- and C-terminal ends facing the cytoplasm and ER lumen, respectively. Furthermore, DPY19L3 has four predicted N-glycosylation sites, and we have demonstrated that DPY19L3 is N-glycosylated at Asn118 and Asn704 but not Asn319 and Asn439 , supporting our topological model. By mass spectrometry, we measured the C-mannosyltransferase activity of N-glycosylation-defective mutants of DPY19L3 and isoform2, a splice variant, which lacks the C-terminal luminal region of DPY19L3. Isoform2 does not possess C-mannosyltransferase activity, indicating the importance of the C-terminal region; however, N-glycosylations of DPY19L3 do not have any roles for its enzymatic activity. These novel findings on DPY19L3 provide important insights into the mechanism of C-mannosylation. PMID- 29405630 TI - Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03. AB - INTRODUCTION: TROG 09.03 prospectively studied the utility of Fluorine-18 Fluorodeoxyglucose (18-FDG) PET in the management of Merkel cell carcinoma of skin. METHODS: Following consent and registration, a pre-treatment FDG-PET/CT was performed. Sites of avid disease were confirmed by cytology where practicable. Following surgery, patients with AJCCv7 Stages IIA-IIIB disease were treated with chemo-radiotherapy and reassessed with a post-treatment PET. RESULTS: Fifty-eight subjects (45 males and 13 females, median age 68 years) were enrolled between 2011 and 2015, 43 patients of whom went on to receive chemo-radiotherapy. An occult primary was present in 22 (37.9%), T1 in 22 (37.9%) and T2 disease in 14 (24.1%). Nodal disease was present in 69% of cases. Fifty per cent of subjects had gross residual disease at the primary site and/or nodal site at the time of registration. 18-FDG PET/CT had a sensitivity of 94.74% (95% CI 82-99.3%) and a specificity of 88.24% (95% CI 63.56-98.54). The positive predictive value was 94.74% (83.01-98.51) and the negative predictive value was 88.24% (95% CI 65.81 96.69). The pre-treatment PET influenced a treatment decision in 27.6% of cases. Upstaging occurred in 15 (25.9%), with no down staging. Other diseases were identified in 4 (6.9%) patients. Univariate analysis failed to demonstrate that pre-treatment SUV levels or a negative post-treatment PET had any impact on overall survival. PET staged patients had 89% 3-year in-field loco-regional control and 76% 3-year overall survival. CONCLUSION: Staging 18-FDG-PET significantly influenced treatment decisions in approximately one-third of cases of MCC and should be considered in the routine pre-treatment work-up. Post treatment PET was not found to be prognostic. Funding through the Medicare Benefits Schedule needs to be considered for high risk MCC. PMID- 29405631 TI - Luminescent properties of novel red-emitting M7 Sn(PO4 )6 :Eu3+ (M = Sr, Ba) for light-emitting diodes. AB - Novel red-emitting phosphors, Eu3+ -activated M7 Sn(PO4 )6 (M = Sr, Ba), were synthesized at 1200 degrees C by conventional solid-state reaction method. The luminescent properties of M7 Sn(PO4 )6 :Eu3+ (M = Sr, Ba) phosphors were investigated, and the critical concentration of the activator (Eu3+ ) concentration were found to be 0.175 mol and 0.21 mol per formula unit for Sr7-x Sn(PO4 )6 :xEu3+ and Ba7-x Sn(PO4 )6 :xEu3+ , respectively. These phosphors presented red luminescence under the excitation of 395 or 465 nm, perfectly matching with the emissions wavelength of near-ultraviolet (UV) light-emitting diodes (LEDs) and InGaN blue LED. PMID- 29405632 TI - Synthesis and Properties of a Decacyclene Monoimide and a Naphthalimide Derivative as Three-Dimensional Acceptor-Donor-Acceptor Systems. AB - A method involving the Diels-Alder (DA) cycloaddition of diacenaphtheno[1,2 b;1',2'-d]thiophenes (DATs) with N-alkylacenaphthylene-5,6-dicarboximides (AIs) was developed to synthesize decacyclene monoimides (DCMIs). The reactions generate the corresponding 1:2 adducts (BAIAs) as major products together with 1:1 adducts (the DCMIs). The molecular structure of BAIAb (N-octyl derivative) was unambiguously assigned as the bis-adduct having an endo,endo spatial disposition of the two acenaphthylene-5,6-dicarboximide moieties by using X-ray crystallographic analysis. Relative to the absorption spectrum of decacyclene triimide (DCTIa, N-2-ethylhexyl derivative), that of the analogous N-2-ethylhexyl substituted monoadduct, DCMIa, is bathochromically shifted despite the fact that it possesses a less delocalized pi-electron system. DCMIa does not fluoresce in various organic solvents, whereas DCTIa emits yellow fluorescence in CH2 Cl2 with a low quantum yield (PhiSN ). Moreover, DCMIa in CDCl3 displays concentration dependent 1 H NMR spectroscopy behavior, which suggests that it self-aggregates with an association constant (Ka ) of (193+/-50) m-1 at 20 degrees C. Despite the presence of four bulky tert-butyl groups in DCMIa, its Ka value for aggregate formation is comparable to that of DCTIa [(495+/-42) m-1 ], which does not contain tert-butyl substituents. Spectroscopic studies with the bis-adduct BAIAa (N-2-ethylhexyl derivative) show that it displays remarkable solvatofluorochromism corresponding to an emission maximum shift (DeltalambdaEM ) of 100 nm. The results of density functional theory calculations on BAIAc (N methyl derivative) demonstrate that a considerable spatial separation exists between the HOMO and LUMO coefficient distributions, which indicates that the ground-to-excited state transition of the novel three-dimensional acceptor-donor acceptor BAIAa system should have intramolecular charge-transfer character. PMID- 29405633 TI - State of the art vs biological variability: Comparison on hematology parameters using Spanish EQAS data. AB - INTRODUCTION: It is important for clinical laboratories to maintain under control the possible sources of error in its analytical determinations. The objective of this work is to perform an analysis of the total error committed by laboratories using the data extracted from the Spanish External Quality Assessment Program in Hematology and to compare them with the specifications based on the biological variability proposed by the Ricos group. MATERIAL AND METHODS: We analyzed a total of 3 89 000 results during the period 2015-2016 from the following quantitative schemes of Spanish External Quality Assessment Program: complete blood count, blood coagulation tests, differential leukocyte count, reticulocytes, hemoglobin A2 , antithrombin, factor VIII, protein C, and von Willebrand factor. It has been considered as an indicator of the current performance the value of total error that 90% of laboratories are able to achieve, taking into account 75% of their results. RESULTS: We found some magnitudes whose biological variability specifications are achievable by most of the laboratories for either minimum, desirable, or optimum criteria: white blood cells, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, platelets, fibrinogen, neutrophils, lymphocytes, eosinophils, von Willebrand factor, and protein C. However, current performance for mean corpuscular hemoglobin concentration and hemoglobin A2 only allows to meet the specifications based on the state of the art. CONCLUSION: Our results reflect the feasibility of establishing specifications based on biological variability criteria or the state of the art, which may help to select the proper criteria for each parameter. PMID- 29405634 TI - Increased central common drive to ankle plantar flexor and dorsiflexor muscles during visually guided gait. AB - When we walk in a challenging environment, we use visual information to modify our gait and place our feet carefully on the ground. Here, we explored how central common drive to ankle muscles changes in relation to visually guided foot placement. Sixteen healthy adults aged 23 +/- 5 years participated in the study. Electromyography (EMG) from the Soleus (Sol), medial Gastrocnemius (MG), and the distal and proximal ends of the Tibialis anterior (TA) muscles and electroencephalography (EEG) from Cz were recorded while subjects walked on a motorized treadmill. A visually guided walking task, where subjects received visual feedback of their foot placement on a screen in real-time and were required to place their feet within narrow preset target areas, was compared to normal walking. There was a significant increase in the central common drive estimated by TA-TA and Sol-MG EMG-EMG coherence in beta and gamma frequencies during the visually guided walking compared to normal walking. EEG-TA EMG coherence also increased, but the group average did not reach statistical significance. The results indicate that the corticospinal tract is involved in modifying gait when visually guided placement of the foot is required. These findings are important for our basic understanding of the central control of human bipedal gait and for the design of rehabilitation interventions for gait function following central motor lesions. PMID- 29405635 TI - Metformin does not affect postabsorptive hepatic free fatty acid uptake, oxidation or resecretion in humans: A 3-month placebo-controlled clinical trial in patients with type 2 diabetes and healthy controls. AB - AIMS: To explore whether the pre-clinical findings that metformin improves lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from re-esterification and resecretion as triglycerides (TGs), can be translated to a human setting. MATERIALS AND METHODS: We performed a 3-month randomized, placebo-controlled, parallel-group clinical trial in patients with type 2 diabetes (T2D; n = 24) and healthy controls (n = 12). Patients with T2D received either placebo (placebo group) or 1000 mg metformin twice daily (metformin group), while healthy subjects were all treated with metformin (control group). Hepatic fatty acid metabolism was measured by [11 C]palmitate positron-emission tomography, hepatic TG secretion and peripheral oxidation by ex vivo labelled [1-14 C]VLDL-TG and VLDL particle size by TG/apolipoprotein B ratio. Body composition was assessed by dual-energy X-ray and whole-body lipid oxidation by indirect calorimetry. RESULTS: Metformin treatment for 3 months produced the anticipated decrease in fasting plasma glucose (FPG) in the metformin group (FPG 7.9 +/- 1.8 mM [study day 1] vs 6.4 +/- 1.1 mM [study day 2]), whereas patients in the placebo group and healthy controls had similar FPG levels before and after the trial (mixed model group vs time interaction; P = .003); however, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation. CONCLUSION: The observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis. PMID- 29405636 TI - Dietary Curcumin Intervention Targets Mouse White Adipose Tissue Inflammation and Brown Adipose Tissue UCP1 Expression. AB - OBJECTIVE: This study aimed to determine whether dietary curcumin intervention targets both white adipose tissue (WAT) inflammation and brown adipose tissue (BAT)-mediated energy expenditure. METHODS: C57BL/6J mice were fed with a low-fat diet, high-fat diet (HFD), or HFD plus curcumin. In addition to assessing the effect of curcumin intervention on metabolic profiles, this study assessed WAT macrophage infiltration and composition and inflammatory cytokine production. Metabolic cages were applied for determining energy expenditure. Raw264.7 (ATCC, Manassas, Virginia) and other cell models were utilized to test the in vitro effect of curcumin treatment. RESULTS: Curcumin intervention reduced WAT macrophage infiltration and altered macrophage functional polarity, as the ratio of M2-like versus M1-like macrophages increased after curcumin intervention. Curcumin treatment reduced M1-like macrophage markers or proinflammation cytokine expression in both macrophages and adipocytes. Curcumin intervention also increased energy expenditure and body temperature in response to a cold challenge. Finally, the in vivo and in vitro investigations suggested that curcumin increased expression of uncoupling protein 1 (UCP1), possibly involving PPAR-dependent and -independent mechanisms. CONCLUSIONS: Curcumin intervention targets both WAT inflammation and BAT UCP1 expression. These observations advanced our knowledge on the metabolic beneficial effects of the curry compound curcumin, bringing us a novel perspective on dietary polyphenol research. PMID- 29405637 TI - Impact of audiovisual biofeedback on interfraction respiratory motion reproducibility in liver cancer stereotactic body radiotherapy. AB - INTRODUCTION: Irregular breathing motion exacerbates uncertainties throughout a course of radiation therapy. Breathing guidance has demonstrated to improve breathing motion consistency. This was the first clinical implementation of audiovisual biofeedback (AVB) breathing guidance over a course of liver stereotactic body radiotherapy (SBRT) investigating interfraction reproducibility. METHODS: Five liver cancer patients underwent a screening procedure prior to CT sim during which patients underwent breathing conditions (i) AVB, or (ii) free breathing (FB). Whichever breathing condition was more regular was utilised for the patient's subsequent course of SBRT. Respiratory motion was obtained from the Varian respiratory position monitoring (RPM) system (Varian Medical Systems). Breathing motion reproducibility was assessed by the variance of displacement across 10 phase-based respiratory bins over each patient's course of SBRT. RESULTS: The screening procedure yielded the decision to utilise AVB for three patients and FB for two patients. Over the course of SBRT, AVB significantly improved the relative interfraction motion by 32%, from 22% displacement difference for FB patients to 15% difference for AVB patients. Further to this, AVB facilitated sub-millimetre interfraction reproducibility for two AVB patients. CONCLUSION: There was significantly less interfraction motion with AVB than FB. These findings demonstrate that AVB is potentially a valuable tool in ensuring reproducible interfraction motion. PMID- 29405638 TI - Reply to 'A mixed-methods study on the use of and attitudes towards safety checklists in interventional radiology'. PMID- 29405639 TI - Continuing Professional Development. PMID- 29405640 TI - CT Colonography in the frail and elderly. PMID- 29405641 TI - The effect of the acute phase response on routine laboratory markers of folate and vitamin B12 status. PMID- 29405643 TI - Women and kidney disease: Reflections on world kidney day 2018. AB - BACKGROUND: Chronic Kidney Disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care and participation in clinical studies. THE ISSUES: Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and on the foetus. Low birth weight children have increased risk of metabolic diseases, CVD and CKD. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. There is little data to guide best practice and limited research in the area. CONCLUSIONS: In this editorial, we focus on what we do and do not know about women, kidney health and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29405644 TI - Variations in subclinical left ventricular dysfunction, functional capacity, and clinical outcomes in different heart failure aetiologies. AB - AIMS: Patients with heart failure (HF) risk factors are described as being in Stage A of this condition (SAHF). Management is directed towards prevention of HF progression, but to date, no evidence has been described to align the intensity of this intervention to HF risk. We sought to what extent SAHF of Type 2 diabetes mellitus (T2DM) and other HF risks showed differences in subclinical left ventricular function, exercise capacity, and prognosis. METHODS AND RESULTS: We recruited 551 elder asymptomatic SAHF patients (age 71 +/- 5 years, 49% men, 290 T2DM) with at least one risk factor from a community-based population with preserved ejection fraction. All underwent a comprehensive echocardiogram including global longitudinal strain (GLS) and a 6 min walk test and were followed for 2 years. The primary endpoints were new-onset HF and all-cause mortality. The T2DM group was associated with reduced 6 min walk test distance (451 +/- 111 vs. 493 +/- 87 m, P < 0.001), worse diastolic function (E/e' 9.2 +/- 2.7 vs. 8.7 +/- 2.4, P = 0.028), and impaired GLS (-17.7 +/- 2.6% vs. -19.0 +/- 2.6%, P < 0.001). Over a median follow-up of 1.6 years, 49 T2DM-SAHF and 27 other SAHF met the primary endpoint. T2DM-SAHF had significantly worse outcome than other-SAHF (P = 0.021). In Cox models, obesity [hazard ratio (HR) = 2.46; P = 0.007], atrial fibrillation (HR = 2.39; P = 0.028), 6 min walk distance (HR = 0.99; P = 0.034), and GLS (HR = 1.14; P = 0.033) were independently associated with the primary endpoint in T2DM-SAHF, independent of age and glycaemic control. CONCLUSIONS: The T2DM-SAHF has worse subclinical left ventricular function, exercise capacity, and prognosis than other-SAHF. Impaired GLS, atrial fibrillation, exercise capacity, and obesity are associated with a worse prognosis in T2DM-SAHF but not in other-SAHF. PMID- 29405645 TI - Goal prediction in 2-year-old children with and without autism spectrum disorder: An eye-tracking study. AB - : This study examined the predictive reasoning abilities of typically developing (TD) infants and 2-year-old children with autism spectrum disorder (ASD) in an eye-tracking paradigm. Participants watched a video of a goal-directed action in which a human actor reached for and grasped one of two objects. At test, the objects switched locations. Across these events, we measured: visual anticipation of the action outcome with kinematic cues (i.e., a completed reaching behavior); goal prediction of the action outcome without kinematic cues (i.e., an incomplete reach); and latencies to generate predictions across these two tasks. Results revealed similarities in action anticipation across groups when trajectory information regarding the intended goal was present; however, when predicting the goal without kinematic cues, developmental and diagnostic differences became evident. Younger TD children generated goal-based visual predictions, whereas older TD children were not systematic in their visual predictions. In contrast to both TD groups, children with ASD generated location-based predictions, suggesting that their visual predictions may reflect visuomotor perseveration. Together, these results suggest differences in early predictive reasoning abilities. Autism Res 2018, 11: 870-882. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The current study examines the ability to generate visual predictions regarding other people's goal-directed actions, specifically reaching and grasping an object, in infants and children with and without autism spectrum disorder. Results showed no differences in abilities when movement information about a person's goal was evident; however, differences were evident across age and clinical diagnoses when relying on previous knowledge to generate a visual prediction. PMID- 29405646 TI - Auxin polar transport flanking incipient primordium initiates leaf adaxial abaxial polarity patterning. AB - The leaves of most higher plants are polar along their adaxial-abaxial axis, and the development of the adaxial domain (upper side) and the abaxial domain (lower side) makes the leaf a highly efficient photosynthetic organ. It has been proposed that a hypothetical signal transported from the shoot apical meristem (SAM) to the incipient leaf primordium, or conversely, the plant hormone auxin transported from the leaf primordium to the SAM, initiates leaf adaxial-abaxial patterning. This hypothetical signal has been referred to as the Sussex signal, because the research of Ian Sussex published in 1951 was the first to imply its existence. Recent results, however, have shown that auxin polar transport flanking the incipient leaf primordium, but not the Sussex signal, is the key to initiate leaf polarity. Here, we review the new findings and integrate them with other recently published results in the field of leaf development, mainly focusing on the early steps of leaf polarity establishment. PMID- 29405647 TI - Deep Generative Models for Molecular Science. AB - Generative deep machine learning models now rival traditional quantum-mechanical computations in predicting properties of new structures, and they come with a significantly lower computational cost, opening new avenues in computational molecular science. In the last few years, a variety of deep generative models have been proposed for modeling molecules, which differ in both their model structure and choice of input features. We review these recent advances within deep generative models for predicting molecular properties, with particular focus on models based on the probabilistic autoencoder (or variational autoencoder, VAE) approach in which the molecular structure is embedded in a latent vector space from which its properties can be predicted and its structure can be restored. PMID- 29405648 TI - Corrigendum. PMID- 29405649 TI - 2D Ultrathin MXene-Based Drug-Delivery Nanoplatform for Synergistic Photothermal Ablation and Chemotherapy of Cancer. AB - Two-dimensional (2D) MXenes, as a new 2D functional material nanosystem, have been extensively explored for broad applications. However, their specific performance and applications in theranostic nanomedicine have still rarely been explored. This work reports on the drug-delivery performance and synergistic therapeutic efficiency of Ti3 C2 MXenes for highly efficient tumor eradication. These Ti3 C2 MXenes not only possess high drug-loading capability of as high as 211.8%, but also exhibit both pH-responsive and near infrared laser-triggered on demand drug release. Especially, based on the high photothermal-conversion capability of Ti3 C2 MXenes, they have been further explored for efficient tumor eradication by synergistic photothermal ablation and chemotherapy, which has been systematically demonstrated both in vitro and in vivo. These Ti3 C2 MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging, showing the potential for diagnostic-imaging guidance and monitoring during therapy. The high in vivo histocompatibility of Ti3 C2 and their easy excretion out of the body have been evaluated and demonstrated, showing the potential high biosafety for further clinical translation. This work paves a new way for broadening biomedical applications of MXenes in nanomedicine where they can exert the high performance and functionality for synergistic therapy, especially on combating cancer. PMID- 29405651 TI - 1,2,3,4-Tetrahydroisoquinolines as inhibitors of HIV-1 integrase and human LEDGF/p75 interaction. AB - Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75-IN interaction in vitro with an IC50 of ~10 MUm. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75-binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non-specific DNA. As reported earlier for the inhibitors of LEDGF/p75-IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV-1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75-IN interaction having a higher potency. PMID- 29405650 TI - Coheredity of a new silent mutation: c.-29G>T, with a severe beta-thal mutation in a patient with beta-thalassemia intermediate. PMID- 29405652 TI - MoS2 Quantum Dots-Modified Covalent Triazine-Based Frameworks for Enhanced Photocatalytic Hydrogen Evolution. AB - MoS2 quantum dots (QDs)-modified covalent triazine-based framework (MoS2 /CTF) composites are synthesized through an in situ photodeposition method. MoS2 QDs are well distributed and stabilized on the layers of CTFs by coordination of the frameworks to MoS2 . The QDs-sheet interactions between MoS2 and CTFs facilitate interfacial charge transfer and separation. As a consequence, the composites exhibit outstanding photocatalytic activity and stability for hydrogen evolution under visible light irradiation (lambda>=420 nm), that exceed those over pristine CTFs and MoS2 -modified g-C3 N4 (MoS2 /g-C3 N4 ) composite, making them promising materials for solar energy conversion. PMID- 29405653 TI - Spatial navigation from same and different directions: The role of executive functions, memory and attention in adults with autism spectrum disorder. AB - : To resolve some of the inconsistencies in existing research into spatial navigation in autism spectrum disorder (ASD), we tested two large age- and ability-matched groups of ASD and typically developing (TD) participants for their spatial navigation abilities in a route learning task, which has been shown to shed light on the strategies participants employ when navigating complex environments. Participants studied a route through a virtual maze by watching a short video of a first-person perspective navigating a maze. The maze included four four-way intersections that were each marked with two unique landmarks in two corners of the intersection. At test, static images of the intersections, either as seen during the video or as approached from a different direction, were presented and participants had to indicate in which direction they would need to travel (straight, left, or right) in order to follow the originally studied route. On both types of test trials, the ASD group performed worse and their difficulties were related to reduced cognitive flexibility. Eye-movement data and follow-up item-memory tests suggested that navigation difficulties may have been related to differences in attention during encoding and less spontaneous use of landmarks as cues for navigation. Spatial navigation performance was best predicted by memory for landmarks as well as by executive functions. The results are discussed in relation to theories of underlying navigation-related brain regions. More research is needed to disentangle the influence of executive functions, memory and attention on spatial navigation. Autism Res 2018, 11: 798 810. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Navigating an environment is difficult for people with ASD independent of whether they are travelling in the same or in a different direction from that which they originally studied. The present study suggests that flexibility in alternating travel directions, difficulties in remembering landmarks as well as reduced attention to landmarks while learning a route play a role in the navigation difficulties in ASD. Guidance at route learning might help autistic individuals to improve their ability to navigate in their environments. PMID- 29405654 TI - Practicing what we preach: A pilot study on oral health practices of dentists in Massachusetts. AB - AIM: Dentists are perceived as leaders and role models of good oral health, but do dentists practice what they preach? The current study was a pilot evaluation dentists of the oral health and oral health practices of dentists in Massachusetts. METHODS: The Massachusetts Dental Society sent emails to 3957 member dentists for whom an email contact was available. One reminder was sent 3 months later, and there was no incentive offered. Institutional review board approval was acquired prior to administering the survey through the Harvard Medical School Committee on Human Studies. RESULTS: A total of 4.9% of dentists had a comprehensive oral examination more than 8 years ago, and 3.1% had diagnostic bitewings 3-5 years ago. Our study revealed that 5.8% had untreated caries and only 70.8% reported having no oral health problems. A total of 37% reported that lack of time was a barrier in seeking care, and 7.8% reported financial barriers. Finally, 4.1% reported that a non-dentist coworker examined and managed their oral health. CONCLUSIONS: The current study revealed that many dentists are not following American Dental Association guidelines for prevention for themselves. Subsequently, many in our profession are recommending preventive care for their patients that they are not adhering to themselves. PMID- 29405655 TI - A case of cardiac sarcoidosis mimicking cardiac amyloidosis on cardiovascular magnetic resonance. AB - A 52-year-old male visited our hospital with abnormal electrocardiogram and exertional fatigue. The electrocardiogram showed first-degree atrioventricular block, complete right bundle branch block, and inverted T waves in Leads II, III, aVF, V3, and V4. Echocardiography showed biventricular wall thickening involving granular sparkling of the interventricular septum. Late gadolinium enhancement on cardiovascular magnetic resonance (CMR) was found at the circumferential right ventricular wall and patchy regions of the left ventricle. Although these findings strongly suggested cardiac amyloidosis, he was finally diagnosed with systemic sarcoidosis due to the following. First, endomyocardial biopsy revealed non-caseating epithelioid granuloma with giant cells. Second, 18 F fluorodeoxyglucose positron emission tomography showed uptake in bilateral hilar lymph nodes, para-aortic lymph nodes, and the biventricular wall of the heart. Although echocardiography and CMR are very useful tools for diagnosis of cardiomyopathies, their specificity and accuracy need to be considered. PMID- 29405656 TI - Drosophila tafazzin mutants have impaired exercise capacity. AB - Cardiolipin (CL) is a mitochondrial phospholipid that helps maintain normal structure of the inner mitochondrial membrane and stabilize the protein complexes of the electron transport chain to promote efficient ATP synthesis. Tafazzin, an acyl-transferase, is required for synthesis of the mature form of CL. Mutations in the tafazzin (TAZ) gene are associated with a human disorder known as Barth syndrome. Symptoms of Barth syndrome often include muscle weakness and exercise intolerance. Previous work demonstrates that Drosophila Taz mutants exhibit motor weakness, as measured by reduced flying and climbing abilities. However, Drosophila TAZ mutants' baseline endurance or response to endurance exercise training has not been assessed. Here, we find that TAZ mutants have reduced endurance and do not improve following a stereotypical exercise training paradigm, indicating that loss of TAZ function leads to exercise intolerance in Drosophila. Although cardiac phenotypes are observed in human Barth syndrome patients, TAZ mutants had normal resistance to cardiac pacing. In the future, endurance may be a useful screening tool to identify additional genetic modifiers of tafazzin. PMID- 29405657 TI - Risk Factors for Carotid Artery Disease and Chronic Kidney Disease: Same or Unique? PMID- 29405658 TI - Role of afferent and efferent renal nerves in the development of AngII-salt hypertension in rats. AB - Hypertension is the leading modifiable risk factor for death worldwide, yet the causes remain unclear and treatment remains suboptimal. Catheter-based renal denervation (RDNX) is a promising new treatment for resistant hypertension, but the mechanisms underlying its antihypertensive effect remain unclear. We recently found that RDNX attenuates deoxycorticosterone acetate-salt hypertension and that this is dependent on ablation of afferent renal nerves and is associated with decreased renal inflammation. To determine if this is common to other models of salt-sensitive hypertension, rats underwent complete RDNX (n = 8), selective ablation of afferent renal nerves (n = 8), or sham denervation (n = 8). Mean arterial pressure (MAP) and heart rate were measure by telemetry and rats were housed in metabolic cages for measurement of sodium and water balance. Rats were then subjected to angiotensin II (AngII)-salt hypertension (10 ng/kg/min, intravenous + 4% NaCl diet) for 2 weeks. At the end of the study, renal T-cell infiltration was quantified by flow cytometry. AngII resulted in an increase in MAP of ~50 mmHg in all three groups with no between group differences, and a transient bradycardia that was blunted by selective ablation of afferent renal nerves. Sodium and water balance were unaffected by AngII-salt treatment and similar between groups. Lastly, AngII infusion was not associated with T-cell infiltration into the kidneys, and T-cell counts were unaffected by the denervation procedures. These results suggest that AngII-salt hypertension in the rat is not associated with renal inflammation and that neither afferent nor efferent renal nerves contribute to this model. PMID- 29405660 TI - Laryngeal ultrasound for the diagnosis of laryngomalacia in infants. AB - INTRODUCTION: Laryngomalacia is the most prevalent cause of congenital stridor. Flexible laryngobronchoscopy (FLB) is the gold standard for diagnosis. However, FLB requires venous access, deep sedation or general anesthesia, and is associated with patient's and parental discomfort and a considerable cost. Laryngeal ultrasound (LUS) has been shown to provide good evaluation of the normal anatomy and the dynamic motion of laryngeal structures. We investigated the yield of LUS in the diagnosis of laryngomalacia in infants with congenital stridor compared to FLB. METHODS: A prospective blind study of consecutive infants referred for FLB due to congenital stridor with unknown cause. The presence of arytenoids adduction on LUS during inspiration was used to diagnose laryngomalacia. LUS was followed by FLB under anesthesia. The physician performing the FLB was blinded to the LUS results. RESULTS: Twenty-four patients participated in the study (54% males). Median (IQR) age and weight were 3.5 (1 7.7) months and 5.1 (4-8.4) kg, respectively. LUS was well tolerated in all infants. Compared to FLB, LUS correctly diagnosed laryngomalacia in 11/14 (78.6%) infants. In 10 infants FLB ruled out laryngomalacia of whom LUS concurred in 9 infants and one was falsely diagnosed with laryngomalacia. LUS had a sensitivity of 78.5% (CI 52-95%), specificity of 90% (CI 49-94%), NPV of 75%, and PPV of 92%. ROC analysis demonstrated AUC of 0.84 (P < 0.01, 95%CI: 0.67-1.0). CONCLUSION: We suggest that LUS has a role in screening congenital stridor in otherwise healthy infants when laryngomalacia is highly probable. PMID- 29405659 TI - Spatial dynamics and mixing of bluefin tuna in the Atlantic Ocean and Mediterranean Sea revealed using next-generation sequencing. AB - The Atlantic bluefin tuna is a highly migratory species emblematic of the challenges associated with shared fisheries management. In an effort to resolve the species' stock dynamics, a genomewide search for spatially informative single nucleotide polymorphisms (SNPs) was undertaken, by way of sequencing reduced representation libraries. An allele frequency approach to SNP discovery was used, combining the data of 555 larvae and young-of-the-year (LYOY) into pools representing major geographical areas and mapping against a newly assembled genomic reference. From a set of 184,895 candidate loci, 384 were selected for validation using 167 LYOY. A highly discriminatory genotyping panel of 95 SNPs was ultimately developed by selecting loci with the most pronounced differences between western Atlantic and Mediterranean Sea LYOY. The panel was evaluated by genotyping a different set of LYOY (n = 326), and from these, 77.8% and 82.1% were correctly assigned to western Atlantic and Mediterranean Sea origins, respectively. The panel revealed temporally persistent differentiation among LYOY from the western Atlantic and Mediterranean Sea (FST = 0.008, p = .034). The composition of six mixed feeding aggregations in the Atlantic Ocean and Mediterranean Sea was characterized using genotypes from medium (n = 184) and large (n = 48) adults, applying population assignment and mixture analyses. The results provide evidence of persistent population structuring across broad geographic areas and extensive mixing in the Atlantic Ocean, particularly in the mid-Atlantic Bight and Gulf of St. Lawrence. The genomic reference and genotyping tools presented here constitute novel resources useful for future research and conservation efforts. PMID- 29405661 TI - In children, the microbiota of the nasopharynx and bronchoalveolar lavage fluid are both similar and different. AB - RATIONALE: Sputum and bronchoalveolar lavage fluid (BALF) are often obtained to elucidate the lower airway microbiota in adults. Acquiring sputum samples from children is difficult and obtaining samples via bronchoscopy in children proves challenging due to the need for anesthesia and specialized procedural expertise; therefore nasopharyngeal (NP) swabs are often used as surrogates when investigating the pediatric airway microbiota. In adults, the airway microbiota differs significantly between NP and BALF samples however, minimal data exist in children. OBJECTIVES: To compare NP and BALF samples in children undergoing clinically indicated bronchoscopy. METHODS: NP and BALF samples were collected during clinically indicated bronchoscopy. Bacterial DNA was extracted from 72 samples (36 NP/BALF pairs); the bacterial V1-V3 region of the 16S rRNA gene was amplified and sequenced on the Illumina Miseq platform. Analysis was performed using mothur software. RESULTS: Compared to NP samples, BALF had increased richness and diversity. Similarity between paired NP and BALF (intra-subject) samples was greater than inter-subject samples (P = 0.0006). NP samples contained more Actinobacteria (2.2% vs 21%; adjusted P = 1.4 * 10-6 ), while BALF contained more Bacteroidetes (29.5% vs 3.2%; adjusted P = 1.2 * 10-9 ). At the genus level several differences existed, however Streptococcus abundance was similar in both sample types (NP 37.3% vs BAL 36.1%; adjusted P = 0.8). CONCLUSION: Our results provide evidence that NP samples can be used to distinguish differences between children, but the relative abundance of organisms may differ between the nasopharynx and lower airway in pediatric patients. Studies utilizing NP samples as surrogates for the lower airway should be interpreted with caution. PMID- 29405662 TI - Bright Photoluminescence of [{(CptBu2 )2 Ce(MU-Cl)}2 ]: A Valuable Technique for the Determination of the Oxidation State of Cerium. AB - The synthesis and photoluminescence properties of the bright-yellow organocerium complex [{(CptBu2 )2 Ce(MU-Cl)}2 ] (CptBu2 =1,3-di(tert-butyl)cyclopentadienyl) are presented. This coordination compound exhibits highly efficient photoluminescence within the yellow-light wavelength range, with a high internal quantum yield of 61(+/-2) % at room temperature. The large red shift is attributed to the delocalizing ability of the aromatic ligands, whilst its quantum yield even makes this compound competitive with Ce3+ -activated LED phosphors in terms of its photoluminescence efficiency (disregarding its thermal stability). A bridging connection between two crystallographically independent Ce3+ ions is anticipated to be the reason for the highly efficient photoluminescence, even up to room temperature. The emission spectrum is characterized by two bands in the orange-light range at both 10 K and room temperature, which are attributed to the parity-allowed transitions 5d1 (2 D3/2 ) >4f1 (2 F7/2 ) and 5d1 (2 D3/2 )->4f1 (2 F5/2 ) of Ce3+ , respectively. The photoluminescence spectra were interpreted in relation to the structure and vibrational modes of the coordination compound. The spectra and optical properties indicate that trivalent cerium ions are the dominant species in the ground state, which also resolves an often-encountered ambiguity in organocerium compounds. This result shows that photoluminescence spectroscopy is a versatile tool that can help elucidate the oxidation state of Ce in such compounds. PMID- 29405663 TI - Cytologic-histologic correlation of programmed death-ligand 1 immunohistochemistry in lung carcinomas. AB - BACKGROUND: Programmed cell death protein 1 inhibitors increasingly are being used to treat patients with advanced lung carcinomas. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in tumor cells (TCs) and tumor-infiltrating immune cells (ICs) is used to select patients for programmed cell death protein 1 inhibition, but few studies have evaluated PD-L1 IHC in cytology specimens. The objective of the current study was to compare PD-L1 IHC in cytology cell blocks and matched surgical specimens. METHODS: A total of 56 cytology specimens obtained between 2013 and 2016 with matching surgical specimens were stained with anti-PD-L1. Membranous positivity was scored as a percentage of the TCs and ICs by 2 pathologists. Results were compared between cytology and surgical specimens, and interobserver concordance was assessed. RESULTS: The average PD-L1 positivity rate was 28% in TCs and 5% in ICs in surgical specimens (standard deviations of 37% and 7%, respectively), and 21% in TCs and 8% in ICs in cytology specimens (standard deviations of 33% and 15%, respectively). Interobserver concordance was high for TCs in surgical and cytology specimens (intraclass correlation coefficients of 0.96 and 0.96, respectively), and was moderate for ICs in surgical and cytology specimens (intraclass correlation coefficients of 0.47 and 0.67, respectively). There was moderate to high correlation between PD-L1 positivity in TCs between surgical and cytology specimens (Spearman correlation coefficient [Spearman r], 0.69), particularly among fine-needle aspiration specimens (Spearman r, 0.78), but not between PD-L1 positivity in ICs in surgical and cytology specimens (Spearman r, 0.14), including among fine-needle aspiration specimens (Spearman r, 0.23). CONCLUSIONS: Tumor PD-L1 IHC positivity in cytology specimens appears to correlate strongly with results obtained from matching surgical specimens. PD-L1 IHC in ICs within cytology specimens does not reflect results in matched surgical specimens and should not be used in clinical decision making. Cancer Cytopathol 2018;126:253-63. (c) 2018 American Cancer Society. PMID- 29405664 TI - Comparison of bronchoscopy and bronchoalveolar lavage findings in three types of suppurative lung disease. AB - BACKGROUND: Endobronchial suppuration is present in children with protracted bacterial bronchitis (PBB), bronchiectasis, and cystic fibrosis (CF). However, no studies have directly compared bronchoscopy and bronchoalveolar lavage (BAL) findings across these conditions within a single center using the same techniques and with shared community pathogens. AIM: To determine; (i) the bronchoscopic findings and BAL microbiology and cellularity among children with these conditions and; (ii) the relationship between bacterial pathogens, airway cellularity and aberrant macroscopic bronchoscopic findings. METHODS: We retrospectively reviewed all bronchoscopy data (undertaken over 6.5-years) from our center in children (<6 years; n = 316) meeting definitions of PBB (n = 125), bronchiectasis (n = 138), and CF (n = 53). RESULTS: The children's median age was 26-months (Interquartile range (IQR) = 16-43). Children with PBB and bronchiectasis had higher rates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae infection, whereas children with CF had frequent Pseudomonas aeruginosa and Staphylococcus aureus infections. Novel findings include detection of cytomegalovirus and Epstein-Barr virus (EBV) (by polymerase chain reaction) in children with PBB (26%, 17%, respectively) and bronchiectasis (27%, 29%). Median airway neutrophil percentage was significantly higher in CF (68%; IQR = 42-83) compared to PBB (36%; IQR = 18-68) and bronchiectasis (22%; IQR = 8-64) (P < 0.0001), despite lower rates of infection. Presence of malacia did not significantly impact on infection or inflammation. CONCLUSION: In this first study to directly compare bronchoscopic data among young children with PBB, bronchiectasis, and CF, microbiological patterns of airway infections and neutrophilia varied. Our findings of cytomegalovirus and EBV detection in children with PBB and bronchiectasis require confirmation and further evaluation. PMID- 29405666 TI - Changes in sensory processing after anesthesia in toddlers. AB - BACKGROUND: Anesthesia and surgery may influence toddlers' sensory processing and consequently postoperative adjustment and behavior. This is the first study to: 1) test pre- to postoperative changes in sensory processing after pediatric anesthesia using the validated Infant/Toddler-Sensory Profile for 7-36 months (ITSP7-36); 2) identify putative predictors of these changes. METHODS: This prospective cohort study included 70 healthy boys (ASA I & II), aged 18-30 months, who underwent circumcision for religious reasons. Exclusion: boys with prior surgery and known developmental delay. PRIMARY OUTCOME: changes in sensory processing from the day of admission to day 14 postoperatively. The accompanying parent completed the ITSP7-36. Putative predictors: 1) child's preoperative emotional/behavioral problems; 2) child's state anxiety at induction; 3) postoperative pain at home. All children received standardized anesthesia and pain management. RESULTS: For 45 boys, assessments were completed at both time points. Significant changes in sensory processing (mean ITSP7-36 scores) were found on: low registration (47.5 to 49.8; P=0.015), sensory sensitivity (45.2 to 48.0; P=0.011), sensation avoiding (48.2 to 51.3; P=0.010), low threshold (93.4 to 99.4; P=0.007), auditory processing (39.3 to 43.3; P=0.000) and tactile processing (53.9 to 58.4; P=0.002). Higher scores on emotional/behavioral problems predicted changes on sensory processing. CONCLUSIONS: Sensory processing of these toddlers had changed after anesthesia. Children with more pre-existent emotional/behavioral problems are more vulnerable to these changes. PMID- 29405665 TI - Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen Synthease-Kinase-3-Beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo. AB - Non-union defects of bone are a major problem in orthopedics, especially for patients with a low healing capacity. Fixation devices and osteoconductive materials are used to provide a stable environment for osteogenesis and an osteogenic component such as autologous human bone marrow (hBM) is then used, but robust bone formation is contingent on the healing capacity of the patients. A safe and rapid procedure for improvement of the osteoanabolic properties of hBM is, therefore, sought after in the field of orthopedics, especially if it can be performed within the temporal limitations of the surgical procedure, with minimal manipulation, and at point-of-care. One way to achieve this goal is to stimulate canonical Wingless (cWnt) signaling in bone marrow-resident human mesenchymal stem cells (hMSCs), the presumptive precursors of osteoblasts in bone marrow. Herein, we report that the effects of cWnt stimulation can be achieved by transient (1-2 hours) exposure of osteoprogenitors to the GSK3beta-inhibitor (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO) at a concentration of 800 nM. Very rapid-exposure-to-BIO (VRE-BIO) on either hMSCs or whole hBM resulted in the long term establishment of an osteogenic phenotype associated with accelerated alkaline phosphatase activity and enhanced transcription of the master regulator of osteogenesis, Runx2. When VRE-BIO treated hBM was tested in a rat spinal fusion model, VRE-BIO caused the formation of a denser, stiffer, fusion mass as compared with vehicle treated hBM. Collectively, these data indicate that the VRE BIO procedure may represent a rapid, safe, and point-of-care strategy for the osteogenic enhancement of autologous hBM for use in clinical orthopedic procedures. Stem Cells Translational Medicine 2018;7:342-353. PMID- 29405667 TI - Sugammadex antagonism of rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing liver resection: a randomized controlled study. AB - BACKGROUND: This randomized controlled study compared the recovery times of sugammadex and neostigmine as antagonists of moderate rocuronium-induced neuromuscular block in patients with liver cirrhosis and controls undergoing liver resection. METHODS: The study enrolled 27 adult patients with Child class "A" liver cirrhosis and 28 patients with normal liver functions. Normal patients and patients with liver cirrhosis were randomized according to the type of antagonist (sugammadex 2 mg/kg or neostigmine 50 ug/kg). The primary outcome was the time from antagonist administration to a train-of-four (TOF) ratio of 0.9 using mechanosensor neuromuscular transmission module. The durations of the intubating and top-up doses of rocuronium, the length of stay in the post anesthesia care unit (PACU), and the incidence of postoperative re-curarization were recorded. RESULTS: The durations of the intubating and top-up doses of rocuronium were prolonged in patients with liver cirrhosis than controls. The times to a TOF ratio of 0.9 were 3.1 (1.0) and 2.6 (1.0) min after sugammadex administration in patients with liver cirrhosis and controls, respectively, P=1.00. The corresponding times after neostigmine administration were longer than sugammadex 14.5 (3.6) and 15.7 (3.6) min, respectively, P<0.001. The duration of PACU stay was shorter with the use of sugammadex compared to neostigmine. We did not encounter postoperative re-curarization after sugammadex or neostigmine. CONCLUSIONS: Sugammadex rapidly antagonize moderate residual rocuronium-induced neuromuscular block in patients with Child class "A" liver cirrhosis undergoing liver resection. Sugammadex antagonism is associated with 80% reduction in the time to adequate neuromuscular recovery compared to neostigmine. PMID- 29405668 TI - Treatment of recent onset low back pain with periradicular injections of meloxicam: a randomized, double blind, placebo controlled cross-over study. AB - BACKGROUND: Low back pain (LBP) is a common and costly illness. This randomized, double-blind, placebo-controlled, cross-over study tested the hypothesis that periradicular injections of meloxicam would reduce LBP and improve physical activity compared to a saline injection at 3 months follow-up. METHODS: After IRB approval, 80 consenting patients suffering LBP of <6 months duration were randomly assigned to the control (C-group, N.=40, receiving 10 mL of saline) or the meloxicam (M-group, N.=40, receiving 10 mg in 10 mL saline). If the pain Numeric Rating Score (NRS) at 24 hours remained >50% of the pretreatment score, the patient was crossed-over to the other group. A successful treatment was NRS<3 at 3 months follow-up. Secondary outcome measures which were assessed included work-absence, physical-assistance, physical-activities limitations and pain related insomnia. RESULTS: The baseline NRS was 9.3 (95% CI: 8.9-9.7) in the C group and 9.2 (95% CI: 8.8-9.6) in the M-group. At the 24 hours follow-up after the initial treatment, the mean NRS was 6.3 (95% CI: 5.4-7.2) in the C-group vs. 3.5 (95% CI: 2.6-4.4) in the M-group (P<0.05). The number of cross-over cases was significantly higher in the C-group (N.=31, 77.5% vs. N.=5, 12.5%, P<0.001). At the 3 months follow-up, 66 patients (35+31) were allocated in the M-group and 54 (82%) reported NRS Score <3, while only 14 (9+5) patients remained in the C-group and eight patients had NRS<3. CONCLUSIONS: Periradicular injection of meloxicam is an effective analgesic treatment for acute/subacute LBP. This novel use of meloxicam also leads to an improvement in the level of physical activity at the 3 month follow-up. PMID- 29405669 TI - Usefulness of postreperfusion lactate clearance for predicting early graft recovery in liver transplant patients: a single center study. AB - BACKGROUND: The role of postreperfusion lactate clearance in assessing graft function has not yet been investigated. The aim of this study was to examine whether lactate clearance, assessed in the postreperfusion phase, can predict poor graft function in liver transplant patients. METHODS: Seventy patients undergoing liver transplantation (LT) were enrolled. Standardized anesthesia and intraoperative monitoring were applied. The lactate levels measured immediately after venous reperfusion and six hours later were used to calculate lactate clearance by the following formula: [(reperfusion lactate - 6 h post-reperfusion lactate)/reperfusion lactate] *100. Student's t-test was performed to evaluate differences in lactate clearance between patients with good and poor graft function. Logistic regression was used to assess predictors of poor graft function. RESULTS: Postreperfusion lactate clearance was lower in patients with poor graft function compared to those with good graft function (P=0.0007). Logistic regression showed that postreperfusion lactate clearance may represent an early predictor of poor graft function (area under receiver operating characteristic curve =0.83). A lactate clearance cut-off of 59.7% was found (90% sensitivity, 38.3% specificity). CONCLUSIONS: Postreperfusion lactate clearance may be useful for the early identification of poor graft function after LT. In patients with lactate clearance <59.7%, it could be useful to search for the underlying cause of poor graft function. PMID- 29405670 TI - Low-concentration distal nerve blocks with 0.125% levobupivacaine versus systemic analgesia for ambulatory trapeziectomy performed under axillary block: a randomized controlled trial. AB - BACKGROUND: Trapeziectomy is one of the most painful procedures in ambulatory surgery. This prospective randomized trial aimed to compare postoperative pain control using distal peripheral nerve blocks (dPNB) with a low concentration of a long-acting local anesthetic versus conventional systemic analgesia. METHODS: Fifty-two patients undergoing trapeziectomy were randomized to receive levobupivacaine 0.125% 5 mL on radial and median nerves at the elbow (dNB group), or not to receive these blocks (control group). In both groups, surgery was performed under axillary block (mepivacaine 1% 20 mL) and the same analgesic regimen was prescribed at discharge. The primary outcome was postoperative pain at 24 and 48 hours after surgery and maximum pain score on the first and second postoperative day. Secondary outcomes were duration of dPNB, rescue analgesia requirements, opioid-related side effects, consumption and effectiveness of antiemetic therapy, and upper limb motor block. RESULTS: Fifty patients were analyzed. Maximum pain intensity was moderate to severe (dPNB vs. control) in 33.3% vs. 92.3% (P=0.002) on the first day after surgery and 20.8% vs. 80.8% (P<0.001) on the second day. The average duration of analgesia after dPNB was 10 hours and no patient reported motor block. dPNB reduced rescue analgesia requirements and the incidence of postoperative nausea and vomiting (PONV). CONCLUSIONS: dPNB on target nerves provided better analgesia than systemic analgesia after trapeziectomy performed under axillary block. Opioid consumption and the incidence of PONV were lower in the dPNB group. PMID- 29405672 TI - Acute renal replacement therapy in patients with major extremity injuries. AB - INTRODUCTION: This narrative review will describe treatment options for patients in the ICU with major extremity injury requiring extracorporeal myoglobin removal and contemporaneous support for systemic complications, such as sepsis, systemic inflammation and coagulation disorders. EVIDENCE ACQUISITION: Peer-reviewed manuscripts indexed in PubMed. A systematic search for articles describing treatment options for patients in the ICU with major extremity injury were included in the analysis. Our group determined by consensus which resources would best inform this review. EVIDENCE SYNTHESIS: Acute renal replacement therapy (ARRT) for renal support may be needed for patients with major extremity trauma developing AKI. Contemporary advances allow the physician to perform a tailored treatment that closely match patient's needs. Techniques and equipment for ARRT can be modulated according to the patient's pathophysiological derangements, maximizing the therapeutic effects and minimizing adverse events. CONCLUSIONS: Most of the clinical reviews available in the literature on this topic limit their focus to the extracorporeal removal of myoglobin. PMID- 29405673 TI - Multimodal analgesia and sedation in the electrophysiology laboratory. PMID- 29405671 TI - Light sedation with dexmedetomidine: a practical approach for the intensivist in different ICU patients. AB - Light sedation, corresponding to a Richmond Agitation-Sedation Scale between 0 and -1 is a priority of modern critical care practice. Dexmedetomidine, a highly selective, central, alpha2-adrenoceptor agonist, is increasingly administered in the intensive care units (ICUs) as an effective drug to induce light sedation, analgesia and a quasi-physiological sleep in critically ill patients. Although in general dexmedetomidine is well tolerated, side effects as bradycardia, hypertension, and hypotension may occur. Although a general dosing range is suggested, different ICU patients may require different and highly precise titration that may significantly vary due to neurological status, cardio respiratory function, base-line blood pressure, heart rate, liver efficiency, age and co-administration of other sedatives. This review analyzes the use of dexmedetomidine in different settings including pediatric, adult, medical and surgical patients starting with some considerations on delirium prevention and sleep quality in critically ill patients and how dexmedetomidine may contribute to these crucial aspects. Dexmedetomidine use in specific sub-populations with unique characteristics will be detailed, with a special attention to a safe use. PMID- 29405674 TI - Mathematical modeling for clinical coagulation management: is this the crystal ball we have been looking for? PMID- 29405675 TI - Patient selection for extracorporeal CO2 removal: a task as challenging as for ECMO therapy. PMID- 29405676 TI - Postoperative analgesia choices in total knee replacement. PMID- 29405677 TI - Opioid consumption after surgery: what is clinically significant? PMID- 29405679 TI - This Healthcare Technology is Off the Blockchain. PMID- 29405678 TI - The Role of Coding and Documentation in the Quality Payment Program. PMID- 29405680 TI - House of Delegates Helping Govern HIM Profession. PMID- 29405682 TI - Three Practical IG Projects You Should Implement Today. PMID- 29405681 TI - [Neuroendocrine effects of helminthiases (A review)]. AB - Nowadays the number of patients diagnosed with helminthiases shows tendency for steadygrowth around the world. During last few years, researches in the field of immunologyhave again turned their attention towards the question of parasitological immunity and tissueresponse. Helminthiases and other parasitic diseases in some instances can induce centralnervous system disorders and violate human behavioral reactions. Studies have suggestedan association between epilepsy and helminth infection, but a causal relationship is notestablished in many helminths, except perhaps with neurocysticercosis. The aim of this reviewis to reveal details of specific mechanisms of the general helminths' impact on thenervous system and the endocrine control level of physiological functions of the host organism.Finally, we discuss the current gaps in knowledge about the interaction between helminths,immunity, and human endocrine system.Key words: helminths, immunity, hormones, cytokines. PMID- 29405683 TI - [Ticks (Acari, ixodidae) of the North Caucasus: Species diversity, host-parasite relationships]. AB - Biological diversity of ixodid tick fauna of the North Caucasus is analyzed. On the whole, 38 tick species are represented in the fauna of the North Caucasus. Their distribution within the region, biotopic features, and host-parasite relationships of different stages of ontogenesis are considered. PMID- 29405684 TI - [The quill mite Syringophilopsis fringilla (Fritsch) (Acari: Trombidiformes: Syringophilidae): The structure of receptor organs providing feeding of the parasite inside the feather quill]. AB - The structure of sensory organs situated on palps and inside the cheliceral stylet of the quill mite Sringophilopsis fringilla (Fritsch, 1958) was examined in scanning and transmitting electron microscopes. Eight sensilla of 3 types were revealed on palptarsus, including two contact chemo-mechanosensory sensilla, a single distant chemosensory (probably olfactory) sensillum, and 5 tactile mechanosensitive sensilla. All other sensilla situated on basas parts of the palp and on the outer surface of gnathosoma are represented by tactile mechanoreceptors. A proprioceptor sensillum was revealed in the movable digit of the chelicera; modified cilia of dendrites of 5 sensory neurons run in the inner non-sclerotized core of the stylet, ending at different levels as electron-dense rods connected with the sclerotized wall of the stylet. The authors assume that the proprioceptor sensillum of the stylet detects the pressing force of the movable digit on the inner wall of the quill during piercing process, while papal sensilla determine the optimal place for piercing. PMID- 29405685 TI - [Gamasid mites of small mammals in the semi-desert territories of the Saratov Trans-Volga region]. AB - The paper contains the data on the species composition and comparative analysis of gamaside mites, parasitizing on small mammals in the semi-desert territories of Saratov trans-Volga region. On the basis of the results of investigations conducted in the Aleksandrovo-Gaisky District in 2008-2013, 18 species of gamaside mites (9 genusus, 5 families) have been recorded. Nine species of maaside mites, which were not found in semi-desert zone earlier were revealed, includiding Hypoaspis (Stratiolaelaps) miles Berlese, 1882, H. (Geolaelaps) heselhausi Oudemans, 1912, H. (G.) lubrica Oudemans et Voigts, 1604, G. et. R. Canestrini, 1881, Haemogamasus citelli Bregetova et Nelzina, 1952, Hirstionyssus eusoricis Bregetova, 1956, Hi. ellobii Bregetova, 1653; five of these species are new for the territory of Saratov Province. As a result of the study of semi desert zone of Saratov trans-Volga region and taking into account literary data, parasitic fauna of small mammals of Aleksandrovo-Gaisky District was expanded up to 21 species, and of Saratov Province, up to 44 species of gamasid mites. PMID- 29405686 TI - RAC Audit Underpayments: Does CMS Owe You Money? PMID- 29405687 TI - Welcome to HIM, Watch Your Step. Unique HIM Role Focuses on Blending Education and Workforce Development to Properly Onboard New Hires and Get Students Vital On the-Job Experience. PMID- 29405688 TI - Advancing HIM and Privacy Roles Through Information Governance. PMID- 29405689 TI - [Influence of meteorological factors on the activity of the adult taiga tick (Ixodes persulcatus Sch., Ixodinae) in St. Petersburg and its environs]. AB - The article deals with influence of meteorolical factors on the activity of the taiga tick Ixodes persulvatus Sch. in St. Petersburg and its environs. The results of correlation analysis of meteorological data (21 index) and data ticks collected in 1980-2012 allowed determining linear dependence between 11 meteorological indices an average amount of ticks. Factor analysis reduced dimentionality down to 3 indices: sum of temperatures higher than +5.0 degrees C, sum of precipitation higher than 5 mm per year, and Selyaninov hydrothermal coefficient. It was demonstrated that, at the background of the general tendency for the decrease of the average number of active ticks in the studied territories, correlation between the amount of ticks and meteorological indices can significantly vary as in the correlation density, so in the character and in dependence of microclimatic features of the collecting site. When variability of the mean abundance of ticks during years of investigation is low, the methods of collecting can significantly affect the results of the statistical analysis. This fact must be taken in consideration during prognosis of both dates of the beginning of epidemiological season and its intensity. PMID- 29405690 TI - [Description of virgulate Cercaria etgesh larva Nov. (Xiphidiocercariae): A new type of virgule organ]. AB - A new species of virgulate cercaria is described. The morphology and chaetotaxy of cercariae are studied. The new type of virgule organ is described. Every description is illustrated by drawings. PMID- 29405691 TI - Facile and Green Approach to the Synthesis of Boron Nitride Quantum Dots for 2,4,6-Trinitrophenol Sensing. AB - A facile and green approach has been developed for synthesis of boron nitride quantum dots (BNQDs). The obtained BNQDs exhibit strong fluorescence and excellent stabilities, including high thermostability, good salt tolerance stability, pH-independence ability, and excellent antiphotobleaching capability. The strong inner filter effect between 2,4,6-trinitrophenol (TNP) and BNQDs resulted in fluorescence quenching of BNQDs. Thus, TNP can be selectively and sensitively detected in the concentration range of 0.25-200 MUM, with a limit detection of 0.14 MUM. The BNQD-based turn-off sensor shows potential prospects for rapidly and selectively detecting TNP in natural water samples without tedious sample pretreatment processes. PMID- 29405692 TI - Heterostructured Bi2S3-Bi2O3 Nanosheets with a Built-In Electric Field for Improved Sodium Storage. AB - Constructing novel heterostructures has great potential in tuning the physical/chemical properties of functional materials for electronics, catalysis, as well as energy conversion and storage. In this work, heterostructured Bi2S3 Bi2O3 nanosheets (BS-BO) have been prepared through an easy water-bath approach. The formation of such unique BS-BO heterostructures was achieved through a controllable thioacetamide-directed surfactant-assisted reaction process. Bi2O3 sheets and Bi2S3 sheets can be also prepared through simply modifying the synthetic recipe. When employed as the sodium-ion battery anode material, the resultant BS-BO displays a reversible capacity of ~630 mA h g-1 at 100 mA g-1. In addition, the BS-BO demonstrates improved rate capability and enhanced cycle stability compared to its Bi2O3 sheets and Bi2S3 sheets counterparts. The improved electrochemical performance can be ascribed to the built-in electric field in the BS-BO heterostructure, which effectively facilitates the charge transport. This work would shed light on the construction of novel heterostructures for high-performance sodium-ion batteries and other energy related devices. PMID- 29405693 TI - Electrokinetic Supercapacitor for Simultaneous Harvesting and Storage of Mechanical Energy. AB - Energy harvesting and storage are two distinct processes that are generally achieved using two separated parts based on different physical and chemical principles. Here we report a self-charging electrokinetic supercapacitor that directly couples the energy harvesting and storage processes into one device. The device consists of two identical carbon nanotube/titanium electrodes, separated by a piece of anodic aluminum oxide nanochannels membrane. Pressure-driven electrolyte flow through the nanochannels generates streaming potential, which can be used to charge the capacitive electrodes, accomplishing simultaneous energy generation and storage. The device stores electric charge density of 0.4 mC cm-2 after fully charging under pressure of 2.5 bar. This work may offer a train of thought for the development of a new type of energy unit for self powered systems. PMID- 29405694 TI - Reversible Silver Electrodeposition from Boron Cluster Ionic Liquid (BCIL) Electrolytes. AB - Electrochemical systems offer a versatile means for creating adaptive devices. However, the utility of electrochemical deposition is inherently limited by the properties of the electrolyte. The development of ionic liquids enables electrodeposition in high-vacuum environments and presents opportunities for creating electrochemically adaptive and regenerative spacecraft components. In this work, we developed a silver-rich, boron cluster ionic liquid (BCIL) for reversible electrodeposition of silver films. This air and moisture stable electrolyte was used to deposit metallic films in an electrochemical cell to tune the emissivity of the cell in situ, demonstrating a proof-of-concept design for spacecraft thermal control. PMID- 29405695 TI - Decoding the Vertical Phase Separation and Its Impact on C8-BTBT/PS Transistor Properties. AB - Disentangling the details of the vertical distribution of small semiconductor molecules blended with polystyrene (PS) and the contact properties are issues of fundamental value for designing strategies to optimize small-molecule:polymer blend organic transistors. These questions are addressed here for ultrathin blends of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) and PS processed by a solution-shearing technique using three different blend composition ratios. We show that friction force microscopy (FFM) allows the determination of the lateral and vertical distribution of the two materials at the nanoscale. Our results demonstrate a three-layer stratification of the blend: a film of C8-BTBT of few molecular layers with crystalline order sandwiched between a PS-rich layer at the bottom (a few nm thick) acting as a passivating dielectric layer and a PS-rich skin layer on the top (~1 nm) conferring stability to the devices. Kelvin probe force microscopy (KPFM) measurements performed in operating organic field-effect transistors (OFETs) reveal that the devices are strongly contact-limited and suggest contact doping as a route for device optimization. By excluding the effect of the contacts, field-effect mobility values in the channel as high as 10 cm2 V-1 s-1 are obtained. Our findings, obtained via a combination of FFM and KPFM, provide a satisfactory explanation of the different electrical performances of the OFETs as a function of the blend composition ratio and by doping the contacts. PMID- 29405696 TI - Mining a Krohnke Pyridine Library for Anti-Arenavirus Activity. AB - Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Kronhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[ b][1,4] dioxin-6-yl)-4'-methoxy-[1,1'-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Krohnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs. PMID- 29405698 TI - Simultaneous Proteoform Analysis of Histones H3 and H4 with a Simplified Middle Down Proteomics Method. AB - Dynamic post-translational modifications of histones regulate transcriptional gene expression in eukaryotes. Unique combinations of modifications, almost exclusively displayed at the flexible N-terminal tails on histones, create distributions of proteoforms that need to be characterized in order to understand the complexity of gene regulation and how aberrant modification patterns influence disease. Although mass spectrometry is a preferred method for the analysis of histone modifications, information is lost when using conventional trypsin-based histone methods. Newer "middle-down" protocols may retain a greater fraction of the full proteoform distribution. We describe a strategy for the simultaneous characterization of histones H3 and H4 with near-complete retention of proteoform distributions, using a conventional proteomics liquid chromatography-tandem mass spectrometry (LC-MS/MS) configuration. The selective prolyl endoprotease neprosin generates convenient peptide lengths for retention and dispersion of modified H3 and H4 peptides on reversed-phase chromatography, offering an alternative to the hydrophilic interaction liquid chromatography typically used in middle-down methods. No chemical derivatizations are required, presenting a significant advantage over the trypsin-based protocol. Over 200 proteoforms can be readily profiled in a single analysis of histones from HeLa S3 cells. An in-gel digestion protocol provides additional options for effective histone analysis. PMID- 29405697 TI - Detection of Bacteria-Specific Metabolism Using Hyperpolarized [2-13C]Pyruvate. AB - The differentiation of bacterial infection from other causes of inflammation is difficult in clinical practice and is critical where patient outcomes rely heavily on early interventions. In addition to physical exam and laboratory markers, several imaging modalities are frequently employed, but these techniques generally target the host immune response, rather than the living microorganisms themselves. Here, we describe a method to detect bacteria-specific metabolism using hyperpolarized (HP) 13C magnetic resonance spectroscopy. This technology allows visualization of the real-time conversion of enriched 13C substrates to their metabolic products, identified by their distinct chemical shifts. We have identified the rapid metabolism of HP [2-13C]pyruvate to [1-13C]acetate as a metabolic signature of common bacterial pathogens. We demonstrate this conversion in representative Gram-negative and Gram-positive bacteria, namely, Escherichia coli and Staphylococcus aureus, and its absence in key mammalian cell types. Furthermore, this conversion was successfully modulated in three mutant strains, corresponding to deletions of relevant enzymes. PMID- 29405699 TI - Investigation of Ion-Solvent Interactions in Nonaqueous Electrolytes Using in Situ Liquid SIMS. AB - Ion-solvent interactions in nonaqueous electrolytes are of fundamental interest and practical importance, yet debates regarding ion preferential solvation and coordination numbers persist. In this work, in situ liquid SIMS was used to examine ion-solvent interactions in three representative electrolytes, i.e., lithium hexafluorophosphate (LiPF6) at 1.0 M in ethylene carbonate (EC)-dimethyl carbonate (DMC) and lithium bis(fluorosulfonyl)imide (LiFSI) at both low (1.0 M) and high (4.0 M) concentrations in 1,2-dimethoxyethane (DME). In the positive ion mode, solid molecular evidence strongly supports the preferential solvation of Li+ by EC. Besides, from the negative spectra, we also found that PF6- forms association with EC, which has been neglected by previous studies due to the relatively weak interaction. In both LiFSI in DME electrolytes, however, no evidence shows that FSI- is associated with DME. Furthermore, strong salt ion cluster signals were observed in the 1.0 M LiPF6 in EC-DMC electrolyte, suggesting that a significant amount of Li+ ions stay in the vicinity of anions. In sharp comparison, weak ion cluster signals were detected in dilute LiFSI in DME electrolyte, suggesting most ions are well separated, in agreement with our molecular dynamics simulation results. These findings indicate that with virtues of little bias on detecting positive and negative ions and the capability of directly analyzing concentrated electrolytes, in situ liquid SIMS is a powerful tool that can provide key evidence for improved understanding on the ion-solvent interactions in nonaqueous electrolytes. Therefore, we anticipate wide applications of in situ liquid SIMS on investigations of various ion-solvent interactions in the near future. PMID- 29405701 TI - Maskless Hydrophilic Patterning of the Superhydrophobic Aluminum Surface by an Atmospheric Pressure Microplasma Jet for Water Adhesion Controlling. AB - Superhydrophobic surfaces with hydrophilic patterns have great application potential in various fields, such as microfluidic systems and water harvesting. However, many reported preparation methods involve complicated devices and/or masks, making fabrication of these patterned surfaces time-consuming and inefficient. Here, we propose a highly efficient, simple, and maskless microplasma jet (MPJ) treatment method to prepare hydrophilic patterns such as dots, lines, and curves on superhydrophobic aluminum substrates. Contact angles, sliding angles, adhesive forces, and droplet impact behavior of the created patterns are investigated and analyzed. The prepared "dot" patterns exhibit great water adhesion, whereas the "line" patterns show anisotropic adhesion. Additionally, the MPJ treatment does not obviously change the surface structures, which makes it possible to achieve repeatable patterning on one substrate. The adhesion behavior of these patterns could be adjusted using MPJs with different diameters. MPJs with larger diameters are efficient for the creation of patterns with high water adhesion, which can be potentially used for open-channel lab-on chip systems (e.g., continuous water transportation), whereas MPJs with smaller diameters are preferable in preparing patterns with low water adhesion for diverse applications in biomedical fields (e.g., lossless liquid droplet mixing and cell screening). PMID- 29405702 TI - Understanding Catalytic Activity Trends in the Oxygen Reduction Reaction. AB - Despite the dedicated search for novel catalysts for fuel cell applications, the intrinsic oxygen reduction reaction (ORR) activity of materials has not improved significantly over the past decade. Here, we review the role of theory in understanding the ORR mechanism and highlight the descriptor-based approaches that have been used to identify catalysts with increased activity. Specifically, by showing that the performance of the commonly studied materials (e.g., metals, alloys, carbons, etc.) is limited by unfavorable scaling relationships (for binding energies of reaction intermediates), we present a number of alternative strategies that may lead to the design and discovery of more promising materials for ORR. PMID- 29405700 TI - X-ray and EPR Characterization of the Auxiliary Fe-S Clusters in the Radical SAM Enzyme PqqE. AB - The Radical SAM (RS) enzyme PqqE catalyzes the first step in the biosynthesis of the bacterial cofactor pyrroloquinoline quinone, forming a new carbon-carbon bond between two side chains within the ribosomally synthesized peptide substrate PqqA. In addition to the active site RS 4Fe-4S cluster, PqqE is predicted to have two auxiliary Fe-S clusters, like the other members of the SPASM domain family. Here we identify these sites and examine their structure using a combination of X ray crystallography and Mossbauer and electron paramagnetic resonance (EPR) spectroscopies. X-ray crystallography allows us to identify the ligands to each of the two auxiliary clusters at the C-terminal region of the protein. The auxiliary cluster nearest the RS site (AuxI) is in the form of a 2Fe-2S cluster ligated by four cysteines, an Fe-S center not seen previously in other SPASM domain proteins; this assignment is further supported by Mossbauer and EPR spectroscopies. The second, more remote cluster (AuxII) is a 4Fe-4S center that is ligated by three cysteine residues and one aspartate residue. In addition, we examined the roles these ligands play in catalysis by the RS and AuxII clusters using site-directed mutagenesis coupled with EPR spectroscopy. Lastly, we discuss the possible functional consequences that these unique AuxI and AuxII clusters may have in catalysis for PqqE and how these may extend to additional RS enzymes catalyzing the post-translational modification of ribosomally encoded peptides. PMID- 29405703 TI - Lanthanide-Doped Core-Shell-Shell Nanocomposite for Dual Photodynamic Therapy and Luminescence Imaging by a Single X-ray Excitation Source. AB - Photodynamic therapy (PDT) could be highly selective and noninvasive, with low side effects as an adjuvant therapy for cancer treatment. Because excitation sources such as UV and visible lights for most of the photosensitizers do not penetrate deeply enough into biological tissues, PDT is useful only when the lesions are located within 10 mm below the skin. In addition, there is no prior example of theranostics capable of both PDT and imaging with a single deep penetrating X-ray excitation source. Here we report a new theranostic scintillator nanoparticle (ScNP) composite in a core-shell-shell arrangement, that is, NaLuF4:Gd(35%),Eu(15%)@NaLuF4:Gd(40%)@NaLuF4:Gd(35%),Tb(15%), which is capable of being excited by a single X-ray radiation source to allow potentially deep tissue PDT and optical imaging with a low dark cytotoxicity and effective photocytotoxicity. With the X-ray excitation, the ScNPs can emit visible light at 543 nm (from Tb3+) to stimulate the loaded rose bengal (RB) photosensitizer and cause death of efficient MDA-MB-231 and MCF-7 cancer cells. The ScNPs can also emit light at 614 and 695 nm (from Eu3+) for luminescence imaging. The middle shell in the core-shell-shell ScNPs is unique to separate the Eu3+ in the core and the Tb3+ in the outer shell to prevent resonance quenching between them and to result in good PDT efficiency. Also, it was demonstrated that although the addition of a mesoporous SiO2 layer resulted in the transfer of 82.7% fluorescence resonance energy between Tb3+ and RB, the subsequent conversion of the energy from RB to generate 1O2 was hampered, although the loaded amount of the RB was almost twice that without the mSiO2 layer. A unique method to compare the wt % and mol % compositions calculated by using the morphological transmission electron microscope images and the inductively coupled plasma elemental analysis data of the core, core-shell, and core-shell-shell ScNPs is also introduced. PMID- 29405704 TI - Response to the Comments on Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice. PMID- 29405705 TI - Mechanical-Stimulation-Triggered and Solvent-Vapor-Induced Reverse Single-Crystal to-Single-Crystal Phase Transitions with Alterations of the Luminescence Color. AB - Luminescence alterations in solid-state materials upon external stimulations have attracted much attention due to their potential for the development of highly functional devices or sensors. We have previously reported the first examples of mechano-induced single-crystal-to-single-crystal (SCSC) phase transitions of gold(I) isocyanide complexes under concomitant emission-color changes. However, the reverse phase transitions of the crystals obtained after mechanical stimulation have not yet been achieved. Herein, a reversible change of the luminescence based on two SCSC phase transitions via mechanical cutting and solvent-vapor adsorption is described. Crystallization of a gold(I) complex that bears CF3 and biaryl moieties from CH2Cl2/MeOH afforded a green-emitting single crystal packed in a polar space group (Pna21). The green-emitting single crystals included MeOH molecules. Upon cutting the crystal under MeOH vapor at 22 degrees C, the green-emitting single crystal spontaneously changed into a centrosymmetric orange-emitting single crystal (P1) under concomitant release of MeOH. Remarkably, the initial green-emitting crystal could be recovered from the orange emitting crystal by a solvent-induced SCSC transition under saturated MeOH vapor. The combination of two different types of SCSC phase transitions enables the reversible structural and photoluminescent alternations. PMID- 29405706 TI - Tuning the Thermal Isomerization of Phenylazoindole Photoswitches from Days to Nanoseconds. AB - The growing interest in light-driven molecular switches and optical oscillators led to the development of molecules that are able to interconvert from a stable to a metastable configuration upon photochemical triggering and to return to the thermodynamically stable form as soon as the light stimulus is removed. Controlling a wide range of back-isomerization lifetimes in the dark is a crucial goal for potential application of these compounds such as molecular machines. We herein present a novel class of easily synthesizable azo photoswitches based on the arylazoindole core. Most notably, minimal modifications of the core, such as methylation, dramatically change the Z-to-E thermal isomerization rate from days (Me in position 1) to the nanosecond range (Me in position 2). Moreover, fine tuning of the Z-to-E lifetimes can be achieved choosing a proper dimethyl sulfoxide-water (or buffered water) solvent mixture. The photochemical and thermal mechanisms have been elucidated by a thorough computational and spectroscopic analysis. This allowed to detect three different pathways of thermal isomerization and to identify the hydrazone tautomer of the phenylazoindole as the major actor in the fast Z-E thermal isomerization of the NH-substituted switch in protic media. PMID- 29405707 TI - Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. AB - Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered in 1963 as a unique modification of histones, acetylation marks are now found on thousands of nonhistone proteins located in virtually every cellular compartment. Here we summarize key findings in the field of protein acetylation over the past 20 years with a focus on recent discoveries in nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these findings have elevated protein acetylation as a major post-translational modification, underscoring its physiological relevance in gene regulation, cell signaling, metabolism, and disease. PMID- 29405708 TI - Inactivation of Laccase by the Attack of As (III) Reaction in Water. AB - Laccase is a multicopper oxidase containing four coppers as reaction sites, including one type 1, one type 2, and two type 3. We here provide the first experimental data showing that As (III) can be effectively removed from water and transformed to As (V) through reactions mediated by laccase with the presence of oxygen. To this end, the As (III) removal, As (V) yields, total protein, active laccase, and copper concentrations in the aqueous phase were determined, respectively. Additionally, electron paramagnetic resonance spectra and UV-vis spectra were applied to probe possible structural changes of the laccase during the reaction. The data offer the first evidence that laccase can be inactivated by As (III) attack thus leading to the release of type 2 copper. The released copper has no reactivity with the As (III). These findings provide new ideas into a significant pathway likely to master the environmental transformation of arsenite, and advance the understanding of laccase inactivation mechanisms, thus providing a foundation for optimization of enzyme-based processes and potential development for removal and remediation of arsenite contamination in the environment. PMID- 29405709 TI - BFEE: A User-Friendly Graphical Interface Facilitating Absolute Binding Free Energy Calculations. AB - Quantifying protein-ligand binding has attracted the attention of both theorists and experimentalists for decades. Many methods for estimating binding free energies in silico have been reported in recent years. Proper use of the proposed strategies requires, however, adequate knowledge of the protein-ligand complex, the mathematical background for deriving the underlying theory, and time for setting up the simulations, bookkeeping, and postprocessing. Here, to minimize human intervention, we propose a toolkit aimed at facilitating the accurate estimation of standard binding free energies using a geometrical route, coined the binding free-energy estimator (BFEE), and introduced it as a plug-in of the popular visualization program VMD. Benefitting from recent developments in new collective variables, BFEE can be used to generate the simulation input files, based solely on the structure of the complex. Once the simulations are completed, BFEE can also be utilized to perform the post-treatment of the free-energy calculations, allowing the absolute binding free energy to be estimated directly from the one-dimensional potentials of mean force in simulation outputs. The minimal amount of human intervention required during the whole process combined with the ergonomic graphical interface makes BFEE a very effective and practical tool for the end-user. PMID- 29405710 TI - Comments on Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice. PMID- 29405711 TI - (3+2) Cycloadditions of Thiouronium Ylides: A Room-Temperature, One-Pot Approach to Dihydrothiophenes. AB - A room-temperature (3+2) cycloaddition sequence for the synthesis of highly substituted dihydrothiophene derivatives has been developed. By utilizing structurally unique thiocarbonyl ylides, the reactivity of these traditionally high-energy intermediates can be modulated, enabling a synthetically useful transformation to proceed under mild conditions. PMID- 29405712 TI - Period of Oscillatory Motion of a Camphor Boat Determined by the Dissolution and Diffusion of Camphor Molecules. AB - Here, we investigated the oscillatory motion of a camphor boat on water to clarify how the dynamics of camphor concentration profile determines the period of oscillation. The boat, which was made of a plastic plate and a camphor disk, was glued below the plate at a distance from the edge. The dependence of oscillation period on temperature and viscosity of the water phase was measured in experiments. We reproduced the experimental results by calculating the period of oscillatory motion by considering the experimental values of physicochemical parameters describing the time evolution of camphor concentration profile and the friction acting on a boat, such as diffusion and dissolution rates of camphor, viscosity of the water phase, and the threshold concentration of camphor necessary to accelerate the boat from the resting state. The increase in the period of oscillatory motion at low temperatures was explained by the reduced dissolution rate of camphor into the water phase. PMID- 29405713 TI - Diastereo- and Enantioselective Synthesis of Spirooxindoles with Contiguous Tetrasubstituted Stereocenters via Catalytic Coupling of Two Tertiary Radicals. AB - The oxidative N-heterocyclic carbene-catalyzed [3 + 2] annulation of beta,beta disubstituted enals and dioxindoles was developed, giving the spirocyclic oxindole-gamma-lactones bearing two contiguous tetrasubstituted stereocenters in good yields with excellent diastereoselectivities and good enantioselectivities. PMID- 29405714 TI - Metabolomics-Guided Discovery of Microginin Peptides from Cultures of the Cyanobacterium Microcystis aeruginosa. AB - We report a mass-spectrometry-based metabolomics study of a laboratory-cultured strain of Microcystis aeruginosa (UTEX LB2385), which has led to the discovery of five peptides (1-5) belonging to the microginin class of linear cyanopeptides. The structures and configurations of these peptides were determined by spectroscopic analyses and chemical derivitization. The microginin peptides described herein are the first reported derivatives containing N-methyl methionine (1, 5) and N-methyl methionine sulfoxide (2-4). The two tripeptide microginin analogues (4, 5) identified represent the smallest members of this peptide family. Their angiotensin-converting enzyme (ACE) inhibitory activity was also investigated. Microginin 527 (4) was the most potent of the group, with an IC50 of 31 MUM. PMID- 29405715 TI - Se-C Cleavage of Hexane Selenol at Steps on Au(111). AB - Selenols are considered as an alternative to thiols in self-assembled monolayers, but the Se-C bond is one limiting factor for their usefulness. In this study, we address the stability of the Se-C bond by a combined experimental and theoretical investigation of gas-phase-deposited hexane selenol (CH3(CH2)5SeH) on Au(111) using photoelectron spectroscopy, scanning tunneling microscopy, and density functional theory (DFT). Experimentally, we find that initial adsorption leaves atomic Se on the surface without any carbon left on the surface, whereas further adsorption generates a saturated selenolate layer. The Se 3d component from atomic Se appears at 0.85 eV lower binding energy than the selenolate-related component. DFT calculations show that the most stable structure of selenols on Au(111) is in the form of RSe-Au-SeR complexes adsorbed on the unreconstructed Au(111) surface. This is similar to thiols on Au(111). Calculated Se 3d core level shifts between elemental Se and selenolate in this structure nicely reproduce the experimentally recorded shifts. Dissociation of RSeH and subsequent formation of RH are found to proceed with high barriers on defect-free Au(111) terraces, with the highest barrier for scissoring R-Se. However, at steps, these barriers are considerably lower, allowing for Se-C bond breaking and hexane desorption, leaving elemental Se at the surface. Hexane is formed by replacing the Se-C bond with a H-C bond by using the hydrogen liberated from the selenol to selenolate transformation. PMID- 29405716 TI - PONy Dyes: Direct Addition of P(III) Nucleophiles to Organic Fluorophores. AB - Nucleophilic addition of phosphinic acid, phosphites, sodium dialkyl phosphites, phosphoramidites, phosphinites, and phosphonites to highly polarized or cationic fluorophores, followed by oxidation, results in new "PONy" dyes with auxochromic phosphinate, phosphonate, or phosphonamidate groups. The reaction was applied to a wide variety of coumarins, (thio)pyronins, and N-alkylacridinium and 5,6 dihydrobenzo[c]xanthen-12-ium salts as well as a meso-chlorinated BODIPY to provide compact dyes with red-shifted absorption and emission bands and Stokes shifts up to 8200 cm-1. PMID- 29405717 TI - Plasmonic Control of Multi-Electron Transfer and C-C Coupling in Visible-Light Driven CO2 Reduction on Au Nanoparticles. AB - Artificial photosynthesis relies on the availability of synthetic photocatalysts that can drive CO2 reduction in the presence of water and light. From the standpoint of solar fuel production, it is desirable that these photocatalysts perform under visible light and produce energy-rich hydrocarbons from CO2 reduction. However, the multistep nature of CO2-to-hydrocarbon conversion poses a significant kinetic bottleneck when compared to CO production and H2 evolution. Here, we show that plasmonic Au nanoparticle photocatalysts can harvest visible light for multielectron, multiproton reduction of CO2 to yield C1 (methane) and C2 (ethane) hydrocarbons. The light-excitation attributes influence the C2 and C1 selectivity. The observed trends in activity and selectivity follow Poisson statistics of electron harvesting. Higher photon energies and flux favor simultaneous harvesting of more than one electron from the photocharged Au nanoparticle catalyst, inducing the C-C coupling required for C2 production. These findings elucidate the nature of plasmonic photocatalysis, which involves strong light-matter coupling, and set the stage for the controlled chemical bond formation by light excitation. PMID- 29405718 TI - Palladium/Light Induced Radical Alkenylation and Allylation of Alkyl Iodides Using Alkenyl and Allylic Sulfones. AB - Alkenylation and allylation of alkyl iodides with alkenyl and allyl sulfones, respectively, took place under Pd/photoirradiation system. The initial alkyl radical, derived from a single electron transfer between Pd(0) and RI, underwent the title transformations. Pd(0) was regenerated through a reductive elimination of PhSO2PdI, which is formed by the combination of the sulfonyl radical and the palladium radical. The addition of water was effective, presumably by pushing the equilibrium through hydrolysis of PhSO2I. PMID- 29405719 TI - Plasmon-Enhanced Photocurrent from Photosystem I Assembled on Ag Nanopyramids. AB - Plasmonic metal nanostructures have been known to tune optoelectronic properties of fluorophores. Here, we report the first-ever experimental observation of plasmon-induced photocurrent enhancements from Photosystem I (PSI) immobilized on Fischer patterns of silver nanopyramids (Ag-NP). To this end, the plasmonic peaks of Ag-NP were tuned to match the PSI absorption peaks at ~450 and ~680 nm wavelengths. Specifically, the plasmon-enhanced photocurrents indicate enhancement factors of ~6.5 and ~5.8 as compared to PSI assembly on planar Ag substrates for nominal excitation wavelengths of 660 and 470 nm, respectively. The comparable enhancement factors from both 470 and 660 nm excitations, in spite of a significantly weaker plasmon absorption peak at ~450 nm for the Ag-NP structures, can be rationalized by previously reported excessive plasmon-induced fluorescence emission losses from PSI in the red region as compared to the blue region of the excitation wavelengths. PMID- 29405720 TI - Integrative Genomic and Proteomic Analysis of the Response of Lactobacillus casei Zhang to Glucose Restriction. AB - Nutrient starvation is an important survival challenge for bacteria during industrial production of functional foods. As next-generation sequencing technology has greatly advanced, we performed proteomic and genomic analysis to investigate the response of Lactobacillus casei Zhang to a glucose-restricted environment. L. casei Zhang strains were permitted to evolve in glucose restricted or normal medium from a common ancestor over a 3 year period, and they were sampled at 1000, 2000, 3000, 4000, 5000, 6000, 7000, and 8000 generations and subjected to proteomic and genomic analyses. Genomic resequencing data revealed different point mutations and other mutational events in each selected generation of L. casei Zhang under glucose restriction stress. The differentially expressed proteins induced by glucose restriction were mostly related to fructose and mannose metabolism, carbohydrate metabolic processes, lyase activity, and amino-acid-transporting ATPase activity. Integrative proteomic and genomic analysis revealed that the mutations protected L. casei Zhang against glucose starvation by regulating other cellular carbohydrate, fatty acid, and amino acid catabolism; phosphoenolpyruvate system pathway activation; glycogen synthesis; ATP consumption; pyruvate metabolism; and general stress-response protein expression. The results help reveal the mechanisms of adapting to glucose starvation and provide new strategies for enhancing the industrial utility of L. casei Zhang. PMID- 29405721 TI - Diastereoselective alpha-Hydroxylation of N-tert-Butanesulfinyl Imidates and N' tert-Butanesulfinyl Amidines with Molecular Oxygen. AB - Diastereoselective alpha-hydroxylation using molecular oxygen has been achieved with chiral alpha-alkyl N-tert-butanesulfinyl imidates and alpha-aryl N'-tert butanesulfinyl amidines. The aza-enolates generated from deprotonation of imidates/amidines can be intercepted by O2 with excellent diastereocontrol and subsequently transformed into alpha-hydroxylation products in the presence of the reductant trimethyl phosphite. PMID- 29405722 TI - Late relapse in stage I of nonseminomatous germ cell testicular cancer on surveillance. AB - OBJECTIVE: Primary aim was to assess relapse-free survival (RFS) in patients with clinical stage I (CS I) of non-seminomatous germ cell testicular tumors (NSGCTT) undergoing surveillance after orchiectomy. The secondary aim was to examine differences in risk factors in patients with early relapse (ER 2 years) and very late relapse (VLR > 5 years). METHODS: Cross-sectional study analyzed 25-year single-center experiences with 198 CS I NSGCTT patients according the time to relapse. RESULTS: RFS was 160/198 (80.8 %). Relapse occurred in 38 (19.2 %) patients after a median fol-low-up of 7.57 months, 33 (86.8 %) patients had ER after a median follow-up of 7.03 months and 5 patients had LR (13.2 %) after a median follow-up of 26.28 months. One patient (2.63 %) had VLR after follow-up > 5 years (7.17 years). Three relapsed patients died with metastatic disease after a mean follow-up of 5.1 years from the date of diagnosis. Another three patients died without cancer after a mean follow-up of two years. OS was 192/198 (97 %). CONCLUSION: Diagnosis and treatment of late relapsing NSGCTT patients should be performed in experienced centers only. Occurrence of LR is the reason for long term monitoring of NSGCTT survivors (Tab. 1, Fig. 1, Ref. 14). PMID- 29405723 TI - Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients. AB - OBJECTIVE: Colorectal cancer (CRC) is one of the main causes of cancer deaths in the world. This cancer can be divided into non-metastatic and metastatic CRC stages. CD3+CD56+ NKT cell subsets are a minor T cell subset in peripheral blood and conduct the killing of tumor cells in direct manner. Little is obvious about levels and surface markers of these cells such as NKG2D in different cancers, especially in CRC. METHODS: We included 15 non-metastatic (low-grade), 11 non metastatic (high-grade), 10 metastatic colorectal cancer patients and 18 healthy controls. The percentages of CD3+CD56+ NKT cells and NKG2D+CD56+ NKT cells from samples were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs) of samples. RESULTS: We found that there was a significantly lower number of NKG2D+CD3+CD56+ cells in peripheral blood of patients with metastatic colorectal cancer compared with normal controls (77.53 +/- 5.79 % vs 90.74 +/- 9.84 %; p<0.01). CONCLUSION: The fact that frequency of NKG2D+CD56+ NKT cells was significantly lower in patients with metastatic colorectal cancer compared to healthy controls strengthens the hypothesis that NKT cells can play a substantial role in the protection against human colorectal cancer, and this opens up avenues for novel studies about elucidating the other aspects of tumor surveillance in CRC progression and immunotherapy (Tab. 2, Fig. 2, Ref. 46). PMID- 29405724 TI - Histonedeacetylase 1 mRNA has elevated expression in clinical specimen of bladder cancer. AB - OBJECTIVE: HDACs are among transcriptional regulatory elements that regulate key features of proliferation and differentiation in all cell types including cancerous. They may also interfere in such stages of cancer development as migration, invasion, multi-drug resistance and angiogenesis. Proven information about HDAC1 role in development of bladder cancer is limited only to cell lines in vitro. The lack of a comprehensive clinical in vivo study led us to evaluate HDAC1 expression in human clinical specimens. METHODS: We analyzed a large group of bladder cancer patients. The presence of hHDAC1 mRNAs were tracked using specific HDAC1 primers in cancer samples and the quantity of HDAC1 transcripts were quantified using real time qPCR method and was compared to those of normal bladder samples from healthy patients. RESULTS: HDAC1 mRNA expression was significantly elevated in Bladder cancer specimens. To our knowledge, this result is the first, showing an elevation in vivo in HDAC1 mRNA levels in clinically cancerous tissue of patients with bladder cancer. CONCLUSIONS: We conclude that hHDAC1 overexpression might be implicated in bladder cancer tumorigenesis and that the over-expressed HDAC1 mRNA might be a potential diagnostic marker and, a target for treatment of bladder cancer using HDACi-drugs in future (Tab. 2, Fig. 2, Ref. 30). PMID- 29405726 TI - Protective role of microRNA-221 in Parkinson's disease. AB - OBJECTIVE: The present study aimed to explore the role and the underlying mechanism of miR-221 in Parkinson's Disease. MATERIALS AND METHODS: To perform our investigation, a PD cell model was created by using 6-OHDA. Cell viability and proliferation assays, and flow cytometry analysis were performed to detect cell viability and apoptosis. The qRT-PCR and western blotting were used for gene and protein level detection. RESULTS: We found that the expression of miRNA-221 is significantly lower in 6-OHDA treated PC12 pheochromocytoma cells compared to the normal cells. The results of further analysis indicated that miR-221 mimic significantly promoted the cell viability and proliferation of PC12 cells treated with 6-OHDA. MiR-221 mimic significantly inhibited 6-OHDA-treated PC12 cells from apoptosis. These effects were eliminated by PTEN over-expression. We also revealed that PTEN was a direct target gene of miR-221. Moreover, we found miR 221 mimic significantly promoted the phosphorylation of AKT in PC12 cells treated with 6-OHDA, and over-expression of PTEN could eliminate this effect. CONCLUSIONS: MiR-221 plays a protective role in Parkinson's Disease via regulating PC12 cell viability and apoptosis by targeting PTEN. Therefore, miR 221 may serve as a potential therapeutic target for Parkinson's disease treatment (Fig. 3, Ref. 27). PMID- 29405725 TI - MicroRNA-375 regulates proliferation and apoptosis of glioma cancer cells by inhibiting CTGF-EGFR signaling pathway. AB - AIM: To evaluate the correlation between miRNA-375 and cell proliferation and apoptosis in glioma cancer cell. METHODS: Collecting 30 cases of glioma cancer patients and 30 cases of cerebral infarction patients. The miRNA-375 and CTGF protein expressions were evaluated by ISH and IHC methods. In the cell experiment, the U87 cells were divided into 3 groups: NC group (the cells were treated with normal method); BL group (the cells were transfected with empty vector) and miRNA group (the cells were transfected with miRNA-375). The U87 cell proliferation and apoptosis rates and cell cycle of the different groups were measured by MTT and flow cytometry. The relative proteins (CTGF, EGFR, AKT, Erk and P21) expressions were measured by WB assay. RESULTS: The miRNA-375 and CTGF expressions of glioma cancer tissues were significantly different compared with those of no-cancer tissues (p < 0.05, respectively). In the cell experiments, the cell proliferation of miRNA group was significantly decreased compared with that of NC group (p < 0.05); the cell apoptosis and G1 phase rate of miRNA group was significantly decreased compared with NC group (p < 0.05, respectively). Depending on the WB assay, the CTGF, EGFR, AKT, Erk and P21 proteins expressions of miRNA group were significantly different compared with proteins expressions of NC group (p < 0.05, respectively). CONCLUSION: miRNA-375 over-expression suppresses glioma cancer cells development via CTGF-EGFR pathway (Fig. 3, Ref. 30). PMID- 29405727 TI - Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain. AB - INTRODUCTION: Quercetin is a ubiquitous flavonoid found in many plants. Neuroprotective effects of quercetin have been shown in several in vitro and in vivo studies, but its mechanism of action has not been fully defined yet. Brain derived neurotrophic factor (BDNF) is a fundamental neurotrophin with vital functions in the survival of neuronal cells. In the present study, we aimed to investigate the effects of quercetin on expression of BDNF mRNA in the hippocampus of rat brain. METHODS: Male rats were daily gavaged with quercetin (10, 20 or 50 mg/kg.bwt) for 30 days. Hippocampal levels of the BDNF transcripts were assessed using quantitative (q) RT-PCR. RESULTS: Quercetin at doses of 20 and 50 mg/kg caused a significant increase in the mRNA expression of BDNF as compared with the control group. Quercetin treatment at a dose of 10 mg/kg failed to cause any significant changes in the levels of BDNF mRNA CONCLUSION: Our findings suggest that the neuroprotective effects of quercetin may be at least partly due to its inducing effects on the expression levels of the BDNF mRNA (Fig. 1, Ref. 40). PMID- 29405728 TI - Both experimental hypothyroidism and hyperthyroidism increase cardiac irisin levels in rats. AB - Irisin is a newly discovered myokine and adipokine that increases total body energy expenditure. The aim of this study was to determine the effect of experimental hypothyroidism and hyperthyroidism on the levels of irisin in heart tissue in rats. The study was performed on the 40 male Sprague-Dawley rats. Experimental groups were designed as; Control, Hypothyroidism, Hypothyroidism+L Thyroxine, Hyperthyroidism and Hyperthyroidism + PTU. Following 3 weeks experimental period, irisin levels were determined in heart tissues. Hypothyroidism group values of irisin were higher than in the control group, but lower than in the hyperthyroidism group. The hyperthyroidism group had the highest levels of cardiac irisin. The results of the study showed that the experimental hypothyroidism and hyperthyroidism increased the heart irisin levels, but the increase in the hyperthyroidism group was much higher than in the hypothyroidism group. However, treatment of hypothyroidism and hyperthyroidism corrected cardiac irisin levels (Fig. 1, Ref. 28). PMID- 29405729 TI - The effects of resveratrol on hepatic oxidative stress in metabolic syndrome model induced by high fructose diet. AB - BACKGROUND: The purpose of this study was to evaluate probable protective effects of resveratrol treatment on hepatic oxidative events in a rat model of metabolic syndrome (MetS). METHODS: Thirty-two male adult rats were randomly divided into 4 groups: control, fructose, resveratrol, and fructose plus resveratrol. To induce MetS, fructose solution (20 % in drinking water) was used. Resveratrol (10 mg/kg/day) was given by oral gavage. All treatments were given for 8 weeks. Serum lipid profile, glucose and insulin levels, liver total oxidant status (TOS) levels and paraoxonase (PON), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were analyzed. RESULTS: Fructose-fed rats displayed statistically significant increases in TOS levels, and decreases in PON activity compared to the control group. Resveratrol treatment moderately prevented the decrease in liver PON activity caused by fructose. On the other hand, resveratrol, alone or in combination with fructose, did not change the TOS levels when compared to the fructose group. The SOD and CAT activities in all groups did not change. CONCLUSION: In this experimental design, high-fructose consumption led to elevated TOS levels and low PON activities. The resveratrol therapy shown beneficial effects on PON activity. However, it was found to behave like a prooxidant when administered together with fructose and alone in some parameters. Our results can inspire the development of new clinical therapy in patients with MetS (Tab. 2, Ref. 34). PMID- 29405730 TI - Blockade of miR-663b inhibits cell proliferation and induces apoptosis in osteosarcoma via regulating TP73 expression. AB - OBJECTIVE: This study aimed to investigate the exact role of miR-663b in osteosarcoma (OS) progression and further explore the underlying molecular mechanisms. MATERIALS AND METHODS: The miR-663b expression in human OS cell lines was determined by qRT-PCR, and the results suggested that miR-663b was highly expressed in human OS cells. TargetScan was used to predict the potential targets of miR-663b, and the prediction was confirmed by dual-luciferase reporter assay. To investigate the role of miR-663b in OS, miR-663b was down-regulated in U2OS cells using miR-663b inhibitor. CCK8 and flow cytometry were preformed to investigate the proliferation and apoptosis of U2OS cells. Moreover, qRT-PCR and western blot analysis were performed to measure the mRNA and protein expression. RESULTS: We found that miR-663b directly targets TP73 and negatively regulates TP73 expression. MiR-663b inhibitor significantly decreased the proliferation ability of U2OS cells, while the percentage of apoptotic cells was markedly increased. The level of Bcl-2 was notably inhibited by miR-663b inhibitor, while Bax expression was significantly enhanced. Moreover, miR-663b down-regulation promoted p53 and p21 expression in U2OS cells. CONCLUSIONS: MiR-663b down regulation represses proliferation and induces apoptosis in OS by targeting TP73. Therefore, we provide a potential therapeutic target for OS treatment (Fig. 6, Ref. 27). PMID- 29405731 TI - Apelin-13 increased food intake with serum ghrelin and leptin levels in male rats. AB - In this study, we aimed to explain the role of apelin-13 on body weight, food and water intake with serum leptin, ghrelin, neuropeptid Y (NPY) and peptid YY (PYY) levels in male rat. Thirty-two Sprague-Dawley male rats were used for the study. The rats were injected SP (0.9 %) intraperitoneally (i.p) in the control group and 30 (AP30), 100 (AP100) and 300 (AP300) ug/kg apelin-13 in the study groups, respectively, 10 min before the transition to dark period, for 10 days. During the experimental period, with light and dark periods of food and water intake, body weights were recorded in rats. Rats were euthanized and serum samples were obtained. In serum samples leptin, ghrelin, NPY and PYY levels were measured with specific ELISA kit. Apelin-13 was increased body weights in all three (AP30, AP100 and AP300) groups compared with the control group. AP100 and AP300 groups had increased food intake in the dark and the cumulative period, but in the light period food intake values were not significantly increased (p > 0.05). As for the value of water intake, compared with the control group, all dose of apelin-13 increased water intake during the dark and the cumulative period. There was no significant change in water intake in the light period. On the other hand, compared with the control group, serum leptin levels were found to increase in the groups administered 100 and 300 ug/kg of apelin-13 (p < 0.05). Ghrelin levels were found high in all groups treated with apelin-13. Serum levels of NPY decreased only in the 300 ug/kg apelin-13 treated group (p 0.05). Apelin-13 increases body weight in rats as well as food and water intake (dark and cumulative period). Additionally, ghrelin can mediate the orexigenic effect of apelin-13 in the regulation of food intake (Fig. 4, Ref. 37). PMID- 29405732 TI - Histopathological efficiency of amifostine in radiation-induced heart disease in rats. AB - OBJECTIVE: Amifositine is a phosphorylated thiol that holds its radioprotective actions by several indirect mechanisms. The purpose of this study was to evaluate histopathologically whether amifositine administration prior to irradiation would have a long-term protective effect on heart tissue in an experimental rat model. METHODS: Single dose of 18 Gy radiation and sham radiation exposure were used in related groups. A dose of 200 mg/kg of amifostine was injected intraperitoneally 30 min prior to radiation exposure. Analyses were performed 6 months after irradiation. RESULTS: Vascular damage and vasculitis were significantly decreased in amifositine treatment group. At the same time, significant thickening of the medial layer was accompanied by vascular damage in irradiated groups. The number and severity of myocyte necrosis were diminished with amifostine.Nevertheless, it could not prevent epicardial and myocardial fibrosis. Severe myocardial fibrosis was observed prominently in three regions, particularly on the apex, tips of papillary muscles and in sites adjacent to the atrioventricular valves. The anti inflammatory effect of amifostine was not seen. CONCLUSION: The development of vascular damage and vasculitis were prevented by the use of amifostine. There was a correlation between vascular damage and fibrosis development. According to histopathological results, amifostine could be used as a protective agent against the side effects of radiotherapy (Tab. 4, Fig. 2, Ref. 22). PMID- 29405733 TI - miR-16-1-3p targets TWIST1 to inhibit cell proliferation and invasion in NSCLC. AB - In our study, the impact of miR-16-1-3p on cell proliferation and invasion in NSCLC was explored. miR-16-1-3p mimics were transfected to A549 cells for miR-16 1-3p overexpression. qRT- PCR and Western blot were applied to explore the relative expression of mRNA and protein in A549 cells. Furthermore, the cell proliferation capability was determined by MTT assay. Additionally, cell migration and invasion were measured using a scratch assay and transwell assay, respectively. Moreover, TargetScan and luciferase reporter assay was utilized to investigate the target of miR-16-1-3p. The results indicated that miR-16-1-3p was downregulated in NSCLC cells and upregulation of miR-16-1-3p was able to inhibit the expression of TWIST1. In addition, the reduced cell proliferation, inhibited cell migration and invasion were observed in miR-16-1-3p mimic group compared to the negative control group. The luciferase reporter gene showed that TWIST1 was a target of miR-16-1-3p. Therefore, the present study demonstrated that miR-16-1-3p may suppress A549 cell proliferation, migration and invasion by targeting TWIST1. Thus, miR-16-1-3p might play important roles in NSCLC development, which provides a novel aspect for NSCLC investigation (Fig. 6, Ref. 26). PMID- 29405734 TI - Mortality in patients with cardiogenic shock treated with the Impella CP microaxial pump for isolated left ventricular failure. AB - AIMS:: Cardiogenic shock is still associated with high mortality rates of around 50%. Intra-aortic counterpulsation had been frequently used in cardiogenic shock, but was previously found to provide no mortality benefit. We investigated the effect of an interdisciplinary and multiprofessional routine strategy of early invasive haemodynamic support in combination with complete revascularization in patients with cardiogenic shock before admission to our intensive care unit. METHODS AND RESULTS:: We analysed all cardiogenic shock patients (mean age 62+/ 13 years) presenting at our institution between 2013 and mid 2016, who received an Impella CP microaxial pump for isolated left ventricle support ( n=61). Sixty one per cent ( n=37) had been resuscitated before Impella insertion. Overall mortality was 48% ( n=29/61) at 30 days. Thirty-day mortality was higher in resuscitated patients (resuscitated: 65% ( n=24/37); non-resuscitated: 21% ( n=5/24)). When applying the inclusion/exclusion criteria of the SHOCK-II trial, eligible patients ( n=25) had a markedly lower mortality (24% ( n=6/25) at 30 days) compared with the published trial (~40% in both arms). The observed mortality of SHOCK-II-like patients in the registry was also lower compared with their predicted mortality using IABP-Shock II score (49%) and CardShock score (36%). CONCLUSION:: The results of this registry suggest that using a standardized protocol including early active haemodynamic support with Impella CP in cardiogenic shock in patients with isolated left ventricle failure may be associated with improved outcomes and lower than previously reported or predicted mortality rates. Pre-implantation cardiac arrest critically influences observed mortality. The results support the case for a randomized trial. PMID- 29405735 TI - Living with a partner with dementia: a systematic review and thematic synthesis of spouses' lived experiences of changes in their everyday lives. AB - OBJECTIVES: Dementia causes dramatic changes in everyday-living for spouses. Occured changes in marital relationship, force spouses to perform more both mentally and physically. Leading to a spousal perceived burden. To improve understanding of spouses' needs, spouses lived experiences is needed. The aim was to identify and synthesise qualitative studies on spouses' lived experiences of living with a partner with dementia. METHODS: A systematic search was undertaken in January 2017. Six databases (CINAHL, Cochrane Library, Embase, PubMed, PsycINFO and Sociological Abstracts) were searched, using search terms in accordance with PICo. A descriptive synthesis and a thematic synthesis were undertaken. FINDINGS: Fifteen studies met the inclusion criteria. Three themes derived from the analysis 1) Noticing changes in everyday life 2) Transformation to a new marital relation in everyday life, with corresponding sub-themes; changes in marital relationship, management of the transitioned marital relation in everyday life 3) Planning the future. CONCLUSION: Findings provide an overview of how spouses notice changes and transform their marital relationships in everyday-life. Findings offer a deeper understanding of changes that occurs over time while the partner is living at home. Findings contribute with knowledge on spouses' experiences of changes in early-stages of dementia. Interventions supporting spouses are needed. PMID- 29405736 TI - Polyphenols and Bioavailability: an update. AB - Based on many cell culture, animal and human studies, it is well known that the most challenge issue for developing polyphenolics as chemoprevention or anti diabtetic agents is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large inter-individual variations in clinical trials. This review intends to highlight the unscientific evaluation on the basis of the published data regarding in vitro bioactivity of polyphenols, which may sometimes mislead the researchers and to conclude that: first, bio-accessibilities values obtained in the studies for polyphenols should be highly reconsidered in accordance with the abundant newly identified circulating and excreted metabolites, with a particular attention to colonic metabolic products which are obviously contributing much more than expected to their absorptions; second, it is phenolic metabolites, which are formed in the small intestine and hepatic cells,low molecular weight catabolic products of the colonic microflora to travel around the human body in the circulatory system or reach body tissues to elicit bioactive effects. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these molecules interact with human physiological and pathological processes. PMID- 29405737 TI - HIV Positivity per se Does Not Affect Tympanoplasty Outcomes. AB - BACKGROUND: The English language literature finds no clear protocols for otologic surgery for HIV+ patients. OBJECTIVE: To demonstrate that simple tympanoplasty and type III tympanoplasty in HIV+ patients with CD4 >400 cells/cc results in tympanic membrane closures and hearing improvements equivalent to the same procedures in controls. MATERIALS AND METHODS: This retrospective review documents the otologic conditions and operative results of 32 HIV+ patients and 32 controls. The controls were healthy and had no opportunistic infections or other medications. RESULTS: Genders, ages, sizes of tympanic membrane perforations, severity of air bone gaps, and type of operation were equivalent between the HIV+ and the control groups. Thirty of 32 patients in each group had closure of their perforations after 1 operation. Air bone gaps improved significantly for each group ( P = .001): 22 dB (SD = 11 dB) in the HIV+ group and 26 dB (SD = 10 dB) in the control group. And there was no statistically significant difference in change in hearing between the 2 groups. There were no complications of infection, wound dehiscence, worsened sensorineural levels, dizziness, or facial weakness in either group. CONCLUSION: HIV+ patients whose CD4 counts are above 400 cells/cc can undergo simple tympanoplasty or type III tympanoplasty with acceptable outcomes. PMID- 29405739 TI - Is vegetarianism healthy for children? AB - According to the Academy of Nutrition and Dietetics' influential position statement on vegetarianism, meat and seafood can be replaced with milk, soy/legumes, and eggs without any negative effects in children. The United States Department of Agriculture endorses a similar view. The present paper argues that the Academy of Nutrition and Dietetics ignores or gives short shrift to direct and indirect evidence that vegetarianism may be associated with serious risks for brain and body development in fetuses and children. Regular supplementation with iron, zinc, and B12 will not mitigate all of these risks. Consequently, we cannot say decisively that vegetarianism or veganism is safe for children. PMID- 29405738 TI - One-Stage Complete Resection of Cholesteatoma With Labyrinthine Fistula: Hearing Changes and Clinical Outcomes. AB - OBJECTIVES: To evaluate long-term hearing changes and surgical outcomes for middle ear cholesteatoma with labyrinthine fistula following complete surgical removal of the cholesteatoma matrix. METHODS: Consecutive samples of 43 patients who underwent 1-stage complete resection of the cholesteatoma matrix overlying a labyrinthine fistula were obtained. Immediate and long-term hearing changes were analyzed in association with fistula size. Accuracy of various diagnostic examinations was assessed. RESULTS: Immediately postsurgery, the average bone conduction threshold (43.34 dB) did not differ significantly from the preoperative value (36.66 dB, P = .083). There were also minimal changes thereafter (45.63 dB) without recurrent case over an average follow-up time of 38.3 months (range, 17-69 months). More than 10 dB hearing loss was found in 7 patients with a case of intraoperative perilymph leakage (2.3%), although 5 of them had had preoperative air conduction threshold above 90 dB. Their fistulas were significantly larger than those of patients without hearing loss ( P = .027). CONCLUSION: Although caution is required for total removal of a large fistula, owing to increased risk of postoperative hearing deterioration, 1-stage complete resection of cholesteatoma matrix on labyrinthine fistula could be effective in disease control and long-term hearing preservation. PMID- 29405740 TI - Factors Influencing People's Personal Information Disclosure Behaviors in Online Health Communities: A Pilot Study. AB - To effectively facilitate health information sharing and personal information protection in online health communities (OHCs), it is important to examine the factors influencing people's personal information disclosure behavior in OHCs. Five factors were supposed as the predictors of people's personal information disclosure behavior in OHCs. A total of 376 participants in a Chinese online cancer community were analyzed. The empirical results indicate that more participants give more attention to risk factors than motivating factors when they disclose information in OHCs. In a not so severe condition, participants post their personal information to only obtain needed information. In severe disease situations, participants disclose personal information to obtain both needed information and emotional support, and emotional support is prioritized; in addition, they even risk financial loss to seek more useful information or emotional support. OHC managers should make policies to protect people's personal information, and thus encourage them to share more health information in OHCs. PMID- 29405741 TI - Incense Smoke and Increasing Carotid Intima Media Thickness: A Cross-Sectional Study of the Thai-Vietnamese Community. AB - Incense burning, a source of household indoor air pollution, is possible to effect on cardiovascular system. Our study sought to examine the association of long-term exposure to household incense smoke with increased carotid intima-media thickness (CIMT). A cross-sectional study was conducted 132 adults aged >=35 years. Participants were stratified into 3 groups by their long-term household incense use; nonexposed group, non-daily exposed group, and daily exposed group. A combined mean CIMT (mean difference = 0.04 mm; P < .01) and combined maximum CIMT (mean difference = 0.09 mm; P < .01) in the daily exposed group had greater than the nonexposed group. The mean CIMT and maximum CIMT of the left common carotid artery in the daily exposed group was significantly greater than the nonexposed group ( P < .01). These findings suggest that incense burning inside the house may be a risk factor for cardiovascular disease morbidity and mortality. PMID- 29405742 TI - Articular Cartilage Lesion Characteristic Reporting Is Highly Variable in Clinical Outcomes Studies of the Knee. AB - Objective The purpose of this study was to investigate the degree of standardized evaluation and reporting of cartilage lesion characteristics in high-impact clinical studies for symptomatic lesions of the knee. We hypothesized that there are significant inconsistencies in reporting these metrics across orthopedic literature. Design A total of 113 clinical studies on articular cartilage restoration of the knee were identified from 6 high-impact orthopedic journals between 2011 and 2016. Full-text review was used to evaluate sources for details on study methodology and reporting on the following variables: primary procedure, location, size, grade, and morphology of cartilage lesions. Results All studies reported on the type of primary cartilage procedure and precise lesion location(s). Approximately 99.1% reported lesion morphology (chondral, osteochondral, mixed). For lesion size, 32.7% of articles did not report how size was measured and 11.5% did not report units. The lesion sizing method was variable, as 27.4% used preoperative magnetic resonance imaging to measure/report lesion size, 31.0% used arthroscopy, and 8.8% used both. The majority of studies (83.2%) used area to report size, and 5.3% used diameter. Formal grading was not reported in 17.7% of studies. Only 54.8% of studies reported depth when sizing osteochondral defects. Conclusions Recent literature on cartilage restoration provides adequate information on surgical technique, lesion location, and morphology. However, there is wide variation and incomplete reporting on lesion size, depth, and grading. Future clinical studies should include these important data in a consistent manner to facilitate comparison among surgical techniques. PMID- 29405744 TI - Mycins v Microbes Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues by Martin J. Blaser (2014) Holt New York, USA. PMID- 29405743 TI - Person-centred care in clinical assessment. PMID- 29405745 TI - Chemical composition and antimicrobial activity of the essential oil of Tanacetum walteri (Anthemideae-Asteraceae) from Iran. AB - The composition and antimicrobial activity of the essential oil of Tanacetum walteri were studied. Aerial flowering parts of plant were collected from North Khorasan Province of Iran and the essential oil was isolated by hydrodistillation and analysed by GC-FID and GC-MS. Antimicrobial activity of the essential oil was determined by disc diffusion and MIC and MBC determination. Thirty-five compounds were identified in the oil of T. walteri accounting for 94.4% of the total oil. Thymol (22.5%), 1,8-cineole (8.2%), umbellulone (6.9%), alpha-bisabolol (6.3%) and camphor (5.3%) were as the principal constituents. The highest antimicrobial activity of the essential oil was observed against Staphylococcus aureus, Enterococcus faecalis and Klebsiella pneumoniae with MIC value of 0.63 mg/mL. The inhibitory effect of the essential oil of T. walteri could be attributed mainly to the high levels of phenolic compound thymol and oxygenated terpenes in essential oil. PMID- 29405748 TI - Nutrient availability of different batches of wheat distiller's dried grains with solubles for turkeys. AB - Effects of five different batches of wheat distiller's dried grains with solubles (DDGS) were used to investigate bioavailability of energy and nutrients for turkeys. The laboratory analysis of the DDGS showed the largest variations for soluble non-starch polysaccharides, oil and ash. In total, 96 birds were fed one of six mash diets. The basal diet contained per kilogram 535 g wheat and 300 g soya bean meal, corresponding to 247 g crude protein and 12.6 MJ N-corrected apparent metabolisable energy (AMEn). Another five diets contained per kilogram 200 g of each DDGS samples in replacement for basal diet. Each diet was fed to eight pens with two female Premium turkeys following randomisation. The AMEn and the nutrient retention coefficients of the pure DDGS samples were obtained using the substitution method. The AMEn of the DDGS from batch A was higher (p = 0.048) compared to those from batches B and C, but did not differ from DDGS samples D and E. There were no differences in dry matter retention, nitrogen retention and fat digestibility between the DDGS samples tested. The AMEn of the DDGS samples correlated positively (p < 0.05) to the starch (r = 0.895) and the non-soluble non-starch polysaccharides contents (r = 0.940), and the red index of lighting (a) (r = 0.916), respectively. In general, findings from this study indicate bioavailability of energy and most nutrients to be in the range of published data with turkeys, and to vary between batches. PMID- 29405747 TI - Future Directions for Research on Early Intervention for Young Children at Risk for Social Anxiety. AB - Anxiety disorders are common among young children, with earlier onset typically associated with greater severity and persistence. A stable behaviorally inhibited (BI) temperament and subsequent shyness and social withdrawal (SW) place children at increased risk of developing anxiety disorders, particularly social anxiety. In this Future Directions article, we briefly review developmental and clinical research and theory that point to parenting and peer interactions as key moderators of both the stability of BI/SW and risk for later anxiety, and we describe existing interventions that address early BI/SW and/or anxiety disorders in young children. We recommend that future research on early intervention to disrupt the trajectory of anxiety in children at risk (a) be informed by both developmental science and clinical research, (b) incorporate multiple levels of analysis (including both individual and contextual factors), PMID- 29405753 TI - Are Television Deaths Good Deaths? A Narrative Analysis of Hospital Death and Dying in Popular Medical Dramas. AB - This study explores death narratives in the popular international medical dramas Grey's Anatomy (USA), Casualty (UK), All Saints (Australia), and E.R. (USA). Using narrative analysis, we characterize death portrayals in terms of the number and causes of the deaths, the types of characters who die, the narrative structures of the deaths, and themes found within the death stories. We then compare characteristics actual patients, physicians, and caregivers identify as important in a death experience with the characteristics of deaths portrayed in medical dramas. Our narrative analysis shows that death narratives in medical dramas lack narrative fidelity with the characteristics of "good" death experiences described in the literature. PMID- 29405754 TI - Developing Dimensional, Pandiagnostic Inhibitory Control Constructs With Self Report and Neuropsychological Data. AB - Trait markers, or intermediate phenotypes linking different units of analysis (self-report, performance) from the Research Domain Criteria (RDoC) matrix across populations is a necessary step in identifying at-risk individuals. In the current study, 150 healthy controls (HC) and 456 individuals with bipolar disorder (BD) Type I or II, NOS (not otherwise specified) or Schizoaffective BD completed self-report neuropsychological tests of inhibitory control (IC) and executive functioning. Bifactor analyses were used to examine the factor structure of these measures and to evaluate for invariance across groups. Bifactor analyses found modest convergence of items from neuropsychological tests and self-report measures of IC among HC and BD. The factor scores showed evidence of a general IC construct (i.e., subdomain) across measures. Importantly, invariance testing indicated that the same construct was measured equally well across groups. Groups differed on the general factor for three of the four scales. Convergence on a general IC factor and invariance across diagnosis supports the use of combined dimensional measures to identify clinical risk and highlights how prospective RDoC studies might integrate units of analysis. PMID- 29405755 TI - Dynamic Risk Assessment of Sexual Offenders: Validity and Dimensional Structure of the Stable-2007. AB - In this study, the predictive and incremental validity of the Stable-2007 beyond the Static-99 was evaluated in an updated sample of N = 638 adult male sexual offenders followed-up for an average of M = 8.2 years. Data were collected at the Federal Evaluation Center for Violent and Sexual Offenders (FECVSO) in Austria within a prospective-longitudinal research design. Scores and risk categories of the Static-99 (AUC = .721; p < .001) and of the Stable-2007 (AUC = .623, p = .005) were found to be significantly related to sexual recidivism. The Stable 2007 risk categories contributed incrementally to the prediction of sexual recidivism beyond the Static-99. Analyzing the dimensional structure of the Stable-2007 yielded three factors, named Antisociality, Sexual Deviance, and Hypersexuality. Antisociality and Sexual Deviance were significant predictors for sexual recidivism. Sexual Deviance was negatively associated with non-sexual violent recidivism. Comparisons with latent dimensions of other risk assessment instruments are made and implications for applied risk assessment are discussed. PMID- 29405756 TI - Age-Neutrality of a Brief Assessment of the Section III Alternative Model for Personality Disorders in Older Adults. AB - The alternative model for personality disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-5) is considered an important step toward a possibly better conceptualization of personality pathology in older adulthood, by the introduction of levels of personality functioning (Criterion A) and trait dimensions (Criterion B). Our main aim was to examine age-neutrality of the Short Form of the Severity Indices of Personality Problems (SIPP-SF; Criterion A) and Personality Inventory for DSM-5-Brief Form (PID-5-BF; Criterion B). Differential item functioning (DIF) analyses and more specifically the impact on scale level through differential test functioning (DTF) analyses made clear that the SIPP-SF was more age-neutral (6% DIF, only one of four domains showed DTF) than the PID-5-BF (25% DIF, all four tested domains had DTF) in a community sample of older and younger adults. Age differences in convergent validity also point in the direction of differences in underlying constructs. Concurrent and criterion validity in geriatric psychiatry inpatients suggest that both the SIPP-SF scales measuring levels of personality functioning (especially self-functioning) and the PID-5-BF might be useful screening measures in older adults despite age-neutrality not being confirmed. PMID- 29405757 TI - Factor Structure and Convergent Validity of the Stress Index for Parents of Adolescents (SIPA) in Adolescents With ADHD. AB - Parenting stress is common in families with an adolescent with attention deficit/hyperactivity disorder (ADHD). The Stress Index for Parents of Adolescents (SIPA) was developed to assess parenting stress but has not been validated outside of the original development work. This study examined the factor structure and sources of convergent validity of the SIPA in a sample of adolescents diagnosed with ADHD ( Mage = 12.3, N = 327) and their caregivers. Three first-order models, two bifactor models, and one higher order model were evaluated; none met overall model fit criteria but the first-order nine-factor model displayed the best fit. Convergent validity was also assessed and the SIPA adolescent domain was moderately correlated with measures of family impairment and conflict after accounting for ADHD symptom severity. Implications of these findings for use of the SIPA in ADHD samples are discussed along with directions for future research focused on parent stress and ADHD. PMID- 29405758 TI - Application of Spectroscopic and Chromatographic Methods for Chemical Characterization of an Ayurvedic Herbo-Mineral Preparation: Maha Yograja Guggulu. AB - Rasa Shastra is an exclusive branch of ayurveda that uses processed metals and minerals in various combinations. Though the formulations are time tested, safety and quality concerns are being raised since the past two decades. In view of this, it becomes mandatory to generate quality control profiles of such formulations by following available parameters. Considering this, we attempted to develop standard manufacturing procedures of Maha Yogaraja Guggulu and generate preliminary physicochemical profiles using inductively coupled plasma mass spectrometry, X-ray diffraction, and high-performance thin-layer chromatography. The results from high-performance thin-layer chromatography revealed presence of organic constituents from plant material. X-ray diffraction indicated that the prepared drug contained cinnabar (mercury sulfide; Rasa sindhura), cassiterite (tin oxide; Vanga bhasma), litharge (lead oxide; Naga bhasma), and iron dioxide and magnetite (di-iron oxide; Loha and Mandura bhasma). The observations of the present study are preliminary and first of its kind that may be considered as baseline data for future studies. PMID- 29405759 TI - Chemical Composition, Antioxidant and Antibacterial Activity of Bunium persicum, Eucalyptus globulus, and Rose Water on Multidrug-Resistant Listeria Species. AB - This research was aimed at investigating the antioxidant and antibacterial activity of Bunium persicum, Eucalyptus globulus, and rose water on multidrug resistant Listeria species. The antibiotic resistance of Listeria spp obtained from seafood samples were determined by the Kirby-Bauer method. The antioxidant and antibacterial activity of the essential oils and extracts were evaluated using ferric reducing antioxidant power and microdilution methods, respectively. A total 2 samples (1.88%) were positive for Listeria spp. L monocytogenes was found to be resistant to ampicillin, amoxicillin/clavulanic acid, penicillin, vancomycin, and kanamycin. B persicum essential oil showed the greatest antioxidant activity (248.56 +/- 1.09 uM Fe2+/g). The E globulus essential oil showed consistently strong antimicrobial activity against L monocytogenes and L grayi, while rose water showed no antimicrobial activity against any of the tested bacterial strains. The results showed that after adding the B persicum and E globulus essential oils to bacteria, the cell components' release increased significantly. PMID- 29405760 TI - Scorpion Venom Causes Apoptosis by Increasing Reactive Oxygen Species and Cell Cycle Arrest in MDA-MB-231 and HCT-8 Cancer Cell Lines. AB - OBJECTIVES: The objective of this study was to examine the effect of scorpion venoms on cancer cell progression, apoptosis, and cell cycle arrest. Scorpion venoms are known to possess numerous bioactive compounds that act against cancer progression by inducing apoptosis. In this study, we have taken the venoms from the following 2 species of scorpion- Androctonus crassicauda and Leiurus quinquestriatus-and tested the anticancer properties of the venom against breast and colorectal cancer cell lines. METHODS: Milking of scorpion venom and culturing the breast and colorectal cancer cell lines were done according to the standard procedure. The venom cytotoxicity was assessed by MTT methods, and the cellular and nuclear changes were studied with phase contrast and propidium iodide staining, respectively. The cell cycle arrest and accumulation of reactive oxygen species were analyzed on a Muse cell analyzer. RESULTS: The venoms exerted cytotoxic effects on breast and colorectal cell lines in a dose- and time dependent manner. Enhanced apoptotic cells, increase in reactive oxygen species, and cell cycle arrest were observed after challenging these cell lines with scorpion venoms. CONCLUSIONS: Scorpion venom induces apoptosis in breast and colorectal cell lines as reflected by the changes in the cell morphology and cell cycle studies. Furthermore, a high percentage of total reactive oxygen species as well as apoptotic cells also contribute to cell death as observed after venom treatments. To the best of authors' knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest by these species of scorpion venoms. PMID- 29405761 TI - Guided Imagery Improves Mood, Fatigue, and Quality of Life in Individuals With Multiple Sclerosis: An Exploratory Efficacy Trial of Healing Light Guided Imagery. AB - Multiple sclerosis is a disabling and progressive neurological disease that has significant negative effects on health-related quality of life. This exploratory efficacy study examined the effects of Healing Light Guided Imagery (HLGI), a novel variant of guided imagery, compared with a wait-list control in patients with relapsing-remitting multiple sclerosis. Changes in the Beck Depression Inventory, Fatigue Severity Scale, and Multiple Sclerosis Quality of Life instrument (physical and mental components) were compared between groups. Patients who completed HLGI (N = 9) showed significant reductions in depressed mood ( P < .05) and fatigue ( P < .01) and showed significant gains in physical ( P = .01) and mental ( P < .01) quality of life compared with journaling (N = 8). Our results suggest that HLGI can improve self-reported physical and mental well being in patients with relapsing-remitting multiple sclerosis. Further research is needed to study the effectiveness of this therapy, as well as its mind-body mechanisms of action. PMID- 29405762 TI - The Distinction of Hot Herbal Compress, Hot Compress, and Topical Diclofenac as Myofascial Pain Syndrome Treatment. AB - This randomized controlled trial aimed to investigate the distinctness after treatment among hot herbal compress, hot compress, and topical diclofenac. The registrants were equally divided into groups and received the different treatments including hot herbal compress, hot compress, and topical diclofenac group, which served as the control group. After treatment courses, Visual Analog Scale and 36-Item Short Form Health survey were, respectively, used to establish the level of pain intensity and quality of life. In addition, cervical range of motion and pressure pain threshold were also examined to identify the motional effects. All treatments showed significantly decreased level of pain intensity and increased cervical range of motion, while the intervention groups exhibited extraordinary capability compared with the topical diclofenac group in pressure pain threshold and quality of life. In summary, hot herbal compress holds promise to be an efficacious treatment parallel to hot compress and topical diclofenac. PMID- 29405765 TI - Palladium nanoparticle effects on endocrine reproductive system of female rats. AB - The widespread industrial application of nanomaterials (NMs) has dramatically increased the likelihood of environmental and occupational exposure of humans to such xenobiotics. This issue, together with the increasing public health interest in understanding the effects of chemicals on endocrine system, encouraged to investigate the disruptive potential of NMs on the endocrine function. Therefore, the aim of this study was to evaluate the effects of palladium nanoparticles (Pd NPs) on the female reproductive system of Wistar rats, intravenously exposed to different doses (0.12, 1.2, and 12 ug/kg), through the assessment of possible quantitative changes in the serum concentrations of several sex hormones. Our results demonstrated that the highest exposure doses significantly reduced the estradiol and testosterone concentrations, while increased the luteinizing hormone levels in treated animals compared to controls. Such alterations are indicative for an abnormal reproductive axis function. However, further investigations are needed to clarify the role of the different NP physicochemical properties in determining such effects, and possible underlining molecular mechanisms, as well as their relevance for the development of diseases in the female reproductive system. Overall, this may be helpful to define accurate risk assessment and management strategies to protect the health of the general and occupational populations exposed to Pd-NPs. PMID- 29405763 TI - Emission of Biophotons and Adjustable Sounds by the Fascial System: Review and Reflections for Manual Therapy. AB - Every body structure is wrapped in connective tissue or fascia, creating a structural continuity that gives form and function to every tissue and organ. The fascial tissue is uniformly distributed throughout the body, enveloping, interacting with and permeating blood vessels, nerves, viscera, meninges, bones and muscles, creating various layers at different depths and forming a tridimensional metabolic and mechanical matrix. This article reviews the literature on the emission of biophotons and adjustable sounds by the fascial system, because these biological changes could be a means of local and systemic cellular communication and become another assessment tool for manual (therapy) practitioners. This is the first article that discusses these topics in a single text, attempting to bring such information into an area of application that is beneficial to osteopaths, chiropractors, and manual therapists. PMID- 29405766 TI - Urinary bisphenol A levels in Turkish girls with premature thelarche. AB - There is a growing concern over the timing of pubertal breast development and its possible association with exposure to endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA). BPA is abundantly used to harden plastics. The aim of this study was to investigate the relation between premature thelarche (PT) and BPA by comparing the urinary BPA levels of PT girls with those of healthy subjects. Twenty-five newly diagnosed nonobese PT subjects (aged 4-8 years) who were admitted to the Pediatric Endocrinology Department at Akdeniz University were recruited. The control group composed of 25 age-matched girls without PT and other endocrine disorders. Urinary BPA levels were measured by high pressure liquid chromatography. The median urinary concentrations of BPA were found to be significantly higher in the PT group compared to the healthy control group (3.2 vs. 1.62 MUg/g creatinine, p < 0.05). We observed a weak positive correlation between uterus volume and urinary BPA levels. There was a weak correlation between estradiol and urinary BPA levels ( r = 0.166; p = 0.37); and luteinizing hormone and urinary BPA levels ( r = 0.291; p = 0.08) of PT girls. Our results suggest that exposure to BPA might be one of the underlying factors of early breast development in prepubertal girls and EDCs may be considered as one of the etiological factors in the development of PT. PMID- 29405767 TI - Assessment of oxidative stress of platelets among chronic heroin and hashish addicts. AB - INTRODUCTION: Illicit drugs abuse is associated with several clinical life threatening consequences that are primarily mediated by oxidative damage to multiple cellular components with a subsequent cellular dysfunction and death. Primarily, this study aimed to investigate oxidative stress to protein and lipid components of circulatory platelets among chronic heroin and hashish addicts. METHODS: Platelet lysates were prepared from 20 chronic intravenously administrated heroin addicts and 20 chronic smoked hashish addicts. For comparative purposes, two control groups of 20 cigarette smokers and 20 nonsmokers were included in the study. Oxidative stress to platelet's proteins and lipids was investigated using carbonyl group contents assay and thiobarbituric acid reactive substances (TBARS) assay, respectively. RESULTS: In comparison to control groups, carbonyl group contents and TBARS concentration were significantly higher among heroin addicts but not among hashish addicts. Both of these markers were significantly correlated to the duration of addiction but not to the daily administrated dose. While in regard of the timing of the latest administrated dose (TLAD), only carbonyl group contents were significantly correlated to the TLAD. CONCLUSIONS: Considering the contribution of drug's route of administration, drug's pharmacokinetics, and kinetics of circulatory platelet, we concluded that chronic heroin addiction is associated with significant levels of oxidative stress to platelet's proteins and lipids. Due to the high proteomic contents of platelets, protein's oxidative stress is more prominent compared to lipids. Chronic hashish smoking is not associated with significant levels of oxidative stress in platelet's proteins and lipids. PMID- 29405768 TI - Diepoxybutane-induced apoptosis is mediated through the ERK1/2 pathway. AB - Diepoxybutane (DEB) is the most potent active metabolite of butadiene, a regulated air pollutant. We previously reported the occurrence of DEB-induced, p53-dependent, mitochondrial-mediated apoptosis in human lymphoblasts. The present study investigated the role of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathway in DEB-induced apoptotic signaling in exposed human lymphoblasts. Activated ERK1/2 and mitogen-activated protein (MAP) kinase/ERK1/2 kinase (MEK) levels were significantly upregulated in DEB-exposed human lymphoblasts. The MEK inhibitor PD98059 and ERK1/2 siRNA significantly inhibited apoptosis, ERK1/2 activation, as well as p53 and phospho-p53 (serine 15) levels in human lymphoblasts undergoing DEB-induced apoptosis. Collectively, these results demonstrate that DEB induces apoptotic signaling through the MEK ERK1/2-p53 pathway in human lymphoblasts. This is the first report implicating the activation of the ERK1/2 pathway and its subsequent role in mediating DEB induced apoptotic signaling in human lymphoblasts. These findings contribute towards the understanding of DEB toxicity, as well as the signaling pathways mediating DEB-induced apoptosis in human lymphoblasts. PMID- 29405769 TI - Thymoquinone alleviates the experimentally induced Alzheimer's disease inflammation by modulation of TLRs signaling. AB - Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and deposition of amyloid-beta (Abeta) within the brain. Abeta induces detrimental inflammatory responses through toll-like receptors (TLRs) signaling pathway. Thymoquinone (TQ), the main active constituent of Nigella sativa oil, has been reported by several previous studies for its potent anti-inflammatory effect. The aim of this study is to elucidate the effect of TQ in improving learning and memory, using a rat model of AD induced by a combination of aluminum chloride (AlCl3) and d-galactose (d-Gal). TQ was administered orally at doses of 10, 20, and 40 mg/kg/day for 14 days after AD induction. Memory functions were assessed using the step through passive avoidance test. Amyloid plaques were shown to be present using hematoxylin and eosin staining. Tumor necrosis factor-alpha (TNF-alpha) and Interleukin-1beta (IL 1beta) levels in brain were assessed via ELISA and profiling TLR-2, TLR-4, myeloid differential factor 88, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-beta, interferon regulatory factor 3 (IRF-3), and nuclear factor-kappaB (NF-kappaB) expressions via real-time polymerase chain reaction. TQ improved AD rat cognitive decline, decreased Abeta formation and accumulation, significantly decreased TNF-alpha and IL-1beta at all levels of doses and significantly downregulated the expression of TLRs pathway components as well as their downstream effectors NF-kappaB and IRF-3 mRNAs at all levels of doses ( p < 0.05). We concluded that TQ reduced the inflammation induced by d Gal/AlCl3 combination. It is therefore reasonable to assign the anti-inflammatory responses to the modulation of TLRs pathway. PMID- 29405771 TI - Biomarker definitions and their applications. AB - Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice, particularly in the fields of chronic disease and nutrition. Clarification of the definitions of different biomarkers and a better understanding of their appropriate application could result in substantial benefits. This review examines biomarker definitions recently established by the U.S. Food and Drug Administration and the National Institutes of Health as part of their joint Biomarkers, EndpointS, and other Tools (BEST) resource. These definitions are placed in context of their respective uses in patient care, clinical research, or therapeutic development. We explore the distinctions between biomarkers and clinical outcome assessments and discuss the specific definitions and applications of diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. We also explore the implications of current biomarker development trends, including complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies. Finally, we discuss the challenges and potential benefits of biomarker-driven predictive toxicology and systems pharmacology, the need to ensure quality and reproducibility of the science underlying biomarker development, and the importance of fostering collaboration across the entire ecosystem of medical product development. Impact statement Biomarkers are critical to the rational development of medical diagnostics and therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice. Clarification of the definitions of different biomarker classes and a better understanding of their appropriate application could yield substantial benefits. Biomarker definitions recently established in a joint FDA-NIH resource place different classes of biomarkers in the context of their respective uses in patient care, clinical research, or therapeutic development. Complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies, together with biomarker-driven predictive toxicology and systems pharmacology, are reshaping development of diagnostic and therapeutic technologies. An approach to biomarker development that prioritizes the quality and reproducibility of the science underlying biomarker development and incorporates collaborative regulatory science involving multiple disciplines will lead to rational, evidence based biomarker development that keeps pace with scientific and clinical need. PMID- 29405772 TI - Healthy Food Identification: Food Cues and Claims Affect Speeded and Thoughtful Evaluations of Food. AB - This study investigated the impact of food claims, food cues, and objective health characteristics on health categorization speed and accuracy, believability of claims and perceptions of health, and taste for food items. One hundred twenty four young adults were exposed to counterbalanced food item images, which varied by directness of visual food cues, type of food claims (health-related vs. taste related), and objective healthfulness in a fully crossed design across three different food items. Participants categorized the foods as healthy or unhealthy in a speeded task and evaluated the perception of claim believability and perceptions of health and taste after exposure to images of the food items. Direct visual cues, especially when used with health claims, improved health and taste perception ratings and aided believability of health claims even for objectively unhealthy food products. PMID- 29405770 TI - Liquid biopsy and its role in an advanced clinical trial for lung cancer. AB - Liquid biopsy methodologies, for the purpose of plasma genotyping of cell-free DNA (cfDNA) of solid tumors, are a new class of novel molecular assays. Such assays are rapidly entering the clinical sphere of research-based monitoring in translational oncology, especially for thoracic malignancies. Potential applications for these blood-based cfDNA assays include: (i) initial diagnosis, (ii) response to therapy and follow-up, (iii) tumor evolution, and (iv) minimal residual disease evaluation. Precision medicine will benefit from cutting-edge molecular diagnostics, especially regarding treatment decisions in the adjuvant setting, where avoiding over-treatment and unnecessary toxicity are paramount. The use of innovative genetic analysis techniques on individual patient tumor samples is being pursued in several advanced clinical trials. Rather than using a categorical treatment plan, the next critical step of therapeutic decision making is providing the "right" cancer therapy for an individual patient, including correct dose and timeframe based on the molecular analysis of the tumor in question. Per the 21st Century Cures Act, innovative clinical trials are integral for biomarker and drug development. This will include advanced clinical trials utilizing: (i) innovative assays, (ii) molecular profiling with cutting-edge bioinformatics, and (iii) clinically relevant animal or tissue models. In this paper, a mini-review addresses state-of-the-art liquid biopsy approaches. Additionally, an on-going advanced clinical trial for lung cancer with novelty through synergizing liquid biopsies, co-clinical trials, and advanced bioinformatics is also presented. Impact statement Liquid biopsy technology is providing a new source for cancer biomarkers, and adds new dimensions in advanced clinical trials. Utilizing a non-invasive routine blood draw, the liquid biopsy provides abilities to address perplexing issues of tumor tissue heterogeneity by identifying mutations in both primary and metastatic lesions. Regarding the assessment of response to cancer therapy, the liquid biopsy is not ready to replace medical imaging, but adds critical new information; for instance, through a temporal assessment of quantitative circulating tumor DNA (ctDNA) assay results, and importantly, the ability to monitor for signs of resistance, via emerging clones. Adjuvant therapy may soon be considered based on a quantitative cfDNA assay. As sensitivity and specificity of the technology continue to progress, cancer screening and prevention will improve and save countless lives by finding the cancer early, so that a routine surgery may be all that is required for a definitive cure. PMID- 29405773 TI - Brain infarction due to vertebral artery dissection caused by a bone protrusion from the condylar fossa in a juvenile case. AB - A 16-year-old boy presented with multiple posterior circulation ischemic strokes resulting from vertebral artery (VA) dissection. Three-dimensional computed tomography showed aberrant sub-occipital bone protuberance, proximal to the VA dissection. Since the patient was a habitual neck cracker, VA dissection was thought to result from the impact shock of the rotational head movement. This could be due to either the osseous prominence or the compression between the prominence and the C1. Although it is a rare etiology of Bow Hunter's syndrome, VA dissection due to sub-occipital bone spur because of neck cracking should be considered in the diagnosis of Bow Hunter's syndrome in juvenile patients. PMID- 29405774 TI - Nursing and Stereotypes. PMID- 29405775 TI - Impact of a Hypothetical Infectious Disease Outbreak on US Exports and Export Based Jobs. AB - We estimated the impact on the US export economy of an illustrative infectious disease outbreak scenario in Southeast Asia that has 3 stages starting in 1 country and, if uncontained, spreads to 9 countries. We used 2014-2016 West Africa Ebola epidemic-related World Bank estimates of 3.3% and 16.1% reductions in gross domestic product (GDP). We also used US Department of Commerce job data to calculate export-related jobs at risk to any outbreak-related disruption in US exports. Assuming a direct correlation between GDP reductions and reduced demand for US exports, we estimated that the illustrative outbreak would cost from $16 million to $27 million (1 country) to $10 million to $18 billion (9 countries) and place 1,500 to almost 1.4 million export-related US jobs at risk. Our analysis illustrates how global health security is enhanced, and the US economy is protected, when public health threats are rapidly detected and contained at their source. PMID- 29405777 TI - Predictors and Effects of Anti-Obesity Message Fatigue: A Thought-Listing Analysis. AB - The prevalence of messages advocating weight management has likely resulted in considerable anti-obesity message fatigue but the phenomenon remains understudied. This study examined two aspects of antiobesity message fatigue: (1) effects of preexisting anti-obesity message fatigue on cognitive processing of an incoming anti-obesity message and (2) predictors and effects of message fatigue responses expressed after exposure to the message. Results from a two-wave online experiment involving overweight and obese adults in the U.S. (N = 251) showed that preexisting message fatigue (in wave 1) positively predicted counterarguments, while negatively predicting message-consistent and issue relevant thoughts expressed after exposure to an anti-obesity message (in wave 2). Moreover, the experimental findings show that physical health frames generated greater message fatigue responses than mental health frames. Message fatigue responses, in turn, predicted more unfavorable attitude toward message recommendations, completely mediating the effects of physical health frames on attitude. Women and older participants were more likely to express anti-obesity message fatigue responses than their counterparts. These findings underscore the need to recognize message fatigue as a significant barrier to communicating health. PMID- 29405778 TI - Syringomyelia with left knee charcot arthropathy: a case report. AB - We describe a rare case of syringomyelia with left knee Charcot arthropathy in a 35-year-old male, who presented with dissociative sensory disorder, muscle atrophy, painless knee joint swelling and limited joint mobility. Early diagnosis and appropriate treatment are essential in avoiding disease progression. PMID- 29405776 TI - The safe use of long screws in L5/S1 stand-alone anterior interbody fusion for olisthesis cases. AB - BACKGROUND: Stand-alone anterior interbody fusion (STALIF) with poly-ether-ether ketone (PEEK) cages could offer a treatment option in olisthesis cases. The fixation of the PEEK-cage at the L5/S1 inferior endplate with long divergent screws however might endanger neural sacral structures, especially the S1 nerve root. If shorter screws are used, the achieved bony purchase might not be sufficient to resist the pull out and shear forces at the lumbosacral junction. The aim of the present investigation was to evaluate the use of long screws in PEEK-cages for olisthesis cases at the L5/S1 segment and its neurological complications. MATERIAL AND METHODS: 11 Patients (6 males) with a mean age of 47(+/- 15.1) years between 2013-2015 designated for an STALIF at the L5/S1 level were consecutively included in the present study. All patients had a Grade 1 or 2 slippage according to Meyerding. PEEK cages (SynFix-LR(r), Depuy Synthes) were implanted with 30mm screws at the baseplate of L5/S1 in all patients. Perioperative and postoperative long-term complications were evaluated. Furthermore, radiological follow-up was performed (CT-scan at 6 months, X-ray at 6, 12 and 24 months). RESULTS: 6 patients suffered from an isthmic, 1 from a degenerative olisthesis. 4 patients with iatrogenic spondylolisthesis were included. Pre-operative radiculopathy was noted in 10 patients. 9 patients with pre-operative radiculopathy showed relief of symptoms until the last follow-up after 24 months. Fusion was achieved in all patients after 6 months. No screw displacement, breakage or violation of the neural foramen was noted. Furthermore, no implant failure or pull-out fractures were seen. CONCLUSION: In this investigation, no complication due to the use of long divergent locking screws was noted. In addition, the majority of patients showed permanent relief of radiculopathy symptoms at the 2 years follow-up. This study demonstrates the safe usage of long divergent locking screws in the baseplate of L5/S1 in anterior interbody fusion at the L5/S1 level. PMID- 29405779 TI - Caffeine Consumption Is Associated With Higher Level of Physical Activity in Japanese Women. AB - Caffeine has been described as a sports performance-enhancing substance. However, it is unclear whether it can increase the level of physical activity (PA) in nonathletic individuals. This study investigates the relationship between daily caffeine consumption and (a) daily PA/fitness or (b) intervention-induced changes in PA in women and men. On the basis of responses to a dietary habit questionnaire, which included items on caffeinated beverages, 1,032 Japanese adults, were categorized into lower or higher caffeine consumption groups (relative to the median caffeine consumption). In each group, daily step count; sedentary time; and light, moderate, and vigorous PA outcomes were objectively measured. Physical fitness, including peak oxygen consumption, was also evaluated. The relationship between daily caffeine consumption and the change in the levels of PA was investigated in a subgroup of 202 subjects who participated in a 1-year PA counseling intervention. Women in the higher caffeine consumption group presented higher moderate-to-vigorous PA and step count compared with their counterparts in the lower consumption group (4.0 +/- 2.1 vs. 3.3 +/- 2.1 MET hr/day, p < .001; 10,335 +/- 3,499 vs. 9,375 +/- 3,527 steps/day, p < .001). A significant positive correlation was noted between caffeine consumption and peak oxygen consumption among women (r = .15, p < .001). No caffeine-related effects were noted in men. The lower and higher caffeine consumption groups showed no significant differences in their levels of PA at the end of the 1-year intervention. Therefore, caffeine consumption appears to be associated with higher levels of PA in Japanese women. Further studies are needed to clarify this association. PMID- 29405780 TI - Effects of High Versus Low Protein Intake on Body Composition and Maximal Strength in Aspiring Female Physique Athletes Engaging in an 8-Week Resistance Training Program. AB - Aspiring female physique athletes are often encouraged to ingest relatively high levels of dietary protein in conjunction with their resistance training programs. However, there is little to no research investigating higher versus lower protein intakes in this population. This study examined the influence of a high versus low-protein diet in conjunction with an 8-week resistance training program in this population. A total of 17 females (21.2 +/- 2.1 years; 165.1 +/- 5.1 cm; 61 +/- 6.1 kg) were randomly assigned to a high-protein diet (HP: 2.5 g.kg-1.day-1; n = 8) or a low-protein diet (LP: 0.9 g.kg-1.day-1, n = 9) and were assessed for body composition and maximal strength prior to and after the 8-week protein intake and exercise intervention. Fat-free mass increased significantly more in the HP group as compared with the LP group (p = .009), going from 47.1 +/- 4.5 to 49.2 +/- 5.4 kg (+2.1 kg) and from 48.1 +/- 2.7 to 48.7 +/- 2 kg (+0.6 kg) in the HP and LP groups, respectively. Fat mass significantly decreased over time in the HP group (14.1 +/- 3.6 to 13.0 +/- 3.3 kg; p < .01), but no change was observed in the LP group (13.2 +/- 3.7 to 12.5 +/- 3.0 kg). Although maximal strength significantly increased in both groups, there were no differences in strength improvements between the two groups. In aspiring female physique athletes, a higher protein diet is superior to a lower protein diet in terms of increasing fat-free mass in conjunction with a resistance training program. PMID- 29405781 TI - "Simple Methods to Derive Primary Malignant Glioma Cell Lines and Assay of Cellular Damage for Preclinical Studies". AB - Primary malignant glioma cell lines are being used for initial screening of anticancer agents. We utilized a simple mechanical disaggregation method for deriving cell lines from tumor tissues; and a Coverslip Culture-Acridine Orange Staining method to study cellular damage. Cell lines could be grown for up to three passages within three weeks after surgery. Cell proliferation, total cellular damage, and MTT assay were studied as parameters of cytotoxic response. Frequencies of damaged cells varied in different cell lines; and increased after cytotoxic treatments under clinically relevant conditions. These methods could contribute to preclinical evaluation of treatment response before commencement of radio-chemotherapy. PMID- 29405782 TI - Low RMRratio as a Surrogate Marker for Energy Deficiency, the Choice of Predictive Equation Vital for Correctly Identifying Male and Female Ballet Dancers at Risk. AB - Ballet dancers are reported to have an increased risk for energy deficiency with or without disordered eating behavior. A low ratio between measured (m) and predicted (p) resting metabolic rate (RMRratio < 0.90) is a recognized surrogate marker for energy deficiency. We aimed to evaluate the prevalence of suppressed RMR using different methods to calculate pRMR and to explore associations with additional markers of energy deficiency. Female (n = 20) and male (n = 20) professional ballet dancers, 19-35 years of age, were enrolled. mRMR was assessed by respiratory calorimetry (ventilated open hood). pRMR was determined using the Cunningham and Harris-Benedict equations, and different tissue compartments derived from whole-body dual-energy X-ray absorptiometry assessment. The protocol further included assessment of body composition and bone mineral density, blood pressure, disordered eating (Eating Disorder Inventory-3), and for females, the Low Energy Availability in Females Questionnaire. The prevalence of suppressed RMR was generally high but also clearly dependent on the method used to calculate pRMR, ranging from 25% to 80% in males and 35% to 100% in females. Five percent had low bone mineral density, whereas 10% had disordered eating and 25% had hypotension. Forty percent of females had elevated Low Energy Availability in Females Questionnaire score and 50% were underweight. Suppressed RMR was associated with elevated Low Energy Availability in Females Questionnaire score in females and with higher training volume in males. In conclusion, professional ballet dancers are at risk for energy deficiency. The number of identified dancers at risk varies greatly depending on the method used to predict RMR when using RMRratio as a marker for energy deficiency. PMID- 29405783 TI - Identification of PITX3 mutations in individuals with various ocular developmental defects. AB - BACKGROUND: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders. MATERIALS AND METHODS: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea. RESULTS: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract. CONCLUSIONS: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families. PMID- 29405784 TI - Carvacrol nanoemulsion evokes cell cycle arrest, apoptosis induction and autophagy inhibition in doxorubicin resistant-A549 cell line. AB - Carvacrol is a monoterpenoid flavonoid found abundantly in thyme plants. Its physiochemical instability and partial solubility in water is the principal limitation for its industrial use. Hence, we made a carvacrol nanoemulsion (CANE) using ultrasonication method and characterized it by dynamic light scattering (DLS) technique which revealed a negative surface charge (-29.89 mV) with 99.1 nm average droplet size. CANE effectively induced apoptosis in doxorubicin-resistant A549 lung carcinoma cells (A549DR) evident by the elevated expression of apoptotic proteins such as Bax, Cytochrome C, and Cleaved caspase 3 and 9. Also, CANE displayed cell senescence leading to cell cycle arrest by reducing CDK2, CDK4, CDK6, Cyclin E, Cyclin D1 and enhancing p21 protein expression. In addition, a potential role of CANE in the inhibition of autophagy was noted by evaluating the reduced conversion of LC-3 I to II. Beside this, a down-regulation of important autophagy markers ATG5 and ATG7 and upregulation of p62 were detected in response to CANE. We conclude that the synthesized CANE has potential to cause cell senescence, cell cycle arrest, autophagy inhibition and apoptosis in A549DR cells and could be used as a potential candidate for lung cancer therapy. PMID- 29405785 TI - Clinical estimation of alpha/beta values for prostate cancer from isoeffective phase III randomized trials with moderately hypofractionated radiotherapy. AB - BACKGROUND: The alpha/beta values for prostate cancer (PCa) are usually assumed to be low (1.0-1.8 Gy). This study estimated the alpha/beta values of PCa from phase III randomized trials of conventional (CRT) versus hypofractionated (HRT) external beam radiotherapy (RT), reported as isoeffective in terms of their 5 year biochemical (BF) or biochemical and/or clinical failure (BCF) rates. MATERIAL AND METHODS: The alpha/beta for each trial was estimated from the equivalent biological effective doses using the linear-quadratic model for each of their HRT and CRT schedules. The cumulative outcomes of these trials were evaluated by meta-analysis for odds ratio (OR), risk ratio (RR) and risk difference (RD). RESULTS: Eight trials from seven studies, randomized 6993 patients between CRT (n = 2941) and HRT (n = 4052). RT treatment varied between the two treatment groups in terms of dose/fraction, total dose, overall treatment time and %patients on androgen deprivation therapy (ADT). Differences in OR, RR, and RD for both BF and BCF were nonsignificant. The computed alpha/beta ranged from 1.3 to 11.1 Gy (4.9 +/- 3.9 Gy; 95% CI: 1.6-8.2). On multivariate regression, %ADT was the sole determinant of computed alpha/beta (model R2: 0.98, p < .001). CONCLUSIONS: Clinically estimated alpha/beta for PCa from isoeffective randomized trials using known variables in the linear-quadratic expression ranged between 1.3 and 11.1 Gy. The estimated alpha/beta values were inversely related to %ADT usage, which should be considered when planning future RT dose fractionation schedules. PMID- 29405786 TI - The Precompetition Macronutrient Intake of Elite Gaelic Football Players. AB - Competition-related dietary intake has not yet been investigated in Gaelic football. The present study examined the precompetition macronutrient intake of elite male Gaelic football players. Forty players from two teams completed a food diary on the 2 days preceding competition (Day 1 and Day 2) and on the match day prior to the match (match day). Carbohydrate intake was significantly greater on Day 2 compared with Day 1, for both absolute (295 +/- 98 vs. 318 +/- 77 g; p = .048; -23.6 g, 95% confidence interval [-47.3, 0.2]; Cohen's d = 0.27) and relative intake (3.4 +/- 1.1 vs. 3.7 +/- 1.0 g/kg; p = .027; -0.3 g/kg, 95% confidence interval [-0.6, -0.03]; Cohen's d = 0.32). The number of players in accordance with and not in accordance with the guidelines for carbohydrate intake on Day 2 was significantly different to an expected frequency distribution, chi2(1) = 32.400; p <= .001; phi = 0.9, with a greater number of players not meeting the guidelines (observed N = 2 vs. 38). The number of players in accordance with and not in accordance with the recommendations for carbohydrate intake on match day was significantly different to an expected frequency distribution, chi2(1) = 8.100; p = .004; phi = 0.45, with a greater number of players meeting the guidelines (observed N = 29 vs. 11). The major finding from the current investigation was that a significantly greater number of players did not meet carbohydrate intake guidelines on the day before competition. Individualized nutritional interventions are required in order to modify the current prematch dietary intake. PMID- 29405787 TI - The incidence of traumatic brain injury in Tehran, Iran. AB - PRIMARY OBJECTIVE: To assess the demographics, causes, treatment and outcome of traumatic brain injury (TBI) in Tehran, Iran. RESEARCH DESIGN AND METHODS: This retrospective study was conducted in a major trauma centre in south of Tehran using clinical data registry of 3818 traumatic patients who admitted to the hospital from 2009 to 2013. The main factors measured were the external cause of trauma, the type of TBI, and treatment outcome. MAIN OUTCOMES AND RESULTS: The highest rate of TBIs occurred in age categories 21-30 (31.5%), 31-40 (19.2%) and 41-50 (12.3%) years. Transport accidents were the most common cause of TBIs (2915 cases, 76.4%). The most frequent types of head injuries were subarachnoid (1676, 43.9%) subdural (1140, 29.8%), and epidural haemorrhage (974, 25.5%). A binomial logistic regression showed that mortality (612 patients, 16%) was significantly associated with the external cause of TBI, the type of main and additional head injuries, cervical spine injury, intra-abdominal organ injury, having a brain or abdominal surgery, and length of hospital stay. CONCLUSION: The mechanism of TBI, the type of head injuries, and accompanying spine and abdominal injuries were significant prognostic factors in traumatic patients. PMID- 29405789 TI - Is coffee consumption associated with a lower level of serum C-reactive protein? A meta-analysis of observational studies. AB - The association between coffee consumption and the level of C-reactive protein (CRP) has been evaluated in several epidemiological studies with conflicting results. This study aims to examine the relationship between coffee consumption and the serum CRP level. A comprehensive literature search up to August 2017, using PUBMED, EMBASE and Web of Science databases, was conducted to identify the relevant observational studies that examined the association between coffee consumption and the serum CRP level. A total of nine cross-sectional studies were included in this meta-analysis. According to the combined standard mean difference (SMD) between the highest and the lowest coffee intake category, coffee consumption was associated with a lower level of serum CRP level (SMD = 0.34, 95%CI: -0.62 to -0.06; p = .016). Subgroup analysis for CRP marker showed that coffee consumption was associated with a lower level of serum high sensitivity CRP (hsCRP) (SMD = -0.51, 95%CI: -0.88 to -0.14; p = .007), but not standard CRP (SMD = 0.02, 95%CI: -0.28 to 0.32; p = .913). The existing evidence suggested that coffee consumption was associated with a lower level of serum CRP. More well-designed prospective cohort studies are needed to elaborate the concerned issues further. PMID- 29405788 TI - Upregulation of CD4+ T-Lymphocytes by Isomeric Mixture of Quercetin-3-O Rutinoside and Quercetin-3-O-Robinobioside Isolated from Millettia aboensis. AB - BACKGROUND: Millettia aboensis (Hook. F.) Baker (Fabaceae) is popular in ethnomedicine for its acclaimed efficacy in a number of disease conditions. This study evaluated the immunomodulatory effect of the leaf extract as a possible mechanism of its ethnomedicinal uses. METHODS: Humoral and cellular immune responses of Balb/c mice to tetanus toxoid and cyclophosphamide, respectively, were used to monitor immunomodulatory activities of the ethanol leaf extract and fractions of M. aboensis at 200, 300 and 400 mg/kg. Active (butanol) fraction of the extract was subjected to chromatographic purifications to isolate the active compound and the structure elucidated by a combination of 1D and 2D NMR and mass spectrometry. Stimulation of specific T-lymphocytes using intracellular cytokine staining technique was used to evaluate immune-enhancing activity of the isolated compound. RESULTS: The extract and fractions evoked increase in both humoral and cellular immunity. At 400 mg/kg of butanol fraction, the normalized mean secondary production of IgG1 and IgG2a antibodies were 9.0 and 7.7, respectively. Serum cytokine production by butanol fraction following secondary challenge with tetanus toxoid showed that IL-12, IL-17A and IFN-gamma were expressed by 48.14, 41.37 and 38.22%, respectively. Structural elucidation of the active compound revealed presence of isomeric mixtures of quercetin-3-O-rutinoside and quercetin 3-O-robinobioside (Compound 1a/b). Compound 1a/b exhibited in vitro upregulation of specific CD4+ T-lymphocytes that were largely IFNgamma releasing with up to 43.7% stimulation at 6.25 MUg/mL compared to the baseline effect in DMSO vehicle control group. CONCLUSION: M. aboensis expressed strong immune-enhancing properties, which may explain its ethnopharmacological use in disease management. PMID- 29405791 TI - Recent progress in synergistic chemotherapy and phototherapy by targeted drug delivery systems for cancer treatment. AB - Although it's pharmacological effect for cancer therapy, conventional chemotherapy has been compromised by a series of shortcomings such as limited stability, nonspecific tumour targeting ability and severe toxic side effects. To overcome these limitations, multifunctional targeted drug delivery systems for combinatorial therapeutics have been widely explored as novel cancer therapy strategies, showing encouraging results in many pre-clinical animal experiments. Among them, synergistic phototherapy and chemotherapy have demonstrated their abilities to enhance therapeutic efficacies and reduce unwanted side effects via a variety of mechanisms. In this review, we will summarize the latest progress in the development of targeted drug delivery systems with combinations of phototherapy and chemotherapy and discuss the important roles of phototherapy agents involved in those non-conventional therapeutic strategies. PMID- 29405790 TI - Doxorubicin conjugated with a trastuzumab epitope and an MMP-2 sensitive peptide linker for the treatment of HER2-positive breast cancer. AB - HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic YCDGFYACYMDV-NH2 (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDYCDGFYACYMDV-NH2, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX via a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as in vitro model systems and nude mice with BT474 xenografts as an in vivo model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower in vitro IC50, and its in vivo extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K-AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals. PMID- 29405792 TI - Identification and genotype phenotype correlation of novel mutations in SIX6 gene in primary open angle glaucoma. AB - BACKGROUND: Recently SIX1 and SIX6 genes have been associated with primary open angle glaucoma (POAG). This study was planned to do mutation screening in SIX1 and SIX6 genes in North Indian POAG patients and correlate with clinical phenotypes. MATERIALS AND METHODS: SIX1 and SIX6 genes were amplified by PCR and sequenced in 115 POAG cases and 105 controls. Four pathogenecity prediction tools (MutationTaster, PolyPhen-2 HumDiv, PolyPhen-2 HumVar and SIFT) were used to predict the pathogenicity of the missense mutations. Protein modeling studies were done to predict the effect of the missense mutations on the protein structure and function. RESULTS: Two novel mutations p.R116G and p.R116E were observed in the SIX6 gene of patients with POAG. The mutations p.R116G and p.R116E were predicted to be pathogenic and replacement of R116 by G or E might lead to loss of interaction between DNA and R116 of wild type SIX6 protein. The patients with the mutation p.R116E had significantly more visual field damage (MD) and early age of onset of the disease. No sequence variations were observed in the SIX1 gene. CONCLUSION: These results expand the mutation spectrum of SIX6 gene and suggest that SIX6 gene plays an important role in POAG pathogenesis. PMID- 29405794 TI - Assessment of lacrimal resistance using a manometric tear duct irrigation system. AB - Lacrimal surgery aims to provide a low-resistance tear drainage passage. An assessment of lacrimal resistance guides decisions on surgery. We present results of a modified tear duct irrigation system that reliably measures lacrimal outflow resistance. Patients in a specialist lacrimal clinic had a full work-up to the point of tear duct syringing. The tear ducts were irrigated using a manometric system, which applied a fixed, known head of fluid pressure to a lacrimal cannula. Fluid flow is recorded and the lacrimal resistance derived as fluid pressure/fluid flow (units cmH20 secml-1, for simplicity presented as drops per minute, dpm). Patient groups were: A: Asymptomatic, A1: subgroup where the fellow symptomatic eye had a visible cause for watering, B: external visible cause for watering (ocular surface/lid/punctum), C: no externally visible cause, D: post op DCR, E: post syringing and probing, F: mixed/other. 444 tear ducts were examined. Mean flows (dpm) were: A1 (n = 19) 55; B (n = 183) 46; C (n = 142) 22: D (n = 38) 52. Excluding complete obstruction (n = 29), tear duct syringing only detected 48% of those with impaired manometric flow. Of those with a normal tear duct syringing, 53% had impaired manometric flow; 34% had a flow of 0 dpm. Differences in A1 versus C; B versus C and pre versus post dacryocystorhinostomy were all statistically significant (p < 0.05). The manometric system presented reliably measures lacrimal resistance and provides a substantial increase in sensitivity and specificity over conventional lacrimal syringing. PMID- 29405793 TI - Within-Day Energy Deficiency and Metabolic Perturbation in Male Endurance Athletes. AB - Endurance athletes are at increased risk of relative energy deficiency associated with metabolic perturbation and impaired health. We aimed to estimate and compare within-day energy balance in male athletes with suppressed and normal resting metabolic rate (RMR) and explore whether within-day energy deficiency is associated with endocrine markers of energy deficiency. A total of 31 male cyclists, triathletes, and long-distance runners recruited from regional competitive sports clubs were included. The protocol comprised measurements of RMR by ventilated hood and energy intake and energy expenditure to predict RMRratio (measured RMR/predicted RMR), energy availability, 24-hr energy balance and within-day energy balance in 1-hr intervals, assessment of body composition by dual-energy X-ray absorptiometry, and blood plasma analysis. Subjects were categorized as having suppressed (RMRratio < 0.90, n = 20) or normal (RMRratio > 0.90, n = 11) RMR. Despite there being no observed differences in 24-hr energy balance or energy availability between the groups, subjects with suppressed RMR spent more time in an energy deficit exceeding 400 kcal (20.9 [18.8-21.8] hr vs. 10.8 [2.5-16.4], p = .023) and had larger single-hour energy deficits compared with subjects with normal RMR (3,265 +/- 1,963 kcal vs. -1,340 +/- 2,439, p = .023). Larger single-hour energy deficits were associated with higher cortisol levels (r = -.499, p = .004) and a lower testosterone:cortisol ratio (r = .431, p = .015), but no associations with triiodothyronine or fasting blood glucose were observed. In conclusion, within-day energy deficiency was associated with suppressed RMR and catabolic markers in male endurance athletes. PMID- 29405795 TI - Oral mucosa grafting in periorbital reconstruction. AB - To provide an extensive literature review on the clinical indications of oral mucosa grafts (OMG) and minor salivary gland grafts (MSGG) in periorbital reconstruction together with safe practice graft harvesting techniques to minimize donor-site morbidity. A literature review was performed by searching the databases of PUBMED, EMBASE, and COCHRANE library using the keywords: minor salivary glands; oral mucosal graft; orbit; and eye. The bibliographies of the pertinent articles were examined for additional papers. Indications for OMG include treatment of recurrent pterygia; socket contracture in anophthalmic patients; repair of eyelid deformities; ocular surface and fornix reconstruction following tumour resection, cicatricial ocular surface disorders, or chemical burns. More novel uses include repair of glaucoma aqueous drainage device erosions or leaking trabeculectomy blebs; scleral buckle exposure; and keratoprosthesis-related corneal melts as well as lining the dacryocystorhinostomy tract to prevent closure. Simultaneous MSGG transplantation may be used in the treatment of severe dry eyes or dry anophthalmic cavities. Harvesting from the inner cheek is preferred to lower lip as it causes less post operative discomfort and neurosensory deficits. Suturing is recommended for smaller ovoid grafts as it allows less painful closure without tension, while larger rectangular defects are best left to heal by secondary intention. OMG and MSGG transplantation is a viable alternative to replace conjunctiva and restore the ocular surface. The donor site is readily accessible and widely available in most patients, grafting is fast and cheap, and the same site may undergo repeated harvesting with few donor site complications. PMID- 29405796 TI - Running in people with cerebral palsy: A systematic review. AB - BACKGROUND: Running is a fundamental motor skill which is important for participation in recreational activities throughout the lifespan. AIM: To identify, appraise, and synthesize the evidence related to running in people with cerebral palsy (CP). METHOD: A search of electronic databases was conducted in April 2016. Articles were reviewed by two assessors and had to meet the following criteria: 1) population included people with CP; and 2) included information about running. Articles were assessed for quality using the Checklist for Measuring Study Quality by Downs and Black. RESULTS: Of 2607 articles initially identified, 56 underwent full-text review and 17 were included. Quantitative analysis was not possible. The quality of descriptive studies was fair-good, while intervention studies scored poor-good. Four of the 12 descriptive studies reported kinematic and kinetic data. Five intervention studies included running as an outcome measure, although running was not the focus of intervention. A few studies showed that sprint speed, agility, and running efficiency are impaired in people with CP, but mechanisms underlying these impairments have yet to be reported. INTERPRETATION: Research on running in people with CP is limited, methodology and findings are inconsistent and studies are generally fair quality. Further investigation is warranted. PMID- 29405797 TI - New Immobilization Guidelines Change EMS Critical Thinking in Older Adults With Spine Trauma. AB - OBJECTIVE: The impact of immobilization techniques on older adult trauma patients with spinal injury has rarely been studied. Our advisory group implemented a change in the immobilization protocol used by emergency medical services (EMS) professionals across a region encompassing 9 trauma centers and 24 EMS agencies in a Rocky Mountain state using a decentralized process on July 1, 2014. We sought to determine whether implementing the protocol would alter immobilization methods and affect patient outcomes among adults >=60 years with a cervical spine injury. METHODS: This was a 4-year retrospective study of patients >=60 years with a cervical spine injury (fracture or cord). Immobilization techniques used by EMS professionals, patient demographics, injury characteristics, and in hospital outcomes were compared before (1/1/12-6/30/14) and after (7/1/14 12/31/15) implementation of the Spinal Precautions Protocol using bivariate and multivariate analyses. RESULTS: Of 15,063 adult trauma patients admitted to nine trauma centers, 7,737 (51%) were >=60 years. Of those, 237 patients had cervical spine injury and were included in the study; 123 (51.9%) and 114 (48.1%) were transported before and after protocol implementation, respectively. There was a significant shift in the immobilization methods used after protocol implementation, with less full immobilization (59.4% to 28.1%, p < 0.001) and an increase in the use of both a cervical collar only (8.9% to 27.2%, p < 0.001) and not using any immobilization device (15.5% to 31.6%, p = 0.003) after protocol implementation. While the proportion of patients who only received a cervical collar increased after implementing the Spinal Precautions Protocol, the overall proportion of patients who received a cervical collar alone or in combination with other immobilization techniques decreased (72.4% to 56.1%, p = 0.01). The presence of a neurological deficit (6.5% vs. 5.3, p = 0.69) was similar before and after protocol implementation; in-hospital mortality (adjusted odds ratio = 0.56, 95% confidence interval: 0.24-1.30, p = 0.18) was similar post-protocol implementation after adjusting for injury severity. CONCLUSIONS: There were no differences in neurologic deficit or patient disposition in the older adult patient with cervical spine trauma despite changes in spinal restriction protocols and resulting differences in immobilization devices. PMID- 29405798 TI - The Effect of Core Stability Training on Functional Movement Patterns in Collegiate Athletes. AB - CONTEXT: Pre-participation examinations are the standard approach for assessing poor movement quality that would increase musculoskeletal injury risk. However, little is known about how core stability influences functional movement patterns. OBJECTIVE: The primary purpose of this study was to determine the effect of an 8 week core stability program on functional movement patterns in collegiate athletes. The secondary purpose was to determine if the core stability training program would be more effective in those with worse movement quality (i.e. <=14 baseline FMS score). DESIGN: Quasi-experimental design. SETTING: Athletic Training Facility. PARTICIPANTS: One-hundred collegiate athletes. MAIN OUTCOME MEASURES: Functional movement patterns included the Functional Movement Screen (FMS), Lateral step down (LSD) and Y balance test (YBT) and were assessed before and after the 8-week program. INTERVENTION: Participants were placed into 1 of the 2 groups: intervention and control. The intervention group was required to complete a core stability training program that met 3 times per week for 8-week. RESULTS: Significant group x time interactions demonstrated improvements in FMS, LSD and YBT scores in the experimental group relative to the control group (p<0.001). Independent sample t-tests demonstrate that change scores were larger (greater improvement) for the FMS total score and Hurdle step (p<0.001) in athletes with worse movement quality. CONCLUSIONS: An 8-week core stability training program enhances functional movement patterns and dynamic postural control in collegiate athletes. The benefits are more pronounced in collegiate athletes with poor movement quality. PMID- 29405799 TI - Female psychopharmacology matters! Towards a sex-specific psychopharmacology. AB - There is increasing recognition that women have a higher prevalence of certain psychiatric illnesses, and a differential treatment response and course of illness compared to men. Additionally, clinicians deal with a number of disorders like premenstrual syndrome, premenstrual dysphoric disorder, and postpartum depression, which affect women specifically and for which treatment and biological pathways are still unclear. In this article we highlight recent research which suggests that different biological mechanisms may underlie sex differences in responsiveness to stress. Sex differences are evident at the receptor level; where the corticotropin-releasing factor receptor shows differential coupling to adaptor proteins in males and females. The neuropeptide oxytocin also shows sex-specific effects in a range of social behaviors. It may act as a biomarker in post-traumatic stress disorder where sex differences are evident. Studies in women using hormonal contraception show that some of these oxytocin-mediated effects are likely influenced by sex hormones. In female rats rapid changes in circulating progesterone levels are associated with exaggerated behavioral responses to mild stress and blunted responses to benzodiazepines that could be prevented by acute treatment with low-dose fluoxetine. Perceived barriers in research on women have hindered progress. The development of a sex specific psychopharmacology as a basis for translating this type of research into clinical practice is vital to improve treatment outcomes for women. PMID- 29405800 TI - Sirolimus-induced regression of a large orbital lymphangioma. AB - Microcystic lymphatic malformations are difficult to treat surgically, especially when located in the orbital apex. Recently, pharmacologic inhibition of the mTOR pathway by sirolimus was reported as a safe and efficacious treatment option for lymphatic malformations (also known as lymphangiomas). We report the case of a young male patient in which a unilateral, retrobulbar lymphatic malformation regressed to a large extent under treatment with 1 mg sirolimus given orally twice a day over a period of six months. PMID- 29405801 TI - Operationalizing wait lists: Strategies and experiences in three hospital outpatient physiotherapy departments in Montreal. AB - In Canada, limited resources and increasing demand place pressure on the public healthcare system, something that is likely to increase. In this context, wait lists in outpatient physiotherapy departments (OPD) will get longer, system inefficiencies will arise, and frustrations and ethical concerns will be experienced by patients and staff. To better understand the perceptions of OPD staff regarding priority setting, treatment frequency, treatment duration, and wait list management strategies, we conducted an Interpretive Description study involving semi-structured interviews in three OPDs in Montreal. Participants discussed factors that influenced their decision making about who was prioritized to receive care, strategies that were used to respond to an imbalance between needs and resources in the OPDs and procedures to manage wait lists to help improve access to care. While clinical needs are central in approaches to prioritization, other non-clinical factors relating to the patient, the physiotherapist, and the institution also influence decisions. We examine these findings through the lens of complexity theory, providing insight into opportunities and obstacles for the implementation of management strategies in OPDs. These strategies will need to be carefully evaluated in order to create evidence-based guidelines for wait list management in other settings. PMID- 29405802 TI - The Motivational Climate and Intrinsic Motivation in the Rehabilitation Setting. AB - CONTEXT: The motivational climate created by the athletic trainer in rehabilitation may be critical in influencing athletes' intrinsic motivation and other psychosocial outcomes in the rehabilitation and the recovery processes. OBJECTIVE: To examine intercollege athletes' perceptions of the motivational climate in the rehabilitation setting. Specifically, examining if perceptions of the motivational climate can predict athletes' levels of intrinsic motivation with rehabilitation as well as the relationship between perceptions of the motivational climate and athlete demographics (gender, starter status, athletic trainer gender, etc). DESIGN: Cross-sectional, descriptive research. SETTING: College sport team and athletic training center. PARTICIPANTS: National Collegiate Athletic Association Division II intercollege athletes from one institution (n = 187; 125 males and 62 females). MAIN OUTCOME MEASURES: Paper based survey measuring mastery and performance perceptions of the motivational climate in rehabilitation, athletes' goal orientation in sport, and athletes' levels of motivation in rehabilitation. RESULTS: Perceptions of a performance climate were positively related to intrinsic motivation effort-improvement (effect size = 25.34%). Perceptions of a mastery climate were positively related to interest-enjoyment and perceived competence and negatively related to tension pressure (effect size = 39.03%). In general, female athletes, as well as athletes with a female athletic trainer, had significantly higher perceptions of mastery motivational climate effort-improvement than male athletes and athletes with male athletic trainers. While male athletes and athletes with male athletic trainers had higher perceptions of intrateam member rivalry in rehabilitation. CONCLUSIONS: The athlete's gender and goal orientation, as well as the gender of the athletic trainer creating the motivational climate, can influence whether the environment is perceived as more mastery or performance. The recovering athletes' perceptions of the climate in rehabilitation can, in turn, affect their intrinsic motivation toward the therapeutic interventions. PMID- 29405803 TI - Prehospital Rapid Sequence Intubation by Intensive Care Flight Paramedics. AB - OBJECTIVE: Rapid sequence intubation (RSI) is an advanced airway procedure for critically ill or injured patients. Paramedic-performed RSI in the prehospital setting remains controversial, as unsuccessful or poorly conducted RSI is known to result in significant complications. In Victoria, intensive care flight paramedics (ICFPs) have a broad scope of practice including RSI in both the adult and pediatric population. We sought to describe the success rates and characteristics of patients undergoing RSI by ICFPs in Victoria, Australia. METHODS: A retrospective data review was conducted of adult (>= 16 years) patients who underwent RSI by an ICFP between January 1, 2011, and December 31, 2016. Data were sourced from the Ambulance Victoria data warehouse. RESULTS: A total of 795 cases were included in analyses, with a mean age of 45 (standard deviation = 19.6) years. The majority of cases involved trauma (71.7%), and most patients were male (70.1%). Neurological pathologies were the most common clinical indication for RSI (68.3%). The first pass success rate of intubation was 89.4%, and the overall success rate was 99.4%. Of the 5 failed intubations (0.6%), all patients were safely returned to spontaneous respiration. Two patients were returned via bag/valve/mask (BVM) support alone, two with BVM and oropharyngeal airway, and one via supraglottic airway. No surgical airways were required. Overall, we observed transient cases of hypotension (5.2%), hypoxemia (1.3%), or both (0.1%) in 6.6% of cases during the RSI procedure. CONCLUSION: A very high RSI procedural success rate was observed across the study period. This supports the growing recognition that appropriately trained paramedics can perform RSI safely in the prehospital environment. PMID- 29405804 TI - A touch of divinity: The example of Reverend William Arthur Johnson (1816-1880). AB - Except if it be in the shadow of his worshipful student William Osler (1849 1919), the life of Reverend William Arthur Johnson (1816-1880), a 19th century English-Canadian clerical naturalist, teacher, and early mentor to 'the Father of Modern Medicine', has escaped special scrutiny over the years. Written in commemoration of his 200th birthday, this recollection will aim to more purposefully categorise what is currently known of Johnson's life and work, not only in his important relations to the revered Osler, but also in the context of his own personal achievements, life story, and legacy. PMID- 29405805 TI - Comparison of predicted intrinsic hepatic clearance of 30 pharmaceuticals in canine and feline liver microsomes. AB - 1. Known cytochrome P450 (CYP) substrates in humans are used in veterinary medicine, with limited knowledge of the similarity or variation in CYP metabolism. Comparison of canine and feline CYP metabolism via liver microsomes report that human CYP probes and inhibitors demonstrate differing rates of intrinsic clearance (CLint). 2. The purpose of this study was to utilize a high throughput liver microsome substrate depletion assay, combined with microsomal and plasma protein binding to compare the predicted hepatic clearance (CLhep) of thirty therapeutic agents used off-label in canines and felines, using both the well-stirred and parallel tube models. 3. In canine liver microsomes, 3/30 substrates did not have quantifiable CLint, while midazolam and amitriptyline CLint was too rapid for accurate determination. A CLhep was calculated for 29/30 substrates in feline microsomes. Overall, canine CLhep was faster compared to the feline, with fold differences ranging from 2-20-fold. 4. A comparison between the well-stirred and parallel tube model indicates that the parallel tube model reports a slighter higher CLhep in both species. 5. The differences in CYP metabolism between canine and feline highlight the need for additional research into CYP expression and specificity. PMID- 29405806 TI - Delayed Sequence Intubation by Intensive Care Flight Paramedics in Victoria, Australia. AB - OBJECTIVE: Delayed sequence intubation (DSI) involves the administration of ketamine to facilitate adequate preoxygenation in the agitated patient. DSI was introduced into the Clinical Practice Guideline for Intensive Care Flight Paramedics in Victoria in late 2013. We aimed to describe the clinical characteristics of patients receiving DSI. METHODS: A retrospective analysis was undertaken of patients who received DSI between January 1, 2014, and December 31, 2016, during both primary response and retrieval missions. Patients' clinical characteristics, DSI success rates, and complications were determined from electronic patient care records. RESULTS: Forty patients received DSI during the study period. Of these, 32 were intubated to manage traumatic injury and the remaining 8 were intubated for medical reasons. On arrival of the first road ambulance, median oxygen saturation was 96.5%, and immediately prior to DSI the median was 98.0%. One patient had a period of self-limiting apnea (< 15 seconds) following ketamine administration. Oxygen saturation was either maintained or increased prior to laryngoscopy in all patients. Post-intubation, one patient experienced bradycardia (heart rate < 60 beats per minute), two patients had a systolic blood pressure drop of > 20 mm Hg, one patient experienced an increase in heart rate of > 20 beats per minute, and two patients had transient oxygen desaturation (< 85%). No patients experienced cardiac arrest or required surgical airway intervention. All patients were successfully intubated. After DSI, the median oxygen saturation was 100%. CONCLUSIONS: DSI provides a reasonably safe and effective approach for intensive care flight paramedics in the preoxygenation of agitated, hypoxic patients in order to decrease the risk of peri-intubation desaturation and related hypoxic injury. PMID- 29405807 TI - Interaction of deoxyschizandrin and schizandrin B with liver uptake transporters OATP1B1 and OATP1B3. AB - 1. Deoxyschizandrin and schizandrin B have diverse pharmacological effects, including hepatoprotective activity. We aim to study their hepatic uptake and their effects on the hepatic uptake of other clinical drugs mediated by OATP1B1 and OATP1B3. 2. Deoxyschizandrin exhibited a high affinity for OATP1B1 with Km of 17.61 +/- 0.43 MUM but a low affinity for OATP1B3. Similarly, schizandrin B also showed a strong affinity for OATP1B1 with Km of 18.45 +/- 1.23 MUM but a weak affinity for OATP1B3. 3. Atorvastatin and rifampicin could inhibit the uptake of deoxyschizandrin and schizandrin B mediated by OATP1B1. 4. Intriguingly, both deoxyschizandrin and schizandrin B significantly promoted the uptake of atorvastatin (with EC50 of 50.58 +/- 8.08 and 24.70 +/- 5.82 uM, respectively) and rosuvastatin (with EC50 of 13.46 +/- 2.70 and 8.99 +/- 4.73 uM, respectively) mediated by OATP1B1. Deoxyschizandrin could markedly promote the uptake of fluvastatin but inhibit the uptake of sodium taurocholate (TCNa) mediated by OATP1B1. 5. The promotion on hepatic uptake of statins mediated by OATP1B1 might lead to enhanced efficacy of cholesterol lowering and reduced risk of myopathy for hyperlipidemia patients when given statins together with deoxyschizandrin or schizandrin B. PMID- 29405808 TI - Functional Performance Measures Used for Return-to-Sport Criteria in Youth Following Lower-Extremity Injury. AB - CONTEXT: As sport participation increases globally, so will injury-related risks. The process used to determine return-to-sport following injury is vital to future sport participation and injury prevention. Early specialization along with poor management of sport participation causes an increase in injury risk and potential long-term health consequences for youth athletes. OBJECTIVES: Previous injury is a common intrinsic risk factor for new injuries. Identifying functional performance deficits, defined by return-to-sport criteria, minimizes these risk factors and provides athletes with guidelines to return safely to sport. The purposes of this clinical commentary and literature review are to provide a summary of current concepts and clinical practices and to identify functional performance measures as clinical assessment tools for return-to-play criteria in the youth population. EVIDENCE: A literature review was completed using numerous databases, where 154 relevant articles were reviewed and 22 articles were included in this commentary. Of the 22 articles using functional performance measures for return-to-sport criteria, 6 were specific to youth, 12 had mixed populations of adults and youth, and 4 were normative samples for specific youth populations. Acquisition: The gaps in the literature pertaining to functional performance measures in the youth population are addressed, and future research needs for return-to-sport criteria are identified. EVIDENCE SYNTHESIS: This descriptive literature review identifies 22 articles that meet the search criteria for the youth population discussing the use of clinical functional performance measures in order to identify return-to-sport criteria for lower extremity injuries. CONCLUSIONS: Due to the inconsistencies in terminology, definitions, and standardization of clinical assessment tools, it seems necessary to create a comprehensive functional performance test battery for the lower extremity that can be used as return-to-sport criteria. PMID- 29405809 TI - Impairment-Based Rehabilitation Increases Lower Leg Muscle Volumes and Strength in Chronic Ankle Instability Patients: A Preliminary Study. AB - CONTEXT: Chronic ankle instability (CAI) patients have demonstrated atrophy of foot and ankle musculature and deficits in ankle strength. The effect of rehabilitation on muscle morphology and ankle strength has not previously been investigated in CAI patients. OBJECTIVE: Our objective was to analyze the effect of impairment-based rehabilitation on intrinsic and extrinsic foot and ankle muscle volumes and strength in CAI patients. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS: Five young adults with CAI. INTERVENTION: 12 sessions of supervised impairment-based rehabilitation that included range of motion, strength, balance, and functional exercises. MAIN OUTCOME MEASURES: Measures of extrinsic and intrinsic foot muscle volume and ankle strength measured before and after 4 weeks of supervised rehabilitation. Novel fast acquisition MRI was used to scan from above the femoral condyles through the entire foot. The perimeter of each muscle was outlined on each axial slice and then the 2D area was multiplied by the slice thickness (5mm) to calculate muscle volume. Plantar flexion, dorsiflexion, inversion, and eversion isometric strength were measured using a hand-held dynamometer. RESULTS: Rehabilitation resulted in hypertrophy of all extrinsic foot muscles except for the flexor hallucis longus and peroneals. Large improvements were seen in inversion, eversion, and plantar flexion strength following rehabilitation. Effect sizes for significant differences following rehabilitation were all large and ranged from 1.54 to 3.35. No significant differences were identified for intrinsic foot muscle volumes. CONCLUSION: Preliminary results suggest impairment-based rehabilitation for CAI can induce hypertrophy of extrinsic foot and ankle musculature with corresponding increases in ankle strength. PMID- 29405810 TI - Multifamily Therapy for Children With ADHD in Hong Kong: The Different Impacts on Fathers and Mothers. AB - OBJECTIVE: Medication combined with psychosocial intervention is the recommended treatment for ADHD. What is not clear is which of the parents participate in psychosocial interventions, and whether the impacts are different for fathers and mothers. This is important because of the different roles fathers and mothers have in shaping their child's development. This article examines the impact of multifamily therapy on a sample of fathers and mothers from Hong Kong whose children suffer from ADHD. METHOD: Fathers and mothers ratings on ADHD severity, parent-child relationship, parenthood stress, and parental self-esteem were compared between those who attended multifamily therapy and those who attended psychoeducation talks. RESULTS: Fathers and mothers of the multifamily group, but not the psychoeducational group, reported reduction of child ADHD symptom severity. When the reduction was clinically significant, mothers reported an increased sense of competence while fathers reported improved father-child relationship. CONCLUSION: Fathers and mothers experienced different gains from attending MFT. Fathers' involvement in their child's treatment should be encouraged and facilitated. PMID- 29405811 TI - The Effect of Pain Neuroscience Education on Sports Therapy and Rehabilitation Students' Knowledge, Attitudes, and Clinical Recommendations Toward Athletes With Chronic Pain. AB - CONTEXT: Pain education is a fundamental part of a holistic approach to athlete injury management. OBJECTIVE: To investigate the effect of pain neuroscience education (PNE) on sports therapy and rehabilitation students (1) knowledge of persistent pain, (2) attitudes toward athletes with persistent pain, and (3) clinical recommendations for athletes with persistent pain. DESIGN: Parallel groups, single-blind randomized control trial. SETTING: A university in the United Kingdom. PARTICIPANTS: Sixty-one undergraduate and postgraduate sports therapy and rehabilitation students. INTERVENTIONS: The PNE session (intervention group) provided detailed information on the neuroscience of persistent pain, the modulating role of psychosocial factors on pain biology, and how this information could be used to inform clinical practice. The red flags (control group) session provided information on screening patients with persistent pain for serious/sinister pathologies. Each education session lasted 70 minutes. OUTCOME MEASURES: (1) Knowledge-the Revised Pain Neurophysiology Questionnaire; (2) Attitudes-the Health Care Pain Attitudes and Impairment Relationship Scale; and (3) Clinical recommendations-an athlete case vignette. RESULTS: Posteducation, the PNE group had a greater increase in pain neuroscience knowledge (mean difference 3.2; 95% confidence interval [95% CI], 2.1 to 4.3; P < .01) and improved attitudes (mean difference -10.1; 95% CI, -16.6 to -3.6; P < .01). In addition, students in the PNE group were more likely to make appropriate clinical recommendations (odds ratio [OR]; 95% CI) regarding return-to-work (OR = 6.1; 95% CI, 1.1 to 32.3; P = .03), exercise (OR = 10.7; 95% CI, 2.6 to 43.7; P <= 01), and bed rest (OR = 4.3; 95% CI, 1.5 to 12.8; P = 01). CONCLUSION: A brief PNE session can, in the immediate term, increase sports therapy and rehabilitation students' knowledge of pain neuroscience, improve attitudes toward athletes with pain, and shift their clinical recommendations in line with current guidelines. Such changes could lead to enhanced rehabilitation for athletes with persistent pain. PMID- 29405812 TI - Same-Sex Contact and Lifetime Sexually Transmitted Disease Diagnoses Among Older Adults. AB - OBJECTIVE: This study examines difference in sexually transmitted disease (STD) prevalence between sexual minority and heterosexual older adults using lifetime experience of same-sex contact (SSC) as a measure of sexual orientation. METHOD: Data from the National Social Life, Health, and Aging Project ( N = 2,519) are analyzed using negative binomial regression and propensity matching models to test for differences in average STD counts by sexual orientation. RESULTS: Older adults who report any SSC have higher lifetime counts of STDs. This difference persists even when controlling for sex, race, education, age, military status, and incarceration. Propensity matching models show that this difference persists when respondents are matched on several factors that may influence SSC prior to STD contraction. DISCUSSION: The present results call for greater attention from policy makers and researchers because the sexual orientation differences in STDs may exacerbate disparities in overall health status and quality of life. PMID- 29405813 TI - Differences in depressive symptoms between rural and urban Chinese labor force: The mediating effects of community factors. AB - PURPOSE: This study aimed to examine differences in depressive symptoms between urban and rural workers in mainland China and to identify community factors that could contribute to such residential differences. METHODS: This study used nationally representative data from the 2014 China's Labor Force Dynamic Survey. Data were collected through face-to-face interviews on a sample of 22,073 participants from 29 provinces of China, including 15,098 rural workers (Mage = 44.92, standard deviation ( SD) = 14.85) and 6,975 urban workers (Mage = 43.28, SD = 13.62). Mediators included community cohesion, foreseeable community threat, supportive network size and medical benefit coverage. Mediation analyses were conducted using Hayes' SPSS Macro Process for multiple mediators. RESULTS: Urban participants reported fewer depressive symptoms than their rural counterparts. Lower levels of community cohesion, higher community foreseeable threat and poorer medical coverage were related to fewer depressive symptoms. Rural-urban differences were mediated by community cohesion ( B = -0.12, p < .01), foreseeable community threat ( B = -0.08, p < .01) and medical benefit coverage ( B = 0.25, p < .01). CONCLUSION: This study sheds light on distinctive roles of community factors in explaining rural-urban differences in depressive symptoms. Policies or programs should be designed to promote strengths and address weaknesses in rural communities. PMID- 29405814 TI - Corrigendum. PMID- 29405815 TI - The impact of breathing rate on the cardiac autonomic dynamics among children with cerebral palsy compared to typically developed controls. AB - PURPOSE: To describe the immediate effect of breathing rate on heart rate (HR) and heart rate variability (HRV) in children with cerebral palsy (CP) and a control group of typically developed (TD) age and gender-matched children. METHODS: Twenty children with CP at gross motor function classification system levels I-III and 20 TD children aged 6-11 participated in the study. HR was monitored at rest and during paced breathing with biofeedback. Respiratory measures were assessed by KoKo spirometry. RESULTS: Children with CP have lower spirometry and HRV values at rest compared to TD children. The mean reduction of breathing rate during paced breathing among children with CP was significantly smaller. Nonetheless, while practicing paced breathing, both groups reduced their breathing rate and increased their HRV. CONCLUSIONS: The results of the current work present the immediate effect of paced breathing on HRV parameters in CP and TD children. Further studies are needed to investigate the effect of long-term treatment focusing on paced breathing for children with CP. PMID- 29405816 TI - The legacy of Douglas Guthrie (1885-1975), surgeon and medical historian. AB - After graduating in medicine Douglas Guthrie embarked on a career as an ENT surgeon. When his Edinburgh hospital appointment ended in 1936 he began to write History of Medicine, which, thanks to a favourable review by George Bernard Shaw, became a worldwide best seller when first published in 1945. This marked the start of Guthrie's second career as a lecturer in history of medicine at the University of Edinburgh where his prime responsibility was delivering systematic lectures on medical history to medical undergraduates. At a time when history of medicine was virtually the exclusive preserve of medical doctors, Guthrie promoted to them the historiography techniques of the academic historian. His vision that social historians should become involved in the field and that history of medicine should be taught in arts and humanities faculties began to be adopted in British universities a decade or so after Guthrie made the recommendation. His legacy includes the Scottish Society of the History of Medicine and the British Society for the History of Medicine, both of which he helped to found. His name is commemorated in various charitable trusts which he established to promote the study of history of medicine. PMID- 29405817 TI - Philipp Bozzini (1773-1809): The earliest description of endoscopy. AB - The widespread use of endoscopy in today's clinical arena underscores its utility and growing significance within the field of medicine. Primitive forms of endoscopy have existed for hundreds of years, but it was not until the early 19th century that Dr Philipp Bozzini invented an endoscope that would form the basis of modern endoscopy. Born into an influential Italian family, Bozzini practiced medicine in a time and place of conflict and political unrest. His passion, ingenuity, and important social connections allowed him to create and introduce to the medical profession the Lichtleiter (light-conductor), which overcame two key issues plaguing endoscopy: inadequate lighting and poor penetration. A combination of professional rivalry and his premature passing stifled enthusiasm and further work on the Lichtleiter, but its value would not be lost forever. The advancements in the field of endoscopy that have come since the time of the Lichtleiter all build upon the principles of Bozzini, who became widely acknowledged as the father of modern endoscopy. PMID- 29405818 TI - Comparison of Muscle Temperature Increases Produced by Moist Hot Pack and ThermoStim Probe. AB - BACKGROUND: ThermoStim Probe (TSP) has recently joined the market as a superficial heating modality. While there is limited research into the intramuscular heating capability of superficial heating modalities in general (moist hot pack, paraffin, warm whirlpool), no previous research has examined intramuscular heating capability of TSP. OBJECTIVE: Evaluate rate and magnitude of intramuscular heating via TSP as compared to hydrocollator moist hot pack (MHP); determine if TSP can increase tissue temperature 3-4 degrees C (vigorous heating range). DESIGN: Repeated-measures counterbalanced study. SETTING: Multi site trial; two college/university research laboratories. PATIENTS OR OTHER PARTICIPANTS: 18 healthy college-aged participants (11 females, 7 males, age: 23.0+/-2.1, weight: 74.64+/-18.64kg, height: 168.42+/-9.66cm, subcutaneous adipose: 0.71+/-0.17cm) with calf subcutaneous adipose <1.2cm. INTERVENTIONS: Moist hot pack (MHP) and ThermoStim Probe (TSP) were applied to the posterior aspect of the non-dominant calf for 20-minutes; participants underwent each treatment in a counterbalanced order. MAIN OUTCOME MEASUREMENTS: Muscle temperature at a depth of 1.5cm was measured via 21-gauge catheter thermocouple. Temperatures were recorded at baseline and during the 20-minute treatment. RESULTS: There was a significant treatment-by-time interaction during the treatment period (F(5,85)= 14.149, p < .001), as well as significant main effects for treatment (F(1,17) =7.264, p=.015) and for time (F(5,85)= 34.028, p < .001). Muscle temperature increased an average of 1.7 degrees +/-0.9 degrees for the MHP and 0.6 degrees +/-1.0 degrees for the TSP. Pairwise comparisons of the interaction (using least significant difference adjustment for multiple comparisons) indicated that MHP heated faster than TSP at minutes 12 (p=.017), 16 (p=.002), and 20 (p=.001). There was no significant correlation between subcutaneous adipose thickness and maximum temperature increase obtained with either MHP (r=-.033, p=.896) or TSP (r=-.080, p=.753). CONCLUSIONS: MHP increased intramuscular temperature significantly more than TSP, however neither modality was capable of producing a 3-4 degrees C temperature increase associated with increased tissue extensibility. PMID- 29405819 TI - Effect of 12-week- Rebound Therapy Exercise on Static Stability of Patients with Spinal Cord Injury. AB - BACKGROUND: In order to resolve the impairments associated with SCI such as decreased balance, patients have been recommended to undergo various therapeutic strategies, including the use of different physical exercise methods. The aim of this study was to evaluate the efficiency of using rebound therapy (exercise on a trampoline) on SCI individuals' static stability. METHODS: Sixteen SCI people (ASIA classification: A=6, B=6, C=2, D=2) were randomly assigned to an experimental (rebound exercise) group or a control group. The rebound therapy exercise program, lasting 12 weeks, was performed by means of a modified trampoline. During the said period, the experimental group received rebound therapy exercise for 10-30 minutes three sessions a week. Standing stability parameters (i.e. excursion, velocity, and path length of COP in ML and AP plan) were assessed before and after the exercise intervention by Kistler force plate (50*60 cm). Data were analyzed by RM-ANOVA. RESULTS: Significant interactions were observed for all six dependent variables except excursion of COP in ML and the path length of COP in AP plane (P < 0.01). This means that the control group had no progress, while the experimental group made a significant improvement in terms of static stability. CONCLUSION: The results of this study confirmed that rebound therapy could reinforce the static stability of SCI individuals during motionless standing. It suggests that rebound exercise is a useful sports rehabilitation method for patients with SCI and other wheelchair-bound individuals. PMID- 29405820 TI - The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells. AB - The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRalpha and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels. Preventing autophagosome formation by expressing activated mTOR or knocking down of Beclin1, or knock down of the autolysosome protein cathepsin B, reduced drug combination lethality. The drug combination caused an endoplasmic reticulum stress response as judged by enhanced eIF2alpha phosphorylation that was responsible for reducing MCL-1 and BCL-XL levels and increasing ATG5 and Beclin1 expression. Knock down of BIM, but not of BAX or BAK, reduced cell killing. Expression of activated MEK1 prevented the drug combination increasing BIM expression and reduced cell killing. Downstream of the mitochondrion, drug lethality was partially reduced by knock down of AIF, but expression of dominant negative caspase 9 was not protective. Our data demonstrate that neratinib and niraparib interact to kill ovarian cancer cells through convergent DNA damage and endoplasmic reticulum stress signaling. Cell killing required the induction of autophagy and was cathepsin B and AIF -dependent, and effector caspase independent. PMID- 29405822 TI - Incidence of Shoulder Injury in Elite Wheelchair Athletes Differ Between Sports: A Critically Appraised Topic. AB - : Clinical Scenario: Until recently, injury epidemiology data on elite Paralympic athletes were limited. Current data suggest high rates of shoulder injury in wheelchair athletes. Differences in shoulder injury rates between sports have not been reported in this population. CLINICAL QUESTION: Is the incidence of shoulder injury in elite wheelchair athletes different between sports? Summary of Key Findings: Shoulder injury rates are high in elite wheelchair athletes, particularly in sports such as field events and fencing that require a stable base (eg, trunk, core control) from which to perform. Wheelchair racing requires repetitive motions that contribute to shoulder injuries, but rates are lower than field sports and fencing. Wheelchair curling and sledge hockey have low shoulder injury risk. Clinical Bottom Line: Shoulder injury rates vary based on sport in elite wheelchair athletes. In addition to incorporating shoulder complex specific rehabilitation for overuse shoulder injuries, clinicians should focus on core and trunk stabilization in elite wheelchair athletes competing in sports, such as field events and fencing. Strength of Recommendation: Grade C evidence exists that reports shoulder injury rates among elite wheelchair athletes differ based on sport participation. PMID- 29405821 TI - Modulatory upregulation of an insulin peptide gene by different pathogens in C. elegans. AB - When an animal is infected, its innate immune response needs to be tightly regulated across tissues and coordinated with other aspects of organismal physiology. Previous studies with Caenorhabditis elegans have demonstrated that insulin-like peptide genes are differentially expressed in response to different pathogens. They represent prime candidates for conveying signals between tissues upon infection. Here, we focused on one such gene, ins-11 and its potential role in mediating cross-tissue regulation of innate immune genes. While diverse bacterial intestinal infections can trigger the up-regulation of ins-11 in the intestine, we show that epidermal infection with the fungus Drechmeria coniospora triggers an upregulation of ins-11 in the epidermis. Using the Shigella virulence factor OpsF, a MAP kinase inhibitor, we found that in both cases, ins-11 expression is controlled cell autonomously by p38 MAPK, but via distinct transcription factors, STA-2/STAT in the epidermis and HLH-30/TFEB in the intestine. We established that ins-11, and the insulin signaling pathway more generally, are not involved in the regulation of antimicrobial peptide gene expression in the epidermis. The up-regulation of ins-11 in the epidermis does, however, affect intestinal gene expression in a complex manner, and has a deleterious effect on longevity. These results support a model in which insulin signaling, via ins-11, contributes to the coordination of the organismal response to infection, influencing the allocation of resources in an infected animal. PMID- 29405823 TI - Antibody-based intervention against the pore-forming toxins of Staphylococcus aureus. PMID- 29405824 TI - The VraSR regulatory system contributes to virulence in Streptococcus suis via resistance to innate immune defenses. PMID- 29405827 TI - Polymicrobial infections: Do bacteria behave differently depending on their neighbours? AB - Despite the number of examples that correlate interspecies interactions in polymicrobial infections with variations in pathogenicity and antibiotic susceptibility of individual organisms, antibiotic therapies are selected to target the most relevant pathogen, with no consideration of the consequences that the presence of other bacterial species may have in the pathogenicity and response to antimicrobial agents. In this issue of Virulence, Garcia-Perez et al. [ 10 ] applied replica plating of used wound dressings to assess the topography of distinct S. aureus types in chronic wounds of patients with the genetic blistering disease epidermolysis bullosa, which is characterized by the development of chronic wounds upon simple mechanical trauma. This approach led to the identification of two strains of S. aureus coexisting with Bacillus thuringiensis and Klebsiella oxytoca. S. aureus is highly prevalent in chronic wound infections, whereas B. thuringiensis and K. oxytoca are regarded as opportunistic pathogens. These bacterial species did not inhibit each other's growth under laboratory conditions, suggesting that they do not compete through the production of inhibitory compounds. Using a top-down proteomic approach to explore the inherent relationships between these co-existing bacteria, the exoproteomes of the staphylococcal isolates in monoculture and co-culture with B. thuringiensis or K. oxytoca were characterized by Mass Spectrometry. PMID- 29405826 TI - Anaerobic 4-hydroxyproline utilization: Discovery of a new glycyl radical enzyme in the human gut microbiome uncovers a widespread microbial metabolic activity. AB - The discovery of enzymes responsible for previously unappreciated microbial metabolic pathways furthers our understanding of host-microbe and microbe-microbe interactions. We recently identified and characterized a new gut microbial glycyl radical enzyme (GRE) responsible for anaerobic metabolism of trans-4-hydroxy-l proline (Hyp). Hyp dehydratase (HypD) catalyzes the removal of water from Hyp to generate Delta1-pyrroline-5-carboxylate (P5C). This enzyme is encoded in the genomes of a diverse set of gut anaerobes and is prevalent and abundant in healthy human stool metagenomes. Here, we discuss the roles HypD may play in different microbial metabolic pathways as well as the potential implications of this activity for colonization resistance and pathogenesis within the human gut. Finally, we present evidence of anaerobic Hyp metabolism in sediments through enrichment culturing of Hyp-degrading bacteria, highlighting the wide distribution of this pathway in anoxic environments beyond the human gut. PMID- 29405825 TI - O-specific polysaccharide confers lysozyme resistance to extraintestinal pathogenic Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of bloodstream and other extraintestinal infections in human and animals. The greatest challenge encountered by ExPEC during an infection is posed by the host defense mechanisms, including lysozyme. ExPEC have developed diverse strategies to overcome this challenge. The aim of this study was to characterize the molecular mechanism of ExPEC resistance to lysozyme. For this, 15,000 transposon mutants of a lysozyme-resistant ExPEC strain NMEC38 were screened; 20 genes were identified as involved in ExPEC resistance to lysozyme-of which five were located in the gene cluster between galF and gnd, and were further confirmed to be involved in O-specific polysaccharide biosynthesis. The O-specific polysaccharide was able to inhibit the hydrolytic activity of lysozyme; it was also required by the complete lipopolysaccharide (LPS)-mediated protection of ExPEC against the bactericidal activity of lysozyme. The O-specific polysaccharide was further shown to be able to directly interact with lysozyme. Furthermore, LPS from ExPEC strains of different O serotypes was also able to inhibit the hydrolytic activity of lysozyme. Because of their cell surface localization and wide distribution in Gram-negative bacteria, O-specific polysaccharides appear to play a long overlooked role in protecting bacteria against exogenous lysozyme. PMID- 29405828 TI - A vaccine targeting basic fibroblast growth factor elicits a protective immune response against murine melanoma. AB - Tumor growth and metastasis are closely related to angiogenesis. Basic fibroblast growth factor(bFGF) is an angiogenic factor, and up-regulated expression of bFGF plays a crucial role in the development and metastasis of melanoma. Therefore, in this study, we sought to achieve antitumor activity by immunity targeting bFGF which would inhibit tumor angiogenesis and simultaneously induce bFGF specific cytotoxic T lymphocytes to kill melanoma cells. A human bFGF protein was used as exogenous antigen, coupled with a saponin-liposome adjuvant formulation to enhance CTL response. The results showed that the immunity induced strong immune response and produced prominent anti-cancer activities. CD31 immunohistochemistry and alginate-encapsulated tumor cell assay displayed that tumor angiogenesis was effectively inhibited. Further, the higher production of IFN-gamma and cytotoxic T lymphocyte killing assay suggested that the anti-cancer activities may mainly depend on cellular immune response, which could cause the inhibition of tumor angiogenesis and specific killing of tumor cells by bFGF-specific cytotoxic T lymphocytes. We concluded that immunotherapy targeting bFGF may be a prominent strategy for melanoma, and that the adjuvant formulation of saponin-liposome is very desirable in enhancing cytotoxic T lymphocytes response. PMID- 29405829 TI - Novel insight into the pathogenicity of Streptococcus gallolyticus subsp. gallolyticus belonging to the Streptococcus bovis/Streptococcus equinus complex. PMID- 29405831 TI - Do attentional capacities and processing speed mediate the effect of age on executive functioning? AB - The executive processes are well known to decline with age, and similar data also exists for attentional capacities and processing speed. Therefore, we investigated whether these two last nonexecutive variables would mediate the effect of age on executive functions (inhibition, shifting, updating, and dual task coordination). We administered a large battery of executive, attentional and processing speed tasks to 104 young and 71 older people, and we performed mediation analyses with variables showing a significant age effect. All executive and processing speed measures showed age-related effects while only the visual scanning task performance (selective attention) was explained by age when controlled for gender and educational level. Regarding mediation analyses, visual scanning partially mediated the age effect on updating while processing speed partially mediated the age effect on shifting, updating and dual-task coordination. In a more exploratory way, inhibition was also found to partially mediate the effect of age on the three other executive functions. Attention did not greatly influence executive functioning in aging while, in agreement with the literature, processing speed seems to be a major mediator of the age effect on these processes. Interestingly, the global pattern of results seems also to indicate an influence of inhibition but further studies are needed to confirm the role of that variable as a mediator and its relative importance by comparison with processing speed. PMID- 29405833 TI - Evidence-Based Use of Perioperative Antibiotics in Otolaryngology. AB - Objective To identify and clarify current evidence supporting and disputing the effectiveness of perioperative antibiotic use for common otolaryngology procedures. Data Sources PubMed, Embase (OVID), and CINAHL (EBSCO). Review Methods English-language, original research (systematic reviews/meta-analyses, randomized control trials, prospective or retrospective cohort studies, case control studies, or case series) studies that evaluated the role of perioperative antibiotic use in common otolaryngology surgeries were systematically extracted using standardized search criteria by 2 investigators independently. Conclusions Current evidence does not support routine antibiotic prophylaxis for tonsillectomy, simple septorhinoplasty, endoscopic sinus surgery, clean otologic surgery (tympanostomy with tube placement, tympanoplasty, stapedectomy, and mastoidectomy), and clean head and neck surgeries (eg, thyroidectomy, parathyroidectomy, salivary gland excisions). Antibiotic prophylaxis is recommended for complex septorhinoplasty, skull base surgery (anterior and lateral), clean-contaminated otologic surgery (cholesteatoma, purulent otorrhea), and clean-contaminated head and neck surgery (violation of aerodigestive tract, free flaps). In these cases, antibiotic use for 24 to 48 hours postoperatively has shown equal benefit to longer duration of prophylaxis. Despite lack of high quality evidence, the US Food and Drug Administration suggests antibiotic prophylaxis for cochlear implantation due to the devastating consequence of infection. Data are inconclusive regarding postoperative prophylaxis for nasal packing/splints after sinonasal surgery. Implications for Practice Evidence does not support the use of perioperative antibiotics for most otolaryngologic procedures. Antibiotic overuse and variability among providers may be due to lack of formal practice guidelines. This review can help otolaryngologists understand current evidence so they can make informed decisions about perioperative antibiotic usage. PMID- 29405834 TI - Effect of ozonation on minocycline degradation and N-Nitrosodimethylamine formation. AB - The objective of this study was to assess reactivity of Minocycline (MNC) towards ozone and determine the effects of ozone dose, pH value, and water matrix on MNC degradation as well as to characterize N-Nitrosodimethylamine (NDMA) formation from MNC ozonation. The MNC initial concentration of the solution was set in the range of 2-20 mg/L to investigate NDMA formation during MNC ozonation. Four ozone doses (22.5, 37.2, 58.0, and 74.4 mg/min) were tested to study the effect of ozone dose. For the evaluation of effects of pH value, pH was adjusted from 5 to 9 in the presence of phosphate buffer. MNC ozonation experiments were also conducted in natural water to assess the influence of water matirx. The influence of the typical component of natural water was also investigated with the addition of HA and NaHCO3 solution. Results indicated that ozone was effective in MNC removal. Consequently, NDMA and dimethylamine (DMA) were generated from MNC oxidation. Increasing pH value enhanced MNC removal but led to greater NDMA generation. Water matrices, such as HCO3- and humic acid, affected MNC degradation. Conversely, more NDMA accumulated due to the inhibition of NDMA oxidation by oxidant consumption. Though ?OH can enhance MNC degradation, ozone molecules were heavily involved in NDMA production. Seven transformation products were identified. However, only DMA and the unidentified tertiary amine containing DMA group contributed to NDMA formation. PMID- 29405835 TI - Social Media among Medical Students and Personnel Here to Stay. AB - Social media is no longer new, even in the professional medical world. It is an established and relatively public medium, and all users would do well to understand the risks associated with it. Medical personnel-whether medical student or staff physician-must familiarize themselves with it to ensure positive outcomes. As with other technologies, best practices will evolve with time, but existing and ongoing research can establish working use guidelines. PMID- 29405832 TI - Beyond sepsis: Staphylococcus epidermidis is an underestimated but significant contributor to neonatal morbidity. AB - Staphylococcus epidermidis accounts for the majority of cases of neonatal sepsis. Moreover, it has been demonstrated to be associated with neonatal morbidities, such as bronchopulmonary dysplasia (BPD), white matter injury (WMI), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP), which affect short-term and long-term neonatal outcome. Imbalanced inflammation has been considered to be a major underlying mechanism of each entity. Conventionally regarded as a harmless commensal on human skin, S. epidermidis has received less attention than its more virulent relative Staphylococcus aureus. Particularities of neonatal innate immunity and nosocomial environmental factors, however, may contribute to the emergence of S. epidermidis as a significant nosocomial pathogen. Neonatal host response to S. epidermidis sepsis has not been fully elucidated. Evidence is emerging regarding the implication of S. epidermidis sepsis in the pathogenesis of neonatal inflammatory diseases. This review focuses on the interplay among S. epidermidis, neonatal innate immunity and inflammation-driven organ injury. PMID- 29405836 TI - Expanded Transcanal Transpromontorial Approach: A Novel Surgical Technique for Cerebellopontine Angle Vestibular Schwannoma Removal. AB - Objective Vestibular schwannoma (VS) is a benign tumor of the lateral skull base. Different microscopic surgical techniques are described in literature: the retrosigmoid and translabyrinthine approaches are used to treat big tumors located in the cerebellopontine angle, and the middle cranial fossa approach is utilized for small tumors with good hearing preservation. The expanded transcanal transpromontorial (ExpTT) approach is a combined microscopic-endoscopic technique previously indicated for Koos stage I and II VS and now proposed for larger VS, up to 3 cm in diameter, with linear progression into the cerebellopontine angle and touching the brainstem. Study Design The study was a retrospective case series of patients who underwent ExpTT surgery for VS in our ear, nose, and throat department. Setting We reviewed the surgical videos and electrophysiologic data recorded during the surgical operations. Subjects and Methods From January 2015 to January 2017, 20 patients affected by Koos stage II and III VS underwent surgery in our department with the ExpTT approach. This novel technique is described step by step, with a focus on the surgical procedure and anatomic landmarks; outcomes are detailed in terms of early and late complications. The mean follow-up was 15 months. Results The ExpTT approach permitted, in all patients, gross total resection of the tumor without any complication and with preservation of facial nerve function. All patients had a good postoperative recovery. Conclusion The ExpTT technique is a new approach that combines the advantages of a microscopic technique with the ones offered by the endoscope in removal of VS. PMID- 29405837 TI - Asymmetric Hearing Loss Prompting MRI Referral in a Military Population: Redefining Audiometric Criteria. AB - Objective To reevaluate asymmetric sensorineural hearing loss (ASNHL) criteria used to justify magnetic resonance imaging (MRI) in the evaluation of retrocochlear tumors in a military population. Study Design Retrospective case control study. Setting Tertiary care military medical center. Subjects and Methods Patients with military service and a history of ASNHL prompting referral for MRI, with or without retrocochlear tumors, were compared between 2005 and 2016. Predictor variables included pure tone ASNHL, speech audiometry, and a history of noise exposure. Logistic regression models for hearing asymmetries were performed, and receiver operator curves were used to calculate sensitivity and specificity. Results Thirty-eight retrocochlear tumors were identified. The MRI diagnosis rate for patients with ASHNL was 0.85%. Patients with tumors were slightly older (42 vs 37 years, P = .021) and had less noise exposure (47% vs 85%, P < .001). A sensitivity of 0.83 and a specificity of 0.58 were calculated for asymmetries >=10 dB at 2000 Hz without adjusting for noise exposure. Instituting this imaging threshold would have reduced the number of MRI scans by half while missing 16% of tumors. Conclusion The tumor diagnosis rate among those undergoing MRI for ASNHL is low in the military population, likely because service-related noise exposure commonly causes ASNHL. Optimal MRI referral criteria should conserve resources while balancing the risks of over- and underdiagnosis. For those with a history of military service, an asymmetry >=10 dB at 2000 Hz among patients meeting current ANSHL referral criteria is most predictive of a retrocochlear tumor. PMID- 29405838 TI - Hb Nouakchott [alpha114(GH2)Pro->Leu; HBA1: c.344C>T], A Second and Third Case Described in Two Unrelated Dutch Families. AB - We report two families, members of which are carriers of a hemoglobin (Hb) variant previously described as Hb Nouakchott [alpha114(GH2)Pro->Leu; HBA1: c.344C>T; p.Pro115Leu]. In the first family of Dutch origin, the proband, a 32 year-old male and his 65-year-old father, were both carriers of Hb Nouakchott. Of the second family we tested, only the proband, a 56-year-old Dutch female was a Hb Nouakchott carrier. Hematological analyses of these cases showed the anomaly behaves as a silent Hb variant without clinical consequences. The Hb variant remained unnoticed using high performance liquid chromatography (HPLC), while an additional peak was detected by capillary electrophoresis (CE). These independent findings of Hb Nouakchott indicate that this Hb variant might not be very rare, but simply remains under diagnosed depending on the Hb separation technique used. PMID- 29405839 TI - Assessing potential impacts of phosphate precipitation on nitrous oxide emissions and the carbon footprint of wastewater treatment plants. AB - Metal salts are widely used for the precipitation of phosphorus during wastewater treatment transforming soluble orthophosphate to an insoluble salt. In practice, more complex reactions are taking place including a reduction of the chemical solubility of dissolved greenhouse gases, such as nitrous oxide, present in the wastewater stream. In this respect, it was postulated that phosphorous precipitation will lead to artificial N2O stripping and hence to an increased carbon footprint of wastewater treatment plants. From lab-scale experiments utilizing N2O-saturated synthetic sewage solutions, it was evidenced that metal salt addition leads to N2O stripping with 20.8 g N2O per liter for a FeCl2-based precipitant to 26.4 g N2O per liter for a Aln(OH)mCl3n-m-based precipitant. Taking this maximum potential stripping effect into account for a carbon footprint analysis, a potential contribution of 16.11 kg CO2,eq.PE-1.a-1 was calculated in a case study, where FeCl3 was considered. With respect to the defined system boundary conditions, the overall on-site and off-site CO2 emissions were raised by 34% from 46.87 kg CO2,eq.PE-1.a-1 to 62.97 kg CO2,eq.PE 1.a-1 through CO2,eq coming from phosphorous precipitation. PMID- 29405840 TI - Changes in Transcranial Ultrasound Velocities in Children with Sickle Cell Disease Undergoing Adenotonsillectomy. AB - Objectives (1) To assess for changes in cerebral blood flow velocity in children with sickle cell disease and obstructive sleep apnea (OSA) following adenotonsillectomy. (2) To determine if clinical factors such as OSA severity affect cerebral blood flow velocity values. Study Design Case series with chart review over 10 years. Settings Two tertiary children's hospitals. Subjects and Methods Children aged 2 to 18 years with a history of sickle cell disease and OSA, as defined by an apnea hypopnea index (AHI) >1 on polysomnography, were eligible for inclusion. Transcranial Doppler ultrasonography was used to assess cerebral blood flow velocity before and after adenotonsillectomy. Results Fifteen patients met inclusion criteria; 73% (n = 11) were female. The mean preoperative AHI was 8.9 (range, 1.2-22.2). Six (40%) patients had severe OSA (AHI >10). Following adenotonsillectomy, there was a significant reduction in mean (95% CI) cerebral blood flow velocities of the left terminal internal cerebral artery, 91.2 (79.4-103.1) to 75.7 (61.7-89.8; P = .018), and the right middle cerebral artery, 134.3 (119.2-149.3) to 116.5 (106.5-126.5; P = .003). There was not a significant correlation between baseline AHI and change in cerebral blood flow velocities. Conclusion Adenotonsillectomy may result in a reduction in some cerebral blood flow velocities. Further research is needed to determine if changes in cerebral velocities as assessed by transcranial Doppler ultrasonography translate into a reduced risk of stroke for children with sickle cell disease and OSA. PMID- 29405841 TI - Polish Adaptation of the Death Attitude Profile-Revised. AB - The article presents the results of work on the Polish adaptation of the Death Attitude Profile-Revised by Wong, Reker, and Gesser (1994). The psychometric properties of the Polish version of the tool have been described. The results are consistent with the original version of the questionnaire and confirm that the Polish version of Death Attitude Profile-Revised fulfils the psychometric requirements for psychological tests and, as a result, can be applied in scientific research. The final version of the questionnaire consists of 32 items (including 31 diagnostic ones) that make up five dimensions of attitudes toward death: (a) Fear of Death, (b) Death Avoidance, (c) Neutral Acceptance, (d) Escape Acceptance, and (e) Approach Acceptance. The questionnaire was tested on 1,285 subjects aged 13 to 90 years ( M = 47.27, SD = 18.21). Reliability values (Cronbach's alpha) for individual scales vary from alpha = .63 to alpha = .89. Confirmatory factor analysis was used to evaluate the validity of the questionnaire. PMID- 29405842 TI - Familiarization, validity and smallest detectable difference of the isometric squat test in evaluating maximal strength. AB - Isometric multi-joint tests are considered reliable and have strong relationships with 1RM performance. However, limited evidence is available for the isometric squat in terms of effects of familiarization and reliability. This study aimed to assess, the effect of familiarization, stability reliability, determine the smallest detectible difference, and the correlation of the isometric squat test with 1RM squat performance. Thirty-six strength-trained participants volunteered to take part in this study. Following three familiarization sessions, test-retest reliability was evaluated with a 48-hour window between each time point. Isometric squat peak, net and relative force were assessed. Results showed three familiarizations were required, isometric squat had a high level of stability reliability and smallest detectible difference of 11% for peak and relative force. Isometric strength at a knee angle of ninety degrees had a strong significant relationship with 1RM squat performance. In conclusion, the isometric squat is a valid test to assess multi-joint strength and can discriminate between strong and weak 1RM squat performance. Changes greater than 11% in peak and relative isometric squat performance should be considered as meaningful in participants who are familiar with the test. PMID- 29405843 TI - Conceptualizing depression in Vietnam: Primary health care providers' explanatory models of depression. AB - The purpose of this qualitative study was to elicit the explanatory models (EMs) of primary healthcare providers (PHPs) in Vietnam in order to (a) understand if and how the concept of depression is understood in Vietnam from the perspective of nonspecialist providers and community members, and (b) to inform the process of introducing services for depression in primary care in Vietnam. We conducted semistructured interviews with 30 PHPs in one rural and one urban district of Hanoi, Vietnam in 2014. We found that although PHPs possess low levels of formal knowledge about depression, they provide consistent accounts of its symptoms and aetiology among their patient population, suggesting that depression is a relevant concept in Vietnam. PHPs describe a predominantly psychosocial understanding of depression, with little mention of either affective symptoms or neurological aetiology. This implies that, with enhanced training, psychosocial approaches to depression care would be appropriate and acceptable in this context. Distinctions were identified between rural and urban populations in both understandings of depression and help-seeking, suggesting that enhanced services should account for the diversity of the Vietnamese context. Alcohol misuse among men emerged as a considerable concern, both in relation to depression and as stand-alone issue facing Vietnamese communities, indicating the need for further research in this area. Low help-seeking for depression in primary care implies the need for enhanced community outreach. The results of this study demonstrate the value of eliciting EMs to inform planning for enhanced mental health service delivery in a global context. PMID- 29405844 TI - Repair of rabbit radial bone defects using bone morphogenetic protein-2 combined with 3D porous silk fibroin/beta-tricalcium phosphate hybrid scaffolds. AB - Our study aimed to investigate the effect of bone morphogenetic protein-2 (BMP-2) bound to silk fibroin and beta-tricalcium phosphate (SF/beta-TCP) hybrid on the healing of critical-size radial defects in rabbits. A 15-mm critical-size defect was induced at mid-diaphysis in the left radius of 20 New Zealand white rabbits (average age, 3.5 months; weight, 2.5-3.0 kg). The animals were randomized into Group 1 (SF/beta-TCP combined with BMP-2), Group 2 (SF/beta-TCP alone), and Group 3 (nothing implanted). Radiographs were obtained every 2 weeks and euthanasia was performed after 8 weeks for visual, radiological, micro-computed tomography (micro-CT), and histological studies. Eight weeks after implantation (SF/beta-TCP combined with BMP-2), radiographs showed that new bone formed on the surface of the implant and had bridged the defect in Group 1. Micro-CT imaging also confirmed the formation of new bone around the implant, and the newly formed bone was quantified. Histological examination revealed newly formed bone in the implanted area. Meanwhile, there was no formation of new bone in Group 3. Among the groups, most active formation of new bones was found in Group 1, while there was no difference between Group 2 and Group 3. Based on these results, we concluded that BMP-2-SF/beta-TCP showed significant improvement in healing of critical-size defects. Therefore, the combination of BMP-2 and SF/beta-TCP would be useful in the field of bone tissue engineering. PMID- 29405845 TI - Areas for Quality Improvement for Airway Dilation in Children: NSQIP-Pediatric 30 Day Outcomes. AB - Objective To identify predictors of adverse events and highlight areas for quality improvement for children who underwent laryngeal or tracheal dilation, without prior tracheostomy placement. Study Design Cross-sectional analysis using a US national database. Setting American College of Surgeons (ACS) National Surgical Quality Improvement Program (ACS NSQIP-pediatric), years 2012 to 2015. Subjects and Methods Patients 18 years and younger were included. Patients without prior tracheostomy placement were identified using 2017 Current Procedural Terminology ( CPT) codes: 31528, 31529, and 31630. Results We identified a total of 160 children who met inclusion criteria. Forty-three (26.9%) patients experienced an adverse event. Mortality was observed postoperatively in 1 patient (0.6%) 1 day after the operation. Younger age, increased number of days from hospital admission to operation, and increased number of days from operation to discharge were noted to be associated with adverse events. Last, the risk of adverse events appears to be mitigated by concurrent other laryngeal procedures. Conclusions There is a high rate of adverse events reported with airway dilation in children. Unplanned reoperations and hospital readmissions are highlighted areas for quality improvement. Airway dilation in children appears to avoid tracheostomy and open laryngotracheoplasty in most cases for at least 30 days postoperatively. Further investigation may be helpful to understand if younger age and delayed operative intervention contribute to increased adverse events. PMID- 29405846 TI - The Role of Prototype Matching in Science Pursuits: Perceptions of Scientists That Are Inaccurate and Diverge From Self-Perceptions Predict Reduced Interest in a Science Career. AB - Self-to-prototype matching is a strategy of mental comparisons between the self concept and the typical or "representative" member of a group to make some judgment. Such a process might contribute to interest in pursuing a science career and, relatedly, women's underrepresentation in physical science, technology, engineering, and mathematics (pSTEM) fields. Across four studies, we measured self-scientist discrepancies on communal, agentic, and scientific dimensions, and assessed participants' interest in a science career. The most consistent predictor of science interest was the discrepancy between self and scientist on the scientific dimension (e.g., intelligent, meticulous). Study 4 established that students with larger self-scientist discrepancies also had less accurate perceptions of students pursuing science, and that inaccuracy was related to lower science interest. Thus, students with lower science interest do not just perceive scientists differently from themselves but also erroneously. Discrepancy and inaccuracy together explained a significant portion of the gender gap in pSTEM interest. PMID- 29405847 TI - Stimulated by Novelty? The Role of Psychological Needs and Perceived Creativity. AB - In the current research, we aimed to address the inconsistent finding in the brainstorming literature that cognitive stimulation sometimes results from novel input, yet other times from non-novel input. We expected and found, in three experiments, that the strength and valence of this relationship are moderated by people's psychological needs for structure and autonomy. Specifically, the effect of novel input (vs. non-novel input), through perceived creativity, on cognitive stimulation was stronger for people who were either low in need for structure or high in need for autonomy. Also, when the input people received did not fit their needs, they experienced less psychological cognitive stimulation from this input (i.e., less task enjoyment and feeling more blocked) compared with when they did not receive any input. Hence, to create the ideal circumstances for people to achieve cognitive stimulation when brainstorming, input novelty should be aligned with their psychological needs. PMID- 29405848 TI - Development and initial evaluation of an instrument to assess physiotherapists' clinical reasoning focused on clients' behavior change. AB - BACKGROUND AND AIM: A systematically developed and evaluated instrument is needed to support investigations of physiotherapists' clinical reasoning integrated with the process of clients' behavior change. This study's aim was to develop an instrument to assess physiotherapy students' and physiotherapists' clinical reasoning focused on clients' activity-related behavior and behavior change, and initiate its evaluation, including feasibility and content validity. METHODS: The study was conducted in three phases: 1) determination of instrument structure and item generation, based on a model, guidelines for assessing clinical reasoning, and existing measures; 2) cognitive interviews with five physiotherapy students to evaluate item understanding and feasibility; and 3) a Delphi process with 18 experts to evaluate content relevance. RESULTS: Phase 1 resulted in an instrument with four domains: Physiotherapist; Input from client; Functional behavioral analysis; and Strategies for behavior change. The instrument consists of case scenarios followed by items in which key features are identified, prioritized, or interpreted. Phase 2 resulted in revisions of problems and approval of feasibility. Phase 3 demonstrated high level of consensus regarding the instrument's content relevance. CONCLUSIONS: This feasible and content-validated instrument shows potential for use in investigations of physiotherapy students' and physiotherapists' clinical reasoning, however continued development and testing are needed. PMID- 29405849 TI - Which is most sensitive? Assessing responses of mice and rats in toxicity bioassays. AB - Rodent species are commonly used in traditional toxicology testing guidelines to predict human health toxicity outcomes. The use of a consistent species in test guidelines is important for maintaining consistency and comparability between tests and testing guidelines. This recommendation was operationalized for this study as the implicit assumption of uniform species and species-sex sensitivities. This investigation analyzed the uniformity assumption using data from National Toxicology Program Technical Reports (and where applicable Toxicity Reports), which provide data from both short-term and chronic rodent toxicity tests. These data were extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Minimum best-fit benchmark doses (BMD) and benchmark dose lower limits (BMDL) were determined and a minimum best-fit BMD10 and BMDL10 estimated for every chemical and study duration. Endpoints of interest included non-neoplastic lesions, final mean body weights, and mean organ weights. The distribution of findings was then assessed to determine the most sensitive species and species-sex combinations associated with the minimum best-fit BMDL10. Data indicated that species and species-sex sensitivity for this group of chemicals is not uniform and that rats are significantly more sensitive than mice for non-cancerous outcomes observed, depending upon study duration. There are also indications that male rats may be more sensitive than other species-sex groups in certain situations. PMID- 29405850 TI - Unilateral Vocal Fold Paralysis and Risk of Pneumonia: A Nationwide Population Based Cohort Study. AB - Objective To investigate pneumonia risk among patients with unilateral vocal fold paralysis (UVFP). Study Design Retrospective population-based cohort study. Setting This study used data from the National Health Insurance Research Database of Taiwan, a nationwide population-based database. Subjects and Methods A total of 419 patients newly diagnosed with UVFP between January 1, 1997, and December 31, 2013, were identified from the Longitudinal Health Insurance Database 2000, a nationally representative database of 1 million randomly selected patients. Moreover, 1676 patients without UVFP were matched to patients with UVFP at a 1:4 ratio based on age, sex, socioeconomic status, urbanization level, and site specific cancers. Patients were followed up until death or the end of the study period (December 31, 2013). The primary outcome was the occurrence of pneumonia. Results The cumulative incidence of pneumonia was significantly higher for patients with UVFP than those without UFVP ( P < .001). The adjusted Cox proportional hazard model showed that UVFP was significantly associated with a higher incidence of pneumonia (hazard ratio, 1.97; 95% CI, 1.35-2.86; P < .001). Subgroup analyses demonstrated that UVFP was an independent risk factor of pneumonia for 4 subgroups: young (18-50 years), older (>=51 years), male, and cancer. Conclusion This is the first nationwide population-based cohort study to investigate the association between UVFP and pneumonia. The findings indicate that UVFP is an independent risk factor of pneumonia. Given the study results, physicians should be aware of the potential for pneumonia occurrence following UVFP. PMID- 29405851 TI - Effect of warning placement on the information processing of college students reading an OTC drug facts panel. AB - OBJECTIVE: To compare three over-the-counter (OTC) Drug Facts panel versions for information processing optimization among college students. PARTICIPANTS: University of Houston students (N = 210) participated in a cross-sectional survey from January to May 2010. METHODS: A current FDA label was compared to two experimental labels developed using the theory of CHREST to test information processing by re-positioning the warning information within the Drug Facts panel. Congruency was defined as placing like information together. Information processing was evaluated using the OTC medication Label Evaluation Process Model (LEPM): label comprehension, ease-of-use, attitude toward the product, product evaluation, and purchase intention. RESULTS: Experimental label with chunked congruent information (uses-directions-other information-warnings) was rated significantly higher than the current FDA label and had the best average scores among the LEPM information processing variables. CONCLUSION: If replications uphold these findings, the FDA label design might be revised to improve information processing. PMID- 29405852 TI - James Herrick (1861-1954): Consultant physician and cardiologist. AB - In 1910, James Bryan Herrick published the first clinical and laboratory description of sickle cell anemia. Two years later, he published a case report on coronary thrombosis. Together, these case reports solidified his reputation as one of the premier diagnosticians of his generation. Now regarded as a central figure in the history of American medicine, Herrick played an integral role in the clinical adoption of the electrocardiograph and the professionalization of cardiology in the United States. Although a full decade passed before the medical profession recognized his clinical description of coronary thrombosis and myocardial infarction, it has had profound implications for cardiovascular medicine and prevention over the past hundred years. As a consultant physician, Herrick advocated in favor of incorporating chemistry and laboratory evaluation into clinical practice. PMID- 29405853 TI - Keep Faith in Yourself! A Pilot Study on the Relevance of Specific Self-Efficacy for Modifying Sexual Interest in Children Among Men With a Risk to Sexually Abuse Children. AB - Among 26 pedophilic/hebephilic men, we investigated (1) the relationship between "specific self-efficacy for modifying a sexual interest in children" (SSIC) and actual sexual interest in children and (2) whether changes in SSIC are associated with changes in sexual interest in children. Results showed that the more clients believe they are able to influence their sexual interest in children, the less strong they perceive their sexual interest in children to be. Furthermore, an increase in SSIC is associated with a decrease in sexual interest in children. We suggest avoiding generalized statements about the immutability of sexual interest in children. PMID- 29405854 TI - Unblurring the lines of sexual consent with a college student-driven sexual consent education campaign. AB - OBJECTIVE: To test the effectiveness of a college student-driven sexual consent education campaign to improve college students' sexual consent understanding. PARTICIPANTS: Undergraduate students (N = 992) at a large, public Midwestern university between March and December 2015. METHODS: Three online survey questionnaires assessing relevant outcome measures were distributed to the university's undergraduate student population before, during, and after the campaign's implementation over two consecutive academic semesters. RESULTS: Exposure to the campaign and the sexual consent understanding of the student population improved over time. College men and members of university-affiliated social sororities or fraternities resulted in greater improvement than their respective counterparts (i.e., college women, nonmembers). CONCLUSIONS: Sexual consent education campaigns for college students that are student-driven and address relevant sociocultural factors while authentically interacting with students can improve students' sexual consent understanding. These type of campaigns also have the opportunity to reach historically hard-to-reach audiences, such as college men. PMID- 29405855 TI - Acknowledgement and support matter: A brief report on gender identity and sexual orientation at a large, urban university. AB - OBJECTIVE: To examine reporting trends of students identifying as LGBTQIA+ following changes made to the ACHA-NCHA-II survey about gender identity and sexual orientation. METHODS: Data were analyzed from two sources for the purpose of triangulation: the ACHA-NCHA-II 2016 survey specific to our university and an electronic audience response survey. PARTICIPANTS: Primary analyses included first-year students from the ACHA-NCHA-II data (N = 158; spring 2016) and the audience response survey (N = 1,452; August 2016). RESULTS: Five percent of students did not identify as cis-gender and 21% did not identify as straight/heterosexual. The sexual orientation trend was confirmed by the audience response survey. CONCLUSIONS: The percentage of students identifying as LGBTQIA+ increased nationally between the ACHA-NCHA-II 2014 and 2016 survey samples, a trend which was confirmed using an independent audience response survey. This information has implications for university programming and inclusivity efforts nationwide. PMID- 29405857 TI - Peer, social media, and alcohol marketing influences on college student drinking. AB - OBJECTIVE: To investigate how alcohol marketing and peers may promote college students' alcohol use through social media. PARTICIPANTS: College students (N = 682) aged 18 to 22 years from a large Southern university completed paper surveys in April 2014. METHODS: Structural equation modeling was used to investigate relationships among variables as well as moderation by gender and race. RESULTS: Drinking behavior was directly related to perceived norms and attitudes toward alcohol that develop, in part, from direct and indirect interactions with their online and offline peers, as well as engagement with alcohol-related content on social media. Gender and ethnicity moderated some effects. CONCLUSIONS: College student drinking is influenced by friends' alcohol-related content posted on social networking sites and by greater engagement with traditional and online alcohol marketing. College campus alcohol misuse interventions should include components to counter peer influences and alcohol marketing on social media. PMID- 29405856 TI - A multivariate analysis of adverse childhood experiences and health behaviors and outcomes among college students. AB - OBJECTIVE: This study investigated associations between adverse childhood experiences (ACE) prior to age 18 years and multiple health behaviors (eg, cigarette and other substance use) and outcomes (eg, obesity, depression) for a large college sample. PARTICIPANTS: 2,969 college students from seven universities in the state of Georgia were included in the analysis. METHODS: Web based surveys were completed by students (45-60 minutes) during the spring semester, 2015. RESULTS: Findings indicate that more ACEs are associated with higher levels of depressive symptoms, ADHD symptoms, cigarette use, alcohol use, marijuana use, and BMI, in addition to lower levels of fruit and vegetable intake, and sleep. CONCLUSION: ACEs may carry forward in the lifespan to influence a range of unhealthy outcomes among college students. College intervention programs may benefit by recognizing the pervasiveness of ACEs and their associations with health behaviors and outcomes, and include interventions across more than one health behavior. PMID- 29405858 TI - Unmet demand for short-acting hormonal and long-acting reversible contraception among community college students in Texas. AB - OBJECTIVE: To identify preferences for and use of short-acting hormonal (e.g., oral contraceptives, injectable contraception) or long-acting reversible contraception (LARC) among community college students in Texas. PARTICIPANTS: Female community college students, ages 18 to 24, at risk of pregnancy, sampled in Fall 2014 or Spring 2015 (N = 966). METHODS: We assessed characteristics associated with preference for and use of short-acting hormonal or LARC methods (i.e., more-effective contraception). RESULTS: 47% preferred short-acting hormonal methods and 21% preferred LARC, compared to 21% and 9%, respectively, who used these methods. A total of 63% of condom and withdrawal users and 78% of nonusers preferred a more effective method. Many noted cost and insurance barriers as reasons for not using their preferred more-effective method. CONCLUSIONS: Many young women in this sample who relied on less-effective methods preferred to use more-effective contraception. Reducing barriers could lead to higher uptake in this population at high risk of unintended pregnancy. PMID- 29405859 TI - Harm reduction for cannabis: Factor analysis of a protective behavioral strategies survey. AB - OBJECTIVE: To examine the psychometric properties of a measure of cannabis specific Protective Behavioral Strategies (PBS), which assesses ways in which students may reduce cannabis-related risk. PARTICIPANTS: Respondents to the American College Health Association - National College Health Assessment II (N = 580) during Spring 2015. METHODS: Exploratory Factor Analysis (EFA) and Exploratory Structural Equation Modeling (ESEM) were used to identify and replicate the factor structure of the measure. RESULTS: Results support a four factor model (Respiratory Health, Frequency/Quantity, Socializing, and General Health) with close approximate fit (Chi2 (310) = 565.96, p < .001, RMSEA = .038 (.033, .043; 90% CI), CFI = .961, TLI = .929, SRMR = .033). Support for the convergent validity and construct validity of the measure was also found. CONCLUSIONS: This is the initial step in the development of a standard, psychometrically validated measure of cannabis PBS that has the potential to inform future research and interventions. PMID- 29405860 TI - Body dissatisfaction, neuroticism, and female sex as predictors of calorie tracking app use amongst college students. AB - OBJECTIVE: This study investigated body dissatisfaction, neuroticism, and sex as potential predictors of calorie-tracking app usage amongst undergraduate college students. PARTICIPANTS: College students (N = 491) were recruited from a large northeastern university in October 2015. METHODS: Participants completed an online survey asking about their sex, body dissatisfaction, neuroticism, and use of apps that track calories. RESULTS: Analyses revealed that female sex and body dissatisfaction-but not neuroticism-were direct predictors of calorie-tracking app usage. Analyses also provided support for a causal sequence wherein neuroticism and body dissatisfaction mediate, in serial, the relationship between female sex and calorie-tracking app usage. CONCLUSIONS: The results from this study suggest that female college students are more likely to use calorie tracking apps-a phenomenon which may be attributable to their higher levels of neuroticism and subsequent increased body dissatisfaction. PMID- 29405861 TI - Ractopamine hydrochloride induces behavioral alterations and oxidative status imbalance in zebrafish. AB - The occurrence of ractopamine (RAC) hydrochloride in water bodies is of significant concern due to its ecological impacts and toxicity to humans. RAC hydrochloride is a beta-adrenergic agonist drug used as a feed additive to (1) improve feed efficiency, (2) rate of weight gain, and (3) increase carcass leanness in animals raised for their meat. This drug is excreted by animals in urine and introduced into the environment affecting nontarget organisms including fish. In wastewater released from farms, RAC concentrations were detected from 0.124 ug/L to 30.1 ug/L, and in levels ranging from 1.3 * 10-5 to 5.4 * 10-4 MUg/L in watersheds. The aim of this study was to examine the effects of exposure to RAC at 0.1, 0.2, 0.85, 8.5, or 85 ug/L dissolved in water on behavior and oxidative status in adult zebrafish. At 0.85 ug/L, RAC treatment increased exploratory behavior of zebrafish; while at 8.5 ug/L, decreased locomotor and exploratory activities were noted. With respect to oxidative stress biomarkers, results showed that RAC at 0.2 ug/L induced lipid peroxidation and elevated total thiol content in zebrafish brain. All drug tested concentrations produced a fall in nonprotein thiol content. Finally, RAC at 0.85, 8.5, or 85 ug/L increased catalase enzyme activity. Our results demonstrated that the exposure to RAC induced behavioral alterations and oxidative stress in zebrafish. PMID- 29405862 TI - Mental health consequences of sexual assault among first-year college women. AB - OBJECTIVE: One in five college women experience unwanted sexual contact while in college, with first-year women being at the greatest risk. Given these data, we investigate how first-semester sexual assault impacts college women's mental health. PARTICIPANTS: 483 female first-year students enrolled in the study during the first month of college. METHODS: All participants completed a health questionnaire when they arrived on campus and again at the end of their first semester. RESULTS: Twelve percent of participants reported sexual assault during the first semester of college. After controlling for baseline mental health and precollege sexual assault history, sexual assault during the first semester predicted clinically significant levels of anxiety and depression at the end of that semester. CONCLUSIONS: The occurrence of sexual assault early in college has adverse mental health consequences. PMID- 29405863 TI - Effect of Seminar on Compassion on student self-compassion, mindfulness and well being: A randomized controlled trial. AB - OBJECTIVE: Mindfulness-based interventions have been shown to have psychological benefits in college students. We explored the effects of an academic Seminar on Compassion on student psychological health. PARTICIPANTS: Forty-one participants (14 male, 27 female, mean age 19.8 +/- 1.4 years) were assessed pre- and post- spring semesters 2013 and 2014. METHODS: Students were randomized to the Seminar on Compassion or a wait-list control group. Participants completed self-report measures on anxiety, depression, perceived stress, self-compassion, compassion and mindfulness. Salivary alpha-amylase was also assessed. RESULTS: At baseline, self-compassion and mindfulness were negatively correlated with depression, anxiety, and perceived stress. There were significant changes between the intervention and control group from Time 1 to Time 2 in mindfulness, self compassion, compassion, and salivary alpha-amylase; however, there were no significant changes in depression, anxiety, and perceived stress. CONCLUSIONS: The course was effective in increasing mindfulness, self-compassion and compassion, and decreasing a salivary marker of stress. PMID- 29405864 TI - What "likes" have got to do with it: Exposure to peers' alcohol-related posts and perceptions of injunctive drinking norms. AB - OBJECTIVE: Examine 1) whether observed social reinforcements (i.e., "likes") received by peers' alcohol-related social media posts are related to first-year college students' perceptions of peer approval for risky drinking behaviors; and 2) whether associations are moderated by students' alcohol use status. PARTICIPANTS: First-year university students (N = 296) completed an online survey in September, 2014. METHOD: Participants reported their own alcohol use, friends' alcohol use, perceptions of the typical student's approval for risky drinking, and ranked 10 types of social media posts in terms of the relative numbers of "likes" received when posted by peers. RESULTS: Observed social reinforcement (i.e., "likes") for peers' alcohol-related posts predicted perceptions of peer approval for risky drinking behaviors among non-drinking students, but not drinking students. CONCLUSIONS: For first-year college students who have not yet initiated drinking, observing peers' alcohol-related posts to receive abundant "likes" may increase perceptions of peer approval for risky drinking. PMID- 29405865 TI - Bystander programs addressing sexual violence on college campuses: A systematic review and meta-analysis of program outcomes and delivery methods. AB - OBJECTIVES: This systematic review and meta-analysis evaluates the effectiveness of bystander programs that address sexual violence on college campuses. Program effects on student attitudes/beliefs and bystander behavior were examined. Durability of program outcomes and the influence of program-delivery methods (e.g., facilitator-led programs vs. video, online or poster campaign programs) and program-parameters (e.g., program length) were also evaluated. METHODS: Twenty-four studies met criteria for inclusion in the meta-analysis, and 207 separate results from these studies were coded. RESULTS: Students who participated in a bystander program, compared to those who had not, had more pro social attitudes/beliefs about sexual violence and intervening to prevent it, and engaged in more bystander behavior. Program effects diminished over time, but meaningful changes persisted for at least three months following program delivery. Longer programs had greater effects than shorter programs on attitudes/beliefs. CONCLUSIONS: Bystander programs can be a valuable addition to colleges' violence prevention efforts. PMID- 29405866 TI - Sexual misconduct policies and administrator perceptions among 4-year colleges and universities in Georgia. AB - OBJECTIVES: Following changes in federal regulations, the current study was an examination of differences in institutional responses to sexual violence among Georgia colleges and universities during 2013 and 2014. PARTICIPANTS: A total of 24 four-year institutions located in the state of Georgia were included. METHOD: Data were collected from various sources in phases from March 2013 to December 2015 and included institutional characteristics from each college website, a content analysis of college annual security reports and sexual misconduct policies, and a college administrator online survey. RESULTS: Seventy percent of the institutions were deemed "Clery compliant" in 2013 but only 12%, in 2014. There was substantial variability in definitions used in sexual misconduct policies and with respect to the description of investigation and adjudication procedures. CONCLUSIONS: There is extensive variability in institutional responses to sexual violence across universities and colleges despite recent media attention and federal guidance. PMID- 29405867 TI - The escalation dating abuse workshop for college students: Results of an efficacy RCT. AB - OBJECTIVE: Assess the efficacy of a college dating abuse (DA) prevention workshop. PARTICIPANTS: 85 students from Greek organizations. METHODS: Two fraternities and two sororities were randomized to intervention or waitlist control. Participants completed a baseline and 3-month follow-up survey. Data were analyzed using MANOVA. RESULTS: As compared to those in the control group, students assigned to the DA workshop felt more prepared to act as bystanders at follow-up and were more convinced that DA was a problem on campus. Those who saw the workshop also recognized more opportunities when they could intervene as bystanders with friends and strangers at follow-up than did controls. CONCLUSIONS: The DA workshop appears to have influenced students in the desired way, although not substantially. It is likely that a longer follow-up period and larger sample would reveal more meaningful changes from pre- to post-test. PMID- 29405868 TI - Examination of the relationships between dietary restraint, alcohol, and adverse problems among women. AB - OBJECTIVE: Women who report greater chronic dieting consume more alcohol, drink more frequently, and experience greater problems than women who report less chronic dieting. Alcohol may also temporarily disrupt a woman's dietary rules, leading to increased caloric intake and subsequent restriction. This study examined whether alcohol use mediated the relationship between dietary restraint and alcohol problems in a woman's daily life. PARTICIPANTS: Women (N = 59) completed the study by the fall of 2013. METHODS: Participants completed up to six assessments for 10 days, including intended dietary restraint, alcohol use, and problems. RESULTS: Drinking quantity partially mediated the relationship between dietary restraint and alcohol problems. For each drink consumed, there was a 1.4 times greater likelihood of eating after drinking, which was associated with greater intention to subsequently restrict calories. CONCLUSIONS: The types of drinks consumed and reasons for restricting one's caloric intake may inform the relationship between these behaviors. PMID- 29405869 TI - US campus fraternities and sororities and the young adult injury burden. AB - OBJECTIVE: To investigate whether the presence of fraternities and sororities was associated with a higher local injury rate among undergraduate-age youth. METHODS: In 2016 we compared the rate of 2010-2013 youth (18-24 years) emergency department (ED) visits for injuries in Hospital Service Areas (HSA) with and without fraternities and sororities. ED visits were identified in the State Emergency Department Database (n=1,560 hospitals, 1,080 HSAs, 16 states). US Census Bureau and National Center for Education Statistics sources identified HSA population and campus (n=659) characteristics. A proprietary database identified campuses with fraternities and sororities (n=287). ED visits explicitly linked to fraternities and sororities in the National Electronic Injury Surveillance System All Injury Program were used to identify injury causes for sub-group analysis. RESULTS: HSAs serving campuses with fraternities and sororities had lower age 18 24 injury rates for all causes except firearm injuries (no difference). CONCLUSIONS: Fraternities and sororities were not associated with a higher injury rate at the population level among undergraduate-age youth. A major limitation is not being able to observe campus health services utilization. PMID- 29405870 TI - George Riddoch and Ludwig Guttmann: Wartime correspondence 1940-1947. AB - Recently discovered primary sources in the form of letters, memoranda and private communications between George Riddoch and Ludwig Guttmann provide much information on the setting up of spinal units in the United Kingdom during the Second World War. The two men developed a close relationship and in Guttmann, Riddoch found a man who had the knowledge, the ability and the energy to implement this shared vision. PMID- 29405871 TI - Exploring patterns of personal growth initiative and posttraumatic stress: A latent profile analysis. AB - OBJECTIVE: This study examined the inconsistent relationship found between personal growth initiative (PGI) and posttraumatic stress symptoms (PTSS) by exploring potential subgroups. In addition, after identifying the subgroups, potential predictors of these subgroups were examined. PARTICIPANTS: Participants were 534 undergraduate students who experienced a potentially traumatic event (PTE). Data collection occurred from March 2013 to December 2014. METHODS: Because this was a preliminary study, archival data was used. Participants consisted of students who experienced a PTE within the past three years. RESULTS: Latent profile analysis indicated a five-class model as the best-fitting model. Direct exposure and intentionality of the event were significant predictors of class membership; length of time since event and gender did not predict class membership. CONCLUSIONS: The current study provides a potential explanation of the inconsistent results between PGI and PTSS and also highlights the importance of acknowledging subgroups when utilizing PGI after a PTE. PMID- 29405872 TI - Short-term Effects of Kinesio Taping(r) on Electromyographic Characteristics of Paraspinal Muscles, Pain and Disability in Patients with Lumbar Disc Herniation. AB - CONTEXT: Kinesio taping(r) (KT) is a therapeutic modality frequently used in the clinical practice for the treatment of various musculoskeletal disorders. It is often applied in patients with chronic low back pain (CLBP) to decrease pain and improve functional capacity. However, it is not known, whether thoracolumbar fascia Kinesio Taping(r) (KT) technique can decrease back pain, restore normal activity of paraspinal muscles and improve functional capacity in patients with lumbar disc herniation (LDH). OBJECTIVE: To evaluate the impact of 7-day new KT stabilizing application on lumbar paraspinal muscles function, pain perception and disability in patients with LDH. DESIGN: A randomized controlled trial. SETTING: Human Performance Laboratory. Patients 38 patients with LDH were randomized into KT (n=19) and placebo taping (PT, n=19) groups. INTERVENTIONS: Both groups received the same "x" type application running over the back along fibres of superficial lamina of posterior layer of thoracolumbar fascia. MAIN OUTCOME MEASURES: The primary outcome measures were flexion-relaxation (FRR) and extension-relaxation (ERR) ratios calculated from electromyographic activity of lumbar multifidus and longissimus thoracic muscles. Pain intensity rating (Quadruple Visual Analogue Scale), pressure pain thresholds (PPTs) of lower back, Roland-Morris Disability Questionnaire score, back extension force and flexion ROM were among secondary outcomes. RESULTS: KT application did not affect the lumbar multifidus and longissimus thoracic muscles FRR and ERR, lower back PPTs, back flexion ROM and back extension force (no time * group interaction). KT and PT comparably decreased disability level (time effect, TE: F(1,36)=22.817, p=0.000; group*time interaction, GTI: F(1,36)=0.189, p=0.667), average pain (TE: F(1,36)=39.648, p=0.000; GTI: F(1,36)=2.553, p=0.119) and the worst pain (TE: F(1,36)=36.039, p=0.000; GTI: F(1,36)=0.003, p=0.956) intensity. CONCLUSION: Seven-day KT does not normalize lumbar paraspinal muscle function and is not superior to placebo in reducing disability and pain intensity in patients with LDH. PMID- 29405873 TI - Adolescent Effortful Control as Moderator of Father's Psychological Control in Externalizing Problems: A Longitudinal Study. AB - This longitudinal study investigates the moderating role of a temperamental trait, the effortful control, in the relation between father's psychological control and externalizing problems. In Wave 1, the participants included 507 adolescents attending the second classes of two public schools situated in two Italian cities; in Wave 2, 482 adolescents attending the fifth classes of high school participated again in the study. The results demonstrated a positive contribution of paternal achievement-oriented psychological control to externalizing problems and a moderator effect of effortful control in the relationship between the father's psychological control and externalizing problems. These findings extend current knowledge on the role of the father in the difficult task of balancing the promotion of individuality without falling into psychological control that can trigger externalizing problems among adolescents, especially when the temperament of the latter does not foresee the availability of self-regulating abilities that mediate disadvantageous reactivity. PMID- 29405874 TI - The state of sexual health services at U.S. Colleges and Universities. AB - OBJECTIVE: To describe the array of sexual health care services provided at US colleges and universities. PARTICIPANTS: During 2014-2015, 885 colleges were surveyed about their provision of sexual health services. METHODS: 55% of colleges responded. Data were weighted and stratified by minority-serving institutions (MSIs), 2-year and 4-year institutions. RESULTS: 70.6% of colleges reported having a health center (HC), of which 73.0% offered STI diagnosis/treatment (4 years vs. 2 years; 77.9% vs. 53.1%) and contraceptive services (70.1% vs. 46.4%), all p < .001. HCs less frequently offered LARC (19.7%), express STI testing (24.4%) and self-collection (31.4%). Condoms were available on 66.8% of campuses. HPV vaccination was available at more 4-year colleges (73.7% vs. 48.5%, p < .003) and non-MSIs (74.4% vs. 58.5, p = .019). Regarding MSM-targeted services, 54.6% offered pharyngeal and 51.8% rectal STI testing. CONCLUSIONS: 2-year colleges may require additional support with providing sexual health care. Improvements could entail increasing express testing, extra-genital STI testing, and LARC. PMID- 29405875 TI - Monitoring of airborne particulates near industrial silica sand mining and processing facilities. AB - To quantify risk of ambient exposure to airborne particulates around industrial silica sand operations, this study used EPA-certified federal reference method monitors to measure the levels of PM10 and PM2.5 particulate matter. The monitoring sites were chosen based upon EPA siting criteria, dichotomous samplers were calibrated before and after sampling, and pre- and post-weight filter weights were recorded. PM2.5 levels were significantly higher (paired t-tests) at both sites - averages of 7.70 +/- 6.15 and 22.7 +/- 31.714;ug/m3 - than concurrent background levels of 5.11 and 6.57ug/m3 respectively; and 98th percentile values were 24.9 and 111 ug/m3, respectively. Average PM10 levels were 24.2 and 49.0 ug/m3, and second-highest annual levels were 45.5 and 69.1 ug/m3 (two years) and 62.9 ug/m3 (2015) and 61.5 ug/m3 (2016), respectively for the two sites. Neither precipitation nor wind speed or direction appeared to affect PM2.5 or PM10 concentrations. PMID- 29405877 TI - Understanding contributing factors to verbal coercion while studying abroad. AB - OBJECTIVE: Verbal coercion (VC) is a common sexual assault (SA) tactic whereby men and women can be victims or perpetrators. College study abroad students report engagement in casual sex, alcohol consumption, and immersion in a sexualized environment (eg, an environment that supports or encourages sexual activity); factors highly associated with SA in general. The purpose of this study was to examine casual sex, alcohol use, and sexualized environments with VC victimization (VCV) and perpetration (VCP) while abroad. METHOD: Study abroad students (N = 130) completed questionnaires on alcohol use, casual sex, immersion in a sexualized environment, and VC experiences. RESULTS: Participants were more likely to report both VCV and VCP while abroad if they immersed themselves in a sexualized environment; identifying as male was associated with VCP. CONCLUSION: Results can inform intervention by providing directors with specific constructs to discuss in pre-departure meetings, such as the influence of the environment on VC. PMID- 29405878 TI - Associations between measures of health-related physical fitness and cardiometabolic risk factors in college students. PMID- 29405876 TI - Effects of social support on the association between precollege sexual assault and college-onset victimization. AB - OBJECTIVE: This study examined the moderating and mediating effects of perceived social support on the association between precollege sexual assault (SA) and college-onset SA. PARTICIPANTS: A representative sample of 6,132 undergraduates. METHODS: The PLUM procedure in SPSS was used to test the moderation model, with individual regressions conducted in a hierarchical fashion. A weighted least squared mean and variance adjusted (WLSMV) mediation model was used to examine the mediating effect of social support. RESULTS: Precollege SA significantly predicted college-onset SA. Social support significantly mediated the relation between precollege SA and college-onset SA. Social support was not a significant moderator of this relationship. CONCLUSIONS: Given the high prevalence of SA among college populations, as well as the high rates of SA revictimization, identification of factors that may be related to repeated SA (eg, low social support) within this population are essential and may inform intervention, policy, and university student services. PMID- 29405879 TI - Barriers to self-management behaviors in college students with food allergies. AB - OBJECTIVE: This study examined barriers to engagement in self-management behaviors among food-allergic college students (1) within the frameworks of the health belief model (HBM) and common sense self-regulation model (CS-SRM) and (2) in the context of overall risky behaviors. PARTICIPANTS: Undergraduate college students who reported having a physician-diagnosed food allergy (N = 141). Research was conducted from February 2015 through May 2016. METHODS: Participants were recruited from college campuses through email and social media. The frequency of adherence to self-management behaviors was measured along with HBM, CS-SRM, and risk-taking behaviors through a self-report survey. RESULTS: Among all participants, HBM and CS-SRM constructs and Tobacco Use explained 30.6% of the variance in adherence. CS-SRM constructs and Tobacco Use explained 44.8% of the variance for participants with self-injectable epinephrine (SIE). CONCLUSIONS: Food-allergic college students demonstrate inconsistent adherence, and interventions designed to improve adherence should take both SIE prescription status and contextual factors into consideration. PMID- 29405880 TI - A live vaccine to Staphylococcus aureus infection. PMID- 29405881 TI - A grounded theory of how social support influences physical activity in adolescent girls. AB - PURPOSE: Adolescent girls are not sufficiently active to achieve health benefits. Social support from friends and family has been positively associated with physical activity in adolescent girls; however it is unclear how social support influences physical activity behaviour. This study aimed to develop a grounded theory of how social support influences physical activity in adolescent girls. METHODS: A qualitative, constructivist grounded theory approach was adopted. Individual interviews explored adolescent girls' perspectives of how significant others' influenced their physical activity through providing social support, and through modelling physical activity. RESULTS: Participants perceived social support to influence physical activity behaviour through performance improvements, self-efficacy, enjoyment, motivation and by enabling physical activity. Improvements in performance and self-efficacy were also linked to motivation to be active. Girls perceived modelling to influence behaviour through providing opportunities for them to be physically active, and by inspiring them to be active. CONCLUSION: The grounded theory outlines adolescent girls' perceptions of how significant others influence their physical activity and provides a framework for future research examining the role of social support on physical activity. PMID- 29405882 TI - Factors associated with the use of social workers for assistance with lifetime and 12-month behavioral health disorders. AB - This study examined the use of social workers for assistance with a behavioral health disorder. Data were from the Collaborative Psychiatric Epidemiology Surveys. The analytic sample included respondents who reported using professional services for assistance with a behavioral health disorder during their lifetime (n = 5,585). Logistic regression was used to examine the use of a social worker during the respondent's lifetime or 12 months prior to the interview. Ten percent of respondents visited a social worker for help with a behavioral health disorder during their lifetime and 3% did so in the 12 months prior to the interview. Women were less likely than men to report using a social worker. Those who visited a social worker tended to also use other professionals for a behavioral health disorder although overall respondents reported visiting social workers less frequently for this reason than other types of professionals. PMID- 29405884 TI - Diet and nutritional considerations for an FtM transgender male: A case report. PMID- 29405883 TI - The importance of the clinical examination of the lower sacral segments: Four case reports. AB - CONTEXT: In our practice, in a spinal cord injury unit, clinical examinations include anal sensation and voluntary anal contraction, which are essential for neurological classification of spinal cord injury according to international standards (ISNCSCI), but we also always examine the integrity of the sacral segments, testing anal tone and anal and bulbocavernosus reflexes (S2-S4 segments) and the dartos reflex to evaluate the thoracolumbar sympathetic pathway. FINDINGS: In this paper, we describe four case reports of bladder dysfunction in which a clinical examination of the lower sacral segments was decisive to identify the neurological etiology. CONCLUSION/CLINICAL RELEVANCE: These cases, in patients with unexplained bladder dysfunction, highlight the importance of clinical testing the sacral segments, as part of the neurological examination, otherwise sacral lesions may remain undetected. PMID- 29405885 TI - Risk Factors for Intraoperative and Postoperative Cerebrospinal Fluid Leaks in Endoscopic Transsphenoidal Sellar Surgery. AB - Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques. PMID- 29405886 TI - The TEMPO Trial at 5 Years: Transoral Fundoplication (TIF 2.0) Is Safe, Durable, and Cost-effective. AB - BACKGROUND: Questions remain about the therapeutic durability of transoral incisionless fundoplication (TIF). In this study, clinical outcomes were evaluated at 5 years post-TIF 2.0. METHODS: A total of 63 chronic gastroesophageal reflux disease (GERD) sufferers with troublesome symptoms refractory to proton pump inhibitor (PPI) therapy, absent or <=2 cm hiatal hernia, and abnormal esophageal acid exposure were randomized to the TIF group or PPI group. Following the 6-month evaluation, all patients in the PPI group elected for crossover to TIF; therefore, all 63 patients underwent TIF 2.0 with EsophyX2 device. Primary outcome was elimination of daily troublesome regurgitation and atypical symptoms at the 5-year follow-up. Secondary outcomes were improvement in symptom scores, PPI use, reoperations, and patient health satisfaction. The cost-effectiveness of TIF 2.0 was also estimated. RESULTS: Of 63 patients, 60 were available at 1 year, 52 at 3 years, and 44 at 5 years for evaluation. Troublesome regurgitation was eliminated in 88% of patients at 1 year, 90% at 3 years, and 86% at 5 years. Resolution of troublesome atypical symptoms was achieved in 82% of patients at 1 year, 88% at 3 years, and 80% at 5 years. No serious adverse events occurred. There were 3 reoperations by the end of the 5-year follow-up. At the 5-year follow-up, 34% of patients were on daily PPI therapy as compared with 100% of patients at screening. The total GERD Health related quality-of-life score improved by decreasing from 22.2 to 6.8 at 5 years ( P < .001). CONCLUSION: In this patient population, the TIF 2.0 procedure provided safe and sustained long-term elimination of troublesome GERD symptoms. PMID- 29405887 TI - Arthroscopic Coracoclavicular Ligament Reconstruction Using a Synthetic Polycaprolactone-Based Polyurethane Urea Tendon Graft: A Report of 5 Cases. AB - BACKGROUND: Several techniques have been introduced to treat acromioclavicular (AC) separation using the semitendinosus tendon as a graft for coracoclavicular (CC) ligament reconstruction. However, the tendon may have been used previously or the patient may not want it harvested. Hence, synthetic tendon transfers have become increasingly popular. METHODS: Five patients with chronic AC separations were treated. A synthetic polyurethane urea tendon graft (Artelon Tissue Reinforcement [ATR]) was chosen for its ability to partially transform into connective tissue. The patient follow-up period lasted 45 to 60 months. RESULTS: The mean preoperative Constant Score increased from 64.8 to 100 postoperatively. The mean preoperative Simple Shoulder Test increased from 7.2 to 12 postoperatively. The mean postoperative increase of the CC distance was 1.5 mm. The mean expansion of the clavicular drill hole from the original was 2.1 mm. According to the postoperative magnetic resonance imaging, the grafts had healed well and the cross-sections of the grafts were up to 10.5 mm between the coracoid and the clavicle. DISCUSSION: The synthetic ATR tendon strip was a practical method for reconstructing a torn CC ligament complex. The ATR graft appears promising for future CC ligament reconstructions. PMID- 29405888 TI - Cardiovascular dynamics of Canadian Indigenous peoples. AB - Limited understanding of Indigenous adults' cardiovascular structure and function exists despite high rates of cardiovascular disease. This investigation characterised cardiovascular structure and function among young Indigenous adults and compared to age- and sex-matched European descendants. Echocardiographic assessments included apical two- and four-chamber images, parasternal short-axis images and Doppler. Analyses included cardiac volumes, dimensions, velocities and strains. Cardiovascular structure and function were similar between Indigenous (n=10, 25 +/- 3 years, 4 women) and European-descendant (n=10, 24 +/- 4 years, 4 women,) adults, though European descendants demonstrated greater systemic vascular resistance (18.19 +/- 3.94 mmHg?min-1?L-1 vs. 15.36 +/- 2.97 mmHg?min 1?L-1, p=0.03). Among Indigenous adults, women demonstrated greater arterial elastance (0.80 +/- 0.15 mmHg.mL-1.m-2 vs. 0.55 +/- 0.17 mmHg.mL-1.m-2, p=0.02) and possibly greater systemic vascular resistance (17.51 +/- 2.20 mmHg?min-1?L-1 vs. 13.93 +/- 2.61 mmHg?min-1?L-1, p=0.07). Indigenous men had greater cardiac size, dimensions and output, though body size differences accounted for cardiac size differences. Similar cardiac rotation and strains were observed across sexes. Arterial elastance and cardiac size were different between Indigenous men and women while cardiovascular structure and function may be similar between Indigenous and European descendants. PMID- 29405890 TI - College alcohol beliefs and drinking consequences: A multiple mediation analysis of norms, expectancies, and willingness to experience drinking consequences. AB - OBJECTIVE: We explored the potential mediating role of willingness to experience drinking consequences and other traditional alcohol outcome predictors (descriptive norms, injunctive norms, positive alcohol expectancies) in explaining the association between college alcohol beliefs 1 (CABs) and the actual experience of drinking consequences among college students. PARTICIPANTS: The sample consisted of 415 college students tested in October 2014. METHODS: Participants responded to an online survey. RESULTS: When compared to both types of norms and positive alcohol expectancies, CABs demonstrated the strongest associations to both willingness to experience drinking consequences and actual drinking consequences among college students. A multiple mediation analysis revealed that the impact of CABs on students' actual drinking consequences was mediated only through their willingness to experience drinking consequences. CONCLUSIONS: Students' college alcohol beliefs and their corresponding willingness to experience drinking consequences should be targeted in prevention and intervention programs designed to address the problem of college student drinking. PMID- 29405891 TI - Campus sexual assault climate surveys: A brief exploration of publicly available reports. AB - OBJECTIVE: Despite popularity of climate surveys as a tool produce accurate data on campus sexual assault, little is known about how campuses are administering these surveys, what they are assessing, and what they are finding. PARTICIPANTS: A sample of 105 campus climate survey reports was located with an internet search during the 2015-2016 academic year. METHODS: Review of climate survey reports assessed the methodology used, such as sampling method, use of incentives and sample size and response rate. Document review also assessed the topics included in the climate survey reports and key findings related to victimization, perpetration, and student knowledge of resources. RESULTS: Most campuses reported victimization rates, but few reported perpetration rates. Students generally express confidence in their knowledge of campus resources, but reporting of sexual violence was low. CONCLUSION: Climate surveys are inconsistent and do not always use scientifically sound measurement. Suggestions for improving climate surveys are discussed. PMID- 29405889 TI - Psychiatric service staff perceptions of implementing a shared decision-making tool: a process evaluation study. AB - PURPOSE: Shared decision making, SDM, in psychiatric services, supports users to experience a greater sense of involvement in treatment, self-efficacy, autonomy and reduced coercion. Decision tools adapted to the needs of users have the potential to support SDM and restructure how users and staff work together to arrive at shared decisions. The aim of this study was to describe and analyse the implementation process of an SDM intervention for users of psychiatric services in Sweden. METHOD: The implementation was studied through a process evaluation utilizing both quantitative and qualitative methods. In designing the process evaluation for the intervention, three evaluation components were emphasized: contextual factors, implementation issues and mechanisms of impact. RESULTS: The study addresses critical implementation issues related to decision-making authority, the perceived decision-making ability of users and the readiness of the service to increase influence and participation. It also emphasizes the importance of facilitation, as well as suggesting contextual adaptations that may be relevant for the local organizations. CONCLUSION: The results indicate that staff perceived the decision support tool as user-friendly and useful in supporting participation in decision-making, and suggest that such concrete supports to participation can be a factor in implementation if adequate attention is paid to organizational contexts and structures. PMID- 29405892 TI - Natural disaster preparedness in college students: Implications for institutions of higher learning. AB - OBJECTIVE: There is growing interest in the effectiveness of disaster preparedness at universities. Although several studies have examined student preparedness perceptions, a better understanding of factors that may influence actual preparedness is needed. PARTICIPANTS: Seven hundred sixty-five undergraduate and graduate students at a southeastern U.S. university completed an online survey in September 2013. METHODS: Participants were administered an online survey that included questions regarding disaster preparedness and their experiences with disasters. RESULTS: Students' disaster concern was more related to perceived preparedness over actual preparedness; disaster experience significantly predicted both actual and perceived preparedness. Perceived university preparedness was a significant predictor of disaster concern. CONCLUSION: The results suggest that perceived and actual preparedness are related but not entirely equivalent, which emphasizes the importance of differentiating the two constructs. Limitations of the current study and recommendations for future research are provided. PMID- 29405893 TI - What older adolescents expect from physical activity: Implicit cognitions regarding health and appearance outcomes. AB - OBJECTIVE: To explore older adolescents' reflective and impulsive thoughts about health- and social/appearance-related physical activity (PA) outcomes and investigate how those thoughts relate to their PA behavior. PARTICIPANTS: One hundred and forty-four undergraduate students (109 women; 35 men) aged 17-19 years (M = 18.11, SD = 0.65) participated in this study in October 2015. METHODS: Participants completed a Go/No-go Association Task that assessed automaticity of associations between PA words and either health outcomes or social/appearance outcomes. Questionnaires assessing PA behavior, attitudes, outcome expectations, and body image were also completed. RESULTS: Participants demonstrated a positive automatic association between PA and social/appearance outcomes, F(1, 136) = 4.403, p < .05, eta2 = .031, but they showed no difference in their associations between PA and desirable or undesirable health outcomes, F(1, 136) = 2.405, p = .123, eta2 = .017. CONCLUSIONS: Older adolescents implicitly attend to the social/appearance outcomes of PA more than potential health outcomes, indicating that social recognition and a desirable physique may be the key PA motivators for adolescents. PMID- 29405894 TI - Problematic alcohol use and sexting as risk factors for sexual assault among college women. AB - : Sexual assault is a major public health concern and college women are four times more likely to experience sexual assault than any other group. We investigated whether sexting is a mechanism by which alcohol use increases risk for college women to be targeted for sexual assault. We hypothesized that sexting would mediate the relationship between problem drinking and sexual assault, such that drinking (T1 = beginning fall semester) would contribute to increased sexting (T2 = end fall semester), and in turn increase the risk of being targeted for sexual assault (T3 = end spring semester). RESULTS: Among 332 undergraduate women (M(SD)age = 19.15(1.69), 76.9% Caucasian), sexting (T2) predicted sexual assault (T3; b = 3.98, p = .05), controlling for baseline sexual assault (b = 0.82, p < .01). Further, sexting (T2) mediated the relationship between problem drinking (T1) and sexual assault (T3) (b = 0.04, CI[.004,.12]). CONCLUSION: Findings suggest that sexting is one mechanism through which drinking increases the risk of college women being targeted for sexual assault. PMID- 29405895 TI - Problem drinking among at-risk college students: The examination of Greek involvement, freshman status, and history of mental health problems. AB - OBJECTIVE: Scarce research has examined the combined effect of mental health difficulties and demographic risk factors such as freshman status and Greek affiliation in understanding college problem drinking. The current study is interested in looking at the interaction among freshman status, Greek affiliation, and mental health difficulties. PARTICIPANTS AND METHODS: Undergraduate students (N = 413) from a private and public Midwestern university completed a large online survey battery between January 2009 and April 2013. Data from both schools were aggregated for the analyses. RESULTS: After accounting for gender, age, and school type, the three-way interaction indicated that the highest drinking levels were reported in freshman students who reported a history of mental health problems although were not involved in Greek life. CONCLUSIONS: Findings are discussed in the context of perceived social norms, as well as alcohol-related screenings and intervention opportunities on college campuses. PMID- 29405896 TI - HIV knowledge mediates the relationship between HIV testing history and stigma in college students. AB - OBJECTIVE: HIV-related stigma is one of the strongest barriers to prevention and treatment. HIV prevalence in U.S. college students is estimated around 0.02%, but is thought to be drastically underreported. We examined the influence of HIV knowledge on the relationship between HIV testing history and stigma in college students. PARTICIPANTS: A random sample of 2343 students, over the age of 18, attending a large university in the southeastern United States completed the survey in January 2016. METHODS: A mediation model was constructed in regression framework to explore the relationship between HIV testing history, knowledge, and stigma. RESULTS: HIV testing history was associated with higher knowledge scores (a path: B = 4.08, p < .001) and higher knowledge scores were associated with lower stigma (b path: B = .01, p < .001). These results suggest that HIV knowledge partially mediates the relation between HIV testing history and stigma in college students. CONCLUSIONS: HIV testing history may decrease stigma by increasing knowledge. Results can be used to inform college health promotion practice on developing programs and services. PMID- 29405897 TI - The moderating effect of alcohol use on protective and risky sex behaviors among college students in the Southeast United States. AB - OBJECTIVE: College students are a high-risk population for new human immunodeficiency viruses (HIV) diagnoses. Although condom use self-efficacy and HIV knowledge can protect against risky sexual behavior (RSB), these same protective factors have been shown to exacerbate RSB. The influence of alcohol use can further complicate these protective factors to influence RSB. PARTICIPANTS: 689 African American/Black and non-Hispanic White college students attending a public university in the Southeast United States. METHOD: This study sought to examine the relations between condom use self-efficacy and HIV knowledge with RSB and the moderating effect of alcohol use. RESULTS: Findings showed positive associations between RSB and HIV knowledge and alcohol use. Unexpectedly, low frequency drinkers with high condom use self-efficacy were at increased risk for RSB compared to high frequency drinking counterparts. CONCLUSIONS: Findings point to the need to target prevention services for low risk drinkers in college settings. PMID- 29405898 TI - Efficacy and safety of tigecycline monotherapy versus combination therapy for the treatment of hospital-acquired pneumonia (HAP): a meta-analysis of cohort studies. AB - The broad spectrum antibiotic tigecycline shows promising efficacy against many multiple drug resistant (MDR) pathogens. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is unclear. Several studies have reported on the treatment failures of tigecycline monotherapy, suggesting that it may not be sufficient to control severe infections. Combination therapy has become an option to treat MDR bacterial infections. We conducted a literature search using PubMed, Cochrane Library, Embase, Elsevier and the Web of Knowledge databases up to 29 February 2017 to identify relevant published studies. Studies were considered eligible if they were a cohort study that assessed mortality and the safety of tigecycline monotherapy versus combination therapy with other antimicrobial agents for HAP. The primary outcome was treatment mortality rate, while the secondary outcomes were adverse events. Meta-analysis was done using fixed-effects models. Five trials were included. The monotherapy tigecycline had a higher mortality compared to the combination therapy group. There was a significant difference for the treatment of HAP. However, two prospective cohort studies showed that there was no significant difference in mortality rate between the tigecycline monotherapy and the tigecycline combination therapy. Three retrospective cohort studies showed that tigecycline monotherapy had a high mortality rate. Tigecycline combination therapy efficiently treats HAP. There is a great need for well-designed studies to evaluate the effectiveness and safety of combination therapies as they compare to tigecycline monotherapy. PMID- 29405899 TI - Frequency, serotype distribution, and antimicrobial susceptibility patterns of Salmonella in small poultry flocks in California. AB - Backyard poultry operations are increasingly popular and commonplace in both rural and suburban locations. Although Salmonella surveillance programs are well established for large commercial poultry systems, information on smaller operations is lacking. We identified the occurrence and serotype distribution of Salmonella spp. recovered from backyard flock cases submitted to the California Animal Health and Food Safety Laboratory System (Davis, CA) in 2012-2015, and evaluated minimum inhibitory concentration for 12 antimicrobials as well as the lesions associated with Salmonella spp. in these cases. From records of 2,347 backyard flock cases with 2,627 samples, 44 samples (1.7%) were positive for Salmonella spp. DNA by PCR, and 41 (1.6%) of these samples yielded a Salmonella isolate by culture for further characterization. Seventeen different serotypes, including 3 isolates identified to the serogroup level, were identified from these isolates. Antimicrobial resistance was infrequent; however, 2 multidrug resistant isolates were identified. Enteric or systemic lesions associated with Salmonella recovery were uncommon, with 77.3% of cases having no disease attributable to Salmonella. Recovered serotypes overlap with those seen in commercial poultry as well as in foodborne outbreaks reported by the Centers for Disease Control and Prevention in humans. Zoonotic risks via contact and food product contamination make monitoring of backyard flocks for Salmonella a critical part of flock surveillance programs, and we propose a potential sampling scheme. PMID- 29405900 TI - Development and validation of a probe hybridization reverse-transcription quantitative PCR for detection of mamastrovirus 2 in domestic cats. AB - Astroviruses are viral pathogens that have been associated with enteric and neurologic disease in a variety of species. The domestic cat is a prominent host, with reports of astroviral infection being both highly prevalent and widely distributed in the feline population. Despite the potential for inducing significant disease, especially within shelter environments, there is currently only one reliable method of detection: standard reverse-transcription PCR using pan-astrovirus degenerate primers (consensus RT-PCR) with product sequencing. Unfortunately, this process is relatively slow and costly. Quantitative real-time PCR (qPCR) represents an efficient, economical alternative, with the added benefit of viral load quantification. We developed a RT-qPCR assay using probe hybridization technique to detect conserved regions of mamastrovirus 2 extracted from fecal samples of domestic cats. Known positive and negative samples were tested, and results were compared with gold standard consensus RT-PCR and sequencing. A standard curve was employed to determine limits of detection. In order to assess analytic specificity, we tested several additional samples that had been collected from non-felid species and were known to contain non-target astroviruses. Discrepant results between consensus RT-PCR and RT-qPCR testing were further analyzed with a validation RT-PCR assay, using mamastrovirus 2 specific primers. Our probe hybridization RT-qPCR assay is reliable and effective for the detection of mamastrovirus 2. This assay will allow rapid, affordable detection and facilitate further research on astroviral infection within domestic cats. PMID- 29405902 TI - The prevalence of constant supportive observations in high, medium and low secure services. AB - : Aims and method We explored the prevalence and use of constant supportive observations (CSO) in high, medium and low secure in-patient services in a single National Health Service (NHS) mental health trust. From clinical records, we extracted data on the length of time of CSO, the reason for the initiation of CSO and associated adverse incidents for all individuals who were placed on CSO between July 2013 and June 2014. RESULTS: A small number of individuals accounted for a disproportionately large proportion of CSO hours in each setting. Adverse incident rates were higher on CSO than when not on CSO. There was considerable variation between different settings in terms of CSO use and the reasons for commencing CSO. Clinical implications The study describes the prevalence and nature of CSO in secure forensic mental health services and the associated organisational costs. The marked variation in CSO use between settings suggests that mental health services continue to face challenges in balancing risk management with minimising restrictive interventions. Declaration of interest A.B. and J.L.I. are both directly employed by the NHS trust in which the study was conducted. PMID- 29405901 TI - Poisoning by Brunfelsia uniflora in sheep and donkeys. AB - Farmers in the State of Piaui in northeastern Brazil reported nervous signs in ruminants and donkeys after ingestion of Brunfelsia uniflora at the start of the rainy season when the plant is flowering. Leaves of the plant, collected at the start or at the end of the rainy season, were administered in single doses of 5 20 g/kg body weight to 8 sheep and 3 donkeys. Two sheep and 1 donkey that ingested 10 g/kg of the plant in November at the start of the rainy season, when the plant was flowering, developed severe convulsions and diarrhea. One sheep was euthanized and autopsied, and no significant lesions were found. The other sheep and the donkey recovered. Four sheep and one donkey that ingested 10 or 20 g/kg of leaves collected in April, at the end of the rainy season, did not show clinical signs. One donkey that ingested 5 g/kg of leaves collected in November developed diarrhea and recovered. These results demonstrate the toxicity of B. uniflora for livestock and suggest that the plant is toxic at these doses only during the start of the rainy season. PMID- 29405903 TI - Prostate cancer patients' experience and preferences for acquiring information early in their care. AB - INTRODUCTION: Prostate cancer patients' information needs are well-described, but little is known about their preferred sources and media for obtaining information. We sought to determine prostate cancer patients' experiences and preferences for acquiring information after diagnosis, a time of high information need. METHODS: Population surveys were conducted in four Canadian provinces in 2014-2015. Each provincial cancer registry surveyed a random sample of prostate cancer patients diagnosed in late 2012. RESULTS: A total of 1366 patients responded across provinces. Respondents most frequently tried to obtain information from their urologist; 86% found that easy and 9% found it difficult. Seventy-nine percent of respondents who saw only a urologist felt well-informed compared to 86% of those who saw both a urologist and a radiation oncologist. Eighty-five percent of respondents wanted printed information; 68% wanted it electronically. Respondents' most frequent barriers to obtaining information from physicians were: not actually having enough time (31%), worrying about having enough time (23%), and worrying about asking too many questions (18%). Their most frequent barriers related to internet/printed information, respectively, were uncertainty about quality (63%/49%) and unclear if personally applicable (56%/49%). Recommended facilitators were having a navigator (85%), providing printed information (85%), and someone to answer questions: in person (90%), by phone (66%), or via email (58%). CONCLUSIONS: Prostate cancer patients want urologists to provide them with information and are more likely to report being informed if they see both a urologist and a radiation oncologist. Optimal information provision requires that it be provided both on the internet and in print. PMID- 29405904 TI - Case - Bladder paraganglioma in a pediatric patient. PMID- 29405905 TI - Case - Laparoscopic transperitoneal partial nephrectomy of T3a renal cell carcinoma within a horseshoe kidney. PMID- 29405906 TI - Case - Temporary chemical castration in the management of recurrent priapism. PMID- 29405908 TI - Spotlight - Management of pyelovesical bypass device stones. PMID- 29405907 TI - Replacing surveillance cystoscopy with urinary biomarkers in followup of patients with non-muscle-invasive bladder cancer: Patients' and urologic oncologists' perspectives. AB - INTRODUCTION: Urinary biomarkers are being developed to detect bladder cancer recurrence/progression in patients with non-muscle-invasive bladder cancer (NMIBC). We conducted a questionnaire-based study to determine what diagnostic accuracy and cost would such test(s) need for both patients and urologic oncologists to comfortably forgo surveillance cystoscopy in favour of these tests. METHODS: Surveys were administered to NMIBC patients at followup cystoscopy visit and to physician members of the Society of Urologic Oncology. Participants were questioned about acceptable false-negative (FN) rates and costs for such alternatives, in addition to demographics that could influence chosen error rates and costs. RESULTS: A total of 137 patient and 51 urologic oncologist responses were obtained. Seventy-seven percent of patients were not comfortable with urinary biomarker(s) alternatives to repeat cystoscopy, with a further 14% willing to accept such alternatives only if the FN rate were 0.5% or lower. Seventy-five percent of urologic oncologists were comfortable with an alternative urinary biomarker test(s), with 37% and 33% willing to accept FN rates of 5% and 1%, respectively. Forty-seven percent of patients were not willing to pay out-of pocket for such tests, while 61% of urologic oncologists felt that a price range of $100-500 would be reasonable. CONCLUSIONS: This is the first survey evaluating patient and urologic oncologist perspectives on acceptable error rates and costs for urinary biomarker alternatives to surveillance cystoscopy for patients with NMIBC. Despite potential responder bias, this study suggests that urinary biomarker(s) will require sensitivity equivalent to that of cystoscopy in order to completely replace it in surveillance of patients with NMIBC. PMID- 29405909 TI - Developing improved tissue-engineered buccal mucosa grafts for urethral reconstruction. AB - INTRODUCTION: We aimed to compare alternative synthetic scaffolds suitable for future implantation and to examine the use of an inhibitor of lysyl oxidase (beta amino-propionitrile [beta-APN]) to reduce contraction in these implants. METHODS: Three synthetic scaffolds were compared to natural dermis as substrates for the production of tissue-engineered skin. For natural dermis, Euroskin was used to provide a cell-free cadaveric dermis. Synthetic scaffolds consisted of microfibrous poly-L-lactic acid (PLA), nanofibrous poly(3-hydroxybutyrate-co-3 hydroxyvalerate) (PHBV), and a micro-/nanofibrous trilayer of PLA-PHBV-PLA. The latter were all electrospun and then all four scaffolds (three synthetic, one natural) were placed in six well plates. A culture well was formed on the scaffold using a 1 cm diameter stainless steel ring and 1.5*105 oral fibroblasts were seeded one side; after two days of culture, the ring was placed on the other side of the scaffolds and 3*105 oral keratinocytes were seeded on to the scaffolds and cultured with keratinocytes uppermost. After a further two days of culture, scaffolds were cut to 1 cm2 and raised to an air-liquid interface on stainless steel grids; some were treated with 200 MUg/mL beta-APN throughout the culture period (28 days). Contraction in vitro was assessed by serial digital photography of cell-seeded scaffolds and cell-free scaffolds three times a week for 28 days. All cell-seeded scaffolds were assessed for cell metabolic activity, mechanical properties, histology, and morphology by scanning electron microscopy (SEM). RESULTS: The mean fibre diameters and pore sizes of PLA and PHBV scaffolds were 2.4+/-0.77, 0.85+/-0.21 MUm (p<0.001), and 10.8+/-2.3, 4.3+/-1.1 MUm (p<0.001), respectively. Oral fibroblasts and keratinocytes were tightly adhered and grew well on both surfaces of trilayer. The ultimate tensile strength (UTS) and Young's modulus (YM) of PLA samples were significantly lower than Euroskin (p<0.001 and p<0.05, respectively); only the UTS of the trilayer samples was slightly significantly lower (p<0.05). Metabolic activity was significantly increased for cells on all scaffolds, without significant differences between them from Day 0 to Day 28. There were no adverse effects of beta-APN on cell viability. With respect to contraction, cells on trilayer and PHBV monolayers did not undergo any significant contraction; however, cells on PLA monolayer and Euroskin contracted 25.3% and 56.4%, respectively, over 28 days. The addition of 200 MUg/ml beta-APN significantly reduced contraction of Euroskin compared with the control (p<0.01); however, beta-APN did not affect PLA contraction during this culture period (p>0.05). CONCLUSIONS: This study shows that a trilayer micro nano-3D porous synthetic scaffold is suitable for oral keratinocyte and fibroblast growth with good cell viability and minimal contraction. This material also has good mechanical properties and histological analyses showed its ability to mimic normal human oral mucosal morphology. Furthermore, synthetic trilayer scaffolds have advantages over biological scaffolds - there is no risk of disease transmission or immunological rejection and they appear resistant to contraction. We suggest they present a good alternative to allodermis for future use in urethral reconstruction. PMID- 29405910 TI - Case - Uretero-internal iliac artery fistula presenting with multiple negative angiographic studies. PMID- 29405911 TI - Evaluating the role for renal biopsy in T1 and T2 renal masses: A single-centre study. AB - INTRODUCTION: Once used primarily in the identification of renal metastasis and lymphomas, various urological bodies are now adopting an expanded role for the renal biopsy. We sought to evaluate the role of the renal biopsy in a Canadian context, focusing on associated adverse events, radiographic burden, and diagnostic accuracy. METHODS: This retrospective review incorporated all patients undergoing ultrasound (US)/computed tomography (CT)-guided biopsies for T1 and T2 renal masses. There were no age or lesion size limitations. The primary outcome of interest was the correlation between initial biopsy and final surgical pathology. A binomial logistic regression analysis was conducted to determine any confounding factors. Secondary outcomes included the accuracy of tumour cell typing, grading, the safety profile, and radiographic burden associated with these patients. RESULTS: A total of 148 patients satisfied inclusion criteria for this study. Mean age and lesions size at detection were 60.9 years (+/-12.4) and 3.6 cm (+/-2.0), respectively. Most renal masses were identified with US (52.7%) or CT (44.6%). Three patients (2.0%) experienced adverse events of note. Eighty six patients (58.1%) proceeded to radical/partial nephrectomy. Our biopsies held a diagnostic accuracy of 90.7% (sensitivity 96.2%, specificity 87.5%, positive predictive value 98.7%, negative predictive value 70.0%, kappa 0.752, p<0.0005). Binomial logistic regression revealed that age, lesion size, number of radiographic tests, time to biopsy, and modality of biopsy (US/CT) had no influence on the diagnostic accuracy of biopsies. CONCLUSIONS: Renal biopsies are safe, feasible, and diagnostic. Their role should be expanded in the routine evaluation of T1 and T2 renal masses. PMID- 29405912 TI - Case - Foamy, high-grade prostatic intraepithelial neoplasia: A false positive for prostate cancer on multiparametric magnetic resonance imaging? PMID- 29405913 TI - Routine histopathological examination of the foreskin after circumcision for clinically suspected lichen sclerosus in children: Is it a waste of resources? AB - INTRODUCTION: Circumcision is one of the most widely performed procedures in the world. One of the indications for circumcision is lichen sclerosis (LS). The natural history of LS in children is not as well-documented as in adult patients. Surgeons use the appearance of the foreskin or meatus to predict the diagnosis of LS. Indeed, if the diagnosis of LS is made in childhood, does it change management in the long-term? Pathological analysis of the excised foreskin is routinely done if there is suspicion of LS. Our aim is to assess the concordance between the clinical and pathological diagnosis of suspected LS and to assess the need for sending the foreskin for pathological examination. METHODS: We conducted a retrospective chart review of 64 of 420 boys who underwent circumcision in a tertiary children's hospital from June 2005 to June 2014, and who had their foreskin sent for pathology due to the clinical suspicion of LS. Demographics, presenting symptoms, presumed clinical diagnosis, pathological findings, and followup data were collected and analyzed. RESULTS: Over the review period, 64 patients underwent circumcision for presumed LS. The mean age of the children was 9.7 years (range 3-16.5). All the children who had circumcision for presumed LS diagnosis were symptomatic. LS was confirmed in 47 of 64 foreskins (73.5%). Balanitis xerotica obliterans (BXO) was clinically suspected in 40 (85%) of the 47 patients. The mean followup was 10 months (range 1-15), with seven recurrences (15%) during that period. The recurrences required revision surgery in two patients and five were managed with steroids only. CONCLUSIONS: In our series, the clinical diagnosis correlated with the pathological diagnosis in most cases. A clinical suspicion of LS without routine foreskin pathological assessment will reduces the overall cost to the healthcare system. Appropriate counselling of the patient/parents and their primary caregiver is imperative, as recurrence is common. PMID- 29405915 TI - Presidential Address: Are the Obsessive-Compulsive Related Disorders Related to Obsessive-Compulsive Disorder? A Critical Look at DSM-5's New Category. AB - The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) includes a new class of obsessive-compulsive and related disorders (OCRDs) that includes obsessive-compulsive disorder (OCD) and a handful of other putatively related conditions. Although this new category promises to raise awareness of underrecognized and understudied problems, the empirical validity and practical utility of this new DSM category is questionable. This article critically examines the arguments underlying the new OCRD class, illuminates a number of problems with this class, and then discusses implications for clinicians and researchers. PMID- 29405914 TI - Wilms Tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair. AB - Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b+cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b+sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b+and entpd5+ cells constitute separate, tightly-associated subpopulations. Surprisingly, wt1b expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments. PMID- 29405916 TI - Do Self-Incentives and Self-Rewards Change Behavior? A Systematic Review and Meta Analysis. AB - Encouraging people to self-incentivize (i.e., to reward themselves in the future if they are successful in changing their behavior) or self-reward (i.e., prompt people to reward themselves once they have successfully changed their behavior) are techniques that are frequently embedded within complex behavior change interventions. However, it is not clear whether self-incentives or self-rewards per se are effective at bringing about behavior change. Nine databases were searched alongside manual searching of systematic reviews and online research registers. One thousand four hundred papers were retrieved, spanning a range of behaviors, though the majority of included papers were in the domain of "health psychology". Ten studies matched the inclusion criteria for self-incentive but no studies were retrieved for self-reward. The present systematic review and meta analysis is therefore the first to evaluate the unique effect of self-incentives on behavior change. Effect sizes were retrieved from 7 of the 10 studies. Analysis of the 7 studies produced a very small pooled effect size for self incentives (k = 7, N = 1,161), which was statistically significant, d+ = 0.17, CI [0.06, 0.29]. The weak effect size and dearth of studies raises the question of why self-incentivizing is such a widely employed component of behavior change interventions. The present research opens up a new field of inquiry to establish: (a) whether or not self-incentivizing and self-rewarding are effective behavior change techniques, (b) whether self-incentives and self-rewards need to be deployed alongside other behavior change techniques, and, (c) when and for whom self-incentives and self-rewards could support effective behavior change. PMID- 29405917 TI - Can a Mediator Moderate? Considering the Role of Time and Change in the Mediator Moderator Distinction. AB - The concepts of mediation and moderation are important for specifying ways in which psychological treatments work and for whom they are most beneficial. Historically, the terms were confused and used interchangeably, so a rich body of scholarly literature makes clear their distinction. Researchers are also becoming increasingly aware that mediation and moderation can be integrated and that such integration can advance theory development and testing. One question that has not received sufficient attention is whether a mediator can simultaneously moderate. We tackle this question in this paper, and in doing so we expand on the MacArthur conceptualizations of mediation and moderation. The result is a presentation of a meta-theoretical model that illustrates how a construct that is initially a mediator can, not simultaneously but over time, evolve into a construct that moderates. When this occurs, a construct that changed for the better as a result of an intervention can later promote more positive change during a later intervention. Various implications of this novel paradigm for future research are discussed, including the importance of this model in the emerging context of managed health care. PMID- 29405918 TI - Economic Impact of Third-Wave Cognitive Behavioral Therapies: A Systematic Review and Quality Assessment of Economic Evaluations in Randomized Controlled Trials. AB - The term third-wave cognitive behavioral therapy (CBT) encompasses new forms of CBT that both extend and innovate within CBT. Most third-wave therapies have been subject to randomized controlled trials (RCTs) focused on clinical effectiveness; however, the number and quality of economic evaluations in these RCTs has been unknown and may be few. Evidence about efficiency of these therapies may help support decisions on efficient allocation of resources in health policies. The main aim of this study was to systematically review the economic impact of third wave therapies in the treatment of patients with physical or mental conditions. We conducted a systematic literature search in PubMed, PsycINFO, EMBASE, and CINALH to identify economic evaluations of third-wave therapies. Quality and Risk of Bias (RoB) assessment of economic evaluations was also made using the Drummond 35-item checklist and the Cochrane Collaboration's tool for assessing risk of bias, respectively. Eleven RCTs were included in this systematic review. Mindfulness-Based Cognitive Therapy (MBCT), Mindfulness-Based Stress Reduction (MBSR), Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), and extended Behaviour Activation (eBA) showed acceptable cost effectiveness and cost-utility ratios. No study employed a time horizon of more than 3 years. Quality and RoB assessments highlight some limitations that temper the findings. There is some evidence that MBCT, MBSR, ACT, DBT, and eBA are efficient from a societal or a third-party payer perspective. No economic analysis was found for many third-wave therapies. Therefore, more economic evaluations with high methodological quality are needed. PMID- 29405919 TI - Prospective Associations Between Sleep Disturbance and Repetitive Negative Thinking: The Mediating Roles of Focusing and Shifting Attentional Control. AB - Although considerable evidence has linked sleep disturbance to symptoms of psychopathology, including repetitive negative thinking, few studies have examined how sleep disturbance may predict repetitive negative thinking over time. Further, no study to date has examined specific mechanisms that may account for this relationship. The present study sought to address these gaps in the literature by testing focusing and shifting attentional control as two potential mediators of the relationship between sleep disturbance and repetitive negative thinking over a 6-month period. A final sample of 445 unselected community participants completed measures of sleep disturbance and repetitive negative thinking at Time 1, measures of focusing and shifting attentional control 3 months later, and measures of repetitive negative thinking again 6 months later. Results revealed that focusing, but not shifting, attentional control mediated the relationship between sleep disturbance and repetitive negative thinking, specifically, worry, rumination, and obsessions. These findings provide preliminary evidence for focusing attentional control as a candidate mechanism that may explain the causal role of sleep disturbance in the development of repetitive negative thinking observed in various disorders. PMID- 29405920 TI - Comparing Children's Memories for Negative Versus Positive Events in the Context of Posttraumatic Stress Symptoms. AB - How well children remember negative events is not fully understood. Previous research has failed to simultaneously test memory and perceptions of memory for both negative and positive events. Children (n = 38, 7-17 years) recruited from a hospital following accidental injury were tested for their memory of an injury producing accident (negative event) and a positive event (unexpectedly receiving a $50 gift voucher). Objective accuracy of memory, memory quality characteristics (e.g., how coherently the event was recalled), children's judgments of their memory (meta-cognitive), and posttraumatic stress (PTS) symptoms were assessed 2 months post-injury. Children's memories for their experiences were verified using witness/parent reports. Memory quality characteristics of children's free recollection were coded with a previously used standardized system. Overall, children showed high levels of accuracy for both events, with little degradation over time. High PTS children showed little evidence of deficits in coherence or organization in their narratives relative to low PTS children. Although in some instances high PTS children judged their memory quality to be poor compared to low PTS children, this depended on how this was assessed (e.g., self-report questionnaire vs. coded narratives). In terms of limitations, it is unclear whether the findings will generalize for memories of repeated events. Witness verification of the accident details itself could be prone to error. In conclusion, the findings are broadly supportive of the proposal made by theorists who argue that trauma memories are recalled no less accurately than other distinctive memories. The role of meta-cognitive elements of children's memory and reporting in PTS is less clear. PMID- 29405922 TI - PTSD Symptom Severity and Emotion Regulation Strategy Use During Trauma Cue Exposure Among Patients With Substance Use Disorders: Associations With Negative Affect, Craving, and Cortisol Reactivity. AB - The co-occurrence of posttraumatic stress disorder (PTSD) pathology with a substance use disorder (SUD) is associated with emotion regulation deficits. However, studies in this area generally rely on trait-based emotion regulation measures, and there is limited information on the relation of PTSD pathology to the use of specific emotion regulation strategies in response to trauma-related distress among SUD patients or the consequences of these strategies for trauma cue reactivity. This study examined the relation of PTSD symptom severity to the use of specific emotion regulation strategies during trauma cue exposure among trauma-exposed SUD patients, as well as the indirect relations of PTSD symptom severity to changes in negative affect, cravings, and cortisol levels pre- to posttrauma cue exposure through different emotion regulation strategies. Participants were 133 trauma-exposed SUD patients. Participants listened to a personalized trauma script and reported on emotion regulation strategies used during the script. Data on negative affect, cravings, and cortisol were collected pre- and postscript. PTSD symptom severity related positively to the use of more adaptive (e.g., distraction) and maladaptive (e.g., suppression) regulation strategies. Moreover, evidence for the indirect effects of PTSD symptom severity on negative affect and cortisol reactivity through both adaptive and maladaptive emotion regulation strategies was found. Implications of findings are discussed. PMID- 29405921 TI - Benchmarking Treatment Response in Tourette's Disorder: A Psychometric Evaluation and Signal Detection Analysis of the Parent Tic Questionnaire. AB - This study assessed the psychometric properties of a parent-reported tic severity measure, the Parent Tic Questionnaire (PTQ), and used the scale to establish guidelines for delineating clinically significant tic treatment response. Participants were 126 children ages 9 to 17 who participated in a randomized controlled trial of Comprehensive Behavioral Intervention for Tics (CBIT). Tic severity was assessed using the Yale Global Tic Severity Scale (YGTSS), Hopkins Motor/Vocal Tic Scale (HMVTS) and PTQ; positive treatment response was defined by a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impressions - Improvement (CGI-I) scale. Cronbach's alpha and intraclass correlations (ICC) assessed internal consistency and test-retest reliability, with correlations evaluating validity. Receiver- and Quality-Receiver Operating Characteristic analyses assessed the efficiency of percent and raw-reduction cutoffs associated with positive treatment response. The PTQ demonstrated good internal consistency (alpha = 0.80 to 0.86), excellent test-retest reliability (ICC = .84 to .89), good convergent validity with the YGTSS and HM/VTS, and good discriminant validity from hyperactive, obsessive-compulsive, and externalizing (i.e., aggression and rule-breaking) symptoms. A 55% reduction and 10-point decrease in PTQ Total score were optimal for defining positive treatment response. Findings help standardize tic assessment and provide clinicians with greater clarity in determining clinically meaningful tic symptom change during treatment. PMID- 29405924 TI - Multi-Informant Assessments of Adolescent Social Anxiety: Adding Clarity by Leveraging Reports from Unfamiliar Peer Confederates. AB - Adolescent social anxiety (SA) assessments often include adolescent and parent reports, and low reporting correspondence results in uncertainties in clinical decision-making. Adolescents display SA within non-home contexts such as peer interactions. Yet, current methods for collecting peer reports raise confidentiality concerns, though adolescent SA assessments nonetheless would benefit from context-specific reports relevant to adolescent SA (i.e., interactions with unfamiliar peers). In a sample of 89 adolescents (30 Evaluation Seeking; 59 Community Control), we collected SA reports from adolescents and their parents, and SA reports from unfamiliar peer confederates who interacted with adolescents during 20-minute mock social interactions. Adolescents and parents completed reports on trait measures of adolescent SA and related concerns (e.g., depressive symptoms), and adolescents completed self-reports of state arousal within mock social interactions. Adolescents' SA reports correlated with reports on parallel measures from parents in the .30s and with peer confederates in the .40s to .50s, whereas reports from parent-confederate dyads correlated in the .07 to .22 range. Adolescent, parent, and peer confederate SA reports related to reports on trait measures of adolescent SA and depressive symptoms, and distinguished Evaluation-Seeking from Community Control Adolescents. Confederates' SA reports incrementally predicted adolescents' self-reported SA over and above parent reports, and vice versa, with combined Rs ranging from .51 to .60. These combined Rs approximate typical correspondence levels between informants who observe adolescents in the same context (e.g., mother-father). Adolescent and peer confederate (but not parent) SA reports predicted adolescents' state arousal in social interactions. These findings have implications for clarifying patterns of reporting correspondence in clinical assessments of adolescent SA. PMID- 29405923 TI - Effectiveness of Web- and Mobile-Based Treatment of Subthreshold Depression With Adherence-Focused Guidance: A Single-Blind Randomized Controlled Trial. AB - Evidence for the impact of psychological Interventions for subthreshold depression (sD) is conflicting. Moreover, human resources to deliver such treatments are limited. This study aimed to evaluate the effectiveness of a web based intervention with adherence-focused guidance in the treatment of sD. Participants with sD (CES-D>= 16, no Major Depressive Disorder according to DSM IV criteria, N = 204) recruited via a large health insurance were randomly allocated to a web-based mobile-supported cognitive-behavioral intervention or to a waitlist control condition with unrestricted access to usual care. The primary outcome was the reduction in depressive symptom severity as measured by blind diagnostic raters using the Quick Inventory of Depressive Symptomatology (QIDS) at posttreatment. There was a statistically significant between-group difference in QIDS scores at posttreatment in favor of the intervention group, F(1, 201) = 11.31, p = .001, corresponding to a medium effect size of d = 0.37 (95% CI 0.09 0.64) and a NNT of 7 (95%-CI 3.7-41.2). Significant effects in favour of the intervention group were also found for secondary outcomes such as quality of life, anxiety, and insomnia severity. Web-based self-help interventions with adherence-focused guidance could be an acceptable and effective approach to reduce a range of negative consequences associated with subclinical depression. PMID- 29405925 TI - Parameters of Time-out: Research Update and Comparison to Parenting Programs, Books, and Online Recommendations. AB - In reviews published more than 30 years ago, eight parameters important to the use of time-out were identified and available research was summarized. The purpose of the current paper is to provide an updated summary of existing research for each parameter of time-out. Within each parameter, we conducted a thorough review of the published literature and identified all peer-reviewed articles addressing each parameter. We identified and summarized a total of 46 articles across the eight parameters, including 32 not cited in previous reviews. Sufficient findings were available to draw conclusions regarding time-out warning, schedule of time-out, contingent versus noncontingent release, and duration. Tentative conclusions based on only a few studies could be drawn in regard to instructional versus physical administration and verbalized reason for time-out. No conclusions could be drawn regarding time-out signal and specific time-out location. While we know much more today regarding effective implementation of time-out, there is a clear need for further exploration within these identified parameters. In addition to summarizing the literature, we reviewed recommendations made by behavioral parent training programs, parenting books, and parenting Web sites, and compared how well their recommendations matched current research based on the conclusions drawn from our review. We found that parenting sources made strong and specific recommendations on several of the parameters that were either not consistent with available research or simply lacked a sufficient research base. PMID- 29405926 TI - TINS Turns 40. PMID- 29405927 TI - The Hippocampus: From Memory, to Map, to Memory Map. AB - The hippocampus is one of the brain's great mysteries. Historically, theories of its function included emotion, response inhibition, general memory and spatial perception/learning, with memory versus space emerging as a particular focus of more recent debates. A 1978 paper by Olton and colleagues captured this dichotomy by exploiting their newly developed radial maze task to reveal a profound deficit in the ability of hippocampally lesioned rats to execute a spatial memory task. This finding supported the emerging spatial map theory of hippocampal function, and helped pave the way for the subsequent uncovering of an entire brain system linking space and memory. PMID- 29405928 TI - Structural Identification of the Nicotinic Receptor Ion Channel. AB - The structural identification of the cationic channel of the acetylcholine nicotinic receptor involved its biochemical tagging by channel blockers, followed by site-directed mutagenesis analyses reported in two papers in 1988. The ion channel was demonstrated to be lined by the transmembrane segment MII, in which the binding sites of channel blockers are "framed" by anionic rings. PMID- 29405929 TI - Discovery of Hypocretin/Orexin Ushers in a New Era of Sleep Research. AB - Prior to the 21st century, genetic mechanisms that regulate sleep were largely unknown. In 1998, de Lecea et al. [1] (Proc. Natl. Acad. Sci. U. S. A. 1998; 95:322-327) and Sakurai et al. [2] (Cell 1998; 92: 573-585) reported the discovery of a gene they named hypocretin and orexin, respectively, which led to a revolution in our understanding of genetic and neuronal mechanisms that regulate sleep. PMID- 29405930 TI - MeCP2 as an Activator of Gene Expression. AB - Rett syndrome is a neurodevelopmental disorder that primarily affects females and is caused by mutations in the methyl-CpG-binding-protein 2 (MECP2) gene. Initially, MeCP2 had been shown to be a repressor of gene transcription. In their 2008 paper, Chahrour and colleagues (DOI: 10.1126/science.1153252) reported that MeCP2 could also function as a transcriptional activator. PMID- 29405931 TI - Hypophosphatasia: better knowledge for better care.... PMID- 29405932 TI - Genetics of hypophosphatasia. AB - Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited. Genetic counseling is complicated by the coexistence of the two modes of inheritance, the incomplete penetrance of the dominant forms, the markedly variable expression of the disease, including intra-familial expression, and the existence of a benign prenatal form that may sometimes be difficult to distinguish from the severe prenatal form. The disease is due to loss-of-function mutations in the Alkaline Phosphatase-Liver (ALPL) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). The great variety of missence mutations and the dominant negative effect of some mutations largely explain the clinical heterogeneity. Directed mutagenesis studies allowed further elucidation of the cellular pathophysiology of HPP, classification of the alleles in terms of their severity and dominant negative effect, and molecular explanations of the dominant inheritance mode. Genetics significantly contributed to show that there are in fact two HPPs, rare, severe and recessive HPP, and mild recessive or mild dominant HPP, which is markedly more frequent and probably under-diagnosed. The prevalence of the severe forms of HPP has been estimated to be 1/300,000 in France and Northern Europe while the prevalence of the moderate forms of HPP may reach 1/6,370. PMID- 29405933 TI - Laboratory diagnosis of hypophosphatasia. AB - The laboratory diagnosis of hypophosphatasia (HPP) is primarily based on the precise analysis of circulating serum alkaline phosphatase (ALP) activity, determined by biochemical assays. This analysis requires specific conditions of implementation and interpretation and should always be viewed in the light of the clinical and radiological data. Concerns regarding the normal ranges of ALP with respect to age, regarding ALP values that may overlap those of normal subjects in HPP patients, regarding apparently normal ALP values in cases of proven HPP, regarding differential diagnoses that may be responsible for low ALP values outside of HPP will be discussed. High levels of pyridoxal phosphate, a substrate of APL, are of supportive value in the diagnosis of HPP. PMID- 29405935 TI - Hypophosphatasia in children and adolescents: clinical features and treatment. AB - Hypophosphatasia (HPP) is a rare genetic disease due to loss of function mutations in the gene that encodes for Alkaline Phosphatase-Liver (ALPL) that encodes for tissue non-specific alkaline phosphatase (TNSALP) or ALP. Juvenile HPP is, by definition, diagnosed between 6 months of age and adulthood. The clinical signs and symptoms of juvenile HPP are very heterogeneous in their presentation, severity and course. The bone (impaired bone mineralization, leg deformations, pain, rickets, growth abnormalities) and dental (premature loss of deciduous teeth) abnormalities are the best known. However, in juveniles, muscular and joint abnormalities are frequently predominant. Treatment options currently remain limited to the symptomatic treatment of pain and impaired function. Promising results of the enzyme replacement therapy have been demonstrated in severely affected children with HPP. Efficacy and long term benefits in patients affected with the juvenile form are still to be proven. PMID- 29405934 TI - Perinatal and infantile hypophosphatasia: clinical features and treatment. AB - Hypophosphatasia (HPP) is a rare hereditary disease characterized by defective skeletal mineralization, and with a broad severity spectrum. The perinatal forms, lethal and non-lethal, are associated with severe neonatal respiratory distress, potential seizures, hypotrophy and marked hypotonia. The diagnosis is rapidly suggested by a combination of typical radiological signs, hypercalcemia, hyperphosphatemia and low alkaline phosphatase (ALP) activity. In the infantile form, the clinical signs appear before the age of six months, but the patients usually have no or very mild signs at birth. The diagnosis should be considered in the event of early deformation of the pectus, feeding difficulties, hypotonia, frequent respiratory tract infections, hypercalcemia, and even early constitution of craniosynostosis. Radiological signs may be less obvious characterized by irregular metaphyses and generalized hypomineralization. Management is initially symptomatic, and adjusted to the symptoms. Care should be provided by a multidisciplinary team, in close collaboration with Reference Centers experts for the disease. Currently, recombinant enzyme replacement therapy (ERT) is under development for the severe form of HPP. The course of the disease, depending on the degree of severity and the various types of management, requires long-term evaluation through joint prospective follow-up to assess the long-term outcomes of these patients. Multidisciplinary follow up is needed to identify the medical and socio-economic outcomes of children and adults affected by HPP. PMID- 29405936 TI - Adult hypophosphatasia. AB - In adults, hypophosphatasia (HPP) may be revealed by fractures, mainly metatarsal and femoral, and by crystal-related joint diseases. Low alkaline phosphatase levels are often overlooked. There is no established treatment for adults but the diagnosis is important to prevent the use of therapies that promote bone resorption in this context of bone fragility. PMID- 29405937 TI - Hypophosphatasia: the contribution of imaging. AB - Radiography and imaging are necessary for the diagnosis of hypophosphatasia (HPP) at all stages of life, from the antenatal period to the complications of adulthood, and in the forms of variable severity. The consequences of alkaline phosphatase activity deficiency, namely defective mineralization and bone fragility, may be detected by radiological tools and share features that distinguish them from other diseases responsible for mineralization defects. Radiography and imaging are also fundamental for the screening and diagnosis of the complications of HPP, some of which are related to the episodes of hypercalcemia and hyperphosphatemia (nephrocalcinosis). Radiologists should be aware of the particularities of HPP to efficiently orient the patients toward optimal medical care. PMID- 29405938 TI - Hypophosphatasia: oral cavity and dental disorders. AB - Dental anomalies exist in every subtype of hypophosphatasia (HPP), from the most severe to the most moderate, called odontohypophosphatasia. The forms are defined by the age at onset of the initial symptoms. These anomalies affect all dental mineralized tissues from enamel, dentin and cementum to alveolar bone in a gradient proportional to the severity of the disease. Early loss of the deciduous teeth, before 3 years of age, and then possibly of the permanent teeth, is due to an abnormality of the cementum, the tissue attaching the teeth to alveolar bone, and is the most frequent abnormality. Tooth loss is a very important diagnostic sign and needs to be recognized. Patients with HPP need specialized oral and dental care in coordination with the reference and expert centers. The oral and dental signs and their treatment remain poorly known. The recording of the abnormalities and their treatment in a registry is indispensable in order to enhance patient management and oral and dental health. PMID- 29405939 TI - Neuromuscular features of hypophosphatasia. AB - The pathophysiology of the neuromuscular manifestations of hypophosphatasia (HPP) remains unknown. Pyridoxine-sensitive seizures characterize severe forms of infantile HPP. Young children and infants affected with severe forms of HPP, but also adults often present with myopathy characterized by hypotonia or muscle weakness. Chronic pain, of unclear mechanism is also often present. Tissue-non specific alkaline phosphatase (Alkaline Phosphatase-Liver/Bone/Kidney [ALPL]) is expressed in brain neuronal cell and in muscle cells during development and adulthood. The knockout of the ALPL impacts neuronal functions in animal models. This may occur through metabolic anomalies involving gamma-aminobutyric acid (GABA) and other neurotransmitters via the metabolism of pyridoxal phosphate (vitamin B6) and phosphoethanolamine. In this context, a greater understanding of the neuromuscular pathophysiology of HPP is critical to assess the potential impact of new therapies. PMID- 29405940 TI - Craniosynostosis and hypophosphatasia. AB - Hypophosphatasia (HPP) when diagnosed at a young age may induce premature fusion of one or several cranial sutures, resulting in a craniocerebral disproportion. The main forms of craniosynostosis associated with HPP are loss of the sagittal suture (scaphocephaly), alone or associated with loss of the coronal sutures (oxycephaly) or associated with loss of the coronal and lambdoid sutures (pansynostosis). Craniosynostosis is accompanied by putatively functional consequences. Diagnosis must thus be early and lead to management by a specialized team. PMID- 29405941 TI - Renal impairment in hypophosphatasia. AB - Renal impairment in hypophosphatasia (HPP) has been described but remains poorly understood: hypercalciuria, nephrocalcinosis and sometimes even chronic kidney failure secondary to chronic hypercalcemia/hypercalciuria or exposure to toxic agents. The objectives of this review are to describe the different renal lesions observed in HPP, and the therapeutic measures that can be applied (in particular, thiazide diuretics). PMID- 29405942 TI - Hypophosphatasia: the patient's and patient's family's point of view. AB - Today, public opinion and the French authorities are more aware of rare diseases, in particular due to the implementation of national plans for rare diseases (PNMR I: 2005-2008 and PNMR II: 2011-2016), the existence of national networks and the current organization of the reference expert centers for rare diseases. While the management of rare diseases is now better structured, it remains long for the patients to be diagnosed. It is not always easy for physicians to clearly identify one of the 7,000 rare diseases even though they increasingly ask themselves the question: is this a rare disease? A person diagnosed with a rare disease lives in a familial, social and professional environment that has not prepared him or her, suddenly or after years of uncertainty, for such an experience. It may be temptng to take refuge in isolation. The patient's pathway is a real challenge and include the recognition to his/her 'difference' and the right to benefit from the expert medical and social care. Patients affected with hypophosphatasia, a very rare bone and dental disease, are not exceptions to the rule, despite the dynamic support of Hypophosphatasie Europe, the first patient association, created in 2004. In twelve years, the overall understanding of hypophosphatasia has dramatically improved, including through the discovery of novel therapies. Yet, diagnostic errance, transition between childhood and adulthood and management and care of affected adults remain unsolved issues. PMID- 29405943 TI - Q&A: Key points for IDF Diabetes Atlas 2017. PMID- 29405944 TI - Experimental effects of acute exercise on episodic memory acquisition: Decomposition of multi-trial gains and losses. AB - OBJECTIVE: Research demonstrates that acute exercise may enhance retention of multi-trial episodic memories. Previous work has examined the effects of exercise on the mean level of memory recall. However, no study has examined whether exercise can influence the acquisition of new items, which was the purpose of this experiment. METHODS: Using a randomized controlled trial design, participants (young adults; Mage=22yrs) completed either a high-intensity bout of treadmill exercise for 15-min (n=22) or sat (n=22) prior to completing a multi trial episodic memory task. This task involved recalling 15 words for six successive trials, as well as after a 20-min delay (Trial 7). The performance on the multiple trials was categorized into gains (items not recalled on Trial n that were recalled on Trial n+1) and losses (items recalled on Trial n that were not recalled on Trial n+1). RESULTS: The exercise group recalled more words on Trial 6 (11.4 vs. 9.7; P=0.009) and after the 20-min delay (10.9 vs. 9.4; P=0.01). The exercise group (vs. control) had a smaller proportion of losses from Trial 3-4 (10.4% vs. 20.3%; P=0.04) and had a greater proportion of gains from Trial 5-6 (38.5% vs. 14.8%; P=0.01). CONCLUSIONS: The exercise-induced multi trial memory effect may be influenced by greater item gains. PMID- 29405946 TI - Driven to distraction: A lack of change gives rise to mind wandering. AB - How does the dynamic structure of the external world direct attention? We examined the relationship between event structure and attention to test the hypothesis that narrative shifts (both theoretical and perceived) negatively predict attentional lapses. Self-caught instances of mind wandering were collected while 108 participants watched a 32.5 min film called The Red Balloon. We used theoretical codings of situational change and human perceptions of event boundaries to predict mind wandering in 5-s intervals. Our findings suggest a temporal alignment between the structural dynamics of the film and mind wandering reports. Specifically, the number of situational changes and likelihood of perceiving event boundaries in the prior 0-15 s interval negatively predicted mind wandering net of low-level audiovisual features. Thus, mind wandering is less likely to occur when there is more event change, suggesting that narrative shifts keep attention from drifting inwards. PMID- 29405945 TI - Inhibition accumulates over time at multiple processing levels in bilingual language control. AB - It is commonly assumed that bilinguals enable production in their nondominant language by inhibiting their dominant language temporarily, fully lifting inhibition to switch back. In a re-analysis of data from 416 Spanish-English bilinguals who repeatedly named a small set of pictures while switching languages in response to cues, we separated trials into different types that revealed three cumulative effects. Bilinguals named each picture (a) faster for every time they had previously named that same picture in the same language, an asymmetric repetition priming effect that was greater in their nondominant language, and (b) more slowly for every time they had previously named that same picture in the other language, an effect that was equivalent across languages and implies symmetric lateral inhibition between translation equivalents. Additionally, (c) bilinguals named pictures in the dominant language more slowly for every time they had previously named unrelated pictures in the nondominant language, exhibiting asymmetric language-wide global inhibition. These mechanisms dynamically alter the balances of activation between languages and between lemmas, providing evidence for an oft-assumed but seldom demonstrated key mechanism of bilingual control (competition between translations), resolving the mystery of why reversed language dominance sometimes emerges (the combined forces of asymmetrical effects emerge over time in mixed-language blocks), and also explaining other longer-lasting effects (block order). Key signatures of bilingual control can depend on seemingly trivial methodological details (e.g., the number of trials in a block) because inhibition is applied cumulatively at both local and global levels, persisting long after each individual act of selection. PMID- 29405947 TI - Class IC antiarrhythmic drugs for suspected premature ventricular contraction induced cardiomyopathy. AB - BACKGROUND: Class IC antiarrhythmic drugs (IC-AADs) can effectively suppress premature ventricular contractions (PVCs). However, IC-AADs increase mortality in patients with PVCs and left ventricular dysfunction after myocardial infarction. Whether IC-AADs can be safely used to treat premature ventricular contraction induced cardiomyopathy (PVC-CM) remains to be established. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of IC-AADs in patients suspected of having PVC-CM. METHODS: The electronic medical records at the Hospital of the University of Pennsylvania were screened to identify all patients suspected of having PVC-CM treated with flecainide or propafenone. Clinical, electrocardiographic, and imaging studies were reviewed. RESULTS: Twenty patients suspected of having PVC-CM were treated with IC-AADs. Patients had undergone an average of 1.3 +/- 0.2 previous unsuccessful ablations. Six had an implantable or wearable defibrillator. With IC-AAD treatment, mean PVC burden decreased from 36.2% +/- 3.5% to 10.0% +/- 2.4% (P <.001). Mean left ventricular ejection fraction (LVEF) increased from 37.4% +/- 2.0% to 49.0% +/- 1.9% (P <.001). Seven patients with myocardial delayed enhancement on cardiac magnetic resonance imaging (all <5% of the total myocardium) experienced similar improvement in LVEF (from 36.8% +/- 4.3% before IC-AAD to 51.7% +/- 3.7% afterward; P <.01). Over an average 3.8 +/- 0.9 treatment-years, no sustained ventricular arrhythmias or sudden cardiac deaths occurred. CONCLUSION: In patients suspected of having PVC CM, IC-AADs effectively suppressed PVCs, leading to LVEF recovery in the majority. No adverse events occurred in this small cohort. PMID- 29405948 TI - Class IC antiarrhythmic agents in structural heart disease: Is nothing CAST in stone? PMID- 29405949 TI - Unusual termination of a wide QRS tachycardia. PMID- 29405950 TI - Letter from the Editor: The Aging Brain. PMID- 29405951 TI - A Primer on Secondary Brain Neoplasms: The Essentials. PMID- 29405952 TI - State of the Art Treatment and Surveillance Imaging of Glioblastomas. PMID- 29405953 TI - Case of the Season: Multinodular and Vacuolating Neuronal Tumor. PMID- 29405954 TI - Response Assessment in Treated Brain Tumors: The Fundamentals. PMID- 29405955 TI - Current Clinical State of Advanced Magnetic Resonance Imaging for Brain Tumor Diagnosis and Follow Up. PMID- 29405956 TI - Approach to Brain Neoplasms: What the Oncologist Wants to Know. PMID- 29405957 TI - Is It or Is It Not? Brain Tumor Mimics. PMID- 29405958 TI - Pediatric Brain Tumors: A Different Ball Game. PMID- 29405959 TI - ? PMID- 29405960 TI - ? PMID- 29405961 TI - Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. AB - INTRODUCTION: Placental insufficiency, arising from abnormal trophoblast differentiation and function, is a major cause of fetal growth restriction. Sirtuin-1 (Sirt1) is a ubiquitously-expressed NAD-dependent protein deacetylase which plays a key role in numerous cellular processes, including cellular differentiation and metabolism. Though Sirt1 has been widely studied, its role in placentation and trophoblast differentiation is unclear. METHOD: Sirt1 heterozygous mice were mated and evaluated at various points during embryogenesis. In situ hybridization and immunohistochemistry were used to further characterize the placental phenotype of Sirt1-null mice. Wild-type (WT) and Sirt1-null mouse trophoblast stem cell (TSC) lines were derived from e3.5 littermate blastocysts. These cells were then evaluated at various points following differentiation. Differentiation was evaluated by expression of lineage specific markers using qPCR and flow cytometry, as well as Matrigel invasion assays. Global gene expression changes were evaluated using microarray-based RNA profiling; changes in specific pathways were validated using qPCR and western blot. RESULTS: In the absence of Sirt1, both embryos and placentas were small, with placentas showing abnormalities in both the labyrinthine layer and junctional zone. Sirt1-null TSCs exhibited an altered phenotype in both undifferentiated and differentiated states, phenotypes which corresponded to changes in pathways relevant to both TSC maintenance and differentiation. Specifically, Sirt1-null TSC showed blunted differentiation, and appeared to be suspended in an Epcamhigh trophoblast progenitor state. DISCUSSION: Our results suggest that Sirt1 is required for proper TSC differentiation and placental development. PMID- 29405962 TI - Progesterone attenuates hypertension and autoantibody levels to the angiotensin II type 1 receptor in response to elevated cadmium during pregnancy. AB - INTRODUCTION: Preeclampsia is associated with the presence of pathogenic angiotensin-receptor-activating autoantibodies. Cadmium is an increasingly prevalent environmental pollutant that can mimic oestrogens, which may enhance immunoglobulin production. Progesterone exerts opposite effects to oestrogen. METHODS: We measured the levels of cadmium and progesterone in preeclamptic patients and controls. Pregnant rats exposed to cadmium (0.125 mg/kg body weight) from gestational day 9-12 were treated with/without progesterone (3 mg/kg) beginning from gestational day 9 to delivery. We analysed the main features of preeclampsia and circulating level of the angiotensin II type 1 receptor agonistic autoantibody. We also measured the expression of activation-induced cytosine deaminase in B cells. RESULTS: There were higher cadmium levels and lower progesterone levels in the blood of preeclamptic women than in the blood of those with a healthy pregnancy. Based on this finding, a rat model of preeclampsia was established by intraperitoneally administrating low-dose cadmium on gestational days 9-12. Rats were then treated with/without progesterone. Key features of preeclampsia, including hypertension, proteinuria and placental abnormalities, appeared in pregnant rats after cadmium injection and improved after treatment with progesterone. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies, by increasing the expression of activation-induced cytosine deaminase in B cells; progesterone exerted an opposite effect. CONCLUSION: Cadmium induced immune abnormalities that may be a key pathogenic contributor to preeclampsia. Progesterone supplementation to correct hormonal imbalance may be a viable strategy for preeclampsia management. PMID- 29405963 TI - Relationship between second-trimester amniotic fluid levels of Prokineticin-1 and Matrix Metalloproteinase-2 with adverse pregnancy outcome. AB - To investigate the levels of Prokineticin-1 (PROK1) and matrix metalloproteinase 2 (MMP-2) in second-trimester amniotic fluid (AF). AF samples were investigated in 81 patients. AF-PROK1 and AF-MMP-2 were not significantly associated with adverse pregnancy outcomes (preeclampsia, intrauterine growth retardation, spontaneous preterm birth, gestational diabetes, gestational hypertension). AF PROK1 levels in patients with abnormal first-trimester screening were significantly higher than those who underwent amniocentesis due to abnormal second-trimester screening tests (p = .04). AF-PROK1 or AF-MMP-2 do not have a role in the prediction of adverse pregnancy outcomes. PMID- 29405964 TI - New insights in the pathophysiology of complete hydatidiform mole. AB - OBJECTIVE: The majority of complete hydatidiform moles (CHM) are detected on ultrasound examination by the end of the first trimester when they present as multiple sonolucent cysts. To better understand the pathophysiology of this unique placental pathology and improve its prenatal diagnosis and management we have reviewed the ultrasound features of CHM before the appearance of cystic changes. STUDY DESIGN: We searched our database to identify all women diagnosed with a complete hydatidiform mole confirmed by histopathology who had an ultrasound examination before 9 weeks' gestation. We reviewed their ultrasound reports and all the corresponding images. RESULTS: The study group included 39 women with a positive pregnancy test and vaginal bleeding, 36 of whom had at least two ultrasound examinations before 9 weeks' gestation. At the first scan (mean gestation age 7 + 1 weeks; SD 1.1), 29 out 39 (74.4%) of CHM presented as a heterogeneous hyperechogenic mass with or without gestational sac and the remaining ten (25.6%) cases as a regular 4-week gestational sac. Cystic molar changes became apparent from the end of the second month of gestation. CONCLUSION: The development of a CHM follows a well-defined pattern starting with a macroscopically normal gestation sac at 4 weeks, which transforms into a polypoid mass between 5 and 7 weeks of gestation. The hydropic changes of the villous tissue is progressive and rarely visible in utero on ultrasound before 8 weeks of gestation. These findings should allow an earlier diagnosis and assist in the management counselling of women with CHM. PMID- 29405965 TI - Trinucleate uterine epithelial cells as evidence for White-tail Deer trophoblast binucleate cell migration and as markers of placental binucleate cell dynamics in a variety of wild ruminants. AB - INTRODUCTION: The unicellular trophoblast epithelium of all ruminants so far investigated contains 15-20% binucleate cells with numerous secretory granules. Electron microscope (EM) studies of the domesticated cow, ewe, goat and deer species have established that these BNC migrate out of the trophoblast epithelium to fuse with the apposed maternal uterine epithelial cells or derivative to form fetomaternal tissue throughout pregnancy. However there is one careful EM study of the trophoblast of a wild ruminant, the White-tail deer, which found the usual number of BNC but no evidence of any migration or fusion. Since there are up to 200 species of wild ruminants, it was important to establish whether there really are two possible scenarios for BNC function. MATERIALS AND METHODS: This paper reports a light microscope (LM) immunocytochemical study of cell dynamics in ruminant placentas using 1-2 mMU deresinated sections. RESULTS: The results clearly demonstrate that the White-tail deer and all of the other 15 (see Table 1) randomly selected wild ruminants show the same BNC migration and fusion pattern. DISCUSSION: These results suggest that this remarkable cellular behaviour is fundamental to the ruminant evolutionary success. PMID- 29405966 TI - Decreased expression of fibroblast growth factor 13 in early-onset preeclampsia is associated with the increased trophoblast permeability. AB - OBJECTIVE: Intracellular protein fibroblast growth factor 13 (FGF13) is highly expressed in human placenta, although its biological function remains unexplored. The aims of this study were to investigate the expression of FGF13 in placentae with early-onset preeclampsia (PE) and the associated mechanisms in the pathophysiology of PE. METHODS: The expression levels of FGF13 in placentae obtained from patients with early-onset PE and normal pregnancies were assessed using immunofluorescent staining, Western blot assays and quantitative PCR. We knocked down FGF13 in trophoblast cell lines BeWo and HTR8/SVneo, and analyzed cell permeability. Clinical trophoblast cell-cell junctions were identified by cytokeratin 7 (CK7) immunofluorescent staining of human placental sections. The expressions of FGF13 were manipulated in BeWo and HTR8/SVneo cell lines, and the expressions of E-cadherin were quantified by reverse transcription followed by quantitative PCR, Western blot assays and immunofluorescent staining. The expressions of FGF13 and E-cadherin were further confirmed in the isolated human primary trophoblasts. RESULTS: Downregulation of FGF13 along with trophoblast disarrangement were found in human placentae with early-onset PE. In trophoblast cell lines decreased FGF13 expression resulted in increased cell permeability and decreased E-cadherin expression. The FGF13 insufficiency-mediated loss of E cadherin was further confirmed in the human villous trophoblasts isolated from PE patients. CONCLUSION: FGF13 was downregulated in human placentae with early-onset PE. FGF13 played an important role in maintaining placental trophoblast permeability via the modulation of E-cadherin. PMID- 29405967 TI - Identification of haptoglobin switch-on status in archived placental specimens indicates antenatal exposure to inflammation and potential participation of the fetus in triggering preterm birth. AB - OBJECTIVE: Haptoglobin (Hp) has key immunoregulatory roles that vary with phenotype (Hp1-1, Hp2-1, Hp2-2). Cord blood Hp expression is switched-off in the normal fetus. We hypothesized that in the setting of fetal inflammation placenta becomes inundated with Hp of fetal origin that in turn modulates the output of PGE2 and MMP-9 in a phenotype dependent manner. METHODS: Placentas from 40 pregnancies complicated by preterm birth (PTB) (<37 weeks), without (n = 15) or with (n = 25) intra-amniotic infection and histological chorioamnionitis (HCA) were scored for intensity of Hp immunostaining. Hp mRNA levels were evaluated by PCR. Cord blood Hp levels, switch-on status and phenotypes were determined by ELISA and Western blotting. Using a villous trophoblast explant system we investigated if Hp can modulate the release of PGE2 and MMP-9 in the presence or absence of lipopolysaccharide (LPS). RESULTS: All cases with HCA had positive Hp immunoreactivity within fetal vascular spaces. Hp staining intensity correlated with cord blood Hp levels and IL-6. Placentas with and without HCA had similar Hp mRNA levels suggesting Hp immunostaining in the fetal spaces is of fetal rather than placental origin. Both Hp1-1 and Hp2-2 up-regulated PGE2 release in the presence of LPS (2-fold over the LPS level, P < .05), without affecting MMP-9 concentrations. CONCLUSIONS: Fetal Hp switch-on status, a marker of antenatal exposure to intra-amniotic infection/inflammation, can be reliably established through evaluation of archived placental specimens. In the setting of infection/inflammation, Hp enhances placental PGE2 output thereby supporting the role of the fetus in triggering parturition. PMID- 29405968 TI - Detyrosinated tubulin is decreased in fetal vessels of preeclampsia placentas. AB - INTRODUCTION: Preeclampsia is a hypertensive, gestational disease, which is still the leading cause of pregnancy related morbidity and mortality. The impairment of placental angiogenesis and vascularization is discussed to be of etiopathologic relevance. Deytrosination and tyrosination of alpha-tubulin is important for the stability and dynamics of microtubules. An increase of alpha-tubulin detyrosination leads to microtubule stabilization, which is an essential prerequisite for physiologic vascular tube morphogenesis during angiogenesis. So far, little is known about the specific localization of detyrosinated (detyr) and tyrosinated (tyr) tubulin in the placenta and its relevance for preeclampsia. METHODS: Placental expression of detyr- and tyr-tubulin was analyzed by immunohistochemistry, immunofluorescence and western blot. For western blot quantification we used biopsies from healthy placentas (n = 21) and placentas from pregnancies complicated with small for gestational age (n = 5), preeclampsia (n = 5) or both (n = 5). RESULTS: Specific placental localization of detyr tubulin was detected in the fetal endothelial cells of the placenta. Villous and extravillous trophoblasts as well as villous stroma cells were tyr-tubulin positive. Detyr-tubulin protein expression was significantly decreased in placentas complicated by preeclampsia. CONCLUSIONS: In summary, we report an accumulation of detyr-tubulin in villous vessels of the placenta and a significantly reduced level of detyr-tubulin in placental biopsies of preeclampsia cases. The reduction of placental detyr-tubulin in preeclampsia could suggest a deficit in villous vascular plasticity and might be associated with the impaired arborization of the disease. PMID- 29405969 TI - Ultrasound screening of umbilical cord abnormalities and delivery management. AB - With the improvement of prenatal diagnoses of foetuses, the prevalence of stillbirth due to foetal anomaly after mid-gestation decreased, whereas that of stillbirth associated with umbilical cord factors tended to increase. Prenatal detection of umbilical cord abnormalities and appropriate management during the antenatal period and delivery based on the ultrasound diagnosis will improve the perinatal morbidity and mortality rates. In the present review, the strategy to reduce the incidence of foetal compromise due to umbilical cord problems is discussed considering the current knowledge regarding the physiological and pathological aspects of umbilical cord abnormalities. PMID- 29405970 TI - Placental leptin expression is mediated by NFkappaB signaling. PMID- 29405971 TI - Diagnostic performance of uric acid for prediction of preeclampsia. PMID- 29405972 TI - Combination of first trimester serum afamin levels and three-dimensional placental bed vascularization as a possible screening method to detect women at risk for adverse pregnancy complications like pre-eclampsia and gestational diabetes mellitus in low-risk pregnancies. AB - OBJECTIVE: Aim of the study was to assess the correlation of first trimester serum afamin levels with three-dimensional placental bed vascularization in pregnant women and its prognostic value for predicting pre-eclampsia and future fetal and maternal complications during pregnancy. METHODS: In this nested case control study all pregnant women registered for delivery during a period of 3 years were routinely screened in the first trimester. Serum afamin levels were assessed in 764 women and correlated to 5 pregnancy outcome groups: gestational hypertension (n = 76), pre-eclampsia (n = 33), intrauterine growth restriction (n = 91), pre-term birth (n = 39), gestational diabetes mellitus (n = 170); In addition, measurements of first trimester myometrial vascularization index were performed and, in combination with afamin tested as a possible screening method to detect women at-risk for the development of adverse complications in low-risk pregnancies at the time of the first trimester. RESULTS: The results showed significantly higher serum afamin levels in women with pre-eclampsia (P<.05) and gestational diabetes mellitus (P<.05) compared to healthy pregnant women. There was no significant difference in serum afamin levels between all other pregnancy outcome groups and healthy controls. In women developing pre-eclampsia during pregnancy, afamin (OR = 1.0197, P < .05) and myometrial vascular index (OR = 0.9235, P < .001) were verified to have a significant prognostic value. Detection of pre-eclampsia in first trimester screening by a combination of afamin and myometrial vascular index performed best (AUC = 0.818). DISCUSSION: Hence, first trimester screening for pre-eclampsia could be provided by a combination of afamin and placental bed vascularization. Moreover, the combination of first trimester serum afamin levels with BMI could provide a possible screening for gestational diabetes mellitus. PMID- 29405973 TI - Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells. AB - For several years, it has been known that histone deacetylase inhibitors have the potential to alter the immunogenicity of tumor cells exposed to checkpoint inhibitory immunotherapy antibodies. HDAC inhibitors can rapidly reduce expression of PD-L1 and increase expression of MHCA in various tumor types that subsequently facilitate the antitumor actions of checkpoint inhibitors. Recently, we have discovered that drug combinations which cause a rapid and intense autophagosome formation also can modulate the expression of HDAC proteins that control tumor cell immunogenicity via their regulation of PD-L1 and MHCA. These drug combinations, in particular those using the irreversible ERBB1/2/4 inhibitor neratinib, can result in parallel in the internalization of growth factor receptors as well as fellow-traveler proteins such as mutant K-RAS and mutant N RAS into autophagosomes. The drug-induced autophagosomes contain HDAC proteins/signaling proteins whose expression is subsequently reduced by lysosomal degradation processes. These findings argue that cancer therapies which strongly promote autophagosome formation and autophagic flux may facilitate the subsequent use of additional antitumor modalities using checkpoint inhibitor antibodies. PMID- 29405974 TI - Recent Advances in Nanoparticle-Based Cancer Drug and Gene Delivery. AB - Effective and safe delivery of anticancer agents is among the major challenges in cancer therapy. The majority of anticancer agents are toxic to normal cells, have poor bioavailability, and lack in vivo stability. Recent advancements in nanotechnology provide safe and efficient drug delivery systems for successful delivery of anticancer agents via nanoparticles. The physicochemical and functional properties of the nanoparticle vary for each of these anticancer agents, including chemotherapeutics, nucleic acid-based therapeutics, small molecule inhibitors, and photodynamic agents. The characteristics of the anticancer agents influence the design and development of nanoparticle carriers. This review focuses on strategies of nanoparticle-based drug delivery for various anticancer agents. Recent advancements in the field are also highlighted, with suitable examples from our own research efforts and from the literature. PMID- 29405975 TI - A Theoretical Basis for the Efficacy of Cancer Immunotherapy and Immunogenic Tumor Dormancy: The Adaptation Model of Immunity. AB - In the past decades, a variety of strategies have been explored to cure cancer by means of immunotherapy, which is less toxic compared with chemotherapy or radiation therapy, and could establish memory for long-lasting protection against tumor recurrence. These endeavors have been successful in offering therapeutic antibodies, vaccines, or cellular immunotherapies, which resulted in prolonging survival of some cancer patients; however, complete cures have not been consistently achieved. The conception, design, and implementation of these promising immunotherapeutic strategies have been influenced by two schools of thought in immunology, which include the "self-nonself" (SNS) model and the "danger" model. Further progress in cancer immunotherapy to achieve consistent cancer cures requires an evolution in our understanding of how the immune system works. The purpose of this review is to revisit premises and limitations of the SNS and danger models based on the outcomes of cancer immunotherapies by suggesting that both models are two sides of the same coin describing how the immune response is induced against cancer. However, neither explains how the immune response succeeds or fails in eliminating the tumor. To this end, the adaptation model has been proposed to explain efficacy of the immune response for achieving cancer cure. PMID- 29405976 TI - Evaluation of Resveratrol in Cancer Patients and Experimental Models. AB - Cancer is one of the top three causes of death in the United States. The treatment regimen for controlling cancer includes a number of approaches depending on the classification of the tumor. Treatment may include radiation, surgery, and cancer chemotherapy agents as well as other interventions. Natural products have been identified for centuries to contain active pharmacologic activity and have been a starting point for numerous drugs which are currently on the market. Resveratrol (RES) is a natural product generated in plants in response to environmental stress and growing conditions. RES has been recognized since 1997 to possess anticancer activity. This review discusses the dietary sources of RES and the relative amounts present in the various food sources. A few limited clinical studies have explored RES effects in patients with prostate and colorectal cancer and have suggested some beneficial results. Future studies need to expand the sample size for clinical examination of RES in order to provide a better profile for the potential benefit of RES in cancer patients. This review also describes the potential mechanisms of RES as an antioxidant and in alteration of cell signaling. Another aspect for the role of RES in cancer may be in the interaction with cancer chemotherapy agents. Cisplatin is a cancer chemotherapy agent used for the treatment of bladder, testicular, ovarian, and many other cancers. Cisplatin usage is associated with a high risk of nephrotoxicity. Experimental studies suggest that RES may reduce cisplatin renal toxicity. The proposed mechanisms of protection are reviewed. PMID- 29405977 TI - Bcl-2 Antiapoptotic Family Proteins and Chemoresistance in Cancer. AB - Cancer is a daunting global problem confronting the world's population. The most frequent therapeutic approaches include surgery, chemotherapy, radiotherapy, and more recently immunotherapy. In the case of chemotherapy, patients ultimately develop resistance to both single and multiple chemotherapeutic agents, which can culminate in metastatic disease which is a major cause of patient death from solid tumors. Chemoresistance, a primary cause of treatment failure, is attributed to multiple factors including decreased drug accumulation, reduced drug-target interactions, increased populations of cancer stem cells, enhanced autophagy activity, and reduced apoptosis in cancer cells. Reprogramming tumor cells to undergo drug-induced apoptosis provides a promising and powerful strategy for treating resistant and recurrent neoplastic diseases. This can be achieved by downregulating dysregulated antiapoptotic factors or activation of proapoptotic factors in tumor cells. A major target of dysregulation in cancer cells that can occur during chemoresistance involves altered expression of Bcl-2 family members. Bcl-2 antiapoptotic molecules (Bcl-2, Bcl-xL, and Mcl-1) are frequently upregulated in acquired chemoresistant cancer cells, which block drug induced apoptosis. We presently overview the potential role of Bcl-2 antiapoptotic proteins in the development of cancer chemoresistance and overview the clinical approaches that use Bcl-2 inhibitors to restore cell death in chemoresistant and recurrent tumors. PMID- 29405978 TI - New Insights Into Beclin-1: Evolution and Pan-Malignancy Inhibitor Activity. AB - Autophagy is a functionally conserved self-degradation process that facilitates the survival of eukaryotic life via the management of cellular bioenergetics and maintenance of the fidelity of genomic DNA. The first known autophagy inducer was Beclin-1. Beclin-1 is expressed in multicellular eukaryotes ranging throughout plants to animals, comprising a nonmonophyllic group, as shown in this report via aggressive BLAST searches. In humans, Beclin-1 is a haploinsuffient tumor suppressor as biallelic deletions have not been observed in patient tumors clinically. Therefore, Beclin-1 fails the Knudson hypothesis, implicating expression of at least one Beclin-1 allele is essential for cancer cell survival. However, Beclin-1 is frequently monoallelically deleted in advanced human cancers and the expression of two Beclin-1 allelles is associated with greater anticancer effects. Overall, experimental evidence suggests that Beclin-1 inhibits tumor formation, angiogenesis, and metastasis alone and in cooperation with the tumor suppressive molecules UVRAG, Bif-1, Ambra1, and MDA-7/IL-24 via diverse mechanisms of action. Conversely, Beclin-1 is upregulated in cancer stem cells (CSCs), portending a role in cancer recurrence, and highlighting this molecule as an intriguing molecular target for the treatment of CSCs. Many aspects of Beclin 1's biological effects remain to be studied. The consequences of these BLAST searches on the molecular evolution of Beclin-1, and the eukaryotic branches of the tree of life, are discussed here in greater detail with future inquiry focused upon protist taxa. Also in this review, the effects of Beclin-1 on tumor suppression and cancer malignancy are discussed. Beclin-1 holds significant promise for the development of novel targeted cancer therapeutics and is anticipated to lead to a many advances in our understanding of eukaryotic evolution, multicellularity, and even the treatment of CSCs in the coming decades. PMID- 29405979 TI - The NMR 'split peak effect' in cell suspensions: Historical perspective, explanation and applications. AB - The physicochemical environment inside cells is distinctly different from that immediately outside. The selective exchange of ions, water and other molecules across the cell membrane, mediated by integral, membrane-embedded proteins is a hallmark of living systems. There are various methodologies available to measure the selectivity and rates (kinetics) of such exchange processes, including several that take advantage of the non-invasive nature of NMR spectroscopy. A number of solutes, including particular inorganic ions, show distinctive NMR behaviour, in which separate resonances arise from the intra- and extracellular solute populations, without the addition of shift reagents, differences in pH, or selective binding partners. This 'split peak effect/phenomenon', discovered in 1984, has become a valuable tool, used in many NMR studies of cellular behaviour and function. The explanation for the phenomenon, based on the differential hydrogen bonding of the reporter solutes to water, and the various ways in which this phenomenon has been used to investigate aspects of cellular biochemistry and physiology, are the topics of this review. PMID- 29405980 TI - Multiscale nuclear magnetic relaxation dispersion of complex liquids in bulk and confinement. AB - The nuclear magnetic relaxation dispersion (NMRD) technique consists of measurement of the magnetic-field dependence of the longitudinal nuclear-spin lattice relaxation rate 1/T1. Usually, the acquisition of the NMRD profiles is made using a fast field cycling (FFC) NMR technique that varies the magnetic field and explores a very large range of Larmor frequencies (10 kHz < omega0/(2pi) <40 MHz). This allows extensive explorations of the fluctuations to which nuclear spin relaxation is sensitive. The FFC technique thus offers opportunities on multiple scales of both time and distance for characterizing the molecular dynamics and transport properties of complex liquids in bulk or embedded in confined environments. This review presents the principles, theories and applications of NMRD for characterizing fundamental properties such as surface correlation times, diffusion coefficients and dynamical surface affinity (NMR wettability) for various confined liquids. The basic longitudinal and transverse relaxation equations are outlined for bulk liquids. The nuclear relaxation of a liquid confined in pores is considered in detail in order to find the biphasic fast exchange relations for a liquid at proximity of a solid surface. The physical-chemistry of liquids at solid surfaces induces striking differences between NMRD profiles of aprotic and protic (water) liquids embedded in calibrated porous disordered materials. A particular emphasis of this review concerns the extension of FFC NMR relaxation to industrial applications. For instance, it is shown that the FFC technique is sufficiently rapid for following the progressive setting of cement-based materials (plasters, cement pastes, concretes). The technique also allows studies of the dynamics of hydrocarbons in proximity of asphaltene nano-aggregates and macro-aggregates in heavy crude oils as a function of the concentration of asphaltenes. It also gives new information on the wettability of petroleum fluids (brine and oil) embedded in shale oil rocks. It is useful for understanding the relations and correlations between NMR relaxation times T1 and T2, diffusion coefficients D, and viscosity eta of heavy crude oils. This is of particular importance for interpreting T1, T2, 2D T1-T2 and D-T2 correlation spectra that could be obtained down-hole, thus giving a valuable tool for investigating in situ the molecular dynamics of petroleum fluids. Another domain of interest concerns biological applications. This is of particular importance for studying the complex dynamical spectrum of a folded polymeric structure that may span many decades in frequency or time. A direct NMRD characterization of water diffusional dynamics is presented at the protein interface. NMR experiments using a shuttle technique give results well above the frequency range accessible via the FFC technique; examples of this show protein dynamics over a range from fast and localized motions to slow and delocalized collective motions involving the whole protein. This review ends by an interpretation of the origin of the proton magnetic field dependence of T1 for different biological tissues of animals; this includes a proposal for interpreting in vivo MRI data from human brain at variable magnetic fields, where the FFC relaxation analysis suggests that brain white-matter is distinct from grey-matter, in agreement with diffusion-weighted MRI imaging. PMID- 29405981 TI - Environmental metabolomics with data science for investigating ecosystem homeostasis. AB - A natural ecosystem can be viewed as the interconnections between complex metabolic reactions and environments. Humans, a part of these ecosystems, and their activities strongly affect the environments. To account for human effects within ecosystems, understanding what benefits humans receive by facilitating the maintenance of environmental homeostasis is important. This review describes recent applications of several NMR approaches to the evaluation of environmental homeostasis by metabolic profiling and data science. The basic NMR strategy used to evaluate homeostasis using big data collection is similar to that used in human health studies. Sophisticated metabolomic approaches (metabolic profiling) are widely reported in the literature. Further challenges include the analysis of complex macromolecular structures, and of the compositions and interactions of plant biomass, soil humic substances, and aqueous particulate organic matter. To support the study of these topics, we also discuss sample preparation techniques and solid-state NMR approaches. Because NMR approaches can produce a number of data with high reproducibility and inter-institution compatibility, further analysis of such data using machine learning approaches is often worthwhile. We also describe methods for data pretreatment in solid-state NMR and for environmental feature extraction from heterogeneously-measured spectroscopic data by machine learning approaches. PMID- 29405982 TI - Simultaneous detections of genetic fragment and single nucleotide mutation with a three-tiered output for tuberculosis diagnosis. AB - Tuberculosis (TB) remains one of the major infectious diseases worldwide. The pathogenic bacterium, Mycobacterium tuberculosis (M.tb), continuously evolves strains carrying drug-resistance genes, thus posing a growing challenge to TB prevention and treatment. We report a diagnostic system that uses a molecular beacon probe and an assistant strand as the core to simultaneously interact with an M.tb-specific fragment (in IS6110) and a single nucleotide substitution (SNS) encoded segment (in rpoB) associated with drug resistance. A single fluorescent output in three-tiered levels was produced for combinatorial interpretations based on formation of a four-way DNA junction (4WJ). The SNS caused the 4WJ to partially dissociate, thus resulting in medium-level fluorescence. By contrast, high- and low-level fluorescence, represented the complete complementary complex and absence of either targeted fragments, respectively. Manipulating the length of the analyte-binding arm realized the medium output. The thermodynamics and kinetics of 4WJ construction were investigated to maximize the tiered-output performance. Biocatalytic amplification driven by the Klenow Fragment and Nt.AlwI was incorporated into the method to enhance the signal 64-fold and ensure long term stability of the three-tiered output. The detection accuracy of the sensing system was verified using unpurified amplicons with templates of extracted DNA and boiled bacterial solutions. The tiered-output mechanism was usable at bacterial loads ranging from 4 * 100 to 4 * 103 CFU per reaction. The interference caused by nontuberculous mycobacteria was minimal. The results demonstrated the integrity of the sensing method as an alternative strategy for rapid screening of M.tb and detecting rifampin-resistance. PMID- 29405983 TI - Additive Partial Least Squares for efficient modelling of independent variance sources demonstrated on practical case studies. AB - A model recalibration method based on additive Partial Least Squares (PLS) regression is generalized for multi-adjustment scenarios of independent variance sources (referred to as additive PLS - aPLS). aPLS allows for effortless model readjustment under changing measurement conditions and the combination of independent variance sources with the initial model by means of additive modelling. We demonstrate these distinguishing features on two NIR spectroscopic case-studies. In case study 1 aPLS was used as a readjustment method for an emerging offset. The achieved RMS error of prediction (1.91 a.u.) was of similar level as before the offset occurred (2.11 a.u.). In case-study 2 a calibration combining different variance sources was conducted. The achieved performance was of sufficient level with an absolute error being better than 0.8% of the mean concentration, therefore being able to compensate negative effects of two independent variance sources. The presented results show the applicability of the aPLS approach. The main advantages of the method are that the original model stays unadjusted and that the modelling is conducted on concrete changes in the spectra thus supporting efficient (in most cases straightforward) modelling. Additionally, the method is put into context of existing machine learning algorithms. PMID- 29405984 TI - A high resolution atmospheric pressure matrix-assisted laser desorption/ionization-quadrupole-orbitrap MS platform enables in situ analysis of biomolecules by multi-mode ionization and acquisition. AB - Introduced in 2000, atmospheric pressure (AP)/matrix-assisted laser desorption/ionization (MALDI) has attracted substantial attention in the mass spectrometry community due to its ease of sample introduction and handling, interchangeability with ESI source and capability of analyzing volatile species. In this study, an AP/MALDI source with ultra-high spatial resolution was coupled to a Q Exactive HF orbitrap mass spectrometer for high resolution in situ analysis by MALDI, laserspray ionization (LSI) and matrix assisted ionization (MAI) without instrument modification. LSI and MAI generated multiply charged ions, which expanded the mass detection range and improved fragmentation efficiency. Full MS, targeted MS/MS, data dependent acquisition (DDA) and parallel reaction monitoring (PRM) acquisitions were performed on peptide and protein standards, tissue extracts and tissue sections for in depth characterization of various biomolecules. High resolution full MS and MS/MS images were obtained from crustacean and rat tissues with pixel size less than 30 MUm. Overall, AP/MALDI-Q-Orbitrap is a fast scanning instrument that is capable of performing multiple types of ionization and multiple acquisition modes without instrument modification. This instrument platform provides an attractive alternative to other high resolution MALDI instruments. PMID- 29405985 TI - Single cell patterning for high throughput sub-cellular toxicity assay. AB - Cell population based toxicity assays cannot distinguish responses of single cells and sub-cellular organelles; while single cell assays are limited by low statistical power due to small number of cells examined. This article reports a new single cell array based toxicity assay, in which cell responses at population level, single cell level and sub-cellular level can be obtained simultaneously at high throughput. The single cell array was produced by microcontact printing and selected area cell attachment, and exposed to damaging X-ray radiation, which was followed by fluorescence imaging after staining. Two image processing softwares written in Python and MATLAB were used to determine the expressions of proteins associated with cell migration and invasion, and production of reactive oxygen species (ROS), respectively. The results showed significant differences in responses at single cell level and distinctive molecular heterogeneity at sub cellular level in a large population of cells upon exposure to radiation. PMID- 29405986 TI - Rotational paper-based electrochemiluminescence immunodevices for sensitive and multiplexed detection of cancer biomarkers. AB - This paper describes a novel rotational paper-based analytical device (RPAD) to implement multi-step electrochemiluminescence (ECL) immunoassays. The integrated paper-based rotational valves can be easily controlled by rotating paper discs manually and this advantage makes it user-friendly to untrained users to carry out the multi-step assays. In addition, the rotational valves are reusable and the response time can be shortened to several seconds, which promotes the rotational paper-based device to have great advantages in multi-step operations. Under the control of rotational valves, multi-step ECL immunoassays were conducted on the rotational device for the multiplexed detection of carcinoembryonic antigen (CEA) and prostate specific antigen (PSA). The rotational device exhibited excellent analytical performance for CEA and PSA, and they could be detected in the linear ranges of 0.1-100 ng mL-1 and 0.1-50 ng mL-1 with detection limits down to 0.07 ng mL-1 and 0.03 ng mL-1, respectively, which were within the ranges of clinical concentrations. We hope this technique will open a new avenue for the fabrication of paper-based valves and provide potential application in clinical diagnostics. PMID- 29405987 TI - Citrate-capped silver nanoparticles as a probe for sensitive and selective colorimetric and spectrophotometric sensing of creatinine in human urine. AB - Urinary creatinine concentration is a critical physiological parameter that enables reliable assessment of patient renal function and diagnosis of a broad spectrum of diseases. In this study, a simple and inexpensive sensor comprising monodisperse, citrate-capped silver nanoparticles (cc-AgNPs) was developed, which enabled rapid, sensitive and selective quantitation of creatinine directly in unprocessed urine. The mechanism of this sensor entails the creatinine-mediated aggregation of the cc-AgNPs (within 1 min) under alkaline conditions (pH 12). This is attributed to the tautomerization of creatinine to its amino anionic species at alkaline pH, which cross-link the cc-AgNPs via hydrogen bond networks with the negatively charged citrate caps. Creatinine elicited visibly-discernable color changes of the cc-AgNPs colloids in a concentration-dependent manner up to 10 MUM. UV-visible spectroscopic analyses of the cc-AgNPs revealed that creatinine elicited a concentration-dependent decrease in intensity of the localized surface plasmon resonance (LSPR) band centered around 403 nm, with a concomitant increase in intensity of the red-shifted LSPR band at 670 nm. This observation denotes a creatinine-mediated increase in cc-AgNP particle size via aggregation, as confirmed by transmission electron microscopy analysis. The cc AgNP sensor exhibited a linear correlation between the A670/A403 extinction ratio and creatinine concentration range of 0-4.2 MUM in aqueous solutions (R2 = 0.996), and a low detection limit of 53.4 nM. Hence, the simplicity, short assay time, and high sensitivity and selectivity of our cc-AgNP sensor affirms its utility as a creatinine monitoring assay for low-resource, point-of-care settings. PMID- 29405988 TI - Double-enhanced lateral flow immunoassay for potato virus X based on a combination of magnetic and gold nanoparticles. AB - This study presents the joint use of magnetic nanoparticles (MNPs) and gold nanoparticles (GNPs) for double enhancement in a lateral flow immunoassay (LFIA). The study realizes two types of enhancement: (1) increasing the concentration of analytes in the samples using conjugates of MNPs with specific antibodies and (2) increasing the visibility of the label through MNP aggregation caused by GNPs. The proposed strategy was implemented using a LFIA for potato virus X (PVX), a significant potato pathogen. MNPs conjugated with biotinylated antibodies specific to PVX and GNPs conjugated with streptavidin were synthesized and characterized. The LFIAs with and without the proposed enhancements were compared. The double-enhanced LFIA achieved the highest sensitivity, equal to 0.25 ng mL-1 and 32 times more sensitivity than the non-enhanced LFIA (detection limit: 8 ng mL-1). LFIAs using one of the types of amplification (magnetic concentration without GNPs-causing aggregation or MNP aggregation without the concentration stage) showed intermediate levels of sensitivity. The double enhanced LFIA was successfully used for PVX detection in potato leaves. The results for PVX detection in the infected plants were similar for the double enhanced LFIA developed and the conventional LFIA based on the GNP conjugates; however, the new system provided significant coloring enhancement. This study confirmed that a simple combination of MNPs and GNPs has great potential for high sensitivity detection and could possibly be adopted for LFIAs of other compounds. PMID- 29405989 TI - The label-free immunosensor based on rhodium@palladium nanodendrites/sulfo group functionalized multi-walled carbon nanotubes for the sensitive analysis of carcino embryonic antigen. AB - In this work, bimetallic core-shell rhodium@palladium nanodendrites (Rh@Pd NDs) loaded on sulfo group functionalized multi-walled carbon nanotubes (MWCNTs-SO3H) were combined to form Rh@Pd NDs/MWCNTs-SO3H nanocomposites. And the composites were used to construct a simple and label-free electrochemical immunosensor for carcino embryonic antigen (CEA) detection using differential pulse voltammetry (DPV). Rh@Pd NDs with dendritic nanostructure not only provide abundant catalytically active sites, but also increase the loading of antibody, which could improve the analytical performance and result in high sensitivity. In addition, the MWCNTs-SO3H could further enhance electrochemical properties due to the excellent conductivity, good solubility and high surface area. Taking advantages of both Rh@Pd NDs and MWCNTs-SO3H, the proposed immunosensor showed a broad linear range from 25 fg mL-1 to 100 ng mL-1 for CEA detection and a low detection limit of 8.3 fg mL-1 (signal-to-noise ratio of 3) under optimal experimental conditions. Moreover, the expected immunosensor exhibited good reproducibility and high sensitivity, which could achieve excellent analysis of CEA in human serum with satisfactory results. Therefore, the Rh@Pd NDs/MWCNTs SO3H nanocomposites may be considered as a sensing platform for fabrication of simple, ultrasensitive and label-free electrochemical immunosensor. PMID- 29405990 TI - Simultaneous determination of 11 phthalate esters in bottled beverages by graphene oxide coated hollow fiber membrane extraction coupled with supercritical fluid chromatography. AB - Phthalate esters (PAEs) are a group of serious environmental pollutants, which lead to carcinogenicity or tumorigenicity in human body. In this study, a rapid, sensitive and green method by graphene oxide coated hollow fiber membrane extraction (GO-HFME) coupled with supercritical fluid chromatography (SFC) was proposed for the determination of 11 phthalate esters in bottled beverages. Graphene oxide (GO) was prepared and coated onto a porous hollow fiber membrane (HFM) to reinforce the efficiency of membrane extraction. The modified hollow fiber membrane was employed for the extraction of phthalate esters from bottled beverages prior to the determination by the supercritical fluid chromatography with UV detection. To achieve the maximum extraction efficiency, several parameters were investigated including GO concentration, extraction time, desorption solution and desorption time. SFC variables including stationary phase, modifier composition and percentage, column temperature, flow rate and backpressure were studied to improve the separation conditions. Under these optimized conditions, all the studied 11 phthalate esters were well separated and simultaneously determined in 7 min by SFC. The performance of the developed method was evaluated. Good linearity was observed (R >= 0.999) in the range of 0.02-10.0 MUg/mL with limit of detection (LOD, S/N = 3) ranging from 1.5 to 3.0 ng/mL. Recoveries of all the PAEs for the spiked samples were between 92.1% and 99.3% with satisfactory relative standard deviations (RSD) less than 5.9%. The proposed method is time-saving, green, simple and robust, which will be an alternative way to the analysis of PAEs in real samples. PMID- 29405991 TI - SVAtools for junction detection of genome-wide chromosomal rearrangements by mate pair sequencing (MPseq). AB - Mate-pair sequencing (MPseq), using long-insert, paired-end genomic libraries, is a powerful next-generation sequencing-based approach for the detection of genomic structural variants. SVAtools is a set of algorithms to detect both chromosomal rearrangements and large (>10 kb) copy number variants (CNVs) in genome-wide MPseq data. SVAtools can also predict gene disruptions and gene fusions, and characterize the genomic structure of complex rearrangements. To illustrate the power of SVAtools' junction detection methods to provide comprehensive molecular karyotypes, MPseq data were compared against a set of samples previously characterized by traditional cytogenetic methods. Karyotype, FISH and chromosomal microarray (CMA), performed for 29 patients in a clinical laboratory setting, collectively revealed 285 breakpoints in 87 rearrangements. The junction detection methods of SVAtools detected 87% of these breakpoints compared to 48%, 42% and 57% for karyotype, FISH and CMA respectively. Breakpoint resolution was also reported to 1 kb or less and additional genomic rearrangement complexities not appreciable by standard cytogenetic techniques were revealed. For example, 63% of CNVs detected by CMA were shown by SVAtools' junction detection to occur secondary to a rearrangement other than a simple deletion or tandem duplication. SVAtools with MPseq provides comprehensive and accurate whole-genome junction detection with improved breakpoint resolution, compared to karyotype, FISH, and CMA combined. This approach to molecular karyotyping offers considerable diagnostic potential for the simultaneous detection of both novel and recurrent genomic rearrangements in hereditary and neoplastic disorders. PMID- 29405992 TI - Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients. AB - Lynch syndrome (LS) is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, MSH6, and PMS2. Most of genetic variants in the MMR genes predisposing to LS are point mutations, small deletions and insertions but large genomic rearrangements in the MMR genes also predisposing to Lynch syndrome. In this study, we report a novel, large rearrangement of the MSH2 gene, manifested by a duplication spanning a 14,846-bps region from intron 7 through intron 9. The breakpoints of this rearrangement were characterized by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Finally, this large duplication was identified in three unrelated patients. Breakpoint analysis revealed the same junction fragments of introns 7 and 8 in the three index cases, suggesting a recurrent duplication or, alternatively, identity of the respective alleles by descent. PMID- 29405993 TI - Molecular approaches identify a cryptic MECOM rearrangement in a child with a rapidly progressive myeloid neoplasm. AB - Myeloid neoplasms are a heterogeneous group of hematologic disorders with divergent patterns of cell differentiation and proliferation, as well as divergent clinical courses. Rare recurrent genetic abnormalities related to this group of cancers are associated with poor outcomes. One such abnormality is the MECOM gene rearrangement that typically occurs in cases with chromosome 7 abnormalities. MECOM encodes a transcription factor that plays an essential role in cell proliferation and maintenance and also in epigenetic regulation. Aberrant expression of this gene is associated with reduced survival. Hence, its detailed characterization provides biological and clinical information relevant to the management of pediatric myeloid neoplasms. In this work, we describe a rare karyotype harboring three copies of MECOM with overexpression of the gene in a child with a very aggressive myeloid neoplasm. Cytogenetic studies defined the karyotype as 46,XX,der(7)t(3;7)(q26.2;q21.2). Array comparative genomic hybridization (aCGH) revealed a gain of 26.04 Mb in the 3q26.2-3qter region and a loss of 66.6 Mb in the 7q21.2-7qter region. RT-qPCR analysis detected elevated expression of the MECOM and CDK6 genes (458.5-fold and 35.2-fold, respectively). Overall, we show the importance of performing detailed molecular cytogenetic analysis of MECOM to enable appropriate management of high-risk pediatric myeloid neoplasms. PMID- 29405994 TI - ALK-TPM3 rearrangement in adult renal cell carcinoma: Report of a new case showing loss of chromosome 3 and literature review. AB - Seven cases of translocation-associated renal cell carcinoma involving ALK (ALK tRCC) were referenced in the last World Health Organization's classification (2016), in a group of emerging/provisional RCC. The first three cases were pediatric, medullary-based, associated with sickle-cell trait and showed a fusion of ALK with VCL. Thirteen cases have been further described. They displayed clinical, morphological and genomic heterogeneity. Most of them occurred in adults. None of the patients was affected by sickle-cell disease. We report a new case of ALK-tRCC in a 55-year-old woman. Genomic profile showed losses of chromosomes 3, 9 and 14, anomalies often observed in clear cell RCC. VHL mutation or morphological features suggesting a clear cell RCC were not detected. We identified an unbalanced rearrangement of ALK and TPM3. Review of the literature identified similar features in our case and previously published cases: heterogeneous solid architecture, eosinophilic cells, mucinous cytoplasmic elements, rhabdoid cells and intracytoplasmic lumina. These elements may constitute the basis of a pathological definition of ALK-tRCC. Their observation in a RCC should lead to perform molecular detection of ALK rearrangement. This may have a crucial importance for metastatic patients treatment since ALK rearrangements confer sensitivity to tyrosine kinases inhibitors such as crizotinib. PMID- 29405995 TI - Survey of gynecological carcinosarcomas in families with breast and ovarian cancer predisposition. AB - Carcinosarcomas (CSs) are biphasic neoplasms composed of high grade, malignant, epithelial and mesenchymal elements. The incidence of gynecological CSs (GCSs) is 0.4/100,000 women per year. Patients affected with GCSs have been occasionally reported in Hereditary Breast Ovarian Cancer (HBOC) families, including a few cases with pathogenic variants in BRCA1/BRCA2 genes. The prevalence and the association of GCSs in HBOC families have not been systematically investigated. Thus, we searched for families with GCSs in the HBOC registry of the National Cancer Institute of Milan. Eleven families, including four BRCA1-positive and four BRCA2-positive, presented a case of GCS. In the three BRCA1-mutated patients for whom surgical specimens were available, DNA fragment and sequencing analyses revealed the loss of the constitutionally wild-type BRCA1 allele. All tumors presented also TP53 mutations and stained negative for the expression of the protein product by immunohistochemistry. Our results suggest that GCSs may be found not infrequently in HBOC families and assimilate the analyzed CSs to BRCA1 related breast/ovarian carcinomas, where the above findings are frequently observed. Exploring the role of BRCA genes in prospective unselected series of GCSs might improve the knowledge of the genesis of these malignancies and guide the proposition of prophylactic surgery and targeted therapy. PMID- 29405996 TI - Familial Esophageal Squamous Cell Carcinoma with damaging rare/germline mutations in KCNJ12/KCNJ18 and GPRIN2 genes. AB - In Iran, esophageal cancer is the fourth common cancers in women and sixth common cancers in men. Here we evaluated the importance of familial risk factors and the role of genetic predisposition in Esophageal Squamous Cell Carcinoma (ESCC) using Whole-Exome Sequencing (WES). Germline damaging mutations were identified in WES data from 9 probands of 9 unrelated ESCC pedigrees. Mutations were confirmed with Sanger sequencing and evaluated amplification-refractory mutation system Polymerase Chain Reaction (ARMS-PCR) in 50 non-related ethnically matched samples and in complete genomics database. Sixteen candidate variants were detected in ESCC 9 probands. Four of these 16 variants were rare damaging mutations including novel mutations in KCNJ12/KCNJ18, and GPRIN2 genes. This WES study in Iranian patients with ESCC, provides insight into the identification of novel germline mutations in familial ESCC. Our data suggest an association between specific mutations and increased risk of ESCC. PMID- 29405998 TI - Urban diabetes in India. PMID- 29405997 TI - Mathematical model of the MenD-catalyzed 1,4-addition (Stetter reaction) of alpha ketoglutaric acid to acrylonitrile. AB - The Stetter reaction, a conjugate umpolung reaction, is well known for cyanide catalyzed transformations of mostly aromatic aldehydes. Enzymatic Stetter reactions, however, have been largely unexplored, especially with respect to preparative transformations. We have investigated the kinetics of the MenD catalyzed 1,4-addition of alpha-ketoglutaric acid to acrylonitrile which has shown that acrylonitrile, while an interesting candidate, is a poor substrate for MenD due to low affinity of the enzyme for this substrate. The kinetic model of the reaction was simplified to double substrate Michaelis-Menten kinetics where the reaction rate linearly depends on acrylonitrile concentration. Experiments at different initial concentrations of acrylonitrile under batch, repetitive batch, and fed-batch reactor conditions were carried out to validate the developed mathematical model. Thiamine diphosphate dependent MenD proved to be quite a robust enzyme; nevertheless, enzyme operational stability decay occurs in the reactor. The spontaneous reactivity of acrylonitrile towards polymerization was also taken into account during mathematical modeling. Almost quantitative conversion of acrylonitrile was achieved in all batch reactor experiments, while the yield of the desired product was dependent on initial acrylonitrile concentration (i.e., the concentration of the stabilizer additive). Using the optimized reactor parameters, it was possible to synthesize the product, 6-cyano 4-oxohexanoic acid, in a concentration of 250 mM. The highest concentration of product was achieved in a repetitive batch reactor experiment. A fed-batch reactor experiment also delivered promising results, especially regarding the short reaction time needed to achieve a 200 mM concentration of product. Hence, the enzymatic Stetter reaction with a highly reactive acceptor substrate can be performed on a preparative scale, which should enable similar transformations with acrylate, methacrylate, and methyl vinyl ketone. PMID- 29405999 TI - Congenital Hypothyroidism. AB - Congenital hypothyroidism is common and can cause severe neurodevelopmental morbidity. Prompt diagnosis and treatment are critical to optimizing long-term outcomes. Universal newborn screening is an important tool for detecting congenital hypothyroidism, but awareness of its limitations, repeated screening in high-risk infants, and a high index of clinical suspicion are needed to ensure that all affected infants are appropriately identified and treated. Careful evaluation will usually reveal the etiology of congenital hypothyroidism, which may inform treatment and prognosis. Early and adequate treatment with levothyroxine results in excellent neurodevelopmental outcomes for most patients with congenital hypothyroidism. PMID- 29406001 TI - Turner Syndrome: Diagnostic and Management Considerations for Perinatal Clinicians. AB - The perinatal clinician needs to understand certain essential concepts when encountering an infant with a suspected or confirmed diagnosis of Turner syndrome. This article describes the key clinical features that should prompt testing, the appropriate diagnostic workup, the necessary screening required after diagnosis, and how to best approach family counseling. PMID- 29406002 TI - Mineral Homeostasis and Effects on Bone Mineralization in the Preterm Neonate. AB - Most bone formation and mineralization occurs late in gestation. Accretion of adequate minerals is a key element of this process and is often interrupted through preterm birth. In utero, mineral transport is accomplished via active transport across the placenta and does not require fetal hormone input. Postnatal mineral homeostasis requires a balance of actions of parathyroid hormone, calcitonin, and vitamin D on target organs. Preterm birth, asphyxia, acidosis, and prolonged parenteral nutrition increase the risk of mineral imbalance and metabolic bone disease (MBD). Aggressive postnatal nutrition is key to preventing and treating MBD in preterm infants. PMID- 29406000 TI - Neonatal Cushing Syndrome: A Rare but Potentially Devastating Disease. AB - Neonatal Cushing syndrome (CS) is most commonly caused by exogenous administration of glucocorticoids and rarely by endogenous hypercortisolemia. CS owing to adrenal lesions is the most common cause of endogenous CS in neonates and infants, and adrenocortical tumors (ACTs) represent most cases. Many ACTs develop in the context of a TP53 gene mutation, which causes Li-Fraumeni syndrome. More rarely, neonatal CS presents as part of other syndromes such as McCune-Albright syndrome or Beckwith-Wiedemann syndrome. Management usually includes resection of the primary tumor with or without additional medical treatment, but manifestations may persist after resolution of hypercortisolemia. PMID- 29406003 TI - Appendices A to C. PMID- 29406004 TI - Thyroid Function in the Neonatal Intensive Care Unit. AB - Patients in the neonatal intensive care unit (NICU) are at high risk for abnormal thyroid function testing because of illness and preterm birth. Preterm infants are born before hypothalamic-pituitary-thyroid axis maturation and the normal feedback mechanisms that regulate thyroid hormone production remain immature. Preterm and sick infants may develop hypothyroidism even if routine thyroid screening tests collected in the first several days after birth are normal. This article reviews normal hypothalamic-pituitary-thyroid axis maturation, thyroid hormone testing and interpretation in the NICU, and the current evidence for and against levothyroxine treatment of NICU patients with borderline abnormal thyroid function testing. PMID- 29406005 TI - Neonatal Thyrotoxicosis. AB - Neonatal thyrotoxicosis (hyperthyroidism) is less prevalent than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. Most cases are transient, secondary to maternal autoimmune hyperthyroidism (Graves disease [GD]). This article summarizes recommendations for screening and management of hyperthyroidism in both the fetal and neonatal periods, with a focus on neonatal thyrotoxicosis secondary to maternal GD. Early monitoring and treatment are crucial for optimizing short-term and long-term patient outcomes. PMID- 29406007 TI - Hyperinsulinism in the Neonate. AB - Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Prompt recognition and treatment, independent of whether infants have transient or permanent HI, are essential to decrease risk of neurologic damage. The most common form of congenital HI is due to inactivating mutations of the beta-cell ATP-sensitive potassium (KATP) channel (KATP-HI) and is typically diazoxide unresponsive. KATP-HI occurs in diffuse and focal forms. Distinguishing between the 2 forms is crucial, because pancreatectomy is curative in the focal form but palliative in the diffuse form. The 18-fluoro-L-3,4-dihydroxyphenylalanine PET scan has revolutionized HI management by allowing accurate localization of focal lesions prior to surgery. PMID- 29406008 TI - Congenital Hypopituitarism. AB - Mutations of growth hormone genes and pituitary transcription factors account for a small proportion of cases of severe congenital hypopituitarism. Most cases show characteristic MRI findings of pituitary stalk interruption syndrome. Clinical suspicion should prompt assessment of cortisol, free T4, thyroid-stimulating hormone, and growth hormone levels together with MRI of the hypothalamic and pituitary regions. PMID- 29406009 TI - Use of Glucocorticoids for the Fetus and Preterm Infant. AB - The soon-to-be-delivered fetus and preterm infant have been treated with glucocorticoids to prepare for postnatal life, historically for more than 40 years. The use of glucocorticoids is as much for replacement of cortisol in the setting of a poorly functioning hypothalamic-pituitary-adrenal axis in the preterm infant, as it is for prevention of long-term lung dysfunction. Potential negative effects of glucocorticoid treatment on brain development and function have been observed more often with dexamethasone therapy than with use of other glucocorticoids. Overall, glucocorticoid treatment has improved the outcome of the preterm infant. PMID- 29406006 TI - Neonatal Diabetes Mellitus: An Update on Diagnosis and Management. AB - Neonatal diabetes mellitus is likely to be due to an underlying monogenic defect when it occurs at less than 6 months of age. Early recognition and urgent genetic testing are important for predicting the clinical course and raising awareness of possible additional features. Early treatment of sulfonylurea-responsive types of neonatal diabetes may improve neurologic outcomes. It is important to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in newborns. Other causes include infection, stress, inadequate pancreatic insulin production in preterm infants, among others. This review explores the diagnostic approach, mutation types, management, and clinical course of neonatal diabetes. PMID- 29406015 TI - Hormonal Regulation of Human Development. PMID- 29406010 TI - Endocrinology. PMID- 29406016 TI - Perinatal Endocrine Challenges. PMID- 29406017 TI - Examining the effectiveness of acetylcholinesterase inhibitors and stimulant based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. AB - We sought to examine the effectiveness of acetylcholinesterase inhibitors (AChEIs) and stimulant-based medications for improving cognitive performance in patients with multiple sclerosis (MS). An electronic database search was conducted on 25th March 2017. Eligible studies were double-blind, randomised, placebo-controlled trials that examined the efficacy of compounds that act primarily as AChEIs or stimulants (administered daily for >=1 week) on cognitive outcome measures in patients with MS. Where suitable data was reported, we generated effect sizes and corresponding 95% confidence intervals and performed meta-analyses using random-effects models to investigate the effectiveness of these drug types across cognitive domains. Sixteen trials were included in the systematic review, with eleven trials (N = 734 MS patients) providing sufficient data for meta-analysis. Whilst there was only a limited pool of relatively small trials and a number of different compounds, we found that collectively, both AChEIs (donepezil and rivastigmine) and stimulants (methylphenidate, modafinil, l amphetamine sulfate and lisdexamfetamine dimesylate) offered no significant benefits over placebo on measures of processing speed, working memory, verbal fluency, verbal memory, visuospatial memory or executive functioning. PMID- 29406019 TI - Community Reintegration, Participation, and Employment Issues in Veterans and Service Members With Traumatic Brain Injury. AB - Traumatic brain injury (TBI) has been called the signature injury of the post 9/11 wars in Iraq, Afghanistan, and neighboring countries. Although similarities exist between veterans and service members with TBI, levels of severity and different constellations of coexisting comorbid conditions affect them differently. These conditions affect physical, cognitive, and emotional function, which in turn can complicate community reintegration (CR), or the ability to return to family, vocational, and community life. This special supplement of the Archives of Physical Medicine and Rehabilitation consists of articles written by accomplished teams from multiple disciplines, including anthropology, neuropsychology, nursing, occupational therapy, psychology, and rehabilitation sciences. Each article brings a different perspective to bear on what CR means for veterans and service members from examination of predictors and perceptions of veterans and service members and others to measurement studies. Collectively, this group of articles represents current thinking about CR and lays the groundwork for testing interventions to improve CR outcomes for veterans and service members (eg, employment, living situation, family life). PMID- 29406021 TI - A Simple Vista en Este Numero. PMID- 29406020 TI - This Issue at a Glance. PMID- 29406022 TI - ? PMID- 29406024 TI - High efficiency and fast separation of active proteins by HIC chromatographic pie with sub-2 MUm polymer packings. AB - This paper reports the development of hydrophobic interaction chromatography (HIC) by synthesizing sub-2 MUm polymer packings which was packed into a chromatographic pie for fast separation of native proteins at low pressures demonstrating high efficiency. Using styrene as monomer and ethylene dimethacrylate (EDMA)as swelling agent, the polystyrene seeds with an average particle size of 0.8 MUm and monodisperse polymeric microspheres with a particle size of 1.5-5.0 MUm were synthesized through dispersion polymerization and one step swelling method, respectively. In order to separate active proteins, the microspheres were modified to hydrophobic chromatographic packings through covalent bonding with benzene methanol. Compared with the traditional column chromatography, the sub-2 MUm polymer packings in chromatographic pie exhibited higher column efficiency for protein separation at lower column pressures, even at higher flow rates. The van Deemter curve showed that the flow rate had insignificant effect on column efficiency of chromatographic pie. Seven example proteins were clearly separated within 3 min at a flow rate of 10 mL/min. The applicability of this method was further demonstrated by the separation of human serum samples. The results indicated that this chromatographic mode can be potentially applied for the fast separation of complex active proteins, such as protein drugs from natural products. PMID- 29406023 TI - Simultaneous determination of eight cyclopolypeptide antibiotics in feed by high performance liquid chromatography coupled with evaporation light scattering detection. AB - A high throughput, reliable and reproducible analysis strategy based on high performance liquid chromatography combined to evaporative light scattering detector (HPLC-ELSD) was developed for simultaneous determination of eight cyclopolypeptide antibiotics including vancomycin, polymyxin B (polymyxin B1 and polymyxin B2), polymyxin E (colistin A and colistin B), teicoplanin, bacitracin A, daptomycin and virginiamycin M1 in animal Feed. Feed samples were extracted with methanol-2% formic acid aqueous solution, followed by a solid-phase extraction step using a HLB cartridge. Under the optimum chromatographic conditions and ELSD parameters, target compounds were separated well on a short column filled with biphenyl stationary phase. The method was developed in accordance with pig complete feed and then extended to detect polypeptide antibiotics in piglet premix, pig feed additive, poultry complete feed and fattening pig premix. The results showed that logarithmic calibration curves of eight analytes were linear (r2 > 0.99) within the concentration range of 5-200 mg mL-1. The developed method provided good accuracy and precision for quantification of eight polypeptides in five kinds of feeds with recoveries ranging from 72.0% to 105.4% with relative standard deviations <9.5%. The limits of detection ranged from 2 to 5 mg kg-1. Finally, the method was successfully applied to analyze polypeptide antibiotics in commercial feed. PMID- 29406025 TI - Trisaminohexyl isocyanurate, a urinary biomarker of HDI isocyanurate exposure. AB - Biological monitoring of occupational exposure to 1,6-hexamethylene diisocyanate (HDI)-containing spray-paints is limited to analysis of metabolites of HDI monomer although polymeric HDI isocyanurate constitutes the predominant inhalation and skin exposure for workers in the automotive paint industry. A novel method using nanoflow ultra-performance liquid chromatography coupled to nano-electrospray ionization tandem mass spectrometry (nano-UPLC-ESI-MS/MS) was developed to quantify trisaminohexyl isocyanurate (TAHI), a hydrolysis product of HDI isocyanurate, in the urine of spray-painters. Analytical and internal standards were synthesized in-house and weighted linear regression calibration curves were generated using spiked control urine from non-exposed persons (0.06 7.98 MUg/L; N = 13; w = x-2; r = 0.998). Urine samples collected from 15 exposed workers (N = 111) were subjected to acid hydrolysis and extracted with dichloromethane, then derivatized with acetic anhydride. The derivatized product, trisacetamidohexyl isocyanurate (TAAHI), was analyzed using nano-UPLC-ESI-MS/MS. The protocol was sensitive and specific for analysis of TAHI in the urine of exposed workers with a method detection limit at 0.03 MUg/L. TAHI was detected in 33 of 111 urine samples and in 11 of 15 workers. This biomarker for HDI isocyanurate is critical to determine the relative potency and dose-relationships between the monomer and oligomer exposure on the development of diisocyanate induced health effects in future studies. PMID- 29406026 TI - Method development, matrix effect, and risk assessment of 49 multiclass pesticides in kiwifruit using liquid chromatography coupled to tandem mass spectrometry. AB - In the present study, a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with a minimal matrix effect (ME) was developed and validated for simultaneous determination of a diverse range of pesticides (49) in kiwifruit. Samples extracted by the quick, easy, cheap, effective, rugged, and safe (QuEChERS) citrate-buffered method were analyzed either without purification or following purification (with primary secondary amine (PSA) or PSA + graphitized carbon black (GCB)). With the addition of a clean-up step, the suppression of the ME decreased, with a higher number of pesticides determined by the application of PSA + GCB. The method exhibited good linearity with coefficients of determination (R2) >= 0.9972 and satisfactory recoveries (70 120%) with a relative standard deviations (RSDs) <10%. The limits of quantification (LOQ) were lower than the maximum residue limits (MRLs) set by the Korean Ministry of Food and Drug Safety (MFDS) and the CODEX Alimentarius. The developed method was applied to the real samples and the results indicated that the quantitated levels of all pesticides, except for pyraclostrobin and carbendazim, are lower than the MRLs set by the regulatory authorities. The percentage of the acceptable daily intake was <20%, suggesting that there is no risk associated with the intake of residual pesticides through kiwifruit. PMID- 29406027 TI - Rapid and sensitive determination of formamidines and metabolites with HPLC-MS/MS using core-shell columns. AB - A number of poisoning and suicide cases involving formamidine pesticides have been reported, thus developing a rapid and low cost determination method is crucial. In this work, a rapid, sensitive and low-cost method for the simultaneous determination of formamidine pesticides (amitraz, chlordimeform, formetanate) and their main metabolites, N-(2,4-dimethylphenyl)-N-methyl formamidine, 2,4-dimethylformamidine, 2,4-dimethylaniline, 4-chloro-2 methylaniline and 3-hydroxyacetanilide in human blood by high-performance liquid chromatography with tandem mass spectrometry is developed. The application of columns with core-shell particles significantly reduced the analysis time. Very low LODs (0.01-0.04 MUg L-1) were obtained for formamidine pesticides and their metabolites. The method was successfully applied to the analysis of human blood samples from a real forensic case. The significantly reduced analysis time, high sensitivity and low cost are the primary advantages of the developed method. This methodology provides important value for sensitive and rapid determination of residue pesticides and metabolites, study of residue pesticides behavior in human body, as well as application in real forensic cases. PMID- 29406029 TI - LC-MS/MS bioassay of four proton pump inhibitors. AB - A new validated bio-analytical LC-MS/MS method was developed for the simultaneous extraction and determination of four proton pump inhibitors: esomeprazole, lansoprazole, pantoprazole and rabeprazole in human plasma using escitalopram as an internal standard. The proteins in plasma samples were precipitated using acetonitrile for the extraction of analytes which is a simple economic method. The separation was accomplished using a mobile phase composed of 10 mM ammonium formate: acetonitrile: methanol (20:40:40% v/v) at a flow rate of 0.8 mL/min in isocratic mode on a reversed phase C18 INERTSIL ODS-3 (5 MUm, 150 * 4.6 mm) and column temperature of 40 degrees C. Positive mode electrospray ionization source was used prior to multiple reaction monitoring (MRM) detection using parent and daughter ions: m/z 346.2 -> 198.1 for esomeprazole, m/z 370.1 -> 252 for lansoprazole, m/z 384.2 -> 200.2 for pantoprazole, m/z 360.1 -> 242.1 for rabeprazole and m/z 325.2 -> 109 for escitalopram. The calibration curves were constructed, and the method was linear in the range of 20-5000 ng/mL applying weighted (1/X2) linear regression coefficient for all drugs. The method was fully validated following US-FDA and EMA guidelines. PMID- 29406028 TI - Development and in-house validation of a sensitive LC-MS/MS method for simultaneous quantification of gelsemine, koumine and humantenmine in porcine plasma. AB - Three monomers of G. elegans indole alkaloids (gelsemine, koumine and humantenmine) were simultaneously detected in porcine plasma for the first time with the development and validation of a sensitive and reliable LC-ESI-MS/MS method. Using a gradient mobile phase at a constant flow rate of 0.2 mL/min via electrospray ionization (positive ion mode) in a multiple reaction monitoring (MRM) scan, gelsemine, koumine and humantenmine were eluted, separated and detected at an appropriate retention time. The porcine plasma was prepared using protein precipitation with 1% formic acid-acetonitrile: methanol (2:1, v/v). Using matrix-matched calibration curves and weighted least squares linear regression, a good linearity (r2 > 0.99) was achieved with a concentration range of 0.1-200 MUg/L for gelsemine, koumine and humantenmine; estimated LOD and LOQ values were 0.10 MUg/L and 0.2 MUg/L, respectively. The mean of the recoveries was in the range of 82.68-100.35% of porcine plasma at four different levels, and the intra-day and inter-day precision (CV) were lower than 15% with a range of 2.46-8.76% and 2.73-10.83%, respectively. The proposed method has proved to be suitable for accurate, quantitative determination of gelsemine, koumine and humantenmine in porcine plasma. PMID- 29406030 TI - Comprehensive investigation of in-vivo ingredients and action mechanism of iridoid extract from Gardeniae Fructus by liquid chromatography combined with mass spectrometry, microdialysis sampling and network pharmacology. AB - Gardeniae Fructus is a widely used Traditional Chinese Medicines in treating various diseases. However, the absorbed components and metabolites of its main bioactive iridoid ingredients from iridoid extract of the fruits of Gardeniae Fructus in rat plasma need further study. In this study, a systematic method based on ultra-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) technique was developed to speculate the absorbed components and metabolites of iridoid extract in rat plasma after oral administration. A total of 19 compounds, including 9 prototype components and 10 metabolites were identified in plasma. 5 metabolites containing 4 new metabolites (M1, M2, M7, M10) were tentatively determined in rat plasma. Besides, Microdialysis-intensity-fading mass spectrometry (MD-IF-MS) method was originally employed to reveal the binding affinities with alpha-glucosidase for in-vivo prototype components and their metabolites. Finally, the absorbed constituents and the corresponding target proteins were used to generate compound-target network to find the related diseases and action pathways by a network pharmacology method. The results provide useful information for further study of pharmacology and in vivo mechanism of action of iridoid extract from the fruits of Gardeniae Fructus. PMID- 29406031 TI - Supercritical fluid extraction (SFE) of ketamine metabolites from dried urine and on-line quantification by supercritical fluid chromatography and single mass detection (on-line SFE-SFC-MS). AB - On-line solid-phase supercritical fluid extraction (SFE) and chromatography (SFC) coupled to mass spectrometry (MS) has been evaluated for its usefulness with respect to metabolic profiling and pharmacological investigations of ketamine in humans. The aim of this study was to develop and validate a rapid, highly selective and sensitive SFE-SFC-MS method for the quantification of ketamine and its metabolites in miniature amounts in human urine excluding liquid-liquid extraction (LLE). Several conditions were optimized systematically following the requirements of the European Medicines Agency: selectivity, carry-over, calibration curve parameters (LLOQ, range and linearity), within- and between-run accuracy and precision, dilution integrity, matrix effect, and stability. The method, which required a relatively small volume of human urine (20 MUL per sample), was validated for pharmacologically and toxicologically relevant concentrations ranging from 25.0 to 1000 ng/mL (r2 > 0.995). The lower limit of quantification (LLOQ) for all compounds was found to be as low as 0.5 ng. In addition, stability of analytes during removal of water from the urine samples using different conditions (filter paper or ISOLUTE(r) HM-N) was studied. In conclusion, the method developed in this study can be successfully applied to studies of ketamine metabolites in humans, and may pave the way for routine application of on-line SFE-SFC-MS in clinical investigations. PMID- 29406032 TI - Direct detection of glucuronide metabolites of lidocaine in sheep urine. AB - The anaesthetic lidocaine is metabolised quickly to produce a series of metabolites, including several hydroxylated metabolites, which are further metabolised by addition of a glucuronic acid moiety. Analysis of these glucuronide metabolites in urine is performed indirectly by cleaving the glucuronic acid group using beta-glucuronidase. However, direct analysis of intact glucuronide conjugates is a more straightforward approach as it negates the need for long hydrolysis incubations, and minimises the oxidation of sensitive hydrolysis products, while also distinguishing between the two forms of hydroxylated metabolites. A method was developed to identify three intact glucuronides of lidocaine in sheep urine using LC-MS/MS, which was further confirmed by the synthesis of glucuronide derivatives of 3OH-MEGX and 4OH-LIDO. Direct analysis of urine allowed the detection of the glucuronide metabolites of hydroxylidocaine (OH-LIDO), hydroxyl-monoethylglycinexylidide (OH-MEGX), and hydroxy-2,6-xylidine (OH-XYL). Analysis of urine before and after beta glucuronidase digestion showed that the efficiency of hydrolysis of these glucuronide metabolites may be underestimated in some studies. Analysis of urine in the current study from three different sheep with similar glucuronide metabolite concentrations resulted in different hydrolysis efficiencies, which may have been a result of different levels of substrate binding by matrix components, preventing enzyme cleavage. The use of direct analysis of intact glucuronides has the benefit of being less influenced by these matrix effects, while also allowing analysis of unstable metabolites like 4OH-XYL, which rapidly oxidises after hydrolysis. Additionally, direct analysis is less expensive and less time consuming, while providing more information about the status of hydroxylated metabolites in urine. PMID- 29406033 TI - Determination and long-term stability of twenty-nine cathinones and amphetamine type stimulants (ATS) in urine using gas chromatography-mass spectrometry. AB - A method was developed for the screening and quantification of seven amphetamine type stimulants (ATS) and 22 cathinones, including three metabolites, in urine with Gas Chromatography-Mass Spectrometry. This method allowed the detection and quantification of ATS and cathinones group molecules using one procedure. A study of the stability of the drug mixtures for a period of 201 days in human urine samples under three different conditions has been carried. The ATS and cathinones include amphetamine, methamphetamine, MDA, MDEA, MDMA, PMA, PMMA, cathinone, methcathinone, 3'-position-substituted, ring-substituted, methylenedioxy substituted, N-alkyl-substituted and pyrrolidinyl-substituted. Twenty drugs out of twenty-nine were validated with a quantitative method. This method can be applied to the nine remaining drugs as a screening method. The linearity of the assay was from 50 to 2000 ng/ml, with limits of detection of 0.5 to 10 ng/ml. In terms of accuracy, between-run and within-run precision were <=20% for 20 compounds with good selectivity. No carryover was seen, and the recovery was between 80 and 120% for most drugs tested. ATS and pyrrolidinyl-substituted groups were conducted to be stable compounds under all conditions. All compounds tested were stable at -20 degrees C. Some cathinones were primarily degraded after 21 days at 4 degrees C. They were detectable but unstable after 201 days at 4 degrees C. Most cathinones were unstable after a day and completely lost after 28 days at RT. PMID- 29406034 TI - A Message from the Editor - January 2018. PMID- 29406036 TI - Infection-Related Mortality in Patients With Cirrhosis. PMID- 29406035 TI - Genetic Predisposition and Effect of Race in Achalasia. PMID- 29406037 TI - Research Ethics in Behavioral Interventions Among Special Populations: Lessons From the Peer Approaches to Lupus Self-Management Study. AB - BACKGROUND: Research involving a homogenous cohort of participants belonging to a special population must make considerations to recruit and protect the subjects. This study analyses the ethical considerations made in the peer approaches to lupus self-management project which pilot tested a peer mentoring intervention for African American women with systemic lupus erythematosus. METHODS: Considerations made at the outset of the project are described and their justifications and reasoning are given. Through analysis of feedback from a postintervention focus group and mentors' logs, implications on program outcomes and participant satisfaction are discussed. RESULTS: Feedback indicated the importance of recruiting and training capable mentors, consistent contact from study staff to avert adverse events and avert fear or mistrust and careful consideration that must go into the pairing of mentors and mentees. Participant feedback also indicated that sensitive topics must be addressed carefully to prevent distress and dissatisfaction. CONCLUSIONS: Applying the lessons learned from this work as well as the considerations that proved successful may improve the contextualization and ethical conduct of behavioral interventions in special populations resulting in improved tailoring and acceptability toward historically underserved individuals. PMID- 29406038 TI - Cardiac Sarcoidosis: A Review of Contemporary Challenges in Diagnosis and Treatment. AB - Sarcoidosis is a systemic disease characterized by noncaseating granulomas and is often a diagnosis of exclusion. The actual prevalence of cardiac sarcoidosis (CS) is unknown, as studies have demonstrated mixed data. CS may be asymptomatic and is likely more frequently encountered than previously thought. Sudden death may often be the presenting feature of CS. Most deaths attributed to CS are caused by arrhythmias or conduction system disease, and congestive heart failure may occur. Current expert consensus on diagnosis of CS continues to rely on endomyocardial biopsy, in the absence of which, histologic proof of extracardiac sarcoid involvement is necessitated. Emergence of newer noninvasive imaging modalities such as cardiac magnetic resonance imaging and positron emission tomography, have become increasingly popular tools utilized in patients with both clinical and asymptomatic CS, and have demonstrated good diagnostic capability. The main therapeutic approaches in patients with CS can be broadly divided into the following 2 categories: pharmacological management and invasive or device oriented. However, much remains unknown about the optimal screening protocols of asymptomatic patients with extracardiac sarcoidosis and treatment of biopsy proven CS. Our knowledge about CS has amplified significantly over the last 30 years and the growing realization that this process is often asymptomatic is paving the way for better screening protocols and earlier detection of this serious condition. PMID- 29406039 TI - The Effect of Race in Patients with Achalasia Diagnosed With High-Resolution Esophageal Manometry. AB - BACKGROUND: The advent of the Chicago Classification for esophageal motility disorders allowed for clinically reproducible subgrouping of patients with achalasia based on manometric phenotype. However, there are limited data with regards to racial variation using high-resolution esophageal manometry (HREM). The aim of our study was to evaluate the racial differences in patients with achalasia diagnosed with HREM using the Chicago Classification. We evaluated the clinical presentation, treatment decisions and outcomes between blacks and non blacks with achalasia to identify potential racial disparities. MATERIALS AND METHODS: We performed a retrospective review of consecutive patients referred for HREM at a single tertiary referral center from June 2008 through October 2012. All patients diagnosed with achalasia on HREM according to the Chicago Classification were included. Demographic, clinical and manometric data were abstracted. All studies interpreted before the Chicago Classification was in widespread use were reanalyzed. Race was defined as black or non-black. Patients who had missing data were excluded. Proportions were compared using chi-squared analysis and means were compared using the Student's t-test. RESULTS: A total of 1,268 patients underwent HREM during the study period, and 105 (8.3%) were manometrically diagnosed with achalasia (53% female, mean age: 53.8 +/- 17.0 years) and also met the aforementioned inclusion and exclusion criteria. A higher percentage of women presented with achalasia in blacks as compared to whites or other races (P < 0.001). Non-blacks were more likely to present with reflux than blacks (P = 0.01), while blacks were more likely to be treated on the inpatient service than non-blacks (P < 0.001). There were no other significant differences noted in clinical presentation, treatment decisions and treatment outcomes among blacks and non-blacks. CONCLUSIONS: Our study highlights possible racial differences between blacks and non-blacks, including a higher proportion of black women diagnosed with achalasia and most blacks presenting with dysphagia. There is possibly a meaningful interaction of race and sex in the development of achalasia that might represent genetic differences in its pathophysiology. Further prospective studies are required to identify such differences. PMID- 29406040 TI - Community- or Healthcare-Associated Bacterial Infections Increase Long-Term Mortality in Patients With Acute Decompensation of Cirrhosis. AB - BACKGROUND: The aim of the present study was to determine the specific role of different types of bacterial infections (BIs) on the prognosis of cirrhotic patients with acute decompensation (AD). METHODS: We performed a prospective, observational cohort study consisting of 492 cirrhotic patients with AD at our center from February 2014 to March 2015. Clinical, laboratory and survival data were collected. The relationship between BIs and mortality was analyzed. RESULTS: BIs were identified in 157 of 492 patients at the time of admission or during the hospital stay. Among the patients, 65 had community-acquired (CA) or healthcare associated (HCA) BIs, 54 developed hospital-acquired (HA) BIs, and 38 had CA/HCA with HA BIs. Patients with CA/HCA BIs had higher 90-day, 1-year and 2-year mortality rates (29.2%, 44.6% and 52.3%, respectively) and CA/HCA BIs remained an independent risk factor for long-term mortality on multivariate analysis (1 year: hazard ratio = 1.60; 95% CI: 1.07-2.41; P = 0.023 and 2 year: hazard ratio = 1.54; 95% CI: 1.05-2.25; P = 0.026). In contrast, patients with HA BIs had a higher 28-day mortality rate than patients with CA/HCA BIs. Logistic regression analysis showed previous ascites and prior BIs within 3 months were independent risk factors for CA/HCA BIs, whereas invasive minor surgical procedures with acute-on-chronic liver failure throughout the hospital stay and high chronic liver failure-sequential organ failure assessment scores were associated with nosocomial BIs. CONCLUSIONS: CA/HCA BIs were associated with increased long-term mortality in cirrhotic patients with AD, whereas nosocomial BIs may be related to poor short-term prognosis. PMID- 29406041 TI - Geographic and Individual Correlates of Subclinical Atherosclerosis in an Asymptomatic Rural Appalachian Population. AB - BACKGROUND: This study aimed to examine the association between subclinical atherosclerosis (ascertained as coronary artery calcium [CAC]) in asymptomatic individuals in the Central Appalachian region of the United States and individual and geographic-level factors. MATERIALS AND METHODS: Data were obtained from participants in CAC screening between 2012 and 2016. CAC score was assessed as CAC = 0 (no plaque), 1 <= CAC <= 99 (mild plaque), 100 <= CAC <= 399 (moderate plaque) and CAC >= 400 (severe plaque). Additionally, data on demographics (age, sex and race), medical conditions, lifestyle factors and family history of coronary artery disease were obtained. Further, zip codes of place of residence for participants were used to generate geographic-level data. Descriptive statistics were used to estimate the prevalence of CAC, and multinomial logistic regression models were used to delineate significant factors. RESULTS: Of 1,512 participants, 57.6% had CAC > 0. The prevalence of mild, moderate and severe plaques was 31.6%, 16.3% and 9.7%, respectively. Demographics (age and sex), medical conditions, lifestyle factors and family history of coronary artery disease were associated with increased risk for subclinical atherosclerosis. Further, the proportion of minority residents significantly increased the risk for severe plaque (relative risk ratio = 1.06, P = 0.04) and the proportion of residents on government assistance significantly decreased the risk for mild plaque (relative risk ratio = 0.93, P = 0.03). CONCLUSIONS: The results imply that the proportion of minority residents in a geographic area is associated with increased relative risk for subclinical atherosclerosis, while the proportion of residents on government assistance decreased such risk. However, future geographic or neighborhood-level studies with a larger sample size are needed to delineate further the consistency of these results in the Central Appalachian population. PMID- 29406042 TI - First Trimester Neck Circumference as a Predictor for the Development of Gestational Diabetes Mellitus. AB - BACKGROUNDS: This study aimed to evaluate the relationship between neck circumference (NC) and gestational diabetes mellitus (GDM), and the efficacy of NC in predicting GDM by comparing with pregestational body mass index (preBMI) in southern Chinese woman. MARERIALS AND METHODS: A total of 371 pregnant women (97 GDM and 274 normal pregnant women) were recruited from the third affiliated hospital of Sun Yat-Sen University, Guangzhou, China. NC was measured at 11-13+6 gestational weeks. GDM was diagnosed through a 75-g oral glucose tolerance test at 24-28 gestational weeks. Using the receiver-operator characteristic (ROC) curve analysis, we evaluated the association between NC and GDM. RESULTS: The area under the receiver operator characteristic curves were 0.65 (95% CI: 0.60 0.70) for NC and 0.64 (95% CI: 0.59-0.69) for preBMI in diagnosing GDM and no difference was found between them (P = 0.66). NC >= 33.8cm was determined to be the best cut-off level for identifying subjects with GDM (sensitivity 68.04% and specificity 59.12%). Multivariate logistic regression analysis showed that a large NC in the first trimester was an independent risk factor for the development of GDM (odds ratio [OR] = 1.29, 95% CI: 1.72-7.45). CONCLUSIONS: NC, as well as preBMI, might be a novel anthropometric index for GDM screening. The increase of NC could be an independent risk factor for GDM in first trimester pregnancy. PMID- 29406043 TI - Fibromyalgia and Risk of Dementia-A Nationwide, Population-Based, Cohort Study. AB - BACKGROUND: Fibromyalgia is a syndrome of chronic pain and other symptoms and is associated with patient discomfort and other diseases. This nationwide matched cohort population-based study aimed to investigate the association between fibromyalgia and the risk of developing dementia, and to clarify the association between fibromyalgia and dementia. MATERIALS AND METHODS: A total of 41,612 patients of age >=50 years with newly diagnosed fibromyalgia between January 1, and December 31, 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 124,836 controls matched for sex and age. After adjusting for any confounding factors, Fine and Gray competing risk analysis was used to compare the risk of developing dementia during the 10 years of follow-up. RESULTS: Of the study subjects, 1,704 from 41,612 fibromyalgia patients (21.23 per 1,000 person-years) developed dementia when compared to 4,419 from 124,836 controls (18.94 per 1,000 person-years). Fine and Gray competing risk analysis revealed that the study subjects were more likely to develop dementia (hazard ratio: 2.29, 95% CI: 2.16-2.42; P < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region of residence and comorbidities the hazard ratio was 2.77 (95% CI: 2.61-2.95, P < 0.001). Fibromyalgia was associated with increased risk of all types of dementia in this study. CONCLUSIONS: The study subjects with fibromyalgia had a 2.77-fold risk of dementia in comparison to the control group. Therefore, further studies are needed to elucidate the underlying mechanisms of the association between fibromyalgia and the risk of dementia. PMID- 29406044 TI - Reciprocal ST-Segment Changes in Myocardial Infarction: Ischemia at Distance Versus Mirror Reflection of ST-Elevation. AB - BACKGROUND: Reciprocal ST-depression in the electrocardiograms (ECGs) of patients with ST-elevation myocardial infarction (STEMI) results from either true ischemia at a distance via collateral circulation diverting blood to the infarcted region or an electrical phenomenon that results from a mirror reflection of ST elevation. We aimed to identify the role of reciprocal ECG changes in predicting collateral circulation to the infarcted area determined angiographically. METHODS: In a retrospective study, ECG and angiography of 53 STEMI patients admitted to SUNY Upstate Medical University in 2014 were reviewed independently by experts blinded to the results of ECG and coronary angiography. RESULTS: Reciprocal changes (RC) in ECG were present in 41 patients (77%) and on angiography, 14 patients (26%) exhibited collateral vessels to the ischemic areas. No correlation was found between the presence of RC and collateral circulation (P = 0.384), or between the depth of reciprocal ST-depression and the degree of the collateral circulation (P = 0.195). However, 84% of patients without collaterals exhibited resolution of RC after successful percutaneous coronary intervention (PCI) (P = 0.036), suggesting that the ST depressions that resolved after reperfusion were directly caused by the culprit vessel. Patients without RC presented late after symptom onset (9.25 versus 3.83 hours, P = 0.004), also suggesting time related resolution. CONCLUSIONS: RC had no relation to or predictive value for collaterals on angiography. Among late presenting patients, RC were less frequent. Thus, reciprocal ST-depression may represent subendocardial ischemia from the primary coronary event or simply an electrical phenomenon, rather than ischemia at distance from impaired collateral circulation. PMID- 29406045 TI - Comparing Changes in Carotid Flow Time and Stroke Volume Induced by Passive Leg Raising. AB - BACKGROUND: Determining volume responsiveness in critically ill patients is challenging. We sought to determine if passive leg raise (PLR) induced changes in pulsed wave Doppler of the carotid artery flow time could predict fluid responsiveness in critically ill patients. MATERIALS AND METHODS: Medical intensive care unit patients >=18 years old with a radial arterial line and FloTrac/Vigileo monitor in place were enrolled. Pulsed wave Doppler of the carotid artery was performed to measure the change in carotid flow time (CFTC) in response to a PLR. Patients were categorized as fluid responders if stroke volume increased by >=15% on a Vigileo monitor. The main outcome measure was the accuracy of CFTC to detect a change in response to a PLR. We also calculated the percentage increase in CFTC that could predict fluid responsiveness. RESULTS: We enrolled 22 patients. Using an increase of >=24.6% in the CFTC in response to PLR to predict fluid responsiveness there was a sensitivity of 60%, specificity of 92%, positive likelihood ratio of 7.2, negative likelihood ratio of 0.4, positive predictive value of 86%, negative predictive value of 73% and receiver operating characteristic of 0.75 (95% CI: 0.54-0.96). CONCLUSIONS: CFTC performs well compared to stroke volume measurements on a Vigileo monitor. The use of CFTC is highlighted in resource-limited environments and when time limits the use of other methods. CFTc should be validated in a larger study with more operators against a variety of hemodynamic monitors. PMID- 29406046 TI - Effect of Chronic Total Occlusion Percutaneous Coronary Intervention on Clinical Outcomes in Elderly Patients. AB - BACKGROUND: There are little published data reporting the effect of coronary artery chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on the prognosis of elderly patients with identified CTOs. We sought to evaluate the clinical effect of CTO PCI on the prognosis of elderly patients with CTOs. METHODS: A total of 445 consecutive patients diagnosed with a CTO by angiography from January 2011 to December 2013 were enrolled. We compared long-term clinical outcomes between the elderly group (>=75 years; n = 120, 27.0%), and the nonelderly group (<75 years; n = 325, 73.0%) as well as between patients with unopened CTOs and patients with CTOs who were recanalized by PCI either during the index hospitalization or at a staged procedure within 30 days after discharge from the index hospitalization. The primary endpoint was defined as the composite of hospitalization from angina, reinfarction, heart failure or repeat revascularization and cardiac death at the 3-year follow-up. RESULTS: More elderly CTO patients had left main (LM) disease (25.0 versus 15.1%, P = 0.015), 3 vessel disease (96.4% versus 73.8%, P < 0.001) and a Japan-CTO score >=2 (36.7% versus 23.7%, P = 0.006) than nonelderly CTO patients. Furthermore, elderly patients had a higher syntax score than nonelderly patients (27.0 [25.0, 30.0] versus 26.0 [23.0, 30.0], P = 0.006). PCI was attempted for 33 out of 135 CTO lesions (24.4%) in the elderly group, and 127 out of 378 lesions (33.6%) in the nonelderly group (P = 0.049); however, there were no statistically significant differences in the CTO PCI success rates between the 2 groups (69.7% versus 82.7%, P = 0.097). The 3-year cardiac mortality rate was 15.0% and 4.6% (P < 0.011) for the elderly and nonelderly groups, respectively. Elderly patients with CTOs who were recanalized by PCI and those with unopened CTOs exhibited comparable 3-year cardiac mortality rates (15.0% versus 16.0%, P = 1.000). There was no significant difference in primary endpoint incidence (25.0% versus 33.0%, P = 0.486). Multivariate analysis revealed that after corrections for baseline and procedural differences, right coronary artery CTO (odds ratio = 4.600, 95% CI: 1.320-16.031; P = 0.017) and LM disease combined with 3-vessel disease (odds ratio = 4.296, 95% CI: 1.166-15.831; P = 0.028) were independent predictors of 3 year cardiac mortality among elderly patients with CTOs. CONCLUSIONS: Elderly patients with CTOs presented with seriously diseased coronary arteries and poor prognoses. CTO PCI did not seem to significantly improve long-term clinical outcomes among elderly patients with CTOs. Right coronary artery CTO and LM disease combined with 3-vessel disease might be independent predictors of 3-year cardiac mortality in elderly CTO patients. PMID- 29406047 TI - Iron Enhances Hepatic Fibrogenesis and Activates Transforming Growth Factor-beta Signaling in Murine Hepatic Stellate Cells. AB - BACKGROUND: Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC). MATERIALS AND METHODS: We evaluated the effects of excess iron on fibrogenesis and transforming growth factor beta (TGF-beta) signaling in murine HSC. Cells were treated with holotransferrin (0.005-5g/L) for 24 hours, with or without the iron chelator deferoxamine (10uM). Gene expressions (alpha-SMA, Col1-alpha1, Serpine 1, TGF-beta, Hif1-alpha, Tfrc and Slc40a1) were analyzed by quantitative real time-polymerase chain reaction, whereas TfR1, ferroportin, ferritin, vimentin, collagen, TGF-beta RII and phospho-Smad2 proteins were evaluated by immunofluorescence, Western blot and enzyme-linked immunosorbent assay. RESULTS: HSC expressed the iron-uptake protein transferrin receptor 1 (TfR1) and the iron export protein ferroportin. Holotransferrin upregulated TfR1 expression by 1.8 fold (P < 0.03) and ferritin accumulation (iron storage) by 2-fold (P < 0.01), and activated HSC with 2-fold elevations (P < 0.03) in alpha-SMA messenger RNA and collagen secretion, and a 1.6-fold increase (P < 0.01) in vimentin protein. Moreover, holotransferrin activated the TGF-beta pathway with TGF-beta messenger RNA elevated 1.6-fold (P = 0.05), and protein levels of TGF-beta RII and phospho Smad2 increased by 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01), respectively. In contrast, iron chelation decreased ferritin levels by 30% (P < 0.03), inhibited collagen secretion by 60% (P < 0.01), repressed fibrogenic genes alpha-SMA (0.2 fold; P < 0.05) and TGF-beta (0.4-fold; P < 0.01) and reduced levels of TGF-beta RII and phospho-Smad2 proteins. CONCLUSIONS: HSC express iron-transport proteins. Holotransferrin (iron) activates HSC fibrogenesis and the TGF-beta pathway, whereas iron depletion by chelation reverses this, suggesting that this could be a useful adjunct therapy for patients with fibrosis. Further studies in primary human HSC and animal models are necessary to confirm this. PMID- 29406048 TI - Paraganglioma of the Urinary Bladder: A Rare Cause of Hypertension and Urinary Tract Infections. AB - Pheochromocytoma is a neoplasm, which develops from cells of the chromaffin tissues that are derived from the ectodermic neural system and mostly situated within the adrenal medulla. Approximately 15% of pheochromocytoma cases arise from extra-adrenal chromaffin tissue. Pheochromocytoma of the bladder is rare and accounts for less than 0.06% of all bladder neoplasms and less than 1% of all pheochromocytomas. We report a case of a young woman who presented with uncontrolled hypertension, recurrent urinary tract infections and micturition attacks and was found to have a metastatic bladder paraganglioma. In addition, we provide a summary table of the clinical manifestations of paragangliomas based on anatomic locations. PMID- 29406049 TI - Hypocomplementemic Urticarial Vasculitis Syndrome With Crescentic Glomerulonephritis. AB - Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease characterized by multiple organ system involvement, including renal disease, with low complement levels. We report the case of a 31-year-old woman who presented with nonspecific symptoms including fatigue, diarrhea, macular rash and abdominal pain with acute renal failure leading to end-stage kidney disease. Laboratory results showed hematuria, nephrotic range proteinuria, worsening creatinine and low C1q levels. Left kidney biopsy showed proliferative glomerulonephritis with crescent formation. She was treated with 6 months of intravenous cyclophosphamide, followed by 2 doses of intravenous rituximab (1g each), thereafter maintained on mycophenolate mofetil and glucocorticoid-based therapy. She experienced a full recovery of renal function after 12 months of dialysis dependence. Hypocomplementemic urticarial vasculitis syndrome with crescentic glomerulonephritis is a rare disease with only 5 other reported cases in literature. In our case, we document a delayed but excellent renal recovery during a 2-year follow-up. PMID- 29406050 TI - Lymphocyte-Variant Hypereosinophilic Syndrome With Eosinophilic Myocarditis Treated With Steroids and Pegylated Interferon Alfa-2a. PMID- 29406051 TI - Trichuriasis. PMID- 29406052 TI - Aortic Intramural Hemorrhage Secondary to Penetrating Atherosclerotic Ulcers. PMID- 29406054 TI - Prostate Cancer: A Contemporary Approach to Treatment and Outcomes. AB - Given the high incidence of prostate cancer and the need for shared decision making before screening, it is imperative that primary care providers understand treatment options and treatment adverse effects. In this review article, the treatment options for the localized and metastatic prostate cancer are discussed, including the different modalities and their indications, adverse effects, oncologic outcomes, posttreatment monitoring, and potential treatment options following cancer recurrence. PMID- 29406055 TI - Kidney, Ureteral, and Bladder Cancer: A Primer for the Internist. AB - Malignancies of the urinary tract (kidney, ureter, and bladder) are distinct clinical entities. Hematuria is a unifying common presenting symptom for these malignancies. Surgical management of localized disease continues to be the mainstay of treatment, and early detection is important in the prognosis of disease. Patients often require life-long follow-up and assessment for recurrence. PMID- 29406053 TI - Prostate Cancer Screening. AB - During the prostate-specific antigen-based prostate cancer (PCa) screening era there has been a 53% decrease in the US PCa mortality rate. Concerns about overdiagnosis and overtreatment combined with misinterpretation of clinical trial data led to a recommendation against PCa screening, resulting in a subsequent reversion to more high-risk disease at diagnosis. Re-evaluation of trial data and increasing acceptance of active surveillance led to a new draft recommendation for shared decision making for men aged 55 to 69 years old. Further consideration is needed for more intensive screening in men with high-risk factors. PCa screening significantly reduces PCa morbidity and mortality. PMID- 29406056 TI - Testicular Cancer: Epidemiology, Diagnosis, and Management. AB - There were an estimated 8720 new cases of testicular cancer (TC) in the United States in 2016. The cause of the disease is complex, with several environmental and genetic risk factors. Although rare, the incidence has been steadily increasing. Fortunately, substantial advances in treatment have occurred over the last few decades, making TC one of the most curable malignancies. However, because TC typically occurs in younger men, considerations of the treatment impact on fertility, quality of life, and long-term toxicity are paramount; an individualized approach must be taken with patients based on their clinical and pathologic findings. PMID- 29406057 TI - Urinary Stone Disease: Diagnosis, Medical Therapy, and Surgical Management. AB - Clinical suspicion of urolithiasis should be evaluated with low-dose computed tomography as the first-line imaging modality for nonpregnant, adult patients. A period of observation may be appropriate for ureteral stones less than 10 mm, and medical expulsive therapy may be beneficial for facilitating passage of distal ureteral stones. Regardless of stone type, patients should adhere to a low-sodium diet and attempt to achieve a urine volume of more than 2.5 L daily. Individuals with calcium stones should maintain a normal calcium diet, and if stones persist, citrate therapy or thiazide diuretics in the setting of hypercalciuria may be indicated. PMID- 29406058 TI - Cutaneous Lesions of the External Genitalia. AB - Individuals with cutaneous diseases of the external genitalia often initially present to their primary care provider. When present, these conditions may be associated with considerable physical symptoms and psychological distress. Dermatoses affecting the genitals may be of infectious, inflammatory, or neoplastic cause, and can be processes confined to the genitalia or a manifestation of a more widespread dermatologic condition. This article provides a guide to recognizing and managing common genital dermatoses and when to refer for specialist opinion. PMID- 29406059 TI - Lower Urinary Tract Symptoms, Benign Prostatic Hyperplasia, and Urinary Retention. AB - Lower urinary tract symptoms (LUTS) consist of a common set of urologic symptoms that can affect the elderly. The prevalence of LUTS is expected to rise owing to the continued increase of numbers of the elderly. Although benign prostatic hyperplasia is considered a common cause of LUTS, the broader potential causes of LUTS are myriad. A wide range of diagnostic modalities and treatments are available to manage patients with LUTS and their utilization should not be limited to the urologist. PMID- 29406060 TI - Female Voiding Dysfunction and Urinary Incontinence. AB - Female voiding dysfunction and incontinence are common in the general population and symptoms have been shown to have a significant negative impact on health related quality of life. This article highlights the epidemiology, evaluation, diagnosis, pharmacologic therapies, and surgical treatment for overactive bladder, stress urinary incontinence, and urogenital fistulas. PMID- 29406061 TI - Penile and Urethral Reconstructive Surgery. AB - Penile and urethral reconstructive surgical procedures are used to treat a variety of urologic diagnoses. Urethral stricture disease can lead to progressive lower urinary tract symptoms and may require multiple surgical procedures to improve patient's symptoms. Male stress urinary incontinence is associated with intrinsic sphincter deficiency oftentimes associated with radical prostatectomy. Men suffering from urethral stricture disease and stress urinary incontinence should be referred to a urologist because multiple treatment options exist to improve their quality of life. PMID- 29406062 TI - Male Infertility Diagnosis and Treatment in the Era of In Vitro Fertilization and Intracytoplasmic Sperm Injection. AB - As assisted reproductive technologies use increases, the evaluation of male factor infertility has often become overlooked. However, male evaluation remains critically important, with benefits seen in overall health, as well as in natural and assisted pregnancy and birth rates. A comprehensive assessment of the male partner should be offered to all couples seeking infertility care. PMID- 29406063 TI - Sexual Dysfunction: Behavioral, Medical, and Surgical Treatment. AB - Sexual dysfunction affects both men and women and is responsible for 1 in 5 visits to urologist and/or gynecologists. It is important that treating providers use a logical and methodical approach to the diagnosis and treatment of this disorder. Behavioral therapy, coupled with oral medications, are very successful in treating erectile dysfunction. Complex and invasive therapies are used for more severe cases of sexual dysfunction and are best deployed by specialists. PMID- 29406064 TI - Hypogonadism: Therapeutic Risks, Benefits, and Outcomes. AB - Hypogonadism is a common condition defined by the presence of low serum testosterone levels and hypogonadal symptoms, and most commonly treated using testosterone therapy (TTh). The accuracy of diagnosis and appropriateness of treatment, along with proper follow-up, are increasingly important given the large increase in testosterone prescriptions and the recent concern for cardiovascular (CV) risk associated with TTh. In March of 2015, the US Food and Drug Administration required that testosterone product labels disclose a potential CV risk, despite the evidence base for this association being weak and inconclusive. However, TTh may improve CV outcomes rather than increase risks. PMID- 29406065 TI - Urologic Emergencies. AB - Urologic emergencies can involve the kidneys, ureters, bladder, urethra, penis, scrotum, or testicles. History and physical examination are essential to diagnosis, whereas imaging is increasingly used to confirm diagnoses. Acute urinary retention should be relieved with Foley placement. Penile emergencies include paraphimosis, which can be treated by foreskin reduction, whereas penile fracture and priapism require urologic intervention. Fournier gangrene and testicular torsion are scrotal emergencies requiring emergent surgery. Nephrolithiasis, although painful, is not an emergency unless there is concern for concomitant urinary tract infection, both ureters are obstructed by stones, or there is an obstructing stone in a solitary kidney. PMID- 29406066 TI - The Current State of Telemedicine in Urology. AB - Telemedicine use in urology is an evolving practice. In this article, the authors review the early experience of telemedicine specifically as it relates to urologic practice and discuss the future implications and the utility of telemedicine as it applies to other fields. PMID- 29406067 TI - The Intersection of Medicine and Urology: An Emerging Paradigm of Sexual Function, Cardiometabolic Risk, Bone Health, and Men's Health Centers. AB - Men's mental health and how they think about their health are critical to the future of men's health. Poor health choice patterns are established under age 50, when men are twice as likely to die than women. As the future of medicine focuses on quality and value, a better understanding of the social determinants of men's health will identify areas for improvement. The presentation of a man to a clinician's office with a sexual health complaint presents an opportunity for more complete evaluation. The future of men's health will be well served by integrated men's health centers that focus on the entire man. PMID- 29406068 TI - Urology. PMID- 29406073 TI - Go with the Flow. PMID- 29406074 TI - Urology and Medicine. PMID- 29406075 TI - Risk profile for Leishmania infection in dogs coming from an area of visceral leishmaniasis reemergence. AB - Until the 1980s, visceral leishmaniasis was concentrated in poor rural areas of Brazil. The Vale do Rio Doce, located in the Southeastern Brazilian state of Minas Gerais, was an endemic area with high numbers of human and canine cases. Prophylactic measures adopted since the 1960s reduced the number of cases and the region became a 'controlled endemic' area. In the early 1990s, however, the program was interrupted, and the human disease reemerged in 2008. This cross sectional study evaluated the prevalence and the risk profile of infection of dogs with Leishmania spp in this reemergence area of visceral leishmaniasis. Among a population of approximately 280,000 people, a total of 3835 dog owners were interviewed about socioeconomic conditions, housing, peridomicile features, and their dogs' characteristics and behavior. Blood samples were collected from 5822 dogs of an estimated canine population of 20,000 and anti-Leishmaniasis antibodies were identified using Dual-Path Platform and ELISA. We observed that 1282 of the 5822 dogs were seropositive for the protozoan indicating a seroprevalence of 22%. The risk factors associated with Leishmania infection in dogs were: non-paved backyard (OR 1.4; 95%CI 1.2-1.7); the presence of dry leaves and decaying fruit in the backyard (OR 1.3; 95%CI 1.1-1.5); medium-sized (OR 1.3; 95% 1.1-1.5) or big-sized dogs (OR 1.8; 95%CI 1.5-2.3); short-haired dogs (OR 1.8; 95%CI 1.5-2.1); dogs that slept in the backyard (OR 2.6; 95%CI 1.8-3.6) or in the balcony (OR 1.6; 95%CI 1.1-2.3); and history of canine visceral leishmaniasis in the household (OR 1.3; 95%CI 1.1-1.5). Our results suggest a strong reemergence of canine visceral leishmaniasis after the discontinuation of the control programs. Also, the observed risk factors reinforce the role of health education and environmental management measures to the effective control of the disease. PMID- 29406076 TI - An epidemiological investigation of the early phase of the porcine epidemic diarrhea (PED) outbreak in Canadian swine herds in 2014: A case-control study. AB - The first case of porcine epidemic diarrhea (PED) in Canada was diagnosed in January 2014 in Ontario, approximately 9 months after PED emerged in the United States. An early investigation of the Canadian outbreak suspected that the probable source of the virus was contaminated feed. The objective of this study was to evaluate the role of feed and other possible factors in the early phase of the PED outbreak in Canadian swine herds. The study period of interest for this case-control study was January 22nd to March 1st, 2014. A case herd was defined as a swine herd with a confirmed positive laboratory diagnostic test (RT-PCR) results for PED virus, along with pigs exhibiting typical clinical signs at the herd level during the study period. A questionnaire was administered to participating producers from the 22 Canadian swine herds enrolled (n = 9 case and n = 13 control herds). Case herd producers were asked to provide information from the initial day of onset of clinical signs and 30 days prior to that day. Control herds were matched to a case herd on the basis of province, herd type and approximate size. The period of interest for a control herd was matched to the initial day of clinical signs of PED for the case herd, along with the 30 days prior to this day. The questionnaire questions focused on herd demographics, biosecurity protocols, live animal movements onto and off sites, deadstock movements, feed and people movements for both the case and control herds. The questionnaire for control herds were based on their matched case's period of interest, and together with case herds formed a matched stratum. Multivariable exact conditional logistic regression and mixed multivariable logistic regression models, with the matched stratum as a random effect, were used to assess the association between various risk factors and the odds of PED introduction into a herd. After adjusting for biosecurity practices, the odds of a PED occurrence was 38.1 (95% CI: 2.7-531.3) times greater for herds receiving feed from a single feed company that provided potentially contaminated feed (P = 0.007) than herds that did not. The number of live pigs delivered onto sites, semen deliveries and the frequency of deadstock pickups were not associated with PED status during the initial phase of the outbreak in univariable analyses. This study supports the role of potentially contaminated feed from a single feed company as a significant risk factor for PED viral introduction during the early phase of the Canadian outbreak. PMID- 29406077 TI - Milking machine and udder health management factors associated with bulk milk somatic cell count in Uruguayan herds. AB - This paper describes the findings of static milking machine tests and milking observations on Uruguayan dairy farms. The aim of this study was to investigate the association between both milking machine performance and udder health management factors and bulk milk somatic cell count (BMSCC) in Uruguayan dairy herds. Data from 907 visits were used for the analysis. The farm visits were made between April 2006 and November 2015 and farms were located in 17 of the 19 departments of Uruguay. Each visit involved a short static machine test and observation of the milking process; the use of blanket dry cow therapy was also recorded. The BMSCC was the variable of interest. Univariable analysis was applied to explore the best set of predictors to be included in the multivariable model. A multivariable linear regression model was fitted. The median BMSCC over the years was 376 thousand cells/mL (interquartile range = 280,000-500,000 cells/mL). The final model showed a lower BMSCC for herds that used post-milking teat disinfection, applied the teat cups to dry teats and maintained the pulsation system in good working order. There was no significant association between BMSCC and blanket dry cow therapy in the final model. The association of these milking machine and udder health management factors with the BMSCC under Uruguayan conditions is relevant information for a dairy industry that needs low BMSCCs to compete on the world market. PMID- 29406078 TI - The reporting characteristics of bovine respiratory disease clinical intervention trials published prior to and following publication of the REFLECT statement. AB - The goal of the REFLECT Statement (Reporting guidElines For randomized controLled trials in livEstoCk and food safeTy) (published in 2010) was to provide the veterinary research community with reporting guidelines tailored for randomized controlled trials for livestock and food safety. Our objective was to determine the prevalence of REFLECT Statement reporting of items 1-19 in controlled trials published in journals between 1970 and 2017 examining the comparative efficacy of FDA-registered antimicrobials against naturally acquired BRD (bovine respiratory disease) in weaned beef calves in Canada or the USA, and to compare the prevalence of reporting before and after 2010, when REFLECT was published. We divided REFLECT Statement, items 3, 5, 10, and 11 into subitems, because each dealt with multiple elements requiring separate assessment. As a result, 28 different items or subitems were evaluated independently. We searched MEDLINE(r) and CABI (CAB Abstracts(r) and Global Health(r)) (Web of ScienceTM) in April 2017 and screened 2327 references. Two reviewers independently assessed the reporting of each item and subitem. Ninety-five references were eligible for the study. The reporting of the REFLECT items showed a point estimate for the prevalence ratio >1 (i.e. a higher proportion of studies published post-2010 reported this item compared to studies published pre-2010), apart from items 10.3, i.e., item 10, subitem 3 (who assigned study units to the interventions), 13 (the flow of study units through the study), 16 (number of study units in analysis), 18 (multiplicity), and 19 (adverse effects). Fifty-three (79%) of 67 studies published before 2010 and all 28 (100%) papers published after 2010 reported using a random allocation method in either the title, abstract, or methods (Prevalence ratio = 1.25; 95% CI (1.09,1.43)). However, 8 studies published prior to 2010 and 7 studies published post-2010 reported the term "systematic randomization" or variations of this term (which is not true randomization) to describe the allocation procedure. Fifty-five percent (37/67) of studies published pre-2010 reported blinding status (blinded/not blinded) of outcome assessors, compared to 24/28 (86%) of studies published post-2010 (Prevalence ratio = 1.5, 95% CI (1.19, 2.02)). The reporting of recommended items in journal articles in this body of work is generally improving; however, there is also evidence of confusion about what constitutes a random allocation procedure, and this suggests an educational need. As this study is observational, this precludes concluding that the publication of the REFLECT Statement was the cause of this trend. PMID- 29406079 TI - Bovine herpesvirus-1 in three major milk sheds of Ethiopia: Serostatus and association with reproductive disorders in dairy cattle. AB - Bovine herpesvirus-1 (BHV-1) causes infectious bovine rhinotracheitis (IBR), and infectious pustular vulvovaginitis (IPV) in cows and infectious pustular balanopostitis (IPB) in bulls worldwide. Infection of seronegative cattle with BHV-1 leads to abortion, retention of fetal membranes, increased service per conception, metritis and oophoritis. As part of an ongoing study on infectious causes of reproductive disorders in Ethiopia, this investigation aims at assessing the role of BHV-1 in the disorders and the risk factors affecting its seroprevalence. A cross-sectional study was conducted on a total of 1379 randomly selected dairy cattle from 149 herds. These dairy cattle were sampled from milks sheds of central (n = 555), western (n = 195) and southern (n = 629) Ethiopia. Blocking enzyme-linked immunosorbent assay (B-ELISA) was applied to detect antibodies specific to BHV-1. Additionally, a semi-structured questionnaire was administered and farm records were assessed to capture potential risk factors associated with BHV-1 seropositivity. Univariable and multivariable random effects logistic regression analyses were used to assess potential risk factors associated with BHV-1 serostatus. Model fitness and reliability were assessed using the Hosmer and Lemeshow method and the receiver operating curve (ROC) respectively. An overall herd level BHV-1 seroprevalence of 81.8% (95% confidence interval (CI): 74.7-87.7%) and individual animal level seroprevalence of 41.0% (95% CI: 38.4-43.7%) were found. In a random-effects multivariable logistic regression model, the seroprevalence of BHV-1 exposure was higher in dairy cattle from breeding (Odds ratio [OR] = 1.3; p = 0.036) than in commercial (OR = 0.9; p = 0.137) and small-holder farms. Geographically, the prevalence was higher in western (OR = 1.4; p < 0.001) and southern Ethiopia (OR = 1.2; p < 0.001) than in central regions. BHV-1 seropositive cows had higher (p < 0.05) odds of clinical reproductive disorders including abortion, retained fetal membranes, stillbirth, birth of weak calf and metritis compared to seronegative cows. Thus, it is suggested that BHV-1 should be considered as differential diagnosis among improved dairy cattle herds with reproductive disorders in Ethiopia. PMID- 29406080 TI - Impact of subclinical mastitis on greenhouse gas emissions intensity and profitability of dairy cows in Norway. AB - Impaired animal health causes both productivity and profitability losses on dairy farms, resulting in inefficient use of inputs and increase in greenhouse gas (GHG) emissions produced per unit of product (i.e. emissions intensity). Here, we used subclinical mastitis as an exemplar to benchmark alternative scenarios against an economic optimum and adjusted herd structure to estimate the GHG emissions intensity associated with varying levels of disease. Five levels of somatic cell count (SCC) classes were considered namely 50,000 (i.e. SCC50), 200,000, 400,000, 600,000 and 800,000cells/mL (milliliter) of milk. The effects of varying levels of SCC on milk yield reduction and consequential milk price penalties were used in a dynamic programming (DP) model that maximizes the profit per cow, represented as expected net present value, by choosing optimal animal replacement rates. The GHG emissions intensities associated with different levels of SCC were then computed using a farm-scale model (HolosNor). The total culling rates of both primiparous (PP) and multiparous (MP) cows for the five levels of SCC scenarios estimated by the model varied from a minimum of 30.9% to a maximum of 43.7%. The expected profit was the highest for cows with SCC200 due to declining margin over feed, which influenced the DP model to cull and replace more animals and generate higher profit under this scenario compared to SCC50. The GHG emission intensities for the PP and MP cows with SCC50 were 1.01kg (kilogram) and 0.95kg carbon dioxide equivalents (CO2e) per kg fat and protein corrected milk (FPCM), respectively, with the lowest emissions being achieved in SCC50. Our results show that there is a potential to reduce the farm GHG emissions intensity by 3.7% if the milk production was improved through reducing the level of SCC to 50,000cells/mL in relation to SCC level 800,000cells/mL. It was concluded that preventing and/or controlling subclinical mastitis consequently reduces the GHG emissions per unit of product on farm that results in improved profits for the farmers through reductions in milk losses, optimum culling rate and reduced feed and other variable costs. We suggest that further studies exploring the impact of a combination of diseases on emissions intensity are warranted. PMID- 29406081 TI - A probabilistic approach to the interpretation of milk antibody results for diagnosis of Johne's disease in dairy cattle. AB - Johne's disease is a serious wasting disease of ruminants that is of high economic importance for the dairy sector in particular. The chronic nature of the disease, the fluctuations in antibody levels and the limited ability of diagnostic tests to identify cows at early stages of infection are huge challenges for the control of the disease. In the United Kingdom, the latter is commonly based on repeated milk ELISA testing of lactating cows, followed by selected culling and improved management practices around calving. In this paper, the dataset built through a large quarterly screening programme conducted in the United Kingdom since 2010 is used to investigate the use of milk ELISA testing for Johne's disease management. Over the study period, 13,509 out of 281,558 cows were identified as high-risk of being infected and shedding mycobacteria in the faeces, based on a case definition of at least two consecutive positive milk ELISA results. Around a third of them were kept in the dairy herd a year or more after being classified as high-risk. However, 16% of these cows did not have any further positive test, suggesting that they might be uninfected animals. The mean specificity and sensitivity of the milk ELISA test were estimated at 99.5% and 61.8%, respectively. The cows in the dataset are categorised in different result groups according to the number of positive test results and whether they are classified as high-risk according to the programme's case definition. The posterior probability of infection is calculated after each test in order to investigate the impact of repeated testing on the belief in a cow's infection status. The interpretation of the results show that most cows classified as high risk are very likely to be infected, while some other groups that do not match the case definition could reasonably be considered as infected too. Our results show that there is considerable potential for more targeted use of serological testing, including adjusting the testing frequency and implementing the posterior probability approach. PMID- 29406083 TI - A targeted investigation to demonstrate the freedom of West Timor from HPAI H5N1. AB - In early 2004 highly pathogenic avian influenza (HPAI) H5N1 virus caused major outbreaks of disease in poultry in Indonesia. The disease was first reported in West Timor in eastern Indonesia in the same year, resulting in the death of approximately one hundred chickens from both commercial and backyard farms; however no evidence of disease has subsequently been reported in West Timor since 2007. A targeted survey was undertaken in 2013 in 2 districts of West Timor. Three hundred village and commercial poultry (292 chickens and 8 Muscovy ducks) from 10 villages and 5 live bird markets (LBMs) were sampled between August and October 2013. Swabs of the cloaca and trachea of the sampled birds were tested using the Anigen(r) Rapid Test (Bionote). All samples were negative on testing (0%; 95%CI: 0.0-1.2%). From these results it was concluded with a high level of confidence (100%, 95%CI: 99.988, 100) that this population is not infected, and these results, along with a lack of clinical evidence of disease, support the conclusion that West Timor was free from HPAI infection at the time of the survey. PMID- 29406082 TI - Survival time and effect of selected predictor variables on survival in owned pet cats seropositive for feline immunodeficiency and leukemia virus attending a referral clinic in northern Italy. AB - Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are among the most important feline infectious diseases worldwide. This retrospective study investigated survival times and effects of selected predictor factors on survival time in a population of owned pet cats in Northern Italy testing positive for the presence of FIV antibodies and FeLV antigen. One hundred and three retrovirus seropositive cats, 53 FIV-seropositive cats, 40 FeLV-seropositive cats, and 10 FIV+FeLV-seropositive cats were included in the study. A population of 103 retrovirus-seronegative age and sex-matched cats was selected. Survival time was calculated and compared between retrovirus-seronegative, FIV, FeLV and FIV+FeLV seropositive cats using Kaplan-Meier survival analysis. Cox proportional-hazards regression analysis was used to study the effect of selected predictor factors (male gender, peripheral blood cytopenia as reduced red blood cells - RBC- count, leukopenia, neutropenia and lymphopenia, hypercreatininemia and reduced albumin to globulin ratio) on survival time in retrovirus-seropositive populations. Median survival times for seronegative cats, FIV, FeLV and FIV+FeLV-seropositive cats were 3960, 2040, 714 and 77days, respectively. Compared to retrovirus seronegative cats median survival time was significantly lower (P<0.000) in FeLV and FIV+FeLV-seropositive cats. Median survival time in FeLV and FIV+FeLV seropositive cats was also significant lower (P<0.000) when compared to FIV seropositive cats. Hazard ratio of death in FeLV and FIV+FeLV-seropositive cats being respectively 3.4 and 7.4 times higher, in comparison to seronegative cats and 2.3 and 4.8 times higher in FeLV and FIV+FeLV-seropositive cats as compared to FIV-seropositive cats. A Cox proportional-hazards regression analysis showed that FIV and FeLV-seropositive cats with reduced RBC counts at time of diagnosis of seropositivity had significantly shorter survival times when compared to FIV and FeLV-seropositive cats with normal RBC counts at diagnosis. In summary, FIV seropositive status did not significantly affect longevity of cats in this study, unlike FeLV and FIV+FeLV-seropositivity. Reduced RBC counts at time of FIV and FeLV diagnosis could impact negatively on the longevity of seropositive cats and therefore blood counts should always be evaluated at diagnosis and follow-up of retrovirus-seropositive cats. PMID- 29406084 TI - Model-guided suggestions for targeted surveillance based on cattle shipments in the U.S. AB - Risk-based sampling is an essential component of livestock health surveillance because it targets resources towards sub-populations with a higher risk of infection. Risk-based surveillance in U.S. livestock is limited because the locations of high-risk herds are often unknown and data to identify high-risk herds based on shipments are often unavailable. In this study, we use a novel, data-driven network model for the shipments of cattle in the U.S. (the U.S. Animal Movement Model, USAMM) to provide surveillance suggestions for cattle imported into the U.S. from Mexico. We describe the volume and locations where cattle are imported and analyze their predicted shipment patterns to identify counties that are most likely to receive shipments of imported cattle. Our results suggest that most imported cattle are sent to relatively few counties. Surveillance at 10 counties is predicted to sample 22-34% of imported cattle while surveillance at 50 counties is predicted to sample 43%-61% of imported cattle. These findings are based on the assumption that USAMM accurately describes the shipments of imported cattle because their shipments are not tracked separately from the remainder of the U.S. herd. However, we analyze two additional datasets - Interstate Certificates of Veterinary Inspection and brand inspection data - to ensure that the characteristics of potential post-import shipments do not change on an annual scale and are not dependent on the dataset informing our analyses. Overall, these results highlight the utility of USAMM to inform targeted surveillance strategies when complete shipment information is unavailable. PMID- 29406085 TI - Analysing the opinions of UK veterinarians on practice-based research using corpus linguistic and mathematical methods. AB - The use of corpus linguistic techniques and other related mathematical analyses have rarely, if ever, been applied to qualitative data collected from the veterinary field. The aim of this study was to explore the use of a combination of corpus linguistic analyses and mathematical methods to investigate a free-text questionnaire dataset collected from 3796 UK veterinarians on evidence-based veterinary medicine, specifically, attitudes towards practice-based research (PBR) and improving the veterinary knowledge base. The corpus methods of key word, concordance and collocate analyses were used to identify patterns of meanings within the free text responses. Key words were determined by comparing the questionnaire data with a wordlist from the British National Corpus (representing general English text) using cross-tabs and log-likelihood comparisons to identify words that occur significantly more frequently in the questionnaire data. Concordance and collocation analyses were used to account for the contextual patterns in which such key words occurred, involving qualitative analysis and Mutual Information Analysis (MI3). Additionally, a mathematical topic modelling approach was used as a comparative analysis; words within the free text responses were grouped into topics based on their weight or importance within each response to find starting points for analysis of textual patterns. Results generated from using both qualitative and quantitative techniques identified that the perceived advantages of taking part in PBR centred on the themes of improving knowledge of both individuals and of the veterinary profession as a whole (illustrated by patterns around the words learning, improving, contributing). Time constraints (lack of time, time issues, time commitments) were the main concern of respondents in relation to taking part in PBR. Opinions of what vets could do to improve the veterinary knowledge base focussed on the collecting and sharing of information (record, report), particularly recording and discussing clinical cases (interesting cases), and undertaking relevant continuing professional development activities. The approach employed here demonstrated how corpus linguistics and mathematical methods can help to both identify and contextualise relevant linguistic patterns in the questionnaire responses. The results of the study inform those seeking to coordinate PBR initiatives about the motivators of veterinarians to participate in such initiatives and what concerns need to be addressed. The approach used in this study demonstrates a novel way of analysing textual data in veterinary research. PMID- 29406086 TI - Co-infection with Fasciola hepatica may increase the risk of Escherichia coli O157 shedding in British cattle destined for the food chain. AB - Escherichia coli O157 is a zoonotic bacterium that can cause haemorrhagic diarrhoea in humans and is of worldwide public health concern. Cattle are considered to be the main reservoir for human infection. Fasciola hepatica is a globally important parasite of ruminant livestock that is known to modulate its host's immune response and affect susceptibility to bacterial pathogens such as Salmonella Dublin. Shedding of E. coli O157 is triggered by unknown events, but the immune system is thought to play a part. We investigated the hypothesis that shedding of E. coli O157 is associated with F. hepatica infection in cattle. Three hundred and thirty four cattle destined for the food chain, from 14 British farms, were tested between January and October 2015. E. coli O157 was detected by immunomagnetic separation and bacterial load enumerated. F. hepatica infection status was assessed by copro-antigen ELISA. A significant association (p=0.01) was found between the log percent positivity (PP) of the F. hepatica copro antigen ELISA and E. coli O157 shedding when the fixed effects of day of sampling and the age of the youngest animal in the group, plus the random effect of farm were adjusted for. The results should be interpreted cautiously due to the lower than predicted level of fluke infection in the animals sampled. Nevertheless these results indicate that control of F. hepatica infection may have an impact on the shedding of E. coli O157 in cattle destined for the human food chain. PMID- 29406087 TI - Factors associated with farm-level infection of porcine epidemic diarrhea during the early phase of the epidemic in Japan in 2013 and 2014. AB - The objective of this study was to investigate factors that caused rapid spread during the early phase of the porcine epidemic diarrhea (PED) epidemic in Japan in 2013 and 2014. Anonymized datasets from all pig farms were provided by Kagoshima (709 farms) and Miyazaki Prefectures (506 farms). Semi-parametric survival analysis was conducted using the first 180 days from the first case on December 3, 2013 in Kagoshima Prefecture. To compare the hazard between different farm management types, univariable survival analysis was conducted. As farm sizes varied among different farm types, bivariable survival analysis was conducted for farm size categories and farm density per km2 for each management type. A case control study using a postal questionnaire survey was conducted in September 2014, and risk factor analysis was performed using generalized linear models with binomial errors. The hazard was significantly higher in farrow-to-finish farms than fattening farms [hazard ratio (HR) = 1.6, p < 0.01], but was not significantly different between reproduction and fattening farms (HR = 1.3, p = 0.16). In separate bivariable survival analyses for each farm type, large- and middle-scale farms had higher hazard than small-scale farms in fattening (HR = 5.8 and 2.6, respectively, both p < 0.01) and reproduction farms (HR = 4.0 and 3.6, respectively, both p < 0.01). In farrow-to-finish farms, large-scale farms had higher hazard than small-scale farms (HR = 2.8, p < 0.01), and higher farm density per km2 was also a risk factor (HR = 7.6, p < 0.01). In the case-control study, questionnaires were returned from 78 PED virus-infected and 91 non infected farms. The overall response rate was 34%. Risk factors of the final model were occurrence of porcine reproductive and respiratory syndrome in the past 5 years [odds ratio (OR) = 1.97, 95% confidence interval (CI): 0.97-4.00, p = 0.054], use of a common compost station (OR = 2.51, 95%CI: 1.08-5.83, p = 0.03), and use of a pig excrement disposal service (OR = 2.64, 95%CI: 1.05-6.63, p = 0.04). High hazard in farrow-to-finish farms suggested transmission from slaughterhouses to susceptible suckling piglets. Hazard associated with large scale farms and high density might be due to frequent vehicle entrance and transmission by roads. Improvement of farm hygiene management and avoidance of risky practices associated with contact with pig excrement were keys in preventing invasion of PED virus to a farm. PMID- 29406088 TI - Characterization of hazards, welfare promoters and animal-based measures for the welfare assessment of dairy cows: Elicitation of expert opinion. AB - An expert opinion elicitation, based on a modified Delphi technique, was organized to collect the opinion of 16 Italian veterinarians with the aim of conducting a hazard and a welfare promoter characterization for defining and weighing a list of management and housing factors potentially associated with negative or positive welfare outcomes in dairy cows kept in loose housing systems. In addition, the 16 experts judged a set of animal-based measures in order to rate them by appropriateness and by the level of animal pain and suffering due to the welfare consequences they measure. Veterinary experts were asked to score 52 hazards, 47 welfare promoters and 18 animal-based measures. Management and housing hazards, that were determined to be associated with a very high impact on the welfare of dairy cows, were mainly referred to lactating cows (absence of bedding material, presence of inadequate or slippery floor in walking areas, wrong design of the lying area), but also the use of harmful tools for animal handling and the lack of scheduled foot inspection, trimming and foot bathing reached very high impact scores. Management and housing welfare promoters dealing with optimal cow comfort around resting obtained the highest ratings, together with the presence of experienced and trained stockpersons, the implementation of an attentive animal grouping strategy and the control of temperature, humidity and ventilation. Considering animal-based measures, the highest ranking of importance was given to observation of lameness, records of mortality of adult cows and calves, observation of integument alterations and body condition scoring. This study has been the starting point for the development of the first Italian national protocol for the assessment of the welfare of dairy cows farmed in loose housing systems. PMID- 29406089 TI - Automatic classification of farms and traders in the pig production chain. AB - The trade in live pigs is an essential risk factor in the spread of animal diseases. Traders play a key role in the trade network, as they are logistics hubs and responsible for large animal movements. In order to implement targeted control measures in case of a disease outbreak, it is hence strongly advisable to use information about the holding type in the pig production chain. However, in many datasets the types of the producing farms or the fact whether the agent is a trader are unknown. In this paper we introduce two indices that can be used to identify the position of a producing farm in the pig production chain and more importantly, identify traders. This was realized partially through a novel dynamic programming algorithm. Analyzing the pig trade network in Germany from 2005 to 2007, we demonstrate that our algorithm is very sensitive in detecting traders. Since the methodology can easily be applied to trade networks in other countries with similar infrastructure and legislation, we anticipate its use for augmenting the datasets in further network analyses and targeting control measures. For further usage, we have developed an R package which can be found in the supplementary material to this manuscript. PMID- 29406092 TI - Reporting Visual Acuities. PMID- 29406090 TI - Investigation of three outbreaks of Porcine Epidemic Diarrhea in Germany in 2016 demonstrates age dependent differences in the development of humoral immune response. AB - Porcine epidemic diarrhea (PED) has reemerged in Europe since 2014. Characterized by a rapid onset of diarrhea in pigs of all ages, morbidity can reach up to 100% whereas mortality is variable. The virus strains involved in the recent European outbreaks all cluster together with US strains (S INDEL) that lead to less severe clinical signs. In this study, fattening pigs and suckling piglets (n = 105) on farms with no prior PED history were monitored after an acute outbreak of the disease, caused by an S INDEL strain of PED virus (PEDV). For diagnostic investigations in the affected farms, real time RT-PCR was performed to detect PEDV RNA in individually taken fecal samples, and two commercial ELISA kits, both based on the N protein of PEDV, were used to detect IgG in serum samples of pigs experiencing acute signs of the disease. PEDV RNA could be detected in fecal samples up to 14 days after initial sampling. Comparing both ELISAs by Cohens Kappa showed substantial agreement (kappa = 0,771). Antibodies were detectable in all fattening pigs (100%) within 10 days after the occurrence of first clinical signs and remained detectable for about two months at least in 20.6% (farm 1) and 45.7% (farm 2) of the animals, respectively. In contrast, only 18 of 34 (52.9%) suckling piglets seroconverted. Although, PEDV RNA was found in fecal samples of all piglets, 13 piglets did not demonstrate antibodies at any sampling day. PCR to detect PEDV RNA in fecal samples seems to be a reliable diagnostic tool during and after the acute outbreak. In the present study, IgG ELISA kits proved to be a feasible diagnostic tool, but age dependent differences in detection rate and persistence of antibodies need to be considered. PMID- 29406091 TI - Abnormal swelling of the peritrophic membrane in Eri silkworm gut caused by MLX56 family defense proteins with chitin-binding and extensin domains. AB - MLX56 family defense proteins, MLX56 and its close homolog LA-b, are chitin binding defense proteins found in mulberry latex that show strong growth inhibitions against caterpillars when fed at concentrations as low as 0.01%. MLX56 family proteins contain a unique structure with an extensin domain surrounded by two hevein-like chitin-binding domains, but their defensive modes of action remain unclear. Here, we analyzed the effects of MLX56 family proteins on the peritrophic membrane (PM), a thin and soft membrane consisting of chitin that lines the midgut lumen of insects. We observed an abnormally thick (>1/5 the diameter of midgut) hard gel-like membrane consisted of chitin and MLX56 family proteins, MLX56 and LA-b, in the midgut of the Eri silkworms, Samia ricini, fed a diet containing MLX56 family proteins, MLX56 and LA-b. When polyoxin AL, a chitin synthesis-inhibitor, was added to the diet containing MLX56 family proteins, the toxicity of MLX56 family proteins disappeared and PM became thinner and fragmented. These results suggest that MLX56 family proteins, through their chitin-binding domains, bind to the chitin framework of PM, then through their extensin-domain (gum arabic-like structure), which functions as swelling agent, expands PM into an abnormally thick membrane that inhibits the growth of insects. This study shows that MLX56 family proteins are plant defense lectins with a totally unique mode of action, and reveals the functions of extensin domains and arabinogalactan proteins as swelling (gel-forming) agents of plants. PMID- 29406093 TI - Formation of water disinfection byproduct 2,6-dichloro-1,4-benzoquinone from chlorination of green algae. AB - We report that green algae in lakes and rivers can serve as precursors of halobenzoquinone (HBQ) disinfection byproducts (DBPs) produced during chlorination. Chlorination of a common green alga, Chlorella vulgaris, produced 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), the most prevalent HBQ DBP in disinfected water. Under varying pH conditions (pH6.0-9.0), 2,6-DCBQ formation ranged from 0.3 to 2.1MUg/mg C with maximum formation at pH8.0. To evaluate the contribution of organic components of C. vulgaris to 2,6-DCBQ formation, we separated the organics into two fractions, the protein-rich fraction of intracellular organic matter (IOM) and the polysaccharide-laden fraction of extracellular organic matter (EOM). Chlorination of IOM and EOM produced 1.4MUg/mg C and 0.7MUg/mg C of 2,6-DCBQ, respectively. The IOM generated a two fold higher 2,6-DCBQ formation potential than the EOM fraction, suggesting that proteins are potent 2,6-DCBQ precursors. This was confirmed by the chlorination of proteins extracted from C. vulgaris: the amount of 2,6-DCBQ produced is linearly correlated with the concentration of total algal protein (R2=0.98). These results support that proteins are the primary precursors of 2,6-DCBQ in algae, and control of green algal bloom outbreaks in source waters is important for management of HBQ DBPs. PMID- 29406094 TI - Characteristics of microbial community functional structure of a biological coking wastewater treatment system. AB - Nitrogenous heterocyclic compounds are key pollutants in coking wastewater; however, the functional potential of microbial communities for biodegradation of such contaminants during biological treatment is still elusive. Herein, a high throughput functional gene array (GeoChip 5.0) in combination with Illumina HiSeq2500 sequencing was used to compare and characterize the microbial community functional structure in a long run (500days) bench scale bioreactor treating coking wastewater, with a control system treating synthetic wastewater. Despite the inhibitory toxic pollutants, GeoChip 5.0 detected almost all key functional gene (average 61,940 genes) categories in the coking wastewater sludge. With higher abundance, aromatic ring cleavage dioxygenase genes including multi ring1,2diox; one ring2,3diox; catechol represented significant functional potential for degradation of aromatic pollutants which was further confirmed by Illumina HiSeq2500 analysis results. Response ratio analysis revealed that three nitrogenous compound degrading genes- nbzA (nitro-aromatics), tdnB (aniline), and scnABC (thiocyanate) were unique for coking wastewater treatment, which might be strong cause to increase ammonia level during the aerobic process. Additionally, HiSeq2500 elucidated carbozole and isoquinoline degradation genes in the system. These findings expanded our understanding on functional potential of microbial communities to remove organic nitrogenous pollutants; hence it will be useful in optimization strategies for biological treatment of coking wastewater. PMID- 29406095 TI - Multiresidue determination and potential risks of emerging pesticides in aquatic products from Northeast China by LC-MS/MS. AB - A simple method for determining 33 pesticides with a wide polarity range (logKow 0.6-4.5) in aquatic products was developed based on LC-MS/MS. The target analytes included three types of widely used pesticides: insecticides, fungicides and herbicides. Based on the optimization of ultrasonic assisted extraction and GPC clean-up procedures, the matrix effect, extraction recoveries and LOD were improved distinctively. LOQ of this method was below 0.5ng/g for all pesticides, which is superior to values in the literature, and the matrix effect was reduced effectively (-14.7% to 7.5%). The method was successfully applied to investigate the pesticide residue levels of twenty-five samples including seven common kinds of fishes from Northeast China. The results showed that all targeted pesticides were present in the fish samples; however, their levels were low, except for atrazine, linuron, ethoprophos, tetrachlorvinphos, acetochlor and fenthion. Atrazine and linuron caught our attention because the concentrations of atrazine in fish samples from Liaoning province were in the range of 0.5-8ng/g (w/w) with mean concentration of 2.3ng/g, which were far above those of other pesticides. The levels of linuron were in the range of 0.6-6ng/g (mean concentration 2.8ng/g), which were the highest among all targeted pesticides in the Inner Mongolia. This is the first systematic investigation on the characteristics and levels of these pesticides in aquatic products from northeast China. Considering their toxicity and bioaccumulation, the potential risk of atrazine and linuron from consuming aquatic products should be paid more attention. PMID- 29406096 TI - Exposure to difenoconazole inhibits reproductive ability in male marine medaka (Oryzias melastigma). AB - Difenoconazole (DFZ) is a triazole fungicide which has been detected in the aquatic environment, including estuaries and embayments. However, few studies addressing the reproductive toxicity and transgenerational effects of DFZ on marine fishes are available. The present study was conducted to investigate the effects of DFZ on male marine medaka (Oryzias melastigma). After exposure of the embryo to 1, 10, 100 and 1000ng/L DFZ for 180days, the gonadosomatic index was significantly decreased in the 1000ng/L treatment. The number of sperm was reduced while the abundances of spermatocytes and spermatogonia in the testes were increased in all the treatments. The mRNA levels of salmon-type gnrh (sgnrh), the luteinizing hormone (lhbeta) and the follicle-stimulating hormone (fshbeta) genes in the brain all exhibited a significant down-regulation, the expression of androgen receptors (aralpha and arbeta) was decreased and that of estrogen receptor beta and cytochrome P450 aromatase (cyp19B) was increased in the testes. The expression levels of cyp19A and cyp19B were increased in the liver. The decrease of ars mRNA levels might be one of the reasons causing the reduction of sperm. The down-regulation of sgnrh, lhbeta and fshbeta mRNA levels suggested that DFZ might impact the spermatogenesis via the brain-pituitary-gonad pathway. The decrease of the fertilization success, the hatch ability and the swim-up success in the F1 generation indicated that DFZ pollution at environmental levels might cause a decrease of wild fish populations. PMID- 29406097 TI - Elevated 8-oxo-7,8-dihydro-2'-deoxyguanosine in genome of T24 bladder cancer cells induced by halobenzoquinones. AB - Halobenzoquinones (HBQs) are an emerging class of halogenated disinfection byproducts (DBPs) in drinking water, which raised public concerns due to potential carcinogenic effects to human bladder. Our previous work demonstrated that HBQs and hydrogen peroxide (H2O2) together generated oxidative DNA damage via a metal-independent and intercalation-enhanced oxidation mechanism in vitro. This study further investigated the efficiency of various HBQs to induce oxidative DNA damage in T24 bladder cancer cells. Compared with T24 cells without treatment (3.1 lesions per 106 dG), the level of 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxodG) significantly increased by 1.4, 3.2, 8.8, and 9.2 times after treatment with tetrabromo-1,4-benzoquinone (TBBQ), terachloro-1,4 benzoquinone (TCBQ), 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) and 2,5-dichloro 1,4-benzoquinone (2,5-DCBQ) for 24hr, respectively. Interestingly, we found that the oxidative potency of HBQs in T24 cells (2,5-DCBQ~2,6-DCBQ>TCBQ>TBBQ) is inconsistent with that of in vitro dsDNA oxidation (TCBQ>TBBQ>2,5-DCBQ>2,6-DCBQ), suggesting HBQs induce oxidative lesions in cellular genomic DNA probably involved with a complex mechanism. PMID- 29406098 TI - Molecular characterization of effluent organic matter in secondary effluent and reclaimed water: Comparison to natural organic matter in source water. AB - Municipal wastewater reclamation is becoming of increasing importance in the world to solve the problem of water scarcity. A better understanding of the molecular composition of effluent organic matter (EfOM) in the treated effluents of municipal wastewater treatment plants (WWTPs) is crucial for ensuring the safety of water reuse. In this study, the molecular composition of EfOM in the secondary effluent of a WWTP in Beijing and the reclaimed water further treated with a coagulation-sedimentation-ozonation process were characterized using a non target Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) method and compared to that of natural organic matter (NOM) in the local source water from a reservoir. It was found that the molecular composition of EfOM in the secondary effluent and reclaimed water was dominated by CHOS formulas, while NOM in the source water was dominated by CHO formulas. The CHO formulas of the three samples had similar origins. Anthropogenic surfactants were responsible for the CHOS formulas in EfOM of the secondary effluent and were not well removed by the coagulation-sedimentation-ozonation treatment process adopted. PMID- 29406099 TI - Algal removal from cyanobacteria-rich waters by preoxidation-assisted coagulation flotation: Effect of algogenic organic matter release on algal removal and trihalomethane formation. AB - The cyanobacteria-bloom in raw waters frequently causes an unpredictable chemical dosing of preoxidation and coagulation for an effective removal of algal cells in water treatment plants. This study investigated the effects of preoxidation with NaOCl and ClO2 on the coagulation-flotation effectiveness in the removal of two commonly blooming cyanobacteria species, Microcystis aeruginosa (MA) and Cylindrospermopsis raciborskii (CR), and their corresponding trihalomethane (THM) formation potential. The results showed that dual dosing with NaOCl plus ClO2 was more effective in enhancing the deformation of cyanobacterial cells compared to single dosing with NaOCl, especially for CR-rich water. Both preoxidation approaches for CR-rich water effectively reduced the CR cell count with less remained dissolved organic carbon (DOC), which benefited subsequent coagulation flotation. However, preoxidation led to an adverse release of algogenic organic matter (AOM) in the case of MA-rich water. The release of AOM resulted in a poor removal in MA cells and a large amount of THM formation after oxidation-assisted coagulation-flotation process. The reduction in THM formation potential of CR rich waters is responsible for effective algae and DOC removal by alum coagulation. It is concluded that the species-specific characteristic of cyanobacteria and their AOM released during chlorination significantly influences the performance of coagulation-flotation for AOM removal and corresponding THM formation. PMID- 29406100 TI - Review on utilization of biochar for metal-contaminated soil and sediment remediation. AB - Biochar is a carbon-neutral or even carbon-negative material produced through thermal decomposition of plant- and animal-based biomass under oxygen-limited conditions. Recently, there has been an increasing interest in the application of biochar as an adsorbent, soil ameliorant and climate mitigation approach in many types of applications. Metal-contaminated soil remediation using biochar has been intensively investigated in small-scale and pilot-scale trials with obtained beneficial results and multifaceted effects. But so far, the study and application of biochar in contaminated sediment management has been very limited, and this is also a worldwide problem. Nonetheless, there is reason to believe that the same multiple benefits can also be realized with these sediments due to similar mechanisms for stabilizing contaminants. This paper provides a review on current biochar properties and its use as a sorbent/amendment for metal contaminated soil/sediment remediation and its effect on plant growth, fauna habits as well as microorganism communities. In addition, the use of biochar as a potential strategy for contaminated sediment management is also discussed, especially as regards in-situ planning. Finally, we highlight the possibility of biochar application as an effective amendment and propose further research directions to ensure the safe and sustainable use of biochar as an amendment for remediation of contaminated soil and sediment. PMID- 29406101 TI - Characterization of submicron particles during autumn in Beijing, China. AB - In this study, we performed a highly time-resolved chemical characterization of non-refractory submicron particles (NR-PM1) in Beijing by using an Aerodyne high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). The results showed the average NR-PM1 mass concentration to be 56.4+/-58.0MUg/m3, with a peak at 307.4MUg/m3. Due to the high frequency of biomass burning in autumn, submicron particles significantly increased in organic content, which accounted for 51% of NR-PM1 on average. Secondary inorganic aerosols (sulfate+nitrate+ammonium) accounted for 46% of NR-PM1, of which sulfate, nitrate, and ammonium contributed 15%, 20%, and 11%, respectively. To determine the intrinsic relationships between the organic and inorganic species, we used the positive matrix factorization (PMF) model to merge the high-resolution mass spectra of the organic species and NO+ and NO2+ ions. The PMF analysis separated the mixed organic and nitrate (NO+ and NO2+) spectra into four organic factors, including hydrocarbon-like organic aerosol (HOA), oxygenated organic aerosol (OOA), cooking organic aerosol (COA), and biomass burning organic aerosol (BBOA), as well as one nitrate inorganic aerosol (NIA) factor. COA (33%) and OOA (30%) contributed the most to the total organic aerosol (OA) mass, followed by BBOA (20%) and HOA (17%). We successfully quantified the mass concentrations of the organic and inorganic nitrates by the NO+ and NO2+ ions signal in the organic and NIA factors. The organic nitrate mass varied from 0.01-6.8MUg/m3, with an average of 1.0+/-1.1MUg/m3, and organic nitrate components accounted for 10% of the total nitrate mass in this observation. PMID- 29406102 TI - Removing ammonium from water and wastewater using cost-effective adsorbents: A review. AB - Ammonium is an important nutrient in primary production; however, high ammonium loads can cause eutrophication of natural waterways, contributing to undesirable changes in water quality and ecosystem structure. While ammonium pollution comes from diffuse agricultural sources, making control difficult, industrial or municipal point sources such as wastewater treatment plants also contribute significantly to overall ammonium pollution. These latter sources can be targeted more readily to control ammonium release into water systems. To assist policy makers and researchers in understanding the diversity of treatment options and the best option for their circumstance, this paper produces a comprehensive review of existing treatment options for ammonium removal with a particular focus on those technologies which offer the highest rates of removal and cost effectiveness. Ion exchange and adsorption material methods are simple to apply, cost-effective, environmentally friendly technologies which are quite efficient at removing ammonium from treated water. The review presents a list of adsorbents from the literature, their adsorption capacities and other parameters needed for ammonium removal. Further, the preparation of adsorbents with high ammonium removal capacities and new adsorbents is discussed in the context of their relative cost, removal efficiencies, and limitations. Efficient, cost-effective, and environmental friendly adsorbents for the removal of ammonium on a large scale for commercial or water treatment plants are provided. In addition, future perspectives on removing ammonium using adsorbents are presented. PMID- 29406103 TI - Interactions between engineered nanoparticles and dissolved organic matter: A review on mechanisms and environmental effects. AB - Dissolved organic matter (DOM) is ubiquitous in the environment and has high reactivity. Once engineered nanoparticles (ENPs) are released into natural systems, interactions of DOM with ENPs may significantly affect the fate and transport of ENPs, as well as the bioavailability and toxicity of ENPs to organisms. However, because of the complexity of DOM and the shortage of useful characterization methods, large knowledge gaps exist in our understanding of the interactions between DOM and ENPs. In this article, we systematically reviewed the interactions between DOM and ENPs, discussed the effects of DOM on the environmental behavior of ENPs, and described the changes in bioavailability and toxicity of ENPs caused by DOM. Critical evaluations of published references suggest further need for assessing and predicting the influences of DOM on the transport, transformation, bioavailability, and toxicity of ENPs in the environment. PMID- 29406104 TI - Reactive oxygen species may play an essential role in driving biological evolution: The Cambrian Explosion as an example. AB - The Cambrian Explosion is one of the most significant events in the history of life; essentially all easily fossilizable animal body plans first evolved during this event. Although many theories have been proposed to explain this event, its cause remains unresolved. Here, we propose that the elevated level of oxygen, in combination with the increased mobility and food intake of metazoans, led to increased cellular levels of reactive oxygen species (ROS), which drove evolution by enhancing mutation rates and providing new regulatory mechanisms. Our hypothesis may provide a unified explanation for the Cambrian Explosion as it incorporates both environmental and developmental factors and is also consistent with ecological explanations for animal radiation. Future studies should focus on testing this hypothesis, and may lead to important insights into evolution. PMID- 29406105 TI - Simultaneous size characterization and mass quantification of the in vivo core biocorona structure and dissolved species of silver nanoparticles. AB - Size characterization of silver nanoparticles with biomolecule corona (AgNP@BCs) and mass quantification of various silver species in organisms are essential for understanding the in vivo transformation of AgNPs. Herein, we report a versatile method that allows simultaneous determination of the size of AgNP@BCs and mass concentration of various silver species in rat liver. Both particulate and ionic silver were extracted in their original forms from the organs by alkaline digestion, and analyzed by size exclusion chromatography combined with inductively coupled plasma mass spectrometry (SEC-ICP-MS). While the silver mass concentrations were quantified by ICP-MS with a detection limit of 0.1MUg/g, the effective diameter of AgNP@BCs was determined based on the retention time in SEC separation with size discrimination of 0.6-3.3nm. More importantly, we found that the BC thickness of AgNP@BCs is core size independent, and a linear correlation was found between the effective diameter and core diameter of AgNP@BCs in extracted tissues, which was used to calibrate the core diameter with standard deviations in the range of 0.2-1.1nm. The utility of this strategy was demonstrated through application to rat livers in vivo. Our method is powerful for investigating the transformation mechanism of AgNPs in vivo. PMID- 29406106 TI - Characteristics and formation mechanism of regional haze episodes in the Pearl River Delta of China. AB - To investigate the characteristics and the specific mechanism of continuous haze, comprehensive measurements were conducted from 15 October to 19 November in the Atmospheric Environment Monitoring Super-Station in Heshan of Guangdong province. Five haze episodes occurred in October and November 2014 in the Pearl River Delta (PRD) region. The meteorological parameters, gas data, chemical compositions, and optical parameters of the aerosols were obtained. Among these events, the second haze episode, with the highest concentration of PM2.5 of 187.51MUg/m3, was the most severe. NO3- was always higher than SO42-, which indicated that motor vehicles played an important role in the haze, even though the oxidation rate from SO2 to SO42- was faster than that of NOX to NO3-. The difference between the hourly averages of Na+ and K+ during the haze episode and clean days was small, implying that straw combustion and sea salt had no significant effect on the occurrence of haze, and the backward trajectories of the air masses also conformed with this result. The air pollutants were difficult to disperse because of the significant decrease in the planetary boundary layer (PBL) height. Relative humidity played a crucial role in the formation of haze by leading to hygroscopic growth of the diameter of aerosols. PMID- 29406107 TI - Effective adsorption of sulfamethoxazole, bisphenol A and methyl orange on nanoporous carbon derived from metal-organic frameworks. AB - Nanoporous carbons (NPCs) derived from metal-organic frameworks (MOFs) are attracting increasing attention in many areas by virtue of their high specific surface area, large pore volume and unique porosity. The present work reports the preparation of an NPC with high surface area (1731m2/g) and pore volume (1.68cm3/g) by direct carbonization of MOF-5. We examined the adsorption of three typical contaminants from aqueous solutions, i.e., sulfamethoxazole (SMX), bisphenol A (BPA) and methyl orange (MO), by using the as-prepared NPC. The results demonstrated that NPC could adsorb the contaminants effectively, with adsorption capacity (qm) of 625mg/g (SMX), 757mg/g (BPA) and 872mg/g (MO), respectively. These values were approximately 1.0-3.2 times higher than those obtained for single-walled carbon nanotubes (SWCNTs) and commercial powder active carbon (PAC) under the same conditions. With its high surface area and unique meso/macropore structure, the enhanced adsorption of NPC most likely originates from the cooperative interaction of a pore-filling mechanism, electrostatic interaction, and hydrogen bonding. In particular, the pH value has a crucial impact on adsorption, suggesting the significant contribution of electrostatic interaction between NPC and the contaminants. This study provides a proof-of concept demonstration of MOF-derived nanoporous carbons as effective adsorbents of contaminants for water treatment. PMID- 29406108 TI - Dioxin induces expression of hsa-miR-146b-5p in human neuroblastoma cells. AB - Dioxin can cause a series of neural toxicological effects. MicroRNAs (miRs) play important roles in regulating nervous system function and mediating cellular responses to environmental pollutants, such as dioxin. Hsa-miR-146b-5p appears to be involved in neurodegenerative diseases and brain tumors. However, little is known about effects of dioxin on the expression of hsa-miR-146b-5p. We found that the hsa-miR-146b-5p expression and its promoter activity were significantly increased in dioxin treated SK-N-SH cells, a human-derived neuroblastoma cell line. Potential roles of hsa-miR-146b-5p in mediating neural toxicological effects of dioxin may be due to the regulation of certain target genes. We further confirmed that hsa-miR-146b-5p significantly suppressed acetylcholinesterase (AChE) activity and targeted the 3'-untranslated region of the AChE T subunit, which has been down-regulated in dioxin treated SK-N-SH cells. Functional bioinformatic analysis showed that the known and predicted target genes of hsa-miR-146b-5p were involved in some brain functions or cyto toxicities related to known dioxin effects, including synapse transmission, in which AChE may serve as a responsive gene for mediating the effect. PMID- 29406109 TI - Effects of oxygen and water content on microbial distribution in the polyurethane foam cubes of a biofilter for SO2 removal. AB - The performance of a biofilter for off-gas treatment relies on the activity of microorganisms and adequate O2 and H2O. In present study, a microelectrode was applied to analyze O2 in polyurethane foam cubes (PUFCs) packed in a biofilter for SO2 removal. The O2 distribution varied with the density and water-containing rate (WCR) of PUFCs. The O2 concentration dropped sharply from 10.2 to 0.8mg/L from the surface to the center of a PUFC with 97.20% of WCR. The PUFCs with high WCR presented aerobic-anoxic-aerobic areas. Three-dimensional simulated images demonstrated that the structure of PUFCs with high WCR consisted of an aerobic "shell" and an anoxic "core", with high-density PUFCs featuring a larger anoxic area than low-density PUFCs. Moreover, the H2O distribution in the PUFC was uneven and affected the O2 concentration. Whereas aerobic bacteria were observed in the PUFC surface, facultative anaerobic microorganisms were found at the PUFC core, where the O2 concentration was relatively low. O2 and H2O distributions differed in the PUFCs, and the distribution of microorganisms varied accordingly. PMID- 29406111 TI - Observations of atmospheric pollutants at Lhasa during 2014-2015: Pollution status and the influence of meteorological factors. AB - Atmospheric pollutants including SO2, NO2, CO, O3 and inhalable particulate matter (PM2.5 and PM10) were monitored continuously from March 2014 to February 2015 to investigate characteristics of air pollution at Lhasa, Tibetan Plateau. Species exhibited similar seasonal variations except O3, with the peaks in winter but low valleys in summer. The maximum O3 concentration was observed in spring, followed by summer, autumn, and winter. The positive correlation between O3 and PM10 in spring indicated similar sources of them, and was assumed to be turbulent transport. Temperature was the dominant meteorological factor for most species in spring. High temperature accelerates O3 photochemistry, and favors air disturbance which is conductive to dust resuspension in spring. Relative humidity (RH) and atmospheric pressure were the main meteorological factors in summer. RH showed negative correlations with species, while atmospheric pressure posed opposite situation. Wind speed (WS) was the dominant meteorological factor in autumn, the negative correlations between WS and species indicated diffusion by wind. Most species showed non-significant correlations with meteorological factors in winter, indicating the dependence of pollution on source emission rather than restriction by meteorology. Pollution weather character indicated that emissions were from biomass burning and dust suspension, and meteorological factors also played an important role. Air stream injection from the stratosphere was observed during O3 pollution period. Air parcels from Southwest Asia were observed during air pollution period in winter. An enhancement in air pollutants such as O3 would be expected in the future, more attention should be given to countermeasures for prevention of air pollution in the future. PMID- 29406110 TI - Source apportionment of PM2.5 light extinction in an urban atmosphere in China. AB - Haze in China is primarily caused by high pollution of atmospheric fine particulates (PM2.5). However, the detailed source structures of PM2.5 light extinction have not been well established, especially for the roles of various organic aerosols, which makes haze management lack specified targets. This study obtained the mass concentrations of the chemical compositions and the light extinction coefficients of fine particles in the winter in Dongguan, Guangdong Province, using high time resolution aerosol observation instruments. We combined the positive matrix factor (PMF) analysis model of organic aerosols and the multiple linear regression method to establish a quantitative relationship model between the main chemical components, in particular the different sources of organic aerosols and the extinction coefficients of fine particles with a high goodness of fit (R2=0.953). The results show that the contribution rates of ammonium sulphate, ammonium nitrate, biomass burning organic aerosol (BBOA), secondary organic aerosol (SOA) and black carbon (BC) were 48.1%, 20.7%, 15.0%, 10.6%, and 5.6%, respectively. It can be seen that the contribution of the secondary aerosols is much higher than that of the primary aerosols (79.4% versus 20.6%) and are a major factor in the visibility decline. BBOA is found to have a high visibility destroying potential, with a high mass extinction coefficient, and was the largest contributor during some high pollution periods. A more detailed analysis indicates that the contribution of the enhanced absorption caused by BC mixing state was approximately 37.7% of the total particle absorption and should not be neglected. PMID- 29406112 TI - Inhibition of thrombin by functionalized C60 nanoparticles revealed via in vitro assays and in silico studies. AB - The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C60 NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C60 NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C60 NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C60 NPs, of greater hydrophobicity and hydrogen bond (HB) donor acidity or acceptor basicity, acted as competitive inhibitors of thrombin by directly interacting with the active site of thrombin. A simple quantitative nanostructure-activity relationship model relating the surface substituent properties to the inhibition potential was then established for the six competitive inhibitors. Molecular docking analysis revealed that the intermolecular HB interactions were important for the specific binding of C60 NPs to the active site canyon, while the additional stability provided by the surface groups through van der Waals interaction also play a key role in the thrombin binding affinity of the NPs. Our results suggest that thrombin is a possible target of the surface-functionalized C60 NPs relevant to their anticoagulation effect. PMID- 29406114 TI - Study on the effects of organic matter characteristics on the residual aluminum and flocs in coagulation processes. AB - Characteristics of organic matter may affect the residual aluminum after the coagulation process. This study reported the results of a survey for one drinking water treatment plant and measured the concentration of residual aluminum species with different molecular weights. Survey results indicated that humic acid or organic matter whose molecular weight was smaller than 1500Da had significant effects on residual aluminum. All the treatment processes were ineffective in removing dissolved organic matter whose molecular weight was smaller than 1500Da. These results also indicated that the addition of sand or polyacrylamide in the coagulation process could greatly decrease the concentration of humic acid, and the concentration of residual aluminum also decreased. These results revealed that for all water samples after filtration, the majority of total residual aluminum existed in the form of total dissolved aluminum, accounting for 70%-90%. The concentration of residual aluminum produced in bovine serum albumin solutions indicated that when the DOC was larger than 4.0mg/L, there were still significant differences when the solution pH value varied from 4.0 to 9.0. PMID- 29406113 TI - Effects of biochars on the bioaccessibility of phenanthrene/pyrene/zinc/lead and microbial community structure in a soil under aerobic and anaerobic conditions. AB - The immobilization of co-contaminants of organic and inorganic pollutants by biochar is an efficient remediation strategy. However, the effect of biochar amendments on the bioaccessibility of the co-contaminants in dry versus flooded soils has rarely been compared. In batch experiments, bamboo-derived biochar (BB) had a higher sorption capacity for phenanthrene (Phe)/pyrene (Pyr)/zinc (Zn) than corn straw-derived biochar (CB), while CB had a higher sorption capacity for lead (Pb) than BB. After 150days of incubation, the amendments of 2% CB, 0.5% BB and 2% BB effectively suppressed the dissipation and reduced the bioaccessibility of Phe/Pyr by 15.65%/18.02%, 17.07%/18.31% and 25.43%/27.11%, respectively, in the aerobic soils. This effectiveness was more significant than that in the anaerobic soils. The accessible Zn/Pb concentrations were also significantly lower in the aerobic soils than in the anaerobic soils, regardless of treatments. The Gram negative bacterial biomass and the Shannon-Weaver index in the aerobic soil amended with 2% CB were the highest. The soil microbial community structure was jointly affected by changes in the bioaccessibility of the co-contaminants and the soil physiochemical properties caused by biochar amendments under the two conditions. Therefore, dry land farming may be more reliable than paddy soil cultivation at reducing the bioaccessibility of Phe/Pyr/Zn/Pb and enhancing the soil microbial diversity in the short term. PMID- 29406115 TI - Pre-treatment of pyridine wastewater by new cathodic-anodic-electrolysis packing. AB - A novel cathodic-anodic-electrolysis packing (CAEP) used in the treatment of pyridine wastewater was researched, which mainly consisted of 4,4'-diamino-2,2' disulfonic acid (DSD acid) industrial iron sludge. The physical properties and morphology of the packing were studied. The CAEP was used in a column reactor during the pretreatment of pyridine wastewater. The influence of pH, hydraulic retention time (HRT), the air-liquid ratio (A/L) and the initial concentration of pyridine were investigated by measuring the removal of total organic carbon (TOC) and pyridine. The characterization results showed that the bulk density, grain density, water absorption percentage and specific surface area were 921kg/m3, 1086kg/m3, 25% and 29.89m2/g, respectively; the removal of TOC and pyridine could reach 50% and 58% at the optimal experimental conditions (pH=3, HRT=8hr, A/L=2). Notably, the surface of the packing was renewed constantly during the running of the filter, and the handling capacity was stable after running for three months. PMID- 29406116 TI - Nitrate removal and extracellular polymeric substances of autohydrogenotrophic bacteria under various pH and hydrogen flow rates. AB - In recent years there has been an increasing interest in the use of autohydrogenotrophic bacteria to treat nitrate from wastewater. However, our knowledge about the characteristics of extracellular polymeric substances (EPS) releasing by these activities is not yet very advanced. This study aimed to investigate the change in EPS compositions under various pH values and hydrogen flow rates, taking into consideration nitrogen removal. Results showed that pH7.5 and a hydrogen flow rate of 90mL/min were the optimal operating conditions, resulting in 100% nitrogen removal after 6hr of operation. Soluble and bound polysaccharides decreased, while bound proteins increased with increasing pH. Polysaccharides increased with increasing hydrogen flow rate. No significant change of bound proteins was observed at various hydrogen flow rates. PMID- 29406117 TI - Phytotoxicity and groundwater impacts of leaching from thermal treatment residues in roadways. AB - The use of coal fly ash (CFA), municipal solid waste incinerator bottom ash (MSWIBA) and flue gas desulfurization residue (FGDR) in road construction has become very common owing to its economical advantages. However, these residues may contain toxic constituents that pose an environmental risk if they leach out and flow through the soil, surface water and groundwater. Therefore, it is necessary to assess the ecotoxicity and groundwater impact of these residues before decisions can be made regarding their utilization for road construction. In this study, the physico-chemical characteristics, leaching and phytotoxicity of these residues were investigated. Specifically, multivariate analyses were used to evaluate the contributions of the leaching constituents of the CFA, MSWIBA and FGDR leachates to the germination index of wheat seeds. B, Ba, Cr, Cu, Fe and Pb were found to be more toxic to the wheat seeds than the other heavy metals. Furthermore, the leached concentrations of the constituents from the CFA, MSWIBA and FGDR were below the regulatory threshold limits of the Chinese identification standard for hazardous wastes. Analyses conducted using a numerical groundwater model (WiscLEACH) indicated that the predicted field concentrations of metals from the CFA, MSWIBA and FGDR increased with time up to about 30years at the point of compliance, then decreased with time and distance. Overall, this study demonstrated that the risks resulting from MSWIBA, CFA and FGDR leaching could be assessed before its utilization for road construction, providing crucial information for the adoption of these alternative materials. PMID- 29406118 TI - Application of Ag/AgBr/GdVO4 composite photocatalyst in wastewater treatment. AB - Ag/AgBr/GdVO4 composite photocatalysts were designed and synthesized in this paper. The physical and chemical structures, as well as optical properties of the synthesized composite were investigated via XRD, XPS, TEM, and UV-vis. It is found that the composite showed a ternary heterojunction structure of Ag, AgBr and GdVO4. Meanwhile, it has a high intensity of light current, indicating its high separation efficiency of electron and hole. Photocatalytic oxidation of rhodamine B (RhB) under visible light irradiation was performed to investigate the activity of the Ag/AgBr/GdVO4 composite. Result indicates that it shows excellent photocatalytic activity. Under visible light irradiation for 12min, about 80% of RhB (30MUmol/L) was degraded. The degradation rate is estimated to be 0.253 min-1, which is three times higher than that of pure AgBr. The high photoactivity can be ascribed to the synergetic effect of AgBr, GdVO4, and Ag nanoparticle in separation of electron-hole pairs. PMID- 29406119 TI - Intranasal administration of tetrabromobisphenol A bis(2-hydroxyethyl ether) induces neurobehavioral changes in neonatal Sprague Dawley rats. AB - Tetrabromobisphenol A (TBBPA) and its derivatives are now being highly concerned due to their emerging environmental occurrence and deleterious effects on non target organisms. Considering the potential neurotoxicity of TBBPA derivatives which has been demonstrated in vitro, what could happen in vivo is worthy of being studied. Tetrabromobisphenol A bis(2-hydroxyethyl ether) (TBBPA-BHEE), a representative TBBPA derivative, was selected for a 21-day exposure experiment on neonatal Sprague Dawley (SD) rats through intranasal administration. The neurobehavioral, histopathological changes, and differentially expressed genes based on RNA microarray were investigated to evaluate the neurological effects of this chemical. The results indicated that TBBPA-BHEE exposure significantly compromised the motor co-ordination performance and the locomotor activities (p<0.05). The neurobehavioral phenotype could be attributed to the obvious histopathological changes in both cerebrum and cerebellum, such as neural cell swelling, microglial activation and proliferation. A total of 911 genes were up regulated, whereas 433 genes were down-regulated. Gene set enrichment analysis showed multiple signaling pathways, including ubiquitin-mediated proteolysis and wingless-int (Wnt) signaling pathway etc. were involved due to TBBPA-BHEE exposure. The gene ontology enrichment analysis showed the basic cellular function and the neurological processes like synaptic transmission were influenced. The toxicological effects of TBBPA-BHEE observed in this study suggested the potential neuronal threaten from unintended exposure, which would be of great value in the biosafety evaluation of TBBPA derivatives. PMID- 29406121 TI - Purification and molecular weight distribution of a key exopolysaccharide component of Bacillus megaterium TF10. AB - Extracellular polymeric substances (EPS) are organic metabolic compounds excreted by microorganisms. They largely impact microbial aggregate structures and functions. Extracellular polysaccharides (EP) in EPS are responsible for the formation of microbial aggregates. In this work, we successfully separated and characterized EP from EPS of the bacterium Bacillus megaterium TF10. Extraction of EP from EPS was optimized using Sevag's reagent. Chemical characteristics, functional groups, and molecular weight (MW) distribution of EP were compared with the harvested EPS and soluble microbial products (SMP). We found that the polymers of lower MW and free proteins were successfully removed by Sevag's reagent. The higher MW components of EPS were predominantly polysaccharides, while the polymers of lower MW tended to secrete to the supernatant and were described as SMP. A part of the proteins in the EP was polysaccharide-bonded. Our results can be further used in elucidating the complex flocculation mechanisms in which EP play a major role. PMID- 29406120 TI - Air pollution and inhalation exposure to particulate matter of different sizes in rural households using improved stoves in central China. AB - Household air pollution is considered to be among the top environmental risks in China. To examine the performance of improved stoves for reduction of indoor particulate matter (PM) emission and exposure in rural households, individual inhalation exposure to size-resolved PM was investigated using personal portable samplers carried by residents using wood gasifier stoves or improved coal stoves in a rural county in Central China. Concentrations of PM with different sizes in stationary indoor and outdoor air were also monitored at paired sites. The stationary concentrations of size-resolved PM in indoor air were greater than those in outdoor air, especially finer particles PM0.25. The daily averaged exposure concentrations of PM0.25, PM1.0, PM2.5 and total suspended particle for all the surveyed residents were 74.4+/-41.1, 159.3+/-74.3, 176.7+/-78.1 and 217.9+/-78.1MUg/m3, respectively. Even using the improved stoves, the individual exposure to indoor PM far exceeded the air quality guideline by WHO at 25MUg/m3. Submicron particles PM1.0 were the dominant PM fraction for personal exposure and indoor and outdoor air. Personal exposure exhibited a closer correlation with indoor PM concentrations than that for outdoor concentrations. Both inhalation exposure and indoor air PM concentrations in the rural households with gasifier firewood stoves were evidently lower than the reported results using traditional firewood stoves. However, local governments in the studied rural areas should exercise caution when widely and hastily promoting gasifier firewood stoves in place of improved coal stoves, due to the higher PM levels in indoor and outdoor air and personal inhaled exposure. PMID- 29406122 TI - Comparison of the effects of aluminum and iron(III) salts on ultrafiltration membrane biofouling in drinking water treatment. AB - Coagulation plays an important role in alleviating membrane fouling, and a noticeable problem is the development of microorganisms after long-time operation, which gradually secrete extracellular polymeric substances (EPS). To date, few studies have paid attention to the behavior of microorganisms in drinking water treatment with ultrafiltration (UF) membranes. Herein, the membrane biofouling was investigated with different aluminum and iron salts. We found that Al2(SO4)3.18H2O performed better in reducing membrane fouling due to the slower growth rate of microorganisms. In comparison to Al2(SO4)3.18H2O, more EPS were induced with Fe2(SO4)3.xH2O, both in the membrane tank and the sludge on the cake layer. We also found that bacteria were the major microorganisms, of which the concentration was much higher than those of fungi and archaea. Further analyses showed that Proteobacteria was dominant in bacterial communities, which caused severe membrane fouling by forming a biofilm, especially for Fe2(SO4)3.xH2O. Additionally, the abundances of Bacteroidetes and Verrucomicrobia were relatively higher in the presence of Al2(SO4)3.18H2O, resulting in less severe biofouling by effectively degrading the protein and polysaccharide in EPS. As a result, in terms of microorganism behaviors, Al-based salts should be given preference as coagulants during actual operations. PMID- 29406123 TI - Treatment delivery verification in brachytherapy: Prospects of technology innovation. PMID- 29406124 TI - Comparing the RTOG/EORTC and LENT-SOMA scoring systems for the evaluation of late skin toxicity after 125I seed brachytherapy for parotid gland cancer. PMID- 29406125 TI - Technique adaptation, strategic replanning, and team learning during implementation of MR-guided brachytherapy for cervical cancer. AB - PURPOSE: MR-guided brachytherapy (MRgBT) with interstitial needles is associated with improved outcomes in cervical cancer patients. However, there are implementation barriers, including magnetic resonance (MR) access, practitioner familiarity/comfort, and efficiency. This study explores a graded MRgBT implementation strategy that included the adaptive use of needles, strategic use of MR imaging/planning, and team learning. METHODS AND MATERIALS: Twenty patients with cervical cancer were treated with high-dose-rate MRgBT (28 Gy in four fractions, two insertions, daily MR imaging/planning). A tandem/ring applicator alone was used for the first insertion in most patients. Needles were added for the second insertion based on evaluation of the initial dosimetry. An interdisciplinary expert team reviewed and discussed the MR images and treatment plans. RESULTS: Dosimetry-trigger technique adaptation with the addition of needles for the second insertion improved target coverage in all patients with suboptimal dosimetry initially without compromising organ-at-risk (OAR) sparing. Target and OAR planning objectives were achieved in most patients. There were small or no systematic differences in tumor or OAR dosimetry between imaging/planning once per insertion vs. daily and only small random variations. Peer review and discussion of images, contours, and plans promoted learning and process development. CONCLUSIONS: Technique adaptation based on the initial dosimetry is an efficient approach to implementing MRgBT while gaining comfort with the use of needles. MR imaging and planning once per insertion is safe in most patients as long as applicator shifts, and large anatomical changes are excluded. Team learning is essential to building individual and programmatic competencies. PMID- 29406126 TI - Selective attention to the mouth is associated with expressive language skills in monolingual and bilingual infants. AB - Infants increasingly attend to the mouths of others during the latter half of the first postnatal year, and individual differences in selective attention to talking mouths during infancy predict verbal skills during toddlerhood. There is some evidence suggesting that trajectories in mouth-looking vary by early language environment, in particular monolingual or bilingual language exposure, which may have differential consequences in developing sensitivity to the communicative and social affordances of the face. Here, we evaluated whether 6- to 12-month-olds' mouth-looking is related to skills associated with concurrent social communicative development-including early language functioning and emotion discriminability. We found that attention to the mouth of a talking face increased with age but that mouth-looking was more strongly associated with concurrent expressive language skills than chronological age for both monolingual and bilingual infants. Mouth-looking was not related to emotion discrimination. These data suggest that selective attention to a talking mouth may be one important mechanism by which infants learn language regardless of home language environment. PMID- 29406127 TI - Past and future. PMID- 29406128 TI - CHEST Reviewers 2017. PMID- 29406129 TI - A decision-making tool to prescribe knee orthoses in daily practice for patients with osteoarthritis. AB - OBJECTIVE: To develop a decision-making tool (DMT) to facilitate the prescription of knee orthoses for patients with osteoarthritis (OA) in daily practice. METHODS: A steering committee gathered a multidisciplinary task force experienced in OA management/clinical research. Two members performed a literature review with qualitative analysis of the highest-quality randomized controlled trials and practice guidelines to confirm evidence concerning knee orthosis for OA. A first DMT draft was presented to the task force in a 1-day meeting in January 2016. The first version of the DMT was criticized and discussed regarding everyday practice issues. Every step was discussed and amended until consensus agreement was achieved within the task force. Then 4 successive consultation rounds occurred by electronic communication, first with primary- and secondary-care physicians, then with international experts. All corrections and suggestions by each member were shared with the rest of the task force and included to reach final consensus. The final version was validated by the steering committee. RESULTS: The definition and indication of several types of knee orthoses (sleeve, patello-femoral, hinged or unicompartmental offloading braces) were detailed. Orthoses may be proposed in addition to first-line non-pharmacological treatment if patient acceptance is considered good. At every step, a specific clinical assessment is needed. DISCUSSION/CONCLUSION: Based on the latest high-level evidence, practice guidelines, and an expert panel, a DMT to facilitate daily practice prescription of knee orthoses for OA patients was designed. An evaluation of DMT implementation in a wide range of health professionals is still needed. PMID- 29406130 TI - Faculty Making the Grade. PMID- 29406131 TI - Voices of chief nursing executives informing a doctor of nursing practice program. AB - The purpose of this article is to describe the business case framework used to guide doctor of nursing practice (DNP) program enhancements and to discuss methods used to gain chief nurse executives' (CNEs) perspectives for desired curricular and experiential content for doctor of nursing practice nurses in health care system executive roles. Principal results of CNE interview responses were closely aligned to the knowledge, skills and/or attitudes identified by the national leadership organizations. Major conclusions of this article are that curriculum change should include increased emphasis on leadership, implementation science, and translation of evidence into practice methods. Business, information and technology management, policy, and health care law content would also need to be re-balanced to facilitate DNP graduates' health care system level practice. PMID- 29406132 TI - AACN's DNP essential II prepares clinicians for academic leadership: Three DNP graduates share their leadership journey. PMID- 29406133 TI - Implementing healthy work environment standards in an academic workplace: An update. AB - In 2005 the American Association of Critical Care Nurses defined six Healthy Work Environment (HWE) standards for the clinical setting (AACN, 2005), which were reaffirmed and expanded in 2016 (AACN, 2016). These clinical standards were adapted for use in the academic setting by Fontaine, Koh, and Carroll in 2012. The intention of this article is threefold: to present a revised version of the academic workplace standards which are appropriate for all School of Nursing (SON) employees, staff as well as faculty; to proposes the addition of a seventh standard, self-care, which provides the foundation for all standards; and to describe the continuing implementation of these seven standards at the University of Virginia School of Nursing (UVA SON). PMID- 29406134 TI - The internalization of professional nursing values in baccalaureate nursing students. PMID- 29406135 TI - Transforming nursing education in a 140-character world: The efficacy of becoming social. AB - A generational gap exists across educational settings today. The potential and actual mismatch of learning styles and curriculum delivery suggests that the current educational models are in need of change. The advent of social media has transformed students from passive recipients of information to co-creators and engaged members of a global and information rich community. Responding proactively with social media integration through a responsive curriculum delivery system would serve to enhance student engagement and improve collaborative learning opportunities. Future implications for social media use in research and education will allow for rapid and efficient research to practice dissemination. PMID- 29406136 TI - Social media use and cybercivility guidelines in U.S. nursing schools: A review of websites. AB - This research analyzes to what extent U.S. nursing schools use social media, their policies or guidelines on cybercivility in social media, online classrooms, and email correspondence, and whether these protocols are readily available to students. This website-based study employs a descriptive, cross-sectional, non experimental search design. Data were collected in nursing schools offering master's programs (n=197) and online graduate programs in master's degree (n=110) listed in the 2017 edition of U.S. News and World Report. School ranking was positively correlated with the total number of social networking sites being used in the schools, but not with the presence of cybercivility guidelines. About a third of the nursing schools in the sample had policies/guidelines concerning social media, while fewer than 10% had policies/guidelines about online classroom conduct (n=14) or email use (n=16). Key features of these protocols were professionalism, expected behaviors, and consequences. Establishing and implementing policies and guidelines regarding cybercivility is a vital step to promote a culture of civility online. It is especially important to do so in nursing schools where standards should reflect the values of the profession. PMID- 29406137 TI - Navigating unfamiliar waters: Men in nursing academia. AB - INTRODUCTION: Despite small numbers, men in nursing faculty positions provide unique diverse perspectives that are important to the strength of the profession. Nationwide, calls for increased numbers of diverse faculty continue. Despite this, the numbers of male nurses entering academic remain low. The purpose of this study was to identify and describe experiences of male nursing faculty in an effort to better understand what attracts male nurses to a role in academia, and what advice is most important when considering entering academia. METHOD: A qualitative descriptive approach was utilized to describe the findings from 12 participant interviews. RESULTS: The following themes immerged: reasons why men enter into academia, navigation of unfamiliar waters, and being the odd man out. PMID- 29406138 TI - Spiritual formation, secularization, and reform of professional nursing and education in antebellum America. AB - The origin story of professional nursing associated with antebellum American faith communities is all but lost. This paper provides historical evidence for professional nursing for that period using a case study approach that examines three faith communities: the Sisters and Daughters of Charity, the Shakers, and the Church of Jesus Christ of Latter Day Saints. The purpose is to present an historical analysis of the three communities' health beliefs, recipes and remedies that were foundational to the spiritual formation and education of professional nurses within their communities. The focus of the analysis is to place the evidence for professional nursing in these faith communities within the broader context of the contemporary American narrative of the "secularization" of professional nursing associated with the adoption of the Nightingale Training Model after 1873. Nursing became a profession in America because of the courage and passion of many for spiritual formation in community around a need to relieve suffering and demonstrate kindness. The history of American nursing is comprised of stories of powerful nurse ancestors that have the potential to inspire and unite us in that same purpose today despite the ambiguities that may still exist around spirituality, religiosity, and secularization. PMID- 29406139 TI - Lateral violence in nursing: Implications and strategies for nurse educators. PMID- 29406140 TI - A call for future nurses: School counselors' perceptions of the nursing role: A preliminary study. PMID- 29406141 TI - Blending the liberal arts and nursing: Creating a portrait for the 21st century. AB - The liberal arts and sciences serve as a core part of the educational discipline in nursing curriculum and are believed to undergird abilities for critical thinking, creativity, and holistic care (Hermann, 2004; McKie, 2012). Over time, science has taken on a more central role in nursing education, despite the acknowledged importance and contributions of liberal arts. The humanities are an essential part of liberal arts education and generally include disciplines such as history, literature, religion, philosophy, architecture, or fine arts (e.g., music, painting, sculpture, drama, or film) (Hermann, 2004). Nursing students identify that liberal arts improve their skills to communicate, think globally, navigate diversity, make decisions, and improve their human selves (McKie, 2012), therefore the purposeful inclusion of liberal arts and humanities into nursing pedagogy should be assured. Schools of nursing seated within liberal arts universities are in a position to take advantage of campus environments that seek to improve student knowledge, skills, abilities, and values (Scott, 2014). When caring for patients with complex medical, psychosocial, spiritual, and economic concerns, the ability to differentiate between what is true among a myriad of competing issues, and to identify solutions to these problems, are critical skills (Scott, 2014). This manuscript describes one type of focused effort by school of nursing (SON) faculty to integrate the humanities on a small, liberal arts campus into the nursing curriculum. The desire to do this led to a large, interdisciplinary project intended to enhance campus, community, faculty, and student opportunities to understand and ponder the complexities involved in caring for patients with Alzheimer's disease (AD). PMID- 29406142 TI - A Clinical Nurse Leader (CNL) practice development model to support integration of the CNL role into microsystem care delivery. AB - The Veterans Health Administration (VHA) Office of Nursing Services (ONS) was an early adopter of Clinical Nurse Leader (CNL) practice, generating some of the earliest pilot data of CNL practice effectiveness. In 2011 the VHA ONS CNL Implementation & Evaluation Service (CNL I&E) piloted a curriculum to facilitate CNL transition to effective practice at local VHA settings. In 2015, the CNL I&E and local VHA setting stakeholders collaborated to refine the program, based on lessons learned at the national and local level. The workgroup reviewed the literature to identify theoretical frameworks for CNL practice and practice development. The workgroup selected Benner et al.'s Novice-to-Expert model as the defining framework for CNL practice development, and Bender et al.'s CNL Practice Model as the defining framework for CNL practice integration. The selected frameworks were cross-walked against existing curriculum elements to identify and clarify additional practice development needs. The work generated key insights into: core stages of transition to effective practice; CNL progress and expectations for each stage; and organizational support structures necessary for CNL success at each stage. The refined CNL development model is a robust tool that can be applied to support consistent and effective integration of CNL practice into care delivery. PMID- 29406143 TI - Response to "Nursing students assaulted". PMID- 29406144 TI - Response to Dr. Phillip Greiner's letter to the editor. PMID- 29406145 TI - Building the pipeline of diverse nursing leaders: Reflections from the AACN Deans' mentoring program. PMID- 29406146 TI - Challenges and new horizons for sickle cell disease. PMID- 29406147 TI - Rituximab maintenance is efficacious, but is it useful? PMID- 29406148 TI - Revisiting WHO haemoglobin thresholds to define anaemia in clinical medicine and public health. PMID- 29406149 TI - Why is the synesthete's "A" red? Using a five-language dataset to disentangle the effects of shape, sound, semantics, and ordinality on inducer-concurrent relationships in grapheme-color synesthesia. AB - Grapheme-color synesthesia is a neurological phenomenon in which viewing a grapheme elicits an additional, automatic, and consistent sensation of color. Color-to-letter associations in synesthesia are interesting in their own right, but also offer an opportunity to examine relationships between visual, acoustic, and semantic aspects of language. Research using large populations of synesthetes has indeed found that grapheme-color pairings can be influenced by numerous properties of graphemes, but the contributions made by each of these explanatory factors are often confounded in a monolingual dataset (i.e., only English speaking synesthetes). Here, we report the first demonstration of how a multilingual dataset can reveal potentially-universal influences on synesthetic associations, and disentangle previously-confounded hypotheses about the relationship between properties of synesthetic color and properties of the grapheme that induces it. Numerous studies have reported that for English speaking synesthetes, "A" tends to be colored red more often than predicted by chance, and several explanatory factors have been proposed that could explain this association. Using a five-language dataset (native English, Dutch, Spanish, Japanese, and Korean speakers), we compare the predictions made by each explanatory factor, and show that only an ordinal explanation makes consistent predictions across all five languages, suggesting that the English "A" is red because the first grapheme of a synesthete's alphabet or syllabary tends to be associated with red. We propose that the relationship between the first grapheme and the color red is an association between an unusually-distinct ordinal position ("first") and an unusually-distinct color (red). We test the predictions made by this theory, and demonstrate that the first grapheme is unusually distinct (has a color that is distant in color space from the other letters' colors). Our results demonstrate the importance of considering cross-linguistic similarities and differences in synesthesia, and suggest that some influences on grapheme-color associations in synesthesia might be universal. PMID- 29406151 TI - Acknowledgements 2017. PMID- 29406150 TI - Neurolinguistic processing when the brain matures without language. AB - The extent to which development of the brain language system is modulated by the temporal onset of linguistic experience relative to post-natal brain maturation is unknown. This crucial question cannot be investigated with the hearing population because spoken language is ubiquitous in the environment of newborns. Deafness blocks infants' language experience in a spoken form, and in a signed form when it is absent from the environment. Using anatomically constrained magnetoencephalography, aMEG, we neuroimaged lexico-semantic processing in a deaf adult whose linguistic experience began in young adulthood. Despite using language for 30 years after initially learning it, this individual exhibited limited neural response in the perisylvian language areas to signed words during the 300-400 ms temporal window, suggesting that the brain language system requires linguistic experience during brain growth to achieve functionality. The present case study primarily exhibited neural activations in response to signed words in dorsolateral superior parietal and occipital areas bilaterally, replicating the neural patterns exhibited by two previously case studies who matured without language until early adolescence (Ferjan Ramirez N, Leonard MK, Torres C, Hatrak M, Halgren E, Mayberry RI. 2014). The dorsal pathway appears to assume the task of processing words when the brain matures without experiencing the form-meaning network of a language. PMID- 29406152 TI - CRISPR-Cas Antiviral Strategies. PMID- 29406153 TI - Contact reductions from live poultry market closures limit the epidemic of human infections with H7N9 influenza. AB - An early steep increase in the number of humans infected with avian influenza A(H7N9) virus was observed in China, raising great public concern domestically and internationally. Little is known about the dynamics of the transmission contacts between poultry and human populations, although such understanding is essential for developing effective strategies to control this zoonosis. In this study, we evaluated the effects of contact reductions from live poultry markets (LPMs) closures on the transmission of H7N9 virus during epidemics in Guangdong Province, China. A mathematical model of the poultry-to-person transmission dynamics of H7N9 virus was constructed. The parameters in the model were estimated from publicly available data on confirmed cases of human infection and information on LPMs closure during 2013-2017. By fitting the model, we measured the time-dependent contact quantity of the susceptible population to LPMs. The results showed that periodic intervention strategies can greatly reduce the magnitude of outbreaks, and the earlier interventions for policy are implemented, the smaller is the outbreak. The control efforts for LPMs to decrease the contact quantity are critical in preventing epidemics in the long term. This model should provide important insights for the development of a national intervention strategy for the long-term control of avian influenza virus epidemics. PMID- 29406154 TI - Meningococcal disease and control in China: Findings and updates from the Global Meningococcal Initiative (GMI). AB - The Global Meningococcal Initiative (GMI) is a global expert group, including scientists, clinicians and public health officials from a wide range of specialities. The goal of the GMI is to prevent meningococcal disease worldwide through education, research, and co-operation. The Chinese GMI roundtable meeting was held in June 2017. The GMI met with local experts to gain insight into the meningococcal disease burden in China and current prevention and vaccination strategies in place. China experienced five epidemics of serogroup A meningococcal disease (MenA) between 1938 and 1977, with peak incidence of 403/100,000 recorded in 1967. MenA incidence rates have significantly declined following the universal introduction of the MenA polysaccharide vaccine in China in the 1980s. Further, surveillance data indicates changing meningococcal epidemiology in China with the emergence of new clones of serogroup B from serogroup C clonal complex (cc) 4821 due to capsular switching, and the international spread of serogroup W cc11. The importance of carriage and herd protection for controlling meningococcal disease was highlighted with the view to introduce conjugate vaccines and serogroup B vaccines into the national immunization schedule. Improved disease surveillance and standardized laboratory techniques across and within provinces will ensure optimal epidemiological monitoring. PMID- 29406156 TI - News & Notes. PMID- 29406158 TI - News Beyond Our Pages. PMID- 29406155 TI - Free water determines diffusion alterations and clinical status in cerebral small vessel disease. AB - INTRODUCTION: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. METHODS: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability). RESULTS: Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (R2 up to 34%, P < .0001). Findings were consistent across patients with CADASIL and sporadic SVD. DISCUSSION: Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization. PMID- 29406159 TI - Correction. PMID- 29406160 TI - Correction. PMID- 29406161 TI - [Henneguya wolinensis (Myxosporea: Myxobolidae), a new for Russian fauna parasite from the perch Perca fluviatilis L.]. AB - The infection of the perch Perea fluviatilis L. with myxosporean Henneguya wolinensis Romuk-Wodoracki, 1990 has been detected. This is the second finding of this parasite after its original descriptin and the first for Russia. Plasmodium of this species develops in the epidermis under scales throughout the body causing the formation of white cysts up to 1 mm. Spores are fusiform, large, their average length constitutes 25.5 MUm without the caudal appendages and 62 MUm with them. Slight morphological differences in spore structure comparing to original description have been revealed. PMID- 29406162 TI - 8th International Symposium on Fish Endocrinology. PMID- 29406164 TI - Sponsoring Societies. PMID- 29406165 TI - Table of Contents (Color: CMYK pg 1 only; other TOC pages are bw). PMID- 29406166 TI - Perineural dexamethasone: the dilemma of systematic reviews and meta-analyses. PMID- 29406167 TI - Saline studies: how (not) to put nails in the coffin. PMID- 29406168 TI - Postoperative fluid therapy on the ward: another job for anaesthetists? PMID- 29406169 TI - Airway management inside and outside operating rooms-circumstances are quite different. PMID- 29406170 TI - Modified supraglottic airway for gastroscopy: an advance in patient safety? PMID- 29406171 TI - Co-administration of dexamethasone with peripheral nerve block: intravenous vs perineural application: systematic review, meta-analysis, meta-regression and trial-sequential analysis. AB - BACKGROUND: I.V. and perineural dexamethasone have both been found to prolong loco-regional analgesia compared with controls without dexamethasone. It is unclear whether perineural administration offers advantages when compared with i.v. dexamethasone. METHODS: A systematic literature search was performed to identify randomized controlled double-blind trials that compared i.v. with perineural dexamethasone in patients undergoing surgery. Using the random effects model, risk ratio (for binary variables), weighted mean difference (for continuous variables) and 95% confidence intervals were calculated. We applied trial sequential analysis to assess the risks of type I and II error, meta regression for the study of the doseresponsive relationship, and the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: We identified 10 randomized controlled double-blind trials (783 patients). When using conventional meta-analysis of nine low risk of bias trials, we found a statistically significantly longer duration of analgesia, our primary outcome with perineural dexamethasone (241 min, 95%CI, 87, 394 min). When trial sequential analysis was applied, this result was confirmed. Meta-regression did not show a dose-response relationship. Despite the precision in the results, using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE), we assessed the quality of the evidence for our primary outcome as low. CONCLUSIONS: There is evidence that perineural dexamethasone prolongs the duration of analgesia compared with i.v. dexamethasone. Using GRADE, this evidence is low quality. PMID- 29406173 TI - Analgesic efficacy of bilateral superficial cervical plexus block for thyroid surgery: meta-analysis and systematic review. AB - BACKGROUND: Thyroid surgery is moderately painful, but is increasingly being considered as a day-case procedure. Bilateral superficial cervical plexus block (BSCPB) provides an adjuvant technique to facilitate this approach, but there is great evidential heterogeneity in randomised controlled trials (RCTs) about its use. METHODS: A systematic search, critical appraisal, and analysis of RCTs was performed. Trials investigating preoperative or postoperative BSCPB compared with control in patients undergoing thyroid surgery via neck incision were included. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous data, whilst continuous data were analysed using standard mean difference. Primary outcome was rescue analgesic requirement in the first 24 postoperative hours. Secondary outcomes were visual analogue scale (VAS) scores at 0, 4, and 24 h, time until first analgesic request, intraoperative analgesic requirements, length of hospital stay, and incidence of postoperative nausea and vomiting (PONV). RESULTS: Fourteen RCTs published between 2001 and 2016 including 1154 patients were included. The overall effect of BSCPB compared with control showed a reduction in analgesic requirement (OR 0.30; 95% CI 0.18, 0.51; P<0.00001). There was improvement in VAS scores (P<0.002) and time to first analgesic requirement in the BSCPB group (P<0.00001). Length of hospital stay was reduced by 6 h by use of BSCPB. There was no significant change in the incidence of PONV with its use (OR 0.82; 95% CI 0.49-1.37; P=0.44). CONCLUSIONS: BSCPB offers analgesic efficacy in the early postoperative period for up to 24 h after thyroid surgery, with reduced length of hospital stay, but without any beneficial effect on PONV. PMID- 29406172 TI - The impact of neuraxial clonidine on postoperative analgesia and perioperative adverse effects in women having elective Caesarean section-a systematic review and meta-analysis. AB - Neuraxial clonidine improves postoperative analgesia in the general surgical population. The efficacy and safety of neuraxial clonidine as a postoperative analgesic adjunct in the Caesarean section population still remains unclear. This systematic review and meta-analysis aims to evaluate the effect of perioperative neuraxial clonidine on postoperative analgesia in women having Caesarean section under neuraxial anaesthesia. We included randomized controlled trials comparing the analgesic efficacy of the perioperative administration of neuraxial clonidine alone or in combination with a local anaesthetic and/or opioids in women having elective Caesarean section under neuraxial anaesthesia when compared with placebo. PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE were searched until February 2017. Eighteen studies were included in the meta analysis. Neuraxial clonidine reduced 24 h morphine consumption [mean difference (MD): -7.2 mg; 95% confidence interval (CI): -11.4, -3.0 mg; seven studies] and prolonged time to first analgesic request (MD: 135 min; 95% CI: 102, 168 min; 16 studies) when compared with the control group. Neuraxial clonidine increased intraoperative hypotension [odds ratio (OR): 2.849; 95% CI: 1.363, 5.957], intraoperative sedation (OR: 2.355; 95% CI: 1.016, 5.459), but reduced the need for intraoperative analgesic supplementation (OR: 0.224; 95% CI: 0.076, 0.663). The effect of clonidine on intraoperative bradycardia, intraoperative and postoperative nausea and vomiting, postoperative sedation, and pruritus were inconclusive. Neuraxial clonidine did not negatively impact neonatal umbilical artery pH or Apgar scores. This review demonstrates that neuraxial clonidine enhances postoperative analgesia in women having Caesarean section with neuraxial anaesthesia, but this has to be balanced against increased maternal adverse effects. PMID- 29406174 TI - High-dose versus low-dose local anaesthetic for transversus abdominis plane block post-Caesarean delivery analgesia: a meta-analysis. AB - BACKGROUND: The optimal local-anaesthetic (LA) dose for transversus-abdominis plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for Caesarean delivery (CD) with low-dose (LD) LA demonstrated non-inferiority in terms of analgesic efficacy, compared with high-dose (HD) LA. METHODS: A literature search was performed for randomised controlled trials examining the analgesic efficacy of TAP blocks vs control after CD. The different dosing used in these studies was classified as HD or LD (bupivacaine equivalents >50 or <=50 mg per block side, respectively). The pooled results of each dose group vs control were indirectly compared using the Q test. The primary outcome was 24 h opioid consumption. Secondary outcomes included 6 and 24 h postoperative pain scores, time to first analgesia, 6 h opioid consumption, opioid-related side effects, and maternal satisfaction. RESULTS: Fourteen studies consisting of 770 women (389 TAP and 381 control) were included. Compared with controls, the 24 h opioid consumption (milligram morphine equivalents) was lower in HD [mean difference (MD) 95% confidence interval (CI) -22.41 (-38.56, -6.26); P=0.007; I2=93%] and LD [MD 95% CI -16.29 (-29.74, -2.84); P=0.02; I2=98%] TAP groups. However, no differences were demonstrated between the HD and LD groups (P=0.57). There were also no differences between the HD and LD groups for the 6 h opioid consumption, time to first analgesia, 6 and 24 h pain scores, postoperative nausea and vomiting, pruritus, and maternal satisfaction. CONCLUSIONS: Low-dose TAP blocks for Caesarean delivery provide analgesia and opioid-sparing effects comparable with the high-dose blocks. This suggests that lower doses can be used to reduce local anaesthetic toxicity risk without compromising the analgesic efficacy. PMID- 29406175 TI - Competency-based assessment tools for regional anaesthesia: a narrative review. AB - Competency-based assessment tools are used in regional anaesthesia to measure the performance of study participants, trainees, and consultants. This narrative review was performed to appraise currently published assessment tools for regional anaesthesia. A literature search found 397 citations of which 28 peer reviewed studies met the inclusion criteria of primary psychometric evaluation of assessment tools for regional anaesthesia. The included studies were diverse in the type of assessment and the skill set being assessed. The types of assessments included multiple-choice questions, hand-motion analysis, cumulative sum, visuospatial and psychomotor screening, checklists, and global rating scales. The skill sets that were assessed included holistic regional anaesthesia technical and non-technical performance observed at the bedside, to isolated part-tasks, such as needle tip visualisation under ultrasound. To evaluate validity and reliability, we compared the studies against published medical education consensus statements on ideal assessment tools. We discuss the relative merits of different tools when used to assess regional anaesthesia, the importance of psychometrically robust assessment tools in competency-based anaesthesia education, and directions for future education research in regional anaesthesia. PMID- 29406176 TI - Normal saline versus a balanced crystalloid for goal-directed perioperative fluid therapy in major abdominal surgery: a double-blind randomised controlled study. AB - BACKGROUND: This double-blind randomised controlled trial investigated whether normal saline or a balanced crystalloid has distinct effects on vasopressor use in patients undergoing major abdominal surgery. METHODS: Patients received either normal saline 0.9% or an acetate-buffered crystalloid for intraoperative volume replacement in a goal-directed fashion. The primary outcome was need for vasopressors; the secondary outcomes were the total dose of catecholamines, total perioperative fluid, and unplanned intensive care admissions. RESULTS: This study was terminated early for safety reasons. A total of 60 out of the planned 240 patients were randomized. Thirty patients received normal saline and 30 patients received the balanced crystalloid, with a total volume of 3427 (2732-4130) ml and 3144 (1673-4926), respectively. The normal-saline group developed hyperchloraemic metabolic acidosis. More patients needed vasopressors for circulatory support in the normal-saline group compared with the buffered crystalloid group (97% vs 67%, respectively; P=0.033). The median weight and anaesthesia duration-adjusted dose of norepinephrine were 0.11 (0.00-0.45) ng kg-1 min-1 and 0.00 (0.00-0.00) kg-1 min-1 in the normal-saline and balanced-crystalloid groups, respectively (P=0.003). Cox regression revealed that the need for vasopressors was related to a high volume of administered fluid, normal-saline resuscitation, and lower mean arterial blood pressure. There was no difference between the groups in total perioperative fluid and unplanned intensive-care-unit admissions. Between-group differences in the duration of anaesthesia did not influence the necessity for a vasopressor. CONCLUSIONS: Compared with patients receiving a balanced crystalloid, normal saline in patients undergoing major abdominal surgery was associated with an increased need for vasopressor support. This should be interpreted in view of the large volume of fluid resuscitation and the small sample size because of the preliminary termination of the study. CLINICAL TRIAL REGISTRATION: EudraCT 2014-004867-19, NCT 02414555. PMID- 29406177 TI - Could patient-controlled thirst-driven fluid administration lead to more rapid rehydration than clinician-directed fluid management? An early feasibility study. AB - BACKGROUND: Fluid management is a major factor determining perioperative outcome, yet in reality, fluid administration practice is variable. Thirst however, is a highly sensitive and reliable indicator of fluid deficits. We explored the use of thirst sensation to trigger i.v. fluid boluses to guide individualized fluid management. METHODS: We performed a randomised double crossover trial on 16 healthy male volunteers, of mean age 31 yr and BMI 24.4 kg m-2. Twice, after administrations of oral furosemide (40 mg) and 12 h of oral fluid restriction, participants received a 4-h i.v. fluid infusion. In the experimental arm, participants pressed a trigger to relieve their thirst, administering a 200 ml bolus. In the control arm, i.v. fluid was infused following National Institute for Health and Clinical Excellence (NICE) guidelines at 1.25 ml kg-1 h-1 with a clinician delivered 500 ml i.v. bolus in response to clinical signs of dehydration. Plasma osmolality and urine specific gravity were measured before and after each infusion. RESULTS: More fluid was infused in response to thirst than by adherence to NICE guidelines, with a mean difference of 743 ml (P=0.0005). Thirst-driven fluid administration was fitted to an exponential function of time, plateauing after a mean half-life of 98.8 min. In the experimental arm there was a greater reduction in urine specific gravity and thirst score with mean differences 0.0053 g cm-3 (P=0.002) and 3.3 (P=0.003), respectively. Plasma osmolality demonstrated no fluid overload. CONCLUSIONS: A system delivering i.v. fluid in response to subjective thirst corrects fluid deficits in healthy participants. A clinical feasibility study will assess the potential use of this system in the perioperative setting. CLINICAL TRIAL REGISTRATION: NCT 03176043. PMID- 29406179 TI - Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging. AB - BACKGROUND: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. METHODS: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. RESULTS: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. CONCLUSIONS: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. CLINICAL TRIAL REGISTRATION: NCT0061015. PMID- 29406178 TI - High-sensitivity cardiac troponin T in young, healthy adults undergoing non cardiac surgery. AB - BACKGROUND: It is unclear if isolated postoperative cardiac-troponin elevation, often referred to as myocardial injury, represents a pathological event, as control studies in otherwise healthy adults are lacking. METHODS: In this single centre prospective observational cohort study, serial high-sensitivity cardiac troponin T (hscTnT) plasma concentrations were obtained from young, healthy adults undergoing elective orthopaedic surgery at three time points: before operation, 2-6 h, and 18-30 h after surgery. End points were hscTnT increases after surgery: >=20% (exceeding analytical variability), >=50% (exceeding short term biological variability), and >=85% (exceeding long-term biological variability). The secondary end point was myocardial injury, defined as new postoperative hscTnT elevation >99th % upper reference limit (URL) (women >10 ng litre-1; men >15 ng litre-1). RESULTS: Amongst the study population (n=95), no hscTnT increase >=20% was detected in 68 patients (73%). A hscTnT increase between 20% and 49% was observed in 17 patients (18%), 50-84% in seven patients (7%), and >=85% in three patients (3%). Twenty patients (21%) had an absolute DeltahscTnT between 0 and 2 ng litre-1, 12 patients (13%) between 2 and 4 ng litre-1, three patients between 4 and 6 ng litre-1, and one patient (1%) between 6 and 8 ng litre-1. Myocardial injury (new hscTnT elevation >99th%) was diagnosed in one patient (1%). The median hscTnT concentrations did not increase after operation, and were 4 (3.9-5, inter-quartile range) ng litre-1 at baseline, 4 (3.9-5) ng litre-1 at 2-6 h after surgery, and 4 (3.9-5) ng litre-1 on postoperative day 1. CONCLUSIONS: One in four young adult patients without known cardiovascular disease developed a postoperative hscTnT increase, but without exceeding the 99th% URL and without evidence of myocardial ischaemia. These results may have important ramifications for the concept of postoperative myocardial injury, as they suggest that, in some patients, postoperative cardiac troponin increases may be the result of a normal physiological process in the surgical setting. CLINICAL TRIAL REGISTRATION: NCT 02394288. PMID- 29406180 TI - Intravenous dexamethasone fails to prolong psoas compartment block when assessed by objective pinprick sensory testing: a prospective, randomised, dose-dependent, placebo-controlled equivalency trial. AB - BACKGROUND: Recent studies have concluded that i.v. dexamethasone can prolong the duration of peripheral nerve blockade. We hypothesized that a 4 mg dose would equally prolong the duration of psoas compartment blocks (PCBs) when compared with 8 mg, and that both doses would prolong the duration when compared with placebo. METHODS: This was a prospective, randomized, placebo-controlled, dose dependent, equivalency trial with 115 patients undergoing total hip arthroplasty. The patients received a PCB. Subsequently, 15 patients received i.v. normal saline (placebo), 50 patients received i.v. dexamethasone 4 mg, and 50 patients received i.v. dexamethasone 8 mg. The primary outcome was the duration in hours of PCB, determined by serial pinprick assessments. Secondary outcomes included pain scores, time to first analgesic, and opioid consumption. An intention-to treat-analysis (ITA) and per-protocol analysis (PPA) were performed. RESULTS: The ITA showed that block duration in the 4 and 8 mg groups was equivalent [mean (standard deviation), 18.5 h (8.0) vs 18.1 h (7.1)]. However, neither group differed from placebo [19.6 h (6.7), (4 mg vs placebo), P=0.97; (8 mg vs placebo), P=0.77)]. Postoperative pain scores and opioid consumption were not different between groups. Time to first analgesic was not different between the 4 and 8 mg groups, or the 4 mg and placebo groups. The 8 mg group, however, had a longer time to first analgesic (median of 533 vs 432 min, P=0.047) when compared with placebo, although the significance was not observed in the PPA (P=0.058). CONCLUSIONS: I.V. dexamethasone did not prolong PCB when duration was objectively assessed, or decrease total opioid consumption. However, dexamethasone 8 mg prolonged the time to first analgesic. CLINICAL TRIAL REGISTRATION: NCT 02464176. PMID- 29406181 TI - Local anaesthetic dosage of peripheral nerve blocks in children: analysis of 40 121 blocks from the Pediatric Regional Anesthesia Network database. AB - BACKGROUND: The knowledge regarding appropriate dosage of local anaesthetics for peripheral nerve blocks in children is very scarce. The main objective of the current investigation was to evaluate dosing patterns of local anaesthetics in children receiving peripheral nerve blocks across multiple paediatric hospitals in the USA. We also sought to estimate the incidence of local anaesthetic systemic toxicity. METHODS: This is an observational study using the Pediatric Regional Anesthesia Network (PRAN) database. Data on every peripheral nerve block in patients aged <18 years placed from April 1, 2007 to May 31, 2015 were examined as a subset of the PRAN protocol. Data were examined for the type and dose of local anaesthetic and for the presence of local anaesthetic systemic toxicity. RESULTS: In total, 40 121 peripheral nerve blocks in children were analysed. Individual analyses of block type demonstrated large local anaesthetic dose variability with a five- to 10-fold spread depending on the block type. Two patients developed local anaesthetic systemic toxicity, resulting in an estimated incidence (95% CI) per blocks performed of 0.005% (0.001-0.015%). None of the patients had any short- or long-term complications or sequelae. CONCLUSIONS: We detected a large variability in the local anaesthetic dosing practices for peripheral nerve blocks in children across multiple hospitals in the USA. Nonetheless, the risk of local anaesthetic systemic toxicity was very low. Due to the lack of dose findings studies, our results suggest the need to develop practice guidelines to minimize variability of regional anaesthesia practices in children. PMID- 29406182 TI - Guidelines for the management of tracheal intubation in critically ill adults. AB - These guidelines describe a comprehensive strategy to optimize oxygenation, airway management, and tracheal intubation in critically ill patients, in all hospital locations. They are a direct response to the 4th National Audit Project of the Royal College of Anaesthetists and Difficult Airway Society, which highlighted deficient management of these extremely vulnerable patients leading to major complications and avoidable deaths. They are founded on robust evidence where available, supplemented by expert consensus opinion where it is not. These guidelines recognize that improved outcomes of emergency airway management require closer attention to human factors, rather than simply introduction of new devices or improved technical proficiency. They stress the role of the airway team, a shared mental model, planning, and communication throughout airway management. The primacy of oxygenation including pre- and peroxygenation is emphasized. A modified rapid sequence approach is recommended. Optimal management is presented in an algorithm that combines Plans B and C, incorporating elements of the Vortex approach. To avoid delays and task fixation, the importance of limiting procedural attempts, promptly recognizing failure, and transitioning to the next algorithm step are emphasized. The guidelines recommend early use of a videolaryngoscope, with a screen visible to all, and second generation supraglottic airways for airway rescue. Recommendations for emergency front of neck airway are for a scalpel-bougie-tube technique while acknowledging the value of other techniques performed by trained experts. As most critical care airway catastrophes occur after intubation, from dislodged or blocked tubes, essential methods to avoid these complications are also emphasized. PMID- 29406183 TI - Efficacy of a new dual channel laryngeal mask airway, the LMA(r)GastroTM Airway, for upper gastrointestinal endoscopy: a prospective observational study. AB - BACKGROUND: Significant cardiorespiratory events are frequent in patients undergoing gastrointestinal endoscopy. Central to the occurrence of respiratory events is an unsecured airway. This study sought to determine the efficacy of a new laryngeal mask airway, the LMA(r)GastroTM Airway (Teleflex Medical, Athlone, Ireland), in patients undergoing upper gastrointestinal endoscopy. New design features include a dedicated channel for oesophageal intubation and separate channel with terminal cuff for lung ventilation. METHODS: In a prospective, open label, observational study, 292 ASA physical status classification 1 and 2 patients at low risk of pulmonary aspiration undergoing upper gastrointestinal endoscopy received i.v. propofol anaesthesia and standardized insertion of the LMA(r)GastroTM Airway. Endoscopy outcomes included insertion success, first attempt success, and ease of endoscope insertion. LMA(r)GastroTM Airway outcomes included insertion success, first attempt success, ease of insertion, lowest oxygen saturation, airway compromise, laryngospasm, bloodstained device, and sore throat. RESULTS: Per protocol analysis (n=290), the endoscopy success rate amongst the cohort with successful LMA(r)GastroTM Airway insertion was 99% [95% confidence interval (CI): 98, 100]. LMA(r)GastroTM Airway insertion success rate (n=292) was 99% (95% CI: 98, 100). For endoscopy and LMA(r)GastroTM Airway insertion success, the lower limit of the 95% CIs was at least 98%, indicating LMA(r)GastroTM Airway efficacy. Median (inter-quartile range) lowest intraoperative oxygen saturation was 98% (98, 99). Only one serious adverse event occurred (re-admission for sore throat and inability to tolerate fluids) and was reported to the Tasmanian Health and Medical Human Research Ethics Committee. CONCLUSIONS: The LMA(r)GastroTM Airway appears effective for clinical use in upper gastrointestinal endoscopy. CLINICAL TRIAL REGISTRATION: ACTRN12616001464459. PMID- 29406184 TI - Effect of preoxygenation using non-invasive ventilation before intubation on subsequent organ failures in hypoxaemic patients: a randomised clinical trial. AB - BACKGROUND: Previous data showed that non-invasive ventilation (NIV) applied for 3 min before tracheal intubation ensured better oxygenation compared with using a non-rebreather bag-valve-mask. We aimed to determine whether preoxygenation using NIV is effective in reducing the incidence of organ dysfunction in hypoxaemic, critically ill patients in intensive care. METHODS: A multicentre, randomised, open-label trial evaluating 100% FiO2 administered with NIV (99 patients) vs with face mask (102 patients) for 3 min before tracheal intubation. The primary endpoint was the maximal value of Sequential Organ Failure Assessment score within 7 days after intubation. RESULTS: The median (inter-quartile range) values of the maximal value of the Sequential Organ Failure Assessment score within 7 days post-intubation were not significantly different between the two randomised groups: nine (6-12) in the NIV group vs 10 (6-12) in the face mask group (P=0.65). In patients treated by NIV prior to the randomisation, there was a significant increase in the occurrence in adverse events in patients randomised to face mask [odds ratio=5.23 (1.61;16.99), P=0.0059]. CONCLUSIONS: This study failed to demonstrate any benefits of using NIV as a preoxygenation method to reduce organ dysfunction compared with usual preoxygenation in hypoxaemic, critically ill patients requiring tracheal intubation for invasive ventilation. NIV should not be discontinued for preoxygenation in the cases of patients treated by NIV before the decision to intubate. CLINICAL TRIAL REGISTRATION: NCT00472160. PMID- 29406185 TI - Differential effects of sevoflurane on the metastatic potential and chemosensitivity of non-small-cell lung adenocarcinoma and renal cell carcinoma in vitro. AB - BACKGROUND: Increasing evidence suggests that perioperative factors including anaesthetics influence cancer recurrence and metastasis after surgery. This study investigated the influence of sevoflurane on the response of lung and renal cancer cells to cisplatin, with focus on transforming growth factor-beta (TGF beta) and osteopontin (OPN) that are both closely associated with cancer tumorigenesis and metastasis. METHODS: Non-small cell lung adenocarcinoma (A549) and renal cell carcinoma (RCC4) cells were exposed to 3.6% sevoflurane for two hrs. Malignant potential represented by cell viability, migration, chemosensitivity to cisplatin was evaluated. Expression of OPN, TGF-beta1, TGF beta receptor type II (TGF-betaRII) and the canonical downstream effector Smad3 was assessed. SiRNA knockdown of TGF-beta1 and OPN and chemical inhibition of TGF betaRI/II was performed. RESULTS: Sevoflurane reduced cell viability (0.394) versus control (0.459) (P < 0.01), enhanced chemosensitivity but had no effect on migration of A549 cells. It enhanced viability (0.467) versus control (0.347) (P < 0.001), chemoresistance and migration of RCC4. In A549, there was enhanced nuclear Smad3. In RCC4, TGF-betaRII and OPN were upregulated, while TGF-beta1 was over- expressed with reduced nuclear Smad3. TGF-betaRII inhibition and OPN knockdown abolished sevoflurane-mediated viability, and migration, respectively, in RCC4. CONCLUSIONS: Sevoflurane promotes the metastatic potential of renal carcinoma, but not of non-small cell lung cancer. This may be associated with its differential effect on cellular signalling including TGF-beta. Our findings indicate that sevoflurane may have different effects on the metastatic potential and chemosensitivity of different tumour types. PMID- 29406186 TI - Current concepts of fluid management in enhanced recovery pathways. AB - Perioperative fluid management impacts outcomes and plays a pivotal role in enhanced recovery pathways (ERPs). There have been major advances in understanding the effects of fluid therapy and administration during the perioperative period. Improving fluid management during this period leads to a decrease in complications, decrease in length of stay (LOS), and enhanced patient outcomes. It is important to consider preoperative and postoperative fluid management to be just as critical as intraoperative management given multiple associated benefits to the patients. Preoperative hydration with (complex) carbohydrate drinks up until 2 h before surgery is safe and should be encouraged, as this helps improve metabolism, decrease insulin resistance, reduce anxiety, and reduce nausea and vomiting. During the intraoperative period, the goals of fluid management are to maintain euvolemia using an individualized plan for fluid and haemodynamic management, matching the needs for monitoring with patient and surgical risk through goal-directed therapy (GDT). By combining the use of fluids and inotropes, GDT uses measurements and indicators of cardiac output and stroke volume to improve blood flow intraoperatively, and ultimately reduce LOS and complications. In the postoperative period, an early transition to oral hydration helps to enhance the conditions for healing and recovery from surgery. I.V. fluid therapy should be kept at a minimum, and urine output should not be the driving force for fluid administration. The optimization of perioperative fluid management is critical to ERPs as it helps improve pulmonary function, tissue oxygenation, gastrointestinal motility, and wound healing. PMID- 29406187 TI - Choice of fluid type: physiological concepts and perioperative indications. AB - The consensus that i.v. resuscitation fluids should be considered as drugs with specific dose recommendations, contraindications, and side-effects has led to an increased attention for the choice of fluid during perioperative care. In particular, the debate concerning possible adverse effects of unbalanced fluids and hydroxyethyl starches resulted in a re-evaluation of the roles of different fluid types in the perioperative setting. This review provides a concise overview of the current knowledge regarding the efficacy and safety of distinct fluid types for perioperative use. First, basic physiological aspects and possible side effects are explained. Second, we focus on considerations regarding fluid choice for specific perioperative indications based on an analysis of available randomized controlled trials. PMID- 29406188 TI - Intravenous fluids: effects on renal outcomes. AB - Intravenous fluid therapy is the most commonly prescribed inpatient medication in hospitals around the world. Intravenous fluids are drugs and have an indication, a dose, and expected and unintended effects. The type and amount of fluid given to patients are both important, and can either hasten or slow recovery depending on how they are administered. This narrative review provides a brief summary of the effect of intravenous fluid administration on kidney function and on renal outcome measures of relevance to both patients and clinicians. Several large clinical trials of fluid therapy are currently underway, the results of which are likely to change clinical practice. PMID- 29406190 TI - Predicting successful supraclavicular brachial plexus block using pulse oximeter perfusion index: is it really an objective outcome? PMID- 29406189 TI - Non-opioid analgesic use and concerns for impaired organ protection. PMID- 29406191 TI - Response to 'Lack of benefit of near-infrared spectroscopy monitoring for improving patient outcomes. Case closed?' PMID- 29406192 TI - Supplementary fibrinogen in the management of bleeding: re-evaluation of data from clinical trials. PMID- 29406193 TI - Positive end-expiratory pressure in obese patients during general anaesthesia. The role of intra-abdominal pressure. PMID- 29406194 TI - Response to: 'Positive end-expiratory pressure in obese patients during general anaesthesia. The role of intra-abdominal pressure'. PMID- 29406195 TI - Response to: 'Postoperative pulmonary complications, pulmonary and systemic inflammatory responses after lung resection surgery with prolonged one-lung ventilation. Randomised controlled trial comparing intravenous and inhalational anaesthesia'. PMID- 29406196 TI - Adrenergic blockade inhibits bacterial quorum sensing and reverses Warburg effect in septic shock. PMID- 29406197 TI - Response to 'Septic shock, Warburg effect, quorum sensing, and adrenergic blockers'. PMID- 29406198 TI - Clinically significant reductions in morphine consumption need to take account of baseline risk: presentation of a novel meta-analysis methodology. PMID- 29406199 TI - In the February issue.... PMID- 29406200 TI - Evidence, Not Evangelism, for Dietary Recommendations. PMID- 29406201 TI - Proton Pump Inhibitors: Review of Emerging Concerns. AB - First introduced in 1989, proton pump inhibitors (PPIs) are among the most widely utilized medications worldwide, both in the ambulatory and inpatient clinical settings. The PPIs are currently approved by the US Food and Drug Administration for the management of a variety of gastrointestinal disorders including symptomatic peptic ulcer disease, gastroesophageal reflux disease, and nonulcer dyspepsia as well as for prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. PPIs inhibit gastric acid secretion, and the most commonly associated adverse effects include abdominal pain, diarrhea, and headache. Although PPIs have had an encouraging safety profile, recent studies regarding the long-term use of PPI medications have noted potential adverse effects, including risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B12 deficiency, chronic kidney disease, and dementia. These emerging data have led to subsequent investigations to assess these potential risks in patients receiving long-term PPI therapy. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. Hence, when clinically indicated, PPIs can be prescribed at the lowest effective dose for symptom control. PMID- 29406202 TI - Diagnosis and Management of Headache in Older Adults. AB - Headache is a common, disabling neurologic problem in all age groups, including older adults. In older adults, headache is most likely a primary disorder, such as tension-type headache or migraine; however, there is a higher risk of secondary causes, such as giant cell arteritis or intracranial lesions, than in younger adults. Thus, based on the headache history, clinical examination, and presence of headache red flags, a focused diagnostic evaluation is recommended, ranging from blood tests to neuroimaging, depending on the headache characteristics. Regardless of the primary or secondary headache disorder diagnosis, treatment options may be limited in older patients and may need to be tailored to the presence of comorbid medical conditions. The purpose of this review is to provide an update on the management of headache in older adults, from diagnosis to treatment. PMID- 29406203 TI - In Reply-Diaphragmatic Pacemaker for Perry Syndrome. PMID- 29406204 TI - Diaphragmatic Pacemaker for Perry Syndrome. PMID- 29406205 TI - A Stony Gland! PMID- 29406206 TI - Mucinous Neoplasm of the Appendix and Pseudomyxoma Peritonei. PMID- 29406207 TI - Water Lily, Black-eyed Susan, Fern by Yulia Hanansen. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 29406208 TI - Highlights from the Current Issue - Audiovisual Summary. PMID- 29406209 TI - Retraction notice to Doxycycline Alters the Expression of Matrix Metalloproteases in the Endometrial Cells Exposed to Ovarian Steroids and Pro-inflammatory Cytokine JRI 73/2 (April 2017);118-129. PMID- 29406210 TI - Inhaled Corticosteroids and Fractures in COPD: Can We Finally Put This to Bed? PMID- 29406211 TI - Does OSA Upregulate Cardioprotective Pathways to an Ischemic Insult? PMID- 29406212 TI - The 10,000-Piece Puzzle of Lymphangioleiomyomatosis. PMID- 29406213 TI - Giants in Chest Medicine: Professor Nan-shan Zhong, MD. PMID- 29406214 TI - Miss Discomfit's Physical. PMID- 29406215 TI - Sympathy for the Intern. PMID- 29406216 TI - Worrywart. PMID- 29406217 TI - Concierge Pulmonary Medicine: Protest Against the Current Health-care System. PMID- 29406218 TI - Response. PMID- 29406219 TI - Ramped Position: What the "Neck"! PMID- 29406220 TI - Response. PMID- 29406221 TI - Increased Arterial Stiffness Might Be Caused by Sympathetic Activation. PMID- 29406222 TI - Response. PMID- 29406223 TI - Critical Care Echocardiography: Look Before We TEE Off. PMID- 29406224 TI - Response. PMID- 29406225 TI - Partners in Healing: Postsurgical Outcomes After Family Involvement in Nursing Care. PMID- 29406226 TI - Adherence to Upper-Airway Stimulation in the Treatment of OSA. PMID- 29406227 TI - The Impact of Fluctuations in Pack-Year Smoking History in the Electronic Health Record on Lung Cancer Screening Practices. PMID- 29406228 TI - Response. PMID- 29406229 TI - Statins in COPD: Selection Modalities and Mortalities. PMID- 29406230 TI - Atorvastatin in Bronchiectasis With Chronic Pseudomonas Infection. PMID- 29406231 TI - Response. PMID- 29406232 TI - Improving CPR Performance. PMID- 29406233 TI - Response. PMID- 29406234 TI - Mounier-Kuhn Syndrome Mimicking Lymphangioleiomyomatosis. AB - We present the case of a man with Mounier-Kuhn syndrome (MKS), or tracheobronchomegaly, who was referred to the National Institutes of Health Clinical Research Center because of a potential diagnosis of lymphangioleiomyomatosis (LAM), a rare condition in men. The patient was evaluated using ongoing protocols and provided written informed consent. The case demonstrates the presence of chronic inflammation surrounding the dilated airways and histologic changes of the lung parenchyma with emphysematouslike disruption in areas adjacent to the dilated airways. This finding suggests that damage to the lung parenchyma is an ongoing phenomenon in MKS. Moreover, our analysis of CT images indicates similar abnormalities in areas remote from the dilated airways. Finally, because of increased anatomic dead space, calculation of lung diffusion capacity by the single-breath method yielded abnormally low values that required making a correction for the large anatomic dead space, which can be measured by the single-breath nitrogen washout test. PMID- 29406235 TI - A 70-Year-Old Woman With Recent Intracranial Hemorrhage Presenting With Profound Shock. PMID- 29406236 TI - Shock After Myocardial Infarction. PMID- 29406237 TI - A 68-Year-Old Man With Chronic Myelogenous Leukemia and a Large Unilateral Pleural Effusion. AB - CASE PRESENTATION: A 68-year-old man with chronic myelogenous leukemia presents for evaluation of 2 months of dyspnea with exertion. He denies cough, fever, chest pain, weight gain, orthopnea, and edema. Since diagnosis of chronic myelogenous leukemia 5 years ago, he has been treated with dasatinib, with recent BCR-ABL1 assay showing no detectable disease in the peripheral blood. Medical history also includes hyperlipidemia, prostate enlargement, and hypothyroidism, but no prior heart or lung disease. Born in the Middle East, he immigrated to the United States 30 years ago and is working as a physician. He received the Bacillus Calmette-Guerin vaccine as a child. Quantiferon Gold test 1 year ago was positive (TB antigen response 0.91, reference range in <0.35), but he has not received treatment for this. He is a lifelong nonsmoker and rarely drinks alcohol. Medications include dasatinib, rosuvastatin, levothyroxine, tamsulosin, and dutasteride. PMID- 29406238 TI - A 74-Year-Old Man Presenting With Cough, Malaise, and Mediastinal Lymphadenopathy. AB - CASE PRESENTATION: A 74-year-old white male farmer was admitted from his primary care physician's office after he presented with symptoms of cough productive of clear sputum, malaise, weakness, fatigue, and shortness of breath on exertion for 3 weeks. He was an ex-smoker with a history of hypertension, hyperlipidemia, and coronary artery bypass graft surgery. He did not report any chills, night sweats, or fevers during this presentation. PMID- 29406239 TI - Coagulopathic side effect of L-asparaginase on fibrinogen level in childhood acute lymphoblastic leukemia during induction phase. AB - BACKGROUND: L-asparaginase is chemotherapeutic agent commonly used in treatment of Acute Lymphoblastic Leukemia. Thromboembolic and to a lesser extent bleeding events are serious complications associated with administration of this drug during the induction phase in ALL especially in children resulting from reduced synthesis of proteins such as Antithrombin & fibrinogen. OBJECTIVE: Evaluation of the coagulopathic side effect of L-asparaginase during the induction phase in treatment of ALL in children by measuring fibrinogen levels before & after administration of this drug. SUBJECTS & METHOD: An interventional prospective study was performed on 30 newly diagnosed children with ALL, all of them received 9 cycles of L-asparaginase during the induction phase according to UKALL 2003 Protocol. Fibrinogen was measured before & after treatment with L-asparaginase and the results are compared to a control group of 30 healthy children age & sex matched. RESULTS: Reduced fibrinogen level is observed in 13 out of 30 patients (43.3%) after treatment with L-asparaginase ranging from 25 to 110 mg/dl with means fibrinogen before & after treatment of 252 +/- 16.40 mg/dl & 158.97 +/- 17.88 mg/dl respectively (p < .0001). CONCLUSION: Significant reduction in fibrinogen level occurred in childhood ALL patients after treatment with L asparaginase. PMID- 29406240 TI - Ibritumomab tiuxetan (Zevalin) and elevated serum human anti-murine antibody (HAMA). AB - Ibritumomab Tiuxetan (Zevalin) is an anti CD-20 murine monoclonal antibody linked to the radio-isotope 90-yttrium (90Y) by the chelator Tiuxetan. It is FDA approved for treatment of relapsed low grade or follicular B-cell Non-Hodgkin's Lymphoma (NHL) or newly diagnosed follicular NHL following an initial response to first-line chemotherapy. Patients may develop Human Anti-Murine Antibodies (HAMA), following exposure to murine antibodies. There is a concern for development of hypersensitivity reactions with Ibritumomab, especially in patients with an elevated HAMA titer. Here we describe a case of a 66 year old male with elevated HAMA titer successfully treated with Zevalin without any hypersensitivity reactions. Existing literature supports our observation that Zevalin can be safely used in most patients with elevated HAMA titers. PMID- 29406241 TI - Immunization with Pseudomonas aeruginosa outer membrane vesicles stimulates protective immunity in mice. AB - Pseudomonas aeruginosa is an opportunistic pathogen responsible for a wide range of severe nosocomial and community acquired infections, these infections are major health problems for cystic fibrosis patients and immune-compromised individuals. The emergence of multidrug-resistant isolates highlights the need to develop alternative strategies for treatment of P. aeruginosa infections. Outer membrane vesicles (OMVs) are spherical nanometer-sized proteolipids that are secreted from numerous of pathogenic Gram-negative bacteria, and a number of studies have confirmed the protective efficacy for use of OMVs as candidate vaccines. In this study, OMVs from P. aeruginosa (PA_OMVs) were isolated, formulated with aluminum phosphate adjuvant and used as a vaccine in a mouse model of acute lung infection. The results confirmed that active immunization with PA_OMVs was able to reduce bacterial colonization, cytokine secretion and tissue damage in the lung tissue, thus protecting mice from lethal challenge of P. aeruginosa. Cytokines assay validated that immunization with PA_OMVs was efficient to induce a mixed cellular immune response in mice. Further, high level of specific antibodies was detected in mice immunized with PA_OMVs, and results from opsonophagocytic killing assay and passive immunization suggested that humoral immune response may be critical for PA_OMVs mediated protection. These findings demonstrated that PA_OMVs may be served as a novel candidate vaccine for the prevention of P. aeruginosa infection. PMID- 29406242 TI - Live recombinant Lactococcuslactis expressing avian hepatitis virus ORF2 protein: Immunoprotection against homologous virus challenge in chickens. AB - Avian hepatitis E virus (aHEV) is a pathogen associated with hepatitis splenomegaly syndrome in chickens. To date, no commercial vaccine is available for preventing aHEV infection. In this study, three recombinant LactococcuslactisNZ9000experimental live vaccines expressing cytoplasmic, secreted, and cell wall-anchored forms of aHEV truncated ORF2 protein spanning amino acids 249-606 (DeltaORF2) were constructed using pTX8048 vector and characterized. Each chicken was immunized three times at two-week intervals with one of the three live aHEV ORF2 vaccines (experimental group) or with live vaccine containing empty vector only (control group). Both groups were then challenged with aHEV and evaluated to compare immune responses and immunogenic effects. Serum IgG levels, secretory IgA (sIgA) levels in bile and jejunal lavage fluid, and mRNA expression levels ofIL-2 and IFN-gamma in liver and spleen were significantly higher in experimental chickens than in controls. Meanwhile, post challenge serum and fecal virus loads were significantly lower in experimental chickens versus controls. Moreover, on day 7 post infection (PI), serum lactose dehydrogenase (LDH) levels were significantly higher in controls than experimental chickens. Furthermore, at day 28 PI, obvious gross pathological lesions and histopathological changes typical for aHEV infection were observed in control livers and spleens, with only moderate pathological changes observed in the experimental group. The results of this study collectively demonstrate that an oral vaccineusing L.lactisNZ9000 as a delivery vector for aHEV immunogenic antigen could effectively control aHEV infection of chickens. PMID- 29406243 TI - Incorporation of a recombinant Eimeria maxima IMP1 antigen into nanoparticles confers protective immunity against E. Maxima challenge infection. AB - The purpose of this study was to determine if conjugating a recombinant Eimeria maxima protein, namely EmaxIMP1, into 20 nm polystyrene nanoparticles (NP) could improve the level of protective immunity against E. maxima challenge infection. Recombinant EmaxIMP1 was expressed in Escherichia coli as a poly-His fusion protein, purified by NiNTA chromatography, and conjugated to 20 nm polystyrene NP (NP-EmaxIMP1). NP-EMaxIMP1 or control non-recombinant (NP-NR) protein were delivered per os to newly-hatched broiler chicks with subsequent booster immunizations at 3 and 21 days of age. In battery cage studies (n = 4), chickens immunized with NP-EMaxIMP1 displayed complete protection as measured by weight gain (WG) against E. maxima challenge compared to chickens immunized with NP-NR. WG in the NP-EMaxIMP1-immunized groups was identical to WG in chickens that were not infected with E. maxima infected chickens. In floor pen studies (n = 2), chickens immunized with NP-EMaxIMP1 displayed partial protection as measured by WG against E. maxima challenge compared to chickens immunized with NP-NR. In order to understand the basis for immune stimulation, newly-hatched chicks were inoculated per os with NP-EMaxIMP1 or NP-NR protein, and the small intestine, bursa, and spleen, were examined for NP localization at 1 h and 6 h post inoculation. Within 1 h, both NP-EMaxIMP1 and NP-NR were observed in all 3 tissues. An increase was observed in the level of NP-EmaxIMP1 and NP-NR in all tissues at 6 h post-inoculation. These data indicate that 20 nm NP-EmaxIMP1 or NP NR reached deeper tissues within hours of oral inoculation and elicited complete to partial immunity against E. maxima challenge infection. PMID- 29406245 TI - Progress and challenges in deep brain stimulation for obsessive-compulsive disorder. AB - This narrative review summarizes the recent literature on deep brain stimulation for treatment resistant obsessive-compulsive disorder highlighting both progress and challenges of this novel treatment. Common targets of psychiatric deep brain stimulation involve both white matter trajectories (anterior limb of the internal capsule, inferior thalamic peduncle, and medial forebrain bundle) and grey matter subcortical nuclei (nucleus accumbens, nucleus subthalamicus, and bed nucleus of the stria terminalis) each of which have been reported with a relevant beneficial effect on obsessive-compulsive symptoms. The mechanisms of action are only partially understood but increasing evidence points towards network effects involving the prefrontal cortex, the striatum and possibly anxiety-related anatomical structures. Deep brain stimulation is a promising therapeutical technique for otherwise treatment refractory patients, but many major issues are unresolved and thorough investigations are needed. Relevant topics for future investigations include treatment predictors and therapeutical augmentation. An international registry of patients treated with deep brain stimulation could improve our understanding of adverse events and target specific effects. In order to step forward, researchers must face inconvenient questions and outperform the status quo of clinical research in this field. PMID- 29406244 TI - Vitexin protects isoproterenol induced post myocardial injury by modulating hipposignaling and ER stress responses. AB - The molecular mechanisms involved in ER stress-induced post myocardial injury remain elusive. In this study, we have investigated the molecular mechanism of ER stress-mediated myocyte death in Isoproterenol (ISO) induced myocardial infarction and its inhibition by a potent anti oxidant and anti-apoptotic bioflavonoid, Vitexin. ISO mediated apoptosis was found to be associated with ER permeabilization and characterized by enhanced production of ROS, activation of caspase-3, modulation of Bcl2 family proteins and activation of bnip3. Moreover, post treatment with Vitexin inhibits the ISO induced translocation of CHOP to nucleus during MI. Further results have demonstrated that, activation of Mst1 through ER stress was diminished upon treatment with Vitexin. In addition to this, Vitexin treatment significantly downregulated the expression of p-Yap and p Mst1 which were enhanced during post myocardial injury. Taken together, our data indicate that co-ordinated activation of ER stress and hipposignaling by ISO was ameliorated by the potent cardioprotective effects of Vitexin. PMID- 29406246 TI - Circular RNA and its mechanisms in disease: From the bench to the clinic. AB - The emerging recognition of the functional roles of circular RNAs (circRNAs) has given rise to a new perspective regarding our understanding of cellular physiology and disease pathogenesis. Unlike linear RNAs, circRNAs are covalently closed continuous loops that act as gene regulators in mammals, and their sequence composition determines the mode of circRNA biogenesis. The availability and integrated use of advanced genome analysis platforms have allowed the identification of a large number of these molecules. Their high abundance, stability and evolutionary conservation among species endow circRNAs with numerous potential functions, such as acting as microRNA (miRNA) sponges or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. Moreover, circRNAs have been shown to be expressed in a tissue-specific manner and in pathological conditions, which has stimulated significant interest in their role in human disease and cancer. In this concise review, we outline the characteristics, functions and mechanisms of action of circRNAs as well as their involvement in different diseases. Although their exact roles and mechanisms of gene regulation remain to be clarified, circRNAs have potential applications as disease biomarkers and novel therapeutic targets. PMID- 29406247 TI - Tinnitus, depression, and suicidal ideation in adults: A nationally representative general population sample. AB - Tinnitus is strongly associated with psychiatric symptoms, including depression and suicidality. We aimed to further investigate the association of tinnitus with depressive mood and/or suicidal ideation, and explore the shared risk factors for these within a representative sample of the adult general population. We also investigated potential mediation pathways among tinnitus, suicidal ideation, depression, shared risk factors, and perceived stress levels. We analysed data from 28,930 adults (aged >=19 years) from the fourth and fifth Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2008 to 2012 in South Korea. We investigated the presence and severity of tinnitus, depressive mood, suicidal ideation, perceived usual stress level, and socioeconomic and health-related variables. We conducted logistic regression and mediation analyses. Tinnitus and its severity were significantly associated with depressive mood and suicidal ideation. Tinnitus, depressive mood, and suicidal ideation shared common socioeconomic and health-related risk factors. Tinnitus significantly mediated the association of shared risk factors for depressive mood and suicidal ideation. Perceived usual stress level mediates the association of tinnitus with depressive mood and suicidal ideation. The correlation of perceived usual stress levels with depression and suicidal ideation was also mediated by tinnitus. Our findings implicate that tinnitus may contribute substantially to the development of depressive symptom and suicidal ideation in adults via apparent interactions with shared risk factors and stress levels. PMID- 29406248 TI - Welcome to Associate Editors. PMID- 29406249 TI - Nonmetastatic Excised Gestational Choriocarcinoma: To Treat or Not to Treat. PMID- 29406250 TI - Matrix metalloproteinases in emphysema. AB - Several studies have implicated a causative role for specific matrix metalloproteinases (MMPs) in the development and progression of cigarette smoke induced chronic obstructive pulmonary disease (COPD) and its severe sequela, emphysema. However, the precise function of any given MMP in emphysema remains an unanswered question. Emphysema results from the degradation of alveolar elastin - among other possible mechanisms - a process that is often thought to be caused by elastolytic proteinases made by macrophages. In this article, we discuss the data suggesting, supporting, or refuting causative roles of macrophage-derived MMPs, with a focus on MMPs-7, -9, -10, -12, and 28, in both the human disease and mouse models of emphysema. Findings from experimental models suggest that some MMPs, such as MMP-12, may directly breakdown elastin, whereas others, particularly MMP 10 and MMP-28, promote the development of emphysema by influencing the proteolytic and inflammatory activities of macrophages. PMID- 29406251 TI - A brief summary of the articles appearing in this issue of Biological Psychiatry. PMID- 29406252 TI - Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: a narrative review. AB - OBJECTIVE: Population-based cohort studies suggest an association between osteoarthritis (OA) and cerebrovascular disease, yet the mechanisms underlying vascular comorbidities in OA remain unclear. The purpose of this narrative review is to discuss the literature examining inflammation in OA with a focus on physiological mechanisms, and whether overlapping mechanisms exist in cerebrovascular dysfunction. METHOD: A literature search was conducted in PubMed using combinations of search terms: osteoarthritis, cerebrovascular (disease/dysfunction/risk), cardiovascular (disease/dysfunction/risk), aging/ageing, inflammation, inflammatory mediators, cytokine, c-reactive protein, interleukin, advanced glycation end-products, metabolic syndrome, reactive oxidative species, cognitive impairment, (vascular-related) dementia, small cerebral vessel disease, endothelial function, blood-brain barrier, gender/sex, hypertension, peripheral vascular health, and physical activity. Reference lists of identified articles were also researched manually. RESULTS: Overlapping inflammatory factors that may contribute to onset and progression of both OA and cerebrovascular dysfunction are presented. We describe oxidative mechanisms involving pro-inflammatory cytokines and oxidative species, advanced glycation end-products, sex hormones, microvascular dysfunction and osteoprotegerin, and their specific roles in potentially contributing to OA and cerebrovascular dysfunction. CONCLUSION: Synthesis of the current literature suggests future investigations may benefit from directly testing cerebrovascular hemodynamics and cognitive function in individuals with or at risk of OA to elucidate common physiological mechanisms. PMID- 29406253 TI - Scalpel Versus Diathermy in Wound Healing After Mucosal Incisions: A Split-Mouth Study. AB - PURPOSE: The aim of this study was to analyze and compare the healing of scalpel and diathermy incision wounds in the oral mucosa. MATERIALS AND METHODS: This is a prospective split-mouth study conducted from January 2015 to April 2017 among patients undergoing either Le Fort I or anterior maxillary osteotomy (or both). The study groups were classified based on the different techniques used to make the incision (group A, incision made by a scalpel; group B, incision made by diathermy). Wound healing was assessed on the first, third, seventh, and tenth postoperative days using the Southampton scoring system. Data were statistically analyzed using the Student t test for continuous variables and the chi2 test for categorical variables, and P < .05 was considered significant. RESULTS: Among the 113 participants included in the study, the age range was 16 to 35 years and male patients comprised 50.4%. The rates of postoperative complications of wound healing were 68.1% (n = 77) in group A and 77% (n = 87) in group B. Wound healing showed a statistically significant difference between the techniques (P < .001). CONCLUSIONS: The findings of this study suggest that wounds caused by scalpel incisions healed better than those caused by diathermy incisions in the oral mucosa. PMID- 29406254 TI - Factors Affecting Survival in Surgically Salvaged Locoregional Recurrences of Squamous Cell Carcinoma of the Tongue. AB - PURPOSE: To determine the factors affecting outcomes in surgically salvaged, locoregionally recurrent squamous cell carcinoma of the tongue (SCCT). MATERIALS AND METHODS: In a retrospective cohort of patients who underwent successful salvage of locoregionally recurrent SCCT, we performed this observational analytical study to determine survival and its determinants. Details extracted from our database were patient characteristics (age, gender, tobacco use), treatment characteristics, and characteristics of recurrent disease (stage and adverse pathologic features [APFs] such as grade, perineural invasion, and lymphovascular invasion). Overall survival (OS) curves were plotted using the Kaplan-Meier method. A Cox proportional hazards model was used to determine the impact of patient, disease, and treatment characteristics on OS. RESULTS: Of 52 patients with locoregional recurrences of surgically treated SCCT, 25 (48.1%) underwent surgical salvage with curative intent. The median overall OS for this cohort was 26 months. Factors predictive of worse OS were previous adjuvant therapy (P = .016) and increasing APFs in recurrent tumor histology (P = .008). Lymphovascular invasion in recurrent tumor histology and patients with a disease free interval of less than 6 months showed worse survival (P = .008 and P = .058, respectively). CONCLUSIONS: Among patients with locoregional recurrence, the number who are eligible for curative-intent surgical salvage is small. Those who received previous adjuvant therapy and those with increasing APFs in recurrent tumors had poor outcomes despite attempts at surgical salvage, particularly patients with early recurrence. PMID- 29406255 TI - The Effect of Exercise on Range of Movement and Pain After Temporomandibular Joint Arthrocentesis. AB - PURPOSE: Arthrocentesis is an effective treatment modality for temporomandibular disorders, especially in patients who have pain and limited mouth opening. Surgeons generally suggest physical exercises after arthrocentesis and arthroscopy procedures; however, there has been no study in the literature evaluating the effects of exercise on clinical outcomes. This study investigated whether physical exercises after arthrocentesis would result in early improvements in clinical symptoms in patients with temporomandibular joint disc displacement without reduction (TMJ DDw/oR). MATERIALS AND METHODS: The study group was composed of 27 patients with TMJ DDw/oR. Patients who needed arthrocentesis after failed conservative nonsurgical treatment were enrolled in the study. Group 1 was composed of 14 patients who were not started on a physiotherapy program after the arthrocentesis procedure. Group 2 was composed of 13 patients who were started on a self-administered physiotherapy program immediately after the arthrocentesis procedure. Physiotherapy included a 6-week exercise program. Patients were followed for 3 months. Range of maximal mouth opening (MMO) and joint pain as measured by the visual analog scale (VAS) were examined to determine clinical efficacy before and after treatment. RESULTS: In groups 1 and 2, mouth opening increased and pain scores decreased at 1-week and 1 and 3-month follow-ups (P < .05). No relevant relation was found between the 2 groups according to MMO for all time points and VAS scores at 1 week. A relevant relation was found between the 2 groups according to VAS scores at 1 and 3 months. CONCLUSION: Physical exercise after arthrocentesis has no effect on range of mouth opening but does decrease pain. PMID- 29406256 TI - Males With Rheumatoid Arthritis Often Evidence Carotid Atheromas on Panoramic Imaging: A Risk Indicator of Future Cardiovascular Events. AB - PURPOSE: Males with rheumatoid arthritis (RA) are at an exceedingly high risk of adverse intraoperative ischemic events, given the role of systemic inflammation in the atherogenic process. We hypothesized that their panoramic images would demonstrate calcified carotid artery atheromas (CCAPs) significantly more often than those from a general population of similarly aged men. PATIENTS AND METHODS: We implemented a retrospective observational study. The sample was composed of male patients older than 55 years of age who had undergone panoramic imaging studies. The predictor variable was the diagnosis of RA confirmed by a positive rheumatoid factor (RF) titer, and the outcome variable was the prevalence rate of CCAPs. The other major study variable was the level of RF among the patients evidencing CCAPs. The prevalence of CCAPs among the patients with RA was then compared with that of a historical general population of similarly aged men. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: Of the 100 men (mean age 69.89 +/- 8.927 years) with RA, 29 (29%; mean age 72.10 +/- 7.68 years) had atheromas (CCAP+). Of these 29 men, 25 (86%; mean age 71.88 +/- 7.43 years) had a RF titer of >=41 IU/mL, twice that of normal. A statistically significant (P < .05) association was found between a diagnosis of RA and the presence of an atheroma on the panoramic image compared with the 3% rate found in the historical cohort. CONCLUSIONS: The results of the present study suggest that CCAP, a risk indicator of future adverse cardiovascular events, is frequently seen on panoramic images of male patients with RA and that these individuals routinely manifest high titer levels of RF, a biologic marker of inflammation. Oral and maxillofacial surgeons planning surgery for male patients with RA must be uniquely vigilant for the presence of these lesions. PMID- 29406257 TI - High Expression of Prospero-Related Homeobox-1 (PROX1) Is Associated With Poor Prognosis in Patients With Salivary Adenoid Cystic Carcinoma. AB - PURPOSE: Prospero-related homeobox-1 (PROX1) plays an important role in the invasion and metastasis of many human cancers. However, the expression pattern of PROX1 in salivary adenoid cystic carcinoma (SACC) remains unclear. The aim of this study was to investigate PROX1 expression and its prognostic value in SACC. MATERIALS AND METHODS: PROX1 expression was determined by immunohistochemistry (IHC) in SACC tissue specimens. Correlations between PROX1 expression and clinicopathologic features were investigated. The Kaplan-Meier method was used to analyze the correlation between PROX1 expression and survival. Independent prognostic factors associated with overall survival (OS) were analyzed using Cox regression analysis. RESULTS: The IHC data showed that the PROX1 positivity rate in SACC tissue specimens was significantly higher than that in normal salivary gland tissues (71.1 vs 13.3%; P < .05). PROX1 expression was detected mainly in the nucleolus. In addition, PROX1 expression was correlated with perineural invasion, local regional recurrence, and distant metastasis of patients with SACC (P < .05), and no significant association was found between PROX1 expression and other clinicopathologic parameters. Data indicated that patients with positive PROX1 expression had poor OS compared with those with negative PROX1 expression (P = .0005). Multivariate analysis showed that PROX1 expression, local regional recurrence, and distant metastasis were independent prognostic factors for OS. CONCLUSIONS: These findings showed that PROX1 expression was statistically higher in SACC specimens. Positive expression of PROX1 might serve as a potential predictor of prognosis in SACC. PMID- 29406258 TI - A 3-Dimensional Analysis of Nasal Cavity Volume After Maxillary Le Fort I Osteotomy. AB - PURPOSE: Two- and 3-dimensional studies on changes of the pharyngeal airway after a Le Fort I osteotomy have been conducted, but there are few studies on the change of nasal structure. The nasal cavity is the first passage through which air enters during respiration. Movement of the maxilla by Le Fort I osteotomy affects the shape of the nasal cavity and the shape of other parts of the airway. This study compared preoperative and postoperative changes of the nasal cavity volume after a maxillary Le Fort I osteotomy. MATERIALS AND METHODS: Pre- and postoperative computed tomograms of 32 patients were assessed for nasal cavity volume according to the direction of maxillary movement. RESULTS: Thirty-two patients (22 men and 10 women) were classified according to the direction of maxillary movement: maxillary impaction (group I; 8 men and 6 women) and maxillary impaction and advancement (group II; 14 men and 4 women). Nasal cavity volume was markedly decreased after the Le Fort I osteotomy in groups I and II. Group I showed a positive correlation between the ratio of impaction and the ratio of volume difference. Group II showed no correlation between the ratio of impaction or advancement and the ratio of volume difference. CONCLUSION: Impaction and advancement of the maxilla decreased nasal volume. PMID- 29406259 TI - Tube Decompression for Staged Treatment of a Calcifying Odontogenic Cyst. PMID- 29406260 TI - Skull Base Erosion Resulting From Primary Tumors of the Temporomandibular Joint and Skull Base Region: Our Classification and Reconstruction Experience. AB - PURPOSE: We sought to introduce our classification and reconstruction protocol for skull base erosions in the temporomandibular joint and skull base region. PATIENTS AND METHODS: Patients with neoplasms in the temporomandibular joint and skull base region treated from January 2006 to March 2017 were reviewed. Skull base erosion was classified into 3 types according to the size of the defect. RESULTS: We included 33 patients, of whom 5 (15.2%) had type I defects (including 3 in whom free fat grafts were placed and 2 in whom deep temporal fascial fat flaps were placed). There were 8 patients (24.2%) with type II defects, all of whom received deep temporal fascial fat flaps. A total of 20 patients (60.6%) had type III defects, including 17 in whom autogenous bone grafts were placed, 1 in whom titanium mesh was placed, and 2 who received total alloplastic joints. The mean follow-up period was 50 months. All of the patients exhibited stable occlusion and good facial symmetry. No recurrence was noted. CONCLUSIONS: Our classification and reconstruction principles allowed reliable morpho-functional skull base reconstruction. PMID- 29406261 TI - Comparison of the Effects of Ultrasonic and Conventional Surgery on the Neurosensory Disturbance After Bilateral Sagittal Split Osteotomy. AB - PURPOSE: According to the literature, ultrasonic surgery reduces the incidence of neurosensory disturbance (NSD) of the inferior alveolar nerve (IFAN) after bilateral sagittal split osteotomy (BSSO). The purpose of this study was to evaluate the effects of ultrasonic surgery and the anatomic position of the IFAN canal on NSD after BSSO. PATIENTS AND METHODS: This retrospective cohort study included skeletal mandibular prognathism cases operated on with an ultrasonic bone scalpel or a reciprocating saw. The primary predictor variable was osteotomy technique (ultrasonic or conventional surgery). The primary outcome variable was NSD. Other variables included age, gender, operator, degree of setback, surgical duration, blood loss, and IFAN position. Comparisons of 2 variables were performed by use of the Student t test or Fisher exact test. A regression model was used to examine the relationship between the presence or absence of NSD and other variables. The level of significance was set at P < .05 for all statistical tests. RESULTS: The ultrasonic group was composed of 35 patients, whereas the conventional group was composed of 32. Three months after surgery, NSD was observed on 16 of 70 sides (22.9%) in the ultrasonic group and 28 of 64 sides (43.8%) in the conventional group; this difference was significant. Furthermore, recovery from NSD at 3 months after BSSO was significantly more common in the ultrasonic group than in the conventional group. In the ultrasonic group, even when the distance from the buccal aspect of the IFAN canal to the outer buccal cortical margin was shorter, NSD of the IFAN was less frequent. CONCLUSIONS: Ultrasonic surgery may be an effective technique to reduce the incidence of NSD after BSSO, and it contributed to recovery from NSD. The use of an ultrasonic device for BSSO is recommended when the distance from the buccal aspect of the IFAN canal to the outer buccal cortical margin is shorter on computed tomography. PMID- 29406262 TI - Accuracy of Orthognathic Surgical Outcomes Using 2- and 3-Dimensional Landmarks The Case for Apples and Oranges? AB - PURPOSE: To verify predicted versus obtained surgical movements in 2-dimensional (2D) and 3-dimensional (3D) measurements and compare the equivalence between these methods. MATERIALS AND METHODS: A retrospective observational study of bimaxillary orthognathic surgeries was performed. Postoperative cone-beam computed tomographic (CBCT) scans were superimposed on preoperative scans and a lateral cephalometric radiograph was generated from each CBCT scan. After identification of the sella, nasion, and upper central incisor tip landmarks on 2D and 3D images, actual and planned movements were compared by cephalometric measurements. One-sample t test was used to statistically evaluate results, with expected mean discrepancy values ranging from 0 to 2 mm. Equivalence of 2D and 3D values was compared using paired t test. RESULTS: The final sample of 46 cases showed by 2D cephalometry that differences between actual and planned movements in the horizontal axis were statistically relevant for expected means of 0, 0.5, and 2 mm without relevance for expected means of 1 and 1.5 mm; vertical movements were statistically relevant for expected means of 0 and 0.5 mm without relevance for expected means of 1, 1.5, and 2 mm. For 3D cephalometry in the horizontal axis, there were statistically relevant differences for expected means of 0, 1.5, and 2 mm without relevance for expected means of 0.5 and 1 mm; vertical movements showed statistically relevant differences for expected means of 0, 0.5, 1.5 and 2 mm without relevance for the expected mean of 1 mm. Comparison of 2D and 3D values displayed statistical differences for the horizontal and vertical axes. CONCLUSIONS: Comparison of 2D and 3D surgical outcome assessments should be performed with caution because there seems to be a difference in acceptable levels of accuracy between these 2 methods of evaluation. Moreover, 3D accuracy studies should no longer rely on a 2-mm level of discrepancy but on a 1-mm level. PMID- 29406263 TI - Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities. AB - There are numerous hurdles hindering the clinical translation of nanomedicines. The major challenges are: reproducible manufacturing and scale-up, availability of appropriate characterization methods, instability under in vivo environments, safety issues, poor understanding of the disease heterogeneity and patient preselection strategies, regulatory barriers and inadequate understanding of the biophysical and chemical interactions of nanoformulations. Thus, a better understanding of key physicochemical attributes and their characterization methods, in vivo behavior and the in-vitro-in-vivo characterization cascade of stability, safety and efficacy testing is needed to accelerate nanomedicine translation. Technologies such as quality-by-design, process analytical techniques and microfluidics could significantly accelerate the translation of nanomedicines. However, these approaches require further learning and an adequate regulatory background. Overall, to achieve an efficient clinical translation, collaboration among academia, industry and regulatory bodies is required to ensure safe and effective nanomedicine products. This review discusses the challenges and opportunities to facilitate the translation of nanomedicines to a commercial product. PMID- 29406264 TI - Opportunities and pitfalls in clinical proof-of-concept: principles and examples. AB - Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a strong pharmacological underpinning; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown. The general process of model-based trial design and analysis is described and several examples demonstrate the value in historical data, simulation-guided design, model-based analysis and trial adaptation informed by interim analysis. PMID- 29406265 TI - Glecaprevir/Pibrentasvir: The Final Piece in the Hepatitis C Virus Treatment Puzzle? PMID- 29406267 TI - Brain Mechanisms Underlying Reading the Mind from Eyes, Voice, and Actions. AB - Evidence from cognitive and social neuroscience research suggests that Theory of Mind (ToM), the ability to attribute mental states to others, is mediated by a group of brain regions collectively known as the ToM network. Nevertheless, there is significant variability in the functional activation of regions within this network across tasks. The goal of the present functional magnetic resonance imaging (fMRI) study was to examine the common and differential neural mechanisms of two aspects of ToM processing (emotion/mental-state recognition and intentional attribution) using three distinct, but complementary ToM tasks (Reading the Mind in the Eyes (RMIE), Reading the Mind in the Voice (RMIV), and Intentional Causal Attribution) in healthy adults. Participant accuracy was significantly worse in the ToM compared to the control condition across all tasks. Brain activation analyses replicated previously reported activation in inferior frontal gyrus (IFG) and middle temporal gyrus extending to posterior superior temporal sulcus (pSTS) in RMIE. Activation in the fusiform gyrus and bilateral middle temporal gyrus extending to temporo-parietal junction (TPJ) was unique to causality task. A region-of-interest analysis revealed shared activation in left IFG for RMIE and RMIV as well as TPJ recruitment specific to the causality task. The role of right TPJ in the causality task was further supported by a percent signal change analysis. A conjunction analysis revealed overlap in left IFG, left precentral gyrus, and left superior frontal gyrus activity across all tasks. These findings highlight common and differential recruitment of ToM regions according to task demand. PMID- 29406268 TI - Therapeutic N-Acetyl-Cysteine (Nac) Following Initiation of Maternal Inflammation Attenuates Long-Term Offspring Cerebral Injury, as Evident in Magnetic Resonance Imaging (MRI). AB - OBJECTIVE: Maternal infection/inflammation may induce fetal inflammatory responses, which have been associated with long-term offspring cerebral injury. We previously demonstrated that prophylactic N-Acetyl-Cysteine (NAC), administered prior to and following maternal lipopolysaccharide (LPS), reduced offspring cerebral injury as evident on MRI. In the present study, we used MRI to examine the effect of therapeutic NAC following maternal LPS-induced inflammation on neonatal brain injury. STUDY DESIGN: Pregnant Sprague-Dawley dams (n = 6) at day 18 of gestation received either intraperitoneal injection of LPS or saline (Control) at time 0. Animals were randomized to receive intravenous injection (tail vein) of NAC or saline at time +30 min. Pups were delivered spontaneously and allowed to mature until postnatal day 25. Male offspring (6-8 per group) were examined by MRI and analyzed using voxel-based analysis. Diffusion Tensor Imaging (DTI), an advanced MRI technique, was performed and quantitative parameters extracted (mean and radial diffusivity) and used to assess white and gray matter brain injury. RESULTS: Offspring of LPS-treated dams exhibited significantly increased mean, axial and radial diffusivity (RD) levels in white and gray matter consistent with cerebral injury. In contrast, offspring of NAC-treated LPS PS dams demonstrated reduced mean, axial and RD levels in most regions; similar to the saline group. CONCLUSION: Maternal NAC treatment following maternal inflammation significantly influenced brain micro-structure integrity as demonstrated by MRI-DTI scans. These findings suggest that maternal NAC therapy may be effective in human pregnancies associated with maternal/fetal inflammation, such as preterm rupture of membranes and chorioamnionitis. PMID- 29406266 TI - Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density. AB - Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-beta deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGTf/fCre+) mice using a Cre/LoxP system under the CAMKIIalpha promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGTf/fCre+ mice compared with GGTf/fCre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGTf/fCre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain. PMID- 29406269 TI - Hippocampus and Hypothalamus RNA-sequencing of WFS1-deficient Mice. AB - Wolfram syndrome is caused by mutations in the WFS1 gene. WFS1 protein dysfunction results in a range of neuroendocrine syndromes and is mostly characterized by juvenile-onset diabetes mellitus and optic atrophy. WFS1 has been shown to participate in membrane trafficking, protein processing and Ca2+ homeostasis in the endoplasmic reticulum. Aim of the present study was to find the transcriptomic changes influenced by WFS1 in the hypothalamus and hippocampus using RNA-sequencing. The WFS1-deficient mice were used as a model system to analyze the changes in transcriptional networks. The number of differentially expressed genes between hypothalami of WFS1-deficient (Wfs1KO) and wild-type (WT) mice was 43 and between hippocampi 311 with False Discovery Rate (FDR) <0.05. Avpr1a and Avpr1b were significantly upregulated in the hypothalamus and hippocampus of Wfs1KO mice respectively. Trpm8 was the most upregulated gene in the hippocampus of Wfs1KO mice. The functional analysis revealed significant enrichment of networks and pathways associated with protein synthesis, cell-to cell signaling and interaction, molecular transport, metabolic disease and nervous system development and function. In conclusion, the transcriptomic profiles of WFS1-deficient hypothalamus and hippocampus do indicate the activation of degenerative molecular pathways causing the clinical occurrences typical to Wolfram syndrome. PMID- 29406270 TI - Early-life Photoperiod Influences Depression-like Behavior, Prepulse Inhibition of the Acoustic Startle Response, and Hippocampal Astrogenesis in Mice. AB - Environmental factors during early life stages affect behavioral and physiological phenotypes in adulthood. We examined the effect of photoperiods during development on neurogenesis and affective behaviors during adolescence/adulthood using C57BL/6J mice. Mice were born and raised until weaning under long-day conditions (LDs) or short-day conditions (SDs), followed by a 12L12D cycle until adulthood. Adult mice born under SD showed a shorter latency to first immobility in the forced swim test when compared with the mice born under LD. The mice born under SD also exhibited significantly lower prepulse inhibition, which is a characteristic of schizophrenia. However, the mice exposed to SD and LD during the prenatal period only did not show differences in prepulse inhibition. At 4 weeks of age, there were less 5-bromo-2'-deoxyuridine (BrdU) positive cells in the dentate gyrus (DG) of the hippocampus of mice born under SD when compared with mice born under LD. Double immunostaining showed that the mice born under SD showed less BrdU/glial fibrillary acidic protein (GFAP, an astrocyte marker) cells when compared with mice born under LD. Furthermore, expression of the glucocorticoid receptor in the DG was higher in mice born under SD, and the photoperiod-dependent changes in the number of BrdU-positive cells in the DG were abolished by administration of RU486, a glucocorticoid receptor antagonist. These results suggest that the photoperiod in early life alters astrogenesis in the hippocampus via the hypothalamic-pituitary-adrenal axis and may relate to affective behaviors in adulthood. PMID- 29406271 TI - The Protective Effects of IGF-I against beta-Amyloid-related Downregulation of Hippocampal Somatostatinergic System Involve Activation of Akt and Protein Kinase A. AB - Somatostatin (SRIF), a neuropeptide highly distributed in the hippocampus and involved in learning and memory, is markedly reduced in the brain of Alzheimer's disease patients. The effects of insulin-like growth factor-I (IGF-I) against beta amyloid (Abeta)-induced neuronal death and associated cognitive disorders have been extensively reported in experimental models of this disease. Here, we examined the effect of IGF-I on the hippocampal somatostatinergic system in Abeta treated rats and the molecular mechanisms associated with changes in this peptidergic system. Intracerebroventricular Abeta25-35 administration during 14 days (300 pmol/day) to male rats increased Abeta25-35 levels and cell death and markedly reduced SRIF and SRIF receptor 2 levels in the hippocampus. These deleterious effects were associated with reduced Akt and cAMP response element binding protein (CREB) phosphorylation and activation of c-Jun N-terminal kinase (JNK). Subcutaneous IGF-I co-administration (50 ug/kg/day) reduced hippocampal Abeta25-35 levels, cell death and JNK activation. In addition, IGF-I prevented the reduction in the components of the somatostatinergic system affected by Abeta infusion. Its co-administration also augmented protein kinase A (PKA) activity, as well as Akt and CREB phosphorylation. These results suggest that IGF-I co administration may have protective effects on the hippocampal somatostatinergic system against Abeta insult through up-regulation of PKA activity and Akt and CREB phosphorylation. PMID- 29406272 TI - When Patients with Congenital Urological Problems Become Adults. PMID- 29406273 TI - Editorial Comment. PMID- 29406274 TI - Editorial Comment. PMID- 29406275 TI - Reply by Authors. PMID- 29406278 TI - Association of TNF-alpha, IL-10 and IL-6 promoter polymorphisms in pulmonary tuberculosis patients and their household contacts of younger age group. AB - Single nucleotide polymorphisms (SNPs) of cytokine genes have been found to be involved in the clinical outcome of Tuberculosis. The present study was aimed to identify the high risk genotypes in Tuberculosis patients and their household contacts. A total of 490 subjects were studied which includes 150 active pulmonary tuberculosis patients (APTB), 190 household contacts (HHC) and 150 healthy controls (HC). The SNPs of TNF-alpha (-308A/G), IL-10(-1082G/A) and IL-6( 174G/C) were performed by ARMs PCR. The IL-10 GA genotype showed significant association in APTB and HHC and was 2.3 times higher risk in APTB and 3.7 times in HHC compared to HCs. The A allele was found to be significantly associated with the risk of disease. The CC genotype of IL-6 was found to be significantly associated in APTB and an insignificant positive association in HHCs. The multifactor dimensionality reduction (MDR) analysis indicated that the genotypes of IL-6 were showing high risk with GA genotype of IL-10. In conclusion the gene interaction may be useful for identification of genotypes as biomarkers to distinguish high risk individuals. PMID- 29406277 TI - Parasitic load and histological aspects in different regions of the spleen of dogs with visceral leishmaniasis. AB - Leishmania infantum causes from subclinical infection to severe disease in humans and dogs. The spleen is one of the organs most affected by the infection. Although evidence exists that the parasitic load distribution and histological alterations may not be homogeneous in the affected organs of naturally infected individuals, it has not been formally demonstrated using the current techniques used for studying the disease. In six dogs naturally infected with Leishmania, parasitic load and histological changes were compared in samples collected from the lower, middle and upper third of the spleen. Parasitic load in the spleen of the group of dogs was variable, revealing a difference of 61 times between animals with the lowest and the highest parasitism. The set of parasitic load values of each dog showed a cluster trend, when compared to the other animals. Nevertheless, the parasitic load values of each dog showed a variation ranging from 3.2 to 34.7 times between lowest and highest value. Histological changes showed recognizable variation in frequency (granulomas) or intensity (perisplenitis) in the spleen of 2 out of the 6 dogs. The agreement of histological findings between samples collected from the different thirds of the spleen was good (kappa coeficient, 0.61-0.80) very good (0.81-0.99) or perfect (1.00), for most of the parameters analyzed. Variability of parasitic load and, to a lesser extent, histological changes in spleen of dogs with visceral leishmaniasis is observed. Such variability may be taken in account in the design of studies on pathogenesis, vaccine and therapeutic drug development. PMID- 29406276 TI - Acute phase proteins response in cats naturally infected by hemotropic mycoplasmas. AB - Information about the acute phase proteins (APP) response in cats naturally infected with hemoplasmas and in cats co-infected with different species of hemoplasmas is lacking. This study evaluated serum amyloid A (SAA), haptoglobin (Hp) and albumin in 48 cats naturally infected with hemoplasmas, including 25 with Candidatus Mycoplasma haemominutum and 23 co-infected with different hemoplasmas agents; and in 10 healthy control cats. Infected cats had significantly higher Hp and lower albumin than controls. Symptomatic cats had significantly higher SAA and Hp, and lower albumin than asymptomatic animals, and also than controls. Asymptomatic cats had significantly higher Hp than controls. Concentrations of APP were not significantly different between single infected and co-infected cats. According with these results, hemoplasmosis should be considered when alterations in APP are detected in diseased cats with compatible clinical signs. Furthermore, a subclinical infection should be considered in apparently healthy cats from endemic areas with increased Hp. PMID- 29406280 TI - Absence of protection from West Nile virus disease and adverse effects in red legged partridges after non-structural NS1 protein administration. AB - The red-legged partridge (Alectoris rufa) is a competent host for West Nile virus (WNV) replication and highly susceptible to WNV disease. With the aim to assess in this species whether the inoculation of non-structural protein NS1 from WNV elicits a protective immune response against WNV infection, groups of partridges were inoculated with recombinant NS1 (NS1 group) or an unrelated recombinant protein (mock group), and challenged with infectious WNV. A third group received no inoculation prior to challenge (challenge group). The NS1 group failed to elicit detectable antibodies to NS1 while in the mock group a specific antibody response was observed. Moreover, no protection against WNV disease was observed in the NS1 group, but rather, it showed significantly higher viral RNA load and delayed neutralizing antibody response, and suffered a more severe clinical disease, which resulted in higher mortality. This adverse effect has not been observed before and warrants further investigations. PMID- 29406279 TI - Hemotropic mycoplasmas infection in water buffaloes (Bubalus bubalis) from northeastern Brazil. AB - Two species of hemotropic mycoplasmas (HM) are known to infect large domestic ruminants, Mycoplasma wenyonii and 'Candidatus Mycoplasma haemobos'. Although HM has been described in cattle worldwide, data in water buffaloes (Bubalus bubalis) remain scarce. Accordingly, the aim was to determine the occurrence of HM in water buffaloes from northeastern Brazil. A total of 101/290 (34.83%) buffaloes were positive for HM (16 M. wenyonii alone, 6 'Ca. M. haemobos' alone and 79 both). This was the first report of M. wenyonii infection in ruminants from Brazil. Clinical signs of hemoplasmosis in buffaloes remain unknown. PMID- 29406281 TI - Q fever epidemic in Cayenne, French Guiana, epidemiologically linked to three toed sloth. AB - A Q fever epidemic occurred in 2013 in a small military residential area in Cayenne, French Guiana. A retrospective cohort study was conducted to identify Q fever risk factors. Confirmed acute Q fever case was defined as positive serology (IgM >= 50 and phase II IgG >= 200) and/or positive qPCR on serum or blood. In addition, wild mammals were captured at the study site and tested by serology and real-time PCR performed on blood, vaginal swabs and ticks. The attack rate was 20 percent (11/54). All the cases were symptomatic with fever >38.5 degrees C and community-acquired pneumonia for four cases. Log binomial multivariate models identified two independent risk factors associated with Q fever: to clean the house (RRa = 7.5 CI95% [1.03-55.3]) and to carry a three-toed sloth in arms (RRa = 2.6 CI95% [1.1-5.8]). Eighteen marsupial individuals were captured, all PCRs were negative but 17% (3/18) had a positive serology. Another study conducted after the epidemic found only one (1/4) three-tooth sloth (Bradypus tridactylus) with feces highly infectious for C. burnetii MST17. The same strain C. burnetii genotype 17 has been laboratory- confirmed in this mammal and in human cases. These results support the implication of three-toed-sloth in this epidemic. Human contamination mainly occurs through inhalation of infectious aerosols as suggested by high relative risk associated with house cleaning activities and pulmonary forms of the disease, and through direct contact with three- toed sloth. Positive serological results among marsupials confirm wildlife exposure and suggest a more complex sylvatic transmission cycle among wild mammals. PMID- 29406282 TI - Prevalence of Cryptosporidium species isolated from HIV/AIDS patients in southwest of Iran. AB - This study aimed to determine the prevalence and species of Cryptosporidium among HIV/AIDS patients in southwest of Iran. Two hundred fifty faecal samples from HIV patients were examined for the presence of Cryptosporidium oocysts using a conventional coproscopic approach. Such oocysts were detected in 18 (7.2%) out of 250 faecal samples. Genomic DNAs from 250 samples were then subjected to a nested PCR-RFLP technique targeting different loci of 18S rRNA gene for species identification. Out of 250 samples, 27 (10.8%) were positive for different Cryptosporidium spp; Restriction patterns resulting from the digestion of the nested amplicon with restriction endonucleases VspI and SspI showed that C. parvum (70.38%) was the most prevalent species, followed by C. hominis (25.92%) and C. meleagridis (3.7%), respectively. The mean CD4+ T-cell count was 215 cells/MUL. There was a strong association between cryptosporidiosis and CD4+ T cell count (P = 0.000) with the highest prevalence recorded among patients with CD4+ T-cell count < 200 cells/MUL. This confirms that there is a low opportunity for this parasite to get established as the patients CD4+ T-cell count increases. Also HIV infection increased the risk of having Cryptosporidium. Our epidemiological findings are useful for any preventive intervention to control disease diffusion. PMID- 29406283 TI - Novel reassortant H5N6 highly pathogenic influenza A viruses in Vietnamese quail outbreaks. AB - Avian influenza A H5N6 virus is a highly contagious infectious agent that affects domestic poultry and humans in South Asian countries. Vietnam may be an evolutionary hotspot for influenza viruses and therefore could serve as a source of pandemic strains. In 2015, two novel reassortant H5N6 influenza viruses designated as A/quail/Vietnam/CVVI01/2015 and A/quail/Vietnam/CVVI03/2015 were isolated from dead quails during avian influenza outbreaks in central Vietnam, and the whole genome sequences were analyzed. The genetic analysis indicated that hemagglutinin, neuraminidase, and polymerase basic protein 2 genes of the two H5N6 viruses are most closely related to an H5N2 virus (A/chicken/Zhejiang/727079/2014) and H10N6 virus (A/chicken/Jiangxi/12782/2014) from China and an H6N6 virus (A/duck/Yamagata/061004/2014) from Japan. The HA gene of the isolates belongs to clade 2.3.4.4, which caused human fatalities in China during 2014-2016. The five other internal genes showed high identity to an H5N2 virus (A/chicken/Heilongjiang/S7/2014) from China. A whole-genome phylogenetic analysis revealed that these two outbreak strains are novel H6N6 like PB2 gene reassortants that are most closely related to influenza virus strain A/environment/Guangdong/ZS558/2015, which was detected in a live poultry market in China. This report describes the first detection of novel H5N6 reassortants in poultry during an outbreak as well as genetic characterization of these strains to better understand the antigenic evolution of influenza viruses. PMID- 29406284 TI - Isolation and phylogenetic analysis of Bartonella species from Rusa deer (Rusa timorensis) in Thailand. AB - The aim of the present study is to investigate the prevalence of Bartonella infection in deer in Thailand and to characterize the isolates by biochemical, morphological and genetic analysis. A total of 247 blood samples were collected from Rusa deer (Rusa timorensis) in a livestock breeding facility in Thailand. Bartonella bacteria were isolated in 3.6% of the blood samples. Three out of 110 (2.7%) males and 6 of 137 (4.4%) females were positive for Bartonella. A higher prevalence of Bartonella was observed in young deer under 4 years of age compared to adults over 4 years of age, but no Bartonella was isolated from deer over 8 years of age. Phylogenetic analysis of concatenated sequences of seven loci of Bartonella indicated that all the isolates from Rusa deer in Thailand were identical and formed a distinct cluster from other known Bartonella species. PMID- 29406285 TI - Clarithromycin suppresses induction of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 and improves pathological changes in the lungs and heart of mice infected with influenza A virus. AB - The influenza A virus (IAV)-cytokine-trypsin/matrix metalloproteinase-9 (MMP-9) cycle is one of the important mechanisms of multiple organ failure in severe influenza. Clarithromycin, a macrolide antibiotic, has immune modulatory and anti inflammatory effects. We analyzed the effects of clarithromycin on the induction of chemokines, cytokines, MMP-9, trypsin, vascular hyper-permeability and inflammatory aggravation in mice with IAV infection. IAV/Puerto Rico/8/34(H1N1) infection increased the levels of monocyte chemoattractant protein-1 (MCP-1) and cytokines in serum, and MMP-9 and trypsin in serum and/or the lungs and heart. Clarithromycin significantly suppressed the induction of serum MCP-1 and MMP-9 and vascular hyperpermeability in these organs in the early phase of infection, but did not suppress the induction of trypsin, IL-6 or IFN-gamma. Histopathological examination showed that clarithromycin tended to reduce inflammatory cell accumulation in the lungs and heart. These results suggest that clarithromycin suppresses infection-related inflammation and reduces vascular hyperpermeability by suppressing the induction of MCP-1 and MMP-9. PMID- 29406286 TI - Using Geographic Information Systems to Visualize Relationships Between Perinatal Outcomes and Neighborhood Characteristics When Planning Community Interventions. AB - OBJECTIVE: To describe maternal morbidity, birth outcomes, and neighborhood characteristics of urban women from a racially segregated city with the use of a geographic information system (GIS). DESIGN: Exploratory neighborhood-level study. Existing birth certificate data were linked and aggregated to neighborhood level data for spatial analyses. SETTING: Southern city in New Jersey. SAMPLE: Women and their 7,858 live births that occurred between 2009 and 2013. METHODS: Secondary analyses of extant sources were conducted. Maternal health and newborn birth outcomes were geocoded and then aggregated to the neighborhood level for further exploratory spatial analyses through our GIS database. An iterative process was used to generate meaningful visual representations of the data through maps of maternal and infant health in 19 neighborhoods. RESULTS: The racial and ethnic residential segregation and neighborhood patterns of associations of adverse birth outcomes with poverty and crime were illustrated in GIS maps. In 43% of the births, women had a documented medical risk. Significantly more preterm births occurred for Black women (p < .01) and women older than 35 years of age (p = .01). The rate of diabetes was greater in Hispanic women, and the rate of pregnancy-related hypertensive disorders was greater in Black women. CONCLUSION: Data-driven maps can provide clear evidence of maternal and infant health and health needs based on the neighborhoods where mothers live. This research is important so that maternity care providers can understand contextual factors that affect mothers in their communities and guide the design of interventions. PMID- 29406287 TI - Predicting Need for Follow-Up Due to Severe Anxiety and Depression Symptoms After Perinatal Loss. AB - OBJECTIVE: To evaluate the ability of the Perinatal Grief Intensity Scale (PGIS) when used within 8 weeks of perinatal loss to predict intense anxiety and severe depression symptoms in women 3 months later (Time 2 [T2]). DESIGN: Prospective survey. SETTING: Participants were recruited from hospitals in Louisville, KY and via the Internet. PARTICIPANTS: Women (N = 103) who experienced perinatal loss. METHODS: Data were collected using the PGIS, Beck Anxiety Inventory, and the Center for Epidemiologic Studies Depression Scale. We used logistic regression, odds ratios, and receiver operating characteristic curve analysis. RESULTS: The PGIS had 97.9% sensitivity and 29.6% specificity to predict severe depression symptoms and 95.2% sensitivity and 56.2% specificity to predict intense anxiety at T2. A baseline PGIS score greater than or equal to 3.53 predicted severe depression symptoms (odds ratio = 1.82, 95% confidence interval [CI] [1.46, 2.18], p = .014) and intense anxiety (odds ratio = 1.43, 95% CI [1.07, 1.82], p = .029) at T2. The receiver operating characteristic curves of the PGIS suggest the PGIS performs well at predicting (screening positive) for severe depression symptoms (area under the curve = 0.86, 95% CI [0.79, 0.94], p < .001) and intense anxiety (area under the curve = 0.86, 95% CI [0.78, 0.93], p < .001) after perinatal loss. CONCLUSION: The PGIS accurately predicted intense anxiety and severe depression symptoms 3 to 5 months after perinatal loss. This instrument may help health care providers identify women who need further mental health evaluation after perinatal loss. PMID- 29406288 TI - Emotional Effect of the Loss of One or Both Fetuses in a Monochorionic Twin Pregnancy. AB - OBJECTIVE: To examine the psychological effect on women of the loss of one or both fetuses during a monochorionic twin pregnancy and to identify associated protective and risk factors. DESIGN: Descriptive, cross-sectional, correlational study. SETTING: Maternity unit of the Vall d'Hebron University Hospital in Barcelona, Spain. PARTICIPANTS: Twenty-eight White Spanish women who lost one or both fetuses during a monochorionic twin pregnancy. METHODS: In an individual interview with each participant, we collected sociodemographic information, psychiatric history, and clinical data regarding the pregnancy. Participants also completed the following questionnaires: Spanish Short Version of the Perinatal Grief Scale, Impact of Event Scale-Revised, Beck Depression Inventory, and the State-Trait Anxiety Inventory. RESULTS: Greater levels of grief after fetal loss during a monochorionic twin pregnancy were associated with increased symptoms of depression, anxiety, and posttraumatic stress. The intensity of grief did not depend on the number of weeks of pregnancy at which the loss occurred, a history of miscarriage, the survival of one of the twins, the presence of living children, or any of the sociodemographic variables considered. CONCLUSION: Fetal loss in a monochorionic twin pregnancy has a considerable emotional effect and leaves the mother vulnerable to psychological problems. The survival of one of the twins or the presence of living children is no guarantee that the grieving mother's mental health will be less affected. PMID- 29406289 TI - Randomized Controlled Trial of a Prenatal Breastfeeding Self-Efficacy Intervention in Primiparous Women in Iran. AB - OBJECTIVE: To determine the effects of a prenatal breastfeeding self-efficacy intervention on breastfeeding self-efficacy and breastfeeding outcomes. DESIGN: Randomized controlled trial. SETTING: Four health centers in Ahvaz, Iran. PARTICIPANTS: A total of 120 low-risk, nulliparous women between 35 and 37 weeks gestation who intended to breastfeed their singleton infants. METHODS: Women were randomly assigned to receive the breastfeeding self-efficacy intervention (n = 60) or standard care (n = 60). The intervention was multifaceted and included two prenatal group sessions, an information package with breastfeeding images, and text messages until 8 weeks postpartum to promote exclusive breastfeeding. The primary outcome was breastfeeding self-efficacy measured with the Breastfeeding Self-Efficacy Scale-Short Form, translated into Persian, at 8 weeks postpartum. Additional outcomes included rates of breastfeeding exclusivity, duration, practices, satisfaction, and problems. RESULTS: At 8 weeks postpartum, participants in the intervention group had significantly higher mean Breastfeeding Self-Efficacy Scale-Short Form scores and rates of exclusive breastfeeding than those in the control group. No significant group differences were found with regard to breastfeeding duration. CONCLUSION: Emerging evidence supports the use of breastfeeding self-efficacy interventions to improve breastfeeding self-efficacy and rates of exclusive breastfeeding. Further evaluation of this prenatal intervention is warranted. PMID- 29406290 TI - Interplay between habitat subdivision and minimum resource requirement in two species competition. AB - This paper explores the effects of increasing spatial subdivision of habitat on competition between two species. An increase in the degree of subdivision without any increase in the total amount of resources in the environment leads to smaller patch sizes, and thus, fewer individuals supported per patch. This fact suggests that when the degree of subdivision is high, the minimum resources that an individual must obtain before reproduction become important. Competition equations derived from first-principles that incorporate the minimum resource requirement are employed to investigate the effects of spatial subdivision and how these effects depend on the minimum requirements of the two species, type of resource competition such as scramble or contest, and spatial aggregation level of individuals. The results show that increased subdivision leads to changes in "effective fecundities" of the species, and consequently, affects their competitive superiority. Species coexistence is promoted at intermediate subdivision levels, especially if there is a trade-off between the minimum resource requirement and inherent fecundity. The range of subdivision in which coexistence occurs depends on the spatial aggregation of individuals and inequality in competitive ability between the species. PMID- 29406291 TI - Why Do Wounds Itch? AB - Everyone has experienced itch. It might simply be the nuisance of a mosquito bite or a transient itch on the scalp that is relieved by a simple scratch. For wounds such as venous ulcers, itch may be present but is usually mild. For some of the 40% of people with neuropathic itch or pain that can develop and persist following mastectomy, itch can be overwhelming, intractable, not widely appreciated by the medical community, and poorly responsive to current treatment regimens. Why are some wounds in some patients itchy whereas seemingly equivalent ones in the same or other patients not? Why is the sensation of itch present in the wound itself in some cases while in the surrounding skin in others? Why are burns so frequently associated with itch? How commonly do wounds itch? Detailed answers to these questions are lacking, but this area is beginning to be explored. Herein, the author provides an overview of the current understanding of the physiology of itch. An effort is made to place that understanding in the context of wounds, and therapeutic approaches that may be outside of the conventional toolkit are made based on this background. PMID- 29406292 TI - Descriptors for Itch Related to Chronic Wounds. AB - INTRODUCTION: Wound-related itch can be a source of great discomfort for patients with chronic wounds. Although itch is common among patients with chronic wounds, it is an understudied phenomenon. A greater understanding of itch is needed in order for clinicians to more effectively manage it. OBJECTIVE: The purpose of this study is to identify descriptors for wound-related itch based on patient responses. METHODS: Data from structured interviews of patients with chronic wounds were analyzed. Those patients who described wound-related itch were asked to rate how much various descriptors matched their itch on a scale of 0 (not at all) to 4 (to a great extent). Analysis included descriptive statistics and principal components factor analysis. RESULTS: Fifty-six of 199 (28%) patients with wound-related itch rated descriptors, and 5 categories of descriptors were identified. A concise set of 15 descriptors of itch related to chronic wounds was defined from this. CONCLUSIONS: This list of descriptors for wound-related itch can be tested further for clinical use and for research purposes when wound related itch is being explored. PMID- 29406293 TI - Itching for Knowledge About Wound and Scar Pruritus. AB - Chronic itch continues to be a problem that plagues millions of humans and animals. Pruritus has a negative impact on patient quality of life and many patients experience sleep deprivation, anxiety, and depression, similar to patients with chronic pain. This review provides an overview of clinical pruritus research with special emphasis on itch that wound care providers may see. In addition, the need for using multifactorial questionnaires for better research in pruritus is summarized. Similarities and differences in itch characteristics, triggers, and relievers in various patient populations are discussed. A brief overview of itch receptors and pathways is provided to help the reader better understand the complexity of the resultant itch sensation. Also, some nonpharmacological and pharmacological antipruritic therapies and their mechanisms of action are included. PMID- 29406294 TI - Evidence Corner: Taking Itch Seriously. AB - Dear Readers, Itching (pruritus) of a wound, scar, or dermatologic disorder can negatively impact a patient's quality of life, resulting in injurious scratching1 or impeded rehabilitation.2 Like pain, itch can cause the su erer to lose sleep and appetite or even consider suicide.3,4 Clinical measures of pruritus have proved reliable and valid in individuals with burn wounds, dermatologic conditions, or urticaria5-7 or resulting scars,2 allowing studies to clarify its impact on human experience and compare the e ects of interventions to reduce itching. This Evidence Corner explores the e ects on pruritus of interventions applied at 2 very different stages of wound healing: the rst during early healing stages after hemorrhoidectomy8 and the other in postburn hypertrophic scarring with contracture.9 Each condition generates distressing levels of pruritus from which patients eagerly seek relief. PMID- 29406295 TI - Postburn Itch: A Review of the Literature. AB - The problem of postburn itch has been underevaluated and undertreated in the past. However, recently published data have expanded the evidence base, which provides clinicians and their patients with new evaluation and treatment options that can help reduce and potentially eliminate the prolonged distress experienced by burn survivors faced with postburn itch. Although a gold standard evaluation method has not yet been agreed upon, there are a number of tools that have been published that clinicians can use for assessment. Epidemiological evidence has confirmed that the vast majority of both adult and pediatric burn survivors experience itch for years following injury. At discharge from the acute care hospital, 93% of burn survivors with major burn injuries report postburn itch that is still experienced by 44% of adult burn survivors 30 years postburn. Although larger surface area injuries are more likely to require a multimodal treatment approach to reduce the itch intensity as well as the episode duration and frequency, burn survivors with small surface area injuries also experience itch that needs to be addressed. A number of treatment protocols have been described that commonly call for concurrent administration of both pharmacological and nonpharmacological treatment approaches. These protocols provide clinicians with a structured, systematic approach to treatment decisions that are evidence-based. Although many questions require further investigation, the current state of the science creates an ethical imperative that all burn survivors' itch experience should be quantitatively evaluated and appropriate treatment options explored until satisfactory outcomes are obtained. PMID- 29406296 TI - Abdominal Catastrophe in Crohn's Disease Surgery. AB - INTRODUCTION: Performing surgery on patients with Crohn's disease is a true challenge due to the elevated risk of complications related to the chronic proinflammatory response. Stenosis is the leading cause of intestinal resection in these patients. CASE REPORT: The authors present the case of a 50-year-old woman with inflammatory stenosis of the terminal ileum due to Crohn's disease. The patient underwent a laparoscopic ileocecal resection, which was complicated by a small anastomotic dehiscence with localized peritonitis. Several perforations and dehiscences were observed and necessitated an end ileostomy and an open abdomen treated with negative pressure wound therapy. Multiple surgical interventions in the abdomen were performed and negative pressure was maintained until all fistulas were sealed and granulation tissue formed. Patient was discharged after 134 days of hospitalization with both the abdomen and the ileostomy closed. After several months, a hernia repair was performed with bilateral component separation and polypropylene mesh without complications. CONCLUSIONS: Anastomotic dehiscence after intestinal resection can lead to an abdominal catastrophe. Severe peritonitis with enteric fistulas and an open abdomen demands a multidisciplinary approach. Negative pressure wound therapy and nutritional support are key treatments. In these patients, stoma closure and abdominal wall reconstruction after recovery from the acute event represents another surgical challenge. PMID- 29406297 TI - Sacral Pressure Ulcer-induced Fournier's Gangrene Extending to the Retroperitoneum: A Case Report. AB - INTRODUCTION: Fournier's gangrene (FG) is a type of necrotizing fasciitis of the perineum and scrotum that is characterized by very rapid progression. Sacral pressure ulcers are one of the causes of FG. CASE REPORT: An 85-year-old man was referred to the National Hospital Organization Nagasaki Medical Center (Ohmura City, Japan) with a diagnosis of FG extending to the retroperitoneum caused by a sacral pressure ulcer. Immediate debridement was performed; however, it was not possible to remove all necrotic tissue from the pelvis. The wound was cleansed with continuous irrigation combined with negative pressure wound therapy, which brought the infection under control. The exposed rectum was resurfaced with a gracilis musculocutaneous flap, and the remaining wound in the sacral region was covered with a gluteal artery perforator flap. CONCLUSIONS: The authors consider continuous irrigation combined with negative pressure wound therapy as extremely useful for patients with FG in whom sufficient debridement cannot be performed. PMID- 29406298 TI - Attitude Isn't the Only Thing, It's Everything: Humanistic Care of the Bariatric Patient Using Donabedian's Perspective on Quality of Care. AB - Comprehensive care of bariatric patients is challenging. Although structural knowledge exists about safe care given correct equipment and supplies, care processes also must be humane. The literature suggests morbidly obese patients may fear the health system because of past negative experiences. The purpose of this literature review was to examine quality issues in the care of bariatric patients in light of Donabedian's structure-process-outcomes model, emphasizing process components. Using the Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, and PsycINFO; the criteria English language and years 2005 to 2017; and the search terms morbid obesity, obesity, bariatric, attitudes, health professionals, health clinicians, and patient care yielded 150 articles. Of those, 35 were pertinent to the review. A subsequent search using the terms Donabedian, care, and quality in MEDLINE and CINAHL resulted in 68 and 36 citations, respectively; 4 were used. When the searches were combined, no articles were identified. Findings show care providers generally understand structure aspects (knowledge or what to do) but need increased understanding of optimal care interventions (process issues or how to perform an intervention), including physical and psychological aspects. Organizations have a responsibility to ensure appropriate equipment and supportive services are available to achieve desired outcomes. Structure components will not overcome barriers or prevent complications if uncaring attitudes (processes) interfere with interpersonal interactions. Implications for clinical practice include requisite reflection on personal belief systems and empathetic understanding of precursors to morbid obesity development. Research needs to analyze what process issues are hampering quality care delivery and how to eradicate deficiencies. Health professionals can promote optimal bariatric patient outcomes by developing necessary insight and clinical wisdom. Obesity is a worldwide epidemic and those affected deserve improved care now. PMID- 29406299 TI - A Qualitative Study to Explore the Impact of Simulating Extreme Obesity on Health Care Professionals' Attitudes and Perceptions. AB - Extremely obese patients pose significant challenges for those who strive to provide care. The prevalence and consequences of weight bias and stigma in health care have been well documented, but research on how to reduce weight bias and stigma is limited. To assess the impact of simulating obesity on the attitudes and perceptions of health professionals toward extreme obesity, a qualitative study involving 6 registered nurses and 1 registered physiotherapist was conducted between November 2015 and May 2016. Health professionals who had regular contact with persons with obesity were recruited through poster advertisement in 1 hospital and 2 universities. Participants completed a demographic survey that included their physical measurements (height, weight, and waist circumference). They then wore a suit simulating the shape and size of a person with extreme obesity for approximately 2 hours and engaged in activities such as taking public transport or visiting a cafe. Audiotaped, semistructured interviews were conducted before and after the suit exercise and transcribed verbatim for conventional content analysis that identified 3 main categories: 1) insights into the physical challenges facing people with extreme obesity; 2) awareness of social consequences for people with extreme obesity; and 3) changes in participants' attitudes toward people with extreme obesity. Following the exercise, personal attitudes were found to be less judgmental and more empathetic. Using a simulation suit may increase awareness among health professionals regarding issues facing persons with obesity and may be a positive influence on diffusing weight stigma and bias in health care settings, particularly in the area of wound prevention and management where excess weight often requires additional nursing care that may exacerbate existing biases. Ethical guidance needs to be developed in conjunction with further research to explore the risks and benefits of using simulation suits in clinical practice and education. PMID- 29406300 TI - A Retrospective, Cost-minimization Analysis of Disposable and Traditional Negative Pressure Wound Therapy Medicare Paid Claims AB - Traditional negative pressure wound therapy (NPWT) systems are considered durable. The pump is designed for use by numerous patients over a period of several years. Recently developed smaller, disposable devices are designed for single-patient use. A retrospective analysis of 2012-2014 national Medicare claims data was used to examine payments associated with the use of traditional and disposable NPWT systems. Data extracted included NPWT episodes from the Limited Data Set Standard Analytic Files including the 5% sample for traditional NPWT and 100% sample for disposable NPWT. NPWT episodes were identified using claim service dates and billing codes. Mean costs per episode were compared and analyzed using chi-squared tests for comparisons between patients who received traditional and those who used disposable NPWT. For continuous variables, statistical significance was assessed using Mann-Whitney U tests. The data included traditional (n = 2938; mean age 66.6 years) and disposable (n = 3522; mean age 67.6 years) episodes for the 2 NPWT groups. Wound types differed for NPWT groups (P <.0001) and included surgical (1134 [39%] versus 764 [22%]), generic open (850 [29%] versus 342 [10%]), skin ulcers (561 [19%] versus 1301 [37%]), diabetic ulcers (240 [8%] versus 342 [10%]), and circulatory system wounds (105 [4%] versus 563 [16%]). Average payment amounts were $4650 +/- $2782 for traditional and $1532 +/- $1767 per disposable NPWT episode (P <.0001). Payment differences were not affected by wound or comorbidity characteristics. Using the 2016 rates, average payments were $3501 for traditional and $1564 for disposable NPWT. Considering the rate of NPWT use in the United States and the results of this study suggesting substantial potential cost savings, additional analyses and cost-effectiveness studies are warranted. PMID- 29406301 TI - The History of Mind (Psyche)-Body (Soma) Medicine: Practical Examples. AB - This article discusses the relationship between health and disease, considering the mind/body dichotomy that has occurred in the history of medicine, both in Western and Eastern cultures. The author begins by referring to the magical concept of disease, passing through the classical Greek period, and the medieval and Renaissance vision, to the evolution of modern concepts proposed by psychoanalysis. The author references some practical examples about the importance of the mind-body relationship, such as the psychological steps experienced by the oncological patient, as well as the psychiatric disorder. PMID- 29406302 TI - Brief Report: Knowledge of, Interest in, and Willingness to Try Behavioral Interventions in Individuals With Parkinson's Disease. AB - Purpose/Objective * Behavioral interventions hold enormous promise for managing a variety of motor and nonmotor symptoms in Parkinson's disease (PD). Despite this, prior studies have suggested that the utilization of these interventions is relatively low. The current study seeks to understand factors that could relate to the utilization of PD behavioral strategies. Specifically, the study evaluates the self-described knowledge of, interest in, and willingness to participate in behavioral interventions in a community-dwelling sample of individuals with PD. Research Method/Design * Forty-five individuals with PD completed a survey that assessed knowledge, interest, and willingness to participate in 5 behavioral interventions: hypnosis, relaxation training, mindfulness/meditation, computerized "brain games," and counseling. In addition, participants self reported their quality of life across several domains; these domain scores were correlated with overall ratings of interest and willingness to participate in behavioral interventions. Results * Self-reported knowledge of behavioral interventions was low, but interest and willingness to participate was moderate to high across modalities. Statistically significant correlations were noted between perceived knowledge of the techniques and interest (r = 0.29, P = .05) as well as willingness to participate (r = 0.32, P = .03) in these techniques. Interest and willingness were also correlated with self-reported bodily discomfort (r = 0.36, P = .02). Conclusions/Implications * The participants of the current sample were interested and willing to participate in behavioral interventions but had limited knowledge of the potential for these techniques to manage their symptoms. The reported high level of willingness to participate in behavioral interventions suggests that it is feasible to provide behavioral interventions in this population. PMID- 29406303 TI - Yoga Intervention for an Adolescent With Juvenile Idiopathic Arthritis: A Case Study. AB - Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease associated with pain, stiffness, and psychosocial difficulties. The purpose of this case study was to investigate the impact of a yoga intervention on pain and morning stiffness in an adolescent female with JIA. A secondary aim was to assess the impact of this intervention on self-efficacy, mindfulness, health-related quality of life, and disease activity. A 17-y-old female with JIA participated in 3 yoga groups and home yoga practice with a digital video disc. She engaged in daily self-monitoring of pain and stiffness and completed questionnaires assessing psychosocial functioning and disease activity at pre- and postintervention, and psychosocial functioning at 3-mo follow-up. Primary outcomes were evaluated using quasi-experimental single-case design structure (ie, ABAB), with emphasis on the report of means. Results suggested that yoga reduced pain intensity, stiffness intensity, and duration of morning stiffness. Outcomes for disease activity also suggested improvements. Modest changes were revealed on psychosocial outcome measures, however not consistently in the direction of hypotheses. Anecdotal reports from the participant indicated acceptability of the intervention and improvements in pain and stiffness attributed to engaging in the yoga intervention. More research is warranted to further explore the impact of yoga for youth with JIA as an adjunctive component of multidisciplinary treatment targeting pain, stiffness, disease activity, and psychosocial factors. PMID- 29406304 TI - Metallic MoN Layer and its Application as Anode for Lithium-ion Batteries. AB - Recently, two-dimensional (2D) metallic MoN was manufactured successfully in experiment, while its intrinsic properties remain to be explored theoretically in depth. The intrinsic properties of MoN monolayer are investigated by first principles calculations. Distinct geometric properties of the outmost Mo and N surfaces are discovered. We predict an extremely high work function of 6.3 eV of the N surface, which indicates great value of the 2D MoN for application in the semiconductor industry. We further explore the potential of 2D MoN as anode material for lithium-ion batteries. It is found that adsorption energy of the single Li atom on MoN surface can be as low as - 4.04 eV. The small diffusion barriers (0.41 eV) and high theoretical maximum capacity (406 mAh?g-1 with the inclusion of multilayer adsorption) all imply the outstanding lithium-ion batteries performance by 2D MoN. PMID- 29406305 TI - Phase division multiplexed EIT for enhanced temporal resolution. AB - OBJECTIVE: The most commonly used EIT paradigm (time division multiplexing) limits the temporal resolution of impedance images due to the need to switch between injection electrodes. Advances have previously been made using frequency division multiplexing (FDM) to increase temporal resolution, but in cases where a fixed range of frequencies is available, such as imaging fast neural activity, an upper limit is placed on the total number of simultaneous injections. The use of phase division multiplexing (PDM) where multiple out of phase signals can be injected at each frequency is investigated to increase temporal resolution. APPROACH: TDM, FDM and PDM were compared in head tank experiments, to compare transfer impedance measurements and spatial resolution between the three techniques. A resistor phantom paradigm was established to investigate the imaging of one-off impedance changes, of magnitude 1% and with durations as low as 500 us (similar to those seen in nerve bundles), using both PDM and TDM approaches. MAIN RESULTS: In head tank experiments, a strong correlation (r > 0.85 and p < 0.001) was present between the three sets of measured transfer impedances, and no statistically significant difference was found in reconstructed image quality. PDM was able to image impedance changes down to 500 us in the phantom experiments, while the minimum duration imaged using TDM was 5 ms. SIGNIFICANCE: PDM offers a possible solution to the imaging of fast moving impedance changes (such as in nerves), where the use of triggering or coherent averaging is not possible. The temporal resolution presents an order of magnitude improvement of the TDM approach, and the approach addresses the limited spatial resolution of FDM by increasing the number of simultaneous EIT injections. PMID- 29406306 TI - Effect of sulphur vacancy and interlayer interaction on the electronic structure and spin splitting of bilayer MoS2. AB - Molybdenum disulfide (MoS2) is one of candidate materials for nanoelectronics and optoelectronics devices in future. The electronic and magnetic properties of MoS2 can be regulated by interlayer interaction and vacancy effect. Nevertheless, the combined effect of these two factors on MoS2 is not clearly understood. In this study, we have investigated the impact of single S vacancy combined with interlayer interaction on the properties of bilayer MoS2. Our calculated results show that S vacancy brings impurity states in the band structure of bilayer MoS2, and the energy level of the impurity states can be affected by interlayer distance, which finally disappears in bulk state when the layer distance is relatively small. Moreover, during the compressing of bilayer MoS2, the bottom layer, where S vacancy stays, gets additional charge due to interlayer charge transfer, which first increases, and then decreases due to gradually forming the interlayer S-S covalent bond, as interlayer distance decreases. The change of the additional charge is consistent with the change of the total magnetic moment of bottom layers, no magnetic moment has been found in top layer. The distribution of magnetic moment mainly concentrates on the three Mo atoms around S vacancy, each of whose magnetic moment is very much related to the Mo-Mo length. Our conclusion is that the interlayer charge transfer and S vacancy codetermine the magnetic properties of this system, which maybe a useful way to regulate the electronic and magnetic properties of MoS2 for potential applications. PMID- 29406307 TI - The elusive role of NbLi bound polaron energy in hopping charge transport in Fe : LiNbO3. AB - Charge transport due to small polarons hopping among defective (bound polarons) and regular (free polarons) sites is shown to depend in a non-trivial way from the value of the stabilization energy provided by the lattice distortion surrounding the charge carriers. This energy, normally not directly accessible for bound polarons by spectroscopic techniques, is here determined by a combination of experimental and numerical methods for the important case of small electron polarons bound to ?mathrm{Nb}_{?mathrm{Li}} defects in the prototype ferroelectric oxide lithium niobate. Our findings provide an estimation of the ?mathrm{Nb}_{?mathrm{Li}} polaron stabilization energy E_{GP}=?unit[(0.75?pm0.05)]{eV} and point out that in lithium niobate both free and bound polarons contributes to charge transport already at room temperature, explaining the fast decays of the light-induced bound polaron population observed by transient absorption spectroscopy. PMID- 29406308 TI - Comparison of two telemetric intestinal temperature devices with rectal temperature during exercise. AB - OBJECTIVE: The discomfort caused by rectal probes and esophageal probes for the estimation of body core temperature has triggered the development of gastrointestinal (GI) capsules that are easily accepted by athletes and workers due to their non-invasive characteristics. We compare two new GI capsule devices with rectal temperature during cycle ergometer exercise and rest. APPROACH: Eight participants followed a protocol of (i) 30 min exercise with a power output of 130 W, (ii) 5 min rest, (iii) 10 min self-paced maximum exercise, and (iv) 15 min rest. Core temperature was measured using two GI-capsule devices (e-Celsius and myTemp) and rectal temperature. MAIN RESULTS: The myTemp system provided only slightly different temperatures to the rectal temperature probe during rest and exercise. However, the factory-calibrated e-Celsius system showed a systematic rectal temperature underestimation of 0.2 degrees C that is corrected in the 2018 versions. Both GI capsules reacted faster to temperature changes in the body compared to the rectal temperature probe during the rest period following maximum exercise. SIGNIFICANCE: The GI-capsules react faster to temperature changes in the body compared to the rectal temperature probe, in particular during the rest period following exercise. PMID- 29406309 TI - Addition of internal electrodes is beneficial for focused bioimpedance measurements in the lung. AB - OBJECTIVE: Bioimpedance measurements such as bioimpedance spectroscopy (BIS) or electrical impedance tomography (EIT) are used in many biomedical applications. While BIS measures and analyzes the impedance in a frequency range at constant electrode positions, EIT aims to reconstruct images of the conductivity distribution from multiple measurements at different electrode positions. Our aim is to add spatial information to tetrapolar BIS measurements by using electrode positions that focus measurements on desired regions of interest. In this paper, we aim to investigate, whether internal electrodes that can be integrated into breathing or gastroesophageal tubes, can improve the local sensitivity of bioimpedance spectroscopy measurements. APPROACH: We present the results of a simulation study, in which we investigated more than 4 M different electrode configurations on their ability to monitor specific regions of interest (ROI) in the lung. Based on the sensitivity, which describes the impact of a conductivity change on the measured impedance, we define three main criteria which we use to evaluate our simulation results: the selectivity [Formula: see text], which describes the impact of a conductivity change inside the region of interest compared to a conductivity change outside the ROI; the homogeneity [Formula: see text], which describes the distribution of the sensitivity inside the ROI; and the absolute impedance contribution ratio [Formula: see text], which describes the contribution of the ROI to the measured impedance. MAIN RESULTS: Depending on the region of interest, electrode configurations using internal electrodes are between 9.8 % and 90 % better with respect to these criteria than configurations using external electrodes only. SIGNIFICANCE: The combination of internal and external electrodes improves the focusing ability of tetrapolar impedance measurements on specific lung regions, which may be especially beneficial for lung monitoring in intensive care. PMID- 29406310 TI - Spin-flop and magnetodielectric reversal in Yb substituted GdMnO3. AB - The evolution of various spin structures in Yb doped GdMnO3 distorted orthorhombic perovskite system was investigated from their magnetic, dielectric and magnetodielectric characteristics. The Gd1 xYbxMnO3 (0 <= x <= 0.15) revealed an enhanced magnetodielectric coupling when their magnetic structure is guided from ab to bc-cycloidal spin structure upon Yb doping. The compounds exhibit magnetic field and temperature controlled spin-flop from c to a-axis. Additionally, magnetodielectric reversal is observed for x = 0.1 sample which depends on both magnetic field and temperature. The resultant correlation between magnetic and electric orderings is discussed in the frame of symmetric and antisymmetric exchange interaction models. These findings provide further insight in understanding the magnetoelectric materials and importantly show a way to tune the magnetic and magnetodielectric properties towards better application potential. PMID- 29406311 TI - Cross-flow-assembled ultrathin and robust graphene oxide membranes for efficient molecule separation. AB - A graphene oxide (GO) membrane is promising for molecule separation. However, it is still a big challenge to achieve highly stable pristine GO membranes, especially in water. In this work, an ultrathin and robust GO membrane is assembled via the cross-flow method. The as-prepared 12 nm thick GO membrane (GOCF membrane) presents high stability with water permeance of 1505 +/- 65 litres per hour per square meter per bar (LHM bar-1) and Evans Blue (EB) rejection of 98.7 +/- 0.4%, 21-fold enhancement in water permeance compared with that of a pristine GO membrane (50-70 LHM bar-1) and 100 times higher than that of commercial ultrafiltration membranes (15 LHM.bar-1, GE2540F30, MWCO 1000, GE Co., Ltd) with similar rejection. Attributed to the surface cross-flow, the GO nanosheets will be refolded, crumpled, or wrinkled, resulting in a very strong inter-locking structure among the GO membrane, which significantly enhances the stability and facilitates their separation performance. This cross-flow assembling technique is also easily extended to assemble GO membranes onto other various backing filter supports. Based on the Donnan effect and size sieving mechanism, selective membrane separation of dyes with a similar molecular structure from their mixture (such as Rhodamine B (RhB) and Rose Bengal, and RhB and EB) are achieved with a selectivity of 133 +/- 10 and 227 +/- 15, respectively. Assembly of this ultrathin GO membrane with high stability and separation performance, via a simple cross-flow method, shows great potential for water purification. PMID- 29406312 TI - Transmission/reflection behaviors of surface plasmons at an interface between two plasmonic systems. AB - Although surface plasmon polaritons (SPPs) have been intensively studied in past years, the transmission/reflection properties of SPPs at an interface between two plasmonic media are still not fully understood. In this article, we employ a mode expansion method (MEM) to systematically study such a problem based on a model system jointing two superlattices, each consisting of a periodic stacking of dielectric and plasmonic slabs with different material properties. Such a generic model can represent two widely used plasmonic structures (i.e. interfaces between two single dielectric/metal systems or between two metal-insulator-metal waveguides) under certain conditions. Our MEM calculations, in excellent agreement with full-wave simulations, uncover the rich physics behind the SPP reflections at generic plasmonic interfaces. In particular, we successfully derive from the MEM several analytical formulas that can quantitatively describe the SPP reflections at different plasmonic interfaces, and show that our formulas exhibit wider applicable regions than previously proposed empirical ones. PMID- 29406313 TI - Relaxation of strongly coupled electron and phonon fields after photoemission and high-energy part of ARPES spectra of cuprates. AB - An approach to considering systems with a high concentration of correlated carriers and strong long-range electron-phonon interaction and to calculating the high-energy part of the angle-resolved photoemission spectroscopy (ARPES) spectra of such systems is suggested. Joint relaxation of strongly coupled fields-a field of correlated electrons and phonon field-after photoemission is studied to clarify the nature of characteristic features observed in the high-energy part of the ARPES spectra of cuprate superconductors. Such relaxation occurs in systems with strong predominantly long-range electron-phonon interaction at sufficiently high carrier concentration due to the coexistence of autolocalized and delocalized carriers. A simple method to calculate analytically a high-energy part of the ARPES spectrum arising is proposed. It takes advantage of using the coherent states basis for the phonon field in the polaron and bipolaron states. The approach suggested yields all the high-energy spectral features like broad Gaussian band and regions of 'vertical dispersion' being in good quantitative agreement with the experiments on cuprates at any doping with both types of carriers. Demonstrated coexistence of autolocalized and delocalized carriers in superconducting cuprates changes the idea about their ground state above the superconducting transition temperature that is important for understanding transport and magnetic properties. High density of large-radius autolocalized carriers revealed may be a key to the explanation of charge ordering in doped cuprates. PMID- 29406314 TI - Intsy: a low-cost, open-source, wireless multi-channel bioamplifier system. AB - OBJECTIVE: Multi-channel electrical recordings of physiologically generated signals are common to a wide range of biomedical fields. The aim of this work was to develop, validate, and demonstrate the practical utility of a high-quality, low-cost 32/64-channel bioamplifier system with real-time wireless data streaming capability. APPROACH: The new 'Intsy' system integrates three main off-the-shelf hardware components: (1) Intan RHD2132 bioamplifier; (2) Teensy 3.2 microcontroller; and (3) RN-42 Bluetooth 2.1 module with a custom LabView interface for real-time data streaming and visualization. Practical utility was validated by measuring serosal gastric slow waves and surface EMG on the forearm with various contraction force levels. Quantitative comparisons were made to a gold-standard commercial system (Biosemi ActiveTwo). MAIN RESULTS: Intsy signal quality was quantitatively comparable to that of the ActiveTwo. Recorded slow wave signals had high SNR (24 +/- 2.7 dB) and wavefront propagation was accurately mapped. EMG spike bursts were characterized by high SNR (?10 dB) and activation timing was readily identified. Stable data streaming rates achieved were 3.5 kS s-1 for wireless and 64 kS s-1 for USB-wired transmission. SIGNIFICANCE: Intsy has the highest channel count of any existing open-source, wireless-enabled module. The flexibility, portability and low cost ($1300 for the 32-channel version, or $2500 for 64 channels) of this new hardware module reduce the entry barrier for a range of electrophysiological experiments, as are typical in the gastrointestinal (EGG), cardiac (ECG), neural (EEG), and neuromuscular (EMG) domains. PMID- 29406315 TI - A microbeam grazing-incidence approach to L-shell x-ray fluorescence measurements of lead concentration in bone and soft tissue phantoms. AB - OBJECTIVE: L-shell x-ray fluorescence (LXRF) is a non-invasive approach to lead (Pb) concentration measurements in the human bone. The first studies were published in the early 1980s. In the same period the K-shell x-ray fluorescence (KXRF) method using a Cd-109 radionuclide source was developed and later improved and refined. Lower sensitivity and calibration difficulties associated with the LXRF method led the KXRF to be the most adopted method for in vivo human bone Pb studies. In the present study a microbeam-based grazing-incidence approach to Pb LXRF measurements was investigated. APPROACH: The microbeam produced by an integrated x-ray tube and polycapillary x-ray lens (PXL) unit was used to excite cylindrical plaster-of-Paris (poP) bone phantoms doped with Pb in seven concentrations: 0, 8, 16, 29, 44, 59, and 74 ug g-1. Two 1 mm- and 3 mm-thick cylindrical shell soft tissue phantoms were made out of polyoxymethylene (POM) plastic. Three bone-soft tissue phantom sets corresponding to the 0, 1, and 3 mm POM thickness values resulted. Each phantom was placed between the microbeam and the detector; its position was controlled using a positioning stage. Small steps (0.1-0.5 mm) and short 30 s x-ray spectra acquisitions were used to find the optimal phantom position according to the maximum observed Sr Kalpha peak height. At the optimal geometry, five 180 s x-ray spectra were acquired for each phantom set. Calibration lines were obtained using the fitted peak heights of the two observed Pb Lalpha and Pb Lbeta peaks. MAIN RESULTS: The lowest detection limit (DL) values were (2.9 +/- 0.2), (4.9 +/- 0.3), and (23 +/- 3) ug g-1, respectively. The order of magnitude of the absorbed radiation dose in the POM plastic for the 180 s irradiation was estimated to be <1 mGy. SIGNIFICANCE: The results are superior to a relatively recently published LXRF phantom study and show promise for future designs of in vivo LXRF measurements. PMID- 29406316 TI - Core-shell titanium dioxide-titanium nitride nanotube arrays with near-infrared plasmon resonances. AB - Titanium nitride (TiN) is a ceramic with high electrical conductivity which in nanoparticle form, exhibits localized surface plasmon resonances (LSPRs) in the visible region of the solar spectrum. The ceramic nature of TiN coupled with its dielectric loss factor being comparable to that of gold, render it attractive for CMOS polarizers, refractory plasmonics, surface-enhanced Raman scattering and a whole host of sensing applications. We report core-shell TiO2-TiN nanotube arrays exhibiting LSPR peaks in the range 775-830 nm achieved by a simple, solution based, low cost, large area-compatible fabrication route that does not involve laser-writing or lithography. Self-organized, highly ordered TiO2 nanotube arrays were grown by electrochemical anodization of Ti thin films on fluorine-doped tin oxide-coated glass substrates and then conformally coated with a thin layer of TiN using atomic layer deposition. The effects of varying the TiN layer thickness and thermal annealing on the LSPR profiles were also investigated. Modeling the TiO2-TiN core-shell nanotube structure using two different approaches, one employing effective medium approximations coupled with Fresnel coefficients, resulted in calculated optical spectra that closely matched the experimentally measured spectra. Modeling provided the insight that the observed near-infrared resonance was not collective in nature, and was mainly attributable to the longitudinal resonance of annular nanotube-like TiN particles redshifted due to the presence of the higher permittivity TiO2 matrix. The resulting TiO2-TiN core shell nanotube structures also function as visible light responsive photocatalysts, as evidenced by their photoelectrochemical water-splitting performance under light emitting diode illumination using 400, 430 and 500 nm photons. PMID- 29406317 TI - Electrohysterography in the diagnosis of preterm birth: a review. AB - : Preterm birth (PTB) is one of the most common and serious complications in pregnancy. About 15 million preterm neonates are born every year, with ratios of 10-15% of total births. In industrialized countries, preterm delivery is responsible for 70% of mortality and 75% of morbidity in the neonatal period. Diagnostic means for its timely risk assessment are lacking and the underlying physiological mechanisms are unclear. Surface recording of the uterine myoelectrical activity (electrohysterogram, EHG) has emerged as a better uterine dynamics monitoring technique than traditional surface pressure recordings and provides information on the condition of uterine muscle in different obstetrical scenarios with emphasis on predicting preterm deliveries. OBJECTIVE: A comprehensive review of the literature was performed on studies related to the use of the electrohysterogram in the PTB context. APPROACH: This review presents and discusses the results according to the different types of parameter (temporal and spectral, non-linear and bivariate) used for EHG characterization. MAIN RESULTS: Electrohysterogram analysis reveals that the uterine electrophysiological changes that precede spontaneous preterm labor are associated with contractions of more intensity, higher frequency content, faster and more organized propagated activity and stronger coupling of different uterine areas. Temporal, spectral, non-linear and bivariate EHG analyses therefore provide useful and complementary information. Classificatory techniques of different types and varying complexity have been developed to diagnose PTB. The information derived from these different types of EHG parameters, either individually or in combination, is able to provide more accurate predictions of PTB than current clinical methods. However, in order to extend EHG to clinical applications, the recording set-up should be simplified, be less intrusive and more robust-and signal analysis should be automated without requiring much supervision and yield physiologically interpretable results. SIGNIFICANCE: This review provides a general background to PTB and describes how EHG can be used to better understand its underlying physiological mechanisms and improve its prediction. The findings will help future research workers to decide the most appropriate EHG features to be used in their analyses and facilitate future clinical EHG applications in order to improve PTB prediction. PMID- 29406318 TI - Interface bonding in silicon oxide nanocontacts: interaction potentials and force measurements. AB - The interface bonding between two silicon-oxide nanoscale surfaces has been studied as a function of atomic nature and size of contacting asperities. The binding forces obtained using various interaction potentials are compared with experimental force curves measured in vacuum with an atomic force microscope. In the limit of small nanocontacts (typically <103 nm2) measured with sensitive probes the bonding is found to be influenced by thermal-induced fluctuations. Using interface interactions described by Morse, embedded atom model, or Lennard Jones potential within reaction rate theory, we investigate three bonding types of covalent and van der Waals nature. The comparison of numerical and experimental results reveals that a Lennard-Jones-like potential originating from van der Waals interactions captures the binding characteristics of dry silicon oxide nanocontacts, and likely of other nanoscale materials adsorbed on silicon oxide surfaces. The analyses reveal the importance of the dispersive surface energy and of the effective contact area which is altered by stretching speeds. The mean unbinding force is found to decrease as the contact spends time in the attractive regime. This contact weakening is featured by a negative aging coefficient which broadens and shifts the thermal-induced force distribution at low stretching speeds. PMID- 29406319 TI - Enhanced photocatalytic CO2 reduction to CH4 over separated dual co-catalysts Au and RuO2. AB - A spatially separated, dual co-catalyst photocatalytic system was constructed by the stepwise introduction of RuO2 and Au nanoparticles (NPs) at the internal and external surfaces of a three dimensional, hierarchically ordered TiO2-SiO2 (HTSO) framework (the final photocatalyst was denoted as Au/HRTSO). Characterization by HR-TEM, EDS-mapping, XRD and XPS confirmed the existence and spatially separated locations of Au and RuO2. In CO2 photocatalytic reduction (CO2PR), Au/HRTSO (0.8%) shows the optimal performance in both the activity and selectivity towards CH4; the CH4 yield is almost twice that of the singular Au/HTSO or HRTSO (0.8%, weight percentage of RuO2) counterparts. Generally, Au NPs at the external surface act as electron trapping agents and RuO2 NPs at the inner surface act as hole collectors. This advanced spatial configuration could promote charge separation and transfer efficiency, leading to enhanced CO2PR performance in both the yield and selectivity toward CH4 under simulated solar light irradiation. PMID- 29406320 TI - Straightforward measurement of anisotropic thermal properties of a Bi2Se3 single crystal. AB - We demonstrate here a simple measurement protocol which allows the thermal properties of anisotropic crystalline materials to be determined. This protocol is validated by the measurement of Bi2Se3, a layered material consisting of covalently bonded sheets with weak van-der-Waals bonds between each layer, which has highly anisotropic thermal properties. Thermoreflectance microscopy measurements were carried out on a single-crystal Bi2Se3 sample, firstly on the bare sample and then after capping wih a 100 nm thick gold layer. Whereas on the bare sample lateral heat diffusion is dominated by the in-plane thermal diffusivity, on the metal-capped substrate heat diffusion perpendicular to the sample surface dominates. Using a simple theoretical model, we show how this double measurement protocol allows the anisotropic thermal conductivity coefficients of bulk Bi2Se3 to be evaluated. PMID- 29406321 TI - Mechanochemical synthesis of fluorescent carbon dots from cellulose powders. AB - A novel mechanochemical method was firstly developed to synthesize carbon nanodots (CNDs) or carbon nano-onions (CNOs) through high-pressure homogenization of cellulose powders as naturally abundant resource depending on the treatment times. While CNDs (less than 5 nm in size) showed spherical and amorphous morphology, CNOs (10-50 nm in size) presented polyhedral shape, and onion-like outer lattice structure, graphene-like interlattice spacing of 0.36 nm. CNOs showed blue emissions, moderate dispersibility in aqueous media, and high cell viability, which enables efficient fluorescence imaging of cellular media. PMID- 29406322 TI - Gait Speed and Dynamic Stability Decline Accelerates Only in Late Life: A Cross sectional Study in Community-Dwelling Older Adults. AB - BACKGROUND AND PURPOSE: Incidence of falls increases with age whereas gait speed declines. The purposes of this study were to examine (1) whether gait speed and center-of-mass (COM) velocity declined steadily across ages in a linear fashion among community-dwelling older adults, and (2) whether such decline corresponded to the similar decline in dynamic stability, which is governed by the control of their COM position and COM velocity relative to base of support (BOS). METHODS: A total of 184 community-dwelling older adults (>=65 years) participated in the cross-sectional study. The participants were categorized into 5 age groups (65 69, 70-74, 75-79, 80-84, and 85+ years) and were asked to walk on the 7-m walkway at their preferred walking speed. Their speed, gait pattern, relative COM position, and relative COM velocity were measured. RESULTS: Very close relationship was confirmed between a clinical gait speed measurement and the COM velocity (R = 0.875, P < .05), which enabled us to use the 2 terms interchangeably. Gait speed decline was not noticeable from 65 to 84 years of age (P > .05), but it accelerated after 85 years of age. This decline was most likely influenced by a reduction in both step length (P < .05) and cadence (P < .05). Similarly, dynamic stability against backward loss of balance changed little between 65 and 84 years of age (P > .05). Yet, it declined significantly after 85 years of age (P < .05), primarily affected by the reduction in the COM velocity relative to the BOS, whereby the COM position relative to the BOS remained constant during their walking. CONCLUSION: Expected steady decline in gait speed and in the control of gait stability cannot be confirmed. Rather, we found that both declined precipitously only after 85 years of age, when the risk of falls is likely to increase correspondingly. PMID- 29406323 TI - The Role of Emotional Competence in Takotsubo Cardiomyopathy. AB - OBJECTIVE: The current study examined the role of emotional competences and depression in takotsubo cardiomyopathy (TTC). METHODS: We compared 37 TTC patients who experienced emotion triggers (TTC-t: M (SD) age = 66.4 (12.8) years, 33 women) with 37 TTC patients who did not experience emotion triggers (TTC-nt: M (SD) age = 65.8 (11.1) years, 33 women) and 37 patients with acute myocardial infarction who experienced an emotion trigger (AMI-t: M (SD) age = 66.1 (10.1) years, 33 women). Three aspects of emotional competence (emotional intelligence, metacognitive beliefs, and emotional processing deficits) were assessed using the Trait Meta-Mood Scale (TMMS), the Meta-Cognitions Questionnaire 30, and the Emotional Processing Scale. Differences between-group means were evaluated using multivariate analysis of covariance, adjusting for depressive symptom (Hamilton Rating Scale for Depression). RESULTS: Compared with the TTC-nt and AMI-t comparison groups, TTC-t patients had low scores on emotional intelligence (TMMS Attention: F(2, 184) = 23.10, p < .001; TMMS Repair: F(2, 184) = 11.98, p < .001) and high scores in metacognitive beliefs and emotional processing deficits (e.g., Meta-Cognitions Questionnaire 30 Negative Beliefs about Thoughts: F(2, 184) = 56.93, p < .001), independent of the levels of depressive symptom. TTC-nt patients also had significantly lower scores on the Hamilton Rating Scale for Depression scale compared with AMI-t (p = .021) and TTC-t (p = .004) patients. CONCLUSIONS: TTC-t patients showed a specific dysfunctional profile of emotional competence, even after adjusting for depressive symptom. These results provided a better understanding of the psychological factors that contribute to TTC. PMID- 29406324 TI - Socioeconomic Position and Age-Related Disparities in Regional Cerebral Blood Flow Within the Prefrontal Cortex. AB - OBJECTIVE: Socioeconomic position (SEP) is associated with cerebrovascular health and brain function, particularly in prefrontal cortex and medial temporal lobe regions that exhibit plasticity across the life course. However, it is unknown whether SEP associates with resting cerebral blood flow (CBF), an indicator of baseline brain function, in these regions in midlife, and whether the association is (a) period specific, with independent associations for childhood and adulthood SEP, or driven by life course SEP, and (b) explained by a persistent disparity, widening disparity, or the leveling of disparities with age. METHODS: To address these questions, we analyzed cerebral perfusion derived by magnetic resonance imaging in a cross-sectional study of healthy adults (N = 443) who reported on childhood and adult SEP. Main effects were examined as an index of persistent disparity and age by SEP interactions as reflecting widening or leveling disparities. RESULTS: Stable high SEP across the lifespan was associated with higher global CBF and regional CBF (rCBF) in inferior frontal gyrus. However, childhood SEP was associated with rCBF in middle frontal gyrus, as moderated by age (beta = 0.04, p = .035): rCBF was inversely associated with age only for those whose parents had a high school education or below. No associations were observed for the hippocampus or amygdala. CONCLUSIONS: Life course SEP associations with rCBF in prefrontal cortex are suggestive of persistent disparities, whereas the age by childhood SEP interaction suggests that childhood disadvantage relates to a widening disparity, independent of global differences. These differential patterns in midlife may relate to disparities in later-life cerebrovascular and neurocognitive outcomes. PMID- 29406325 TI - Neuroscience. PMID- 29406326 TI - Accuracy of the WatchBP office ABI device for office blood pressure measurement over a wide range of arm sizes. AB - The aim of this study was to determine the accuracy of the WatchBP Office ABI monitor for office blood pressure measurement over a wide range of arm circumferences using the ANSI/AAMI/ISO 81060-2:2013 protocol. The device accuracy was tested in 88 participants whose mean+/-SD age was 54.5+/-17.6 years, whose arm circumference was 30.6+/-8.3 cm (range: 15-46 cm), and whose entry blood pressure (BP) was 138.3+/-23.4 mmHg for systolic and 83.7+/-14.6 mmHg for diastolic BP. Four cuffs (small, standard, large, and extra-large) suitable for arm circumferences ranging from 14.0 to 52.0 cm were used. The mean device observer difference in the 264 separate BP data pairs was 0.7+/-3.8 mmHg for systolic BP and was 0.0+/-3.7 mmHg for diastolic BP. These data were in agreement with criterion 1 of the ANSI/AAMI/ISO 81060-2:2013 standard requirements (<=5+/-8 mmHg). Moreover, criterion 2 was satisfied, the mean+/-SD device-observer difference of the 88 participants being 0.7+/-3.1 and 0.0+/-3.2 mmHg, respectively, for systolic and diastolic BP. Good agreement between observer and device was present across the whole range of arm circumferences. These data show that the Microlife WatchBP Office ABI monitor satisfied the ANSI/AAMI/ISO 81060 2:2013 standard requirements across a wide range of arm sizes. PMID- 29406327 TI - Validation of the iHealth ambulatory blood pressure monitor in adults according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization standard. AB - OBJECTIVE: To assess the accuracy of the iHealth oscillometric ambulatory blood pressure (BP) monitor in adults according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 standard. METHODS: Adults were recruited to fulfil the age, sex, BP and cuff distribution criteria of the ANSI/AAMI/ISO standard using the same-arm sequential BP measurement method. Two cuffs of the test device were used for arm circumferences 22-34 and 30-42 cm. RESULTS: A total of 100 individuals were recruited and 85 were included in the analysis. For validation criterion 1, the mean+/-SD of the differences between the test device and reference BP was -0.7+/ 6.0/0.7+/-4.8 mmHg (systolic/diastolic). For criterion 2, the SD of the averaged BP differences between the test device and reference per participant was 4.72/3.97 mmHg (systolic/diastolic). CONCLUSION: The iHealth ambulatory BP monitor fulfilled the requirements of the ANSI/AAMI/ISO validation standard in adults and can be recommended for clinical use. PMID- 29406328 TI - Novel FOXC2 Mutation and Distichiasis in a Patient With Lymphedema-Distichiasis Syndrome. AB - A 4 year-old-boy was referred for distichiasis of the upper and lower lids of both eyes that had been present since at least 1 year of age. The patient's family history was notable for distichiasis and lymphedema affecting numerous family members. The patient was found to have a novel heterozygous variant (c.741_742insGG) in the FOXC2 gene. Mutations in the FOXC2 gene are associated with lymphedema-distichiasis syndrome. An important feature of lymphedema distichiasis syndrome is that distichiasis is typically present prior to the onset of lymphedema. PMID- 29406329 TI - No BRAF V600E Mutation Identified in 28 Periocular Pyogenic Granuloma. AB - PURPOSE: BRAF V600E mutations were recently identified in some pyogenic granulomas of skin, particularly lesions arising in patients with port wine stains. In this study, the authors analyzed BRAF gene status in 28 periocular pyogenic granulomas to determine its role in their pathogenesis. METHODS: Retrospective review of ophthalmic pathology archives from 2007 to 2016 was used to identify pyogenic granulomas of the conjunctiva, eyelid, and orbit. Three eyelid nevi were also analyzed as positive controls. BRAF V600E status was assessed by pyrosequencing of DNA extracted from excess formalin-fixed, paraffin embedded surgical material. RESULTS: Microscopic examination of the periocular pyogenic granuloma specimens revealed proliferative vascular lesions, with radiating capillary channels surrounded by variable degrees of acute and chronic inflammation. Sequencing did not identify a BRAF V600E mutation in any of the 28 sporadic pyogenic granulomas, including 13 on the eyelid. In contrast, mutation analyses performed in parallel in melanocytic nevi of the eyelid identified BRAF V600E alterations in all 3 cases. CONCLUSIONS: The lack of BRAF V600E mutations in 28 sporadic pyogenic granulomas of the conjunctiva and eyelid suggests that such alterations are not a common driver in the pathogenesis of these periocular vascular lesions. PMID- 29406330 TI - Photochemically Induced Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Assessing Potentiality in Animal Tissue. AB - PURPOSE: An experimental study to demonstrate in animal eyelids that the controlled exposure of excised tarsal plate to ultraviolet-A radiation can induce a rigidification effect due to photochemical crosslinking of the constitutive collagen. METHODS: Excised strips of sheep tarsus were irradiated with ultraviolet-A rays (wavelength 365 nm) at low and high irradiances, in the presence of riboflavin as a photosensitizer, using radiation sources available for corneal collagen crosslinking procedure. The tensile strength and Young's modulus (stiffness) of irradiated and control samples were measured in a mechanical tester and analyzed statistically. Histologic examination of the specimens was carried out to evaluate the effect of radiation on the meibomian glands and collagen organization. RESULTS: Mechanical evaluation showed that irradiation induced both stiffening and strengthening of the tarsal plate specimens, and this effect was enhanced at the higher levels of irradiance. The changes in mechanical properties can be attributed to a process of photochemically induced crosslinking of tarsal collagen. Histology revealed no changes in the meibomian glands or in the fibrous collagen system of the tarsus. CONCLUSIONS: These findings indicate that irradiation of tarsal collagen leading to tissue stiffening could be a safe procedure for treating lax eyelid conditions in human patients. PMID- 29406331 TI - Reduced Immunohistochemical Expression of Hnf1beta and FoxA2 in Liver Tissue Can Discriminate Between Biliary Atresia and Other Causes of Neonatal Cholestasis. AB - Biliary atresia (BA) is a necroinflammatory occlusive cholangiopathy that affects infants. Genetic and environmental factors has been proposed for its occurrence. The objectives of this study was to investigate the protein expression of 2 important genes regulating ductal plate remodeling, hepatocyte nuclear factor 1 beta (Hnf1beta) and the fork head box protein A2 (FoxA2) in liver tissue from patients with BA and to compare their expression with other causes of neonatal cholestasis (NC). This retrospective study included 60 pediatric patients, 30 with BA and 30 with NC. Immunohistochemistry of Hnf1beta and FoxA2 was performed on liver tissues from studied patients as well as 20 healthy subjects. Statistical analysis between immunohistochemistry results and other parameters was performed. Liver tissue from patients with BA revealed reduced Hnf1beta and FoxA2 immunoexpression. A strong significant statistical difference between BA and NC group (P<0.0001) with regard to Hnf1beta and FoxA2 immunoexpression was evident. Moreover, Hnf1beta was significantly correlated with FoxA2 immunoexpression, stage of fibrosis, bile ductular proliferation, and bile plugs in bile ductules. Hnf1beta immunoreaction in BA cases showed 76.7% sensitivity, 90% specificity, 88.5% positive predictive value, 79.4% negative predictive value, and 83.4% accuracy. FoxA2 expression in BA cases revealed 70.0% sensitivity, 80.0% specificity, 77.8% positive predictive value, 72.7% negative predictive value, 75.0% accuracy. Hnf1beta and FoxA2 immunoexpression could differentiate between BA from other cause of NC. PMID- 29406332 TI - Immunohistochemical Expression of Different Subtypes of Cytokeratins by Endometrial Stromal Sarcoma. AB - Endometrial stromal sarcomas (ESS) are rare and understudied gynecologic mesenchymal neoplasms. These tumors can be confused with many other gynecologic and nongynecologic tumors due to their variegated morphologic appearance and nonspecific immunohistochemical profile. ESS can express cytokeratin (CK) and, therefore, may be misdiagnosed as carcinoma especially in extrauterine locations and when recurrence/metastasis is present. In this study, we investigated the expression of a wide spectrum of CKs consisting of AE1/3, CAM 5.2, HMCK, MNF116, CK5, CK6, CK7, CK8/18, CK14, CK17, CK19, and CK20 in 6 low-grade and 5 high-grade ESS. In addition, staining for estrogen receptor, progesterone receptor, CD10, and cyclin D1 was performed. Our results showed that CKs AE1/3, CAM 5.2, MNF116, and CK8/18 are more expressed in low-grade ESS, whereas high-grade ESS express more AE1/3 and CAM 5.2. In problematic cases, especially in recurrences or metastases, the immunohistochemical panel of antibodies AE1/3, MNF116, CAM 5.2, and CK8/18, together with other classic immunohistochemical markers CD10, cyclin D1, estrogen receptor, and progesterone receptor, may be helpful in the differential diagnosis between ESS and other gynecologic and nongynecologic malignancies. PMID- 29406333 TI - A Case Report of an Adenomatoid Tumor of the Uterus Mimicking an Endometrioid Adenocarcinoma on Endometrial Curetting: a Diagnostic Pitfall. AB - Adenomatoid tumors (AT) arising in the female genital tract are usually incidental findings occurring most often in the fallopian tube and uterine serosa and rarely in the myometrium. In the myometrium, they appear grossly as deep seated, small, firm, ill circumscribed nodules mimicking leiomyoma. Histologically they show a glandular and invasive pattern making well differentiated/low-grade endometrioid adenocarcinoma a major differential diagnosis. However, this differential is rarely encountered in practice because myometrial AT is usually seen on the hysterectomy specimen, because of their anatomic position in the deep myometrium, and only rarely in endometrial curettings. Our case is the first to report an AT, which presented as a polyp with associated fibroid on hysterescopic examination. Microscopically, the endometrial curetting and myomectomy showed irregular glands and cystic structures with occasional cytokeratin positive single signet-ring like cells invading into the myometrium, features consistent with low-grade endometrioid adenocarcinoma. On hysterectomy specimen, there was an ill-defined 5 cm mass in the myometrium with protrusion into the endometrium. The morphology was similar to that seen in the endometrial curetting. A larger panel of immunostains was done and the neoplastic cells were positive for AE1/3, CK7, CAM5.2, calretinin, and D2-40 and negative for CD34. A diagnosis of AT was rendered and no further treatment was required. Although AT is rarely seen in endometrial curetting, they should be in the differential diagnosis of glandular lesions to avoid pitfalls and unnecessary management especially in young patients desiring fertility. PMID- 29406334 TI - HMGA2 Gene Expression in Fine-needle Aspiration Samples of Thyroid Nodules as a Marker for Preoperative Diagnosis of Thyroid Cancer. AB - There is a great interest in molecular markers that would help in the preoperative diagnosis of malignant thyroid nodules in cases of indeterminate fine-needle aspiration cytology. The aim of this study was to determine the diagnostic accuracy of HMGA2 gene expression in discriminating benign from malignant thyroid nodules. In this study, 237 preoperative thyroid fine-needle aspiration samples were analyzed prospectively for the expression of the HMGA2 gene by real-time reverse transcription polymerase chain reaction. The results were evaluated against the postoperative histopathologic diagnosis or definitive cytologic diagnosis in cases of nodular goiter and Hashimoto thyroiditis. Among 237 samples from patients with thyroid nodules that were analyzed, 231 were adequate for real-time reverse transcription polymerase chain reaction analysis. With a cutoff value of 8.71 for relative gene expression, HMGA2 was positive in 19 (16.4%) of 116 nodular goiter, 1 (2.6%) of 39 Hashimoto thyroiditis, 9 (28.1%) of 32 follicular adenoma, 0 (0%) of 5 Hurthle cell adenoma, 32 (88.9%) of 36 papillary carcinoma, and 3 (100%) of 3 follicular carcinoma samples. In discriminating between malignant and benign thyroid nodules, HMGA2 has shown specificity of 84.5%, sensitivity of 91.9%, positive predictive value of 53.1%, and negative predictive value of 98.2%. High sensitivity and negative predictive value of HMGA2 for preoperative detection of malignant thyroid nodules shown in this study indicate that it may have a role as an ancillary marker in cytology in the management of patients with thyroid nodules. PMID- 29406335 TI - Fish/shellfish intake and the risk of head and neck cancer. AB - Fish intake and other dietary sources of omega-3 fatty acids have been shown to be associated with a reduced risk for some cancers. Although previous studies of head and neck cancer have reported associations with different dietary factors, including reduced risks for fruits and vegetables and putatively healthy dietary patterns, associations specific to fish intake are unclear. This study investigated the association between fish/shellfish intake and risk of squamous cell carcinoma of the head and neck (SCCHN) using data from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study conducted in 46 North Carolina counties with cases recruited from 2002 through 2006. Controls were frequency matched to the cases on age, sex, and race; the final sample size was 1039 cases and 1375 controls. Demographic, lifestyle, and dietary information were collected using an in-person interviewer-administered structured questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with unconditional logistic regression. Patients whose fish/shellfish intake was among the highest tertile had a 20% lower odds of SCCHN compared with those in the lowest tertile (OR: 0.80; 95% CI: 0.60-1.07) after adjustment for the matching and other factors (income, energy intake, fruit intake, cigarette smoking, and alcohol intake). The inverse association was more pronounced for oral cavity and oropharyngeal tumors, for African Americans, and for females, but CIs were wide. To further investigate this potential risk reduction strategy for SCCHN, future studies should consider examining specific fish/shellfish, cooking practices, and other omega-3 fatty acid sources. PMID- 29406336 TI - Swedish women's awareness of human papillomavirus, and health-related quality of life, anxiety, and depression after a notification of an abnormal Pap smear result: a cross-sectional study. AB - This study aims to assess (a) women's awareness of the human papillomavirus (HPV), (b) women's health-related quality of life (HRQoL) and levels of anxiety and depression symptoms, and (c) to compare the outcomes between women who are aware of the sexually transmitted nature of the HPV infection and women who are not. Swedish women who have been notified of an abnormal Pap smear result completed a questionnaire. This questionnaire consisted of sociodemographic characteristics, items on awareness of HPV, and how to cope with the Pap smear result and the instruments: the Functional Assessment of Chronic Illness Therapy Cervical Dysplasia and the Hospital Anxiety and Depression Scale (HADS). Data were analyzed using descriptive statistics, Student's t-test, chi-tests, Fisher's exact test, the Mann-Whitney U-test, and Fisher-Freeman-Halton exact test. In total, 122 women participated. The women reported a median (quartile 1-quartile 3) score of 87.6 on the Functional Assessment of Chronic Illness Therapy - Cervical Dysplasia (81.8-107.0), compatible with a good HRQoL. The median (quartile 1-quartile 3) scores on HADS-anxiety and HADS-depression were 7.0 (4.0 10.0) and 3.0 (1.0-5.3), respectively; however, 48.4% of the women reported anxiety (compared with 20% in a normal population). There were no statistically significant differences in the median scores in any of the scales, including the prevalence of distress between the subgroups. Women with abnormal Pap smear results have a good HRQoL; they can become anxious, but not depressed. Awareness of HPV as a sexually transmitted infection is low, but being aware does not impact on women's HRQoL or on anxiety and depression. PMID- 29406337 TI - Infographics and Video Summaries Come to JBJS. PMID- 29406338 TI - Excess Opioid Medication and Variation in Prescribing Patterns Following Common Orthopaedic Procedures. AB - BACKGROUND: Postoperative pain management in orthopaedic surgery accounts for a substantial portion of opioid medications prescribed in the United States. Understanding prescribing habits and patient utilization of these medications following a surgical procedure is critical to establishing appropriate prescribing protocols that effectively control pain while minimizing unused opioid distribution. We evaluated prescribing habits and patient utilization following elective orthopaedic surgical procedures to identify ways of improving postoperative opioid-prescribing practices. METHODS: We performed a review of prescribing data of 1,199 procedures and gathered telephone survey results from 557 patients to determine the number of opioid pills prescribed postoperatively and the number of unused pills. The data were collected from adult patients who underwent 1 of the 5 most common elective orthopaedic procedures at our institution in fiscal year 2015: total hip arthroplasty, total knee arthroplasty, endoscopic carpal tunnel release, arthroscopic rotator cuff repair, or lumbar decompression. We converted all dosages to opioid equivalents of oxycodone 5 mg and performed analyses of prescribing patterns, patient utilization, and patient disposal of unused opioids. RESULTS: Prescribing patterns following the 5 orthopaedic procedures showed wide variation. The median numbers of oxycodone 5 mg equivalent opioid pills prescribed upon discharge were 90 pills (range, 20 to 330 pills) for total hip arthroplasty, 90 pills (range, 10 to 200 pills) for total knee arthroplasty, 20 pills (range, 0 to 168 pills) for endoscopic carpal tunnel release, 80 pills (range, 18 to 100 pills) for arthroscopic rotator cuff repair, and 80 pills (range, 10 to 270 pills) for lumbar decompression. Thirty seven percent of patients overall requested and received at least 1 refill. The mean number of total pills prescribed (and standard deviation) including refills was 113.6 +/- 75.7 for total hip arthroplasty, 176.4 +/- 108.0 for total knee arthroplasty, 24.3 +/- 29.0 for carpal tunnel release, 98.2 +/- 59.6 for rotator cuff repair, and 107.4 +/- 64.4 for lumbar decompression. Participants reported unused opioid medication in 61% of cases. During the study year, >43,000 unused opioid pills were prescribed. Forty-one percent of patients reported appropriate disposal of unused opioid pills. CONCLUSIONS: Prescribing patterns vary widely, and a large amount of opioid medications remains unused following elective orthopaedic surgical procedures. Effective prescribing protocols are needed to limit this source of potential abuse and opioid diversion within the community. PMID- 29406339 TI - Implications of Introducing New Technology: Comparative Survivorship Modeling of Metal-on-Metal Hip Replacements and Contemporary Alternatives in the National Joint Registry. AB - BACKGROUND: New medical technologies are often used widely without adequate supporting data, a practice that can lead to widespread catastrophic failure such as occurred with metal-on-metal (MoM) hip replacements. We determined both how revision rates would have differed if, instead of receiving MoM hip replacements, patients had received existing alternatives and the subsequent cumulative re revision rates of the patients who did receive MoM hip replacements compared with alternatives. METHODS: This study is a population-based longitudinal cohort study of patient data recorded in the National Joint Registry (NJR) for England, Wales and Northern Ireland between April 2003 and December 2014. We ascertained implant failure rates separately among stemmed MoM total hip replacement (THR) and hip resurfacing procedures and, using flexible parametric survival modeling, compared them with the failure rates that would have been expected had existing alternatives been used. We used Kaplan-Meier survivorship analysis to compare cumulative re-revision of patients who received stemmed MoM primary replacements that failed and of those who underwent hip resurfacing that failed with those whose non-MoM THRs had failed. RESULTS: In all, 37,555 patients underwent MoM hip resurfacing, with a 10-year revision rate of 12.6% (95% confidence interval [CI]: 12.2% to 13.1%) compared with a predicted revision rate of 4.8% if alternative implants had been used. The 32,024 stemmed MoM THRs had a 19.8% (95% CI: 18.9% to 20.8%) 10-year failure rate compared with an expected rate of 3.9% if alternatives had been used. For every 100 MoM hip-resurfacing procedures, there were 7.8 excess revisions by 10 years, and for every 100 stemmed MoM THR procedures, there were 15.9, which equates to 8,021 excess first revisions. Seven year re-revision rates were 14.9% (95% CI: 13.8% to 16.2%) for stemmed non-MoM THRs, 18.0% (95% CI: 15.7% to 20.7%) for MoM hip resurfacing, and 19.8% (95% CI: 17.0% to 23.0%) for stemmed MoM THRs. CONCLUSIONS: This study highlights the consequences of widespread and poorly monitored adoption of a medical technology. Over 1 million MoM hip prostheses were implanted worldwide. The excess failure on a global scale will be enormous. This practice of adopting new technologies without adequate supporting data must not be repeated. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29406340 TI - An Easy-to-Use Prognostic Model for Survival Estimation for Patients with Symptomatic Long Bone Metastases. AB - BACKGROUND: A survival estimation for patients with symptomatic long bone metastases (LBM) is crucial to prevent overtreatment and undertreatment. This study analyzed prognostic factors for overall survival and developed a simple, easy-to-use prognostic model. METHODS: A multicenter retrospective study of 1,520 patients treated for symptomatic LBM between 2000 and 2013 at the radiation therapy and/or orthopaedic departments was performed. Primary tumors were categorized into 3 clinical profiles (favorable, moderate, or unfavorable) according to an existing classification system. Associations between prognostic variables and overall survival were investigated using the Kaplan-Meier method and multivariate Cox regression models. The discriminatory ability of the developed model was assessed with the Harrell C-statistic. The observed and expected survival for each survival category were compared on the basis of an external cohort. RESULTS: Median overall survival was 7.4 months (95% confidence interval [CI], 6.7 to 8.1 months). On the basis of the independent prognostic factors, namely the clinical profile, Karnofsky Performance Score, and presence of visceral and/or brain metastases, 12 prognostic categories were created. The Harrell C-statistic was 0.70. A flowchart was developed to easily stratify patients. Using cutoff points for clinical decision-making, the 12 categories were narrowed down to 4 categories with clinical consequences. Median survival was 21.9 months (95% CI, 18.7 to 25.1 months), 10.5 months (95% CI, 7.9 to 13.1 months), 4.6 months (95% CI, 3.9 to 5.3 months), and 2.2 months (95% CI, 1.8 to 2.6 months) for the 4 categories. CONCLUSIONS: This study presents a model to easily stratify patients with symptomatic LBM according to their expected survival. The simplicity and clarity of the model facilitate and encourage its use in the routine care of patients with LBM, to provide the most appropriate treatment for each individual patient. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29406341 TI - Femoral Version Abnormalities Significantly Outweigh Effect of Cam Impingement on Hip Internal Rotation. AB - BACKGROUND: The purpose of this study was to investigate the effects of femoral version, cam-type femoroacetabular impingement (FAI), and the combination of the 2 on the passive hip range of motion (ROM). METHODS: We prospectively analyzed a consecutive cohort of 220 patients (440 hips) who presented with unilateral or bilateral hip pain. The passive hip ROM was measured bilaterally with the patient in prone, supine, and lateral positions. Femoral version was measured and the presence of cam-type deformity was determined on preoperative computed tomography (CT) scans. Diagnostic findings of cam-type FAI included an alpha angle of >50 degrees on CT radial sequences of the head-neck junction and a femoral head-neck offset ratio of <0.18 on both radiographs and CT. RESULTS: Multivariate linear regression analysis confirmed that femoral version, as compared with the presence of a cam lesion, was a stronger independent predictor of internal rotation ROM. Conversely, the presence of a cam lesion resulted in a significant decrease in the passive hip flexion ROM (p < 0.001) with no additional effects due to the degree of femoral version. The passive hip internal rotation ROM in neutral flexion/extension and with the hip in 90 degrees of flexion were maximized in patients with femoral anteversion and decreased significantly with each incremental decrease in femoral version (p < 0.001). CONCLUSIONS: Abnormalities in femoral version significantly outweigh the effect of cam-type impingement on the passive hip internal rotation ROM. In contrast, the presence of a cam lesion significantly decreases the hip flexion ROM, irrespective of the degree of femoral version. These findings help to inform surgical decision-making for patients with cam-type FAI or femoral version abnormalities. CLINICAL RELEVANCE: It is common clinical practice to ascribe loss of hip internal rotation to the presence of a cam lesion and to assume that arthroscopic femoral osteoplasty will substantially improve internal rotation postoperatively. Our study shows that the cam lesion is more intimately tied to hip flexion than to hip internal rotation. This result directly impacts the clinical assessment of a patient presenting with radiographic findings of FAI. PMID- 29406342 TI - The Medial Sural Artery Perforator Flap: The First Choice for Soft-Tissue Reconstruction About the Knee. AB - BACKGROUND: The gastrocnemius muscle flap may be considered the first choice in many cases of soft-tissue reconstruction about the knee. Limited arc of rotation and reach of the flap as well as unsightly muscle bulk are major disadvantages and were the impetus to look for a local alternative. The aim of this study is to present a consecutive series of patients with a reconstruction about the knee involving the medial sural artery perforator flap (MSAPF). METHODS: A consecutive series of 17 cases of defect reconstructions about the knee using the MSAPF is described, with an emphasis on early postoperative complications. RESULTS: No major flap-related complications occurred except 1 case of tip necrosis that healed uneventfully after excision and secondary suture. Two patients with direct donor-site closure had a minor complication that required no revision, and 2 had partial skin-graft loss. CONCLUSIONS: In summary, use of this pedicled perforator flap represents a reliable technique for soft-tissue reconstruction about the knee with an acceptable complication rate and optimal contour reconstruction without the need for a skin graft and secondary debulking procedures. The range of motion associated with the MSAPF in comparison to the range associated with the gastrocnemius muscle flap is increased so that more proximal and lateral defects can be covered. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29406343 TI - Intermediate-Term Hip Survivorship and Patient-Reported Outcomes of Periacetabular Osteotomy: The Washington University Experience. AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) is an alternative to arthroplasty for treating symptomatic acetabular dysplasia, but there have been few studies on the intermediate-term outcomes of this procedure. In the present study, we assessed intermediate-term hip survival and patient-reported outcomes of PAO used to treat symptomatic acetabular dysplasia. METHODS: From July 1994 to August 2008, 238 hips (206 patients) were treated with PAO. Sixty-two had a diagnosis other than classic acetabular dysplasia, and 22 were lost to follow-up. The remaining 154 hips (129 patients) were evaluated at an average of 10.3 years postoperatively. Kaplan-Meier analysis was used to assess survivorship with an end point of total hip arthroplasty (THA). Hips were evaluated using the University of California at Los Angeles (UCLA) Activity Score, modified Harris hip score (mHHS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score. A WOMAC pain subscale score of >=10 and/or an mHHS of <=70 were considered to indicate a clinically symptomatic hip. RESULTS: Kaplan-Meier analysis revealed a hip survival rate of 92% (95% confidence interval [CI]: 82% to 97%) at 15 years postoperatively. Eight hips (5%) underwent THA at a mean (and standard deviation) of 6.8 +/- 5.2 years. Twenty-four additional hips (16%) were considered symptomatic based on a WOMAC pain score of >=10 and/or an mHHS of <=70. One hundred and twenty-two hips (79%) did not undergo THA and did not meet the criteria for symptoms, and these hips had a mean mHHS of 92.4 +/- 8.4, WOMAC pain subscale score of 1.2 +/- 1.9, and UCLA Activity Score of 7.7 +/- 2.0 at a mean of 10.1 years. A higher risk of failure was associated with fair or poor preoperative joint congruency (odds ratio [OR]: 8.65; 95% CI: 1.18 to 63.55; p = 0.034) and with a postoperative lateral center edge angle of >38 degrees (OR: 8.04; 95% CI: 2.01 to 32.22). A concurrent head neck osteochondroplasty was associated with a decreased risk of failure (OR: 0.27; 95% CI: 0.09 to 0.78; p = 0.016). CONCLUSIONS: This study demonstrates the durability of the Bernese PAO. Fair or poor preoperative joint congruency and excessive postoperative femoral head coverage were found to be predictors of failure, while concurrent head-neck osteochondroplasty in patients with an inadequate range of motion after PAO was associated with a decreased risk of failure. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29406344 TI - Digital Radiography in Total Hip Arthroplasty: Technique and Radiographic Results. AB - BACKGROUND: Obtaining the ideal acetabular cup position in total hip arthroplasty remains a challenge. Advancements in digital radiography and image analysis software allow the assessment of the cup position during the surgical procedure. This study describes a validated technique for evaluating cup position during total hip arthroplasty using digital radiography. METHODS: Three hundred and sixty-nine consecutive patients undergoing total hip arthroplasty were prospectively enrolled. Preoperative supine anteroposterior pelvic radiographs were made. Intraoperative anteroposterior pelvic radiographs were made with the patient in the lateral decubitus position. Radiographic beam angle adjustments and operative table adjustments were made to approximate rotation and tilt of the preoperative radiograph. The target for cup position was 30 degrees to 50 degrees abduction and 15 degrees to 35 degrees anteversion. Intraoperative radiographic measurements were calculated and final cup position was determined after strict impingement and range-of-motion testing. Postoperative anteroposterior pelvic radiographs were made. Two independent observers remeasured all abduction and anteversion angles. RESULTS: Of the cups, 97.8% were placed within 30 degrees to 50 degrees of abduction, with a mean angle (and standard deviation) of 39.5 degrees +/- 4.6 degrees . The 2.2% of cups placed outside the target zone were placed so purposefully on the basis of intraoperative range-of-motion testing and patient factors, and 97.6% of cups were placed between 15 degrees and 35 degrees of anteversion, with a mean angle of 26.6 degrees +/- 4.7 degrees . Twenty-eight percent of cups were repositioned on the basis of intraoperative measurements. Subluxation during range-of-motion testing occurred in 3% of hips despite acceptable measurements, necessitating cup repositioning. There was 1 early anterior dislocation. CONCLUSIONS: Placing the acetabular component within a target range is a critical component to minimizing dislocation and polyethylene wear in total hip arthroplasty. Using digital radiography, we positioned the acetabular component in our desired target zone in 97.8% of cases and outside the target zone, purposefully, in 2.2% of cases. When used in conjunction with strict impingement testing, digital radiography allows for predictable cup placement in total hip arthroplasty. PMID- 29406345 TI - State Variation in Medicaid Reimbursements for Orthopaedic Surgery. AB - BACKGROUND: Medicaid reimbursements are determined by each state and are subject to variability. We sought to quantify this variation for commonly performed inpatient orthopaedic procedures. METHODS: The 10 most commonly performed inpatient orthopaedic procedures, as ranked by the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample, were identified for study. Medicaid reimbursement amounts for those procedures were benchmarked to state Medicare reimbursement amounts in 3 ways: (1) ratio, (2) dollar difference, and (3) dollar difference divided by the relative value unit (RVU) amount. Variability was quantified by determining the range and coefficient of variation for those reimbursement amounts. RESULTS: The range of variability of Medicaid reimbursements among states exceeded $1,500 for all 10 procedures. The coefficients of variation ranged from 0.32 (hip hemiarthroplasty) to 0.57 (posterior or posterolateral lumbar interbody arthrodesis) (a higher coefficient indicates greater variability), compared with 0.07 for Medicare reimbursements for all 10 procedures. Adjusted as a dollar difference between Medicaid and Medicare per RVU, the median values ranged from -$8/RVU (total knee arthroplasty) to -$17/RVU (open reduction and internal fixation of the femur). CONCLUSIONS: Variability of Medicaid reimbursement for inpatient orthopaedic procedures among states is substantial. This variation becomes especially remarkable given recent policy shifts toward focusing reimbursements on value. PMID- 29406346 TI - Effect of Posterior Malleolus Fracture on Syndesmotic Reduction: A Cadaveric Study. AB - BACKGROUND: Syndesmotic malreduction and fractures of the posterior malleolus negatively influence outcomes of rotational ankle fractures. Recent data have shown that posterior malleolus fixation contributes to the stability of the syndesmosis. The purpose of this study was to analyze syndesmotic reduction within the context of different sizes of posterior malleolus fracture fragments and different qualities of reduction. METHODS: A model of stage-IV supination external rotation injury was created in 9 through-the-knee cadaveric specimens. The specimens were randomized to receive either a small (one-third of the incisura, n = 4) or a large (two-thirds of the incisura, n = 5) posterior malleolus fracture. High-resolution computed tomography (CT) scans were obtained of each intact specimen and then with clamp reduction of the syndesmosis along with a fracture fragment that was (1) unreduced, (2) anatomically reduced, or (3) fixed with a 4.8-mm-gap malreduction. Syndesmotic reduction in both the anterior posterior and the medial-lateral direction was assessed relative to the intact specimen. RESULTS: Clamp reduction of the syndesmosis increased medial translation of the distal part of the fibula in the specimens with an unfixed or an anatomically fixed posterior malleolus fracture fragment and caused lateral displacement of the distal part of the fibula in the specimens with gap malreduction of the posterior malleolus fracture. Clamp reduction of the syndesmosis caused a slight anterior shift of the fibula in the specimens with a small unfixed or anatomically fixed posterior malleolus fracture fragment and caused a posterior shift of the fibula in the specimens with gap malreduction of a large fragment. CONCLUSIONS: The overall anterior-posterior reduction of the syndesmosis was generally unaffected by a posterior malleolus fracture except when there was malreduction of a large fragment. Medial-lateral syndesmotic reduction was affected by the conditions of the posterior malleolus fixation, with malreduction of the posterior malleolus leading to syndesmotic malreduction. CLINICAL RELEVANCE: When posterior malleolus fractures occur with syndesmotic injury, anatomic fracture reduction and fixation are paramount as they can affect syndesmotic reduction, especially with larger fragments. PMID- 29406347 TI - The Cost-Effectiveness of Surgical Fixation of Distal Radial Fractures: A Computer Model-Based Evaluation of Three Operative Modalities. AB - BACKGROUND: There is no consensus on the optimal fixation method for patients who require a surgical procedure for distal radial fractures. We used cost effectiveness analyses to determine which of 3 modalities offers the best value: closed reduction and percutaneous pinning, open reduction and internal fixation, or external fixation. METHODS: We developed a Markov model that projected short term and long-term health benefits and costs in patients undergoing a surgical procedure for a distal radial fracture. Simulations began at the patient age of 50 years and were run over the patient's lifetime. The analysis was conducted from health-care payer and societal perspectives. We estimated transition probabilities and quality-of-life values from the literature and determined costs from Medicare reimbursement schedules in 2016 U.S. dollars. Suboptimal postoperative outcomes were determined by rates of reduction loss (4% for closed reduction and percutaneous pinning, 1% for open reduction and internal fixation, and 11% for external fixation) and rates of orthopaedic complications. Procedural costs were $7,638 for closed reduction and percutaneous pinning, $10,170 for open reduction and internal fixation, and $9,886 for external fixation. Outputs were total costs and quality-adjusted life-years (QALYs), discounted at 3% per year. We considered willingness-to-pay thresholds of $50,000 and $100,000. We conducted deterministic and probabilistic sensitivity analyses to evaluate the impact of data uncertainty. RESULTS: From the health-care payer perspective, closed reduction and percutaneous pinning dominated (i.e., produced greater QALYs at lower costs than) open reduction and internal fixation and dominated external fixation. From the societal perspective, the incremental cost-effectiveness ratio for closed reduction and percutaneous pinning compared with open reduction and internal fixation was $21,058 per QALY and external fixation was dominated. In probabilistic sensitivity analysis, open reduction and internal fixation was cost effective roughly 50% of the time compared with roughly 45% for closed reduction and percutaneous pinning. CONCLUSIONS: When considering data uncertainty, there is only a 5% to 10% difference in the frequency of probability combinations that find open reduction and internal fixation to be more cost-effective. The current degree of uncertainty in the data produces difficulty in distinguishing either strategy as being more cost-effective overall and thus it may be left to surgeon and patient shared decision-making. LEVEL OF EVIDENCE: Economic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29406348 TI - Development of a Questionnaire to Measure Impact and Outcomes of Brachial Plexus Injury. AB - BACKGROUND: The physical and psychological impact of brachial plexus injury (BPI) has not been comprehensively measured with BPI-specific scales. Our objective was to develop and test a patient-derived questionnaire to measure the impact and outcomes of BPI. METHODS: We developed a questionnaire in 3 phases with preoperative and postoperative patients. Phase 1 included interviews of patients using open-ended questions addressing the impact of BPI and improvement expected (preoperative patients) or received (postoperative patients). Phase 2 involved assembling a draft questionnaire and administering the questionnaire twice to establish test-retest reliability. Phase 3 involved selecting final items, developing a scoring system, and assessing validity. Patient scores using the questionnaire were assessed in comparison with scores of the Disabilities of the Arm, Shoulder and Hand (DASH) and RAND-36 measures. RESULTS: Patients with partial or complete plexopathy participated. In Phase 1 (23 patients), discrete categories were discerned from open-ended responses and became items for the preoperative and postoperative versions of the questionnaire. In Phase 2 (50 patients [14 from Phase 1]), test-retest reliability was established, with weighted kappa values of >=0.50 for all items. In Phase 3, 43 items were retained and grouped into 4 subscales: symptoms, limitations, emotion, and improvement expected (preoperative) or improvement received (postoperative). A score for each subscale, ranging from 0 to 100, can be calculated, with higher scores indicating more symptoms, limitations, and emotional distress, and greater improvement expected (or received). Preoperative scores were worse than postoperative scores for the symptoms, limitations, and emotion subscales (composite score of 48 compared with 38; p = 0.05), and more improvement was expected than was received (69 compared with 53; p = 0.01). Correlations with the DASH (0.44 to 0.74) and RAND-36 (0.23 to 0.80) for related scales were consistent and moderate, indicating that the new questionnaire is valid and distinct. CONCLUSIONS: We developed a patient-derived questionnaire that measures the physical and psychological impact of BPI on preoperative and postoperative patients and the amount of improvement expected or received from surgery. This BPI-specific questionnaire enhances the comprehensive assessment of this population. PMID- 29406349 TI - The Role of Extracorporeal Shockwave Treatment in Musculoskeletal Disorders. PMID- 29406350 TI - What's Important: From Syria to the United States for an Orthopaedic Surgery Residency. PMID- 29406351 TI - An Evaluation of Reporting Guidelines and Clinical Trial Registry Requirements Among Orthopaedic Surgery Journals. AB - BACKGROUND: The responsibility for ensuring that studies are adequately reported is primarily that of those conducting the study; however, journal policies may influence how thoroughly authors choose to report their research. The use of reporting guidelines and prospective trial registration are promising avenues for ensuring that published studies adhere to the highest methodological standards. The purpose of this study is to evaluate orthopaedic surgery journal policies regarding reporting guidelines and trial registration, and to evaluate the effects that these policies have on adherence to reporting. METHODS: We conducted a cross-sectional survey of journal policies and "Instructions for Authors" to determine the journals' policies and guidance regarding use of reporting guidelines and study registration. We also examined whether trials published in journals referencing CONSORT (Consolidated Standards of Reporting Trials) had higher rates of compliance with publishing a CONSORT flow diagram and whether journals with trial registration policies were more likely to contain registered trials than journals without these requirements. RESULTS: Of the 21 orthopaedic surgery journals, 6 (29%) did not mention a single guideline, and clinical trial registration was required by 11 (52%) orthopaedic surgery journals and recommended by 2 (10%). Of the 21 general medical journals, 3 (14%) did not mention a single guideline, and trial registration was required by 13 (62%) general medical journals and recommended by 5 (24%) others. Furthermore, journals that referenced CONSORT were more likely to publish trials with a CONSORT flow diagram. Journals with trial registration policies were more likely to publish registered trials. CONCLUSIONS: Reporting guidelines and trial registration are suboptimally required or recommended by orthopaedic surgery journals. These 2 mechanisms may improve methodology and quality, and should be considered for adoption by journal editors in orthopaedic surgery. CLINICAL RELEVANCE: Because orthopaedic surgeons rely on high-quality research to direct patient care, measures must be taken to ensure that published research is of the highest quality. The use of reporting guidelines and prospective clinical trial registration may improve the quality of orthopaedic research, thereby improving patient care. PMID- 29406352 TI - What Leads to Lead: Results of a Nationwide Survey Exploring Attitudes and Practices of Orthopaedic Surgery Residents Regarding Radiation Safety. AB - BACKGROUND: Excessive radiation to health-care providers has been linked to risks of cancer and cataracts, but its negative effects can be substantially reduced by lead aprons, thyroid shields, and leaded glasses. Hospitals are required to provide education and proper personal protective equipment, yet discrepancies exist between recommendations and compliance. This article presents the results of a survey of U.S. orthopaedic surgery residents concerning attitudes toward radiation exposure and personal protective equipment behavior. METHODS: An invitation to participate in a web-based, anonymous survey was distributed to 46 U.S. allopathic orthopaedic surgery residency programs (1,207 potential resident respondents). The survey was conceptually divided into the following areas: demographic characteristics, training and attitudes concerning occupational hazards, personal protective equipment provision and use, and general safety knowledge. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for the association between these characteristics and compliance with thyroid shield or lead gown wear. RESULTS: In this study, 518 surveys were received, with 1 survey excluded because of insufficient response, leaving 517 surveys for analysis (42.8% response rate). Ninety-eight percent of residents believed that personal protective equipment should be provided by the hospital or residency program. However, provision of personal protective equipment was not universal, with 33.8% reporting none and 54.2% reporting provision of a gown and thyroid shield. The prevalence of leaded glasses usage was 21%. Poor lead gown compliance and thyroid shield wear were associated with difficulty finding the corresponding equipment: PR, 2.51 (95% CI, 1.75 to 3.62; p < 0.001) for poor lead gown compliance and PR, 2.14 (95% CI, 1.46 to 3.16; p < 0.0001) for poor thyroid shield wear. Not being provided with personal protective equipment was also significantly associated with low compliance with both lead gowns (PR, 1.47 [95% CI, 1.04 to 2.08]; p = 0.03) and thyroid shields (PR, 1.69 [95% CI, 1.18 to 2.41]; p = 0.004). Respondents from the Southeast, West, or Midwest had lower compliance with lead gown usage. Forgetting was the number 1 reason to not wear a lead apron (42%). CONCLUSIONS: Radiation exposure is associated with increased risk of serious health problems. Our findings identified that the availability of lead personal protective equipment leads to increased compliance among residents surveyed. In addition to yearly occupational hazard training specific to orthopaedic surgery, greater efforts by residency programs and hospitals are needed to improve access to lead personal protective equipment and compliance for orthopaedic residents. PMID- 29406353 TI - Opioids After Orthopaedic Surgery: There Is a Need for Universal Prescribing Recommendations: Commentary on an article by Matthew J. Sabatino, MD, MS, et al.: "Excess Opioid Medication and Variation in Prescribing Patterns Following Common Orthopaedic Procedures". PMID- 29406354 TI - Is This "Easy-to-Use" Tool the Best Way to Predict Survival?: Commentary on an article by J.J. Willeumier, MD, et al.: "An Easy-to-Use Prognostic Model for Survival Estimation for Patients with Symptomatic Long Bone Metastases". PMID- 29406355 TI - Is Cam-Type Deformity That Important?: Commentary on an article by Matthew J. Kraeutler, MD, et al.: "Femoral Version Abnormalities Significantly Outweigh Effect of Cam Impingement on Hip Internal Rotation". PMID- 29406357 TI - What Contributions Did Kazimierz Karaffa-Korbutt Make to Occupational Health and Fatigue Prevention in Poland? PMID- 29406356 TI - Gastrointestinal Bleeding in Left Ventricular Assist Device: Octreotide and Other Treatment Modalities. AB - Left ventricular assist devices (LVADs) offer a therapeutic strategy for patients with end-stage heart failure. Increased device utilization has also increased the incidence of device-related complications including gastrointestinal bleeding (GIB). Multiple mechanisms have been proposed in the pathophysiology of continuous-flow LVAD-associated GIB including physiologic changes associated with high shear and nonpulsatile flow such as gastrointestinal arteriovenous malformations and acquired von Willebrand syndrome. Strategies to minimize the morbidity and mortality of LVAD-associated GIB are needed. Octreotide, a somatostatin analogue, has been described as an adjunct to current therapies and interventions. Factors that contribute to LVAD-associated GIB may be targeted by the pharmacologic effects of octreotide, including improved platelet aggregation, increased vascular resistance, and decreased splanchnic circulation. Octreotide has demonstrated clinical benefit in several case series and clinical trials for the treatment of LVAD-associated GIB. The focus of this article will be to review the pathophysiology of LVAD-associated GIB, discuss pharmacologic and nonpharmacologic treatment modalities, and review available literature on the role of octreotide in the management of LVAD-associated GIB. PMID- 29406358 TI - Sjogren Syndrome and Non-Sjogren Sicca Syndrome: Do They Affect the Vulva? PMID- 29406359 TI - Asthma exacerbation prediction: recent insights. AB - PURPOSE OF REVIEW: Asthma attacks are frequent in children with asthma and can lead to significant adverse outcomes including time off school, hospital admission and death. Identifying children at risk of an asthma attack affords the opportunity to prevent attacks and improve outcomes. RECENT FINDINGS: Clinical features, patient behaviours and characteristics, physiological factors, environmental data and biomarkers are all associated with asthma attacks and can be used in asthma exacerbation prediction models. Recent studies have better characterized children at risk of an attack: history of a severe exacerbation in the previous 12 months, poor adherence and current poor control are important features which should alert healthcare professionals to the need for remedial action. There is increasing interest in the use of biomarkers. A number of novel biomarkers, including patterns of volatile organic compounds in exhaled breath, show promise. Biomarkers are likely to be of greatest utility if measured frequently and combined with other measures. To date, most prediction models are based on epidemiological data and population-based risk. The use of digital technology affords the opportunity to collect large amounts of real-time data, including clinical and physiological measurements and combine these with environmental data to develop personal risk scores. These developments need to be matched by changes in clinical guidelines away from a focus on current asthma control and stepwise escalation in drug therapy towards inclusion of personal risk scores and tailored management strategies including nonpharmacological approaches. SUMMARY: There have been significant steps towards personalized prediction models of asthma attacks. The utility of such models needs to be tested in the ability not only to predict attacks but also to reduce them. PMID- 29406360 TI - Asthma in inner city children: recent insights: United States. AB - PURPOSE OF REVIEW: Children living in US inner cities experience disparate burdens of asthma, especially in severity, impairment, exacerbations, and morbidity. Investigations seeking to better understand the factors and mechanisms underlying asthma prevalence, severity, and exacerbation in children living in these communities can lead to interventions that can narrow asthma disparities and potentially benefit all children with asthma. This update will focus on recent (i.e. late 2016-2017) advances in the understanding of asthma in US inner city children. RECENT FINDINGS: Studies published in the past year expand understanding of asthma prevalence, severity, exacerbation, and the outcomes of guidelines-based management of these at-risk children, including: asthma phenotypes in US inner city children that are severe and difficult-to-control; key environmental determinants and mechanisms underlying asthma severity and exacerbations (e.g. allergy-mediated exacerbation susceptibility to rhinovirus); the importance of schools as a place for provocative exposures (e.g. mouse allergen, nitrogen dioxide) as well as a place where asthma care and outcomes can be improved; and the development and validation of clinically useful indices for gauging asthma severity and predicting exacerbations. SUMMARY: These recent studies provide a trove of actionable findings that can improve asthma care and outcomes for these at-risk children. PMID- 29406361 TI - Precision medicine in the treatment of primary immunodeficiency diseases. AB - PURPOSE OF THE REVIEW: Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients. RECENT FINDINGS: Immune deficiencies associated with gain-of function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase delta syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described. SUMMARY: In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations. PMID- 29406362 TI - Kaiser's School of Nursing: A 70-Year Legacy of Disruptive Innovation Corrigendum. PMID- 29406363 TI - Controversies in vascular access. AB - PURPOSE OF REVIEW: There is renewed interest in vascular access research, fueled by new perspectives and a critical re-examination of traditional thinking. This review summarizes important developments in vascular access from the past year, highlight areas of controversy, and makes recommendations for future research. RECENT FINDINGS: Recent studies provide an innovative and critical look at the assumptions underlying the promotion of fistulas as the preferred form of vascular access and highlight the need for a randomized comparison of different forms of access. Promising work that will help determine predictors of fistula maturation and potentially improve patient selection is ongoing. The role of early cannulation grafts continues to generate interest, and new approaches to reducing the risk of catheter-related bacteremia show promise. SUMMARY: The scientific community should capitalize on this opportunity to critically re examine fundamental questions that have gone unanswered to date. High-quality randomized trials are needed to quantify the magnitude of benefit of different vascular access strategies, gather information about the risks, benefits, and cost-effectiveness of different approaches, and to get a clear view of the patient experience and how it is impacted by choice of vascular access. PMID- 29406364 TI - Gender differences in hypertension. AB - PURPOSE OF REVIEW: The review is a short discussion of sex/gender differences in blood pressure control with a focus on gender differences in hypertension awareness, prevalence, and treatment, the new American College of Cardiology/American Heart Association Guidelines, and recent discoveries in animal models and humans on mechanisms responsible for sex/gender differences in hypertension. RECENT FINDINGS: Hypertension awareness is greater in women than men, the prevalence of hypertension is higher in men than women until after menopause, and although the American College of Cardiology/American Heart Association Guidelines recommend similar treatment for men and women, this is not currently the case in practice. New studies into mechanisms responsible for sex/gender differences in hypertension include the role of the kidneys, the renin angiotensin system, relaxin, and developmental programming. SUMMARY: Specific guidelines for hypertension treatment in women and men have yet to be developed. However, numerous animal and human studies have shown differences in the mechanisms responsible for blood pressure control between the sexes. Thus more research into the sex/gender differences in mechanisms responsible for hypertension are needed to determine the best treatment options that will reduce the risk of hypertension and subsequent cardiovascular diseases in both genders. PMID- 29406366 TI - Lack of Prognostic Model Validation in Low Back Pain Prediction Studies: A Systematic Review. AB - OBJECTIVE: The objective of this study was to investigate the frequency with which prediction studies for low back pain outcomes utilize prospective methods of prognostic model validation. METHOD: Searches of Medline and Embase for terms "predict/predictor," "prognosis," or "prognostic factor." The search was limited to studies conducted in humans and reported in the English language. Included articles were all those published in 2 Spine specialty journals (Spine and The Spine Journal) over a 13-month period, January 2013 to January 2014. Conference papers, reviews, and letters were excluded. The initial screen identified 55 potential studies (44 in Spine, 11 in The Spine Journal); 34 were excluded because they were not primary data collection prediction studies; 23 were not prediction studies and 11 were review articles. This left 21 prognosis papers for review, 19 in Spine, 2 in The Spine Journal. RESULTS: None of the 21 studies provided validation for the predictors that they documented (neither internal or external validation). On the basis of the study designs and lack of validation, only 2 studies used the correct terminology for describing associations/relationships between independent and dependent variables. DISCUSSION: Unless researchers and clinicians consider sophisticated and rigorous methods of statistical/external validity for prediction/prognostic findings they will make incorrect assumptions and draw invalid conclusions regarding treatment effects and outcomes. Without proper validation methods, studies that claim to present prediction models actually describe only traits or characteristics of the studied sample. PMID- 29406365 TI - Acute Pain Assessment in Sedated Patients in the Postanesthesia Care Unit. AB - CONTEXT: Acute postoperative pain remains inadequately assessed and managed. A valid instrument that assesses acute pain in sedated postanesthesia care unit (PACU) patients is needed. OBJECTIVES: Two behavioral pain assessment instruments, the NonVerbal Pain Scale Revised (NVPS-R) and Critical-care Pain Observation Tool (CPOT), were used to determine whether these instruments adequately assess acute pain in the PACU. METHODS: A crossover study design was used. The study was conducted in the Medical Services Administration at the Puerto Rico Medical Center. Upon PACU arrival, patient sedation levels were evaluated using the Richmond Agitation Sedation Scale. Acute pain was assessed using the CPOT (scored, 0 to 8) and the NVPS-R (scored, 0 to 10) at timepoints 0, 15, 30, 45, 60, 90, and 120 minutes. Descriptive statistics and mixed model regression analysis were used to compare pain score assessment between instruments. RESULTS: Clinically significant increases in vital signs and respiratory indicators using the NVPS-R were not seen in patients with significant pain at time 0, 15, and 120 minutes. The CPOT vocalization indicator was more frequent in patients with significant pain. CONCLUSIONS: Findings suggest that NVPS-R and CPOT can assess acute pain in sedated PACU patients. In patients with significant pain, the CPOT vocalization indicator was more consistent than physiological and respiratory indicators in detecting acute pain. Thus, our data do not support the exclusive use of vital sign indicators to assess acute pain, suggesting the superiority of the CPOT for the assessment of acute pain in sedated PACU patients. PMID- 29406367 TI - Opioid Use During Pregnancy, Observations of Opioid Use, and Secular Trend From 2006 to 2014 at HealthPartners Medical Group. AB - OBJECTIVES: To determine the prevalence of opioid use before, during, and after pregnancy and describe its use based on patient-specific characteristics. Determine secular trend of opioid use 2006 to 2014. MATERIALS AND METHODS: Retrospective cohort study. A large Upper Midwest integrated health care system and insurer. Female individuals age 10 to 50 years with a delivery diagnosis from July 1, 2006 through June 30, 2014. MAIN OUTCOME MEASURE: prevalence of opioid use before, during, and after pregnancy; description of opioid use during these time periods. RESULTS: From 11,565 deliveries among 9690 unique women, 862 (7.5%) deliveries were associated with significant opioid use. Significant opioid use was associated with single marital status, Cesarean section, Medicaid coverage, tobacco use, depression, anxiety, bipolar disorder, substance use disorder, nonopioid analgesic use, and referral to physical therapy, psychotherapy, or pain specialists. From 2006 to 2014 opioid use decreased from 9% to 6% before, during, and after pregnancy with a rate of change per year of -0.2%. DISCUSSION: Known risk factors including tobacco and alcohol use, mental health diagnoses, substance use disorder, or Medicaid enrollment may enable enhanced assessments and targeted interventions to reduce unnecessary prescribing and use of opioids among pregnant women and those who might become pregnant. Strategies to decrease opioid use during pregnancy should be considered by health care systems and health plans to reduce opioid prescribing in this patient population. PMID- 29406368 TI - Left entorhinal cortex and object recognition. AB - The present research explored the role of the medial temporal lobes in object memory in the unique patient MR, who has a selective lesion to her left lateral entorhinal cortex. Two experiments explored recognition memory for object identity and object location in MR and matched controls. The results showed that MR had intact performance in an object location task [MR=0.70, controls=0.69, t(6)=0.06, P>0.05], but was impaired in an object identity task [MR=0.62, controls=0.84, t(6)=-4.12, P<0.05]. No differences in correct recollection or familiarity emerged. These results suggest a differential role of the entorhinal cortex in object recognition memory. The current research is therefore the first patient study to show the role of the lateral entorhinal cortex in object identity recognition and suggests that current medial temporal lobe theoretical models on both object and recognition memory require a theoretical re-think to account for the contributions of the entorhinal cortex in these processes. PMID- 29406369 TI - Silencing of Tctex1 impairs autophagy lysosomal degradation of alpha-synuclein and cell viability. AB - Tctex1 is an important element of the dynein motor unit in mammalian cells that helps move targets along microtubules and toward the centrosome for degradation. Here, we analyzed the role of Tctex1 in the alpha-synuclein autophagy-lysosome degradation pathway using Tctex1-siRNA in SH-SY5Y cells. Results showed that siRNA silencing of Tctex1 suppressed cellular viability and promoted cell apoptosis. Protein and mRNA expression of Tctex1 and dynein decreased after Tctex1 knockdown, whereas alpha-synuclein, LC3-II, and LAMP2 increased. Consistently, fluorescence intensity of Tctex1 was weaker in siRNA-Tctex1 transfected cells, and that of alpha-synuclein, LC3-II, and LAMP2 was increased. Tctex1 inhibition reduced cell viability and promoted apoptosis. These results show that Tctex1 plays an important role in alpha-synuclein autophagic degradation and in maintaining cellular homeostasis. PMID- 29406370 TI - Abnormal spontaneous brain activity in patients with generalized anxiety disorder revealed by resting-state functional MRI. AB - This study aimed to examine the spontaneous hemodynamic fluctuations and the dysfunctional brain regions in patients with generalized anxiety disorder (GAD) using resting-state functional MRI. Previous studies have demonstrated some neural networks that are different in this patient group compared with healthy controls. However, there is still a need for precise anatomical localization of the aberrantly operating networks. We used resting-state functional MRI to measure the hemodynamic fluctuations in 31 GAD patients and 31 control participants matched for sex, age, and education. On the basis of the hemodynamic fluctuations, we calculated regional homogeneity (ReHo) for our comparisons as this measure reflects coherent fluctuations in adjacently located brain regions. The Hamilton Anxiety Rating Scale was used to assess symptom severity of the GAD patients. There were no significant differences with respect to age, sex, handedness, and education. However, compared with controls, GAD patients showed higher Hamilton Anxiety Rating Scale scores (16.90+/-1.94, P<0.05). We identified decreased ReHo measures in the right inferior frontal gyrus and the left caudate nucleus in the GAD group compared with the healthy controls. In addition, we found increased ReHo measures within the left cingulate gyrus. This study further complements the network characteristics in anxiety patients and presents new and more accurate anatomical positioning about GAD patients. PMID- 29406371 TI - Pediatric Specialty Care Model for Management of Chronic Respiratory Failure: Cost and Savings Implications and Misalignment With Payment Models. AB - OBJECTIVE: To describe program design, costs, and savings implications of a critical care-based care coordination model for medically complex children with chronic respiratory failure. DESIGN: All program activities and resultant clinical outcomes were tracked over 4 years using an adapted version of the Care Coordination Measurement Tool. Patient characteristics, program activity, and acute care resource utilization were prospectively documented in the adapted version of the Care Coordination Measurement Tool and retrospectively cross validated with hospital billing data. Impact on total costs of care was then estimated based on program outcomes and nationally representative administrative data. SETTING: Tertiary children's hospital. SUBJECTS: Critical Care, Anesthesia, Perioperative Extension and Home Ventilation Program enrollees. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The program provided care for 346 patients and families over the study period. Median age at enrollment was 6 years with more than half deriving secondary respiratory failure from a primary neuromuscular disease. There were 11,960 encounters over the study period, including 1,202 home visits, 673 clinic visits, and 4,970 telephone or telemedicine encounters. Half (n = 5,853) of all encounters involved a physician and 45% included at least one care coordination activity. Overall, we estimated that program interventions were responsible for averting 556 emergency department visits and 107 hospitalizations. Conservative monetization of these alone accounted for annual savings of $1.2-2 million or $407/pt/mo net of program costs. CONCLUSIONS: Innovative models, such as extension of critical care services, for high-risk, high-cost patients can result in immediate cost savings. Evaluation of financial implications of comprehensive care for high-risk patients is necessary to complement clinical and patient-centered outcomes for alternative care models. When year-to-year cost variability is high and cost persistence is low, these savings can be estimated from documentation within care coordination management tools. Means of financial sustainability, scalability, and equal access of such care models need to be established. PMID- 29406372 TI - Epidemiology of Pediatric Critical Care Transport in Northern Alberta and the Western Arctic. AB - OBJECTIVE: Specialized pediatric critical care transport teams are essential to pediatric retrieval systems. This study aims to describe the contemporary transports performed by a Canadian pediatric critical care transport team and to compare the treatment and outcomes of children referred from high-level care (hospitals offering pediatric services where an adult ICU exists) and nonhigh level care (all other hospitals) hospitals. DESIGN: A descriptive cohort study. SETTING: The Stollery Children's Hospital in Edmonton, Alberta, Western Canada. PATIENTS: Children younger than 17 years old transported by the transport team from referral hospitals within the Stollery Children's Hospital catchment area to Stollery Children's Hospital between 1998 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characteristics of transports, patient demographics presenting vital signs, and outcomes were described overall and compared by transport-related time and referral hospital types (high-level care and nonhigh-level care). In total, 3,352 transports met the inclusion criteria; 1,049 were retrieved from eight high-level care hospitals and 2,303 from 53 nonhigh-level care hospitals; the median one-way transport distance was 383 kilometers, and 70% of the transports were air transports. The annual number of transports has increased during the study period. The PICU admission rate was between 40% and 55%. Transports from high-level care hospitals had significantly higher odds of being admitted to the PICU (odds ratio, 1.96; 95% CI, 1.31-2.93). The odds of intubation at the referral hospital were higher in the high-level care group, but the odds of intubation upon PICU admission was similar between the two groups. Mortality during or after transport was not significantly different between high-level care and nonhigh-level care hospitals. CONCLUSIONS: The current transport system has multiple priorities with regard to efficiency and quality. The medical services at referral hospitals may affect the likelihood of PICU admission and subsequent PICU length of stay; however, no negative impact was observed in other outcomes including mortality. PMID- 29406373 TI - Creating a High-Frequency Electronic Database in the PICU: The Perpetual Patient. AB - OBJECTIVE: Our objective was to construct a prospective high-quality and high frequency database combining patient therapeutics and clinical variables in real time, automatically fed by the information system and network architecture available through fully electronic charting in our PICU. The purpose of this article is to describe the data acquisition process from bedside to the research electronic database. DESIGN: Descriptive report and analysis of a prospective database. SETTING: A 24-bed PICU, medical ICU, surgical ICU, and cardiac ICU in a tertiary care free-standing maternal child health center in Canada. PATIENTS: All patients less than 18 years old were included at admission to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between May 21, 2015, and December 31, 2016, 1,386 consecutive PICU stays from 1,194 patients were recorded in the database. Data were prospectively collected from admission to discharge, every 5 seconds from monitors and every 30 seconds from mechanical ventilators and infusion pumps. These data were linked to the patient's electronic medical record. The database total volume was 241 GB. The patients' median age was 2.0 years (interquartile range, 0.0-9.0). Data were available for all mechanically ventilated patients (n = 511; recorded duration, 77,678 hr), and respiratory failure was the most frequent reason for admission (n = 360). The complete pharmacologic profile was synched to database for all PICU stays. Following this implementation, a validation phase is in process and several research projects are ongoing using this high-fidelity database. CONCLUSIONS: Using the existing bedside information system and network architecture of our PICU, we implemented an ongoing high-fidelity prospectively collected electronic database, preventing the continuous loss of scientific information. This offers the opportunity to develop research on clinical decision support systems and computational models of cardiorespiratory physiology for example. PMID- 29406374 TI - Cerebral Oxygen Metabolism Before and After RBC Transfusion in Infants Following Major Surgical Procedures. AB - OBJECTIVE: Although infants following major surgery frequently require RBC transfusions, there is still controversy concerning the best definition for requirement of transfusion in the individual patient. The aim of this study was to determine the impact of RBC transfusion on cerebral oxygen metabolism in noncardiac and cardiac postsurgical infants. DESIGN: Prospective observational cohort study. SETTING: Pediatric critical care unit of a tertiary referral center. PATIENTS: Fifty-eight infants (15 after pediatric surgery and 43 after cardiac surgery) with anemia requiring RBC transfusion were included. INTERVENTIONS: RBC transfusion. MEASUREMENTS AND MAIN RESULTS: We measured noninvasively regional cerebral oxygen saturation and microperfusion (relative cerebral blood flow) using tissue spectrometry and laser Doppler flowmetry before and after RBC transfusion. Cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen were calculated. Fifty-eight RBC transfusions in 58 patients were monitored (15 after general surgery, 24 after cardiac surgery resulting in acyanotic biventricular physiology and 19 in functionally univentricular hearts including hypoplastic left heart following neonatal palliation). The posttransfusion hemoglobin concentrations increased significantly (9.7 g/dL vs 12.8 g/dL; 9.7 g/dL vs 13.8 g/dL; 13.1 g/dL vs 15.6 g/dL; p < 0.001, respectively). Posttransfusion cerebral oxygen saturation was significantly higher than pretransfusion (61% [51-78] vs 72% [59-89]; p < 0.001; 58% [35-77] vs 71% [57-88]; p < 0.001; 51% [37-61] vs 58% [42-73]; p = 0.007). Cerebral fractional tissue oxygen extraction decreased posttransfusion significantly 0.37 (0.16-0.47) and 0.27 (0.07-039), p = 0.002; 0.40 (0.2-0.62) vs 0.26 (0.11-0.57), p = 0.001; 0.42 (0.23-0.52) vs 0.32 (0.1-0.42), p = 0.017. Cerebral blood flow and approximated cerebral metabolic rate of oxygen showed no significant change during the observation period. The increase in cerebral oxygen saturation and the decrease in cerebral fractional tissue oxygen extraction were most pronounced in patients after cardiac surgery with a pretransfusion cerebral fractional tissue oxygen extraction greater than or equal to 0.4. CONCLUSION: Following RBC transfusion, cerebral oxygen saturation increases and cerebral fractional tissue oxygen extraction decreases. The data suggest that cerebral oxygenation in postoperative infants with cerebral fractional tissue oxygen extraction greater than or equal to 0.4 may be at risk in instable hemodynamic or respiratory situations. PMID- 29406375 TI - Fifty Years of Pediatric Critical Care: An Interview With Dr. Jack Downes. PMID- 29406376 TI - Blood Cultures Drawn From Arterial Catheters Are Reliable for the Detection of Bloodstream Infection in Critically Ill Children. AB - OBJECTIVES: Arterial catheters may serve as an additional source for blood cultures in children when peripheral venipuncture is challenging. The aim of the study was to evaluate the accuracy of cultures obtained through indwelling arterial catheters for the diagnosis of bloodstream infections in critically ill pediatric patients. DESIGN: Observational and comparative. SETTING: General and cardiac ICUs of a tertiary, university-affiliated pediatric medical center. PATIENTS: The study group consisted of 138 patients admitted to the general or cardiac PICU in 2014-2015 who met the following criteria: presence of an indwelling arterial catheter and indication for blood culture. INTERVENTIONS: Blood was drawn by peripheral venipuncture and through the arterial catheter for each patient and sent for culture (total 276 culture pairs). MEASUREMENTS AND MAIN RESULTS: Two specialists blinded to the blood source evaluated each positive culture to determine if the result represented true bloodstream infection or contamination. The sensitivity, specificity, and positive and negative predictive values of the arterial catheter and peripheral cultures for the diagnosis of bloodstream infection were calculated. Of the 56 positive cultures, 41 (15% of total samples) were considered diagnostic of true bloodstream infection. In the other 15 (5%), the results were attributed to contamination. The rate of false positive results was higher for arterial catheter than for peripheral venipuncture cultures (4% vs 1.5%) but did not lead to prolonged unnecessary antibiotic treatment. On statistical analysis, arterial catheter blood cultures had high sensitivity (85%) and specificity (95%) for the diagnosis of true bloodstream infection, with comparable performance to peripheral blood cultures. CONCLUSION: Cultures of arterial catheter-drawn blood are reliable for the detection of bloodstream infection in PICUs. PMID- 29406377 TI - Survey of Bedside Clinical Neurologic Assessments in U.S. PICUs. AB - OBJECTIVE: To understand how routine bedside clinical neurologic assessments are performed in U.S. PICUs. DESIGN: Electronic survey. SETTING: Academic PICUs throughout the United States. SUBJECTS: Faculty representatives from PICUs throughout the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We surveyed how routine bedside neurologic assessments are reported to be performed in U.S. PICUs and the attitudes of respondents on the utility of these assessments. The survey contained questions regarding 1) components of neurologic assessments; 2) frequency of neurologic assessments; 3) documentation and communication of changes in neurologic assessment; and 4) optimization of neurologic assessments. Surveys were received from 64 of 67 institutions (96%). Glasgow Coma Scale and pupillary reflex were the most commonly reported assessments (80% and 92% of institutions, respectively). For patients with acute brain injury, 95% of institutions performed neurologic assessments hourly although assessment frequency was more variable for patients at low risk of developing brain injury and those at high risk for brain injury, but without overt injury. In 73% of institutions, any change detected on routine neuroassessment was communicated to providers, whereas in 27%, communication depended on the severity or degree of neurologic decline. Seventy percent of respondents thought that their current practice for assessing and monitoring neurologic status was suboptimal. Only 57% felt that the Glasgow Coma Scale was a valuable tool for the serial assessment of neurologic function in the ICU. Ninety two percent felt that a standardized approach to assessing and documenting preillness neurologic function would be valuable. CONCLUSIONS: Routine neurologic assessments are reported to be conducted in nearly all academic PICUs in the United States with fellowship training programs although the content, frequency, and triggers for communication vary between institutions. Most physicians felt that the current paradigms for neurologic assessments are suboptimal. These data suggest that optimizing and standardizing routine bedside nursing neurologic assessments may be warranted. PMID- 29406379 TI - Conceptualizing Post Intensive Care Syndrome in Children-The PICS-p Framework. AB - CONTEXT: Over the past several decades, advances in pediatric critical care have saved many lives. As such, contemporary care has broadened its focus to also include minimizing morbidity. Post Intensive Care Syndrome, also known as "PICS," is a group of cognitive, physical, and mental health impairments that commonly occur in patients after ICU discharge. Post Intensive Care Syndrome has been well conceptualized in the adult population but not in children. OBJECTIVE: To develop a conceptual framework describing Post Intensive Care Syndrome in pediatrics that includes aspects of the experience that are unique to children and their families. DATA SYNTHESIS: The Post Intensive Care Syndrome in pediatrics (PICS-p) framework highlights the importance of baseline status, organ system maturation, psychosocial development, the interdependence of family, and trajectories of health recovery that can potentially impact a child's life for decades. CONCLUSION: Post Intensive Care Syndrome in pediatrics will help illuminate the phenomena of surviving childhood critical illness and guide outcomes measurement in the field. Empirical studies are now required to validate and refine this framework, and to subsequently develop a set of core outcomes for this population. With explication of Post Intensive Care Syndrome in pediatrics, the discipline of pediatric critical care will then be in a stronger position to map out recovery after pediatric critical illness and to evaluate interventions designed to mitigate risk for poor outcomes with the goal of optimizing child and family health. PMID- 29406378 TI - Downward Trend in Pediatric Resident Laryngoscopy Participation in PICUs. AB - OBJECTIVES: As of July 2013, pediatric resident trainee guidelines in the United States no longer require proficiency in nonneonatal tracheal intubation. We hypothesized that laryngoscopy by pediatric residents has decreased over time, with a more pronounced decrease after this guideline change. DESIGN: Prospective cohort study. SETTING: Twenty-five PICUs at various children's hospitals across the United States. PATIENTS: Tracheal intubations performed in PICUs from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Prospective cohort study in which all primary tracheal intubations occurring in the United States from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children) were analyzed. Participating PICU leaders were also asked to describe their local airway management training for residents. Resident participation trends over time, stratified by presence of a Pediatric Critical Care Medicine fellowship and airway training curriculum for residents, were described. A total of 9,203 tracheal intubations from 25 PICUs were reported. Pediatric residents participated in 16% of tracheal intubations as first laryngoscopists: 14% in PICUs with a Pediatric Critical Care Medicine fellowship and 34% in PICUs without one (p < 0.001). Resident participation decreased significantly over time (3.4% per year; p < 0.001). The decrease was significant in ICUs with a Pediatric Critical Care Medicine fellowship (p < 0.001) but not in ICUs without one (p = 0.73). After adjusting for site-level clustering, patient characteristics, and Pediatric Critical Care Medicine fellowship presence, the Accreditation Council for Graduate Medical Education guideline change was not associated with lower participation by residents (odds ratio, 0.86; 95% CI, 0.59-1.24; p = 0.43). The downward trend of resident participation was similar regardless of the presence of an airway curriculum for residents. CONCLUSION: Laryngoscopy by pediatric residents has substantially decreased over time. This downward trend was not associated with the 2013 Accreditation Council for Graduate Medical Education change in residency requirements. PMID- 29406381 TI - Optimal Insertion Depth for Endotracheal Tubes in Extremely Low-Birth-Weight Infants. AB - OBJECTIVE: To determine the optimal endotracheal tube insertion depth in extremely low-birth-weight infants based on the association between endotracheal tube depth and gestational age, body weight, body length, and head and chest circumferences at birth. DESIGN: Retrospective chart review. SETTING: Neonatal ICU at a medical center. PATIENTS: Fifty-two hospitalized extremely low-birth weight infants in our neonatal ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data regarding gestational age, body weight, body length (crown-heel length), head and chest circumferences, and final endotracheal tube depth were retrieved from the medical records of 52 newborn infants weighing less than or equal to 1,000 g at birth (boys, 29; girls, 23). The mean gestational age was 25.1 (range, 22-32) weeks, and the mean body weight was 724.5 (range, 400-1,000) g. Of the endotracheal tubes used, 3%, 87%, and 10% of endotracheal tubes were of size 2.0, 2.5, and 3.0, respectively. Linear regression analysis revealed a significant association between endotracheal tube depth and gestational age, body weight, body length, head, and chest circumferences (p < 0.001). Body weight had the highest coefficient of determination (r = 0.497), followed by body length (0.458), with all other variables having values of less than 0.4. CONCLUSIONS: In extremely low-birth-weight infants, a linear association exists between endotracheal tube insertion depth and gestational age, body weight, body length, chest, and head circumferences at birth. Although body weight is the most accurate method for predicting endotracheal tube insertion depth, body length is also appropriate and is more favorable than body weight in delivery room resuscitation. Although no substitute for radiologic confirmation exists, a tape measure that can convert body length to endotracheal tube depth may be helpful. PMID- 29406380 TI - Progressive Diaphragm Atrophy in Pediatric Acute Respiratory Failure. AB - OBJECTIVES: Diaphragm atrophy is associated with delayed weaning from mechanical ventilation and increased mortality in critically ill adults. We sought to test for the presence of diaphragm atrophy in children with acute respiratory failure. DESIGN: Prospective, observational study. SETTING: Single-center tertiary noncardiac PICU in a children's hospital. PATIENTS: Invasively ventilated children with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS: Diaphragm thickness at end-expiration and end-inspiration were serially measured by ultrasound in 56 patients (median age, 17 mo; interquartile range, 5.5-52), first within 36 hours of intubation and last preceding extubation. The median duration of mechanical ventilation was 140 hours (interquartile range, 83-201). At initial measurement, thickness at end-expiration was 2.0 mm (interquartile range, 1.8 2.5) and thickness at end-inspiration was 2.5 mm (interquartile range, 2-2.8). The change in thickness at end-expiration during mechanical ventilation between first and last measurement was -13.8% (interquartile range, -27.4% to 0%), with a -3.4% daily atrophy rate (interquartile range, -5.6 to 0%). Thickening fraction = ([thickness at end-inspiration - thickness at end-expiration]/thickness at end inspiration) throughout the course of mechanical ventilation was linearly correlated with spontaneous breathing fraction (beta coefficient, 9.4; 95% CI, 4.2-14.7; p = 0.001). For children with a period of spontaneous breathing fraction less than 0.5 during mechanical ventilation, those with exposure to a continuous neuromuscular blockade infusion (n = 15) had a significantly larger decrease in thickness at end-expiration compared with children with low spontaneous breathing fraction who were not exposed to a neuromuscular blockade infusion (n = 18) (-16.4%, [interquartile range, -28.4% to -7.0%] vs -7.3%; [interquartile range, -10.9% to -0%]; p = 0.036). CONCLUSIONS: Diaphragm atrophy is present in children on mechanical ventilation for acute respiratory failure. Diaphragm contractility, measured as thickening fraction, is strongly correlated with spontaneous breathing fraction. The combination of exposure to neuromuscular blockade infusion with low overall spontaneous breathing fraction is associated with a greater degree of atrophy. PMID- 29406382 TI - Review of Routes to Administer Medication During Prolonged Neonatal Resuscitation. AB - OBJECTIVE: During neonatal cardiopulmonary resuscitation, early establishment of vascular access is crucial. We aimed to review current evidence regarding different routes for the administration of medications during neonatal resuscitation. DATA SOURCES: We reviewed PubMed, EMBASE, and Google Scholar using MeSH terms "catheterization," "umbilical cord," "delivery room," "catecholamine," "resuscitation," "simulation," "newborn," "infant," "intraosseous," "umbilical vein catheter," "access," "intubation," and "endotracheal." STUDY SELECTION: Articles in all languages were included. Initially, we aimed to identify only neonatal studies and limited the search to randomized controlled trials. DATA EXTRACTION: Due to a lack of available studies, studies in children and adults, as well as animal studies and also nonrandomized studies were included. DATA SYNTHESIS: No randomized controlled trials comparing intraosseous access versus peripheral intravascular access versus umbilical venous catheter versus endotracheal tube versus laryngeal mask airway or any combination of these during neonatal resuscitation in the delivery room were identified. Endotracheal tube: endotracheal tube epinephrine administration should be limited to situations were no vascular access can be established. Laryngeal mask airway: animal studies suggest that a higher dose of epinephrine for endotracheal tube and laryngeal mask airway is required compared with IV administration, potentially increasing side effects. Umbilical venous catheter: European resuscitation guidelines propose the placement of a centrally positioned umbilical venous catheter during neonatal cardiopulmonary resuscitation; intraosseous access: case series reported successful and quick intraosseous access placement in newborn infants. Peripheral intravascular access: median time for peripheral intravascular access insertion was 4-5 minutes in previous studies. CONCLUSIONS: Based on animal studies, endotracheal tube administration of medications requires a higher dose than that by peripheral intravascular access or umbilical venous catheter. Epinephrine via laryngeal mask airway is feasible as a noninvasive alternative approach for drug delivery. Intraosseous access should be considered in situations with difficulty in establishing other access. Randomized controlled clinical trials in neonates are required to compare all access possibilities described above. PMID- 29406383 TI - Meeting Review: 8th Annual Egyptian International Conference of Hand and Microsurgery. PMID- 29406384 TI - Reconstruction of Defects in the Weight-Bearing Plantar Area Using the Innervated Free Medial Plantar (Instep) Flap. AB - BACKGROUND: Defects in the weight-bearing heel or forefoot are commonly derived from chronic wounds, acute trauma, or tumor excision. Reconstruction of such defects pose a significant challenge to provide a flap that is stable, durable, and sensate. Several flaps have been described for reconstruction of plantar defects, but recurrent ulcerations and/or the need of additional procedures are common. This article provides the approach and outcomes of innervated free medial plantar flap for weight-bearing plantar defects reconstruction. METHODS: Chart review was performed of 17 consecutive patients with defects in the weight bearing heel and/or forefoot who were treated with innervated free medial plantar flaps between the years 1999 and 2016. Eleven patients were male, and 6 patients were female. The mean age was 29.5 years (range, 4-52 years). One case was combined heel/forefoot defect, 7 were heel defects, and 9 were forefoot defects. Indications were acute trauma, secondary reconstruction after trauma, and tumor excision. RESULTS: The mean defect size was 8.0 +/- 5.4 cm * 5.1 +/- 2.1 cm, and mean flap size was 9.7 +/- 1.4 cm * 6.4 +/- 0.9 cm. One flap suffered from arterial thrombosis, which necessitated reoperation, and was salvaged. For the remaining cases, the postoperative course was uneventful. The mean follow-up time was 59.3 (+/-51.3.6) months. Two patients received minor flap corrections due to hyperkeratosis and hypertrophic scar, and 2 patients required donor site correction owing to partial loss of skin graft. One patient succumbed within 1 year owing to metastatic disease. All patients that were followed more than 1 year (n = 15) could sense blunt touch of the flap. Ten patients underwent 2-point discrimination test. No patient had recurrence of ulceration. CONCLUSIONS: The innervated medial plantar flap is an excellent solution for treatment of medium to-large defects in the weight-bearing heel or forefoot. It provides glabrous skin that is stable, durable, and sensate. The long-term results are good, with no patient afflicted by recurrent ulceration during the follow-up time. PMID- 29406385 TI - Fingertip Replantation Without and With Palmar Venous Anastomosis: Analysis of the Survival Rates and Vein Distribution. PMID- 29406386 TI - Low shear stress upregulates the expression of fractalkine through the activation of mitogen-activated protein kinases in endothelial cells. AB - : Fractalkine (FKN) is a cytokine which plays an important role in atherosclerosis and other inflammatory diseases. Studies have shown that FKN induces integrin-independent leukocyte adhesion to primary endothelial cells under physiological flow conditions. Further, increased expression of FKN has been demonstrated in atherosclerotic lesions induced by low shear stress. However, the signal transduction mechanisms involved in low shear stress-induced FKN upregulation are not well characterized. In this study, EA.hy926 cells were subjected to varying intensity of fluid shear stress for different time durations. Further, mRNA and protein expressions of FKN were assessed by quantitative real-time PCR and Western blotting, respectively. Upregulation of FKN expression, which was induced via activation of mitogen-activated protein kinases signaling pathway under conditions of low shear stress, was studied both in the presence and absence of inhibitors. Low shear stress (~4.58 dyne/cm) for more than 1 h promoted FKN expression and activated the extracellular signal regulated kinase (ERK)1/2, p38, and Jun N-terminal kinase (JNK) mitogen-activated protein kinases signaling pathways by their phosphorylation. Inhibitors of ERK1/2, p38, and JNK pathways downregulated the FKN expression. In this study, fluid shear stress affected FKN expression in endothelial cells via activation of ERK1/2, p38, and JNK in a time-dependent manner. Our findings serve to advance the theoretical basis for prevention and treatment of atherosclerosis. PMID- 29406387 TI - In silico thrombin and factor Xa generation profiles in adult patients after Fontan operation. AB - : Single-ventricle defects are associated with increased risk of thromboembolic events. To analyze the prothrombotic potential in a long-term follow-up on Fontan patients via plasma contribution to thrombin and factor (F)Xa generation profiles. Thrombin and FXa generation was simulated from plasma concentrations of FII, FV, FVII, FVIII, FIX, FX, antithrombin and tissue factor (TF) pathway inhibitor from Fontan patients (n = 48) and healthy controls (n = 34). TF and thrombin-antithrombin complex (TAT) were measured by ELISA. Fontan patients had significantly reduced procoagulant protein concentrations and increased anticoagulant protein concentrations over controls, resulting in a lowered procoagulant potential. However, Fontan patients showed increased hemostatic activation as evidenced by increased TF and TAT. Modeling this increased TF showed a more prothrombotic profile. Observed changes in procoagulant and anticoagulant proteins may be a compensatory mechanism aimed at mitigating the underlying disease effects characterized by elevated TF and TAT. PMID- 29406388 TI - Brachial embolism from mechanical mitral valve thrombosis: multimodality imaging guided successful thrombolysis. AB - : We report the administration of low-dose (25 mg) prolonged infusion (25 h) of tissue-typed plasminogen activator (t-PA) in the treatment of brachial arterial thromboembolism (BAT) secondary to prosthetic valve thrombosis (PVT), under the guidance of multimodality imaging. BAT is a rare disorder with serious consequences. The case of BAT secondary to mitral PVT was successfully treated with low-dose prolonged infusion of t-PA under the guidance of multimodality imaging with upper extremity duplex Doppler ultrasonography, multislice computerized tomographic angiography, coventional angiography and advanced transesophageal echocardiography. This case has demonstrated that low-dose prolonged infusion of t-PA may be adequate in the treatment of BAT. PMID- 29406389 TI - Development and Validation of the Work-Related Well-Being Index: Analysis of the Federal Employee Viewpoint Survey. AB - OBJECTIVE: To describe development and validation of the work-related well-being (WRWB) index. METHODS: Principal components analysis was performed using Federal Employee Viewpoint Survey (FEVS) data (N = 392,752) to extract variables representing worker well-being constructs. Confirmatory factor analysis was performed to verify factor structure. To validate the WRWB index, we used multiple regression analysis to examine relationships with burnout associated outcomes. RESULTS: Principal Components Analysis identified three positive psychology constructs: "Work Positivity", "Co-worker Relationships", and "Work Mastery". An 11 item index explaining 63.5% of variance was achieved. The structural equation model provided a very good fit to the data. Higher WRWB scores were positively associated with all three employee experience measures examined in regression models. CONCLUSIONS: The new WRWB index shows promise as a valid and widely accessible instrument to assess worker well-being. PMID- 29406390 TI - December 2017 Volume 59, Issue 12, Supplement 1: Erratum. PMID- 29406393 TI - Trends and predictors of prehospital delay in patients undergoing primary coronary intervention. AB - OBJECTIVE: Delay in seeking medical care following symptom onset in patients with acute ST-elevation myocardial infarction (STEMI) is related to increased morbidity and mortality. Actual trends of prehospital delays in patients hospitalized with STEMI have not been well characterized. We evaluated trends in the length of time that had elapsed from symptom onset to hospital presentation among STEMI patients admitted to our hospital. PATIENTS AND METHODS: We retrospectively studied 2203 consecutive patients hospitalized for acute STEMI who underwent primary percutaneous coronary intervention (PCI) between January 2008 and December 2016. Information on the delay in time from symptom onset to presentation at hospital was extracted from the patients' medical records. RESULTS: Over the 9-year study period, the median duration of prehospital delay for patients undergoing primary PCI showed significant variations, being maximal between the years 2013 and 2014 (150 vs. 90 min, respectively, P<0.001). A significant increase was found in the proportion of patients with prehospital delay less than 2 h, being maximal between the years 2011 and 2013 (64 vs. 47%, P=0.001). An opposite trend was found for decrease in patients with prehospital delay more than 6 h, being maximal between 2008 and 2015 (32 vs. 23%, P=0.001). Multivariate logistic regression model showed that older age, diabetes, female sex, and first STEMI were associated independently with prehospital delay more than 2 h. CONCLUSION: Prehospital delay periods for patients undergoing primary PCI showed variations over time. More efforts are needed to educate at-risk populations about seeking early medical assistance. PMID- 29406394 TI - Using an Interactive Video Simulator to Improve Certified Nursing Assistants' Dressing Assistance and Nursing Home Residents' Dressing Performance: A Pilot Study. AB - This pilot study examined the initial effects and estimated effect size of a computer-based simulation education program on certified nursing assistants' level of assistance when dressing nursing home residents with dementia and on residents' dressing performance. Nine dyads, assigned to either the experimental or control group, completed the study. Both groups received a traditional 1-hour education module delivered by a research assistant. The experimental group was then instructed to undertake an additional 2-hour intervention using a video simulator that enabled nursing assistants to practice level of assistance skills. The appropriateness of dressing assistance from nursing assistants and residents' dressing performance was measured before and 6 weeks after the intervention. The results showed that the two groups did not significantly differ in either appropriate levels of dressing assistance (P = .42) or residents' dressing performance (P = .38). A lack of effort by some assistants to properly assist residents and low statistical power may explain the lack of significance. The effect sizes of the experimental intervention on appropriate levels of dressing assistance and resident dressing performance were 0.69 and 0.89, respectively. Incorporating a strategy to improve motivation should be considered in future studies. PMID- 29406395 TI - Benefits of Implementing and Improving Collection of Sexual Orientation and Gender Identity Data in Electronic Health Records. AB - Individuals in lesbian, gay, bisexual, and transgender communities experience several disparities in physical and mental health (eg, cardiovascular disease and depression), as well as difficulty accessing care that is compassionate and relevant to their unique needs. Access to care is compromised in part due to inadequate information systems that fail to capture identity data. Beginning in January 2018, meaningful use criteria dictate that electronic health records have the capability to collect data related to sexual orientation and gender identity of patients. Nurse informaticists play a vital role in the process of developing new electronic health records that are sensitive to the needs and identities of the lesbian, gay, bisexual, and transgender communities. Improved collection of sexual orientation and gender identity data will advance the identification of health disparities experienced by lesbian, gay, bisexual, and transgender populations. More inclusive electronic health records will allow providers to monitor risk behavior, assess progress toward the reduction of disparities, and provide healthcare that is patient and family centered. Concrete suggestions for the modification of electronic health record systems are presented, as well as how nurse informaticists may be able to bridge gaps in provider knowledge and discomfort through interprofessional collaboration when implementing changes in electronic health records. PMID- 29406396 TI - Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small cell lung cancer in patients with viral hepatitis: a case series. AB - Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in patients with metastatic melanoma. Limited evidence exists on the safety and efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections as these patients have traditionally been excluded from clinical trials because of a theoretical risk of immune reconstitution inflammatory syndrome. We aim to determine the safety and efficacy of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for either metastatic melanoma or metastatic NSCLC in the setting of chronic or past HBV/HCV infection. The safety and efficacy of treatment were analysed retrospectively by examining response to treatment, alanine transaminase (ALT) trends and viral load trends. One patient showed an increase in ALT of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to the normal range following treatment of his HCV infection with ledipasvir 90 mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of CTCAE grade 1 severity. The remaining two patients experienced no hepatic toxicity, with stable disease continuing after more than 24 cycles of nivolumab. Efficacy was similar to the data of published trials. Our results indicate that patients with metastatic melanoma and NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated. PMID- 29406397 TI - Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in-situ hybridization. AB - Isolation of circulating tumor cells (CTCs) from blood of melanoma patients has been difficult owing to inconsistent expression of surface antigens. Here we report on the isolation, detection, and characterization of CTCs from blood of melanoma patients using microfiltration and fluorescent in-situ hybridization (FISH). Two tubes of blood from 15 patients with advanced melanoma were collected. These two tubes subsequently underwent filtration through a membrane with pore sizes of 7.5 MUm. Isolated cells from one tube were analyzed by FISH for RREB1 (6p24), MYB (6q32), SE6 (D6Z1), and CCND1 (11q13) and the other paired specimen was analyzed by immunofluorescence for HMB45, melanoma-associated antigen recognized by T cells-1, tyrosinase and melanogenesis associated transcription factor. We identified CTCs in 10 out of 13 melanoma samples by immunofluorescence (2.5-99 CTCs/3 ml of blood) and in 13 specimens by FISH (7.2 76 CTCs/3 ml of blood) with more CTCs identified by FISH in 10 out 13 samples. Two filters failed. Our results show that CTCs are detectable in the majority of patients with advanced melanoma. These tools will be useful in characterizing treatment related changes of melanoma in CTCs. PMID- 29406398 TI - Resuscitation room management of critically ill nontraumatic patients in a German emergency department (OBSERvE-study). AB - BACKGROUND: Management of critically ill nontrauma (CINT) patients in the resuscitation room (RR) of the emergency department (ED) is very challenging. Detailed data describing the characteristics and management of this population are lacking. This observational study describes the epidemiology, management and outcome in CINT ED patients in the RR. PATIENTS AND METHODS: From September 2014 to August 2015, data were collected prospectively on adult CINT patients admitted to the RR of a single German University ED. Patient characteristics, out-of hospital/in-hospital treatment, admission-related diseases, time intervals for diagnostics and interventions plus outcome were recorded using a self-developed questionnaire. RESULTS: A total of 34 303 patients were admitted to the ED; of these 21 074 patients were admitted for nontrauma emergencies and because of acute life-threatening problems. Five hundred and thirty-two CINT patients were admitted to the RR (median age: 71 years, 58.3% men). The main problems on admission were obstructed airway (3.8%, A), respiratory insufficiency (26.5%, B), shock (35.5%, C), unconsciousness (33.3%, D) or other (0.9%, E). Out-of-hospital and in-hospital management included intravenous access (96.8 vs. 76.9%), 12-lead ECG (50.0 vs. 86.5%), invasive airway management (30.1 vs. 27.1%), noninvasive and invasive ventilation (7.0 vs. 16.4% and 30.1 vs. 57.2%), catecholamines (16.2 vs. 24.1%), arterial line (0.2 vs. 58.1%) and cardiopulmonary resuscitation (18.4 vs. 12.2%). The mean length of stay was 34+/-24 min. At day 30, all-cause mortality was 34.2% (patients with and without cardiopulmonary resuscitation: 72.7 vs. 24.0%, P<0.001). CONCLUSION: Observation of critically ill patients in the resuscitation room of the Emergency Department shows the challenge of care for CINT patients in the ED. With high levels of mortality, there is an urgent need for structured ED management guidelines. PMID- 29406399 TI - Development and Psychometric Evaluation of the Simulation Culture Organizational Readiness Survey. AB - Expensive high-fidelity simulators sit unused in nursing programs worldwide. One cause of this is failure to ensure organizational readiness to integrate simulation into the curriculum. The Simulation Culture Organizational Readiness Survey (SCORS) was developed to assist administrators in evaluating institutional and program readiness for simulation integration. Psychometric analysis finds the SCORS to be a valid, reliable tool for use by administrators to determine organizational readiness for simulation integration. PMID- 29406400 TI - What's Your Style? Enhanced Interprofessional Communication and Practice Using the Communication Wheel. AB - Today's health care environment requires collaborative teams to provide safe, effective care. This study assessed the extent to which a face-to-face workshop increased nursing and premedical students' awareness of varying communication styles and their potential impact on interprofessional communication and practice. A self-assessment tool was administered before, immediately after, and 1 month after the workshop. Significant increases in familiarity working on interprofessional teams, identifying different communication styles, and ability to apply communication strategies were found immediately after and 1 month after the workshop. PMID- 29406401 TI - Relationship of Spinal Cord Injury Level and Duration to Peak Aerobic Capacity With Arms-Only and Hybrid Functional Electrical Stimulation Rowing. AB - OBJECTIVE: The aim of the study was to assess the relationship of spinal cord injury level and duration to peak aerobic capacities during arms-only rowing compared with hybrid Functional Electrical Stimulation (FES)-rowing. DESIGN: Comparison of peak aerobic capacity (VO2), peak ventilation, peak respiratory exchange ratio, and peak heart rate were measured during arms-only rowing and FES rowing obtained from graded exercise tests. RESULTS: Peak aerobic values were strongly related to injury level and injury duration for both arms-only rowing (r = 0.67, P < 0.05) and FES-rowing (r = 0.61, P < 0.05). Peak aerobic capacities were greater across all injury levels and durations with FES-rowing compared with arms-only rowing. Differences in VO2 were inversely related to injury level (r = 0.55, P < 0.05) with greater increases in VO2 in higher level injuries. Injury durations of less than 2 yrs had greater percent increases in VO2 with FES rowing. CONCLUSIONS: FES-rowing acutely post injury may have the greatest effect to maintain function and improve VO2. This impact seems to be greatest in those with higher level injuries. PMID- 29406402 TI - Impaired Cognitive Performance in Endothelial Nitric Oxide Synthase Knockout Mice After Ischemic Stroke: A Pilot Study. AB - OBJECTIVES: Cognitive dysfunction and dementia are common following ischemic stroke. Endothelial nitric oxide synthase (eNOS) has been found to play an important role in neurologic function and cognition. The purpose of the present study was to assess the specific role of eNOS in cognitive performance after stroke. DESIGN: Male wild-type and mice lacking eNOS (eNOS) underwent middle cerebral artery occlusion or sham-surgery. Primary outcomes were repeated measures of neurologic score, limb asymmetry, sensory/motor function, and spatial memory/learning assessed at intervals up to 28 days postsurgery. Group differences in brain microglia activation and infiltration and levels of interferon-gamma were examined. RESULTS: There was no genotype * surgery interaction effect on the pattern of change in neurologic score, limb asymmetry, or sensory motor function across the 28 days postsurgery. In the Morris water maze, eNOS middle cerebral artery occlusion mice displayed learning and memory deficits not evident in wild-type middle cerebral artery occlusion mice. Poorer spatial memory and learning in eNOS middle cerebral artery occlusion mice was associated with a reduction in the number of activated microglia in the striatum on the lesion side and decreased brain tissue levels of interferon-gamma. CONCLUSIONS: This study's data support a role for eNOS in cognitive performance after stroke. This finding may lead to the development of novel interventions to treat poststroke cognitive deficits. PMID- 29406403 TI - Amputee Locomotion: Joint Moment Adaptations to Running Speed using Running Specific Prostheses after Unilateral Transtibial Amputation. AB - OBJECTIVE: The objective of this study was to investigate 3D lower extremity joint moment differences between limbs and speed influences on these differences in individuals with lower extremity amputations using running-specific prostheses. DESIGN: 8 individuals with unilateral transtibial amputations and 8 control subjects with no amputations ran overground at three constant velocities (2.5, 3.0, and 3.5 m/s). A 2x2x3 (group x leg x speed) repeated-measures ANOVA with Bonferroni adjustments determined statistical significance. RESULTS: The prosthetic limb generated significantly greater peak ankle plantarflexion moments and smaller peak ankle varus, knee stance extension, knee swing flexion, knee internal rotation, hip stance flexion, hip swing flexion, hip swing extension, hip valgus, and hip external rotation moments than the intact limb. The intact limb had greater peak hip external rotation moments than control limbs, but all other peak moments were similar between these limbs. Increases in peak hip stance and knee swing flexion moments associated with speed were greater in the intact limb than the prosthetic limb. CONCLUSION: Individuals with amputation relied on the intact limb more than the prosthetic limb to run at a particular speed when wearing running-specific prostheses, but the intact joints were not overloaded relative to the control limbs. PMID- 29406404 TI - Sonographic Evaluation of the Posterior Interosseous Nerve in a Patient With Wrist Drop. PMID- 29406405 TI - Quantifying Effect of Onabotulinum Toxin A on Passive Muscle Stiffness in Children with Cerebral Palsy Using Ultrasound Shear Wave Elastography. AB - OBJECTIVE: A pilot study was conducted to longitudinally quantify effect of onabotulinum toxin A (BoNT-A) on passive muscle properties in children with cerebral palsy using ultrasound shear wave elastography. DESIGN: This was a prospective longitudinal cohort study. RESULTS: Between 1 and 3 mos post-BoNT-A, a significant improvement in the shear modulus of the lateral gastrocnemius was found at 10-degrees plantar flexion (PF) (-7.57 [-10.98, -5.07], P = 0.02) and 0 degrees PF (-14.74 [-18.21, -9.38], P = 0.03). There was a notable, but nonsignificant, difference in shear modulus at 20-degrees PF, 10-degrees PF, and 0-degrees PF between pre-BoNT-A and 1 mo post-BoNT-A. Pre-BoNT-A shear modulus was not significantly different from 3 mos post-BoNT-A at all foot positions. No significant differences in ankle passive range of motion or spasticity were found. CONCLUSION: Despite no significant change in ankle range of motion or spasticity, shear wave elastography was able to detect a difference in lateral gastrocnemius passive muscle properties in children with cerebral palsy after BoNT-A injections. The difference in passive muscle properties resolved by 3 mos post-BoNT-A. PMID- 29406406 TI - Two-year effectiveness of risperidone and aripiprazole in the maintenance treatment of patients with recent-onset or chronic schizophrenia and related psychotic disorders: a retrospective multicenter study. AB - This study aimed to assess the comparative effectiveness of risperidone (RIS) versus aripiprazole (ARP) in patients with recent-onset or chronic schizophrenia during maintenance treatment and to examine the interaction between illness duration and the effectiveness of the treatment. All adult patients with schizophrenia and related disorders discharged from four psychiatric hospitals between 2006 and 2012 were screened and the 2-year continuation rates of monotherapy using RIS or ARP after discharge were examined retrospectively. The treatment continuation of the two drugs in patients with recent-onset (illness duration <5 years) or chronic schizophrenia (illness duration >=5 years) and the moderator effect of illness duration on the effectiveness of the treatment were analyzed. Of 328 patients, 233 received RIS and 95 received ARP. No significant difference was found between the two drugs in the treatment continuation for the entire sample. However, there was a significant difference favoring ARP in the recent-onset subgroup mainly because of differences in tolerability, whereas RIS tended to present better outcomes in patients with chronic illness. Furthermore, there was a significant variation in the effectiveness of the treatment between recent-onset and chronic schizophrenia. Our results suggest that illness duration is an important moderator in terms of the long-term effectiveness of the two drugs. PMID- 29406407 TI - The State-of-the-Art of Interventional Magnetic Resonance Imaging: Part 1. PMID- 29406408 TI - iMRI Symposium: Past-Present-Future. PMID- 29406410 TI - Techniques for Interventional MRI Guidance in Closed-Bore Systems. AB - Efficient image guidance is the basis for minimally invasive interventions. In comparison with X-ray, computed tomography (CT), or ultrasound imaging, magnetic resonance imaging (MRI) provides the best soft tissue contrast without ionizing radiation and is therefore predestined for procedural control. But MRI is also characterized by spatial constraints, electromagnetic interactions, long imaging times, and resulting workflow issues. Although many technical requirements have been met over the years-most notably magnetic resonance (MR) compatibility of tools, interventional pulse sequences, and powerful processing hardware and software-there is still a large variety of stand-alone devices and systems for specific procedures only.Stereotactic guidance with the table outside the magnet is common and relies on proper registration of the guiding grids or manipulators to the MR images. Instrument tracking, often by optical sensing, can be added to provide the physicians with proper eye-hand coordination during their navigated approach. Only in very short wide-bore systems, needles can be advanced at the extended arm under near real-time imaging. In standard magnets, control and workflow may be improved by remote operation using robotic or manual driving elements.This work highlights a number of devices and techniques for different interventional settings with a focus on percutaneous, interstitial procedures in different organ regions. The goal is to identify technical and procedural elements that might be relevant for interventional guidance in a broader context, independent of the clinical application given here. Key challenges remain the seamless integration into the interventional workflow, safe clinical translation, and proper cost effectiveness. PMID- 29406409 TI - Enabling Technology for MRI-Guided Intervention. AB - The use of magnetic resonance imaging (MRI) for image-guided intervention poses both great opportunity and challenges. Although MRI is distinguished by its excellent contrast resolution and lack of ionizing radiation, it was not till the 1990s that technologic innovations allowed for adoption of MRI as a guidance modality for intervention. With advances in magnet, protocol, coil, biopsy needle, and ablation probe design, MRI has emerged as a viable, and increasingly, preferable alternative to other image guidance modalities. With the development of targeting software, augmented reality, robotic assist devices, and MR thermometry, the future of MRI-guided interventions remains promising. PMID- 29406411 TI - Robotics in MRI-Guided Interventions. AB - Robots have been found to be a useful tool in magnetic resonance imaging (MRI) guided intervention. The utility of robots in MRI-guided therapy ranges from aid for precision targeting to high-dexterity surgical tools to improve or even enable new MRI-guided therapy options. The objective of this article is to review the technical aspects of robotics in MRI-guided interventions, highlight the role of MRI robots in prostate interventions, and finally discuss the future contribution of emerging robotics technology useful in MRI-guided intervention. PMID- 29406412 TI - Creating a Clinical Interventional MRI Service. AB - The expansive technological developments that occurred over the past decades have clearly moved the field of Interventional MRI beyond the arena of the "proof of concept" to a viable option for minimally invasive diagnosis and therapy. State of-the-art MRI technology can currently be employed to identify an occult target pathology, confidently steer an interventional device into complex anatomy, accurately deliver a device, drug, or energy, and/or monitor the real time effect of a treatment. Implementing a full-scope interventional MRI service requires substantial physical and conceptual modifications of the traditional diagnostic MRI environment. As such, it is essential to recognize that interventional MRI does not only involve the actual MRI-guided interventional event but should rather be perceived as a whole foundation of technology, development, set-up, conceptual training, and an institutional culture that realizes the opportunities offered by and understands the challenges and limitations of MRI-guided interventions. At Emory University, we had the privilege to build a de novo interventional MRI suite and to subsequently operate a high volume clinical interventional MRI service. The Emory program was launched with the goal of establishing a destination site for a comprehensive clinical service of MRI guided interventions. The experience gained and the lessons learned are shared with the readers in this article. PMID- 29406413 TI - How to Perform a Routine Cryoablation Under MRI Guidance. AB - In the last decade, the spectrum of interventional magnetic resonance imaging (MRI)-guided procedures, including percutaneous ablation, has substantially grown, and among the available MRI-compatible ablative techniques, cryoablation is progressively gaining a predominant position.The aim of the present narrative review is to discuss the technical requirements necessary to perform a percutaneous MRI-guided cryoablation in a closed-bore machine; to highlight the relative advantages and drawbacks; and to briefly summarize the results available in the literature. PMID- 29406414 TI - Pediatric Musculoskeletal Interventional MRI. AB - Minimally invasive procedures play a crucial role in the diagnosis and treatment of many pediatric musculoskeletal conditions. Although computed tomography and fluoroscopy are commonly used for image guidance, the associated exposure to ionizing radiation is especially concerning in pediatric patients. Ultrasonography may be used successfully in a subset of interventions, but it is often not useful for complex, deep, and osseous targets. Interventional magnetic resonance imaging (iMRI) facilitates targeting and treatment of musculoskeletal lesions at many locations with high accuracy due to its excellent tissue contrast. Furthermore, MRI provides imaging guidance without the use of ionizing radiation and as such complies with the ALARA practice mandate in a formidable fashion. MRI guidance is our method of choice for lesion that are not visible by other modalities or when other techniques and modalities failed. MRI guidance is especially useful for selective targeting of complex lesions, intra-articular lesions, cyst aspirations in difficult locations of the body, and lesions that are located adjacent to surgical hardware. Tumor-related diagnostic sampling is more frequently performed under MRI; however, MRI guidance is also exquisitely well suited for a variety of therapeutic percutaneous osseous or articular conditions, such as osteoid osteoma, epiphyseal bone bridging, osteochondritis dissecans lesions, and aneurysmal bone cysts. In this article, we will describe the technical aspects and clinical indications of a variety of MRI-guided pediatric procedures in the musculoskeletal system. PMID- 29406415 TI - Magnetic Resonance Imaging-guided High-intensity Focused Ultrasound Applications in Pediatrics: Early Experience at Children's National Medical Center. AB - Magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) is a novel technology that integrates magnetic resonance imaging with therapeutic ultrasound. This unique approach provides a completely noninvasive method for precise thermal ablation of targeted tissues with real-time imaging feedback. Over the past 2 decades, MR-HIFU has shown clinical success in several adult applications ranging from treatment of painful bone metastases to uterine fibroids to prostate cancer and essential tremor. Although clinical experience in pediatrics is relatively small, the advantages of a completely noninvasive and radiation-free therapy are especially attractive to growing children. Unlike elderly patients, young children must deal with an entire lifetime of negative effects related to collateral tissue damage associated with invasive surgery, side effects of chemotherapy, and risk of secondary malignancy due to radiation exposure. These reasons provide a clear rationale and strong motivation to further advance clinical utility of MR-HIFU in pediatrics. We begin with an introduction to MR-HIFU technology and the clinical experience in adults. We then describe our early institutional experience in using MR-HIFU ablation to treat symptomatic benign, locally aggressive, and metastatic tumors in children and young adults. We also review some limitations and challenges encountered in treating pediatric patients and highlight additional pediatric applications which may be feasible in the near future. PMID- 29406416 TI - Motion Correction in Proton Resonance Frequency-based Thermometry in the Liver. AB - The unique ability of magnetic resonance imaging to measure temperature noninvasively, in vivo, makes it an attractive tool for monitoring interventional procedures, such as radiofrequency or microwave ablation in real-time. The most frequently used approach for magnetic resonance-based temperature measurement is proton resonance frequency (PRF) thermometry. Although it has many advantages, including tissue-independence and real-time capability, the main drawback is its motion sensitivity. This is likely the reason PRF thermometry in moving organs, such as the liver, is not commonly used in the clinical arena. In recent years, however, several developments suggest that motion-corrected thermometry in the liver is achievable. The present article summarizes the diverse attempts to correct thermometry in the liver. Therefore, the physical principle of PRF is introduced, with additional references for necrosis zone estimation and how to deal with fat phase modulation, and main magnetic field drifts. The primary categories of motion correction are presented, including general methods for motion compensation and library-based approaches, and referenceless thermometry and hybrid methods. Practical validation of the described methods in larger patient groups will be necessary to establish accurate motion-corrected thermometry in the clinical arena, with the goal of complete liver tumor ablation. PMID- 29406418 TI - Fructose metabolism and noncommunicable diseases: recent findings and new research perspectives. AB - PURPOSE OF REVIEW: There is increasing concern that dietary fructose may contribute to the development of noncommunicable diseases. This review identifies major new findings related to fructose's physiological or adverse effects. RECENT FINDINGS: Fructose is mainly processed in splanchnic organs (gut, liver, kidneys) to glucose, lactate, and fatty acids, which can then be oxidized in extrasplanchnic organs and tissues. There is growing evidence that splanchnic lactate production, linked to extrasplanchnic lactate metabolism, represents a major fructose disposal pathway during and after exercise. Chronic excess fructose intake can be directly responsible for an increase in intrahepatic fat concentration and for the development of hepatic, but not muscle insulin resistance. Although it has long been thought that fructose was exclusively metabolized in splanchnic organs, several recent reports provide indirect that some fructose may also be metabolized in extrasplanchnic cells, such as adipocytes, muscle, or brain cells; the quantity of fructose directly metabolized in extrasplanchnic cells, and its physiological consequences, remain however unknown. There is also growing evidence that endogenous fructose production from glucose occurs in humans and may have important physiological functions, but may also be associated with adverse health effects. SUMMARY: Fructose is a physiological nutrient which, when consumed in excess, may have adverse metabolic effects, mainly in the liver (hepatic insulin resistance and fat storage). There is also concern that exogenous or endogenously produced fructose may be directly metabolized in extrasplanchnic cells in which it may exert adverse metabolic effects. PMID- 29406417 TI - Is beta-hydroxy beta-methylbutyrate an effective anabolic agent to improve outcome in older diseased populations? AB - PURPOSE OF REVIEW: beta-Hydroxy beta-methylbutyrate (HMB) has been used for many years in athletes for muscle buildup and strength, and endurance enhancement. In recent years, its interest quickly expanded in older (diseased) populations and during (exercise) rehabilitation and recovery from hospitalization and surgery. We will discuss recent literature about HMB metabolism, its pharmacokinetics compared with the frequently used metabolite leucine, effectiveness of HMB to improve outcome in older diseased adults, and novel approaches for HMB use. RECENT FINDINGS: HMB supplementation resulted in positive outcomes on muscle mass and functionality, related to its anabolic and anticatabolic properties and prolonged half-life time in blood. Furthermore, it was able to increase the benefits of (exercise) rehabilitation programs to enhance recovery from illness or medical procedures. There is promising evidence that HMB might support bone density, improve cognitive function, and reduce abdominal obesity, which is of importance particularly in the older (diseased) population. SUMMARY: The older diseased population might benefit from dietary HMB because of its established positive properties as well as its long lasting (pharmacological) effect. In addition to evaluating its efficacy and application in various clinical conditions, more research is needed into the mechanisms of action, the optimal dosage, and its potential additional beneficial effects on outcome. PMID- 29406419 TI - Is Heparin-Binding Protein Inhibition a Mechanism of Albumin's Efficacy in Human Septic Shock? AB - OBJECTIVES: Our objectives were to determine first whether albumin prevents heparin-binding protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma heparin-binding protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. DESIGN: In vitro human endothelial and renal cell model and observation cohort of septic shock. SETTINGS: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). PATIENTS: Adult septic shock (norepinephrine dose > 5 MUg/min for > 6 hr). INTERVENTIONS: In vitro: heparin-binding protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. MEASUREMENTS AND MAIN RESULTS: Transendothelial electrical resistance-a marker of permeability-of human endothelial cells was measured using a voltohmmeter. We measured plasma heparin binding protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an heparin-binding protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited heparin-binding protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher heparin-binding protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and heparin-binding protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest heparin-binding protein-to-albumin ratio (> 3.05), heparin-binding protein quartiles (> 69.8), and heparin-binding protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-binding protein and heparin-binding protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of heparin-binding protein-to-albumin ratio and heparin binding protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. CONCLUSIONS: Albumin inhibits heparin-binding protein-induced increased human endothelial cell permeability and heparin-binding protein greater than 30 ng/mL and heparin-binding protein-to-albumin ratio greater than 3.01-but not serum albumin-identified patients at increased risk for acute kidney injury in septic shock. PMID- 29406420 TI - Reporting of Sepsis Cases for Performance Measurement Versus for Reimbursement in New York State. AB - OBJECTIVES: Under "Rory's Regulations," New York State Article 28 acute care hospitals were mandated to implement sepsis protocols and report patient-level data. This study sought to determine how well cases reported under state mandate align with discharge records in a statewide administrative database. DESIGN: Observational cohort study. SETTING: First 27 months of mandated sepsis reporting (April 1, 2014, to June 30, 2016). PATIENTS: Hospitalizations with sepsis at New York State Article 28 acute care hospitals. INTERVENTION: Sepsis regulations with mandated reporting. MEASUREMENTS AND MAIN RESULTS: We compared cases reported to the New York State Department of Health Sepsis Clinical Database with discharge records in the Statewide Planning and Research Cooperative System database. We classified discharges as 1) "coded sepsis discharges"-a diagnosis code for severe sepsis or septic shock and 2) "possible sepsis discharges," using Dombrovskiy and Angus criteria. Of 111,816 sepsis cases reported to the New York State Department of Health Sepsis Clinical Database, 105,722 (94.5%) were matched to discharge records in Statewide Planning and Research Cooperative System. The percentage of coded sepsis discharges reported increased from 67.5% in the first quarter to 81.3% in the final quarter of the study period (mean, 77.7%). Accounting for unmatched cases, as many as 82.7% of coded sepsis discharges were potentially reported, whereas at least 17.3% were unreported. Compared with unreported discharges, reported discharges had higher rates of acute organ dysfunction (e.g., cardiovascular dysfunction 63.0% vs 51.8%; p < 0.001) and higher in hospital mortality (30.2% vs 26.1%; p < 0.001). Hospital characteristics (e.g., number of beds, teaching status, volume of sepsis cases) were similar between hospitals with a higher versus lower percent of discharges reported, p values greater than 0.05 for all. Hospitals' percent of discharges reported was not correlated with risk-adjusted mortality of their submitted cases (Pearson correlation coefficient 0.11; p = 0.17). CONCLUSIONS: Approximately four of five discharges with a diagnosis code of severe sepsis or septic shock in the Statewide Planning and Research Cooperative System data were reported in the New York State Department of Health Sepsis Clinical Database. Incomplete reporting appears to be driven more by underrecognition than attempts to game the system, with minimal bias to risk-adjusted hospital performance measurement. PMID- 29406421 TI - Outcomes and Costs of Patients Admitted to the ICU Due to Spontaneous Intracranial Hemorrhage. AB - OBJECTIVES: Spontaneous intracranial hemorrhage, including subarachnoid hemorrhage and intracerebral hemorrhage, is associated with significant morbidity and mortality. Although many of these patients will require ICU admission, little is known regarding their outcomes and the costs incurred. We evaluated this population in order to identify outcomes and cost patterns. DESIGN: Retrospective cohort analysis of a health administrative database. SETTING: Two ICUs within a single hospital system. PATIENTS: Eight-thousand four-hundred forty-seven patients admitted to ICU from 2011 to 2014, of whom 332 had a diagnosis of spontaneous intracranial hemorrhage. Control patients were defined as randomly selected age, sex, and comorbidity index-matched nonintracranial hemorrhage ICU patients (1:4 matching ratio). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean age of ICU intracranial hemorrhage patients was 60.1 years, and 120 (36.1%) died prior to discharge. Intracranial hemorrhage was associated with a mean total cost of $75,869, compared with $52,471 in control patients (p < 0.01). Mean cost per survivor of intracranial hemorrhage patients was $118,813. Subarachnoid hemorrhage was associated with significantly higher mean total costs than intracerebral hemorrhage ($92,794 vs $53,491; p < 0.01) and higher mean cost per day ($4,377 vs $3,604; p < 0.01). Patients with intracranial hemorrhage who survived to hospital discharge were significantly costlier than decedents ($100,979 vs $30,872; p < 0.01). Intracranial hemorrhage associated with oral anticoagulant use had a mean total cost of $152,373, compared with $66,548 in nonoral anticoagulant intracranial hemorrhage (p < 0.01). CONCLUSIONS: Patients admitted to ICU with intracranial hemorrhage have high costs and high mortality, leading to elevated cost per survivor. Subarachnoid hemorrhage patients incur greater costs than intracerebral hemorrhage patients, and oral anticoagulant associated intracerebral hemorrhage is particularly costly. Our findings provide novel information regarding financial impact of this common ICU population. PMID- 29406422 TI - Equilibration Time Required for Respiratory System Compliance and Oxygenation Response Following Changes in Positive End-Expiratory Pressure in Mechanically Ventilated Children. AB - OBJECTIVES: Increases in positive end-expiratory pressure are implemented to improve oxygenation through the recruitment and stabilization of collapsed alveoli. However, the time it takes for a positive end-expiratory pressure change to have maximum effect upon oxygenation and pulmonary compliance has not been adequately described in children. Therefore, we sought to quantify the time required for oxygenation and pulmonary system compliance changes in children requiring mechanical ventilation. DESIGN: Retrospective analysis of continuous data. SETTINGS: Multidisciplinary ICU of a pediatric university hospital. PATIENTS: Mechanically ventilated pediatric subjects. INTERVENTIONS: A case was eligible for analysis if during a 90-minute window following an increase in positive end-expiratory pressure, no other changes to the ventilator were made, ventilator and physiologic data were continuously available and a positive oxygenation response was observed. Time to 90% (T90) of the maximum change in oxygenation and compliance was computed. Differences between oxygenation and compliance T90 were compared using a paired t test. The effect of severity of illness (by oxygen saturation index) upon oxygenation and compliance was analyzed. MEASUREMENTS AND MAIN RESULTS: A total of 200 subjects were enrolled and 1,150 positive end-expiratory pressure change cases were analyzed. Of these, 54 subjects with 171 positive end-expiratory pressure change case were included in the analysis (67% were responders).Changes in dynamic compliance (T90 = 38 min) preceded changes in oxygenation (T90 = 71 min; p < 0.001). Oxygenation response differed depending on severity of illness quantified by oxygen saturation index; lung dysfunction was associated with a longer response time (p = 0.001). CONCLUSIONS: T90 requires 38 and 71 minutes for dynamic pulmonary compliance and oxygenation, respectively; the latter was directly observed to be dependent upon severity of illness. To our knowledge, this is the first report of oxygenation and compliance equilibration data following positive end-expiratory pressure increases in pediatric mechanically ventilated subjects. PMID- 29406423 TI - Activator Protein-1 Decoy Oligodeoxynucleotide Transfection Is Beneficial in Reducing Organ Injury and Mortality in Septic Mice. AB - OBJECTIVES: Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-kappaB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. DESIGN: Laboratory and animal/cell research. SETTINGS: University research laboratory. SUBJECTS: Male BALB/c mice (8 10 wk old). INTERVENTIONS: Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. MATERIALS AND MAIN RESULTS: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. CONCLUSIONS: Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure. PMID- 29406424 TI - Peripheral Monochromatic Aberrations in Young Adult Caucasian and East Asian Eyes. AB - SIGNIFICANCE: Myopia prevalence rates differ between racial groups. If the growth of the eye is sensitive to differences in optical input, the difference in spherical aberration between East Asian and Caucasian eyes found in this study may be important in understanding myopia development. PURPOSE: The aim of this study was to determine differences in peripheral wavefront aberrations between two racial groups. METHODS: Wavefront aberrations were measured using a COAS-HD aberrometer across the 42 * 32 degrees central visual field on 37 right eyes of young adults (18 Caucasians, 19 East Asians; mean age 21.5 +/- 2.4 years). The mean spherical equivalent refraction was -1.94 +/- 1.63 diopters (D) with a range of -5.87 to +0.16 D. Effect of race and visual field position on refractions, individual Zernike aberration coefficients up to the fourth order, higher-order root-mean-square aberration, and total root-mean-square aberration were assessed by repeated-measures analysis of covariance. RESULTS: Caucasians and East Asians had similar relative peripheral myopia across the visual field. All higher-order aberration coefficients were affected by visual field position. Race had no significant effect on any higher-order Zernike coefficient, but the difference in mean vertical coma coefficient (Equation is included in full-text article.)across the visual field (i.e., average of 38 field locations) approached significance, being less positive in Caucasians than in East Asians (P = .08). When correction was made for the Caucasian group being slightly less myopic than the East Asian group, spherical aberration coefficient (Equation is included in full-text article.)was less positive in Caucasians than in East Asians by 0.04 MUm (P = .001). The rates of change of coma coefficients across the field were not affected by race. CONCLUSIONS: Caucasians and East Asians had similar relative peripheral myopia, but with less positive spherical aberration coefficient in Caucasians than in East Asians. It remains to be determined whether aberrations have a role in the difference of myopia prevalence rates in different countries. PMID- 29406425 TI - Vulvar and vaginal fractional CO2 laser treatments for genitourinary syndrome of menopause. AB - Many healthcare providers are offering women treatment with the fractionated CO2 laser for a myriad of gynecologic issues, including genitourinary syndrome of menopause (GSM). Because existing data are limited, providing guidance is challenging. This Practice Pearl addresses what we know and don't know about the use of the fractionated CO2 laser for the treatment of GSM. PMID- 29406426 TI - History of vasomotor symptoms, extent of coronary artery disease, and clinical outcomes after acute coronary syndrome in postmenopausal women. AB - OBJECTIVE: Vasomotor symptoms (VMS) during menopausal transition have been linked to a higher burden of cardiovascular risk factors, subclinical vascular disease, and subsequent vascular events. We aim to investigate the association of VMS with the extent of coronary disease and their prognostic role after an acute coronary syndrome. METHODS: The Ladies Acute Coronary Syndrome study enrolled consecutive women with an acute coronary syndrome undergoing coronary angiography. A menopause questionnaire was administered during admission. Angiographic data underwent corelab analysis. Six out of 10 enrolling centers participated in 1 year follow-up. Outcome data included the composite endpoint of all-cause mortality, recurrent myocardial infarction, stroke, and rehospitalization for cardiovascular causes within 1 year. RESULTS: Of the 415 women with available angiographic corelab analysis, 373 (90%) had complete 1-year follow-up. Among them, 202 women had had VMS during menopausal transition. These women had the same mean age at menopause as those without VMS (50 years in both groups), but were younger at presentation (median age 71 vs 76 years; P < 0.001), despite a more favorable cardiovascular risk profile (chronic kidney dysfunction 4.5% vs 15.9%; P = 0.001; prior cerebrovascular disease 4.5 vs 12.2%; P = 0.018). Extent of coronary disease at angiography was similar between groups (mean Gensini score 49 vs 51; P = 0.6; mean SYNTAX score 14 vs 16; P = 0.3). Overall cardiovascular events at 1 year did not differ between groups (19% vs 22%; P = 0.5). CONCLUSIONS: In postmenopausal women with an acute coronary syndrome, a history of VMS was associated with younger age at presentation, despite a lower vascular disease burden and similar angiographically defined coronary disease as compared with women without VMS. No difference could be found in terms of overall clinical outcomes. These results should be interpreted cautiously as all analyses were unadjusted and did not account for risk factor differences between women with and without a history of VMS. PMID- 29406427 TI - Comparisons of low-intensity versus moderate-intensity combined aerobic and resistance training on body composition, muscle strength, and functional performance in older women. AB - OBJECTIVE: This study aimed to examine the effects of exercise order of combined aerobic and low- or moderate-intensity resistance training into the same session on body composition, functional performance, and muscle strength in healthy older women. Furthermore, this study compared the effects of different (low- vs moderate-) intensity combined training. METHODS: A total of 60 healthy older women (age 61-81 y) were randomly assigned to five groups that performed aerobic exercise before low-intensity resistance training (AR-L, n = 12) or after resistance training (RA-L, n = 12), performed aerobic exercise before moderate intensity resistance training (AR-M, n = 12) or after resistance training (RA-M, n = 12), or nonintervention control conditions (CON, n = 12). Body composition, functional performance, and muscle strength were evaluated before and after the 10-week training. RESULTS: No effects of exercise order of combined aerobic and low- or moderate-intensity resistance training (AR-L vs RA-L, AR-M vs RA-M) were observed in body composition, functional performance, or muscle strength, whereas the effects of training intensity of combined training (AR-L vs AR-M, RA-L vs RA M) were observed on functional performance. All combined trainings significantly increased muscle strength and gait ability (P < 0.01, respectively). Functional reach test significantly increased in the AR-M and RA-M groups (P < 0.01, respectively), and there were significant group differences between AR-L and AR-M (P = 0.002), RA-L and RA-M (P = 0.014). CONCLUSIONS: Preliminary findings suggest that combined aerobic and low- or moderate-intensity resistance training increases muscle strength and improves gait ability, regardless of the exercise order. Also, greater improvement in dynamic balance capacity, a risk factor associated with falling, is observed in moderate-intensity combined training. PMID- 29406429 TI - Mobile Health Intervention to Reduce HIV Transmission: A Randomized Trial of Behaviorally Enhanced HIV Treatment as Prevention (B-TasP). AB - OBJECTIVES: We conducted a randomized clinical trial to test a mobile health behavioral intervention designed to enhance HIV treatment as prevention (B-TasP) by simultaneously increasing combination antiretroviral therapies (cART) adherence and improving the sexual health of people living with HIV. METHODS: A cohort of sexually active men (n = 383) and women (n = 117) living with HIV were enrolled. Participants were baseline assessed and randomized to either (1) B-TasP adherence and sexual health intervention or (2) general health control intervention. Outcome measures included HIV RNA viral load, cART adherence monitored by unannounced pill counts, indicators of genital tract inflammation, and sexual behaviors assessed over 12 months. RESULTS: Eighty-six percent of the cohort was retained for 12-month follow-up. The B-TasP intervention demonstrated significantly lower HIV RNA, OR = 0.56, P = 0.01, greater cART adherence, Wald chi = 33.9, P = 0.01, and fewer indicators of genital tract inflammation, Wald chi = 9.36, P = 0.05, over the follow-up period. Changes in sexual behavior varied, with the B-TasP intervention showing lower rates of substance use in sexual contexts, but higher rates of condomless sex with non-HIV positive partners occurred in the context of significantly greater beliefs that cART reduces HIV transmission. CONCLUSIONS: Theory-based mobile health behavioral interventions can simultaneously improve cART adherence and sexual health in people living with HIV. Programs aimed to eliminate HIV transmission by reducing HIV infectiousness should be bundled with behavioral interventions to maximize their impact and increase their chances of success. PMID- 29406430 TI - Brief Report: Abacavir/Lamivudine and Tenofovir/Emtricitabine in Pregnant Women With HIV: Laboratory and Clinical Outcomes in an Observational National Study. AB - BACKGROUND: Abacavir-lamivudine (ABC/3TC) and tenofovir-emtricitabine (TDF/FTC) represent in the guidelines of several countries, including Italy and United States, the preferred nucleoside/nucleotide backbones of antiretroviral regimens. We assessed their profile in pregnancy using data from a national observational study. METHODS: Laboratory measures (CD4, HIV-RNA, lipid profile, glucose, hemoglobin, and alanine transferase) and pregnancy outcomes (preterm delivery, low birthweight, nonelective cesarean section, birthweight Z-score, congenital defects, HIV transmission, maternal weight gain, and pregnancy complications) were compared after prenatal exposure to ABC/3TC or TDF/FTC. RESULTS: The study evaluated 913 pregnancies (ABC/3TC: 252; TDF/FTC: 661). At entry in pregnancy, women on TDF/FTC were older (33.6 vs. 32.4 years, P = 0.005), less frequently on treatment (66.9% vs. 80.2%, P < 0.001), and had lower CD4 counts (475/mm vs. 533/mm, P = 0.003) and higher plasma HIV-RNA levels (2.48 vs. 2.22 log10 copies/mL, P = 0.003). Women on ABC/3TC had more commonly hypertension/nephropathy (5.2% vs. 2.0%, P = 0.013). No major differences were observed in the main pregnancy outcomes and in rates of undetectable HIV-RNA at third trimester. In a subgroup analysis that evaluated at third trimester only cases with regular 3-drug treatment during pregnancy, women on TDF/FTC had lower hemoglobin levels (median: 11.1 vs. 11.8 g/dL, P = 0.002) and women on ABC/3TC had higher levels of total cholesterol (median: 230 vs. 216 mg/dL, P = 0.023) and low-density lipoprotein-cholesterol (133 vs. 111 mg/dL, P = 0.030). CONCLUSIONS: In this study, use of TDF/FTC and ABC/3TC in pregnancy was associated with similar pregnancy outcomes and with some differences in laboratory measures that might guide physicians' prescriptions in mothers with hematologic or metabolic risk factors. PMID- 29406428 TI - Hepatotoxicity During Isoniazid Preventive Therapy and Antiretroviral Therapy in People Living With HIV With Severe Immunosuppression: A Secondary Analysis of a Multi-Country Open-Label Randomized Controlled Clinical Trial. AB - BACKGROUND: Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART. SETTING: Multicenter study in resource-limited settings with high burden of tuberculosis. METHODS: We conducted a secondary analysis of data from 1 randomized arm of the REMEMBER trial. The analysis includes participants with pre ART CD4 cell counts of <50 cells/MUL receiving IPT and ART for 24 weeks. Hepatotoxicity was defined as elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 * upper limit of normal or symptomatic hepatitis during IPT and ART. Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan-Meier method. RESULTS: Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/uL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (odds ratio [OR] 3.6, 95% confidence interval [CI]: 1.7 to 7.7) and hepatitis B surface antigen (HBsAg) seropositivity at baseline (OR 4.7, 95% CI: 1.7 to 12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI: 5.3 to 74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline. CONCLUSIONS: The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg seropositivity need closer monitoring for hepatotoxicity. PMID- 29406431 TI - Brief Report: HIV Assisted Partner Services Among Those With and Without a History of Intimate Partner Violence in Kenya. AB - BACKGROUND: HIV assisted partner services (APS) are a notification and testing strategy for sex partners of HIV-infected index patients. This cluster-randomized controlled trial secondary data analysis investigated whether history of intimate partner violence (IPV) modified APS effectiveness and risk of relationship dissolution. SETTING: Eighteen HIV testing and counseling sites in Kenya randomized to provide immediate APS (intervention) or APS delayed for 6 weeks (control). METHODS: History of IPV was ascertained at study enrollment and defined as reporting ever experiencing physical or sexual IPV. Those reporting IPV in the month before enrollment were excluded. We tested whether history of IPV modified intervention effectiveness and risk of relationship dissolution using population-averaged Poisson and log-binomial generalized estimating equation models. Exploratory analyses investigated associations between history of IPV and events that occurred after HIV diagnosis using log-binomial generalized estimating equation models. RESULTS: The study enrolled 1119 index participants and 1286 partners. Among index participants, 81 (7%) had history of IPV. History of IPV did not modify APS effectiveness in testing, newly diagnosing, or linking partners to care. History of IPV did not modify the association between receiving immediate APS and relationship dissolution during the study. CONCLUSIONS: Among participants who had not experienced IPV in the last month but had experienced IPV in their lifetimes, our results suggest that APS is an effective and safe partner notification strategy in Kenya. As APS is scaled up in different contexts, these data support including those reporting past IPV and closely monitoring adverse events. PMID- 29406432 TI - Pseudomyogenic Hemangioendothelioma: Case Report and Review of the Literature. AB - Pseudomyogenic hemangioendothelioma (PHE; epithelioid sarcoma-like hemangioendothelioma) is a rare entity, with 129 reported cases. It is a rarely metastasizing, low-grade vascular tumor that can histologically mimic epithelioid sarcoma and often presents as multiple discontinuous nodules in the extremities. PHEs characteristically and consistently show immunoreactivity for cytokeratins and endothelial markers. We present a case in the thigh of a 65-year-old-man with a 3-month history of painful lesions in the dermis and review the published literature. In our case, the lesion exhibited the characteristic histologic findings and immunoprofile of a PHE: a solid proliferation of spindled to epithelioid cells with abundant eosinophilic cytoplasm and frequent rhabdoid cells. Cytologic atypia and mitotic figures were inconspicuous. The tumor cells were immunoreactive for CD31, ERG, AE1/3, and CK7 and negative for D2-40, P53, HMB45, desmin, CD34, SMA, EMA, and S100 protein. A balanced reciprocal translation between chromosomes 7 and 19 was present; this translocation seems unique to PHE. PHE is a unique and commonly misdiagnosed entity; therefore, we review the literature to describe the characteristics of this tumor. PMID- 29406433 TI - Ulnar Collateral Ligament Injuries of the Elbow in the Throwing Athlete. AB - UPDATE: This article was updated on February 26, 2018, because of a previous error. On pages 1 and 7, in the author byline section, the authors' names that had read "Andrew Harris" and "Brett Owens" now reads "Andrew P. Harris" and "Brett D. Owens." PMID- 29406434 TI - Team Approach: Preventing Surgical Site Infections in Pediatric Scoliosis Surgery. PMID- 29406435 TI - Diagnostic performance of a new noninvasive test for nonalcoholic steatohepatitis using a simplified histological reference. AB - BACKGROUND: One of the unmet needs in patients with metabolic risks is the prediction of metabolic liver disease (MLD) by noninvasive tests (NITs). OBJECTIVE: The primary aim of this study was to construct a new quantitative test for the diagnosis of nonalcoholic steatohepatitis (NASH) using a simplified histological definition. PATIENTS AND METHODS: As a reference, we used a simplified histological definition of NASH derived from the FLIP-CRN-definition that does not require the presence of steatosis and the presence of both lobular inflammation and ballooning. We analyzed 1081 patients from two prospective cohorts at risk of MLD who had biopsies and contemporaneous blood samples. These patients were divided randomly into a training group (n=541) and a control group (n=540) for internal validation. The new test was compared with standard tests, and applied in two large populations at risk of MLD. RESULTS: Out of 1081 patients with biopsy, 39 (3.6%) cases with significant inflammatory activity or fibrosis (A2orF2) were missed by the current histological definitions. The combination of 11 parameters permitted to construct a test (NIT-NASHs) predicting NASH with an area under the receiver operating characteristic curve (AUROC) of 0.773 (95% confidence interval: 0.730-0.810), confirmed in the control group 0.814 (0.774-0.847). The AUROCs of NIT-NASHs were higher (all P<0.001) than those of ActiTest, FIB4, BARD, and nonalcoholic fatty liver disease scores. A combination of NIT-NASHs with FibroTest (AUROC=0.800; 0.759-0.835) enabled a better prediction (P<0.0001) of significant MLD, A2orF2, than the ActiTest FibroTest combination. CONCLUSION: These results suggested that this new test enables a quantitative assessment of NASH, and when associated with the FibroTest, identifies cases with clinically significant MLD. An external validation is needed. PMID- 29406436 TI - Clinical practice guidelines from the French National Society of Coloproctology in treating chronic constipation. AB - Chronic constipation is a common symptom that regularly affects the quality of life of adult patients. Its treatment is mainly based on dietary rules, laxative drugs, perineal rehabilitation and surgical treatment. The French National Society of Coloproctology offers clinical practice recommendations on the basis of the data in the current literature, including those on recently developed treatments. Most are noninvasive, and the main concepts include the following: stimulant laxatives are now considered safe drugs and can be more easily prescribed as a second-line treatment; biofeedback therapy remains the gold standard for the treatment of anorectal dyssynergia that is resistant to medical treatment; transanal irrigation is the second-line treatment of choice in patients with neurological diseases, but it may also be proposed for patients without neurological diseases; and although interferential therapy may be a new promising treatment, it needs further evaluation. PMID- 29406437 TI - Combining eastern and western practices for safe and effective endoscopic resection of large complex colorectal lesions. AB - BACKGROUND: Endoscopic resection of large colorectal polyps is well established. However, significant differences in technique exist between eastern and western interventional endoscopists. We report the results of endoscopic resection of large complex colorectal lesions from a specialist unit that combines eastern and western techniques for assessment and resection. PATIENTS AND METHODS: Endoscopic resections of colorectal lesions of at least 2 cm were included. Lesions were assessed using magnification chromoendoscopy supplemented by colonoscopic ultrasound in selected cases. A lesion-specific approach to resection with endoscopic mucosal resection or endoscopic submucosal dissection (ESD) was used. Surveillance endoscopy was performed at 3 (SC1) and 12 (SC2) months. RESULTS: Four hundred and sixty-six large (>=20 mm) colorectal lesions (mean size 54.8 mm) were resected. Three hundread and fifty-six were resected using endoscopic mucosal resection and 110 by ESD or hybrid ESD. Fifty-one percent of lesions had been subjected to previous failed attempts at resection or heavy manipulation (>=6 biopsies). Nevertheless, endoscopic resection was deemed successful after an initial attempt in 98%. Recurrence occurred in 15% and could be treated with endoscopic resection in most. Only two patients required surgery for perforation. Nine patients had postprocedure bleeding; only two required endoscopic clips. Ninety-six percent of patients without invasive cancer were free from recurrence and had avoided surgery at last follow-up. CONCLUSION: Combining eastern and western practices for assessment and resection results in safe and effective organ-conserving treatment of complex colorectal lesions. Accurate assessment before and after resection using magnification chromoendoscopy and a lesion specific approach to resection, incorporating ESD where appropriate, are important factors in achieving these results. PMID- 29406439 TI - Oxygen and preterm infant resuscitation: what else do we need to know? AB - PURPOSE OF REVIEW: To evaluate current evidence for the use of lower or higher oxygen strategies for preterm infant resuscitation RECENT FINDINGS: The equipoise for using higher fraction of inspired oxygen (FiO2) (>0.4) to initiate preterm infant respiratory stabilization has been lost. Recent meta-analyses of randomized controlled trials assessing outcomes after using higher (FiO2 >= 0.6) vs. lower (FiO2 <= 0.3) oxygen strategies to initiate preterm resuscitation shows no difference in the rates of death or major morbidities. However, not achieving pulse oximetry saturations of at least 80% by 5 min of age, whether it was due to iatrogenic oxygen insufficiency or poor infant pulmonary function, was associated with lower heart rates (mean difference -8.37, 95% confidence interval: -15.73, 1.01) and major intraventricular hemorrhage. There remains scarce neurodevelopmental data in this area and information about the impact of oxygen targeting strategies in low resourced areas. These knowledge gaps are research priorities that must be addressed in large, well designed randomized controlled trials. SUMMARY: Most clinicians now use lower oxygen strategies to initiate respiratory support for all infants, including preterm infants with significant lung disease. However, the impact of such strategies, particularly for neurodevelopmental outcomes and for lower resourced areas, remains uncertain and must be urgently addressed. PMID- 29406438 TI - The child health exposure analysis resource as a vehicle to measure environment in the environmental influences on child health outcomes program. AB - PURPOSE OF REVIEW: Demonstrate the role of environment as a predictor of child health. RECENT FINDINGS: The children's health exposure analysis resource (CHEAR) assists the Environmental influences on child health outcomes (ECHO) program in understanding the time sensitive and dynamic nature of perinatal and childhood environment on developmental trajectories by providing a central infrastructure for the analysis of biological samples from the ECHO cohort awards. CHEAR will assist ECHO cohorts in defining the critical or sensitive period for effects associated with environmental exposures. Effective incorporation of these principles into multiple existing cohorts requires extensive multidisciplinary expertise, creativity, and flexibility. The pursuit of life course - informed research within the CHEAR/ECHO structure represents a shift in focus from single exposure inquiries to one that addresses multiple environmental risk factors linked through shared vulnerabilities. CHEAR provides ECHO both targeted analyses of inorganic and organic toxicants, nutrients, and social-stress markers and untargeted analyses to assess the exposome and discovery of exposure-outcome relationships. SUMMARY: Utilization of CHEAR as a single site for characterization of environmental exposures within the ECHO cohorts will not only support the investigation of the influence of environment on children's health but also support the harmonization of data across the disparate cohorts that comprise ECHO. PMID- 29406441 TI - The genesis of systems of care for transition to adulthood services: emerging models in primary and subspecialty care. AB - PURPOSE OF REVIEW: Transitioning adolescents and young adults with chronic conditions can be complex. Expert recommendations support a transition process that starts in early adolescence, provides continuous guidance and support and allows for care opportunities with patients and caregivers, with the patient alone and between paediatric and adult providers. As most of the guidance is focused on individual patients, providers and clinical programmes, much less is known about how health systems as a whole might support effective transitions of care. RECENT FINDINGS: Many intervention studies focus on the preparation necessary to successfully transition adolescents, young adults and their families to adult care. Although randomized controlled trials of transition interventions are few and standards of care not yet established, promising models are being developed and tested. This review will describe the development and implementation of emerging models of transitional care in primary and subspecialty care, paying special attention to evaluation outcomes that can inform model selection. SUMMARY: The emerging models described here highlight the importance of and guidance for invested clinicians and health systems to create effective methods for successful transition. Additional research using rigorous methodology is necessary. PMID- 29406440 TI - Measurement framework for the Environmental influences on Child Health Outcomes research program. AB - PURPOSE OF REVIEW: Diverse methodological approaches pose significant challenges to assess environmental exposure effects on child health outcomes. Although transdisciplinary research efforts offer unique opportunities for understanding the complex and multidimensional facets of lifespan health and disease trajectories, a shared measurement strategy is necessary for ensuring cohesion and comprehensibility across disciplines and domains. RECENT FINDINGS: Exposure science often focuses on one life stage, one primary outcome domain and/or one environmental context without regard for understanding the complexity of exposome pathways and outcomes across a developmental continuum. As part of the National Institutes of Health Environmental influences on Child Health Outcomes Program, the Person Reported Outcomes Core developed a unifying measurement framework that takes a lifespan development approach to assess physical, mental and social health outcomes within the complex matrix of environmental exposure pathways. SUMMARY: The proposed framework offers a shared methodological approach to health outcome assessment, with a particular emphasis on person-reported outcomes. This framework will be instrumental for future large-scale consortia and transdisciplinary team science efforts by providing a common structure, measurement guidance and consistent terminology. PMID- 29406444 TI - Brief Summary Report From the 14th Biennial Meeting of the International Xenotransplantation Association. AB - The fourteenth meeting of the International Xenotransplantation Association (IXA) 2017, was held at University of Maryland, Baltimore, between September 19th and 23rd, 2017. This monograph summarizes reported progress in the field. PMID- 29406443 TI - Extended Pancreas Donor Program-The EXPAND Study: A Prospective Multicenter Trial Testing the Use of Pancreas Donors Older Than 50 Years. AB - BACKGROUND: Pancreas transplantation is the only curative treatment option for patients with juvenile diabetes. Organ shortage and restrictive allocation criteria are the main reasons for increasing waitlists, leading to severe morbidity and mortality. We designed a study to increase the donor pool with extended donor criteria (EDC) organs (donor age, 50-60 years; body mass index, 30 34 kg/m). METHODS: Utilization of EDC organs required the implementation of a new allocation system within Eurotransplant. The study was a prospective, multicenter, 2-armed trial. The primary endpoint was pancreas function after 3 months. Rejection episodes, kidney function, and waitlist time were secondary endpoints. Patients receiving an EDC organ were study group patients; recipients of standard organs were control group patients. Follow-up was 1 year. RESULTS: Seventy-nine patients were included in 12 German centers, 18 received EDC organs and 61 received standard organs. Recipient demographics were similar. Mean EDC donor age was 51.4 +/- 5 years versus 31.7 +/- 12 in the control group. Insulin free graft survival was 83.3% for EDC and 67.2% for standard organs (P = 0.245) after 3 months. One-year pancreas survival was 83.3% and 83.5% in the EDC versus standard group. One-year kidney allograft survival was approximately 94% in both groups. Rejection episodes and morbidity were similar. CONCLUSIONS: The Extended Pancreas Donor Program (EXPAND) shows in a prospective trial that selected EDC organs of donors older than 50 years can be used with outcomes similar to standard-criteria organs, therefore showing potential to reduce organ shortage and waiting times. This study substantiates the full implementation of EDC organs in a pancreas allocation system. PMID- 29406442 TI - Genetic risk of APOL1 and kidney disease in children and young adults of African ancestry. AB - PURPOSE OF REVIEW: Understanding the genetic risk of APOL1 in children and young adults is important given the lifetime risk of hypertension and kidney disease among children of African descent. We review recent epidemiologic and biologic findings on the effects of APOL1 and kidney disease. RECENT FINDINGS: APOL1 in children and young adults is associated with hypertension, albuminuria and more rapid decline in kidney function and progression to end-stage kidney disease, especially among those with glomerular causes of kidney disease, and those affected by sickle cell disease or HIV. There are conflicting data on the APOL1 association with cardiovascular disease in children and young adults. APOL1 functions as part of the innate immune system. Podocyte expression of APOL1 likely contributes to the development of kidney disease. In cell culture and model organisms, APOL1 expression disrupts autophagic and ion flux, leads to defects in mitochondrial respiration and induces cell death. SUMMARY: APOL1 explains almost 70% of the excess risk of kidney disease in those of African descent, and is common in children with glomerular disease. An evolving understanding of the pathogenesis of APOL1-mediated kidney damage may aid in personalized medicine approaches to APOL1 attributable kidney disease. PMID- 29406445 TI - Protecting Donor Livers During Normothermic Machine Perfusion With Stem Cell Extracellular Vesicles. PMID- 29406446 TI - Comparison of Different Scoring Systems in the Assessment of Estrogen Receptor Status for Predicting Prognosis in Endometrial Cancer. AB - The objective of this article is to compare the effectiveness of various estrogen receptor (ER) scoring systems for predicting prognosis in endometrial cancer (EC). We retrospectively analyzed 195 cases of primary EC with complete follow-up information. Three different methods-the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criterion, histochemistry score (H-score), and Allred scoring system-were used to assess the degree of staining, and comparisons were made to determine which method correlated best with clinical outcomes. The ASCO/CAP criterion, H-score (cutoff value, 51-300), and Allred (cutoff value, 4-8) scoring systems showed high concordance in the following aspects: the ER status was significantly associated with subtype (type I vs. type II EC), newly recommended histologic type (grade 1-2, type I vs. grade 3, type I+type II EC), progesterone receptor status, overall survival, and cancer specific survival in EC patients. Considering International Federation of Gynecology and Obstetrics stage, lymphovascular space invasion, and lymph node metastasis, the ASCO/CAP criterion significantly exceeded the other 2 scoring systems. Furthermore, cases judged as ER positive by the ASCO/CAP criterion, but ER negative by the other 2 scoring systems, displayed similarly favorable outcomes to those cases that were consistently admitted as ER positive by all 3 scoring systems. The ASCO/CAP criterion was superior to both H-score and Allred score in terms of predictive and prognostic values. This easy, simple, and highly efficient criterion should be recommended for routine assessment of ER in EC patients. PMID- 29406448 TI - Hepatocellular carcinoma in the wait-listed patient with hepatitis C virus. AB - PURPOSE OF REVIEW: To highlight the current data for treatment of hepatitis C virus (HCV) in patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplant and incorporation of various factors to decide the optimal time to initiate HCV therapy. RECENT FINDINGS: Viral eradication on the waiting list has been found to lead to significant clinical improvement in approximately 20% of HCV-positive patients. However, there have been concerns raised for direct acting antiviral (DAA) therapy in patients listed with HCC. DAA therapy leading to rapid HCV clearance has been reported to be associated with an increased risk of HCC recurrence, especially when DAA therapy is initiated in close proximity to HCC therapy. Additionally, the presence of viable HCC may significantly lower the chances of achieving sustained virologic response. Lastly, sustained virologic response can decrease the organ pool in HCV-positive waitlisted patients. SUMMARY: The decision to treat HCV in patients listed for HCC pre vs. postliver transplant will require additional research. PMID- 29406447 TI - Bartholin Gland Carcinoma: Clinicopathologic Features, Including p16 Expression and Clinical Outcome. AB - Bartholin gland carcinomas are rare forms of vulvar malignancy and it is unclear what proportion is associated with high-risk human papilloma virus (HPV) infection. Our hospital archives were searched for all cases of Bartholin gland carcinoma from 1984 to 2017 (n=16). We excluded 3 adenoid cystic carcinomas, which were the subject of a previous study, leaving 13 cases. We reviewed all slides and performed immunostains for p16 as a surrogate biomarker for high-risk HPV. There were 12 squamous cell carcinomas (SCCs), including 1 SCC with transitional-like morphology and 1 papillary SCC, and 1 adenocarcinoma. All SCCs showed diffuse and intense p16 expression consistent with the presence of HPV. The single case of poorly differentiated adenocarcinoma showed patchy staining. Patient age ranged from 38 to 72 yr (mean, 58.3 yr). Most tumors were low stage. All patients were treated with radical vulvectomy and inguinofemoral lymphadenectomy. Mean clinical follow-up was 53.7 mo (range, 3-181 mo), 9 patients were free of disease (75%), recurrence occurred in 3 cases, with death due to disease in 2 of the patients with recurrence, including the single patient with adenocarcinoma. All SCC of Bartholin gland expressed p16 diffusely and intensely regardless of histologic features and grade. Our results support the etiologic role of HPV in the pathogenesis of SCC of Bartholin gland. In this small study we observed SCC as the predominant histotype, and most tumors presented at early stage and were associated with relatively favorable outcomes. PMID- 29406449 TI - Long-term results of surgery for bowel lengthening: how many transplants are avoided, for which patients? AB - PURPOSE OF REVIEW: One of the biggest successes of intestinal rehabilitation programs is that more patients achieve enteral autonomy without transplantation. Many factors are responsible of this accomplishment including new parenteral formulas, better catheter management, surgical management, and the experience of the teams. The purpose of this review is to analyze recent published papers regarding intestinal lengthening procedures trying to find out how many transplantations are avoided and for which patients. RECENT FINDINGS: A trend towards performing less intestinal transplants has been identified in the last years. The general improvement of intestinal rehabilitation accounts for this step forward. However, the role of intestinal lengthening has not been clarified. SUMMARY: Surgical techniques for autologous reconstructive surgery are not limited to bowel lengthening. Longitudinal intestinal lengthening and tailoring and serial transverse enteroplasty offered good results in terms of intestinal adaptation, long-term survival, and subsequent need of intestinal transplantation. In recent series, less than one quarter of patients who underwent intestinal lengthening required salvage intestinal transplantation. PMID- 29406450 TI - Feedback to Patients About Patient-reported Outcomes Does Not Improve Empowerment or Satisfaction. AB - BACKGROUND: Although patient-reported outcome measures (PROMs) are helpful to define whether an intervention has improved a patient's status in ways the patient feels are important, they may also serve an empowering educational role; specifically, sharing a patient's scores might help the patient understand his or her progress during treatment. However, whether sharing PROM scores in this way improves the sense of empowerment or satisfaction with the process of care has not been well explored. Also, less is known whether specific demographic factors or coping strategies are associated with empowerment. QUESTIONS/PURPOSES: We asked the following: (1) Does giving patients feedback on their PROM scores improve a patient's sense of empowerment or satisfaction? (2) Do demographic factors, duration of disability, or self-efficacy correlate with patient empowerment? METHODS: In this prospective cohort study, we assigned patients with osteoarthritis of the knee or hip sequentially such that the first 70 patients did not receive the intervention and the next 72 did. Patients enrolled in the control cohort were managed according to standard care, whereas patients enrolled in the intervention cohort completed web-based questionnaires measuring their physical function and pain. After filling out the questionnaires, a printout with the scores was given to the patients providing feedback about their physical function and pain. The primary outcome measure was patient empowerment, as measured by the Patient Activation Measure. Secondary outcomes were patient satisfaction, as measured by an 11-point Likert scale and Patient Doctor Relation Questionnaire. Independent variables were demographic factors and coping, measured by the Pain Self-efficacy Questionnaire. Bivariate and multivariable analyses were performed to determine the influence of the feedback. Although no minimum clinically important differences have been defined for the patient empowerment or satisfaction scales, we believe that differences smaller than 10% are unlikely to be clinically important, even if they are statistically significant. RESULTS: Although the group that received PROM feedback had higher scores for empowerment than the group that did not, the effect size was small and likely not to have been clinically important (2.8 +/- 0.85 versus 3.1 +/- 0.811; mean difference -0.31; 95% confidence interval, 2.8-3.1; p = 0.037). With the numbers available, there were no differences between the group given PROM feedback and the group that did not receive such feedback in terms of satisfaction scores (8.6 +/- 1.4 versus 8.8 +/- 1.2; mean difference -0.19; p = 0.39). After controlling for demographic factors such as level of education and duration of complaint, we found that the group that received PROM feedback and who had a higher level of self-efficacy had higher scores for empowerment than the group that did not, although the effect size was small. CONCLUSIONS: PROM feedback did not have a clinically important impact on empowerment or satisfaction. This might indicate that counseling based on PROMs during a single visit may be ineffective. The most important positive finding is that more effective coping strategies are associated with greater patient empowerment. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29406451 TI - Is Use of a Psychological Workbook Associated With Improved Disabilities of the Arm, Shoulder and Hand Scores in Patients With Distal Radius Fracture? AB - BACKGROUND: Symptom intensity and magnitude of limitations correlate with stress, distress, and less effective coping strategies. It is unclear if interventions to target these factors can be used to improve outcomes after distal radius fracture in either the short- or longer term. QUESTIONS/PURPOSES: (1) Are there any factors (including the use of a workbook aimed at optimizing psychological response to injury, demographic, radiographic, medical, or psychosocial) associated with improved Disabilities of the Arm, Shoulder and Hand (DASH) and Numerical Rating Scale pain (NRS pain) scores at 6 weeks after management of distal radius fracture? (2) Are any of these factors associated with improved DASH and NRS pain scores at 6 months after management of distal radius fracture? METHODS: We conducted a double-blind randomized controlled trial comparing a workbook designed to optimize rehabilitation by improving psychological response to injury using recognized psychological techniques (the LEARN technique and goal setting) versus a workbook containing details of stretching exercises in the otherwise routine management of distal radius fracture. Patients older than 18 years of age with an isolated distal radius fracture were recruited within 3 weeks of injury from a single academic teaching hospital between March and August 2016. During recruitment, 191 patients who met the inclusion criteria were approached; 52 (27%) declined participation and 139 were enrolled. Eight patients (6%) were lost to followup by 6 weeks. The remaining cohort of 129 patients was included in the analysis. DASH scores and NRS pain scores were recorded at 6 weeks and 6 months after injury. Multivariable regression analysis was used to identify factors associated with outcome scores. RESULTS: At 6 weeks after distal radius fracture, when compared with an information-only workbook, use of a psychologic workbook was not associated with improved DASH (workbook DASH: 38 [range, 21-48]; control DASH: 35 [range, 21-53]; difference of medians: 3; p = 0.949) nor NRS pain scores (workbook NRS: 3 [range, 1-5]; control NRS: 2 [range, 1-4]; difference of medians: 1; p = 0.128). Improved DASH scores were associated with less radial shortening (beta = 0.2, p = 0.009), less dorsal tilt (beta = 0.2, p = 0.035), and nonoperative treatment (beta = 0.2, p = 0.027). Improved NRS pain scores were associated with nonoperative treatment (beta = 0.2, p = 0.021) and no posttraumatic stress disorder (PTSD) (beta = 0.2, p = 0.046). At 6 months, use of a psychologic workbook was not associated with improved DASH (workbook DASH: 11 [range, 5-28]; control DASH: 11 [range, 3-20]; difference of medians: 0; p = 0.367) nor NRS pain scores (workbook NRS: 1 [range, 0-2]; control NRS: 1 [range, 0-2]; difference of medians: 0; p = 0.704). Improved DASH score at 6 months was associated with having fewer medical comorbidities (beta = 0.3, p < 0.001) and lower enrollment PTSD (beta = 0.3, p < 0.011). Lower NRS pain scores at 6 months were associated with having fewer medical comorbidities (beta = 0.2, p = 0.045), lower enrollment PTSD (beta = 0.3, p = 0.008), and lower enrollment Tampa Scale for Kinesiophobia (beta = 0.2, p = 0.042). CONCLUSIONS: Our study demonstrates that there is no benefit from the untargeted use of a psychological workbook based on the LEARN approach and goal-setting strategies in patients with distal radius fracture. Future research should investigate if there is a subgroup of patients with a negative psychological response to injury that benefits from psychological intervention and, if so, how best to identify these patients and intervene. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29406452 TI - CORR Insights(r): Do Injured Adolescent Athletes and Their Parents Agree on the Athletes' Level of Psychologic and Physical Functioning? PMID- 29406453 TI - CORR Insights(r): Feedback to Patients About Patient-reported Outcomes Does Not Improve Empowerment or Satisfaction. PMID- 29406454 TI - What Is the Long-term Survivorship of Cruciate-retaining TKA in the Finnish Registry? AB - BACKGROUND: Survival of cruciate-retaining (CR) TKA is generally good, but there may be important differences in survivorship among devices, and different designs may not all be equally patellar-friendly. Large registry databases are needed to identify small but important differences between devices. QUESTIONS/PURPOSES: The purposes of this study were (1) to assess the long-term survivorship of the most common CR TKA devices with revision for any reason as the endpoint and compare the revision risk of these devices after controlling for the potentially confounding variables of age, sex, hospital volume, and primary diagnosis; and (2) to analyze these same devices with revision for secondary resurfacing of the patella as a separate endpoint. METHODS: Data were collected from the Finnish Arthroplasty Register. Over 95% of all primary TKAs are captured in the Finnish Register. We assessed Kaplan-Meier (KM) survivorship for each of the four most frequently used CR TKA designs used between years 2005 and 2015: Triathlon CR (n = 34,337), Nexgen CR Flex (n = 15,723), PFC Sigma CR (n = 15,541), and Vanguard CR (n = 9461), with revision for any reason as the endpoint. Revision was defined as a reoperation in which at least one of the components was exchanged (including insert exchange). Revisions in which the patella was not resurfaced at the primary operation and was resurfaced in the revision were studied as a separate endpoint. The mean followup times were 4.0 (range, 0-11.0) years for Triathlon CR, 3.8 (range, 0-11.0) years for Nexgen CR Flex, 5.1 (range, 0-11.0 ) years for PFC Sigma CR, and 4.9 (range, 0-10.9) years for Vanguard CR (p < 0.001). The group demographics were clinically comparable. We compared the risk of revision of these devices in the Cox multiple regression model with adjustment for hospital volume, age, sex, and primary diagnosis. There were some differences in the incidence of patellar resurfacing at the time of index arthroplasty (Nexgen CR flex 18.7%, PFC Sigma CR 18.4%, Triathlon CR 11.3%, Vanguard CR 14.4%), which was controlled by the Cox model. Implant survival analyses for Triathlon CR, Nexgen CR Flex, and PFC Sigma CR were also performed at the hospital level for the 25 largest TKA providers in Finland. RESULTS: The overall 10-year KM survivorships were 96% (95% confidence interval [CI], 95-96) for Nexgen CR Flex, 96% (95% CI, 96-97) for PFC Sigma CR, 94% (95% CI, 93-95) for Triathlon CR, and 94% (95% CI, 93-95) for Vanguard CR. After controlling for potential confounding variables like age, sex, hospital volume, and primary diagnosis, both Triathlon CR (hazard ratio [HR], 1.4; 95% CI, 1.2-1.6; p < 0.01) and Vanguard CR (HR, 1.4; 95% CI, 1.2-1.6; p < 0.01) had an increased risk for revision compared with the Nexgen CR Flex (the reference device). When revision with patellar resurfacing served as the endpoint, after controlling for those same confounding variables, Triathlon CR had a higher risk for revision than Nexgen CR Flex (HR, 1.8; 95% CI, 1.4-2.2; p < 0.01). CONCLUSIONS: Despite slight differences among the studied devices, the overall 10-year survivorship of the current devices studied was good. However, there were differences in implant survival between the study devices, especially when revision for late patellar resurfacing was analyzed. Further studies adjusted for additional hospital and surgeon variables will be needed to examine and confirm our results. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29406455 TI - CORR Insights(r): Patients With Limited Health Literacy Have Similar Preferences but Different Perceptions in Shared Decision-making for Carpal Tunnel Release. PMID- 29406456 TI - CORR Insights(r): Hand Posturing Is a Nonverbal Indicator of Catastrophic Thinking for Finger, Hand, or Wrist Injury. PMID- 29406457 TI - Bearing Dislocation and Progression of Osteoarthritis After Mobile-bearing Unicompartmental Knee Arthroplasty Vary Between Asian and Western Patients: A Meta-analysis. AB - BACKGROUND: Implant survivorship is reported to be lower and complications, particularly bearing dislocation, are reported to be more frequent in Asian than in Western patients with medial knee osteoarthritis (OA) undergoing Oxford(r) Phase III unicompartmental knee arthroplasty (UKA). To date, however, these complications have not been compared between these groups of patients. QUESTIONS/PURPOSES: The purpose of this study was to perform a meta-analysis comparing the standardized incidence rates of (1) all-cause reoperation; (2) reoperation related to bearing dislocation; and (3) reoperation related to progression of lateral compartment arthritis in Asian and Western patients with medial knee OA who underwent Oxford Phase III UKA. METHODS: We searched MEDLINE(r) (January 1, 1976, to May 31, 2017), EMBASE(r) (January 1, 1985, to May 31, 2017), and the Cochrane Library (January 1, 1987, to May 31, 2017) for studies that reported complications of Oxford Phase III UKAs. Studies were included if they reported reoperation rates attributable to bearing dislocation and/or progression of lateral knee OA after surgery with this implant. Twenty seven studies were included in this systematic review and 16 studies with followups > 5 years were included in the meta-analysis. These rates were converted to standardized incidence rate (that is, reoperations per 100 observed component years) based on mean followup and number of involved knees in each study. After applying prespecified inclusion and exclusion criteria, the studies were categorized into two groups, Asian and Western, based on hospital location. Twenty-five studies, containing 3152 Asian patients and 5455 Western patients, were evaluated. Study quality was assessed by the modified Coleman Methodology score (MCMS). Although all studies were Level IV, their mean MCMS score was 66.92 (SD, 8.7; 95% confidence interval [CI], 63.5-70.3), indicating fair quality. Because the heterogeneity of all subgroup meta-analyses was high, a random effects model was used with estimations using the restricted maximum likelihood method. RESULTS: There was no difference in the proportion of Asian patients versus Western patients undergoing reoperation for any cause calculated as 100 component observed years (1.022 of 3152 Asian patients; 95% CI, 0.810-1.235 versus 1.300 of 5455 Western patients; 95% CI, 1.067-1.534; odds ratio, 0.7839; 95% CI, 0.5323-1.1545; p = 0.178). The mean reoperation rate attributable to bearing dislocation per 100 observed years was higher in Asian than in Western patients (0.525; 95% CI, 0.407-0.643 versus 0.141; 95% CI, 0.116-0.166; odds ratio, 3.7378; 95% CI, 1.694-8.248; p = 0.001) Conversely, the mean reoperation rate attributable to lateral knee OA per 100 observed years was lower in Asian than in Western patients (0.093; 95% CI, 0.070-0.115 versus 0.298; 95% CI, 0.217 0.379; odds ratio, 0.3114; 95% CI, 0.0986-0.9840; p < 0.001). CONCLUSIONS: Although total reoperation rates did not differ in the two populations, reoperation for bearing dislocation was more likely to occur in Asian than in Western patients, whereas reoperation for lateral knee OA progression was more likely to occur in Western than in Asian patients after Oxford Phase III UKA. Although possible explanations for these findings may be hypothesized, additional randomized, prospective comparative studies are needed. However, better survival outcomes after UKA may require consideration of ethnicity and lifestyle choices in addition to traditional surgical technique and perioperative care. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29406458 TI - CORR Insights(r): Do Patients Live Longer After THA and Is the Relative Survival Diagnosis-specific? PMID- 29406459 TI - CORR Insights(r): Does a Brief Mindfulness Exercise Improve Outcomes in Upper Extremity Patients? A Randomized Controlled Trial. PMID- 29406460 TI - CORR Insights(r): Is Total Femur Replacement a Reliable Treatment Option for Patients With Metastatic Carcinoma of the Femur? PMID- 29406462 TI - 30 years of Current Opinion in Obstetrics and Gynecology: looking back and looking forward. PMID- 29406461 TI - Zika virus: a public health perspective. AB - PURPOSE OF REVIEW: Zika virus' impact on pregnancy became widely known in 2015 with a dramatic increase in the number of babies born with microcephaly in Recife, Brazil. A mosquito-borne virus resulting in congenital anomalies is unique, and Zika's ability to cause neurological defects on a large scale was a grim reminder of the Rubella epidemic in the 1950s. Over the past 2 years, studies have provided insight on how Zika virus (ZIKV) infects cells and causes disease, but much remains unknown about the long-term risks of Zika exposure on infant growth and development. RECENT FINDINGS: The impact of ZIKV on pregnancy extends beyond microcephaly and may only first be identified in infancy. The virus has a long latency in semen and can be transmitted sexually. Transplacental passage occurs through infection of Hofbauer cells in the trophoblast. A major difficulty in management of ZIKV disease is that most infections are asymptomatic and the diagnostic methods are not ideal, making both diagnosis and ascertainment of timing of infection problematic. Several different types of vaccines are in development. Large studies are ongoing to determine the risk and total spectrum of anomalies based on the timing of infection and other environmental exposures. SUMMARY: This review will summarize the epidemic, what we have learned, what we hope to learn, and current recommendations for care and management. PMID- 29406463 TI - Malnutrition, Growth Response and Metabolic Changes Within the First 24 Months After ART Initiation in HIV-infected Children Treated Before the Age of 2 Years in West Africa. AB - BACKGROUND: There is limited information about malnutrition, growth evolution and metabolic changes among children initiated early on lopinavir-based antiretroviral therapy (ART) in Africa. METHODS: HIV-1-infected children, age <2 years were initiated on ART, as part of the MONOD ANRS 12206 project, conducted in Burkina Faso and Cote d'Ivoire. Weight-for-age, height-for-age and weight-for height Z scores defined malnutrition [Z score less than -2 standard deviations (SDs)] using World Health Organization growth references. Biologic data were collected every 6 months. Factors associated with baseline malnutrition were evaluated using multivariate logistic regression, and with growth evolution in the first 24 months on ART using linear mixed models. RESULTS: Between 2011 and 2013, 161 children were enrolled: 64% were from Abidjan, 54% were girls. At ART initiation, median age was 13.7 months (interquartile range 7.7; 18.4), 52% were underweight (weight-for-age), 52% were stunted (height-for-age) and 36% were wasted (weight-for-height). Overall, baseline malnutrition was more likely for children living in Burkina Faso, with low birth weight, never breastfed and older age (12-24 months). Growth improved on ART, mainly within the first 6 months for weight, and was greater for the most severely malnourished children at baseline, but 8%-32% remained malnourished after 24 months. Over the 24-month period of ART, there was a significant increase of hypercholesterolemia and decrease of anemia and hypoalbuminemia. CONCLUSIONS: Prevalence of malnutrition was high before ART initiation. Even though growth improved on ART, some children remained malnourished even after 2 years of ART, highlighting the need for more active nutritional support. PMID- 29406464 TI - Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany. AB - BACKGROUND: Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany? METHODS: Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score. RESULTS: A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57; sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score. CONCLUSIONS: None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy. PMID- 29406465 TI - Randomized Multicenter Study Comparing Safety and Efficacy of Daptomycin Versus Standard-of-care in Pediatric Patients With Staphylococcal Bacteremia. AB - BACKGROUND: Staphylococcus aureus, including community-associated methicillin resistant S. aureus, is an important cause of pediatric bacteremia. Daptomycin is a well-established treatment option for Gram-positive bacteremia in adults, but its safety and efficacy in children require confirmation. METHODS: This was a randomized (2:1), evaluator-blinded, multicenter, phase 4 clinical trial comparing intravenous daptomycin with standard-of-care (SOC) for treatment of S. aureus bacteremia in 1- to 17-year-old patients (Clinicaltrials.gov: NCT01728376). Total treatment duration (intravenous followed by oral step-down therapy) was 5-42 days. Daptomycin was dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg and 1-6 years, 12 mg/kg. The primary objective was to evaluate daptomycin safety in children who received >=1 dose; secondary objectives included comparing daptomycin efficacy with SOC (the trial was not designed to confirm noninferiority) and pharmacokinetic analysis. RESULTS: Fifty-five children were randomized to daptomycin and 27 to SOC (primarily vancomycin or cefazolin); 90% had S. aureus. In both groups, 15% of patients had drug-related adverse events, primarily diarrhea (4% daptomycin, 8% SOC) and increased creatine phosphokinase (4% daptomycin, 0% SOC). Clinical success (blinded evaluator-assessed complete/partial resolution of bacteremia signs and symptoms 7-14 days after end-of-treatment) rates were similar for daptomycin (88%) and SOC (77%; 95% confidence interval for difference: -9% to 31%). Daptomycin plasma levels across age groups were comparable with those in adults receiving daptomycin at 6 mg/kg. CONCLUSIONS: Once-daily, age-appropriate daptomycin was well tolerated in children with staphylococcal bacteremia; efficacy was comparable with SOC. Daptomycin in age-adjusted doses is a safe treatment alternative in this setting. PMID- 29406466 TI - Effect of Rotavirus Vaccination on Acute Diarrheal Hospitalizations Among Low and Very Low Birth Weight US Infants, 2001-2015. AB - BACKGROUND: The effectiveness of rotavirus vaccines in low and very low birth weight infants (LBW and VLBW) weighing <2500 and <1500 g at birth, respectively, a high-risk population for severe rotavirus gastroenteritis, has not been well examined. METHODS: We analyzed inpatient commercial claims data for US children <5 years of age from July 2001 to June 2015. Claims for acute gastroenteritis (AGE) and rotavirus-coded hospitalizations and LBW, VLBW and normal birth weight (NBW) infants were identified. Receipt of rotavirus vaccine was defined using Current Procedural Terminology. Rate reductions were calculated using prevaccine (2001-2006) and postvaccine (2007-2015) annual AGE and rotavirus hospitalization rates. RESULTS: As of December 2014, rotavirus vaccine coverage was 87%, 82% and 64%, for NBW, LBW and VLBW infants, respectively. For 2014-2015, among NBW, LBW and VLBW children <5 years of age, AGE hospitalization rate reductions relative to the prevaccine introduction period were 60% [95% confidence interval (CI): 58% 61%], 64% (95% CI: 57%-70%) and 55% (95% CI: 39%-67%), respectively. Rotavirus hospitalization rate reductions were 91% (95% CI: 90%-92%), 98% (95% CI: 93% 100%) and 93% (95% CI: 70%-98%). Rotavirus vaccines resulted in a 62% (95% CI: 51%-71%), 72% (95% CI: 44%-86%) and 71% (95% CI: 7%-91%) reduction in AGE hospitalization rates comparing vaccinated versus unvaccinated NBW, LBW and VLBW children 3-23 months of age, respectively. CONCLUSIONS: Rotavirus vaccines have substantially reduced AGE hospitalizations and are highly effective in LBW and VLBW infants, similar to NBW infants. Efforts to improve vaccination coverage, particularly in LBW and VLBW infants, should continue. PMID- 29406467 TI - Subtype-specific Clinical Presentation, Medical Treatment and Family Impact of Influenza in Children 1-5 Years of Age Treated in Outpatient Practices in Germany During Three Postpandemic Years, 2013-2015. AB - BACKGROUND: Limited data on the influenza burden in pediatric outpatients are available, especially regarding direct comparison of the cocirculating (sub)types A(H1N1)pdm09, A(H3N2) and B. METHODS: Children 1-5 years of age, unvaccinated against influenza and presenting with febrile acute respiratory infections (ARIs), were enrolled in 33 pediatric practices in Germany from 2013 to 2015 (January-May). Influenza was confirmed by multiplex polymerase chain reaction from pharyngeal swabs and (sub)typed. RESULTS: In 805 children with ARI, influenza was the most frequently detected respiratory virus (n = 305; 37.9%). Of 217 influenza patients included, 122 (56.2%) were infected with A(H3N2), 56 (25.8%) with A(H1N1)pdm09 and 39 (18.0%) with B. Median age was 3.7 years [interquartile range (IQR), 2.1-4.8]; 11% had underlying conditions. Median fever duration was 4 days (IQR, 3-5), and the disease duration was 9 days (IQR, 7-12). Most frequent diagnoses were pharyngitis (26%), bronchitis (18%) and acute otitis media (10%). Children received mainly antipyretics (86%) and adrenergic nasal drops/spray (53%); 9% received antibiotics and 3% oseltamivir. Thirty-six percent required at least 1 additional practice visit; 1% was hospitalized. Median absences from childcare were 5 days (IQR, 3-7); parents lost 4 workdays (IQR, 2 6). Symptoms, severity and impact on the family were largely unrelated to (sub)type. However, patients with A(H1N1)pdm09 had fewer underlying conditions (P = 0.017), whereas patients with B more often had pharyngitis (P = 0.022), acute otitis media (P = 0.012) and stenosing laryngotracheitis (P = 0.007). CONCLUSIONS: Influenza was the most frequently detected viral pathogen in outpatient children with febrile, mostly uncomplicated ARI. In this setting, clinical manifestations and severity were similar across the (sub)types prevalent during the postpandemic seasons. PMID- 29406468 TI - Impact of Cerebrospinal Fluid Multiplex Assay on Diagnosis and Outcomes of Central Nervous System Infections in Children: A Before and After Cohort Study. AB - BACKGROUND: This study evaluated the performance of cerebrospinal fluid multiplex assay in the diagnosis of pediatric central nervous system (CNS) infection, and assessed for the effect on clinical management. METHODS: A 15-month prospective cohort of pediatric patients with confirmed CNS infection was compared with a 15 month retrospective cohort from the Top End region of the Northern Territory, Australia. The study characterized all the CNS infections over the 30-month period and compared the time to organism identification and antibiotic management before and after the introduction of the multiplex assay. RESULTS: Thirty-six cases of pediatric CNS infection were diagnosed before the introduction of the multiplex assay, and 29 afterwards. Multiplex assay was performed on 26/29 (90%) of the cerebrospinal fluid isolates from children with confirmed CNS infections in the prospective cohort. Enterovirus was the most common causative organism identified in 14 children, followed by human parechovirus in 4 children. The multiplex assay performed with 93.8% sensitivity and 90.0% specificity when compared with microbiologic culture or reference laboratory results. The median time to organism identification reduced from 6.0 to 2.0 days (P value <0.001), the median duration of antibiotic therapy from 3.0 to 2.0 days (P value <0.001) and median hospitalization reduced from 5.0 to 3.0 days (P value 0.016) after introduction of the multiplex assay. CONCLUSIONS: The multiplex assay is a useful adjunct diagnostic tool enabling prompt organism identification and reducing antibiotic treatment and hospitalization duration. The assay would be of most value to hospitals that do not have access to an onsite molecular laboratory. PMID- 29406469 TI - A General Lack of IgG Against Pertussis Toxin in Chinese Pregnant Women and Newborns. AB - BACKGROUND: To investigate the level of pertussis-related antibodies in pregnant women and newborns. METHODS: A total of 286 serum samples from healthy pregnant women and 221 cord samples from newborns were collected in 2016 in Beijing. A routine blood sample from pregnant women was obtained at 35 weeks of gestational age, and cord samples were collected in 20 minutes after delivery. The values from cord samples were used as the infant values. Anti-pertussis toxin (PT) IgG concentration was measured by ELISA (Euroimmun, Lubeck, Germany) using purified PT as a coating antigen. Newborns with anti-PT IgG <=40 IU/mL in cord samples were considered to be unprotected against pertussis. Anti-PT IgG >=100 IU/mL was considered to be indicative of a recent pertussis infection in pregnant women. RESULTS: The anti-PT IgG concentration below the lower limit of detection (<5 IU/mL) occurred in 74.1% (212/286) of pregnant women and 66.5% (147/221) of newborns. Even with detectable anti-PT antibodies, the majority of pregnant women (79.7%, 59/74) and newborns (73.0%, 54/74) had antibody level of 5 to <20 IU/mL, and 13.5% (10/74) of pregnant and 14.9% (11/74) of newborns had antibody level of 20 to <40 IU/mL. The 75% percentiles for anti-PT IgG of pregnant women and newborns were 5.08 and 6.98 IU/mL, respectively. The prevalence of unprotected newborns as defined by anti-PT IgG <=40 IU/mL was 95.9% (202/211). The prevalence of recent pertussis infection in pregnant women as defined by anti-PT IgG >=100 was 0.7% (2/286). CONCLUSIONS: The pregnant women and newborns were generally lack of protective antibody and are vulnerable to pertussis in Beijing, China. Although acellular pertussis vaccine is administrated in infancy in China, a booster vaccination to pregnant women should be considered for protecting young infants who are too young to start pertussis vaccination. PMID- 29406470 TI - BIMANUAL MICROINCISION VITREOUS SURGERY FOR SEVERE PROLIFERATIVE DIABETIC RETINOPATHY: OUTCOME IN MORE THAN 300 EYES. AB - PURPOSE: To evaluate the visual and anatomical outcomes and safety of bimanual microincision vitreous surgery for severe proliferative diabetic retinopathy. METHODS: Retrospective review of 315 eyes of 282 patients who underwent 23-gauge or 25-gauge pars plana vitrectomy with bimanual membrane dissection for diabetic tractional detachment from January 2007 to September 2016. Minimum follow-up was 3 months, and the average duration of follow-up was 23 months (range 3-100 months; median 15 months). Outcome measures were best-corrected visual acuity, anatomical success, and postoperative complications. RESULTS: Postoperatively, 84.3% of eyes improved (>2 lines), 10.5% were stable, and 5.4% worsened (>2 lines). Comparing gauges, two-line improvement was seen in 87.4% of 23-gauge eyes compared with 79.7% of 25-gauge eyes (P = 0.029). Mean peak best-corrected visual acuity improved from 20/930 (1.67 +/- 0.63) preoperatively to 20/120 (0.78 +/- 0.63) postoperatively (P < 0.001). Primary reattachment was achieved in 310 eyes (98.4%) and final reattachment in 312 eyes (99%). Recurrent vitreous hemorrhage was the commonest postoperative complication (18.4%). Lower incidence of recurrent vitreous hemorrhage was seen with 25 gauge (13.5%) compared with 23 gauge (22%, P = 0.038). Epiretinal membrane formation (7.9%), intractable glaucoma (2.5%), and endophthalmitis (0.6%) were some of the other postoperative complications. CONCLUSION: Sustained visual improvement, anatomical restoration, and low complication rates were obtained in complex situations with bimanual microincision vitreous surgery in a large series. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula, and eyes with extensive membranes and with silicone oil as tamponade. Both 23-gauge and 25 gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative and postoperative complications. PMID- 29406471 TI - Life-Threatening Accidental Intravenous Epinephrine Overdose in a 12-Year-Old Boy. AB - Reports on accidental intravenous epinephrine overdose in children are extremely rare, although medication errors in the management of pediatric anaphylaxis seem to be frequent. We report a case of a 12-year-old boy presenting with a long lasting skin rash and dyspnea who was incorrectly diagnosed with early anaphylactic shock and was treated with 10-fold the recommended dose administered by the wrong route (intravenous instead of intramuscular). He reacted with acute loss of consciousness and acute cardiorespiratory failure due to arterial hypotension, ischemic heart failure, and severe pulmonary edema. He responded rapidly to mechanical ventilation, treatment with diuretics, and low-dose inotropes and recovered without sequelae. Despite this ultimately favorable outcome, we report this case to remind the scientific community that inadvertent and accidental epinephrine overdosing is probably an underrecognized event, which can result in potentially lethal complications. Heightening the awareness of the personnel, implementing safety precautions for the dosage and the route of administration, stocking of prefilled intramuscular dose syringes for emergency use in anaphylaxis and, ideally, introducing a standardized drug order form should reduce potential risks and facilitate proper and optimal treatment for all acutely ill children. PMID- 29406472 TI - Novel Approach to Emergency Departments' Pediatric Readiness Across a Health System. AB - STUDY OBJECTIVE: A gap analysis of emergency departments' (EDs') pediatric readiness across a health system was performed after the appointment of a service line health system pediatric emergency medicine (PEM) quality director. METHODS: A 55-question survey was completed by each eligible ED to generate a weighted pediatric readiness score (WPRS). The survey included questions regarding volume, ED configuration, presence of a pediatric emergency care coordinator (PECC), quality initiatives, policies and procedures, and equipment. Surveys were completed from June 1 to November 12, 2016.Analysis of variance was used to compare the 4 groups of EDs based upon their annual pediatric volume as a continuous measure (low, <1800 visits; medium, 1800-4999 visits; medium-high, 5000-9999 visits; high, >10,000 visits). The Fisher exact test was used to compare the 4 groups for the remaining categorical variables represented as frequencies and percentages. A result was considered statistically significant at the P < 0.05 level of significance. RESULTS: There were a total of 16 hospitals (after the exclusion of the children's hospital, the hub for pediatric care in the health system, and 1 adult-only hospital) with the following pediatric capability: 7 basic (no inpatient pediatrics), 7 general (inpatient pediatrics, with/without a neonatal intensive care unit), and 2 comprehensive (inpatient pediatrics, pediatric intensive care unit, and a neonatal intensive care unit). In 12 EDs, adults and children are treated in the same space. These EDs see a total of 800,000 annual visits including 120,000 pediatric visits. Two low pediatric volume EDs had a median WPRS of 69, range of 62 to 76 (national median, 61.4); 6 medium pediatric volume EDs had a median WPRS of 51, range of 42 to 81 (national median, 69.3); 4 medium-high pediatric volume EDs had a median WPRS of 69.3, range of 45 to 98 (national medium, 74.8); 4 high pediatric volume EDs had a WPRS score of 84.5, range of 58 to 100 (national medium, 89.8). There were 4 sites with PECCs: 1 medium-high volume and 3 high volume, with a median WPRS of 98.5, range of 81 to 100 (national medium, 89.8). Two low-volume EDs have Neonatal Resuscitation Program training for nurses (P < 0.0083). One medium-high volume ED requires specific pediatric competency evaluations for advanced level practitioners staffing the ED. Pediatric-specific quality programs are present in the 2 low volume EDs, 3 of the 6 EDs in the medium group, 3 of 4 EDs in the medium-high group, and all 4 high volume hospitals. After the implementation of the health system PEM quality director, all EDs have a doctor and nurse PECC with a median WPRS of 81. In additiona, a committee was formed with the following key stakeholders: PECCs, pediatric nursing educators, pediatric quality, pharmacy, obstetrics, behavioral health, and neonatology. The committee is part of the health system quality program within both pediatrics and emergency medicine and is spearheading the standardization of code carts and medications, dissemination of pediatric clinical guidelines, and the development of a pediatric quality program across the health system. CONCLUSIONS: Pediatric emergency care coordinators play an important role in ED readiness to care for pediatric patients. In a large health system, a service line PEM quality director with the support of emergency medicine and pediatrics, a committee with solid frontline ED base, and a diverse array of stakeholders can foster the engagement of all EDs and improve compliance with published guidelines. PMID- 29406473 TI - Characteristics of Pediatric Patient Transferred From Hospital-Based General Emergency Departments to Acute-Care Facilities: An Analysis of the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample. AB - STUDY OBJECTIVE: The objective of this study was to analyze the characteristics of pediatric patients transferred from a hospital-based general emergency department (ED) to an acute care facility. METHODS: Study data were abstracted from the 2010 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample database. A multivariate logistic regression was constructed for pediatric patients (<18 years old) who require a transfer to an acute care facility from a general ED. Independent variables included in the model were age (<1, 1-4, 5-9, 10-14, 15-17 age in years), sex, insurance/payment method, and diseases/body systems using International Classification of Diseases, Ninth Revision, coding. RESULTS: In the Healthcare Cost and Utilization Project/Nationwide Emergency Department Sample, 5.5 million ED visits were for children less than 18 years. About 1.5% of visits resulted in transfer. Children younger than 1 year had higher transfer rates as compared with 15 to 17 year old group (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.089-1.146). Patients with Medicaid and self-pay compared with private insurance/health maintenance organization had 4% (OR, 0.96; 95% CI, 0.944-0.976) and 9% (OR, 0.91; 95% CI, 0.886-0.945), respectively, lower likelihood of being transferred. Patients with circulatory (OR, 8.43; 95% CI, 7.8-9.1), endocrine (OR, 5.9; 95% CI, 5.6-6.2), mental (OR, 5.44; 95% CI, 5.3-5.6), nervous system (OR, 5.2; 95% CI, 4.9-5.5), congenital anomalies (OR, 5.14; 95% CI, 4.5-5.9), hematology oncology (OR, 4.49; 95% CI, 4.2-4.8), digestive, (OR, 1.52; 95% CI, 1.5-1.6), and other disorders (OR, 1.33; 95% CI, 1.3-1.4) had a higher odds of being transferred as compared with trauma/injury and poisoning, whereas patients with disorders related to genitourinary (OR, 0.96; 95% CI, 0.91-1.0), respiratory (OR, 0.79; 95% CI, 0.77-0.81), musculoskeletal (OR, 0.63; 95% CI, 0.58-0.68), skin (OR, 0.47; 95% CI, 0.45-0.50), infectious and parasitic (OR, 0.23; 95% CI, 0.22 0.25), and eyes/ears/nose/throat (OR, 0.09; 95% CI, 0.079-0.094) had a lower odds of being transferred as compared with trauma/injury and poisoning. CONCLUSIONS: Children younger than 1 year had relatively higher transfer rates. Patients covered by Medicaid and self-pay had the lowest likelihood of transfer. Transfer rates varied significantly by condition and the high-transfer diagnostic categories were related to circulatory, endocrine, nervous, hematology-oncology, and mental disorders as well as congenital anomalies, which may be related to a lack of ED or inpatient resources to care for children with problems that require more complex care. PMID- 29406474 TI - Childhood Drowning: Review of Patients Presenting to the Emergency Departments of 2 Large Tertiary Care Pediatric Hospitals Near and Distant From the Sea Coast. AB - OBJECTIVE: Drowning is a leading cause of death among infants and toddlers. Unique physiological and behavioral factors contribute to high mortality rates. Drowning incidents predominantly occur during warmer months and holidays. The aim of this study was to describe the characteristics of pediatric drowning victims who attended 2 different emergency departments (EDs), 1 near and 1 distant from the sea coast, to recognize risk factors, complications, causes of death, and the educational needs of families and caregivers. METHODS: Retrospective cohort analysis of incident history, clinical presentation, treatments, and outcomes of drowning victims was performed. Data were analyzed both by age group and proximity of institution to the sea coast. RESULTS: From 2005 to 2015, 70 drowning patients presented to the 2 institutions; there was no difference in incident history or outcomes based on proximity to the sea coast. Fifty-six percent of patients were younger than 6 years, the majority drowning in pools. More of the older children drowned in the sea (48% vs 23%). Half of all patients were treated and followed in the ED or ward, and the other half were treated in the pediatric intensive care unit; 12 suffered severe complications, including 5 diagnosed with brain death. Cardiopulmonary resuscitation was performed in 80% of the fatal group and 23% of the nonfatal group (P = 0.006). Seven children who experienced a cardiac arrest with hypothermia were treated before arrival in the ED, and 5 had ongoing cardiac arrest upon arrival in the ED (these were the 5 suffering brain death). DISCUSSION: Most of patients younger than 6 years drowned in swimming pools, suggesting that parents are perhaps less vigilant in these circumstances, even though they may remain in close proximity. Active adult supervision entails attention, proximity, and continuity. Educational efforts should be aimed at reminding parents of this, especially in the summer months. PMID- 29406475 TI - Pediatric Emergency Provider Sexually Transmitted Infection Screening Practices in Adolescents With Oropharyngeal or Anorectal Chief Complaints. AB - OBJECTIVES: Sexually transmitted infections (STIs) may present with oropharyngeal or anorectal symptoms. Little is known about the evaluation of adolescents with these complaints in the pediatric emergency department (PED). This study aimed to determine the frequency of and factors associated with STI consideration and testing in this population. METHODS: Retrospective chart review of patients aged 13 to 18 years who presented to an urban PED with oropharyngeal or anorectal chief complaints between June 2014 and May 2015. Sexually transmitted infection consideration was defined as sexual history documentation, documentation of STI in differential diagnosis, and/or diagnostic testing. Multivariate logistic regression models were used to identify factors associated with consideration. RESULTS: Of 767 visits for oropharyngeal (89.4%), anorectal (10.4%), or both complaints, 153 (19.9%) had STI consideration. Of the 35 visits (4.6%) that included gonorrhea and/or chlamydia testing, 12 (34.3%) included testing at the anatomic site of complaint. Of those 12 tests, 50.0% were the incorrect test. Patients with older age (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI] = 1.3-1.7), female sex (aOR = 1.6, 95% CI = 1.03-2.5), or anorectal complaints (aOR = 2.4, 95% CI = 1.3-4.3) were more likely to have STI consideration. CONCLUSIONS: In an urban PED, only 20% of visits for adolescents with oropharyngeal or anorectal symptoms included STI consideration. Testing was performed in only 5% of cases and often at an inappropriate anatomic site or with the incorrect test. Interventions to increase awareness of appropriate STI consideration and testing for individuals presenting with possible extragenital complaints may help reduce STIs among adolescents. PMID- 29406477 TI - Intoxication From Accidental Marijuana Ingestion in Pediatric Patients: What May Lie Ahead. AB - Marijuana is the most commonly used illicit drug. In young children, there are relatively few reports in the literature of acute marijuana intoxication. Here, we describe the case of a previously healthy 2-year-old girl who presented with clinical seizures. A urine toxicology screen showed elevated levels of tetrahydrocannabinol. The source of the drug was not identified. After a short stay in the hospital, the patient fully recovered with only supportive measures. In this report, we also summarize all domestic and international cases of marijuana intoxication in children younger than 6 years, in conjunction with the number of exposures in children of similar age identified by the US National Poison Data System. This report highlights what is becoming a more common problem. As cannabis continues to be decriminalized across the United States with its increasingly diverse modes of delivery, the potential for accidental exposure in infants and young children also rises. Clinicians should now routinely consider marijuana intoxication in children who present with acute neurological abnormalities. PMID- 29406476 TI - Intravenous Thrombolysis at 3.5 Hours From Onset of Pediatric Acute Ischemic Stroke. AB - Acute thrombolysis has a proven benefit for adults presenting with acute ischemic stroke, but data within the pediatric population are extremely limited. We report the case of a 14-year-old girl who presented with right-sided weakness and ataxia, loss of sensation, and altered mental status. Magnetic resonance imaging with diffusion-weighted imaging showed an acute lesion in the distribution of the left posterior cerebral artery, and magnetic resonance angiogram demonstrated occlusion of the third branch of the left posterior cerebral artery. With parental consent, clinicians decided to infuse an adult dose of weight-adjusted intravenous alteplase at 3.5 hours from onset of symptoms, with subsequent improvement in National Institutes of Health Stroke Scale score from 11 to 3. Computed tomography angiogram at 24 hours showed recanalization of the occluded vessel with no evidence of intracranial hemorrhage. Stroke Scale score at discharge was 3, with modified Rankin Scale scores at discharge of 1 and at 90 days of 0. This case highlights the importance of magnetic resonance imaging in diagnosing pediatric acute ischemic stroke and suggests consideration of thrombolysis in select confirmed pediatric stroke cases. However, a rigorous evidence base is lacking, and clinical trials have not been successful in recruiting patients. PMID- 29406478 TI - The Use of Chest Computed Tomographic Angiography in Blunt Trauma Pediatric Population. AB - INTRODUCTION: Blunt chest trauma in children is common. Although rare, associated major thoracic vascular injuries (TVIs) are lethal potential sequelae of these mechanisms. The preferred study for definitive diagnosis of TVI in stable patients is computed tomographic angiography imaging of the chest. This imaging modality is, however, associated with high doses of ionizing radiation that represent significant carcinogenic risk for pediatric patients. The aim of the present investigation was to define the incidence of TVI among blunt pediatric trauma patients in an effort to better elucidate the usefulness of computed tomographic angiography use in this population. METHODS: A retrospective cohort study was conducted including all blunt pediatric (age < 14 y) trauma victims registered in Israeli National Trauma Registry maintained by Gertner Institute for Epidemiology and Health Policy Research between the years 1997 and 2015. Data collected included age, sex, mechanism of injury, Glasgow Coma Scale, Injury Severity Score, and incidence of chest named vessel injuries. Statistical analysis was performed using SAS statistical software version 9.2 (SAS Institute Inc, Cary, NC). RESULTS: Among 433,325 blunt trauma victims, 119,821patients were younger than 14 years. Twelve (0.0001%, 12/119821) of these children were diagnosed with TVI. The most common mechanism in this group was pedestrian hit by a car. Mortality was 41.7% (5/12). CONCLUSIONS: Thoracic vascular injury is exceptionally rare among pediatric blunt trauma victims but does contribute to the high morbidity and mortality seen with blunt chest trauma. Computed tomographic angiography, with its associated radiation exposure risk, should not be used as a standard tool after trauma in injured children. Clinical protocols are needed in this population to minimize radiation risk while allowing prompt identification of life-threatening injuries. PMID- 29406479 TI - Application of the Rochester Criteria to Identify Febrile Infants With Bacteremia and Meningitis. AB - OBJECTIVES: The Rochester criteria were developed to identify febrile infants aged 60 days or younger at low-risk of bacterial infection and do not include cerebrospinal fluid (CSF) testing. Prior studies have not specifically assessed criteria performance for bacteremia and bacterial meningitis (invasive bacterial infection). Our objective was to determine the sensitivity of the Rochester criteria for detection of invasive bacterial infection. METHODS: Retrospective cohort study of febrile infants aged 60 days or younger with invasive bacterial infections evaluated at 8 pediatric emergency departments from July 1, 2012, to June 30, 2014. Potential cases were identified from the Pediatric Health Information System using International Classification of Diseases, Ninth Revision diagnosis codes for bacteremia, meningitis, urinary tract infection, and fever. Medical record review was then performed to confirm presence of an invasive bacterial infection and to evaluate the Rochester criteria: medical history, symptoms or ill appearance, results of urinalysis, complete blood count, CSF testing (if obtained), and blood, urine, and CSF culture. An invasive bacterial infection was defined as growth of pathogenic bacteria from blood or CSF culture. RESULTS: Among 82 febrile infants aged 60 days or younger with invasive bacterial infection, the sensitivity of the Rochester criteria were 92.7% (95% confidence interval [CI], 84.9%-96.6%) overall, 91.7% (95% CI, 80.5%-96.7%) for neonates 28 days or younger, and 94.1% (95% CI, 80.9%-98.4%) for infants aged 29 to 60 days old. Six infants with bacteremia, including 1 neonate with bacterial meningitis, met low-risk criteria. CONCLUSIONS: The Rochester criteria identified 92% of infants aged 60 days or younger with invasive bacterial infection. However, 1 neonate 28 days or younger with meningitis was classified as low-risk. PMID- 29406480 TI - Evaluation of Predictors of Mortality Associated With Childhood Heart Failure in Nigeria: A 2-Center Study. AB - OBJECTIVE: The aim of this study was to evaluate the predictors of mortality in childhood heart failure (HF) in 2 tertiary hospitals. METHODS: A 51-month retrospective review of case notes of children with HF admitted into children's emergency rooms of 2 tertiary centers in Southern Nigeria was done. Bio-data and certain sociodemographic variables including mortality were abstracted. Bivariate and multivariate analyses were done to evaluate the predictors of mortality in HF. RESULTS: The case notes of 289 children were analyzed, consisting of 153 males (52.9%) and 142 infants (49.1%). Lower respiratory tract infections, 121 (41.9%), were the commonest causes of HF. Twenty-eight children (9.7%) died. In multivariate analyses, only late presentation (P < 0.0001) was an independent predictor of mortality in HF. CONCLUSION: Education of the populace about early presentation to hospital is imperative to prevent unnecessary deaths associated with HF. PMID- 29406481 TI - Precise isometric hand grip learning of hemiparetic stroke patients. AB - Rehabilitation of hand movements after stroke aims at skills that can be well retained and transferred to novel conditions. These functions may be altered by training schedules such as constant and variable practice. A total of 36 participants with hemiparesis completed one of these schedules counterbalanced. Precise isometric hand grip force production was practiced for 4 days with a target force of 25% maximum voluntary contraction. The constant group practiced only the target force, whereas the variable group practiced the same amount including +/-5 and 10% maximum voluntary contraction. Target force presentation and feedback were provided visually. Results indicated that both practice schedule led to learning. Variable practice resulted in a superior performance in retention and transfer tests, suggesting that it may be effective not only in the healthy population but also in stroke rehabilitation. PMID- 29406483 TI - Reconstruction of Large Nasal Dorsum Defects. PMID- 29406482 TI - Randomized, Double-Blinded, Sham-Controlled, Split-Hand Trial Evaluating the Safety and Efficacy of Triamcinolone Acetate Injection After Calcium Hydroxylapatite Volume Restoration of the Dorsal Hand. AB - BACKGROUND: Calcium hydroxylapatite (CaHA) is currently the only FDA-approved soft-tissue filler indicated for augmentation of the dorsal hand. Although the treatment is generally safe and effective, adverse side effects such as swelling and edema postinjection are common and can sometimes be debilitating. OBJECTIVE: In this study, the authors explore the utility of triamcinolone acetate coinjection with CaHA to the dorsal hands to mitigate adverse effects and improve patient experience. PATIENTS AND METHODS: After obtaining informed consent, 20 subjects were enrolled in this double-blind, randomized, split-hand, sham controlled clinical trial. Subject hands were randomized to receive either CaHA with triamcinolone acetate or CaHA with sham saline coinjection. Follow-up evaluations were performed by a blinded investigator at Days 7, 14, 30, 90, 180, 270, and 360 and consisted of the validated Merz Hand Grading Scale and assessments of erythema, edema, modules, bruising, and skin atrophy. Subjects also kept a daily diary for the first 30 days postinjection documenting bruising, itching, pain, redness, swelling, difficulty in performing activities with hands, and sensory alteration in hands. RESULTS: There were no significant differences in treatment efficacy between the 2 groups. Post-treatment swelling was significantly reduced between Days 6 and 19 in the triamcinolone acetate coinjection group. CONCLUSION: The addition of triamcinolone acetate coinjection with CaHA for dorsal hand augmentation did not negatively impact treatment efficacy but significantly reduced adverse side effects. This strategy represents a safe and effective way to improve patient experience and treatment tolerability. PMID- 29406484 TI - Psoriasis Postlaser Hair Removal: A Rare Occurrence. PMID- 29406485 TI - A Perineurioma Treated With Mohs Micrographic Surgery. PMID- 29406486 TI - Web App- and Text Message-Based Patient Education in Mohs Micrographic Surgery-A Randomized Controlled Trial. AB - BACKGROUND: Consent and wound care (WC) videos are used for education in Mohs micrographic surgery (MMS). Postoperative text messaging is poorly studied. OBJECTIVE: Develop and evaluate perioperative resources for MMS patients-video modules (DermPatientEd.com) and postoperative text messaging (DermTexts.com). MATERIALS AND METHODS: A study was conducted on 90 MMS patients. Patients were randomized 1:1:1:1 to videos with text messages, videos-only, text messages-only, or control. Primary outcomes included preoperative anxiety and knowledge of MMS and postoperative care. The secondary outcome included helpfulness/preference of interventions. RESULTS: Patients experienced a 19% reduction in anxiety as measured by a visual analog scale after the MMS video (p = .00062). There was no difference in knowledge after the WC video (p = .21498). Patients were more likely to report the WC video "very helpful" when compared with the pamphlet in understanding postoperative WC (p = .0016). Patients in text messaging groups were not more likely to report the service as "very helpful" when compared with the pamphlet (p = .3566), but preferred to receive WC instructions by text message for future visits (p = .0001). CONCLUSION: These resources proved helpful and effective in reducing preoperative anxiety. Patients prefer text message based WC instructions over pamphlets after experiencing the service, but do not find them more helpful. PMID- 29406487 TI - Novel Technique for Retention of Cell Suspension in Melanocyte-Keratinocyte Transplantation Procedure Using Glued Nylon Suture or Mesh. PMID- 29406488 TI - Ectopic Extramammary Paget Disease Occurring on the Nose. PMID- 29406489 TI - Congenital Unilateral Lower Lip Palsy With Concurrent Hypoplasia of the Platysma Muscle. PMID- 29406490 TI - Senior Commentary to "Long-Term Follow-Up Results of Topical Imiquimod Treatment in Basal Cell Carcinoma". PMID- 29406491 TI - Prolonged Inflammatory Reaction After Fractional Radiofrequency Microneedle Treatment. PMID- 29406492 TI - Determining the Most Likely Source of Infection: An Application to Neisseria Gonorrhoeae Among Men Who Have Sex with Men. AB - BACKGROUND: The source of an infection is often unknown. To inform directed prevention measures, it is useful to know the location and partner type with the highest transmission risk. We developed a method to estimate infection risk of Neisseria gonorrhoeae per meeting location among men who have sex with men (MSM). METHODS: In 2008-2009, we collected information from 2,438 MSM attending the sexually transmitted infections clinic of Amsterdam. For up to four partners per participant (8,028 in total), we asked for details on meeting location, partner, and partnership characteristics. We used logistic regression to relate these to the participant's infection risk, accounting for unobserved transmission information in the likelihood. Based on the model estimates, we predicted the probability of a partner having N. gonorrhoeae. The probability that a partner was the source was proportional to his predicted infection risk. Each source was linked to the meeting location. We used a Bayesian method. RESULTS: Rectal N. gonorrhoeae was diagnosed in 157 MSM who reported data on 422 possible source partners, urethral N. gonorrhoeae in 126 reporting 285 possible sources, and pharyngeal N. gonorrhoeae in 162 reporting 451 possible sources. We estimated that most infections were acquired from long-lasting steady partners (21%; 95% CI = 17, 24). Partners met in an Amsterdam street with gay venues posed the highest transmission risk (13%; 95% CI = 7.9, 18). CONCLUSIONS: The presented method estimates the source of infection when there are multiple possible sources and enables the summation over various kinds of epidemiologic characteristics (here, meeting locations) that are relevant for prevention. PMID- 29406493 TI - Putting a number on neoepitope quality. PMID- 29406495 TI - Spark's gene therapy price tag: $850,000. PMID- 29406494 TI - Approval of first tumor gene panel sends shockwaves through labs. PMID- 29406497 TI - Roche pays $1.7 billion to target tumors' genetic signatures. PMID- 29406498 TI - Around the world in a month. PMID- 29406499 TI - Gut bacteria link to immunotherapy sparks interest. PMID- 29406500 TI - Rationalizing governance of genetically modified products in developing countries. PMID- 29406501 TI - Recent patents in neoantigens and neoepitopes. PMID- 29406502 TI - US tax reform may jeopardize orphans. PMID- 29406503 TI - 2017-venture funding goes into overdrive. PMID- 29406505 TI - California voters and CIRM-will lightning strike twice? PMID- 29406507 TI - Corrigendum: Reproducing with DNA. PMID- 29406506 TI - Corrigendum: Assisted reproductive technologies to prevent human mitochondrial disease transmission. PMID- 29406509 TI - Drug pipeline: 4Q17. PMID- 29406508 TI - Tertiary patenting on drug-device combination products in the United States. PMID- 29406510 TI - PrePAIRing Cas9s for screening success. PMID- 29406512 TI - FDA warns public of dangers of DIY gene therapy. PMID- 29406511 TI - Making brain proteomics true to type. PMID- 29406513 TI - Erratum: Increasing the efficiency of homology-directed repair for CRISPR-Cas9 induced precise gene editing in mammalian cells. PMID- 29406515 TI - No research in Correspondence. PMID- 29406514 TI - An alternative proposal to the destruction of abandoned human embryos. PMID- 29406517 TI - A less than ideal Deal. PMID- 29406516 TI - Corrigendum: Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea. PMID- 29406518 TI - Gridded global datasets for Gross Domestic Product and Human Development Index over 1990-2015. AB - An increasing amount of high-resolution global spatial data are available, and used for various assessments. However, key economic and human development indicators are still mainly provided only at national level, and downscaled by users for gridded spatial analyses. Instead, it would be beneficial to adopt data for sub-national administrative units where available, supplemented by national data where necessary. To this end, we present gap-filled multiannual datasets in gridded form for Gross Domestic Product (GDP) and Human Development Index (HDI). To provide a consistent product over time and space, the sub-national data were only used indirectly, scaling the reported national value and thus, remaining representative of the official statistics. This resulted in annual gridded datasets for GDP per capita (PPP), total GDP (PPP), and HDI, for the whole world at 5 arc-min resolution for the 25-year period of 1990-2015. Additionally, total GDP (PPP) is provided with 30 arc-sec resolution for three time steps (1990, 2000, 2015). PMID- 29406520 TI - Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention. AB - This corrects the article DOI: 10.1038/ijo.2017.220. PMID- 29406519 TI - RNA-seq transcriptomic analysis of adult zebrafish inner ear hair cells. AB - Although hair cells are the sensory receptors of the auditory and vestibular systems in the ears of all vertebrates, hair cell properties are different between non-mammalian vertebrates and mammals. To understand the basic biological properties of hair cells from non-mammalian vertebrates, we examined the transcriptome of adult zebrafish auditory and vestibular hair cells. GFP-labeled hair cells were isolated from inner-ear sensory epithelia of a pou4f3 promoter driven GAP-GFP line of transgenic zebrafish. One thousand hair cells and 1,000 non-sensory surrounding cells (nsSCs) were separately collected for each biological replicate, using the suction pipette technique. RNA sequencing of three biological replicates for the two cell types was performed and analyzed. Comparisons between hair cells and nsSCs allow identification of enriched genes in hair cells, which may underlie hair cell specialization. Our dataset provides an extensive resource for understanding the molecular mechanisms underlying morphology, function, and pathology of adult zebrafish hair cells. It also establishes a framework for future characterization of genes expressed in hair cells and the study of hair cell evolution. PMID- 29406521 TI - Increasing low-energy-dense foods and decreasing high-energy-dense foods differently influence weight loss trial outcomes. AB - BACKGROUND/OBJECTIVE: Although reducing energy density (ED) enhances weight loss, it is unclear whether all dietary strategies that reduce ED are comparable, hindering effective ED guidelines for obesity treatment. This study examined how changes in number of low-energy-dense (LED) (<4.186 kJ/1.0 kcal g-1) and high energy-dense (HED) (>12.56 kJ/3.0 kcal g-1) foods consumed affected dietary ED and weight loss within an 18-month weight loss trial. METHODS: This secondary analysis examined data from participants randomized to an energy-restricted lifestyle intervention or lifestyle intervention plus limited non-nutrient dense, energy-dense food variety (n=183). Number of daily LED and HED foods consumed was calculated from three, 24-h dietary recalls and anthropometrics were measured at 0, 6 and 18 months. Multivariable-adjusted generalized linear models and repeated measures mixed linear models examined associations between 6-month changes in number of LED and HED foods and changes in ED, body mass index (BMI), and percent weight loss at 6 and 18 months. RESULTS: Among mostly female (58%), White (92%) participants aged 51.9 years following an energy-restricted diet, increasing number of LED foods or decreasing number of HED foods consumed was associated with 6- and 18-month reductions in ED (beta=-0.25 to -0.38 kJ g-1 (-0.06 to -0.09 kcal g-1), P<0.001). Only increasing number of LED foods consumed was associated with 6- and 18-month reductions in BMI (beta=-0.16 to -0.2 kg m-2, P<0.05) and 6 month reductions in percent weight loss (beta=-0.5%, P<0.05). Participants consuming ?2 HED foods per day and ?6.6 LED foods per day experienced better weight loss outcomes at 6- and 18-month than participants only consuming ?2 HED foods per day. CONCLUSION: Despite similar reductions in ED from reducing number of HED foods or increasing number of LED foods consumed, only increasing number of LED foods related to weight loss. This provides preliminary evidence that methods used to reduce dietary ED may differentially influence weight loss trajectories. Randomized controlled trials are needed to inform ED recommendations for weight loss. PMID- 29406522 TI - Hemiparkinsonism after unilateral traumatic midbrain hemorrhage in a young woman. AB - The relationship between head trauma and parkinsonism has been debated since James Parkinson's first description of the shaking palsy in the late 19th century. We observed in our outpatient clinic a young woman in whom hemiparkinsonism developed within 3 weeks of sustaining closed head trauma with loss of consciousness. The patient had a discrete unilateral midbrain hemorrhage on head MRI which involved the contralateral substantia nigra. The condition responded well to carbidopa/levodopa. This patient is a convincing example of posttraumatic midbrain hemorrhage causing parkinsonism. PMID- 29406523 TI - Surgical cystotomy for refractory diabetic cystoid macular edema. PMID- 29406525 TI - Championing advocacy: Changes start with us. PMID- 29406524 TI - Formularies, costs, and quality of care: Limiting formularies is not harmful to patients. PMID- 29406526 TI - Supreme Court decision on the Affordable Care Act: What does it mean for neurology? AB - In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act (the Act or ACA), which is felt to be the most comprehensive reform to health care in the United States since the enactment of Medicare/Medicaid in 1965. Nothing this big happens overnight and without controversy. Numerous concerns were raised from all demographics and from both sides of the political aisle. Some of the concerns were legal questions regarding constitutionality and so legal processes began to address this issue. In June 2012, the Supreme Court decided in a 5-4 vote that the Act is constitutional. This has allowed the legislation to stand and over the next few years the more transforming parts will start to be implemented. It is important to understand the issues surrounding the Supreme Court decision and the impact this may have on health care and specifically the practice of neurology. PMID- 29406527 TI - Improving medical students' participation in research. PMID- 29406528 TI - Corrigendum: Taheebo Polyphenols Attenuate FFA-Induced Inflammation in Murine and Human Macrophage Cell Lines As Inhibitor of COX-2. AB - [This corrects the article on p. 63 in vol. 4, PMID: 29312947.]. PMID- 29406529 TI - Mobile medical applications in neurology. AB - Smartphone or mobile applications (apps) are increasingly used in clinical practice. Apps have evolved from electronic pocket references to interactive utilities, ranging from dynamic visual references, interactive and analytic clinical tools, remote desktops, and scheduling and communication platforms. Additionally, apps designed for patient monitoring, advising, data collection, and documentation are useful for clinicians, researchers, and patients. This report aims to provide an introduction to several valuable mobile apps for neurologists and students of neurology. PMID- 29406530 TI - Alternative devices for obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a relatively common condition which is most often treated with continuous positive airway pressure (CPAP). Given the compliance issues associated with CPAP, it is important for neurologists (and anyone who treats OSA) to be aware of what other treatment devices exist for this disease. This article reviews mandibular advancement devices, nasal expiratory airway pressure devices, hypoglossal nerve stimulators, and oral pressure therapy devices in terms of their mechanism of action, efficacy, and practicality. PMID- 29406531 TI - Neurology and the military: Five new things. AB - The current Iraq and Afghanistan conflicts have seen the highest survival rates in US service members ever, despite staggering numbers of traumatic brain injury and limb loss cases. The improvement in survival can be attributed at least in part to advances in far-forward, rapid medical treatment, including the administration of hypertonic saline solutions and decompressive craniectomies to manage elevated intracranial pressure. After evacuation to military hospitals in the continental United States, service members who have had limb loss face extensive rehabilitation. The growing amputee population has led to a burgeoning interest in the treatment of phantom limb pain and in the development of advanced prostheses. PMID- 29406532 TI - Artificial pearls in the brain. PMID- 29406533 TI - Topographic disorientation following mesial left temporo-occipital hemorrhage. PMID- 29406534 TI - Erratum: Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab [Corrigendum]. AB - [This corrects the article on p. 2751 in vol. 10, PMID: 29263689.]. PMID- 29406535 TI - EMG/NCS in the evaluation of spine trauma with radicular symptoms. AB - In the management of spine trauma with radicular symptoms (STRS), EMG/nerve conduction studies (NCS) often have low combined sensitivity and specificity in confirming root injury. The anatomic level of injury may not correspond to the root level. Paraspinal studies are nonlocalizing and can be falsely positive and negative. Unlike MRI and CT imaging, EMG/NCS do not reveal the biological morphology of the lesion. There are no studies that confirm the efficacy of EMG/NCS in the management of STRS. EMG/NCS may be indicated if there is a differential diagnosis between a root and distal neuropathic/myopathic lesion. Otherwise, as shown in this series of cases typically referred for outpatient EMG/NCS testing, there is limited evidence to support the use of often uncomfortable and costly EMG/NCS in STRS. PMID- 29406536 TI - The man with hemi-cape dysesthesias. PMID- 29406537 TI - Seeking practical advice. PMID- 29406538 TI - Corrigendum: Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant. AB - [This corrects the article on p. 1687 in vol. 8, PMID: 29259604.]. PMID- 29406539 TI - Corrigendum: Heparan Sulfate: A Potential Candidate for the Development of Biomimetic Immunomodulatory Membranes. AB - [This corrects the article on p. 54 in vol. 5, PMID: 28983481.]. PMID- 29406540 TI - Corrigendum: Quantifying the Beauty of Words: A Neurocognitive Poetics Perspective. AB - [This corrects the article on p. 622 in vol. 11, PMID: 29311877.]. PMID- 29406541 TI - On the mechanism of rapid metal exchange between thiolate-protected gold and gold/silver clusters: a time-resolved in situ XAFS study. AB - The fast metal exchange reaction between Au38 and AgxAu38-x nanoclusters in solution at -20 degrees C has been studied by in situ X-ray absorption spectroscopy (time resolved quick XAFS) in transmission mode. A cell was designed for this purpose consisting of a cooling system, remote injection and mixing devices. The capability of the set-up is demonstrated for second and minute time scale measurements of the metal exchange reaction upon mixing Au38/toluene and AgxAu38-x/toluene solutions at both Ag K-edge and Au L3-edge. It has been proposed that the exchange of gold and silver atoms between the clusters occurs via the SR(-M-SR)n (n = 1, 2; M = Au, Ag) staple units in the surface of the reacting clusters during their collision. However, at no point during the reaction (before, during, after) evidence is found for cationic silver atoms within the staples. This means that either the exchange occurs directly between the cores of the involved clusters or the residence time of the silver atoms in the staples is very short in a mechanism involving the metal exchange within the staples. PMID- 29406543 TI - Organocatalytic asymmetric synthesis of benzazepinoindole derivatives with trifluoromethylated quaternary stereocenters by chiral phosphoric acid catalysts. AB - An enantioselective aza-Friedel-Crafts reaction of trifluoromethyl dihydrobenzoazepinoindoles with pyrroles catalyzed by a chiral spirocyclic phosphoric acid was developed. This methodology provides a facile route to CF3- and pyrrole-containing benzazepinoindoles bearing quaternary stereocenters in good yields and with moderate to excellent enantioselectivities (up to 93% ee). Indoles were also investigated as electron-rich aromatic substrates to afford the corresponding chiral heterocycles with good yields and considerable enantioselectivities. The introduction of CF3 shows a remarkable fluorine effect and increases the activation and stereoinduction. PMID- 29406542 TI - Protein-engineered hydrogels enhance the survival of induced pluripotent stem cell-derived endothelial cells for treatment of peripheral arterial disease. AB - A key feature of peripheral arterial disease (PAD) is damage to endothelial cells (ECs), resulting in lower limb pain and restricted blood flow. Recent preclinical studies demonstrate that the transplantation of ECs via direct injection into the affected limb can result in significantly improved blood circulation. Unfortunately, the clinical application of this therapy has been limited by low cell viability and poor cell function. To address these limitations we have developed an injectable, recombinant hydrogel, termed SHIELD (Shear-thinning Hydrogel for Injectable Encapsulation and Long-term Delivery) for cell transplantation. SHIELD provides mechanical protection from cell membrane damage during syringe flow. Additionally, secondary in situ crosslinking provides a reinforcing network to improve cell retention, thereby augmenting the therapeutic benefit of cell therapy. In this study, we demonstrate the improved acute viability of human induced pluripotent stem cell-derived endothelial cells (iPSC ECs) following syringe injection delivery in SHIELD, compared to saline. Using a murine hind limb ischemia model of PAD, we demonstrate enhanced iPSC-EC retention in vivo and improved neovascularization of the ischemic limb based on arteriogenesis following transplantation of iPSC-ECs delivered in SHIELD. PMID- 29406544 TI - Correction: The applicability of proton transfer reaction-mass spectrometry (PTR MS) for determination of isocyanic acid (ICA) in work room atmospheres. AB - Correction for 'The applicability of proton transfer reaction-mass spectrometry (PTR-MS) for determination of isocyanic acid (ICA) in work room atmospheres' by Mikolaj Jan Jankowski et al., Environ. Sci.: Processes Impacts, 2014, 16, 2423 2431. PMID- 29406545 TI - A double-click approach to the protecting group free synthesis of glycoconjugates. AB - The use of a bi-functional linker, containing an alkyne and an alkene, allows the protecting group free conjugation of reducing sugars to thiols via a double click process. Firstly the linker is attached to the sugar via one-pot glycosyl azide formation and Cu-catalysed azide-alkyne cycloaddition. Photochemical thiol-ene click reaction then allows conjugation to a range of thiols, including cysteine residues of peptides. PMID- 29406546 TI - One-step chemical vapor deposition of MoS2 nanosheets on SiNWs as photocathodes for efficient and stable solar-driven hydrogen production. AB - Silicon nanowires (SiNWs) are widely used as photocathodes because of their large electrochemically available surface-area density and inherent ability to decouple light absorption from the transport of minority carriers. In order to minimize overpotential for solar-driven hydrogen (H2) production, a combination of an ultrathin molybdenum disulfide (MoS2) layer with SiNWs as photocathode has attracted much attention. Herein, for the first time, this study presents the synthesis of a composite photocathode via direct growth of ultrathin MoS2 nanosheets on SiNWs (referred to as SiNWs/MoS2) by one-step chemical vapor deposition (CVD). Due to the high surface-area density of the arrays of SiNWs, the discontinuous MoS2 nanosheets grown on the SiNWs achieved a much higher density of active sites. Moreover, the coating of MoS2 on the SiNWs was found to protect the photocathode during the photoelectrochemical (PEC) reaction. A high efficiency with photocurrent jsc of 16.5 mA cm-2 (at 0 V vs. reversible hydrogen electrode) and an excellent stability over 48 h of PEC operation were achieved under a simulated 1 sun irradiation. PMID- 29406547 TI - The effect of vitamin C and iron on dopamine-mediated free radical generation: implications to Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. The oxidative stress and DA derived quinones have been proposed to be closely related to the progression of PD. To examine the possibility of the application of ascorbate (Asc) as a therapeutic strategy in PD, the effect of Asc on the fate of iron both in the absence and presence of DA was investigated. The results of this study indicate that, in the absence of iron, the presence of high concentrations of Asc is of great benefit in view of the alleviation in oxidative stress and formation of DA derived quinones by quenching radicals, such as O2- and DA-. As a well-known reductant, the presence of high concentrations of Asc in iron enriched solution results in elevation in the concentration of active Fe(ii), which poses a potential threat to health as a result of inefficient oxygenation. While a competition exists between Asc and DA, the higher affinity of DA towards iron coupled with the formation of the more stable FeIIIDA2 complex renders Asc unlikely to reduce the DA bound iron. The results of this study suggest that while the application of Asc alone may aggravate the progression of PD in view of the possible peroxidation of Asc bound Fe(ii), a combination therapy of Asc and strong clinically used iron chelator would appear to be a promising direction for the treatment of PD as a result of the enhanced iron chelation and attenuation in oxidative stress and toxicity induced by DA derived quinones. PMID- 29406548 TI - A liquid crystalline precursor incorporating chlorhexidine acetate and silver nanoparticles for root canal disinfection. AB - Lyotropic liquid crystals (LLC) have received increasing attention as a drug delivery system. In this study, a novel intra-canal disinfectant based on the glycerol monooleate (GMO) LLC precursor incorporation with chlorhexidine (CHX) and silver nanoparticles (Ag-NPs) was designed and evaluated. The LLC precursor with excellent fluidity was able to penetrate deeply into the complex tiny collateral branch root canals. The transformation of cubic LLC in root canals upon coming into contact with water provided long-lasting disinfection against multidrug-resistant bacteria to avoid the endodontic reinfection and follow-up visits. The GMO-ethanol-water (48% : 12% : 40%, w/w) formulation containing 0.5% CHX and 0.02% Ag-NPs was selected for further studies. The low viscosity of the precursor presented excellent injectability and flowabilities. From the in vitro release test, the release behaviours were found to be influenced by CHX and Ag-NP contents, allowing the optimized precursor to obtain a 28-day release profile. The CHX-Ag-NP containing LLC precursor exhibited an excellent and sustained sterilization effect on Enterococcus faecalis for more than one month with a bacterial inactivation rate of >=98.5%, which was far more than the minimum clinical requirement (7 days). Furthermore, no in vitro toxicity was observed in the cytotoxicity evaluation. The CHX-Ag-NP containing LLC precursor was proved to be a promising intra-canal disinfectant in our study. PMID- 29406549 TI - Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration. AB - Peptide nanodrugs have been developed as promising antitumor chemotherapeutics because they partially overcome the drawbacks of free peptide drugs, but insufficient tumor penetration and interference of peptide function limit their further application. In this work, we have developed multifunctional peptide conjugated dendrimers for improving tumor penetration, cancer cell-specific peptide delivery and anticancer ability. The cytotoxic peptide KLAK, cell penetrating peptide TAT and matrix metalloproteinase 2 (MMP2)-sensitive peptide poly(ethylene glycol) (PEG) were conjugated onto dendrimers by one-pot synthesis to gain PKT-S-PEG. The enzyme-sensitive properties and incubation stability of the dendrimers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the cell viability, internalization pathway, mitochondria-regulated apoptosis and tumor penetration ability were measured by CCK-8 assay, lysosome colocalization, JC-1 assay and multicellular spheroid (MCS) experiments, respectively, in human primary glioblastoma (U87) cells. PKT-S-PEG showed significantly enhanced intracellular delivery performance, antitumor efficacy and deep tumor penetration capacity compared to a control non-MMP2 sensitive dendrimer PKT-C-PEG. The MMP2 overexpressing tumor microenvironment caused deprotection by removal of PEG, resulting in the decrease of particle size and exposure of KLAK and TAT, which enhanced tumor penetration, the entry of bioactive peptides into cells and subsequently the effective disruption of mitochondria. We believe that the peptide-dendrimer conjugate has potential for specific and effective delivery of peptide-based therapeutics into tumors. PMID- 29406550 TI - ? AB - Pupils in the 6th grade of compulsory schools (age 11-12 years) in representative municipalities in Sweden, participated in a study of cognitive capacity and "neurodevelopmental functioning" in relation to the new Swedish educational goals, set up by the National Agency for Education. Results from four subtests of the WISC-IV, the ESSENCE-Questionnaire, covering concerns regarding different developmental areas, information about educational support and about final subject grades were analysed. Of a total of 396 pupils, 229 (58%) agreed to participate. Pupils who had failed at least one subject had significantly lower cognitive test results and significantly more ESSENCE concerns, compared to those who passed in all subjects. In the group of pupils who had at least one failed subject, 89% had been given special educational support. The knowledge requirements in the new national curriculum need to be reviewed and adapted to these circumstances. PMID- 29406551 TI - ? PMID- 29406552 TI - ? PMID- 29406553 TI - ? PMID- 29406554 TI - ? PMID- 29406555 TI - ? AB - Trauma care at an accident site is of great importance for patient survival. The purpose of the study was to observe the compliance of ambulance nurses with the Prehospital Trauma Life Support (PHTLS) concept of trauma care in a simulation situation. The material consisted of video recordings in trauma simulation and an observation protocol was designed to analyze the video material. The result showed weaknesses in systematic exam and an ineffective use of time at the scene of injury. Development of observation protocols in trauma simulation can ensure the quality of ambulance nurses' compliance with established concepts. Our pilot study shows that insufficiencies in systematic care lead to an ineffective treatment for trauma patients which in turn may increase the risk of complications and mortality. PMID- 29406557 TI - ? PMID- 29406556 TI - ? PMID- 29406558 TI - ? PMID- 29406559 TI - ? AB - The purpose of this case report and discussion is to heighten the awareness of Lemierres syndrome (postanginal sepsis). Affected patients present in various fields of medicine and an increased incidence of "the forgotten disease" may be expected. Fusobacterium necrophorum is the most common pathogen. The clinical course includes a primary head or neck infection with thrombosis of the internal jugular vein with subsequent septic pulmonary embolization. The syndrome bears considerable morbidity and even mortality. People aged 15-25 years are commonly affected. Early diagnosis through positive blood culture and confirmation of jugular vein thrombosis combined with prompt antibiotic treatment and source control is mandatory in the management of Lemierre's syndrome. Assessment of vital organ function is recommended across the continuum of care as this facilitates recognition and initiation of therapeutic measures to counteract a complicated clinical course. PMID- 29406560 TI - ? AB - A new genetic test - expanded carrier screening Due to recent advances in molecular genetic testing, massive parallel sequencing has become possible at an affordable cost for health care. Thus, it is now possible to test healthy young persons for carriership of mutations in many genes for severe recessive genetic conditions - extended genetic carrier testing. The introduction of this test in Swedish health care must be accompanied by ethical considerations, education of stakeholders, health care staff and the public. PMID- 29406561 TI - ? PMID- 29406562 TI - Synovial cell sarcoma in a dog: A misnomer-Cytologic and histologic findings and review of the literature. AB - A 4-year-old Irish Setter was presented with a history of progressive left pelvic limb lameness. Orthopedic examination revealed pain on manipulation of the left stifle. Radiographs showed an osteolytic lesion in the subchondral bone of the medial tibial condyle. Fine-needle aspirates were taken, and cytology revealed numerous cohesive clusters of plump, oval to spindloid cells often with perivascular distribution and moderate cellular atypia. A diagnosis of sarcoma was made with synovial cell sarcoma (SCS) and histiocytic sarcoma being the 2 main differentials. Histopathology confirmed the diagnosis of sarcoma and provided the same differentials. All neoplastic cells were positive for vimentin, and approximately 5% of them also stained with pan-cytokeratin using immunohistochemical staining methods. Neoplastic cells did not express CD18. The combination of this immunohistochemical profile and cell morphology was consistent with an SCS. Synovial cell sarcoma is a rare and poorly understood canine tumor entity. This is the first extensive description of the cytologic features of this neoplasm. The literature was also reviewed, focusing on comparative aspects of dogs and people, with a special emphasis on the cell of origin and diagnostic tools. Controversies regarding the nomenclature of this tumor are also presented. The authors propose a new term (cytokeratin-positive joint-associated sarcoma) for addressing this neoplasm until the cell of origin of this tumor is elucidated. PMID- 29406563 TI - Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. AB - Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000. PMID- 29406564 TI - Current but not past hepatitis B virus infection is associated with a decreased risk of nonalcoholic fatty liver disease in the Chinese population: A case control study with propensity score analysis. AB - The relation between hepatitis B virus (HBV) infection and fatty liver has been addressed by several observational studies, but their results remain controversial. To date, no study has precisely investigated the association of current and past HBV infection with the risk of nonalcoholic fatty liver disease (NAFLD) in the Chinese population. Therefore, we conducted a hospital-based case control study in southwestern China to clarify this issue. A total of 631 newly ultrasound-diagnosed NAFLD cases and 2357 controls were selected from 123 243 consecutive patients admitted to a tertiary-care hospital between January 2015 and December 2016. Multivariate logistic regression was employed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). A propensity score was developed for adjustment and matching. Subgroup analysis was conducted to identify potential effect modifiers. Current and past HBV infection had an overall prevalence of 9.7% and 55.2%, respectively. In the fully adjusted model, current HBV infection was associated with a decreased risk of NAFLD (OR 0.64; 95% CI 0.42-0.95). A similar inverse association was observed in both propensity score-adjusted (OR 0.58; 95% CI 0.40-0.86) and propensity-score-matched analyses (OR 0.61; 95% CI 0.40-0.92).The inverse association was stronger in patients with hypertension than in those without (Pinteraction = .018).No significant association between past HBV infection and NAFLD risk was found. In conclusion, current but not past HBV infection is associated with a decreased risk of NAFLD in the Chinese population. The corresponding biological mechanisms remain to be elucidated. PMID- 29406566 TI - Influence of mouthguards and their palatal design on the stress-state of tooth periodontal ligament-bone complex under static loading. AB - BACKGROUND/AIM: The mouthguard (MG) is an effective device to reduce the risk of dental traumatic injuries, but the mechanical effects of wearing a MG and its design are not fully understood. The aim of this study was to evaluate the mechanical influence of wearing a MG and its palatal design on the tooth periodontal ligament-bone complex (TPBC) by computational analysis using the finite element method. MATERIAL AND METHODS: Three-dimensional subject-specific geometry of the TPBC was reconstructed from medical computed tomography (CT) images. Two patterns of MG geometries were constructed which covered the palatal domain or not (the position of these palatal margins was set at -8 mm (pattern 1) and 4 mm (pattern 2) from the cervical line. Five cases of static mechanical analysis were conducted by changing the location of the loading points from near the cervical line to the tip of the tooth. RESULTS: Wearing a MG decreased strain concentration around the loading point and cervical domain regardless of the MG palatal design. Elastic energy in the periodontal ligament (PDL) and tooth (including enamel and dentin) decreased when the MG was worn, whereas the MG palatal design slightly affected the degree of reduction in the elastic energies. The location of the loading points remarkably affected the elastic energy in the TPBC components and the extent of its reduction due to the MG. CONCLUSIONS: These findings indicated that the protection ability of the MG exerted in the restricted situations of traumatic events occurs regardless of the MG design. PMID- 29406565 TI - QTL mapping and GWAS reveal candidate genes controlling capsaicinoid content in Capsicum. AB - Capsaicinoids are unique compounds produced only in peppers (Capsicum spp.). Several studies using classical quantitative trait loci (QTLs) mapping and genomewide association studies (GWAS) have identified QTLs controlling capsaicinoid content in peppers; however, neither the QTLs common to each population nor the candidate genes underlying them have been identified due to the limitations of each approach used. Here, we performed QTL mapping and GWAS for capsaicinoid content in peppers using two recombinant inbred line (RIL) populations and one GWAS population. Whole-genome resequencing and genotyping by sequencing (GBS) were used to construct high-density single nucleotide polymorphism (SNP) maps. Five QTL regions on chromosomes 1, 2, 3, 4 and 10 were commonly identified in both RIL populations over multiple locations and years. Furthermore, a total of 109 610 SNPs derived from two GBS libraries were used to analyse the GWAS population consisting of 208 C. annuum-clade accessions. A total of 69 QTL regions were identified from the GWAS, 10 of which were co-located with the QTLs identified from the two biparental populations. Within these regions, we were able to identify five candidate genes known to be involved in capsaicinoid biosynthesis. Our results demonstrate that QTL mapping and GBS-GWAS represent a powerful combined approach for the identification of loci controlling complex traits. PMID- 29406568 TI - Toward Thiophene-Annulated Graphene Nanoribbons. AB - Narrow thiophene-edged graphene nanoribbons (GNRs) were prepared from polychlorinated thiophene-containing poly(p-phenylene)s using the photochemical, metal-free cyclodehydrochlorination (CDHC) reaction. 1 H NMR and Raman spectroscopy confirmed the structures of the GNRs. The regioselectivity of the CDHC reaction allows the preparation of both laterally symmetrical and unsymmetrical GNRs and, consequently, the modulation of their optical and electronic properties. PMID- 29406567 TI - Safety and efficacy of leukocytapheresis in elderly patients with ulcerative colitis: The impact in steroid-free elderly patients. AB - BACKGROUND AND AIM: The number of elderly patients with ulcerative colitis (UC) is increasing. Several new therapies for UC have improved patient outcomes. Leukocytapheresis (LCAP) is an extracorporeal therapy for UC. However, its efficacy and safety for elderly UC patients has not been reported. METHODS: We conducted a post hoc analysis of data from a large, prospective, observational study of LCAP, conducted at 116 medical facilities in Japan between May 2010 and December 2012. Of 847 patients included in this analysis, LCAP was used in 75 (8.9%) elderly patients (>= 65 years) and 772 (91.1%) non-elderly patients. RESULTS: There were no serious adverse events in the elderly, and the rate of adverse events between the non-elderly and elderly was not different. Overall rate of remission was also not different between the two groups. In patients who were not on concomitant treatment with corticosteroids, the rate of remission was significantly higher in the elderly group than in the non-elderly group (90.9% [20/22] vs 64.6% [135/209], P = 0.02). CONCLUSIONS: Real-world data demonstrate that the safety and tolerability of LCAP were comparable in the elderly and non elderly groups, indicating that it is well tolerated by elderly UC patients. PMID- 29406569 TI - Neospora caninum and Ehrlichia canis co-infection in a dog with meningoencephalitis. AB - An 8-year-old mixed-breed dog was presented for acute, progressive weakness and ataxia, inappetence, and weight loss. The patient was mentally normal, but nonambulatory, with a right head tilt, right positional ventral strabismus, and slight head tremors. A neurologic lesion was localized to the cerebellum and right brainstem. Cerebrospinal fluid (CSF) analysis showed a markedly increased protein concentration and mixed pleocytosis, with eosinophil predominance (44%), intracytoplasmic inclusions within eosinophils, consistent with Ehrlichia canis (E canis) morulae, and Toxoplasma gondii (T gondii) or Neospora caninum (N caninum) tachyzoites within eosinophils and monocytes. A serum indirect immunofluorescent antibody test was positive for N caninum (titer 1:12 800) and negative for T gondii. Both blood and CSF PCR results were N caninum- and E canis positive and T gondii- and Anaplasma phagocytophilum-negative, and blood PCR, but not CSF PCR, was Hepatozoon canis-positive. The dog was treated for 30 days with clindamycin, sulfamethoxazole-trimethoprim, doxycycline, prednisone, and cephalosporin, but did not improve neurologically, and was euthanized. Brain histopathology showed moderate multifocal, subacute meningoencephalitis with necrosis and gliosis. The neurologic disease was mostly attributed to central nervous system (CNS) neosporosis, with the possible contribution of ehrlichiosis, which was likely a manifestation of blood-brain barrier disruption. Hepatozoonosis was probably a result or cause of underlying immunosuppression. To our knowledge, this is the first report of CNSN caninum and E canis co-infection detected by both CSF PCR and cytology and E canis morulae identified within CSF eosinophils. PMID- 29406570 TI - New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcgammaRIIB (CD32B). AB - The Fc gamma receptor IIB (FcgammaRIIB/CD32B) was generated million years ago during evolution. It is the sole inhibitory receptor for IgG, and has long been associated with the regulation of humoral immunity and innate immune homeostasis. However, new and surprising functions of FcgammaRIIB are emerging. In particular, FcgammaRIIB has been shown to perform unexpected activatory roles in both immune signaling and monoclonal antibody (mAb) immunotherapy. Furthermore, although ITIM signaling is an integral part of FcgammaRIIB regulatory activity, it is now clear that inhibition/activation of immune responses can occur independently of the ITIM. In light of these new findings, we present an overview of the established and noncanonical functions of FcgammaRIIB and discuss how this knowledge might be exploited therapeutically. PMID- 29406571 TI - A comprehensive bioinformatic analysis of hepatitis D virus full-length genomes. AB - In association with hepatitis B virus (HBV), hepatitis delta virus (HDV) is a subviral agent that may promote severe acute and chronic forms of liver disease. Based on the percentage of nucleotide identity of the genome, HDV was initially classified into three genotypes. However, since 2006, the original classification has been further expanded into eight clades/genotypes. The intergenotype divergence may be as high as 35%-40% over the entire RNA genome, whereas sequence heterogeneity among the isolates of a given genotype is <20%; furthermore, HDV recombinants have been clearly demonstrated. The genetic diversity of HDV is related to the geographic origin of the isolates. This study shows the first comprehensive bioinformatic analysis of the complete available set of HDV sequences, using both nucleotide and protein phylogenies (based on an evolutionary model selection, gamma distribution estimation, tree inference and phylogenetic distance estimation), protein composition analysis and comparison (based on the presence of invariant residues, molecular signatures, amino acid frequencies and mono- and di-amino acid compositional distances), as well as amino acid changes in sequence evolution. Taking into account the congruent and consistent results of both nucleotide and amino acid analyses of GenBank available sequences (recorded as of January, 2017), we propose that the eight hepatitis D virus genotypes may be grouped into three large genogroups fully supported by their shared characteristics. PMID- 29406572 TI - 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome: Concerns regarding presentation of previous studies. PMID- 29406573 TI - Phenotypic characterization of KCTD3-related developmental epileptic encephalopathy. AB - The association between KCTD3 gene and neurogenetic disorders has only been published recently. In this report, we describe the clinical phenotype associated with 2 pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from 4 consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myelination. One patient also had a multicystic kidney. Whole exome sequencing revealed 2 probably pathogenic homozygous variants in KCTD3 gene that fully segregated with the disease. KCTD3 gene belongs to a family of accessory subunits that regulate the biophysical properties of ion channels, and is highly expressed in the kidney and brain. In this largest series to date on KCTD3 mutated patients, we show that biallelic loss of function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy and abnormal cerebellum on brain imaging. PMID- 29406574 TI - UVB- and NGF-induced cutaneous sensitization in humans selectively augments cowhage- and histamine-induced pain and evokes mechanical hyperknesis. AB - Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre-established inflammatory hyperalgesia (ultraviolet-B-irradiation; "UVB") and non-inflammatory neurotrophic pain sensitization (nerve growth factor; "NGF") alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with <=2 * minimal erythemal dose, and two non-irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 MUg intradermally injected (4 * 50 MUL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB- and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses. PMID- 29406575 TI - PeCHYR1, a ubiquitin E3 ligase from Populus euphratica, enhances drought tolerance via ABA-induced stomatal closure by ROS production in Populus. AB - Drought, a primary abiotic stress, seriously affects plant growth and productivity. Stomata play a vital role in regulating gas exchange and drought adaptation. However, limited knowledge exists of the molecular mechanisms underlying stomatal movement in trees. Here, PeCHYR1, a ubiquitin E3 ligase, was isolated from Populus euphratica, a model of stress adaptation in forest trees. PeCHYR1 was preferentially expressed in young leaves and was significantly induced by ABA (abscisic acid) and dehydration treatments. To study the potential biological functions of PeCHYR1, transgenic poplar 84K (Populus alba * Populus glandulosa) plants overexpressing PeCHYR1 were generated. PeCHYR1 overexpression significantly enhanced H2 O2 production and reduced stomatal aperture. Transgenic lines exhibited increased sensitivity to exogenous ABA and greater drought tolerance than that of WT (wild-type) controls. Moreover, up-regulation of PeCHYR1 promoted stomatal closure and decreased transpiration, resulting in strongly elevated WUE (water use efficiency). When exposed to drought stress, transgenic poplar maintained higher photosynthetic activity and biomass accumulation. Taken together, these results suggest that PeCHYR1 plays a crucial role in enhancing drought tolerance via ABA-induced stomatal closure caused by hydrogen peroxide (H2 O2 ) production in transgenic poplar plants. PMID- 29406576 TI - Seasonal variability of the vitamin C content of fresh fruits and vegetables in a local retail market. AB - BACKGROUND: Seasonal variation of vitamin C in fresh fruits and vegetables is not reflected in food composition database average values, yet many factors influence content and retention. RESULTS: Fresh fruits and vegetables were sampled on three occasions in each season, from the same local retail outlets, for 1 or 2 years. Vitamin C was significantly higher in winter-sampled spinach (436 mg kg-1 ) compared with spring (298 mg kg-1 ) and summer/fall (180 mg kg-1 ); in potatoes in summer/fall (156 mg kg-1 ) versus winter/spring (106 mg kg-1 ); and in oranges in winter (616 mg kg-1 ), spring (592 mg kg-1 ), and summer (506 mg kg-1 ). Ranges were dramatic among sampling occasions for broccoli, oranges, potatoes, and spinach (700-1210 mg kg-1 , 420-780 mg kg-1 , 70-280 mg kg-1 , and 90-660 mg kg-1 respectively). Mean values for apples, bananas, tomatoes, and potatoes differed from the USDA National Nutrient Database for Standard Reference (SR) average by >=10% of the daily recommended intake (90 mg). For broccoli, oranges, and spinach, vitamin C was substantially above or below the SR range in 50-100% of the samples. For spinach, the average content did not differ from SR, but vitamin C in winter was 55% higher than SR. CONCLUSION: Database average values for vitamin C in fresh produce can significantly over- or underestimate the content in a specific food supply. (c) 2018 Society of Chemical Industry. PMID- 29406577 TI - The center effect in liver transplantation in the Eurotransplant region: a retrospective database analysis. AB - Apart from donor and recipient risk factors, the effect of center-related factors has significant impact on graft survival after liver transplantation (LT). To investigate this effect in Eurotransplant, a retrospective database analysis was performed, including all LT's in adult recipients (>=18 years) in the Eurotransplant region from 1.1.2007 until 31.12.2013. Additionally, a survey was sent out to all transplant centers requesting information on surgeons' experience and exposure. In total, 10 265 LT's were included (median follow-up 3.3 years), performed in 39 transplant centers. Funnel plots showed significant differences in graft survival between the transplant centers. After correction for donor and recipient risk, with the Eurotransplant donor risk index (ET-DRI) and the simplified recipient risk index (sRRI) and random effects, these differences diminished. Mean historical volume (in the preceding 5 years) was a significant (P < 0.001), nonlinear marker for graft survival in the multivariate analysis. This study demonstrates that funnel plots can be used for benchmarking purposes in LT. Case-mix correction can be performed with the use of the ET-DRI and sRRI. The center effect encompasses the entire complex process of preoperative workup, operation to follow-up. PMID- 29406578 TI - N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications. AB - INTRODUCTION: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown. METHODS: Clinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from 10 patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1-specific antibodies. RESULTS: In addition to disease-defining NR1-IgG, serum NR1-IgM was found in 6 of 10 patients. NR1-IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+ CD27++ CD38++ antibody-secreting cells in vitro and, from 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1-IgG in culture. INTERPRETATION: Serum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis. Ann Neurol 2018;83:553-561. PMID- 29406579 TI - Intraoperative interventions for preventing surgical site infection: an overview of Cochrane Reviews. AB - BACKGROUND: Surgical site infection (SSI) rates vary from 1% to 5% in the month following surgery. Due to the large number of surgical procedures conducted annually, the costs of these SSIs can be considerable in financial and social terms. Many interventions are used with the aim of reducing the risk of SSI in people undergoing surgery. These interventions can be broadly delivered at three stages: preoperatively, intraoperatively and postoperatively. The intraoperative interventions are largely focused on decontamination of skin using soap and antiseptics; the use of barriers to prevent movement of micro-organisms into incisions; and optimising the patient's own bodily functions to promote best recovery. Both decontamination and barrier methods can be aimed at people undergoing surgery and operating staff. Other interventions focused on SSI prevention may be aimed at the surgical environment and include methods of theatre cleansing and approaches to managing theatre traffic. OBJECTIVES: To present an overview of Cochrane Reviews of the effectiveness and safety of interventions, delivered during the intraoperative period, aimed at preventing SSIs in all populations undergoing surgery in an operating theatre. METHODS: Published Cochrane systematic reviews reporting the effectiveness of interventions delivered during the intraoperative period in terms of SSI prevention were eligible for inclusion in this overview. We also identified Cochrane protocols and title registrations for future inclusion into the overview. We searched the Cochrane Library on 01 July 2017. Two review authors independently screened search results and undertook data extraction and 'Risk of bias' and certainty assessment. We used the ROBIS (risk of bias in systematic reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the certainty of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. MAIN RESULTS: We included 32 Cochrane Reviews in this overview: we judged 30 reviews as being at low risk of bias and two at unclear risk of bias. Thirteen reviews had not been updated in the past three years. Two reviews had no relevant data to extract. We extracted data from 30 reviews with 349 included trials, totaling 73,053 participants. Interventions assessed included gloving, use of disposable face masks, patient oxygenation protocols, use of skin antiseptics for hand washing and patient skin preparation, vaginal preparation, microbial sealants, methods of surgical incision, antibiotic prophylaxis and methods of skin closure. Overall, the GRADE certainty of evidence for outcomes was low or very low. Of the 77 comparisons providing evidence for the outcome of SSI, seven provided high- or moderate-certainty evidence, 39 provided low-certainty evidence and 31 very low-certainty evidence. Of the nine comparisons that provided evidence for the outcome of mortality, five provided low-certainty evidence and four very low-certainty evidence.There is high- or moderate-certainty evidence for the following outcomes for these intraoperative interventions. (1) Prophylactic intravenous antibiotics administered before caesarean incision reduce SSI risk compared with administration after cord clamping (10 trials, 5041 participants; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.81; high-certainty evidence - assessed by review authors). (2) Preoperative antibiotics reduce SSI risk compared with placebo after breast cancer surgery (6 trials, 1708 participants; RR 0.74, 95% CI 0.56 to 0.98; high-certainty evidence assessed by overview authors). (3) Antibiotic prophylaxis probably reduce SSI risk in caesarean sections compared with no antibiotics (82 relevant trials, 14,407 participants; RR 0.40, 95% CI 0.35 to 0.46; moderate-certainty evidence; downgraded once for risk of bias - assessed by review authors). (4) Antibiotic prophylaxis probably reduces SSI risk for hernia repair compared with placebo or no treatment (17 trials, 7843 participants; RR 0.67, 95% CI 0.54 to 0.84; moderate-certainty evidence; downgraded once for risk of bias - assessed by overview authors); (5) There is currently no clear difference in the risk of SSI between iodine-impregnated adhesive drapes compared with no adhesive drapes (2 trials, 1113 participants; RR 1.03, 95% CI 0.66 to 1.60; moderate-certainty evidence; downgraded once for imprecision - assessed by review authors); (6) There is currently no clear difference in SSI risk between short-term compared with long-term duration antibiotics in colorectal surgery (7 trials; 1484 participants; RR 1.05 95% CI 0.78 to 1.40; moderate-certainty evidence; downgraded once for imprecision - assessed by overview authors). There was only one comparison showing negative effects associated with the intervention: adhesive drapes increase the risk of SSI compared with no drapes (5 trials; 3082 participants; RR 1.23, 95% CI 1.02 to 1.48; high-certainty evidence - rated by review authors). AUTHORS' CONCLUSIONS: This overview provides the most up-to-date evidence on use of intraoperative treatments for the prevention of SSIs from all currently published Cochrane Reviews. There is evidence that some interventions are useful in reducing SSI risk for people undergoing surgery, such as antibiotic prophylaxis for caesarean section and hernia repair, and also the timing of prophylactic intravenous antibiotics administered before caesarean incision. Also, there is evidence that adhesive drapes increase SSI risk. Evidence for the many other treatment choices is largely of low or very low certainty and no quality-of-life or cost-effectiveness data were reported. Future trials should elucidate the relative effects of some treatments. These studies should focus on increasing participant numbers, using robust methodology and being of sufficient duration to adequately assess SSI. Assessment of other outcomes such as mortality might also be investigated as part of non-experimental prospective follow-up of people with SSI of different severity, so the risk of death for different subgroups can be better understood. PMID- 29406580 TI - Body mass index and gastrointestinal cancer mortality in Korean adults: A prospective cohort study. AB - BACKGROUND: The association between body mass index (BMI) and mortality from gastrointestinal (GI) cancer remains unclear, especially in Asian populations. METHODS: A total of 510 148 Korean adults who participated in routine health examinations during the period 2002-2003 were followed up until 2013. RESULTS: During a mean follow up of 10.5 years, 7831 individuals died of GI cancer. Various associations with BMI were found: U-curve (overall GI, colorectal, liver, and gallbladder cancer), L-curve (stomach cancer), linear (esophageal, extrahepatic bile duct [EBD], and small intestine cancer), and none (pancreatic cancer). Overall GI cancer mortality was lowest at approximately 23.5-26 kg/m2 . For cancers with linear associations, the multivariable adjusted hazard ratios per each 5 kg/m2 higher BMI were 0.53 (95% confidence interval = 0.43-0.65, esophagus), 1.19 (1.02-1.40, EBD), and 0.64 (0.41-0.999, small intestine). For cancers with U-curve or L-curve associations, the corresponding hazard ratios >=25 kg/m2 were 1.19 (1.08-1.32, overall GI), 1.30 (1.04-1.64, colorectal), 1.28 (1.07-1.53, liver), and 1.30 (0.85-1.97, gallbladder), while in the range of <25 kg/m2 , they were 0.81 (0.76-0.87, overall GI), 0.43 (0.32-0.58, esophagus), 0.70 (0.62-0.79, stomach), and 0.77 (0.65-0.90, colorectal), and these inverse associations did not weaken after excluding the first 7 years of follow up and ever smokers. CONCLUSIONS: Both low and high BMIs were associated with excess mortality from GI cancers in Korean adults. EBD cancer had a positive association, while esophageal and small intestine cancers had inverse associations. Above 25 kg/m2 , liver and colorectal cancers had positive associations with BMI, whereas below 25 kg/m2 , stomach and colorectal cancers had inverse associations. PMID- 29406582 TI - High complement levels in astrocyte-derived exosomes of Alzheimer disease. AB - OBJECTIVE: Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms. METHODS: To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasma samples of AD patients and matched controls for enzyme-linked immunosorbent assay quantification of complement proteins. RESULTS: ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b, and C5b-C9 terminal complement complex, but not mannose-binding lectin, normalized by the CD81 exosome marker were significantly higher for AD patients (n = 28) than age- and gender-matched controls (all p < 0.0001). ADE normalized levels of interleukin (IL)-6, tumor necrosis factor-alpha, and IL-1beta were significantly higher for AD patients than controls, but there was greater overlap between the two groups than for complement proteins. Mean ADE levels of complement proteins for AD patients in a longitudinal study were significantly higher (n = 16, p < 0.0001) at the AD2 stage of moderate dementia than at the AD1 preclinical stage 5 to 12 years earlier, which were the same as for controls. ADE levels of complement regulatory proteins CD59, CD46, decay-accelerating factor (DAF), and complement receptor type 1, but not factor I, were significantly lower for AD patients than controls (p < 0.0001 for CD59 and DAF), were diminished by the AD1 stage, and were further decreased at the AD2 stage. INTERPRETATION: ADE complement effector proteins in AD are produced by dysregulated systems, attain higher levels than in controls, and may potentially damage neurons in the late inflammatory phase of AD. Ann Neurol 2018;83:544-552. PMID- 29406581 TI - Corticotropin-releasing factor receptor 2-deficiency eliminates social behaviour deficits and vulnerability induced by cocaine. AB - BACKGROUND AND PURPOSE: Poor social behaviour and vulnerability to stress are major clinical features of stimulant use disorders. The corticotropin-releasing factor (CRF) system mediates stress responses and might underlie substance use disorders; however, its involvement in social impairment induced by stimulant substances remains unknown. CRF signalling is mediated by two receptor types, CRF1 and CRF2 . In the present study we investigated the role of the CRF2 receptor in social behaviour deficits, vulnerability to stress and related brain alterations induced by cocaine administration and withdrawal. EXPERIMENTAL APPROACH: CRF2 receptor-deficient (CRF2 -/-) and littermate wild-type mice were repeatedly tested in the three-chamber task for sociability (i.e. preference for an unfamiliar conspecific vs. an object) and social novelty preference (SNP; i.e. preference for a novel vs. a familiar conspecific) before and after chronic cocaine administration. An in situ hybridization assay was used to assess gene expression of the stress-responsive arginine vasopressin (AVP) and oxytocin (OT) neuropeptides in the hypothalamus. KEY RESULTS: CRF2 receptor deficiency eliminated the sociability deficit induced by cocaine withdrawal. Moreover, CRF2 /- mice did not show either the stress-induced sociability deficit or the increased AVP and OT expression associated with long-term cocaine withdrawal, indicating resilience to stress. Throughout, wild-type and CRF2 -/- mice displayed SNP, suggesting that cocaine withdrawal-induced sociability deficits were not due to impaired detection of social stimuli. CONCLUSIONS AND IMPLICATIONS: These findings demonstrate a central role for the CRF2 receptor in social behaviour deficits and biomarkers of vulnerability induced by cocaine withdrawal, suggesting new therapeutic strategies for stimulant use disorders. PMID- 29406584 TI - First person: Ali Bazarbachi, MD, PhD: The professor at the American University of Beirut has advanced the treatment of leukemia and cancer research in the Middle East and worldwide. PMID- 29406583 TI - Mutual inversion of flurbiprofen enantiomers in various rat and mouse strains. AB - Flurbiprofen (F) is a nonsteroidal anti-inflammatory drug (NSAID) used therapeutically as the racemate of (R)-enantiomer and (S)-enantiomer. The inversion of RF to SF and vice versa was investigated in C57Bl/6 and SJL mice and Dark Agouti and Lewis rats. The enzyme alpha-methylacyl-CoA racemase (AMACR) is involved in the chiral inversion pathway that converts members of the 2 arylpropionic acid NSAIDs from the R-enantiomer to the S-enantiomer. We studied C57Bl/6 mice deficient in AMACR postulating that they should show reduced inversion of RF to SF. In line with the data of others in mice, (R)-inversion to (S)-inversion was relatively high in both the C57Bl/6 and SJL mice (fraction inverted, FI = 37.7% and 24.7%, respectively). In contrast, in AMACR deficient mice, there was no measurable peak for SF after administration of RF. The results in both rat strains (Dark Agouti and Lewis rats, FI = 1.4% and 4.1%, respectively) confirm the low chiral inversion of the enantiomers of flurbiprofen in the rat, as observed by other authors in the Sprague-Dawley strain (<5%). From the present results, we conclude that for the study of flurbiprofen enantiomers, the rat is more suitable than the mouse as a model for the human in which (R) inversion to (S)-inversion is negligible. PMID- 29406585 TI - Erratum: Chang Y-J, Wang Y, Mo X-D, et al. Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: Long-term outcomes of a prospective randomized trial. Cancer. 2017;123: 2881-2892. PMID- 29406586 TI - Erratum: Epperla N, Maddocks KJ, Salhab M, et al. C-MYC-positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional "hits" and outcomes with subsequent therapy. Cancer. 2017;123:4411-4418. PMID- 29406588 TI - Patients with breast cancer who are treated with chemotherapy risk long-term nerve damage. PMID- 29406587 TI - Retraction: Genome-wide association study identifies common genetic variants associated with salivary gland carcinoma and its subtypes by Xu L, Tang H, Chen DW, El-Naggar AK, Wei P, Sturgis EM. PMID- 29406589 TI - Study on the HPLC-based separation of some ezetimibe stereoisomers and the underlying stereorecognition process. AB - The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode. The use of prohibited solvents as nonstandard mobile phase gave rise to better resolution than that of standard mobile phases (n-hexane/alcohol system). In addition, the presence of ethanol in nonstandard mobile phase has played an important role in enhancing chromatographic efficiency and resolution between ezetimibe stereoisomers. Various attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Moreover, possible solute-mobile phase-stationary phase interactions were derived to explain how stationary and mobile phases affected the separation. Then the method validation with respect to selectivity, linearity, precision, accuracy, and robustness was carried out, which was demonstrated to be suitable and accurate for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug. PMID- 29406591 TI - Meta-analysis of the prognostic value of the neutrophil-to-lymphocyte ratio in oral squamous cell carcinoma. AB - BACKGROUND: A number of studies have assessed the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in oral squamous cell carcinoma (OSCC), but their results regarding the predictive value of NLR in OSCC are inconsistent. We therefore performed a meta-analysis to clarify the association between NLR and clinical outcome in OSCC. METHODS: We searched the MEDLINE and Web of Science to identify potential studies investigating the association between NLR and survival in OSCC. RESULTS: A total of 10 studies, enrolling 2135 patients with OSCC, were included. A higher NLR was a negative predictor for both disease-specific survival (hazard ratio [HR] = 1.93, 95% CI: 1.47-2.54) and overall survival (HR = 1.56, 95% CI: 1.28-1.90). CONCLUSION: This suggests a higher NLR is predictive of a poorer prognosis in OSCC. Because determination of NLR is non-invasive and cost effective, it could be widely used for predicting prognosis in OSCC. PMID- 29406592 TI - Chronic inflammatory demyelinating polyneuropathy misdiagnosis: A clinical more than electrophysiogical problem? PMID- 29406590 TI - Cirrhosis, high age and high body mass index are risk factors for persisting advanced fibrosis after sustained virological response in chronic hepatitis C. AB - We aimed to assess fibrosis with liver stiffness measurement long-term after sustained virological response of chronic hepatitis C and to identify risk factors associated with persisting fibrosis. In this cross-sectional study, patients with chronic hepatitis C and pretreatment advanced fibrosis or cirrhosis treated successfully at Karolinska University Hospital with an interferon containing regimen underwent liver stiffness measurement with FibroScan. The impact of potential risk factors for persisting fibrosis was estimated. We included 269 patients with a median follow-up time of 7.7 years (range 0-20), 84 with a follow-up time of >=10 years. Patients with pretreatment cirrhosis had a significantly higher median liver stiffness level (8.5 kPa 95% CI 7-9.1) at follow-up, than patients with advanced fibrosis (6 kPa 95% CI 5.5-6.4). A majority improved their fibrosis stage after sustained virological response, but 24% had persisting advanced fibrosis with a liver stiffness level of >= 9.5 kPa. Among patients with pretreatment cirrhosis, the proportion with persisting advanced fibrosis diminished with longer follow-up time, from 48% after <5 years to 21% after >10 years. The main risk factors for persisting advanced fibrosis were pretreatment cirrhosis, high age and body mass index. In conclusion, fibrosis improves substantially during long-term follow-up after sustained virological response in hepatitis C patients with pretreatment advanced liver fibrosis. Lifestyle intervention to decrease weight in obese persons and treatment before establishment of cirrhosis should therefore be recommended to avoid persistence of advanced fibrosis after virological cure. PMID- 29406593 TI - Unsupervised Screening of Vibrational Spectra by Principal Component Analysis for Identifying Molecular Clusters. AB - Vibrational spectra are commonly used to study molecular interactions in solutions. However, the data analysis is often demanding and requires significant experience in order to obtain meaningful results. This study demonstrates that principal component analysis (PCA) can serve as an unsupervised tool for initial screening of non-ideal mixture systems. Taking the aqueous solutions of dimethyl sulfoxide (DMSO) as an example, PCA reveals-easily and fast-the two prominent stoichiometries at 1:2 and 1:1 molar DMSO:water ratio and significantly outperforms elaborate spectral profile analysis or common algorithms as indirect hard modeling (IHM) or multivariate curve resolution (MCR). The corresponding molecular 1:1 and 1:2 clusters are known to be dominating configurations in the solutions. PMID- 29406594 TI - Reply to response to 'Gum chewing aids bowel function return and analgesic requirements after bowel surgery: a randomized controlled trial'. PMID- 29406595 TI - Tritrichomonas foetus and Mycoplasma felis coinfection in the upper respiratory tract of a cat with chronic purulent nasal discharge. AB - A 5-year-old indoor male neutered Siamese cat was presented with clinical signs of sneezing and chronic bilateral purulent nasal discharge. Multiple nasal cavity swabs were submitted for bacterial cultures, Mycoplasma felis-DNA qPCR, and cytology. M felisqPCR was positive and cytomorphologic diagnosis was severe, acute, purulent, rhinitis with intralesional protozoal microorganisms consistent with a Trichomonas spp. Nested PCR (nPCR) confirmed the diagnosis of Tritrichomonas foetus. Systemic therapy with doxycycline for M felis and metronidazole for T foetus was started with remission of clinical signs within 2 weeks; however, symptoms relapsed shortly after therapy was discontinued. This study represents the first documented case of T foetus associated with chronic nasal discharge in a cat, which supports the hypothesis that T foetus can live in the nasal cavity. It is also the first reported case of M felis and T foetus coinfection, which indicates that with mycoplasmal feline upper respiratory tract infections, T foetus should be considered as a coinfecting agent. PMID- 29406596 TI - Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns. AB - Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by a developmentally inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity and impulsivity. Despite onset in early childhood, ADHD may continue into adulthood with substantial impairment in social, academic and occupational functioning. A new animal model of this disorder was developed in rats with genetic deletion of the dopamine transporter (DAT) gene (dopamine transporter knockout rats; DAT-KO rats). We analyzed the behavior of DAT-KO rats for a deeper phenotypical characterization of this model. We first tested rats of the 3 genotypes at different ages (preadolescent, adolescent and adult), in a novelty-seeking test using a black/white box (Experiment 1). After that, we tested adult rats in a novelty-preference test using a 3-chamber apparatus with different shapes (Experiment 2). Experiment 1: as evidenced by analysis of time spent in the novel environment, adult DAT heterozygous (DAT-HET) rats show an increased curiosity-driven exploration compared with wild-type (WT) controls while DAT-KO rats did not recognize novelty. The locomotor activity data show a minimal difference between genotypes at adolescent age while the preadolescent and adult DAT-KO rats have significantly increased activity rate compared with WT and DAT-HET subjects. Experiment 2: in this case, due to more clearly evident spatial differences, time spent in novel environment was not significantly different among genotypes. During first 10 minutes, DAT-KO rats showed a decreased hyperactivity, apparently related to curiosity and attention to the new environments. In conclusion, DAT-KO rats may show some inattention while more novelty-seeking traits appear in DAT HET rats. PMID- 29406597 TI - Arabidopsis replication factor C4 is critical for DNA replication during the mitotic cell cycle. AB - Replication factor C (RFC) is a conserved eukaryotic complex consisting of RFC1/2/3/4/5. It plays important roles in DNA replication and the cell cycle in yeast and fruit fly. However, it is not very clear how RFC subunits function in higher plants, except for the Arabidopsis (At) subunits AtRFC1 and AtRFC3. In this study, we investigated the functions of AtRFC4 and found that loss of function of AtRFC4 led to an early sporophyte lethality that initiated as early as the elongated zygote stage, all defective embryos arrested at the two- to four cell embryo proper stage, and the endosperm possessed six to eight free nuclei. Complementation of rfc4-1/+ with AtRFC4 expression driven through the embryo specific DD45pro and ABI3pro or the endosperm-specific FIS2pro could not completely restore the defective embryo or endosperm, whereas a combination of these three promoters in rfc4-1/+ enabled the aborted ovules to develop into viable seeds. This suggests that AtRFC4 functions simultaneously in endosperm and embryo and that the proliferation of endosperm is critical for embryo maturation. Assays of DNA content in rfc4-1/+ verified that DNA replication was disrupted in endosperm and embryo, resulting in blocked mitosis. Moreover, we observed a decreased proportion of late S-phase and M-phase cells in the rfc4-1/ FIS2;DD45;ABI3pro::AtRFC4 seedlings, suggesting that incomplete DNA replication triggered cell cycle arrest in cells of the root apical meristem. Therefore, we conclude that AtRFC4 is a crucial gene for DNA replication. PMID- 29406598 TI - Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus. AB - Maturity-onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic beta-cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus. PMID- 29406599 TI - Cross multivariate correlation coefficients as screening tool for analysis of concurrent EEG-fMRI recordings. AB - Over the past decade, the simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) data has garnered growing interest because it may provide an avenue towards combining the strengths of both imaging modalities. Given their pronounced differences in temporal and spatial statistics, the combination of EEG and fMRI data is however methodologically challenging. Here, we propose a novel screening approach that relies on a Cross Multivariate Correlation Coefficient (xMCC) framework. This approach accomplishes three tasks: (1) It provides a measure for testing multivariate correlation and multivariate uncorrelation of the two modalities; (2) it provides criterion for the selection of EEG features; (3) it performs a screening of relevant EEG information by grouping the EEG channels into clusters to improve efficiency and to reduce computational load when searching for the best predictors of the BOLD signal. The present report applies this approach to a data set with concurrent recordings of steady-state-visual evoked potentials (ssVEPs) and fMRI, recorded while observers viewed phase-reversing Gabor patches. We test the hypothesis that fluctuations in visuo-cortical mass potentials systematically covary with BOLD fluctuations not only in visual cortical, but also in anterior temporal and prefrontal areas. Results supported the hypothesis and showed that the xMCC-based analysis provides straightforward identification of neurophysiological plausible brain regions with EEG-fMRI covariance. Furthermore xMCC converged with other extant methods for EEG-fMRI analysis. PMID- 29406600 TI - Nondestructive prediction and visualization of plumpness in live Eriocheir sinensis using low-field 1 H magnetic resonance imaging. AB - BACKGROUND: The plumpness of hepatopancreas and gonad tissues in live Chinese mitten crabs (Eriocheir sinensis) depends on the grading scale and its commercial value. In this work, a low-field T1 -weighted 1 H magnetic resonance imaging (LF 1 H MRI) technique was developed to nondestructively analyze the plumpness of hepatopancreas and gonad tissues in live E. sinensis. Both male and female E. sinensis were characterized by two-dimensional (2D) LF-1 H MRI. Moreover, a three dimensional (3D) LF-1 H MRI model that quantitatively integrated the total volume of lipid tissues in live E. sinensis was used. RESULTS: The results showed 2D LF 1 H MRI could accurately discriminate the plumpness of hepatopancreas and gonad tissues in live E. sinensis. The results of the 3D LF-1 H MRI model displayed that the lipid volume of E. sinensis could be used to quantify lipid accumulation in lipid tissues. CONCLUSION: LF-1 H MRI technology was successfully developed to accurately discriminate the development of E. sinensis hepatopancreas and gonad tissues in a nondestructive manner, indicating its application potential in grading commercial live crabs or advising crab farmers on breeding and fattening processes. (c) 2018 Society of Chemical Industry. PMID- 29406601 TI - The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. AB - The type I intermediate filament keratin 16 (K16) is constitutively expressed in ectoderm-derived appendages and is inducibly expressed in the epidermis upon barrier-compromising challenges. Dominantly acting missense alleles in KRT16 are causative for pachyonychia congenita (PC), a genodermatosis involving debilitating palmoplantar keratoderma (PPK), nail dystrophy, oral lesions and, frequently, alterations in glands and hair. C57Bl/6;Krt16-/- mice develop oral lesions early after birth and PC-like PPK lesions as young adults. These PPK lesions have a marked dysregulation of skin barrier-related genes and innate immunity effectors (eg danger-associated molecular patterns) and are preceded by oxidative stress secondary to hypoactive Nrf2 signalling. These molecular features are present in PPK lesions of PC patients. Here, we report that all components of the C57Bl/6;Krt16-/- mouse phenotype occur as well in the FVB strain background, albeit less severely so, a significant observation in the light of variations in the clinical presentation of individuals harbouring disease-causing mutations in the KRT16 gene. PMID- 29406602 TI - Comparison between the urine dipstick and the pH-meter to assess urine pH in sheep and dogs. AB - BACKGROUND: Urine pH is an integral part of a complete urinalysis, and is commonly measured in veterinary practice using semiquantitative reagent strips. OBJECTIVE: The aim of this study was to compare the urine pH of dogs and sheep, using visual interpretation of dipstick reactions, and using a pH-meter as the reference method. Agreement between the 2 methods was also assessed. An additional objective was to compare the urine pH before and after centrifugation. METHODS: A total of 50 voided urine samples from sheep and 52 from dogs were collected into sterile containers. For pH measurements, 2 methods were used, a pH meter and urine dipstick reagent pads. Measurements were performed using urine samples before (whole urine) and after centrifugation (urine supernatant). For comparison of the 2 methods, Passing and Bablok regression analysis and Bland Altman plots were used. RESULTS: The equation created to assess agreement between the 2 methods in dogs showed a constant bias at -0.14 and a positive proportional bias at 0.98. From a clinical standpoint, total bias was below and above the maximum acceptable bias in sheep and dogs, respectively. Clinically acceptable bias was also found using centrifuged urine samples in sheep, but the urine pH values before and after centrifugation were nearly identical in dogs. CONCLUSION: Urine dipstick reagent pads and pH-meters can be used interchangeably to determine urine pH in sheep without needing centrifugation. In contrast, pH meters provide more accurate pH measurements than urine dipstick pads in canine urine, which is not improved by centrifugation. PMID- 29406603 TI - Editors' note: Special issue honoring Prof J. Gawronski. PMID- 29406604 TI - Allelic variation for broad-spectrum resistance and susceptibility to bacterial pathogens identified in a rice MAGIC population. AB - Quantitative trait loci (QTL) that confer broad-spectrum resistance (BSR), or resistance that is effective against multiple and diverse plant pathogens, have been elusive targets of crop breeding programmes. Multiparent advanced generation intercross (MAGIC) populations, with their diverse genetic composition and high levels of recombination, are potential resources for the identification of QTL for BSR. In this study, a rice MAGIC population was used to map QTL conferring BSR to two major rice diseases, bacterial leaf streak (BLS) and bacterial blight (BB), caused by Xanthomonas oryzae pathovars (pv.) oryzicola (Xoc) and oryzae (Xoo), respectively. Controlling these diseases is particularly important in sub Saharan Africa, where no sources of BSR are currently available in deployed varieties. The MAGIC founders and lines were genotyped by sequencing and phenotyped in the greenhouse and field by inoculation with multiple strains of Xoc and Xoo. A combination of genomewide association studies (GWAS) and interval mapping analyses revealed 11 BSR QTL, effective against both diseases, and three pathovar-specific QTL. The most promising BSR QTL (qXO-2-1, qXO-4-1 and qXO-11-2) conferred resistance to more than nine Xoc and Xoo strains. GWAS detected 369 significant SNP markers with distinguishable phenotypic effects, allowing the identification of alleles conferring disease resistance and susceptibility. The BSR and susceptibility QTL will improve our understanding of the mechanisms of both resistance and susceptibility in the long term and will be immediately useful resources for rice breeding programmes. PMID- 29406605 TI - Salvage skull base reconstruction in the endoscopic era: Vastus lateralis free tissue transfer. AB - BACKGROUND: When locoregional flaps fail to reconstruct the skull base, the microvascular surgeon faces several reconstructive challenges. We present our technique and results of salvage anterior skull base reconstruction utilizing the vastus lateralis free tissue transfer (VLFTT). METHODS: Four patients with anterior skull base defects after previous locoregional flap failure underwent free tissue transfer reconstruction with VLFTT. RESULTS: The success rate of free tissue transfer was 100%. Complete separation of the intracranial and sinonasal cavities was achieved in all patients; thus, resolving the cerebrospinal fluid (CSF) leakage in all patients. The VLFTT was inset through a minimally invasive approach utilizing an anterior maxillotomy via a gingivobuccal incision, an endoscopic medial maxillectomy, and endoscopic inset in all patients. No vein grafts were needed. CONCLUSION: This technique permits endoscopic endonasal inset and placement of reliable, well vascularized free tissue that may be utilized for complex, secondary reconstruction of the skull base. PMID- 29406606 TI - What is your diagnosis? Corneal scrape from a dog. PMID- 29406607 TI - Remission of hyperglycemia after withdrawal of oral antidiabetic drugs in Japanese patients with early-stage type 2 diabetes. AB - AIMS/INTRODUCTION: To assess whether intervention with oral antidiabetic drug in Japanese patients with the early stage of type 2 diabetes could provide a significant remission of the disease process. MATERIALS AND METHODS: Patients with diabetes duration <5 years were randomized to the lifestyle modification (LFS), pioglitazone (PIO) or sulfonylurea (SU) treatment group. In phase 1 as the on-treatment period and in phase 2 as the off-treatment period, the duration that glycated hemoglobin (HbA1c) was maintained at less than the target was compared among groups. RESULTS: A total of 278 patients were assigned to LFS (n = 84), PIO (n = 101) and SU (n = 93), and 212 patients completed phase 1. The number of patients that dropped out because of HbA1c elevation was larger in the LFS group, and the duration of HbA1c being maintained at <7.9% was longer in the SU group than the other groups. The duration of HbA1c being maintained at <7.4% in phase 2 was significantly shorter in the SU group than in the other groups. The proportion of patients who achieved HbA1c <6.9% or 6.2% at the end of phase 1 was obviously less in the LFS group than other groups. The duration of HbA1c being maintained at <6.2% in phase 2 was longer in the PIO group than other groups, although not significant statistically. An increase in serum adiponectin and decreases in high-sensitivity C-reactive protein and homeostatic model assessment of insulin resistance were shown in patients treated with PIO, but not LFS and SU, in phase 1, but were canceled in the drug-off phase 2 period. CONCLUSIONS: PIO treatment provided a prolonged remission of hyperglycemia after stopping the dosage in patients with the early stage of type 2 diabetes. PMID- 29406609 TI - Collagen VI-related myopathy: Expanding the clinical and genetic spectrum. AB - INTRODUCTION: We aimed to analyze the clinical and genetic characteristics of collagen VI-related myopathy. METHODS: We analyzed the clinical course and mutation spectrum in patients with collagen VI gene mutations among our congenital muscular dystrophy cohort. RESULTS: Among 24 patients with mutations in collagen VI coding genes, 13 (54.2%) were categorized as Ullrich type, and 11 (45.8%) as non-Ullrich type. Congenital orthopedic problems were similarly observed in both types, yet multiple joint contractures were found only in the Ullrich type. Clinical courses and pathology findings varied between patients. Mutations in COL6A1, COL6A2, and COL6A3 were found in 15 (65%), 3 (13%), and 5 (22%) patients, respectively, without genotype-phenotype association. Five novel variants were detected. DISCUSSION: We verified clinical heterogeneity of collagen VI-related myopathy, which emphasizes the importance of genetic testing. Genotype-phenotype association or early predictors for progression were not identified. Multiple joint contractures predict rapid deterioration. Muscle Nerve 58: 381-388, 2018. PMID- 29406608 TI - The optimal timing of hepatitis C therapy in liver transplant-eligible patients: Cost-effectiveness analysis of new opportunities. AB - Different strategies of DAAs treatment are currently possible both pre- and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost-effectiveness. A decision analytical model was created to simulate the progression of HCV-infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12-week course of DAAs prior to transplantation (PRE-LT), (ii) a 4-week course of DAAs starting at the time of transplantation (PERI-LT) and (iii) a 12-week course of DAAs administered at disease recurrence (POST-LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE-LT treatment strategy was dominant for DCC patients with MELD<16 and cost-effective for those with MELD16-20, while POST-LT strategy emerged as cost-effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE-LT as the cost-effective strategy for patients with MELD<=20. In conclusion, PRE-LT treatment is cost-effective for patients with MELD<=20 without HCC, while treatments after LT are cost-effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant-related factors. PMID- 29406610 TI - The nature of social cognitive deficits in children and adults with Klinefelter syndrome (47,XXY). AB - About 1 in 650 boys are born with an extra X chromosome (47,XXY or Klinefelter syndrome). 47,XXY is associated with vulnerabilities in socio-emotional development. This study was designed to assess types of cognitive deficits in individuals with 47,XXY that may contribute to social-emotional dysfunction, and to evaluate the nature of such deficits at various levels: ranging from basic visuospatial processing deficits, impairments in face recognition (FR), to emotion expression impairments. A total of 70 boys and men with 47,XXY, aged 8 to 60 years old, participated in the study. The subtests feature identification, FR and identification of facial emotions of the Amsterdam Neuropsychological Tasks were used. Level of intellectual functioning was assessed with the child and adult versions of the Wechsler Intelligence Scales. Reaction time data showed that in the 47,XXY group, 17% had difficulties in visuospatial processing (no social load), 26% had difficulties with FR (medium social load) and an even higher number of 33% had difficulties with facial expressions of emotions (high social load). Information processing impairments increased as a function of "social load" of the stimuli, independent of intellectual functioning. Taken together, our data suggest that on average individuals with XXY may have more difficulties in information processing when "social load" increases, suggesting a specific difficulty in the higher-order labeling and interpretation of social cues, which cannot be explained by more basic visuospatial perceptual skills. Considering the increased risk for social cognitive impairments, routine assessment of social cognitive functioning as part of neuropsychological screening is warranted. PMID- 29406611 TI - Near-infrared spectroscopy-based analysis to study sensory parameters on pork loins as affected by cooking methods and conditions. AB - BACKGROUND: The main objectives of this study were to evaluate the use of near infrared spectroscopy (NIRS) to classify pork loins under different methods and cooking conditions, and to predict sensory attributes of this product. RESULTS: Samples were oven cooked at two temperatures (150 and 180 degrees C) for different times (45, 60 and 75 min) and confit cooked for different times (120, 180 and 240 min). All cooked loin samples were subjected to a Quantitative Descriptive Analysis by a trained panel. For classification, principal component analysis was performed based on the NIRS database, showing a good discrimination between loins samples subjected to different cooking conditions. Regarding prediction, a data mining technique (multiple linear regression) was applied on a database constructed with data from NIRS and sensory analysis. CONCLUSION: The correlation coefficient and the mean absolute error obtained suggest that the calculated prediction equations of this study are valid to predict the changes in the sensory attributes depending on the cooking method and conditions used for pork loins. (c) 2018 Society of Chemical Industry. PMID- 29406612 TI - 2'-Fluoro-6'-methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti-HBV agent, active against drug-resistant HBV mutants. AB - Chronic hepatitis B (CHB) is one of the major causes of morbidity and mortality worldwide. Currently, clinically approved nucleos(t)ide analogs (NAs) are very efficient in reducing the load of hepatitis B virus (HBV) with minimum side effects. However, the long-term administration of antiviral drugs promotes HBV for potential drug resistance. To overcome this problem, combination therapies are administered, but HBV progressively altered mutations remain a threat. Therefore, optimally designed NAs are urgently needed to treat drug-resistant HBV. Herein, 2'-fluoro-6'-methylene carbocyclic adenosine (FMCA) and its phosphoramidate (FMCAP) have been discovered, which may be utilized in combination therapies for curing drug-resistant chronic hepatitis B. In preclinical studies, these carbocyclic NAs demonstrated potential anti-HBV activity against adefovir, as well as lamivudine (LMV/LAM) drug-resistant mutants. In vitro, these molecules have demonstrated significant activity against LMV/entecavir (ETV) triple mutants (L180M + S202G + M204V). Also, preliminary studies of FMCA/FMCAP in chimeric mice and female Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models having the LMV/ETV triple mutant have shown a high rate of reduction of HBV DNA levels compared to ETV. In this review, we have summarized preclinical studies of FMCA and its phosphoramidate prodrug (FMCAP). PMID- 29406613 TI - Arene-Ligand-Free Ruthenium(II/III) Manifold for meta-C-H Alkylation: Remote Purine Diversification. AB - meta-Selective C-H alkylations of bioactive purine derivatives were accomplished by versatile ruthenium catalysis. Thus, the arene-ligand-free complex [Ru(OAc)2 (PPh3 )2 ] enabled remote C-H functionalizations with ample scope and excellent levels of chemo- and positional selectivities. Detailed experimental and computational mechanistic studies provided strong support for a facile C-H activation within a ruthenium(II/III) manifold. PMID- 29406614 TI - Activation and Migration of Adventitial Fibroblasts Contributes to Vascular Remodeling. AB - The rat carotid artery balloon injury model was used to prove the activation and migration of adventitial fibroblasts. We found that at day 7 after injury, adventitial fibroblasts proliferated, transformed into myofibroblasts under transmission electron microscopy in the model group. Simultaneously, we proved that the adventitial cells migrated to the media and intima on seventh day after injury by directly labeled the adventitial cells by the in vivo gene transfer technique. Moreover, we captured the precise moment when the adventitial fibroblasts migrated from the adventitia to the media through the external elastic plate under transmission electron microscope. This study provides direct evidences that adventitial fibroblasts activate and migrate to the media and intima, then actively take part in revascularization. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29406615 TI - Application of the ideal profile method to identify an ideal sufu for nonregular consumers. AB - BACKGROUND: Sufu is a fermented soybean food with unique odor, flavor, and texture, which might not be appreciated by nonregular consumers. To identify the attributes that nonregular consumers appreciated, 12 commercial products bought from a Hong Kong market were tested by 113 consumers according to the ideal profile method (IPM), and rated on 22 attributes. RESULTS: Data provided from nonregular consumers were consistent at both panel and consumer levels. The predicted ideal profile received a higher hedonic score (7.0) than the tested products (6.0). Compared with commercial samples, the ideal sufu has low intensity in the attributes of fermented (aroma and flavor), moldy (aroma), and hard (texture), but high intensity in the soybean-like (aroma and flavor) and sesame oil-like (aroma and flavor) attributes. CONCLUSION: IPM could be used as an alternative approach to collect sensory profiles and preference data directly from consumers for product characterization. It could also be applied to identify the attributes that nonregular consumers appreciated. (c) 2018 Society of Chemical Industry. PMID- 29406616 TI - Reply. PMID- 29406617 TI - Electrochemical Water Oxidation and Stereoselective Oxygen Atom Transfer Mediated by a Copper Complex. AB - Water oxidation by copper-based complexes to form dioxygen has attracted attention in recent years, with the aim of developing efficient and cheap catalysts for chemical energy storage. In addition, high-valent metal-oxo species produced by the oxidation of metal complexes in the presence of water can be used to achieve substrate oxygenation with the use of H2 O as an oxygen source. To date, this strategy has not been reported for copper complexes. Herein, a copper(II) complex, [(RPY2)Cu(OTf)2 ] (RPY2=N-substituted bis[2 pyridyl(ethylamine)] ligands; R=indane; OTf=triflate), is used. This complex, which contains an oxidizable substrate moiety (indane), is used as a tool to monitor an intramolecular oxygen atom transfer reaction. Electrochemical properties were investigated and, upon electrolysis at 1.30 V versus a normal hydrogen electrode (NHE), both dioxygen production and oxygenation of the indane moiety were observed. The ligand was oxidized in a highly diastereoselective manner, which indicated that the observed reactivity was mediated by metal centered reactive species. The pH dependence of the reactivity was monitored and correlated with speciation deduced from different techniques, ranging from potentiometric titrations to spectroscopic studies and DFT calculations. Water oxidation for dioxygen production occurs at neutral pH and is probably mediated by the oxidation of a mononuclear copper(II) precursor. It is achieved with a rather low overpotential (280 mV at pH 7), although with limited efficiency. On the other hand, oxygenation is maximum at pH 8-8.5 and is probably mediated by the electrochemical oxidation of an antiferromagnetically coupled dinuclear bis(MU-hydroxo) copper(II) precursor. This constitutes the first example of copper-centered oxidative water activation for a selective oxygenation reaction. PMID- 29406618 TI - Behavior of new hydroxyapatite/glucan composite in human serum. AB - Biomaterials for bone tissue regeneration, including polymer-based composites, are typically evaluated in vitro prior to the clinical trials. However, such composites tested in vivo may behave different due to the specific body conditions. For example, some composites implanted into the tissue acidified due to transient postoperative inflammation may unexpectedly swell which delays the wound healing. Such massive swelling in acidic medium was previously observed for new elastic hydroxyapatite (HAp)/beta-glucan biomaterial. However, in further clinical cases concerning the composite implantation in patients without significant inflammation indicators, no side effects were observed. Therefore, it was reasonable to test the effect of human serum of neutral pH (typical for noninflamed tissues) on the composite parameters, in particular volume changes. Thus, this article shows the characterization of physicochemical parameters of the composite after incubation (5 days) in human serum of neutral pH by means of weight and volume measurement, scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, microcomputed tomography, mercury intrusion, and biochemical techniques. Results showed that human serum collected from healthy people caused no uncontrolled changes in weight and volume, porosity and mechanical properties of the composite. Therefore, this suggests the lack of volume change-related side effects of HAp/glucan composite in bone defects treatment if postoperative inflammation is prevented. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2653-2664, 2018. PMID- 29406619 TI - Oral injuries related to Ice Hockey in the province of Alberta, Canada: Trends over the last 15 years. AB - BACKGROUND/AIMS: Ice hockey players of all ages experience oral and dental injuries. The aim of this study was to evaluate the rates of ice hockey-related oral injuries, time lost due to oral injury, and mechanisms of oral injuries in the province of Alberta during a 15-year period (2001-2016). METHODS: Hockey Alberta, the governing body for minor ice hockey associations across the province, collects injury report forms from injured participants in sanctioned events. Fifteen years (2001-2016) of this database was examined for total respondents suffering oral injuries. Data on total injuries, estimated time lost, and injury mechanism were analyzed. RESULTS: Overall, 12 433 ice hockey-related injuries were recorded. The oral region was the third most common body part (16% of total injuries) to be injured after the arms and legs. Oral injuries have been occurring at a relatively constant rate each year from 2001 to 2016, with a maximum of 174 and minimum of 99 reported. Oral injuries usually result in a short absence from the sport of 1 week or less and tend to occur through being struck by a stick or the hockey puck. This differs from total injuries, which tend to occur through collisions with the boards or other players. CONCLUSIONS: Rates of oral injuries in Alberta due to ice hockey comprise a significant portion of the injuries that players sustain. Oral injuries occur mostly when a player is struck with a puck or stick, and the rest of the body is injured primarily through collisions. Dental practitioners can help ice hockey athletes prevent oral and dental injuries through encouraging the use of mouthguards (custom over boil and bite) and continuing to wear full-face protection. PMID- 29406620 TI - The impact of lignin downregulation on alfalfa yield, chemical composition, and in vitro gas production. AB - BACKGROUND: Lignin is a complex, phenolic polymer found in plant cell walls that is essential for mechanical support, water and mineral transport, and defense in vascular plants. Over ten different enzymes play a role in the synthesis of lignin in plants. Suppression of any one enzyme or combinations of these enzymes may change the concentration and composition of lignin in the genetically transformed plants. Two lines of alfalfa that were downregulated for caffeoyl coenzyme A O-methyltransferase were used to assess the impact of lignin downregulation on chemical composition and fermentation rate and extent using an in vitro gas production technique. A total of 64 samples consisting of two reduced lignin (RL) and two controls (CL), four field replicates, two cutting intervals (CIs; 28 and 35 days), and two cuts (Cut-1 and Cut-3) were used. RESULTS: No differences were detected in yield, crude protein, neutral detergent fiber (aNDF), and acid detergent fiber between the lines when harvested at the 28 day CI. The acid detergent lignin (ADL) concentration in RL alfalfa lines was significantly (P < 0.001) lower than in the CL. In alfalfa harvested at the 35 day CI, the RL alfalfa resulted in lower (P < 0.001) yield than CL. RL alfalfa lines had 24% and 22% lower (P < 0.001) ADL in Cut-1 and Cut-3 respectively than CL lines. The in vitro dry matter digestibility and aNDF digestibility (both as determined by the near-infrared reflectance method) were greater (P < 0.001) in RL than in CL lines harvested at the 35-day CI. In alfalfa harvested at the 35 day CI, extent of in vitro gas production and metabolizable energy content were greater in RL than in CL alfalfa. RL lines had 3.8% indigestible aNDF per unit ADL, whereas CL had 3.4% (P < 0.01). The positive effect of lignin downregulation was more pronounced when intervals between harvests were longer (35-day CI compared with the 28-day CI). CONCLUSION: Lignin downregulation in alfalfa offers an opportunity to extend harvesting time (CI) for higher yield without compromising the nutritional quality of the alfalfa forage for dairy and livestock feeding. However, the in vitro results reported here warrant further study using in vivo methods. (c) 2018 Society of Chemical Industry. PMID- 29406622 TI - FCS-like zinc finger 6 and 10 repress SnRK1 signalling in Arabidopsis. AB - SNF1-related protein kinase 1 (SnRK1) is a central regulator of plant growth during energy starvation. The FCS-like zinc finger (FLZ) proteins have recently been identified as adaptor proteins which facilitate the interaction of SnRK1 with other proteins. In this study, we found that two starvation-induced FLZ genes, FLZ6 and FLZ10, work as repressors of SnRK1 signalling. The reduced expression of these genes resulted in an increase in the level of SnRK1alpha1, which is the major catalytic subunit of SnRK1. This lead to a concomitant increase in phosphorylated protein and SnRK1 activity in the flz6 and flz10 mutants. FLZ6 and FLZ10 specifically interact with SnRK1alpha subunits in the cytoplasmic foci, which co-localized with the endoplasmic reticulum. In physiological assays, similar to the SnRK1alpha1 overexpression line, flz mutants showed compromised growth. Further, growth promotion in response to favourable growth conditions was found to be attenuated in the mutants. The enhanced SnRK1 activity in the mutants resulted in a reduction in the level of phosphorylated RIBOSOMAL S6 KINASE and the expression of E2Fa and its targets, indicating that TARGET OF RAPAMYCIN-dependent promotion of protein synthesis and cell cycle progression is impaired. Taken together, this study uncovers a plant-specific modulation of SnRK1 signalling. PMID- 29406623 TI - Reply. PMID- 29406621 TI - MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma. AB - : Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a posttranscriptional regulation, possibly involving microRNAs (miRNAs). Here, we describe that at least two HDAC6 targeting miRNAs, miR-433 and miR-22, are down-regulated in CCA both in vitro and in vivo. Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, short hairpin RNA (shRNA) depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. CONCLUSION: These data suggest that down-regulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. (Hepatology 2018). PMID- 29406624 TI - Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration. AB - INTRODUCTION: Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS: Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS: On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION: Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018. PMID- 29406625 TI - Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex. AB - Adverse life experiences increase the lifetime risk to several stress-related psychopathologies, such as anxiety or depressive-like symptoms following stress in adulthood. However, the neurochemical modulations triggered by stress have not been fully characterized. Neuropeptides play an important role as signaling molecules that contribute to physiological regulation and have been linked to neurological and psychiatric diseases. However, little is known about the influence of stress on neuropeptide regulation in the brain. Here, we have performed an exploratory study of how neuropeptide expression at adulthood is modulated by experiencing a period of multiple stressful experiences. We have targeted hippocampus and prefrontal cortex (PFC) brain areas, which have previously been shown to be modulated by stressors, employing a targeted liquid chromatography-mass spectrometry (LC-MS) based approach that permits broad peptide coverage with high sensitivity. We found that in the hippocampus, Met enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu were upregulated, while Leu-enkephalin and Little SAAS were downregulated after stress. In the PFC area, Met-enkephalin-Arg-Phe, Met-enkephalin-Arg-Gly-Leu, peptide PHI-27, somatostatin-28 (AA1-12), and Little SAAS were all downregulated. This systematic evaluation of neuropeptide alterations in the hippocampus and PFC suggests that stressors impact neuropeptides and that neuropeptide regulation is brain-area specific. These findings suggest several potential peptide candidates, which warrant further investigations in terms of correlation with depression associated behaviors. PMID- 29406626 TI - Spanking revisited. PMID- 29406627 TI - Use of Multimedia or Mobile Devices By Adolescents for Health Promotion and Disease Prevention: A Literature Review. AB - The purpose of this literature review is to summarize studies of the use of multimedia technology by adolescents to engage in their healthcare promotion and disease prevention. A systematic literature review of relevant peer-reviewed research published between 2009 and 2014 was performed. The 16 articles reviewed were a combination of quantitative and mixed-method methodology based on the efficacy of multimedia, mobile technology, Short Messaging Services (SMS) texting, and social networking (e.g., Facebook(r)), to engage adolescents ages 10 to 20 years in health promotion and disease prevention. Although adolescents have high attrition rates in the studies, they demonstrated advantages in using SMS texting features and social networking, especially the chat function, in relation to health promotion and disease prevention. Some small gains were noticed in health promotion and disease prevention in the majority of the studies, though some were not significant due to attrition. Additional research, especially nursing research, is necessary. Mobile and multimedia technology allows for a promising correlation between adolescents and increased healthcare knowledge, health promotion, and disease prevention. PMID- 29406628 TI - Sleep Issues in Children with AutismSpectrum Disorder. AB - Sleep issues are more prevalent in children with autism spectrum disorder (ASD)than in typically developing children. Parents often seek help from providers toimprove their child's ability to fall asleep, stay asleep longer, and decrease awakeningsthrough the night. The pathophysiology of ASD, as well as sleep issuesin children with ASD, are not well understood, which poses certain difficulties inchoosing the most effective and appropriate treatment options. This article discussesprobable causes of sleep problems in children with ASD, existing treatments,and implications for clinical practice and future research. PMID- 29406629 TI - Better Together: A Win-Win Pediatric Academic Partnership. AB - As healthcare facilities and academic nursing programs are challenged to be efficient and effective in light of an ever-changing healthcare system, recent literature has focused on the value of creating academic practice partnerships. Using the American Association of Colleges of Nursing (AACN) and American Organization of Nurse Executives (AONE) Academic Practice Partnership Guiding Principles, a children's hospital and state university are working collaboratively to improve evidence-based practice and research, create innovative educational opportunities for undergraduate and advanced practice students, promote academic progression that enables nurses to advance their education, improve access to health care services for underserved families, and implement initiatives that improve patient- and family-centered care. This article will describe the initiatives, processes, and outcomes of this fruitful partnership. The examples we provide using the Academic Practice Partnership Guiding Principles can be adapted in other healthcare facilities and nursing programs. PMID- 29406630 TI - Parent Perspectives on Appointment Nonattendance: A Descriptive Study. AB - Appointment nonattendance is a phenomenon that has been studied in a variety of settings. Increased nonattendance rates may result in lost productivity, patient and provider dissatisfaction, and difficulty recruiting staff and physicians. In addition, needed care for patients may be delayed. The purpose of this descriptive study was to examine parental perspectives regarding appointment nonattendance in pediatric specialty care clinics in order to better understand the facilitators and barriers to successful appointment attendance. An exploratory, descriptive approach was chosen for this study. Eight parents of children ages five years and younger were interviewed regarding appointment attendance in specialty care clinics, and conventional content analysis was used to identify themes. Findings suggest that multiple factors are associated with nonattendance, including child/family system and provider/healthcare system factors. Reducing wait times for specialty appointments (from time of scheduling to appointment date), coordinating multiple services, and offering convenient appointment times may be beneficial in optimizing appointment attendance. PMID- 29406631 TI - Is Descriptive Research Worth Doing? PMID- 29406632 TI - Mentoring Practice and Mentoring Benefit 3: Teaching the Job and Competence - An Overview and Application to Practice Using Mentoring Activities. PMID- 29406633 TI - Empowered by Nurses. AB - Before Justice Hope Coleman was born, nurses in an antenatal testing center provided her parents with support and encouragement, the first steps in empowering them in their roles as parents of a child with multiple disabilities and complex medical needs. Over time, other nurses supported Justice's parents as they learned to communicate clearly and collaboratively with professionals; to provide a high level of care for their daughter in a loving, family-oriented way; and to advocate not only for Justice and their family as a whole, but also for other children and families in the healthcare system. This article describes the important role nurses played in empowering Justice's parents. PMID- 29406634 TI - Screening for Disordered Eating Behaviors in Adolescents and Young Adults with Type 1 Diabetes. PMID- 29406635 TI - Growing Pains: Ethical Considerations for Transitioning to Adult Care with Childhood-Onset Conditions. PMID- 29406636 TI - Use Your Words: Healing Communication with Children and Teens in Healthcare Settings. PMID- 29406637 TI - Patient Safety and Leadership Intentions: Is There a Match? PMID- 29406638 TI - Is the Key to Successful Teambuilding Puzzling? Exactly! PMID- 29406639 TI - Current Recommendations on Management of Pediatric Concussions. AB - Concussions are a form of traumatic brain injury (TBI). Concussion is defined by the American Academy of Neurology as a "trauma-induced alteration in mental status that may or may not involve loss of consciousness" (Kirkwood, Yeates, & Wilson, 2012, p. 1360). At least 1.7 million TBIs occur annually, with 75% being in the form of concussion. Almost half a million patients ages 14 years and younger visit emergency rooms annually for TBI (Centers for Disease Control and Prevention [CDC], 2011). Diagnosing a concussion can be difficult because symptoms vary among individuals and may be subtle and vague, and neuro-radiologic imaging studies typically reveal no abnormalities. Due to the varying degree of symptomatology and recovery, there are no specific recommendations on when it is safe for patients to resume normal activity. Complications can arise if a second injury occurs prior to complete healing from the initial concussion. This literature review identifies current recommendations on the screening and management of concussion in the pediatric population. A clear, concise definition of concussion is presented, as well as recommendations for concussion management. Return to play and return to learn guidelines are explored. The nursing role in concussion management is discussed, and future implications are explored. PMID- 29406640 TI - Infants with Delirium: A Primer on Prevention, Recognition, and Management. AB - Delirium is a serious neuropsychiatric condition that emerges acutely in all age groups, including infants, children, and adolescents. Delirium serves as an urgent signal of distress that a young child's brain is in trouble. Prevention, recognition, and management of infants with delirium is often especially challenging due to their pre-verbal status and still immature cognitive development. This article presents an overview of delirium in infants, offers details regarding the presentation of delirium in infants, discusses the challenges to screening and identification of infants with delirium, and provides evidence-based suggestions for pediatric nurses to optimize nursing care for infants at risk for or exhibiting delirium. PMID- 29406641 TI - Concurrent Medical Conditions in Autism Spectrum Disorders. AB - Long thought to be purely psychological in origin, current research lends credenceto the idea that autism has a medical basis. Patients with autism can be among themost challenging patients that a healthcare provider may care for. Often the presentingsymptoms of autism make these patients difficult to examine and may alsomask underlying concurrent conditions. This article reviews some of the more commonconditions found concurrently in the autistic population. PMID- 29406642 TI - Evaluation of Identified Stressors in Children and Adolescents After Super Storm Sandy. AB - Super Storm Sandy, one of the largest storms endured by the East Coast of theUnited States, devastated New Jersey and the eastern seaboard. Although naturaldisasters affect individuals of all ages, children are particularly vulnerable becausetheir sense of normalcy is altered. The purpose of this study was to explore theeffects that exposure to Super Storm Sandy had on children who resided in NewJersey. This was a non-experimental, quantitative, cross-sectional research study.Study participants were recruited via printed flyers at disaster resource sites and ona dedicated research team's Facebook site. Each participant completed theHurricane Stressors Assessment Tool for Children and Adolescents as a webbasedsurvey related to their experiences with the hurricane. One hundred andforty-one (141) children participated in this study. Age groups (preschool, child, andadolescent) had varied results based upon developmental level. Age was positivelyassociated with finding it harder to concentrate and pay attention (r = 0.18, p =0.04); feeling sad, down, or depressed (r = 0.17, p < 0.05); being quiet and withdrawn (r = 0.16, p = 0.05); feeling irritable and grouchy (r = 0.26, p < 0.05); and findingit harder to complete schoolwork (r = 0.32, p < 0.001). Certain parental perceptionsof their child's behavior were negatively associated with the age of the child.Children had varying degrees of experiences after Sandy. Adolescents were shownto be more aware and affected by the storm than younger children. Observationscan be used for intervention initiatives in the post natural disaster period, encouraginghealthcare providers to acknowledge family and community healing to provideadequate mental health referrals in the post disaster period. PMID- 29406643 TI - Natural Disasters: Looking at the Consequences. PMID- 29406644 TI - Making Positive Health Changes in Obese/Overweight Children with Hypertension. AB - Well-child visits can be ideal times for health education of children, parents, and caregivers. A trusting relationship with both children and their parents is the foundation for acceptance of any changes in health behaviors. Children grow rapidly, and poor health conditions during this time could be unfavorable or detrimental to their long-term wellbeing. Clinicians play pivotal roles in helping children understand the importance of working toward healthier lifestyles and preventing hypertension and obesity. Hypertension in obese and overweight children continues to increase, but these two conditions are preventable and can also be reversible if managed early. Data from four studies reviewed here indicate that diet and exercise can help reduce the incidence of hypertension in overweight/obese children. Primary care providers can incorporate specifically pointed physical activity and dietary change education into their daily practices, with attention directed toward helping children with hypertension to decrease their blood pressure for life. PMID- 29406645 TI - Empowering Staff Nurses as Primary Educators to Children with Type 1 Diabetes. AB - Patient and family education is a critical element of diabetes management. Manychildren with new onset type 1 diabetes present with symptoms of diabeticketoacidosis (DKA) and are hospitalized at diagnosis. These children and theirfamilies receive their initial education in the hospital setting. As soon as bloodglucose levels are stabilized and the acidosis is corrected, the patient is dischargedhome, usually within three days (Nettles, 2005). There is little time toprovide the skills and education, as well as emotional support, for a smooth transitionto home. It is a challenge to achieve these goals if the only resource personfor diabetes education is the clinical nurse specialist (CNS). The CNS for a 14-bed pediatric unit sought to expand the role of the bedside nurse to being the primaryeducator of patients with diabetes through education and support. All nursesattended an eight-hour workshop on diabetes. A DKA protocol was developedthrough multidisciplinary collaboration, and nurses were educated on this protocol.Additionally, the CNS organized a diabetes resource cart that contains thetools for diabetes education. The protocol and education materials wereuploaded in the Pediatric SharePoint site to make them accessible to nurses. Most importantly, the CNS developed a structured patient education plan that isoutcome-oriented, and based on review of current literature and practices in theunit. This initiative resulted in an increase in nursing confidence and expertiserelated to diabetes care as demonstrated by competencies met by nurses andanecdotal evidence from nurses and patients' caregivers. PMID- 29406646 TI - Mentoring Practice and Mentoring Benefit 4: Supporting the Transition and Professional Growth - An Overview and Application to Practice Using Mentoring Activities. PMID- 29406647 TI - Empowering Children with Autism Spectrum Disorder and Their Families within the Healthcare Environment. AB - Patient and family education is a critical element of diabetes management. Many children with new onset type 1 diabetes present with symptoms of diabetic ketoacidosis (DKA) and are hospitalized at diagnosis. These children and their families receive their initial education in the hospital setting. As soon as blood glucose levels are stabilized and the acidosis is corrected. The patient is discharged home, usually within three days (Nettles, 2005). There is little time to provide the skills and education, as well as emotional support, for a smooth transition to home. It is a challenge to achieve these goals if the only resource person for diabetes education is the clinical nurse specialist (CNS). The CNS for a 14-bed pediatric unit sought to expand the role of the bedside nurse to being the primary educator of patients with diabetes through education and support. All nurses attended an eight-hour workshop on diabetes. A DKA protocol was developed through multidisciplinary collaboration, and nurses were educated on this protocol. Additionally, the CNS organized a diabetes resource cart that contains the tools for diabetes education. The protocol and education materials were uploaded in the Pediatric Share Point site to make them accessible to nurses. Most importantly, the CNS developed a structured patient education plan that is outcome-oriented, and based on review of current literature and practices in the unit. This initiative resulted in an increase in nursing confidence and expertise related to diabetes care as demonstrated by competencies met by nurses and anecdotal evidence from nurses and patients' caregivers. PMID- 29406648 TI - Implementing a Pediatric Fall Prevention Policy and Program. AB - Preventing patient falls begins with an accurate assessment of a patient's risk of falling followed by the initiation and continued evaluation of a fall prevention program based on patient-specific identified risks. Children have a normal tendency to fall based on developmental growth, and each child is different in physical and cognitive abilities. Falls may occur both in and out of the hospital setting. Prevention programs that have revealed the most favorable restuls include the use of a validated fall risk assessment tool. The Humpty Dumpty fall Scale is a screening tool specifically developed for pediatric patients to assess risk for fall. This project developed a pediatric fall prevention policy and implemented an inpatient pediatric fall prevention program. Pediatric staff contributed to the development of this policy and program by providing feedback, support, and cooperation, which was instrumental in the success of this program resulting in no falls after implementation. PMID- 29406649 TI - Balancing Life after Concussion:An Update. PMID- 29406650 TI - Evidence-Based Recommendations for Reducing Pediatric Distress During Vaccination. AB - Vaccinations are often associated with anxiety, avoidance, and considerable distress for children and parents. These issues can also impair coping during future health care visits. Parents, children, and clinicians can benefit from strategies designed to enhance coping. However, an important barrier to implementation of coping strategy interventions is lack of knowledge among both parents and staff. We produced two sets of tailored handouts designed to enhance education for primary care staff and parents using 41 clinical guidelines, reviews, and randomized controlled trials. Articles were selected from vaccine specific literature by relevance and practicality for primary care. Handouts provide suggestions for parent and staff interventions before, during, and after vaccinations, focusing on techniques that are effective, cost-efficient, and adaptable. For children of all ages, tailored adult vocabulary and tone can also support coping. PMID- 29406651 TI - Understanding and Supporting Grieving Adolescents and Young Adults. AB - The adolescent and young adult years are a time of growth, change, and challenge. Experiencing the loss of a family member or friend during this period of life can have a profound effect on a young person's social functioning, physical and mental health, and development. Research demonstrates that the grief reactions of adolescents and young adults differ from those of adults, and that loss is an individual experience that varies widely throughout each developmental stage. Further, youth who struggle to cope with a significant loss without support and guidance are more likely to experience a greater intensity of grief and distress. When providing support to a grieving adolescent or young adult, it is important to understand normal development, appreciate common grief responses, and identify deviations. It is also important to know about available interventions and supportive strategies, specifically for this age group. With this knowledge, pediatric nurses and other helping professionals can tailor guidance, support, and referrals to suit the specific needs of individual bereaved youth. PMID- 29406652 TI - Evaluation of an Educational Program to Improve School Nursing Staff Perceptions of Bullying In Pinellas County, Florida. AB - The purpose of this project was to determine if a bullying educational program for school nurses and certified nursing assistants/health technicians (CNAs/HTs) would increase knowledge of bullying, probability of reporting a bully, and probability of assisting a bullied victim. This educational program and evaluation employed a retrospective, post-then-pre-test design. Instruments used included a 17-item demographic questionnaire and the 12-item Reduced Aggression/ Victimization Scale Bullying Assessment Tool (BAT), a 5-point Likert Scale de - signed to assess school nurses' and CNAs'/HTs' understanding of bullying, the probability of reporting bullies, and the probability of assisting bullied victims before and after the educational presentation. Findings of this educational evaluation program indicated that the majority of school nurses and CNAs/HTs had an increased understanding of bullying, higher probability of reporting a bully, and assisting a bullied victim after the presentation. PMID- 29406653 TI - Pediatric Diabetes Telemedicine Program Improves Access to Care for Rural Families: Role of APRNs. AB - Type 1 diabetes mellitus has increased in children by 23% from 2001 to 2009. Rural communities additionally have increased disparities related to access barriers and a large minority population with poorer overall health. Research evidence supports telemedicine as an effective alternative to bring preventive diabetes care to remote areas. This article presents an overview of the leadership role of advanced practice registered nurses (APRNs) with the implementation and evaluation of a pediatric diabetes telemedicine program at a rural pediatric outpatient specialty clinic in partnership with a tertiary center telemedicine network. The telemedicine program quality improvement (QI) project explored caregiver satisfaction with a convenience sample of caregivers (N = 14) using a nine-item Telemedicine Diabetes Caregiver Satisfaction Survey (TDCSS), with responses ranging from 1 = strongly disagree to 5 = strongly agree. Findings indicate caregivers were highly satisfied with communication/ privacy (M = 4.8), access to care (M = 4.1), and quality of services (M = 5.0). The multidisciplinary collaborative teamwork, continuous QI, and dependable technology were integral to the quality of the telemedicine clinical initiative. APRNs provided technology expertise, interdisciplinary collaboration leadership, care coordination, and advocacy for policy changes. Results demonstrate that telemedicine and APRN leadership can help implement innovative programs into rural communities to improve access to care, healthcare cost, and outcomes. PMID- 29406654 TI - Innovative Programs Highlighting Patient and Family Engagement. PMID- 29406655 TI - Everyday Ethics for Every Child. PMID- 29406656 TI - How Heroes Saved My Life. PMID- 29406657 TI - Evaluation: What Is All the Fuss About? PMID- 29406658 TI - Mentoring Practice and Mentoring Benefit 5: Providing Protection and Security - An Overview and Application To Practice Using Mentoring Activities. PMID- 29406659 TI - Sharing a Room: Updated Recommendations for a Safe Infant Sleeping Environment. PMID- 29406660 TI - The Lived Experiences of Nurses Caring For Dying Pediatric Patients. AB - Nurses and healthcare professionals may have difficulty adjusting to and comprehending their experiences when a patient's life ends. This has the potential to interfere with patient care. Reflection on past events and actions enables critical discovery of strategies to benefit both nurses and patients. This qualitative phenomenological study explores the lived experiences of nurses caring for dying pediatric patients. The philosophical underpinning of Merleau Ponty (2008), in combination with the research method of van Manen (1990), was used for this study. The Roy Adaptation Model (RAM) (Roy, 2009; Roy & Andrews, 1991) was the nursing model that guided the study to help understand that nurses are an adaptive system, using censoring as a compensatory adaptive process to help function for a purposeful cause. Nine female nurse participants with one to four years of experience were interviewed. The context of the experiences told by nurses caring for dying pediatric patents uncovered seven essential themes of empathy, feelings of ambivalence, inevitability, inspiration, relationship, self preservation, and sorrow, and these themes demonstrated a connection formed between the nurse and the patient. PMID- 29406661 TI - The Heart of Nursing. PMID- 29406662 TI - Including Parents in the Treatment of Pediatric Complex Regional Pain Syndrome. AB - Complex regional pain syndrome (CRPS) is a clinically diagnosed chronic pain syndrome characterized by severe pain and functional disability following a minor injury. The affected limb often has evidence of changes in sensory, vasomotor, sudomotor/edema, and/or motor/tropic function. The diagnosis of CRPS in the pediatric population is increasingly common, especially among female adolescents. The pain experience of adolescents with CRPS is best understood using the biopsychosocial framework, and the most effective treatment programs target biological, psychological, and social factors. Treatment for CRPS is multidisciplinary and typically includes physical therapy, occupational therapy, and psychology. The parent-child dyad that develops when the child has CRPS is complex and characterized by significant psychological distress, ineffective parenting, and poor coping. The purpose of this article is to describe the role of parents in the treatment of adolescents with CRPS. To promote successful remission from pain and restoration of functional ability, parents should be included in treatment programs. Nurses caring for adolescents with CRPS can assist parents in developing adaptive parenting skills. PMID- 29406663 TI - Impacting Parental Vaccine Decision-Making. AB - An increase in vaccine hesitancy is contributing to an increase of vaccine refusal and the use of an alternative vaccine schedule (AVS) in the United States. Increasing vaccine knowledge and correcting vaccine misinformation has the potential of shifting parental attitudes, decreasing vaccine hesitancy, and increasing parental intent to vaccinate. The aim was to examine the impact of a voice-over PowerPointTM presentation on vaccine education and decision-making by vaccine-hesitant parents in a pediatric primary care clinic. A quasi-experimental study using the Parent Attitude about Childhood Vaccine (PACV) Survey was conducted in a suburban pediatric clinic to explore the impact of vaccine education on decision-making by vaccine-hesitant parents. PACV Survey scores were collected over three months. Surveyed parents reported they trust their healthcare provider. Unfortunately, although parents trust the information their medical providers give them on vaccine safety, they continue to be concerned about vaccine side effects. Mothers tended to provide more vaccine-hesitant scores than fathers related to safety and efficacy concerns. The utilization of the PACV Survey and voice-over PowerPoint presentation on vaccine education is an intervention that may be used in pediatric clinics to assist in vaccine education and identify vaccine-hesitant parents. The study contributes to the addition of evidence- based vaccine education. PMID- 29406664 TI - Parental Knowledge about Urban Preschool Children's Oral Health Risk. AB - Dental caries is one of the most prevalent and significant health problems in the United States. According to the American Academy of Pediatric Dentistry, more than one-fourth of children between the ages of two and five years experience early childhood caries before entering kindergarten. The purpose of this study was to explore parent's knowledge of preschool children's oral health risk factors. A descriptive design was used with a convenience sample of 87 parents of children who attended day care centers and preschools. Seventeen knowledge questions were used to assess parents' knowledge of their child's oral health. Results showed that parents lacked knowledge in some aspects of oral health care. The majority of parents knew that baby teeth are important, and both baby and permanent teeth should be brushed. Fewer, however, perceived that cavities in baby teeth lead to cavities in permanent teeth. Similarly, parents knew the role of food in the dental caries, but fewer perceived that cavities may be caused by using a bottle or infant drinking cup to drink fluid other than water and frequent snacking. Findings illuminate the knowledge gaps in this sample of parents of preschoolers. Pediatric nurses can play a key role in promoting children's oral health and preventing dental caries by proving anticipatory guidance and education to children and their parents at well child visits, during hospitalization, and in school and community settings. PMID- 29406665 TI - Children's Exposure to Secondhand Smoke, Parental Nicotine Dependence, and Motivation to Quit Smoking. AB - More than 600,000 people die each year as a result of exposure to secondhand smoke (SHS); 28% of those deaths are children. Most exposure for children occurs in the home and is due to a parent smoking. Parental awareness and understanding of the exposure to SHS and the risk that parental smoking brings to the child may be an effective impetus for smoke avoidance and parental tobacco cessation. This descriptive, correlational study used data provided by a convenience sample of 184 smoking parental-figures, representing 376 children, recruited in community settings. Seven research questions were posed regarding the exposure of children to parental figures who smoke, the degree of the parents' dependence on nicotine, and their level of motivation to stop smoking. Comparisons were made between income levels and ethnic/racial groups. Children's exposure to SHS was low; Asian children had the highest likelihood of exposure. The areas of most frequent exposure were multiunit residential communities and in a vehicle. Parents' dependence on nicotine was moderately high, and parental motivation to quit smoking was high. However, parents who were the most dependent on nicotine were the least motivated to quit. Nurses working with both adult and pediatric populations should address the opportunities for exposure to SHS for their patient population. Community health nurses should specifically target workplaces, businesses, and communities with high numbers of Asian residents for public health education related to childhood exposure to SHS. PMID- 29406666 TI - Mentoring Practice and Mentoring Benefit 6: Equipping for Leadership and Leadership Readiness - An Overview and Application to Practice Using Mentoring Activities. PMID- 29406667 TI - Supporting Youth Aging Out of Foster Care. AB - Over 400,000 children are in foster care in the United States, and more than 100,000 of them are waiting to be adopted. Yet many will age out of foster care into adulthood without an adoptive family. Teens and young adults aging out of foster care, even those with preparation and training for the transition, often do not fare well in young adulthood. Many face challenges in areas of education, employment, homelessness, finances, the criminal justice system, and meeting health and mental healthcare needs. Research demonstrates what only makes sense: teens with tangible support from meaningful adult relationships fare better than those without. This article describes an innovative program that connects teens in foster care with supportive adults through social events that can lead to meaningful long-term teen-adult connections - including friendships, mentoring, and even, in some cases, adoption. Pediatric nurses, aware of the challenges these teens face adjusting to adulthood, can begin to explore referral and support options for such teens in their own locales using the resources herein. PMID- 29406668 TI - Weight Management Clinic for the Treatment of a 14-Year-Old Female with Sudden Weight Gain. PMID- 29406669 TI - Transitioning to Electronic Clinical Quality Measures in the Informatics Era. PMID- 29406670 TI - [In process]. PMID- 29406671 TI - Does Your Forms Committee Need a Facelift? Standardizing Best Practices for HIM focused Committees--A Case Study in the Physician Practice Setting. PMID- 29406672 TI - [In process]. PMID- 29406673 TI - [In process]. PMID- 29406674 TI - [In process]. PMID- 29406675 TI - [In process]. PMID- 29406676 TI - HIM Students Help Build an Innovative Path to Information Governance. PMID- 29406677 TI - [In process]. PMID- 29406678 TI - [In process]. PMID- 29406679 TI - [In process]. PMID- 29406680 TI - [In process]. PMID- 29406681 TI - [In process]. PMID- 29406683 TI - Information Asset Inventory for Information Governance. PMID- 29406682 TI - [In process]. PMID- 29406684 TI - [In process]. PMID- 29406685 TI - [In process]. PMID- 29406686 TI - [In process]. PMID- 29406687 TI - The Evolution of Coding Information/Resources to an Organization-wide Portal Site. PMID- 29406688 TI - CY 2017 OPPS Update. PMID- 29406689 TI - Send in the (Potentially Life-Saving) Drones. PMID- 29406691 TI - Nanoporous Gold-Based Biofuel Cells on Contact Lenses. AB - A lactate/O2 enzymatic biofuel cell (EBFC) was prepared as a potential power source for wearable microelectronic devices. Mechanically stable and flexible nanoporous gold (NPG) electrodes were prepared using an electrochemical dealloying method consisting of a pre-anodization process and a subsequent electrochemical cleaning step. Bioanodes were prepared by the electrodeposition of an Os polymer and Pediococcus sp. lactate oxidase onto the NPG electrode. The electrocatalytic response to lactate could be tuned by adjusting the deposition time. Bilirubin oxidase from Myrothecium verrucaria was covalently attached to a diazonium-modified NPG surface. A flexible EBFC was prepared by placing the electrodes between two commercially available contact lenses to avoid direct contact with the eye. When tested in air-equilibrated artificial tear solutions (3 mM lactate), a maximum power density of 1.7 +/- 0.1 MUW cm-2 and an open circuit voltage of 380 +/- 28 mV were obtained, values slightly lower than those obtained in phosphate buffer solution (2.4 +/- 0.2 MUW cm-2 and 455 +/- 21 mV, respectively). The decrease was mainly attributed to interference from ascorbate. After 5.5 h of operation, the EBFC retained 20% of the initial power output. PMID- 29406690 TI - High-Index Faceted Porous Co3O4 Nanosheets with Oxygen Vacancies for Highly Efficient Water Oxidation. AB - Because of sluggish kinetics of the oxygen evolution reaction (OER), designing low-cost, highly active, and stable electrocatalysts for OER is important for the development of sustainable electrochemical water splitting. Here, {112} high index facet exposed porous Co3O4 nanosheets with oxygen vacancies on the surface have been successfully synthesized via a simple hydrothermal method followed by NaBH4 reduction. As compared with the pristine and other faceted porous Co3O4 nanosheets (e.g., {110} and {111}), the as-prepared {112} faceted porous nanosheets exhibit a much lower overpotential of 318 mV at a current density of 10 mA cm-2. Importantly, these nanosheets also give excellent electrochemical stability, displaying an insignificant change in the required overpotential at a current density of 10 mA cm-2 even after a 14 h long-term chronoamperometric test. All these superior OER activity and stability could be attributed to their unique hierarchical structures assembled by ultrathin porous nanosheets, {112} high-index exposed facets with higher ratio of Co2+/Co3+ and oxygen vacancies on the surface, which can substantially enhance the charge transfer rate and increase the number of active sites. All these findings not only demonstrate the potency of our Co3O4 nanosheets for efficient water oxidation but also provide further insights into developing cost-effective and high-performance catalysts for electrochemical applications. PMID- 29406692 TI - Inhibition of the Replication of Different Strains of Chikungunya Virus by 3-Aryl [1,2,3]triazolo[4,5- d]pyrimidin-7(6 H)-ones. AB - The re-emergence of chikungunya virus (CHIKV) is a serious global health threat. CHIKV is an alphavirus that is transmitted to humans by Aedes mosquitoes; therefore, their wide distribution significantly contributes to the globalization of the disease. Unfortunately, no effective antiviral drugs are available. We have identified a series of 3-aryl-[1,2,3]triazolo[4,5- d]pyrimidin-7(6 H)-ones as selective inhibitors of CHIKV replication. New series of compounds have now been synthesized with the aim to improve their physicochemical properties and to potentiate the inhibitory activity against different CHIKV strains. Among these newly synthesized compounds modified at position 3 of the aryl ring, tetrahydropyranyl and N- t-butylpiperidine carboxamide derivatives have shown to elicit potent antiviral activity against different clinically relevant CHIKV isolates with 50% effective concentration (EC50) values ranging from 0.30 to 4.5 MUM in Vero cells, as well as anti-CHIKV activity in human skin fibroblasts (EC50 = 0.1 MUM), a clinically relevant cell system for CHIKV infection. PMID- 29406693 TI - Comprehensive Profiling of Fecal Metabolome of Mice by Integrated Chemical Isotope Labeling-Mass Spectrometry Analysis. AB - Gut microbiota plays important roles in the host health. The host and symbiotic gut microbiota coproduce a large number of metabolites during the metabolism of food and xenobiotics. The analysis of fecal metabolites can provide a noninvasive manner to study the outcome of the host-gut microbiota interaction. Herein, we reported the comprehensive profiling of fecal metabolome of mice by an integrated chemical isotope labeling combined with liquid chromatography-mass spectrometry (CIL-LC-MS) analysis. The metabolites are categorized into several submetabolomes based on the functional moieties (i.e., carboxyl, carbonyl, amine, and thiol) and then analysis of the individual submetabolome was performed. The combined data from the submetabolome form the metabolome with relatively high coverage. To this end, we synthesized stable isotope labeling reagents to label metabolites with different groups, including carboxyl, carbonyl, amine, and thiol groups. We detected 2302 potential metabolites, among which, 1388 could be positively or putatively identified in feces of mice. We then further confirmed 308 metabolites based on our established library of chemically labeled standards and tandem mass spectrometry analysis. With the identified metabolites in feces of mice, we established mice fecal metabolome database, which can be used to readily identify metabolites from feces of mice. Furthermore, we discovered 211 fecal metabolites exhibited significant difference between Alzheimer's disease (AD) model mice and wild type (WT) mice, which suggests the close correlation between the fecal metabolites and AD pathology and provides new potential biomarkers for the diagnosis of AD. PMID- 29406694 TI - In Situ Living Cell Protein Analysis by Single-Step Mass Spectrometry. AB - In situ living cell protein analysis would enable the structural identification and functional interrogation of intracellular proteins in native cellular environments. Previously, we have presented an in situ mass spectrometry (MS) strategy to identify protein and protein/metal ion complex with relatively small molecular weight ( Anal. Chem. 2016, 88, 10860-10866). However, it is still challenging to directly identify larger proteins and protein/ligand complexes in cell, due to numerous nonspecific bindings of ligands, solvents, and other cellular constituents. Here we present a versatile single-step mass spectrometric strategy, "in-cell" mass spectrometry ("in-cell" MS), for in situ protein identification and dynamic protein-ligand interaction monitoring directly from living cells. "In-cell" MS combined all-ion-fragmentation mode with our previous method; thus, on a high-resolution MS instrument, we can greatly improve the signal/noise ratio of the larger proteins and protein/ligand complexes. Meanwhile, we also achieved a much wider mass range for protein complex and detection of 17 proteins with molecular weight ranging from 4 to 44 kDa. In addition, "in-cell" MS could also monitor dynamic protein interactions in living cells. Calcium-regulated calmodulin-melittin interaction was tested to demonstrate the proof of concept. "In-cell" MS provides an alternative for in situ analysis of living cells, which might contribute to rapid protein analysis and quality control in biochemistry laboratories, protein engineering, and even protein industry. PMID- 29406695 TI - Neutralizing the Detrimental Effect of an N-Hydroxysuccinimide Quenching Reagent on Phosphopeptide in Quantitative Proteomics. AB - One of the most common chemistries used to label primary amines utilizes N hydroxysuccinimide (NHS), which is also structurally incorporated in various quantitative proteomic reagents such as isobaric tags for relative and absolute quantification (iTRAQ) and tandem mass tags (TMT). In this paper we report detrimental effect of hydroxylamine, a widely used quenching reagent for excess NHS, on phosphopeptides. We found an impairment in the degree of phosphopeptide identification when hydroxylamine-quenched TMT-labeled samples were vacuum-dried and desalted compared to the nondried (just diluted) and desalted ones prior to phosphoenrichment. We have also demonstrated that vacuum-drying in the presence of hydroxylamine promotes beta-elimination of phosphate groups from phosphoserine and phosphothreonine while having a minimalistic effect on phosphotyrosine. Additionally, we herein report that this negative impact of hydroxylamine could be minimized by direct desalting after appropriate dilution of quenched samples. We also found a 1.6-fold increase in the number of phosphopeptide identifications after employing our optimized method. The above method was also successfully applied to human tumor tissues to quantify over 15000 phosphopeptides from 3 mg TMT 6-plex labeled-peptides. PMID- 29406696 TI - Reversible Control of Network Properties in Azobenzene-Containing Hyaluronic Acid Based Hydrogels. AB - Biomimetic hydrogels fabricated from biologically derived polymers, such as hyaluronic acid (HA), are useful for numerous biomedical applications. Due to the dynamic nature of biological processes, it is of great interest to synthesize hydrogels with dynamically tunable network properties where various functions (e.g., cargo delivery, mechanical signaling) can be changed over time. Among the various stimuli developed to control hydrogel properties, light stands out for its exquisite spatiotemporal control; however, most light-based chemistries are unidirectional in their ability to manipulate network changes. Here, we report a strategy to reversibly modulate HA hydrogel properties with light, using supramolecular cross-links formed via azobenzene bound to beta-cyclodextrin. Upon isomerization with 365 nm or 400-500 nm light, the binding affinity between azobenzene and beta-cyclodextrin changed and altered the network connectivity. The hydrogel mechanical properties depended on both the azobenzene modification and isomeric state (lower for cis state), with up to a 60% change in storage modulus with light exposure. Furthermore, the release of a fluorescently labeled protein was accelerated with light exposure under conditions that were cytocompatible to encapsulated cells. These results indicate that the developed hydrogels may be suitable for applications in which temporal regulation of material properties is important, such as drug delivery or mechanobiology studies. PMID- 29406697 TI - DNA Repair: Unconventional Lesions Require Unconventional Repair. PMID- 29406698 TI - Modular, Bioorthogonal Strategy for the Controlled Loading of Cargo into a Protein Nanocage. AB - Virus capsids, i.e., viruses devoid of their genetic material, are suitable nanocarriers for biomedical applications such as drug delivery and diagnostic imaging. For this purpose, the reliable encapsulation of cargo in such a protein nanocage is crucial, which can be accomplished by the covalent attachment of the compounds of interest to the protein domains positioned at the interior of the cage. This approach is particularly valid for the capsid proteins of the cowpea chlorotic mottle virus (CCMV), which have their N-termini located at the inside of the capsid structure. Here, we examined several site-selective modification methods for covalent attachment and encapsulation of cargo at the N-terminus of the CCMV protein. Initially, we explored approaches to introduce an N-terminal azide functionality, which would allow the subsequent bioorthogonal modification with a strained alkyne to attach the desired cargo. As these methods showed compatibility issues with the CCMV capsid proteins, a strategy based on 2 pyridinecarboxaldehydes for site-specific N-terminal protein modification was employed. This method allowed the successful modification of the proteins, and was applied for the introduction of a bioorthogonal vinylboronic acid moiety. In a subsequent reaction, the proteins could be modified further with a fluorophore using the tetrazine ligation. The application of capsid assembly conditions on the functionalized proteins led to successful particle formation, showing the potential of this covalent encapsulation strategy. PMID- 29406699 TI - Multifunctional Serine Protease Inhibitor-Coated Water-Soluble Gold Nanoparticles as a Novel Targeted Approach for the Treatment of Inflammatory Skin Diseases. AB - The overexpression and increased activity of the serine protease Kallikrein 5 (KLK5) is characteristic of inflammatory skin diseases such as Rosacea. The use of inhibitors of this enzyme-such as 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF.HCl) or the anti-human recombinant Kallikrein 5 (anti-KLK5) antibody-in the treatment of the disease has been limited due to their low bioavailability, for which their immobilization in drug delivery agents can contribute to making serine protease inhibitors clinically useful. In this work, we synthesized gold nanoparticles (GNP) coated with a mixture of hydroxyl- and carboxyl-terminated thiolates (GNP.OH/COOH), whose carboxyl groups were used to further functionalize the nanoparticles with the serine protease inhibitor AEBSF.HCl either electrostatically or covalently (GNP.COOH AEBSF and GNP.AEBSF, respectively), or with the anti-KLK5 antibody (GNP.antiKLK5). The synthesized and functionalized GNP were highly water-soluble, and they were extensively characterized using UV-vis absorption spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Thermogravimetric Analysis (TGA). GNP.OH/COOH and their subsequent functionalizations effectively inhibited KLK5 in vitro. Internalization of fluorophore-coated GNP.OH/COOH in human keratinocytes (HaCaT cells) was proven using confocal fluorescence microscopy. Cell viability assays revealed that the cytotoxicity of free AEBSF is importantly decreased when it is incorporated in the nanoparticles, either ionically (GNP.COOH AEBSF) or, most importantly, covalently (GNP.AEBSF). The functionalized nanoparticles GNP.AEBSF and GNP.antiKLK5 inhibited intracellular KLK5 activity in HaCaT cells and diminished secretion of IL-8 under inflammatory conditions triggered by TLR-2 ligands. This study points to the great potential of these GNP as a new intracellular delivery strategy for both small drugs and antibodies in the treatment of skin diseases such as Rosacea. PMID- 29406700 TI - Electrochemical Difluoromethylarylation of Alkynes. AB - An unprecedented radical difluoromethylarylation reaction of alkynes has been developed by discovering a new difluoromethylation reagent, CF2HSO2NHNHBoc. This air-stable and solid reagent can be prepared in one step from commercially available reagents CF2HSO2Cl and NH2NHBoc. The CF2H radical, generated through ferrocene-mediated electrochemical oxidation, participates in an unexplored alkyne addition reaction followed by a challenging 7-membered ring-forming homolytic aromatic substitution step to afford fluorinated dibenzazepines. PMID- 29406702 TI - Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists. AB - CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue. PMID- 29406701 TI - Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking. AB - A new method for cysteine-lysine cross-linking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a cross-link. The linkage so formed is stable toward acid, base, oxygen, and external thiol nucleophiles. This method was applied to cross-link cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular cross linking between a peptide and a protein based on the p53-MDM2 interaction. These studies demonstrate the potential for palladium-mediated methods to serve as a platform for the development of future cross-linking techniques for peptides and proteins with natural amino acid residues. PMID- 29406703 TI - Rhodium(III) and Iridium(III) Bipyricorrole Complexes: Syntheses, Structures, and Properties. AB - Rhodium(III) and iridium(III) bipyricorrole complexes have been unprecedentedly reported. Single-crystal X-ray diffraction studies unambiguously evinced the molecular structures of metal complexes in octahedral geometry. The monoanionic platform of bipyricorrole effectively stabilizes metal ions in their higher oxidation states. It is worth mentioning that the fluorescence quantum yield of the rhodium(III) complex is 3-fold higher than that of free-base bipyricorrole. PMID- 29406704 TI - Global Atmospheric Concentrations of Brominated and Chlorinated Flame Retardants and Organophosphate Esters. AB - Polyurethane foam (PUF) disk passive air samples, deployed during 2014 in the Global Atmospheric Passive Sampling (GAPS) Network, were analyzed for a range of flame retardants (FRs) including polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), brominated and chlorinated novel FRs, and organophosphate esters (OPEs). Mean concentrations of PBDEs and novel FRs at the 48 sites monitored ranged from 0.097 to 93 pg/m3 for Sigma14PBDEs and from below detection limits to 126 pg/m3 for Sigma15novel FRs. For PBDEs, the detected concentrations were similar to those previously reported from samples collected in 2005 at GAPS sites, suggesting global background atmospheric concentrations of PBDEs have not declined since regulatory measures were implemented. OPEs were detected at every GAPS site, with Sigma18OPEs ranging from 69 to 7770 pg/m3. OPE concentrations were at least an order of magnitude higher than the PBDEs. This study presents the first data on global distributions of OPEs in the atmosphere, obtained from a single passive sampling monitoring network. Challenges that can arise in passive air sampling campaigns are also highlighted and addressed with suggested recommendations for future campaigns. PMID- 29406706 TI - Crystallographic and Spectroscopic Characterization of Americium Complexes Containing the Bis[(phosphino)methyl]pyridine-1-oxide (NOPOPO) Ligand Platform. AB - The crystal structures of americium species containing a common multifunctional phosphine oxide ligand, reported for its ability to extract f elements from acidic solutions, namely, 2,6-[Ph2P(O)CH2]2C5H3-NO, L, were finally determined after over three decades of separations studies involving these species and their surrogates. The molecular compounds Am(L)(NO3)3, Am 1:1, and [Am(L)2(NO3)][2(NO3)], Am 2:1, along with their neodymium and europium analogues, were synthesized and characterized using single-crystal X-ray crystallography, attenuated total reflectance Fourier transform infrared spectroscopy, and luminescence spectroscopy to provide a comprehensive comparison with new and known analogous complexes. PMID- 29406705 TI - High Activity and Efficient Turnover by a Simple, Self-Assembled "Artificial Diels-Alderase". AB - The Diels-Alder (DA) reaction is a cornerstone of synthesis, yet Nature does not use catalysts for intermolecular [4+2] cycloadditions. Attempts to create artificial "Diels-Alderases" have also met with limited success, plagued by product inhibition. Using a simple Pd2L4 capsule we now show DA catalysis that combines efficient turnover alongside enzyme-like hallmarks. This includes excellent activity (kcat/kuncat > 103), selective transition-state stabilization comparable to the most proficient DA catalytic antibodies, and control over regio and chemoselectivity that would otherwise be difficult to achieve using small molecule catalysts. Unlike other catalytic approaches that use synthetic capsules, this method is not defined by entropic effects; instead multiple H bonding interactions modulate reactivity, reminiscent of enzymatic action. PMID- 29406707 TI - Free Energy Calculations of Membrane Permeation: Challenges Due to Strong Headgroup-Solute Interactions. AB - Understanding how different classes of molecules move across biological membranes is a prerequisite to predicting a solute's permeation rate, which is a critical factor in the fields of drug design and pharmacology. We use biased molecular dynamics computer simulations to calculate and compare the free energy profiles of translocation of several small molecules across 1,2-dioleoyl- sn-glycero-3 phosphocholine (DOPC) lipid bilayers as a first step toward determining the most efficient method for free energy calculations. We study the translocation of arginine, a sodium ion, alanine, and a single water molecule using the metadynamics, umbrella sampling, and replica exchange umbrella sampling techniques. Within the fixed lengths of our simulations, we find that all methods produce similar results for charge-neutral permeants, but not for polar or positively charged molecules. We identify the long relaxation time scale of electrostatic interactions between lipid headgroups and the solute to be the principal cause of this difference and show that this slow process can lead to an erroneous dependence of computed free energy profiles on the initial system configuration. We demonstrate the use of committor analysis to validate the proper sampling of the presumed transition state, which in our simulations is achieved only in replica exchange calculations. On the basis of these results we provide some useful guidance to perform and evaluate free energy calculations of membrane permeation. PMID- 29406708 TI - Oxygen Reduction by Homogeneous Molecular Catalysts and Electrocatalysts. AB - The oxygen reduction reaction (ORR) is a key component of biological processes and energy technologies. This Review provides a comprehensive report of soluble molecular catalysts and electrocatalysts for the ORR. The precise synthetic control and relative ease of mechanistic study for homogeneous molecular catalysts, as compared to heterogeneous materials or surface-adsorbed species, enables a detailed understanding of the individual steps of ORR catalysis. Thus, the Review places particular emphasis on ORR mechanism and thermodynamics. First, the thermochemistry of oxygen reduction and the factors influencing ORR efficiency are described to contextualize the discussion of catalytic studies that follows. Reports of ORR catalysis are presented in terms of their mechanism, with separate sections for catalysis proceeding via initial outer- and inner sphere electron transfer to O2. The rates and selectivities (for production of H2O2 vs H2O) of these catalysts are provided, along with suggested methods for accurately comparing catalysts of different metals and ligand scaffolds that were examined under different experimental conditions. PMID- 29406709 TI - Kinetically Controlled Lifetimes in Redox-Responsive Transient Supramolecular Hydrogels. AB - It remains challenging to program soft materials to show dynamic, tunable time dependent properties. In this work, we report a strategy to design transient supramolecular hydrogels based on kinetic control of competing reactions. Specifically, the pH-triggered self-assembly of a redox-active supramolecular gelator, N,N'-dibenzoyl-l-cystine (DBC) in the presence of a reducing agent, which acts to disassemble the system. The lifetimes of the transient hydrogels can be tuned simply by pH or reducing agent concentration. We find through kinetic analysis that gel formation hinders the ability of the reducing agent and enables longer transient hydrogel lifetimes than would be predicted. The transient hydrogels undergo clean cycles, with no kinetically trapped aggregates observed. As a result, multiple transient hydrogel cycles are demonstrated and can be predicted. This work contributes to our understanding of designing transient assemblies with tunable temporal control. PMID- 29406710 TI - Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy. AB - We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors. PMID- 29406712 TI - "New" Reactive Nitrogen Chemistry Reshapes the Relationship of Ozone to Its Precursors. AB - Tropospheric ozone pollution has been a major environmental issue, and mitigation of this persistent problem requires a comprehensive understanding of the sensitivity of ozone to its precursors, i.e., nitrogen oxides (NO x) and volatile organic compounds (VOCs). Recent studies have proposed several "new" reactive nitrogen chemical processes, including additional sources of nitrous acid, heterogeneous uptake of dinitrogen pentoxide, and production of nitryl chloride. These processes significantly affect the budgets of radicals and NO x and hence the formation of ozone. In present study, we aim to investigate to what extent these processes alter the relationships between ozone and its precursors. A revised Weather Research and Forecasting model coupled with Chemistry incorporating the "new" nitrogen chemistry was adopted to simulate the ozone sensitivity regime in China in summer. The results showed that nitrogen chemistry changed the ozone sensitivity regime for approximately 40% of the simulated area with human influence, mostly from VOC-sensitive or NO x-sensitive regimes to mixed-sensitive regime. The nitrogen chemistry changed the isopleth plots of the ozone peak values for major cities, suggesting a different strategy for controlling ozone pollution. This study underscores the need to consider unconventional nitrogen chemistry in air quality models used in the design of ozone control strategies. PMID- 29406711 TI - ISCU(M108I) and ISCU(D39V) Differ from Wild-Type ISCU in Their Failure To Form Cysteine Desulfurase Complexes Containing Both Frataxin and Ferredoxin. AB - Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (NIA)2, exhibits a requirement for frataxin (FXN), in yeast, ISCU variant M108I has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that variants ISCU(M108I) and ISCU(D39V) of human ISCU populate only the structured state. We have compared the properties of ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and the overall Fe-S cluster assembly reaction catalyzed by (NIA)2. In the cysteine desulfurase step with dithiothreitol (DTT) as the reductant, FXN was found to stimulate cysteine desulfurase activity with both the wild-type and structured variants, although the effect was less prominent with ISCU(D39V) than with the wild-type or ISCU(M108I). In overall Fe-S cluster assembly, frataxin was found to stimulate cluster assembly with both the wild type and structured variants when the reductant was DTT; however, with the physiological reductant, reduced ferredoxin 2 (rdFDX2), FXN stimulated the reaction with wild-type ISCU but not with either ISCU(M108I) or ISCU(D39V). Nuclear magnetic resonance titration experiments revealed that wild-type ISCU, FXN, and rdFDX2 all bind to (NIA)2. However, when ISCU was replaced by the fully structured variant ISCU(M108I), the addition of rdFDX2 to the [NIA-ISCU(M108I) FXN]2 complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I). PMID- 29406714 TI - Synthesis of N-(Hetero)aryl Carbamates via CuI/MNAO Catalyzed Cross-Coupling of (Hetero)aryl Halides with Potassium Cyanate in Alcohols. AB - An efficient route to N-(hetero)aryl carbamates was developed through CuI/MNAO [2 ((2-methylnaphthalen-1-yl)amino)-2-oxoacetic acid] catalyzed cross-coupling of (hetero)aryl chlorides with potassium cyanate in alcohols at 120-130 degrees C. This method utilizes broadly available substrates to afford various N (hetero)aryl carbamates in good to excellent yields. Moreover, (hetero)aryl bromides and (hetero)aryl iodides were also reacted at low catalyst loadings and relatively low temperatures to provide N-(hetero)aryl carbamates. PMID- 29406713 TI - Time-Resolved Photoelectron Imaging of Molecular Coherent Excitation and Charge Migration by Ultrashort Laser Pulses. AB - Charge migration is a fundamental and important process in the photochemistry of molecules and has been explored by time-resolved photoelectron angular distributions. A scheme based on UV pump and polarized soft X-ray probe techniques shows that photoelectron diffraction effects enable us to reconstruct electronic coherences encoding the information of the charge migration with extreme time resolutions. We discuss how probe pulse helicity influences the probing photoelectron spectra in the presence of molecular nonspherical Coulomb potentials. This phenomenon is analyzed theoretically and simulated via ab initio calculations for the molecular hydrogen ion, offering a reliable approach for measurements of charge migration and for the exploration of molecular structure in attosecond science. PMID- 29406715 TI - Fourier Transform Microwave Spectroscopic and ab Initio Study of the Rotamers of 2-Fluorobenzaldehyde and 3-Fluorobenzaldehyde. AB - The rotational spectra of 2-fluorobenzaldehyde (2-FBD) and 3-fluorobenzaldehyde (3-FBD) were recorded using Fourier transform microwave (FTMW) spectroscopy from 4 to 26 GHz. Two planar rotamers were observed for each species that correspond to structures in which the carbonyl bond is directed toward (O-cis) or away from (O-trans) the C1-C2 bond. Observation of transitions due to heavy atom isotopes (13C, 18O) in natural abundance allowed derivation of the ground state effective (r0) structures and mass dependence (rm) structures for the lowest energy rotamer of 2-FBD (O-trans) and both rotamers of 3-FBD, which compare favorably with ab initio estimates of the equilibrium (re) geometries at the MP2/aug-cc-pVTZ level. The resultant parameters are consistent with the introduction of bond length alternation in the benzene ring, which is dependent on the orientation of the aldehyde group. Careful study of the experimental structure and results of natural bond orbital (NBO) analysis do not support the presence of intramolecular hydrogen bonding as the source of its stabilization of O-trans 2-FBD over its cis counterpart. Furthermore, calculations of the interconversion pathways between rotamers suggest that despite being 9.39 kJ/mol higher in energy, the O-cis 2-FBD moiety is metastable in the molecular beam, which has allowed the observation of its microwave spectrum for the first time. PMID- 29406716 TI - Organocatalytic Asymmetric Sequential 1,6-Addition/Acetalization of 1-Oxotetralin 2-carbaldehyde to ortho-Hydroxyphenyl-Substituted para-Quinone Methides for Synthesis of Spiro-3,4-dihydrocoumarins. AB - A chiral squaramide catalyzed approach constructing spiro-3,4-dihydrocoumarin motif by the enantioselective 1,6-addition/acetalization reactions of 1 oxotetralin-2-carbaldehydes and ortho-hydroxyphenyl-substituted para-quinone methides followed by an oxidation was developed. The reactions proceeded smoothly with a wide range of p-QMs and 1-oxotetralin-2-carbaldehydes to generate corresponding products in high yields with excellent diastereoselectivities (>19:1 dr) and enantioselectivities (up to 99% ee). PMID- 29406718 TI - Metabolomics Analysis Reveals that Ethylene and Methyl Jasmonate Regulate Different Branch Pathways to Promote the Accumulation of Terpenoid Indole Alkaloids in Catharanthus roseus. AB - The medicinal plant Catharanthus roseus accumulates large numbers of terpenoid indole alkaloids (TIAs), including the pharmaceutically important vinblastine, vincristine, ajmalicine, and serpentine. The phytohormone ethylene or methyl jasmonate (MeJA) can markedly enhance alkaloid accumulation. The interaction between ethylene or MeJA in the regulation of TIA biosynthesis in C. roseus is unknown. Here, a metabolomics platform is reported that is based on liquid chromatography (LC) coupled with time-of-flight mass spectrometry to study candidate components for TIA biosynthesis, which is controlled by ethylene or MeJA in C. roseus. Multivariate analysis identified 16 potential metabolites mostly associated with TIA metabolic pathways and seven targeted metabolites, outlining the TIA biosynthesis metabolic networks controlled by ethylene or MeJA. Interestingly, ethylene and MeJA regulate the 2-C-methyl-d-erythritol 4-phosphate (MEP) and acetate-mevalonate (MVA) pathways through AACT and HMGS and through DXS, respectively, to induce TIA biosynthesis in C. roseus. Overall, both nontargeted and targeted metabolomics, as well as transcript analysis, were used to reveal that MeJA and ethylene control different metabolic networks to induce TIA biosynthesis. PMID- 29406719 TI - Comment on "Millimeter-Sized Hole Damming". AB - In a recent article, Ng and co-workers (Langmuir 2017, 33, 13892-13898; doi: 10.1021/acs.langmuir.7b03290) demonstrated the ability of containers with a small hole in their bottom to resist the drainage of water. They used Laplace's capillary rise equation to explain their results, which grossly underestimated the onset of drainage. In this comment, an alternative analysis is offered. Equations are derived specifically for the drainage of liquid from a small hole in a horizontal surface. This approach yielded reasonably accurate predictions for Ng's experimental data. PMID- 29406720 TI - Polyaniline Nanofibers: Their Amphiphilicity and Uses for Pickering Emulsions and On-Demand Emulsion Separation. AB - The wetting property of nanomaterials is of great importance to both fundamental understanding and potential applications. However, the study on the intrinsic wetting property of nanomaterials is interfered by organic capping agents, which are often used to lower the surface energy of nanomaterials and avoid their irreversible agglomeration. In this work, the wetting property of the nanostructured polyaniline that requires no organic capping agents is investigated. Compared to hydrophilic granular particulates, polyaniline nanofibers are amphiphilic and have an excellent capability of creating Pickering emulsions at a wide range of pH. It is suggested that polyaniline nanofibers can be easily wetted by water and oil. Furthermore, the amphiphilic polyaniline nanofibers as building blocks can be used to construct filtration membranes with a small pore size. The wetting layer of the continuous phase of emulsions in the porous nanochannels efficiently prevents the permeation of the dispersed phase, realizing high-efficiency on-demand emulsion separation. PMID- 29406721 TI - Gold Nanorod-Based Engineered Cardiac Patch for Suture-Free Engraftment by Near IR. AB - Although cardiac patches hold a promise for repairing the infarcted heart, their integration with the myocardium by sutures may cause further damage to the diseased organ. To address this issue, we developed facile and safe, suture-free technology for the attachment of engineered tissues to organs. Here, nanocomposite scaffolds comprised of albumin electrospun fibers and gold nanorods (AuNRs) were developed. Cardiac cells were seeded within the scaffolds and assembled into a functioning patch. The engineered tissue was then positioned on the myocardium and irradiated with a near IR laser (808 nm). The AuNRs were able to absorb the light and convert it to thermal energy, which locally changed the molecular structure of the fibrous scaffold, and strongly, but safely, attached it to the wall of the heart. Such hybrid biomaterials can be used in the future to integrate any engineered tissue with any defected organs, while minimizing the risk of additional injury for the patient, caused by the conventional stitching methods. PMID- 29406723 TI - Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones and Piperazin-2 ones. AB - An expedient two-step synthesis of 3,4-dihydropyrrolopyrazinones has been achieved via a Vilsmeier-Haack reaction of ketones, followed by an annulation of the corresponding chloroaldehydes with commercially available piperazin-2-ones. A variety of cyclic and acyclic ketones and piperazin-2-ones participated in this two-step chemistry, affording the desired 3,4-dihydropyrrolopyrazinones in up to 78% yield. PMID- 29406722 TI - Access to Bicyclo[4.2.0]octene Monomers To Explore the Scope of Alternating Ring Opening Metathesis Polymerization. AB - Bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides undergo alternating ring-opening metathesis polymerization (AROMP) with cyclohexene. Herein, a general method for the preparation of bicyclo[4.2.0]oct-(8)-ene-8-carboxy derivatives is described. The central 8-cyano intermediate provides entry to five different functional group substituents on the alkene. These monomers were tested as potential substrates for AROMP with cyclohexene. In addition to the carboxamide, the carboxynitrile and carboxaldehyde are also substrates for AROMP. In the case of the carboxaldehyde, the polymer is regioregular. However, the addition of carboxynitrile is stereoirregular and slow. PMID- 29406724 TI - Predicting Two-Dimensional C3B/C3N van der Waals p-n Heterojunction with Strong Interlayer Electron Coupling and Enhanced Photocurrent. AB - The interlayer coupling in 2D van der Waals (vdW) heterostructures (HTS) plays the main role in generating new physics. However, the interlayer coupling is often weak, and little information on the strength of interlayer interaction in HTS is available. On the basis of density functional theory, we demonstrate that an effective electron coupling can be created in 2D C3B/C3N vdW HTS. The experimentally synthesized monolayers C3B and C3N are p- and n-type doped large gap semiconductors, respectively. However, the formed vdW HTS exhibits novel Dirac fermion. The strong interlayer electron coupling results in a large interlayer built-in electric field and improved optical properties of the 2D C3B/C3N vdW HTS. Moreover, a simple tight-binding model of C3B/C3N HTS with the nonzero interlayer hopping parameters captures the physical picture of interlayer coupling. Our results demonstrate the importance of interlayer electron coupling in the modulation of materials properties of 2D vdW HTS. PMID- 29406725 TI - Cation-Assisted Reversible Folding and Anion Binding by a Naphthalenediimide Based Ditopic Ion-Pair Receptor. AB - A novel heteroditopic ion-pair receptor was synthesized by tethering two pi acidic naphthalenediimide units with a tridentate bisimine linker. Upon chelating a ZnII or CdII ion with the linker, it adopts a U-conformation allowing the parallel NDI arms to sandwich charge-diffuse anions, and two such folded receptor molecules interlock with each other forming an [R3.MII.R3.X-] ion-pair complex. Extraction of the guest cation with a tetraazacrown ether returns the receptor to its original unfolded form. PMID- 29406726 TI - Synthesis of 5-C-Methylated d-Mannose, d-Galactose, l-Gulose, and l-Altrose and Their Structural Elucidation by NMR Spectroscopy. AB - C5/C6-Spirocyclopropanation of exocyclic enol esters followed by alkali ring opening of the three-membered ring was used for the diastereoselective preparation of 5-C-methylated d-mannose, d-galactose, l-gulose, and l-altrose. Extensive NMR studies demonstrated an increase of furanose form by 5-C methylation in almost all cases. PMID- 29406728 TI - Development of a Light-Controlled Nanoplatform for Direct Nuclear Delivery of Molecular and Nanoscale Materials. AB - Research on nanomedicines has rapidly progressed in the past few years. However, due to the limited size of nuclear pores (9-12 nm), the nuclear membrane remains a difficult barrier to many nucleus-targeting agents. Here, we report the development of a general platform to effectively deliver chemical compounds such as drug molecules or nanomaterials into cell nuclei. This platform consists of a polyamine-containing polyhedral oligomeric silsesquioxane (POSS) unit, a hydrophilic polyethylene glycol (PEG) chain, and the photosensitizer rose bengal (RB), which can self-assemble into nanoparticles (denoted as PPR NPs). Confocal fluorescence imaging showed that PPR NPs mainly located in lysosomes after cellular internalization. After mild light irradiation, however, PPR NPs effectively disrupted lysosomal structures by singlet oxygen (1O2) oxidation and substantially accumulated on nuclear membranes, which enabled further disruption of the membrane integrity and promoted their final nuclear entry. Next, we selected two chemotherapeutic agents (10-hydroxycamptothecine and docetaxel) and a fluorescent dye (DiD) as payloads of PPR NPs and successfully demonstrated that this nanocarrier could efficiently deliver them into cell nuclei in a light controlled manner. In addition to molecular compounds, we have also demonstrated that PPR NPs could facilitate the nuclear entry of nanomaterials, including Prussian blue NPs as well as gold nanorods. Compared to traditional strategies for nuclear delivery, this highly controllable nanoplatform avoids complicated modification of nucleus-targeting ligands and is generally applicable to both molecular compounds and nanomaterials. PMID- 29406729 TI - Anion Exchange in II-VI Semiconducting Nanostructures via Atomic Templating. AB - Controlled chemical transformation of nanostructures is a promising technique to obtain precisely designed novel materials, which are difficult to synthesize otherwise. We report high-temperature vapor-phase anion-exchange reactions to chemically transform II-VI semiconductor nanostructures (100-300 nm length scale) while retaining the single crystallinity, crystal structure, morphology, and even defect distribution of the parent material via atomic templating. The concept of atomic templating is employed to obtain kinetically controlled, thermodynamically metastable structural phases such as zincblende CdSe and CdS from zincblende CdTe upon complete chemical replacement of Te with Se or S. The underlying transformation mechanisms are explained through first-principles density functional theory calculations. Atomic templating is a unique path to independently tune materials' phase and composition at the nanoscale, allowing the synthesis of novel materials. PMID- 29406727 TI - Distinguishing Active Site Characteristics of Chlorite Dismutases with Their Cyanide Complexes. AB - O2-evolving chlorite dismutases (Clds) efficiently convert chlorite (ClO2-) to O2 and Cl-. Dechloromonas aromatica Cld ( DaCld) is a highly active chlorite decomposing homopentameric enzyme, typical of Clds found in perchlorate- and chlorate-respiring bacteria. The Gram-negative, human pathogen Klebsiella pneumoniae contains a homodimeric Cld ( KpCld) that also decomposes ClO2-, albeit with an activity 10-fold lower and a turnover number lower than those of DaCld. The interactions between the distal pocket and heme ligand of the DaCld and KpCld active sites have been probed via kinetic, thermodynamic, and spectroscopic behaviors of their cyanide complexes for insight into active site characteristics that are deterministic for chlorite decomposition. At 4.7 * 10-9 M, the KD for the KpCld-CN- complex is 2 orders of magnitude smaller than that of DaCld-CN- and indicates an affinity for CN- that is greater than that of most heme proteins. The difference in CN- affinity between Kp- and DaClds is predominantly due to differences in koff. The kinetics of binding of cyanide to DaCld, DaCld(R183Q), and KpCld between pH 4 and 8.5 corroborate the importance of distal Arg183 and a p Ka of ~7 in stabilizing complexes of anionic ligands, including the substrate. The Fe-C stretching and FeCN bending modes of the DaCld-CN- (nuFe-C, 441 cm-1; deltaFeCN, 396 cm-1) and KpCld-CN- (nuFe-C, 441 cm-1; deltaFeCN, 356 cm-1) complexes reveal differences in their FeCN angle, which suggest different distal pocket interactions with their bound cyanide. Conformational differences in their catalytic sites are also reported by the single ferrous KpCld carbonyl complex, which is in contrast to the two conformers observed for DaCld-CO. PMID- 29406730 TI - Quantified Uncertainties in Comparative Life Cycle Assessment: What Can Be Concluded? AB - Interpretation of comparative Life Cycle Assessment (LCA) results can be challenging in the presence of uncertainty. To aid in interpreting such results under the goal of any comparative LCA, we aim to provide guidance to practitioners by gaining insights into uncertainty-statistics methods (USMs). We review five USMs-discernibility analysis, impact category relevance, overlap area of probability distributions, null hypothesis significance testing (NHST), and modified NHST-and provide a common notation, terminology, and calculation platform. We further cross-compare all USMs by applying them to a case study on electric cars. USMs belong to a confirmatory or an exploratory statistics' branch, each serving different purposes to practitioners. Results highlight that common uncertainties and the magnitude of differences per impact are key in offering reliable insights. Common uncertainties are particularly important as disregarding them can lead to incorrect recommendations. On the basis of these considerations, we recommend the modified NHST as a confirmatory USM. We also recommend discernibility analysis as an exploratory USM along with recommendations for its improvement, as it disregards the magnitude of the differences. While further research is necessary to support our conclusions, the results and supporting material provided can help LCA practitioners in delivering a more robust basis for decision-making. PMID- 29406732 TI - Ruthenium-Catalyzed Asymmetric Reduction of Isoxazolium Salts: Access to Optically Active Delta4-Isoxazolines. AB - A tethered MsDPEN-ruthenium catalyst reduces a series of isoxazolium salts, affording optically active Delta4-isoxazolines in moderate to good yields and enantioenrichment. The redundancy of heating or high pressures allowed for chemoselective reduction with no subsequent heterocyclic ring opening. Our results reinforce our understanding of the workings of these Noyori-class catalysts. PMID- 29406731 TI - Interaction of Tyrosine Analogues with Quaternary Ammonium Head Groups at the Micelle/Water Interface and Contrasting Effect of Molecular Folding on the Hydrophobic Outcome and End-Cap Geometry. AB - The surface property of the cationic micelles of cetyltrimethylammonium bromide (CTAB) in an aqueous medium is highly modified in the presence of tyrosineoctyl ester (TYOE) and tyrosinedodecyl ester (TYDE), the models for aromatic amino acid side chains of transmembrane proteins. While the synergistic interaction between the quaternary ammonium head group of CTAB and the pi-electron cloud of aromatic amino acid ester is influenced by the relative orientation and the unusual molecular geometry of the latter, this eventually triggers a morphology transition of the spherical micelle to cylindrical/wormlike micelles and imparts a strong viscoelasticity in the medium. Physical characteristics of the elongated micelles have been investigated by high resolution transmission electron microscopy (HRTEM) and the small angle neutron scattering (SANS) technique; the complex fluidic nature of the system is investigated by a dynamic rheological measurement. The intermolecular interactions have been recognized via 1H NMR and 2D nuclear Overhauser effect spectroscopy (NOESY), and the unambiguous geometry of the end-caps of the rods has been ascertained for the first time. While the interplay between lipids and transmembrane proteins is thought to be crucial in controlling the membrane shape of the cells during many vital events such as cellular fission, fusion, and virus entry, the observed tuning of the micellar surface curvature via the cation-pi interaction involving tyrosine analogues is thought provoking and opens up an avenue for new physical chemistry research on a vital biological phenomena. PMID- 29406733 TI - Extraction of Boron Nitride Nanotubes and Fabrication of Macroscopic Articles Using Chlorosulfonic Acid. AB - Due to recent advances in high-throughput synthesis, research on boron nitride nanotubes (BNNTs) is moving toward applications. One future goal is the assembly of macroscopic articles of high-aspect-ratio, pristine BNNTs. However, these articles are presently unattainable because of insufficient purification and fabrication methods. We introduce a solution process for extracting BNNTs from synthesis impurities without sonication or the use of surfactants and proceed to convert the extracted BNNTs into thin films. The solution process can also be used to convert as-synthesized material-which contains significant amounts of hexagonal boron nitride ( h-BN)-into mats and aerogels with controllable structure and dimension. The solution extraction method, combined with further advances in synthesis and purification, contributes to the development of all BNNT macroscopic articles, such as fibers and 3-D structures. PMID- 29406734 TI - Capsicodendrin from Cinnamosma fragrans Exhibits Antiproliferative and Cytotoxic Activity in Human Leukemia Cells: Modulation by Glutathione. AB - Capsicodendrin (CPCD, 1), an epimeric mixture of a dimeric drimane-type sesquiterpene, is one of the major compounds present in the three endemic species of Madagascan traditional chemopreventive plants: Cinnamosma species ( C. fragrans, C. macrocarpa, and C. madagascariensis). Despite the popular use of Cinnamosma in Madagascan traditional medicine and the reported antiproliferative properties of CPCD, elucidation of its mechanism(s) of action is still to be accomplished. In the present study, CPCD at low micromolar concentrations was cytotoxic and induced apoptosis in human myeloid leukemia cells in a time- and concentration-dependent manner. The activity of CPCD in HL-60 and K562 cells was modulated by glutathione (GSH), since depletion of this intracellular thiol-based antioxidant with buthionine sulfoximine resulted in significantly ( p < 0.05) greater potency in antiproliferation assays. GSH depletion also significantly potentiated the cytotoxic activity in CPCD-treated human HL-60 cells. Single-cell gel electrophoresis (Comet) assays revealed that GSH depletion in HL-60 cells enhanced the formation of DNA strand breaks in the presence of CPCD. Although CPCD does not contain an obvious Michael acceptor in its structure, 1H NMR analyses indicated that cinnamodial (2), a monomer of CPCD, was formed within a few hours when dissolved in DMSO- d6 and interacts with GSH to form a covalent bond via Michael addition at the C-7 carbon. Together the results strongly suggest that 2 is responsible for the DNA-damaging, pro-apoptotic, and cytotoxic effects of CPCD and that depletion of GSH enhances overall activity by diminishing covalent interaction between GSH and this 2-alkenal decomposition product of CPCD. PMID- 29406735 TI - Mixing O-Containing and N-Containing Directing Groups for C-H Activation: A Strategy for the Synthesis of Highly Functionalized 2,2'-Biaryls. AB - A strategy combining O- and N-containing directing groups has been developed for the synthesis of 2,2'-biaryl via Pd-mediated C-H bond activation and oxidative coupling. This new transformation may proceed through a mechanism involving Pd(II) and Pd(IV) intermediates. We found the use of PTSA and HFIP to be critical for the reaction and suggest that these reagents could serve as efficient ligands for this C-C bond formation. This methodology provides broad functional group tolerance, excellent reactivity, and high yields. PMID- 29406736 TI - Determination of Formulation Conditions Allowing Double Emulsions Stabilized by PGPR and Sodium Caseinate to Be Used as Capsules. AB - Water-in-oil-in-water (W1/O/W2) double emulsions stabilized by polyglycerol polyricinoleate (PGPR), a lipophilic food grade small polymer, and sodium caseinate, a hydrophilic milk protein, were developed to encapsulate vitamin B12, a model hydrophilic substance easy to titrate. Using rheology, sensitive to drop size evolution and water fluxes, static light scattering, and microscopy both giving the evolution of drops' size and vitamin B12 titration assessing the encapsulation, we were able to detect independently the double emulsion drop size, the encapsulation loss, and the flux of water as a function of time. By differentiating the PGPR required to cover the W1-droplets' surface from PGPR in excess in the oil phase, we built a PGPR-inner droplet volume fraction diagram highlighting the domains where the double emulsion is stable toward encapsulation and/or water fluxes. We demonstrated the key role played by nonadsorbed PGPR concentration in the intermediate sunflower oil phase on the emulsion stability while, surprisingly, the inner droplet volume fraction had no effect on the emulsion stability. At low PGPR concentration, a release of vitamin B12 was observed and the leakage mechanism of coalescence between droplets and oil-water interface of the oily drops (also called globules hereafter), was identified using confocal microscopy. For high enough PGPR content, the emulsions were stable and may therefore serve as efficient capsules without need of an additional gelling, thickening, complexion or interface rigidifying agent. We generalized these results with the encapsulation of an insecticide: Cydia pomonella granulovirus used in organic arboriculture. PMID- 29406737 TI - Air-Stable Anisotropic Monocrystalline Nickel Nanowires Characterized Using Electron Holography. AB - Nickel is capable of discharging electric and magnetic shocks in aerospace materials thanks to its conductivity and magnetism. Nickel nanowires are especially desirable for such an application as electronic percolation can be achieved without significantly increasing the weight of the composite material. In this work, single-crystal nickel nanowires possessing a homogeneous magnetic field are produced via a metal-organic precursor decomposition synthesis in solution. The nickel wires are 20 nm in width and 1-2 MUm in length. The high anisotropy is attained through a combination of preferential crystal growth in the ?100? direction and surfactant templating using hexadecylamine and stearic acid. The organic template ligands protect the nickel from oxidation, even after months of exposure to ambient conditions. These materials were studied using electron holography to characterize their magnetic properties. These thin nanowires display homogeneous ferromagnetism with a magnetic saturation (517 +/- 80 emu cm-3), which is nearly equivalent to that of bulk nickel (557 emu cm-3). Nickel nanowires were incorporated into carbon composite test pieces and were shown to dramatically improve the electric discharge properties of the composite material. PMID- 29406738 TI - Organocatalytic Oxa-Michael/Michael/Michael/Aldol Condensation Quadruple Domino Sequence: Asymmetric Synthesis of Tricyclic Chromanes. AB - An efficient and highly stereoselective one-pot, four-component synthesis of functionalized tricyclic chromanes has been achieved through an organocatalyzed quadruple domino reaction. The reaction sequence involves an oxa Michael/Michael/Michael/aldol condensation between alcohols, 2 equiv of acrolein, and nitrochromenes to generate the pharmaceutically important tricyclic chromanes bearing three contiguous stereogenic centers including a chiral tetrasubstituted carbon center in good domino yields (30-70%) and excellent diastereo- and enantioselectivities (>20:1 dr and >99% ee). PMID- 29406739 TI - The Role of Citric Acid in the Stabilization of Nanoparticles and Colloidal Particles in the Environment: Measurement of Surface Forces between Hafnium Oxide Surfaces in the Presence of Citric Acid. AB - The interactions between colloidal particles and nanoparticles determine solution stability and the structures formed when the particles are unstable to flocculation. Therefore, knowledge of the interparticle interactions is important for understanding the transport, dissolution, and fate of particles in the environment. The interactions between particles are governed by the surface properties of the particles, which are altered when species adsorb to the surface. The important interactions in the environment are almost never those between the bare particles but rather those between particles that have been modified by the adsorption of natural organic materials. Citric acid is important in this regard not only because it is present in soil but also as a model of humic and fulvic acids. Here we have studied the surface forces between the model metal oxide surface hafnia in the presence of citric acid in order to understand the stability of colloidal particles and nanoparticles. We find that citric acid stabilizes the particles over a wide range of pH at low to moderate ionic strength. At high ionic strength, colloidal particles will flocculate due to a secondary minimum, resulting in aggregates that are dense and easily redispersed. In contrast, nanoparticles stabilized by citric acid remain stable at high ionic strengths and therefore exist in solution as individual particles; this will contribute to their dispersion in the environment and the uptake of nanoparticles by mammalian cells. PMID- 29406740 TI - The Synthesized Plant Metabolite 3,4,5-Tri-O-Galloylquinic Acid Methyl Ester Inhibits Calcium Oxalate Crystal Growth in a Drosophila Model, Downregulates Renal Cell Surface Annexin A1 Expression, and Decreases Crystal Adhesion to Cells. AB - The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) model were investigated. Membrane, cytosolic, and total annexin A1 (AxA1), alpha-enolase, and heat shock protein 90 (HSP90) amounts were examined by Western blot analysis after subcellular fractionation, then confirmed by immunofluorescence staining of cultured cells. Pretreatment of MDCKI cells with TGAME for up to 6 h significantly diminished COM crystal binding in a concentration-dependent manner. TGAME significantly inhibited AxA1 surface expression by immunofluorescence microscopy, whereas intracellular AxA1 increased. Western blot analysis confirmed AxA1 expression changes in the membrane and cytosolic fractions of compound treated cells, whereas whole cell AxA1 remained unchanged. TGAME also significantly decreased the size, number, and growth of calcium oxalate (CaOx) crystals induced in a Drosophila melanogaster MT model and possessed a potent antioxidant activity in a DPPH assay. PMID- 29406741 TI - Copper Metal-Organic Framework Nanoparticles Stabilized with Folic Acid Improve Wound Healing in Diabetes. AB - The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu2+, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST 1 NPs is a simple, safe, and promising approach to control Cu2+ release, thus enabling the direct application of Cu-MOF NPs to wounds. PMID- 29406742 TI - Novel Dimensionally Controlled Nanopore Forming Template in Forward Osmosis Membranes. AB - To lower the unfavorable internal concentration polarization effect in forward osmosis (FO) membranes, support layers of highly porous interconnected structures with specifically large surface-to-volume ratios are indispensable. Herein, zinc oxide (ZnO) has been introduced as a new template to manipulate the porous structure of poly(ether sulfone) (PES) support layer. The ZnO can be readily synthesized as desired in different dimensionally controlled nanostructures. The performance of the FO membrane was initially ameliorated in terms of permeability and selectivity through simple incorporation of ZnO nanostructures in the PES support layer. The PES support layer was blended with appropriate amounts of ZnO nanostructures, casted on a glass plate, and subsequently acid washed to leach out the embedded ZnO nanostructures. Different nanoporous structures were achieved when ZnO of different nanostructures was used to modify the PES support layer. The experimental results indicated that the permeability of FO membranes could be simply improved by incorporation of ZnO nanostructures in PES support layer. Higher hydrophilicity and formation of suitable internal pores were mainly responsible for such observation. Although surface hydrophilicity of the support layers was reduced after being acid washed, water permeation through the membrane was intensified due to the formation of interconnected porous structure. PMID- 29406744 TI - Amine-Reactive Poly(pentafluorophenyl acrylate) Brush Platforms for Cleaner Protein Purification. AB - Reactive pentafluorophenyl acrylate (PFPA) polymer brushes grafted on silica particles were prepared using surface-initiated reversible addition and fragmentation chain transfer polymerization. The polymer brush was successfully immobilized with antibody, then used for protein separation. The immunoprecipitated proteins showed successful enrichment of target protein, with reduced nonspecific background and less contamination from eluted antibodies. To further improve protein recovery, the hydrophobic poly(PFPA) brush was modified with hydrophilic poly(ethylene glycol) (PEG). The partially PEG-substituted poly(PFPA) brush showed better dispersion in aqueous solution, leading to improved antibody immobilization efficiency. By optimizing both the brush molecular weight and the degree of PEG substitution, an optimal balance between surface hydrophilicity and number of available PFP units was found, leading to efficient target protein purification. This study shows that poly(PFPA) platform offers a versatile approach to prepare biomolecule-activated surfaces with tunable surface property, which has potential applications in protein separation and other areas. PMID- 29406743 TI - Evaluation of an Air Quality Health Index for Predicting the Mutagenicity of Simulated Atmospheres. AB - No study has evaluated the mutagenicity of atmospheres with a calculated air quality health index (AQHI). Thus, we generated in a UV-light-containing reaction chamber two simulated atmospheres (SAs) with similar AQHIs but different proportions of criteria pollutants and evaluated them for mutagenicity in three Salmonella strains at the air-agar interface. We continuously injected into the chamber gasoline, nitric oxide, and ammonium sulfate, as well as either alpha pinene to produce SA-PM, which had a high concentration of particulate matter (PM): 119 ppb ozone (O3), 321 ppb NO2, and 1007 MUg/m3 PM2.5; or isoprene to produce SA-O3, which had a high ozone (O3) concentration: 415 ppb O3, 633 ppb NO2, and 55 MUg/m3 PM2.5. Neither PM2.5 extracts, NO2, or O3 alone, nor nonphoto oxidized mixtures were mutagenic or cytotoxic. Both photo-oxidized atmospheres were largely direct-acting base-substitution mutagens with similar mutagenic potencies in TA100 and TA104. The mutagenic potencies [(revertants/h)/(mgC/m3)] of SA-PM (4.3 +/- 0.4) and SA-O3 (9.5 +/- 1.3) in TA100 were significantly different ( P < 0.0001), but the mutation spectra were not ( P = 0.16), being ~54% C -> T and ~46% C -> A. Thus, the AQHI may have some predictive value for the mutagenicity of the gas phase of air. PMID- 29406745 TI - Elucidation of the Molecular-Mechanisms and In Vivo Evaluation of the Anti inflammatory Effect of Alginate-Derived Seleno-polymannuronate. AB - Alginate-derived polymannuronate (PM) is a type of polysaccharide found in edible brown seaweeds. Seleno-polymannuronate (Se-PM) was prepared from PM via synthesis using sulfation- and selenation-replacement reactions. The anti-inflammatory activity of Se-PM and its corresponding molecular mechanisms were investigated. In lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells, Se-PM significantly attenuated the production of nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS); the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); and the secretion of proinflammatory cytokines. Moreover, Se-PM remarkably suppressed the LPS-induced activation of the nuclear-factor (NF)-kappaB and mitogen-activated-protein-kinase (MAPK) signaling pathways in RAW264.7 cells. Furthermore, Se-PM also decreased the production of proinflammatory mediators in LPS-triggered primary murine macrophages. Additionally, Se-PM inhibited the inflammatory response in the air pouch inflammation model. These results might contribute to the overall understanding of the potential health benefits of Se-PM for food and drug applications. PMID- 29406746 TI - Carboxymethyl Chitosan and Its Hydrophobically Modified Derivative as pH Switchable Emulsifiers. AB - The emulsification properties of carboxymethyl chitosan (CMChi) and hydrophobically modified carboxymethyl chitosan (h-CMChi) were studied as a function of pH and dodecane/water ratio. The pH was varied between 6-10, and the oil/water ratio between 0.1-2.0. In CMChi solution, the emulsion stability increased as the pH was lowered from 10 to 7, and the phase inversion was shifted from oil/water ratio 1.0 to 1.8, respectively. The system behaved differently in pH 6 due to the aggregation of CMChi and the formation of nanoparticles (~200-300 nm). No phase inversion was observed and the maximum amount of emulsified oil was reached at oil/water ratio 1.2. The h-CMChi showed similar behavior as a function of pH but, due to hydrophobic modification, the phase inversion was shifted to higher values in pH 7-10. In pH 6, the behavior was similar, but the maximum amount of emulsified oil was higher compared to CMChi. The amount of adsorbed particles correlated with the emulsified amount of oil. Reversible emulsification of dodecane was demonstrated by pH adjustment using CMChi and h-CMChi solutions. The formed emulsions were gel-like, suggesting particle-particle interaction. PMID- 29406747 TI - Cryo IR Spectroscopy of N2 and H2 on Ru8+: The Effect of N2 on the H-Migration. AB - We present the cryo IR-PD spectra of the coadsorbed [Ru8(H2)1(N2)4]+ and [Ru8(N2)4(H2)1]+ species differing in the adsorption sequence of H2 and N2, which we record via application of tandem cryo ion trapping. We observe strong evidence for dissociative H2 adsorption, and the spectra reveal differences in the Ru-H stretching region, which we assign to distal and proximal hydrogen atom locations on the Ru8+ cluster, their migration likely hindered by preloaded nitrogen molecules and unaffected by subsequent N2 adsorption. PMID- 29406748 TI - Accurate Lattice Energies for Molecular Crystals from Experimental Crystal Structures. AB - Using four different benchmark sets of molecular crystals, we establish the level of confidence for lattice energies estimated using CE-B3LYP model energies and experimental crystal structures. [ IUCrJ 2017 , 4 , 575 - 587 10.1107/S205225251700848X .] We conclude that they compare very well with available benchmark estimates derived from sublimation enthalpies, and in many cases they are comparable with, and sometimes better than, more computationally demanding approaches, such as those based on periodic DFT plus dispersion methodologies. The performance over the complete set of 110 crystals indicates a mean absolute deviation from benchmark energies of only 6.6 kJ mol-1. Applications to polymorphic crystals and larger molecules are also presented and critically discussed. The results highlight the importance of recognizing the consequences of different sets of crystal/molecule geometries when different methodologies are compared, as well as the need for more extensive benchmark sets of crystal structures and associated lattice energies. PMID- 29406749 TI - Maximum Caliber Can Characterize Genetic Switches with Multiple Hidden Species. AB - Gene networks with feedback often involve interactions between multiple species of biomolecules, much more than experiments can actually monitor. Coupled with this is the challenge that experiments often measure gene expression in noisy fluorescence instead of protein numbers. How do we infer biophysical information and characterize the underlying circuits from this limited and convoluted data? We address this by building stochastic models using the principle of Maximum Caliber (MaxCal). MaxCal uses the basic information on synthesis, degradation, and feedback-without invoking any other auxiliary species and ad hoc reactions-to generate stochastic trajectories similar to those typically measured in experiments. MaxCal in conjunction with Maximum Likelihood (ML) can infer parameters of the model using fluctuating trajectories of protein expression over time. We demonstrate the success of the MaxCal + ML methodology using synthetic data generated from known circuits of different genetic switches: (i) a single gene autoactivating circuit involving five species (including mRNA), (ii) a mutually repressing two-gene circuit (toggle switch) with seven species (including mRNA) considering stochastic time traces of two proteins, and (iii) the same toggle switch circuit considering stochastic time traces of only one of the two proteins. To further challenge the MaxCal + ML inference scheme, we repeat our analysis for the second and third scenario with traces expressed in noisy fluorescence instead of protein number to closely mimic typical experiments. We show that, for all of these models with increasing complexity and obfuscation, the minimal model of MaxCal is still able to capture the fluctuations of the trajectory and infer basic underlying rate parameters when benchmarked against the known values used to generate the synthetic data. Importantly, the model also yields an effective feedback parameter that can be used to quantify interactions within these circuits. These applications show the promise of MaxCal's ability to characterize circuits with limited data, and its utility to better understand evolution and advance design strategies for specific functions. PMID- 29406750 TI - Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells. AB - DNA origami is a promising molecular delivery system for a variety of therapeutic applications including cancer therapy, given its capability to fabricate homogeneous nanostructures whose physicochemical properties (size, shape, surface chemistry) can be precisely tailored. However, the correlation between DNA origami design and internalization efficiency in different cancer cell lines remains elusive. We investigated the cellular uptake of four DNA-origami nanostructures (DONs) with programmed sizes and shapes in multiple human cancer cell lines. The cellular uptake efficiency of DONs was influenced by size, shape, and cell line. Scavenger receptors were responsible for the internalization of DONs into cancer cells. We observed distinct stages of the internalization process of a gold nanoparticle (AuNP)-tagged rod-shape DON, using high-resolution transmission electron microscopy. This study provides detailed understanding of cellular uptake and intracellular trafficking of DONs in cancer cells, and offers new insights for future optimization of DON-based drug delivery systems for cancer treatment. PMID- 29406751 TI - Reversible Protein Adsorption on Mixed PEO/PAA Polymer Brushes: Role of Ionic Strength and PEO Content. AB - Proteins at interfaces are a key for many applications in the biomedical field, in biotechnologies, in biocatalysis, in food industry, etc. The development of surface layers that allow to control and manipulate proteins is thus highly desired. In previous works, we have shown that mixed polymer brushes combining the protein-repellent properties of poly(ethylene oxide) (PEO) and the stimuli responsive adsorption behavior of poly(acrylic acid) (PAA) could be synthesized and used to achieve switchable protein adsorption. With the present work, we bring more insight into the rational design of such smart thin films by unravelling the role of PEO on the adsorption/desorption of proteins. The PEO content of the mixed PEO/PAA brushes was regulated, on the one hand, by using PEO with different molar masses and, on the other hand, by varying the ratio of PEO and PAA in the solutions used to synthesize the brushes. The influence of ionic strength on the protein adsorption behavior was also further examined. The behavior of three proteins-human serum albumin, lysozyme, and human fibrinogen, which have very different size, shape, and isoelectric point-was investigated. X ray photoelectron spectroscopy, quartz crystal microbalance, atomic force microscopy, and streaming potential measurements were used to characterize the mixed polymer brushes and, in particular, to estimate the fraction of each polymer within the brushes. Protein adsorption and desorption conditions were selected based on previous studies. While brushes with a lower PEO content allowed the higher protein adsorption to occur, fully reversible adsorption could only be achieved when the PEO surface density was at least 25 PEO units per nm2. Taken together, the results increase the ability to finely tune protein adsorption, especially with temporal control. This opens up possibilities of applications in biosensor design, separation technologies, nanotransport, etc. PMID- 29406752 TI - Broadside Nanoantennas Made of Single Silver Nanorods. AB - Directional optical nanoantennas are often realized by nanostructured systems with ingenious or complex designs. Herein we report on the realization of directional scattering of visible light from a simple configuration made of single Ag nanorods supported on Si substrates, where the incident light can be routed toward the two flanks of each nanorod. Such an intriguing far-field scattering behavior, which has not been investigated so far, is proved to result from the near-field coupling between high-aspect-ratio Ag nanorods and high refractive-index Si substrates. A simple and intuitive model is proposed, where the complicated plasmon resonance is found to be equivalent to several vertically aligned electric dipoles oscillating in phase, to understand the far-field properties of the system. The interference among the electric dipoles results in wavefront reshaping and sidewise light routing in a similar manner to the broadside antenna described in the traditional antenna theory, allowing for the naming of these Si-supported Ag nanorods as "broadside nanoantennas". We have carried out comprehensive experiments to understand the physical origins behind and the affecting factors on the directional scattering behavior of such broadside nanoantennas. PMID- 29406753 TI - Computational Alanine Scanning with Interaction Entropy for Protein-Ligand Binding Free Energies. AB - In protein-ligand binding, only a few residues contribute significantly to the ligand binding. Quantitative characterization of binding free energies of specific residues in protein-ligand binding is extremely useful in our understanding of drug resistance and rational drug design. In this paper, we present an alanine scanning approach combined with an efficient interaction entropy method to compute residue-specific protein-ligand binding free energies in protein-drug binding. In the current approach, the entropic components in the free energies of all residues binding to the ligand are explicitly computed from just a single trajectory MD simulation by using the interaction entropy method. In this approach the entropic contribution to binding free energy is determined from fluctuations of individual residue-ligand interaction energies contained in the MD trajectory. The calculated residue-specific binding free energies give relative values between those for ligand binding to the wild type protein and those to the mutants when specific results mutated to alanine. Computational study for the binding of two classes of drugs (first and second generation drugs) to target protein ALK and its mutant was performed. Important or hot spot residues with large contributions to the total binding energy are quantitatively characterized and the mutation effect for the loss of binding affinity for the first generation drug is explained. Finally, it is very interesting to note that the sum of those individual residue-specific binding free energies are in quite good agreement with the experimentally measured total binding free energies for this protein-ligand system. PMID- 29406754 TI - One-Step Synthesis of Tunable-Size Gold Nanoplates on Graphene Multilayers. AB - Au nanoplates (quasi-two-dimensional single crystals) are most commonly synthesized using a mixture of Au precursors via approaches involving multiple processing steps and the use of seed crystals. Here, we report the synthesis of truncated-hexagonal {111}-oriented micrometer-scale Au nanoplates on graphene multilayers using only potassium tetrabromoaurate (KAuBr4) as the precursor. We demonstrate that the nanoplate sizes can be controllably varied from tens of nanometers up to a few micrometers by introducing desired concentrations of chloroauric acid (HAuCl4) to KAuBr4 and their thicknesses from ~13 to ~46 nm with the synthesis time. Through a series of experiments carried out as a function of synthesis time and precursor composition [mixtures of HAuCl4 and KAuBr4, KBr, or ionic liquid 1-butyl-3-methylimidazolium bromide ([Bmim]Br)], we identify the optimal HAuCl4 and KAuBr4 concentrations and synthesis times that yield the largest and the thinnest size nanoplates. We show that the nanoplates are kinetically limited morphologies resulting from preferential growth of {111} facets facilitated by bromide ions in KAuBr4 solutions; we suggest that the presence of chloride ions enhances the rate of Au deposition and the relative concentration of chloride and bromide ions determines the shape anisotropy of resulting crystals. Our results provide new insights into the kinetics of nanoplate formation and show that a single precursor containing both Au and Br is sufficient to crystallize nanoplates on graphitic layers, which serve as reducing agent while enabling the nucleation and growth of Au nanoplates. We suggest that a similar approach may be used for the synthesis of nanoplates of other metals on weakly interacting van der Waals layers for, potentially, a variety of new applications. PMID- 29406755 TI - Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations. AB - Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino-acid peptide, co-secreted with insulin, and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., fibrillar oligomers) formed with sequences of naturally occurring variants from cat, rat, and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP fibril models built from solid-state NMR data. Results from this study are in agreement with experimental observations regarding their respective relative aggregation propensities. We analyze in detail the specific structural characteristics and infer mechanisms that modulate the conformational stability of amylin fibrils. Results provide a platform for further studies and the design of new drugs that could interfere with amylin aggregation and its cytotoxicity. One particular mutation, N31K, has fibril destabilizing properties, and could potentially improve the solubility of therapeutic amylin analogs. PMID- 29406756 TI - Fourier Transform Surface Plasmon Resonance of Nanodisks Embedded in Magnetic Nanorods. AB - In this study, we demonstrate the synthesis and application of magnetic plasmonic gyro-nanodisks (GNDs) for Fourier transform surface plasmon resonance based biodetection. Plasmonically active and magnetically responsive gyro-nanodisks were synthesized using electrochemical methods with anodized aluminum templates. Due to the unique properties of GNDs (magnetic responsiveness and surface plasmon bands), periodic extinction signals were generated under an external rotating magnetic field, which is, in turn, converted into frequency domains using Fourier transformation. After the binding of a target on GNDs, an increase in the shear force causes a shift in the frequency domain, which allows us to investigate biodetection for HA1 (the influenza virus). Most importantly, by modulating the number and the location of plasmonic nanodisks (a method for controlling the hydrodynamic forces by rationally designing the nanomaterial architecture), we achieved enhanced biodetection sensitivity. We expect that our results will contribute to improved sensing module performance, as well as a better understanding of dynamic nanoparticle systems, by harnessing the perturbed periodic fluctuation of surface plasmon bands under the modulated magnetic field. PMID- 29406757 TI - Global Lithium Flow 1994-2015: Implications for Improving Resource Efficiency and Security. AB - Lithium has been widely recognized as an essential metal for next-generation clean technologies. With the aim of identifying opportunities for improving lithium resource efficiency and security, this study establishes a long-term trade-linked material flow analysis framework to analyze lithium flow throughout the technological life cycle and across national boundaries during the 1994-2015 period. The results indicate that with broader purposes identified, global lithium production and consumption experienced rapid growth over the past decades. A widely distributed, actively functioning lithium trade network has been established, with the United States, China, the European Union, Chile, and Australia playing essential roles. Global lithium in-use stock, which is mainly embodied in ceramics and glass, reached 29 kilotons in 2015. The lithium stock contained in battery-related applications, together with the huge potential production of stock in future decades, represents a major opportunity for secondary lithium recovery. In the context of intensive international trade, international cooperation on lithium waste management is extremely important. It is also suggested that there is a high risk of lithium shortage for countries with strong dependence on lithium import. The establishment of domestic lithium reserves may be an option for these countries. PMID- 29406758 TI - Anodically Coupled Electrolysis for the Heterodifunctionalization of Alkenes. AB - The emergence of new catalytic strategies that cleverly adopt concepts and techniques frequently used in areas such as photochemistry and electrochemistry has yielded a myriad of new organic reactions that would be challenging to achieve using orthodox methods. Herein, we discuss the strategic use of anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events, as a complementary approach to existing methods for redox organic transformations. Specifically, we demonstrate anodically coupled electrolysis in the regio- and chemoselective chlorotrifluoromethylation of alkenes. PMID- 29406759 TI - Self-Anchored Catalyst Interface Enables Ordered Via Array Formation from Submicrometer to Millimeter Scale for Polycrystalline and Single-Crystalline Silicon. AB - Defying text definitions of wet etching, metal-assisted chemical etching (MacEtch), a solution-based, damage-free semiconductor etching method, is directional, where the metal catalyst film sinks with the semiconductor etching front, producing 3D semiconductor structures that are complementary to the metal catalyst film pattern. The same recipe that works perfectly to produce ordered array of nanostructures for single-crystalline Si (c-Si) fails completely when applied to polycrystalline Si (poly-Si) with the same doping type and level. Another long-standing challenge for MacEtch is the difficulty of uniformly etching across feature sizes larger than a few micrometers because of the nature of lateral etching. The issue of interface control between the catalyst and the semiconductor in both lateral and vertical directions over time and over distance needs to be systematically addressed. Here, we present a self-anchored catalyst (SAC) MacEtch method, where a nanoporous catalyst film is used to produce nanowires through the pinholes, which in turn physically anchor the catalyst film from detouring as it descends. The systematic vertical etch rate study as a function of porous catalyst diameter from 200 to 900 nm shows that the SAC MacEtch not only confines the etching direction but also enhances the etch rate due to the increased liquid access path, significantly delaying the onset of the mass-transport-limited critical diameter compared to nonporous catalyst c-Si counterpart. With this enhanced mass transport approach, vias on multistacks of poly-Si/SiO2 are also formed with excellent vertical registry through the polystack, even though they are separated by SiO2 which is readily removed by HF alone with no anisotropy. In addition, 320 MUm square through-Si-via (TSV) arrays in 550 MUm thick c-Si are realized. The ability of SAC-MacEtch to etch through poly/oxide/poly stack as well as more than half millimeter thick silicon with excellent site specificity for a wide range of feature sizes has significant implications for 2.5D/3D photonic and electronic device applications. PMID- 29406761 TI - [Is Ethic the Use of Electroconvulsive Therapy?] AB - Electroconvulsive therapy (ECT) is an effective and safety medical procedure, broadly utilized in several countries for the treatment of multiple mental disorders, including major depressive disorder, which is a prevalent disease. However, due the records of their use, technical inappropriate of application, adverse effects and even cases of death associated to the procedure, it has been stigmatized, disused and considered unethical treatment. This paper reviews the main components of ECT and discuss in it is a bioethical treatment. PMID- 29406762 TI - [Critical Review of Gender Ideology in the Light of Metaphysical Realism]. AB - The implementing of gender ideology in the imaginary of current welfare-state societies owes much to a long process in the history of thought, which has culminated in an accommodation of post-feminist discourse. This paper sets out the epistemological principles that are present in gender ideology, as a response to both its recent and more-remote antecedents. It is furthermore framed by an urge for emancipation that began with medieval scholasticism, the latest manifestation of which lies in the post-structuralist deconstructionism that outlines the concept of queer. This concept has dissociated the categories of sex and gender to the point of making them irrelevant for the determination of sexual identity, leaving the latter susceptible to being infinitely de- and reconstructed. This article also reviews the liberal-hedonistic context of the new postmodern setting, while showing how the concepts of "a subjective feeling of happiness" and "a life fulfilled" do not express similar content. The paper goes on to challenge the theory of gender from the perspective of metaphysic realism; stressing that the human being only appears as a real person via the possibility of anticipating another's contemplation, thereby cancelling out the abstraction of pure subjectivity. It finally offers its conclusions, with certain substantive recommendations in the field of education. PMID- 29406760 TI - Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis Enhanced Synergistic Cancer Therapy. AB - Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials ( i. e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS2) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS2 NSs were found to be internalized through three pathways: clathrin -> early endosomes -> lysosomes, caveolae -> early endosomes -> lysosomes, and macropinocytosis -> late endosomes -> lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis induced efflux of MoS2 NSs. Based on these findings, we developed a strategy to achieve effective and synergistic in vivo cancer therapy with MoS2 NSs loaded with low doses of drug through inhibiting exocytosis pathway-induced loss. To the best of our knowledge, this is the first systematic experimental report on the nano-bio interaction of 2D nanomaterials in cells and their application for anti exocytosis-enhanced synergistic cancer therapy. PMID- 29406763 TI - [Surrogacy in Maternity. A Depersonalising Human Relationship Phenomenology]. AB - Ethical and bioethical problems, which are typical of the practice of surrogate motherhood, refer to its protagonists: the couple that orders it, due to its demand to satisfy the desire of paternity and maternity and the promptness of having a female body to fulfill its aspirations; the expectant mother, and the physical and psychic repercussions coming from the role performed in the surrogacy contract, as well as the risks of manipulation and exploitation, related to her position; the baby and his right to grow counting on the certainty of his parental relationships and on the preservation of his emotional balance. The human and anthropological importance of these issues, along with the growing development of this practice in the world, has questioned our moral conscience. In this context, the expectant mother, the weakest and the most affected part among the parts involved in the surrogacy contract, demands a particular attention. In this sense, the aim of this work is to lead a phenomenological analysis of the different steps of the practice of surrogacy, from the first stage of collection and classification of the information referring to the candidates, to the stage of the insemination and of its consequences about to the private life of the expectant. On the other hand, this work tries to justify the existence of a parallelism, as for the exploitation of the female body, between the practice of surrogate motherhood and prostitution. Finally, the issue relating to the effective social emancipation of the surrogate women in poor countries, the real autonomy and the freedom of their decision, as well as the typical features of the desire of paternity of the ordering couple are dealt with. The carried out study has allowed to conclude that this practice always implies a degree of physical, psychic and moral exploitation of the expectant mother, which suggests its prohibition at global level. PMID- 29406764 TI - [Doctor-Patient Relationship from the Perspective of Medical Students' Portfolio]. AB - Doctor-patient relationship is of paramount importance for a good medical practice, however as long as medicine has been increasingly influenced by technology and science, it may be at risk of losing contact with basic human values of respect for the beliefs and preferences of the other person. In this study, we have analyzed the deontological vision of the physician-patient relationship perceived through clinical situations reflected in the portfolios carried out by 225 students of the 5th year of the Degree of Medicine at the University of Cordoba, during the courses 2014/15 and 2015/16. 201 out of 833 deontological considerations on articles of the Code of Medical Ethics constitute non-compliances. It is noteworthy that these breaches to the Code of Medical Ethics considered refer mainly (73%) to Chapter III (doctor-patient relationship). It is particularly interesting that the problems most frequently detected are those related to attitude, forms or language and lack of understanding/confidence of the physician with the patient (article 8 with 46 noncompliances), as well as problems in providing information (articles 12.1 and 15, with 18 and 42 noncompliances respectively). PMID- 29406766 TI - [Retraction notice: Is Sexual Identity Optional? A Study of the Genetics of Transsexuality. Cuadernos de Bioetica. 2017; 28 (94): 343-353]. PMID- 29406767 TI - Self-efficacy level among patients with type 2 diabetes living in rural areas. AB - INTRODUCTION: This study aims to determine the disease management self-efficacy level for patients with type 2 diabetes living in a rural area of Turkey. METHODS: The study sample consisted of 216 adult patients with type 2 diabetes. Data were collected between April and June of 2015 using the Self-Efficacy Scale for Type 2 Diabetes. The relationship between independent variables and self efficacy level was evaluated with t-test and one-way ANOVA in independent groups. A multiple regression analysis was performed to identify the determinants of self efficacy level. RESULTS: Diabetes patients living in rural areas had a moderate level of self-efficacy. Female and unemployed patients, and those who had a low educational level, who spent their lives in a village and did not receive disease management training constituted a risk group in terms of self-efficacy. The multiple regression analysis demonstrated that using oral antidiabetics or insulin (β= –0.122), lack of education on diabetes complications (β= –0.125) and insufficient self-management of diabetes (β= –0.484) reduced the self-efficacy score. CONCLUSIONS: Metabolic control parameters suggest that type diabetes patients living in rural areas of Turkey had a poor disease management level and a moderate self-efficacy level. Measures to improve the self-efficacy levels call for a diabetes education program that includes lifestyle modifications and available resources in rural areas, as well as more frequent monitoring of patients living in rural areas. PMID- 29406765 TI - [Descriptive Study on the Application of Informed Consent in Health Centers of Galicia Spain]. AB - OBJECTIVES: The aims of this study were to know the opinion and general knowledge of patients about the informed consent (IC), and their participation in the decision-making (DM) process. MATERIAL AND METHODS: A descriptive, transversal, observational, qualitative and quantitative study was designed with 120 patients randomly surveyed at the 8 University Hospital Complexes of Galicia, Spain. RESULTS AND DISCUSSION: The mean age was 52.14 years, with 50% of men. 84.21% of the ICs provided by non-medical personnel were limited to delivering and reading it. 90% of patients after signing the IC, trust their doctor. Only 50% of the professionals tried to involve the patient in DM. 53.33% of the patients participated in DM. 45.83% patients signed for having understood and accepted the explanation, being completely satisfied 95 of the patients surveyed (79.17%). CONCLUSIONS: It is essential to change the attitude of non-medical health professionals involved in the DM process, because their involvement is not being promoted. Although less than half of the respondents have signed the IC for having understood, the degree of satisfaction and confidence in the doctor was not compromised. PMID- 29406768 TI - Using the International Classification of Functioning, Disability, and Health Model to Gain Perspective of the Benefits of Yoga in Stroke, Multiple Sclerosis, and Children to Inform Practice for Children with Cerebral Palsy: A Meta Analysis. AB - OBJECTIVE: Research pertaining to yoga and children with cerebral palsy (CP) is negligible. The primary purpose of this study was to determine the domains of the International Classification of Functioning, Disability, and Health (ICF) model and levels of evidence for yoga and adults with stroke and multiple sclerosis (MS), and children. A secondary purpose was to decide whether any inferences could be made for children with CP. DESIGN: This study included a meta-analysis. INTERVENTIONS: A systematic review was performed of yoga and said populations. Outcome measures were categorized according to the ICF model domains of body structures and function, activity, and quality of life. Effect sizes (ESs) were calculated by using Cohen's d. Since there were few commonalities among outcome measures and reporting of outcomes within and among diagnostic groups, direct comparisons of ESs were difficult. Hence, we chose to evaluate the impact of yoga as compared with the control group or other physical exercise by using a General Linear Mixed Model. RESULTS: There were 5 yoga studies with stroke, 15 with MS, and 12 with children. Studies with children used outcomes related to body structure and function, whereas those with stroke and MS used outcomes across all three domains of the ICF. ESs varied from negligible to medium for stroke, from negligible to large for MS and children. CONCLUSIONS: The findings of this meta analysis indicate that yoga is no better or worse than other exercise modalities as a treatment intervention for adults with stroke and MS, and children. Group yoga classes are typically social environments that can contribute to increased physical progress and feelings that contribute to quality of life, which may benefit individuals with CP. More research on yoga and particularly in children and adults with CP would yield valuable information for creating effective and safe yoga programs with a rich array of benefits. PMID- 29406769 TI - Mass Incarceration and Pulmonary Health: Guidance for Clinicians. PMID- 29406770 TI - Statistics About Recent Journal Performance. PMID- 29406771 TI - Chronic Obstructive Pulmonary Disease: Recent Advances and Controversies in Inhaler Therapies. PMID- 29406773 TI - A safe procedure: best practice for intravenous peripheral cannulation. PMID- 29406772 TI - beta-Blocker Therapy and Clinical Outcomes in Patients with Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk. An Observational Substudy of SUMMIT. AB - RATIONALE: Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease. Although beta-blockers can be used safely in patients with chronic obstructive pulmonary disease, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long acting beta-agonists. OBJECTIVES: To compare the differential effects of long acting beta-agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with beta blockers. METHODS: We examined data from 16,485 participants in the SUMMIT study (Study to Understand Mortality and Morbidity in COPD) who were randomized to once daily inhaled fluticasone furoate, vilanterol, fluticasone furoate/vilanterol combination, or placebo and examined the associations between treatment allocation and lung function, chronic obstructive pulmonary disease exacerbations, cardiovascular events, and all-cause mortality, stratified by baseline beta-blocker therapy. RESULTS: Baseline beta-blocker therapy was used by 31% (n = 5,159) of SUMMIT participants. There was no evidence of an interaction between baseline beta-blocker therapy and the association between inhaled treatments and forced expiratory volume in 1 second at 3 months (P = 0.27), 6 months (P = 0.14), or 12 months (P = 0.33). The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the vilanterol-alone group were 58 ml (95% confidence interval, 38-78) in those receiving baseline beta-blocker therapy and 51 ml (95% confidence interval, 38 65) in those not receiving baseline beta-blocker therapy. The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the combination fluticasone furoate/vilanterol group were 85 ml (95% confidence interval, 65-105) in those receiving baseline beta-blocker therapy and 68 ml (95% confidence interval, 54-82) in those not receiving baseline beta blocker therapy. Overall, there was no evidence of interaction by randomized treatment, including vilanterol alone or in combination with fluticasone furoate, for chronic obstructive pulmonary disease exacerbations (P = 0.18), cardiovascular composite events (P = 0.33), and all-cause mortality (P = 0.41). CONCLUSIONS: There is no evidence to suggest that baseline beta-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting beta-agonists in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk. Clinical trial registered with www.clinicaltrials.gov (NCT01313676). PMID- 29406774 TI - Photorealistic Avatar and Teen Physical Activity: Feasibility and Preliminary Efficacy. AB - OBJECTIVE: Exergames played with a photorealistic avatar may enhance motivation to play, in addition to frequency, duration, and intensity of game-play. This article reports the feasibility and preliminary efficacy of an exergame played with a photorealistic avatar on physical activity (PA) intensity in a laboratory based study. MATERIALS AND METHODS: Teens (12-14 years old) were recruited from a large, metropolitan area of the southwestern United States. Parents provided written informed consent. Teens completed online data collection, played an exergame with a photorealistic avatar in an observed laboratory setting, and then participated in postassessment data collection that included online questionnaires and a telephone interview. RESULTS: The program was feasible: 42 out of 48 teens recruited (87.5%) completed all data collection activities; game enjoyment was 21.9 +/- 8.4 out of possible score of 32; immersion, 49.7 +/- 15.6 out of a possible score of 88; avatar identification, 43.9 +/- 16.5 out of a possible score of 68; and program satisfaction, 15.6 +/- 3.6 out of possible score of 20. Objectively assessed PA indicated that 15.88 minutes of the laboratory-based gameplay session (74.9% of total time) was in vigorous PA; small effect sizes were observed in autonomy (ES = 0.45; P = 0.01) and competence (ES = 0.36; P = 0.03). Little change was observed in relatedness (ES = 0.04; P = 0.82) Qualitative data confirmed participants enjoyed playing the game with a photorealistic avatar and provided suggestions to enhance the gameplay experience. CONCLUSION: Playing an exergame with a photorealistic avatar holds promise as a method for increasing PA among youth. Additional research is needed to further explore its effects on gameplay frequency, intensity, and duration in nonlaboratory setting. PMID- 29406775 TI - Response of Catatonia to Amisulpride and Lorazepam in an Adolescent with Schizophenia. PMID- 29406776 TI - Genotypic Characterization of Arcobacter spp. Isolated from Chicken Meat in Brazil. AB - Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii are Gram negative pathogenic microorganisms that cause watery diarrhea and septicemia in humans. The aims of this study were to detect the presence of Arcobacter spp. in chicken meat from butcher shops in Sao Paulo (Brazil) and to verify their virulence genes and genotypic profiles. A total of 300 chicken cuts were analyzed. The results show the presence of Arcobacter spp. in 18.3% of samples, which were identified as A. butzleri (63.6%) and A. cryaerophilus (36.3%). All strains were positive for the virulence genes ciaB and mviN, followed by cj1349 (98%), pldA (94.4%), cadF (72.7%), tlyA (92.7%), hecA (49%), irgA (47.2%), and hecB (34.5%). These strains were subjected to single-enzyme amplified fragment length polymorphism. Nineteen genotypic profiles were obtained for A. butzleri, and 17 for A. cryaerophilus. These results confirm the presence of virulent strains of A. butzleri and A. cryaerophilus in the chicken meat in Brazil. The presence of potentially virulent strains of Arcobacter highlights a possible public health risk, particularly with respect to ingestion of undercooked foods and cross-contamination from uncooked foods during food preparation and contaminated utensils. PMID- 29406777 TI - Evaluating for Bronchiolitis Obliterans with Low-Attenuation Computed Tomography Three-Dimensional Reconstructions. PMID- 29406778 TI - The First Year of Global Cleft Surgery Education Through Digital Simulation: A Proof of Concept. AB - INTRODUCTION: Parallel to worldwide disparities in patient access to health care, the operative opportunities of surgical trainees are increasingly restricted across the globe. Efforts have been directed toward enhancing surgical education outside the operating room and reducing the wide variability in global trainee operative experience. However, high costs and other logistical concerns may limit the reproducibility and sustainability of nonoperative surgical education resources. METHODS: A partnership between the academic, nonprofit, and industry sectors resulted in the development of an online virtual surgical simulator for cleft repair. First year global access patterns were observed. RESULTS: The simulator is freely accessible online and includes 5 normal and pathologic anatomy modules, 5 modules demonstrating surgical markings, and 7 step-by-step procedural modules. Procedural modules include high-definition intraoperative footage to supplement the virtual animation in addition to include multiple choice test questions. In its first year, the simulator was accessed by 849 novel users from 78 countries; 70% of users accessed the simulator from a developing nation. CONCLUSION: The Internet shows promise as a platform for surgical education and may help address restrictions and reduce disparities in surgical training. The virtual surgical simulator presented may serve as the foundation for the development of a global curriculum in cleft repair. PMID- 29406780 TI - Acute activation of pyruvate dehydrogenase increases glucose oxidation in muscle without changing glucose uptake. AB - Pyruvate dehydrogenase (PDH) activity is a key component of the glucose/fatty acid cycle hypothesis for the regulation of glucose uptake and metabolism. We have investigated whether acute activation of PDH in muscle can alleviate the insulin resistance caused by feeding animals a high-fat diet (HFD). The importance of PDH activity in muscle glucose disposal under insulin-stimulated conditions was determined by infusing the PDH kinase inhibitor dichloroacetate (DCA) into HFD-fed Wistar rats during a hyperinsulinemic-euglycemic clamp. Acute DCA infusion did not alter glucose infusion rate, glucose disappearance, or hepatic glucose production but did decrease plasma lactate levels. DCA substantially increased muscle PDH activity; however, this did not improve insulin-stimulated glucose uptake in insulin-resistant muscle of HFD rats. DCA infusion increased the flux of pyruvate to acetyl-CoA and reduced glucose incorporation into glycogen and alanine in muscle. Similarly, in isolated muscle, DCA treatment increased glucose oxidation and decreased glycogen synthesis without changing glucose uptake. These results suggest that, although PDH activity controls the conversion of pyruvate to acetyl-CoA for oxidation, this has little effect on glucose uptake into muscle under insulin-stimulated conditions. PMID- 29406781 TI - Epigenetics and developmental origins of diabetes: correlation or causation? AB - The incidence of metabolic disorders like type 2 diabetes (T2D) and obesity continue to increase. Although it is evident that the increasing incidence of diabetes confers a global societal and economic burden, the mechanisms responsible for the increased incidence of T2D are not well understood. Extensive efforts to understand the association of early-life perturbations with later onset of metabolic diseases, the founding principle of developmental origins of health and disease, have been crucial in determining the mechanisms that may be driving the pathogenesis of T2D. As the programming of the epigenome occurs during critical periods of development, it has emerged as a potential molecular mechanism that could occur early in life and impact metabolic health decades later. In this review, we critically evaluate human and animal studies that illustrated an association of epigenetic processes with development of T2D as well as intervention strategies that have been employed to reverse the perturbed epigenetic modification or reprogram the naturally occurring epigenetic marks to favor improved metabolic outcome. We highlight that although our understanding of epigenetics and its contribution toward developmental origins of T2D continues to grow, whether epigenetics is a cause, consequence, or merely a correlation remains debatable due to the many limitations/challenges of the existing epigenetic studies. Finally, we discuss the potential of establishing collaborative research efforts between different disciplines, including physiology, epigenetics, and bioinformatics, to help advance the developmental origins field with great potential for understanding the pathogenesis of T2D and developing preventive strategies for T2D. PMID- 29406782 TI - Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain. AB - Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding. PMID- 29406779 TI - At the Root: Defining and Halting Progression of Early Chronic Obstructive Pulmonary Disease. PMID- 29406783 TI - WNT16 overexpression partly protects against glucocorticoid-induced bone loss. AB - Therapeutic use of glucocorticoids (GCs) is a major cause of secondary osteoporosis, but the molecular mechanisms responsible for the deleterious effects of GCs in bone are only partially understood. WNT16 is a crucial physiological regulator of bone mass and fracture susceptibility, and we hypothesize that disturbed WNT16 activity might be involved in the deleterious effects of GC in bone. Twelve-week-old female Obl-Wnt16 mice (WNT16 expression driven by the rat procollagen type I alpha1 promoter) and wild-type (WT) littermates were treated with prednisolone (7.6 mg.kg-1.day-1) or vehicle for 4 wk. We first observed that GC treatment decreased the Wnt16 mRNA levels in bone of female mice (-56.4 +/- 6.1% compared with vehicle, P < 0.001). We next evaluated if WNT16 overexpression protects against GC-induced bone loss. Dual energy X-ray absorptiometry analyses revealed that GC treatment decreased total body bone mineral density in WT mice (-3.9 +/- 1.2%, P = 0.028) but not in Obl Wnt16 mice (+1.3 +/- 1.4%, nonsignificant). Microcomputed tomography analyses showed that GC treatment decreased trabecular bone volume fraction (BV/TV) of the femur in WT mice ( P = 0.019) but not in Obl-Wnt16 mice. Serum levels of the bone formation marker procollagen type I N-terminal propeptide were substantially reduced by GC treatment in WT mice (-50.3 +/- 7.0%, P = 0.008) but not in Obl Wnt16 mice (-3.8 +/- 21.2%, nonsignificant). However, the cortical bone thickness in femur was reduced by GC treatment in both WT mice and Obl-Wnt16 mice. In conclusion, GC treatment decreases Wnt16 mRNA levels in bone and WNT16 overexpression partly protects against GC-induced bone loss. PMID- 29406784 TI - Resistance training recovers attenuated APPL1 expression and improves insulin induced Akt signal activation in skeletal muscle of type 2 diabetic rats. AB - Adapter protein containing Pleckstrin homology (PH) domain, phosphotyrosine binding (PTB) domain, and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin-stimulated Akt activation. The expression of APPL1 is reduced in skeletal muscles of type 2 diabetic (T2D) animals, implying that APPL1 may be an important factor affecting insulin sensitivity. However, the regulation of APPL1 expression and the physiological interventions modulating these effects are unclear. Accordingly, we first confirmed that APPL1 expression and insulin-induced Akt phosphorylation were significantly attenuated in skeletal muscles of T2D rats. Additionally, we found that APPL1 expression levels were significantly correlated with fasting blood glucose levels. Next, we identified important signals involved in the expression of APPL1. APPL1 mRNA expression increased upon AMP-activated protein kinase, calcium, p38 mitogen-activated protein kinase, and insulin-like growth factor-1 signal activation. Moreover, acute resistance exercise in vivo significantly activated these signaling pathways. Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin-induced Akt signaling in skeletal muscles of rats with T2D. Furthermore, variations in APPL1 expression (i.e., the difference between control and RT muscles) significantly correlated with variations in insulin-stimulated Akt phosphorylation under the same conditions. Therefore, chronic RT recovered attenuated APPL1 expression and improved insulin-stimulated Akt phosphorylation in skeletal muscles of T2D rats. Accordingly, APPL1 may be a key regulator of insulin resistance in skeletal muscle, and RT may be an important physiological treatment increasing APPL1 expression, which is attenuated in T2D. PMID- 29406785 TI - Burden of Disease. PMID- 29406786 TI - New JACM Column Partnership with the Osher Collaborative for Integrative Medicine. PMID- 29406788 TI - Defining the Term "Overuse": An Evidence-Based Review of Sports Epidemiology Literature. AB - : Reference/Citation: Roos KG, Marshall SW. Definition and usage of the term "overuse injury" in the US high school and collegiate sport epidemiology literature: a systematic review. Sports Med. 2014;44(3):405-421. CLINICAL QUESTION: What is the current context of the term overuse in the epidemiologic sports injury literature? DATA SOURCES: The authors performed a database search of PubMed and SPORTDiscus. The Boolean phrases athletics AND injury and overuse OR epidemiology were searched. STUDY SELECTION: Studies were included in the review based on the following criteria: (1) epidemiologic in nature, (2) involved US high school or collegiate athletes, and (3) published in English between 1996 and 2012. In addition, a study was classified as epidemiologic in nature if appropriate exposure data were collected in order to calculate injury incidence rates. One reviewer initially read the titles or abstracts of the studies to determine their relevance for the systematic review. Studies were excluded if they (1) were biomechanical or anatomical in nature, (2) were clinical in nature, or (3) assessed the effectiveness of an intervention. DATA EXTRACTION: The reviewer extracted statistics and definitions of the word and phrase overuse and no contact. The reviewer adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as much as possible. MAIN RESULTS: A total of 5182 titles of articles were initially identified in the databases searched. Then 232 studies were read to determine if they included overuse statistics. A total of 35 articles were included in the final review. Two main surveillance programs were used in these studies, with the authors of 12 articles (n = 12/35, 34.3%) using data from the High School Reporting Information Online (RIO) and the authors of 13 articles (n = 13/35, 37.1%) using data from the National Collegiate Athletic Association's Injury Surveillance System (ISS). One group (n = 1/35, 2.9%) used both surveillance systems, whereas 9 groups (n = 9/35, 25.7%) used other surveillance systems. Articles were categorized as (1) high school or collegiate studies using neither ISS nor RIO data, (2) high school studies using RIO data, or (3) collegiate studies using ISS data. The authors of only 1 article of the 35 (2.9%) provided a comprehensive definition of the word overuse. Collectively, 14 groups classified overuse as a mechanism of injury, 7 classified it as a category of diagnosis, and 8 classified it as both a mechanism of injury and a category of diagnosis. Specifically, 12 of the 35 articles combined overuse with other terms such as chronic, gradual onset, and repetitive stress, whereas 4 of the 35 articles defined overuse in the context of no-contact injuries. CONCLUSIONS: A great deal of inconsistency exists within the sports injury epidemiological literature regarding the term overuse. The authors of the systematic review recommended using the term overuse when referencing the mechanism of injury. A working definition of the term overuse should be used in injury surveillance such that injuries due to overuse are characterized by a mechanism of gradual onset and an underlying pathogenesis of repetitive microtrauma. PMID- 29406787 TI - The Lymphangioleiomyomatosis Lung Cell and Its Human Cell Models. AB - Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle-like LAM cells, with mutations and loss of heterozygosity in the TSC1 or, more frequently, TSC2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture, and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells. A clonal population of LAM lung cells has not been established, making analysis of the cells challenging. Cell lines have been established from angiomyolipomas, a common manifestation of LAM, and from tumors from patients with TSC. Circulating LAM cells have also been isolated from blood and other body fluids. LAM cells may also be identified in clusters apparently derived from lymphatic vessels. Genetics, patterns of antigen expression, and signaling pathways have been studied in LAM lung tissue and in LAM cell models, although rarely all in the same study. We show here that LAM cells manifest differences in these characteristics, depending on the source investigated, suggesting further studies. PMID- 29406790 TI - Identification of Biological Phenotypes in Acute Respiratory Distress Syndrome. From Biomarkers to Clinical Outcome. PMID- 29406789 TI - Automatic Detection and Estimation of Unannounced Meals for Multivariable Artificial Pancreas System. AB - BACKGROUND: Automatically attenuating the postprandial rise in the blood glucose concentration without manual meal announcement is a significant challenge for artificial pancreas (AP) systems. In this study, a meal module is proposed to detect the consumption of a meal and to estimate the amount of carbohydrate (CHO) intake. METHODS: The meals are detected based on qualitative variables describing variation of continuous glucose monitoring (CGM) readings. The CHO content of the meals/snacks is estimated by a fuzzy system using CGM and subcutaneous insulin delivery data. The meal bolus amount is computed according to the patient's insulin to CHO ratio. Integration of the meal module into a multivariable AP system allows revision of estimated CHO based on knowledge about physical activity, sleep, and the risk of hypoglycemia before the final decision for a meal bolus is made. RESULTS: The algorithm is evaluated by using 117 meals/snacks in retrospective data from 11 subjects with type 1 diabetes. Sensitivity, defined as the percentage of correctly detected meals and snacks, is 93.5% for meals and 68.0% for snacks. The percentage of false positives, defined as the proportion of false detections relative to the total number of detected meals and snacks, is 20.8%. CONCLUSIONS: Integration of a meal detection module in an AP system is a further step toward an automated AP without manual entries. Detection of a consumed meal/snack and infusion of insulin boluses using an estimate of CHO enables the AP system to automatically prevent postprandial hyperglycemia. PMID- 29406791 TI - Functional abdominal pain disorders in children. AB - INTRODUCTION: Chronic abdominal pain is a common problem in pediatric practice. The majority of cases fulfill the Rome IV criteria for functional abdominal pain disorders (FAPDs). At times, these disorders may lead to rather serious repercussions. Area covered: We have attempted to cover current knowledge on epidemiology, pathophysiology, risk factors related to pathophysiology, clinical evaluation and management of children with FAPDs. Expert commentary: FAPDs are a worldwide problem with a pooled prevalence of 13.5%. There are a number of predisposing factors and pathophysiological mechanisms including stressful events, child maltreatment, visceral hypersensitivity, altered gastrointestinal motility and change in intestinal microbiota. It is possible that the environmental risk factors intricately interact with genes through epigenetic mechanisms to contribute to the pathophysiology. The diagnosis mainly depends on clinical evaluation. Commonly used pharmacological interventions do not play a major role in relieving symptoms. Centrally directed, nonpharmacological interventions such as hypnotherapy and cognitive behavioral therapy have shown both short and long term efficacy in relieving pain in children with FAPDs. However, these interventions are time consuming and need specially trained staff and therefore, not currently available at grass root level. Clinicians and researchers should join hands in searching for more pragmatic and effective therapeutic modalities to improve overall care of children with FAPDs. PMID- 29406792 TI - Functional Predominance of msr(D), Which Is More Effective as mef(A)-Associated Than mef(E)-Associated, Over mef(A)/mef(E) in Macrolide Resistance in Streptococcus pyogenes. AB - Although mef(A) and its subclass mef(E) genes have long been considered to play a central role in macrolide efflux-based resistance, we have previously demonstrated that the msr(D) gene located immediately downstream of the mef(A) gene plays a predominant role in Streptococcus pyogenes macrolide resistance. The mef(A) and mef(E) genes are carried by different genetic elements and the resistance associated with mef(A) was reported to be higher than that associated with mef(E); therefore, we further investigated the functional relevance of mef(A)/mef(E) and its associated msr(D). We established additional mef(A)-, mef(E)-, and their associated msr(D)-knockout strains and confirmed the predominance of msr(D) over mef(A)/mef(E). In addition, we performed experiments introducing mef(A), mef(E), and their associated msr(D) genes into mef(A)/mef(E) msr(D) double-knockout and mef(A)/mef(E) negative strains. Neither mef(A) nor mef(E) genes had effects on erythromycin resistance. However, both associated msr(D) showed significant effects, and the mef(A)-associated msr(D) exhibited more effect than the mef(E)-associated one. These results suggest that an overall functional predominance of msr(D) over mef(A)/mef(E) is conceivable in efflux based macrolide resistance in at least some S. pyogenes strains. Furthermore, the higher resistance of mef(A) system over mef(E) system could be derived at least in part from functional differences of mef(A)- and mef(E)-associated msr(D). PMID- 29406793 TI - Development and Evaluation of a Novel Microemulsion of Dexamethasone and Tobramycin for Topical Ocular Administration. AB - PURPOSE: The purpose of this study was to develop and evaluate a novel dexamethasone- and tobramycin-loaded microemulsion for its potential for treating anterior segment eye infections. METHODS: The microemulsion was evaluated for pH, particle size, zeta potential, light transmittance, morphology, and in vitro drug release. Sterility of the microemulsion was evaluated by direct as well as plate inoculation methods. Anti-inflammatory activity of dexamethasone, bactericidal activity of tobramycin, and cytotoxicity of the microemulsion were assessed and compared to that of the marketed eye drop suspension (Tobradex(r)). Histological evaluation was performed in bovine corneas to assess the safety of microemulsion in comparison to Tobradex suspension. In addition, the stability of the microemulsion was studied at 4 degrees C, 25 degrees C, and 40 degrees C. RESULTS: The pH of the microemulsion was close to the pH of tear fluid. The microemulsion displayed an average globule size under 20 nm, with light transmittance around 95%-100%. The aseptically prepared microemulsion remained sterile for up to 14 days. The cytotoxicity of the microemulsion in bovine corneal endothelial cells was comparable to that of the Tobradex suspension. The anti-inflammatory activity of dexamethasone and the antibacterial activity of tobramycin from the microemulsion were significantly higher than those of the Tobradex suspension (P < 0.05). Histological evaluation showed an intact corneal epithelium without any signs of toxicity, and the developed microemulsion was found to be stable at 4 degrees C and 25 degrees C for 3 months. CONCLUSION: In conclusion, the developed microemulsion could be explored as a suitable alternative to the marketed suspension for treating anterior segment eye infections. PMID- 29406794 TI - Evidence-Based Medicine in Otolaryngology Part 7: Introduction to Shared Decision Making. AB - Shared decision making (SDM) is a collaborative process in which patients, families, and clinicians develop a mutually agreed upon treatment plan when more than one reasonable treatment option exists. This cooperative engagement fosters improvements in patient satisfaction, disease management, and outcomes and also has the capacity to promote evidence-based care. Thus, this seventh installment of our Evidence-Based Medicine in Otolaryngology series focuses on SDM. We introduce SDM, including its potential to reduce decisional conflict and decisional regret, when it should be used, its potential benefits, barriers to implementation, and its role in the management of chronic disease and otolaryngological conditions. PMID- 29406795 TI - Venous Thromboembolism Risk in Head and Neck Cancer: Significance of the Preoperative Platelet-to-Lymphocyte Ratio. AB - Objective We aimed to investigate the association between the preoperative platelet-to-lymphocyte ratio (PLR) and venous thromboembolism (VTE) in patients with head and neck cancer (HNC) undergoing major surgery. Study Design Retrospective cohort study. Setting Academic tertiary hospital from 2011 to 2017. Subjects and Methods Patients with confirmed HNC undergoing major surgery were included in this study. The preoperative PLR was recorded for all patients. Known VTE risk factors, including Caprini score, age, sex, smoking, body mass index, prior VTE, and anticoagulation, were also recorded. Risk factors were screened in univariate analysis using Wilcoxon's rank sum test and chi2 test (Bonferroni corrected). Significant covariates were included in a multivariate regression model. Bootstrap techniques were used to obtain credible confidence intervals (CIs). Results There were 306 patients enrolled with 7 cases of VTE (6 deep vein thromboses and 1 pulmonary embolism. On univariate analysis, length of stay ( P = .0026), length of surgery ( P = .0029), and PLR ( P = .0002) were found to have significant associations with VTE. A receiver operator characteristic (ROC) curve was constructed that yielded an area under the ROC of 0.905 (95% CI, 0.82-0.98). Using an optimized cutoff, the multivariate model showed that length of surgery (beta 95% CI, 0.0001-0.0006; P = .0056) and PLR (beta 95% CI, 5.3256-5.3868; P < .0001) were significant independent predictors of VTE. Conclusion This exploratory pilot study has shown that PLR offers a potentially accurate risk stratification measure as an adjunct to current tools in VTE risk prediction, without additional cost to health systems. PMID- 29406796 TI - Active Monitoring of Travelers for Ebola Virus Disease-New York City, October 25, 2014-December 29, 2015. AB - The CDC recommended active monitoring of travelers potentially exposed to Ebola virus during the 2014 West African Ebola virus disease outbreak, which involved daily contact between travelers and health authorities to ascertain the presence of fever or symptoms for 21 days after the travelers' last potential Ebola virus exposure. From October 25, 2014, to December 29, 2015, the New York City Department of Health and Mental Hygiene (DOHMH) monitored 5,359 persons for Ebola virus disease, corresponding to 5,793 active monitoring events. Most active monitoring events were in travelers classified as low (but not zero) risk (n = 5,778; 99%). There were no gaps in contact with DOHMH of >=2 days during 95% of active monitoring events. Instances of not making any contact with travelers decreased after CDC began distributing mobile telephones at the airport. Ebola virus disease-like symptoms or a temperature >=100.0 degrees F were reported in 122 (2%) active monitoring events. In the final month of active monitoring, an optional health insurance enrollment referral was offered for interested travelers, through which 8 travelers are known to have received coverage. Because it is possible that active monitoring will be used again for an infectious threat, the experience we describe might help to inform future such efforts. PMID- 29406797 TI - Sequelae of Index Complications following Inpatient Head and Neck Surgery: Characterizing Secondary Complications. AB - Objective To characterize patterns of secondary complications after inpatient head and neck surgery. Study Design Retrospective cohort study. Setting National Surgical Quality Improvement Program (2005-2015). Subjects and Methods We identified 18,584 patients who underwent inpatient otolaryngologic surgery. Four index complications were studied: pneumonia, bleeding or transfusion event (BTE), deep/organ space surgical site infection (SSI), and myocardial infarction (MI). Each patient with an index complication was matched to a control patient based on propensity for the index event and event-free days. Rates of 30-day secondary complications and mortality were compared. Results Index pneumonia (n = 254) was associated with several complications, including reintubation (odds ratio [OR], 11.7; 95% confidence interval [CI], 5.2-26.4), sepsis (OR, 8.8; 95% CI, 4.5 17.2), and death (OR, 5.3; 95% CI, 1.9-14.9). Index MI (n = 50) was associated with increased odds of reintubation (OR, 17.2; 95% CI, 3.5-84.1), ventilatory failure (OR, 5.8; 95% CI, 1.8-19.1), and death (OR, 24.8; 95% CI, 2.9-211.4). Index deep/organ space SSI (n = 271) was associated with dehiscence (OR, 7.2; 95% CI, 3.6-14.2) and sepsis (OR, 38.3; 95% CI, 11.6-126.4). Index BTE (n = 1009) increased the odds of cardiac arrest (OR, 3.9; 95% CI, 1.8-8.5) and death (OR, 2.9; 95% CI, 1.6-5.1). Conclusions Our study is the first to quantify the effect of index complications on the risk of specific secondary complications following inpatient head and neck surgery. These associations may be used to identify patients most at risk postoperatively and target specific interventions aimed to prevent or interrupt further complications. PMID- 29406798 TI - Successful Treatment of Adolescents and Young Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia by Novel L-Asparaginase-Intensified Induction Therapy and Cord Blood Transplantation: A Single-Center Decade Report. AB - A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence. Our results indicate scope for further development of both induction therapy and postremission therapy. PMID- 29406799 TI - Management of Pediatric Urolithiasis Using a Combination of Laparoscopic Lithotomy and Pyeloscopy. AB - BACKGROUND: Minimally invasive procedures have become the standard option for treatment of urinary stones; the use of more invasive techniques is not a common practice currently. This emergent technology is not always available and laparoscopy is the alternative option. There are few reports of laparoscopic management for urinary lithiasis in pediatric patients. This study is about the use of laparoscopic surgery combined with pyeloscopy as a feasible first-line treatment for pediatric urolithiasis in renal and proximal ureteral locations. PATIENTS AND METHODS: We reviewed the records of 14 patients with renal and proximal ureteral stones who underwent laparoscopic pyelolithotomy and pyeloscopy in a period from January 2011 to July 2016. The outcome measures were needed for auxiliary procedures, treatment success, and complication rates. RESULTS: A total of 16 procedures were carried out in 14 patients, 15 transperitoneal and 1 retroperitoneal laparoscopic pyelolithotomies were done. It was necessary to perform upper ureterolithotomies to remove ureteral stones in 2 cases. The holmium laser and/or pneumatic lithotripter were used to fragment staghorn calculi. Some of the complications were blood transfusion in 12.5% and self limited urinary leak in 18.7% of the patients. The success rate after undergoing one procedure was 92.8%. CONCLUSIONS: Transperitoneal or retroperitoneal laparoscopic lithotomy is a safe and feasible procedure for the treatment of pediatric urolithiasis. It can be an alternative to shock-wave lithotripsy and percutaneous nephrolithotomy when these are not feasible or possible. PMID- 29406800 TI - Rapid molecular diagnostics for multi-drug resistant tuberculosis in India. AB - INTRODUCTION: Rapid molecular diagnostic methods help in the detection of TB and Rifampicin resistance. These methods detect TB early, are accurate and play a crucial role in reducing the burden of drug resistant tuberculosis. Areas covered: This review analyses rapid molecular diagnostic tools used in the diagnosis of MDR-TB in India, such as the Line Probe Assay and GeneXpert. We have discussed the burden of MDR-TB and the impact of recent diagnostic tools on case detection and treatment outcomes. This review also discusses the costs involved in establishing these new techniques in India. Expert commentary: Molecular methods have considerable advantages for the programmatic management of drug resistant TB. These include speed, standardization of testing, potentially high throughput and reduced laboratory biosafety requirements. There is a desperate need for India to adopt modern, rapid, molecular tools with point-of-care tests being currently evaluated. New molecular diagnostic tests appear to be cost effective and also help in detecting missing cases. There is enough evidence to support the scaling up of these new tools in India. PMID- 29406802 TI - Reply to Y. Yagi et al. PMID- 29406801 TI - Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid Induced Constipation and Cancer. PMID- 29406803 TI - Controversies Regarding Service Animals in the Ambulatory Oncology Setting. PMID- 29406804 TI - Comparative Evaluation of Broth Microdilution with Polystyrene and Glass-Coated Plates, Agar Dilution, E-Test, Vitek, and Disk Diffusion for Susceptibility Testing of Colistin and Polymyxin B on Carbapenem-Resistant Clinical Isolates of Acinetobacter baumannii. AB - INTRODUCTION: With the increasing threat of multidrug-resistant organisms, such as Acinetobacter baumannii, the polymyxin class of drugs (colistin and polymyxin B) has become popular in clinical practice. A better understanding of antimicrobial susceptibility testing methods for colistin and polymyxin B is needed for optimal patient management. MATERIALS AND METHODS: Forty-two carbapenem-resistant A. baumannii isolates were subjected to susceptibility testing for colistin and polymyxin B using the following methods: broth microdilution (BMD) (glass-coated plates [BMD-Gs] and polystyrene plates [BMD Ps]), agar dilution (AD), E-test(r), Vitek(r), and disk diffusion. Using BMD as the gold standard, comparative analysis between different methods was carried out. RESULTS: With BMD-Gs as reference, reliability was high for BMD-Ps and moderate for AD and Vitek for both the drugs. Similar results were obtained when the BMD-P was used as reference, but drug-polystyrene interaction was observed. CONCLUSION: Different susceptibility testing methods for polymyxins show great variation in their results and BMD using glass-coated plates can be considered the best candidate for gold standard. PMID- 29406805 TI - A Systems Approach to Agricultural Biosecurity. AB - This article highlights the importance of systems approaches in addressing agricultural biosecurity threats. On the basis of documentary analysis and stakeholder interaction, a brief survey of agricultural biosecurity threats and vulnerabilities from global and Indian perspectives is provided, followed by an exploration of technological and institutional capabilities. Finally, a perspective on the agricultural disease diagnostic networks is provided, drawing instances from global developments. Technical barriers to agroterrorism are lower than those to human-targeted bioterrorism, and the sector is unique as even a very small disease outbreak could prompt international export restrictions. Key vulnerabilities in the agriculture sector stem from, among others, the structure of agricultural production; insufficient monitoring, surveillance, and controls systems at the borders and in the food chain; inefficient systems for reporting unusual occurrences and outbreaks of disease; and lack of sufficiently trained human resources capable of recognizing or treating transboundary pathogens and diseases. An assessment of technology and institutions pertaining to crop and animal protection management suggests certain gaps. Investment in developing new technologies for civilian application in agriculture, as well as for legitimate actions pertaining to defense, detection, protection, and prophylaxis, and in upgrading laboratory facilities can increase the agricultural sector's level of preparedness for outbreaks. To address potential threats and vulnerabilities of agroterrorism effectively requires the development of a comprehensive strategy and a combined, interagency approach, ideally on an international level. It is proposed that a systems-oriented approach for developing knowledge and innovation networks and strengthening skills and capacities would enable a more resilient agricultural biosecurity system. PMID- 29406806 TI - Laparoscopic Versus Conventional Open Abdominoperineal Resection for Rectal Cancer: An Updated Systematic Review and Meta-Analysis. AB - BACKGROUND: Laparoscopic abdominoperineal resection (LAPR) for rectal cancer (RC) treatment is still controversial, so we conducted this meta-analysis comparing LAPR with conventional open abdominoperineal resection (OAPR) to explore the safety and feasibility of LAPR for RC treatment. METHODS: A systematic literature search with no limits was performed in PubMed, and Ovid. The last search was performed on June 6, 2017. The outcomes of interests included intraoperative outcomes, pathological outcomes, postoperative outcomes, and survival outcomes. RESULTS: Twenty-one articles published between 1997 and 2016 with a total of 20,343 patients were enrolled in this meta-analysis. Compared with OAPR, LAPR showed comparable operative time, less blood loss and intraoperative blood transfusion, smaller length of hospital day and postoperative hospital day, faster recovery of bowel functions, and less postoperative complications, especially less abdominal wound infection. As for pathological outcomes, LAPR was not inferior to OAPR. Besides, LAPR was comparable to OAPR in recurrence rate, 3 year survivals and 5-year survivals. CONCLUSIONS: LAPR can reduce postoperative complications, lead faster postoperative recovery. In addition, LAPR is not inferior to OAPR in terms of oncological clearance, recurrence rate, and long time survivals. So LAPR is safe and feasible for RC treatment. Further, more perspective randomized trials can be conducted to compare LAPR and OAPR in the future. PMID- 29406807 TI - Quantifying the Additional Difficulty of Pediatric Robot-Assisted Laparoscopic Re Do Pyeloplasty: A Comparison of Primary and Re-Do Procedures. AB - BACKGROUND: Re-do pyeloplasty after failed open or laparoscopic ureteropelvic junction (UPJ) obstruction correction can be a challenging procedure because of scar formation at the previous anastomosis site and decreased vascularity of the ureter. This study compared the perioperative parameters for pediatric robot assisted laparoscopic (RAL) primary and re-do pyeloplasties with an emphasis on the intra-operative parameters. MATERIALS AND METHODS: We compared the perioperative parameters of pediatric RAL procedures performed by a single surgeon at a tertiary care children's hospital for both primary ureteropelvic junction obstruction (UPJO) and recurrent UPJO after a previous open or laparoscopic procedure over 2013-2015. The operative time was subdivided as total operative time, console time, port placement time, dissection time to UPJ, and anastomosis time. RESULTS: A total of 65 pediatric RAL pyeloplasty procedures for UPJO were performed (55 primary and 10 re-do pyeloplasties) during the study period. The console times were 43.3% longer for re-do pyeloplasties than for primary pyeloplasties (133.0 +/- 30.7 versus 92.8 +/- 24.0 minutes, respectively, P < .01). The re-do cases had longer operative times, especially for UPJ exposure (52.2 +/- 21.0 versus 28.0 +/- 14.0 minutes, P < .01). There were no conversions to open surgery or significant perioperative complications. There was no difference in hospital pain medication usage and hospital length of stay between the 2 groups. The treatment success rates were 98.2% (54/55) and 100% (10/10), respectively. CONCLUSIONS: RAL re-do pyeloplasty is associated with significantly longer operative times as compared with primary pyeloplasties, especially during the exposure of the UPJ, but it is overall a safe and effective surgical modality for persistent/recurrent UPJO in children. As surgeons are increasingly asked for more accurate predictions of operative time lengths when scheduling cases, this information can be helpful for surgeons when scheduling these cases and with counseling families. PMID- 29406808 TI - Application of Three-Dimensional Visualization Technology in Laparoscopic Surgery for Pheochromocytoma/Paraganglioma: A Single-Center Experience. AB - OBJECTIVE: To compare the feasibility of three-dimensional visualization technology (3DVT) with that of routine computed tomography (CT) examination during planning of laparoscopic surgery for pheochromocytoma (PHEO) and paraganglioma (PGL) and the effects on operative and postoperative outcomes. PATIENTS AND METHODS: The clinical data for 36 patients who underwent laparoscopic surgery for PHEO/PGL in our department from January 2016 to April 2017 were analyzed retrospectively. Fourteen patients underwent laparoscopic surgery for PHEO/PGL after preoperative 3DVT-based assessment and 22 after conventional CT examination. The demographic parameters, surgical procedures used, and perioperative outcomes were compared between the two groups. Data were entered into a Microsoft Excel worksheet and analyzed using SPSS version 24.0. RESULTS: No significant differences were found between the groups with regard to age, gender, body mass index, tumor size, surgical approach, estimated blood loss, mean length of hospital stay, number of hypertensive and hypotensive episodes during surgery, peak blood pressure (BP) values during tumor handling, and minimum values after tumor excision. However, the operating time was significantly shorter and the fluctuations in BP were significantly lower in the 3DVT group. CONCLUSIONS: 3DVT is a feasible and useful preoperative assessment method in patients undergoing laparoscopic surgery for PHEO/PGL. This imaging technique accurately shows the relationship between the tumor and peripheral structures and aids the surgeon's understanding of the anatomic structure in the operative area and in surgical planning. PMID- 29406809 TI - Radiation-Induced Lens Opacities among Interventional Cardiologists: Retrospective Assessment of Cumulative Eye Lens Doses. AB - This study describes the retrospective lens dose calculation methods developed and applied within the European epidemiological study on radiation-induced lens opacities among interventional cardiologists. While one approach focuses on self reported data regarding working practice in combination with available procedure specific eye lens dose values, the second approach focuses on the conversion of the individual whole-body dose to eye lens dose. In contrast with usual dose reconstruction methods within an epidemiological study, a protocol is applied resulting in an individual distribution of possible cumulative lens doses for each recruited cardiologist, rather than a single dose estimate. In this way, the uncertainty in the dose estimate (from measurement uncertainty and variability among cardiologists) is represented for each individual. Eye lens dose and whole body dose measurements have been performed in clinical practice to validate both methods, and it was concluded that both produce acceptable results in the framework of a dose-risk evaluation study. Optimal results were obtained for the dose to the left eye using procedure-specific lens dose data in combination with information collected on working practice. This method has been applied to 421 interventional cardiologists resulting in a median cumulative eye lens dose of 15.1 cSv for the left eye and 11.4 cSv for the right eye. From the individual cumulative eye lens dose distributions obtained for each cardiologist, maxima up to 9-10 Sv were observed, although with low probability. Since whole-body dose values above the lead apron are available for only a small fraction of the cohort and in many cases not for the entire working career, the second method has only been used to benchmark the results from the first approach. This study succeeded in improving the retrospective calculation of cumulative eye lens doses in the framework of radiation-induced risk assessment of lens opacities, but it remains dependent on self-reported information, which is not always reliable for early years. However, the calculation tools developed can also be used to make an assessment of the eye lens dose in current practice. PMID- 29406810 TI - Response to the 'Comments on "Cellular Therapies for Treatment of Radiation Injury after a Mass Casualty Incident" (Radiat Res 2017; 188:242-45)' by Drouet et al. (Letters to the Editor, Radiat Res 2017; 188:463). PMID- 29406811 TI - Vedolizumab for the treatment of Crohn's disease. AB - INTRODUCTION: Crohn's disease (CD) is an immune-mediated condition characterized by inflammation of the gut tissue, associated with progressive damage of the affected intestinal tract and possible complications. A treat-to-target approach is strongly advocated, consisting of early and aggressive inflammatory control. However, a great proportion of affected subjects lack response or are intolerant to conventional therapy. Even though the first-line biologic therapy targeting tumor necrosis factor-alfa (TNF-alpha) is associated with improvement of inflammation in some patients, others do not respond at first or lose response over time. These findings brought about the possibility of different mechanisms being involved in perpetuating the chronic inflammatory state. Novel drugs targeting different inflammatory pathways have been studied in CD, specifically addressed to leucocyte trafficking. Areas covered: We aim to review the relevant data available in the literature and briefly summarize the efficacy and safety profile of vedolizumab in the treatment of CD. Expert commentary: Vedolizumab has shown, from pivotal and real-life data, significant clinical benefit among CD patients, in addition to a singular safety profile. Future studies will provide helpful data concerning its use in special situations. PMID- 29406812 TI - Femoroacetabular impingement: a common cause of hip pain. AB - Femoroacetabular impingement (FAI) is a common cause of hip pain that can affect a wide range of patients. It is due to altered bony morphology of the proximal femur and acetabulum, resulting in decreased function and progression to early osteoarthritis. Until the early 2000s, little was known or understood about the significance of FAI as a clinical entity. The field of hip preservation has grown exponentially since that time, and has led to many advances in caring for those with symptomatic impingement. This review details the early diagnosis and proper management of femoroacetabular impingement for the sports medicine practitioner. PMID- 29406813 TI - Reading cytosine modifications within chromatin. AB - Zinc-finger and homeodomain transcription factors have been shown in vitro to bind to recognition motifs containing a methylated CpG. However, accessing these motifs in vivo might be seriously impeded by the inclusion of DNA in nucleosomes and by the condensed structure adopted by chromatin formed on methylated DNA. Here, we discuss how oxidation of 5-methylcytosine into 5-hydroxymethylcytosine could provide the initial destabilizing clue for such transcription factors to get access to nucleosomal DNA and read epigenetic information. PMID- 29406814 TI - A Randomized Controlled Trial of Video Education versus Skill Demonstration: Which Is More Effective in Teaching Sterile Surgical Technique? AB - BACKGROUND: Video education has many advantages over traditional education including efficiency, convenience, and individualized learning. Learning sterile surgical technique (SST) is imperative for medical students, because proper technique helps prevent surgical site infections (SSIs). We hypothesize that video education is at least as effective as traditional skill demonstration in teaching first-year medical students SST. METHODS: A video series was created to demonstrate SST ( https://www.youtube.com/playlist?list=PLcRU gvOmxE2mwMWkowouBkxGXkLZ8Uis ). A randomized controlled trial was designed to assess which education method best teaches SST: video education or skill demonstration. First-year medical students (n = 129) were consented and randomly assigned into two groups: those who attended a skill demonstration (control group; n = 70) and those who watched the video series (experimental group; n = 59). The control group attended a pre-existing 90-minute nurse educator-led skill demonstration. Participants then completed a 30-item multiple choice quiz to test their knowledge. Each group then received the alternate education method and completed a 23-item follow-up survey to determine their preferred method. RESULTS: Seven 2- to 6-minute videos (30 minutes total) were created on surgical attire, scrubbing, gowning and gloving, and maintaining sterility. The experimental group (n = 51) scored higher on the quiz compared with the control group (n = 63) (88% +/- 1% versus 72% +/- 1%; p < 0.0001). Students preferred the videos when it came to convenience, accessibility, efficiency, and review, and preferred the skill demonstration when it came to knowledge retention, preparedness, and ease of completion. CONCLUSIONS: Video education is superior to traditional skill demonstration in providing medical students with knowledge of SST. Students identified strengths to each method of teaching. Video education can augment medical students' knowledge prior to their operating room experience to ensure that a sterile environment is maintained for patients. The ultimate goal is to reduce SSIs. PMID- 29406815 TI - Dysregulation of Tryptophan Catabolism in Metabolic Syndrome. AB - OBJECTIVE: Obesity and metabolic syndrome are preventable complex-multifactorial disorders that severely increase risk of cardiovascular disease (CVD). Indoleamine 2,3-dioxygenase (IDO) enzyme converts tryptophan (TRP) to kynurenine (KYN); besides, KYN/TRP ratio has been shown to predict major coronary events and all-cause mortality in patients with coronary artery disease. However, their role in metabolic syndrome is not understood. METHODS: In a cross-sectional study (n = 161, mean population age in years = 32 +/- 7.5, and sex = 53% female), standard anthropometric parameters, blood chemistry, high-sensitivity C-reactive protein, TRP, KYN, and KYN/TRP ratio were measured and compared with uric acid (UA), metabolic syndrome, and body mass index (BMI). RESULTS: KYN/TRP ratio was significantly elevated in individuals with hyperuricemia (UA >=7) (P < 0.0001), metabolic syndrome (P = 0.0066), and obesity (P = 0.0349), compared to their respective control groups. Moreover, increased presence of TRP does not correlate with increased TRP conversion to KYN, thus inflammation drives IDO enzyme activity. KYN/TRP levels were positively correlated with UA (R2 = 0.1083, P < 0.0001), BMI (R2 = 0.05267, P = 0.0036), and triglycerides (R2 = 0.08053, P = 0.0003). Receiver operating characteristic curve implied that KYU/TRP ratio (AUC 0.7032, P < 0.0001) was more effective in stratifying CVD risk in combination with UA, and a gamma regression model (P < 0.001) demonstrated dependence of UA, BMI, and low-density lipoprotein along with KYN/TRP in CVD risk. CONCLUSIONS: TRP catabolism is altered in metabolic syndrome; however, further studies are needed to understand role of kynurenine in pathology and disease outcomes. PMID- 29406816 TI - Accuracy and the Proper Use of the Point-of-Care Analysis in Hemoglobin A1C Measurement. AB - BACKGROUND: Diabetes Mellitus is one of the most common chronic diseases in the United States and worldwide. In 2009 the American Diabetes Association (ADA) recommended using A1C greater than 6.5% to diagnose diabetes. Hemoglobin A1C can be measured by laboratory and Point-of-Care (POC) methods. It is important to compare results obtained by the two modalities to determine the proper use of these tests. METHODS: One hundred fifteen patients were identified to have both POC and laboratory A1C values obtained on the same day, between August 2013 and August 2014. The differences were analyzed and the average difference and coefficient of determination (R2) was calculated. In addition, a Bland-Altman plot was generated; Kappa statistic calculated. We also computed the sensitivity and specificity of the POC method in diagnosing diabetes while using laboratory analysis as the gold standard. RESULTS: The differences between the two measurements ranged from 0 to 3.2 with an average difference of 0.2% of A1C. The Kappa statistic is 0.761 and R2 was 0.938. Laboratory results were greater than POC in 84% of cases. Interestingly, the Bland-Altman graph also indicates that the variability between the two sets of data increases with higher values of A1C especially for A1C greater than 10%. The POC method has a sensitivity of 88.6% and specificity of 96.3% in diagnosing diabetes. CONCLUSIONS: Per ADA guidelines, the POC method is not recommended to be used to diagnose diabetes. Based on our findings 10.3% of individuals would be missed if one used the POC method to diagnose diabetes. However, given its accuracy supported by our findings it is adequate to be used during routine diabetes follow-up visits. The finding from our study can help improve healthcare quality by reducing unnecessary blood draws and clinic visits. PMID- 29406817 TI - Evaluation of Surgical Devices Using an Artificial Pediatric Thoracic Model: A Comparison Between Robot-Assisted Thoracoscopic Suturing Versus Conventional Video-Assisted Thoracoscopic Suturing. AB - BACKGROUND: Pediatric robot-assisted surgery is increasingly being performed, but it is difficult to perform this procedure in infants. A pediatric thoracoscopic model of a 1-year-old patient was developed in our previous study, and this model was used to evaluate the use of a surgical robot for infant surgery. METHODS: Eight pediatric surgeons performed an intracorporeal suturing and knot-tying task using the da Vinci Xi Robotic Surgical System. The task completion time, number of needle manipulations, and force applied during suturing of the robot-assisted thoracoscopic surgery (RATS) group were compared with those of the video-assisted thoracoscopic surgery (VATS) group whose data had been collected from the same 8 surgeons in our previous study. RESULTS: The RATS group showed a significantly shorter completion time than the VATS group in the knot-tying phase (P = .016) and in the total phase (P = .0078). The RATS group showed a significantly smaller number of manipulations than the VATS group in the total phase (P = .039). The RATS group showed a significantly smaller pushing force index than the VATS group in the suturing phase (P = .031), knot-tying phase (P = .031), and in the total phase (P = .031). A seventh rib in the model was dislocated in all RATS group cases. CONCLUSIONS: The da Vinci Surgical System might be useful in infants because of fast movement and small pushing force. However, the robotic 8 mm instruments were too large for use in the thoracic cavity of the 1-year-old infant. PMID- 29406818 TI - Determination of the Target Temperature Required to Block Increases in Extracellular Glutamate Levels During Intraischemic Hypothermia. AB - This study aimed to determine a target temperature for intraischemic hypothermia that can block increases in extracellular glutamate levels. Two groups of 10 rats each formed the normothermia and intraischemic hypothermia groups. Extracellular glutamate levels, the extracellular potential, and the cerebral blood flow were measured at the adjacent site in the right parietal cerebral cortex. Cerebral ischemia was induced by occlusion of the bilateral common carotid arteries and hypotension. In the intraischemic hypothermia group, brain hypothermia was initiated immediately after the onset of membrane potential loss. In the normothermia group, extracellular glutamate levels began to increase simultaneously with the onset of membrane potential loss and reached a maximum level of 341.8 +/- 153.1 MUmol.L-1. A decrease in extracellular glutamate levels was observed simultaneously with the onset of membrane potential recovery. In the intraischemic hypothermia group, extracellular glutamate levels initially began to increase, similarly to those in the normothermia group, but subsequently plateaued at 140.5 +/- 105.4 MUmol.L-1, when the brain temperature had decreased to <32.6 degrees C +/- 0.9 degrees C. A decrease in extracellular glutamate levels was observed simultaneously with the onset of membrane potential recovery, similarly to the findings in the normothermia group. The rate of decrease in extracellular glutamate levels was the same in both groups (-36.6 and -36.0 MUmol.L-1 in the normothermia and intraischemic hypothermia groups, respectively). In conclusion, the target temperature for blocking glutamate release during intraischemic hypothermia was found to be 32.6 degrees C +/- 0.9 degrees C. Our results suggest that the induction of intraischemic hypothermia can maintain low glutamate levels without disrupting glutamate reuptake. Institutional protocol number: OKU-2016146. PMID- 29406820 TI - The Association Between Obstructive Sleep Apnea, Metabolic Derangements, and Poor Quality of Sleep. PMID- 29406819 TI - Successful Implant Placement in a Case of Florid Cemento-Osseous Dysplasia: A Case Report and Literature Review. AB - Florid cemento-osseus dysplasia (FCOD) has been described as a reactive process in which normal bone is replaced by fibrous connective tissues and cementum-like materials. Radiographically it appears as dense, lobulated masses, often occurring bilaterally with symmetric involvement. In this case report, a successful implant placement has been reported in a 62-year-old Caucasian woman with a chief complaint of mandibular partial edentulous. Radiographic images showed the bilateral radiopaque lesions in edentulous regions of mandible, and mandibular anterior teeth alike. All mandibular teeth were vital and no root resorption was detected. The findings of X-ray images were attributable to FCOD. A highly conservative step-by-step 2-stage implant surgery was performed. After 6 months the implants loaded with fixed prosthesis. 2, 4, 6, 12, and 18 months after the surgery radiographic images were taken, which revealed an optimal functional rehabilitation and complete integration of implants. This report confirms that treating the edentulous area near the FCOD lesions could be planned, if conservative step- by-step implant placement been considered. To the best of our knowledge, a case of FCOD with successful implant placement has not been reported previously. More studies in more patients are needed to confirm results of such a therapeutic modality. PMID- 29406821 TI - Effect of Goiter Dispersion Formula on Serum Cytokines in Hyperthyroidism Patients with Neurologic Manifestations of Graves' Disease: A Randomized Trial on 80 Cases. AB - PURPOSE: This study is aimed to explore the combined use of goiter dispersion formula and antithyroid drugs in the treatment of patients with neurologic manifestations of Graves' disease by examining its modulating effects on patients' cytokines. METHODS: A total of 80 patients with Graves' disease were randomly divided into treatment and control groups. Patients of the treatment group received goiter dispersion formula and antithyroid drugs (methimazole or propylthiouracil), whereas those of the control group received antithyroid drug alone. FT3, FT4, and TSH contents were detected by chemiluminescence immunoassay at pre- and post-treatment; interleukin (IL)-2, IL-8, and IL-17 serum levels before and after the treatment were detected by radioimmunoassay; thyroid B-mode ultrasound and liver and renal function tests were performed in all patients of both groups. An additional cohort of 40 healthy subjects was recruited for baseline measurement. RESULTS: All the enrolled patients completed the trial. The effective treatment rate was higher in the treatment group than in the control group, of which the difference was statistically significant (treatment group, 95%; control group, 75%, p < 0.01). For blood cytokine, before treatment, IL-2 was reduced whereas IL-8 and IL-17 were increased significantly in both groups of patients with Graves' disease comparing with those in healthy subjects (p < 0.01). For patients of the treatment group, after treatment, their IL-2 levels were increased (p < 0.01) with concomitant decreases in IL-8 and IL-17 levels (p < 0.05). There were no significant changes in blood cytokine levels before and after treatment in the control group. CONCLUSIONS: Goiter dispersion formula significantly improved the treatment outcomes of antithyroid drug in hyperthyroidism patients with neurologic manifestations of Graves' disease by modulating IL-2, IL-8, and IL-17. The data supported the rationale for the use of goiter dispersion formula in Graves' disease treatment. PMID- 29406822 TI - World Health Organization Joint External Evaluations in the Eastern Mediterranean Region, 2016-17. AB - By 2014, only 33% of countries had self-reported compliance with the International Health Regulations (2005), including 8 countries from the Eastern Mediterranean Region (EMR). During the Ebola epidemic, the discovery of a gap between objective assessment and self-reports for certain IHR capacities prompted the World Health Organization (WHO) to review and update the IHR monitoring and evaluation framework to include a voluntary objective review process, called Joint External Evaluation (JEE), that did not exist before. The regional committee for the EMR approved the JEE and encouraged its 21 member states to volunteer for reviews. Standardized processes and procedures were developed for conducting JEEs. Of the 52 JEEs completed to date globally, 14 (27%) are from the EMR. Three (21%) of 14 member states completing the JEE in the EMR have also worked on a post-JEE national action plan for health security (NAPHS). A survey conducted about the JEE experience from focal points in EMR member states underlined the strengths of the JEE process: its multisectoral and open discussion approach; standardization of the JEE process; WHO's critical role in supporting JEE preparation and conduct; and the need for guidance development for a costed NAPHS. The success of JEEs depends not only on proper preparations and completion of the JEE but also on the development of a country-led, owned, and costed NAPHS and its implementation, including financial commitments along with donor and partners' engagement and coordination. PMID- 29406823 TI - Biomarkers: Their Role in CFTR Modulator Therapies from Early Development to the Clinic. PMID- 29406824 TI - Effects of copper on the composition and diversity of microbial communities in laboratory-scale swine manure composting. AB - This study investigated the effects of adding copper at 3 treatment levels (0 (control: CK), 200 (low: L), and 2000 (high: H) mg.kg-1 treatments) on the bacterial communities during swine manure composting. The abundances of the bacteria were determined by quantitative PCR and their compositions were evaluated by high-throughput sequencing. The results showed that the abundance of bacteria was inhibited by the H treatment during days 7-35, and principal component analysis clearly separated the H treatment from the CK and L treatments. Actinobacteria, Firmicutes, and Proteobacteria were the dominant bacterial taxa, and a high copper concentration decreased the abundances of bacteria that degrade cellulose and lignin (e.g., class Bacilli and genus Truepera), especially in the mesophilic and thermophilic phases. Moreover, network analysis showed that copper might alter the co-occurrence patterns of bacterial communities by changing the properties of the networks and the keystone taxa, and increase the competition by increasing negative associations between bacteria during composting. Temperature, water-soluble carbohydrates, and copper significantly affected the variations in the bacterial community according to redundancy analysis. The copper content mainly contributed to the bacterial community in the thermophilic and cooling phases, where it had positive relationships with potentially pathogenic bacteria (e.g., Corynebacterium_1 and Acinetobacter). PMID- 29406825 TI - The Meaning and Predictive Value of Self-rated Mental Health among Persons with a Mental Health Problem. AB - Self-rated health is a valid measure of health that predicts quality of life, morbidity, and mortality. Its predictive value reflects a conceptualization of health that goes beyond a traditional medical model. However, less is known about self-rated mental health (SRMH). Using data from the Medical Expenditure Panel Survey ( N = 2,547), we examine how rating your mental health as good-despite meeting criteria for a mental health problem-predicts outcomes. We found that 62% of people with a mental health problem rated their mental health positively. Persons who rated their mental health as good (compared to poor) had 30% lower odds of having a mental health problem at follow-up. Even without treatment, persons with a mental health problem did better if they perceived their mental health positively. SRMH might comprise information beyond the experience of symptoms. Understanding the unobserved information individuals incorporate into SRMH will help us improve screening and treatment interventions. PMID- 29406826 TI - Accelerated gastric ulcer healing in thyroxine-treated rats: roles of gastric acid, mucus, and inflammatory response. AB - The roles of gastric acid, mucus, and inflammation on the pro-ulcer-healing effect of thyroid hormone were investigated. Male Wistar rats were randomly divided into four groups: control, thyroidectomised, thyroidectomised with thyroxine treatment (100 MUg.kg-1.day-1), and sham-operated animals treated with thyroxine. Thirty-five days after thyroidectomy, sham surgery, or thyroxine treatment, an ulcer was experimentally induced. Healing was assessed 3, 7, and 10 days post-ulceration by measurement of the ulcer area, gastric mucus and acid secretion, and neutrophil lymphocyte ratio (NLR) as an index of inflammation. By day 10, the ulcer area had decreased in all groups. Recovery was significantly greater (P < 0.05) in thyroxine-treated rats (78.5% +/- 1.6% reduction in ulcer area) than in controls (72.3% +/- 1.2% reduction) or thyroidectomised rats (63.3% +/- 1.9% reduction). Thyroxine-treated animals also had the highest reduction in NLR (65.0% +/- 2.5%). Mucus secretion was significantly lower (P < 0.05) in thyroidectomised rats by days 3 and 7. Furthermore, by day 10, the concentration of basal acid decreased by 77.4% +/- 2.6% in thyroxine-treated, 65.0% +/- 0.0% in control, and 51.5% +/- 3.3% in thyroidectomised rats. We conclude that thyroxine accelerates gastric ulcer healing by altering mucus and acid secretion and reducing NLR. PMID- 29406827 TI - Pyoderma gangrenosum: a review of pathogenesis and treatment. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a complex neutrophilic dermatosis that can occur as an idiopathic disease, in association with systemic conditions such as inflammatory bowel disease, as part of an inherited inflammatory syndrome. It can be challenging to treat, as it occurs in a wide variety of clinical settings and there is a lack of a standardized treatment approach. The main limitations to treatment have been an incomplete understanding of the pathogenesis. However, recent advances have been made in understanding the pathogenesis of this condition, and PG is now considered an autoinflammatory disease process. Areas covered: This review discusses the newest studies that further define our understanding of this disease and the relevant literature on treatment options for pyoderma gangrenosum. Expert commentary: The presence of abnormal neutrophils and T-cells lead to immune dysregulation, leading to lesions of PG. Increased levels of inflammatory mediators including IL-1beta, IL-8, IL-17, and TNF-alpha contribute to the development of the disease but there are still several unknown factors, including the trigger for immune dysregulation and additional contributory components of the immune system. We provide our approach to the management of PG lesions, which involves a multi-faceted approach including wound care, topical therapy, and systemic medications in most cases. PMID- 29406828 TI - Prevalence and correlates of screen time among Brazilian adolescents: findings from a country-wide survey. AB - The purpose of this study was to evaluate the distribution, prevalence, and correlates of excessive screen time (>2 h/day) among Brazilian adolescents. The Study of Cardiovascular Risks in Adolescents (ERICA) is a national, school-based, cross-sectional multicenter study. Information about time spent in front of screens was assessed by questionnaire. Poisson regression models were used to examine the associations between following correlates (region, sex, age, skin color, income, Internet access, and number of TVs at home) and excessive screen time. A total of 66 706 Brazilian adolescents (aged 12-17 years) were included. The overall mean time in front of screens was 3.25 h/day (95% confidence interval (95%CI): 3.20-3.31) and the prevalence of excessive screen time was 57.3% (95%CI: 55.9-58.6). Moreover, excessive screen time also differs across Brazilian regions, being higher in Southeast and South, respectively. In adjusted models stratified by region, the socioeconomic status was associated with excessive screen time in North, Northeast, and Midwest. In all regions, having a computer with Internet access was associated with higher prevalence of excessive screen time. In conclusion, prevalence of excessive screen time in Brazilian adolescents is high. It presents regional variations and facility for Internet access. PMID- 29406829 TI - Human skeletal muscle contains no detectable guanidinoacetic acid. AB - We analyzed data from previously completed trials to determine the effects of supplemental guanidinoacetic acid (GAA) on markers of muscle bioenergetics in healthy men using 1.5 T magnetic resonance spectroscopy. No detectable GAA (<0.1 MUmol/L) was found in the vastus medialis muscle at baseline nor at follow-up. This implies deficient GAA availability in the human skeletal muscle, suggesting absent or negligible potential for creatine synthesis from GAA inside this tissue, even after GAA loading. PMID- 29406830 TI - Triiodothyronine attenuates the progression of renal injury in a rat model of chronic kidney disease. AB - This study was designed to investigate whether and how triiodothyronine (T3) affects renal function in an experimental model of chronic kidney disease. Twenty four female rats were divided into the following groups: sham-operated control group (n = 8), 5/6 nephrectomized group (Nx, n = 8), and 5/6 nephrectomized group treated with T3 for 2 weeks (T3-Nx, n = 8). T3 administration significantly decreased serum levels of urea, creatinine, tumour necrosis factoralpha, and interleukin-6 compared with serum levels in the Nx group. The levels of malondialdehyde, transforming growth factor beta, fibronectin, and collagen IV, as well as the expression of inducible nitric oxide synthase, nuclear factor kappaB, poly(ADP-ribose) polymerase, caspase-3, and Bax were all significantly decreased, though not normalized, in the remnant kidney of rats in the T3-Nx group compared with Nx rats. Glutathione, heme oxygenase-1 levels, as well as endothelial nitric oxide synthase expression were increased in the remnant kidney of the T3-Nx group. Histological studies revealed focal necrosis of renal tubules associated with inflammatory cell infiltration and fibrosis in the Nx group. These changes were alleviated in T3-Nx rats. This study showed that T3 administration attenuated the clinical and histological signs of renal injury in 5/6 nephrectomized rats by mitigating renal oxidative stress, inflammation, apoptosis, and fibrosis. PMID- 29406831 TI - Contribution of spinal 5-HT5A receptors to the antinociceptive effects of systemically administered cannabinoid agonist WIN 55,212-2 and morphine. AB - The antinociceptive effects of cannabinoids and opioids have been known for centuries. Serotonin and its receptors are also known to play important roles in nociception. However, the contribution of spinal 5-HT5A receptors in antinociceptive effects of cannabinoids and opioids has not been studied. We conducted this study to clarify spinal mechanisms of the actions of the antinociceptive effects of cannabinoids and opioids. Hot plate and tail flick tests were used to assess the antinociceptive activity in Balb/c mice. WIN 55,212 2, a nonselective CB1 and CB2 agonist, and morphine exerted significant antinociceptive effects at 1, 3, and 10 mg/kg doses administered intraperitoneally in both hot plate and tail flick tests. The selective 5-HT5A receptor antagonist SB-699551 (10 nmol/mouse) was administered intrathecally 10 min before the agonists. SB-699551 significantly reduced the antinociceptive effect of both WIN 55,212-2 and morphine. In the rotarod test, WIN 55,212-2 disrupted the motor coordination at a dose of 10 mg/kg, while morphine did not affect this function at any dose. Our findings show that spinal 5-HT5A receptors are involved in the antinociceptive effects of WIN 55,212-2 and morphine. PMID- 29406832 TI - Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. Coagonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are under clinical investigation for the treatment of obesity and type 2 diabetes. In this study, we have demonstrated the effect of a balanced coagonist in the treatment of NAFLD using mouse models. GLP-1R agonist exendin-4, glucagon, and coagonist (Aib2 C24 chimera2) were administered to C57BL6/J mice, in which NAFLD was induced by carbon tetrachloride (CCl4) treatment after high-fat diet (HFD) feeding, and choline-deficient, L-amino-acid defined HFD (CDAHFD) feeding. Repeated dose administration of coagonist significantly attenuated liver inflammation and steatosis induced by acute and long-term treatment with CCl4 in HFD-fed mice. Coagonist markedly attenuated the CDAHFD-induced expression of TIMP-1, MMP-9, TNF-alpha, MCP-1, COL1A1, and alpha SMA. It also inhibited progression of hepatic steatosis and fibrosis in mice. Exendin-4 was better than glucagon, but coagonist was most effective in reduction of hepatic inflammation as well as steatosis. Coagonist of GLP-1R and GCGR improved NAFLD in C57BL6/J mice. This effect is mediated by reduction in lipotoxicity and inflammation in liver. PMID- 29406833 TI - CORRIGENDUM. PMID- 29406834 TI - CORRIGENDUM. PMID- 29406835 TI - Pragmatically Applied Cervical and Thoracic Nonthrust Manipulation Versus Thrust Manipulation for Patients With Mechanical Neck Pain: A Multicenter Randomized Clinical Trial. AB - Study Design Randomized clinical trial. Background The comparative effectiveness between nonthrust manipulation (NTM) and thrust manipulation (TM) for mechanical neck pain has been investigated, with inconsistent results. Objective To compare the clinical effectiveness of concordant cervical and thoracic NTM and TM for patients with mechanical neck pain. Methods The Neck Disability Index (NDI) was the primary outcome. Secondary outcomes included the Patient-Specific Functional Scale (PSFS), numeric pain-rating scale (NPRS), deep cervical flexion endurance (DCF), global rating of change (GROC), number of visits, and duration of care. The covariate was clinical equipoise for intervention. Outcomes were collected at baseline, visit 2, and discharge. Patients were randomly assigned to receive either NTM or TM directed at the cervical and thoracic spines. Techniques and dosages were selected pragmatically and applied to the most symptomatic level. Two-way mixed-model analyses of covariance were used to assess clinical outcomes at 3 time points. Analyses of covariance were used to assess between-group differences for the GROC, number of visits, and duration of care at discharge. Results One hundred three patients were included in the analyses (NTM, n = 55 and TM, n = 48). The between-group analyses revealed no differences in outcomes on the NDI (P = .67), PSFS (P = .26), NPRS (P = .25), DCF (P = .98), GROC (P = .77), number of visits (P = .21), and duration of care (P = .61) for patients with mechanical neck pain who received either NTM or TM. Conclusion NTM and TM produce equivalent outcomes for patients with mechanical neck pain. The trial was registered with ClinicalTrials.gov (NCT02619500). Level of Evidence Therapy, level 1b. J Orthop Sports Phys Ther 2018;48(3):137-145. Epub 6 Feb 2018. doi:10.2519/jospt.2018.7738. PMID- 29406836 TI - Differential Diagnosis in a Patient Presenting With Both Systemic and Neuromusculoskeletal Pathology: Resident's Case Problem. AB - Study Design Resident's case problem. Background Patients presenting with multiple symptomatic areas pose a diagnostic challenge for the physical therapist. Though musculoskeletal and nonmusculoskeletal symptoms typically present separately, they can occur simultaneously and mimic each other. Consequently, the ability to differentiate between musculoskeletal and nonmusculoskeletal symptoms is an important skill for physical therapists. The purpose of this resident's case problem was to describe the clinical-reasoning process leading to medical and physical therapy management of a patient presenting with upper and lower back pain, bilateral radiating arm and leg pain, and abdominal pain. Diagnosis The patient was a 30-year-old woman referred to physical therapy for upper and lower back pain. A detailed history and thorough examination revealed that the patient had signs and symptoms consistent with a possible abdominal aortic aneurysm. She was referred for medical management and was diagnosed with symptomatic cholelithiasis. She subsequently had a cholecystectomy, which ultimately resolved her abdominal pain and reduced her pain in other areas significantly. Although many of her symptoms resolved postoperatively, her pain in other areas remained and was potentially musculoskeletal in origin. Following re-evaluation and 3 physical therapy treatments over a 2-month period, she was relatively symptom free at discharge and had achieved all functional rehabilitation goals. Discussion This resident's case problem provides an opportunity to discuss the differential diagnosis, clinical reasoning, and outcome of a patient who presented with both systemic and neuromusculoskeletal pathology. Level of Evidence Differential diagnosis, level 5. J Orthop Sports Phys Ther 2018;48(6):496-503. Epub 6 Feb 2018. doi:10.2519/jospt.2018.7652. PMID- 29406837 TI - Optimization of Medication Use at Accountable Care Organizations. AB - BACKGROUND: Optimized medication use involves the effective use of medications for better outcomes, improved patient experience, and lower costs. Few studies systematically gather data on the actions accountable care organizations (ACOs) have taken to optimize medication use. OBJECTIVES: To (a) assess how ACOs optimize medication use; (b) establish an association between efforts to optimize medication use and achievement on financial and quality metrics; (c) identify organizational factors that correlate with optimized medication use; and (d) identify barriers to optimized medication use. METHODS: This cross-sectional study consisted of a survey and interviews that gathered information on the perceptions of ACO leadership. The survey contained a medication practices inventory (MPI) composed of 38 capabilities across 6 functional domains related to optimizing medication use. ACOs completed self-assessments that included rating each component of the MPI on a scale of 1 to 10. Fisher's exact tests, 2 proportions tests, t-tests, and logistic regression were used to test for associations between ACO scores on the MPI and performance on financial and quality metrics, and on ACO descriptive characteristics. RESULTS: Of the 847 ACOs that were contacted, 49 provided usable survey data. These ACOs rated their own system's ability to manage the quality and costs of optimizing medication use, providing a 64% and 31% affirmative response, respectively. Three ACOs achieved an overall MPI score of 8 or higher, 45 scored between 4 and 7.9, and 1 scored between 0 and 3.9. Using the 3 score groups, the study did not identify a relationship between MPI scores and achievement on financial or quality benchmarks, ACO provider type, member volume, date of ACO creation, or the presence of a pharmacist in a leadership position. Barriers to optimizing medication use relate to reimbursement for pharmacist integration, lack of health information technology interoperability, lack of data, feasibility issues, and physician buy-in. CONCLUSIONS: Compared with 2012 data, data on ACOs that participated in this study show that they continue to build effective strategies to optimize medication use. These ACOs struggle with both notification related to prescription use and measurement of the influence optimized medication use has on costs and quality outcomes. Compared with the earlier study, these data find that more ACOs are involving pharmacists directly in care, expanding the use of generics, electronically transmitting prescriptions, identifying gaps in care and potential adverse events, and educating patients on therapeutic alternatives. ACO level policies that facilitate practices to optimize medication use are needed. Integrating pharmacists into care, giving both pharmacists and physicians access to clinical data, obtaining physician buy-in, and measuring the impact of practices to optimize medication use may improve these practices. DISCLOSURES: This research was sponsored and funded by the National Pharmaceutical Council (NPC), an industry funded health policy research group that is not involved in lobbying or advocacy. Employees of the sponsor contributed to the research questions, determination of the relevance of the research questions, and the research design. Specifically, there was involvement in the survey and interview instruments. They also contributed to some data interpretation and revision of the manuscript. Leavitt Partners was hired by NPC to conduct research for this study and also serves a number of health care clients, including life sciences companies, provider organizations, accountable care organizations, and payers. Westrich and Dubois are employed by the NPC. Wilks, Krisle, Lunner, and Muhlestein are employed by Leavitt Partners and did not receive separate compensation. Study concept and design were contributed by Krisle, Dubois, and Muhlestein, along with Lunner and Westrich. Krisle and Muhlestein collected the data, and data interpretation was performed by Wilks, Krisle, Muhlestein, along with Dubois and Westrich. The manuscript was written primarily by Wilks, along with Krisle and Muhlestein, and revised by Wilks, Westrich, Lunner, and Krisle. Preliminary versions of this work were presented at the following: National Council for Prescription Drug Programs Educational Summit, November 1, 2016; Academy Health 2016 Annual Research Meeting, June 27, 2016; Accountable Care Learning Collaborative Webinar, June 16, 2016; the 21st Annual PBMI Drug Benefit Conference, February 29, 2016; National Value-Based Payment and Pay for Performance Summit, February 17, 2016; National Accountable Care Congress, November 17, 2015; and American Journal of Managed Care's ACO Emerging Healthcare Delivery Coalition, Fall 2015 Live Meeting, October 15, 2015. PMID- 29406838 TI - Real-World Characteristics and Treatment Patterns in Patients with Urticaria Initiating Omalizumab in the United States. AB - BACKGROUND: Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) in patients aged 12 years or older with persistent hives that are not adequately controlled by H1 antihistamines. While its safety and efficacy in CIU patients have been evaluated in multiple clinical trials, real-world use of omalizaumab in CIU has not been well characterized. OBJECTIVE: To assess demographics, clinical characteristics, and treatment patterns of CIU patients who initiated omalizumab to better understand the usage of this agent in CIU management in the real world. METHODS: This retrospective cohort study used medical and pharmacy claims data in the United States from the HealthCore Integrated Database to identify patients with CIU newly treated with omalizumab (>= 4 omalizumab claims within 6 months of the initial claim) between March 21, 2014, and October 31, 2015 (study intake period). The index date was defined as the date of the first claim for omalizumab during the study intake period. Demographic and clinical characteristics were described for patients treated with omalizumab, as were treatment patterns associated with omalizumab and concomitant medications associated with CIU treatment. Descriptive and inferential statistics were reported. The Kaplan-Meier method was used to examine omalizumab treatment patterns. RESULTS: This study included 298 omalizumab-treated patients (mean [SD] age of 43.5 [13.64] years; 70.8% female); approximately 84% were seen by an allergist/immunologist. All patients had >= 12 months of continuous enrolment and a subset of 138 patients had >= 18 months of follow-up. For patients with >= 12 months of post-index follow-up, 12.1% (n = 36), 28.5% (n = 85), and 32.9% (n = 98) discontinued omalizumab within the 6-month, 12-month, and the entire post index periods (mean 530 days), respectively; the mean number of days patients were continuously treated with omalizumab was 443.1 (95% CI = 425.0-461.3); the probabilities of continuous treatment (95% CI) were 0.879 (0.836-0.911), 0.711 (0.656-0.759), and 0.647 (0.585-0.703) for the 6-, 12-, and 18-month post-index periods, respectively. For the 98 patients who discontinued omalizumab during the entire post-index period, 28.6% restarted omalizumab after the first discontinuation within the post-index period (mean time from first discontinuation to first restart=329 days). Use of medications such as oral corticosteroids, montelukast, cyclosporine, and prescription H1 and H2 antihistamines decreased during the 1- to 6-month and 7- to 12-month post-index periods compared with those within the 6-month pre-index period. CONCLUSIONS: In this cohort of CIU patients who were newly prescribed omalizumab, the majority were treated by allergists/immunologists as expected, and approximately 60% of patients continued on therapy beyond 18 months. Concomitant medication use decreased after omalizumab initiation. These data on the real-world use of omalizumab for CIU may help to better inform decision-making processes for health care payers by quantifying omalizumab and concomitant medication treatment patterns over a longer time frame relative to previous studies. DISCLOSURES This study was sponsored by Novartis Pharmaceuticals, which provided funding support for the conduct of the study. Kavati, Ortiz, and Paknis are employees of Novartis Pharmaceuticals. Ke, Wertz, Huang, Wang, Willey, and Stephenson are employees of HealthCore, an independent research organization that received funding from Novartis Pharmaceuticals for the conduct of this study. Beck is an employee of the University of Rochester Medical Center, who was under contract with Novartis Pharmaceuticals to provide consulting services to this study, and reports grants from Genentech, outside the currently submitted work. Bernstein is affiliated with Bernstein Clinical Research Center, which was under contract with Novartis Pharmaceuticals to provide consulting services to this study, and reports receiving grants and personal fees from Novartis Pharmaceuticals, grants and personal fees from Genentech outside of the submitted work, and is an author on the Joint Task Force for Practice Parameters for Urticaria and the GALEN international guidelines for urticaria under preparation. Study concept and design were primarily contributed by Kavati, Ortiz, and Paknis, with assistance from the other authors. Huang, Wang, and Ke took the lead in data collection, with assistance from Wertz, Willey, and Stephenson. Data interpretation was performed by Ke, Wertz, and Willey, assisted by the other authors. The manuscript was written by Stephenson, Ke, and Wang, along with Willey, Wertz, and Huang, and revised by Bernstein and Beck, with assistance from the other authors. Selected study data were presented in a poster at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 22nd Annual International Meeting on May 20-24, 2017, in Boston, Massachusetts. A poster based on this dataset was presented at the 2017 American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting on October 26-30, 2017, in Boston, Massachusetts. PMID- 29406839 TI - Allergic rhinitis management: what's next? AB - INTRODUCTION: Allergic rhinitis (AR) is characterized by the presence of congestion, postnasal drainage, sneezing and rhinorrhea. AR contributes to reduced productivity and significant morbidity worldwide. Areas covered: We review data emphasizing that the most effective therapy to alter the course of AR is allergen-specific immunotherapy, either subcutaneous or sublingual. However, significant advancements in developing alternative forms of therapies have opened the door for potential novel avenues of treating patients with AR. We discuss novel therapies currently under investigation or recently approved, which may provide a more effective and safer treatment option. Expert commentary: Novel therapies for this common disorder which causes significant impaired quality of life are under investigation and will hopefully lead to better therapeutic options. PMID- 29406840 TI - Prostacyclin Use Among Patients with Pulmonary Arterial Hypertension in the United States: A Retrospective Analysis of a Large Health Care Claims Database. AB - BACKGROUND: Prostacyclins play an important role in the management of pulmonary arterial hypertension (PAH). Intravenous prostacyclin was the first disease specific treatment for patients with PAH. Subcutaneous and nonparenteral (oral or inhaled) formulations have subsequently become available. However, data are lacking on how these different prostacyclin formulations are being used in clinical practice. OBJECTIVES: To (a) conduct retrospective analyses of a large U.S. health care claims database to describe the characteristics of patients with PAH initiating prostacyclin therapy, and (b) evaluate their treatment patterns, health care resource use, and associated costs. METHODS: Truven Commercial and Medicare databases were used to define annual cohorts of adults with PAH between January 1, 2010, and October 31, 2015. These patients were identified based on claims with ICD-9-CM diagnoses indicative of PAH (codes 416.0 or 416.8) and claims for PAH-specific medications and PAH-related procedures. Patients with evidence of receiving a prostacyclin were identified, and prostacyclin use was categorized as parenteral versus nonparenteral. Health care costs were assessed alternatively employing an all-cause and PAH-related perspective. RESULTS: Of 13,633 adults with identified PAH, 3,006 (22.0%) received a prostacyclin during at least 1 year of the study period, and annual prevalence of prostacyclin use ranged from 19.9% to 22.6%. Across calendar years, the median age of prostacyclin users ranged from 56 to 58 years, and 71.9%-75.8% were female. Among prostacyclin users, parenteral prostacyclin use declined from 63.2% in 2010 to 46.5% in 2015, while use of nonparenteral prostacyclins increased from 39.7% to 56.2% over the same period (both P < 0.001). Few patients (2.7%-4.1%) received both parenteral and nonparenteral formulations in a given calendar year. Among patients using prostacyclins, receipt of other PAH-specific medications increased from 62.1% in 2010 to 79.2% in 2015. Comparing the 6 months preceding the first prostacyclin prescription (any formulation) to the 6 months subsequent, mean overall health care costs rose from $61,243 to $119,283, and PAH-related health care costs increased from $58,815 to $116,661, driven mainly by PAH-specific medications, spending on which increased from $15,053 to $73,705 (all P < 0.001). CONCLUSIONS: While overall use of prostacyclins was relatively constant from 2010 to 2015, our findings revealed a shift from parenteral to nonparenteral formulations, coupled with increased prescribing of PAH-related medications from other drug classes. Further research is needed to better understand how these changes in patterns of prostacyclin use affect levels of health care resource utilization and costs and patients' overall quality of life. DISCLOSURES: This research was funded by Actelion Pharmaceuticals US, a Janssen pharmaceutical company of Johnson & Johnson. Burger has received grant funding from Actelion, Gilead Sciences, and United Therapeutics; personal fees from Actelion and Gilead Sciences; and nonfinancial support from Actelion. Pruett, Lickert, and Drake are employees of Actelion. Pruett and Lickert own shares in Actelion. Berger and Murphy are employees of Evidera, a consultancy that received payment from Actelion to conduct this research. Pruett, Lickert, Berger, and Drake contributed to study conception and participated with Burger in study design. Lickert and Murphy performed the data analyses. Burger, Pruett, Lickert, Murphy, and Drake interpreted the data. All authors participated in manuscript drafting and/or critical revision, approved the final manuscript, and agree to be accountable for all aspects of the work. PMID- 29406841 TI - Slow Titration and Delayed Intensification of Basal Insulin Among Patients with Type 2 Diabetes. AB - BACKGROUND: Clinical inertia in type 2 diabetes mellitus (T2DM) refers to the failure of clinicians to intensify therapy when indicated. Many T2DM patients remain suboptimally controlled after initiating basal insulin. OBJECTIVE: To examine the prevalence of patients treated with basal insulin but in poor glycemic control (hemoglobin A1c [A1c] >= 7%) after initiation and subsequent treatment intensification patterns and glycemic outcomes in a real-world setting. METHODS: Adults diagnosed with T2DM newly initiating a basal insulin analog (insulin glargine or detemir) from January 2010 to September 2014 were identified in the QuintilesIMS Real-World Data Adjudicated Claims linked to the QuintilesIMS Real-World Data Electronic Medical Records. Patients were previously naive to insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), were persistent on therapy for >= 6 months, and had >= 12 months of continuous health plan enrollment after initiation. First treatment intensification (increase in basal insulin dose [of >= 10%], addition of bolus insulin, GLP-1 RA, or a new oral antidiabetic drug [OAD]) was assessed among patients in poor glycemic control at 6 months after initiation over the available (minimum >= 12-month) follow-up. Subsequent glycemic outcomes and treatment intensification were assessed. Kaplan-Meier (KM) analysis evaluated time-to-treatment intensification and time to A1c goal. RESULTS: Of 427 eligible patients with A1c available at 6 months, 59.3% were male; mean age was 53.9 years; mean follow-up was 29.4 months; and mean dose of the initiated prescription was 29.6 insulin units (U) (median 24U). Six months after initiating basal insulin, 81.0% of patients (n = 346) remained in poor glycemic control, and mean basal insulin dose was 31.0U (median 25U). Most (88.4%; n = 306) of these uncontrolled patients subsequently intensified treatment over the available follow-up. Using KM analysis, these patients intensified treatment in a median of 58 days (range: 17.5 days [GLP-1 RA addition] to 52 days [increase in basal insulin dose]) from the first elevated A1c measurement taken after 6 months, and 72.5% (GLP-1 RA addition) to 91.1% (OAD addition) of patients continued to remain in poor glycemic control at 12 months after intensification. Most patients (66.8%; n = 231/346) first intensified treatment by increasing their basal insulin dose, and mean dose increased to 61.7U (median 38U) at intensification. Six months following basal insulin increase, almost all patients remained on basal insulin therapy and among those with available A1c, 92.1% (140 of 152) were in poor glycemic control. In the subsequent 12 months, only a third (34%) of uncontrolled patients added another antihyperglycemic agent. CONCLUSIONS: The vast majority of patients remained uncontrolled in the 6 months following basal insulin initiation. Basal insulin up titration was slow and insufficient in the 6 months after initiation, indicating treatment inertia. Subsequently, most patients failed to achieve glycemic targets despite intensification with basal insulin. This finding suggests a substantial unmet need for effective treatment intensification among T2DM patients treated with basal insulin who remain uncontrolled. Improved provider education and guidelines on appropriate intensification are warranted. DISCLOSURES: This study was funded by Novo Nordisk. Mocarski, Guerrero, Langer, and Thorsted are employees and shareholders of Novo Nordisk. Yeaw, Divino, and DeKoven are employed by QuintilesIMS, which received remuneration from Novo Nordisk for work on this study. Study concept and design were contributed by Mocarski, DeKoven, Langer, and Thorsted. Yeaw took the lead in data collection, along with Divino and DeKoven. Data interpretation was performed by Yeaw, Divino, DeKoven, and Guerrero. The manuscript was written by Mocarski and Divino and revised by Guerrero, Langer, and Thorsted, along with Yeaw and DeKoven. Some of the data from this study were presented via poster at the AMCP Annual Meeting in March 2017 and at the 53rd EASD Annual Meeting in September 2017. PMID- 29406842 TI - A Unique Publication Model that Works. PMID- 29406843 TI - Factors Affecting Surgical Decision-making-A Qualitative Study. AB - BACKGROUND: Guidelines and Class 1 evidence are strong factors that help guide surgeons' decision-making, but dilemmas exist in selecting the best surgical option, usually without the benefit of guidelines or Class 1 evidence. A few studies have discussed the variability of surgical treatment options that are currently available, but no study has examined surgeons' views on the influential factors that encourage them to choose one surgical treatment over another. This study examines the influential factors and the thought process that encourage surgeons to make these decisions in such circumstances. METHODS: Semi-structured face-to-face interviews were conducted with 32 senior consultant surgeons, surgical fellows, and senior surgical residents at the University of Toronto teaching hospitals. An e-mail was sent out for volunteers, and interviews were audio-recorded, transcribed verbatim, and subjected to thematic analysis using open and axial coding. RESULTS: Broadly speaking there are five groups of factors affecting surgeons' decision-making: medical condition, information, institutional, patient, and surgeon factors. When information factors such as guidelines and Class 1 evidence are lacking, the other four groups of factors medical condition, institutional, patient, and surgeon factors (the last mentioned likely being the most powerful)-play a significant role in guiding surgical decision-making. CONCLUSIONS: This study is the first qualitative study on surgeons' perspectives on the influential factors that help them choose one surgical treatment option over another for their patients. PMID- 29406844 TI - An Insight into the Effect of Exercises on the Prevention of Osteoporosis and Associated Fractures in High-risk Individuals. AB - The purpose of this review was to investigate what type of exercises can potentially prevent osteoporosis (OP) and its associated fractures in high-risk populations. MEDLINE was searched for work relevant to various types of exercises used to prevent osteoporotic fractures in high-risk population, from the year 1995 onwards. Twelve articles were identified, and, from them, four were deemed suitable to the objective. The studies reviewed show that various types of exercise are effective and safe in preventing the onset of OP. For example, high intensity progressive resistance training (HiPRT) has been shown to increase vertebral height and femoral neck bone mineral density (BMD), in addition to improving functional performance. Additional studies reviewed suggested that bone reabsorption levels may be positively impacted by low-impact exercise, such as walking. This review provides insight into the effectiveness of various types of exercise to combat and possibly prevent OP for high-risk individuals, which include postmenstrual Caucasian females, people with multiple comorbidities, individuals who smoke or consume alcohol, and the frail elderly population. The prevention of OP should reduce both the social (emotional) and economic burdens faced by patients, caregivers, and health-care systems. Moving forward, research that identifies and bridges pharmaceutical treatment and exercise should be conducted, in addition to the comparison of passive versus active forms of exercise to determine which treatment best prevents OP in high-risk populations. PMID- 29406845 TI - Learning from Job: A Rare Genetic Disease and Lessons of Biblical Proportions. AB - Dominant negative mutations in STAT3, a critical signaling molecule and transcription factor in multiple organ systems, lead to a rare monogenic disease called the STAT3 loss-of-function, autosomal dominant hyper-IgE syndrome (STAT3LOF AD-HIES). The original name for this syndrome, Job's syndrome, was derived from the observation that patients had a propensity to develop skin boils, reminiscent of the affliction cast upon the biblical Job. Many fascinating observations have been made regarding the pathogenesis of the disease and the role STAT3 plays in human health and disease. Additionally, quite a few phenotypic descriptions from the Book of Job are similar to those seen in patients with STAT3LOF AD-HIES, beyond just the boils. This complex multisystem genetic disorder is a challenge clinically and scientifically, but it also brings into question how we approach genetic syndromes beyond just the technical aspects of research and treatment. PMID- 29406846 TI - Six Values Never to Silence: Jewish Perspectives on Nazi Medical Professionalism. AB - An ideological case study based on medical profession norms during the Third Reich will be used to exemplify the importance of diversity in the manifestations of professional ethics. The German professional medical community banned their Jewish colleagues from treating German citizens. This included legally mandated employment discrimination and outright censure which led to a professional ethic devoid of diverse voices. While the escalation to the T-4 program and medicalized genocide was influenced by many causes, the intentional, ethnocentric-based exclusion of voices was an important contributing element to the chronicled degradation of societal mores. For illustration, six core Jewish values-life, peace, justice, mercy, scholarship, and sincerity of intention-will be detailed for their potential to inspire health-care professionals to defend and protect minorities and for readers to think critically about the role of medical professionalism in Third Reich society. The Jewish teachings highlight the inherent professional obligations physicians have toward their patients in contrast to the Third Reich's corruption of patient-centered professionalism. More fundamentally, juxtaposing Jewish and Nazi teachings exposes the loss of perspective when a profession's identity spurns diversity. To ensure respect for persons in all vulnerable minorities, the first step is addressing professional inclusion of minority voices. PMID- 29406847 TI - Outer Limits of Biotechnologies: A Jewish Perspective. AB - A great deal of biomedical research focuses on new biotechnologies such as gene editing, stem cell biology, and reproductive medicine, which have created a scientific revolution. While the potential medical benefits of this research may be far-reaching, ethical issues related to non-medical applications of these technologies are demanding. We analyze, from a Jewish legal perspective, some of the ethical conundrums that society faces in pushing the outer limits in researching these new biotechnologies. PMID- 29406848 TI - Unilateral Vocal Cord Paralysis of a Great Jewish Opera Singer. AB - George London was one of the most compelling vocal artists of the early twentieth century. At the age of 47, the great bass-baritone retired from singing. It has been suggested that the premature ending of his operatic career was due to unilateral vocal cord palsy (UVCP). When London retired, the common belief was that this UVCP was caused by viral hepatitis, although there is no evidence to support such an etiology. London's medical records eliminate the possible etiology of a neck neoplasm, and the long period of time between a heart attack he experienced and his diagnosis of UVCP makes a cardiovascular etiology an unlikely causative factor. London's relatively young age, the diagnosis of laryngitis prior to his UVCP, and the course of his disease indicate that the underlying cause of the termination of his singing career was post-viral neuropathy. This paper describes the clinical evidence related to London's vocal cord function and explores the possible causes for his UVCP, which apparently led to his early retirement. PMID- 29406849 TI - Abstracts from the Fourteenth Rambam Research Day, December 7, 2017. PMID- 29406852 TI - Evaluating Patients With Low-Flow, Low-Gradient Aortic Stenosis by Dobutamine Echocardiography: It's Complicated. PMID- 29406850 TI - Associations of postpartum sleep, stress, and depressive symptoms with LPS stimulated cytokine production among African American and White women. AB - BACKGROUND: Postpartum is a period of unique psychosocial stress characterized by sleep disturbance, risk for depressed mood, and heightened parenting stress. However, data on effects of these exposures on inflammatory immune function are limited. METHODS: This study examined associations among sleep, psychosocial stress (i.e., parenting stress, general perceived stress), mood (i.e., depressive symptoms), serum cytokine levels, and LPS-stimulated proinflammatory cytokine production among 69 women (32 African American, 37 White) assessed at 7-10weeks postpartum. RESULTS: No associations between behavioral measures and serum cytokine levels were observed among women of either race. In African American women, but not Whites, poorer sleep quality, greater parenting stress, and greater depressive symptoms were associated with greater LPS-stimulated IL-6 and IL-8 production (ps<=0.05). Also in African Americans, greater general perceived stress was associated with greater IL-8 production, and greater depressive symptoms with greater stimulated TNF-alpha production (ps<=0.05). Simple mediation models highlighted the bidirectional relationship between stress and sleep in relation to inflammation among African American women. CONCLUSIONS: Significant effects of both stress/distress and poor sleep quality on proinflammatory cytokine production during postpartum were observed uniquely among African American women. These data are consistent with an allostatic load model which predicts that conditions of chronic stress impart vulnerability to dysregulated responses to novel stressor exposures. The bidirectional nature of the stress-sleep relationship has clinical relevance. Studies examining whether interventions focused on one or both of these psychological factors during postpartum is beneficial for inflammatory profiles would be informative. In addition, examination of these models in relation to maternal health at postpartum, including delivery related wounds and other infections, is warranted. PMID- 29406851 TI - Dobutamine Stress Echocardiography for Management of Low-Flow, Low-Gradient Aortic Stenosis. AB - BACKGROUND: In the American College of Cardiology/American Heart Association guidelines, patients are considered to have true-severe stenosis when the mean gradient (MG) is >=40 mm Hg with an aortic valve area (AVA) <=1 cm2 during dobutamine stress echocardiography (DSE). However, these criteria have not been previously validated. OBJECTIVES: The aim of this study was to assess the value of these criteria to predict the presence of true-severe AS and the occurrence of death in patients with low-flow, low-gradient aortic stenosis (LF-LG AS). METHODS: One hundred eighty-six patients with low left ventricular ejection fraction (LVEF) LF-LG AS were prospectively recruited and underwent DSE, with measurement of the MG, AVA, and the projected AVA (AVAProj), which is an estimate of the AVA at a standardized normal flow rate. Severity of AS was independently corroborated by macroscopic evaluation of the valve at the time of valve replacement in 54 patients, by measurement of the aortic valve calcium by computed tomography in 25 patients, and by both methods in 8 patients. According to these assessments, 50 of 87 (57%) patients in the study cohort had true-severe stenosis. RESULTS: Peak stress MG >=40 mm Hg, peak stress AVA <=1 cm2, and the combination of peak stress MG >=40 mm Hg and peak stress AVA <=1 cm2 correctly classified AS severity in 48%, 60%, and 47% of patients, respectively, whereas AVAProj <=1 cm2 was better than all the previous markers (p < 0.007), with 70% correct classification. Among the subset of 88 patients managed conservatively (47% of the cohort), 52 died during a follow-up of 2.8 +/- 2.5 years. After adjustment for age, sex, functional capacity, chronic kidney failure, and peak stress LVEF, peak stress MG and AVA were not predictors of mortality in this subset. In contrast, AVAProj <=1 cm2 was a strong predictor of mortality under medical management (hazard ratio: 3.65; p = 0.0003). CONCLUSIONS: In patients with low LVEF LF-LG AS, the DSE criteria of a peak stress MG >=40 mm Hg, or the composite of a peak stress MG >=40 mm Hg and a peak stress AVA <=1 cm2 proposed in the guidelines to identify true-severe AS and recommend valve replacement, have limited value to predict actual stenosis severity and outcomes. In contrast, AVAProj better distinguishes true-severe AS from pseudo-severe AS and is strongly associated with mortality in patients under conservative management. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis [TOPAS]; NCT01835028). PMID- 29406853 TI - Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. AB - BACKGROUND: Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events. OBJECTIVES: The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial. METHODS: Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months. RESULTS: A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HRadj]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HRadj: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds. CONCLUSIONS: Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562). PMID- 29406854 TI - Impact of Ticagrelor in Patients With Prior MI and MVD for Reducing Cardiovascular Events. PMID- 29406855 TI - Effect of Plaque Burden and Morphology on Myocardial Blood Flow and Fractional Flow Reserve. AB - BACKGROUND: Atherosclerotic plaque characteristics may affect downstream myocardial perfusion, as well as coronary lesion severity. OBJECTIVES: This study sought to evaluate the association between quantitative plaque burden and plaque morphology obtained using coronary computed tomography angiography (CTA) and quantitative myocardial perfusion obtained using [15O]H2O positron emission tomography (PET), as well as fractional flow reserve (FFR) derived invasively. METHODS: Two hundred eight patients (63% men; age 58 +/- 8.7 years) with suspected coronary artery disease were prospectively included. All patients underwent 256-slice coronary CTA, [15O]H2O PET, and invasive FFR measurements. Coronary CTA-derived plaque burden and morphology were assessed using commercially available software and compared with PET perfusion and FFR. RESULTS: Atherosclerotic plaques were present in 179 patients (86%) and 415 of 610 (68%) evaluable coronary arteries. On a per-vessel basis, traditional coronary plaque burden indexes, such as plaque length and volume, minimal lumen area, and stenosis percentage, were significantly associated with impaired hyperemic myocardial blood flow (MBF) and FFR. In addition, morphological features, such as partially calcified plaques, positive remodeling (PR), and low attenuation plaque, displayed a negative impact on hyperemic MBF and FFR. Multivariable analysis revealed that the morphological feature of PR was independently related to impaired hyperemic MBF as well as an unfavorable FFR (p = 0.004 and p = 0.007, respectively), next to stenosis percentage (p = 0.001 and p < 0.001, respectively) and noncalcified plaque volume (p < 0.001 and p = 0.010, respectively). CONCLUSIONS: PR and noncalcified plaque volume are associated with detrimental downstream hyperemic myocardial perfusion and FFR, independent of lesion severity. PMID- 29406856 TI - Coronary Plaque Volume and Stenosis: Important Determinants of Myocardial Ischemia. PMID- 29406858 TI - Molecular Characterization of High-Risk Aortic Aneurysms: Imaging Beyond Anatomy. PMID- 29406857 TI - 18F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study. AB - BACKGROUND: Fluorine-18-sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque. OBJECTIVES: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. METHODS: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture. RESULTS: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 +/- 7 years, 85% men, baseline aneurysm diameter 48.8 +/- 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 +/- 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5* more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3* as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043). CONCLUSIONS: Fluorine-18 NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758). PMID- 29406860 TI - STOP the TRAFfic and Reduce the Plaque. PMID- 29406861 TI - Use of Cardiac Magnetic Resonance Imaging in Assessing Mitral Regurgitation: Current Evidence. AB - Accurate quantification of regurgitant volume is a central component to the management of mitral regurgitation. Cardiac magnetic resonance imaging (CMR) accurately quantifies mitral regurgitation as the difference between left ventricular stroke volume and forward stroke volume using steady state free precession and phase contrast imaging. The CMR measurement of mitral regurgitant volume is reproducible and can quantify mitral regurgitation in patients without regard to regurgitant jet morphology, such as patients with multiple and eccentric jets. It can be used to quantify regurgitant volume in patients with multiple valve lesions and concomitant intracardiac shunts without the use of intravenous contrast. Studies have highlighted the accuracy and reproducibility of CMR in quantifying mitral regurgitation and have begun to link CMR to clinical outcomes. PMID- 29406859 TI - Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. AB - BACKGROUND: Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40 TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. OBJECTIVES: This study evaluates the potential of TRAF-STOP treatment in atherosclerosis. METHODS: The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe-/-) mice. Recombinant high density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages. RESULTS: TRAF-STOP treatment of young Apoe-/- mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe-/- mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and beta2 integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-kappaB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe-/- mice. CONCLUSIONS: TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis. PMID- 29406863 TI - Cardiovascular Health System Leadership: An Evolving Model. PMID- 29406862 TI - Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases. AB - The World Health Organization (WHO) Model List of Essential Medicines (EML) is a key tool for improving global access to medicines for all conditions, including cardiovascular diseases (CVDs). The WHO EML is used by member states to determine their national essential medicine lists and policies and to guide procurement of medicines in the public sector. Here, we describe our efforts to modernize the EML for global CVD prevention and control. We review the recent history of applications to add, delete, and change indications for CVD medicines, with the aim of aligning the list with contemporary clinical practice guidelines. We have identified 4 issues that affect decisions for the EML and may strengthen future applications: 1) cost and cost-effectiveness; 2) presence in clinical practice guidelines; 3) feedback loops; and 4) community engagement. We share our lessons to stimulate others in the global CVD community to embark on similar efforts. PMID- 29406864 TI - Heart Block After Discharge in Patients Undergoing TAVR With Latest-Generation Valves. PMID- 29406865 TI - Magnetic Resonance Imaging-Based Screening Study in a General Population of Adolescents. PMID- 29406866 TI - Vascular Endothelial Growth Factor D, Pulmonary Congestion, and Incidence of Heart Failure. PMID- 29406867 TI - Alcohol: Cardiovascular Disease and Cancer. PMID- 29406868 TI - Reply: Alcohol: Cardiovascular Disease and Cancer. PMID- 29406869 TI - Left Ventricular Twist: An Often Ignored But Crucial Determinant of Left Ventricular Function. PMID- 29406870 TI - Reply: Left Ventricular Twist: An Often Ignored But Crucial Determinant of Left Ventricular Function. PMID- 29406871 TI - Graphing Ratio Measures on Forest Plot. PMID- 29406873 TI - Correction. PMID- 29406872 TI - Reply: Graphing Ratio Measures on Forest Plot. PMID- 29406874 TI - Correction. PMID- 29406875 TI - Correction. PMID- 29406876 TI - Correction. PMID- 29406878 TI - Audio Summary. PMID- 29406885 TI - Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome. AB - BACKGROUND: Cerebellar and cognitive dysfunction can occur early in clinically isolated syndrome (CIS). Eye tracking is a reliable tool for the evaluation of both subtle cerebellar symptoms and cognitive impairment. OBJECTIVES: To investigate the early cognitive profile using neuropsychological and ocular motor (OM) testing in CIS with and without cerebellar dysfunction with OM testing compared to healthy subjects (HS). METHODS: Twenty-eight patients and 12 HC underwent OM and neuropsychological testing. Cerebellar impairment was defined by the registration of saccadic intrusions and/or at least 10% of dysmetria during ocular motor recording. Visually guided saccade (VGS), memory-guided saccade (MGS) and antisaccade (AS) paradigms were compared to neuropsychological assessments. RESULTS: The group of patients with cerebellar dysfunction (n=16) performed worse on MGS latencies and error rates, and had worse working memory, executive function and information processing speed (IPS) z scores than patients without cerebellar dysfunction. IPS was correlated with the AS error rate in all patients and with the VGS error rate and the MGS final eye position ratio in cerebellar patients. CONCLUSION: Eye tracking is a sensitive tool to assess cognitive and cerebellar dysfunctions in CIS. In CIS patients, cerebellar impairment is associated with working memory, executive functions and IPS slowness. PMID- 29406886 TI - Effects of intestinal Levodopa infusion on freezing of gait in Parkinson disease. AB - OBJECTIVE: To determine the impact of levodopa-carbidopa intestinal gel (LCIG) infusion on different subtypes of freezing of gait (FoG) classified according to levodopa responsiveness in advanced Parkinson disease (PD) patients. METHODS: We retrospectively assessed the presence and severity of FoG in 32 advanced PD patients based on the Unified PD Rating Scale (UPDRS) item 14 score. Different FoG subtypes were inferred from the score variation with oral dopaminergic medications. Modifications following long-term LCIG infusion were analysed. Motor symptoms and motor complications were assessed by UPDRS part III and IV respectively. RESULTS: FoG related UPDRS score varied from 2.6+/-0.9 in OFF condition to 0.9+/-0.8 in the ON condition at baseline and improved to 0.6+/-0.7 with LCIG infusion (p=0.027). After a mean of 2.59+/-1.12years of continuous LCIG infusion, Pseudo-ON-FoG improved to a greater extent with LCIG infusion than with oral therapy in 12 patients (38%) and equally well in 8 patients (25%), OFF-type FoG was controlled equally well in 8 patients (25%) and worsened slightly in 3 patients (9%). Unresponsive-FoG, present in one patient (3%), was unmodified by LCIG infusion. CONCLUSIONS: Even though limited by the subjective simple measure of FoG, this study suggests that patients undergoing LCIG infusion maintain a good long-term control of FoG. Pseudo-on-FoG improves in a considerable percentage of patients and OFF-type-FoG remains well controlled with LCIG infusion. Further studies with a larger number of patients and objective measures of FoG are needed to confirm these findings. PMID- 29406887 TI - Serum levels of S100B from jugular bulb as a biomarker of poor prognosis in patients with severe acute brain injury. AB - AIMS/BACKGROUND: To evaluate the correlation between protein S100B concentrations measured in the jugular bulb as well as at peripheral level and the prognostic usefulness of this marker. METHODS: A prospective study of all patients admitted to the intensive care unit with acute brain damage was carried out. Peripheral and jugular bulb blood samples were collected upon admission and every 24h for three days. The endpoints were brain death diagnosis and the Glasgow Outcome Scale score after 6months. RESULTS: A total of 83 patients were included. Jugular protein S100B levels were greater than systemic levels upon admission and also after 24 and 72h (mean difference>0). Jugular protein S100B levels showed acceptable precision in predicting brain death both upon admission [AUC 0.67 (95% CI 0.53-0.80)] and after 48h [AUC 0.73 (95% CI 0.57-0.89)]. Similar results were obtained regarding the capacity of jugular protein S100B levels upon admission to predict an unfavourable outcome (AUC 0.69 (95% CI 0.56-0.79)). The gradient upon admission (jugular-peripheral levels) showed its capacity to predict the development of brain death [AUC 0.74 (95% CI 0.62-0.86)] and together with the Glasgow Coma Scale constituted the independent factors associated with the development of brain death. CONCLUSION: Regional protein S100B determinations are higher than systemic determinations, thus confirming the cerebral origin of protein S100B. The transcranial protein S100B gradient is correlated to the development of brain death. PMID- 29406888 TI - Tamoxifen treatment and occurrence of dural arteriovenous fistulas: An observational study on a series of patients presenting tamoxifen history and diagnosis of DAVf. PMID- 29406889 TI - Endothelial Progenitor Cells influence acute and subacute stroke hemodynamics. AB - BACKGROUND: Endothelial Progenitor Cells (EPCs) are a circulating stem cell population with in vivo capacity of promoting angiogenesis after ischemic events. Despite the promising preclinical data, their potential integration with reperfusion therapies and hemodynamic evolution of stroke patients is still unknown. Our aim was to determine the association of EPCs with acute, subacute and chronic hemodynamic features. METHODS: In this prospective study, we included consecutive patients with ages between 18 and 80years and non-lacunar ischemic stroke within the territory of a middle cerebral artery. All patients were subject to hemodynamic evaluation by ultrasound at baseline, seven days and three months. We quantified cerebral blood flow (CBF) and assessed early recanalization and collateral flow. Hemorrhagic transformation was graded in Magnetic Resonance imaging performed at seven days. EPCs were isolated from peripheral venous blood collected in the first 24h and seven days, counted and submitted to functional in vitro tests. RESULTS: We included 45 patients with a median age of 70+/-10years. The angiogenic and migratory capacities of EPCs were associated with increased collateral flow in the acute stage and day seven CBF, without statistically significant associations with recanalization nor haemorrhagic transformation. The number of EPCs was not associated with any hemodynamic variable. CONCLUSIONS: The functional properties of EPCs are associated with acute and subacute stroke hemodynamics, with no effect on haemorrhagic transformation. PMID- 29406890 TI - Shaky and unsteady: Dynamic posturography in essential tremor. AB - BACKGROUND: The spectrum of symptoms exhibited by patients with essential tremor (ET) extends far beyond the classical tremor. This study aims to explore and establish the presence of subtle balance abnormalities in ET using dynamic posturography (DP). METHODS: DP was performed on 18 patients with ET and 26 controls. Diagnosis of ET was based on the Consensus Statement of the Movement Disorder Society on Tremor. Dynamic stability which included the overall balance index, anterior-posterior index and mediolateral index, and limits of stability were measured. RESULTS: Patients with ET had significantly impaired balance indices. Impairment of dynamic stability revealed poor static balance control in all directions. Lower limits of stability scores indicated a smaller range of motion prior to which patients have to shift foot balance. No correlations were observed between age at evaluation, age at onset, duration of illness and the balance indices. CONCLUSIONS: Dynamic posturography reveals significant balance impairment in patients with ET which is unrelated to the age at onset, age at evaluation or duration of illness. This finding concurs with pre-existing reports and adds to the growing body evidence of cerebellar involvement in ET. PMID- 29406891 TI - Demyelination with preferential MAG loss: A complex message from MS paraffin blocks. AB - Multiple sclerosis (MS) is generally considered to be a demyelinating autoimmune disorder. However, neuropathological examinations of MS lesions do not support this concept. Demyelination with preferential loss of myelin-associated glycoprotein (MAG) is a common finding in MS tissues and has been reported by several groups. As MAG is located in ad-axonal myelin layers and is not accessible to infiltrating immune cells, demyelination with preferred loss of MAG may be suggestive of a primary oligodendrocytopathy in MS. Moreover, it has been shown that oligodendrocytopathy may precede the infiltration of inflammatory cells at the lesion site. In this paper, we review studies of neuropathology of MS tissues that reported this type of demyelination and then we discuss three emerging explanations that are trying to interpret this mismatched observation. PMID- 29406892 TI - Could istradefylline be a treatment option for postural abnormalities in mid stage Parkinson's disease? AB - BASEGROUND: Postural abnormalities are refractory complications observed in mid- to late-stage Parkinson's disease (PD). METHODS: We analyzed the effects of istradefylline, a selective adenosine A2A receptor antagonist, on posture in 21 levodopa-treated PD patients from the subanalysis of a three-month open-label study. RESULTS: The subitem score of posture (3.13) on the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III significantly improved following istradefylline treatment (baseline, 1.3+/ 1.0 points vs 3months, 0.9+/-0.9 points; p<0.05). Among 18 patients who had postural abnormalities at baseline, defined as 1 point or greater on MDS-UPDRS part III subitem 3.13, posture improved in 9 (50%) and was unchanged in 9 (50%) patients after istradefylline treatment. Improved and unchanged groups did not show differences in baseline characteristics, except for tendency for a higher rate of Hoehn and Yahr stage IV and V (Off state) observed in the improved group. Changes in scores of posture (3.13) did not correlate with those of other MDS UPDRS part III items, PD Questionnaire-8, PD Sleep Scale-2 and Epworth Sleepiness Scale. CONCLUSION: Based on our preliminary findings, istradefylline could be an effective treatment option for postural abnormalities in mid-stage PD patients. PMID- 29406893 TI - Dopamine transporter imaging predicts motor responsiveness to levodopa challenge in patients with Parkinson's disease: A pilot study of DATSCAN for subthalamic deep brain stimulation. AB - Imaging studies are necessary prior to subthalamic deep brain stimulation (STN DBS). Dopamine transporter (DAT) imaging is a powerful tool for visualizing dopamine terminals in the striatum, but its usefulness in STN-DBS is unclear. Here, we retrospectively investigated the relationship between motor symptoms and the specific binding ratio (SBR) on DAT imaging in patients with Parkinson's disease (PD). We included 23 consecutive patients (9 female; 14 male) who were evaluated for DBS eligibility between October 2013 and October 2014 and subsequently received bilateral STN-DBS. Correlation and simple regression analyses were performed on SBR values and clinical parameters before and after surgery. SBR value was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the "ON" state before surgery (rs=-0.637, p=0.001) and positively correlated with the reduction of the levodopa equivalent daily dose by surgery (r=0.422, p=0.045). A simple regression analysis revealed that SBR value was positively correlated with UPDRS motor score improvement after levodopa challenge before surgery (p=0.001, R2=0.423). DAT imaging may be useful in STN-DBS candidate selection and the identification of the therapeutic mechanism of STN-DBS in patients with advanced PD and motor symptom fluctuations. PMID- 29406894 TI - Neurologic illness in Zambia: A neurointensivist's experience. AB - INTRODUCTION: Management of critically ill patients in dedicated intensive care units (ICUs) is the standard of care in high income countries (HICs), but remains uncommon in low and middle-income countries (LMICs). We sought to determine the prevalence of neurologic disorders in the ICU of a LMIC and examine if resource appropriate specialized neurocritical care training could benefit these patients. METHODS: From February to March 2017, a trained neurocritical care intensivist recorded encounters in the sole ICU at the University Teaching Hospital (UTH) in Lusaka, Zambia. We stratified each patient by demographics, presence of primary or secondary neurologic deficit, comorbidities, and outcome. RESULTS: Of the 33 patients seen during this period, 26 (78.8%) had a neurologic deficit. An equal number of patients carried a primary neurologic diagnosis (13) versus a secondary neurologic diagnosis (13). Primary neurologic disorders included spinal cord injury/tumor/abscess, intracranial hemorrhage, Guillain-Barre syndrome, and traumatic brain injury. CONCLUSIONS: Over three-quarters of critically ill patients in the observation period carried a neurologic diagnosis. Future research should aim to identify if resource appropriate neurocritical care training of frontline providers may lead to improved clinical outcomes. PMID- 29406895 TI - Spastic paraparesis and sensorineural hearing loss: keep brucellosis in mind. PMID- 29406896 TI - Fatal reversible cerebral vasoconstriction syndrome. AB - We report four fatal cases of fulminant reversible cerebral vasoconstriction syndrome, all initially diagnosed as primary central nervous system vasculitis and treated with corticosteroids. Although reversible cerebral vasoconstriction syndrome is usually self-limiting without permanent neurologic deficits, rarely it can be fatal and worse outcomes have been associated with corticosteroid treatment. PMID- 29406897 TI - Survival analysis of a cohort of Chinese patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) based on clinical features. AB - BACKGROUND: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a common mitochondrial syndrome. The aim of this study was to conduct a survival analysis based on the clinical features of a Chinese MELAS patient cohort. METHODS: This is a retrospective single-center study. The MELAS patients were followed up for 1-8years (median 4years). The disease severity was evaluated by the modified Rankin Scale (mRS). The survival analysis was performed using Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: A total of 138 subjects were enrolled, and the median disease duration was 7years [interquartile range (IQR) 4-11years]. The stroke-like episodes were the most common initial symptoms (70.3%). Seventeen (17.3%) subjects lost to follow-up. Of the 121 subjects who successfully completed the follow-up, 28 subjects died (mortality rate 23.1%). An acute stroke-like episode and/or status epilepticus were the predominant causes of death (42.9%). Among the surviving patients (n=93), 39.8% (37/93) required assistance in daily life (mRS scores 3-5). The mRS scores were inversely correlated with the age of onset (r=-0.28, P=0.0022) but not with the disease duration (r=0.10, P=0.2709). The survival rate declined mainly within 12years after the disease onset. The stroke-like episode as the initial symptom was an independent risk factor for death (hazard ratio=2.86, 95% CI 1.03-7.94, P=0.043). CONCLUSIONS: MELAS had high mortality and morbidity in this cohort of Chinese patients. The early onset of stroke-like episodes might indicate the more severe form of the disease, highlighting the importance of management of stroke-like episodes to improve the prognosis. PMID- 29406898 TI - Identification of delirium and dementia in older medical inpatients in Tanzania: A comparison of screening and diagnostic methods. AB - BACKGROUND: In sub-Saharan Africa, there are no validated screening tools for delirium in older adults. This study assesses clinical utility of two instruments, the IDEA cognitive screen and the Confusion Assessment Method (CAM) for identification of delirium in older adults admitted to medical wards of a tertiary referral hospital in Tanzania. METHOD: The IDEA cognitive screen and CAM were administered to a consecutive cohort of older individuals on admission to Kilimanjaro Christian Medical Centre using a blinded protocol. Consensus diagnosis for delirium was established against DSM-5 criteria and dementia by DSM IV criteria. RESULTS: Of 507 admission assessments, 95 (18.7%) had DSM-5 delirium and 95 (18.7%) had DSM-IV dementia (33 (6.5%) delirium superimposed on dementia). The CAM and IDEA cognitive screen had very good diagnostic accuracy for delirium (AUROC curve 0.94 and 0.87 respectively). However, a number of participants (10.5% and 16.4% respectively) were unable to complete these screening assessments due to reduced consciousness, or other causes of reduced verbal response and were excluded from this analysis; many of whom met DSM-5 criteria for delirium. Secondary analysis suggests that selected cognitive and observational items from the CAM and IDEA cognitive screen may be as effective as the full screening tools in identifying delirium even in unresponsive patients. CONCLUSION: Both instruments appeared useful for delirium screening in this inpatient setting, but had significant limitations. The combination of assessment items identified may form the basis of a brief, simple delirium screening tool suitable for use by non-specialist clinicians. Further development work is needed. PMID- 29406899 TI - High intensity signal in the plaque on routine 3D-TOF MRA is associated with ischemic stroke in the patients with low-grade carotid stenosis. AB - BACKGROUND AND PURPOSE: Carotid artery stenosis is one of the major causes of ischemic strokes. However, degree of stenosis is not always correlated with frequency of ischemic strokes. The aim of this study was to evaluate relationships between high intensity signal (HIS) in the carotid plaques on maximum intensity projection (MIP) images detected by routine three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) and ischemic strokes in the patients with low-grade stenosis. METHODS: One hundred fifty two patients with low-grade carotid artery stenosis (30%-49%) were included. The presence of HIS located in the plaque but having no connection to the lumen in all projections on MIP images of 3D-TOF MRA was defined as HIS-positive using the previously reported criteria. We analyzed the relationship between the presence of HIS and prior ischemic strokes. RESULTS: Prior ipsilateral ischemic strokes were observed more frequently in HIS-positive group (12 of 56, 21.4%) than HIS negative group (1 of 96: 1%) (p<0.001). In multivariate logistic regression analysis, the presence of HIS (odds ratio: 31.8, 95% confidential interval (CI): 3.81-264, p=0.001) and hyperlipidemia (odds ratio: 10.45, 95% CI: 1.01-13.4, p=0.048) were independent determinants of prior ischemic strokes after adjustment for age. CONCLUSIONS: HIS in plaques on MIP images of 3D-TOF MRA was an independent determinant of prior ischemic strokes. PMID- 29406900 TI - Symptomatic orthostatic hypotension in Parkinson's disease patients: Prevalence, associated factors and its impact on balance confidence. AB - BACKGROUND: Orthostatic hypotension (OH) is a commonly reported sign of the cardiovascular autonomic dysfunctions associated with Parkinson's disease (PD). Patients might suffer from a variety of the clinical symptoms of OH, including dizziness, lightheadedness, or problems with vision and fatigue. OBJECTIVES: To determine the prevalence of, and factors associated with, symptomatic orthostatic hypotension (OH) in Parkinson's disease (PD) and to identify any relationships between the clinical symptoms of OH and balance confidence in this patient population. METHODS: Symptomatic OH was defined as a systolic or diastolic BP fall of >=20 or >=10mmHg respectively, within 3min of standing and an Orthostatic Hypotension Questionnaire (OHQ) score of more than zero. Factors related to symptomatic OH were identified from a multivariate logistic regression analysis. Pearson's correlation test was used to reveal any relationships between the clinical symptoms of OH and a patient's confidence in their ability to balance, assessed using the Activities-specific Balance Confidence (ABC) scale. RESULTS: 100 Thai PD patients were consecutively recruited into this study. The prevalence of symptomatic OH was 18%, asymptomatic OH was 4%, while 78% were patients without OH. Factors associated with symptomatic OH were age (OR, 95%CI: 1.06, 1.003-1.115, p=0.038) and hypertension (OR, 95%CI: 6.16, 1.171-32.440, p=0.032). A significant and negative correlation (r=-0.229, p=0.022) between OHQ composite scores and item 3 of the ABC scale (picking up slippers from floor), one of the movements in a vertical orientation, was found. CONCLUSION: Elderly PD patients and with a co-morbidity of essential hypertension should be closely evaluated for the presence of symptomatic OH. In addition, they should be advised to change positions slowly, especially those in a vertical orientation. PMID- 29406901 TI - Scan without evidence of dopaminergic deficit (SWEDD) in degenerative parkinsonism and dementia with Lewy bodies: A prospective study. AB - BACKGROUND: 123I-FP-CIT SPECT imaging is a reliable method to assess presynaptic dopaminergic pathways in degenerative parkinsonisms and dementia with Lewy bodies (DLB). METHODS: We aimed at examining sensitivity of combined visual and semi quantitative 123I-FP-CIT SPECT analyses in a prospective cohort of subjects with DLB and degenerative parkinsonisms - Parkinson's disease (PD), multiple system atrophy (MSA), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) to determine prevalence and clinical significance of scans without evidence of dopaminergic deficit (SWEDD). 372 scans performed from 2013 to 2016 with the same SPECT acquisition and processing protocol were analyzed. We identified 155 patients with degenerative parkinsonism and 53 with DLB. Diagnoses relied on validated clinical criteria for each condition. Semi-quantitative assessment was based on previously established local reference limits (including striatal volumes of interest uptake, caudate-to-putamen ratio and striatal asymmetry index). RESULTS: 3/155 (2.1%) subjects with degenerative parkinsonism (1 CBS, 1 MSA-C and 1 PD) and 1/53 (1.9%) with DLB had a normal visual SPECT. Subsequent semi-quantitative analysis showed mild striatal uptake impairment for the DLB and the PD subject. Therefore, only two patients (1 CBS and 1 MSA) had a strictly normal combined assessment. CONCLUSIONS: The present study shows that SWEDD cases represent a negligible proportion of patients with degenerative conditions (1.3%), when stringent diagnostic criteria are applied, a thorough follow-up is performed and visual SPECT analysis is combined with precise semi-quantitative assessment. PMID- 29406902 TI - Autoimmune and paraneoplastic movement disorders: An update. AB - Movement disorders (MDs) are common in patients with autoimmune disorders affecting the central and peripheral nervous system. They may be observed in autoimmune disorders triggered by an infectious agent, such as streptococcus in Sydenham's chorea, or in basal ganglia encephalitis with antibodies against the dopamine-D2 receptors. In these patients chorea or dystonia are usually the most prominent hyperkinetic MDs. MDs are also observed in patients with diffuse or limbic encephalitis with antibodies directed against neuronal cell-surface antigens. Anti-NMDA receptor encephalitis is one of the most common and may present with a variety of MDs, including: chorea, stereotypies, dystonia and myorhythmia. The recognition of other abnormal motor phenomena such as "faciobrachial dystonic seizures" and neuromyotonia, observed in patients with LGI1 and Caspr-2 antibodies, is important because they may herald the onset of overt limbic encephalitis. Autoimmunity directed against the intracellular enzyme glutamic acid decarboxylase usually presents with MDs, most commonly stiff-person syndrome or cerebellar ataxia. Chorea may be observed in rheumatologic disorders such as systemic lupus erythematosus or antiphospholipid syndrome. Disorders with uncertain autoimmune mechanisms such as Hashimoto's encephalitis and idiopathic opsoclonus-myoclonus syndrome commonly present with tremor, myoclonus and ataxia. A rapid diagnosis of an autoimmune disorder, which typically presents with subacute onset, is critical as early therapeutic intervention improves long-term prognosis and may be life-saving. Treatment usually involves some form of immunotherapy and symptomatic therapy of the abnormal movements with dopamine depleters, dopamine receptor antagonists, or GABAergic drugs. Detection and removal of an underlying tumor is essential for optimal outcome. PMID- 29406903 TI - The effect and evolution of patient selection on outcomes in endoscopic third ventriculostomy for hydrocephalus: A large-scale review of the literature. AB - Endoscopic third ventriculostomy (ETV) has become a popular technique for the treatment of hydrocephalus, but small sample size has limited the generalizability of prior studies. We performed a large-scale review of all available studies to help eliminate bias and determine how outcomes have changed and been influenced by patient selection over time. A systematic literature search was performed for studies of ETV that contained original, extractable patient data, and a meta-analytic model was generated for correlative and predictive analysis. A total of 130 studies were identified, which included 11,952 cases. Brain tumor or cyst was the most common hydrocephalus etiology, but high-risk etiologies, post-infectious or post-hemorrhagic hydrocephalus, accounted for 18.4%. Post-operative mortality was very low (0.2%) and morbidity was only slightly higher in developing than in industrialized countries. The rate of ETV failure was 34.7% and was higher in the first months and plateaued around 20months. As anticipated, ETV is less successful in high-risk etiologies of hydrocephalus and younger patients. Younger patient age and high-risk etiologies predicted failure. ETVs were performed more often in high-risk etiologies over time, but, surprisingly, there was no overall change in ETV success rate over time. This study should help to influence optimal patient selection and offer guidance in predicting outcomes. PMID- 29406904 TI - Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and lower dosages of rituximab among patients with neuromyelitis optica spectrum disorder. AB - OBJECTIVE: To observe and compare the efficacy and tolerability of azathioprine (AZA), mycophenolate mofetil (MMF) and lower dosages of rituximab (RTX) among patients with neuromyelitis optica spectrum disorder. METHODS: In this prospective cohort, AQP4-IgG-seropositive patients with neuromyelitis optica spectrum disorder (NMOSD) were enrolled and randomly divided into three groups, using AZA, MMF or lower dosages of RTX (defined as 100mg RTX intravenous injection, once per week for 4 consecutive weeks) respectively. Annualized relapse rate (ARR), EDSS scores, CD19+ B-cell counts in peripheral blood, serum AQP-4-IgG titre and drug adverse reactions were compared between three groups. RESULTS: In the AZA group (n=22), MMF group (n=30) and RTX group (n=20), 54.5%, 60.0% and 65.0% of patients reached a relapse-free state and EDSS score improved in 90.9%, 83.3% and 90.0% of patients respectively. In addition, there was significant reduction in ARR in all the three groups. Reduced dosage of RTX exerted a significant effect in reducing CD19+ B-cell counts (P<0.01). Compared with the AZA group, the MMF group and the RTX group decreased the AQP-4-IgG titre evidently and caused fewer adverse events. Neither the Kaplan-Meier survival curves nor the Cox proportional hazard model indicated a significant difference in relapse among the three groups (P>0.05). CONCLUSIONS: AZA, MMF and reduced dosages of rituximab are all effective in reducing ARR and improving the clinical symptom of patients with NMOSD. Lower dosages of RTX are more effective than the others in decreasing the CD19 B-cell counts. MMF and reduced RTX decrease AQP-4 IgG titre more and cause fewer adverse events than AZA. However, more multicentre studies are still needed to find more effective therapeutic regimen. PMID- 29406905 TI - Autoimmunity in multiple sclerosis: role of sphingolipids, invariant NKT cells and other immune elements in control of inflammation and neurodegeneration. AB - Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is classified as being an autoimmune response in the genetically susceptible individual to a persistent but unidentified antigen(s). Both the adaptive and the innate immune systems are likely to contribute significantly to MS pathogenesis. This review summarizes current understanding of the characteristics of MS autoimmunity in the initiation and progression of the disease. In particular we find it timely to classify the autoimmune responses by focusing on the immunogenic features of myelin-derived lipids in MS including molecular mimicry; on alterations of bioactive sphingolipids mediators in MS; and on functional roles for regulatory effector cells, including innate lymphocyte populations, like the invariant NKT (iNKT) cells which bridge adaptive and innate immune systems. Recent progress in identifying the nature of sphingolipids recognition for iNKT cells in immunity and the functional consequences of the lipid-CD1d interaction opens new avenues of access to the pathogenesis of demyelination in MS as well as design of lipid antigen-specific therapeutics. PMID- 29406906 TI - Reversible sub-acute cognitive deterioration in cerebral amyloid angiopathy: A case report. PMID- 29406908 TI - Extrastriatal degeneration correlates with deficits in the motor domain subscales of the UHDRS. AB - INTRODUCTION: Striatal degeneration has significant behavioral effects in patients with Huntington's disease (HD). However, there is scant evidence of the possible contribution of extrastriatal regions to the motor alterations assessed within the different domains of the Unified Huntington's Disease Rating Scale (UHDRS). OBJECTIVE: Analyze if extrastriatal grey matter decrease in patients with HD correlates with motor performance assessed with the UHDRS and its different domains. METHOD: Twenty-two molecular diagnosed patients with incipient HD, and twenty-two control participants matched for sex and age participated in this study. Voxel-based morphometry (VBM) analyses were done to identify grey matter decrease in the HD patients, and its relationship with the motor deterioration measured with the UHDRS motor scale. To further explore this relationship, a principal component analysis (PCA) was done on the UHDRS domains scores. Then the average of each component was used as a covariate in a VBM analysis. Finally, individual sub-scores from each domain were also tested for correlations with the VBM results. RESULTS: In addition to the striatal degeneration, the VBM analysis showed significant negative correlations between the global UHDRS scores and the cerebellum, insula and precuneus atrophy. The UHDRS PCA showed component-related negative correlations suggesting a specific impact of individual degnerations. Further analyses with the individual sub scores showed more specific corelations, including: chorea, with right caudate and left posterior cingulate gyrus; ocular pursuit, with left precentral gyrus, left superior temporal gyrus, cerebellum culmen and right temporal lobe. Saccadic movements with left postcentral gyrus and left middle occipital gyrus. CONCLUSION: In the early stages of HD, it is possible to find correlations between behavioral alterations as measured with the UHDRS motor domains, and extrastriatal regions, including specific areas of the cerebellum, and insular, parietal and frontal cortices. These areas could contribute to the HD related impairments along with the classical deficits associated with the striatal degeneration. PMID- 29406907 TI - Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients. AB - : One of the biggest challenges in multiple sclerosis (MS) is the definition of treatment response/failure in order to optimize treatment decisions in affected patients. The objective of this consensus was to review how disease activity should be assessed and to propose recommendations on the identification of treatment failure in RRMS patients in Argentina. METHODS: A panel of experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2016 and 2017 to carry out a consensus recommendation on the identification of treatment failure in RRMS patients. To achieve consensus, the methodology of "formal consensus-RAND/UCLA method" was used. RESULTS: Recommendations were established based on published evidence and the expert opinion. Recommendations focused on disease management, disease activity markers and treatment failure identification were determined. Main consensus were: >=2 relapses during the first year of treatment and/or >=3 new or enlarged T2 or T1 GAD+ lesions and/or sustained increase of >=2 points in EDSS or >=100% in T25FW defines treatment failure in RRMS patients. CONCLUSIONS: The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Argentina. PMID- 29406909 TI - Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study. AB - INTRODUCTION: Chronic activation of microglia accelerates the neurodegenerative process in multiple sclerosis (MS). Although disease modifying therapy (DMT) is reportedly effective for neuroinflammatory responses in MS, the progression of neuroinflammation after DMT remains unclear. METHODS: We evaluated microglial activation in six clinically stable relapsing-remitting MS patients after DMT by quantifying changes in translocator protein (TSPO) density using PET with [11C]DPA713, a selective TSPO tracer for microglial activation. All patients underwent [11C]DPA713 PET scans twice, and the scans were conducted one year apart. The binding potential (BPND) of the tracer was estimated using a simplified reference tissue model. RESULTS: [11C]DPA713 BPND measured at 6months after DMT was significantly higher in the MS group than that in the control group. Compared with the first PET measurement, the one-year PET measurement revealed significantly elevated [11C]DPA713 BPND in broader brain regions covering the temporal and parietal cortices after one year of DMT. CONCLUSIONS: The current results indicate that microglial activation may proceed in the entire brain of clinically stable MS patients even after receiving DMT. PMID- 29406910 TI - Immunohistochemistry and electrophysiological findings in swine abattoir workers with immune-mediated polyradiculoneuropathy. AB - IMPORTANCE: Workers exposed to aerosolized brain in a swine-processing plant developed immune-mediated polyradiculoneuropathy (IP) possibly triggered by an immune response. OBJECTIVE: Immunohistochemistry results were correlated with electrophysiological variables to examine the immunopathogenesis of this disorder. DESIGN/SETTING: Laboratory studies used normal nerve tissue that was exposed to sera from 12 IP patients; 10 exposed controls; and 10 unexposed controls. Clinical and electrophysiological data from IP patients were obtained from medical record reviews. MAIN OUTCOME MEASURES: Analysis included electromyography results of IP patients and nerve conduction studies examining CMAP amplitude, distal motor latency, motor conduction velocity, F-wave latency, sensory nerve action potential amplitude, and sensory nerve conduction velocity. Case and control results were compared relative to distance from exposure. RESULTS: Electrodiagnostic findings revealed prolongation of the distal and f wave latencies suggestive of demyelination at the level of the nerve root and distal nerve terminals. Immunohistochemical results identified an antibody to the peripheral nerve, with staining at the level of the axolemma. Thus, IP may be a primary axonopathy with secondary paranodal demyelination causing the conduction changes. Staining of the distal and proximal portions of the nerve appears consistent with easier access through the blood-nerve barrier. CONCLUSIONS AND RELEVANCE: IP is an immune-mediated neuropathy related to antibodies to an axon based antigen on peripheral nerves. Secondary paranodal demyelination is likely. Further studies to identify the primary axonal antigenic target would be useful. PMID- 29406911 TI - Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis. AB - Bladder dysfunction is common in persons with MS (PwMS), often due to detrusor muscle overactivity. Anticholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched-cohort study was to determine if anticholinergic medications affect objective measures of cognition in PwMS. We recruited PwMS starting either oxybutynin or tolterodine (cases). Cases and controls were tested with the Brief International Cognitive Assessment for MS (BiCAMS) battery prior to starting anticholinergic medications and 12weeks later. The primary outcome was change on the Symbol Digit Modalities Test (SDMT) between groups; secondary outcomes were changes on the other BiCAMS measures. Analysis of Covariance with baseline measures as covariates to assess the significance of between group differences was performed at 12weeks. Forty eight PwMS starting anticholinergic medications and 21 matched PwMS controls were recruited. There was a significant difference (p<0.001) in the change on the cognitive measures over 12weeks between groups. The controls demonstrated improvement, consistent with practice effect, while the cases remained unchanged. This study demonstrates that anticholinergic medications may have a negative effect on cognition in PwMS; further confirmatory studies are needed. PMID- 29406912 TI - TNF-alpha -308 G/A and -238 G/A promoter polymorphisms and sporadic Parkinson's disease in an Italian cohort. AB - The etiology of sporadic Parkinson's disease is (PD) still not understood but it is believed that a complex interplay between environmental and genetic factors could trigger the pathology. Pro-inflammatory TNF-alpha is released by activated microglia and is up-regulated in the brain and cerebrospinal fluid of PD patients; TNF-alpha modulates neuroinflammation and can activate the molecular mechanisms that lead to neurotoxicity and neuronal death. We analyzed two functional SNPs within the TNF-alpha gene promoter (rs361525 and rs1800629) in 354 Italian PD patients and 443 healthy controls (HC). In our cohort of patients, no significant associations could be observed between rs361525 and rs1800629 SNPs and either PD onset risk or PD-associated clinical parameters including age at onset of fluctuations, UPDRS-ME (Unified Parkinson Disease Rating Scale-Motor Examination), Schwab & England, Hohen & Yahr stage scale, and MMSE (Mini-Mental State Examination) score. Conflicting results on the role played by TNF-alpha rs1800629 SNP on PD onset risk are present in the literature. We could not find any association between TNF-alpha rs361525 and rs1800629 and PD. PMID- 29406913 TI - Targeting the enhanced ER stress response in Marinesco-Sjogren syndrome. AB - BACKGROUND AND OBJECTIVE: Marinesco-Sjogren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells. METHODS: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined. RESULTS: MSS LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1alpha (IRE1alpha)-X-box binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis. CONCLUSION: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies. PMID- 29406914 TI - Cerebral vasoreactivity and intima-media thickness in Down syndrome: A case control study. AB - Subjects with Down Syndrome (DS) have high prevalence of cerebral vascular amyloidosis, cognitive decline and dementia. In Alzheimer Disease, impaired vasoreactivity has been reported as the results of vascular amyloid deposition. Aim of our study was to verify presence of impaired cerebral vasoreactivity and to study carotid intima media-thickness (IMT) by carotid and transcranial ultrasound. We studied 25 DS and compared them with 25 age- and sex-matched normal controls. Vasomotor reactivity was evaluated by means of breath-holding index (BHI) test. There was no difference in IMT, both considering the two side separately (left: 0.70+/-0.10 vs 0.69+/-0.12mm, p=0.6) (right: 0.67+/-0.13 vs 0.68+/-0.10mm, p=0.5), and considering the sum of both sides (1.38+/-0.22 vs 1.38+/-0.23mm, p=1). There was a significant difference in peak systolic velocities (PSV) (139.75+/-27.67 vs. 123.89+/-25.73cm/s, p=0.04) and in pulsatility index (PI) (0.95+/-0.14 vs. 0.86+/-0.12, p=0.02). BHI was significantly lower in DS than in controls (1.15+/-0.38 vs 1.88+/-0.72, p<0.001). In conclusion, subjects with DS have increased PSV and PI, and show a reduction of BHI, expression of impaired vasomotor reserve, possibly due to micro-vascular impairment. Larger study with longitudinal design is needed to verify our data. PMID- 29406915 TI - Validation of the Modified Fatigue Impact Scale and the relationships among fatigue, pain and serum interleukin-6 levels in patients with neuromyelitis optica spectrum disorder. AB - Fatigue and pain are disabling symptoms in patients with neuromyelitis optica spectrum disorder (NMOSD). The Modified Fatigue Impact Scale (MFIS) has not yet been validated in patients with NMOSD, and anti-interleukin-6 (IL-6) receptor antibody was reported to decrease pain and fatigue in patients with NMOSD. The aim of this study was to validate MFIS and to investigate the relationships among fatigue, pain and serum IL-6 levels in patients with NMOSD. MFIS and the Multidimensional Fatigue Inventory (MFI), an established scale for fatigue, were administered to patients with NMOSD and age- and sex-matched healthy controls (HCs). The Pain Effects Scale score and serum IL-6 levels were also measured in patients with NMOSD. Correlations among clinical characteristics, laboratory data and each score were investigated. To validate MFIS in patients with NMOSD, MFIS was administered twice within 4days from the first administration. Fifty-one patients answered the first MFIS, and 26 patients answered the second MFIS. There was no difference between the first and second MFIS scores. Patients with NMOSD had higher MFIS and MFI scores than HCs. No correlations were observed between serum IL-6 levels and either score. MFIS was validated in patients with NMOSD. Serum IL-6 levels may not be involved in the pathogenesis of fatigue and pain in patients with NMOSD. PMID- 29406916 TI - Quantitative transcranial sonography in Wilson's disease and healthy controls: Cut-off values and functional correlates. AB - To compare transcranial sonography (TCS) findings in patients with predominantly neurological Wilson's disease (WD) to those from controls, and to correlate TCS data with the clinical profile of WD. Patients with WD (n=40/f=18) and healthy, matched controls (n=49/f=20) were assessed in terms of TCS, serum copper and iron parameters, and clinical scales, such as the Unified Wilson's Disease Rating Scale (UWDRS), Addenbrooke's Cognitive Examination-Revised (ACE-R), Mini Mental State Examination (MMSE), and Beck Depression Inventory. Lenticular nuclei and substantia nigra echogenic area cut-off values clearly differentiated WD patients from controls (area under the curve: 95.4% and 79.4%). Substantia nigra echogenic area was significantly larger in male than in female patients (p=0.001). Compared with controls, patients showed hyperechogenicity also in thalami and midbrain tegmentum/tectum; third ventricle width was increased and midbrain axial area was reduced. In the WD group, male gender correlated with substantia nigra echogenic area (r=0.515, p=0.0007) and serum ferritin levels (r=0.479, p=0.002); lenticular nuclei hyperechogenicity correlated with dystonia (r=0.326, p=0.04) and dysarthria (r=0.334, p=0.035); third ventricle width correlated with dystonia (r=0.439 p=0.005), dysarthria (r=0.449, p=0.004), parkinsonism (r=0.527, p<0.001), UWDRS neurological and total scores (both r=0.504, p=0.0009), MMSE (r= 0.496, p=0.001), and ACE-R (r=-0.534, p=0.0004). Lenticular nuclei echogenic area allowed highly accurate discrimination between patients and controls. The gender differences in substantia nigra echogenicity and iron metabolism are of interest in further studies in WD. TCS reflects different dimensions of WD pathology clearly differentiable from healthy controls and correlating with various clinical characteristics of WD. PMID- 29406917 TI - Lack of an association between attention-deficit/hyperactivity disorder (ADHD) and amyotrophic lateral sclerosis (ALS). AB - BACKGROUND: Lule, Ludolph, and Ludolph (2008) hypothesized that there may be a pathophysiological link between attention-deficit/hyperactivity disorder (ADHD) and amyotrophic lateral sclerosis (ALS). They summarized common clinical features, specifically enhanced physical and psychological activity, which have been described typically for ADHD patients and also as common personality traits before disease onset in patients with ALS. METHODS: We assessed the lifetime prevalence rate of ADHD in 104 patients with ALS using valid self-report instruments for ADHD symptoms in childhood (WURS-k) and adulthood (ADHD-SB). Results were compared with a population-based sample (n=2069) and with patients with Parkinson's disease (PD, n=52) using regression analyses and adjusting for sociodemographic differences. Physical activity was assessed by the 21-item exercise dependency scale (EDS-21). RESULTS: ALS patients reported a lower prevalence of childhood ADHD compared to the general population. Both clinical groups reported significantly lower scores on the WURS-k scale and the attention deficit subscale of the ADHD-SB. The EDS-21 showed significantly longer exercise times in ALS and PD patients. CONCLUSIONS: We could not show that ADHD is more common in ALS patients. However, our results revealed shared personality traits in ALS and PD with lower rates of premorbid attention deficit symptoms and increased physical activity. PMID- 29406918 TI - IgG4-related disease and intracranial hypertenstion: Case report of a novel mechanistic association. PMID- 29406919 TI - Correlation between serum uric acid and diabetic peripheral neuropathy in T2DM patients. AB - AIM: To investigate the correlation between serum uric acid (SUA) and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. METHODS: Two hundred T2DM patients were divided into four groups at the cut-off points of 5, 7, and 9mg/dL of SUA levels. Nerve conduction studies (NCS), Semmes-Weinstein monofilament testing (SWMT), and vibration perception threshold (VPT) tests were performed on these patients. RESULTS: Significant differences in motor/sensory nerve amplitude and conduction velocity (CV) parameters among different SUA level groups were observed (all P<0.05). SUA levels were negatively correlated with the means of motor/sensory nerve amplitude and CV (all P<0.05). Duration of T2DM >10years, SUA >9mg/dL and total cholesterol (TC) >5.2mmol/L were found to be significantly associated with DPN (all P<0.05). Receiver-operating characteristic (ROC) analysis revealed that the cut-off points of T2DM duration combined with SUA and TC were 9years, 7.8mg/dL, and 4.97mmol/L, respectively (AUC=0.65; 95% CI: 0.53-0.77; sensitivity, 70.6%; specificity, 65.2%, P=0.009). CONCLUSION: There is a significant association between elevated SUA levels and DPN, and T2DM duration, SUA, and TC may be valuable indicators to predict the occurrence of DPN in T2DM patients. PMID- 29406920 TI - Alcohol use and hospital readmissions following stroke: A safety net hospital experience. AB - OBJECTIVE: The purpose of this study is to identify predictors of stroke-related readmissions at 30days on a safety net hospital level and suggest interventions to reduce the number of readmissions. BACKGROUND: Hospital readmissions are an important measure of the quality of health care services. Readmissions indicate unresolved problems from the index admission, inadequate post-hospitalization care, or a mixture of these factors. Additionally, hospital readmissions are associated with a substantial economic burden on the health care system. The study's purpose is to identify predictors of stroke-related readmissions within 30days on a hospital level and suggest interventions to reduce the number of readmissions. METHODS: We conducted a single-center retrospective study of patients admitted to Boston Medical Center (BMC) and diagnosed with ischemic and hemorrhagic stroke. Unadjusted and adjusted logistic regressions were used to evaluate possible predictors of stroke related readmissions. RESULTS: Of 352 patients admitted with a diagnosis of ischemic or hemorrhagic stroke at BMC during the study period, 44 (12.5%) patients were readmitted to BMC within 30days. Current alcohol abuse was significantly associated with readmission (OR 95% CI 1.03-5.62). Discharge against medical advice was also associated, though the sample size was small. CONCLUSIONS: These results suggest that early inpatient and post-hospitalization interventions to address alcohol abuse during the index hospital admission may reduce the rate of hospital readmission within 30days. The results have prompted interventions on the stroke service such as early inpatient social work and addiction medicine involvement for patients with risk factors of alcohol abuse. PMID- 29406921 TI - Paraspinal muscle involvement in herpes zoster-induced abdominal wall pseudohernia revealed by electrophysiological and radiological studies. AB - Segmental zoster paresis is an uncommon complication of herpes zoster, and abdominal wall pseudohernia is rare. Previous reports have emphasized the involvement of anterior rami of spinal nerves, while the involvement of posterior rami has been less frequently reported. We aimed to elucidate the involvement of posterior rami of spinal nerves in abdominal wall pseudohernia. Four patients with a diagnosis of abdominal wall pseudohernia underwent needle electromyography (nEMG) and magnetic resonance imaging (MRI). In three patients, nEMG of affected paraspinal muscles showed denervation potentials, and MRI showed hyperintensity of these muscles on short T1 inversion recovery imaging. These results suggested involvement of paraspinal muscles, and indicated that posterior rami of spinal nerves are also often affected in abdominal wall pseudohernia. MRI as well as nEMG could be useful for evaluating paraspinal muscle involvement and for the diagnosis. PMID- 29406923 TI - CLIPPERS with longitudinally extensive transverse myelitis: Role of T versus B cells. PMID- 29406922 TI - A nomogram to predict the probability of mortality after first-ever acute manifestations of cerebral small vessel disease. AB - BACKGROUND AND PURPOSE: Symptomatic lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent the acute manifestations of type 1 cerebral small vessel disease (cSVD). Recently, two studies showed that the risk factor profile of dICH differs from that associated with LS in subjects with biologically plausible cSVD; however, the prognostic predictors after acute manifestations are currently lacking. We aimed to develop a nomogram for individualized prediction of the mortality probability in a cohort of patients with a first-ever acute manifestation of biologically plausible cSVD. METHODS: We conducted a retrospective analysis of data collected from consecutive patients with acute symptomatic non-embolic LS or primary dICH. The outcome measure was 3-month mortality. Based on multivariate logistic model, the nomogram was generated. RESULTS: Of the 288 patients who entered into the study for biologically plausible cSVD, 131 (45%) experienced a LS and 157 (55%) a dICH. After multivariate logistic regression, 5 variables remained predictors of mortality to compose the nomogram: dICH (OR:11.36; p=0.001), severe presentation (OR:8.08; p<0.001), age (OR:1.08; p=0.001), glucose (OR:1.23; p=0.003) and creatinine (OR:1.01; p=0.024) at admission were predictors of mortality. The discriminative performance of nomogram assessed by using the area under the receiver operating characteristic curve (AUC-ROC) was 0.898. The model was internally validated by using bootstrap (1000 samples) with AUC-ROC of 0.895 and cross-validation (deleted-d method repeated 1000 times) with AUC-ROC of 0.895. CONCLUSIONS: We developed the first nomogram for prediction of the mortality probability in a cohort of patients with a first-ever acute manifestation of biologically plausible cSVD. PMID- 29406924 TI - White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease. AB - BACKGROUND: In dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. METHODS: We retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. RESULTS: WMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. CONCLUSION: Our results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes. PMID- 29406925 TI - Wide-area transepithelial sampling with 3-dimensional cytology: Does it detect more dysplasia or yield more hype? PMID- 29406926 TI - Esophageal leiomyomas: Making mole hills out of mole hills? PMID- 29406927 TI - Endoscopic screening for hereditary diffuse gastric cancer: one size does not fit all. PMID- 29406928 TI - Keep calm under pressure: a paradigm shift in managing postsurgical leaks. PMID- 29406929 TI - Using statistical measurements rather than case numbers to determine learning curves: a practice that has application for all endoscopic procedures. PMID- 29406930 TI - Be "routinely selective" when performing second-look endoscopy in peptic ulcer bleeding! PMID- 29406931 TI - Biodegradable pancreatic stent: A 1-step "magical" procedure to resolve pancreatic duct strictures? PMID- 29406932 TI - Seven-day postcolonoscopy emergency department visits: What do they really measure? PMID- 29406933 TI - Endoscopic submucosal dissection for resection of submucosal tumors of the colon and rectum: Within reach, or the edge of tomorrow? PMID- 29406934 TI - A plea for quality management and organ-preserving endoscopic resection. PMID- 29406935 TI - The little engine that could. PMID- 29406936 TI - Full-thickness resection: Are we realizing the "full" story? PMID- 29406937 TI - State of the Heart: An Overview of the Disease Burden of Cardiovascular Disease from an Epidemiologic Perspective. AB - Cardiovascular diseases are prevalent worldwide and have significant impact on morbidity, mortality, and overall health care costs. Common risk factors include obesity, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and smoking. Both modifiable and nonmodifiable risks should be accounted for when evaluating and managing patients with cardiovascular diseases. The complex nature of cardiovascular disease is not fully understood. Therefore, primary care physicians must balance what is known, what is suspected, and each patient's individual preferences to create an optimal treatment plan. PMID- 29406939 TI - Cardiovascular Disease in Women. AB - Cardiovascular disease in women as a distinct disease entity is underappreciated relative to other female-specific diseases. A perception that cardiovascular disease affects men more commonly and a lack of understanding about the underlying pathophysiology of cardiovascular disease in women contribute to this phenomenon. Hormonal changes, pregnancy-related conditions, and cancer therapies have an impact on endothelial function, vascular anatomy, and myocardial contractility. Women with heart disease often present later, receive care not consistent with accepted guidelines, and have less access to diagnostic and therapeutic resources. Understanding the differences and challenges of treating cardiovascular disease in women is essential to improving population health. PMID- 29406938 TI - Metabolic Syndrome: Systems Thinking in Heart Disease. AB - Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors. MetS is associated with approximately 4-fold increase in the likelihood of developing type 2 diabetes mellitus (T2DM) and a 2-fold increase in the incidence of cardiovascular disease complications. MetS is a progressive, proinflammatory, prothrombotic condition that manifests itself along a broad spectrum of disease. It is associated with hypertension, obstructive sleep apnea, fatty liver disease, gout, and polycystic ovarian syndrome. Intervening in and reversing the pathologic process become more difficult as the disease progresses, highlighting the needs for increased individual and community surveillance and primary prevention. PMID- 29406940 TI - Heart Disease in Children. AB - The pediatric cardiology field has developed rapidly over the past few decades. More children than ever born with congenital heart disease (CHD) are growing into adulthood. Primary care providers play a key role in diagnosis, management, and referral of children with CHD because many common cardiac complaints (eg, feeding intolerance, cyanosis, chest pain, palpitations, and syncope) are first addressed in the primary care setting. The spectrum of heart disease in children ranges from common complaints to complex single-ventricle physiology, acute myocarditis, and heart transplantation. This article reviews the pathophysiology and management of the most frequent cardiac conditions encountered in primary care. PMID- 29406941 TI - Cardiac Imaging Modalities and Appropriate Use. AB - Cardiovascular imaging with calcium scoring computed tomography (CT), coronary CT angiography (CCTA), and cardiac MRI (CMR) have advanced rapidly over recent years. These imaging modalities have increased in availability, accessibility, and clinical practicality due to technological advances allowing for significant radiation dose reduction for high-quality CCTA and for rapid and reliable imaging techniques in CMR. Hardware and software developments are continually increasing efficiency and accuracy of postprocessing. In the context of these rapidly developing imaging modalities, it is critical for ordering physicians and providers to be aware of the fundamentals of each modality, imaging challenges and appropriate use criteria. PMID- 29406942 TI - Heavy Heart: The Economic Burden of Heart Disease in the United States Now and in the Future. AB - The United States spends more on health care than any other industrialized nation. In 2016, health care expenditure reached an estimated $3.35 trillion or $10,345 per individual. Cardiovascular disease represents the leading cause of death and disability as well as the most significant source of health care spending. This article reviews the current economic burden of heart disease in the United States, presents future projections, and explores factors driving cost growth in cardiovascular care. PMID- 29406943 TI - Prevention of Cardiovascular Disease. AB - Cardiovascular disease remains the leading cause of death in the United States and worldwide. Prevention of cardiovascular disease is an achievable goal. A rigorous 2010 analysis by the World Health Organization suggests that reducing risk factors in young adults and maintaining an optimum risk profile through age 50 could prevent 90% of atherosclerotic cardiovascular disease events. Misinformation and poor implementation of proven preventive strategies, misplaced fears of medications, or incorrect understanding of ideal dietary and lifestyle choices all contribute to poor risk profiles. Every patient deserves an individualized prescription for cardiovascular disease prevention incorporating strategies to control modifiable cardiovascular risk factors. PMID- 29406944 TI - Coronary Artery Disease: Diagnosis and Management. AB - This review focuses on the outpatient assessment and management of coronary artery disease based on current guidelines and recommendations. The management of acute coronary syndrome and unstable angina is not included. Pharmacologic and nonpharmacotherapy options, including lifestyle modifications, are discussed with evidence to support recommendations and suggested management. PMID- 29406945 TI - Heart Failure: Optimizing Recognition and Management in Outpatient Settings. AB - Heart failure represents a growing chronic medical condition with major implications on patient morbidity, mortality, and cost to health care systems. In this article, the heart failure syndrome is reviewed from a perspective of diagnosis and management, with updated therapeutic options reflected in major guidelines published since this topic was last reviewed in Primary Care Clinics in Office Practice in 2013. An emphasis is placed on the use of the American Heart Association/American College of Cardiology's staging system as a framework to improve early identification and treatment of patients at risk of symptomatic heart failure. PMID- 29406946 TI - Valvular Heart Disease. AB - This article outlines the diagnosis and management of commonly occurring valvular heart diseases for the primary care provider. Basic understanding of pathologic murmurs is important for appropriate referral. Echocardiography is the gold standard for diagnosis and severity grading. Patients with progressive valvular heart disease should be followed annually by cardiology and imaging should be performed based on the severity of valvular dysfunction. Surgery or intervention is recommended only when symptoms dictate or when changes in left ventricular function occur. Surgery or intervention should be performed after discussion by a heart team, including cardiologists and cardiac surgeons. PMID- 29406947 TI - Preparticipation Screening of Young Athletes: Identifying Cardiovascular Disease. AB - The most common cause of sudden cardiac death (SCD) in young athletes in the United States is "autopsy-negative sudden unexplained death." This makes it extremely difficult to screen for and diagnose predisposing cardiovascular conditions before athletic participation. The goal of the preparticipation physical examination is to detect risk factors for SCD, make risk-based decisions regarding the need for further workup, and ultimately recommend for or against participation. Current evidence recommends universal screening of young athletes using the 14-point American Heart Association preparticipation cardiovascular checklist. Electrocardiograms and echocardiograms are not currently recommended in the United States to screen athletes. PMID- 29406953 TI - The Price of the Heart. PMID- 29406954 TI - Be Still My Beating Heart: Cardiovascular Disease in the United States. PMID- 29406955 TI - Diagnosis, treatment of bacteremia associated with the use of, vascular catheters: That provides a new clinical practice guide. PMID- 29406956 TI - Diagnosis and treatment of catheter-related bloodstream infection: Clinical guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology and (SEIMC) and the Spanish Society of Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC). AB - Catheter-related bloodstream infections (CRBSI) constitute an important cause of hospital-acquired infection associated with morbidity, mortality, and cost. The aim of these guidelines is to provide updated recommendations for the diagnosis and management of CRBSI in adults. Prevention of CRBSI is excluded. Experts in the field were designated by the two participating Societies (the Spanish Society of Infectious Diseases and Clinical Microbiology and [SEIMC] and the Spanish Society of Spanish Society of Intensive and Critical Care Medicine and Coronary Units [SEMICYUC]). Short-term peripheral venous catheters, non-tunneled and long term central venous catheters, tunneled catheters and hemodialysis catheters are covered by these guidelines. The panel identified 39 key topics that were formulated in accordance with the PICO format. The strength of the recommendations and quality of the evidence were graded in accordance with ESCMID guidelines. Recommendations are made for the diagnosis of CRBSI with and without catheter removal and of tunnel infection. The document establishes the clinical situations in which a conservative diagnosis of CRBSI (diagnosis without catheter removal) is feasible. Recommendations are also made regarding empirical therapy, pathogen-specific treatment (coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus spp., Gram-negative bacilli, and Candida spp.), antibiotic lock therapy, diagnosis and management of suppurative thrombophlebitis and local complications. PMID- 29406957 TI - Erratum to "Can a 15s FLAIR replace conventional FLAIR sequence in stroke MR protocols?" [J Neuroradiol 44 (2017) 192-197]. PMID- 29406958 TI - Discordant manifestations in Italian brothers with GNE myopathy. PMID- 29406959 TI - The association of adult vaccination with the risk of cerebrovascular ischemia: A systematic review and meta-analysis. AB - There is mounting evidence supporting infection as an independent risk factor for ischemic stroke (IS), while preliminary data indicate that vaccination may prevent IS. We performed a systematic review and meta-analysis of available randomized clinical trials (RCTs) or prospective observational cohorts reporting associations of influenza vaccination (IV) and/or pneumococcal vaccination (PV) with IS. We identified a total of 12 studies (543,311 patients; 47.4% vaccinated). Vaccination was not related to the risk of IS (RR=1.06, 95%CI: 0.74 1.51, p=0.77), with no significant differences (p=0.26) among RCTs (RR=0.66, 95%CI: 0.30-1.47) and observational studies (RR=1.11, 95%CI: 0.76-1.61). Evidence of considerable heterogeneity was identified within observational studies (I2=98%), but not within RCTs (I2=0%). In subgroup analyses according to vaccination type, IV was associated with a significantly lower risk of IS (RR=0.87, 95%CI: 0.79-0.96, p=0.004) with moderate evidence of heterogeneity (I2=53%). No association was seen for PV (RR=1.38, 95%CI: 0.60-3.16, p=0.45), where considerable heterogeneity was identified (I2=97%). In the additional adjusted analyses of observational studies, vaccination tended to be associated with lower risk of IS (HRadjusted=0.87; 95%CI: 0.75-1.01; p=0.07). The findings of this meta-analysis indicate that IV may be associated with a lower risk of IS. This association was not reproduced for PV or the combination of two vaccines. Substantial heterogeneity was detected across observational studies for all outcome events, while moderate to low heterogeneity was identified across included RCTs. These preliminary findings require independent validation in large RCTs. PMID- 29406960 TI - Cognition in multiple sclerosis: Between cognitive reserve and brain volume. AB - BACKGROUND: Several correlations between cognitive impairment (CI), radiologic markers and cognitive reserve (CR) have been documented in MS. OBIECTIVE: To evaluate correlation between CI and brain volume (BV) considering CR as possibile mitigating factor. METHODS: 195 relapsing MS patients underwent a neuropsychological assessment using BICAMS. BV was estimated using SIENAX to obtain normalized volume of brain (NBV), white matter (NWV), gray matter (NGV) and cortical gray matter (CGV). CR was estimated using a previously validated tool. RESULTS: Pearson test showed a correlation between the symbol digit modality test (SDMT) score and NBV (r=0.38; p<0.000) NGV(r=0.31; p<0.000), CGV (r=0.35; p<0.000) and CRI score(r=0.42; p<0.000). Linear regression (dependent variable:SDMT) showed a relationship with CR scores (p=0.000) and NGV(p<0.000). A difference was detected between cognitive impaired and preserved patients regarding mean of NBV(p=0.002), NGV(p=0.007), CGV(p=0.002) and CR Scores (p=0.007). Anova showed a association between the presence of CI (dependent variable) and the interaction term CRIQ * CGV (p=0.004) whit adjustment for age and disability evaluated by EDSS. CONCLUSIONS: Our study shows a correlation between cognition and BV, in particular gray matter volume. Cognitive reserve is also confirmed as an important element playing a role in the complex interaction to determine the cognitive functions in MS. PMID- 29406961 TI - Feasibility study of a targeted self-management intervention for reducing stroke risk factors in a high-risk population in Uganda. AB - INTRODUCTION: Stroke remains a global concern due to increasing lifespan, patterns of industrialization, adoption of harmful western diets, and an increasing prevalence of risk factors such as hypertension, obesity, and diabetes. We investigated an adopted novel self-management intervention, TargetEd mAnageMent Intervention (TEAM) to reduce modifiable stroke risk factors in Uganda. METHODS: A six-month, uncontrolled, prospective pilot study to establish feasibility, acceptability and preliminary efficacy of TEAM in Ugandans at high risk for stroke was conducted. The primary outcome was change in systolic BP from baseline to 24-week follow-up. Secondary outcomes included change in diastolic BP, serum cholesterol, high and low density lipoprotein (HDL, LDL) and triglycerides. RESULTS: Mean (SD) baseline systolic BP was 162.9 (+/-25.6) mmHg while mean (SD) baseline diastolic BP was 99.1 (+/-13.8) mmHg. There was a significant reduction in mean baseline blood pressure of 163/98.8mmHg to blood pressure of 147.8/88.0mmHg at 24weeks, P=0.023. There were also significant reductions in the serum total cholesterol levels at 24weeks with P=0.001. CONCLUSION: Targeted training in self-management (TEAM) adapted to the Ugandan setting is feasible, highly acceptable to participants and appears to be associated with reduced blood pressure, improved lipid profiles and improved glucose control in diabetics. PMID- 29406962 TI - Altered spontaneous brain activity in MRI-negative refractory temporal lobe epilepsy patients with major depressive disorder: A resting-state fMRI study. AB - OBJECTIVE: To investigate alterations in spontaneous brain activity in MRI negative refractory temporal lobe epilepsy patients with major depressive disorder using resting-state functional magnetic resonance imaging (RS-fMRI). METHODS: Eighteen MRI-negative refractory temporal lobe epilepsy patients with major depressive disorder (PDD), 17 MRI-negative refractory temporal lobe epilepsy patients without major depressive disorder (nPDD), and 21 matched healthy controls (HC) were recruited from West China Hospital of SiChuan University from April 2016 to June 2017. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 17-item Hamilton Depression Rating Scale were employed to confirm the diagnosis of major depressive disorder and assess the severity of depression. All participants underwent RS-fMRI scans using a 3.0T MRI system. MRI data were compared and analyzed using the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo) to measure spontaneous brain activity. These two methods were both used to evaluate spontaneous cerebral activity. RESULTS: The PDD group showed significantly altered spontaneous brain activity in the bilateral mesial prefrontal cortex, precuneus, angular gyrus, right parahippocampal gyrus, and right temporal pole. Meanwhile, compared with HC, the nPDD group demonstrated altered spontaneous brain activity in the temporal neocortex but no changes in mesial temporal structures. CONCLUSION: The PDD group showed regional brain activity alterations in the prefrontal-limbic system and dysfunction of the default mode network. The underlying pathophysiology of PDD may be provided for further studies. PMID- 29406963 TI - Isolated persistent acute global amnesia after acute abuse of 3,4-methylenedioxy methamphetamine (MDMA). PMID- 29406964 TI - Comparison of clinical features among Parkinson's disease subtypes: A large retrospective study in a single center. AB - INTRODUCTION: Tremor dominant (TD), postural instability/gait difficulty (PIGD), and akinetic-rigid (AR) subtypes are widely used in classifying patients with Parkinson's disease (PD). METHODS: We compared clinical characteristics between PD subtypes in a large retrospective cohort. Between 1998 and 2016, we included a total of 1003 patients with PD in this retrospective study. Six hundred ninety four patients had more than one visit. Data were collected regarding motor/non motor symptoms at the initial/final visits. Based on the prominent symptom at the initial visit, we classified patients into one of the four subtypes: TD, AR, gait difficulty, and mixed. Rapid progression was defined by emergence of falls, dementia, or dependency within 5years after onset. RESULTS: TD was the most prevalent subtype (44%), followed by AR (29%), mixed (18%), and gait difficulty (9%). Rapid progression was observed more frequently in gait difficulty compared to AR (OR: 3.59 P<0.001). Hallucinations at the final visit were more likely to occur in AR (OR: 2.36, P=0.005) and mixed (OR: 3.28, P<0.001) compared to TD. CONCLUSIONS: Our findings provide support for a distinction of four different PD subtypes: TD, AR, gait difficulty, and mixed. The gait difficulty subtype was distinguishable from the AR subtype. PMID- 29406966 TI - Quantifying iron deposition within the substantia nigra of Parkinson's disease by quantitative susceptibility mapping. AB - BACKGROUND: Iron deposition within the substantia nigra (SN) has been postulated to play a vital role in Parkinson's disease (PD). The aim of this study was to explore the inherent link of PD patients between their substantia nigra iron accumulation and clinical status using quantitative susceptibility mapping (QSM) which is now considered to be the only quantitative imaging technique of brain iron deposition. METHODS: 44 PD patients and 31 age- and gender-matched healthy controls underwent quantitative susceptibility mapping (QSM) were recruited in this study. We firstly divided the patients into mild symptom severity (MSP) and advanced symptom severity (ASP) groups concerning their disease stage, aiming to illuminate the relationship between iron deposition in SN of PD and disease progression. Then, we classified the patients with Parkinson's disease into three subgroups: tremor-dominant PD (TD), akinetic/rigidity-dominant PD (AR), mixed-PD (M) according to their dominant motor symptoms in order to investigate whether there are any effects of SN iron accumulation to different subtypes of PD patients. RESULTS: Compared to healthy controls, patients with PD have increased QSM magnetic values in the substantia nigra (138.039+/-37.320 vs 179.553+/ 65.715; P=0.001). More prominent statistically significance of the difference of SN iron deposition between healthy controls (HC) and advanced symptom severity (ASP) subgroup was displayed (138.039+/-37.320 vs 232.827+/-92.040; P<0.001). Besides, among the three clinical phenotypes both TD and AR subgroup showed significant difference compared with healthy controls concerning the QSM values (138.039+/-37.320 vs 185.864+/-99.851; P=0.013; 188.148+/-52.958 vs 138.039+/ 37.320; P=0.001). Furthermore, the iron content in the SN of PD patients was significantly correlated with the Hoehn-Yahr stage, the Unified Parkinson's Disease Rating Scale (UPDRS), Montgomery Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAMA) scores (r=0.417, P=0.005; r=0.300, P=0.048; r=0.540, P<0.001; r=0.553, P<0.001). In MSP the significantly correlation was displayed only in MADRS, HAMA scores (r=0.429, P=0.013; r=0.492, P=0.004), when disease progressed into advanced severity stage all these clinical measures (Hoehn-Yahr stage, UPDRS-3, UPDRS, HAMA, and MADRS scores) we had recruited into this study shown prominent correlation to SN iron content (r=0.650, P=0.030; r=0.709, P=0.015; r=0.708, P=0.015; r=0.758, P=0.007; r=0.683, P=0.020). In the three phenotypes the correlation between iron content and MADRS, HAMA scores (r=0.686, P=0.002; r=0.633, P=0.006) was found in AR subgroups exclusively. CONCLUSIONS: Patients with PD exhibited significantly higher magnetic susceptibility values, especially in those who are in advanced disease severity stage, which confirmed that iron accumulation in the SN is in line with Parkinson's disease progression. Furthermore, we testified that there are actually some inherent effects of substantia nigra iron deposition to the clinical symptoms of Parkinson's disease. Moreover, it seems that akinetic/rigidity-dominant PD subgroup was affected most by SN iron accumulation. PMID- 29406967 TI - Water-level sign: A vivid pictorial expression for a known neuroradiological phenomenon hitherto differently described. PMID- 29406968 TI - Lovastatin promotes myelin formation in NPC1 mutant oligodendrocytes. AB - Niemann-Pick Type C (NPC) disease is a rare neurovisceral disorder caused by mutations of either NPC1 or NPC2 gene and characterized by defective intracellular transport of cholesterol and glycosphingolipids, leading to neuron loss and myelin aberration in the central nervous system. In this study, by comparing protein expression in the cortical white matter tracts from mice at different postnatal days, we identified that in the NPC1 mutant (NPC1-/-) mice, the onset of myelination is delayed and the amount of the major myelin protein MBP and PLP, and oligodendrocyte regulatory factor Olig1 and Olig2, but not NG2 and Sox10, decreased significantly, suggesting a disruption of oligodendrocyte differentiation. Furthermore, in in vitro oligodendrocyte cultivation, NPC1-/- oligodendrocytes showed less response to the stimulation of neuron-conditioned medium (CdM), indicating a defect of oligodendrocyte per se. Interestingly, lovastatin restores the number of mature myelin-forming oligodendrocytes by increasing Olig1 and Olig2 expressions. Our data suggest a potential strategy for improving myelination using lovastatin in NPC disease. PMID- 29406965 TI - Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein. AB - The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), causes variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. While it is assumed that all cases of vCJD attributed to a dietary aetiology are related to cattle BSE, sheep and goats are susceptible to experimental oral challenge with cattle BSE prions and farmed animals in the UK were undoubtedly exposed to BSE-contaminated meat and bone meal during the late 1980s and early 1990s. Although no natural field cases of sheep BSE have been identified, it cannot be excluded that some BSE-infected sheep might have entered the European human food chain. Evaluation of the zoonotic potential of sheep BSE prions has been addressed by examining the transmission properties of experimental brain isolates in transgenic mice that express human prion protein, however to-date there have been relatively few studies. Here we report that serial passage of experimental sheep BSE prions in transgenic mice expressing human prion protein with methionine at residue 129 produces the vCJD phenotype that mirrors that seen when the same mice are challenged with vCJD prions from patient brain. These findings are congruent with those reported previously by another laboratory, and thereby strongly reinforce the view that sheep BSE prions could have acted as a causal agent of vCJD within Europe. PMID- 29406969 TI - Socioeconomic class and universal healthcare: Analysis of stroke cost and outcomes in US military healthcare. AB - OBJECTIVE: Do socioeconomic disparities exist in the US military healthcare system with ischemic stroke admissions? METHODS: Civilian healthcare in the United States is paid for by a variety of payers. Significant disparities exist in this system based upon socioeconomic status (SES). In contrast, the military healthcare system (MHS) is a universal healthcare system. Military rank is a SES surrogate. Data was collected from the MHS database for years 2010 through 2015. All admissions to military health care facilities with a primary diagnosis of ischemic stroke were reviewed. Military rank was compared for primary outcomes of: Disposition (In-hospital mortality and discharge destination setting) and IV tPA administration and for secondary outcomes of: Total cost of hospitalization and Length of hospital stay (LoS). All adjusted for relevant demographics and co morbidities. RESULTS: Military rank was identified with 1895 (52.3%) of the 3623 admissions. The ranks identified were: Junior Enlisted 100 (2.7%), Senior Enlisted/Warrant Officers 1390 (38.4%), Junior Officers 59 (1.6%) and Senior Officers 346 (9.6%). Statistically significant results included: Lower SES group/ranks were more likely to have poor discharge destination setting while the highest SES group/ranks and had lower rates of in-hospital mortality, shorter lengths of stay and higher hospitalization costs after controlling for relevant variables. CONCLUSION: Higher military ranks (Higher SES) had shorter hospitalization stays, higher costs and less in-hospital mortality in the military's universal healthcare system. This suggests aggregate characteristics of SES plays a large role in the outcomes among SES groups. PMID- 29406970 TI - Adjuvant intra-arterial rt-PA injection at the initially deployed solitaire stent enhances the efficacy of mechanical thrombectomy in acute ischemic stroke. AB - BACKGROUND: Both intra-arterial recombinant tissue plasminogen activator (rt-PA) and stent retrieval are effective for treating acute ischemic stroke. The goal of this study was to evaluate the effectiveness of stent retrieval combined with intra-arterial rt-PA administration via micro-catheter (called the complex technique) in acute ischemic stroke. MATERIAL AND METHODS: A retrospective analysis was performed of 93 consecutive patients treated between 2015 and 2017 for occlusions of the intracranial large artery using the complex technique (n=37) or stent retrieval alone (n=56) in our stroke center. Data on procedure duration, number of passes, and angiographic findings were collected. Successful recanalization was defined as the accomplishment of grade 3 or 2b modified Treatment in Cerebral Ischemia recanalization in 1 or 2 passes. RESULTS: Compared to the stent retrieval group, complex technique group had a higher successful revascularization rate with 1 or 2 passes with the stent retriever (81.1% versus 51.8%, P=0.004), a shorter procedure time (59+/-34min versus 94+/-56min, P<0.001), fewer passes of the stent retriever (1.8+/-1.1 versus 2.5+/-1.4, P=0.012), a better prognosis (70.3% versus 48.2%, P=0.035), a lower embolic complication rate (18.9% versus 39.3%, P=0.038), similar mortality (13.5% versus 21.4%, P=0.334) and similar intracranial hemorrhage symptoms (2.7% versus 12.5%, P=0.204). Intra-arterial rt-PA administration was an independent negative predictor of procedure time (OR=-0.292, P=0.003). CONCLUSION: Mechanical thrombectomy utilizing stent retrieval combined with intra-arterial rt-PA administration in the anterior circulation of acute ischemic stroke patients improved the angiographic results and shortened the procedure duration without increasing adverse events. PMID- 29406972 TI - Norovirus Illnesses in Children and Adolescents. AB - Norovirus is a leading cause of childhood vomiting and diarrhea in the United States and globally. Although most illnesses caused by norovirus are self resolving, severe outcomes may occur from dehydration, including hospitalization and death. A vast majority of deaths from norovirus occur in developing countries. Immunocompromised children are at risk for more severe outcomes. Treatment of norovirus illness is focused on early correction of dehydration and maintenance of fluid status and nutrition. Hand hygiene, exclusion of ill individuals, and environmental cleaning are important for norovirus outbreak prevention and control, and vaccines to prevent norovirus illness are currently under development. PMID- 29406973 TI - Syphilis in Children. AB - Syphilis, caused by Treponema pallidum, is transmitted both sexually and transplacentally. Untreated syphilis is a progressive disease that may result in death or disability in children and adults. Syphilis diagnosis requires 2-stage serologic testing for nontreponemal and treponemal antibodies. Congenital syphilis diagnosis requires careful review of maternal testing and treatment, comparison of maternal and neonatal nontreponemal antibody titers, and clinical evaluation of the neonate. In this review, we present the current epidemiology of syphilis, and the clinical manifestations, diagnosis, and management of syphilis as they relate to pediatric practice, specifically, congenital syphilis and acquired syphilis in adolescents and pregnant women. PMID- 29406974 TI - Fever in the Returning Traveler. AB - Millions of children travel annually, whether they are refugees, international adoptees, visitors, or vacationers. Although most young travelers do well, many develop a febrile illness during or shortly after their trips. Approaching a fever in the returning traveler requires an appropriate index of suspicion to diagnose and treat in a timely manner. As many as 34% of patients with recent travel history are diagnosed with routine infections, but serious infections such as malaria, enteric fever, and dengue fever should be on the differential diagnosis due the high morbidity and mortality in children. PMID- 29406971 TI - The Growing Threat of Antibiotic Resistance in Children. AB - Antimicrobial resistance is a global public health threat and a danger that continues to escalate. These menacing bacteria are having an impact on all populations; however, until recently, the increasing trend in drug-resistant infections in infants and children has gone relatively unrecognized. This article highlights the current clinical and molecular data regarding infection with antibiotic-resistant bacteria in children, with an emphasis on transmissible resistance and spread via horizontal gene transfer. PMID- 29406975 TI - Zika Virus Infection in Children. AB - Zika virus is a mosquito-borne Flavivirus responsible for symptomatic and asymptomatic infections in humans. Zika was first identified in Africa as a cause of sporadic febrile illness. Beginning in 2015, Zika virus infection was identified in Brazil and linked with several symptomatic infections. Notably, congenital infections were observed with marked neurologic abnormalities. Diagnosis relies on detection of Zika virus by real-time polymerase chain reaction or by the presence of anti-Zika antibodies. Treatment of this viral illness remains supportive; however, proactive screening and interventions are indicated in the treatment of infants with symptomatic congenital infection. PMID- 29406976 TI - Overview of Infections Complicating Pediatric Hematopoietic Cell Transplantation. AB - Hematopoietic cell transplantations (HCT) are increasingly being performed in children for the treatment of malignant and nonmalignant diseases. Infections remain an important cause of morbidity and mortality after HCT, where the type and timing of infection is influenced by host, transplant, and pathogen-related factors. Herein, an overview of the epidemiology of infections is presented and organized by timing before and after HCT, understanding that infection may occur at any time point until there is successful immune reconstitution. PMID- 29406977 TI - Emerging Respiratory Viruses in Children. AB - Respiratory viral infections are a leading cause of pediatric disease. Emerging respiratory viruses can cause outbreaks with significant morbidity and mortality or circulate routinely. The rapid identification of pathogens, epidemiologic tracing, description of symptoms, and development of preventative and therapeutic measures are crucial to limiting the spread of these viruses. Some emerging viruses, such as rhinovirus C and influenza C, circulate yearly but were previously undetected due to limited diagnostic methods. Although some pathogens have a geographic focus, globalization dictates that providers be aware of all emerging diseases in order to recognize outbreaks and diagnose and treat patients. PMID- 29406978 TI - Updates on Influenza Vaccination in Children. AB - Influenza vaccination is recommended for all children 6 months of age and older who do not have contraindications. This article provides an overview of information concerning burden of influenza among children in the United States; US-licensed influenza vaccines; vaccine immunogenicity, effectiveness, and safety; and recent updates relevant to use of these vaccines in pediatric populations. Influenza antiviral medications are discussed. Details concerning vaccine-related topics may be found in the current US Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices recommendations for use of influenza vaccines (https://www.cdc.gov/vaccines/hcp/acip-recs/vacc specific/flu.html). Additional information on influenza antivirals is located at https://www.cdc.gov/flu/professionals/antivirals/index.htm. PMID- 29406979 TI - Pediatric Considerations for Postexposure Human Immunodeficiency Virus Prophylaxis. AB - Exposures that carry risk of transmission of blood-borne disease are rare in pediatrics, but expose patients and families to great anxiety. Specialists in pediatric infectious diseases are often asked about initial antimicrobial prophylaxis in these cases. Guidelines for nonoccupational postexposure prophylaxis for human immunodeficiency virus have evolved as new formulations and medications become available and greater experience obtained in assessing relative risks of different exposures and relative costs and benefits for different interventions. This article discusses the evidence behind recent updates to Centers for Disease Control and Prevention guidelines for nonoccupational postexposure prophylaxis for human immunodeficiency virus, focusing on application in the pediatric population. PMID- 29406985 TI - Old and New Infections of Childhood. PMID- 29406986 TI - Was Ugo Foscolo (1778-1827) affected by alpha-1 antitrypsin deficiency? AB - Niccolo Ugo Foscolo (1778-1827), known as Ugo, is one of the masters of the Italian poetry. A writer and a revolutionary, he embraced the ideals of the French Revolution and took part in the stormy political discussions, which the fall of the Republic of Venice had provoked. Despite his poor health, Foscolo lived an adventurous life serving as a volunteer in the Guardia Nazionale and in the Napoleonic army. Following Napoleon's fall (1814), he went into voluntary exile in early 1815. He reached London in Sept. 1816 and lived in poverty at Turnham Green (Chiswick) until his premature death. Foscolo's medical history has been poorly investigated and the cause of his death remains unclear. In an attempt to shed light on his clinical history, we analyzed his Correspondence (Epistolario), a series of more than 3000 letters written between 1794 and 1827. From the age of 26 (1808), Foscolo had frequent episodes of cough and dyspnea that progressively worsened. Four acute respiratory exacerbations occurred in 1812. Between September 1812 and April 1813, he had breathlessness as that of asthma. Frail and ailing, he developed a chronic liver disease in 1826. In August 1827, weakness, dyspepsia and drowsiness further increased and dropsy became manifest. He went into coma on September 7, 1827 and died aged 49 three days later. Based on a brief history of urethritis and urinary obstructions (1811 1812), previous scholars have suggested that Foscolo had urethral stenosis that caused a chronic bladder outlet obstruction and led to consequent renal failure. This hypothesis, however, does not mention the respiratory symptomatology present since 1804, which is a pivotal feature of Foscolo's illness. We surmise that Foscolo suffered from alpha-1 anti trypsin (AAT) deficiency, a rare genetic disease, which caused his premature death and support our interpretation with documental evidence. PMID- 29406987 TI - Multimodal imaging questions etiology of idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome (IRVAN syndrome). AB - Idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome is a rare entity of unknown etiology for which many hypotheses have been proposed with inflammation being the most commonly accepted hypothesis. We report cases of a 9 year old girl and a 22 year old male patient with diagnosis of IRVAN syndrome. The conclusions drawn from the clinical examination and multimodal imaging including optical coherence tomography angiography of the patients are discussed. Our conclusions and interpretation point towards IRVAN being a developmental vascular anomaly rather than a consequence of inflammation. It is thus proposed to be renamed as Idiopathic retinal arteriolar aneurysm syndrome (IRAA). PMID- 29406988 TI - Dry eye disease in strabismus patients: Does eye deviation harm ocular surface? AB - INTRODUCTION: Dry eye disease is a multifactorial disease which affects the ocular surface system, and determines ocular discomfort symptoms and visual disturbance. Various types of ocular surgery, including strabismus one, represents a recognized cause for iatrogenic dry eye. However, it is not uncommon that strabismus patients, even not undergone to surgery, report symptoms of ocular discomfort and dryness. Hypothesis We hypothesize that two possible mechanisms may determine dry eye in strabismus patients by setting up a specific vicious circle: firstly, the increased exposure of the area of the bulbar conjunctiva located on the opposite side compared to the deviation may cause the thinning of the tear film lipid layer, with increased tear film instability; secondly, the dysfunctional lubricity secondary to the altered relationship between the eyelids and the deviated globe may cause blinking-related microtrauma, and thus inflammation and tear hyperosmolarity. These two entry points into the vicious circle of dry eye may determine a cascade of detrimental mechanisms, leading to further damage of the tear film, thus closing the disease circle. DISCUSSION: Strabismus patients may be affected by signs and symptoms of dry eye syndrome. The increased exposure of the bulbar conjunctival area along with the dysfunctional lubricity between the eyelids and the deviated eye could be the main underlying pathophysiological mechanisms acting as entry points into the vicious circle of dry eye disease. If our hypothesis was to be confirmed, ocular surface parameters should be routinely investigated in strabismus patients, whilethe use of tear substitutes with the aim of moistening and nourishing the ocular surface could help in reducing dry eye signs and symptoms. PMID- 29406989 TI - Excessive fetal movements are a sign of fetal compromise which merits further examination. AB - Changes in fetal movement are associated with increased risk of stillbirth after 28 weeks of pregnancy. The majority of studies have focussed on maternal perception of reduced fetal movements, which is associated with stillbirth via placental dysfunction. Recent studies have also described an association between a single episode of excessive fetal movements and late stillbirth. We present a hypothesis that a sudden episode of excessive fetal activity indicates fetal compromise relating to underlying disturbance of the in utero environment, which if it persists can lead to fetal death. The origin of the excessive fetal movements is unknown; they may represent fetal seizures induced by asphyxia or infection, an attempt to release cord entanglement or a change in fetal behaviour (inducing signs of distress) in response to a noxious stimulus. It is also possible that an increase in maternal anxiety may lead to increased perception of fetal activity. Current evidence regarding excessive fetal movements is sparse; there is no clinical guidance regarding how reporting of this symptom might relate to a fetus at risk and which management might reduce the risk of subsequent stillbirth. This could be addressed by prospective observational studies of mothers presenting with excessive fetal movements which could both explore the underlying pathophysiology and determine which investigations could identify fetal compromise in this population. The presence of fetal seizures or umbilical cord entanglement could be evaluated at the time of presentation by cardiotocography and ultrasonography of the fetus and cord. Exposure to infection or noxious stimuli could be evaluated by maternal history and measurement of maternal blood for inflammatory markers or toxins. Maternal anxiety could be assessed by validated anxiety scores. Fetal outcome following excessive fetal movements can be recorded after birth. In addition, the presence of perinatal asphyxia can be assessed using Apgar scores, assessment of fetal acidaemia or measurement of stress-related factors in umbilical cord blood. The placenta and cord can be systematically examined for signs of hypoxia, infection or umbilical cord compression. Such studies would provide evidence regarding the underlying cause of excessive fetal movement and how this symptom might relate to in utero compromise and stillbirth. Ultimately, this approach will determine whether excessive fetal movements can be used alongside reduced fetal movements as a tool to reduce the perinatal mortality rate. PMID- 29406990 TI - Understanding pluripotency under folic acid deficiency using embryonic stem cells as an in vitro model. AB - Innumerable studies have been carried out by people to trace out those elements, find out the mechanisms that are vital to the maintenance of stemness. Amongst them, the one which is gaining importance in the recent past is the metabolism of stem cells, especially One carbon metabolism. Being associated directly or indirectly, with DNA and Histone methylation, One carbon metabolism has an important role to play as far as epigenetic regulation of stemness is concerned. Folic acid being a methyl donor, forms an important component of One Carbon metabolism, and thus its availability has a significant effect on the methylation reactions. The present hypothesis says, using embryonic stem cells grown in vitro as a model system, one can study how deficiency of Folate during pre implantation embryonic development influence the self renewal as well as pluripotency of stem cells, from the perspective of One carbon metabolism and epigenetic mechanisms. Findings from such a study can possibly provide an explanation for the observed intra uterine growth retardation seen under maternal micronutrient deficiency. PMID- 29406991 TI - A new etiologic model for Alzheimers Disease. AB - This etiologic model proposes that Alzheimers Disease (AD) arises when an unusually rapid increase in ventricle volume triggers axon stretch that culminates in the physical separation of trans-synaptic proteins. As a result, these proteins, such as neurexin, neuroligin, N-Cadherin and Amyloid Precursor Protein (APP), experience a change in the configuration of their cytoplasmic tail, so that instead of transmitting signals to create and maintain synaptic structure they activate enzymes, and generate molecules, that stimulate neurite growth; for example, the transformation of the N-Cadherin tail dissolves its complex with presenilin and beta-catenin triggering activation of glycogen synthase kinase 3 beta (GSK3beta) and cytoskeletal disruption. This disruption leads to an increase in pro nerve growth factor (proNGF), a molecule that stimulates neurite growth via the p75 neurotrophin receptor (p75). GSK3beta contributes to this growth by increasing microtubule instability through the phosphorylation of tau. Separation of trans-synaptic APPs leads to their cis dimerization and this stimulates production of amyloid beta (Abeta), an autocrine growth factor that interacts with both the p75 and alpha 7 nicotinic acetylcholine receptors. Cis dimerization of APPs may also allow the autophosphorylation of Y682 and T668 in the APP cytoplasmic tail, triggering activation of c-Jun N terminal kinase, Abelson kinase and cyclin dependent kinase 5, all of which play a role in neurite growth. ProNGF, Abeta and the kinase cascades work together to transform synapses into growth cones and stimulate sprouting of neuropil threads in an attempt to reconnect axons and dendrites. Neurofibrillary tangles, located in neural cell soma, consist of neurofilaments and microtubules needed to fuel this renewal of neurite growth. The model suggests that the best way to treat AD is to prevent synaptic separation by identifying individuals experiencing unusually high rates of ventricle growth and reducing this to more normal levels by shunting or some other technique. PMID- 29406992 TI - Disturbed purine nucleotide metabolism in chronic kidney disease is a risk factor for cognitive impairment. AB - Chronic kidney disease (CKD) is an increasing global health burden. Disturbance in purine metabolism pathway and a higher level of serum uric acid, called hyperuricemia, is a risk factor of CKD, and it has been linked to increased prevalence and progression of the disease. In a recent study, it has been demonstrated that purine nucleotides and uric acid alter the activity of acetylcholinesterase (AChE). Thus, we hypothesize that adenine, hypoxanthine, xanthine, 2,8-dihydroxyadenine and uric acid may potentially interfere with the activity of AChE. The hypothesis has been tested using computational tools. Uric acid has been found to be the most potent inhibitor of AChE, with a binding affinity higher than the known inhibitors of the enzyme. Further, since depleted AChE activity is associated with dementia and cognitive impairment, the present study suggest that disturbed purine nucleotide metabolism in CKD is a risk factor for cognitive impairment. PMID- 29406993 TI - A novel bimodal approach for treating atrophic bone non-unions with extracorporeal shockwaves and autologous mesenchymal stem cell transplant. AB - We propose a novel approach for the treatment of atrophic bone non-unions via parallel applications of extracorporeal shock wave therapy (ESWT) and an autologous mesenchymal stem cell transplant. The hypothesis resides on the potentiality of shock waves (SWs) to act as a tool for manipulating the patient's mesenchymal stem cells (MSCs). In addition to the conventional physical stimulus achieved by delivering SWs at the site of non-union to stimulate the well-known trophic effects on bone tissue, a series of concomitant ESWT would be administered in tandem at a bone marrow donor site, such as the iliac crest, to precondition resident bone marrow stromal cells (BMSCs) in vivo, priming resident MSCs by enlarging and conditioning their population prior to bone marrow aspiration. The resulting sample could then be treated to further augment cell concentration and injected, under fluoroscopic control, into the non-union site through a percutaneous approach. PMID- 29406994 TI - Corrigendum to "Endothelial dysfunction mediated by interleukin-18 in patients with ischemic heart disease undergoing coronary artery bypass grafting surgery" [Med. Hypotheses 104 (2017) 20-24]. PMID- 29406995 TI - Functional neurological symptom disorder (conversion disorder): A role for microglial-based plasticity mechanisms? AB - Functional Neurological Symptom Disorder (FND) is a relatively common neurological condition, accounting for approximately 3-6% of neurologist referrals. FND is considered a transient disorder of neuronal function, sometimes linked to physical trauma and psychological stress. Despite this, chronic disability is common, for example, around 40% of adults with motor FND have permanent disability. Building on current theoretical models, this paper proposes that microglial dysfunction could perpetuate functional changes within acute motor FND, thus providing a pathophysiological mechanism underlying the chronic stage of the motor FND phenotypes seen clinically. Core to our argument is microglia's dual role in modulating neuroimmunity and their control of synaptic plasticity, which places them at a pathophysiological nexus wherein coincident physical trauma and psychological stress could cause long-term change in neuronal networks without producing macroscopic structural abnormality. This model proposes a range of hypotheses that are testable with current technologies. PMID- 29406996 TI - The role of antimalarial quality in the emergence and transmission of resistance. AB - The emergence and transmission of antimalarial resistance is hampering malaria eradication efforts and is shortening the useful therapeutic life of currently available antimalarials. Drug selection pressure has been identified as a contributing factor to the emergence and transmission of resistance, especially population treatment coverage and sub-therapeutic concentrations of active pharmaceutical ingredient (API) in the bloodstream. Medicine quality can be defined as good quality or poor quality. Poor quality antimalarials can be falsified, substandard or degraded and are estimated to make up between 10 and 50% of the antimalarial market in developing countries, and can be a source of sub-therapeutic doses of antimalarial API(s). The availability and use of poor quality antimalarials and the non-recommended use of quality assured monotherapies have historically been linked to treatment failure and in some cases, have coincided with the emergence and transmission of resistance in regions. We propose and outline the hypotheses that the use of poor quality antimalarial treatments and non-recommended quality assured monotherapies promote the (i) emergence and/or (ii) transmission of antimalarial resistance. PMID- 29406997 TI - Subcutaneous accessory pain system (SAPS): A novel pain pathway for myofascial trigger points. AB - Despite the accumulating neuro-physiological evidence of myofascial pain, many clinicians are skeptical about its existence as a separate disease entity. No single theory can fully explain the four cardinal features of MPS; taut bands, local tenderness, local twitching and the characteristic pattern of referred pain. Bridging the gap between basic and clinical knowledge mandates coupling the local trigger point changes with the clinically seen distant somatically innervated referred pain. The main question addressed by the present theory is why do trigger points behave differently in comparison to the surrounding muscle tissue and are trigger points the primary problem or secondary to a primary pathology. We propose that trigger points have an extra-innervation system that connect them with other spinal structures such as the facet, the annulus and other trigger points with a role for the subcutaneous fascia as part of trigger points pathogenesis or passage for the extra-innervation. The extra-innervation system is Subcutaneous accessory pain system (SAPS). The novel SAPS system connecting trigger points to the spinal segments via dorsal rami is presented. Individuals with this accessory pathway are prone to myofascial pain, trigger point activation and segmental referred somatic pain similar to other axial spinal structures. Despite the high prevalence of myofascial pain, the mechanism is not universally agreed upon. Why do the trigger points act differently from surrounding muscle tissue and are almost constant in location in different individuals is controversial. Why does myofascial pain and its two components, trigger points and referred pain, exist or are more prevalent in some individuals than in others is unexplained. The correlation between axial spinal structures pathology and the trigger points is not explored well. The existing theories about trigger point formation and referred pain is scientifically credible for each separate component and the SAPS novel system can provide the link between the two. PMID- 29406998 TI - Prophylactic use of colchicine in preventing radiation induced coronary artery disease. AB - Radiation therapy is one of the primary treatments in fighting breast cancer, one of the most common cancers in the US. One of the dose limiting factors of this therapy is radiation induced heart damage that results from mediastinal radiation. Recently statins, a medication typically used to lower cholesterol levels, have been suggested as a prophylactic treatment to potentially mitigate this process. Similarly, we hypothesized whether colchicine, an anti-inflammatory medication that is presently used in the treatment of gout and pericarditis, might be used to prevent coronary artery disease induced by radiation therapy. We hypothesize that colchicine may help prevent the deleterious effect on coronary arteries induced by radiation therapy by inhibiting inflammation and platelet aggregation. The pathophysiology of radiation induced coronary artery disease is similar to that of coronary artery disease in the general population. Inflammation, fibrosis and platelet aggregation play a key role in this process. After radiation therapy, inflammation occurs, recruiting leukocytes, particularly neutrophils and monocytes. Neutrophils are fibrotic mediators, and macrophages form foam cells in the intimal layer of the vessel wall, leading to the build-up of atherosclerotic plaques. Platelet aggregation, both initially and upon plaque rupture, is also a culprit in exacerbating radiation damage. Colchicine is known to inhibit microtubule polymerization and therefore inhibits mitosis, neutrophil motility and has been shown to decrease platelet aggregation. Its anti inflammatory properties have been attributed to several different effects based on microtubule dysfunction. Colchicine has also been shown to affect the expression of adhesion molecules on endothelial cells, leukocytes, and to decrease activation of thrombin induced platelet aggregation. There is evidence to suggest that colchicine may be beneficial in the treatment of radiation induced coronary artery disease due to its anti-inflammatory and anti-coagulant properties. This idea would be beneficial for future studies. PMID- 29406999 TI - Serum cholecalciferol may be a better marker of vitamin D status than 25 hydroxyvitamin D. AB - Vitamin D is produced in the skin upon sun-exposure or obtained through the diet. Vitamin D is hydroxylated to 25-hydroxyvitamin D (25(OH)D) in the liver and to the active form 1,25-dihydroxyvitamin D (1,25(OH)2D) in the kidneys. To exert its effect 1,25(OH)2D has to bind to the nuclear vitamin D receptor VDR. Lack of vitamin D leads to rickets in children and to osteomalacia in adults. 25(OH)D is used as a marker of a subject's vitamin D status. Low serum 25(OH)D levels are associated with a number of diseases, risk factors for disease and increased mortality. However, intervention studies with vitamin D have generally been disappointing. Many, if not most cells have the hydroxylases necessary for intra cellular activation of vitamin D. It is likely that more vitamin D diffuses or are transported into the cells than 25(OH)D and 1,25(OH)2D, and accordingly, most of the 1,25(OH)2D that bind to the VDR are derived from intra-cellular hydroxylation of vitamin D. Therefore, our hypothesis is that serum vitamin D is a better marker of a subject's vitamin D status than 25(OH)D. Since the half-life in serum for vitamin D is approximately one day, giving vitamin D weekly or monthly will result in short-lived serum vitamin D peaks with periods of vitamin D deficiency in between. On the other hand, serum 25(OH)D, which has a half-life of weeks, will show high and stable serum levels throughout. Important vitamin D effects may have been missed in studies with intermittent dosing, and vitamin D in intervention trials should be given daily. Likewise, in epidemiological studies and clinical practice 25(OH)D has uniformly been used as marker. This may lead to gross misclassification of individuals that do not have a stable influx of vitamin D from sun-exposure or diet. In epidemiological studies serum vitamin D should be measured as well as 25(OH)D, and in clinical practice a 25(OH)D measurement should be interpreted in view of recent sun-exposure and diet history. PMID- 29407000 TI - The arteriolar injury in hypertension. AB - In 1937, Drs. Moritz and Oldt described arteriolar injuries in the kidneys (and other viscera) in hypertension, across the age range, in both sexes, and, in different races. This hypothesis proposes that injuries to vasomotor nerves cause the arteriolar injury in the kidney in hypertension, (as well as that in the uterus in preeclampsia). Different patterns of perivascular hyalinisation in different viscera are clues to the varying causes and consequences of arteriolar injury. In the uterus there is a symmetrical, perivascular "halo of hyalinisation" that marks the lines of extension of regenerating, injured nerves to the placental bed, whereas in the kidney there is a disordered and asymmetrical "halo of hyalinisation" where persistent, and recurrent, increases in intravascular pressures interrupt development of regenerating nerves. Consequences of injuries to vasomotor nerves include releasing a "soup" of cytokines that cause regeneration of "new" nerves expressing primitive, pain and stretch receptors including TRPV-1 and P2X3 purinergic "stretch" receptors that may be significant in the afferent mechanism in preeclampsia. There is also concurrent, "background" hyperplasia of denervated tunica media and intima leading to narrowing of the arterioles and a further drive to hypertension through renal ischaemia (Goldblatt, 1942). These observations require support from animal studies and other investigations to establish causation. This hypothesis may provide a number of potential mechanisms that reinforce, or accelerate, the physiological processes that contribute to hypertension. PMID- 29407001 TI - Subacute sclerosing panencephalitis and immune thrombocytopenia: More than a coincidence? AB - Subacute sclerosing panencephalitis (SSPE) is a progressive disease caused by persistent measles virus (MV). It has an incidence of 0.4-2.0/million in Turkey. Immune thrombocytopenia (ITP) is a bleeding disorder whose estimated incidence is 4.2/100.000 person/years in the pediatric age group. We observed three cases with ITP in our cohort of 315 pediatric SSPE cases, an incidence higher than coincidentally expected in the general population. We hypothesize an association between SSPE and ITP. Our three cases had measles 1-2 years before the onset of ITP and 8-10 years before first symptoms of SSPE. A common immunogenetic background creating susceptibility to infection and autoimmunity might play a role. Alternatively, chronic antigenic stimulation by the MV leading to synthesis of cross-reacting antibodies against platelets, or treatment of ITP with immunoglobulins or steroids might affect or alter the development and manifestation of SSPE. The co-occurrence of these two disorders of viral and immune pathogenesis may draw attention to similar observations and provide clues for their mechanisms. PMID- 29407002 TI - A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors. AB - Androgenic alopecia, also known as pattern hair loss, is a chronic progressive condition that affects 80% of men and 50% of women throughout a lifetime. But despite its prevalence and extensive study, a coherent pathology model describing androgenic alopecia's precursors, biological step-processes, and physiological responses does not yet exist. While consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, questions remain regarding dihydrotestosterone's exact role in androgenic alopecia onset. What causes dihydrotestosterone to increase in androgenic alopecia-prone tissues? By which mechanisms does dihydrotestosterone miniaturize androgenic alopecia-prone hair follicles? Why is dihydrotestosterone also associated with hair growth in secondary body and facial hair? Why does castration (which decreases androgen production by 95%) stop pattern hair loss, but not fully reverse it? Is there a relationship between dihydrotestosterone and tissue remodeling observed alongside androgenic alopecia onset? We review evidence supporting and challenging dihydrotestosterone's causal relationship with androgenic alopecia, then propose an evidence-based pathogenesis model that attempts to answer the above questions, account for additionally-suspected androgenic alopecia mediators, identify rate limiting recovery factors, and elucidate better treatment targets. The hypothesis argues that: (1) chronic scalp tension transmitted from the galea aponeurotica induces an inflammatory response in androgenic alopecia-prone tissues; (2) dihydrotestosterone increases in androgenic alopecia-prone tissues as part of this inflammatory response; and (3) dihydrotestosterone does not directly miniaturize hair follicles. Rather, dihydrotestosterone is a co-mediator of tissue dermal sheath thickening, perifollicular fibrosis, and calcification - three chronic, progressive conditions concomitant with androgenic alopecia progression. These conditions remodel androgenic alopecia-prone tissues - restricting follicle growth space, oxygen, and nutrient supply - leading to the slow, persistent hair follicle miniaturization characterized in androgenic alopecia. If true, this hypothetical model explains the mechanisms by which dihydrotestosterone miniaturizes androgenic alopecia-prone hair follicles, describes a rationale for androgenic alopecia progression and patterning, makes sense of dihydrotestosterone's paradoxical role in hair loss and hair growth, and identifies targets to further improve androgenic alopecia recovery rates: fibrosis, calcification, and chronic scalp tension. PMID- 29407003 TI - No incision and tension-free vaginal sling for stress urinary incontinence: The role of knotless barbed suture. AB - Midurethral mesh sling is the most performed incontinence procedure. This hypotheses propose knotless barbed suture could be positioned as a tension-free trans-vaginal sling under the mid-urethra without vaginal incision. Knotless suture sling support and stabilize mid-urethra when intraabdominal pressure increase. This procedure is designed to replace midurethral mesh sling operation, aiming at reducing complications. It is completed in a similar way with retropubic mesh sling procedure, and less invasive. This involve the passage of fine needle from suprapubic skin to midurethral vaginal wall, and knotless suture passing through in fine needle as a U shape. The foundational promises for this hypothesis pertain to two clinical facts: midurethral sling procedure is a gold standard treatment, and the knotless suture offer superior tissue holding or fixation strength originated from the unique barbed design. PMID- 29407004 TI - Breast milk is conditionally perfect. AB - Breast milk is the universal preferred nutrition for the newborn human infant. New mother have been encouraged to exclusively breastfeed by health care professionals and consumer-advocacy forums for years, citing "breast milk is the perfect food". The benefits are numerous and include psychological, convenience, economical, ecological and nutritionally superior. Human milk is a composite of nutritional choices of the mother, commencing in the pre-conceptual era. Events influencing the eventual nutritional profile of breast milk for the neonate start with pre-conceptual dietary habits through pregnancy and finally to postpartum. Food choices do affect the nutritional profile of human breast milk. It is not known who coined the phrase "breast milk is the perfect food" but it is widely prevalent in the literature. While breast milk is highly nutritive, containing important immunological and growth factors, scientific investigation reveals a few short-falls. Overall, human breast milk has been found to be low in certain nutrients in developed countries: vitamin D, iodine, iron, and vitamin K. Additional nutrient deficiencies have been documented in resource-poor countries: vitamin A, vitamin B 12, zinc, and vitamin B 1/thiamin. Given these findings, isn't it more accurate to describe breast milk as "conditionally perfect"? Correcting the impression that breast milk is an inherently, automatically comprehensive enriched product would encourage women who plan to breastfeed an opportunity to concentrate on dietary improvement to optimizes nutrient benefits ultimately to the neonate. The more immediate result would improve pre-conceptual nutritional status. Here, we explore the nutritional status of groups of young women; some of whom will become pregnant and eventually produce breast milk. We will review the available literature profiling vitamin, mineral, protein and caloric content of breast milk. We highlight pre-existing situations needing correction to optimize conception and fetal development. While alternative forms of infant nutrition carry standard product labels of nutrient adequacy, this information does not apply universally to all breast milk. Infant formulas are fortified with various amounts of vitamins, minerals, supplemental protein concentrates, nucleic factors, omega 3 fatty acids and any important new nutritional finding. Infant formulas are manufactured to be consistent in composition and are monitored closely for quality. Not true for human breast milk. Any nutrient deficiency existing in pregnancy will ultimately be carried forward via lactation. It is a biological impossibility for a lactating woman to transfer nutrients via breast milk she does not have! PMID- 29407005 TI - Would glucagon-like peptide-1 receptor agonists have efficacy in binge eating disorder and bulimia nervosa? A review of the current literature. AB - Binge eating, eating an abnormally large amount of food in a discrete period of time with a sense of loss of control over eating, is a defining feature of the eating disorders binge eating disorder (BED) and bulimia nervosa (BN). Both BED and BN are important public health problems for which there are few medical treatments. However, almost all drugs with central nervous system-mediated weight loss properties studied thus far in randomized, placebo-controlled trials in persons with BED or BN have been efficacious for reducing binge eating behavior. Glucagon-like peptide-1 (GLP-1) receptor agonists, marketed for type 2 diabetes and chronic weight management, produce weight loss in a dose dependent manner and have favorable psychiatric adverse event profiles. We hypothesize that GLP-1 receptor agonists will safely reduce binge eating behavior in individuals with BED or BN, including those with co-occurring psychiatric disorders, and propose that randomized, placebo-controlled clinical trials of GLP-1 receptor agonists be conducted in persons with BED and those with BN. To support this hypothesis, we review studies of GLP-1 and GLP-1 receptor agonists in preclinical models of binge eating, studies of GLP-1 levels in individuals with BED or BN, and preliminary data of GLP-1 receptor agonists in humans with abnormal eating behavior. PMID- 29407006 TI - Stroke Prevention for High-Risk Atrial Fibrillation in the Emergency Setting: The Emergency Physician Perspective. AB - Atrial fibrillation is a frequent reason for presentation to an emergency department (ED), and the number of these visits are increasing. This creates an opportunity to improve the suboptimal rate of oral anticoagulation (OAC) use in patients with atrial fibrillation who are at high risk of stroke. However, there are very few data on whether OAC initiation in the ED, compared with referral to the longitudinal health care provider to initiate it, results in better long-term use. Moreover, for ethical and medicolegal reasons, physicians who initiate a chronic medication are obliged to reassess the patient at a later date, to check for medication side effects and the need for dose adjustment. More research is needed to determine whether OAC should be prescribed in the ED, by a physician who will never see the patient again. Patients who are cardioverted in the ED might be an exception, secondary to the increased risk of stroke after cardioversion. If ED OAC prescribing is associated with better outcomes, these results must be placed into context with the care and outcomes of the other patients in the ED. If there is a net benefit, the findings should be disseminated to practicing emergency physicians, preferably via emergency physician opinion leaders. An implementation science-based approach, which addresses the barriers to ED OAC prescribing (eg, the competing demands of running an ED and lack of guaranteed follow-up care after discharge from an ED), should be used to support prescribing of OAC in the ED. Potential solutions are described. PMID- 29407007 TI - New Insights Into the Use of the 12-Lead Electrocardiogram for Diagnosing Acute Myocardial Infarction in the Emergency Department. AB - The 12-lead electrocardiogram (ECG) remains the most immediately accessible and widely used initial diagnostic tool for guiding management in patients with suspected myocardial infarction (MI). Although the development of high sensitivity cardiac troponin assays has improved the rule-in and rule-out and risk stratification of acute MI without ST elevation, the immediate management of the subset of acute MI with acute coronary occlusion depends on integrating clinical presentation and ECG findings. Careful interpretation of the ECG might yield subtle features suggestive of ischemia that might facilitate more rapid triage of patients with subtle acute coronary occlusion or, conversely, in identification of ST-elevation MI mimics (pseudo ST-elevation MI patterns). Our goal in this review article is to consider recent advances in the use of the ECG to diagnose coronary occlusion MIs, including the application of rules that allow MI to be diagnosed on the basis of atypical ECG manifestations. Such rules include the modified Sgarbossa criteria allowing identification of acute MI in left bundle branch block or ventricular pacing, the 3- and 4-variable formula to differentiate normal ST elevation (formerly called early repolarization) from subtle ECG signs of left anterior descending coronary artery occlusion, the differentiation of ST elevation of left ventricular aneurysm from that of acute anterior MI, and the use of lead aVL in the recognition of inferior MI. Improved use of the ECG is essential to improving the diagnosis and appropriate early management of acute coronary occlusion MIs, which will lead to improved outcomes for patients who present with acute coronary syndrome. PMID- 29407008 TI - Cardiac Intensive Care Unit Management of Patients After Cardiac Arrest: Now the Real Work Begins. AB - Survival with a good quality of life after cardiac arrest continues to be abysmal. Coordinated resuscitative care does not end with the effective return of spontaneous circulation (ROSC)-in fact, quite the contrary is true. Along with identifying and appropriately treating the precipitating cause, various components of the post-cardiac arrest syndrome also require diligent observation and management, including post-cardiac arrest neurologic injury and myocardial dysfunction, systemic ischemia-reperfusion phenomenon with potential consequent multiorgan failure, and the various sequelae of critical illness. There is growing evidence that an early invasive approach to coronary reperfusion with percutaneous coronary intervention, together with active targeted temperature management and optimization of hemodynamic, ventilator, and metabolic parameters, may improve survival and neurologic outcomes in cardiac arrest survivors. Neuroprognostication is complex, as are survivorship issues and long-term rehabilitation. Our paramedics, emergency physicians, and resuscitation specialists are all to be congratulated for ever-increasing success with ROSC... but now the real work begins. PMID- 29407009 TI - A Population-Based Study of Syncope in the Young. AB - BACKGROUND: The prevalence, hospitalization patterns, and outcomes of pediatric and adolescent syncope have not been rigorously characterized. METHODS: Patients < 20 years presenting to an emergency department (ED) with a primary diagnosis of syncope (International Classification of Diseases, 10th revision, code R55) between fiscal year (FY) 2006/2007 and FY 2013/2014 in the province of Alberta, Canada were grouped according to discharge status from the ED, ie, (1) admitted to hospital and (2) discharged without admission. Temporal trends and differences in baseline characteristics, medication use, and outcomes between admitted and discharged patients were examined. RESULTS: The prevalence of syncope increased from 143/100,000 population in FY 2006/2007 to 166/100,000 population in FY 2013/2014 (P < 0.01). The majority of the 11,488 patients who presented to the ED with syncope were discharged home (n = 11,214 [98%]). Cardiac disease was present in 12.7% and thoracic conditions were present in 8% of the study population. A majority of patients (66.2% admitted and 56.4% discharged; P = 0.018) were taking a prescription drug in the year before presentation. By 30 days, 26.1% of admitted patients had a second ED presentation and 8.1% had a rehospitalization. Among discharged patients, the 30-day repeated ED presentation rate was 11.7% and the hospitalization rate was 1.1%. By 1 year, the rates of repeated ED visits increased to 64.1% and 47.5%, and rehospitalization rates increased to 21.4% and 6.8% among admitted and discharged patients, respectively. CONCLUSIONS: Our data suggest that pediatric and adolescent syncope is increasing in prevalence and represents a growing public health problem. This population has a high burden of comorbidities that likely contribute to increased health care resource use and polypharmacy. PMID- 29407010 TI - Where you Live in Nova Scotia Can Significantly Impact Your Access to Lifesaving Cardiac Care: Access to Invasive Care Influences Survival. AB - BACKGROUND: Invasive cardiac care is the preferred method of treatment for patients with acute coronary syndromes (ACS) complicated by cardiogenic shock (CS). In Nova Scotia, invasive cardiac care is only available in Halifax at the Queen Elizabeth II Health Sciences Centre (QEII-HSC). METHODS: All consecutive patients diagnosed with ACS and CS in 2009-2013 in Nova Scotia were included. Data were obtained from the clinical database of Cardiovascular Health Nova Scotia. The primary outcome was in-hospital mortality. RESULTS: A total of 418 patients with ACS and CS were admitted to the hospital. Access to invasive care was limited to 309 (73.9%) of these patients. For those who presented elsewhere in the province, 64.2% were transferred to the QEII-HSC. The mortality rate among the 309 patients with access to invasive care was significantly lower than that among the 109 patients who did not have access (41.7% vs 83.5%; P < 0.0001). Unadjusted mortality was lowest among patients undergoing primary percutaneous coronary intervention (33.1%). After adjustment for clinical differences, access to cardiac catheterization remained an independent predictor of survival (odds ratio, 0.2; 95% confidence interval, 0.11-0.36). Heat map analysis revealed that access was lowest in regions furthest from Halifax. CONCLUSIONS: ACS complicated by CS has a high mortality rate. We demonstrate that access to health care centres offering cardiac catheterization is independently associated with survival, and public health initiatives that improve access should be considered. Patients presenting furthest from Halifax were the least likely to be transferred, suggesting that geography remains an important barrier to livesaving care. PMID- 29407011 TI - The de Winter ECG Pattern in the Absence of Acute Coronary Artery Occlusion. AB - A 26-year-old man presented to the emergency department with chest pain and electrocardiogram (ECG) changes compatible with the de Winter pattern. Emergent coronary angiography was used to rule out the presence of significant stenosis. Cardiac magnetic resonance imaging confirmed the diagnosis of myocarditis. This case underlines the lack of data regarding the positive predictive value of this ECG pattern for the diagnosis of acute myocardial infarction. Until further prospective studies are available, we believe that the de Winter ECG pattern should be considered as an "ST-elevation equivalent" when myocardial ischemia is suspected. PMID- 29407012 TI - President's Page. PMID- 29407013 TI - Contemporary Emergency Department Management of Patients with Chest Pain: A Concise Review and Guide for the High-Sensitivity Troponin Era. AB - This article synthesizes current best evidence for the evaluation of patients with suspected acute coronary syndrome (ACS) using high-sensitivity troponin assays, enabling physicians to effectively incorporate them into practice. Unlike conventional assays, high-sensitivity assays can precisely measure blood cardiac troponin concentrations in the vast majority of healthy individuals, facilitating the creation of rapid diagnostic algorithms. Very low troponin concentrations on presentation accurately rule out acute myocardial infarction (AMI) and enable the discharge of approximately 20% of patients after a single test, whereas an additional 30%-40% of patients can be safely discharged after short-interval serial sampling in as little as 1 or 2 hours. In contrast, highly abnormal troponin concentrations on presentation (more than 5 times the upper reference limit) or rapidly rising levels on serial testing can rapidly rule in AMI with high specificity. However, approximately one-third of patients remain in a biomarker-indeterminate "observation zone" even after serial sampling. These patients pose a disposition challenge to clinicians because although the differential diagnosis of elevated troponin concentrations is broad, these patients have an increased risk for short-term major adverse cardiac events. Use of repeated serial troponin sampling and structured clinical prediction tools may assist disposition for these patients, because no validated pathways currently exist to guide clinicians. Ongoing research to tailor diagnostic thresholds to individual patient characteristics may enable improved diagnostic accuracy and usher in a new era of personalized medicine in the evaluation of suspected ACS. PMID- 29407014 TI - Changing culture to end FGM. PMID- 29407015 TI - Yellow fever: a major threat to public health. PMID- 29407016 TI - Editing the human genome: balancing safety and regulation. PMID- 29407017 TI - Should basic science matter to clinicians? PMID- 29407019 TI - Offline: Adolescent health-vulnerable and under threat. PMID- 29407018 TI - The global fight against cancer: challenges and opportunities. PMID- 29407020 TI - FGM in Sierra Leone. PMID- 29407021 TI - Prospects for dementia research. PMID- 29407022 TI - Developing countries in the digital revolution. PMID- 29407023 TI - A new paradigm for the MRC Units in The Gambia and Uganda. PMID- 29407024 TI - Virtual care for improved global health. PMID- 29407025 TI - Superbugs and us. PMID- 29407026 TI - The medical suffragettes. PMID- 29407027 TI - Fotis Kafatos. PMID- 29407028 TI - Can the scientific world positively influence decision makers on planetary health? PMID- 29407029 TI - Influenza vaccination and prevention of cardiovascular disease mortality. PMID- 29407030 TI - The growing problem of loneliness. PMID- 29407031 TI - Influenza vaccination and prevention of cardiovascular disease mortality - Authors' reply. PMID- 29407032 TI - Challenges of measuring the Healthcare Access and Quality Index. PMID- 29407033 TI - Challenges of measuring the Healthcare Access and Quality Index - Authors' reply. PMID- 29407034 TI - Challenges of measuring the Healthcare Access and Quality Index. PMID- 29407035 TI - Trans people and the myth of homogeneous societies. PMID- 29407036 TI - The burning light. PMID- 29407037 TI - Sharp physic. PMID- 29407038 TI - Chesmal Siriwardhana. PMID- 29407039 TI - A role for glutamine 183 in the folate oxidative half-reaction of methylenetetrahydrofolate reductase from Escherichia coli. AB - The flavoprotein methylenetetrahydrofolate reductase (MTHFR) from Escherichia coli catalyzes a ping-pong reaction with NADH and 5,10-methylenetetrahydrofolate (CH2-H4folate) to produce NAD+ and 5-methyltetrahydrofolate (CH3-H4folate). This work focuses on the function of the invariant, active-site aminoacyl residue Gln183. X-ray structures of the enzyme complexes Ered(wild-type)*NADH and Eox(Glu28Gln)*CH3-H4folate indicate that Gln183 makes key hydrogen-bonding interactions with both NADH and folate in their respective half-reactions, suggesting roles in binding each substrate. We propose that the polarity of Gln183 may also aid in stabilizing the proposed 5-iminium cation intermediate during catalysis in the oxidative half-reaction with folate. We have prepared mutants Gln183Ala and Gln183Glu, which we hypothesize to have altered charge/polarity and hydrogen bonding properties. We have examined the enzymes by steady-state and stopped-flow kinetics and by measurement of the flavin redox potentials. In the reductive half-reaction, NADH binding affinity and the rate of flavin reduction have not been hindered by either mutation. By contrast, our results support a minor role for Gln183 in the oxidative half-reaction. The Gln183Ala variant exhibited a 6-10 fold lower rate of folate reduction and bound CH2-H4folate with 7-fold lower affinity, whereas the Gln183Glu mutant displayed catalytic constants within 3-fold of the wild-type enzyme. PMID- 29407040 TI - Teriparatide persistence and tolerance in patients with osteoporosis: Observational data from clinical practice. PMID- 29407041 TI - High bone mass in adults. AB - A finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of >=+2.5 or >=+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co receptor). PMID- 29407042 TI - Contribution of ultrasound to diagnosing a phosphaturic mesenchymal tumor. PMID- 29407043 TI - 2018 update of French Society for Rheumatology (SFR) recommendations about the everyday management of patients with spondyloarthritis. AB - OBJECTIVE: To update French Society for Rheumatology recommendations about the management in clinical practice of patients with spondyloarthritis (SpA). SpA is considered across the range of clinical phenotypes (axial, peripheral, and entheseal) and concomitant manifestations. Psoriatic arthritis is included among the SpA phenotypes. METHODS: According to the standard procedure advocated by the EULAR for developing recommendations, we first reviewed the literature published since the previous version of the recommendations issued in June 2013. A task force used the results to develop practice guidelines, which were then revised and graded using AGREE II. RESULTS: Four general principles and 15 recommendations were developed. The first four recommendations deal with treatment goals and general considerations (assessment tools and comorbidities). Recommendations 5 and 6 are on non-pharmacological treatments. Recommendation 7 is about nonsteroidal anti-inflammatory drugs, which are the cornerstone of the treatment, and recommendations 8 to 10 are on analgesics, glucocorticoid therapy, and conventional disease-modifying antirheumatic drugs. Biologics are the focus of recommendations 11 through 14, which deal with newly introduced drug classes, including their indications (active disease despite conventional therapy and, for nonradiographic axial SpA, objective evidence of inflammation) and monitoring, and with patient management in the event of treatment failure or disease remission. Finally, recommendation 15 is about surgical treatments. CONCLUSION: This update incorporates recent data into a smaller number of more simply formulated recommendations, with the goal of facilitating their use for guiding the management of patients with SpA. PMID- 29407044 TI - Computer simulations of the activity of RND efflux pumps. AB - The putative mechanism by which bacterial RND-type multidrug efflux pumps recognize and transport their substrates is a complex and fascinating enigma of structural biology. How a single protein can recognize a huge number of unrelated compounds and transport them through one or just a few mechanisms is an amazing feature not yet completely unveiled. The appearance of cooperativity further complicates the understanding of structure-dynamics-activity relationships in these complex machineries. Experimental techniques may have limited access to the molecular determinants and to the energetics of key processes regulating the activity of these pumps. Computer simulations are a complementary approach that can help unveil these features and inspire new experiments. Here we review recent computational studies that addressed the various molecular processes regulating the activity of RND efflux pumps. PMID- 29407045 TI - Antibiofilm activity of bioactive hop compounds humulone, lupulone and xanthohumol toward susceptible and resistant staphylococci. AB - Bacterial biofilms pose a serious medical problem due to their significant resistance to antimicrobials, and staphylococci are recognized as the most frequent cause of biofilm-associated infections. The hop plant (Humulus lupulus L.) contains substances that have been determined to act as anti-infective agents against bacteria, mainly in planktonic form. Therefore, we decided to investigate the antibiofilm properties of H. lupulus L.-derived compounds (humulone, lupulone and xanthohumol) against a selected group of Staphylococcus spp., including methicillin-susceptible and resistant strains. All tested hop compounds were shown to possess antimicrobial properties against all tested staphylococci, both planktonic and biofilm-dwelling, with no significant difference between resistant and susceptible strains. All compounds lowered the number of bacterial cells released from the biofilm, with the strongest effect seen for lupulone, followed by xanthohumol. Moreover, lupulone and xanthohumol were not only able to penetrate the biofilm and reduce the number of bacteria within it, but their higher concentrations (~60 MUg/mL for xanthohumol and ~125 MUg/mL for lupulone) reduced the number of surviving bacterial cells to zero. PMID- 29407046 TI - The Evolving Epidemiology of Atherosclerotic Cardiovascular Disease in People with Diabetes. AB - Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of death and accounts for most deaths among individuals with diabetes. This article reviews the latest observational and trial data on changes in the relationship between diabetes and ASCVD risk, remaining gaps in how the role of each risk factor is understood, and current knowledge about specific interventions. Differences between high-income countries and low-income and middle-income countries are examined, barriers and facilitators are discussed, and a discussion around the concept of ideal cardiovascular health factors (Life's Simple 7) is focused on. PMID- 29407047 TI - Heart Failure: Epidemiology, Pathophysiology, and Management of Heart Failure in Diabetes Mellitus. AB - This article briefly discusses the epidemiology of heart failure and diabetes and summarizes the key findings from the recent cardiovascular outcome trials in patients with type 2 diabetes, with a focus on heart failure as an endpoint. PMID- 29407048 TI - Personalizing Glucose-Lowering Therapy in Patients with Type 2 Diabetes and Cardiovascular Disease. AB - Twelve drug categories are marketed in the United States to lower blood glucose concentrations in type 2 diabetes mellitus (T2DM). After metformin, there is disagreement about the optimal next choice for combination therapy. Guidelines advise balancing potency, risks, benefits, and costs. For T2DM and cardiovascular disease (CVD), emerging evidence suggests that certain options may have specific advantages. Specific members of the thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, and glucagon-like peptide-1 receptor agonist classes have been associated with significant reductions in major adverse cardiovascular events, generally in those with established CVD. A personalized approach should consider these evidence-based therapies to optimize clinical outcomes. PMID- 29407049 TI - Managing Dyslipidemia in Type 2 Diabetes. AB - Cardiovascular disease is the most frequent cause of morbidity and mortality among individuals with diabetes and although there has been significant reduction in excess risk, these individuals remain at least twice as likely to sustain atherosclerotic events. Aggressive management of traditional factors, such as dyslipidemia, remains the cornerstone of risk mitigation. Diabetes and its associated insulin resistance generate qualitative and quantitative changes in lipid profile, which complicate effective treatment. This review summaries the background to diabetic dyslipidemia and provides a precis of the available management options. PMID- 29407050 TI - Blood Pressure Control and Cardiovascular/Renal Outcomes. AB - Hypertension is an important and modifiable risk factor for the macrovascular and microvascular complications of diabetes. Prior literature outlines the significance of lowering blood pressure and subsequent cardiovascular and microvascular benefits. Blood pressure targets of less than 140/90 mm Hg are recommended in all adults with diabetes, with lower blood pressure targets of less than 130/80 mm Hg beneficial for those with higher cardiovascular disease risk. Treatment to lower blood pressure is primarily based on a foundation of lifestyle modifications, low sodium diet, exercise, and good sleep hygiene coupled with multiple medication classes such as renin angiotensin system inhibitors. PMID- 29407051 TI - Hyperglycemia in Acute Coronary Syndromes: From Mechanisms to Prognostic Implications. AB - Numerous studies have documented that hyperglycemia is frequent in patients hospitalized with acute coronary syndromes, affects patients with and without established diabetes, and is associated with adverse outcomes, with incremental increase in risk of mortality and complications observed across the spectrum of glucose elevations. This article reviews present knowledge about the association between glucose levels and outcomes of patients hospitalized with acute coronary syndromes; describes available data regarding inpatient glucose management in this patient group, and comparative data across the spectrum of critically ill hospitalized patients; addresses some controversies in this field; and offers practical recommendations for patient management based on existing data. PMID- 29407053 TI - Antiplatelet Therapy in Diabetes. AB - Cardiovascular disease (CVD) is a significant cause of morbidity and mortality among patients with diabetes mellitus (DM). Increased platelet reactivity among patients with DM contributes to disproportionately high levels of atherothrombotic CVD. Consequently, there has been tremendous interest in exploring the role of antiplatelet therapies in DM to reduce the development of and frequency of future cardiovascular events. PMID- 29407052 TI - Perioperative Management of Hyperglycemia and Diabetes in Cardiac Surgery Patients. AB - Perioperative hyperglycemia is common after cardiac surgery, reported in 60% to 90% of patients with diabetes and in approximately 60% of patients without history of diabetes. Many observational and prospective randomized trials in critically-ill cardiac surgery patients support a strong association between hyperglycemia and poor clinical outcome. Despite ongoing debate about the optimal glucose target, there is strong agreement that improved glycemic control reduces perioperative complications. PMID- 29407056 TI - Pathogenesis of Cardiovascular Disease in Diabetes. AB - The most common cause of death among adults with diabetes is cardiovascular disease (CVD). In this concise review on pathogenesis of CVD in diabetes, the 4 common conditions, atherosclerosis, microangiopathy, diabetic cardiomyopathy, and cardiac autonomic neuropathy, are explored and illustrated to be caused by interrelated pathogenetic factors. Each of these diagnoses can present alone or, commonly, along with others due to overlapping pathophysiology. Although the spectrum of physiologic abnormalities that characterize the diabetes milieu is broad and go beyond hyperglycemia, the authors highlight the most relevant evidence supporting the current knowledge of potent factors that contribute to CVD in diabetes. PMID- 29407054 TI - Managing Diabetes and Cardiovascular Risk in Chronic Kidney Disease Patients. AB - We discuss mechanisms of increased cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and strategies for managing cardiovascular (CV) risk in these patients. Our focus was mainly on decreasing CV events and progression of microvascular complications by reducing levels of glucose and lipids. We searched PubMed with no limit on the date of the article. All articles were discussed among all authors. We chose pertinent articles, and searched their references in turn for additional relevant publications. PMID- 29407057 TI - Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes Mellitus: Implications of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 30-Year Follow-up. AB - Type 1 diabetes mellitus, an autoimmune disorder characterized by beta-cell destruction and absolute insulin deficiency, is associated with significantly increased cardiovascular disease risk but the mechanisms underlying this enhanced risk are unclear. Results of the pivotal Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study have shown that compared to conventional therapy, intensive glycemic control results in decreased cardiovascular morbidity and mortality. Evidence from this study also revealed contributions of blood pressure, renal disease, body weight, and lipids to cardiovascular disease in type 1 diabetes mellitus. Extrapolating from existing evidence, this article addresses clinical strategies to mitigate cardiovascular risks. PMID- 29407058 TI - Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes Mellitus. AB - People with type 2 diabetes mellitus are at high risk of morbidity and mortality from cardiovascular disease (CVD). Based on observed relationships between hyperglycemia and CVD, several large clinical trials have investigated the ability of treatment strategies to achieve hemoglobin A1c less than 7% (53 mmol/mol) as a way of reducing this risk. These studies demonstrate that intensified glycemic therapy may reduce CVD risk in younger patients with recent onset type 2 diabetes mellitus but not in high-risk older individuals with established disease. Attention to blood pressure and lipid-lowering therapies with modified glycemic goals for older high-risk individuals is recommended. PMID- 29407055 TI - Prediabetes and Cardiovascular Disease: Pathophysiology and Interventions for Prevention and Risk Reduction. AB - Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. This review discusses the pathophysiology and macrovascular complications of prediabetes. The pathophysiologic defects underlying prediabetes include insulin resistance, alpha- and beta-cell dysfunction, increased lipolysis, inflammation, and suboptimal incretin effect. Recent studies have revealed that the long-term complications of diabetes manifest in some people with prediabetes; these complications include microvascular and macrovascular disorders. Finally, we present an overview of randomized control trials aimed at preventing progression from prediabetes to type 2 diabetes and discuss their implications for macrovascular risk reduction. PMID- 29407059 TI - Cardiovascular Outcomes Trials of Glucose-Lowering Drugs or Strategies in Type 2 Diabetes. AB - As recently as 20 years ago there were no randomized controlled trials of potentially cardiovascular protective therapies in people with type 2 diabetes. The ongoing cardiovascular trials bring needed evidence. Both primary and subsidiary analyses have transformed diabetes from a largely eminence based specialty to one that is firmly evidence based. These studies have provided evidence supporting glucose-lowering drugs for patients with cardiovascular risk factors. Randomized controlled trials such as those described here will continue to challenge assumptions and create new approaches and paradigms that can be pursued to reduce and hopefully eliminate serious cardiovascular and other consequences of diabetes. PMID- 29407065 TI - Diabetes and Atherosclerotic Cardiovascular Disease. PMID- 29407066 TI - Diabetes and Atherosclerotic Cardiovascular Disease: Novel Insights and Therapeutic Strategies. PMID- 29407067 TI - Introducing...ImageGuideEcho! PMID- 29407070 TI - Incorporating Vascular Imaging Training into the Cardiology Fellowship Curriculum. PMID- 29407069 TI - Council on Cardiovascular Sonography Review of the Recently Released ASE Statement on Sonographer Involvement in the Performance of TEE. PMID- 29407071 TI - Amputation versus conservative treatment in severe open lower-limb fracture: A functional and quality-of-life study. AB - INTRODUCTION: Severe lower-limb trauma is a major event in a patient's life, and treatment is a challenge that has not been sufficiently studied. The main objective of the present study was to assess the difference in disability between amputees and patients who kept their leg after severe open lower-limb fracture. HYPOTHESIS: The study hypothesis was that amputation allows better functional recovery and quality of life, in the same time-frame. MATERIALS AND METHODS: All male and female patients aged over 18 years admitted to one of the trauma centers of Marseille (France) for major lower-limb trauma with Gustilo IIIb or IIIc fracture were included. Minimum follow-up was 2 years. Two groups were distinguished according to primary treatment: lower-limb salvage, or amputation. Rates of infection and of surgical revision, hospital stay, functional parameters (walking distance, standing, use of canes, running, jumping, driving, and physical and occupational activity) and quality of life (MOS SF-36 score) were compared between groups. RESULTS: The conservative treatment group comprised 27 patients, and the amputation group 24. Rates of infection and of surgical revision and hospital stay were significantly lower in the amputation group (P<0.02). All functional parameters (except return to work) and overall quality of life were significantly better in the amputation group. There was no significant inter-group difference in MOS mental score. CONCLUSION: In severe lower-limb trauma, amputation seems to give better functional and quality-of-life results. It did not, however, improve return to work, and was not better accepted psychologically than long and complex conservative management. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 29407072 TI - Poor outcomes of fusion with Trabecular Metal implants after failed total ankle replacement: Early results in 11 patients. AB - INTRODUCTION: One of the reasons for revision of total ankle replacement (TAR) implants is loosening due to subchondral cysts. Reconstruction and fusion of the ankle is often the first choice for revision procedures due to the large bone defects, which are typically filled with autograft and/or allograft. Filling the defect with a trabecular metal tantalum implant is a potential alternative given the biomechanical properties of this component. HYPOTHESIS: Using tantalum as a spacer provides primary stability and contributes to fusion of the ankle joint after removal of failed TAR implants. METHODS: Eleven patients underwent arthrodesis an average of 6.9 years after TAR. The mean height of the bone defect was 32mm. It was filled with a specially designed quadrangular implant (Trabecular MetalTM, Zimmer/Biomet) combined with an iliac crest graft. Ten patients underwent tibio-talo-calcaneal (TTC) arthrodesis fixed with an angled retrograde nail and one patient underwent talocrural arthrodesis fixed with two plates (anterolateral and anteromedial). The clinical, functional (AOFAS and SF36 scores) and radiological (plain X-rays and CT scan) outcomes were determined. RESULTS: At a mean follow-up of 19.3 months, the mean total AOFAS score was 56 (21-78) and the mean SF36 score was 60.5 (19-84). One patient was lost to follow up and four patients still had pain. The tantalum implant was integrated in six patients. Five patients achieved fusion of the subtalar joint and 8 achieved fusion of the talocrural joint. Three patients required surgical revision. DISCUSSION: Our hypothesis was not confirmed. The clinical outcomes after more than 1 year of follow-up are disappointing, as was the large number of nonunion cases and the lack of tantalum integration. These technical failures can be explained by insufficient construct stability and/or insufficient implant porosity. LEVEL OF EVIDENCE: IV (retrospective cohort study). PMID- 29407073 TI - Maurice Green - A pioneering virologist. PMID- 29407074 TI - Corrigendum to " A critical sp1 element in the rhesus rhadinovirus (RRV) Rta promoter confers high-level activity that correlates with cellular permissivity for viral replication" [Virology 448 (2014) 196-209]. PMID- 29407075 TI - Corrigendum to: "KSHV attachment and entry are dependent on alphaVbeta3 integrin localized to specific cell surface microdomains and do not correlate with the presence of heparan sulfate" [Virology 464-465 (2014) 118-133]. PMID- 29407076 TI - The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: A systematic review and meta-analysis. AB - AIMS: Coronary vascular dysfunction is linked with poor cardiovascular prognosis in patients without obstructive coronary artery disease (CAD) but a critical appraisal of the literature is lacking. METHODS AND RESULTS: We performed a systematic review and meta-analysis to quantify the cardiovascular risk associated with endothelial dependent and non-endothelial dependent coronary vascular dysfunction in patients with normal or non-obstructive CAD (epicardial stenosis <50%). Prospective cohort studies that reported coronary vascular dysfunction at baseline and cardiovascular outcomes at follow-up were included. We identified 52 papers of which 26 were included in the meta-analyses. Study populations included stable angina (n=15), heart failure (n=4), diabetes (n=2), hypertrophic obstructive cardiomyopathy (n=2), chronic kidney disease, aortic stenosis and left atrial enlargement (each n=1): RR estimates were similar in patients with stable angina and other patient groups. For epicardial endothelial dependent dysfunction (six studies, 243 events in 1192 patients) the summarized RR was 2.38 (95% confidence intervals (95% CI) 1.74-3.25), for non-endothelial dependent dysfunction assessed as coronary flow velocity reserve (CFVR) by echocardiography (10 studies, 428 events in 5134 patients) RR was 4.58 (95% CI 3.58-5.87) and for coronary flow reserve (CFR) by PET (10 studies, 538 events in 3687 patients) RR was 2.44 (95% CI 1.80-3.30). However, RR estimates were robust in a series of sensitivity analyses. CONCLUSION: The presence of coronary vascular dysfunction in patients with normal or non-obstructive CAD predicts adverse cardiovascular outcome. Multicentre studies and uniform guidelines for assessing coronary vascular dysfunction are encouraged. PMID- 29407077 TI - Development and external validation of a post-discharge bleeding risk score in patients with acute coronary syndrome: The BleeMACS score. AB - BACKGROUND: Accurate 1-year bleeding risk estimation after hospital discharge for acute coronary syndrome (ACS) may help clinicians guide the type and duration of antithrombotic therapy. Currently there are no predictive models for this purpose. The aim of this study was to derive and validate a simple clinical tool for bedside risk estimation of 1-year post-discharge serious bleeding in ACS patients. METHODS: The risk score was derived and internally validated in the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registry, an observational international registry involving 15,401 patients surviving admission for ACS and undergoing percutaneous coronary intervention (PCI) from 2003 to 2014, engaging 15 hospitals from 10 countries located in America, Europe and Asia. External validation was conducted in the SWEDEHEART population, with 96,239 ACS patients underwent PCI and 93,150 without PCI. RESULTS: Seven independent predictors of bleeding were identified and included in the BleeMACS score: age, hypertension, vascular disease, history of bleeding, malignancy, creatinine and hemoglobin. The BleeMACS risk score exhibited a C-statistic value of 0.71 (95% CI 0.68-0.74) in the derivation cohort and 0.72 (95% CI 0.67-0.76) in the internal validation sample. In the SWEDEHEART external validation cohort, the C-statistic was 0.65 (95% CI 0.64-0.66) for PCI patients and 0.63 (95% CI 0.62-0.64) for non-PCI patients. The calibration was excellent in the derivation and validation cohorts. CONCLUSIONS: The BleeMACS bleeding risk score is a simple tool useful for identifying those ACS patients at higher risk of serious 1-year post-discharge bleeding. ClinicalTrials.govIdentifier: NCT02466854. PMID- 29407078 TI - Long term survival of hypoplastic left heart syndrome infants: Meta-analysis comparing outcomes from the modified Blalock-Taussig shunt and the right ventricle to pulmonary artery shunt. AB - BACKGROUND: Stage 1 palliation of hypoplastic left heart syndrome (HLHS) involves the Norwood procedure combined with a modified Blalock-Taussig shunt (mBTS) or right ventricle to pulmonary artery shunt (RVPAS). Short-term survival has been described previously, whereas longer-term outcomes remain a subject of debate. This meta-analysis aimed to describe the short and long-term survival outcomes of these two shunts, and explore factors that might influence survival. METHODS: Medline, Cochrane Libraries and EMBASE were systematically searched, and 32 studies were included for statistical synthesis, comprising 1348 mBTS and 1258 RVPAS patients. RESULTS: While early in-hospital survival was superior in the RVPAS group (RR=1.5, p<0.05, 95% CI: 1.21-1.85), this difference was lost from 2years post-stage 1 palliation (RR=0.91, p>0.05, 95% CI: 0.79-1.04), and maintained unchanged up to 6years. This shift in survival was also reflected in inter-stage survival, with superior RVPAS outcomes between stage 1 and 2 (RR=1.62, p<0.05, 95% CI: 1.39-1.88), and equivalent outcomes between stage 2 and 3. Potential contributors to this included a significantly higher rate of pulmonary artery stenosis in the RVPAS group and an increased requirement for shunt re-intervention in this group prior to stage 2. CONCLUSIONS: Despite early advantages, RVPAS and mBTS for palliation of hypoplastic left heart syndrome produced comparable long-term survival. The RVPAS patients experienced more pulmonary artery stenosis and requirement for shunt re-intervention. The impact of shunt type on quality and survival with a Fontan is yet to be assessed. PMID- 29407079 TI - Identification, risk assessment, and management of patients with atrial fibrillation in a large primary care cohort. AB - BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of cardiovascular disease (CVD) complications including stroke. We investigated the assessment and management of cardiovascular risk among patients with AF aged 35 74years, by ethnic group, in a large cohort of people receiving a CVD risk assessment in primary care (PREDICT). METHODS: PREDICT was linked to national dispensing, hospitalisation and mortality records. AF was present if recorded in PREDICT or during a prior hospitalisation; medications were those dispensed <=6months before or after a PREDICT assessment; the CHA2DS2-VASc score and a New Zealand (NZ) adjusted Framingham CVD risk were calculated. Data were linked to outcomes of stroke or major adverse cardiovascular event (MACE). RESULTS: 12,739 (2.8%) of 447,020 people aged 35-74years had AF. Maori, the indigenous population of NZ, had the highest proportion of AF, which by age group, was similar to that among Europeans 10years older. 77% were at high stroke risk, of whom 42% received anticoagulation; 54% were at high CVD risk, of whom 67% received both lipid- and blood pressure-lowering medication. Per category of predicted risk, stroke risk was overestimated and risk of MACE was underestimated. CONCLUSIONS: The burden of AF and risk factors differed by ethnic group thus recommendations to screen for AF above a universal age threshold may introduce inequity in the detection and management of associated risk. The high burden of comorbidities at younger ages among many ethnic groups contributes to the poor performance of available risk assessment tools, further compounding potential inequity. PMID- 29407080 TI - Arterial hypertension in patients with atrial fibrillation in Europe: A report from the EURObservational Research Programme pilot survey on atrial fibrillation. AB - BACKGROUND: Hypertension (HTN) is the most prevalent co-morbidity among atrial fibrillation (AF) patients; the relationship between the two is bidirectional, with an incremental effect on adverse outcomes. PURPOSE: To study clinical features, treatment patterns and 1year outcomes amongst AF patients with HTN in the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry, a prospective multi-national survey conducted by the European Society of Cardiology in 9 European countries. METHODS: Of 3119 enrolled AF patients, 2194 were diagnosed with HTN (AF-HTN) and 909 were normotensive (AF-NT) (16 patients had unknown HTN status). We compared baseline clinical features, management strategy and 1-year outcomes in terms of all-cause death, cardiovascular (CV) death, and any thrombosis-related event (TE: stroke, transient ischemic attack, acute coronary syndrome, coronary intervention, cardiac arrest, peripheral/pulmonary embolism) in AF-HTN vs AF-NT patients. RESULTS: The AF-HTN patients had more prevalent CV risk factors and comorbidities (median CHA2DS2-VASc score (IQR) 4 (3, 5) in AF-HTN, versus 2 (1, 3) in AF-NT; p<0.01). Crude rate of all-cause death and any TE event was higher in AF-HTN (194 (11.2%) versus 60 (8.2%), p=0.02). Kaplan-Meier analysis curves for death by hypertensive status showed no significant differences between the subgroups (log rank test, p=0.22). On logistic regression analysis, HTN did not emerge as an independent risk factor for outcomes (OR 1.08, 95% CI 0.76-1.54). CONCLUSION: AF HTN patients have a higher prevalence of comorbidities and this conferred a higher risk for a composite endpoint of all-cause death and thromboembolic events. In this cohort HTN did not independently predict all-cause mortality at 1 year. PMID- 29407081 TI - Major bleeding and intracranial hemorrhage risk prediction in patients with atrial fibrillation: Attention to modifiable bleeding risk factors or use of a bleeding risk stratification score? A nationwide cohort study. AB - BACKGROUND: While modifiable bleeding risks should be addressed in all patients with atrial fibrillation (AF), use of a bleeding risk score enables clinicians to 'flag up' those at risk of bleeding for more regular patient contact reviews. We compared a risk assessment strategy for major bleeding and intracranial hemorrhage (ICH) based on modifiable bleeding risk factors (referred to as a 'MBR factors' score) against established bleeding risk stratification scores (HEMORR2HAGES, HAS-BLED, ATRIA, ORBIT). METHODS: A nationwide cohort study of 40,450 AF patients who received warfarin for stroke prevention was performed. The clinical endpoints included ICH and major bleeding. Bleeding scores were compared using receiver operating characteristic (ROC) curves (areas under the ROC curves [AUCs], or c-index) and the net reclassification index (NRI). RESULTS: During a follow up of 4.60+/-3.62years, 1581 (3.91%) patients sustained ICH and 6889 (17.03%) patients sustained major bleeding events. All tested bleeding risk scores at baseline were higher in those sustaining major bleeds. When compared to no ICH, patients sustaining ICH had higher baseline HEMORR2HAGES (p=0.003), HAS BLED (p<0.001) and MBR factors score (p=0.013) but not ATRIA and ORBIT scores. When HAS-BLED was compared to other bleeding scores, c-indexes were significantly higher compared to MBR factors (p<0.001) and ORBIT (p=0.05) scores for major bleeding. C-indexes for the MBR factors score was significantly lower compared to all other scores (De long test, all p<0.001). When NRI was performed, HAS-BLED outperformed all other bleeding risk scores for major bleeding (all p<0.001). C indexes for ATRIA and ORBIT scores suggested no significant prediction for ICH. CONCLUSION: All contemporary bleeding risk scores had modest predictive value for predicting major bleeding but the best predictive value and NRI was found for the HAS-BLED score. Simply depending on modifiable bleeding risk factors had suboptimal predictive value for the prediction of major bleeding in AF patients, when compared to the HAS-BLED score. PMID- 29407082 TI - Late arrhytmias after repair of atrioventricular septal defect: Down's Syndrome is not the culprit. PMID- 29407083 TI - Optimizing bleeding risk assessment in patients with atrial fibrillation: To score or not to score? PMID- 29407084 TI - The dangerous combination of atrial fibrillation and hypertension: An urgent need to handle complexity. PMID- 29407085 TI - Drug-induced type 1 Brugada ECG: Lights and shadows. PMID- 29407086 TI - Are NOACs safer than phenprocoumon in patients undergoing pulmonary vein isolation with the cryoballoon technique using purse-string suture closure? PMID- 29407087 TI - Atrial fibrillation in the setting of takotsubo cardiomyopathy: Just the tip of the iceberg? PMID- 29407088 TI - Programmed ventricular stimulation predicts arrhythmic events and survival in hypertrophic cardiomyopathy. AB - BACKGROUND: Sudden cardiac death (SCD) risk stratification in hypertrophic cardiomyopathy (HCM) in the context of primary prevention remains suboptimal. The purpose of this study was to examine the additional contribution of programmed ventricular stimulation (PVS) on established risk assessment. METHODS: Two hundred-and-three consecutive patients with diagnosed HCM and >=1 noninvasive risk factors were prospectively enrolled over 19years. Patients were risk stratified, submitted to PVS and received an implantable cardioverter defibrillator (ICD) according to then-current American Heart Association (AHA) guidelines and inducibility. Participants were prospectively followed-up for primary endpoint occurrence (appropriate ICD therapy or SCD). Contemporary (2015) AHA and European Society of Cardiology (ESC) guidelines were retrospectively assessed. RESULTS: During a median follow-up period of 60months the primary endpoint occurred in 20 patients, 19 of whom were inducible and received an ICD. Overall, 79 patients (38.9%) were inducible and 92 patients (45.3%) received an ICD (PVS sensitivity=95%, specificity=67.2%, positive predictive value=24%, negative predictive value=99.2%). AHA and ESC guidelines application misclassified 3 and 9 primary endpoint-meeting patients, respectively. Inducibility was the most important determinant of event-free survival in multivariate Cox regression (hazard ratio=33.3). A combined approach of ESC score>=6% or AHA indication for ICD with PVS inducibility yielded absolute sensitivity and negative predictive value, the former at a more cost-effective and specific way. CONCLUSIONS: Inducibility at PVS predicts SCD or appropriate device therapy in HCM. Non-inducibility is associated with prolonged event-free survival, while the procedure was proven safe. Reintegration of PVS into established risk stratification models in HCM may improve patient assessment. PMID- 29407089 TI - Basal functional status predicts one-year mortality after a heart failure hospitalization in elderly patients - The RICA prospective study. AB - BACKGROUND: Dependence for basic activities of the daily living (ADL) relates to adverse outcomes in elderly acute heart failure (AHF) patients. METHODS: We evaluated patients >=75years admitted because of AHF, divided according to preadmission Barthel Index (BI) category: severe (BI 0-60), moderate (BI 61-90) and slight dependence or independence for basic ADL (BI 91-100). We compared their baseline characteristics and used logistic regression models to determine whether a BI<=60 confers higher one-year mortality risk. RESULTS: We included 2195 patients, mean age 83years; 57% women, Charlson Index 3, 65% with preserved left ventricular ejection fraction. Their median preadmission BI was 90 (65-100); 21.7% had BI<=60. Patients with BI<=60 were older, more often females, with higher comorbid and cognitive burden and more likely to be institutionalized. 560 patients (26%) died within the follow-up period. A preadmission BI<=60 was significantly associated with higher risk of 12-month mortality (HR 1.42, 95% CI 1.14-1.77) together with male sex (1.27, 1.04-1.54), valve disease (1.49, 1.20 1.83), worse preadmission NYHA class (1.44, 1.20-1.73), stage IV chronic kidney disease (1.70, 1.35-2.15), pulmonary edema (1.33, 1.01-1.76), no family support (1.47, 1.06-2.06), and higher Charlson Comorbidity Index (1.09, CI 1.05-1.13) and Pfeiffer cognitive screening questionnaire scores (1.10, 1.05-1.14). CONCLUSION: Among elderly AHF patients, the presence of severe (BI<=60) preadmission dependence for basic ADL confers a significant and independent risk of one-year post-discharge mortality. PMID- 29407090 TI - Long-term prognostic significance of urinary sodium concentration in patients with acute heart failure. AB - BACKGROUND: Lower urinary sodium concentration (UNa) may reflect impaired renal perfusion, higher neurohormonal activity and diuretic resistance. However, the prognostic impact of UNa in patients with acute heart failure (AHF) has not been fully elucidated. METHODS: We investigate the association between UNa and clinical outcomes in 669 patients admitted with AHF in our prospective registry. Patients were stratified into tertiles based on UNa in a spot urine sample on admission. RESULTS: Patients with lower UNa were more likely to have a history of prior heart failure admission, beta-blockers and diuretics use, and had lower blood pressure and serum sodium level, and higher blood urea nitrogen, estimated glomerular filtration rate, blood glucose and troponin T levels on admission than those with higher UNa. Plasma renin activity, aldosterone, cortisol and dopamine levels were also significantly higher in patients with lower UNa (all p<0.001). Furthermore, patients with lower UNa had significantly less weight loss, lower net fluid loss/furosemide equivalent dose and higher incidence of worsening renal function during hospitalization than those with higher UNa (all p<0.01). During a median follow-up period of 560days, lower UNa was significantly associated with the composite of all-cause death and worsening heart failure (p<0.001). In multivariable Cox-proportional hazards model, UNa remained an independent determinant of long-term adverse events (HR, 1.24, 95% CI, 1.06-1.45, p=0.006). CONCLUSIONS: Lower UNa was associated with worse long-term clinical outcomes along with increased neurohormonal activities, impaired response to diuretics and higher incidence of worsening renal function in patients with AHF. PMID- 29407091 TI - Estradiol protection against toxic effects of catecholamine on electrical properties in human-induced pluripotent stem cell derived cardiomyocytes. AB - BACKGROUND AND PURPOSE: Previous studies revealed that Takotsubo cardiomyopathy (TTC), a transient disorder of ventricular dysfunction affecting predominantly postmenopausal women, is associated with acquired long QT syndrome and arrhythmias, but the exact pathophysiologic mechanism is unknown. Our aim is to investigate the electrophysiological mechanism for QT-prolongation in TTC patients by using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: hiPSC-CMs, which were generated from human skin fibroblasts of three healthy donors, were treated by estradiol (10MUM for one week) and a toxic concentration of isoprenaline (Iso, 1mM for 2h). Patch clamp techniques, qPCR and fluorescence-activated cell sorting (FACS) were employed for the study. KEY RESULTS: Iso enhanced late INa and suppressed Ito and thus prolonged the action potential duration (APD), suggesting possible reasons for arrhythmias in TTC. Iso elevated the production of reactive oxygen species (ROS). N acetylcystein (1mM), a ROS-blocker, abolished the effects of Iso on late INa and Ito. H2O2 (100MUM) mimicked Iso effects on late INa and Ito. These data indicate that the effects of Iso were mediated by ROS. Metoprolol (1mM), a beta-blocker, prevented the effects of Iso on late INa and APD, confirming the adrenoceptor dependent effects of Iso. Estradiol treatment prevented the APD-prolongation, attenuated the enhancement of INa, diminished the reduction of Ito, suppressed ROS-production induced by Iso and reduced the expression levels of adrenoceptors, suggesting protective effects of estragon against toxic effects of catecholamine. CONCLUSIONS: Estradiol has protective effects against catecholamine excess and hence reduction in estrogen level may increase the risk of acquired long QT syndrome in TTC. PMID- 29407092 TI - Different relationships between pulse pressure and mortality in heart failure with reduced, mid-range and preserved ejection fraction. AB - OBJECTIVES/BACKGROUND: In heart failure (HF), pulse pressure (PP) may reflect both vascular stiffness and left ventricular function, but its prognostic role in relation to ejection fraction (EF) is poorly understood. METHODS: In the Swedish Heart Failure Registry, we investigated the association between PP and 1-year mortality in patients with HF and reduced (HFrEF, <40%), mid-range (HFmrEF, 40 49%) and preserved EF (HFpEF, >=50%), using multivariable logistic regression and restricted cubic splines. RESULTS: Among 36,770 patients discharged alive or enrolled as out-patients with 1-year follow-up (mean age 74+/-12years, 63% men, 56% HFrEF, 21% HFmrEF, 23% HFpEF), crude one-year mortality was 18%. Mean PP increased across EF groups: 51+/-16 in HFrEF, 57+/-18 in HFmrEF, 60+/-19mmHg in HFpEF. In crude regression splines, the association between PP and mortality was U-shaped in HFmrEF and HFpEF, but curvilinear with only low PP associated with mortality in HFrEF. In multivariable analyses, a significant interaction by EF group and PP was observed (pinteraction=0.015): low PP was associated with higher mortality in HFrEF (adjusted OR [1st vs. 4th quintile]=1.40, 95% CI 1.18-1.67) and HFpEF (1.43, 1.14-1.81) but only by trend in HFmrEF; high PP had a trend towards higher mortality in HFmrEF (5th vs. 3rd quintile=1.30, 1.00-1.69) and HFpEF (1.25, 0.98-1.61). CONCLUSIONS: The association between PP and mortality in HF was influenced by EF. Low PP was independently associated with mortality in HFrEF and HFpEF and by trend in HFmrEF. High PP was independently associated with mortality by trend in HFmrEF and HFpEF. PMID- 29407093 TI - Evolution of natriuretic peptide biomarkers in heart failure: Implications for clinical care and clinical trials. AB - Natriuretic peptides (NPs) are recommended by international guidelines to exclude non-heart failure causes of acute dyspnea and to assess prognosis. NPs are commonly used as an entry criterion for clinical trials, to minimize enrollment of misdiagnosed patients, or to ensure enrollment of a sufficiently at-risk population. NP values used to select trial populations to date have been inconsistent across studies. Future trials should consider using standardized thresholds for NP levels, with protocol-specified adaptations appropriate for the specific study and patient population to account for factors that can influence the NP level. NPs have been used as an endpoint for proof-of-concept or phase 2 clinical trials, although it is important to remember that positive results in early phase studies may be unstable due to small numbers and the play of chance, and they are not always reproducible in phase 3 trials. Likewise, failure to reduce NP in phase 2 may not necessarily indicate that a drug will be ineffective on clinical outcomes in phase 3. NP guided therapy has been intensively studied, but the clinical outcome benefits of this approach remain uncertain. Neprilysin inhibitors have stimulated further exploration of the NP system and how it influences, and is potentially influenced by, heart failure therapies. This paper discusses the utility of NPs in the current clinical research and practice environment and addresses areas in need of further research from the perspectives of academic clinical trialists, clinicians, biostatisticians, regulators, and pharmaceutical industry scientists who participated in the 13th Global Cardiovascular Clinical Trialists Forum. PMID- 29407094 TI - Addition or removal of guideline directed medical therapy in ambulatory patients with heart failure with reduced ejection fraction relative to change in symptom severity: An analysis from the PINNACLE (Practice Innovation and Clinical Excellence) Registry(r). PMID- 29407095 TI - Determinants of exercise intolerance in heart failure with preserved ejection fraction: A systematic review and meta-analysis. AB - BACKGROUND: Severe exercise intolerance (EI), demonstrated by impaired peak oxygen consumption, intrinsically characterizes heart failure with preserved ejection fraction (HFpEF). Controversy exists on the determinants of EI in patients with HFpEF according to case-control studies. The purpose of this study is to systematically review and clarify the main (Fick) determinants of EI in HFpEF. METHODS: We conducted a systematic search of MEDLINE, Scopus and Web of Science since their inceptions until January 2017 for articles assessing peak cardiac output and/or arteriovenous oxygen difference (a-vO2diffpeak) with incremental exercise in patients diagnosed with HFpEF and age-matched control individuals. Meta-analyses were performed to determine the standardized mean difference (SMD) in peak cardiac index (CIpeak) and a-vO2diffpeak between HFpEF and control groups. Subgroup and meta-regression analyses were used to evaluate potential moderating factors. RESULTS: Ten studies were included after systematic review, comprising a total of 213 HFpEF patients and 179 age-matched control individuals (mean age=51-73years). After data pooling, CIpeak (n=392, SMD=-1.42; P<0.001) and a-vO2diffpeak (n=228, SMD=-0.52; P=0.002) were impaired in HFpEF patients. In subgroup analyses, a-vO2diffpeak was reduced in HFpEF versus healthy individuals (n=114, SMD=-0.85; P<0.001) but not compared with control patients without heart failure (n=92, SMD=-0.12; P=0.57). The SMD in a-vO2diffpeak was negatively associated with age (B=-0.05, P=0.046), difference in % females (B= 0.01, P=0.026) and prevalence of hypertension (B=-0.01, P=0.015) between HFpEF and control groups. CONCLUSIONS: HFpEF is associated with a predominant impairment of CIpeak, accompanied by sex- and comorbidity-dependent reduced oxygen extraction at peak exercise. PMID- 29407096 TI - Impact of Late Gadolinium Enhancement on mortality, sudden death and major adverse cardiovascular events in ischemic and nonischemic cardiomyopathy: A systematic review and meta-analysis. AB - BACKGROUND: The central role of left ventricular ejection fraction (LVEF) as the definitive risk marker of adverse outcomes in ischemic and nonischemic cardiomyopathy is increasingly uncertain. The current study aimed to conduct a systematic review and meta-analysis with the objective of evaluating the prognostic importance of Late Gadolinium Enhancement (LGE) in ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM) on the key endpoints of all-cause mortality, cardiovascular mortality and sudden death. METHODS: The study was prospectively registered in PROPSERO (CRD 42016039034). Electronic databases and reference lists were searched for studies evaluating the impact of LGE-CMR on all-cause mortality, cardiovascular mortality, ventricular arrhythmia or sudden death, or major adverse cardiovascular events. Data were extracted from 36 studies including n=7882 patients. RESULTS: LGE was strongly associated with all-cause mortality HR 2.96 (95%CI: 2.37, 3.70, P<0.001), cardiovascular mortality HR 3.27 (95% CI: 2.05, 5.22, P<0.001), ventricular arrhythmia and sudden cardiac death HR 3.76 (95% CI: 3.14, 4.52, P<0.001), and major adverse cardiovascular events HR 3.24 (95% CI: 2.32, 4.52, P<0.001). In subgroup analyses, LGE was associated with all-cause mortality and cardiovascular mortality in both LVEF<=35% and LVEF>35% patients (P<0.001 all endpoints), as well as in nonischemic and ischemic cardiomyopathy. CONCLUSION: Late Gadolinium Enhancement (LGE) in CMR predicts all-cause mortality, cardiovascular mortality, ventricular arrhythmia and sudden death, and major adverse cardiovascular events, independent of LVEF. Future trials of investigational therapies in NICM and ICM should consider the utilization of LGE to identify patients at risk of adverse outcomes. PMID- 29407097 TI - Was a mistake made when programmed electrical stimulation was eliminated as a sudden death risk marker in hypertrophic cardiomyopathy? PMID- 29407098 TI - The Barthel Index in elderly acute heart failure patients. Frailty matters. PMID- 29407099 TI - Underprescription of disease-modifying drugs in chronic heart failure: More is better? PMID- 29407100 TI - Urinary sodium excretion in acute heart failure: Interaction between heart and kidney. PMID- 29407101 TI - Effect of sex hormones in Takotsubo cardiomyopathy: Just matter of arrhythmias or also outcomes? PMID- 29407102 TI - Exercise intolerance in heart failure with preserved ejection fraction: A reappraisal of central mechanisms? PMID- 29407103 TI - The gap in heart failure: Understanding pulse pressure across heart failure phenotypes in the real world. PMID- 29407104 TI - Natriuretic peptides. D'ou venons-nous? Que sommes-nous? Ou allons-nous? PMID- 29407105 TI - Vascular expansion during worsening of heart failure: Effects on clinical features and its determinants: Methodological issues to avoid misinterpretation. PMID- 29407106 TI - Pleiotropic effects and biological activities of atorvastatin: The sun never set. PMID- 29407107 TI - Protection against reperfusion injury by 3',4'-dihydroxyflavonol in rat isolated hearts involves inhibition of phospholamban and JNK2. AB - BACKGROUND: Flavonols, including 3',4'-dihydroxyflavonol (DiOHF), reduce myocardial ischemia and reperfusion (I/R) injury but their mechanism remains uncertain. To better understand the mechanism of the cardioprotective actions of flavonols we investigated the effect of DiOHF on cardiac function and the activation of protective and injurious signalling kinases after I/R in rat isolated hearts. METHODS: We assessed the effect of global ischemia (20min) and reperfusion (5-30min) on cardiac function and injury in rat isolated, perfused hearts in the absence or presence of DiOHF (10MUM) during reperfusion. Western blotting was used to assess changes in the phosphorylation state of kinases known to be involved in injury or protection. RESULTS: DiOHF improved cardiac contractility and reduced perfusion pressure and cell death in the isolated hearts. Phosphorylation of p38MAPK and CaMKII increased during ischemia with no further increase during reperfusion. Phosphorylation of other kinases increased during reperfusion. Phosphorylation of phospholamban (PLN) peaked at 5min of reperfusion whereas phosphorylation of Akt, Erk, STAT3 and JNK2 was highest after 30min. The presence of DiOHF during reperfusion significantly inhibited the activation of PLN and JNK without affecting phosphorylation of the protective kinases Erk1/2 and STAT3. Experiments in vitro demonstrated that DiOHF inhibited CaMKII by competing with ATP but not Ca2+/calmodulin. CONCLUSIONS: It is proposed that DiOHF confers protection against myocardial reperfusion injury by inhibiting CaMKII and subsequent PLN-induced leak of Ca2+ from the sarcoplasmic reticulum as well as by inhibiting JNK2 activation to reduce apoptosis. PMID- 29407108 TI - A 3-gene panel improves the prediction of left ventricular dysfunction after acute myocardial infarction. AB - BACKGROUND: Identification of patients at risk of poor outcome after acute myocardial infarction (MI) would allow tailoring healthcare to each individual. However, lack of prognostication tools renders this task challenging. Previous investigations suggested that blood transcriptome analysis may inform about prognosis after MI. We aim to independently confirm the value of gene expression profiles in the blood to predict left ventricular (LV) dysfunction after MI. METHODS AND RESULTS: Five genes (LMNB1, MMP9, TGFBR1, LTBP4 and TNXB) selected from previous studies were measured in peripheral blood samples obtained at reperfusion in 449 MI patients. 79 patients had LV dysfunction as attested by an ejection fraction (EF) <=40% at 4-month follow-up and 370 patients had a preserved LV function (EF>40%). LMNB1, MMP9 and TGFBR1 were up-regulated in patients with LV dysfunction and LTBP4 was down-regulated, as compared with patients with preserved LV function. The 5 genes were significant univariate predictors of LV dysfunction. In multivariable analyses adjusted with traditional risk factors and corrected for model overfitting, a panel of 3 genes - TNXB, TGFBR1 and LTBP4 - improved the prediction of a clinical model (p=0.00008) and provided a net reclassification index of 0.45 [0.23-0.69], p=0.0002 and an integrated discrimination improvement of 0.05 [0.02-0.09], p=0.001. Bootstrap internal validation confirmed the incremental predictive value of the 3-gene panel. CONCLUSION: A 3-gene panel can aid to predict LV dysfunction after MI. Further independent validation is required before considering these findings for molecular diagnostic assay development. PMID- 29407109 TI - A potential therapeutic approach to cardiac remodeling: JDP2. PMID- 29407111 TI - Endothelial cell and vascular smooth muscle cell dysfunction in chronic kidney disease. PMID- 29407110 TI - Chronic kidney disease is associated with vascular smooth muscle dysfunction but not with endothelial dysfunction. AB - BACKGROUNDS: Nitroglycerine-induced vasodilation (NID) is usually assessed as a control test for flow-mediated vasodilation (FMD). However, NID per se is impaired in patients with high cardiovascular risk. The purpose of this study was to investigate the associations of chronic kidney disease (CKD) with NID and FMD. METHODS: We measured NID and FMD in a total of 1567 adult subjects without end stage renal disease (ESRD), 28% of whom had CKD as judged by measurements of estimated glomerular filtration rate (995 men and 572 women; mean age, 59.0+/ 16.9years; age range, 18 to 92years). RESULTS: NID was significantly smaller in patients with CKD than in those without CKD (10.8+/-6.0% vs. 12.7+/-5.7%, P<0.001). The prevalence of vascular smooth muscle dysfunction, defined as NID of less than the division point for the lowest quartile, was significantly higher in patients with CKD than in those without CKD (37.5% vs. 21.5%, P<0.001). Multivariate analysis revealed that CKD was independently associated with vascular smooth muscle dysfunction (OR: 1.36, 95% CI: 1.02 to 1.81, P=0.04). FMD was significantly smaller in patients with CKD than in those without CKD (3.1+/ 2.8% vs. 4.0+/-3.0%, P<0.001). The prevalence of endothelial dysfunction, defined as FMD of less than the division point for the lowest quartile, was significantly higher in patients with CKD than in those without CKD (31.7% vs. 23.1%, P=0.002). However, CKD was not independently associated with endothelial dysfunction in an age- and sex-adjusted model (OR: 0.95, 95% CI: 0.71 to 1.26, P=0.72). CONCLUSIONS: Non-ESRD CKD is independently associated with vascular smooth muscle dysfunction but not with endothelial dysfunction. PMID- 29407112 TI - Letter to editor: Mortality in pulmonary arterial hypertension due to congenital heart disease: Serial changes improve prognostication. PMID- 29407113 TI - Cardiovascular disease risk prediction in sub-Saharan African populations - Comparative analysis of risk algorithms in the RODAM study. AB - BACKGROUND: Validated absolute risk equations are currently recommended as the basis of cardiovascular disease (CVD) risk stratification in prevention and control strategies. However, there is no consensus on appropriate equations for sub-Saharan African populations. We assessed agreement between different cardiovascular risk equations among Ghanaian migrant and home populations with no overt CVD. METHODS: The 10-year CVD risks were calculated for 3586 participants aged 40-70years in the multi-centre RODAM study among Ghanaians residing in Ghana and Europe using the Framingham laboratory and non-laboratory and Pooled Cohort Equations (PCE) algorithms. Participants were classified as low, moderate or high risk, corresponding to <10%, 10-20% and >20% respectively. Agreement between the risk algorithms was assessed using kappa and correlation coefficients. RESULTS: 19.4%, 12.3% and 5.8% were ranked as high 10-year CVD risk by Framingham non laboratory, Framingham laboratory and PCE, respectively. The median (25th-75th percentiles) estimated 10-year CVD risk was 9.5% (5.4-15.7), 7.3% (3.9-13.2) and 5.0% (2.3-9.7) for Framingham non-laboratory, Framingham laboratory and PCE, respectively. The concordance between PCE and Framingham non-laboratory was better in the home Ghanaian population (kappa=0.42, r=0.738) than the migrant population (kappa=0.24, r=0.732) whereas concordance between PCE and Framingham laboratory was better in migrant Ghanaians (kappa=0.54, r=0.769) than the home population (kappa=0.51, r=0.758). CONCLUSION: CVD prediction with the same algorithm differs for the migrant and home populations and the interchangeability of Framingham laboratory and non-laboratory algorithms is limited. Validation against CVD outcomes is needed to inform appropriate selection of risk algorithms for use in African ancestry populations. PMID- 29407115 TI - Thyroid function predicts increased cardiovascular risk. PMID- 29407114 TI - Objectively measured physical activity and cardiac biomarkers: A cross sectional population based study in older men. AB - BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity Troponin T (hsTnT) are markers of cardiac injury used in diagnosis of heart failure and myocardial infarction respectively, and associated with increased risk of cardiovascular disease. Since physical activity is protective against cardiovascular disease and heart failure, we investigated whether higher levels of physical activity, and less sedentary behaviour were associated with lower NT-proBNP and hsTnT. METHODS AND RESULTS: Cross sectional study of 1130 men, age 70-91years, from the British Regional Heart Study, measured in 2010 2012. Fasting blood samples were analysed for NT-proBNP and hsTnT. Physical activity and sedentary behaviour were measured using ActiGraph GT3X accelerometers. Relationships between activity and NT-proBNP or hsTnT were non linear; biomarker levels were lower with higher total activity, steps, moderate/vigorous activity and light activity only at low to moderate levels of activity. For example, for each additional 10min of moderate/vigorous activity, NT-proBNP was lower by 35.7% (95% CI -47.9, -23.6) and hsTnT by 8.4% (95% CI 11.1, -5.6), in men who undertook <25 or 50min of moderate/vigorous activity per day respectively. Biomarker levels increased linearly with increasing sedentary behaviour, but not independently of moderate/vigorous activity. CONCLUSION: Associations between biomarkers and moderate/vigorous activity (and between hsTnT and light activity) were independent of sedentary behaviour, suggesting activity is driving the relationships. In these older men with concomitantly low levels of physical activity, activity may be more important in protecting against cardiac health deterioration in less active individuals, although reverse causality might be operating. PMID- 29407116 TI - Exercise decreases cardiovascular risk factors: Now what? PMID- 29407117 TI - Optimalization for pharmacological periconditioning-induced cardioprotection in CABG: Statistical concern for reducing selection bias. PMID- 29407118 TI - Could the stress hyperglycemia ratio predict the clinical outcomes of coronary artery disease patients after percutaneous coronary intervention? PMID- 29407119 TI - Comments on: Prognostic impact of anemia and iron-deficiency anemia in a contemporary cohort of patients undergoing transcatheter aortic valve implantation. PMID- 29407120 TI - Periodic limb movements of sleep and atrial fibrillation in patients with mild sleep-disordered breathing. PMID- 29407122 TI - Extracardiac imaging in amyloidosis: A long and winding (but possible) road. PMID- 29407123 TI - The impact of migration on cardiovascular diseases. PMID- 29407121 TI - Lung uptake during 99mTc-hydroxymethylene diphosphonate scintigraphy in patient with TTR cardiac amyloidosis: An underestimated phenomenon. AB - BACKGROUND: Full body scintigraphy using bone tracers plays an important role in defining the type of amyloidosis and in diagnosing the heart involvement (cardiac amyloidosis, CA). No study has been conducted to explore lung retention (LR) in CA and its correlation to heart retention (HR).We evaluated LR in patients undergoing 99mTc-HMDP scintigraphy during evaluation for suspected CA. METHODS AND RESULTS: We enrolled 93 suspected CA patients. Patients underwent a complete diagnostic work up. After diagnostic process 82 patients resulted affected by certain CA (20 AL and 62 TTR), while 11 subjects showed left ventricular hypertrophy (LVH) not caused by CA. 99mTc-HMDP cardiac uptake was evaluated using the Perugini visual score while the modified Janssen score was used for LR estimation (grade 0 no uptake, grade 1 less than ribs, grade 2 more than ribs). RESULTS: 99mTc-HMDP LR was observed in 1/20 AL patient (5%), while 36/62 (58%) TTR patients showed LR with 29 grade 1 (47%) and 7 grade 2 (11%). No LR was observed in patients with LVH and no CA. LR was not evident in patients without HR, present in 1/3 (33%) of the patients with Perugini 1 HR and 11/24 (46%) and 26/36 (72%) of the patients showing respectively a Perugini 2 and a Perugini 3. CONCLUSION: 99mTc-HMDP scintigraphy shows LR in about 60% of TTR subjects, related to the grade of HR. In AL amyloidosis LR is less frequent than in TTR amyloidosis suggesting an aetiological tropism that seems comparable to the already known TTR related cardiac tropism. PMID- 29407124 TI - Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: The randomized AMERICA Study. AB - BACKGROUND: The prevalence and associated-risk of asymptomatic multisite artery disease (MSAD) in high risk coronary patients are unknown. Whether systematic identification and aggressive management of asymptomatic MSAD is clinically relevant in high risk coronary patients has not been evaluated. METHODS: We randomly assigned 521 high risk coronary patients defined by the presence of three-vessel coronary disease (n=304) or recent acute coronary syndrome beyond the age of 75years (n=215) to either a strategy of systematic detection of asymptomatic MSAD combined with an aggressive secondary prevention (n=263) or to a more conventional strategy based on treatment of coronary artery disease only with standard of care (n=258). The primary end point was the time to first occurrence of death, any organ failure or ischemic event leading to re hospitalization through two years of follow-up. RESULTS: The pro-active strategy identified asymptomatic MSAD in 21.7% of patients with few revascularizations (3.6%); the pro-active pharmacological secondary prevention was obtained in >85% of patients and life-style changes in <60% of patients. At 2-year follow-up, the primary end point occurred in 44.9% of patients in the pro-active group and 43.0% of patients in the conventional group (HR 1.03; 95% confidence interval [CI], 0.80 to 1.34]. The rate of major bleeding did not differ significantly between groups (4.6% vs 5.0%; HR, 0.97; 95% CI, 0.40 to 1.91). CONCLUSION: In high risk coronary patients, there is no apparent benefit of a systematic detection of asymptomatic extra-coronary atherothrombotic disease and intensified treatment over a 2-year follow-up period. (Funded by the Academic Allies in Cardiovascular Trials Initiatives and Organized Networks and Institut de l'Atherothrombose; AMERICA ClinicalTrials.gov number, NCT00445835). PMID- 29407125 TI - The emergence of the coronary vasomotor dysfunction era. PMID- 29407126 TI - Predicting risk for bleeding after PCI: Another step in the right direction but work remains. PMID- 29407127 TI - Predicting the future after acute myocardial infarction: A gaze into the crystal ball of gene expression profile. PMID- 29407128 TI - Is serum uric acid a pretty accurate prognostic predictor of ST elevated acute coronary syndrome? PMID- 29407129 TI - LncRNA MALAT1 sponges miR-133 to promote NLRP3 inflammasome expression in ischemia-reperfusion injured heart. PMID- 29407130 TI - Colchicine in coronary artery disease: Role of anti-inflammatory medications redefined. PMID- 29407131 TI - Reply concerning "Colchicine in coronary artery disease: Role of anti inflammatory medications redefined": Prime time for anti-inflammatory agents for the management of cardiovascular diseases. PMID- 29407132 TI - Comparison of mid-term clinical outcomes after treatment of ostial right coronary artery lesions with early and new generation drug-eluting stents: Insights from an international multicenter registry. AB - BACKGROUND: There are only a limited number of studies comparing clinical outcomes after treatment of right coronary artery (RCA) aorto-ostial (AO) lesions with early (E-) and new (N-) generation drug-eluting stents (DES). METHODS: From January 2005 to December 2013, 334 de novo RCA AO lesions treated with DES (E :142 lesions, N-:192 lesions) at 2 high-volume centers (Italy and Japan) were included in this study. The primary endpoint was target lesion failure (TLF) defined as composite of cardiac mortality, target vessel myocardial infarction, and target lesion revascularization (TLR). RESULTS: Baseline and lesion characteristics were well balanced between the 2 groups. The size of the stents deployed (3.35+/-0.37mm vs 3.39+/-0.33mm, p=0.29) and non-compliant balloons used for post-dilatation (3.55+/-0.38mm vs 3.62+/-0.47mm, p=0.21) were similar between the two groups. The median follow-up period was 1432 (IQR: 703-2197) days in total population. The cumulative rate of TLF at 3years was significantly higher in E-DES group when compared with N-DES group (37.7% vs 14.2%, p<0.001), which was mainly driven by TLR (38.0% vs 11.0%, p<0.001). Multivariable analysis revealed that N-DES [HR 0.22 (0.13-0.38), p<0.001], stent underexpansion [HR 10.59 (6.23-17.97), p<0.001], excessive aortic stent protrusion [HR 3.12 (1.87 5.23), p<0.001], and proximal stent overlap [HR 1.74 (1.03-2.95), p=0.03] were independent predictors of TLF. CONCLUSION: For the treatment of RCA AO lesions, N DES were associated with a lower incidence of TLF at 3years when compared with E DES. N-DES use and suboptimal implantation characteristics were independent predictors of TLF. PMID- 29407133 TI - Incomplete revascularization and long-term survival after coronary artery bypass surgery. AB - BACKGROUND: We sought to investigate the impact of incomplete revascularization (IR) on long-term survival after isolated coronary artery bypass grafting (CABG). The possible interaction between IR and off-pump surgery was also explored. METHODS: A total of 13,701 patients with multivessel disease undergoing CABG were included in the analysis. All patients received left internal thoracic artery (LITA) to the left anterior descending artery (LAD) territory. IR was defined as at least one diseased arterial territory (right coronary artery [RCA] and/or circumflex [CX] artery) incompletely revascularized. RESULTS: Overall, 3107 (22.7%) patients received IR. After propensity score matching, IR did not increase all-cause death in the overall group (HR 1.09; 95%CI 0.96-1.22; P=0.17). However, when both RCA and CX artery were incompletely revascularized, late survival was significantly lower (HR 2.15; 95%CI 1.57-2.93). IR was associated with a higher risk of death after off-pump (HR 1.26; 95%CI 1.05-1.49) regardless the extent of IR. After on-pump, IR significantly affected survival only when both RCA and CX artery only were incompletely revascularized (HR 2.32; 95%CI 1.27 4.22). CONCLUSIONS: The present analysis shows that in patients with LITA-LAD graft the impact of IR on survival is marginal when only one coronary territory is left ungrafted. When both the RCA and CX territory remain unrevascularized the survival rate is significantly reduced. IR after off-pump CABG is associated with significantly lower survival and affects long-term outcome even when only one coronary territory is not revascularized. PMID- 29407134 TI - Effectiveness of new generation drug-eluting stents in ostial right coronary artery lesions. PMID- 29407135 TI - Incomplete myocardial revascularization. A never ending story. PMID- 29407136 TI - Treatment options for the closure of secundum atrial septal defects: A systematic review and meta-analysis. PMID- 29407137 TI - Exploring the optimal ratio of d-glucose/l-aspartic acid for targeting carbon dots toward brain tumor cells. AB - Targeting imaging to the desired site of action can increase the accuracy and effectiveness of diagnostic and treatment. In this work, a series of fluorescent carbon dots (CDs) were prepared by varying molar ratios of d-glucose (Glu) to l aspartic acid (Asp). Their photophysical properties, morphologies and structures were investigated in detail. More important, the targeting ability was screened by confocal laser scanning microscopy and flow cytometry. The results indicate that CDs prepared from the optimal molar ratio of Glu/Asp (7:3) exhibit the highest targeting ability on C6 glioma cells. This work highlights the interplay of molecular design and corresponding functions, and open new possibility of developing state-of-art nanoparticles for biomedical applications. PMID- 29407138 TI - Microwave assisted coating of bioactive amorphous magnesium phosphate (AMP) on polyetheretherketone (PEEK). AB - Polyetheretherketone (PEEK) with great thermal and chemical stability, desirable mechanical properties and promising biocompatibility is being widely used as orthopedic and dental implant materials. However, the bioinert surface of PEEK can hinder direct osseointegration between the host tissue and PEEK based implants. The important signatures of this paper are as follows. First, we report for the formation of osseointegrable amorphous magnesium phosphate (AMP) coating on PEEK surface using microwave energy. Second, coatings consist of nano-sized AMP particles with a stacked thickness of 800nm. Third, coatings enhance bioactivity in-vitro and induce significantly high amount of bone-like apatite coating, when soaked in simulated body fluid (SBF). Fourth, the as-deposited AMP coatings present no cytotoxicity effects and are beneficial for cell adhesion at early stage. Finally, the high levels of expression of osteocalcin (OCN) in cells cultured on AMP coated PEEK samples indicate that AMP coatings can promote new bone formation and hence osseointegration. PMID- 29407139 TI - Polymer-amino-functionalized silica composites for the sustained-release multiparticulate system. AB - This study presents an interesting and promising strategy for producing an oral multiparticulate formulation of the sustained-release of diclofenac sodium (DS) consisting of subunits closed inside hard gelatin capsules (each capsule contains ~50mg of diclofenac sodium). The subunits in the form of beads were produced through the encapsulation of diclofenac sodium dispersed within a nondisintegrating polymer carrier by a silica gel functionalized with the 3 aminopropyl groups. The hybrid silica gel, which plays the role of enteric coating, was fabricated by the gelation of the liquid silica precursors mixture (i.e. tetraethoxysilane (TEOS) and (3-aminopropyl)triethoxysilane (APTES)) in the vapor phase of ammonia. The conducted studies reveal that the introduction of the hybrid silica gel into the solid DS dispersion facilitates prolonged release in the neutral environment of the intestine. Since the ability of the multiparticulate formulation to control the release of the drug depends on the properties of its subunits, studies involving the low temperature N2 sorption, DSC analysis together with spectroscopic techniques (XRD, SEM, 29Si MAS NMR) were conducted. PMID- 29407140 TI - Antibacterial modification of PET with quaternary ammonium salt and silver particles via electron-beam irradiation. AB - Quaternary ammonium compound 2-dimethyl-2-hexadecyl-1-methacryloxyethyl ammonium bromide (DEHMA) was synthesized and grafted onto polyester (PET) fibers with acrylic acid (AA) via electron-beam (EB) irradiation process. The grafted fibers were soaked in AgNO3 solution for further improving antibacterial efficiency. SEM, FTIR, EDX, and XPS were used to characterize the treated PET samples. The antibacterial efficacy testing showed the grafted PET samples inactivated all Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli O157:H7) in 10min. After coated with silver ions, the antibacterial efficacy of the grafted PET with silver against S. aureus improved significantly. The EB irradiation process only caused a small degree of the breaking strength loss of the grafted PET fabrics which is acceptable in practical application. PMID- 29407141 TI - Nano silver decorated polyacrylamide/dextran nanohydrogels hybrid composites for drug delivery applications. AB - Herein, novel biodegradable, stimuli responsive, chemically cross-linked and porous polyacrylamide/dextran (PAM/D) nanohydrogels hybrid composites are synthesized by in situ polymerization technique with incorporation of reduced nano silver. The interaction of nano silver with PAM in presence of dextran is investigated by Fourier transforms infrared spectroscopy (FTIR) and X-ray diffraction (XRD) studies. The elemental composition of the hybrid nanohydrogels is studied by X-ray photoelectron spectroscopy (XPS) whereas; the surface morphology of nanohydrogels hybrid composites is studied by field emission scanning electron microscope (FESEM) by which, it is observed that, the silver nanoparticles are homogeneously dispersed throughout the nanohydrogel network. From high resolution transmission electron microscopy (HRTEM), the average size of silver nanoparticles is found to be 20nm. The swelling, deswelling and water retention properties of nanohydrogels hybrid composites are measured in order to investigate the release rate of the ornidazole drugs. The in vitro release rate of ornidazole drugs is found to be 98.5% in 6h. The antibacterial activities and the cytotoxicity tests along with positive and negative control of hybrid nanohydrogels are investigated. The loss modulus, gain modulus and complex viscosities are determined from rheological behaviour of the nanohydrogels. It is found that, the value of tandelta varies from 0.1 to 0.8. Nano silver decorated PAM/D nanohydrogels are stable, nontoxic with antibacterial behaviour may be suitable for drugs delivery vehicle. PMID- 29407142 TI - pH-responsive mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin against osteosarcoma. AB - Oral or intravenous chemotherapy is an important strategy to treat metastatic cancer, but it may cause systemic toxicity for healthy tissue. Herein, we for the first time fabricated mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin (ZSM-5/CS/DOX) as drug delivery systems against osteosarcoma. The mesoporous ZSM-5 zeolites exhibited disk-like shapes with thicknesses of 100nm and diameters of 300nm, and the mesopores with pore sizes of 3.75nm were originated from desilication treatment. The pH-responsive ZSM 5/CS/DOX nanodisks possessed a great drug loading efficiency of 97.7%, and their controlled release trends of DOX were fitted well with the Korsmeyer-Peppas model. The DOX could be efficiently released the ZSM-5/CS/DOX nanodisks after cellular endocytosis and induced cancer cells apoptosis. Moreover, the pH responsive drug carriers led to efficient tumor inhibition with low side effects, especially cardiac toxicity, as confirmed by pharmacokinetic study, serological examination and H&E staining assays. Therefore, the ZSM-5/CS/DOX nanodisks are a promising pH-responsive drug carrier for targeted cancer therapy. PMID- 29407143 TI - Development of a PCL-silica nanoparticles composite membrane for Guided Bone Regeneration. AB - The pivotal step in Guided Bone Regeneration (GBR) therapy is the insertion of a membrane for support and barrier functions. Here, we studied the effect of the addition of silica nanoparticles (Si-NPs) in electrospun poly(epsilon caprolactone) (PCL) membranes to improve the mechanical and osteoconductive properties of the membranes. To this end, Si-NPs were firstly synthesized and then suspended in PCL solutions containing a polar solvent (2,2,2 trifluroethanol) and water with the addition of an anionic surfactant. Nanocomposite membranes were fabricated from the solutions through an electrospinning technique. Morphology, structure and chemical composition, and tensile properties of the membranes were analyzed. Membrane stability was determined by visual examination of the membranes after immersion in phosphate buffered saline. The effect of the materials on osteoblastic differentiation was evaluated by in vitro culture of the membranes with MC3T3-E1 osteoblastic cells. The results indicated that Si-NPs were successfully incorporated in the interior of the PCL electrospun fibers during the electrospinning process. Tensile modulus was significantly increased for composition S50 and tensile strength significantly increased for compositions S25 and S50. Membranes containing Si-NPs have shown to be cytocompatible. The results obtained demonstrate that the Si-NPs were homogeneously incorporated in the electrospun fibers, resulting in an improvement of the tensile properties of the prepared materials. PMID- 29407144 TI - Novel bilayer wound dressing composed of SIS membrane with SIS cryogel enhanced wound healing process. AB - Full-thickness skin damage is a server issue and sometimes even dangerous to life. Many researches have been done toward full-thickness wound dressing. In this study, we demonstrated a facile and one-step procedure of SIS bilayer wound dressing. The top layer could protect the wound from bacterial infection and provide a moist environment suitable for wound healing, while the cryogel layer could promote cell proliferation. The SIS bilayer wound dressing has sufficient mechanical properties to protect wound from second damage and can maintain a moist environment for cell proliferation and migration at wound site. Bacterial permeation testing demonstrated that the bilayer scaffold had high efficiency in blocking bacteria at the wound site. In vivo tests and qRT-PCR results revealed that the bilayer group possessed a higher tendency toward keratinocyte proliferation and migration. The SIS bilayer has a high potential to use as full thickness wound dressing. PMID- 29407145 TI - Simple fabrication of rough halloysite nanotubes coatings by thermal spraying for high performance tumor cells capture. AB - Here, we reported a fast, low-cost, and effective fabrication method of large area and rough halloysite nanotubes (HNTs) coatings by thermal spraying of HNTs ethanol dispersions. A uniform HNTs coating with high transparence is achieved with tailorable surface roughness and thickness. Compared with normal cells, the tumor cells can be captured effectively with high capture yield by the HNTs coatings (expect HeLa cells), which is attributed to the enhanced topographic interactions between HNTs coating and cancer cells. HNTs coating formed from 2.5% ethanol dispersions shows the highest tumor cells capture yeild (90%), which is related to the appropriate roughness and anti-EpCAM conjugation. The capture yield of HNTs coating towards MCF-7 cells can be further improved to 93% within 2h under dynamic shear using a peristaltic pump. The capture yield increases with the incubation time, and the flow rate with 1.25mL/min leads to the maximum capture yield. The HNTs coatings are also effective for capture of tumor cells spiked in artificial blood samples and blood samples from patients with metastatic breast cancer. More than 90% targeted MCF-7 cells and very small amounts of white blood cells are captured by the anti-EpCAM conjugated HNTs coatings from a blood sample. HNTs are further loaded anticancer drug doxorubicin (DOX) and then thermally sprayed into coatings. The MCF-7 cells captured on DOX loaded HNTs coating display significant membrane rupture characteristic and only 3% cell viability after 16h. The high capture efficiency of tumor cells by HNTs coating fabricated by the thermal spraying method makes them show promising applications in clinical circulating tumor cells capture for early diagnosis and monitoring of cancer patients. The high killing ability of the DOX loaded HNTs coating can also be designed as an implantable therapeutic device for preventing tumor metastasis. PMID- 29407146 TI - Microneedles fabricated from alginate and maltose for transdermal delivery of insulin on diabetic rats. AB - To reduce the inconvenient and painful of subcutaneous needle injection, the calcium ion cross-linked alginate/maltose (Ca2+/Alg-Mal) composite microneedles have been fabricated by a template method. The as-prepared microneedles exhibited strong mechanical properties with the highest failure force around 0.41N/needle. The biological activity and stability of loaded insulin in microneedles were investigated. Due to the good mechanical properties and excellent biocompatibility, the as-prepared microneedles have been applied for transdermal delivery of insulin on diabetic Sprague-Dawley (SD) rat models in vivo. After transdermal administration to the diabetic rats, the released insulin from biodegradable composite microneedles exhibit an obvious and effective hypoglycemic effect with relative pharmacological availability (RPA) and relative bioavailability (RBA) at 94.1+/-5.6% and 93.7+/-4.7% compared with that of subcutaneous injection route. This work suggests that as-prepared Ca2+/Alg-Mal microneedles can be used to encapsulate insulin and have a potential application in diabetes treatment via transdermal ingestion. PMID- 29407147 TI - Development of porous chitosan/tripolyphosphate scaffolds with tunable uncross linking primary amine content for bone tissue engineering. AB - The primary amine along the chitosan backbone plays a key role in biomedical applications. Although chitosan-based porous scaffolds have been widely used in tissue engineering, it remains very challenging to regulate uncross-linking primary amine content (CN) in scaffolds in order to realize particular mechanical and biological properties. In the present study, chitosan/tripolyphosphate (TPP) scaffolds with controlled CN (i.e., degree of cross-linking) were prepared based on the ionic-dependent solubility of chitosan together with the freezing process. The effects of the concentration of TPP (CTPP) and NaCl (CNaCl) in the cross linking solution on CN were studied by infrared spectroscopy, ninhydrin assays and elemental analysis. The results showed that CN decreased with increasing CTPP and decreasing CNaCl. CN affected physicomechanical properties such as swelling behavior and the mechanical strength of the chitosan/TPP scaffolds. The uncross linking primary amine in scaffolds can be used for chemical and biological modifications. The protein loading of the scaffolds demonstrated that the pH responsive adsorption and release behavior was influenced by CN. Cell experiments also illustrated that CN affected the proliferation of bone marrow mesenchymal stem cells (BM-MSCs). All of these results indicate that these porous chitosan/TPP scaffolds containing uncross-linking primary amines are potentially useful for applications in regenerative bone medicine. PMID- 29407148 TI - Human amnion extracellular matrix derived bioactive hydrogel for cell delivery and tissue engineering. PMID- 29407149 TI - Biodegradable nanostructures: Degradation process and biocompatibility of iron oxide nanostructured arrays. PMID- 29407151 TI - Determination of methimazole based on electropolymerized-molecularly imprinted polypyrrole modified pencil graphite sensor. AB - Preparation of a molecularly imprinted polymer (MIP) film and its recognition property for methimazole (MMZ) was investigated. The polypyrrole (PPy) film was prepared by the cyclic voltammetric deposition of pyrrole in the presence of a supporting electrolyte (NaClO4.H2O) with and without MMZ through on a pencil graphite electrode (PGE). A computational study based on density functional theory was developed to evaluate the template-monomer geometry and interaction energy in the prepolymerization mixture. The performance of MIP sensor and non imprinted polymer (NIP) film was evaluated by differential pulse voltammetry (DPV). The most important parameters controlling the performance of sensor were investigated and optimized. The prepared electrode was used for MMZ measurement by a three-step procedure, including analyte extraction in the electrode, electrode washing and electrochemical measurement of MMZ. The molecularly imprinted film exhibited a high selectivity and sensitivity toward methimazole in the experimental conditions. The calibration curve demonstrated linearity over a concentration range of 0.007-6mM with a correlation coefficient (r2) of 0.9808. The accuracy of the method was studied through spiking blank samples showed recovery of 98% with precision of 4%. Limit of detection based on S/N=3 was obtained 3*10-6M. The proposed sensor was applied successfully to determine MMZ in biological model samples and pharmaceuticals. PMID- 29407150 TI - Infection-prevention on Ti implants by controlled drug release from folic acid/ZnO quantum dots sealed titania nanotubes. AB - Bacterial infections and related complications are predominantly responsible for the failure of artificial biomaterials assisted tissue regeneration in clinic. In this work, a hybrid surface system is applied to prolong the drug release duration from dug-loaded titania nanotubes and thus to prevent Ti implants associated bacterial infections. This feature is endowed by conjugating folic acid (FA) onto the surface of ZnO quantum dots (QDs)-NH2 via an amidation reaction. Titania nanotubes (TNTs) loaded with vancomycin (Van) are capped by these FA functionalized ZnO (ZnO-FA) QDs that keep stable in normal physiological environments but dissolves to Zn2+ in the mildly acidic environment after bacterial infections as validated by the drug release profile. The antibacterial ratio of TNTs-Van@ZnO-FA QDs against Staphylococcus aureus is enhanced from 60.8% to 98.8%while this value is only increased from 85.2% to 95.1% for TNTs-Van once the pH value of the environment is decreased from 7.4 to 5.5. This is due to the synergistic effects of Van and Zn2+ because the gradual dissolution of ZnO-FA caps on TNTs with the decrease of pH value can induce the acceleration of both Van and Zn2+ release. In addition, this TNTs-Van@ZnO-FA system also exhibits excellent biocompatibility because of the folic acid and sustained release of Zn ions. Hence, this surface system can be potentially used as a promising bioplatform on Ti-based metallic implants to prevent bacterial infection with a long-lasting effect. PMID- 29407152 TI - Facile construction of luminescent supramolecular assemblies with aggregation induced emission feature through supramolecular polymerization and their biological imaging. AB - Supramolecular polymerization is a novel method for the fabrication of multifunctional polymeric composites that mainly relied on the non-covalent interactions between different components. In this work, a novel and facile strategy has been developed for the construction of fluorescent organic nanoparticles (FONs) with aggregation-induced emission (AIE) characteristic based on the host-guest interaction between beta cyclodextrin terminating polyethylene glycol (beta-CD-PEG) and adamantine (Ad) containing AIE dye (Ph-Ad). Through the host-guest interaction, the fluorescent amphiphiles can be facilely obtained. The characterization results suggested we have successfully prepared the AIE-active FONs through the supramolecular polymerization. The Ph-Ad/beta-CD-PEG FONs possess many advantages such small size, high water dispersibility, desirable fluorescence properties, low cytotoxicity and efficient cell dyeing performance. All of the above results implied that these AIE-active supramolecular assemblies should be promising luminescent probes with great potential for different biomedical applications. PMID- 29407153 TI - BMP2 expressing genetically engineered mesenchymal stem cells on composite fibrous scaffolds for enhanced bone regeneration in segmental defects. AB - The treatment of critical sized bone defect remains a significant challenge in orthopedics. The objective of the study is to evaluate the effect of the combination of bone morphogenetic protein 2 (BMP2) expressing genetically engineered mesenchymal stem cells (MSCs) [MSCs engineered using a multimam vector, pAceMam1, an emerging gene delivery vector] and an osteoconductive scaffold [silica coated nanohydroxyapatite-gelatin reinforced with fibers] in enhancing bone regeneration in critical sized segmental defects. The scaffold with transfected MSCs showed significantly higher viability, proliferation and osteogenic differentiation in vitro. Further, this group augmented union and new bone formation in critical sized rat femoral segmental defect at 12 weeks when compared to control groups (scaffold with MSCs and scaffold alone). These data demonstrated that the MSCs engineered for transient expression of BMP2 can improve the repair of segmental defects, which paves an avenue for using pAceMam1 as a vector for bone tissue regeneration. PMID- 29407154 TI - Porous chitosan microspheres containing zinc ion for enhanced thrombosis and hemostasis. AB - Quick hemostats for non-lethal massive traumatic bleeding in battlefield and civilian accidents are important for reducing mortality and medical costs. Chitosan (CS) has been widely used as a clinic hemostat. To enhance its hemostatic efficiency, Zn2+ in the form of zinc alginate (ZnAlg) was introduced to CS to make porous CS@ZnAlg microspheres with ZnAlg component on the surface. Such microspheres were prepared by successive steps of micro-emulsion, polyelectrolyte adhesion, and thermally induced phase separation. Their structure and hemostatic performance were analyzed by SEM, FT-IR, XPS and a series of in vitro hemostatic experiments including thromboelastography analysis. The composite microspheres had an outer and internal interconnected porous structure. Their size, surface area, and water absorption ratio were ca. 70MUm, 48m2/g, and 1850%, respectively. Compared to the neat chitosan microspheres, the CS@ZnAlg microspheres showed shorter onset of clot formation, much faster in vitro and in vivo whole blood clotting, bigger clot, less blood loss, and shorter hemostatic time in the rat liver laceration and tail amputation models. The synergetic hemostatic effects from (1) the electrostatic attraction between chitosan component and red blood cells, (2) the activation of coagulation factor XII by Zn2+ of zinc alginate component, and (3) physical blocking by microsphere matrix, contributed to the enhanced hemostatic performance of CS@ZnAlg microspheres. PMID- 29407155 TI - Electrospun membranes of PELCL/PCL-REDV loading with miRNA-126 for enhancement of vascular endothelial cell adhesion and proliferation. AB - Surface modification for rapid endothelialization of vascular biomaterials is known as an important way to prevent thrombosis and intimal hyperplasia. Moreover, therapeutical manipulation of microRNAs (miRNAs) expression via local delivery of miRNA mimics or inhibitors by electrospun ultrafine fibers has demonstrated the promise in tissue regeneration. In this work, a dual-functional electrospun membrane was developed by combining Arg-Glu-Asp-Val (REDV) peptide modification of the fiber surface to enhance vascular endothelial cell (VEC) adhesion and encapsulation of miRNA-126 (miR-126) complexes in the electrospun fibers to accelerate VEC proliferation. The electrospun membranes were specially prepared by emulsion electrospinning of poly(ethylene glycol)-b-poly(l-lactide-co epsilon-caprolactone) (PELCL) and REDV-terminated polycaprolactone (PCL) (50/50 mass ratio), in which miR-126 was encapsulated via REDV peptide-modified trimethyl chitosan-g-poly(ethylene glycol). By introduction of REDV-terminated PCL with lower molecular weight, the obtained electrospun fibers could be modified by REDV on their surface, and also achieve a relatively fast release profile of miR-126 in favor of VEC proliferation. Results of direct seeding VECs on the electrospun membranes indicated the enhanced cell adhesion and proliferation. The combination of REDV peptide-modification of the electrospun fibrous membranes and controllable miRNA release may provide a synergistic strategy of surface guidance and biochemical signals to support and modulate VECs for vascular tissue regeneration. PMID- 29407156 TI - Chlorophyll a in cyclodextrin supramolecular complexes as a natural photosensitizer for photodynamic therapy (PDT) applications. AB - Chlorophyll a (Chl a), an amphipathic porphyrin, was employed as natural photosensitizer for photodynamic therapy applications. Due to its lacking solubility in water and high tendency to aggregate, Chl a was included into different modified cyclodextrins (CDs) to form stable water-soluble supramolecular complexes. To achieve this aim, 2-Hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD), 2-Hydroxypropyl-gamma-cyclodextrin (2-HP-gamma-CD), Heptakis(2,6 di-o-methyl)-beta-cyclodextrin (DIMEB) and Heptakis(2,3,6-tri-o-methyl)-beta cyclodextrin (TRIMEB) were used. The chemical physical properties of Chl a/CD complexes in cellular medium were studied by means of UV-Vis absorption spectroscopy. Results demonstrated the good aptitude of 2-HP-gamma-CD, and more particularly of 2-HP-beta-CD, to solubilize the Chl a in cell culture medium in monomeric and photoactive form. Then, Chl a/2-HP-beta-CD and Chl a/2-HP-gamma-CD complexes were evaluated in vitro on human colorectal adenocarcinoma HT-29 cell line, and cytotoxicity and intracellular localization were respectively assessed. Further tests, such as phototoxicity, ROS generation, intracellular localization and mechanism of cell death were then focused exclusively on Chl a/2-HP-beta-CD system. This complex exhibited no dark toxicity and a high phototoxicity toward HT-29 cells inducing cell death via necrotic mechanism. Therefore, it is possible to affirm that Chl a/2-HP-beta-CD supramolecular complex could be a promising and potential formulation for applications in photodynamic therapy. PMID- 29407157 TI - Hybrid PCL/CaCO3 scaffolds with capabilities of carrying biologically active molecules: Synthesis, loading and in vivo applications. AB - Designing advanced biomaterials for tissue regeneration with drug delivery and release functionalities remains a challenge in regenerative medicine. In this research, we have developed novel composite scaffolds based on polymeric polycaprolactone fibers coated with porous calcium carbonate structures (PCL/CaCO3) for tissue engineering and have shown their drug delivery and release in rats. In vivo biocompatibility tests of PCL/CaCO3 scaffolds were complemented with in vivo drug release study, where tannic acid (TA) was used as a model drug. Release of TA from the scaffolds was realized by recrystallization of the porous vaterite phase of calcium carbonate into the crystalline calcite. Cell colonization and tissue vascularization as well as transplantability of developed PCL/CaCO3+TA scaffolds were observed. Detailed study of scaffold transformations during 21-day implantation period was followed by scanning electron microscopy and X-ray diffraction studies before and after in vivo implantation. The presented results demonstrate that PCL/CaCO3 scaffolds are attractive candidates for implants in bone regeneration and tissue engineering with a possibility of loading biologically active molecules and controlled release. PMID- 29407158 TI - Hydrazone crosslinked hyaluronan-based hydrogels for therapeutic delivery of adipose stem cells to treat corneal defects. AB - Corneal blindness is a worldwide problem, plagued by insufficient amount of high quality donor tissue. Cell therapy using human adipose stem cells (hASCs) has risen as an alternative to regenerate damaged corneal stromal tissue, the main structural and refractive layer of the cornea. Herein we propose a method to deliver hASCs into corneal defects in hyaluronan (HA)-based hydrogels, which form rapidly in situ by hydrazone crosslinking. We fabricated two different HA-based hydrazone-crosslinked hydrogels (HALD1-HACDH and HALD2-HAADH), and characterized their swelling, degradation, mechanical, rheological and optical properties and their ability to support hASC survival. To promote hASC attachment and survival, we incorporated collagen I (col I) to the more stable HALD1-HACDH hydrogel, since the HALD2-HAADH hydrogel suffered swift degradation in culture conditions. We then used an organ culture model with excised porcine corneas to study the delivery of hASCs in these three hydrogels for stromal defect repair. Although all hydrogels showed good hASC survival directly after encapsulation, only the collagen-containing HALD1-HACDH-col I hydrogel showed cells with elongated morphology, and significantly higher cell metabolic activity than the HALD1-HACDH gel. The addition of col I also increased the stiffness and reduced the swelling ratio of the resulting hydrogel. Most importantly, the corneal organ culture model demonstrated these hydrogels as clinically feasible cell delivery vehicles to corneal defects, allowing efficient hASC integration to the corneal stroma and overgrowth of corneal epithelial cells. PMID- 29407159 TI - Biodistribution and preliminary toxicity studies of nanoparticles made of Biotransesterified beta-cyclodextrins and PEGylated phospholipids. AB - BACKGROUND: The modification of beta-cyclodextrins (betaCDs) by grafting alkyl chains on the primary and/or secondary face yields derivatives (betaCD-C10) able to self-organize under nanoprecipitating conditions into nanoparticles (betaCD C10-NP) potentially useful for drug delivery. The co-nanoprecipitation of betaCD C10 with polyethylene glycol (PEG) chains yields PEGylated NPs (betaCD-C10-PEG NP) with potentially improved stealthiness. The objectives of the present study were to characterize the in vivo biodistribution of betaCD-C10-PEG-NP with PEG chain length of 2000 and 5000Da using nuclear imaging, and to preliminarily evaluate the in vivo acute and extended acute toxicity of the most suitable system. RESEARCH DESIGN AND METHODS: The in vivo and ex vivo biodistribution features of naked and decorated nanoparticles were investigated over time following intravenous injection of 125I-radiolabeled nanoparticles to mice. The potential toxicity of PEGylated betaCD-C10 nanosuspensions was evaluated in a preliminary in vivo toxicity study involving blood assays and tissue histology following repeated intraperitoneal injections of nanoparticles to healthy mice. RESULTS: The results indicated that betaCD-C10-PEG5000-NP presented increased stealthiness with decreased in vivo elimination and increased blood kinetics without inducing blood, kidney, spleen, and liver acute and extended acute toxicity. CONCLUSIONS: betaCD-C10-PEG5000-NPs are stealth and safe systems with potential for drug delivery. PMID- 29407161 TI - Rational design of curcumin loaded multifunctional mesoporous silica nanoparticles to enhance the cytotoxicity for targeted and controlled drug release. AB - Curcumin has attracted increasing attentions in recent years due to its promising anticancer activities. However, the hydrophobicity of curcumin has limited greatly its efficacy in clinical trials. In this study, folate (FA)-receptor targeting mesoporous silica nanoparticles that promise high loadings of curcumin via pH-sensitive Schiff base reactions were constructed and examined for targeted delivery of curcumin. Such nano-delivery system showed significantly improved stability and biocompatibility of curcumin under physiological conditions. Further investigations demonstrated that this nanocarrier had high values of drug loading efficiency (9.5%) and pH-responsive drug release property. Moreover, the particles could be efficiently internalized by FA-receptor-rich MCF-7 cells through the receptor-mediated endocytosis, whereas FA-receptor-poor HEK-293T normal cells showed much lower endocytosis of the nanoparticles under the same conditions. The in vitro cytotoxicity assay indicated that the curcumin-loaded nanoparticles exhibited significantly enhanced cytotoxicity against MCF-7 cell than HEK-293T cells because of the higher cellular uptake efficiency of nanocarriers. More broadly, this work demonstrates a new type of mesoporous silica nanocarrier particularly useful for targeted and controlled drug release applications. PMID- 29407160 TI - Biomimetic polyurethane/TiO2 nanocomposite scaffolds capable of promoting biomineralization and mesenchymal stem cell proliferation. AB - Scaffolds with extracellular matrix-like fibrous morphology, suitable mechanical properties, biomineralization capability, and excellent cytocompatibility are desired for bone regeneration. In this work, fibrous and degradable poly(ester urethane)urea (PEUU) scaffolds reinforced with titanium dioxide nanoparticles (nTiO2) were fabricated to possess these properties. To increase the interfacial interaction between PEUU and nTiO2, poly(ester urethane) (PEU) was grafted onto the nTiO2. The scaffolds were fabricated by electrospinning and exhibited fiber diameter of <1MUm. SEM and EDX mapping results demonstrated that the PEU modified nTiO2 was homogeneously distributed in the fibers. In contrast, severe agglomeration was found in the scaffolds with unmodified nTiO2. PEU modified nTiO2 significantly increased Young's modulus and tensile stress of the PEUU scaffolds while unmodified nTiO2 significantly decreased Young's modulus and tensile stress. The greatest reinforcement effect was observed for the scaffold with 1:1 ratio of PEUU and PEU modified nTiO2. When incubating in the simulated body fluid over an 8-week period, biomineralization was occurred on the fibers. The scaffolds with PEU modified nTiO2 showed the highest Ca and P deposition than pure PEUU scaffold and PEUU scaffold with unmodified nTiO2. To examine scaffold cytocompatibility, bone marrow-derived mesenchymal stem cells were cultured on the scaffold. The PEUU scaffold with PEU modified nTiO2 demonstrated significantly higher cell proliferation compared to pure PEUU scaffold and PEUU scaffold with unmodified nTiO2. The above results demonstrate that the developed fibrous nanocomposite scaffolds have potential for bone tissue regeneration. PMID- 29407162 TI - Potentiodynamic formation of diaminobenzene films on an electrochemically reduced graphene oxide surface: Determination of nitrite in water samples. AB - An electrode comprised of a polydiaminobenzene (p-DAB) film formed on electrochemically reduced graphene oxide (ERGO) on a glassy carbon (GC) (p DAB@ERGO/GC) was fabricated using a potentiodynamic method for the sensitive and selective determination of nitrite in the presence of a common interference. The p-DAB@ERGO/GC film-modified electrode surfaces were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, electrochemical impedance spectroscopy and cyclic voltammetry. The film fabrication was initiated via the NH2 groups of DAB, which was confirmed by XPS from the peaks corresponding to NH (396.7eV), NH (399.4eV), NN (400.2eV), and N+H (402.2eV). The Raman spectra revealed the characteristic D and G bands at 1348 and 1595cm-1, respectively, which confirmed the fabrication of GO on the GC electrode, and the ratio of the D and G bands was increased after the electrochemical reduction of GO. The surface coverage of the modified electrode was 8.16*10-11molcm-2. The p-DAB@ERGO/GC film-modified electrode was used successfully for the determination of nitrite ions. The p-DAB@ERGO/GC film modified electrode exhibited superior activity for the determination of nitrite compared to the bare GC and p-DAB@GC electrodes. The amperometric current increased linearly with increasing nitrite concentration from 7.0*10-6 to 2.0*10 2M. The detection limit was 30nM (S/N=3). In addition, the modified electrode was used successfully to determine the nitrite ion concentration in the presence of a 100-fold excess of common interferents. The practical application of the modified electrode was demonstrated by determining the nitrite ion concentration in water samples. PMID- 29407163 TI - Intraspecies geographical variability in the South American tigra mariposa (Bothrops venezuelensis Sandner 1952) snake venom activities. AB - Bothrops venezuelensis snake venoms, from five localities in the North-Central Venezuelan regions, showed biochemical and haemostatic differences. In this study, bioactivities of B. venezuelensis venoms from different regions (Aragua state; Waraira Repano (Capital District); Baruta, La Boyera and Lagunetica (Miranda state)) were compared using both natural and synthetic substrates. The protein contents of these venoms were Lagunetica 89%, La Boyera 79%, Baruta 71%, Waraira Repano 68% and Aragua 64%. Toxic activities effects were: Intraperitoneal LD50s: Aragua-14 mg/kg; Waraira Repano-6.4 mg/kg; Baruta: 8.3 mg/kg; La Boyera 4.4 mg/kg; Lagunetica-16.2 mg/kg. The MHD results: Aragua-21.4 MUg/mouse; Waraira Repano-2.5 MUg/mouse; Baruta-1.2 MUg/mouse; La Boyera-1.4 MUg/mouse and Lagunetica-12 MUg/mouse. The hide powder azure results: Aragua-1.24 U/mg; La Boyera-2.26 U/mg; Baruta-2.83 U/mg; Lagunetica-3.28 U/mg and Waraira Repano-5.77 U/mg. Esterase specific activity on BAEE results: Waraira Repano-666.66 U/mg; La Boyera-805.5 U/mg; Baruta-900.00 U/mg; Lagunetica-922.19 U/mg and Aragua-1960.67 U/mg. Casein zymography showed digestion bands in the molecular weight above 100 and at 66.2 and 21.5 kDa. Analysis of casein degradation by SDS-PAGE showed two different degradation patterns. Fibrinolytic activity (mm2/MUg) on fibrin plates results: Aragua-6.07; Lagunetica-27.6; Waraira Repano-35.7; La Boyera-44.27 and Baruta-45.63. In the fibrinogenolytic assay, the five venoms completely degraded the alpha chain after 1 min of incubation. None of the venoms completely degraded the beta and gamma chains after 24 h incubation. The research indicated that venoms of B. venezuelensis of different geographic areas in Venezuela exhibit variances in composition and component concentrations; except the Aragua venom, all of them had high proteolytic activities. PMID- 29407164 TI - Inhibition of the proteasome partially attenuates atrophy in botulinum neurotoxin treated skeletal muscle. AB - Botulinum neurotoxin type A (BoNT/A) is used as a therapeutic tool to induce chemical denervation of spastically contracted muscles, yet the neurotoxin can also cause skeletal muscle atrophy. The underlying proteolytic mechanisms that induce this atrophy remain unclear. Our previous work has highlighted increased ubiquitin proteasome system (UPS) activity in soleus muscle of male Sprague Dawley rats following hind limb injection of BoNT/A, with the chymotrypsin-like activity of the 20s proteasome the most active. Thus, we chose to inhibit 20s proteasome activity in BoNT/A injected hind limb to determine the effect on soleus muscle atrophy. Epoxomicin is commonly used to inhibit the proteasome in vivo, binding specifically and irreversibly to the 20s proteasome catalytic subunits. Daily subcutaneous injections of epoxomicin abolished BoNT/A-induced elevations in 20s chymotrypsin-like activity both 3 days and 10 days post BoNT/A injection. Furthermore, BoNT/A-induced elevations in polyubiquitination remained elevated in BoNT/A + epoxomicin treated muscle, presumably due to epoxomicin's inhibition of the proteasome causing a back-up of polyubiquitinated proteins. Despite inhibition of the proteasome, epoxomicin was insufficient to significantly attenuate soleus muscle fiber atrophy 3 days following BoNT/A injection however, 10 days of daily epoxomicin injection was sufficient to spare ~20% of muscle wasting. The mechanism of the remaining 80% of BoNT/A-induced atrophy presumably occurs via mechanisms outside of the 20s proteasome. PMID- 29407165 TI - Towards flexible and tailored botulinum neurotoxin dosing regimens for focal dystonia and spasticity - Insights from recent studies. AB - Botulinum neurotoxin (BoNT) is an effective, well-tolerated, and well-established option for the treatment of dystonic and spastic movement disorders. However, a single approach does not suit all patients, even within one disease indication. The degree of flexibility in treatment protocols is determined by individual product licenses, which often lag behind real-world clinical experience. A number of patient/practitioner surveys conducted recently have highlighted a desire for greater flexibility than that currently approved, both in BoNT doses and in the intervals between consecutive doses. New evidence arising from research conducted during the last few years has opened new avenues for tailoring BoNT treatment to patients' needs. Data suggest that escalating incobotulinumtoxinA doses enables treatment of a greater number of spasticity patterns than current dose limitations allow, without compromising safety or tolerability. Similarly, in patients with cervical dystonia (CD), repeated injections of incobotulinumtoxinA at intervals as early as 6 weeks after a previous treatment, based on individual patient need, were effective and well tolerated. Here, the BoNT doses and dosing intervals currently indicated in the USA and European Union are reviewed, together with the use of BoNT for the treatment of spasticity, CD, and blepharospasm. Opportunities for tailored BoNT therapy are also discussed. PMID- 29407166 TI - High level expression and immunochemical characterization of botulinum neurotoxin type F light chain. AB - Botulinum neurotoxins (BoNTs) are the most toxic biological substances known. Their potential use as biological warfare agent results in their classification as category A biowarfare agent by Centers for Disease Control and Prevention (CDC), USA. Presently, there are no approved detection system and pharmacological treatments for BoNT intoxication. Although a toxoid vaccine is available for immuno-prophylaxis, vaccines cannot reverse the effect of pre-translocated toxin. Direct handling of the live BoNTs for developing detection and therapeutics may pose fatal danger. This concern was addressed by purifying the recombinant catalytically active light chain of BoNT/F. BoNT/F-LC gene was amplified from the genomic DNA using specifically designed primers and expressed in Escherichia coli. Expression and purification profile were optimized under different conditions for biologically active light chain production. Specific polyclonal antibodies generated against type F illustrates in vivo neutralization in mice and rabbit. These antibodies play key role in conceiving the development of high throughput SPR based detection system which is a highly precise label free technique for protein interaction analysis. The presented work is first of its kind, signifying the production of highly stable and active rBoNT/F-LC and its immunochemical characterization. The study aids in paving the path towards developing a persistent detection system as well as in presenting comprehended scheme for in vitro small molecule therapeutics analysis. PMID- 29407167 TI - The world needs new knowledge. PMID- 29407168 TI - rLj-RGD3, a novel recombinant toxin protein from Lampetra japonica, prevents coronary thrombosis-induced acute myocardial infarction by inhibiting platelet functions in rats. AB - Recombinant Lampetra japonica RGD-peptide (rLj-RGD3), a soluble protein containing three RGD sequences, was acquired from the oral salivary glands of Lampetra japonica using recombinant DNA technology. The aim of this study was to investigate the protective effects of rLj-RGD3 against acute myocardial infarction (AMI) induced by coronary artery thrombosis, as well as the underlying mechanisms. A rat model of AMI caused by ferric chloride-induced thrombosis on the surface of the left anterior descending (LAD) coronary artery was successfully established. Rats were given various doses of rLj-RGD3 (12 MUg/kg, 24 MUg/kg and 48 MUg/kg) via sublingual intravenous delivery 10 min before AMI. ST segment elevation was recorded by electrocardiogram (ECG) until the end of the model. Left ventricular Evans blue content and histopathological changes were examined. Blood samples were collected to determine 5-hydroxytryptamine (5-HT), beta-thromboglobulin (beta-TG), platelet factor 4 (PF4) and cAMP levels. The effects of rLj-RGD3 on platelet aggregation, adhesion and intracellular calcium concentrations were also measured. rLj-RGD3 significantly reduced ST segment elevation, prevented thrombus formation in the coronary artery and decreased Evans blue content in the left ventricular myocardium. Meanwhile, rLj-RGD3 exerted an inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation and blocked platelet adhesion to collagen. Treatment with rLj-RGD3 prevented 5-HT, beta-TG and PF4 release and significantly elevated intracellular cAMP levels in a dose-dependent manner but decreased the level of cytosolic-free Ca2+, an aggregation-inducing molecule. These results show that rLj-RGD3 can effectively reduce coronary thrombosis in AMI rats by strongly inhibiting platelet function, indicating that the recombinant RGD toxin protein rLj-RGD3 may serve as a potent clinical therapeutic agent for AMI. PMID- 29407169 TI - The cucumber mosaic virus movement protein suppresses PAMP-triggered immune responses in Arabidopsis and tobacco. AB - Cucumber Mosaic Virus (CMV) has a small RNA genome that encodes a limited number of proteins, but can infect many plant species, including Arabidopsis thaliana and Nicotiana benthamiana. Virus proteins thus have multiple means of conferring their pathogenicity during the infection process. However, the pathogenic mechanism of CMV remains unclear. Here we discovered that the expression of the CMV movement protein (MP) in A. thaliana and N. benthamiana can suppress reactive oxygen species (ROS) production triggered by multiple pathogen-associated molecular patterns (PAMPs), such as bacteria-derived peptide flg22, elf18, and fungal-derived chitin. Transgenic Arabidopsis plants expressing the MP were compromised in flg22-induced immune activation and were more susceptible to Pseudomonas syringae pv. tomato (Pst) DC3000 hrcC- strain infection. Further analysis revealed that flg22-induced resistance gene expression was also compromised in MP transgenic plants. The CMV MP protein was previously reported to function in cell-to-cell movement processes, and our findings offer a new molecular mechanism for the CMV MP protein in suppression of host PAMP-triggered immune responses. PMID- 29407170 TI - TGFbeta1-induced down-regulation of microRNA-138 contributes to epithelial mesenchymal transition in primary lung cancer cells. AB - The existence of cancer stem cells within the tumor could lead to cancer therapy resistance. TGFbeta1 is considered as one of the most powerful players in the generation of CSCs through induction of epithelial-mesenchymal transition in different types of cancer including lung cancer, however, the detailed mechanisms by which TGFbeta1 contribute to EMT induction and CSC maintenance remains unclear. Here, we showed primary lung cancer cells treated by TGFbeta1 exhibit mesenchymal features, including morphology and expression of mesenchymal marker in a time-dependent manner. We also observed long-term TGFbeta1 exposure leads to an enrichment of a sub-population of CD44+ CD90+ cells which represent CSCs in lung cancer cells. Moreover, the differential expression microRNAs between CSCs and non-CSCs were identified using next-generation sequencing to screen key miRNAs which might contribute to TGFbeta1-induced EMT and CSCs generation. Among those differentially expressed miRNAs, the expression of microRNA-138 was time dependently down-regulated by TGFbeta1 treatment. We further demonstrated primary lung cancer cells, in which we knockdown the expression of miR-138, exhibit mesenchymal phenotypes and stem cell properties. Taken together, these findings indicate TGFbeta1-induced down-regulation of microRNA-138 contributes to EMT in primary lung cancer cells, and suggest that miR-138 might serve as a potential therapeutic target. PMID- 29407171 TI - StPOTHR1, a NDR1/HIN1-like gene in Solanum tuberosum, enhances resistance against Phytophthora infestans. AB - A family of NDR1/HIN1-like (NHL) genes that shows homology to the nonrace specific disease resistance (NDR1) and the tobacco (Nicotiana tabacum) harpin induced (HIN1) genes is reported to be involved in defense. However, little information about NHL genes is available for the potato (Solanum tuberosum). Here, we report that the expression of StPOTHR1, a member of the NHL gene family, is associated with resistance in potato against Phytophthora infestans, and is specifically induced in inoculation sites. Overexpression of StPOTHR1 enhances resistance against P. infestans via restricting rapid pathogen proliferation. Further, suppression of StPOTHR1 does not compromise R-mediated cell death. Subcellular localization and posttranscription modifications (PTMs) analysis reveals that StPOTHR1 is localized in plasma membrane (PM) and undergoes multiple PTMs. Moreover, StPOTHR1 interacts with NbMKK5L, a component of the MAP kinase signaling cascade. Taken together, our results suggest that the PM-localized StPOTHR1 contributes to potato immunity against P. infestans and may be associated with the MAP kinase signaling cascade. PMID- 29407172 TI - Nephron segment-specific gene expression using AAV vectors. AB - AAV9 vector provides efficient gene transfer in all segments of the renal nephron, with minimum expression in non-renal cells, when administered retrogradely via the ureter. It is important to restrict the transgene expression to the desired cell type within the kidney, so that the physiological endpoints represent the function of the transgene expressed in that specific cell type within kidney. We hypothesized that segment-specific gene expression within the kidney can be accomplished using the highly efficient AAV9 vectors carrying the promoters of genes that are expressed exclusively in the desired segment of the nephron in combination with administration by retrograde infusion into the kidney via the ureter. We constructed AAV vectors carrying eGFP under the control of: kidney-specific cadherin (KSPC) gene promoter for expression in the entire nephron; Na+/glucose co-transporter (SGLT2) gene promoter for expression in the S1 and S2 segments of the proximal tubule; sodium, potassium, 2 chloride co transporter (NKCC2) gene promoter for expression in the thick ascending limb of Henle's loop (TALH); E-cadherin (ECAD) gene promoter for expression in the collecting duct (CD); and cytomegalovirus (CMV) early promoter that provides expression in most of the mammalian cells, as control. We tested the specificity of the promoter constructs in vitro for cell type-specific expression in mouse kidney cells in primary culture, followed by retrograde infusion of the AAV vectors via the ureter in the mouse. Our data show that AAV9 vector, in combination with the segment-specific promoters administered by retrograde infusion via the ureter, provides renal nephron segment-specific gene expression. PMID- 29407173 TI - Comparison of two hyoscyamine 6beta-hydroxylases in engineering scopolamine biosynthesis in root cultures of Scopolia lurida. AB - Scopolia lurida, a medicinal plant native to the Tibetan Plateau, is among the most effective producers of pharmaceutical tropane alkaloids (TAs). The hyoscyamine 6beta-hydroxylase genes of Hyoscyamus niger (HnH6H) and S. lurida (SlH6H) were cloned and respectively overexpressed in hairy root cultures of S. lurida, to compare their effects on promoting the production of TAs, especially the high-value scopolamine. Root cultures with SlH6H/HnH6H overexpression were confirmed by PCR and real-time quantitative PCR, suggesting that the enzymatic steps defined by H6H were strongly elevated at the transcriptional level. Tropane alkaloids, including hyoscyamine, anisodamine and scopolamine, were analyzed by HPLC. Scopolamine and anisodamine contents were remarkably elevated in the root cultures overexpressing SlH6H/HnH6H, whereas that of hyoscyamine was more or less reduced, when compared with those of the control. These results also indicated that SlH6H and HnH6H promoted anisodamine production at similar levels in S. lurida root cultures. More importantly, HnH6H-overexpressing root cultures had more scopolamine in them that did SlH6H-overexpressing root cultures. This study not only provides a feasible way of overexpressing H6H to produce high-value scopolamine in engineered root cultures of S. lurida but also found that HnH6H was better than SlH6H for engineering scopolamine production. PMID- 29407174 TI - Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5-induced necroptosis and inflammation in microglia. AB - Multiple sclerosis (MS) is a long-lasting autoimmune disease of the central nervous system. Currently, the etiology of MS is not known. Experimental autoimmune encephalomyelitis (EAE), has been recognized as the most widely used animal models to study the molecular mechanisms underlying MS and the efficacy of potential drugs for treatment of MS. In the present study, we found that Dl-3-n butylphthalide (NBP), a neuroprotective drug in ischemic brain injury, prevented development of disease in experimental autoimmune encephalomyelitis (EAE) and significantly reduced inflammatory factors and necroptosis-associated genes, including PGAM5 in the spinal cord tissues. Similarly, silence of PGAM5 in spinal cord also ameliorated the disease severity in the mice with EAE. Moreover, re expression of PGAM5 counteracted the protective effect of NBP on the pathogenesis of EAE. Importantly, we found that both NBP and silence of PGAM5 inhibited cellular necroptosis and inflammation in microglia induced by TNFalpha plus zVAD fmk. Meanwhile, overexpression of PGAM5 reactivated cellular necroptosis and inflammation suppressed by NBP in vitro. Taken together, our findings provide evidence that NBP can attenuate the progression of EAE by suppressing PGAM5 induced necroptosis and inflammation in microglia and represents a new therapeutic strategy for treating autoimmune diseases. PMID- 29407175 TI - High expression of microRNA-4295 contributes to cell proliferation and invasion of pancreatic ductal adenocarcinoma by the down-regulation of Glypican-5. AB - A growing amount of evidence has documented that Glypican-5 (GPC5) is an important regulator of tumor progression. However, little is known about the role of GPC5 in pancreatic ductal adenocarcinoma (PDAC). In this study, we aimed to investigate the potential function and regulatory mechanism of GPC5 in PDAC. We found that GPC5 expression was significantly down-regulated in PDAC cell lines. The overexpression of GPC5 inhibited cell proliferation and the invasion of PDAC cells. In addition, the overexpression of GPC5 suppressed Wnt/beta-catenin signaling in PDAC cells. Bioinformatic analysis predicted that GPC5 was a target gene of microRNA-4295 (miR-4295). The inhibition of miR-4295 significantly up regulated the expression of GPC5. Moreover, the inhibition of miR-4295 inhibited the proliferation, invasion and Wnt/beta-catenin signaling in PDAC cells. Notably, the knockdown of GPC5 partially reversed the anti-tumor effect of miR 4295 inhibition. Taken together, our results suggest GPC5 as a tumor suppressor in PDAC and its expression is possibly regulated by miR-4295. Our study indicates that the miR-4295/GPC5 axis may play an important role in the pathogenesis of PADC and has potential applications for the development of PDAC therapy. PMID- 29407176 TI - Assessing the safety of an Ephedrae Herba aqueous extract in rats: A repeat dose toxicity study. AB - Ephedrae Herba (EH) has been used in Asian traditional herbal medicine to cure bronchial asthma, cold, flu, chills, fever, headache, nasal congestion, and cough. In this study, we evaluated the subchronic toxicity of an Ephedrae Herba aqueous extract (EHAE) in male and female F344 rats. The EHAE was administered orally daily at doses of 0, 125, 250, 500, and 1000 mg/kg bw/day for 13 weeks. Toxicological assessment was performed to determine mortality, clinical signs, and changes in body weight, food consumption, ophthalmological, urinary, hematological, and serum biochemical parameters, macroscopic and microscopic evaluations, and organ weights. We found that oral administration of EHAE to F344 rats for 13 weeks resulted in histopathological changes in the kidneys and salivary glands. In the kidneys, increased incidence and severity of tubular basophilia were observed in females administered 1000 mg/kg bw/day of the extract. In the salivary glands, acinar cell hypertrophy was observed in males administered 500 mg/kg bw/day and in both sexes administered 1000 mg/kg bw/day of the extract. All test article-treated groups of males and females administered >=250 mg/kg bw/day showed increased absolute and relative salivary gland weights. Therefore, the NOAEL (No Observed Adverse Effect Level) was determined as 125 mg/kg bw/day for both sexes of rats under the present experimental conditions. PMID- 29407177 TI - The roles of ions on bone regeneration. AB - Bone scientists are actively investigating a range of methods to promote skeletal tissue regeneration. A review of recent literature has revealed that several ions are uniquely capable of inducing stem cell differentiation down desired lineages. There exists enormous promise for these ions to be used in bone regenerative medicine. Given that these ions can be released from biodegradable polymeric materials, their long-term delivery can be achieved through a variety of controlled-release strategies compared with the relatively few options available for expensive and fragile polypeptide-based growth factors. In this review, we highlight the developments in using ions in conjunction with biomaterials for bone regeneration. PMID- 29407178 TI - Voltammetric monitoring of linezolid, meropenem and theophylline in plasma. AB - Treatment of healthcare associated Pneumonia (HCAP) caused by Methicillin resistant Staphylococcus aureus (MRSA) requires therapeutic protocols formed of linezolid (LIN) either alone or in combination with meropenem (MERO) and theophylline (THEO). The inter-individual pharmacokinetic variations require the development of reliable therapeutic drug monitoring (TDM) tools especially in immunocompromised patients. A sensitive square wave voltammetric sensor using multiwalled carbon nanotubes (MWCNTs) modified carbon paste electrode in Britton Robinson buffer was developed and validated. Experimental parameters such as pH, percentage of MWCNTs, and pre-concentration time were optimized. The sensor was employed at pH 11.0 for the determination of LIN in plasma within a concentration range of 2.5 * 10-8 - 8.0 * 10-6 mol L-1without interference from co-administered medications. On the other hand, simultaneous monitoring of LIN, MERO and THEO in plasma was feasible at pH 3.0 over concentration ranges of 4.0 * 10-7- 9.0 * 10 5, 8.0 * 10-7- 9.0 * 10-5 and 8.0 * 10-7 - 9.0 * 10-5 mol L-1, respectively. The performance of the proposed sensor was validated and the applicability for TDM has been demonstrated in plasma of healthy volunteers. PMID- 29407179 TI - A liquid chromatography tandem mass spectroscopy approach for quantification of protein methylation stoichiometry. AB - Post-translational modifications are biologically important and wide-spread modulators of protein function. Although methods for detecting the presence of specific modifications are becoming established, approaches for quantifying their mol modification/mol protein stoichiometry are less well developed. Here we introduce a ratiometric, label-free, targeted liquid chromatography tandem mass spectroscopy-based method for estimating Lys and Arg methylation stoichiometry on post-translationally modified proteins. Methylated Lys and Arg were detected with limits of quantification at low fmol and with linearity extending from 20 to 5000 fmol. This level of sensitivity allowed estimation of methylation stoichiometry from microgram quantities of various proteins, including those derived from either recombinant or tissue sources. The method also disaggregated total methylation stoichiometry into its elementary mono-, di-, and tri-methylated residue components. In addition to being compatible with kinetic experiments of protein methylation, the approach will be especially useful for characterizing methylation states of proteins isolated from cells and tissues. PMID- 29407180 TI - Allogeneic hematopoietic cell transplantation in T-cell prolymphocytic leukemia: A single-center experience. AB - BACKGROUND: T- cell prolymphocytic leukemia (T- PLL) is a rare aggressive hematological malignancy. Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is the treatment of choice for remission induction. Allogeneic hematopoietic cell transplantation (allo-HCT) has been described to induce durable remissions and improve survival, but data is limited. PATIENTS AND METHODS: We evaluated clinical outcomes of 11 patients, median age of 56 (range, 43-71) years who underwent allo-HCT for T-PLL. The majority of cases were in the first complete remission (CR1 = 9, CR2 = 1, second partial response PR2 = 1) at time of allo-HCT. Myeloablative conditioning was the most commonly prescribed preparative regimen (n = 8, 73%) and tacrolimus plus sirolimus was most commonly prescribed regimen for graft-versus-host disease prophylaxis (n = 5, 46%). RESULTS: The median follow-up for surviving patients was 48 (range, 6-123) months. The 4-year progression-free survival (PFS) and overall survival (OS) were 45% (95% confidence interval (CI) = 13-78%) and 56% (95% CI = 24-89%), respectively. Cumulative incidence of non-relapse mortality (NRM) at 4-year post transplantation was 34% (95%CI = 14-85%). The 4-year cumulative incidence of relapse/progression was 21% (95% CI = 6-71%). CONCLUSION: Allo-HCT is an effective treatment for T-PLL. Patients must be evaluated for their candidacy for allo-HCT as soon as the diagnosis is confirmed. Efforts are needed to decrease NRM and relapse. PMID- 29407181 TI - Abnormal CD25 expression on hematopoietic cells in myelodysplastic syndromes. AB - OBJECTIVE: To investigate the frequencies and biological characteristics of CD25 positive hematopoietic stem cells (HSC) in myelodysplastic syndromes. METHODS: The expression of CD25 on HSC in bone marrow derived from patients with untreated MDS patients, untreated AML patients and normal controls were accessed by flow cytometry (FCM). The correlation analysis was done between CD25+ HSC and clinical parameters in MDS patients. RESULTS: The expression of CD25 on HSC (CD34+CD38- cells) in MDS patients (28.81%) was significantly higher than that in normal controls (9.41%, P = 0.020), which similar to that in AML patients (32.54%, P = 0.410). The CD25 expression on HSC was positively correlated with the CD123 expression on HSC (r = 0.602, P = 0.008). The expression of CD25 on HSC in high risk MDS group (53.27%) based on IPSS score was significantly higher than that in low-risk MDS group (18.66%, P = 0.003). In MDS patients, CD25+ HSC were negatively correlated with the counts of neutrophils (r = -0.684, P = 0.002) and platelets (r = -0.561, P = 0.015), while positively correlated with the percentage of blasts in bone marrow (r = 0.596, P = 0.009). The CD25 expression on erythroblasts had a significant positive correlation with red blood cell counts in MDS patients (r = 0.536, P = 0.012). CONCLUSIONS: CD25 was over expressed on HSC in MDS patients, especially in high-risk MDS patients. Increased CD25+ HSC was correlated with progression of MDS. Low-expression of CD25 on erythroblasts might correlate with anemia in MDS patients. CD25 could be a specific marker of LSC in MDS, and could involve in the mechanisms of development and progression of MDS. PMID- 29407182 TI - Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML). AB - Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting >=3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML. PMID- 29407184 TI - Prognostic significance of The Wilms' Tumor-1 (WT1) rs16754 polymorphism in acute myeloid leukemia. AB - Acute myeloid leukemia is a genetically heterogeneous disease characterized by the accumulation of mutations in hematopoietic progenitor cells. For its heterogeneity, prognostic markers are very useful for therapeutic choice. The most important prognostic markers are age, white blood cell count, chromosomal alterations and gene mutations. Recent works have studied the prognostic significance of WT1 polymorphisms and mutations, highlighting the role of SNP rs16754 as a positive prognostic factor in AML patients. Nevertheless, the data are still unclear. To investigate the role of WT1 rs16754 polymorphism in AML, we designed a new tool for the detection using PNA directed PCR Clamping technology. Our data were able to establish a correlation between SNP rs16754 and the clinical outcome. Our results support the hypothesis that rs16754 polymorphism is an independent positive prognostic molecular marker that could be useful for therapeutic choice. In view of this, we described a novel assay faster, more sensitive and cheaper than DNA sequencing. The assay allows evaluating WT1 rs16754 polymorphism in diagnostic routine to improve prognostic information faster and without over-costing for diagnostic laboratories. PMID- 29407183 TI - Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS. AB - Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions. PMID- 29407185 TI - Effects of two-dimensional versus three-dimensional landmark geometry and layout on young children's recall of locations from new viewpoints. AB - Spatial memory is an important aspect of adaptive behavior and experience, providing both content and context to the perceptions and memories that we form in everyday life. Young children's abilities in this realm shift from mainly egocentric (self-based) to include allocentric (world-based) codings at around 4 years of age. However, information about the cognitive mechanisms underlying acquisition of these new abilities is still lacking. We examined allocentric spatial recall in 4.5- to 8.5-year-olds, looking for continuity with navigation as previously studied in 2- to 4-year-olds and other species. We specifically predicted an advantage for three-dimensional landmarks over two-dimensional ones and for recalling targets "in the middle" versus elsewhere. However, we did not find compelling evidence for either of these effects, and indeed some analyses even support the opposite of each of these conclusions. There were also no significant interactions with age. These findings highlight the incompleteness of our overall theories of the development of spatial cognition in general and allocentric spatial recall in particular. They also suggest that allocentric spatial recall involves processes that have separate behavioral characteristics from other cognitive systems involved in navigation earlier in life and in other species. PMID- 29407186 TI - The benefits of adding a brief measure of simple reaction time to the assessment of executive function skills in early childhood. AB - Early childhood represents a period of rapid cognitive developmental change in executive function (EF) skills along with a variety of related cognitive processes, including processing speed. This leads to interpretational challenges in that children's performance on EF tasks reflects more than EF skills per se. We tested whether the inclusion of a brief measure of simple reaction time (SRT) during EF assessments could help to partially address this challenge. Data were drawn from a cross-sectional convenience sample of 830 preschool-aged children. Individual differences in SRT were significantly associated with performance on all tasks (R2s = .09-.26); slower performance on the SRT task was associated with poorer performance on each EF task. Age-related differences in individual EF tasks were reduced by approximately one half after accounting for age-related differences in SRT, and EF task scores were less coherent (i.e., less strongly intercorrelated with each other) after the removal of SRT. Age-related differences in EF were smaller (Cohen ds = 1.36 vs. 0.78), and poverty-related differences in EF were larger (Cohen ds = 0.30 vs. 0.46) after accounting for SRT related variation. Finally, consistent with previous studies, SRT-related differences in fluid reasoning were mediated by EF skills. Results are discussed with respect to using a brief measure of SRT to partially address the problem of measurement impurity at the level of individual EF tasks. PMID- 29407187 TI - Impact of rotation angle on crawling and non-crawling 9-month-old infants' mental rotation ability. AB - The current study investigated whether 9-month-old infants' mental rotation performance was influenced by the magnitude of the angle of object rotation and their crawling ability. A total of 76 infants were tested; of these infants, 39 had been crawling for an average of 9.0 weeks. Infants were habituated to a video of a simplified Shepard-Metzler object (Shepard & Metzler, 1971), always rotating forward through a 180 degrees angle around the horizontal axis of the object. After habituation, in two different test conditions, infants were presented with test videos of the same object rotating farther forward through a previously unseen 90 degrees angle and with a test video of its mirror image. The two test conditions differed in the magnitude of the gap between the end of the habituation rotations and the beginning of the test rotations. The gaps were 0 degrees and 54 degrees . The results revealed that the mental rotation performance was influenced by the magnitude of the gaps only for the crawling infants. Their response showed significant transition from a preference for the mirror object rotations toward a preference for the familiar habituation object rotations. Thus, the results provide first evidence that it is easier for 9-month old crawling infants to mentally rotate an object along a small angle compared with a large one. PMID- 29407188 TI - Patterns and dynamics of the human appropriation of net primary production and its components in Tibet. AB - Anthropogenic activities have induced profound changes across the globe. Human appropriation of net primary production (HANPP) is a useful indicator for quantifying anthropogenic influences on natural ecosystems. We applied a detailed HANPP framework to the Tibet Autonomous Region of China for the period 1989-2015 and performed clustering analysis to explore county-level dynamics of HANPP components. The results indicated a continuous increase in HANPP per unit area from 10.3 g C/m2/yr in 1989 to 18.5 g C/m2/yr in 2008, with some fluctuation and a decline to 16.8 C/m2/yr in 2015. As a percentage of potential net primary production (NPPpot), HANPP increased from 6.9% to 13.5%. This rise was mainly driven by the commercialization of animal husbandry and by ecological conservation policies. Animal stocks dominated HANPP in Tibet in 1989, and by 2015 beef or crop production had become predominant in 30 of 73 counties. However, HANPP did not change uniformly across all locations. Changes were mainly concentrated in the south-central river valley area because of the growth in beef and crop production there. While in almost half of the 73 counties located in the northwestern regions, HANPP was dominated by sheep stocks and changed only slightly over the study period. These findings indicate that a comprehensive spatiotemporal analysis of HANPP components in Tibet provides deeper insights into changes in production and livelihood strategies of local residents, aligned with ecological conservation policies and economic development. Moreover, it unravels the complex impacts of human activities on alpine ecosystems, and indicates the need to optimize local ecosystem management and conservation policies. PMID- 29407189 TI - Community-Based Monitoring as the practice of Indigenous governance: A case study of Indigenous-led water quality monitoring in the Yukon River Basin. PMID- 29407190 TI - Analysis of influencing factors on public perception in contaminated site management: Simulation by structural equation modeling at four sites in China. AB - Public perception towards contaminated site management, a not readily quantifiable latent parameter, was linked through structural equation modeling in this paper to 22 measurable/observable manifest variables associated with the extent of information dissemination and public knowledge of soil pollution, attitude towards remediation policies, and participation in risk mitigation processes. Data obtained through a survey of 412 community residents at four remediation sites in China were employed in the model validation. The outcomes showed that public perception towards contaminated site management might be explained through selected measurable parameters in five categories, namely information disclosure, knowledge of soil pollution, expectations of remediation and redevelopment outcomes, public participation, and site policy, along with their interactions. Among these, information dissemination and attitude towards management policies exhibited significant influence in promoting positive public perception. Based on these examples, responsible agencies therefore should focus on public accessibility to reliable information, and encourage public inputs into policies for contaminated site management, in order to gain public confidence during remediation and regeneration projects. PMID- 29407191 TI - Impact of chirality on the Glass Forming Ability and the crystallization from the amorphous state of 5-ethyl-5-methylhydantoin, a chiral poor glass former. AB - The investigation of the glassy state of 5-ethyl-5-methylhydantoin (i.e. 12H, a chiral Active Pharmaceutical Ingredient) was attempted by Differential Scanning Calorimetry (DSC) and Fast Scanning Calorimetry (FSC). This compound exhibits a high crystallization propensity for every enantiomeric composition. Nevertheless, glassy states of pure enantiomer or mixtures between enantiomers were successfully reached by FSC at cooling rates of: 1000 degrees C/s and 300 degrees C/s respectively, even though limitations on the sampling reproducibility were evidenced due to FSC sample size. The Glass Forming Ability (GFA) was proven to increase with the counter-enantiomer content. From the glassy state, pure enantiomer displayed a more pronounced crystallogenic character (with a crystallization occurring 36 degrees C below Tg during ageing) than that of the mixture between enantiomers. Ageing of amorphous 12H promotes a strong nucleation behavior in both samples but enantiopure 12H crystallizes upon ageing while scalemic 12H evolves towards the metastable equilibrium. Finally, potential new phase equilibria (previously not reported) in the enantiomeric phase diagram could have been highlighted by FSC by recrystallization from the amorphous state. PMID- 29407192 TI - The truncated Rv2820c of Mycobacterium tuberculosis Beijing family augments intracellular survival of M. smegmatis by altering cytokine profile and inhibiting NO generation. AB - Genetic variations among genes of Mycobacterium tuberculosis may be associated with antigenic variation and immune evasion, which complicates the pathogenesis of M. tuberculosis. The hyper-virulent M. tuberculosis Beijing strains harbored several large sequence deletions, among which RD207 attributed to the deletion of CRISPR loci and several Cas genes. RD207 also gave rise to a truncated gene Rv2820c-Bj with 60% deletion in length at the 3'-end and a new 3'-end of five amino acid mutations. It has been reported that Rv2820c-Bj correlated with enhanced intracellular survival of M. smegmatis in macrophages when compared to its full-length counterpart Rv2820c in M. tuberculosis, however, the respective contribution of the truncation and the new 3'-end of Rv2820c-Bj to this enhancement was unclear. Here, by infecting THP-1 macrophages with Ms_Rv2820c-Bj, Ms_Rv2820c and MS_Rv2820c-Tr (expressing the truncated Rv2820c without five amino acid mutations at 3'-end), we found only Ms_Rv2820c-Bj was responsible for the enhancement of survival of M. smegmatis in macrophages. Furthermore, we detected that Ms_Rv2820c-Tr and Ms_Rv2820c-Bj induced similar cytokine profile and NO production after infection of macrophages, which was distinctly different from Ms_Rv2820c. However, Ms_Rv2820c-Bj evoked higher levels of interleukin-10 (IL-10) and lower levels of interleukin- 6 (IL-6), interleukin-1beta (IL-1beta) and interleukin-12 (IL-12) in infected THP-1 macrophages than Ms_Rv2820c-Tr. Accordingly, we concluded that the new 3'-end of Rv2820c-Bj was important to dampen host defense and enhance the intracellular survival of M. smegmatis. PMID- 29407193 TI - Genetic susceptibility to invasive pneumococcal disease. AB - BACKGROUND: The pathogenesis of IPD remains unknown, especially among middle-aged individuals without risk factors (WRF). OBJECTIVES: The aim of the present study was to investigate the role of single nucleotide polymorphisms (SNP) within key genes involved in innate immune response on IPD susceptibility. METHODS: Forty three SNPs within 10 immunological genes were investigated in a cohort of 144 Caucasian IPD patients and 280 ethnically matched controls. RESULTS: The allele distribution of the NFKBIA rs1050851 and NFKBIE rs2282151 variants were associated with IPD susceptibility (chi2 = 4.23, p = 0.04 and chi2 = 5.13, p = 0.02, respectively). Additionally, the genotype distribution of NFKBIZ rs645781 (chi2 = 8.25, p = 0.02) and IL1R1 rs3917254 (chi2 = 6.70, p = 0.04) were also associated with IPD risk. When only IPD-WRF patients were considered; the allele distribution of IL1R1 rs2160227 (chi2 = 5.62, p = 0.03), rs13020778 (chi2 = 5.73, p = 0.02), rs3917267 (chi2 = 3.72, p = 0.05) and IL4 rs2227284 (chi2 = 3.76, p = 0.05) and the genotype distribution of IL10 rs3024509 (chi2 = 7.70, p = 0.02), IL1R1 rs3917254 (chi2 = 13.40, p = 0.001), NFKBIZ rs645781 (chi2 = 13.86, p = 0.001) and rs677011 (chi2 = 9.06, p = 0.01) variants were associated with IPD risk. CONCLUSIONS: We found several associations between variants in the IL1R1, IL4, IL10, NFKBIE, NFKBIA, and NFKBIZ genes and risk of IPD. If validated, these biomarkers may help to identify people with higher risk of IPD. PMID- 29407194 TI - Alpha 1 adrenergic receptor-mediated inflammatory responses in human testicular peritubular cells. AB - Stress activates the sympathetic nervous system and is linked to impaired fertility in man. We hypothesized that catecholamines by acting on testicular cells have a role in these events, possibly by fostering an inflammatory environment. The cells of the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), express adrenergic receptors (ADRs) alpha1B, alpha1D, beta1 and beta2. A selective alpha1-ADR agonist, phenylephrine, increased intracellular Ca2+-levels in cultured HTPCs and induced COX-2, IL-6 and MCP-1 mRNA expression without affecting IL-1beta mRNA. These changes were paralleled by a significant increase in the secretion of IL-6 and MCP-1. Epinephrine was also effective, but salbutamol, a selective beta2-ADR agonist was not. Our results suggest that stress-associated elevation of catecholamines may be able to promote inflammatory events by targeting peritubular cells in the human testis. Blockage of alpha1-ADRs may therefore be a novel way to interfere with stress-related impairment of male reproductive functions. PMID- 29407195 TI - Effect of hypoxia on caveolae-related protein expression and insulin signaling in adipocytes. AB - Obesity is characterized by hypertrophy and hyperplasia of adipose tissue, which have been related to the development of hypoxia and insulin resistance. On the other hand, caveolin-1 (Cav-1), one of the main proteins of caveolae, promotes insulin receptor (IR) phosphorylation and the subsequent activation of insulin signaling. In this work we investigated the effect of hypoxia on Cav-1 regulation and the status of insulin signaling in 3T3-L1 adipocytes. Our results showed that hypoxia inhibited adipogenesis and insulin signaling in adipocytes. Furthermore, 48 h of hypoxia reduced insulin-induced glucose uptake while increased basal glucose uptake. This result was consistent with the upregulation of glucose transporter GLUT1 and the downregulation of GLUT4, which also showed defective translocation to plasma membrane when adipocytes were stimulated with insulin. In addition, the expression of caveolae-related proteins was reduced by hypoxia and chromatin immunoprecipitation assay demonstrated that Cav-1 transcription was directly regulated by HIF-1. These results strengthen the role of caveolae in insulin signaling and help to explain adipocyte response to hypoxia. PMID- 29407196 TI - Determination of EPAC2 function using EPAC2 null Min6 sublines generated through CRISPR-Cas9 technology. AB - Min6 cells, a mouse beta cell line derived from transgenic mouse expressing the large T-antigen of SV40 in pancreatic beta cells, are commonly utilized as an in vitro cellular model for investigating targets involved in insulin secretion. Epac2, an exchange protein that can be directly activated by cyclic AMP (cAMP), is critical for pharmacologic stimuli-induced insulin secretion and has been hypothesized to be a direct target of sulfonylurea. Previous loss of function studies only specifically knocked out EPAC2 isoform A, leaving the other two isoforms intact. In this study, we investigated the function of EPAC2 in Min6 cells by generating EPAC2 knock-out sublines using CRISPR-Cas9 technology, by removing all three isoforms of EPAC2. Our results indicate that Min6 cells can be successfully cloned from a single cell after electroporation with plasmids expressing EPAC2 specific guide RNA, Cas9 and GFP, followed by sorting for GFP expressing single cells. Two clones were found to have a single nucleotide deletion in targeted site of EPAC2 gene by sequencing, therefore creating a frame shift in exon 13. The EPAC2 null clones have an unexpectedly increased secretion of insulin at basal level and an elevated total intracellular insulin content. However, EPAC2 deficiency impaires glucose and sulfonylurea induced insulin secretion without affecting sulfonylurea binding to cells. Potassium chloride induced insulin secretion remains intact. Interestingly, cAMP levels remained unchanged in EPAC2 null cells during these processes. To understand the global function of EPAC2, RNA Seq study was performed, which reveals that EPAC2 deficiency affects expression of multiple previously unrecognized genes, suggesting that EPAC2 can function through multiple pathways in addition to being a cAMP sensor. PMID- 29407197 TI - You make me tired: An experimental test of the role of interpersonal operant conditioning in fatigue. AB - Chronic fatigue is highly prevalent in the general population as well as in multiple chronic diseases and psychiatric disorders. Its etiology however remains poorly understood and cannot be explained by biological factors alone. Occurring in a psychosocial context, the experience and communication of fatigue may be shaped by social interactions. In particular, interpersonal operant conditioning may strengthen and perpetuate fatigue complaints. In this experiment, individuals (N = 44) repeatedly rated their currently experienced fatigue while engaging in cognitive effort (working memory task). Subtle social reward was given when fatigue increased relative to the previous rating; or disapproval when fatigue decreased. In the control condition, only neutral feedback was given. Although all participants became more fatigued during cognitive effort, interpersonal operant conditioning led to increased fatigue reporting relative to neutral feedback. This effect occurred independently of conscious awareness. Interestingly, the experimental condition also performed worse on the working memory task. Results suggest that fatigue complaints (and cognitive performance) may become controlled by their consequences such as social reward, and not exclusively by their antecedents such as effort. Results have implications for treatment development and suggest that interpersonal operant conditioning may contribute to fatigue becoming a chronic symptom. PMID- 29407198 TI - Sleep-related attentional bias for tired faces in insomnia: Evidence from a dot probe paradigm. AB - People with insomnia often display an attentional bias for sleep-specific stimuli. However, prior studies have mostly utilized sleep-related words and images, and research is yet to examine whether people with insomnia display an attentional bias for sleep-specific (i.e. tired appearing) facial stimuli. This study aimed to examine whether individuals with insomnia present an attentional bias for sleep-specific faces depicting tiredness compared to normal-sleepers. Additionally, we aimed to determine whether the presence of an attentional bias was characterized by vigilance or disengagement. Forty-one individuals who meet the DSM-5 criteria for Insomnia Disorder and 41 normal-sleepers completed a dot probe task comprising of neutral and sleep-specific tired faces. The results demonstrated that vigilance and disengagement scores differed significantly between the insomnia and normal-sleeper groups. Specifically, individuals with insomnia displayed difficulty in both orienting to and disengaging attention from tired faces compared to normal-sleepers. Using tired facial stimuli, the current study provides novel evidence that insomnia is characterized by a sleep-related attentional bias. These outcomes support cognitive models of insomnia by suggesting that individuals with insomnia monitor tiredness in their social environment. PMID- 29407199 TI - Paper-based immunosensor with signal amplification by enzyme-labeled anti p16INK4a multifunctionalized gold nanoparticles for cervical cancer screening. AB - The aim of this study was to develop a paper-based immunosensor for cervical cancer screening, with signal amplification by multifunctionalized gold nanoparticles (AuNPs). The AuNPs were functionalized with a highly specific antibody to the p16INK4a cancer biomarker. The signal was amplified using a combination of the peroxidase activity of horseradish peroxidase (HRP) enzyme antibody conjugate and the peroxidase-like activity of the AuNPs. The immune complex of p16INK4a protein and multifunctionalized AuNPs was deposited on the nitrocellulose membrane, and a positive result was generated by catalytic oxidation of peroxidase enzyme substrate 3,3',5,5'-Tetramethylbenzidine (TMB). The entire reaction occurred on the membrane within 30 min. Evaluation in clinical samples revealed 85.2% accuracy with a kappa coefficient of 0.69. This proof of concept study demonstrates the successful development of a highly accurate, paper-based immunosensor that is easy to interpret using the naked eye and that is suitable for cervical cancer screening in low-resource settings. PMID- 29407200 TI - Interplay of gender, age and drug properties on reporting frequency of drug induced liver injury. AB - We examined the effect of gender, age, and drug properties on liver events reporting frequency (RF) to assess patient- and drug-related risks for drug induced liver injury (DILI). We performed a data-mining analysis of the WHO VigiBaseTM to 1) identify drugs with gender- and age-biased RF and 2) characterize drug properties using the Liver Toxicity Knowledge Base. Age-, gender-specific Empirical Bayes Geometric Mean of relative reporting ratio of liver events with 90% confidence interval (CI) was calculated for 375 drugs with DILI potential. Forty-one drugs showed an increased RF in women, which had a higher prevalence of reactive metabolite formation and mitochondrial dysfunction and transporter inhibition. Fifty-nine drugs showed an increased RF in younger women (<50 yrs), many of which had a signature pattern of hepatocellular injury. In contrast, half of 17 drugs that showed an increased RF in men had a cholestatic pattern. In the older group (>=50 yrs), 17 drugs showed an increased RF and had higher transporter inhibition, Cmax, and plasma protein binding, yet shorter plasma elimination. Specific drug properties were associated with gender- and age-biased liver events RF, suggesting possible interactions of drug properties, gender, and age in DILI development. PMID- 29407201 TI - Repeated dose 28-day oral toxicity study of a botanical composition composed of Morus alba and Acacia catechu in rats. AB - Patients with osteoarthritis experience debilitating pain and loss of joint function that requires chronic treatment. While nonsteroidal anti-inflammatory drugs (NSAIDs) have been effective for temporary symptomatic relief, their long term usage has been limited by their associated side-effects. UP1306, a standardized novel composition from the extracts of root barks of Morus alba and the heartwoods of Acacia catechu, has been used in over the counter joint care dietary supplements as a safer alternative. These two medicinal plants have long track records of safe human consumption. Here we evaluated the potential adverse effects of orally administered UP1306 in Sprague Dawley rats following a 28-day repeated oral dose toxicity study. UP1306 at doses of 500, 1000 and 2000 mg/kg/day were administered orally to rats for 4 weeks. A 2-week recovery group from the high dose (2000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Minor aberrations from the normal observed for the main groups were considered reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP1306 was considered to be the highest dose tested, 2000 mg/kg/day, both for male and female rats. PMID- 29407202 TI - A comparison of fish pesticide metabolic pathways with those of the rat and goat. AB - Ecological risk assessments are often limited in their ability to consider metabolic transformations for fish species due to a lack of data. When these types of evaluations are attempted they are often based on parent chemical only, or by assuming similarity to available mammalian metabolic pathways. The metabolism maps for five pesticides (fluazinam, halauxifen-methyl, kresoxim methyl, mandestrobin, and tolclofos-methyl) were compared across three species. A rapid and transparent process, utilizing a database of systematically collected information for rat, goat, and fish (bluegill or rainbow trout), and using data evaluation tools in the previously described metabolism pathway software system MetaPath, is presented. The approach demonstrates how comparisons of metabolic maps across species are aided by considering the sample matrix in which metabolites were quantified for each species, differences in analytical methods used to identify metabolites in each study, and the relative amounts of metabolites quantified. By incorporating these considerations, more extensive rat and goat metabolism maps were found to be useful predictors of the more limited metabolism of the five pesticides in fish. PMID- 29407203 TI - Toxicological evaluation of 3'-sialyllactose sodium salt. AB - The safety of 3'-sialyllactose (3'-SL) sodium salt was evaluated by testing for gene mutations, in vivo and in vitro clastogenic activity, and animal toxicity in beagle dogs and rats. The results of all mutagenicity and genotoxicity tests were negative, indicating that 3'-SL does not have any mutagenic or clastogenic potential. The mean lethal dose (LD50) of 3'-SL sodium salt was well above 20 g/kg body weight (bw) in rats. A dose escalation acute toxicity study in Beagle dogs also indicated no treatment-related abnormalities. Subsequent 28-day and 90 day toxicity studies in Sprague- Dawley (SD) rats involved dietary exposure to 500, 1,000, and 2000 mg/kg bw of 3'-SL sodium salt and a water (vehicle) control. There were no treatment-related abnormalities on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, organ weights, relative organ weights, urinalysis parameters, or necropsy and histopathological findings. The No Observed Adverse Effect Level (NOAEL) of 3'-SL sodium salt was determined to be higher than 2000 mg/kg bw/day in an oral subchronic toxicity study in rats, indicating that the substance is an ordinary carbohydrate with the lowest toxicity rating. Results confirm that 3'-SL sodium salt has a toxicity profile similar to other non-digestible carbohydrates and naturally occurring human milk oligosaccharides (HMOs) and support its safety for human consumption in foods. PMID- 29407204 TI - Dispatcher-assisted bystander cardiopulmonary resuscitation in rural and urban areas and survival outcomes after out-of-hospital cardiac arrest. AB - OBJECTIVES: We investigated the impact of dispatcher-assisted bystander cardiopulmonary resuscitation (DA-BCPR) on survival outcomes after out-of hospital cardiac arrests (OHCAs) that occurred in rural and urban areas. METHODS: This study was a cross-sectional study using nationwide emergency medical services (EMS)-based OHCA registry in Korea. All EMS-treated adults with OHCAs and with presumed cardiac etiology were enrolled between 2012 and 2015, excluding cases witnessed by an EMS provider. BCPR was categorized into 3 groups: BCPR-with DA, BCPR-without-DA, and No-BCPR. The endpoint was good neurologic recovery at discharge. We compared the effects of BCPR on outcomes between rural and urban areas, using a multivariable logistic regression with an interaction term. RESULTS: A total of 53,240 patients (36.3% BCPR-with-DA and 12.8% BCPR-without DA) were included. Among OHCAs that occurred in rural areas (32.3% BCPR-with-DA and 14.0% BCPR-without-DA) and urban areas (36.9% BCPR-with-DA and 12.5% BCPR without-DA), good neurological recovery was demonstrated in 1.6% and 6.8% of the patients in rural and urban areas, respectively (p < 0.01). The patients with OHCAs who received BCPR in both rural and urban areas were more likely to have good neurologic recovery than the No-BCPR group (AORs, 3.53 (1.84-6.77) BCPR-with DA and 2.56 (1.23-5.32) BCPR-without-DA in rural; and 1.59 (1.41-1.79) BCPR-with DA and 1.37 (1.18-1.60) BCPR-without-DA in urban). The effects of the measures of BCPR-with-DA on the outcome were more apparent in rural areas compared to urban areas. CONCLUSIONS: BCPR, regardless of DA, was associated with improved neurologic recovery after OHCA in rural and urban areas. However, the effect of BCPR-with-DA was prominent for OHCA that occurred in rural areas. PMID- 29407205 TI - Women have worse cognitive, functional, and psychiatric outcomes at hospital discharge after cardiac arrest. AB - AIM: To examine gender differences among cardiac arrest (CA) survivors' cognitive, functional, and psychiatric outcomes at discharge. METHODS: This is a prospective, observational cohort of 187 CA patients admitted to Columbia University Medical Center, considered for Targeted Temperature Management (TTM), and survived to hospital discharge between September 2015 and July 2017. Patients with sufficient mental status at hospital discharge to engage in the Repeatable Battery for Neuropsychological Status (RBANS), Modified Lawton Physical Self Maintenance Scale (M-PSMS), Cerebral Performance Category Scale (CPC), Center for Epidemiological Studies Depression Scale (CES-D), and Post-Traumatic Stress Disorder Checklist - Civilian Version (PCL-C) were included. Fisher's exact, Wilcoxon Rank Sum, and regression analysis were utilized. RESULTS: 80 patients (38% women, 44% white, mean age 53 +/- 17 years) were included. No significant gender differences were found for age, race, Charlson Comorbidity Index, premorbid CPC or psychiatric diagnoses, arrest related variables, discharge CPC, or PCL-C scores. Women had significantly worse RBANS (64.9 vs 74.8, p = .01), M PSMS (13.6 vs 10.6, p = .02), and CES-D (22.8 vs 14.3, p = .02) scores. These significant differences were maintained in multivariate models after adjusting for age, initial rhythm, time to return of spontaneous circulation, and TTM. CONCLUSIONS: Women have worse cognitive, functional, and psychiatric outcomes at hospital discharge after cardiac arrest than men. Identifying factors contributing to these differences is of great importance in cardiac arrest outcomes research. PMID- 29407206 TI - Animal models of cardiac arrest: A systematic review of bias and reporting. AB - AIM OF THE REVIEW: Animal models are essential in advancing resuscitation research but are susceptible to various biases compromising internal validity, which may explain unsuccessful transition to human clinical trials. This study aimed to assess risk of bias in animal studies of cardiac arrest. DATA SOURCES: This study was based on a previous systematic review of all animal cardiac arrest studies published between March 8, 2011 and March 8, 2016 in PubMed and EMBASE. For this study, we focused on interventional studies and selected a random sample of 50 pig and 50 rat studies. We used a modified version of the SYRCLE's risk of bias tool for animal studies. Bias assessment was performed by two independent reviewers. RESULTS: 92% of pig studies and 88% of rat studies used randomization to assign interventions, but the methodology was unknown or insufficiently reported in 60% and 68% of the studies, respectively. Correct timing of randomization was lacking or unclear in over half of the studies. 40% of pig studies and 28% of rat studies reported insufficient baseline characteristics. When possible, blinding was not performed/reported in 68% of rat studies and 31% of pig studies. Blinding of outcome assessors was missing or inadequately reported in 65% of pig studies and 60% of rat studies. 80% of all studies lacked a sample size calculation, while 60% of pig and 80% of rat studies omitted a specified primary outcome. CONCLUSION: This study indicates insufficient reporting and methodological shortcomings in animal models of cardiac arrest. PMID- 29407207 TI - Improved detection of grapevine latent viroid by RT-qPCR, its bioassay analysis, and its rare occurrence worldwide. AB - Three of the five well-known viroids infecting grapevine belong to the genus Apscaviroid. Grapevine latent viroid (GLVd) is a novel grapevine viroid. Although GLVd has the typical sequence motifs of the genus Apscaviroid, it is still an unassigned viroid. In this study, a sensitive, convenient, and rapid one-step RT qPCR method using hydrolysis probes for the detection of GLVd was developed. Survey and bioassays were also performed for this viroid. Using this method in the survey of GLVd, a low infection rate of 2/226 in a grapevine germplasm resource nursery and a demonstration vineyard in China was determined. Bioassays using agroinfiltration showed that GLVd can infect 'Kyoho' grapevine but not any of the tested herbaceous plants. Furthermore, sequence variability of GLVd was analyzed in six GLVd-infected grapevines. Sequencing revealed a predominant variant with only a few nucleotide changes compared with the reference variant of GLVd. Therefore, the developed RT-qPCR method should be helpful for determining GLVd in other vineyards of the world. The low infection rate, host range, and sequence variability of GLVd have important implications to further improve our knowledge on this novel grapevine viroid. PMID- 29407208 TI - Assessment of a swab collection method without virus transport medium for PCR diagnosis of coxsackievirus infections. AB - Classically, detection of human enterovirus (EV) infections is based on virus isolation in tissue culture, proper sample collection and handling that optimizes virus viability. Samples are collected in virus transport medium (VTM) to ensure virus stability. High sensitivity and rapid results have made polymerase chain reaction (PCR) analysis increasingly popular for routine diagnosis. The PCR method enables simple sample collection and storage for EV diagnostics, which may eventually allow self-sampling at home. Our aim was to test a modification of the conventional clinical swab sample collection method for molecular diagnosis of EV infection. We compared swabs (cotton or synthetic) without VTM and the classical standard synthetic swabs with VTM. Effects of storage temperature (+4 degrees C or -80 degrees C) and duration were studied. EV-RNA could be detected by reverse transcriptase and nested PCR in both swab types without VTM. Differences depended on the storage duration and temperature. Optimum conditions were immediate processing or storage at -80 degrees C. Storage without VTM at +4 degrees C for longer periods is not advisable. We conclude that swabs without VTM can be considered for clinical EV-diagnostics based on PCR, and ultimately for epidemiological sample collection. PMID- 29407209 TI - Development of a novel digital RT-PCR method for detection of human sapovirus in different matrices. AB - A new nanofluidic digital RT-PCR method was developed for sapovirus (SaV) using control material obtained according to standards for enteric viruses. Primers employed amplify a fragment of 112 bp of the polymerase capsid junction, allowing the detection of human genogroups I, II and IV. Analytical validation was performed in clinical, shellfish and environmental water samples. This novel protocol rendered great effectiveness and repetitiveness, as well as higher sensitivity than real time RT-PCR assay, with differences in quantification ranging from 0.1 to 2.6 log-units. The method described here can constitute a promising tool for standardizing SaV quantification. PMID- 29407210 TI - New design of probe and central-homo primer pairs to improve TaqManTM PCR accuracy for HBV detection. AB - Quantitative PCR (qPCR) assay using TaqManTM probe was widely used in the detection of different nucleic acids. However, this technology has several drawbacks, including false negative results caused by primer-dimer (PD) and false positive issues due to primer-probe aggregations. Here, we designed a modified TaqManTM-Molecular Beacon probe by adding an antisense base and a new type of primer pair named central-homo primer pairs bearing 5-10 bases homologous sequence on the 3' end. Using the HBV qPCR assay as a proof of concept, the new design significantly improved the accuracy of the TaqManTM qPCR assay for HBV detection. Application of the central-homo primer pair led to significantly delayed Ct values by 5-10 cycles compared with conventional primer design. The modified probe containing an antisense base did not produce any detectable signal in repeating primer-probe aggregation experiments. Furthermore, the use of the central-homo primer pair and the non-competitive internal control could solve the false negative problem caused by PD formation. We validated this customized duplex qPCR system using 208 clinical samples collected from patients in clinic showing accuracy was higher than that of the conventional qPCR method. PMID- 29407211 TI - Evaluation of the inactivation of Venezuelan equine encephalitis virus by several common methods. AB - Working with virological samples requires validated inactivation protocols for safe handling and disposal. Although many techniques exist to inactivate samples containing viruses, not all procedures have been properly validated or are compatible with subsequent assays. To aid in the development of inactivation protocols for Alphaviruses, and specifically Venezuelan equine encephalitis virus (VEEV), a variety of methods were evaluated for their ability to completely inactivate a high titer sample of the vaccine strain VEEV TC-83. The methods evaluated include reagents used in RNA extraction, fixation, treatment with a detergent, and heat inactivation. Most methods were successful at inactivating the sample; however, treatment with only Buffer AVL, SDS, and heat inactivation at 58 degrees C for one hour were not capable of complete inactivation of the virus in the sample. These results provide a substantial framework for identifying techniques that are safe for complete inactivation of Alphaviruses and to advise protocol implementation. PMID- 29407212 TI - Development of recombinase polymerase amplification assays for the rapid detection of peste des petits ruminants virus. AB - Peste des petits ruminants (PPR) is a severe infectious disease of small ruminants caused by PPR virus (PPRV). Rapid and sensitive detection of PPRV is critical for controlling PPR. This report describes the development and evaluation of a conventional reverse transcription recombinase polymerase amplification (RT-RPA) assay and a real-time RT-RPA assay, targeting the PPRV N gene. Sensitivity analysis revealed that the conventional RT-RPA assay could detect 852 copies of standard PPRV RNA per reaction at 95% probability within 20 min at 41 degrees C, and the real-time RT-RPA assay could detect 103 copies of RNA molecules per reaction at 95% probability. Specificity analysis showed that both assays have no cross-reactivity with nucleic acid templates prepared from other selected viruses or common pathogens. Clinical evaluation using 162 ovine and hircine serum and nasal swab samples showed that the performance of both the real-time RT-RPA assay and the conventional RT-RPA assay were comparable to that of real-time RT-PCR. The overall agreements between real-time RT-PCR and real time RT-RPA, and conventional RT-RPA were 99.4% (161/162) and 98.8% (160/162), respectively. The R2 value of real-time RT-RPA and real-time RT-PCR was 0.900 by linear regression analysis. Our results suggest that both RT-RPA assays have a potential application in the rapid, sensitive and specific detection of PPRV. PMID- 29407213 TI - Iron released from reactive microglia by noggin improves myelin repair in the ischemic brain. AB - We previously reported that the bone morphogenetic protein (BMP) antagonist, noggin, improved the repair process with an increase in the reactive microglia/macrophage population in the ischemic brain. Since BMP plays a role in intracellular iron homeostasis via the hepcidin/ferroportin axis, and iron is required for myelination, this study was aimed to determine whether noggin affected iron status and remyelination in the brain following ischemic stroke. We further examined the effect of blocking the BMP/hepcidin pathway on reactive microglia (BV2) and myelination of oligodendroglial cells (MO3.13) to define the link between microglial iron status and myelin formation. Following the noggin infusion into the ischemic brain of mice, the induction of hepcidin and ferritin protein levels decreased, and the number of myelinated axons and myelin thickness increased at 8 weeks after ischemic stroke. Noggin repressed the increase in hepcidin and ferritin levels in BV2 exposed to lipopolysaccharide (LPS) and oxygen/glucose deprivation and reperfusion (OGD/R). When MO3.13 were exposed to the conditioned media from noggin-treated BV2 (noggin CM) during reperfusion, OGD/R-induced MO3.13 cell death was reduced. Under normal conditions, noggin CM induced myelin production with an increase in ferritin levels in MO3.13, which was reversed by the iron chelator, deferoxamine. These results indicated that noggin altered the iron status in reactive microglia from the iron-storing to the iron-releasing phenotype, which contributed to myelin synthesis by providing iron. We suggest that the BMP/hepcidin pathway can be a target for the regulation of the iron status in microglia to enhance remyelination in the ischemic brain. PMID- 29407214 TI - Impaired glucocorticoid-mediated HPA axis negative feedback induced by juvenile social isolation in male rats. AB - We previously demonstrated that socially isolated rats at weaning showed a significant decrease in corticosterone and adrenocorticotropic hormone (ACTH) levels, associated with an enhanced response to acute stressful stimuli. Here we shown that social isolation decreased levels of total corticosterone and of its carrier corticosteroid-binding globulin, but did not influence the availability of the free active fraction of corticosterone, both under basal conditions and after acute stress exposure. Under basal conditions, social isolation increased the abundance of glucocorticoid receptors, while it decreased that of mineralocorticoid receptors. After acute stress exposure, socially isolated rats showed long-lasting corticosterone, ACTH and corticotrophin releasing hormone responses. Moreover, while in the hippocampus and hypothalamus of group-housed rats glucocorticoid receptors expression increased with time and reached a peak when corticosterone levels returned to basal values, in socially isolated rats expression of glucocorticoid receptors did not change. Finally, social isolation also affected the hypothalamic endocannabinoid system: compared to group-housed rats, basal levels of anandamide and cannabinoid receptor type 1 were increased, while basal levels of 2-arachidonoylglycerol were decreased in socially isolated rats and did not change after acute stress exposure. The present results show that social isolation in male rats alters basal HPA axis activity and impairs glucocorticoid-mediated negative feedback after acute stress. Given that social isolation is considered an animal model of several neuropsychiatric disorders, such as generalized anxiety disorder, depression, post-traumatic stress disorder and schizophrenia, these data could contribute to better understand the alterations in HPA axis activity observed in these disorders. PMID- 29407215 TI - Involvement of the cystathionine-gamma-lyase/Cav3.2 pathway in substance P induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome. AB - Hydrogen sulfide (H2S) formed by cystathionine-gamma-lyase (CSE) enhances the activity of Cav3.2 T-type Ca2+ channels, contributing to the bladder pain accompanying hemorrhagic cystitis caused by systemic administration of cyclophosphamide (CPA) in mice. Given clinical and fundamental evidence for the involvement of the substance P/NK1 receptor systems in bladder pain syndrome (BPS)/interstitial cystitis (IC), we created an intravesical substance P-induced bladder pain model in mice and analyzed the possible involvement of the CSE/Cav3.2 pathway. Bladder pain/cystitis was induced by i.p. CPA or intravesical substance P in female mice. Bladder pain was evaluated by counting nociceptive behavior and by detecting referred hyperalgesia in the lower abdomen and hindpaw. The isolated bladder tissue was weighed to estimate bladder swelling and subjected to histological observation and Western blotting. Intravesical substance P caused profound referred hyperalgesia accompanied by little bladder swelling or edema 6-24 h after the administration, in contrast to i.p. CPA induced nociceptive behavior/referred hyperalgesia with remarkable bladder swelling/edema and urothelial damage. The bladder pain and/or cystitis symptoms caused by substance P or CPA were prevented by the NK1 receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK1 antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca2+ channel blocker and gene silencing of Cav3.2 abolished the intravesical substance P-induced referred hyperalgesia. The intravesical substance P-induced pain in mice is useful as a model for nonulcerative BPS, and involves the activation of the NK1 receptor/CSE/H2S/Cav3.2 cascade. PMID- 29407217 TI - The role of 19S proteasome associated deubiquitinases in activity-dependent hippocampal synaptic plasticity. AB - Posttranslational modification and degradation of proteins by the ubiquitin proteasome system (UPS) is crucial to synaptic transmission. It is well established that 19S proteasome associated deubiquitinases (DUBs) reverse the process of ubiquitination by removing ubiquitin from their substrates. However, their potential contribution to hippocampal synaptic plasticity has not been addressed in detail. Here, we report that inhibition of the 19S proteasome associated DUBs, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14) by b-AP15 results in an accumulation of polyubiquitinated proteins and a reduction of monomeric ubiquitin without overt effects on 26S proteasome activity. b-AP15 led to a suppression of mTOR-p70S6K signaling and an increase in levels of p-p38 MAPK, two pathways essentially involved in establishing various forms of activity-dependent plasticity. Additionally, b-AP15 impaired the induction of late-phase long-term potentiation (L-LTP), induced the transformation of mGluR-mediated protein synthesis-independent long-term depression (early-LTD) to L-LTD and promoted heterosynaptic stabilization through synaptic tagging/capture (STC) in the hippocampal CA1 region of mice. The activity of 19S proteasome associated DUBs was also required for the enhancement of short-term potentiation (STP) induced by brain-derived neurotrophic factor (BDNF). Altogether, these results indicate an essential role of 19S proteasome associated DUBs in regulating activity-dependent hippocampal synaptic plasticity. PMID- 29407216 TI - Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays. AB - The sigma 1 receptor (sigma1R) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of sigma1R are poorly understood, and molecular interactions of selective ligands with sigma1R have not been elucidated. The recent crystallographic determination of sigma1R as a homo-trimer provides the foundation for mechanistic elucidation at the molecular level. Here we report novel bioluminescence resonance energy transfer (BRET) assays that enable analyses of ligand-induced multimerization of sigma1R and its interaction with BiP. Haloperidol, PD144418, and 4-PPBP enhanced sigma1R homomer BRET signals in a dose dependent manner, suggesting their significant effects in stabilizing sigma1R multimerization, whereas (+)-pentazocine and several other ligands do not. In non-denaturing gels, (+)-pentazocine significantly decreased whereas haloperidol increased the fraction of sigma1R multimers, consistent with the results from the homomer BRET assay. Further, BRET assays examining heteromeric sigma1R-BiP interaction revealed that (+)-pentazocine and haloperidol induced opposite trends of signals. From molecular modeling and simulations of sigma1R in complex with the tested ligands, we identified initial clues that may lead to the differed responses of sigma1R upon binding of structurally diverse ligands. By combining multiple in vitro pharmacological and in silico molecular biophysical methods, we propose a novel integrative approach to analyze sigma1R-ligand binding and its impact on interaction of sigma1R with client proteins. PMID- 29407218 TI - Membrane cholesterol removal and replenishment affect rat and monkey brain monoamine transporters. AB - The dopamine transporter (DAT) is abundantly expressed in the striatum where it removes extracellular dopamine into the cytosol of presynaptic nerve terminals. It is the target of drugs of abuse and antidepressants. There is a loss of the DAT in Parkinson's disease affecting release of levodopa implicated in levodopa induced dyskinesias. This study investigated the effect of cholesterol on DAT, serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2) in monkey and rat brains in vitro. DAT protein levels measured by Western blot remained unchanged with in vitro methyl-beta-cyclodextrin (MCD) incubations to remove membrane cholesterol or with incubations to increase membrane cholesterol content. By contrast, striatal DAT specific binding labelled with [125I]RTI-121 or with [125I]RTI-55 decreased with increasing concentrations of MCD and increased with cholesterol loading. Moreover, [125I]RTI-121 specific binding of striatal membranes depleted of cholesterol with MCD was restored to initial DAT content with addition of cholesterol showing its rapid and reversible effect. By contrast, striatal VMAT2 and SERT specific binding showed no or limited changes by cholesterol manipulations. Similar results were obtained for monkey caudate nucleus, putamen and nucleus accumbens. Membrane microviscosity was assessed by fluorescence polarization spectroscopy, using the probe 1,6-diphenyl-1,3,5 hexatriene. DAT changes positively correlated with changes of membrane microviscosity in rat and monkey brain regions investigated and with membrane cholesterol contents. Similar findings were observed with desmosterol but to a lower extent than with cholesterol. These results show an important effect of cholesterol on the DAT associated with microviscosity changes that should be considered in drug therapies. PMID- 29407220 TI - Carbon monoxide (CO) modulates hydrogen peroxide (H2O2)-mediated cellular dysfunction by targeting mitochondria in rabbit lens epithelial cells. AB - Mitochondrial components are of great importance for the maintenance of lens transparency. In our previous work, we confirmed that carbon monoxide (CO) can protect human and rabbit lens epithelial cells (LECs) from hydrogen peroxide (H2O2)-mediated apoptosis, while the mechanism remains undefined. Because CO can bind to mitochondrial cytochrome c oxidase (COX), we evaluated the effect of CO on the regulation of mitochondrial biogenesis and function in H2O2-treated rabbit LECs. To evaluate mitochondrial biogenesis, several mitochondrial transcription factors (PGC-1alpha, NRF-1, and mtTFA) were detected by western blot analysis. To assess cellular metabolism, adenosine triphosphate (ATP) levels and COX enzymatic activity were measured. In addition, mitochondrial permeability transition pores (mPTP) opening, dissipation of mitochondrial membrane potential (DeltaPsim), cytochrome c mitochondrial translocation, and apoptotic molecules were also detected to evaluate mitochondrial apoptosis pathway. Furthermore, the interaction of Bcl-2 and COX was assessed by co-immunoprecipitation. Finally, CO mediated regulation of cellular function was detected in Bcl-2-knockdown cells. Our results confirmed that CO pretreatment restored H2O2-induced down-regulation of mitochondrial transcription factors expression, COX activity and ATP production. Moreover, CO pretreatment attenuated mPTP opening, DeltaPsim loss, cytochrome c mitochondrial translocation, and activation of apoptotic molecules. Bcl-2 was identified to bind to COX, and silence of Bcl-2 expression prevented CO regulated cellular metabolism and cytoprotection. These data suggest that CO modulates H2O2-induced cellular dysfunction by increasing mitochondrial biogenesis, enhancing cellular metabolism, and attenuating mitochondrial apoptosis cascade. Moreover, Bcl-2 expression was vital for CO to regulate cellular metabolism and cytoprotection in LECs. PMID- 29407221 TI - Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice. AB - Dry Eye disease causes discomfort and pain in millions of patients. Using a mouse acute desiccating stress (DS) model we show that DS induces a reduction in intraepithelial corneal nerve (ICN) density, corneal sensitivity, and apical extension of the intraepithelial nerve terminals (INTs) that branch from the subbasal nerves (SBNs). Topical application of 0.02% Mitomycin C (MMC) or vehicle alone has no impact on the overall loss of axon density due to acute DS. Chronic dry eye, which develops progressively as C57BL/6 mice age, is accompanied by significant loss of the ICNs and corneal sensitivity between 2 and 24 months of age. QPCR studies show that mRNAs for several proteins that regulate axon growth and extension are reduced in corneal epithelial cells by 24 months of age but those that regulate phagocytosis and autophagy are not altered. Taken together, these data demonstrate that dry eye disease is accompanied by alterations in intraepithelial sensory nerve morphology and function and by reduced expression in corneal epithelial cells of mRNAs encoding genes mediating axon extension. Precis: Acute and chronic mouse models of dry eye disease are used to evaluate the pathologic effects of dry eye on the intraepithelial corneal nerves (ICNs) and corneal epithelial cells. Data show reduced numbers of sensory nerves and alterations in nerve morphology, sensitivity, corneal epithelial cell proliferation, and expression of mRNAs for proteins mediating axon extension accompany the pathology induced by dry eye. PMID- 29407222 TI - Expression of growth hormone gene in the baboon eye. AB - The human growth hormone (GH) locus is comprised by two GH (GH1 and GH2) genes and three chorionic somatomammotropin (CSH1, CSH2 and CSH-L) genes. While GH1 is expressed in the pituitary gland, the rest are expressed in the placenta. However, GH1 is also expressed in several extrapituitary tissues, including the eye. So to understand the role of this hormone in the eye we used the baboon (Papio hamadryas), that like humans has a multigenic GH locus; we set up to investigate the expression and regulation of GH locus in adult and fetal baboon ocular tissues. We searched in baboon ocular tissues the expression of GH1, GH2, CSH1/2, Pit1 (pituitary transcription factor 1), GHR (growth hormone receptor), GHRH (growth hormone releasing hormone), GHRHR (growth hormone releasing hormone receptor), SST (somatostatin), SSTR1 (somatostatin receptor 1), SSTR2 (somatostatin receptor 2), SSTR3 (somatostatin receptor 3), SSTR4 (somatostatin receptor 4), and SSTR5 (somatostatin receptor 5) mRNA transcripts and derived proteins, by qPCR and immunofluorescence assays, respectively. The transcripts found were characterized by cDNA cloning and sequencing, having found only the one belonging to GH1 gene, mainly in the retina/choroid tissues. Through immunofluorescence assays the presence of GH1 and GHR proteins was confirmed in several retinal cell layers. Among the possible neuroendocrine regulators that may control local GH1 expression are GHRH and SST, since their mRNAs and proteins were found mainly in the retina/choroid tissues, as well as their corresponding receptors (GHRH and SSTR1-SSTR5). None of the ocular tissues express Pit1, so gene expression of GH1 in baboon eye could be independent of Pit1. We conclude that to understand the regulation of GH in the human eye, the baboon offers a very good experimental model. PMID- 29407219 TI - GABAA receptor: Positive and negative allosteric modulators. AB - gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABAAR) and Type B (GABABR) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABABR is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABAAR pharmacology, the topic of this article. GABAAR are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABAAR the targets of agonist depressants and antagonist convulsants, but most GABAAR drugs act at other (allosteric) binding sites on the GABAAR proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABAAR subtype dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABAAR subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABAAR subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABAAR subtype-dependent extracellular domain sites. Thus GABAAR subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. This article is part of the "Special Issue Dedicated to Norman G. Bowery". PMID- 29407223 TI - Inflamed site-specific drug delivery system based on the interaction of human serum albumin nanoparticles with myeloperoxidase in a murine model of experimental colitis. AB - To develop a new strategy for inflamed site-specific drug delivery in the colon for the treatment of ulcerative colitis (UC), we leveraged on the interaction between myeloperoxidase (MPO) and human serum albumin (HSA) and prepared nanoparticles (HSA NPs) conjugated with 5-aminosalicylic acid (5-ASA). The 5-ASA HSA NPs (nine molecules of 5-ASA per HSA molecule) were uniform particles with an average particle size of 190 nm, a zeta potential of --11.8 mV, and a polydispersity index of 0.35. This was considered a suitable particle characteristic to pass through the mucus layer and accumulate into the mucosa. The specific interaction between the 5-ASA-HSA NPs and MPO was observed using quartz crystal microbalance analysis in vitro. In addition, the 5-ASA-HSA NPs group containing one thousandth of the dose of the 5-ASA (75 MUg/kg) showed significantly lower disease activity index values and colon weight/length ratios in UC model mice as similar to large amount of neat 5-ASA group (75 mg/kg), indicating that the therapeutic effect of the 5-ASA-HSA NP formulation was confirmed in vivo. Microscopic images of tissue sections of colon extracted from UC model mice demonstrated that HSA NPs and MPO were both localized in the colon, and this specific interaction between HSA NPs and MPO would be involved the in the therapeutic effect in vivo. Furthermore, in the 5-ASA and 5-ASA-HSA NPs groups, some inflammatory damage was observed in the colon, but the degree of damage was mild compared with the control and HSA NPs groups, suggesting mucosal repair and replacement with fibrous granulation tissue had occurred. Therefore, these data demonstrated that an HSA NP formulation has the potential to specifically deliver 5-ASA to an inflamed site where MPO is highly expressed. PMID- 29407224 TI - Spheronization of solid lipid extrudates: Elucidation of spheroid formation mechanism. AB - To explain the rounding mechanism of extrudates by spheronization method, two main concepts are found in literature: one proposed by Rowe (1985) and one proposed by Baert et al. (1993). These concepts are based on wet extrusion spheronization method using microcrystalline cellulose as mains excipient. However, there are no concepts for the spheronization mechanism of extrudates based on solid lipids as spheronization aid. Therefore, the aim of this study is to systematically investigate the mechanism of pellet formation of lipid based extrudates by lipid spheronization method. Different lipid based extrudate formulations were spheronized and particle size distribution and shape of the pellets, at each minute of the process, were characterized. Additionally, visual investigations of the morphological alterations were performed by optical and scanning electron microscopy. Two main material temperature phases were identified as presenting important influence on the pellet formation during the process: (1) a "brittle phase", where the extrudates are broken into smaller particles and (2) a "plastic phase", where the material starts to partially melt, allowing the particles to deform. By the same token, different morphological stages, from cylindrical rods to sphere-shaped passing through a dumbbell-shaped particle, were observed and showed to be highly dependent on temperature and process time. Moreover, a new particle shape, defined as "two-spheres", was recognized and a sequential material overlapping (covering) phenomenon was identified. This particular dislocation of material, from the edges to the central region of the particles (increasing their mean diameter), was recognized at longer process times and led to the formation of a smooth surface and the final spherical shape. At the end, a new concept of pellet formation from lipid extrudates is presented considering the observed changes in the morphology and particle size of the pellets during the spheronization process. PMID- 29407225 TI - Chilling causes perivitelline granule formation in activated zebrafish oocytes. AB - Chilling sensitivity in oocytes of the zebrafish represents a potential obstacle to their successful cryopreservation. Here, we report the first cryomicroscopic observations of the response of zebrafish oocytes to chilling conditions. In activated stage V oocytes that had been exposed to hypothermic temperatures, we observed a latent effect of chilling, manifesting as a granular precipitate that appeared in the perivitelline fluid upon return to 28.5 degrees C. The granules were visible in unstained oocytes under transmitted light microscopy, and the resulting perivitelline turbidity increased in a dose-dependent manner with decreasing chilling temperature (p < 0.001), as well as with increasing time of hypothermic exposure (p < 0.0001). The change in appearance of the perivitelline space in oocytes that had been chilled and rewarmed became statistically significant after a 7-min exposure to 10 degrees C and after only 30 s at 1 degrees C (p < 0.05). Thus, even moderate chilling exposures can lead to detectable changes in activated zebrafish oocytes. PMID- 29407227 TI - Efficacy of Injected Corticosteroid Type, Dose, and Volume for Pain in Large Joints: A Narrative Review. AB - : Corticosteroid injections are commonly used in the treatment of disorders of the large joints. This review assimilates the available literature on corticosteroid injections into the glenohumeral joint, subacromial space, hip joint, and knee joint. A systematic method to review available literature revealed 84 articles that fit the inclusion criteria. For each injection location, four items were examined: overall efficacy of injection, superior type of steroid, superior dose of steroid, and superior volume of injectate. Most research demonstrates positive short-term outcomes in pain and function for corticosteroid injections of the large joints. Methylprednisolone and triamcinolone seem similar in efficacy, with minor differences seen in specific studies. Larger doses may last longer, but need to be balanced with the systemic effects from higher doses. Volume has not been studied extensively. Due to heterogeneity in study types, subject populations, and outcomes, it is not possible to identify a single defining trend for a superior type, dose, or volume of steroid. Future prospective studies examining these factors may better reveal the optimum regimen for each injection location. LEVEL OF EVIDENCE: III. PMID- 29407226 TI - Dose-Response Effects of Tai Chi and Physical Therapy Exercise Interventions in Symptomatic Knee Osteoarthritis. AB - BACKGROUND: Therapeutic exercise is a currently recommended nonpharmacological treatment for knee osteoarthritis (KOA). The optimal treatment dose (frequency or duration) has not been determined. OBJECTIVE: To examine dose-response relationships, minimal effective dose, and baseline factors associated with the timing of response from 2 exercise interventions in KOA. DESIGN: Secondary analysis of a single-blind, randomized trial comparing 12-week Tai Chi and physical therapy exercise programs (Trial Registry #NCT01258985). SETTING: Urban tertiary care academic hospital PARTICIPANTS: A total of 182 participants with symptomatic KOA (mean age 61 years; BMI 32 kg/m2, 70% female; 55% white). METHODS: We defined dose as cumulative attendance-weeks of intervention, and treatment response as >=20% and >=50% improvement in pain and function. Using log rank tests, we compared time-to-response between interventions, and used Cox regression to examine baseline factors associated with timing of response, including physical and psychosocial health, physical performance, outcome expectations, self-efficacy, and biomechanical factors. MAIN OUTCOME MEASURES: Weekly Western Ontario and McMasters Osteoarthritis Index (WOMAC) pain (0-500) and function (0-1700) scores. RESULTS: Both interventions had an approximately linear dose-response effect resulting in a 9- to 11-point reduction in WOMAC pain and a 32- to 41-point improvement in function per attendance-week. There was no significant difference in overall time-to-response for pain and function between treatment groups. Median time-to-response for >=20% improvement in pain and function was 2 attendance-weeks and for >=50% improvement was 4-5 attendance weeks. On multivariable models, outcome expectations were independently associated with incident function response (hazard ratio = 1.47, 95% confidence interval 1.004-2.14). CONCLUSIONS: Both interventions have approximately linear dose-dependent effects on pain and function; their minimum effective doses range from 2-5 weeks; and patient perceived benefits of exercise influence the timing of response in KOA. These results may help clinicians to optimize patient centered exercise treatments and better manage patient expectations. LEVEL OF EVIDENCE: II. PMID- 29407228 TI - Double silencing of relevant genes suggests the existence of the direct link between DNA replication/repair and central carbon metabolism in human fibroblasts. AB - Genetic evidence for a link between DNA replication and glycolysis has been demonstrated a decade ago in Bacillus subtilis, where temperature-sensitive mutations in genes coding for replication proteins could be suppressed by mutations in genes of glycolytic enzymes. Then, a strong influence of dysfunctions of particular enzymes from the central carbon metabolism (CCM) on DNA replication and repair in Escherichia coli was reported. Therefore, we asked if such a link occurs only in bacteria or it is a more general phenomenon. Here, we demonstrate that effects of silencing (provoked by siRNA) of expression of genes coding for proteins involved in DNA replication and repair (primase, DNA polymerase iota, ligase IV, and topoisomerase IIIbeta) on these processes (less efficient entry into the S phase of the cell cycle and decreased level of DNA synthesis) could be suppressed by silencing of specific genes of enzymes from CMM. Silencing of other pairs of replication/repair and CMM genes resulted in enhancement of the negative effects of lower expression levels of replication/repair genes. We suggest that these results may be proposed as a genetic evidence for the link between DNA replication/repair and CMM in human cells, indicating that it is a common biological phenomenon, occurring from bacteria to humans. PMID- 29407229 TI - Combined analysis of DNA methylation and gene expression profiles of osteosarcoma identified several prognosis signatures. AB - Osteosarcoma (OS) is a common primary malignancy in children and adolescents with relative high survival rate after chemotherapy. While, the toxicity of chemotherapy and personalized different response to chemotherapy makes it difficult for the selection of therapeutics and improvement of diagnosis. In this study, we conducted a combined analysis of two types of microarray datasets (gene expression and DNA methylation) from the Gene Expression Omnibus (GEO). Differential methylation sites (DMS) were identified by the IMA package and differential expression genes (DEGs) were screened out via the limma package. A total of 11,242 DMS (corresponding to 3080 genes (DMGs)) and 337 DEGs, with 40 overlaps (OS genes) between DEGs and DMGs, were identified. Enriched functions of OS genes were obtained through the Database for Annotation, Visualization and Integrated Discovery (DAVID). The OS genes were mainly enriched in the biological processes related to inflammatory/immune response and Pertussis pathways and Hematopoietic cell lineage pathways. Besides, OS-specific disease network was obtained, and found that UBS and NRF1 were regulated by multiple OS genes. Kaplan Meier analysis of OS genes identified BHMT2, DOCK2, DNALI1 and RIPK3 as significant OS survival-related genes. SEMA3A and PRAME are included in the 40 OS genes and within the top 10 most up-regulated DEGs. Their expression changes were further validated in U2OS osteosarcoma cell lines and hOB normal cell lines through quantitative PCR (qPCR) and consistent result with microarray analysis was obtained. Based on this study, some novel targets were identified for OS, which would be helpful in its early diagnosis and treatment. PMID- 29407230 TI - The multi-faceted potential of plant-derived metabolites as antimicrobial agents against multidrug-resistant pathogens. AB - Multidrug-resistant (MDR) pathogens are currently causing serious problems globally in the medical setting. Improper and extensive usage of antibiotics results in a selective pressure supporting the rise of antibiotic-resistant microbes. Many key cellular bacterial components, including enzymes and small noncoding RNAs (sRNAs), and their involvement in MDR have been well studied, but exploiting such components in eradicating these pathogens requires further study. Delineation of many mechanisms that underpin the known MDR pathways necessitates urgent development of new specific strategies to control the rise of MDR pathogens. Botanical derivatives are comparatively safer than currently used antibiotics and exert multiple therapeutic benefits associated with their high efficacy. Numerous plant-derived compounds display synergistic activity with antibiotics against many MDR pathogens. Such plant derivatives include alkaloids, flavonoids, terpenoids, and tannins. A synthetic biological approach, e.g., metabolic engineering of secondary metabolites, can be utilized to exploit the natural metabolic pathways against MDR microbes. In this review, we focused on the major threats of antibiotic resistance, and the utilization of plant-derived compounds as alternative therapeutic agents to limit the rise of MDR pathogens. PMID- 29407231 TI - Synthesis of silver nanoparticles from Bacillus brevis (NCIM 2533) and their antibacterial activity against pathogenic bacteria. AB - The present study is focused on the biological synthesis of silver nanoparticles (AgNPs) from the Bacillus brevis (NCIM 2533) was investigated. The synthesized AgNPs were characterized by various spectroscopic and microscopic techniques and confirmed the AgNPs having the surface Plasmon resonance peak at 420 nm and in the size range of 41-68 nm with spherical in shape by AFM and SEM analysis. It was confirmed and ascertained the presence of bioactive compounds in the AgNPs using TLC and FTIR. The In-vitro antibacterial activity of AgNPs showaed potential antibacterial property against multi-drug resistant pathogens such as Salmonella typhi and Staphylococcus aureus. The biosynthesized AgNPs could be utilized as antimicrobial agents for effective disease management. PMID- 29407232 TI - T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection. AB - Helicobacter pylori (H. pylori) is one of the most prevalent human pathogen and a persistent infection with this bacterium causes common pathologies, such as gastritis or peptic ulcers, and also less common but more serious pathologies, such as gastric cancer or gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The clinical outcome of gastrointestinal infection sustained by H. pylori is determined by the reciprocal interactions between virulence factors of the bacterium and host factors, including immune response genes. Although H. pylori induces a strong immune response, the bacterium is not eliminated. The eradication failure could be attributed to the bacterial capability to regulate helper T (Th) cell-related responses. H. pylori specific CD4+ T cells play a fundamental role in regulating host immunity and immunopathologic events. It has been documented that Th1, Th2, Th9, Th17, Th22 and T regulatory (Treg) cells, separately or in coordination with each other, can affect the outcome of the infection sustained by of H. pylori. Some studies indicated that both Th1 and Th17 cells may be protective or pathogenic, whereas Treg and Th2 cells perform anti-inflammatory impacts during H. pylori infection. This review gathers recent information regarding the association of the CD4+ T cells-mediated immunological responses and the clinical consequence of H. pylori infection. PMID- 29407233 TI - Efficacy of dietary curcumin supplementation as bactericidal for silver catfish against Streptococcus agalactiae. AB - The antibiotics were frequently used for combating bacterial infections in aquaculture, but this treatment causes antibiotic resistance, negative impact on the environment and on health, and accumulation of residual in edible tissues. Several evidences have considered the dietary supplementation with natural products an interesting alternative to antibiotics, as the use of curcumin, a polyphenol with anti-inflammatory, antioxidant and antimicrobial properties. Thus, the aim of this study was to evaluate whether fish fed with a diet containing 150 mg curcumin/kg feed is able to enhance the resistance of silver catfish to Streptococcus agalactiae infection. Our results demonstrated that curcumin dietary supplement exerts potent bactericidal action against S. agalactiae, presenting 100% of therapeutic efficacy when compared to infected and non-supplemented animals. Also, the treatment prevented the occurrence of clinical signs of disease, as erratic swimming, corneal opacity, skin lesions in the fin and tail, and loss of appetite. In summary, curcumin can be a promising dietary supplement for improving disease resistance. PMID- 29407234 TI - Pathogenic features of Streptococcus mutans isolated from dental prosthesis patients and diagnosed cancer patients with dental prosthesis. AB - : Though S. mutans, virulence, and pathogenesis are characterized, reports are limited to the status of its carriage and virulence in patients with oral cancer and prosthesis. In this present study, we investigated the pathogenic characteristics of twenty strains of S. mutans of healthy subjects, fifteen of prosthesis patients, and eleven from oral cancer. The putative virulence gene and other factors, such as the ability to adhere to the oral epithelial cells, production of glycan and lactic acid of these strains were examined. Few of representative isolates of each group were used to see their activity on oral cancer cell line using cell cytotoxicity assay. The isolation rate of S. mutans was significantly more in carcinoma than prosthesis patients and control health group. The production of glycan and latic acid was together high in those isolates derived from prosthesis patients and patients with cancer. Adherence ability of strains isolated from prosthesis patients and cancer patients with oral prosthesis were significantly higher, compared to one isolated from a healthy individual. From our study results, we conclude that prosthesis patients and cancer patients with prosthesis carried a high number of S. mutans in their oral cavities. SIGNIFICANCE AND IMPACT OF STUDY: This study report that prosthesis patients and cancer patients with prosthesis carried a high number of S. mutans in their oral cavities. However, the S mutans are commensals still they have the capability to raise the severity of disease condition due to their ability to produce glycan and lactic acid. In our study, we proved that the adherence to buccal epithelial cells was significantly increased in S. mutans isolates of prosthesis patients and cancer patients. These indicate that in prosthesis patients as well as in cancerous patient's microbes had more potential to cause infection and increase the severity. PMID- 29407235 TI - Proteomics analysis of crude squid ink isolated from Sepia esculenta for their antimicrobial, antibiofilm and cytotoxic properties. AB - The present study deals with the proteomics analysis of crude squid ink isolated from Sepia esculenta for their antibacterial, antifungal, antibiofilm and cytotoxic properties. To achieve this, SDS-PAGE was used to separate proteins as bands, In-gel trypsin digested and analyzed by MALDI-TOF mass spectrometry. A total of 4 bands were identified by MASCOT search analysis namely astacin-like squid metalloprotease type I (ASMT-I), 70 kDa neurofilament protein (NP), uncharacterized protein LOC106181966 isoform X1 (UP-Iso-X1) and Ommochrome binding protein (Oc-BP). Further, the obtained crude squid proteins were subjected to antimicrobial and antibiofilm activities against pathogenic bacterial and fungal strains respectively. Further, MTT assay was also carried out to deliberately explain the cytotoxic ability of crude squid ink protein against MCF-7 breast cancer cell lines. The results from the study revealed that, the proteins are shown to be toxic against pathogenic strains and breast cancer cell lines in a dose-dependent manner. More importantly, the proteins are well enough to eradicate biofilms substantiated by light and confocal laser scanning microscopic observations. Altogether, the crude squid ink proteins hampered the growth of breast cancer cells with an IC50 value of 65.3 +/- 0.46 MUg mL-1. In conclusion, it is believed that the proteins from crude squid ink will provide new insights in hampering bacterial biofilms and cancer in near future. PMID- 29407236 TI - Drug resistance profile and molecular characterization of extended spectrum beta lactamase (ESbetaL)-producing Pseudomonas aeruginosa isolated from burn wound infections. Essential oils and their potential for utilization. AB - OBJECTIVES: Pseudomonas aeruginosa producing extended spectrum beta-lactamase (ESbetaL) enzyme had the ability for antimicrobial resistance mechanisms and its multidrug-resistant (MDR) phenotype, has been increasingly reported as a major clinical concern worldwide. The aim of this study was to (i) characterize ESbetaL producing MDR P. aeruginosa isolated from burn wound infections phenotypically and molecularly, (ii) evaluate the antibacterial activity of some essential oils (EOs) against selected ESbetaL-producing drug resistant P. aeruginosa and (iii) characterize a promising EO. METHODS: Identification and antibiotic susceptibility tests were performed for all isolates. ESbetaL production was detected phenotypically by an initial screening test (IST) and a phenotypic confirmatory test (PCT). Additionally, ESbetaL-producing isolates were also characterized molecularly. The antibacterial activity was detected using a disc diffusion method. Mechanisms of antibacterial action, the fatty acid profile, and functional groups characterization of the promising EO were analyzed using scanning and transmission electron microscopy (SEM & TEM), gas chromatography mass spectrometry (GC-MS), and Fourier transform infrared (FTIR) spectroscopy, respectively. RESULTS: A total of 50 non duplicated P. aeruginosa isolates from the wound samples of burn patients were identified. Of these, MDR and pan-drug resistance (PDR) showed a high prevalence in 38 (76%) isolates obtained from 10 clusters, while 21 (42%) were identified as ESbetaL-producing MDR or PDR P. aeruginosa isolates. Phenotypic detection of ESbetaL production showed that 20% were considered positive ESbetaL-producing P. aeruginosa using the IST, and were increased to 56% by the PCT. The most prevalent ESbetaL-encoding gene was blaOXA 2 (60.7%), followed by blaIMP-7 (53.6%) and blaOXA-50 (42.8%). Ginger oil is the most efficient antibacterial agent and its antibacterial action mechanism is attributed to the morphological changes in bacterial cells. The oil characterization revealed that 9,12-Octadecadienoic acid methyl ester is the major fatty acid (50.49%) identified. CONCLUSION: The high incidence of drug resistance in ESbetaL-producing P. aeruginosa isolated from burn wounds is alarming. As proven in vitro, EOs may represent promising natural alternatives against ESbetaL-producing PDR or MDR P. aeruginosa isolates. PMID- 29407237 TI - Extracellular enzymes and adhesive properties of medically important Candida spp. strains from landfill leachate. AB - The virulence properties of Candida spp. presents in landfill leachate still unknown until today and they constitutes a serious source of potential danger for humans. We investigate the antifungal susceptibility, production of hydrolytic enzymes and biofilm formation on polystyrene as well as glass in Candida spp. strains isolated from a landfill leachate treatment station in Borj Chakir (Tunisia). 37 yeast strains were isolated belonging to the following species: C. robusta, C. lusitaniae, C. tropicalis, C. krusei. Most isolated yeast strains were resistant to Amphotericin B, produced several hydrolytic enzymes (67.56% produced phospholipase, 86.04% protease, 64.86% esterase) and most of them are able to degrade hemoglobin. All assayed Candida strains have been able to form biofilm on polystyrene depending on the species and strain of Candida. Landfills receiving clinical waste are a potential source of Candida ssp. strains with several virulence properties which allow them to survive in different aquatic biotopes. PMID- 29407238 TI - Outbreak of Zika virus pathogenesis and quest of its vaccine development: Where do we stand now? AB - Zika virus (ZIKV) infection is a life-threatening tropical infection, mainly caused by mosquito bite. After a very long period of quietness, ZIKV infections have become a problematic issue again. Previously, the virus was limited to Africa and Asia only but later it emerged in Brazil, South America, and other parts of the world in 2015. In 2016, there are emerging new cases of sexually transmitted ZIKV infection as well. At present, there is no proper treatment and available pronounced vaccines for the treatment of ZIKV infection. The prime focal point of this review is not only to provide imperative epidemiological information on ZIKV infection in brief but also the current situation of vaccines testing on animal model as well as in clinical trial phases. Currently there is no human vaccine for this pestiferous viral infection. Therefore, prevention, proper management, and up-to-date recommendation are crucial to mitigate the possible risk of vector and non-vector transmission of ZIKV. PMID- 29407239 TI - Seroprevalence and risk factor analysis of human leptospirosis in distinct climatic regions of Pakistan. AB - Leptospirosis is a worldwide emerging infectious disease of zoonotic importance and large epidemics and epizootics have been reported all over the globe. A cross survey study was conducted to estimate seroprevalence of human leptospirosis in climatically distinct regions of Pakistan and to identify the risk factors associated with the disease. Blood samples from 360 humans were collected through convenient sampling, 120 from each of three study areas. Serological testing was performed using ELISA kit as per manufacturer's recommendations. The results showed an overall prevalence of 40.83% (95% CI; 35.71-46.11). Statistical analysis showed significant (P < .05) differences in leptospiral seroprevalence in three different geographic locations, with highest in humid sub-tropical climatic region (50.83%; 95% CI; 41.55-60.07), followed by semi-arid region (44.16%; 95% CI; 35.11-53.52) and lowest in hot and dry region (27.50%; 95% CI; 19.75-36.40). After multivariate analysis age, gender, exposure to flooding water, source of water usage, disinfection schedule of surroundings and history of cut and wound were found significantly associated with the seropositivity of Leptospira. The present study, first to uncover seroprevalence of human Leptospira in different climatic regions of Pakistan, alarms about effect of climate on prevalence of Leptospira in the region. PMID- 29407241 TI - Cross-race correlations in the abilities to match unfamiliar faces. AB - The other-race effect in face identification has been documented widely in memory tasks, but it persists also in identity-matching tasks, in which memory contributions are minimized. Whereas this points to a perceptual locus for this effect, it remains unresolved whether matching performance with same- and other race faces is driven by shared cognitive mechanisms. To examine this question, this study compared Arab and Caucasian observers' ability to match faces of their own race with their ability to match faces of another race using one-to-one (Experiment 1) and one-to-many (Experiment 2) identification tasks. Across both experiments, Arab and Caucasian observers demonstrated reliable other-race effects at a group level. At an individual level, substantial variation in accuracy was found, but performance with same-race and other-race faces correlated consistently and strongly. This indicates that the abilities to match same- and other-race faces share a common cognitive mechanism. PMID- 29407240 TI - Effects of non-symbolic arithmetic training on symbolic arithmetic and the approximate number system. AB - The approximate number system (ANS) is an innate cognitive template that allows for the mental representation of approximate magnitude, and has been controversially linked to symbolic number knowledge and math ability. A series of recent studies found that an approximate arithmetic training (AAT) task that draws upon the ANS can improve math skills, which not only supports the existence of this link, but suggests it may be causal. However, no direct transfer effects to any measure of the ANS have yet been reported, calling into question the mechanisms by which math improvements may emerge. The present study investigated the effects of a 7-day AAT and successfully replicated previously reported transfer effects to math. Furthermore, our exploratory analyses provide preliminary evidence that certain ANS-related skills may also be susceptible to training. We conclude that AAT has reproducible effects on math performance, and provide avenues for future studies to further explore underlying mechanisms - specifically, the link between improvements in math and improvements in ANS skills. PMID- 29407242 TI - The influence of vision, touch, and proprioception on body representation of the lower limbs. AB - Numerous studies have shown that the representation of the hand is distorted. When participants are asked to localize unseen points on the hand (e.g. the knuckle), it is perceived to be wider and shorter than its physical dimensions. Similar distortions occur when people are asked to judge the distance between two tactile points on the hand; estimates made in the longitudinal direction are perceived as significantly shorter than those made in the transverse direction. Yet, when asked to visually compare the shape and size of one's own hand to a template hand, individuals are accurate at estimating the size of their own hands. Thus, it seems that body representations are, at least in part, a function of the most prominent underlying sensory modality used to perceive the body part. Yet, it remains unknown if the representations of other body parts are similarly distorted. The lower limbs, for example, are structurally and functionally very different from the hands, yet their representation(s) are seldom studied. What does the body representation for the leg look like? And is leg representation dependent on which sense is probed when making judgments about its shape and size? In the current study, we investigated what the representation of the leg looks like in visually-, tactually-, and proprioceptively-guided tasks. Results revealed that the leg, like the hand, is distorted in a highly systematic manner. Distortions seem to rely, at least partly, on sensory input. This is the first study, to our knowledge, to systematically investigate leg representation in healthy individuals. PMID- 29407243 TI - Examining the effect of state anxiety on compensatory and strategic adjustments in the planning of goal-directed aiming. AB - The anxiety-perceptual-motor performance relationship may be enriched by investigations involving discrete manual responses due to the definitive demarcation of planning and control processes, which comprise the early and late portions of movement, respectively. To further examine the explanatory power of self-focus and distraction theories, we explored the potential of anxiety causing changes to movement planning that accommodate for anticipated negative effects in online control. As a result, we posed two hypotheses where anxiety causes performers to initially undershoot the target and enable more time to use visual feedback ("play-it-safe"), or fire a ballistic reach to cover a greater distance without later undertaking online control ("go-for-it"). Participants were tasked with an upper-limb movement to a single target under counter-balanced instructions to execute fast and accurate responses (low/normal anxiety) with non contingent negative performance feedback (high anxiety). The results indicated that the previously identified negative impact of anxiety in online control was replicated. While anxiety caused a longer displacement to reach peak velocity and greater tendency to overshoot the target, there appeared to be no shift in the attempts to utilise online visual feedback. Thus, the tendency to initially overshoot may manifest from an inefficient auxiliary procedure that manages to uphold overall movement time and response accuracy. PMID- 29407244 TI - Who is more flexible?-Awareness of changing context but not working memory capacity modulates inhibitory control. AB - The present study examines how a person's working memory capacity (WMC) and awareness of change in context influences modulating inhibitory control. Context was manipulated by changing the predictive validity of a prime to a following target (i.e., the proportion of prime repetition) across three phases in a single prime negative priming task. The prime was a distractor for the following target when the proportion was 25% (in the first and third phases) and a useful cue when the proportion rose to 75% (in the second phase). Participants' WMCs were measured and whether they were aware of the change of the prime-repetition proportion was determined in interviews at the end of the experiment. We found that when the stimulus-onset asynchrony (SOA) was short (Experiment 1), participants aware of the change of prime-repetition proportion showed a null negative priming effect when the contingency increased from 25% to 75%, and then rebooted the effect when it decreased back to 25%, thus indicating an ability to modulate inhibitory control as context varied. In contrast, the unaware participants kept inhibiting primes all the time. When SOA was long (Experiment 2), participants with awareness even showed a positive priming effect when the prime-repetition proportion increased. Surprisingly, participants' WMCs did not matter except for the conscious strategy used in the long-SOA condition. This is the first study simultaneously investigating how WMC and awareness can affect people's ability to modulate inhibitory control and reveals that awareness plays a more direct role in such modulation than does WMC. PMID- 29407245 TI - Working memory cannot regulate overt emotional capture. AB - Individual differences in working memory capacity partly arise from variability in attention control, a process influenced by negative emotional content. Thus, individual differences in working memory capacity should predict differences in the ability to regulate attention in emotional contexts. To address this hypothesis, a complex-span working memory task was modified so that negative arousing images or neutral images subtended the background during the encoding phase. Across three experiments, negative arousing images impaired working memory encoding relative to neutral images, resulting in impoverished symmetry span scores. Contrary to the primary hypothesis, individual differences in working memory capacity derived from three complex span tasks failed to moderate the effect of negative arousing images on working memory encoding across two large scale studies. Additionally, in Experiment 3, both negative and arousing images captured attention and were processed despite their incongruence with task goals which led to increased memory for the images in a subsequent recognition task. Implications for theories of working memory and attention control in emotional contexts will be discussed. PMID- 29407246 TI - Using more different and more familiar targets improves the detection of concealed information. AB - When embedded among a number of plausible irrelevant options, the presentation of critical (e.g., crime-related or autobiographical) information is associated with a marked increase in response time (RT). This RT effect crucially depends on the inclusion of a target/non-target discrimination task with targets being a dedicated set of items that require a unique response (press YES; for all other items press NO). Targets may be essential because they share a feature - familiarity - with the critical items. Whereas irrelevant items have not been encountered before, critical items are known from the event or the facts of the investigation. Target items are usually learned before the test, and thereby made familiar to the participants. Hence, familiarity-based responding needs to be inhibited on the critical items and may therefore explain the RT increase on the critical items. This leads to the hypothesis that the more participants rely on familiarity, the more pronounced the RT increase on critical items may be. We explored two ways to increase familiarity-based responding: (1) Increasing the number of different target items, and (2) using familiar targets. In two web based studies (n = 357 and n = 499), both the number of different targets and the use of familiar targets facilitated concealed information detection. The effect of the number of different targets was small yet consistent across both studies, the effect of target familiarity was large in both studies. Our results support the role of familiarity-based responding in the Concealed Information Test and point to ways on how to improve validity of the Concealed Information Test. PMID- 29407247 TI - Effects of modality and repetition in a continuous recognition memory task: Repetition has no effect on auditory recognition memory. AB - Previous research has shown that auditory recognition memory is poorer compared to visual and cross-modal (visual and auditory) recognition memory. The effect of repetition on memory has been robust in showing improved performance. It is not clear, however, how auditory recognition memory compares to visual and cross modal recognition memory following repetition. Participants performed a recognition memory task, making old/new discriminations to new stimuli, stimuli repeated for the first time after 4-7 intervening items (R1), or repeated for the second time after 36-39 intervening items (R2). Depending on the condition, participants were either exposed to visual stimuli (2D line drawings), auditory stimuli (spoken words), or cross-modal stimuli (pairs of images and associated spoken words). Results showed that unlike participants in the visual and cross modal conditions, participants in the auditory recognition did not show improvements in performance on R2 trials compared to R1 trials. These findings have implications for pedagogical techniques in education, as well as for interventions and exercises aimed at boosting memory performance. PMID- 29407248 TI - Time flies faster under time pressure. AB - We examined the effects of time pressure on duration estimation in a verbal estimation task and a production task. In both temporal tasks, participants had to solve mazes in two conditions of time pressure (with or without), and with three different target durations (30 s, 60 s, and 90 s). In each trial of the verbal estimation task, participants had to estimate in conventional time units (minutes and seconds) the amount of time that had elapsed since they started to solve the maze. In the production task, they had to press a key while solving the maze when they thought that the trial's duration had reached a target value. Results showed that in both tasks, durations were judged longer with time pressure than without it. However, this temporal overestimation under time pressure did not increase with the length of the target duration. These results are discussed within the framework of scalar expectancy theory. PMID- 29407249 TI - Detection of relationships between SUDOSCAN with estimated glomerular filtration rate (eGFR) in Chinese patients with type 2 diabetes. AB - OBJECTIVE: SUDOSCAN (Impeto Medical, Paris, France) has been proved to be a new and non-invasive method in detecting renal dysfunction in type 2 diabetes mellitus (T2DM) patients. In this study, we sought to compare the result of diabetic kidney dysfunction score (DKD-score) of SUDOSCAN with estimated glomerular filtration rate (eGFR) by using quantile regression analysis, which was completely different from previous studies. METHODS: A total number of 223 Chinese T2DM patients were enrolled in the study. SUDOSCAN, renal function test (including blood urea nitrogen, creatinine and uric acid) and 99mTc diethylenetriamine pentaacetic acid (99mTc-DTPA) renal dynamic imaging were performed in all T2DM patients. DKD-score of SUDOSCAN was compared with eGFR detected by 99mTc-DTPA renal dynamic imaging through quantile regression analysis. Its validation and utility was further determined through bias and precision test. RESULTS: The quantile regression analysis demonstrated the relationship with eGFR was inverse and significant for almost all percentiles of DKD-score. The coefficients decreased as the percentile of DKD-score increased. And in validation data set, both the bias and precision were increased with the eGFR (median difference, -21.2 ml/min/1.73 m2 for all individuals vs. -4.6 ml/min/1.73 m2 for eGFR between 0 and 59 ml/min/1.73 m2; interquartile range [IQR] for the difference, -25.4 ml/min/1.73 m2 vs. -14.7 ml/min/1.73 m2). The eGFR category misclassification rate were 10% in eGFR 0-59 ml/min/1.73 m2 group, 57.3% in 60-90 group, and 87.2% in eGFR > 90 ml/min/1.73 m2 group. CONCLUSION: DKD-score of SUDOSCAN could be used to detect renal dysfunction in T2DM patients. A higher prognostic value of DKD-score was detected when eGFR level was lower. PMID- 29407250 TI - Comparison of the outcomes of pediatric tibial shaft fractures treated by different types of orthopedists: A prospective cohort study. AB - BACKGROUND: The objective of this study was to compare the outcomes of pediatric tibial shaft fractures treated with titanium elastic nail (TEN) by pediatric orthopedists and non-pediatric orthopedists. MATERIALS AND METHODS: We conducted a prospective cohort study of 90 children of tibial shaft fractures, who were randomized to operative stabilization either by pediatric orthopedists (Group A, 45 cases) or by non-pediatric orthopedists (Group B, 45 cases) from April 2010 to May 2015. Demographic data and clinical characteristics (age, sex, weight, fracture side and type, cause of injury, number of fibula fracture and time from injury to operation) were comparable between the two groups before surgery. Clinical data, complications and functional outcomes between the two groups were recorded. RESULTS: A total of 10 patients were lost to follow-up for various reasons and each group remained 40 cases. The mean follow-up period was 14.9 +/- 1.9 months for Group A and 15.3 +/- 2.2 months for Group B (P = 0.451). There was no significant difference in length of hospitalization, full weight-bearing time, fracture union time and TEN outcome scores between the two groups (P = 0.917, P = 0.352, P = 0.404, P = 506, respectively). However, Group A exhibited significantly shorter operation duration and less fluoroscopy times than Group B (P < 0.001 and P < 0.001, respectively). Also, there was a trend for patients of Group A to have lower rate of open reduction than Group B (P = 0.019). When comparing the total complications, no significant difference existed between the groups (P = 0.764). CONCLUSIONS: Our results indicated that pediatric tibial shaft fractures treated surgically by pediatric orthopedists offered potential advantages including a shorter operating time, less times of fluoroscopy and a lower rate of open reduction. However, both pediatric and non-pediatric orthopedists could achieve satisfactory clinical results in treatment of these injuries. PMID- 29407251 TI - Variability in the prescribing of intravenous fluids: A cross sectional multicentre analysis of clinical practice. AB - AIMS: Intravenous (IV) fluid administration continues to be a mainstay of care in General Surgery. Yet if they are prescribed incorrectly significant morbidity including electrolyte abnormalities, renal impairment and cardiac failure can develop. Despite this, it is frequently the responsibility of the most junior staff to prescribe IV fluids. We aim to analyse the understanding of IV fluid prescribing amongst junior doctors and to describe variability in clinical practice. METHODS: We undertook a multicentre questionnaire study. Foundation doctors and specialty trainees were invited to undertake a two part paper-based questionnaire. Part one analysed baseline knowledge of the concentration of commonly prescribed fluids. Part two consisted of four clinical vignettes requiring a IV fluid prescribing decision by the surveyed doctor. RESULTS: A total of 143 Doctors working in 8 hospitals were recruited. 65 (45.5%) doctors correctly stated the daily maintenance fluid requirements of water for an adult (25-30 mls/kg/day), while only 54 (37.8%) knew the sodium concentration of 0.9% NaCl. Lack of postgraduate experience (p = 0.011), qualifying from a medical school outside the United Kingdom (p < 0.0001) and working in one of the eight hospitals in this study (p < 0.0001) were associated with a lower knowledge level. There was limited consensus in prescribing in the responses to the 4 clinical scenarios, with 69 unique combinations of fluid choice, rate and volume prescribed. CONCLUSIONS: Knowledge of the constituents of common IV fluids and routine requirement for fluid and common electrolytes is poor across junior doctors of all grades, driving large variation in clinical practice. PMID- 29407252 TI - Pretransplant Gut Colonization with Intrinsically Vancomycin-Resistant Enterococci (E. gallinarum and E. casseliflavus) and Outcomes of Allogeneic Hematopoietic Cell Transplantation. AB - Pretransplant gut colonization with intrinsically vancomycin-resistant enterococci (iVRE) (Enterococcus gallinarum and Enterococcus casseliflavus) is uncommon and with unknown clinical impact. In a matched-pairs analysis of patients with versus without iVRE colonization (n = 18 in each group), we demonstrated significantly higher 2-year overall survival (86% [95% confidence interval, 52% to 96%] versus 35% [95% confidence interval, 8% to 65]; P <.01) and lower nonrelapse mortality (P <.01) among colonized patients. Putative metabolomes differentiated iVRE from E. faecalis/faecium and may contribute to a healthier gut microbiome in iVRE-colonized patients. PMID- 29407253 TI - Relationship between information-seeking behavior and innovative behavior in Chinese nursing students. AB - BACKGROUND: In the information-based economy, information literacy has become the foundation of scientific literacy, and provides the basis for innovative growth. Exploring the relationship between information-seeking behaviors and innovative behaviors of nursing students could help guide the development of information literacy education and training for nursing students. The relationship between information-seeking behavior and innovative behavior in nursing students has received little attention, however. OBJECTIVE: This study aims to explore the relationship between information-seeking behavior and innovative behavior of nursing students. METHODS: Nursing students in Xiangya Medical School, Central South University and Medical School of Hunan Normal University in the Chinese Province of Hunan were surveyed with an information-seeking behavior scale and an innovative behavior scale. RESULTS: A total of 1247 nursing students were included in the final analysis. The results showed that both information-seeking behavior and innovative behavior were significantly better in undergraduates than in junior college nursing students (P < .01), and in postgraduates than in undergraduates (P < .01). The overall level of nursing students' information seeking behavior was positively related to innovative behavior (r = 0.63, P < .01), and the 7 dimensions of information-seeking behavior were also correlated with innovative behavior in varying degrees. Furthermore, information utilization was proved to be the strongest predictor of innovative behavior. CONCLUSION: Information-seeking behavior is positively associated with innovative behavior among nursing students. There is a need to integrate information literacy education with information retrieval courses, especially in the aspects of information utilization, retrieval, and assessment. PMID- 29407254 TI - Nursing genetics and genomics: The International Society of Nurses in Genetics (ISONG) survey. AB - BACKGROUND: The International Society of Nursing in Genetics (ISONG) fosters scientific and professional development in the discovery, interpretation, and application of genomic information in nursing research, education, and clinical practice. OBJECTIVES: Assess genomic-related activities of ISONG members in research, education and practice, and competencies to serve as global leaders in genomics. DESIGN: Cross-sectional survey (21-items) assessing genomic-related training, knowledge, and practice. SETTINGS: An email invitation included a link to the anonymous online survey. PARTICIPANTS: All ISONG members (n = 350 globally) were invited to partake. METHODS: Descriptive statistics and Wilcoxon Rank Sum Test for between-group comparisons. RESULTS: Respondents (n = 231, 66%), were mostly Caucasian, female, with a master's degree or higher. Approximately 70% wanted to incorporate genomics in research, teaching, and practice. More than half reported high genomic competency, and over 95% reported that genomics is relevant the next 5 years. CONCLUSIONS: Findings provide a foundation for developing additional educational programs for an international nursing workforce in genomics. PMID- 29407255 TI - Using research evidence to inform staff learning needs in cross-cultural communication in aged care homes. AB - BACKGROUND: Developed countries worldwide are facing an unprecedented demand for aged care services, with recent migrants of diverse linguistic and cultural backgrounds increasingly recruited as care workers while at the same time there is growing cultural diversity among aged care residents. This situation is compounded by rapidly changing technology and varied educational levels of care workers from diverse backgrounds. OBJECTIVES: The objectives were threefold: to identify staff learning needs to enable them to provide high-quality cross cultural care; to improve team cohesion; and identify preferred learning approaches. DESIGN: An interpretive qualitative study utilising focus group and interview data informed the development of an education resource. PARTICIPANTS AND SETTINGS: Fifty six care workers from four residential aged care facilities participated in either focus groups or interviews conducted in private meeting rooms within the care facilities. Participants included personal care attendants, registered and clinical nurses, managers, hospitality staff and allied health professionals. METHODS: Focus group and interview data were categorised and thematically analysed. Data relevant to cross-cultural care, team cohesion and preferred learning approaches informed education resource development, including case studies. RESULTS: Major themes identified the need to promote cultural awareness and understanding, and strategies for cross-cultural care and communication. Themes related to team cohesion demonstrated that staff were already sympathetic and sensitive to cross-cultural issues, and that culturally and linguistically diverse staff add value to the workforce and are supported by the organisation. Staff required clear, uncomplicated education resources to equip them with skills to address problematic cultural situations. Preferred learning approaches varied and highlighted the need for varied educational materials and approaches, as well as time efficient, opportunistic education strategies for the busy workplace. CONCLUSION: An education package was developed to value cultural diversity in the aged care workplace for staff and residents, and provide an exemplar for evidence informed education. PMID- 29407256 TI - The influence of situation awareness training on nurses' confidence about patient safety skills: A prospective cohort study. AB - BACKGROUND: Several studies report that patient safety skills, especially non technical skills, receive scant attention in nursing curricula. Hence, there is a compelling reason to incorporate material that enhances non-technical skills, such as situation awareness, in nursing curricula in order to assist in the reduction of healthcare related adverse events. OBJECTIVES: The objectives of this study were to: 1) understand final year nursing students' confidence in their patient safety skills; and 2) examine the impact of situation awareness training on final year nursing students' confidence in their patient safety skills. METHODS: Participants were enrolled from a convenience sample comprising final year nursing students at a Western Australia university. Self-reported confidence in patient safety skills was assessed with the Health Professional in Patient Safety Survey before and after the delivery of a situation awareness educational intervention. Pre/post educational intervention differences were examined by repeated measures ANOVA. RESULTS: No significant differences in confidence about patient safety skills were identified within settings (class/clinical). However, confidence in patient safety skills significantly decreased between settings i.e. nursing students lost confidence after clinical placements. CONCLUSION: The educational intervention delivered in this study did not seem to improve confidence in patient safety skills, but substantial ceiling effects may have confounded the identification of such improvement. Further studies are required to establish whether the findings of this study can be generalised to other university nursing cohorts. PMID- 29407257 TI - The effect of role assignment in high fidelity patient simulation on nursing students: An experimental research study. AB - BACKGROUND: Previous studies have evaluated the effectiveness of high fidelity patient simulators (HFPS) on nursing training; however, a gap exists on the effects of role assignment on critical thinking, self-efficacy, and situation awareness skills in team-based simulation scenarios. OBJECTIVES: This study aims to determine if role assignment and the involvement level related to the roles yields significant effects and differences in critical thinking, situation awareness and self-efficacy scores in team-based high-fidelity simulation scenarios. DESIGN: A single factorial design with five levels and random assignment was utilized. SETTING: A public university-sponsored simulation center in the United States of America. PARTICIPANTS: A convenience sample of 69 junior level baccalaureate nursing students was recruited for participation. METHODS: Participants were randomly assigned one of five possible roles and completed pre simulation critical thinking and self-efficacy assessments prior to the simulation beginning. Playing within their assigned roles, participants experienced post-partum hemorrhaging scenario using an HFPS. After completing the simulation, participants completed a situation awareness assessment and a post simulation critical thinking and self-efficacy assessment. RESULTS: Role assignment was found to have a statistically significant effect on critical thinking skills and a statistically significant difference in various areas of self-efficacy was also noted. However, no statistical significance in situation awareness abilities was found. CONCLUSIONS: Results support the notion that certain roles required the participant to be more involved with the simulation scenario, which may have yielded higher critical thinking and self-efficacy scores than roles that required a lesser level of involvement. PMID- 29407258 TI - Emotional intelligence and health students' well-being: A two-wave study with students of medicine, physiotherapy and nursing. AB - This study aims to analyze the role of emotional intelligence as a predictor of health students' well-being (i.e., burnout and life satisfaction) over time. A longitudinal, 1 year lagged study was conducted at 2 points in time with a sample of 303 Spanish students of Medicine, Physiotherapy and Nursing. The results indicated that others' emotion appraisals and use of emotion had a positive direct effect on satisfaction with life, and self-emotion appraisals had a positive indirect effect on burnout. This research represents a contribution within the framework of health students' well-being concerns, providing significant practical implications for future consideration by health education institutions for graduate doctors, physiotherapists and nurses, who will present higher levels of emotional intelligence and, consequently, greater well-being and better quality care for future patients. PMID- 29407259 TI - Pre-departure preparation and co-curricular activities for Students' intercultural exchange: A mixed-methods study. AB - BACKGROUND: Nurses are required to be culturally competent to provide quality care to an increasingly diverse and ageing population. International exchange programmes were developed to support the traditional nursing curriculum. These programmes have often overlooked the importance of pre-departure preparation and co-curricular activities to the development of intercultural competency. OBJECTIVES: To explore the influence of pre-departure and co-curricular activities on the intercultural learning experiences of both exchange and host students in a short-term international summer programme. DESIGN: A mixed-methods study. SETTING: Students were recruited from international and mainland exchange partners, with host students as ambassadors. The international summer programme involved a week of online pre-departure activities and two weeks of face-to-face meetings. PARTICIPANTS: A convenience sample of 62 students from diverse cultural backgrounds was recruited on a voluntary basis. The participants were aged between 19 and 27. METHODS: Data were collected from students' pre- and post visit questionnaires, discussions within the workshops, their online discussion threads, and focus group discussions. RESULTS: The quantitative findings suggested that students' cultural intelligence improved significantly after the exchange programme. Qualitatively, three themes emerged as: 1) Students' motivation to engage in intercultural learning; 2) Barriers to intercultural communication; 3) Enablers of intercultural communication. CONCLUSION: Pre departure preparation enabled students to discuss their common goals and expectations, while exploring differences, asked for practical living information, and used the basic intercultural concepts in their discussion on the care of elderly. This virtual encounter has lay the foundation for students' subsequent discussions about the why and how the differences that inform their own practices and about global ageing and poverty issues during their co curricular activities. While the pre-departure preparation could serve as a stimulus, the value of this programme for intercultural learning also rests with the importance of debriefing to further students' reflective and experiential learning. PMID- 29407260 TI - Qualities, teaching, and measurement of compassion in nursing: A systematic review. AB - BACKGROUND: Compassion has global implications for nursing care. However, failure to provide compassionate care is reported by patients. Nursing and nurse education have been scrutinized about the impact training can have on student's compassion. Furthermore, there is a paucity of standardised measures to assess levels of nurses' compassion. OBJECTIVES: To identify (1) the qualities of a compassionate nurse, (2) how compassion is taught to nursing students, and (3) the instruments used to measure compassion in nursing. DESIGN: Systematic literature review. DATA SOURCES: CINHAL, EBSCO, SCOPUS, PubMed, Ovid Nursing. SEARCH METHODS: A systematic review of published research was conducted with. No limitations in the search timeframe were used. Articles were included if they were (1) nurses (2) nursing students (3) educators and (4) patient groups, (5) written in English. Articles that were, peer reviewed, research articles, or articles grounded in evidence based practice were also included. RESULTS: Fourteen studies (6 UK, 3 USA, 2 Canada, 1 Korea, 1 Thailand, and 1 Netherlands) identified eleven characteristics of a compassionate nurse. Two UK and one Australian study investigated teaching compassion to nursing students. Four articles reported on instruments used to measure compassion in nursing. Three were American, and one Korean. CONCLUSION: This review identified only 21 papers overall. Several qualities of a compassionate nurse were found. In addition, few studies have explored how compassion is taught to nursing students. Also, there are a limited number of instruments for measuring compassion in nursing. More research is needed in nurse education to develop a teaching approach and psychometric measure for nurses' compassion. PMID- 29407261 TI - Evaluation of strategies designed to enhance student engagement and success of indigenous midwifery students in an Away-From-Base Bachelor of Midwifery Program in Australia: A qualitative research study. AB - BACKGROUND: A strategy to close the gap in relation to Indigenous health is the employment of more Indigenous health professionals. However, despite government reviews, research studies and educational initiatives, Indigenous students' retention and completion rates of tertiary education remains below those of non Indigenous Australians. OBJECTIVE: To evaluate two enhancements to an Away-from Base Bachelor of Midwifery program for Indigenous students, namely the appointment of an Indigenous Academic Liaison Midwife to provide academic and cultural support and an additional clinical placement in a high-volume tertiary hospital. METHOD: In this qualitative study, 10 Indigenous students enrolled in the Away-from-Base Bachelor of Midwifery program participated in one of two focus groups. Focus group transcriptions were subjected to a manual thematic analysis, and key themes were identified and explored. FINDINGS: The role of the Indigenous Academic Liaison Midwife was highly valued as students had access to a resource who provided cultural and academic support, and who encouraged and advocated for them. Regular contact with the Indigenous Academic Liaison Midwife enabled students to stay connected with and focussed on their study. Students were overwhelmingly positive about the opportunity to undertake the additional clinical placement, as it exposed them to complex clinical cases they may not have seen in their home communities. CONCLUSIONS: The introduction of an Indigenous Academic Liaison Midwife and an additional clinical placement in a high-volume tertiary hospital were perceived as valuable additions to the range of support mechanisms already in place for Indigenous Away-from-Base Bachelor of Midwifery students. These interventions have had a direct impact on retention, course progression and completion rates for Indigenous students. Students expressed enhanced clinical learning and knowledge retention as a result of the additional clinical placement, and the Indigenous Academic Liaison Midwife provided culturally sensitive support for students undertaking remote learning, and during on-campus intensive sessions. PMID- 29407262 TI - The effect of a multifaceted evidence-based practice programme for nurses on knowledge, skills, attitudes, and perceived barriers: A cohort study. AB - BACKGROUND: The Dutch professional nursing standard of 2012 stipulates that Dutch nursing practices are to be evidence-based. Not all practicing nurses can satisfy these requirements, therefore, an educational programme about Evidence-Based Practice (EBP) was developed for a Dutch teaching hospital. OBJECTIVE: The aim of this study was to measure the effects of a six month in-house EBP programme on knowledge, skills, attitudes, and perceived barriers of nurses (four European Credits equals two US Credit Hours). METHODS: A multiple-cohort study was conducted with a pre-post-test design. In the period of 2011-2015, a total of 58 nurses (9 cohorts) followed the programme. Baseline and follow-up assessments consisted of three questionnaires each: the Dutch Modified Fresno, the two subscales of the McColl questionnaire, and the BARRIER scale to assess knowledge and skills, attitudes, and perceived barriers, respectively. RESULTS: Fifty nurses completed both assessments. The results demonstrated that actual knowledge and skills significantly increased by approximately 40%. Self-perceived knowledge increased significantly, while attitudes towards EBP remained (moderately) positive. Perceived barriers did not notably change except for the Research subscale which received many "no opinion" responses prior to the programme but fewer afterwards. CONCLUSIONS: Our multifaceted in-house EBP programme led to a significant improvement of approximately 40% in EBP knowledge and skills of participating nurses. Most nurses who followed the EBP programme are currently applying their knowledge and skills in practice. Managerial support and allocated time for EBP are important facilitators for its implementation. Furthermore, to maintain and expand nurses' EBP knowledge and skills and translate them into practice, follow-up interventions, such as journal clubs, may well be beneficial. Based on the positive results of our programme, we will implement it throughout the hospital with an emphasis on training more groups of nurses. PMID- 29407263 TI - Comparison of the Readiness for Interprofessional Learning and the rate of contact among students from nine different healthcare courses. AB - BACKGROUND: Despite the growth in the interprofessional literature, there are still few studies that have evaluated the differences among courses and periods in relation to Readiness for Interprofessional Learning. Likewise, the relationship between the influences of contact among students from different professions is still controversial. OBJECTIVES: To evaluate whether greater contact among students from diverse health courses could be associated with improved Readiness for Interprofessional Learning (RIPLS) at the undergraduate level and to compare the RIPLS among healthcare courses, analyzing differences among courses and periods of their academic training. DESIGN: Cross-sectional study. SETTING: A Brazilian public university. PARTICIPANTS: Students enrolled in the first and final periods of nine healthcare courses. METHODS: The rates of contact between students and the Readiness for Interprofessional Learning were assessed. A comparison between students from these nine healthcare courses was carried out. RESULTS: A total of 545 (73.45%) students answered the questionnaire. The highest RIPLS scores were from Nursing (42.39), Dentistry (41.33) and Pharmacy students (40.72) and the lowest scores were from Physical Education (38.02), Medicine (38.17) and Psychology (38.66) students. The highest rates of contact between students (RC) were from Physical Education, Nutrition and Psychology students and the lowest RC were from Pharmacy, Social service and Dentistry. There was a significant effect of "healthcare course" on RIPLS. Comparing RIPLS and RC between the first and final years we found that, considering all courses, there was an increase in the RC, whereas a decrease in RIPLS scores. No correlation was found between RIPLS and RC in general. CONCLUSION: The current study found that RIPLS scores are very different between healthcare students. Although we found a significant increase in the RC, there was a decrease in the RIPLS scores. These findings lead to a greater understanding of the difficulties facing and potential for interprofessional education. PMID- 29407264 TI - Improving evidence based practice in postgraduate nursing programs: A systematic review: Bridging the evidence practice gap (BRIDGE project). AB - BACKGROUND: The nursing profession has a significant evidence to practice gap in an increasingly complex and dynamic health care environment. OBJECTIVE(S): To evaluate effectiveness of teaching and learning strategies related to a capstone project within a Masters of Nursing program that encourage the development of evidence based practice capabilities. DESIGN: Systematic review that conforms to the PRISMA statement. SAMPLE: Master's Nursing programs that include elements of a capstone project within a university setting. DATA SOURCES/REVIEW METHODS: MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, ERIC and PsycInfo were used to search for RCT's or quasi experimental studies conducted between 1979 and 9 June 2017, published in a peer reviewed journal in English. RESULTS: Of 1592 studies, no RCT's specifically addressed the development of evidence based practice capabilities within the university teaching environment. Five quasi experimental studies integrated blended learning, guided design processes, small group work, role play and structured debate into Masters of Nursing research courses. All five studies demonstrated some improvements in evidence based practice skills and/or research knowledge translation, with three out of five studies demonstrating significant improvements. CONCLUSIONS: There is a paucity of empirical evidence supporting the best strategies to use in developing evidence based practice skills and/or research knowledge translation skills for Master's Nursing students. As a profession, nursing requires methodologically robust studies that are discipline specific to identify the best approaches for developing evidence-based practice skills and/or research knowledge translation skills within the university teaching environment. Provision of these strategies will enable the nursing profession to integrate the best empirical evidence into nursing practice. PMID- 29407265 TI - 'It's complicated': Staff nurse perceptions of their influence on nursing students' learning. A qualitative descriptive study. AB - BACKGROUND: During both teacher-led clinical practica and precepted practica, students interact with, and learn from, staff nurses who work on the clinical units. It is understood that learning in clinical practice is enhanced by positive interactions between staff nurses and nursing students. While much is known about preceptors' experiences of working with nursing students, there is little evidence to date about staff nurses' perspectives of their interactions with students in teacher-led practica. PURPOSE: To understand teacher-led clinical practica from the perspective of staff nurses. METHOD: A qualitative descriptive approach answers the question: How do staff nurses perceive their contributions to nursing students' learning during teacher-led practica? Nine staff Registered Nurses (RNs) working within a regional acute care hospital in western Canada were interviewed using semi-structured interviews. Interview transcripts were analyzed using cross case analysis to discover themes and findings were checked by several experienced RNs. RESULTS: Analysis showed that nurses' interactions with nursing students are complicated. Nurses want to "train up" their future colleagues but feel a heavy burden of responsibility for students on the wards. This sense of burden for the staff nurses is influenced by several factors: the practice environment, the clinical instructor, the students themselves, and the nurses' understanding of their own contributions to student learning. CONCLUSIONS: Staff nurses remain willing to support student learning despite multiple factors that contribute to a sense of burden during teacher-led practica. Workplace environment, nursing program, and personal supports are needed to support their continuing engagement in student learning. Nurses need to know how important they are as role models, and the impact their casual interactions have on student nurses' socialization into the profession. PMID- 29407266 TI - Evaluating service user pedagogy in UK higher education: Validating the Huddersfield Service User Pedagogy Scale. AB - BACKGROUND: There is global recognition that the inclusion of service users in the education of health and social care students in higher education can lead to more compassionate professional identities which will enable better decision making. However, to date there is no systematic tool to explore learning and service user involvement in the curriculum. OBJECTIVES: To generate and validate a psychometric instrument which will allow educators to evaluate service user pedagogy. DESIGN: Construction and validation of a new scale. PARTICIPANTS AND SETTINGS: 365 undergraduate students from health and social care departments in two universities. RESULTS: A two correlated factor scale. Factor 1 - perceived presence of service users in the taught curriculum and factor 2 - professionals and service users working together (correlation between factor 1 and factor 2 - r = 0.32). CONCLUSIONS: The Huddersfield Service User Pedagogy Scale provides a valid instrument for educators to evaluate student learning. In addition, the tool can contribute to student reflections on their shifting professional identities as they progress through their studies. PMID- 29407267 TI - A feasibility study of dementia communication training based on the VERA framework for pre-registration nurses: Part II impact on student experience. AB - BACKGROUND: People living with dementia have complex communication needs, especially during acute hospital admissions. The VERA framework (validation, emotion, reassurance, activity) was designed to promote person centred communication between student nurses and people living with dementia, but there is limited evaluation of its impact. AIM: To measure the impact of dementia communication training (based on VERA) plus older adult unit (OAU) placement on students' ability to recognise opportunities for person centred (PC) communication compared to OAU placement alone. METHOD: A control pre-post-study design was used. Dementia communication training plus follow-up during OAU placement was delivered to 51 students (5 OAU, two hospitals) while 66 students (7 OAUs, five hospitals) acted as controls. The primary outcome was students' ability to recognise PC communication assessed using case vignettes. Data were collected using electronic survey and focus group interviews. Data analysis used independent non-parametric Mann-Whitney U test and thematic analysis. RESULTS: In total 52 students (response rate 40%) completed surveys at the end of placements (38 intervention, 14 control group students). In the intervention group, participants were significantly more likely to identify PC responses with a mean score of 10.5 (SD 3.0) compared with 7.5 (SD 3.0) in the control group (p = 0.006). In focus group interviews (n = 19 students), the main themes were connecting with patients, VERA in practice, communication challenges, and learning environment. VERA was described as a flexible approach that added to participants' communication toolkit. The learning environment, complexity of patients and organisational resources were important contextual factors. CONCLUSION: The VERA framework has potential as a foundation level dementia communication training intervention, but it requires more rigorous testing. Nursing can lead the way in developing and embedding evidence-based, interdisciplinary dementia communication training in preregistration curricula. PMID- 29407268 TI - A dementia communication training intervention based on the VERA framework for pre-registration nurses: Part I developing and testing an implementation strategy. AB - BACKGROUND: People living with dementia experience progressive difficulty in expressing physical and emotional needs. Health care staff including student nurses require training to develop compensatory communication strategies. However, there is no standardised foundation level dementia communication training within pre-registration curricula. AIM: This article describes the theoretical underpinnings and development of a foundation level dementia communication skills training based on the VERA (Validation, Emotion, Reassurance, Activity) framework. METHOD: The training strategies drew on behavioural change theory using the COM-B model and Gagne's 9 Events of Instruction. The VERA framework was operationalised using a multicomponent teaching strategy. The intervention was refined based on quality improvement Plan Do-Study-Act cycles with feedback from people living with dementia, facilitators and student nurses. Data collection used semi-structured questionnaires (n = 51) and four focus group (n = 19) interviews with students. Data analysis involved descriptive statistics and thematic analysis. RESULTS: The intervention was a 2.5 hour face-to-face training session delivered at the start of students' older adult unit placement with follow-up reflection sessions during placement. Training was delivered to 51 students, all students described the training as useful and would recommend it to their peers. Elements of the training that were highly valued were: opportunities to express concerns in caring for people with dementia, applying the VERA framework using role play and outlining realistic expectations of VERA. Students recognised the need for on-going training especially for more complex patients. CONCLUSION: Combining behaviour change and education theory with stakeholder feedback strengthened the development of VERA as a foundation level dementia communication training for pre-registration nurses. PMID- 29407269 TI - Microstructurally-based constitutive modelling of the skin - Linking intrinsic ageing to microstructural parameters. AB - A multiphasic constitutive model of the skin that implicitly accounts for the process of intrinsic (i.e. chronological) ageing via variation of the constitutive parameters is proposed. The structurally-motivated constitutive formulation features distinct mechanical contributions from collagen and elastin fibres. The central hypothesis underpinning this study is that the effects of ageing on the mechanical properties of the tissue are directly linked to alterations in the microstructural characteristics of the collagen and elastin networks. Constitutive parameters in the model, corresponding to different ages, are identified from published experimental data on bulge tests of human skin. The numerical results demonstrate that degradation of the elastin meshwork and variations in anisotropy of the collagen network are plausible mechanisms to explain ageing in terms of macroscopic tissue stiffening. Whereas alterations in elastin affect the low-modulus region of the skin stress-strain curve, those related to collagen have an impact on the linear region. PMID- 29407270 TI - Soy and the risk of type 2 diabetes mellitus: A systematic review and meta analysis of observational studies. AB - BACKGROUND: Increasing studies have focused on the relationship between soy intake and type 2 diabetes mellitus risk, but the results are inconsistent. We conduct a meta-analysis to evaluate the relationship. METHODS: The databases of PubMed, Web of Science and Embase were searched up to Dec 2016. A random-effect model was used to pool the results of included studies. RESULTS: Eight studies with 19 reports met the inclusion criteria. A significant inverse association was shown between soy intake and type 2 diabetes mellitus risk with an overall RR of 0.77 (95% CI = 0.66-0.91) with high heterogeneity. Besides, there was an obvious relationship between soy protein and isoflavones intake and risk of T2DM with the summary RR was 0.88 (95% CI = 0.80-0.97) with no heterogeneity. In the subgroup analysis, a statistically significant protective effect of soy consumption was observed in women (RR = 0.65; 95% CI = 0.49-0.87), cross-sectional studies (RR = 0.45; 95% CI = 0.30-0.67), and Asian populations (RR = 0.73; 95% CI = 0.61-0.88). CONCLUSIONS: Soy products and soy constituents (soy protein and soy isoflavones) may be associated with a lower risk of type 2 diabetes mellitus. Future studies should focus on the dose-response effect and the mechanism. PMID- 29407271 TI - Extranodal natural killer/T-cell lymphoma masquerading a diabetic foot ulcer. AB - Foot ulcers are among the most frequently recognized complications of diabetes. It's easy to misdiagnose ulcers secondary to malignancy as diabetic foot ulceration because of the clinical similarity. Here we present a case of extranodal natural killer/T-cell lymphoma initially presented as a diabetic foot ulcer. PMID- 29407272 TI - Fear of hypoglycaemia and its relation to hypoglycaemia awareness and symptom intensity in Type 1 diabetes. AB - AIMS: To investigate fear of hypoglycaemia (FoH) in relation to hypoglycaemia awareness, history of severe hypoglycaemia (SH) and hypoglycaemia symptoms in adults with Type 1 diabetes. METHODS: Questionnaire-based cross-sectional survey. We assessed FoH with the Hypoglycaemia Fear Survey-II Worry subscale, hypoglycaemia awareness status with the Gold score, and used the Edinburgh Hypoglycaemia Scale to grade the presence and intensity of hypoglycaemia symptoms. All these measures have previously been validated for research application. We used multivariable linear regression to examine associations between FoH and hypoglycaemia awareness status, history of SH and hypoglycaemia symptom score. RESULTS: Of 636 invitees, 445 (70%) responded, with 435 responses eligible for analyses. Seventy-four persons had IAH (17%). Among those, 47 (64%) reported >= 1 SH during the preceding year, in contrast to this being reported by 113 (31%) of persons with normal awareness. The mean (SD) FoH worry score was 1.33 (0.78). This score was 0.64 (95% CI, 0.45-0.83) higher among people with impaired vs. normal hypoglycaemia awareness and 0.53 (95% CI, 0.33-0.73) higher among people with >= 3 episodes of SH the preceding year vs. people with no such episode. A higher number and intensity of hypoglycaemia symptoms was associated with higher FoH, as demonstrated by an increase in mean FoH worry score of 0.30 (95% CI, 0.23-0.36) per point increase in mean Edinburgh hypoglycaemia score. CONCLUSIONS: Impaired awareness of hypoglycaemia, history of SH and higher Edinburgh hypoglycaemia scores were all associated with increased FoH in adults with Type 1 diabetes. PMID- 29407273 TI - Targeting testosterone measurements to patients with type 2 diabetes mellitus and moderate to severe symptomatic erectile dysfunction. AB - In this study among patients with erectile dysfunction (ED) and type 2 diabetes mellitus, all 25 patients with mild ED were eugonadal. Among patients with moderate ED, 25% were eugonadal while the rest had hypogonadism; while in the severe group only 1 (3%) was eugonadal. This suggests that testosterone measurements in patient with diabetes are better targeted in patients with moderate to severe ED. PMID- 29407274 TI - Wide dissemination of SCCfusC in fusidic acid-resistant coagulase-negative staphylococci and implication for its spread to methicillin-resistant staphylococcus aureus in Taiwan. AB - The fusidic acid (FUS) resistance determinants fusB, fusC, fusD and fusF in coagulase-negative staphylococci (CoNS) clinical isolates were examined. Among 208 FUS-resistant isolates, the fusB gene was the most common resistance determinant in each species, except in Staphylococcus hominis subsp. hominis or in species carrying intrinsic fusD or fusF. In S. hominis subsp. hominis, the fusC gene was the major determinant responsible for FUS resistance. To understand the genetic context of fusC in S. hominis subsp. hominis, 31 fusC-positive S. hominis subsp. hominis isolates were examined. Among these isolates, 14 carried SCCfusC, 3 carried an SCC476-like element and 7 carried a new SCC structure (SCC3390). As shown by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analyses, the S. hominis subsp. hominis clinical isolates showed limited clonality. Taken together, SCCfusC has been found in S. hominis subsp. hominis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus capitis subsp. ureolyticus and Staphylococcus aureus, suggesting its wide distribution and spread among different species of staphylococci. PMID- 29407275 TI - Influence of non-contextual auditory stimuli on navigation in a virtual reality context involving executive functions among patients after stroke. AB - BACKGROUND: Topographical disorientation is frequent among patients after a stroke and can be well explored with virtual environments (VEs). VEs also allow for the addition of stimuli. A previous study did not find any effect of non contextual auditory stimuli on navigational performance in the virtual action planning-supermarket (VAP-S) simulating a medium-sized 3D supermarket. However, the perceptual or cognitive load of the sounds used was not high. OBJECTIVE: We investigated how non-contextual auditory stimuli with high load affect navigational performance in the VAP-S for patients who have had a stroke and any correlation between this performance and dysexecutive disorders. METHODS: Four kinds of stimuli were considered: sounds from living beings, sounds from supermarket objects, beeping sounds and names of other products that were not available in the VAP-S. The condition without auditory stimuli was the control. The Groupe de reflexion pour l'evaluation des fonctions executives (GREFEX) battery was used to evaluate executive functions of patients. RESULTS: The study included 40 patients who have had a stroke (n=22 right-hemisphere and n=18 left hemisphere stroke). Patients' navigational performance was decreased under the 4 conditions with non-contextual auditory stimuli (P<0.05), especially for those with dysexecutive disorders. For the 5 conditions, the lower the performance, the more GREFEX tests were failed. Patients felt significantly disadvantaged by the non-contextual sounds sounds from living beings, sounds from supermarket objects and names of other products as compared with beeping sounds (P<0.01). Patients' verbal recall of the collected objects was significantly lower under the condition with names of other products (P<0.001). Left and right brain-damaged patients did not differ in navigational performance in the VAP-S under the 5 auditory conditions. CONCLUSIONS: These non-contextual auditory stimuli could be used in neurorehabilitation paradigms to train patients with dysexecutive disorders to inhibit disruptive stimuli. PMID- 29407276 TI - Self-motile swimmers: Ultrasound driven spherical model. AB - The concept of ultrasound acoustic driven self-motile swimmers which is the source of autonomous propulsion is the acoustic field generated by the swimmer due to the partial oscillation of its surface is investigated. Limiting the subject to a body with simple spherical geometry, it is analytically shown that the generated acoustic radiation force due to induction by asymmetric acoustic field in host medium is non-zero, which propels the device. Assuming low Reynolds number condition, the frequency-dependent swimming velocity is calculated as a function of design parameters and optimum operating condition is obtained. The proposed methodology will open a new path towards the micro- or molecular-sized self propulsive machines or mechanism with great applications in engineering, medicine and biology. PMID- 29407277 TI - Ultrafast laser pulse chirp effects on laser-generated nanoacoustic strains in Silicon. AB - Nanoacoustic strains are generated in Silicon by chirped femtosecond laser pulses using thin Titanium films as transducers. We investigate the effect that the generating laser pulse chirp has on the amplitude of the induced strains, manifested as Brillouin oscillations observed in degenerate femtosecond pump probe transient reflectivity measurements. The strain amplitude is larger when negatively chirped pulses are used, which is attributed to the more efficient conversion of laser pulse light into acoustic strain in the Titanium transducer. Our present studies clearly show that the dependence of the Brillouin amplitude and the lattice strain is a non-monotonous function of the laser chirp parameter. An optimum negative laser pulse chirp is found for which the strain amplitude is maximized. A detailed thermomechanical model satisfactorily supports the experimental findings. In such a way, it is possible to suppress or enhance the induced nanoacoustic strain amplitude, thus all-optically controlling it by at least a factor of two. PMID- 29407278 TI - Generation and reception of shear horizontal waves using the synthetic face-shear mode of a thickness-poled piezoelectric wafer. AB - The guided wave based inspection technique has been playing an important role in modern industries due to its capability in rapid detection of large structures. Among all the wave modes in plate-like structures, the fundamental shear horizontal wave (SH0) is of great importance since it is the unique non dispersive mode. However, the generation and reception of SH0 wave using piezoelectrics is always a challenge. In this work, we synthesized face-shear deformation mode in a thickness-poled piezoelectric wafer and successfully excited/received SH0 wave in a thin aluminum plate. Firstly, the frequency response of the proposed wafer was analyzed using the finite element method (FEM) to show that the face-shear deformation can be synthesized via applying anti parallel electric fields on different parts of the wafer. Subsequently, time transient FEM simulations were carried out to predict its capacity in generation/reception of SH0 wave. Finally, experiments were conducted to examine the performance of the proposed wafer on SH0 wave generation/reception. The obtained results indicate that the synthetic face-shear piezoelectric wafer can generate SH0 wave along two principal directions (0 degrees and 90 degrees ) with the amplitudes symmetric along the 45 degrees direction. The amplitude of the generated SH0 wave reached its maxima along the principal direction and decreased to nearly zero at 45 degrees direction, which is in good agreement with the FEM results. Besides, the wafer can only receive SH0 wave in a wide range of frequency, i.e., it can act as an inherent wave filter. Due to its compact size and easy fabrication, the proposed wafer has a great potential in promoting the applications of SH0 wave in nondestructive testing and structural health monitoring. PMID- 29407279 TI - Lebedev scheme for ultrasound simulation in composites. AB - The growing use of composite materials for aerospace applications has resulted in a need for quantitative nondestructive evaluation (NDE) methods appropriate for characterizing damage in composite components. NDE simulation tools, such as ultrasound models, can aid in enabling optimized inspection methods and establishing confidence in inspection capabilities. In this paper a mathematical approach using the Lebedev Finite Difference (LFD) method is presented for ultrasonic wave simulation in composites. Boundary condition equations for implementing stress-free boundaries (necessary for simulation of NDE scenarios) are also presented. Quantitative comparisons between LFD guided wave ultrasound simulation results, experimental guided wave data, and dispersion curves are described. Additionally, stability tests are performed to establish the LFD code behavior in the presence of stress-free boundaries and low-symmetry anisotropy. Results show that LFD is an appropriate approach for simulating ultrasound in anisotropic composite materials and that the method is stable in the presence of low-symmetry anisotropy and stress-free boundaries. Studies presented in this paper include guided wave simulation in hexagonal, monoclinic, triclinic and layered composite laminates. PMID- 29407280 TI - Influence of electrical boundary conditions on profiles of acoustic field and electric potential of shear-horizontal acoustic waves in potassium niobate plates. AB - The profiles of an acoustic field and electric potential of the forward and backward shear-horizontal (SH) acoustic waves of a higher order propagating in X Y potassium niobate plate have been theoretically investigated. It has been shown that by changing electrical boundary conditions on a surface of piezoelectric plates, it is possible to change the distributions of an acoustic field and electric potential of the forward and backward acoustic waves. The dependencies of the distribution of a mechanical displacement and electrical potential over the plate thickness for electrically open and electrically shorted plates have been plotted. The influence of a layer with arbitrary conductivity placed on a one or on the both plate surfaces on the profiles under study, phase and group velocities of the forward and backward acoustic waves in X-Y potassium niobate has been also investigated. The obtained results can be useful for development of the method for control of a particle or electrical charge movement inside the piezoelectric plates, as well a sensor for definition of the thin film conductivity. PMID- 29407281 TI - This Month in The Journal. PMID- 29407282 TI - Delayed unpaired extinction as a treatment for hyperarousal of the rabbit nictitating membrane response and its implications for treating PTSD. AB - Treatment for PTSD (Post-traumatic stress disorder) is rarely available immediately after trauma and often delayed for weeks or months after an event. In a rabbit eyeblink conditioning model of PTSD, we have previously shown that presentations of a tone conditioned stimulus (CS) and shock unconditioned stimulus (US) in an explicitly unpaired manner known as unpaired extinction is effective in reducing CS responding and US hyperarousal even if shock intensity is reduced eight-fold and elicits only minimal responding. Here we determined if delayed delivery of unpaired extinction would still be effective in extinguishing hyperarousal. Rabbits were tested for sensitivity to shock before CS-US pairings and after six days of unpaired extinction presented a day, a week or a month after CS-US pairings. Hyperarousal was extinguished a day and a week after conditioning but not after a month suggesting a significant delay in "treatment" can make hyperarousal persist. We next assessed if this persistence of hyperarousal was associative by comparing rabbits given CS-US pairings to those given explicitly unpaired CS and US presentations, measuring hyperarousal a day and a month later, followed by unpaired extinction and hyperarousal assessment. After four weeks, there was an increase in responding for all rabbits but only rabbits receiving CS-US pairings showed a significant increase in associatively mediated hyperarousal. Importantly, both paired and unpaired groups showed increased levels of responding after unpaired extinction suggesting treatment delayed for too long may no longer be effective and could cause generalized hyperarousal. PMID- 29407283 TI - Intrinsic, task-evoked and absolute gamma synchrony during cognitive processing in first onset schizophrenia. AB - Cognitive deficits present from the first onset of schizophrenia are thought to arise from a core problem in neural synchrony. This is the first study to characterize the profile of gamma (30-100 Hz) synchrony (rather than power) and behavioral performance during higher-order cognitive processing in schizophrenia. Gamma synchrony was acquired from the EEG, and elicited by a Continuous Performance Test (CPT). We quantitated synchrony for regions associated with the fronto-parietal attention and visual networks for 59 young people with First Onset Schizophrenia (FOS) and 59 matched controls, facilitated by the BRAINnet.net data sharing initiative. We compared groups on gamma synchrony for intrinsic (pre-stimulus), task-evoked change (relative to baseline) and absolute (not relative to baseline) measures. Relationships between synchrony and CPT accuracy, symptoms and functioning were also assessed. FOS showed a reduced ability to modulate task-evoked changes in gamma synchrony, in the context of generally higher intrinsic and absolute synchrony, particularly in frontal regions. These gamma synchrony abnormalities in FOS were associated with performance on the CPT, but not with symptoms or functioning. Task-relevant changes in synchrony may be constrained by an overall excess of intrinsic background synchrony that is unrelated to specific task demands and this relates to cognitive performance. Results are in line with theoretical accounts of gamma synchrony as a core abnormality in schizophrenia, affecting functional connectivity in central executive circuits and causing cognitive symptoms. This study is the first to demonstrate that these gamma synchrony abnormalities are not limited to perceptual or lower-order cognitive processing. PMID- 29407284 TI - Meta-analysis of neurocognition in young psychosis patients with current cannabis use. AB - OBJECTIVE: Adult psychosis patients (i.e. over the age of 25 years) who are also lifetime cannabis users (CANN+/-) appear to exhibit superior cognition compared to never-using patients (CANN-). The objective of this meta-analysis was to evaluate the cognitive differences between CANN- and patients who currently use cannabis (CANN+) (i.e. during the CANN+/- patients' cannabis-using stage). Specifically, focusing on young patients under the age of 25 years, the typical stage of both psychosis- and cannabis-onset. METHOD: Of the 308 studies identified through database searches and secondary referencing, 14 compared neurocognition of CANN+ and CANN- in young people with psychotic disorders (mean age between 15 and 45 years). Effect sizes were extracted using neurocognitive test performance between CANN+ and CANN- and random effects modelling was conducted on pooled ES and moderator analyses. RESULTS: CANN+ performed worse on several cognitive domains (i.e. premorbid IQ, current IQ, verbal learning, verbal working memory, motor inhibition) compared to CANN-. The association between age and performance in CANN+ cognition was varied, with older age predictive of worse performance in processing speed, sustained attention, verbal memory, and better performance in verbal learning and very fluency. Of note, CANN+ outperformed CANN in tests of conceptual set-shifting. CONCLUSION: These results are consistent with previous findings indicating that CANN+ demonstrate poorer neurocognition than CANN-; and that this is exacerbated with increasing age. Our findings demonstrate significant cognitive differences between patients with CANN+ versus CANN- even at early-onset psychosis, which could suggest a different underlying mechanism towards psychosis for cannabis users. PMID- 29407285 TI - Heart rate variability in patients with bipolar disorder: From mania to euthymia. AB - Bipolar Disorder (BD) is characterized by the occurrence of mania alternating with euthymia. The aim of the present study was to investigate the impact of BD on the autonomic nervous system, as indicated by heart rate variability (HRV). The study was registered in the Clinical Trials Registration (NCT01272518). Nineteen hospitalized, male patients (age: 34.0 +/- 12.3 years) with type I BD were assessed during mania and at discharge on euthymia. HRV data were collected during 20- minutes in supine position at rest, on spontaneous breathing, using the Polar RS 800 CX frequencymeter. HRV measures included variables in time, frequency and non-linear domains. Psychiatric conditions were evaluated by the Mini International Neuropsychiatric Interview (MINI) and the Bech-Rafaelsen mania scale (BRMS). Time domain measures of RMSSD (Cohen's d = 0.668) and pNN50 (Cohen's d = 0.688) increased from first to second assessments. The high frequency component (HFms2) also increased (Cohen's d = 0.586), while the LF/HF ratio decreased (Cohen's d = 0.785). Non-linear domain measures including the SD1 component (Cohen's d = 0.668), and the SD1/SD2 ratio (Cohen's d = 1.2934) extracted from the Poincare plot analysis increased from first to second assessment. The variables Lmean (Cohen's d = 0.9627), Lmax (Cohen's d = 1.2164), REC% (Cohen's d = 1.0595) and EntShannon (Cohen's d = 1.0607) were higher in mania. By contrast, ApEn (Cohen's d = 0.995) and EntSample (Cohen's d = 1.189) were less during mania, all reflecting ANS improvement. Findings are interpreted in the context of recently published models relating to neurovisceral integration across the continuum of time, and the implications for the future health and wellbeing of patients are considered. PMID- 29407286 TI - Examining redox modulation pathways in the post-mortem frontal cortex in patients with bipolar disorder through data mining of microRNA expression datasets. AB - The etiology of redox (reduction and oxidation) alterations in bipolar disorder (BD) is largely unknown. To explore whether microRNAs targeting redox enzymes may have a role in BD, we examined 3 frontal cortex microRNA expression datasets (Perkins [2007], Vladimirov [2009], and Miller [2009]; N for BD = 30-36 per dataset, N for controls = 28-34 per dataset) from the Stanley Neuropathology Consortium. Each dataset was analyzed separately because they were generated using different high-throughput platforms. Following the selection of only redox modulator-targeting microRNAs, microRNAs in the top 10th percentile in feature selection could together discriminate BD and controls at a greater frequency than expected by chance in classification analysis. In pathway enrichment analysis of all three datasets, these classifying microRNAs targeted the cellular nitrogen compound metabolic process pathway, which includes redox enzymes of the mitochondrial electron transport chain and the glutathione system. To see if this pathway would still emerge as significant if all microRNAs (not just redox targeting) were analyzed, all analyses were repeated with the complete set of microRNAs. Cellular nitrogen compound metabolic process pathway was enriched in all 3 datasets in this analysis as well, demonstrating that preselection of redox microRNAs was not a requirement to identify this pathway for the discrimination of BD and controls. While preliminary, our findings suggest that microRNAs that target redox enzymes in this pathway may be good candidates for the exploration of causative factors contributing to redox alterations in BD. Future studies validating these findings in a separate set of central and peripheral samples are warranted. PMID- 29407288 TI - GWAS-based machine learning approach to predict duloxetine response in major depressive disorder. AB - Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is commonly treated with antidepressant drugs. However, large variability is observed in terms of response to antidepressants. Machine learning (ML) models may be useful to predict treatment outcomes. A sample of 186 MDD patients received treatment with duloxetine for up to 8 weeks were categorized as "responders" based on a MADRS change >50% from baseline; or "remitters" based on a MADRS score <=10 at end point. The initial dataset (N = 186) was randomly divided into training and test sets in a nested 5-fold cross-validation, where 80% was used as a training set and 20% made up five independent test sets. We performed genome-wide logistic regression to identify potentially significant variants related to duloxetine response/remission and extracted the most promising predictors using LASSO regression. Subsequently, classification regression trees (CRT) and support vector machines (SVM) were applied to construct models, using ten-fold cross-validation. With regards to response, none of the pairs performed significantly better than chance (accuracy p > .1). For remission, SVM achieved moderate performance with an accuracy = 0.52, a sensitivity = 0.58, and a specificity = 0.46, and 0.51 for all coefficients for CRT. The best performing SVM fold was characterized by an accuracy = 0.66 (p = .071), sensitivity = 0.70 and a sensitivity = 0.61. In this study, the potential of using GWAS data to predict duloxetine outcomes was examined using ML models. The models were characterized by a promising sensitivity, but specificity remained moderate at best. The inclusion of additional non-genetic variables to create integrated models may improve prediction. PMID- 29407287 TI - Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. AB - Schizophrenia and bipolar disorder are among the leading causes of disability, morbidity, and mortality worldwide. In addition to being serious mental illnesses, these disorders are associated with considerable systemic physiological dysfunction, including chronic inflammation and elevated oxidative stress. The advent of sophisticated sequencing techniques has led to a growing interest in the potential role of gut microbiota in human health and disease. Advances in this area have transformed our understanding of a number of medical conditions and have generated a new perspective suggesting that gut microbiota might be involved in the development and maintenance of brain/mental health. Animal models have demonstrated strong though indirect evidence for a contributory role of intestinal microbiota in psychiatric symptomatology and have linked the microbiome with neuropsychiatric conditions. We present a systematic review of clinical studies of microbiome in schizophrenia and bipolar disorder. The published literature has a number of limitations; however, the investigations suggest that these disorders are associated with reduced microbial diversity and show global community differences compared to non-psychiatric comparison samples. In some reports, specific microbial taxa were associated with clinical disease characteristics, including physical health, depressive and psychotic symptoms, and sleep, but little information on the functional potential of those community changes. Studies also suggest increased intestinal inflammation and permeability, which may be among the principal mechanisms by which microbial dysbiosis impacts systemic physiological functioning. We highlight gaps in the current literature and implications for diagnosis and therapeutic interventions, and outline future directions for microbiome research in psychiatry. PMID- 29407289 TI - Efficacy of the I-SOCIAL intervention for loneliness in old age: Lessons from a randomized controlled trial. AB - Loneliness is common among older persons and is associated with adverse health and wellbeing outcomes. We investigated a theory-based intervention that addresses barriers to social contacts and aims at increasing social self efficacy. Individuals that met pre-assessment criteria of cognitive function, physical health, and loneliness levels were randomly assigned either to the I SOCIAL intervention that combined both individual and group sessions to address individuals' unique social challenges, or to the control group. Assessment was administered at baseline, after the completion of the intervention, and after a 3 month follow-up period. The intervention group showed significant decline in loneliness level compared to the control group, both after the intervention and after the follow-up period. This innovative combination of analysis of personal barriers, support provided by the counselors, group activities, and individualized suggestions for social activities in the participant's neighborhood, may account for the success of the intervention in decreasing participants' loneliness levels. PMID- 29407290 TI - Update on Causes of Family Refusal for Organ Donation and the Related Factors: Reporting the Changes Over 6 Years. AB - INTRODUCTION: After significant improvement of the family consent rate to organ donation (OD) in recent years, owing to an increase in cultural activities and social awareness, a plateau has been reached. This study was performed to detect the causes for this plateau. METHODS: We reviewed exact causes of family refusal after providing a list of failed potential donors from July 2015 to December 2016. The expert coordinators responsible for handling the failed cases chose the cause of refusal from the previously prepared list. The list was rechecked by contacting the nondonating families by phone. The results were compared with those obtained from a similar group of families in 2009. RESULTS: In an 18-month period of OD practice, 353 potential brain dead organ donors were referred to our organ procurement unit. The mean age of the cases was 42.6, and 62% were male. The main causes of brain death were cerebrovascular accident and trauma (41.2% and 32.6%, respectively). The family consent rate was 84.4%, and 55 families rejected the request for OD. The leading cause for family refusal was religious beliefs, mainly from Sunni families (43.6% vs 8.6% in 2009). Brain death denial reduced significantly from 44.4% in 2009 to 12.7% in 2015 and 2016 (P < .001 for both causes). Opposite donor wishes, unstable family mood, the belief in body integrity, and expectation of a miracle were the other causes of no reportable changes. CONCLUSIONS: After massive social activities in the media designed to enhance social awareness regarding brain death and OD, people currently do not doubt the irreversibility of death, as in the past. However, the noticeable increase in the consent rate has made the religious cause of family refusal prominent. Therefore, this cause seems to be the next barrier to fight against, requiring a careful approach to religious leaders and societies. PMID- 29407291 TI - Establishment of a Quantitative Polymerase Chain Reaction Assay for Monitoring Chimeric Antigen Receptor T Cells in Peripheral Blood. AB - BACKGROUND: The chimeric antigen receptor (CAR) consists of an antigen recognition moiety from a monoclonal antibody fused to an intracellular signalling domain capable of activating T cells. The specific structure of the CAR molecule has been used in various basic research and clinical settings to detect CAR expression, but it is necessary to develop more specific and simpler monitoring methods to observe real-time changes. MATERIALS AND METHODS: To develop a quantitative assay for the universal detection of DNA from anti-CD19 CAR-T cells, a TaqMan real-time quantitative polymerase chain reaction (qPCR) assay was developed using primers based on FMC63-28Z gene sequences. We identified the numbers of copies of CAR gene on T cells transduced with the CAR gene that were obtained from peripheral blood. RESULTS: The assay had a minimum detection limit of 10 copies/MUL and a strong linear standard curve (y = -3.3682x + 38.594; R2 = 0.999) within the range of the input CAR gene (10-107 copies/MUL). The reproducibility test showed a coefficient of variation ranging from 0.63% 1.65%. Real-time qPCR is a highly sensitive, specific, reproducible, and universal method that can be used to detect anti-CD19 CAR-T cells in peripheral blood. PMID- 29407292 TI - Impact of Interleukin-17F Gene Polymorphisms in Outcome of Kidney Transplantation in Tunisian Recipients. AB - BACKGROUND: Genetic polymorphisms of interleukin (IL)-17F, associated with functional and/or quantitative change in this glycoprotein, have been described as predisposing to various autoimmune diseases. The proinflammatory IL-17 has some roles in renal transplantation. In this context, the relationship between the most common IL-17F polymorphisms with acute renal allograft rejection susceptibility in Tunisian renal recipients has been investigated. METHODS: We examined 93 renal transplant recipients who were enrolled and classified as follows: GI, 48 transplant recipients who developed at least one episode of acute rejection; and GII, 45 controls, kidney recipients who also were followed for at least 1 year and had stable renal function. Single nucleotide polymorphisms (SNPs) of IL-17F gene, including -1507 C/T (rs18889570), 7384 A/G (rs2397084), 7469 C/T (rs11465553), and 7489 A/G (rs763780), were evaluated using direct sequencing. RESULTS: No statistically significant association of the IL-17F SNPs studied with the onset of acute rejection was observed. However, AA genotype on 7489A/G SNP showed anti-HLA antibodies less than other genotypes and a higher graft survival time (P = .017). CONCLUSION: The AA genotype on 7489A/G SNP of IL 17F and the A allele might be associated with a lower risk of acute rejection with better graft survival. PMID- 29407293 TI - Comparison of Rejection-Specific Genes in Peripheral Blood and Allograft Biopsy From Kidney Transplant. AB - BACKGROUND: Although improved understanding and assessment of organ rejection significantly contribute to long-term allograft survival after kidney transplantation, reliable and predictive biomarkers that enable diagnoses of rejection state are lacking. Patient rejection of a kidney graft displays a specific blood and biopsy transcriptional pattern, raising the question of whether transcript biomarkers in blood could reflect events within the allograft. METHODS: Differential expression genes were screened on large-scale transcriptomic data from blood and allograft biopsies, which included recipients undergoing rejection and recipients with stable renal function. RESULTS: We found that the number of rejection-related genes in biopsy samples was much greater than in blood. We observed only one overlapping gene, HIST1H4A, consistently expressed in biopsy samples and blood. Functional association of the identified genes in biopsies implicated a strong involvement of inflammatory-immune pathways. Rejection-related genes in the mammalian target of rapamycin-signaling pathway were down-regulated, and genes related to allograft rejection and graft versus-host disease were up-regulated in allograft biopsy samples. We also recognized the core signaling elements (PIK3R2 and EGFR) in inflammatory-immune pathways based on biopsy samples. CONCLUSIONS: We have expanded our understanding of rejection-specific gene expression pattern in allograft biopsy and peripheral blood, and provided a candidate set of overlapping genes for screening of rejection in kidney transplant recipients. PMID- 29407294 TI - Prevention of Late-Onset Cytomegalovirus Infection and Disease in Donor Positive/Recipient-Negative Kidney Transplant Recipients Using Low-Dose Valganciclovir. AB - BACKGROUND: The main challenge with cytomegalovirus (CMV) prophylaxis in IgG donor-positive/recipient-negative (D+/R-) kidney transplant recipients is late onset CMV disease. We evaluated a novel protocol for the prevention of late-onset CMV infection and disease in D+/R- organ recipients. METHODS: Our prospective, observational, cohort study included 100 adult kidney transplant recipients. Prophylaxis with low-dose valganciclovir (450 mg/d, 3 times a week for 6 months) was administered to D+/R- recipients. Risk factors for CMV infection and disease were identified. Renal function and the outcomes of CMV infection and disease were compared between D+/R- (n = 15) and recipient-positive (R+; n = 81) organ recipients. RESULTS: D+/R- recipients showed significant independent risk factors with high hazard ratios for CMV infection (2.04) and disease (10.3). The proportion of CMV infection in D+/R- and R+ recipients was 80% and 46% (P = .023), and that of CMV disease was 33% and 6.2% (P = .008), repectively. D+/R- recipients developed CMV infection and disease within 6 months after transplantation. However, both CMV infection- and disease-free survival rates beyond 1 year post-transplantation defined as late-onset were stable in D+/R- recipients. Moreover, serum creatinine levels at 1 year post-transplantation were comparable between D+/R- and R+ recipients (1.45 +/- 0.71 vs 1.16 +/- 0.35 mg/dL, P = .26). CONCLUSION: Our novel protocol prevented late-onset CMV infection and disease beyond 1 year post-transplantation in D+/R- recipients. PMID- 29407295 TI - BK Virus-Associated Nephropathy: Current Situation in a Resource-Limited Country. AB - BACKGROUND: Data on BK virus-associated nephropathy (BKVAN) and treatment strategy in a resource-limited country are scarce. This study aimed to evaluate epidemiology of BKVAN and its situation in Thailand. METHODS: A retrospective analysis was conducted among adult kidney transplant recipients at Ramathibodi Hospital from October 2011 to September 2016. Patients' demographic data, information on kidney transplantation, immunosuppressive therapy, cytomegalovirus and BK virus infections, and allograft outcomes were retrieved and analyzed. RESULTS: This study included 623 kidney transplant recipients. Only 327 patients (52.49%) received BK virus infection screening, and 176 of 327 patients had allograft dysfunction as a trigger for screening. BKVAN was identified in 39 of 327 patients (11.93%). Deceased donor transplantation and cytomegalovirus infection were associated with a higher risk of BKVAN (odds ratio = 2.2, P = .024, 95% confidence intervals [1.1, 4.43], and odds ratio = 2.6, P = .006, 95% confidence intervals [1.29, 5.26], respectively). BKVAN patients were at significantly higher risk for allograft rejection (P < .001) and allograft failure (P = .036). At the end of the study, 4 graft losses were documented (12.12%). CONCLUSIONS: BKVAN was associated with high rate of allograft rejection and failure. However, surveillance of its complications has been underperformed at our facility. Implementing a formal practice guideline may improve allograft outcome in resource-limited countries. PMID- 29407296 TI - Oral Vancomycin Monotherapy Versus Combination Therapy in Solid Organ Transplant Recipients With Uncomplicated Clostridium difficile Infection: A Retrospective Cohort Study. AB - INTRODUCTION: Solid organ transplant (SOT) recipients are at high risk of Clostridium difficile infection (CDI) and CDI recurrence due to their suppressed immune systems and antibiotic exposure. A combination of metronidazole and oral vancomycin is often prescribed for SOT recipients with uncomplicated CDI despite any clinical practice guidelines supporting the need for combination therapy. This study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after a first episode of uncomplicated CDI. METHODS: A single-center retrospective cohort study evaluated SOT recipients diagnosed with uncomplicated CDI who were treated with vancomycin monotherapy or vancomycin/metronidazole combination therapy. The primary endpoint was CDI recurrence defined as a second CDI episode within 8 weeks of completing index CDI therapy. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. RESULTS: Fifteen patients (25%) of 61 subjects experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination therapy group (23% versus 27%, respectively; P = .715). The median total length of hospitalization between the vancomycin monotherapy and combination therapy groups was statistically significant (9 versus 14 days, respectively; P = .047). DISCUSSION: There was no difference found in recurrence rate between oral vancomycin monotherapy versus combination therapy. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients. PMID- 29407297 TI - Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era. AB - BACKGROUND: The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. METHODS: Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in pre- and post-KAS periods. RESULTS: The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20-29 y and 13% vs 18% in age group 30-39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50-59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). CONCLUSIONS: The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers. PMID- 29407298 TI - High-dose Valganciclovir Treatment for Resistant Cytomegalovirus Colitis due to UL97 and UL54 Mutations. AB - We report the first case of a ganciclovir-resistant cytomegalovirus (CMV) involving the gastrointestinal tract that was successfully treated with high-dose valganciclovir. A kidney transplant recipient developed drug-resistant CMV colitis which was initially treated with valganciclovir, but his CMV was found to have major resistance to ganciclovir and cidofovir due to UL97 and UL54 mutations. The patient was switched to intravenous foscarnet 40 mg/kg given every twelve hours. However, foscarnet had to be discontinued after 4 days of treatment due to acute kidney injury. Patient was restarted on valganciclovir at a higher target dose of 1800 mg twice a day based on the creatinine clearance. CMV became undetectable 2 weeks after valganciclovir treatment was completed. High-dose valganciclovir along with immune suppression reduction may be a treatment option for CMV colitis with ganciclovir resistance due to dual UL97 and UL54 gene mutations. PMID- 29407299 TI - Slow Progression of Aortic Calcification Is a Potential Benefit of Pre-emptive Kidney Transplantation. AB - PURPOSE: Pre-emptive kidney transplantation (PKT) is expected to improve graft and cardiovascular event-free survival compared with standard kidney transplantation. Aortic calcification is reported to be closely associated with renal dysfunction and cardiovascular events; however, its implication in PKT recipients remains incompletely explored. This aim of this study was to evaluate whether PKT confers a protective effect on aortic calcification, renal function, graft survival, and cardiovascular event-free survival. METHODS: One hundred adult patients who underwent renal transplantation between January 1996 and March 2016 at Hirosaki University Hospital and Oyokyo Kidney Research Institute were included. Among them, 19 underwent PKT and 81 patients underwent pretransplant dialysis. We retrospectively compared pretransplant and post-transplant aortic calcification index (ACI), renal function (estimated glomerular filtration rate [eGFR]), and graft and cardiovascular event-free survivals between the 2 groups. RESULTS: The median age of this cohort was 45 years. Preoperative ACI was significantly lower in PKT recipients. There were no significant differences between the 2 groups regarding postoperative eGFR, graft survival, and cardiovascular event-free survival. However, the ACI progression rate (DeltaACI/y) was significantly lower in PKT recipients than in those who underwent pretransplant dialysis. Higher ACI was significantly associated with poor cardiovascular event-free survival. CONCLUSIONS: PKT is beneficial in that it contributes to the slow progression of after transplantation. Although we could not observe significant differences in graft and cardiovascular event-free survivals between the 2 groups, slow progression of aortic calcification showed a potential to decrease cardiovascular events in PKT recipients during long-term follow-up. PMID- 29407300 TI - Dual Energy X-ray Absorptiometry and Bioimpedance Analysis are Clinically Useful for Measuring Muscle Mass in Kidney Transplant Recipients With Sarcopenia. AB - PURPOSE: Computed tomography (CT) is considered the gold standard method for the diagnosis and characterization of sarcopenia. The aim of the present study was to determine the correlation between the volume of psoas muscle measured using CT and the measurement of muscle mass with dual energy X-ray absorptiometry (DXA) and bioimpedance analysis (BIA) in kidney transplant recipients. METHODS: Fifty eight recipients (42 males and 16 females) were enrolled. Diagnostic criteria for sarcopenia were according to those of the Asia Working Group for Sarcopenia. The volume of psoas muscle was extracted using image recognition software from three dimensional CT images. RESULTS: The volume of psoas muscle was 227.2 +/- 61.3 mL in Group 1 (sarcopenia), 283.9 +/- 75.3 mL in Group 2 (presarcopenia), and 363.7 +/- 138.0 mL in Group 3 (without sarcopenia). Muscle mass measured using DXA was 15.80 +/- 3.19 kg in Group 1, 16.36 +/- 2.49 kg in Group 2, and 21.21 +/- 4.14 kg in Group 3. Additionally, muscle mass assessed using BIA was 17.22 +/- 4.11 kg in Group 1, 17.86 +/- 3.30 kg in Group 2, and 21.48 +/- 5.39 kg in Group 3. There were significant differences in the mean volume of psoas muscle between the 3 groups. There was a significant positive correlation between the volume of psoas muscle and the muscle mass assessed using DXA (r = 0.797; P < .001) and BIA (r = 0.761; P < .001). Furthermore, there was a significant positive correlation between DXA and BIA (r = 0.900; P < .001). CONCLUSIONS: It was suggested that estimating muscle mass using DXA and BIA is a preferred method for diagnosis of sarcopenia in kidney transplant recipients. PMID- 29407301 TI - Improvement of Blood Pressure Control in Renal Transplant Recipients Retrospective Longitudinal Study. AB - BACKGROUND: Hypertension is a very common complication in renal transplant recipients (RTRs). It has been identified as a potent cardiovascular risk factor associated with impaired patient and graft survival. METHODS: A longitudinal retrospective analysis was performed to evaluate adherence to recommended blood pressure (BP) targets and to estimate the tendency in the management of hypertension from 2001 to 2015. A total of 96 RTRs (55 male, 41 female; overall mean age (2001), 41.66 +/- 11.08 years; mean serum creatinine level, 1.45 +/- 0.3 mg/dL; 41.2 +/- 34.9 months after kidney transplantation) with diagnoses of hypertension and monitored continuously in the unit from 2001 to 2015 were included in the study. RESULTS: The average diastolic BP decreased (P < .01) and the average systolic BP did not change in this period. The target values of BP (ie, <140/90 mm Hg) were accomplished by 45.8% (2001) and 53.1% (2015) of patients. When the target BP was corrected by age (<150/90 mm Hg for people >65 years old) the adherence improved to 57.29% in 2015. The average number of antihypertensive agents used per patient increased significantly (P < .001): 2.03 +/- 1.0 (2001) versus 2.69 +/- 1.26 (2015). The most commonly used antihypertensive agents were beta-blockers: 69% and 74% in 2001 and 2015, respectively. There was a significant increase in the percentage of RTRs treated with the use of alpha-blockers (P < .01), angiotensin-converting enzyme inhibitors (P < .001), and angiotensin II receptor blockers (P < .05). CONCLUSIONS: The study showed modest improvement of the hypertension control rate from 2001 to 2015 in RTRs. Greater efforts are needed to implement the guidelines, which would further improve patient and graft outcomes. PMID- 29407302 TI - Encapsulating Peritoneal Sclerosis in Peritoneal Dialysis Patients After Kidney Transplantation. AB - OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is a serious complication for patients with chronic kidney disease (CKD) who were treated with long-term peritoneal dialysis (PD). The risk of EPS was increased after kidney transplantation. In our study we evaluated risk factors for EPS patients after kidney transplantation who were treated before with PD. MATERIALS AND METHODS: In our study, between January 2008 and August 2015, 47 PD patients (12 had EPS) who underwent kidney transplantation were analyzed. Age, gender, time of PD treatment, human leukocyte antigen (HLA) matching, cold ischemia time, kidney function (serum urea, creatinine, etc), comorbidities, immunosuppressive therapy, clinical features, and outcomes of PD patients were retrospectively evaluated in both groups. RESULTS: Mean age was 42 (range, 25-60) years in EPS patients, versus 43 (range, 22-77) years without EPS (P = .798). Distribution of gender was similar in both groups (P = .154). The C-reactive protein levels (P < .001), number of patients with peritonitis (P = .001), length of time on PD (P < .001), and serum ferritin levels (P = .020) were higher in EPS patients. The immunosuppressive therapy was changed; tamoxifen and steroids were used after diagnosis in EPS patients. HLA matching was higher in the non-EPS group (P = .006). EPS was more often seen in patients who were treated with continuous ambulatory peritoneal dialysis (CAPD; 75%; P = .036). EPS was more often detected in cadaveric transplant recipients (83.3%; P = .024). High peritoneal transmittance rate was more identified in EPS (+) patients (P = .001). EPS was more often seen in patients who were treated with icodextrin-based regimens in PD before transplantation (91.7%; P = .037). The length of time on PD and high ferritin levels increased EPS 1.08 and 1.01, respectively (P = .036 and .049, respectively), in multivariate analysis. CONCLUSION: The length of time on PD, type of PD, PD regimens with icodextrin, episodes of peritonitis, and peritoneal transmittance in patients with CKD affect the development of EPS after transplantation. PMID- 29407303 TI - Treatment of Immunoglobulin A Nephropathy Recurrence Post-Renal Transplant. AB - Immunoglobulin A nephropathy (IgAN) is the most commonly occurring glomerulonephritis. Recurrence of disease in the transplanted kidney can significantly reduce allograft survival rates. Currently, there is no definitive management plan for IgAN recurrence in a transplant that reduces the rate of decline of allograft function and prolongs time to dialysis or re transplantation. Herein we present a 48-year-old man who had received a renal transplantation in 2006 following his diagnosis of IgAN. In 2015, the patient was noted to have an elevated blood pressure and proteinuria (urinary protein:creatinine ratio [uPCR] 170 mg/mmol). A transplant biopsy confirmed recurrent IgAN. A year later, he presented with dipstick hematuria, nephrotic range proteinuria (uPCR 820 mg/mmol), and a serum creatinine of 90 to 140 MUmol/L. A second biopsy revealed mesangioproliferative glomerulopathy consistent with crescentic IgAN. An optimal management plan is currently unknown for recurrent crescentic IgAN in the transplanted kidney. We decided to treat this patient with oral cyclophosphamide daily and high-dose prednisolone. The treatment has so far yielded a positive response and managed to preserve allograft function without significant adverse effects for our patient. Our case illustrates the importance of timely biopsies to identify recurrence of disease and highlights an effective therapeutic option for recurrent IgAN with crescent formation in a transplant. PMID- 29407304 TI - Six National University Consortium in Liver Transplant Professionals Training (SNUC-LT) Program in Japan. AB - BACKGROUND: There has been no public structured training program for transplant surgeons in Japan. However, such a program is crucial for optimizing liver transplant surgery and training young professionals in liver transplant surgery. A comprehensive training program was recently developed and the underlying concepts, structure and curriculum, and results of this program are described here. METHODS: We developed a 3-year training program in 2014 called the Six National University Consortium in Liver Transplant Professionals Training (SNUC LT) program supported by the Ministry of Education, Culture, Sports, Science, and Technology. This program is based on strong cooperation among 6 national universities (Kumamoto, Okayama, Nagasaki, Kanazawa, Niigata, and Chiba Universities). The program includes various courses to help trainees learn transplant theory and practice as well as to teach surgical skills required to safely perform transplant surgery. RESULTS: Three trainees completed the specially designed 3-year curriculum. They attended lectures on transplant theory for an average of 59 hours and participated in an average of 44 liver transplant surgeries and 51 liver resections for transplant practice. Trainees from low volume centers had sufficient opportunities to attend operations in high-volume centers because of the cooperative agreement among the universities. After finishing the program, the trainees were certified as talent-proven liver transplant surgeons. CONCLUSIONS: The SNUC-LT program is the first national program in Japan to have strong professional support. Our multicenter program enables young surgeons to have more abundant knowledge, more extensive experience, better surgical skills, and smoother communication skills in the field of liver transplantation. PMID- 29407305 TI - Ab initio Everolimus-based Versus Standard Calcineurin Inhibitor Immunosuppression Regimen in Liver Transplant Recipients. AB - AIM: We designed a retrospective case-control study to determine the efficacy and feasibility of everolimus (EVR) combined with low-dose tacrolimus (Tac) ab initio versus standard-dose Tac after liver transplantation (LT). METHODS: Seventy-one adult LT patients, receiving EVR and low-dose Tac without corticosteroids or induction therapy from postoperative day 1 (EVR group) were compared with a well matched control group of 61 recipients treated with standard-dose Tac in association with antimetabolite. RESULTS: Baseline characteristics for the two groups were comparable. The overall patient and graft survival rates were similar (P = .908). Liver function was stable during the follow-up. In the EVR group, biopsy-proven acute rejection occurred in two cases (2.8%), whereas chronic rejection occurred in one (1.4%). The EVR group experienced a better renal function already after 2 weeks (estimated glomerular filtration rate: 89.85 [36.46 to 115.3] mL/min/1.73 m2 vs. 68.77 [16.11 to 115.42] mL/min/1.73 m2; P = .013), which was also observed after a median time of 27 months (range, 0 to 82 months) from LT (estimated glomerular filtration rate: 80 [45 to 118.3] mL/min/1.73 m2 vs. 70.9 [45 to 88.4] mL/min/1.73 m2; P = .04). After a median time of 27 months, the EVR group showed lower incidence of arterial hypertension and insulin-dependent diabetes mellitus. CONCLUSION: Ab initio EVR-based immunosuppression could be a valid option immediately after surgery in recipients at high-risk for post-LT renal impairment. PMID- 29407306 TI - Short-term Results of Liver Transplantation With Octogenarian Donors. AB - BACKGROUND: There are increasingly more patients awaiting liver transplantation while the number of donors has remained stable. It has been proven that grafts from donors older than 60 years have comparable results with those from younger donors. It is unclear whether this is so with donors older than 80 years old. MATERIAL AND METHODS: This was a retrospective study of all adult liver transplantations at our institution between March 2011 and December 2015. We compared 1-, 3-, 6-, and 12-month graft survival rates from donors <80 years and >=80 years. We also compared postoperative complications: infections, acute kidney injury, need for readmission in the intensive care unit, length of stay, mechanical ventilation, and specific graft complications. We considered differences in each age group regarding the presence of hepatitis C virus (HCV). RESULTS: Of 177 recipients, 38 received grafts from octogenarian donors (21.5%). Survival rates were very similar in the groups (97%, 93%, 91%, and 87% for donors <80 years and 95%, 92%, 87%, and 76% for donors >=80 years). Although for younger grafts, 1-year survival rates were slightly lower for HCV+ patients (80% vs 89%; log-rank 0.205), this difference does not exist for elderly donors. The incidence of postoperative complications was similar in both groups. CONCLUSIONS: Livers from octogenarian donors are acceptable for liver transplantation provided that thorough assessment and selection is made by avoiding other known poor prognosis factors. The presence of HCV did not affect survival rates. PMID- 29407307 TI - Acute Liver Failure due to Amanita phalloides Poisoning: Therapeutic Approach and Outcome. AB - INTRODUCTION: Amanita phalloides poisoning is a potentially fatal cause of acute liver failure. The aim of this study was to analyze the impact of initial patients' characteristics and different treatment modalities on the outcome of patients with liver failure caused by Amanita poisoning. MATERIAL AND METHODS: We retrospectively evaluated 23 patients admitted to our center between July 2007 and August 2016. RESULTS: Mean time interval between Amanita phalloides ingestion and the onset of gastrointestinal symptoms was 12.48 +/- 9.88 hours and the interval between ingestion and hospital admission 26.26 +/- 15.14 hours. The treatment was intiated by oral decontamination using activated charcoal followed by intravenous rehydration and high doses of intravenous N-acetylcysteine and silibinin. Fourteen patients (61%) underwent extracorporeal elimination method. Ten patients had plasmapheresis, 1 patient had hemoperfusion, and 5 patients had fractionated plasma separation and adsorption. Seven patients who met King's College Criteria were listed for urgent liver transplantation; one of them died before transplantation. Six patients underwent liver transplantation; the mean waiting time was 6.5 +/- 12.0 days (range, 1-31 days). One patient died 2 months afterward. All 16 patients who did not meet King's College Criteria and received conservative treatment survived. CONCLUSION: Our results documented a good prognostic value of standard King's College Criteria for indication of urgent liver transplantation in acute liver failure caused by Amanita phalloides poisoning. Fractionated plasma separation and adsorption may contribute to low mortality on the waiting list. Intensive care and extracorporeal elimination methods seem to be crucial points of the conservative treatment. PMID- 29407308 TI - Incidence and Outcome of Small-for-Size Liver Grafts Transplanted in Adult Recipients. AB - Small-for-size liver transplantation (SFS-LT) carries high morbidity and mortality after transplantation. SFS-LT is usually associated with living-donor or deceased-donor split LT; however its incidence and outcome are poorly defined in adult LT recipients who receive whole grafts (WLT). In this study, we retrospectively reviewed our cohort of 3,106 deceased-donor LT in adult recipients. We found that among the 31 split LTs, 11 (35.5%) were SFS. In contrast, there only 1.08% of the whole-graft transplants (31 out of 2,868) were SFS. Although less common, SFS-WLT is associated with poorer long-term outcome of both graft and patient survivals. PMID- 29407309 TI - Clinical Implication of Tests for Prostate-specific Antigen in Brain-dead Organ Donors. AB - BACKGROUND: Although cancer screening tests are not mentioned under brain-dead organ donor care guidelines in Korea, we assessed the level of prostate-specific antigen (PSA), an important prostate cancer marker, and performed prostate biopsies when needed in brain-dead organ donors. We believe that insisting on a screening test for cancer diagnosis in donors' organs is important. MATERIALS AND METHODS: Data were collected between January 2010 and July 2015 from Ajou University Hospital. We retrospectively analyzed the PSA levels and prostate biopsy results in 111 male brain-dead organ donors (mean age, 48.4 years). RESULTS: The mean PSA level was 7.395 ng/mL (range, 0.062 to 61.780; reference, 0 to 4 ng/mL). Ultrasonography or computed tomographic examination did not reveal prostate cancer, and a rectal examination was not performed. After checking the PSA levels, prostate biopsies were performed in 16 patients based on the recommendations of a urologist, and 4 patients (3.6% of 111) were diagnosed with prostate cancer. All cancers involved adenocarcinomas (acinar type) histopathologically. In 2 patients, the Gleason score was 6 (3 + 3), whereas the other 2 showed a score of 7 (3 + 4). Among the patients diagnosed with prostate cancer, 1 donated his liver and corneas, and the remaining 3 could not donate. CONCLUSION: Well-defined cancer screening tests are needed in Korea. Additionally, when the probability of organ transplantation-induced cancer metastasis is low or a recipient is at a high risk owing to not receiving organs, the law should allow organ donation even if prostate cancer is diagnosed in the donor. PMID- 29407310 TI - Liver Transplant Recipients With End-Stage Renal Disease Largely Benefit From Kidney Transplantation. AB - BACKGROUND: The incidence of end-stage renal disease (ESRD) after liver transplant (LT) has increased. The actual benefit of kidney transplantation (KT) is not completely understood in LT recipients with ESRD. METHODS: We analyzed Scientific Registry of Transplant Recipients data for all KT candidates with prior LT from 1998 to 2014; the benefits of KT relative to remaining on dialysis were compared by means of multivariate Cox proportional hazards regression analysis. RESULTS: The number of these KT candidates with prior LT has tripled from 98 in 1998 to 323 in 2015; LT recipients with ESRD remaining on dialysis have a 2.5-times increase in the risk of liver graft failure and a 3.6-times increase in the risk of patient death compared with these patients receiving KT. The adjusted liver graft and patient survival rates after donors from donation after cardiac death or expanded-criteria donor kidney transplantation were significantly higher than in patients remaining on dialysis in LT recipients with ESRD. CONCLUSIONS: The number of referrals to KT with prior LT is increasing at a rapid rate. Remaining on dialysis in LT recipients with ESRD has profound increased risks of liver graft failure and patient death in comparison to receiving a KT. LT recipients with ESRD can benefit from expanded-criteria donor and donation after cardiac death kidney transplantation. PMID- 29407311 TI - Stress (Takotsubo) Cardiomyopathy During Liver Transplantation: Case Study and Literature Review. AB - A case of stress (takotsubo) cardiomyopathy (TC) that occurred intraoperatively during liver transplantation surgery was identified by transesophageal echocardiography. Only a few cases of TC occurring during liver transplantation have been reported to date. Unlike other cases reported, TC occurred during the anhepatic stage of the liver transplantation, with subsequent complete recovery. Notwithstanding the large number of cases of TC in the perioperative settings reported worldwide, the exact reasons of this syndrome occurring intraoperatively as well as precipitating factors and conditions remain mostly unknown. PMID- 29407312 TI - Complication Follow-up With Ultrasonographic Analyses of 91 Cases With Donor Gallbladder Preservation in Living Donor Liver Transplantation of Left Lateral Sectionectomies. AB - BACKGROUND: Preserving the donor's gallbladder during living donor liver transplantation (LDLT) is a better method for liver transplantation surgery, but not enough is known about gallbladder complications after the operation. METHODS: We retrospectively investigated postsurgical donor gallbladder complications in clinical LDLT with gallbladder preservation. The feasibility of retaining the gallbladder during liver graft procurement is discussed. Ninety-one donors with retained gallbladder after LDLT with the hepatic left lateral sectionectomy (from June 2013 to October 2015) were retrospectively analyzed. Donors were followed for 12.6 to 40.7 months after surgery (median 26.1 months). Sonography was used to evaluate gallbladder characteristics before and after surgery. RESULTS: Gallbladder function had recovered to almost normal 1 month after transplantation. Four donors (4.40%) experienced gallbladder enlargement that resolved after 3 days. Thickening of the gallbladder wall in 31 donors (34.07%) was restored within 2 to 75 days. Biliary sludge appeared in 9 donors (9.89%); 6 of them recovered within 3 to 34 days. Three (3.30%) and 1 donor (1.10%) suffered gallstone and gallbladder polyps, respectively, which persisted until the last follow-up. CONCLUSION: The rate of postoperative complications of the gallbladder in donors was relative low. Preserving the gallbladder in liver transplantation donors during liver graft procurement is feasible and safe. PMID- 29407313 TI - Development of Duodenal Ulcers due to the Discontinuation of Proton Pump Inhibitors After the Induction of Sofosbuvir Plus Ledipasvir Therapy: A Report of Two Cases. AB - Sofosbuvir plus ledipasvir (SOF-LDV) combination therapy is a promising therapy for post-transplant hepatitis C virus (HCV) reinfection. It is known that gastric pH elevation induces lower absorption of ledipasvir; therefore, the use of proton pump inhibitors (PPIs) should be considered regarding dose reduction after SOF LDV therapy induction. Here, we report two patients who developed duodenal ulcers due to the discontinuation of PPIs after the induction of SOF-LDV therapy for post-transplant HCV reinfection. The first patient was a 71-year-old man who had undergone living donor liver transplantation due to HCV-related liver cirrhosis. Lansoprazole, 30 mg daily, was discontinued upon SOF-LDV therapy induction. Seven days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. The second patient was a 54-year-old man who had undergone living donor liver transplantation due to HCV-related end-stage liver disease. Similar to the first patient, rabeprazole sodium was discontinued upon the induction of SOF-LDV therapy. Eighteen days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. In both cases, these duodenal ulcers improved after the resumption of the administration of PPIs, and a sustained virologic response at 12 weeks was achieved by SOF-LDV therapy with PPI use. Thus, PPI use should be continued consistently during SOF LDV therapy for post-transplant HCV reinfection. PMID- 29407314 TI - Multimodal Surgical Approach for Adult Patients With Chronic Intestinal Pseudo Obstruction: Clinical and Psychosocial Long-term Outcomes. AB - BACKGROUND: Clinical and psychosocial outcomes of a multimodal surgical approach for chronic intestinal pseudo-obstruction were analyzed in 24 patients who were followed over a 2- to 12-year period in a single center after surgery or intestinal/multivisceral transplant (CTx). METHODS: The main reasons for surgery were sub-occlusion in surgery and parenteral nutrition-related irreversible complications with chronic intestinal failure in CTx. RESULTS: At the end of follow-up (February 2015), 45.5% of CTx patients were alive: after transplantation, improvement in intestinal function was observed including a tendency toward recovery of oral diet (81.8%) with reduced parenteral nutrition support (36.4%) in the face of significant mortality rates and financial costs (mean, 202.000 euros), frequent hospitalization (mean, 8.8/re admissions/patient), as well as limited effects on pain or physical wellness. CONCLUSIONS: Through psychological tests, transplant recipients perceived a significant improvement of mental health and emotional state, showing that emotional factors were more affected than were functional/cognitive impairment and social interaction. PMID- 29407315 TI - Unexpected Neoplasms in Lungs Explanted From Lung Transplant Recipients: A Single Center Experience and Review of Literature. AB - INTRODUCTION: Lung transplantation is a common treatment for various indications, but undiagnosed neoplasms are found in 0.5% to 2.4% of explanted lungs. We report the largest single-institution series of patients with unexpected neoplasms in explanted lungs and compare rates of undiagnosed malignancies before and after the 2005 Lung Allocation Score (LAS) update. METHODS: We reviewed the medical records of patients who underwent lung transplantation at the Cleveland Clinic from 1990 to 2014. In cases of neoplasm discovered on explant, tumor type, pathological stage, recurrence, and date of death were recorded. RESULTS: From January 1, 1990 to June 30, 2014, 1303 patients underwent lung transplantation at the Cleveland Clinic. The overall mean smoking history was 35 pack-years, and 25 undiagnosed lung malignancies were found upon explant in 24 transplant recipients (1.84%). In the post-LAS era (ie, 2005 onward), 20/812 lung transplant recipients had 21 incidental neoplasms in their explanted lungs (2.5%). Seventeen of these 25 tumors occurred in patients with interstitial lung disease; 8 occurred in patients with centrilobular emphysema. Eight tumors recurred (6 in patients with interstitial lung disease and 2 in patients with emphysema). The most common histological tumor types were adenocarcinomas (n = 14) and squamous cell carcinomas (n = 7). CONCLUSIONS: Unexpected neoplasms were found in 1.84% of lung transplant recipients' explanted lungs, with a slightly higher incidence (2.46%) in the post-LAS era. Neoplasms were more common in patients with interstitial lung diseases than in patients with centrilobular emphysema. Explanted lungs should be pathologically examined for evidence of tumor foci because this can impact post-transplantation management. PMID- 29407316 TI - Functional Results of Renal Preservation in Hypothermic Pulsatile Machine Perfusion Versus Cold Preservation: Systematic Review and Meta-Analysis of Clinical Trials. AB - BACKGROUND: Hypothermic pulsatile machine perfusion (HPMP) decreases the rate of delayed graft function (DGF) in kidney grafts, compared with cold storage. However, it is not clear its use in the different subgroups of grafts. The objective was to review systematically all studies with better methodologic quality that compare HPMP versus cold storage. METHODS: A systematic review was performed. The sources were Pubmed, Pubmed Central, Cochrane Library, Clinical Key, and Ovid. All randomized controlled trials that compared HPMP versus cold storage in renal grafts from human donors were considered. Outcomes analyzed were: percentage of DGF, primary nonfunction (PNF), and graft function in each group and for the different types of grafts, brain-death donors (DBDs), and different subgroups of donors after circulatory death (DCDs). RESULTS: Twelve clinical trials, out of 9,867 titles, were included. HPMP improved DGF overall, as well as in DBDs and DCDs. The relative risks [RRs] were 0.79 (95% CI, 0.71 0.88), 0.85 (95% CI, 0.74-0.98), and 0.75 (95% CI, 0.61-0.92), respectively. There were no differences in PNF overall and for DBDs or DCDs. The RRs were 0.92 (95% CI, 0.73-1.16), 0.78 (95% CI, 0.22-2.73), and 1.13 (95% CI, 0.73-1.77), respectively. However, analysis with the better quality studies, overall RR for PNF was 0.62 (95% CI, 0.39-0.96). There were no differences between the graft function at 3 months after transplantation. CONCLUSIONS: HPMP moderately improved the DGF results in grafts from cadaver donors of all types. HPMP could improve the PNF in grafts from DBDs, although more clinical trials are needed to prove that. PMID- 29407317 TI - Graft-versus-host Disease-free, Relapse-free Survival After HLA-identical Sibling Peripheral Blood Stem Cell Transplantation With Tacrolimus-based Graft-versus host Disease Prophylaxis in Japanese Patients. AB - The ideal post-allogeneic hematopoietic cell transplantation recovery is not just the cure of hematologic malignancies but also freedom from ongoing morbidity. Recent studies have revealed that HLA-identical sibling peripheral blood stem cell transplantation (PBSCT) had been providing impaired graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) due to a higher risk of GVHD. Study on GVHD prophylaxis bears clinical reliance when focused on Japanese population because risk of GVHD differs among races. We identified 15 consecutive Japanese patients who received tacrolimus-based GVHD prophylaxis after myeloablative HLA-identical sibling PBSCT. No episode of grade >= II acute GVHD and only one episode of grade III toxicity were documented, with the control of mean weekly blood tacrolimus concentrations during the first 4 weeks at 13 to 17 ng/mL. An estimated 46.7% (95% CI: 21.4% to 71.9%) of the patients enjoyed their GRFS at 3 years after transplantation, and failure in the treatment of chronic GVHD was not reported during the median follow-up period of 1059 days (range, 784 to 1778 days) after the development of chronic GVHD. The results suggest that the application of tacrolimus with the optimization of its blood concentrations may effectively prevent ongoing morbidities after HLA-identical sibling PBSCT. PMID- 29407318 TI - Treatment of High-Risk Acute Myeloid Leukemia With Cladribine, Cytarabine, Mitoxantrone, and Granulocyte Colony-Stimulating Factor Then Subsequent Bridging to Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation: A Case Series. AB - This report preliminarily evaluates the efficacy and safety of cladribine, cytarabine, mitoxantrone, and granulocyte colony-stimulating factor (CLAG-M) as bridging therapy to myeloablative allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of patients with refractory or relapsed acute myeloid leukemia. Five patients with high-risk refractory or relapsed acute myeloid leukemia received the CLAG-M regimen and subsequent bridging to myeloablative allo-HCT between December 2014 and August 2015 in our hospital. The CLAG-M regimen consisted of cladribine 5 mg/m2 on days 1-5, cytarabine 2 g/m2 on days 1 5, granulocyte-colony stimulating factor 300 MUg on days 0-5, and mitoxantrone 10 mg on days 1-5. At 3-8 days after CLAG-M, patients accepted myeloablative allo HCTs. One patient (20%) died before stem cell infusion from treatment toxicity. Four patients (80%) underwent allo-HCT from matched sibling or haploidentical donors and all achieved complete remission. The median follow-up was 25 months (range, 22-31). Three patients (60%) survived, and 1 patient (20%) died owing to relapse 22 months after transplantation. Two patients (40%) among survivors achieved 2-year disease-free survival. The other survivor, who had survived for 31 months, experienced isolated central nervous system relapse 4 months after transplantation, but was cured by intrathecal injecting and cranial radiotherapy. CLAG-M bridging to myeloablative allo-HCT might be a well-tolerated and highly effective salvage regimen in patients with poor risk refractory or relapsed acute myeloid leukemia. PMID- 29407320 TI - Mild Hypothermia Pretreatment Attenuates Liver Ischemia Reperfusion Injury Through Inhibiting c-Jun NH2-terminal Kinase Phosphorylation in Rats. AB - BACKGROUND: Mild hypothermia is known to be protected against ischemia reperfusion (IR) injury. But the exact mechanisms of protection have not yet been fully understood and its usage has been limited. Mild hypothermia pretreatment (MHP) is used to investigate the mechanisms of the protective effects against liver IR injury. METHODS: Anesthetized male Sprague-Dawley rats were randomly divided into five groups including the normal group (N), sham group (S), MHP group, normothermia pretreatment (NP) + IR group, and the MHP + IR group. In the pretreatment groups, mild hypothermia (32.2 +/- 0.3 degrees C) and normothermia (37 +/- 0.5 degrees C) pretreatment were applied for 2 hours, respectively. Then the IR groups suffered partial (70%) hepatic ischemia for 1 hour and reperfusion for 6 hours. At last, hepatic injury, apoptosis, and protein expression were assessed. RESULTS: Levels of serum alanine transaminase, hepatic injury, hepatocyte apoptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were significantly higher in the IR groups. But when compared to NP, all these changes induced by IR were markedly attenuated by MHP. Serum alanine transaminase levels were 383.4 +/- 13.1U/L in the MHP + IR group and 951.3 +/- 39.4 U/L in the NP + IR group. The histologic score of liver injury in the MHP + IR group was 4.83 +/- 1.17, whereas in the NP + IR group it was 10.5 +/- 1.05. The proportion of apoptotic cells in the MHP + IR group was 11.58 +/- 0.60, but in the NP + IR group, it was 44.95 +/- 1.61. The phosphorylation of JNK was also significantly reduced in the MHP + IR group. All these differences are statistically significant (P < .05). CONCLUSIONS: MHP could markedly reduce liver IR injury, and these protective effects may be mainly exerted via inhibition of JNK phosphorylation. PMID- 29407319 TI - Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury. AB - BACKGROUND: Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS: Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS: Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, intracellular adhesion molecule-1, nuclear factor-kappaB, hypoxia inducible factor-1alpha, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS: Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury. PMID- 29407321 TI - Protective Effect of a Novel Technique for Liver Transplantation in the Rat. AB - The rat orthotopic liver transplantation model with extremely short anhepatic phase was established to study its protective effect on the recipients and graft. One hundred fifty adult male Wistar rats were randomly divided into three groups: group A (n = 30), using magnetic rings for the suprahepatic vena cava reconstruction; group B (n = 30), using 7/0 Prolene sutures for suprahepatic vena cava running anastomosis as control; and a sham-operated group (n = 30) as a blank control group. The changes in liver enzyme, serum creatinine, endotoxin, and cytokine levels and histopathology were recorded. The serum creatinine, potassium, alanine transaminase, and alkaline phosphatase levels at different points in time in group A were lower than those in group B (P < .05). The level of portal vein blood endotoxin in group A was significantly lower than that in group B at each point (P < .01). At the same time, all the cytokines in group B were higher than those in group A, and the two groups were higher than those in the sham operation group. The mean levels of tumor necrosis factor-alpha (TNF alpha), interferon-gamma, (IFN-gamma), and interleukin-1beta (IL-1beta) at 3 hours were higher than at 6 hours in group A. IL-10 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were all higher at 3 hours in groups A and B. Levels of monocyte chemotactic protein-1, L-selectin, and TIMP-1 in group A and IL-10, monocyte chemotactic protein-1, L-selectin, and TIMP-1 in group B were higher in blood than in the liver. Levels of TNF-alpha, IFN-gamma, IL-1, IL-10, and intracellular adhesion molecule-1 in group A and TNF-alpha, IFN-gamma IL-1beta, and intracellular adhesion molecule-1 in group B were higher in the liver than in blood. We conclude that the extremely short anhepatic phase has protective effects on recipients and grafts in rat liver transplantation because it is related to alleviating ischemia-reperfusion injury and reducing the endotoxin release. PMID- 29407322 TI - Induction of Regulatory CD4+ Cells and Prolongation of Fully Major Histocompatibility Complex Mismatched Murine Cardiac Allograft by Shigyakusan. AB - Shigyakusan (also known as Tsumura Japan [TJ]-35) is composed of peony, bitter orange, licorice, and Bupleuri radix is used for cholecystitis and gastritis as an anti-inflammatory agent. We investigated the effect of TJ-35 on alloimmune response in a murine heart transplantation model. CBA mice that underwent transplantation of a C57BL/6 (B6) heart were assigned to four groups: no treatment, TJ-35-exposed, each component-exposed, or each component missing exposed. The four groups above each received oral administration of TJ-35, each component, or TJ-35 with each component missing from the day of transplantation until 7 days, respectively. Untreated CBA recipients rejected B6 cardiac grafts acutely (median survival time [MST], 7 days). TJ-35-exposed CBA recipients had significantly prolonged B6 allograft survival (MST, 20.5 days). However, MSTs of CBA recipients that had been administered each component and TJ-35 with each component missing did not reach that of TJ-35-exposed recipients. Adoptive transfer of CD4+ splenocytes from TJ-35-exposed primary allograft recipients resulted in significant prolonged allograft survival in naive secondary recipients (MST, 63 days). Flow cytometry studies showed that the percentage of CD4+CD25+Foxp3+ cell population was increased in TJ-35-exposed CBA recipients. In conclusion, TJ-35-induced prolongation of fully allogeneic cardiac allografts and may generate regulatory CD4+CD25+Foxp3+ cells in our model. The effect seemed to require all components of TJ-35. PMID- 29407323 TI - Rikkunshito (TJ-43) Improved Reduction of Food Intake in a Murine Cardiac Transplantation Model. AB - Rikkunshito (TJ-43), an eight-component traditional Japanese herbal medicine, has been used in clinics for gastritis, vomiting, and appetite loss. We investigated the effects of TJ-43 on the amelioration of appetite loss in the surgical-exposed model of murine cardiac allograft transplantation. CBA mice underwent transplantation of a CBA (syngeneic group) or C57BL/6 heart (allogeneic group) and received oral administration of 2 g/kg/d of TJ-43 from the day of transplantation until 7 days afterward. The amount of food intake (FI) and weight change after operation were recorded from 1 to 28 postoperative days. The allogeneic group had less average amounts of FI for 1 week compared with the syngeneic group (FI was 1.90 +/- 0.43 g and 2.66 +/- 0.46 g, respectively). Average FIs between the syngeneic and allogeneic groups with TJ-43 for 1 week were 2.36 +/- 0.44 g and 2.30 +/- 0.13 g, respectively, and those with distilled water were 2.66 +/- 0.46 g and 1.90 +/- 0.43 g, respectively, suggesting that exposure with TJ-43 tended to ameliorate the reduction of FI. Similarly, the effect on the amelioration of average FI in syngeneic and allogeneic groups exposed for 2 weeks was confirmed. However, exposure to with TJ-43 had no effects on FI after 4 weeks. TJ-43 could prevent reduction of average FI induced by the surgical-exposed model of murine cardiac allograft transplantation. PMID- 29407324 TI - Expression Pattern of Tumor Necrosis Factor-alpha-Induced Protein 8-Like 2 in Acute Rejection of Cardiac Allograft. AB - BACKGROUND: Tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) is a negative regulator of innate immunity and cellular immunity, yet the expression pattern of TIPE2 in acute rejection of cardiac allograft remain enigmatic. METHODS: We developed cardiac transplantation models and divided into 3 groups: a naive group, a syngeneic group, and an allogeneic group. Then, we detected the messenger RNA and protein of TIPE2 in cardiac allografts. Real-time polymerase chain reaction showed expression of CD4 and CD8 in the donor heart, and immunofluorescence assay revealed the association between T cells and TIPE2. RESULTS: In our study, we first found that the expression of TIPE2 in cardiac allografts is upregulated compared with the syngeneic control, and increases in a time-dependent manner. The immunocytochemistry of heart grafts revealed a strong expression of TIPE2 in the inflammatory cells, but not in the cardiomyocytes. Finally, we proved that CD4+ and CD8+ T cells infiltrated cardiac allografts abundantly, which express ample TIPE2. CONCLUSIONS: The upregulated expression of TIPE2 in cardiac allografts, mainly came from T cells, which infiltrated the donor heart. This finding indicates that there may be an association between TIPE2 and acute cardiac allograft rejection. PMID- 29407325 TI - Dexamethasone Prolongs Cardiac Allograft Survival in a Murine Model Through Myeloid-derived Suppressor Cells. AB - BACKGROUND: Recently, myeloid-derived suppressor cells (MDSCs) have attracted considerable attention because of their cancer-promoting and immunosuppressive effects. The glucocorticoid dexamethasone (Dex) is an important immunosuppressive agent used to treat autoimmune diseases and organ transplant rejection. However, the mechanism by which it modulates the immune system is not completely understood. MATERIAL AND METHODS: In this study, we investigated the mechanisms by which Dex modulated the immune response in mice given an allogeneic cardiac transplant. RESULTS: Dex injection significantly prolonged heart graft survival compared with phosphate-buffered saline-injected controls. Dex treatment increased the number of splenic MDSCs. Moreover, Gr-1high/CD11b+ MDSCs and CD3+/CD4+/Foxp3+ regulatory T cells (Tregs) were significantly increased in the Dex group compared with controls. Administration of anti-Gr-1 antibody (Ab) to the Dex group significantly shortened mouse heart graft survival. In addition, anti-Gr-1 Ab treatment significantly reduced Tregs in the Dex + anti-Gr-1 co treatment group compared with the Dex group. These observations suggest that Dex treatment increased both MDSCs and Tregs, and that MDSCs regulated the incidence of Tregs in this immunosuppressive pathway. CONCLUSION: An important role of Dex in the prevention of the rejection of cardiac grafts in mice is to expand MDSCs and Tregs. PMID- 29407327 TI - Erratum. PMID- 29407326 TI - Quantitative Survey of Laypersons' Attitudes Toward Organ Transplantation in Japan. AB - BACKGROUND: In comparison with foreign countries, living-organ transplantations (LOT) have been performed more frequently than dead organ transplants, including brain-dead organ transplantation (BOT) in Japan. This situation has given rise to organ transplantation tourism. Therefore, we clarify laypersons' preferences regarding organ transplantation that are producing the current situation in Japan, to suggest a possible framework for further efforts. METHODS: Voluntary completion of a quantitative and anonymous survey was promoted online (a sample size of 1030). The questionnaire had two types of variables concerning demographic characteristics and organ transplantation-related issues. RESULTS: LOT was favored over BOT. However, for willingness to donate to family members, the participants showed a significantly more positive attitude toward brain-dead organ donors (BODs) than living organ donors (LODs). In the evaluation of each transplantation technology, BOT and LOT were positioned in the middle, between transplantation that does not depend on others and the utilization of animal organs. CONCLUSIONS: Although LOT was favored over BOT, for participants hypothesized to be in a position to donate and receive organs, BODs received a conversely better reputation than LODs. Our survey and discussion suggest that the present conditions of organ transplantation in Japan might be because there is a lack of deliberation on transplantation tourism and LOT. Therefore, more surveys concerning LOT cases and the implications of avoidance of organs from brain-dead bodies, coupled with more discussions based on these surveys, are necessary to formulate a Japanese transplantation policy for the future. PMID- 29407328 TI - Outcomes of Controlled Donation After Cardiac Death Compared With Donation After Brain Death in Liver Transplantation: A Systematic Review and Meta-analysis. AB - BACKGROUND: Controlled donation after cardiac death (CDCD) is increasingly common for liver transplantation due to donor shortage. However, the outcomes, in terms of grafts and recipients, remain unclear. The current study is a systematic review and meta-analysis that compared CDCD with donation after brain death (DBD). METHODS: We conducted an electronic search of MEDLINE, EMBASE, and the Cochrane Database (from January 2007 to May 2017). Studies reporting Maastricht category III or IV CDCD liver transplantation were screened for inclusion. We appraised studies using the Newcastle-Ottawa scale and meta-analyzed using a fixed or random effects model. RESULTS: A total of 21 studies, with 12,035 patients, were included in data analysis. CDCD did not differ from DBD in patient survival (hazard ration: 1.20; 95% confidence interval [CI]: 0.98 to 1.47; P = .07), graft survival (hazard ratio: 1.24; 95% CI: 0.99 to 1.56; P = .06), primary nonfunction (odds ratio [OR]: 1.74; 95% CI: 1.00 to 3.03; P = .05), hepatic artery thrombosis (OR: 1.17; 95% CI: 0.78 to 1.74; P = .45). However, CDCD was associated with biliary complications (OR: 2.48; 95% CI: 2.05 to 3.00), retransplantation (OR: 2.54; 95% CI: 1.99 to 3.26), and peak alanine aminotransferase (weighted mean difference: 330.88; 95% CI: 259.88 to 401.87). A subgroup analysis that included only hepatitis C virus (HCV)-positive recipients showed no significant difference between CDCD and DBD in biliary complications (P = .16), retransplantion (P = .15), HCV recurrence (P = .20), and peak alanine aminotransferase (P = .06). CONCLUSIONS: CDCD transplantation is the most viable alternative to DBD transplantation in the current critical shortage of liver organs. HCV infection may not be the inferior factor of postoperative outcomes and survival. PMID- 29407329 TI - Multivariate Analysis of Health-related Quality of Life in Donors After Live Kidney Donation. AB - BACKGROUND: Live-kidney donation has a low mortality rate. Evidence suggests that live-kidney donors experience a quality of life (QoL) comparable to or even superior to that of the general population. There is limited information on factors associated with a decrease in QoL in particular for baseline factors, which would improve information to the donor, donor selection, and convalescence. METHODS: QoL data on 501 live donors included in three prospective studies between 2001 and 2010 were used. The 36-item short form health survey (SF-36) was used to measure QoL up to 1 year after the procedure. Longitudinal effects on both the mental (MCS) and physical component scales (PCS) were analyzed with multilevel linear regression analyses. Baseline variables were age, gender, body mass index (BMI), pain, operation type, and comorbidity. Other covariates were loss of the graft, glomerular filtration rate, and recipient complications. RESULTS: After 1 year we observed a small decrease in PCS (effect size = -0.24), whereas the MCS increased (effect size = 0.32). Both PCS and MCS were still well above the norm of the general Dutch population. Factors associated with a change in PCS were BMI (Cohen's d = -0.17 for 5 BMI points) and age (d = -0.13 for each 10 years older). CONCLUSIONS: Overall, QoL after live-donor nephrectomy is excellent. A lowered PCS is related to age and body weight. Expectations towards a decreased postoperative QoL at 1 year are unjustified. However, one should keep in mind that older and obese donors may develop a reduced physical QoL after live kidney donation. PMID- 29407330 TI - Kidneys With Small Renal Cell Carcinoma Used in Transplantation After Ex Vivo Partial Nephrectomy. AB - BACKGROUND: The increase in the prevalence of end-stage renal disease in developed countries and the shortage of deceased donors have made it necessary to increase the graft pool by means of several strategies, such as living donation, non-heart-beating organ donors, and expanded-criteria donors. This study aimed to assess the short-term outcomes of donor kidneys with small (<=3.5 cm) renal cell carcinoma (sRCC) and to evaluate the possibility of using marginal kidneys in renal transplantation. METHODS: Patients undergoing nephrectomy for sRCC who agreed to donate their kidneys were enrolled in the study. Seven dialysis patients aged 27-54 years agreed to undergo transplantation with sRCC kidneys. All of the transplantations were performed in Shandong Province Qianfoshan Hospital from May 2012 to March 2017. The function of transplanted kidneys was evaluated after surgery by testing and comparing parameters such as creatinine clearance rate, delayed graft function, and tumor recurrence. RESULTS: The graft function of the transplanted kidneys was recovered to normal in all of the 7 patients who received sRCC kidneys. The latest serum creatinine levels before publication ranged from 59 to 102 MUmol/L in the 7 recipients (normal range of serum creatinine: men, 54-106 MUmol/L; women, 44-97 MUmol/L). No tumor recurrence was noted 31-58 months after surgery in the recipients. CONCLUSIONS: According to short-term follow up (3-5 years), kidney transplantation in selected patients can be considered for kidneys having small incidental tumors. The use of marginal organs, such as those with sRCC, can increase the donor pool for kidney transplantation. PMID- 29407331 TI - Safety and Efficacy of Induction Therapy With Thymoglobulin in AB0-Incompatible Kidney Transplantation. AB - INTRODUCTION: Data suggest an additional role of T cells in antibody-mediated rejections. In 2001 a protocol for AB0-incompatible kidney transplantation based on B-cell-depleting anti-CD20 antibody rituximab, antigen-specific blood group IgG immunoadsorption, intravenous immunoglobulins, and triple immunosuppression was introduced in Europe, which used induction therapy with the use of interleukin-2 receptor antibody (IL2-RA) basiliximab. We used thymoglobulin in AB0-incompatible patients as induction in the face of high immunologic risk. METHODS: We retrospectively evaluated a cohort of 9 AB0i living donation (LD) recipients from 2011 to 2014. Desensitization included blood group-specific immunoadsorption. Eighteen AB0-compatible LD recipients receiving induction therapy with thymoglobulin served as control subjects. Another control group consisted of 18 AB0-compatible LD recipients receiving basiliximab. Follow-up was 24 months. We captured graft function by estimating glomerular filtration rate (eGFR by Modification of Diet in Renal Disease formula), rejection episodes, and bacterial and viral infections. RESULTS: All patients experienced immediate graft function. No significant or clinical differences were observed regarding graft function, rejection rates, or infections between the groups, although there seemed to be slightly higher cytomegalovirus infection rates due to preemptive therapy strategy. CONCLUSIONS: Thymoglobulin appears to be similar in safety and efficacy to IL-2-antagonists in AB0i kidney transplantation. PMID- 29407332 TI - Antibody Drug Treatment for Steroid-Resistant Rejection After Pediatric Living Donor Liver Transplantation: A Single-Center Experience. AB - BACKGROUND: Antibody drugs have been used to treat steroid-resistant rejection (SRR) after liver transplantation. Although anti-thymocyte globulin has been used for SRR after liver transplantation in place of muromonab-CD3 since 2011 in Japan, the effectiveness of anti-thymocyte globulin after pediatric living-donor liver transplantation (LDLT) has not yet been reported. The aim of this study was to evaluate the effectiveness of antibody drug treatment for SRR after pediatric LDLT in our single center. METHODS: Between May 2001 and December 2013, 220 pediatric LDLTs were performed. Initial immunosuppression after LDLT included tacrolimus and methylprednisolone therapy. Acute rejection was diagnosed by use of a liver biopsy and the administration of steroid pulse treatment, and SRR was defined as acute rejection refractory to the steroid pulse treatment. RESULTS: Acute rejection and SRR occurred in 74 (33.6%) and 16 patients (7.3%), respectively. The graft survival rates of non-SRR and SRR were 92.4% and 87.5%, respectively (P = .464). The median concentration of alanine aminotransferase before and after the administration of antibody drug was 193.5 mU/mL (range, 8 508) and 78 mU/mL (range, 9-655), respectively (P = .012). The median rejection activity index before and after the administration of antibody drugs was 5 (range, 2-9) and 1 (range, 0-9), respectively (P = .004). After antibody drug treatment, 12 patients had cytomegalovirus infections, 2 patients had Epstein Barr virus infections, 3 patients had respiratory infections, and 1 patient had encephalitis. The cause of death in 1 patient with SRR was recurrence of infant fulminant hepatic failure. CONCLUSIONS: Antibody drug treatment for SRR after pediatric LDLT is safe and effective. PMID- 29407333 TI - Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group Incompatible Renal Transplantation. AB - Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety. PMID- 29407334 TI - Intravenous Immunoglobulins in the Prevention of Rejection of a Second or Third Kidney Graft. AB - BACKGROUND: Intravenous immunoglobulin (IVIg) reduces acute rejection episodes in kidney transplantation, but adverse events (AEs) are common. The aim of this study was to assess whether human IVIg enhances immunosuppressive effects without increasing AEs in the prevention of acute kidney graft rejection. METHODS: Patients receiving a second or third kidney graft were treated with standard immunosuppressant therapy with (n = 18) or without (n = 10) IVIg. The primary efficacy endpoint was biopsy-proven acute rejection (BPAR) rate at 3 months, and secondary endpoints included acute rejection rate at 12 months, intensity of rejection, and patient survival. RESULTS: Patients in the experimental arm received 3 infusions of IVIg. The BPAR rate decreased with IVIg versus standard immunosuppression alone over 12 months of follow-up. Experimental versus control rates of survival without BPAR were 94% versus 63% and 82% versus 63% at 3 and 12 months. The intensity of the acute rejection episodes (BANFF 97 grade) was similar between groups. One patient from each group died during the 12-month follow-up period. Treatment-emergent AEs were reported in 100% and 94.4% of the control and experimental arms. Most AEs were considered unrelated or unlikely to be related to treatment. CONCLUSIONS: This study supports the efficacy and safety of IVIg in highly sensitized transplant patients for improving transplant rates and reducing graft rejection episodes. PMID- 29407335 TI - Late Steroid Withdrawal Following AB0-Incompatible Renal Transplantation. AB - BACKGROUND: Current evidence on steroid withdrawal following AB0-incompatible (AB0i) renal transplantation is low. We compared clinical outcomes of patients who agreed to late steroid withdrawal and patients who remained on steroid treatment. METHODS: Steroid withdrawal was carried out in 11 patients at >=12 months after transplantation (group W). For comparison, we analyzed 19 patients who remained on triple immunosuppression including steroids (group M). Minimum follow-up was 24 months following transplantation and 12 months after steroid withdrawal. RESULTS: Baseline characteristics, including observation times, were not different between groups W and M. Graft survival was 100% in group W compared with 84% (16/19) in group M (P = .15). In group M, 1 patient experienced graft failure because of suspected antibody-mediated rejection (ABMR) following temporary cessation of mycophenolate treatment after a diagnosis of cryptococcal pneumonia. Two patients died with functioning graft because of sepsis. In group W, we observed 1 episode of ABMR following steroid withdrawal. At the end of follow-up, estimated glomerular filtration rates (eGFR) were 54 (19-91) versus 60 (15-85) mL/min/1.73 m2 in group W versus M, respectively (P = .67). CONCLUSIONS: Late steroid withdrawal following AB0i transplantation is feasible at a moderate risk of rejection. We recommend close monitoring of renal function and HLA antibodies during and after steroid withdrawal. On the other hand, the occurrence of severe infections causing death and graft loss in patients on triple maintenance immunosuppression including steroids should remind us to consider the overall immunosuppressive burden. PMID- 29407336 TI - Perfusion Parameters of Donation After Cardiac Death Kidneys Predict Early Transplant Outcomes Based on Expanded Criteria Donor Designation. AB - BACKGROUND: Donation after cardiac death is the only source of the deceased donor in China at present. Hypothermic machine perfusion has been used increasingly over the years. We determined the hypothermic machine perfusion parameters associated with early transplant outcomes based on the expanded criteria donor (ECD) designation. METHODS: There were 446 consecutive kidneys donated after cardiac death and preserved by hypothermic machine perfusion (LifePort) in our center that were included in this study. The database was divided into 2 groups: ECD and non-ECD groups. LifePort parameters and other pretransplant factors were analyzed. Logistic regression analysis was used to determine the significant factors for delayed graft function (DGF). Recovery time for renal function and 6 months serum creatinine were investigated. RESULTS: The DGF rates were 20.25% and 11.72% in ECD and non-ECD group by our definition, respectively (P = .042). Higher pressures allowed comparable increases of flow in ECD kidneys despite still greater resistance. For non-ECD kidneys with an initial flow of <=80 mL/min, the DGF rate of the subgroup with a terminal flow of >=100 mL/min was significantly lower compared with that of other terminal flow subgroups (<=80 and 90-100 mL/min; P < .05), and showed a trend toward significance when compared with the terminal flow subgroup of 80 to 90 mL/min (P = .098). Terminal resistance was the most significant parameter predicting DGF (odds ratio 2.44; P < .001), and remained significant after adjusted for other relevant pretransplant variables. Logistic model for DGF (model: terminal resistance, hypotension in agonal phase, terminal serum creatinine, and cause of death) had good predictive ability (c-statistic 0.851; 95% confidence interval, 0.799-0.903). CONCLUSIONS: LifePort parameters provided a granular measurement easily accessible in evaluating the quality of kidneys donated after cardiac death that added information to ECD criterion. PMID- 29407337 TI - Prospective Comparison of Equations Based on Creatinine and Cystatin C for the Glomerular Filtration Rate Estimation in Chinese Renal Transplant Recipients. AB - BACKGROUND: Currently, there is no dedicated equation to estimate glomerular filtration rate (GFR) for transplanted kidneys. This study aimed to compare the performance of serum creatinine (Scr)- and cystatin C (CysC)-based equations in Chinese renal transplant recipients. METHODS: A total of 252 stable renal transplant recipients were enrolled in this study. The plasma clearance of 99mTc DTPA (rGFR) was used as a reference standard. The Scr, CysC, and rGFR of the patients were measured on the same day. The bias, precision, accuracy (percentage of estimates within 10%, 30%, and 50% of rGFR), and agreements of 8 Scr and 5 CysC eGFR equations were assessed. The factors affecting the accuracy were also evaluated. RESULTS: Among the Scr-based equations, the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) equation had the best overall performance with a bias of -6.2 mL/min/1.73 m2, and 96.1% of its estimates were within 30% of the rGFR. For the CysC-based equations, the Filler equation had the best performance with a bias of -3.9 mL/min/1.73 m2, and 93.7% of its estimates were within 30% of the rGFR. Overall, the CysC-based equations showed better performance than the Scr-based equations. In addition, significant differences were observed between bias and gender and between bias and rGFR value in some equations, whereas transplantation time and immunosuppressive regimens were not correlated with the bias. CONCLUSION: The JSN-CKDI equation provides the best estimation of the GFR equations, and the CysC-based equations performed better than the Scr-based equations in this population. PMID- 29407338 TI - Mobile Technology Affinity in Renal Transplant Recipients. AB - BACKGROUND: Medication nonadherence is a common problem in renal transplant recipients (RTRs). Mobile health approaches to improve medication adherence are a current trend, and several medication adherence apps are available. However, it is unknown whether RTRs use these technologies and to what extent. In the present study, the mobile technology affinity of RTRs was analyzed. We hypothesized significant age differences in mobile technology affinity and that mobile technology affinity is associated with better cognitive functioning as well as higher educational level. METHODS: A total of 109 RTRs (63% male) participated in the cross-sectional study, with an overall mean age of 51.8 +/- 14.2 years. The study included the Technology Experience Questionnaire (TEQ) for the assessment of mobile technology affinity, a cognitive test battery, and sociodemographic data. RESULTS: Overall, 57.4% of the patients used a smartphone or tablet and almost 45% used apps. The TEQ sum score was 20.9 in a possible range from 6 (no affinity to technology) to 30 (very high affinity). Younger patients had significantly higher scores in mobile technology affinity. The only significant gender difference was found in having fun with using electronic devices: Men enjoyed technology more than women did. Mobile technology affinity was positively associated with cognitive functioning and educational level. CONCLUSIONS: Young adult patients might profit most from mobile health approaches. Furthermore, high educational level and normal cognitive functioning promote mobile technology affinity. This should be kept in mind when designing mobile technology health (mHealth) interventions for RTRs. For beneficial mHealth interventions, further research on potential barriers and desired technologic features is necessary to adapt apps to patients' needs. PMID- 29407339 TI - Emergency Kidney Transplantation in Recipients With Iliocaval Thrombosis Using Splenic Vessel Anastomosis After Splenectomy: A Case Series. AB - BACKGROUND: The external iliac vein is the standard site used for venous anastomosis in kidney transplantation. When a pre-transplantation diagnosis of iliocaval thrombosis is established, a different and suitable venous drainage for the renal outflow must be identified for successful transplant. METHODS: We report 4 cases of kidney transplantation, performed from 2004 to 2016, in recipients presenting with thrombosis of the inferior vena cava and iliac system needing, because of the lack of access for dialysis, urgent kidney transplantations. The splenic vessels were used in all cases for the graft's vascular anastomosis after splenectomy. RESULTS: Kidney transplantation after splenectomy, with anastomosis of the renal vessels to the splenic ones, was completed in all 4 patients. All of the cases were technically successful with good renal function on discharge. During the follow-up, no graft losses were registered as due to thrombotic event or inadequate renal venous outflow. A normal vascular inflow and outflow was confirmed by means of follow-up ultrasound. Two grafts were lost at 31 months and 91 months, both to noncompliance with immunosuppressive therapy. The other 2 are currently functioning well. Notably, the kidney's position in the left upper quadrant has not caused technical difficulties in urologic reconstruction. CONCLUSIONS: In our experience, kidney transplantation using splenic vessels for vascular anastomosis is technically feasible and very useful in the setting of complete iliocaval thrombosis. PMID- 29407340 TI - Azithromycin-loaded respirable microparticles for targeted pulmonary delivery for the treatment of pneumonia. AB - Pneumonia is a major contributor to infection-based hospitalizations and deaths in the United States. Antibiotics such as azithromycin (AZM), although effective at managing pneumonia, often suffer from off-target diffusion and poor bioavailability when administered orally or via intravenous injection. The formation of biofilms at the disease sites makes the treatment more complicated by protecting bacteria from antimicrobial agents and thus necessitating a much higher dosage of antibiotics to eradicate the biofilms. As such, targeted pulmonary delivery of antibiotics has emerged as a promising alternative by providing direct access to the lung while also allowing higher local therapeutic concentrations but minimal systemic exposure. In this study, AZM was encapsulated in N-fumaroylated diketopiperazine (FDKP) microparticles for efficient pulmonary delivery. Both in vitro and in vivo results demonstrated that AZM@FDKP-MPs administered via intratracheal insufflation achieved at least a 3.4 times higher local concentration and prolonged retention times compared to intravenous injection and oral administration, suggesting their potential to better manage bacterial pneumonia. PMID- 29407341 TI - Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy. AB - Therapeutic efficacy of a systemic drug delivery largely depends on the targeting design of the delivery system, which tackles with circulatory traffic and prevents the nonspecific distribution of the drug in the wide range of vital organs. A drawing attention has been given to a biomimetic cloaking of the synthetic drug delivery nanoparticle using mammalian cell-ghosts, which has shown the installment of the biological complexity of the original cells thereby acting as naive cells, to precisely delivery drug to the intended target. Align towards this direction; we developed a membrane camouflage fusogenic liposomal delivery system "NKsome" for targeted tumor therapy using Natural Killer (NK) cell-ghost, which naturally undergoes immunosurveillance of diseased/stress cells. The engineered NKsome shows successful retention of NK cell membrane-associated targeting protein on its surface. With its excellent biocompatibility, NKsome shows a higher affinity towards cancer than normal cells as demonstrated by in vitro flow-passage assay, and exhibits enhanced tumor homing efficiency in-vivo with an extended plasma residence time of 18 h. Moreover, the therapeutic potential of doxorubicin-loaded NKsome shows promising antitumor activity in vivo against MCF-7 induced tumor model. Overall results illustrate the therapeutic advantages of NK cell biomimicry capable of communicating like immune cells for cooperative drug delivery. PMID- 29407342 TI - Layer-by-layer cell coating technique using extracellular matrix facilitates rapid fabrication and function of pancreatic beta-cell spheroids. AB - Tissue engineering of insulin-secreting cells using alternatives to islet transplantation has been fueled by the development of available materials and fabrication techniques. We have established a cell coating technique that enables the cell surface to be coated with extracellular matrix based on the concept of a layer-by-layer (LbL) assembly. The present study evaluated whether this technique is beneficial for fabricating pancreatic beta-cell spheroids using a mouse beta cell line. The well-structured and dense spheroids could immediately be constructed by the LbL-coated cells. In the functional analysis, spheroids with the LbL-coated cells had greater insulin secretion ability with increased expression of the insulin and glucose transporter 2 genes versus spheroids with non-coated cells. In addition, we found that the expression of connexin 36, a gap junction molecule, was upregulated by the LbL cell coating. When spheroids with the LbL-coated cells were syngeneically transplanted in diabetic mice, blood glucose levels immediately decreased and glucose sensitivity significantly improved after intraperitoneal glucose stimulation compared to spheroids with non coated cells. This cell coating technique would be a clinically applicable approach for fabricating pancreatic beta-cell spheroids and treating type 1 diabetes mellitus. PMID- 29407343 TI - A bifunctional scaffold with CuFeSe2 nanocrystals for tumor therapy and bone reconstruction. AB - Bone tumor is one of major challenging issues clinically. After surgical intervention, a few bone tumor cells still remain around bone defects and then proliferate over days. Fabrication of specific biomaterials with dual functions of bone tumor therapy and bone regeneration is of great significance. In order to achieve this aim, we managed to prepare bioactive glass (BG) scaffolds functionalized by the CuFeSe2 nanocrystals (BG-CFS) by combining 3D printing technique with solvothermal method. During the solvothermal reaction process, CuFeSe2 nanocrystals could in situ grow on the strut surface of BG scaffolds and thus endow BG scaffolds excellent photothermal performance. The photothermal performance of BG-CFS scaffolds could be well regulated through altering the content of CuFeSe2 nanocrystals and laser power density when exposed to the near infrared laser (808 nm). The BG-CFS scaffolds could not only effectively ablate the bone tumor cells (Saos-2 cells) in vitro, but also significantly inhibit bone tumor growth in vivo. Moreover, BG-CFS scaffolds could stimulate osteogenic gene expressions of rabbit bone marrow stromal cells (rBMSCs) and finally facilitate the formation of new bone in the bone defects. Our study, for the first time, combined the photothermal performance of semiconductor CuFeSe2 nanocrystals with the bone-forming activity of bioactive glass scaffolds, which can offer a more extensive horizon for developing novel biomaterials with dual functions of bone tumor therapy and bone regeneration. PMID- 29407344 TI - The impact of emotional intelligence in health care professionals on caring behaviour towards patients in clinical and long-term care settings: Findings from an integrative review. AB - BACKGROUND: Over recent years there has been criticism within the United Kingdom's health service regarding a lack of care and compassion, resulting in adverse outcomes for patients. The impact of emotional intelligence in staff on patient health care outcomes has been recently highlighted. Many recruiters now assess emotional intelligence as part of their selection process for health care staff. However, it has been argued that the importance of emotional intelligence in health care has been overestimated. OBJECTIVES: To explore relationships between emotional intelligence in health care professionals, and caring behaviour. To further explore any additional factors related to emotional intelligence that may impact upon caring behaviour. DESIGN: An integrative review design was used. DATA SOURCES: Psychinfo, Medline, CINAHL Plus, Social Sciences Citation Index, Science Citation Index, and Scopus were searched for studies from 1995 to April 2017. REVIEW METHODS: Studies providing quantitative or qualitative exploration of how any healthcare professionals' emotional intelligence is linked to caring in healthcare settings were selected. RESULTS: Twenty two studies fulfilled the inclusion criteria. Three main types of health care professional were identified: nurses, nurse leaders, and physicians. Results indicated that the emotional intelligence of nurses was related to both physical and emotional caring, but emotional intelligence may be less relevant for nurse leaders and physicians. Age, experience, burnout, and job satisfaction may also be relevant factors for both caring and emotional intelligence. CONCLUSIONS: This review provides evidence that developing emotional intelligence in nurses may positively impact upon certain caring behaviours, and that there may be differences within groups that warrant further investigation. Understanding more about which aspects of emotional intelligence are most relevant for intervention is important, and directions for further large scale research have been identified. PMID- 29407345 TI - Factors related to intention to stay in the current workplace among long-term care nurses: A nationwide survey. AB - BACKGROUND: Keeping long-term care nurses employed is necessary to sustain the current and future demand for high-quality long-term care services. Understanding the factors relating to intention to stay among long-term care nurses is limited by the scarcity of studies in long-term care settings, lack of investigation of multiple factors, and the weakness of existing explanatory models. OBJECTIVE: To identify the factors associated with long-term care nurses' intention to stay in their current workplace. DESIGN: A cross-sectional questionnaire survey. SETTING: Two hundred and fifty-seven hospitals with long-term care wards across Japan. PARTICIPANTS: A total of 3128 staff nurses and 257 nurse managers from the long term care wards of the participating hospitals. METHOD: The questionnaire assessed nurses' intention to continue working in the current workplace as well as potential related factors, including individual factors (demographic data, reason for choosing current workplace, burnout, work engagement, somatic symptom burden) and unit factors (unit size, nurse-manager-related data, patients' medical acuity, average number of overtime hours, recreational activities, social support, perceived quality of care process, educational opportunities, feeling of loneliness, and ability to request days off). Multilevel logistic regression analysis was used to determine which variables best explained nurses' intention to stay in their workplace. RESULTS: Only 40.1% of the respondents reported wanting to continue working at their current workplace. The regression analysis revealed that long-term care nurses' intention to stay was positively associated with nurses' age (odds ratio [95% confidence interval]: 1.02 [1.01-1.03]), work engagement (1.24 [1.14-1.35]), getting appropriate support from nurse managers (2.78 [1.60-4.82]), perceived quality of care process (1.04 [1.01-1.06]), educational opportunities (1.06 [1.0-1.13]), and various specific reasons for choosing their workplace (e.g., a good workplace atmosphere, being interested in gerontological nursing, and a high salary). By contrast, intention to stay was negatively associated with emotional exhaustion (0.93 [0.91-0.95]) and depersonalization (0.91 [0.89-0.93]). Intention to stay was associated with neither nurses' qualifications nor patient medical acuity. CONCLUSION: Reason for choosing the workplace, work engagement, getting support from the nurse manager, and perceived quality of care process are significant predictors of long-term care nurses' intention to stay in the workplace. Promoting such nurses' work engagement, provision of high-quality care, and access to educational opportunities might augment long-term care nurses' intention to stay. PMID- 29407346 TI - Associations between nurse education and experience and the risk of mortality and adverse events in acute care hospitals: A systematic review of observational studies. AB - OBJECTIVES: To provide knowledge from the summarization of the evidence on the: a) associations between nurse education and experience and the occurrence of mortality and adverse events in acute care hospitals, and; b) benefits to patients and organizations of the recent Institute of Medicine's recommendation that 80% of registered nurses should be educated at the baccalaureate degree by 2020. DATA SOURCES: A systematic search of English and French literature was conducted in six electronic databases: 1) Medline, 2) PubMed, 3) CINAHL, 4) Scopus, 5) Campbell, and 6) Cochrane databases. Additional studies were identified by searching bibliographies, prior reviews, and by contacting authors. REVIEW METHOD: Studies were included if they: a) were published between January 1996 and August 2017; b) were based on a quantitative research design; c) examined the associations between registered nurse education or experience and at least one independently measured adverse event, and; d) were conducted in an adult acute care setting. Data were independently extracted, analysed, and synthesized by two authors and discrepancies were resolved by consensus. The methodological heterogeneity of the reviewed studies precluded the use of meta analysis techniques. However, the methodological quality of each study was assessed using the STROBE criteria. FINDINGS: Among 2109 retrieved articles, 27 studies (24 cross-sectional and three longitudinal studies) met our inclusion criteria. These studies examined 18 distinct adverse events, with mortality and failure to rescue being the most frequently investigated events. Overall, higher levels of education were associated with lower risks of failure to rescue and mortality in 75% and 61.1% of the reviewed studies pertaining to these adverse events, respectively. Nurse education was inconsistently related to the occurrence of the other events, which were the focus of only a small number of studies. Only one study examined the 80% threshold proposed by the Institute of Medicine and found evidence that it is associated with lower odds of hospital readmission and shorter lengths of stay, but unrelated to mortality. Nurse experience was inconsistently related to adverse event occurrence. CONCLUSION: While evidence suggests that higher nurse education is associated with lower risks of mortality and failure to rescue, longitudinal studies are needed to better ascertain these associations and determine the specific thresholds that minimize risks. Further studies are needed to better document the association of nurse education and experience with other nursing-sensitive adverse events, as well as the benefits to patients and organizations of the Institute of Medicine's recommendation. PMID- 29407347 TI - The inclusion of retracted studies in systematic reviews: A response to Gray et al. (2018). PMID- 29407348 TI - Brexit: A response to McCrae (2018). PMID- 29407349 TI - Interventions promoting exclusive breastfeeding up to six months after birth: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The World Health Organization (WHO) recommends that mothers practice exclusive breastfeeding (EBF) of their infants for 6 months. Various breastfeeding support interventions have been developed to encourage mothers to maintain breastfeeding practices. Research aim: This study aims to review how effectively breastfeeding support interventions enable mothers to practice EBF for 6 months and to suggest the best intervention strategies. METHODS: Six databases were searched, including MEDLINE, EMBASE, Cochrane, CINAHL, PsycINFO, and KoreaMed. The authors independently extracted data from journals written in English or Korean and published between January 2000 and August 2017. Randomized controlled trials (RCTs) reporting EBF until 6 months were screened. RESULTS: A total of 27 RCTs were reviewed, and 36,051 mothers were included. The effectiveness of breastfeeding support interventions to promote EBF for 6 months was significant (odds ratio [OR] = 2.77; 95% confidence interval [CI]: 1.81 3.76). A further subgroup analysis of intervention effects shows that a baby friendly hospital initiative (BFHI) intervention (OR = 5.21; 95% CI: 2.15-12.61), a combined intervention (OR = 3.56; 95% CI: 1.74-7.26), a professional provider led intervention (OR = 2.76; 95% CI: 1.76-4.33), having a protocol available for the provider training program (OR = 2.87; 95% CI: 1.89-4.37) and implementation during both the prenatal and postnatal periods (OR = 3.32; 95% CI: 1.83-6.03) increased the rate of EBF for 6 months. CONCLUSION: We suggest considering a multicomponent intervention as the primary strategy and implementing BFHI interventions within hospitals. Evidence indicates that intervention effectiveness increases when a protocol is available for provider training, when interventions are conducted from the pre- to postnatal period, when the hospital and community are connected, and when healthcare professionals are involved. PMID- 29407350 TI - In vivo study of paraspinal muscle weakness using botulinum toxin in one primate model. AB - BACKGROUND: It has been generally speculated that paraspinal muscle weakness is related to the spinal degeneration including intervertebral disc failure. The purpose of this study was to investigate the effects of paraspinal muscle weakness induced by the botulinum toxin type-A on the lumbar spine and behavior pattern in an in-vivo primate model which has an upright locomotion similar to that of humans. METHODS: Botox injections into paraspinal muscle of one cynomolgus monkey were conducted biweekly up to 19 weeks at L2-L3, L3-L4 and L4 L5. MRIs were performed for measurement of muscle cross-sectional areas and behavioral data were collected using a high-resolution portable digital video camera. FINDINGS: The cross-sectional areas of the paraspinal muscles at L2-L3, L3-L4 and L4-L5 decreased by 8%, 12% and 8% at 21 weeks after the Botox injection, respectively. Intervertebral disc thickness at L2-L3, L3-L4 and L4-L5 decreased by 6%, 8% and 5% at 21 weeks after initial Botox injection, respectively. After the Botox injections, locomotion and movement activity of the monkey was decreased. The duration of sitting increased from 21% to a maximum of 97% at 9 weeks after the Botox injection, while stance time decreased from 9% to a minimum of 1% at 11 weeks post Botox injection. INTERPRETATION: The findings of this study revealed that paraspinal muscle atrophy affects intervertebral disc morphology and locomotion activity of a primate and may lead to an onset of intervertebral disc degeneration. PMID- 29407351 TI - Superior cortical screw in osteoporotic lumbar vertebrae: A biomechanics and microstructure-based study. AB - BACKGROUND: Osteoporosis reduces the bone-screw purchase, potentially reducing pullout strength and other biomechanical properties. However, the existing pedicle screw approach may not compensate for the detrimental effects of decreased vertebral bone mineral density. METHODS: Two methods of screw insertion were performed in thirteen cadaveric osteoporotic lumbar vertebrae: Magerl's method in the left pedicle, and superior cortical screw method in the right (its entry point located vertically 3 mm above Magerl's point). Before screw fixations, the pedicle and its corresponding vertebral body were divided into six equal layers from cranial to caudal by performing micro-CT and tested for microstructure properties, such as bone mineral density, trabecular bone volume fraction, trabecular thickness, trabecular separation and trabecular number. Further, pedicle was horizontally divided into three regions and tested. After screw fixations, microstructure properties of the bone surrounding the screws were analyzed. Finally, the screw pullout strength was tested biomechanically. FINDINGS: The bone structure is denser in the upper third of the pedicle and its corresponding vertebral body. A similar microstructure is seen within the pedicle. This study reveals that the pullout strength is significantly correlated to the bone mineral density, trabecular bone volume fraction and trabecular thickness. Biomechanical test showed pullout strength in the superior cortical screw group with mean 613.3 N (SD 200.4) was 22.4% higher than that in the Magerl group with mean 501.2 N (SD 256.6). INTERPRETATION: The superior cortical screw method can be a reliable alternative, to provide better pullout strength for posterior lumbar instrumentation, especially in osteoporotic patients. PMID- 29407352 TI - The relationship between balance performance, lumbar extension strength, trunk extension endurance, and pain in participants with chronic low back pain, and those without. AB - BACKGROUND: Chronic low back pain is associated with lumbar extensor deconditioning. This may contribute to decreased neuromuscular control and balance. However, balance is also influenced by the hip musculature. Thus, the purpose of this study was to examine balance in both asymptomatic participants and those with chronic low back pain, and to examine the relationships among balance, lumbar extension strength, trunk extension endurance, and pain. METHODS: Forty three asymptomatic participants and 21 participants with non-specific chronic low back pain underwent balance testing using the Star Excursion Balance Test, lumbar extension strength, trunk extension endurance, and pain using a visual analogue scale. FINDINGS: Significant correlations were found between lumbar extension strength and Star Excursion Balance Test scores in the chronic low back pain group (r = 0.439-0.615) and in the asymptomatic group (r = 0.309 0.411). Correlations in the chronic low back pain group were consistently found in posterior directions. Lumbar extension strength explained ~19.3% to ~37.8% of the variance in Star Excursion Balance Test scores for the chronic low back pain group and ~9.5% to ~16.9% for the asymptomatic group. INTERPRETATION: These results suggest that the lumbar extensors may be an important factor in determining the motor control dysfunctions, such as limited balance, that arise in chronic low back pain. As such, specific strengthening of this musculature may be an approach to aid in reversing these dysfunctions. PMID- 29407354 TI - [For 2018, a new editorial board for Annales de Pathologie]. PMID- 29407353 TI - Scapular kinematics in professional wheelchair tennis players. AB - BACKGROUND: Participating in wheelchair tennis increases the demands placed on the shoulder and could increase the risk of developing shoulder pain and injury that might be associated with differences in scapular kinematics. The aim of the study was to examine the presence of shoulder pain and scapular kinematics in professional wheelchair tennis players. METHOD: Scapular kinematics were obtained in 11 professional wheelchair tennis players, 16 people with shoulder impingement and 16 people without shoulder impingement during humeral elevation and lowering. Clinical examination of the wheelchair tennis players was undertaken using the Wheelchair Users Shoulder Disability Index (WUSPI) and clinical signs of shoulder impingement. FINDINGS: The WUSPI questionnaire (mean = 28 SD 13.8) demonstrated wheelchair tennis participants experienced little shoulder pain and clinical examination revealed negative impingement tests. Wheelchair tennis players had greater scapular posterior tilt during humeral elevation (3.9 degrees SE 1.71; P = 0.048) and lowering (4.3 degrees SE 1.8; P = 0.04) on the dominant compared to non-dominant side. The dominant scapulae of wheelchair tennis players were significantly (P = 0.014) more upwardly rotated (21 degrees SD 6.7) than the scapulae of people with shoulder impingement (14.1 degrees SD 7.0) during scapular plane humeral elevation. INTERPRETATION: This first study of scapular kinematics in professional wheelchair tennis athletes demonstrated bilateral asymmetries and differences to able-bodied participants with shoulder impingement. Understanding the role of sport participation on shoulder function in wheelchair users would assist in the development of preventative and treatment exercise programmes for wheelchair users at risk of shoulder injury and pain. PMID- 29407355 TI - [Welcome to the new editorial board!] PMID- 29407356 TI - Behavioural mimicry and loneliness in borderline personality disorder. AB - INTRODUCTION: Interpersonal problems together with feelings of intense loneliness constitute a core symptom domain in borderline personality disorder (BPD). Mimicry is one social behaviour that serves the forming of social affiliation and building a sense of belonging. In the present study, we investigated whether behavioural mimicry is altered in BPD and whether it is linked to the patient's feeling of loneliness. METHODS: Individuals with BPD (N = 26) and healthy participants (HC, N = 25) performed a finger tapping task with a congruent or incongruent finger movement displayed preceding the presentation of the task relevant stimulus. Additional trials showing an immobile hand were used as a control condition. Mimicry strength was estimated as response facilitation after congruent and response interference after incongruent cues. RESULTS: Both HC and BPD patients showed facilitated responses after congruent finger movements. Only BPD patients exhibited interference by incongruent cues. The lonelier the BPD patients felt, the weaker was the interference of the incongruent cues. In contrast, interference increased with the level of loneliness in the HC group. CONCLUSIONS: Behavioural mimicry was increased in BPD. However, this effect was less pronounced in those BPD patients who reported the highest levels of loneliness. Our findings emphasize that mimicry is a complex construct and only some of the involved processes are altered in BPD. Future studies must further disentangle the contribution of cognitive and social cognitive processes, address a potential causality in the link between loneliness and mimicry in BPD, and relate alterations of mimicry to interpersonal dysfunction during every-day life. PMID- 29407357 TI - Measuring racing thoughts in healthy individuals: The Racing and Crowded Thoughts Questionnaire (RCTQ). AB - Racing thoughts refer to an acceleration and overproduction of thoughts, which have been associated with manic and mixed episodes. Phenomenology distinguishes 'crowded' from 'racing' thoughts, associated with mixed depression and mania, respectively. Recent data suggest racing thoughts might also be present in healthy individuals with sub-affective traits and symptoms. We investigated this assumption, with a 34-item self-rating scale, the Racing and Crowded Thoughts Questionnaire (RCTQ), and evaluated its reliability, factor structure, and concurrent validity. 197 healthy individuals completed the RCTQ, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego - autoquestionnaire (TEMPS-A), the Beck Depression Inventory (BDI), the Altman Self-Rating Mania scale (ASRM), and the Ruminative Response Scale (RRS). Exploratory factor analysis yielded a three-factor solution, labeled 'thought overactivation', 'burden of thought overactivation', and 'thought overexcitability'. Internal consistency of each of the three subscales of the RCTQ was excellent. The TEMPS-A cyclothymia score was associated with the three factors, suggesting good concurrent validity. The 'thought activation' subscale was selectively associated with current elated mood and included items conveying both the notion of increased amount and velocity of thoughts, whereas the 'burden of thought overactivation' subscale was associated with current low mood. The 'thought overexcitability' subscale included items conveying the notion of distractibility, and was associated with both elated and low mood. Rumination was not a significant predictor of RCTQ subscores. These results suggest that the RCTQ has good psychometric properties. Racing and crowded thoughts, as measured by the RCTQ, are a multi-faceted phenomenon, distinct from rumination, and particularly associated with mood instability even in its milder forms. PMID- 29407358 TI - Abnormal perceptual sensitivity in body-focused repetitive behaviors. AB - OBJECTIVE: Several compulsive grooming habits such as hair pulling, skin picking, and nail biting are collectively known as body-focused repetitive behaviors (BFRBs). Although subclinical BFRBs are common and benign, more severe and damaging manifestations exist that are difficult to manage. Researchers have suggested that BFRBs are maintained by various cognitive, affective, and sensory contingencies. Although the involvement of cognitive and affective processes in BFRBs has been studied, there is a paucity of research on sensory processes. METHODS: The current study tested whether adults with subclinical or clinical BFRBs would report abnormal patterns of sensory processing as compared to a healthy control sample. RESULTS: Adults with clinical BFRBs (n = 26) reported increased sensory sensitivity as compared to persons with subclinical BFRBs (n = 48) and healthy individuals (n = 33). Elevations in sensation avoidance differentiated persons with clinical versus subclinical BFRBs. Sensation seeking patterns were not different between groups. Unexpectedly, BFRB severity was associated with lower registration of sensory stimuli, but this finding may be due to high psychiatric comorbidity rates in the BFRB groups. CONCLUSIONS: These findings suggest that several sensory abnormalities may underlie BFRBs. Implications for the etiology and treatment of BFRBs are discussed. PMID- 29407359 TI - Characterizing gender differences in nonsuicidal self-injury: Evidence from a large clinical sample of adolescents and adults. AB - While nonsuicidal self-injury (NSSI) is common in both men and women, research exploring the intersection of NSSI and gender has been limited by the use of small samples of males drawn primarily from non-clinical populations. To address these limitations, we analyzed data from a large sample of patients enrolled in an NSSI partial hospitalization program (PHP) to compare males and females across several variables, including NSSI characteristics, correlates, and pre-post treatment outcomes. Results indicated similar NSSI characteristics and treatment outcomes for males and females, with few exceptions. Males notably reported lower severity levels for most NSSI correlates (e.g., psychopathology, suicidality), highlighting the need to screen males for NSSI even when reporting comparatively less impairment. Finally, our results also suggest that PHP treatment for NSSI can be beneficial for both males and females. These findings have implications for the assessment, diagnosis, conceptualization, and treatment of NSSI in males and females. PMID- 29407360 TI - Bereaved families are still embittered after the Sewol ferry accident in Korea: A follow-up study 18 and 30months after the disaster. AB - INTRODUCTION: The Sewol ferry accident that occurred in April 2014 was one of the most tragic human-made disasters in Korean history. Due to the deaths of hundreds of children, bereaved families likely feel embittered; however, there is little extant research documenting embitterment among those who experienced the disaster. Consequently, we investigated bereaved family members' embitterment and other psychiatric symptoms 18months and 30months after the disaster. METHODS: Data from a cross-sectional survey were obtained 18months (Time 1) and 30months (Time 2) after the disaster. We ascertained socio-demographic variables and variables obtained from a self-reporting questionnaire (i.e., depression, anxiety, posttraumatic stress disorder, complicated grief, and embitterment) among 56 bereaved family members. RESULTS: Bereaved families showed substantial embitterment at Time 1 (64.3%), which increased at Time 2 (76.8%, t=1.761, p=0.084). The participants who displayed increased embitterment at Time 2 also increased in anxiety, post-traumatic stress symptoms, and complicated grief (but not depression). Furthermore, participants who displayed decreased embitterment at Time 2 also decreased in all other psychiatric symptoms. (time*group interaction in depression (F 0.644, p=0.426), anxiety (F 4.970, p=0.030), PTSD (F 10.699, p=0.002), and complicated grief (F 8.389, p=0.005)). CONCLUSIONS: Embitterment of bereaved families had not ceased after 18months and even increased 1year later. Additionally, as embitterment increased, many other psychiatric symptoms also increased, and vice versa. Our results suggest that embitterment is associated or can even influence other psychiatric symptoms; therefore, embitterment should be examined after disasters. PMID- 29407361 TI - Association between body mass index and suicidal ideation among seniors in Shandong, China. AB - BACKGROUND: Recently, an emerging group of studies has reported the association between Body Mass Index (BMI) and suicidal ideation in the Western countries. However, this relationship is still unclear with controversial results, and we have little knowledge about this relationship in China which is one of few countries reported higher suicide rates. METHODS: This study aims to analyze the association between BMI and suicidal ideation among seniors (>=60 years old) in Shandong, China. A total of 3313 seniors were included in the data analysis. Suicidal ideation, weight, height, socio-demographic and psychological variables were evaluated in this study. Logistic regression was conducted to explore the association between BMI and suicidal ideation among male and female seniors. RESULTS: The results showed that 4.2% of the seniors reported suicidal ideation, and 3.4% for men, 4.9% for women. After controlling social-demographic variables, economic status, physical disease, social support and mental health, an inverse relationship between BMI and suicidal ideation was found for men, but not for women. Mental health was still an important factor associated with suicidal ideation. CONCLUSION: The results inform health care professors that underweight in male seniors can be associated with higher risk of suicidal ideation in China. PMID- 29407363 TI - Society of Family Planning clinical guidelines pain control in surgical abortion part 1 - local anesthesia and minimal sedation. AB - Satisfactory pain control for women undergoing surgical abortion is important for patient comfort and satisfaction. Clinicians ought to be aware of the safety and efficacy of different pain control regimens. This document will focus on nonpharmacologic modalities to reduce pain and pharmacologic interventions up to the level of minimal sedation. For surgical abortion without intravenous medications, a multimodal approach to pain control may combine a dedicated emotional-support person, visual or auditory distraction, administration of local anesthesia to the cervix with buffered lidocaine and a preoperative nonsteroidal anti-inflammatory drug. Oral opioids do not decrease procedural pain. Oral anxiolytics decrease anxiety but not the experience of pain. Further research is needed on alternative options to control pain short of moderate or deep sedation. PMID- 29407362 TI - Simultaneous quantitation of multiple contraceptive hormones in human serum by LC MS/MS. AB - OBJECTIVE: The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) and apply this method to human serum samples. STUDY DESIGN: We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. We analyzed serum collected from women self reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). RESULTS: Limits of quantitation were 0.010ng/mL for E2, EE2 and P4; 0.020ng/mL for ENG, LNG and MPA; and 0.040ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%-108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. CONCLUSIONS: We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. IMPLICATIONS: This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing. PMID- 29407364 TI - Evolution of cooperation with interactive identity and diversity. AB - Interactive identity and interactive diversity are generally regarded as two typical interaction patterns in living systems. The former describes that in each generation every individual behaves identically to all of its opponents, and the latter allows each individual to behave diversely to its distinct opponents. Most traditional research on the evolution of cooperation, however, has been confined to populations with a uniform interaction pattern. Here we study the cooperation conundrum in a diverse population comprising players with interactive identity and with interactive diversity. We find that in homogeneous networks a small fraction of players taking interactive diversity are enough to stabilize cooperation for a wide range of payoff values even in a noisy environment. When assigned to heterogeneous networks, players in high-degree nodes taking interactive diversity significantly strengthen systems' resilience against the shifty environment and enlarge the survival region of cooperation. However, they fail to establish a homogeneous strategy 'cloud' in the neighborhood and thus can not coordinate players in low-degree nodes to reach a socially optimal cooperation level. The most favorable outcome emerges when players in high-degree nodes take interactive identity and meanwhile others adopt interactive diversity. Our findings reveal the significance of the two typical interaction patterns and could be a good heuristic in coordinating them to achieve the social optimum in cooperation. PMID- 29407365 TI - p-Cresyl sulfate decreases peripheral B cells in mice with adenine-induced renal dysfunction. AB - Infection is a major cause of mortality in chronic kidney disease (CKD) patients. Although immune dysfunction is a risk factor for infection in CKD patients, its causes are not fully elucidated. In the present study, we evaluated whether p cresyl sulfate (pCS), an intestinal bacteria-derived uremic toxin, was involved in immune dysfunction in CKD. We used osmotic pumps to establish adenine-induced renal dysfunction mice with a chronically high blood pCS concentration. Analysis of lymphocyte subsets revealed that pCS significantly reduced peripheral B cells in renal dysfunction mice. In vitro, pCS inhibited interleukin (IL)-7-induced proliferation of CD43+ B-cell progenitors and suppressed IL-7-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) in these cells. Cell cycle analysis showed that pCS significantly decreased the percentage of CD43+ B-cell progenitors in S phase and increased that in G1 phase. These results suggest that pCS suppressed IL-7-induced STAT5 signaling and inhibited B-cell progenitor proliferation, leading to reduction of peripheral B cells in adenine-induced renal dysfunction mice. Therefore, pCS decreases peripheral B cells by inhibiting proliferation of CD43+ B-cell progenitors and is a likely cause of immune dysfunction in CKD patients. PMID- 29407366 TI - Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF kappaB activation and acceleration of intrinsic myelin repair. AB - Cuprizone (Cup) is a copper chelating agent frequently used to study factors that affect oligodendrocytes (OLGs) death and acute demyelination. Triptolide (TP), a nuclear factor-kappaB (NF-kappaB) blocker, is a major bioactive component of Tripterygium wilfordii Hook f. (TWHf) with various therapeutic activities. In this study, we examined the effects of TP on neuroglia activation, inflammation, apoptosis, demyelination, and behavioral deficits in the Cup-induced toxic model of multiple sclerosis (MS). C57BL/6 J mice were fed with chow containing 0.2% Cup for 6 weeks to induce detectable neuroinflammation and myelin loss. TP was administered intraperitoneally at different doses (125, 250 or 500 MUg/kg/day) during the last week of the Cup challenge. Although TP substantially decreased Cup-induced NF-kappaB extra activation, TNF-alpha and IL-1 over expression, and gliosis in a dose-dependent manner, only low dose of TP (TP-125) was able to raise the number of OLGs precursor cells (NG-2+/O4+), reduce Bax/Bcl-2 ratio and improve behavioral deficits. In addition, TP-125 decreased NF-kappaB activation on GFAP+ astrocytes more than MAC-3+ microglial and MOG+ oligodendrocytes which suggested the possibility of specific dampening of NF-kappaB signaling in reactive astrocytes. Behavioral assessments by open-field and rota-rod tests showed that only TP-125 notably improved motor function and motor coordination compared to the Cup group. These findings highlight the pivotal role of NF-kappaB signaling in the oligodendrogenesis and lesion reduction in demyelination diseases such as MS. PMID- 29407368 TI - Emerging trends in the treatment of advanced basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer worldwide. In most patients, BCC can be effectively treated with standard surgical excision, Mohs micrographic surgery, curettage and electrodessication, radiotherapy, and/or superficial field therapies (including 5-fluorouracil, imiquimod, and photodynamic therapy); however, a minority of patients develop advanced BCC, for which treatment can be challenging and outcomes are poorer. Advanced BCC encompasses a heterogeneous assortment of cases, including metastatic BCC as well as locally advanced BCC (for which no formal definition exists but which generally includes large, deep, aggressive, or recurrent tumors). Locally advanced BCC may be broadly categorized as cases for which (further) surgery is considered inappropriate or would be substantially disfiguring and radiation is considered inappropriate as a single modality or second-line treatment. Several therapies are being investigated for the treatment of advanced BCC. In particular, hedgehog pathway inhibitors have emerged as an important treatment option for this population. Two hedgehog pathway inhibitors-vismodegib and sonidegib-have received regulatory approval for the treatment of certain subsets of patients with advanced BCC after demonstrating clinical efficacy and safety in large, international phase 2 clinical trials. Here we review the available treatment options for BCC, focusing on the treatment of advanced BCC. Clinical data from studies evaluating vismodegib and sonidegib in patients with advanced BCC are also discussed. As more clinical trial and real-world data on the use of hedgehog pathway inhibitors become available, better-informed decisions can be made for the treatment of patients with advanced BCC. PMID- 29407367 TI - Investigating mitochondrial dysfunction in human lung cells exposed to redox active PM components. AB - Exposure to ambient particulate matter (PM) causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress. 1,2-naphthoquinone (1,2-NQ) is a ubiquitous component of PM and a potent redox-active electrophile. We previously reported that 1,2-NQ increases mitochondrial H2O2 production through an unidentified mechanism. We sought to characterize the effects of 1,2 NQ exposure on mitochondrial respiration as a source of H2O2 in human airway epithelial cells. We measured the effects of acute exposure to 1,2-NQ on oxygen consumption rate (OCR) in the human bronchial epithelial cell line BEAS-2B and mitochondrial preparations using extracellular flux analysis. Complex-specific assays and NADPH depletion by glucose deprivation distinguished between mitochondrial and non-mitochondrial oxygen utilization. 1,2-NQ exposure of BEAS cells caused a rapid, marked dose-dependent increase in OCR that was independent of mitochondrial respiration, exceeded the OCR observed after mitochondrial uncoupling, and remained sensitive to NADPH depletion, implicating extra mitochondrial redox cycling processes. Similar effects were observed with the environmentally relevant redox-cycling quinones 1,4-naphthoquinone and 9,10 phenanthrenequinone, but not with quinones that do not redox cycle, such as 1,4 benzoquinone. In mitochondrial preparations, 1,2-NQ caused a decrease in Complex I-linked substrate oxidation, suggesting impairment of pyruvate utilization or transport, a novel mechanism of mitochondrial inhibition by an environmental exposure. This study also highlights the methodological utility and challenges in the use of extracellular flux analysis to elucidate the mechanisms of action of redox-active electrophiles present in ambient air. PMID- 29407370 TI - Authors' Reply. PMID- 29407369 TI - Immune checkpoint inhibitors for metastatic bladder cancer. AB - Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. PMID- 29407371 TI - G-protein coupled receptors Mc4r and Drd1a can serve as surrogate odorant receptors in mouse olfactory sensory neurons. AB - In the mouse, most mature olfactory sensory neurons (OSNs) express one allele of one gene from the repertoire of ~1100 odorant receptor (OR) genes, which encode G protein coupled receptors (GPCRs). Axons of OSNs that express a given OR coalesce into homogeneous glomeruli, which reside at conserved positions in the olfactory bulb. ORs are intimately involved in ensuring the expression of one OR per OSN and the coalescence of OSN axons into glomeruli. But the mechanisms whereby ORs accomplish these diverse functions remain poorly understood. An experimental approach that has been informative is to substitute an OR genetically with another GPCR that is normally not expressed in OSNs, in order to determine in which aspects this GPCR can serve as surrogate OR in mouse OSNs. Thus far only the beta2-adrenergic receptor (beta2AR, Ardb2) has been shown to be able to serve as surrogate OR in OSNs; the beta2AR could substitute for the M71 OR in all aspects examined. Can other non-olfactory GPCRs function equally well as surrogate ORs in OSNs? Here, we have generated and characterized two novel gene targeted mouse strains in which the mouse melanocortin 4 receptor (Mc4r) or the mouse dopamine receptor D1 (Drd1a) is coexpressed with tauGFP in OSNs that express the OR locus M71. These alleles and strains are abbreviated as Mc4r -> M71-GFP and Drd1a -> M71-GFP. We detected strong Mc4r or Drd1a immunoreactivity in axons and dendritic knobs and cilia of OSNs that express Mc4r or Drd1a from the M71 locus. These OSNs responded physiologically to cognate agonists for Mc4r (Ro27-3225) or Drd1a (SKF81297), and not to the M71 ligand acetophenone. Axons of OSNs expressing Mc4r -> M71-GFP coalesced into glomeruli. Axons of OSNs expressing Drd1a -> M71-GFP converged onto restricted areas of the olfactory bulb but did not coalesce into glomeruli. Thus, OR functions in OSNs can be substituted by Mc4r or Drd1a, but not as well as by beta2AR. We attribute the weak performance of Drd1a as surrogate OR to poor OSN maturation. PMID- 29407373 TI - Spumaretroviruses: Updated taxonomy and nomenclature. AB - Spumaretroviruses, commonly referred to as foamy viruses, are complex retroviruses belonging to the subfamily Spumaretrovirinae, family Retroviridae, which naturally infect a variety of animals including nonhuman primates (NHPs). Additionally, cross-species transmissions of simian foamy viruses (SFVs) to humans have occurred following exposure to tissues of infected NHPs. Recent research has led to the identification of previously unknown exogenous foamy viruses, and to the discovery of endogenous spumaretrovirus sequences in a variety of host genomes. Here, we describe an updated spumaretrovirus taxonomy that has been recently accepted by the International Committee on Taxonomy of Viruses (ICTV) Executive Committee, and describe a virus nomenclature that is generally consistent with that used for other retroviruses, such as lentiviruses and deltaretroviruses. This taxonomy can be applied to distinguish different, but closely related, primate (e.g., human, ape, simian) foamy viruses as well as those from other hosts. This proposal accounts for host-virus co-speciation and cross-species transmission. PMID- 29407375 TI - Behind the scenes of HIV-1 replication: Alternative splicing as the dependency factor on the quiet. AB - Alternative splicing plays a key role in the HIV-1 life cycle and is essential to maintain an equilibrium of mRNAs that encode viral proteins and polyprotein isoforms. In particular, since all early HIV-1 proteins are expressed from spliced intronless and late enzymatic and structural proteins from intron containing, i.e. splicing repressed viral mRNAs, cellular splicing factors and splicing regulatory proteins are crucial for the replication capacity. In this review, we will describe the complex network of cis-acting splicing regulatory elements (SREs), which are mainly localized in the neighbourhoods of all HIV-1 splice sites and warrant the proper ratio of individual transcript isoforms. Since SREs represent binding sites for trans-acting cellular splicing factors interacting with the cellular spliceosomal apparatus we will review the current knowledge of interactions between viral RNA and cellular proteins as well as their impact on viral replication. Finally, we will discuss potential therapeutic approaches targeting HIV-1 alternative splicing. PMID- 29407374 TI - Characterization of interaction between Trim28 and YY1 in silencing proviral DNA of Moloney murine leukemia virus. AB - Moloney Murine Leukemia Virus (M-MLV) proviral DNA is transcriptionally silenced in embryonic cells by a large repressor complex tethered to the provirus by two sequence-specific DNA binding proteins, ZFP809 and YY1. A central component of the complex is Trim28, a scaffold protein that regulates many target genes involved in cell cycle progression, DNA damage responses, and viral gene expression. The silencing activity of Trim28, and its interactions with corepressors are often regulated by post-translational modifications such as sumoylation and phosphorylation. We defined the interaction domains of Trim28 and YY1, and investigated the role of sumoylation and phosphorylation of Trim28 in mediating M-MLV silencing. The RBCC domain of Trim28 was sufficient for interaction with YY1, and acidic region 1 and zinc fingers of YY1 were necessary and sufficient for its interaction with Trim28. Additionally, we found that residue K779 was critical for Trim28-mediated silencing of M-MLV in embryonic cells. PMID- 29407376 TI - Detection and phylogenetic analysis of torque teno virus (TTV) carried by murine rodents and house shrews in China. AB - Between May 2015 and May 2017, 496 animals (473 murine rodents and 23 house shrews) were captured in six regions of China. A total of 22.8% (113/496) of throat swabs, 29.1% (142/488) of fecal samples and 23.8% (54/227) of serum samples tested positive for rodent torque teno virus 3 (RoTTV3). The positive rate in Rattus norvegicus was higher than the rate in Rattus tanezumi and Rattus losea. Of 23 house shrews, one throat swab and one serum sample were positive for RoTTV3. Ten murine rodents were simultaneously positive for RoTTV3 in throat swab, fecal and serum samples. Phylogenetic analysis showed that the 12 near-full length genomes of RoTTVs sequences obtained in this study represented a novel RoTTV genotype (RoTTV3). In conclusion, high prevalence rates of RoTTV3 were found in three common murine rodents in China, and the RoTTV3 obtained in this study were classified as a novel genotype of RoTTV. PMID- 29407377 TI - Analysis of enterovirus types in patients with symptoms of aseptic meningitis in 2014 in Shandong, China. AB - We reviewed the epidemiological and clinical characteristics of 927 aseptic meningitis patients in Shandong in 2014, and the phylogeny of predominant enterovirus (EV) types causing this disease was analyzed. A total of 209 patients that were positive for EV were identified by both cell culture and a reverse transcription-seminested PCR in cerebrospinal fluid samples. The positive patients were most likely to be children within 15 years of age, had symptoms such as fever, vomiting and nausea (P< .05). The 209 EV sequences belonged to 11 types, and coxsackievirus B5, echovirus types 6 and 30 were predominant types. VP1 analysis exhibited multiple lineages were co-circulating. The significance of the study could come from the fact that surveillance is important to monitor the prevalence of EV types in population, which shows enterovirus meningitis maintains an important public health problem in China. PMID- 29407378 TI - Phylogenetic and molecular epidemiological studies reveal evidence of recombination among Marek's disease viruses. AB - Marek's disease has brought enormous loss in chicken production worldwide and the increasing virulence of Marek's disease virus (MDV) became a severe problem. To better understand the genetic basis underlying, a Chinese MDV strain HNGS101 isolated from immunized chickens was sequenced. Phylogenetic analysis implied that HNGS101 showed more relatedness to Eurasian strains than GaHV-2 circulating in North America. Recombination networks analysis showed the evidence of recombination among MDV strains, and several recombination events in the UL and US region were found. Further analysis indicated that the HNGS101 strain seemed to be generated by the recombination of the earliest Eurasian strains and North American strains in the US region, which may be responsible for the MD outbreaks in China. In summary,this is the first report to demonstrate recombination events among MDV strains, which may shed light on the mechanism of virulence enhancement. PMID- 29407379 TI - Molecular evolution of hepatitis C virus in China: A nationwide study. AB - The evolutionary and epidemic history and the regional differences of hepatitis C virus (HCV) are complex and remain unclear in the vast territory China. Here we recruited 1540 HCV-RNA positive patients sampled in 29 provinces across whole China, which is the largest sample capacity and the most comprehensive geographic coverage of China to our knowledge. 1b, 2a, 3b, 6a and 3a were the major subtypes in China. 1b was the most predominant subtype which presented in every province. The second most predominant subtype, 2a, appeared to concentrate in the north of China. Subtypes 3a and 3b were mainly found in the Southwest region, while 6a was restricted in the South region. We further estimated the origins of the dominating subtypes and discovered for the first time that a Chinese-specific transmission pattern for some strains of subtype 2a which was restricted in north China, and Chinese subtype 3b originated from Thailand. PMID- 29407380 TI - Attenuation of Marek's disease virus by codon pair deoptimization of a core gene. AB - Marek's disease virus (MDV) is an oncogenic alphaherpesvirus of Gallus gallus, the domesticated chicken. Control strategies rely upon vaccination with live attenuated viruses of antigenically similar avian herpesviruses or attenuated strains of MDV. Recent studies in other viruses have shown that recoding certain viral genes to employ synonymous but rarely-used codon pairs resulted in viral attenuation. We deoptimized two MDV proteins, UL54/ICP27 and UL49/VP22, and demonstrate that the more severely deoptimized variant of UL54 accumulates significantly less gene product in vitro. Using these UL54 deoptimized mutants, we further demonstrate that animals infected with the UL54-recoded recombinant virus exhibited decreased viral genome copy number in lymphocytes, reduced lymphoid atrophy and reduced tumor incidence. This study demonstrates that codon pair deoptimization of a single viral gene can produce attenuated strains of MDV. This approach may be useful as a rational way of making novel live attenuated virus vaccines for MDV. PMID- 29407382 TI - Cryo-EM structure of a Marseilleviridae virus particle reveals a large internal microassembly. AB - Nucleocytoplasmic large DNA viruses (NCLDVs) blur the line between viruses and cells. Melbournevirus (MelV, family Marseilleviridae) belongs to a new family of NCLDVs. Here we present an electron cryo-microscopy structure of the MelV particle, with the large triangulation number T = 309 constructed by 3080 pseudo hexagonal capsomers. The most distinct feature of the particle is a large and dense body (LDB) consistently found inside all particles. Electron cryo tomography of 147 particles shows that the LDB is preferentially located in proximity to the probable lipid bilayer. The LDB is 30 nm in size and its density matches that of a genome/protein complex. The observed LDB reinforces the structural complexity of MelV, setting it apart from other NCLDVs. PMID- 29407381 TI - Isolation, characterization and prevalence of a novel Gammaherpesvirus in Eptesicus fuscus, the North American big brown bat. AB - Little is known about the relationship of Gammaherpesviruses with their bat hosts. Gammaherpesviruses are of interest because of their long-term infection of lymphoid cells and their potential to cause cancer. Here, we report the characterization of a novel bat herpesvirus isolated from a big brown bat (Eptesicus fuscus) in Canada. The genome of the virus, tentatively named Eptesicus fuscus herpesvirus (EfHV), is 166,748 base pairs. Phylogenetically EfHV is a member of Gammaherpesvirinae, in which it belongs to the Genus Rhadinovirus and is closely related to other bat Gammaherpesviruses. In contrast to other known Gammaherpesviruses, the EfHV genome contains coding sequences similar to those of class I and II host major histocompatibility antigens. The virus is capable of infecting and replicating in human, monkey, cat and pig cell lines. Although we detected EfHV in 20 of 28 big brown bats tested, these bats lacked neutralizing antibodies against the virus. PMID- 29407383 TI - Logic of two antagonizing intra-species quorum sensing systems in bacteria. AB - Bacteria release signaling molecules into the surrounding environment and sense them when present in their proximity. Using this strategy, a cell estimates the number of neighbors in its surrounding. Upon sensing a critical number of individuals, bacteria coordinate a number of cellular processes. This density dependent control of gene expression and physiology is called quorum sensing (QS). Quorum sensing controls a wide variety of functions in bacteria, including those related to motility, growth, virulence etc. Quorum sensing has been widely observed in bacteria while the individuals of the same species or different species compete and cooperate each other. Interestingly, many species possess more than one QS system (intra-species) and these QS systems interact each other to perform quorum sensing. Thus, several logical arrangements can be possible based on the interaction among intra-species QS systems - parallel, series, antagonizing, and agonizing. In this work, we perform simulations to understand the logic of interaction between two antagonizing intra-species QS systems. In such an interaction, one QS system gets fully expressed and the other only gets partially expressed. This is found to be dictated by the interplay between autoinducer's diffusivity and antagonizing strength. In addition, we speculate an important role of the intracellular regulators (eg. LuxR) in maintaining the uniform response among the individual cells from the different localities. We also expect the interplay between the autoinducer's diffusivity and distribution of cells in fine tuning the collective response. Interestingly, in a localized niche with a heterogeneous cell distribution, the cells are expected to perform a global quorum sensing via fully expressed QS system and a local quorum sensing via partially expressed QS system. PMID- 29407384 TI - Regulation of compensatory growth by molecular mechanism in Labeo rohita juveniles under different feeding regimes. AB - A study was carried out to assess the regulation of compensatory growth under different restriction feeding regimes in Labeo rohita juveniles by the interaction of various feed intake and growth regulating genes. A 60 day feeding trial was conducted with five treatment groups, Control (3% body weight, bw), T1 (alternate days), T2 (0.5% bw), T3 (1% bw) and T4 (2% bw) and feeding was done for first 30 days of the trial. For next 30 days, all the treatment groups were fed at a rate of 3% bw as in the control group. There was significant (p < 0.05) difference in the weight gain among the treatment groups with lowest FCR and highest PER was found in T2 group. Ghrelin gene mRNA levels were upregulated during first 30th days of the trial with highest expression levels in the T2 group. The expression levels of leptin gene mRNA were found significantly different (p < 0.05) among the treatments, which was down-regulated during initial 30 days and upregulated as the experiment progress towards 60th day. The IGF-1 mRNA expression levels were upregulated more in liver compared to the muscle tissue. The results of the study suggest that increased ghrelin levels and decreased leptin levels lead to hyperphagia during the onset of refeeding, which further triggers the compensatory growth in L. rohita. The present study describes the molecular mechanism behind the compensatory growth following a different feed restriction regime in L. rohita which is regulated due to the interaction of different energy homeostasis and growth regulating genes. PMID- 29407386 TI - Impact of Lactobacillus curvatus 54M16 on microbiota composition and growth of Listeria monocytogenes in fermented sausages. AB - Lactobacillus curvatus 54M16 produced bacteriocins sak X, sak Talpha, sak Tbeta and sak P. The aim of this study was to investigate the anti-listerial activity of the bacteriocins-producing strain against Listeria monocytogenes in vitro co culture experiments and during the manufacture of fermented sausages. In MRS broth, Lb. curvatus 54M16 was able to inhibit L. monocytogenes to undetectable levels after 48 h at 20 degrees C or 5 days at 15 degrees C. Anti-listerial activity was lower during the production of fermented sausages with pathogen inoculation at levels of approximately 4 Log CFU g-1. However, total inhibition of L. monocytogenes native to the raw ingredients was achieved over the course of the fermentation. Moreover, 16S rRNA-based analysis revealed the ability of Lb. curvatus 54M16 to dominate and affect the bacterial ecosystem, whereas spoilage associated bacterial genera, such as Brochothrix, Psychrobacter, Pseudomonas and some Enterobacteriaceae, were found until the end of ripening in sausages without Lb. curvatus 54M16. The use of the bacteriocins-producing Lb. curvatus 54M16 in fermented sausages could be an important contribution to product safety, provided that eco-physiological factors and other preservation methods are maintained at levels required for the inhibition of pathogens in controlled conditions. PMID- 29407385 TI - Cell-based assay using glutathione-depleted HepaRG and HepG2 human liver cells for predicting drug-induced liver injury. AB - Immortalized liver cells have been used for evaluating the toxicity of compounds; however, excessive glutathione is considered to lessen cytotoxicity. In this study, we compared the effects of glutathione depletion on cytotoxicities of drugs using HepaRG and HepG2 cells, which express and lack drug-metabolizing enzymes, respectively, for predicting drug-induced liver injury (DILI) risks. These cells were pre-incubated with L-buthionine-S,R-sulfoximine (BSO) and then exposed to 34 test compounds with various DILI risks for 24 h. ATP level exhibited the highest predictability of DILI among tested parameters. BSO treatment rendered cells susceptible to drug-induced cytotoxicity when evaluated by cell viability and caspase 3/7 activity with the sensitivity of cell viability from 50% in non-treated HepaRG cells to 71% in BSO-treated HepaRG cells. These results indicate that cytotoxicity assays using GSH-depleted HepaRG cells improve the predictability of DILI risks. However, HepaRG cells were not always superior to HepG2 cells when assessed by ATP level. The combination of HepG2 and HepaRG cells index produced the best prediction in the cases of caspase 3/7 acitivity and ATP level. In conclusions, the developed highly sensitive cell-based assay using GSH-reduced cells would be useful for predicting potential DILI risks at an early stage of drug development. PMID- 29407387 TI - Bacterial and fungal microbiota of spontaneously fermented Chinese products, Rubing milk cake and Yan-cai vegetable pickles. AB - The Rubing milk cake from Yunnan and the Yan-cai vegetable pickles from Guangdong are traditional spontaneously fermented foods in China. We evaluated the microbial properties of these products with the analysis of their bacterial and fungal microbiota using classical culture-dependent and culture-independent methods, including a 16S rDNA gene (V4) and an internal transcribed spacer (ITS) region pyrosequencing method with MiSeq system. The viable lactic acid bacteria (LAB) count was 8 and 6 log colony-forming units (CFU)/g in Rubing and Yan-cai samples, respectively. The yeast count was approximately 100-1000 times less than the LAB count in most samples, except one Yan-cai sample. In addition, the gram negative rod count in half of the samples was similar to the LAB count. Pyrosequencing results revealed the high abundance (10%-20%) of gram-negative Pseudomonas spp. and Enterobacteriaceae in these samples. These results suggest that some of these traditional foods are undesirable as ready-to-eat (RTE) foods, even when these are typical lactic acid fermented foods. PMID- 29407388 TI - Effects of lowering water activity by various humectants on germination of spores of Bacillus species with different germinants. AB - The effect of water activity (aw), as lowered by different dietary humectants, on the germination of Bacillus subtilis, Bacillus megaterium and Bacillus cereus spores with germinants that act by different mechanisms has been investigated and compared. Germination of spores of these species by all of the germinants investigated was inhibited as aw decreased, with the general order of efficacy for these non-ionic humectants being sucrose > trehalose > glycerol. The effect of lowering aw on germination by germinant receptor (GR)-dependent germinants was not appreciably altered by varying germinant concentrations, was generally not much more effective with spores lacking coats or an outer membrane, and was less pronounced with heat-activated spores. Analysis of the effect of aw on spore germination via different mechanisms showed that GR-dependent germination was least sensitive to aw, while germination via activation of spore cortex peptidoglycan hydrolysis or dipicolinic acid release was more sensitive. However, germination by high hydrostatic pressure was less sensitive to inhibition by low aw, than was germination by other germinants. Examination of the GR-dependent germination of individual spores indicated that aw acted most strongly in inhibiting the commitment step of germination, while exerting smaller effects on dipicolinic acid release or cortex peptidoglycan hydrolysis. PMID- 29407390 TI - Evaluation of fingerprinting techniques to assess genotype variation among Zygosaccharomyces strains. AB - Molecular typing techniques are key tools in surveillance of food spoilage yeasts, in investigations on intra-species population diversity, and in tracing selected starters during fermentation. Unlike previous works on strain typing of Zygosaccharomyces spoilage species, here Zygosaccharomyces mellis and the Zygosaccharoymces rouxii complex yeasts, which include Z. rouxii, Zygosaccharomyces sapae, and a mosaic lineage (ML) of putatively hybrids, were evaluated by three typing methods for intra- and inter-species resolution. Overall these yeasts are relevant for food fermentation and spoilage, but are quite difficult to discriminate at strain and species level as they evolved by reticulation. A pool of 76 strains from different sources were typed by M13 and (GTG)5 MSP-PCR fingerprinting and PCR-RFLP of ribosomal intergenic spacer region (IGS). We demonstrated that M13 overcame (GTG)5 fingerprinting to group Z. sapae, Z. rouxii, Z. mellis and the ML isolates in congruent distinct clusters. Even if (GTG)5 primer yielded a number of DNA fingerprints comparable with those obtained by M13 primer, it failed to discriminate Z. sapae, Z. mellis and Z. rouxii at species level. Clustering of IGS RFLP patterns obtained with three endonucleases produced groups congruent with species assignment and highlighted intra-species diversity similar to that observed by M13 fingerprinting. However, IGS PCR amplification failed for 14 ML and 6 Z. mellis strains under the experimental conditions tested here, indicating that this marker could be less easy to use in fast typing protocol. Finally, our results posit that the genetic diversity within Z. sapae and Z. mellis could be shaped by isolation source. The information generated in this study would facilitate the monitoring of these yeasts during food processing and storage, and provides preliminary evidences about Z. sapae and Z. mellis intra-species diversity. PMID- 29407389 TI - Antimicrobial behavior of phage endolysin PlyP100 and its synergy with nisin to control Listeria monocytogenes in Queso Fresco. AB - Hispanic-style fresh cheeses, such as Queso Fresco (QF), have been linked to numerous listeriosis outbreaks in the United States. In this work, we have studied the antilisterial behavior and effectiveness of the Listeria phage endolysin PlyP100 in QF, as well as the potential synergy between PlyP100 and nisin. PlyP100 showed similar bacterial reduction regardless of varying L. monocytogenes inoculum size in QF, and when the inoculation size was 1 Log CFU/g, no pathogen recovery after cheese enrichment was observed. PlyP100 was stable in QF for up to 28 days of cold storage exhibiting similar antilisterial activity regardless of when contamination with L. monocytogenes occurred. PlyP100 alone exhibited a strong listeriostatic effect in QF, on the contrary, nisin alone was not effective to control the pathogen in QF during cold storage. The combination of nisin and PlyP100 showed a strong synergy in QF with non-enumerable levels of L. monocytogenes after 4 weeks of refrigerated storage. Moreover, L. monocytogenes isolates from cheeses treated with nisin, PlyP100, and their combination did not develop resistance to nisin or PlyP100. Our results support the use of PlyP100 combined with nisin as an efficient L. monocytogenes control measure in QF. PMID- 29407391 TI - Effect of several packaging conditions on the microbiological, physicochemical and sensory properties of ostrich steaks during refrigerated storage. AB - A total of 365 ostrich steaks were packaged in air (AIR), vacuum (VAC), MAP1 (70% O2 + 30% CO2), MAP2 (30% O2 + 30% N2 + 40% CO2), MAP3 (20% O2 + 30% N2 + 50% CO2), MAP4 (50% N2 + 50% CO2), MAP5 (20% N2 + 80% CO2) or MAP6 (100% CO2). Microbial counts (10 groups), pH, Aw and sensory properties (nine-point hedonic scale) were determined on days 0, 1, 3, 7 and 15 of storage (4 degrees C). On day 0, microbial counts (log10 cfu/g) ranged from undetectable levels (Brochothrix thermosphacta, enterococci) to 3.21 +/- 0.63 (total aerobic counts TAC-). The highest and the lowest microbial loads throughout storage were observed in AIR and MAP6, respectively. On day 15 TAC as high as 9.96 +/- 0.20 log10 cfu/g were found in AIR. The shelf-life (time until overall acceptability score fell below 5) was 3 days (MAP1, MAP2), 7 days (MAP3, AIR) or 15 days (MAP4, MAP5, MAP6). Only for VAC the shelf-life limit extended beyond 15 days. PMID- 29407392 TI - Comparison of the effect of saturated and superheated steam on the inactivation of Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes on cantaloupe and watermelon surfaces. AB - The purpose of this study was evaluation of the effectiveness of superheated steam (SHS) on inactivation of foodborne pathogens on cantaloupes and watermelons. Saturated steam (SS) treatment was performed at 100 degrees C and that of SHS at 150 and 200 degrees C. Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes-inoculated cantaloupes and watermelons were exposed for a maximum of 30 s and 10 s, respectively. Populations of the three pathogens on cantaloupes and watermelons were reduced by more than 5 log after 200 degrees C steam treatment for 30 s and 10 s, respectively. After SHS treatment of cantaloupes and watermelons for each maximum treatment time, color and maximum load values were not significantly different from those of untreated controls. By using a noncontact 3D surface profiler, we found that surface characteristics, especially surface roughness, is the main reason for differences in microbial inactivation between cantaloupes and watermelons. The results of this study suggest that SHS treatment can be used as an antimicrobial intervention for cantaloupes and watermelons without inducing quality deterioration. PMID- 29407393 TI - Functional cream cheese supplemented with Bifidobacterium animalis subsp. lactis DSM 10140 and Lactobacillus reuteri DSM 20016 and prebiotics. AB - The aim of this study was to develop a functional fresh cream cheese with Bifidobacterium animalis subsp. lactis DSM 10140 or Lactobacillus reuteri DSM 20016 and prebiotics (inulin, FOS and lactulose). The research was divided into two steps: in vitro evaluation of the effects of prebiotic compounds; validation at laboratory level with production of functional cream mini-cheeses. Prebiotics showed a protective effect: B. animalis subsp. lactis DSM 10140 cultivability on Petri dishes was positively influenced by lactulose, whereas fructooligosaccharides (FOS) were the prebiotic compounds able to prolong Lb. reuteri DSM 20016 cultivability. At 30 degrees C, a prolongation of the death time (more than 300 days) was observed, while the controls showed death time values about 100 days. At 45 degrees C, death time values increased from 32.2 (control) to 33, 35, and 38 days in the samples added with FOS, inulin and lactulose, respectively. Lactulose and FOS were chosen to be added to cream mini cheeses inoculated with B. animalis subsp. lactis DSM 10140 and Lb. reuteri DSM 20016, respectively; the proposed functional cream cheese resulted in a product with favourable conditions for the viability of both probiotics which maintained cultivable cells above the recommended level during 28 days of storage at 4 degrees C with good sensory characteristics. PMID- 29407394 TI - Probability models for growth and aflatoxin B1 production as affected by intraspecies variability in Aspergillus flavus. AB - The probability of growth and aflatoxin B1 (AFB1) production of 20 isolates of Aspergillus flavus were studied using a full factorial design with eight water activity levels (0.84-0.98 aw) and six temperature levels (15-40 degrees C). Binary data obtained from growth studies were modelled using linear logistic regression analysis as a function of temperature, water activity and time for each isolate. In parallel, AFB1 was extracted at different times from newly formed colonies (up to 20 mm in diameter). Although a total of 950 AFB1 values over time for all conditions studied were recorded, they were not considered to be enough to build probability models over time, and therefore, only models at 30 days were built. The confidence intervals of the regression coefficients of the probability of growth models showed some differences among the 20 growth models. Further, to assess the growth/no growth and AFB1/no- AFB1 production boundaries, 0.05 and 0.5 probabilities were plotted at 30 days for all of the isolates. The boundaries for growth and AFB1 showed that, in general, the conditions for growth were wider than those for AFB1 production. The probability of growth and AFB1 production seemed to be less variable among isolates than AFB1 accumulation. Apart from the AFB1 production probability models, using growth probability models for AFB1 probability predictions could be, although conservative, a suitable alternative. Predictive mycology should include a number of isolates to generate data to build predictive models and take into account the genetic diversity of the species and thus make predictions as similar as possible to real fungal food contamination. PMID- 29407395 TI - Antimicrobial efficacy of Syzygium antisepticum plant extract against Staphylococcus aureus and methicillin-resistant S. aureus and its application potential with cooked chicken. AB - For the past decades, there has been a growing demand for natural antimicrobials in the food industry. Plant extracts have attracted strong research interests due to their wide-spectrum antimicrobial activities, but only a limited number have been investigated thoroughly. The present study aimed at identifying a novel anti staphylococcal plant extract, to validate its activity in a food model, and to investigate on its composition and antimicrobial mechanism. Four plant extracts were evaluated against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in vitro, with Syzygium antisepticum leaf extract showing the strongest antimicrobial activity (MIC = 0.125 mg/mL). Relatively high total phenolic content (276.3 mg GAE/g extract) and antioxidant activities (90.2-138.0 mg TE/g extract) were measured in S. antisepticum extract. Food validation study revealed that higher extract concentration (32 mg/mL) was able to inhibit or reduce staphylococcal growth in cooked chicken, but caused color change on meat surface. By GC-MS, beta-caryophyllene (12.76 area%) was identified as the dominant volatile compound in extract. Both crude extract and pure beta-caryophyllene induced membrane damages in S. aureus. These results suggested good anti staphylococcal properties of S. antisepticum plant extract, identified its major volatile composition and its membrane-damaging antimicrobial mechanism. PMID- 29407396 TI - Effects of microbial diversity on nitrite concentration in pao cai, a naturally fermented cabbage product from China. AB - Pao cai is a spontaneously fermented cabbage where native bacteria may have an important influence on nitrite content during fermentation. In this research, we used metagenomic-based 16S rRNA gene amplicon sequencing to analyze differences in bacterial composition of pao cai from Hohhot City (northern China) and Guiyang City (southern China). Alongside this, metagenome functional features from the 16S rRNA genes of the microbiome were predicted and correlated with the nitrite content of pao cai. Nitrite-reducing bacterial genera were identified including Lactobacillus (73.37%), Pediococcus (0.93%), Acinetobacter (0.74%), Leuconostoc (0.31%), Weissella (0.14%), Streptococcus (0.09%), Megamonas (0.08%), Enterococcus (0.07%), and Alistipes (0.06%). Lactobacillus was the predominant genus in both the northern and the southern pao cai samples and was significantly negatively correlated with nitrite content; it was more abundant in southern samples than northern samples. Based on determination of alpha and beta diversities of the microbiome in samples, differences in the microbiome of northern and southern pao cai were demonstrated that may influence nitrogen metabolism. This research suggests that 16S rRNA gene amplicon sequencing is an effective way to comprehensively study the microbes with potential nitrite formation or decomposition ability instead of investigating the individual bacterial genera. PMID- 29407397 TI - Influence of ethanol adaptation on Salmonella enterica serovar Enteritidis survival in acidic environments and expression of acid tolerance-related genes. AB - Cross-protection to environmental stresses by ethanol adaptation in Salmonella poses a great threat to food safety because it can undermine food processing interventions. The ability of Salmonella enterica serovar Enteritidis (S. Enteritidis) to develop acid resistance following ethanol adaptation (5% ethanol for 1 h) was evaluated in this study. Ethanol-adapted S. Enteritidis mounted cross-tolerance to malic acid (a two-fold increase in minimum bactericidal concentration), but not to acetic, ascorbic, lactic, citric and hydrochloric acids. The population of S. Enteritidis in orange juice (pH 3.77) over a 48-h period was not significantly (p > 0.05) influenced by ethanol adaptation. However, an increased survival by 0.09-1.02 log CFU/ml was noted with ethanol adapted cells of S. Enteritidis compared to non-adapted cells in apple juice (pH 3.57) stored at 25 degrees C (p < 0.05), but not at 4 degrees C. RT-qPCR revealed upregulation of two acid tolerance-related genes, rpoS (encoding sigmaS) and SEN1564A (encoding an acid shock protein), following ethanol adaptation. The relative expression level of the acid resistance gene hdeB did not change. The resistance phenotypes and transcriptional profiles of S. Enteritidis suggest some involvement of rpoS and SEN1564A in the ethanol-induced acid tolerance mechanism. PMID- 29407398 TI - Survival of foodborne pathogens on commercially packed table grapes under simulated refrigerated transit conditions. AB - We examined the survival of Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella enterica Thompson inoculated on commercially packed table grapes under simulated refrigerated transit conditions (1.1 +/- 0.5 degrees C; 90% RH). Grapes were placed in perforated polyethylene cluster bags, within a commercial expanded polystyrene box equipped with either a SO2-generating pad; a perforated polyethylene box liner; a SO2-generating pad and a box liner; or none of them. L. monocytogenes was most sensitive to SO2-generating pad. SO2-generating pad or SO2 generating pad with box liner inactivated this pathogen completely on day 12 following the inoculation. S. enterica Thompson displayed a similar cold sensitivity as L. monocytogenes, but was more resistant to SO2-generating pad than L. monocytogenes. While SO2-generating pad eliminated S. enterica Thompson on day 20, a combination of box liner with SO2-generating pad inactivated this pathogen completely on day 13. E. coli O157:H7 had the highest tolerance to transit temperature and to SO2-generating pad; SO2-generating pad inactivated this pathogen completely on Day 20. Our data suggest that use of SO2-generating pad combined with box liner is effective in reducing foodborne pathogens L. monocytogenes and S. enterica Thompson, while the use of SO2-generating pad alone was more effective on E. coli O157:H7. PMID- 29407399 TI - Assessment of Salmonella spp. and Escherichia coli O157:H7 growth on lettuce exposed to isothermal and non-isothermal conditions. AB - This study aimed to assess the growth of Salmonella and Escherichia coli O157:H7 on lettuce exposed to isothermal and non-isothermal conditions. Pathogens were inoculated on lettuce separately and stored under isothermal condition at 5 degrees C, 10 degrees C, 25 degrees C, 37 degrees C for both bacteria, at 40 degrees C for Salmonella and 42 degrees C for E. coli O157:H7. Growth curves were built by fitting the data to the Baranyi's DMFit, generating R2 values greater than 0.92 for primary models. Secondary models were fitted with Ratkowsky equations, generating R2 values higher than 0.91 and RMSE lower than 0.1. Experimental data showed that both bacteria could grow at all temperatures. Also, the growth of both pathogens under non-isothermal conditions was studied simulating temperatures found from harvest to supermarkets in Brazil. Models were analysed by R2, RMSE, bias factor (Bf) and accuracy factor (Af). Salmonella and E. coli O157:H7 were able to grow in this temperature profile and the models could predict the behavior of these microorganisms on lettuce under isothermal and non-isothermal conditions. Based on the results, a negligible growth time (sigma) was proposed to provide the time which lettuce could be exposed to a specific temperature and do not present an expressive growth of bacteria. The sigma was developed based on Baranyi's primary model equation and on growth potential concept. sigma is the value of lag phase added of the time necessary to population grow 0.5 log CFU/g. The sigma of lettuce exposed to 37 degrees C was 1.3 h, while at 5 degrees C was 3.3 days. PMID- 29407400 TI - Mechanistic modelling of the inhibitory effect of pH on microbial growth. AB - Modelling and simulation of microbial dynamics as a function of processing, transportation and storage conditions is a useful tool to improve microbial food safety and quality. The goal of this research is to improve an existing methodology for building mechanistic predictive models based on the environmental conditions. The effect of environmental conditions on microbial dynamics is often described by combining the separate effects in a multiplicative way (gamma concept). This idea was extended further in this work by including the effects of the lag and stationary growth phases on microbial growth rate as independent gamma factors. A mechanistic description of the stationary phase as a function of pH was included, based on a novel class of models that consider product inhibition. Experimental results on Escherichia coli growth dynamics indicated that also the parameters of the product inhibition equations can be modelled with the gamma approach. This work has extended a modelling methodology, resulting in predictive models that are (i) mechanistically inspired, (ii) easily identifiable with a limited work load and (iii) easily extended to additional environmental conditions. PMID- 29407401 TI - Antibiotic susceptibility of methicillin-resistant staphylococci (MRS) of food origin: A comparison of agar disc diffusion method and a commercially available miniaturized test. AB - Methicillin-resistant staphylococci (MRS) are a major concern to public and animal health. Thirty MRS (Staphylococcus aureus, S. cohnii, S. epidermidis, S. haemolyticus, S. hominis, S. lentus, S. lugdunensis, S. sciuri, and S. xylosus) isolates from meat and poultry preparations were tested for antimicrobial susceptibility to 11 antimicrobials (belonging to seven different categories) of clinical significance using both the standard agar disc diffusion method and a commercially available miniaturized system (Sensi Test Gram-positive). It is worth stressing that 16 isolates (53.33%) exhibited an extensively drug-resistant phenotype (XDR). The average number of resistances per strain was 4.67. These results suggest that retail meat and poultry preparations are a likely vehicle for the transmission of multi-drug resistant MRS. Resistance to erythromycin was the commonest finding (76.67% of strains), followed by tobramycin, ceftazidime (66.67%), ciprofloxacin (56.67%) and fosfomycin (53.33%). An agreement (kappa coefficient) of 0.64 was found between the two testing methods. Using the agar disc diffusion as the reference method, the sensitivity, specificity and accuracy of the miniaturized test were 98.44%, 69.44% and 83.33%, respectively. Most discrepancies between the two methods were due to isolates that were susceptible according to the disc diffusion method but resistant according to the miniaturized test (false positives). PMID- 29407402 TI - Detection of Cronobacter species in powdered infant formula using immunoliposome based immunomagnetic concentration and separation assay. AB - Cronobacter species are foodborne pathogens that can affect the human central nervous system. Survivors of Cronobacter infections often suffer from severe neurological impairments, including hydrocephalus, quadriplegia, and developmental delays in all ages, especially in infants and the immunocompromised. Moreover, Cronobacter species pose a high risk in powdered infant formula (PIF) because PIF is a major source of nutrition for infants worldwide. To develop a rapid and sensitive detection method for Cronobacter species in PIF, immunoliposomes and immunomagnetic nanoparticles were synthesized, after which an immunoliposome-based immunomagnetic concentration and separation assay was developed and applied to PIF for the detection of Cronobacter species. The detection limits of the developed assay were 5.9 * 103 +/- 0.7-4.8 * 104 +/- 0.2 CFU/mL for Cronobacter species in pure culture with no cross-reactivity with 13 other tested non-Cronobacter strains. Additionally, the developed assay could provide results in 3 h when the contaminated level was higher than 104 CFU/25 g PIF and in 9 h when the contaminated level was 10 CFU/25 g PIF. The developed immunoliposome-based immunomagnetic concentration and separation assay is rapid, sensitive, and simple and thus has great potential for use in the detection of Cronobacter species in PIF. PMID- 29407403 TI - Proteomic analysis of Lactobacillus pentosus for the identification of potential markers involved in acid resistance and their influence on other probiotic features. AB - Acidity often prevents the undesirable microbial colonization both in fermented foods and under gastric conditions. Thus, the acid resistance of Lactobacillus pentosus strains used as starter cultures and/or probiotics requires further understanding. This was investigated by means of comparative proteomic approach using three strains representing the phenotypes: resistant (AP2-15), intermediate (AP2-18) and sensitive (LP-1) to acidic conditions. Proteomic analysis of constitutive phenotypes revealed that the intrinsic resistance of L. pentosus is associated with the over-production of three principal proteins: 2,3 bisphosphoglycerate-dependent phosphoglycerate mutase 2 (PGAM-d), elongation factor G and 50S ribosomal protein L10, and additionally on ATP synthase subunit beta and chaperone protein DnaK; they are associated with metabolic pathways of proteins and carbohydrates, energy production and stress responses. Suggested protein biomarkers for acid resistance in L. pentosus include elongation factor G and PGAM-d, both being abundantly found in the constitutive proteome of the resistant phenotype under standard and acidic conditions. Furthermore, L. pentosus strains pre-exposed to acids displayed enhanced probiotic function such as auto-aggregation ability via surface proteins. We conclude that pre-exposure of probiotic L. pentosus strains to acid may strategically enhance their performance as starter cultures and probiotics. PMID- 29407404 TI - Novel sanitization approach based on synergistic action of UV-A light and benzoic acid: Inactivation mechanism and a potential application in washing fresh produce. AB - Antimicrobial activity of the simultaneous UV-A light and benzoic acid (BA) treatment against stationary phase Escherichia coli O157:H7 was investigated. While 15 mM BA or UV-A light exposure for 30 min alone caused < 1 logarithmic reduction in the bacterial population, > 5 logarithmic reductions were induced by the simultaneous application of UV-A and 15 mM BA in 30 min, demonstrating a synergistic antimicrobial effect. Due to its ability to increase cell membrane permeability, addition of EDTA (1 mM) was able to decrease the required concentration of BA in the simultaneous treatment from 15 to 8 mM. Microbial inactivation was a result of simultaneous membrane damage, intracellular acidification, and intracellular oxidative stress. The simultaneous treatment was effective in the presence of organic load of up to 500 mg/L of chemical oxygen demand (COD) and was able to lower cross-contamination risk during simulated washing of spinach (Spinacia oleracea) without adversely affecting its color. PMID- 29407405 TI - Bioflavoring by non-conventional yeasts in sequential beer fermentations. AB - Non-conventional yeast species have great capacity for producing diverse flavor profiles in production of alcoholic beverages, but their potential for beer brewing, in particular in consecutive fermentations with Saccharomyces cerevisiae, has only poorly been explored. We have screened 17 non-conventional yeast species for production of an appealing profile of flavor esters and phenolics in the first phase of alcoholic fermentation, followed by inoculation with S. cerevisiae to complete the fermentation. For measurement of phenolic compounds and their precursors we developed an improved and highly sensitive methodology. The results show that non-conventional yeast species possess promising potential for enhancement of desirable flavors in beer production. Notable examples are increasing isoamyl acetate (fruity, banana flavor) by application of P. kluyverii, augmenting ethyl phenolic compounds (spicy notes) with Brettanomyces species and enhancing 4-vinyl guaiacol (clove-like aroma) with T. delbrueckii. All Pichia strains also produced high levels of ethyl acetate (solvent-like flavor). This might be selectively counteracted by selection of an appropriate S. cerevisiae strain for the second fermentation phase, which lowers total ester profile. Hence, optimization of the process conditions and/or proper strain selection in sequentially inoculated fermentations are required to unlock the full potential for aroma improvement by the non-conventional yeast species. PMID- 29407406 TI - Effect of Aureobasidium pullulans strains against Botrytis cinerea on kiwifruit during storage and on fruit nutritional composition. AB - Kiwifruit, wounded at the equator or by pedicel removal, to simulate the stem end wound, were treated with Aureobasidium pullulans (L1 and L8 strains) and subsequently inoculated with conidia of Botrytis cinerea. Fruits were stored at 1 degrees C in normal refrigeration (NR) or in controlled atmosphere (CA) (2% O2; 4.5% CO2). After 4 months, both antagonists significantly reduced the disease in all experiments, L1 better than L8. In NR, their efficacy was higher than 80%. In CA, the disease reduction was lower: between 30% (L1) and 60% (L8). The ability of both strains to compete with the pathogen for nutrients was tested in kiwifruit juice (0.5%) by in vitro experiments. Antagonists significantly reduced pathogen conidia germination in water and in juice. An HPLC analysis was performed to define the amino acid composition of kiwifruit juice upon L1 and L8 treatment. L1 and L8 greatly increased the concentration of both glutamic and aspartic acids and stimulated the production of new amino acids, although at low concentrations. Each amino acid displayed an antifungal effect against mycelium growth of B. cinerea. Finally, L1 and L8, cold tolerant and active strains in CA, can be effectively applied to control the stem end rot of kiwifruit in long storage. PMID- 29407407 TI - Influence of heat processing on the volatile organic compounds and microbial diversity of salted and vacuum-packaged silver carp (Hypophthalmichthys molitrix) fillets during storage. AB - Ready-to-eat products have become popular with most of the busy people in modern cities. Heat processing combined with vacuum-packaging is one of the most common methods to make ready-to-eat products with an extended shelf-life. In this study, the influence of heat processing [80 degrees C (LT) and 98 degrees C (HT) in water bath] on the quality of salted and vacuum-packaged silver carp (Hypophthalmichthys molitrix) fillets, stored at 20 +/- 1 degrees C, was investigated by sensory analysis, biochemical analysis, and microbial diversity. SPME-GC/MS indicated the presence of 27 volatile organic compounds (VOCs) in fillets, and major VOCs were aldehydes and alcohols. Acids tended to increase during storage and caused a fetid odor at the end of storage. Culture-dependent method indicated that Bacillus dominated the spoiled LT and HT samples. In addition, Bacillus was identified as the main spoiler of deteriorated heated fillets by high-throughput sequencing. Sphingomonas and Brevibacillus dominated the indigenous bacteria of fresh raw fillets. After heat processing, LT samples exhibited higher organoleptic quality than HT samples on day 0. HT samples showed extended shelf-life at 20 degrees C storage compared to LT samples. PMID- 29407408 TI - Molecular characterization and drug susceptibility of non-O1/O139 V. cholerae strains of seafood, environmental and clinical origin, Italy. AB - Toxigenic and antimicrobial susceptibility patterns and genetic relatedness of 42 non-O1/O139 V. cholerae strains, the majority of them isolated from seafood and marine water of the Adriatic sea, Italy, and 9 clinical strains, two of which with seawater of the Adriatic as the source of infection, were studied. All strains had hlyA El Tor gene but lacked ctxA gene. Four and two isolates, respectively, also had stn/sto and tcpA Class genes. More than 90% of strains showed susceptibility to cefotaxime, ciprofloxacin, cloramphenicol, tetracycline, trimethoprim + sulfamethoxazole and intermediate or full resistance to tetracycline and erythromycin. Six strains of seafood and clinical source were multi-drug resistant. PFGE analysis allowed to type all the strains with 50 banding patterns. Twenty-one strains, 11 and 8 from seafood and seawater, respectively, and 2 of clinical origin, were grouped into 9 different clusters. We report the presence of toxigenic and multidrug resistant non-O1/O139 V. cholerae strains in Adriatic, some of which genetically related, and support that they represent a potential reservoir of toxin and antibiotic resistance genes. PMID- 29407409 TI - Rationalizing and advancing the 3-MPBA SERS sandwich assay for rapid detection of bacteria in environmental and food matrices. AB - Bacterial foodborne illness continues to be a pressing issue in our food supply. Rapid detection methods are needed for perishable foods due to their short shelf lives and significant contribution to foodborne illness. Previously, a sensitive and reliable surface-enhanced Raman spectroscopy (SERS) sandwich assay based on 3 mercaptophenylboronic acid (3-MBPA) as a capturer and indicator molecule was developed for rapid bacteria detection. In this study, we explored the advantages and constraints of this assay over the conventional aerobic plate count (APC) method and further developed methods for detection in real environmental and food matrices. The SERS sandwich assay was able to detect environmental bacteria in pond water and on spinach leaves at higher levels than the APC method. In addition, the SERS assay appeared to have higher sensitivity to quantify bacteria in the stationary phase. On the other hand, the APC method was more sensitive to cell viability. Finally, a method to detect bacteria in a challenging high-sugar juice matrix was developed to enhance bacteria capture. This study advanced the SERS technique for real applications in environment and food matrices. PMID- 29407410 TI - Effect of storage conditions in the response of Listeria monocytogenes in a fresh purple vegetable smoothie compared with an acidified TSB medium. AB - In this study, growth and/or inactivation of Listeria monocytogenes 4032 at different inoculum levels in a vegetable smoothie with purple colour, (previously heat stabilised at 95 degrees C for 3 min) was evaluated. Growth/inactivation was compared with acidified TSB medium at the same pH level with HCl. Samples were stored at different temperatures (5, 10, 15 and 25 degrees C). All the smoothies stored at 15 and 25 degrees C showed growth up to 7.5-8.0 log CFU/mL and at 10 degrees C growth was only observed at the highest inoculum level. Growth was only observed at 25 degrees C in acidified TSB. In the case of the smoothies inoculated and stored at 5 degrees C, L. monocytogenes was not able to grow but survived for a long period of time, whereas at the lower inocula at 10 degrees C they presented a slow inactivation for an extended time. Acidified TSB inoculated and stored showed inactivation at 5, 10 and 15 degrees C. Best inactivation modelling alternatives are proposed. The differences between the smoothie and TSB medium about growth or survival in this study, even at relatively low pH values, were due to the favorable nutritional composition of the smoothie compared to a laboratory medium. Results in this study can allow to design safe conditions for smoothie production. PMID- 29407411 TI - Chronic amphetamine treatment affects collicular-dependent behaviour. AB - Distractibility can be defined as an attention deficit where orientation toward irrelevant targets cannot be inhibited. There is now mounting evidence that the superior colliculus is a key neural correlate of distractibility, with increased collicular-activity resulting in heightened distractibility. Heightened distractibility is reduced by amphetamine, which acutely suppresses collicular responsiveness. However, when amphetamine is used to treat distractibility, it is given chronically, yet no data exist on whether chronic amphetamine treatment affects the colliculus. Here, the effect of chronic amphetamine treatment was assessed in healthy hooded lister rats on two collicular dependent behaviours following a twenty-eight day treatment period: i) orienting to visual stimuli, and ii) height-dependent modulation of air-righting. We found no significant impact of amphetamine treatment on visual orienting despite showing dose dependent decreases in orienting to repeated stimuli. However, we did find that treatment with amphetamine significantly reduced the ability to modulate righting according to the height the animal is dropped from - a function known to be dependent on the colliculus. We suggest that the results are in line with previous research showing acute amphetamine suppresses collicular activity and we speculate that the psychostimulant may increase receptive field size, altering time-to-impact calculations carried out by the colliculus during air-righting. PMID- 29407412 TI - Nicotine-enhanced Pavlovian conditioned approach is resistant to omission of expected outcome. AB - Conditioned stimuli contribute to the resilience of nicotine addiction in that nicotine-associated cues can influence smokers and promote relapse. These stimuli are thought to acquire incentive motivational properties through a Pavlovian mechanism, and this phenomenon can be measured in animals by observing conditioned approach to the conditioned stimulus (sign-tracking) or to the location of unconditioned stimulus delivery (goal-tracking). Goal-tracking is thought to be more flexible than sign-tracking in response to changes in expected outcome. Nicotine exposure can increase the expression of conditioned responses, and we hypothesized that animals exposed to nicotine would also exhibit less flexible conditioned responses after a change in the expected unconditioned stimulus. Adult male rats were exposed to nicotine (0.4mg/kg, s.c.) or saline before Pavlovian conditioned approach training sessions. After training, animals underwent test sessions that reduced (water substitution) or withheld (omission) the unconditioned stimulus (US, 20% sucrose). As expected, nicotine enhanced sign and goal-tracking. Water substitution moderately and nonspecifically reduced both sign- and goal-tracking in all rats. In contrast, US omission only reduced goal-tracking, with robust effects in saline-exposed rats and smaller effects in nicotine-exposed rats. These data support the hypothesis that both sign-tracking and nicotine exposure confer behavioral inflexibility under US omission. PMID- 29407414 TI - Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome. AB - 3MC syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism and multiple anomalies. It is caused by biallelic mutations in one of three genes, MASP1, COLEC11 and COLEC10, all encoding factors of the lectin complement pathway. In MASP1, either truncating mutations or missense variants in exon 12 encoding the C-terminal serine protease domain specific for isoform MASP-3 are causative. By trio exome sequencing we now identified a novel, homozygous 2kb deletion, partially affecting exon 12 in an adult female with the typical facial gestalt of 3MC syndrome and hearing loss, but without the main feature cleft lip/palate, and without intellectual disability, or short stature. We therefore expand the MASP1 associated mutational and clinical spectrum and describe the development of her clinical presentation over a period of 21 years. As the homozygous deletion in our patient was only found by thorough and visual evaluation of the whole exome sequencing data, such deletions might escape detection in some routine diagnostic workflows and might explain a few of the so far molecularly unconfirmed cases of 3MC syndrome. PMID- 29407413 TI - Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein. AB - Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner. PMID- 29407415 TI - Waardenburg syndrome: Novel mutations in a large Brazilian sample. AB - This paper deals with the molecular investigation of Waardenburg syndrome (WS) in a sample of 49 clinically diagnosed probands (most from southeastern Brazil), 24 of them having the type 1 (WS1) variant (10 familial and 14 isolated cases) and 25 being affected by the type 2 (WS2) variant (five familial and 20 isolated cases). Sequential Sanger sequencing of all coding exons of PAX3, MITF, EDN3, EDNRB, SOX10 and SNAI2 genes, followed by CNV detection by MLPA of PAX3, MITF and SOX10 genes in selected cases revealed many novel pathogenic variants. Molecular screening, performed in all patients, revealed 19 causative variants (19/49 = 38.8%), six of them being large whole-exon deletions detected by MLPA, seven (four missense and three nonsense substitutions) resulting from single nucleotide substitutions (SNV), and six representing small indels. A pair of dizygotic affected female twins presented the c.430delC variant in SOX10, but the mutation, imputed to gonadal mosaicism, was not found in their unaffected parents. At least 10 novel causative mutations, described in this paper, were found in this Brazilian sample. Copy-number-variation detected by MLPA identified the causative mutation in 12.2% of our cases, corresponding to 31.6% of all causative mutations. In the majority of cases, the deletions were sporadic, since they were not present in the parents of isolated cases. Our results, as a whole, reinforce the fact that the screening of copy-number-variants by MLPA is a powerful tool to identify the molecular cause in WS patients. PMID- 29407416 TI - Extracellular biosynthesis of magnetic iron oxide nanoparticles by Bacillus cereus strain HMH1: Characterization and in vitro cytotoxicity analysis on MCF-7 and 3T3 cell lines. AB - Discovery of new properties and special functionalities at the nanoscale materials caused nanotechnology to become one of the leading parts in all sciences namely biology and medicine. Magnetic iron oxide nanoparticles (MIONPs) are among interesting nanomaterials in biomedical arena, which have attracted the attention of many researchers owing to their extensive capabilities. Due to the simple, cost-effective and environmentally-friendly production processes, biosynthesis is of paramount importance between different methods of nanoparticles production. In the current study, we succeeded to synthesize MIONPs using a newly extracted bacteria supernatant. Produced nanoparticles were characterized using FE-SEM, DLS, VSM, UV-vis, FT-IR and EDS spectroscopy. Analysis showed that the average particle size of very stable spherical MIONPs is about 29.3 nm. The bacteria protein profile obtained by SDS-PAGE analysis indicated induction of different proteins. In vitro cytotoxicity of nanoparticles on the viability of MCF7 and 3T3 cell lines was assessed by MTT assay. The results show that toxicity of the produced nanoparticles (IC50, MCF-7 > 5 mg/ml and IC50, 3T3 > 7.5 mg/ml) follows a concentration dependent manner. PMID- 29407417 TI - Construction of genetically engineered Candida tropicalis for conversion of l arabinose to l-ribulose. AB - For the biological production of l-ribulose, conversion by enzymes or resting cells has been investigated. However, expensive or concentrated substrates, an additional purification step to remove borate and the requirement for cell cultivation and harvest steps before utilization of resting cells make the production process complex and unfavorable. Microbial fermentation may help overcome these limitations. In this study, we constructed a genetically engineered Candida tropicalis strain to produce l-ribulose by fermentation with a glucose/l-arabinose mixture. For the uptake of l-arabinose as a substrate and conversion of l-arabinose to l-ribulose, two heterologous genes coding for l arabinose transporter and l-arabinose isomerase, were constitutively expressed in C. tropicalis under the GAPDH promoter. The Arabidopsis thaliana-originated l arabinose transporter gene (STP2)-expressing strain exhibited a high l-arabinose uptake rate of 0.103 g/g cell/h and the expression of l-arabinose isomerase from Lactobacillus sakei 23 K showed 30% of conversion (9 g/L) from 30 g/L of l arabinose. This genetically engineered strain can be used for l-ribulose production by fermentation using mixed sugars of glucose and l-arabinose. PMID- 29407418 TI - Soil metagenome-derived 3-hydroxypalmitic acid methyl ester hydrolases suppress extracellular polysaccharide production in Ralstonia solanacearum. AB - Autoinducers are indispensable for bacterial cell-cell communication. However, due to the reliance on culture-based techniques, few autoinducer-hydrolyzing enzymes are known. In this study, we characterized soil metagenome-derived unique enzymes capable of hydrolyzing 3-hydroxypalmitic acid methyl ester (3-OH PAME), an autoinducer of the plant pathogenic bacterium Ralstonia solanacearum. Among 146 candidate lipolytic clones from a soil metagenome library, 4 unique enzymes capable of hydrolyzing the autoinducer 3-OH PAME, termed ELP86, ELP96, ELP104, and EstDL33, were selected and characterized. Phylogenetic analysis revealed that metagenomic enzymes were novel esterase/lipase candidates as they clustered as novel subfamilies of family I, V, X, and family XI. The purified enzymes displayed various levels of hydrolytic activities towards 3-OH PAME with optimum activity at 40-50 degrees C and pH 7-10. Interestingly, ELP104 also displayed N (3-oxohexanoyl)-L-homoserine lactone hydrolysis activity. Heterologous expression of the gene encoding 3-OH PAME hydrolase in R. solanacearum significantly decreased exopolysaccharide production without affecting bacterial growth. mRNA transcription analysis revealed that genes regulated by quorum-sensing, such as phcA and xpsR, were significantly down-regulated in the stationary growth phase of R. solanacearum. Therefore, metagenomic enzymes are capable of quorum quenching by hydrolyzing the autoinducer 3-OH PAME, which could be used as a biocontrol strategy against bacterial wilt. PMID- 29407419 TI - School exposure and asthma. AB - OBJECTIVE: To provide a comprehensive overview of common school exposures and the association between school exposures and pediatric asthma morbidity. DATA SOURCES: A comprehensive literature review was performed using PubMed. STUDY SELECTIONS: Full-length, peer-reviewed studies published in English were considered for review. In vivo, in vitro, and animal studies were excluded. Studies of school exposure to cockroach, mouse, dust mite, dog, cat, molds, pollution, and endotoxin associated with asthma and asthma morbidity were considered. RESULTS: The current literature establishes an association between school exposure and pediatric asthma morbidity. There is a need for ongoing research to evaluate the effects of school-based environmental interventions on asthma morbidity. CONCLUSION: It is evident that the indoor school environment is a significant reservoir of allergens, molds, pollutants, and endotoxin and that there is an association between school exposure and pediatric asthma morbidity. School-based interventions have the potential for substantial individual, community, and public health benefit. It is important that researchers continue to study the health effects associated with school exposures and assess cost effectiveness of multifaceted school-based interventions. PMID- 29407421 TI - Common variable immunodeficiency associated with stiff-person syndrome. PMID- 29407420 TI - Changes in emergency department concordance with guidelines for the management of stinging insect-induced anaphylaxis: 1999-2001 vs 2013-2015. AB - BACKGROUND: Changes in emergency department (ED) concordance with guidelines for the management of stinging insect-induced anaphylaxis (SIIA) are not known. OBJECTIVE: To describe temporal changes in ED concordance with guidelines for the management of SIIAs. METHODS: We analyzed data from 2 multicenter retrospective studies of patients with stinging insect-related acute allergic reactions seen in 1 of 14 North American EDs during 2 periods: 1999 through 2001 and 2013 through 2015. Visits were identified similarly across studies (eg, using International Classification of Diseases, Ninth Revision, Clinical Modification codes 989.5, 995.0, and 995.3). Anaphylaxis was defined as an acute allergic reaction with involvement of at least 2 organ systems or hypotension. We compared concordance between periods with 4 guideline recommendations: (1) treatment with epinephrine, (2) discharge prescription for epinephrine auto-injector, (3) referral to an allergist/immunologist, and (4) instructions to avoid the offending allergen. RESULTS: We compared 182 patients with SIIA during 1999 to 2001 with 204 during 2013 to 2015. Any treatment with epinephrine (before arrival to the ED or in the ED) increased over time (30% vs 49%; P < .001). Prescriptions for epinephrine auto-injector at discharge increased significantly (34% vs 57%; P < .001), whereas documentation of referral to an allergist/immunologist decreased (28% vs 12%; P = .002), and instructions to avoid the offending allergen did not change (23% vs 24%; P = .94). Receipt of at least 3 guideline recommendations increased over time; however, the comparison was not statistically significant (10% vs 16%; P = .15). CONCLUSION: During the nearly 15-year study interval, we observed increased ED concordance with epinephrine-related guideline recommendations for the management of SIIA. Reasons for the decrease in allergy/immunology referrals merit further study. PMID- 29407422 TI - Effect of active immunization using a novel GnRH vaccine on reproductive function in rats. AB - To investigate the effect of gonadotropin-releasing hormone 2-multiple antigen peptide (GnRH2-MAP) on reproductive function. In our study, 20-day-old male rats (n = 90) were randomly allocated to one of three treatment groups: GnRH2-MAP immunization, GnRH2 immunization, and non-immunized control groups. The immunized animals were administered three doses of GnRH2-MAP or GnRH2 vaccines from 0 to 6 weeks at 2-week intervals. The control group only received oil adjuvant. Blood and right testis samples were collected, and the left testis was weighed and its volume was measured at 0, 2, 4, 6, 8, 10 and 12 weeks after the first immunization. The serum antibody titer and testosterone concentration were determined by ELISA, and the right testis samples were collected for histological analysis. The results revealed that the serum of vaccinated rats elicited a significantly higher antibody titer and a lower T concentration compared with the control group two weeks after the first immunization (P < 0.05), but the highest antibody titer and lowest T concentration were found in animals treated with GnRH2-MAP (P < 0.05). The second immunization resulted in a significant decrease in testicular weight and volume (P < 0.05) in both immunized groups compared to the control, but these values were significantly lower in the GnRH2-MAP group than in the GnRH2 group. Furthermore, seminiferous tubules revealed more significant atrophy in the GnRH2-MAP group than in the GnRH2 group, and no sperm were observed in rats of the GnRH2-MAP group. Thus, GnRH2-MAP may be an effective antigen and a potential immunocastration vaccine with higher effectiveness. PMID- 29407423 TI - Vaginal temperature measurement by a wireless sensor for predicting the onset of calving in Japanese Black cows. AB - We evaluated the utility of the continuous measurement of vaginal temperature by a wireless sensor and wireless connection for predicting the onset of calving and for clarifying the relationships among dystocia, calf conditions, and temperature changes at a commercial beef cattle farm in Japan. A total of 625 effective delivery data was collected. The temperature sensor inserted to the vagina on 7 days before the expected due date and collected the vaginal temperature every 5 min. The sensor detected two alerts according to the temperature change, one was the vaginal temperature of 4 h moving average compared to the same time temperature of last two days decreased more than 0.4 degrees C (Alert 1) and the other was the rupture of the allantoic sac and the dropped sensor temperature reached to the ambient temperature (Alert 2). The detection rates of Alert 1 and Alert 2 were 88.3% and 99.4%, respectively. The average time between Alert 1 and Alert 2 (Time 1) was 22 h, and that between Alert 2 and delivery (Time 2) was 2 h. These results indicated that the continuous measurement of vaginal temperature is effective for predicting the calving time. The necessity of assistance was correlated with dystocia, calf birth weight (BW), sex, and gestation periods. Interestingly, the durations of Times 1 and 2 were also associated with dystocia. The calf BW, sex, and gestation periods affected the length of Time 2. Our findings indicate that the BW of the calf is the most important factor for dystocia risk, and that the continuous measurement of vaginal temperature could become a good indicator for predicting not only the onset of calving, but also the necessity of assistance. PMID- 29407424 TI - Expression patterns of Toll-like receptors in the ovine corpus luteum during the early pregnancy and prostaglandin F2alpha-induced luteolysis. AB - The aim of this study was to elucidate the expression profiles of Toll-like receptors (TLRs) in the ovine corpus luteum (CL) during early pregnancy and prostaglandin F2alpha (PGF2alpha)-induced luteolysis. For this purpose, multiparous Anatolian Merino ewes were selected and randomly allotted into cyclic (including those in the induced luteolysis group, n = 20) and pregnant (n = 12) groups. All of the ewes were scheduled to be slaughtered for predetermined days/hour during the estrous cycle, early pregnancy, and PGF2alpha induced luteolysis. The CLs were collected from both cyclic and pregnant ewes on days 12 (C12 and P12; n = 8) and 16 (C16 and P16; n = 8) and pregnant ewes on day 22 (P22; n = 4). For the induced luteolysis model, ewes were injected with PGF2alpha on day 12 of the estrous cycle and CLs were collected at 1 h (PG1h; n = 4), 4 h (PG4h; n = 4), and 16 h (PG16h, n = 4) after injection. Quantitative polymerase chain reaction (qPCR) was used to evaluate the expression profiles of TLR2, TLR4, TLR6, TLR8, and TLR10, while free-floating in situ hybridization and immunohistochemistry were used to define the spatial localization of TLR2, TLR4, and TLR7 in the CL. Data were then analyzed by one-way ANOVA and were considered statistically significant when P values were lower than 0.05. Expression of TLR2 was upregulated in both early and late stages of luteolysis (P < .05). An upregulation of TLR4 was detected at PG16h, while TLR6 was decreased at PG4h (P < .05). Expression of TLR7 and TLR8 was significantly increased during early pregnancy, at both PG16h and regressed groups (C16, P < .05). In contrast, TLR10 was downregulated during PGF2alpha-induced luteolysis and on P16 (P < .05). TLR4 and TLR7 proteins were particularly localized in endothelial cells on C12/PG0h, but prominent signals corresponding to TLR4 and TLR7 were detected in luteal cells at PG16h. The results suggest an involvement of TLRs in the luteolytic mechanism in ovine CL, as indicated by differential expression levels of TLRs during PGF2alpha-induced luteolysis. Moreover, the present study indicates that early pregnancy-mediated changes in TLR expression in the CL may contribute to the establishment and maintenance of ovine pregnancy. PMID- 29407425 TI - Evaluation of porcine beta defensins-1 and -2 as antimicrobial peptides for liquid-stored boar semen: Effects on bacterial growth and sperm quality. AB - The present study evaluated whether two different antimicrobial peptides (AMP): porcine beta defensins-1 (PBD1) and -2 (PBD2) at three concentrations (1.5 MUM, 3 MUM and 5 MUM) could be a suitable alternative to antibiotics in liquid-stored boar semen. Two separate experiments were conducted with liquid-stored boar semen preserved at 17 degrees C for 9-10 days. In the first one, we evaluated the impact of adding three concentrations of each AMP on the bacterial growth and sperm quality of boar semen stored for 10 days. In the second experiment, the ability of these AMPs to control bacterial growth was determined over a 9-day period, following artificial inoculation with Escherichia coli at 107 and 108 CFU mL-1. In both experiments, sperm viability was assessed through flow cytometry, sperm motility was determined with Computer Assisted Sperm Analysis (CASA) and the inhibitory effect on microbial growth was evaluated by bacteria culture on Luria Bertani agar. PBD1 and PBD2 were found to significantly (P < 0.05) decrease sperm motility at 5 MUM (% total motile spermatozoa at day 10, Control: 31.6% +/- 1.2% vs. PBD1: 6.5% +/- 0.3% and PBD2: 5.6% +/- 0.4%). Although the highest inhibitory effect on bacterial growth was observed at 3 MUM (day 10, PBD1: 1.4 * 106 +/- 6.2 * 105 CFU mL-1 and PBD2: 9.1 * 105 +/- 2.4 * 105 CFU mL-1) and 5 MUM (day 10, PBD1: 1.2 * 105 +/- 5.1 * 104 CFU mL-1; PBD2: 8.7 * 104 +/- 2.9 * 104 CFU mL-1), the control with antibiotic was found to be more effective (day 10, 8.3 * 103 +/- 1.6 * 103 CFU mL-1). In conclusion, PBD1 and PBD2 may be added to antibiotic-free extenders for boar semen at a concentration of 3 MUM, but do not completely control all bacterial growth. PMID- 29407426 TI - Screening language skills at 2;0. AB - Early screening of children at risk for language difficulties is challenging. This study aimed to analyze the specificity and sensitivity of two screening methods at 2;0 years of age. In addition, the matter of what kind of information the use of word combinations and parental concern provide for screening was analyzed. The subjects were 78 children. The screening methods used were the Finnish versions of the short-form version of the MacArthur Communicative Development Inventories (FinCDI-SF) and the Communication and Symbolic Behavior Scales, Developmental Profile, Infant-Toddler Checklist (FinCSBS). The specificity and sensitivity of the screening methods were analyzed based on result of the Reynell Developmental Language Scales III. Both screening methods had high specificity but only moderate sensitivity. The use of word combinations and parental concern provided relevant information on early language development. The results imply that it is important to take into consideration receptive language development in early screening. PMID- 29407427 TI - Visual attention control differences in 12-month-old preterm infants. AB - There have been few previous attempts to assess the development of early markers of executive function in infants born preterm despite well-established deficits reported for older preterm children that have been closely linked to poorer academic functioning. The present study investigates early attention control development in healthy 12-month-old age-corrected pre-term infants who were born less than 30 weeks and compares their performance to full-term infants. Eye tracking methodology was used to measure attention control. Preterm Infants spent less time focused on the target and were slower to fixate attention, with lower gestational age associated with poorer target fixation and slower processing speed. There were no significant group differences observed for inhibition of return or interference control. These findings suggest that specific emerging deficits in attention control may be observed using eye tracking methodology in very preterm infants at this early stage of development, despite scores within the average range on the Bayley Scales of Infant Development. PMID- 29407428 TI - Changes in infant visual attention when observing repeated actions. AB - Infants' early visual preferences for faces, and their observational learning abilities, are well-established in the literature. The current study examines how infants' attention changes as they become increasingly familiar with a person and the actions that person is demonstrating. The looking patterns of 12- (n = 61) and 16-month-old infants (n = 29) were tracked while they watched videos of an adult presenting novel actions with four different objects three times. A face-to action ratio in visual attention was calculated for each repetition and summarized as a mean across all videos. The face-to-action ratio increased with each action repetition, indicating that there was an increase in attention to the face relative to the action each additional time the action was demonstrated. Infant's prior familiarity with the object used was related to face-to-action ratio in 12-month-olds and initial looking behavior was related to face-to-action ratio in the whole sample. Prior familiarity with the presenter, and infant gender and age, were not related to face-to-action ratio. This study has theoretical implications for face preference and action observations in dynamic contexts. PMID- 29407429 TI - Concurrent validity between instruments of assessment of motor development in infants exposed to HIV. AB - BACKGROUND: Exposure to HIV during pregnancy is a risks to development. Exposed child should have assessed its development since birth. Alberta Infant Motor Scale is a tool which assess gross motor skills, with easy application and low cost. Up to now, this scale had not proven its validity for the population exposed to HIV. It's necessary to compare its with a gold standard tool, Bayley scale, which assess gross and fine motor skills, has a high cost and longer application time required. Studies compare results of Alberta with Bayley's total motor score (gross + fine). However, it's also necessary to compare Alberta's result with only Bayley's gross motor result, because it's what both evaluate in common. AIMS: to verify the concurrent validity of AIMS in infants exposed to HIV; to verify the correlation of AIMS and BSITD III for this population and to compare if these coefficients differ in the central age groups and extremities of the AIMS. METHODS: 82 infants exposed to HIV evaluated in 1st, 2nd, 3rd, 4th, 8th, 12th, 15th, 16th, 17th and 18th months, with Alberta Infant Motor Scale and Bayley Scale (motor subscale). For analysis of concurrent validity, results of raw scores of the scales were compared with the correlation analysis. First analysis: Alberta's score with Bayley's total (gross + fine) motor score. Second analysis: Alberta's score with Bayley's gross motor score. RESULTS: In the first correlation analysis, results were: r = 0.62 in 1 st month, r = 0.64 in 2nd month, r = 0.08 in 3rd month, r = 0.45 in 4th month; r = 0.62 in 8th month, r = 0.60 in the 12th month. In the second correlation analysis, results were: r = 0.69 in 1 st month; r = 0.58 in 2nd month; r = 0.25 in 3rd month; r = 0.45 in the 4th month; r = 0.77 in 8th month; r = 0.73 in 12th month. Analyzes of the 15th, 16th, 17th and 18th months couldn't be performed because at these ages all the children had already reached the maximum score in the AIMS. Results were significant and indicate correlation between scales. Found results agree with other studies that found high correlations between the scales in premature and risk groups. However, these studies compare results of gross motor skills assessments with gross and fine motor skills assessments. Our results show that correlation only between the gross motor skills have higher coefficient values, and we believe this is the best way to compare the scales, with what both assessed in common. CONCLUSIONS: Alberta scale has correlation with Bayley scale in assessing of children exposed to HIV, and can be a substitute to Bayley in assessing of these children. Results are stronger when comparing only what both scales assess in common. PMID- 29407430 TI - Identifying the level of trunk control of healthy term infants aged from 6 to 9 months. AB - This study identified the level of trunk control of healthy term infants aged from six to nine months. This cross-sectional study included fifty-five infants aged from six to nine months. The levels of trunk control was investigated by using the Segmental Assessment Trunk Control (SATCo). The infants remained seated on a wooden bench and a neutral pelvic position was maintained. The SATCo score was considered as dependent variable. The results showed that infants aged six and seven months presented levels of trunk control in the thoracic region while infants aged from eight to nine months presented full trunk control. These results demonstrate that younger infants present less levels of trunk control while older infants present full trunk control, confirming that trunk control development takes place in a segmental way and in a cephalocaudal direction. These results also might be used as a reference to distinguish infants that show a delay in trunk control from those who have suitable motor development and, thus intervene at an early stage to minimize later delays in these infants global motor development. PMID- 29407431 TI - Local Regulation of Thyroid Hormone Signaling. AB - Thyroid hormone (TH) plays important signaling roles in mammalian growth, development, and thermogenesis. Traditionally its actions were thought to be regulated predominately through modulation of free plasma concentrations, intracellular breakdown by deiodinase enzymes and nuclear processing by thyroid receptors. In the past decade, however, there has been some departure from this classical model, whereby regulatory changes at different levels of organization simultaneously modulate its bioavailability and bioactivity. Here I review the recent literature to emphasize how subtle changes at these various levels of regulation can underlie tissue-specific and temporal (development and disease) changes in mammalian systems. For instance, it has become increasingly clear that TH acts both centrally to control sympathetic output and peripherally to regulate metabolism in target tissues. An interesting caveat is that central actions by TH may simultaneously alter its effects at peripheral tissues. In addition to T3, other TH derivatives (e.g., rT3 and T2) have also been shown to possess physiological activity, meaning intracellular processing by deiodinase enzymes is likely more complex than previously thought. Importantly, these TH derivatives can act both through the traditional genomic thyroid receptor pathways for transcriptional control, or more direct, fast-acting, nongenomic mechanisms. This fine-tuning means tissue-specific, ontogenic, and pathological changes in TH processing at any one level can have different consequences for TH bioavailability and bioactivity depending on parallel changes in upstream and/or downstream pathways. PMID- 29407432 TI - Thyroid Autoimmunity: An Interplay of Factors. AB - : The literature on thyroid autoimmunity has identified many potential factors at play for the initiation and progression of autoimmune thyroid diseases. These factors include genetic susceptibility, environmental factors, some drugs, iodine and selenium, infection, molecular mimics, and immune system defects. The sheer number of feasible factors makes sorting out the necessary agents from the fellow travelers difficult. In addition, many of these factors have the capability to interact-further confusing the picture. Another difficulty in interpreting these data is that most proposed mechanisms are not able to accomplish the triggering event in which the tolerance to self-antigens is actually overcome. In addition, some findings may be describing the conditions present after a disease is diagnosed and may be consequences of the disease rather than a cause. Recent description of the role of adipokines, which include leptin, tumor necrosis factor-alpha, and interleukin-6, in contributing to the inflammatory environment of the thyroid, along with the presence of thyroid Toll-like receptors for pathogen-associated patterns have the potential to deliver that necessary adjuvant signal to break tolerance, seen as necessary in animal autoimmune models. An additional factor, vitamin D3, due to its interaction both with white adipose tissue (WAT) and the immune system, has a complicated and somewhat controversial story with respect to thyroid autoimmunity. Conflicting results can result when not all factors are considered together. AIMS: To describe the many factors at play in thyroid autoimmunity and how they interact. CONCLUSION: Thyroid autoimmunity is the result of an interplay of factors, with adipokines produced by WAT and vitamin D providing immune modulating signals external to the thyroid, while thyrocyte innate responses to environmental conditions provide the necessary adjuvant signal. Shaping the response to be reactive to particular self antigens and likelihood of a response are due to genetics and molecular mimics. PMID- 29407433 TI - Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules. AB - Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. PMID- 29407434 TI - Thyroid Hormone Stimulation of Adult Brain Fatty Acid Oxidation. AB - Thyroid hormone is a critical modulator of brain metabolism, and it is highly controlled in the central nervous system. Recent research has uncovered an important role of thyroid hormone in the regulation of fatty acid oxidation (FAO), an energetic process essential for neurodevelopment that continues to support brain metabolism during adulthood. Thyroid hormone stimulation of FAO has been shown to be protective in astrocytes and mouse models of brain injury, yet a clear mechanism of this relationship has not been elucidated. Thyroid hormone interacts with multiple receptors located in the nucleus and the mitochondria, initiating rapid and long-term effects via both genomic and nongenomic pathways. This has complicated efforts to isolate and study-specific interactions. This chapter presents the primary signaling pathways that have been identified to play a role in the thyroid hormone-mediated increase in FAO. Investigation of the impact of thyroid hormone on FAO in the adult brain has challenged classical models of brain metabolism and widened the window of potential neuroprotective strategies. A detailed understanding of these pathways is essential for any researchers aiming to expand the field of neuroenergetics. PMID- 29407435 TI - Thyroid Hormone Transport and Transporters. AB - Thyroid hormones orchestrate developmental processes and are among the most important regulators of energy metabolism. Thyroid hormone actions are mostly, but not exclusively, mediated by nuclear hormone receptors. As amino acid derivatives, thyroid hormones need plasma membrane transporters in order to reach their nuclear receptors. Several transporters from different gene families mediate thyroid hormone uptake into cells. Monocarboxylate transporter 8 is a specific thyroid hormone transporter found mutated in patients with severe psychomotor retardation and strangely abnormal thyroid hormone constellations. These patients display a syndrome in which some organs are exposed to increased thyroid hormone signaling, while other organs are lacking thyroid hormone signaling due to complete lack of thyroid hormone uptake. Investigations in many organ systems using mouse models of thyroid hormone transmembrane transporter deficiency have helped complete our picture of thyroid hormone metabolism and action in the body during development and under different physiological conditions. Incorporating the concept of thyroid hormone transmembrane transport has helped understand previously enigmatic drug interactions and may explain how the hormonal set points in the hypothalamus-pituitary-thyroid axis are established. PMID- 29407436 TI - The NF-kappaB Family of Transcription Factors and Its Role in Thyroid Physiology. AB - The nuclear factor (NF)-kappaB signaling pathway controls a variety of important biological functions, including immune and inflammatory responses, differentiation, cell growth, tumorigenesis, and apoptosis. Two distinct pathways of NF-kappaB activation are known. The classical, canonical pathway is found virtually in all mammalian cells and NF-kappaB activation is mediated by the IKK complex, consisting of the IKK1/IKKalpha and IKK2/IKKbeta catalytic kinase subunits and the NF-kappaB essential modulator (NEMO)/IKKgamma protein. The NF kappaB-driven transcriptional responses to many different stimuli have been widely characterized in the pathophysiology of the mammalian immune system, mainly because this transcription factor regulates the expression of cytokines, growth factors, and effector enzymes in response to ligation of cellular receptors involved in immunity and inflammation. However, an impressive literature produced in the last two decades shows that NF-kappaB signaling plays an important role also outside of the immune system, performing different roles and functions depending on the type of tissue and organ. In thyroid, NF-kappaB signaling is crucial for thyrocytes survival and expression of critical thyroid markers, including Nis, Ttf1, Pax8, Tpo, and thyroglobulin, making this transcription factor essential for maintenance of normal thyroid function. PMID- 29407437 TI - Thyroid Hormone Regulation of Adult Neurogenesis. AB - Thyroid hormone is classically known to play a crucial role in neurodevelopment. The potent effects that thyroid hormone exerts on the adult mammalian brain have been uncovered relatively recently, including an important role in the modulation of progenitor development in adult neurogenic niches. This chapter extensively reviews the current understanding of the influence of thyroid hormone on distinct stages of adult progenitor development in the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) that lines the lateral ventricles. We discuss the role of specific thyroid hormone receptor isoforms, in particular TRalpha1, which modulates cell cycle exit in neural stem cells, progenitor survival, and cell fate choice, with both a discrete and overlapping nature of regulation noted in SGZ and SVZ progenitors. The balance between liganded and unliganded TRalpha1 can evoke differing consequences for adult progenitor development, and the relevance of this to conditions such as adult-onset hypothyroidism, wherein unliganded thyroid hormone receptors (TRs) dominate, is also a focus of discussion. Although a detailed molecular understanding of the specific thyroid hormone target genes that contribute to the neurogenic actions of thyroid hormone is currently lacking, we highlight the current state of knowledge and discuss avenues for future investigation. The goal of this chapter is to provide a comprehensive and detailed analysis of the effects of thyroid hormone on adult neurogenesis, to discuss putative molecular mechanisms that mediate these effects, and the behavioral, functional, and clinical implications of the neurogenic actions of thyroid hormone. PMID- 29407438 TI - Thyroid Hormone and the White Matter of the Central Nervous System: From Development to Repair. AB - The role of thyroid hormone (TH) on brain development, and particularly in myelination, is well known since many decades, as testified by the severe structural and functional consequences of congenital hypothyroidism. This role during development, the consideration that the early TH supplementation restores myelination capability, and the fact the cell responsible for developmental myelination and remyelination is the same, i.e., the oligodendrocyte precursor cell (OPC), claimed the attempt to improve myelin repair in the adulthood via TH supplementation. In this chapter, the impact of TH on development, homeostasis, and repair of the myelin in the CNS will be reviewed, focusing on the regulation of the TH tissue signaling during physiological and pathological conditions affecting myelination and/or myelin repair during early postnatal age and during the adulthood. The impact of the tissue inflammation on molecular mediators of the TH cellular action and metabolism will be discussed, with regard to the consequences on the biology of the OPC. PMID- 29407440 TI - Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction. AB - The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5 triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. PMID- 29407439 TI - Thyroid Hormone and Astrocyte Differentiation. AB - Thyroid hormones (THs) have important contributions to the development of the mammalian brain, targeting its actions on both neurons and glial cells. Astrocytes, which constitute about half of the glial cells, characteristically undergo dramatic changes in their morphology during development and such changes become necessary for the proper development of the brain. Interestingly, a large number of studies have suggested that THs play a profound role in such morphological maturation of the astrocytes. This review discusses the present knowledge on the mechanisms by which THs elicit progressive differentiation and maturation of the astrocytes. As a prelude, information on astrocyte morphology during development and its regulations, the role of THs in the various functions of astrocyte shall be dealt with for a thorough understanding of the subject of this review. PMID- 29407441 TI - Thyroid Hormone Signaling in Retinal Development, Survival, and Disease. AB - Thyroid hormone (TH) is essential in numerous physiological functions and developmental processes. It acts through TH receptors (TRs) to regulate gene expression. The retina is the light-sensitive tissue lining the back of the eye and functions as the first step of the visual process. Rod and cone photoreceptors are specialized sensory neurons in the retina that initiate phototransduction. Rods are responsible for dim light vision, whereas cones are responsible for daytime vision, color vision, and visual acuity. TH signaling regulates retinal development and maintenance. The requirement of TH signaling is typically manifested as its regulation in the cone maturation and expression of the light-sensing pigment protein (cone opsin). There are two components of this regulation. First, TRbeta2, a TH-activated transcription factor, is expressed in immature cones and regulates cone differentiation and cone opsin expression; activation of TRbeta2 suppresses the expression of short-wave-sensitive opsin 1, induces the expression of medium-wave-sensitive opsin 1, and promotes dorsal ventral opsin patterning. Second, hypothyroid mouse models display abnormalities in cone opsin expression, supporting the necessity of TH itself in retinal development. TH has been linked to photoreceptor survival. Excessive TH signaling leads to death of developing photoreceptors in healthy and diseased retina, whereas suppressing TH signaling preserves cones in mouse models of retinal degeneration. Some eye diseases, including age-related macular degeneration, have been associated with elevated circulation TH levels. Future work should aim to better understand how TH regulates retinal development, functionality, and survival, to examine the role of TH signaling in the pathogenesis of retinal degeneration, and to explore the potential of TH signaling manipulation for photoreceptor protection. Hopefully, these knowledge bases will lead to the identification of novel strategies for retinal disease prevention and management. PMID- 29407442 TI - Thyroid Hormone Signaling in the Development of the Endochondral Skeleton. AB - Thyroid hormone (TH) is an established regulator of skeletal growth and maintenance both in clinical studies and in laboratory models. The clinical consequences of altered thyroid status on the skeleton during development and in adulthood are well known, and genetic mouse models in which elements of the TH signaling axis have been manipulated illuminate the mechanisms which underlie TH regulation of the skeleton. TH is involved in the regulation of the balance between proliferation and differentiation in several skeletal cell types including chondrocytes, osteoblasts, and osteoclasts. The effects of TH are mediated primarily via the thyroid hormone receptors (TRs) alpha and beta, ligand inducible nuclear receptors which act as transcription factors to regulate target gene expression. Both TRalpha and TRbeta signaling are important for different stages of skeletal development. The molecular mechanisms of TH action in bone are complex and include interaction with a number of growth factor signaling pathways. This review provides an overview of the regulation and mechanisms of TH action in bone, focusing particularly on the role of TH in endochondral bone formation during postnatal growth. PMID- 29407443 TI - Thyroid Hormone and Skeletal Development. AB - Thyroid hormone (TH) is essential for skeletal development from the late fetal life to the onset of puberty. During this large window of actions, TH has key roles in endochondral and intramembranous ossifications and in the longitudinal bone growth. There is evidence that TH acts directly in skeletal cells but also indirectly, specially via the growth hormone/insulin-like growth factor-1 axis, to control the linear skeletal growth and maturation. The presence of receptors, plasma membrane transporters, and activating and inactivating enzymes of TH in skeletal cells suggests that direct actions of TH in these cells are crucial for skeletal development, which has been confirmed by several in vitro and in vivo studies, including mouse genetic studies, and clinical studies in patients with resistance to thyroid hormone due to dominant-negative mutations in TH receptors. This review examines progress made on understanding the mechanisms by which TH regulates the skeletal development. PMID- 29407444 TI - Nuclear Import and Export of the Thyroid Hormone Receptor. AB - The thyroid hormone receptors, TRalpha1 and TRbeta1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRalpha1 and TRbeta1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRalpha1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain. Three nuclear export signal (NES) motifs reside in the ligand-binding domain. A combined approach of shRNA-mediated knockdown and coimmunoprecipitation assays revealed that nuclear entry of TRalpha1 is facilitated by importin 7, likely through interactions with NLS-2, and importin beta1 and the adapter importin alpha1 interacting with both NLS-1 and NLS-2. Interestingly, TRbeta1 lacks NLS-2 and nuclear import depends solely on the importin alpha1/beta1 heterodimer. Heterokaryon and fluorescence recovery after photobleaching shuttling assays identified multiple exportins that play a role in nuclear export of TRalpha1, including CRM1 (exportin 1), and exportins 4, 5, and 7. Even single amino acid changes in TRs dramatically alter their intracellular distribution patterns. We conclude that mutations within NLS and NES motifs affect nuclear shuttling activity, and propose that TR mislocalization contributes to the development of some types of cancer and Resistance to Thyroid Hormone syndrome. PMID- 29407445 TI - Thyroid Hormone Role and Economy in the Developing Testis. AB - Thyroid hormones (TH) exhibit pleiotropic regulatory effects on growth, development, and metabolism, and it is becoming increasingly apparent that the developing testis is an important target for them. Testicular development is highly dependent on TH status. Both hypo- and hyperthyroidism affect testis size and the proliferation and differentiation of Sertoli, Leydig, and germ cells, with consequences for steroidogenesis, spermatogenesis, and male fertility. These observations suggest that an appropriate content of TH and by implication TH action in the testis, whether the result of systemic hormonal levels or regulatory mechanisms at the local level, is critical for normal testicular and reproductive function. The available evidence indicates the presence in the developing testis of a number of transporters, deiodinases and receptors that could play a role in the timely delivery of TH action on testicular cells. These include the thyroid hormone receptor alpha (THRA), the MCT8 transporter, the TH activating deiodinase DIO2, and the TH-inactivating deiodinase DIO3, all of which appear to modulate testicular TH economy and testis outcomes. PMID- 29407446 TI - Signaling Pathways in Thyroid Cancer. AB - The morbidity of thyroid cancer is increasing gradually year by year, showing an increasing tendency in nationality, sex, age, tumor size, and tumor staging. The changes of thyroid cell genes, signaling pathways, and related molecular dysfunction promote the occurrence, development, invasion, and metastasis of thyroid cancer. Surgical operation, radioiodine, and endocrinotherapy models can achieve a better prognosis for most patients with thyroid cancer. Although targeted therapeutic drugs bring possible therapeutic opportunities for refractory thyroid cancer, there is a great gap between their predictive value and their actual efficacy. Currently, there is still no completely effective drug for the treatment. Based on the signaling pathways, the "reclaim therapy" for residual tumor and systemic intervention aims to increase anticancer ability and to encourage new directions and thoughts in the treatment of refractory thyroid cancer. PMID- 29407447 TI - Roles of Thyroid Transcription Factor 1 in Lung Cancer Biology. AB - Thyroid transcription factor 1 (TTF-1 or NKX2-1) is a transcription factor of fundamental importance in driving lung maturation and morphogenesis. In the last decade, scientists began to appreciate the functional roles of TTF-1 in lung tumorigenesis. This movement was triggered by the discoveries of genetic alterations of TTF-1 in the form of gene amplification in lung cancer. Many downstream target genes of TTF-1 relevant to the lung cancer biology of TTF-1 have been documented. One of the most surprising findings was that TTF-1 may exhibit either pro- or antitumorigenic activities, an outcome with the complexity exceeding the original anticipation purely based on the fact that TTF-1 undergoes gene amplification in lung cancer. In the coming decade, we believe, we will witness additional surprises as the research exploring the cancer roles of TTF-1 progresses. PMID- 29407448 TI - Molecular Basis of Nongenomic Actions of Thyroid Hormone. AB - Nongenomic actions of thyroid hormone are initiated by the hormone at receptors in the plasma membrane, in cytoplasm, or in mitochondria and do not require the interaction of nuclear thyroid hormone receptors (TRs) with their primary ligand, 3,5,3'-triiodo-l-thyronine (T3). Receptors involved in nongenomic actions may or may not have structural homologies with TRs. Certain nongenomic actions that originate at the plasma membrane may modify the state and function of intranuclear TRs. Reviewed here are nongenomic effects of the hormone-T3 or, in some cases, l-thyroxine (T4)-that are initiated at (a) truncated TRalpha isoforms, e.g., p30 TRalpha1, (b) cytoplasmic proteins, or (c) plasma membrane integrin alphavbeta3. p30 TRalpha1 is not transcriptionally competent, binds T3 at the cell surface, and consequently expresses a number of important functions in bone cells. Nongenomic hormonal control of mitochondrial respiration involves a TRalpha isoform, and another truncated TRalpha isoform nongenomically regulates the state of cellular actin. Cytoplasmic hormone-binding proteins involved in nongenomic actions of thyroid hormone include ketimine reductase, pyruvate kinase, and TRbeta that shuttle among intracellular compartments. Functions of the receptor for T4 on integrin alphavbeta3 include stimulation of proliferation of cancer and endothelial cells (angiogenesis) and regulation of transcription of cancer cell survival pathway genes. T4 serves as a prohormone for T3 in genomic actions of thyroid hormone, but T4 is a hormone at alphavbeta3 and more important to cancer cell function than is T3. Thus, characterization of nongenomic actions of the hormone has served to broaden our understanding of the cellular roles of T3 and T4. PMID- 29407449 TI - The Mechanism of Negative Transcriptional Regulation by Thyroid Hormone: Lessons From the Thyrotropin beta Subunit Gene. AB - Thyroid hormone (T3) activates (positive regulation) or represses (negative regulation) target genes at the transcriptional level. The molecular mechanism of the former has been elucidated in detail; however, the mechanism for negative regulation has not been established. The best example of the gene that is negatively regulated by T3 is the thyrotropin (thyroid-stimulating hormone) beta subunit (TSHbeta) gene. Analogous to the T3-responsive element (TRE) in positive regulation, a negative TRE (nTRE) has been postulated in the TSHbeta gene. However, TSHbeta promoter analysis, performed in the presence of transcription factors Pit1 and GATA2, which are determinants of thyrotroph differentiation in the pituitary, revealed that the nTRE is dispensable for inhibition by T3. We propose a tethering model in which the T3 receptor is tethered to GATA2 via protein-protein interaction and inhibits GATA2-dependent transactivation of the TSHbeta gene in a T3-dependent manner. PMID- 29407451 TI - Preface. PMID- 29407452 TI - BMAA-protein interactions: A possible new mechanism of toxicity. AB - beta-N-methylamino-L-alanine (BMAA) has been shown to accumulate in organisms by associating with host proteins. It has been proposed that this association is the result of misincorporation of BMAA into the primary structure of proteins, specifically in the place of L-serine, and that this misincorporation causes protein misfolding resulting in the tangle formation typically associated with neurodegenerative diseases. However, more recent studies have questioned the validity of the BMAA misincorporation hypothesis. Furthermore, BMAA association with proteins in the absence of de novo protein synthesis has been demonstrated although the nature of these associations has not yet been characterized. We therefore sought to investigate the effects of these undescribed interactions on protein functioning, and to identify the site(s) of these interactions. We present data here to show that BMAA can inhibit the activity of certain enzymes, interfere with protein folding in the absence of de novo protein synthesis, and associate in vitro with commercial proteins to such an extent that it cannot be removed by protein precipitation or denaturation. Based on the observed effects of these interactions on protein functioning, we suggest that this might constitute an additional mechanism of toxicity that could help to explain the role of BMAA in the development of neurodegenerative diseases. PMID- 29407453 TI - The Light at the End of the Scope: The History of Electro Surgical Instrument Co and the Mignon Lamp. PMID- 29407454 TI - The Use of Tissue Glue for Circumcision in Children: Systematic Review and Meta analysis. AB - OBJECTIVE: To evaluate the efficacy of tissue glue in pediatric circumcision. MATERIALS AND METHODS: A systematic review and meta-analysis of the English literature (1997-2017) was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement on children who underwent circumcision with tissue glue. Meta-analysis was conducted using RevMan 5.3, Comprehensive Meta-Analysis 2, and MedCalc 18. P values <.05 were considered significant. RESULTS: The search returned 15 studies for a total of 4567 circumcisions, of which 3045 (66%) were performed with tissue glue. The systematic review indicated that overall complication rates were 4.3% (tissue glue) and 5.9% (sutures). The use of tissue glue was associated with reduced postoperative pain, better cosmetic results, and reduced cost. Meta-analysis showed that there was no difference between the incidence of total postoperative complications (relative risk [RR] 0.86 [95% confidence interval {CI}: 0.62-1.19], P = .36) and wound infection and dehiscence between the 2 groups (RR 0.95 [95% CI: 0.59-1.56], P = .85). Postoperative bleeding and hematoma formation were reduced with the use of tissue glue (RR 0.55 [95% CI: 0.32-0.95], P = .03). Tissue glue also significantly shorten the operative time (mean difference -0.22 [95% CI: -0.39 to -0.05], P = .01). CONCLUSION: The incidence of postoperative bleeding and hematoma formation in pediatric circumcision is reduced with the use of tissue glue. Tissue glue has reduced operative time; furthermore, it might be associated with reduced postoperative pain, less overall cost, and superior cosmetic results. PMID- 29407455 TI - The role of chemotherapy in localized and locally advanced rectal cancer: A systematic revision. AB - Curative treatment of rectal cancer depends on an optimal surgical resection, with the addition of neoadjuvant radiotherapy (RT) with or without concomitant chemotherapy (ChT) in more advanced tumors. The role of adjuvant ChT is controversial and a more intensified neoadjuvant approach with the addition of ChT before or after RT, or even as single modality, is currently being explored in trials. A systematic review selecting randomised phase II and III trials on the role of ChT in localized rectal cancer was performed. Data show that neoadjuvant ChRT improves locoregional control in resected rectal cancer. Short course RT (SCRT) could give similar outcomes to ChRT. The addition of oxaliplatin to neoadjuvant ChRT marginally increases the pathological complete remission rate without improving survival and increasing toxicity. A more intensified approach remains investigational as trials to date have not shown significant advantages. Adjuvant ChT trials after preoperative ChRT are contentious, although the addition of oxaliplatin in high risk patients may benefit outcomes. Despite a wide heterogeneity in the target population, different staging procedures and diverse treatment approaches among different trials, this systematic review confirms the role of ChT in combination with neoadjuvant long-course RT. Adjuvant ChT could be of value in selected patients with high-risk features, mainly if they do not respond to neoadjuvant RT. Further investigation is warranted on more intensified neoadjuvant regimens including ChT for MRI-defined high-risk patients. PMID- 29407456 TI - A stereotaxic breed-averaged, symmetric T2w canine brain atlas including detailed morphological and volumetrical data sets. AB - Stereotaxic systems and automatic tissue segmentation routines enable neuronavigation as well as reproducible processing of neuroimage datasets. Such systems have been developed for humans, non-human-primates, sheep, and rodents, but not for dogs. Although dogs share important neurofunctional and -anatomical features with humans, and in spite of their importance in translational neuroscience, little is known about the variability of the canine brain morphology and, possibly related, function. Moreover, we lack templates, tissue probability maps (TPM), and stereotaxic brain labels for implementation in standard software utilities such as Statistical Parametric Mapping (SPM). Hence, objective and reproducible, image-based investigations are currently impeded in dogs. We have created a detailed stereotaxic reference frame for dogs including TPM and tissue labels, enabling inter-individual and cross-study neuroimage analysis. T2w datasets were acquired from 16 neurologically inconspicuous dogs of different breeds by 3T MRI. The datasets were averaged after initial preprocessing using linear and nonlinear registration algorithms as implemented in SPM8. TPM for gray (GM) and white matter (WM) as well as cerebrospinal fluid (CSF) were created. Different cortical, subcortical, medullary, and CSF regions were manually labeled to create a spatial binary atlas being aligned with the template. A proof-of-concept for automatic determination of morphological and volumetrical characteristics was performed using additional canine datasets (n = 64) including a subgroup of laboratory beagles (n = 24). Overall, 21 brain regions were labeled using the segmented tissue classes of the brain template. The proof-of-concept trial revealed excellent suitability of the created tools for image processing and subsequent analysis. There was high intra-breed variability in frontal lobe and hippocampus volumes, and noticeable inter-breed corpus callosum volume variation. The T2w brain template provides important, breed-averaged canine brain anatomy features in a spatial standard coordinate system. TPM allows automatic tissue segmentation using SPM and enables unbiased automatic image processing or morphological characterization in different canine breeds. The reported volumetric and morphometric results may serve as a starting point for further research aimed at in vivo analysis of canine brain anatomy and function. PMID- 29407457 TI - Cortical parcellation based on structural connectivity: A case for generative models. AB - One of the major challenges in systems neuroscience is to identify brain networks and unravel their significance for brain function -this has led to the concept of the 'connectome'. Connectomes are currently extensively studied in large-scale international efforts at multiple scales, and follow different definitions with respect to their connections as well as their elements. Perhaps the most promising avenue for defining the elements of connectomes originates from the notion that individual brain areas maintain distinct (long-range) connection profiles. These connectivity patterns determine the areas' functional properties and also allow for their anatomical delineation and mapping. This rationale has motivated the concept of connectivity-based cortex parcellation. In the past ten years, non-invasive mapping of human brain connectivity has led to immense advances in the development of parcellation techniques and their applications. Unfortunately, many of these approaches primarily aim for confirmation of well known, existing architectonic maps and, to that end, unsuitably incorporate prior knowledge and frequently build on circular argumentation. Often, current approaches also tend to disregard the specific apertures of connectivity measurements, as well as the anatomical specificities of cortical areas, such as spatial compactness, regional heterogeneity, inter-subject variability, the multi scaling nature of connectivity information, and potential hierarchical organisation. From a methodological perspective, however, a useful framework that regards all of these aspects in an unbiased way is technically demanding. In this commentary, we first outline the concept of connectivity-based cortex parcellation and discuss its prospects and limitations in particular with respect to structural connectivity. To improve reliability and efficiency, we then strongly advocate for connectivity-based cortex parcellation as a modelling approach; that is, an approximation of the data based on (model) parameter inference. As such, a parcellation algorithm can be formally tested for robustness -the precision of its predictions can be quantified and statistics about potential generalization of the results can be derived. Such a framework also allows the question of model constraints to be reformulated in terms of hypothesis testing through model selection and offers a formative way to integrate anatomical knowledge in terms of prior distributions. PMID- 29407459 TI - In Memoriam: Marilyn McGinnis Lumia (11/04/1941-07/16/2017). PMID- 29407458 TI - Mechanistic substrates of a life history transition in male prairie voles: Developmental plasticity in affiliation and aggression corresponds to nonapeptide neuronal function. AB - Although prairie vole (Microtus ochrogaster) social behavior is well characterized in adults, surprisingly little is known about the development of social behavior in voles. Further, the overwhelming majority of studies in prairie voles examine social behavior in a reproductive context. Here, we examine developmental plasticity in affiliation and aggression and their underlying neural correlates. Using sexually naive males, we characterized interactions with an age-matched, novel, same-sex conspecific in four different age groups that span pre-weaning to adulthood. We found that prosocial behavior decreased and aggression increased as males matured. Additionally, pre-weaning males were more prosocial than nonsocial, whereas post-weaning males were more nonsocial than prosocial. We also examined nonapeptide neural activity in response to a novel conspecific in brain regions important for promoting sociality and aggression using the immediate early gene cFos. Assessment of developmental changes in neural activity showed that vasopressin neurons in the medial bed nucleus of the stria terminalis exhibit functional plasticity, providing a potential functional mechanism that contributes to this change in sociality as prairie voles mature. This behavioral shift corresponds to the transition from a period of allopatric cohabitation with siblings to a period of time when voles disperse and presumably attempt to establish and defend territories. Taken together our data provide a putative mechanism by which brain and behavior prepare for the opportunity to pairbond (characterized by selective affiliation with a partner and aggression toward unfamiliar conspecifics) by undergoing changes away from general affiliation and toward selective aggression, accounting for this important life history event. PMID- 29407460 TI - TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson's disease. AB - Triggering receptor expressed on myeloid cells-2 (TREM2) was a newly identified receptor expressed on microglia. Several observations support the hypothesis that TREM2 variation may confer susceptibility to Parkinson's disease (PD). Therefore, in this paper, we explored the role of TREM2 in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of PD. Our results revealed that overexpression of TREM2 remarkably reduced MPTP-induced neuropathology including the dopaminergic neurodegeneration and neuroinflammation in vivo. Further mechanistic study revealed that TREM2 inhibited neuroinflammation by negatively regulating the TRAF6/TLR4-mediated activation of the MAPK and NF-kappaB signaling pathways. Taken together, our data suggest that TREM2 may have important neuroprotective effects against PD by critically modulating neuroinflammatory responses. These findings provide insights into the role of TREM2 in PD pathogenesis, and highlight TREM2 as a potential therapeutic target for this kind of disease. PMID- 29407462 TI - Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review. AB - Memantine is an NMDA receptor antagonist clinically used for the treatment of moderate to severe Alzheimer's disease. Currently, it is the only NMDA receptor antagonist drug marketed against this disease. Despite the large number of publications regarding its clinical and therapeutic use, studies related to its mechanism of action are still inconclusive. Knowledge of drug interactions with cell membranes may lead to the development of novel drugs for neurodegenerative diseases. The present mini-review aims to give an overview of the latest findings regarding the interaction of memantine with cell membranes, specifically with that of the human erythrocyte. PMID- 29407461 TI - Co-localization patterns of neurotensin receptor 1 and tyrosine hydroxylase in brain regions involved in motivation and social behavior in male European starlings. AB - Animals communicate in distinct social contexts to convey information specific to those contexts, such as sexual or agonistic motivation. In seasonally-breeding male songbirds, seasonal changes in day length and increases in testosterone stimulate sexually-motivated song directed at females for courtship and reproduction. Dopamine and testosterone may act in the same brain regions to stimulate sexually-motivated singing. The neuropeptide neurotensin, acting at the neurotensin receptor 1 (NTR1), can strongly influence dopamine transmission. The goal of this study was to gain insight into the degree to which seasonal changes in physiology modify interactions between neurotensin and dopamine to adjust context-appropriate communication. Male European starlings were examined in physiological conditions that stimulate season-typical forms of communication: late summer/early fall non-breeding condition (low testosterone; birds sing infrequently), late fall non-breeding condition (low testosterone; birds produce non-sexually motivated song), and spring breeding condition (high testosterone; males produce sexually-motivated song). Double fluorescent immunolabeling was performed to detect co-localization patterns between tyrosine hydroxylase (TH; the rate-limiting enzyme in dopamine synthesis) and NTR1 in brain regions implicated in motivation and song production (the ventral tegmental area, medial preoptic nucleus, periaqueductal gray, and lateral septum). Co-localization between TH and NTR1 was present in the ventral tegmental area for all physiological conditions, and the number of co-localized cells did not differ across conditions. Immunolabeling for TH and NTR1 was also present in the other examined regions, although no co-localization was seen. These results support the hypothesis that interactions between NTR1 and dopamine in the ventral tegmental area may modulate vocalizations, but suggest that testosterone- or photoperiod induced changes in NTR1/TH co-localization do not underlie seasonally-appropriate adjustment of communication. PMID- 29407463 TI - Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults. AB - Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages. PMID- 29407465 TI - Hypermetabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation. AB - Structural deterioration and volume loss of the hippocampal formation is observed in many diseases associated with memory decline. Paradoxically, glucose metabolism of the hippocampal formation can be increased at the same time. This might be a consequence of compensatory (beneficial) or maladaptive (detrimental) mechanisms. Aim of this study was to differentiate between compensation and maladaptation by analyzing the association between glucose metabolism in the hippocampal formation measured by positron emission tomography with the glucose analogue 18F-fluorodeoxyglucose and cognitive performance as characterized by the extended Consortium to Establish a Registry for Alzheimer's Disease test battery in a sample of 87 patients (81.8 +/- 5.4 years) with mild cognitive impairment or mild dementia and varying etiological diagnoses. Glucose metabolism in the hippocampal formation was negatively correlated with the performance in several cognitive subdomains, most pronounced for verbal semantic fluency, independent of overall neuronal dysfunction, presence of clinical Alzheimer's disease, and overall cognitive performance. This finding provides evidence that increased glucose metabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation rather than a beneficial compensatory reaction. Excess glucose metabolism in the hippocampal formation might be a useful therapeutic target in these patients. PMID- 29407464 TI - Abnormalities of resting-state functional cortical connectivity in patients with dementia due to Alzheimer's and Lewy body diseases: an EEG study. AB - Previous evidence showed abnormal posterior sources of resting-state delta (<4 Hz) and alpha (8-12 Hz) rhythms in patients with Alzheimer's disease with dementia (ADD), Parkinson's disease with dementia (PDD), and Lewy body dementia (DLB), as cortical neural synchronization markers in quiet wakefulness. Here, we tested the hypothesis of additional abnormalities in functional cortical connectivity computed in those sources, in ADD, considered as a "disconnection cortical syndrome", in comparison with PDD and DLB. Resting-state eyes-closed electroencephalographic (rsEEG) rhythms had been collected in 42 ADD, 42 PDD, 34 DLB, and 40 normal healthy older (Nold) participants. Exact low-resolution brain electromagnetic tomography (eLORETA) freeware estimated the functional lagged linear connectivity (LLC) from rsEEG cortical sources in delta, theta, alpha, beta, and gamma bands. The area under receiver operating characteristic (AUROC) curve indexed the classification accuracy between Nold and diseased individuals (only values >0.7 were considered). Interhemispheric and intrahemispheric LLCs in widespread delta sources were abnormally higher in the ADD group and, unexpectedly, normal in DLB and PDD groups. Intrahemispheric LLC was reduced in widespread alpha sources dramatically in ADD, markedly in DLB, and moderately in PDD group. Furthermore, the interhemispheric LLC in widespread alpha sources showed lower values in ADD and DLB than PDD groups. At the individual level, AUROC curves of LLC in alpha sources exhibited better classification accuracies for the discrimination of ADD versus Nold individuals (0.84) than for DLB versus Nold participants (0.78) and PDD versus Nold participants (0.75). Functional cortical connectivity markers in delta and alpha sources suggest a more compromised neurophysiological reserve in ADD than DLB, at both group and individual levels. PMID- 29407466 TI - Age differences in neural correlates of feedback processing after economic decisions under risk. AB - This study examines age-related differences in behavioral responses to risk and in the neurophysiological correlates of feedback processing. Our sample was composed of younger, middle-aged, and older adults, who were asked to decide between 2 risky options, in the gain and loss domains, during an EEG recording. Results evidenced group-related differences in early and later stages of feedback processing, indexed by differences in the feedback-related negativity (FRN) and P3 amplitudes. Specifically, in the loss domain, younger adults showed higher FRN amplitudes after non-losses than after losses, whereas middle-aged and older adults had similar FRN amplitudes after both. In the gain domain, younger and middle-aged adults had higher P3 amplitudes after gains than after non-gains, whereas older adults had similar P3 amplitudes after both. Behaviorally, older adults had higher rates of risky decisions than younger adults in the loss domain, a result that was correlated with poorer performance in memory and executive functions. Our results suggest age-related differences in the outcome related expectations, as well as in the affective relevance attributed to the outcomes, which may underlie the group differences found in risk-aversion. PMID- 29407467 TI - Neuroprotective effects of voluntary running on cognitive dysfunction in an alpha synuclein rat model of Parkinson's disease. AB - Parkinson's disease (PD) is no longer primarily classified as a motor disorder due to increasing recognition of the impact on patients of several nonmotor PD symptoms, including cognitive dysfunction. These nonmotor symptoms are highly prevalent and greatly affect the quality of life of patients with PD, and so, therapeutic interventions to alleviate these symptoms are urgently needed. The aim of this study was to investigate the potential neuroprotective effects of voluntary running on cognitive dysfunction in an adeno-associated virus-alpha synuclein rat model of PD. Bilateral intranigral administration of adeno associated virus-alpha-synuclein was found to induce motor dysfunction and a significant loss of nigral dopaminergic neurons, neither of which were rescued by voluntary running. Overexpression of alpha-synuclein also resulted in significant impairment on hippocampal neurogenesis-dependent pattern separation, a cognitive task; this was rescued by voluntary running. This was substantiated by an effect of running on neurogenesis levels in the dorsal dentate gyrus, suggesting that the functional effects of running on pattern separation were mediated via increased neurogenesis. PMID- 29407468 TI - Visual and visuomotor interhemispheric transfer time in older adults. AB - Older adults typically experience reductions in the structural integrity of the anterior channels of the corpus callosum. Despite preserved structural integrity in central and posterior channels, many studies have reported that interhemispheric transfer, a function attributed to these regions, is detrimentally affected by aging. In this study, we use a constrained event related potential analysis in the theta and alpha frequency bands to determine whether interhemispheric transfer is affected in older adults. The crossed uncrossed difference and lateralized visual evoked potentials were used to assess interhemispheric transfer in young (18-27) and older adults (63-80). We observed no differences in the crossed-uncrossed difference measure between young and older groups. Older adults appeared to have elongated transfer in the theta band potentials, but this effect was driven by shortened contralateral peak latencies, rather than delayed ipsilateral latencies. In the alpha band, there was a trend toward quicker transfer in older adults. We conclude that older adults do not experience elongated interhemispheric transfer in the visuomotor or visual domains and that these functions are likely attributed to posterior sections of the corpus callosum, which are unaffected by aging. PMID- 29407469 TI - Age-related differences in the neural correlates of empathy for pleasant and unpleasant touch in a female sample. AB - Empathy is essential for successful social interactions and relationships. The neural underpinnings of empathy have predominantly been studied in the young adult population, thus little is known about how they evolve across the life span. In the present study, we used functional magnetic resonance imaging to investigate age-related differences in brain activity associated to empathy for positive and negative emotions. Female participants of 3 age groups-adolescents, young, and older adults-underwent an experimental paradigm inducing both first hand and empathic experience of pleasant and unpleasant touch. Group comparisons and regression analyses revealed that older adults showed lower activation within the anterior insula with respect to young adults, during both empathy conditions. Further analyses provided evidence that years of education, theory of mind ability, gray matter volume, and first-hand affect processing did not account for these effects. These findings indicate that the neural bases of empathy change across different age groups, from adolescence to old age. Different ages and in particular older age seem to significantly influence the way in which we represent and share others' positive and negative emotions. PMID- 29407470 TI - Anticarcinogenic activities of sulforaphane are influenced by Nerve Growth Factor in human melanoma A375 cells. AB - Melanoma is a severe form of cancer, resistant to conventional therapies. According to in vitro studies, sulforaphane, a dietary component, has been considered a promising antineoplastic candidate. The present study analyzes the in vitro biological effects of sulforaphane in A375 melanoma cell line with or without the addition of Nerve Growth Factor. For the first time, our results show that a supplementation of Nerve Growth Factor partially reverses the sulforaphane induced: i) inhibition of cell migration, ii) pro apoptotic changes in cell cycle and iii) modulation of active caspase-3. Furthermore, we report the sulforaphane induced modulation in the expression of Nerve Growth Factor receptors TrKA and p75NTR, shifting their ratio from pro survival to pro apoptotic. In conclusion, the present study evidences that in vivo the antineoplastic effects of sulforaphane may be reduced by the contemporaneous presence of other biological elements such as Nerve Growth Factor and it contributes to a better definition of the real in vivo potentiality of sulforaphane as antineoplastic candidate. PMID- 29407471 TI - Biological, chemical and in silico fingerprints of Dianthus calocephalus Boiss.: A novel source for rutin. AB - Extracts (methanol, ethyl acetate, and water) from Dianthus calocephalus Boiss. prepared by different extraction techniques (maceration, Soxhlet, and ultrasonication) were studied for possible inhibitory action against key enzymes (alpha-amylase, alpha-glucosidase, acetyl cholinesterase, butyryl cholinesterase, and tyrosinase). Antioxidant potential was established using a battery of assays and phenolic compounds profiled by RP-HPLC. Binding pose of tyrosinase with rutin was studied by means of molecular docking. Methanol extracts showed the highest phenolic (39.35-40.25 mgGAE/g) content and rich in rutin (61.38-72.07 mg/g extract). Ethyl acetate extracts of D. calocephalus were potent inhibitors of acetyl (1.45-1.48 mgGALAE/g) and butyryl (2.44-2.74 mgGALAE/g) cholinesterases. Docking studies showed that rutin interacts with the side chains of the key amino acid residues and to the copper atom found at the active site of tyrosinase. Methanol extracts showed highest antioxidant capacity. D. calocephalus showed interesting biological properties that could be further studied to manage diabetes, neurodegenerative diseases, Alzheimer's disease, and hyperpigmentation. PMID- 29407472 TI - Hibiscus sabdariffa anthocyanins-rich extract: Chemical stability, in vitro antioxidant and antiproliferative activities. AB - Hibiscus sabdariffa calyx is a rich source of anthocyanins and other bioactive compounds but no study reported the effects of experimental conditions on the extraction of these chemical compounds. Therefore, the effects of time and extraction temperature on the bioactive compounds and antioxidant activity of Hibiscus sabdariffa calyx were evaluated. In addition, the effects of copigmentation and pH on the stability of anthocyanins were assessed and the cytotoxic effects (LC50, IC50, and GC50) of the extracts were determined in relation to tumor cell lines - Caco-2, HepG-2, HCT8, and A549. The temperature significantly influenced the total anthocyanins and flavonoids contents. The interaction between time/temperature influenced the total phenolic content and ascorbic acid. The t1/2 and the percentage of colour retention decreased markedly at temperatures above 80 degrees C. Variations in pH conserved the antioxidant activity of the anthocyanins, and the protonation-deprotonation process of the extract was reversible. The treatment of cells with purified anthocyanin extract or crude extracts at 5-800 MUg mL-1 did not show significant cytotoxic effects on the cell lines, corroborating the chemical antioxidant effect of the extracts (DPPH assay). Cyanidin-3-glucoside, delphinidin-3-sambubioside, delphinidin-3 glucoside, and cyanidin-3-sambubioside were identified in the extracts by LC-ESI MS. PMID- 29407473 TI - Concentration of lead and mercury in collected vegetables and herbs from Markazi province, Iran: a non-carcinogenic risk assessment. AB - The current study was undertaken to determine the concentration of Hg and Pb in ten types of collected green leafy vegetables and herbs from different agricultural sites of Markazi province, Iran as well as the gathered water and soil around them using inductively coupled plasma-optical emission spectroscopy (ICP-OES). Also, the potential health risk assessment by using target hazard quotient (THQ) and hazard index (HI) parameters was estimated. Based on the accumulation order, Artemisia dracunculus L with 56.147 +/- 17.30 MUg/kg and Spinacia oleracea L with 1733.62 +/- 2264.7 MUg/kg can uptake and accumulate more concentration of Pb and Hg in their tissues, respectively. Regarding gathered soil around vegetables, the concentration of Hg and Pb were measured as 52.056 +/ 16.25 MUg/kg and 4993.83 +/- 1287.8 MUg/kg, respectively. The transfer factor (TF) demonstrated that vegetables and herbs could absorb a high amount of Hg from the soil while these plants uptake less concentration of Pb thought their green leaves. The non-carcinogenic risk assessment showed the minimum, and maximum THQ was related to 15-24 and 35-44 age groups in the urban and rural consumers. Also, HI in the urban and rural areas was calculated as 8.492 and 9.012, respectively. Since HI > 1, exposure of the urban and rural areas of Markazi province to non carcinogenic risk by consuming the green leafy vegetables and herbs is a source of concern. PMID- 29407474 TI - Anti-inflammatory effects of soyasapogenol I-alphaa via downregulation of the MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. AB - The crude extract of soyasaponins was reported to possess anti-inflammatory activity. We determined the new purity group I saponin, I-alphaa and I-gammaa that was isolated from wild soybean (Glycine soja) in terms of its efficacy in protecting RAW 264.7 macrophages from lipopolysaccharide (LPS)-stimuli. Cells were treated with soyasaponin I-alphaa/I-gammaa (30-300 MUMU) and LPS (0.1 MUg/mL) for 24 h. Soyasaponin I-alphaa inhibited nitric oxide (NO) production at 100 MUg/mL, while soyasaponin I-gammaa demonstrated this effect at a higher concentration (200 MUg/mL). The expression levels of iNOS and COX-2 enzymes were downregulated by both soyasaponins. Soyasaponin I-alphaa exerted its effect via the TNF-alpha and IL-1beta cytokines. However, soyasaponin I-gammaa only inhibited the expression of TNF-alpha. The inflammatory effect of group I soyasaponin was mainly mediated via the phosphorylation of the p38 and JNK proteins. Collectively, these results suggested the potential anti-inflammatory effects of soyasaponins. PMID- 29407476 TI - Forensic proteomics for the evaluation of the post-mortem decay in bones. AB - : Current methods for evaluation the of post-mortem interval (PMI) of skeletal remains suffer from poor accuracy due to the great number of variables that affect the diagenetic process and to the lack of specific guidelines to address this issue. During decomposition, proteins can undergo cumulative decay over the time, resulting in a decrease in the range and abundance of proteins present (i.e., the proteome) in different tissues as well as in an increase of post translational modifications occurring in these proteins. In this study, we investigate the applicability of bone proteomic analyses to simulated forensic contexts, looking for specific biomarkers that may help the estimation of PMI, as well as evaluate a previously discovered marker for the estimation of biological age. We noticed a reduction of particular plasma and muscle proteins with increasing PMIs, as well as an increased deamidation of biglycan, a protein with a role in modulating bone growth and mineralization. We also corroborated our previous results regarding the use of fetuin-A as a potential biomarker for the estimation of age-at-death, demonstrating the applicability and the great potential that proteomics may have towards forensic sciences. SIGNIFICANCE: The estimation of the post-mortem interval has a key role in forensic investigations, however nowadays it still suffers from poor reliability, especially when body tissues are heavily decomposed. Here we propose for the first time the application of bone proteomics to the estimation of the time elapsed since death and found several new potential biomarkers to address this, demonstrating the applicability of proteomic analyses to forensic sciences. PMID- 29407475 TI - Systematic review and health risk assessment of arsenic and lead in the fished shrimps from the Persian gulf. AB - The ingestion of heavy metals through contaminated seafood can causes significant outcomes on human health. In recent years, consume fishes and shrimps has increased in Iran, and several study about heavy metals content in fishes and shrimps from Persian Gulf were carried out to check their food safety. The aims of these systematic reviews and meta-analysis was to summarize the evidence on the relation of the intakes of Arsenic (As) and lead (Pb) levels, based on the origin and sub-groups of shrimp species consumed, Hence that we can estimate the risk of oral cancer induced by Pb and As in these groups of shrimp from the persian gulf. We carried out a search of all suitable studies published between 1995 and 2017 in Scopus, Science Direct, PubMed and Web of Science databases. Since the heterogeneity among studied was significant, we used the random effect model (REM) to perform meta-analysis of data. Data were obtained from 9 articles (14 studies), with 511 samples, and it was reported that pooled levels of As and Pb in the muscle shrimps were 1.37 (95% CI: 0.66-2.08 mg/kg d.w.) and 0.58 (95% CI: 0.33-0.82 mg/kg d.w.), respectively. This pooled levels in muscle shrimps were higher than safe dose reported on Food and Agriculture Organization/World Health Organization guidelines (FAO/WHO). The rank order of shrimps species based on As was Panulirus homarus > Penaeus semisulcatus and for the Pb levels was Litopenaeus vannamei > Panulirus homarus > Fenneropenaeus indicus > Metapenaeus affinis. The lowest and highest risk levels of oral cancer, divided by consumers age groups, were respectively 45-54 (6.94E-04) and 15-24 (8.42E-04) for the Pb, and 45-54 (2.87E-01) and 15-24 (3.51E-01) for arsenic. Incremental Lifetime Cancer Risk (ILCR) of Pb and As was higher than 10-4 and 10-3, respectively. All groups (age) of consumers are subject to the cancer risk of due to the consumption of shrimps contaminated by Pb and As, therefore, should be started a control plan for the reduction of the heavy metal bioaccumulation levels in shrimps of the Persian Gulf coupled to a capillary food safety communication. PMID- 29407477 TI - Mutually augmenting interactions of dextromethorphan and sazetidine-A for reducing nicotine self-administration in rats. AB - A variety of nicotinic drug treatments have been found to decrease nicotine self administration. However, interactions of drugs affecting different nicotinic receptor subtypes have not been much investigated. This study investigated the interactions between dextromethorphan, which blocks nicotinic alpha3beta2 receptors as well as a variety of other receptors with sazetidine-A which is a potent and selective alpha4beta2 nicotinic receptor partial agonist with desensitizing properties. This interaction was compared with dextromethorphan combination treatment with mecamylamine, which is a nonspecific nicotinic channel blocker. Co-administration of dextromethorphan (either 0.5 or 5 mg/kg) and lower dose of sazetidine-A (0.3 mg/kg) caused a significant reduction in nicotine SA. With regard to food-motivated responding, 3 mg/kg of sazetidine-A given alone caused a significant decrease in food intake. However, the lower 0.3 mg/kg sazetidine-A dose did not significantly affect food-motivated responding even when given in combination with the higher 5 mg/kg dextromethorphan dose which itself caused a significant decrease in food motivated responding. Interestingly, this higher dextromethorphan dose significantly attenuated the decrease in food motivated responding caused by 3 mg/kg of sazetidine-A. Locomotor activity was increased by the lower 0.3 mg/kg sazetidine-A dose and decreased by the 5 mg/kg dextromethorphan dose. Mecamylamine at the doses (0.1 and 1 mg/kg) did not affect nicotine SA, but at 1 mg/kg significantly decreased food-motivated responding. None of the mecamylamine doses augmented the effect of dextromethorphan in reducing nicotine self-administration. These studies showed that the combination of dextromethorphan and sazetidine-A had mutually potentiating effects, which could provide a better efficacy for promoting smoking cessation, however the strength of the interactions was fairly modest. PMID- 29407478 TI - Binge ethanol effects on prefrontal cortex neurons, spatial working memory and task-induced neuronal activation in male and female rats. AB - Excessive alcohol intake is associated with a multitude of health risks, especially for women. Recent studies in animal models indicate that the female brain is more negatively affected by alcohol, compared to the male brain. Among other regions, excessive alcohol consumption damages the frontal cortex, an area important for many functions and decision making of daily life. The objective of the present study was to determine whether the medial prefrontal cortex (mPFC) in female rats is selectively vulnerable to alcohol-induced damage. In humans, loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss is not necessarily due to a decrease in the number of neurons. We therefore quantified both number and nuclear volume of mPFC neurons following binge alcohol, as well as performance and neuronal activation during a prefrontal-dependent behavioral task. Adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well established 4-day model of alcohol-induced neurodegeneration. Both males and females had significantly smaller average neuronal nuclei volumes than their respective control groups immediately following alcohol binge, but neither sex showed a decrease in neuron number. Binged rats of both sexes initially showed spatial working memory deficits. Although they eventually achieved control performance, binged rats of both sexes showed increased c-Fos labeling in the mPFC during rewarded alternation, suggesting decreased neural efficiency. Overall, our results substantiate prior evidence indicating that the frontal cortex is vulnerable to alcohol, but also indicate that sex-specific vulnerability to alcohol may be brain region-dependent. PMID- 29407479 TI - LvCdc42 is a potential negative regulator of Lvp53 in Litopenaeus vannamei exposed to Vibrio alginolyticus stress. AB - As a crucial molecular switch, Cdc42 is a signal regulation hub which is involved in a wide range of cellular processes, including cytokinesis, gene expression, cell cycle progression and apoptosis. It has been reported that this GTPase promotes host defense against fatal infection and plays a vital role in the innate immunity system of mammals. But whether and how Cdc42 participates in innate immunity in invertebrates, such as the shrimp Litopenaeus vannamei, is still unknown. In this study, confocal microscopy analysis showed that LvCdc42 located in both cytoplasm and nucleus of S2 cells depended on its structure. The silencing LvCdc42 induced an increase in the expression of Lvp53 and Lvcaspase-3. When LvCdc42-silenced shrimps were stressed with Vibrio alginolyticus, the expression of Lvp53 and Lvcaspase-3 was markedly up-regulated. Moreover, the increase in the apoptosis rate in hemocytes and in cumulative mortality were in line with Lvp53 mRNA expression. These data suggest that the molecular switch LvCdc42 acts as a negative regulator of Lvp53 and participates in the apoptosis of hemocytes when L. vannamei is challenged with V. alginolyticus. PMID- 29407480 TI - Characterisation of chicken OX40 and OX40L. AB - The Tumour Necrosis Factor superfamilies of receptors and ligands play a crucial role in the regulation of effective immune responses against pathogens and malignant cells. In chickens, only few members have been identified. Here, we characterise the chicken homologues for mammalian costimulatory molecules OX40 and OX40L, which are involved in sustaining T cell responses. Both genes were identified by virtue of their genomic localisation close to highly conserved genes and their structural relationship to their mammalian homologues. Following cloning and expression of soluble and cell-associated chicken OX40 and OX40L, we confirmed their mutual interaction via ELISA and flow cytometric analyses. In addition, we showed the application of soluble OX40-Fc in staining of chicken cells. Whereas non-activated cells did not express OX40L, activation by IL-2 and IL-12 resulted in upregulation of OX40L on alphabeta and gammadelta T cell populations. Our results demonstrate the existence of the costimulatory OX40 OX40L system in the chicken and provide the basis for further investigations of chicken T cell responses. PMID- 29407481 TI - On defining a unique phylogenetic tree with homoplastic characters. AB - This paper discusses the problem of whether creating a matrix with all the character state combinations that have a fixed number of steps (or extra steps) on a given tree T, produces the same tree T when analyzed with maximum parsimony or maximum likelihood. Exhaustive enumeration of cases up to 20 taxa for binary characters, and up to 12 taxa for 4-state characters, shows that the same tree is recovered (as unique most likely or most parsimonious tree) as long as the number of extra steps is within 1/4 of the number of taxa. This dependence, 1/4 of the number of taxa, is discussed with a general argumentation, in terms of the spread of the character changes on the tree used to select character state distributions. The present finding allows creating matrices which have as much homoplasy as possible for the most parsimonious or likely tree to be predictable, and examination of these matrices with hill-climbing search algorithms provides additional evidence on the (lack of a) necessary relationship between homoplasy and the ability of search methods to find optimal trees. PMID- 29407482 TI - A jungle tale: Molecular phylogeny and divergence time estimates of the Desmopsis Stenanona clade (Annonaceae) in Mesoamerica. AB - The predominantly Asian tribe Miliuseae (Annonaceae) includes over 37 Neotropical species that are mainly distributed across Mesoamerica, from southern Mexico to northern Colombia. The tremendous ecological and morphological diversity of this clade, including ramiflory, cauliflory, flagelliflory, and clonality, suggests adaptive radiation. Despite the spectacular phenotypic divergence of this clade, little is known about its phylogenetic and evolutionary history. In this study we used a nuclear DNA marker and seven chloroplast markers, and maximum parsimony, maximum likelihood and Bayesian inference methods to reconstruct a comprehensive time-calibrated phylogeny of tribe Miliuseae, especially focusing on the Desmopsis-Stenanona clade. We also perform ancestral area reconstructions to infer the biogeographic history of this group. Finally, we use ecological niche modeling, lineage distribution models, and niche overlap tests to assess whether geographic isolation and ecological specialization influenced the diversification of lineages within this clade. We reconstructed a monophyletic Miliuseae that is divided into two strongly supported clades: (i) a Sapranthus-Tridimeris clade and (ii) a Desmopsis-Stenanona clade. The colonization of the Neotropics and subsequent diversification of Neotropical Miliuseae seems to have been associated with the expansion of the boreotropical forests during the late Eocene and their subsequent fragmentation and southern displacement. Further speciation within Neotropical Miliuseae out of the Maya block seems to have occurred during the last 15 million years. Lastly, the geographic structuring of major lineages of the Desmopsis-Stenanona clade seems to have followed a climatic gradient, supporting the hypothesis that morphological differentiation between closely related species resulted from both long-term isolation between geographic ranges and adaptation to environmental conditions. PMID- 29407483 TI - Persistent ventricular preexcitation despite right bundle branch block. AB - A 44-year-old man with a history of ventricular preexcitation and supraventricular tachycardia was evaluated. The baseline electrocardiogram exhibited ventricular preexcitation with a normal PR interval and a minimally negative delta wave in lead V1 and positive delta waves in the inferior leads. The administration of adenosine resulted in a progressive prolongation of the PR interval with a fixed preexcitation degree, suggesting the presence of antegrade conduction over the fasciculo-ventricular pathway. When complete right bundle branch block occurred, the degree of preexcitation never changed. These findings suggested that the fasciculo-ventricular pathway was likely to be connected to the left-sided His-Purkinje system. PMID- 29407485 TI - Presence and inter-individual variability of carboxylesterases (CES1 and CES2) in human lung. AB - Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4 methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (Vmax) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol. In these cellular fractions, the Vmax of pNPA, as CES1 marker, were much greater (30-50-fold) than those of FD, as a specific CES2 marker. Conversely, the Km values were comparable suggesting the involvement of the same enzymes. Inhibition studies revealed that the FD hydrolysis was inhibited by bis-p-nitrophenylphosphate, phenylmethanesulfonyl fluoride, and loperamide (specific for CES2), whereas the pNPA and 4-MUA hydrolysis inhibition was limited. Inhibitors selective for other esterases missed having any effect on above-mentioned activities. In cytosol and microsomes of 20 lung samples, inter individual variations were found for the hydrolysis of pNPA (2.5-5-fold), FD or 4 MUA (8-15-fold). Similar variations were also observed in CES1 and CES2 gene expression, although determined in a small number (n = 9) of lung samples. The identification of CES1 and CES2 and their variability in human lungs are important for drug metabolism and design of prodrugs which need to be activated in this organ. PMID- 29407484 TI - Crotonaldehyde exposure in U.S. tobacco smokers and nonsmokers: NHANES 2005-2006 and 2011-2012. AB - INTRODUCTION: Crotonaldehyde is an alpha,beta-unsaturated carbonyl compound that is a potent eye, respiratory, and skin irritant. Crotonaldehyde is a major constituent of tobacco smoke and its exposure can be quantified using its urinary metabolite N-acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (HPMM). A large-scale biomonitoring study is needed to determine HPMM levels, as a measure of crotonaldehyde exposure, in the general U.S. POPULATION: MATERIALS AND METHODS: Urine samples were obtained as part of the National Health and Nutrition Examination Survey 2005-2006 and 2011-2012 from participants who were at least six-years-old (N = 4692). Samples were analyzed for HPMM using ultra performance liquid chromatography - tandem mass spectrometry. Exclusive tobacco smokers were distinguished from non- tobacco users through a combination of self-reporting and serum cotinine data. RESULTS: Detection rate of HPMM among eligible samples was 99.9%. Sample-weighted, median urinary HPMM levels for smokers and non-users were 1.61 and 0.313 mg/g creatinine, respectively. Multivariable regression analysis among smokers showed that HPMM was positively associated with serum cotinine, after controlling for survey year, urinary creatinine, age, sex, race, poverty level, body mass index, pre-exam fasting time, and food intake. Other significant predictors of urinary HPMM include sex (female > male), age (children > non-user adults), race (non-Hispanic Blacks < non-Hispanic Whites). CONCLUSIONS: This study characterizes U.S. population exposure to crotonaldehyde and confirms that tobacco smoke is a major exposure source. Urinary HPMM levels were significantly higher among exclusive combusted tobacco users compared to non-users, and serum cotinine and cigarettes per day were significant predictors of increased urinary HPMM. This study also found that sex, age, ethnicity, pre-exam fasting time, and fruit consumption are related to urinary HPMM levels. PMID- 29407486 TI - Antiviral and anti-inflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation. AB - Human rhinovirus (HRV) infection causes more than 80% of all common colds and is associated with severe complications in patients with asthma and chronic obstructive pulmonary disease. To identify antiviral drug against HRV infection, we screened 800 FDA-approved drugs and found budesonide as one of the possible drug candidates. Budesonide is a corticosteroid, which is commonly used to prevent exacerbation of asthma and symptoms of common cold. Budesonide specifically protects host cells from cytotoxicity following HRV infection, which depend on the expression of glucocorticoid receptor. Intranasal administration of budesonide lowered the pulmonary HRV load and the levels of IL-1beta cytokine leading to decreased lung inflammation. Budesonide regulates IL-1beta production following HRV infection independent of inflammasome activation. Instead, budesonide induces mitochondrial reactive oxygen species followed by activation of autophagy. Further, the inhibition of autophagy following chloroquine or bafilomycin A1 treatment reduced the anti-viral effect of budesonide against HRV, suggesting that the antiviral activity of budesonide was mediated via autophagy. The results suggest that budesonide represents a promising antiviral and anti inflammatory drug candidate for the treatment of human rhinovirus infection. PMID- 29407487 TI - The way it was, the way it ought to be, the way it is, and the way it will be. PMID- 29407488 TI - Odontogenic keratocyst: the pitfalls of uncoordinated multidisciplinary care. PMID- 29407489 TI - Authors' response. PMID- 29407490 TI - Surgery-first approach vs traditional approach. PMID- 29407491 TI - Authors' response. PMID- 29407493 TI - A friend in need. PMID- 29407494 TI - Which orthodontic appliance is best for oral hygiene? A randomized clinical trial. AB - INTRODUCTION: Clear aligners and to a lesser extent self-ligated brackets are considered to facilitate better oral hygiene than traditional fixed orthodontic appliances. This 3-arm parallel-group prospective randomized clinical trial compared the long-term and short-term effects of clear aligners, self-ligated brackets, and conventional (elastomeric-ligated) brackets on patients' oral hygiene during active orthodontic treatment. METHODS: Seventy-one participants (41 boys, 30 girls; mean age, 15.6 years) undergoing orthodontic treatment were randomly allocated through a computer-generated randomization schedule to one of the groups based on the choice of intervention: Clear Aligners (CLA) (Align Technology, San Jose, Calif) (n = 27), preadjusted edgewise fixed appliance with self-ligated brackets (SLB) (Carriere, Carlsbad, Calif (n = 22), or preadjusted edgewise fixed appliance with elastomeric ligated brackets (ELB) (Ortho Organizers Inc., Carlsbad, CA) (n = 22). For each participant, the primary outcome, plaque index (PI), and secondary outcomes, gingival Index (GI) and periodontal bleeding index (PBI), were measured at baseline (T0), after 9 months of treatment (T1), and after 18 months of treatment (T2). Blinding of the clinicians and the patients to the intervention was impossible. It was only done for outcome assessment and for the statistician. Ten participants did not receive the allocated intervention for various reasons. RESULTS: The means and standard deviations of PI at T0 (CLA, 0.50 +/- 0.51; SLB, 0.65 +/- 0.49; ELB, 0.70 +/- 0.73), T1 (CLA, 0.83 +/- 0.48; SLB, 1.38 +/- 0.72; ELB, 1.32 +/- 0.67), and T2 (CLA, 0.92 +/- 0.58; SLB, 1.07 +/- 0.59; ELB, 1.32 +/- 0.67) were similar. The odds ratio (OR) for plaque index (0 or >=1) comparing SLB or CLA to ELB was not significant. OR for SLB vs ELB = 1.54 at T0 (95% CI, 0.39-6.27), 0.88 at T1 (95% CI, 0.03-24.69), and 0.83 at T2 (95% CI, 0.02-27.70); OR for CLA vs ELB = 1.07 at T0 (95% CI, 0.30-3.88), 0.24 at T1 (95% CI, 0.01-1.98), and 0.17 at T2 (95% CI, 0.01-1.71). However, the odds ratios comparing CLA with ELB for GI (OR = 0.14; P = 0.015) and PBI (OR = 0.10; P = 0.012) were statistically significant at T1. CONCLUSIONS: In this prospective randomized clinical trial, we found no evidence of differences in oral hygiene levels among clear aligners, self-ligated brackets, and conventional elastomeric ligated brackets after 18 months of active orthodontic treatment. REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT02745626). PROTOCOL: The protocol was not published before trial commencement. PMID- 29407495 TI - Identification and appraisal of outcome measures used to evaluate hypodontia care: A systematic review. AB - INTRODUCTION: Identification and appraisal of the outcome measures that have been used to evaluate hypodontia treatment and deliver services are essential for improving care. A lack of alignment between outcomes and patient values can limit the scope for patient-centered care. Our objectives were to identify and appraise the outcomes selected to evaluate hypodontia care. METHODS: Data sources included 10 electronic databases and grey literature, searched using terms for hypodontia and its treatment methods. Study eligibility included mixed study designs to ensure comprehensive identification of outcomes, excluding case reports and case series with fewer than 10 participants and nonsystematic reviews. Participants and interventions involved people with hypodontia receiving any dental treatment to manage their hypodontia. Simulated treatment, purely laboratory-based interventions, and future treatments still in development were excluded. Research outcomes were identified and synthesised into 4 categories: clinical indicators, and patient-reported, clinician-reported, and lay-reported outcomes. No synthesis of efficacy data was planned, and consequently no methodologic quality appraisal of the studies was undertaken. RESULTS: The search identified 497 abstracts, from which 106 eligible articles were retrieved in full. Fifty-six studies and 8 quality-improvement reports were included. Clinical indicators were reported in 49 studies (88%) including appearance, function, dental health, treatment longevity, treatment success and service delivery. Patient-reported outcomes were given in 22 studies (39%) including oral health-related quality of life, appearance, function, symptoms of temporomandibular dysfunction, and patient experience. Clinician-reported outcomes were limited to appearance. Variability was seen in the tools used for measuring outcomes. CONCLUSIONS: There is a lack of rationale and consistency in the selection of outcome measures used to evaluate hypodontia care. Outcomes are largely clinician and researcher-driven with little evidence of their relevance to patients. There was a paucity of outcomes measuring access to care, quality of care, and cost. Evidence from hypodontia research is clinician-focused and likely to have limited value to support patients during decision making. Attempts to synthesise the evidence base for translation into practice will be challenging. There is a need for a core outcomes set with a patient-centric approach to drive improvements in health services. PMID- 29407496 TI - Predictable method to deliver physiologic force for extrusion of palatally impacted maxillary canines. AB - INTRODUCTION: Orthodontic treatment of palatally impacted maxillary canines raises many difficulties; to minimize complications, careful planning of orthodontic extrusion and the use of physiologic force are crucial. The aim of this study was to quantitatively evaluate a simple and reproducible system for orthodontic extrusion of impacted canines that can provide the correct amount of force. METHODS: Ten specimens were constructed, consisting of a cantilever made with a 0.6-mm or 0.7-mm stainless steel wire modeled around a transpalatal bar with 3, 5, or 7 loops in the shape of a helical torsion spring. A mechanical testing machine was used to measure the force produced by the cantilever at 3, 6, 9, 12, and 15 mm of activation. RESULTS: The force values ranged from 1.24 +/- 0.13 N for the 0.7-mm wire with 3 loops to 0.48 +/- 0.04 N for the 0.6-mm wire with 7 loops. The forces measured for the 0.6-mm wire with 3 loops and the 0.7-mm wire with 7 loops were similar at 15 mm of deflection. CONCLUSIONS: The proposed system has a simple and robust design, is easy to construct and manage, and can provide the desired amount of force by changing the wire diameter and number of loops. PMID- 29407497 TI - Physical properties of root cementum: Part 26. Effects of micro-osteoperforations on orthodontic root resorption: A microcomputed tomography study. AB - INTRODUCTION: Studies have demonstrated the potential efficacy of micro osteoperforations in accelerating tooth movement by amplifying the expression of inflammatory markers. The aim of this investigation was to examine the effects of micro-osteoperforations on orthodontic root resorption with microcomputed tomography. METHODS: This prospective controlled clinical trial involved 20 subjects requiring extraction of the maxillary first premolars as part of their orthodontic treatment. A buccal tipping force of 150 g was applied to both premolars. Using the Propel appliance (Propel Orthodontics, San Jose, Calif), micro-osteoperforations were applied at a depth of 5 mm on the mesial and distal aspects in the midroot region of the experimental side of the first premolar root; the contralateral side served as the control. After 28 days, both premolars were extracted. The teeth were scanned under microcomputed tomography, and the volumes of root resorption craters were calculated and compared. RESULTS: Premolars treated with micro-osteoperforation exhibited significantly greater average total amounts of root resorption than did the control teeth (0.576 vs 0.406 mm3). The total average volumetric root loss of premolars treated with micro-osteoperforation was 42% greater than that of the control teeth. CONCLUSIONS: This 28-day trial showed that micro-osteoperforations resulted in greater orthodontic root resorption. However, these results should be verified in patients who are undergoing full-length orthodontic treatment. PMID- 29407499 TI - Long-term changes in oral health-related quality of life of standard, cleft, and surgery patients after orthodontic treatment: A longitudinal study. AB - INTRODUCTION: The aim of this study was to assess long-term changes and describe the trajectories of oral health-related quality of life (OHRQoL) in a cohort of cleft, surgery, and standard patients who received orthodontic treatment. METHODS: Standard (n = 16), cleft (n = 19), and orthognathic surgery (n = 22) patients completed the short-form of the Oral Health Impact Profile (OHIP-14) before treatment, immediately posttreatment, and approximately 5 years posttreatment. RESULTS: An overall reduction in OHIP-14 scores (improvement in OHRQoL) occurred after orthodontic treatment; however, this was only significant for the surgery and standard groups (P <0.05). The total OHIP-14 score increased significantly from posttreatment to 5 years follow-up for all 3 study groups (P <0.05). Relative to pretreatment, however, there were significant reductions in total OHIP-14 scores at 5 years posttreatment in the surgery group (-57.4%; P <0.05), but not in the standard sample (-24.2%; P >0.05). By contrast, the OHIP 14 score in the cleft group increased but not significantly (40.2%; P >0.05). Using a mixed model analysis, a significant interaction was detected between patient group and time (ie, study time point) (F = 6.0; P <0.0001), after adjusting for age and sex. CONCLUSIONS: Distinct patient groups showed different OHRQoL trajectories after orthodontic treatment. Treatment-related improvements in OHRQoL are maintained over time for surgery patients, but not for those with standard malocclusions and orofacial clefts. PMID- 29407498 TI - No association between types of unilateral mandibular condylar abnormalities and facial asymmetry in orthopedic-treated patients with juvenile idiopathic arthritis. AB - INTRODUCTION: Dentofacial asymmetries are often observed in patients with juvenile idiopathic arthritis (JIA) and temporomandibular joint (TMJ) involvements. The aim of this split-face study was to associate types of radiologic TMJ abnormalities with the degree of dentofacial asymmetry in patients with unilateral TMJ involvements assessed with cone-beam computed tomography. METHODS: Forty-seven JIA patients and 19 nonarthritic control subjects were included in the study. Normal condylar radiologic cone-beam computed tomography appearance in at least 1 TMJ was the inclusion criterion for all patients with JIA. The contralateral TMJ was thereafter scored as either "normal," "deformed," or "erosive," consistent with predefined criteria. Based on the bilateral radiologic TMJ appearances, 3 JIA groups were assigned: normal/normal, normal/deformed, and normal/erosive. The severity of the dentofacial asymmetry was compared between the JIA groups and control subjects. Dentofacial asymmetry was expressed as interside ratios and angular measurements. RESULTS: Eighty-seven percent of the JIA patients were being treated or had previously received treatment with a functional orthopedic appliance at the time of the cone-beam computed tomography. Significantly greater dentofacial asymmetries were observed in the 2 groups of JIA patients with unilateral condylar abnormalities (deformation or erosion) than in the other groups. A similar degree of dentofacial asymmetry was observed in JIA patients with bilateral normal TMJs and in the nonarthritic control group. CONCLUSIONS: JIA patients with unilateral condylar abnormalities (deformation or erosion) exhibited significantly more severe dentofacial asymmetries than did the JIA patients without condylar abnormalities and the control subjects. We found the same degree of dentofacial asymmetry when dividing patients with condylar abnormalities into deformation and erosion groups. PMID- 29407500 TI - Clinical effectiveness of 2 orthodontic retainer wires on mandibular arch retention. AB - INTRODUCTION: The aim of this study was to evaluate and compare the clinical success of 2 lingual retainer wires. METHODS: The 120 patients included in the study were divided into 2 groups randomly. In group 1, 0.0175-in 6-strand stainless steel wire (Ortho Technology, Lutz, Fla) was used, the lingual retainers were fabricated on plaster models, and a silicon transfer key was used. In group 2, 0.0195-in dead-soft coaxial wire (Respond; Ormco, Orange, Calif) was used, and the lingual retainers were fabricated directly in the patient's mandibular arch without a study model. Pretreatment, posttreatment, and posttreatment 3-month, 6-month, 9-month, and 12-month 3-dimensional orthodontic models were evaluated. Failure rates, mandibular arch irregularity values, intercanine distances, and arch lengths were compared. RESULTS: The clinical bond failure rates were 13.2% for the 0.0175-in 6-strand stainless steel wire and 18.9% for the 0.0195-in dead-soft wire. The difference in bond failures between the 2 groups was not statistically significant. There was a statistically significant increase in mandibular arch irregularity in both groups during the 12 month follow-up. However, the increase was significantly higher in the second group than in the first one. Furthermore, the intercanine distance decreased over time in the second group. CONCLUSIONS: Our findings regarding mandibular arch measurements indicate that fabrication of lingual retainers can be more safely accomplished with 0.0175-in 6-strand stainless steel wire than with 0.0195-in dead-soft coaxial wire. PMID- 29407501 TI - A novel approach for treatment of skeletal Class II malocclusion: Miniplates based skeletal anchorage. AB - INTRODUCTION: The objective of this study was to evaluate the effect of a new approach-bimaxillary miniplates-based skeletal anchorage-in the treatment of skeletal Class II malocclusion compared with untreated subjects. METHODS: The study (miniplates) group comprised 28 patients (14 boys, 14 girls) with skeletal Class II malocclusion due to mandibular retrusion, with a mean age of 11.83 years. After 0.017 * 0.025-in stainless steel archwires were placed in both arches, 4 miniplates were fixed bilaterally, 2 in the maxillary anterior areas and 2 in the mandibular posterior areas, and used for skeletal treatment with elastics. Twenty-four Class II untreated subjects (11 boys, 13 girls), with a mean age of 11.75 years, were included as controls. Skeletal and dental changes were evaluated using pretreatment and posttreatment or observational lateral cephalometric radiographs. The treatment changes were compared with the growth changes observed in the control group using independent t tests. RESULTS: Compared with the minimal changes induced by growth in the control group, the skeletal changes induced by miniplates were more obvious. The mandibular length increased significantly (3 mm), and the mandible moved forward, with a significant restraint in the sagittal position of the maxilla (P <0.001). The overjet correction (-4.26 mm) was found to be a net result of skeletal changes (A Y-axis = -1.18 mm and B-Y-axis = 3.83 mm). The mandibular plane was significantly decreased by 2.75 degrees (P <0.001). CONCLUSIONS: This new technique, bimaxillary miniplates-based skeletal anchorage, is an effective method for treating patients with skeletal Class II malocclusions through obvious skeletal, but minimal dentoalveolar, changes. PMID- 29407502 TI - Monomer release from orthodontic retentions: An in vitro study. AB - INTRODUCTION: The adhesives used to bond orthodontic retentions are low-loaded composite resins with a resinous matrix containing bisphenol A diglycidyl ether dimethacrylate synthesized from bisphenol A (BPA), fluidizers such as triethylene glycol dimethacrylate (TEGDMA) and hydrophilic polymers such as hydroxyethylmethacrylate. BPA disrupts the endocrine balance, and TEGDMA has high risks for human health: eg, allergies and cytotoxicity. The aim of this study was to evaluate in vitro the release of monomers from orthodontic bonded retentions. METHODS: A reproducible model of bonded retentions was carried out using calibrated molds. We analyzed the release of monomers by gas phase chromatography coupled with mass spectrometry. RESULTS: This model allowed us to qualitatively and quantitatively evaluate the in-vitro release of monomers from orthodontic adhesives. The quantitative and qualitative analyses showed no BPA release above the 0.02 ppm detection limit. A greater release of TEGDMA was observed with Transbond LR (31.7 MUg/mL) than with Transbond XT (13.12 MUg/mL) (both, 3M Unitek, Monrovia, Calif). Other toxic components (iodobenzene, iodobiphenyl, triphenyl stibine, and so on) were also identified. CONCLUSIONS: Toxic and carcinogenic molecules not mentioned in the material safety data sheets were identified. PMID- 29407503 TI - Relationship between matrilin-1 gene polymorphisms and mandibular retrognathism. AB - INTRODUCTION: Mandibular retrognathism is a type of malocclusion that refers to an abnormal posterior position of the mandible as a result of a developmental abnormality. From the literature, it is evident that the mandibular growth pattern is determined by the intramembranous ossification of the mandibular body and endochondral ossification of the condyle. Matrilin-1 is a cartilage extracellular matrix protein, and matrilin-1 gene (MATN1) polymorphisms have been found to be involved in dental malocclusions of humans. In this study, we aimed to examine the association between MATN1 polymorphisms and the risk of mandibular retrognathism, in a case-control study with a South Indian population. METHODS: Eighty-one patients with mandibular retrognathism (SNB, <78 degrees ) and 71 controls having an orthognathic mandible (SNB, 80 degrees +/- 2 degrees ) were recruited. In both the patient and control groups, subjects with an orthognathic maxilla (SNA, 82 degrees +/- 2 degrees ) were included. Three single nucleotide polymorphisms of the MATN1 gene (rs1149048, rs1149042, and rs1065755) were genotyped using polymerase chain reaction-restriction fragment length polymorphism. The statistical association analysis was performed using the chi square test. Pair-wise linkage disequilibrium was computed, and haplotypes were compared between subjects and controls. Nonparametric tests were used to compare cephalometric measurements between groups. RESULTS: No polymorphic site deviated from Hardy-Weinberg equilibrium in the controls. The rs1149042 genotypes and alleles were found to be associated with reduced risk of mandibular retrognathism. Furthermore, rs1149042 genotypes were associated with mandibular measurements (SNB and ANB). There was no strong and consistent linkage disequilibrium linkage disequilibrium across two different single nucleotide polymorphisms and haplotypes were not associated with mandibular retrognathism. CONCLUSIONS: The results of our study suggest an association between the MATN1 gene polymorphisms and mandibular retrognathism. PMID- 29407504 TI - Skeletal and dentoalveolar effects of hybrid rapid palatal expansion and facemask treatment in growing skeletal Class III patients. AB - INTRODUCTION: The purpose of this study was to describe the skeletal and dentoalveolar changes in a group of growing skeletal Class III patients treated with hybrid rapid palatal expansion and facemask. METHODS: Twenty-eight growing patients with skeletal Class III malocclusion were treated using a rapid maxillary expander with hybrid anchorage according to the ALT-Ramec protocol (SKAR III; E.P.), followed by 4 months of facemask therapy. Palatal miniscrew placement was accomplished via digital planning and the construction of a high precision, individualized surgical guide. Pretreatment and posttreatment cephalometric tracings were analyzed, comparing dental and skeletal measurements. RESULTS: Point A advanced by a mean of 3.4 mm with respect to the reference plane Vert-T. The mandibular plane rotated clockwise, improving the ANB (+3.41 degrees ) and the Wits appraisal (+4.92 mm). The maxillary molar had slight extrusion (0.42 mm) and mesialization (0.87 mm). CONCLUSIONS: The use of a hybrid-anchorage expander followed by 4 months of facemask treatment improves the skeletal Class III relationship with minimal dental effects, even in older patients (mean age, 11 years 4 months, +/- 2.5 years). PMID- 29407505 TI - Role of cone-beam computed tomography with a large field of view in Goldenhar syndrome. AB - INTRODUCTION: Goldenhar syndrome is a rare disease with hemifacial microsomia and craniofacial disorders originating from the first and second branchial arches, such as ocular, auricular, and vertebral anomalies. The complexity and variety of the ways in which the disease presents itself usually need several examinations. In this study, we aimed to evaluate both craniofacial and vertebral skeletal anomalies and asymmetries between the nonaffected and affected sides in patients with Goldenhar syndrome by using cone-beam computed tomography. METHODS: Ten patients (7-14 years old; 6 boys, 4 girls) were evaluated via NewTom 5G cone-beam computed tomography (QR srl, Verona, Italy) with a large field of view (18 * 16 cm). Ten anatomic facial landmarks were identified to measure the following distances bilaterally: sella turcica (ST)-mandibular angle, ST-condyle, ST mastoid, ST-mental foramen, ST-fronto zygomatic suture, ST-zygomatic temporal suture, ST-zygomatic facial foramen, ST-sphenopalatine fossa, mandibular angle mandibular symphysis, and mandibular angle-condyle. The following 6 volumes were calculated bilaterally: orbit, maxillary sinus, condyle, external ear canal, middle ear, and internal auditory canal. These measurements were performed to assess skeletal asymmetries to compare the nonaffected side with the affected side by the Wilcoxon test. Cervical spine anomalies were classified into fusion anomalies and posterior arch deficiencies. RESULTS: All patients showed a deficit of skeletal development on the affected side. Statistically significant differences (0.001 <= P value <= 0.043) between the nonaffected and affected sides were recorded for all measurements, except for ST-frontozygomatic suture, mandibular angle-mandibular symphysis, and maxillary sinus volume. Vertebral fusion anomalies and posterior arch deficiencies were found in 7 and 4 patients, respectively. CONCLUSIONS: Cone-beam computed tomography with a large field of view was able to accurately identify craniofacial and vertebral skeletal anomalies, and to quantify asymmetries between the nonaffected and affected sides for an efficient maxillofacial treatment planning. PMID- 29407506 TI - Interdisciplinary treatment of a patient with multiple missing teeth and periodontitis. AB - A 49-year-old woman with several missing and periodontically compromised teeth was referred to the orthodontic department of National Health Insurance Service Ilsan Hospital by the periodontic department for interdisciplinary treatment. Multiple posterior teeth had been extracted 10 days earlier. Her chief complaint was crowding of the anterior teeth, and she wanted to improve both esthetics and function. Orthodontic, periodontic, and prosthodontic treatments were undertaken in the proper timing and sequence with an interdisciplinary approach. As a result, improved periodontal health and a stable occlusion and vertical dimension were achieved. Although there were limited teeth and alveolar bone for anchorage, good esthetic and functional treatment results were obtained through the application of temporary anchorage devices and proper biomechanics. PMID- 29407507 TI - Bone-anchored maxillary protraction in a patient with complete cleft lip and palate: A case report. AB - Sagittal maxillary deficiency is frequently observed in patients with operated unilateral complete cleft of the lip and palate. Treatment for moderate to severe Class III malocclusion usually relies on LeFort I surgery for maxillary advancement after the end of growth. This case report describes bone-anchored maxillary protraction in a 10-year-old white boy with unilateral complete cleft of the lip and palate. His interarch relationship was diagnosed as GOSLON index 5 before treatment with a negative overjet of 3.2 mm. The orthopedic traction was started 4 months after secondary alveolar bone graft surgery and before comprehensive orthodontic treatment. Class III elastics were used full time for 18 months. After treatment, the interarch relationship was GOSLON index 1 with a positive overjet. The SNA angle increased by 6.50 degrees and A-Na Perp increased by 3.8 mm, leading to marked improvement in facial convexity (+14.6 degrees ). No posterior rotation of the mandible occurred with a slight closure of the gonial angle. Visualization of 3-dimensional color-coded maps showed an overall forward maxillary displacement. The bone-anchored maxillary protraction results for this patient are a promising orthopedic therapy for patients with unilateral complete cleft of the lip and palate, with the advantage of achieving much earlier improvement of facial esthetics and functional occlusion, compared with LeFort I surgery at skeletal maturity. PMID- 29407508 TI - Accuracy of bracket positions with a CAD/CAM indirect bonding system in posterior teeth with different cusp heights. AB - INTRODUCTION: Our objective was to evaluate the effect of cusp height of posterior teeth (first premolar, second premolar, first molar) on the accuracy of the computer-aided design and computer-aided manufacturing (CAD-CAM) indirect bonding system. MATERIAL: Five kinds of maxillary arch models, without attrition, were divided into 2 groups: control group (with 0.5 mm of grinding) and experimental group (with the addition of 0.5 mm of wax to the cusp tip). Rapid prototype models were printed for both groups. Transfer jigs of the individual tooth brackets were designed using a digital model. 3-dimensional program to evaluate the differences between the intended digital bracket position and actual bracket position after indirect bonding. The differences were measured in the linear (mesiodistal, buccolingual, vertical) and angular (angulation, rotation, torque) dimensions. The Wilcoxon signed rank test was used for statistical analyses; significance was defined as P <0.05. RESULTS: Both groups had similar frequencies of errors between the intended and actual bracket positions. The frequencies of vertical errors over 0.5 mm were 3.3% and 6.7% in the control and experimental groups, respectively. The frequencies of angulation, rotation, and torque errors over 1 degrees were 53.3%, 43.3%, and 60%, respectively, for the control group; and 60%, 60%, and 73.3%, respectively, for the experimental group. CONCLUSIONS: A difference in cusp height of maxillary posterior teeth did not produce a statistically significant difference in the linear and angular dimensions of bracket placement with the CAD/CAM indirect bonding system. However, given the tendency for a higher frequency in bracket placement errors in posterior teeth with larger cusp tips, cusp height should be considered when using a CAD/CAM indirect bonding system. PMID- 29407509 TI - Reliability of different radiographic methods for the localization of displaced maxillary canines. AB - INTRODUCTION: The purpose of this study was to evaluate the reliability of the radiographic images of the main conventional x-ray techniques compared with the information from cone-beam computed tomography (CBCT). METHODS: Twenty patients with unilateral or bilateral impaction of the maxillary canines had radiographic examinations by means of periapical x-rays, occlusal x-rays, panoramic x-rays, and CBCT scans. Three experienced orthodontists examined all x-rays from each patient and evaluated the radiographic images of the impacted canines. The examiners were asked to detect resorption in adjacent teeth and the buccal palatal position of the impacted canines. Agreement between examiners was statistically tested. RESULTS: Different diagnoses were produced by the 3 examiners regarding localization of the impacted canines and the presence or absence of root resorption of the adjacent teeth in conventional radiographic images. It appears that whereas panoramic x-ray is more sensitive in detecting resorption and tooth position, occlusal and periapical imaging have higher specificity and positive predictive value. The examiners were in good or excellent agreement when occlusal and periapicals were used for the definite diagnosis of resorption and tooth position. There was no disagreement of the examiners in CBCT images, which were used as the gold standard. CONCLUSIONS: Conventional radiographic methods demonstrated a more subjective diagnostic procedure compared with CBCT images. CBCT is a more accurate and precise examination method compared with conventional radiography for the localization of impacted teeth and root resorption of the adjacent teeth. PMID- 29407510 TI - I don't really feel comfortable doing that. PMID- 29407511 TI - Statistical testing against baseline. PMID- 29407512 TI - Maternal depression, antidepressant use and placental oxytocin receptor DNA methylation: Findings from the MPEWS study. AB - The aim of this study was to investigate placental DNA methylation of the oxytocin receptor gene (OXTR) in women with depression in pregnancy. We also explored the role of antidepressant medication in pregnancy on placental OXTR methylation. Data were obtained from 239 women in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a selected pregnancy cohort. Current depressive disorders were diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID-IV). Depressive symptoms were measured during the third trimester in pregnancy using the Edinburgh Postnatal Depression Scale (EPDS). Plasma levels of antidepressant drugs were measured in maternal and cord blood obtained at delivery. OXTR DNA methylation was measured in placenta samples. Depressive symptoms in pregnancy were not associated with significant changes in DNA methylation of OXTR in the placenta. Cord plasma antidepressant levels were more strongly associated than maternal antidepressant dose or circulating blood antidepressant levels with increased DNA methylation of a specific unit within the promotor region of OXTR. This study provides preliminary data to suggest that antidepressant use during pregnancy can alter OXTR methylation in placental tissue. Our findings also indicate that the way exposures are measured in pregnancy can influence the direction and strength of findings. Future studies should investigate whether altered OXTR methylation might mediate the impacts of maternal antidepressant treatment on pregnancy and offspring outcomes. PMID- 29407513 TI - Dissociable roles of glucocorticoid and noradrenergic activation on social discounting. AB - People often exhibit prosocial tendencies towards close kin and friends, but generosity decreases as a function of increasing social distance between donor and recipient, a phenomenon called social discounting. Evidence suggests that acute stress affects prosocial behaviour in general and social discounting in particular. We tested the causal role of the important stress neuromodulators cortisol (CORT) and noradrenaline (NA) in this effect by considering two competing hypotheses. On the one hand, it is possible that CORT and NA act in concert to increase generosity towards socially close others by reducing the aversiveness of the cost component in costly altruism and enhancing the emotional salience of vicarious reward. Alternatively, it is equally plausible that CORT and NA exert dissociable, opposing effects on prosocial behaviour based on prior findings implicating CORT in social affiliation, and NA in aggressive and antagonistic tendencies. We pharmacologically manipulated CORT and NA levels in a sample of men (N = 150) and found that isolated hydrocortisone administration promoted prosocial tendencies towards close others, reflected in an altered social discount function, but this effect was offset by concurrent noradrenergic activation brought about by simultaneous yohimbine administration. These results provide inceptive evidence for causal, opposing roles of these two important stress neuromodulators on prosocial behaviour, and give rise to the possibility that, depending on the neuroendocrine response profile, stress neuromodulator action can foster both tend-and-befriend and fight-or-flight tendencies at the same time. PMID- 29407514 TI - Prenatal stress and genetic risk: How prenatal stress interacts with genetics to alter risk for psychiatric illness. AB - Risk for neuropsychiatric disorders is complex and includes an individual's internal genetic endowment and their environmental experiences and exposures. Embryonic development captures a particularly complex period, in which genetic and environmental factors can interact to contribute to risk. These environmental factors are incorporated differently into the embryonic brain than postnatal one. Here, we comprehensively review the human and animal model literature for studies that assess the interaction between genetic risks and one particular environmental exposure with strong and complex associations with neuropsychiatric outcomes-prenatal maternal stress. Gene-environment interaction has been demonstrated for stress occurring during childhood, adolescence, and adulthood. Additional work demonstrates that prenatal stress risk may be similarly complex. Animal model studies have begun to address some underlying mechanisms, including particular maternal or fetal genetic susceptibilities that interact with stress exposure and those that do not. More specifically, the genetic underpinnings of serotonin and dopamine signaling and stress physiology mechanisms have been shown to be particularly relevant to social, attentional, and internalizing behavioral changes, while other genetic factors have not, including some growth factor and hormone-related genes. Interactions have reflected both the diathesis-stress and differential susceptibility models. Maternal genetic factors have received less attention than those in offspring, but strongly modulate impacts of prenatal stress. Priorities for future research are investigating maternal response to distinct forms of stress and developing whole-genome methods to examine the contributions of genetic variants of both mothers and offspring, particularly including genes involved in neurodevelopment. This is a burgeoning field of research that will ultimately contribute not only to a broad understanding of psychiatric pathophysiology but also to efforts for personalized medicine. PMID- 29407515 TI - Turning Data Into Information: Opportunities to Advance Rehabilitation Quality, Research, and Policy. AB - Attention to health care quality and safety has increased dramatically. The internal focus of an organization is not without influence from external policy and research findings. Compared with other specialties, efforts to align and advance rehabilitation research, practice, and policy using electronic health record data are in the early stages. This special communication defines quality, applies the dimensions of quality to rehabilitation, and illustrates the feasibility and utility of electronic health record data for research on rehabilitation care quality and outcomes. Using data generated at the point of care provides the greatest opportunity for improving the quality of health care, producing generalizable evidence to inform policy and practice, and ultimately benefiting the health of the populations served. PMID- 29407516 TI - Preoperative Risk Factors for Postoperative Falls in Persons Undergoing Hip or Knee Arthroplasty: A Longitudinal Study of Data From the Osteoarthritis Initiative. AB - OBJECTIVE: To identify preoperative risk factors associated with posthospitalization falls over an approximate 2-year postoperative period in patients undergoing both hip and knee arthroplasty. DESIGN: A longitudinal cohort design. SETTING: Communities surrounding 4 urban university-based medical centers. PARTICIPANTS: Adults (N = 596) with hip or knee arthroplasty over a 9 year period and followed yearly. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome measure was a self-reported history of falls over the 2-year postoperative period. A fall was recorded when the participant reported landing on the floor or ground. Preoperative predictors of falls derived from previous evidence included preoperative fall history, depressive symptom severity, narcotic use, age, activity level, and comorbidity. Multinomial regression analysis was performed to determine factors that predicted either a single fall or multiple falls during a 2-year postoperative period. RESULTS: Preoperative predictors of multiple postoperative falls were a preoperative history of falls, depressive symptoms, and hip vs knee arthroplasty. Patients with hip arthroplasty were more than twice as likely (odds ratio, 2.26; 95% confidence interval, 1.21-4.20) as patients with knee arthroplasty to have multiple self-reported falls in the first 2 postoperative years. No predictors were found for persons who reported falling only once postoperatively. Findings were generally supported in a sensitivity analysis. CONCLUSIONS: Clinicians involved in the pre- and postoperative care of persons undergoing hip or knee arthroplasty can use these findings to inform fall risk screening and intervention delivery to reduce fall risk in patients who are at risk for multiple falls after hip or knee arthroplasty. PMID- 29407517 TI - Responsiveness of the Traumatic Brain Injury-Quality of Life (TBI-QOL) Measurement System. AB - OBJECTIVE: To assess the responsiveness of the Traumatic Brain Injury-Quality of Life (TBI-QOL) measurement system. DESIGN: Participants completed the 20 TBI-QOL item banks and the Participation Assessment with Recombined Tools-Objective (PART O) Productivity Subscale at baseline and 6-month follow-up assessments. Participants were categorized into 4 groups (increased productivity, unchanged productivity, and decreased productivity) based on PART-O Productivity scores. Paired sample t tests were used to compare TBI-QOL scores at baseline and 6 months, and standardized response means and Cohen's d were computed to estimate effect sizes. SETTING: Three traumatic brain injury (TBI) Model Systems rehabilitation centers in the United States. PARTICIPANTS: Two hundred one community-dwelling adults with TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: 20 TBI-QOL item banks. RESULTS: As expected, given that there was no intervention, group mean TBI-QOL subdomain scores for the entire sample showed no change or small improvement over the 6-month study period. At the follow-up assessment, 72 participants reported increased productivity, 71 reported decreased productivity, and 58 reported the same level of productivity as they had 6 months prior. When compared with participants who reported unchanged or decreased productivity, participants who reported increased productivity on the PART-O subscale had clinically meaningful (d>=0.30) improvements on 7 TBI-QOL measures. The largest improvement was in the Independence subdomain (mean change, 7.06; df=0.84), with differences also observed in the Mobility, Positive Affect and Well-Being, Resilience, Grief/Loss, Ability to Participate, and Satisfaction with Participation subdomains. CONCLUSIONS: The 20 TBI-QOL item banks demonstrate responsiveness to change and measurement stability in a community-dwelling sample. Researchers may use the TBI-QOL to detect changes in HRQOL after a clinical intervention and clinicians may use it in their daily practices to monitor patient recovery. PMID- 29407518 TI - Hospital Readmission in Total Hip Replacement Patients in 2009 and 2014. AB - OBJECTIVE: To document changes in 30-day hospital readmission rates and causes for returning to the hospital for care in THR patients. DESIGN: Retrospective cross-sectional descriptive design. SETTING: Community-based acute care hospitals. PARTICIPANTS: Total sample size (N=142,022) included THR patients (identified as ICD-9-CM procedure code 81.51) in 2009 (n=31,232) and (n=32,863) in 2014. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: 30-Day hospital readmission. RESULTS: The overall readmission rate decreased by 1.3% from 2009 to 2014. The decrease in readmission rates varied by groups, with lesser improvements seen in THR patients who were younger, with private insurance, and residing in lower-income and rural communities. Device complications were the leading cause of readmission in THR patients, increasing from 19.8% in 2009 to 23.9% in 2014. CONCLUSIONS: There has been little decrease in hospital 30-day readmission rates for US community hospitals between 2009 and 2014. Findings from this brief report indicate patient groups at greater risk for 30-day hospital readmission as well as leading causes for readmission in THR patients which can inform the development of tailored interventions for reduction. PMID- 29407519 TI - Predictors for Employment Status in People With Multiple Sclerosis: A 10-Year Longitudinal Observational Study. AB - OBJECTIVE: To identify predictors for employment status after 10 years in a cohort of people with multiple sclerosis (MS), with the aim to increase knowledge concerning factors present at an early stage that are important for working life and work-life balance. DESIGN: A 10-year longitudinal observational cohort study. SETTING: University hospital. PARTICIPANTS: A consecutive sample of people with MS (N=154) of working age were included at baseline, of which a total of 116 people participated in the 10-year follow-up; 27 people declined participation and 11 were deceased. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Baseline data on personal factors and functioning were used as independent variables. Employment status 10 years after baseline, categorized as full-time work, part-time work, and no work, was used as the dependent variable. A generalized ordinal logistic regression was used to analyze the predictive value of the independent variables. RESULTS: Predictors for full- or part-time work after 10 years were young age (P=.002), low perceived physical impact of MS (P=.02), fatigue (P=.03), full-time work (P=.001), and high frequency of social/lifestyle activities (P=.001) at baseline. Low perceived physical impact of MS (P=.02) at baseline also predicted full-time work after 10 years. CONCLUSIONS: This study underlines the complexity of working life for people with MS, and indicates that it may be valuable to give more attention to the balance between working and private life, both in clinical practice and future research, to achieve a sustainable working life over time. PMID- 29407520 TI - Effect of Whole-Body Vibration on Sagittal Plane Running Mechanics in Individuals With Anterior Cruciate Ligament Reconstruction: A Randomized Crossover Trial. AB - OBJECTIVE: To examine the effect of whole-body vibration (WBV) on running biomechanics in individuals with anterior cruciate ligament reconstruction (ACLR). DESIGN: Single-blind randomized crossover trial. SETTING: Research laboratory. PARTICIPANTS: Individuals (N=20) with unilateral ACLR (age [+/- SD]=22.3 [+/-3.3] years; mass=71.8 [+/-15.3] kg; time since ACLR=44.9 [+/-22.8] months; 15 females, 10 patellar tendon autograft, 7 hamstrings autograft, 3 allograft; International Knee Documentation Committee Score=83.5 [+/-9.3]). MAIN OUTCOME MEASURE: Participants performed isometric squats while being exposed to WBV or no vibration (control). WBV and control conditions were delivered in a randomized order during separate visits separated by 1-week washout periods. Running biomechanics of the injured and uninjured limbs were evaluated before and immediately after each intervention. Dependent variables included peak vertical ground reaction force (GRF) and loading rate (LR), peak knee flexion angle and external moment, and knee flexion excursion during the stance phase of running. RESULTS: There was an increase in knee flexion excursion (+4.1 degrees , 95% confidence interval [CI]: 0.65, 7.5 degrees ) and a trend toward a reduction in instantaneous LR after WBV in the injured limb (-4.03 BW/sec-1, 95% CI -0.38, 7.69). No effect was observed on peak GRF, peak knee flexion angle, or peak external knee flexion moment, and no effect was observed in the uninjured limb. CONCLUSIONS: Our findings indicate that a single session of WBV acutely increases knee flexion excursion. WBV could be useful to improve running characteristics in individuals with knee pathology. PMID- 29407521 TI - Investigating the Variability in Mild Traumatic Brain Injury Definitions: A Prospective Cohort Study. AB - OBJECTIVE: To prospectively compare the proportion of traumatic brain injuries (TBIs) that would be classified as mild by applying different published definitions of mild TBI to a large prospectively collected dataset, and to examine the variability in the proportions included by various definitions. DESIGN: Prospective observational study. SETTING: Hospital emergency departments. PARTICIPANTS: Children (N=11,907) aged 3 to 16 years (mean age, 8.2+/-3.9y). Of the participants, 3868 (32.5%) were girls, and 7374 (61.9%) of the TBIs were the result of a fall. Median Glasgow Coma Scale score was 15. MAIN OUTCOME MEASURES: We applied 17 different definitions of mild TBI, identified through a published systematic review, to children aged 3 to 16 years. Adjustments and clarifications were made to some definitions. The number and percentage identified for each definition is presented. RESULTS: Adjustments had to be made to the 17 definitions to apply to the dataset: none in 7, minor to substantial in 10. The percentage classified as mild TBI across definitions varied from 7.1% (n=841) to 98.7% (n=11,756) and varied by age group. CONCLUSIONS: When applying the 17 definitions of mild TBI to a large prospective multicenter dataset of TBI, there was wide variability in the number of cases classified. Clinicians and researchers need to be aware of this variability when examining literature concerning children with mild TBI. PMID- 29407522 TI - NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis. AB - NGF is a well-studied neurotrophic factor, and TrkA is a receptor tyrosine kinase for NGF. The NGF-TrkA system supports the survival and maintenance of NGF dependent neurons during development. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder due to loss-of function mutations in the NTRK1 gene encoding TrkA. Individuals with CIPA lack NGF-dependent neurons, including NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. Thus, the pathophysiology of CIPA can provide intriguing findings to elucidate the unique functions that NGF dependent neurons serve in humans, which might be difficult to evaluate in animal studies. Preceding studies have shown that the NGF-TrkA system plays critical roles in pain, itching and inflammation. This review focuses on the clinical and neurobiological aspects of CIPA and explains that NGF-dependent neurons in the peripheral nervous system play pivotal roles in interoception and homeostasis of our body, as well as in the stress response. Furthermore, these NGF-dependent neurons are likely requisite for neurobiological processes of 'emotions and feelings' in our species. PMID- 29407523 TI - High anxiety trait: A vulnerable phenotype for stress-induced depression. AB - A great deal of research aims to identify risk factors related to individual vulnerability to develop stress-induced psychopathologies. Here, we summarize evidence that point at anxiety trait as a significant contributor to inter individual differences in stress-vulnerability. Specifically, we underscore high anxiety trait as a key vulnerability phenotype. Highly anxious individuals show both behavioral alterations and cognitive deficits, along with more reactive physiological stress responses. We discuss efforts and progress towards the identification of genetic variants and polygenetic scores that explain differences in trait anxiety and vulnerability to stress. We then summarize molecular alterations in the brain of individuals with high anxiety trait that can help explaining the increased vulnerability to stress of these individuals. Variation in such systems can act as risk factors, which in combination with severe/prolonged stressful life events can pave the way towards the development of depression. Our viewpoint implies that the consideration of high anxiety trait as a key vulnerability phenotype in stress research can support the overall aim to obtain improved or novel therapeutic approaches. PMID- 29407525 TI - Numerical modeling of fluid and oxygen exchanges through microcirculation for the assessment of microcirculation alterations caused by type 2 diabetes. AB - Type 2 diabetes mellitus (DM2) is frequently accompanied by microcirculation complications, including structural and functional alterations, which may have serious effects on substance exchanges between blood and interstitial tissue and the health of organs. In this paper, we aim to study the influence of microcirculation alterations in DM2 patients on fluid and oxygen exchanges through a model analysis. A fluid flow and oxygen transport model were developed by considering the interplay between blood in capillary network and interstitial tissue. The two regions were separately represented by 1D network model and 3D volume model, and the immersed boundary method (IBM) was adopted to solve fluid and mass transfer between these two regions. By using the model, the steady flow field and the distributions of oxygen in capillary network and surrounding tissue were firstly simulated. In the interstitial volume, fluid pressure and oxygen tension decreased with the increase of distance from the network; in the network, oxygen tension in blood plasma dropped from 100 mm Hg at the entrance to about 40 mm Hg at the exit. We further tested several structural and functional disorders related to diabetic pathological conditions. Simulated results show that the impaired connectivity of the network could result in poor robustness in maintaining blood flow and perfused surface; under high fluid permeability conditions of capillary walls, the pressure gradient was much larger around the capillary bed, and this alteration led to a saturation level of the interstitial pressure when lymphatic flow drainage can't work effectively; the variations in network connectivity and permeability of capillary wall also had unfavorable influence on oxygen distributions in interstitial tissue. In addition, when the oxygen releasing capacity of hemoglobin was confined by glycosylated hemoglobin (HbA1) in the case of diabetes, the plasma could not be complemented with adequate oxygen and thus the hypoxic tissue range will be extended. This study illustrates that when microcirculation disturbances, including the structure of capillary network, the wall osmosis property and the capacity of blood binding oxygen occur in DM2, some negative impacts are raised on microvascular hemodynamics and metabolism circumstance of interstitial tissue. PMID- 29407526 TI - Measurement of food-related approach-avoidance biases: Larger biases when food stimuli are task relevant. AB - Strong implicit responses to food have evolved to avoid energy depletion but contribute to overeating in today's affluent environments. The Approach-Avoidance Task (AAT) supposedly assesses implicit biases in response to food stimuli: Participants push pictures on a monitor "away" or pull them "near" with a joystick that controls a corresponding image zoom. One version of the task couples movement direction with image content-independent features, for example, pulling blue-framed images and pushing green-framed images regardless of content ('irrelevant feature version'). However, participants might selectively attend to this feature and ignore image content and, thus, such a task setup might underestimate existing biases. The present study tested this attention account by comparing two irrelevant feature versions of the task with either a more peripheral (image frame color: green vs. blue) or central (small circle vs. cross overlaid over the image content) image feature as response instruction to a 'relevant feature version', in which participants responded to the image content, thus making it impossible to ignore that content. Images of chocolate-containing foods and of objects were used, and several trait and state measures were acquired to validate the obtained biases. Results revealed a robust approach bias towards food only in the relevant feature condition. Interestingly, a positive correlation with state chocolate craving during the task was found when all three conditions were combined, indicative of criterion validity of all three versions. However, no correlations were found with trait chocolate craving. Results provide a strong case for the relevant feature version of the AAT for bias measurement. They also point to several methodological avenues for future research around selective attention in the irrelevant versions and task validity regarding trait vs. state variables. PMID- 29407524 TI - Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target. AB - The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in peripheral and brain lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation. The sEH enzyme and its oxylipin products are elevated post-mortem in MDD, BD and schizophrenia. Preliminary clinical data suggest that oxylipins increase with symptoms in seasonal MDD and anorexia nervosa, requiring confirmation in larger studies and other cohorts. In rats, a soluble sEH inhibitor mitigated the development of depressive-like behaviors. We discuss sEH inhibitors under development for cardiovascular diseases, post-ischemic brain injury, neuropathic pain and diabetes, suggesting new possibilities to address the mood and cognitive symptoms of psychiatric disorders, and their most common comorbidities. PMID- 29407528 TI - The interplay between HIF-1 and calcium signalling in cancer. AB - The interplay between hypoxia-inducible factor-1 (HIF-1) and calcium in cancer has begun to be unravelled with recent findings demonstrating the relationships between the two in different cancer types. This is an area of significance considering the crucial roles of both HIF-1 and calcium signalling in cancer progression and metastasis. This review summarises the experimental evidence of the crosstalk between HIF-1 and specific calcium channels, pumps and regulators in the context of cancer. HIF-1 as a master regulator of hypoxic transcriptional responses, mediates transcription of several calcium modulators. On the other hand, specific calcium channels and pumps regulate HIF-1 activity through controlling its transcription, translation, stabilisation, or nuclear translocation. Identifying the interplay between HIF-1 and components of the calcium signal will give new insights into mechanisms underlying cellular responses to physiological and pathophysiological cues, and may provide novel and more efficient therapeutic strategies for the control of cancer progression. PMID- 29407527 TI - Mindfulness and laboratory eating behavior in adolescent girls at risk for type 2 diabetes. AB - Mindfulness-based intervention has become increasingly popular to address disinhibited eating in obesity and type 2 diabetes (T2D). Theoretically, present moment attention promotes the ability to recognize and respond to internal hunger cues and to differentiate physiological hunger from other stimuli. Yet, there is limited research describing the relationship of mindfulness with disinhibited eating patterns in adolescents. In this study, we evaluated the relationship of dispositional mindfulness to laboratory eating in 107 adolescent (12-17 years) girls at risk for T2D. Adolescents reported dispositional mindfulness, were evaluated for recent loss-of-control-eating (LOC-eating) by interview, and participated in two successive, standardized laboratory test meals to assess eating when hungry as well as eating in the absence of hunger (EAH). Adolescents rated state appetite throughout the test meal paradigms. In analyses adjusting for body composition and other possible confounds, mindfulness was inversely related to caloric intake during the EAH paradigm. Mindfulness did not relate to energy intake when hungry. Instead, there was a significant interaction of reported LOC-eating by state hunger, such that girls with recent, reported LOC eating and high state hunger consumed more calories when hungry, regardless of mindfulness. Findings suggest that in girls at risk for T2D, mindfulness may play a role in disinhibited eating. A propensity for LOC-eating may be most salient for overeating in a high hunger state. PMID- 29407529 TI - Cost-effectiveness of community screening for glaucoma in rural India: a decision analytical model. AB - OBJECTIVES: Studies in several countries have demonstrated the cost-effectiveness of population-based screening for glaucoma when targeted at high-risk groups such as older adults and with familial history of disease. This study conducts a cost effective analysis of a hypothetical community screening and subsequent treatment programme in comparison to opportunistic case finding for glaucoma in rural India. STUDY DESIGN: A hypothetical screening programme for both primary open angle glaucoma and angle-closure disease was built for a population aged between 40 and 69 years in rural areas of India. METHODS: A decision analytical model was built to model events, costs and treatment pathways with and without a hypothetical screening programme for glaucoma for a rural-based population aged between 40 and 69 years in India. The treatment pathway included both primary open-angle glaucoma and angle-closure disease. The data on costs of screening and treatment were provided by an administrator of a tertiary eye hospital in Eastern India. The probabilities for the screening and treatment pathway were derived from published literature and a glaucoma specialist. The glaucoma prevalence rates were adapted from the Chennai Glaucoma Study findings. RESULTS: An incremental cost-effectiveness ratio value of ?7292.30 per quality-adjusted life year was calculated for a community-screening programme for glaucoma in rural India. The community screening for glaucoma would treat an additional 2872 cases and prevent 2190 person-years of blindness over a 10-year period. CONCLUSIONS: Community screening for glaucoma in rural India appears to be cost-effective when judged by a ratio of willingness-to-pay thresholds as per WHO-CHOICE guidelines. For community screening to be cost-effective, adequate resources, such as trained medical personnel and equipment would need to be made available. PMID- 29407530 TI - From sublexical facilitation to lexical competition: ERP effects of masked neighbor priming. AB - Interactive-activation models posit that visual word recognition involves co activation of orthographic neighbors (e.g., note, node) and competition among them via lateral inhibitory connections. Behavioral evidence of this lexical competition comes from masked priming paradigms, in which target words elicit slower responses when preceded by a neighbor (e.g., note-NODE) than when preceded by an unrelated word (e.g., kiss-NODE). In the present study, we used ERPs to investigate how masked high frequency word primes influence processing of low frequency word and pseudoword targets. Word targets preceded by a neighbor prime elicited larger negativities within the N400 window than those preceded by an unrelated prime across bilateral anterior sites, which we call a reversed N400 priming effect. Consistent with the behavioral literature, the size of the reversed N400 priming effect was larger for targets from high-density orthographic neighborhoods and for participants who scored higher on a behavioral measure of spelling recognition. Indeed, the opposite effect (i.e., smaller negativities within the N400 window for word targets preceded by a neighbor) was observed for words from low-density orthographic neighborhoods and for less skilled spellers. Traditional priming was also observed within the N250 window for word targets and within both the N250 or N400 windows for pseudoword targets. The specificity of the reversed N400 priming effect to situations in which both words have precise lexical representations suggests that it, like the behavioral interference effect, indexes lexical competition during visual word recognition. PMID- 29407531 TI - Food for thought: Exploring how people think and talk about food online. AB - This exploratory study examined the ways in which people communicate about food online by analyzing food-related conversations on Reddit, a social news networking site. The Meaning Extraction Helper (MEH) was used to analyze 2 corpora and define central themes related to online food talk. In light of these themes, the researchers discuss socio-cultural components shaping the food conversations in our society in general as well as healthy versus unhealthy communities, and provided specific directions for future empirical research. PMID- 29407532 TI - The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice. AB - Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories. PMID- 29407533 TI - Are affective temperaments determinants of quality of life in euthymic patients with bipolar disorder? AB - BACKGROUND: Bipolar disorder (BD) is a disabling illness that is associated with low quality of life (QoL). This low QoL goes further than mood episodes, which suggests that stable traits, such as affective temperaments, can cause functional impairment. OBJECTIVE: Our study analyses the impact of affective temperaments on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of QoL in euthymic BD patients. METHODS: A multicentre study was conducted in 180 euthymic BD patients and 95 healthy controls. Firstly, statistical analyses were performed to compare QoL and affective temperaments between the two groups. Secondly, Adaptive Lasso Analysis was carried out to identify the potential confounding variables and select the affective temperaments as potential predictors on the PCS and MCS of QoL in BD patients, as well as the control group. RESULTS: QoL scores in terms of PCS and MCS in BD patients were significantly lower than in healthy individuals. Whereas anxious temperament, anxiety disorder comorbidity, and age were the best predictors of PCS impairment in BD patients, anxious temperament, subclinical depressive symptoms, and age were the best predictors of MCS impairment. LIMITATIONS: Further longitudinal studies with unaffected high risk relatives are needed to examine the potential interaction between affective temperament and psychopathology. CONCLUSIONS: Anxious temperament has an impact on QoL in BD in terms of both the physical component and the mental component. Systematic screening of temperament in BD would give clinicians better knowledge of QoL predictors. Further research should allow more individualized treatment of BD patients based on temperamental factors. PMID- 29407534 TI - Social and academic functioning in adolescents with anxiety disorders: A systematic review. AB - BACKGROUND: Anxiety disorders are highly prevalent during adolescence. Although literature points out that anxiety symptoms are related to problems in social and academic functioning, the extent of these problems among adolescents with clinical anxiety disorders has not been systematically reviewed before. METHODS: Electronic databases were searched up to October 2017, with keywords representing anxiety disorders, adolescents, and social or academic functioning. The inclusion criteria were studies with a sample of adolescents (10-19 years) with anxiety disorders that provided data regarding their social or academic functioning. 3431 studies were examined, of which 19 met the inclusion criteria. RESULTS: Adolescents with anxiety disorders had a lower social competence relative to their healthy peers. They reported more negativity within interpersonal relationships, higher levels of loneliness, and victimization. Most adolescents with anxiety disorders felt impaired at school, however, findings of their average school results, compared to peers, were mixed. In addition, they had a higher risk for school refusal and entered higher education less often. Impairments in social and academic functioning differed across type and the number of anxiety disorders. LIMITATIONS: Most studies examined social phobia or anxiety disorders in general and methodological approaches varied widely between studies. CONCLUSIONS: This systematic review indicates that adolescents with anxiety disorders experience a range of significant problems in both social and academic functioning. These findings suggest that the assessment and treatment of anxiety disorders in adolescence should focus on improving functioning across domains. PMID- 29407535 TI - Change in 1-year hospitalization of overall and older patients with major depressive disorder after second-generation antipsychotics augmentation treatment. AB - BACKGROUND: Studies on second-generation antipsychotics (SGA) augmentation treatment for older adults with major depressive disorder (MDD) remain limited. We aimed to investigate the effectiveness of SGA augmentation for overall and older patients with MDD inpatient history by assessing the change in 1-year hospitalization before and after SGA augmentation using the latest National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: The samples were MDD patients (ICD-9 CM code: 296.2 and 296.3) who had psychiatric inpatient history. A total of 2602 MDD patients including 430 elderly subjects (age >= 60 years) who received SGA augmentation for 8 weeks between January 1998 and December 2012 were included in this 1-year mirror-image study. Outcome measures included number and length of psychiatric and all-cause hospitalizations. RESULTS: After 8-week continuous SGA augmentation in the study subjects, the total number and days of psychiatric hospitalizations among overall patients reduced by 33.57% (p < .0001) and 18.24% (p < .0001), respectively; the total number and days of psychiatric hospitalizations among older patients (age >= 60) reduced by 44.52% (p < .0001) and 27.95% (p < .0001), respectively. Similarly, the total number and days of all-cause hospitalizations were significantly reduced. LIMITATIONS: MDD patients without inpatient history were not included due to data limitation; hence, the results may not be generalized to all patients. CONCLUSIONS: The results support that SGA may be effective in reducing psychiatric and all-cause hospitalization among overall and elderly MDD patients. More studies focusing on the safety of SGA among older MDD patients is warranted. PMID- 29407536 TI - Differential associations between patterns of child maltreatment and comorbidity in adult depressed patients. AB - BACKGROUND: Types of maltreatment often co-occur and it is unclear how maltreatment patterns impact on comorbidity in depressed patients. METHODS: We analysed associations of maltreatment patterns with a broad range of comorbidities assessed with diagnostic interviews in 311 treatment-seeking depressed outpatients. RESULTS: Latent class analyses identified a "no maltreatment class" (39%), a "mild to moderate abuse and neglect class" (34%), a "severe abuse and neglect class" (14%) and a "severe neglect class" (13%). We found a dose-response association for the first three classes with comorbid disorders, a general psychopathology factor and an interpersonal insecurity factor. Patients in the "severe abuse and neglect" class had increased odds ratios (OR) of suffering from an anxiety disorder (OR 3.58), PTSD (OR 7.09), Borderline personality disorder (OR 7.97) and suicidality (OR 10.04) compared to those without child maltreatment. Patients in the "severe neglect" class did not have a higher risk for comorbidity than those in the "no maltreatment" class. LIMITATIONS: Class sizes in the "severe abuse and neglect" and the "severe neglect" classes were small and findings should be replicated with other clinical and population samples. CONCLUSIONS: A higher severity rather than the constellation of types of child abuse and neglect was associated with more comorbid disorders. An exception were patients reporting solely severe emotional and physical neglect who had a similar risk for comorbidity as patients without a history of child maltreatment. This may be associated with distinct learning experiences and may inform treatment decisions. PMID- 29407537 TI - Loneliness is closely associated with depression outcomes and suicidal ideation among military veterans in primary care. AB - BACKGROUND: Although the substantial influence of social relationships on health is well-known, studies that concurrently examine the influence of varying dimensions of social connectedness on major depression are more limited. This study's aim was to determine to what degree several facets of social connectedness (number of confidants, social support, interpersonal conflict, social norms, and loneliness) are correlated with depression-related outcomes. METHODS: Participants were primary care patients (n = 301) with probable major depression at a Veterans Health Administration hospital and its satellite clinics. Social connectedness was primarily measured using multi-item instruments from the NIH Toolbox of Adult Social Relationship Scales. Primary outcomes were clinical symptoms (depression and suicidal ideation) and secondary outcomes were self-reported health-related behaviors (medication adherence, patient activation, and help-seeking intentions). RESULTS: In multivariate models adjusting for potential confounders and other facets of connectedness, loneliness was associated with higher levels of depression and suicidal ideation, as well as lower patient activation and help-seeking intentions. Social support and social norms about depression treatment were each associated with higher patient activation and help-seeking intentions. Social connectedness was not associated with medication adherence. LIMITATIONS: The limitations of this study are primarily related to its cross-sectional survey design and study population. CONCLUSIONS: Multiple aspects of social connectedness are associated with depression outcomes among military veterans with depression. Loneliness may represent the most important component of connectedness, as it is associated with depression severity, suicidality, and health-related behaviors. PMID- 29407538 TI - Measurement of depression treatment among patients receiving HIV primary care: Whither the truth? AB - BACKGROUND: Prescription records, manual chart review, and patient self-report are each imperfect measures of depression treatment in HIV-infected adults. METHODS: We compared antidepressant prescription records in an electronic data warehouse with antidepressant treatment and psychotherapy identified via manual chart review and self-report for patients at 6 academic HIV treatment centers. We examined concordance among these three sources, and used latent class analysis (LCA) to estimate sensitivity and specificity of each measure. RESULTS: In our charts sample (n = 586), 59% had chart indication of "any depression treatment" and 46% had a warehouse prescription record. Antidepressant use was concordant between charts and data warehouse for 77% of the sample. In our self-report sample (n = 677), 52% reported any depression treatment and 43% had a warehouse prescription record. Self-report of antidepressant treatment was consistent with prescription records for 71% of the sample. LCA estimates of sensitivity and specificity for "any depression treatment" were 67% and 90% (warehouse), 87% and 75% (self-report), and 96% and 77% (chart). LIMITATIONS: There is no gold standard to measure depression treatment. Antidepressants may be prescribed to patients for conditions other than depression. The results may not be generalizable to patient populations in non-academic HIV clinics. Regarding LCA, dependence of errors may have led to overestimation of sensitivity and specificity. CONCLUSIONS: Prescription records were largely concordant with self report and chart review, but there were discrepancies. Studies of depression in HIV-infected patients would benefit from using multiple measures of depression treatment or correcting for exposure misclassification. PMID- 29407539 TI - A pilot study of minocycline for the treatment of bipolar depression: Effects on cortical glutathione and oxidative stress in vivo. AB - BACKGROUND: The antibiotic minocycline appears to promote neuroprotection through antioxidant and other mechanisms that may be relevant to the pathophysiology of bipolar disorder. The present study assessed the efficacy of minocycline in bipolar depression and examined the association between minocycline treatment and brain glutathione (GSH), an essential regulator of oxidative stress. METHOD: Twenty patients with bipolar disorder experiencing acute depressive symptoms enrolled in an 8-week, open-label trial of adjuvant minocycline. Depression was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and proton magnetic resonance spectroscopy (1H MRS) measures of cortical GSH within a voxel prescribed in the precuneus and aspects of the occipital cortex were obtained from a subset of patients (n=12) before and after treatment. RESULTS: The daily dose of minocycline at study end was 256mg (SD: 71mg). Treatment was associated with improvements in depression severity [MADRS score change: -14.6 (95% CI: -7.8 to -21.3)]. Ten patients (50%) were classified as responders based on a >=50% reduction in MADRS score and 8 patients (40%) were classified as remitters (MADRS score <= 9). Higher baseline GSH levels were associated with greater improvement in MADRS score following treatment (rho=0.51, p=0.05). Increases in GSH levels at study end were higher in non-responders than in responders (p=0.04). LIMITATIONS: Small sample size, lack of a placebo group. CONCLUSION: Minocycline may be an effective adjuvant treatment for bipolar depression, particularly in patients with high baseline GSH levels. Further research is needed to evaluate the potential of minocycline in this population. PMID- 29407540 TI - Physical exercise for late-life depression: Effects on symptom dimensions and time course. AB - BACKGROUND: Physical exercise is increasingly recognized as a treatment for major depression, even among older patients. However, it is still unknown which depressive symptoms exercise affects most, (e.g. somatic vs. affective) and the timing of its effects. Thus, the aim of this study was to examine the changes of depressive symptoms after treatment with exercise. METHODS: We analyzed data from the SEEDS study, a trial comparing the antidepressant effectiveness of sertraline (S) and sertraline plus exercise (S+EX). Exercise was delivered thrice weekly in small groups and monitored by heart rate meters. Patients with late life depression (n=121) were assessed at baseline, 4, 8, 12 and 24 weeks with the Hamilton Depression Scale. Scores of affective, vegetative, anxiety and agitation/insight factors were analyzed using Multilevel Growth Curve Models and sensitivity analyses (multiple imputation). RESULTS: Compared with the S group, patients in the S+EX group displayed significantly greater improvements of the affective symptom dimension (total effect size = 0.79) with largest changes in the first 4 weeks and last 12 weeks. Improvements were mainly driven by depressed mood and psychomotor retardation. LIMITATIONS: Sample size; lack of an exercise only treatment arm CONCLUSIONS: Adding exercise to antidepressant drug treatment may offer significant advantages over affective symptoms of depression, rather than somatic symptoms or other dimensions of depression. Compared with standard antidepressant treatment, clinical advantages should be expected both at an early (first 4 weeks) and later stage (after 12 weeks). PMID- 29407542 TI - Effects of emotion regulation strategy use in response to stressors on PTSD symptoms: An ecological momentary assessment study. AB - BACKGROUND: Although a burgeoning line of research identifies emotion regulation difficulties as a potential maintenance factor for posttraumatic stress disorder (PTSD), little is known in regard to what emotion regulation strategies individuals with PTSD use in their daily lives, their predictors, and their consequences on later PTSD symptoms. METHOD: The current study utilized ecological momentary assessment (EMA) design to explore prospective relationships between maladaptive and adaptive emotion regulation strategy use and PTSD symptoms in participants with PTSD (N = 30). Participants completed 4 EMAs per day over 8 days, assessing stressors, emotional response, and emotion regulation strategy use. RESULTS: Individuals with PTSD most commonly used avoidance as an emotion regulation strategy. Multilevel modeling indicated that baseline PTSD symptoms predicted maladaptive emotion regulation strategy use. After covarying for morning PTSD symptoms, maladaptive emotion regulation prospectively predicted increased PTSD symptoms later in the day. Adaptive emotion regulation strategies did not uniquely predict later PTSD symptoms. CONCLUSION: In line with conceptualizations of difficulties in emotion regulation as a transdiagnostic maintenance factor in PTSD, findings indicate that maladaptive emotion regulation strategies in response to stressors exacerbate PTSD symptoms. The use of adaptive emotion regulation strategies had no positive or negative impact on subsequent PTSD symptoms. LIMITATIONS: Future studies should utilize longer-term prospective designs. PMID- 29407541 TI - Unique trajectories of anxiety among Chinese-Canadian women across the first postpartum year: A longitudinal cohort study. AB - BACKGROUND: Our objectives were to identify subtypes of Chinese-Canadian women with unique trajectories of anxiety symptomatology over the first postpartum year, investigate covariates associated with group membership, and determine if mental healthcare utilization varies by group membership. METHODS: This was a longitudinal cohort study of 570 Chinese immigrant and Canadian-born women in Toronto, Canada with live births in 2010-2014. Covariates were age, immigrant status, income, fatigue, social support, acculturative stress, and depression. Mental healthcare utilization included visits at 4-24 weeks postpartum. Anxiety symptomatology was measured using the State-Trait Anxiety Inventory-State. Growth mixture modeling was used to identify latent classes corresponding to trajectories of anxiety symptomology at 4-52 weeks. RESULTS: Three groups were identified: "consistently non-anxious" (74%, stable low levels of anxiety), "consistently anxious" (19.5%, clinically meaningful anxiety at baseline and across time), and "anxious-improving" (6.5%, high anxiety at baseline followed by decline). Compared to consistently non-anxious women, consistently anxious women were more likely to report baseline fatigue, depression, and acculturative stress; anxious-improving women were more likely to report baseline fatigue, depression, and history of depression before pregnancy. At 12-24 weeks, 13.8% of anxious-improving women sought mental healthcare compared to 8.6% of consistently anxious women and 4.7% of non-anxious women (p = .06). LIMITATIONS: Our sample comprised Chinese immigrant and Canadian-born women; results should be replicated in other groups. CONCLUSIONS: We identified three subtypes of postpartum anxiety trajectories. These groups of women may respond differently to interventions due to exposure to various combinations of risk factors. PMID- 29407543 TI - Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. AB - BACKGROUND: Natural speech analytics has seen some improvements over recent years, and this has opened a window for objective and quantitative diagnosis in psychiatry. Here, we used a machine learning algorithm applied to natural speech to ask whether language properties measured before psilocybin for treatment resistant can predict for which patients it will be effective and for which it will not. METHODS: A baseline autobiographical memory interview was conducted and transcribed. Patients with treatment-resistant depression received 2 doses of psilocybin, 10 mg and 25 mg, 7 days apart. Psychological support was provided before, during and after all dosing sessions. Quantitative speech measures were applied to the interview data from 17 patients and 18 untreated age-matched healthy control subjects. A machine learning algorithm was used to classify between controls and patients and predict treatment response. RESULTS: Speech analytics and machine learning successfully differentiated depressed patients from healthy controls and identified treatment responders from non-responders with a significant level of 85% of accuracy (75% precision). CONCLUSIONS: Automatic natural language analysis was used to predict effective response to treatment with psilocybin, suggesting that these tools offer a highly cost effective facility for screening individuals for treatment suitability and sensitivity. LIMITATIONS: The sample size was small and replication is required to strengthen inferences on these results. PMID- 29407545 TI - Exploring cross-lagged associations between spiritual struggles and risk for suicidal behavior in a community sample of military veterans. AB - BACKGROUND: There is consensus that struggles with religious faith and/or spirituality likely contribute to risk for suicidal behavior in military populations. However, a lack of longitudinal information has limited the ability to clarify the temporal associations between these variables. METHODS: This study examined cross-lagged associations between key types of spiritual struggles (divine, morality, ultimate meaning, interpersonal relations, and doubting) and indices of risk for suicidal behavior (suicidal ideation and probability of future attempt) in a community sample of veterans who completed assessments spaced apart by six months. RESULTS: Greater severity of all forms of spiritual struggles was generally concurrently associated with indices of suicidal behavior at both time points. Of the possible models for predicting suicide risk, structural equation modeling analyses revealed that a cross-lagged option with spiritual struggles predicting risk provided the best-fitting solution for veterans' responses on study measures. In addition to PTSD and MDD symptomatology, issues with ultimate meaning at Time 1 were uniquely predictive of veterans' perceived likelihood of making a suicide attempt beyond the second assessment, after accounting for autoregressive effects and other variables in this model. LIMITATIONS: This sample was recruited from a single geographic region with disproportionate ties to Christian religious traditions. In addition, reliance on self-report instrumentation potentially limited the accuracy of gauging suicide risk in some cases. CONCLUSIONS: Findings highlight the prognostic value of spiritually integrated models for assessing suicide risk in military veterans that account for mental health conditions along with possible expressions of suffering in the spiritual domain. PMID- 29407546 TI - Aromadendrene oxide 2, induces apoptosis in skin epidermoid cancer cells through ROS mediated mitochondrial pathway. AB - AIMS: Aromadendrene oxide 2 (AO-(2)) is an oxygenated sesquiterpene naturally found as a chemical component of essential oils. In the present study anticancer activity of AO-(2) has been investigated on A431 human epidermoid cancer and precancerous HaCaT cells. MATERIAL AND METHODS: Cell viability was used to detect cytotoxic activity. Mechanism of cell death induced by AO-(2) treatments was studied using Annexin V-FITC/PI binding, cell cycle analysis, measurement of MMP and ROS generation by flow cytometry. Expression of apoptosis related proteins was investigated by western blot. KEY FINDINGS: AO-(2) inhibited the growth and colony formation ability of A431 and HaCaT cells in concentration dependent manner. It induced cell cycle arrest at G0/G1 phase and apoptosis through intracellular ROS accumulation. Inhibition of intracellular ROS by ascorbic acid and N-acetyl cysteine treatment completely blocked apoptotic effect. N-acetyl cysteine treatment significantly reversed G0/G1 arrest induced by AO-(2). AO-(2) treatment caused loss of mitochondrial membrane potential (DeltaPsim), increase in Bax/Bcl-2 ratios, cytochrome c release, activation of caspases (cleaved caspase-3 and caspase-9) and PARP cleavage. AO-(2) also significantly inhibited the growth of multicellular tumor spheroids of A431 and HaCaT cells. SIGNIFICANCE: The results of the present study reveals that AO-(2) a chemical component of essential oils induces apoptosis in A431 and HaCaT cells. PMID- 29407544 TI - Toward subtyping of suicidality: Brief suicidal ideation is associated with greater stress response. AB - BACKGROUND: Suicide is a heterogeneous phenomenon, and thus defining more homogeneous subgroups may help in understanding its underlying biology and ultimately in its prevention. Suicidal ideation is far more common than suicidal behavior and predicts future suicide attempts. Hypothalamic-pituitary-adrenal (HPA)-axis reactivity has been implicated in individuals with suicidal ideation but findings are mixed with some studies showing increased and others demonstrating decreased reactivity. This suggests that dysregulation of HPA-axis is related to a specific character of suicidal ideation. We hypothesized that individuals with brief suicidal ideation are more stress responsive than those with longer/continuous ideation. METHODS: Thirty-five individuals with major depressive disorder (MDD) and 23 healthy volunteers (HVs), aged 18-65 years, underwent the Trier Social Stress Test (TSST). Salivary cortisol was measured at 6 time-points before and during TSST. Total severity and duration of current suicidal ideation were assessed using the Beck Scale for Suicidal Ideation (SSI). Brief suicidal ideators (N = 18), longer/continuous ideators (N = 17) and HVs were compared regarding cortisol response, baseline cortisol and total output. RESULTS: Participants with brief suicidal ideation had greater cortisol response compared to those with longer/continuous ideation and HVs, even after controlling for relevant covariates. However, total SSI score was not associated with cortisol response. Baseline cortisol and total output were not related to overall severity or duration of suicidal ideation. LIMITATIONS: The cross-sectional design and modest sample limit generalizability of the results. CONCLUSIONS: Hyper-responsiveness of HPA-axis to social stress is associated with brief suicidal ideation, possibly defining a pathway for exploring the biological subtyping of suicidal individuals. PMID- 29407547 TI - Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems. AB - An etiologically complex disorder, Attention Deficit Hyperactivity Disorder (ADHD), is often associated with various levels of cognitive deficit. Folate/vitamin B9 is crucial for numerous biochemical pathways including neural stem cell proliferation and differentiation, regulation of gene expression, neurotransmitter synthesis, myelin synthesis and repair, etc. and a scarcity has often been linked to cognitive deficit. Our pilot study in the field revealed significant association of few genetic variants with ADHD. Mild hyperhomocysteinemia and vitamin B12 deficiency was also noticed in the probands. In the present study additional genetic variants, folate and vitamin B6, which may affect folate-homocysteine metabolic pathway, were investigated in 866 individuals including nuclear families with ADHD probands (N=221) and ethnically matched controls (N=286) to find out whether ADHD associated traits are affected by these factors. Population based analysis revealed significant over representation of MTRR rs1801394 "G" allele and "GG" genotype in all as well as male probands. Stratified analysis showed significantly higher frequency of RFC1 rs1051266 and BHMT rs3733890 "AG" genotypes in full term and prematurely delivered ADHD probands respectively. Probands with rs1801394 "GG" genotype and BHMT rs3733890 "G" allele showed association with hyperhomocysteinemia. MTHFR rs1801131, MTR rs1805087 and BHMT rs3733890 also showed association with ADHD index. While rs1051266, rs1801131, and rs1805087 showed association with behavioral problems, rs3733890 was associated with ODD score. Conduct problem exhibited association with RFC1 rs1051266, MTHFR rs1801133 and MTRR rs1801394. Gene-gene interaction analysis revealed positive synergistic interactions between rs1051266, rs1801131 and rs1801394 in the probands as compared to the controls. It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism. PMID- 29407548 TI - UV-B radiation modulates physiology and lipophilic metabolite profile in Olea europaea. AB - Ultraviolet-B (UV-B) radiation plays an important role in plant photomorphogenesis. Whilst the morpho-functional disorders induced by excessive UV irradiation are well-known, it remains unclear how this irradiation modulates the metabolome, and which metabolic shifts improve plants' tolerance to UV-B. In this study, we use an important Mediterranean crop, Olea europaea, to decipher the impacts of enhanced UV-B radiation on the physiological performance and lipophilic metabolite profile. Young olive plants (cv. 'Galega Vulgar') were exposed for five days to UV-B biologically effective doses of 6.5 kJ m-2 d-1 and 12.4 kJ m-2 d-1. Cell cycle/ploidy, photosynthesis and oxidative stress, as well as GC-MS metabolites were assessed. Both UV-B treatments impaired net CO2 assimilation rate, transpiration rate, photosynthetic pigments, and RuBisCO activity, but 12.4 kJ m-2 d-1 also decreased the photochemical quenching (qP) and the effective efficiency of PSII (PhiPSII). UV-B treatments promoted mono/triperpene pathways, while only 12.4 kJ m-2 d-1 increased fatty acids and alkanes, and decreased geranylgeranyl-diphosphate. The interplay between physiology and metabolomics suggests some innate ability of these plants to tolerate moderate UV-B doses (6.5 kJ m-2 d-1). Also their tolerance to higher doses (12.4 kJ m-2 d-1) relies on plants' metabolic adjustments, where the accumulation of specific compounds such as long-chain alkanes, palmitic acid, oleic acid and particularly oleamide (which is described for the first time in olive leaves) play an important protective role. This is the first study demonstrating photosynthetic changes and lipophilic metabolite adjustments in olive leaves under moderate and high UV-B doses. PMID- 29407549 TI - Key acclimation responses to phosphorus deficiency in maize plants are influenced by exogenous nitric oxide. AB - Improving phosphorus (P) acquisition and utilization in crops is of great importance in order to achieve a good plant nutritional state and maximize biomass production while minimizing the addition of fertilizers, and the concomitant risk of eutrophication. This study explores to which extent key processes involved in P-acquisition, and other acclimation mechanisms to low P supply in maize (Zea mays L.) plants, are affected by the addition of a nitric oxide (NO) donor (S-nitrosoglutathione, GSNO). Plants grown in a complete culture solution were exposed to four treatments performed by the combination of two P levels (0 and 0.5 mM), and two GSNO levels (0 and 0.1 mM), and responses to P deprivation were then studied. Major plant responses related to P-deprivation were affected by the presence of the NO donor. In roots, the activity of acid phosphatases was significantly increased in P-depleted plants simultaneously exposed to GSNO. Acidification of the culture solution also increased in plants that had been grown in the presence of the NO donor. Furthermore, the potential capability displayed by roots of P-deprived plants for P-uptake, was higher in the plants that had been treated with GSNO. These results indicate that exogenous NO addition affects fundamental acclimation responses of maize plants to P scarcity, particularly and positively those that help plants to sustain P acquisition under low P availability. PMID- 29407550 TI - Impact of galactoglucomannan oligosaccharides and Cd stress on maize root growth parameters, morphology, and structure. AB - Biologically active oligosaccharides, including galactoglucomannan oligosaccharides (GGMOs), affect plant growth and development. The impact of GGMOs is dependent on their concentration, and the plant species and plant parts affected. The aim of this article is to ascertain the effects of GGMOs, GGMOs + Cd2+, on growth parameters, morphology, and the structure of maize (Zea mays L.) roots. We undertook this research because, in monocots, the effect of these oligosaccharides is so far unknown. In our study, GGMOs stimulated primary root elongation, induction and elongation of lateral roots, and biomass production. Their effect was dependent on the concentration used. Simultaneously, GGMOs moderated the negative effect of Cd2+ on root elongation growth. Besides, GGMOs affected the primary root structure, proven in the earlier development of xylem and Casparian bands, but not of suberin lamellae (compared to the control). The presence of Cd2+ shifted the apoplasmic barriers closer to the root apex in comparison to samples treated with GGMOs + Cd2+. GGMOs do not inhibit Cd uptake into the root directly, but they moderate its effect, and therefore their influence at the structural and metabolic level seems possible. Their positive impact on plant vitality, even in contaminated conditions, strongly indicates their potential application in remediation technologies. PMID- 29407551 TI - A cold-induced pectin methyl-esterase inhibitor gene contributes negatively to freezing tolerance but positively to salt tolerance in Arabidopsis. AB - Plant pectin methyl-esterase (PME) and PME inhibitor (PMEI) belong to large gene families whose members are proposed to be widely involved in growth, development, and stress responses; however, the biological functions of most PMEs and PMEIs have not been characterized. In this study, we studied the roles of CbPMEI1, a cold-induced pectin methyl-esterase inhibitor (PMEI) gene from Chorispora bungeana, under freezing and salt stress. The putative CbPMEI1 peptide shares highest similarity (83%) with AT5G62360 (PMEI13) of Arabidopsis. Overexpression of either CbPMEI1 or PMEI13 in Arabidopsis decreased tissue PME activity and enhanced the degree of methoxylation of cell wall pectins, indicating that both genes encode functional PMEIs. CbPMEI1 and PMEI13 were induced by cold but repressed by salt stress and abscisic acid, suggesting distinct roles of the genes in freezing and salt stress tolerance. Interestingly, transgenic Arabidopsis plants overexpressing CbPMEI1 or PMEI13 showed decreased freezing tolerance, as indicated by survival and electrolyte leakage assays. On the other hand, the salt tolerance of transgenic plants was increased, showing higher rates of germination, root growth, and survival under salinity conditions as compared with non-transgenic wild-type plants. Although the transgenic plants were freezing-sensitive, they showed longer roots than wild-type plants under cold conditions, suggesting a role of PMEs in balancing the trade-off between freezing tolerance and growth. Thus, our study indicates that CbPMEI1 and PMEI13 are involved in root growth regulation under cold and salt stresses, and suggests that PMEIs may be potential targets for genetic engineering aimed to improve fitness of plants under stress conditions. PMID- 29407552 TI - Investigation of the Phaseolus vulgaris circadian clock and the repressive role of the PvTOC1 factor by a newly established in vitro system. AB - The circadian clock is crucial for the synchronization of an organism's physiology and metabolism with the geophysical time. In plants, previous work on the common bean (Phaseolus vulgaris) has identified various differing aspects of clock function compared to the widely studied Arabidopsis thaliana clock. However, transformation of legumes for the study of the circadian clock regulatory mechanisms is extremely laborious. In the present work, we describe an easy-to-follow and rapid method of preparing bean leaf protoplasts with high transformation potential and a functional circadian clock. In this system, we show that application of trichostatin A differentially changes the expression levels of several clock genes. More importantly, we investigate the effect of the clock protein PvTOC1 (Phaseolus vulgaris TIMING OF CAB EXPRESSION 1) on the activity of bean circadian promoters. We present new evidence on the function of PvTOC1 as a repressor of the promoter activity of its own gene, mediated by its conserved CCT (CONSTANS, CO-LIKE and TOC1) domain. Using our protoplast system we were able to uncover functions of the bean circadian clock and to identify an additional target of the PvTOC1clock transcription factor, not previously reported. PMID- 29407553 TI - Circadian regulation of grapevine root and shoot growth and their modulation by photoperiod and temperature. AB - Some plant species demonstrate a pronounced 24 h rhythm in fine root growth but the endogenous and exogenous factors that regulate these diel cycles are unclear. Photoperiod and temperature are known to interact with diel patterns in shoot growth but it is uncertain how these environmental factors are interrelated with below-ground growth. In this particular study, the fine root system of two grapevine species was monitored over a period of ten days with a high resolution scanner, under constant soil moisture and three different photoperiod regimes. Pronounced diel rhythms in shoot and root growth rates were apparent under a fixed 14 h photoperiod. Maximal root growth rate occurred 1-2 h prior to- and until 2 h after the onset of darkness. Subsequently, during the latter part of the dark period, root growth rate decreased and reached minimal values at the onset of the light period. Relative to 22 degrees C, exposure to a 30 degrees C air and soil temperature halved root growth but stimulated shoot growth. Notably, the shoot extension rate peak shifted from late afternoon to midnight at this higher temperature zone. When plants were exposed to a delayed photoperiod or progressively shortening photoperiod, the diel changes in root growth rate followed the same pattern as in the fixed photoperiod, regardless of whether the plant was in light or dark. This suggests that light was not the predominant trigger for stimulating root elongation. Conversely, shoot growth rates were not fixed to a clock, with minimum growth consistently at the completion of the dark period regardless of the time of day. In summary, fine root growth of grapevines was found to have a pronounced diel pattern and an endogenous circadian clock appears to orchestrate this rhythm. Soil temperature modified the amplitude of this pattern, but we argue here that, as evidenced from exhausted starch reserves within root tips by early morning, carbon supply from photosynthesis is also required to maintain maximum root growth. PMID- 29407554 TI - Topical formulations of delta-aminolevulinic acid for the treatment of actinic keratosis: Characterization and efficacy evaluation. AB - Actinic keratosis (AK) is a pre-cancerous disease, with worldwide increasing incidence, which consists in squamous cutaneous lesion caused by excessive exposure to ultraviolet radiation. An established treatment option is photodynamic therapy (PDT), based on light, oxygen and a photosensitizer. The most widely used is 5-aminolevulinic acid (ALA) which however, being a hydrophilic molecule, has difficultly penetrating the skin to achieve the desired therapeutic effect. To solve this limit, the present study provides for the development of three galenic gel formulations (Natrosol, Sepigel and Carbopol) containing 10% w/w of ALA for the treatment of AK with PDT and their comparison with a lipophilic cream used in the Hospital. The aim of this study is to offer an appealing topical treatment that improves patients' observance and compliance. Formulations were characterized in terms of chemical, physical and microbiological stability, viscosity and pH. An HPLC-DAD analytical method was also developed and validated. Sepigel gel resulted the best gel formulation in terms of technological characteristics and stability. A comparative study between this gel and the lipophilic cream was assessed, by evaluating the therapeutic efficacy and the compliance of the patients. PMID- 29407555 TI - Enhanced transdermal delivery of ondansetron using nanovesicular systems: Fabrication, characterization, optimization and ex-vivo permeation study-Box-Cox transformation practical example. AB - This study aimed to formulate suitable nanovesicles (NVs) for transdermal delivery of Ondansetron. It also illustrated a practical example for the importance of Box-Cox transformation. A 23 full factorial design was used to enable testing transfersomes, ethosomes, and transethosomes of Ondansetron simultaneously. The independent variables (IVs) studied were sodium taurocholate amount, ethanol volume in hydration medium and sonication time. The studied dependent variables (DVs) were: particle size (PS), zeta potential (ZP) and entrapment efficiency (EE). Polynomial equations were used to study the influence of IVs on each DV. Numerical multiple response optimization was applied to select an optimized formula (OF) with the goals of minimizing PS and maximizing ZP absolute value and EE. Box-Cox transformation was adopted to enable modeling PS raised to the power of 1.2 with an excellent prediction R2 of 1.000. ZP and EE were adequately represented directly with prediction R2 of 0.9549 and 0.9892 respectively. Response surface plots helped in explaining the influence of IVs on each DV. Two-sided 95% prediction interval test and percent deviation of actual values from predicted ones proved the validity of the elucidated models. The OF was a transfersomal formula with desirability of 0.866 and showed promising results in ex-vivo permeation study. PMID- 29407556 TI - Topically used corticosteroids: What is the big picture of drug product degradation? AB - Corticosteroids are widely used in topical formulations such as creams (aqueous) and ointments (non-aqueous). The generally used corticosteroids show large molecular resemblance, where especially the 20-keto-21-hydroxyl group bound to the 17 carbon is important for their chemical stability. Oxidation in both aqueous and non-aqueous environment occurs for triamcinolone acetonide (TCA), hydrocortisone (HC) and desoximethasone (DS). Besides the 20-keto-21-hydroxyl group, TCA, HC and DS have different other moieties attached to the same C17. These moieties are shown to influence not only the type of degradation product formed but also the degradation kinetics. Seven degradation products are found in total and a degradation mechanism is proposed. Furthermore the transesterfication of betamethasone-17-valerate to betamethasone-21-valerate is shown to occur both in aqueous and non-aqueous environment. Finally, a comprehensive scheme of degradation pathways is presented that is applicable for both aqueous and non aqueous formulations. PMID- 29407557 TI - International Neurosurgical Care: Attending to Those in Need. PMID- 29407558 TI - Enhanced utilization of fluorene by Paenibacillus sp. PRNK-6: Effect of rhamnolipid biosurfactant and synthetic surfactants. AB - The present investigation was to study the effect of different non-ionic surfactants (Tween-80, Tween-60, Tween-40, Tween-20, Triton X-100) and a rhamnolipid biosurfactant on the degradation of fluorene by Paenibacillus sp. PRNK-6. An enhancement in the growth, as well as fluorene utilization by this strain were observed in the presence of biosurfactant and non-ionic surfactants except Tween-20 and Triton X-100. Triton X-100 and Tween-20 were toxic to this bacterium. The strain PRNK-6 utilized 75% of fluorene (280mg/L) in 24h in an unamended condition. On the other hand, the complete utilization of higher concentration fluorene (320mg/L) by this strain was noticed when the medium was amended with Tween-80 (1.5% v/v) within 24h of incubation. Whereas, 90.6%, 96.5% and 96.7% of fluorene (280mg/L) was utilized when amended with Tween-60 (3.5% v/v), Tween-40 (3% v/v) and biosurfactant (25mg/L) respectively. Biosurfactant promoted the fluorene degradation potential of PRNK-6 as 96.2% of 320mg/L fluorene was degraded within 24h. Further, the added tween series surfactants and a biosurfactant have increased the cell surface hydrophobicity of the PRNK-6. Thus correlating with the enhanced degradation of the fluorene. PMID- 29407559 TI - Heavy metal contents and enrichment characteristics of dominant plants in wasteland of the downstream of a lead-zinc mining area in Guangxi, Southwest China. AB - A field investigation on the content of heavy metals in soils and 17 kinds of dominant plants from wasteland of the downstream of a Pb-Zn mine in Northwest Guangxi Zhuang Autonomous Region was carried out. The absorption and accumulation characteristics of heavy metals between plants and soil were compared, and the candidate species for ecosystem restoration of the area were selected. The results indicated that the soils had been subjected to pollution of heavy metals in varying degrees. The concentrations of Cd, Pb, Zn were 46.5, 57.3 and 23.7 times higher than their corresponding background values, respectively. The contents of Cd, Pb and Zn in the most analyzed plants exceed the normal ranges and the phytotoxic level. C. crepidioides, S. nigrum, B. pilosa, C. Canadensis, A. conyzoides, I. denticulata and E. crusgali showed strong capability in accumulation and transport of Cd, and they could be used as good candidates for Cd- phytoextraction. Among which, Cd concentration in the aerial part of C. crepidioides exceeded the threshold of Cd-hyperaccumulator. Thus, C. crepidioides demonstrated the basic characteristics of a Cd-hyperaccumulator. The lower translocation ratios for Cd, Cu, Zn and Pb in P. vittata and C. chinensis make them suitable for phytostabilization in the study area. PMID- 29407560 TI - Effects of voltage on sulfadiazine degradation and the response of sul genes and microbial communities in biofilm-electrode reactors. AB - Few studies have been performed on both the potential and the risks of biofilm electrode reactors (BERs) with regard to the removal of antibiotics. This study used 33 BERs to investigate the removal rate and degradation pathway of sulfadiazine (SDZ). Furthermore, the effects of additional electrons on sul genes and microbial community composition were examined. The study found that rapid elimination rates of 20mg/L SDZ were observed during the first 3h with different DC voltage rates. Even high concentrations (160mg/L) could be rapidly removed after 24h of system operation. Pyrimidin-2ylsulfamic acid and aniline were noted to be principal products, and an SDZ degradation mechanism was proposed. The study identified 41 species of microorganism; based on bacterial community divergence caused by voltage, and six samples were grouped into four clusters. The relative abundances of sul genes from biofilm were in the following order: sulII >sulIII >sulI >sulA. The sulI, sulII, and sulA genes were enhanced with electrical stimulation in the cathode layer. It is noteworthy that sul genes were not detected in the effluent after 24h of operation. PMID- 29407561 TI - Myco-phytoremediation of arsenic- and lead-contaminated soils by Helianthus annuus and wood rot fungi, Trichoderma sp. isolated from decayed wood. AB - In the present study, Helianthus annuus grown in arsenic- (As) and lead- (Pb) contaminated soil were treated with plant-growth promoting fungi Trichoderma sp. MG isolated from decayed wood and assessed for their phytoremediation efficiency. The isolate MG exhibited a high tolerance to As (650mg/L) and Pb (500mg/L), and could remove > 70% of metals in aqueous solution with an initial concentration of 100mg/L each. In addition, the isolate MG was screened for plant-growth-promoting factors such as siderophores, 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, indole acetic acid (IAA) synthesis, and phosphate solubilisation. Phytoremediation studies indicated that treatment of H. annuus with the isolate MG had the maximum metal-accumulation in shoots (As; 67%, Pb; 59%). Furthermore, a significant increase in the soil extracellular enzyme-activities was observed in myco-phytoremediated soils. The activities of phosphatase (35 U/g dry soil), dehydrogenase (41mg TPF/g soil), cellulase (37.2mg glucose/g/2h), urease (55.4mgN/g soil/2h), amylase (49.3mg glucose/g/2h) and invertase (45.3mg glucose/g/2h) significantly increased by 12%, 14%, 12%, 22%, 19% and 14% in As contaminated soil, respectively. Similarly, the activities of phosphatase (31.4U/g dry soil), dehydrogenase (39.3mg TPF/g soil), cellulase (37.1mg glucose/g/2h), urease (49.8mgN/g soil/2h), amylase (46.3mg glucose/g/2h), and invertase (42.1mg glucose/g/2h) significantly increased by 11%, 15%, 11%, 18%, 20% and 14% in Pb contaminated soil, respectively. Obtained results indicate that the isolate MG could be a potential strain for myco-phytoremediation of As and Pb contaminated soil. PMID- 29407562 TI - Sex of sexual partners and disordered weight control behaviors in a nationally representative sample of South Korean adolescents. AB - Eating disorders are a serious and life-threatening health issue associated with physical and mental health problems. Stigma associated with sexual orientation is thought to be one contributor to eating disorders symptoms in U.S. adolescents. Additional research on disordered weight control behaviors in diverse populations is needed to better understand their etiology. To examine the association of sex of sexual partners with disordered weight control behaviors among South Korean adolescents, we analyzed survey data from 67,266 adolescents, ages 12-18 years, from the 2015 Korea Youth Risk Behavior Web-based Survey. Adolescents were grouped based on self-reported sex of sexual partners. Disordered weight control behaviors included fasting, vomiting, or use of unprescribed diet pills for weight control in the past month. Among both girls and boys, those reporting partners of both sexes had higher odds and those with no sexual partners had lower odds of disordered weight control behaviors. Those with same-sex partners only were not significantly different in disordered weight control behaviors from those with other-sex partners only for girls or boys. Our findings demonstrate the need for further research identifying ways to mitigate risk for this vulnerable group. PMID- 29407563 TI - Affective temperaments play an important role in the relationship between child abuse and the diagnosis of bipolar disorder. AB - In previous studies, various components such as environmental and genetic factors have been shown to contribute to the development of bipolar disorder (BD). This study investigated how multiple factors, including child abuse, adult life events, and affective temperaments, are interrelated and how they affect the diagnosis of BD. A total of 170 healthy controls and 75 BD patients completed the following self-administered questionnaires: the Patient Health Questionnaire-9 evaluating the severity of depressive symptoms; the Child Abuse and Trauma Scale (CATS) evaluating child abuse; the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire (TEMPS-A) evaluating affective temperaments; and the Life Experiences Survey (LES) evaluating negative and positive adult life events. The data were subjected to univariate analysis, multivariable analysis, and structural equation modeling. The structural equation modeling showed that the diagnosis of BD was indirectly predicted by the neglect and sexual abuse scores of the CATS through four affective temperaments (depressive, cyclothymic, irritable, and anxious) of the TEMPS-A and directly predicted by these four affective temperaments. This study suggested that affective temperament plays an important role as a mediator in the influence of child abuse on BD diagnosis. PMID- 29407564 TI - Computerized response inhibition training for children with trichotillomania. AB - Evidence suggests that trichotillomania is characterized by impairment in response inhibition, which is the ability to suppress pre-potent/dominant but inappropriate responses. This study sought to test the feasibility of computerized response inhibition training for children with trichotillomania. Twenty-two children were randomized to the 8-session response inhibition training (RIT; n = 12) or a waitlisted control (WLT; n = 10). Primary outcomes were assessed by an independent evaluator, using the Clinical Global Impression Improvement (CGI-I), and the NIMH Trichotillomania Severity (NIMH-TSS) and Impairment scales (NIMH-TIS) at pre, post-training/waiting, and 1-month follow up. Relative to the WLT group, the RIT group showed a higher response rate (55% vs. 11%) on the CGI-I and a lower level of impairment on the NIMH-TIS, at post training. Overall symptom reductions rates on the NIMH-TSS were 34% (RIT) vs. 21% (WLT) at post-training. The RIT's therapeutic gains were maintained at 1-month follow-up, as indicated by the CGI-I responder status (= 66%), and a continuing reduction in symptom on the NIMH-TSS. This pattern of findings was also replicated by the 6 waitlisted children who received the same RIT intervention after post-waiting assessment. Results suggest that computerized RIT may be a potentially useful intervention for trichotillomania. PMID- 29407565 TI - Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia. AB - Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1- and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug's greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality. PMID- 29407566 TI - Self-compassion in somatoform disorder. AB - 'Third wave' cognitive-behavioral therapies have given a boost to the study of resilience factors, such as self-compassion. To get an indication of the potential clinical relevance of self-compassion for somatoform disorder, this study examined whether self-compassion in patients with somatoform disorder is lower than in the general population, and whether self-compassion is associated with number of symptoms and health-related quality of life. Two-hundred-and thirty-six participants with somatoform disorder and 236 subjects from the general population, matched on sex and age, filled out questionnaires regarding self-compassion (SCS), number of symptoms (PSC) and health-related quality of life (EQ-5D). The difference in self-compassion between the patient group (Mean 3.53, SD .96) and the general population (Mean 4.16, SD .98) was significant with a medium effect size (d = -.65). Multiple regression analyses showed that having a somatoform disorder and low self-compassion were independently associated with number of symptoms and reduced health-related quality of life. The lower level of self-compassion in somatoform disorder and its association with more physical symptoms and lower health-related quality of life, indicate that self-compassion is a potential clinically relevant factor that may influence therapy outcome and that can be a therapeutic target in patients with somatoform disorder. PMID- 29407567 TI - Description and prediction of time-to-attainment of excellent recovery for borderline patients followed prospectively for 20 years. AB - One purpose of this study was to determine the cumulative rates of excellent recovery for borderline patients and axis II comparison subjects followed prospectively for 20 years. Another purpose was to find the best set of baseline predictors of excellent recovery for borderline patients. A total of 290 inpatients meeting rigorous criteria for borderline personality disorder and 72 axis II comparison subjects completed semistructured interviews and self-report measures during their index admission. Subjects were reassessed prospectively over 10 contiguous two-year waves of follow-up. Thirty-nine percent of borderline patients and 73% of personality-disordered comparison subjects met our operationalized definition of excellent recovery (concurrent remission of borderline or another primary personality disorder, good social and full-time vocational functioning, and absence of an axis I disorder associated decreased social and/or vocational functioning). Five variables formed our multivariate predictive model of excellent recovery for borderline patients: higher IQ, good childhood work history, good adult vocational record, lower trait neuroticism, and higher trait agreeableness. The results of this study suggest that complete recovery is difficult for borderline patients to achieve even over long periods of time. They also suggest that competence displayed in both childhood and adulthood is the best predictor of this important outcome. PMID- 29407568 TI - Evaluation of cognitive functions in individuals with synthetic cannabinoid use disorder and comparison to individuals with cannabis use disorder. AB - The use of synthetic cannabinoid has been increasing throughout the world and has become a major public health problem. The present study aims to investigate the attention, memory, visuospatial and executive functions in individuals with synthetic cannabinoid use disorder and compare the results with findings obtained from individuals with cannabis use disorder and healthy volunteers with no substance use. Fifty-two patients with synthetic cannabinoid use disorder, 45 patients with cannabis use disorder and 48 healthy control group males were included in the study. The neuropsychological test battery was designed to involve ten studies evaluating a large series of cognitive functions. Impairments in attention, memory, executive and visuospatial functions were identified in individuals with synthetic cannabinoid use disorder and these impairments were found to be significantly greater than in individuals with cannabis use disorder and healthy controls. In line with the data obtained from this study; the evaluation of each cognitive function with more comprehensive test batteries and supporting these evaluations with sensitive brain imaging studies are important topics for future research. PMID- 29407569 TI - Social anxiety and detection of facial untrustworthiness: Spatio-temporal oculomotor profiles. AB - Cognitive models posit that social anxiety is associated with biased attention to and interpretation of ambiguous social cues as threatening. We investigated attentional bias (selective early fixation on the eye region) to account for the tendency to distrust ambiguous smiling faces with non-happy eyes (interpretative bias). Eye movements and fixations were recorded while observers viewed video clips displaying dynamic facial expressions. Low (LSA) and high (HSA) socially anxious undergraduates with clinical levels of anxiety judged expressers' trustworthiness. Social anxiety was unrelated to trustworthiness ratings for faces with congruent happy eyes and a smile, and for neutral expressions. However, social anxiety was associated with reduced trustworthiness rating for faces with an ambiguous smile, when the eyes slightly changed to neutrality, surprise, fear, or anger. Importantly, HSA observers looked earlier and longer at the eye region, whereas LSA observers preferentially looked at the smiling mouth region. This attentional bias in social anxiety generalizes to all the facial expressions, while the interpretative bias is specific for ambiguous faces. Such biases are adaptive, as they facilitate an early detection of expressive incongruences and the recognition of untrustworthy expressers (e.g., with fake smiles), with no false alarms when judging truly happy or neutral faces. PMID- 29407570 TI - The temporal relationship between premonitory urges and covert compulsions in patients with obsessive-compulsive disorder. AB - Recent studies in patients with obsessive-compulsive disorder (OCD) have shown that many compulsions are associated with urges rather than obsessions. Premonitory urges are uncomfortable sensory feelings or a rising inner tension, often likened to the urge to scratch, yawn or blink. We studied premonitory urges preceding mental compulsions in 19 patients with OCD and preceding eye blinks in 16 healthy controls. Urge intensity was assessed continuously over 20 min using a real-time urge intensity monitor; compulsions and blinks were measured as discrete events in a free compulsion/blinking and a compulsion/blink suppression condition. Urge intensity showed an inverted U-shaped relationship (increase then decrease) around compulsions within a time-window of approximately 60 s in patients with OCD and within 13 s around blinks in healthy controls. Urge intensity was higher during compulsion / blink suppression and varied more independently of compulsion execution in patients with OCD. There is a close temporal relationship between premonitory sensations and compulsion execution that changes when compulsions are suppressed, indicating that urge intensity might drive the execution of and is then alleviated by compulsions. Suppression weakens the association between urge intensity and compulsion execution. PMID- 29407571 TI - Reliability of two social cognition tests: The combined stories test and the social knowledge test. AB - Deficits in social cognition are common in psychiatric disorders. Validated social cognition measures with good psychometric properties are necessary to assess and target social cognitive deficits. Two recent social cognition tests, the Combined Stories Test (COST) and the Social Knowledge Test (SKT), respectively assess theory of mind and social knowledge. Previous studies have shown good psychometric properties for these tests, but the test-retest reliability has never been documented. The aim of this study was to evaluate the test-retest reliability and the inter-rater reliability of the COST and the SKT. The COST and the SKT were administered twice to a group of forty-two healthy adults, with a delay of approximately four weeks between the assessments. Excellent test-retest reliability was observed for the COST, and a good test retest reliability was observed for the SKT. There was no evidence of practice effect. Furthermore, an excellent inter-rater reliability was observed for both tests. This study shows a good reliability of the COST and the SKT that adds to the good validity previously reported for these two tests. These good psychometrics properties thus support that the COST and the SKT are adequate measures for the assessment of social cognition. PMID- 29407572 TI - Borderline personality disorder and sexual abuse: A systematic review. AB - Although sexual abuse (SA) is known to be frequent among borderline personality disorder (BPD) patients, few reviews evaluating that relationship have been published. This systematic review aimed to investigate SA (including adulthood) as a predictor of BPD diagnosis, clinical presentation and prognosis. Studies written in English or Portuguese from January 1997 until January 2017 were identified by searching the following keywords in three international databases: "borderline personality disorder" OR "borderline disorder" AND "sexual abuse" OR "sexual violence" OR "sexual victimization" OR "sexual assault" OR "rape". Forty articles met the eligibility criteria. Overall, SA was found to play a major role in BPD, particularly in women. Childhood sexual abuse (CSA) is an important risk factor for BPD. Adult sexual abuse (ASA) rates are significantly higher in BPD patients compared with other personality disorders (PDs). SA history predicts more severe clinical presentation and poorer prognosis. Suicidality has the strongest evidence, followed by self-mutilation, post-traumatic stress disorder (PTSD), dissociation and chronicity of BPD. Future research should study more ASA and include more males, milder BPD patients and documented or corroborated SA cases. The impact of other traumatic experiences (e.g., emotional abuse) on BPD must also be systematically reviewed. PMID- 29407573 TI - Identification of duck IL-4 and its inhibitory effect on IL-17A expression in R. anatipestifer-stimulated splenic lymphocytes. AB - As the dysregulation of IL-17 is implicated in the pathogenesis of various autoimmune and inflammatory diseases, the suppression of IL-17 production by Th2 cytokines could alleviate the development of these diseases. Previously, we confirmed that inflammatory cytokines including IL-17A are strongly associated with R. anatipestifer infection, which is one of the most important bacterial pathogens in the duck industry. Here, we found that IL-4 treatment downregulated the expression of IL-17A and IL-17F transcripts in splenic lymphocytes stimulated with R. anatipestifer. Moreover, duck IL-4 (duIL-4) treatment in R. anatipestifer stimulated lymphocytes suppressed the expression of IL-23p19 and IL-12p40 transcripts compared to untreated and stimulated lymphocytes. Conversely, duIL-4 increased levels of IFN-gamma and IL-10. We identified a full-length duIL-4 cDNA encoding 136 amino acids from ConA-activated splenic lymphocytes that shares 49.3 50% amino acid sequence identity with chicken and quail IL-4 and 21-29.7% with mammalian and piscine homologues. Low or moderate levels of duIL-4 transcript were observed in healthy tissues, including the spleen, bursa, and thymus, whereas duIL-4 expression was higher in the kidney and lung. Levels of duIL-4 were generally upregulated in mitogen-activated splenic lymphocytes but lower in the liver and spleen of R. anatipestifer-infected ducks compared to those of infected chickens. Recombinant duIL-4 promoted nitric oxide synthesis in duck macrophages stimulated by R. anatipestifer compared to untreated and stimulated control macrophages. These results demonstrate that IL-4 is an important Th2 cytokine that inhibits inflammatory responses in splenic lymphocytes stimulated with R. anatipestifer. PMID- 29407574 TI - Pathogenicity of duck hepatitis A virus type 3 and innate immune responses of the ducklings to virulent DHAV-3. AB - Duck virus hepatitis caused by duck hepatitis A virus (DHAV) is an acute and contagious disease. To better understand the pathogenic mechanism of DHAV-3 in ducklings, an infection experiment was performed. Our results showed that typical symptoms were observed in the infected ducklings. DHAV-3 could infect many tissues, leading to pathological lesions, especially on the livers and spleen, and the host immune responses are activated in infection. Real-time quantitative PCR demonstrated that expression of many innate immune-related genes was mostly up-regulated in the livers and spleen, and antiviral innate immune response was established, but not sufficient to restrict the virus replication of lethal dose. Many major pattern recognition receptors (PRRs) (RIG-1, MDA5, and TLR7) are involved in the host immune response to DHAV-3, and the expression of interferon (IFNalpha, IFNbeta and IFNgamma) and antiviral proteins (MX, OAS and PKR) are also up-regulated in the liver and spleen. The expression of most cytokines (IL 1beta, IL-2 and IL-6) was also up-regulated to different degrees and was various; the expression of IL-2 increased most significantly in liver. Our data provide a foundation for further study of the pathogenicity of duck virus hepatitis and extend our understanding of the immune responses of ducklings to DHAV-3 infection. PMID- 29407575 TI - Anti-inflammatory effects of anisalcohol on lipopolysaccharide-stimulated BV2 microglia via selective modulation of microglia polarization and down-regulation of NF-kappaB p65 and JNK activation. AB - Inflammation plays a pivotal role in the pathogenesis of ischemic stroke. The inhibition of inflammation appears to be a potential therapeutic strategy for neuro-inflammatory injury after ischemic stroke. In response to cerebral ischemia, resident microglia and infiltrated macrophages from the damaged blood brain barrier are activated. Microglia activation appears to be a double-edged sword. Activated microglia migrate to the damaged neuron, change their phenotype to M1 or M2, and become involved in nerve damage and repair. M1 phenotype microglia express multiple inflammatory factors to exacerbate secondary brain injury, while those of M2 phenotype release anti-inflammatory factors to promote brain recovery after ischemic stroke. Therefore, the regulation of microglia M1/M2 phenotype after ischemic stroke is crucial for brain repair. The present study aimed to investigate the anti-inflammatory effect of anisalcohol (p methoxybenzyl alcohol, PMBA), a phenolic compound from Gastrodia elata Blume, which has been shown to reduce cerebral ischemic injury in rodents. However, no studies have specifically addressed whether PMBA can selectively modulate microglia polarization. In this study, lipopolysaccharide-stimulated BV2 microglia were used to assess the anti-inflammatory effect of PMBA. The results revealed that PMBA significantly reduced the lipopolysaccharide-induced production of tumour necrosis factor alpha, prostaglandin E2, and nitric oxide, without causing cell toxicity. In addition, it increased anti-inflammatory interleukin-10 and transforming growth factor-beta. Phenotypic analysis of LPS stimulated BV2 microglia showed that PMBA significantly down-regulated the expression of the M1 marker CD16/32 and up-regulated that of the M2 marker CD206. Moreover, PMBA suppressed NF-kappaB activation and inhibited the phosphorylation of JNK in LPS-stimulated BV2 microglia. Collectively, our data demonstrate that PMBA can inhibit M1 transformation and promote M2 transformation of microglia, thus attenuating the production of inflammatory mediators and cytokines. The modulation of microglia M1/M2 polarization may involve multiple mechanisms, mainly, the inhibition of NF-kappaB and MAPK activation. These findings suggest that PMBA acts as an anti-inflammatory factor and is a possible therapeutic candidate for diseases such as ischemic stroke, where inflammation is a central hallmark. PMID- 29407576 TI - The genes involved in asthma with the treatment of human embryonic stem cell derived mesenchymal stem cells. AB - BACKGROUND: Asthma is affecting more than 300 million people worldwide, which represents the most common chronic disease among children. We previously found that mesenchymal stem cells (MSCs) derived from induced pluripotent stem cells (iPSCs) modulated the immune response on Th2-mediated asthma in vivo and in vitro. This study further evaluated the immunomodulatory effects of MSCs from human embryonic stem cells (hESCs) on asthma. METHODS: Multipotent hESC-MSCs were obtained using a feeder-free method. The hESC-MSCs were analysed for the expression of stem cell surface markers by flow cytometry, their differentiation potentials were analysed using in vitro trilineage differentiation methods hESC MSCs were transplanted into the murine model with ovalbumin (OVA)-induced airway allergic inflammation. The expression levels of allergic related genes were measured by the mRNA PCR arrays. RESULTS: The hESC-MSCs expressed classical MSC markers and held the capability of differentiation into multiple mesoderm-type cell lineages. hESC-MSCs were able to suppress allergic inflammation by modulating Th2 cells and eosinophils in the mice, and reversed the reduction of regulatory T cells. By using PCR array, 5 mRNAs- chemokine (C-C motif) ligand 11 (Ccl11), Ccl24, interleukin13 (Il13), Il33 and eosinophil-associated, ribonuclease A family, member 11 (Ear11) were identified the most relevant in murine airway allergic inflammation and hESC-MSCs treatment. CONCLUSIONS: The therapeutic effects of hESC-MSCs were identified in the murine model of airway allergic inflammation with key mRNAs involved. This study will provide a better understanding regarding the mechanisms underlying hESC-MSCs therapeutic application in airway allergic inflammation. PMID- 29407577 TI - Maintenance of cyclic GMP-AMP homeostasis by ENPP1 is involved in pseudorabies virus infection. AB - In a previous study, we demonstrated that porcine cyclic GMP-AMP (cGAMP) synthase (cGAS) catalyzes cGAMP production and is an important DNA sensor for the pseudorabies virus (PRV)-induced activation of interferon beta (IFN-beta). Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) has recently been identified as the hydrolase of cGAMP in rodents, but its role in porcine cells is not clear. Our recent study demonstrated that porcine ENPP1 is responsible for the homeostasis of cGAMP and is critical for PRV infection. Porcine ENPP1 mRNA is predominantly expressed in muscle. PRV infection was enhanced by ENPP1 overexpression and attenuated by silencing of ENPP1. During PRV infection, the activation of IFN-beta and NF-kappaB was reduced in ENPP1 overexpressed cells and promoted in ENPP1 knockdown cells. Investigation of the molecular mechanisms of ENPP1 during PRV infection showed that ENPP1 hydrolyzed cGAMP in PRV-infected or cGAMP-transfected cells and inhibited IRF3 phosphorylation, reducing IFN-beta secretion. These results, combined with those for porcine cGAS, demonstrate that ENPP1 acts coordinately with cGAS to maintain the reservoir of cGAMP and participates in PRV infection. PMID- 29407579 TI - Skin and scale regeneration after mechanical damage in a teleost. AB - Skin wound healing has been widely studied in mammalian models but the information on teleost cutaneous healing is sparse and frequently considered in the context of viral or bacterial infections or parasitic infestations in aquaculture. In the present study a detailed time course (0 h, 6 h, 1, 2, 3 and 4 days) coupled to morphology and gene expression analysis revealed rapid regeneration of skin without scarring in a marine teleost after a superficial wound caused by the loss of a large area of scales. The integrity of the integument, as assessed by quantification of extracellular matrix (ECM) gene transcripts (fn1a, colIalpha1, colValpha2, colXalpha1, ogn1, ogn2, crtac1a, cyr61, pcna, krt2 and mmp9) was restored within 2 days. Epithelial-mesenchyme interactions assessed by expression of edar and shh were associated with epidermal closure, the re-establishment of the basement membrane and also scale eruption. Histological observations suggested tissue re-epithelialization was independent of inflammation and that transcripts representing the humoral and cellular elements of the immune response (mpo, cyba and csf1r, cd48 and cd200) were modulated in the early stages of sea bream (Sparus aurata) skin repair after injury. Overall, the results indicate that after superficial skin damage tissue reconstitution started immediately with re-epithelialization, followed by ECM deposition and finally tissue maturation, indicating that in the skin regenerative process, reconstitution of the physical barrier was the priority over other integument functions, including immune surveillance. PMID- 29407578 TI - A rapid and transient innate immune response to avian influenza infection in mallards. AB - The vertebrate innate immune system provides hosts with a rapid, non-specific response to a wide range of invading pathogens. However, the speed and duration of innate responses will be influenced by the co-evolutionary dynamics of specific host-pathogen combinations. Here, we show that low pathogenic avian influenza virus (LPAI) subtype H1N1 elicits a strong but extremely transient innate immune response in its main wildlife reservoir, the mallard (Anas platyrhynchos). Using a series of experimental and methodological improvements over previous studies, we followed the expression of retinoic acid inducible gene 1 (RIG-I) and myxovirus resistance gene (Mx) in mallards semi-naturally infected with low pathogenic H1N1. One day post infection, both RIG-I and Mx were significantly upregulated in all investigated tissues. By two days post infection, the expression of both genes had generally returned to basal levels, and remained so for the remainder of the experiment. This is despite the fact that birds continued to actively shed viral particles throughout the study period. We additionally show that the spleen plays a particularly active role in the innate immune response to LPAI. Waterfowl and avian influenza viruses have a long co-evolutionary history, suggesting that the mallard innate immune response has evolved to provide a minimum effective response to LPAIs such that the viral infection is brought under control while minimising the damaging effects of a sustained immune response. PMID- 29407580 TI - A simple and effective method for detecting precipitated proteins in MALDI-TOF MS. AB - MALDI-TOF MS has developed rapidly into an essential analytical tool for the life sciences. Cinnamic acid derivatives are generally employed in routine molecular weight determinations of intact proteins using MALDI-TOF MS. However, a protein of interest may precipitate when mixed with matrix solution, perhaps preventing MS detection. We herein provide a simple approach to enable the MS detection of such precipitated protein species by means of a "direct deposition method" -- loading the precipitant directly onto the sample plate. It is thus expected to improve routine MS analysis of intact proteins. PMID- 29407581 TI - Reactivity-driven cleanup of 2-Aminobenzamide derivatized oligosaccharides. AB - N-glycan profiling is commonly accomplished by the derivatization of the enzymatically released oligosaccharides with a fluorophore, thereby facilitating their analysis by hydrophilic-interaction liquid chromatography (HILIC). These fluorescent dyes are often present in large excess during derivatization reactions, and their removal is typically required to minimize chromatographic interference. Herein, we report a reactivity-driven 2-phase extraction protocol with the aldehyde reagent octanal, which demonstrated efficient 2-aminobenzamide cleanup as well as high derivatized N-glycan recovery. This cleanup method can be performed within minutes, and therefore provides an alternative sample preparation route for N-glycan profiling with improved time efficiency and operational simplicity. PMID- 29407582 TI - NM23 downregulation and lysophosphatidic acid receptor EDG2/lpa1 upregulation during myeloid differentiation of human leukemia cells. AB - The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA) induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels. PMID- 29407583 TI - Pegaspargase-related high-grade hepatotoxicity in a pediatric-inspired adult acute lymphoblastic leukemia regimen does not predict recurrent hepatotoxicity with subsequent doses. AB - Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes. Preliminary results are promising, but hepatotoxicity rates with long acting pegaspargase are greater in adults than children. However, adult pegaspargase-related hepatotoxicity is not as clearly defined despite being the commonest adult toxicity. We studied the frequency and characteristics of high grade pegaspargase-related hepatotoxicity in newly diagnosed adults on a pediatric-inspired regimen that included six planned pegaspargase doses, 2000 IU/m2/dose intravenously, with doses given at least four weeks apart and not discontinued or dose-reduced for previous hepatotoxicity. Pegaspargase-related toxicity was monitored weekly after 185 delivered doses and reported by NCI CTCAE v3.0. Fifty-one patients, aged 18-57, received 192 pegaspargase doses (3.8 doses/patient). High-grade hyperbilirubinemia occurred in 16 (31.4%) patients and 23 (12.4%) doses; high-grade transaminitis occurred in 33 (64.7%) patients and 62 (33.5%) doses. Of 11 patients with high-grade hyperbilirubinemia who received at least one subsequent pegaspargase dose, six (54.5%) experienced recurrent toxicity; of 24 patients with high-grade transaminitis who received at least one subsequent pegaspargase dose, 15 (62.5%) developed recurrent toxicity. Pegaspargase at this dose and interval is associated with high hepatotoxicity rates, but patients can be rechallenged despite earlier pegaspargase-related hepatotoxicity. PMID- 29407584 TI - The combination of TRAIL and MG-132 induces apoptosis in both TRAIL-sensitive and TRAIL-resistant human follicular lymphoma cells. AB - We have previously shown that the human follicular lymphoma cell line, HF28GFP, is sensitive to TRAIL-mediated apoptosis. Nevertheless, when the same cells overexpress anti-apoptotic Bcl-2 family protein, Bcl-xL (HF28Bcl-xL), they become resistant to TRAIL. Thus, these cell lines help us to investigate the action of novel apoptosis inducing candidate drugs. In the present study, we examined the effects of MG-132 (a proteasome inhibitor), LiCl (a glycogen synthase kinase-3 inhibitor) and/or TRAIL on pro-apoptotic Bcl-2 family proteins such as Bim and Bid. Here we demonstrate that the combination of MG-132 and TRAIL induced significant apoptotic cell death in both cell lines, HF28GFP and HF28BclxL. Apoptosis correlated with a decrease of phospho-ERK1/2, the accumulation of Bim and translocation of truncated Bid (tBid) and jBid. In addition, the combination of MG-132 and TRAIL seemed to target other apoptotic factors, which led to the accumulation of active capsase-3. Furthermore, co-stimulation of LiCl and TRAIL induced apoptosis in HF28GFP cells. However, HF28Bcl-xL cells were far less sensitive to the combinatorial effects of LiCl and TRAIL. Interestingly, we observed that LiCl did not target Bim and Bid proteins. In conclusion, these data show that targeting of pro-apoptotic Bcl-2 family proteins simultaneously through a selective proteasome inhibition might help to overcome TRAIL resistance caused by overexpression of anti-apoptotic Bcl-2 family proteins. Moreover, the data may provide new strategies to develop targeted therapies against lymphomas. PMID- 29407585 TI - Regulatory T cell inhibition by dasatinib is associated with natural killer cell differentiation and a favorable molecular response-The final results of the D first study. AB - We evaluated the effects of regulatory T cell (Treg) inhibition during dasatinib treatment on the anticancer immune response, particularly on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Fifty-two newly diagnosed Japanese patients with chronic myeloid leukemia (CML) in the chronic phase were enrolled in the D-first study; all received 100 mg of dasatinib once daily and were followed for at least 36 months. The cumulative deep molecular response (DMR, MR4) rate was 65% by 36 months; the 3-year overall survival was 96%. CD4+ T cell counts were stable, whereas the proportion of CD4+CD25+CD127low (Treg) cells decreased in a time-dependent manner. The DMR rate by18 months was significantly better in low Treg patients (<5.7% at 12 months) compared to the remaining patients (odds ratio 4.07). NK cell and CTL counts at several time points were inversely correlated with Treg counts. Furthermore, the degree of NK cell differentiation (CD3-CD57+/CD3-CD56+) was closely and inversely correlated with the proportion of Treg cells throughout the observation period, and showed a gradually increasing trend. In conclusion, our results demonstrate that Treg inhibition by dasatinib contributes to better treatment response through enhancement of the immune system, particularly via NK cell differentiation. PMID- 29407586 TI - 8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid dendritic cell neoplasms. AB - 8q24/MYC rearrangements resulting in MYC overexpression occur most frequently in lymphoid neoplasms. MYC rearrangements rarely have been described in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Over an 8-year period in our hospital, 5 of 41 (12%) patients with BPDCN were shown 8q24/MYC rearrangements, including 2 with t(6;8)(p21;q24), 1 with t(8;14)(q24;q32), 1 with t(X;8)(q24;q24), and 1 with t(3;8)(p25;q24). 8q24/MYC rearrangement was present in the stemline in 4 patients and in the sideline in one; the latter was a patient with primary myelofibrosis who then developed BPDCN. MYC overexpression by immunohistochemistry was variable, but largely correlated with the percentage of blasts. Four patients were treated with acute lymphoblastic leukemia-type chemotherapy regimens and 3 had a good response; 1 patient was treated with acute myeloid leukemia-type regimens and was refractory to therapy. By the end of the follow-up, 3 patients died and 2 were alive in complete remission. We conclude that 8q24/MYC rearrangements occur in 10-15% of BPDCN, often partnered with non immunoglobulin chromosomal loci, and may play a role in BPDCN pathogenesis. In this small patient sample, patients with BPDCN and MYC rearrangement often responded to therapy with acute lymphoblastic leukemia-type chemotherapy regimens. PMID- 29407587 TI - High frequency of intermediate and poor risk copy number abnormalities in pediatric cohort of B-ALL correlate with high MRD post induction. AB - Copy number abnormalities (CNAs) and recurrent fusion transcripts are important genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia (B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and correlated the data with standard risk factors and early treatment outcome parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 region viz., CSF2RA, IL3RA,P2RY8, SHOX region and CRLF2 were analyzed by multiplex ligation dependent probe amplification assay and were detected in 70% (47/67) of cases, with predominantly deletions in CDKN2A/B (36%), PAX5 (18%) and IKZF1 (16%). A statistically significant association of intermediate/poor risk CNAs was noted with high WBC count (p = 0.001), NCI group (p = 0.02) and minimal residual disease at Day35 (p < 0.0001). IKZF1 and CDKN2A/B deletion revealed poor EFS of 56% at 24 months as compared to EFS of 80% in rest of the cases (p = 0.05) suggesting their potential role in early risk stratification. PMID- 29407588 TI - Comparison of induction therapy in non-high risk acute promyelocytic leukemia with arsenic trioxide or in combination with ATRA. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is a curable form of acute myeloid leukemia; in recent years, the use of new treatment strategies, such as combination therapy, have led to improved APL outcomes. Here, outcomes of patients treated with a combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are compared against patients treated with single ATO therapy. PATIENTS AND METHODS: In total, 67 patients with non-high-risk APL were evaluated. A group of 30 patients received ATO, and another group of 37 patients received ATO plus ATRA. ATO infusion at a dose of 0.15 mg/kg/day was continued till complete remission was achieved or till 60 days of consumption, and after 28 days of rest, second ATO course was initiated for 28 days as consolidation. Four courses separated by 28-day rest were planned. In the second group, 45 mg/m2/day ATRA was added to ATO protocol. RESULTS: All patients except one in the ATO group and all patients in the ATO plus ATRA group were alive after a median follow-up of 18 and 17 months, respectively; 2.5-year overall survival in the ATO group was 86% (p-value = .32). Five patients in the ATO group experienced relapse, and 2.5 year leukemia-free survival in this group was 60%. No relapse occurred in the ATO plus ATRA group (p-value = .01). Differences in the mean of white blood cell (p value = .67), platelet (p-value = .15), liver (p-value = .37), and renal (p-value = .95) dysfunctions were not significant. CONCLUSION: Although ATO has been considered a first-line therapy in patients with APL, several studies have reported improved outcomes with a combination of ATO plus ATRA. This study demonstrated a significant decrease in relapse with this combination compared with single ATO therapy and supported the importance of ATRA in APL treatment. PMID- 29407589 TI - Prognostic implications of low transferrin saturation in patients with primary myelofibrosis. AB - OBJECTIVES: Transferrin saturation (TSAT) 20% or less is considered to represent functional iron deficiency in the context of malignant disease, phenomenon mediated through inflammatory changes of iron homeostasis. We aimed to investigate clinical and prognostic significance of low TSAT in patients with primary (PMF) and secondary myelofibrosis (SMF), malignant diseases characterized by strong inflammatory milieu. METHODS: We retrospectively analyzed 87 patients with myelofibrosis and compared TSAT with disease specific parameters. RESULTS: One-third of patients had TSAT <=20%. Lower TSAT was significantly associated with Janus-kinase-2 (JAK2) mutation (P = 0.007), transfusion independency (P = 0.003), higher platelets (P = 0.004), lower mean-corpuscular-volume (P < 0.001), lower ferritin (P < 0.001), higher absolute-neutrophil-count (P = 0.027), lower absolute-lymphocyte-count (P = 0.041) and lower albumin (P = 0.018). PMF patients presenting with low TSAT (<=20%) experienced significantly shorter overall survival (OS) (HR = 2.43; P = 0.017), whereas TSAT did not affect OS of SMF patients (HR = 1.48; P = 0.623). Low TSAT remained significantly associated with inferior OS in PMF in a series of multivariate Cox regression models comparing its properties to anemia, transfusion dependency, ferritin and Dynamic International-Prognostic-System (DIPSS). CONCLUSIONS: Low TSAT has detrimental effect on survival of PMF patients. This effect is independent of anemia and of ferritin levels that seem to be better at representing iron overload in PMF patients. PMID- 29407590 TI - Alkyl indole-based cannabinoid type 2 receptor tools: Exploration of linker and fluorophore attachment. AB - Cannabinoid type 2 (CB2) receptor continues to emerge as a promising drug target for many diseases and conditions. New tools for studying CB2 receptor are required to further inform how this receptor functions in healthy and diseased states. The alkyl indole scaffold is a well-recognised ligand for cannabinoid receptors, and in this study the indole C5-7 positions were explored for linker and fluorophore attachment. A new high affinity, CB2 receptor selective inverse agonist was identified (16b) along with a general trend of C5-substituted indoles acting as agonists versus C7-substituted indoles acting as inverse agonists. The indole C7 position was found to be the most tolerant to linker extension and resulted in a high affinity inverse agonist with a medium length linker (19). Although a high affinity fluorescent ligand for CB2 receptor was not identified in this study, the indole C7 position shows great promise for fluorophore or probe attachment. PMID- 29407592 TI - Spontaneous imitative movements induced by an illusory embodied fake hand. AB - In the rubber hand illusion (RHI), individuals perceive a fake hand as their own when the hidden real hand and visible fake hand are synchronously stroked. Several RHI studies have reported that visual manipulation of the embodied fake hand inversely affects the perceptual processing of the observer's own hand (e.g., thermal or pain sensitivity). In this study, we examined whether motor manipulation of the fake hand similarly affects the observer's motor system. Our study employed a novel RHI paradigm wherein stroking was interrupted by unexpected movement of the fake hand (i.e., finger spreading) while measuring electroencephalography (EEG). We found that participants often spontaneously moved their hands in accordance with the movement of the fake hand only in the RHI (synchronous) sessions. EEG analyses revealed enhanced neural activation (mu rhythm desynchronization) of the motor system during observation of the fake hand movement. Moreover, motor activation was greater in the synchronous than in the asynchronous condition and significantly correlated with the feeling of body ownership over the fake hand. These findings provide strong behavioral and neurophysiological evidence of 'motor back projection', in which the movement of an illusory embodied body part is inversely transferred to the sensorimotor system of the observer. PMID- 29407593 TI - The processing of mispredicted and unpredicted sensory inputs interact differently with attention. AB - Prediction and attention are fundamental brain functions in the service of perception. Interestingly, previous investigations found prediction effects independent of attention in some cases but attention-dependent in other cases. The discrepancy might be related to whether the prediction effect was revealed by comparing mispredicted event (where there is incorrect prediction) or unpredicted event (where there is no precise prediction) against predicted event, which are associated with different precision-weighted prediction error. Here we conducted a joint analysis on four published electroencephalography (EEG) datasets which allow for proper dissociation of mispredicted and unpredicted conditions when there was orthogonal manipulation of prediction and attention. We found that the mispredicted-versus-predicted contrast revealed an attention-independent effect of prediction suppression, whereas the unpredicted-versus-predicted contrast revealed a prediction effect that was reversed by attention on auditory N1. The results suggest that mispredicted and unpredicted processing interact with attention in distinct manners. PMID- 29407591 TI - Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects. AB - Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2 (2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1 yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development. PMID- 29407594 TI - Overexpression of perilipin1 protects against atheroma progression in apolipoprotein E knockout mice. AB - BACKGROUND AND AIMS: Perilipin1 (PLIN1), a lipid droplet-associated protein, plays an important role in the regulation of lipolysis and lipid storage in adipocytes. PLIN1 has recently been reported to be expressed in macrophages within atheroma plaques, suggesting PLIN1 may play a role in the accumulation of lipids at the arterial wall and in the development of atherosclerosis. To clarify the role of PLIN1 in the pathophysiology of atherosclerosis, we assessed the progression of atherosclerosis in PLIN1 transgenic mice (Plin1Tg). METHODS: Plin1Tg were crossed with apolipoprotein E knockout mice (ApoeKO). C57BL/6J mice, ApoeKO and Plin1Tg/ApoeKO received a normal chow diet for 20 weeks. Body weight, gonadal fat mass and plasma lipid concentrations were measured. Aortas were collected for quantification of atheroma lesions and histological analysis by Oil Red O staining. RESULTS: Body weight, gonadal adipose mass and plasma triglyceride concentrations were not significantly different among the three groups. In contrast, the atherosclerotic lesion area was significantly increased in ApoeKO (14.2 +/- 3.2%; p < .01) compared with C57BL/6J mice (3.3 +/- 1.2%) and Plin1Tg/ApoeKO (5.6 +/- 1.9%). CONCLUSIONS: Overexpressed PLIN1 in macrophages had a protected role against atheroma progression in ApoeKO in the absence of changes in gonadal fat mass or plasma lipid levels, presumably due to modification of the stability and/or inflammatory profile of macrophages. PMID- 29407595 TI - Post-transplant hypocomplementemia: A novel marker of cardiovascular risk in kidney transplant recipients? AB - BACKGROUND AND AIMS: Cardiovascular disease (CVD) is a leading cause of mortality after kidney transplantation (KT). The potential role of the complement system in the pathogenesis of post-transplant CVD remains unexplored. METHODS: Serum complement (C3 and C4) levels were measured at baseline and post-transplant months 1 and 6 in 447 kT recipients. The study outcome was post-transplant atherothrombotic event (PAE), a composite of acute coronary syndrome, critical peripheral arterial disease, stroke and/or transient ischemic attack. RESULTS: After a median follow-up of 4.2 years, 48 PAEs occurred in 43 patients (cumulative incidence: 9.6%; incidence rate: 2.6 events per 100 transplant years). No differences were found in C3 and C4 levels at baseline or month 1 between patients with or without PAE. However, C3 levels at month 6 were significantly lower in patients developing PAE beyond that point (i.e., late PAE) (96.9 +/- 22.3 vs. 109.6 +/- 24.0 mg/dL; p = 0.013). The presence of C3 hypocomplementemia at month 6 was associated with a lower PAE-free survival (p = 0.002). After adjusting for conventional CVD risk factors and acute graft rejection, C3 hypocomplementemia at month 6 remained as an independent risk factor for late PAE in all the exploratory models (minimum hazard ratio: 3.24; p = 0.011). With respect to a model exclusively based on clinical variables, the inclusion of C3 levels at month 6 improved predictive capacity (areas under ROC curves: 0.788 and 0.812, respectively). CONCLUSIONS: Post-transplant monitoring of serum C3 levels might be useful to identify KT recipients at increased risk of CVD. PMID- 29407596 TI - Association of time spent in physical activities and sedentary behaviors with carotid-femoral pulse wave velocity: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Increased arterial stiffness is linked to increased risk of cardiovascular disease and mortality. Studies have reported conflicting results regarding the relationship between arterial stiffness and time spent in sedentary behavior (SB) and physical activity (PA). The objective of this systematic review and meta-analysis was to assess the relationship between objectively measured light PA (LPA), moderate to vigorous PA (MVPA), and SB with the gold standard measurement of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV). METHODS: PubMed, Scopus, and Web of Science were searched for relevant studies published until November 2016. Studies reporting the correlation of objectively measured PA and SB with cfPWV in human adults >18 years old were included in this analysis. Correlation coefficients (CCs) were converted to Z scores via Fisher's z values for the analysis of summary effects, using a random-effects model. RESULTS: Twelve studies were included in the systematic review. The meta-analysis showed a negative correlation between cfPWV and LPA (CC -0.16; 95% CI: -0.29 to 0.03; p=0.02) and MVPA (CC -0.16; 95% CI: -0.26 to -0.06; p<0.01), and a positive relationship between cfPWV and SB (CC 0.23; 95% CI: 0.12 to 0.35; p<0.01). CONCLUSIONS: Time spent in light and moderate physical activities is associated with lower arterial stiffness, while time spent in SB is related to higher arterial stiffness. It suggests that PA at any intensity is favorable for arterial stiffness, whereas SB leads to increased arterial stiffness. Considering that cfPWV has an independent prognostic value, these associations may have important clinical implications. PMID- 29407597 TI - Role of dual lipid-lowering therapy in coronary atherosclerosis regression: Evidence from recent studies. AB - Despite recent therapeutic advances, there is an unmet need in cardiovascular disease prevention. Clinical trials and meta-analyses have established that LDL-C lowering, particularly by statin therapy, reduces the progression of coronary atherosclerosis and the risk of coronary events. Insufficient LDL-C reduction and high residual risk in a significant proportion of statin-treated patients signify that additional therapies are required to deliver more effective coronary care. Pharmacological inhibition of cholesterol absorption (with ezetimibe) and PCSK9 activity (with evolocumab or alirocumab) provides potentially useful approaches for the therapeutic modulation of LDL-C metabolism in statin-treated patients. In recent trials, combination strategies involving a statin and non-statin agent (ezetimibe or evolocumab) have been shown to promote coronary atherosclerosis regression and improve cardiovascular outcomes in patients with moderate-to-high cardiovascular risk. This review summarizes recent evidence on the effects of dual lipid-lowering therapy on coronary atherosclerosis. PMID- 29407598 TI - Hyperuricemia as a prognostic factor after acute coronary syndrome. AB - BACKGROUND AND AIMS: Many studies have reported the independent association between uric acid and cardiovascular disease, its role as a risk predictor for outcomes in people with acute coronary syndrome remains controversial. This study aims to assess the association between hyperuricemia and medium/long-term clinical outcomes in people with acute coronary syndrome and determine whether adding hyperuricemia to the GRACE score improves its predictive capability. METHODS: This cohort study included patients admitted for acute coronary syndrome between 2008 and 2013. Outcomes were cardiovascular and total mortality, and major cardiovascular events. We used a multivariate model to adjust for potential confounding covariates and presented event rates with Kaplan-Meier curves. After adding hyperuricemia to the GRACE score, we compared scores from the reclassification table and the net reclassification improvement. RESULTS: 1119 participants were included and followed-up for a mean of 36 months. Multivariate models showed hyperuricemia was independently associated with higher cardiovascular mortality (HR:1.91; 95% CI:1.32-2.76; p < 0.01), higher all-cause mortality (HR:1.59; 95% CI:1.18-2.15; p < 0.01) and higher major cardiovascular event rates (HR:1.36; 95% CI:1.11-1.67; p < 0.01). The hyperuricemia addition to GRACE score led to reclassifying 26% of the participants, and net reclassification improvement was 34%. However, the area under the curve increase was 0.009 and not statistically significant (p > 0.05). CONCLUSIONS: Hyperuricemia is associated with higher medium/long-term mortality and major cardiovascular event rates in patients following acute coronary syndrome. The addition of hyperuricemia to the GRACE score seems to improve risk classification but the discrimination of the new predictive model did not change. Hyperuricemic patients had higher all-cause mortality in medium and high-risk score categories. PMID- 29407599 TI - Angiotensin receptor-binding molecule in leukocytes in association with the systemic and leukocyte inflammatory profile. AB - BACKGROUND AND AIMS: The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS: Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS: The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1beta, tumor necrosis factor-alpha and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1beta mRNA level was significantly upregulated in bone marrow ATRAP deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS: These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs. PMID- 29407601 TI - Contour interpolation: A case study in Modularity of Mind. AB - In his monograph Modularity of Mind (1983), philosopher Jerry Fodor argued that mental architecture can be partly decomposed into computational organs termed modules, which were characterized as having nine co-occurring features such as automaticity, domain specificity, and informational encapsulation. Do modules exist? Debates thus far have been framed very generally with few, if any, detailed case studies. The topic is important because it has direct implications on current debates in cognitive science and because it potentially provides a viable framework from which to further understand and make hypotheses about the mind's structure and function. Here, the case is made for the modularity of contour interpolation, which is a perceptual process that represents non-visible edges on the basis of how surrounding visible edges are spatiotemporally configured. There is substantial evidence that interpolation is domain specific, mandatory, fast, and developmentally well-sequenced; that it produces representationally impoverished outputs; that it relies upon a relatively fixed neural architecture that can be selectively impaired; that it is encapsulated from belief and expectation; and that its inner workings cannot be fathomed through conscious introspection. Upon differentiating contour interpolation from a higher-order contour representational ability ("contour abstraction") and upon accommodating seemingly inconsistent experimental results, it is argued that interpolation is modular to the extent that the initiating conditions for interpolation are strong. As interpolated contours become more salient, the modularity features emerge. The empirical data, taken as a whole, show that at least certain parts of the mind are modularly organized. PMID- 29407600 TI - Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients. AB - BACKGROUND AND AIMS: This study examined the impact of CD14++CD16+ monocytes on coronary plaque vulnerability, as assessed by optical coherence tomography (OCT), and investigated their association with daily glucose fluctuation. Although increased CD14++CD16+ monocyte levels have been reported to increase cardiovascular events, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without diabetes mellitus (DM) remains unclear. METHODS: This prospective observational study included 50 consecutive patients with CAD, receiving lipid-lowering therapy and undergoing coronary angiography and OCT. Patients were divided into 3 tertiles according to the CD14++CD16+ monocyte percentages assessed by flow cytometry. Standard OCT parameters were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30-70%). Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). RESULTS: CD14++CD16+ monocytes negatively correlated with fibrous cap thickness (r = -0.508, p < 0.01). The presence of thin-cap fibroatheroma (TCFA) was increased stepwise according to the tertile of CD14++CD16+ monocytes (0 [tertile 1] vs. 5 [tertile 2] vs. 10 [tertile 3], p < 0.01). CD14++CD16+ monocytes were a significant determinant of TCFA (OR 1.279, p = 0.001). In non-DM patients, a significant relationship was found between CD14++CD16+ monocytes and MAGE (r = 0.477, p = 0.018). CONCLUSIONS: CD14++CD16+ monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14++CD16+ monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14++CD16+ monocytes could be a possible therapeutic target for coronary plaque stabilization. PMID- 29407602 TI - Adding statistical regularity results in a global slowdown in visual search. AB - Current statistical learning theories predict that embedding implicit regularities within a task should further improve online performance, beyond general practice. We challenged this assumption by contrasting performance in a visual search task containing either a consistent-mapping (regularity) condition, a random-mapping condition, or both conditions, mixed. Surprisingly, performance in a random visual search, without any regularity, was better than performance in a mixed design search that contained a beneficial regularity. This result was replicated using different stimuli and different regularities, suggesting that mixing consistent and random conditions leads to an overall slowing down of performance. Relying on the predictive-processing framework, we suggest that this global detrimental effect depends on the validity of the regularity: when its predictive value is low, as it is in the case of a mixed design, reliance on all prior information is reduced, resulting in a general slowdown. Our results suggest that our cognitive system does not maximize speed, but rather continues to gather and implement statistical information at the expense of a possible slowdown in performance. PMID- 29407603 TI - Switching between lift and use grasp actions. AB - Switching between competing grasp postures incurs costs on speeded performance. We examined switch costs between lift versus use actions under task conditions that required subjects to identify familiar objects. There were no asymmetrical interference effects, though reliable costs occurred when the same object required a different action on consecutive trials. In addition, lift actions were faster to objects targeted for a prospective use action than objects irrelevant to this intended goal. The benefit of a lift-then-use action sequence was not merely due to the production of two different actions in short order on the same object; use actions to an object marked for the distal goal of a lift action were not faster than use actions applied to another object. We propose that the intention to use an object facilitates the prior action of lifting it because the motor sequence lift-then-use is habitually conscripted to enact the proper function of an object. PMID- 29407604 TI - Investing in commitment: Persistence in a joint action is enhanced by the perception of a partner's effort. AB - Can the perception that one's partner is investing effort generate a sense of commitment to a joint action? To test this, we developed a 2-player version of the classic snake game which became increasingly boring over the course of each round. This enabled us to operationalize commitment in terms of how long participants persisted before pressing a 'finish' button to conclude each round. Our results from three experiments reveal that participants persisted longer when they perceived what they believed to be cues of their partner's effortful contribution (Experiment 1). Crucially, this effect was not observed when they knew their partner to be an algorithm (Experiment 2), nor when it was their own effort that had been invested (Experiment 3). These results support the hypothesis that the perception of a partner's effort elicits a sense of commitment, leading to increased persistence in the face of a temptation to disengage. PMID- 29407605 TI - Dynamic competition account of men's perceptions of women's sexual interest. AB - This work applies a dynamic competition framework of decision making to the domain of sexual perception, which is linked theoretically and empirically to college men's risk for exhibiting sexual coercion and aggression toward female acquaintances. Within a mouse-tracking paradigm, 152 undergraduate men viewed full-body photographs of women who varied in affect (sexual interest or rejection), clothing style (provocative or conservative), and attractiveness, and decided whether each woman currently felt sexually interested or rejecting. Participants' mouse movements were recorded to capture competition dynamics during online processing (throughout the decisional process), and as an index of the final categorical decision (endpoint of the decisional process). Participants completed a measure of Rape-Supportive Attitudes (RSA), a well-established correlate of male-initiated sexual aggression toward female acquaintances. Mixed effects analyses revealed greater curvature toward the incorrect response on conceptually incongruent trials (e.g., rejecting and dressed provocatively) than on congruent trials (e.g., rejecting and dressed conservatively). This suggests that the two decision alternatives are simultaneously active and compete continuously over time, consistent with a dynamic competition account. Congruence effects also emerged at the decisional endpoint; accuracy was typically lower when stimulus features were incongruent, rather than congruent. RSA potentiated online congruence effects (intermediate states of behavior) but not offline congruence effects (endpoint states of behavior). In a hierarchical regression analysis, online processing indices accounted for unique variability in RSA above and beyond offline accuracy rates. The process-based account of men's sexual interest judgments ultimately may point to novel targets for prevention strategies designed to reduce acquaintance-initiated sexual aggression on college campuses. PMID- 29407606 TI - Family poly-victimization and cyberbullying among adolescents in a Chinese school sample. AB - The sustained increase in their use of social networking facilitates the development of adolescents but comes with the risk of cyberbullying, which creates new challenges in regard to adolescent protection. Past evidence shows that family victimization may play an essential role in the way adolescents learn cyberbullying behaviors. Yet, research on the co-occurrence of family victimization and cyberbullying is limited. This study aims to investigate the associations between cyberbullying and family victimization among adolescents, and to examine the health correlates of cyberbullying and family poly victimization. A large sample of 18,341 students, aged 15-17, from six cities in China, collected between 2009 and 2010 is employed in the present study, which investigated the association between various kinds of family victimization and adolescent cyberbullying. Data analysis was conducted in 2017. In-law conflict, intimate partner violence, elder abuse and neglect, and child maltreatment were associated with a higher possibility of children becoming internet victims. Parents' divorce and separation, low family income, mother's low level of education, and father's unemployment were all associated with cyberbullying victimization. Cyber victimization was positively correlated to symptoms of PTSD and depression, self-harm, and other physical and mental health variables. Possible explanations for the relationships found in this study are discussed and implications for future research and services are provided. Proactive screening for family poly-victimization and cyberbullying is suggested. Schools are highly recommended to cooperate with parents to promote cyber safety. PMID- 29407607 TI - Are emotions controllable? Maltreated and non-maltreated youth's implicit beliefs about emotion and aggressive tendencies. AB - Although child maltreatment places youth at substantial risk for difficulties with emotion regulation and aggression, not all maltreated youth show these adverse effects, raising important questions about characteristics that discriminate those who do versus do not evidence long-term negative outcomes. The present investigation examined whether implicit beliefs about emotion moderated the association between maltreatment and aggression. Maltreated (n = 59) and community-matched (n = 66) youth were asked regarding their beliefs about emotion and aggressive behaviors. Beliefs about emotion were more strongly associated with aggression among maltreated youth, particularly physically abused youth. Maltreated youth who believed they had poor ability to control emotion reported significantly higher levels of aggression than comparison youth. However, maltreated youth who believed they had high ability to control emotion did not differ significantly in aggression from that of comparison youth. Findings offer unique insight into a factor that may increase or buffer maltreated youth's risk for aggression and thus highlight potential directions for interventions to reduce aggressive tendencies. PMID- 29407608 TI - Therapeutic cancer vaccines: From initial findings to prospects. AB - With the approval of the first therapeutic cancer vaccine by US Food and Drug Administration, numerous therapeutic cancer vaccines have been under clinical trials with an inspiring antitumor immune response in cancer patients. Though there is no therapeutic cancer vaccine showing clinical efficacy in phase III trials, recent advances in personalized cancer vaccine based on neoantigens have emerged as an efficient way to induce tumor regression. In this review, we discuss the selection methods of tumor specific antigen and mainly focus on the development of therapeutic cancer vaccine strategies. Besides, we highlight the newly developed personalized cancer vaccine as a novel therapeutic approach for cancer patients. Finally, we outline the recent development of therapeutic cancer vaccine in clinical trials. PMID- 29407609 TI - Regulation of alternative oxidase 1 in Chlamydomonas reinhardtii during sulfur starvation. AB - The mitochondrial respiratory chain in plants, some protists and many fungi consists of the ATP-coupling cyanide-sensitive cytochrome pathway and the cyanide resistant alternative respiratory pathway. The alternative pathway is mediated by alternative oxidase (AOX). Although AOX has been proposed to play essential roles in nutrient stress tolerance of plants and protists, the effects of sulfur (S) deprivation, on AOX are largely unknown. The unicellular green alga Chlamydomonas reinhardtii reacts to S limitation conditions with the induced expression of many genes. In this work, we demonstrated that exposure of C. reinhardtii to S deprivation results in the up-regulation of AOX1 expression and an increased AOX1 protein. Furthermore, S-deprived C. reinhardtii cells display the enhanced AOX1 capacity. Moreover, nitrate assimilation regulatory protein (NIT2) is involved in the control of the AOX1 gene expression in the absence of S. Together, the results clearly indicate that AOX1 relates to S limitation stress responses and is regulated in a NIT2-dependent manner, probably together with yet-unknown regulatory factor(s). PMID- 29407610 TI - Trophic-functional patterns of biofilm-dwelling ciliates at different water depths in coastal waters of the Yellow Sea, northern China. AB - Vertical variations in trophic-functional patterns of biofilm-dwelling ciliates were studied in coastal waters of the Yellow Sea, northern China. A total of 50 species were identified and assigned to four trophic-functional groups (TFgrs): algivores (A), bacterivorous (B), non-selective (N) and raptors (R). The trophic functional structures of the ciliate communities showed significant variability among different water depths: (1) with increasing water depth, relative species numbers and relative abundances of groups A and R decreased sharply whereas those of groups B and N increased gradually; (2) in terms of the frequency of occurrences, group A dominated at depths of 1-3.5 m whereas group B dominated at 5 m, while in terms of the probability density function of the trophic-functional spectrum, group A was the highest contributor at 1 m and group B was highest at the other three depths; (3) distance-based redundancy analyses revealed significant differences in trophic-functional patterns among the four depths, except between 2 and 3.5 m (P > 0.05); and (4) the trophic-functional trait diversity increased from 1 to 3.5 m and decreased sharply at 5 m. Our results suggest that the biofilm-dwelling ciliates maintain a stable trophic-functional pattern and high biodiversity at depths of 1-3.5 m. PMID- 29407611 TI - Functional characterization of tumor necrosis factor receptor-associated factor 3 of sea perch (Lateolabrax japonicas) in innate immune. AB - Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a multifunctional regulator implicated in both bacterial defense and antiviral immunity. Here, a TRAF3 gene from the seawater fish sea perch, designated as LjTRAF3, was characterized. The full-length cDNA of LjTRAF3 was 2972 bp including a 5' untranslated region (UTR) of 243 bp, a 3'UTR of 941 bp and a putative open reading frame of 1608 bp encoding a putative protein of 536 amino acid. The deduced LjTRAF3 protein contained a RING finger, two zinc fingers, a coiled-coil, and a meprin and TRAF-C homology domain. Phylogenetic analysis showed that LjTRAF3 shared the closest genetic relationship with Larimichthys crocea TRAF3. Gene expression analyses suggested that LjTRAF3 mRNA was ubiquitously expressed in all the tissues tested, and was up-regulated post red spotted grouper nervous necrosis virus (RGNNV) infection in vivo and in vitro. Reporter gene assay showed that LjTRAF3 significantly activated zebrafish type I interferon (IFN) promoter in vitro. During RGNNV infection, ectopic expression of LjTRAF3 significantly reduced the RNA dependent RNA polymerase transcription of RGNNV, and enhanced the expression of RIG-I-like receptors (RLR), janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway related genes and IFN stimulated genes (ISGs), including ISG15, PKR, VIG and TRIM39. Taken together, our results suggested that LjTRAF3 might trigger the expression of various ISGs to counter RGNNV infection by regulating the RLR-induced IFN and JAK-STAT signaling pathways. PMID- 29407612 TI - Alterations in haemolymph proteome of Mytilus galloprovincialis mussel after an induced injury. AB - A proteomic and biochemical approach was performed to assess the effects of an induced muscle injury on the haemolymph of bivalve molluscs. For this purpose, Mytilus galloprovincialis were exposed to puncture of adductor muscle for three consecutive days, and their haemolymph proteome was then compared to healthy animals using 2-dimensional electrophoresis (2-DE) to identify proteins that differed significantly in abundance. Those proteins were then subjected to tandem mass spectrometry and 6 proteins, namely myosin, tropomyosin, CuZn superoxide dismutase (SOD), triosephosphate isomerase, EP protein and small heat shock protein were identified. SOD and tropomyosin changes were verified by spectrophotometric measurements and western blotting, respectively. As some of the proteins identified are related to muscular damage and oxidative stress, other biomarkers associated with these processes that can be evaluated by automatic biochemical assays were measured including troponin, creatine kinase (CK), and aspartate aminotransferase (AST) for muscle damage, and SOD, trolox equivalent antioxidant capacity (TEAC) and esterase activity (EA) for oxidative stress. Significantly higher concentrations of troponin, CK, AST, and TEAC were observed in mussels after puncture, being also possible biomarkers of non specific induced damage. PMID- 29407613 TI - Effects of ammonia-N exposure on the concentrations of neurotransmitters, hemocyte intracellular signaling pathways and immune responses in white shrimp Litopenaeus vannamei. AB - The effects of ammonia-N exposure (transferred from 0.07 to 2, 10 and 20 mg L-1) on the mechanism of neuroendocrine-immunoregulatory network were investigated in Litopenaeus vannamei. The results showed that biogenic amines (dopamine, noradrenaline, 5-hydroxytryptamine) concentrations in treatment groups increased significantly within 12 h. The gene expression of guanylyl cyclase increased significantly from 3 h to 24 h. And dopamine receptor D4 and alpha2 adrenergic receptor gene expression in treatment groups decreased significantly within 12 h, whereas the mRNA expression of 5-HT7 receptor increased significantly within 3 h and reached the peak levels at 6 h. The second messengers (cAMP, cGMP) and Calmodulin (CaM) increased significantly in treatment groups after 3 h. The concentrations of protein kinases (PKA, PKG) shared a similar trend in cAMP and cGMP which were up-regulated and reached the peak value at 6 h, while the PKC decreased within 3 h and arrived at its bottom at 6 h. The nuclear factor kappa-b and cAMP-response element binding protein mRNA expression levels of treatment shrimps increased sharply and reached maximum values at 6 h. The total hemocyte count, phagocytic activity, antibacterial activity in treatment groups decreased dramatically within 48 h. Whereas the phenoloxidase activities slightly up regulated. Then it was decreased significantly up to 48 h. alpha2-macroglobulin activity decreased at the first 3 h-stress. Then they up-regulated significantly in 6 h. The results suggest that there are two crucial neuroendocrine substances (biogenic amine and CHH), which play a principal role in adapting to ammonia-N exposure and cause immune response through cAMP-, CaM- and cGMP-dependent pathways. PMID- 29407614 TI - Molecular characterization of diphthamide biosynthesis protein 7 in Marsupenaeus japonicus and its role in white spot syndrome virus infection. AB - Diphthamide biosynthesis protein 7 (Dph7) is a vital protein for diphthamide biosynthesis in archaea and eukaryotes. The 1143 bp cDNA sequence of Dph7 was cloned from the gills of Marsupenaeus japonicus using RT-PCR and RACE. Data showed that Dph7 was highly expressed in the gills and digestive gland of M. japonicus. Furthermore, the expression of dph7 was induced by infection with white spot syndrome virus (WSSV). When Dph7 was knocked down, immune genes such as toll, prophenoloxidase (proPO), p53, tumor necrosis factor-alpha (TNF-alpha) and signal transducer and activator of transcription (STAT) were significantly down-regulated (P < 0.01) in hemocytes. First, we demonstrated that Dph7 is very important in the progression of WSSV infection and that the time of death for WSSV-infected shrimp was significantly advanced following RNAi targeting of Dph7. We also investigated the effect of Dph7 on apoptosis rate in M. japonicas and found that Dph7-dsRNA treatment caused lower levels of apoptosis in hemocytes, both in the disease-free group and the WSSV group. Knock-down of Dph7 affected the activity of both phenoloxidase (PO) and superoxide dismutase (SOD), and total hemocyte count (THC) after infection with WSSV, indicating that Dph7 plays a regulatory role in the immunological reaction of shrimp in response to WSSV infection. Thus, we conclude that Dph7 may promote the anti-WSSV immune response of shrimp by regulating apoptosis, SOD and PO activity, and can influence the progression of WSSV infection. PMID- 29407615 TI - Dual roles of cystatin A in the immune defense of the pacific oyster, Crassostrea gigas. AB - Cystatins are a large family of the proteins that function as reversible and tight-binding inhibitors of cysteine proteases, which consequently regulate multiple physiological activities including apoptosis and innate immunity. In the present study, we cloned a gene from Crassostrea gigas encoding cystatin, which is related to cystatin A superfamily. CgCytA was comprised of a cystatin-like domain with two conserved glycine residues (GG) near the N-terminal and a highly conserved glutamine-valine-glycine (Q-X-V-X-G) motif in the form of QVVAG loop. Transcription analysis of CgCytA indicated its constitutive expression in all tissues including mantle, gill, digestive tract, hemocytes, heart, adductor muscle, and gonads. Immune challenge with Vibrio alginolyticus, resulted in significant down-regulation of CgCytA expression at the initial stages of infection (till 12 h post infection) and the expression of cystatin increased 48 h post infection. Protease assay demonstrated the concentration of cystatin needed to inhibit half of the maximum biological response of cysteine protease is 14.4 MUg/L (IC50). Furthermore, RNAi of CgCytA resulted in increase of apoptotic cell population in hemocytes of C. gigas, suggesting protection role of CgCytA from hemocytes apoptosis. Unexpectedly, knockdown of CgCytA leaded to enhancement of bacterial clearance in vivo, implying that CgCytA may negatively regulate immune defense by suppressing endogenous cysteine protease. Therefore, CgCytA plays dual roles in protection of host hemocytes from apoptosis and control of bacterial clearance, which may server as one of key endogenous balancer between apoptosis and innate immunity in oyster. PMID- 29407616 TI - Effect of dietary prebiotics and probiotics on snakehead (Channa striata) health: Haematology and disease resistance parameters against Aeromonas hydrophila. AB - This study examined the effect of dietary prebiotics and probiotics after 16 weeks, followed by 8 weeks of post feeding trial with the control unsupplemented diet on haematological and immune response against Aeromonas hydrophila infection in Channa striata fingerlings. Fish were raised on a 40% protein and 12% lipid feed containing three commercial prebiotics (beta-glucan, GOS or galacto oligosaccharide, MOS or mannan-oligosaccharide); and two probiotics- (Saccharomyces cerevisiae, Lactobacillus acidophilus), respectively and a control. Throughout the study, supplementation with dietary prebiotics and probiotics led to significant (P < 0.05) improvement in the red blood cells, white blood cells, packed cell volume, haemoglobin concentration and serum protein level and lysozyme activities; and these improvements were effective significantly (P < 0.05) when the fish were challenged with Aeromonas hydrophila at the dose of 2 * 106. The disease resistance against A. hydrophila was higher significantly (P < 0.05) in fish fed with probiotic feed supplements (L.acidophilus was highest) compared to prebiotics and control. The study is the first to report the absence of differences in sustaining the efficacies attained after intake of beta-glucan, GOS and MOS upon post-feeding with an unsupplemented feed, over a prolonged period. PMID- 29407617 TI - Marine actinomycetes as bioremediators in Penaeus monodon rearing system. AB - Actinomycetes (277 Nos) isolated from marine environment and shrimp culture pond sediments were tested for hydrolytic enzyme production and biogranulation property. Potential isolates were screened for their efficacy in bioremediation of shrimp culture system. Based on the BOD reduction efficiency and water quality parameters, five actinomycete isolates viz., Streptomyces coelicoflavus (A6), Streptomyces diastaticus (A44), Nocardiopsis alba (A55), Streptomyces parvus (A56) and Streptomyces champavatii (R32) were subjected for tertiary screening in Penaeus monodon larval rearing system and the animals were challenged with white spot syndrome virus (WSSV). The bioremediating effect of actinomycete treatments were assessed by analysing the expression profile of five antimicrobial peptide (AMP) genes viz., anti-lipopolysaccharide factor (ALF), crustin-2, crustin-3, penaeidin-3 and penaeidin-5 and eight immune genes viz., alpha-2-macroglobulin (alpha-2-M), astakine, glutathione-S-transferase, haemocyanin, peroxinectin, pmCathepsinC, prophenol oxidase (proPO) and Rab-7. Expression of eight WSSV genes viz., DNA polymerase, endonuclease, protein kinase, immediate early gene, latency related gene, ribonucleotide reductase, thymidine kinase and VP28 were also analyzed to detect the presence and intensity of viral infection in the experimental animals post-challenge. Theapplication of consortia (1 g/5 L water) yields better results in terms of significant reduction in BOD of shrimp rearing system showing the bioremediation potential of the marine actinomycete strains. The application of marine actinomycetes viz., Streptomyces coelicoflavus (A6), Streptomyces diastaticus (A44), Nocardiopsis alba (A55), Streptomyces parvus (A56) and Streptomyces champavatii (R32) in granulated form were found to be potential bioremediators in shrimp rearing system. PMID- 29407618 TI - Transcriptome analysis of 'Huanghai No. 2' Fenneropenaeus chinensis response to WSSV using RNA-seq. AB - White spot syndrome (WSS) is one of the most damaging phenomena in the culturing of shrimp. To characterize the mechanisms of the molecular responses to WSSV infection in 'Huanghai No. 2'' Fenneropenaeus chinensis, we used next-generation sequencing to observe the transcriptome after oral infection. A total of 108.6 million clean reads were obtained and assembled into 64,103 final unigenes with an average length of 845 bp (N50 = 1534 bp). The assembled unigenes contained 14,263 significant unigenes after BLASTX against the Nr database (E-value cut-off of 10-5). After comparison of digital gene expression data between challenged and control shrimp, a total of 896 DEGs after WSSV infection were identified. Gene pathway analysis indicated that 92, 131 and 142 metabolic pathways were affected at early, peak and late phases respectively. Some pathways were related to the immune response, such as the phagosome, complement and coagulation cascades, the antigen processing and presentation pathway and so on. Many immune-related genes were also identified after pathway analysis. Interestingly, some growth-related genes, such as cathepsin L, myosin regulatory light chain 2 smooth muscle, and alpha-amylase were also differentially expressed after WSSV infection, and the correlation between growth trait and WSSV-resistance trait need further research. The expression patterns of eight DEGs were confirmed by quantitative real-time reverse transcription polymerase chain reaction, and there was good agreement between RNA-seq and qRT-PCR. These data will provide valuable information for characterizing the immune mechanism of the response of shrimp's to WSSV. PMID- 29407619 TI - Production, characterization and application of monoclonal antibodies to the coelomocytes of sea urchin Strongylocentrotus intermedius. AB - Sea urchin is one of marine animals with high economic and great scientific research values. Axial organ is a glandular organ that has been presumed as coelomocytes origin site. In this paper, two monoclonal antibodies (3G10 and 6B3) against coelomocytes of sea urchin Strongylocentrotus intermedius were developed by hybridoma technique. The mAbs were characterized by indirect immunofluorescence assay test (IIFAT), flow cytometry (FCM) and western blot assay. Results showed that mAb 3G10 recognized a protein of a molecular weight of 17 kDa in the spherule cells, while mAb 6B3 reacted with a protein of a molecular weight of 35 kDa in the phagocytes. Furthermore, specificity analysis revealed that the two mAbs could react with the coelomocytes of sea urchin S. nudus and Hemicentrotus pulcherrimus, but not with those of other common echinoderms including sea cucumber Apostichopus japonicus and starfish Asterias rollestoni. To determine whether the coelomocytes exist in the axial organ of sea urchin, the IIFAT assays were carried out based on the two mAbs. Result showed that positive fluorescence signals were distributed in the organ. It was revealed that the axial organ was rich in coelomocytes, which suggests that the organ may play as a producing source or reservoir in the ontogenesis of coelomocytes of sea urchin. PMID- 29407620 TI - Point of Care Testing (POCT) to assess drug concentration in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) do not need routine laboratory monitoring but measurement of drug concentration is important in emergency conditions. Specific laboratory tests are not readily available or not implemented in every hospital. Point-of-Care Tests (POCT) may bridge this gap and be used as a bedside solution. OBJECTIVES: Feasibility of POCT to assess plasma levels of dabigatran, rivaroxaban and apixaban. PATIENTS/METHODS: Activated Coagulation Time-Low Range (ACT - LR) using a portable Hemochron Signature Elite for dabigatran and prothrombin time (expressed as INR) by Coaguchek XS Pro for rivaroxaban and apixaban were obtained at trough and peak in 136 consecutive patients taking NOACs (70 on dabigatran, 45 on rivaroxaban and 20 on apixaban). Using a paired study design, drug concentrations were concurrently determined by functional specific tests. RESULTS AND CONCLUSIONS: The correlation between NOACs concentration and the values obtained using the POCTs was high for dabigatran and rivaroxaban (r = 0.80 and r = 0.82, respectively) and low for apixaban (r = 0.21). ACT-LR <= 188 s better detected dabigatran levels <= 50 ng/ml, with a sensitivity of 87.5% and a specificity of 84.1%. ACT-LR values > 217 s better discriminated value of dabigatran > 200 ng/ml, with a sensitivity of 86.7% and a specificity of 81.4%. INR Coaguchek values <= 1.2 better identified patients with rivaroxaban values < 100 ng/ml, with sensitivity of 90%, specificity of 88.5%. This analysis was not possible for apixaban. CONCLUSION: In emergency situations POCT use may provide useful immediate information on dabigatran and rivaroxaban concentration. PMID- 29407621 TI - Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy. AB - INTRODUCTION: Interferon (IFN)-alpha and IFN-beta approved for treatment of chronic hepatitis C viral infection and multiple sclerosis respectively have been linked to thrombotic microangiopathy (TMA) affecting renal function. Since the molecular mechanisms underlying this severe complication remain largely unclear, we aimed to investigate whether IFN affects directly in vitro endothelial cell functions associated with angiogenesis and blood haemostasis, as well as endothelial cell-derived vasodilators of nitric oxide (NO) and prostacyclin. METHODS: Proliferation and survival of human umbilical vein endothelial cells (HUVECs) were measured by BrdU incorporation and alamarBlue assays. Angiogenesis was evaluated in co-cultures of HUVECs and human dermal fibroblasts. Fibrinolysis molecules were measured with ELISA. NO and prostacyclin were measured using a fluorescent NO-specific probe and a competitive enzyme immunoassay, respectively. RESULTS: HUVEC proliferation was dose-dependently inhibited by IFN-beta1a and IFN beta1b, but not by IFN-alpha2a and IFN-alpha2b. Consistently, IFN-beta1a and IFN beta1b also reduced survival of HUVECs, but this again was not observed with IFN alpha. However, both IFN subtypes inhibited VEGF-induced development of capillary like structures, but the effect of IFN-alpha was less potent than IFN-beta. In addition, both IFN subtypes upregulated interferon inducible protein 10 production from treated co-cultures while suppressing angiogenesis. Furthermore, intracellular NO generation was reduced by IFN-alpha2a and IFN-beta1a, whereas prostacyclin release from HUVECs was not affected by IFN. Importantly, both IFN beta1a- and IFN-beta1b-treated HUVECs showed a marked reduction in urokinase-type plasminogen activator release and a much greater secretion of plasminogen activator inhibitor-1 than tissue-type plasminogen activator compared with untreated cells, suggesting decreased fibrinolytic activity. IFN-alpha, however was less effective in modulating the fibrinolysis system. CONCLUSIONS: We demonstrate the detrimental effects of IFN on endothelial cell functions mediated with angiogenesis and fibrinolysis, which could potentially cause the loss of physiological endothelium thromboresistance and facilitate the development of vascular complications in a clinical setting. Mechanistically, our findings have implications for understanding how IFN therapy can foster the development of TMA. PMID- 29407622 TI - Simple method for removing DOACs from plasma samples. AB - AIM: To evaluate a simple method using an adsorbent product (DOAC Stop) for extracting direct oral anti-coagulants (DOACs) from plasmas. METHOD: DOAC Stop was tested on normal and a range of abnormal plasmas initially using activated partial thromboplastin time (APTT) tests and a more DOAC-sensitive Russells viper venom-based clotting test (DOAC Test). Further tests for prothrombin time/International Normalized Ratio (PT/INR), lupus anticoagulants, activated protein C (APC) resistance, antithrombin, plasminogen, protein C and S were carried out on various patient samples. RESULTS: DOAC Stop was found to remove all types of DOACs including dabigatran, apixaban, rivaroxaban and edoxaban from test plasmas with minimal effect on any of the (mainly clotting) tests considered in this study. SUMMARY: DOAC Stop can be used to identify plasmas containing DOAcs using simple clotting tests. It reduces the false positivity for lupus anticoagulants observed in dilute Russells viper venom time (dRVVT) tests on DOAC containing plasmas and could be useful for eliminating unwanted effects of DOACs on routine coagulation testing. PMID- 29407623 TI - Prognostic significance of electrocardiogram at presentation in patients with pulmonary embolism of different severity. AB - BACKGROUND: Several electrocardiographic (ECG) abnormalities have been described in patients with acute pulmonary embolism (PE), with discordant reportings about their prognostic value. METHODS: Consecutive patients with echocardiography performed within 48 h from admission and ECG at presentation, were included in this analysis. The primary study outcome was in-hospital death for high-risk patients and in-hospital death or clinical deterioration for intermediate-risk patients. As secondary outcomes, the associations among ECG abnormalities and both right ventricular dysfunction at echocardiography and baseline troponin elevation were considered. RESULTS: 1194 patients were included in this analysis: 13.8% of patients were at high risk of early death, 61.7% were at intermediate risk and 24.5% were at low risk. ECG signs of RV strain showed a continuously decreasing prevalence from high-risk to intermediate-risk and low-risk patients. Differently, the prevalence of T- wave inversion was similar in high and intermediate-risk patients. In high-risk-patients, Qr pattern in lead V1 was the only ECG abnormality associated with in-hospital mortality, but this sign was detected in only 15.9% of this risk category; the presence of at least one ECG abnormality was not associated with the risk of in-hospital death. In not high risk patients, the presence of at least one ECG abnormality was significantly associated with RVD and this association was confirmed for each individual ECG abnormality. Similar results were obtained as regards the baseline troponin elevation in 816 patients. CONCLUSIONS: Among the electrocardiographic signs of RV strain/ischemia, Qr pattern in lead V1 was the only ECG abnormality associated with in-hospital mortality in high-risk patients. In not high-risk patients the demonstrated association among baseline ECG signs of RV strain/ischemia and RV dysfunction at echocardiography or troponin elevation highlights the need for early further investigations in patients with such ECG abnormalities. PMID- 29407624 TI - Initial strides for invent-VTE: Towards global collaboration to accelerate clinical research in venous thromboembolism. AB - Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year. PMID- 29407625 TI - Effectiveness and safety of outpatient rivaroxaban versus warfarin for treatment of venous thromboembolism in patients with a known primary hypercoagulable state. AB - INTRODUCTION: Screening for primary hypercoagulable states (PHSs) in venous thromboembolism (VTE) patients was not mandated in the EINSTEIN trials; and therefore, few patients with a known PHS were available for analysis. We sought to assess the effectiveness and safety of rivaroxaban versus warfarin for treatment of VTE in patients with a known PHS. METHODS: Using MarketScan claims data from 1/2012-9/2015, we identified adults with a primary diagnosis of VTE during a hospitalization/emergency department visit (the index event), with >=180 days of continuous insurance coverage prior to the index event, a documented diagnosis for a PHS and newly-initiated as an outpatient on rivaroxaban or warfarin within 30-days of the index VTE. Rivaroxaban and warfarin users were 1:1 propensity-score matched. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (<0.1 considered well-balanced). Patients were followed up to 12-months from the index event or until occurrence of an endpoint, switch/discontinuation of index oral anticoagulation or insurance disenrollment. Rates of recurrent VTE and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We matched 403 rivaroxaban and 403 warfarin patients with VTE and a known PHS. All baseline covariates had a standardized difference < 0.1. Rivaroxaban use was associated with a non-significant reduction in recurrent VTE (HR = 0.70, 95%CI = 0.33-1.49) and major bleeding (HR = 0.55, 95%CI = 0.16-1.86) versus warfarin. CONCLUSIONS: In routine practice, the effectiveness and safety of rivaroxaban versus warfarin in VTE patients with a known PHS appears to be similar to that observed in the EINSTEIN trial program. PMID- 29407626 TI - Laboratory biomarkers for venous thromboembolism risk in patients with hematologic malignancies: A review. AB - INTRODUCTION: Despite high rates of venous thromboembolism (VTE) among patients with hematologic malignancies, few tools exist to assist providers in identifying those patients at highest risk for this potentially fatal complication. Laboratory biomarkers, such as d-dimer, have demonstrated utility in some clinical settings to distinguish patients at increased risk. MATERIALS AND METHODS: We performed a systematic review of the literature utilizing search terms including "biomarker", "venous thromboembolism", "hematologic malignancy", "lymphoma", "myeloma" and "leukemia" in the Medline database. A total of 25 studies investigating laboratory biomarkers of increased thrombotic risk in the setting of hematologic malignancy were identified and included in this review. RESULTS AND CONCLUSIONS: The most studied biomarkers, d-dimer and fibrinogen, demonstrated some degree of efficacy in identifying high-risk patients at levels >4.0 mg/L or <1.0 g/L respectively. Additional markers which demonstrated promise included thrombin generation, mean platelet volume, soluble VEGF, soluble P selectin and extracellular vesicles. Other biomarkers reviewed, which did not consistently demonstrate significant associations with VTE included prothrombin fragments F1 + 2, factor VIII, protein C, protein S, von Willebrand antigen and activity, antithrombin, thrombin antithrombin complex, antiphospholopid antibody, plasminogen activator inhibitor, tissue factor pathway inhibitor and several variants associated with known hypercoagulable states (factor V Leiden, prothrombin gene variant, methylenetetrahydrofolate reductase variant). Data to support any of the biomarkers discussed here in routine clinical decision-making are currently lacking, but additional investigation in clinical studies, ideally in combination with clinical factors known to be associated with increased thrombotic risk, is warranted. PMID- 29407627 TI - Transition of care for patients with venous thromboembolism: Rationale, design and implementation of a quality intervention project conducted at American Thrombosis and Hemostasis Network (ATHN) affiliated sites. AB - INTRODUCTION: Medication errors frequently occur during transition from the inpatient to outpatient setting. Anticoagulants are associated with serious medical errors, including major bleeding. Standardized transition of care (TOC) techniques in patients with venous thromboembolism (VTE) have not been developed. METHODS: This ongoing project conducted by the American Thrombosis and Hemostasis Network (ATHN) aims to improve TOC for newly diagnosed VTE patients on anticoagulation from the inpatient to outpatient setting, and identify characteristics of patients on direct oral anticoagulants (DOACs) and their TOC. There are two main phases, a Pre-Intervention and a Quality Intervention Phase. For both phases data are collected regarding patient demographics, VTE characteristics, and patients' knowledge and feedback regarding their VTE and anticoagulant discharge instructions. In addition, for the Quality Intervention Phase, a standardized comprehensive discharge instruction module specific for each anticoagulant is administered followed by a one-week phone call. RESULTS: Sixteen ATHN-affiliated sites are participating. There are 218 patients enrolled in the Pre-Intervention Phase. The majority are adults (58.5%), women (52.4%) and non-Hispanic ethnicity (82.2%). The main risk factors for VTE were length of hospital stay of more than seven days and obesity in the pediatric and adult population respectively. Enoxaparin and DOACs were predominantly prescribed for the pediatric and adult population respectively. CONCLUSION: This TOC quality intervention initiative for newly diagnosed patients with VTE aims to demonstrate that implementation of a standardized TOC model is feasible and can improve patient knowledge, satisfaction, compliance, reduce anticoagulant complications and hospital readmissions in both the pediatric and adult populations. PMID- 29407628 TI - Intraplatelet reactive oxygen species (ROS) correlate with the shedding of adhesive receptors, microvesiculation and platelet adhesion to collagen during storage: Does endogenous ROS generation downregulate platelet adhesive function? AB - Platelets storage lesion is mainly orchestrated by platelet activating signals during storage. Reactive oxygen species (ROS) are being considered as important signaling molecules modulating platelet function while their production has also been shown to be augmented by platelet activation. This study investigated to what extent endogenous ROS generation during platelet storage could be correlated with platelet receptor shedding, microvesiculation and adhesive function. 10 PRP platelet concentrates were subjected to flow cytometry analysis to examine the generation of intraplatelet ROS on days 1, 5 and 7 after storage. In 5 day-stored platelets considering 40% of ROS generation as a cutoff point, samples were divided into two groups of those with higher or lower levels of ROS. The expression of adhesion receptors (GPVI, GPIbalpha), the amount of microparticles and phosphatidylserine exposure in each group were then examined by flow cytometry. Platelet receptor shedding and adhesion to collagen matrix were respectively measured by western blotting and microscopic assays. Our data showed lowered expression of GPIbalpha (p < 0.05) and GPVI in samples with ROS > 40% than those with ROS <= 40%, whereas receptors shedding and microvesiculation were (p < 0.05) elevated in platelets with higher levels of ROS. Functionally, we observed significantly (p < 0.05) lower levels of platelet adhesion to collagen matrix in samples with ROS generation more than 40%. Taken together, we showed correlations between intraplatelet ROS generation and either platelet receptors or microparticle shedding as well as platelet adhesive capacity to collagen. These findings suggest that augmented ROS generation during storage might be relevant to down-regulation of platelet adhesive function. PMID- 29407629 TI - Effect of increased time in the therapeutic range on atrial fibrillation outcomes within a centralized anticoagulation service. AB - BACKGROUND: Clinical pharmacy anticoagulation services have improved the quality of anticoagulant therapy and are associated with lower rates of bleeding and thromboembolism compared to usual care. Several studies have found that higher time-in-therapeutic range (TTR) during warfarin therapy is associated with better warfarin outcomes. However, whether increasing TTR over time within an established anticoagulation service is associated with further reduction in bleeding and thromboembolic outcomes is unknown. METHODS: This was a retrospective cohort study of patients with atrial fibrillation conducted at an integrated healthcare delivery system with a centralized, pharmacist-managed anticoagulation service. Clinical outcomes (clinically-relevant bleeding, ischemic stroke or systemic embolism, and all-cause mortality) and TTR were compared between two distinct time periods: 1/1/2006 through 12/31/2007 (control group) and 1/1/2012 through 12/31/2013 (observation group) with regression modeling to adjustment for potential confounders. RESULTS: There were 3641 and 4764 patients in the control and observation groups, respectively. The mean age was 74.3 years and 54.4% of the cohort was female. Mean TTR was higher in the observation group (70.5% vs. 63.4%, p < 0.001). The composite outcome of clinically-relevant bleeding, thromboembolism and all-cause mortality occurred in 4.6% and 3.6% of the control and observation groups, respectively (adjusted odds ratio = 0.69; 95% confidence interval 0.54-0.87). Individual rates of stroke/systemic embolism and all-cause mortality were each lower in the observation group (both p < 0.05) while clinically-relevant bleeding was not significantly different (p = 0.256). CONCLUSION: Increased TTR within a clinical pharmacy anticoagulation management service was associated with a lower risk of the composite outcomes of bleeding, thromboembolism and death in a large atrial fibrillation population receiving warfarin. PMID- 29407630 TI - Low-molecular-weight heparin treatment for portal vein thrombosis in liver cirrhosis: Efficacy and the risk of hemorrhagic complications. AB - INTRODUCTION: Portal vein thrombosis (PVT) is a well-known complication in patients with liver cirrhosis (LC). The aim of this study is to investigate the outcomes of cirrhotic patients with PVT treated with low-molecular-weight heparin (LMWH). METHOD: Ninety-one LC patients with PVT were treated with dalteparin or enoxaparin for six months. Patients with major bleeding during the last three months, severe thrombocytopenia, or impaired renal function were excluded. RESULTS: The median age was 62.9 years, and 59 patients had hepatocellular carcinoma. The overall recanalization rate was 61.5%. Patients with a favorable Child-Pugh class and those recently diagnosed as having a thrombus showed significantly better responses. In those who responded to the anticoagulation therapy, the post-treatment bilirubin and platelet levels were improved compared to those in the pre-treatment state. The relapse rate for PVT was 56.6%, and the median time to relapse was 4.0 months. Bleeding was reported in 13 patients (14.4%), and two patients died due to fatal bleeding. A history of variceal bleeding and low serum albumin were risk factors for bleeding. CONCLUSION: LMWH therapy for PVT in LC is effective. Advanced LC and a delayed start of anticoagulation treatment decrease the effect of LMWH. Despite its effectiveness, there is a risk of hemorrhage, hence anticoagulation should be carefully considered, especially in patients with advanced LC and a history of variceal bleeding. PMID- 29407631 TI - Genetic mutations in PEAR1 associated with cardiovascular outcomes in Chinese patients with acute coronary syndrome. AB - OBJECTIVE: To investigate the association between PEAR1 (platelet endothelial aggregation receptor-1) polymorphisms and cardiovascular outcomes in acute coronary syndrome (ACS) in patients treated with aspirin and clopidogrel. METHODS: We genotyped eight common PEAR1 SNPs (rs2768759, rs12566888, rs12041331, rs11264579, rs2644592, rs822441, rs822442, and rs4661012), also CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) in 196 Chinese patients with ACS. We assessed the association between PEAR1 polymorphisms and platelet inhibition rate (PIR) measured by thromboelastography (TEG). The ischemic events over 12 months were recorded, and the relationship between PEAR1 polymorphisms and ischemic events was analyzed. RESULTS: Genetic mutations in rs822441, rs822442, and CYP2C19*2/*3 alleles were significantly associated with a decrease in PIR induced by adenosine diphosphate (ADP). Carriers of the T allele in rs11264579 were less likely to have ischemic events compared with non-carriers (HR: 0.53, 95% CI: 0.30 0.94, P = .031). By contrast, carriers of the A allele in rs822442 had increased risk of ischemic events (HR: 1.82, 95% CI: 1.02-3.24, P = .043). However, these significant associations disappeared after controlling family-wise error rate. CONCLUSIONS: For Chinese patients with ACS treated with aspirin and clopidogrel, genetic mutations in rs822441/rs822442 in PEAR1 correlated significantly with platelet activity after adjusting for CYP2C19 *2/*3 alleles. The rs11264579 T allele might be a protective factor for ischemic events; rs11264579, rs822441, and rs822442 might be genetic markers worthy of further research. PMID- 29407632 TI - What have we learned from real-world NOAC studies in venous thromboembolism treatment? AB - Venous thromboembolism (VTE) remains a substantial clinical and health-economic burden worldwide and effective anticoagulant treatment is necessary immediately after VTE is suspected to reduce short- and long-term VTE related morbidity and mortality. For decades, low molecular weight heparin (LMWH), fondaparinux and Vitamin K antagonists (VKAs) have been the standard of anticoagulant therapy for VTE patients but these treatment options had clinically relevant drawbacks and limitations. The introduction of non-VKA oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa have resolved many of these drawbacks because these new compounds exhibit a rapid onset and offset of action, fewer food and drug interactions and a predictable anticoagulant effect. All NOACs have successfully completed their respective phase-III trial programs consisting of many large randomized controlled trials, leading to approval for acute VTE treatment around the world. Nevertheless, their introduction into daily care practice is challenging and a careful evaluation of the effectiveness and safety of NOACs in less selected cohorts outside carefully monitored clinical trials is essential. This review introduces the different types of real-world evidence (RWE) and explores the available data for VTE treatment with NOACs, based on a literature search using the key words "venous thromboembolism" or "VTE" in combination with "NOAC", "DOAC", "apixaban", "dabigatran", "edoxaban" and "rivaroxaban" on June 30; 2017, followed by data extraction from studies that reported real-world outcome data for VTE treatment with NOACs, although available evidence is almost exclusively limited to rivaroxaban. PMID- 29407633 TI - The lectin pathway and coagulation in lung cancer patients undergoing lobectomy - A randomised controlled trial. AB - BACKGROUND: Lectin pathway proteases activate coagulation and may theoretically play a role in the increased thrombosis risk in cancer, which is especially high during surgery. AIMS: To investigate lectin pathway proteins during lung cancer surgery, the influence of low molecular weight heparin (LMWH) on lectin pathway proteins, and correlations between lectin pathway proteins and coagulation. METHODS: Fifty lung cancer patients undergoing video-assisted thoracoscopic surgery lobectomy were randomised to LMWH, n = 26, or no anticoagulant (control), n = 24. Pre-, intra- and postoperative lectin pathway protein concentrations (mannose-binding lectin (MBL), H- and M-ficolin, collectin liver-1, MBL associated serine protease (MASP)-1, -2 and -3, MBL-associated proteins MAp44 and MAp19) were assessed using a time-resolved immunofluorometric assay, and fibrinogen, fibrin d-dimer, and thrombin generation were analysed. RESULTS: For all proteins except MASP-1, concentrations decreased during surgery in both groups; most markedly M-ficolin which decreased 49% (median: 2836 [quartiles:2297 3505] to 1424 [1187-2199] ng/ml) (LMWH group) and 43% (2974 [2539-3510] to 1685 [1391-2076] ng/ml) (control group), while MBL decreased 12% (1936 [823-2801] to 1702 [676-2830] ng/ml) (LMWH) and 23% (1526 [250-2412] to 1175 [229-1947]) (controls). No differences in postoperative change were observed between groups except for MAp19 (p = 0.03) which decreased 9% (401 [337-467] to 364 [288-416] ng/ml) (LMWH) vs 28% (370 [272-468] to 268 [212-379] ng/ml) (controls). No correlation was found between lectin pathway proteins and coagulation (r = -0.23 0.28, p > 0.06) except for M-ficolin and fibrinogen (r = 0.29-0.36, p = 0.01 0.04). CONCLUSION: Lectin pathway proteins were influenced by surgery but not by LMWH. No consistent correlation was found between lectin pathway proteins and coagulation. PMID- 29407634 TI - Structure, property, and function of sheepshead (Archosargus probatocephalus) teeth. AB - OBJECTIVES: This paper studies A. probatocephalus teeth and investigates the mechanical properties and chemical composition of the enameloid and dentin. DESIGN: Nanoindentation tests with a max load of 1000 MUN and X-ray Energy Dispersive Spectroscopy (EDS) were performed along the diameter of the polished sample. Microstructural analysis of the dentin tubules was performed from SEM images. RESULTS: From nanoindentation testing, the dentin of the sheepshead teeth has a nanoindentation hardness of 0.89 +/- 0.21 (mean +/- S.D.) GPa and a reduced Young's modulus of 23.29 +/- 5.30 GPa. The enameloid of A. probatocephalus has a hardness of 4.36 +/- 0.44 GPa and a mean reduced Young's modulus of 98.14 +/- 6.91 GPa. Additionally, nanoindentation tests showed that the enameloid's hardness and modulus increased closer to the surface of the tooth. X-ray Energy Dispersive Spectroscopy (EDS) data further suggests that the gradient may be a result of the wt% fluoride within the enameloid, where an increase in fluoride results in an increase in reduced Young's modulus and hardness. CONCLUSION: The microstructural characterization of the number density and area of the dentin tubules were used to address the porosity effect in the dentin to achieve the experimentally validated microhardness. The mechanical properties of the sheepshead teeth were also compared with previous nanoindentation tests from other aquatic species. The sheepshead teeth exhibit a greater reduced Young's modulus and hardness compared to shark and piranha teeth. PMID- 29407635 TI - MicroRNA-186 serves as a tumor suppressor in oral squamous cell carcinoma by negatively regulating the protein tyrosine phosphatase SHP2 expression. AB - OBJECTIVE: MicroRNAs (miRs) have been shown to play critical roles in the pathogenesis of oral squamous cell carcinoma (OSCC), the current study is designed to identify the potential role of miR-186 in OSCC. MATERIALS AND METHODS: Realtime polymerase chain reaction was used to determine miR-186 expression in paired tissue samples (OSCC and adjacent normal tissues) and multiple oral cell lines (normal oral keratinocyte HOK cell and OSCC cell lines). Cell viability, colony formation and flow cytometry assays were used to assess the biological function of miR-186. Furthermore, luciferase and western blot assays were used to verify the predicted target of miR-186. RESULTS: We found that miR-186 expression was significantly downregulated in OSCC tissues and cell lines. Overexpression of miR-186 produced an anti-growth effect and induced apoptosis in Tca8113 and SCC-25 cells. Luciferase assay revealed that miR-186 directly targeted PTPN11 (a gene encodes the protein tyrosine phosphatase SHP2) mRNA 3' untranslated region and suppressed its expression. Consistently, MiR-186 and SHP2 were negatively correlated in OSCC tissues. Consequently, miR-186 inhibited signaling activities of Extracellular Regulated protein Kinases (ERK) and Protein kinase B (AKT), which act downstream of SHP2 and are critical for growth of cancer cells. CONCLUSION: We identify that miR-186 serves as a tumor suppressor in OSCC. Downregulation of this microRNA may lead to a higher expression of oncogenic factor SHP2, which leads to activation of growth promoting signaling. Thus, miR-186 may be a novel and effective therapeutic agent for the treatment of OSCC. PMID- 29407636 TI - Comparative proteomic profiling of human dental pulp stem cells and periodontal ligament stem cells under in vitro osteogenic induction. AB - OBJECTIVE: This study aimed to compare the proteomic profiling of human dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) under in vitro osteogenic induction, which imitates the microenvironment during osteo /odontogenesis of DPSCs and PDLSCs. DESIGN: The proteomic profiles of osteoinduced DPSCs and PDLSCs from a single donor were compared using the isobaric tag for relative and absolute quantitation (iTRAQ) technique and subsequent bioinformatics analysis. RESULTS: A total of 159 differentially expressed proteins in PDLSCs and DPSCs were identified, 82 of which had a higher expression level in PDLSCs, while 77 were more highly expressed in DPSCs. Among these enriched proteins, certain members from the collagen, heat shock protein and protein S100 families may distinguish osteoinduced PDLSCs and DPSCs. Gene ontology (GO) classification revealed that a large number of the enriched terms distinguishing PDLSCs and DPSCs are involved in catalytic activity, protein binding, regulation of protein metabolic processes and response to stimulus. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated several involved pathways, including the fatty acid biosynthesis pathway, pantothenate and CoA biosynthesis pathway, arachidonic acid metabolism pathway and PPAR signaling pathway. Further verification showed that the mineralization and migration capacities of PDLSCs were greater than those of DPSCs, in which heat shock protein beta-1, Protein S100-A10 and S100-A11 may play a part. CONCLUSIONS: Less than 5% of the differentially expressed proteins make up the comparative proteomic profile between osteoinduced PDLSCs and DPSCs. This study helps to characterize the differences between osteoinduced PDLSCs and DPSCs in vitro. PMID- 29407637 TI - Planning to speak in L1 and L2. AB - The leading theories of sentence planning - Hierarchical Incrementality and Linear Incrementality - differ in their assumptions about the coordination of processes that map preverbal information onto language. Previous studies showed that, in native (L1) speakers, this coordination can vary with the ease of executing the message-level and sentence-level processes necessary to plan and produce an utterance. We report the first series of experiments to systematically examine how linguistic experience influences sentence planning in native (L1) speakers (i.e., speakers with life-long experience using the target language) and non-native (L2) speakers (i.e., speakers with less experience using the target language). In all experiments, speakers spontaneously generated one-sentence descriptions of simple events in Dutch (L1) and English (L2). Analyses of eye movements across early and late time windows (pre- and post-400 ms) compared the extent of early message-level encoding and the onset of linguistic encoding. In Experiment 1, speakers were more likely to engage in extensive message-level encoding and to delay sentence-level encoding when using their L2. Experiments 2 4 selectively facilitated encoding of the preverbal message, encoding of the agent character (i.e., the first content word in active sentences), and encoding of the sentence verb (i.e., the second content word in active sentences) respectively. Experiment 2 showed that there is no delay in the onset of L2 linguistic encoding when speakers are familiar with the events. Experiments 3 and 4 showed that the delay in the onset of L2 linguistic encoding is not due to speakers delaying encoding of the agent, but due to a preference to encode information needed to select a suitable verb early in the formulation process. Overall, speakers prefer to temporally separate message-level from sentence-level encoding and to prioritize encoding of relational information when planning L2 sentences, consistent with Hierarchical Incrementality. PMID- 29407638 TI - Vertical distribution of 137Cs in grassland soils disturbed by moles (Talpa europaea L.). AB - Activity of biota is one of the factors influencing vertical migration of radionuclides deposited from the atmosphere onto the ground surface. The goal of this work was to study the vertical distribution of 137Cs in grassland soils disturbed by moles (Talpa europaea L.) in comparison with undisturbed grassland soils. Field observations and soil sampling were carried out in the areas of eight settlements in the Klintsovskiy, Krasnogorskiy and Novozybkovskiy districts of the Bryansk region, Russia in six years during the period 1999-2016. The study sites had been heavily contaminated by Chernobyl fallout in 1986. Activity of 137Cs in soil samples was determined by gamma-ray spectrometry. 137Cs surface ground contamination levels at the studied plots (n = 17) ranged from 327 kBq m-2 to 2360 kBq m-2 with a mean of 1000 kBq m-2 and a median of 700 kBq m-2. The position of the 137Cs migration centre in the soil in 2010-2016 was significantly (the Mann-Whitney U test, P < .01) deeper at mole-disturbed plots (median = 5.99 cm or 6.64 g cm-2, n = 6) compared to the undisturbed ones (median = 2.48 cm or 2.35 g cm-2, n = 6). The 137Cs migration rate at mole-disturbed plots (median = 0.26 g cm-2 y-1, mean = 0.31 g cm-2 y-1) was significantly higher (by a factor of 3) than at undisturbed plots (median = 0.08 g cm-2 y-1, mean = 0.10 g cm-2 y-1). The difference in the migration rates between the mole-disturbed and undisturbed plots (median = 0.18 g cm-2 y-1, mean = 0.21 g cm-2 y-1) reasonably corresponded to the mass of soil that might be ejected by moles per unit area per year. The results of this study indicate that the burrowing activity of moles has increased vertical migration of Chernobyl-derived radiocaesium in the grassland soils. PMID- 29407639 TI - Validation of an advanced analytical procedure applied to the measurement of environmental radioactivity. AB - In this work, an advanced analytical procedure was applied to calculate radioactivity in spiked water samples in a close geometry gamma spectroscopy. It included MCNP-CP code in order to calculate the coincidence summing correction factor (CSF). The CSF results were validated by a deterministic method using ETNA code for both p-type HPGe detectors. It showed that a good agreement for both codes. Finally, the validity of the developed procedure was confirmed by a proficiency test to calculate the activities of various radionuclides. The results of the radioactivity measurement with both detectors using the advanced analytical procedure were received the ''Accepted'' statuses following the proficiency test. PMID- 29407640 TI - Anthropogenic 137Cs on atmospheric aerosols in Bratislava and around nuclear power plants in Slovakia. AB - Nuclear power plants (NPPs) have been one of the sources of anthropogenic radionuclides in the environment. This work combines the results from monitoring stations around NPPs in Slovakia (Mochovce and Jaslovske Bohunice) and academic measurements at the Comenius University campus in Bratislava. Most of the atmospheric 137Cs in this region come from the resuspension of the Chernobyl derived 137Cs, as well as caesium produced during nuclear weapons testing. By comparison of the obtained results at NPPs with Bratislava data, radiation impacts of the NPPs on the local environments have been estimated to be negligible. PMID- 29407641 TI - Tritium and radiocarbon in the western North Pacific waters: post-Fukushima situation. AB - Impact of the Fukushima Dai-ichi Nuclear Power Plant (FNPP1) accident on tritium (3H) and radiocarbon (14C) levels in the water column of the western North Pacific Ocean in winter 2012 is evaluated and compared with radiocesium (134,137Cs) data collected for the same region. Tritium concentrations in surface seawater, varying between 0.4 and 2.0 TU (47.2-236 Bq m-3), follow the Fukushima radiocesium trend, however, some differences in the vertical profiles were observed, namely in depths of 50-400 m. No correlation was visible in the case of 14C, whose surface Delta14C levels raised from negative values (about -400/00) in the northern part of transect, to positive values (~680/00) near the equator. Homogenously mixed 14C levels in the subsurface layers were observed at all stations. Sixteen surface (from 30 in total) and 6 water profile (from 7) stations were affected by the Fukushima tritium. Surface and vertical profile data together with the calculated water column inventories indicate that the total amount of the FNPP1-derived tritium deposited to the western North Pacific Ocean was 0.7 +/- 0.3 PBq. No clear impact of the Fukushima accident on 14C levels in the western North Pacific was observed. PMID- 29407642 TI - An aerosol particle containing enriched uranium encountered in the remote upper troposphere. AB - We describe a submicron aerosol particle sampled at an altitude of 7 km near the Aleutian Islands that contained a small percentage of enriched uranium oxide. 235U was 3.1 +/- 0.5% of 238U. During twenty years of aircraft sampling of millions of particles in the global atmosphere, we have rarely encountered a particle with a similarly high content of 238U and never a particle with enriched 235U. The bulk of the particle consisted of material consistent with combustion of heavy fuel oil. Analysis of wind trajectories and particle dispersion model results show that the particle could have originated from a variety of areas across Asia. The source of such a particle is unclear, and the particle is described here in case it indicates a novel source where enriched uranium was dispersed. PMID- 29407643 TI - Impacts of virus processing on human norovirus GI and GII persistence during disinfection of municipal secondary wastewater effluent. AB - Noroviruses cause significant global health burdens and waterborne transmission is a known exposure pathway. Chlorination is the most common method of disinfection for water and wastewater worldwide. The purpose of this study was to investigate the underlying causes for discrepancies in human norovirus (hNoV) resistance to free chlorine that have been previously published, and to assess hNoV GI and GII persistence during disinfection of municipal secondary wastewater (WW) effluent. Our results reveal that choice of hNoV purification methodology prior to seeding the viruses in an experimental water matrix influences disinfection outcomes in treatment studies. Common hNoV purification processes such as solvent extraction and 0.45-MUm filtration were ineffective in removing high levels of organics introduced into water or wastewater samples when seeding norovirus positive stool. These methods resulted in experimental water matrices receiving an additional 190 mg/L as Cl2 of 15-s chlorine demand and approximately 440 mg/L as Cl2 of 30-min chlorine demand due to seeding norovirus positive stool at 1% w/v. These high organic loads impact experimental water chemistry and bias estimations of hNoV persistence. Advanced purification of norovirus positive stool using sucrose cushion ultracentrifugation and ultrafiltration reduced 15-s chlorine demands by 99% and TOC by 93% for loose (i.e. unformed diarrhea) stools. Using these methods, hNoV GI and GII persistence was investigated during free chlorination of municipal WW. A suite five of kinetic inactivation models was fit to viral reverse transcription-qPCR reduction data, and model predicted CT values for 1, 2, and 3 log10 reduction of hNoV GI in municipal WW by free chlorine were 0.3, 2.1, and 7.8 mg-min/L, respectively. Model predicted CT values for reduction of hNoV GII in WW were 0.4, 2.0, and 7.0 mg-min/L, respectively. These results indicate that current WW treatment plant disinfection practices employing free chlorine are likely protective for public health with regards to noroviruses, and will achieve at least 3-log reduction of hNoV GI and GII RNA despite previous reports of high hNoV resistance. PMID- 29407644 TI - Unraveling the catalyzing behaviors of different iron species (Fe2+ vs. Fe0) in activating persulfate-based oxidation process with implications to waste activated sludge dewaterability. AB - Dewatering of waste activated sludge (WAS) is of major interest in its volume reduction, transportation and ultimate disposal. Persulfate-based oxidation process is a newly developed option for enhancing WAS dewaterability through the generation of powerful sulfate radicals (SO4-.). However, the enhancement in WAS dewaterability by persulfate differs with the species of iron catalysts used. In this study, two types of iron catalysts (i.e. Fe2+ vs. Fe0) were employed to initiate the persulfate (S2O82-), and the catalyzing behaviors and the underlying principles in enhancing WAS dewaterability were investigated and compared. The Fe2+ exhibited the high effectiveness in catalyzing the decomposition of persulfate to sulfate radicals (SO4-.), inducing the greater improvement in WAS dewatering. The WAS dewaterability (indicated by dry solids content after filtration) increased with the added S2O82-/Fe2+ dosages, with the dry solids content reaching up to 5.1 +/- 0.8 wt% at S2O82-/Fe2+ dosages of 1.2/1.5 mmol/g VS after only 30 s' filtration, roughly 1.8-fold increase than raw WAS (1.8 +/- 0.1 wt%). In contrast, the influence of the persulfate oxidation when activated with Fe0 on WAS dewaterability was statistically insignificant. The WAS dewaterability remained nearly unchanged (i.e. dry solids content of 2.0 +/- 0.0 wt%), irrespective of the employed S2O82-/Fe0 dosages. Further analysis demonstrated that the WAS dewaterability negatively corresponded to loosely bound extracellular polymeric substances (LB-EPS) and tightly bound EPS (TB-EPS). The abundant SO4-. from S2O82-/Fe2+ system could effectively disrupt the gel-like EPS matrix, break apart the cells and subsequently arouse the release of the water inside EPS and cells, facilitating water-solid separation. In the case of S2O82 /Fe0, the dissolution of Fe0 particles was the rate-limiting step, due to the formation of oxide iron layer near Fe0 metallic surface, which resulted in the slow SO4-. production and thus hardly promoted WAS dewaterability. The pH adjustment could accelerate Fe0 dissolution and enhance the dewatering performance of S2O82-/Fe0 process to a certain degree, but the effect was unsatisfactory. Additionally, the observations regarding the dissolved organic matters and ammonium collectively revealed that except for enhancing WAS dewatering, S2O82-/Fe2+ oxidation could concurrently degrade COD and ammonia from WAS filtrate, lighten the burden of the subsequent sewage treatment facilities and reduce operational expense. Hence, from an environmental and economic perspective, the S2O82-/Fe2+ system possesses much greater promise for WAS dewatering. PMID- 29407645 TI - Efficacy of microbial sampling recommendations and practices in sub-Saharan Africa. AB - Current guidelines for testing drinking water quality recommend that the sampling rate, which is the number of samples tested for fecal indicator bacteria (FIB) per year, increases as the population served by the drinking water system increases. However, in low-resource settings, prevalence of contamination tends to be higher, potentially requiring higher sampling rates and different statistical methods not addressed by current sampling recommendations. We analyzed 27,930 tests for FIB collected from 351 piped water systems in eight countries in sub-Saharan Africa to assess current sampling rates, observed contamination prevalences, and the ability of monitoring agencies to complete two common objectives of sampling programs: determine regulatory compliance and detect a change over time. Although FIB were never detected in samples from 75% of piped water systems, only 14% were sampled often enough to conclude with 90% confidence that the true contamination prevalence met an example guideline (<=5% chance of any sample positive for FIB). Similarly, after observing a ten percentage point increase in contaminated samples, 43% of PWS would still require more than a year before their monitoring agency could be confident that contamination had actually increased. We conclude that current sampling practices in these settings may provide insufficient information because they collect too few samples. We also conclude that current guidelines could be improved by specifying how to increase sampling after contamination has been detected. Our results suggest that future recommendations should explicitly consider the regulatory limit and desired confidence in results, and adapt when FIB is detected. PMID- 29407646 TI - Antibiotic resistome in landfill leachate from different cities of China deciphered by metagenomic analysis. AB - High throughput sequencing-based metagenomic analysis and network analysis were applied to investigate the broad-spectrum profiles of ARGs in landfill leachate from 12 cities in China. In total, 526 ARG subtypes belonging to 21 ARG types were detected with abundances ranging from 1.1 * 10-6 to 2.09 * 10-1 copy of ARG/copy of 16S rRNA gene. 68 ARG subtypes that accounted for 73.4%-93.4% of the total ARG abundances were shared by all leachate samples. The four most abundant ARGs, sul1, sul2, aadA and bacA can be served as ARG indicators to quantitatively predict the total abundances by linear functions (r2 = 0.577-0.819, P < 0.001). No distinct regional distribution pattern of the ARGs was observed among different cities in China, while the ARG compositions of the leachate were clearly distinct from those of other environmental sample types. Nearly 90% ARG subtypes in the anaerobic digestion sludge from sewage treatment plants (STPADS) were shared by the leachate and the abundances of leachate and STPADS ARGs generalists accounted for 84.5% and 87.7% of total abundances in these two types of anaerobic samples, respectively. Furthermore, Procrustes analysis suggested that microbial community composition might be the determining factor of ARG compositions in landfill leachate. ARGs within the same type or among the different types showed higher incidences of non-random co-occurrence and 17 genera might be potential hosts of multiple ARGs. This study highlighted that landfill leachate is an important reservoir of various ARGs and provided a useful reference for the surveillance and risk management of ARGs in landfill environments. PMID- 29407647 TI - Effects of COD/N ratio on soluble microbial products in effluent from sequencing batch reactors and subsequent membrane fouling. AB - The relative ratios of chemical oxygen demand (COD) to nitrogen (N) in wastewater are known to have profound effects on the characteristics of soluble microbial products (SMP) from activated sludge. In this study, the changes in the SMP characteristics upon different COD/N ratios and the subsequent effects on ultrafiltration (UF) membrane fouling potentials were examined in sequencing batch reactors (SBR) using excitation emission matrix-parallel factor analysis (EEM-PARAFAC) and size exclusion chromatography (SEC). Three unique fluorescent components were identified from the SMP samples in the bioreactors operated at the COD/N ratios of 100/10 (N rich), 100/5 (N medium), and 100/2 (N deficient). The tryptophan-like component (C1) was the most depleted at the N medium condition. Fulvic-like (C2) and humic-like (C3) components were more abundant with N rich wastewater. Greater abundances of large size biopolymer (BP) and low molecular weight neutrals (LMWN) were found under the N deficient and N rich conditions, respectively. SMPs from various COD/N exhibited a greater degree on membrane fouling following the order of 100/2 > 100/10 > 100/5. C1 and C2 had close associations with reversible and irreversible fouling, respectively, while the reversible fouling potential of C3 depended on the COD/N ratios. No significant impact of COD/N ratio was observed on the relative contributions of SMP size fractions to either reversible or irreversible fouling potential. However, the COD/N ratios likely altered the BP foulants' composition with greater contribution of proteinaceous substances to reversible fouling under the N deficient condition than at other N richer conditions. The opposite trend was observed for irreversible fouling. Our results provided further insight into changes in different SMP constitutes and their membrane fouling in response to microbial activities under different COD/N ratios. PMID- 29407648 TI - Development of nanoscale zirconium molybdate embedded anion exchange resin for selective removal of phosphate. AB - Development of a selective adsorbent with an enhanced removal efficiency for phosphate from wastewater is urgently needed. Here, a hybrid adsorbent of nanoscale zirconium molybdate embedded in a macroporous anion exchange resin (ZMAE) is proposed for the selective removal of phosphate. The ZMAE consists of a low agglomeration of zirconium molybdate nanoparticles (ZM NPs) dispersed within the structure of the anion exchange (AE) resin. As major results, the phosphate adsorption capacity of the ZMAE (26.1 mg-P/g) in the presence of excess sulfate (5 mM) is superior to that of the pristine AE resin (1.8 mg-P/g) although their phosphate uptake capacity was similar in the absence of sulfate and these results were supported by the high selectivity coefficient of the ZMAE toward phosphate over sulfate (SPO4/SO4) more than 100 times compared to the pristine AE resin. This superior selective performance of the ZMAE for phosphate in the presence of sulfate ions is well explained by the role of the ZM NPs that contributed to 69% of the phosphate capacity which is based on an observation that the phosphate adsorption capacity of the ZM NPs is not affected by the presence of sulfate. In addition, the behavior of the selective phosphate removal by the ZMAE was well demonstrated by not only in the batch mode experiment with simulated Mekong river water and representative wastewater effluent but also in a column test. PMID- 29407649 TI - Synergistic adsorption of phosphorus by iron in lanthanum modified bentonite (Phoslock(r)): New insight into sediment phosphorus immobilization. AB - Iron redox cycle plays a primary role in controlling the mobility of P in sediments. It is crucial to better understand how lanthanum (La) modified bentonite (LMB, Phoslock(r)), an increasingly employed capping agent, immobilizes P from sediments by altering Fe redox-coupled P cycling. Batch adsorption experiments found that LMB effectively adsorbed Fe(II) with a capacity of 8.51 mg g-1. Fe(II)-preloaded LMB effectively retained P during a 518-hour equilibration, while up to 16.7% of adsorbed P was release-sensitive in LMB without Fe(II) preloading. A 60-day incubation experiment was performed using sediment cores, with an LMB amendment dosage of up to 200 LMB/Pmob (w/w, Pmob denotes the amount of mobile P in the surface 40 mm sediment layer). The concentrations of pore water soluble reactive P (SRP) and labile P were measured by high resolution dialysis (HR-Peeper) and by diffusive gradient in thin films (DGT), respectively, at a vertical millimeter scale. They stratified into static layers with extremely low concentration distribution in the top 16-22 mm sediments (mean SRP <= 0.28 mg L-1 and mean DGT-labile P <= 0.051 mg L-1) and active layers with decreased upward diffusion potential (<=5.85 for SRP and <=12.7 for DGT-labile P) below the static layer, when the applied dosage reached 60 LMB/Pmob. The LMB amendment reduced the pore water Fe and DGT-labile Fe in sediments, while considerable amounts of Fe and Fe-bound P existed in the LMB binding layer (25% of the total P in 200 LMB/Pmob treatment). These findings show that the adsorption of Fe by LMB plays a significant role in the stabilization of LMB-bound P, possibly by adsorbing release-sensitive P initially bound to the rhabdophane surface. LMB adsorbed Fe and P were not released until the redox potential decreased to extremely reductive conditions (-150 mV to -300 mV), possibly due to the re adsorption of Fe and P by LMB. This study reveals synergistic effects of Fe adsorption and provides new insight into the immobilization mechanisms of P by LMB application. PMID- 29407650 TI - Degradation of organic compounds during the corrosion of ZVI by hydrogen peroxide at neutral pH: Kinetics, mechanisms and effect of corrosion promoting and inhibiting ions. AB - The corrosion of zero valent iron (ZVI) by hydrogen peroxide (H2O2) generates hydroxyl (?OH) and other radical oxygen species (ROS) that degrade organic materials. To better understand the factors that govern the ROS formation during the H2O2-induced corrosion, we investigated the degradation of an organic probe compound (acesulfame (ACE)) in slurries of ZVI powder in unbuffered laboratory water at pH 6.5 +/- 0.5. Chloride ions accelerated the corrosion of ZVI by H2O2 and the formation ROS and, therefore, the degradation of organic materials. Conversely, slowing corrosion by phosphate buffer inhibited ROS formation and the degradation of organic compounds. The rate of H2O2 decomposition was correlated with the liberation of Fe2+(aq) and the ACE degradation rate. The kinetics of H2O2 decomposition was pseudo-first-order and zero-order at low (<0.04 mM/mg) and high [H2O2]/[ZVI] initial ratios, respectively, and was consistent with Langmuir kinetics. The H2O2 decomposition rate was proportional to the ZVI reactive surface area (SA) and nearly independent of the extent of ZVI oxidation, the presence of a Fe2+(aq) chelating agent, and ?OH quenchers (methanol and tert butanol). Kinetic data suggest a mechanism involving rapid cathodic reduction of H2O2 at the metallic ZVI surface which causes the liberation of Fe2+(aq) that generate ?OH via the homogeneous Fenton reaction. The stoichiometric efficiency (SE) of organics degradation ranged from 0.0008% to 0.014% and increased with decreasing H2O2 decomposition rate. PMID- 29407651 TI - Enhancing sludge methanogenesis with improved redox activity of extracellular polymeric substances by hematite in red mud. AB - Different conductive materials have been employed to stimulate direct interspecies electron transfer (DIET) during methanogenesis, but few studies have been concerned with the interaction between conductive materials and extracellular polymeric substances (EPS) such as the effect on sludge aggregation and redox activity of EPS. This study aims to systematically investigate the role of red mud with 45.46 wt% hematite on methanogenesis during the anaerobic digestion of waste activated sludge. The results showed that the multivalent cations from hematite effectively promoted the formation of large and compact aggregates, which might contribute to the rapid direct electron exchange during the DIET process. Meanwhile, more redox-active mediators including c-type cytochromes (c-Cyts) and humic substances, particularly in tight-bound EPS (TB EPS), and more redox-active metals such as Fe introduced by red mud could take part in the interspecies electron transfer process between syntrophic bacteria and methanogenic archaea, which also promoted methane production (35.52 +/- 2.64% increase compared with the control). This study provided initial scientific evidence to comprehensively assess the role of conductive materials during methanogenesis, with important implications for the biogeochemical redox processes of conductive minerals in natural and engineered environments. PMID- 29407652 TI - Kinetic evaluation of graphene oxide based heterogenous catalytic ozonation for the removal of ibuprofen. AB - In this study, the performance of graphene oxide (GO) in ozonation process was kinetically evaluated using the modified Rct concept since GO may act as initiator, promoter and inhibitor in ozone radical chain reaction. The applicability of the modified Rct concept was demonstrated using different GO suspensions (GO alone, GO/TiO2, GO/Fe3O4, GO/TiO2/Fe3O4) in ozonation process. Results showed that ozone exposure and *OH exposure were found to be higher for GO/Fe3O4 and GO/TiO2/Fe3O4 compared to other GO suspensions, which was almost equivalent to O3/H2O2 process. The determined initiation and inhibition rate constants of GO alone, were 1 fold higher than GO/Fe3O4 and GO/TiO2/Fe3O4, since the GO alone suspension possesses higher O3 decomposition but lower organic degradation because that GO does not yield *OH. Moreover, GO/Fe3O4 suspension, along with natural organic matter (NOM), was proven to be helpful in degrading ibuprofen in ozonation process, but the effect was minimal when compared to O3/H2O2 process. These results exhibited that the surface modified GO suspensions could be utilized as future alternative AOPs. PMID- 29407653 TI - Adaptive forecasting of phytoplankton communities. AB - The global proliferation of harmful algal blooms poses an increasing threat to water resources, recreation and ecosystems. Predicting the occurrence of these blooms is therefore needed to assist water managers in making management decisions to mitigate their impact. Evaluation of the potential for forecasting of algal blooms using the phytoplankton community model PROTECH was undertaken in pseudo-real-time. This was achieved within a data assimilation scheme using the Ensemble Kalman Filter to allow uncertainties and model nonlinearities to be propagated to forecast outputs. Tests were made on two mesotrophic lakes in the English Lake District, which differ in depth and nutrient regime. Some forecasting success was shown for chlorophyll a, but not all forecasts were able to perform better than a persistence forecast. There was a general reduction in forecast skill with increasing forecasting period but forecasts for up to four or five days showed noticeably greater promise than those for longer periods. Associated forecasts of phytoplankton community structure were broadly consistent with observations but their translation to cyanobacteria forecasts was challenging owing to the interchangeability of simulated functional species. PMID- 29407654 TI - Influence of gas injection on viscous and viscoelastic properties of Xanthan gum. AB - Xanthan gum is widely used as a model fluid for sludge to mimic the rheological behaviour under various conditions including impact of gas injection in sludge. However, there is no study to show the influence of gas injection on rheological properties of xanthan gum specifically at the concentrations at which it is used as a model fluid for sludge with solids concentration above 2%. In this paper, the rheological properties of aqueous xanthan gum solutions at different concentrations were measured over a range of gas injection flow rates. The effect of gas injection on both the flow and viscoelastic behaviour of Xanthan gum (using two different methods - a creep test and a time sweep test) was evaluated. The viscosity curve of different solid concentrations of digested sludge and waste activated sludge were compared with different solid concentrations of Xanthan gum and the results showed that Xanthan gum can mimic the flow behaviour of sludge in flow regime. The results in linear viscoelastic regime showed that increasing gas flow rate increases storage modulus (G'), indicating an increase in the intermolecular associations within the material structure leading to an increase in material strength and solid behaviour. Similarly, in creep test an increase in the gas flow rate decreased strain%, signifying that the material has become more resistant to flow. Both observed behaviour is opposite to what occurs in sludge under similar conditions. The results of both the creep test and the time sweep test indicated that choosing Xanthan gum aqueous solution as a transparent model fluid for sludge in viscoelastic regime under similar conditions involving gas injection in a concentration range studied is not feasible. However Xanthan gum can be used as a model material for sludge in flow regime; because it shows a similar behaviour to sludge. PMID- 29407655 TI - Development of an electronic nose to characterize odours emitted from different stages in a wastewater treatment plant. AB - Wastewater treatment plants have widely been described as a significant source of odour nuisance, which has led to an increase of neighbourhood complaints. Therefore, to mitigate the negative impact of odours, the detection and analysis of these emissions are required. This paper presents a measurement system based on an electronic nose for quantitative and qualitative odour analysis of samples collected from six different stages on a wastewater plant. Hence, two features vectors were performed in order to represent quantitative trends of the gaseous mixture sampled on the facility. In addition, odour fingerprints and a PCA were computed to discriminate odours from its sources and to detect relationships among the samples. This approach also comprises a dynamic dilution olfactometer. A PLS regression model was performed to predict the odour concentration by the electronic nose in term of odour units per cubic meter. The results show that the developed electronic nose is a promising and feasible instrument to characterize odours from wastewater plants. PMID- 29407656 TI - Mathematical model and intervention strategies for mitigating tuberculosis in the Philippines. AB - Tuberculosis (TB) is the sixth leading cause of morbidity and mortality in the Philippines. Although significant progress has been made in the detection and cure of TB under the Directly Observed Treatment Short Course, battling against the disease is still a burdensome task. It demands a concerted effort for specific and effective interventions. In this work, a mathematical TB model fitted to the Philippine data is developed to understand its transmission dynamics. Different control strategies such as distancing, latent case finding, case holding, active case finding controls, and combinations thereof are investigated within the framework of optimal control theory. This study proposes optimal control strategies for reducing the number of high-risk latent and infectious TB patients with minimum intervention implementation costs. Results suggest that distancing control is the most efficient control strategy when a single intervention is utilized. However, full scale employment of the distancing control measure is a daunting task. This burden can be circumvented by the combination of other control interventions. Our noble finding in this study is that enhancing active case finding control instead of case holding control together with distancing and latent case finding control is shown to have significant potential for curtailing the spread of TB in the Philippines. PMID- 29407657 TI - Modeling of passengers' safety perception for buses on mountainous roads. AB - This study had developed a passenger safety perception model specifically for buses taking into consideration the various factors, namely driver characteristics, environmental conditions, and bus characteristics using Bayesian Network. The behaviour of bus driver is observed through the bus motion profile, measured in longitudinal, lateral, and vertical accelerations. The road geometry is recorded using GPS and is computed with the aid of the Google map while the perceived bus safety is rated by the passengers in the bus in real time. A total of 13 variables were derived and used in the model development. The developed Bayesian Network model shows that the type of bus and the experience of the driver on the investigated route could have an influence on passenger's perception of their safety on buses. Road geometry is an indirect influencing factor through the driver's behavior. The findings of this model are useful for the authorities to structure an effective strategy to improve the level of perceived bus safety. A high level of bus safety will definitely boost passenger usage confidence which will subsequently increase ridership. PMID- 29407658 TI - Alcohol and non-alcohol-related motor vehicle crashes in Perth, Australia: Do alcohol outlets make a difference? AB - This study examined the effects of distance from alcohol outlets to motor vehicle crashes across the Perth metropolitan area. A retrospective population-based study was undertaken using measures of alcohol- and non-alcohol-related crashes, and their proximity to alcohol outlets, using a geographic information system. Two logistic regression models were developed with the following outcomes: i) crashes including drivers with BAC >= 0.05%, and ii) weekend single vehicle night time crashes, a surrogate measure of alcohol-related crashes. The surrogate measures of non-alcohol-related crashes for these models were all day-time and single vehicle day-time crashes respectively. The major predictors of alcohol related crashes were number of on-premise outlets and bottleshops in buffer zones up to 2 km, 2 km-5 km, 5 km-10 km and 10 km-20 km from crashes. The distance from the central business district (CBD) and sociodemographic factors were controlled for. The study included 341,467 crashes that occurred between 2005 and 2015. The highest crash incidence rates occurred in the CBD. The statistical models indicated that crashes with a higher number of on-premise outlets in adjacent buffer zones were more likely to be alcohol-related than non-alcohol-related crashes. Crashes with a higher number of on-premise outlets less than 2 km, 2 km 5 km, 5 km-10 km, and 10 km-20 km from the crashes were significantly more likely to be weekend single vehicle night-time crashes than day-time crashes (OR = 1.014; 95% CI:1.002-1.027, OR = 1.022; 95% CI:1.014-1.029, OR = 1.019; 95% CI:1.014-1.024, and OR = 1.017; 95% CI:1.014-1.020 respectively). There was some evidence that crashes with lower number of bottleshops in adjacent buffer zones were more likely to be alcohol-related crashes, although this was not consistent across both models and all buffer zones. When other predictors were controlled for, alcohol-related crashes were more likely to occur further from the CBD, than in the CBD. Recommendations about the timing and location of roadside alcohol testing are made. PMID- 29407659 TI - Errors versus speed on the trail making test: Relevance to driving performance. AB - BACKGROUND/OBJECTIVES: Many studies have demonstrated that speed to complete items on the Trail Making Tests (TMT A and TMT B) is useful in the prediction of driving safety. However, there is no consensus regarding optimal "cut scores" to discriminate between safe and unsafe drivers. In this study, we examine TMT speed and errors in drivers referred for a road test. DESIGN: Retrospective analysis. SETTING: Patients referred for a DriveWise(r) evaluation at Beth Israel Deaconess Medical Center in Boston, Massachusetts. PARTICIPANTS: Drivers age 65 or older were included (total n = 373). Forty-five percent of the sample had been diagnosed with Cognitive Impairment (CI) whereas the remaining participants were in the No Cognitive Impairment (NCI) group. MEASUREMENTS: TMT Parts A & B, Folstein Mini Mental Status Examination, Washington University Road Test. RESULTS: CI drivers with TMT A speed exceeding 46 s were more likely to fail the road test whereas TMT B speed was not a sensitive metric in this group. In the No Cognitive Impairment (NCI) group, TMT B speed exceeding 131 s predicted driving impairment whereas TMT A speed was not sensitive. Error scores were not useful in the determination of driving fitness for either group. CONCLUSIONS: This study provides useful criteria for health providers working with older people in the determination of driving fitness. Results suggest that TMT speed, but not error rate, is associated with road test performance. Based on our work, we advocate that pre-existing dementia should be taken into consideration when using TMT performance as a screen for driving. PMID- 29407660 TI - Lives saved by laws and regulations that resulted from the Bloomberg road safety program. AB - OBJECTIVE: To estimate lives saved during 2008-2023 by traffic safety laws passed in six developing countries while participating in the Bloomberg Road Safety Program (BRSP). METHODS: BRSP-funded local staff identified relevant laws and described enforcement to the study team. We analyzed road crash death estimates for 2004-2013 from the Global Burden of Disease and projected estimates absent intervention forward to 2023. We amalgamated developing country and US literature to estimate crash death reductions by country resulting from laws governing drink driving, motorcycle helmets, safety belt use, and traffic fines. RESULTS: BRSP helped win approval of traffic safety laws in Brazil, China, Kenya, Mexico, Turkey, and Vietnam. In 2008-2013, those laws saved an estimated 19,000 lives. Many laws only took effect in 2014. The laws will save an estimated 90,000 lives in 2014-2023. Of the 109,000 lives saved, drink driving laws will account for 84%, increased motorcyclist protection for 13%, increased fines and penalty points for 2%, and safety belt usage mandates for 1%. Drink driving reductions in China will account for 56% of the savings and reduced drink driving and motorcycling deaths in Vietnam for 35%. The savings in China will result from a narrow intervention with just 4% estimated effectiveness against drink driving deaths. As a percentage of deaths anticipated without BRSP effort, the largest reductions will be 11% in Vietnam and 5% in Kenya. CONCLUSIONS: Viewed as a public health measure, improving traffic safety provided large health gains in developing nations. PMID- 29407661 TI - Investigating the safety impact of roadway network features of suburban arterials in Shanghai. AB - With rapid changes in land use development along suburban arterials in Shanghai, there is a corresponding increase in traffic demand on these arterials. To accommodate the local traffic needs of high accessibility and efficiency, an increased number of signalized intersections and accesses have been installed. However, the absence of a defined hierarchical road network, together with irregular signal spacing and access density, tends to deteriorate arterial safety. Previous studies on arterial safety were generally based on a single type of road entity, either intersection or roadway segment, and they analyzed the safety contributing factors (e.g. signal density and access density) on only that type of road entity, while these suburban arterial characteristics could significantly influence the safety performance of both intersections and roadway segments. Macro-level safety modeling was usually applied to investigate the relationships between zonal crash frequencies and demographics, road network features, and traffic characteristics, but the previous researchers did not consider the specific arterial characteristics of signal density and access density. In this study, a new modeling strategy was proposed to analyze the safety impacts of zonal roadway network features (i.e., road network patterns and road network density) along with the suburban arterial characteristics of signal density and access density. Bayesian Conditional Autoregressive Poisson Log normal models were developed for suburban arterials in 173 traffic analysis zones in the suburban area of Shanghai. Results identified that the grid pattern road network with collector roads parallel to arterials was associated with fewer crashes than networks without parallel collectors. On the other hand, lower road network density, higher signal density and higher access density tended to increase the crash occurrence on suburban arterials. PMID- 29407662 TI - Assessing rear-end collision risk of cars and heavy vehicles on freeways using a surrogate safety measure. AB - This study analyzes rear-end collision risk of cars and heavy vehicles on freeways using a surrogate safety measure. The crash potential index (CPI) was modified to reflect driver's reaction time and estimated by types of lead and following vehicles (car or heavy vehicle). CPIs were estimated using the individual vehicle trajectory data from a segment of the US-101 freeway in Los Angeles, U.S.A. It was found that the CPI was generally higher for the following heavy vehicle than the following car due to heavy vehicle's lower braking capability. This study also validates the CPI using the simulated traffic data which replicate the observed traffic conditions a few minutes before the crash time upstream and downstream of the crash locations. The observed data were obtained from crash records and loop detectors on a section of the Gardiner Expressway in Toronto, Canada. The result shows that the values of CPI were consistently higher during the traffic conditions immediately before the crash time (crash case) than the normal traffic conditions (non-crash case). This demonstrates that the CPI can be used to capture rear-end collision risk during car-following maneuver on freeways. The result also shows that rear-end collision risk is lower for heavy vehicles than cars in the crash case due to their shorter reaction time and lower speed when spacing is shorter. Thus, it is important to reflect the differences in driver behavior and vehicle performance characteristics between cars and heavy vehicles in estimating surrogate safety measures. Lastly, it was found that the CPI-based crash prediction model can correctly identify the crash and non-crash cases at higher accuracy than the other crash prediction models based on detectors. PMID- 29407663 TI - Multimodal crash frequency modeling: Multivariate space-time models with alternate spatiotemporal interactions. AB - Enhancement of safety for all transportation mode users plays an essential role in the implementation of multimodal transportation systems. Compared with crash frequency models dedicated to motorized mode users, the use of these models has been considerably scarce in the multimodal literature. To fill this research gap, the authors aimed to develop and evaluate three multivariate space-time models with different temporal trends and spatiotemporal interactions. The model estimates justified the use of mode-varying coefficients for explanatory variables as the impact of these factors varied across different crash modes. Largely, a similar set of influential covariates was generated by the three models which indicate their robustness. However, notable differences were observed from the assessment of evaluation criteria pertaining to predictive accuracy based on criteria assessing the training and test errors. The model with time-varying spatial random effects demonstrated superior performance for training and test errors. However, due to the significant increase in number of effective parameters that were utilized for model development, this model appeared to have the largest value of deviance information criterion (DIC). In terms of the comparison between models based on site ranking performance, the time-varying spatial random effects model demonstrated the best performance in both site consistency and method consistency. In other words, the superiority of the model's predictive performance could be transferred to yield more accurate result at site ranking. PMID- 29407664 TI - The Driver Behaviour Questionnaire for older drivers: Do errors, violations and lapses change over time? AB - The aim of the current study was to examine how self-reported aberrant driving behaviours change across a three time-points in a group of older drivers. Two hundred and twenty-seven older drivers (males = 69.6%) from the Candrive/Ozcandrive longitudinal study completed the Driving Behaviour Questionnaire (DBQ) each yearacross three time-points (i.e., Year 1, Year 2, Year 3). At the third time-point, older drivers ranged in age from 77 to 96 years (M = 81.74 years; SD = 3.44 years). A longitudinal confirmatory factor analysis showed that a modified 21-item, 3-factor (errors, lapses and violations) DBQ was invariant across the time period, suggesting that the structure of the questionnaire was stable across each time-point. Further, multiple domain latent growth analysis on the resultant factors for errors, lapses and violations showed that the frequency of errors remained similar across the three-year period, while violations and lapses showed very marginal decreases in frequency. These changes were independent of the absolute number of these behaviours; Drivers with higher violations or lapses in Year one, showed similar decreases in frequency as those who self-reported lower frequencies of the behaviours. These results suggest that the DBQ is a reliable tool to measure older drivers' self-reported aberrant driving behaviours, and that these behaviours do not show much change across time. Future research should validate the self-reported responses from the DBQ with more objective measures such as those collected through naturalistic driving study (NDS) methodology or on-road driving tasks. PMID- 29407665 TI - Risky driving and the persistent effect of a randomized intervention focusing on impulsivity: The role of the serotonin transporter promoter polymorphism. AB - Road traffic accidents are a serious public health issue, and real-life traffic offences are an excellent indicator of the behavioural tendencies of impulsivity and risk-taking. We have previously reported on short-term efficacy of a brief intervention in driving schools to reduce traffic risks (Paaver et al., Accid. Anal. Prev., 2013; 50, 430-437), and have now addressed the question of whether does the impact of the intervention last for a few years, and whether traffic behaviour and the intervention effect are associated with the serotonin transporter polymorphism (5-HTTLPR) genotype as the central serotonin system is strongly associated with impulse control. Participants of the study were 1866 novice car-drivers (mean age 23.0, SD = 7.2 years). Data on traffic violations were obtained four years after intervention from the police database and on traffic collisions from the national traffic insurance database. DNA samples were available for 767 participants and 5-HTTLPR genotypes were classified using the triallelic model. For the observation period after the intervention, speeding, drunk driving and involvement in traffic accidents were significantly lower in the intervention group. 5-HTTLPR genotype was associated with traffic behaviour: The S'-allele carriers had significantly lower odds for speeding offences and traffic accidents. The lower prevalence of S'-allele carriers among those who had committed speeding offences was statistically significant in females, while the lower prevalence of having been involved in a traffic accident was rather observed in males. Statistically significant intervention effects were observed only in the L'/L' homozygotes who had higher prevalence of traffic incidents. Conclusively, the brief intervention in traffic schools had a significant impact on traffic safety within subsequent four years, and traffic behaviour was associated with the serotonin transporter genotype. These findings suggest that subjects who are less likely to self-regulate their driving habits while gaining experience would benefit from training of impulsivity recognition. PMID- 29407666 TI - A contextual and temporal algorithm for driver drowsiness detection. AB - This study designs and evaluates a contextual and temporal algorithm for detecting drowsiness-related lane. The algorithm uses steering angle, pedal input, vehicle speed and acceleration as input. Speed and acceleration are used to develop a real-time measure of driving context. These measures are integrated with a Dynamic Bayesian Network that considers the time dependencies in transitions between drowsiness and awake states. The Dynamic Bayesian Network algorithm is validated with data collected from 72 participants driving the National Advanced Driving Simulator. The algorithm has a significantly lower false positive rate than PERCLOS-the current gold standard-and baseline, non contextual, algorithms under design parameters that prioritize drowsiness detection. Under these parameters, the algorithm reduces false positive rate in highway and rural environments, which are typically problematic for vehicle-based detection algorithms. This algorithm is a promising new approach to driver impairment detection and suggests contextual factors should be considered in subsequent algorithm development processes. It may be combined with comprehensive mitigation methods to improve driving safety. PMID- 29407667 TI - A cross-comparison of different techniques for modeling macro-level cyclist crashes. AB - Despite the recognized benefits of cycling as a sustainable mode of transportation, cyclists are considered vulnerable road users and there are concerns about their safety. Therefore, it is essential to investigate the factors affecting cyclist safety. The goal of this study is to evaluate and compare different approaches of modeling macro-level cyclist safety as well as investigating factors that contribute to cyclist crashes using a comprehensive list of covariates. Data from 134 traffic analysis zones (TAZs) in the City of Vancouver were used to develop macro-level crash models (CM) incorporating variables related to actual traffic exposure, socio-economics, land use, built environment, and bike network. Four types of CMs were developed under a full Bayesian framework: Poisson lognormal model (PLN), random intercepts PLN model (RIPLN), random parameters PLN model (RPPLN), and spatial PLN model (SPLN). The SPLN model had the best goodness of fit, and the results highlighted the significant effects of spatial correlation. The models showed that the cyclist crashes were positively associated with bike and vehicle exposure measures, households, commercial area density, and signal density. On the other hand, negative associations were found between cyclist crashes and some bike network indicators such as average edge length, average zonal slope, and off-street bike links. PMID- 29407669 TI - Prevalence, attitudes, and knowledge of in-vehicle technologies and vehicle adaptations among older drivers. AB - The purpose of the present study was to gain a better understanding of the types of in-vehicle technologies being used by older drivers as well as older drivers' use, learning, and perceptions of safety related to these technologies among a large cohort of older drivers at multiple sites in the United States. A secondary purpose was to explore the prevalence of aftermarket vehicle adaptations and how older adults go about making adaptations and how they learn to use them. The study utilized baseline questionnaire data from 2990 participants from the Longitudinal Research on Aging Drivers (LongROAD) study. Fifteen in-vehicle technologies and 12 aftermarket vehicle adaptations were investigated. Overall, 57.2% of participants had at least one advanced technology in their primary vehicle. The number of technologies in a vehicle was significantly related to being male, having a higher income, and having a higher education level. The majority of respondents learned to use these technologies on their own, with "figured-it-out-myself" being reported by 25%-75% of respondents across the technologies. Overall, technologies were always used about 43% of the time, with wide variability among the technologies. Across all technologies, nearly 70% of respondents who had these technologies believed that they made them a safer driver. With regard to vehicle adaptations, less than 9% of respondents had at least one vehicle adaptation present, with the number of adaptations per vehicle ranging from 0 to 4. A large majority did not work with a professional to make or learn about the aftermarket vehicle adaptation. PMID- 29407670 TI - Estimating the expected number of crashes with traffic conflicts and the Lomax Distribution - A theoretical and numerical exploration. AB - This paper justifies the Lomax distribution for counterfactual modeling of the probability of crash given a traffic conflict. The pre-crash process leading to a conflict or a crash as the result of a failure is discussed as this conceptualization is the basis for proposing a simple model of the probability of a crash at the moment when a conflict is still progressing. Then, a model applicable to heterogeneous conditions is derived; and the model's relevance, useful properties, and limitations are discussed. The published concepts and study results that support the derived model are provided in the paper. The existing Maximum Likelihood Estimate (MLE) method and the Probability-Weighted Moments (PWM) method of estimating the probability of crash and the expected number of crashes based on the proposed theory are presented. Then, a new Single Parameter Estimation (SPE) method is proposed and evaluated with extensive Monte Carlo experiments. The performance of the MLE, PWM, and SPE methods are compared. The SPE method is found more accurate and efficient than the other two methods. Unlike the benchmark methods, the proposed method produces real estimates in each case. The most important outcome of the presented study is confirmation that traffic conflicts claimed based on sufficiently small threshold separation (such as Time to Collision) allow unbiased estimation of the expected number of crashes during the conflicts observation period. A practical procedure of estimating safety is proposed that identifies the longest suitable threshold separation for each case based on the trends in the estimation results. PMID- 29407668 TI - Diagnosed dementia and the risk of motor vehicle crash among older drivers. AB - Older adults are an active and growing segment of drivers in the United States. We compared the risk of motor vehicle crash among older licensed drivers diagnosed with dementia to crash risk among older licensed drivers without diagnosis of dementia. This retrospective cohort study used data from Group Health (GH), a Washington State health maintenance organization. Research participants were members of GH, aged 65-79 during the study who lived in Washington State from 1999-2009. Participant health records were linked with police-reported crash and licensure records. We estimated the risk of crash for older drivers diagnosed with dementia compared to older drivers without diagnosis of dementia using a Cox proportional hazards model with robust standard errors, accounting for recurrent events (crashes). Multivariable models were adjusted for age, sex, history of alcohol abuse or depression, comorbidities, and medications. There were 29,730 eligible individuals with an active driving license. Approximately 6% were diagnosed with dementia before or during the study. The police-reported crash rate was 14.7 per 1000 driver-years. The adjusted hazard ratio of crash among older drivers with diagnosed dementia was 0.56 (95% CI 0.33, 0.95) compared to those without diagnosed dementia. On-road and simulator-based research showed older adults with dementia demonstrated impaired driving skill and capabilities. The observed lower crash risk in our study may result from protective steps to limit driving among older adults diagnosed with dementia. Future research should examine driving risk reduction strategies at the time of dementia diagnosis and their impact on reducing crash risk. PMID- 29407671 TI - Walking the talk: Comparing pedestrian 'activity as imagined' with 'activity as done'. AB - The safety of vulnerable road users, including pedestrians, is an important issue worldwide. In line with the shift towards systems thinking in transport safety, the aim of this study was to compare the normal performance of pedestrians as they navigate the road system with that imagined by road system managers to gain insights into how safety management can be improved for this vulnerable road user group. The Event Analysis of Systemic Teamwork framework was used to compare pedestrian activity 'as imagined' and 'as done' at signalised road intersections and railway level crossings. Data regarding 'activity as imagined' was derived from documentation review, and data on 'activity as done' was derived from a semi naturalistic study of ten participants. It is concluded that in both environments pedestrians exhibited more diversity and variability than anticipated by system managers. Insights for improving the design of the road environment for pedestrians are provided. Further, it is argued that wider changes to the processes used in the design and management of road systems are needed. PMID- 29407672 TI - Towards unpacking older drivers' visual-motor coordination: A gaze-based integrated driving assessment. AB - Visual information for a driver is predominant during driving. Linking drivers' visual search patterns with motor behaviour helps understand how drivers perceived spatial and hazardous information to regulate their physical movements. Visual-motor coordination performance can be a sensitive indicator for driver competency assessment. Due to age-related cognitive decline, older drivers are likely inefficient in visual-motor coordination. While poor visual-motor coordination can cause risky behaviour behind the wheel, it is yet challenging to examine it owing to the complexity of driving behaviour. By reviewing how vision guides driving, we proposed a gaze-based integrated driving assessment approach. The empirical data were from 38 older drivers aged 60 to 81 years, who completed an on-road driving assessment recorded by eye tracking and vehicle movement tracking. Their visual search attributes were extracted from eye tracking video frames and linked to vehicle positions. Driving data, drivers' cognitive condition and driving section were encapsulated into an integrated database, allowing interrogating multi-faceted driver-vehicle-environment interactions. Exploratory analysis results show that older drivers' performed different visual search patterns at roundabout and intersection manoeuvres. Older drivers with better executive function skills performed more frequent eye fixations on the curves and inside vehicle features. The investigation of visual-motor coordination performance demonstrated the feasibility and effectiveness of using the integrated approach in assessing older drivers' performance. PMID- 29407673 TI - Definition of run-off-road crash clusters-For safety benefit estimation and driver assistance development. AB - Single-vehicle run-off-road crashes are a major traffic safety concern, as they are associated with a high proportion of fatal outcomes. In addressing run-off road crashes, the development and evaluation of advanced driver assistance systems requires test scenarios that are representative of the variability found in real-world crashes. We apply hierarchical agglomerative cluster analysis to define similarities in a set of crash data variables, these clusters can then be used as the basis in test scenario development. Out of 13 clusters, nine test scenarios are derived, corresponding to crashes characterised by: drivers drifting off the road in daytime and night-time, high speed departures, high angle departures on narrow roads, highways, snowy roads, loss-of-control on wet roadways, sharp curves, and high speeds on roads with severe road surface conditions. In addition, each cluster was analysed with respect to crash variables related to the crash cause and reason for the unintended lane departure. The study shows that cluster analysis of representative data provides a statistically based method to identify relevant properties for run-off-road test scenarios. This was done to support development of vehicle-based run-off road countermeasures and driver behaviour models used in virtual testing. Future studies should use driver behaviour from naturalistic driving data to further define how test-scenarios and behavioural causation mechanisms should be included. PMID- 29407674 TI - Biopolymer strategy for the treatment of Wilson's disease. AB - Wilson's disease is a genetic disorder that causes excessive accumulation of copper in the body, leading to toxic damage, especially in the liver and nervous system. The current treatment cause burdensome side effects. We describe the use of chemically modified biopolymer carriers based on microcrystalline cellulose and chitosan containing the highly specific copper chelator 8-hydroxyquinoline as a new type of therapy for Wilson's disease. The chelators can scavenges copper ions released from food during digestion and copper ions present in secretions in the gastrointestinal tract. Because the chelator is covalently bound to indigestible biopolymer carriers (crosslinked chitosan or modified cellulose), it is not taken up by the gastrointestinal tract and it can be eliminated through the feces, avoiding unwanted side effects. This concept was tested on Wistar rats, which received a radioactive 64CuCl2 solution together with the polymers with covalently bound 8-hydroxyquinoline through a gastric probe. 64Copper complex uptake from the gastrointestinal tract was significantly inhibited by both chelating polymers. With the modified polymers, the presence of 64Cu was detected mostly in the gastrointestinal tract, not in the internal organs. These findings indicate modified cellulose and crosslinked chitosan, with covalently bound 8-hydroxyquinoline exhibited the potential to be excellent therapeutics for treating Wilson's disease. PMID- 29407675 TI - Delivery of lethal dsRNAs in insect diets by branched amphiphilic peptide capsules. AB - Development of new and specific insect pest management methods is critical for overcoming pesticide resistance and collateral off-target killings. Gene silencing by feeding dsRNA to insects shows promise in this area. Here we described the use of a peptide nano-material, branched amphiphilic peptide capsules (BAPCs), that facilitates cellular uptake of dsRNA by insects through feeding. The insect diets included dsRNA with and without complexation with BAPCs. The selected insect species come from two different orders with different feeding mechanisms: Tribolium castaneum and Acyrthosiphon pisum. The gene transcripts tested (BiP and Armet) are part of the unfolded protein response (UPR) and suppressing their translation resulted in lethality. For Acyrthosiphon pisum, ingestion of BiP-dsRNA associated with BAPCs led to the premature death of the aphids (t1/2=4-5days) compared to ingestion of the same amounts of free BiP dsRNA (t1/2=11-12days). Tribolium castaneum was effectively killed using a combination of BiP-dsRNA and Armet-dsRNA complexed with BAPCs; most dying as larvae or during eclosion (~75%). Feeding dsRNA alone resulted in fewer deaths (~30%). The results show that complexation of dsRNA with BAPCs enhanced the oral delivery of dsRNA over dsRNA alone. PMID- 29407677 TI - Ultrasound and microbubble mediated plasmid DNA uptake: A fast, global and multi mechanisms involved process. AB - Ultrasound application combined with microbubbles has shown great potential for intracellular gene delivery. However, the fundamental mechanistic question of how plasmid DNA enters the intracellular space mediated by ultrasound and microbubble has not been fully explored and understood. The goal of this study is to unveil the detailed intracellular uptake process of plasmid DNA stimulated by ultrasound and microbubbles, uniquely highlighting the role of microbubbles play in this process. The usage of targeted microbubbles pinpointed the subcellular membrane site, where ultrasound exerted acoustic force onto the cell membrane. With the combination of high-speed video microscopy and 3D confocal fluorescence microscopy, we show the spatiotemporal correlation between the microbubble dynamics and intracellular plasmid DNA distribution. Two ultrasound modes (high pressure short pulse and low pressure long pulse) were chosen to trigger different plasmid DNA uptake routes. We found that reversible cell membrane disruption, induced by high pressure short pulse ultrasound, permitted plasmid DNA passage across cell membrane, but not in an exclusive way. Under both ultrasound modes, with or without cell membrane disruption, global plasmid DNA internalization, even nuclear-localization, was observed immediately post ultrasound application. Our results show that plasmid DNA uptake evoked by localized acoustically excited microbubbles is a fast (<2min), global (not limited to the site where microbubbles were attached), and multi-mechanisms involved process. PMID- 29407676 TI - Tunable degradation of acetalated dextran microparticles enables controlled vaccine adjuvant and antigen delivery to modulate adaptive immune responses. AB - Subunit vaccines are often poorly immunogenic, and adjuvants and/or delivery vehicles, such as polymeric microparticles (MPs), can be used to enhance immune responses. MPs can also be used to understand cell activation kinetics and the significant impact antigen and adjuvant release has on adaptive immune responses. By controlling antigen and adjuvant release, we can determine if it is important to have precise temporal control over release of these elements to optimize the peak and duration of protective immunity and improve vaccine safety profiles. In order to study the effect of tunable adjuvant or antigen delivery on generation of adaptive immunity, we used acetalated dextran (Ace-DEX) MPs. Ace-DEX MPs were used because their tunable degradation can be controlled based on polymer cyclic acetal coverage (CAC). Ace-DEX MPs of varying degradation profiles were used to deliver murabutide or ovalbumin (OVA) as a model adjuvant or antigen, respectively. When murabutide was encapsulated within Ace-DEX MPs to test for controlled adjuvant delivery, fast-degrading MPs exhibited higher humoral and cellular responses in vivo at earlier time points, while slow-degrading MPs resulted in stronger responses at later time points. When OVA was encapsulated within Ace-DEX MPs to test for controlled antigen delivery, fast-degrading MPs induced greater antibody and cytokine production throughout the length of the experiment. This differential response suggests the need for distinct, flexible control over adjuvant or antigen delivery and its impact on immune response modulation. PMID- 29407678 TI - Stimuli-responsive nanocarriers for delivery of bone therapeutics - Barriers and progresses. AB - The development of stimuli-responsive nanomedicines with tunable cargo release is gathering an increased applicability in bone regeneration and precision biomedicine. Yet, the formulation of nanocarriers that explore skeletal-specific stimuli remains remarkably challenging to materialize due to several endogenous and disease-specific barriers that must be considered during particle design stages. Such anatomo-physiological constrains ultimately hinder nanocarriers bioavailability in target bone tissues and impact the overall therapeutic outcome. This review aims to showcase and critically discuss the hurdles encountered upon responsive nanocarriers delivery in the context of skeletal diseases or tissue regeneration scenarios. Such focus is complemented with an in depth and up-to-date analysis of advances in the development of stimuli responsive, bone-focused delivery systems. In a holistic perspective, a deeper knowledge of human osteology combined with advances in materials functionalization via simple precision-chemistry is envisioned to incite the manufacture of stimuli-triggered nanomedicines with more realistic potential for clinical translation. PMID- 29407680 TI - Factors associated with successful vs. unsuccessful smoking cessation: Data from a nationally representative study. AB - INTRODUCTION: A substantial proportion of smokers who attempt to stop smoking relapse in the first months. Yet to date, there is limited understanding of the predictors of smoking attempts and their success. We examine the role of tobacco use characteristics, other substance-related factors, as well as socio demographic characteristics in relation to successful and unsuccessful smoking cessation. METHODS: DePICT (Description des Perceptions, Images, et Comportements lies au Tabagisme) is a nationally representative sample of adults aged between 18 and 64years residing in metropolitan France, who were interviewed by telephone survey (n=4342). Among current or former smokers (n=2110) we distinguished participants characterized by: a) no quit attempt or quit <6months; b) unsuccessful smoking cessation (current smokers who previously quit smoking >=6months); c) successful smoking cessation (>=6months). Factors associated with successful vs. unsuccessful smoking cessation were studied using multivariate multinomial logistic regression analyses. RESULTS: Successful and unsuccessful smoking cessation share some predicting factors including no cannabis use, older age, and intermediate or high occupational grade. Factors specifically associated with successful smoking cessation included no e-cigarette use, no environmental tobacco exposure, fear of the health consequences of smoking, perceived harmfulness of smoking, and high educational attainment and a good overall health. CONCLUSIONS: Smokers' environmental tobacco exposure, concurrent cannabis use, and the perception of the health consequences of smoking should be taken into account in efforts aiming to promote smoking cessation at the individual as well as collective levels. Our data also suggest that e-cigarette use is associated with unsuccessful rather than successful smoking cessation, which should be verified in additional, longitudinal, studies. PMID- 29407679 TI - Motives and perceptions regarding electronic nicotine delivery systems (ENDS) use among adults with mental health conditions. AB - BACKGROUND: Smoking rates are disproportionately high among adults with mental health conditions (MHC), and recent research suggests that among former smokers, those with MHC are more likely to use electronic nicotine delivery systems (ENDS). This study investigated reasons for ENDS use and related risk perceptions among individuals with versus without MHC. METHODS: Among adult current ENDS users (n=550), associations between self-reported MHC diagnoses and motives for ENDS use and ENDS risk perceptions were examined, stratified by smoking status. RESULTS: There were no significant associations between MHC status and ENDS motives or perceptions in the overall sample. However, current smokers with MHC indicated thinking more about how ENDS might improve their health, and former smokers with MHC reported thinking less about how ENDS might harm their health, compared to their counterparts without MHC. Former smokers with MHC rated several reasons for ENDS use (e.g., less harmful than regular cigarettes; to quit smoking; appealing flavors) as more important than did those without MHC. CONCLUSIONS: Current and former smokers with MHC may be especially optimistic about health benefits of ENDS. However, they might also be prone to health risks of continued ENDS use or concurrent use with traditional cigarettes. It will be important for public health messaging to provide this population with accurate information about benefits and risks of ENDS. PMID- 29407681 TI - Drinking to cope mediates the relationship between depression and alcohol risk: Different pathways for college and non-college young adults. AB - BACKGROUND: It is well-established that drinking to cope with negative affective states mediates the relationship between depressed mood and alcohol risk outcomes among college students. Whether non-college emerging adults exhibit a similar pathway remains unknown. In the current study, we compared the mediating role of coping motives in the relationship between depressive symptoms and drinking risk outcomes (heavy episodic drinking and alcohol problems) in college and non college emerging adult subgroups. METHODS: Participants were three hundred forty one community-recruited 18-25year olds reporting past month alcohol use. We used a structural equation modeling (SEM) for our primary mediation analysis and bias corrected bootstrap resampling for testing the statistical significance of mediation. RESULTS: Participants averaged 20.8 (+/-1.97) years of age, 49% were female, 67.7% were White, 34.6% were college students, and 65.4% were non-college emerging adults. College and non-college emerging adults reported similar levels of drinking, alcohol problems, and drinking to cope with negative affect, and drinking to cope was associated with alcohol-related problems in both samples. However, while drinking to cope mediated the relationship between depressed mood and alcohol problems among students, it did not mediate the pathway among non college emerging adults. CONCLUSIONS: These findings caution against extending college-based findings to non-college populations and underscore the need to better understand the role of coping motives and other intervening factors in pathways linking depressed mood and alcohol-related risk in non-college emerging adults. PMID- 29407682 TI - Sociodemographic and psychopathological predictors of criminal behavior in women with gambling disorder. AB - INTRODUCTION: Women have been underrepresented in the empirical research of gambling disorder (GD), a psychiatric condition included in the Diagnostic and Statistical Manual of Mental Health Disorders (DSM-5). More specifically, no studies to date have been carried out exploring the clinical phenotype of women with GD who have committed gambling-related illegal acts. AIMS: In this study, we sought to delineate the clinical, personality and psychopathological differences between treatment-seeking women with GD, with and without a criminal record. Furthermore, we aimed to identify the variables that best predict the presence of illegal acts in this clinical group. MATERIAL AND METHODS: Data corresponded to n=273 treatment-seeking women who met criteria for GD. Two groups were compared: women with a history of criminal behavior (n=61, 22.34%) to those who did not (n=212, 77.66%) taking psychopathology, clinical and personality data into account. RESULTS: Women who engaged in criminal acts were younger and endorsed higher psychopathology, GD severity, and novelty seeking levels than the other clinical group. Regarding the predictive model, women with higher levels of novelty seeking and lower levels of reward dependence were at higher risk of having a criminal record. DISCUSSION, CONCLUSIONS AND IMPLICATIONS FOR PRACTICE AND/OR POLICY: Our findings uphold that women with GD and a history of illegal acts are especially vulnerable in terms of comorbid psychopathology and dysfunctional personality traits. Therefore, this population could potentially benefit from public policies that target their mental health needs. PMID- 29407683 TI - Associations between coping and marijuana use in a nationally representative sample of adolescents in the United States. AB - Maladaptive coping strategies have been linked with substance use. Little is known, however, about associations between coping and marijuana use in the general U.S. adolescents. We used nationally representative data to examine associations between coping and marijuana use among U.S. adolescents. We hypothesized that marijuana use would be positively associated with both avoidance and distraction coping and negatively associated with problem solving. We calculated adjusted prevalence ratios and odds ratios to assess associations of three coping styles (avoidance, distraction, problem solving) and six coping profiles based on combinations of the styles (adaptive, low on all styles, distracted, high on all styles, avoidant, maladaptive) with lifetime marijuana use and past 12-month frequency of use using data from the National Comorbidity Survey: Adolescent Supplement (n=8476, ages 14-18years). Avoidance and distraction coping were positively and problem solving was negatively associated with lifetime marijuana use. Avoidance coping was positively associated, and problem solving negatively associated, with past 12-month frequency of use. Compared to the adaptive coping profile (low avoidance and distraction, high problem solving), maladaptive profile (high avoidance and distraction, low problem solving) and avoidance profile (high avoidance, low distraction and problem solving) were each positively associated with lifetime marijuana use and past 12-month frequency of use. Avoidance coping, especially in combination with limited problem solving, was positively associated with lifetime marijuana use and past 12-month frequency of use. Our findings have potential to inform interventions for reducing adolescent marijuana use. PMID- 29407684 TI - Menthol cigarette smoking among individuals in treatment for substance use disorders. AB - There are higher rates of menthol cigarette smoking within certain population subgroups. Limited research has examined menthol use among individuals in treatment for substance use disorders (SUD), a population with a high prevalence of cigarette smoking, poor smoking cessation outcomes, and high tobacco disease burden. Survey data were collected from 863 smokers sampled from 24 SUD treatment programs affiliated with the NIDA Clinical Trials Network (CTN) in the United States. Prevalence of menthol cigarette smoking was examined for the sample. Bivariate and multivariate analyses were used to examine demographic and tobacco use characteristics associated with menthol cigarette smoking. Overall, the prevalence of menthol smoking among individuals in SUD treatment was 53.3%. Smoking menthol versus non-menthol cigarettes was associated with being female (AOR=1.61, p=0.003), African American (AOR=7.89, p<0.001), Hispanic/Latino (AOR=3.39, p<0.001), and lower odds of having a college degree (AOR=0.49, p=0.015). Controlling for demographic factors, menthol smokers were more likely to report marijuana (AOR=3.33, p<0.007) as their primary drug compared to alcohol. Lastly, menthol smokers were more likely to report interest in getting help for quitting smoking (AOR=1.53, p=0.01), although they were not more likely to report making a past year quit attempt. In conclusion, use of menthol cigarettes was higher among smokers in SUD treatment than in general population smokers. Regulatory policies targeting the manufacture, marketing, or sale of menthol cigarettes may benefit vulnerable populations, including smokers in SUD treatment. PMID- 29407685 TI - Alcohol expectancies pre-and post-alcohol use disorder treatment: Clinical implications. AB - BACKGROUND AND AIMS: Modification of elevated positive expectations of alcohol consumption (alcohol outcome expectancies; AOEs) is a key feature of Cognitive Behaviour Therapy (CBT) approaches to Alcohol Use Disorders (AUDs). Despite extensive research supporting the efficacy of CBT for AUD, few studies have examined AOE change. This study aimed to assess AOE change following completion of CBT for AUD and its association with drinking behaviour. METHOD: One-hundred and seventy-five patients who completed a 12-week CBT program for AUD were administered the Drinking Expectancy Questionnaire (DEQ) at pre-treatment assessment and upon completion of treatment. Abstinence was achieved by 108 (61.7%) of completing patients. For patients who lapsed, the mean proportion of abstinent days was 93%. RESULTS: DEQ scales assessing expectations of positive alcohol effects on tension reduction, assertiveness, and cognitive enhancement were significantly lower post-treatment (p<0.001). Expectations of negative effects on mood were higher post-treatment (p<0.001). The largest AOE change occurred on the tension reduction scale. Greater percentage of abstinent days over treatment was associated with lower pre-and post-treatment tension reduction expectancy scores (p<0.05). Drinking during treatment was associated with smaller changes in expectations of negative effects of alcohol on mood (p<0.05). CONCLUSIONS: Individuals who completed CBT treatment for AUD showed significant AOE change. Tension reduction and affective change expectancies may be particularly important for abstinence and useful markers of lapse risk. PMID- 29407686 TI - Predictive validity of the tobacco marketing receptivity index among non-smoking youth. AB - INTRODUCTION: In a previous cross-sectional study of early adolescents, we developed a marketing receptivity index (MRI) that integrates point-of-sale (PoS) marketing exposures, brand recall, and ownership of branded merchandise. The MRI had independent, positive associations with smoking susceptibility among never smokers and with current smoking behavior. The current longitudinal study assessed the MRI's predictive validity among adolescents who have never smoked cigarettes METHODS: Data come from a longitudinal, school-based survey of 33 secondary schools in Argentina. Students who had never smoked at baseline were followed up approximately 17months later (n=1700). Questions assessed: PoS marketing exposure by querying frequency of going to stores where tobacco is commonly sold; cued recall of brand names for 3 cigarette packages from dominant brands but with the brand name removed; and ownership of branded merchandise. A four-level MRI was derived: 1.low PoS marketing exposure only; 2. high PoS exposure or recall of 1 brand; 3. recall of 2 or more brands; and 4. ownership of branded merchandise. Logistic regression models regressed smoking initiation by follow up survey on the MRI, each of its components, and students' willingness to try a brand, adjusting for sociodemographics, social network smoking, and sensation seeking. RESULTS: The MRI had an independent positive association with smoking initiation. When analyzed separately, each MRI component was associated with outcomes except branded merchandise ownership. CONCLUSIONS: The MRI and its components were associated with smoking initiation, except for branded merchandise ownership, which may better predict smoking progression than initiation. The MRI appears valid and useful for future studies. PMID- 29407687 TI - Cognitive deficits in individuals with methamphetamine use disorder: A meta analysis. AB - BACKGROUND: Methamphetamine has long been considered as a neurotoxic substance causing cognitive deficits. Recently, however, the magnitude and the clinical significance of the cognitive effects associated with methamphetamine use disorder (MUD) have been debated. To help clarify this controversy, we performed a meta-analysis of the cognitive deficits associated with MUD. METHODS: A literature search yielded 44 studies that assessed cognitive dysfunction in 1592 subjects with MUD and 1820 healthy controls. Effect size estimates were calculated using the Comprehensive Meta-Analysis, for the following 12 cognitive domains: attention, executive functions, impulsivity/reward processing, social cognition, speed of processing, verbal fluency/language, verbal learning and memory, visual learning and memory, visuo-spatial abilities and working memory. RESULTS: Findings revealed moderate impairment across most cognitive domains, including attention, executive functions, language/verbal fluency, verbal learning and memory, visual memory and working memory. Deficits in impulsivity/reward processing and social cognition were more prominent, whereas visual learning and visuo-spatial abilities were relatively spared cognitive domains. A publication bias was observed. DISCUSSION: These results show that MUD is associated with broad cognitive deficits that are in the same range as those associated with alcohol and cocaine use disorder, as recently shown by way of meta-analysis. The prominent effects of MUD on social cognition and impulsivity/reward processing are based on a small number of studies, and as such, these results will need to be replicated. The functional consequences (social and occupational) of the cognitive deficits of methamphetamine will also need to be determined. PMID- 29407688 TI - In pursuit of a self-sustaining college alcohol intervention: Deploying gamified PNF in the real world. AB - Our recent work (Boyle, Earle, LaBrie, & Smith, 2017) showed that the efficacy of personalized normative feedback-based (PNF) college alcohol interventions can be improved through the addition of gamified elements including points, chance, competition, and personal avatars. However, participants in that study were compensated with subject pool credit. In the current study, we piloted an upgraded, smartphone-based version of the game, which was designed to be truly self-sustaining (i.e., engaging enough that students play voluntarily without the presence of external motivators). First-year students were invited to play the game weekly for six rounds, with participants submitting and voting on their own questions each week and receiving a novel type of feedback in addition to standard descriptive PNF: opposite peers' judgments of participants' self reported drinking behavior, or reflective norms. With no play-based incentives, 222 first-year college students voluntarily played the game, CampusGANDR. ANCOVA models revealed that, relative to participants randomized to receive feedback on control topics during the three intervention rounds, those who received both descriptive and reflective feedback on peer alcohol use had significantly reduced normative perceptions and reduced alcohol use two months post intervention. This was especially true among heavy drinkers. The results suggest that our gamified "GANDR" approach shows promise as a self-sustaining intervention and, further, that high-risk drinkers may benefit disproportionately from this methodology. Thus, self-sustaining interventions represent an encouraging avenue for future research and development and may hold the potential to impact risky college drinking on a large scale. PMID- 29407689 TI - Affect and cortisol mechanisms through which acute exercise attenuates cigarette cravings during a temporary quit attempt. AB - INTRODUCTION: A number of mechanisms have been proposed to explain how exercise attenuates cravings among temporarily abstinent smokers; however, research has presented mixed findings. The aim of this study was to further investigate the mechanistic role of positive and negative affect and cortisol in the exercise craving reduction relationship. METHODS: Adult smokers (N=110, male=56, M age=33.1, M cigarettes/day=15.4) provided baseline affective and cortisol data (T1). After an 18-h period of abstinence, participants were randomized to a passive sitting (PSG) or moderate exercise group (MEG; 40-68% of heart rate reserve) for 10min. Affect and cortisol data were also collected immediately before (T2) and after (T3) the condition. RESULTS: The smoking abstinence manipulation increased cravings (p<0.001, eta=0.40) and negative affect (p<0.001, eta=0.17), as well as decreased positive affect (p<0.001, eta=0.08) and cortisol (trending, p=0.07, eta2=0.04). As expected, a significant reduction in cravings from T2 to T3 was found for MEG but not PSG (p<0.001, eta=0.25). Mediation was tested using Sobel and bootstrapping tests with residual change scores of mediators and cravings. Findings showed that both positive and negative affect, but not cortisol, mediated the relationship between exercise and cravings. CONCLUSIONS: Understanding the mechanisms by which exercise induces craving reductions will better allow researchers and healthcare professionals to infer causality and implement interventions guided by the processes that yield such desirable outcomes. PMID- 29407690 TI - Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: A meta-analysis containing 8252 patients. AB - Several studies were carried out to explore the prognostic role of neutrophil-to lymphocyte ratio (NLR) in pancreatic cancer, however, with contradictory results. The objectives of this study were to summarize the prognostic value of NLR in pancreatic cancer. Embase, PubMed and Cochrane Library were comprehensively retrieved. All the cohort studies focusing on the prognostic value of NLR in pancreatic cancer were eligible. 37 papers containing 43 cohort studies with pancreatic cancer were finally included into this study. The results presented that patients with low NLR might have longer OS when compared to the patients with high NLR (HR = 1.81, 95%CI = 1.59-2.05, P < 0.00001; I2 = 82%). Similar results were detected in the subgroup analyses of OS, which was based on the analysis model, ethnicity, treatment, sample size and cut-off value. In additions, low NLR was significantly associated with longer DFS when compared to high NLR in pancreatic cancer (HR = 1.66, 95%CI = 1.17-2.35, P = 0.005; I2 = 67%). Moreover, patients with low NLR had significantly smaller tumor size (P = 0.0007), better differentiation (P = 0.003), earlier stage (P = 0.02) and low CA 199 level (P = 0.007). In conclusion, it was revealed that low NLR was a favorable predictor of OS and DFS in patients with pancreatic cancer, and NLR is a promising prognostic biomarker for pancreatic cancer. PMID- 29407691 TI - Detection of alpha-defensin in blister fluids as potential biomarkers for bullous pemphigoid patients by matrix-assisted laser desorption ionization/time-of-flight mass spectrometry. AB - BACKGROUND: Bullous pemphigoid (BP) is a chronic blistering disease that manifests as multiple tense bullae on the limbs and body. Detecting biomarkers present in skin fluids may assist in the early diagnosis and treatment of BP. In this study, a modern mass spectrometric method was developed for screening biomarkers in blister fluids collected from patients. METHODS: Blister fluids collected from BP patients and physically injured patients were analyzed and compared using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The blister fluids were mixed with MALDI matrix solution on the target plate; after drying, they were analyzed by MALDI-TOF MS. RESULTS: Alpha-defensins 1-3 were detected in the samples collected from all BP patients and absent in all patients with physical injuries. Therefore, alpha defensins 1-3 are potential biomarkers for BP and can be used to differentiate between blisters caused by BP and those caused by physical injuries. Compared to traditional skin biopsy methods that use immunofluorescent stains, analyzing biomarkers in blister fluids using MALDI-TOF is a more rapid and less invasive method. CONCLUSIONS: MALDI-TOF-MS is a non-invasive and efficient method that is able to rapidly distinguish between blisters caused by BP and those caused by physical injuries. PMID- 29407692 TI - Blood clot parameters: Prejudgment of fibrinolysis in thromboelastography. AB - BACKGROUND: Thromboelastography (TEG) is a physical method to simulate the whole process of coagulation and fibrinolysis in the human body environment, and then it also can quickly determine whether patients with hypercoagulable, low coagulation, fibrinolysis or other symptoms. The first step in the diagnosis is based on two parameters: Estimated percentage of lysis (EPL) or the Lysis at 30 min (LY30). These two parameters are used to determine whether the sample has fibrinolysis. However, the determination of LY30 takes a long time, although EPL can reflect real-time fibrinolysis, sometimes the secondary fibrinolysis is not obvious. MATERIALS AND METHODS: We have an extensive database of results from TEG of fibrinolysis and healthy whole blood (WB). These results were generated using citrated WB, followed by the addition of CaCl2, to initiate clot formation. RESULTS: According to the characteristics of fibrinolysis, a new parameter clot retention time (CRT) was proposed to predict the status of fibrinolysis, and the normal range of the parameters was obtained in this paper. CONCLUSION: It is essential for the clinician to determine the fibrinolytic and ultimately contribute to the treatment of patients. We believe this parameter will add to the standardization of TEG parameters. The new parameter will also shorten the measurement time of non-fibrinolytic samples, which has definite physiological and pathological significance. PMID- 29407693 TI - The value of red blood cell distribution width in diagnosis of patients with colorectal cancer. AB - BACKGROUND: Red blood cell distribution width (RDW) is a parameter of standard full blood count tests that reflects the size variability of erythrocytes In recent studies, RDW levels have been associated with ischemic heart disease, acute and chronic heart failure, hypertension, and inflammatory bowel disease. However, it is unclear whether RDW is associated with colorectal cancer. METHODS: Eighty-five patients were diagnosed with colorectal cancer. Fifty-four other patients each diagnosed with colon polyps during the same period served as the control group. The patients were classified according to the seventh edition of the AJCC Cancer Staging Manual of 2009 into groups of different cancer stages, and simultaneously divided into groups with or without metastasis. The multigroup metering data was tested by a non-parametric Kruskal-Wallis H test, and the two subsets of patients formed above were compared using a Mann-Whitney U test. The association between continuous variables was assessed by Spearman correlation analysis while the association between RDW and colorectal cancer metastasis was estimated by receiver operating characteristic (ROC) curve analysis. RESULTS: Increased RDW was observed in patients with colorectal cancer. The RDW was significantly different for each subgroup of colorectal cancer as follows: stage III + IV > stage III, T3 + T4 > T1 + T2, N1 + N2 > N0, and M1 > M0 (P < 0.05). The area under the receiver-operating characteristic curve of the RDW in the diagnosis of colorectal cancer metastasis was 0.721 (95% confidence interval of 0.612-0.831). CONCLUSIONS: The value of RDW is closely related to colorectal cancer metastasis. PMID- 29407694 TI - Influence of dissolved organic matter and activated carbon pore characteristics on organic micropollutant desorption. AB - By simulating decreasing inflow concentrations, the extent of desorption of organic micropollutants (OMP) from three activated carbons (AC) was examined in laboratory batch tests. The tested AC showed strong differences in pore size distribution and could therefore be characterized as typical micro-, meso- and macroporous AC, respectively. Adsorption and desorption conditions were varied by using drinking water (containing dissolved organic matter (DOM)) and DOM-free pure water as background solutions to examine the influence of DOM on OMP desorption for the different AC. Under ideal conditions (adsorption and desorption in pure water) adsorption of the tested OMP was found to be highly up to completely reversible for all tested AC. Under real conditions (adsorption and desorption in drinking water) additional DOM adsorption affects desorption in different ways depending on the AC pore structure. For the micro- and mesoporous AC, an increased irreversibility of OMP adsorption was found, which shows that DOM adsorption prevents OMP desorption. This could be referred to pore blockage effects that occur during the parallel adsorption of DOM and OMP. For the macroporous AC, DOM adsorption led to an enhanced OMP desorption which could be attributed to displacement processes. These results show that smaller pores tend to be blocked by DOM which hinders OMP from desorption. The overall larger pores of the macroporous AC do not get blocked which could allow (i) OMP to desorb and (ii) DOM to enter and displace OMP. PMID- 29407695 TI - Establishment and convergence of photosynthetic microbial biomats in shallow unit process open-water wetlands. AB - The widespread adoption of engineered wetlands designed for water treatment is hindered by uncertainties in system reliability, resilience and management associated with coupled biological and physical processes. To better understand how shallow unit process open-water wetlands self-colonize and evolve, we analyzed the composition of the microbial community in benthic biomats from system establishment through approximately 3 years of operation. Our analysis was conducted across three parallel demonstration-scale (7500 m2) cells located within the Prado Constructed Wetlands in Southern California. They received water from the Santa Ana River (5.9 +/- 0.2 mg/L NO3-N), a water body where the flow is dominated by municipal wastewater effluent from May to November. Phylogenetic inquiry and microscopy confirmed that diatoms and an associated aerobic bacterial community facilitated early colonization. After approximately nine months of operation, coinciding with late summer, an anaerobic community emerged with the capability for nitrate attenuation. Varying the hydraulic residence time (HRT) from 1 to 4 days the subsequent year resulted in modest ecological changes across the three parallel cells that were most evident in the outlet regions of the cells. The community that established at this time was comparatively stable for the remaining years of operation and converged with one that had previously formed approximately 550 km (350 miles) away in a pilot-scale (400 m2) wetland in Northern California. That system received denitrified (20.7 +/- 0.7 mg/L NO3-N), secondary treated municipal wastewater for 5 years of operation. Establishment of a core microbiome between the two systems revealed a strong overlap of both aerobic and anaerobic taxa with approximately 50% of the analyzed bacterial sequences shared between the two sites. Additionally the same species of diatom, Stauirsa construens var. venter, was prolific in both systems as the putative dominant primary producer. Our results indicate that despite differences in scale, geographic location and source waters, the shallow open-water wetland design can select for a rapid convergence of microbial structure and functionality associated with the self-colonizing benthic biomat. This resulting biomat matures over the first growing season with operational parameters such as HRT further exerting a modest selective bias on community succession. PMID- 29407696 TI - Trace analysis of 61 natural and synthetic progestins in river water and sewage effluents by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A broad number of natural and synthetic progestins are widely used in human and veterinary therapies. Although progestins exhibit adverse effects in aquatic organisms, information about environmental occurrence and fate have been limited to several compounds, hampering the accuracy of risk assessments of the compounds. In this study, a selective and sensitive analytical method was established to simultaneously determine 19 natural and 42 synthetic progestins in environmental waters, and the synthetic progestins included 19-nortestosterone, 17alpha-hydroxyprogesterone and progesterone derivatives. All of the target compounds were effectively separated using an HSS T3 column, and the recoveries for effluent and river samples were 80-115% and 75-105%, respectively. The detection limits for the 61 analytes were in the range of 0.05-0.60 ng/L and 0.03 0.40 ng/L for the effluent and river samples, respectively. The developed method is applied to analyze the target progestogens in sewage effluent and river water samples from Beijing. The detected concentrations of natural progesterone metabolites (3alpha-hydroxy-5beta-tetrahydroprogesterone) were up to 63 times higher than those of the parent compound. Of the three groups of synthetic progestins, the progesterone derivatives were detected for the first time and had the highest concentrations followed by the 19-nortestosterone and 17alpha hydroxyprogesterone derivatives. In contrast to previous studies, the predominant derivative compounds of 19-nortestosterone were found to be 19-nortestosterone, gestodene and mifepristone, and those of 17alpha-hydroxyprogesterone were 6-epi medroxy progesterone 17-acetate and melengestrol acetate. The toxicities and environmental risk of these emerging progestins deserves more attention in the future. PMID- 29407697 TI - Mechanisms driving phosphorus release during algal blooms based on hourly changes in iron and phosphorus concentrations in sediments. AB - Algal growth causes a drastic change in aquatic conditions over a diel cycle, which may induce sensitive feedback systems in sediments, causing P release. In this study, a microcosm experiment was performed using a suction sampler (Rhizon) to observe changes in soluble reactive phosphorus (SRP) and soluble Fe(II) concentrations in the top 20 mm sediment layer on a 3-h time interval, at different phases of harmful algal bloom (HAB) development. The results showed that the algal blooms prevailed up to 15 days after incubation, after which the process of bloom collapse proceeded until the 70th day. The concentrations of pore-water soluble Fe(II) and SRP increased throughout the incubation period. Compared to day 1, maximum increases of 214% in soluble Fe(II) and 387% in SRP were observed at night during the bloom and collapse periods, respectively. The diffusive fluxes of Fe and P at the sediment-water interface (SWI) generally corresponded to their changes in concentrations. Hourly fluctuation in soluble Fe(II) and SRP concentrations were observed with two distinct concentration peaks occurred at 21:00 p.m. and 06:00 a.m. (or 03:00 a.m.), respectively. These findings suggest that Fe-P coupling mechanisms are responsible for the release of P from sediments. During the collapse period, soluble Fe(II) concentrations were suppressed by the increase of labile S(-II) at night. Meanwhile, SRP concentrations were decoupled from Fe cycling with small fluctuations (<11% RSD) on an hourly timescale, and the decomposition of algae was a dominant source contributing to the release of P from sediments. These results significantly improved the understanding of processes and mechanisms behind the stimulated release of P from sediments during HABs. PMID- 29407698 TI - Elucidating the stimulatory and inhibitory effects of dissolved sulfide on sulfur oxidizing bacteria (SOB) driven autotrophic denitrification. AB - Autotrophic denitrification has been widely studied for odor mitigation, corrosion control and nitrogen removal in recent years. This paper examines the response of sulfur-oxidizing bacteria (SOB) driven autotrophic denitrification under short-term stress of dissolved sulfide. A series of batch tests were conducted to investigate the effect of different sulfide concentrations (0-1600 mg-total dissolved sulfide (TDS)/L) on autotrophic denitrification and sulfide oxidation by SOB-enriched sludge. Our results show that autotrophic denitrification (NO3- to N2) was stimulated up to 200 mg-TDS/L with a maximum denitrification rate of 9.4 mg-N/g-volatile suspended solids (VSS)/h, and the nitrite reduction was a rate limiting step. When sulfide concentration was higher than 200 mg-TDS/L, it inhibited nitrate reductase, and nitrate reduction became the rate limiting step according to Edwards and Aiba inhibition models. Sulfide oxidation, however, was not inhibited and the maximum rate of 100.3 mg-TDS/g VSS/h was obtained at sulfide concentration of 1000 mg-TDS/L. It is important to point out that the transient inhibition on autotrophic denitrification caused by high sulfide stress was resilient and non-lethal with no significant changes in cell viability even under sulfide concentration of 1000 mg-TDS/L. This study reveals the stimulatory and inhibitory effects of dissolved sulfide on SOB driven autotrophic denitrification and its possible underlying mechanism with discussion on engineering implications. PMID- 29407699 TI - Enhanced removal of Se(VI) from water via pre-corrosion of zero-valent iron using H2O2/HCl: Effect of solution chemistry and mechanism investigation. AB - Although the removal of Se(VI) from water by using zero-valent iron (ZVI) is a promising method, passivation of ZVI severely inhibits its performance. To overcome such issue, we proposed an efficient technique to enhance Se(VI) removal via pre-corrosion of ZVI with H2O2/HCl in a short time (15 min). The resultant pcZVI suspension was weakly acidic (pH 4.56) and contained abundant aqueous Fe2+. 57Fe Mossbauer spectroscopy showed that pcZVI mainly consisted of Fe0 (66.2%), hydrated ferric oxide (26.3%), and Fe3O4 (7.5%). Efficient removal of Se(VI) from sulfate-rich solution was achieved by pcZVI compared with ZVI (in the absence and presence of H2O2) and acid-pretreated ZVI. Moreover, the efficient removal of Se(VI) by pcZVI sustained over a broad pH range (3-9) due to its strong buffering power. The presence of chloride, carbonate, nitrate, and common cations (Na+, K+, Ca2+, and Mg2+) posed negligible influence on the removal of Se(VI) by pcZVI, while the inhibitory effect induced by sulfate, silicate, and phosphate indicated the significance of Se(VI) adsorption as a prerequisite step for its removal. The consumption of aqueous Fe2+ was associated with Se(VI) removal, and X-ray absorption near edge structure revealed that the main pathway for Se(VI) removal by pcZVI was a stepwise reduction of Se(VI) to Se(IV) and then Se0 as the dominant final state (78.2%). Moreover, higher electron selectivity of pcZVI was attributed to the enhanced enrichment of Se oxyanions prior to their reduction. PMID- 29407700 TI - Occurrence and fate of emerging contaminants in municipal wastewater treatment plants from different geographical regions-a review. AB - Emerging contaminants, such as antibiotics, pharmaceuticals, personal care products, hormones, and artificial sweeteners, are recognized as new classes of water contaminants due to their proven or potential adverse effects on aquatic ecosystems and human health. This review provides comprehensive data on the occurrence of 60 emerging contaminants (ECs) in influent, treated effluent, sludge, and biosolids in wastewater treatment plants (WWTPs). In particular, data on the occurrence of ECs in the influents and effluents of WWTPs are systematically summarized and categorized according to geographical regions (Asia, Europe, and North America). The occurrence patterns of ECs in raw influent and treated effluents of WWTPs between geographical regions were compared and evaluated. Concentrations of most ECs in raw influent in Asian region tend to be higher than those in European and North American countries. Many antibiotics were detected in the influents and effluents of WWTPs at concentrations close to or exceeding the predicted no-effect concentrations (PNECs) for resistance selection. The efficacy of EC removal by sorption and biodegradation during wastewater treatment processes are discussed in light of kinetics and parameters, such as sorption coefficients (Kd) and biodegradation constants (kbiol), and physicochemical properties (i.e. log Kow and pKa). Commonly used sampling and monitoring strategies are critically reviewed. Analytical research needs are identified, and novel investigative approaches for future monitoring studies are proposed. PMID- 29407702 TI - Anaerobic digestion of 30-100-year-old boreal lake sedimented fibre from the pulp industry: Extrapolating methane production potential to a practical scale. AB - Since the 1980s, the pulp and paper industry in Finland has resulted in the accumulation of fibres in lake sediments. One such site in Lake Nasijarvi contains approximately 1.5 million m3 sedimented fibres. In this study, the methane production potential of the sedimented fibres (on average 13% total solids (TS)) was determined in batch assays. Furthermore, the methane production from solid (on average 20% TS) and liquid fractions of sedimented fibres after solid-liquid separation was studied. The sedimented fibres resulted in fast methane production and high methane yields of 250 +/- 80 L CH4/kg volatile solids (VS). The main part (ca. 90%) of the methane potential was obtained from the solid fraction of the sedimented fibres. In addition, the VS removal from the total and solid sedimented fibres was high, 61-65% and 63-78%, respectively. The liquid fraction also contained a large amount of organics (on average 8.8 g COD/L), treatment of which also has to be considered. The estimations of the methane production potentials in the case area showed potential up to 40 million m3 of methane from sedimented fibres. PMID- 29407701 TI - Responses of wastewater biofilms to chronic CeO2 nanoparticles exposure: Structural, physicochemical and microbial properties and potential mechanism. AB - With the accelerated application of CeO2 nanoparticles (NPs), wastewater treatment plants will increasingly receive CeO2 NPs, thus inevitably causing CeO2 NPs to encounter microaggregates. Here, we comprehensively elucidate the responses in the structural, physicochemical and microbial properties of wastewater biofilms to chronic exposure (75 days) to different CeO2 NPs concentrations, with a particular emphasis on the protective mechanisms of stratified extracellular polymeric substances (EPSs). Chronic exposure to 0.1 mg/L CeO2 NPs boosted the content and broadened the distribution of alpha-d glucopyranose polysaccharides (PS), while the sharply increased production and breadth of beta-d-glucopyranose PS, forming a formidable shield, was a response to 10 mg/L CeO2 NPs. After the bacteria were exposed to CeO2 NPs, loosely bound EPSs (LB-EPSs) aggregated into macromolecules (increasing in apparent molecular weight (AMW)) but at a lower abundance, whereas the average AMW in tightly bound EPSs (TB-EPSs) decreased. The acetyl content and (alpha-helix+3-turn helix)/beta sheet value of TB-EPSs increased to resist CeO2 NPs. Furthermore, long-term exposure to CeO2 NPs decreased cell viability, reduced microbial diversity and shifted the microbial composition. N-acylated-l-homoserine lactone concentrations increased with increased density of Pseudomonas, which was associated with PS regulated control, thus promoting PS production in EPSs in response to CeO2 NPs. These results expand the understanding of how microaggregates resist environmental stress caused by NPs. PMID- 29407703 TI - Organic contaminants degradation from the S(IV) autoxidation process catalyzed by ferrous-manganous ions: A noticeable Mn(III) oxidation process. AB - Remarkable atrazine degradation in the S(IV) autoxidation process catalyzed by Fe2+-Mn2+ (Fe2+/Mn2+/sulfite) was demonstrated in this study. Competitive kinetic experiments, alcohol inhibiting methods and electron spin resonance (ESR) experiments proved that sulfur radicals were not the major oxidation species. Mn(III) was demonstrated to be the primary active species in the Fe2+/Mn2+/sulfite process based on the comparison of oxidation selectivity. Moreover, the inhibiting effect of the Mn(III) hydrolysis and the S(IV) autoxidation in the presence of organic contaminants indicated the existence of three Mn(III) consumption routes in the Fe2+/Mn2+/sulfite process. The absence of hydroxyl radical and sulfate radical was interpreted by the competitive dynamics method. The oxidation capacity of the Fe2+/Mn2+/sulfite was independent of the initial pH (4.0-6.0) because the fast decay of S(IV) decreased initial pH below 4.0 rapidly. The rate of ATZ degradation was independent of the dissolved oxygen (DO) because that the major DO consumption process was not the rate determining step during the production of SO5*-. Phosphate and bicarbonate were confirmed to have greater inhibitory effects than other environmental factors because of their strong pH buffering capacity and complexing capacity for Fe3+. The proposed acetylation degradation pathway of ATZ showed the application of the Fe2+/Mn2+/sulfite process in the research of contaminants degradation pathways. This work investigated the characteristics of the Fe2+/Mn2+/sulfite process in the presence of organic contaminants, which might promote the development of Mn(III) oxidation technology. PMID- 29407704 TI - Occurrence, identification and removal of microplastic particles and fibers in conventional activated sludge process and advanced MBR technology. AB - Wastewater treatment plants (WWTPs) are acting as routes of microplastics (MPs) to the environment, hence the urgent need to examine MPs in wastewaters and different types of sludge through sampling campaigns covering extended periods of time. In this study, the efficiency of a municipal WWTP to remove MPs from wastewater was studied by collecting wastewater and sludge samples once in every two weeks during a 3-month sampling campaign. The WWTP was operated based on the conventional activated sludge (CAS) process and a pilot-scale membrane bioreactor (MBR). The microplastic particles and fibers from both water and sludge samples were identified by using an optical microscope, Fourier Transform Infrared (FTIR) microscope and Raman microscope. Overall, the retention capacity of microplastics in the studied WWTP was found to be 98.3%. Most of the MP fraction was removed before the activated sludge process. The efficiency of an advanced membrane bioreactor (MBR) technology was also examined. The main related finding is that MBR permeate contained 0.4 MP/L in comparison with the final effluent of the CAS process (1.0 MP/L). According to this study, both microplastic fibers and particles are discharged from the WWTP to the aquatic environment. PMID- 29407705 TI - Persulfate activation by glucose for in situ chemical oxidation. AB - Sodium persulfate has become the most popular oxidant source for the in situ chemical oxidation (ISCO) treatment of organic contaminants in the subsurface. The most common persulfate activators, iron chelates and base, are often ineffective in initiating the generation of reactive oxygen species in field applications. In this study, glucose was investigated as a persulfate activator in systems containing varying concentrations of sodium hydroxide using nitrobenzene as a hydroxyl radical probe and hexachloroethane as a reductant + nucleophile probe. Glucose activation of persulfate increased as a function of sodium hydroxide addition, but was still effective at circumneutral pH regimes. Use of central composite rotatable experimental designs showed that hydroxyl radical and reductant + nucleophile generation rates increased as a function of persulfate at near-neutral pH regimes. Glucose activation of persulfate has the advantages over other activation pathways of more options and flexibility for effective process chemistry and of minimizing or eliminating the mass of sodium hydroxide added to the subsurface. The results of this research can be applied in the field by first evaluating glucose activation compared to base and iron chelate activation of persulfate in laboratory treatability studies. PMID- 29407706 TI - Differences in behaviour of three biopolymer constituents in coagulation with polyaluminium chloride: Implications for the optimisation of a coagulation membrane filtration process. AB - Coagulation is often applied as a pre-treatment for membrane processes to reduce dissolved organic matter and to prevent membrane fouling. Biopolymers (BPs) have repeatedly been reported as major organic foulants, and coagulation conditions such as pH or dose have been optimised to minimise the remaining BPs. Optimisation however remains problematic because of the complex and heterogenetic nature of BP. In this study, the behaviour of several BP fractions in a coagulation process was investigated by excitation-emission matrix-parallel factor analysis (EEM-PARAFAC) following liquid chromatography (LC)-fractionation. Using a series of jar tests, we found that BP removal depends on the type of source water, reflecting differences in charge neutralisation conditions in three samples of natural water despite nearly identical processes for removing humic substances. This result demonstrates the complexity of optimisation for BP coagulation. Fractionation of EEM-PARAFAC to BP by LC showed that at least three organic component groups (C1, C2 and C3) constitute BP. C1 is tryptophan-like organic matter that is often found in wastewater effluent, C2 is tyrosine-like organic matter that has a phenolic chemical structure, and C3 is a humic-like substance. C1 was removed thoroughly at acidic pH but not at neutral pH, while the removal of C2 was inefficient even with a significant change in pH or dose, indicating similar difficulties in a coagulation process. The difference in components C1 and C2 may partly explain the difference in efficiencies of removal of BP in water from different sources. Our investigation suggests that the optimisation or selection of appropriate pre-treatment processes for membrane systems should be substantially based on the composition of BPs (e.g., C1 and C2 components). PMID- 29407707 TI - Size exclusion chromatography with online ICP-MS enables molecular weight fractionation of dissolved phosphorus species in water samples. AB - Phosphorus (P) is an important and often limiting element in terrestrial and aquatic ecosystem. A lack of understanding of its distribution and structures in the environment limits the design of effective P mitigation and recovery approaches. Here we developed a robust method employing size exclusion chromatography (SEC) coupled to an ICP-MS to determine the molecular weight (MW) distribution of P in environmental samples. The most abundant fraction of P varied widely in different environmental samples: (i) orthophosphate was the dominant fraction (93-100%) in one lake, two aerosols and DOC isolate samples, (ii) species of 400-600 Da range were abundant (74-100%) in two surface waters, and (iii) species of 150-350 Da range were abundant in wastewater effluents. SEC DOC of the aqueous samples using a similar SEC column showed overlapping peaks for the 400-600 Da species in two surface waters, and for >20 kDa species in the effluents, suggesting that these fractions are likely associated with organic matter. The MW resolution and performance of SEC-ICP-MS agreed well with the time integrated results obtained using conventional ultrafiltration method. Results show that SEC in combination with ICP-MS and DOC has the potential to be a powerful and easy-to-use method in identifying unknown fractions of P in the environment. PMID- 29407708 TI - Free ammonia enhances dark fermentative hydrogen production from waste activated sludge. AB - Ammonium and/or free ammonia (the unionized form of ammonium) are generally thought to inhibit the activities of microbes involved in anaerobic digestion of waste activated sludge. It was found in this work, however, that the presence of ammonium (NH4+-N) largely enhanced dark fermentative hydrogen production from alkaline pretreated-sludge. With the increase of initial NH4+-N level from 36 to 266 mg/L, the maximal hydrogen production from alkaline (pH 9.5) pretreated sludge increased from 7.3 to 15.6 mL per gram volatile suspended solids (VSS) under the standard condition. Further increase of NH4+-N to 308 mg/L caused a slight decrease of hydrogen yield (15.0 mL/g VSS). Experimental results demonstrated that free ammonia instead of NH4+-N was the true contributor to the enhancement of hydrogen production. It was found that the presence of free ammonia facilitated the releases of both extracellular and intracellular constituents, which thereby provided more substrates for subsequent hydrogen production. The free ammonia at the tested levels (i.e., 0-444 mg/L) did not affect acetogenesis significantly. Although free ammonia inhibited all other bio processes, its inhibition to the hydrogen consumption processes (i.e., homoacetogenesis, methanogenesis, and sulfate-reducing process) was much severer than that to the hydrolysis and acidogenesis processes. Further investigations with enzyme analyses showed that free ammonia posed slight impacts on protease, butyrate kinase, acetate kinase, CoA-transferase, and [FeFe] hydrogenase activities but largely suppressed the activities of coenzyme F420, carbon monoxide dehydrogenase, and adenylyl sulfate reductase, which were consistent with the chemical analyses performed above. PMID- 29407709 TI - Reducing uncertainty in estimating virus reduction by advanced water treatment processes. AB - Treatment of wastewater for potable reuse requires the reduction of enteric viruses to levels that pose no significant risk to human health. Advanced water treatment trains (e.g., chemical clarification, reverse osmosis, ultrafiltration, advanced oxidation) have been developed to provide reductions of viruses to differing levels of regulatory control depending upon the levels of human exposure and associated health risks. Importance in any assessment is information on the concentration and types of viruses in the untreated wastewater, as well as the degree of removal by each treatment process. However, it is critical that the uncertainty associated with virus concentration and removal or inactivation by wastewater treatment be understood to improve these estimates and identifying research needs. We reviewed the critically literature to assess to identify uncertainty in these estimates. Biological diversity within families and genera of viruses (e.g. enteroviruses, rotaviruses, adenoviruses, reoviruses, noroviruses) and specific virus types (e.g. serotypes or genotypes) creates the greatest uncertainty. These aspects affect the methods for detection and quantification of viruses and anticipated removal efficiency by treatment processes. Approaches to reduce uncertainty may include; 1) inclusion of a virus indicator for assessing efficiency of virus concentration and detection by molecular methods for each sample, 2) use of viruses most resistant to individual treatment processes (e.g. adenoviruses for UV light disinfection and reoviruses for chlorination), 3) data on ratio of virion or genome copies to infectivity in untreated wastewater, and 4) assessment of virus removal at field scale treatment systems to verify laboratory and pilot plant data for virus removal. PMID- 29407710 TI - Ozonation control and effects of ozone on water quality in recirculating aquaculture systems. AB - To address the undesired effect of chemotherapeutants in aquaculture, ozone has been suggested as an alternative to improve water quality. To ensure safe and robust treatment, it is vital to define the ozone demand and ozone kinetics of the specific water matrix to avoid ozone overdose. Different ozone dosages were applied to water in freshwater recirculating aquaculture systems (RAS). Experiments were performed to investigate ozone kinetics and demand, and to evaluate the effects on the water quality, particularly in relation to fluorescent organic matter. This study aimed at predicting a suitable ozone dosage for water treatment based on daily ozone demand via laboratory studies. These ozone dosages will be eventually applied and maintained at these levels in pilot-scale RAS to verify predictions. Selected water quality parameters were measured, including natural fluorescence and organic compound concentration changes during ozonation. Ozone reactions were described by first order kinetics. Organic matter, assessed as chemical oxygen demand and fluorescence, decreased by 25% (low O3), 30% (middle O3) and 53% (high O3), while water transmittance improved by 15% over an 8-day period. No fish mortality was observed. Overall, this study confirms that ozone can improve RAS water quality, provides a better understanding of the ozone decay mechanisms that can be used to define further safe ozone treatment margins, and that fluorescence could be used as a monitoring tool to control ozone. This study might be used as a tool to design ozone systems for full-scale RAS by analysing water sample from the specific RAS in the laboratory. PMID- 29407711 TI - Photodegradation of sulfasalazine and its human metabolites in water by UV and UV/peroxydisulfate processes. AB - The widespread occurrence of pharmaceuticals and their metabolites in natural waters has raised great concerns about their potential risks on human health and ecological systems. This study systematically investigates the degradation of sulfasalazine (SSZ) and its two human metabolites, sulfapyridine (SPD) and 5 aminosalicylic acid (5-ASA), by UV and UV/peroxydisulfate (UV/PDS) processes. Experimental results show that SPD and 5-ASA were readily degraded upon UV 254 nm direct photolysis, with quantum yields measured to be (8.6 +/- 0.8) * 10-3 and (2.4 +/- 0.1) * 10-2 mol Einstein-1, respectively. Although SSZ was resistant to direct UV photolysis, it could be effectively removed by both UV/H2O2 and UV/PDS processes, with fluence-based pseudo-first-order rate constants determined to be 0.0030 and 0.0038 cm2 mJ-1, respectively. Second-order rate constant between SO4* and SSZ was measured as (1.33 +/- 0.01) * 109 M-1s-1 by competition kinetic method. A kinetic model was established for predicting the degradation rate of SSZ in the UV/PDS process. Increasing the dosage of PDS significantly enhanced the degradation of SSZ in the UV/PDS process, which can be well predicted by the developed kinetic model. Natural water constituents, such as natural organic matter (NOM) and bicarbonate (HCO3-), influenced the degradation of SSZ differently. The azo functional group of SSZ molecule was predicted as the reactive site susceptible to electrophilic attack by SO4*- by frontier electron densities (FEDs) calculations. Four intermediate products arising from azo bond cleavage and SO2 extrusion were identified by solid phase extraction-liquid chromatography-triple quadrupole mass spectrometry (SPE-LC-MS/MS). Based on the products identified, detailed transformation pathways for SSZ degradation in the UV/PDS system were proposed. Results reveal that UV/PDS could be an efficient approach for remediation of water contaminated by SSZ and its metabolites. PMID- 29407712 TI - Degradation of recalcitrant naphthenic acids from raw and ozonated oil sands process-affected waters by a semi-passive biofiltration process. AB - In this study, a fixed-bed biofiltration system (biofilter) that utilized indigenous microorganisms was developed for the reclamation of oil sands process affected water (OSPW). With the assistance of quantitative polymerase chain reaction (qPCR) and confocal laser scanning microscopy (CLSM), indigenous microorganisms from OSPW were able to attach to the surface of sand media and form biofilms. The number of total bacteria on the biofilter media reached a steady state (109/g) after 23 days of operation. Ultra Performance Liquid Chromatography/High Resolution Mass Spectrometry (UPLC/HRMS) analysis showed that 21.8% of the classical naphthenic acids (NAs) removal was achieved through the circulation of raw OSPW on the biofilter for 8 times (equivalent to a hydraulic retention time of 16 h). When ozonation with utilized ozone dose of 30 mg/L was applied as pretreatment, the classical NAs in the ozonated OSPW were removed by 89.3% with an accelerated biodegradation rate of 0.5 mg/L/h. Compared with other biofilm reactors such as moving bed biofilm reactor (MBBR), ozonation pretreatment could benefit the biodegradation of NAs in the biofilter more (classical NA removal: 89.3% vs. 34.4%), especially for those with high carbon number and cyclicity. The combined ozonation-biofiltration process could remove 92.7% of classical NAs from raw OSPW in 16 h. Although both ozonation and biofiltration alone did not show degradation of oxidized NAs from raw OSPW, the combined process led to a 52.9% and 42.6% removal for O3-NAs and O4-NAs, respectively, which were the dominant oxidized NA species in OSPW. Metagenomic sequencing analysis showed that Rhodococcus was the dominant bacterial genus on the sand media, which may play a crucial role during the NA biodegradation. With the advantage of high NA removal efficiency, the combined ozonation-biofiltration process is a promising approach for NA degradation and shows high potential to be scaled up for in-situ OSPW treatment. PMID- 29407713 TI - Calcium ion- and rhamnolipid-mediated deposition of soluble matters on biocarriers. AB - Start-up of biofilm process initiated by the deposition of soluble matters on biocarriers is a very important yet time-consuming procedure. However, rapid start-up methods especially in the enhancement of soluble matters deposition have been rarely addressed. In this study, a quartz crystal microbalance with dissipation monitoring (QCM-D) was applied to investigate the influences of calcium ion and rhamnolipid (RL) on the deposition of soluble matters from real and synthetic industrial wastewaters with different configurations of organics (bovine serum albumin and sodium alginate) and ionic strength on the model biocarriers polystyrene and polyamide. Results showed that deposition was effectively promoted by the addition of Ca2+ and along with the increase in Ca2+ content. However, RL enhanced the deposition effectively only in hyperhaline wastewater through breaking hydration repulsion and decreased the deposition in low-salinity wastewater, and its influence to the deposited layer property exhibited characteristics of negative feedback. The combined use of Ca2+ and RL had a better enhancement effect than that of separate use and the mechanism involved can not be soundly explained only by Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The strategy of mediating the deposition of soluble matters on different biocarriers by adding Ca2+ and RL has important implications for regulating biofilm formation to accelerate the start-up process in attached growth bioreactors. PMID- 29407714 TI - Plasma-activation of tap water using DBD for agronomy applications: Identification and quantification of long lifetime chemical species and production/consumption mechanisms. AB - Cold atmospheric plasmas are weakly ionized gases that can be generated in ambient air. They produce energetic species (e.g. electrons, metastables) as well as reactive oxygen species, reactive nitrogen species, UV radiations and local electric field. Their interaction with a liquid such as tap water can hence change its chemical composition. The resulting "plasma-activated liquid" can meet many applications, including medicine and agriculture. Consequently, a complete experimental set of analytical techniques dedicated to the characterization of long lifetime chemical species has been implemented to characterize tap water treated using cold atmospheric plasma process and intended to agronomy applications. For that purpose, colorimetry and acid titrations are performed, considering acid-base equilibria, pH and temperature variations induced during plasma activation. 16 species are quantified and monitored: hydroxide and hydronium ions, ammonia and ammonium ions, orthophosphates, carbonate ions, nitrite and nitrate ions and hydrogen peroxide. The related consumption/production mechanisms are discussed. In parallel, a chemical model of electrical conductivity based on Kohlrausch's law has been developed to simulate the electrical conductivity of the plasma-activated tap water (PATW). Comparing its predictions with experimental measurements leads to a narrow fitting, hence supporting the self-sufficiency of the experimental set, I.e. the fact that all long lifetime radicals of interest present in PATW are characterized. Finally, to evaluate the potential of cold atmospheric plasmas for agriculture applications, tap water has been daily plasma-treated to irrigate lentils seeds. Then, seedlings lengths have been measured and compared with untreated tap water, showing an increase as high as 34.0% and 128.4% after 3 days and 6 days of activation respectively. The interaction mechanisms between plasma and tap water are discussed as well as their positive synergy on agronomic results. PMID- 29407715 TI - DNA extraction in Echinococcus granulosus and Taenia spp. eggs in dogs stool samples applying thermal shock. AB - The extraction of DNA in taeniid eggs shows complications attached to the composition of stool samples and the high resistance of eggs to degradation. The objective of this study was to test a method of DNA extraction in taeniid eggs by applying a thermal shock to facilitate the chemical-enzymatic degradation of these elements. A group of six tubes containing 1 ml of dog stool sample was spiked with eggs of Echinococcus granulosus and another group of six with Taenia pisiformis. Samples were floated with supersaturated sugar solution and centrifuged. The upper portion of each tube (500 MUl) was aspirated and deposited in 1.5 ml tubes. Three tubes from each group were incubated at -20 degrees C and then at 90 degrees C, the remaining three from each group, incubated at room temperature. Proteinase K and lysis buffer were added to each tube and incubated for 12 h at 58 degrees C. The lysis effect was evaluated by microscopy at 3, 6 and 12 h and integrity by electrophoresis in 1% agarose gels. With the same experimental scheme, the thermal shock effect was evaluated in extractions of 1, 2, 3 and 4 eggs of each species and the DNA was quantified. Additionally, the protocol was applied in samples of 4 dogs diagnosed with natural infection by Taeniidae worms. Finally, all the extractions were tested by PCR amplification. Both E. granulosus and T. pisiformis eggs showed a similar response in the tests. In samples without treatment, the lysis effect was poor and showed no differences over time, but in those subjected to thermal shock, eggs degradation increased with time. In both treatments, there was no DNA loss integrity. The protocol applied to limited amounts of eggs yielded PCR products in 100% of the samples exposed to thermal shock, allowing PCR amplifications up to 1 egg. In non-exposed samples, the results were not replicable. However, DNA quantification showed low values in both treatments. In turn, DNA extractions with thermal shock in infected dog samples finally yielded PCR amplifications in 100%. It was concluded that thermal shock facilitates the DNA extraction for molecular analysis in taeniid eggs. The technique is effective extracting DNA even from a single egg and also to analyze natural infections samples with a relatively simple implementation. PMID- 29407716 TI - Moderating role of positive aspects of caregiving in the relationship between depression in persons with Alzheimer's disease and caregiver burden. AB - Improving caregivers' positive perception of their role may be important in reducing their subjective burden when caring for Alzheimer's disease (AD) patients with depression. The purpose of present study was to explore the moderating role of the positive aspects of caregiving (PAC) on the subjective burden on family caregivers when managing depressive behaviors. We conducted a cross-sectional study including 200 pairs of patients with mild AD and their caregivers from three communities and two hospitals in Taiyuan, China in October 2014. The latent variable interaction model based on a two stage least squares (2SLS) regression was fitted. A significant moderating effect of the PAC was found on the relationship between depression in patients with AD and the caregiver burden they cause. Caregivers dealing with patients with low levels of depression but with high levels of the PAC had significantly lower levels of caregiver burden compared to those caregivers with the low levels of PAC. Continuously detecting the patient's mental state combined with caregivers having an optimistic attitude towards life may improve the quality of life for both patients and caregivers. PMID- 29407717 TI - Everyday false memories in older persons with depressive disorder. AB - Generally we tend to think that memory in daily living is complete and accurate in healthy persons. However, current memory research has revealed inconspicuous memory faults. Rarely omissions and distortions of memory are researched with tasks resembling everyday life. We investigated healthy older control subjects (HC) and patients with depressive disorder (DD). Cognitive function was assessed with a comprehensive neuropsychological test battery and mood with the Montgomery Asberg Depression Scale (MADRS). We assessed everyday veridical and distorted memories on showing participants original news and commercials. In most aspects of attention, executive functions, and memory, patients with DD performed worse than HC. Regarding memory content on viewing news or commercials the difference between patients with DD and HC was more pronounced for false memory content than for veridical memory content. Linear regression analysis showed the extent of false memory content being associated with mental flexibility as assessed with the Trail Making Test and mood as assessed with the MADRS for both information obtained on viewing news and commercials. Increase of false memories impedes overall accuracy of memory more than decrease of veridical memories in older persons with depressive disorder. Diminished executive functions and depressive mood partly explain these memory distortions. PMID- 29407719 TI - Measuring bias against disconfirmatory evidence: An evaluation of BADE task scoring methods and the case for a novel method. AB - Research suggests that bias against disconfirmatory evidence (BADE) may help maintain delusions in the face of overwhelming evidence against them. Much of this research has employed Woodward and colleagues' BADE task. Different methods of scoring this task, many of which have significant drawbacks, are currently used by researchers, making it difficult to compare results across studies of BADE. Continued advancement of BADE research demands a scoring method with more favorable psychometric properties that is used more consistently by researchers. Here, we take a data-driven but theory-informed approach to the development of a new method for scoring the BADE task. This new scoring procedure is more parsimonious than previous metrics of BADE but captures the vast majority of their predictive variance in relation to delusions. This new method may therefore be capable of inspiring consensus use among BADE researchers. If so, it could significantly increase the ease of comparing future studies of BADE. PMID- 29407718 TI - Neurocognitive correlates of treatment response in children with Tourette's Disorder. AB - This paper examined neurocognitive functioning and its relationship to behavior treatment response among youth with Tourette's Disorder (TD) in a large randomized controlled trial. Participants diagnosed with TD completed a brief neurocognitive battery assessing inhibitory functions, working memory, and habit learning pre- and post-treatment with behavior therapy (CBIT, Comprehensive Behavioral Intervention for Tics) or psychoeducation plus supportive therapy (PST). At baseline, youth with tics and Attention Deficit Hyperactivity Disorder (ADHD) exhibited some evidence of impaired working memory and simple motor inhibition relative to youth with tics without ADHD. Additionally, a small negative association was found between antipsychotic medications and youth's performance speed. Across treatment groups, greater baseline working memory and aspects of inhibitory functioning were associated with a positive treatment response; no between-group differences in neurocognitive functioning at post treatment were identified. Within the behavior therapy group, pre-treatment neurocognitive status did not predict outcome, nor was behavior therapy associated significant change in neurocognitive functioning post-treatment. Findings suggest that co-occurring ADHD is associated with some impairments in neurocognitive functioning in youth with Tourette's Disorder. While neurocognitive predictors of behavior therapy were not found, participants who received behavior therapy exhibited significantly reduced tic severity without diminished cognitive functioning. PMID- 29407720 TI - The association between satisfaction with husband's participation in housework and suicidal ideation among married working women in Korea. AB - Although married women are increasingly participating in paid labor, housework remains their primary responsibility. This uneven distribution of housework could have a negative impact on their mental health. In this study, we examined the association between satisfaction with husbands' participation in housework and suicidal ideation in married working women. Data were obtained from 3544 participants of the fourth and fifth waves of the Korean Longitudinal Survey of Women and Families. Satisfaction with husbands' participation in housework was classified as satisfactory, less satisfactory, and dissatisfactory. A generalized estimating equations model was used to examine the association. Those who were dissatisfied with their husbands' participation in housework were 2.65 times more likely to think about suicide than those who were satisfied. Subgroup analysis showed that women with an egalitarian gender ideology or low job dissatisfaction were more likely to think about suicide when they were dissatisfied with their husbands' participation in housework. In conclusion, married working women who were dissatisfied with their husbands' participation in housework are more likely to think about suicide than those who are satisfied. Therefore, fostering an environment of fair distribution of housework is necessary for alleviating their stress from the dual burden of work and family. PMID- 29407721 TI - Comparison of residual depressive symptoms and functional impairment between fully and partially remitted patients with major depressive disorder: a multicenter study. AB - This study compared residual depressive and somatic symptoms and functional impairment between remitted and partially remitted patients with major depressive disorder (MDD), and explored the associations of functioning with demographic and clinical characteristics including residual depressive symptoms. Altogether, 1503 outpatients with MDD formed the study sample. Residual symptoms and psychosocial functioning were measured using standardized instruments. Approximately half (51.2%) of the patients who responded to antidepressant treatment achieved remission ('remitters'), while the rest who responded to treatment achieved only partial remission ('non-remitters'). Residual mood symptoms in remitters included sleep disturbances (66.6%), fatigue (32.3%), decreased concentration (31.3%), appetite/weight disturbances (28.8%), psychomotor changes (23.2%), sad mood (21.9%) and loss of interest (21.1%) measured by the Quick Inventory of Depressive Symptomatology-Self-Report. Residual somatic symptoms included headache (31.9%), intestinal complaints (31.3%), heart pounding/racing (26.3%), gastric complaints (22.3%), dizziness (22.2%) and stomach pain (20.6%) measured by the Patient Health Questionnaire-15. Such residual symptoms were even more frequent in the 'non-remitters' group. Residual symptoms of fatigue, psychomotor changes, sleep disturbance and appetite/weight disturbance contributed to impairment of all functional domains. Given the negative impact of residual symptoms on psychosocial functioning, more attention needs to be paid to the assessment and treatment of residual depressive symptoms. PMID- 29407722 TI - Validation of the Spanish and Catalan versions of the Health of the Nation Outcome Scale for Children and Adolescents (HoNOSCA). AB - Outcome measurement in outpatient and day-care mental health facilities for children and adolescents in Spain remains limited, in part due to a lack of validated scales. To address this issue, we translated HoNOSCA (glossary, score sheet, self-rated questionnaire, and parent/legal guardian questionnaire) into Spanish and Catalan using a reverse translation approach. We ascertained the validity and psychometric quality of the HoNOSCA in Spanish by assessing correlation with the Children's Global Assessment Scale (C-GAS). We recruited 64 participants 7-17 years of age in five day-care Psychiatry hospitals in Catalonia (Spain). Two evaluators administered both instruments twice, two weeks apart. Patients and parents/legal guardians completed the corresponding HoNOSCA versions. We calculated Cronbach's alpha for assessing internal consistency, intra-class correlation coefficients (ICC) for inter-rater and test-retest reliability, and Pearson's correlation coefficients for validity. We found that all HoNOSCA versions in Spanish presented satisfactory internal consistency, inter-rater and test-retest reliability. Concurrent validity for HoNOSCA-Glossary was also acceptable, with Pearson's coefficients of -0.543 and -0.519 for evaluators in the first administration, and of -0.675 and -0.685 in the second administration. HoNOSCA was also successfully translated into Catalan; acceptability was determined using cognitive interviews. PMID- 29407723 TI - The Recovery Assessment Scale - Domains and Stages (RAS-DS): Sensitivity to change over time and convergent validity with level of unmet need. AB - There is a need for robust outcome measures for use in psychiatric services. Particularly lacking are self-rated recovery measures with evidence of sensitivity to change. This study was established to examine the convergent validity and sensitivity to change over time (responsiveness) of the Recovery Assessment Scale - Domains and Stages (RAS-DS), in comparison to level of unmet need as measured by the Camberwell Assessment of Need - Short Appraisal Scale (CANSAS). Convergent validity was examined through cross-sectional correlations between 540 CANSAS and RAS-DS scores collected on the same day for the same individuals. Sensitivity to change was examined using correlations between change scores in CANSAS and RAS-DS where both were collected on the same day and the two time points were separated by 90 days or more (n = 498). Results demonstrated moderate, significant cross-sectional correlations between CANSAS scores and RAS DS total and domain scores and between change scores of both instruments. Results suggest that the RAS-DS is sensitive enough to detect change over time. Only moderate correlation between the RAS-DS and CANSAS suggests that, in the context of recovery-oriented service provision, it is important to measure self-reported recovery in addition to level of unmet needs. PMID- 29407724 TI - A taxometric investigation of psychopathy in women. AB - The taxonomic status of psychopathy is the topic of considerable research interest. The latent structure of psychopathy will latent structure will guide the determination of the best assessment approaches, maximize the reliability and validity, will help to establish optimal cutting scores that minimize decision errors and will also facilitate the selection of the best research designs to advance the study of the construct. In the present study, taxometric analyses were used for assessing taxonicity, and they were applied to Psychopathy Checklist-Revised (PCL-R) ratings of 1218 female offenders. Hare's four-factor solution to the PCL-R was used as the bases of the analyses. The results of the various analytical strategies obtained dimensional solutions and corroborated that for females, as well as for males, psychopathy as measured by the PCL-R, may best be conceptualized as distinct configurations of extreme scores on personality traits rather than as a distinct, nonarbitrary class. These results reaffirm the fact that cut-off scores of are arbitrary in nature. PMID- 29407725 TI - Heart rate reactivity to trauma-related imagery as a measure of PTSD symptom severity: Examining a new cohort of Veterans. AB - For over three decades, there has been considerable research documenting increased physiological reactivity to trauma-related stimuli as a characteristic feature of posttraumatic stress disorder (PTSD). The present study explored the potential for physiological assessment to aid in defining and validating screening criteria for the presence of significant PTSD-related symptoms in a sample of OEF/OIF/OND Veterans seeking care in a VA post-deployment health clinic. Heart rate reactivity scores during the imagining phase of the script driven imagery paradigm were compared across groups of individuals with and without probable PTSD diagnoses, as defined by PCL-IV cutoff scores ranging from 40 to 60. Significant differences were found for groups defined by PCL-IV cutoff scores of 50 and 60, with 50 producing the largest effect size. Diagnosing PTSD is made challenging by the presence of overlapping symptoms shared with other diagnoses, as well as by the necessity for patients to accurately report their symptoms. An objective physiological measure capable of accurately differentiating individuals with and without PTSD provides potential adjunctive diagnostic and treatment information to clinicians. The present findings support the validity of physiological reactivity during SDI as a NIMH RDoC measure that can be used in research and clinical applications assessing trauma-related symptom severity. PMID- 29407726 TI - Clinical predictors of gaming abstinence in help-seeking adult problematic gamers. AB - Research into the effectiveness of interventions for problematic gaming has been limited by a lack of data concerning the clinical characteristics of voluntary treatment-seekers; the nature and history of their gaming problems; and, their reasons for seeking help. The study aimed to identify variables predictive of short-term commitment to gaming abstinence following initial voluntary contact with an online help service. A total of 186 adult gamers with gaming-related problems were recruited online. Participants completed the DSM-5 Internet gaming disorder (IGD) checklist, Depression Anxiety Stress Scales-21, Internet Gaming Cognition Scale, Gaming Craving Scale, and Gaming Quality of Life Scale. A one week follow up survey assessed adherence with intended gaming abstinence. Abstainers were less likely to have withdrawal symptoms and less likely to play action shooting games. Participants with mood symptoms (40% of the total) reported significantly more IGD symptoms, stronger maladaptive gaming cognitions (e.g., overvaluing game rewards), more previous occurrences of gaming problems, and poorer quality of life. However, mood symptoms did not predict abstinence from or continuation of gaming. Adults with gaming disorder seeking help to reduce their gaming may benefit initially from strategies that manage withdrawal and psychoeducation about riskier gaming activities. PMID- 29407727 TI - DNA redox modulations and global DNA methylation in bipolar disorder: Effects of sex, smoking and illness state. AB - DNA redox modulations and methylation have been associated with bipolar disorder (BD) pathophysiology. We aimed to investigate DNA redox modulation and global DNA methylation and demethylation levels in patients with BD during euthymia, mania or depression in comparison to non-psychiatric controls. The roles of sex and smoking as susceptibility factors for DNA redox modulations and global DNA methylation and demethylation were also explored. Levels of 5-methylcytosine (5 mC), 5-hydroxymethylcytosine (5-hmC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were assessed in DNA samples of 75 patients with DSM-IV BD type I (37 euthymic, 18 manic, 20 depressive) in comparison to 60 non-psychiatric controls. Levels of 5-mC and 5-hmC were assessed using Dot Blot as a screening process, and verified using ELISA. Levels of 8-OHdG were assessed using ELISA. The levels of 8-OHdG significantly differed among non-psychiatric control, euthymia, mania and depression groups [F (3,110) = 2.771, p = 0.046], whereas there were no alterations in the levels of 5-hmC and 5-mC. Linear regression analyses revealed the significant effects of smoking (p = 0.031) and sex (p = 0.012) as well as state of illness on the levels of 8-OHdG (p = 0.025) in patients with BD. Our results suggest that levels of 8-OHdG may be affected by sex, illness states and smoking in BD. PMID- 29407728 TI - Strain differences in the development of cisplatin-induced pica behavior in mice. AB - INTRODUCTION: Pica behavior, kaolin ingestion, in rats and mice can be used as an assessment of nausea and vomiting; however, we observed that the incidence of pica behavior in ICR strain mice varied markedly. We investigated the susceptibility of four strains of mice (ICR, BALB/c, C57BL/6, and DBA/2) to the development of pica behavior. METHODS: Mice received cisplatin (7.5 mg/kg, i.p.) with or without a serotonin 5-HT3 receptor antagonist (granisetron: 0.1 mg/kg, i.p.) or tachykinin NK1 receptor antagonist (fosaprepitant: 30 mg/kg, i.p.), and then their daily kaolin intake was measured for 2 days. We examined the expression of preprotachykinin (PPT)-A mRNA in the medulla of cisplatin-treated mice 8 and 32 h after drug administration. RESULTS: All mice except for ICR strain significantly increased kaolin intake after cisplatin administration. Among the tested strains, DBA/2 mice compared to BALB/c and C57BL/6 mice notably showed pica behavior on both days (P < 0.0001). The expression of PPT-A mRNA was significantly increased 8 h after cisplatin administration in all strains, but the increase remained on the second day only in DBA/2 mice (P < 0.05). Granisetron significantly inhibited pica behavior in DBA/2 mice on the first day (P < 0.0001), but not the second day; however, fosaprepitant completely inhibited the pica behavior on both days (P < 0.001). DISCUSSION: These results indicate that cisplatin-induced pica behavior in mice is likely to be influenced by the genotype, and that DBA/2 mice are useful to analyze the emetogenic or anti-emetic potential of drugs in preclinical studies. PMID- 29407730 TI - Physiological and psychosocial factors in spiritual needs attainment for community-dwelling older adults. AB - BACKGROUND: Spiritual well-being enhances older persons' health status. Factors that optimize their spiritual well-being are not well-established. OBJECTIVE: To describe spiritual needs attainment and identify factors associated with such attainment among community-dwelling older persons. DESIGN: Cross-sectional. SETTING: Sixty-five U.S. continuing care retirement communities or independent housing facilities. SUBJECTS: 4077 persons entering the facilities between January 1, 2007 and November 30, 2016. METHODS: Standardized Community Health Assessment and Wellness Survey instruments were used to determine the proportion of subjects reporting their spiritual needs were met. Multivariate logistic regression identified characteristics independently associated with this outcome. RESULTS: Among the 4077 subjects (mean age 81.6 +/- 7.5; male, 28.8%; and White race, 70.7%), 93.4% stated their spiritual needs were met. Factors independently associated with a greater likelihood of spiritual needs attainment were: satisfaction with life (adjusted odds ratio (AOR) 2.81, 95% confidence interval (CI) 2.00, 3.96; p < 0.001), feeling valued (AOR 2.51, 95% CI 1.61, 3.92; p < 0.001), strong and supportive family relationship (AOR 1.99, 95% CI 1.20, 3.29; p = 0.008), sufficient sleep (AOR 1.59, 95% CI 1.15, 2.19; p = 0.005), no pain (AOR 1.35, 95% CI 1.01, 1.82; p = 0.046), and having someone to talk to about death among those interested in doing so (AOR 0.39, 95% CI 0.29, 0.54; p < 0.001). CONCLUSIONS: The majority of community-dwelling older persons reported their spiritual needs were met. Adequate sleep, pain relief, and having a person with whom to discuss death are potentially modifiable factors that may promote spiritual needs attainment in this population, which in turn, may improve their health outcomes. PMID- 29407729 TI - Dissipation of transmembrane potassium gradient is the main cause of cerebral ischemia-induced depolarization in astrocytes and neurons. AB - Membrane potential (VM) depolarization occurs immediately following cerebral ischemia and is devastating for the astrocyte homeostasis and neuronal signaling. Previously, an excessive release of extracellular K+ and glutamate has been shown to underlie an ischemia-induced VM depolarization. Ischemic insults should impair membrane ion channels and disrupt the physiological ion gradients. However, their respective contribution to ischemia-induced neuronal and glial depolarization and loss of neuronal excitability are unanswered questions. A short-term oxygen glucose deprivation (OGD) was used for the purpose of examining the acute effect of ischemic conditions on ion channel activity and physiological K+ gradient in neurons and glial cells. We show that a 30 min OGD treatment exerted no measurable damage to the function of membrane ion channels in neurons, astrocytes, and NG2 glia. As a result of the resilience of membrane ion channels, neuronal spikes last twice as long as our previously reported 15 min time window. In the electrophysiological analysis, a 30 min OGD-induced dissipation of transmembrane K+ gradient contributed differently in brain cell depolarization: severe in astrocytes and neurons, and undetectable in NG2 glia. The discrete cellular responses to OGD corresponded to a total loss of 69% of the intracellular K+ contents in hippocampal slices as measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). A major brain cell depolarization mechanism identified here is important for our understanding of cerebral ischemia pathology. Additionally, further understanding of the resilient response of NG2 glia to ischemia-induced intracellular K+ loss and depolarization should facilitate the development of future stroke therapy. PMID- 29407731 TI - Evaluating health-related quality of life impact of chronic conditions among older adults from a rural town in Suzhou, China. AB - This study aimed to estimate the loss of health-related quality of life (HRQOL) associated with common chronic conditions in older Chinese population.Weitang Geriatric Diseases Study is a community-based health survey on 5557 Chinese aged 60 years or older. The study population was measured with EQ-5D-3L for HRQOL assessment. We also assessed the coexisting chronic conditions of depression, cognitive dysfunction, stroke, heart disease, diabetes, hypertension, obesity, hyperlipidemia and visual impairment based on self-completed questionnaires, biomarkers and medical records. Ordinary Least Square regression was performed to model the relationship between the conditions and the EQ-5D-3L index scores. The robust standard error (RSE) estimator was adopted to calculate 95% confidence interval (CI) for coefficients. The mean EQ-5D-3L representing overall HRQOL was 0.954 (standard deviation: 0.081) with 70% of participants reporting full health. After controlling for socio-demographic characteristics and comorbidities, depression, stroke, heart disease and cognitive dysfunction had significantly adverse impact on the EQ-5D index score. The respective coefficients (95% CI) of each condition were -0.191 (-0.233, -0.150), -0.052 (-0.086, -0.019), -0.019 ( 0.029, -0.010), and -0.016 (-0.024, -0.008). Chronic conditions were found to contribute to HRQOL loss in older Chinese population. The utility and utility decrement estimated can be used for quality-adjusted life-year calculation. PMID- 29407732 TI - Trace elements in Polytrichum commune and Polytrichastrum formosum from the Karkonosze Mountains (SW Poland). AB - The Karkonosze National Park, an unique mountainous biosphere reserve, is influenced by long-distance anthropogenic atmospheric transport of among others trace elements and additionally by local tourist centres, which may be supplementary sources of pollution. Discharged trace elements are non-degradable, and their level must be precisely monitored. Therefore, the concentrations of As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Rb and Zn in Polytrichum commune and Polytrichastrum formosum collected from the Karkonosze sites influenced only by long-range pollution and from sites in the vicinity of local tourist centres were established. P. commune and P. formosum revealed the ability to accumulate higher concentrations of trace elements while growing in locally contaminated sites in comparison with sites free from such pollution. Therefore, both species may be utilised for bioindication in the Karkonosze National Park. Elevated levels of trace elements in both species (except for Hg) in comparison with concentrations typical for mosses from unpolluted sites point to the existence of pollution of this area. P. commune was a better bioindicator of Cd, Co, Cr, Cu, Mo, Ni, Pb and Rb than P. formosum, probably because of the larger gametophytes and its morphology, which appears prone to an increased uptake of trace elements from the atmosphere. PMID- 29407733 TI - Ability of natural attenuation and phytoremediation using maize (Zea mays L.) to decrease soil contents of polycyclic aromatic hydrocarbons (PAHs) derived from biomass fly ash in comparison with PAHs-spiked soil. AB - A 120-day pot experiment was conducted to compare the ability of natural attenuation and phytoremediation approaches to remove polycyclic aromatic hydrocarbons (PAHs) from soil amended with PAHs-contaminated biomass fly ash. The PAH removal from ash-treated soil was compared with PAHs-spiked soil. The removal of 16 individual PAHs from soil ranged between 4.8% and 87.8% within the experiment. The natural attenuation approach led to a negligible total PAH removal. The phytoremediation was the most efficient approach for PAH removal, while the highest removal was observed in the case of ash-treated soil. The content of low molecular weight (LMW) PAHs and the total PAHs in this treatment significantly decreased (P <.05) over the whole experiment by 47.6% and 29.4%, respectively. The tested level of PAH soil contamination (~1600 ug PAH/kg soil dry weight) had no adverse effects on maize growth as well on the biomass yield. In addition, the PAHs were detected only in maize roots and their bioaccumulation factors were significantly lower than 1 suggesting negligible PAH uptake from soil by maize roots. The results showed that PAHs of ash origin were similarly susceptible to removal as spiked PAHs. The presence of maize significantly boosted the PAH removal from soil and its aboveground biomass did not represent any environmental risk. PMID- 29407734 TI - Short-term assessment of cadmium toxicity and uptake from different types of Cd based Quantum Dots in the model plant Allium cepa L. AB - We report on the toxicity and bioaccumulation of three different types of Cd based quantum dots (QDs), dispersed in aqueous medium, for a model plant Allium cepa L. It is believed that encapsulation of nanoparticles should reduce their toxicity and increase their stability in different environments; in this work we studied how QD encapsulation affects their phytotoxicity. Core, core/shell, and core/shell/shell QDs (CdTe, CdTe/ZnS, and CdTe/CdS/ZnS QDs capped by 2 mercaptopropionic acid) were tested and CdCl2 was used as a positive control. After 24-h and 72-h exposure, total Cd content (MCd) and bioaccumulation factors (BAFs) were determined in all parts of A. cepa plants (roots, bulb, shoot), and the total length of the root system was monitored as a toxicity end-point. Measurements of total Cd content versus free Cd2+ content (with Differential Pulse Voltammetry, DPV) in exposure media showed differences in chemical stability of the three QD types. Correspondingly, selected QDs showed different toxicity for A. cepa and different Cd bioaccumulation patterns. CdTe QDs were the most toxic; their effect was similar to CdCl2 due to the release of free Cd2+, which was confirmed by the DPV measurements. Plants exposed to CdTe QDs also bioaccumulated the most Cd among all QD exposure groups. CdTe/ZnS QDs showed no toxicity and very low bioaccumulation of Cd in A. cepa; the main source of measured Cd in the plants were QDs adsorbed on their roots, which was confirmed by fluorescence microscopy. On the contrary, CdTe/CdS/ZnS QD toxicity and bioaccumulation patterns were similar to those of CdTe QDs and pointed to unstable CdS/ZnS shells. PMID- 29407735 TI - Energetic contaminants inhibit plant litter decomposition in soil. AB - Individual effects of nitrogen-based energetic materials (EMs) 2,4-dinitrotoluene (2,4-DNT), 2-amino-4,6-dinitrotoluene (2-ADNT), 4-amino-2,6-dinitrotoluene (4 ADNT), nitroglycerin (NG), and 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (CL 20) on litter decomposition, an essential biologically-mediated soil process, were assessed using Orchard grass (Dactylis glomerata) straw in Sassafras sandy loam (SSL) soil, which has physicochemical characteristics that support "very high" qualitative relative bioavailability for organic chemicals. Batches of SSL soil were separately amended with individual EMs or acetone carrier control. To quantify the decomposition rates, one straw cluster was harvested from a set of randomly selected replicate containers from within each treatment, after 1, 2, 3, 4, 6, and 8 months of exposure. Results showed that soil amended with 2,4-DNT or NG inhibited litter decomposition rates based on the median effective concentration (EC50) values of 1122 mg/kg and 860 mg/kg, respectively. Exposure to 2-ADNT, 4-ADNT or CL-20 amended soil did not significantly affect litter decomposition in SSL soil at >= 10,000 mg/kg. These ecotoxicological data will be helpful in identifying concentrations of EMs in soil that present an acceptable ecological risk for biologically-mediated soil processes. PMID- 29407736 TI - Assessment of exposure to polybrominated diphenyl ethers associated with consumption of market hens in Guangzhou. AB - To evaluate contamination by polybrominated diphenyl ethers (PBDEs) in market hens and human PBDE exposure via hen consumption in Guangzhou, hens were collected and their muscle, liver, fat, blood, yolk, and ingluvies tissues were analyzed for 13 PBDE congeners. The median highest concentration of ?PBDEs was found in the ingluvies (5.30 ng/g lw), followed by the muscle (2.53 ng/g lw), with the lowest located in the yolk (0.09 ng/g lw). The concentrations of PBDEs in the muscle tissue of market hens in Guangzhou were at medium levels compared to others reported around the world. BDE-47, -153, -99, and -183 were the predominant congeners. The daily intake concentrations of PBDEs from hen muscle were estimated to range from 0.08 to 0.31 ng/kg/day in this study, with a Hazard Quotient (HQ) below 1.0. These results suggest that the health risk of PBDEs for the general population, through the consumption of market hens in Guangzhou, was generally low. However, the intake of PBDEs via food consumption may be one major exposure pathway for the general population of Guangzhou. PMID- 29407737 TI - Enhancing the fathead minnow fish embryo toxicity test: Optimizing embryo production and assessing the utility of additional test endpoints. AB - The fathead minnow fish embryo toxicity (FET) test has been identified as a potential alternative to toxicity test methods that utilize older fish. However, several challenges have been identified with the fathead minnow FET test, including: 1) difficulties in obtaining appropriately-staged embryos for FET test initiation, 2) a paucity of data comparing fathead minnow FET test performance to the fathead minnow larval growth and survival (LGS) test and 3) a lack of sublethal endpoints that could be used to estimate chronic toxicity and/or predict adverse effects. These challenges were addressed through three study objectives. The first objective was to optimize embryo production by assessing the effect of breeding group composition (number of males and females) on egg production. Results showed that groups containing one male and four females produced the largest clutches, enhancing the likelihood of procuring sufficient numbers of embryos for FET test initiation. The second study objective was to compare the performance of the FET test to that of the fathead minnow LGS test using three reference toxicants. The FET and LGS tests were similar in their ability to predict the acute toxicity of sodium chloride and ethanol, but the FET test was found to be more sensitive than the LGS test for sodium dodecyl sulfate. The last objective of the study was to evaluate the utility and practicality of several sublethal metrics (i.e., growth, developmental abnormalities and growth- and stress-related gene expression) as FET test endpoints. Developmental abnormalities, including pericardial edema and hatch success, were found to offer the most promise as additional FET test endpoints, given their responsiveness, potential for predicting adverse effects, ease of assessment and low cost of measurement. PMID- 29407738 TI - Effects of treated industrial wastewaters and temperatures on growth and enzymatic activities of duckweed (Lemna minor L.). AB - The efficacy of the removal of contaminants from wastewater depends on physico chemical properties of pollutants and the efficiency of treatment plant. Sometimes, low amounts of toxic compounds can be still present in the treated sewage. In this work we considered the effects of contaminant residues in treated wastewaters and of temperatures on Lemna minor L. Treated effluent waters were collected, analyzed and used as duckweed growth medium. In order to better understand the effects of micropollutants and seasonal variation, the plants were grown under ambient conditions for seven days in summer and winter. Relative growth rate, pigments and phenolic compounds concentrations were determined, as well as the activities of catalase (CAT), ascorbate peroxidase (APX), guaiacol peroxidase (G-POD) and polyphenol oxidase (PPO). The pollutant concentrations varied in the two seasons, depending on the industrial and municipal activities and efficiency of treatments. Treated waters contained heavy metals, nitrogenous and phosphorus compounds, surfactants and hydrocarbons. Compared to the control, duckweed growth of treated plants decreased by 25% in summer, while in the winter due to the lower temperatures and the presence of pollutants was completely impeded. The amounts of photosynthetic pigments of treated plants were not significantly affected in the summer, while they were higher than the control in the winter when the effluent had a high nitrogen amount. High CAT activity was registered in both seasons. Treated plants had significantly lower APX activity in the summer (53%) and winter (59%) respect to the controls. The observed inhibition of the peroxidase activities in the exposed plants, confirms the controversy existing in the literature about the variability of enzymatic response in stress condition. PMID- 29407739 TI - Fish as a bioindicator of heavy metals pollution in aquatic ecosystem of Pluszne Lake, Poland, and risk assessment for consumer's health. AB - Heavy metals content (Zn, Cu and Hg) were measured in gills, liver, gonads and muscles of perch, Perca fluviatilis (L.) and roach, Rutilus rutilus (L.) from Lake Pluszne (north-eastern Poland). Correlations between heavy metals levels and total length, weight, HSI, GSI and FCF were examined. As expected, muscles contained the significantly highest values of Hg (P <= .05). The concentrations of Zn were significantly higher in gills of roach and gonads of perch (P <= .05), while the liver of fish accumulated significantly more Cu than other organs (P <= .05). In all organs of perch the higher content of mercury was found (P <= .05). The value of Zn and Cu was highest in organs of roach (P <= .05) (with the exception of Zn in muscles P > .05). Sequence of metals in both species was Zn > Cu > Hg. Only in muscle tissue, Hg was significantly positive correlated with weight of roach (r = 0.811, P = .045) and perch (r = 0.652, P = .041), and total length of roach (r = 0.806, P = .005). A positive relationship was also observed between Zn concentration in gills of perch and their weight (r = 0.634, P = .049). In contrary, Zn in gills of roach decreased with weight (r = -0.693, P = .026)) and length (r = -0.668, P = .035). Cu concentration in liver of perch was statistically positively correlated with HSI (r = 0.717, P = .020), whereas Hg content in muscle tissue of roach with FCF (r = 0.643, P = .045). There was negative relationship between Hg in perch gonads and GSI (r = -0.808, P = .005). Metal pollution index (MPI) in gills, liver, gonads and muscles of roach was 7.68, 7.24, 6.77 and 3.13, respectively, whereas in these organs of perch was 3.25 (gills), 4.75 (liver), 5.84 (gonads) and 4.44 (muscles), therefore the contamination of each tissue ranged from very low contamination to low contamination. The concentration of mercury was lower than the maximum acceptable limit estimated by the Commission Regulation (EC) No 629/2008 of 2 July 2008. The values of HI and THQ were below 1, which means that consumption of these fish is not hazardous to the consumer. PMID- 29407740 TI - Use of portable X-ray fluorescence spectroscopy and geostatistics for health risk assessment. AB - Laboratory analysis of trace metals using inductively coupled plasma (ICP) spectroscopy is not cost effective, and the complex spatial distribution of soil trace metals makes their spatial analysis and prediction problematic. Thus, for the health risk assessment of exposure to trace metals in soils, portable X-ray fluorescence (PXRF) spectroscopy was used to replace ICP spectroscopy for metal analysis, and robust geostatistical methods were used to identify spatial outliers in trace metal concentrations and to map trace metal distributions. A case study was carried out around an industrial area in Nanjing, China. The results showed that PXRF spectroscopy provided results for trace metal (Cu, Ni, Pb and Zn) levels comparable to ICP spectroscopy. The results of the health risk assessment showed that Ni posed a higher non-carcinogenic risk than Cu, Pb and Zn, indicating a higher priority of concern than the other elements. Sampling locations associated with adverse health effects were identified as 'hotspots', and high-risk areas were delineated from risk maps. These 'hotspots' and high risk areas were in close proximity to and downwind from petrochemical plants, indicating the dominant role of industrial activities as the major sources of trace metals in soils. The approach used in this study could be adopted as a cost effective methodology for screening 'hotspots' and priority areas of concern for cost-efficient health risk management. PMID- 29407741 TI - Molecular interaction of triclosan with superoxide dismutase (SOD) reveals a potentially toxic mechanism of the antimicrobial agent. AB - In this article, the interaction mechanism between the superoxide dismutase (SOD) and the triclosan (TCS), a kind of antimicrobial agent which is of widely application with potential effects both on environment and human health, was explored through a series of spectroscopic methods, animal experiment and the molecular docking simulation. The negative free energy change ?G, enthalpy change (?H = 162.21 kJmol-1) and entropy change (?S = 615 Jmol-1K-1) demonstrated that TCS could combine with SOD spontaneously through hydrophobic interaction to form a complex. The binding constants of Ka293 and Ka313 were 1.706 * 103 and 1.2 * 105 Lmol-1, respectively. Furthermore, the interaction could also influence the skeleton structure and secondary contents of SOD. The molecular docking analysis revealed the TCS located between two subunits of SOD, and there was a hydrogen bond between TCS and the residue Asn51 of SOD, which influenced the structure of protein and resulted in a decrease of enzyme activity. This work could help understand the interaction mechanism between SOD and TCS. Moreover, it could also be used to consult for toxicity assessment of TCS at molecular level. PMID- 29407742 TI - Single and mixture toxicity of strobilurin and SDHI fungicides to Xenopus tropicalis embryos. AB - The decline in amphibian populations is a critical threat to global biodiversity, and pesticide pollution is considered as one of the major factors. Although effects of single pesticides on amphibians have been documented, toxicological interactions prevailing in mixtures of pesticides have not been well elucidated. Strobilurin and succinate dehydrogenase inhibitor (SDHI) fungicides are new types of commonly used pesticides. In this study, effects of three strobilurins (pyraclostrobin, trifloxystrobin and azoxystrobin), two SDHIs (isopyrazam and bixafen), and their mixtures on X. tropicalis embryos were fully investigated. Results showed that exposure to individual fungicides induced lethal and teratogenetic effects; and malformed embryos displayed similar phenotypes including microcephaly, hypopigmentation, somite segmentation and narrow fin. Exposure to two strobilurins or two SDHIs at equitoxic concentrations caused additive or synergetic effects at environmentally relevant concentrations. TU for mixtures of isopyrazam and bixafen was 0.53 and 0.30 for lethal and teratogenic toxicity, respectively. Finally, binary mixtures of strobilurins and SDHIs also exhibited additive or synergetic effects on amphibian embryos. Overall, these results reveal that the mixtures of multiple fungicides caused a higher incidence of lethality and teratogenicity of amphibian embryos, compared to a single fungicide at the corresponding doses. Our findings provide important data about the ecotoxicology of agricultural fungicides on non-target organisms, which is useful for guiding management practices for pesticides. PMID- 29407743 TI - Removal characteristic of surfactants in typical industrial and domestic wastewater treatment plants in Northeast China. AB - Surfactants are widely used in household and industrial products for cleaning and/or solubilization in our daily life. Therefore, they are finally discharged into wastewater treatment plants (WWTPs), which may be the major point pollution source for environment if they were not completely removed during wastewater treatment. In this study, two typical industrial and domestic WWTPs with different wastewater treatment technologies were considered for the topic. Totally, two types of surfactants were analyzed in 24 h influent and each processing unit effluent. Four linear alkylbenzene sulfonates (LASs) with the alkyl chain from C10 to C13, and two benzalkonium chlorides (BACs) with the alkyl chain of C12 and C14 were selected as target compounds. The total concentrations of LASs in influent varied from 19.2 to 1889 MUg/L and LAS-C11 and LAS-C12 were the predominant compounds with the concentration from 6.01 to 641 MUg/L and 8.02 674 MUg/L, respectively. The total concentrations of BACs were much lower than those of LASs, with the concentration ranging from 0.00935 to 1.85 MUg/L. Significant positive correlations were observed between concentrations of LASs and BACs in influent, indicating their same and/or similar sources. Compared with the concentration of influent, the concentration of effluent was much lower, indicating the high removal efficiency by the two wastewater treatment processes. Biological treatment unit and cyclic activated sludge system were the main treatment units for the removing of surfactants, which suggested that these two types of surfactants can be easily degraded under aerobic condition. Seasonal variation indicated that the removal efficiencies of surfactants in autumn were a little higher than those in winter. The results of this study provided new insights into the environmental fate of surfactants in wastewater treatment system. PMID- 29407744 TI - Iron plaque formation and heavy metal uptake in Spartina alterniflora at different tidal levels and waterlogging conditions. AB - Tidal flat elevation in the estuarine wetland determines the tidal flooding time and flooding frequency, which will inevitably affect the formation of iron plaque and accumulations of heavy metals (HMs) in wetland plants. The present study investigated the formation of iron plaque and HM's (copper, zinc, lead, and chromium) accumulation in S. alterniflora, a typical estuarine wetland species, at different tidal flat elevations (low, middle and high) in filed and at different time (3, 6, 9, 12 h per day) of waterlogging treatment in greenhouse conditions. Results showed that the accumulation of copper, zinc, lead, and chromium in S. alterniflora was proportional to the exchangeable fraction of these metals in the sediments, which generally increased with the increase of waterlogging time, whereas the formations of iron plaque in roots decreased with the increase of waterlogging time. Under field conditions, the uptake of copper and zinc in the different parts of the plants generally increased with the tidal levels despite the decrease in the metals' exchangeable fraction with increasing tidal levels. The formation of iron plaque was found to be highest in the middle tidal positions and significantly lower in low and high tidal positions. Longer waterlogging time increased the metals' accumulation but decreased the formation of iron plaque in S. alterniflora. The binding of metal ions on iron plaque helped impede the uptake and accumulation of copper and chromium in S. alterniflora. PMID- 29407745 TI - Steps toward understanding the impact of early emotional experiences on disordered eating: The role of self-criticism, shame, and body image shame. AB - In research, it has been suggested that early threatening emotional experiences, characterized by abuse, rejection, neglect or absence of affiliative signals may activate maladaptive defensive responses. Further, several studies have emphasised the association between the recall of early emotional experiences and eating psychopathology. However, this relationship does not seem to be direct. Thus, the current study explored the mediator roles of self-criticism and shame (general and body image-focused shame) in the link between early emotional experiences and the engagement in disordered eating, while controlling for the effect of body mass index. The sample of this study included 552 female participants, aged between 18 and 40 years old. The path analysis indicated that the absence of early positive emotional experiences was associated with disordered eating behaviours, through an increased perception of being negatively perceived as inferior or unattractive by others, self-critical attitudes, and body image-focused shame. The tested model accounted for 63% of body image shame and for 67% of disordered eating's variance, and showed an excellent model fit. These findings suggest that shame and self-criticism are defensive mechanisms associated with early threatening emotional experiences, which may trigger disordered eating behaviours. These data appear to offer important research and clinical implications supporting the development of intervention community programs for body and eating difficulties, that specifically target shame (general and body image-focused shame) and self-criticism, through the development of more adaptive emotional regulation strategies. PMID- 29407746 TI - Premenstrual appetite and emotional responses to foods among women with premenstrual dysphoric disorder. AB - The aim of the study was to evaluate changes in late-luteal appetite for highly sweet (HS) and highly salty and fatty (HSF) foods in women with premenstrual dysphoric disorder (PMDD). After initial assessment in a psychiatric interview, the premenstrual symptoms screening tool (PSST) was used to identify women with moderate-to-severe premenstrual symptoms. Sixty-seven women with PMDD and 74 healthy controls were evaluated in the early-follicular and late-luteal (pre menstrual) phases of the menstrual cycle. Because the PSST is designed to assess symptoms only in the late-luteal phase, an 11-point Likert scale was used to rate PMDD symptoms once a week in the evaluation mentioned previously and the following two menstrual cycles. Participants were shown pictures of 15 highly sweet (HS) and 15 highly salty and fatty (HSF) foods, desire to eat each food was rated on an eleven-point Likert scale (0, "none at all"; 10, "extreme desire"), and sweet-food craving was rated using the food craving-state questionnaire. Emotional responses to the foods were measured with a four-point Likert scale we previously validated. Depression, irritability, and impulsivity were measured with standard psychiatric instruments. Women with PMDD, but not control women, had late-luteal phase elevations in desire to eat HS food, sweet-food craving and emotional responses to HS foods. Desire to eat for HSF foods did not differ significantly across the menstrual cycle between groups. There were significant correlations between emotional responses to and desire to eat HS foods. Moreover, late-luteal phase irritability and impulsivity scores were associated with desire to eat HS foods. These data suggest that targeted assessment of increased late luteal appetites for HS foods may facilitate clinical interventions in women with PMDD. PMID- 29407747 TI - Pre- and postprandial variation in implicit attention to food images reflects appetite and sensory-specific satiety. AB - Implicit attentional processes are biased toward food-related stimuli, with the extent of that bias reflecting relative motivation to eat. These interactions have typically been investigated by comparisons between fasted and sated individuals. In this study, temporal changes in implicit attention to food were assessed in relation to natural, spontaneous changes in appetite occurring before and after an anticipated midday meal. Non-fasted adults performed an emotional blink of attention (EBA) task at intervals, before and after consuming preferred, pre-selected sandwiches to satiety. Participants were required to detect targets within a rapid visual stream, presented after task-irrelevant food (preferred or non-preferred sandwiches, or desserts) or non-food distractor images. All categories of food distractor preferentially captured attention even when appetite levels were low, but became more distracting as appetite increased preprandially, reducing task accuracy maximally as hunger peaked before lunch. Postprandially, attentional capture was markedly reduced for images of the specific sandwich type consumed and, to a lesser extent, for images of other sandwich types that had not been eaten. Attentional capture by images of desserts was unaffected by satiation. These findings support an important role of selective visual attention in the guidance of motivated behaviour. Naturalistic, meal-related changes in appetite are accompanied by changes in implicit attention to visual food stimuli that are easily detected using the EBA paradigm. Preprandial enhancement of attention capture by food cues likely reflects increases in the incentive motivational value of all food stimuli, perhaps providing an implicit index of wanting. Postprandial EBA responses confirm that satiation on a particular food results in relative inattention to that food, supporting an important attentional component in the operation of sensory specific satiety. PMID- 29407748 TI - Characterization of a bioactive Jagged1-coated polycaprolactone-based membrane for guided tissue regeneration. AB - OBJECTIVE: The aim of the present study was to develop a Jagged1-coated polycaprolactone (PCL) membrane and to evaluate the response of human periodontal ligament cells (hPDL) on this membrane in vitro. METHODS: Membranes were prepared from PCL and PCL-incorporated hydroxyapatite (PCL/HA). The membranes' surface roughness, surface wettability, and mechanical properties were examined. An indirect affinity immobilization technique was used to coat the membranes with Jagged1. Membrane cytotoxicity was evaluated using LIVE/DEAD and MTT assays. The morphology of the cells on the membranes was observed using scanning electron microscopy. hPDL alkaline phosphatase (ALP) enzymatic activity and mineral deposition were examined using an ALP assay and Alizarin Red S staining, respectively. Notch target gene mRNA expression was determined using real-time polymerase chain reaction. RESULTS: The PCL/HA membranes exhibited a significantly reduced surface contact angle, decreased maximum tensile strain, and ultimate tensile stress. However, the surface roughness parameters were significantly increased. The PCL and PCL/HA membranes were not cytotoxic to hPDL in vitro. hPDLs attached and spread on both membrane types. Further, indirect affinity immobilized Jagged1 on the membranes upregulated hPDL Notch target gene expression. After culturing in osteogenic medium, Jagged1-immobilized PCL/HA membranes significantly enhanced hPDL ALP enzymatic activity. CONCLUSION: Indirect immobilized Jagged1 PCL/HA membranes could be further developed as an alternative guided tissue regeneration membrane to promote osteogenic differentiation in periodontal defects. PMID- 29407749 TI - Differentiation of stem cells from human deciduous and permanent teeth into spiral ganglion neuron-like cells. AB - OBJECTIVE: Stem cells from pulp tissue are a promising cell-based therapy for neurodegenerative patients based on their origin in the neural crest. The aim of this study was to differentiate and evaluate the ability of human dental pulp stem cells from permanent teeth (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) to differentiate into spiral ganglion neurons. DESIGN: After isolation and characterization of mesenchymal stem cell properties, DPSC and SHED were treated with the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell-derived neurotrophic factor (GDNF). The differentiation was identified by immunostaining and qRT-PCR analysis of neuronal markers and measuring intracellular calcium activity. RESULTS: After 2 weeks of induction, morphological changes were observed in both DPSC and SHED. The differentiated cells expressed neuron-specific class III beta-tubulin, GATA binding protein 3 (GATA3) and tropomyosin receptor kinase B, protein markers of spiral ganglion neurons. These cells also showed upregulation of the genes encoding these proteins, namely GATA3 and neurotrophic receptor tyrosine kinase 2. Intracellular calcium dynamics that reflect neurotransmitter release were observed in differentiated DPSC and SHED. CONCLUSION: These results demonstrate that dental pulp stem cells from permanent and deciduous teeth can differentiate into spiral ganglion neuron-like cells. PMID- 29407750 TI - Inhibitory effects of beta-caryophyllene on Streptococcus mutans biofilm. AB - OBJECTIVE: The biofilm of Streptococcus mutans is associated with induction of dental caries. Also, they produce glucan as an extracellular polysaccharide through glucosyltransferases and help the formation of cariogenic biofilm. beta caryophyllene has been used for therapeutic agent in traditional medicine and has antimicrobial activity. The purpose of this study was to investigate the effect of beta-caryophyllene on S. mutans biofilm and the expression of biofilm-related factor. DESIGN: The susceptibility assay of S. mutans for beta-caryophyllene was performed to investigate inhibitory concentration for S. mutans growth. To evaluated the effect of beta-caryophyllene on S. mutans biofilm, beta caryophyllene was treated on S. mutans in the various concentrations before or after the biofilm formation. Live S. mutans in the biofilm was counted by inoculating on Mitis-salivarius agar plate, and S. mutans biofilm was analyzed by confocal laser scanning microscope after staining bacterial live/dead staining kit. Finally, the expression of glucosyltransferases of S. mutans was investigated by real-time RT-PCR after treating with beta-caryophyllene at the non-killing concentration of S. mutans. RESULTS: The growth of S. mutans was inhibited by beta-caryophyllene in above concentration of 0.078%, S. mutans biofilm was inhibited by beta-caryophyllene in above 0.32%. Also, 2.5% of beta caryophyllene showed anti-biofilm activity for S. mutans biofilm. beta caryophyllene reduced the expression of gtf genes at a non-killing concentration for S. mutans. On the basis on these results, beta-caryophyllene may have anti biofilm activity and the inhibitory effect on biofilm related factor. CONCLUSIONS: beta-caryophyllene may inhibit cariogenic biofilm and may be a candidate agent for prevention of dental caries. PMID- 29407751 TI - Validation of a multiplex qPCR assay for the identification and quantification of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis: In vitro and subgingival plaque samples. AB - OBJECTIVE: To validate a multiplex qPCR (m-qPCR) assay for the simultaneous identification and quantification of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in subgingival samples. MATERIAL AND METHODS: In vitro samples: DNA combinations of A. actinomycetemcomitans and P. gingivalis in similar or different concentrations were prepared. qPCR and m-qPCR were performed using the same primers and hydrolysis probes specific for 16SrRNA genes. Results were analyzed using intra-class (ICCs) and Lin's correlation coefficients (r) based on quantification cycle (Cq) values. Subgingival plaque samples: a cross sectional study analyzing subgingival plaque samples harvested from periodontally healthy and chronic periodontitis patients. Samples were processed by either qPCR or m-qPCR targeting both bacteria. Sensitivity, specificity, predictive values and Lins correlation coefficients (r) were calculated using CFU/mL as primary outcome. RESULTS: In vitro samples: m-qPCR yielded a good reproducibility (coefficients of variation around 1% and ICCs > 0.99) for both bacterial species. m-qPCR achieved detection limits and specificity similar to qPCR. An excellent concordance (r = 0.99) was observed between m-qPCR and qPCR for A. actinomycetemcomitans and P. gingivalis without statistical significant differences between both methods Subgingival plaque samples: a high sensitivity (above 80%) and specificity (100%) was obtained with the m-qPCR for both bacteria. The m-qPCR yielded a good concordance in Cq values, showing a good level of agreement between qPCR and m-qPCR. CONCLUSION: The tested m-qPCR method was successful in the simultaneous quantification of A. actinomycetemcomitans and P. gingivalis, with a high degree of sensitivity and specificity on subgingival plaque samples. PMID- 29407752 TI - Presence of the esp gene in Enterococcus faecium derived from oropharyngeal microbiota of haematology patients. AB - OBJECTIVES: Antibiotic use and immunocompromised status in haematology patients have been shown to determine the constituents of commensal microbiota with highly increased resistance, including vancomycin resistant enterococci. We compared the carriage of virulence factor genes and the capacity for biofilm formation in vancomycin resistant enterococci (VRE) originating from the oropharyngeal and stool cultures of haematology patients. DESIGN: PCR tests were used to investigate the presence of genes encoding pathogenicity factors (esp and hyl) in VRE isolates. The genotype of vancomycin resistance was investigated by multiplex PCR tests for vanA and vanB genes. PFGE typing was conducted to exclude the duplicate isolates. RESULTS: Of 3310 pharyngeal swabs taken from inpatients at a clinic for haematology, Enterococcus species were recovered in 6.46%. All VRE investigated were identified as Enterococcus faecium and were highly vancomycin resistant. VanA genotype was confirmed in all. In the group of oropharyngeal carriers (n = 8 patients), 15 strains were recovered from oropharyngeal specimens and PFGE typing revealed 5 types and 3 subtypes. Identical types of VRE in the oropharynx and stool cultures were found in three patients from this group. In the group of stool carriers (n = 24 patients) VRE were obtained from stools only and placed in 21 macro-restriction patterns. The esp gene was more common in VRE isolated from the oropharynx than in isolates from stools (p = 0.014). Results were not significant when we compared the presence of hyl genes in oropharyngeal isolates with those from stool cultures (p = 0.66) or when we investigated the association between esp and hyl gene carriage and capability of biofilm formation in non-repeated VRE. CONCLUSIONS: In the present study, isolation of VRE from the oropharynx in haematology patients was associated with esp gene carriage. Further research is needed to investigate the clinical and long-term effects of this finding. PMID- 29407753 TI - Schisandrin C enhances odontoblastic differentiation through autophagy and mitochondrial biogenesis in human dental pulp cells. AB - OBJECTIVE: To investigate the role of Schisandrin C in odontoblastic differentiation, and its relations between autophagy and mitochondrial biogenesis in human dental pulp cells (HPDCs). DESIGN: Fresh third molars were used, and cultured for HDPCs. Western blotting technique, Alizarin red S staining, alkaline phosphatase (ALP) activity, and confocal microscopy were used to detect autophagy, mitochondrial biogenesis, and odontoblastic differentiation. To understand the mechanism of Schisandrin C, the HDPCs were treated with lipopolysaccharide (LPS), autophagy and heme oxygenase-1 (HO-1) inhibitors: 3 Methyladenine (3-MA) and Zinc protoporphyrin IX (ZnPP), respectively. RESULTS: LPS decreased the expression of autophagy molecules [autophagy protein 5 (ATG-5), beclin-1, and microtubule-associated protein 1A/1B light chain 3 (LC3-I/II)] and mitochondrial biogenesis molecules [heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha)], and disrupted odontoblastic differentiation. The down-regulation of autophagy and mitochondrial biogenesis with 3-MA and ZnPP inhibited odontoblastic differentiation. However, Schisandrin C restored the expression of all the above molecules, even with LPS and inhibitor treatment. This result demonstrates that autophagy and mitochondrial biogenesis plays an essential role in odontoblastic differentiation, and Schisandrin C activates these systems to promote odontoblastic differentiation of HDPCs. CONCLUSION: Schisandrin C has potential characters to regulate odontoblastic differentiation, and may be recommended for use as a compound for pulp homeostasis. PMID- 29407754 TI - Assessment of static and perfusion methods for decellularization of PCL membrane supported periodontal ligament cell sheet constructs. AB - OBJECTIVES: Decellularization aims to harness the regenerative properties of native extracellular matrix. The objective of this study was to evaluate different methods of decellularization of periodontal ligament cell sheets whilst maintaining their structural and biological integrity. DESIGN: Human periodontal ligament cell sheets were placed onto melt electrospun polycaprolactone (PCL) membranes that reinforced the cell sheets during the various decellularization protocols. These cell sheet constructs (CSCs) were decellularized under static/perfusion conditions using a) 20 mM ammonium hydroxide (NH4OH)/Triton X 100, 0.5% v/v; and b) sodium dodecyl sulfate (SDS, 0.2% v/v), both +/- DNase besides Freeze-thaw (F/T) cycling method. CSCs were assessed using a collagen quantification assay, immunostaining and scanning electron microscopy. Residual fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were assessed with Bio-plex assays. RESULTS: DNA removal without DNase was higher under static conditions. However, after DNase treatment, there were no differences between the different decellularization methods with virtually 100% DNA removal. DNA elimination in F/T was less efficient even after DNase treatment. Collagen content was preserved with all techniques, except with SDS treatment. Structural integrity was preserved after NH4OH/Triton X-100 and F/T treatment, while SDS altered the extracellular matrix structure. Growth factor amounts were reduced after decellularization with all methods, with the greatest reduction (to virtually undetectable amounts) following SDS treatment, while NH4OH/Triton X-100 and DNase treatment resulted in approximately 10% retention. CONCLUSIONS: This study showed that treatment with NH4OH/Triton X-100 and DNase solution was the most efficient method for DNA removal and the preservation of extracellular matrix integrity and growth factors retention. PMID- 29407755 TI - An RNA-seq screen of P. gingivalis LPS treated human gingival fibroblasts. AB - BACKGROUND: In gingival tissues, lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) is the most critical stimulator for inducing inflammatory response. Human gingival fibroblasts (HGFs) are the major constituents of gingival connective tissues. The aim of this study was to investigate P. gingivalis LPS induced whole transcriptional profile in HGFs and the potential crosstalk between microRNAs (miRNAs) and inflammatory cytokines. METHODS: RNA-seq was performed on HGFs with and without P. gingivalis LPS treatment. The gene expression of selected inflammatory cytokines and miRNAs induced by LPS at different time points was evaluated by quantitative RT-PCR. The protein expression of chemokines was further confirmed by ELISA. RESULTS: Interestingly, most of the significantly changed genes (198/204) were up regulated at 4 h after 10 MUg/ml LPS stimulation, including inflammatory cytokines and miRNAs. Confirmed by quantitative RT-PCR, the mRNA levels of IL 1beta, IL-6 and IL-8 showed single up-regulation peak (4 h/6 h) after 1 MUg/ml and 10 MUg/ml LPS treatment. Similarly, 1 MUg/ml LPS induced single up-regulation peak (8 h) of miRNA-146a, -146b and -155 expression. However, 10 MUg/ml LPS induced the increased expression of miRNA-146a and -155 at both early stage (2 h/4 h) and late stage (24 h). CONCLUSION: Taken together, we investigated P. gingivalis LPS induced whole transcriptional profile, and the different behaviors of miRNA expression induced by different doses of LPS in HGFs. PMID- 29407756 TI - Optimization and comparison of three spatial interpolation methods for electromagnetic levels in the AM band within an urban area. AB - A comparative study was made of three methods of interpolation - inverse distance weighting (IDW), spline and ordinary kriging - after optimization of their characteristic parameters. These interpolation methods were used to represent the electric field levels for three emission frequencies (774kHz, 900kHz, and 1107kHz) and for the electrical stimulation quotient, QE, characteristic of complex electromagnetic environments. Measurements were made with a spectrum analyser in a village in the vicinity of medium-wave radio broadcasting antennas. The accuracy of the models was quantified by comparing their predictions with levels measured at the control points not used to generate the models. The results showed that optimizing the characteristic parameters of each interpolation method allows any of them to be used. However, the best results in terms of the regression coefficient between each model's predictions and the actual control point field measurements were for the IDW method. PMID- 29407757 TI - Oil extraction in the Amazon basin and exposure to metals in indigenous populations. AB - Most oil extraction areas in the Peruvian Amazon are within indigenous territories. Poor environmental practices have exposed the indigenous population to metals. We conducted a survey in two indigenous Kukama communities to assess body burdens of metals after the occurrence of two major oil spills in 2014. Urine levels above those recommended by the Peruvian Ministry of Health were observed in 50% and 17% of the study population for mercury and cadmium, respectively. PMID- 29407758 TI - European common frog Rana temporaria (Anura: Ranidae) larvae show subcellular responses under field-relevant Bacillus thuringiensis var. israelensis (Bti) exposure levels. AB - Bacillus thuringiensis var. israelensis (Bti) is presumed to be an environmental friendly agent for the use in either health-related mosquito control or the reduction of nuisance associated with mosquitoes from seasonal wetlands. Amphibians inhabiting these valuable wetlands may be exposed to Bti products several times during their breeding season. Up until now, information regarding effects on the non-targeted group of amphibians has to be considered rather inconsistent. On this account, we evaluated how three repeated exposures to frequently used Bti formulations (VectoBac(r)12AS, VectoBac(r)WG) in field relevant rates affect European common frog (Rana temporaria) larvae. In a laboratory approach, we assessed potential effects with regard to enzymatic biomarkers (glutathione-S-transferase (GST), glutathione reductase (GR), acetylcholine esterase (AChE)), development, body condition and survival until the end of metamorphosis. Although survival and time to metamorphosis were not significantly affected, larval development tended to be shortened in the Bti treated water phase. Furthermore, exposure to Bti induced significant increases of GST (37-550%), GR (5-140%) and AChE (38-137%) irrespectively of the applied formulation, indicating detoxification, antioxidant responses as well as an alteration of neuronal activity. GST activity increased twice as much after two repeatedly executed Bti applications within a time period of 6 days. The examination of several biochemical markers is needed to fully evaluate the ecotoxicological risk of Bti for amphibian populations, especially in the context of worldwide amphibian declines. Nevertheless, following the precautionary principle, it may be advisable to implement certain thresholds for application numbers and intervals in order to ensure environmentally friendly mosquito control programs, especially in areas designated for nature conservation. PMID- 29407759 TI - Endotoxin enhances respiratory effects of phthalates in adults: Results from NHANES 2005-6. AB - Phthalates have been associated with respiratory symptoms in adults; they may enhance effects of inflammatory compounds. To assess the potential interactions of phthalates and endotoxin on respiratory and allergic symptoms in adults, we used cross-sectional information from the 1091 adults with complete data on urinary phthalates and house dust endotoxin from NHANES 2005-2006. We used multivariable logistic regression to assess whether endotoxin levels modified the association between nine phthalate metabolites and four current allergic symptoms (asthma, wheeze, hay fever, and rhinitis). Endotoxin was classified into tertiles (<10, 10-25, >25EU/mg dust). Urinary phthalate and dust endotoxin levels were not correlated (r < |0.02|). Under low endotoxin conditions, no associations between phthalates and respiratory outcomes were observed. Under medium or high endotoxin conditions, exposure-response relationships were observed between specific phthalates and wheeze and asthma. For wheeze, three phthalates (mono-benzyl phthalate (MBzP), mono(carboxyoctyl) phthalate (MCOP), and di-ethylhexyl phthalate (DEHP) had significant interactions with endotoxin); for asthma, two phthalates (MCOP and mono(carboxyoctyl) phthalate (MCNP)) had significant interactions. Endotoxin did not modify the associations between phthalates and hay fever or rhinitis. These results are consistent with the hypothesis that endotoxin enhances the respiratory toxicity of phthalates; however this cross sectional study cannot address key temporal issues. The lack of an association between wheeze or asthma and phthalates when endotoxin exposure was low suggests that phthalates alone may not increase these symptoms. PMID- 29407760 TI - Mercury-induced vascular dysfunction is mediated by angiotensin II AT-1 receptor upregulation. AB - Low doses of mercury (Hg) promote deleterious effects on cardiovascular system, but the mechanisms implicated remain unclear. This study analyzed whether angiotensin II AT-1 receptors are involved in the vascular dysfunction caused by chronic exposure to low HgCl2 doses. For this, rats were divided into four groups and untreated (saline by im injections and tap water by gavage) or treated for 30 days as follows: Mercury (HgCl2im, first dose of 4.6 ug kg-1 and subsequent doses of 0.07 ug kg-1 day-1, and tap water by gavage); Losartan (saline im and losartan, 15 mg kg-1 day-1, by gavage); Losartan-Mercury (HgCl2im and Losartan by gavage). Systolic blood pressure was measured by tail plethysmography, vascular reactivity in aorta by isolated organ bath, oxidative stress by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and antioxidant capacity (FRAP) and protein expression of AT-1 receptors by Western Blot. As results, co-treatment with losartan prevented the increased aortic vasoconstrictor responses to phenylephrine (Phe), the involvement of ROS and prostanoids on the response to Phe and the reduced negative endothelial modulation by nitric oxide on these responses. Moreover, this co-treatment avoided the increase in plasmatic and vascular oxidative stress and AT-1 protein expression in aorta. In conclusion, these results suggest that AT-1 receptors upregulation might play a key role in the vascular damage induced by Hg exposure by increasing oxidative stress and probably by reducing NO bioavailability. PMID- 29407761 TI - Macro and trace elements in Paracentrotus lividus gonads from South West Atlantic areas. AB - Sea urchin represents one of the most valuable seafood product being harvested and explored for their edible part, the gonads or roe. This species is generally considered a sentinel organism for ecotoxicological studies being widely used in monitoring programs to assess coastal aquatic environments quality, because is directly exposed to anthropogenic contaminants in their habitat. In this context, the aim of this study is to evaluate the concentrations of macro (Cl, K, P, Ca, S) and trace (Zn, Br, Fe, Sr, I, Se, Rb, Cu, Cr, Ni, As, iAs, Cd, Pb, Hg) elements in Paracentrotus lividus gonads from three South West Atlantic production areas subjected to distinct environmental and anthropogenic pressures. In all studied areas, the elements profile in sea urchin gonads was Cl > K > P > Ca > S > Zn > Br > Fe > Sr > I > Rb > Cu > Se > Cr > Ni, suggesting an element guide profile with special interest for sea urchin farming development. Concerning toxic elements, the profile was the following: As > Cd > Pb > Hg > iAs. The results evidenced higher levels of Pb and Hg in open areas. Distinct area characteristics and anthropogenic pressures of production areas evidence the importance of biomonitoring contaminants, particularly toxic elements. In general, the levels of these elements were below maximum levels in foodstuffs (MLs) which pose a minimal health risk to consumers. PMID- 29407763 TI - When a duck is not a duck; a new interdisciplinary synthesis for environmental radiation protection. AB - This consensus paper presents the results of a workshop held in Essen, Germany in September 2017, called to examine critically the current approach to radiological environmental protection. The meeting brought together participants from the field of low dose radiobiology and those working in radioecology. Both groups have a common aim of identifying radiation exposures and protecting populations and individuals from harmful effects of ionising radiation exposure, but rarely work closely together. A key question in radiobiology is to understand mechanisms triggered by low doses or dose rates, leading to adverse outcomes of individuals while in radioecology a key objective is to recognise when harm is occurring at the level of the ecosystem. The discussion provided a total of six strategic recommendations which would help to address these questions. PMID- 29407762 TI - Distribution and predictors of urinary concentrations of phthalate metabolites and phenols among pregnant women in the Healthy Start Study. AB - BACKGROUND: Phthalates and phenols are suspected endocrine disrupting chemicals that may adversely impact fetal outcomes following in utero exposure. Understanding predictors of exposure to phthalates and phenols during the prenatal period is important. METHODS: We measured urinary concentrations of 15 phthalate metabolites and 11 phenols in 446 pregnant women enrolled in the Healthy Start pre-birth cohort. Creatinine-adjusted geometric means (GM) for each urinary biomarker were compared across categories of potential sociodemographic and dietary predictors. To assess the independent relationship between each significant food group predictor and biomarker we used multivariable models, adjusted for sociodemographic predictors. RESULTS: The phthalate metabolites with the highest concentrations were monoethyl phthalate (GM: 41.1ug/g creatinine) and monocarboxyisooctyl phthalate (GM: 20.5ug/g creatinine). Benzophenone-3 (GM: 124.6ug/g creatinine) and methyl paraben (GM: 119.9ug/g creatinine) were the phenols with the highest concentrations. Concentrations of the metabolites of di n-butyl phthalate and di(2-ethylhexyl) phthalate were significantly higher in younger, unmarried or unemployed mothers, those who were overweight or obese, those with lower educational attainment, or those of minority race/ethnicity (p values < 0.05). Metabolites of di-n-butyl phthalate concentrations were 18% lower in those who consumed milk >= 7 times per week (95% CI: 30-4%). Benzophenone-3 and triclosan concentrations were significantly higher in older, married, or employed mothers, those with normal body mass index, higher educational attainment, higher household income, or who were non-Hispanic white (p-values < 0.05). Benzophenone-3 concentrations were 62% higher in those who consumed seafood >= 5 times per month (95% CI: 16-127%). CONCLUSIONS: We observed differences in urinary concentrations of phthalates and phenol biomarkers by sociodemographic predictors in an ethnically diverse cohort of pregnant women. These results and future analyses from this prospective cohort will help inform targeted interventions to reduce exposure to these potential endocrine disrupting chemicals during pregnancy. PMID- 29407764 TI - Rimonabant, a potent CB1 cannabinoid receptor antagonist, is a Galphai/o protein inhibitor. AB - Rimonabant is a potent and selective cannabinoid CB1 receptor antagonist widely used in animal and clinical studies. Besides its antagonistic properties, numerous studies have shown that, at micromolar concentrations rimonabant behaves as an inverse agonist at CB1 receptors. The mechanism underpinning this activity is unclear. Here we show that micromolar concentrations of rimonabant inhibited Galphai/o-type G proteins, resulting in a receptor-independent block of G protein signaling. Accordingly, rimonabant decreased basal and agonist stimulated [35S]GTPgammaS binding to cortical membranes of CB1- and GABAB-receptor KO mice and Chinese Hamster Ovary (CHO) cell membranes stably transfected with GABAB or D2 dopamine receptors. The structural analog of rimonabant, AM251, decreased basal and baclofen-stimulated GTPgammaS binding to rat cortical and CHO cell membranes expressing GABAB receptors. Rimonabant prevented G protein-mediated GABAB and D2 dopamine receptor signaling to adenylyl cyclase in Human Embryonic Kidney 293 cells and to G protein-coupled inwardly rectifying K+ channels (GIRK) in midbrain dopamine neurons of CB1 KO mice. Rimonabant suppressed GIRK gating induced by GTPgammaS in CHO cells transfected with GIRK, consistent with a receptor-independent action. Bioluminescent resonance energy transfer (BRET) measurements in living CHO cells showed that, in presence or absence of co expressed GABAB receptors, rimonabant stabilized the heterotrimeric Galphai/o protein complex and prevented conformational rearrangements induced by GABAB receptor activation. Rimonabant failed to inhibit Galphas-mediated signaling, supporting its specificity for Galphai/o-type G proteins. The inhibition of Galphai/o protein provides a new site of rimonabant action that may help to understand its pharmacological and toxicological effects occurring at high concentrations. PMID- 29407765 TI - Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline. AB - Xanomeline (3-(Hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5 thiadiazole) is a muscarinic agonist that is considered to be functionally selective for the M1/M4 receptor subtypes. Part of xanomeline binding is resistant to washing. Wash-resistant xanomeline activates muscarinic receptors persistently, except for the M5 subtype. Mutation of leucine 6.46 to isoleucine at M1 or M4 receptors abolished persistent activation by wash-resistant xanomeline. Reciprocal mutation of isoleucine 6.46 to leucine at the M5 receptor made it sensitive to activation by wash-resistant xanomeline. Lowering of membrane cholesterol made M1 and M4 mutants and M5 wild type receptors sensitive to activation by wash-resistant xanomeline. Molecular docking revealed a cholesterol binding site in the groove between transmembrane helices 6 and 7. Molecular dynamics showed that interaction of cholesterol with this binding site attenuates receptor activation. We hypothesize that differences in cholesterol binding to this site between muscarinic receptor subtypes may constitute the basis for xanomeline apparent functional selectivity and may have notable therapeutic implications. Differences in receptor-membrane interactions, rather than in agonist-receptor interactions, represent a novel possibility to achieve pharmacological selectivity. Our findings may be applicable to other G protein coupled receptors. PMID- 29407766 TI - Dopamine D3 receptor blockade rescues hyper-dopamine activity-induced deficit in novel object recognition memory. AB - Patients afflicted with bipolar disorder demonstrate significant impairments in recognition and episodic memory during acute depressive and manic episodes. These impairments and the related pathophysiology may result from over-activation of the brain dopamine (DA) system. In order to model overactive DA transmission in a well-established novel object recognition (NOR) memory test, we used DA transporter knockdown (DAT-KD) mice, which exhibit reduced DAT expression and display hyper-dopaminergic phenotypes. DAT-KD mice exhibited impaired NOR memory compared to wild-type (WT) mice. This impairment was prevented by administration of FAUC365, a DA D3 receptor (D3R) selective antagonist, prior to object learning. Similarly, D3R knockout (KO)/DAT-KD double mutant mice displayed performance in the NOR test that was comparable to WT mice, suggesting that deficiencies in NOR performance in DAT-KD mice can be compensated by diminishing D3R signaling. GBR12909, a DAT blocker, also impaired NOR performance in WT mice, but not in D3R KO mice. Impaired NOR performance in GBR12909-treated WT mice was also prevented by pretreatment with FAUC365. Together, these findings indicate that reduced DAT activity can impair recognition memory in the NOR test, and D3R appears to be necessary to mediate this effect. PMID- 29407768 TI - A new approach to precise thermodynamic characterization of hybridization properties of modified oligonucleotides: Comparative studies of deoxyribo- and glycine morpholine pentaadenines. AB - The development of new derivatives and analogues of nucleic acids for the purposes of molecular biology, biotechnology, gene diagnostics, and medicine has been a hotspot for the last two decades. Methylenecarboxamide (glycine) morpholine oligomer analogues (gM) seem to be promising therapeutic candidates because of the ability to form sequence specific complexes with DNA and RNA. In this paper we describe new approaches to the determination of thermodynamic parameters for hybridization of tandem oligonucleotide complexes with the complementary template. It makes possible to determine changes in enthalpy and entropy corresponding to the binding of an individual oligomer with the template, and to the formation of cooperative contact at the helix-helix interface of two neighboring duplex fragments (in the nick). We have experimentally analyzed the series of model tandem complexes of different length at various oligomer concentrations, ionic strength, and pH. The analysis of thermodynamic parameters of complex formation for native and modified oligomers revealed higher Gibbs free energy values of hybridization and cooperative interaction of morpholine containing complexes at the helix-helix interface under standard conditions (1M NaCl, pH7.2). Further comparative analysis of the hybridization properties of modified oligomers at ionic strength and pH allows us to determine the charge state of the morpholine backbone and the thermodynamic origin of the effects observed. It was found that the decrease in pH to 5.5 led to the protonation of internal morpholine nitrogens. The obtained results prove the veracity of the proposed model and the possibility to evaluate thermodynamic parameters of short native and modified oligomers with high accuracy. PMID- 29407767 TI - Involvement of glycine receptor alpha1 subunits in cannabinoid-induced analgesia. AB - Some cannabinoids have been shown to suppress chronic pain by targeting glycine receptors (GlyRs). Although cannabinoid potentiation of alpha3 GlyRs is thought to contribute to cannabinoid-induced analgesia, the role of cannabinoid potentiation of alpha1 GlyRs in cannabinoid suppression of chronic pain remains unclear. Here we report that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, significantly suppresses chronic inflammatory pain caused by noxious heat stimulation. This effect may involve spinal alpha1 GlyRs since the expression level of alpha1 subunits in the spinal cord is positively correlated with CFA-induced inflammatory pain and the GlyRs antagonist strychnine blocks the DH-CBD-induced analgesia. A point-mutation of S296A in TM3 of alpha1 GlyRs significantly inhibits DH-CBD potentiation of glycine currents (IGly) in HEK-293 cells and neurons in lamina I-II of spinal cord slices. To explore the in vivo consequence of DH-CBD potentiation of alpha1 GlyRs, we generated a GlyRalpha1S296A knock-in mouse line. We observed that DH-CBD-induced potentiation of IGly and analgesia for inflammatory pain was absent in GlyRalpha1S296A knock in mice. These findings suggest that spinal alpha1 GlyR is a potential target for cannabinoid analgesia in chronic inflammatory pain. PMID- 29407769 TI - Biophysical evidence for differential gallated green tea catechins binding to membrane type-1 matrix metalloproteinase and its interactors. AB - Membrane type-1 matrix metalloproteinase (MT1-MMP) is a transmembrane MMP which triggers intracellular signaling and regulates extracellular matrix proteolysis, two functions that are critical for tumor-associated angiogenesis and inflammation. While green tea catechins, particularly epigallocatechin gallate (EGCG), are considered very effective in preventing MT1-MMP-mediated functions, lack of structure-function studies and evidence regarding their direct interaction with MT1-MMP-mediated biological activities remain. Here, we assessed the impact in both cellular and biophysical assays of four ungallated catechins along with their gallated counterparts on MT1-MMP-mediated functions and molecular binding partners. Concanavalin-A (ConA) was used to trigger MT1-MMP mediated proMMP-2 activation, expression of MT1-MMP and of endoplasmic reticulum stress biomarker GRP78 in U87 glioblastoma cells. We found that ConA-mediated MT1 MMP induction was inhibited by EGCG and catechin gallate (CG), that GRP78 induction was inhibited by EGCG, CG, and gallocatechin gallate (GCG), whereas proMMP-2 activation was inhibited by EGCG and GCG. Surface plasmon resonance was used to assess direct interaction between catechins and MT1-MMP interactors. We found that gallated catechins interacted better than their ungallated analogs with MT1-MMP as well as with MT1-MMP binding partners MMP-2, TIMP-2, MTCBP-1 and LRP1-clusterIV. Overall, current structure-function evidence supports a role for the galloyl moiety in both direct and indirect interactions of green tea catechins with MT1-MMP-mediated oncogenic processes. PMID- 29407770 TI - Study of Al3+ interaction with AMP, ADP and ATP in aqueous solution. AB - The interaction of Al3+ and nucleotide ligands, namely adenosine-5' monophosphate, (AMP), adenosine-5'-diphosphate, (ADP), adenosine-5'-triphosphate, (ATP), has been studied in aqueous solution at T = 298.15 K and I = 0.15 mol L-1 in NaCl (only for Al3+-ATP system at I = 0.1 mol L-1). Formation constants and speciation models for the species formed are discussed on the basis of potentiometric results. The speciation models found for the three systems include ML and ML2 species in all the cases, and for Al3+-ADP and ATP systems, MLH, MLOH and ML2OH species as well. The formation constant value for ML species shows the trend, AMP < ADP < ATP. 1H NMR spectroscopy was also employed for the study of Al3+-ATP system. The 1H NMR results are in agreement with the speciation model obtained from analysis of potentiometric titration data, confirming the stabilities of the main species. Enthalpy change values were obtained by titration calorimetry; for the main Al3+-ATP species (at T = 298.15 K and I = 0.1 mol L-1 in NaCl), they resulted always higher than zero, as typical for hard-hard interactions. The dependence of formation constants on ionic strength over the range I = 0.1 to 1 mol L-1 in NaCl is also reported for Al3+-ATP system. The sequestering ability of the nucleotides under study towards Al3+ was also evaluated by the empirical parameter pL0.5. PMID- 29407771 TI - Triptolide induces mitochondria-mediated apoptosis of Burkitt's lymphoma cell via deacetylation of GSK-3beta by increased SIRT3 expression. AB - Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma with rapid growth and dissemination propensity. Triptolide (TP), an active component extracted from Chinese herb Tripterygium wilfordii Hook f., has broad-spectrum anti-tumor activities. This study aimed to explore the in vitro and in vivo anti cancer effects of TP on BL and the potential molecular mechanisms. In this study, the in vitro anti-tumor activity of TP was determined by CCK-8 and flow cytometry assays in Raji, NAMALWA and Daudi cells. The expression of SIRT3, phosphorylation and acetylation of glycogen synthase kinase-3beta (GSK-3beta) were analyzed by Western blot assay. Moreover, we examined the mitochondrial membrane potential by JC-1 method and measured apoptosis related protein using Western blot assay. BL xenograft model in NOD/SCID mice were established to evaluate the in vivo anti cancer effect of TP. We discovered that TP inhibited BL cell growth and induced apoptosis in a dose-dependent manner. Loss of SIRT3 provides growth advances for BL cells. However, TP could up-regulate SIRT3 expression, which resulted in suppression of BL cells proliferation. GSK-3beta was activated by SIRT3-mediated deacetylation, which subsequently induced mitochondrial translocation and accumulation of Bax and decrease of mitochondrial membrane potential. Anti-tumor studies in vivo showed that TP (0.36 mg/kg) inhibited the growth of BL xenografts in NOD/SCID mice with an inhibitory rate of 73.13%. Our data revealed that TP triggered mitochondrial apoptotic pathway in BL by increasing SIRT3 expression and activating SIRT3/GSK-3beta/Bax pathway. This study indicated that TP is a potential anti-cancer Chinese herbal medicine against BL. PMID- 29407772 TI - Safety assessment of starch-based personal care products: Nanocapsules and pickering emulsions. AB - The safety profile of the ingredients used in topical dosage forms and its evaluation is an issue of utmost importance. A suitable equilibrium between safety and efficacy is crucial before promoting a dermatological product. The aim of this work was to assess the safety and biological effects of starch-based vehicles (St-BV) used in such products. The hazard, exposure and dose-response assessment were used to characterize the risk of each ingredient. The EpiSkinTM assay and human repeat insult patch tests were performed to compare the theoretical safety assessment to in vitro and in vivo data. The efficacy of the St-BV was studied using biophysical measurements in human volunteers during 28 days, showing that all ingredients and their combinations were safe for the consumer. Tissue viability determined using the EpiSkinTM testing reached values between 84.0 +/- 5.0% and 98.0 +/- 8.6% after application of St-BV, which were considered as non-irritant to the skin. These observations were confirmed by the in vivo studies where the St-BV did not induce any sensitization on the volunteers, being safe for human use. Moreover, St-BV increased skin hydration and microcirculation, emerging as an attractive alternative to chemical raw materials. PMID- 29407773 TI - Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys. AB - The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL 11 (PEG-IL11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2=6.9h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1-0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100MUg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11. PMID- 29407774 TI - Relevance to investigate different stages of pregnancy to highlight toxic effects of nanoparticles: The example of silica. AB - Amorphous silica nanoparticles (SiO2NPs) have been recognized as safe nanomaterial, hence their use in biomedical applications has been explored. Data, however, suggest potential toxicity of SiO2 NPs in pregnant individuals. However, no studies relating nanoparticle biokinetic/toxicity to the different gestational stages are currently available. In this respect, we have investigated the possible embryotoxic effects of three-size and two-surface functionalization SiO2NPs in mice. After intravenous administration of different concentrations at different stages of pregnancy, clinical and histopathological evaluations, performed close to parturition, did not show signs of maternal toxicity, nor effects on placental/fetal development, except for amino-functionalized 25 nm NPs. Biodistribution was studied by ICP-AES 24 h after administration, and demonstrates that all particles distributed to placenta and conceptuses/fetuses, although size, surface charge and gestational stage influenced biodistribution. Our data suggest the need of comprehensive toxicological studies, covering the entire gestation to reliably assess the safety of nanoparticle exposure during pregnancy. PMID- 29407775 TI - Different effects of ursodeoxycholic acid on intrahepatic cholestasis in acute and recovery stages induced by alpha-naphthylisothiocyanate in mice. AB - The aim of this study was to determine the effect of ursodeoxycholic acid (UDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced acute and recovery stage of cholestasis model mice. In the acute stage of model mice, pretreatment with UDCA (25, 50, and 100 mg.kg-1, ig) for 12 days prior to ANIT administration (50 mg.kg 1, ig) resulted in the dramatic increase in serum biochemistry, with aggrevation of bile infarcts and hepatocyte necrosis. The elevation of beta-muricholic acid (beta-MCA), cholic acid (CA), and taurocholic acid (TCA) in serum and liver, and reduction of these bile acids (BAs) in bile was observed. In contrast, in the recovery stage of model mice, treatment with UDCA (25, 50, and 100 mg.kg-1, ig) for 7 days after ANIT administration (50 mg.kg-1, ig) resulted in the significant decrease in levels of serum alanine aminotransferase (ALT) and total bile acid (TBA). Liver injury was attenuated, and the levels of TBA, CA, TCA, and beta-MCA in the liver were significantly decreased. Additionally, UDCA can upregulate expression of BSEP, but it cannot upregulate expression of AE2. UDCA, which induced BSEP to increase bile acid-dependent bile flow, aggravated cholestasis and liver injury when the bile duct was obstructed in the acute stage of injury in model mice. In contrast, UDCA alleviated cholestasis and liver injury induced by ANIT when the obstruction was improved in the recovery stage. PMID- 29407776 TI - Biodegradation of Diclofenac by the bacterial strain Labrys portucalensis F11. AB - Diclofenac (DCF) is a widely used non-steroidal anti-inflammatory pharmaceutical which is detected in the environment at concentrations which can pose a threat to living organisms. In this study, biodegradation of DCF was assessed using the bacterial strain Labrys portucalensis F11. Biotransformation of 70% of DCF (1.7 34 MUM), supplied as the sole carbon source, was achieved in 30 days. Complete degradation was reached via co-metabolism with acetate, over a period of 6 days for 1.7 uM and 25 days for 34 MUM of DCF. The detection and identification of biodegradation intermediates was performed by UPLC-QTOF/MS/MS. The chemical structure of 12 metabolites is proposed. DCF degradation by strain F11 proceeds mainly by hydroxylation reactions; the formation of benzoquinone imine species seems to be a central step in the degradation pathway. Moreover, this is the first report that identified conjugated metabolites, resulting from sulfation reactions of DCF by bacteria. Stoichiometric liberation of chlorine and no detection of metabolites at the end of the experiments are strong indications of complete degradation of DCF by strain F11. To the best of our knowledge this is the first report that points to complete degradation of DCF by a single bacterial strain isolated from the environment. PMID- 29407777 TI - Assessing the influence of 1-dodecyl-3-methylimidazolium chloride on soil characteristics and Vicia faba seedlings. AB - Imidazolium-based ionic liquids (ILs) have attracted increasing attention in recent years. The IL 1-dodecyl-3-methylimidazolium chloride ([C12mim]Cl) has been widely used in the chemical industry. In this study, the influence of [C12mim]Cl on Vicia faba seedlings, soil physicochemical properties and soil enzyme activities was investigated for the first time. Meanwhile, the variation of [C12mim]Cl concentrations in soil was monitored during the exposure period. The present results showed that the concentration of [C12mim]Cl remained stable in the tested soil with a change rate of no more than 10% during the exposure period. The 50% effective concentration (EC50) values for shoot length, root length and dry weight were 188, 69 and 132 mg kg-1, respectively. At 200 mg kg-1 and 400 mg kg-1, [C12mim]Cl had significant influence on soil organic matter content, pH value and conductivity value. At 40 mg kg-1, the reactive oxygen species (ROS) levels were obviously enhanced, resulting in oxidative stress effects in Vicia faba seedling leaves. Additionally, the soil enzyme activities changed significantly at 40 mg kg-1. PMID- 29407778 TI - Low hazard of silver nanoparticles and silver nitrate to the haematopoietic system of rainbow trout. AB - Silver nanoparticles (Ag NPs) are known for their antibacterial properties and are used in a growing number of nano-enabled products, with inevitable concerns for releases to the environment. Nanoparticles may also be antigenic and toxic to the haematopoietic system, but the immunotoxic effect of Ag NPs on non-target species such as fishes is poorly understood. This study aimed to assess the effect of Ag NP exposure via the water on the haematopoietic system of rainbow trout, Oncorhynchus mykiss, and to determine whether or not the hazard from Ag NPs was different from that of AgNO3. Fish were exposed for 7 days to a control (dechlorinated Plymouth freshwater), dispersant control, 1ugl-1 Ag as AgNO3 or 100ugl-1 Ag NPs. Animals were sampled on days 0, 4 and 7 for haematology, tissue trace metal concentration, biochemistry for evidence of oxidative stress/inflammation in the spleen and histopathology of the blood cells and spleen. The Ag NP treatment significantly increased the haematocrit, but the haematological changes were within the normal physiological range of the animal. Thrombocytes in spleen prints at day 4, and melanomacrophage deposits at day 7 in the spleen, of Ag NP exposed-fish displayed significant increases compared to all the other treatments within the time point. A dialysis experiment confirmed that dissolution rates were very low and any pathology observed is likely from the NP form rather than dissolved metal released from it. Overall, the data showed subtle differences in the effects of Ag NPs compared to AgNO3 on the haematopoietic system. The lack of pathology in the circulating blood cells and melanomacrophage deposits in the spleen suggests a compensatory physiological effort by the spleen to maintain normal circulating haematology during Ag NP exposure. PMID- 29407779 TI - Bisphenol A (BPA) modulates the expression of endocrine and stress response genes in the freshwater snail Physa acuta. AB - Bisphenol A (BPA), a known endocrine disrupting chemical (EDC) that can mimic the action of oestrogens by interacting with hormone receptors, is potentially able to influence reproductive functions in vertebrates and invertebrates. The freshwater pulmonate Physa acuta is a sensitive organism to xenobiotics appropriate for aquatic toxicity testing in environmental studies. This study was conducted to explore the effects of BPA on the Gastropoda endocrine system. The effects following a range of exposure times (5-96h) to BPA in P. acuta were evaluated at the molecular level by analysing changes in the transcriptional activity of the endocrine-related genes oestrogen receptor (ER), oestrogen related receptor (ERR), and retinoid X receptor (RXR), as well as in genes involved in the stress response, such as hsp70 and hsp90. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis showed that BPA induced a significant increase in the mRNA levels of ER, ERR, and RXR, suggesting that these receptors could be involved in similar pathways or regulation events in the endocrine disruptor activity of this chemical at the molecular level in Gastropoda. Additionally, the hsp70 expression was upregulated after 5 and 72h of BPA exposures, but hsp90 was only upregulated after 5h of BPA exposure. Finally, we assessed the glutathione-S-transferase (GST) activity after BPA treatment and found that it was affected after 48h. In conclusion, these data provide, for the first time, evidences of molecular effects produced by BPA in the endocrine system of Gastropoda, supporting the potential of ER, ERR and RXR as biomarkers to analyse putative EDCs in ecotoxicological studies. Moreover, our results suggest that P. acuta is an appropriate sentinel organism to evaluate the effect of EDCs in the freshwater environment. PMID- 29407780 TI - Soil incubation studies with Cry1Ac protein indicate no adverse effect of Bt crops on soil microbial communities. AB - Bt crops that are transgenic crops engineered to produce Bt toxins which occur naturally with Bacillus thuringiensis (Bt) have been widely planted and its environmental risk assessment has been heavily debated. The effects of Bt crops on soil microbial communities are possible through changing the quantity and quality of C inputs and potential toxic activity of Bt protein on soil organisms. To date, the direct effects of Bt protein on soil microorganisms is unclear. Here we added Cry1Ac, one of the most commonly used Bt protein in Bt crops, to the soil and monitored changes in soil bacterial, fungal and archaeal diversities and community structures using ribosomal DNA-fingerprinting method, as well as their population sizes by real-time PCR over a 100-day period. Despite the fact that variations were observed in the indices of evenness, diversity and population sizes of bacteria, fungi and archaea with different Cry1Ac addition rates up to 100ngg-1 soil, the indices of soil microbial diversities and evennesses did not significantly shift with Cry1Ac protein addition, nor did population sizes change over time. The diversities of the dominant bacteria, fungi and archaea were not significantly changed, given Cry1Ac protein addition rates over a period of 100 days. These results suggested that Bt protein derived by cultivations of transgenic Bt crops is unlikely to cause transient or even persisting significant changes in soil microorganisms in field. PMID- 29407781 TI - Use of GLM approach to assess the responses of tropical trees to urban air pollution in relation to leaf functional traits and tree characteristics. AB - Responses of urban vegetation to air pollution stress in relation to their tolerance and sensitivity have been extensively studied, however, studies related to air pollution responses based on different leaf functional traits and tree characteristics are limited. In this paper, we have tried to assess combined and individual effects of major air pollutants PM10 (particulate matter <= 10 um), TSP (total suspended particulate matter), SO2 (sulphur dioxide), NO2 (nitrogen dioxide) and O3 (ozone) on thirteen tropical tree species in relation to fifteen leaf functional traits and different tree characteristics. Stepwise linear regression a general linear modelling approach was used to quantify the pollution response of trees against air pollutants. The study was performed for six successive seasons for two years in three distinct urban areas (traffic, industrial and residential) of Varanasi city in India. At all the study sites, concentrations of air pollutants, specifically PM (particulate matter) and NO2 were above the specified standards. Distinct variations were recorded in all the fifteen leaf functional traits with pollution load. Caesalpinia sappan was identified as most tolerant species followed by Psidium guajava, Dalbergia sissoo and Albizia lebbeck. Stepwise regression analysis identified maximum response of Eucalyptus citriodora and P. guajava to air pollutants explaining overall 59% and 58% variability's in leaf functional traits, respectively. Among leaf functional traits, maximum effect of air pollutants was observed on non-enzymatic antioxidants followed by photosynthetic pigments and leaf water status. Among the pollutants, PM was identified as the major stress factor followed by O3 explaining 47% and 33% variability's in leaf functional traits. Tolerance and pollution response were regulated by different tree characteristics such as height, canopy size, leaf from, texture and nature of tree. Outcomes of this study will help in urban forest development by selection of specific pollutant tolerant tree species and leaf traits, which is suitable as air pollution mitigation measure. PMID- 29407782 TI - Manual or automated measuring of antipsychotics' chemical oxygen demand. AB - Antipsychotic (AP) drugs are becoming accumulated in terrestrial and aqueous resources due to their actual consumption. Thus, the search of methods for assessing the contamination load of these drugs is mandatory. The COD is a key parameter used for monitoring water quality upon the assessment of the effect of polluting agents on the oxygen level. Thus, the present work aims to assess the chemical oxygen demand (COD) levels of several typical and atypical antipsychotic drugs in order to obtain structure-activity relationships. It was implemented the titrimetric method with potassium dichromate as oxidant and a digestion step of 2h, followed by the measurement of remained unreduced dichromate by titration. After that, an automated sequential injection analysis (SIA) method was, also, used aiming to overcome some drawbacks of the titrimetric method. The results obtained showed a relationship between the chemical structures of antipsychotic drugs and their COD values, where the presence of aromatic rings and oxidable groups give higher COD values. It was obtained a good compliance between the results of the reference batch procedure and the SIA system, and the APs were clustered in two groups, with the values ratio between the methodologies, of 2 or 4, in the case of lower or higher COD values, respectively. The SIA methodology is capable of operating as a screening method, in any stage of a synthetic process, being also more environmentally friendly, and cost-effective. Besides, the studies presented open promising perspectives for the improvement of the effectiveness of pharmaceutical removal from the waste effluents, by assessing COD values. PMID- 29407783 TI - The significance of nanomaterial post-exposure responses in Daphnia magna standard acute immobilisation assay: Example with testing TiO2 nanoparticles. AB - One of the most widely used aquatic standarized tests for the toxicity screening of chemicals is the acute toxicity test with the freshwater crustacean Daphnia magna, which has also been applied in the toxicity screening of manufactured nanoparticles (NPs). However, in the case of non-soluble NPs most of the results of this test have showed no effect. The aim of the work presented here was to modify the standardized test by the least possible extent to make it more sensitive for non-soluble particles. The standard acute immobilisation assay with daphnids was modified by prolonging the exposure period and by measuring additional endpoints. Daphnids were exposed to TiO2 NPs in a standard acute test (48h of exposure), a standard acute test (48h of exposure) followed by 24h recovery period in clean medium or a prolonged exposure in the NPs solutions totaling 72h. Together with immobility, the adsorption of NPs to body surfaces was also observed as an alternative measure of the NPs effects. Our results showed almost no effect of TiO2 NPs on D. magna after the 48h standard acute test, while immobility was increased when the exposure period to TiO2 NPs was prolonged from 48h to 72h. Even when daphnids were transferred to clean medium for additional 24h after 48h of exposure to TiO2 NPs the immobility increased. We conclude that by transferring the daphnids to clean medium at the end of the 48h exposure to TiO2 NPs, the delayed effects of the tested material can be seen. This methodological step could improve the sensitivity of D. magna test as a model in nanomaterial environmental risk assessment. PMID- 29407784 TI - Effect of selenium induced seed priming on arsenic accumulation in rice plant and subsequent transmission in human food chain. AB - The south-east Asian countries are facing a serious threat of arsenic (As) toxicity due to extensive use of As contaminated groundwater for rice cultivation. This experiment was configured to assess the consequences of rice seed priming with selenium (Se) and cultivation in As free and As contaminated soil. The experiment was arranged in a factorial complete randomized design having two factors viz. seed priming and soil As stress with total twenty-five treatment combinations replicated thrice. Seed priming with Se promotes growth, yield under both As free and As stressed conditions. Se supplementation considerably enhanced the tiller numbers, chlorophyll content, plant height, panicle length and test weight of rice by 23.1%, 23.4%, 15.6% and 30.1%, respectively. When cultivated in As spiked soil and compared with control, Se primed plant enhance growth and yield by reducing As translocation from root to aerial parts, expressed as translocation factor (TF). A reduction of TF root to shoot (46.96%), TF root to husk (36.78-38.01%), TF root to grain (39.63%) can be seen among the Se primed plants than unprimed plants both cultivated in similar As stress. Besides these, a noteworthy reduction in estimated daily intake (EDI) and cancer risk (CR) were also noticed with the consumption of cooked rice obtained after cooking of brown rice of Se primed plants than their unprimed counterparts. PMID- 29407785 TI - Toxicological effects of CdSe nanocrystals on the marine diatom Phaeodactylum tricornutum: The first mass spectrometry-based proteomic approach. AB - : In the marine environment, benthic diatoms from estuarine and coastal sediments are among the first targets of nanoparticle pollution whose potential toxicity on marine organisms is still largely unknown. It is therefore relevant to improve our knowledge of interactions between these new pollutants and microalgae, the key players in the control of marine resources. In this study, the response of P. tricornutum to CdSe nanocrystals (CdSe NPs) of 5 nm (NP5) and 12 nm (NP12) in diameter was evaluated through microscopic, physiological, biochemical and proteomic approaches. NP5 and NP12 affected cell growth but oxygen production was only slightly decreased by NP5 after 1-d incubation time. In our experimental conditions, a high CdSe NP dissolution was observed during the first day of culture, leading to Cd bioaccumulation and oxidative stress, particularly with NP12. However, after a 7-day incubation time, proteomic analysis highlighted that P. tricornutum responded to CdSe NP toxicity by regulating numerous proteins involved in protection against oxidative stress, cellular redox homeostasis, Ca2+ regulation and signalling, S-nitrosylation and S-glutathionylation processes and cell damage repair. These proteome changes allowed algae cells to regulate their intracellular ROS level in contaminated cultures. P. tricornutum was also capable to control its intracellular Cd concentration at a sufficiently low level to preserve its growth. To our knowledge, this is the first work allowing the identification of proteins differentially expressed by P. tricornutum subjected to NPs and thus the understanding of some molecular pathways involved in its cellular response to nanoparticles. SIGNIFICANCE: The microalgae play a key role in the control of marine resources. Moreover, they produce 50% of the atmospheric oxygen. CdSe NPs are extensively used in the industry of renewable energies and it is regrettably expected that these pollutants will sometime soon appear in the marine environment through surface runoff, urban effluents and rivers. Since estuarine and coastal sediments concentrate pollutants, benthic microalgae which live in superficial sediments will be among the first targets of nanoparticle pollution. Thus, it is relevant to improve our knowledge of interactions between diatoms and nanoparticles. Proteomics is a powerful tool for understanding the molecular mechanisms triggered by nanoparticle exposure, and our study is the first one to use this tool to identify proteins differentially expressed by P. tricornutum subjected to CdSe nanocrystals. This work is fundamental to improve our knowledge about the defence mechanisms developed by algae cells to counteract damage caused by CdSe NPs. PMID- 29407786 TI - Cadmium uptake, accumulation, and remobilization in iron plaque and rice tissues at different growth stages. AB - Rice consumption is considered the main source of human dietary Cd intake in Southeast Asia. This study aimed to investigate Cd uptake, accumulation, and remobilization in iron plaque and rice (Oryza sativa L. cv. 'Xiangwanxian 12') tissues at different growth stages. A pot experiment was performed in two Cd contaminated paddy soils. Cd concentrations in iron plaque and rice tissues at five different growth stages (tillering, booting, milky, dough, and maturing) were measured. Cd concentrations in iron plaque and rice tissues (roots, stems, leaves, spikelet, husks, and brown rice) varied with growth stage. Cd accumulation in rice plants increased with extending growth in both soils, reaching 15.3 and 35.4MUg/pot, respectively, at the maturing stage. The amounts of Cd in brown rice increased from the milky to maturing stages, with the greatest percentage uptake during the maturing stage. Cd amount in iron plaque significantly affected the uptake and accumulation of Cd in roots and aerial parts of rice plants. Accumulated Cd in leaves was remobilized and transported during the booting to maturing stages, and the contributions of Cd transportation from leaves to brown rice were 30.0% and 22.5% in the two soils, respectively. A large amount of Cd accumulated in brown rice during the maturing stage. The transportation of remobilized Cd from leaves was also important for the accumulation of Cd in brown rice. PMID- 29407787 TI - Pollution patterns and underlying relationships of benzophenone-type UV-filters in wastewater treatment plants and their receiving surface water. AB - The environmental behaviors of emerging pollutants, benzophenone-type UV filters (BP-UV filters) and their derivatives were investigated in four wastewater treatment plants (WWTPs), and their receiving surface waters in Shanghai. The concentration level of selected BP-UV filters in the WWTPs was detected from ngL 1 to MUgL-1. BP (621-951ngL-1) and BP-3 (841-1.32 * 103ngL-1) were the most abundant and highest detection frequency individuals among the target BP-UV filters in influents, whereas BP (198-400ngL-1), BP-4 (93.3-288ngL-1) and BP-3 (146-258ngL-1) were predominant in effluents. BP-UV filters cannot be completely removed and the total removal efficiency varied widely (-456% to 100%) during the treatment process. It can be inferred that the usage of BP and BP-3 are higher than other BP-UV filters in the study area. The lowest and highest levels were BP 2 (ND-7.66ngL-1) and BP-3 (68.5-5.01 * 103ng L-1) in the receiving surface water, respectively. Interestingly, the seasonal variation of BP-3 is larger than those of other BP-UV filters in surface water from Shanghai. There is no obvious pollution pattern of BP-UV filters in the surface water from the cosmetic factory area. The correlation analysis of BP-UV filters between WWTPs effluents and nearby downstream water samples suggested that BP-UV filters emitted from some WWTPs might be the main source of receiving surface water. Preliminary risk assessment indicated that the levels of BP-UV filters detected by the effluent posed medium to high risk to fish as well as other aquatic organisms. PMID- 29407788 TI - Reduced inter-hemispheric interference in ageing: Evidence from a divided field Stroop paradigm. AB - One of the most important structural changes that occur in the brain during the course of life relates to the corpus callosum, the largest neural pathway that connects the two cerebral hemispheres. It has been shown that the corpus callosum, and in particular its anterior sections, endures a process of degeneration in ageing. Hence, a primary question is whether such structural changes in the brain of older adults have functional consequences on inter hemispheric communication. In particular, whether the atrophy of the corpus callosum in ageing may lead to a higher or lower level of inter-hemispheric interference is currently unknown. To investigate this question, we asked young and healthy older adults to perform modified versions of the classic Stroop paradigm in which the target and distracter were spatially separated. Across two experiments, we found that the Stroop effect was significantly reduced in older adults when the two stimuli were distributed in two different hemifields as opposed to the same single hemifield. This new finding suggests that age-related callosal thinning reduces inter-hemispheric interference by facilitating the two hemispheres to process information in parallel. PMID- 29407789 TI - Association of the N100 TMS-evoked potential with attentional processes: A motor cortex TMS-EEG study. AB - The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = -0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition. PMID- 29407790 TI - Alteration of mice cerebral cortex development after prenatal exposure to cypermethrin and deltamethrin. AB - Pyrethroids, a group of insecticides with high efficiency, low toxicity and wide spectrum, are used for pest control in agriculture. Here, we administered two representative pyrethroids (cypermethrin and deltamethrin) and an equal volume of vehicle (corn oil) to the pregnant ICR mice. This study investigated the effects of cypermethrin and deltamethrin on cerebral cortex development in mice as well as possible mechanisms in proliferation and differentiation. The results showed that histopathologic change did not occurred in the cerebral cortex using Hematoxylin and Eosin staining, however, the observation of fetuses exposed to cypermethrin and deltamethrin revealed reduction of neuronal proliferation, maturation and differentiation. Moreover, cypermethrin/deltamethrin-induced apoptosis of nerve cell was significantly higher in treated groups than that in control group by using flow cytometry, Western blot and TUNEL. It was worth mentioning that the newborns exposed to cypermethrin and deltamethrin did not showed abnormal neuronal distribution. These findings suggested that prenatal cypermethrin and deltamethrin exposure impaired corticogenesis. PMID- 29407791 TI - Studies on the interaction of BDE-47 and BDE-209 with acetylcholinesterase (AChE) based on the neurotoxicity through fluorescence, UV-vis spectra, and molecular docking. AB - The neurotoxicity of polybrominated diphenyl ethers (PBDEs) has been of concern. Acetylcholinesterase (AChE) is a critical enzyme in the central and peripheral nervous system related to neurotoxicity. The interaction between BDE-47, BDE-209, and AChE was investigated through fluorescence and UV-vis spectra combined with molecular docking. Both BDE-47 and BDE-209 bound with AChE and changed the microenvironment of some amino acid residues, resulting in a change of AChE conformation. Hydrophobic interaction is the main binding force between BDE-47, BDE-209, and AChE, and electrostatic interaction exists according to the thermodynamic parameters of the interaction between them. A hydrophobic interaction of BDE-47-AChE and BDE-209-AChE has been confirmed through molecular docking to dominate the binding force. The binding constants of BDE-47-AChE and BDE-209-AChE were 4.2 * 104 and 4.1 * 104 L/mol, respectively, and the lowest binding energies of BDE-47-AChE and BDE-209-AChE were -7.8 and -5.9 kJ/mol, respectively. BDE-47 is more likely to bind with AChE than BED-209. PMID- 29407792 TI - Structure and function of heme proteins regulated by diverse post-translational modifications. AB - Heme proteins are crucial for biological systems by performing diverse functions. Nature has evolved diverse approaches to fine-tune the structure and function of heme proteins, of which post-translational modification (PTM) is a primary method. As reviewed herein, a multitude of PTMs have been discovered for heme proteins in the last several decades, including heme-protein cross-links with heme side chains (Cys-heme, Tyr-heme and Asp/Glu-heme, etc) or porphyrin ring (Lys-heme and Tyr-heme, etc), heme modifications (sulfheme and nitriheme, etc), amino acids cross-links between two or among multiple residues (Cys-Cys, Tyr-His, Tyr-Cys, Met-Tyr-Trp, etc), and amino acids modifications by oxidation, nitration, phosphorylation and glycation, etc. With the development of research methods and advances in research techniques, deep insights have been obtained for the formation mechanisms of PTMs, as well as their effects on the structure and function of heme proteins. Moreover, some positive PTMs have been successfully applied to create artificial heme proteins with advanced functions, whereas some negative PTMs have been regulated by rational design of inhibitors. The tremendous progress, together with those ongoing, will make it possible to rationally control the diverse PTMs of heme proteins, especially those associated with human diseases, toward our desired goals for a better life. PMID- 29407793 TI - Promoter analysis and transcriptional regulation of human carbonic anhydrase VIII gene in a MERRF disease cell model. AB - Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial neuromuscular disease. We previously reported a significant decrease of mRNA and protein levels of nuclear DNA-encoded carbonic anhydrase VIII (CA8) in MERRF cybrids harboring A8344G mutation in mitochondrial DNA (mtDNA). In this study, we established a reporter construct of luciferase gene carrying hCA8 promoter containing several putative transcription factor-binding sites, including GC-box, AP-2 and TATA-binding element in the 5'flanking region of the hCA8 gene. Using a series of mutated hCA8 promoter constructs, we demonstrated that a proximal GC-box, recognized by Sp1 and other Sp family members, may be a key cis-element functioning at the promoter. Additionally, a significant increase of the hCA8 promoter activity was observed in the wild-type and mutant cybrids with over-expression of eGFP-Sp1, but no detectable increase in the CA8 protein expression. In contrast, over-expression of Flag-Sp1 and Flag Sp4 significantly increased the hCA8 promoter activity as well as endogenous CA8 protein expression in neuron-like HEK-293 T cells. However, down-regulation of Sp1, but not Sp4, in 293 T cells revealed a significant reduction of CA8 expression, suggesting that Sp1 is a predominant transcription factor for regulation of CA8 activity. Furthermore, our data indicate that chromatin structure may be involved in the expression of hCA8 gene in MERRF cybrids. Taken together, these results suggest that Sp1 transactivates hCA8 gene through the proximal GC box element in the promoter region. The key modulator-responsive factor to the mtDNA mutation and how it may affect nuclear hCA8 gene transcription need further investigations. PMID- 29407795 TI - Beyond regulation of pol III: Role of MAF1 in growth, metabolism, aging and cancer. AB - MAF1 was discovered as a master repressor of Pol III-dependent transcription in response to diverse extracellular signals, including growth factor, nutrient and stress. It is regulated through posttranslational mechanisms such as phosphorylation. A prominent upstream regulator of MAF1 is the mechanistic target of rapamycin (mTOR) pathway. mTOR kinase directly phosphorylates MAF1, controlling its localization and transcriptional activity. In mammals, MAF1 has also been shown to regulate Pol I- and Pol II-dependent transcription. Interestingly, MAF1 modulates Pol II activity both as a repressor and activator, depending on specific target genes, to impact on cellular growth and metabolism. While MAF1 represses genes such as TATA-binding protein (TBP) and fatty acid synthase (FASN), it activates the expression of PTEN, a major tumor suppressor and an inhibitor of the mTOR signaling. Increasing evidence indicates that MAF1 plays an important role in different aspects of normal physiology, lifespan and oncogenesis. Here we will review the current knowledge on MAF1 in growth, metabolism, aging and cancer. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena. PMID- 29407796 TI - Bisphenol risk in fish exposed to a contamination gradient: Triggering of spatial avoidance. AB - Bisphenol A (BPA) is an emerging contaminant widely used in various industrial products. Sublethal toxicity of BPA on aquatic organisms is expected to occur at a concentration of around 500 MUg L-1, which is much higher than environmentally realistic concentrations found in water bodies (up to 0.41 MUg L-1). However, there is no information concerning how a BPA contamination gradient could affect the spatial displacement of organisms. We hypothesized that fish might be able to detect an environmentally realistic BPA contamination gradient and avoid potential toxic effects due to continuous exposure. Therefore, the objectives of this work were: (i) to determine if BPA could trigger an avoidance response in the freshwater fish Poecilia reticulata; (ii) to assess whether BPA-driven avoidance occurs at environmentally relevant concentrations; and (iii) to estimate the population immediate decline (PID) at the local scale, considering avoidance and mortality as endpoints. Avoidance experiments were performed in a seven-compartment non-forced exposure system, in which a BPA contamination gradient was simulated. The results indicated that BPA triggered avoidance in P. reticulata. In a traditional forced acute toxicity test, lethal effects in 50% of the population occurred at a BPA concentration of 1660 MUg L-1, while in the non forced system with a BPA concentration gradient, avoidance of 50% of the population occurred at a concentration four orders of magnitude lower (0.20 MUg L 1). At environmentally relevant BPA concentrations, PID was mainly determined by the avoidance response. Avoidance in P. reticulata populations is expected to occur at BPA concentrations below those that cause sublethal effects on fish and are considered safe by international agencies (<=1 MUg L-1). The approach used in the present study represents a valuable tool for use in environmental risk assessment strategies, providing a novel and ecologically relevant response that is complementary to traditional ecotoxicological tests. PMID- 29407797 TI - The effect of vitamin C on Cyprinus carpio survival in water environment with chemical toxicants. Some comments. PMID- 29407794 TI - A critical review of assays for hazardous components of air pollution. AB - Increased mortality and diverse morbidities are globally associated with exposure to ambient air pollution (AAP), cigarette smoke (CS), and household air pollution (HAP). The AAP-CS-HAP aerosols present heterogeneous particulate matter (PM) of diverse chemical and physical characteristics. Some epidemiological models have assumed the same health hazards by PM weight for AAP, CS, and HAP regardless of the composition. While others have recognized that biological activities and toxicity will vary with components, we focus particularly on oxidation because of its major role in assay outcomes. Our review of PM assays considers misinterpretations of some chemical measures used for oxidative activity. Overall, there is low consistency across chemical and cell-based assays for oxidative and inflammatory activity. We also note gaps in understanding how much airborne PM of various sizes enter cells and organs. For CS, the body burden per cigarette may be much below current assumptions. Synergies shown for health hazards of AAP and CS suggest crosstalk in detoxification pathways mediated by AHR, NF-kappaB, and Nrf2. These complex genomic and biochemical interactions frustrate resolution of the toxicity of specific AAP components. We propose further strategies based on targeted gene expression based on cell-type differences. PMID- 29407798 TI - Environmentally-realistic concentration of cadmium combined with polyunsaturated fatty acids enriched diets modulated non-specific immunity in rainbow trout. AB - Nutrition is crucial to grow healthy fish particularly in a context of pollution, overcrowding and pathogen risks. Nowadays, the search for food components able to improve fish health is increasingly developing. Here, the influence of four dietary polyunsaturated fatty acids (PUFAs) that are alpha-linolenic acid (ALA, 18:3n-3), linoleic acid (LA, 18:2n-6), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) on the sensitivity of rainbow trout (Oncorhynchus mykiss) juveniles to environmentally realistic cadmium (Cd, 0.3 MUg/L) concentration was investigated. Fish diets were designed to ensure the specific abundance of one of these individual PUFAs, and were given for a 4-week pre-conditioning period followed by a 6-week Cd exposure period. Focus was put on growth performance and immune responses following a short (24 h) and a long-term (6 weeks) Cd exposure. For each experimental condition, some fish were submitted to a bacterial challenge (24 h) with Aeromonas salmonicida achromogenes at the end of Cd conditioning period. DHA-enriched diet improved growth performances as compared to LA-enriched diet, but also increased ROS production (after short-term exposure to Cd) that could lead to a higher inflammation status, and some immunity-related genes (at short and long-term exposure). We notably highlighted the fact that even a low, environmentally-realistic concentration, Cd can strongly impact the immune system of rainbow trout, and that specific dietary PUFA enrichment strategies can improve growth performance (DHA-enriched diet), provide protection against oxidative stress (ALA- and EPA-enriched diet) and stimulate non-specific immunity. PMID- 29407799 TI - Toxicity assessment of pyriproxyfen in vertebrate model zebrafish embryos (Danio rerio): A multi biomarker study. AB - Pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy) ethoxy] pyridine) (PPF), a pyridine-based pesticide widely used to control agricultural insect pests and mosquitoes in drinking water sources. However, its ecotoxicological data is limited in aquatic vertebrates particularly in fish. Hence, the present study aimed to evaluate the adverse effect of PPF in zebrafish embryo development (Danio rerio). In order to investigate the impact of PPF, embryos were exposed to 0.16, 0.33 and 1.66 MUg/mL (0.52, 1.04 and 5.2 MUM, respectively) for 96 hpf and various biomarker indices such as developmental toxicity (edema formation, hyperemia, heart size and scoliosis), oxidative stress (reactive oxygen species (ROS), lipid peroxidation (LPO) and nitric oxide (NO)), antioxidant responses (superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx) and reduced glutathione (GSH)), biochemical (lactate dehydrogenase (LDH) and acid phosphatase (AP)), neurotoxicity (acetylcholinesterase (AChE)), genotoxicity (apoptosis and DNA damage) and histopathological changes were determined. The results showed that severe developmental deformities and changes in heart rate were observed in embryos treated with highest (1.66 MUg/mL) concentration than the control (P < 0.05). Heart size measurement showed that, significant change in heart size (P < 0.01) was observed in embryos of 96 hpf only at 1.66 MUg/mL PPF exposure. The oxidative stress was apparent at highest test concentration (1.66 MUg/mL) as reflected by the elevated ROS, LPO and NO and changes in antioxidant enzyme activities including SOD, CAT, GST and GPx (P < 0.05). Besides, GSH level and AChE activity were significantly lowered in 1.66 MUg/mL PPF exposed group than the control. After 96 hpf of PPF exposure, no significant changes were found in AP activity whereas, a biphasic response was observed in the LDH activity. There was no genotoxic effect in embryos exposed to PPF at 0.16 and 0.33 MUg/mL, while significant (P < 0.05) DNA damage and apoptosis were found in 1.66 MUg/mL treated group. Histopathological analysis revealed that exposure to PPF at 1.66 MUg/mL resulted in thinning of heart muscles, pericardial edema and hyperemia while there was no obvious changes were observed in other treatment groups. Hence, the results of the present study demonstrate that PPF could cause adverse effect on early developmental stages of zebrafish at higher concentration. PMID- 29407800 TI - Novel aspects of uptake patterns, metabolite formation and toxicological responses in Salmon exposed to the organophosphate esters-Tris(2-butoxyethyl)- and tris(2-chloroethyl) phosphate. AB - Given the compound differences between tris(2-butoxyethyl)- and tris(2 cloroethyl) phosphate (TBOEP and TCEP, respectively), we hypothesized that exposure of juvenile salmon to TBOEP and TCEP will produce compound-specific differences in uptake and bioaccumulation patterns, resulting in potential formation of OH-metabolites. Juvenile salmon were exposed to waterborne TCEP or TBOEP (0.04, 0.2 and 1 mg/L) for 7 days. The muscle accumulation was measured and bioconcentration factor (BCF) was calculated, showing that TCEP was less accumulative and resistant to metabolism in salmon than TBOEP. Metabolite formations were only detected in TBOEP-exposed fish, showing seven phase I biotransformation metabolites with hydroxylation, ether cleavage or combination of both reactions as important metabolic pathways. In vitro incubation of trout S9 liver fraction with TBOEP was performed showing that the generated metabolite patterns were similar to those found in muscle tissue exposed in vivo. However, another OH-TBOEP isomer and an unidentified metabolite not present in in vivo exposure were observed with the trout S9 incubation. Overall, some of the observed metabolic products were similar to those in a previous in vitro report using human liver microsomes and some metabolites were identified for the first time in the present study. Toxicological analysis indicated that TBOEP produced less effect, although it was taken up faster and accumulated more in fish muscle than TCEP. TCEP produced more severe toxicological responses in multiple fish organs. However, liver biotransformation responses did not parallel the metabolite formation observed in TBOEP-exposed fish. PMID- 29407801 TI - Effects of copper and butyltin compounds on the growth, photosynthetic activity and toxin production of two HAB dinoflagellates: The planktonic Alexandrium catenella and the benthic Ostreopsis cf. ovata. AB - Controlled laboratory experiments were conducted to test the effects of copper (Cu2+) and butyltins (BuT) on the growth, photosynthetic activity and toxin content of two HABs (Harmful Algal Blooms) dinoflagellates, the planktonic Alexandrium catenella and the benthic Ostreopsis cf. ovata. Microalgae were exposed to increasing concentrations of Cu2+ (10-4 to 31 nM) or BuT (0.084 to 84 nM) for seven days. When considering the growth, EC50 values were 0.16 (+/-0.09) nM and 0.03 (+/-0.02) nM of Cu2+ for A. catenella and O. cf. ovata, respectively. Regarding BuT, EC50 was 14.2 (+/-6) nM for O. cf. ovata, while A. catenella growth inhibition appeared at BuT concentrations >=27 nM. Photosynthetic activity of the studied dinoflagellates decreased with increasing Cu and BuT concentrations. For O. cf. ovata, the response of this physiological parameter to contamination was less sensitive than the biomass. Cu exposure induced the formation of temporary cysts in both organisms that could resist adverse conditions. The ovatoxin-a and -b concentrations in O. cf. ovata cells increased significantly in the presence of Cu. Altogether, the results suggest a better tolerance of the planktonic A. catenella to Cu and BuT. This could result in a differentiated selection pressure exerted by these metals on phytoplankton species in highly polluted waters. The over-production of toxins in response to Cu stress could pose supplementary health and socio-economic threats in the contaminated marine ecosystems where HABs develop. PMID- 29407802 TI - Effects of domestic effluent discharges on mangrove crab physiology: Integrated energetic, osmoregulatory and redox balances of a key engineer species. AB - Mangroves are increasingly used as biofiltering systems of (pre-treated) domestic effluents. However, these wastewater discharges may affect local macrofauna. This laboratory study investigates the effects of wastewater exposure on the mangrove spider crab Neosarmatium meinerti, a key engineering species which is known to be affected by waste waters in effluent-impacted areas. These effects were quantified by monitoring biological markers of physiological state, namely oxygen consumption, the branchial cavity ventilation rate, gill physiology and morphology, and osmoregulatory and redox balance. Adults acclimated to clean seawater (SW, 32 ppt) and freshwater (FW, ~0 ppt) were compared to crabs exposed to wastewater for 5 h (WW, ~0 ppt). Spider crabs exposed to WW increased their ventilation and whole-animal respiration rates by 2- and 3-fold respectively, while isolated gill respiration increased in the animals exposed to FW (from 0.5 to 2.3 and 1.1 nmol O2 min-1 mg DW-1 for anterior and posterior gills, respectively) but was not modified in WW-exposed individuals. WW exposure also impaired crab osmoregulatory capacity; an 80 mOsm kg-1 decrease was observed compared to FW, likely due to decreased branchial NKA activity. ROS production (DCF fluorescence in hemolymph), antioxidant defenses (superoxide dismutase and catalase activities) and oxidative damage (malondialdehyde concentration) responses varied according to animal gender. Overall, this study demonstrates that specific physiological parameters must be considered when focusing on crabs with bimodal breathing capacities. We conclude that spider crabs exposed to WW face osmoregulatory imbalances due to functional and morphological gill remodeling, which must rapidly exhaust energy reserves. These physiological disruptions could explain the ecological changes observed in the field. PMID- 29407803 TI - Comparative effects of Bisphenol S and Bisphenol A on the development of female reproductive system in rats; a neonatal exposure study. AB - Bisphenol A (BPA) has been well documented for its endocrine disrupting potential however, very little is known about endocrine disrupting abilities of bisphenol S (BPS). The present study aimed to compare the endocrine disrupting potentials of BPS with BPA, using female rats as an experimental animal model. On postnatal day 1 (PND 1) female pups born were randomly assigned to seven different treatments. Control group received subcutaneous injection of castor oil (50 MUL) from PND 1 to PND 10. Three groups of female pups were injected subcutaneously with different concentrations (0.5, 5 and 50 mg/kg in 50 MUL castor oil) of BPS, while remaining three groups were treated with 0.5, 5 and 50 mg/kg BPA. Highest doses treatments of both compounds resulted in delayed puberty onset and altered estrous cyclicity. Final body weight was significantly high in the highest dose treated groups of both BPS and BPA. Gonadosomatic index, absolute and relative weight of uteri was significantly reduced in BPS (5 and 50 mg/kg) and BPA (5 and 50 mg/kg) treated groups than control. Plasma concentrations of testosterone and estradiol were significantly increased, while plasma progesterone, Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) concentrations were significantly reduced in highest doses treated groups. Dose dependent increase in the number of cystic follicles in the ovaries was evident along with an increase in the number of atratic follicles. The results suggest that neonatal exposure to higher concentrations of BPS can lead to BPA like structural and endocrine alterations in female rats. PMID- 29407804 TI - Mobility of multiple heavy metalloids in contaminated soil under various redox conditions: Effects of iron sulfide presence and phosphate competition. AB - The mobility of heavy metalloids including As, Sb, Mo, W, and Cr in soil was investigated under both reducing and oxidizing conditions. The effects of soil mineralogy and the presence of competitive anions were studied as important factors affecting the mobility of these contaminants. Batch experiments conducted with the addition of oxidized and fresh FeS exhibited enhanced sorption rates for As and W under oxidizing conditions, and for Mo under reducing conditions. The inhibitory effect of phosphate on the sorption rates was most apparent for As and Mo under both oxidizing and reducing conditions, while only a small phosphate effect was observed for Sb and W. For Sb and W mobility, pH was determined to be the most important controlling factor. The results of long-term batch experiments revealed that differences in the mobility of metalloids, particularly As, were also influenced by microbial activity in the oxidizing and reducing conditions. PMID- 29407805 TI - Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae. AB - Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants (BFRs), has resulted in worldwide environmental contamination. TBBPA has been reported as a thyroid endocrine disruptor and a potential neurotoxicant. However, the underlying mechanism is still not clear. In this study, zebrafish (Danio rerio) embryos (2 h post-fertilization, hpf) were exposed to different concentrations of TBBPA (50, 100, 200 and 400 MUg/L) alone or in combination with 3,3',5-triiodo-l-thyronine (T3, 20 MUg/L + TBBPA, 200 MUg/L). The results confirmed that TBBPA could evoke thyroid disruption by observations of increased T4 contents and decreased T3 contents, accompanied by up-regulated tshbeta, tg mRNA and down-regulated ttr and trbeta mRNA levels in zebafish larvae. TBBPA induced neurodevelopmental toxicity was also indicated by down-regulated transcription of genes related to central nervous system (CNS) development (e.g., alpha1-tubulin, mbp and shha), and decreased locomotor activity and average swimming speed. Our results further demonstrated that treatment with T3 could reverse or eliminate TBBPA-induced effects on thyroidal and neurodevelopmental parameters. Given the above, we hypothesize that the observed neurodevelopmental toxicity in the present study could be attributed to the thyroid hormone disruptions by TBBPA. PMID- 29407806 TI - Chemical speciation of lead in secondary fly ash using X-ray absorption spectroscopy. AB - In this study, fly ash samples were collected from bag houses in a Chinese municipal solid waste incinerator (MSWI) and secondary fly ash (SFA) samples were collected from a high-temperature tubular electric furnace by thermal treatment of MSWI fly ash at 1050, 1100, 1150, 1200, and 1250 degrees C.We determined the speciation and atomic coordinates of lead in SFA using X-ray absorption spectroscopy (XAS) techniques. The results obtained by X-ray absorption near edge structure (XANES) spectra revealed that the mass fraction of PbO in MSWI fly ash was 57.9% (wt %) while PbCl2 and PbS were the dominant species in SFA. Extended X ray absorption fine structure (EXAFS) data analysis indicated the atomic coordinates of Pb were proportional to the weights of PbCl2 and PbS, in good agreement with the XANES spectra. These findings highlight lead evaporation processes in the MSWI fly ash during heat treatment and provide a method for consistent speciation analysis of environmental samples using XAS. PMID- 29407807 TI - pH-dependent roles of polycarboxylates in electron transfer between Cr(VI) and weak electron donors. AB - This study reports that the redox reactions between weak electron donors and Cr(VI) can be significantly accelerated by many environmentally occurring or industrially produced polycarboxylates (PolyCAs). The results demonstrate that oxalic acid (OA) can act as a redox mediator to accelerate the reduction of Cr(VI) by As(III) in pH range of 2.0-5.0, as well as a reductant donating electron for Cr(VI) reduction at pH < 4.0. Density functional theory calculation results indicate that the coordination of OA with Cr(VI) can remarkably enhance the reactivity of the CrO bond in HCrO4- toward oxygen atom transfer or the protonation of oxo groups during Cr(VI) reduction. Moreover, the ligand field effect can also cause instability in the tetrahedral Cr(VI) species, which probably lowers the reaction barrier in the transformation of tetrahedral Cr(VI) to octahedral Cr(III), and therefore favors the reduction of Cr(VI) to Cr(III). Similar to OA, other aliphatic and amino PolyCAs can also accelerate the reduction of Cr(VI), which depends significantly on both the electron transfer capabilities of PolyCAs and their abilities to coordinate chromium species. In general, our findings indicate the novel effect of the interplay between PolyCAs and chromium species on Cr(VI) reduction and provide significant information to develop remediation strategies for Cr(VI) contamination. PMID- 29407808 TI - Phytoremediation of VOCs from indoor air by ornamental potted plants: A pilot study using a palm species under the controlled environment. AB - Volatile organic compounds (VOCs) in indoor air have recently raised public concern due to their adverse health effects. One of hazardous VOC is Formaldehyde which can cause sensory irritation and induce nasopharyngeal cancer. The aim of this study was to investigate potted plant-soil system ability in formaldehyde removal from indoor air. We applied one of common interior plant from the palm species, Chamaedorea elegans, inside a chamber under the controlled environment. Entire plant, growing media and roots contribution in formaldehyde were evaluated by continuously introduction of different concentrations of formaldehyde into the chamber (0.66-16.4 mg m-3) each over a 48-h period. Our findings showed that the plant efficiently removed formaldehyde from polluted air by 65-100%, depending on the inlet concentrations, for a long time exposure. A maximum elimination capacity of 1.47 mg/m2. h was achieved with an inlet formaldehyde concentration of 14.6 mg m-3. The removal ratio of areal part to pot soil and roots was 2.45:1 (71%: 29%). The plants could remove more formaldehyde in light rather than dark environment. Concentrations up to 16.4 mg m-3 were not high enough to affect the plants growth. However, a trivial decrease in chlorophyll content, carotenoid and water content of the treated plants was observed compared to the control plants. Thus, the palm species tested here showed high tolerance and good potential of formaldehyde removal from interior environments. Therefore, phytoremediation of VOCs from indoor air by the ornamental potted plants is an effective method which can be economically applicable in homes and offices. PMID- 29407809 TI - Development of a lipovitellin-based sandwich ELISA for determination of vitellogenin in the marine medaka Oryzias melastigma. AB - A lipovitellin (Lv) based sandwich enzyme-linked immunosorbent assay (ELISA) was developed to quantify vitellogenin (Vtg) in marine medaka (Oryzias melastigma). Lv and Vtg were purified from the unfertilized eggs and the whole body homogenates (WBH) of estradiol (E2)-exposed fish. The purified Lv sample appeared as three clear bands (118, 112 and 100 kDa) in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and was identified as an Lvs mixture from VtgAa and VtgAb by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Polyclonal antibody against marine medaka VtgAa was also raised. Compared with Vtg, Lv was more stable to heat stress (37 degrees C for 8 h or 4 degrees C for a week) and repeated freeze/thaw stress. In addition, western blot analysis revealed that marine medaka Vtg and Lv had similar immunogenicity. Therefore, in this study, Lv was applied instead of Vtg as the standard to establish an ELISA. The Lv standard curve was parallel to serial WBH dilutions of E2-exposed fish, and the absorbance values were very low in control male samples, suggesting the specificity and feasibility of the method for Vtg quantification. The developed assay was sensitive with the detection limit of 3.1 ng/mL and had a working range between 15.6 and 500 ng/mL. The intra- and inter-assay coefficients of variation were both below 5%. Moreover, the standard curves of Lv antigen treated under different stresses were almost identical, indicating high robustness of the assay. Overall, our study provides an important methodology reference for quantification of marine medaka Vtg. PMID- 29407810 TI - Highly effective catalytic peroxymonosulfate activation on N-doped mesoporous carbon for o-phenylphenol degradation. AB - As a broad-spectrum preservative, toxic o-phenylphenol (OPP) was frequently detected in aquatic environments. In this study, N-doped mesoporous carbon was prepared by a hard template method using different nitrogen precursors and carbonization temperatures (i.e., 700, 850 and 1000 degrees C), and was used to activate peroxymonosulfate (PMS) for OPP degradation. For comparison, mesoporous carbon (CMK-3) was also prepared. Characterization results showed that the N doped mesoporous carbon samples prepared under different conditions were perfect replica of their template. In comparison with ethylenediamine (EDA) and dicyandiamide (DCDA) as the precursors, N-doped mesoporous carbon prepared using EDA and carbon tetrachloride as the precursors displayed a higher catalytic activity for OPP degradation. Increasing carbonization temperature of N-doped mesoporous carbon led to decreased N content and increased graphitic N content at the expense of pyridinic and pyrrolic N. Electron paramagnetic resonance (EPR) analysis showed that PMS activation on N-doped mesoporous carbon resulted in highly active species and singlet oxygen, and catalytic PMS activation for OPP degradation followed a combined radical and nonradical reaction mechanism. Increasing PMS concentration enhanced OPP degradation, while OPP degradation rate was independent on initial OPP concentration. Furthermore, the dependency of OPP degradation on PMS concentration followed the Langmuir-Hinshelwood model, reflecting that the activation of adsorbed PMS was the rate controlling step. Based on the analysis by time-of-flight mass spectrometry, the degradation pathway of OPP was proposed. PMID- 29407811 TI - Enhanced Nitrobenzene reduction by zero valent iron pretreated with H2O2/HCl. AB - In this study a novel iron-based reducing agent of highly effective reduction toward nitrobenzene (NB) was obtained by pretreating zero valent iron (ZVI) with H2O2/HCl. During the H2O2/HCl pretreatment, ZVI undergoes an intensive corrosion process with formation of various reducing corrosion products (e.g., Fe2+, ferrous oxides/hydroxides, Fe3O4), yielding a synergetic system (prtZVI) including liquid, suspensions and solid phase. The pretreatment process remarkably enhances the reductive performance of ZVI, where a rapid reduction of NB (200 mg L-1) in the prtZVI suspension was accomplished in a broad pH range (3 9) and at low dosage. Nitrosobenzene and phenylhydroxylamine are identified as the intermediates for NB reduction with the end-product of aniline. Compared with the virgin ZVI as well as another nanosized ZVI, the prtZVI system exhibits much higher electron efficiency for NB reduction as well as higher utilization ratio of Fe0. A rapid reduction of various nitroaromatics in an actual pharmaceutical wastewater further demonstrated the feasibility of the prtZVI system in real wastewater treatment. PMID- 29407812 TI - Performance of nanoscale zero-valent iron in nitrate reduction from water using a laboratory-scale continuous-flow system. AB - Nanoscale zero-valent iron (nZVI) is a versatile treatment reagent that should be utilized in an effective application for nitrate remediation in water. For this purpose, a laboratory-scale continuous-flow system (LSCFS) was developed to evaluate nZVI performance in removal of nitrate in different contaminated-water bodies. The equipment design (reactor, settler, and polisher) and operational parameters of the LSCFS were determined based on nZVI characterization and nitrate reduction kinetics. Ten experimental runs were conducted at different dosages (6, 10 and 20 g) of nZVI-based reagents (nZVI, bimetallic nZVI-Cu, CuCl2 added nZVI). Effluent concentrations of nitrogen and iron compounds were measured, and pH and ORP values were monitored. The major role exhibited by the recirculation process of unreacted nZVI from the settler to the reactor succeeded in achieving overall nitrate removal efficiency (RE) of >90%. The similar performance of both nZVI and copper-ions-modified nZVI in contaminated distilled water was an indication of LSCFS reliability in completely utilizing iron nanoparticles. In case of treating contaminated river water and simulated groundwater, the nitrate reduction process was sensitive towards the presence of interfering substances that dropped the overall RE drastically. However, the addition of copper ions during the treatment counteracted the retardation effect and greatly enhanced the nitrate RE. PMID- 29407813 TI - Carotenoid and superoxide dismutase are the most effective antioxidants participating in ROS scavenging in phenanthrene accumulated wheat leaf. AB - Polycyclic aromatic hydrocarbons (PAHs) are a kind of pollutants which could stimulate stress reaction in plant cells. In this study, we systematically verify that PAHs could induce an oxidative stress in plants, and describe their damages on wheat leaf subcellular structure and organelle, together with the contributions of antioxidants working against reactive oxygen species. The observation of transmission electron microscope exhibits that cell structures become plasmolyzed and distorted, and organelles disappear under phenanthrene (a model PAH) treatments. Osmiophilic granules arise with increasing phenanthrene concentrations, displaying the evidence for oxidative stress. As more H2O2 produce, and the accumulation of H2O2 is a fatal reason for cell death under PAH treatments. Through cluster analysis, Pearson correlation coefficient, principal component analysis and redundancy analysis, carotenoid and superoxide dismutase are the two most effective antioxidants to scavenge superoxide radicals among nine major antioxidants (ascorbate, glutathione, polyamines, alpha-tocopherol, carotenoid, catalases, ascorbate peroxidase, superoxide dismutase and glutathione S-transferase), glutathione-S-transferase is a potential antioxidant, and Asa-GSH cycle would turn active under higher phenanthrene treatments. Ascorbate peroxidase and alpha-tocopherol would cause leaf moisture increase. Thus, this work provides better comprehension on the antioxidant performances and their potential application to improving plants' resistance under PAH pollution in the environment. PMID- 29407814 TI - Polymer dots grafted TiO2 nanohybrids as high performance visible light photocatalysts. AB - As a new member of carbon dots (CDs), Polymer dots (PDs) prepared by hydrothermal treatment of polymers, usually consist of the carbon core and the connected partially degraded polymer chains. This type of CDs might possess aqueous solubility, non-toxicity, excellent stability against photo-bleaching and high visible light activity. In this research, PDs were prepared by a moderate hydrothermal treatment of polyvinyl alcohol, and PDs grafted TiO2 (PDs-TiO2) nanohybrids with TiOC bonds were prepared by a facile in-situ hydrothermal treatment of PDs and Ti (SO4)2. Under visible light irradiation, the PDs-TiO2 demonstrate excellent photocatalytic activity for methyl orange degradation, and the photocatalytic rate constant of PDs-TiO2 is 3.6 and 9.5 times higher than that of pure TiO2 and commercial P25, respectively. In addition, the PDs-TiO2 exhibit good recycle stability under UV-Vis light irradiation. The interfacial TiOC bonds and the pi-conjugated structures in PDs-TiO2 can act as the pathways to quickly transfer the excited electrons between PDs and TiO2, therefore contribute to the excellent photocatalytic activity. PMID- 29407815 TI - Mineralization of sulfolane in aqueous solutions by Ozone/CaO2 and Ozone/CaO with potential for field application. AB - Mineralization of sulfolane in aqueous systems by CaO2/O3 and CaO/O3 was investigated in this study. If 1.6 g/L of oxidants (CaO2 and CaO) were used along with 5 L/min of O3 in a batch reactor, degradation of sulfolane followed a pseudo first order kinetics model. Both sulfolane and TOC were totally removed in less than 40 and 150 min respectively. For these treatments, the pH of the aqueous solutions was above 11, which made O3 more effective in removing sulfolane. However, the high pH of the solution didn't improve TOC removal. For TOC removal the presence of CaO2 and CaO was necessary. Once these conditions were optimised in the lab, field experiments were designed and evaluated to treat contaminated ground water samples. The field tests were successful in mineralization of sulfolane within a reasonable time (4 h). Sulfolane degradation took 150 min in these experiments. The pH of the water samples was brought to near neutral (pH = 6.5) by bubbling CO2. PMID- 29407816 TI - Addressing bystander exposure to agricultural pesticides in life cycle impact assessment. AB - Residents living near agricultural fields may be exposed to pesticides drifting from the fields after application to different field crops. To address this currently missing exposure pathway in life cycle assessment (LCA), we developed a modeling framework for quantifying exposure of bystanders to pesticide spray drift from agricultural fields. Our framework consists of three parts addressing: (1) loss of pesticides from an agricultural field via spray drift; (2) environmental fate of pesticide in air outside of the treated field; and (3) exposure of bystanders to pesticides via inhalation. A comparison with measured data in a case study on pesticides applied to potato fields shows that our model gives good predictions of pesticide air concentrations. We compared our bystander exposure estimates with pathways currently included in LCA, namely aggregated inhalation and ingestion exposure mediated via the environment for the general population, and general population exposure via ingestion of pesticide residues in consumed food crops. The results show that exposure of bystanders is limited relative to total population exposure from ingestion of pesticide residues in crops, but that the exposure magnitude of individual bystanders can be substantially larger than the exposure of populations not living in the proximity to agricultural fields. Our framework for assessing bystander exposure to pesticide applications closes a relevant gap in the exposure assessment included in LCA for agricultural pesticides. This inclusion aids decision-making based on LCA as previously restricted knowledge about exposure of bystanders can now be taken into account. PMID- 29407817 TI - Interactive effects of chronic dietary selenomethionine and cadmium exposure in rainbow trout (Oncorhynchus mykiss): A preliminary study. AB - The present study investigated the interactive effects of dietary cadmium (Cd) and selenium (Se) on the tissue-specific (liver, kidney, and muscle) accumulation of these two elements, hepatic oxidative stress response, and morphometrics in rainbow trout (Oncorhynchus mykiss) during chronic exposure. Fish were exposed to elevated dietary Cd (45 MUg g-1 dry wt.), and medium (10 MUg g-1 dry wt.) or high (45 MUg g-1 dry wt.) dietary selenium (added as selenomethionine), both alone and in combination, for 30 days. Exposure to dietary Cd alone caused oxidative stress in fish as reflected by reduced thiol redox (GSH:GSSG), increased lipid peroxidation, and induction of anti-oxidative enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in the liver. Also, an increase in tissue specific Cd burden and impaired morphometrics (hepato-somatic index and condition factor) were also recorded in fish following exposure to dietary Cd. In contrast, the dietary co-exposure to Cd and Se (at both medium and high doses) resulted in a decrease in Cd burden in the liver and kidney of fish. However, co-exposure to medium, but not high, dose of dietary Se completely alleviated Cd-induced oxidative stress and impaired morphometrics in fish, indicating that the reduced Cd tissue burden might not have been the primary factor behind the amelioration of Cd toxicity by Se. Overall, our study demonstrated that the protective effect of Se against the chronic Cd toxicity in fish is mainly mediated by the anti oxidative properties of Se, but this protective effect is dose-specific and occurs only at a moderate exposure dose. PMID- 29407818 TI - Ciprofloxacin by-products in seawater environment in the presence and absence of gilt-head bream. AB - The widespread use of pharmaceuticals has caused a growing concern on the presence of pharmaceuticals such as the antibiotic ciprofloxacin (CIPRO) in the aquatic environment, since they may exert adverse effects on non-target organisms, including fish. In order to study the uptake, distribution in different tissues (liver, muscle, brain and gill) and biofluids (plasma and bile), metabolism and elimination of CIPRO in gilt-head bream (Sparus aurata), controlled dosing experiments for 8 days at 200 MUg/L concentration were carried out. CIPRO was only observed in bile at concentration up to 315 +/- 4 ng/mL, probably due to its low octanol-water partition coefficient (log P = -2.4 at pH 7.4) and the zwitterionic behavior (pKa1 = 5.76 and pKa2 = 8.68). CIPRO by products (BPs) were also identified in seawater environment, both in presence and absence of fish. The analysis done by means of liquid chromatography-high resolution mass spectrometry (hybrid quadrupole-Orbitrap) permitted the annotation of up to 35 BPs of CIPRO in seawater and bile, from which 30 structures were reported for the first time. These results confirm that CIPRO is very susceptible to photolysis, and that it goes through various phase I and phase II metabolisms in the fish. All these results suggested that, for a complete characterization of CIPRO exposure, BPs should also be included in the biomonitoring campaigns since they might also be toxicologically relevant. PMID- 29407819 TI - Photolysis mechanism of sulfonamide moiety in five-membered sulfonamides: A DFT study. AB - Quantum chemical calculations have been performed to investigate the photolysis mechanism of relatively susceptible sulfonamide moiety of five-membered sulfonamide (SA) antibiotics, such as sulfamethoxazole, sulfisoxazole, sulfamethizole, and sulfathiazole. The results show that the .OH-mediated indirect photolysis of sulfonamide linkage has two possible multi-step reaction pathways, viz., H-abstraction and electrophilic C1-attack, which is contrast to previously reported one-step cleavage manner. The newly proposed indirect photolysis mechanisms could be applied to six-membered SAs such as sulfadimethoxine. It has been found that the dissociation of SN bond is easier in direct photolysis than .OH-mediated indirect photolysis. Wiberg bond index and LUMO-HOMO energy gap are investigated to clarify the origin of the discrepant reactivity of sulfonamide moiety of SAs at singlet and triplet states. In comparison with singlet states, the SN bond of SAs is weaker at triplet states of SAs and thus results in higher reactivity of sulfonamide moiety, as also suggested by smaller LUMO-HOMO energy gap. This study could add better understanding to the photolysis mechanisms of SAs, which would be also helpful in utilizing quantum chemistry calculation to investigate the behavior and fate of antibiotics in the aquatic environment. PMID- 29407820 TI - A novel method for synthesis of polyaniline and its application for catalytic degradation of atrazine in a Fenton-like system. AB - Recently, polyaniline (PANI) has received widespread attention for the free volume, optical transmittance and electrical conductivity. In this study, a chemical vapor deposition method was developed to synthesize the conductive PANI clay composite catalyzed by Fe(III)-saturated attapulgite (Fe(III)-ATTP). The reaction is initiated by the electron transfer from aniline (ANI) to Fe(III), subsequently generating ANI radical cation. The radical could further polymerize and form PANI in the constrained micropore structure of ATTP. The Raman, Fourier transform infrared and X-ray photoelectron spectra confirmed the formation of PANI on Fe(III)-ATTP surface by comparison with the PANI standard. The newly synthesized Fe(III)-ATTP-PANI composite exhibited superior reactivity as indicated by the efficient dissipation of atrazine in the presence of hydrogen peroxide (H2O2), and the degradation rate increased up to almost 150 times compared to Fe(III)-ATTP. The higher reactivity of Fe(III)-ATTP-PANI/H2O2 system was attributed to the accelerated electron transfer, the formation of ferrous ions, and the enhanced adsorption of atrazine onto attapulgite. Furthermore, our experimental results demonstrated that Fe(III)-ATTP-PANI showed good stability and it could be reused for several reaction cycles with high reactivity. This new material could act as an environmental-friendly catalyst in Fenton-like reaction system and show promising potential to effectively eliminate many persistent organic contaminants. PMID- 29407821 TI - A human exposure based mixture of persistent organic pollutants affects the stress response in female mice and their offspring. AB - Persistent organic pollutants (POPs) are found in the food chain of both humans and animals and exert a wide spectrum of potentially adverse effects. The present experiment aimed to investigate whether a defined mixture of 29 POPs, based on the dietary intake of Scandinavians, could affect the stress response in female mice exposed through ingestion, and in their offspring. Female mice 129:C57BL/6F0 hybrids were exposed from weaning, throughout pregnancy, and up until necropsy, to either 5000 * or 100 000 * the estimated daily intake for Scandinavians. The offspring were fed a reference diet containing no POPs. Both the mothers and their offspring were tested for basal and stress responsive corticosterone levels, and in an open field test to measure locomotor activity and anxiety-like behaviours. We found mothers to have elevated basal corticosterone levels, as well as a prolonged stress response following POP exposure. In the offspring, there was no effect of POPs on the stress response in females, but the exposed males had an over-sensitised stress response. There was no effect on behaviour in either the mothers or the offspring. In conclusion, we found a human relevant POP mixture can lead to subtle dysregulation of the hypothalamus-pituitary-adrenal axis in mice. As HPA axis dysregulation is commonly associated with neurological disorders, further studies should explore the relevance of this outcome for humans. PMID- 29407822 TI - Synthesis of graphene/SiO2@polypyrrole nanocomposites and their application for Cr(VI) removal in aqueous solution. AB - A novel hybrid nanocomposite, polypyrrole nanoparticles (PPy) anchored on the graphene/silica nanosheets with the high specific surface area (polypyrrole graphene/silica, GS-PPy), was synthesized by a facile in situ polymerization and shows great potential to remove hexavalent chromium [Cr(VI)] in aqueous solutions. Characterizations by XRD, TEM, SEM, BET, FT-IR and XPS, have confirmed that the PPy nanoparticles were well-distributed on the surface of GS nanosheets. The effects of pH, contact time, the concentration of Cr(VI), temperature, coexisting ions and the number of adsorption-desorption cycles were studied. The maximum adsorption capacity of the GS-PPy for Cr(VI) was 429.2 mg g-1 at 298 K at pH 2, which was much higher than PPy nanoparticles and other related materials. The adsorption data fitted to the pseudo-second-order model and Langmuir isotherm model. The removal mechanism involved in electrostatic attraction, ion exchange and reduction process that partial adsorbed Cr(VI) was reduced to Cr(III). And Cr(III) was still retained on the surface of GS-PPy. The GS-PPy nanocomposite will be a potential candidate for the removal of Cr(VI) from the industrial waste water. PMID- 29407823 TI - Surface-promoted hydrolysis of 2,4,6-trinitrotoluene and 2,4-dinitroanisole on pyrogenic carbonaceous matter. AB - This study investigates the fate of sorbed nitroaromatics on the surface of pyrogenic carbonaceous matter (PCM) to assess the feasibility of a PCM-promoted hydrolysis. The degradation of two nitroaromatic compounds, 2,4,6-trinitrotoluene (TNT) and 2,4-dinitroanisole, was observed at pH 7 in the presence of graphite powder, a model PCM. By contrast, no decay occurred without graphite. Using TNT as a model compound, our results suggest that TNT decay demonstrated a strong pH dependence, with no reaction at pH 3-5 but rapid degradation at pH 6-10. Moreover, by fitting TNT decay at different pH conditions along with its sorption kinetics to the Langmuir Kinetic Model, our results suggest that the base catalyzed hydrolysis was important. The activation energy for TNT decay was obtained by measuring reaction rates at different temperatures with or without graphite and no significant difference was observed. However, the addition of tetramethylammonium cation was able to promote TNT decay possibly due to its ability to attract more OH- from the aqueous solution, leading to an increase in the sorbed OH- concentrations. Nitrite and a Meisenheimer complex were identified as degradation products for TNT. Other PCM, such as biochar, also demonstrated a comparable ability in promoting TNT decay at pH 7. Furthermore, a rapid degradation of TNT at pH 7 was observed when biochar was used as a soil amendment (4% by weight). Our results suggest that PCM can facilitate TNT and 2,4 dinitroanisole decay via a surface-promoted hydrolysis at neutral pH conditions, suggesting a promising alternative for in situ soil remediation. PMID- 29407824 TI - Developmental toxicity induced by PM2.5 through endoplasmic reticulum stress and autophagy pathway in zebrafish embryos. AB - The aims of this study were to investigate the mechanism underlying the developmental toxicity of fine particulate matter (PM2.5) and provide a more thorough understanding of the toxicity of PM2.5 in an ecological environment. Zebrafish embryos at 4 h post-fertilization were exposed to PM2.5 at doses of 200, 300, 400, 500, 600 and 800 MUg/mL for 120 h. The mortality, hatching rate, morphology score, body length, locomotor capacity, histological changes, antioxidant defense system, leukocyte migration, inflammation-related gene mRNA expression, endoplasmic reticulum stress (ERS) and autophagy were evaluated to study PM2.5-induced developmental toxicity and its underlying mechanisms. PM2.5 exposure significantly increased the mortality and malformations and reduced the hatching rate and body length of the zebrafish. PM2.5 significantly reduced the locomotor capacity of zebrafish larvae, increased the levels of ROS and disturbed the antioxidant defense system in zebrafish larvae. In addition, a histological examination showed that the heart, liver, intestines and muscle of the PM2.5 treated zebrafish exhibited abnormal changes and a significant increase in cellular autophagic accumulation. RT-PCR showed that the expression of genes related to inflammation (tgfbeta and cox2), ERS (hspa5, chop, ire1, xbp1s, and atf6) and autophagy (lc3, beclin1 and atg3) pathways was significantly increased in the PM2.5-treated zebrafish, indicating that PM2.5 induced inflammation and promoted ERS and autophagy responses via the activation of the IRE1-XBP1 and ATF6 pathways. Together, our data indicate that PM2.5 induced a dose- and time dependent increase in developmental toxicity to zebrafish embryos. Additionally, ERS and autophagy may play important roles in PM2.5-induced developmental toxicity. PMID- 29407825 TI - Biomonitoring of trace elements in urine samples of children from a coal-mining region. AB - Biomonitoring through urine samples is important for evaluating environmental exposure, since urine is the main form of excretion for most chemical elements. Children are considered more vulnerable to adverse environmental conditions, especially children in developing countries. This study aimed to biomonitor trace elements in urine samples in children from a coal-mining region in the extreme south of Brazil. A cross-sectional study was conducted on 96 children between 6 and 11 years of age. Socioeconomic data and urine samples were collected to estimate the concentration of iron, zinc, selenium, lead, and cadmium. The prevalence of metals above the reference values was 52.0% for Se, followed by 15.6% for Zn. The data point toward a vulnerability to adverse environmental conditions in these children. Although the concentrations of the elements did not reveal intoxication cases, biomonitoring should be carried out continuously in order to assess exposure to metals and ensure the health of the population. This article provides data that help determine natural levels of metallic elements in children, specifically in South America, which have not yet been established. PMID- 29407827 TI - Intuitionistic fuzzy analytical hierarchical processes for selecting the paradigms of mangroves in municipal wastewater treatment. AB - Municipal wastewater discharge is widespread and one of the sources of coastal eutrophication, and is especially uncontrolled in developing and undeveloped coastal regions. Mangrove forests are natural filters of pollutants in wastewater. There are three paradigms of mangroves for municipal wastewater treatment and the selection of the optimal one is a multi-criteria decision making problem. Combining intuitionistic fuzzy theory, the Fuzzy Delphi Method and the fuzzy analytical hierarchical process (AHP), this study develops an intuitionistic fuzzy AHP (IFAHP) method. For the Fuzzy Delphi Method, the judgments of experts and representatives on criterion weights are made by linguistic variables and quantified by intuitionistic fuzzy theory, which is also used to weight the importance of experts and representatives. This process generates the entropy weights of criteria, which are combined with indices values and weights to rank the alternatives by the fuzzy AHP method. The IFAHP method was used to select the optimal paradigm of mangroves for treating municipal wastewater. The entropy weights were entrained by the valid evaluation of 64 experts and representatives via online survey. Natural mangroves were found to be the optimal paradigm for municipal wastewater treatment. By assigning different weights to the criteria, sensitivity analysis shows that natural mangroves remain to be the optimal paradigm under most scenarios. This study stresses the importance of mangroves for wastewater treatment. Decision-makers need to contemplate mangrove reforestation projects, especially where mangroves are highly deforested but wastewater discharge is uncontrolled. The IFAHP method is expected to be applied in other multi-criteria decision-making cases. PMID- 29407826 TI - Activated carbon as a means of limiting bioaccumulation of organochlorine pesticides, triclosan, triclocarban, and fipronil from sediments rich in organic matter. AB - Addition of activated carbon to contaminated sediment is an established means of remediation but its applicability to sediments high in organic carbon is presently unknown. We evaluated the effects of adding either granular activated carbon (GAC) or pelletized fine-grained activated carbon (PfAC, containing ~ 50% AC) to contaminated sediments from Lake Apopka featuring a very high total organic carbon content (~39% w/w dry). Sediments showing background levels of legacy pesticides were spiked with a mixture of 5 chemicals (p,p'-DDE, dieldrin, triclosan, triclocarban, and fipronil) to a nominal concentration of 2 MUg/g sediment for each chemical. Following incubation of spiked sediments with the addition of activated carbon for 30 days, we assessed the success on limiting bioaccumulation using Lumbriculus variegatus (blackworm). In contaminant-spiked sediments amended with PfAC, blackworm body burdens of triclosan, triclocarban, and fipronil decreased by >50% and those of p,p'-DDE and dieldrin decreased by <30%. GAC addition to spiked sediments was less impactful, and yielded notable benefits in worm body burden reduction only for fipronil (40%). Fipronil achieved high treatment efficiency within the 30 day amendment with both GAC and PfAC. This is the first study to examine AC treatment in artificially contaminated sediments intrinsically very rich in organic matter content. PfAC exhibited superior performance over GAC for mitigating the uptake of certain organochlorines by aquatic organisms. These results indicate that further studies focusing on additional types of sediments and a broader spectrum of hydrophobic pollutants are warranted. PMID- 29407828 TI - Prevalence of quinolone resistance genes, copper resistance genes, and the bacterial communities in a soil-ryegrass system co-polluted with copper and ciprofloxacin. AB - The presence of high concentrations of residual antibiotics and antibiotic resistance genes (ARGs) in soil may pose potential health and environmental risks. This study investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) genes, copper resistance genes (CRGs), and the bacterial communities in a soil-ryegrass pot system co-polluted with copper and ciprofloxacin (CIP; 0, 20, or 80 mg kg-1 dry soil). Compared with the samples on day 0, the total relative abundances of the PMQR genes and mobile genetic elements (MGEs) were reduced significantly by 80-89% in the ryegrass and soil by the cutting stage (after 75 days). The abundances of PMQR genes and MGEs were reduced by 63-81% in soil treated with 20 mg kg-1 CIP compared with the other treatments, but the abundances of CRGs increased by 18-42%. The presence of 80 mg kg-1 CIP affected the microbial community structure in the soil by increasing the abundances of Acidobacteria and Thaumarchaeota, but decreasing those of Firmicutes. Redundancy analysis indicated that the pH and microbial composition were the main factors that affected the variations in PMQR genes, MGEs, and CRGs, where they could explain 42.2% and 33.3% of the variation, respectively. Furthermore, intI2 may play an important role in the transfer of ARGs. We found that 80 mg kg-1 CIP could increase the abundances of ARGs and CRGs in a soil ryegrass pot system. PMID- 29407829 TI - Enantioselective biodegradation of the pyrethroid (+/-)-lambda-cyhalothrin by marine-derived fungi. AB - The contamination of agricultural lands by pesticides is a serious environmental issue. Consequently, the development of bioremediation methods for different active ingredients, such as pyrethroids, is essential. In this study, the enantioselective biodegradation of (+/-)-lambda-cyhalothrin ((+/-)-LC) by marine derived fungi was studied. Experiments were performed with different fungi strains (Aspergillus sp. CBMAI 1829, Acremonium sp. CBMAI 1676, Microsphaeropsis sp. CBMAI 1675 and Westerdykella sp. CBMAI 1679) in 3% malt liquid medium with 100 mg L-1 of (+/-)-LC. All strains biodegraded this insecticide and the residual concentrations of (+/-)-LC (79.2-55.2 mg L-1, i.e., 20.8-44.8% biodegradation), their enantiomeric excesses (2-42% ee) and the 3-phenoxybenzoic acid (PBAc) concentrations (0.0-4.1 mg L-1) were determined. In experiments for 28 days of biodegradation in the absence and presence of artificial seawater (ASW) with the most efficient strain Aspergillus sp. CBMAI 1829, increasing concentrations of PBAc with (0.0-4.8 mg L-1) and without ASW (0.0-15.3 mg L-1) were observed. In addition, a partial biodegradation pathway was proposed. All the evaluated strains biodegraded preferentially the (1R,3R,alphaS)-gamma-cyhalothrin enantiomer. Therefore, marine-derived fungi enantioselectively biodegraded (+/-) LC and can be applied in future studies for bioremediation of contaminated areas. This enantioselective biodegradation indicates that the employment of the most active enantiomer GC as insecticide not only enable the use of a lower amount of pesticide, but also a more easily biodegradable product, reducing the possibility of environmental contamination. PMID- 29407830 TI - Shear-thinning fluids for gravity and anisotropy mitigation during soil remediation in the vadose zone. AB - Surfactant foam has been proposed as an effective treatment fluid for in situ environmental remediation of soils. In the vadose zone, it could improve treatment homogeneity, but its use remains challenging. To better understand and predict foam formation and propagation in vadose zone, we studied them in 24 soils with wide range of properties (including permeability: 2 10-12 to 3.3 10-9 m2). Foam rheology showed to be complex and mostly influenced by soil permeability and grading. Below 2 10-11 m2, foam propagation velocity was not influenced by permeability. Conversely, slight shear thinning to Newtonian behavior was observed for higher permeabilities. Benefits for remediation in anisotropic vadose zones and the injection strategies (mobility control agent or blocking agent) were discussed. Moreover, different methods of foam injection were compared over the range of soil permeability. It showed that "surfactant alternating gas" method was the most suitable for soil permeability lower than 5 10-10 m2 to avoid soil fracturing. Conversely, in higher permeability soils, pre generated foam was required to get high viscosity foam. Foam and xanthan polymer solution behaviors were compared across the range of permeability studied. They show similarities, and the benefits of one among the other should be evaluated for each specific case. PMID- 29407831 TI - Efficient degradation of 2,4-dichlorophenol in aqueous solution by peroxymonosulfate activated with magnetic spinel FeCo2O4 nanoparticles. AB - Magnetic spinel FeCo2O4 nanoparticles (NPs) were synthesized and proposed as a catalyst of peroxymonosulfate (PMS) for the degradation of 2,4-dichlorophenol (2,4-DCP). The catalyst was characterized by XRD, TEM, XPS, nitrogen adsorption desorption isotherms, and magnetization curve. In addition, the effects of parameters, such as initial pH, PMS dosage, FeCo2O4 addition, and initial concentration of 2,4-DCP were studied. The results showed that FeCo2O4 NPs exhibit good properties for the degradation and mineralization of 2,4-DCP, achieving 95.8% and 44.7% removal of 2,4-DCP and TOC, respectively, within 90 min under reaction conditions of 4 mM PMS, 0.06 g L-1 FeCo2O4, 100 mg L-1 2,4-DCP, pH = 7.0, and T = 30 degrees C. Furthermore, SO4- and HO were main radical species in the reaction system was explored. The 2,4-DCP degradation efficiency could reach 91.8% even after FeCo2O4 NPs were used for the fifth run. Moreover, the degradation efficiencies of metronidazole (MNZ), methylene blue (MB), and rhodamine B (RhB) could reach 74.8%, 86.7%, and 96.1% under the same reaction conditions, respectively. Results revealed that the FeCo2O4/PMS system shows potential for degrading contaminants in the environment. PMID- 29407832 TI - Emerging brominated flame retardants and dechlorane-related compounds in European eels (Anguilla anguilla) from Latvian lakes. AB - Fifteen halogenated flame retardants (HFRs) including seven emerging brominated flame retardants (EBFRs) and eight dechlorane-related compounds (DRCs) were analyzed in eels (Anguilla anguilla) sampled from five Latvian lakes. Out of the seven EBFRs, hexabromocyclododecane (HBCD) and decabromodiphenyl ethane (DBDPE) were found in eels in quantifiable concentrations, up to 6.58 and 33.0 ng g-1 lipid weight (l.w.), respectively. The mean total concentration of DRCs (?DRC) in the samples was 0.62 ng g-1 l.w. and the geographical distribution of DRC contamination was nearly uniform among the selected lakes. Dechlorane 602 (Dec 602) was the predominant component, whereas the composition of mixture containing syn- and anti-Dechlorane Plus (DP) stereoisomers showed a pronounced enrichment of the anti-DP isomer and was close to the composition of OxyChem(r) DP commercial product. The determined concentrations of HFRs were lower than in other studies of aquatic biota from Europe and Asia, and the obtained results reflect the acceptable environmental status of Latvian lakes with regard to the total content of HBCD (?HBCD), considering the environmental quality standards (EQS) stated in the Directive 2013/39/EU. The highest ?HBCD levels were observed in eels from lakes corresponding to the industrialization of those areas, while the results of principal component analysis (PCA) showed that the concentration of HBCD depended on the particular sampling lake, reflecting non-uniform contamination of the Latvian environment with this EBFR. PMID- 29407833 TI - Partitioning and potential mobilization of aluminum, arsenic, iron, and heavy metals in tropical active and post-active acid sulfate soils: Influence of long term paddy rice cultivation. AB - Drainage of potential acid sulfate soils (PASS) for paddy rice cultivation results in the formation of active acid sulfate soils (AASS) and subsequently post-active acid sulfate soils (PAASS). The drainage of PASS causes severe environmental problems including acidification and metal contamination of soil and water resources. This study examined the vertical distribution and partitioning of Al, As, Co, Cu, Fe, Mn, Ni, Pb, and Zn in six tropical acid sulfate soils representing AASS and PAASS under long-term paddy rice cultivation (>145 years). The bulk soil samples were analyzed for total concentrations of Al, As, Co, Cu, Fe, Mn, Ni, Pb, and Zn. The partitioning of these elements was examined by a sequential extraction procedure. Labile Al is higher in ASS which is associated with low soil pH. During drainage, mobilization of As, Cu, and Pb is limited by coprecipitation with (poorly) crystalline Fe oxides minerals in the topsoil and partly oxidized layer of both soil types. These elements are associated with iron (mono) sulfides in unoxidized layer. When PASS are exposed to air, Co, Mn, Ni, and Zn are leached from the soils and are dominantly associated with iron sulfides in the unoxidized sediments. Labile Mn, Ni, and Zn are elevated in the unoxidized layer of PAASS because these elements are leached from the partly oxidized layers and adsorbed onto soil constituents. Cobalt is probably precipitated or adsorbed onto (poorly) crystalline minerals. PMID- 29407834 TI - The insects as an assessment tool of ecotoxicology associated with metal toxic plants. AB - In this article, the assessment of lethal effects of Copper (Cu) on Luffa acutangula and Spinacia oleracea plants investigated in relation to the presence of insect species Oxycarenus hyalinipennis. The analysis of Cu-treated plants displays the information of rapid growth of Oxycarenus hyalinipennis species in triplicate. However, results showed that the impact of metal toxicity appeared as the reduced growth rate of plants, and dense growth of the insect species Oxycarenus halinipennis followed by the chewing/degradation of the toxic plant. The insect's inductees into polluted plants were justified by morphological and primary molecular level using plant stress hypothesis through analysis of the primary chemistry of leaves and roots. That includes various sugar contents which substantiated that these compounds act as the best feeding stimulant from oviposition to adult stage of the insects and accountable for the enactment of insects in the toxic plants. The relationship of these insects to the toxic plants linked with the higher contents of glucose, carbohydrates, and cellulose. The higher carbohydrate and cellulose content in both plants species under Cu accumulation exhibited more signs of insect mutilation over control plants and the lack of chemical resistances allowed the adult insects to spread, survive, reproduce and live long. The presence of insects developed relationships that assimilate all developmental, biological, and the interactive toxicity of Cu in both plant species which indicate the risk associated with these plants. PMID- 29407835 TI - Occurrence of polybrominated diphenylethers, hexabromocyclododecanes, bromophenols and tetrabromobisphenols A and S in Irish foods. AB - The occurrence of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), tetrabromobisphenol A (TBBPA) and other phenolic brominated flame retardants (BFRs) in Irish foodstuffs has been assessed. A total of 53 food samples including eggs, milk, fish, fat and offal were tested. Eighty-one percent of the samples contained at least one measurable PBDE congener. The most abundant and frequently occurring congeners were BDE-47, BDE-49, BDE-99, BDE-100 and BDE 209 with the highest concentrations found in fish, fat and eggs. Summed concentrations for the measured PBDEs ranged from 0.02 MUg/kg to 1.37 MUg/kg whole weight. At least one HBCD stereoisomer was found in twenty-six percent of the samples with alpha-HBCD being the most frequently detected. The highest concentrations were found in fat and oily fish samples. TBBPA was only detected in one farmed salmon sample at 0.01 MUg/kg. Bromophenol residues were found in fourteen out of the 53 samples, specifically in eggs and fish, with concentrations ranging from 0.28 to 0.98 MUg/kg whole weight. These data contribute to the EU-wide EFSA risk assessment on these contaminants that is currently underway. PMID- 29407836 TI - First report of metallic elements in loggerhead and leatherback turtle eggs from the Indian Ocean. AB - Bio-monitoring of pollutants in long-lived animals such as sea turtles is an important tool in ecotoxicology. We present the first report on metallic elements in sea turtle eggs from the Indian Ocean. Eggs of the leatherback and loggerhead turtle that breed on the Indian Ocean coast of South Africa were analysed for 30 elements. The eggshells and egg contents of the loggerhead turtle, the smaller of the two species, had higher or significantly higher concentrations than leatherbacks, except for strontium - the reason is unknown. Elemental concentrations in eggshells and contents were the same or lower compared with other studies. The differences in concentrations in the egg contents and eggshells between the two species are likely due to different trophic levels, migration patterns, life histories, age, and growth, as well as differences in pollution sources and the uptake, retention and elimination characteristics of the different elements by the different species. We found no congruence between patterns in eggshells and corresponding egg contents, for both species. However, eggshells and egg contents showed congruence between species. The lack of congruence between eggshells and contents within each species precludes using eggshell concentrations as a proxy for egg content concentrations. Copper, strontium, and selenium occurred at concentrations higher than available toxic reverence values. Further research is warranted, including the analyses of POPs, as well as possible deme discrimination based on compositional pattern differences. Turtles serve as 'active samplers' returning to the same location to breed-something that is not practical with marine mammals or elasmobranchs. PMID- 29407837 TI - Enhanced phytoremdiation of Robinia pseudoacacia in heavy metal-contaminated soils with rhizobia and the associated bacterial community structure and function. AB - Heavy metals can cause serious contamination of soils, especially in mining regions. A detailed understanding of the effects of heavy metals on plants and root-associated microbial communities could help to improve phytoremediation systems. In this study, black locust (Robinia pseudoacacia) seedlings with or without rhizobial inoculation were planted in soils contaminated with different levels of heavy metals. Bacterial communities in rhizosphere and bulk soil samples were analyzed using 16S rRNA gene sequencing on the Illumina MiSeq platform and shotgun metagenome sequencing on the Illumina HiSeq platform. Soil bacterial communities varied significantly depending on the level of soil contamination, and planting also had some influence. Although inoculation of Mesorhizobium loti HZ76 (a natural microsymbiont of R. pseudoacacia) was a relatively minor factor, it did influence the soil bacterial community. Under the selective pressure, plant growth promotion-related biomarkers in the rhizosphere increased after inoculation compared with non-inoculated controls, especially those associated with Mesorhizobium, Variovorax, Streptomyces, and Rhodococcus genera. Genes encoding ATP-binding cassette transporters were up-regulated in the rhizosphere after inoculation compared with genes related to sulfur/nitrogen metabolism. These results provide insight into soil bacterial communities and their functions in the R. pseudoacacia rhizosphere in response to rhizobial inoculation and heavy metal contamination. This knowledge may prove useful for improving phytoremediation of metal-contaminated soils. PMID- 29407838 TI - Cr, Cu, Hg and Ni release from incineration bottom ash during utilization in land reclamation - based on lab-scale batch and column leaching experiments and a modeling study. AB - Incineration bottom ash (IBA) as potential material for land reclamation was investigated, based on leaching tests, sorption studies and simulation models. Based on batch and column leaching tests, Cr, Cu, Hg and Ni in the IBA leachates were measured as high as 510 MUg/L, 20330 MUg/L, 5.1 MUg/L and 627 MUg/L, respectively, presenting potential environmental risks. Sorption study was then performed with various concentrations of IBA leachates on sands and excavated materials. Partitioning coefficients of targeting metals were determined to be 6.5 (Cr), 18.4 (Cu), 16.6 (Hg), and 1.8 (Ni) for sands, while 17.4 (Cr), 13.6 (Cu), 67.1 (Hg), and 0.9 (Ni) for excavated materials, much lower than literature in favor of their transportation. Deterministic and Monte Carlo simulation was further performed under designated boundaries, combined with measured geotechnical parameters: density, porosity, permeability, partitioning coefficient, observed diffusivity, hydraulic gradient, etc., to quantitatively predict metals' fate during IBA land reclamation. Environmental risks were quantitatively unveiled in terms of predicted time of breakthrough for the targeting metals (comparing to US EPA criterion for maximum or continuous concentration). Sands were of little effects for all metals' breakthrough (1 month or less) under advection, while excavated materials sufficiently retained metals from thousands up to millions of years, under diffusion or advection. Permeability next to the IBA layer as the major risk-limiting factor, dominated transport of IBA leachates into the field. The current study provides discrimination of environmental risks associated with metals and a quantitative guidance of project design for IBA utilization in land reclamation. PMID- 29407839 TI - Humic acid alleviates the ecotoxicity of graphene-family materials on the freshwater microalgae Scenedesmus obliquus. AB - The extensive application of graphene-family materials (GFMs) has increased its potential risk to aquatic organisms. However, the influence of humic acid (HA) on the biotoxicity of GFMs has not clarified. Here, we conduct a study on the toxicity of four GFMs, i.e. graphene (G), graphene oxide (GO), carboxyl-modified graphene (G-COOH) and amine-modified graphene (G-NH2), with or without HA, using Scenedesmus obliquus (S. obliquus) as model organism. Our results showed that the four GFMs induced significant inhibition on cell growth and Chlorophyll-a (Chl-a) synthesis, loss of cell viability and membrane integrity as well as mitochondrial membrane potential (MMP), where G exhibited the highest toxicity with median effect concentration (EC50) of 8.2 mg L-1, and G-NH2 exhibited the lowest toxicity with EC50 of 84.0 mg L-1. Meanwhile, HA mitigated the toxicity of GFMs in the order of G-NH2 > G-COOH > GO > G for the most of endpoints. Furthermore, three possible mechanisms of the HA alleviation on toxicity were speculated as: (1) reduce the contact of GFMs with algae cells through regulating the structures and surface negative charges of GFMs; (2) mitigate physical penetration and damage through decreasing the deposition of GFMs on cells by interacting with HA; (3) react as an antioxidant with intracellular reactive oxygen species (ROS) and extracellular hydroxyl radical (OH). This work provides useful information for the environmental toxicity of GFMs and the possible antidotal mechanisms in the presence of HA, which could aid to avoiding the overestimation of potential risk of GFMs in natural aquatic environment. PMID- 29407840 TI - Iron oxide - clay composite vectors on long-distance transport of arsenic and toxic metals in mining-affected areas. AB - Mine wastes from abandoned exploitations are sources of high concentrations of hazardous metal(oid)s. Although these contaminants can be attenuated by sorbing to secondary minerals, in this work we identified a mechanism for long-distance dispersion of arsenic and metals through their association to mobile colloids. We characterize the colloids and their sorbed contaminants using spectrometric and physicochemical fractionation techniques. Mechanical action through erosion may release and transport high concentrations of colloid-associated metal(oid)s towards nearby stream waters, promoting their dispersion from the contamination source. Poorly crystalline ferrihydrite acts as the principal As-sorbing mineral, but in this study we find that this nanomineral does not mobilize As independently, rather, it is transported as surface coatings bound to mineral particles, perhaps through electrostatic biding interactions due to opposing surface charges at acidic to circumneutral pH values. This association is very stable and effective in carrying along metal(oid)s in concentrations above regulatory levels. The unlimited source of toxic elements in mine residues causes ongoing, decades-long mobilization of toxic elements into stream waters. The ferrihydrite-clay colloidal composites and their high mobility limit the attenuating role that iron oxides alone show through adsorption of metal(oid)s and their immobilization in situ. This may have important implications for the potential bioavailability of these contaminants, as well as for the use of this water for human consumption. PMID- 29407841 TI - A comprehensive review of phosphorus recovery from wastewater by crystallization processes. AB - The presence of phosphorus (P) in discharged wastewater can lead to water pollution events and eutrophication. Given the increasing consumption of phosphate (PO43-) rocks, wastewater containing large quantities of P is deemed as a potential source of P recovery. Crystallization of P is an ideal way to recover P because of its simple design, ease of operation, high efficiency, and limited environmental impact. This paper provides a comprehensive review of P recovery by crystallization processes with respect to the mechanisms involved, operational parameters that influence the quality of the crystal, and available seed materials for inducing crystallization. Various operational parameters including pH, molar ratio of participating ions, mixing intensity, reactor type, and seeding conditions, were detailedly investigated. Different kinds of seeds were reviewed critically with regard to their principal properties, application, and long-term prospects. Crystallized products with a high P content can be used directly as slow-release fertilizers for agricultural production, and some test methods have been developed to determine their efficiency as a fertilizer and to evaluate their availability for plants. Further, the feasibility of P recovery by crystallization was evaluated in terms of economic benefits and environmental sustainability. This work serves as a basis for future research of P recovery by crystallization processes and responses to the increasingly stringent problems of eutrophication and the growing depletion of P resources. PMID- 29407842 TI - Polychlorinated dibenzo-P-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBS) in bivalve mollusk from Galician Rias (N. W., SPAIN). AB - The concentrations of PCDD/Fs (2,3,7,8-chlorosubstituted) and three dioxin-like PCBs (PCB 77, PCB 126 and PCB169) were analyzed in bivalve mollusk collected in several Galician Rias between 2006 and 2014. Levels of Total PCDD/Fs ranged from 0.03 to 0.62 pg WHO-TEQ g-1 wet weight. Total dl-PCBs values were higher than Total PCDD/Fs and ranged from 0.01 to 2.11 pg WHO-TEQ g-1 wet weight. These concentrations were below those considered safe for human consumption. The PCDD/Fs profile was dominated by 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF with a percentage of 24.95 and 23.87 of the Total PCDD/Fs, respectively. In relation to Total dl-PCBs, CB126 was the priority congener with the highest TEF value (0.1). Principal component analysis (PCAs) indicated a clear separation between the northern (Rias de Ferrol and Coruna) and southern Rias (Ria de Pontevedra and Vigo). The northern Rias were the highest contaminated one. Temporal trends showed important reduction rates suggesting that the regulations on dioxin like contaminants have been effective for quality waters in Galician Rias. PMID- 29407843 TI - Ultrafiltration membrane fouling induced by humic acid with typical inorganic salts. AB - Severe ultrafiltration (UF) membrane fouling is always induced by humic acid (HA). However, little attention has been paid to the influence of inorganic salts, and even the studies related have been limited to only a single kind of salt. In addition, the concentration of the inorganic salts reported in previous studies is much high. Herein, the effect of HA on UF membrane performance was investigated in the presence of typical inorganic salts, with concentrations similar to those in natural waters or actually used in most current water plants. The results showed that membrane performance was influenced little by monovalent inorganic salts (NaCl and KCl), while divalent inorganic salts (CaCl2 and MgCl2) could exacerbate the membrane fouling. For trivalent inorganic salts (AlCl3.6H2O and FeCl3.6H2O), floc adsorption was the dominant HA removing mechanism, and AlCl3.6H2O behaved better than FeCl3.6H2O. Relating to the floc properties, severe membrane fouling occurred with low dosage, while it was mitigated with high dosage. Compared with the trivalent inorganic salts, more severe membrane fouling was caused by divalent inorganic salts. Additionally, little synergistic or inhibitory effect occurred with mixtures of divalent inorganic salts and trivalent inorganic salts. Furthermore, analysis with the classical fouling models showed that cake filtration was the main fouling mechanism with/without inorganic salts. Based on the findings, we believe these different HA behaviors exhibited during coagulation process with inorganic salts will have a large potential application in UF membrane fouling alleviation in water treatment. PMID- 29407844 TI - Iron and sulfur cycling in acid sulfate soil wetlands under dynamic redox conditions: A review. AB - Acid sulfate soils (ASS) contain substantial quantities of iron sulfide minerals or the oxidation reaction products of these sulfidic minerals. Transformation of iron (Fe) and sulfur (S) bearing minerals is an important process in ASS wetlands with fluctuating redox conditions. A range of potentially toxic metals and metalloids can either be adsorbed on or incorporated into the structure of Fe and S bearing minerals. Therefore, transformation of these minerals as affected by dynamic redox conditions may regulate the mobility and bioavailability of associated metals/metalloids. Better understanding of the interaction between Fe/S biogeochemistry and trace metal/metalloid mobility under fluctuating redox conditions is important for assessing contaminant risk to the environment. This review paper provides an overview of current knowledge regarding cycling of Fe, S and selected trace metal/metalloids in ASS wetlands under fluctuating redox conditions and outlines future research challenges and directions on this subject. PMID- 29407845 TI - Bimetallic Au-Pd nanoparticles on 2D supported graphitic carbon nitride and reduced graphene oxide sheets: A comparative photocatalytic degradation study of organic pollutants in water. AB - Novel and sustainable bimetallic nanoparticles of Au-Pd on 2D graphitic carbon nitride (g-C3N4) and reduced graphene oxide (rGO) sheets was designed adopting an eco-friendly chemical route to obtain Au-Pd/g-C3N4 and Au-Pd/rGO, respectively. Elimination of hazardous pollutants, particularly phenol from water is urgent for environment remediation due to its significant carcinogenicity. Considering this aspect, the Au-Pd/g-C3N4 and Au-Pd/rGO nanocomposites are used as photocatalyst towards degradation of toxic phenol, 2-chlorophenol (2-CP) and 2-nitrophenol (2 NP) under natural sunlight and UV light irradiation. Au-Pd/g-C3N4 nanocomposite exhibited higher activity then Au/g-C3N4, Pd/g-C3N4 and Au-Pd/rGO nanocomposites with more than 95% degradation in 180 min under sunlight. The obtained degradation efficiency of our materials is better than many other reported photocatalysts. Incorporation of nitrogen atoms in the carbon skeleton of g-C3N4 provides much better properties to Au-Pd/g-C3N4 nanocomposite than carbon based Au-Pd/rGO leading to its higher degradation efficiency. Due to the presence of these nitrogen atoms and some defects, g-C3N4 possesses appealing electrical, chemical and functional properties. Photoluminescence results further revealed the efficient charge separation and delayed recombination of photo-induced electron-hole pairs in the Au-Pd/g-C3N4 nanocomposite. Generation of reactive oxygen species during photocatalysis is well explained through photoluminescence study and the sustainability of these photocatalyst was ascertained through reusability study up to eight and five consecutive cycles for Au-Pd/g-C3N4 and Au Pd/rGO nanocomposites, respectively without substantial loss in its activity. Characterization of the photocatalysts after reaction signified the stability of the nanocomposites and added advantage to our developed photocatalytic system. PMID- 29407846 TI - Occupancy time in sets of states for demographic models. AB - As an individual moves through its life cycle, it passes through a series of states (age classes, size classes, reproductive states, spatial locations, health statuses, etc.) before its eventual death. The occupancy time in a state is the time spent in that state over the individual's life. Depending on the life cycle description, the occupancy times describe different demographic variables, for example, lifetime breeding success, lifetime habitat utilisation, or healthy longevity. Models based on absorbing Markov chains provide a powerful framework for the analysis of occupancy times. Current theory, however, can completely analyse only the occupancy of single states, although the occupancy time in a set of states is often desired. For example, a range of sizes in a size-classified model, an age class in an age*stage model, and a group of locations in a spatial stage model are all sets of states. We present a new mathematical approach to absorbing Markov chains that extends the analysis of life histories by providing a comprehensive theory for the occupancy of arbitrary sets of states, and for other demographic variables related to these sets (e.g., reaching time, return time). We apply this approach to a matrix population model of the Southern Fulmar (Fulmarus glacialoides). The analysis of this model provides interesting insight into the lifetime number of breeding attempts of this species. Our new approach to absorbing Markov chains, and its implementation in matrix oriented software, makes the analysis of occupancy times more accessible to population ecologists, and directly applicable to any matrix population models. PMID- 29407847 TI - Synthesis of graphenized Au/ZnO plasmonic nanocomposites for simultaneous sunlight mediated photo-catalysis and anti-microbial activity. AB - Sunlight mediated photo-degradation and anti-bacterial activity of hetero junctioned plasmonic binary (Au/ZnO, RGO/ZnO) and ternary (RGO/Au/ZnO) nanocomposites (NC) have been reported. Higher photo-charge carrier generation, increased charge separation, improved active sites for catalysis, enhanced LSPR and larger photo-response regions have been achieved. Decoration with Au nanoparticles (ca. 11 +/- 3 and 48 +/- 5 nm) and RGO of ZnO (3D/1D) microstructures (aspect ratio 15.18) provides ternary NCs an edge over mono/bi component catalysts. The ternary NC have shown improved dye degradation capacity with 100% efficiency (5 MUM MB solution) and average adsorption degradation capacity (Q degrees ) of 83.34 mg/g within 30 min of sunlight exposure (900 +/- 30 Wm-2). Elaborated studies by varying reaction parameters like initial dye concentration, contact time, type of NCs and initial loading of NCs reveals pseudo first order degradation kinetics. 100% microbial killing of Gram positive S.aureus strain with 60 MUg/ml of NC using sunlight as activator has proven the simultaneous multiple functionality of the NC. Further, facile green one pot hydrothermal synthesis with water as reaction medium, absence of photo-corrosion of NCs, regeneration ability (ca. 90% for 10 MUM solution) of NCs, projects a broader potential application of the synthesized NCs and could reduce the continuous requirement of such material, limiting the environmental toxicity. PMID- 29407848 TI - Leptospirosis in Caspian Sea littoral, Gilan Province, Iran. AB - In Iran, leptospirosis is endemic to Caspian Sea littoral. The disease appears as a seasonal infection mostly affecting people in rural areas involved in farming. We investigated the prevalence of this infection among suspected patients in Gilan Province by an indirect immunofluorescent assay (IFA), and two PCR protocols, a nested-PCR and a real-time PCR (qPCR), targeting rrs and lipL32 genes, respectively. We also identified the common Leptospira species by sequencing a partial sequence of rrs gene. Out of the 128 sera examined by IFA, 25.78% were positive with the antibody titers >=1/80. The antibody titer in 39.06% of sera ranged from 1/10 to 1/140, and 35. 16% showed no antibodies, all considered negative. Nested PCR and qPCR detected Leptospira DNA in 20.31% and 18.75% of the sera, respectively. The two PCR assays had 98.43% agreement (K = 0.93) and showed an inverse correlation with the IFA titers. Also, three pathogenic Leptospira species, L. kirschneri (n = 10), L. introgans (n = 8), and L. borgpetersenii (n = 2) were identified from the clinical specimens in the study area. In our hands both PCR assays proved very efficient for early diagnosis of illness and could be used in combination with IFA for both diagnosis and epidemiological studies, but nested PCR was cheaper and appeared more appropriate for our laboratories in rural settings. PMID- 29407849 TI - Morphological and ssrDNA sequence based molecular characterization of a novel Thelohanellus species (Myxosporea: Myxobolidae) infecting the fins of Goldfish, Carassius auratus L. with special reference to its histopathological alteration. AB - A new species of myxozoan, Thelohanellus goldi n. sp. is described using morphological and molecular data, parasitizing the fin filaments from 18 of 25 host specimens (72.5%) of Carassius auratus collected from different ornamental fish farms of India. Mature spore of the new species were oval to spherical in frontal view having rounded posterior ends and tapering anterior end measures 8.7 10.26 (9.50) * 4.10-7.89 (5.84) MUm. The single large polar capsule, round to oval in shape but slightly pointed at the anterior end measuring 4.91-7.63 (5.60) * 2.3-3.1 (2.96) MUm and located just below the anterior end of the spore. Polar filament only at distal end with 5-6 loose coils. The most differentiating feature from closely related species was carried out by morpho-taxonomic affinities with previously described species which are tremendously supported by molecular taxonomy by partial sequencing of the 18S rDNA gene resulted in a total of 2124 bp fragment of newly obtained small subunit ribosomal RNA gene sequence of the new species which Exhibit 93-95% homogeneity with other closely related species available in GenBank. The BLAST search and high genetic diversity of distance matrix of Myxobolus sp. did not properly match with any available sequences in GenBank and make sister clade with Thelohanellus caudatus and Thelohanellus habibpuri in the Thelohanellus clade including most of Thelohanellus spp. The study of evolutionary history enables us to understand the evolution of modern species and supports some uncertain topologies which are being presented regarding the morphometric analysis. The severity of myxozoan infection has been assessed in this article by observing the histopathological changes of fins of the C. auratus along with the diversity, distribution and taxonomic description of the new Thelohanellus species with their new host and locality records. PMID- 29407850 TI - In vivo treatment with IL-17A attenuates hydatid cyst growth and liver fibrogenesis in an experimental model of echinococcosis. AB - We aimed to assess the effect of exogenous Interleukin (IL)-17A in experimental model of echinococcosis. Swiss mice were inoculated intra-peritoneally with viable protoscoleces (PSCs). Then, IL-17A was administered at 100, 125 or 150 pg/mL two weeks after cystic echinococcosis (CE) induction. Cyst development and hepatic damage were macroscopically and histologically analyzed. We observed that in vivo IL-17A treatment at 100, 125, and 150 pg/mL, reduced metacestode growth by 72.3%, 93.8%, and 96.9%, respectively. Interestingly an amelioration of liver architecture was noted at 125 pg/mL without toxic effect. In this context, we showed less fibrosis reaction and reduced expression of iNOS, TNF-alpha, NF kappab and CD68 in hepatic parenchyma of treated mice by 125 pg/mL of IL-17A. Collectively, our results indicate an antihydatic effect and immunoprotective properties of IL-17A and suggest its potential therapeutic value against Echinococcus granulosus infection. PMID- 29407851 TI - Intergenerational transmission of harsh discipline: The moderating role of parenting stress and parent gender. AB - The present study examined the intergenerational transmission of harsh discipline (psychological aggression and corporal punishment) and the moderating effects of parenting stress and parent gender in Chinese societies. Utilizing a sample of 634 Chinese father-mother dyads with preschoolers, findings revealed that both mothers' and fathers' harsh discipline were transmitted across generations and the strength of transmission varied by the severity of harsh discipline and the parent gender. For both mothers and fathers, high parenting stress intensified the intergenerational transmission of psychological aggression and corporal punishment, whereas low parenting stress weakened the transmission of psychological aggression and even disrupted the transmission of corporal punishment. Moreover, the moderating effects of parenting stress on the transmission were stronger for mothers than for fathers. Findings from the present study highlight the importance of considering how the proximal environmental factors (such as parenting stress) may influence the intergenerational transmission of harsh discipline. PMID- 29407852 TI - National survey of hospital child protection teams in Japan. AB - This study aimed to investigate the penetration rate of child protection teams (CPTs) in medical institutions and associations between CPT functions and hospital services. We collected data in October of 2015 from 377 hospitals in Japan offering pediatric organ transplantation. The questionnaire included questions regarding the existence of a CPT, the number of child maltreatment cases discussed and reported per year, CPT functions including 21 items about staffing, manuals, meeting, prevention, education, and collaboration, and the services provided by the hospital. Of the 377 institutions, 122 (32.4%) answered the survey. There were significant associations between CPT functions and the number of pediatric beds (r = .27), number of pediatricians (r = .27), number of outpatients (r = .39), number of emergency outpatients (r = .28), and emergency medical care (p = .009). In a multiple regression analysis, CPT functions were significantly associated with the number of CPT members, pediatric outpatient numbers, and pediatric emergency outpatient numbers. Japan has no CPT guidelines that outline what CPTs should offer in terms of structure, staffing, functions, and systems. Hospitals with many pediatric and emergency outpatients are expected to play major roles in providing services such as specialty care, intensive care, and education. They are also expected to play a role in detecting and managing child maltreatment, and have, by their own initiative, improved their capacities to achieve these goals. PMID- 29407853 TI - The relationship between child protection contact and mental health outcomes among Canadian adults with a child abuse history. AB - Despite being a primary response to child abuse, it is currently unknown whether contact with child protection services (CPS) does more good than harm. The aim of the current study was to examine whether contact with CPS is associated with improved mental health outcomes among adult respondents who reported experiencing child abuse, after adjusting for sociodemographic factors and abuse severity. The data were drawn from the 2012 Canadian Community Health Survey-Mental Health (CCHS-2012), which used a multistage stratified cluster design (household-level response rate = 79.8%). Included in this study were individuals aged 18 years and older living in the 10 Canadian provinces (N = 23,395). Child abuse included physical abuse, sexual abuse, and exposure to intimate partner violence (IPV). Mental health outcomes included lifetime mental disorders, lifetime and past year suicidal ideation, plans, and attempts, and current psychological well-being and functioning and distress. All models were adjusted for sociodemographic factors and severity of child abuse. For the majority of outcomes, there were no statistically significant differences between adults with a child abuse history who had CPS contact compared to those without CPS contact. However, those with CPS contact were more likely to report lifetime suicide attempts. These findings suggest that CPS contact is not associated with improved mental health outcomes. Implications are discussed. PMID- 29407854 TI - Domestic violence, parental substance misuse and the decision to substantiate child maltreatment. AB - Families that experience domestic violence and parental substance misuse are disproportionately involved with the child welfare system. Prior research suggests that child protective services (CPS) caseworkers are more likely to substantiate maltreatment allegations when domestic violence and parental substance misuse are identified during the investigation, pointing to one possible mechanism for this disproportionate involvement. While previous studies have relied on nationally representative data sets, the current study used administrative records from a large Midwestern child welfare agency that accounts for state-level variation in child welfare policy and practice. A total of 501,060 substantiation decisions made between 2009 and 2013 were examined to assess the influence of caseworker-perceived domestic violence and parental substance misuse on the decision to substantiate reported maltreatment. Results from multilevel modeling suggest that the identification of domestic violence and parental substance misuse during an investigation significantly increased the probability that an allegation would be substantiated. The implication of these findings for child welfare practice are considered in light of the fact that many child welfare agencies do not consider exposure to domestic violence and parental substance misuse in and of themselves to constitute child maltreatment. PMID- 29407855 TI - Developmental effects of childhood household adversity, transitions, and relationship quality on adult outcomes of socioeconomic status: Effects of substantiated child maltreatment. AB - The degree to which child maltreatment interacts with other household adversities to exacerbate risk for poor adult socioeconomic outcomes is uncertain. Moreover, the effects of residential, school, and caregiver transitions during childhood on adult outcomes are not well understood. This study examined the relation between household adversity and transitions in childhood with adult income problems, education, and unemployment in individuals with or without a childhood maltreatment history. The potential protective role of positive relationship quality in buffering these risk relationships was also tested. Data were from the Lehigh Longitudinal Study (n = 457), where subjects were assessed at preschool, elementary, adolescent, and adult ages. Multiple group path analysis tested the relationships between childhood household adversity; residential, school, and caregiver transitions; and adult socioeconomic outcomes for each group. Caregiver relationship quality was included as a moderator, and gender as a covariate. Household adversity was negatively associated with education level and positively associated with income problems for non-maltreated children only. For both groups, residential transitions was negatively associated with education level and caregiver transitions was positively associated with unemployment problems. Relationship quality was positively associated with education level only for non maltreated children. For children who did not experience maltreatment, reducing exposure to household adversity is an important goal for prevention. Reducing exposure to child maltreatment for all children remains an important public health priority. Results underscore the need for programs and policies that promote stable relationships and environments. PMID- 29407856 TI - Suggestibility in neglected children: The influence of intelligence, language, and social skills. AB - We administered the GSS-2, a standardised measure of suggestibility, to 5- to 12 year-old children to ascertain whether neglected children's responses to leading questions distinguish them from those of their non-neglected counterparts. Neglected children (n = 75) were more likely than an age-matched sample of non neglected children (n = 75) to yield to leading questions, despite no difference in their ability to recall the test stimuli. Subsequent collection of individual difference data from the neglected sample revealed that this effect could not be attributed to intelligence, language ability, problem behaviours, age at onset of neglect, or time spent in out-of-home care. With respect to social skill, however, suggestibility was positively correlated with communicative skill, and marginally positively correlated with assertion and engagement. While on the surface our social skills findings seem counter-intuitive, it is possible that maltreated children with relative strengths in these areas have learned to comply with adults in their environment as a way to protect themselves or even foster belonging. Our data, while preliminary, raise interesting questions about whether targeted interventions could help these children to more actively participate in decisions about their lives. PMID- 29407857 TI - "Movement of the sacroiliac joint during the active straight leg raise test in patients with long-lasting severe sacroiliac joint pain"-A letter to the editor. PMID- 29407858 TI - Biomechanical and physiological age differences in a simulated forward fall on outstretched hands in women. AB - BACKGROUND: Falling on the outstretched hands, a protective mechanism to arrest the body and avoid injury, requires upper limb and trunk motor control for effective body descent. Older women are particularly susceptible to injury from a forward fall, but the biomechanical and physiological (e.g., muscle strength) factors related to this increased risk are poorly understood. Determining age differences in the modifiable neuromuscular factors related to a forward fall landing and descent could help to inform injury prevention strategies. The purpose was to investigate age related differences in upper extremity strength and fall arrest strategy differences during a simulated fall and to evaluate the relationships between muscle strength and biomechanical variables. METHODS: Nineteen younger (mean age 23.0 yrs., SD 3.8) and 16 older (mean age 68.2 yrs., SD 5.3) women performed five trials of simulated falls. Biomechanical measures and electromyographic muscle activity were recorded during the descents. Concentric, isometric and eccentric strength of the non-dominant upper limb was measured via a dynamometer using a customized protocol. FINDINGS: Older women demonstrated lower concentric elbow extension strength compared to younger women (p = 0.002). Landing strategies differed where younger women had significantly greater elbow joint angle (p = 0.006) and velocity (p = 0.02) at impact. Older women demonstrated diminished capacity to absorb energy and control descent on outstretched hands compared to younger women (p = 0.001). INTERPRETATION: The landing strategy used by older women along with decreased energy absorption may increase risk of fall-related injury and increase the likelihood of trunk or head impact with the ground. PMID- 29407859 TI - An index to quantify deviations from normal trunk mobility: Clinical correlation and initial test of validity. AB - BACKGROUND: In case of people suffering from chronic low back pain, specific movements of the hip, pelvis, and trunk are associated with pain. Comparing range of motion measurements for multiple planes and from different segments and lines in reference to those of healthy individuals seems interesting but present interpretations challenge in relation to important number of variables and correlation with clinical data. METHODS: The proposed index is based on using principal component analysis to quantify differences in trunk mobility between patients with chronic low back pain and a control group. Kinematic data were recorded for the cervical and thoracic vertebrae, the lumbar spine, and the pelvic and scapular belts during repeated trials (hip flexion and extension, hip bending, and trunk twists). Angular motion values were calculated. Principal component analysis was used to convert 10 discrete variables (kinematical data) extracted from control data into 10 independent variables. FINDINGS: The proposed index comprises the sum of the variables. Initial demonstration of its clinical utility and statistical tests of this index validity were revealed. It establishes correlations between the psychosocial impact of chronic low back pain, trunk mobility (as summarized by the index) and the positive effects of functional restoration program. INTERPRETATION: This index let to assess the absolute potential benefits of rehabilitation in term of kinematic motion. Functional restoration program promotes the physical functioning of patients by increasing their range of motion. This index uses kinematic motion to assess the potential benefits of such rehabilitation program. PMID- 29407860 TI - Biomechanical evaluation of pyrocarbon proximal interphalangeal joint arthroplasty: An in-vitro analysis. AB - BACKGROUND: Pyrocarbon proximal interphalangeal joint arthroplasty provided patients with excellent pain relief and joint motion, however, overall implant complications have been very variable, with some good outcomes at short-medium term follow-up and some bad outcomes at longer-term follow-up. Implant loosening with migration, dislocation and implant fracture were the main reported clinical complications. The aim of the present work was to test the hypothesis that the magnitude proximal interphalangeal joint cyclic loads in daily hand functions generates stress-strain behaviour which may be associated with a risk of pyrocarbon component loosening in the long-term. METHODS: This study was performed using synthetic proximal and middle phalanges to experimentally predict the cortex strain behaviour and implant stability considering different load conditions for both intact and implanted states. Finite element models were developed to assess the structural behaviour of cancellous-bone and pyrocarbon components, these models were validated against experimentally measured cortex strains. FINDINGS: Cortex strains showed a significant increase at dorsal side and reduction at palmar side between intact and implanted states. Cancellous-bone adjacent to the condylar implant base components suffers a two to threefold strain increase, comparing with the intact condition. INTERPRETATION: The use of pyrocarbon implant changes the biomechanical behaviour of the joint phalanges and is associated with a potential risk of support cancellous-bone suffer fatigue failure in mid to long term due to the strain increase for cyclic loads in the range of daily hand activities, this risk is more prominent than the risk of bone resorption due to strain-shielding effect. PMID- 29407861 TI - Answer to Hu Hai on the letter to the editor about the article "Movement of the Sacroiliac Joint during the Active Straight Leg Raise test in patients with long lasting severe sacroiliac joint pain". PMID- 29407862 TI - The effects of body weight unloading on kinetics and muscle activity of overweight males during Overground walking. AB - BACKGROUND: Excess body weight has become a major worldwide health and social epidemic. Training with body weight unloading, is a common method for gait corrections for various neuromuscular impairments. In the present study we assessed the effects of body weight unloading on knee and ankle kinetics and muscle activation of overweight subjects walking overground under various levels of body weight unloading. METHODS: Ten overweight subjects (25 <= BMI < 29.9 kg/m2) walked overground under a control and three (0%, 15%, 30%) body weight unloading experimental conditions. Gait parameters assessed under these conditions included knee and ankle flexion moments and the Electromygraphic activity of the Tibialis Anterior, Lateral Gastrocnemius and Vastus Lateralis. FINDINGS: Increasing body weight unloading levels from 0% to 30% was found to significantly reduce the peak knee flexion and ankle plantarflexion moments. Also observed was a significant reduction in muscle activity of the Tibialis Anterior, Lateral Gastrocnemius and Vastus Lateralis under the three body-weight unloading conditions. INTERPRETATION: Our results demonstrate that a reduction of up to 30% overweight subjects' body weight during gait is conducive to a reduction in the knee and ankle flexion moments and in the balancing net quadriceps moment and ankle flexors moment. The newly devised body weight unloading device is therefore an effective method for reducing joint loads allowing overweight people who require controlled weight bearing scenarios to retrain their gait while engaging in sustained walking exercise. PMID- 29407863 TI - Biomechanics of a cemented short stem: Standard vs. line-to-line cementation techniques. A biomechanical in-vitro study involving six osteoporotic pairs of human cadaver femurs. AB - BACKGROUND: Short-stem total hip arthroplasty (THA) potentially offers advantages compared to conventional THA, including sparing bone and soft tissue and being a facilitated and less traumatic implantation. However, the indication is limited to patients with sufficient bone quality. Cemented short-stem THA might provide an alternative to conventional cemented THA. To date, no cemented short stem is available on the market. METHODS: In the present in vitro study, primary stability of a new cemented short stem was evaluated, comparing standard (undersized stem) versus line-to-line (same-sized stem) cementing techniques, using six pairs of human cadaver femurs. Primary stability, including reversible micromotion and irreversible migration, was assessed in a dynamic material testing machine. Fracture load was tested and fracture pattern analyzed. FINDINGS: Both cementation techniques (standard vs. line-to-line) displayed comparable results with respect to primary stability without any statistical differences (micromotion: 17.5 MUm vs. 9.6 MUm (p = 0.063); migration: 9.5 MUm vs. 38.2 MUm (p = 0.188)). Regarding fracture load, again, no difference was observed (3670 N vs. 3687 N (p = 0.063)). In all cases, proximal fractures of Vancouver type B3 occurred. INTERPRETATION: The present in vitro study demonstrates that the line-to-line cementation technique, which is favourable regarding the philosophy of short stem THA, can be further pursued in the course of the development of a cemented short stem. Further investigations should address how well the cemented short stem compares to well-established cemented straight-stem designs. PMID- 29407864 TI - Local bone quality measurements correlates with maximum screw torque at the femoral diaphysis. AB - BACKGROUND: Successful fracture fixation depends critically on the stability of the screw-bone interface. Maximum achievable screw torque reflects the competence of this interface, but it cannot be quantified prior to screw stripping. Typically, the surgeon relies on the patients' bone mineral density and radiographs, along with experience and tactile feedback to assess whether sufficient compression can be generated by the screw and bone. However, the local bone quality would also critically influence the strength of the bone-screw interface. We investigated whether Reference Point Indentation can provide quantitative local bone quality measures that can inform subsequent screw-bone competence. METHODS: We examined the associations between the maximum screw torque that can be achieved using 3.5 mm, 4.5 mm, and 6.5 mm diameter stainless steel screws at the distal femoral metaphysis and mid-diaphysis from 20 cadavers, with the femoral neck bone mineral density and the local measures of bone quality using Reference Point Indentation. FINDINGS: Indentation Distance Increase, a measure of bone's resistance to microfracture, correlated with the maximum screw stripping torque for the 3.5 mm (p < 0.01; R = 0.56) and 4.5 mm diameter stainless steel screws (p < 0.01; R = 0.57) at the femoral diaphysis. At the femoral metaphysis, femoral neck bone mineral density significantly correlated with the maximum screw stripping torque achieved by the 3.5 mm (p < 0.01; R = 0.61), 4.5 mm (p < 0.01; R = 0.51), and 6.5 mm diameter stainless steel screws (p < 0.01; R = 0.56). INTERPRETATION: Reference Point Indentation can provide localized measurements of bone quality that may better inform surgeons of the competence of the bone-implant interface and improve effectiveness of fixation strategies particularly in patients with compromised bone quality. PMID- 29407865 TI - An investigation of the pH dependence of copper-substituted anthrax lethal factor and its mechanistic implications. AB - Anthrax lethal factor (LF) is a zinc-dependent endopeptidase involved in the cleavage of proteins critical to the maintenance of host signaling pathways during anthrax infections. Although zinc is typically regarded as the native metal ion in vivo, LF is highly tolerant to metal substitution, with its replacement by copper yielding an enzyme (CuLF) 4.5-fold more active than the native zinc protein (at pH 7). The current study demonstrates that by careful choice of the buffer, ionic strength, pH and substrate, the activity ratio of CuLF and native LF can be increased to >40-fold. Using a fluorogenic LF substrate, such optimized assay conditions can be exploited to detect LF concentrations as low as 2 pM. In contrast to the zinc form, CuLF was found to be inhibited by bromide and iodide ions, to be resistant to metal loss under acidic conditions, and to display a sharp pH dependence with significantly shifted alkaline limb towards more acidic conditions. The alkaline limb in the enzyme's pH profile is suggested to originate from changes in the protonation state of the metal-bound water molecule which serves as the nucleophile in the catalytic mechanism. Based on these observations and studies on other zinc proteases, a minimal mechanism for LF is proposed. PMID- 29407866 TI - Synthesis, characterization and cytotoxic activity of novel copper(II) complexes with aroylhydrazone derivatives of 2-Oxo-1,2-dihydrobenzo[h]quinoline-3 carbaldehyde. AB - Three new 2-oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde terminal substituted aroylhydrazone ligands (2-Oxo-1,2-dihydrobenzo[h]quinoline-3-carbaldehyde(2' hydroxybenzoyl)hydrazine, H2L1, 1, 2-Oxo-1,2-dihydrobenzo[h]quinoline-3 carbaldehyde(2'-hydroxybenzoyl)hydrazine, H2L2, 2, 2-Oxo-1,2 dihydrobenzo[h]quinoline-3-carbaldehyde(2'-hydroxybenzoyl)hydrazine, H2L3, 3) and the corresponding novel copper(II) complexes [Cu(L)(CH3OH)(NO3)](L = HL1 (4), HL2 (5), HL3 (6-6+), have been synthesized to compare their coordination behaviour and biological activity with respect to the presence of an OH group in different positions of the phenyl ring in the hydrazone moieties. The new ligands and their copper complexes were characterized by elemental analysis and spectroscopic techniques. The molecular structures of the new complexes 4 and 6-6+ were determined by single crystal X-ray diffraction. The interactions of the free ligands and their copper complexes with calf thymus DNA were tested by absorption measurements and ethidium bromide competitive studies which revealed that all compounds may interact with calf thymus DNA through intercalation. Furthermore, a comparative analysis of the cytotoxic effect of the compounds on a panel of human cancer cell lines showed that the copper complexes exhibited in vitro antitumor activity significantly higher than that of the free ligands and also of cisplatin. PMID- 29407867 TI - Tuning the MnII2/MnIII2 redox cycle of a phenoxo-bridged diMn catalase mimic with terminal carboxylate donors. AB - A new phenoxo-bridged diMnIII complex, Na[Mn2L(OH)2(H2O)2].5H2O (1), obtained with the ligand L5- = 5-methyl-2-hydroxo-1,3-xylene-alpha,alpha-diamine-N,N,N',N' tetraacetato, has been prepared and characterized. Mass spectrometry, conductivity, UV-visible, EPR and 1H NMR spectroscopic studies showed that the complex exists in solution as a monoanionic diMnIII complex. Complex 1 catalyzes H2O2 disproportionation with second-order rate constant kcat = 305(9) M-1 min-1 and without a time-lag phase. Based on spectroscopic results, the catalase activity of complex 1 in methanol involves a MnIII2/MnII2 redox cycle, which distinguishes this catalyst from other phenoxo-bridged diMn complexes that cycle between MnIIMnIII/MnIIIMnIV species. Addition of base stabilizes the catalyst, restrains demetallation during catalysis and causes moderate enhancement of catalase activity. The terminal carboxylate donors of 1 not only contribute as internal bases to assist deprotonation of H2O2 but also favor the formation of active homovalent diMn species, just as observed for the enzyme. PMID- 29407868 TI - Carboxyl groups of citric acid in the process of complex formation with bivalent and trivalent metal ions in biological systems. AB - Binary complexes of citric acid (H3L - protonated form, H2L and HL - partly protonated forms, L - fully deprotonated) with d- and f-electron metal ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data, electron paramagnetic resonance, infrared, visible as well as luminescence spectroscopies. The overall stability constants of the complexes were determined. Analysis of the equilibrium constants of the reactions and spectroscopic data has allowed determination of the type of coordination and effectiveness of the carboxyl groups in the process of complex formation. On the basis of potentiometric titration for d-electron were found dimeric and monomeric type of complexes and for f-electron four type of complexes: MHL, ML, ML(OH) and ML(OH)2. PMID- 29407869 TI - Europium(III)-doped yttrium vanadate nanoparticles reduce the toxicity of cisplatin. AB - The aim of this study was to evaluate the antitumor efficiency of chemotherapy with cisplatin alone and incorporated into europium(III)-doped yttrium vanadate nanoparticles functionalized with 3-chloropropyltrimethoxysilane with folic acid and without folic acid in a syngeneic mouse melanoma model. Histopathological, biochemical and genotoxic analyses of treated animals were performed to assess the toxicity of treatments. The treatment of the animals with cisplatin alone and the nanoparticles functionalized with cisplatin at a dose of 5 mg/kg b.w. for 5 days reduced tumor weight about 86% and 65%, respectively. Histopathological analysis showed lower mean frequency of mitoses in tumor tissue of the groups receiving cisplatin alone (90% reduction) and the nanoparticles functionalized with cisplatin (70% reduction) compared to the tumor control group. A reduction in body and liver weight and an increase in serum creatinine and urea levels were observed in animals treated with CDDP, but not in those receiving the nanoparticles functionalized with cisplatin. Genotoxicity assessment by the comet assay revealed lower frequencies of DNA damage in animals treated with the nanoparticles functionalized with cisplatin (mean score = 140.80) compared to those treated with cisplatin alone (mean score = 231.80). Marked toxic effects were observed in animals treated with cisplatin alone, while treatment with the nanoparticles functionalized with cisplatin showed no toxicity. Moreover, folic acid in the inorganic nanoparticles reduced the genotoxicity of cisplatin in the bone marrow micronucleus test (10 +/- 1.4 and 40 +/- 0.0 micronucleus, respectively). These results demonstrate the antitumor efficiency and significantly reduced systemic toxicity of the nanoparticles compared to CDDP. PMID- 29407870 TI - Contributions of the snake venoms of Bothrops asper, Crotalus simus and Lachesis stenophrys to the paraspecificity of the Central American polyspecific antivenom (PoliVal-ICP). AB - PoliVal-ICP antivenom is produced from plasma of horses immunized toward the venoms of Bothrops asper, Crotalus simus and Lachesis stenophrys. The antibody response induced by these venoms confers PoliVal-ICP the capacity to neutralize the venoms of the most important Central American viperids, including not only homologous venoms (i.e., venoms used as immunogen), but many heterologous venoms (i.e., venoms not used as immunogen). In this work, the individual contributions of homologous venoms to the paraspecificity of PoliVal-ICP were inferred from the capacity of experimental monospecific antivenoms toward venoms of B. asper (anti Ba), C. simus (anti-Cs) and L. stenophrys (anti-Ls), and an experimental polyspecific antivenom (anti-Ba/Cs/Ls) to neutralize the lethality induced by different venoms in mice. It was found that all antivenoms neutralized their corresponding homologous venoms. Moreover, the anti-Ba antivenom cross neutralized the venoms of Agkistrodon howardgloydi, Atropoides picadoi, Bothriechis lateralis, Bothriechis supraciliaris and Porthidium ophryomegas; the anti-Cs antivenom cross-neutralized the venoms of B. lateralis, B. supraciliaris, Cerrophidion sasai and Porthidium nasutum; and the anti-Ls antivenom cross neutralized the venoms of B. lateralis, B. supraciliaris, C. sasai and Lachesis melanocephala. All venoms neutralized by any monospecific antivenom were also neutralized by the anti-Ba/Cs/Ls antivenom. Venoms of Atropoides mexicanus, Bothriechis nigroviridis and Bothriechis schlegelii were not neutralized by any experimental antivenom, thus explaining the limitations of PoliVal-ICP to neutralize these venoms. Consequently, an enlargement of the neutralization scope of PoliVal-ICP could be achieved by including these venoms in the group of those used as immunogens. PMID- 29407871 TI - L-amino acid oxidase from snake venom and its anticancer potential. AB - L-amino acid oxidase (LAAO) is a protein toxin commonly found in snake venom. It has many applications, ranging from biotechnology to potential anticancer therapeutics. LAAO converts L-amino acid into alpha-keto acid and release ammonia and hydrogen peroxide as by-products. Induction of oxidative stress in cancer cells is one of the cancer treatment strategies as controlled and targeted release of hydrogen peroxide can theoretically induce sufficient oxidative stress to kill cancer cells. Furthermore, L-amino acid oxidase has been shown to selectively bind to cell membranes of specific phospholipid composition and deliver the hydrogen peroxide to localized regions on the cell surface. In this mini review, we discuss the relevance of L-amino acid oxidase, in terms of its structure and enzyme activity, its potential as a cytotoxic agent and exploitation of its cytotoxic nature as an anticancer therapeutic. PMID- 29407872 TI - Early postnatal treatment with clomipramine induces female sexual behavior and estrous cycle impairment. AB - Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems. PMID- 29407873 TI - Environmental enrichment facilitates cocaine abstinence in an animal conflict model. AB - In this study, we sought to discover if housing in an enriched environment (EE) is an efficacious intervention for encouraging abstinence from cocaine seeking in an animal "conflict" model of abstinence. Sixteen Long-Evans rats were trained in 3-h daily sessions to self-administer a cocaine solution (1 mg/kg/infusion) until each demonstrated a stable pattern of drug-seeking. Afterward, half were placed in EE cages equipped with toys, obstacles, and a running wheel, while the other half were given clean, standard laboratory housing. All rats then completed daily 30-min sessions during which the 2/3 of flooring closest to the self administration levers was electrified, causing discomfort should they approach the levers; current strength (mA) was increased after every day of drug seeking until the rat ceased activity on the active lever for 3 consecutive sessions (abstinence). Rats housed in EE abstained after fewer days and at lower current strengths than rats in standard housing. These results support the idea that EE administered after the development of a cocaine-taking habit may be an effective strategy to facilitate abstinence. PMID- 29407874 TI - Statistical moments in modelling of swelling, erosion and drug release of hydrophilic matrix-tablets. AB - Statistical moments were evaluated as suitable parameters for describing swelling and erosion processes (along with drug release) in hydrophilic controlled release matrix tablets. The effect of four independent formulation variables, corresponding to the quantity of four polymeric matrix excipients (namely polyethylene glycol, povidone, and two grades of hydroxyl-propylmethyl cellulose) on statistical moments describing swelling (mean swelling time, MST), erosion (mean erosion time, MET) and drug-release (mean dissolution time, MDT) was evaluated with the aid of multi-linear regression (MLR) and artificial neural networks (ANNs) based on a central composite experimental design. Results were compared to conventional model fitting, where the rate of water uptake during swelling (a), the maximum % water uptake (Smax), the time at which Smax is achieved (tmax), the constant of apparent matrix-tablet erosion rate (ke) and the release exponent (n) from Korsmeyer-Peppas drug-release equation were used as model parameters. Fitting to an external validation test set revealed superior prediction efficacy for statistical moments compared to conventional model fitting, while the combination of statistical moments with ANNs presented the most efficient approach (R2 and RMSEp values of 0.922, 0.833, 0.987 and 0.443, 0.691, 0.173 for MST, MET, and MDT, respectively). PMID- 29407875 TI - Study of a low-dose capsule filling process by dynamic and static tests for advanced process understanding. AB - Precise filling of capsules with doses in the mg-range requires a good understanding of the filling process. Therefore, we investigated the various process steps of the filling process by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular laboratory dosator filling machine. Static tests were conducted using a novel filling system developed by us. Three grades of lactose excipients were filled into size 3 capsules with different dosing chamber lengths, nozzle diameters and powder bed heights, and, in the dynamic mode, with two filling speeds (500, 3000 caps/h). The influence of the gap at the bottom of the powder container on the fill weight and variability was assessed. Different gaps resulted in a change in fill weight in all materials, although in different ways. In all cases, the fill weight of highly cohesive Lactohale 220 increased when decreasing the gap. Furthermore, experiments with the stand-alone static test tool indicated that this very challenging powder could successfully be filled without any pre-compression in the range of 5 mg-20 mg with acceptable RSDs. This finding is of great importance since for very fine lactose powders high compression ratios (dosing-chamber length-to-powder-bed height compression ratios) may result in jamming of the piston. Moreover, it shows that the static mode setup is suitable for studying fill weight and variability. Since cohesive powders, such as Lactohale 220, are hard to fill, we investigated the impact of vibration on the process. Interestingly, we found no correlation between the reported fill weight changes in dynamic mode at 3000 cph and static mode using similar vibration. However, we could show that vibrations during sampling in the static mode dramatically reduced fill weight variability. Overall, our results indicate that by fine tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling. PMID- 29407876 TI - Cardiovascular disease in systemic lupus erythematosus is associated with increased levels of biomarkers reflecting receptor-activated apoptosis. AB - BACKGROUND AND AIMS: There is convincing evidence that adaptive immune responses affect the development of atherosclerosis and thrombosis and several autoimmune diseases are associated with increased cardiovascular risk. However, our understanding of the underlying mechanisms remains limited. We investigated how biomarkers reflecting four aspects of autoimmunity: apoptosis, inflammation, tissue degradation and repair, associate with cardiovascular disease (CVD) in subjects with systemic lupus erythematosus (SLE). METHODS: We investigated 484 well-characterized SLE patients, 69 of whom had CVD (coronary artery disease, cerebrovascular disease or peripheral artery disease), and 253 controls. Occurrence of carotid plaques was investigated with ultrasound. Plasma levels of biomarkers reflecting apoptosis (Fas, TNF receptor 1, TRAIL receptor 2), inflammation (IL-6, IL-8, monocyte chemotactic protein-1), tissue degradation (matrix metalloproteinase (MMP)-1, MMP-3, MMP-7), and tissue repair (platelet derived growth factor, epidermal growth factor and stem cell factor) were analyzed by Proximity Extension Assay. RESULTS: Subjects with SLE had markedly elevated plasma levels of biomarkers reflecting apoptosis, inflammation and tissue degradation as compared to controls. SLE patients with CVD had higher levels of Fas, TNF receptor 1, TRAIL receptor 2, MMP-1 and -7 than those without CVD. The same associations were found for the presence of a carotid plaque. When controlling for the factors included in the Framingham risk score, all biomarkers except MMP-1 remained associated with the presence of a carotid plaque, while only TRAIL receptor 2 levels remained significantly associated with CVD. CONCLUSIONS: Our findings argue that the cardiovascular risk in SLE is associated with increased cell death by apoptosis and tissue degradation. PMID- 29407877 TI - Association of cholesterol efflux capacity with plasmalogen levels of high density lipoprotein: A cross-sectional study in chronic kidney disease patients. AB - BACKGROUND AND AIM: Current research suggests that dysfunctional high-density lipoprotein (HDL) with low cholesterol efflux capacity may accelerate atherosclerosis, particularly in chronic kidney disease (CKD). We previously reported that serum levels of plasmalogens closely correlated with HDL concentration, and could serve as a novel biomarker for atherosclerosis. In the present study, we analyzed the association of cholesterol efflux capacity of HDL with clinical and biochemical parameters, including plasmalogens, in CKD patients. METHODS: We enrolled 24 mild-to-moderate CKD patients (CKD-3-4) and 33 end-stage renal disease (ESRD) patients nearing hemodialysis (CKD-5), and assessed physiological atherosclerotic scores, cholesterol efflux capacity, and plasmalogens levels in HDL. Furthermore, the effect of plasmalogen on cholesterol efflux capacity of HDL was examined by in vitro studies with re-constituted HDL (rHDL) and HDL prepared from CKD-5 patient (ESRD-HDL) with additional phospholipids. RESULTS: There were significant differences in many parameters between the two groups. In particular, plasmalogens levels and cholesterol efflux capacity of HDL were significantly reduced in the CKD-5 group compared to those in the CKD-3-4 group (-35.1%, p < 0.001, -36.8%, p < 0.001, respectively). Multivariate linear regression analyses revealed that ethanolamine plasmalogen levels of HDL were independently associated with cholesterol efflux capacity (p = 0.045) and plaque scores (p = 0.035). In vitro studies also indicated that additional plasmalogens augmented cholesterol efflux ability of HDL. CONCLUSIONS: High plasmalogens concentrations in HDL may correlate with acceleration of cholesterol efflux and their decreased levels may promote atherosclerosis in advanced CKD patients. PMID- 29407878 TI - Association of carotid atherosclerosis and stiffness with abdominal aortic aneurysm: The atherosclerosis risk in communities (ARIC) study. AB - BACKGROUND AND AIMS: Individuals with atherosclerosis and stiffness often have increased abdominal aortic diameters, but prospective evidence linking them to the risk of abdominal aortic aneurysm (AAA) is limited. METHODS: We prospectively examined the relationship of carotid atherosclerosis and stiffness with future risk of AAA in ARIC. At Visits 1 (1987-89) or 2 (1990-1992), we assessed carotid atherosclerosis (represented by greater carotid intima-media thickness [cIMT] or presence of atherosclerotic plaque) and lower carotid distensibility (reflected by a higher carotid Beta Index). We identified incident, clinical AAAs during follow-up through 2011 using hospital discharge codes, Medicare outpatient diagnoses, or death certificates. RESULTS: Participants' mean age at baseline was 54.2 years (SD 5.8), 45% were male and 73% white. During a median of 22.5 years of follow-up, 542 clinical AAAs were ascertained. After multivariable adjustment, the presence of carotid atherosclerotic plaque at baseline was associated with 1.31 (95% CI: 1.10-1.57; p = 0.003) times higher risk of clinical AAA. Greater cIMT and Beta Index were also associated with clinical AAA with a dose-response across quartiles (p trend for both: 0.006; hazard ratios [95% CI] for the highest vs. lowest quartiles: 1.55 [1.13-2.11] and 1.68 [1.16-2.43], respectively). The associations of cIMT and Beta Index with AAA were independent of each other. CONCLUSIONS: This prospective population-based study found that indices of greater carotid atherosclerosis and lower carotid distensibility are markers of increased AAA risk. PMID- 29407880 TI - The protective effect of resveratrol on vascular aging by modulation of the renin angiotensin system. AB - BACKGROUND AND AIMS: This study evaluated the effects of resveratrol on arterial aging and the renin-angiotensin system (RAS) in mice and vascular smooth muscle cells (VSMCs). METHODS: Aging mice were divided into control and resveratrol groups. Histological changes, inflammation, oxidative stress, RAS components, and the expression of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor-gamma co activator 1alpha (PGC-1alpha), and anti-oxidative enzymes was measured in thoracic aortas of 24-month-old mice. The effect of resveratrol on fibrosis, cell senescence, and RAS components was also investigated in VSMCs stimulated by angiotensin (Ang) II. RESULTS: Aorta media thickness, inflammation, fibrosis, and oxidative stress were significantly lower in the resveratrol group than in the control group. Resveratrol treatment decreased serum Ang II level and the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE), and increased serum Ang-(1-7) level and the expression of ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR). Resveratrol increased the expression of phosphorylated AMPK, SIRT1, PGC-1alpha, phosphorylated endothelial nitric oxide synthase and superoxide dismutase 1 and 2, and decreased that of NADPH oxidase 2 and 4. In Ang II-stimulated VSMCs, resveratrol treatment markedly decreased the number of senescence associated beta-galactosidase stained cells and pro-fibrotic protein expression and increased the expression of AT2R and MasR. CONCLUSIONS: Resveratrol protects against arterial aging and this effect is associated with reduced activity of the PRR-ACE-Ang II axis and stimulation of the ACE2-Ang-(1-7) ATR2-MasR axis. PMID- 29407879 TI - Lipoprotein profile assessed by 2D-1H-NMR and subclinical atherosclerosis in children with familial hypercholesterolaemia. AB - BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is underdiagnosed in children. In addition to lipid concentrations, lipoprotein particle quantity and quality could influence cardiovascular risk. We aimed to perform a comprehensive plasma lipid study, including lipoprotein particle number and size assessment by two-dimensional nuclear magnetic resonance (2D-1H-NMR), in children with FH compared to non-affected children and to evaluate the clinical value of these factors as subclinical atherosclerosis biomarkers. METHODS: One hundred eighty three children participating in the broad "Hypercholesterolemia Early Detection Programme" (Decopin Project) were recruited. They were categorized as FH, if they had either a positive genetic test or clinical certainty, or as control children (CCh). Medical history, anthropometry and clinical variables were recorded. Standard biochemical measurements were performed. The lipoprotein profile was studied by 2D-1H-NMR. Carotid intima-media thickness (cIMT) was assessed by sonography in 177 children. RESULTS: FH children had a significant 36% increase in LDL particles. The small LDL fraction was increased by 33% compared to CCh. The relative relationship between large, medium and small LDL and the mean LDL particle size was similar between FH children and CCh. The total and small LDL particle numbers were directly associated with and contributed to the determination of the mean cIMT according to bivariate and multivariate analyses in FH children. CONCLUSIONS: The higher cholesterol levels of FH children are due to an overall increased number of all LDL particle subclasses, including a notable 33% increase in small LDL. Total and small LDL particle number shows a good correlation with cIMT in FH children. PMID- 29407882 TI - The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland. AB - BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) elevates the cholesterol level and increases the risk of coronary events and death. Early detection and treatment reduce this risk. We aimed to determine the cost-effectiveness of FH screening in Poland in children, first job takers, and after an acute coronary syndrome (ACS) event, each followed by a cascade screening in the relatives of the positively-diagnosed subjects. METHODS: A decision tree was constructed to model the diagnosis process. We considered scenarios with and without genetic testing. A life-time Markov was built to investigate the effectiveness (life years gained, LYG; and quality-adjusted life years, QALY) and cost (public payer perspective) of treatment in FH-affected subjects. The clinical benefits result from early treatment reducing the risk of coronary heart disease (and death, in result). Model parameters were based on published data and experts' opinions. The costs (patients visits, tests, drugs) were estimated from the National Health Fund data and other publicly-available sources. RESULTS: Screening ACS patients below 55/65 years of age in men/women is the most cost-effective strategy: the cost of one LYG (QALY) amounts to 100 EUR (110 EUR). Removing the age limit or using genetic tests reduced cost-effectiveness; nonetheless, all strategies remained cost effective: the cost of one LYG or QALY was <5040 EUR, much lower than the official threshold of ca. 29,800 EUR/QALY. CONCLUSIONS: Screening for FH is highly cost-effective in Poland. The strategies are complementary, and using a combination thereof is recommended. PMID- 29407881 TI - Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease. AB - BACKGROUND AND AIMS: Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbimortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. We hypothesized that OPG, OPN and sTWEAK levels may be associated with a higher prevalence of cardiovascular outcomes in patients with CKD. METHODS: The presence of calcified or non calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA Study. Biochemical measurements and OPG, OPN and sTWEAK serum levels were analyzed. Patients were followed for cardiovascular outcomes (41 +/- 16 months). RESULTS: At recruitment, 26% of CKD patients had VC. The adjusted odds ratios for having VC were 2.22 (1.32-3.75); p=.003 for OPG, and 0.45 (0.24 0.84); p=.01 for sTWEAK concentrations. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut off points had an adjusted higher risk of cardiovascular events [HR: 2.10 (1.49 3.90); p=.02; 1.65 (1.02-2.65); p=.04; 2.05 (1.28-3.29), p=.003; respectively]. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events [HR: 9.46 (3.80 23.5) p < .001]. A composite score of these three biomarkers increased the C statistic and net reclassification index beyond conventional risk factors and VC. CONCLUSIONS: The combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes. PMID- 29407883 TI - Vasodilator response to galvanic current stimulation of the skin accurately detects acetylsalicylic acid intake: A study in 400 vascular patients. AB - BACKGROUND AND AIMS: The first cause of low-dose acetylsalicylic-acid (ASA) inefficacy is poor adherence to treatment. No non-invasive technique is available to assess ASA intake. Current-induced vasodilation (CIV) was found abolished in healthy volunteers after low-dose ASA intake. We tested clinical characteristics, treatments, and comorbid conditions influencing CIV amplitude in vascular patients. METHODS: CIV was tested in 400 patients (277 males and 123 females, aged 65.4 +/- 13.4 years). We focused on clinical characteristics, treatments, and comorbid conditions as covariates of CIV amplitude. We studied the CIV amplitude to covariate relationships with multivariate linear regression and receiver operating characteristics (ROC). RESULTS: The multivariate linear model determined that ASA intake within the last 48 h and the interaction between ASA intake and body mass index (BMI) were the sole covariates associated with CIV amplitude. For the whole population, the area under the ROC curve (AUC) for CIV to predict ASA intake was 0.853 [95% confidence interval (CI): 0.814-0.892]. Considering separately the areas observed for non-obese (BMI <=30, n = 303) and obese (BMI>30, n = 93) patients, the AUC [95% CI] was 0.873 [0.832-0.915] and 0.776 [0.675-0.878], respectively (p = 0.083). CONCLUSIONS: ASA is the only drug that affects the amplitude of CIV response observed after galvanic current application to the skin of vascular patients. CIV depends on BMI but not age or gender. As such, CIV appears to be a potential objective marker of ASA intake and could facilitate future non-invasive assessments of adherence to ASA treatment. PMID- 29407884 TI - The relationship between oxidized low-density lipoprotein and the NIHSS score among patients with acute ischemic stroke: The SOS-Stroke Study. AB - BACKGROUND AND AIMS: Oxidized low-density lipoprotein (oxLDL) has a defined role in the genesis and development of atherosclerosis, however, whether it is related to severity of neurological deficits is rarely reported. The aim of our study was to investigate the potential association between oxLDL and the National Institutes of Health Stroke Scale (NIHSS) score among patients with acute ischemic stroke. METHODS: Between January 2014 and October 2014, we recruited 4111 patients with acute ischemic stroke (AIS), who were admitted within 7 days 43 hospitals in China, and participated in the SOS-Stroke Study. We collected detailed clinical data and then tested the relationship between oxLDL and the NIHSS score using a multivariate linear regression analysis. RESULTS: After adjusting for age, gender, ethnicity, marriage and other confounding variables, the elevated NIHSS score was significantly associated with increased oxLDL levels, and each 1-MUg/dL elevation in oxLDL concentration resulted in an increase of 0.027 in the NIHSS score. CONCLUSIONS: A positive correlation was found between plasma levels of oxLDL and the NIHSS score in patients with acute ischemic stroke. Higher plasma levels of oxLDL potentially suggest a worse prognosis in AIS patients. PMID- 29407885 TI - High serum triglyceride concentrations in patients with homozygous familial hypercholesterolemia attenuate the efficacy of lipoprotein apheresis by dextran sulfate adsorption. AB - BACKGROUND AND AIMS: Maximizing the acute reduction of LDL-cholesterol (C) and lipoprotein (a) (Lp(a)) concentrations in patients with homozygous familial hypercholesterolemia (HoFH) is the main goal of lipoprotein apheresis (LA). The objective of this study was to examine how the pre-LA serum TG concentrations influence the efficacy of LA to acutely reduce LDL-C and Lp(a) concentrations in HoFH patients. METHODS: Data from 1761 LA treatments of HoFH patients (n = 10) and compound heterozygous patients (n = 5) collected between 2008 and 2016 were analyzed. These data included the pre- and post-LA concentrations of LDL-C, TGs and Lp(a); volume of filtered plasma; type of LA system used (dextran sulfate adsorption (DSA) or heparin-induced extracorporeal LDL precipitation (HELP)); and interval between treatments. RESULTS: A significant association between the pre LA TG concentrations and acute LA-induced reduction in LDL-C, modified by the type of LA system used, was observed (ppre-LA TG quartile*LA system = .04). Using the DSA system, the acute reduction of the LDL-C concentrations was attenuated by 3.9% when the pre-LA TG concentrations were >2.09 mmol/L vs. <=0.93 mmol/L (highest vs. lowest quartiles: -59.4% vs. -63.3%, p = .007). Using the HELP system, no significant difference was observed in the reduction of LDL-C between the highest and the lowest quartiles of serum TGs (-65.8% vs. -66.4%, p = .9). No association was observed between pre-LA TG concentrations and acute LA-induced decrease in Lp(a) (p = .2). CONCLUSIONS: The efficacy of LA is inversely associated with pre-LA TG concentrations in HoFH patients who used the DSA system instead of the HELP system. PMID- 29407886 TI - Noncanonical NF-kappaB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction. AB - BACKGROUND AND AIMS: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-kappaB inducing kinase (NIK)-mediated noncanonical NF-kappaB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. METHODS: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. RESULTS: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40% had an increased number of NIK+EC and higher content of immune cells (p < .05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p < .05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p < .05). NIK+EC were increased in lesions with lipid content >40% (p < .05) and more abundant in coronary artery lesions implicated in MI (p < .05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p < .05). Transcriptomic profiling demonstrated components of noncanonical NF kappaB pathway were also upregulated in ruptured plaques (p < .05). CONCLUSIONS: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-kappaB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease. PMID- 29407887 TI - A nation-wide survey of patients with homozygous familial hypercholesterolemia phenotype undergoing LDL-apheresis in Turkey (A-HIT 1 registry). AB - BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by lethally high levels of low-density lipoprotein cholesterol (LDL-C) from birth, and requires rapid and aggressive intervention to prevent death due to coronary heart disease and/or atherosclerosis. Where available, lipoprotein apheresis (LA) is the mainstay of treatment to promote survival. METHODS: A-HIT1 registry was conducted with the aim of providing insight to the real-life management of HoFH patients undergoing LA in Turkey, where LA procedures are fully reimbursed and widely available. Participating centers provided patient information, including family history, treatment patterns and relevant laboratory values, via a standard questionnaire. RESULTS: The study evaluated 88 patients (mean age: 27 +/- 11 years, 41 women) in 19 centers. All patients were receiving regular LA with a clinical diagnosis of HoFH. Mean age at first symptom disease was 10 +/- 10 years, and at diagnosis it was 12 +/- 11 years; 74.7% were diagnosed before age 15 years; and only 31% before the age of 7. First referral of most patients was to pediatricians. Early onset coronary artery disease was present in 57.8% of patients. Mean age at first LA was 21 +/- 12 years. Only 11 (12.5%) patients were undergoing LA weekly. Mean frequency of apheresis sessions was 19 +/- 13 days. For the last four LA sessions, LDL-C levels reached the target in only in 5.7% of patients. CONCLUSIONS: Diagnosis of HoFH is delayed, and LDL targets are not reached. LA frequencies are not optimal. Urgent attention is needed to support the survival of patients with HoFH. PMID- 29407889 TI - MicroRNA-24 aggravates atherosclerosis by inhibiting selective lipid uptake from HDL cholesterol via the post-transcriptional repression of scavenger receptor class B type I. AB - BACKGROUND AND AIMS: Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SR-BI expression leads to high HDL-C levels in the circulation and an increased risk of atherosclerosis. Furthermore, macrophage SR-BI mediates bidirectional cholesterol flux and may protect against atherogenesis. Previous studies have revealed that miR-24 is closely related to cardiovascular disease (CVD) progression. We aimed to investigate the molecular mechanisms by which miR-24 participates in SR-BI-mediated selective HDL cholesteryl ester (HDL-CE) uptake and further atherogenesis in apoE-/- mice. METHODS: Bioinformatic predictions and luciferase reporter assays were utilized to detect the association between miR-24 and the SR-BI 3' untranslated region (3' UTR), and RT-PCR and western blotting were used to evaluate SR-BI mRNA and protein expression, respectively. The effects of miR-24 on Dil-HDL uptake were determined by flow cytometry assay. Double-radiolabeled HDL (125I-TC-/[3H] CEt HDL) was utilized to measure the effects of miR-24 on HDL and CE binding and SLU in HepG2 and PMA-treated THP-1 cells. In addition, total cholesterol (TC) levels in HepG2 cells were analyzed using enzymatic methods, and macrophage lipid content was evaluated by high-performance liquid chromatography (HPLC) assay. Small interfering RNA (siRNA) and pcDNA3.1(-)-hSR-BI plasmid transfection procedures were utilized to confirm the role of SR-BI in the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels in both cell types. Hepatic SR-BI level in apoE-/- mice was measured by western blotting. Liver TC, FC and CE levels and plasma triglycerides (TG), TC and HDL-C levels were evaluated enzymatically using commercial test kits. Atherosclerotic lesion sizes were measured using Oil Red O and hematoxylin-eosin staining. RESULTS: miR-24 directly repressed SR-BI expression by targeting its 3'UTR. In addition, miR-24 decreased Dil-HDL uptake and SLU in HepG2 and THP-1 macrophages. In the presence of HDL, miR-24 decreased TC levels in HepG2 cells and TC, free cholesterol (FC) and CE levels in macrophages. Overexpression and down-regulation assays showed that SR BI mediated the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels. Lastly, miR-24 administration decreased hepatic SR-BI expression and promoted atheromatous plaque formation in apoE-/- mice, findings in line with those of our in vitro studies. CONCLUSIONS: These findings indicate that miR-24 accelerates atherogenesis by repressing SR-BI-mediated SLU from HDL-C. PMID- 29407888 TI - Inflammation and coronary artery calcification in South Asians: The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. AB - BACKGROUND AND AIMS: Inflammatory biomarkers and adipocytokines (IBA) may contribute to atherosclerosis by promoting vascular inflammation. The association between IBA and coronary artery calcium (CAC), a marker of subclinical atherosclerosis, is not well defined in South Asians (SA). We hypothesized that IBA (high sensitivity C-reactive protein [hsCRP], tumor necrosis factor alpha [TNF-alpha], adiponectin, and leptin) were independently associated with and improved discrimination of CAC among SA. METHODS: We analyzed IBA and CAC among participants in the prospective Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. We used logistic regression models to examine cross-sectional associations of IBA with CAC presence (CAC >0) and severity (CAC >100), and C-statistics to assess the incremental contribution of each IBA to traditional risk factors (TRF) from the AHA/ACC Pooled Cohort Equations (PCE) for discrimination of CAC. RESULTS: Among 906 participants in the MASALA study, women (n = 420) had significantly higher levels of hsCRP, adiponectin, and leptin but lower levels of TNF-alpha than men (p < .01 for all). There was no significant association between any of the four IBA and either CAC category in multivariable adjusted models, respectively. Lastly, none of the four IBA improved discrimination of CAC presence or severity when added to elements of the PCE. CONCLUSIONS: IBA were not associated with CAC presence or severity in the MASALA population. IBA did not help identify SA at risk of subclinical atherosclerosis, although associations with ASCVD events remain unclear. In SA, CAC may have a distinct pathophysiology independent of inflammation as measured by IBA. PMID- 29407890 TI - Selective inhibition of endothelial NF-kappaB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice. AB - BACKGROUND AND AIMS: Chronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-kappaB signaling in the atherogenic response to CIH. METHODS: We created ApoE-ECI-kappaBmt mice that are deficient in the apolipoprotein E gene (ApoE-/-) and overexpress an I-kappaBalpha mutant (I-kappaBmt) selectively in endothelial cells. ApoE-/- and ApoE-ECI kappaBmt mice were fed a normal chow diet (NCD) or high cholesterol diet (HCD) and exposed to sham or CIH, and atherosclerotic lesions were quantified. RESULTS: CIH exposure activated NF-kappaB in aortas, and induced the expression of endothelial-specific and NF-kappaB-dependent genes, E-selectin and vascular cell adhesion molecule (VCAM)-1, in the aortas and hearts. Endothelial I-kappaBmt overexpression in ApoE-ECI-kappaBmt mice significantly inhibited CIH-induced NF kappaB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-kappaB inhibition in ApoE-ECI-kappaBmt mice. ApoE-/- mice, on NCD, developed mild atherosclerotic lesions spontaneously, and developed advanced and larger areas of atherosclerotic plaques when exposed to CIH. ApoE-/- mice also developed advanced atherosclerotic lesions when fed an HCD alone. The HCD-induced atherosclerotic plaques became more advanced, and plaque area was doubled in mice exposed to HCD + CIH. Endothelial I-kappaBmt overexpression in ApoE-ECI-kappaBmt mice attenuated spontaneously developed atherosclerotic lesions, abrogated CIH induced atherosclerosis and mitigated CIH-mediated facilitation of HCD-induced atherosclerosis. CONCLUSIONS: These results suggest that endothelial intrinsic NF kB signaling may play a pivotal role in CIH-induced atherosclerosis. PMID- 29407891 TI - Fluid shear stress regulates the expression of Lectin-like oxidized low density lipoprotein receptor-1 via KLF2-AP-1 pathway depending on its intensity and pattern in endothelial cells. AB - BACKGROUND AND AIMS: Vascular endothelial cells (ECs) are exposed to fluid shear stress (FSS), which modulates vascular pathophysiology. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is crucial in endothelial dysfunction and atherosclerosis. We elucidated the mechanism regulating LOX-1 expression in ECs by FSS. METHODS: Human umbilical vein endothelial cells were exposed to laminar shear stress (LSS) of indicated intensities using a unidirectional steady flow, or to oscillatory shear stress (OSS) using a bidirectional disturbed flow. In vivo studies were performed in a mouse model of partial carotid ligation and human pulmonary artery sections. RESULTS: Within ECs, OSS upregulated LOX-1 expression, while LSS (20 dyne/cm2) downregulated it. We confirmed that OSS induced LOX-1 expression was suppressed when the mechanotransduction was inhibited by knockdown of the mechanosensory complex. In addition, we demonstrated that Kruppel-like factor 2 (KLF2) has an inhibitory role on OSS induced LOX-1 expression. Next, we determined that activator protein-1 (AP-1) was the key transcription factor inducing LOX-1 expression by OSS, which was inhibited by KLF2 overexpression. To explore whether the intensity of LSS affects LOX-1 expression, we tested three different intensities (20, 60, and 120 dyne/cm2) of LSS. We observed higher LOX-1 expression with high shear stresses of 120 dyne/cm2 compared to 20 and 60 dyne/cm2, with OSS-like KLF2-AP-1 signaling patterns. Furthermore, ECs within disturbed flow regions showed upregulated LOX-1 expression in vivo. CONCLUSIONS: We concluded that LOX-1 expression on ECs is regulated via FSS depending on its intensity as well as pattern. Furthermore, this is mediated through the KLF2-AP1 pathway of mechanotransduction. PMID- 29407892 TI - The impact of myocardial bridge on coronary artery spasm and long-term clinical outcomes in patients without significant atherosclerotic stenosis. AB - BACKGROUND AND AIMS: Myocardial bridge (MB) and coronary artery spasm (CAS) can induce a sustained chest pain, acute coronary syndrome (ACS) and even sudden cardiac death. The aim of this study is to evaluate the relationship between MB and CAS and its impact on long-term clinical outcomes. METHODS: A total of 812 patients with MB without significant coronary artery disease (CAD), who underwent acetylcholine (ACH) provocation test, were enrolled. Significant CAS was defined as >=70% temporary narrowing by ACH test, and MB was defined as the characteristic phasic systolic compression of the coronary artery with a decrease of more than 30% in diameter on the angiogram after intracoronary nitroglycerin infusion. To adjust baseline confounders, logistic regression analysis was performed. The primary endpoint was incidence of CAS, and secondary endpoints were major adverse cardiac events (MACE) and recurrent angina requiring repeat coronary angiography (CAG) at 5 years. RESULTS: MB is closely implicated in a high incidence of CAS, spontaneous spasm, ischemic ECG change and chest pain during ACH provocation test. In addition, MB of various severity and reference vessel size was substantially implicated in CAS incidence, and severe MB was a strong risk factor of CAS. MB patients with CAS were shown to have a higher rate of recurrent angina compared with MB patients without CAS, up to a 5-year follow up. However, there were no differences regarding the incidence of MACE. CONCLUSIONS: Severe MB was associated with high incidence of CAS, and MB patients with CAS were likely to have a higher incidence of recurrent angina. Intensive medical therapy and close clinical follow-up are needed for better clinical outcomes in MB patients with CAS. PMID- 29407893 TI - Atherosclerotic intracranial internal carotid artery calcification and intravenous thrombolytic therapy for acute ischemic stroke. AB - BACKGROUND AND AIMS: Intracranial internal carotid artery calcification (IICAC) is a frequent and readily available finding in acute stroke patients treated with intravenous (IV) tissue plasminogen activator (tPA). We aimed to investigate the effects of IICAC subtype (medial and intimal) on the response to IV tPA. METHODS: In this retrospective study, 91 (57% female, age 69 +/- 13 years) consecutive acute anterior circulation stroke patients treated with IV tPA were included. IICAC were diagnosed and classified according to Kockelkoren's methods. RESULTS: IV tPA was effective at 24 h in 48% of patients with no IICAC (n = 27), 60% of intimal IICAC (n = 50) and 43% of medial IICAC (n = 14) (p=0.408). Presence of medial IICAC tended to be linked negatively to early dramatic response to IV tPA (p=0.052). IICAC status had no significant effect on the third month good (mRS<=2; 48% in no IICAC, 36% in intimal IICAC and 29% in medial IICAC; p=0.189) and favorable outcome (mRS<=1; 56% in no IICAC, 48% in intimal IICAC, 43% in medial IICAC, p=0.411). Frequency of symptomatic post-tPA cerebral hemorrhage was marginally higher in patients with non-intimal IICAC (21% vs. 4% in no-IICAC, 4% in intimal-IICAC, p=0.052). Exploratory multivariate analysis documented that this effect was stable (p=0.004) after adjustment for age, admission NIHSS and door-to-needle time. CONCLUSIONS: Medial type IICAC has been associated with numerical increase of symptomatic intracerebral hemorrhage and decrease of early dramatic response in stroke patients receiving IV tPA. Acknowledging that these preliminary observations should be replicated in larger cohorts, it is currently reasonable to say that "the treatment" is still useful in these patients and the presence of medial IICAC does not justify withholding IV tPA. PMID- 29407894 TI - Low sleep quality is associated with progression of arterial stiffness in patients with cardiovascular risk factors: HSCAA study. AB - BACKGROUND AND AIMS: Improvement in sleep quality is considered to be a viable target for prevention and treatment of cardiovascular diseases. To gain insight into its underlying mechanisms, we evaluated the significance of objectively measured sleep quality in patients with regard to progression of arterial stiffness over a 3-year follow-up period. METHODS: This prospective cohort study included 306 serial patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. In addition to classical cardiovascular risk factors (body mass index, current smoking, past history of cardiovascular disease, dyslipidemia, diabetes mellitus), the participants were examined for ambulatory blood pressure (BP), apnea-hypopnea index (AHI), standard deviation of the NN (RR) interval (SDNN) for heart rate variability (HRV), and objective sleep quality using actigraphy findings. Brachial-ankle pulse wave velocity (baPWV) was measured at both baseline and follow-up (36.6 +/- 6.8 months) as a parameter of arterial stiffness. RESULTS: Increases in PWV (%) were greater (p = 0.03) in the low sleep quality (LSQ) group (5.75 +/- 1.15%) as compared to the normal sleep quality group (2.69 +/- 0.85%). Patients with the greatest increase (>=20%) from baseline exhibited a significantly (p < 0.05) larger percentage of LSQ (75% vs. 49.6%) as compared to those without PWV progression (<0%), with the association still significant (odds ratio 3.62, 95% confidence interval 1.04-12.55, p = 0.04) even after adjustment for other clinical risk factors. For all subjects, univariate logistic regression analyses showed that diabetes and LSQ were significantly associated with the greatest increase of PWV. Comparisons of characteristics among specific subgroups showed more prominent associations of LSQ with the greatest increase of PWV in patients with greater age, dyslipidemia, and higher AHI. CONCLUSIONS: LSQ was associated with progression of arterial stiffness over a 3-year period, independent of cardiovascular risk factors such as BP, AHI, and HRV. PMID- 29407895 TI - Innate antiviral immune response against infectious bronchitis virus and involvement of prostaglandin E2 in the uterine mucosa of laying hens. AB - Infectious bronchitis virus (IBV) is an enveloped RNA virus that causes deformities in eggshells. The aim of this study was to investigate the innate immune response to IBV, and to determine whether prostaglandin (PG) E2, which is synthesized during inflammation, is involved in the innate immune response in the uterine mucosa. The effects of intra-oviductal inoculation with attenuated IBV (aIBV) on the expression of viral RNA recognition receptors and innate antiviral factors were examined by real-time PCR and immunohistochemistry, and on PGE2 levels by ELISA. Then, the effects of PGE2 on the expression of innate antiviral factors in cultured uterine mucosal cells were examined. The results showed that the expression of RNA virus pattern recognition receptors (TLR3, 7, and MDA5), antimicrobial peptides (avian beta-defensins, including AvBD1, 2, 4-6 and cathelicidins, including CATH1 and 3), and interferons (IFNalpha, beta, gamma, lambda) were upregulated, and the expression of cyclooxygenase 2 (PG synthase) and the level of PGE2 were increased in the uterine mucosa following aIBV inoculation. The number of AvBD2-positive cells in the mucosa also increased in response to aIBV. In cultured mucosal cells (mainly epithelial), the expression of AvBD4, 10-13 and IFNalpha, beta, and lambda was upregulated following incubation with 500 nM PGE2. These results suggest that the expression of viral RNA-recognition receptors, AvBDs, CATHs, and IFNs and PGE2 are induced by the IBV antigen, and that the expression of a different set of AvBDs is also induced by PGE2 in the cultured uterine mucosal cells. These antiviral factors may play a role in the protection of the uterine mucosa from IBV infection. PMID- 29407896 TI - Free gossypol supplementation frequency and reproductive toxicity in young bulls. AB - The aim of the present study was to analyze seminal quality of young bulls subjected to different frequencies of gossypol supplementation. Forty-eight Nellore bulls, with 19 months of age and weighing 357.8 +/- 7.2 kg, were used in this study. Animals were fed with 10.5 kg of standard supplement containing free gossypol from whole cottonseed (WCS) at the following frequency: 3x/week (G3x), 5x/week (G5x) or 7x/week (G7x - Control). Additionally, a negative control was provided, and the treated animals received only mineral supplement (MM) ad libtum. The experiment lasted for 84 days and semen was collected at the beginning and at the end for analysis and cryopreservation. Fresh semen was used for initial analysis and plasma membrane integrity and sperm morphology were also determined. General motility using computer assisted sperm analysis (CASA), plasma and acrosomal membranes integrity, mitochondrial activity, and induced oxidative stress were assessed in post-thawed semen. The study design was completely randomized. Parametric data were analyzed by ANOVA and non-parametric data by the Wilcoxon test, using the statistical program SAS. Level of significance was set at 5%. Supplementation with WCS, regardless the frequency, increased total (P = .009) and head (P = .005) defects in comparison to animals receiving only forage and mineral supplement. Infrequent supplementation, particularly 5 times in the week (G5X), increased head (P = .026) and midpiece (P = .014) abnormalities. Sperm motility in fresh semen was lower in animals that received daily supplementation than those supplemented on alternate days (P = .021). Additionally, animals supplemented daily showed lower percentage of spermatozoa with intact acrosome compared to those supplemented on alternate days (P = .005). Thus, regardless the frequency of supplementation, free-gossypol supplementation affects sperm quality. Although the amount of free gossypol supplied weekly was the same among treatments, daily supplementation compromised sperm kinetics, differently from infrequent supplementation that led to sperm defects developed during spermatogenesis. PMID- 29407897 TI - Species-specific expression of phosphoglycerate kinase 2 (PGK2) in the developing porcine testis. AB - Whereas stage-specific markers for spermatogonial cells have been well investigated in mouse, the specific markers of germ cells in the testis of domestic animals have not been well defined. Phosphoglycerate kinase (PGK), an enzyme that converts 1,3-bisphosphoglycerate and adenosine diphosphate to 3 phosphoglycerate and adenosine triphosphate, has two isozymes: PGK1 and PGK2. In mouse, PGK1 exists only during the early stages of spermatogenesis, and PGK2 is then expressed during the pachytene spermatocyte stage. In this study, we investigated the localization of PGK2 in the developing porcine testis, and compared the similarities and differences in its expression with that of the PGK2 in mouse. The PGK2 protein was found to be exclusively expressed in spermatids of the adult mouse testis, whereas PGK2-positive cells were observed in the prepubertal and postpubertal testes of pigs. Based on this result, we examined the expression of PGK2 in in vitro-cultured porcine undifferentiated spermatogonia and found it to be maintained in the cultured cells. To verify this result and identify the spermatogonial stem cell-like potential in recipient testes, PKH26 dye-stained PGK2-positive cells were transplanted into the testes of busulfan-treated immunodeficient mouse that had been depleted of both testicular germ cells and somatic cells. The transplanted cells colonized the recipient testis at 8 weeks post transplantation, and fluorescence microscopy identified the cells in the basement membranes of the seminiferous tubules of the injected mouse. Taken together, our results suggest that PGK2 is expressed differently in the testes of mouse and pigs according to developmental stage. This finding should contribute to the study of spermatogenesis and the production of transgenic domestic animals through in vitro spermatogonial sperm cell culture. PMID- 29407898 TI - Social dominance affects the development of sexual behaviour but not semen output in yearling bucks. AB - Goats are polygynous seasonal mammals that establish dominant-subordinate relationships, especially in bucks. The aims of this study were to: 1) compare the reproductive development of dominant and subordinate young bucks allocated in dyads, and 2) determine if their previous dominant position affect their response to grouping. Twenty-four young bucks were allocated in dyads when they were 4 mo old, and the dominance position (DP) [dominant (DB) or subordinate buck (SB)] was determined with a test of competition for food. Body weight, scrotal circumference, semen quality and sexual behaviour toward an oestrous ewe were weekly determined during 8 weeks beginning when the bucks were 8 mo old. Body weight, scrotal circumference, and seminal parameters were not affected by DP. Dominant bucks tended to begin sexual courtship earlier than SB bucks (P = .09), but displayed less flehmen (P = .0008) and tended to display less ano-genital sniffings (P = .053). However, DB bucks displayed more lateral approaches (P = .019), attempted to mount, mounted, and mated the oestrous doe more times (P < .0001, P = .0002 and P < .0001, respectively) than SB bucks. In the 9th week, all the bucks were grouped, cortisol and testosterone serum concentrations were measured, and agonistic and sexual behaviour between bucks were recorded during the first day. Semen was collected and evaluated 4 and 9 days after grouping. Cortisol concentration increased (P = .037), but testosterone decreased (P < .0001), after grouping the animals, without differences according to their DP. The DB tended to display more lateral approaches toward other bucks than SB bucks (P = .06), but there were no effects of DP in any other behaviour. Sperm concentration and the total number of sperm in the ejaculate decreased after grouping (P = .01 and P = .009 respectively. In conclusion, in the conditions of this study, dominance relationships affected sexual behaviour but not body or testicular size or semen output in young bucks allocated in dyads. Dominant bucks were more effective displaying sexual consummatory behaviours. Grouping all the bucks together displayed a strong stress response that affected testosterone secretion and sperm output which was of similar magnitude in bucks that were dominant or subordinate individuals before. PMID- 29407899 TI - The relationship between external auditory canal temperature and onset of estrus and ovulation in beef heifers. AB - The aim of this study was to evaluate the relationship of body temperature fluctuations, as measured by external auditory canal temperature, to the onset of estrus and ovulation. Beef heifers (n = 44, mean age 23.5 +/- 0.4 months, mean weight 603.3 +/- 5.7 kg) were fitted with a Boviminder(r) ear tag 2 weeks before the start of the estrous synchronization protocol to allow acclimatization. The device recorded the temperature, accurate to 0.01 degrees Fahrenheit, every 10 min and transmitted the data via a base station over the internet where it could be accessed remotely. The estrous cycles of all heifers were synchronized using an 8-day progesterone-based synchronization program; on day 0 a PRID was inserted in conjunction with an injection of GnRH, and PGF2alpha was administered the day before PRID removal. Heifers were checked for signs of estrus at 4-h intervals (i.e., 6 times per day) commencing 24 h after PRID withdrawal. Beginning 12 h after the onset of estrus, the ovaries were ultrasound scanned at 4-h intervals to determine the time of ovulation. Body temperature was recorded every 10 min and averaged to hourly means for the following 4 periods relative to the detected oestrus onset (=Time 0): Period I: -48 h to -7 h, Period II: -6 h to +6 h, Period III +7 h to ovulation, and Period IV: ovulation to 48 h post ovulation. Data were analysed using a Mixed Model ANOVA in SAS in a completely randomized design to observe effects of induced estrus on external auditory canal temperature. The mean (+/-SD) interval from removal of the PRID to onset of estrus activity was 46.6 +/- 14.7 h. The mean duration of estrus was 16.0 +/- 5.67 h and the mean interval from estrus onset to ovulation was 27.9 +/- 7.68 h. Highest temperatures (100.95 +/- 0.03 degrees F) were observed in Period II around estrus onset, whereas lowest temperatures were observed in the 48 h preceding estrus onset (100.28 +/- 0.03 degrees F; Period I) and around ovulation (100.30 +/- 0.2 degrees F; Period III)(P < .001). Indeed, around the time of estrus onset (Period II) mean temperature was 0.66 degrees F (P < .001) higher compared with Period I. Diurnal temperature rhythms were similar (P > .10) before (Period I) and after oestrus (Period III). In conclusion, a significant elevation in external auditory canal temperature was associated with estrus in beef heifers and was followed by a decline in temperature leading up to ovulation approximately 28 h later. Future studies are required to assess pregnancy rates following AI based on changes in external auditory canal temperature. PMID- 29407900 TI - Advancement of puberty and enhancement of seminal characteristics by supplementation of trace minerals to bucks. AB - Attainment of puberty in animals is dependent on their age, body weight, nutritional status, genetic and environmental conditions. Nutritionally, organic minerals are suggested to improve semen production, sperm motility and male fertility. In this context, role of organic zinc (Zn) and copper (Cu) in advancing male puberty and semen characters in Osmanabadi goats were studied. Forty one (n = 41) bucks (Aged 5 months) were divided into ten groups and the dietary treatments comprised of a control group (basal diet; without additional trace mineral supplementation) and nine treatment groups that received, in addition to the basal diet, various doses of trace minerals (mg) on per kg dry matter basis, organic Zn as low Zn20, medium Zn40 and high Zn60, organic Cu as low Cu12.5, medium Cu25, high Cu37.5 and combination of organic Zn + Cu as low Zn20 + Cu12.5, medium Zn40 + Cu25, high Zn60 + Cu37.5, respectively fed for a period of 8 months. Bucks fed organic trace minerals reached puberty 28-35 days earlier than control group. In addition, improvement (P < .01) in testosterone hormone (ng/ml) levels (control: 1.63 +/- 0.07 VS Zn60: 2.54 +/- 0.02; Cu12.5: 6.17 +/- 0.05; Cu25: 3.01 +/- 0.04; Cu37.5: 2.39 +/- 0.06; Zn20 + Cu12.5: 1.94 +/ 0.02; Zn60 + Cu37.5: 2.44 +/- 0.16 at 240 days), semen production capacity (sperm concentration, volume, mass motility) and semen quality (higher progressive motility, velocity, sperm membrane integrity and acrosome integrity) were observed in supplemented groups (P < .05) than the control bucks. The present study demonstrated that, additional feeding of organic Zn and Cu to growing male goats advanced onset of puberty and improved quantitative and qualitative semen characteristics. The results also implied that the organic Cu had a significant effect on overall performances of bucks as compared to Zn alone or Zn and Cu in combination. PMID- 29407901 TI - Effect of superstimulation on the expression of microRNAs and genes involved in steroidogenesis and ovulation in Nelore cows. AB - To better understand the impact of ovarian superstimulation on bovine follicular microenvironment, Nelore cows (Bos taurus indicus) were subjected to ovarian superstimulation with follicle stimulating hormone (FSH, n = 10; P-36 protocol) or FSH combined with eCG (n = 10; P-36/eCG protocol). Follicular fluid was analyzed for cholesterol concentration. Granulosa cells were analyzed by RT-qPCR to assess the expression of genes involved in steroidogenic and ovulatory and expression of microRNAs involved in final follicular development and luteinizing hormone/choriogonadotropin receptor (LHCGR) expression. Plasma concentration of estradiol was also measured. Follicular fluid from the P-36 group showed higher concentration of cholesterol than that of control (non-superstimulated) cows. Plasma concentration of estradiol was higher in the P-36/eCG group. Abundance of STAR and FSHR mRNAs were lower in granulosa cells from the P-36/eCG group. In contrast, LHCGR mRNA abundance was higher in superstimulated granulosa cells from the P-36 group and showed a pattern opposite to that of miR-222 expression. Ovarian superstimulation did not affect the expression of other markers (mmu-miR 202-5p, has-miR-873, has-miR-144, and their target genes, CREB, TGFBR2, and ATG7) of antral follicle development. However, the mRNA expression of VEGF pathway components was modulated by P-36 treatment. Taken together, these results demonstrate that superstimulatory protocols modify steroidogenic capacity, increase plasma estradiol, and regulate the abundance of VEGF system, LHCGR mRNA and suppress the expression of miR-222 in bovine granulosa cells. PMID- 29407902 TI - Dietary supplementation of n-3 polyunsaturated fatty acid alters endometrial expression of genes involved in prostaglandin biosynthetic pathway in breeding sows (Sus scrofa). AB - The present investigation was designed to study the effect of dietary supplementation of omega-3 (n-3) PUFA on endometrial expression of fertility related genes in breeding sows. Sixteen crossbred sows were randomized to receive diets containing 4% (wt/wt) flaxseed oil as n-3 PUFA source (TRT group) or iso nitrogenous, iso-caloric standard control diet (CON group), starting from the first day of estrus up to 40 days and were artificially bred on the second estrus. Endometrial samples were collected during days 10-11 and 15-16 post mating for studying relative expression profile of candidate genes viz. Prostaglandin F Synthase (PGFS), microsomal Prostaglandin E Synthase-1 (mPGES-1) and Carbonyl Reductase-1 (CBR-1) using quantitative Real-Time PCR. Expression level of mPGES-1 gene transcript was 2.1-fold higher (P < 0.05) during 10-11 days of pregnancy and 1.4-fold higher (P > 0.05) during 15-16 days of pregnancy in TRT group as compared to CON group. Relative expression of PGFS gene transcript was significantly lower (P < 0.05) during 10-11 days of pregnancy in TRT group while there was no significant effect (P > 0.05) of dietary supplementation during 15 16 days of pregnancy. Endometrial mRNA level of CBR1 was significantly lower (P < 0.05) with 3.93-fold decrease in TRT group during 10-11 days of pregnancy whereas 2.82-fold reduction in expression (P > 0.05) was observed subsequently during 15 16 days of pregnancy as compared to CON group. Collectively, these results indicate that dietary n-3 PUFA supplementation can modulate gene expression of key enzymes in prostaglandin biosynthetic pathway during early gestation, which in turn might have beneficial impact on overall reproductive response in breeding sows. These findings partly support strategic dietary supplementation of plant based source of n-3 PUFA with an aim to improve overall reproductive performance in sows. PMID- 29407903 TI - Effects of maternal undernutrition on the growth, development and antioxidant status of ovine placentome subtypes during late pregnancy. AB - This study investigated the effects of maternal undernutrition on the growth, development and antioxidant status of ovine placentome subtypes during late pregnancy. Eighteen time-mated Mongolian ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.18 MJ ME . kg BW-0.75 . d-1, n = 6), Restricted Group 2 (RG2, 0.33 MJ ME . kg BW-0.75 . d-1, n = 6) and Control Group (CG, ad libitum, 0.67 MJ ME . kg BW -0.75 . d -1, n = 6). All animals were supplied chopped hay during the restriction period. At 140 days of pregnancy, the gravid uterus was removed; then individual fetuses and placentae were weighed. The numbers and weight of the placentome subtypes were examined. The number of vessels of the placentome subtypes were observed in sections stained with hematoxylin-eosin. The indexes of antioxidant capacity and oxidative stress, including total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity and mal-ondialdehyde (MDA) concentration, were measured by spectrometric kits. The fetal weights, placental weights and the numbers of Type A placentomes in both restricted groups were reduced (P < .05). Decreased fetal/placental weight ratio and increased total weight of the Type A placentome were found in the RG1 group compared to CG (P < .05). The total weights and the numbers of the Type B, Type C and Type D increased with severe maternal undernutrition in RG1 compared to CG (P < .05), as well as the increased numbers of Type B in the RG2 group compared to the CG group (P < .05). The placentome subtypes in RG1, including Type A, Type B and Type C, exhibited decreased concentrations of T-AOC and SOD activities, but higher MDA concentration and GSH-Px activity than those in CG (P < .05). For the RG2 group, the decreased T-AOC and SOD and increased GSH-Px were found in Type A placentome compared to CG (P < .05). For the same subtype placentome, there were no differences in the number of vessels among CG, RG2 and RG1 (P > .05); however, the number of vessels and MDA concentration of Type C and Type D placentome were higher than those of the Type A and Type B (P < .05). These results indicate that the growth and development of ovine Type A placentome was altered during late pregnancy. More and more Type B, Type C and Type D were formed from the Type A associated with maternal undernutrition. Oxidative stress occurred in all types of placentomes for the RG1 group, and the more flattening placentomes that were converted, the worse the antioxidant/pro-oxidant imbalance that was induced. PMID- 29407904 TI - Development of CDK-targeted scoring functions for prediction of binding affinity. AB - Cyclin-dependent kinase (CDK) is an interesting biological macromolecule due to its role in cell cycle progression, transcription control, and neuronal development, to mention the most studied biological activities. Furthermore, the availability of hundreds of structural studies focused on the intermolecular interactions of CDK with competitive inhibitors makes possible to develop computational models to predict binding affinity, where the atomic coordinates of binary complexes involving CDK and ligands can be used to train a machine learning model. The present work is focused on the development of new machine learning models to predict binding affinity for CDK. The CDK-targeted machine learning models were compared with classical scoring functions such as MolDock, AutoDock 4, and Vina Scores. The overall performance of our CDK-targeted scoring function was higher than the previously mentioned scoring functions, which opens the possibility of increasing the reliability of virtual screening studies focused on CDK. PMID- 29407905 TI - Location of fluorescent probes (2'-hydroxy derivatives of 2,5-diaryl-1,3-oxazole) in lipid membrane studied by fluorescence spectroscopy and molecular dynamics simulation. AB - 2'-Hydroxy derivatives of 2,5-diaryl-1,3-oxazole are known as environment sensitive ratiometric excited-state intramolecular proton transfer (ESIPT) fluorescent probes, which are used to monitor physicochemical properties of lipid membranes. However, because of their heterogeneous membrane distribution, accurate experimental determination of the probe position is difficult. To estimate the location of the ESIPT probes in lipid membranes we have performed fluorescence measurements and molecular dynamics (MD) simulations. In the series composed of 2-(2'-hydroxy-phenyl)-5-phenyl-1,3-oxazole (1), 2-(2'-hydroxy-phenyl) 5-(4'-biphenyl)-1,3-oxazole (2), and 2-(2'-hydroxy-phenyl)-phenanthro[9,10-d]-1,3 oxazole (3), the structure of the ESIPT-moiety of 2-(2'-hydroxy-phenyl)-oxazole was varied by either aromatic ring substitution or annealing, leading to the systematical increase in the hydrophobic character of the probes. The comparison of the fluorescence behavior of probes 1-3 in a wide variety of solvents with those in phospholipid vesicles revealed that all three probes prefer to reside inside a membrane. Our MD results demonstrate that the probes locate from the glycerol residues and the polar carbonyl groups of phospholipids up to hydrophobic acyl chain units. It has been found that the probe location correlates well with the size of the aromatic moiety, being gradually shifted from 11.1 A to 7.6 A from the bilayer center for probes 1 to 3, respectively. Our results may be useful for the design of novel fluorescent probes for fluorescence sensing of specific regions within a lipid membrane. PMID- 29407906 TI - Theoretical studies of the second step of the nitric oxide synthase reaction: Electron tunneling prevents uncoupling. AB - Nitric oxide (NO.) is a messenger molecule with diverse physiological roles including host defense, neurotransmission and vascular function. The synthesis of NO. from l-arginine is catalyzed by NO-synthases and occurs in two steps through the intermediary Nomega-hydroxy-l-arginine (NHA). In both steps the P450-like reaction cycle is coupled with the redox cycle of the cofactor tetrahydrobiopterin (H4B). The mechanism of the second step is studied by Density Functional Theory calculations to ascertain the canonical sequence of proton and electron transfer (PT and ET) events. The proposed mechanism is controlled by the interplay of two electron donors, H4B and NHA. Consistent with experimental data, the catalytic cycle proceeds through the ferric-hydroperoxide complex (Cpd 0) and the following aqua-ferriheme resting state, and involves interim partial oxidation of H4B. The mechanism starts with formation of Cpd 0 from the ferrous dioxy reactant complex by PT from the C-ring heme propionate coupled with hole transfer to H4B through the highest occupied pi-orbital of NHA as a bridge. This enables PT from NHA+. to the proximal oxygen leading to the shallow ferriheme H2O2 oxidant. Subsequent Fenton-like peroxide bond cleavage triggered by ET from the NHA-derived iminoxy-radical leads to the protonated Cpd II diradicaloid singlet stabilized by spin delocalization in H4B, and the closed-shell coordination complex of HO- with iminoxy-cation. The complex is converted to the transient C-adduct, which releases intended products upon PT to the ferriheme-HO- complex coupled with ET to the H4B+.. Deferred ET from the substrate or undue ET from/to the cofactor leads to side products. PMID- 29407907 TI - Silver complex of salicylic acid and its hydrogel-cream in wound healing chemotherapy. AB - The known metallotherapeutic [Ag(salH)]2 (AGSAL-1) of salicylic acid (salH2), was used for the development of new efficient silver based material for wounds healing. AGSAL-1 was characterized by spectroscopic techniques and X-ray crystallography. The wound healing epithelialization of AGSAL-1 was investigated by the means of scratch assay against immortalized human keratinocytes (HaCaT) cells. The anti-inflammatory activity of AGSAL-1 was evaluated by monitoring the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX). The antibacterial activity of AGSAL-1 was evaluated against bacterial species which colonize wounds, such as: Pseudomonas aeruginosa (PAO1), Staphylococcus epidermidis and Staphylococcus aureus, by the means of Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and their Inhibition Zone (IZ). Moreover, the influence of AGSAL-1 against the formation of biofilm of PAO1 and St. aureus was also evaluated by the mean of Biofilm Elimination Concentration (BetaEpsilonC). A hydrogel material CMC@AGSAL 1, based on the dispersion of AGSAL-1 in to carboxymethyl cellulose (CMC) was tested for its antimicrobial activity. Molecular Docking was performed, to explore the molecular interaction of AGSAL-1 with (i) the transcriptional regulator of PAO1, LasR. (ii) the mevalonate pathway for the biosynthesis of isoprenoids which is essential for gram-positive bacteria St. epidermidis and St. aureus. The toxicity of AGSAL-1 was examined against the HaCaT cells. Its genotoxicity was evaluated using Allium cepa model, in vivo. No genotoxicity was detected, indicating that AGSAL-1 is a candidate towards the development on a new efficient medication of the silver based metallodrugs. PMID- 29407908 TI - RTHLVFFARK-NH2: A potent and selective modulator on Cu2+-mediated amyloid-beta protein aggregation and cytotoxicity. AB - Dysfunctional accumulation of amyloid-beta (Abeta) protein stimulated by Cu2+ is considered as a key process in the pathogenesis of Alzheimer's disease (AD). Thus, bifunctional substances capable of chelating Cu2+ and inhibiting Abeta aggregation are promising therapeutic agents against AD. Herein, a novel bifunctional decapeptide RTHLVFFARK-NH2 (RK10) was developed by integrating a metal chelating tripeptide (RTH) and an Abeta aggregation inhibitor Ac-LVFFARK NH2 (LK7). The high selectivity of RK10 for Cu2+ over other biologically relevant metal ions was demonstrated by isothermal titration calorimetry. RK10 bound Cu2+ with a dissociation constant of 0.02 MUM. This enabled RK10 to sequester Cu2+ from Abeta40-Cu2+ species and to arrest the production of reactive oxygen species (ROS) catalyzed by Cu2+ or Abeta40-Cu2+ species. Extensive physical, biophysical and biological studies indicate that RK10 targeted free and Cu2+-bound Abeta40 species, suppressed Abeta40 aggregation, and diminished the cytotoxicity induced by Abeta40 and Cu2+-mediated Abeta40 in cultured SH-SY5Y cells. Taken together, the results proved the excellent selective roles of RK10 in inhibiting Cu2+ mediated Abeta40 aggregation and eliminating ROS generation catalyzed by Cu2+/Abeta40-Cu2+ species. Thus, this work provided new insight into the design and development of potent bifunctional inhibitors against Abeta aggregation and cytotoxicity. PMID- 29407909 TI - Dynamics of dehaloperoxidase-hemoglobin A derived from NMR relaxation spectroscopy and molecular dynamics simulation. AB - Dehaloperoxidase-hemoglobin is the first hemoglobin identified with biologically relevant oxidative functions, which include peroxidase, peroxygenase and oxidase activities. Herein we report a study of the protein backbone dynamics of DHP using heteronuclear NMR relaxation methods and molecular dynamics (MD) simulations to address the role of protein dynamics in switching from one function to another. The results show that DHP's backbone helical regions and turns have average order parameters of S2 = 0.87 +/- 0.03 and S2 = 0.76 +/- 0.08, respectively. Furthermore, DHP is primarily a monomer in solution based on the overall tumbling correlation time taum is 9.49 +/- 1.65 ns calculated using the prolate diffusion tensor model in the program relax. A number of amino acid residues have significant Rex using the Lipari-Szabo model-free formalism. These include Lys3, Ile6, Leu13, Gln18, Arg32, Ser48, Met49, Thr56, Phe60, Arg69, Thr71 Cys73, Ala77, Asn81, Gly95, Arg109, Phe115, Leu127 and Met136, which may experience slow conformational motions on the microseconds-milliseconds time scale according to the model. Caution should be used when the model contains >4 fitting parameters. The program caver3.0 was used to identify tunnels inside DHP obtained from MD simulation snapshots that are consistent with the importance of the Xe binding site, which is located at the central intersection of the tunnels. These tunnels provide diffusion pathways for small ligands such as O2, H2O and H2O2 to enter the distal pocket independently of the trajectory of substrates and inhibitors, both of which are aromatic molecules. PMID- 29407910 TI - Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(eta6-toluene) complexes of picolinate derivatives. AB - Five Ru(II)(eta6-toluene) complexes formed with 2-picolinic acid and its various derivatives have been synthesized and characterized. X-ray structures of four complexes are also reported. Complex formation processes of [Ru(II)(eta6 toluene)(H2O)3]2+ organometallic cation with the metal-free ligands were studied in aqueous solution in the presence of chloride ions by the combined use of 1H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with in vitro cytotoxic and antiproliferative activity in cancer cell lines being sensitive and resistant to classic chemotherapy and in normal cells as well. Formation of mono complexes such as [Ru(eta6 toluene)(L)(Z)]+/0 (L: completely deprotonated ligand; Z = H2O/Cl-) with high stability and [Ru(eta6-toluene)(L)(OH)] was found in solution. The pKa values (8.3-8.7) reflect the formation of low amount of mixed hydroxido species at pH 7.4 at 0.2 M KCl ionic strength. The complexes are fairly hydrophilic and show moderate chloride ion affinity and fast chloride-water exchange processes. The studied complexes exhibit no cytotoxic activity in human cancer cells (IC50 > 100 MUM), only complexes formed with 2-picolinic acid (1) and its 3-methyl derivative (2) represented a moderate antiproliferative effect (IC50 = 84.8 (1), 79.2 MUM (2)) on a multidrug resistant colon adenocarcinoma cell line revealing considerable multidrug resistant selectivity. Complexes 1 and 2 bind to human serum albumin covalently and relatively slowly with moderate strength at multiple binding sites without ligand cleavage. PMID- 29407911 TI - Label-free proteomic analysis to characterize ginger from China and Ghana. AB - Ginger is a popular spice used in food and beverages. In this study, we sought to characterize and differentiate ginger samples of Ghana and China origin using label-free proteomic and untargeted metabolomic analyses. As result, a total of 180 proteins significantly changed between the ginger samples from both studied countries. Among them, 17 proteins were specifically identified in the Chinese ginger, while 23 proteins were only identified in the Ghanaian ginger. Function and bioinformatics analyses indicated that changes in carbon metabolism, secondary metabolites biosyntheses, citrate acid cycle, and amino acids biosyntheses-related pathways contributed to the differences. These results were confirmed through the identification of 14 significantly changed metabolites including diarylheptanoids and gingerols. Importantly, change tendencies of these metabolites corresponded to changes in abundance of the protein enzymes involved in their syntheses. These results suggest that changes in metabolism-related protein enzymes are responsible for the intraspecies difference of the ginger samples. PMID- 29407912 TI - Exploring high hydrostatic pressure-mediated germination to enhance functionality and quality attributes of wholegrain brown rice. AB - This investigation aims to evaluate the effects of high hydrostatic pressure (HHP) applied prior to germination on functionality and quality of wholegrain germinated brown rice (GBR). Wholegrain brown rice (WBR) were firstly stressed by HHP treatments (50-350 MPa/20 min), and then incubated at 37 degrees C to obtain GBR grains after a 2-day soaking period. Gama-aminobutyric acid contents significantly depended on the pressure applied, showing 25% increment in 50 MPa stressed grains compared to the control. HHP shock led to significantly improved in vitro starch digestibility, which was related to the transformation of crystalline starch granules into amorphous form as consistently revealed by scanning electron microscope imaging and Fourier-transform infrared spectroscopy. HHP-pretreated samples achieved markedly enhanced storability by influencing kinetic curves of lipid hydrolysis and oxidation. These results suggested that metabolic response to HHP during germination could significantly improve functional and quality characteristics of WBR products. PMID- 29407913 TI - Combined in vivo and in silico approaches for predicting the release of bioactive peptides from meat digestion. AB - We studied the kinetics of peptide release during the gastric digestion of meat proteins in vivo, in view to predicting the release of bioactive peptides further on in the digestive tract. Six mini pigs fitted with gastric cannulas received a meal with cooked beef as protein source. Digesta was collected at regular time intervals up to 51/2 h. The peptides generated by the gastric digestion of meat were identified and quantified using label-free LC MS, thereafter subjected to in silico digestion mimicking the action of intestinal enzymes. Three clusters of proteins presenting similar evolutions according to their dynamic hydrolysis were obtained. This study clearly improves the in silico prediction of the intestinal release of bioactive peptides by mapping meat protein degradation in the stomach in an in vivo model. Knowledge of the conformation of the peptides released in the stomach further improves this prediction. PMID- 29407914 TI - Subcritical water extraction, UPLC-Triple-TOF/MS analysis and antioxidant activity of anthocyanins from Lycium ruthenicum Murr. AB - In this work, it has been developed an efficient method for extraction of anthocyanin from Lycium ruthenicum Murr. and the antioxidative activities research. Subcritical water extraction was investigated as a green technology for the extraction of anthocyanin from L. ruthenicum. Several key parameters affecting extraction efficiency were investigated and optimized by response surface methodology (RSM) combined with Box-Behnken design (BBD). The optimum extraction conditions and the desirability of model were the time of extraction = 55 min and the flow rate was 3 mL/min at 170 degrees C. At this operating condition, the content of anthocyanin was high to 26.33%. Subcritical water extraction was more efficient than using hot water or methyl alcohol for the extraction of anthocyanin. The composition of anthocyanins from L. ruthenicum has been investigated by high-performance liquid chromatography with diode array detector (HPLC-DAD) and Ultra Performance Liquid Chromatography-Triple-Time of Flight Mass Spectrometer (UPLC-Triple-TOF/MS). Seven anthocyanins have been detected, all of which were identified and quantified. Furthermore, the anthocyanins extracted by SWE showed significantly better antioxidant activity than the anthocyanins extracted by hot water or methyl alcohol according to DPPH and ABTS assay. SWE with significantly higher anthocyanin and antioxidant activity were achieved compared to conventional methods. PMID- 29407915 TI - Physicochemical, functional, and biological properties of water-soluble polysaccharides from Rosa roxburghii Tratt fruit. AB - Water-soluble polysaccharides (RTFP) were extracted from Rosa roxburghii Tratt fruit by hot water method. The physicochemical, functional, and hypoglycemic properties of RTFP were investigated. The results revealed that RTFP mainly contained carbohydrates (63.79 +/- 0.73%, g/g), uronic acids (14.8 +/- 0.06%, g/g), and proteins (4.10 +/- 0.58%, g/g). RTFP was composed of arabinose, galactose, glucose, mannose, xylose, and fucose with molar percentages of 33.8, 37.3, 20.7, 1.74, 3.43, and 2.95%, respectively. Functional analyses indicated that RTFP had good oil-holding capacity, foaming properties, and emulsifying capacity. The rheological results showed that RTFP exhibited typical shear thinning behavior and viscoelastic properties influenced by sample concentration, temperature and inorganic salt. Additionally, RTFP exhibited favorable inhibitory activities against alpha-glucosidase in a mixed inhibition type, and against alpha-amylase in an uncompetitive inhibition type. These results suggest that RTFP can be exploited as a multi-functional additive or hypoglycemic agent in foods, pharmaceuticals and cosmetics. PMID- 29407916 TI - An ultrasensitive aptasensor based on fluorescent resonant energy transfer and exonuclease-assisted target recycling for patulin detection. AB - Patulin (PAT) is a type of mycotoxin which can compromise both food quality and human health. Due to its harmful effects, strict monitoring of PAT contents in food systems is necessary. A novel kind of bioassay was proposed for determining PAT based on the fluorescent resonant energy transfer (FRET) strategy. The exonuclease-catalyzed target recycling strategy was employed to improve the sensitivity of the FRET system. The results showed that the linear range extends from 0.01 ng/mL to 100 ng/mL. Furthermore, the average recoveries ranged from 93.33% to 105.21%, confirming the reliability of this method. The total analysis time for our assay developed is about 50 min. Compared to traditional analytical methods, the developed assay is more stable and has a significantly lower detection of limit (0.003 ng/mL). We believe the approach developed in this study would be useful for high-throughput screening of PAT in food industry and government laboratory. PMID- 29407917 TI - Effects of processing method and age of leaves on phytochemical profiles and bioactivity of coffee leaves. AB - The use of coffee leaves as a novel beverage has recently received consumer interest, but there is little known about how processing methods affect the quality of final product. We applied tea (white, green, oolong and black tea) processing methods to process coffee leaves and then investigated their effects on phytochemical composition and related antioxidant and anti-inflammatory properties. Using Japanese-style green tea-processing of young leaves, and black tea-processing of mature (BTP-M) coffee leaves, produced contrasting effects on phenolic content, and associated antioxidant activity and nitric oxide (NO) inhibitory activity in IFN-gamma and LPS induced Raw 264.7 cells. BTP-M coffee leaves also had significantly (P < .05) higher responses in NO, iNOS, COX-2, as well as a number of cytokines, in non-induced Raw 264.7. Our findings show that the age of coffee leaves and the type of processing method affect phytochemical profiles sufficiently to produce characteristic antioxidant and anti-inflammatory activities. PMID- 29407918 TI - A biodegradable colorimetric film for rapid low-cost field determination of formaldehyde contamination by digital image colorimetry. AB - A biodegradable colorimetric film was fabricated on the lid of portable tube for in-tube formaldehyde detection. Based on the entrapment of colorimetric reagents within a thin film of tapioca starch, the yellow reaction product was observed with formaldehyde. Intensity of the blue channel from the digital image of yellow product showed a linear relationship in the range of 0-25 mg L-1 with low detection limit of 0.7 +/- 0.1 mg L-1. Inter-day precision of 0.61-3.10%RSD were obtained with less than 4.2% relative error from control samples. The developed method was applied for various food samples in Phuket and formaldehyde concentration range was non-detectable to 1.413 mg kg-1. The quantified concentrations of formaldehyde in fish and squid samples provided relative errors of -7.7% and +10.8% compared to spectrophotometry. This low cost sensor (~0.04 USD/test) with digital image colorimetry was thus an effective alternative for formaldehyde detection in food sample. PMID- 29407919 TI - 3D confocal Raman imaging of oil-rich emulsion from enzyme-assisted aqueous extraction of extruded soybean powder. AB - The understanding of the structure morphology of oil-rich emulsion from enzyme assisted extraction processing (EAEP) was a critical step to break the oil-rich emulsion structure in order to recover oil. Albeit EAEP method has been applied as an alternative way to conventional solvent extraction method, the structure morphology of oil-rich emulsion was still unclear. The current study aimed to investigate the structure morphology of oil-rich emulsion from EAEP using 3D confocal Raman imaging technique. With increasing the enzymatic hydrolysis duration from 1 to 3 h, the stability of oil-rich emulsion was decreased as visualized in the 3D confocal Raman images that the protein and oil were mixed together. The subsequent Raman spectrum analysis further revealed that the decreased stability of oil-rich emulsion was due to the protein aggregations via SS bonds or protein-lipid interactions. The conformational transfer in protein indicated the formation of a compact structure. PMID- 29407921 TI - New insight into the unresolved HPLC broad peak of Cabernet Sauvignon grape seed polymeric tannins by combining CPC and Q-ToF approaches. AB - Polymeric tannins from grapes have always been reported as an unresolved broad peak in HPLC chromatograms, and this has severely limited their identification to date. This study aimed to disassemble this broad peak and explore the polymeric tannin molecules inside. By applying centrifugal partition chromatography (CPC), an efficient separation approach was developed to split the broad peak of grape seed tannins into fractions. Then, the fractions were analyzed by Q-ToF (quadrupole time-of-flight mass spectrometry) to determine the corresponding structures of the tannins. The results suggest that grape seed polymeric tannins were eluted consecutively according to their degree of polymerization (DP). Condensed tannins identified in wine grape seed have a range of DP and degree of galloylation (DG) up to 20 and 11, respectively. The molecular mass of the largest molecule detected was 6067. To our knowledge, this is the first report to offer an insight into the broad peak of polymeric tannins found with HPLC and to characterize the tannins with a DP up to 20 as shown by HRMS and MS/MS data. PMID- 29407920 TI - Microfluidic paper-based chip platform for benzoic acid detection in food. AB - An integrated microfluidic platform comprising a microfluidic paper-based analytical device (uPAD) and a portable detection system is proposed for the concentration detection of benzoic acid via Janovsky reaction theory. In the proposed approach, the reaction zone of the uPAD is implanted with 5 N sodium hydroxide and dried at 30 degrees C for 20 min. The benzoic acid sample is derived to 3,5-Dinitrobenzoic acid using KNO3 and H2SO4 at 40 degrees C for 40 min and is then dripped on the reaction zone of the uPAD. Finally, the uPAD is transferred to the portable detection system and heated at a temperature of 45 degrees C for 20 min on a hot plate to prompt a Janovsky reaction. The resulting color change of the detection zone is observed using a CMOS camera. The reaction color image is delivered to a smartphone via a connector and the benzoic acid concentration is determined using self-written RGB analysis software. The experimental results obtained using control samples with known benzoic acid concentrations in the range of 500-4000 ppm show that the R(ed) + B(lue) intensity (Y) and benzoic acid concentration (X) are related as Y = -0.0264 X + 408.79. Moreover, the correlation coefficient is equal to R2 = 0.9953. The proposed detection platform is used to measure the benzoic acid concentrations of twenty-one commercial food samples. It is shown that the concentration measurements deviate by no more than 6.6% from those obtained using a standard HPLC macroscale method. Overall, the results presented in this study show that the proposed integrated microfluidic paper-based chip platform provides a compact and reliable tool for benzoic acid concentration measurement purposes. PMID- 29407922 TI - Quality development and main chemical components of Tieguanyin oolong teas processed from different parts of fresh shoots. AB - The Tieguanyin oolong tea is popular in China. However, the quality development and chemical change during processing were still unclear. This study aimed to investigate the chemical compositions and quality of Tieguanyin oolong teas processed from different leaves of fresh shoots. The results showed the fermentation degree of oolong teas decreased from the first leaves to the fourth fifth leaves, and was associated with the changes in infusion color (b*) and chroma, as well as the contents of total theaflavins, (E)-nerolidol and indole. After shaking and setting, the differences in the water contents and the activities of polyphenoloxidase, peroxidase, and beta-glucosidase of the tea leaves, significantly influenced the oxidation of catechins. The hydrolysis of volatile compounds might influence the fermentation degrees of the oolong teas processed from different leaves of fresh shoots. The results generated from the present study can be used in guiding the production of oolong teas. PMID- 29407923 TI - Identification of menaquinones (vitamin K2 homologues) as novel constituents of honey. AB - Our recent research indicated that honey active macromolecules form colloidal particles that scatter the light and produce elaborate UV spectral profile dominated by double absorption peaks at 240-250 nm. The absorption at 240-250 nm signified the stable honey conformation that supported antibacterial activity and hydrogen peroxide production. Our aim was to identify the bioactive constituent relevant to this absorption. The methodology included activity-guided fractionation of honey through size-exclusion chromatography, solid-phase extraction and UPLC-UV-MS. UV spectral analysis of UPLC peaks revealed compounds with UV lambda (max) typical of naphtoquinones. The MS chromatograms showed mass ions differing by [M-68n] indicating a polyisoprene structure and the fragmentation patterns typical for menaquinones. The exact mass measurements of menaquinones using a quadrupole-Orbitrap mass spectrometry confirmed their identification as a series of MK-3 to MK-7 aptimers. Detection of menaquinones, previously unknown constituents of honey, suggests that they might play role in honey redox and antibacterial activities. PMID- 29407924 TI - Effects of conjugated linoleic acid (CLA) on fat accumulation, activity, and proteomics analysis in Caenorhabditis elegans. AB - Conjugated linoleic acid (CLA) has been reported to reduce fat storage in cell culture and animal models. In the current study, the effects of CLA on the fat accumulation, activities, and proteomics were investigated using Caenorhabditis elegans. 100 uM CLA-TG nanoemulsion significantly reduced fat accumulation by 29% compared to linoleic acid (LA)-TG treatment via sir-2.1 (the ortholog of Sirtuin 1), without altering the worm size, growth rate, and pumping rate of C. elegans. CLA significantly increased moving speed and amplitude (the average centroid displacement over the entire track) of wild type worms compared to the LA group and these effects were dependent on aak-2 (AMPKalpha ortholog) and sir-2.1. Proteomics analysis showed CLA treatment influences various proteins associated in reproduction and development, translation, metabolic processes, and catabolism and proteolysis, in C. elegans. We have also confirmed the proteomics data that CLA reduced the fat accumulation via abs-1 (ATP Synthase B homolog). However, there were no significant effects of CLA on brood size, progeny numbers, and hatchability compared to LA treatment. PMID- 29407925 TI - Minimizing quality changes of cloudy apple juice: The use of kiwifruit puree and high pressure homogenization. AB - Cloud loss, enzymatic browning, and flavor changes are important quality defects of cloudy fruit juices determining consumer acceptability. The development of clean label options to overcome such quality problems is currently of high interest. Therefore, this study investigated the effect of kiwifruit puree (clean label ingredient) and high pressure homogenization on quality changes of cloudy apple juice using a multivariate approach. The use of kiwifruit puree addition and high pressure homogenization resulted in a juice with improved uniformity and cloud stability by reducing particle size and increasing viscosity and yield stress (p < 0.01). Furthermore, kiwifruit puree addition reduced enzymatic browning (DeltaE* < 3), due to the increased ascorbic acid and contributed to a more saturated and bright yellow color, a better taste balance, and a more fruity aroma of juice. This work demonstrates that clean label options to control quality degradation of cloudy fruit juice might offer new opportunities. PMID- 29407926 TI - Influence of acylglycerol emulsifier structure and composition on the function of shortening in layer cake. AB - The effect of the structure and composition of acylglycerol emulsifiers on the functionality of a palm-based shortening and quality of layer cake was investigated. The emulsifiers evaluated were distilled monoacylglycerol (DMG) and four acylglycerols (40% monoacylglycerol content) of octanoic acid (8:0), palmitic acid (16:0), stearic acid (18:0), and linoleic acid (18:2), designated as GMOct40, GMP40, GMS40, and GML40, respectively. The addition of GMP40 and GMS40 led to shortening with a higher solid fat content, finer crystals, and higher proportion of beta' form. These changes enhanced shortening's function in aiding air incorporation and retention in cake batter, which improved the cake's volume and crumb structure. However, the high monoacylglycerol content in DMG did not improve the properties of shortening and cake as compared to GMP40. In contrast, GML40 and GMOct40 had adverse effects on the functionality of shortening, which generated cakes with inferior crumb structure. PMID- 29407927 TI - Feasibility of biodegradable based packaging used for red meat storage during shelf-life: A pilot study. AB - This study was designated to ascertain the effectiveness of polylactic acid (PLA) based packaging solution to store red fresh meat during its refrigerated shelf life. Recently the attention in the packaging industry regarding the use of bioplastics has been shifting from compostable/biodegradable materials toward biobased materials. Steaks obtained from semimembranous muscle of Piemontese beef were packaged in PLA trays closed with a lid made of PLA film and for comparison purposed in a conventional reference package consisting of a amorphous polyethylene terephthalate/polyethylene (APET/PET) trays and wrapped in plastic film of polyvinyl chloride (PVC). The packaging under modified atmosphere MAP was carried out by using a gas mixture of 66% O2, 25% CO2 and 9%N2. By using PLA packaging combination it was possible to maintain an optimum red colour together with a reduced content of volatile compounds associated to off-flavours of meat samples particularly related to the oxidation phenomena. PMID- 29407928 TI - A novel N,N'-bis(acetylacetone)ethylenediimine functionalized silica-core shell magnetic nanosorbent for manetic dispersive solid phase extraction of copper in cereal and water samples. AB - Determination of heavy metals at trace levels has a great deal of importance due to their undesirable effects on human life. In this study, N,N'-bis (acetyl acetone) ethylenediimine (Fe3O4@SiO2-EDN) was synthesized and applied for dispersive solid phase extraction of copper in water and cereal samples followed by FAAS. Sorbent characterization was investigated by SEM, FT-IR, EDX and VSM. The effective parameters were optimized using a central composite design. Under the optimal conditions, LOD (S/N = 3) and LOQ, preconcentration factor and RSD% were found to be 1.5 ng mL-1, 4.0 ng mL-1, 13 and 2.3%, respectively. The calibration curve was linear within the range of 4.0-175 ng mL-1 with r2 > 0.998. Relative recoveries were achieved within the range of 90.0-95.0%. With thanks of the good resulting analytical performance in this work, the proposed method can be applied as a suitable alternative for trace analysis of copper. PMID- 29407929 TI - Method for the determination of Pb, Cd, Zn, Mn and Fe in rice samples using carbon nanotubes and cationic complexes of batophenanthroline. AB - Among cereals, rice is the second most cultivated staple crop in the world. It may be contaminated by toxic heavy metals present in water or soil. Therefore, monitoring the presence of heavy metals in rice and its products is a matter of a great importance from the nutritional and toxicological view. In this paper, a simple and effective analytical procedure based on dispersive micro solid-phase extraction with the use of oxidized multiwalled carbon nanotubes and batophenanthroline was developed for the determination of lead, cadmium, zinc, manganese and iron in white and wild rice samples. Due to the high preconcentration factor of 200, the optimized procedure allows obtaining detection limits between 0.13 and 0.35 ng mL-1 using flame atomic absorption spectrometry (FAAS). Novel preconcentration method can successfully be applied in food analysis with accuracy better than 7% rel. and repeatability lower than 3%. PMID- 29407930 TI - PVP-coated gold nanoparticles for the selective determination of ochratoxin A via quenching fluorescence of the free aptamer. AB - This paper describes an aptamer/gold nanoparticle-based assay for ochratoxin A (OTA) detection. This assay is based on the use of an aptamer labeled with carboxyfluorescein (FAM) at its 5'-end and gold nanoparticles (AuNPs) that act as quenchers of fluorescence. When OTA is absent in the system, the fluorescently labeled aptamers are adsorbed on the surface of AuNPs. The fluorescence signal of the fluorescein-labeled OTA aptamer generated is quenched by the fluorescence resonance energy transfer effect of AuNPs. When OTA is present in the system, the fluorescently labeled aptamer binds to OTA and forms a folded structure, which can resist the adsorption of AuNPs. Thus, the fluorescent signal can be retained. The detection limit of this sensing platform is 5 nM, and the linear detection range is 10-1000 nM (R2 = 0.994). The procedure was validated by the quantitation of OTA in spiked ginger powder samples and were found to be free of interference by the sample matrix. The recoveries and the relative standard deviation varied from 89.0% to 117.8% and from 1.9% to 6.3%, respectively. PMID- 29407931 TI - Stability of spray-dried beetroot extract using oligosaccharides and whey proteins. AB - The properties and stability of spray-dried beetroot extract using maltodextrin (MD), inulin (IN), and whey protein isolate (WPI) as carrier agents were evaluated. The values of moisture, betalains content, and retention were 3.33 4.24%, 348.79-385.47 mg/100 g (dry-basis), and 88.45-95.69%, respectively. Higher values of antioxidant activity were observed for the treatments using WPI. The treatment with inulin alone presented higher hygroscopicity in the moisture adsorption isotherms at 25 degrees C and lower thermal stability when evaluating the thermogravimetric curves. When stored at 60 degrees C, the use of WPI alone conferred lower stability to the beetroot extract powder. In general, the simultaneous use of IN and WPI as carrier agents resulted in good stability of the beetroot extract powder, representing an opportunity for innovation in food products. PMID- 29407932 TI - Effects of fermentation on SDS-PAGE patterns, total peptide, isoflavone contents and antioxidant activity of freeze-thawed tofu fermented with Bacillus subtilis. AB - To develop a new healthy functional tofu product, the pH, total cell number, SDS PAGE patterns, contents of reducing sugar, peptide, isoflavones, antioxidant activity and digestibility of freeze-thawed tofu, fermented with Bacillus subtilis for various time periods, were investigated. In SDS-PAGE patterns, the band intensities of 7S and 11S globulins were slightly decreased and new protein bands of lower molecular weight appeared by fermentation for 12 h. After 18 h, the bands of 7S globulin and the acidic subunit of 11S globulin had almost entirely disappeared and the basic subunit band of 11S globulin was fainter. An 18 h of fermentation was thought to be the most desirable, because the contents of reducing sugar, total peptide, and isoflavone aglycones (daidzein and genistein), as well as antioxidant activities and digestibility of freeze-thawed tofu were more increased by the fermentation for 18 h. PMID- 29407933 TI - Bioaccessibility, cellular uptake and transport of luteins and assessment of their antioxidant activities. AB - A rapid method for producing 9Z- and 13'Z-isomers from all-E-lutein was developed using I-TiO2 as catalyst. In a simulated in vitro gastrointestinal digestion model, both trans-cis isomerization of all-E-lutein and cis-trans isomerization of Z-luteins occurred during the intestinal phase. The bioaccessibility of all isomers was between 14 and 23%, and it was higher for Z-luteins. In a Caco-2 cell monolayer model, all isomers were relatively stable during cellular uptake and transport across the membrane as no significant isomerization and degradation was detected, but all-E-lutein exhibited significantly higher cellular uptake and transport efficiencies. These results suggest that Z-luteins found in human plasma may likely be formed before intestinal absorption. 13'Z-Lutein also exhibited highest antioxidant activity in FRAP, DPPH and ORAC-L assays, but no significant difference in cell-based antioxidant assay compared with other isomers. Future studies on the different antioxidant activities of cis isomers of lutein in vivo will provide further explanation. PMID- 29407934 TI - Pesticide determination in sweet peppers using QuEChERS and LC-MS/MS. AB - In this work, a rapid, effective, and safe method, generating only a small amount of waste, based on the citrate version of QuEChERS was optimized and validated for multiresidue determination of pesticides of different classes in sweet green peppers, determined by liquid chromatography coupled with tandem mass spectrometry. The matrix components influenced the measurement of the pesticides by the developed analysis technique, so that, analytical curves were prepared using pesticide-free matrix extracts for quantification of the analytes. The method provides satisfactory accuracy verified by recoveries of 70-120%, and good precision (coefficients of variation <=20%). It also showed selectivity, linearity of response, and lower limits of quantification than the maximum limit of residue for each compound, as established by ANVISA and Codex Alimentarius. PMID- 29407935 TI - Quantitative phosphoproteomic analysis among muscles of different color stability using tandem mass tag labeling. AB - A quantitative analysis of protein phosphorylation in ovine LTL muscle with different color stability was performed in the present study using TMT labeling in combination with TiO2 phosphopeptide enrichment. A total of 3412 phosphopeptides assigned to 1070 phosphoproteins were identified by mass spectrometry, of which 243 proteins were detected to be differentially phosphorylated between muscles of different color stability. Among these differentially phosphorylated proteins, 27 phosphoproteins were identified to be key color-related proteins by informatics analysis. Proteins involved in carbohydrate metabolism, especially glycolytic enzymes, were the largest cluster of protein determined to be color-related. In addition, the phosphorylation of myoglobin at Ser133 plays a negative role in the regulation of meat color stability. In summary, this study revealed that the phosphorylation of some glycolytic enzymes and myoglobin at specific serine residues may play critical roles in the regulation of meat color stability. PMID- 29407936 TI - Determination of total avilamycin residues as dichloroisoeverninic acid in porcine muscle, fat, and liver by LC-MS/MS. AB - A sensitive and reliable method for determining the total avilamycin residues was developed using LC-MS/MS. Avilamycin (consisting of avilamycin A and 15 other minor factors) and its metabolites in porcine muscle, fat, and liver were analysed as the marker residue dichloroisoeverninic acid (DIA), in accordance with the maximum residue limit (MRL) established by international organisations such as Codex Alimentarius Commission and other regulatory bodies. The analytes were extracted from samples with acetone, hydrolysed to DIA, partitioned into ethyl acetate, and cleaned up prior to the LC-MS/MS analysis. The method was validated at Codex MRL and 0.01 mg/kg. The results show excellent recoveries ranging from 100 to 108%, with the relative standard deviations <6%. Matrix effects were negligible for all types of samples, indicating effective sample clean-up. The absence of interfering peaks close to the retention time in blank samples demonstrates high selectivity. Overall, this method is reliable and suitable for regulatory-purpose analysis. PMID- 29407937 TI - The contribution of minor folates to the total vitamin B9 content of Infant formula and clinical nutrition products. AB - In the present study an optimization of trienzyme treatment combining alpha amylase, protease and gamma-carboxy peptidase allowing complete sample preparation within a working day for the analysis of vitamin B9 (folate) in infant formula and adult/pediatric nutritional products is presented. The optimized sample preparation was applied to a set of samples representing most of the products in the marketplace. Results on Standard Reference Material 1849a were well in agreement with certified values. The main contributor to total folate was folic acid, 5-methyl-tetrahydrofolate was the only minor contributor in milk-based products. Soy-based formulas contained polyglutamates of 5-formyl tetrahydrofolate. The relative contribution of polyglutamates to the total folate content remained low in the types of product included in this study. The results suggest that a simple di-enzyme treatment could be enough for these products, nevertheless, this should be carefully evaluated prior to making a decision on the use of tri- or di-enzyme treatment. PMID- 29407938 TI - Colorimetric aptasensors for determination of tobramycin in milk and chicken eggs based on DNA and gold nanoparticles. AB - Colorimetric aptasensors were designed for detection of tobramycin (TOB) based on unmodified gold nanoparticles (AuNPs) and single-strand DNA (ssDNA). In the absence of TOB, the DNA aptamer was coated on the surface of AuNPs to keep it against salt-induced aggregation. In the presence of TOB, aptamer will bind with TOB and detach from the surface of AuNPs because of higher affinities between aptamer and TOB. Then less protection of DNA may result in the aggregation of AuNPs by salt and an apparent color change from red to purple-blue. The developed aptasensors showed a high selectivity and sensitivity for TOB detection. The linearity range and the detection limit were 40-200 nM and 23.3 nM respectively. The validity of the procedure and applicability of aptasensors were successfully used to detect TOB in milk and chicken eggs, and the results were excellent in accord with the values obtained by spectrofluorimetric detection. PMID- 29407939 TI - Role development of community health workers for cardiovascular disease prevention in India. AB - Cardiovascular disease (CVD) is the leading cause of mortality in India. Since community health workers (CHWs) have historically played a pivotal role in improving maternal and child health, it has been hypothesized that they have the potential to mitigate the impact of CVD in countries such as India. Project SEHAT is a cluster RCT to test the hypothesis that CHWs can improve the control of cardiovascular risk factors in a community in West Bengal, India. This study sought to quantitatively assess the training outcomes of CHWs recruited for Project SEHAT, and qualitatively assess their recruitment, training and fieldwork experiences. CHWs were recruited through a 2 step process- a written test and an interview. Upon completion of training, their knowledge and experiences were assessed. All intervention CHWs scored > 80% on the knowledge test, implying a high rate of knowledge retention. Important themes identified during a focus group discussion with CHWs included satisfaction with a 2 step recruitment process, emphasis on communication skills, a preference for audio-visual aids in training and recognition of the importance of a supportive supervisory framework. Respect from society and a positive impact on people was consistently cited as the most satisfying aspects of the job, followed by financial compensation. Recruitment and training processes for CHWs in CVD programs should be more standardized to enable replication, scalability and adequate assessment of their potential to mitigate CVD mortality in countries such as India. PMID- 29407940 TI - Daniel Stufflebeam and The World Bank. AB - Circa 2000 when The Evaluation Center on the campus of Western Michigan University was undergoing a renovation, staff were encouraged to clean out their filing cabinets. One of the authors rescued two manila files from the garbage dealing with a presentation that Daniel Stufflebeam made to The World Bank on 13 December 1993 and a subsequent World Bank conference on evaluation and development in which he participated 5-6 December 1994. In these documents, Dan set out some of his early thinking on international evaluation and other topics. The authors used these materials to write a tribute article to Dan publishing some of these ideas for the historical record. PMID- 29407942 TI - Neuropsychological correlates of cognitive, emotional-affective and auto activation apathy in Alzheimer's disease. AB - Apathy symptoms include different dimensions: cognitive (C), emotional-affective (E-Aff) and auto-activation; they have been related to dysfunctions of the dorsolateral, orbito-basal prefrontal cortex and the subcortical frontal connections to the basal ganglia, respectively. In Alzheimer's disease (AD), an association has been found between apathy severity and both executive deficits and atrophy of the dorso-lateral prefrontal cortex; however, it is not clear whether these associations concern only the cognitive aspects of apathy. Furthermore, whether there is an association in AD between E-aff apathy and theory of mind (ToM),the cognitive functions subsumed by the orbito-basal prefrontal cortex, has not been investigated. Aim of the study was to investigate the relationship between C, E-Aff and auto-activation apathy and performance on tasks investigating executive and ToM cognitive functions in AD. For this purpose, 20 AD patients with apathy and 20 matched controls were submitted to an executive and ToM neuropsychological assessment. Apathy was assessed with a weekly diary (ApD) created specifically to assist caregivers in quantifying the C, E-Aff and auto-activation symptomatology of apathy. Correlational analyses showed that AD patients' scores on the Modified Card Sorting Test (MCST) and Emotion Attribution tasks were correlated with most ApD scores. However, regression analyses showed that C diary scores were predicted by MCST performance, E-Aff diary scores by performance on the E-Attribution task and ApD scores measuring auto-activation apathy were predicted by both the MCST and the Emotion Attribution scores. These results confirm the co-occurrence of apathy and executive-function deficits in AD and suggest a specific association between AD patients' executive deficits and the cognitive component of apathy. Furthermore, they document, for the first time, an association between poor performance on tests assessing ToM abilities and the emotional-affective component of apathy in AD patients. Finally, these results are in line with the view that auto activation apathy reflects the sum of emotional and cognitive processing deficits. PMID- 29407941 TI - Active inference and the anatomy of oculomotion. AB - Given that eye movement control can be framed as an inferential process, how are the requisite forces generated to produce anticipated or desired fixation? Starting from a generative model based on simple Newtonian equations of motion, we derive a variational solution to this problem and illustrate the plausibility of its implementation in the oculomotor brainstem. We show, through simulation, that the Bayesian filtering equations that implement 'planning as inference' can generate both saccadic and smooth pursuit eye movements. Crucially, the associated message passing maps well onto the known connectivity and neuroanatomy of the brainstem - and the changes in these messages over time are strikingly similar to single unit recordings of neurons in the corresponding nuclei. Furthermore, we show that simulated lesions to axonal pathways reproduce eye movement patterns of neurological patients with damage to these tracts. PMID- 29407943 TI - First homology model of Plasmodium falciparum glucose-6-phosphate dehydrogenase: Discovery of selective substrate analog-based inhibitors as novel antimalarial agents. AB - In Plasmodium falciparum the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfG6PD-6PGL) is involved in the catalysis of the first reaction of the pentose phosphate pathway. Since this enzyme has a key role in parasite development, its unique structure represents a potential target for the discovery of antimalarial drugs. Here we describe the first 3D structural model of the G6PD domain of PfG6PD-6PGL. Compared to the human enzyme (hG6PD), the 3D model has enabled the identification of a key difference in the substrate-binding site, which involves the replacement of Arg365 in hG6PD by Asp750 in PfG6PD. In a prospective validation of the model, this critical change has been exploited to rationally design a novel family of substrate analog-based inhibitors that can display the necessary selectivity towards PfG6PD. A series of glucose derivatives featuring an alpha-methoxy group at the anomeric position and different side chains at position 6 bearing distinct basic functionalities has been synthesized, and their PfG6PD and hG6PD inhibitory activities and their toxicity against parasite and mammalian cells have been assessed. Several compounds displayed micromolar affinity (Ki up to 23 MUM), favorable selectivity (up to > 26-fold), and low cytotoxicity. Phenotypic assays with P. falciparum cultures revealed high micromolar IC50 values, likely as a result of poor internalization of the compounds in the parasite cell. Overall, these results endorse confidence to the 3D model of PfG6PD, paving the way for the use of target-based drug design approaches in antimalarial drug discovery studies around this promising target. PMID- 29407944 TI - Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases. AB - Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3 O-(6'-O-octanoyl)-beta-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug. PMID- 29407945 TI - Synthesis and biological evaluation of pyridazinone derivatives as potential anti inflammatory agents. AB - Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells. PMID- 29407947 TI - Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P glycoprotein-based multidrug resistance. AB - Five new (1-5) and ten known (6-15) jatrophane diterpenoids were isolated from the fructus of Euphorbia sororia and their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1 and 4 were confirmed by X-ray crystallographic analysis. Cytotoxicity and anti multidrug resistance effects of these jatrophane diterpenoids were evaluated in multidrug-resistant MCF-7/ADR breast cancer cells with an overexpression of P glycoprotein (P-gp). Eight compounds (1, 2, 4, 6, 8, 10, 11, and 15) showed promising chemoreversal abilities compared to verapamil (VRP). The most potent compound, Euphosorophane A (1), possessed many advantages, including (1) high potency (EC50 = 92.68 +/- 18.28 nM) in reversing P-gp-mediated resistance to doxorubicin (DOX), low cytotoxicity, and a high therapeutic index, (2) potency in reversing resistance to other cytotoxic agents associated with MDR, and (3) inhibition of P-gp-mediated Rhodamine123 (Rh123) efflux function in MCF-7/ADR cells. The results of the Western blot analysis indicated that the multidrug resistance (MDR) reversal induced by 1 was not due to the inhibiton of P-gp expression. Compound 1 stimulated P-gp-ATPase activity and caused the dose dependent inhibition of DOX transport activity. Lineweaver-Burk and Dixon plots implied that 1 was a competitive inhibitor to DOX in the binding site of P-gp with a Ki of 0.49-0.50 MUM. Our data suggested that 1 had a high binding affinity toward the DOX recognition site of P-gp. This resulted in inhibiting DOX transport, increasing intracellular DOX concentration, and finally resensitizing MCF-7/ADR to DOX. In addition, we discussed some added contents in the structure activity relationship (SAR) of jatrophane diterpenoids. PMID- 29407946 TI - Design, synthesis and in vitro biological evaluation of novel [1,2,3]triazolo[4,5 d]pyrimidine derivatives containing a thiosemicarbazide moiety. AB - A series of hybrid molecules containing [1,2,3]triazolo[4,5-d]pyrimidine and thiosemicarbazide moieties were designed, synthesized and evaluated for their antiproliferative activities against MGC-803, NCI-H1650 and PC-3 human cancer cells. Some of the synthesized compounds showed moderate to good activity against three selected cancer cell lines. Among these compounds, compound 29 displayed the most potent antiproliferative activity as well as good selectivity between cancer cells and normal cells. Further mechanism studies revealed that compound 29 could obviously inhibit the colony formation and migration of MGC-803 as well as induced apoptosis. PMID- 29407948 TI - Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 agonists. AB - The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues. PMID- 29407949 TI - Synthesis and biological evaluation of 4,6-diphenyl-2-(1H-pyrrol-1 yl)nicotinonitrile analogues of crolibulin and combretastatin A-4. AB - A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1 yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a-d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors. PMID- 29407950 TI - Design, synthesis and biological evaluation of water-soluble per-O-methylated cyclodextrin-C60 conjugates as anti-influenza virus agents. AB - The most common fullerene member C60 displays many biological applications, such as, anticancer, human immunodeficiency virus and hepatitis C virus inhibitors, O2 uptake inhibitor and vectors for drug and DNA. Nevertheless, the innate hydrophobicity of C60 constrains its further development. We introduced cyclodextrins to enhance the water-solubility of C60. Nine cyclodextrin-C60 conjugates, including seven alpha-cyclodextrin-C60 conjugates and two gamma cyclodextrin-C60 conjugates, were designed and synthesized. All of these conjugates did not show obvious cytotoxicity. The anti-influenza virus activity of nine conjugates was assessed. Two gamma-cyclodextrin-C60 conjugates, which were relatively more water-soluble, exerted higher inhibition with IC50 values of 87.73 MUM and 75.06 MUM, respectively, than seven alpha-cyclodextrin-C60 conjugates. PMID- 29407951 TI - Design, synthesis and biological evaluation of novel indole-benzimidazole hybrids targeting estrogen receptor alpha (ER-alpha). AB - In the course of efforts to develop novel selective estrogen receptor modulators (SERMs), indole-benzimidazole hybrids were designed and synthesised by fusing the indole nucleus with benzimidazole. All the compounds were first inspected for anti-proliferative activity using ER-alpha responsive T47D breast cancer cell lines and ER-alpha binding assay. From this study, two representative bromo substituted compounds 5f and 8f were found to be most active and thus were escalated for gene expression studies for targeting ER-alpha. Cell imaging experiment clearly suggest that compounds were able to cross cell membrane and accumulate thus causing cytotoxicity. RT-PCR and Western blotting experiments further supported that both compounds altered the expression of mRNA and receptor protein of ER-alpha, thereby preventing the further transactivation and signalling pathway in T47D cells lines. Structural investigation from induced fit simulation study suggest that compound 5f and 8f bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these results strongly indicate that compound 5f and 8f represents a novel potent ER-alpha antagonist properties and will proved promising in the discovery of SERM for the management of breast cancer. PMID- 29407952 TI - Discovery of C-1 modified oseltamivir derivatives as potent influenza neuraminidase inhibitors. AB - Inspired by our initial discovery about a series of neuraminidase (NA) inhibitors targeting the 150-cavity, in present study, we designed, synthesized, and biologically tested a panel of novel oseltamivir derivatives with C-1 modification, targeting the 430-cavity, an additional binding site which widely and stably existed in both group-1 and group-2 NAs. Some of the synthesized compounds displayed robust anti-influenza potencies against H5N1 and H5N6 viruses. Among them, compound 8b exerted the greatest inhibition, with IC50 values of 0.088 and 0.097 MUM and EC50 values of 4.26 and 1.31 MUM against H5N1 and H5N6 strains, respectively, which are similar to those of oseltamivir carboxylate (OSC). And its potency against mutant H5N1-H274Y NA was just 7-fold weaker than OSC. Molecular modeling revealed the elongated group at C-1 position being projected toward the 430-cavity. Notably, although compound 8b was not sensitive toward H5N1 strain relative to OSC in the embryonated egg model, it displayed greater anti-influenza virus effect against H5N6 strain than OSC at the concentration of 10 mmol/L. Overall, this work provided unique insights in the discovery of potent inhibitors against both group-1 and group-2 NAs. PMID- 29407953 TI - Design, semisynthesis, alpha-glucosidase inhibitory, cytotoxic, and antibacterial activities of p-terphenyl derivatives. AB - Terphenyllin (1), a naturally abundant p-terphenyl metabolite, was isolated from the coral derived fungus Aspergillus candidus together with four natural analogues 2-5. To evaluate their potency and selectivity, a series of new derivatives of 1 were designed and semisynthesized. They were evaluated for their alpha-glucosidase inhibitory, cytotoxic, and antibacterial activities. Compounds 1, 3, 4, 7, 8, 10, 11, 14, 15, 21, 23, 24, 29, 39, and 40 showed significant alpha-glucosidase inhibitory activity with IC50 values of 4.79-15 MUM, which were stronger than that of the positive controls, 1-deoxynojirimycin (IC50 = 192.0 MUM) and acarbose (IC50 = 707.9 MUM). Compounds 7 and 10 have relatively higher therapeutic indices (CC50/IC50 = 17 and 10, respectively), representing potential promising leads. The enzyme kinetic studies of compounds 1 and 24 showed a non competitive inhibition on alpha-glucosidase with Ki values of 1.50 and 3.45 MUM, respectively. Additionally, compounds 14, 21, 26, 29, 32, 35, and 37 were found to exhibit strong cytotoxicity against three tumor cell lines A549 (lung adenocarcinoma epithelial), HeLa (cervical carcinoma), and HepG2 (hepatocellular liver carcinoma) with IC50 values ranging from 0.15 to 5.26 MUM. Further study indicated that 32 could induce S-phase arrest in the cell cycle progression. PMID- 29407954 TI - Unravelling the binding mechanism of benproperine with human serum albumin: A docking, fluorometric, and thermodynamic approach. AB - The interaction between benproperine (BEN) and human serum albumin (HSA) has been simulatively and experimentally investigated based on docking, fluorometric, thermodynamic, and spectroscopic approach. The blind Autodock docking study first recognized the hydrophobic cavity of HSA at Domain IB as the probable binding site for BEN. BEN bound to HSA via a static quenching mechanism, resulting in the formation of BEN-HSA complex confirmed by fluorescence quenching and time resolved fluorescence. Fluorescence titration and isothermal titration calorimetry (ITC) revealed that the binding mode between BEN and HSA owning moderate affinity (binding constant at 104 magnitude) was mainly driven by electrostatic attraction and hydrophobic interaction. Circular dichroism (CD) spectra suggested upon Addition of BEN induced the conformational changes on HSA with alpha-helix decreasing. Due to the conformational rearrangements, BEN-HSA complex was stabilized by several non-covalent bonds. This work first clarified the progress in binding mechanism of benproperine with human serum albumin and then provided fresh insights into this drug transportation and metabolism. PMID- 29407955 TI - Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination proteasome degradation pathway. AB - Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau. Peptide 1 showed strong in vitro binding with Keap1 and Tau. With proper cell permeability, peptide 1 was found to colocalize with cellular Keap1 and resulted in the coimmunoprecipitation of Tau and Keap1. The results of flow cytometry and western blotting assays showed that peptide 1 can downregulate the intracellular Tau level in both time- and concentration dependent manner. The application of Keap1 siRNA silencing and the proteasome inhibitor MG132 confirmed that peptide 1 could promote the Keap1-dependent poly ubiquitination and proteasome-dependent degradation of Tau. The results suggested that using PROTACs to recruit Keap1 to induce the degradation of Tau may show promising character in the treatment of neurodegenerative disease. Besides, our research demonstrated that Keap1 should be a promising E3 ligase adaptor to be used in the design of novel PROTACs. PMID- 29407956 TI - Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production. AB - A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a g) and their reaction intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS generation during the metabolic phase of phagocytosis in a dose dependent manner where compounds 5d and 5e were the most potent samples with higher inhibitory activities (IC50 values 3.3 and 1.4 MUM, respectively) than that of the reference acetylsalicylic acid (IC50 = 9.7 MUM). Results for the determination of potential antioxidant properties of the synthesized compounds showed that compounds 5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even comparable to Trolox. Compounds 3d-f and 5d-f with the least IC50 values in MTT assay were tested against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical study were performed to determine the consequence of exposure to chronic low dose of chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by co-treatment with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies were performed to explore the binding mode of the most active compounds against EGFR and BRAF kinases. PMID- 29407957 TI - Synthesis and leishmanicidal activity of eugenol derivatives bearing 1,2,3 triazole functionalities. AB - In this paper, it is described the synthesis and the evaluation of the leishmanicidal activity of twenty-six eugenol derivatives bearing 1,2,3-triazole functionalities. The evaluation of the compounds on promastigotes of Leishmania amazonensis (WHOM/BR/75/Josefa) showed that eugenol derivatives present leishmanicidal activities with varying degrees of effectiveness. The most active compound, namely 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H 1,2,3-triazole (7k) (IC50 = 7.4 +/- 0.8 MUmol L-1), also targeted Leishmania parasites inside peritoneal macrophages (IC50 = 1.6 MUmol L-1) without interfering with cell viability. The cytotoxicity of 7k against macrophage cells presented IC50 of 211.9 MUmol L-1 and the selective index was equal to 132.5. Under similar conditions, compound 7k was more effective than glucantime and pentamidine, two drugs currently in the clinic. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that eugenol bearing 1,2,3-triazole functionalities may represent a scaffold to be explored toward the development of new agents to treat leishmaniasis. PMID- 29407958 TI - Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease. AB - A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced beta-amyloid (Abeta) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027 MUM for hAChE) and good inhibition of Abeta aggregation (40.19% at 25 MUM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD. PMID- 29407959 TI - The selectivity and bioavailability improvement of novel oral anticoagulants: An overview. AB - Anticoagulants have exhibited a critical role in the prevention and/or treatment of thrombotic diseases. Up to now, kinds of novel oral anticoagulants, inhibiting plasma serine proteases in the coagulation cascade, have been developed to overcome the clinical limitations of classical anticoagulants (like warfarin and heparins). Some of them, such as Apixaban, Rivaroxaban, Edoxaban, and Dabigatran, have been approved by FDA in recent years. This review summarizes the discovery and optimization of representative novel oral anticoagulants with the aim to improve selectivity and bioavailability of compounds. The impact of different targets in the cascade on bleeding risk also is discussed. We hope some more effective, selective, and safer anticoagulants can be developed in the future on the basis of these design experiences. PMID- 29407960 TI - An overview on crystal structures of InhA protein: Apo-form, in complex with its natural ligands and inhibitors. AB - The enoyl-ACP reductase InhA from the mycobacterial fatty acid biosynthesis pathway has become a target of interest for the development of new anti tubercular drugs. This protein has been identified as essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis, and as the main target of two pro-drugs: isoniazid, the frontline anti-tubercular drug, and ethionamide, a second-line medicine. Since most cases of resistance to isoniazid and ethionamide result from mutations in the mycobacterial activating enzyme (KatG for isoniazid and EthA for ethionamide), research of direct InhA inhibitors, avoiding the activation step, has emerged as a promising strategy for combating tuberculosis. Thereby, InhA is drawing much attention and its three dimensional structure has been particularly studied. A better understanding of key sites of interactions responsible for InhA inhibition arises thus as an essential tool for the rational design of new potent inhibitors. In this paper, we propose an overview of the 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors. We will first discuss structural and mechanistic aspects in order to highlight key features of the protein before delivering thorough inventory of structures of InhA in the presence of synthetic ligands to underline the key interactions implicated in high affinity inhibition. PMID- 29407961 TI - Unexplored antifungal activity of linear battacin lipopeptides against planktonic and mature biofilms of C. albicans. AB - Novel antifungal agents are required against pathogenic fungi such as Candida albicans. We report the anticandidal activity of battacin lipopeptide antibiotics with previously unexplored antifungal activity. From amongst sixteen battacin lipopeptides tested against C. alibicans (SC5314) the 4-methyl hexanoyl conjugated trimeric lipopeptide 13 emerged as the lead candidate with a MIC of 6.25 MUM and negligible haemolysis of mouse red blood cells. The potency of this lipopeptide was maintained under acidic conditions. Additionally, antifungal activity was further enhanced with amphotericin B at its non-haemolytic concentrations. Herein we have demonstrated for the first time that battacin lipopeptides prevent C. albicans biofilm colonisation as well as inhibit pre formed biofilms of this fungal pathogen. XTT biofilm assays revealed that 13 prevented colonisation of C. albicans biofilms at its MIC (6.25 MUM) and, at a higher concentration, eradicated 24 h (25 MUM) and 48 h (62.5 MUM) old preformed biofilms. In comparison, we found that amphotericin at much lower concentrations prevented biofilm colonisation (0.78 MUM) and inhibited 24 h old preformed biofilms (6.25 MUM), however was completely inactive against 48 h old preformed biofilms. Thus, lipopeptide 13 is more effective than amphotericin at eradicating more mature C. albicans biofilms. The membrane lytic mechanism of action of compound 13 was validated by a colorimetric assay using lipid vesicles mimicking fungal membranes in which compound 13 effected an immediate dark purple to red colour transition of suspended vesicles upon peptide interaction. In addition, TEM images of C. albicans cells exposed to 13 showed clearly disrupted cellular membranes. Interestingly, compound 13 increased the endogenous generation of reactive oxygen species (ROS) in a concentration dependent manner. In the presence of an antioxidant, ascorbic acid, ROS production was diminished yet antifungal activity persisted, possibly indicating that ROS production is a secondary effect from membrane lysis caused by lipopeptide 13. The lipopeptide was non-haemolytic against mouse red blood cells at the highest tested concentration (1 mM). PMID- 29407962 TI - Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting cancer cell apoptosis by inhibiting KLF5 expression. Nevertheless, its anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive anticancer profile against TNBC via suppressing KLF5 expression. PMID- 29407963 TI - Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities. AB - A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging. PMID- 29407964 TI - Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro. AB - The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2. PMID- 29407965 TI - Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation. AB - A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4 trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6 dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP specific PDE isoenzymes resulted in a strong anti-TNF-alpha effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively. PMID- 29407966 TI - Advances on photodynamic therapy of melanoma through novel ring-fused 5,15 diphenylchlorins. AB - The synthesis, photophysical behaviour and photosensitization ability of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused 5,15-diphenylchlorins against melanoma cells are described. All studied chlorins were found to be extremely active against melanoma cell lines A375 showing IC50 values below 20 nM. Furthermore, a dihydroxymethyl diphenylchlorin was identified as an excellent candidate to allow modulating of different types of cell death, apoptosis vs. necrosis, by varying its concentration. This can be explored as a tool to improve the effectiveness of PDT since inflammatory response resulting from necrotic cell death after PDT can activate the antitumor immune response with implications also regarding the vascular damage. This feature combined with very low cytotoxicity against human melanoma cells in the absence of light activation and against human fibroblast HFF-1 cells makes this chlorin a candidate of choice as a photosensitizer for PDT. A comprehensive photophysical investigation including the determination of quantum yields for fluorescence, singlet oxygen sensitization and internal conversion, lifetimes and rate constants of all the excited state deactivation processes has been undertaken. PMID- 29407967 TI - Optimization of the metabolic stability of a fluorinated cannabinoid receptor subtype 2 (CB2) ligand designed for PET studies. AB - The central CB2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [18F]7a was reported, which shows high CB2 affinity and high selectivity over the CB1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (Ki = 7.9 nM) and the ketone 26a (Ki = 8.6 nM) displayed high CB2 affinity and CB2:CB1 selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD7.4 value of 5.56 +/- 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification. PMID- 29407968 TI - Aryl thiosemicarbazones for the treatment of trypanosomatidic infections. AB - Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50 = 2.31 MUM, LiEC50 = 6.14 MUM, TcEC50 = 1.31 MUM) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2 ((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti-parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6-fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs. PMID- 29407969 TI - Pt(IV) complexes conjugating with chalcone analogue as inhibitors of microtubule polymerization exhibited selective inhibition in human cancer cells. AB - Six novel of Pt(IV) complexes comprising chalcone analogues were synthesized and evaluated for anti-proliferative activity using MTT assay. In vitro evaluation revealed that all Pt(IV) complexes showed better and more potent activity against three human cancer cells including CDDP resistant cells than that of their corresponding mother Pt(II) species. Among them, two representative complexes, 14 and 17, exhibited better cell selectivity between cancer cells and normal cells than CDDP. Molecular docking study indicated that complexes 14 and 17 could bind to the colchicine site of tubulin. Moreover, complexes 14 and 17 also remarkably displayed inhibition of cell migration against HUVEC cells in vitro. Molecular mechanism studies suggested that 14 and 17 induced production of reactive oxygen species (ROS), cell cycle arrest at the G2/M phase, and mitochondria-mediated apoptosis by regulating the expression of Bcl-2 family members. PMID- 29407970 TI - High anticancer potency on tumor cells of dehydroabietylamine Schiff-base derivatives and a copper(II) complex. AB - Five bioactive dehydroabietylamine Schiff-base derivatives (L1-L5) had been synthesized from Dehydroabietylamine (L0), and the complex Cu(L1)2 had been obtained from the compound L1 and copper(II) acetate. Their activities against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver) and HUVEC (umbilical vein, normal cell) in vitro were investigated. The toxicity of L1-L5 and Cu(L1)2 was all lower than L0. For MCF-7 cell, L1, L3, L4, L5 and Cu(L1)2 had higher antitumor activity than L0. The smallest IC50 value was 2.58 MUM of L5. For A549 cell, the IC50 value of the compound L4 was smaller than L0, which indicated that the compound L4 had higher anti-A549 activity than L0. For HepG2 cell, the IC50 value of L4(0.24 MUM) and L5 (0.14 MUM) were much smaller than L0, which suggested L4 and L5 had higher anti-HepG2 activity. L5 was 180 times more effective at inhibiting cultured HepG2 cells survival than normal cells, with average IC50 values of 0.14 and 25.56 MUM. Furthermore, L0, L4 and L5 contrasting with Doxorubicin had been measured with the ability to induce apoptosis. It turned out that L4 and L5 could induce more HepG2 cells apoptosis, which suggested they may be potential antitumor drugs. PMID- 29407971 TI - Design, synthesis and biological evaluation of novel 4-aminoquinazolines as dual target inhibitors of EGFR-PI3Kalpha. AB - The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and PI3K has therapeutic advantage and was an attractive approach against tumors. In this work, based on the molecular docking and previous studies, a series of 4 aminoquinazolines derivatives containing 6-sulfonamide substituted pyridyl group were rationally designed and identified as potent EGFR and PI3K dual inhibitors. The cytotoxicity experiment results showed that this series of compounds could effectively inhibit cell growth. The kinase assay demonstrated that 6c and 6i had high inhibition for EGFR and selectivity for PI3Kalpha distinguished from other isoforms. Further experiments showed that 6c could induce cell cycle arrest in G1 phase and apoptosis in BT549 cells. The western blot assay indicated that 6c inhibited the proliferation of BT549 cell through EGFR and PI3Kalpha/Akt signaling pathway. Our study suggested that compound 6c was a potential dual inhibitors of EGFR and PI3Kalpha. PMID- 29407972 TI - Structural investigations on coumarins leading to chromeno[4,3-c]pyrazol-4-ones and pyrano[4,3-c]pyrazol-4-ones: New scaffolds for the design of the tumor associated carbonic anhydrase isoforms IX and XII. AB - Human carbonic anhydrases (hCAs, EC 4.2.1.1) IX and XII are overexpressed in a wide variety of cancers and are considered available drug targets for anti-tumor therapy since their inhibition has been shown to reduce tumor growth and metastasis. A set of coumarin derivatives (1-10) and several 1-aryl and 2-aryl substituted chromeno[4,3-c]pyrazol-4-ones (11-37) and pyrano[4,3-c]pyrazol-4-ones (38-39) were synthesized and tested against the tumor-associated hCAs IX and XII and the cytosolic isoforms hCAs I and II. Several compounds were potent (Ki < 41 nM) and selective inhibitors of the hCA IX (13, 14, 19, 21, 25, 31, 33, 37 and 39), some derivatives (6, 11 and 17) were active against both hCA IX and XII isoforms (Ki = 5.6-9.6 nM), while none were effective against the off-target cytosolic hCAs I and II. Some selected inhibitors (6, 11, 13, 19, 21, 25, 31 and 39) showed activity as antiproliferative agents on HT-29 colon cancer cell lines both in normoxic and hypoxic conditions. This finding led us to hypothesize for these derivatives more than one mechanism of action, involving hCAs IX and XII inhibition in hypoxia and other not identified target(s) in normoxia. PMID- 29407973 TI - Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents. AB - The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2 selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl 1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small molecule Mcl-1 inhibitors from 2012 to 2017. PMID- 29407974 TI - Structure activity relationships, multidrug resistance reversal and selectivity of heteroarylphenyl ABCG2 inhibitors. AB - An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5 yl)phenyl)benzamide (43) exhibited a high potency (IC50 = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 MUM. PMID- 29407975 TI - Novel vitexin-inspired scaffold against leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Up to a quarter of ALL patients relapse and face poor prognosis. To identify new compound leads, we conducted a phenotypic screen using terrestrial natural product (NP) fractions against immortalized ALL cellular models. We identified vitexin, a flavonoid, as a promising hit with biological activity (EC50 = 30 MUM) in pre-B cell ALL models with no toxicity against normal human tissue (BJ cells) at the tested concentrations. To develop more potent compounds against ALL and elucidate its potential mode of action, a vitexin-inspired compound library was synthesized. Thus, we developed an improved and scalable protocol for the direct synthesis of 4-quinolone core heterocycles containing an N-sulfonamide using a one-pot condensation reaction protocol. The newly generated compounds represent a novel molecular scaffold against ALL as exemplified by compounds 13 and 15, which demonstrated EC50 values in the low micromolar range (0.3-10 MUM) with little to no toxicity in normal cellular models. Computational studies support the hypothesis that these compounds are potential CDK inhibitors. The compounds induced apoptosis, caused cell arrest at G0/G1 and G2/M, and induced ROS in cancer cells. PMID- 29407976 TI - Regioselective synthesis of 3,4-diaryl-5-unsubstituted isoxazoles, analogues of natural cytostatic combretastatin A4. AB - 4,5-Diarylisoxazoles are potent antiproliferative tubulin-targeting agents. Their isomeric 3,4-diaryl-5-unsubstituted isoxazoles are hardly accessible. The synthesis of 3,4-diaryl-5-unsubstituted isoxazoles 13 was designed based on a condensation of arylbenzaldehydes, arylnitromethanes, and ethoxycarbonylmethylpyridinium bromide followed by a selective one-step transformation of intermediate 3,4-diaryl-5-ethoxycarbonyl-4,5-dihydroisoxazole 2 oxides 8. The orientation of aryl rings in relation to isoxazole heterocycle was confirmed by X-ray crystallography. Targeted compounds were evaluated for antimitotic microtubule destabilizing activity using a phenotypic sea urchin embryo assay. 3-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)isoxazole 13e and 13h with a single methoxy substituent were the most potent. Compound 13e showed strong cytotoxicity in NCI60 screen with GI50 for NCI-H522 human lung cancer cell line of 0.023 MUM. PMID- 29407977 TI - Effects of rigidity on the selectivity of protein kinase inhibitors. AB - Established strategies for discovering selective kinase inhibitors are target centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors. PMID- 29407978 TI - New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity. AB - Tuberculosis (TB) is one of the leading causes of death worldwide. The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) and TB-HIV co infection are major public health challenges. The anti-TB drugs of first choice were developed more than 4 decades ago and present several adverse effects, making the treatment of TB even more complicated and the development of new chemotherapeutics for this disease imperative. In this work, we synthesized two series of new acylhydrazides and evaluated their activity against different strains of Mtb. Derivatives of isoniazid (INH) showed important anti-Mtb activity, some being more potent than all anti-TB drugs of first choice. Moreover, three compounds proved to be more potent than INH against resistant Mtb. The Ames test showed favorable results for two of these substances compared to INH, one of which presented expressly lower toxicity to HepG2 cells than that of INH. This result shows that this compound has the potential to overcome one of the main adverse effects of this drug. PMID- 29407979 TI - Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis. AB - Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators. PMID- 29407980 TI - Fluoroquinolone derivatives and their anti-tubercular activities. AB - Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, around one-third of the world's population harbor a latent infection by Mycobacterium tuberculosis (MTB), and 5-10% eventually develop an active TB. The emergency of MTB new virulent forms as well as the co-infection between MTB and HIV alarming the serious problem in TB control and demanding the need for new drugs more potent than earlier with safe ADME profile. Fluoroquinolones are emerged as a large family of synthetic broad spectrum antibiotics, and some of them were recommended as the second-line agents for the treatment of TB mainly in cases involving resistance or intolerance to first-line anti-TB therapy by WHO. Numerous of FQs derivatives have been synthesized for seeking for new anti-TB agents, and some of them exhibited promising potency. This review aims to summarize the recent advances made towards the discovery of FQs derivatives as anti-TB agents and the structure-activity relationship of these derivatives. PMID- 29407981 TI - The lead optimization of the polyamine conjugate of flavonoid with a naphthalene motif: Synthesis and biological evaluation. AB - Polyamine conjugated flavonoid with a naphthalene moiety (ZYY14) displayed excellent therapeutic activity against hepatocellular carcinoma. In this study, three different series of novel flavonoid-polyamine conjugates were designed and screened against tumor cell lines. The structure-activity relationship study demonstrated the importance of the naphthalene moiety (as the B-ring), the basic side chains in the A-ring, and the methoxy group linked to the C-ring. The optimized compound 9b displayed better antitumor potency in vitro and in vivo than the lead compound ZYY14. Fluorescent assays revealed that 9b could enter cancer cells via polyamine transporter (PAT) and locate in mitochondria and endoplasmic reticulum. Compound 9b and ZYY14 demonstrated similar apoptotic mechanism in the cytotoxicity studies and stimulated the expression of apoptosis related proteins, such as p-p38, p-JNK, p53 and Bax. In addition, 9b can initiate autophagy which inhibited the occurrence of apoptosis. Thus, 9b can be used as a valuable lead for the future development of antitumor agents. PMID- 29407982 TI - New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling. AB - In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX 2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE2 inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme. PMID- 29407983 TI - Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics. AB - Natural derived enmein-type diterpenoids exert cytotoxicity against a wide range of human cancer cells. Yet their medicinal applications are hindered by insufficient potency for chemotherapy. Hence, a series of novel enmein-type diterpenoid hybrids coupled with nitrogen mustards were designed and synthesized to increase antitumor efficacy while reducing systemic toxicity. Most conjugates exhibited stronger antiproliferative activities than parent diterpenoids and nitrogen mustards, especially for multidrug-resistant tumor cell line Bel-7402/5 FU. Among them, compound E2 showed the most potent inhibitory activities in human leukemia HL-60 cells, human prostate cancer PC-3 cells, human liver cancer Bel 7402 cells and drug-resistant human liver cancer Bel-7402/5-FU cells with IC50 values of 7.83 MUM, 3.97 MUM, 0.77 MUM and 2.07 MUM, respectively. Additionally, high selectivity with selectivity index over 130 was also observed from cytotoxic evaluation between L-02 human normal liver cells and Bel-7402 malignant liver cells. Further studies on mechanism of action indicated that E2 induced both apoptosis and G1 phase cell cycle arrest in Bel-7402 hepatoma cells. Moreover, the dysfunction in mitochondrial pathway was also involved in E2 initiated apoptotic activation, which entailed the loss of mitochondrial membrane potential followed by upregulating the bax/bcl-2 ratio and increasing the expression of cytochrome c, p53, caspase-3 and -9. Overall, E2 has the potential to emerge as a promising drug candidate for cancer therapy. PMID- 29407984 TI - Ciprofloxacin derivatives and their antibacterial activities. AB - Bacterial infections represent a significant health threat globally, and are responsible for the majority of hospital-acquired infections, leading to extensive mortality and burden on global healthcare systems. The second generation fluoroquinolone ciprofloxacin which exhibits excellent antimicrobial activity and pharmacokinetic properties as well as few side effects is introduced into clinical practice for the treatment of various bacterial infections for around 3 decades. The emergency and widely spread of drug-resistant pathogens making ciprofloxacin more and more ineffective, so it's imperative to develop novel antibacterials. Numerous of ciprofloxacin derivatives have been synthesized for seeking for new antibacterials, and some of them exhibited promising potency. This review aims to summarize the recent advances made towards the discovery of ciprofloxacin derivatives as antibacterial agents and the structure-activity relationship of these derivatives was also discussed. PMID- 29407985 TI - Chemoenzymatically synthesized GM3 analogues as potential therapeutic agents to recover nervous functionality after injury by inducing neurite outgrowth. AB - Ganglioside GM3 is implicated in a variety of physiological and pathological processes. Due to GM3 exposes on the outer surface of cell membranes, it is strongly associated with cell adhesion, motility and differentiation. Neurite outgrowth is a key process in the development of functional neuronal circuits and regeneration of the nervous system after injury. In the present study, we used enzymatic hydrolysis and chemical synthesis to obtain novel galactose containing GM3 analogues. By enzymatic hydrolysis to prepare GM3 building block, we can avoid multiple chemical procedures. Next, we employed the PC12 cells as a model to evaluate the effects of GM3 analogues on neurite outgrowth with or without NGF induction. The biological tests showed that GM3 analogues could induce neurite outgrowth, which provides the valuable sights for potential nervous system treatment after injury. PMID- 29407986 TI - Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines. AB - The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 +/- 0.007, 2.36 +/- 0.016 and 0.73 +/- 0.002 MUM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC50 values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11. PMID- 29407987 TI - Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death. AB - Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. Here, we report preparation of several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide (R8, a so-called cell-penetrating peptide) inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. RID-F conjugated to hydrophobic peptides also inhibited the 26S proteasome but failed to induce cell death, suggesting poor penetration into cells. We infer that the R8 peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. In the presence of ATPgammaS, RID-F conjugates containing R8 inhibited the 26S proteasome more potently than in the presence of ATP, suggesting efficient entry of drugs into the catalytic chamber in a similar fashion to the substrate. Taken together with docking simulations of RID-F conjugate interactions with proteasome active sites, the second function of R8 peptide is plausible. Thus, the conjugation of nonpeptidic proteasome inhibitors to a cell-penetrating peptide could represent a viable strategy for overcoming the drug-resistance of tumor cells. PMID- 29407988 TI - Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity. AB - Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R2 = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures. PMID- 29407989 TI - Design, synthesis and biological evaluation of 1-hydroxy-2-phenyl-4-pyridyl-1H imidazole derivatives as xanthine oxidase inhibitors. AB - In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5 carboxylic acid derivatives that presented excellent in vitro xanthine oxidase inhibitory potency. As a continuation study, a series of 1-hydroxy-2-phenyl-1H imidazole derivatives containing a pyridine moiety (4a-g and 5a-g) at the 4 position was designed and synthesized. Evaluation of in vitro xanthine oxidase inhibition demonstrated that the 4a-g series was more potent than the 5a-g series. Compound 4f was the most promising derivative in the series with an IC50 value of 0.64 MUM. A Lineweaver-Burk plot revealed that compound 4f acted as a mixed-type xanthine oxidase inhibitor. An iso-pentyloxy group at the 4'-position improved the inhibitory potency. More interestingly, structure-activity relationship analysis indicated that the pyridine para-N atom played a crucial role in the inhibition. Molecular modeling provided a reasonable explanation for the structure-activity relationships observed in this study. In addition, a three dimensional quantitative structure-activity relationships model which possessed reasonable statistics (q2 = 0.885 and r2 = 0.993) was conducted to further understand the structural basis of these compounds as xanthine oxidase inhibitors. These compounds, especially compound 4f, have good potential for further investigations. PMID- 29407990 TI - Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates. AB - Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water under ultrasound irradiation. Two diastereoisomers were formally identified by X ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC50 values of 0.33 and 0.39 MUM for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index >=200 MUM. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs. PMID- 29407991 TI - Part III: Novel checkpoint kinase 2 (Chk2) inhibitors; design, synthesis and biological evaluation of pyrimidine-benzimidazole conjugates. AB - Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC50 = 5.56 nM - 46.20 nM). The studied candidates exhibited remarkable antitumor activity against MCF-7 (IG50 = 6.6 MUM - 24.9 MUM). Compounds 10a-c, 14 and 15 significantly potentiated the activity of the studied genotoxic drugs, whereas, compounds 9b and 20-23 antagonized their activity. Moreover, the combination of compound 10b with cisplatin revealed the best apoptotic effect as well as combination of compound 10b with doxorubicin led to complete arrest of the cell cycle at S phase where more than 40% of cells are in the S phase with no cells at G2/M. Structure activity relationship was discussed on the basis of molecular modeling study using Molecular modeling Environment program (MOE). PMID- 29407992 TI - New insights in Au-NHCs complexes as anticancer agents. AB - Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004-2016, and critically analyses biological data (mainly IC50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported. PMID- 29407993 TI - Synthesis of coumarin-theophylline hybrids as a new class of anti-tubercular and anti-microbial agents. AB - A series of novel coumarin-theophylline hybrids were synthesized and examined for their anti-tubercular activity in vitro against Mycobacterium tuberculosis H37Rv, anti-microbial activity in vitro against gram-positive bacteria (Staphylococcus aureus) and gram-negative bacterias (Escherichia coli, Salmonella typhi) as well as fungi (Candida albicans). The compound (3a) has shown excellent anti tubercular activity with MIC of 0.12 MUg/mL. Electron donating compounds (3a, 3f) have displayed significant anti-microbial activity. The compounds have also been precisely elucidated using single crystal X-ray diffraction techniques. Molecular docking study has been performed against 4DQU enzyme of Mycobacterium tuberculosis showed good binding interactions and is in agreement with the in vitro results. PMID- 29407994 TI - Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects. AB - A series of neuroprotective hybrid compounds was synthesized by conjugation of the flavonolignan silibinin with natural phenolic acids, such as ferulic, cinnamic and syringic acid. Selective 7-O-esterfication without protection groups was achieved by applying the respective acyl chlorides. Sixteen compounds were obtained and SARs were established by evaluating antioxidative properties in the physicochemical FRAP assay, as well as in a cell-based neuroprotection assay using murine hippocampal HT-22 cells. Despite weak activities in the FRAP assay, esters of the alpha,beta-unsaturated acids showed pronounced overadditive effects at low concentrations greatly exceeding the effects of equimolar mixtures of silibinin and the respective acids in the neuroprotection assay. Cinnamic and ferulic acid esters (5a and 6a) also showed overadditive effects regarding inhibition of microglial activation, PC12 cell differentiation, in vitro ischemia as well as anti-aggregating abilities against Abeta42 peptide and tau protein. Remarkably, the esters of ferulic acid with silybin A and silybin B (11a and 11b) showed a moderate but significant difference in both neuroprotection and in their anti-aggregating capacities. The results demonstrate that non-toxic natural antioxidants can be regioselectively connected as esters with medium-term stability exhibiting very pronounced overadditive effects in a portfolio of biological assays. PMID- 29407995 TI - Snoring classified: The Munich-Passau Snore Sound Corpus. AB - OBJECTIVE: Snoring can be excited in different locations within the upper airways during sleep. It was hypothesised that the excitation locations are correlated with distinct acoustic characteristics of the snoring noise. To verify this hypothesis, a database of snore sounds is developed, labelled with the location of sound excitation. METHODS: Video and audio recordings taken during drug induced sleep endoscopy (DISE) examinations from three medical centres have been semi-automatically screened for snore events, which subsequently have been classified by ENT experts into four classes based on the VOTE classification. The resulting dataset containing 828 snore events from 219 subjects has been split into Train, Development, and Test sets. An SVM classifier has been trained using low level descriptors (LLDs) related to energy, spectral features, mel frequency cepstral coefficients (MFCC), formants, voicing, harmonic-to-noise ratio (HNR), spectral harmonicity, pitch, and microprosodic features. RESULTS: An unweighted average recall (UAR) of 55.8% could be achieved using the full set of LLDs including formants. Best performing subset is the MFCC-related set of LLDs. A strong difference in performance could be observed between the permutations of train, development, and test partition, which may be caused by the relatively low number of subjects included in the smaller classes of the strongly unbalanced data set. CONCLUSION: A database of snoring sounds is presented which are classified according to their sound excitation location based on objective criteria and verifiable video material. With the database, it could be demonstrated that machine classifiers can distinguish different excitation location of snoring sounds in the upper airway based on acoustic parameters. PMID- 29407997 TI - Cluster based statistical feature extraction method for automatic bleeding detection in wireless capsule endoscopy video. AB - Wireless capsule endoscopy (WCE) is capable of demonstrating the entire gastrointestinal tract at an expense of exhaustive reviewing process for detecting bleeding disorders. The main objective is to develop an automatic method for identifying the bleeding frames and zones from WCE video. Different statistical features are extracted from the overlapping spatial blocks of the preprocessed WCE image in a transformed color plane containing green to red pixel ratio. The unique idea of the proposed method is to first perform unsupervised clustering of different blocks for obtaining two clusters and then extract cluster based features (CBFs). Finally, a global feature consisting of the CBFs and differential CBF is used to detect bleeding frame via supervised classification. In order to handle continuous WCE video, a post-processing scheme is introduced utilizing the feature trends in neighboring frames. The CBF along with some morphological operations is employed to identify bleeding zones. Based on extensive experimentation on several WCE videos, it is found that the proposed method offers significantly better performance in comparison to some existing methods in terms of bleeding detection accuracy, sensitivity, specificity and precision in bleeding zone detection. It is found that the bleeding detection performance obtained by using the proposed CBF based global feature is better than the feature extracted from the non-clustered image. The proposed method can reduce the burden of physicians in investigating WCE video to detect bleeding frame and zone with a high level of accuracy. PMID- 29407996 TI - Carotid plaque segmentation from three-dimensional ultrasound images by direct three-dimensional sparse field level-set optimization. AB - Total plaque volume (TPV) measured from 3D carotid ultrasound has been shown to be able to predict cardiovascular events and is sensitive in detecting treatment effects. Manual plaque segmentation was performed in previous studies to quantify TPV, but is tedious, requires long training times and is prone to observer variability. This article introduces the first 3D direct volume-based level-set algorithm to segment plaques from 3D carotid ultrasound images. The plaque surfaces were first initialized based on the lumen and outer wall boundaries generated by a previously described semi-automatic algorithm and then deformed by a direct three-dimensional sparse field level-set algorithm, which enforced the longitudinal continuity of the segmented plaque surfaces. This is a marked advantage as compared to a previously proposed 2D slice-by-slice plaque segmentation method. In plaque boundary initialization, the previous technique performed a search on lines connecting corresponding point pairs of the outer wall and lumen boundaries. A limitation of this initialization strategy was that an inaccurate initial plaque boundary would be generated if the plaque was not enclosed entirely by the wall and lumen boundaries. A mechanism is proposed to extend the search range in order to capture the entire plaque if the outer wall boundary lies on a weak edge in the 3D ultrasound image. The proposed method was compared with the previously described 2D slice-by-slice plaque segmentation method in 26 three-dimensional carotid ultrasound images containing 27 plaques with volumes ranging from 12.5 to 450.0 mm3. The manually segmented plaque boundaries serve as the surrogate gold standard. Segmentation accuracy was quantified by volume-, area- and distance-based metrics, including absolute plaque volume difference (|DeltaPV|), Dice similarity coefficient (DSC), mean and maximum absolute distance (MAD and MAXD). The proposed direct 3D plaque segmentation algorithm was associated with a significantly lower |DeltaPV|, MAD and MAXD, and a significantly higher DSC compared to the previously described slice-by-slice algorithm (|DeltaPV|:p=0.012, DSC: p=2.1*10-4, MAD: p=1.3*10-4, MAXD: p=5.2*10-4). The proposed 3D volume-based algorithm required 72+/-22 s to segment a plaque, which is 40% lower than the 2D slice-by-slice algorithm (114+/ 18 s). The proposed automatic plaque segmentation method generates accurate and reproducible boundaries efficiently and will allow for streamlining plaque quantification based on 3D ultrasound images. PMID- 29407998 TI - Critical texture pattern feature assessment for characterizing colonies of induced pluripotent stem cells through machine learning techniques. AB - The objectives of this study are to assess various automated texture features obtained from the segmented colony regions of induced pluripotent stem cells (iPSCs) and confirm their potential for characterizing the colonies using different machine learning techniques. One hundred and fifty-one features quantified using shape-based, moment-based, statistical and spectral texture feature groups are extracted from phase-contrast microscopic colony images of iPSCs. The forward stepwise regression model is implemented to select the most appropriate features required for categorizing the colonies. Support vector machine (SVM), random forest (RF), multilayer perceptron (MLP), decision tree (DT), and adaptive boosting (Adaboost) classifiers are used with ten-fold cross validation to evaluate the texture features within each texture feature group and fused-features group to characterize healthy and unhealthy colonies of iPSCs. Overall, based on the classification performances of the four texture feature groups using the five classifier models, statistical features always exhibit a high predictive capacity (>87.5%). However, the classification performance using fused texture patterns with statistical, shape-based, and moment-based features was found to be robust and reliable with fewer false positive and false negative values compared to the features when either one is used for the classification of colonies of iPSCs. Furthermore, the results showcase that the SVM, RF and Adaboost classifiers deliver better classification performances than DT and MLP. Our findings suggest that the proposed automated fused statistical, shape-based, and moment-based texture pattern features trained with machine learning techniques are potentially more appropriate and helpful to biologists for characterizing colonies of stem cells. PMID- 29407999 TI - Pilot study for supervised target detection applied to spatially registered multiparametric MRI in order to non-invasively score prostate cancer. AB - BACKGROUND: Gleason Score (GS) is a validated predictor of prostate cancer (PCa) disease progression and outcomes. GS from invasive needle biopsies suffers from significant inter-observer variability and possible sampling error, leading to underestimating disease severity ("underscoring") and can result in possible complications. A robust non-invasive image-based approach is, therefore, needed. PURPOSE: Use spatially registered multi-parametric MRI (MP-MRI), signatures, and supervised target detection algorithms (STDA) to non-invasively GS PCa at the voxel level. METHODS AND MATERIALS: This study retrospectively analyzed 26 MP-MRI from The Cancer Imaging Archive. The MP-MRI (T2, Diffusion Weighted, Dynamic Contrast Enhanced) were spatially registered to each other, combined into stacks, and stitched together to form hypercubes. Multi-parametric (or multi-spectral) signatures derived from a training set of registered MP-MRI were transformed using statistics-based Whitening-Dewhitening (WD). Transformed signatures were inserted into STDA (having conical decision surfaces) applied to registered MP MRI determined the tumor GS. The MRI-derived GS was quantitatively compared to the pathologist's assessment of the histology of sectioned whole mount prostates from patients who underwent radical prostatectomy. In addition, a meta-analysis of 17 studies of needle biopsy determined GS with confusion matrices and was compared to the MRI-determined GS. RESULTS: STDA and histology determined GS are highly correlated (R = 0.86, p < 0.02). STDA more accurately determined GS and reduced GS underscoring of PCa relative to needle biopsy as summarized by meta analysis (p < 0.05). CONCLUSION: This pilot study found registered MP-MRI, STDA, and WD transforms of signatures shows promise in non-invasively GS PCa and reducing underscoring with high spatial resolution. PMID- 29408000 TI - Design of complex bone internal structure using topology optimization with perimeter control. AB - Large facial bone loss usually requires patient-specific bone implants to restore the structural integrity and functionality that also affects the appearance of each patient. Titanium alloys (e.g., Ti-6Al-4V) are typically used in the interfacial porous coatings between the implant and the surrounding bone to promote stability. There exists a property mismatch between the two that in general leads to complications such as stress-shielding. This biomechanical discrepancy is a hurdle in the design of bone replacements. To alleviate the mismatch, the internal structure of the bone replacements should match that of the bone. Topology optimization has proven to be a good technique for designing bone replacements. However, the complex internal structure of the bone is difficult to mimic using conventional topology optimization methods without additional restrictions. In this work, the complex bone internal structure is recovered using a perimeter control based topology optimization approach. By restricting the solution space by means of the perimeter, the intricate design complexity of bones can be achieved. Three different bone regions with well-known physiological loadings are selected to illustrate the method. Additionally, we found that the target perimeter value and the pattern of the initial distribution play a vital role in obtaining the natural curvatures in the bone internal structures as well as avoiding excessive island patterns. PMID- 29408001 TI - Morphology-based realization of a rapid scoliosis correction simulation system. AB - OBJECTIVE: Scoliosis is a complex spinal deformity in 3D space that commonly occurs in teenagers, especially teenage girls, and judging the actual deformed spine situation using only CT images is difficult. However, using 3D finite element models to help doctors analyse the deformed spine is also time-consuming and laborious. Therefore, software that can quickly and easily perform scoliosis correction analysis is needed. To achieve rapid preoperative simulation of scoliosis correction in 3D space and help doctors construct surgical programmes faster, a morphology-based system was developed for simulating scoliosis correction performance. METHODS: The simulation system first takes advantage of the centre point of each vertebra on the entire spine model to fit a space curve. Then the system obtains information from the models and the space curve, and finally, uses the information to simulate scoliosis correction. The deformed spine model in the system can be corrected to a better state. RESULTS: During the simulation process, doctors can easily and clearly see how the vertebral models move, and the deformed spine parameters are also updated and shown. Using this system, doctors can easily simulate scoliosis correction according to their experience and quickly construct a surgical programme. CONCLUSIONS: The experimental results show that this system is capable of simulating scoliosis correction according to a doctor's own experience to speed up the operation and provides a scientific basis for the development of surgical programmes. PMID- 29408002 TI - Optimization of cochlear implant stimulation resolution using an intracochlear electric potential model. AB - Designing an electrode array with a high stimulation resolution (SR) is the main challenge in cochlear implant development. In this work, a thin-film electrode array (TFEA) and partial tripolar (pTP) mode were combined in the design stage to optimize the SR. A finite-element model of the intracochlear electric potential Ve incorporating a TFEA and pTP mode was built and validated using previous experimental measurements. Based on this model, the SR was analyzed by using a defined stimulation factor Vs, which takes both the amplitude and bandwidth of Ve into account. A co-simulation method integrating the model and genetic algorithm was employed to maximize Vs with an optimized parameter set including the electrode diameter d, electrode interval g, and compensation coefficient sigma. The results indicated that a TFEA combined with pTP mode outperforms their individual utilization to improve the SR and that d has an independent negative correlation with the SR, but it is more effective and feasible to consider all three parameters in the design stage with the proposed model and co-simulation optimization method. In our design, the optimized parameters were d = 150 MUm, g = 200.5 MUm, and sigma = 0.746. PMID- 29408003 TI - Application of carboxymethyl cellulose and chitosan coatings containing Mentha spicata essential oil in fresh strawberries. AB - The aim of the present study was to investigate the effects of carboxymethyl cellulose (CMC) and chitosan (CH) coatings containing Mentha spicata essential oil (MSO 0.1 and 0.2%) on survival of Listeria monocytogenes, and physicochemical (weight loss, titratable acidity and pH), microbial (total viable count, psychrotrophic bacteria as well as yeasts and molds) and sensory (appearance, color, texture and overall acceptability) properties of fresh strawberries during refrigerated storage. The treatments of fruits with CH+MSO 0.2% and CMC+MSO 0.2% resulted in the best microbial, physicochemical and organoleptic properties after 12days storage. The final population of L. monocytogenes in treated samples was decreased by 3.92-3.69 compared to control groups. It can be concluded that CH and CMC coatings enriched with MSO can be used as appropriate active packaging materials to preserve fresh strawberries in the food industry. PMID- 29408004 TI - Enhancement stability and catalytic activity of immobilized alpha-amylase using bioactive phospho-silicate glass as a novel inorganic support. AB - alpha-Amylase enzyme was immobilized on bioactive phospho-silicate glass (PS glass) as a novel inorganic support by physical adsorption and covalent binding methods using glutaraldehyde and poly glutaraldehyde as a spacer. Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) studies confirmed the glass-enzyme linkage. Dissolution of PS-glass in acidic and neutral pH is higher than that of alkaline pH. Some immobilization variables were optimized using statistical factorial design (Central Composite Design). Optimized immobilization variables enhanced the immobilization yield (IY) from 27.9 to 79.9% (2.9-fold). It was found that the immobilized enzyme had higher optimum temperature, higher half-life time (t1/2), lower activation energy (Ea), lower deactivation constant rate (kd) and higher decimal reduction time (D values) within the temperature range of 40-60 degrees C. Differential scanning calorimetry analysis (DSC) confirmed the thermalstability of the immobilized enzyme. The immobilized enzyme was stable at a wide pH range (5.0-8.0). Kinetic studies of starch hydrolysis demonstrated that immobilized enzyme had lower Michaelis constant (Km), maximum velocity (Vmax) and catalytic efficiency (Vmax/Km) values. The storage stability and reusability of the immobilized enzyme were found to be about 74.7 and 62.5% of its initial activity after 28days and 11cycles, respectively. Enhanced alpha-amylase stabilities upon immobilization make it suitable for industrial application. PMID- 29408005 TI - Microcalorimetry of the intestinal mucus: Hydrogen bonding and self-assembly of mucin. AB - The effect of mucin hydrogen bonding on the structure of intestinal mucus has been studied with micro-differential scanning mirocalorimetry (MU-DSC), supported by spectroscopy. The experiments were performed in water-dimethyl sulfoxide (DMSO) solutions, using either water-DMSO mixtures of an appropriate DMSO content or water as blanks, as to isolate the effects of the solvent to hydrogen bonding. When using matched water-DMSO blanks, thermal events at low temperatures are linked to the negation of mucin-DMSO interactions, while events at higher temperatures are linked to the break-up of hydrogen bonds connecting the sugars of the individual macromolecules. When using a matched solvent as blank, alterations in Cp, such as increases at 10% and 15% DMSO, have been linked to the break-up and creation of quaternary structures. In the case of water as blank, a monotonic but not linear decrease in enthalpy, hence extent of hydrogen bonding, is observed. The above are complemented by UV spectroscopy: A blue shift of the conjugated aminoacids in the presence of DMSO suggests that the inherent stability of mucin is not only due to steric volume exclusions, but also due to extensive hydrogen bonding on behalf of the sugar moieties. PMID- 29408006 TI - Investigation the interaction between procyanidin dimer and alpha-amylase: Spectroscopic analyses and molecular docking simulation. AB - Procyanidins were reported to have an inhibitory effect on alpha-amylase, but the interaction mechanism between procyanidins and alpha-amylase was rarely reported. Spectroscopic and molecular docking techniques were utilized to explore the interaction between porcine pancreatic alpha-amylase (PPA) and B-type procyanidin dimer (PB2). PB2 decreased the intrinsic fluorescence and surface hydrophobicity of PPA, indicating that an interaction occurred and complex formed. The binding process of complex was spontaneous and the main interaction was hydrophobic force. Circular dichroism showed conformational changes of PPA with an increasing of alpha-helix and beta-sheet structure. Molecular docking speculated that PB2 could form hydrophobic force with PPA by bind to the active sit (Asp 167, Asn 100, Arg 158, His 201). This research can offer new insights into the mechanism of PB2 in inhibiting PPA catalysis and provide useful information on dietary recommendation of PB2 for the treatment of type 2 diabetes. PMID- 29408007 TI - Neuropharmacological characterization of frutalin in mice: Evidence of an antidepressant-like effect mediated by the NMDA receptor/NO/cGMP pathway. AB - In this study we evaluated the effect of frutalin (FTL) on mouse behavior. Mice (n=6/group) were treated (i.p.) with FTL (0.25; 0.5 or 1mg/kg) or vehicle and submitted to several tests (hole-board/HBT, elevated plus maze/PMT, open field/OFT, tail suspension/TST, or forced swimming/FST). Yohimbine, ketamine, l NAME, aminoguanidine, 7-NI, methylene blue, l-arginine or dl-serine was administered 30min before FTL (0.5mg/kg). To evaluate the subchronic effect, animals were injected with FTL or vehicle for 7days and submitted to the FST. Molecular docking was simulated using FTL against NOS and the NMDA receptor. No changes were observed in the HBT or the OFT. FTL (0.25mg/kg) increased the number of entries into enclosed arms in the PMT. FTL reduced immobility in the TST (0.25 and 0.5mg/kg) and the FST (0.25mg/kg; 0.5mg/kg). The effect of FTL was dependent on carbohydrate interaction and protein structure integrity and was reduced by ketamine, l-NAME, aminoguanidine, 7-NI and methylene blue, but not by l-arginine, yohimbine or dl-serine. The antidepressant-like effect remained after subchronic treatment. The molecular docking study revealed a strong interaction between FTL and NOS and NMDA. FTL was found to have an antidepressant-like effect mediated by the NMDA receptor/NO/cGMP pathway. PMID- 29408008 TI - Takifugu rubripes cation independent mannose 6-phosphate receptor: Cloning, expression and functional characterization of the IGF-II binding domain. AB - Mannose 6-phosphate/IGF-II receptor mediated lysosomal clearance of insulin-like growth factor-II is significantly associated with the evolution of placental mammals. The protein is also referred to as the IGF-II receptor. Earlier studies suggested relatively low binding affinity between the receptor and ligand in prototherian and metatherian mammals. In the present study, we cloned the IGF-II binding domain of the early vertebrate fugu fish and expressed it in bacteria. A 72000Da truncated receptor containing the IGF-II binding domain was obtained. Analysis of this protein (covering domains 11-13 of the CIMPR) for its affinity to fish and human IGF-II by ligand blot assays and ELISA showed that the expressed receptor can specifically bind to both fish and human IGF-II. Additionally, a peptide-specific antibody raised against the region of the IGF-II binding domain also was able to recognize the IGF-II binding regions of mammalian and non-mammalian cation independent MPR protein. These interactions were further characterized by Surface Plasma resonance support that the receptor binds to fish IGF-II, with a dissociation constant of 548nM. Preliminary analysis suggests that the binding mechanism as well as the affinity of the fish and human receptor for IGF-II may have varied according to different evolutionary pressures. PMID- 29408009 TI - Design of peptide mimetics to block pro-inflammatory functions of HA fragments. AB - Hyaluronan is a simple extracellular matrix polysaccharide that actively regulates inflammation in tissue repair and disease processes. The native HA polymer, which is large (>500 kDa), contributes to the maintenance of homeostasis. In remodeling and diseased tissues, polymer size is strikingly polydisperse, ranging from <10 kDa to >500 kDa. In a diseased or stressed tissue context, both smaller HA fragments and high molecular weight HA polymers can acquire pro-inflammatory functions, which result in the activation of multiple receptors, triggering pro-inflammatory signaling to diverse stimuli. Peptide mimics that bind and scavenge HA fragments have been developed, which show efficacy in animal models of inflammation. These studies indicate both that HA fragments are key to driving inflammation and that scavenging these is a viable therapeutic approach to blunting inflammation in disease processes. This mini review summarizes the peptide-based methods that have been reported to date for blocking HA signaling events as an anti-inflammatory therapeutic approach. PMID- 29408011 TI - BH3 mimetics as anti-fibrotic therapy: Unleashing the mitochondrial pathway of apoptosis in myofibroblasts. AB - Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases. In this Review, we discuss recent findings that have demonstrated that activated myofibroblasts, traditionally viewed as apoptosis resistant cells, are actually "primed for death". In this state, mitochondria of activated myofibroblasts are loaded with proapoptotic BH3 proteins, which creates a cellular "addiction" to individual antiapoptotic proteins to block prodeath signaling and ensure survival. This creates a novel therapeutic opportunity to treat organ fibrosis by inducing myofibroblast apoptosis with the so-called BH3 mimetic drugs, which have recently shown potent antifibrotic activities in experimental models. Finally, we discuss the potential use of BH3 profiling as a functional tool to diagnose myofibroblast addiction to individual antiapoptotic proteins, which may serve to guide and assign the most effective BH3 mimetic drug for patients with fibrotic disease. PMID- 29408012 TI - Biomarkers in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, fibrotic lung disease leading to respiratory failure and ultimately to death. Being the prototype of interstitial lung diseases, IPF is characterized by marked heterogeneity regarding its clinical course. Despite significant progress in the understanding of its pathogenesis, we still cannot reliably predict the course of the disease and the response to treatment of an individual patient. Non-invasive biomarkers, in particular serum biomarkers, for the (early) diagnosis, differential diagnosis, prognosis and prediction of therapeutic response are urgently needed. Numerous molecules involved in alveolar epithelial cell injury, fibroproliferation and matrix remodeling as well as immune regulation have been proposed as potential biomarkers. Furthermore, genetic variants of TOLLIP, MUC5B, and other genes are associated with a differential response to treatment and with the development and/or the prognosis of IPF. Additionally, the bacterial signature in IPF lungs, as shown from microbiome analyses, as well as mitochondrial DNA seem to have promising roles as biomarkers. Moreover, combination of multiple biomarkers may identify comprehensive biomarker signatures in IPF patients. However, there is still a long way until these potential biomarkers complete or substitute for the clinical and functional parameters currently available for IPF. PMID- 29408010 TI - Distinct roles for hyaluronan in neural stem cell niches and perineuronal nets. AB - Adult neurogenesis in mammals is a tightly regulated process where neural stem cells (NSCs), especially in the subgranular zone (SGZ) of the hippocampal dentate gyrus, proliferate and differentiate into new neurons that form new circuits or integrate into old circuits involved in episodic memory, pattern discrimination, and emotional responses. Recent evidence suggests that changes in the hyaluronan (HA)-based extracellular matrix of the SGZ may regulate neurogenesis by controlling NSC proliferation and early steps in neuronal differentiation. These studies raise the intriguing possibility that perturbations in this matrix, including HA accumulation with aging, could impact adult neurogenesis and cognitive functions, and that alterations to this matrix could be beneficial following insults to the central nervous system that impact hippocampal functions. PMID- 29408013 TI - The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. AB - Scarring is part of the normal healing response to tissue injury in all organs and required to rapidly repair acute damages, mostly with extracellular matrix. A variety of different cells are activated into myofibroblasts to produce and remodel the scar matrix. Temporal and spatial coordination of myofibroblast activities with inflammatory macrophages is crucial for the controlled healing process. Miscommunication can result in either insufficient (chronic) or exacerbated (fibrotic) repair. In addition to soluble biochemical signals and intercellular contacts, cell-to-cell communication is mediated by biophysical and chemical signals transmitted through the extracellular matrix. Over the course of healing, the matrix takes over the role of a master coordinator; failure to do so produces poor healing outcomes that reduce organ function. Understanding the mechanical and chemical state of the matrix and its effects on cellular processes will be essential to address diseases that are characterized by dysfunctional matrix, such as fibrosis. PMID- 29408014 TI - DRESS Syndrome due to benzylpenicillin with cross-reactivity to amoxicillin. PMID- 29408015 TI - Endocrine regulation of migratory departure from stopover: Evidence from a longitudinal migratory restlessness study on northern wheatears. AB - Most migrating birds make stopovers to replenish fuel stores. The decision to resume migration from stopover to a large extent shapes the temporal organization of migration. This decision is known to be shaped by a suite of intrinsic and extrinsic factors such as the bird's fuel stores and current weather conditions. However, how departures from stopover are physiologically regulated is largely unknown. We here present data that strongly indicate that corticosterone, a hormone with a stimulatory effect on locomotion, acts as a mediator between fuel stores and departure from stopover. In migrating northern wheatears (Oenanthe oenanthe) temporarily caged at stopover, we observed a positive relationship between the change in fuel stores and the concurrent change in glucocorticoid metabolite (GCM) levels measured in the birds' droppings. We also found a positive relationship between the change in GCM levels and the change in the intensity of nocturnal migratory restlessness. As in northern wheatears nocturnal migratory restlessness is an accurate proxy for stopover departure likelihood, our results indicate that corticosterone mediates between fuel stores and the decision to resume migration. Our unique longitudinal study represents a considerable advance in our understanding of the endocrine regulation of avian migration. PMID- 29408016 TI - Clostridioides (Clostridium) difficile infection in hospitalized patients with antibiotic-associated diarrhea: A systematic review and meta-analysis. AB - Clostridium difficile is the main infectious cause of antibiotic associated diarrhea (AAD). The objective of this study was to determine the frequency of C. difficile AAD in hospitalized patients. We searched MEDLINE (Pubmed), Embase, Web of Science and Cochrane library for subject headings and text words related to C. difficile AAD. Studies that investigated the prevalence or frequency of C. difficile AAD in health care settings were considered eligible. Using a random effects model, data obtained from the identified studies were combined. Of the 2464 citations identified, twenty studies (5496 patients) met the inclusion criteria of the present study. Pooling all studies, the frequency of C. difficile among AAD patients was 20.0% (95% CI 13.0-28.0). The most frequently used antibiotics in health care settings were the following: Clindamycin, fluoroquinolones and cephalosporins. The current systematic review demonstrated the significant presence of C. difficile among patients with AAD. The limited and rational use of broad spectrum antibiotics and implementation of standard infection control measures are recommended to reduce the risk of C. difficile associated infections in hospitalized patients. PMID- 29408017 TI - Effect of the ionophore monensin and tannin extracts supplemented to grass silage on populations of ruminal cellulolytics and methanogens in vitro. AB - This study examined whether the methane-decreasing effect of monensin (~21%) and different hydrolysable tannins (24%-65%) during in vitro fermentation of grass silage was accompanied by changes in abundances of cellulolytics and methanogens. Samples of liquid (LAM) and solid (SAM) associated microbes were obtained from two rumen simulation technique experiments in which grass silage was either tested in combination with monensin (0, 2 or 4 mg d-1) or with different tannin extracts from chestnut, valonea, sumac and grape seed (0 or 1.5 g d-1). Total prokaryotes were quantified by 4',6-diamidino-2-phenylindol (DAPI) staining of paraformaldehyde-ethanol-fixed cells and relative abundances of ruminal cellulolytic and methanogenic species were assessed by real time quantitative PCR. Results revealed no change in absolute numbers of prokaryotic cells with monensin treatment, neither in LAM nor in SAM. By contrast, supplementation of chestnut and grape seed tannins decreased total prokaryotic counts compared to control. However, relative abundances of total methanogens did not differ between tannin treatments. Thus, the decreased methane production by 65% and 24% observed for chestnut and grape seed tannins, respectively, may have been caused by a lower total number of methanogens, but methane production seemed to be also dependent on changes in the microbial community composition. While the relative abundance of F. succinogenes decreased with monensin addition, chestnut and valonea tannins inhibited R. albus. Moreover, a decline in relative abundances of Methanobrevibacter sp., especially M. ruminantium, and Methanosphaera stadtmanae was shown with supplementation of monensin or chestnut tannins. Proportions of Methanomicrobium mobile were decreased by monensin in LAM while chestnut and valonea had an increasing effect on this methanogenic species. Our results demonstrate a different impact of monensin and tannins on ruminal cellulolytics and gave indication that methane decrease by monensin and chestnut tannins was associated with decreased abundances of M. ruminantium and M. stadtmanae. PMID- 29408018 TI - Cigarette Smoking in Persons Living with Hepatitis C: The National Health and Nutrition Examination Survey (NHANES), 1999-2014. AB - BACKGROUND: Cigarette smoking is common in persons living with hepatitis C (hepatitis C+), but national statistics on this harmful practice are lacking. A better understanding of smoking behaviors in hepatitis C+ individuals may help in the development of targeted treatment strategies. METHODS: We extracted data from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2014. Hepatitis C+ were compared with hepatitis C- adults in the entire sample and in the subset of current smokers. Measures included demographics, current smoking, cigarettes/day, nicotine dependence, other tobacco use, substance use, and medical and psychiatric comorbidities. RESULTS: Complete smoking and hepatitis C virus (HCV) data were available for 39,472 (90.1%) of 43,793 adult participants in NHANES during the study years. Hepatitis C+ smoked at almost triple the rate of hepatitis C- adults (62.4% vs 22.9%), with no significant difference between hepatitis C+ men and women (64.5% vs 58.2%). Hepatitis C+ smokers were more likely to smoke daily than hepatitis C- smokers (87.5% vs 80.0%), but had similar levels of nicotine dependence. Hepatitis C+ smokers were more likely to be older (mean age: 47.1 vs 41.5 years), male (69.4% vs 54.4%), Black (21.2% vs 12.1%), less educated (any college: 31.8% vs 42.9%), poor (mean family monthly poverty index: 1.80 vs 2.47), uninsured (43.9% vs 30.4%), use drugs (cocaine: 11.1% vs 3.2%; heroin: 4.0% vs 0.6%), and be depressed (33.2% vs 13.5%). Multivariate analyses revealed significant associations of both hepatitis C infection and cigarette smoking with current depression and hypertension. CONCLUSIONS: There is a cigarette smoking epidemic embedded within the hepatitis C epidemic in the United States. The sociodemographic profile of hepatitis C+ smokers suggests that the implementation of effective tobacco treatment will be challenging. Thoughtful treatment strategies that are mindful of the unique characteristics of this group are needed. PMID- 29408019 TI - Impact of Atrial Fibrillation on Cognitive Function, Psychological Distress, Quality of Life, and Impulsiveness. AB - OBJECTIVE: Atrial fibrillation is the most common cardiac arrhythmia and a known risk factor for cerebrovascular stroke. Atrial fibrillation and longstanding hypertension may produce ischemic lesions leading to progressive cognitive impairment. The impact of atrial fibrillation alone on cognitive impairment has not been evaluated. Our objective was to compare cognitive function, quality of life, psychological distress, and impulsiveness in people with atrial fibrillation and a matched control group. METHODS: The study included 60 patients. The first group of patients were >=55 years of age, with >=5 years history of atrial fibrillation, without hypertension (or with well-controlled hypertension), without previous dementia, compared with a matched group of 30 healthy control participants. Demographic and clinical characteristics were recorded. Subjects underwent the following rating scales: Mini-Mental State Examination, Hospital Anxiety and Depression, Heart Quality of Life, and Barratt Impulsiveness Scale. RESULTS: In the atrial fibrillation group there were 63% male (n = 19) and 37% female (n = 11) patients; the control group was 33% male (n = 10) and 67% female (n = 20). Age range was from 55 to 81 years in both groups, mean = 63.9 years (+/-6.4) in the atrial fibrillation group and 66.1 years (+/ 8.0) in controls. In the atrial fibrillation group, 23.3% had primary or general education, college - 23.3% and university - 53.3%; in the control group - 20%, 23.3%, and 56.7%, respectively. Mini-Mental State Examination score was 27.6 (+/ 1.6) in the atrial fibrillation group vs 29.5 (+/-0.73) in the control group (P < .0001). Anxiety disorders were observed in 20 patients (66.7%) in atrial fibrillation vs 8 patients (26.67%) in the control group (P = .009). Heart Quality of Life mean score was 1.4 (+/-0.65) in the atrial fibrillation and 2.6 (+/-0.35) in the control group (P < .0001). Physical subscale mean scores were 1.4 (+/-0.74) in atrial fibrillation vs 2.8 (+/-0.18) in the control group (P < .0001). CONCLUSION: Individuals with atrial fibrillation are more likely to develop anxiety disorder. Cognitive status is significantly lower in the atrial fibrillation group. In comparison with healthy subjects, individuals with atrial fibrillation have worse quality of life. PMID- 29408020 TI - Emergence of H3N8 equine influenza virus in donkeys in China in 2017. AB - Equine influenza virus is a major respiratory pathogen in horses. Although both horses and donkeys belong to the genus Equus, donkey infection with influenza viruses is rare. In March 2017, an influenza outbreak occurred in donkeys in Shandong province, China. The causative virus, A/donkey/Shandong/1/2017(H3N8), was isolated from a dead donkey. Genetic analysis indicated that the virus originated from influenza A (H3N8) clade 2 of the Florida sub-lineage that has been circulating in Asian equine populations. Comparison of the deduced amino acid sequence of the HA gene of this causative virus with that of the A/equine/Richmond/1/2007 vaccine strain showed that substitutions had occurred in the antigenic regions A, B, and C. This study provides insight into the currently circulating and newly emerging H3N8 strains in donkeys in China. PMID- 29408021 TI - Protective efficacy of a bivalent live attenuated vaccine against duck hepatitis A virus types 1 and 3 in ducklings. AB - Duck hepatitis A virus (DHAV) infection is characterized by an acute, rapidly spreading that affects young ducklings. DHAV-1 or DHAV-3 infection is prevalent, and simultaneous co-infection with both viruses has recently become increasingly frequent in the domestic duck farms. In this study, we developed a bivalent live attenuated vaccine (DHV-HSBP100 and AP-04203P100) for DHAV-1 and DHAV-3 and reported the protective efficacy and safety of the vaccine. At 1-day-old, the ducklings received a bivalent vaccine via intramuscular injection. The immunized ducklings showed effective and rapid protection against virulent DHAV-1 and DHAV 3 at 2 or 3 days post vaccination. Moreover, the ducklings showed a potent humoral immune response that peaked at 3 weeks and were maintained at 6 weeks after vaccination. The bivalent vaccine was safe; ducklings administered 10 doses of bivalent vaccines showed no clinical signs, mortality, gross lesions, and body weight changes compared with those observed in the negative controls. Ducklings vaccinated with a bivalent vaccine were evaluated for tissue tropism and viral replication of vaccine strains. Both bivalent vaccine strains were detected in various organs, and the highest virus replication was detected in the kidneys, among the tested organs. No interference occurred during the replication of both vaccine strains. Thus, these experiments suggest that bivalent vaccines would be useful as a promising and practical strategy for control DHAV outbreaks caused by DHAV-1 and DHAV-3 in duck farms. PMID- 29408022 TI - Vaccination with a porcine reproductive and respiratory syndrome virus vaccine at 1-day-old improved growth performance of piglets under field conditions. AB - A porcine reproductive and respiratory syndrome virus (PRRSV) modified live-virus (MLV) vaccine was evaluated under field conditions for registration as recommended by the Republic of Korea's Animal, Plant & Fisheries Quarantine & Inspection Agency. A single dose of the vaccine was administered to 1-day-old piglets and their growth performance was monitored under field conditions. Three separate farms were selected based on their history of PRRSV-associated respiratory diseases. On each farm, 40 pigs were randomly allocated to one of two treatment groups: (i) vaccinated (n = 20) and (ii) unvaccinated (n = 20) pigs at 1 day of age. Vaccinated pigs showed an increase of their market weight of 6.23 kg/pig compared to the unvaccinated pigs (98.01 kg in vaccinated group vs. 91.78 kg in unvaccinated group; P < 0.05) and exhibited a decrease in mortality rate by 6.7% (3.3% in vaccinated group vs. 10% in unvaccinated group; P < 0.05). The pigs had a sufficiently mature immune system for the vaccine to elicit humoral and cell-mediated immunity (as measured by anti-PRRSV antibodies and PRRSV-specific interferon-gamma secreting cells, respectively) at 1 day of age even in the presence of maternally derived antibodies. The results presented in this study demonstrate that the PRRSV MLV vaccine is effective in improving growth performance from day 1 all the way to day 182 in endemic farms suffering with PRRSV-2 infection or both PRRSV-1 and PRRSV-2 infection. PMID- 29408023 TI - Broad anti-herpesviral activity of alpha-hydroxytropolones. AB - Herpesviruses are ubiquitous in animals and cause economic losses concomitant with many diseases. Most of the domestic animal herpesviruses are within the subfamily Alphaherpesvirinae, which includes human herpes simplex virus 1 (HSV 1). Suppression of HSV-1 replication has been reported with alpha hydroxytropolones (alphaHTs), aromatic ring compounds that have broad bioactivity due to potent chelating activity. It is postulated that alphaHTs inhibit enzymes within the nucleotidyltransferase superfamily (NTS). These enzymes require divalent cations for nucleic acid cleavage activity. Potential targets include the nuclease component of the herpesvirus terminase (pUL15C), a highly conserved NTS-like enzyme that cleaves viral DNA into genomic lengths prior to packaging into capsids. Inhibition of pUL15C activity in biochemical assays by various alphaHTs previously revealed a spectrum of potencies. Interestingly, the most potent anti-pUL15C alphaHT inhibited HSV-1 replication to a limited extent in cell culture. The aim of this study was to evaluate three different alphaHT molecules with varying biochemical anti-pUL15C activity for a capacity to inhibit replication of veterinary herpesviruses (BoHV-1, EHV-1, and FHV-1) and HSV-1. Given the known discordant potencies between anti-pUL15C and HSV-1 replication inhibition, a second objective was to elucidate the mechanism of action of these compounds. The results show that alphaHTs broadly inhibit herpesviruses, with similar inhibitory effect against HSV-1, BoHV-1, EHV-1, and FHV-1. Based on immunoblotting, Southern blotting, and real-time qPCR, the compounds were found to specifically inhibit viral DNA replication. Thus, alphaHTs represent a new class of broadly active anti-herpesviral compounds with potential veterinary applications. PMID- 29408024 TI - Detection of porcine reproductive and respiratory syndrome virus (PRRSV)-specific IgM-IgA in oral fluid samples reveals PRRSV infection in the presence of maternal antibody. AB - The ontogeny of PRRSV antibody in oral fluids has been described using isotype specific ELISAs. Mirroring the serum response, IgM appears in oral fluid by 7days post inoculation (DPI), IgA after 7 DPI, and IgG by 9 to 10 DPI. Commercial PRRSV ELISAs target the detection of IgG because the higher concentration of IgG relative to other isotypes provides the best diagnostic discrimination. Oral fluids are increasingly used for PRRSV surveillance in commercial herds, but in younger pigs, a positive ELISA result may be due either to maternal antibody or to antibody produced by the pigs in response to infection. To address this issue, a combined IgM-IgA PRRSV oral fluid ELISA was developed and evaluated for its capacity to detect pig-derived PRRSV antibody in the presence of maternal antibody. Two longitudinal studies were conducted. In Study 1 (modified-live PRRS vaccinated pigs), testing of individual pig oral fluid samples by isotype specific ELISAs demonstrated that the combined IgM-IgA PRRSV ELISA provided better discrimination than individual IgM or IgA ELISAs. In Study 2 (field data), testing of pen-based oral fluid samples confirmed the findings in Study 1 and established that the IgM-IgA ELISA was able to detect antibody produced by pigs in response to wild-type PRRSV infection, despite the presence of maternal IgG. Overall, the combined PRRSV IgM-IgA oral fluid ELISA described in this study is a potential tool for PRRSV surveillance, particularly in populations of growing pigs originating from PRRSV-positive or vaccinated breeding herds. PMID- 29408025 TI - Shift of uterine microbiota associated with antibiotic treatment and cure of metritis in dairy cows. AB - Broad-spectrum antibiotics such as ceftiofur and ampicillin are recommended for the treatment of metritis in dairy cows. Nonetheless, little is known about the impacts of antibiotics on the uterine microbiota. Here, we evaluated the shift in uterine microbiota after treating metritic cows with ceftiofur or ampicillin, and also gained insight into the uterine microbiota associated with cure of metritis. Uterine swabs from ceftiofur-treated, ampicillin-treated, and untreated metritic Holstein cows were collected on the day of metritis diagnosis (D1) and on D6 and then used for genomic DNA extraction and sequencing of the V4 hypervariable region of the 16S rRNA gene on the Illumina MiSeq platform. The uterine microbiota consolidated over time by decreasing species richness and increasing evenness; therefore, becoming more homogeneous. The uterine microbial community showed distinct clustering patterns on D6 according to antibiotic treatment, which could be attributed to more dynamic changes in the microbial structure from D1 to D6 in ceftiofur-treated cows. Ceftiofur led to significant changes at the community level, phylum level, and genus level, whereas the changes in ampicillin and untreated cows, although following the same pattern, were mostly non significant. Bacteroidetes was significantly increased in ceftiofur-treated cows but was not changed after ampicillin and no treatment. Different responses to antibiotics were observed in Porphyromonas, which increased in relative abundance with ceftiofur and decreased with ampicillin. Regardless of treatment group, failure to cure metritis was associated with a decrease in diversity of uterine microbiota and an increase in the relative abundance of Bacteroides, Porphyromonas, and Fusobacterium. PMID- 29408026 TI - Injectable antimicrobials in commercial feedlot cattle and their effect on the nasopharyngeal microbiota and antimicrobial resistance. AB - Beef cattle in North America that are deemed to be at high risk of developing bovine respiratory disease (BRD) are frequently administered a metaphylactic antibiotic injection to control the disease. Cattle may also receive in-feed antimicrobials to prevent specific diseases and ionophores to improve growth and feed efficiency. Presently, attempts to evaluate the effects that these medications have on antibiotic resistance in the bovine nasopharyngeal microbiota have been focused on culturable bacteria that are associated with BRD. Therefore, we assessed the effects of injectable antibiotics on the nasopharyngeal microbiota of commercial feedlot cattle in Alberta, Canada, through the first 60 d on feed. Although all cattle in the study were also receiving in-feed chlortetracycline and monensin, the administration of a single injection of either oxytetracycline or tulathromycin at feedlot placement altered the nasopharyngeal microbiota in comparison with the cattle receiving only in-feed antibiotics. Oxytetracycline significantly (P < 0.05) reduced the relative abundance of Mannheimia spp. from feedlot entry to exit (>=60 d) and both oxytetracycline and tulathromycin treated cattle had a significantly lower relative abundance of Mycoplasma spp. at feedlot exit compared with the in-feed antibiotic only group. The proportion of the tetracycline resistance gene tet(H) was significantly increased following oxytetracycline injection (P < 0.05). Oxytetracycline also reduced both the number of OTUs and the Shannon diversity index in the nasopharyngeal microbiota (P < 0.05). These results demonstrate that in feedlot cattle receiving subtherapeutic in-feed antimicrobials, the administration of a single injection of either oxytetracycline or tulathromycin resulted in measurable changes to the nasopharyngeal microbiota during the first 60 d following feedlot placement. PMID- 29408027 TI - Comparison of cytokine profiles in peripheral blood mononuclear cells between piglets born from Porcine circovirus 2 vaccinated and non-vaccinated sows. AB - This study was aimed to evaluate the effect of Porcine circovirus 2 (PCV2) sow vaccination on cell-mediated immune responses in sows and their progeny. At 7 weeks before farrowing, fifteen PCV2 PCR negative pregnant sows with medium-low antibody values were selected and randomly distributed in two groups according to the antibody levels. Seven sows were vaccinated with a commercial PCV2 vaccine and eight were injected with phosphate-buffered saline at 6 and 3 weeks before farrowing. Blood samples were taken from sows and their piglets (n = 90) during the study duration. PCV2 DNA and antibodies were tested in sera, and cytokine (IFN-alpha, IFN-gamma, IL-12p40, TNF-alpha, IL-1beta, IL-8, IL-4, IL-6 and IL-10) levels were assessed in supernatant from cultured peripheral blood mononuclear cells. All sows and piglets were negative by PCV2 PCR throughout the study. Significantly higher PCV2 antibody levels were detected in vaccinated sows after vaccination and in their offspring after colostrum ingestion compared to the non vaccinated counterparts. Vaccinated sows did not show significant differences in cytokine secretion levels at farrowing compared to unvaccinated dams. In contrast, piglets from vaccinated sows had significantly higher levels of cytokines linked to Th1 memory cells (IFN-gamma and TNF-alpha) in comparison to the ones from non-vaccinated dams. In conclusion, PCV2 sow vaccination, apart from triggering a humoral immunity response in sows and their progeny, might be associated to an increased transfer of cell-mediated immunity from the dam to the piglet. PMID- 29408028 TI - C-terminal 20 residues of ORF3 protein of duck circovirus genotype 2 regulates the nuclear localization and inhibits apoptotic activity of ORF3 protein. AB - Duck circovirus (DuCV) is divided into genotypes 1 and 2. The DuCV ORF3 protein is a newly identified viral protein with apoptotic activity. In this study, the differences in the gene sequences, subcellular localization, and apoptotic activities of the ORF3 proteins of DuCV genotypes 1 and 2 were analyzed. A T-to-A point mutation at nucleotide 236 (T236A) in the ORF3 gene sequence of DuCV genotype 1 was observed, which generates a premature stop codon (TAG) and resulted in a truncated ORF3 protein. The ORF3 protein of DuCV genotype 2 is 20 amino acids longer at its C-terminus than the truncated ORF3 protein of genotype 1. A variant monopartite-type nuclear localization signal (RRLRTCNCRACRTLK) was identified within the C-terminal region of the ORF3 protein of DuCV genotype 2, which is essential for the nuclear localization of the protein. The 20 C-terminal residues of the DuCV genotype 2 ORF3 protein also inhibits the apoptotic activity of the protein. Our findings provide insight into the biological and functional characteristics of the DuCV ORF3 protein. PMID- 29408029 TI - Characterization of a genetically distinct subpopulation of Staphylococcus haemolyticus isolated from milk of cows with intramammary infections. AB - The aim of this paper is to describe a novel subpopulation of Staphylococcus haemolyticus isolated from intramammary gland infections (IMI) in cattle. In total, eight isolates originating from milk samples from two unrelated dairy farms were examined phenotypically (using the ID 32 STAPH system) and genotypically. These isolates had almost identical sequences of each of the housekeeping genes examined (dnaJ, rpoB and sodA) but these sequences displayed similarity of only ~92.5%, 95.0% and 96.8%, respectively, with known S. haemolyticus sequences. The atypical isolates could also be distinguished biochemically by the positive beta-galactosidase test (with 2-naphthyl-beta-d galactopyranoside as the substrate). All the isolates were identified as S. haemolyticus upon MALDI-TOF analysis but half of them, that achieved scores 1.7 1.999 (not reliable species identification), required expanding the commercial database for secure identification. Our study has shown that IMI in cattle may be caused by two distinct subpopulations of S. haemolyticus, differing clearly by some genotypic and phenotypic properties. The first of these subpopulations seems to be common to many hosts (including humans), whereas the second (possibly at the subspecies rank) is, so far, found only in cattle. PMID- 29408030 TI - Molecular typing and genetic relatedness of 72 clinical Candida albicans isolates from poultry. AB - Candida albicans is the most prevalent opportunistic fungus of humans and animals. While most studies focus on human isolates, they rarely focus on poultry isolates. In this study, C. albicans strains were recovered from poultry in the southern Hebei Province (China) and identified. Molecular typing and analyses were performed to understand the molecular epidemiology and genetic relatedness of the strains. The fungi were isolated from live birds with presumed candidiasis or their corpses. The isolates were identified based on morphology, differential medium culture, and rDNA internal transcribed spacer sequencing. The identified C. albicans strains were analyzed by ABC genotyping and multilocus sequence typing. Clonal groups were identified using the eBURST (version 3.0) software, and an UPGMA phylogenetic tree was constructed using the MEGA (version 6.06) software. Overall, 72 isolates were divided into three genotypes (A, B, and C), 48 novel sequence types (STs), five groups with 10 singletons, and four clades. Results indicated that candidiasis is common in poultry in the southern Hebei Province, and that the genetic composition of the C. albicans poultry population from the area is relatively complicated. Based on the eBURST analysis for the STs in this study and others, we suggest that C. albicans poultry isolates were relatively independent but not completely separated from human isolates. The strains with the same or closely related genotypes but recovered from both birds and humans could have transferred and evolved between the two types of host. PMID- 29408031 TI - Genotypes of Mycobacterium bovis strains isolated from domestic animals and wildlife in Canada in 1985-2015. AB - Two internationally recognised and standardised genotyping methods, mycobacterial interspersed repetitive unit and variable number tandem repeat analysis (MIRU VNTR) and spoligotyping, were applied to characterise genetic variations among 137 Mycobacterium bovis isolates recovered from Canadian domestic and wild animals during 1985-2015. Spoligotyping generated seven types that were discriminated further into12 MIRU-VNTR types. The discriminatory power indexes were estimated as 0.71 and 0.77 for spoligotyping and MIRU-VNTR typing approaches, respectively. In total, 6 prominent clusters of isolates were observed by the genotyping schemes. Four genotype clusters were exclusively observed in farmed animals. Three of these four clusters were affiliated with localised tuberculosis outbreaks, and each cluster corresponded to a single specific spoligotype (SB0140, SB0673, and SB1069) and a MIRU-VNTR profile. The fourth genotype cluster, with spoligotype SB0265 which segregated into two MIRU VNTR types, was associated with bovine tuberculosis outbreaks in several farms across Canada during 1990-2002. Two genotype clusters of M. bovis stains were associated with wildlife reservoirs: a spoligotype SB0130 with 3 unique MIRU-VNTR profiles were observed in wood bison in Wood Buffalo National Park, and unique spoligotypes SB1070 and 1071 represented by four MIRU-VNTR profiles were recovered from cervidae species in and around the Riding Mountain National Park of Manitoba. Genotyping data confirmed M. bovis transmission between wildlife and livestock in Manitoba in 1990-2008. Overall, notwithstanding the low level of genetic diversity of Canadian M. bovis strains, the spoligotyping and MIRU-VNTR typing were useful tools in monitoring transmission of endemic strains and defining new introductions to Canada. The majority of genotypes were most likely introduced into domestic animals through live animal trade, and subsequently eliminated as a result of bovine tuberculosis outbreak investigation and eradication activities. PMID- 29408032 TI - Transposon-associated lincosamide resistance lnu(C) gene identified in Brachyspira hyodysenteriae ST83. AB - Treatment of Swine Dysentery (SD) caused by Brachyspira hyodysenteriae (B. hyodysenteriae) is carried out using antimicrobials such as macrolides, lincosamides and pleuromutilins leading to the selection of resistant strains. Whole genome sequencing of a multidrug-resistant B. hyodysenteriae strain called BH718 belonging to sequence type (ST) 83 revealed the presence of the lincosamide resistance gene lnu(C) on the small 1724-bp transposon MTnSag1. The strain also contains an A to T substitution at position 2058 (A2058T) in the 23S rRNA gene which is known to be associated with macrolide and lincosamide resistance in B. hyodysenteriae. Testing of additional strains showed that those containing lnu(C) exhibited a higher minimal inhibitory concentration (MIC) of lincomycin (MIC >= 64 mg/L) compared to strains lacking lnu(C), even if they also harbor the A2058T mutation. Resistance to pleuromutilins could not be explained by the presence of already reported mutations in the 23S rRNA gene and in the ribosomal protein L3. This study shows that B. hyodysenteriae has the ability to acquire mobile genetic elements conferring resistance to antibiotics. PMID- 29408033 TI - Relative performance of antimicrobial susceptibility assays on clinical Escherichia coli isolates from animals. AB - The assessment of antimicrobial resistance in bacteria derived from animals is often performed using the disc diffusion assay. However broth-microdilution is the preferred assay for national antimicrobial resistance surveillance programs. This study aimed to evaluate the accuracy of disc diffusion relative to broth microdilution across a panel of 12 antimicrobials using data from a collection of 994 clinical Escherichia coli isolates from animals. Disc diffusion performance was evaluated by diagnostic sensitivity, specificity, likelihood ratio pairs and receive-operating characteristic (ROC) analysis. Data was dichotomised using CLSI susceptible and resistant clinical breakpoints. In addition, disc diffusion breakpoints produced using diffusion Breakpoint Estimation Testing Software (dBETS) were evaluated. Analysis revealed considerable variability in performance estimates for disc diffusion susceptible and resistant breakpoints (AUC ranges: 0.78-0.99 and 0.92-1.0, respectively) across the panel of antimicrobials. Ciprofloxacin, tetracycline, and ampicillin estimates were robust across both breakpoints, whereas estimates for several antimicrobials including amoxicillin clavulanic acid, cefoxitin and gentamicin were less favourable using susceptible breakpoints. Overall performance estimates were moderately improved when dBETS susceptible breakpoints were applied. For most antimicrobials, disc diffusion was accurate at predicting resistance of clinical E. coli from animals that could otherwise be determined by broth-microdilution. While disc diffusion is suboptimal for assessing the proportion of fully susceptible isolates for some drugs, sensitivity and specificity estimates provided here allow for the use of standard formula to correct this. For this reason, disc diffusion has applicability in national surveillance provided the performance of the assay is taken into account. PMID- 29408034 TI - Insights into leghorn male hepatocellular cells response to fowl adenovirus serotype 4 infection by transcriptome analysis. AB - Fowl adenovirus serotype 4 (FAdV-4), a member of the Aviadenovirus genus of the Adenoviridae family, causes hepatitis-hydropericardium syndrome (HHS) in chickens. It causes mortality of up to 80% in 3-6-week-old broilers, posing a substantial threat to the poultry industry. However, the specific host responses to the virus are not well understood. To better understand the interactions between the host and FAdV-4 and to explore the pathogenesis of this virus, a high throughput RNA-seq technology was utilized with leghorn male hepatocellular (LMH) cells at 12, 24, and 48 h after FAdV-4 infection. We identified a total of 7000 differentially expressed genes (DEGs), which were enriched in a variety of biological processes and pathways using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Several immune related pathways, including Toll-like receptor (TLR) signaling pathway and cytokine-cytokine receptor interaction pathway, were activated after the FAdV-4 infection. The transcriptional data were validated by quantitative real-time PCR. The expression profiles of 10 genes involved in FAdV-4-infected chicken livers, including TLR2A, TLR3, TLR5, MyD88, IL12B, IL15, IL18, CCL20, TNFRSF21, and CD30, were consistent with RNA-seq profiles. By transfecting small interfering RNA into LMH cells, our results confirmed that MyD88 mediated FAdV-4-induced inflammation. To our knowledge, this was the first study to use transcriptome analysis to investigate host responses to FAdV-4 infection. These findings provide insights into the mechanisms of FAdV-4 pathogenesis and host-FAdV-4 interaction. PMID- 29408035 TI - Increase of zinc resistance in German human derived livestock-associated MRSA between 2000 and 2014. AB - PROBLEM ADDRESSED: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA), particularly of the clonal complex (CC) 398, emerged as zoonotic pathogens predominantly among humans with direct or indirect livestock contact, but also in healthcare settings. The factors contributing to the success of LA-MRSA are only poorly understood. OBJECTIVE: During the past years, the use of heavy metal compounds as feed-supplements was found to influence the co selection of LA-MRSA in pig herds. This study aimed to determine the prevalence of zinc resistance among MRSA CC398 isolated from patients of a German university hospital located in a pig farming-dense area. METHODS AND APPROACH: In comparison to concurrent healthcare-associated MRSA (HA-MRSA), LA-MRSA CC398 comprising isolates from their first appearance in 2000 to recent isolates from 2014 were included. RESULTS: Among MRSA CC398, the overall resistance rate towards zinc chloride was 57% compared to only 3% among concurrently isolated HA-MRSA. Zinc resistance correlated with the presence of the czrC gene in 100% of the MRSA CC398 and in 67% of the HA-MRSA. CONCLUSIONS: The zinc resistance rate in MRSA CC398 significantly increased from 2009 to 2014 with a maximum in 2014. Alarmingly, zinc resistance has become a frequent phenotype of human LA-MRSA in Germany potentially facilitating co-selection of antibiotic resistance genes. PMID- 29408036 TI - First detection of feline hemoplasmas in free-ranging jaguars (Panthera onca). AB - Species of hemoplasmas have been described worldwide, but little information is available for wild felids. Between February 2000 and January 2010, blood samples were collected from 30 jaguars (Panthera onca) and 22 domestic cats (Felis catus) from the Cerrado, Pantanal and Amazon biomes of Brazil. In all samples molecular tests were performed for Mycoplasma haemofelis/Mycoplasma haemocanis (Mhf/Mhc), 'Candidatus Mycoplasma haemominutum' (CMhm) and 'Candidatus Mycoplasma turicensis' (CMt). Twenty-two (73.4%) jaguars and four domestic cats (18.2%) tested positive for infection with at least one feline hemoplasma: 73.4% jaguars from the three areas were positive for CMhm, 13.6% jaguars from the Pantanal and 50.0% from the Amazon were positive for Mhf/Mhc, and 9.1% of individuals from the Pantanal tested positive for CMt. Domestic cats from the Cerrado (28.6%) and the Pantanal (30.0%) were positive for feline hemoplasma. All but one jaguar from the three sites are healthy. One female adult jaguar showed low body weight and dehydration. This is the first record of feline hemoplasmas in free-ranging jaguars. The high prevalence of CMhm suggest the participation of jaguars in the maintenance of this hemoplasma in nature. Although susceptible to Mhf/Mhc and CMt, jaguars did not appear to participate in the maintenance of these agents in the environment. The involvement of domestic cats in the transmission of any of these hemoplasmas cannot be excluded. PMID- 29408037 TI - Characterization of Brachyspira communities from clinical cases of swine mucohaemorrhagic diarrhea through deep sequencing of the NADH oxidase (nox) gene. AB - Swine dysentery is traditionally associated with Brachyspira hyodysenteriae, but the re-emergence of Brachyspira-associated disease in North America associated with a novel causative species, B. hampsonii, is now a concern for swine producers. The pathogenesis of Brachyspira-associated disease is not completely understood, and it is not known whether mixed infections of Brachyspira spp. are important in disease development. Deep sequencing of partial sequences of the nox gene amplified with genus-specific primers was used to detect Brachyspira spp. in 55 fecal samples from clinical cases of mucohaemorrhagic diarrhea in pigs from Western Canada that had been identified as positive for one or more Brachyspira species using established diagnostic tests. Synthetic mixtures of Brachyspira genomic DNA were included in the study to define detection limits for the technique and identify biases in detection of different species. Multiple species were detected in all clinical cases for which sufficient nox sequence data were generated (n = 47), indicating that mixed species Brachyspira infections are common, although in most cases, one species accounted for at least half of the sequences identified. In all cases, the species detected in the original diagnostic investigation of each case was also detected by nox sequencing. Results from synthetic communities indicated that the method was highly reproducible, but also indicated potential PCR bias against B. hampsonii genomovar I. Deep sequencing of the nox gene target is a suitable method for simultaneous detection of multiple Brachyspira species in clinical case material that may offer advantages over current, more targeted diagnostic approaches for investigating the significance of mixed infections in disease development. PMID- 29408039 TI - Epidemiological analysis of porcine rotavirus A genotypes in Germany. AB - Group A porcine rotaviruses are a global threat to animal health in stock breeding. While certain genotypes have shown predominance in other countries, data from Europe's second largest swine population is still scarce. Therefore, porcine rotaviruses taken from different areas of Germany were genotyped to create a basis for comparison with data from neighboring countries. In addition, the potential predominance and regionality based on regions (federal states) have been investigated by examining 101 samples. The study revealed the dominance of the VP7 genotypes G9, G4, G5 as well as VP4 genotypes P[23], P[6], P[32]. The most common genotype combinations were G9P[23], G4P[6], and G9P[32]. Analysis focusing on the regionality aspect revealed that areas with high pig populations promote the emergence of dominant genotype combinations. However, pig populations in Germany cannot be considered individually and therefore results were put into international context, taken from already published genotyping data. In consequence, our data contributes to the fundamental understanding of regional and supraregional rotavirus epidemiology. The detected genotypes provide a basis for prospective porcine rotavirus surveillance, that first of all helps to identify interspecies transmission. Furthermore it may provide supporting data for the selection of particular genotypes, suitable for the production of porcine rotavirus A vaccine candidates. PMID- 29408038 TI - Spectrum of antibody profiles in tuberculous elephants, cervids, and cattle. AB - Using multi-antigen print immunoassay and DPP(r) VetTB Assay approved in the United States for testing captive cervids and elephants, we analyzed antibody recognition of MPB83 and CFP10/ESAT-6 antigens in Asian elephants (Elephas maximus) infected with Mycobacterium tuberculosis and in white-tailed deer (Odocoileus virginianus), fallow deer (Dama dama), elk (Cervus elaphus), and cattle (Bos taurus) infected with Mycobacterium bovis. Serum IgG reactivity to MPB83 was found in the vast majority of tuberculous cattle and cervid species among which white-tailed deer and elk also showed significant CFP10/ESAT-6 recognition rates with added serodiagnostic value. In contrast, the infected elephants developed antibody responses mainly to CFP10/ESAT-6 with MPB83 reactivity being relatively low. The findings demonstrate distinct patterns of predominant antigen recognition by different animal hosts in tuberculosis. PMID- 29408040 TI - Evaluation of a peroxygen-based disinfectant for inactivation of porcine epidemic diarrhea virus at low temperatures on metal surfaces. AB - Porcine epidemic diarrhea virus (PEDV) spread rapidly across the United States in part due to contaminated livestock trailers. The objective of this study was to test a peroxygen-based disinfectant for the ability to inactivate PEDV on aluminum surfaces at 4 degrees C or -10 degrees C. Forty 3-week-old individually housed barrows were used as a bioassay to determine the infectivity of PEDV after treatment with either a 1:100 or 1:600 dilution of a peroxygen based disinfectant with 10 or 30 min of contact time. One coupon matched to one pig was the experimental unit. Coupons in the positive control and disinfectant treatment groups were contaminated with 2 mL of feces spiked with PEDV. A negative control group was contaminated with PEDV-negative feces. Following treatment, the feces and disinfectant remaining in the coupons was collected and administered to pigs intragastrically. Rectal swabs were collected from pigs 3 and 7 days post-inoculation (DPI) and tested for PEDV by RT-qPCR. Samples from all coupons, except the negative control, were positive by RT-qPCR for PEDV before and after treatment. All rectal swabs from the pigs in the negative control and the seven disinfectant treatment groups were RT-qPCR negative for PEDV on 3 and 7 DPI. All pigs in the positive control at 4 degrees C and 3 of 4 pigs in the positive control conducted at -10 degrees C were RT-qPCR positive for PEDV on 3 and 7 DPI. Both the 1:100 and 1:600 dilutions of peroxygen-based disinfectant successfully inactivated PEDV under the conditions of this study. PMID- 29408043 TI - Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease. AB - Arachidonic acid is metabolized by cyclooxygenases (COX-1 and COX-2) into various prostanoids which exert different functions in mammalian physiology. One of these prostanoids, prostaglandin E2 (PGE2), interacts with four different G protein coupled receptors, named EP1, EP2, EP3 and EP4, to initiate different downstream signalling pathways. Prostanoid receptors are diversely expressed throughout different tissues all over the body and PGE2 is responsible for a large variety of beneficial and disadvantageous effects. We have recently achieved a greater understanding of the biology of prostanoid E receptors and the potential for specific drug targeting with the advent of potent and selective EP receptor agonists and antagonists. This has important implications for lung health and disease as PGE2-mediated EP receptor activation impacts upon migration of airway smooth muscle cells, airway microvascular leak, tone regulation of pulmonary blood vessels, mast cell degranulation, bronchodilatation, cough, angiogenesis and airway inflammation, to name a few. In this review, we overview the EP receptor family and the related signalling pathways, summarize a variety of EP1-4 receptor agonists and antagonists, provide an overview of pharmacological tools used to implicate EP receptor function in the context of respiratory health and disease and finally highlight some of the more selective pharmacological reagents that have recently been developed. The availability of selective pharmacological agonists and antagonists for the distinct EP receptors, as well as the development of specific prostanoid receptor knock-out mice, offer hitherto unattainable opportunities for achieving an in depth understanding of the role and function of PGE2 in respiratory disease and the exciting potential of targeting EP receptors more broadly. PMID- 29408042 TI - H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. AB - Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel alpha-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs. PMID- 29408041 TI - Low-level arsenic causes proteotoxic stress and not oxidative stress. AB - Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10MUg/L, but levels>50-1000MUg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure. PMID- 29408044 TI - Effect of lipopolysaccharide on the responsiveness of equine bronchial tissue. AB - Recurrent airway obstruction (RAO) is a main characteristic of horses with severe equine asthma syndrome. The presence of bacterial lipopolysaccharide (LPS) in the airways of horses is thought to play a crucial role in the clinical expression of this disorder. This study pharmacologically characterized the effect of LPS on the responsiveness of equine bronchial tissue. Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml) and then stimulated by electrical field stimulation (EFS). The role of capsaicin sensitive-sensory nerves (capsaicin desensitization treatment), neurokinin-2 (NK2) receptors (blocked by GR159897), transient receptor potential vanilloid type 1 receptors (TRPV1; blocked by SB366791), and neurokinin A (NKA) were investigated. Untreated bronchi were used as control tissues. LPS (1 ng/ml) significantly increased the EFS evoked contractility of equine bronchi compared with control tissues (+742 +/- 123 mg; P < 0.001). At higher concentrations LPS induced desensitization to airways hyperresponsiveness (AHR; EC50: 5.9 +/- 2.6 ng/ml). Capsaicin desensitization and GR159897 significantly prevented AHR induced by LPS at EFS1 50Hz (-197 +/- 25%; P < 0.01). SB366791 inhibited AHR at very low EFS frequency (EFS1Hz -193 +/- 29%; P < 0.01 vs. LPS-treated bronchi). LPS (1 ng/ml) significantly (P < 0.01) increased 3.7 +/- 0.7 fold the release of NKA compared with control bronchi. LPS induces biphasic dysfunctional bronchial contractility due to the stimulation of capsaicin sensitive-sensory nerves, increased release of NKA, and activation of NK2 receptors, whereas TRPV1 receptors appear to play a marginal role in this response. The overnight challenge with low concentrations of LPS represents a suitable model to investigate pharmacological options that may be of value in the treatment of equine RAO. PMID- 29408045 TI - Effects of electroformation protocol parameters on quality of homogeneous GUV populations. AB - Giant unilamellar vesicles (GUVs) have become one of extensively studied biological bilayer models especially when investigating topological and mechanical properties of cell membranes. They are also used to visualize membrane related phenomena. However, the method of preparation and the effects of parameters of preparation on the vesicular structure are extensively varied. Therefore, it is important to understand how the process of formation of GUVs influences the outcome population, as it can influence the outcome of the experiment that is planned. Therefore, in this study, we investigated the effects of protocol parameters of electroformation on properties of homogeneous population of POPC GUVs. The parameters investigated in this study are duration of electroformation, usage of electrodes and frequency of applied AC field and its voltage. The properties investigated, which can be used to describe GUV populations are average diameter of vesicle, the amount of lipid molecules in population, and structure of vesicles. According to our results, prolonged time (greater than 4 h) does not influence outcome; however, parameters of applied electrical field (voltage and frequency) did significantly influence the properties of obtained POPC GUV populations. PMID- 29408046 TI - Maleimide-acetylcholine headed bolaamphiphilic vesicles made from ricinoleic acid: Prospective active targeted drug delivery systems. AB - Based on ricinoleic acid, two asymmetric bolaamphiphiles with unsymmetrical hydrophobic skeletons and two different hydrophilic head groups were designed and synthesized. The first bola compound had acetylcholine (ACh) and maleimide (MAL) head groups while the second was derived from the first bolaamphiphile by thiol ene conjugation of its maleimide moiety with l-glutathione and possessed ACh and l-glutathione-MAL head groups. Both synthetic bolaamphiphiles were characterized by common spectroscopic methods. The asymmetric bola compound with ACh and MAL head groups was investigated for its ability to self-aggregate into nanoparticles and showed to form in aqueous media nano-sized vesicles that were stable, positively charged and had symmetrical monolayer membrane with antiparallel packing. These vesicles prepared with or without membrane stabilizers such as cholesterol (CHOL) and cholesteryl hemisuccinate (CHEMS) were able to encapsulate carboxyfluorescein (CF), a water soluble and self-quenching marker and particularly those without additives were more CF encapsulating. The synthesis of bolaamphiphile with ACh-l-glutathione-MAL head groups gives evidence that the bola with ACh and MAL head groups can be utilized as a precursor of a plethora of asymmetric bolas. PMID- 29408048 TI - Oestrogen, an evolutionary conserved regulator of T cell differentiation and immune tolerance in jawed vertebrates? AB - In teleosts, as in mammals, the immune system is tightly regulated by sexual steroid hormones, such as oestrogens. We investigated the effects of 17beta oestradiol on the expression of several genes related to T cell development and resulting T cell subpopulations in sea bass, Dicentrarchus labrax, for a primary lymphoid organ, the thymus, and two secondary lymphoid organs, the head-kidney and the spleen. In parallel, the oxidative burst capacity was assessed in leucocytes of the secondary lymphoid organs. Apoptosis- and proliferation-related genes, indicative of B and T cell clonal selection and lymphoid progenitor activity, were not affected by elevated oestrogen-levels. Sex-related oestrogen responsiveness in T cell and antigen-presenting cell markers was observed, the expression of which was differentially induced by oestrogen-exposure in the three lymphoid organs. Remarkably, in the spleen, oestrogen increased regulatory T cell related gene expression was associated with a decrease in oxidative burst capacity. To the best of our knowledge, this study indicates for the first time that physiological levels of oestrogen are likely to promote immune tolerance by modulating thymic function (i.e., T cell development and output) and peripheral T cells in teleosts, similar to previously reported oestrogenic effects in mammals. PMID- 29408047 TI - Phenotypic and functional modulations of porcine macrophages by interferons and interleukin-4. AB - Considering that macrophage functions are strongly impacted by the local tissue environment and the type of immune response, the aim of this study was to carefully set the methodological baseline for phenotype and functions of polarized porcine monocyte-derived macrophages. To this end, macrophages were generated in autologous serum alone or with colony-stimulating factor (CSF)-1 or CSF-2, and subsequently polarized with interferon (IFN)gamma, interleukin-4 or IFNbeta. IFNgamma promoted expression of MHC class I, MHC class II, CD11a, and CD40 as well as LPS-induced IL-6 and IL-12. A hallmark of interleukin-4 was Arginase 1 and CD203a upregulation, without abrogating pro-inflammatory cytokine production. IFNbeta induced CD169, MHC class I, CD40, CD80/86, but suppressed IL 6, IL-12 and tumor-necrosis-factor secretion. CSF-2 alone altered macrophage differentiation and promoted an IFNgamma-like polarization. Altogether, the results provide a comprehensive overview of porcine macrophage polarization, and demonstrate commonalities with other species as well as peculiarities of the pig. PMID- 29408049 TI - The interaction between baculoviruses and their insect hosts. AB - Baculoviruses are double-stranded circular DNA viruses that infect arthropods via the midgut. Because of their superiority as eukaryotic expression systems and their importance as biopesticides, extensive research on the functions of baculovirus genes as well as on the host response to baculovirus infection has been carried out, including transcriptomic and proteomic analyses of the midgut. The morphological and cellular changes caused by baculovirus infection are also important to better understand the infection pathway. Thanks to these previous studies, we now have a clearer picture of the mechanisms of action of the virus and of host immunity. In this paper, we systematically reviewed studies on the interaction between baculoviruses and their insect hosts. By better understanding these interactions, baculoviruses can be developed for use as more efficient biopesticides to improve agricultural development in the future. PMID- 29408051 TI - Working mechanisms of a general positivity approach-avoidance training: Effects on action tendencies as well as on subjective and physiological stress responses. AB - BACKGROUND AND OBJECTIVES: The general positivity training, a Cognitive Bias Modification procedure modifying individuals' approach-avoidance tendencies to positively and negatively valenced pictures by means of a joystick task, has been proven effective in attenuating stress reactivity in dysphoric students. The present study explored which training component (pull positive pictures, push negative pictures, or both) is the active one in changing action tendencies and stress responses. METHODS: Two-hundred-and-thirteen students completed one of four approach-avoidance trainings before being exposed to a stressful speech task: The general positivity training (pull positive and push negative pictures), a training to approach positive pictures and avoid empty pictures (ApP), a training to avoid negative pictures and approach empty pictures (AvN), or a sham training. RESULTS: The pattern of results suggests that the groups trained to avoid negative pictures showed a stronger increase in positive approach-avoidance tendencies than the other two groups. However, only the positivity training induced significant within-group changes in positive bias. The groups further did not differ in self-report or cardiovascular measures of anxiety in response to the stress-task. Instead, the training affected mood directly: Exposure to negative pictures during the training increased state anxiety. LIMITATIONS: Generalizability of the findings is limited by using an unselected student sample. Also, the use of empty pictures as neutral stimuli in the ApP and AvN could have weakened training effects in these groups. CONCLUSIONS: Although our results hint at the importance of avoiding negative pictures for modifying an approach-avoidance bias, only the positivity training with both components may effectively induce a positive bias. Remarkably, we failed to replicate and extend previously reported effects of the training on stress-responses. Hence, it remains questionable whether the changes in bias reflect changes in underlying cognitive processing tendencies or task-specific learning effects. PMID- 29408050 TI - Effect of expressive and neutral writing on respiratory sinus arrhythmia response over time. AB - BACKGROUND AND OBJECTIVES: Parasympathetic activity, as indexed by respiratory sinus arrhythmia (RSA), underlies key aspects of emotional and cognitive self regulation. Examining time-varying RSA response during expressive writing about trauma may help inform theory about mechanisms of this intervention. The present study investigated changes in RSA during expressive writing. METHODS: Participants (N = 246, Mage = 21.5 years, 72% female) were randomly assigned to expressive or neutral writing conditions and wrote for three 20-min sessions. RSA was measured continuously during the first and third writing session. RESULTS: Linear mixed model analyses of RSA changes within and across sessions by writing groups found that neutral writers, but not expressive writers, exhibited change in RSA. The overall RSA changes during expressive and neutral writing are consistent with theory about the relationship between cognitive and emotional processing mechanisms and vagal activation. LIMITATIONS: As the present study was not a clinical sample selected on trauma exposure, findings should be considered preliminary. Additionally, engagement of affective and cognitive processes was only hypothesized, as manipulation checks were not performed. CONCLUSIONS: The present study illustrates the benefits of examining changes in RSA over time. Future work with clinical samples should include additional measures and tasks to better define these mechanisms and rule out alternative hypotheses. PMID- 29408052 TI - A computerized neuropsychological evaluation of cognitive functions in a subclinical obsessive-compulsive sample. AB - BACKGROUND AND OBJECTIVES: Ample research in obsessive-compulsive disorder (OCD) reveals a moderate degree of underperformance on various neuropsychological tasks. Less is known about neuropsychological function in subclinical obsessive compulsive (OC) samples. Most analogue OCD studies did not use a comprehensive neuropsychological battery and none utilized a fully computerized battery. To fill this gap in the literature, the present study aimed at assessing cognitive functions in a subclinical OC sample using a validated computerized neuropsychological battery. METHODS: Initially, a sample of 165 students completed the Obsessive-Compulsive Inventory-Revised (OCI-R). Using a psychometrically valid methodology, a high OC (HOC, n = 29) and low OC (LOC, n = 29) groups were selected based on scores in the upper and lower quartiles on the OCI-R. The two groups completed the NeuroTrax computerized neuropsychological battery and clinical questionnaires. RESULTS: Although the HOC group underperformed on most outcome measures, controlling for state-anxiety and depression symptoms, no significant differences were found on major domains (i.e., memory, attention, executive functions, processing speed, visuospatial functions, verbal functions, and motor skills), and subdomains. Normalized scores, produced using population norms, indicated that both groups performed within the normative range. LIMITATIONS: Not all neuropsychological subdomains were assessed. CONCLUSIONS: Results are consistent with the general picture in analogue OC samples, and may be more reliable than paper-pencil testing, given that a full computerized neuropsychological battery minimizes examiner-examinee interactions, and increases timing accuracy. In sum, analogue OC samples, characterized by equivalent symptom severity but high functioning compared to OCD samples, do not present with cognitive deficits. PMID- 29408053 TI - Orbitofrontal neurons signal reward predictions, not reward prediction errors. AB - Neurons in the orbitofrontal cortex (OFC) fire in anticipation of and during rewards. Such firing has been suggested to encode reward predictions and to account in some way for the role of this area in adaptive behavior and learning. However, it has also been reported that neural activity in OFC reflects reward prediction errors, which might drive learning directly. Here we tested this question by analyzing the firing of OFC neurons recorded in an odor discrimination task in which rats were trained to sample odor cues and respond left or right on each trial for reward. Neurons were recorded across blocks of trials in which we switched either the number or the flavor of the reward delivered in each well. Previously we have described how neurons in this dataset fired to the predictive cues (Stalnaker et al., 2014); here we focused on the firing in anticipation of and just after delivery of each drop of reward, looking specifically for differences in firing based on whether the reward number or flavor was unexpected or expected. Unlike dopamine neurons recorded in this setting, which exhibited phasic error-like responses after surprising changes in either reward number or reward flavor (Takahashi et al., 2017), OFC neurons showed no such error correlates and instead fired in a way that reflected reward predictions. PMID- 29408054 TI - Paradoxical accentuation of motivation following accumbens-pallidum disconnection. AB - The nucleus accumbens (NAc) and ventral pallidum (VP) are reciprocally connected, and activity within this circuit is thought to promote reward learning. Inconsistent with this notion, we find that disconnecting NAc medial shell and VP greatly enhances the attribution of value to a cue that is paired with reward. This result suggests that medial NAc shell and VP are both needed for attributing value to cues yet can also oppose one-another's functional contribution. PMID- 29408055 TI - Methylphenidate induces state-dependency of social recognition learning: Central components. AB - Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus. PMID- 29408056 TI - The epigenetic factor KDM2B regulates cell adhesion, small rho GTPases, actin cytoskeleton and migration in prostate cancer cells. AB - The histone demethylase KDM2B is an epigenetic factor with oncogenic properties that is regulated by the basic fibroblasts growth factor (FGF-2). It has recently been shown that KDM2B co-operates with Polycomb Group proteins to promote cell migration and angiogenesis in tumors. In the present study we addressed the role of KDM2B in regulating actin cytoskeleton signaling, cell-cell adhesion and migration of prostate tumor cells. We report here that KDM2B is functionally expressed in DU-145 prostate cancer cells, activated by FGF-2 and regulates EZH2. KDM2B knockdown induced potent up-regulation of gene transcription and protein expression of the epithelial markers E-cadherin and ZO-1, while KDM2B overexpression down-regulated the levels of both markers, suggesting control of cell adhesion by KDM2B. RhoA and RhoB protein expression and activity were diminished upon KDM2B-knockdown and upregulated in KDM2B-overexpressing cell clones. In accordance, actin reorganization with formation of stress fibers became evident in KDM2B-overexpressing cells and abolished in the presence of the Rho inhibitor C3 transferase. DU-145 cell migration was significantly enhanced in KDM2B overexpressing cells and abolished in C3-pretreated cells. Conversely, the retardation of cell migration observed in KDM2B knockdown cells was enhanced in C3-pretreated cells. These results establish a clear functional link between the epigenetic factor KDM2B and the regulation of cell adhesion and Rho-GTPases signaling that controls actin reorganization and cell migration. PMID- 29408058 TI - Investigation of a new double-stage aerobic-anoxic continuous-flow cyclic baffled bioreactor efficiency for wastewater nutrient removal. AB - Nitrogen and phosphorus are among the potential pollutants of receptive water sources entering into these water sources via sewage, which are not sufficiently treated. The purpose of this study is to investigate the efficiency of a new two stage aerobic-anoxic continuous-flow baffled cycling reactor (CFBCR) to reduce nitrogen and phosphorus load from wastewater. Therefore, a double-stage baffled reactor was used in which the second part was integrated with the settling part causing the sludge to be spontaneously returned to the second reservoir. Additionally, the effect of different concentrations of chemical oxygen demand (COD) of 400-800 mg/L, ammonia of 40-60 mg/L, phosphate of 12-20 mg/L, internal rate of return of 100-200% and the retention time of 18-30 h was investigated. Furthermore, to investigate the performance of this reactor, four phases with different aeration and mixing conditions were designed. The percentage of ammonia removal with influent concentration of 40 mg/L in phase 2 with intermittent mixing and one-hour aeration time was 98.7%; effluent nitrate average concentration was 8.4 mg/L NO3-N, and phosphate removal percent was 83%. The best nutrient removal efficiency was with the retention time of 24 h and internal return rate of 150%. In conclusion, CFBCR reactor with continuous influent and effluent and reduction of the need for sludge return, has the potential to be applied to remove nutrients from wastewater. PMID- 29408057 TI - Heparan sulfate mediates cell uptake of alphaB-crystallin fused to the glycoprotein C cell penetration peptide. PMID- 29408059 TI - Coconut endocarp and mesocarp as both biosorbents of dissolved hydrocarbons in fuel spills and as a power source when exhausted. AB - Health and environmental problems associated with the presence of toxic aromatic compounds in water from oil spills have motivated research to develop effective and economically viable strategies to remove these pollutants. In this work, coconut shell (endocarp), coconut fiber (mesocarp) and coconut shell with fiber (endocarp and mesocarp) obtained from coconut (Cocos nucifera) waste were evaluated as biosorbents of benzene, toluene and naphthalene from water, considering the effect of the solution pH (6-9) and the presence of dissolved organic matter (DOM) in natural water (14 mg/L). In addition, the heat capacity of saturated biosorbents was determined to evaluate their potential as an alternative power source to conventional fossil fuels. Tests of N2 physisorption, SEM, elemental and fiber analysis, ATR-FTIR and acid-based titrations were performed in order to understand the materials' characteristics, and to elucidate the biosorbents' hydrocarbon adsorption mechanism. Coconut fiber showed the highest adsorption capacities (222, 96 and 5.85 mg/g for benzene, toluene and naphthalene, respectively), which was attributed to its morphologic characteristics and to its high concentration of phenolic groups, associated with the lignin structure. The pH of the solution did not have a significant influence on the removal of the contaminants, and the presence of DOM improved the adsorption capacities of aromatic hydrocarbons. The adsorption studies showed biphasic isotherms, which highlighted the strong affinity between the molecules adsorbed on the biosorbents and the aromatic compounds remaining in the solution. Finally, combustion heat analysis of coconut waste saturated with soluble hydrocarbons showed that the heat capacity increased from 4407.79 cal/g to 5064.43 +/- 11.6 cal/g, which is comparable with that of woody biomass (3400-4000 cal/g): this waste biomass with added value could be a promising biofuel. PMID- 29408060 TI - Utilization of centrate from urban wastewater plants for the production of Scenedesmus sp. in a raceway-simulating reactor. AB - This work investigates the production of the native microalgae strain Scenedesmus sp. in semi-continuous mode at lab scale in open raceway-simulating reactors and using centrate as the culture medium. The biomass productivity and nutrient removal capacity of Scenedesmus sp. at different dilution rates were investigated indoors as well as its tolerance to centrate as the culture medium at different concentrations. A biomass productivity of 7.80 g/m2 day was obtained at 200 MUE/m2 s, 5 cm culture depth, 0.30 1/day of dilution rate and 60% centrate while nitrogen and phosphorus removal rates were 1.50 g/m2 day and 0.15 g/m2 day, respectively. The produced biomass characterization under these conditions showed a lipid content of 12.60% d wt. along with a favorable fatty acids profile with 57.70% of total fatty acids composed of saturated and monounsaturated fatty acids. Subsequently, the effect of light intensity and culture depth on biomass productivity and nutrient uptake as well as the biochemical composition and fatty acids profile was studied using two irradiance levels (200 and 1000 MUE/m2 s) and four culture depths (5 cm, 10 cm, 15 cm and 20 cm). Under optimal conditions of 1000 MUE/m2 s, 60% centrate, 0.30 1/day dilution rate and 15 cm culture depth, a maximum biomass productivity of 22.20 g/m2 day was obtained. Nitrogen and phosphorus removal rates of 2.00 gN/m2 day and 0.40 gP/m2 day, respectively, were recorded. An amount of 11.70% d wt. of lipids was determined along with a suitable fatty acids profile for biofuel production. PMID- 29408062 TI - Biotechnology in the management and resource recovery from metal bearing solid wastes: Recent advances. AB - Solid metalliferous wastes (sludges, dusts, residues, slags, red mud and tailing wastes) originating from ferrous and non-ferrous metallurgical industries are a serious environmental threat, when waste management practices are not properly followed. Metalliferous wastes generated by metallurgical industries are promising resources for biotechnological extraction of metals. These wastes still contain significant amounts of valuable non-ferrous metals, sometimes precious metals and also rare earth elements. Elemental composition and mineralogy of the metallurgical wastes is dependent on the nature of mining site and composition of primary ores mined. Most of the metalliferous wastes are oxidized in nature and contain less/no reduced sulfidic minerals (which can be quite well processed by biohydrometallurgy). However, application of biohydrometallurgy is more challenging while extracting metals from metallurgical wastes that contain oxide minerals. In this review, origin, elemental composition and mineralogy of the metallurgical solid wastes are presented. Various bio-hydrometallurgical processes that can be considered for the extraction of non-ferrous metals from metal bearing solid wastes are reviewed. PMID- 29408061 TI - Developing robust arsenic awareness prediction models using machine learning algorithms. AB - Arsenic awareness plays a vital role in ensuring the sustainability of arsenic mitigation technologies. Thus far, however, few studies have dealt with the sustainability of such technologies and its associated socioeconomic dimensions. As a result, arsenic awareness prediction has not yet been fully conceptualized. Accordingly, this study evaluated arsenic awareness among arsenic-affected communities in rural India, using a structured questionnaire to record socioeconomic, demographic, and other sociobehavioral factors with an eye to assessing their association with and influence on arsenic awareness. First a logistic regression model was applied and its results compared with those produced by six state-of-the-art machine-learning algorithms (Support Vector Machine [SVM], Kernel-SVM, Decision Tree [DT], k-Nearest Neighbor [k-NN], Naive Bayes [NB], and Random Forests [RF]) as measured by their accuracy at predicting arsenic awareness. Most (63%) of the surveyed population was found to be arsenic aware. Significant arsenic awareness predictors were divided into three types: (1) socioeconomic factors: caste, education level, and occupation; (2) water and sanitation behavior factors: number of family members involved in water collection, distance traveled and time spent for water collection, places for defecation, and materials used for handwashing after defecation; and (3) social capital and trust factors: presence of anganwadi and people's trust in other community members, NGOs, and private agencies. Moreover, individuals' having higher social network positively contributed to arsenic awareness in the communities. Results indicated that both the SVM and the RF algorithms outperformed at overall prediction of arsenic awareness-a nonlinear classification problem. Lower-caste, less educated, and unemployed members of the population were found to be the most vulnerable, requiring immediate arsenic mitigation. To this end, local social institutions and NGOs could play a crucial role in arsenic awareness and outreach programs. Use of SVM or RF or a combination of the two, together with use of a larger sample size, could enhance the accuracy of arsenic awareness prediction. PMID- 29408063 TI - Heterogeneous photocatalysis using TiO2 modified with hydrotalcite and iron oxide under UV-visible irradiation for color and toxicity reduction in secondary textile mill effluent. AB - The objective of this study was to evaluate ADMI color removal from a biologically treated textile mill effluent by heterogeneous photocatalysis with UV-visible irradiation (UV-vis) using a novel catalyst composed of TiO2 supported on hydrotalcite and doped with iron oxide (HT/Fe/TiO2). Simulated biological treatment of solutions of the dyes (50 mg/L) used in the greatest amounts at the mill where the textile effluent was collected resulted in no color removal in reactive dye solutions and about 50% color removal in vat dye solutions, after 96 h, indicating that the secondary effluent still contained a large proportion of anionic reactive dyes. Photocatalytic treatments were carried out with TiO2 and HT/Fe/TiO2 of Fe:Ti molar ratios of 0.25, 0.5, 0.75 and 1, with varying catalyst doses (0-3 mg/L), initial pH values (4-10) and UV-vis times (0-6 h). The highest ADMI color removal with unmodified TiO2 was found at a dose of 2 g/L and pH 4, an impractical pH value for industrial application. The most efficient composite was HT/Fe/TiO2 1 at pH 10, also at a dose of 2 g/L, which provided more complete ADMI color removal, from 303 to 9 ADMI color units (96%), than unmodified TiO2, from 303 to 37 ADMI color units (88%), under the same conditions. Hydroxyl radicals were responsible for the color reduction, since when 2-propanol, an OH scavenger, was added color removal was very low. For this reason, the HT/Fe/TiO2 1 composite performed better at pH 10, because the higher concentration of hydroxide ions present at higher pH favored hydroxyl radical formation. COD reductions were relatively low and similar, approximately 20% for both catalysts after 6 h under UV-vis, because of the low initial COD (78 mg/L). Secondary effluent toxicity to Daphnia similis (EC50 = 70.7%) was reduced by photocatalysis with TiO2 (EC50 = 95.0%) and the HT/Fe/TiO2 1 composite (EC50 = 78.6%). HT/Fe/TiO2 1 was reused five times and still lowered secondary effluent ADMI color below local discharge limits. Benefits of the HT/Fe/TiO2 1 catalyst compared to TiO2 include its lower bandgap energy (2.34 eV vs 3.25 eV), higher ADMI color removal and its magnetic nature that facilitated its recovery and would reduce treatment costs. PMID- 29408064 TI - Effects of sea-level rise and freshwater management on long-term water levels and water quality in the Florida Coastal Everglades. AB - Since the 1880s, hydrological modification of the Greater Florida Everglades has reduced water levels and flows in Everglades National Park (ENP). The Comprehensive Everglades Restoration Program (CERP) began in 2000 to restore pre drainage flows and preserve the natural landscape of the Everglades. However, sea level rise (SLR) was not considered in the development of CERP. We used long-term data (2001-2016) from the Florida Coastal Everglades-Long Term Ecological Research Program to quantify and model the spatial dynamics of water levels, salinity, and nutrients in response to changes in climate, freshwater management and SLR in the Shark River Slough (SRS), ENP. Results indicate that fresh-to marine head difference (FMHD) was the single most important factor affecting marine-to-freshwater hydrologic connectivity and transport of salinity and phosphorous upstream from the Gulf of Mexico. Sea-level has increasingly exceeded ground surface elevation at the most downstream freshwater site in SRS, thereby reducing the FMHD. We showed a higher impact of SLR in the dry season when there was practically no freshwater inflow to raise FMHD. We also demonstrated effectiveness of inflow depends more on the monthly distribution than the total annual volume. Hence, the impact per unit volume of inflow is significantly higher in the dry season in preventing high salinity and marine-derived nutrient levels. We advocate that FMHD needs to be factored into water management decisions to reduce adverse and likely irreversible effects of SLR throughout the Everglades landscape. PMID- 29408065 TI - Closing the loop on human urine: Plant availability of zeolite-recovered nutrients in a peat-based substrate. AB - Recycling mineral nutrients from household wastewater is a central step in the development of a circular economy based society. The objective of this study was to evaluate plant availability of mineral elements and plant performance in a peat substrate containing nutrient-enriched zeolite (NEZ) obtained by nutrient recovery from human urine in a source separated wastewater system. Substrate content of potentially available mineral nutrients was determined by CaCl2/DTPA extraction during a 12 weeks incubation experiment for 20:80 (R20) and 30:70 (R30) volume % of NEZ:sphagnum peat, limed R20 (R20L), and 20:80 vol% of unloaded zeolite:sphagnum peat (Z20). Plant availability of mineral elements from R20, R20L, R30 and Z20 was compared with conventionally fertilised sphagnum peat (P100) for sunflower (Helianthus annuus L.) cv. 'Topolino' in a pot experiment. Recovery of nutrients in a potentially available form in the R20 substrate after 12 weeks was 3% (K), 23% (N, P), 34% (Mg) and 90% (S). Liming increased the recovery of mineral N to 39%, suggesting that nitrification was an important driver for the release of NH4+. For R20, estimated recovery of urine-derived N in sunflower shoots was 30-36%. Shoot biomass was similar in R20 and in conventionally fertilised peat (P100). However, P100 plants had more leaves and flowers+buds. Initial addition of ammonium phosphate or supplemental fertilisation with a complete nutrient solution increased flower+bud number in R20. For the NEZ-treatments, Cu and B shoot concentrations were in the low or marginal range while Zn and Mn were high or in excess. Shoot growth and nutrient uptake of sunflower were highly restricted in the unloaded zeolite control (Z20). We conclude that 20% NEZ in a peat substrate was effective as a macronutrient source for sunflower, producing similar biomass as in conventionally fertilised peat. However, micronutrient balance and early P supply may need to be adjusted for optimal plant performance. PMID- 29408066 TI - Seeding plants for long-term multiple ecosystem service goals. AB - The historical management of agroecological systems, such as California's rangelands, have received criticism for a singular focus on agricultural production goals, while society has shifting expectations to the supply of multiple ecosystem services from these working landscapes. The sustainability and the multiple benefits derived from these complex social-ecological systems is increasingly threatened by weed invasion, extreme disturbance, urban development, and the impacts of a rapidly changing and increasingly variable climate. California's grasslands, oak savannas, and oak woodlands are among the most invaded ecosystems in the world. Weed eradication efforts are rarely combined with seeding on these landscapes despite support for the inclusion of the practice in a weed management program. Depending on seed mix choice, cost and long-term uncertainty, especially for native seed, is an impediment to adoption by land managers. We investigated four seeding mixes (forage annual, native perennial, exotic perennial, and exotic-native perennial) to evaluate how these treatments resist reinvasion and support the delivery of simultaneous multiple ecosystem services (invasion resistance, native richness, nitrogen fixing plants, pollinator food sources, plant community diversity, forage quality, and productivity). We found the increase of exotic and native perennial cover will drive resistance to an invading weedy summer flowering forb Centaurea solstitialis but provides a mixed response to resisting invasive annual grasses. The resistance to invasion is coupled with little tradeoff in forage productivity and quality and gains in plant diversity and native cover. PMID- 29408067 TI - Multiwall carbon nanotube reinforced teflon fibrils for oil spill clean up and its effective recycling as textile dye sorbent. AB - Surface functionalized multiwall carbon nanotube (MWCNT) reinforced teflon fibrils (MWCNT@Teflon) were successfully tested as an - oil - absorbent that can be used as a potential oil recovery material at the time of oil spill accidents in water. We found that oleic acid functionalization of MWCNTs was important for their adhesion onto teflon fibrils and at the same time prevented the MWCNT leaching into oil/water interface. The fibrils had displayed superior mechanical and thermal stability and provided a new insight to oil spill clean-up applications with easy recovery of absorbed oil by simple squeezing. Recycling of exhausted MWCNT@Teflon fibrils after oil recovery applications was conducted by pyrolysis under inert atmosphere in presence of magnetic clay. The magnetic clay absorbed the pyrolysis products, resulting in a heterostructured magnetic clay carbon composite (MCC) which was found super paramagnetic and chemically stable in all pH. The MCC was found capable of adsorbing textile dye from water ultra fast with in a maximum contact time of 2 min and magnetically separable after adsorption experiments. PMID- 29408068 TI - Nutrient exports from watersheds with varying septic system densities in the North Carolina Piedmont. AB - Septic systems (SSs) have been shown to be a significant source of nitrogen and phosphorus to nutrient-sensitive coastal surface and groundwaters. However, few published studies have quantified the effects of SSs on nutrient inputs to water supply watersheds in the Piedmont region of the USA. This region consists of rolling hills at the surface underlain by clayey soils. There are nearly 1 million SSs in this region, which accounts for approximately 50% of all SSs in North Carolina. The goal of this study was to determine if significant differences in nutrient concentrations and exports exist between Piedmont watersheds with different densities of SSs. Water quality was assessed in watersheds with SSs (n = 11) and a sewer and a forested watershed, which were designated as controls. Stream flow and environmental readings were recorded and water samples were collected from the watersheds from January 2015-December 2016. Additional samples were collected from sand filter watersheds in April 2015-March 2016 to compare to septic and control watersheds. Samples were analyzed for total dissolved nitrogen (TDN) and orthophosphate (PO4-P). Results indicated that watersheds served by a high-density (HD) of SSs (4.9 kg-N yr-1 ha-1; 0.2 kg-P yr 1 ha-1) exported more than double the median masses of TDN and PO4-P, respectively, relative to low-density (1.0 kg-N yr-1 ha-1; <0.1 kg-P yr-1 ha-1) and control watersheds (1.4 kg-N yr-1 ha-1; <0.1 kg-P yr-1 ha-1) during baseflow. Isotopic analysis indicated that wastewater was the most likely source of nitrate N in HD watersheds. In all other watersheds, isotopic results suggested non wastewater sources as the dominant nitrate-N provider. These findings indicated that SS density was a significant factor in the delivery of septic-derived nutrients to these nutrient-sensitive, water supply watersheds of the North Carolina Piedmont. PMID- 29408069 TI - Effect of triclosan and its photolysis products on marine bacterium V. fischeri and freshwater alga R. subcapitata. AB - The use of antibacterial agents in consumer products may lead to adverse effects in waters receiving treated wastewater. Triclosan is one of the antibacterial agents used widely in the world and its high usage leads to relatively high concentrations in wastewater effluents. In this study, the probable effect of triclosan in receiving waters was assessed using different organisms. The EC50 values were 668 +/- 80 MUg/L and 7.8 +/- 0.1 MUg/L, for Vibrio fischeri and Raphidocelis subcapitata, respectively, indicating the higher sensitivity of the alga. The toxicity of triclosan upon exposure to UV light decreased for both species, as suggested by the increase in EC50 values (1300 +/- 50 MUg/L and 8.7 +/- 0.6 MUg/L for V. fischeri and R. subcapitata, respectively). The effect of photolysis on toxicity reduction was higher for V. fischeri and the EC50 values were similar for direct and indirect photolysis. LC-MS/MS analysis of samples with and without UV exposure suggested a decrease in triclosan concentration as well as formation of photolysis byproducts upon photolysis. PMID- 29408070 TI - Optimization of HNO3 leaching of copper from old AMD Athlon processors using response surface methodology. AB - The present study investigates the optimization of HNO3 leaching of Cu from old AMD Athlon processors under the effect of nitric acid concentration (%), temperature ( degrees C) and ultrasonic power (W). The optimization study is carried out using response surface methodology with central composite rotatable design (CCRD). The ANOVA study concludes that the second degree polynomial model is fitted well to the fifteen experimental runs based on p-value (0.003), R2 (0.97) and Adj-R2 (0.914). The study shows that the temperature is the most significant process variable to the leaching concentration of Cu followed by nitric acid concentration. However, ultrasound power shows no significant impact on the leaching concentration. The optimum conditions were found to be 20% nitric acid concentration, 48.89 degrees C temperature and 5.52 W ultrasound power for attaining maximum concentration of 97.916 mg/l for Cu leaching in solution. PMID- 29408072 TI - Zero-truncated panel Poisson mixture models: Estimating the impact on tourism benefits in Fukushima Prefecture. AB - This study proposes an estimation approach to panel count data, truncated at zero, in order to apply a contingent behavior travel cost method to revealed and stated preference data collected via a web-based survey. We develop zero truncated panel Poisson mixture models by focusing on respondents who visited a site. In addition, we introduce an inverse Gaussian distribution to unobserved individual heterogeneity as an alternative to a popular gamma distribution, making it possible to capture effectively the long tail typically observed in trip data. We apply the proposed method to estimate the impact on tourism benefits in Fukushima Prefecture as a result of the Fukushima Nuclear Power Plant No. 1 accident. PMID- 29408071 TI - Degradation of sodium isopropyl xanthate from aqueous solution using sonocatalytic process in the presence of chalcocite nanoparticles: Insights into the degradation mechanism and phyto-toxicity impacts. AB - In the present work, the sonocatalytic degradation of sodium isopropyl xanthate (SIPX) was investigated in the presence of Cu2S nanoparticles. Cu2S nanoparticles were produced by means of a high-energy planetary mechanical ball milling method within the processing times of 0.5, 1.5, 3 and 4.5 h. The physical and chemical characteristics of Cu2S particles were studied before and after ball milling process using various analytical techniques, including X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM) coupled Energy-dispersive X-ray spectroscopy (EDX), atomic absorption spectroscopy (AAS) and nanoparticles size distribution (NSD). The XRD pattern of the samples confirmed the presence of tetragonal and cubic crystalline phases of Cu2S. In addition, the results of SEM and NSD analysis showed that the increase in the ball milling time from 0.5 to 4.5 h notably decreased the size of nanoparticles to the range of 20-40 nm. Furthermore, AAS result showed that the concentration of Cu+ ions was much lower than that of the accepted value in the aqueous media (0.009 mg/L) after 60 min of the sonocatalysis. The study on the effects of the main key parameters showed that 93.99% of SIPX (10 mg/L) was removed during 60 min of the sonocatalytic process under the optimum conditions: pH of 7.3, Cu2S concentration of 1.5 g/L, and ultrasonic power of 150 W. The sonocatalytic degradation mechanism was thoroughly examined in the presence of different organic and inorganic scavenger compounds, including ethanol, EDTA, NaCl and Na2SO4. The obtained results confirmed OH and holes (h+) as the dominant oxidizing species in Cu2S catalyzed sonolysis. In order to get the benefits of the integrated sonocatalytic process, different rate enhancing compounds were introduced into the system. For the first time, the S2O82- and Cu2S catalyzed sonolysis (US/Cu2S/S2O82-) system was introduced as an efficient and novel sonocatalytic system for fast degradation of SIPX. Moreover, the phyto toxicological assessments proved the reduction in the toxicity of the sonocatalytic-treated SIPX solution by increase in the reaction time, from 20 to 60 min. PMID- 29408073 TI - Agronomic and economic evaluation of Vetiver grass (Vetiveria zizanioides L.) as means for phytoremediation of diesel polluted soils in Israel. AB - Soil pollution in Israel, due to diesel contamination, is a major concern, with gas stations, factories and refineries being the main polluters (>60%). Vetiver grass (Vetiveria zizanioides L.) is a perennial grass belonging to the Poaceae family, and is recognized world-wide for its potential as a plant with phytoremediation traits to contaminated soils. It is demonstrated here to decrease diesel contamination in field and court-yard trials. Chemical soil analysis indicated up to a 79% decrease (P < .05) in diesel pollution of contaminated soil planted with Vetiver; and at high soil contamination levels of 10 L/m2, a significant (P < .05) reduction of 96, 96 and 87% was recorded at soil depths of 0-20, 20-40 and 40-60 cm, respectively. Furthermore, in field plots contaminated with diesel and planted with Vetiver, weeds' biomass recovered to non-polluted levels following 8 to 9 months of Vetiver treatment. An economic evaluation conducted based on the cost-benefit analysis (CBA) principles, utilizing the Net Present Value (NPV) compared phytoremediation to other currently used decontamination procedures. The economic comparison showed that phytoremediation cleanup costs are lower and more beneficial to society at large, primarily from an ecosystem services perspective. Combining the results of the agronomic examination with the economic valuation, this research pointed out that phytoremediation with Vetiver has a non-negligible potential, making it a good solution for cleansing diesel from soils on a state-wide scale in Israel and worthy of further research and development. PMID- 29408075 TI - A tree from waste: Decontaminated dredged sediments for growing forest tree seedlings. AB - The sediments dredged from a waterway and decontaminated through a phytoremediation process have been used as substrates alternatively to the traditional forest nursery substrate for pot productions of holm oak (Quercus ilex L.) planting stocks. The substrates, made by mixing decontaminated sediments to agricultural soil at different degrees, were tested in order to evaluate their suitability as growth substrates. The experiment was carried out at the nursery of the Department of Agricultural, Food and Forestry Systems of the University of Florence (Italy). The experimental design consisted of four randomized blocks with six pots as replicates for each of the following treatments: 100% sediments, 66% sediments, 33% sediments, 100% agronomic soil and 100% traditional peat based substrate. In each pot, one holm oak acorn was seeded. Germination and both physiological and morphological traits of the seedlings were analysed during and at the end of the first growing season. Holm oak grown in phytoremediated sediments at higher concentrations showed germination levels comparable to those in the traditional substrate, and survival capacity (especially in 66% sediments) slightly higher than in 100% soil. Physiological performance of seedlings resembled that on the traditional substrate which required the addition of fertilizer, at least for the first growing season. Seedlings grown in mixed substrates with higher sediment concentrations occasionally showed better photosynthetic capacity with improved connectivity between the units of the photosystem II. At the end of the first growing season, height as well as the number of growth flushes of the seedlings grown in sole sediment or soil-sediment substrates were similar to what generally is observed for forest nursery stock of Quercus spp.. Regarding the root-system articulation and growth in depth, results in the mixed substrates were comparable to those for seedlings grown in the traditional forest nursery media, and higher than seedlings grown in 100% agronomic soil. According to our results, the reclamation of dredged sediments can provide appropriate nursery substrate for germination beds for forestry species. PMID- 29408074 TI - Biochar feedstock and pyrolysis temperature effects on leachate: DOC characteristics and nitrate losses from a Brazilian Cerrado Arenosol mixed with agricultural waste biochars. AB - Dissolved organic carbon (DOC) leached from Brazilian Cerrado Arenosols can lead to carbon (C) losses and lower soil fertility, while excessive nutrient, e.g. nitrate (NO3-), leaching can potentially cause water contamination. As biochar has been shown to stabilize C and retain soil nutrients, a greenhouse experiment was conducted to test different biochars' contributions to DOC and NO3- leaching from a sandy soil. Biochars were made from four local agricultural waste feedstocks (cotton residue, swine manure, eucalyptus sawmill residue, sugarcane filtercake) pyrolysed at 400, 500 and 600 degrees C. Biochar was mixed with soil at 5% weight in pots and maize seeds planted. Leachate was collected weekly for six weeks and analyzed for DOC and NO3- concentrations, while fluorescence spectroscopy with parallel factor analysis (PARAFAC) was used to interpret DOC characteristics. Cotton and swine manure biochar treatments had higher DOC and NO3- losses than eucalyptus biochar, filtercake biochar, and control treatments. Cotton and swine manure biochar treatments at high temperatures lost mostly terrestrial, humified DOC, while swine manure, filtercake, and eucalyptus biochars at low temperatures lost mostly labile, microbially-derived DOC. Through the practical use of fluorescence spectroscopy, our study identified filtercake and eucalyptus biochars as most promising for retaining DOC and NO3- in a Cerrado Arenosol, potentially reducing stable C and nutrient losses. PMID- 29408076 TI - Elimination of micropollutants by activated carbon produced from fibers taken from wastewater screenings using hydrothermal carbonization. AB - Activated Carbon (AC) can be used to reduce organic micropollutants (OMPs) in wastewater treatment plants (WWTPs). While producing ACs conventionally still damages the environment, this can be reduced by using renewable raw material from waste streams und producing AC locally. In this study, fibers (toilet paper) were separated out of wastewater by screening WWTP influents in full scale and then used as a no-cost, carbon-rich and heavy metal-poor raw material to produce ACs. Pretreatment was hydrothermal carbonization (HTC). Thereafter, they were activated using KOH to generate activated carbons (HTC-ACs). Their functional groups were characterized using FT-IR, and the alteration of their chemical composition was traced by elementary analysis. Adsorption tests were performed with nitrogen (BET surface) and methylene blue as standard tests. The adsorption capacity was tested with WWTP effluent and the removal of UVA254 as a surrogate for OMP removal was measured. After HTC and activation 13-16% of the fibers dry mass was obtained as HTC-ACs. Higher dehydration and formation of aromatic structures on the HTC-ACs were detected with FT-IR as HTC and activation temperature increased. BET surface and methylene blue adsorption of some HTC-ACs was higher than the Reference AC. Nevertheless, their ability to reduce OMPs is still lower than the Reference AC due to the different nature of their functional groups and their microporous structure that is not fully accessible for OMPs in real wastewater. Further research has to be carried out to adjust the production process so as to obtain mesoporous HTC-ACs tailored to reduce OMP concentrations and to close the carbon loop within WWTPs. PMID- 29408077 TI - Bioleaching of toxic metals from sewage sludge by co-inoculation of Acidithiobacillus and the biosurfactant-producing yeast Meyerozyma guilliermondii. AB - The aim of this research is to evaluate the influence of co-inoculation of Acidithiobacillus bacteria and the biosurfactant-producing yeast Meyerozyma guilliermondii in bioleaching processes. The tests were carried out using sewage sludge from UASB reactors co-inoculated with cultures of Acidithiobacillus and M. guilliermondii to promote the solubilization of Cd, Cr, Cu, Ni, Pb and Zn which were determined by Inductively Coupled Plasma - Optical Emission Spectrometry (ICP- OES). After 10 days of incubation, 76.5% of Zn, 59.8% of Ni, 22.0% of Cu, 9.8% of Cd, 9.8% Cr and 7.1% of Pb were solubilized. It was observed that the presence of yeast accelerated the time required for Cd solubilization from 240 to 96 h and there was a 20.1% reduction in nitrogen concentration and 7.6% for phosphorus in this assay. After the bioleaching and co-inoculation assays, the product obtained reached the maximum permissible concentrations for soil disposal for all the analyzed metals in the State of Sao Paulo, United States and also European Community standards. PMID- 29408078 TI - Enzyme activity and microbial biomass availability in artificial soils on rock cut slopes restored with outside soil spray seeding (OSSS): Influence of topography and season. AB - Large-scale railway construction has resulted in large areas of bare-cut-slope, and outside soil spray seeding (OSSS), a frequently used technique, has been adopted for slope restoration for many years. However, compared with natural slope soils, the quality of artificial soils on rock-cut slopes is low. Enzyme activity and microbial biomass are the main indices used for estimating soil quality; thus, our objective was to explore the influence of slope position, slope aspect, and season on two important factors that positively influence the plant growth capability in artificial soil. Further, we suggest modifications of the proportions of OSSS ingredients, not only to manage cut slopes more economically but also to provide a new framework for managing desertification. We chose a bare-cut-slope that had been restored five years ago near the Suiyu Railway (Chongqing-Suining), in Sichuan Province, China, as our study plot. Soil samples were collected at a depth of 10 cm. We conclude that natural slopes exhibited higher urease, sucrase, and catalase activity and higher microbial biomass than cut slopes. The protease and polyphenoloxidase enzyme activities and the microbial biomass were higher on the cut slopes in the months of October and January, with the highest protease activity in October, and the highest polyphenoloxidase activity in January. The enzyme activity and microbial biomass were always lower on lower slopes, with the exception of polyphenoloxidase activity. The slope aspect influenced soil enzyme activity, resulting in higher activity on north-facing slopes than on south-facing slopes. These results provided scientific support for artificial revegetation methods in an ecological context. PMID- 29408079 TI - Quantitative evaluation of legacy phosphorus and its spatial distribution. AB - A phosphorus resource crisis threatens the security of global crop production, especially in developing countries like China and Brazil. Legacy phosphorus (legacy-P), which is left behind in agricultural soil by over-fertilization, can help address this issue as a new resource in the soil phosphorus pool. However, issues involved with calculating and defining the spatial distribution of legacy P hinder its future utilization. To resolve these issues, this study applied remote sensing and ecohydrological modeling to precisely quantify legacy-P and define its spatial distribution in China's Sanjiang Plain from 2000 to 2014. The total legacy-P in the study area was calculated as 579,090 t with an annual average of 38,600 t; this comprises 51.83% of the phosphorus fertilizer applied annually. From 2000 to 2014, the annual amount of legacy-P increased by more than 3.42-fold, equivalent to a 2460-ton increase each year. The spatial distribution of legacy-P showed heterogeneity and agglomeration in this area, with peaks in cultivated land experiencing long-term agricultural development. This study supplies a new approach to finding legacy-P in soil as a precondition for future utilization. Once its spatial distribution is known, legacy-P can be better utilized in agriculture to help alleviate the phosphorus resource crisis. PMID- 29408080 TI - Establishment of an eco-compensation fund based on eco-services consumption. AB - Eco-compensation is a type of institutional arrangement that uses economic measures to adjust the relationships among stakeholders in order to conserve and/or sustainably use ecosystem services. The externality of the value of ecosystem services is one of the theoretical bases for eco-compensation. Different types of ecosystem services are consumed by people from different regions. Some are consumed by people living where the services originate, while some are carried by rivers, wind, vehicles or other natural or manmade means to other areas. Thus, the flow and consumption of ecosystem services should be seen as the basis for establishing eco-compensation funds. This paper uses satellite images of the Zhang-Cheng area near Beijing in 2013 to discuss how to establish an eco-compensation fund for stakeholders in this area. Firstly, six important types of ecosystem services in the Zhang-Cheng area were identified based on ecological function zoning, and the value of these ecosystem services was calculated based on ecological pricing methods. Secondly, the field intensity model from physics was used to analyze where Zhang-Cheng area ecosystem services flowed and calculate how much of these services were used by other areas. Thirdly, based on this analysis and calculation, the paper proposes the rates that different stakeholders should invest in the eco-compensation fund, based on their consumption of eco-services. PMID- 29408081 TI - Elemental sulfur-based autotrophic denitrification and denitritation: microbially catalyzed sulfur hydrolysis and nitrogen conversions. AB - The hydrolysis of elemental sulfur (S0) coupled to S0-based denitrification and denitritation was investigated in batch bioassays by microbiological and modeling approaches. In the denitrification experiments, the highest obtained NO3--N removal rate was 20.9 mg/l.d. In the experiments with the biomass enriched on NO2 , a NO2--N removal rate of 10.7 mg/l.d was achieved even at a NO2--N concentration as high as 240 mg/l. The Helicobacteraceae family was only observed in the biofilm attached onto the chemically-synthesized S0 particles with a relative abundance up to 37.1%, suggesting it was the hydrolytic biomass capable of S0 solubilization in the novel surface-based model. S0-driven denitrification was modeled as a two-step process in order to explicitly account for the sequential reduction of NO3- to NO2- and then to N2 by denitrifying bacteria. PMID- 29408082 TI - Economics of social trade-off: Balancing wastewater treatment cost and ecosystem damage. AB - We have developed a social optimization model that integrates the financial and ecological costs associated with wastewater treatment and ecosystem damage. The social optimal abatement level of water pollution is determined by finding the trade-off between the cost of pollution control and its resulting ecosystem damage. The model is applied to data from the Lake Taihu region in China to demonstrate this trade-off. A wastewater treatment cost function is estimated with a sizable sample from China, and an ecological damage cost function is estimated following an ecosystem service valuation framework. Results show that the wastewater treatment cost function has economies of scale in facility capacity, and diseconomies in pollutant removal efficiency. Results also show that a low value of the ecosystem service will lead to serious ecological damage. One important policy implication is that the assimilative capacity of the lake should be enhanced by forbidding over extraction of water from the lake. It is also suggested that more work should be done to improve the accuracy of the economic valuation. PMID- 29408083 TI - Preparation of magnetite nanoparticles by high-energy planetary ball mill and its application for ciprofloxacin degradation through heterogeneous Fenton process. AB - In this study, the heterogeneous Fenton oxidation of ciprofloxacin (CIP) in an aqueous solution was examined over the nano-sized magnetite (Fe3O4) as a catalyst supplied through high-energy planetary ball milling process. To characterize the magnetite samples after and before ball milling operation, the X-ray diffraction (XRD), High-resolution scanning electron microscopy (HR-SEM), energy-dispersive X ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET) and Fourier transform infrared spectroscopy (FTIR) analysis were applied. The catalytic properties of the magnetite were considerably improved because of the enhancement in its physical properties, resulted from milling process. The findings also indicated that 6 h ball-milled magnetite demonstrated better properties for elimination of CIP of about 89% following 120 min reaction at optimal conditions of H2O2 12 mM, Fe3O4 1.75 g L-1, CIP 10 mg L-1 and pH 3.0. The effects of various operational parameters, including the initial pH of the solution, H2O2 initial concentration, catalyst dosage, milling time and CIP initial concentration was investigated. Application of organic and inorganic scavengers considerably decreased the CIP removal efficiency. Correspondingly, with respect to the leached iron values at pH 3, it was concluded that CIP elimination was mainly occurred through heterogeneous Fenton procedure. This process included the adsorption and oxidation phases in which the hydroxyl radicals (OH) played a significant role. GC-MS analysis was used for recording of the generated intermediates of the CIP removal in the course of heterogeneous Fenton process. PMID- 29408084 TI - Preparation of activated petroleum coke for removal of naphthenic acids model compounds: Box-Behnken design optimization of KOH activation process. AB - This study employed Box-Behnken design and response surface methodology to optimize activation parameters for the production of activated petroleum coke (APC) adsorbent from petroleum coke (PC) to achieve highest adsorption capacity for three model naphthenic acids. Activated petroleum coke (APC) adsorbent with a BET surface area of 1726 m2/g and total pore volume of 0.85 cc/g was produced at the optimum activation conditions (KOH/coke mass ratio) of 3.0, activation temperature 790 degrees C, and activation time 3.47 h). Effects of the activation parameters on the adsorption pefromances (adsortion capaciy and kinetics) were investigated. With the APC obtained at the optimum activation condition, the maximum adsorption capacity of 451, 362, and 320 (mg/g) was achieved for 2-naphthoic acid, diphenylacetic acid and cyclohexanepentanoic acid (CP), respectively. Although, generally APC adsorbents with a higher specific surface area and pore volume provide better adsorption capacity, the textural properties (surface areas and pore volume) are not the only parameters determining the APC adsorbents' adsorption capacity. Other parameters such as surface functionalities play effective roles on the adsorption capacity of the produced APC adsorbents for NAs. The KOH activation process, in particular the acid washing step, distinctly reduced the sulfur and metals contents in the raw PC, decreasing the leaching potential of metals from APC adsorbents during adsorption. PMID- 29408085 TI - Synthesis of mesoporous bismuth-impregnated aluminum oxide for arsenic removal: Adsorption mechanism study and application to a lab-scale column. AB - High mobility and toxicity of arsenic [As (III)] limit its removal from an aquatic environment and pose a threat to human health. In this work, batch adsorption experiments were conducted to investigate the adsorption capacity of bismuth-impregnated aluminum oxide (BiAl). Continuous application of As (III) removal was achieved via a lab-scale column reactor. Bismuth impregnation decreased the specific surface area of aluminum oxide and affected its pore size distribution. However, because of its abundant and well-proportioned mesoporous character, it also enhanced its adsorption capacity through the surface complexation of As (III). Batch adsorption experiments demonstrated a suitable Freundlich model and a fitted pseudo-second-kinetic model for As (III) adsorption. The main mechanism was chemisorption with both bismuth and aluminum atoms; however, physisorption also contributed to arsenic adsorption at the initial stage of the reaction. The Adams-Bohart model better described the breakthrough curves than the Thomas model. BiAl exhibited efficient As (III) adsorption over a wide pH range and could be applied to As (III) removal from wastewater. A high As (III) removal efficiency (91.6%) was obtained at an initial As (III) concentration of 5 mg L-1 at a flow rate of 1 mL min-1. This study indicates the potential for the practical application of BiAl in As (III) removal. PMID- 29408086 TI - Catalytic ozonation for the treatment of synthetic and industrial effluents - Application of mesoporous materials: A review. PMID- 29408087 TI - Forest cover correlates with good biological water quality. Insights from a regional study (Wallonia, Belgium). AB - Forested catchments are generally assumed to provide higher quality water in opposition to agricultural and urban catchments. However, this should be tested in various ecological contexts and through the study of multiple variables describing water quality. Indeed, interactions between ecological variables, multiple land use and land cover (LULC) types, and water quality variables render the relationship between forest cover and water quality highly complex. Furthermore, the question of the scale at which land use within stream catchments most influences stream water quality and ecosystem health remains only partially answered. This paper quantifies, at the regional scale and across five natural ecoregions of Wallonia (Belgium), the forest cover effect on biological water quality indices (based on diatoms and macroinvertebrates) at the riparian and catchment scales. Main results show that forest cover - considered alone - explains around one third of the biological water quality at the regional scale and from 15 to 70% depending on the ecoregion studied. Forest cover is systematically positively correlated with higher biological water quality. When removing spatial, local morphological variations, or population density effect, forest cover still accounts for over 10% of the total biological water quality variation. Partitioning variance shows that physico-chemical water quality is one of the main drivers of biological water quality and that anthropogenic pressures often explain an important part of it (shared or not with forest cover). The proportion of forest cover in each catchment at the regional scale and across all ecoregions but the Loam region is more positively correlated with high water quality than when considering the proportion of forest cover in the riparian zones only. This suggests that catchment-wide impacts and a fortiori catchment wide protection measures are the main drivers of river ecological water quality. However, distinctive results from the agricultural and highly human impacted Loam region show that riparian forests are positively linked to water quality and should therefore be preserved. PMID- 29408088 TI - Obsessive-compulsive symptoms in adults with Lyme disease. AB - OBJECTIVE: This study examined the phenomenology and clinical characteristics of obsessive compulsive symptoms (OCS) in adults diagnosed with Lyme disease. METHOD: Participants were 147 adults aged 18-82 years (M = 43.81, SD = 12.98) who reported having been diagnosed with Lyme disease. Participants were recruited from online support groups for individuals with Lyme disease, and completed an online questionnaire about their experience of OCS, Lyme disease characteristics, and the temporal relationship between these symptoms. RESULTS: OCS were common, with 84% endorsing clinically significant symptoms, 26% of which endorsed symptoms onset during the six months following their Lyme disease diagnosis and another 51% believed their symptoms were temporally related. Despite the common occurrence of OCS, only 44% of these participants self-identified these symptoms as problematic. Greater frequency of Lyme disease symptoms and disease-related impairment was related to greater OCS. In the majority of cases, symptom onset was gradual, and responded well to psychological and pharmacological treatment. Around half of participants (51%) reported at least some improvement in OCS following antibiotic treatment. CONCLUSIONS: This study highlights the common co occurrence of OCS in patients with Lyme disease. It is unclear whether OCS are due to the direct physiological effects of Lyme disease or associated immunologic response, a psychological response to illness, a functional somatic syndrome, or some combination of these. PMID- 29408089 TI - Anti-allodynic effects of N-demethylsinomenine, an active metabolite of sinomenine, in a mouse model of postoperative pain. AB - Sinomenine, a major bioactive ingredient isolated from traditional Chinese medicine Sinomenium acutum, has been reported to have analgesic effects in various pain animal models. N-demethylsinomenine, the N-demethylated product of sinomenine, has been identified to be the major metabolite of sinomenine and is also a natural component extracted from Sinomenium acutum. This study examined the anti-allodynic effects of N-demethylsinomenine in a mouse model of postoperative pain. A significant and sustained mechanical allodynia that lasted for 4 days was induced by making a surgical incision on the right hind paw in mice. Acute treatment with N-demethylsinomenine (10-40 mg/kg, s.c.) relieved the mechanical allodynia in a dose-dependent manner. Although there was no difference in maximal analgesic effect between N-demethylsinomenine (40 mg/kg, s.c.) and sinomenine (40 mg/kg, s.c.), the onset of action of N-demethylsinomenine was quicker than sinomenine. Repeated treatment with N-demethylsinomenine (10-40 mg/kg/day, s.c.) also dose-dependently exerted sustained antinociception against postoperative allodynia and did not produce analgesic tolerance and carry-over effect. The anti-allodynia induced by N-demethylsinomenine (40 mg/kg, s.c.) was attenuated by bicuculline, a selective gamma-aminobutyric acid type A (GABAA) receptor antagonist. In addition, the doses of N-demethylsinomenine used here did not alter the locomotor activity in mice. Our findings demonstrated that N demethylsinomenine exerts behaviorally-specific anti-allodynia against postoperative allodynia mediated through the GABAA receptors, suggesting it may be a useful novel pharmacotherapy for the control of postoperative pain. PMID- 29408090 TI - Effects of ralfinamide in models of nerve injury and chemotherapy-induced neuropathic pain. AB - Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of ralfinamide on cardiovascular function and locomotor activity. Oral ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to ralfinamide. PMID- 29408091 TI - Aspirin induces Beclin-1-dependent autophagy of human hepatocellular carcinoma cell. AB - Aspirin not only reduces the incidence of hepatocellular carcinoma (HCC) but also plays a synergistic role with chemotherapy for HCC treatment. However, the underlying mechanisms remain incompletely elucidated. Given that autophagy triggers cancer cell death, the present study examined the autophagic effect of aspirin on HCC cells. Results showed that aspirin increased LC3II/LC3I ratio, decreased p62 expression, and enhanced autophagic flux (autophagosome and autolysosome puncta) in Hep3B, HepG2, or SMMC-7721 cells, reflecting the autophagy of HCC cells. The autophagic effects of aspirin depended on Beclin-1 expression. Aspirin disrupted the interaction between Bcl-2 and Beclin-1. In addition to activating the AMP-activated protein kinase, c-Jun N-terminal kinase, and Glycogen synthase kinase-3 pathways, aspirin inhibited the mammalian-target of rapamycin-S6K1/4E-BP1 signaling. Aspirin induced autophagy of HCC cell. This study contributes to understanding the chemoprotective and inhibitory effects of aspirin on HCC development. PMID- 29408092 TI - Topical application of Hydroxysafflor Yellow A accelerates the wound healing in streptozotocin induced T1DM rats. AB - To investigate the effects of Hydroxysafflor Yellow A (HSYA), which is derived from safflower, on the proliferation, migration and angiogenesis of cells in vitro and its potential efficacy in vivo when topically applied to a diabetic wound. Human umbilical vein endothelial cells (HUVECs) and mouse macrophage cells (RAW264.7) were used to evaluate angiogenesis and anti-inflammatory activities, respectively. The influence of HSYA on the wound scratch assay was investigated in keratinocytes. A splinted excisional wound model in rats with TIDM induced by streptozotocin was used to assess the effects of wound healing. Collagen disposition and secretion of vascular growth factors (VEGF) as well as transforming growth factor-beta1 (TGF-beta1) were evaluated by an ELISA assay and histological staining. The in vitro results showed that HSYA could significantly enhance both the neovascularization of HUVECs and the migration of keratinocytes. It showed the significant inhibitory effect on nitric oxide production, indicating the anti-inflammatory activity of HSYA. In vivo, the topical application of HSYA significantly enhanced the wound closure rate, and the time to complete wound closure was 17 days, whereas 30 days were needed with PBS treatment. Further, treatment with HSYA exhibited significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis according to Masson's trichrome staining evaluation, VEGE and TGF-beta1 ELISA measurement. In conclusion, HSYA application could be considered a promising therapeutic strategy for treating chronic non-healing diabetic foot ulcers. PMID- 29408094 TI - Learning to cope with anxiety: Long-term links from adolescence to adult career satisfaction. AB - This study examined the long-term effect of anxiety on career satisfaction for young adults in the United States. The abilities to positively cope with stress and function competently as an adult were examined as potential moderators of this link, and adolescent developmental precursors of these abilities were also investigated. Analyses revealed a negative association between anxiety at age 21 and career satisfaction at age 27. However, this association was ameliorated for youth with better coping skills and functional competence at age 24. Autonomy and relatedness behaviors with best friends and mothers were examined as potential predictors of these moderators, with positive autonomy and relatedness from friends at age 13 emerging as the sole predictor of these skills. Results suggest that although anxiety may inhibit career satisfaction for many youth, positive coping and adult functional competence skills may allow anxious individuals to achieve career satisfaction. Moreover, these skills may be promoted through peer relationships in early adolescence. PMID- 29408093 TI - Analysis of the pharmacological properties of JWH-122 isomers and THJ-2201, RCS-4 and AB-CHMINACA in HEK293T cells and hippocampal neurons. AB - Synthetic cannabinoids are marketed as legal alternatives to Delta9-THC, and are a growing worldwide concern as these drugs are associated with severe adverse effects. Unfortunately, insufficient information regarding the physiological and pharmacological effects of emerging synthetic cannabinoids (ESCs) makes their regulation by government authorities difficult. One strategy used to evade regulation is to distribute isomers of regulated synthetic cannabinoids. This study characterized the pharmacological properties of a panel of ESCs in comparison to Delta9-THC, as well as six JWH-122 isomers relative to its parent compound (JWH-122-4). Two cell-based assays were used to determine the potency and efficacy of ESCs and a panel of reference cannabinoids. HEK293T cells were transfected with human cannabinoid receptor 1 (CB1) and pGloSensor-22F, and the inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live cells. All ESCs examined were classified as agonists, with the following rank order of potency: Win 55,212-2 > CP 55,940 > JWH-122-4 > Delta9-THC ~ RCS-4 ~ THJ-2201 > JWH-122-5 > JWH-122-7 > JWH-122-2 ~ AB-CHMINACA > JWH-122-8 > JWH-122-6 > JWH-122-3. Evaluation of ESC-stimulated Ca2+ transients in cultured rat primary hippocampal neurons confirmed the efficacy of four of the most potent ESCs (JWH-122-4, JWH-122-5, JWH-122-7 and AB-CHMINACA). This work helps regulatory agencies make informed decisions concerning these poorly characterized recreational drugs. PMID- 29408095 TI - Promoting or suppressing resilience to mental health outcomes in at risk young people: The role of parental and peer attachment and school connectedness. AB - Adolescent attachment relationships formed with parents are salient predictors of mental health. Few studies, however, have demonstrated whether peer attachment or school connectedness can predict resilience to mental health difficulties when a young person is at risk due to poor parental attachment. Ninety adolescents (44 females and 46 males) living in economically disadvantaged areas and attending informal schooling projects in and around Guatemala City participated. Participants completed self-report measures of parental and peer attachment, school connectedness and mental health. Resilience to mental health difficulties was predicted by more secure school connectedness but lower levels of secure peer attachment. School connectedness may provide a role in promoting resilience for mental health for adolescents living in risk, whereas the potential negative influence that secure attachments to peers exerts, in context of poor parental attachment, needs to be explored further. PMID- 29408096 TI - School engagement and intentional self-regulation: A reciprocal relation in adolescence. AB - Students' gradual disconnection from school in adolescence, as reflected in decreased school engagement, has been demonstrated in several cultures and is of great concern to educators. At the same time, intentional self-regulation (ISR) has been shown to be a precursor, mediator, and outcome of school engagement. However, the relation between school engagement and ISR during adolescence is poorly understood. In this research, we explored the reciprocal relation between school engagement and ISR during adolescence. Based on a sample of 561 adolescents in Iceland (46% girls; Mage at Wave 1 = 14.3 years; SD = 0.3) and four waves of data collected during Grades 9 and 10, the results demonstrated a reciprocal relation between school engagement and ISR after controlling for several covariates (e.g., gender and academic achievement). The results suggest that school engagement and ISR are highly related, yet distinct concepts, which mutually reinforce each other during adolescence. PMID- 29408097 TI - The role of identity and psychosomatic symptoms as mediating the relationship between discrimination and risk behaviors among first and second generation immigrant adolescents. AB - The study examines psychosomatic symptoms, and host and heritage identities as mediators of the relationship between discrimination and aggressive behavior and substance use. Israeli data from the 2013-14 Health Behaviors of School-aged Children study included a representative sample of 1503 first- and second generation immigrant adolescents aged 11-17 years (45.2% male) from the Former Soviet Union and Ethiopia in Israel. Structural equation modeling, controlling for age, gender, family affluence and immigrant generation, showed different pathways for the two groups. For FSU-heritage adolescents, the relationship between discrimination and aggressive behavior and substance use was partially mediated by psychosomatic symptoms. Lower host and heritage identities also predicted psychosomatic symptoms. For Ethiopian-heritage adolescents, the relationship between discrimination and outcomes was fully mediated by psychosomatic symptoms and a weaker host identity. Results support an externalizing model, whereby discrimination leads to a weaker host identity and increased psychosomatic symptoms, associated with substance use and aggressive behavior. PMID- 29408098 TI - Parental documentation status and academic attitudes and expectations among early adolescent latinos. AB - Many Latino youth are U.S. citizens but live with parents whose immigration status is unauthorized. The association between parental documentation status and early adolescent academic attitudes and expectations is unclear. Using a general population sample of urban 7th grade students who self-identified as Latino in the South Central U.S. (n = 514), we examine the associations between parental documentation status and youth attitudes about the importance of graduating high school and college and expectations of the likelihood of completing high school and attending college. Findings suggest that parent documentation status is not associated with attitudes toward the importance of high school and college among Latino early adolescents, but it is significantly associated with perceptions of the likelihood of achievement. Thus, parent immigration status may be an educational barrier that needs to be addressed early for Latino youth, as efforts in high school may be too late for some students. PMID- 29408100 TI - Negative emotions and behaviour: The role of regulatory emotional self-efficacy. AB - The objective of this study is to test a longitudinal model that analyses the direct effect of negative emotions (anger, depression and anxiety, wave 1) on prosocial and aggressive behaviour (wave 2) in adolescents. And the indirect effect of negative emotions (wave 1) on prosocial and aggressive behaviour (wave 2) through regulatory emotional self-efficacy. Data was obtained from 417 adolescents in a two-wave longitudinal study (225 girls, M age = 14.70 years) from schools located in Valencia, Spain. SEM was employed to explore longitudinal models. The results showed that anger had a direct relationship with prosocial behaviour and aggression, measured two years later. However, the depression and anxiety states did not predict prosociality and aggressiveness. The mediation role of regulatory emotional self-efficacy between negative emotion and behaviours was only partially confirmed. Finally, only the perception of self efficacy in expressing positive affect is related to prosociality and aggressiveness. PMID- 29408099 TI - Individual assets and problem behaviors in at-risk adolescents: A longitudinal cross-lagged analysis. AB - Autoregressive cross-lagged structural equation modeling was conducted to examine longitudinal relationships between individual assets (social competence, positive values and identity) and problem behaviors in 373 adolescents (174 boys, 199 girls) who participated in a prospective study on the effects of prenatal cocaine exposure from birth. More behavioral problems at age 12 were related to fewer individual assets at age 15, while greater individual assets were related to more behavioral problems, with a non-significant yet nuanced (p = .076) gender difference. More problem behaviors were associated with decreased individual assets in girls, yet greater individual assets were associated with more problem behaviors in boys. Efforts to promote individual assets may not lower the risk of engaging in problem behaviors especially among boys. Continued studies into adulthood will uncover how individual assets and problem behaviors in childhood and adolescence may affect social and vocational adjustment in this high risk population. PMID- 29408101 TI - Tin sulphide nanoflowers anchored on three-dimensional porous graphene networks as high-performance anode for sodium-ion batteries. AB - The SnS2 nanoflowers anchored on three dimensional porous graphene were easily constructed with nickel foam (NF) as supported backbone through the dip-coating method followed by one-step controllable hydrothermal growth and mild reduction. The interconnected SnS2 nanoflowers with cross-linking nanosheets and rich pores assembled to form one layer of continuous network structure, which tightly adhered on the surface of graphene. The porous graphene supported by NF built a conductively integral highway that is preferable for the charge transfer kinetics, while the hierarchical pores from the SnS2 nanoflowers and NF are particularly beneficial for mitigating the volume expansion and promoting electrolyte penetration. The as-constructed Ni foam/reduced graphene oxide/SnS2 (NF/RGO/SnS2) composite exhibited dramatically enhanced reversible capacity, remarkable rate capability, and long-term cycling stabilities without the use of any binders and conductive additives. Especially, NF/RGO/SnS2 composite remained the specific capacity as high as 561.9 mA h g-1 at the current densities of 1000 mA g-1 after continuous tests for 160 cycles, which is much higher than conventional SnS2/RGO composite. With the advantages of unique architecture and excellent sodium storage performances, the NF/RGO/SnS2 composite shows promising application potential in the sodium ion batteries. PMID- 29408102 TI - Effect of graphitic carbon modification on the catalytic performance of Fe@SiO2 GC catalysts for forming lower olefins via Fischer-Tropsch synthesis. AB - Mesoporous silica-encapsulated iron materials contribute to the suppression of self-aggregation and thereby enhances the Fischer-Tropsch synthesis activity. However, constructing Fe-based supported catalysts with high activity and selectivity in the Fischer-Tropsch synthesis to lower olefins (FTO) by a conventional mesoporous silica support has been proven challenging due to its low hydrothermal stability and low reducibility. Herein, we developed a core-shell Fe@SiO2-GC structure with an optimized interface of the catalyst by introducing graphitic carbon (GC) that weakened the Fe-SiO2 interaction. Transmission electron microscopy and nitrogen adsorption-desorption characterization proved GC modified catalysts had well-defined core-shell structures. The Fe@SiO2-GC-2 containing the optimal GC content had the largest surface area and pore volume, and outperformed Fe2O3@SiO2 in terms of CO conversion (60.1%) and C2-C4 olefin selectivity (40.7%) within 100 h. The significant improvement of FTO performance was attributed to the rigid porous framework of GC, which allowed free access of syngas and inhibited mesoporous channel collapse during FTO, so the catalytic activity and stability were improved by the synergism between higher Fe dispersion and reducibility. Moreover, the narrow well-defined mesoporous channel also exerted a modest spatial restriction effect, which inhibited the formation of long-chain hydrocarbon and tailored the product distribution toward lower distillate, thus improving the selectivity toward C2-C4. PMID- 29408103 TI - High-performance silver nanoparticles coupled with monolayer hydrated tungsten oxide nanosheets: The structural effects in photocatalytic oxidation of cyclohexane. AB - The photocatalytic properties of silver nanoparticles (Ag NPs) coupled with tungsten oxide (WO3) nanocrystals are investigated to understand structural effects of the WO3 nanocrystals in selective oxidation of cyclohexane (CyH). The photocatalytic activity of monolayer hydrated WO3 nanosheet - Ag nanoparticle composites (WO3 NSs-Ag NPs) is 1.3 times higher than that of WO3 nanocube - Ag nanoparticle composites (WO3 NCs-Ag NPs). The highest cyclohexane conversion of 40.2% with cyclohexanol and cylohexanone (KA oil) selectivity of 97.0% is achieved by the photocatalyst of WO3 NSs-Ag NPs under solar-light irradiation at room temperature. The WO3 NSs-Ag NPs shows good photocatalytic stability without evident decline of catalytic activity after ten cycles. The improved photocatalytic activity in the oxidation of cyclohexane by WO3 NSs-Ag NPs is mainly due to the facilitated generation of high-reactive hydroxyl radical (OH), which is caused by the enhanced light absorption by surface plasmon resonance (SPR) effect of Ag NPs, and the effective charge transfer on the surface of WO3 monolayer structure. The design and structural analysis of the WO3 NSs-Ag NPs in this research may provide a novel approach for the further development of high performance photocatalyst. PMID- 29408104 TI - Effect of soluble surfactants on pinch-off of moderately viscous drops and satellite size. AB - HYPOTHESIS: Surfactant redistribution in a liquid bridge close to drop detachment depends on competition between the bridge deformation rate and surfactant equilibration rate. Surfactant effect can be different in situations when diffusion coefficient changes independently of thinning kinetics or in line with it. Using moderately viscous liquids should allow both situations to be explored experimentally. EXPERIMENTS: Formation of liquid drops at the tip of capillary is studied experimentally for silicone oils and for surfactant-laden and surfactant free water/glycerol mixtures of moderate viscosity with particular attention to the kinetics of liquid bridge close to pinch-off and formation of satellite droplets. FINDINGS: Effect of surfactant depends on the dynamic regime of the bridge thinning. In the presence of surfactant, inertial kinetics slows down close to pinch-off demonstrating effective surface tension smaller than dynamic surface tension. An acceleration of thinning kinetics caused by depletion of surfactant from the liquid bridge was observed in viscous and visco-inertial regimes. The size of satellite droplets has a maximum versus viscosity; increasing with surfactant concentration at smaller viscosities and decreasing with an increase of surfactant concentration at largest studied viscosity, where inversion of the pinch-off point was observed for surfactant solutions. PMID- 29408105 TI - Carbon dots synthesized by hydrothermal process via sodium citrate and NH4HCO3 for sensitive detection of temperature and sunset yellow. AB - In this work, the carbon dots (CDs) were synthesized by an one-pot portable hydrothermal method from sodium citrate and NH4HCO3. The obtained CDs were found to show high fluorescence quantum yield (31%), excitation-wavelength independence, outstanding water-soluble, excellent chemical and optical stability. Interestingly, it was discovered that sunset yellow (SY) was sensitive and effective in quenching the fluorescence of CDs. Based on this observation, CDs could be applied as a novel fluoescent probe for detection of SY. The analytical potential of this probe was evaluated and illustrated a good linear relationship at the concentration range from 0.25 to 56.0 MUmol L-1 with a detection limit (3sigma/k) of 74.49 nmol L-1. Meanwhile, the practicality of this nanosensor for SY determination in real samples was validated with good accuracy and precision. In addtion, long time UV radiation and high ionic strength hardly influenced on the fluorescence intensity of CDs. However, the fluorescence intensity of CDs decreased at higher temperature and the fluorescence was recovered when temperature back to 5 degrees C. Therefore, CDs could be also employed as an fluorescent temperature sensor with significant sensitivity, linearity and remarkable reversibility. PMID- 29408106 TI - Sustainable and long-time 'rejuvenation' of biomimetic water-repellent silica coating on polyester fabrics induced by rough mechanical abrasion. AB - The economical use of water-repellent coatings on polymeric materials in commercial and industrial applications is limited by their mechanical wear robustness and long-term durability. In this study, we demonstrate that polyethylene terephthalate (PET) fabric modified with inorganic, methyltrimethoxysilane (MTMS)-based coatings shows excellent resistance against various types of wear damage, thereby mimicking superhydrophobic biological materials. These features were facilitated by the rational design of coating processing that also enabled tunable hierarchical surface structure. A series of custom and standard testing protocols revealed that coating-to-substrate adhesion was remarkably high, as was the resistance to various mechanical abradents. The most intriguing characteristic observed during aging and abrasion cycles was the enhancement in non-wettability or 'rejuvenation' reflected by water droplet roll off behavior, a characteristic of self-cleaning materials. Water-repellent properties of coated polyester were also enhanced by prolonged thermal annealing and were maintained after custom laundry. The developed technology offers opportunities to design low cost, durable and functional textiles for both indoor and outdoor applications. PMID- 29408107 TI - Fabrication of phosphorus nanostructures/TiO2 composite photocatalyst with enhancing photodegradation and hydrogen production from water under visible light. AB - As the world faces serious environmental pollution and energy shortage, developing Vis-light-driven photocatalysts for water splitting is highly attractive in clean energy utilization. Fabricating heterostructures has been proposed to be an efficient system to enhance the photocatalytic activity. However, synthesizing heterostructures with good contact and understanding charge transfer dynamics are still unresolved issues. In this work, a facile calcination approach was used to synthesize red phosphorus (RP) nanostructures/TiO2 heterostructured composites. The RP nanostructures were directly grown on the TiO2 nanoparticles with an intimate surface contact. By adjusting the molar ratio of amorphous RP to TiO2 and the synthesizing temperature, thin nanorod-like RP nanostructures with a large exposed surface and a good surface contacting with TiO2 were obtained. The synergetic effect of heterostructured RP/TiO2 composites leads to an enhanced charge separation and transfer, and a better utilization of visible-light. As expected, the RP/TiO2-700 degrees C composites exhibit good photocatalytic activity of degrading RhB and the optimal H2 evolution rate. This work not only provides a method to prepare earth abundant elemental phosphorus well-contacted heterostructures, expand the well-known UV-active TiO2 photocatalyst to visible active, but also deepens understanding of charge transfer dynamics in heterostructured photocatalyst. PMID- 29408108 TI - Reverse micelles enhance the formation of clathrate hydrates of hydrogen. AB - HYPOTHESIS: Clathrate hydrates of hydrogen form at relatively low pressures (e.g., ca. 10 MPa) when a co-former compound is added. In that case, however, the gravimetric amount of stored hydrogen drops to less than 1 wt% from ca. 5.6 wt% without a co-former. Another factor hindering the entrapment of hydrogen into a clathrate matrix appears to be of a kinetic origin, in that the mass transfer of hydrogen into clathrates is limited by the macroscopic scale of the gas-water interfaces involved in their formation. Thus, the enhanced formation of binary (hydrogen + co-former) hydrates would represent a major achievement in the attempt to exploit those materials as a convenient means for storing hydrogen. EXPERIMENTS: Here, we present a simple process for the enhanced formation of binary hydrates of hydrogen and several co-formers, which is based on the use of reverse micelles for reducing the size of hydrate-forming gas-water interfaces down to tens of nanometers. This reduction of particle size allowed us to reduce the kinetic hindrance to hydrate formation. FINDINGS: The present process was able to (i) enhance the kinetics of the formation process; and (ii) assist clathrate formation when using water-insoluble coformers (e.g., cyclopentane, tetrahydrothiophene). PMID- 29408109 TI - Ultrasonication of spray- and freeze-dried cellulose nanocrystals in water. AB - The structural and rheological properties of aqueous suspensions of spray-dried cellulose nanocrystals (CNCs) were investigated and compared to those of freeze dried. The cellulose nanocrystals were obtained from sulfuric acid hydrolysis of wood pulp. Ultrasonication was used to disperse cellulose nanocrystals in Milli-Q water and the power applied during ultrasonication was shown to be the controlling parameter for their dispersion, more than total energy. Dynamic light scattering measurements showed a decrease of the average hydrodynamic diameter down to the same limiting value, i.e. ~75 nm, for both spray and freeze-dried cellulose nanocrystals. Since the same maximum dispersion state was reached for both CNC types, it indicated that the spray drying process did not limit dispersion, provided that sufficient ultrasonication was provided. Moreover, no desulfation occurred during ultrasonication at ambient temperature. Strong ultrasonication also caused a decrease of intrinsic viscosity, along with an increase in maximum packing concentration. These properties were correlated to agglomerates break-up, which released both ions and water in suspension. The ionic strength increase may lead to a thinner electrostatic double layer surrounding the cellulose nanocrystals, reducing their apparent concentration. PMID- 29408110 TI - Dynamics of simultaneously impinging drops on a dry surface: Role of inhomogeneous wettability and impact shape. AB - HYPOTHESIS: The quality of the printed lines in applications such as ink-jet printing and additive manufacturing is affected by the interactions between the impinging drops. Impact shape and the inhomogeneity in surface wettability govern the spreading and recoiling dynamics of the interacting drops. Hence, understanding the role of these factors on the interaction dynamics is essential to optimize these applications. NUMERICAL EXPERIMENTS: Phase-field based lattice Boltzmann method solver has been employed to investigate the interaction dynamics of two simultaneously impinging drops onto a dry surface. A geometry-based contact angle scheme is used to model the moving contact line. FINDINGS: Numerical simulations reveal that the previously identified interaction modes (Raman et al., 2017) are sensitive to the contact angle hysteresis, resulting in different impact outcomes. Two different interaction mechanisms have been discerned when drops impinge on a surface with a wettability gradient. It is shown that the deviation from the spherical geometry of the impact shape leads to different spreading behaviors and droplet morphology around the connecting region. With the increase in the cross-sectional aspect ratio, the interaction dynamics of oblate-oblate combination is similar to its spherical counterpart, albeit at a faster recoiling rate. PMID- 29408111 TI - Dispersion mechanism of polyacrylic acid-coated nanoparticle in protic ionic liquid, N,N-diethylethanolammonium trifluoromethanesulfonate. AB - HYPOTHESIS: Ionic liquids (ILs) are extremely concentrated electrolyte solutions. The ubiquitous presence of ions induces specific behaviors for chemical reactions compared to reactions in water solutions. This is also the case for the stability of colloidal dispersions, for which the DLVO model cannot be applied as the ionic strength is out of the model range. In a previous work, in the protic IL ethylammonium nitrate (doi: https://doi.org//10.1016/j.jcis.2015.04.059), we observed an unexpected influence of the pH on the stability of dispersion of maghemite nanoparticles coated with poly(acrylic acid) (pAA). EXPERIMENTS: To clarify and generalize these observations, we investigated here the pH response of the dispersion in a second protic ionic liquid with a different acid-base nature, diethylethanolammonium trifluoromethanesulfonate. pH titrations of the dispersions were achieved with an IS-FET electrode and the associated thermodynamic constants determined. The colloid structural properties were examined by small angle X-ray scattering. FINDINGS: Under acidic or mildly basic condition, a stable dispersion was obtained, i.e., when the degree of dissociation of pAA, alpha, was alpha < 0.1 or alpha > 0.7. Dispersions form quite dense but reversible aggregates in the intermediate alpha range. A model for the solvation layer around the particles is proposed and generalizes the former findings. PMID- 29408112 TI - 2D, 3D mesostructured silicas templated mesoporous manganese dioxide for selective catalytic reduction of NOx with NH3. AB - Employing nanocasting method, mesoporous MnO2 catalysts with large specific surface area and regular pore structure were synthesized by using three different types of mesostructure silicas (KIT-6, SBA-15, MCM-41) as hard templates. The physical and chemical properties of the three different mesostructured manganese oxide materials were comparatively and systematically characterized by using XRD, FT-IR, N2 adsorption-desorption, TEM, NH3-TPD, H2-TPR, XPS. The NH3-SCR performance of the mesoporous MnO2 was also evaluated on SCR self-assembly device. It was discovered that the mesostructure of the template would influence the amount and the kind of acid site, the reduction ability and then influence the catalytic performance of the materials. Mesoporous MnO2 templated from KIT-6 exhibited better catalytic performance than other mesoporous MnO2, indicating that the mesostructure of the materials has significant influence on the NH3-SCR performance. The KIT-6 templated MnO2 could induce 100% NOx conservation ratio range from 75 degrees C to 275 degrees C and exhibit good resistance of SO2 and H2O. PMID- 29408113 TI - Polydopamine-coated magnetic nanochains as efficient dye adsorbent with good recyclability and magnetic separability. AB - High adsorption ability and good separation functionality are necessary to an excellent adsorbent for organic dye removal from wastewater. In this study, core@shell nanostructured magnetic Fe-Fe2O3@polydopamine (PDA) nanochains (defined as Fe-Fe2O3@PDA NCs) were facilely synthesized through self polymerization of dopamine on the surface of Fe-Fe2O3 NCs. The dye adsorption performance, recyclability and magnetic separability of the Fe-Fe2O3@PDA NCs were investigated through selecting malachite green (MG) as a model organic dye. The effects of initial MG concentration, initial solution pH, temperature, and contact time on dye adsorption were systematically studied. Results show that the adsorption capacity of the Fe-Fe2O3@PDA NCs for MG was 61.22 mg/g at 25 degrees C. Both pi-pi stacking and electrostatic interactions might be responsible for the adsorption of MG on Fe-Fe2O3@PDA NCs. The adsorption kinetic follows both pseudo-second-order kinetic and Weber's intraparticle diffusion models. And the adsorption isothermal models fit Langmuir well. Besides, the Fe-Fe2O3@PDA NCs exhibit good recyclable adsorption property towards MG dye. PMID- 29408114 TI - Trichloroacetic acid-modulated synthesis of polyoxometalate@UiO-66 for selective adsorption of cationic dyes. AB - In this study, POM@UiO-66 nanoparticles were fabricated by encapsulation of POM (K6P2W18O62 polyoxometalate) into mesoporous UiO-66 metal organic framework through a solvothermal method with trichloroacetic acid as a modulator to promote the defects formation of UiO-66. The as-prepared samples were characterized by TEM, SEM, PXRD, TG, XPS, and EDX elemental mapping, and the successful combination of POM and UiO-66 was confirmed. Two cationic dyes, rhodamine B and malachite green, and one anionic dye orange G were employed to investigate the adsorption performance of POM@UiO-66. The adsorption data showed that the removal process of cationic dyes by POM@UiO-66 matched well with the pseudo-second-order model and Langmuir isothermal model. The resulting POM@UiO-66 nanoparticles exhibited high adsorption to cationic dyes but low adsorption to anionic dyes, and the adsorption capacities of rhodamine B, malachite green, and anionic dye orange G were 222.6, 190.6 and 40 mg g-1, respectively. Furthermore, the cationic dyes could be selectively removed from a cationic-anionic dye binary system. These results suggested that the novel polyoxometalate-based UiO-66 material is a promising candidate for the adsorption of cationic dyes from effluent. PMID- 29408115 TI - Model lipid bilayers mimic non-specific interactions of gold nanoparticles with macrophage plasma membranes. AB - Understanding the interaction between nanomaterials and biological interfaces is a key unmet goal that still hampers clinical translation of nanomedicine. Here we investigate and compare non-specific interaction of gold nanoparticles (AuNPs) with synthetic lipid and wild type macrophage membranes. A comprehensive data set was generated by systematically varying the structural and physicochemical properties of the AuNPs (size, shape, charge, surface functionalization) and of the synthetic membranes (composition, fluidity, bending properties and surface charge), which allowed to unveil the matching conditions for the interaction of the AuNPs with macrophage plasma membranes in vitro. This effort directly proved for the first time that synthetic bilayers can be set to mimic and predict with high fidelity key aspects of nanoparticle interaction with macrophage eukaryotic plasma membranes. It then allowed to model the experimental observations according to classical interface thermodynamics and in turn determine the paramount role played by non-specific contributions, primarily electrostatic, Van der Waals and bending energy, in driving nanoparticle-plasma membrane interactions. PMID- 29408116 TI - A novel integrated method for quantification of interfacial interactions between two rough bioparticles. AB - Quantification of interfacial interactions between particles provides a way to regulate the interface behaviors of particles related with adhesion, aggregation, flotation, flocculation, membrane fouling, etc. Existing methods are based on assumptions of smooth particles although real particle surfaces are rather rough. This study proposed a new method to quantify interfacial interactions between two rough particles. In this study, a rigorous mathematical equation was firstly introduced to construct surface topography. In the framework of surface element integration (SEI) method, the spatial relationship between two rough particles was significantly explored, resulting in establishment of a formula of double integrals for interaction quantification. Thereafter, surface properties of the microbial aggregations obtained from a membrane bioreactor (MBR) were experimentally measured. With these data, the interfacial interactions between two rough microbial aggregations were numerically quantified according to composite Simpson's rule. The new method was compared with Derjaguin approximation (DA) method. It was found that ripple frequency and particle radius had profound effects on the total interfacial interaction. This method has extensive application foreground in interfacial behavior research. PMID- 29408117 TI - Synthesis of Cs3PMo12O40/Bi2O3 composite with highly enhanced photocatalytic activity under visible-light irradiation. AB - A novel visible-light-active Cs3PMo12O40/Bi2O3 (CsPMo/Bi2O3) composite was prepared by a simple dissolution-precipitation method. The as-prepared samples were characterized by XRD, XPS, FT-IR, SEM, UV-Vis DRS, N2 adsorption-desorption isotherms and electrochemical analysis. The results revealed that Bi2O3 was successfully modified by trace CsPMo. After the addition of H3PMo12O40 acid (HPMo), the surface of Bi2O3 can be roughed. Subsequently, the presence of Cs2CO3 can neutralize the protons of HPMo forming CsPMo precipitate on Bi2O3. Comparing to naked Bi2O3 and CsPMo, the binary composite exhibited many beneficial characteristics in charge generation and separation, such as formation of p-n heterojunction, decreased band gap, enhanced photocurrent response and greatly reduced charge transfer resistance. The photocatalytic activities of the as prepared samples were evaluated by the degradation of phenol under visible light. The calculated pseudo-first-order rate constants for phenol degradation were 2.7 and 14.8 times relative to that on Bi2O3 and CsPMo, respectively. Dramatically enhanced photocatalytic performance can be observed when the optimal CsPMo/Bi2O3 composite (2.5% CsPMo) was applied. The major active species involved in the degradation process are in the following order: superoxide radical (O2-) > hydroxyl radical (OH) ~ hole (h+). Besides, the CsPMo/Bi2O3 composite also displayed good stability in cyclic experiments. PMID- 29408118 TI - Estimation of structural film viscosity based on the bubble rise method in a nanofluid. AB - When a single bubble moves at a very low capillary number (10-7) through a liquid with dispersed nanoparticles (nanofluid) inside a vertical tube/capillary, a film is formed between the bubble surface and the tube wall and the nanoparticles self layer inside the confined film. We measured the film thickness using reflected light interferometry. We calculated the film structural energy isotherm vs. the film thickness from the film-meniscus contact angle measurements using the reflected light interferometric method. Based on the experimental measurement of the film thickness and the calculated values of the film structural energy barrier, we estimated the structural film viscosity vs. the film thickness using the Frenkel approach. Because of the nanoparticle film self-layering phenomenon, we observed a gradual increase in the film viscosity with the decreasing film thickness. However, we observed a significant increase in the film viscosity accompanied by a step-wise decrease in the bubble velocity when the film thickness decreased from 3 to 2 particle layers due to the structural transition in the film. PMID- 29408119 TI - Removal of aniline from air and water by polymers of intrinsic microporosity (PIM 1) electrospun ultrafine fibers. AB - This research aims to investigate the possibility of electrospun fibers from Polymers of Intrinsic Microporosity (PIM-1) as an alternative adsorbent for aniline removal from both air and aqueous solution. Adsorption properties of electrospun PIM-1 fibers were compared with powder and film form of PIM-1. While electrospun PIM-1 nanofibrous mat can adsorb 871 mg g-1 aniline from air, it can also adsorb 78 +/- 5.4 mg g-1 aniline from aqueous environment when 50 mg L-1 aniline solution is used. The experimental maximum adsorption capacity of electrospun PIM-1 fibers was found as (qe) 138 mg g-1. Langmuir and Freundlich isotherm models have been studied and Langmuir model found more appropriate for aniline adsorption on electrospun PIM-1 fibers. The study reveals that self standing electrospun fibrous mat of PIM-1 has shown potential to be used as an efficient adsorbent material for the adsorption of VOCs from air and aqueous system thanks to its fast kinetic and high adsorption capacity. PMID- 29408120 TI - Poly-l-lysine mediated synthesis of palladium nanochain networks and nanodendrites as highly efficient electrocatalysts for formic acid oxidation and hydrogen evolution. AB - The morphology- and size-tunable synthesis of nanocatalysts has attracted substantial research interest especially in catalysis. In this work, we synthesized free-standing Pd nanochain networks (Pd NCNs) and Pd nanodendrites (Pd NDs) through a direct poly-l-lysine (PLL)-mediated one-pot aqueous method. The presence of PLL and its concentrations were critical in this regard, showing PLL as the structure-directing and capping agents during the nucleation and crystal growth procedures. The synthesized architectures exhibited improved catalytic activity and enhanced durability towards formic acid oxidation and hydrogen evolution reactions relative to commercial Pd black catalyst. Moreover, the electrochemical active surface area and the electrocatalytic performance of Pd NCNs were dramatically enhanced in comparison to Pd NDs mainly owing to the unique network-like structure of Pd NCNs. PMID- 29408121 TI - Design and evaluation of galactosylated chitosan/graphene oxide nanoparticles as a drug delivery system. AB - We investigated a novel drug delivery system comprising nanoparticles based on galactosylated chitosan/graphene oxide/doxorubicin (GC-GO-DOX) for the therapeutic treatment of cancer. The drug delivery system was synthesized by loading a drug sample with galactosylated chitosan (GC) on a graphene oxide (GO) carrier. The results showed that the drug loading capacity was as high as 1.08 mg/mg (drug per polymer). The nanoparticles remained stable under physiological conditions, and the drug was released in a low pH environment (i.e., a tumor environment) and was pH-responsive. Cell uptake experiments and a cell proliferation analysis demonstrated that the nanoparticles had higher cytotoxicity for HepG2 and SMMC-7721 cells than chitosan/graphene oxide/doxorubicin (CS-GO-DOX) nanoparticles. Compared with CS-GO-DOX nanoparticles, the GC-GO-DOX nanoparticles exhibited a higher fluorescence intensity in tumor cells. In vivo anti-tumor experiments demonstrated that the GC GO-DOX nanoparticles inhibit tumors better than the CS-GO-DOX nanoparticles. Nude mouse weight, tumor weight and tumor volume data indicated that the GC-GO-DOX tumor inhibition effect was better than that of the control group and the blank group. In summary, the nanoparticle investigated in this article is significant for tumor therapy. PMID- 29408122 TI - Hydrothermal assisted decoration of NiS2 and CoS nanoparticles on the reduced graphene oxide nanosheets for sunlight driven photocatalytic degradation of azo dye: Effect of background electrolyte and surface charge. AB - The semiconductor NiS2 nanoparticles with an average size of 10 +/- 0.317 nm were successfully deposited on the reduced graphene oxide (rGO) sheets by simple hydrothermal method. The synthesized nanocomposite was characterized by various instrumental techniques like XRD, FTIR, FESEM, EDX, HRTEM, fluorescence spectrophotometer analysis. In this study we mainly focus on the determination of the surface potential values of NiS2-rGO and CoS-rGO nanocomposite under different experimental conditions and evaluated the photodegradation efficiency towards azo dye Congo Red (CR) molecule under natural sunlight irradiation. We found that the surface charge (zeta potential) of the both nanocomposite materials in presence of different inorganic ions salt solutions like NaCl, NaNO3, Na2SO4, MgCl2, CaCl2 etc. is varied based on the polarizability of the ions as well as pH of the suspension. Different inorganic ions present in the catalyst suspension can alter the surface charge of the catalyst by forming a double layer around the molecule and thus change the electrostatic interaction between the dye molecule and the catalyst surface which change the degradation efficiency of the photocatalyst towards CR molecule. The photocatalytic efficiency of NiS2-rGO and CoS-rGO nanocomposite towards CR degradation was found to be 97.03% and 88.03% in 40 min, respectively under same experimental condition whereas NiS2 and CoS nanoparticles without support exhibited photodegradation efficiency 57.89% and 50.52%, respectively. The observed improved photocatalytic activity of the metal sulfide-rGO nanocomposite results the presence of synergistic effect between the metal sulfide nanoparticles and the rGO sheets of the photocatalysts which inhibits the recombination rate of photogenerated electrons and holes. The mechanism of the degradation process was investigated by photoluminescence study in presence of terephthalic acid and also quenching experiment in presence of isopropanol and benzoquinone. The photocatalyst was characterized after degradation process and found that the crystallinity and the morphology of the nanocomposite remained unchanged. The ion-chromatography experiment confirms the formation of non-toxic products after degradation. The present study focuses on the importance of the use of metal sulphide-rGO nanocomposite towards environment remediation process and study of the influence of inorganic salts on the surface charge of the photocatalyst as well as on the degradation process. PMID- 29408123 TI - Controlled fabrication of well-dispersed AgPd nanoclusters supported on reduced graphene oxide with highly enhanced catalytic properties towards 4-nitrophenol reduction. AB - To realize the efficient and complete removal of organic pollutants in waste water, it is highly urgent for scalable synthesis of either self-supported bimetallic nanocatalysts or anchored on carbon-based materials. In this study, a simple one-pot coreduction method was developed for preparing well-dispersed AgPd alloyed nanoclusters uniformly dispersed on reduced graphene oxide (AgPd NCs/rGO) at room temperature by utilizing 5-azacytosine as the capping agent. The nanocomposites were characterized by a set of physical characterizations. The formation mechanism and catalytic mechanism were discussed in some details. Moreover, the prepared AgPd NCs/rGO exhibited dramatically increased catalytic properties towards the reduction of 4-nitrophenol (4-NP) in the presence of NaBH4 when compared to commercial Pd/C (20 wt.%). PMID- 29408124 TI - Synthesis of manganese oxide nanorods and its application for potassium ion sensing in water. AB - Potassium is an important body mineral that control the cellular and electrical functions in the body. The potassium ion concentration change in human serum causes the risk of acute cardiac arrhythmia. Hence, it is important to monitor the potassium level in drinking water/food to control the intake and prevent its effect. This paper reports synthesis of manganese oxide (MnO2) nanorods using low temperature sol-gel method for the fabrication of non-enzymatic potassium ion sensor. The detailed investigation of the as-synthesized MnO2 nanorods were carried out using field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), and transmission electron microscopy (TEM). The morphological and structural observations revealed that this method yield small nanorods with average length and diameters of about 210 +/- 10 nm and 20 +/- 3 nm, respectively. Further, as-synthesized alpha-MnO2 nanorods were used to fabricate non-enzymatic potassium ion sensor following the deposition of alpha-MnO2 nanorods on glassy carbon electrode (GCE) with the help of conductive binder. The electrochemical characterizations of fabricated non-enzymatic potassium sensor showed good sensing performance (i.e. sensitivity, selectivity, long term stability, and reproducibility). Moreover, applicability of the sensor to detect potassium ion in water samples were also demonstrated. PMID- 29408125 TI - Synthesis of nickel entities: From highly stable zerovalent nanoclusters to nanowires. Growth control and catalytic behavior. AB - Non-noble metal nanoclusters synthesis is receiving increased attention due to their unique catalytic properties and lower cost. Herein, the synthesis of ligand free Ni nanoclusters with an average diameter of 0.7 nm corresponding to a structure of 13 atoms is presented; they exhibit a zero-valence state and a high stability toward oxidation and thermal treatment. The nanoclusters formation method consists in the electroreduction of nickel ions inside an ordered mesoporous alumina; also, by increasing the current density, other structures can be obtained reaching to nanowires of 10 nm diameter. A seed-mediated mechanism is proposed to explain the growth to nanowires inside these mesoporous cavities. The size dependence on the catalytic behavior of these entities is illustrated by studying the reduction of methylene blue where the nanoclusters show an outstanding performance. PMID- 29408126 TI - Application of novel hierarchical niobium-containing zeolites for synthesis of alkyl lactate and lactic acid. AB - Novel hierarchical niobium-containing zeolites were synthesized for the first time and applied for isomerization of dihydroxyactetone to alkyl lactate and lactic acid (95-97% yield). These materials possess secondary mesoporosity, thus facilitating access to active sites of the material by larger reagent molecules, preserving acidity and crystallinity of the zeolites. PMID- 29408127 TI - Surface phosphorylation of nanoparticles by hexokinase: A powerful tool for cellular uptake improvement. AB - The aim of the study was to develop zeta potential changing nanoparticles (NPs) via surface phosphorylation in order to improve their uptake by epithelial cells. Polymeric NPs were formed via in situ gelation between chitosan (CS) and chondroitin sulphate (ChS). Phosphorylation of these NPs was carried out by using hexokinase. The resulting phosphorylated NPs (p-NPs) were characterized in respect of their size and zeta potential. Phosphate release was quantified by incubating the particles with isolated as well as cell-associated intestinal alkaline phosphatase (AP). In parallel, resulting change in zeta potential was monitored. In-vitro mucus permeation of these particles was evaluated on porcine intestinal mucus. Furthermore, toxicity and cellular uptake studies were performed on Caco-2 cells. p-NPs exhibited a mean size of 412 +/- 3.24 nm and a zeta potential of -12.4 mV. When these p-NPs were incubated with isolated as well as cell-associated AP, a significant amount of phosphate was released within 4 h and zeta potential raised up to -1.2 mV. p-NPs showed improved mucus permeation in comparison to unmodified NPs. Due to de-phosphorylation by AP, cellular uptake of p-NPs increased almost 2-fold. Moreover, particles displayed no toxicity. Findings of this study show that zeta potential changing p-NPs provide effective mucus permeation and enhanced cellular uptake. PMID- 29408128 TI - A Novel method for the preparation of fluorescent C60 poly(amino acid) composites and their biological imaging. AB - Recently, fullerene (C60) and its derivatives have been widely explored for many applications owing to their enriched physical and chemical properties. Specifically, the synthesis and biomedical applications of fluorescent C60 have been extensively investigated previously. However, the preparation of polymer functionalized fluorescent C60 has not been reported thus far. In this study, water-dispersible fluorescent C60 polymer composites were successfully synthesized through the combination of the thiol-ene click reaction and subsequent ring-opening polymerization. First, 2-aminoethanethiol was introduced on the surface of C60 by the thiol-ene click reaction. The surface of amino group functionalized C60 (C60-NH2) was further modified with poly(amino acid)s via ring open polymerization of GluEG N-carboxyanhydrides (NCAs). The morphology, functional groups, optical properties and biocompatibility were examined by a number of characterization equipment and assays in detail. We demonstrated that the resultant fluorescent C60 poly(amino acid) (C60-GluEG) composites have a small size (about 5 nm), high water dispersibility, intense fluorescence and high photostability. Cell viability results implied that the C60-GluEG composites possess low cytotoxicity. Moreover, these C60-GluEG composites can easily penetrate into live cells, indicating their great potential for biological imaging applications. PMID- 29408129 TI - Synergistic effect of mixing cationic and nonionic surfactants on corrosion inhibition of mild steel in HCl: Experimental and theoretical investigations. AB - We studied the inhibition performances of IMB (imidazoline quaternary salt (IM) and benzotriazole (BTAH)) and IMO (IM and octyl phenol ethoxylates (OP)) mixtures as inhibitors of L245 steel placed in 10 vol% HCl solution at 298 K using experimental methods and theoretical calculations. We found that the mixtures adsorb on the steel by an endothermic spontaneous process, and the adsorption model follows Langmuir isotherm. The mixtures exhibit good synergistic inhibition effect, and the inhibition efficiency enhanced in turn (IMB < IMO). The relationship between synergistic effect of organic inhibitors and their energetic position of molecular frontier orbitals was discussed. PMID- 29408130 TI - Immobilization of Pt nanoparticles in hollow mesoporous silica nanocapsules: An aggregation- and leaching-resistant catalyst. AB - In this study, hollow mesoporous silica nanocapsules (h-mNSiO2) with uniformly dispersed Pt nanoparticles (Pt NPs) in their hollow core (Pt@h-mNSiO2) were successfully fabricated. The as-synthesized Pt@h-mNSiO2 was core@shell like structure with silica shells and Pt-rich cores. The catalyst was synthesised in an oil-water biphasic stratification system, then the self-assembly of reactants occurred in the oil-water interface for one-pot sustaining interfacial growth. The as-prepared Pt@h-mNSiO2 catalyst exhibited superior activity for hydrogen generation from the hydrolysis of ammonia borane, with a turnover frequency of 371.7 molH2 mol-1Pt min-1 at ambient temperature, probably owing to the abundant mesopores and high surface area, leading to a considerable increase in the accessible active sites. Besides, almost no Pt NP aggregation was observed during reusability tests. Notably, Pt leaching was not observed during the reaction, possibly related to the protective effect of the mesoporous silica shell. Thus, this study provides a facile route to synthesise aggregation- and leaching resistant catalysts with superior activity, accessibility, and recyclability for the environment and energy chemistry. PMID- 29408131 TI - Co-entrapped, N-doped mesoporous carbons prepared from melamine formaldehyde resins with CoCl2 as template for hydrogen evolution. AB - Cobalt-entrapped, nitrogen-doped mesoporous carbon materials have been prepared using melamine formaldehyde resin (MF resin) as precursor and CoCl2 as template. A fraction of CoCl2 can be reduced to Co nanoparticles and wrapped by the nitrogen doped carbon. Meanwhile, the ratio of MF resin to CoCl2 is an important parameter determining the mesoporous structures of the final products. The surface area of the obtained material decreases with the increase in the ratio of MF resin to CoCl2. Electrocatalytic tests show that the obtained catalysts are highly active for hydrogen evolution reaction in both acidic and basic media, achieving a current density of 10 mA cm-2 at 171 and 186 mV under acidic and alkaline conditions, respectively. Additionally, these catalysts also show good long-term stabilities. PMID- 29408132 TI - Choosing mineral flotation collectors from large nanoparticle libraries. AB - Polystyrene nanoparticles can promote froth flotation of mineral particles if the nanoparticles are sufficiently hydrophobic and are colloidally stable in the high ionic strength solutions typical of commercial flotation operations. A library of 80 unique polystyrene nanoparticle types was prepared with click chemistry and used to determine if particles that were sufficiently hydrophilic to be colloidally stable in high ionic strength and high pH solutions, were also capable of promoting flotation. The conflicting requirements of colloidal stability and hydrophobicity can be achieved in 9 mM sodium carbonate, a very challenging environment. Instead of testing all 80 samples with laborious flotation testing, automated assays measuring colloid stability and nanoparticle hydrophobicity were employed. The colloid stability assay measured the critical coagulation concentrations (CCC). Nanoparticle hydrophobicity was characterized by water contact angle, measurements (CA). A smaller cohort of the most promising nanoparticle candidates for detailed flotation testing were identified by mapping nanoparticle properties on the CA versus CCC plain - a "Flotation Domain Diagram". We believe that this work was the first time that combinatorial synthesis and high throughput screening have been used in the development of flotation chemicals. Finally, based on the accumulated evidence, effective nanoparticle flotation collectors are likely to be ~50 nm in diameter, with a soft hydrophobic polymer shell and with surface functional group densities in the order of magnitude of 0.1 nm-2. PMID- 29408133 TI - Modeling adsorption of copper(II), cobalt(II) and nickel(II) metal ions from aqueous solution onto a new carboxylated sugarcane bagasse. Part II: Optimization of monocomponent fixed-bed column adsorption. AB - In the second part of this series of studies, the monocomponent adsorption of Cu2+, Co2+ and Ni2+ onto STA adsorbent in a fixed-bed column was investigated and optimized using a 22 central composite design. The process variables studied were: initial metal ion concentration and spatial time, and the optimized responses were: adsorption capacity of the bed (Qmax), efficiency of the adsorption process (EAP), and effective use of the bed (H). The higher Qmax for Cu2+, Co2+ and Ni2+ were 1.060, 0.800 and 1.029 mmol/g, respectively. The breakthrough curves were modeled by the original Thomas and Bohart-Adams models. The changes in enthalpy (DeltaadsH degrees ) of adsorption of the metal ions onto STA were determined by isothermal titration calorimetry (ITC). The values of DeltaadsH degrees were in the range of 3.0-6.8 kJ/mol, suggesting that the adsorption process involved physisorption. Desorption (Edes) and re-adsorption (Ere-ads) of metal ions from the STA adsorbent were also investigated in batch mode, and the optimum conditions were applied for three cycles of adsorption/desorption in a fixed bed column. For these cycles, the lowest values of Edes and Ere-ads were 95 and 92.3%, respectively, showing that STA is a promising candidate for real applications on a large scale. PMID- 29408134 TI - Links between nanoscale and macroscale surface properties of natural root mucilage studied by atomic force microscopy and contact angle. AB - Soil water repellency originating from organic coatings plays a crucial role for soil hydraulics and plant water uptake. Focussing on hydrophobicity in the rhizosphere induced by root-mucilage, this study aims to explore the link between macroscopic wettability and nano-microscopic surface properties. The existing knowledge of the nanostructures of organic soil compounds and its effect on wettability is limited by the lack of a method capable to assess the natural spatial heterogeneity of physical and chemical properties. In this contribution, this task is tackled by a geostatistical approach via variogram analysis of topography and adhesion force data acquired by atomic force microscopy and macroscopic sessile drop measurements on dried films of mucilage. The results are discussed following the wetting models given by Wenzel and Cassie-Baxter. Undiluted mucilage formed homogeneous films on the substrate with contact angles >90 degrees . For diluted samples contact angles were smaller and incomplete mucilage surface coverage with hole-like structures frequently exhibited increased adhesion forces. Break-free distances of force curves indicated enhanced capillary forces due to adsorbed water films at atmospheric RH (35 +/- 2%) that promote wettability. Variogram analysis enabled a description of complex surface structures exceeding the capability of comparative visual inspection. PMID- 29408135 TI - Adsorption and self-assembly in methyl ester sulfonate surfactants, their eutectic mixtures and the role of electrolyte. AB - The alpha-methyl ester sulfonate, MES, anionic surfactants are a potentially important class of sustainable surfactants for a wide range of applications. The eutectic-like Kraft point minimum in the C16 and C18-MES mixtures is an important feature of that potential. Understanding their individual adsorption properties and the surface mixing of the eutectic mixtures are key to their wider exploitation. Neutron reflectivity has been used to investigate the adsorption at the air-water interface of the C16 and C18-MES surfactants and the eutectic mixture of C16 and C18-MES, in aqueous solution and in electrolyte. The micelle mixing of the eutectic mixture is investigated using small angle neutron scattering. The adsorption isotherms for C14 to C18-MES are found to scale with their critical micelle concentration value. The surface and micelle compositions of the C16 and C18-MES eutectic mixture differ from the eutectic composition; with compositions in the limit of high concentrations richer in C16-MES. The mixing properties are described by the pseudo phase approximation with a repulsive interaction between the two surfactants. The impact of the multivalent ions Al3+ on the adsorption at the air-water interface results in a transition from monolayer to multilayer adsorption. PMID- 29408136 TI - Enzyme activity of horseradish peroxidase in surfactant-free microemulsions. AB - In the present contribution, we investigated the influence of the structuring of surfactant-free microemulsions (SFME) (water/1-propanol/limonene and water/tert butanol/limonene) on the enzyme activity of horseradish peroxidase (HRP). To this purpose, the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) with hydrogen peroxide was chosen as a model reaction. Enzymatic activities in SFMEs of varying compositions were investigated by UV-Vis spectroscopy and compared to the enzyme activity in pure buffer solution. Dynamic light, small-angle-X-ray scattering and conductivity measurements were performed in order to obtain structural information on the used SFMEs. Findings presented in this study revealed that the ability of short-chain alcohols to form mesostructures (aqueous aggregates in oil) has a crucial effect on the enzyme activity in SFMEs. Mesoscale structuring with 1-propanol (NPA) was found to be more pronounced than for the more hydrophobic tert-butanol (TBA). It was concluded that the most pronounced mesoscale-structured SFMEs lead to the highest enzymatic activities. PMID- 29408137 TI - Facile synthesis of prickly platinum-palladium core-shell nanocrystals and their boosted electrocatalytic activity towards polyhydric alcohols oxidation and hydrogen evolution. AB - Herein, prickly platinum-palladium core-shell nanocrystals (Pt@Pd NCs) were prepared by a facile one-pot aqueous method, only taking sodium pyrrolidone carboxylate (PCA-Na) as the structure director and stabilizing agent. The products were mainly characterized by microscopic analysis, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), followed by discussing the formation mechanism in details. The electrochemical characterizations were examined by cyclic voltammetry (CV), linear sweep voltammetry (LSV) and chronoamperometry (CA). The results revealed that the prepared architectures had the biggest current density (58.4 mA cm-2) for ethylene glycol oxidation, which is 3.5-fold, 1.2-fold, 2.3-fold and 2.4-flod enhancement relative to those of home-made single Pt nanoparticles (NPs) and Pd NPs, commercial Pt black and Pd black catalysts, respectively. Also, the obtained Pt@Pd NCs showed improved catalytic activity and stability towards glycerol oxidation and hydrogen evolution reactions compared to the references. PMID- 29408138 TI - Microwave synthesis of three-dimensional nickel cobalt sulfide nanosheets grown on nickel foam for high-performance asymmetric supercapacitors. AB - A facile and cost-effective microwave method is developed to prepare ternary nickel cobalt sulfide (NiCo2S4) interconnected nanosheet arrays on nickel foam (NF). When acting as an electrochemical supercapacitor electrode material, the as prepared NiCo2S4/NF shows a high specific capacitance of 1502 F g-1 at a current density of 1 A g-1, and outstanding cycling stability of 91% capacitance retention after 8000 cycles. In addition, a asymmetric supercapacitor (ASC) is composed of NiCo2S4/NF as positive electrode and activated carbon as negative electrode, which exhibits a high energy density of 34.7 W h kg-1 at a power density of 750 W kg-1 and long-term cyclic stability (83.7% capacity retention after 8000 cycles). Even at a high power density of 15 kW kg-1, it still remains an energy density of 17.9 W h kg-1, which is able to light up a light-emitting diode. These findings provide a new and facile approach to fabricate high performance electrode for supercapacitors. PMID- 29408140 TI - Direct and one-step synthesis of polythiophene/gold nanoparticles thin films through liquid/liquid interfacial polymerization. AB - This work demonstrates a simple and one-step synthesis of polythiophene/gold nanoparticles (PT/Au) nanocomposite thin films, through a liquid-liquid (L/L) interfacial polymerization route. Starting from an aqueous solution of tetrachloroauric acid (acting both as metallic gold source and oxidizing agent to start the oxidative polymerization of thiophene), and a solution of thiophene in n-hexane, a biphasic L/L system was originated. In the following, the interface acted as a meeting-point for the reactants, and the polymerization reaction took place, leading to self-assembled PT/Au film between the two immiscible liquids. These films were easily deposited over different substrates (glass, silicon, plastics) and characterized through different techniques. The influence of both the reactants ratio and the reaction time on the structure and morphology of the films were evaluated. The films obtained with a shorter reaction time exhibited spherical gold nanoparticles (around 3 nm diameter) homogeneously dispersed into a polymeric matrix. The increase of both the reaction time and the thiophene/gold precursor ratio led to agglomerated and anisotropic gold structures wrapped by a thin layer of polythiophene. Overall, PT/Au films are transparent, homogeneous, stable, flexible and presented reversible electrochromic properties, which make them suitable for application in different systems and devices, as demonstrated here for electrochromic application. PMID- 29408139 TI - Hyaluronated mesoporous silica nanoparticles for active targeting: influence of conjugation method and hyaluronic acid molecular weight on the nanovector properties. AB - We have prepared and evaluated the physico-chemical and biological properties of four different hyaluronated mesoporous silica nanoparticles (MSNs) samples (MSN/HA). Hyaluronic acid (HA) with two different molecular weights (200 and 6.4 kDa) was used for the conjugation of aminopropyl-functionalized MSN (NH2-MSN), following two different procedures. Namely, samples HA200A and HA6.4A were prepared by reacting activated HA with NH2-MSN (method A), while samples HA200B and HA6.4B were obtained carrying out HA activation in the presence of the nanoparticles (method B). The four samples showed similar hydrophilicity, but clear differences in the HA loading, textural properties, surface charge and stability of the suspensions. More in detail, conjugation using low molecular weight HA with method A resulted in low HA loading, with consequent scarce effects on dispersity and stability in physiological media. The highest yield and corresponding best performances were obtained with method B using high molecular weight HA. HA loading and molecular weight also influenced in a concerted way the biological response towards the MSNs of CD44 target cancer cells (CD44+) and control cells (CD44-): MDA-MB-231 and A2780, respectively. The absence of cytotoxicity was assessed. Moreover, the targeting ability of the best performing MSN/HA was confirmed by cellular uptake studies. PMID- 29408141 TI - The formation of visible light-driven Ag/Ag2O photocatalyst with excellent property of photocatalytic activity and photocorrosion inhibition. AB - Ag/Ag2O composites were prepared via an extremely simple solvent-free chemical technique. The obtained Ag/Ag2O samples exhibited superior visible-light degradation efficiency for methyl orange removal. The degradation rate constant of as-obtained composite is almost 2 times as that of commercial Ag2O, and has only little change after five cycles of utilization. The excellent photocatalytic properties of Ag/Ag2O materials could be ascribed to desirable absorption property and surface plasmon resonance of metal silver on the surface of semiconductor Ag2O. Meanwhile, the unstable and photo-sensitive disadvantages of commercial Ag2O due to the photocorrosion could be largely suppressed in the presence of metallic Ag for Ag/Ag2O composites, which plays an important role as an electron sink to receive the photo-generated electrons from Ag2O, accordingly restraining the reduction of Ag+ in Ag2O and improving the recyclability of Ag2O. With the assistance of scavengers and ESR technique, the h+ and O2- were proved to be crucial reactive species in the pathways of photocatalytic degradation reaction. PMID- 29408142 TI - "On-off-on" fluorescent system for detection of Zn2+ in biological samples using quantum dots-carbon dots ratiometric nanosensor. AB - In this work, a novel strategy for Zn2+ detection was established by using an "on off-on" ratiometric fluorescent nanosensor with the help of ethylene diaminetetraacetic acid (EDTA), a common metal chelating agent. The simple and practical ratiometric fluorescent nanosensor was synthesized by covalently binding CdTe quantum dots (QDs) and carbon dots (CDs), possessing two emission peaks at 525 nm and 450 nm under a single wavelength excitation of 360 nm, respectively. The CdTe QDs served as the response signal label, and the CDs, having no response to the analytes, acted as the reference signal. The fluorescence emission of the nanosensor was turned off to create a low-level "off" state when EDTA was added, and turned on dramatically with the addition of the target Zn2+. Under the optimal conditions, the change of the fluorescence intensity ratio of the nanosensor at 525 nm and 450 nm (DeltaF525/F450) had good linearity against the concentrations of Zn2+ within a dynamic linear range of 0.50-40 MUM. The limit of detection was as low as 0.33 MUM (3sigma/K), which was low enough for the detection of Zn2+ in human body. The proposed method was successfully applied to the detection of Zn2+ in human urine and plasma with RSDs less than 10%. The results show that the as-prepared QDs-CDs ratiometric nanosensor has potential application of clinical detection of Zn2+ in the human body. PMID- 29408143 TI - An electrochemical method through hydroxyl radicals oxidation and deposition of ferric phosphate for hypophosphite recovery. AB - Phosphorus is an essential and irreplaceable element of the ecosystem. In this work, phosphorus has been recovered using an electro-Fenton process. The effects of current intensity, initial pH and H2O2 concentration on the recovery of hypophosphite were investigated. When the current intensity, pH value, and H2O2 concentration were 0.2 A, 3.0 and 90 mM, respectively, hypophosphite was completely oxidized to phosphate. Under such conditions, the phosphate was recovered through the generation of deposition. In order to determine the mechanism of hypophosphite recovery, the morphology and microstructure of the deposition were analyzed using X-ray diffraction, scanning electron microscopy, energy dispersive X-ray, high resolution transmission electron microscopy, Fourier transform infrared and X-ray photoelectron spectra. The generation of hydroxyl radicals was confirmed using electron spin resonance technique. This method is a clean process for phosphorus recovery, and does not generate hazardous substances. PMID- 29408144 TI - A facile route to the synthesis of anilinic electroactive colloidal hydrogels for neural tissue engineering applications. AB - An innovative drug-loaded colloidal hydrogel was synthesized for applications in neural interfaces in tissue engineering by reacting carboxyl capped aniline dimer and gelatin molecules. Dexamethasone was loaded into the gelatin-aniline dimer solution as a model drug to form an in situ drug-loaded colloidal hydrogel. The conductivity of the hydrogel samples fluctuated around 10-5 S/cm which appeared suitable for cellular activities. Cyclic voltammetry was used for electroactivity determination, in which 2 redox states were observed, suggesting that the short chain length and steric hindrance prevented the gel from achieving a fully oxidized state. Rheological data depicted the modulus decreasing with aniline dimer increment due to limited hydrogen bonds accessibility. Though the swelling ratio of pristine gelatin (600%) decreased by the introduction and increasing the concentration of aniline dimer because of its hydrophobic nature, it took the value of 300% at worst, which still seems promising for drug delivery uses. Degradation rate of hydrogel was similarly decreased by adding aniline dimer. Drug release was evaluated in passive and stimulated patterns demonstrating tendency of aniline dimer to form a vesicle that controls the drug release behavior. The optimal cell viability, proper cell attachment and neurite extension was achieved in the case of hydrogel containing 10 wt% aniline dimer. Based on tissue/organ behavior, it was promisingly possible to adjust the characteristics of the hydrogels for an optimal drug release. The outcome of this simple and effective approach can potentially offer additional tunable characteristics for recording and stimulating purposes in neural interfaces. PMID- 29408145 TI - Fabrication of sensitive non-enzymatic nitrite sensor using silver-reduced graphene oxide nanocomposite. AB - There are increasing demands of more sensitive sensors for monitoring potential hazards in real water that may cause serious problems to human health. Herein, we report the development of a non-enzymatic nitrite sensor using nanocomposite of reduced graphene oxide decorated with silver nanoparticle (Ag-rGO). First, Ag-rGO nanocomposite was synthesized using a facile and cost-effective microwave assisted approach. Then, as-synthesized Ag-rGO nanocomposite was used to modify glassy carbon electrode (GCE) and applied for the sensitive and selective detection of nitrite in the aqueous medium with increasing concentration of nitrite. Under optimized conditions, sensor achieved high sensitive response (18.4 MUA/MUM.cm2) in a wide linear range (0.1-120 MUM), low limit of detection (~0.012 MUM), and good selectivity using differential pulse voltammograms (DPV). The applicability of fabricated non-enzymatic nitrite sensor was checked in real sample with satisfactory results. PMID- 29408146 TI - Hollow porous zinc cobaltate nanocubes photocatalyst derived from bimetallic zeolitic imidazolate frameworks towards enhanced gaseous toluene degradation. AB - Aiming at promoting the photocatalytic performance of spinel oxides, an efficient method of constructing hollow porous zinc cobaltate (ZnxCo3-xO4) nanocubes was established in this work. Bimetallic zeolitic imidazolate frameworks (ZIFs) were prepared through a facile self-assembly strategy, then hollow ZnxCo3-xO4 nanocubes were obtained by calcining the bimetallic ZIFs precursor. The structural features and optical properties of the ZnxCo3-xO4 nanocubes were comprehensively investigated by a series of characterization techniques. With higher specific surface area (about 100 m2 g-1), enhanced light absorbance in the whole range of 350-800 nm and lowered recombination of photogenerated electron hole pairs, these hollow nanocubes demonstrated attractive photocatalytic activity in degrading gaseous toluene, superior to traditional stoichiometric ZnCo2O4 nanoparticles. The photocatalytic process and related mechanism of toluene degradation were further investigated with in situ Fourier transform infrared (FTIR) spectroscopy and electron paramagnetic resonance (EPR) techniques. Photo-induced O2- and holes were assigned as main reactive species in the photocatalytic system with hollow ZnxCo3-xO4 nanocubes. PMID- 29408147 TI - Polymer nanosheets derived porous carbon nanosheets as high efficient electrocatalysts for oxygen reduction reaction. AB - Porous carbon nanosheets and corresponding heteroatom doped porous carbon nanosheets have shown great potential as active materials for energy conversion and storage in recent years. However, it remains great challenge to prepare such kind of new two-dimensional (2D) polymer nanosheets without using any templates. In this work, thiadiazole-containing expanded heteroazaporphyrinoid was designed as the building blocks for preparation of free-standing N/S-containing polymer nanosheets (PN) without using any templates. Most importantly, such PN can coordinate with transition metal ions to prepare Fe, N, and S containing PN-Fe. By using these PN-Fe as precursors, Fe/N/S co-doped porous carbon nanosheets (PCN FeNS) can be facilely prepared by direct pyrolysis under inert condition. The N and S contents of PCN-FeNS can reach up to 6.4 at.% and 0.8 at.%, respectively. For proof-of-concept, PCN-FeNS were further used as electrochemical catalysts for oxygen reduction reaction (ORR) in both alkaline and neutral media. Benefiting from the high surface area and rich-doping character, PCN-FeNS exhibited relatively high half-wave potential of down to 0.71 V, via a four-electron transfer mechanism (n = 3.87 at 0.65 V), as well as high diffusion limiting current density (JL = 5.02 mA cm-2), which are comparable to commercial precious metal based electrocatalysts. This study not only offers a new method to prepare conjugated polymer nanosheets, but also provides a new strategy to fabricate Fe/N/S co-doped porous carbon nanosheets for versatile energy-related applications. PMID- 29408148 TI - How struggling adult readers use contextual information when comprehending speech: Evidence from event-related potentials. AB - We investigated how struggling adult readers make use of sentence context to facilitate word processing when comprehending spoken language, conditions under which print decoding is not a barrier to comprehension. Stimuli were strongly and weakly constraining sentences (as measured by cloze probability), which ended with the most expected word based on those constraints or an unexpected but plausible word. Community-dwelling adults with varying literacy skills listened to continuous speech while their EEG was recorded. Participants, regardless of literacy level, showed N400 effects yoked to the cloze probability of the targets, with larger N400 amplitudes for less expected than more expected words. However, literacy-related differences emerged in an earlier time window of 170 300 ms: higher literacy adults produced a reduced negativity for strongly predictable targets over anterior channels, similar to previously reported effects on the Phonological Mapping Negativity (PMN), whereas low-literacy adults did not. Collectively, these findings suggest that in auditory sentence processing literacy may not notably affect the incremental activation of semantic features, but that comprehenders with underdeveloped literacy skills may be less likely to engage predictive processing. Thus, basic mechanisms of comprehension may be recruited differently as a function of literacy development-even in spoken language. PMID- 29408149 TI - Resting heart rate variability is associated with ex-Gaussian metrics of intra individual reaction time variability. AB - The relationships between vagally mediated heart rate variability (vmHRV) and the cognitive mechanisms underlying performance can be elucidated with ex-Gaussian modeling-an approach that quantifies two different forms of intra-individual variability (IIV) in reaction time (RT). To this end, the current study examined relations of resting vmHRV to whole-distribution and ex-Gaussian IIV. Subjects (N = 83) completed a 5-minute baseline while vmHRV (root mean square of successive differences; RMSSD) was measured. Ex-Gaussian (sigma, tau) and whole-distribution (standard deviation) estimates of IIV were derived from reaction times on a Stroop task. Resting vmHRV was found to be inversely related to tau (exponential IIV) but not to sigma (Gaussian IIV) or the whole-distribution standard deviation of RTs. Findings suggest that individuals with high vmHRV can better prevent attentional lapses but not difficulties with motor control. These findings inform the differential relationships of cardiac vagal control to the cognitive processes underlying human performance. PMID- 29408150 TI - First do no harm - The impact of financial incentives on dental X-rays. AB - This article assesses the impact of dentist remuneration on the incidence of potentially harmful dental X-rays. We use unique panel data which provide details of 1.3 million treatment claims by Scottish NHS dentists made between 1998 and 2007. Controlling for unobserved heterogeneity of both patients and dentists we estimate a series of fixed-effects models that are informed by a theoretical model of X-ray delivery and identify the effects on dental X-raying of dentists moving from a fixed salary to fee-for-service and patients moving from co-payment to exemption. We establish that there are significant increases in X-rays when dentists receive fee-for-service rather than salary payments and when patients are made exempt from payment. PMID- 29408151 TI - Female babies and risk-aversion: Causal evidence from hospital wards. AB - Using ultrasound scan data from paediatric hospitals, and the exogenous 'shock' of learning the gender of an unborn baby, the paper documents the first causal evidence that offspring gender affects adult risk-aversion. On a standard Holt Laury criterion, parents of daughters, whether unborn or recently born, become almost twice as risk-averse as parents of sons. The study demonstrates this in longitudinal and cross-sectional data, for fathers and mothers, for babies in the womb and new-born children, and in a West European nation and East European nation. These findings may eventually aid our understanding of risky health behaviors and gender inequalities. PMID- 29408152 TI - The Great Recession and Workers' Health Benefits. AB - During a recession, cost-sharing of employer-sponsored health benefits could increase to reduce labor costs in the U.S. Using a variation in the severity of recession shocks across industries, I find evidence that the enrollment rate of high deductible health plans (HDHPs) among workers covered by employer-sponsored health benefits increased more among firms in industries that experienced severe recession shocks. As potential mechanisms, I study employer-side and worker-side mechanisms. I find that employers changed health benefit offerings to force or incentivize workers to enroll in HDHPs. But I find little evidence of an increase in workers' demand for HDHPs due to a reduction in income. These results suggest that the HDHP enrollment rate increased during the Great Recession, as employers tried to save costs of offering health benefits. PMID- 29408153 TI - Do medical marijuana laws reduce addictions and deaths related to pain killers? AB - Recent work finds that medical marijuana laws reduce the daily doses filled for opioid analgesics among Medicare Part-D and Medicaid enrollees, as well as population-wide opioid overdose deaths. We replicate the result for opioid overdose deaths and explore the potential mechanism. The key feature of a medical marijuana law that facilitates a reduction in overdose death rates is a relatively liberal allowance for dispensaries. As states have become more stringent in their regulation of dispensaries, the protective value generally has fallen. These findings suggest that broader access to medical marijuana facilitates substitution of marijuana for powerful and addictive opioids. PMID- 29408154 TI - Does long-term care subsidization reduce hospital admissions and utilization? AB - We use quasi-experimental evidence on the expansion of the public subsidization of long-term care to examine the causal effect of a change in caregiving affordability on the delivery of hospital care. More specifically, we examine a reform that both introduced a new caregiving allowance and expanded the availability of publicly funded home care services, on both hospital admissions (both on the internal and external margin) and length of stay. We find robust evidence of a reduction in both hospital admissions and utilization among both those receiving a caregiving allowance and, albeit less intensely, among beneficiaries of publicly funded home care, which amounts to 11% of total healthcare costs. These effects were stronger when regions had an operative regional health and social care coordination plan in place. Consistently, a subsequent reduction in the subsidy, five years after its implementation, is found to significantly attenuate such effects. We investigate a number of potential mechanisms, and show a number of falsification and robustness checks. PMID- 29408155 TI - The full-length Cry1Ac protoxin without proteolytic activation exhibits toxicity against insect cell line CF-203. AB - The new dual model for Bacillus thuringiensis insecticidal mechanism proposed that Cry1A protoxins without proteolytic activation could bind to insect midgut receptors to exert toxicity. To evaluate insecticidal potency of Cry1Ac protoxin at precluding interference of midgut proteases, the cytotoxicity of Cry1Ac protoxin against midgut cell line CF-203 derived from Choristoneura fumiferana was analyzed. It was revealed that Cry1Ac protoxin was toxic to CF-203 cells and there existed certain differences in the cytological changes when treated with protoxin and toxin. Our cell-based study provided direct evidence for the proposed dual model and shed light on exploring the difference between two toxic pathways elicited by intact protoxin and activated toxin. PMID- 29408156 TI - Exposing Metarhizium acridum mycelium to visible light up-regulates a photolyase gene and increases photoreactivating ability. AB - Metarhizium acridum is an entomopathogen currently used against acridids. We have previously reported that exposing mycelium to visible light increases M. acridum tolerance to ultraviolet-B (UV-B) radiation. Here we evaluated if light could also increase tolerance to ultraviolet-C (UV-C) radiation. We observed that, as opposed to UV-B radiation, light did not increase tolerance to UV-C radiation under dark repair conditions. However, light did increase tolerance to UV-C radiation if photoreactivating light was present after UV-C exposure. Quantitative PCR experiments revealed that light up-regulates a photolyase gene. This is the first report showing that light regulates photoreactivating ability in M. acridum. PMID- 29408157 TI - Insulin resistance as estimated by homeostasis model assessment predicts incident post-stroke depression in Chinese subjects from ischemic stroke. AB - OBJECTIVE: Previous studies suggested that insulin resistance (IR) may be a significant causal risk factor for cardiovascular events and depression independent of other risk factors. In this prospective, we assess the value of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at admission to predict post-stroke depression (PSD) later developed at 3 months follow-up. METHODS: This prospective, multicenter cohort study was conducted from January 2015 through December 2016 in China. Clinical information and HOMA-IR was assessed at admission. Neurological and neuropsychological evaluations were conducted at the 3-month follow-up. RESULTS: In the study population, 56.6% were male and the median age was 59 years (interquartile range [IQR]: 51-69). One hundred and eighty-six patients (26.6%) showed depression at 3 months after admission and in 53 patients (28.5%) this depression was classified as severe. For each 1-unit increase of HOMA-IR, the unadjusted and adjusted risk of PSD increased by 63% (odds ratios [OR]: 1.63; 95% confidence interval [CI]:1.44-1.85; P < 0.001) and 27% (1.27; 1.13-1.39; P = 0.002). In a multivariate model using the fourth quartiles of HOMA-IR vs. quartiles 1 through 3 together with the clinical variables, the marker displayed prognostic information (PSD: OR for fourth quartile, 2.76 [95% CI, 1.66-3.73; P = 0.003]). CONCLUSIONS: The data suggests that the HOMA-IR may be of potential clinical relevance in identifying stroke patients at risk of developing depression, independent of the well established predictors. PMID- 29408158 TI - Course, risk factors, and mental health outcomes of excessive daytime sleepiness in rural Chinese adolescents: A one-year prospective study. AB - BACKGROUND: This study aimed to examine the one-year incidence and persistence of excessive daytime sleepiness (EDS) in rural Chinese adolescents and their risk factors. In addition, we also aimed to explore the potential bidirectional associations of EDS with anxiety symptoms and depressive symptoms. METHODS: A total of 3736 adolescents from 5 high schools from rural area in the south China were eligible for follow-up. Among them, 2787 responded to follow-up after one year. EDS was defined as having a total score of the Epworth Sleepiness Scale over 10. RESULTS: The one-year persistence rate and incidence rate of EDS were 27.6% and 9.3%, respectively. After controlling for age and sex, new incident EDS was significantly associated with perceived high study stress, depressive symptoms, insomnia symptoms, and high life events at baseline. Baseline EDS predicted new onsets of depression and anxiety at follow-up. Cross-lagged analyses further revealed that there were bidirectional associations between EDS and anxiety symptom and between EDS and depressive symptoms. Persistent EDS was only associated with eveningness chronotype. In particular, short sleep duration and obesity were associated with neither new incidence nor persistence of EDS in this population. LIMITATIONS: All measures relied on self-reported questionnaires rather than objective assessments, which might have led to report bias. CONCLUSIONS: We have identified a number of risk factors of the one-year incidence of EDS (such as perceived high study stress, depressive symptoms, insomnia symptoms, and high life events) and persistence of EDS (eveningness chronotype) in rural adolescents. There is a reciprocal relationship of EDS with anxiety and depression. In this population, sleep loss and obesity seem not related to the course of EDS. PMID- 29408159 TI - A NATURALISTIC EXPLORATORY STUDY OF OBSESSIVE-COMPULSIVE BIPOLAR COMORBIDITY IN YOUTH. AB - BACKGROUND: Growing evidence supports the comorbidity between bipolar disorder (BD) and obsessive-compulsive disorder (OCD) in children and adolescents. Our aim is to further explore clinical and treatment implications of this comorbidity, as it appears in clinical practice. METHOD: The sample included 429 consecutive patients with BD and/or OCD as primary diagnoses, followed for a mean period of 6 months (range 4-9 months), 172 with BD (102 males, mean age 13.7+/-2.9 years), 169 with OCD (118 males, mean age of 13.2+/-2.7 years) and 88 with comorbid BD+OCD (56 males, mean age 14.2+/-2.6 years, 52 with BD as the primary diagnosis), followed for a mean period of 6 months (range 4-9 months). The comorbid group was compared to pure BD and OCD groups, to explore differential clinical and treatment features. RESULTS: The BD-OCD comorbidity was found in 33.8% of the BD patients and in 34.2% of the OCD patients. Age at onset of BD and OCD were not different in pure and "comorbid" groups. The comorbid group presented a higher occurrence of BD type II and hoarding symptoms, and more frequently received a psychotherapy and second generation antipsychotics, but it presented the poorest outcome in terms of response to treatments. Severity at baseline (clinical severity and functional impairment), hoarding obsessions and compulsions, and conduct disorder comorbidity were associated with a treatment non-response. LIMITATIONS: A selection bias may have increased the rate of comorbidity, as most of the patients were referred to our tertiary hospital for severe BD and/or OCD and pharmacological treatment. We have used CGI-I as an outcome measure, not a specific measure of BD or OCD symptoms' severity and improvement. The short duration of the follow-up may limit our conclusions. CONCLUSIONS: The timely identification of BD-OCD comorbidity may have relevant clinical implications in terms of symptomatology, course, treatment and outcome. PMID- 29408160 TI - Ten-year prediction of suicide death using Cox regression and machine learning in a nationwide retrospective cohort study in South Korea. AB - BACKGROUND: Death by suicide is a preventable public health concern worldwide. The aim of this study is to investigate the probability of suicide death using baseline characteristics and simple medical facility visit history data using Cox regression, support vector machines (SVMs), and deep neural networks (DNNs). METHOD: This study included 819,951 subjects in the National Health Insurance Service (NHIS)-Cohort Sample Database from 2004 to 2013. The dataset was divided randomly into two independent training and validation groups. To improve the performance of predicting suicide death, we applied SVM and DNN to the same training set as the Cox regression model. RESULTS: Among the study population, 2546 people died by intentional self-harm during the follow-up time. Sex, age, type of insurance, household income, disability, and medical records of eight ICD 10 codes (including mental and behavioural disorders) were selected by a Cox regression model with backward stepwise elimination. The area of under the curve (AUC) of Cox regression (0.688), SVM (0.687), and DNN (0.683) were approximately the same. The group with top .5% of predicted probability had hazard ratio of 26.21 compared to that with the lowest 10% of predicted probability. LIMITATIONS: This study is limited by the lack of information on suicidal ideation and attempts, other potential covariates such as information of medication and subcategory ICD-10 codes. Moreover, predictors from the prior 12-24 months of the date of death could be expected to show better performances than predictors from up to 10 years ago. CONCLUSIONS: We suggest a 10-year probability prediction model for suicide death using general characteristics and simple insurance data, which are annually conducted by the Korean government. Suicide death prevention might be enhanced by our prediction model. PMID- 29408161 TI - Stimuli that signal the availability of reward break into attentional focus. AB - Mounting evidence has shown that a task-irrelevant, previously reward-associated stimulus can capture attention even when attending to this stimulus impairs the processing of the current target. Here we investigate whether a stimulus that merely signals the availability of reward could capture attention and interfere with target processing when it is located outside of attentional focus. In three experiments, a target was always presented at the bottom of the lower visual field to attract focal attention. A distractor signalling high or low reward availability for the current trial was presented around the target with a variable distance between them. This distractor was task-irrelevant; getting distracted by it could potentially result in an omission of reward. For the high reward condition, the distractor located adjacent to the target more severely interfered with target processing than the distractor at a relatively distant location; for the low-reward condition, distractors at different locations had the same impact upon target processing. Relative to the low-reward distractor, the high-reward distractor impaired target processing, but only at the location adjacent to the target. When the target location was uncertain such that attention was unable to be directed to the target in advance, the high-reward distractor interfered with target processing at both the adjacent and distant locations. Overall, these results suggest that a task-irrelevant stimulus can break into focus of attention by simply signalling the availability of reward even when getting distracted by this stimulus is counterproductive to obtaining reward. PMID- 29408162 TI - Sensory and motor differences in Autism Spectrum Conditions and developmental coordination disorder in children: A cross-syndrome study. AB - Recent research has shown that Developmental coordination disorder (DCD) can present with some similar symptomology as Autism Spectrum Conditions (ASC). This paper therefore explored the similarities and differences in coordination and sensory responsivity between DCD and ASC. 77 children took part: 42 (35 male, 7 female) with ASC (ages 7-21: mean age 12.23 years), 26 (19 male, 7 female) with DCD (ages 7-21; mean age 11.07 years) and 9 (2 male, 7 female) with ASC and DCD (ages 8-15; mean age 12.27). All groups completed a battery of validated parent report measures online that included motor coordination (DCDQ), sensory responsivity (SPC-R) and social communication measures (AQ). Results showed no significant differences in coordination, and some significant differences in sensory responsivity between ASC and DCD (increased visual and auditory responsivity and decreased proprioception). Exploratory analysis showed that these differences showed good validity in identifying the diagnosis of ASC and DCD. These results elucidate the underlying causes of motor coordination difficulties in both conditions. Specifically, ASC coordination difficulties appear linked to visual processing impairments, whilst DCD coordination difficulties appear to be linked to spatial processing. This may aid better diagnosis and intervention for these conditions. PMID- 29408163 TI - Effects of motor imagery and action observation on hand grip strength, electromyographic activity and intramuscular oxygenation in the hand gripping gesture: A randomized controlled trial. AB - The aim of this study was to evaluate the effects of motor imagery and action observation combined with a hand grip strength program on the forearm muscles. Sixty subjects were selected and randomized into three groups: motor imagery (n = 20), action observation (n = 20), or a control group (n = 20). Outcome measures included hand grip strength, electromyographical activity and intramuscular oxygenation. The hand grip strength significantly increased in the motor imagery (p < .001) and action observation (p < .001) groups compared with the control group, although there were no differences between the both groups (p = .30). In the electromyographical activity, intra-group significant differences were found in motor imagery (p = .002) and action observation (p = .003) groups, although there were no differences between the both groups (p = 1.00) Intramuscular oxygenation results did not show any statistically significant differences between any of the study groups (p > .05). Our results suggest that both motor imagery and action observation training, combined with a hand grip strength program, present a significant strength gain and significant change in the strength and electromyographical activity of the forearm muscles, however no change was found in intramuscular oxygenation. PMID- 29408164 TI - The limits of aerial techniques for producing twist in forward 11/2 somersault dives. AB - An angle-driven computer simulation model of aerial movement was used to determine the maximum amount of twist that can be produced in a forward 11/2 somersault dive from a three-metre springboard using various aerial twisting techniques. The segmental inertia parameters of an elite springboard diver were used in the simulations and lower bounds were placed on the durations of arm and hip angle changes based on recorded performances of twisting somersaults. A limiting dive was identified as that producing the largest possible whole number of twists. Simulations of the limiting dives were found using simulated annealing optimisation to produce the required amounts of somersault, tilt and twist after a flight time of 1.5 s. Additional optimisations were then run to seek solutions with the arms less adducted during the twisting phase. It was found that the upper limits ranged from two to five twists with arm abduction ranges lying between 6 degrees and 17 degrees . Similar results were obtained when the inertia parameters of two other springboard divers were used. PMID- 29408165 TI - Electrodeposition to construct mechanically robust chitosan-based multi-channel conduits. AB - A series of electrodeposited chitosan-based multi-channel conduits (ECMC) with potential for peripheral nerve tissue engineering were constructed using a novel electrodeposition method combined with homemade molds. The structural and mechanical properties of the ECMC were characterized by scanning electron microscopy, Fourier-transformed infrared spectroscopy, X-ray diffraction patterns and mechanical testing. The results showed that the electrodeposition process did not change the chemical structure of the chitosan molecules, but endowed the ECMC with high levels of flexibility and elasticity. Hemocompatibility and cytocompatibility of the ECMC were evaluated by hemolysis assay, MTT assay and live/dead assay. The results indicated that the ECMC had a low hemolysis rate, and can promote cell proliferation and support cell adhesion. This work provides a safe and feasible electrodeposition method to construct chitosan-based conduits with potential applications for peripheral nerve tissue engineering. PMID- 29408166 TI - An endoglycosidase-assisted LC-MS/MS-based strategy for the analysis of site specific core-fucosylation of low-concentrated glycoproteins in human serum using prostate-specific antigen (PSA) as example. AB - Recently, site-specific fucosylation of glycoproteins has attracted attention as it can be associated with several types of cancers including prostate cancer. However, individual glycoproteins, which might serve as potential cancer markers, often are very low-concentrated in complex serum matrices and distinct glycan structures are hard to detect by immunoassays. Here, we present a mass spectrometry-based strategy for the simultaneous analysis of core-fucosylated and total prostate-specific antigen (PSA) in human serum in the low ng/ml concentration range. Sample preparation comprised an immunoaffinity capture step to enrich total PSA from human serum using anti-PSA antibody coated magnetic beads followed by consecutive two-step on-bead partial deglycosylation with endoglycosidase F3 and tryptic digestion prior to LC-MS/MS analysis. The method was shown to be linear from 0.5 to 60 ng/ml total PSA concentrations and allows the simultaneous quantification of core-fucosylated PSA down to 1 ng/ml and total PSA lower than 0.5 ng/ml. The imprecision of the method over two days ranged from 9.7-23.2% for core-fucosylated PSA and 10.3-18.3% for total PSA depending on the PSA level. The feasibility of the method in native sera was shown using three human specimens. To our knowledge, this is the first MS-based method for quantification of core-fucosylated PSA in the low ng/ml concentration range in human serum. This method could be used in large patient cohorts as core fucosylated PSA may be a diagnostic biomarker for the differentiation of prostate cancer and other prostatic diseases, such as benign prostatic hyperplasia (BPH). Furthermore, the described strategy could be used to monitor potential changes in site-specific core-fucosylation of other low-concentrated glycoproteins, which could serve as more specific markers ("marker refinement") in cancer research. PMID- 29408167 TI - Predicting cardiogenic pulmonary edema in heart failure patients by using an N terminal pro-b-type natriuretic peptide (NT-pro BNP) -based score. AB - BACKGROUND: Cardiogenic pulmonary edema (CPE) is a life-threatening emergency necessitating aggressive management. We conducted this study to test the hypothesis that a combination of N-terminal pro-b-type natriuretic peptide (NT pro-BNP) and some relevant clinical factors may provide better predictability for CPE in heart failure (HF) patients. METHODS: This retrospective study enrolled adult HF patients hospitalized during January 2011 to December 2013. After determining the independent predictors for the occurrence of CPE, a novel NT-pro BNP-based diagnostic score for predicting CPE was established. RESULTS: A total of 269 patients (mean age, 74.5 +/- 13.6 years; female, 53.9%) were enrolled, and categorized into CPE group (n = 80, 29.7%) and non-CPE group (n = 189, 70.3%). Several factors such as "Serum NT-pro-BNP level > 6980 mg/dl," "systemic blood pressure > 170 mm Hg," "heart rate > 120 bpm," "with rales in breathing sound," "with jugular vein engorgement," "with NYHA Fc III/IV," "with chronic lung disease" and "with angiotensin converting enzyme inhibitors/angiotensin receptor blocker" were found to be associated with the existence of CPE. A novel NT-pro BNP based scoring system containing these risk factors was proposed and proven excellent in predicting CPE. CONCLUSIONS: The NT-pro-BNP scoring system could predict CPE in HF patients. PMID- 29408168 TI - Relationship between postprandial lipemia and atherogenic factors in healthy subjects by considering gender differences. AB - BACKGROUND: Postprandial triglyceride concentrations are clinically significant and independent predictor of cardiovascular disease risk. The purpose of this study was to determine postprandial TG ranges in healthy subjects by considering gender differences. Secondly, assess the relationship between postprandial lipemia and atherogenic indicators. Finally, investigate the use of the postprandial 4h TG test instead of the area under the curve (AUC). METHODS: Postprandial lipemia was investigated using the standardized oral fat tolerance test (OFTT) in 96 healthy subjects (45 female/51 male). Study group was categorized into tertiles based on AUC calculated using TG concentrations at fasting and 2, 4 and 6h after OFTT. Lipid, lipoproteins, apolipoproteins, LDL subfractions and oxidized LDL (oxLDL) were evaluated in tertiles in both sex groups. RESULTS: The cut-off concentrations for postprandial 4-hour TG concentrations in female and male were 3.20 mmol/L and 4.59 mmol/L, respectively. We observed higher concentrations for atherogenic indicates like small dense-low density lipoprotein (sdLDL), oxLDL values in top tertiles for both groups (P < 0.05). Cohen's kappa coefficients for the agreement of AUC and 4h postprandial TG tests were 0.935, 0.970, 0.469 (P = 0.0001) in female, male and total study group, respectively. CONCLUSION: Due to predominant effects of gender differences on postprandial lipemia, postprandial TG cut-off values for female and male subjects should be determined separately. Postprandial lipemia may be associated with atherogenic tendency by changing lipids, lipoproteins, sdLDL and oxLDL concentrations, especially in males. Four-hour postprandial TG concentrations emerged as a useful and reliable marker for evaluation of postprandial lipemia. PMID- 29408169 TI - Association between obesity and bladder cancer recurrence: A meta-analysis. AB - BACKGROUND: The association between obesity and bladder cancer prognosis is not well-defined. This meta-analysis was performed to explore whether obesity is related to overall survival (OS) and bladder cancer recurrence. METHODS: Relevant English-language studies were identified by searching PubMed(r) up to November 1, 2017. We pooled the hazard ratios (HR) and 95% confidence intervals (CIs) using a random effect model. Dose-response relationship, subgroup and sensitivity were also analyzed. RESULTS: Eleven studies were included. Recurrence rate of bladder cancer was significantly greater in obese (HR = 1.76, 95% CI: 1.36-2.28) vs normal weight patients. Stratification analysis showed that females had higher recurrence risk than males (HR = 1.17, 95% CI: 1.05-1.31). Obesity was not significantly associated with bladder cancer OS (HR = 1.21, 95% CI: 0.97-1.52). Dose-response relationship analysis revealed a linear association between BMI and risk of recurrence. Each one kg/m2 increase in BMI was related to a 1.3% increased risk of bladder cancer recurrence (HR = 1.01, 95% CI = 1.01 to 1.02). CONCLUSIONS: This meta-analysis revealed that obesity may be a risk factor for bladder cancer recurrence. PMID- 29408170 TI - Acute phase reactant, Pentraxin 3, as a novel marker for the diagnosis of rheumatoid arthritis. AB - INTRODUCTION: Pentraxins are a group of highly conserved acute-phase reactant proteins and play crucial role as modulators of inflammatory processes. Pentraxin 3 (PTX3) is primarily produced and released by vascular cell wall, hence, we attempt to establish the role of PTX3 as a biomarker for Rheumatoid Arthritis (RA) compared to CRP. METHODS: Thirty patients having active RA as cases and 30 osteoarthritis (OA) patients as controls were recruited. Paired serum and synovial fluid samples were analysed for concentrations of both PTX3 and CRP by using high sensitivity ELISA kit and ROC curve was plotted. RESULTS: Concentrations of PTX3 and CRP were significantly higher in RA patient serum (p < 0.0001) as well as in synovial fluid (p < 0.0001) and correlated with disease severity. Upon correlation analysis, positive correlation was found between serum and synovial fluid concentrations of PTX3 and CRP. The diagnostic potential of PTX3 was observed in synovial fluid while combination of PTX3 and CRP showed better sensitivity in serum. CONCLUSION: PTX3 found to be sensitive non-invasive indicator of clinical arthritic activity in RA patients when compared to traditional markers like CRP. Combination of PTX3 and CRP could serve as better differential diagnostic markers for RA after validation in larger patient cohort. PMID- 29408171 TI - Serum S100A12 as a prognostic biomarker of severe traumatic brain injury. AB - BACKGROUND: S100A12 is related to acute brain injury and inflammation. We investigated the clinical prognostic value of serum S100A12 in patients with severe traumatic brain injury (sTBI). METHODS: Serum S100A12, S100B, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) concentrations were measured in 102 healthy controls and 102 sTBI patients. We recorded 30-day mortality and in-hospital major adverse events (IMAEs) including acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. Trauma severity was assessed by admission Glasgow Coma Scale scores. RESULTS: When compared to the controls, serum S100A12, S100B, CRP, IL-6 and TNF-alpha concentrations were significantly increased in the patients. Serum concentrations of S100A12 significantly correlated with admission Glasgow Coma Scale scores and serum concentrations of S100B, CRP, IL-6 and TNF alpha. Patients with any IMAEs or non-survivors within 30 days had obviously higher serum concentrations of S100A12, S100B, CRP, IL-6 and TNF-alpha than other remaining ones. Serum S100A2 was independently associated with IMAEs and 30-day mortality and overall survival. Receiver operating characteristic curve analysis showed that S100A12 concentrations had significant discriminatory ability for patients at risk of any IMAEs and death within 30 days. CONCLUSION: S100A12 might be associated with brain inflammation and evaluation of serum concentrations of S100A12 could be helpful in the early prognostic prediction in sTBI patients. PMID- 29408172 TI - Association of serum bilirubin with renal outcomes in Han Chinese patients with chronic kidney disease. AB - BACKGROUND: Oxidative stress and inflammation play pivotal roles in chronic kidney disease (CKD). Bilirubin is an endogenous anti-inflammatory antioxidant. However, the relationship between serum bilirubin and renal outcomes in CKD is controversial. We explored the association of serum bilirubin levels with renal outcomes in Han Chinese patients with CKD. METHODS: Clinical and laboratory data were collected from 316 patients with CKD. The primary clinical endpoint was renal replacement therapy or death. The association between serum bilirubin and clinical parameters was assessed by correlation analysis. Multiple Cox regression analysis was used to explore the relationship between serum bilirubin and renal outcomes in patients with CKD. RESULTS: Serum total and indirect bilirubin were positively correlated with estimated glomerular filtration rate, but negatively correlated with 24-h urine protein in patients with CKD. Serum total and indirect bilirubin were inversely associated with CKD stages in patients with CKD stages 1 5. Multiple Cox regression analysis demonstrated that the higher concentration of serum total bilirubin was independently associated with better renal outcomes in CKD. CONCLUSIONS: Our results suggest that serum total bilirubin may have protective effects on kidneys. PMID- 29408173 TI - PTEN in kidney cancer: A review and meta-analysis. AB - BACKGROUND: Kidney cancer is one of the most common cancers in the USA causing 14,400 deaths per year. The phosphatase and tensin homolog (PTEN) has been extensively documented as a tumor suppresser gene in cancer. However, there is unclear evidence for its clinicopathological and prognostic role in kidney cancer. METHODS: A systematic review of literature assessing PTEN expression and clinical outcome in patients with kidney cancer. Web of Science, PubMed, Embase, and Chinese databases were searched for collecting for the eligible studies providing sufficient information. Pooled odds ratios (ORs) and hazard ratios (HRs) were respectively used to evaluate the association between PTEN levels and the clinicopathological features and clinical outcomes. RESULTS: A total of 35 studies enrolling 4532 patients were finally included in this study. For the survival outcome, the result suggested that shorter overall survival (OS) was correlated with low PTEN expression (HR = 0.57, 95% CIs: 0.45-0.74, P < 0.0001). The meta-analysis indicated a significantly increased risk of tumorigenesis in the PTEN low-level group relative to the control group (OR = 0.098, 95% CIs: 0.067-0.143, P < 0.001). Moreover, the results displayed the positive correlation between poorer differentiation (OR = 0.234, 95% CIs: 0.133-0.410, P < 0.001), distant metastasis (OR = 0.179, 95% CIs: 0.092-0.350, P = 0.001), lymph node metastasis (OR = 0.252, 95% CIs: 0.113-0.563, P < 0.001), advanced clinical stages (OR = 0.233, 95% CI: 0.133, 0.406, P < 0.001) and low PTEN expression. Finally, there was no obvious publication bias found in the meta-analysis. CONCLUSIONS: Decreased PTEN was associated with poorer survival outcomes of patients with kidney cancer and PTEN acts as a tumor suppressor in tumorigeneses and progression in kidney cancer. PMID- 29408176 TI - Microwave-assisted enzymatic hydrolysis of DNA for mass spectrometric analysis: A new strategy for accelerated hydrolysis. AB - Study of DNA base composition, DNA adducts and modification in its primary structure is a subject of interest in different fields of scientific research. Various methods like immunochemistry, capillary electrophoretic separation, chromatographic separation coupled with mass spectrometric (LC-MS/MS) detection have been developed for DNA analysis. During the past decade LC-MS/MS has emerged as a more sensitive and selective technique and now frequently used for the analysis of DNA. The workflow for the DNA analysis include DNA extraction, hydrolysis of DNA into mononucleosides and analysis. Though high-throughput methods are available for the analysis DNA hydrolysis oftentimes is a rate limiting step. Conventional enzymatic hydrolysis of DNA using a multienzyme mixture will take a minimum of 6-17 h to complete the hydrolysis. In this work, we developed an accelerated enzymatic hydrolysis of DNA using microwave technology for the first time. 1.00 MUg of calf thymus DNA was used to demonstrate the microwave assisted enzymatic hydrolysis of DNA. The resultant mononucleosides were separated on Atlantis T3 (50 * 2.1 mm i.d.; 3 MU particle size) C18 column and analyzed on ABSCIEX QTRAP 5500 LC/MS system. The sample through put and recovery of microwave-assisted digestion were compared with the conventional enzymatic hydrolysis. Efficient digestion of DNA with a performance similar to that obtained by the conventional overnight digestion procedure was attained in just 30 min with a hydrolysis yield of >=90%. Furthermore, our method was found to be much more accurate and easier to perform. Thus, this new application of microwave technology to DNA enzymatic digestion will facilitate the application of DNA analysis in biological and clinical research. PMID- 29408174 TI - Improved artefact removal from EEG using Canonical Correlation Analysis and spectral slope. AB - BACKGROUND: Contamination of scalp measurement by tonic muscle artefacts, even in resting positions, is an unavoidable issue in EEG recording. These artefacts add significant energy to the recorded signals, particularly at high frequencies. To enable reliable interpretation of subcortical brain activity, it is necessary to detect and discard this contamination. NEW METHOD: We introduce a new automatic muscle-removal approach based on the traditional Blind Source Separation Canonical Correlation Analysis (BSS-CCA) method and the spectral slope of its components. We show that CCA-based muscle-removal methods can discriminate between signals with high correlation coefficients (brain, mains artefact) and signals with low correlation coefficients (white noise, muscle). We also show that typical BSS-CCA components are not purely from one source, but are mixtures from multiple sources, limiting the performance of BSS-CCA in artefact removal. We demonstrate, using our paralysis dataset, improved performance using BSS-CCA followed by spectral-slope rejection. RESULT: This muscle removal approach can reduce high-frequency muscle contamination of EEG, especially at peripheral channels, while preserving steady-state brain responses in cognitive tasks. COMPARISON WITH EXISTING METHODS: This approach is automatic and can be applied on any sample of data easily. The results show its performance is comparable with the ICA method in removing muscle contamination and has significantly lower computational complexity. CONCLUSION: We identify limitations of the traditional BSS-CCA approach to artefact removal in EEG, propose and test an extension based on spectral slope that makes it automatic and improves its performance, and results in performance comparable to competitors such as ICA-based artefact removal. PMID- 29408177 TI - Recombinase polymerase amplification applied to plant virus detection and potential implications. AB - Several isothermal techniques for the detection of plant pathogens have been developed with the advent of molecular techniques. Among them, Recombinase Polymerase Amplification (RPA) is becoming an important technique for the rapid, sensitive and cost-effective detection of plant viruses. The RPA technology has the advantage to be implemented in field-based scenarios because the method requires a minimal sample preparation, and is performed at constant low temperature (37-42 degrees C). The RPA technique is rapidly becoming a promising tool for use in rapid detection and further diagnostics in plant clinics and monitoring quarantine services. This paper presents a review of studies conducted using RPA for detection/diagnosis of plant viruses with either DNA genomes (Banana bunchy top virus, Bean golden yellow mosaic virus, Tomato mottle virus, Tomato yellow leaf curl virus) or RNA genomes (Little Cherry virus 2, Plum pox virus and Rose rosette virus). PMID- 29408178 TI - Characterization of fatty acid amide hydrolase activity by a fluorescence-based assay. AB - Fatty acid amide hydrolase (FAAH) is involved in many human diseases, particularly cancer, pain and inflammation as well as neurological, metabolic and cardiovascular disorders. Therefore, FAAH is an attractive target for the development of low-molecular-weight inhibitors as therapeutics, which requires robust assays that can be used for high-throughput screening (HTS) of compound libraries. Here, we report the development of a fluorometric assay based on FAAH's ability to effectively hydrolyze medium-chain fatty acid amides, introducing N-decanoyl-substituted 5-amino-2-methoxypyridine (D-MAP) as new amide substrate. D-MAP is cleaved by FAAH with an 8-fold larger specificity constant than the previously reported octanoyl-analog Oc-MAP (Vmax/Km of 1.09 and 0.134 mL min-1 mg-1, respectively), with both MAP derivatives possessing superior substrate properties and much increased aqueous solubility compared to the respective p-nitroaniline compounds D-pNA and Oc-pNA. The new assay with D-MAP as substrate is highly sensitive using a lower enzyme concentration (1 MUg mL-1) than literature-reported fluorimetric FAAH assays. In addition, D-MAP was validated in comparison to the substrate Oc-MAP for the characterization of FAAH inhibitors by means of the reference compounds URB597 and TC-F2 and was shown to be highly suitable for HTS in both kinetic and endpoint assays (Z' factors of 0.81 and 0.78, respectively). PMID- 29408179 TI - Kinetic studies of serine protease inhibitors in simple and rapid 'active barrier' model systems - Diffusion through an inhibitor barrier. AB - A model based on gelatin for protease activity studies was designed. The model is also extended to study the efficiency of inhibitors in a separate protective layer covering the layer containing the target substrate. A good correlation between protease concentration and the size of erosion wells formed in a plain gelatin layer was observed. Similarly, increased concentration of inhibitors gave a systematic decrease in well area. Kinetic analyses of the two-layer model in a spectrophotometric plate reader with a fixed concentration of substrate in the bottom layer displayed a strict dependence of both inhibitor concentration and thickness of the top "protective" layer. An apparent, but weaker inhibition effect was also observed without inhibitors due to diffusional and erosion delay of enzyme transport to the substrate-containing layer. PMID- 29408180 TI - Enhancing patient-level clinical data access to promote evidence-based practice and incentivize therapeutic innovation. AB - Clinical trials are crucial to determining the human safety and efficacy of new therapeutic innovations. Extraordinary amounts of human experiential data are generated over the course of any clinical trial, however, much of these data is never made publicly accessible. Improved, reliable data sharing is essential to inform clinical decisions and incentivize further therapeutic improvements; this need, and the call and concept to enhance patient-level clinical trial data accessibility is not new. Several recent public and private shifts in clinical data sharing policies and procedures promise to improve access and data utility to reduce waste in research and increase efficiency of evidence synthesis. Nonetheless, pharmaceutical industry remain reluctant to share full clinical data sets at some level to protect their commercial interests and avoid misuse of their data. Here, we review the landscape of emerging regulations related to the sharing of patient level data and current clinical data access models of major pharmaceutical companies. We also summarize the different measures that could satisfy both clinical data producers and users in achieving the benefits of accessing patient-level data while mitigating any associated risks. PMID- 29408181 TI - Extracellular vesicles as modulators of wound healing. AB - Impaired healing of cutaneous wounds and ulcers continues to have a major impact on the quality of life of millions of people. In recent years, the capacity for stem and progenitor cells to promote wound repair has been investigated with evidence that secreted factors are responsible for the observed therapeutic benefits. This review addresses current evidence in support of stem/progenitor cell-derived extracellular vesicles (EVs) as a regenerative therapy for acceleration of wound healing. Encouraging results for local or systemic administration of EVs have been reported in a range of clinically-relevant animal models of cutaneous wounds. Furthermore, a number of plausible mechanisms involving EV-mediated transfer of proteins and RNAs that trigger pro-repair pathways in target cells have been demonstrated experimentally. However, for successful clinical translation in the coming years, further emphasis on standardized experimental protocols, detailed methodological reporting and clear definition of EV-based therapeutic products will be required. PMID- 29408183 TI - Invasive pulmonary aspergillosis mimicking organizing pneumonia after mTOR inhibitor therapy: A case report. AB - A 67-year-old man presented to the hospital with complaints of fever and cough. He had a past medical history of renal cell carcinoma and had just started treatment with temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor. A 1-week course of antibiotics did not have any effect on his symptoms. A chest computed tomography (CT) scan showed the reversed halo sign (RHS). Organizing pneumonia induced by mTOR inhibitor treatment was initially considered. However, transbronchial biopsy revealed clusters of fungal organisms, suggesting infection with Aspergillus spp. Within just 2 weeks, a CT scan showed drastic enlargement of the cavitary lesion, with multiple newly formed consolidations. The patient was diagnosed with invasive pulmonary aspergillosis. Concomitant treatment with voriconazole and micafungin was started. Two weeks after the initiation of treatment, he became afebrile with gradual regression of the cavitary lesion and consolidations. PMID- 29408184 TI - "US-detonated nano bombs" facilitate targeting treatment of resistant breast cancer. AB - Reversal of drug resistance and targeted therapy are the keys but remain challenging in resistant breast cancer treatment. Herein, low frequency ultrasound detonated "nano bombs" were rationally designed and used for treatment of resistant breast cancer. For the 'nano bombs', the ammunition (Doxorubicin, DOX) was loaded into the ammunition depot (hollow mesoporous TiO2, MTNs), and the safety device (dsDNA) was wrapped on the surface of MTNs to avoid the unexpected DOX release. We found the "US-detonated explosive" abilities of "nano bomb" MTNs (NBMTNs), including explosive generation of ROS, explosive release of DOX, US triggered lysosome escape and mitochondrial targeting in the in vitro and in vivo studies. More importantly, the drug resistance of MCF-7/ADR cells could be reversed via the inhibition of mitochondrial energy supply approach caused by the "explosion" of NBMTNs. Furthermore, NBMTNs combined the superior chemotherapy efficacy of DOX and potent SDT efficacy in one single platform and significantly enhanced the anticancer efficacy. Our results demonstrate an approach for reversing resistance and specific targeting of tumors using 'US-detonated nano bombs'. PMID- 29408185 TI - Short primiparous women are at an increased risk for gestational diabetes mellitus. AB - OBJECTIVES: Both short stature and adiposity are risk factors for gestational diabetes mellitus (GDM). The aim of this study was to simultaneously evaluate the importance of stature and degree of adiposity on development of GDM in primiparous women. STUDY DESIGN: Longitudinal cohort study. METHODS: In the city of Vantaa, Finland, between 2009 and 2015, all together 7750 primiparous women without previously diagnosed diabetes mellitus gave birth. Of these, 5223 women were >=18 years of age with information on height, weight, and complete data from a 75 g 2-h oral glucose tolerance test composing the study participants of this study. RESULTS: A 155-cm tall woman with a body mass index (BMI) of 25.5 kg/m2 had a similar risk for GDM as a 175-cm tall woman with a BMI of 27.1 kg/m2. Women shorter than 159 cm had the highest prevalence of GDM, 28.7%, whereas women with height between 164 and 167 cm had the lowest prevalence of GDM, 19.9% (P < 0.001). Height was inversely and significantly associated with both 1- and 2-h glucose values (both P < 0.001). CONCLUSIONS: To avoid over diagnosis of GDM, an unbiased strategy is needed to determine and diagnose GDM in women with different stature and degree of adiposity. PMID- 29408182 TI - Polymeric microneedles for transdermal protein delivery. AB - The intrinsic properties of therapeutic proteins generally present a major impediment for transdermal delivery, including their relatively large molecule size and susceptibility to degradation. One solution is to utilize microneedles (MNs), which are capable of painlessly traversing the stratum corneum and directly translocating protein drugs into the systematic circulation. MNs can be designed to incorporate appropriate structural materials as well as therapeutics or formulations with tailored physicochemical properties. This platform technique has been applied to deliver drugs both locally and systemically in applications ranging from vaccination to diabetes and cancer therapy. This review surveys the current design and use of polymeric MNs for transdermal protein delivery. The clinical potential and future translation of MNs are also discussed. PMID- 29408187 TI - An innovative approach to address homelessness in regional Australia: Participant evaluation of a co-payment model. AB - OBJECTIVES: Homelessness is not only about lack of secure housing, it is sometimes caused by simple reasons such as lack of money to travel home. The purpose of this study was to investigate whether the participant co-funded assistance program ('Return to Country' [R2C]), when offered to low socio economic individuals experiencing homelessness, represented an effective use of scarce resources. STUDY DESIGN: In northern Australia, a remote and sparsely populated area, Indigenous persons who travel to regional centres cannot always afford airfares home; they therefore become stranded away from their 'country' leading to rapidly deteriorating health, isolation and separation from family and kin. The R2C program was designed to facilitate travel for persons who were temporarily stranded and were voluntarily seeking to return home. The program provided operational support and funding (participants co-funded AU$99) to participants to return home. METHODS: Using a descriptive, case series research design, university researchers independently evaluated the R2C program using semi structured interviews with 37 participants. RESULTS: An investment of AU$970 per participant in the program with partial co-payment was associated with high participant acceptability and satisfaction in-line with harms reduction around substance and criminal abuse, which is suggestive of long-term success for the model. CONCLUSIONS: Findings from this study can contribute to the development of best practice guidelines and policies that specifically address the needs of this unique population of stranded persons, who are seeking to return home. The acceptance of the co-payment model can be adopted by policy makers involved in homelessness prevention in other locations in Australia or internationally as an add-on service provision to mainstream housing support. PMID- 29408186 TI - Physical activity correlates in people with mild cognitive impairment: findings from six low- and middle-income countries. AB - OBJECTIVES: Despite promising research showing that physical activity (PA) might improve cognitive functioning in people with mild cognitive impairment (MCI), people with MCI are less physically active compared with the general population. Therefore, the aim of this study was to assess PA correlates among community dwelling older people with MCI in six low- and middle-income countries. DESIGN: Cross-sectional data from the World Health Organization's Study on Global Ageing and Adult Health were analysed. METHODS: PA level was assessed by the Global Physical Activity Questionnaire. 4854 participants with MCI (mean age 64.4 years; 55.1% females) were grouped into those who do and do not (low PA) meet the 150 min of moderate-to-vigorous PA per week recommendation. Associations between PA and the correlates were examined using multivariable logistic regressions. RESULTS: The prevalence of low PA was 27.4% (95% confidence interval = 25.0 30.0). In the multivariable analysis, older age and unemployment were the only sociodemographic correlates of low PA. The significant positive correlates of low PA in other domains included depression, being underweight, obesity, asthma, chronic lung disease, hearing problems, visual impairment, slow gait, weak grip strength, poor self-rated health, and lower levels of social cohesion. CONCLUSIONS: The current data illustrate that a number of sociodemographic and health factors are associated with PA levels among older people with MCI. The promotion of social cohesion may increase the efficacy of public health initiatives while from a health care perspective, somatic co-morbidities, muscle strength and slow gait need to be considered when activating those at risk for dementia. PMID- 29408188 TI - A retrospective assessment of the completeness and timeliness of meningococcal disease notifications in the Republic of Ireland over a 16-year period, 1999 2015. AB - OBJECTIVES: To assess how invasive meningococcal disease (IMD) records held by the Irish Meningitis & Sepsis Reference Laboratory (IMSRL) compare to records of IMD notifications reported on the national integrated electronic Computerised Infectious Disease Reporting (CIDR) system. STUDY DESIGN: We assessed the completeness, data quality and timeliness of IMD notifications and reference laboratory records for the period between 01 July 1999 and 30 June 2015 by identifying discrepant and/or missing data items in a matched case data set and by measuring the timeliness of case reporting. METHODS: We matched anonymised cases notified to CIDR to records based at the IMSRL using birth, reporting and onset dates with gender and laboratory parameters of meningococcal strain characteristics and method of confirmation. Completeness, data quality and the timeliness of notifications were assessed by a stratified sensitivity-based technique and by calculating the average difference between IMSRL and CIDR reporting dates. RESULTS: CIDR recorded a total of 3163 notifications, of which 2759 (87.2%) were matched to IMSRL records. Completeness of IMD case classification as confirmed was estimated to be >99%. Examining the levels of discrepant or missing data in both matched CIDR and IMSRL records as a measure of data quality, recording of demographic items and meningococcal group showed least differences, recording of laboratory case confirmation method and meningococcal strain characteristics were less well recorded, with detail on clinical presentation/diagnosis least well recorded. Overall average annual difference between CIDR and IMSRL recording dates was 3.2 days (95% confidence interval 2.6 3.8). CONCLUSIONS: A high quality of IMD surveillance in Ireland was demonstrated, but scope for improvements in timeliness and capture of enhanced surveillance data regarding date of onset and strain-specific characteristics were identified. PMID- 29408189 TI - Dual-process models of health-related behaviour and cognition: a review of theory. AB - OBJECTIVE: The aim of this review was to synthesise a spectrum of theories incorporating dual-process models of health-related behaviour. STUDY DESIGN: Review of theory, adapted loosely from Cochrane-style systematic review methodology. METHODS: Inclusion criteria were specified to identify all relevant dual-process models that explain decision-making in the context of decisions made about human health. Data analysis took the form of iterative template analysis (adapted from the conceptual synthesis framework used in other reviews of theory), and in this way theories were synthesised on the basis of shared theoretical constructs and causal pathways. Analysis and synthesis proceeded in turn, instead of moving uni-directionally from analysis of individual theories to synthesis of multiple theories. Namely, the reviewer considered and reconsidered individual theories and theoretical components in generating the narrative synthesis' main findings. RESULTS: Drawing on systematic review methodology, 11 electronic databases were searched for relevant dual-process theories. After de duplication, 12,198 records remained. Screening of title and abstract led to the exclusion of 12,036 records, after which 162 full-text records were assessed. Of those, 21 records were included in the review. Moving back and forth between analysis of individual theories and the synthesis of theories grouped on the basis of theme or focus yielded additional insights into the orientation of a theory to an individual. Theories could be grouped in part on their treatment of an individual as an irrational actor, as social actor, as actor in a physical environment or as a self-regulated actor. CONCLUSIONS: Synthesising identified theories into a general dual-process model of health-related behaviour indicated that such behaviour is the result of both propositional and unconscious reasoning driven by an individual's response to internal cues (such as heuristics, attitude and affect), physical cues (social and physical environmental stimuli) as well as regulating factors (such as habit) that mediate between them. PMID- 29408190 TI - Seroepidemiology of diphtheria and pertussis in Chongqing, China: serology-based evidence of Bordetella pertussis infection. AB - OBJECTIVES: In order to gain further insight into the seroepidemiology of Bordetella pertussis infection and immunity against diphtheria in Chongqing, China, the concentrations of antibodies to pertussis toxin (PT) and diphtheria toxin (DT) were investigated in a healthy population. STUDY DESIGN: Cross sectional study. METHODS: In total, 1080 healthy people were recruited into this study. Sera antibodies to DT and PT were measured quantitatively using commercial enzyme-linked immunosorbent assay kits. Age-specific incidence of infection with B. pertussis was estimated and compared with notified cases of pertussis. RESULTS: The mean concentration of anti-DT IgG was 0.71 IU/ml (95% confidence interval [CI] = 0.60-0.82), with a positive rate (>0.01 IU/ml) of 97.41% (1052/1080). The mean concentration of anti-PT IgG was 7.65 IU/ml (95% CI = 6.65 8.65), with a positive rate (>100 IU/ml) of 1.17% (11/944). The estimated pertussis infection rate was 7290/100,000, which was far higher than the reported incidence of 1.29/100,000 in 2015. The peaks of estimated incidence of infection were found in subjects aged 7-14 years (9971/100,000) and >=20 years (13,898/100,000). CONCLUSIONS: B. pertussis infection occurs frequently in young infants and adolescents/adults; the latter are often responsible for the transmission of pertussis to young infants. The existing surveillance system may underestimate the true incidence of pertussis in older age groups in Chongqing, and the immunisation programme should be improved to provide protection against pertussis for adolescents and young adults. PMID- 29408191 TI - Factors influencing seasonal influenza vaccination behaviour among elderly people: a systematic review. AB - OBJECTIVES: To explore the behaviour-related factors influencing influenza vaccination among elderly people using a framework derived from the Health Belief Model (HBM) and the Theory of Reasoned Action (TRA). STUDY DESIGN: Systematic review. METHODS: Five databases were searched using predetermined strategies in March 2016, and 1927 citations were identified. Articles were selected according to inclusion and exclusion criteria. Key information was extracted from selected studies using a predesigned sheet. Both authors assessed study quality using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) or Critical Appraisal Skills Programme (CASP) checklist. RESULTS: Thirty-six articles were selected. A new framework was proposed that contributes to shared understanding of factors influencing health behaviour. Possible determinants of influenza vaccination among elderly people were knowledge, health promotion factors, all constructs of the HBM, and some concepts of the TRA. Key factors were threat perception, behavioural beliefs, subjective norms, recommendations, past behaviour and perceived barriers. CONCLUSIONS: This is the first systematic review to analyse the factors influencing influenza vaccination behaviour of elderly people using a framework integrating the HBM and the TRA. The framework identified key factors of influenza vaccination and presented the inter-relation of behaviour-related variables. However, further well-designed studies are required to explore the inter-relationships accurately and comprehensively. PMID- 29408192 TI - Sociodemographic and lifestyle determinants of non-attendance for cervical cancer screening in Lithuania, 2006-2014. AB - OBJECTIVES: In 2004, Lithuania started the Nationwide Cervical Cancer Screening Programme. The aim of the study was to estimate the trend in the uptake of cervical cancer (CC) screening in Lithuania during 2006-2014 and to identify sociodemographic and lifestyle factors associated with non-attendance for screening. STUDY DESIGN: Cross-sectional studies. METHODS: The data of 4248 women aged 25-60 years who participated in population-based cross-sectional surveys of Lithuanian Health Behaviour Monitoring were analysed. The postal surveys of independent random samples were conducted every second year. Participation in screening was determined by asking women whether they have had a Pap smear test within the last 3 years. Associations of non-attendance with sociodemographic characteristics and lifestyle factors were assessed by multivariate logistic regression analysis. RESULTS: The proportion of women who reported taking a test for CC within 3 years was continuously increasing from 60.0% in 2006 to 74.2% in 2014. The likelihood of not being screened was lower among older as compared to younger women (odds ratio=0.70; 95% confidence interval = 0.61-0.82). Non attendance was associated with lower education, being single, having rare contacts with a doctor, low physical activity, and obesity. In addition, older women who smoked and consumed alcohol at least once a week were more likely to have never been screened. CONCLUSIONS: Established social and behavioural determinants of non-attendance for CC screening should be used for optimising CC prevention in Lithuania. The implementation of organised screening programme using innovative screening methods might increase attendance and reduce inequalities. PMID- 29408193 TI - Global incidence and mortality rates in pancreatic cancer and the association with the Human Development Index: decomposition approach. AB - OBJECTIVES: Pancreatic cancer has a lower morbidity yet higher case fatality rates (CFRs) compared with other gastrointestinal cancers. The effects of socio economic components on pancreatic cancer rates have been acknowledged; however, the effects of the Human Development Index (HDI) inequality are not. In this study, we aimed to determine the contribution of important socio-economic components on pancreatic cancer rates using a decomposition approach. STUDY DESIGN: Global ecological study. METHODS: Incidence and mortality rates of pancreatic cancer were obtained for 172 countries from GLOBOCAN and the United Nations Development Program. The World Bank database was also used to obtain the HDI and its gradient for 169 countries. Inequality in pancreatic cancer age specific incidence and mortality rates was calculated according to the HDI using the concentration index (CI). We decomposed the CI to determine main contributors of the inequality. RESULTS: The CI for incidence and mortality of pancreatic cancer in both genders according to the HDI was 0.26 (95% confidence interval: 0.21-0.30) and 0.25 (95% confidence interval: 0.21-0.30), respectively, which indicated more concentrated inequality in advantaged countries. About 80% of the inequality sources were predicted by socio-economic component in both rates of pancreatic cancer. The main contributors to inequality were the mean years of schooling, life expectancy at birth, expected years of schooling, and urbanization. CONCLUSION: Global inequalities exist in pancreatic cancer incidence and mortality rates according to the HDI; in addition, inequality was more concentrated in countries with higher score of HDI. PMID- 29408194 TI - Association between air pollution and upper respiratory tract infection in hospital outpatients aged 0-14 years in Hefei, China: a time series study. AB - OBJECTIVE: To investigate the association between air pollution and upper respiratory tract infection (URTI) in children aged 0-14 years in Hefei, China in 2014-2015. STUDY DESIGN: An ecological method (i.e. generalised additive model [GAM]) was used to explore the effects of air pollutants on paediatric hospital outpatients with URTI. METHODS: GAM was used to evaluate the lag effects (including lag0 to lag6, lag01 and lag06) between daily changes in particulate matter (PM10), fine particulate matter (PM2.5), sulphur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and carbon monoxide (CO) and the number of hospital outpatients with URTI in 2014-2015, after controlling for the confounding effects of long-term trends, seasonality, day of the week, public holidays and meteorological factors. RESULTS: PM10, PM2.5, SO2, NO2 and CO in the single pollutant models had significant positive effects on the number of paediatric hospital outpatients with URTI. It was found that per 10 MUg/m3 increasing in concentrations of PM10 at lag3, PM2.5, SO2, NO2 and CO at lag06 were associated with an increase of Excess risk (ER) with 0.15% (95% CI: 0.07%~0.23%), 0.38% (95% CI: 0.17%~0.60%), 2.92% (95% CI: 1.88%~3.97%), 4.47% (95% CI: 3.69%~5.25%) and 0.05% (95% CI: 0.02%~0.08%), respectively. Only NO2 remained significantly positively associated with the number of hospital outpatients with URTI in the full-pollutant models, and ERs were 4.72% (95% CI = 3.76%-5.69%) and 4.70% (95% CI = 3.76%-5.65%) per 10 MUg/m3 increase in NO2 in Model 1 (including PM10, SO2, NO2, O3 and CO) and Model 2 (including PM2.5, SO2, NO2, O3 and CO), respectively. CONCLUSION: This study showed that short-term exposure to air pollution was associated with increased risk of URTI among paediatric hospital outpatients aged 0-14 years in Hefei. NO2 was the major air pollutant affecting the daily number of paediatric hospital outpatients with URTI. PMID- 29408196 TI - Defective p27 phosphorylation at serine 10 affects vascular reactivity and increases abdominal aortic aneurysm development via Cox-2 activation. AB - Phosphorylation at serine 10 (S10) is the major posttranslational modification of the tumor suppressor p27, and is reduced in both human and mouse atherosclerosis. Moreover, a lack of p27-phospho-S10 in apolipoprotein E-null mice (apoE-/-) leads to increased high-fat diet-induced atherosclerosis associated with endothelial dysfunction and augmented leukocyte recruitment. In this study, we analyzed whether p27-phospho-S10 modulates additional endothelial functions and associated pathologies. Defective p27-phospho-S10 increases COX-2 activity in mouse aortic endothelial cells without affecting other key regulators of vascular reactivity, reduces endothelium-dependent dilation, and increases arterial contractility. Lack of p27-phospho-S10 also elevates aortic COX-2 expression and thromboxane A2 production, increases aortic lumen diameter, and aggravates angiotensin II induced abdominal aortic aneurysm development in apoE-/- mice. All these abnormal responses linked to defective p27-phospho-S10 are blunted by pharmacological inhibition of COX-2. These results demonstrate that defective p27-phospho-S10 modifies endothelial behavior and promotes aneurysm formation via COX-2 activation. PMID- 29408195 TI - Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK. AB - BACKGROUND: Hydrogen sulfide (H2S) is an important regulator of mitochondrial bioenergetics, but its role in regulating mitochondrial biogenesis is not well understood. Using both genetic and pharmacological approaches, we sought to determine if H2S levels directly influenced cardiac mitochondrial content. RESULTS: Mice deficient in the H2S-producing enzyme, cystathionine gamma-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild type hearts. In contrast, mice overexpressing CSE (CSE Tg) and mice supplemented with the orally active H2S-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac H2S levels influenced the nuclear localization and transcriptional activity of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) with higher levels having a positive influence and lower levels having a negative influence. Studies aimed at evaluating the underlying mechanisms found that H2S required AMP activated protein kinase (AMPK) to induce PGC1alpha signaling and mitochondrial biogenesis. Finally, we found that restoring H2S levels with SG-1002 in the setting of heart failure increased cardiac mitochondrial content, improved mitochondrial respiration, improved ATP production efficiency, and improved cardiac function. CONCLUSIONS: Together, these results suggest that hydrogen sulfide is an important regulator of cardiac mitochondrial content and establishes that exogenous hydrogen sulfide can induce mitochondrial biogenesis via an AMPK-PGC1alpha signaling cascade. PMID- 29408197 TI - Long noncoding RNA LISPR1 is required for S1P signaling and endothelial cell function. AB - Sphingosine-1-Phosphate (S1P) is a potent signaling lipid. The effects of S1P are mediated by the five S1P receptors (S1PR). In the endothelium S1PR1 is the predominant receptor and thus S1PR1 abundance limits S1P signaling. Recently, lncRNAs were identified as a novel class of molecules regulating gene expression. Interestingly, the lncRNA NONHSAT004848 (LISPR1, Long intergenic noncoding RNA antisense to S1PR1), is closely positioned to the S1P1 receptors gene and in part shares its promoter region. We hypothesize that LISPR1 controls endothelial S1PR1 expression and thus S1P-induced signaling in endothelial cells. In vitro transcription and translation as well as coding potential assessment showed that LISPR1 is indeed noncoding. LISPR1 was localized in both cytoplasm and nucleus and harbored a PolyA tail at the 3'end. In human umbilical vein endothelial cells, as well as human lung tissue, qRT-PCR and RNA-Seq revealed high expression of LISPR1. S1PR1 and LISPR1 were downregulated in human pulmonary diseases such as COPD. LISPR1 but also S1PR1 were induced by inflammation, shear stress and statins. Knockdown of LISPR1 attenuated endothelial S1P-induced migration and spheroid outgrowth of endothelial cells. LISPR1 knockdown decreased S1PR1 expression, which was paralleled by an increase of the binding of the transcriptional repressor ZNF354C to the S1PR1 promoter and a reduction of the recruitment of RNA Polymerase II to the S1PR1 5'end. This resulted in attenuated S1PR1 expression and attenuated S1P downstream signaling. Collectively, the disease relevant lncRNA LISPR1 acts as a novel regulatory unit important for S1PR1 expression and endothelial cell function. PMID- 29408198 TI - Cryotherapy by encapsulation-dehydration is effective for in vitro eradication of latent viruses from 'Marubakaido' apple rootstock. AB - Apple stem pitting virus (ASPV), Apple chlorotic leaf spot virus (ACLSV) and Apple stem grooving virus (ASGV) are several major viral pathogens of apple trees, responsible for substantial damage to the world's apple industry. This study aimed to evaluate the effectiveness of the encapsulation-dehydration cryopreservation technique to eradicate these viral pathogens from in vitro shoot tips excised from 'Marubakaido' apple rootstock cultures. Axillary shoot tips were excised from in vitro cultures, encapsulated in alginate beads, precultured in MS salts, dehydrated in a laminar flow hood, immersed in liquid nitrogen, then warmed and recovered on medium. After LN exposure, in vitro rooting and acclimatization, recovered 'Marubakaido' plants exhibited 52% survival and 35% regrowth without callus formation. After 8 months of regrowth, PCR analyses revealed that all the plants were free of ACLSV and ASPV, but 2 out of 20 recovered plants were still infected with ASGV. This is the first report in Brazil of the application of cryotherapy to eradicate viral complexes in Malus. Cryotherapy can facilitate the production of virus-free plants by producing high quality plant material. PMID- 29408199 TI - Bioreactors in solid state fermentation technology: Design, applications and engineering aspects. AB - In recent years, substantial credibility in employing Solid-State Fermentation (SSF) technique has been witnessed owing to its numerous advantages over submerged fermentation (SmF). In spite of enormous advantages, true potential of SSF technology has not been fully realized at industrial scale. The lack of rational and scalable bioreactor designs backed by mathematical models and automated control system that could successfully address heterogeneity with respect to heat and mass, and also operate aseptically, remains the prime reason for it. As a result, there still exists vast scope in SSF bioreactor research and development to facilitate broad spectrum of biotechnological applications. The present article reviews state-of-the-art in SSF technology with focus on bioreactors that have been employed for bioprocess applications, in particular, enzyme production. Based on the mode of operation, bioreactors are divided into four categories with emphasis on design features, effect of operating conditions on productivity, applications and limitations. Selected modeling studies developed over the years, have been revised and presented in problem specific manner in order to address the limitations. Some interesting designs including few recent ones that have been proposed and/or employed at pilot and industrial levels are discussed in more detail. PMID- 29408200 TI - Highly affine and selective aptamers against cholera toxin as capture elements in magnetic bead-based sandwich ELAA. AB - Aptamers are single-stranded DNA or RNA oligonucleotides, which have been emerging as recognition elements in disease diagnostics and food control, including the detection of bacterial toxins. In this study, we employed the semi automated just in time-selection to identify aptamers that bind to cholera toxin (CT) with high affinity and specificity. CT is the main virulence factor of Vibrio cholerae and the causative agent of the eponymous disease. For the selected aptamers, dissociation constants in the low nanomolar range (23-56 nM) were determined by fluorescence-based affinity chromatography and cross reactivity against related proteins was evaluated by direct enzyme-linked aptamer assay (ELAA). Aptamer CT916 has a dissociation constant of 48.5 +/- 0.5 nM and shows negligible binding to Shiga-like toxin 1B, protein A and BSA. This aptamer was chosen to develop a sandwich ELAA for the detection of CT from binding buffer and local tap water. Amine-C6- or biotin-modified CT916 was coupled to magnetic beads to serve as the capture element. Using an anti-CT polyclonal antibody as the reporter, detection limits of 2.1 ng/ml in buffer and 2.4 ng/ml in tap water, with a wide log-linear dynamic range from 1 ng/ml to 1000 ng/ml and 500 ng/ml, respectively, were achieved. PMID- 29408201 TI - Laccase-mediated functionalization of chitosan with 4-hexyloxyphenol enhances antioxidant and hydrophobic properties of copolymer. AB - An effective method to functionalize chitosan with 4-hexyloxyphenol (HP) under homogeneous reaction conditions was developed using laccase as the catalyst. The resulting copolymer was characterized for chemical structure, grafted-HP content, surface morphology, thermal stability, antioxidant capacity, hydrophobic properties and tensile strength. Solid-state 13C NMR spectrum confirmed the incorporation of HP onto chitosan. X-ray diffraction (XRD) showed a decrease in the degree of crystallinity for laccase/HP treated chitosan compared to pure chitosan. The grafted-HP content in laccase/HP-treated chitosan first increased and then declined with increase of the initial HP/chitosan ratio. A heterogeneous surface with spherical particles on the laccase/HP treated chitosan was observed by environmental scanning electron microscopy (ESEM) and scanning probe microscopy (SPM). The laccase/HP treatment of chitosan improved the thermal stability of copolymer. More significantly, the HP functionalized chitosan showed greatly improved ABTS+ and DPPH radicals scavenging capacity, compared with pure chitosan. The hydrophobicity property of the HP functionalized chitosan also significantly increased although its tensile strength decreased. This new type of composite with double functionalities (i.e., antioxidant and hydrophobic) could potentially be used as food packaging materials or coating agents. PMID- 29408203 TI - Reprogramming tumor stroma using an endogenous lipid lipoxin A4 to treat pancreatic cancer. AB - Pancreatic stellate cells (PSCs) are the precursors of cancer-associated fibroblasts (CAFs), which potentiate pancreatic tumor growth and progression. In this study, we investigated whether Lipoxin A4 (LXA4), an endogenous bioactive lipid, can inhibit the differentiation of human PSCs (hPSCs) into CAF-like myofibroblasts and thereby hPSC-induced pro-tumorigenic effects. LXA4 significantly inhibited TGF-beta-mediated differentiation of hPSCs by inhibiting pSmad2/3 signalling. Furthermore, treatment with LXA4 abolished the paracrine effects (proliferation and migration of Panc-1 tumor cells) of hPSCs in vitro. These data demonstrated that LXA4 can interrupt pro-tumoral paracrine signalling of hPSCs. Furthermore, LXA4 treatment significant decreased the size and growth rate of 3D-heterospheroids comprised of hPSC and Panc-1 and these effects were exhibited due to inhibition of hPSC-induced collagen1 expression. In vivo, we examined the therapeutic efficacy of LXA4 in a co-injection (Panc-1 and hPSCs) subcutaneous tumor model. Intriguingly, LXA4 significantly abolished the tumor growth (either injected intratumor or intraperitoneally), attributed to a significant reduction in fibrosis, shown with collagen1 expression. Altogether, this study proposes LXA4 as a potent inhibitor for hPSCs which can be applied to reprogram tumor stroma in order to treat pancreatic cancer. PMID- 29408202 TI - Resolvin D1 blocks H2O2-mediated inhibitory crosstalk between SHP2 and PP2A and suppresses endothelial-monocyte interactions. AB - In recent years, various studies have demonstrated a role for endogenously derived specialized proresolving mediators such as resolvins in the resolution of inflammation. In exploring the signaling mechanisms, in the present study we show that Resolvin D1 (RvD1) reduces LPS-induced endothelial cell (EC)-monocyte interactions via blocking H2O2-mediated PP2A inactivation, NFkappaB activation and ICAM1 and VCAM1 expression. In addition, we found that H2O2-mediated SHP2 inhibition leads to tyrosine phosphorylation and inactivation of PP2A by LPS, which in turn, accounts for increased NFkappaB activation and ICAM1 and VCAM1 expression facilitating EC-monocyte interactions and all these LPS-mediated responses were reduced by RvD1. Furthermore, the suppression of NFkappaB activation, ICAM1 and VCAM1 expression and EC and monocyte interactions by RvD1 involved its receptors ALX/FPR2 and GPR32 as inhibition or neutralization of these receptors negated its effects. Besides, pertussis toxin completely prevented the effects of RvD1 on inhibition of LPS-induced H2O2 production, SHP2 and PP2A inactivation, NFkappaB activation, ICAM1 and VCAM1 expression and EC and monocyte interactions. Together, these observations suggest that RvD1 via activation of Gi-coupled ALX/FPR2 and GPR32 receptors blocks LPS-induced H2O2 mediated SHP2 and PP2A inactivation, NFkappaB activation, ICAM1 and VCAM1 expression and EC-monocyte interactions, which could be one of the several possible mechanisms underlying the anti-inflammatory actions of this specialized proresolving mediator. PMID- 29408204 TI - High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma. AB - Cutaneous melanoma is an aggressive tumor that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super enhancers. We also show that melanoma cells are highly sensitive to CDK7 inhibition both in vitro and in vivo and that THZ1 can dismantle the super enhancer apparatus at MITF and SOX10 in some cell lines, thereby extinguishing their intracellular levels. Our results show a dimension to MITF regulation in melanoma cells and point to CDK7 inhibition as a potential strategy to deprive oncogenic transcription and suppress tumor growth in melanoma. PMID- 29408205 TI - Risks of Melanoma and Other Cancers in Melanoma-Prone Families over 4 Decades. AB - : Since 1976, melanoma-prone families have been followed at the National Cancer Institute to identify etiologic factors for melanoma. We compared risks of melanoma and other cancers in 1,226 members of 56 families followed for up to 4 decades with population rates in the Surveillance, Epidemiology, and End Results program. All families were tested for mutations in CDKN2A and CDK4; 29 were mutation-positive and 27 mutation-negative. We compared rates of invasive melanomas, both first and second, by family mutation status, with Surveillance, Epidemiology, and End Results program. Comparing three calendar periods of the study, risk of first primary melanoma decreased slightly. Risks of melanoma after first examination, however, were approximately one-third the risks prior to the first examination in both mutation-positive and mutation-negative families. Among patients with melanoma, risk of a second melanoma was increased 10-fold in all families; risk was somewhat higher in mutation-positive families. Risks of other second cancers were increased only for pancreatic cancer after melanoma in mutation-positive families. Over 4 decades, prospective risk of melanoma has decreased substantially in both mutation-positive and mutation-negative families, when melanoma has greatly increased in the general population. TRIAL REGISTRATION: NCI 02-C-0211, ClinicalTrials.gov ID NCT00040352. PMID- 29408206 TI - The 5T4 oncofetal glycoprotein does not act as a general organizer of the CXCL12 system in cancer cells. AB - The chemokine, CXCL12, promotes cancer growth and metastasis through interaction with either CXCR4 and/or CXCR7. This tumor-specific organization of the CXCL12 system obscures current therapeutic approaches, aiming at the selective inactivation of CXCL12 receptors. Since it has been previously suggested that the cellular use of CXCR4 or CXCR7 is dictated by the 5T4 oncofetal glycoprotein, we have now tested whether 5T4 would represent a general and reliable marker for the organization of the CXCL12 system in cancer cells. The CXCR4 antagonist, AMD3100, as well as the CXCR7 antagonist, CCX771, demonstrated that the cancer cell lines A549, C33A, DLD-1, MDA-231, and PC-3 use either CXCR7 and/or CXCR4 for mediating CXCL12-induced chemotaxis and cell proliferation. The use of CXCL12 receptors as well as their subcellular localization remained unchanged in most cell lines following siRNA-mediated depletion of 5T4. In distinct cell lines, inhibition of 5T4 expression, however, modulated tumor cell migration and proliferation per se. Collectively our analyses fail to demonstrate general organizational influences of 5T4 of the CXCL12 system in different cancer cell lines, and, hence, dismiss its future use as a diagnostic marker. PMID- 29408207 TI - Examining the epidemiology and microbiology of Clostridium difficile carriage in elderly patients and residents of a healthcare facility in southern Ontario, Canada. AB - BACKGROUND: Whereas Clostridium difficile has been extensively studied in acute care facilities (ACFs), there is limited information about long-term care facilities (LTCFs), despite the high occurrence of putative risk factors (e.g. age, antimicrobial use, healthcare system contact). AIM: To evaluate C. difficile colonization in elderly patients and residents from one ACF and its associated LTCF. METHODS: Stool swabs were collected from 884 LTCF and elderly (>65 years) hospital patients. Selective culture, polymerase chain reaction ribotyping and toxin gene characterization were performed. FINDINGS: C. difficile was isolated from 92/410 (22.4%) ACF and 89/474 (18.8%) LTCF samples. Ribotypes 027 (35%) and 020 (10.4%) predominated in the LTCF whereas ribotypes AI-82/1 (20.7%) and ribotype O (14.1%) predominated at the ACF (P = 0.031). In the LTCF, C. difficile colonization was associated with a history of proton pump inhibitor (PPI) use, and the interaction terms of male residents with prior medical leave of absence, and a prior history of C. difficile infection (CDI) combined with fluoroquinolone use. In the ACF, C. difficile colonization was associated with length of stay, feeding through a tube, antibiotic use, immunosuppressive therapy and VRE colonization, as well as the interaction terms for cephalosporin and fluoroquinolone use, prior CDI and cephalosporin use, and prior CDI and fluoroquinolone use. CONCLUSION: C. difficile colonization by ACF and LTCF residents was common, despite a low apparent incidence of CDI. The association with PPI provides further evidence of the potential importance of this widely used drug class in C. difficile colonization. Wide genetic diversity was present, highlighting the likelihood of multiple unidentified routes of C. difficile acquisition. PMID- 29408208 TI - Effect of glucocorticoids on miRNA expression spectrum of rat femoral head microcirculation endothelial cells. AB - The study profiled the differential miRNA expression from femoral head bone microvascular endothelial cells (BMECs) between model group and control group to explore the pathogenesis of steroid-induced osteonecrosis of femoral head (ONFH). Twenty 8-week-old Female Sprague-Dawley (SD) rats were randomly divided into control and model groups. Rats in model group received an intraperitoneal injection of 20-MUg/kg lipopolysaccharide (LPS) at an interval of 24 h. Then, 24 h later, rats received three doses of 40-mg/kg methylprednisolone by intramuscular injection at intervals of 24 h. In control group, rats received the same volume of normal saline. After 4 weeks, the femoral heads were sectioned to confirm the establishment of the model. To replicate the animal model ex vivo, BMECs were isolated. Different miRNAs were screened using Agilent Gene Spring GX software, and real-time quantitative polymerase chain reaction (qPCR) was used to confirm the results of miRNA microarray analysis. The differentially expressed miRNA were assessed by bioinformatics analysis. Four differentially expressed miRNAs were identified (two upregulated: miR-132-3p, miR-335 and two down regulated: miR-466b-2-3p, let-7c-1-3p). qPCR results were consistent with the gene-chip results. Steroid-induced ONFH may cause miRNA changes in BMSCs. miR-132 3p and miR-335 may be important in steroid-induced ONFH. PMID- 29408209 TI - The effects of the botanical estrogen, isoliquiritigenin on delayed spatial alternation. AB - Age-related declines in cognitive function can impair working memory, reduce speed of processing, and alter attentional resources. In particular, menopausal women may show an acceleration in the rate of cognitive decline as well as an increased vulnerability to brain diseases as estrogens may play a neuroprotective and neurotrophic role in the brain. To treat menopausal symptoms, many women turn to botanical estrogens that are promoted as a safe and natural alternative to traditional hormone replacement therapy. However, the majority of these compounds have not been systematically evaluated for efficacy and safety. The current study investigated the efficacy of the commercially available botanical estrogenic compound isoliquiritigenin (ISL) to alter performance on an operant working memory task, delayed spatial alternation (DSA). ISL is a compound found in licorice root that has been shown to have a wide range of effects on different biological systems, including estrogenic properties. This botanical is currently being used in over the counter dietary supplements. Middle-aged (12-month old) Long-Evans female rats were ovariectomized and orally dosed with either 0 mg, 6 mg, 12 mg or 24 mg of ISL 60 min before testing on the DSA task. The DSA task required the rat to alternate its responses between two retractable levers in order to earn food rewards. Random delays of 0, 3, 6, 9 or 18 s were imposed between opportunities to press. ISL treatment failed to alter DSA performance. Previous work from our research group has found that estrogenic compounds, including 17beta-estradiol and the botanical estrogen genistein impair performance on the DSA task. The goal of our botanical estrogens research is to find compounds that offer some of the beneficial effects of estrogen supplementation, without the harmful effects. This work suggests that ISL may not carry the cognitive risks associated with most other estrogenic compounds tested to date. PMID- 29408210 TI - Chitosan hydrogel in combination with marine peptides from tilapia for burns healing. AB - The purpose of this study was to develop a promising burns dressing. Chiosan (CS) has been widely used as biomaterials, in combination with marine peptides (MPs) extracted from seawater cultured Tilapia, the newly developed material Chitosan Marine Peptides hydrogels (CSMP) in this study showed antibacterial activity, pro cell proliferation and migration, well burning healing. Pathological examinations by HE staining demonstrated that CSMP had pronounced wound healing efficiencies. In burn wounds treated with CSMP, reepithelialization and collagen fiber deposition were observed on day 7, the epithelium was completely regenerated by day 14, and the wounds were completely healed by day 21. Furthermore, CSMP can up regulate the expression of FGF2 and VEGF. Collectively, these results suggest that CSMP may enhance cell migration and promote the skin regeneration, which demonstrates the potential application of CSMP in burning healing. PMID- 29408211 TI - Characterization of the inserted mutagenesis dextransucrases from Leuconostoc mesenteroides 0326 to produce hyperbranched dextran. AB - Dextran produced by dextransucrase hold strong potential for industrial applications. The exact determinants of the linkage specificity of glucansucrase enzymes have remained largely unknown. Previous studies have investigated the relationships between structure and linkage specificity of the dextransucrase DSR from Leuconostoc mesenteroides by the site-directed mutagenesis of the catalytic pocket. The glycosidic linkage of dextran produced by mutant enzymes changed slightly by 3% to 20%. The mutagenesis dextransucrases were constructed by inserting an amino acid into a catalytic pocket to investigate the product specificities of dextransucrase thoroughly. The sequence and structural analysis of glycoside-hydrolase family 70 enzymes led to two sequences (Motif II and Motif IV) being targeted, which were inserted by saturation mutagenesis and simultaneously recombined between A552 and V553, D662, and S663. Variants with catalytic activity were screened of the library, which synthesizes high molecular weight alpha-glucans with different proportions of alpha(1-4) linkages, which ranges from 0% to 52%. Mutant sequence analysis, biochemical characterization, and molecular modeling studies revealed the mechanism of product specificities. The mutant dextransucrase, which synthesizes hyperbranched dextran, were obtained by the novel mutagenesis method. The different properties of dextran provide the foundation for subsequent studies and application. PMID- 29408212 TI - Interaction between the immune system and acute myeloid leukemia: A model incorporating promotion of regulatory T cell expansion by leukemic cells. AB - Population dynamics of regulatory T cells (Treg) are crucial for the underlying interplay between leukemic and immune cells in progression of acute myeloid leukemia (AML). The goal of this work is to elucidate the dynamics of a model that includes Treg, which can be qualitatively assessed by accumulating clinical findings on the impact of activated immune cell infusion after selective Treg depletion. We constructed an ordinary differential equation model to describe the dynamics of three components in AML: leukemic blast cells, mature regulatory T cells (Treg), and mature effective T cells (Teff), including cytotoxic T lymphocytes. The model includes promotion of Treg expansion by leukemic blast cells, leukemic stem cell and progenitor cell targeting by Teff, and Treg mediated Teff suppression, and exhibits two coexisting, stable steady states, corresponding to high leukemic cell load at diagnosis or relapse, and to long term complete remission. Our model is capable of explaining the clinical findings that the survival of patients with AML after allogeneic stem cell transplantation is influenced by the duration of complete remission, and that cut-off minimal residual disease thresholds associated with a 100% relapse rate are identified in AML. PMID- 29408213 TI - Spacing extinction sessions as a behavioral technique for preventing relapse in an animal model of voluntary actions. AB - Instrumental extinction has been proposed as a model for understanding the suppression of problematic voluntary actions. Consequently, it has been suggested that response recovery after extinction could model relapse. Four experiments with rats used a free operant procedure to explore the impact of spacing extinction sessions on spontaneous recovery, renewal, reinstatement, and rapid reacquisition of extinguished lever-pressing. Initially, in all experiments, hungry rats were trained to perform two responses (R1 and R2) for food. Then, all responses underwent extinction. For R1, rats experienced a longer intersession interval (72 h) than for R2 (24 h). During the final restoration test, it was observed that using spaced extinction sessions reduced spontaneous recovery, renewal, and reinstatement. However, implementing a longer intersession interval throughout extinction exposure did not slow the rate of reacquisition of operant responses. The present findings suggest that in most cases extinction is more enduring when the extinction sessions are spaced. Since expanding the intersession interval during extinction might be interpreted as conducting extinction in multiple temporal contexts, the overall pattern of results was explained based on contextual modulation. PMID- 29408214 TI - The Relationship between Sleep Disorders and Lower Urinary Tract Symptoms: Results from the NHANES. AB - PURPOSE: It is well established that sleep disorders are associated with the nocturia prevalence in men. While previous literature supports that patients with sleep disorders are at increased risk for nocturia, the risk of daytime lower urinary tract symptoms has not been well established. MATERIALS AND METHODS: We examined the NHANES (National Health and Nutrition Examination Survey) database between 2006 and 2008. Men older than 40 years who completed the sleep, prostate and kidney questionnaires were included in study. The presence of lower urinary tract symptoms was defined as 2 or more symptoms, including hesitancy, incomplete emptying and/or nocturia. Multivariable models using logistic regression were constructed to compare groups of men with and without a sleep disorder. RESULTS: Of the 3,071 men who completed all survey questions 270 (8.8%) reported a sleep disorder. Men with a sleep disorder had a significantly higher body mass index (30.8 vs 27.4 kg/m2), a greater likelihood of reporting diabetes (20.3% vs 10.2%) and more comorbidities (72.6% vs 45.2%, all p <0.01) than men without a sleep disorder. Multivariable logistic regressions demonstrated that men with a sleep disorder were more likely to report nocturia (OR 1.23), 2 or more lower urinary tract symptoms (OR 1.12) and daytime lower urinary tract symptoms (OR 1.27, all p <0.01). CONCLUSIONS: Sleep disorders are associated with an increased risk of nocturia and daytime lower urinary tract symptoms independent of body mass index, diabetes and an increased number of comorbidities. Based on the current data clinicians should consider assessing lower urinary tract symptoms in men with a sleep disorder since intervention could improve lower urinary tract symptoms and sleep disorders as well as daytime urinary symptoms. PMID- 29408215 TI - The Impact of Immediate Salvage Surgery on Corporeal Length Preservation in Patients Presenting with Penile Implant Infections. AB - PURPOSE: Removal of an infected penile implant often results in corporeal fibrosis, irreversible penile shortening and dissatisfaction with future implant surgery. Salvage surgery may avoid these problems but to our knowledge no study to date has evaluated these specific end points. We evaluated patients who presented to our center with an infected implant to determine the impact of salvage surgery on penile length. MATERIALS AND METHODS: We evaluated consecutive patients undergoing removal of an infected penile prosthesis with immediate salvage or delayed reimplantation using a comprehensive, prospective database. Total corporeal length prior to and following immediate salvage or delayed reimplantation were compared. The impact of patient age, comorbidities, bacterial species, initial penile length and time to reimplantation on subsequent total corporeal length was evaluated. RESULTS: The cohort consisted of 40 patients. Overall 81% of salvaged cases were successful, resulting in a mean 0.6 cm (95% CI 0.20 to 1.1) reduction in total corporeal length. Delayed reimplantation resulted in a mean 3.7 cm (95% CI 2.9-4.5) total corporeal length loss. In patients who underwent delayed reimplantation the total corporeal length reduction was directly proportionate to the initial penis size of the patient. No statistically significant impact on penile length was attributable to patient age, diabetes, bacterial species or time to reimplantation. CONCLUSIONS: When possible, salvage surgery should be offered to patients with an infected penile implant. Our data confirmed that successful salvage surgery preserves penile length. When a device is explanted and replaced at a later date, patients can expect to lose 15% to 30% of penile length irrespective of age, diabetes, type of infecting organism and time to reimplantation. PMID- 29408216 TI - Cervical Cancer Screening: What's New? Updates for the Busy Clinician. AB - In the United States, 12,000 women are diagnosed with cervical cancer each year, even though the screening for this disease is safe and effective. There are 3 types of screening options available: cervical cytology (Papanicolaou or "Pap" test), Pap/HPV (human papillomavirus) co-test, and HPV-only test. With simplified options such as HPV-only screening, providers who have been reluctant to incorporate cervical cancer screening into their primary care practice may feel more comfortable with offering these services to women. In this article we review the different cervical cancer screening options that are now available and summarize the various changes in guidelines over the last decade. PMID- 29408217 TI - Autonomic conflict exacerbates long QT associated ventricular arrhythmias. AB - This study tested the hypothesis that concomitant sympathetic and parasympathetic stimulation ("autonomic conflict") may act as a trigger for arrhythmias in long QT syndrome (LQTS). Studies were performed in isolated innervated rabbit hearts treated with clofilium (100 nmol/L); a potassium channel blocker. The influence of vagus nerve stimulation (VNS) on spontaneous ventricular arrhythmias was assessed in the absence/presence of sustained noradrenaline perfusion (100 nmol/L) and with sudden adrenergic stress (injections of noradrenaline into the perfusion line). Hearts were instrumented for a pseudo-electrocardiogram and monophasic action potential recordings. VNS, which slows heart rate, was associated with a stimulation frequency-dependent incidence of spontaneous early after-depolarisations (EADs) and ventricular tachycardia (VT), best predicted by the duration of the electrocardiographic T-wave and by triangulation of the ventricular action potential. In the presence of sustained (steady-state) noradrenaline perfusion, the incidence of EADs and VT with VNS was decreased from 73/55% to 45/27%, respectively. However, sudden adrenergic stress, imposed during periods of sustained VNS, was associated with a transient increase in the incidence of severity of observed arrhythmias, as indicated by an increase in the average arrhythmias score (1.6 +/- 0.4 vs. 2.1 +/- 0.7, p = .01). Analysis of electrophysiological parameters suggests that sudden adrenergic stress is associated with a transient prolongation, and increased triangulation, of the ventricular action potential, which may predispose to triggered activity. This study demonstrates that autonomic conflict is a pro-arrhythmic stimulus in LQTS. However, combined adrenergic and parasympathetic stimulation has a complex relationship with arrhythmogenicity, with differences in the effects of steady state adrenergic activation vs. sudden adrenergic stress. PMID- 29408218 TI - How do memory systems detect and respond to novelty? AB - The efficiency of the memory system lies not only in its readiness to detect and retrieve old stimuli but also in its ability to detect and integrate novel information. In this review, we discuss recent evidence suggesting that the neural substrates sensitive to detecting familiarity and novelty are not entirely overlapping. Instead, these partially distinct familiarity and novelty signals are integrated to support recognition memory decisions. We propose here that the mediodorsal thalamus is critical for familiarity detection, and for combining novelty signals from the medial temporal lobe cortex with the relative familiarity outputs of computations performed in other cortical structures, especially the prefrontal cortex. Importantly, we argue that the anterior hippocampus has a prominent role in detecting novelty and in communicating this with midbrain and striatal structures. We argue that different types of novelty (absolute or contextual) engage different neurotransmitter systems that converge in the hippocampus. We suggest that contextual or unexpected novelty triggers dopaminergic hippocampal-midbrain coupling and noradrenergic-mediated pupil dilation. In contrast, absolute novelty triggers cholinergic-mediated hippocampal encoding accompanied by diminished pupil dilation. These two, distinct hippocampal encoding mechanisms both lead to later recollection but are sensitive to different types of novelty. We conclude that this neurotransmitter-mediated hippocampal encoding establishes the hippocampus in an encoding mode that briefly prevents the engagement of retrieval. PMID- 29408219 TI - Public goods games in populations with fluctuating size. AB - Many mathematical frameworks of evolutionary game dynamics assume that the total population size is constant and that selection affects only the relative frequency of strategies. Here, we consider evolutionary game dynamics in an extended Wright-Fisher process with variable population size. In such a scenario, it is possible that the entire population becomes extinct. Survival of the population may depend on which strategy prevails in the game dynamics. Studying cooperative dilemmas, it is a natural feature of such a model that cooperators enable survival, while defectors drive extinction. Although defectors are favored for any mixed population, random drift could lead to their elimination and the resulting pure-cooperator population could survive. On the other hand, if the defectors remain, then the population will quickly go extinct because the frequency of cooperators steadily declines and defectors alone cannot survive. In a mutation-selection model, we find that (i) a steady supply of cooperators can enable long-term population survival, provided selection is sufficiently strong, and (ii) selection can increase the abundance of cooperators but reduce their relative frequency. Thus, evolutionary game dynamics in populations with variable size generate a multifaceted notion of what constitutes a trait's long-term success. PMID- 29408220 TI - A potent tilapia secreted granulin peptide enhances the survival of transgenic zebrafish infected by Vibrio vulnificus via modulation of innate immunity. AB - Progranulin (PGRN) is a multi-functional growth factor that mediates cell proliferation, survival, migration, tumorigenesis, wound healing, development, and anti-inflammation activity. A novel alternatively spliced transcript from the short-form PGRN1 gene encoding a novel, secreted GRN peptide composed of 20-a.a. signal peptide and 41-a.a. GRN named GRN-41 was identified to be abundantly expressed in immune-related organs including spleen, head kidney, and intestine of Mozambique tilapia. The expression of GRN-41 and PGRN1 were further induced in the spleen of tilapia challenged with Vibrio vulnificus at 3 h post infection (hpi) and 6 hpi, respectively. In this study, we established three transgenic zebrafish lines expressing the secreted GRN-41, GRN-A and PGRN1 of Mozambique tilapia specifically in muscle. The relative percent of survival (RPS) was enhanced in adult transgenic zebrafish expressing tilapia GRN-41 (68%), GRN-A (32%) and PGRN1 (36%) compared with control transgenic zebrafish expressing AcGFP after challenge with V. vulnificus. It indicates tilapia GRN-41 is a potent peptide against V. vulnificus infection. The secreted tilapia GRN-41 can induce the expression of innate immune response-related genes, such as TNFa, TNFb, IL-8, IL-1beta, IL-6, IL-26, IL-21, IL-10, complement C3, lysozyme (Lyz) and the hepatic antimicrobial peptide hepcidin (HAMP), in adult transgenic zebrafish without V. vulnificus infection. The tilapia GRN-41 peptide can enhance the innate immune response by further elevating TNFb, IL-1beta, IL-8, IL-6, and HAMP expression in early responsive time to the V. vulnificus challenge in transgenic zebrafish. Our results suggest that the novel GRN-41 peptide generated from alternative splicing of the tilapia PGRN1 gene is a potent peptide that defends against V. vulnificus in the transgenic zebrafish model by modulation of innate immunity. PMID- 29408221 TI - Molecular characterization and expression of toll-like receptor 5 genes from Pelteobagrus vachellii. AB - Toll-like receptor 5 (TLR5) is an important pathogen recognition receptor (PRR) that recognizes the flagellin protein of pathogenic bacteria and plays a fundamental role in activating the innate immune response. In this study, full length pvTLR5m (membrane) and pvTLR5s (soluble) genes were cloned from darkbarbel catfish Pelteobagrus vachellii, and their expression and that of downstream genes were analyzed following exposure to the Aeromonas hydrophila pathogen. The 3009 bp pvTLR5m cDNA includes a 2652 bp open reading frame (ORF) encoding 884 amino acids. The 2422 bp pvTLR5s cDNA includes a 1944 bp ORF encoding a predicted protein of 648 amino acids. The genes are most closely related to TLR5m (75%) and TLR5s (69%) from Ictalurus punctatus, respectively, and both have a typical TLR structure. Both genes were constitutively expressed in all examined tissues, and most abundantly in the head kidney and spleen. Following pathogen challenge, pvTLR5m and pvTLR5s expression was increased significantly (P <0.05) and peaked at 24 and 12 h post-exposure in the liver, 24 and 12 h in the head kidney, and 48 and 24 h in the spleen, respectively. The downstream genes interleukin-1beta (IL 1beta), IL-12 and tumor necrosis factor-alpha (TNF-alpha) were significantly up regulated following pathogen exposure in spleen, and the NF-kB inhibitor (IkappaB) was down-regulated. These findings indicated that pvTLR5 may play an important role in the immune responses to A. hydrophila. These results provide new insight to elucidate the immune signalling pathways of fish TLR. PMID- 29408222 TI - Mechanistic investigation of transcutaneous protein delivery using solid-in-oil nanodispersion: A case study with phycocyanin. AB - Phycocyanin (PC), a water-soluble protein-chromophore complex composed of hexameric (alphabeta)6 subunits, has important biological functions in blue-green algae as well as pharmacological activities in biomedicine. We have previously developed a solid-in-oil (S/O) nanodispersion method to deliver biomacromolecules through the skin, although the transcutaneous mechanism has not yet been fully elucidated. To study the mechanism of transcutaneous protein delivery, we therefore enabled S/O nanodispersion by coating PC with hydrophobic surfactants and evaluated how the proteinaceous macromolecules formulated in an oil phase might permeate the skin. The extent of S/O nanodispersion of PC was dependent on the type of surfactant, suggesting that the selection of a suitable surfactant is crucial for encapsulating a large protein having a subunit structure. By measuring the intrinsic fluorescence of PC, we found that S/O nanodispersion facilitated the accumulation of PC in the stratum corneum (SC) of Yucatan micropig skin. Furthermore, after crossing the SC layer, the fluorescent recovery of PC was evident, indicating the release of the biologically active form of PC from the SC into the deeper skin layer. PMID- 29408223 TI - Egr-1 is required for neu/HER2-induced mammary tumors. AB - Egr-1 is known to function mainly as a tumor suppressor through direct regulation of multiple tumor suppressor genes. To determine the role of Egr-1 in breast tumors in vivo, we used mouse models of breast cancer induced by HER2/neu. We compared neu-overexpressing Egr-1 knockout mice (neu/Egr-1 KO) to neu overexpressing Egr-1 wild type or heterozygote mice (neu/Egr-1 WT or neu/Egr-1 het) with regard to onset of tumor appearance and number of tumors per mouse. In addition, to examine the role of Egr-1 in vitro, we established neu/Egr-1 WT and KO tumor cell lines derived from breast tumors developed in each mouse. Egr-1 deletion delayed tumor development in vivo and decreased the rate of cell growth in vitro. These results suggest that Egr-1 plays an oncogenic role in HER2/neu driven mammary tumorigenesis. PMID- 29408224 TI - Scanning fluorescence correlation spectroscopy comes full circle. AB - In this article, we review the application of fluorescence correlation spectroscopy (FCS) methods to studies on live cells. We begin with a brief overview of the theory underlying FCS, highlighting the type of information obtainable. We then focus on circular scanning FCS. Specifically, we discuss instrumentation and data analysis and offer some considerations regarding sample preparation. Two examples from the literature are discussed in detail. First, we show how this method, coupled with the photon counting histogram analysis, can provide information on yeast ribosomal structures in live cells. The combination of scanning FCS with dual channel detection in the study of lipid domains in live cells is also illustrated. PMID- 29408225 TI - Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons. AB - Post-traumatic epilepsy is one of the most common and difficult to treat forms of acquired epilepsy worldwide. Currently, there is no effective way to prevent post traumatic epileptogenesis. It is known that abnormalities of interneurons, particularly parvalbumin-containing interneurons, play a critical role in epileptogenesis following traumatic brain injury. Thus, enhancing the function of existing parvalbumin interneurons might provide a logical therapeutic approach to prevention of post-traumatic epilepsy. The known positive effects of brain derived neurotrophic factor on interneuronal growth and function through activation of its receptor tropomyosin receptor kinase B, and its decrease after traumatic brain injury, led us to hypothesize that enhancing trophic support might improve parvalbumin interneuronal function and decrease epileptogenesis. To test this hypothesis, we used the partial neocortical isolation ('undercut', UC) model of posttraumatic epileptogenesis in mature rats that were treated for 2 weeks, beginning on the day of injury, with LM22A-4, a newly designed partial agonist at the tropomyosin receptor kinase B. Effects of treatment were assessed with Western blots to measure pAKT/AKT; immunocytochemistry and whole cell patch clamp recordings to examine functional and structural properties of GABAergic interneurons; field potential recordings of epileptiform discharges in vitro; and video-EEG recordings of PTZ-induced seizures in vivo. Results showed that LM22A-4 treatment 1) increased pyramidal cell perisomatic immunoreactivity for VGAT, GAD65 and parvalbumin; 2) increased the density of close appositions of VGAT/gephyrin immunoreactive puncta (putative inhibitory synapses) on pyramidal cell somata; 3) increased the frequency of mIPSCs in pyramidal cells; and 4) decreased the incidence of spontaneous and evoked epileptiform discharges in vitro. 5) Treatment of rats with PTX BD4-3, another partial TrkB receptor agonist, reduced the incidence of bicuculline-induced ictal episodes in vitro and PTZ induced electrographic and behavioral ictal episodes in vivo. 6) Inactivation of TrkB receptors in undercut TrkBF616A mice with 1NMPP1 abolished both LM22A-4 induced effects on mIPSCs and on increased perisomatic VGAT-IR. Results indicate that chronic activation of the tropomyosin receptor kinase B by a partial agonist after cortical injury can enhance structural and functional measures of GABAergic inhibition and suppress posttraumatic epileptogenesis. Although the full agonist effects of brain-derived neurotrophic factor and tropomyosin receptor kinase B activation in epilepsy models have been controversial, the present results indicate that such trophic activation by a partial agonist may potentially serve as an effective therapeutic option for prophylactic treatment of posttraumatic epileptogenesis, and treatment of other neurological and psychiatric disorders whose pathogenesis involves impaired parvalbumin interneuronal function. PMID- 29408226 TI - Prevalence, genetic relatedness and antibiotic resistance of hospital-acquired clostridium difficile PCR ribotype 018 strains. AB - Clostridium difficile infection (CDI) is a major healthcare-associated infection. The aim of this study was to investigate the genetic relatedness of the endemic C. difficile PCR ribotype 018 strains in an institution and changes to their characteristics during a five-year period. A total of 207 isolates from inpatients at Hanyang University Hospital from 2009 to 2013 were analysed using multilocus variable-number tandem-repeat analysis (MLVA). Minimum inhibitory concentrations (MICs) of several antibiotics were determined. In total, 204 (98.6%) were genetically related, with a summed tandem-repeat distance (STRD) <= 10. Minimum-spanning-tree analysis identified 78 MLVA types, categorized into six clonal complexes (CCs). The largest cluster, CC-I, included 51 MLVA types from 148 isolates (71.5%) and the second largest cluster, CC-II, included 10 MLVA types from 36 isolates (17.4%). Resistance rates for antibiotics were: clindamycin (CLI), 97.6%; moxifloxacin (MXF), 98.6%; vancomycin (VAN), 1.4%; and rifaximin (RFX), 8.2%. All isolates were susceptible to piperacillin/tazobactam (TZP) and metronidazole (MTZ). Comparing the MICs of antibiotics for the isolates each year from 2009 to 2013, MICs of antibiotics that promote CDI, such as CLI, MXF, TZP and RFX, increased over the five-year period (P-value by Kruskal-Wallis test: < 0.0001, <0.0001, <0.0001, and <0.0001 respectively); however, MICs of VAN or MTZ, antibiotics for treatment of CDI, did not increase or decreased over the same time period (P-value by Kruskal-Wallis test: 0.166, <0.0001). C. difficile RT018 isolates in a tertiary hospital over a five-year period presented a close clonal relationship. MICs of antibiotics promoting CDI increased with this clonal expansion. PMID- 29408227 TI - Clinical experience with ceftazidime/avibactam for treatment of antibiotic resistant organisms other than Klebsiella pneumoniae. AB - BACKGROUND: Ceftazidime/avibactam is a newly approved beta-lactam/beta-lactamase inhibitor combination with activity against antibiotic-resistant Gram-negative organisms, including many carbapenem-resistant strains. Although this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant Gram-negative organisms other than Klebsiella pneumoniae is limited. METHODS: A retrospective case series was performed to evaluate patients treated with ceftazidime/avibactam for infections caused by organisms other than K. pneumoniae at our institution over a 1-year period. Patients aged at least 18 years who received at least one dose of ceftazidime/avibactam were eligible for inclusion. Clinical and microbiological data were collected, and investigators assessed adverse effects, microbiological cure, clinical success, and 30-day in-hospital mortality following completion of ceftazidime/avibactam therapy. RESULTS: Ten patients were included. The most common index infection was pneumonia (n = 6/13, 46%) and the most frequently isolated organism was Pseudomonas aeruginosa (n = 8/21, 38%). Fifty percent of patients received ceftazidime/avibactam as monotherapy. Microbiological cure was achieved in 67% (n = 6/9) of patients and 70% (n = 7/10) of patients met criteria for clinical success. The 30-day in-hospital mortality rate was 30%. No patients experienced adverse events because of ceftazidime/avibactam therapy. CONCLUSIONS: For infections caused by antibiotic-resistant Gram-negative organisms other than K. pneumoniae, clinical and microbiological success rates for patients treated with ceftazidime/avibactam were similar to those that have been reported for K. pneumoniae. Ceftazidime/avibactam appears to be a promising treatment option for infections caused by a variety of resistant Gram-negative organisms when limited alternatives exist. PMID- 29408228 TI - Initial electrical frequency predicts survival and neurological outcome in out of hospital cardiac arrest patients with pulseless electrical activity. AB - BACKGROUND: Outcome is generally poor in out of hospital cardiac arrests (OHCA) with initial non-shockable rhythms. Termination of resuscitation rules facilitate early prognostication at the scene to cease resuscitation attempts in futile situations and to proceed advanced life support in promising conditions. As pulseless electrical activity (PEA) is present as first rhythm in every 4th OHCA we were interested if the initial electrical frequency in PEA predicts survival. METHODS: All patients >18 years of age with non-traumatic OHCA and PEA as first rhythm between August 2013 and August 2015 from the Vienna Cardiac Arrest Registry were included in this retrospective observational study. Defibrillator and epidemiological data from the emergency medical system as survival data were processed considering the initial electrical activity in PEA and 30 days survival. RESULTS: Out of 2149 OHCA patients, a total of 504 PEA patients were eligible for analyses. These patients were stratified into 4 groups according the initial electrical frequency in PEA: 10-24/min, 25-39/min, 40-59/min, >60/min. Compared to a frequency >60/min all other subgroups were associated with higher mortality especially those with an initial electrical frequency 10-24 (adjusted OR 0.56 (0.39-0.79) p = .001 for each category chance). QRS duration in PEA did not influence outcome. Patients in the >60/min group showed a 30-days-survival rate of 22% and a good neurological outcome in 15% of all patients - comparable to shockable cardiac arrest rhythms. CONCLUSION: Regardless of other resuscitation factors, higher initial electrical frequency in PEA is associated with increased odds of survival and good neurological outcome. PMID- 29408229 TI - Trends in care processes and survival following prehospital resuscitation improvement initiatives for out-of-hospital cardiac arrest in British Columbia, 2006-2016. AB - BACKGROUND: British Columbia (BC) Emergency Health Services implemented a strategy to improve outcomes for out-of-hospital cardiac arrest (OHCA), focusing on paramedic-led high-quality on-scene resuscitation. We measured changes in care metrics and survival trends. METHODS: This was a post-hoc study of prospectively identified consecutive non-traumatic ambulance-treated adult OHCAs from 2006 to 2016 within BC's four metropolitan areas. The primary outcome was survival to hospital discharge; we also described available favourable neurological outcomes (mRS <=3). We tested the significance of year-by-year trends in baseline characteristics, and calculated risk-adjusted survival rates using multivariable Poisson regression. RESULTS: We included 15 145 patients. In univariate analyses there were significant increases in bystander CPR, chest compression fraction, advanced life support attendance, duration of resuscitation until advanced airway placement, duration of resuscitation until termination, and overall scene time. There was a significant decrease in initial shockable rhythms, bystander witnessed arrests, and transports initiated prior to ROSC. Survival and the proportion of survivors with favourable neurological outcomes increased significantly. In adjusted analyses, there was an improvement in return of spontaneous circulation (risk-adjusted rate 41% in 2006 to 51% in 2016; adjusted rate ratio per year 1.02, 95% CI 1.01-1.02, p < 0.01 for trend) and survival at hospital discharge (risk-adjusted rate 8.6% in 2006 to 16% in 2016; adjusted rate ratio per year 1.05, 95% CI 1.04-1.06, p < 0.01 for trend). CONCLUSION: From 2006 to 2016 BC's provincial ambulance system prioritized paramedic-led on-scene resuscitation, during which time there were significant improvements in patient outcomes. Our data may assist other systems, providing a model for prehospital resuscitation quality improvement. PMID- 29408230 TI - Integrating Mechanical Force into Lung Development. AB - In this issue of Developmental Cell, Tang et al. (2018) and Li et al. (2018) combine genetic manipulation, mechanical perturbation, and live imaging to show how mechanical forces and local growth factors intersect to influence epithelial behavior and cell fate specification within the developing lung. PMID- 29408231 TI - Nrf2s Take the Upper Hand in the Upper Jaw. AB - In this issue of Developmental Cell, new findings from the Crump lab (Barske et al., 2018) highlight a role for Nr2f nuclear receptors in controlling maxilla versus mandible fate, playing an important role in shaping the upper jaw in jawed vertebrates. PMID- 29408232 TI - Transactivator: A New Face of Arabidopsis AGO1. AB - Argonaute (AGO) proteins execute RNA-induced transcriptional and post transcriptional gene silencing. In this issue of Developmental Cell, Liu et al. (2018) uncover a nuclear function for Arabidopsis AGO1 in positively regulating gene expression. AGO1, guided by small RNAs, binds to chromatin to induce target gene transcription in response to environmental stimuli. PMID- 29408233 TI - An Intrinsic Interferon Program Protects Stem Cells from Viral Infection. AB - Specific protection mechanisms are required to safeguard stem cell integrity. In a recent issue of Cell, Wu et al. (2018) show that stem cells are equipped with high intrinsic expression of interferon-stimulated genes (ISGs) but remain refractory to acute interferon signaling. This protects stem cells from viral infection. PMID- 29408234 TI - When Telomerase Causes Telomere Loss. AB - Telomerase counteracts telomere shortening, preventing cellular senescence. Telomerase deficiency causes telomere syndromes because of premature telomere exhaustion in highly proliferative cells. Paradoxically, in a recent issue of Cell, Margalef et al. (2018) demonstrate that telomerase causes telomere loss in cells lacking the RTEL1 helicase, which is defective in Hoyeraal-Hreidarsson syndrome (HHS). PMID- 29408236 TI - The Strength of Mechanical Forces Determines the Differentiation of Alveolar Epithelial Cells. AB - The differentiation of alveolar epithelial type I (AT1) and type II (AT2) cells is essential for the lung gas exchange function. Disruption of this process results in neonatal death or in severe lung diseases that last into adulthood. We developed live imaging techniques to characterize the mechanisms that control alveolar epithelial cell differentiation. We discovered that mechanical forces generated from the inhalation of amniotic fluid by fetal breathing movements are essential for AT1 cell differentiation. We found that a large subset of alveolar progenitor cells is able to protrude from the airway epithelium toward the mesenchyme in an FGF10/FGFR2 signaling-dependent manner. The cell protrusion process results in enrichment of myosin in the apical region of protruded cells; this myosin prevents these cells from being flattened by mechanical forces, thereby ensuring their AT2 cell fate. Our study demonstrates that mechanical forces and local growth factors synergistically control alveolar epithelial cell differentiation. PMID- 29408235 TI - Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis. AB - Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression. PMID- 29408237 TI - Chromatin Modification and Global Transcriptional Silencing in the Oocyte Mediated by the mRNA Decay Activator ZFP36L2. AB - Global transcriptional silencing is a highly conserved mechanism central to the oocyte-to-embryo transition. We report the unexpected discovery that global transcriptional silencing in oocytes depends on an mRNA decay activator. Oocyte specific loss of ZFP36L2 an RNA-binding protein that promotes AU-rich element dependent mRNA decay prevents global transcriptional silencing and causes oocyte maturation and fertilization defects, as well as complete female infertility in the mouse. Single-cell RNA sequencing revealed that ZFP36L2 downregulates mRNAs encoding transcription and chromatin modification regulators, including a large group of mRNAs for histone demethylases targeting H3K4 and H3K9, which we show are bound and degraded by ZFP36L2. Oocytes lacking Zfp36l2 fail to accumulate histone methylation at H3K4 and H3K9, marks associated with the transcriptionally silent, developmentally competent oocyte state. Our results uncover a ZFP36L2 dependent mRNA decay mechanism that acts as a developmental switch during oocyte growth, triggering wide-spread shifts in chromatin modification and global transcription. PMID- 29408239 TI - Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex. AB - Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density. PMID- 29408238 TI - Measuring appetitive conditioned responses in humans. AB - Clinical and preclinical findings suggest that individuals with abnormal responses to reward cues (stimuli associated with reward) may be at risk for maladaptive behaviors including obesity, addiction and depression. Our objective was to develop a new paradigm for producing appetitive conditioning using primary (food) rewards in humans, and investigate the equivalency of several outcomes previously used to measure appetitive responses to conditioned cues. We used an individualized food reward, and multimodal subjective, psychophysiological and behavioral measures of appetitive responses to a conditioned stimulus (CS) that predicted delivery of that food. We tested convergence among these measures of appetitive response, and relationships between these measures and action impulsivity, a putative correlate of appetitive conditioning. 90 healthy young adults participated. Although the paradigm produced robust appetitive conditioning in some measures, particularly psychophysiological ones, there were not strong correlations among measures of appetitive responses to the CS, as would be expected if they indexed a single underlying process. In addition, there was only one measure that related to impulsivity. These results provide important information for translational researchers interested in appetitive conditioning, suggesting that various measures of appetitive conditioning cannot be treated interchangeably. PMID- 29408240 TI - Impact of Medical Therapy on Late Morbidity and Mortality After Aortic Aneurysm Repair for Aortitis. AB - BACKGROUND: Patients with active aortitis who undergo repair of ascending aortic aneurysms have an increased risk of late reoperation and decreased late survival. We aimed to determine the reasons for these poor outcomes and the influence of medical management. METHODS: We reviewed records of 186 patients (median age 73.9 years; 120 women) with noninfectious aortitis after elective ascending aortic aneurysm repair (January 1955 through December 2012). Landmark analysis was used to compare outcomes in patients with isolated aortitis versus with systemic sequelae of aortitis along with outcomes of treatment with glucocorticoids. RESULTS: At 15 years, the overall mortality was 88.3%; at 10 years, the overall reoperation rate was 28.2%. Long-term mortality increased with older age at surgery (hazard ratio [HR] 1.62, 95% confidence interval [CI]: 1.25 to 2.11, p < 0.001), coronary artery disease (HR 1.94, 95% CI: 1.25 to 3.01, p = 0.003), peripheral vascular disease (HR 1.79, 95% CI: 1.09 to 2.94, p = 0.02), and preoperative suspicion of aortitis (HR 4.90, 95% CI: 1.96 to 12.26, p < 0.001). Increased reoperation rate was associated with coronary artery disease (HR 2.69, 95% CI: 1.17 to 6.17, p = 0.02) and peripheral vascular disease (HR 3.92, 95% CI: 1.71 to 8.94, p = 0.001). Among patients free of reoperation at 6 months, systemic sequelae of aortitis were found to be significant, with an unadjusted hazard ratio of 3.59 (95% CI: 1.40 to 9.18, p = 0.008). Treatment with glucocorticoids was not associated with subsequent mortality or reoperation. CONCLUSIONS: The development of systemic illness secondary to aortitis was associated with increased risk of late aortic reoperations. However, glucocorticoid treatment of noninfectious aortitis did not clearly influence survival or need for reoperation. PMID- 29408242 TI - Chylothorax in a 32-Year-Old Patient With Lymphangioleiomyomatosis After Bilateral Lung Transplant. AB - We report the case of a 32-year-old woman with persistent chylothorax after double-lung transplant for lymphangioleiomyomatosis. Dietary restrictions failed to decrease chylous effusions, making surgical revision necessary. The choice of an abdominal approach and postoperative treatment with somatostatin proved successful. The patient showed no recurrence of chylothorax at her 2-year follow up. PMID- 29408241 TI - Major Adverse Renal and Cardiac Events After Coronary Angiography and Cardiac Surgery. AB - BACKGROUND: Patients at high risk for having postprocedural complications may receive iodixanol, an iso-osmolar contrast, during coronary angiography to minimize the risk of renal toxicity. For those who also require cardiac surgery, the wait time between angiography and surgery may be a modifiable factor capable of mitigating poor surgical outcomes; however, there have been inconsistent reports regarding the optimal wait time. We sought to determine the effects of wait time between angiography and cardiac surgery, as well as contrast-induced acute kidney injury on the development of major adverse renal and cardiac events (MARCE). METHODS: We merged datasets to identify adults who underwent coronary angiography with iodixanol and subsequent cardiac surgery. RESULTS: Of 965 patients, 126 (13.1%) had contrast-induced acute kidney injury; 133 (13.8%) had MARCE within 30 days and 253 (26.2%) within 1 year of surgery. After adjusting for contrast-induced acute kidney injury, age, and Thakar acute renal failure score, the effect of wait time lost significance for the full cohort, but remained for the subgroup of 654 who had coronary artery bypass graft surgery. Patients undergoing coronary artery bypass graft surgery within 1 day of coronary angiography had an approximate twofold increase in risk of MARCE (30-day hazard ratio 2.13, 95% confidence interval: 1.16 to 3.88, p = 0.014; 1-year hazard ratio 2.07, 95% confidence interval: 1.32 to 3.23, p = 0.002) compared with patients who waited 5 or more days. CONCLUSIONS: Patients who had contrast-induced acute kidney injury and had cardiac surgery within 1 day of angiography had an increased risk of MARCE. PMID- 29408243 TI - Incremental Value of Increasing Number of Arterial Grafts: The Effect of Diabetes Mellitus. AB - BACKGROUND: Multiarterial coronary grafting with two arterial grafts leads to improved survival compared with conventional single artery based on left internal thoracic artery to left anterior descending artery and saphenous vein grafts. We investigated whether extending arterial grafting to three or more arterial grafts further improves survival, and whether such a benefit is modified by diabetes mellitus. METHODS: We analyzed 15-year coronary artery bypass graft surgery mortality data in 11,931 patients (age 64.3 +/- 10.5 years; 3,484 women [29.2%]; 4,377 [36.7%] with diabetes mellitus) derived from three US institutions (1994 to 2011). All underwent primary isolated left internal thoracic artery to left anterior descending artery grafting with at least two grafts: one artery (n = 6,782; 56.9%); two arteries (n = 3,678; 30.8%); or three or more arteries (n = 1,471; 12.3%). Long-term survival was estimated by Kaplan-Meier methods. Propensity score matching and comprehensive covariate adjustment (Cox regression) were used to derive long-term risk-adjusted hazard ratio (HR) with 95% confidence interval (CI) for increasing number of arterial grafts in the overall cohort and for diabetes and no-diabetes cohorts. RESULTS: Radial artery (94%) and right internal thoracic artery (6%) were used as additional arterial grafts. Multivariate analysis in all patients showed that diabetes was associated with decreased survival (HR 1.43, 95% CI: 1.34 to 53), whereas increasing number of arterial grafts was associated with decreased mortality (one artery HR 1.0 [reference]; two arteries HR 0.87, 95% CI: 0.80 to 0.95; and three arteries HR 0.83, 95% CI: 0.72 to 0.95). Pairwise comparisons also showed an incremental benefit of additional arterial grafts: two arteries versus one artery, HR 0.89 (95% CI: 0.80 to 0.98); and three arteries versus one artery, HR 0.80 (95% CI: 0.68 to 0.94). A three-artery versus two-artery survival advantage trend was also noted, but was not significant in either the overall study cohort (HR 0.90, 95% CI: 0.75 to 1.07), the diabetes cohort (HR 0.79, 95% CI: 0.60 to 1.03), or the no diabetes cohort (HR 01.00, 95% CI: 0.79 to 1.26). Among diabetes patients, the survival advantage of two arteries versus one artery was modest (HR 0.96, 95% CI: 0.72 to 1.11), whereas it was significant for three arteries versus one artery (HR 0.74, 95% CI: 0.58 to 0.96). Analyses of propensity matched subcohorts were also consistent. CONCLUSIONS: Increasing number of arterial grafts improves long term survival and supports extended use of arterial grafts in coronary artery bypass graft surgery, irrespective of diabetes status. PMID- 29408244 TI - Risk Factors for Development and Progression of Scoliosis After Pediatric Cardiothoracic Operations. AB - BACKGROUND: The purpose of this study was to determine the incidence and risk factors for the development and rate of progression of scoliosis and moderate/severe scoliosis in patients undergoing cardiothoracic operations (CTOs). METHODS: Included were patients aged younger than 12 years who underwent CTOs in 1995 to 2006 with a preoperative chest roentgenogram (CRG) and a CRG at least 8 years after CTOs. Scoliosis and moderate/severe scoliosis were defined as a Cobb angle of 10 degrees or more and an angle of 25 degrees or more or the need for surgical intervention, respectively. Risk factors were analyzed using nonparametric and parametric survival analyses. For patients that developed scoliosis, progression rate was analyzed using linear regression models for repeated measures using CRG at 6-month intervals. RESULTS: The study included 871 patients (380 girls [44%]). Median CRG follow-up was 11 years (interquartile range, 9 to 13 years). Overall 10-year incidence of scoliosis and moderate/severe scoliosis was 12% and 3%, respectively. Independent predictors for scoliosis included female sex (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.2 to 2.5), syndrome (HR, 1.9; 95% CI, 1.3 to 2.8), and isolated developmental delay (HR, 2.4; 95% CI, 1.4 to 4.2). For development of moderate/severe scoliosis, independent risk factors included female sex (HR, 2.8; 95% CI, 1.4 to 5.8), syndrome (HR, 3; 95% CI, 1.5 to 6.1), isolated developmental delay (HR, 3.1; 95% CI, 1 to 9.2]), and prematurity for neonates/infants (HR, 2.3; 95% CI, 1 to 5.2). Rate of angle progression was 0.17 times the current angle per year. Age, syndrome, and developmental delay were risk factors for angle progression. CONCLUSIONS: Patients that undergo pediatric CTO, regardless of the operative approach, are at increased risk for development of scoliosis and moderate/severe scoliosis. Long-term follow-up of these patients is warranted, in particular for girls and patients with genetic syndromes or developmental delay. PMID- 29408245 TI - History of the Southern Thoracic Surgical Association President's Award for Best Scientific Paper. AB - The President's Award for best scientific paper is presented to esteemed members at each Southern Thoracic Surgical Association annual meeting to stimulate friendly scientific competition. Between 1964 and 2015, 58 awards were presented for clinical expertise in general thoracic surgery (18), adult cardiac surgery (25), and congenital heart surgery (15). Manuscripts were published by The Annals of Thoracic Surgery, and the average number of subsequent citations in professional medical journals as a measure of scientific importance was 43.7 +/- 60.2. A seemingly prosaic addition of a yearly scientific award has had an enormous impact on the scientific community and membership participation. PMID- 29408246 TI - "Bio-Chimney" Technique for Narrow Mitral Annulus in Adults. AB - Narrow mitral annulus is a common situation faced in adult patients. Choice of prosthetic valve in such cases is unclear. There are reported experiences with supra-annular mitral valve, Manouguian technique, "Chimney technique" with mechanical valve and Melody valve, the latter two being in children. We report a novel "Bio-Chimney" technique in which a bioprosthetic valve of a size appropriate for the patient is sutured to a polyester vascular graft which is then implanted to the native narrow mitral annulus in an adult patient with promising initial results. PMID- 29408247 TI - Peratrial Device Closure of Different Locations of Mitral Paravalvular Leaks. AB - BACKGROUND: The current approaches of transcatheter closure of mitral paravalvular leak (MPVL) have different drawbacks. The challenges come from transseptal puncture, accessing the MPVL site, and the absence of dedicated delivery systems. This study introduces a novel peratrial approach for device closure of different locations of MPVLs using a probe-assisted delivery system under three-dimensional transesophageal echocardiography. METHODS: A 4.0-cm minithoracotomy incision was made in the fourth right interspaces. The right atrium and the interatrial septum were punctured and dilated, followed by a guidewire passing through the septum. A specially designed J-shaped bendable hollow probe was advanced into the left atrium. The steerable probe was adjusted to cross the MPVL and introduced a stiff guidewire into the left ventricle. A 7F short delivery sheath was advanced over the wire through the MPVL into the left ventricle. A proper-sized muscular septal occluder was then selected and deployed. RESULTS: Transesophageal echocardiography revealed complete occlusion in 7 of 8 patients after a follow-up of 6 months to 4 years. Mild residual paravalvular regurgitation occurred in an early patient. In 2 patients with a crescent-shaped MPVL, two guidewires were advanced into the left ventricle across the leak, and double devices were deployed sequentially. All patients' symptoms improved by at least one New York Heart Association functional class. CONCLUSIONS: The peratrial technique can access and close MPVLs at different locations through a right minithoracotomy approach. This technique has the advantages of easy transseptal puncture, easy access to the MPVL site, and no exposure to radiation. PMID- 29408248 TI - Bilateral Opposing Loop Technique for Securing Air Knots. AB - Incompletely seated knots (air knots) during surgical aortic valve replacement can be potentially difficult to repair in anatomically challenging areas around the aortic root. That is especially true with mechanical protheses as subvalvular areas are inaccessible once the valve is seated. In this report, we present a novel and simple technique of tightening air knots from within the aortic root without removing the prosthesis. PMID- 29408249 TI - Melatonin as an endogenous regulator of diseases: The role of autophagy. AB - Melatonin has long been known for its apparent effects on sleep and circadian rhythm. It may participate as a possible therapeutic agent in neurodegenerative, cardiovascular, and endocrine disorders as well. Autophagy is a lysosomal degradation process that occurs in response to starvation and other stresses. Recent studies have reported that melatonin may modulate the autophagy process. We reviewed the current literature that has reported on how different diseases and/or experimental models change autophagy parameters. We also discussed the effect of melatonin on autophagy parameters in the central nervous, cardiovascular, gastrointestinal and endocrine systems as reported in nonclinical studies. Moreover, the molecular targets for melatonin are discussed in details. In summary, melatonin has been reported to enhance significant protective effects in different in vitro and in vivo studies either through enhancement or inhibition of the autophagy process. Melatonin holds promise in the treatment of several major diseases. Regulation of autophagy by melatonin is a determinant parameter that should be considered in the future studies. PMID- 29408250 TI - Chimeric Synergy in Natural Social Groups of a Cooperative Microbe. PMID- 29408251 TI - Response to Lisovski et al. AB - Lisovski et al.[1] describe the widely recognized limitations of light-level geolocator data for identifying short-distance latitudinal movements, recommend that caution be used when interpreting such data, intimated that we did not use such caution and argued that environmental shading likely explained the Golden winged Warbler (Vermivora chrysoptera) movements described in our 2015 report [2]. Lisovski et al.[1] conclude that the bird movements we reported could not be disentangled from estimation error in stationary animals caused by environmental shading. We argue that, to the contrary, these hypotheses can easily be disentangled because the premise that environmental shading caused synchronous and parallel error among geolocators is false. With their assertion that our location estimates could be biased by >3,500 km on a day with no observable local sources of shading, Lisovski et al.[1] have taken a position of incredulity toward all geolocator-based animal movement data published to date. PMID- 29408252 TI - Insect Olfaction: Once Swatted, Twice Shy. AB - While some mosquitoes are known to have an innate penchant for human hosts, new research details that they can learn, what they can learn and how they can learn. PMID- 29408253 TI - Neuroscience: The Rhythms of Speech Understanding. AB - An understanding of the precise role played by certain characteristic brain rhythms in facilitating speech comprehension has been elusive. New research adds important insight by showing that manipulating these rhythms leads to systematic changes in how brains respond to speech. PMID- 29408254 TI - Human Olfaction: It Takes Two Villages. AB - Human olfaction is sensitive but poorly encoded by language. A new study comparing horticulturalists and hunter-gatherers suggests that the strength of odor language is dependent on life-style. This work may stimulate olfactory research at the crossroads between biology and culture. PMID- 29408255 TI - Carbon Fixation: "Let Things Flow Naturally Forward in Whatever Way They Like". AB - Mixed-acid fermentation generates H2 and CO2 from formate. As shown in a recent study, the formate oxidation reaction can be driven backwards when sufficiently high partial pressures of the gases are applied, suggesting potentially interesting biotechnological applications. PMID- 29408256 TI - Colouration Genetics: Pretty Polymorphic Parrots. AB - The bright yellow, green and red feathers of parrots depend on unique pigments termed 'psittacofulvins'. The discovery of a gene underlying psittacofulvin colouration shows that this evolutionary innovation was achieved by co-opting an existing gene into feather development. PMID- 29408257 TI - Evolutionary Biomechanics: The Pathway to Power in Snapping Shrimp. AB - The extraordinary snaps of snapping shrimp evolved through simple morphological transitions with remarkable mechanical results. PMID- 29408258 TI - Cell Division: Single-Cell Physiology Reveals Secrets of Chromosome Condensation. AB - Our understanding of higher order chromosome structure has been transformed through statistical mechanics-based computer simulations of polymer chains. A new study exploring basic electrostatic interactions demystifies how chromosomes regulate their state of compaction over several orders of magnitude. PMID- 29408259 TI - Vascular Permeability: Flow-Mediated, Non-canonical Notch Signalling Promotes Barrier Integrity. AB - The vascular permeability barrier must be maintained in response to changes to vessel calibre, shear stress and blood pressure. A new study reveals a remarkable mechanism for flow-mediated regulation of permeability: Notch1 activation leads to the assembly of GTPase signalling complexes at VE-cadherin contacts and a strengthening of the endothelial barrier. PMID- 29408260 TI - Reproduction: Sperm with Two X Chromosomes and Eggs with None. AB - A new study shows that the nematode Auanema rhodensis manipulates X chromosome segregation in surprising ways that depend on both the sex of the parent and the type of gamete. The result is a complex mating system that produces unusual sex ratios and inheritance patterns. PMID- 29408261 TI - Collision Avoidance: Broadening the Toolkit for Directionally Selective Motion Computations. AB - Visually-guided escape behaviors are critical for survival. New research reveals how neurons selectively coding for local motion directions can be assembled into collision detecting ones using a simple recipe. PMID- 29408262 TI - Multi-level Crowding and the Paradox of Object Recognition in Clutter. AB - In everyday life, we are constantly surrounded by complex and cluttered scenes. In such cluttered environments, visual perception is primarily limited by crowding, the deleterious influence of nearby objects on object recognition. For the past several decades, visual crowding was assumed to occur at a single stage, only between low-level features or object parts, thus dismantling, destroying, or filtering object information. A large and converging body of evidence has demonstrated that this assumption is false: crowding occurs at multiple stages of visual analysis, and information passes through crowding at each of these stages. This converging empirical evidence points to a seeming paradox: crowding happens at multiple levels, which would seem to impair object recognition, and yet visual information at each of those levels is maintained intact and influences subsequent higher-level visual processing. Thus, while crowding impairs the access we have to visual information at many levels, it does not impair the representation of that information. The resolution of this paradox reveals how the visual system strikes a balance between the limits of object selection and the desire to represent multiple levels of visual information throughout cluttered scenes. Understanding crowding is therefore key to resolving the relationship between the richness of object and scene representations and the limits of conscious object recognition. PMID- 29408263 TI - Placozoa. AB - Schierwater & DeSalle introduce the enigmatic phylum Placozoa. PMID- 29408264 TI - Inherent limits of light-level geolocation may lead to over-interpretation. AB - In their 2015 Current Biology paper, Streby et al.[1] reported that Golden-winged Warblers (Vermivora chrysoptera), which had just migrated to their breeding location in eastern Tennessee, performed a facultative and up to ">1,500 km roundtrip" to the Gulf of Mexico to avoid a severe tornadic storm. From light level geolocator data, wherein geographical locations are estimated via the timing of sunrise and sunset, Streby et al.[1] concluded that the warblers had evacuated their breeding area approximately 24 hours before the storm and returned about five days later. The authors presented this finding as evidence that migratory birds avoid severe storms by temporarily moving long-distances. However, the tracking method employed by Streby et al.[1] is prone to considerable error and uncertainty. Here, we argue that this interpretation of the data oversteps the limits of the used tracking technique. By calculating the expected geographical error range for the tracked birds, we demonstrate that the hypothesized movements fell well within the geolocators' inherent error range for this species and that such deviations in latitude occur frequently even if individuals remain stationary. PMID- 29408265 TI - Nuclear translocation of PKM2/AMPK complex sustains cancer stem cell populations under glucose restriction stress. AB - Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future. PMID- 29408267 TI - Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis. AB - Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS) expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism. PMID- 29408266 TI - Ancient diversity and geographical sub-structuring in African buffalo Theileria parva populations revealed through metagenetic analysis of antigen-encoding loci. AB - An infection and treatment protocol involving infection with a mixture of three parasite isolates and simultaneous treatment with oxytetracycline is currently used to vaccinate cattle against Theileria parva. While vaccination results in high levels of protection in some regions, little or no protection is observed in areas where animals are challenged predominantly by parasites of buffalo origin. A previous study involving sequencing of two antigen-encoding genes from a series of parasite isolates indicated that this is associated with greater antigenic diversity in buffalo-derived T. parva. The current study set out to extend these analyses by applying high-throughput sequencing to ex vivo samples from naturally infected buffalo to determine the extent of diversity in a set of antigen encoding genes. Samples from two populations of buffalo, one in Kenya and the other in South Africa, were examined to investigate the effect of geographical distance on the nature of sequence diversity. The results revealed a number of significant findings. First, there was a variable degree of nucleotide sequence diversity in all gene segments examined, with the percentage of polymorphic nucleotides ranging from 10% to 69%. Second, large numbers of allelic variants of each gene were found in individual animals, indicating multiple infection events. Third, despite the observed diversity in nucleotide sequences, several of the gene products had highly conserved amino acid sequences, and thus represent potential candidates for vaccine development. Fourth, although compelling evidence for population differentiation between the Kenyan and South African T. parva parasites was identified, analysis of molecular variance for each gene revealed that the majority of the underlying nucleotide sequence polymorphism was common to both areas, indicating that much of this aspect of genetic variation in the parasite population arose prior to geographic separation. PMID- 29408268 TI - The development of progesterone-loaded nanofibers using pressurized gyration: A novel approach to vaginal delivery for the prevention of pre-term birth. AB - Recent evidence has continued to support the applicability of progesterone in preventing preterm birth, hence the development of an appropriate vaginal delivery system for this drug would be of considerable interest. Here, we describe the development of progesterone-loaded bioadhesive nanofibers using pressurized gyration for potential incorporation into a vaginal insert, with a particular view to addressing the challenges of incorporating a poorly water soluble drug into a hydrophilic nanofiber carrier. Polyethylene oxide and carboxymethyl cellulose were chosen as polymers to develop the carrier systems, based on previous evidence of their yielding mucoadhesive nanofibers using the pressurized gyration technique. The fabrication parameters such as solvent system, initial drug loading and polymer composition were varied to facilitate optimisation of fiber structure and efficiency of drug incorporation. Such studies resulted in the formation of nanofibers with satisfactory surface appearance, diameters in the region of 400 nm and loading of up to 25% progesterone. Thermal and spectroscopic analyses indicated that the drug was incorporated in a nanocrystalline state. Release from the drug-loaded fibers indicated comparable rates of progesterone dissolution to that of Cyclogest, a commercially available progesterone pessary, allowing release over a period of hours. Overall, the study has shown that pressurized gyration may produce bioadhesive progesterone-loaded nanofibers which have satisfactory loading of a poorly water-soluble drug as well as having suitable structural and release properties. The technique is also capable of producing fibers at a yield commensurate with practical applicability, hence we believe that the approach shows considerable promise for the development of progesterone dosage forms for vaginal application. PMID- 29408269 TI - Aedes aegypti antiviral adaptive response against DENV-2. AB - Priming is the conceptual term defining memory phenomenon in innate immune response. Numerous examples of enhanced secondary immune response have been described in diverse taxa of invertebrates; which naturally lacks memory response. In mosquitoes, a previous non-lethal challenge with some specific pathogens modify their immune response against the same microorganism; developing an improved antimicrobial reaction. In this work, we explore the ability of Aedes aegypti to mount a higher antiviral response upon a second oral DENV challenge. When previously challenged with inactive virus, we observed that the posterior infection showed a diminished number of DENV infectious particles in midguts and carcasses. In challenged tissues, we detected higher de novo midgut DNA synthesis than control group, as determined by DNA incorporation of 5-bromo-2-deoxyuridine. We demonstrated that inactive DENV particle are capable to induce DNA synthesis levels comparable to infective DENV. We considered the Drosophila melanogaster hindsight and Delta-Notch mosquitoes orthologues as potential de novo DNA synthesis pathway components (as observed in fly oocyte development and midgut tissue renewal). We showed that Aedes aegypti hindsight transcript relative expression levels were higher than control during DENV infection and inactive DENV particle alimentation. Also, Aedes aegypti second challenge with active DENV induced higher hindsight, Delta and Notch transcriptions in the primed mosquitoes (compared with the primary infection levels). Considering that the mosquito de novo DNA synthesis is concomitant to viral particle reduction, this finding opens a new perspective on the mechanisms underlying the vector antiviral immune response and the effector molecules involved. PMID- 29408270 TI - GABA function may be related to the impairment of learning and memory caused by systemic prenatal hypoxia-ischemia. AB - Intrauterine adverse conditions may be responsible for long-lasting damages which impact health even during adult phase. Hypoxic-ischemic (HI) events are a relevant cause of newborn mortality and the principal factor leading to permanent brain lesions. Using a model in which the ovarian and uterine flux of a pregnant rat is obstructed for 45 min we have described oligodendrocyte death, astrogliosis and neuronal loss. In this work we investigated hippocampal neuronal population and performed a functional evaluation of memory and learning of young rats that had been affected by prenatal HI. Anesthetized Wistar rats on the 18th gestation day had the uterine horns exposed and the ovarian and uterine arteries clamped for 45 min (HI group). Sham-operated rats (SH group) had the horns exposed but no arteries were clamped. We measured the levels of different proteins related to excitatory/inhibitory transmission in the hippocampi of young pups (P45). Histological evaluation was also performed in order to characterize hippocampal neuronal population. Rats from both groups were tested through Novel Object Recognition Test (NORT) using two inter-trial intervals: 5 min and 8 h. Here we show a loss in the total number of hippocampal neurons although the immunostaining of parvalbumin and levels of GAD enzyme were increased in HI group. Functional assessment indicated a marked difference concerning HI learning and memory abilities. Our results reflect permanent damages concerning GABA function which may disturb neurotransmitter homeostasis leading to the observed deficits in learning and memory. PMID- 29408271 TI - Maturity Onset Diabetes of the Young (MODY) in Tunisia: Low frequencies of GCK and HNF1A mutations. AB - Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in beta-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY. A total of 23 unrelated patients, with clinical presentation of MODY were tested for mutations in GCK, HNF1A, HNF4A and INS genes, using Denaturing High Performance Liquid Chromatography (DHPLC), Multiplex Ligation-depend Probe Amplification (MLPA) and sequencing analysis. We identified the previously reported mutation c-169C > T in one patient as well as a new mutation c-457C > T in two unrelated patients. No mutations were detected in the HNF1A and INS genes. Despite restrictive clinical criteria used for selecting patients in this study, the most common genes known for MODY do not explain the majority of cases in Tunisians. This suggests that there are others candidate or unidentified genes contributing to the etiology of MODY in Tunisians families. PMID- 29408272 TI - Prediction of DNA methylation in the promoter of gene suppressor tumor. AB - The epigenetics methylation of cytosine is the most common epigenetic form in DNA sequences. It is highly concentrated in the promoter regions of the genes, leading to an inactivation of tumor suppressors regardless of their initial function. In this work, we aim to identify the highly methylated regions; the cytosine-phosphate-guanine (CpG) island located on the promoters and/or the first exon gene known for their key roles in the cell cycle, hence the need to study gene-gene interactions. The Frommer and hidden Markov model algorithms are used as computational methods to identify CpG islands with specificity and sensitivity up to 76% and 80%, respectively. The results obtained show, on the one hand, that the genes studied are suspected of developing hypermethylation in the promoter region of the gene involved in the case of a cancer. We then showed that the relative richness in CG results from a high level of methylation. On the other hand, we observe that the gene-gene interaction exhibits co-expression between the chosen genes. This let us to conclude that the hidden Markov model algorithm predicts more specific and valuable information about the hypermethylation in gene as a preventive and diagnostics tools for the personalized medicine; as that the tumor-suppresser-genes have relative co-expression and complementary relations which the hypermethylation affect in the samples studied in our work. PMID- 29408273 TI - Impairment in extinction of cued fear memory in syntenin-1 knockout mice. AB - Syntenin-1 is a PDZ domain-containing intracellular scaffold protein involved in exosome production, synapse formation, and synaptic plasticity. We tested whether syntenin-1 can regulate learning and memory through its effects on synaptic plasticity. Specifically, we investigated the role of syntenin-1 in contextual and cued fear conditioning and extinction of conditioned fear using syntenin-1 knockout (KO) mice. Genetic disruption of syntenin-1 had little effect on contextual and cued fear memory. However, syntenin-1 KO mice exhibited selective impairment in cued fear extinction retention. This extinction retention deficit in syntenin-1 KO mice was associated with reduced c-Fos-positive neurons in the basolateral amygdala (BLA) and infralimbic cortex (IL) after extinction training and increased c-Fos-positive neurons in the BLA after an extinction retention test. Our results suggest that syntenin-1 plays an important role in extinction of cued fear memory by modulating neuronal activity in the BLA and IL. PMID- 29408275 TI - A Novel C2 Screw Trajectory: Preliminary Anatomic Feasibility and Biomechanical Comparison. AB - BACKGROUND: Pedicle screw and translaminar screw fixation in C2 may not be applicable in many patients with anatomic abnormalities or narrow laminar thickness and spinous process height. The aim of this study was to assess morphometric and mechanical feasibilities of a novel alternative screw trajectory that pierces the bifid base of C2. METHODS: Anatomic measurements that determined the feasibility of spinous process bifid base (SPB) screw fixation were assessed in 14 cadaveric C2 vertebrae. Pullout tests to assess ultimate fixation strength for 3 screw trajectories (transpedicular, translaminar, and SPB) were performed in cadaveric vertebrae for comparison. RESULTS: Anatomic measurements included mean spinous process height (10.4 +/- 4.2 mm) and mean bilateral bifid base length (10.1 +/- 2.2 mm) and thickness (left, 4.4 +/- 1.0 mm; right, 4.3 +/- 0.9 mm). In 64% (9/14) of specimens, bifid base length was >=9 mm. Mean pullout strength for transpedicle, translaminar, and SPB screws in 9 viable specimens was 648 +/- 305 N, 628 +/- 417 N, and 755 +/- 279 N. CONCLUSIONS: SPB screw fixation may be viable anatomically and mechanically for C2 fixation. Feasibility of SPB screw fixation is determined by length, thickness, and mutual angle of the bilateral bifid bases. Patients with thin (<4 mm) and short (<9 mm) bifid bases are not likely to be suitable candidates. SPB screw fixation shows potential as an alternative approach or a salvage technique for patients with high-riding vertebral arteries or severely thin C2 lamina and warrants further investigation. PMID- 29408276 TI - High-quality endoscope reprocessing decreases endoscope contamination. AB - OBJECTIVES: Several outbreaks of severe infections due to contamination of gastrointestinal (GI) endoscopes, mainly duodenoscopes, have been described. The rate of microbial endoscope contamination varies dramatically in literature. The aim of this multicentre prospective study was to evaluate the hygiene quality of endoscopes and automated endoscope reprocessors (AERs) in Tyrol/Austria. METHODS: In 2015 and 2016, a total of 463 GI endoscopes and 105 AERs from 29 endoscopy centres were analysed by a routine (R) and a combined routine and advanced (CRA) sampling procedure and investigated for microbial contamination by culture-based and molecular-based analyses. RESULTS: The contamination rate of GI endoscopes was 1.3%-4.6% according to the national guideline, suggesting that 1.3-4.6 patients out of 100 could have had contacts with hygiene-relevant microorganisms through an endoscopic intervention. Comparison of R and CRA sampling showed 1.8% of R versus 4.6% of CRA failing the acceptance criteria in phase I and 1.3% of R versus 3.0% of CRA samples failing in phase II. The most commonly identified indicator organism was Pseudomonas spp., mainly Pseudomonas oleovorans. None of the tested viruses were detected in 40 samples. While AERs in phase I failed (n = 9, 17.6%) mainly due to technical faults, phase II revealed lapses (n = 6, 11.5%) only on account of microbial contamination of the last rinsing water, mainly with Pseudomonas spp. CONCLUSIONS: In the present study the contamination rate of endoscopes was low compared with results from other European countries, possibly due to the high quality of endoscope reprocessing, drying and storage. PMID- 29408277 TI - Molecular organization and mechanical properties of the hyaluronan matrix surrounding the mammalian oocyte. AB - Successful ovulation and oocyte fertilization are essential prerequisites for the beginning of life in sexually reproducing animals. In mammalian fertilization, the relevance of the protein coat surrounding the oocyte plasma membrane, known as zona pellucida, has been widely recognized, while, until not too long ago, the general belief was that the cumulus oophorus, consisting of follicle cells embedded in a hyaluronan rich extracellular matrix, was not essential. This opinion was based on in vitro fertilization procedures, in which a large number of sperms are normally utilized and the oocyte can be fertilized even if depleted of cumulus cells. Conversely, in vivo, only very few sperm cells reach the fertilization site, arguing against the possibility of a coincidental encounter with the oocyte. In the last two decades, proteins required for HA organization in the cumulus extracellular matrix have been identified and the study of fertility in mice deprived of the corresponding genes have provided compelling evidence that this jelly-like coat is critical for fertilization. This review focuses on the advances in understanding the molecular interactions making the cumulus environment suitable for oocyte and sperm encounter. Most of the studies on the molecular characterization of the cumulus extracellular matrix have been performed in the mouse and we will refer essentially to findings obtained in this animal model. PMID- 29408274 TI - Running exercise mitigates the negative consequences of chronic stress on dorsal hippocampal long-term potentiation in male mice. AB - In the hippocampus, learning and memory are likely mediated by synaptic plasticity, known as long-term potentiation (LTP). While chronic intermittent stress is negatively correlated, and exercise positively correlated to LTP induction, we examined whether exercise could mitigate the negative consequences of stress on LTP when co-occurring with stress. Mice were divided into four groups: sedentary no stress, exercise no stress, exercise with stress, and sedentary with stress. Field electrophysiology performed on brain slices confirmed that stress alone significantly reduced dorsal CA1 hippocampal LTP and exercise alone increased LTP compared to controls. Exercise with stress mice exhibited LTP that was significantly greater than mice undergoing stress alone but were not different from sedentary no stress mice. An ELISA illustrated increased corticosterone in stressed mice compared to no stress mice. In addition, a radial arm maze was used to examine behavioral changes in memory during 6 weeks of stress and/or exercise. Exercised mice groups made fewer errors in week 2. RT-qPCR was used to examine the mRNA expression of components in the stress and exercise pathways in the four groups. Significant changes in the expression of the following targets were detected: BDNF, TrkB, glucocorticoid, mineralocorticoid, and dopamine 5 receptors. Collectively, exercise can mitigate some of the negative impact stress has on hippocampal function when both occur concurrently. PMID- 29408278 TI - New developments on skin fibrosis - Essential signals emanating from the extracellular matrix for the control of myofibroblasts. AB - Many different diseases are associated with fibrosis of the skin. The clinical symptoms can vary considerably with a broad range from isolated small areas to the involvement of the entire integument. Fibrosis is triggered by a multitude of different stimuli leading to activation of the immune and vascular system that then initiate fibroblast activation and formation of matrix depositing and remodeling myofibroblasts. Ultimately, myofibroblasts deposit excessive amounts of extracellular matrix with a pathological architecture and alterations in growth factor binding and biomechanical properties, which culminates in skin hardening and loss of mobility. Treatment depends certainly on the specific type and cause of the disease, for the autoimmune driven localized and systemic scleroderma therapeutic options are still limited, but recent research has pointed out diverse molecular targets and mechanisms that can be exploited for the development of novel antifibrotic therapy. PMID- 29408280 TI - Reply. PMID- 29408279 TI - Natural history of pain and disability among African-Americans and Whites with or at risk for knee osteoarthritis: A longitudinal study. AB - OBJECTIVE: Compare knee pain and disability between African Americans (AAs) and Whites (WHs), with or at risk of knee osteoarthritis (KOA), over 9 years, and evaluate racial disparities in KOA-related symptoms across socioeconomic and clinical characteristics. DESIGN: Osteoarthritis Initiative (OAI) participants were evaluated annually over 9 years for pain and disability, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a numerical rating scale (NRS) for knee pain severity. Mean annual WOMAC pain, NRS pain, and WOMAC disability levels were estimated by race using mixed effects models, adjusted for age, sex, education, marital status, body mass index (BMI), depression, and baseline Kellgren-Lawrence grade score. Race-specific mean WOMAC pain scores were also estimated in analyses stratified by socioeconomic and clinical characteristics. RESULTS: AAs reported worse mean WOMAC pain compared to WHs at baseline (3.69 vs 2.20; P <= 0.0001) and over 9 years of follow-up, with similar disparities reflected in NRS pain severity and WOMAC disability. Radiographic severity did not account for the differences in pain and disability, as substantial and significant racial disparities were observed after stratification by Kellgren-Lawrence grade. Depression and low income exacerbated differences in WOMAC pain between AAs and WHs by a substantial and significant magnitude. CONCLUSIONS: Over 9 years of follow-up, AAs reported persistently greater KOA symptoms than WHs. Socioeconomically and clinically disadvantaged AAs reported the most pronounced disparities in pain and disability. PMID- 29408281 TI - Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6 RUNX1. AB - Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia. Here we report that Btg1 deficiency enhances the self-renewal capacity of ETV6-RUNX1 positive mouse fetal liver-derived hematopoietic progenitors (FL-HPCs). Combined expression of the fusion protein and a loss of BTG1 drive upregulation of the proto-oncogene Bcl6 and downregulation of BCL6 target genes, such as p19Arf and Tp53. Similarly, ectopic expression of BCL6 promotes the self-renewal and clonogenic replating capacity of FL-HPCs, by suppressing the expression of p19Arf and Tp53. Together these results identify BCL6 as a potential driver of ETV6 RUNX1-mediated leukemogenesis, which could involve loss of BTG1-dependent suppression of ETV6-RUNX1 function. PMID- 29408282 TI - Pharmacological manipulation of GABA activity in nucleus subpretectalis/interstitio-pretecto-subpretectalis (SP/IPS) impairs figure-ground discrimination in pigeons: Running head: SP/IPS in figure-ground segregation. AB - Figure-ground segregation is a fundamental visual ability that allows an organism to separate an object from its background. Our earlier research has shown that nucleus rotundus (Rt), a thalamic nucleus processing visual information in pigeons, together with its inhibitory complex, nucleus subpretectalis/interstitio pretecto-subpretectalis (SP/IPS), are critically involved in figure-ground discrimination (Acerbo et al., 2012; Scully et al., 2014). Here, we further investigated the role of SP/IPS by conducting bilateral microinjections of GABAergic receptor antagonist and agonists (bicuculline and muscimol, respectively) and non-NMDA glutamate receptor antagonist (CNQX) after the pigeons mastered figure-ground discrimination task. We used two doses of each drug (bicuculline: 0.1 mM and 0.05 mM; muscimol: 4.4 mM and 8.8 mM; CNQX: 2.15 mM and 4.6 mM) in a within-subject design, and alternated drug injections with baseline (ACSF). The order of injections was randomized across birds to reduce potential carryover effects. We found that a low dose of bicuculline produced a decrement on figure trials but not on background trials, whereas a high dose impaired performance on background trials but not on figure trials. Muscimol produced an equivalent, dose-dependent impairment on both types of trials. Finally, CNQX had no consistent effect at either dose. Together, these results further confirm our earlier hypothesis that inhibitory projections from SP to Rt modulate figure ground discrimination, and suggest that the Rt and the SP/IPS provide a plausible substrate that could perform figure-ground segregation in avian brain. PMID- 29408283 TI - Crosstalk-free multicolor RICS using spectral weighting. AB - Raster image cross-correlation spectroscopy (ccRICS) can be used to quantify the interaction affinities between diffusing molecules by analyzing the fluctuations between two-color confocal images. Spectral crosstalk compromises the quantitative analysis of ccRICS experiments, limiting multicolor implementations to dyes with well-separated emission spectra. Here, we remove this restriction by introducing raster spectral image correlation spectroscopy (RSICS), which employs statistical filtering based on spectral information to quantitatively separate signals of fluorophores during spatial correlation analysis. We investigate the performance of RSICS by testing how different levels of spectral overlap or different relative signal intensities affect the correlation function and analyze the influence of statistical filter quality. We apply RSICS in vitro to resolve dyes with very similar emission spectra, and carry out RSICS in live cells to simultaneously analyze the diffusion of molecules carrying three different fluorescent protein labels (eGFP, Venus and mCherry). Finally, we successfully apply statistical weighting to data that was recorded with only a single detection channel per fluorophore, highlighting the general applicability of this method to data acquired with any type of multicolor detection. In conclusion, RSICS enables artifact-free quantitative analysis of concentrations, mobility and interactions of multiple species labeled with different fluorophores. It can be performed on commercial laser scanning microscopes, and the algorithm can be easily extended to other image correlation methods. Thus, RSICS opens the door to quantitative multicolor fluctuation analyses of complex (bio-) molecular systems. PMID- 29408285 TI - Management of IVC Injury: Repair or Ligation? A Propensity Score Matching Analysis Using the National Trauma Data Bank. AB - BACKGROUND: Ligation can be used as part of damage-control operations under critical conditions after IVC injury. Inferior vena cava ligation could potentially yield greater survival benefit compared with repair after injury. We hypothesized that ligation significantly improves outcomes compared with repair. STUDY DESIGN: The National Trauma Data Bank dataset for 2007-2014 was reviewed. Eligible patients included those sustaining IVC injury who underwent surgical ligation or repair. Data on demographics, outcomes, and complications were collected. Comparative analysis of demographic characteristics, complications and outcomes were performed. RESULTS: There were 4,865 patients identified in the National Trauma Data Bank with IVC injury. A total of 1,316 patients met inclusion criteria. Four hundred and forty-seven patients (34.0%) underwent ligation and 869 (66.0%) underwent repair. Before matching, the ligation group was sicker than the repair group and the in-hospital mortality was significantly higher in the ligation group (43.8% vs 36.2%; odds ratio [OR] 1.37; 95% CI 1.09 to 1.73). One to one propensity score matching generated 310 pairs. After propensity score matching, in-hospital mortality was similar (41.3% vs 39.0%; OR 1.10; 95% CI 0.80 to 1.52). However, IVC ligation was associated with significantly higher complication rates of extremity compartment syndrome (OR 5.23; 95% CI 1.50 to 18.24), pneumonia (OR 1.76; 95% CI 1.08 to 2.86), deep venous thrombosis (OR 2.83 95% CI 1.70 to 4.73), pulmonary embolism (OR 3.63; 95% CI 1.18 to 11.17), and longer hospital length of stay (17.0 days [interquartile range 1.0 to 35.0 days] vs 9.0 days [interquartile range 1.0 to 22.0 days]; p = 0.002). CONCLUSIONS: Inferior vena cava ligation is not superior to repair in terms of decreasing mortality in patients with IVC injury, but it is associated with higher complication rates and hospital LOS. PMID- 29408284 TI - Family planning providers' role in offering PrEP to women. AB - Pre-exposure prophylaxis (PrEP) provides a radically different HIV prevention option for women. Not only is PrEP the first discrete, woman-controlled method that is taken in advance of exposure, but it is both safe and highly effective, offering over 90% protection if taken daily. While multiple modalities of PrEP are in development ranging from vaginal rings to injectables and implants, only PrEP with oral tenofovir/emtricitabine is currently FDA-approved. Family planning clinics provide key access points for many women to learn about and obtain PrEP. By incorporating PrEP services into family planning care, family planning providers have the opportunity to meet women's expectations, ensure women are aware of and offered comprehensive HIV prevention options, and reverse emerging disparities in PrEP access. Despite real and perceived barriers to integrating PrEP into family planning care, providing PrEP services, ranging from education to onsite provision, is not only possible but an important component of providing high-quality sexual and reproductive healthcare to women. Lessons learned from early adopters will help guide those in family planning settings initiating or enhancing PrEP services. PMID- 29408286 TI - Mitochondrial phylogeny, divergence history and high-altitude adaptation of grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) inhabiting the Tibetan Plateau. AB - Grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) are the most important pests in alpine meadows of the Tibetan Plateau (TP) and have well adapted to high-altitude environments. To further understand the evolutionary history and their adaptation to the TP, we newly determined seven complete TP Gynaephora mitogenomes. Compared to single genes, whole mitogenomes provided the best phylogenetic signals and obtained robust results, supporting the monophyly of the TP Gynaephora species and a phylogeny of Arctiinae + (Aganainae + Lymantriinae). Incongruent phylogenetic signals were found among single mitochondrial genes, none of which recovered the same phylogeny as the whole mitogenome. We identified six best-performing single genes using Shimodaira Hasegawa tests and found that the combinations of rrnS and either cox1 or cox3 generated the same phylogeny as the whole mitogenome, indicating the phylogenetic potential of these three genes for future evolutionary studies of Gynaephora. The TP Gynaephora species were estimated to radiate on the TP during the Pliocene and Quaternary, supporting an association of the diversification and speciation of the TP Gynaephora species with the TP uplifts and associated climate changes during this time. Selection analyses revealed accelerated evolutionary rates of the mitochondrial protein-coding genes in the TP Gynaephora species, suggesting that they accumulated more nonsynonymous substitutions that may benefit their adaptation to high altitudes. Furthermore, signals of positive selection were detected in nad5 of two Gynaephora species with the highest altitude distributions, indicating that this gene may contribute to Gynaephora's adaptation to divergent altitudes. This study adds to the understanding of the TP Gynaephora evolutionary relationships and suggests a link between mitogenome evolution and ecological adaptation to high-altitude environments in grassland caterpillars. PMID- 29408287 TI - Providing context for phosphatidylethanol as a biomarker of alcohol consumption with a pharmacokinetic model. AB - Phosphatidylethanol (PEth) is increasingly used as a biomarker of heavy drinking. Many different forms of PEth can form in red blood cell membranes from the action of the enzyme phospholipase D. PEth has a very long duration in blood because, in contrast to other tissues, RBCs lack the enzymes that degrade PEth. Because this biomarker is relatively new, interpretations of the analytical measurements of PEth may be misinterpreted and the resulting predictions of actual alcohol consumption inaccurate. Hence, a simple pharmacokinetic model of PEth was developed to provide a means of contextualizing these analytical results. A number of alcohol consumption scenarios and current clinical screening levels were examined with the model. PMID- 29408288 TI - Neuroprotective nature of adipokine resistin in the early stages of focal cerebral ischemia in a stroke mouse model. AB - New evidence suggests that resistin may have a therapeutic potential effect in management of neurodegenerative disease; but its role in the pathophysiology of stroke-induced injuries is not understood. However, further investigations are required to elucidate the effect of resistin and explore its possible molecular mechanisms on the ischemic reperfusion injury. Transient focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) in mice. Animal treated with resistin at doses of 25, 50, 100, 200, and 400 ng/mouse, on the MCAO commencement. Neurological function, infarct size, brain edema and Blood-brain barrier (BBB) disruption were measured. Additionally, content of malondialdehyde (MDA), TUNEL-positive cells and apoptosis-related proteins were assessed by immunohistochemistry and western blot techniques. Resistin mRNA was detected at 3 h, 6 h, 12 h and 24 h after MCAO using real-time QRT-PCR method. Central administration of resistin only at doses of 200 and 400 ng/mouse considerably reduced the infarct size and promoted neurological function (p < 0.001). In addition, resistin (400 ng/mouse) significantly decreased brain edema (p < 0.001), evans blue (EB) leakage (p < 0.05), MDA content (p < 0.005), apoptotic cells and apoptosis-related proteins (p < 0.001). Resistin mRNA expression markedly increased at 12-h time point and then returned to basal level at 24 h after MCAO. Our findings revealed that treatment with resistin could attenuate ischemic damage in a dose-dependent approach via suppressing apoptosis and oxidative stress. Application of resistin in clinical settings to treat stroke and brain ischemia warrants further research. PMID- 29408289 TI - Engaging Patients in Setting a Patient-Centered Outcomes Research Agenda in Hematopoietic Cell Transplantation. AB - The goal of patient-centered outcomes research (PCOR) is to help patients and those who care for them make informed decisions about healthcare. However, the clinical research enterprise has not involved patients, caregivers, and other nonproviders routinely in the process of prioritizing, designing, and conducting research in hematopoietic cell transplantation (HCT). To address this need the National Marrow Donor Program/Be The Match engaged patients, caregivers, researchers, and other key stakeholders in a 2-year project with the goal of setting a PCOR agenda for the HCT community. Through a collaborative process we identified 6 major areas of interest: (1) patient, caregiver, and family education and support; (2) emotional, cognitive, and social health; (3) physical health and fatigue; (4) sexual health and relationships; (5) financial burden; and (6) models of survivorship care delivery. We then organized into multistakeholder working groups to identify gaps in knowledge and make priority recommendations for critical research to fill those gaps. Gaps varied by working group, but all noted that a historical lack of consistency in measures use and patient populations made it difficult to compare outcomes across studies and urged investigators to incorporate uniform measures and homogenous patient groups in future research. Some groups advised that additional pre-emptory work is needed before conducting prospective interventional trials, whereas others were ready to proceed with comparative clinical effectiveness research studies. This report presents the results of this major initiative and makes recommendations by working group on priority questions for PCOR in HCT. PMID- 29408291 TI - Model-assisted metabolic engineering of Escherichia coli for long chain alkane and alcohol production. AB - Biologically-derived hydrocarbons are considered to have great potential as next generation biofuels owing to the similarity of their chemical properties to contemporary diesel and jet fuels. However, the low yield of these hydrocarbons in biotechnological production is a major obstacle for commercialization. Several genetic and process engineering approaches have been adopted to increase the yield of hydrocarbon, but a model driven approach has not been implemented so far. Here, we applied a constraint-based metabolic modeling approach in which a variable demand for alkane biosynthesis was imposed, and co-varying reactions were considered as potential targets for further engineering of an E. coli strain already expressing cyanobacterial enzymes towards higher chain alkane production. The reactions that co-varied with the imposed alkane production were found to be mainly associated with the pentose phosphate pathway (PPP) and the lower half of glycolysis. An optimal modeling solution was achieved by imposing increased flux through the reaction catalyzed by glucose-6-phosphate dehydrogenase (zwf) and iteratively removing 7 reactions from the network, leading to an alkane yield of 94.2% of the theoretical maximum conversion determined by in silico analysis at a given biomass rate. To validate the in silico findings, we first performed pathway optimization of the cyanobacterial enzymes in E. coli via different dosages of genes, promoting substrate channelling through protein fusion and inducing substantial equivalent protein expression, which led to a 36-fold increase in alka(e)ne production from 2.8 mg/L to 102 mg/L. Further, engineering of E. coli based on in silico findings, including biomass constraint, led to an increase in the alka(e)ne titer to 425 mg/L (major components being 249 mg/L pentadecane and 160 mg/L heptadecene), a 148.6-fold improvement over the initial strain, respectively; with a yield of 34.2% of the theoretical maximum. The impact of model-assisted engineering was also tested for the production of long chain fatty alcohol, another commercially important molecule sharing the same pathway while differing only at the terminal reaction, and a titer of 1506 mg/L was achieved with a yield of 86.4% of the theoretical maximum. Moreover, the model assisted engineered strains had produced 2.54 g/L and 12.5 g/L of long chain alkane and fatty alcohol, respectively, in the bioreactor under fed-batch cultivation condition. Our study demonstrated successful implementation of a combined in silico modeling approach along with the pathway and process optimization in achieving the highest reported titers of long chain hydrocarbons in E. coli. PMID- 29408290 TI - Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients. AB - Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys )functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC). PMID- 29408292 TI - Effect of aPDT on Streptococcus mutans and Candida albicans present in the dental biofilm: Systematic review. AB - To evaluate the effect of aPDT on S. mutans and C. albicans present in the dental biofilm, using methylene blue as a photosensitizer in different pre-irradiation times. The searches were made on Pubmed, Web of Science, Bireme, Scopus and Cochrane Library, and were complemented by screening the references of selected articles in the attempt to find any article that did not appear in the database search. The searches were performed by two researchers and limited to studies involving human subjects published in the English language. Inclusion criteria included in vitro studies with aPDT; studies that used methylene blue as a photosensitizer; studies that used low power laser; studies that evaluated S. mutans or C. albicans. Studies published in a non-English language, patents, in vivo or in situ studies; case reports, serial case, reviews and animal studies were not included. Studies published before 1996 were also not included. Initially, the search resulted in 68 published studies. 16 records were excluded because they were duplicated. The analysis of titles and abstracts resulted in the exclusion of 48 of the published studies, resulting in 4 studies included in the systematic review. The aPDT was effective in three of the four papers selected for the systematic review and the pre-irradiation time used was 5 or 15 min. This therapy had satisfactory results in both C. albicans and S. mutans when using methylene blue as a photosensitizer. PMID- 29408294 TI - Efficient expression and isolation of recombinant human interleukin-11 (rhIL-11) in Pichia pastoris. AB - Current source of recombinant human interleukin-11 (rhIL-11) is isolated from a fusion protein expressed by E. coli that requires additional enterokinase to remove linked protein, resulting in product heterogeneity of N-terminal sequence. Due to lack of glycosylation, rhIL-11 is suitable to be expressed by yeast cells. However, the only available yeast-derived rhIL-11 presents an obstacle in low production yield, as well as an unamiable process, such as the use of reverse phase chromatography employing plenty of toxic organic solvents. Our findings showed that the low yield was due to self-aggregation of rhIL-11. A novel process recovering bioactive rhIL-11 from the yeast secretory medium therefore has been developed and demonstrated, involving fermentation from Pichia pastoris, followed by a two-phase extraction to precipitate rhIL-11. After renaturing, the protein of interest was purified by a two-column step, comprising a cation-exchanger, and a hydrophobic interaction chromatography in tandem at high sample loads that was facile and cost-effective in future scale-up. Identity and quality assessments confirmed the expected amino acid sequence without N-terminal heterogeneity, as well as high quality in potency and purity. Such a process provides an alternative and adequate supply of the starting material for the PEGylated rhIL 11. PMID- 29408293 TI - Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides. AB - This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 MUg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. PMID- 29408295 TI - KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with the risk of head and neck squamous cell carcinoma in Iranians. AB - BACKGROUND: Activating and inhibitory KIR receptors (aKIR, iKIR) control the development and function of NK cells whose function alterations adjust the tumor microenvironment immunity. This research was conducted to determine the KIRs gene impact on genetic predisposition to Head and Neck Squamous Cell Carcinoma (HNSCC) in Iranians. METHODS: KIR genotyping using sequence-specific primers-polymerase chain reaction (SSP-PCR) method was performed to identify the presence of all 16 KIR genes in 285 HNSCC patients, including laryngeal, oral cavity and pharyngeal SCC and 273 controls (CNs). RESULTS: Comparison of KIRs gene frequency between HNSCC and CNs revealed a highly significant increase in KIR2DL5, 2DS1, 2DS5, 3DS1 and CxT4 genotype and a decrease in KIR2DS4 deleted variant and AA genotype carriers. A significant increase was noted in individuals withhigher iKIRs than aKIRs in HNSCC compared with CNs. Individuals with >=4 iKIR and those with >=5 aKIRs were significantly more common in HNSCC than CNs. 68distinct KIR genotypes were identified in 558 individuals. CONCLUSION: Our findings determined the detrimental impact of KIR2DS1, 2DS5, 3DS1, 2DL5 and CxT4 genotype as well as the protective impact of KIR2DS4del and AA genotype on genetic predisposition to HNSCC in Iranians. PMID- 29408296 TI - GNC-app: A new Cytoscape app to rate gene networks biological coherence using gene-gene indirect relationships. AB - MOTIVATION: Gene networks are currently considered a powerful tool to model biological processes in the Bioinformatics field. A number of approaches to infer gene networks and various software tools to handle them in a visual simplified way have been developed recently. However, there is still a need to assess the inferred networks in order to prove their relevance. RESULTS: In this paper, we present the new GNC-app for Cytoscape. GNC-app implements the GNC methodology for assessing the biological coherence of gene association networks and integrates it into Cytoscape. Implemented de novo, GNC-app significantly improves the performance of the original algorithm in order to be able to analyse large gene networks more efficiently. It has also been integrated in Cytoscape to increase the tool accessibility for non-technical users and facilitate the visual analysis of the results. This integration allows the user to analyse not only the global biological coherence of the network, but also the biological coherence at the gene-gene relationship level. It also allows the user to leverage Cytoscape capabilities as well as its rich ecosystem of apps to perform further analyses and visualizations of the network using such data. AVAILABILITY: The GNC-app is freely available at the official Cytoscape app store: http://apps.cytoscape.org/apps/gnc. PMID- 29408297 TI - Do juvenile developmental and adult body characteristics differ among genotypes at the doublesex locus that controls female-limited Batesian mimicry polymorphism in Papilio memnon?: A test for the "cost of mimicry" hypothesis. AB - Female-limited Batesian mimicry may have evolved because of stronger predation pressure on females than on males, but some physiological costs of mimicry may also hinder the evolution of mimicry in males. In Papilio memnon, which possesses a female-limited Batesian mimicry polymorphism, two alleles at the doublesex (dsx) locus strictly control female phenotypes. To examine whether there are physiological costs associated with mimetic genotypes in the juvenile stage, we compered mortality, juvenile growth and development, and the resultant adult characteristics among three dsx genotypes (HH, Hh, hh) at a constant temperature (25 degrees C) and two differing day lengths (LD 14:10 and LD 12:12; the latter might induce pupal diapause) by crossing individuals heterozygous (Hh) for the dsx allele. All pupae emerged directly without diapause irrespective of day length. The genotype frequencies of the emerged individuals were consistent with the expected 1:2:1 ratio of HH:Hh:hh. The sex ratio was significantly male-biased in one of two families, but not in the other. We found no effect of genotype on any developmental or adult characteristic, although there were sex differences in most traits. The larval development time was longer and growth rate higher in females than in males; pupal weight, forewing length, and total dry mass of the thorax and abdomen were greater in females, whereas the thoracic mass/abdominal mass ratio was greater in males. We also found that the growth rate was higher and pupal period longer with a short day than with a long day. Overall, we found no evidence for physiological costs associated with the mimetic genotypes. However, it is too early to conclude that no physiological cost of mimicry affects the evolution and maintenance of this female-limited Batesian mimicry polymorphism because we have not studied the adults of different genotypes. PMID- 29408298 TI - From Hypothermia to Cephalosomatic Anastomoses: The Legacy of Robert White (1926 2010) at Case Western Reserve University of Cleveland. AB - Dr. Robert J. White (1926-2010) was an eminent neurosurgeon and bioethicist, renowned for his classic work in hypothermia and pioneering mammalian head transplant experiments. He founded the Division of Neurosurgery at the Cleveland Metropolitan General Hospital (currently MetroHealth Medical Center, a level 1 trauma county hospital) and became the youngest full professor at the Case Western Reserve University in Cleveland, Ohio. With over 500 research articles to his credit, he founded the Brain Research Laboratory at what was then the Cleveland Metropolitan General Hospital, which was also home to future leaders in neurosurgery, neurosciences, and allied specialties. He transferred a healthy monkey head onto a surgically beheaded monkey body under deep hypothermic conditions drawing both laurels and criticisms alike. Despite a largely controversial neurosurgical research career, his original contributions to deep hypothermia have found profound clinical applications in modern trauma and vascular neurosurgery. The new fusogens and myelorrhaphy methods being tried in Europe hold promise for a future of reanastomosing 2 homologous or heterologous tracts in the neuraxis. PMID- 29408299 TI - Cervical Epidural Hematoma That Induced Sudden Paraparesis After Cervical Spine Massage: Case Report and Literature Review. AB - BACKGROUND: Most people understand spinal manipulation therapy to be a safe procedure, and in many cases treatment is provided without a diagnosis if there is musculoskeletal pain. Cervical epidural hematoma occurs in extremely rare cases after cervical manipulation therapy. This study reports a case of epidural hematoma that occurred in the anterior spinal cord after cervical massage. CASE DESCRIPTION: A 38-year-old male patient was admitted to the emergency department for sudden weakness in the lower extremity after receiving a cervical spine massage. No fracture was found using cervical radiographs, and there were no particular findings on performing brain computed tomography or diffusion magnetic resonance imaging. However, using cervical magnetic resonance imaging, an acute epidural hematoma was observed in the anterior spinal cord from the C6 and C7 vertebrae to the T1 vertebra, compressing the spinal cord. There were no fractures or ligament injury. No surgical treatment was required as the patient showed spontaneous improvements in muscle strength and was discharged after just 1 week, following observation of the improvement in his symptoms. CONCLUSION: Although cervical epidural hematoma after cervical manipulation therapy is extremely rare, if suspected, a thorough examination must be performed in order to reduce the chances of serious neurologic sequelae. PMID- 29408300 TI - The Potential of Minimally Invasive Surgery to Treat Metastatic Spinal Disease versus Open Surgery: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND OBJECTIVE: Metastasis to the spinal column is a common feature of primary tumors of the breast, prostate, lung, and other organs. Surgical intervention can be performed via the traditional open surgery (OS) approach or the minimally invasive surgery (MIS) approach. This study aims to assess the available evidence of perioperative outcomes of MIS versus OS for patients with metastatic spinal disease. METHODS: We followed recommended PRISMA guidelines for systematic reviews. Six electronic databases were searched to identify all potentially relevant studies published from inception to October 2017. Data were extracted and analyzed using meta-analysis of proportions. RESULTS: Six studies satisfied the criteria for inclusion into this study. There were 292 patients with metastatic spinal disease described in the cohort, treated with either MIS (n = 155, 53%) or OS (n = 137, 47%). Compared with OS, MIS resulted in statistically significant reduction in blood loss (mean difference, -601.48 mL; P < 0.001) and length of stay (mean difference, -4.60 days; P = 0.002). In terms of complications, MIS had a significantly reduced incidence compared with OS (21/155 [14%] and 37/136 [27%], respectively; odds ratio, 0.41; P = 0.005). In terms of operation duration (P = 0.43), postoperative functional (P = 0.76) and pain (P = 0.84) outcomes, MIS was noninferior to OS. CONCLUSIONS: Surgical intervention by an MIS approach in patients with metastatic spinal disease seems to provide equivalent outcomes compared with OS and reduces morbidity and length of stay. Future studies that are larger, prospective, and longer-term will validate the findings of this study and elucidate the optimal role for MIS in the surgical management of metastatic spinal disease. PMID- 29408301 TI - Bradykinin mediates myogenic differentiation in murine myoblasts through the involvement of SK1/Spns2/S1P2 axis. AB - Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration. Growth factors exploit sphingosine kinase (SK), the enzyme that catalyzes the production of sphingosine 1-phosphate (S1P), to exert their biological effects in skeletal muscle. In this paper we show for the first time that bradykinin (BK), the leading member of kinin/kallikrein system, is able to induce myogenic differentiation in C2C12 myoblasts. Moreover, evidence is provided that SK1, the specific S1P-transporter spinster homolog 2 (Spns2) and S1P2 receptor are involved in the action exerted by BK, since pharmacological inhibition/antagonism or specific down-regulation significantly alter BK-induced myogenic differentiation. Moreover, the molecular mechanism initiated by BK involves a rapid translocation of SK1 to plasma membrane, analyzed by time-lapse immunofluorescence analysis. The present study highlights the role of SK1/Spns2/S1P receptor 2 signaling axis in BK-induced myogenic differentiation, thus confirming the crucial involvement of this pathway in skeletal muscle cell biology. PMID- 29408302 TI - The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders. AB - Platelet-derived growth factor (PDGF) was discovered as a serum-derived component necessary for the growth of smooth muscle cells, fibroblasts, and glial cells. The PDGF family is a product of four gene products and consists of five dimeric isoforms: PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the PDGF-AB heterodimer. This growth factor family plays an essential role in embryonic development and in wound healing in the adult. These growth factors mediate their effects by binding to and activating their receptor protein-tyrosine kinases, which are encoded by two genes: PDGFRA and PDGFRB. The functional receptors consist of the PDGFRalpha/alpha and PDGFRbeta/beta homodimers and the PDGFRalpha/beta heterodimer. Although PDGF signaling is most closely associated with mesenchymal cells, PDGFs and PDGF receptors are widely expressed in the mammalian central nervous system. The PDGF receptors contain an extracellular domain that is made up of five immunoglobulin-like domains (Ig-d1/2/3/4/5), a transmembrane segment, a juxtamembrane segment, a protein-tyrosine kinase domain that contains an insert of about 100 amino acid residues, and a carboxyterminal tail. Although uncommon, activating mutations in the genes for PDGF or PDGF receptors have been documented in various neoplasms including dermatofibrosarcoma protuberans (DFSP) and gastrointestinal stromal tumors (GIST). In most neoplastic diseases, PDGF expression and action appear to involve the tumor stroma. Moreover, this family is pro-angiogenic. More than ten PDGFRalpha/beta multikinase antagonists have been approved by the FDA for the treatment of several neoplastic disorders and interstitial pulmonary fibrosis (www.brimr.org/PKI/PKIs.htm). Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-Din). In contrast, type II inhibitors bind to their target with the DFG-D pointing away from the active site (DFG-Dout). We used the Schrodinger induced-fit docking protocol to model the interaction of several antagonists with PDGFRalpha including imatinib, sorafenib, and sunitinib. The results indicate that these antagonists are able to bind to the DFG-Dout conformation of the receptor and are thus classified as type II inhibitors. Owing to the multiplicity of less active protein kinase conformations when compared with the canonical more active conformation, it was hypothesized that type II drugs would be less promiscuous than type I drugs which bind to the typical active conformation. Although type II inhibitors may be more selective, most - if not all - inhibit more than one target protein kinase and the differences are a matter of degree only. PMID- 29408303 TI - Rhythm profiles and survival after out-of-hospital ventricular fibrillation cardiac arrest. AB - OBJECTIVE: Treatment: protocols for cardiac arrest rely upon rhythm analyses performed at two-minute intervals, neglecting possible rhythm changes during the intervening period of CPR. Our objective was to describe rhythm profiles (patterns of rhythm transitions during two-minute CPR cycles) following attempted defibrillation and to assess their relationship to survival. METHODS: The study included out-of-hospital cardiac arrest cases presenting with ventricular fibrillation from 2011 to 2015. The rhythm sequence was annotated during two minute CPR cycles after the first and second shocks of each case, and the rhythm profile of each sequence was classified. We calculated absolute survival differences among rhythm profiles with the same rhythm at the two-minute check. RESULTS: Of 569 rhythm sequences after the first shock, 46% included a rhythm transition. Overall survival was 47%, and survival proportion varied by rhythm at the two-minute check: ventricular fibrillation (46%), organized (58%) and asystole (20%). Survival was similar between profiles which ended with an organized rhythm at the two-minute check. Likewise, survival was similar between profiles with asystole at the two-minute check. However, in patients with ventricular fibrillation at the two-minute check, survival was twice as high in those with a transient organized rhythm (69%) compared to constant ventricular fibrillation (32%) or transient asystole (28%). CONCLUSION: Rhythm transitions are common after attempted defibrillation. Among patients with ventricular fibrillation at the subsequent two-minute check, transient organized rhythm during the preceding two-minute CPR cycle was associated with favorable survival, suggesting distinct physiologies that could serve as the basis for different treatment strategies. PMID- 29408304 TI - Participatory Research to Advance Colon Cancer Prevention (PROMPT): Study protocol for a pragmatic trial. AB - BACKGROUND: Colon cancer is the second leading cause of cancer deaths in the United States. The Participatory Research to Advance Colon Cancer Prevention (PROMPT) study is a collaboration between two research institutions and a federally qualified health center (FQHC). The study seeks to raise colon cancer screening rates using a direct-mail fecal immunochemical testing (FIT) and reminder program in an FQHC serving a predominantly Latino population in California. METHODS: PROMPT is a pragmatic trial enrolling 16 clinics. The study will test automated and live prompts (i.e., alerts, reminders) to a direct-mail FIT program in two phases. In Phase I, we tailored and defined intervention components for the pilot using a community-based participatory research approach called boot camp translation. We then plan to conduct a three-arm patient randomized comparative effectiveness trial in two pilot clinics to compare 1) automated prompts, 2) live prompts, and 3) a combination of automated plus live prompts to alert and remind patients to complete screening. In Phase II, the adapted best practice intervention will be spread to additional clinics within the FQHC (estimated population 27,000) and assessed for effectiveness. Patient and staff interviews will be conducted to explore receptivity to the program and identify barriers to implementation. DISCUSSION: This pragmatic trial applies innovative approaches to engage diverse stakeholders and will test the effectiveness and spread of a direct-mail plus reminder program. If successful, the program will provide a model for a cost-effective method to raise colon cancer screening rates among Latino patients receiving care in FQHCs. TRIAL REGISTRATION: National Clinical Trial (NCT) Identifier NCT03167125. PMID- 29408305 TI - Dopaminergic activity mediates pups' over male preference of postpartum estrous rats. AB - Pups have greater incentive value than males for rats during the postpartum estrus (PPE); a period when females are both maternally and sexually motivated. Mesolimbic dopaminergic system has been proposed as a general motivational circuit; however in the literature it has been more related to the control of the motivational aspects of maternal than sexual motivation of females. Therefore, we aimed to assess the effect of antagonizing dopaminergic neurotransmission of PPE females on their preference for pups over a male. To achieve this objective we tested PPE rats in a Y-maze with three-choice chambers (one containing eight pups, the other a male and the last one no stimulus) after the systemic administration of the dopaminergic antagonist haloperidol (0.0; 0.025 or 0.05 mg/kg). Furthermore, to determine if this dopaminergic antagonist differentially affects maternal and sexual motivations when pups and male are not competing, we evaluated the effect of haloperidol in the preference of females for pups vs. a non-receptive female and for a male vs. a non-receptive female. In the preference test for pups vs. male, both doses of haloperidol decreased the time that females spent in pups' chamber while increased the time that they spent in male's chamber, resulting in a lack of preference between both incentives. Besides, haloperidol reduced the effort -attempts to get access to the stimuli- made by the females to obtain the pups. Conversely, 0.05 mg/kg of haloperidol did not affect the preference for both incentives when they were confronted to a non receptive female. Together, these results indicate that the dopaminergic activity mediates pups' preference over male during the PPE and point toward a more relevant role of this system in females' behavioral output when incentives are competing. PMID- 29408306 TI - Thoracic Skeletal Muscle Is Associated With Adverse Outcomes After Lobectomy for Lung Cancer. AB - BACKGROUND: Assessment of risk associated with lung cancer resection is primarily based on evaluation of cardiopulmonary function and remains imprecise. We investigated the relationship between thoracic muscle and early outcomes after lobectomy. METHODS: Cross-sectional area of skeletal muscle was measured at the level of the fifth thoracic vertebra on computed tomography in 135 consecutive patients before lobectomy for lung cancer. Patients were stratified into low and high muscle groups using the sex-specific muscle median. Primary outcome was a composite of any postoperative complication as per The Society of Thoracic Surgeons General Thoracic Surgical Database. Secondary outcomes included postoperative respiratory complications, postoperative intensive care unit admission, hospital length of stay, and hospital readmission within 30 days of hospital discharge. The chi2 test, adjusted multivariable regression analysis, and likelihood ratio test were performed. RESULTS: Patients with low muscle were significantly more likely to have any postoperative complication and respiratory postoperative complications. Although postoperative intensive care unit admission was similar for low muscle and high muscle groups, low muscle patients had longer hospital length of stay and a higher rate of hospital readmission. Adjusted multivariable regression revealed the independent association of thoracic muscle with all outcomes. The likelihood ratio test suggested that thoracic muscle adds predictive capability to information captured by preoperative pulmonary function testing. CONCLUSIONS: Low thoracic muscle is independently associated with increased postoperative complications and health care utilization among patients undergoing lobectomy for lung cancer. Evaluation of thoracic muscle may enhance risk prediction models. PMID- 29408307 TI - Bilateral Internal Thoracic Artery Use in Dialysis Patients. PMID- 29408308 TI - Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility. AB - INTRODUCTION: Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. METHODS: A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the beta Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. RESULTS: Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1beta-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58-0.94] and OR = 0.71 [95% CI: 0.50-1.01], respectively, p = 0.03). Similar results were observed for the IL-1beta-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59-0.95] and OR = 0.69 [95% CI: 0.46-1.03], respectively, p = 0.03). Survival was not influenced by genotype. CONCLUSIONS: This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer. PMID- 29408309 TI - The protective effect of pentoxifylline versus silymarin on the pancreas through increasing adenosine by CD39 in a rat model of liver cirrhosis: Pharmacological, biochemical and histological study. AB - Impaired glucose homoeostasis due to insulin resistance and decrease sensitivity of pancreatic beta-cells is a feature of liver disease and results into hepatogenous diabetes. Decrease expression of CD39 was linked to inflammation and occurrence of diabetes. Therefore, we performed this study to explore the protective effect of pentoxifylline (PTX) and silymarin administration on the beta-cells of the pancreas in a rat model of thioacetamide induced liver cirrhosis. Biochemical, histological and immunohistochemistry studies of the liver and pancreas were performed and provided an evidence on the protective effect of PTX to pancreatic beta-cells compared to silymarin. Also, silymarin induced a significant improvement of liver cirrhosis compared to PTX. In conclusion, the potential protective effect of PTX against beta-cells deterioration could be attributed to increasing pancreatic CD39 expression and the subsequent increase of adenosine. PMID- 29408311 TI - Carrier-free nanodrug by co-assembly of chemotherapeutic agent and photosensitizer for cancer imaging and chemo-photo combination therapy. AB - : Nanosized drug delivery systems (NDDS) with photothermal therapy (PTT) and photodynamic therapy (PDT) have been extensively exploited to improve the therapeutic performance and bio-safety of chemotherapeutic drugs in cancer. In this work, a carrier-free nanodrug was developed by co-assembly of the anti cancer agent ursolic acid (UA), an asialoglycoprotein receptor (ASGPR), which can recognize the target molecule lactobionic acid (LA), and the near-infrared (NIR) probe dye indocyanine green (ICG) to form UA-LA-ICG NPs by a simple and green self-assembly approach. The UA-LA-ICG NPs had suitable stability, showed controlled release profile of UA drugs, and exhibited preferable temperature response (~59.4 degrees C) under laser irradiation (808 nm, 1 W/cm2). Compared with free ICG, the UA-LA-ICG NPs significantly enhanced the intracellular ICG uptake. Upon irradiation of the NIR laser, co-assembled nanodrugs demonstrated great performance as a reactive oxygen species (ROS) producer and exhibited more anti-proliferative activities on ASGPR-overexpressing HepG2 cells than ASGPR low expressing HeLa cells. Meanwhile, in vivo NIR fluorescence imaging exhibited that the co-assembled nanodrugs were specifically targeted to the tumor by the active targeting property of LA, and its circulation time was much longer than that of free ICG. In addition, UA-LA-ICG NPs + NIR irradiation treatment displayed enhanced inhibitory effect on tumor growth in H22 tumor-bearing mice. Overall, the co-assembly of chemotherapeutic agent and photosensitizer by the self assembly approach might open an alternative avenue and give inspiration to fabricate new carrier-free nanodrugs for cancer imaging and chemo-photo combination therapy. STATEMENT OF SIGNIFICANCE: The present study for the first time reported carrier-free nanoparticles (NPs) by co-assembly of a natural product ursolic acid (UA), an asialoglycoprotein receptor (ASGPR)-recognized sugar molecule lactobionic acid (LA), and the near-infrared dye indocyanine green (ICG) through a simple and green approach. The preparation process of nanodrugs is simple, rapid, effective, and labor-saving. The co-assembled nanodrugs were capable of stabilizing the ICG molecules and specifically targeting to the tumor, which could increase the tumor accumulation in cancer imaging and also enhance the efficacy of chemo-phototherapy. PMID- 29408310 TI - Phytochemical characterization and biological activity evaluation of ethanolic extract of Cinnamomum zeylanicum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: India being a multicultural nation, every region of the country offers a distinct culinary flavor and taste. These flavors are attributed to spices and condiments which form the mainstay of Indian cuisine. Most of these spices and condiments are derived from various biodiversity hotspots in India and form the crux of India's multidiverse and multicultural cuisine. Apart from their varying aromas, flavors and tastes, these spices and condiments are known to possess several medicinal properties also. Most of these spices find considerable mention in Ayurveda, the indigenous system of medicine, as panaceas for several aliments. Cinnamomum zeylanicum (CZ), belonging to family Lauraceae and commonly known as cinnamon is one such spice known to have diverse medicinal properties since time immemorial. AIM OF THE STUDY: In the present study, apoptotic and anti-microbial activity of ethanolic extract of CZ was evaluated against human breast cancer cell line MDA-MB-231 and compared for its effect on normal kidney epithelial cell line Vero. MATERIALS AND METHODS: Ethanolic extract of tree bark of CZ was used to determine the cytotoxic effect on MDA-MB-231 using Trypan blue dye exclusion method and cytometry. The tested dose of the extract was 10-100 ug/mL. Antibacterial activity was determined using disc diffusion method against Staphylococcus aureus and Escherichia coli in the range 2-10 mg/mL. Apoptotic activity was determined using DNA fragmentation assay. RESULTS: Ethanolic extract of CZ was found to have an IC50 value of 25 ug/mL against MDA cell line. On the other hand, CZ extract did not have any significant effect on Vero cells even at 100 ug/mL (IC50 > 100 ug/mL). The ethanolic extract of CZ bark showed significant antibacterial activity against S. aureus at 10 mg/mL while no appreciable activity was detected against E. coli. DNA isolated from extract treated cancer cells showed a fragmentation pattern characteristic of apoptosis. However, no DNA fragmentation was observed in DNA isolated from extract treated Vero cells. CONCLUSION: Ethanolic bark extract of CZ could be potentially beneficial in treating breast cancer and may be of interest for future studies in developing integrative cancer therapy against proliferation, metastasis, and migration of breast cancer cells. PMID- 29408313 TI - TMT-based quantitative proteomics analysis reveals the response of tea plant (Camellia sinensis) to fluoride. AB - : The tea plant is a fluoride hyperaccumulator, and fluoride accumulation in its leaves is closely related to human health. To dissect molecular mechanisms underlying fluoride accumulation/detoxification, the leaves of tea seedlings exposed to different fluoride treatments for 30 days were sampled for physiological and proteomics analyses. The results showed that fluoride had no adverse effects on the growth of tea seedlings in spite of high content fluoride accumulation in their leaves. Through TMT coupled with UPLC MS/MS, 189 differentially accumulated proteins were quantified, of which 41 and 148 were localized in the cell wall and cellular compartments respectively. 41 cell wall proteins were mainly conductive to cell wall structure rearrangement, signaling modulation and the protection cells from damages; 148 cellular compartments proteins mainly contributed to diverse metabolisms reprogramming, energy reallocation and plant defense. Notably, upregulation of several proteins including GHs, smHSPs, DRT100, YLS2-like, primary amine oxidase, GDSL esterase/lipases and citrate synthase probably enhanced the defense of tea seedlings against fluoride. Collectively, our results presented a comprehensive proteomics analysis on the leaves of tea seedlings in response to fluoride, which would contribute to further deciphering of molecular mechanisms underlying fluoride accumulation/detoxification in tea plant. SIGNIFICANCE: The tea plant (Camellia sinensis) is an important economic crop with its made tea occupying up the third non-alcohol beverage in the world. Tea plant is also a fluoride hyperaccumulator with up to 98% fluoride accumulation in the leaves by initiative absorption. Due to the fact that about 40% to 90% of fluoride could be readily released into tea infusion and then absorbed by human body, overaccumulation of fluoride in tea leaves is closely related to human health. Therefore, it is very necessary to deeply dissect the mechanisms underlying fluoride accumulation/detoxification in tea plant. Previously, numerous studies were conducted to investigate fluoride specification and fluoride localization of tea plant at morphological, physiological and biochemical levels, which documented that fluoride was majorly immobilized in the cell walls and stored in the vacuoles in the form of fluoride-ligands complexes. However, the molecular mechanisms governing cell wall immobilization and vacuolar compartmentation of fluoride were still remaining unknown. Thus, a quantitative proteomics study into the leaves of tea seedlings upon exposure to fluoride was performed in current study. Our results showed that 41 and 148 of 189 differentially accumulated proteins were targeted into the cell wall and cellular compartments respectively, revealing that cell wall proteins and cellular compartments proteins played crucial roles in the response of tea seedlings to fluoride. Our results were also in good agreement with the idea that the cell wall was involved in fluoride accumulation/detoxification in tea plant. However, the functions of key interested differentially accumulated proteins need be further analyzed in follow up work. PMID- 29408312 TI - Meta-analysis and systematic review of the literature characterizing auditory mismatch negativity in individuals with autism. AB - A number of past studies have used mismatch negativity (MMN) to identify auditory processing deficits in individuals with autism spectrum disorder (ASD). Our meta analysis compared MMN responses for individuals with ASD and typically developing controls (TD). We analyzed 67 experiments across 22 publications that employed passive, auditory-based MMN paradigms with ASD and TD participants. Most studies lacked design characteristics that would lead to an accurate description of the MMN. Variability between experiments measuring MMN amplitude was smaller when limited to studies that counterbalanced stimuli. Reduced MMN amplitude was found among young children with ASD compared to controls and in experiments that used nonspeech sounds. Still, few studies included adolescents or those with below average verbal IQ. Most studies suffered from small sample sizes, and aggregating these data did not reveal significant group differences. This analysis points to a need for research focused specifically on understudied ASD samples using carefully designed MMN experiments. Study of individual differences in MMN may provide further insights into distinct subgroups within the heterogeneous ASD population. PMID- 29408314 TI - Fibroblast growth factor receptor inhibition induces loss of matrix MCL1 and necrosis in cholangiocarcinoma. AB - BACKGROUND & AIMS: Myeloid cell leukemia 1 (MCL1), a prosurvival member of the BCL2 protein family, has a pivotal role in human cholangiocarcinoma (CCA) cell survival. We previously reported that fibroblast growth factor receptor (FGFR) signalling mediates MCL1-dependent survival of CCA cells in vitro and in vivo. However, the mode and mechanisms of cell death in this model were not delineated. METHODS: Human CCA cell lines were treated with the pan-FGFR inhibitor LY2874455 and the mode of cell death examined by several complementary assays. Mitochondrial oxidative metabolism was examined using a XF24 extracellular flux analyser. The efficiency of FGFR inhibition in patient-derived xenografts (PDX) was also assessed. RESULTS: CCA cells expressed two species of MCL1, a full length form localised to the outer mitochondrial membrane, and an N terminus truncated species compartmentalised within the mitochondrial matrix. The pan-FGFR inhibitor LY2874455 induced non-apoptotic cell death in the CCA cell lines associated with cellular depletion of both MCL1 species. The cell death was accompanied by failure of mitochondrial oxidative metabolism and was most consistent with necrosis. Enforced expression of N terminus-truncated MCL1 targeted to the mitochondrial matrix, but not full-length MCL1 targeted to the outer mitochondrial membrane, rescued cell death and mitochondrial function. LY2874455 treatment of PDX-bearing mice was associated with tumour cell loss of MCL1 and cell necrosis. CONCLUSIONS: FGFR inhibition induces loss of matrix MCL1, resulting in cell necrosis. These observations support a heretofore unidentified, alternative MCL1 survival function, namely prevention of cell necrosis, and have implications for treatment of human CCA. LAY SUMMARY: Herein, we report that therapeutic inhibition of a cell receptor expressed by bile duct cancer cells resulted in the loss of a critical survival protein termed MCL1. Cellular depletion of MCL1 resulted in the death of the cancer cells by a process characterised by cell rupture. Cell death by this process can stimulate the immune system and has implications for combination therapy using receptor inhibition with immunotherapy. PMID- 29408315 TI - Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells. AB - PEDV remains one of the most important swine diseases that infects pigs of all ages. It causes devastating viral enteric disease in piglets with a high mortality rate, leading to significant threats and huge economic loss to the pork industry. In this study, a transcriptomic shotgun sequencing (RNA-Seq) procedure was used to study gene responses against PEDV infection. Genome-wide analysis of differentially expressed genes (DEGs) was performed in Vero E6 cells post-PEDV infection. mTOR signaling pathway activator-MHY1485, and inhibitor-PP242 were used to study the antiviral function. Results revealed that the IRF3 was significantly up-regulated post-PEDV infection. Although most of the IFN regulatory and -related genes evaluated in this study were either down-regulated or remained unchanged, IL11 behaved significantly up-regulated, with the peak at 16 hpi. Nearly 90% of PEDV infections were suppressed in the PP242 pretreated cells whereas the reverse effect was observed in the MYH1485 pretreated cells. Results indicated that the mTOR signaling pathway played a vital role in the PEDV antiviral regulation in the Vero E6 cells. Future studies will contribute to better understand the cellular antiviral mechanism against PEDV. PMID- 29408317 TI - Measurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions. AB - BACKGROUND: Assessment of asthma using clinical measures alone often fails to detect underlying airway inflammation. Fractional exhaled nitric oxide (FeNO) is a recognized biomarker of type 2 airway inflammation in asthma. Measurement of FeNO is instrumental in the assessment and management of patients with corticosteroid-sensitive asthma. OBJECTIVE: To determine the impact of measuring FeNO on asthma management in real-world clinical practices. METHODS: Clinicians from 337 US practices performed a clinical assessment and recorded treatment plans before and after measuring FeNO in 7,901 patients with asthma. Airway inflammation was classified as low, intermediate, or high according to the clinician's usual procedures, including clinical examination, spirometry, and symptoms. Clinicians recorded asthma medication plans, indicating medications to be initiated, continued, or stopped. FeNO measurement was performed, followed by documentation of any change(s) in the treatment plans based on the FeNO value (eg, initiating new medications or changing the dose of or discontinuing existing medications). RESULTS: Clinical assessment was concordant with FeNO measurement in only 56% of cases, matching FeNO more frequently in patients with low inflammation (64%) vs high inflammation (34%). After FeNO measurement, clinicians modified their treatment plan in 31% and altered prescriptions for inhaled corticosteroids in 90% of cases. Inhaled corticosteroids were initiated or their dose increased in 66% of patients with high inflammation but discontinued or their dose decreased in only 9% of patients with low inflammation. CONCLUSION: Measurement of FeNO enabled clinicians to assess underlying airway inflammation, leading to a significant revision of their treatment plans compared with real world clinical assessment of asthma alone. PMID- 29408316 TI - Efficacy of cell free supernatant from Bacillus licheniformis in protecting Artemia salina against Vibrio alginolyticus and Pseudomonas gessardii. AB - Bacterial diseases are widespread in aquaculture farms and causative agents often adapt to biofilm mode of growth. These biofilms are detrimental to aquaculture species as they resist antibiotics and other agents that are used to control them. Two bacterial pathogens isolated from infected prawn samples were identified as Vibrio alginolyticus and Pseudomonas gessardii on the basis of morphological features, biochemical characteristics, 16S r RNA gene sequencing and phylogenetic analysis. Their pathogenic nature was confirmed by performing in vivo challenge experiments using Artemia salina as a model system. Seven days post infection, the mortality observed with V. alginolyticus and P. gessardii was 97 +/- 4.08% and 77.5 +/- 5.24%, respectively. The isolates formed extensive biofilms on polystyrene and glass surfaces. These infections could be controlled in an effective manner by using the cell free supernatant (CFS) of a tropical marine epizoic strain of Bacillus licheniformis D1 that is earlier reported to contain an antimicrobial protein (BLDZ1). The CFS inhibited biofilms in an efficient manner (82.35 +/- 1.69 and 82.52 +/- 1.11% for V. alginolyticus and P. gessardii, respectively) on co-incubation. In addition, pre-formed biofilms of V. alginolyticus and P. gessardii were also removed (84.53 +/- 1.26 and 67.08 +/- 1.43%, respectively). Fluorescence and scanning electron microscopic studies confirmed the antibiofilm potential of this protein on glass surfaces. The antibiofilm nature was due to the anti-adhesion and antimicrobial properties exhibited by the CFS. Treatment of A. salina with CFS (6 h prior to infections) was effective in protecting larvae against infections by field isolates. This study highlights the significance of marine natural products in providing alternative biofilm controlling agents to tackle infections and decreasing the usage of antibiotics in aquaculture settings. PMID- 29408318 TI - Cadmium disrupts signaling of the hypoxia-inducible (HIF) and transforming growth factor (TGF-beta) pathways in placental JEG-3 trophoblast cells via reactive oxygen species. AB - Epidemiologic studies indicate an association between exposure to cadmium (Cd) and placental-related pregnancy disorders. While a precise mechanism is unknown, oxidative imbalance and dysregulation of the hypoxia inducible factor (HIF) and transforming growth factor beta (TGF-beta) pathways have been implicated in placental disease pathogenesis. Here we investigated key oxidative and placentation pathways in JEG-3 placental trophoblast cells treated with Cd alone, environmental water samples predominated by Cd with low concentrations of other metals (e.g. inorganic arsenic (iAs)) collected from a waste-site, and a matched mixture of Cd and iAs prepared in the laboratory. The induction of cytosolic reactive oxygen species (ROS), expression of metallothionein (MT) isoforms, HIF1alpha and downstream targets, and expression of TGFbeta pathway-associated genes and proteins were assessed. Additionally, the effect of pre-treatment with the antioxidant N-acetyl cysteine (NAC) on ROS generation and effects on HIF, MT and TGF-beta signaling pathways was examined. Cd and Cd-mixture treated cells displayed higher levels of ROSs with accompanying disruption of HIF and TGFbeta pathway signaling versus controls, with the Cd-mixture eliciting a greater effect. Conversely, pretreatment with NAC reduced Cd-induced ROS production and disruption of HIF, MT and TGFbeta pathway signaling. The results indicate that treatment of placental trophoblast cells with Cd results in increased production of ROSs that disrupt placentation pathways involved in disease pathogenesis. Also, co-occurrence of Cd with other toxic metals, particularly arsenic, may induce detrimental health effects that are currently underestimated when analyzed as single metals. PMID- 29408319 TI - Cognitive fatigue effects on physical performance: A systematic review and meta analysis. AB - Recent research has examined the effect that undertaking a cognitively fatiguing task for <=90 min has on subsequent physical performance. Cognitive fatigue is claimed to affect subsequent physical performance by inducing energy depletion in the brain, depletion of brain catecholamine neurotransmitters or changes in motivation. Observation of the psychophysiology and neurochemistry literature questions the ability of 90 min' cognitive activity to deplete energy or catecholamine resources. The purpose of this study, therefore, was to examine the evidence for cognitive fatigue having an effect on subsequent physical performance. A systematic, meta-analytic review was undertaken. We found a small but significant pooled effect size based on comparison between physical performance post-cognitive fatigue compared to post-control (g = -0.27, SE = 0.12, 95% CI -0.49 to -0.04, Z(10) = -2.283, p < 0.05). However, the results were not heterogenous (Q(10) = 2.789, p > 0.10, Tau2 < 0.001), suggesting that the pooled effect size does not amount to a real effect and differences are due to random error. No publication bias was evident (Kendall's tau = -0.07, p > 0.05). Thus, the results are somewhat contradictory. The pooled effect size shows a small but significant negative effect of cognitive fatigue, however tests of heterogeneity show that the results are due to random error. Future research should use neuroscientific tests to ensure that cognitive fatigue has been achieved. PMID- 29408320 TI - Crystal structure of thebaine 6-O-demethylase from the morphine biosynthesis pathway. AB - Thebaine 6-O-demethylase (T6ODM) from Papaver somniferum (opium poppy), which belongs to the non-heme 2-oxoglutarate/Fe(II)-dependent dioxygenases (ODD) family, is a key enzyme in the morphine biosynthesis pathway. Initially, T6ODM was characterized as an enzyme catalyzing O-demethylation of thebaine to neopinone and oripavine to morphinone. However, the substrate range of T6ODM was recently expanded to a number of various benzylisoquinoline alkaloids. Here, we present crystal structures of T6ODM in complexes with 2-oxoglutarate (T6ODM:2OG, PDB: 5O9W) and succinate (T6ODM:SIN, PDB: 5O7Y). Both metal and 2OG binding sites display similarity to other proteins from the ODD family, but T6ODM is characterized by an exceptionally large substrate binding cavity, whose volume can partially explain the promiscuity of this enzyme. Moreover, the size of the cavity allows for binding of multiple molecules at once, posing a question about the substrate-driven specificity of the enzyme. PMID- 29408321 TI - Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies. AB - Acute systemic toxicity data are used by a number of U.S. federal agencies, most commonly for hazard classification and labeling and/or risk assessment for acute chemical exposures. To identify opportunities for the implementation of non animal approaches to produce these data, the regulatory needs and uses for acute systemic toxicity information must first be clarified. Thus, we reviewed acute systemic toxicity testing requirements for six U.S. agencies (Consumer Product Safety Commission, Department of Defense, Department of Transportation, Environmental Protection Agency, Food and Drug Administration, Occupational Safety and Health Administration) and noted whether there is flexibility in satisfying data needs with methods that replace or reduce animal use. Understanding the current regulatory use and acceptance of non-animal data is a necessary starting point for future method development, optimization, and validation efforts. The current review will inform the development of a national strategy and roadmap for implementing non-animal approaches to assess potential hazards associated with acute exposures to industrial chemicals and medical products. The Acute Toxicity Workgroup of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), U.S. agencies, non governmental organizations, and other stakeholders will work to execute this strategy. PMID- 29408322 TI - Minimally invasive versus standard approach in LeFort 1 osteotomy in patients with history of cleft lip and palate. AB - OBJECTIVE: Compare literature-reported efficiency and complications of the standard maxillary advancement surgery with those of a minimally invasive mucosal approach in patients with CL/P requiring Le Fort 1 osteotomy. DESIGN: Meta analysis vs. retrospective analysis of 18 consecutive cases. SETTING: Department of maxillofacial surgery at a tertiary-level public general hospital. PARTICIPANTS: The meta-analysis encompassed Medline, Embase and Cochrane, years 1990 to 2014, inclusive. The local series concerned all squeletally mature adolescents with non-syndromic CL/P who underwent orthognathic surgery between 30 April 2004 and 27 January 2012. INTERVENTIONS: Minimally invasive approach and perioperative orthodontics including intermaxillary fixation for 3 months after surgery. MAIN OUTCOME MEASURE(S): Assessment of complications. Standard lateral cephalograms were taken before surgery, then <1 week and 12 months after surgery. Delaire's cephalometric analysis was performed and the position of the maxilla was recorded. RESULTS: There were no significant differences between the literature and our series regarding sex and type of deformity (P=0.634 and 0.779, respectively). The mean horizontal and vertical relapse rates were 0.61 and 1.17mm (vs. 1.29 and 1.48mm in the meta-analysis) and the overall complication rate was 22.2% (vs. 12.76% but P=0.271). There was a significant difference regarding the palatal fistula rate (0 here vs. 21.43% in meta-analysis, P=0.028). CONCLUSIONS: The minimally invasive approach showed trends toward less relapse and less complications than conventional approaches. This technique seems adapted to the management of patients with CL/P sequelae. Other benefiting groups are underway. PMID- 29408323 TI - Individual differences in risk-taking tendencies modulate the neural processing of risky and ambiguous decision-making in adolescence. AB - Although many neuroimaging studies have investigated adolescent risk taking, few studies have dissociated between decision-making under risk (known probabilities) and ambiguity (unknown probabilities). Furthermore, which brain regions are sensitive to individual differences in task-related and self-reported risk taking remains elusive. We presented 198 adolescents (11-24 years, an age-range in which individual differences in risk taking are prominent) with an fMRI paradigm that separated decision-making (choosing to gamble or not) and reward outcome processing (gains, no gains) under risky and ambiguous conditions, and related this to task-related and self-reported risk taking. We observed distinct neural mechanisms underlying risky and ambiguous gambling, with risk more prominently associated with activation in parietal cortex, and ambiguity more prominently with dorsolateral prefrontal cortex (PFC), as well as medial PFC during outcome processing. Individual differences in task-related risk taking were positively associated with ventral striatum activation in the decision phase, specifically for risk, and negatively associated with insula and dorsomedial PFC activation, specifically for ambiguity. Moreover, dorsolateral PFC activation in the outcome phase seemed a prominent marker for individual differences in task-related risk taking under ambiguity as well as self-reported daily-life risk taking, in which greater risk taking was associated with reduced activation in dorsolateral PFC. Together, this study demonstrates the importance of considering multiple risk taking measures, and contextual moderators, in understanding the neural mechanisms underlying adolescent risk taking. PMID- 29408324 TI - Vascular reactivity in small cerebral perforating arteries with 7 T phase contrast MRI - A proof of concept study. AB - Existing cerebrovascular reactivity (CVR) techniques assess flow reactivity in either the largest cerebral vessels or at the level of the parenchyma. We examined the ability of 2D phase contrast MRI at 7 T to measure CVR in small cerebral perforating arteries. Blood flow velocity in perforators was measured in 10 healthy volunteers (mean age 26 years) using a 7 T MR scanner, using phase contrast acquisitions in the semioval center (CSO), the basal ganglia (BG) and the middle cerebral artery (MCA). Changes in flow velocity in response to a hypercapnic breathing challenge were assessed, and expressed as the percentual increase of flow velocity as a function of the increase in end tidal partial pressure of CO2. The hypercapnic challenge increased (fit +/- standard error) flow velocity by 0.7 +/- 0.3%/mmHg in the CSO (P < 0.01). Moreover, the number of detected perforators (mean [range]) increased from 63 [27-88] to 108 [61-178] (P < 0.001). In the BG, the hypercapnic challenge increased flow velocity by 1.6 +/- 0.5%/mmHg (P < 0.001), and the number of detected perforators increased from 48 [24-66] to 63 [32-91] (P < 0.01). The flow in the MCA increased by 5.2 +/- 1.4%/mmHg (P < 0.01). Small vessel specific reactivity can now be measured in perforators of the CSO and BG, using 2D phase contrast at 7 T. PMID- 29408325 TI - Infectious risks associated with medicinal Cannabis: Potential implications for immunocompromised patients? PMID- 29408326 TI - The role of ablation therapy for ventricular tachycardia in patients with tetralogy of Fallot. PMID- 29408327 TI - PBA2 exhibits potent anti-tumor activity via suppression of VEGFR2 mediated-cell proliferation and angiogenesis. AB - VEGFR2 (vascular endothelial growth factor receptor 2) is the main trigger of VEGF-mediated angiogenic signal and targeting VEGFR2 pathway to inhibit tumor angiogenesis represents a promising strategy for cancer therapy. We elucidated that a novel compound, PBA2 exhibited potent anti-tumor effects both in vitro and in vivo with limited toxicity. ELISA assay revealed that PBA2 had a strong suppressive activity against VEGFR2 related to angiogenesis. Furthermore, PBA2 considerably disrupted tube formation of endothelial cells in vitro and systemic administration of PBA2 exerted decreased tumor angiogenesis in vivo. Functional tests demonstrated that PBA2 concentration-dependently impeded the migration and proliferation of endothelial cells. PBA2 had no effects on the expression level of VEGF both in the detected cancer cells and endothelial cells. VEGFR2 and its downstream Akt and Erk pathways were blocked by PBA2 in a concentration-dependent manner both in vitro and in vivo. Overall, we first demonstrated that PBA2, targeting VEGFR2 related to angiogenesis, presented remarkable anti-angiogenic and anti-tumor activities through attenuating VEGFR2 mediated pathway in vitro and in vivo with limited toxicity. These observations posed that PBA2 could be a potential drug candidate for developing anti-angiogenic tyrosine kinase inhibitor in cancer therapy. PMID- 29408328 TI - Ribociclib, a Cdk4/Cdk6 kinase inhibitor, enhances glucocorticoid sensitivity in B-acute lymphoblastic leukemia (B-All). AB - Dysregulation of the cyclin D1-CDK4/CDK6 complex is frequently observed in almost all human cancer and contributes to aberrant cell proliferation and consequent tumorigenesis. Although many reports described the importance of CDK4/CDK6 in different set of human tumors, only few studies have been performed on leukemia. By gene expression analysis performed in a cohort of childhood patients affected by B-acute lymphoblastic leukemia (B-ALL) we found that both CDK4 and CDK6 are highly expressed. Moreover, reverse phase protein array (RPPA) analysis showed that cyclin D1 levels are higher in patients undergoing relapse. Starting from these considerations, we evaluated the effect of dual inhibition of CDK4/CDK6 in B-ALL and if this inhibition could enhance cytotoxic killing of leukemia cells after combination treatment with dexamethasone. We treated B-ALL cell lines with ribociclib, a highly specific CDK4/6 inhibitor. As expected, treatment with ribociclib induced growth inhibition of B-ALL cell lines, accompanied by strong cell cycle arrest in G1 phase, along with a dose-dependent decrease in phosphorylated retinoblastoma protein. Ribociclib exposure strongly synergizes with dexamethasone in SEM and RCH-ACV, two dexamethasone-resistant cell lines, along with a strong decrease in proliferation and a significant increase in apoptotic cell death. These results were also confirmed on primary cultures derived from bone marrow of pediatric patients affected by B-ALL. Immunoblot analysis showed a significant increase in glucocorticoid receptor (GR) along with some of its target genes, after combined treatment with ribociclib and dexamethasone. Altogether our findings support the concept that pharmacologic inhibition of CDK4/CDK6 may represent a useful therapeutic strategy to control cell proliferation in B-ALL and provide new insight in understanding potential mechanism of glucocorticoid resistance. PMID- 29408329 TI - The impact of telemedicine on the quality of newborn resuscitation: A retrospective study. AB - OBJECTIVE: We hypothesized that telemedicine consults provided by neonatologists to local care teams (termed teleneonatology) would improve the quality of high risk newborn resuscitations that occur in community hospitals. METHODS: This retrospective cohort study compared 47 newborns who received a teleneonatology consult during their resuscitation at a community hospital to 45 controls who did not. Controls were matched on gestational age, sex, admission diagnosis, and level of newborn care. A two-person expert panel blinded to the intervention reviewed demographic and resuscitation data for each patient and assigned a resuscitation quality rating using a 1-10 descriptive rating scale. Paired comparisons between groups were evaluated using the Wilcoxon signed rank test for continuous measures and the McNemar's test for dichotomous measures. RESULTS: The median resuscitation quality rating was 7 for the teleneonatology group and 4 for the control group, with a median difference of 1 between matched pairs (P = .002). Neonates who received a teleneonatology consult were more likely to undergo measurement of temperature, glucose, and blood gases. When analyzing the 35 matched pairs that had a consult within one hour of birth, the positive impact of teleneonatology was greater (median rating 8 vs 4, median difference 2, P = .003). Subgroup analysis demonstrated teleneonatology significantly improved the resuscitation of preterm neonates (median rating 8 vs 4, median difference 1.5, P = .004) CONCLUSION: Teleneonatology improves the quality of high-risk newborn resuscitations that occur in community hospitals and increases adherence to process metrics. Earlier teleneonatology consults appear to have greater positive impact. PMID- 29408330 TI - New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy. PMID- 29408331 TI - Influence of oral processing on appetite and food intake - A systematic review and meta-analysis. AB - Food delivers energy, nutrients and a pleasurable experience. Slow eating and prolonged oro-sensory exposure to food during consumption can enhance the processes that promote satiation. This systematic review and meta-analysis investigated the effects of oral processing on subjective measures of appetite (hunger, desire to eat) and objectively measured food intake. The aim was to investigate the influence of oral processing characteristics, specifically "chewing" and "lubrication", on "appetite" and "food intake". A literature search of six databases (Cochrane library, PubMed, Medline, Food Science and Technology Abstracts, Web of Science, Scopus), yielded 12161 articles which were reduced to a set of 40 articles using pre-specified inclusion and exclusion criteria. A further two articles were excluded from the meta-analysis due to missing relevant data. From the remaining 38 papers, detailing 40 unique studies with 70 subgroups, raw data were extracted for meta-analysis (food intake n = 65, hunger n = 22 and desire to eat ratings n = 15) and analyzed using random effects modelling. Oral processing parameters, such as number of chews, eating rate and texture manipulation, appeared to influence food intake markedly but appetite ratings to a lesser extent. Meta-analysis confirmed a significant effect of the direct and indirect aspects of oral processing that were related to chewing on both self-reported hunger (-0.20 effect size, 95% confidence interval CI: -0.30, 0.11), and food intake (-0.28 effect size, 95% CI: -0.36, -0.19). Although lubrication is an important aspect of oral processing, few studies on its effects on appetite have been conducted. Future experiments using standardized approaches should provide a clearer understanding of the role of oral processing, including both chewing and lubrication, in promoting satiety. PMID- 29408332 TI - Cross-sectional associations between maternal self-efficacy and dietary intake and physical activity in four-year-old children of first-time Swedish mothers. AB - BACKGROUND: Healthy dietary and physical activity behaviours are established early in life where children learn by observing their parents. Therefore, parents can act as role models and influence their children toward a healthier lifestyle. Besides a strong association between parental and child health behaviours, parents also influence their children's health behaviours through socio-cognitive processes, where perceived self-efficacy is the central component. The objective was to examine if parental self-efficacy among Swedish mothers was associated with their four-year-old children's dietary and physical activity behaviours. METHODS: This cross-sectional study was based on information from control participants that took part in the Swedish primary prevention trial of childhood obesity (PRIMROSE) (n = 420 mother-child pairs). Linear regression models were used to examine the associations between parental self-efficacy (Parental Self Efficacy for Promoting Healthy Physical Activity and Dietary Behaviours in Children Scale) and children's dietary intake (parent reported) and levels of physical activity (accelerometer) with adjustments for potential confounders. RESULTS: Mothers' efficacy beliefs in promoting healthy dietary or physical activity behaviours in their children were associated with a slightly higher consumption of fruit and vegetables among their children (beta: 0.03 [95%CI: 0.01; 0.04] P < 0.001) and slightly higher levels of moderate-to-vigorous activity (beta: 0.43 [95%CI: 0.05; 0.81] P = 0.03). Mothers' belief in their ability to limit unhealthy dietary and physical activity behaviours was inversely associated with children's intake of unhealthy snacks (beta: -0.06 [95%CI: -0.10; -0.02] P < 0.01). CONCLUSION: Our cross-sectional study suggests weak positive correlations between maternal self-efficacy and healthy dietary and physical activity behaviours, and weak inverse associations between maternal self-efficacy and unhealthy dietary and physical activity behaviours among their children. PMID- 29408334 TI - Outcome of a Salvage Third Autologous Stem Cell Transplantation in Multiple Myeloma. AB - To evaluate the outcomes of salvage third autologous stem cell transplantation (ASCT) in patients with relapsed multiple myeloma. We analyzed 570 patients who had undergone a third ASCT between 1997 and 2010 (European Society for Blood and Marrow Transplantation data), of whom 482 patients underwent tandem ASCT and a third ASCT at first relapse (AARA group) and 88 patients underwent an upfront ASCT with second and third transplantations after subsequent relapses (ARARA group). With a median follow-up after salvage third ASCT of 61 months in the AARA group and 48 months in the ARARA group, the day +100 nonrelapse mortality in the 2 groups was 4% and 7%, the incidence of second primary malignancy was 6% and 7%, the median progression-free survival was 13 and 8 months, and median overall survival (OS) was 33 and 15 months. In the AARA group, according to the relapse free interval (RFI) from the second ASCT, the median OS after the third ASCT was 17 months if the RFI was <18 months, 37 months if the RFI was between 18 and 36 months, and 64 months if the RFI was >=36 months (P < .001). In the ARARA group, the median OS after the third ASCT was 7 months if the RFI was <6 months, 13 months if the RFI was between 6 and 18 months, and 27 months if the RFI was >=18 months (P < .001). In a multivariate analysis of the AARA group, the favorable prognostic factor was an RFI after second ASCT of >=18 months. Progressive disease and a Karnofsky Performance Status score of <70 at third ASCT were unfavorable factors. A salvage third ASCT is of value for patients with relapsed myeloma, particularly for those with a long duration of response and chemosensitive disease at the time of transplantation. PMID- 29408333 TI - Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. AB - OBJECTIVE: Our objective was to describe the risk of hospital admission for virologically confirmed dengue (VCD) and the risk of clinically severe hospitalized VCD occurring up to 4 years after the first dose (years 1 to 4) in three randomized clinical trials comparing tetravalent dengue vaccine with placebo. METHODS: The relative risks (RR) for hospitalized VCD from first dose to year 4 were estimated by year and age-group in individual and combined studies. RESULTS: Overall, from Year 1 to Year 4, 233 and 228 participants had at least one episode of hospitalized VCD in the vaccinated (n = 22 603) and placebo (n = 11 301) groups, respectively (RR = 0.511, 95% CI 0.42-0.62). Among these, 48 and 47 cases, respectively, were classified as clinically severe. In children aged >=9 years, 88 and 136 participants had at least one episode of hospitalized VCD in the vaccinated (n = 17 629) and placebo (n = 8821) groups, respectively (RR = 0.324; 95% CI 0.24-0.43). In vaccinated participants aged <9 years, particularly in those aged 2-5 years, there were more hospitalized VCD cases compared with the control participants in Year 3 but not in Year 4. The overall RR in those aged <9 years for Year 1 to Year 4 was 0.786 (95% CI 0.60-1.03), with a higher protective effect in the 6-8 year olds than in the 2-5 year olds. CONCLUSIONS: The overall benefit-risk remained positive in those aged >=9 years up to year 4, although the protective effect was lower in years 3 and 4 than in years 1 and 2. PMID- 29408335 TI - Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway. AB - Apigetrin (APG), as a flavonoid, has many cellular bioactivities, including regulation of oxidative stress, and induction of apoptosis. However, the means by which APG suppresses human gastric cancer are still little to be understood. In the present study, the anti-cancer effects of APG on human gastric cancer cells were investigated. The results indicated that APG could suppress the proliferation and induce apoptosis in gastric cancer cells. Its role in apoptosis induction was through reducing Bcl-2, and enhancing Bax, Caspase-9/-3 and poly ADP-ribose polymerase (PARP) cleavage. In addition, APG incubation resulted in the generation of intracellular reactive oxygen species (ROS) in cells. Meanwhile, APG suppressed constitutive and interleukin-6 (IL-6)-stimulated signal transducer and activator of transcription 3 (STAT3), Janus kinase 2 gene (JAK2) and Src activation. However, ROS scavenger, N-acety-l-cysteine (NAC), diminished apoptosis induced by APG. And APG-triggered de-phosphorylation of STAT3/JAK2 was rescued by NAC pre-treatment. In vivo, APG administration significantly inhibited the gastric cancer cell xenograft tumorigenesis through inducing apoptosis and inhibiting STAT3/JAK2 pathways. Taken together, the findings above illustrated that APG might be used as a promising candidate against human gastric cancer progression. PMID- 29408336 TI - Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1. AB - Breast cancer resistance to the monoclonal erbB2/HER2 antibody trastuzumab (or herceptin) has become a significant obstacle in clinical targeted therapy of HER2 positive breast cancer. Previous research demonstrated that such drug resistance may be related to dysregulation of miRNA expression. Here, we found that knockdown of the long non-coding RNA, urothelial cancer associated 1 (UCA1), can promote the sensitivity of human breast cancer cells to trastuzumab. Mechanistically, UCA1 knockdown upregulated miR-18a and promoted miR-18a repression of Yes-associated protein 1 (YAP1). A luciferase reporter assay confirmed the association of miR-18a with wild-type UCA1 but not with UCA1 mutated at the predicted miR-18a-binding site. The direct targeting of YAP1 by miR-18a was verified by the observation that miR-18a mimic suppressed luciferase expression from a construct containing the YAP1 3' untranslated region. Meanwhile, reciprocal repression of UCA1 and miR-18a were found to be Argonaute 2 dependent. Knockdown of YAP1 recapitulated the effect of UCA1 silencing by reducing the viability of trastuzumab-treated breast cancer cells, whereas inhibition of miR-18a abrogated UCA1 knockdown-induced improvement of trastuzumab sensitivity in breast cancer cells. These findings demonstrate that the UCA1/miR 18a/YAP1 axis plays an important role in regulating the sensitivity of breast cancer cells to trastuzumab, which has implications for the development of novel approaches to improving breast cancer responses to targeted therapy. PMID- 29408337 TI - Combined intraocular and systemic rituximab for ocular lymphoproliferative disorder with extranodal marginal zone lymphoma-type morphology after heart transplant. AB - Post-transplant lymphoproliferative disorder (PTLD) has rarely been associated with ocular manifestations. We report a case of bilateral ocular involvement by PTLD with histopathologic features of extranodal marginal zone (MALT) lymphoma in an 8-year-old boy following orthotopic heart transplantation. The anterior segment disease was treated successfully using a combination of intraocular and systemic injections of humanized anti-CD20 antibody (rituximab). PMID- 29408339 TI - ICOS activation in combination with electrochemotherapy generates effective anti cancer immunological responses in murine models of primary, secondary and metastatic disease. AB - Electrochemotherapy is an evolving therapy which has recently been shown to induce an immunogenic form of cell death. It is hypothesized that the immunogenic cell death induced by electrochemotherapy may compliment the responses seen with anti-cancer immunotherapies. We therefore examined the effect of electrochemotherapy in combination with ICOS activation, which promotes the activity of previously activated T cells. In comparison to either monotherapy which resulted in no curative outcomes in any model, in a CT26 primary tumour 50% of mice were cured, with 100% of cured mice surviving tumour rechallenge. In a dual flank CT26 model mimicking secondary disease 20% of mice were cured, and 30% of mice were cured using an aggressively metastatic Lewis Lung Carcinoma model. We have shown the novel combination of electrochemotherapy with ICOS activation can inhibit local and distal tumour growth, including total tumour clearance with long lasting immunological memory. PMID- 29408338 TI - A systematic review and meta-analysis of the effects of topical nitrates in the treatment of primary and secondary Raynaud's phenomenon. AB - BACKGROUND: Multiple placebo-controlled trials have assessed locally applied topical nitrate preparations in treating Raynaud's phenomenon (RP). OBJECTIVES: The objective of this meta-analysis was to assess the effects of local topical nitrates in primary and secondary RP with respect to a combined end point integrating parameters of digital blood flow and clinical severity. METHODS: A systematic review was performed using MEDLINE, Embase, and the Cochrane library. Only trials comparing locally applied topical nitrates with placebo comparators were included. Studies were appraised for bias by 2 independent reviewers. RESULTS: A total of 7 placebo-controlled trials including 346 patients were used in the meta-analysis; 4 trials used nitroglycerin ointments, 2 used the nitroglycerin gel vehicle MQX-503, and 1 used compounded nitrite. The meta analysis results supported a moderate-to-large treatment effect in RP (standardized mean difference [SMD] = 0.70; 95% CI, 0.35-1.05; P < .0001). Subgroup analyses showed a large treatment effect in secondary RP (SMD = 0.95; 95% CI, 0.25-1.65; P = .008) and moderate effect in primary RP (SMD = 0.45; 95% CI, 0.05-0.85; P = .03). LIMITATIONS: Limitations include the inclusion of multiple topical nitrate preparations and integration of different outcomes assessments. CONCLUSION: Local topical nitrates have significant efficacy in the treatment of both primary and secondary RP. PMID- 29408340 TI - When a transmembrane channel isn't, or how biophysics and biochemistry (mis)communicate. AB - Annexins are a family of soluble proteins that bind to acidic phospholipids such as phosphatidylserine in a calcium-dependent manner. The archetypical member of the annexin family is annexin A5. For many years, its function remained unknown despite the availability of a high-resolution structure. This, combined with the observations of specific ion conductance in annexin-bound membranes, fueled speculations about the possible membrane-spanning forms of annexins that functioned as ion channels. The channel hypothesis remained controversial and did not gather sufficient evidence to become accepted. Yet, it continues to draw attention as a framework for interpreting indirect (e.g., biochemical) data. The goal of the mini-review is to examine the data on annexin-lipid interactions from the last ~30 years from the point of view of the controversy between the two lines of inquiry: the well-characterized peripheral assembly of the annexins at membranes vs. their putative transmembrane insertion. In particular, the potential role of lipid rearrangements induced by annexin binding is highlighted. PMID- 29408341 TI - Composite films for vaginal delivery of tenofovir disoproxil fumarate and emtricitabine. AB - Prevention of male-to-female HIV transmission remains a huge challenge and topical pre-exposure prophylaxis (PrEP) using microbicides may help overcoming the problem. In this work, different types of films containing the antiretroviral drugs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) were developed. Formulations based in poly(vinyl alcohol) and pectin were produced as single- or double-layered films. Films containing TDF/FTC or TDF/FTC-loaded Eudragit(r) L 100 nanoparticles (NPs) obtained by nano spray-drying were tested for physicochemical, technological and biological properties relevant to microbicide development. All systems featured organoleptic and mechanical properties considered suitable for vaginal use and potentially favoring users' acceptability. Film design (single- or double-layered, and the incorporation or not of NPs) had a greater impact on disintegration time and drug release in a simulated vaginal fluid. Upon film disintegration, pH and osmolality of the fluid remained within values considered compatible with the vaginal environment. Double layered films significantly reduced burst effect and the overall release of both drugs as compared to fast releasing, single-layered films. The effect on delaying drug release was most noticeable when TDF/FTC-loaded NPs were incorporated into double-layered films. This last design seems particularly advantageous for the development of a coitus-independent, on-demand microbicide product. Moreover, all film types were shown potentially safe when evaluated by the MTT metabolic activity and lactate dehydrogenase release assays using HeLa and CaSki cervical cell lines. Overall, results support that proposed films may be suitable for the vaginal delivery of TDF/FTC in the context of topical PrEP. PMID- 29408342 TI - Increasing use of cognitive measures in the operational definition of frailty-A systematic review. AB - Ageing is associated both with frailty and cognitive decline. The quest for a unifying approach has led to a new concept: cognitive frailty. This systematic review explores the contribution of cognitive assessment in frailty operationalization. PubMed, Web of Knowledge and PsycINFO were searched until December 2016 using the keywords aged; frail elderly; aged, 80 and over; frailty; diagnosis; risk assessment and classification, yielding 2863 hits. Seventy-nine articles were included, describing 94 frailty instruments. Two instruments were not sufficiently specified and excluded. 46% of the identified frailty instruments included cognition. Of these, 85% were published after 2010, with a significant difference for publication date (X2 = 8.45, p < .05), indicating increasing awareness of the contribution of cognitive deficits to functional decline. This review identified 7 methods of cognitive assessment: dementia as co morbidity; objective cognitive-screening instruments; self-reported; specific signs and symptoms; delirium/clouding of consciousness; non-specific cognitive terms and mixed assessments. Although cognitive assessment has been increasingly integrated in recently published frailty instruments, this has been heterogeneously operationalized. Once the domains most strongly linked to functional decline will have been identified and operationalized, this will be the groundwork for the identification of reversible components, and for the development of preventive interventional strategies. PMID- 29408343 TI - Enigmatic Colonic Whitish Plaques. PMID- 29408344 TI - Non-corresponding authors in the era of meta-analyses. AB - BACKGROUND AND OBJECTIVE: The exponential growth of the global scientific output requires review articles that summarize such escalating knowledge. The rate of growth in the number of published meta-analyses in the last decade is impressive, with meta-analyses being the most cited form of scientific article. The validity of the pooled estimates of effect heavily rely on the availability of data in the included articles. Unfortunately, inadequate reporting of the findings is common and often makes data extraction cumbersome. However, the response rate of corresponding authors to data requests is dangerously low, which threatens the validity of meta-analytic estimates. The aim of the present communication is to ignite a thoughtful debate to stimulate a higher level of responsibility and correspondence commitment from published authors. METHODS: Commentary on our personal experience as meta-analysts. RESULTS: In line with previous surveys, we observed a low response rate from corresponding authors, typically less than 50%. CONCLUSIONS: Lack of publication follow-up is a serious threat not only to meta analysts and systematic reviewers, whose incomplete data pooling may lead to biased and misleading estimates of effect, but also to clinical practitioners, who heavily rely on the findings generated by meta-analyses for informing and driving their clinical practice. PMID- 29408345 TI - Novel Segmentation of Placed Coils in the Treatment of Cavernous Sinus Dural Arteriovenous Fistulas Provides a Reliable Predictor of the Long-Term Outcome in Abducens Nerve Palsy. AB - OBJECTIVE: Abducens nerve palsy (ANP) after transvenous embolization (TVE) for cavernous sinus (CS) dural arteriovenous fistulas (DAVFs) sometimes persists. The aim of this study was to assess the correlation between the coil mass and the long-term outcome of ANP after TVE. METHODS: Between January 2008 and July 2016, 33 patients with a CS DAVF underwent TVE at our institute. On the basis of the relationship to the internal carotid artery (ICA), we divided the lateral part of the CS into the following 3 portions: anterolateral, anterolateral to the anterior bend of the ICA; middle-lateral (ML), lateral to the horizontal segment of the ICA; and posterolateral, posterolateral to the posterior bend of the ICA. RESULTS: ANP persisted in 4 patients. The number of coils (35.3 vs. 21.9 coils; P = 0.04), coil volume (198.4 vs. 103.6 mm3; P = 0.03), and coil volume in the ML (54.9 vs. 20.3 mm3; P = 0.01) were significantly greater in the ANP group than in the non-ANP group. In the logistic regression analysis, only the ML coil volume was significantly associated with the persistence of ANP (P = 0.04). Based on the receiver operating characteristic curve, the optimal cutoff value of the ML coil volume was 27.9 mm3 (sensitivity, 100%; specificity, 72.4%). CONCLUSIONS: Overpacking in the ML of the CS should be avoided to prevent persistent ANP. The cutoff value of the ML coil volume may provide a good guide for the practical use of TVE for CS DAVFs. PMID- 29408346 TI - True Cortical Saccular Aneurysm Presenting as an Acute Subdural Hematoma. AB - BACKGROUND: Subdural hematoma, without any radiographic evidence of subarachnoid hemorrhage, is a rare presentation of a ruptured intracranial aneurysm. Even more rare is the occurrence of a pure subdural hematoma caused by a ruptured cortical saccular aneurysm. We report the eighth case of pure subdural hematoma secondary to a ruptured nonmycotic cortical berry aneurysm. CASE DESCRIPTION: We report a case of pure subdural hematoma secondary to a ruptured true saccular aneurysm of a cortical artery branch. The lesion was carefully delineated with computed tomography (CT) angiography (CTA) and cerebral angiography, and successfully treated with hematoma evacuation and clip ligation. The patient demonstrates no neurologic deficits 6 months after surgery, and CTA results remain negative. CONCLUSIONS: In the context of a presentation of spontaneous subdural hematoma, intracerebral aneurysm rupture should be considered as a possible etiology. Prompt vascular imaging with careful evaluation of the entire cerebral vasculature, including the cortical vessels, should be considered. PMID- 29408347 TI - The Results of Neuroendoscopic Surgery in Patients with Posttraumatic and Posthemorrhagic Hydrocephalus. AB - BACKGROUND: Posttraumatic hydrocephalus (PTH) and posthemorrhagic hydrocephalus (PHH) were previously considered not suitable for neuroendoscopic treatment. New hydrocephalus theories support possible successful neuroendoscopy in such patients. METHODS: This study presents the results of neuroendoscopy in PTH and PHH with a background analysis. From 130 hydrocephalic patients after neuroendoscopic surgeries, 35 cases with PTH (n = 11) or PHH (n = 24; acute: n = 9, subacute: n = 10, chronic: n = 5) were found. The success rate (Glasgow Outcome Scale [GOS] score 4 or 5 without shunt) and clinical outcome (GOS score) of endoscopic third ventriculostomy (ETV) were analyzed. During the study period, 34 patients had ventriculoperitoneal shunts implanted, including 2 PTH and 5 PHH patients (all chronic). RESULTS: The success rate of ETV in PTH was 54.5%. In acute PHH, the success rate was 33.3%, 42.8% after excluding devastating hematomas. A post-ETV shunt was implanted in 1 patient (massive subarachnoid hemorrhage [SAH]) with final GOS score of 5. In subacute cases, the ETV success rate was 40% (no post-ETV shunts). In chronic PHH, only 1 patient with a GOS score of 5 was shunt-free (20%). The cause of ETV failure was massive SAH. Low final GOS score was caused by the extent of intracerebral bleeding or extracranial problems. The main indications for primary shunt implantation in PTH and PHH were infectious complications. The rate of good outcomes was 0% in PTH and 40% in PHH. CONCLUSIONS: The best results of neuroendoscopy were achieved in PTH and acute PHH. ETV failures were associated with massive SAH; arachnoid cistern blockage and scarring precludes ETV success. PMID- 29408348 TI - Parameters for assessing the aquatic environmental impact of cosmetic products. AB - The cosmetic industry's growing concern about the impact of its supply chain on the environment, sustainability of raw materials, and biodiversity increases the need to ensure that the final product has a lower environmental impact. The objective of this review is to summarize and compare the information available from international organizations and legislation regarding the main criteria used to assess raw materials for aquatic toxicity, as well as the most suitable alternative methods for obtaining assessment parameters. Using the literature available in databases, a review of the scientific literature and international legislation, this work discusses and compares the parameters established by international organizations such as the Environmental Protection Agency (EPA) and Cradle to Cradle (C2C), as well as European legislation, namely, European Regulation 1272/2008, for assessing environmental impact. Defining the ecotoxicity parameters of the main classes of raw materials in rinse-off cosmetic products can enable the development of products that are more environmentally sustainable, prioritizing substances with less environmental impact. PMID- 29408349 TI - Vertebral body replacement using patient-specific three-dimensional-printed polymer implants in cervical spondylotic myelopathy: an encouraging preliminary report. AB - BACKGROUND CONTEXT: Resulting from recent studies that suggest a benefit of implant design on the achievement of fusion and stability in cervical spinal disease management, manufacturing development has increased over the past years. This article attempts to describe how the development of patient-specific implants, which are used during the procedures of anterior cervical corpectomy and vertebral body replacement (VBR), impacts the outcomes of cervical spondylotic myelopathy (CSM) management. MATERIALS AND METHODS: This prospective clinical study included six patients who were implanted with patient-specific VBR for single-level or multilevel CSM. The following clinical scores were collected: visual analog scale (VAS), modified Japanese Orthopaedic Association (mJOA), Neck Dysfunction Index (NDI), and European myelopathy score (EMS), along with radiological measurements. RESULTS: Six patients reached a mean follow-up date of 21months (12-24). Angle measurements remained constant during follow-up, including the C2-C7 Cobb angle and the corpectomy Cobb angle. Furthermore, no deformations, such as hyperlordosis or kyphosis, were detected. The anterior height (Ha) and the posterior height (Hp) of the corpectomy segment remained constant (ratio close to 1) with no severe subsidence (>3 mm) at the last follow up. No height differences were detected between the preoperative and the last follow-up dates, neither for the upper Hp and Ha (0.97+/-0.09 and 1.00+/-0.06, respectively) nor for the lower adjacent vertebrate Hp and Ha (0.96+/-0.04 and 1.02+/-0.12). The mean mJOA and EMS recovery rates were 60.4% (standard deviation [SD] 20.4) and 77.0% (SD 29.7), respectively, at last the follow-up. An EMS of at least 16 of 18 was observed in 83% (5 of 6) of the patients. We recorded a preoperative NDI score at 47.1% (SD 18.6) that improved to 11.2% (SD 4.1) at the last follow-up (p<.01). The preoperative VAS neck (6.3, range 4-7) and the VAS arm (6.1, range 3- 9) scores improved to 1.3 (range 0-3) and 2.8 (range 0-5), respectively, at the last follow-up. CONCLUSIONS: This preliminary report suggests a possible benefit of the use of patient-specific implants in CSM treatment. The favorable clinical and radiological outcomes were associated with a correct achievement rate; these are promising elements toward the development of the concept of personalized therapy. Nonetheless, these encouraging results have to be confirmed now with a longer follow-up and a larger cohort. PMID- 29408350 TI - A pragmatic approach for mortality prediction after surgery in infective endocarditis: optimizing and refining EuroSCORE. AB - OBJECTIVE: To simplify and optimize the ability of EuroSCORE I and II to predict early mortality after surgery for infective endocarditis (IE). METHODS: Multicentre retrospective study (n = 775). Simplified scores, eliminating irrelevant variables, and new specific scores, adding specific IE variables, were created. The performance of the original, recalibrated and specific EuroSCOREs was assessed by Brier score, C-statistic and calibration plot in bootstrap samples. The Net Reclassification Index was quantified. RESULTS: Recalibrated scores including age, previous cardiac surgery, critical preoperative state, New York Heart Association >I, and emergent surgery (EuroSCORE I and II); renal failure and pulmonary hypertension (EuroSCORE I); and urgent surgery (EuroSCORE II) performed better than the original EuroSCOREs (Brier original and recalibrated: EuroSCORE I: 0.1770 and 0.1667; EuroSCORE II: 0.2307 and 0.1680). Performance improved with the addition of fistula, staphylococci and mitral location (EuroSCORE I and II) (Brier specific: EuroSCORE I 0.1587, EuroSCORE II 0.1592). Discrimination improved in specific models (C-statistic original, recalibrated and specific: EuroSCORE I: 0.7340, 0.7471 and 0.7728; EuroSCORE II: 0.7442, 0.7423 and 0.7700). Calibration improved in both EuroSCORE I models (intercept 0.295, slope 0.829 (original); intercept -0.094, slope 0.888 (recalibrated); intercept -0.059, slope 0.925 (specific)) but only in specific EuroSCORE II model (intercept 2.554, slope 1.114 (original); intercept -0.260, slope 0.703 (recalibrated); intercept -0.053, slope 0.930 (specific)). Net Reclassification Index was 5.1% and 20.3% for the specific EuroSCORE I and II. CONCLUSIONS: The use of simplified EuroSCORE I and EuroSCORE II models in IE with the addition of specific variables may lead to simpler and more accurate models. PMID- 29408351 TI - In vivo two-photon imaging of motoneurons and adjacent glia in the ventral spinal cord. AB - BACKGROUND: Interactions between motoneurons and glial cells are pivotal to regulate and maintain functional states and synaptic connectivity in the spinal cord. In vivo two-photon imaging of the nervous system provided novel and unexpected knowledge about structural and physiological changes in the grey matter of the forebrain and in the dorsal white matter of the spinal cord. NEW METHOD: Here, we describe a novel experimental strategy to investigate the spinal grey matter, i.e. the ventral horn motoneurons and their adjacent glial cells by employing in vivo two-photon laser-scanning microscopy (2P-LSM) in anesthetized transgenic mice. RESULTS: After retrograde tracer labelling in transgenic mice with cell-specific expression of fluorescent proteins and surgical exposure of the lumbar intumescence groups of motoneurons could be visualized deeply localized in the ventral horn. In this region, morphological responses of microglial cells to ATP could be recorded for an hour. In addition, using in mice with expression of GCaMP3 in astrocytes, physiological Ca2+ signals could be recorded after local noradrenalin application. COMPARISON WITH EXISTING METHODS: Previous in vivo imaging protocols were restricted to the superficial dorsal white matter or upper layers of the dorsal horn. Here, we modified a multi-step procedure originally established for a root-crush injury. We adapted it to simultaneously visualize motoneurons and adjacent glial cells in living animals. CONCLUSION: A modified surgery approach is presented to visualize fluorescently labelled motoneurons and glial cells at a depth of more than 200 MUm in the grey matter ventral horn of the mouse spinal cord. PMID- 29408352 TI - Promise and challenges for direct small molecule AMPK activators. AB - AMP-activated protein kinase (AMPK) is an evolutionary conserved and ubiquitously expressed serine/threonine kinase playing a central role in the coordination of energy homeostasis. Based on the beneficial outcomes of its activation on metabolism, AMPK has emerged as an attractive target for the treatment of metabolic diseases. Identification of novel downstream targets of AMPK beyond the regulation of energy metabolism has renewed considerable attention in exploiting AMPK signaling for novel therapeutic targeting strategies including treatment of cancer and inflammatory diseases. The complexity of AMPK system with tissue- and species-specific expression of multiple isoform combination regulated by various inputs, post-traductional modifications and subcellular locations presents unique challenges for drug discovery. Here, we review the most recent advances in the understanding of the mechanism(s) of action of direct small molecule AMPK activators and the potential therapeutic opportunities. PMID- 29408353 TI - Impact of Operative Time on Outcomes after Pancreatic Resection: A Risk-Adjusted Analysis Using the American College of Surgeons NSQIP Database. AB - BACKGROUND: Longer operative time (OT) has been associated with negative outcomes in various surgical procedures, but its role in pancreatic resection, a complex, high-acuity endeavor, is not yet well defined. The aim of this study was to analyze the relationship between OT and pancreatectomy outcomes in a risk adjusted fashion. STUDY DESIGN: This retrospective cohort study analyzed patients undergoing pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) between 2014 and 2015 using the procedure-targeted pancreatectomy database of the American College of Surgeons NSQIP. Univariable analyses and multiple backward stepwise conditional logistic regression models were used to assess the impact of OT on postoperative occurrences. RESULTS: Among 10,157 patients, 6,844 PDs and 3,313 DPs were performed. Median operative time was 358 minutes (interquartile range 282 to 444 minutes) for PD and 213 minutes (interquartile range 157 to 285 minutes) for DP. Male sex, younger age, obesity, neoadjuvant treatment, minimally invasive approaches, and vascular/concurrent organ resections were associated with longer OT for both procedures. Morbidity increased in a stepwise manner with increasing OT. After risk adjustment, increasing OT was negatively associated with overall morbidity, major complications, pancreatectomy-specific complications, infectious complications, and prolonged hospital stay. These associations were independent from patients' preoperative characteristics, operative approach, vascular or concurrent organ resection, and postoperative diagnosis. These findings held true for both PD and DP. Conversely, the association between OT and mortality was mainly driven by the excessive operative durations for PDs, and was not significant for DPs. CONCLUSIONS: Longer OT is independently associated with worse perioperative outcomes after pancreatic resection, and should be considered a relevant parameter in risk-adjustment processes for outcomes evaluation. These findings suggest possible areas of quality improvement through individual and system-level initiatives. PMID- 29408354 TI - Increased Gradients After Aortic Valve Replacement With the Perceval Valve: The Role of Oversizing. AB - BACKGROUND: Significant underexpansion or distortion of valved stents may be associated with altered leaflet function, leading to increased transprosthetic gradients and, possibly, early structural degeneration. We investigated the relationship between a computed tomography measure of the degree of oversizing and the early hemodynamic and clinical outcomes in patients undergoing aortic valve replacement with the Perceval sutureless aortic valve (LivaNova, Saluggia, Italy). METHODS: The degree of oversizing of the implanted prosthesis was calculated as the ratio between the patients' aortic annulus cross-sectional area and the ex vivo cross-sectional area of the implanted prosthesis in 151 Perceval patients who underwent preoperative cardiac computed tomography. This value was then entered in a multivariate analysis to ascertain its role as a predictor of increased postoperative gradient. RESULTS: The operative mortality was 1.3%. Procedural success, defined as having a normally functioning valve in the proper anatomical location, was achieved in 150 patients (99.3%). The mean transprosthetic gradient was 13.4 +/- 5.0 mm Hg, and 23 patients (15.2%) showed a gradient of 20 mm Hg or more at discharge or at the 1-month follow-up. The degree of oversizing of the implanted prosthesis was the most important predictor of increased postoperative gradient (odds ratio, 1.264; 95% confidence interval, 1.147 to 1.394; p < 0.0001). Interestingly, other relevant factors (patients' body surface area, prosthesis size) were not associated with increased gradients. CONCLUSIONS: Our study demonstrates that excessive oversizing should be avoided in Perceval patients and suggests that a different sizing algorithm, possibly based on cardiac computed tomography, should be developed. Further studies are needed to optimize the sizing strategy for the Perceval sutureless valve. PMID- 29408355 TI - Molecular cloning, spatiotemporal and functional expression of GABA receptor subunits RDL1 and RDL2 of the rice stem borer Chilo suppressalis. AB - Insect gamma-aminobutyric acid (GABA) receptor (GABAR) is one of the major targets of insecticides. In the present study, cDNAs (CsRDL1A and CsRDL2S) encoding the two isoforms of RDL subunits were cloned from the rice stem borer Chilo suppressalis. Transcripts of both genes demonstrated similar expression patterns in different tissues and developmental stages, although CsRDL2S was ~2 fold more abundant than CsRDL1A throughout all development stages. To investigate the function of channels formed by CsRDL subunits, both genes were expressed in Xenopus laevis oocytes singly or in combination in different ratios. Electrophysiological results using a two-electrode voltage clamp demonstrated that GABA activated currents in oocytes injected with both cRNAs. The EC50 value of GABA in activating currents was smaller in oocytes co-injected with CsRDL1A and CsRDL2S than in oocytes injected singly. The IC50 value of the insecticide fluralaner in inhibiting GABA responses was smaller in oocytes co-injected with different cRNAs than in oocytes injected singly. Co-injection also changed the potency of the insecticide dieldrin in oocytes injected singly. These findings suggested that heteromeric GABARs were formed by the co-injections of CsRDL1A and CsRDL2S in oocytes. Although the presence of Ser at the 2'-position in the second transmembrane segment was responsible for the insensitivity of GABARs to dieldrin, this amino acid did not affect the potencies of the insecticides fipronil and fluralaner. These results lead us to hypothesize that C. suppressalis may adapt to insecticide pressure by regulating the expression levels of CsRDL1A and CsRDL2S and the composition of both subunits in GABARs. PMID- 29408356 TI - All-cellulose composite films with cellulose matrix and Napier grass cellulose fibril fillers. AB - Diverse move has been attempted to use biomass as a filler for the production of biodegradable all-cellulose composites. In this study, cellulose fibrils (CFs) extracted from native African Napier grass (NG) fibres were used as fillers in cellulose matrix and made all-cellulose composites. Napier Grass Cellulose fibrils (NGCFs) loading was varied from 5 to 25 wt% in cellulose matrix in random orientation and the all cellulose composites were made by regeneration process. These composites were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction, thermogravimetric analysis, optical microscopy, and tensile testing. The FTIR spectra indicated not only the presence of minute amounts of hemicelluloses and lignin in the filler but also the possible interaction between the matrix and NGCFs. The crystallinity of the all-cellulose composites was found to be lower than that of the cellulose matrix. The thermal stability of the all-cellulose composites was found to be higher than that of the cellulose matrix and increased with NGCFs filler content. The tensile strength of the all-cellulose composites though was lower than that of the cellulose matrix but still was higher than for commodity polymers. The all-cellulose composites can be considered for wrapping and mulching applications. PMID- 29408357 TI - Evidence on botulinum toxin in selected disorders. AB - Botulinum toxin (BoNT) is a neurotoxin produced by the bacteria Clostridium botulinum that has become widely used for various neurologic indications. The four toxin formulations currently available for use in the United States (approved by the Food and Drug Administration) are onabotulinumtoxinA (Botox(r)), abobotulinumtoxinA (Dysport(r)), incobotulinumtoxinA (Xeomin(r)), and rimabotulinumtoxinB (Myobloc(r)). While the FDA-approved labels indicate that potency conversions should not be done, literature supports relative dose equivalents of approximately 1:1:2-4:50-100, respectively. The aim of this paper is to review the evidence on the use of BoNT formulations available in the United States for specific neurologic disorders, including blepharospasm, cervical dystonia (CD), upper and lower extremity spasticity and chronic migraine. Data from the updated 2016 American Academy of Neurology (AAN) guidelines are presented and the level of evidence for use of the four available preparations of BoNT are discussed (Table 2 in appendix). For the management of blepharospasm, the recommendations are for use of onaBoNT-A and incoBoNT-A injections with level B evidence. For the management of CD, the recommendations are for use of aboBoNT A and rimaBoNT-B with level A evidence. For the management of upper extremity spasticity, the recommendations are for use of aboBoNT-A, incoBoNT-A and onaBoNT A with level A evidence. For the management of lower extremity spasticity, the recommendations are for use of onaBoNT-A and aboBoNT-A with level A evidence. For the management of chronic migraines, the recommendations are for use of onaBoNT-A to help improve headache-free days, with level A evidence. It is important for the clinician to understand that BoNT is for use in symptomatic control for the underlying neurologic disorder and, at present, has not shown a role in disease modification. PMID- 29408359 TI - Meningitis epidemics shift in sub-Saharan belt. AB - Meningococcal meningitis (MCM) poses a serious threat to public health in Africa. Epidemics appear irregularly every 5-12 years, especially in the regions across sub-Saharan 'meningitis belt'. This study investigated the long-term spatiotemporal dynamics of MCM. It appears that dominant epidemic outbreaks in the meningitis belt spread from west to east over the study period 2006-2016. PMID- 29408358 TI - Epidemiological serosurvey of hepatitis B virus among children aged 1-14 years in Guangdong Province, China. AB - OBJECTIVE: A cross-sectional community prevalence survey was conducted to investigate the sero-epidemiological features of hepatitis B virus (HBV) infection among children aged 1-14 years in Guangdong Province in 2013, and to provide baseline data for the evaluation of HBV disease burden and the impacts of HBV control. METHODS: A total of 2765 children aged 1-14 years from 16 villages/streets of eight cities in Guangdong Province were recruited as subjects. A blood sample was obtained from each subject. A chemiluminescence microparticle immunoassay (CMIA) was used to detect hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (HBsAb), and antibody to hepatitis B core antigen (HBcAb). RESULTS: The prevalence rates of HBsAg, HBsAb, and HBcAb among children aged 1-14 years were 1.16%, 61.63%, and 2.35%, respectively. The prevalence of HBsAg and HBcAb increased with increasing age, and the prevalence was lowest in the 1-4 years age group (0.97% for HBsAg and 1.45% for HBcAb). In contrast, the prevalence of HBsAb decreased with increasing age; however the prevalence was also highest in the 1-4 years age group (76.48%). Eastern Guangdong had the highest prevalence of HBsAg and HBcAb, and the lowest prevalence of HBsAb. The prevalence of HBsAg was under 1% in the Pearl River Delta and western Guangdong regions. Children who had received three or more doses of vaccine had a lower prevalence of HBsAg and HBcAb and a higher prevalence of HBsAb compared to those who had received fewer than three doses of vaccine. CONCLUSIONS: The prevalence of HBsAg among children aged 1-14 years in Guangdong in 2013 was 1.2%, showing a dramatic decrease compared to the 1992 provincial-level cross-sectional survey (19.9%). Children aged 1-4 years and children from the Pearl River Delta had the lowest prevalence of HBsAg positivity. High vaccination coverage among children and timely vaccination of newborns has played an important role in reducing the prevalence of HBsAg. PMID- 29408360 TI - Evaluation of the Xpert MTB/RIF assay for the diagnosis of smear-negative pulmonary and extrapulmonary tuberculosis in Madagascar. AB - OBJECTIVE: To evaluate the feasibility of the implementation of a commercial rapid molecular diagnostic test (Xpert MTB/RIF) for the routine diagnosis of smear-negative or extrapulmonary tuberculosis (TB) and its diagnostic accuracy, and to assess HIV prevalence in a real-life setting in Madagascar. This study was set in a tertiary care hospital in Madagascar. METHODS: A prospective cohort study was conducted of all consecutive cases with suspected smear-negative and/or extrapulmonary TB over a 2-year period. Cases were classified as proven, probable, or possible TB cases, or as having an alternative diagnosis. RESULTS: Of the 363 patients included, 183 (50.4%) had suspected smear-negative pulmonary TB and 180 (49.6%) had suspected extrapulmonary TB. For proven cases, the sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF were 82.4%, 98.8%, 98.3%, and 86.6%, respectively; for proven and probable cases grouped together, these values were 65%, 98.8%, 98.5%, and 64%, respectively. The diagnostic accuracy was slightly lower for extrapulmonary TB compared to smear-negative pulmonary TB. The prevalence of HIV infection was 12.1%, but almost half of these cases did not have TB (alternative diagnosis group). CONCLUSIONS: The implementation of a rapid diagnosis programme for TB in a resource-poor setting is feasible. The performance of the Xpert-MTB/RIF was remarkable in this difficult-to-diagnose population. HIV prevalence in this study was much higher than the prevalence reported in the general population in Madagascar, in patients with TB and patients with conditions other than TB. PMID- 29408361 TI - Binding of alpha-synuclein to partially oxidized glyceraldehyde-3-phosphate dehydrogenase induces subsequent inactivation of the enzyme. AB - According to literature data, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) co-localizes with alpha-synuclein in Lewy bodies in Parkinson's disease, which suggests the involvement of this protein in the development of synucleinopathies. The goal of the present work was to investigate the direct interaction between alpha-synuclein and GAPDH and to evaluate possible influence of this interaction on the catalytic properties of GAPDH. Molecular dynamic simulations predicted the binding of alpha-synuclein to the positively charged groove comprising NAD+-binding pocket of GAPDH. The formation of the complex between alpha-synuclein and GAPDH in vitro was confirmed by different experimental approaches. The binding of alpha-synuclein to GAPDH with partially oxidized active site cysteines resulted in the subsequent inactivation of the enzyme, decreased its thermostability and increased its propensity for aggregation. At the same time, the formation of the complex between GAPDH and monomeric alpha-synuclein prevented amyloid transformation of alpha-synuclein. This work presents the first evidence for the fact that the initial oxidation of GAPDH induces the binding of alpha-synuclein to the enzyme, leading to further inactivation of GAPDH and, as a consequence, inhibition of glycolysis. The described mechanism may contribute to the metabolic disorders that are characteristic for synucleinopathies. PMID- 29408363 TI - Dopamine depletion shifts behavior from activity based reinforcers to more sedentary ones and adenosine receptor antagonism reverses that shift: Relation to ventral striatum DARPP32 phosphorylation patterns. AB - The mesolimbic dopamine (DA) system plays a critical role in behavioral activation and effort-based decision-making. DA depletion produces anergia (shifts to low effort options) in animals tested on effort-based decision-making tasks. Caffeine, the most consumed stimulant in the world, acts as an adenosine A1/A2A receptor antagonist, and in striatal areas DA D1 and D2 receptors are co localized with adenosine A1 and A2A receptors respectively. In the present work, we evaluated the effect of caffeine on anergia induced by the VMAT-2 inhibitor tetrabenazine (TBZ), which depletes DA. Anergia was evaluated in a three-chamber T-maze task in which animals can chose between running on a wheel (RW) vs. sedentary activities such as consuming sucrose or sniffing a neutral odor. TBZ caffeine interactions in ventral striatum were evaluated using DARPP-32 phosphorylation patterns as an intracellular marker of DA-adenosine receptor interaction. In the T-maze, control mice spent more time running and much less consuming sucrose or sniffing. TBZ (4.0 mg/kg) reduced ventral striatal DA tissue levels as measured by HPLC, and also shifted preferences in the T-maze, reducing selection of the reinforcer that involved vigorous activity (RW), but increasing consumption of a reinforcer that required little effort (sucrose), at doses that had no effect on independent measures of appetite or locomotion in a RW. Caffeine at doses that had no effect on their own reversed the effects of TBZ on T-maze performance, and also suppressed TBZ-induced pDARPP-32(Thr34) expression as measured by western blot, suggesting a role for D2-A2A interactions. These results support the idea that DA depletion produces anergia, but does not affect the primary motivational effects of sucrose. Caffeine, possibly by acting on A2A receptors in ventral striatum, reversed the DA depletion effects. It is possible that caffeine, like selective adenosine A2A antagonists, could have some therapeutic benefit for treating effort-related symptoms. PMID- 29408364 TI - Comparative proteomic analysis of hepatic effects induced by nanosilver, silver ions and nanoparticle coating in rats. AB - The presence of nano-scaled particles in food and food-related products has drawn attention to the oral uptake of nanoparticles and their interactions with biological systems. In the present study, we used a toxicoproteomics approach to allow for the untargeted experimental identification and comparative analysis of cellular responses in rat liver after repeated-dose treatment with silver nanoparticles, ions, and the coating matrix used for particle stabilization. The proteomic analysis revealed treatment-related effects caused by exposure to silver in particulate and ionic form. Both silver species induced similar patterns of signaling and metabolic alterations. Silver-induced cellular alterations comprised, amongst others, proteins involved in metal homeostasis, oxidative stress response, and energy metabolism. However, we discovered that secondary nano-scaled structures were formed from ionic silver. Furthermore, also the coating matrix alone gave rise to the formation of nano-scaled particles. The present data confirm, complement, and extend previous knowledge on silver toxicity in rodent liver by providing a comprehensive proteomic data set. The observation of secondary particle formation from non-particle controls underlines the difficulties in separating particle-, ion-, and matrix coating-related effects in biological systems. Awareness of this issue will support proper evaluation of nanotoxicology-related data in the future. PMID- 29408365 TI - More clarity needed for contraceptive mobile app Pearl Index calculations. PMID- 29408362 TI - Biosynthesis of human myeloperoxidase. AB - Members of Chordata peroxidase subfamily [1] expressed in mammals, including myeloperoxidase (MPO), eosinophil peroxidase (EPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO), express conserved motifs around the heme prosthetic group essential for their activity, a calcium-binding site, and at least two covalent bonds linking the heme group to the protein backbone. Although most studies of the biosynthesis of these peroxidases have focused on MPO, many of the features described occur during biosynthesis of other members of the protein subfamily. Whereas MPO biosynthesis includes events typical for proteins generated in the secretory pathway, the importance and consequences of heme insertion are events uniquely associated with peroxidases. This Review summarizes decades of work elucidating specific steps in the biosynthetic pathway of human MPO. Discussion includes cotranslational glycosylation and subsequent modifications of the N-linked carbohydrate sidechains, contributions by molecular chaperones in the endoplasmic reticulum, cleavage of the propeptide from proMPO, and proteolytic processing of protomers and dimerization to yield mature MPO. Parallels between the biosynthesis of MPO and TPO as well as the impact of inherited mutations in the MPO gene on normal biosynthesis will be summarized. Lastly, specific gaps in our knowledge revealed by this review of our current understanding will be highlighted. PMID- 29408366 TI - Clarifications concerning contraceptive mobile app Pearl Index calculations. PMID- 29408367 TI - Review: Limb regeneration in humans: Dream or reality? AB - Appendage regeneration occurs by a sequence of events resembling those that take place during development in the embryo. This requires embryonic conditions such as hydration and hyaluronate content where Wnt and other signaling pathways, together with non- coding RNAs, can be re-expressed. These conditions among vertebrates are fully met only in amputated limbs of amphibians, likely because they are neotenic and maintain larval characteristics, including immaturity of their immune system and permanence of numerous stem cells. Although some key genes orchestrating limb regeneration are also present in amniotes, including humans, these genes are not expressed after injury. In amniotes a key problem for regeneration derives from the efficient immune system, largely deficient in anamniotes. As a consequence, wounds and appendage loss tend to scar instead of regenerating. Efforts of regenerative medicine in the attempt to induce the regrowth of limbs in humans must produce outgrowths with high hydration and hyaluronate content in order to create the immune-suppressed conditions similar to those present during development. The induced blastema must be manipulated for long periods of time in order to maintain the same regions present during limb development, an apical epidermal ridge and a polarizing region that forms gradients of expression of Wnt, Shh, FGF, BMP and Hox-genes. Pharmacological treatments to direct the regenerating limb into normal growth without risk of inducing abnormal or tumorigenic growth must be monitored during the course of the regeneration process - a medical treatment lasting years to fully regain the size of the lost appendage. PMID- 29408368 TI - Semantically Congruent Sounds Facilitate the Decoding of Degraded Images. AB - Semantically congruent sounds can facilitate perception of visual objects in the human brain. However, the manner in which semantically congruent sounds affect cognitive processing for degraded visual stimuli remains unclear. We presented participants with naturalistic degraded images and semantically congruent sounds from different conceptual categories in three modalities: degraded visual only, auditory only, and auditory and degraded visual. Functional magnetic resonance imaging was performed to assess variations in brain-activation spatial patterns. In order to account for the facilitation of auditory modulation at different levels, four conceptual categories of stimuli were divided into coarse and fine groups. Conjunction analysis and multivariate pattern analysis were used to investigate integrative properties. Superadditive interactions were found in the visual association cortex and subadditive interactions were observed in the superior temporal sulcus/superior temporal gyrus (STS/STG). Our results demonstrate that the visual association cortex and STS/STG are involved in the integration of auditory and degraded visual information. In addition, the pattern classification results imply that semantically congruent sounds may facilitate identification of degraded images in both coarse and fine groups. Importantly, when naturalistic visual stimuli were further subdivided, facilitation through auditory modulation exhibited category selectivity. PMID- 29408369 TI - Drug targeting of one or more aminoacyl-tRNA synthetase in the malaria parasite Plasmodium falciparum. AB - Malaria remains a major infectious disease and, despite incidence reduction, it threatens resurgence in drug-resistant forms. Antimalarial drugs remain the mainstay of therapeutic options and hence there is a constant need to identify and validate new druggable targets. Plasmodium falciparum aminoacyl-tRNA synthetases (Pf-aaRSs) drive protein translation and are potent targets for development of next-generation antimalarials. Here, we detail advances made in structural-biology-based investigations in Pf-aaRSs and discuss their distribution of druggable pockets. This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria. PMID- 29408370 TI - Genetics of coronary artery disease: fact or fiction? PMID- 29408371 TI - Women in danger: detecting coronary artery disease - Are there any sex differences? PMID- 29408372 TI - Humidity induced collapse in freeze dried cakes: A direct visualization study using DVS. AB - Maintaining low moisture content is seen as crucial to sustaining long term stability in freeze dried (FD) cakes as higher moisture could lead to cake collapse, degradation and a loss of biological potency. Using a combination of gravimetric data and video images captured from a Dynamic Vapour Sorption instrument the onset humidity Collapse Point (RHcp), the humidity onset Crystallisation (RHc) and onset Glass Transition (RHg) points for a series of freeze dried cakes at 10, 25 and 40 degrees C have been determined. The moisture sorption behavior with respect to cake collapse and other morphological phase transitions are reported for a two freeze drying excipients and one product formulation; sucrose, trehalose (both 5% w/w) and an influenza antigen (A/Wisconsin/15/2009 H3N2 NYMCX-183, formulated with 1.1% w/w sucrose). Stability maps for all three formulations tested were reported as a function of %RH and temperature using the methods described in this work, thus the direct visualization of collapse behavior for any FD cake can now be standardized and routinely determined, facilitating the formulation of FD products with improved stability and storage performance. PMID- 29408374 TI - Effect of maternal hypoglycaemia during gestation on materno-foetal nutrient transfer and embryo-foetal development: Evidence from experimental studies focused primarily on the rat. AB - Glucose is the major energy substrate during embryogenesis and the embryo is dependent on glucose from the maternal circulation to ensure normal metabolism and growth. The placenta plays a key role in this nutrient transfer in mammals, both during embryogenesis and after the development of the chorio-allantoic placental circulation. Maternal hypoglycaemia is accompanied by foetal hypoglycaemia and maternal counter-regulatory measures including a priority to keep nutrients in the maternal circulation by restricting their transfer to the foetus. Concomitantly, the foetus initiates its own counter-regulatory attempt to secure nutrients for its development and survival. Despite these measures, there is a general decrease in nutrient transfer to the foetus, which may have severe consequences for foetal development such as malformations and delayed skeletal development. PMID- 29408373 TI - Selective dopaminergic neurotoxicity of three heterocyclic amine subclasses in primary rat midbrain neurons. AB - Heterocyclic amines (HCAs) are primarily produced during high temperature meat cooking. These compounds have been intensively investigated as mutagens and carcinogens. However, converging data suggest that HCAs may also be neurotoxic and potentially relevant to neurodegenerative diseases such as Parkinson's disease (PD). The identification of new potential etiological factors is important because most PD cases are sporadic. Our group previously showed that 2 amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was selectively neurotoxic to dopaminergic neurons. However, PhIP is one of many HCAs, a class of compounds that exhibits wide structural variability. The goal of this study was to determine the neurotoxicity of the most prevalent and best studied HCAs from three subclasses: aminoimidazoaazarenes (AIA), alpha-carbolines, and beta carbolines. Using E17 rat primary midbrain cultures, we tested dopaminergic and non-dopaminergic neurotoxicity elicited by the following compounds: 2-amino-3 methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8 trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), PhIP, 1-methyl-9H-pyrido[3,4 b]indole (harmane), 9H-pyrido[3,4-b]indole (norharmane) and 2-amino-9H-pyrido[2,3 b]indole (AalphaC) at concentrations ranging from 100 nM-5 MUM. All tested HCAs were selectively neurotoxic, though the dose required to elicit selective loss of dopaminergic neurons or decreases in dopaminergic neurite length was compound specific. Non-dopaminergic neurons were unaffected at all tested doses. The sensitivity (determined by threshold dose required to elicit selective neurotoxicity) appears to be unrelated to published mutagenic potency. Both AIA and alpha/beta-carbolines produced oxidative damage, which was magnified in dopaminergic neurons vs. non-dopaminergic neurons as further evidence of selective neurotoxicity. These studies are expected to prompt clinical and mechanistic studies on the potential role of HCA exposure in PD. PMID- 29408375 TI - Germ cell depletion in zebrafish leads to incomplete masculinization of the brain. AB - Zebrafish sex differentiation is under the control of multiple genes, but also relies on germ cell number for gonadal development. Morpholino and chemical mediated germ cell depletion leads to sterile male development in zebrafish. In this study we produced sterile males, using a dead end gene morpholino, to determine gonadal-brain interactions. Germ cell depletion following dnd inhibition downregulated the germ cell markers, vasa and ziwi, and later the larvae developed as sterile males. Despite lacking proper testis, the gonadal 11 ketotestosterone (11-KT) and estradiol (E2) levels of sterile males were similar to wild type males. Qualitative analysis of sexual behavior of sterile males demonstrated that they behaved like wild type males. Furthermore, we observed that brain 11-KT and E2 levels in sterile males remained the same as in the wild type males. In female brain, 11-KT was lower in comparison to wild type males and sterile males, while E2 was higher when compared to wild type males. qRT-PCR analysis revealed that the liver transcript profile of sterile adult males was similar to wild type males while the brain transcript profile was similar to wild type females. The results demonstrate that proper testis development may not be a prerequisite for male brain development in zebrafish but that it may be needed to fully masculinize the brain. PMID- 29408376 TI - HiCTMap: Detection and analysis of chromosome territory structure and position by high-throughput imaging. AB - The spatial organization of chromosomes in the nuclear space is an extensively studied field that relies on measurements of structural features and 3D positions of chromosomes with high precision and robustness. However, no tools are currently available to image and analyze chromosome territories in a high throughput format. Here, we have developed High-throughput Chromosome Territory Mapping (HiCTMap), a method for the robust and rapid analysis of 2D and 3D chromosome territory positioning in mammalian cells. HiCTMap is a high-throughput imaging-based chromosome detection method which enables routine analysis of chromosome structure and nuclear position. Using an optimized FISH staining protocol in a 384-well plate format in conjunction with a bespoke automated image analysis workflow, HiCTMap faithfully detects chromosome territories and their position in 2D and 3D in a large population of cells per experimental condition. We apply this novel technique to visualize chromosomes 18, X, and Y in male and female primary human skin fibroblasts, and show accurate detection of the correct number of chromosomes in the respective genotypes. Given the ability to visualize and quantitatively analyze large numbers of nuclei, we use HiCTMap to measure chromosome territory area and volume with high precision and determine the radial position of chromosome territories using either centroid or equidistant-shell analysis. The HiCTMap protocol is also compatible with RNA FISH as demonstrated by simultaneous labeling of X chromosomes and Xist RNA in female cells. We suggest HiCTMap will be a useful tool for routine precision mapping of chromosome territories in a wide range of cell types and tissues. PMID- 29408377 TI - The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas. AB - More than 40% of glioma patients have tumors that harbor PTEN (phosphatase and tensin homologue deleted on chromosome ten) mutations; this disease is associated with poor therapeutic resistance and outcome. Such mutations are linked to increased cell survival and growth, decreased apoptosis, and drug resistance; thus, new therapeutic strategies focusing on inhibiting glioma tumorigenesis and progression are urgently needed. Melatonin, an indolamine produced and secreted predominantly by the pineal gland, mediates a variety of physiological functions and possesses antioxidant and antitumor properties. Here, we analyzed the relationship between PTEN and the inhibitory effect of melatonin in primary human glioma cells and cultured glioma cell lines. The results showed that melatonin can inhibit glioma cell growth both in culture and in vivo. This inhibition was associated with PTEN levels, which significantly correlated with the expression level of MT1 in patients. In fact, c-fos-mediated MT1 was shown to be a key modulator of the effect of melatonin on gliomas that harbor wild type PTEN. Taken together, these data suggest that melatonin-MT1 receptor complexes represent a potential target for the treatment of glioma. PMID- 29408379 TI - Healthy and sustainable diets: Community concern about the effect of the future food environments and support for government regulating sustainable food supplies in Western Australia. AB - OBJECTIVE: To determine the level of community concern about future food supplies and perception of the importance placed on government regulation over the supply of environmentally friendly food and identify dietary and other factors associated with these beliefs in Western Australia. DESIGN: Data from the 2009 and 2012 Nutrition Monitoring Survey Series computer-assisted telephone interviews were pooled. Level of concern about the effect of the environment on future food supplies and importance of government regulating the supply of environmentally friendly food were measured. Multivariate regression analysed potential associations with sociodemographic variables, dietary health consciousness, weight status and self-reported intake of eight foods consistent with a sustainable diet. SETTING: Western Australia. SUBJECTS: Community-dwelling adults aged 18-64 years (n = 2832). RESULTS: Seventy nine per cent of Western Australians were 'quite' or 'very' concerned about the effect of the environment on future food supplies. Respondents who paid less attention to the health aspects of their diet were less likely than those who were health conscious ('quite' or 'very' concerned) (OR = 0.53, 95% CI [0.35, 0.8] and 0.38 [0.17, 0.81] respectively). The majority of respondents (85.3%) thought it was 'quite' or 'very' important that government had regulatory control over an environmentally friendly food supply. Females were more likely than males to rate regulatory control as 'quite' or 'very' important' (OR = 1.63, 95% CI [1.09, 2.44], p = .02). Multiple regression modeling found that no other factors predicted concern or importance. CONCLUSIONS: There is a high level of community concern about the impact of the environment on future food supplies and most people believe it is important that the government regulates the issue. These attitudes dominate regardless of sociodemographic characteristics, weight status or sustainable dietary behaviours. PMID- 29408378 TI - FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting gamma-catenin K63-linked ubiquitylation. AB - FBW7 is an E3 ubiquitin ligase and frequently mutated in various types of cancer. As a component of SCF ubiquitin ligase complex, FBW7 usually targets the substrates via K11 or K48-linked ubiquitylation and subsequent degradation of target proteins. Nevertheless, the role of FBW7 in mediating non-degradable ubiquitin signaling remains unknown in human cancers. In this study, we identified gamma-catenin as a new binding protein of FBW7 by TAP-MS (tandem affinity purification-mass spectrum). Knockdown of FBW7 did not affect the stability of gamma-catenin, but significantly reduced the K63-linked ubiquitin of gamma-catenin, resulting in decreased expression of gamma-catenin downstream gene 14-3-3sigma. Rescue experiment revealed that gamma-catenin promoted the expression of 14-3-3sigma in a K63-linked ubiquitin signaling dependent manner. Furthermore, we showed that FBW7 cooperated with gamma-catenin to inhibit G2/M cell cycle transition and cell proliferation. Taken together, our study uncovered a novel mechanism that FBW7 associated with gamma-catenin and promoted its K63 linked ubiquitylation, providing new insights in understanding the role of FBW7 in inhibiting G2/M cell cycle transition and tumor cell proliferation. PMID- 29408380 TI - Parent-child feeding practices in a developing country: Findings from the Family Diet Study. AB - BACKGROUND AND AIMS: Given the increasing prevalence of childhood obesity in Malaysia, examination of family environmental factors is warranted. Reviews from developed countries report inconsistent findings on the relationship between parental-child feeding practices and child weight-related health outcomes. The current study aimed to examine parent-child feeding practices by familial-child characteristics in Malaysia. MATERIALS AND METHOD: The Family Diet Study was conducted with urban Malay families and included a child aged 8-12 years and their main carer(s). Seven domains of parent-child feeding practices were assessed using the child feeding questionnaire and familial demographics, including socio-economic status, child anthropometry and dietary intake were collected. Inferential statistics were used to explore the relationships between variables. RESULTS: Of the 315 families enrolled, 236 completed all measures, with the majority of parent-reporters being mothers (n = 182). One-third of the children were classified as overweight/obese. Three domains of parent-child feeding practices had median scores of 4.0 out of 5.0 [concern about child overweight (CCO) (Interquartile range (IQR): 3.3, 4.7); pressure-to-eat (PTE) (IQR: 3.3, 4.5) and food monitoring (IQR: 3.0, 5.0)]. The domain of 'perceived child overweight' was positively associated with child age (r = 0.45, p < 0.001). Children who were overweight (F = 37.4; p < 0.001) and under-reported energy intake (F = 13.1; p = 0.001) had higher median scores for the parental perception of risk of child being overweight. Median scores for the CCO and PTE domains were significantly higher in low-income families (F = 7.87; F = 9.75; p < 0.05, respectively). CONCLUSION: Malay parents in this present study are concerned about their child's weight, particularly for those overweight. Family size, household income, and child weight status significantly influence parent-child feeding practices. Further research examining the cultural context of family environmental factors related to childhood obesity is warranted within Malaysia. PMID- 29408381 TI - Autophosphorylation Is a Mechanism of Inhibition in Twitchin Kinase. AB - Titin-like kinases are muscle-specific kinases that regulate mechanical sensing in the sarcomere. Twitchin kinase (TwcK) is the best-characterized member of this family, both structurally and enzymatically. TwcK activity is auto-inhibited by a dual intrasteric mechanism, in which N- and C-terminal tail extensions wrap around the kinase domain, blocking the hinge region, the ATP binding pocket and the peptide substrate binding groove. Physiologically, kinase activation is thought to occur by a stretch-induced displacement of the inhibitory tails from the kinase domain. Here, we now show that TwcK inhibits its catalysis even in the absence of regulatory tails, by undergoing auto-phosphorylation at mechanistically important elements of the kinase fold. Using mass spectrometry, site-directed mutagenesis and catalytic assays on recombinant samples, we identify residues T212, T301, T316 and T401 as primary auto-phosphorylation sites in TwcK in vitro. Taken together, our results suggest that residue T316, located in the peptide substrate binding P+1 loop, is the dominantly regulatory site in TwcK. Based on these findings, we conclude that TwcK is regulated through a triple-inhibitory mechanism consisting of phosphorylation and intrasteric blockage, which is responsive not only to mechanical cues but also to biochemical modulation. This implies that mechanically stretched conformations of TwcK do not necessarily correspond to catalytically active states, as previously postulated. This further suggests a phosphorylation-dependent desensitization of the TwcK mediated mechanoresponse of the sarcomere in vivo. PMID- 29408382 TI - Molecular characterisation of blaOXA-48 carbapenemase-, extended-spectrum beta lactamase- and Shiga toxin-producing Escherichia coli isolated from farm piglets in India. AB - OBJECTIVES: The aim of this study was to characterise carbapenemase-, extended spectrum beta-lactamase (ESBL)- and Shiga toxin-producing Escherichia coli isolated from farm piglets in India. METHODS: Faecal samples (n=741) from 10 organised pig farms, including non-diarrhoeic (n=546) and diarrhoeic (n=195) piglets, were processed for isolation of carbapenem-resistant and ESBL-producing E. coli. RESULTS: A total of 27 and 243 isolates were phenotypically confirmed as carbapenem-resistant and ESBL-producers, respectively. The meropenem minimum inhibitory concentration (MIC) of carbapenem-resistant isolates ranged from 8 128MUg/mL. On genotypic screening of the 27 carbapenem-resistant isolates, 3 isolates were positive for the blaOXA-48 carbapenemase gene; no other carbapenemase genes were detected. The 243 ESBL-producing isolates were positive for blaCTX-M-1 (n=135), qnrA (n=92), qnrB (n=112), qnrS (n=49), tetA (n=42), tetB (n=45) and sul1 (n=43). The Shiga toxin virulence markers stx1 and stx2 were detected in 41 and 38 of the 243 phenotypic ESBL-producing isolates, respectively. Multilocus sequence typing (MLST) of blaOXA-48-positive E. coli isolates showed ST10- and ST5053-like sequence types. CONCLUSION: This is the first report on the presence of blaOXA-48-carrying E. coli in piglets in India, which pose a potential risk to public health. PMID- 29408383 TI - Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains. AB - OBJECTIVES: Multidrug-resistant (MDR) superbugs, including Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), are a challenge for healthcare professionals. In this study, the synergistic activity of vitamins with antibiotics against resistant bacterial strains was evaluated. METHODS: Synergistic effects between antibiotics and stock solutions of vitamins were evaluated by the Kirby-Bauer disk diffusion assay. Distilled water and propylene glycol were used as solvent for water-soluble and fat-soluble vitamins, respectively. Final concentrations of 10mg/mL for each water-soluble vitamin [B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B12 (methylcobalamin) and C (ascorbic acid)] and 0.1mg/mL for each fat-soluble vitamin [A (retinol), D (cholecalciferol), E (alpha-tocopherol) and K (menadione)] were used in combination with the antibiotics. RESULTS: The results demonstrated that vitamins K and E had good synergistic activity with piperacillin/tazobactam, imipenem and doripenem against A. baumannii, whilst vitamins B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further shown to have better synergism with oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K showed good synergism against Gram negative A. baumannii, whilst the water-soluble vitamins B1, B2 and B12 were effective against MRSA but not against A. baumannii. CONCLUSIONS: This synergistic action of vitamins with antibiotics may be used as a tool to treat MDR superbugs, with further evaluation required at a molecular level. PMID- 29408384 TI - Single-tube biosynthesis and extraction of U-13C and U-14C arachidonic acid from microcultures of Mortierella alpina for in vivo pharmacology and metabolic tracing studies. AB - Heavy and radioisotope labeling are commonly used methods to trace the pharmacological activity and metabolic fate of a biochemical or pharmaceutical in vivo. Recent years witnessed increased demand for molecules uniformly labeled with heavy carbon-13 (U-13C) or radioactive carbon-14 (U-14C) isotopes over singly labeled isotopic versions. Polyunsaturated fatty acids (PUFAs) represent one classic example where uniform 13C or 14C isotopic enrichment of the hydrocarbon backbone has numerous technical, metabolic and pharmacological advantages. PUFAs are usually produced in fungi or algae and uniform 13C or 14C enrichment of the hydrocarbon chain is achieved by feeding the microorganism a suitable U-13C or U-14C substrate. Previous literature methods describing the biosynthesis of U-13C or U-14C fatty acids reported variable isotopic enrichments that were less than anticipated and suffered from inconsistent growth of the microorganism due to radiotoxicity. In the present study, a single-tube method is described for the biosynthesis and extraction of U-13C and U-14C arachidonic acid (AA), a standard PUFA, from microcultures of the soil fungus Mortierella alpina. To produce U-13C-AA, a suspension of fungal spores and mycelial fragments was directly inoculated and grown into submerged cultures in a medium composed of U 13C-glucose and NaNO3 as the respective and only sources of carbon and nitrogen. The total 13C enrichment of AA was in excess of 95% and the percentage of U-13C AA was in the range of 60-70%. These values have not been surpassed by previously reported methods. To produce U-14C-AA, the procedure was modified to limit the radiotoxic effects of 14C on fungal growth. Submerged cultures were initially grown on common 12C-glucose. Then, following glucose depletion, the biomass was collected and immediately cultured on U-14C-glucose. This approach is unprecedented in reported literature and has significantly limited the radiotoxic effects of 14C on the microorganism. Biomass transfer from 12C to 14C substrates was timed to keep an uninterrupted supply of carbon required to sustain the microorganism in the fatty acid synthesis mode and suppress beta-oxidation, a metabolic status that is prerequisite for enhanced isotopic purity of the 14C product. The specific activity of 14C enriched AA was estimated at 864 Ci/mol (range of 708-1020 Ci/mol) suggesting 69.2% (range of 56.7-81.7%) 14C enrichment along the AA hydrocarbon backbone. The present method used a single tube for microbial culture and lipid extraction to minimize manipulative losses and oxidative degradation of the labeled products. Production cost is comparatively cheaper to custom labeling and yields of U-13C and U-14C-AA are comparable to literature methods and sufficient for small scale in vitro and in vivo pharmacological studies. PMID- 29408385 TI - Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma. AB - Asthma is a common inflammatory airway disease for which the most commonly used controller medications are inhaled corticosteroids (ICS). Asthma control is difficult to achieve in individuals with severe asthma, which comprise 5% to 10% of individuals with asthma, even with high doses of ICS and other anti inflammatory drugs. In this clinical context, the adverse effects of ICS (including hypothalamic-pituitary-adrenal axis suppression, reduction in growth velocity, osteoporosis, diabetes, and respiratory infections) become more probable and impacting on the quality of life of severe asthmatics. We here summarize the evidence of ICS-related adverse effects, particularly in patients with asthma. The possibility of using biologic agents earlier for severe asthma has the potential to prevent or reduce the occurrence of corticosteroid-related adverse effects, and also reduce corticosteroid-related costs. PMID- 29408386 TI - Tiotropium Attenuates Refractory Cough and Capsaicin Cough Reflex Sensitivity in Patients with Asthma. AB - BACKGROUND: Asthmatic cough is often refractory to standard treatments such as inhaled corticosteroids (ICS) and long-acting beta2 agonists (LABA). Tiotropium may modulate cough reflex sensitivity of acute viral cough, but its efficacy in asthmatic cough remains unknown. OBJECTIVE: To evaluate whether tiotropium improves cough and cough reflex sensitivity in patients with asthma refractory to ICS/LABA. METHODS: Seventeen consecutive patients with asthma with chronic cough despite the use of ICS/LABA (13 women; 43.4 +/- 19.0 years; average ICS dose, 651 +/- 189 MUg/d; fluticasone equivalent) were additionally treated with tiotropium (5 MUg/d) for 4 to 8 weeks to examine its effects on pulmonary function and capsaicin cough reflex sensitivity (cough thresholds C2 and C5). Cough severity, cough-specific quality of life, and asthma control were also evaluated using cough visual analog scales (VASs), the Japanese version of Leicester Cough Questionnaire (J-LCQ), and Asthma Control Test (ACT), respectively. Patients with an improved cough VAS score of 15 mm or more were considered responders to tiotropium. RESULTS: Tiotropium significantly improved cough VAS, J-LCQ, and ACT scores, but not FEV1. Changes in cough VAS score correlated with those in C2 (r = -0.58; P = .03), C5 (r = -0.58; P = .03), and ACT scores (r = -0.62; P = .02), but not in FEV1 in the overall patients. When analyses were confined to the 11 responders, tiotropium significantly improved capsaicin cough reflex sensitivity within the subgroup (C2: P = .01 and C5: P = .02) and versus the nonresponders (C2: P = .004 and C5: P = .02). CONCLUSION: Tiotropium may alleviate asthmatic cough refractory to ICS/LABA by modulating cough reflex sensitivity but not through bronchodilation. PMID- 29408387 TI - Lateralized asymmetries in distribution of muscular evoked responses: An evidence of specialized motor control over an intrinsic hand muscle. AB - Lateralized neural control over hand muscles has been associated with anatomical and physiological asymmetries in the central nervous system. Some studies suggested that the dominant cerebral hemisphere exhibit larger cortical representation areas with lower excitability, while others reported higher cortical excitability in dominant side compared to the contralateral, or even could not find any differences. Thus, neurophysiological lateral asymmetries are still controversial. This study aimed to evaluate differences in dominant and non dominant sides in motor evoked potentials (MEPs) distribution and investigate whether conventional montages and high-density surface electromyography (HD-sEMG) provide reliable measurements of corticospinal excitability. MEPs elicited by transcranial magnetic stimulation (TMS) were recorded from dominant and non dominant sides of healthy right-handed participants with an electrode grid over the abductor pollicis brevis muscle. MEPs amplitude distribution, amplitude, latency and resting motor threshold (MT) were evaluated. MEPs distribution significantly shifted towards the lateral direction on the dominant side. MT, amplitude, and latency did not reveal any asymmetries in functional cortical excitability. MEPs amplitude and latency were different for conventional montages and HD-sEMG. Our results suggest that laterality asymmetries manifest in both levels of cortical representation and muscle recruitment, possibly leading to a more pronounced abduction movement on dominant hemisphere compared to the non dominant side in right-handers. Furthermore, the use of HD-sEMG provided additional insights over conventional electrode montages. A better understanding of laterality asymmetries in fine motor control may help to establish specialized treatments in sensory motor disorders patients. PMID- 29408388 TI - Multiple "Concentric Circles Density" Lesions in the Abdomen. PMID- 29408389 TI - Hospital ownership: a risk factor for nosocomial infection rates? AB - BACKGROUND: In some countries, a relationship between hospital ownership and the occurrence of healthcare-associated infection (HCAI) rates has been described. AIM: To investigate the association between hospital ownership and occurrence of HCAI in Germany. METHODS: Five different components of the German national nosocomial infection surveillance system were analysed with regard to the influence of hospital ownership in the period 2014-2016. Endpoints included ventilator-associated pneumonia, central-venous-catheter-associated bloodstream infections, urinary-catheter-associated urinary tract infections, surgical site infections (SSI) following hip prosthesis and colon surgery, meticillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile infections (CDI) and hand rub consumption per 1000 patient-days. Three hospital ownership types (public, non profit and private) were analysed using univariate and multi-variate methods. FINDINGS: The distribution of hospitals according to the three ownership types was similar in all components. In total, 661 intensive care units (ICUs), 149 departments performing colon procedures, and 349 departments performing hip prosthesis were included. In addition, 568 hospitals provided their MRSA rates and 236 provided their CDI rates, and 1833 ICUs and 12,934 non-ICUs provided their hand rub consumption data. In general, the differences between the hospital types were rather small and not significant for the ICUs. In the multi-variate analysis, public hospitals had a lower SSI rate following hip prosthesis (odds ratio 0.80, 95% confidence interval 0.65-0.99). CONCLUSION: Hospital ownership was not found to have a major influence on the incidence of HCAI in Germany. PMID- 29408390 TI - Metallic Ureteric Stents in Malignant Ureteric Obstruction: A Systematic Review. AB - The effectiveness of metallic stents in the management of malignant ureteric obstruction is unclear. This systematic review evaluates the use of 4 commercially available metallic stents (Resonance, Memokath 051, Uventa, and Allium URS). Twenty-one studies met eligibility criteria. Overall success rates ranged from 88% for the Allium stent to 65% for Memokath 051. Resonance demonstrated the lowest migration rate (1%). Uventa had the lowest obstruction rate (6%). Metallic ureteric stents offer a viable alternative in the management of malignant ureteric obstruction. Further high quality studies are required to assess cost effectiveness and refine specific indications based on etiology and level of the ureteric obstruction. PMID- 29408391 TI - Single-injection ex ovo transplantation method for broad spinal cord engraftment of human pluripotent stem cell-derived motor neurons. AB - BACKGROUND: Transplantation of human pluripotent stem cell (hPSC)-derived neurons into chick embryos is an established preliminary assay to evaluate engraftment potential. Yet, with recent advances in deriving diverse human neuronal subtypes, optimizing and standardizing such transplantation methodology for specific subtypes at their correlated anatomical sites is still required. NEW METHOD: We determined the optimal stage of hPSC-derived motor neuron (hMN) differentiation for ex ovo transplantation, and developed a single injection protocol that implants hMNs throughout the spinal cord enabling broad regional engraftment possibilities. RESULTS: A single injection into the neural tube lumen yielded a 100% chick embryo survival and successful transplantation rate with MN engraftment observed from the rostral cervical through caudal lumbar spinal cord. Transplantation of HB9+/ChAT- hMN precursors yielded the greatest amount of engraftment compared to Pax6+/Nkx6.1+/Olig2+ progenitors or mature HB9+/ChAT+ hMNs. COMPARISON WITH EXISTING METHOD(S): Our single injection hMN transplant method is the first to standardize the optimal hMN phenotype for chick embryo transplantation, provide a rubric for engraftment quantification, and enable broad engraftment throughout the spinal cord with a single surgical intervention. CONCLUSION: Transplantation of HB9+/ChAT- hMN precursors into chick embryos of Hamburger Hamilton (HH) stages 15-18 using a single luminal injection confers a high probability of embryo survival and cell engraftment in diverse regions throughout the spinal cord. PMID- 29408392 TI - Insights on the distribution of substitutions in spruce galactoglucomannan and its derivatives using integrated chemo-enzymatic deconstruction, chromatography and mass spectrometry. AB - Accurate determination of the distribution of substitutions in the primary molecular structure of heteropolysaccharides and their derivatives is a prerequisite for their increasing application in the pharmaceutical and biomedical fields, which is unfortunately hindered due to the lack of effective analytical techniques. Acetylated galactoglucomannan (GGM) is an abundant plant polysaccharide as the main hemicellulose in softwoods, and therefore constitutes an important renewable resource from lignocellulosic biomass for the development of bioactive and functional materials. Here we present a methodology for profiling the intramolecular structure of spruce GGM and its chemical derivatives (cationic, anionic, and benzoylated) by combining chemo-enzymatic hydrolysis, liquid chromatography, and mass spectrometry. Fast identification and qualitative mass profiling of GGM and its derivatives was conducted using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS) and electrospray ionization mass spectrometry (ESI-MS). Tandem mass fragmentation analysis and its hyphenation with hydrophilic interaction liquid chromatography (HILIC-ESI-MS/MS) provide further insights on the substitution placement of the GGM oligosaccharides and its derivatives. This method will be useful in understanding the structure-function relationships of native GGM and their derivatives, and therefore facilitate their potential application. PMID- 29408393 TI - Preparation of nitrogen-doped carbon using graphene Quantum dots-chitosan as the precursor and its supercapacitive behaviors. AB - Nitrogen-doped carbon (N-C) is pyrolytically prepared by using the nanocomposites of graphene Quantum dots (GQDs) and chitosan (CS) as the precursor. Due to the existence of GQDs nanofiller, the three-dimensional (3D) interconnected frameworks of CS are well preserved after the pyrolysis treatment; meanwhile, CS in the nanocomposites functions as nitrogen source for the N-C. The obtained N-C exhibits a considerable specific capacitance (545Fg-1 at 1Ag-1), high rate capability and excellent cyclic stability (88.9% capacitance retention after 5000cycles at 10Ag-1) when it is used as the electrode materials in supercapacitors. The well-preserved 3D frameworks and N-doping are believed to be responsible for the excellent supercapacitive behaviors of the N-C. PMID- 29408394 TI - Production and optimization of polyhydroxyalkanoates from non-edible Calophyllum inophyllum oil using Cupriavidus necator. AB - Polyhydroxyalkanoates (PHA) are biodegradable polymers found in the cellular masses of a wide range of bacterial species and the demand for PHA is steadily growing. In this work we have produced PHA from a low-cost substrate, Calophyllum inophyllum oil, using Cupriavidus necator. Effects of various process parameters such as Oil concentration, Nitrogen source and inoculum size on the production of PHA were studied using Response Surface Methodology. A quadratic equation was used in the model to fit the experimental data. It was found that the model could satisfactorily predict the PHA yield (R2=99.17%). Linear, quadratic and interaction terms used in the model were found to be statistically significant. Maximum PHA yield of 10.6gL-1 was obtained under the optimized conditions of oil concentration - 17.5%, inoculum concentration - 50mL/L and nitrogen content - 1.125gL-1, respectively. The product obtained was characterized using FTIR and NMR to confirm that it was PHA. The results demonstrate that C. inophyllum oil, a non-edible oil, can be potentially used as a low-cost substrate for the production of PHA. PMID- 29408395 TI - The beneficial role of exercise in mitigating doxorubicin-induced Mitochondrionopathy. AB - Doxorubicin (DOX) is a widely used antineoplastic agent for a wide range of cancers, including hematological malignancies, soft tissue sarcomas and solid tumors. However, DOX exhibits a dose-related toxicity that results in life threatening cardiomyopathy. In addition to the heart, there is evidence that DOX toxicity extends to other organs. This general toxicity seems to be related to mitochondrial network structural, molecular and functional impairments. Several countermeasures for these negative effects have been proposed, being physical exercise, not only one of the most effective non-pharmacologic strategy but also widely recommended as booster against cancer-related fatigue. It is widely accepted that mitochondria are critical sensors of tissue functionality, both modulated by DOX and exercise. Therefore, this review focuses on the current understanding of the mitochondrial-mediated mechanisms underlying the protective effect of exercise against DOX-induced toxicity, not only limited to the cardiac tissue, but also in other tissues such as skeletal muscle, liver and brain. We here analyze recent developments regarding the beneficial effects of exercise targeting mitochondrial responsive phenotypes against redox changes, mitochondrial bioenergetics, apoptotic, dynamics and quality control signalling affected by DOX treatment. PMID- 29408396 TI - Functional characterization of calcium-dependent protein kinase (CPK) 2 gene from oilseed rape (Brassica napus L.) in regulating reactive oxygen species signaling and cell death control. AB - Calcium-dependent protein kinases (CPKs), being Ser/Thr protein kinases found only in plants and some protozoans are calcium sensors that regulate diverse biological processes. However, the function and mode of CPKs in oilseed rape (Brassica napus) remain elusive. In this study, we identified CPK2 from oilseed rape as a novel regulator of reactive oxygen species (ROS) and cell death. BnaCPK2 was identified to be located at the endoplasmic reticulum membrane. Expression of BnaCPK2 was induced during Bax-induced cell death. Overexpression of the constitutively active form of BnaCPK2 led to significantly more accumulation of ROS and cell death than the full-length CPK2, which is supported by various measurements of physiological data. In addition, a quantitative RT-PCR survey revealed that the expression levels of a few marker genes are significantly changed as a result of CPK2 expression. Mating-based split ubiquitin system (mbSUS) and bimolecular fluorescence complementation (BiFC) were used to screen and confirm the BnaCPK2 interacting proteins. We identified and confirmed that CPK2 interacted with NADPH oxidase-like respiratory burst oxidase homolog D (RbohD), but not with RbohF. Based on its function and interacting partners, we propose that BnaCPK2 plays an important role in ROS and cell death control through interacting with RbohD. PMID- 29408397 TI - The cognitive neuroscience of person identification. AB - We compare and contrast five differences between person identification by voice and face. 1. There is little or no cost when a familiar face is to be recognized from an unrestricted set of possible faces, even at Rapid Serial Visual Presentation (RSVP) rates, but the accuracy of familiar voice recognition declines precipitously when the set of possible speakers is increased from one to a mere handful. 2. Whereas deficits in face recognition are typically perceptual in origin, those with normal perception of voices can manifest severe deficits in their identification. 3. Congenital prosopagnosics (CPros) and congenital phonagnosics (CPhon) are generally unable to imagine familiar faces and voices, respectively. Only in CPros, however, is this deficit a manifestation of a general inability to form visual images of any kind. CPhons report no deficit in imaging non-voice sounds. 4. The prevalence of CPhons of 3.2% is somewhat higher than the reported prevalence of approximately 2.0% for CPros in the population. There is evidence that CPhon represents a distinct condition statistically and not just normal variation. 5. Face and voice recognition proficiency are uncorrelated rather than reflecting limitations of a general capacity for person individuation. PMID- 29408398 TI - Selection by reinforcement: A critical reappraisal. AB - This essay is a critical reappraisal of the idea of ontogenetic selection by reinforcement, according to which learning, specifically conditioning, in the individual animal is deeply analogous to phylogenetic evolution by natural selection. I focus on two general versions of this idea. The traditional Skinnerian version restricts the idea to operant conditioning and excludes Pavlovian conditioning, based on a sharp dichotomy between the two types of conditioning. The other version extends the idea to Pavlovian conditioning, based on a unified principle of reinforcement that applies to both types of conditioning, and linked to a neural-network model. I criticize both versions on the same grounds, for being: 1) unable to capture Pavlovian conditioning; 2) unnecessary to formulate said model and use it for explanation and prediction (its combination with a genetic algorithm allows for a substantive contact with the theory of evolution by selection, without the idea of selection by reinforcement), and 3) metaphysically unsound. Non-selectionist accounts of conditioning are not only possible but also more intelligible, explanatory, and heuristic. PMID- 29408399 TI - Molecular characterization of a tissue factor gene from ayu: A pro-inflammatory mediator via regulating monocytes/macrophages. AB - Tissue factor (TF) plays an important role in the host's immune system as the principal initiator of coagulation. However, the precise function of TF in teleosts remains unclear. We determined the cDNA sequence of TF from ayu Plecoglossus altivelis (PaTF). The PaTF transcript was expressed in all tested tissues, and changes in expression were observed in tissues and monocytes/macrophages (MO/MF) upon infection with Vibrio anguillarum. PaTF was prokaryotically expressed and purified to prepare anti-PaTF antibodies. Western blot analysis revealed that native PaTF was glycosylated in thrombocytes, but not in ayu MO/MF. Microparticles could transfer PaTF to thrombocytes. PaTF neutralization or knockdown led to anti-inflammatory status in ayu MO/MF upon V. anguillarum infection. PaTF neutralization reduced the apoptosis of ayu MO/MF and improve survival rate in V. anguillarum-infected ayu. Our results indicate that PaTF plays a role in ayu immune response against bacterial infection as a pro inflammatory mediator. PMID- 29408400 TI - Bariatric surgery before elective posterior lumbar fusion is associated with reduced medical complications and infection. AB - BACKGROUND CONTEXT: Severely obese patients with operative spinal pathology present a challenge to the spine surgeon, given the increased complication risk. PURPOSE: We aimed to determine the impact of bariatric surgery (BS) on perioperative complications of posterior lumbar fusion. STUDY DESIGN: This is a retrospective cohort study. PATIENT SAMPLE: Patients undergoing posterior lumbar fusion surgery in the State Inpatient Databases of New York, Florida, North Carolina, Nebraska, Utah, and California comprised the patient sample. OUTCOMES: Thirty-day medical complications, surgical complications (nerve injury, infection, revision), death, readmission, and hospital length of stay (LOS) were the study's outcomes. METHODS: We analyzed 156,517 patients using International Classification of Diseases, Ninth Revision codes. Patients were categorized into three groups: Group 1: history of BS and obesity, Group 2: severe obesity, body mass index (BMI)>40 (severely obese), and Group 3: normal weight, BMI<25 (non obese). Logistic and linear multivariate regressions were performed to compare complications and LOS, respectively, between BS and severely obese groups and BS and non-obese groups while controlling for confounders. There were no sources of funding for this study. RESULTS: There were 590 patients with BS, 5,791 severely obese, and 150,136 non-obese. Comparing BS with severely obese, BS had significantly lower rates of respiratory failure (odds ratio [OR] 0.59, p=.019), urinary tract infection (OR 0.64, p=.031), acute renal failure (OR 0.39, p=.007), overall medical complications (OR 0.59, p<.001), and infection (OR 0.65, p=.025). Bariatric surgery also had significantly lower hospital LOS (B=-0.46, p=.01). Comparing BS with non-obese, there were no significant differences in medical complications; however, BS had significantly higher rates of infection (OR 2.70, p<.001), reoperation (OR 2.05, p=.045), and readmission (OR 1.89, p<.001). CONCLUSION: Bariatric surgery before elective posterior lumbar fusion mitigates risk of medical complications and infection. However, these patients still have increased risk of infection, revision surgery, and readmission compared with patients with normal BMI. Surgeons might consider referral for BS for the severely obese patient before undergoing spine surgery. PMID- 29408401 TI - Modeling of FMISO [F18] nanoparticle PET tracer in normal-cancerous tissue based on real clinical image. AB - Hypoxia as one of the principal properties of tumor cells is a reaction to the deprivation of oxygen. The location of tumor cells could be identified by assessment of oxygen and nutrient level in human body. Positron emission tomography (PET) is a well-known non-invasive method that is able to measure hypoxia based on the FMISO (Fluoromisonidazole) tracer dynamic. This paper aims to study the PET tracer concentration through convection-diffusion-reaction equations in a real human capillary-like network. A non-uniform oxygen pressure along the capillary path and convection mechanism for FMISO transport are taken into account to accurately model the characteristics of the tracer. To this end, a multi-scale model consists of laminar blood flow through the capillary network, interstitial pressure, oxygen pressure, FMISO diffusion and FMISO convection transport in the extravascular region is developed. The present model considers both normal and tumor tissue regions in computational domain. The accuracy of numerical model is verified with the experimental results available in the literature. The convection and diffusion types of transport mechanism are employed in order to calculate the concentration of FMISO in the normal and tumor sub-domain. The influences of intravascular oxygen pressure, FMISO transport mechanisms, capillary density and different types of tissue on the FMISO concentration have been investigated. According to result (Table 4) the convection mechanism of FMISO molecules transportation is negligible, but it causes more accuracy of the proposed model. The approach of present study can be employed in order to investigate the effects of various parameters, such as tumor shape, on the dynamic behavior of different PET tracers, such as FDG, can be extended to different case study problems, such as drug delivery. PMID- 29408402 TI - Part-of-the-sites binding and reactivity in the homooligomeric enzymes - facts and artifacts. AB - For a number of enzymes composed of several subunits with the same amino acid sequence, it was documented, or suggested, that binding of a ligand, or catalysis, is carried out by a single subunit. This phenomenon may be the result of a pre-existent asymmetry of subunits or a limiting case of the negative cooperativity, and is sometimes called "half-of-the-sites binding (or reactivity)" for dimers and could be called "part-of-the-sites binding (or reactivity)" for higher oligomers. In this article, we discuss molecular mechanisms that may result in "part-of-the-sites binding (and reactivity)", offer possible explanations why it may have a beneficial role in enzyme function, and point to experimental problems in documenting this behaviour. We describe some cases, for which such a mechanism was first reported and later disproved. We also give several examples of enzymes, for which this mechanism seems to be well documented, and profitable. A majority of enzymes identified in this study as half-of-the-sites binding (or reactive) use it in the flip-flop version, in which "half-of-the-sites" refers to a particular moment in time. In general, the various variants of the mechanism seems to be employed often by oligomeric enzymes for allosteric regulation to enhance the efficiency of enzymatic reactions in many key metabolic pathways. PMID- 29408403 TI - Predicting patient exposure to nickel released from cardiovascular devices using multi-scale modeling. AB - : Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model. The model links nickel release from an implanted cardiovascular device to concentrations in peri-implant tissue, as well as in serum and urine, which can be readily monitored. The model was parameterized for a specific cardiovascular implant, nitinol septal occluders, using in-vitro nickel release test results, studies of ex-vivo uptake into heart tissue, and in vivo and clinical measurements from the literature. Our results show that the model accurately predicts nickel concentrations in peri-implant tissue in an animal model and in serum and urine of septal occluder patients. The congruity of the model with these data suggests it may provide useful insight to establish nickel exposure limits and interpret biomonitoring data. Finally, we use the model to predict local and systemic nickel exposure due to passive release from nitinol devices produced using a wide range of manufacturing processes, as well as general relationships between release rate and exposure. These relationships suggest that peri-implant tissue and serum levels of nickel will remain below 5 MUg/g and 10 MUg/l, respectively, in patients who have received implanted nitinol cardiovascular devices provided the rate of nickel release per device surface area does not exceed 0.074 MUg/(cm2 d) and is less than 32 MUg/d in total. STATEMENT OF SIGNIFICANCE: The uncertainty in whether in-vitro tests used to evaluate metal ion release from medical products are representative of clinical environments is one of the largest roadblocks to establishing the associated patient risk. We have developed and validated a multi-scale biokinetic model linking nickel release from cardiovascular devices in-vivo to both peri-implant and systemic levels. By providing clinically relevant exposure estimates, the model vastly improves the evaluation of risk posed to patients by the nickel contained within these devices. Our model is the first to address the potential for local and systemic metal ion exposure due to a medical device and can serve as a basis for future efforts aimed at other metal ions and biomedical products. PMID- 29408404 TI - Initial Experience With a New Mitral Ring Designed to Simplify Length Determination of Neochords. AB - BACKGROUND: Artificial chord implantation has become one of the most applied techniques for mitral valve repair (MVR). Many techniques have been described, with the goal of optimizing neochord implantation. A new annuloplasty device designed to simplify the determination of the appropriate neochord length has been recently introduced. We describe our initial experience with this new device. METHODS: The semirigid device is equipped with removable loops on the posterior aspect of the ring. Neochords are tied to the loops, which are subsequently removed. The device was implanted in 47 symptomatic patients from January 2015 to August 2016 through a median sternotomy in 33 patients (70.2%) and a right anterolateral minithoracotomy in 14 (29.8%). The cause of mitral valve insufficiency was degenerative in all patients, and most patients presented with isolated prolapse of the posterior leaflet. Before and after cardiopulmonary bypass, all patients underwent evaluation with transesophageal echocardiography, and transthoracic echocardiography was performed at discharge. RESULTS: A median of 2 neochords were implanted (minimum, 1; maximum, 6). Mean cardiopulmonary bypass time and aortic cross-clamp times were 141.7 +/- 32.3 and 104.8 +/- 28.5 minutes for combined and 133 +/- 53.9 and 98.3 +/- 41.6 minutes for isolated MVR. At discharge, echocardiography revealed no or only mild mitral insufficiency in 45 patients (mean gradient, 2.9 +/- 1.3 mm Hg). CONCLUSIONS: This new annuloplasty ring facilitated determination of appropriate neochord length and was used to successfully treat different degenerative pathologies affecting both leaflets. This new device simplified length determination of the neochords. PMID- 29408405 TI - CpMCA, a novel metacaspase gene from the harmful dinoflagellate Cochlodinium polykrikoides and its expression during cell death. AB - Metacaspases (MCAs) are cysteine proteases that share sequence homology with caspases, and may play roles in programmed cell death (PCD). In the present study, we identified a novel MCA gene (CpMCA) from the red tide dinoflagellate Cochlodinium polykrikoides, and examined its molecular characteristics and gene expression in response to algicide-induced cell death. CpMCA cDNA is 1164 bp in length, containing a dinoflagellate spliced leader sequence (dinoSL), an 879-bp open reading frame (ORF), which codes for a 293-aa protein, and a poly (A) tail. Multi-sequence comparison indicated that CpMCA belongs to type I MCA, but it has a different structure at the N-terminal. Phylogenetic analysis showed that C. polykrikoides may have acquired the MCA gene from bacteria by means of horizontal gene transfer (HGT). In addition, expressions of CpMCA significantly increased following exposure to the common algicides copper sulfate and oxidizing chlorine, which trigger cell death in dinoflagellates, suggesting that CpMCA may be involved in cell death. PMID- 29408406 TI - DNA barcoding for identifying synanthropic flesh flies (Diptera, Sarcophagidae) of Colombia. AB - The first step for a successful use of any insect as indicator in forensic sciences is providing a precise taxonomic identification at species level. Due to morphology-based identification of Sarcophaginae flies (Diptera, Sarcophagidae) is often difficult and requires strong taxonomic expertise, their use as forensic indicators has been limited. Consequently, molecular-based approaches have been accepted as alternative means of identification. Thus, we aimed testing the efficiency of the barcode region of the mitochondrial cytochrome oxidase subunit I (COI) gene for identification of synanthropic flesh flies of several species of the genera Peckia, Oxysarcodexia, Ravinia, and Tricharaea collected in Colombia. The 645-bp fragment of COI was amplified and aligned (215 parsimoniously informative variable sites). We calculated Kimura two-parameter genetic distances and reconstruct a Neighbor-Joining phylogenetic tree. Our Neighbor-Joining tree recovered all species as monophyletic, and confirmed a new species of the genus Ravinia as also indicated by the interspecific genetic divergences and morphological observations. We obtained a 100% of identification success. Thus, the COI barcodes showed efficiency as an alternative mean of identification of species of flesh flies collected on decaying organic matter in Colombia. PMID- 29408407 TI - Antimicrobial susceptibility survey on bacterial agents of canine and feline urinary tract infections: Weight of the empirical treatment. AB - OBJECTIVES: This work characterised the antimicrobial susceptibility of uropathogens isolated from empirically treated dogs and cats. Within-household transmission of uropathogens can involve humans and companion animals. Knowledge on the prevalence and susceptibility pattern of isolates from canine and feline urine samples and the impact of prior antimicrobial treatment is important to prevent the dissemination of antimicrobial resistance. METHODS: A retrospective study was conducted selecting antibiotic-treated companion animals. Urine samples were collected by cystocentesis and were submitted to an Italian diagnostic laboratory over a 2-year period (2013-2015). The antimicrobial susceptibility of the isolates was analysed both using Clinical and Laboratory Standards Institute (CLSI) guidelines and a formula to help select rational antimicrobial therapy. RESULTS: Gram-negative bacteria were clearly prevalent. Gentamicin had the highest impact factors. Amoxicillin/clavulanic acid and doxycycline appeared to be the most effective compounds against Gram-positive infections, whilst marbofloxacin may be a useful option against Gram-negative urinary tract infections (UTIs) as well as doxycycline and trimethoprim/sulfamethoxazole in cats and dogs, respectively. Consulting published studies, a comparable overall trend regarding bacterial species incriminated in canine and feline UTIs and their susceptibilities seems likely, despite different circumstances where the studies were conducted. CONCLUSIONS: Companion animals are potential reservoirs of drug-resistant uropathogens. Judicious use of antibiotics is necessary to maintain the efficacy of antimicrobials in human and veterinary medicine. Antimicrobial susceptibility monitoring programmes are therefore essential to facilitate the choice of antimicrobial agent that is most likely to be effective, particularly in cases of prior antimicrobial treatment. PMID- 29408409 TI - Characterization of a hybrid protein designed with segments of allergens from Blomia tropicalis and Dermatophagoides pteronyssinus. AB - BACKGROUND: Sensitization to allergens of the house dust mites Dermatophagoides pteronyssinnus and Blomia tropicalis is an important risk factor for asthma and allergic diseases. Allergen-specific immunotherapy is currently based on natural allergen extracts, however, in the last years recombinant allergens with different modifications have shown promising immunological properties that may be advantageously applied for developing novel allergy vaccines. METHODS: A hybrid molecule (MAVAC-BD-2) containing epitopes of B. tropicalis (Blo t 5, Blo t 8 and Blo t 10) and D. pteronyssinus (Der p 1, Der p 2, Der p 7 and Der p 8) allergens was constructed, expressed in Escherichia coli and purified by affinity chromatography. Its folding was analyzed by circular dichroism. Antibody reactivities were evaluated by ELISA and non-denaturing dot blot assays using a battery of sera from mite allergic patients and non-allergic subjects. ELISA inhibition and dot blot assays with monoclonal antibodies were used to detect B cell epitopes. Human basophil activation and induction of IgG-blocking antibodies in mice immunized with the hybrid protein were also evaluated. RESULTS: MAVAC-BD 2, expressed as a 22.8 kDa protein, showed a lower frequency and strength of IgE reactivity compared to Blo t 5, Der p 1, Der p 2 and the extracts of B. tropicalis and D. pteronyssinus. MAVAC-BD-2 inhibited 26% of IgE reactivity to Der p 2 and Blo t 5, reacted with anti-Der p 1 and anti-Der p 2 monoclonal antibodies and did not induce relevant basophil activation. MAVAC-BD-2 immunized mice produced specific antibodies that reacted against mite extracts and the purified allergens, as well as IgG antibodies that blocked the human IgE reactivity to mite extracts. CONCLUSION: MAVAC-BD-2 has hypoallergenic characteristics and in mice induces IgG antibodies that block the human IgE reactivity to mite extracts. PMID- 29408408 TI - Combination of CDNF and Deep Brain Stimulation Decreases Neurological Deficits in Late-stage Model Parkinson's Disease. AB - Several neurotrophic factors (NTF) are shown to be neuroprotective and neurorestorative in pre-clinical animal models for Parkinson's disease (PD), particularly in models where striatal dopamine neuron innervation partially exists. The results of clinical trials on late-stage patients have been modest. Subthalamic deep brain stimulation (STN DBS) is a proven treatment for a selected group of advanced PD patients. The cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic protein, but its effects in animal models of late stage PD have remained under-researched. The interactions of NTF and STN DBS treatments have not been studied before. We found that a nigral CDNF protein alone had only a marginal effect on the behavioral deficits in a late-stage hemiparkinsonian rat model (6-OHDA MFB). However, CDNF improved the effect of acute STN DBS on front limb use asymmetry at 2 and 3 weeks after CDNF injection. STN lesion-modeling chronic stimulation-had an additive effect in reducing front limb use in the cylinder test and apomorphine-induced rotation. The combination of CDNF and acute STN DBS had a favorable effect on striatal tyrosine hydroxylase. This study presents a novel additive beneficial effect of NTF and STN DBS, which might be explained by the interaction of DBS-induced endogenous NTFs and exogenously injected CDNF. SNpc can be reached via similar trajectories used in clinical STN DBS, and this interaction is an important area for future studies. PMID- 29408410 TI - The role of mTOR-mediated signaling in the regulation of cellular migration. AB - Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration. Recent attention has focused on the aberrant activation of the PI3K/mTOR pathway in B cell malignancies and there is growing evidence for its involvement in disease pathogenesis, due to its location downstream of other established novel drug targets that intercept B cell receptor (BCR) signals. Shared pharmacological features of BCR signal inhibitors include a striking "lymphocyte redistribution" effect whereby patients experience a sharp increase in lymphocyte count on initiation of therapy followed by a steady decline. Chronic lymphocytic leukemia (CLL) serves as a paradigm for migration studies as lymphocytes are among the most widely travelled cells in the body, a product of their role in immunological surveillance. The subversion of normal lymphocyte movement in CLL is being elucidated; this review aims to describe the migration impairment which occurs as part of the wider context of cancer cell migration defects, with a focus on the role of mTOR in mediating migration effects downstream of BCR ligation and other microenvironmental signals. PMID- 29408411 TI - Teriparatide (human PTH1-34) compensates for impaired fracture healing in COX-2 deficient mice. AB - Genetic ablation of cyclooxygenase-2 (COX-2) in mice is known to impair fracture healing. To determine if teriparatide (human PTH1-34) can promote healing of Cox 2-deficient fractures, we performed detailed in vivo analyses using a murine stabilized tibia fracture model. Periosteal progenitor cell proliferation as well as bony callus formation was markedly reduced in Cox-2-/- mice at day 10 post fracture. Remarkably, intermittent PTH1-34 administration increased proliferation of periosteal progenitor cells, restored callus formation on day 7, and enhanced bone formation on days 10, 14 and 21 in Cox-2-deficient mice. PTH1-34 also increased biomechanical torsional properties at days 10 or 14 in all genotypes, consistent with enhanced bony callus formation by radiologic examinations. To determine the effects of intermittent PTH1-34 for callus remodeling, TRAP staining was performed. Intermittent PTH1-34 treatment increased the number of TRAP positive cells per total callus area on day 21 in Cox-2-/- fractures. Taken together, the present findings indicate that intermittent PTH1-34 treatment could compensate for COX-2 deficiency and improve impaired fracture healing in Cox-2 deficient mice. PMID- 29408413 TI - Regulation of fibrosis in muscular dystrophy. AB - The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies. PMID- 29408412 TI - Chimeric protein identification of dystrophic, Pierson and other laminin polymerization residues. AB - Laminin polymerization is a key step of basement membrane self-assembly that depends on the binding of the three different N-terminal globular LN domains. Several mutations in the LN domains cause LAMA2-deficient muscular dystrophy and LAMB2-deficient Pierson syndrome. These mutations may affect polymerization. A novel approach to identify the amino acid residues required for polymerization has been applied to an analysis of these and other laminin LN mutations. The approach utilizes laminin-nidogen chimeric fusion proteins that bind to recombinant non-polymerizing laminins to provide a missing functional LN domain. Single amino acid substitutions introduced into these chimeras were tested to determine if polymerization activity and the ability to assemble on cell surfaces were lost. Several laminin-deficient muscular dystrophy mutations, renal Pierson syndrome mutations, and Drosophila mutations causing defects of heart development were identified as ones causing loss of laminin polymerization. In addition, two novel residues required for polymerization were identified in the laminin gamma1 LN domain. PMID- 29408414 TI - The doublesex gene integrates multi-locus complementary sex determination signals in the Japanese ant, Vollenhovia emeryi. AB - A female diploid, male haploid sex determination system (haplodiploidy) is found in hymenopteran taxa, such as ants, wasps, bees and sawflies. In this system, a single, complementary sex-determination (sl-CSD) locus functions as the primary sex-determination signal. In the taxa that has evolved this system, females and males are heterozygous and hemi/homozygous at the CSD locus, respectively. While the sl-CSD system enables females to alter sex ratios in the nest, it carries a high cost in terms of inbreeding, as individuals that are homozygous at the CSD locus become sterile diploid males. To counter this risk, some of hymenopteran species have evolved a multi-locus CSD (ml-CSD) system, which effectively reduces the proportion of sterile males. However, the mechanism by which these multiple primary signals are integrated and how they affect the terminal sex differentiation signal of the molecular cascade have not yet been clarified. To resolve these questions, we examined the molecular cascade in the Japanese ant Vollenhovia emeryi, which we previously confirmed has two CSD loci. Here, we showed that the sex-determination gene, doublesex (dsx), which is highly conserved among phylogenetically distant taxa, is responsible for integrating two CSD signals in V. emeryi. After identifying and characterizing dsx, genotypes containing two CSD loci and splicing patterns of dsx were found to correspond to the sexual phenotype, suggesting that two primary signals are integrated into dsx. These findings will facilitate future molecular and functional studies of the sex determination cascade in V. emeryi, and shed light on the evolution and diversification of sex determination systems in insects. PMID- 29408415 TI - Determination of diffusion coefficient for released nanoparticles from developed gelatin/chitosan bilayered buccal films. AB - This study aims at the mathematical optimization by Box-Behnken statistical design, fabrication by ionic gelation technique and in vitro characterization of insulin nanoparticles containing thiolated N- dimethyl ethyl chitosan (DMEC-Cys) conjugate. Then Optimized insulin nanoparticles were loaded into the buccal film, and in-vitro drug release from films was investigated, and diffusion coefficient was predicted. The optimized nanoparticles were shown to have mean particle size diameter of 148nm, zeta potential of 15.5mV, PdI of 0.26 and AE of 97.56%. Cell viability after incubation with optimized nanoparticles and films were assessed using an MTT biochemical assay. In vitro release study, FTIR and cytotoxicity also indicated that nanoparticles made of this thiolated polymer are suitable candidates for oral insulin delivery. PMID- 29408416 TI - Glucofucogalactan, a heterogeneous low-sulfated polysaccharide from Saccharina japonica and its bioactivity. AB - Crude polysaccharide obtained from Saccharina japonica using acid hydrolysis and precipitation was separated into sulfated fuco-oligosaccharide (HDF1) and heteropolysaccharide (HDF2). To further explore the bioactive fraction, HDF2 was successfully separated using membrane filtration into HDF2A and HDF2B, which differed in chemical composition and molecular weight. The bioactivity of all the fractions was tested in vitro, including immunomodulatory activity in RAW 264.7 cells and the protective activity in aristolochic acid (AA)-induced NRK-52E cell injury. HDF1 and HDF2B (low-molecular weight sulfated fucans/fuco oligosaccharides) did not increase the nitric oxide production in RAW 264.7 cells, whereas HDF2 and HDF2A exhibited potential immunomodulatory activity. All the tested compounds showed different degrees of protective activity in AA induced injury; HDF2A exhibited superior protective activity. Through chemical analysis, HPLC analysis, and IR spectroscopy and MS, it was determined that HDF2A was a galactose-enriched heteropolysaccharide- glucofucogalactan with a distinctive 2:1 ratio of galactose to fucose. In addition, HDF2A also contained a high amount of glucose and minor amounts of mannose, rhamnose, and xylose, with a low content of sulfate. Thus, HDF2A, a complex heterogeneous polysaccharide mixture with a unique monosaccharide composition, could be studied for further structural characterization and pharmaceutical applications. PMID- 29408417 TI - Structural, functional, and biological properties of potato peel oligosaccharides. AB - Enzymatic hydrolysis of water-soluble polysaccharides from potato peel waste (PPPW) generates low molecular weight oligosaccharides with a yield of 63%. The oligosaccharides generated from potato peel polysaccharides (OPPP) were purified by Superdex-30 column. The results showed the presence of 8 peaks (OPPP1-OPPP8). The identification of all the fractions by chromatography analysis (GC-FID) illustrated that the most prominent residues were glucose with traces of galactose, arabinose and rhamnose. Finally, mass spectrometry (MALDI-ToF-ToF) analysis showed that the generated oligosaccharides were heterogeneous and contained different degree of polymerization (DP). Indeed, the obtained oligosaccharides fractions OPPP3, OPPP4, OPPP5, OPPP6 and OPPP7 were compose of the following degree of polymerization DP5; DP4; DP2; DP1 and DP1, respectively. Potato peel oligosaccharides (OPPP) efficiency were tested using different concentrations in functional properties. The results showed good foaming and emulsion properties. This study also aimed to investigate the antioxidant activity of OPPP. The items explored included the DPPH radical-scavenging capacity (IC50 OPPP=2.5mg/mL), reducing power (OD: 0.622+/-0.032 at a concentration of 20mg/mL), beta-carotene bleaching inhibition activity (45.335+/ 3.653%), and also the ABTS radical scavenging activity (14.835+/-0.1%).These findings indicate that potato peel oligosaccharides have potent antioxidant activities. Hence, one can suggest that these oligosaccharides might contribute as additives in food, pharmaceutical and cosmetic preparations. PMID- 29408418 TI - Long-Term Follow-Up After Baked Milk Introduction. AB - BACKGROUND: Clinical trials of baked milk (BM) introduction have demonstrated accelerated resolution of milk allergy. OBJECTIVE: Long-term data regarding real world introduction of BM are lacking. We sought to characterize our experience of BM introduction. METHODS: We performed a retrospective chart review of consecutive BM oral food challenges performed in our clinic from 2009 to 2014, with a minimum follow-up of 24 months. RESULTS: Of the 206 patients challenged, 99 (48%) passed and 187 were sent home with detailed instructions to incorporate BM into their diets. After a median of 49 months of follow-up, 43% of the 187 had progressed to direct milk, 20% to less-cooked forms of milk, 10% remained ingesting BM, and 28% were strictly avoiding milk. Higher milk IgE levels were associated with decreased odds of passing a BM challenge and advancing to less cooked forms of milk. Predictors of progressing to less-cooked forms of milk were passing the challenge and younger age. There were 79 reported milk reactions involving 68 patients (33% of total) during follow-up. Of these, 78% were classified as mild, 14% severe, and 6 patients developed eosinophilic esophagitis. Of 11 severe reactions, 4 were accidental exposures, 3 were planned escalations, and 4 occurred with previously tolerated doses. CONCLUSIONS: The majority of patients who underwent a BM challenge, including those who failed their challenge, were able to progress to direct or less-cooked forms of milk. However, adverse reactions were common, and even a successful BM challenge does not guarantee future tolerance of BM or preclude later reactions, even to previously tolerated doses. PMID- 29408419 TI - Chitosan-based nanosystems and their exploited antimicrobial activity. AB - Chitosan is a biodegradable and biocompatible natural polysaccharide that has a wide range of applications in the field of pharmaceutics, biomedical, chemical, cosmetics, textile and food industry. One of the most interesting characteristics of chitosan is its antibacterial and antifungal activity, and together with its excellent safety profile in human, it has attracted considerable attention in various research disciplines. The antimicrobial activity of chitosan is dependent on a number of factors, including its molecular weight, degree of deacetylation, degree of substitution, physical form, as well as structural properties of the cell wall of the target microorganisms. While the sole use of chitosan may not be sufficient to produce an adequate antimicrobial effect to fulfil different purposes, the incorporation of this biopolymer with other active substances such as drugs, metals and natural compounds in nanosystems is a commonly employed strategy to enhance its antimicrobial potential. In this review, we aim to provide an overview on the different approaches that exploit the antimicrobial activity of chitosan-based nanosystems and their applications, and highlight the latest advances in this field. PMID- 29408420 TI - Eco-sustainable systems based on poly(lactic acid), diatomite and coffee grounds extract for food packaging. AB - In the food packaging sector many efforts have been (and are) devoted to the development of new materials in order to reply to an urgent market demand for green and eco-sustainable products. Particularly a lot of attention is currently devoted both to the use of compostable and biobased polymers as innovative and promising alternative to the currently used petrochemical derived polymers, and to the re-use of waste materials coming from agriculture and food industry. In this work, multifunctional eco-sustainable systems, based on poly(lactic acid) (PLA) as biopolymeric matrix, diatomaceous earth as reinforcing filler and spent coffee grounds extract as oxygen scavenger, were produced for the first time, in order to provide a simultaneous improvement of mechanical and gas barrier properties. The influence of the diatomite and the spent coffee grounds extract on the microstructural, mechanical and oxygen barrier properties of the produced films was deeply investigated by means of X-Ray diffraction (XRD), infrared spectroscopy (FT-IR, ATR), scanning electron microscopy (SEM), uniaxial tensile tests, O2 permeabilimetry measurements. An improvement of both mechanical and oxygen barrier properties was recorded for systems characterised by the co presence of diatomite and coffee grounds extract, suggesting a possible synergic effect of the two additives. PMID- 29408421 TI - A rapid, objective and implicit measure of visual quantity discrimination. AB - There is evidence that accurate and rapid judgments of visual quantities form an essential component of human mathematical ability. However, explicit behavioural discrimination measures of visual quantities are readily contaminated both by variations in low-level physical parameters and higher order cognitive factors, while implicit measures often lack objectivity and sensitivity at the individual participant level. Here, with electrophysiological frequency tagging, we show discrimination differences between briefly presented visual quantities as low as a ratio of 1.4 (i.e., 14 vs. 10 elements). From this threshold, the neural discrimination response increases with parametrically increasing differences in ratio between visual quantities. Inter-individual variability in magnitude of the EEG response at this population threshold ratio predicts behavioural performance at an independent number comparison task. Overall, these findings indicate that visual quantities are perceptually discriminated automatically and rapidly (i.e., at a glance) within the occipital cortex. Given its high sensitivity, this paradigm could provide an implicit diagnostic neural marker of this process suitable for a wide range of fundamental and clinical applications. PMID- 29408422 TI - Concordance of self-reported hormonal contraceptive use and presence of exogenous hormones in serum among African women. AB - OBJECTIVES: Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV. STUDY DESIGN: We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography-mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use. RESULTS: Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had >=1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status. CONCLUSION: Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health outcomes. IMPLICATIONS: Research studies investigating associations between hormonal contraceptive use and HIV should consider validating self-reported use by objective measures; because both overreporting and underreporting of use occur, potential misclassification based on self-report could lead to biased results in directions that cannot be easily predicted. PMID- 29408423 TI - Near-infrared spectroscopy assessment of microvasculature detects difference in lower limb vascular responsiveness in obese compared to lean individuals. AB - BACKGROUND: Microvascular dysfunction is an early complication in obesity-related cardiovascular disease (CVD) that can lead to changes in hemodynamic function and endothelial cell expression throughout the vasculature that is vessel specific. This study aimed to evaluate whether the near-infrared spectroscopy (NIRS) combined with a vascular occlusion (VOT) assessment was capable of detecting differences in vascular responsiveness within the microvasculature of the lower limb between lean and obese individuals. METHODS AND RESULTS: Twenty lean (BMI = 21.6 +/- 1.3) and 17 obese individuals (BMI = 33.9 +/- 1.1) participated in the study. Individuals underwent a VOT (5 min of baseline, 5 min of occlusion, and 8 min following cuff release) and vascular responsiveness was evaluated by the Slope 2 (Slope 2 StO2) and the area under the curve (StO2AUC) of oxygen saturation (StO2) signal during reperfusion. The difference between the minimal and the maximal value of StO2 was calculated as the Amplitude of the StO2 response. The Slope 2 StO2 of the obese individuals was smaller (0.68 +/- 0.07%.s 1) than the Slope 2 StO2 of the lean individuals (1.08 +/- 0.13%.s-1;P < 0.05). The StO2AUC of the obese was smaller (978 +/- 169%.s-1) than the StO2AUC of the lean individuals (1708 +/- 168%.s-1; P < 0.001). The amplitude of StO2 was smaller in obese individuals than the lean ones (30.4 +/- 2.9 vs 21.6 +/- 1.3 StO2 (%), respectively; P < 0.05). There was a significant correlation between Slope 2 StO2 and StO2AUC for lean individuals (r = 0.745; P < 0.001). CONCLUSION: This study demonstrated differences in vascular responses within the microvasculature of the lower limb between lean and obese individuals. PMID- 29408424 TI - A photosensitive liposome with NIR light triggered doxorubicin release as a combined photodynamic-chemo therapy system. AB - The targeted drug delivery with the help of nanocarriers and the controlled drug release at the lesion sites are the most effective ways to enhance therapeutic efficacy and reduce side effects. Here, we built a light sensitive liposome (Her2 I&D-LSL) which was formed by a special phospholipid (PLsPC) and a hydrophobically modified photosensitizer (ICG-ODA). DOX was employed as the therapeutic drug, encapsulating in the internal phase of the liposome whose surface was modified by Her2 antibodies for recognizing tumor cells with high Her2 receptor expression. Mediated by NIR light, Her2-I&D-LSL was proved to generate sufficient ROS to realize PDT, which then triggered the release of DOX for combined chemotherapy. The ROS generation and DOX release were verified to be strictly controlled by NIR light and the proportion of ICG-ODA. Thanks to the mediation of Her2 receptor, the specific DOX release and the combination of PDT-chemotherapy triggered by NIR light, Her2-I&D-LSL showed a significant accumulation in MCF7 and SKOV3 tumors, thus leading to the strongest tumor growth inhibition effect compared to PDT alone (I-LSL) or chemotherapy alone (D-LSL). Her2-I&D-LSL also possessed a great biocompatibility due to the targeted treatment, holding promise for future cancer therapy in clinic. PMID- 29408425 TI - Percutaneous Transforaminal Endoscopic Discectomy for Adjacent Segment Disease After Lumbar Fusion in Elderly Patients Over 65 Years Old. AB - OBJECTIVE: To evaluate short-term efficacy and safety of percutaneous transforaminal endoscopic discectomy (PTED) in treatment of symptomatic adjacent segment disease (ASD) after lumbar fusion in elderly patients >65 years old. METHODS: Patients >65 years old who underwent PTED for ASD after lumbar fusion between January 2013 and September 2016 were retrospectively evaluated. Demographics and perioperative clinical data were collected from medical records. MacNab classification, visual analog scale, Oswestry Disability Index, and Japanese Orthopaedic Association scores as well as 36-Item Short-Form Health Survey were used to assess the efficacy of PTED. RESULTS: We evaluated 25 consecutive patients >65 years old with ASD (11 men, 14 women; mean age 74.65 +/- 9.61 years). Mean follow-up time was 37.14 +/- 11.60 months. Of patients, 84.0% (21/25) had excellent or good clinical outcomes, 12.0% (3/25) had fair outcomes, and 4.0% (1/25) had poor outcomes. Complications included 1 dural laceration, 1 postoperative dysesthesia, and 1 recurrence. For patient-reported outcomes, significant improvements were observed postoperatively compared with preoperatively in visual analog scale (P < 0.05), Oswestry Disability Index (P < 0.05), Japanese Orthopaedic Association (P < 0.05), and 36-Item Short-Form Health Survey (P < 0.05). CONCLUSIONS: PTED demonstrated satisfactory short-term efficacy and safety in management of ASD after lumbar fusion in patients >65 years old. PTED may be an alternative choice for elderly patients with ASD after lumbar fusion. PMID- 29408426 TI - Malignant Peripheral Nerve Sheath Tumor of the Trigeminal Nerve Involving the Middle and Posterior Cranial Fossa. AB - BACKGROUND: Although benign trigeminal schwannomas are uncommon, malignant peripheral nerve sheath tumors (MPNSTs) of the trigeminal nerve are extraordinarily rare. CASE DESCRIPTION: A 56-year-old female presented with a 2 month-long history of numbness of the right face and progressive weakness of the left limbs. Preoperative neuroimages indicated a giant tumor involving the middle and posterior cranial fossa with similar radiologic characteristics to benign trigeminal schwannomas. However, histopathologic and immunochemical examinations confirmed the tumor to be an MPNST. A nearly gross total resection was obtained with a combined frontotemporal extradural and subtemporal anterior petrosal approach. The postoperative course was uneventful, and the patient received adjuvant radiotherapy subsequently. There was no recurrence of the tumor with a 6 month-long follow-up. CONCLUSION: MPNSTs of the trigeminal nerve are exceedingly rare. This study described the 21st case of MPNSTs of the trigeminal nerve. MPNSTs of the trigeminal nerve showed similar radiologic characteristics to benign trigeminal schwannomas, and accurate diagnosis depended on pathologic and immunochemical examinations. Gross total resection followed by radiotherapy is the usual treatment. PMID- 29408427 TI - A Comparison of Cerebellar Retraction Pressures in Posterior Fossa Surgery: Extended Retrosigmoid Versus Traditional Retrosigmoid Approach. AB - BACKGROUND: The retrosigmoid approach is broadly applicable to many posterior fossa procedures. However, cerebellar retraction is often necessary for lesions in the cerebellopontine angle, which can lead to complications. An extended retrosigmoid approach skeletonizes the sigmoid sinus and allows a wider corridor with less retraction. This study investigated the differences in retraction pressure between the retrosigmoid and extended retrosigmoid approach in a cadaveric model. METHODS: Anatomic dissection of 2 cadaveric heads was performed for comparison of surgical approaches. Bilateral measurements were obtained on each head, providing 4 sets of data. Retrosigmoid craniotomy was first performed with recording of retraction pressure necessary for 1.5-cm exposure. The exposure was then expanded to an extended retrosigmoid approach, and retraction pressures were recorded. RESULTS: Mean retraction pressure in cadaver 1 for retrosigmoid and extended retrosigmoid approaches was 20.25 +/- 5.9 mm Hg and 10.25 +/- 3.8 mm Hg, respectively; in cadaver 2, values were 11.75 +/- 3.1 mm Hg and 4.75 +/- 1.8 mm Hg, respectively. This corresponded to a mean relative reduction in retraction pressure of 49.4% in cadaver 1 and 59.6% in cadaver 2 by using the extended retrosigmoid approach. Retraction pressures were also significantly less (P < 0.05) for the extended retrosigmoid group when comparing all surgical approaches (N = 4). CONCLUSIONS: The extended retrosigmoid approach gains better visualization with reduced brain retraction. In our study, cerebellar retraction pressures were greatly reduced when using the extended retrosigmoid approach in a cadaveric model. PMID- 29408428 TI - Misclassification of Case-Control Studies in Neurosurgery and Proposed Solutions. AB - OBJECTIVE: Case-control studies (CCS) and cohort studies (CS) are common research designs in neurosurgery. But the term case-control study is frequently misused in the neurosurgical literature, with many articles reported as CCS, even although their methodology does not respect the basic components of a CCS. We sought to estimate the extent of these discrepancies in neurosurgical literature, explore factors contributing to mislabeling, and shed some light on study design reporting. METHODS: We identified 31 top-ranking pure neurosurgical journals and searched them for articles reported as CCS, either in the title or in the abstract. The articles were read to determine if they really were CCS according to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. Article assessment was conducted in duplicate (agreement [kappa statistics] = 99.82%). RESULTS: Two hundred and twenty-four articles met our inclusion criteria, 133 of which (59.38%) correctly labeled the case-control design, whereas 91 (40.62%) misclassified this study design. Cohort studies (CS) were the most common design mislabeled as case-control studies in 76 articles (33.93%), 57 of which (25.45%) were retrospective CS. The mislabeling of CCS impairs the appropriate indexing, classification, and sorting of evidence. Mislabeling CS for CCS leads to a downgrading of evidence as CS represent the highest level of evidence for observational studies. Odds ratios instead of relative risk are reported for these studies, resulting in a distortion of the measurement of the effect size, compounded when these are summarized in systematic reviews and pooled in meta-analyses. CONCLUSIONS: Many studies reported as CCS are not true CCS. Reporting guidelines should include items that ensure that studies are labeled correctly. STROBE guidelines should be implemented in assessment of observational studies. Researchers in neurosurgery need better training in research methods and terminology. We also recommend accrued vigilance from reviewers and editors. PMID- 29408429 TI - Complications of Recognized and Unrecognized Iatrogenic Ureteral Injury at Time of Hysterectomy: A Population Based Analysis. AB - PURPOSE: Ureteral injury represents an uncommon but potentially morbid surgical complication. We sought to characterize the complications of iatrogenic ureteral injury and assess the effect of recognized vs delayed recognition on patient outcomes. MATERIALS AND METHODS: Patients who underwent hysterectomy were identified in the Healthcare Cost and Utilization Project California State Inpatient Database for 2007 to 2011. Ureteral injuries were identified and categorized as recognized-diagnosed/repaired on the day of hysterectomy and unrecognized-diagnosed/repaired postoperatively. We assessed the outcomes of 90 day hospital readmission as well as 1-year outcomes of nephrostomy tube placement, urinary fistula, acute renal failure, sepsis and overall mortality. The independent effects of recognized and unrecognized ureteral injuries were determined on multivariate analysis. RESULTS: Ureteral injury occurred in 1,753 of 223,872 patients (0.78%) treated with hysterectomy and it was unrecognized in 1,094 (62.4%). The 90-day readmission rate increased from a baseline of 5.7% to 13.4% and 67.3% after recognized and unrecognized injury, respectively. Nephrostomy tubes were required in 2.3% of recognized and 23.4% of unrecognized ureteral injury cases. Recognized and unrecognized ureteral injuries independently increased the risk of sepsis (aOR 2.0, 95% CI 1.2-3.5 and 11.9, 95% CI 9.9-14.3) and urinary fistula (aOR 5.9, 95% CI 2.2-16 and 124, 95% CI 95.7 160, respectively). During followup unrecognized ureteral injury increased the odds of acute renal insufficiency (aOR 23.8, 95% CI 20.1-28.2) and death (1.4, 95% CI 1.03-1.9, p = 0032). CONCLUSIONS: Iatrogenic ureteral injury increases the risk of hospital readmission and significant, potentially life threatening complications. Unrecognized ureteral injury markedly increases these risks, warranting a high level of suspicion for ureteral injury and a low threshold for diagnostic investigation. PMID- 29408430 TI - WITHDRAWN: Characterization of the supercomplex formed by the alternative complex III and the terminal aa3 oxidase from Flavobacterium johnsoniae isolated in styrene:maleic acid copolymer nanodiscs. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29408431 TI - Involvement of bone morphogenetic protein-related pathways in the effect of aucubin on the promotion of osteoblast differentiation in MG63 cells. AB - Aucubin, an iridoid glycoside found in several plants, such as Eucommia ulmoide and Rehmannia, has various pharmacological effects. Bone formation is a complex process in which osteoblast differentiation plays an important role. This study aimed to investigate the promotion effects of aucubin on osteoblast differentiation in MG63 cells, a human osteoblast-like cell line. Aucubin not only improved osteoblast differentiation, as shown by enhanced ALP (alkaline phosphatase) concentration and mineralization in cells, but increased the expression of various cytokines, including collagen I, osteocalcin, osteopontin, integrin beta1, and Osterix. Aucubin strongly enhanced the levels of BMP2 (bone morphogenetic proteins-2) in MG63 cells, which play a central role during osteoblast differentiation. Further data show that aucubin exposure after 1 day, 7 days, and 14 days enhanced the expression of Smad1, 5, and 8, and the phosphoresced levels of MAPKs (mitogen-activated protein kinases) family Erk (extracellular signal-regulated kinases), JNK (c-Jun-NH2-terminal kinases), P38, and Akt (serine/threonine protein kinase)/mTOR (mammalian target of rapamycin)/p70s6k in MG63 cells. This study shows the improved effects of aucubin on osteoblast differentiation in MG63 cells, related to the signaling of BMP2 mediated Smads (drosophila mothers against decapentaplegic proteins), MAPKs, and Akt/mTOR/p70S6K. This study indicates the potential of aucubin for osteoporosis treatment. PMID- 29408432 TI - Insights into the toxicity of iron oxides nanoparticles in land snails. AB - The use of manufactured nanoparticles (NPs) is spreading rapidly across technology and medicine fields, posing concerns about their consequence on ecosystems and human health. The present study aims to assess the biological responses triggered by iron oxide NPs (IONPs) and iron oxide NPs incorporated into zeolite (IONPZ) in relation to oxidative stress on the land snail Helix aspersa in order to investigate its use as a biomarker for terrestrial environments. Morphology and structure of both NPs were characterized. Snail food was supplemented with a range of concentrations of IONPs and IONPZ and values of the hemocyte lysosomal membranes' destabilization by 50% were estimated by the neutral red retention (NRRT50) assay. Subsequently, snails were fed with NPs concentrations equal to half of the NRRT50 values, 0.05 mg L-1 for IONPs and 1 mg L-1 for IONPZ, for 1, 5, 10 and 20 days. Both effectors induced oxidative stress in snails' hemocytes compared to untreated animals. The latter was detected by NRRT changes, reactive oxygen species (ROS) production, lipid peroxidation estimation, DNA integrity loss, measurement of protein carbonyl content by an enzyme-linked immunoabsorbent assay (ELISA), determination of ubiquitin conjugates and cleaved caspases conjugates levels. The results showed that the simultaneous use of the parameters tested could constitute possible reliable biomarkers for the evaluation of NPs toxicity. However, more research is required in order to enlighten the disposal and toxic impact of iron oxide NPs on the environment to ensure their safe use in the future. PMID- 29408433 TI - The interventional cardiologist as a resuscitator: a new era of machines in the cardiac catheterization laboratory. PMID- 29408434 TI - Personality and temperament aberrations in patients with vasovagal syncopy. PMID- 29408436 TI - Predicting arrhythmic risk in arrhythmogenic right ventricular cardiomyopathy: A systematic review and meta-analysis. AB - While many studies evaluate predictors of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC), a systematic review consolidating this evidence is currently lacking. Therefore, we searched MEDLINE and Embase for studies analyzing predictors of ventricular arrhythmias (sustained ventricular tachycardia/fibrillation (VT/VF), appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death) in patients with definite ARVC, patients with borderline ARVC, and ARVC-associated mutation carriers. In the case of multiple publications on the same cohort, the study with the largest population was included. This yielded 45 studies with a median cohort size of 70 patients (interquartile range 60 patients) and a median follow-up of 5.0 years (interquartile range 3.3 - 6.7 years). The average proportion of arrhythmic events observed was 10.6%/y in patients with definite ARVC, 10.0%/y in patients with borderline ARVC, and 3.7%/y with mutation carriers. Predictors of ventricular arrhythmias were population dependent: consistently predictive risk factors in patients with definite ARVC were male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF; in patients with borderline ARVC, 2 additional predictors-inducibility during electrophysiology study and strenuous exercise-were identified; and with mutation carriers, all aforementioned predictors as well as ventricular ectopy, multiple ARVC-related pathogenic mutations, left ventricular dysfunction, and palpitations/presyncope determined arrhythmic risk. Most evidence originated from small observational cohort studies, with a moderate quality of evidence. In conclusion, the average risk of ventricular arrhythmia ranged from 3.7 to 10.6%/y depending on the population with ARVC. Male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF consistently predict ventricular arrhythmias in all populations with ARVC. PMID- 29408435 TI - Serological diagnosis and prognostic of tegumentary and visceral leishmaniasis using a conserved Leishmania hypothetical protein. AB - New candidates for serological markers against leishmaniasis are required to be identified, since the presence of high titers of anti-Leishmania antibodies remain detected in sera of treated and cured patients, when current antigens have being employed. In this study, the diagnostic performance of a conserved Leishmania hypothetical protein was evaluated against a human and canine serological panel. The serological follow-up of the patients was also evaluated, using this recombinant antigen (rLiHyS) in ELISA assays. In the results, high sensitivity and specificity values were found when rLiHyS was used in the serological tests, while when the recombinant A2 (rA2) protein or an antigenic Leishmania preparation were used as controls, low sensitivity and specificity were found. Regarding the serological follow-up of the patients, significant reductions in the anti-rLiHyS antibody levels were found and, one year after the treatments, the anti-protein IgG production was similar to this found in the non infected groups, reflecting a drop of the anti-rLiHyS antibody production. In conclusion, the present study shows for the first time a new recombinant antigen used to identify tegumentary and visceral leishmaniasis, as well as being able to serologically distinguish treated and cured patients from those developing active disease. PMID- 29408437 TI - Navigating albumin-based nanoparticles through various drug delivery routes. AB - As a natural polymer, albumin is well-received for being nontoxic, nonimmunogenic, biodegradable and biocompatible. Together with its targeting potential on specific cells, albumin-based nanoparticles appear as an effective carrier for various therapeutics. In recent years, there has been an increasing number of studies investigating the use of albumin-based nanoparticles across different administration routes. Although each route and target tissue presents a distinct anatomical and physiological profile that demands specific consideration, pharmaceuticals could still be delivered effectively via albumin based nanoparticles. Therefore, this review discusses the features that warrant such applications across various delivery routes and explores their possibilities in other administration routes. The challenges associated with its use will also be elaborated to provide a holistic consideration to realise their clinical potentials. PMID- 29408438 TI - Vaccination of healthcare workers against influenza: does a day off make a difference? AB - This article presents the results of actions undertaken to increase influenza vaccine uptake by healthcare workers (HCWs) in Greece during the 2016-2017 influenza season. Influenza vaccination among HCWs increased from 10.9% in acute care hospitals and 24.3% in primary healthcare centres in 2015-2016 to 18% in acute care hospitals and 34.6% in primary healthcare centers in 2016-2017. Vaccination on site at the healthcare facility and use of reward systems were significantly associated with increased vaccination rates. Offering vaccinated HCWs one day off work was associated with the greatest increase in influenza vaccine uptake. PMID- 29408440 TI - Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. AB - BACKGROUND: Studies performed since 1990 on samples of at least 30 subjects with a documented IgE-mediated hypersensitivity to penicillins have found a rate of positive responses to allergy tests with cephalosporins ranging from 0% to 27%. OBJECTIVE: We sought to assess the cross-reactivity with cephalosporins and evaluate the possibility of using cephalosporins in penicillin-allergic subjects. METHODS: We conducted a prospective study of 252 consecutive subjects who had suffered 319 immediate reactions (mostly anaphylaxis) to penicillins and had positive skin tests to at least 1 penicillin reagent. All patients underwent serum specific IgE assays for cefaclor, as well as skin tests with 3 aminocephalosporins (cephalexin, cefaclor, and cefadroxil), cefamandole, cefuroxime, ceftazidime, ceftriaxone, cefotaxime, and cefepime. Patients with negative results for the last 5 cephalosporins were challenged with cefuroxime axetil and ceftriaxone; those with negative results for aminocephalosporins were also challenged with cefaclor and cefadroxil. RESULTS: Ninety-nine participants (39.3%) had positive allergy tests for cephalosporins. Specifically, 95 (37.7%) were positive to aminocephalosporins and/or cefamandole, which share similar or identical side chains with penicillins. All 244 subjects who underwent challenges with cefuroxime axetil and ceftriaxone tolerated them. Of the 170 patients who underwent aminocephalosporin challenges, 3 reacted to cefaclor and 4 to cefadroxil. CONCLUSIONS: Cross-reactivity between penicillins and cephalosporins seems to be mainly related to side chain similarity or identity. Subjects with an IgE-mediated hypersensitivity to penicillins could be treated with cephalosporins such as cefuroxime and ceftriaxone that have side-chain determinants different from those of penicillins and are negative in pretreatment skin testing. PMID- 29408439 TI - Clinician Agreement, Self-Efficacy, and Adherence with the Guidelines for the Diagnosis and Management of Asthma. AB - BACKGROUND: The 2007 Guidelines for the Diagnosis and Management of Asthma provide evidence-based recommendations to improve asthma care. Limited national level data are available about clinician agreement and adherence to these guidelines. OBJECTIVE: To assess clinician-reported adherence with specific guideline recommendations, as well as agreement with and self-efficacy to implement guidelines. METHODS: We analyzed 2012 National Asthma Survey of Physicians data for 1412 primary care clinicians and 233 asthma specialists about 4 cornerstone guideline domains: asthma control, patient education, environmental control, and pharmacologic treatment. Agreement and self-efficacy were measured using Likert scales; 2 overall indices of agreement and self-efficacy were compiled. Adherence was compared between primary care clinicians and asthma specialists. Logistic regression models assessed the association of agreement and self-efficacy indices with adherence. RESULTS: Asthma specialists expressed stronger agreement, higher self-efficacy, and greater adherence with guideline recommendations than did primary care clinicians. Adherence was low among both groups for specific core recommendations, including written asthma action plan (30.6% and 16.4%, respectively; P < .001); home peak flow monitoring, (12.8% and 11.2%; P = .34); spirometry testing (44.7% and 10.8%; P < .001); and repeated assessment of inhaler technique (39.7% and 16.8%; P < .001). Among primary care clinicians, greater self-efficacy was associated with greater adherence. For specialists, self-efficacy was associated only with increased odds of spirometry testing. Guideline agreement was generally not associated with adherence. CONCLUSIONS: Agreement with and adherence to asthma guidelines was higher for specialists than for primary care clinicians, but was low in both groups for several key recommendations. Self-efficacy was a good predictor of guideline adherence among primary care clinicians but not among specialists. PMID- 29408441 TI - Value of a Second Dose of Epinephrine During Anaphylaxis: A Patient/Caregiver Survey. AB - BACKGROUND: Anaphylaxis guidelines recommend prescription of more than 1 epinephrine autoinjector (EAI) for patients at risk. A second epinephrine dose is required in 16% to 36% of patients. OBJECTIVE: To evaluate real-world use of EAIs and understand the patients'/caregivers' adherence to guidelines. METHODS: We collected survey responses from US patients and caregivers with an EAI prescription in November 2015. The survey covered several domains relevant to anaphylaxis and EAI use. RESULTS: The survey was completed by 953 respondents (505 patients and 448 caregivers). Most respondents were women (71%). Most of the respondents had previously administered an EAI (75%). The mean age of the respondents was 28 +/- 14.0 years. A total of 786 (82%) respondents did not carry 2 EAIs all the time, and the main reason given was to have 1 EAI in another location. Most respondents kept at least 1 EAI at home (84%). The percentages of respondents with more than 1 EAI available at locations surveyed were low (patients: 22% at home, 2% at work; caregivers: 27% at home, 10% at school). During training, most respondents (64%) were instructed to always carry 1 EAI and keep the other in another location. Half of the respondents reported the use of a second epinephrine dose in a previous event. Forty-five percent of the 73 respondents who sought emergency care did so because of the unavailability of a second dose. CONCLUSIONS: Our study suggests poor adherence in patients and caregivers to anaphylaxis guidelines recommending more than 1 EAI available at all times and implies that this can result in adverse outcomes. PMID- 29408443 TI - For whom the interferons toll - TLR7 mediated boosting of innate and adaptive immunity against chronic HBV infection. PMID- 29408444 TI - Attenuated cutaneous microvascular function in healthy young African Americans: Role of intradermal l-arginine supplementation. AB - It has been established that endothelial function in conduit vessels is reduced in young African Americans (AA) relative to Caucasian Americans (CA). However, less is known regarding endothelial function in microvasculature of young AA. We hypothesized that microvascular function in response to local heating of skin is attenuated in young AA relative to age-matched CA due largely to the lack of NO bioavailability, which is in turn improved by intradermal l-arginine supplementation and/or inhibition of arginase. Nine AA and nine CA adults participated in this study. Participants were instrumented with four microdialysis membranes in the cutaneous vasculature of one forearm and were randomly assigned to receive 1) lactated Ringer's solution as a control site; 2) 20 mM NG-nitro-l-arginine (l-NAME) to inhibit NO synthase activity; 3) 10 mM l arginine to local supplement l-arginine; or 4) a combination of 5.0 mM (S)-(2 boronoethyl)-l-cysteine-HCL (BEC) and 5.0 mM Nomega-hydroxy-nor-l-arginine (nor NOHA) at a rate of 2.0 MUl/min to locally inhibit arginase activity. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux divided by mean arterial pressure. All CVC data were presented as a percentage of maximal CVC (%CVCmax) that was determined by maximal cutaneous vasodilation induced by 44 degrees C heating plus sodium nitroprusside administration. The response during the 42 degrees C local heating plateau was blunted in the AA at the control site (CA: 84 +/- 12 vs. AA: 62 +/- 6 vs. %CVCmax; P < 0.001). This response was improved in AA at the l-arginine site (Control: 62 +/- 6 vs. l-arginine: 70 +/- 18%CVCmax; P < 0.05) but not in the arginase inhibited site (Control: 62 +/- 6 vs. Arginase inhibited: 62 +/- 13%CVCmax; P = 0.91). In addition, the AA group had an attenuated NO contribution to the plateau phase during 42 degrees C local heating relative to the CA group (CA: 56 +/- 14 vs. AA: 44 +/- 6 Delta %CVCmax; P < 0.001). These findings suggest that 1) cutaneous microvascular function in response to local heating is blunted in young AA when compared to age-matched young CA; 2) this attenuated response is partly related to decrease in NO bioavailability in young AA; and 3) a local infusion of l-arginine, but not arginase inhibition, improves cutaneous microvascular responses to local heating in young AA relative to CA. PMID- 29408442 TI - Porcine reproductive and respiratory syndrome virus neutralizing antibodies provide in vivo cross-protection to PRRSV1 and PRRSV2 viral challenge. AB - Vaccine control and prevention of porcine reproductive and respiratory syndrome (PRRS), the most important disease of swine, is difficult to achieve. However, the discovery of broadly neutralizing antibody activity against porcine reproductive and respiratory syndrome virus (PRRSV) under typical field conditions opens the door to new immunologic approaches for robust protection. We show here that passive administration of purified immunoglobulins with neutralizing antibodies reduced PRRSV2 infection by up to 96%, and PRRSV1 infection by up to 87%, whereas immune immunoglobulins lacking neutralizing activity had no effect on viral infection. Hence, immune competence of passive immunoglobulin transfer was associated specifically with antibody neutralizing activity. Current models of PRRSV infection implicate a minor envelope glycoprotein (GP) complex including GP2, GP3, and GP4, as critical to permissive cell infection. However, conserved peptides comprising the putative cell attachment structure did not attenuate neutralization or viral infection. The results show that immunological approaches aimed at induction of broadly neutralizing antibodies may substantially enhance immune protection against PRRSV. The findings further show that naturally occurring viral isolates are able to induce protective humoral immunity against unrelated PRRSV challenge, thus removing a major conceptual barrier to vaccine development. PMID- 29408445 TI - MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma. AB - Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the amplification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, amplification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function. This observation greatly suggests that the role of MYCN in neuroblastoma should be examined in the context of MAX expression. In this report, we show that, in contrast to what is found in normal cells, MAX expression is significantly different among primary NBs, and that its level appears to correlate with the clinical outcome of the disease. Importantly, controlled modulation of MAX expression in neuroblastoma cells with different extents of MYCN amplification, demonstrates that MAX can instruct gene transcription programs that either reinforce or weaken the oncogenic process enacted by MYCN. In general, our work illustrates that it is the MAX to MYCN ratio that can account for tumour progression and clinical outcome in neuroblastoma and proposes that such a ratio should be considered as an important criterion to the design and development of anti-MYCN therapies. PMID- 29408446 TI - Prenatal substance exposure and offspring development: Does DNA methylation play a role? AB - The period of in utero development is one of the most critical windows during which adverse conditions and exposures may influence the growth and development of the fetus as well as its future postnatal health and behavior. Maternal substance use during pregnancy remains a relatively common but nonetheless hazardous in utero exposure. For example, previous epidemiological studies have associated prenatal substance exposure with reduced birth weight, poor developmental and psychological outcomes, and increased risk for diseases and behavioral disorders (e.g., externalizing behaviors like ADHD, conduct disorder, and substance use) later in life. Researchers are now learning that many of the mechanisms whereby adverse in utero exposures may affect key pathways crucial for proper fetal growth and development are epigenetic in nature, with the majority of work in humans considering DNA methylation specifically. This review will explore the research to date on epigenetic alterations tied to maternal substance use during pregnancy and will also discuss the possible role of DNA methylation in the robust relationship between maternal substance use and later behavioral and developmental sequelae in offspring. PMID- 29408447 TI - Cryopreservation effects on sperm function and fertility in two threatened crane species. AB - The capacity to cryopreserve semen from captive cranes facilitates production of offspring from behaviorally incompatible or geographically separated pairs, and allows for long-term preservation of valuable genetic materials. The present study sought to develop effective cryopreservation protocols for whooping (Grus americana) and white-naped (Grus vipio) cranes, through examining the influences of two permeating (DMA and Me2SO) and one non-permeating (sucrose) cryoprotectants, as well as vitamin E on post-thaw sperm survival. In Study 1, ejaculates (whooping: n = 10, white-naped: n = 8) were collected and cryopreserved in one of six cryo-diluents (crane extender with: DMA; DMA+0.1M sucrose; Me2SO; Me2SO+0.1M sucrose; 0.1M sucrose; 0.2M sucrose) using a two-step cooling method. Frozen samples were thawed and assessed for overall motility, motion characteristics, membrane integrity, morphology, and ability to bind to the inner perivitelline membrane (IPVM). In Study 2, whooping crane ejaculates (n = 17) were frozen in crane extender containing Me2SO alone or with vitamin E (5 MUg/mL or 10 MUg/mL). Frozen samples were thawed and assessed as in Study 1, except the binding assay. White-naped crane sperm were more tolerant to cryopreservation than whooping crane (15% vs 6% post-thawed motility). In both species, sperm cryopreserved in medium containing Me2SO alone displayed higher post thaw survival and ability to bind to IPVM than the other cryodiluent treatments. Vitamin E supplementation exerted no benefits to post thaw motility or membrane integrity. The findings demonstrated that there was species specificity in the susceptibility to cryopreservation. Nevertheless, Me2SO was a preferred cryoprotectant for sperm from both whooping and white-naped cranes. PMID- 29408448 TI - Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2. AB - Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months. Cardiac functions were determined using echocardiography. Oxidative stress, pro inflammatory cytokines and pro-fibrotic markers were determined with commercially available kits, real-time quantitative PCR or western blot techniques. DCM was characterized by diminished cardiac function, accompanied by oxidative stress and enhanced expression of pro-inflammatory cytokines. Diabetic cardiac tissue exhibited marked fibrosis, revealed by extracellular matrix deposition as determined by Sirius red staining of the myocardial tissues. Furthermore, Nrf2 and its downstream effectors were repressed in diabetic myocardium. On the contrary, diabetic animals treated with DMF exhibited blunted oxidative stress, inflammation, fibrosis and this correlated with Nrf2 activation. Our findings suggest that DMF could potentially thwart diabetes-induced myocardial tissue injury, likely via activation of Nrf2 function, providing firm impetus for future repurposing of DMF in the management of DCM. PMID- 29408449 TI - Extraction optimization and UHPLC method development for determination of the 20 hydroxyecdysone in Sida tuberculata leaves. AB - Sida tuberculata (ST) is a Malvaceae species widely distributed in Southern Brazil. In traditional medicine, ST has been employed as hypoglycemic, hypocholesterolemic, anti-inflammatory and antimicrobial. Additionally, this species is chemically characterized by flavonoids, alkaloids and phytoecdysteroids mainly. The present work aimed to optimize the extractive technique and to validate an UHPLC method for the determination of 20 hydroxyecdsone (20HE) in the ST leaves. Box-Behnken Design (BBD) was used in method optimization. The extractive methods tested were: static and dynamic maceration, ultrasound, ultra-turrax and reflux. In the Box-Behnken three parameters were evaluated in three levels (-1, 0, +1), particle size, time and plant:solvent ratio. In validation method, the parameters of selectivity, specificity, linearity, limits of detection and quantification (LOD, LOQ), precision, accuracy and robustness were evaluated. The results indicate static maceration as better technique to obtain 20HE peak area in ST extract. The optimal extraction from surface response methodology was achieved with the parameters granulometry of 710 nm, 9 days of maceration and plant:solvent ratio 1:54 (w/v). The UHPLC-PDA analytical developed method showed full viability of performance, proving to be selective, linear, precise, accurate and robust for 20HE detection in ST leaves. The average content of 20HE was 0.56% per dry extract. Thus, the optimization of extractive method in ST leaves increased the concentration of 20HE in crude extract, and a reliable method was successfully developed according to validation requirements and in agreement with current legislation. PMID- 29408451 TI - Fluorescence imaging of the interaction of amyloid beta 40 peptides with live cells and model membrane. AB - Amyloid beta peptides (Abeta) found in plaques in the brain have been widely recognised as a hallmark of Alzheimer's disease although the underlying mechanism is still unknown. Abeta40 and Abeta40(A2T) peptides were synthesized and their effects on neuronal cells are reported together with the effect of tetramer forms of the peptides. ThT assay revealed that mutation affected the lag time and aggregation and the presence of lipid vesicles changed the fibril formation profile for both peptides. The A2T mutation appeared to reduce cytotoxicity and lessen binding of Abeta40 peptides to neuronal cells. Fluorescence microscopy of the interaction between Abeta40 peptides and giant unilamellar vesicles revealed that both peptides led to formation of smaller vesicles although the tetramer of Abeta(A2T) appeared to promote vesicle aggregation. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29408452 TI - Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women. AB - BACKGROUND: The increase in the prevalence of degenerative brain diseases owing to the growing elderly population is becoming a serious social issue, and regular exercises can be effective in preventing and treating such diseases. Irisin, one of the myokines expressed in the muscles during exercise, is highly associated with the expression of brain-derived neurotrophic factor (BDNF). Therefore, the purpose of this study was to analyze the effect of aquarobic exercises on serum irisin and BDNF levels to help prevent and delay degenerative brain diseases in elderly women. MATERIALS AND METHODS: Twenty-six elderly women voluntarily participated in the study (12 in the control group and 14 in the exercise group). The exercise group underwent a 16-week aquarobic exercise program. The irisin and BDNF levels and liver function were measured in both groups: three times in the exercise group and two times in the control group. RESULTS: Significantly higher serum irisin (p < 0.001) and BDNF (p < 0.05) levels in the aquarobic exercise group than in the control group were found after 16 weeks of exercise, and significant interaction effects of irisin (p < 0.001) and BDNF (p < 0.01) were found in both the control and exercise groups. The serum irisin (p < 0.01 and p < 0.001, respectively) and BDNF (p < 0.05, p < 0.001, respectively) levels were significantly higher 30 min after the first exercise session and 30 min after the last exercise session in the 16th week than during the rest period before the 16 weeks of exercise. CONCLUSIONS: Aquarobic exercises were found to improve the serum irisin and BDNF levels; thus, it could be effective in preventing degenerative brain diseases and enhancing brain function of elderly women. PMID- 29408450 TI - Effect of 25-hydroxycholesterol in viral membrane fusion: Insights on HIV inhibition. AB - Recently, it was demonstrated that 25-hydroxycholesterol (25HC), an oxidized cholesterol derivative, inhibits human immunodeficiency virus type 1 (HIV) entry into its target cells. However, the mechanisms involved in this action have not yet been established. The aim of this work was to study the effects of 25HC in biomembrane model systems and at the level of HIV fusion peptide (HIV-FP). Integration of different biophysical approaches was made in the context of HIV fusion process, to clarify the changes at membrane level due to the presence of 25HC that result in the suppressing of viral infection. Lipid vesicles mimicking mammalian and HIV membranes were used on spectroscopy assays and lipid monolayers in surface pressure studies. Peptide-induced lipid mixing assays were performed by Forster resonance energy transfer to calculate fusion efficiency. Liposome fusion is reduced by 50% in the presence of 25HC, comparatively to cholesterol. HIV-FP conformation was assessed by infrared assays and it relies on sterol nature. Anisotropy, surface pressure and dipole potential assays indicate that the conversion of cholesterol in 25HC leads to a loss of the cholesterol modulating effect on the membrane. With different biophysical techniques, we show that 25HC affects the membrane fusion process through the modification of lipid membrane properties, and by direct alterations on HIV-FP structure. The present data support a broad antiviral activity for 25HC. PMID- 29408454 TI - Effect of Urethroplasty on Anxiety and Depression. AB - PURPOSE: To our knowledge anxiety and depression in patients with urethral stricture disease and the impact of urethroplasty on mental health has never been explored. We hypothesized that patients with urethral stricture disease would have higher than normal anxiety and depression levels, and urethroplasty would improve mental health. MATERIALS AND METHODS: We retrospectively reviewed the records of patients in a multi-institutional reconstructive urology database who underwent anterior urethroplasty. Preoperative and postoperative evaluation of anxiety and depression, and overall health was recorded using the validated EQ 5DTM-3L Questionnaire. Sexual function was evaluated with the IIEF (International Index of Erectile Function) and the Men's Sexual Health Questionnaire. Stricture recurrence was defined as the need for a subsequent procedure. RESULTS: Median followup in the 298 patients who met study inclusion criteria was 4.2 months. Preoperative anxiety and depression was reported by 86 patients (29%). Those with anxiety and depression reported higher rates of marijuana use, a worse preoperative IIEF score (17.5 vs 19.6, p = 0.01) and a lower image of overall health (66 vs 79, p <=0.001). Improvement or resolution of anxiety and depression was experienced by 56% of patients treated with urethroplasty while de novo postoperative anxiety and depression were reported by 10%. These men reported a decreased flow rate (16 vs 25 ml per second, p = 0.01). Clinical failure in 8 patients (2.7%) had no effect on the development, improvement or resolution of anxiety and depression. CONCLUSIONS: Of patients with preoperative anxiety and depression 56% reported improvement or resolution after urethroplasty. Although new onset anxiety and depression was rare, these patients had a significantly lower postoperative maximum flow rate, possibly representing a group with a perceived suboptimal surgical outcome. A urethral stricture disease specific questionnaire is needed to further elucidate the interplay of urethral stricture disease with anxiety and depression. PMID- 29408453 TI - A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. AB - Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs). We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70-93 years; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in TREGS were detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted. PMID- 29408455 TI - Omentin-1 ameliorates the attachment of the leukocyte THP-1 cells to HUVECs by targeting the transcriptional factor KLF2. AB - Oxidation of low-density lipoproteins (ox-LDL) plays a critical role in endothelial dysfunction and the pathological progression of atherosclerosis by causing leukocyte attachment to endothelial surfaces. Omentin-1, an important adipokine primarily secreted by stromal vascular cells, has displayed various biological functions in diverse tissues. However, little information regarding the effects of omentin-1 on ox-LDL- induced endothelial dysfunction has been reported before. In the current study, we found that omentin-1 significantly reduced the attachment of the leukocyte THP-1 cells to human umbilical vein endothelial cells (HUVECs) in a dose dependent manner. Additionally, omentin-1 treatment prevented the expression of cell adhesion molecules such as VCAM-1 and E-selectin at both the mRNA level and the protein level. Notably, we found that omentin-1 significantly restored ox-LDL-induced reduction of KLF2, an important transcriptional factor and regulator of endothelial function. Also, omentin-1 promoted the expression of KLF2 target genes eNOS and PAI-1. Mechanistically, our results indicate that the effects of omentin-1 on KLF2 expression are mediated by p53. These results highlight the potential of omentin-1 in preventing endothelial dysfunction and atherosclerosis. PMID- 29408456 TI - Effect of the NBD-group position on interaction of fluorescently-labeled cholesterol analogues with human steroidogenic acute regulatory protein STARD1. AB - Steroidogenic acute regulatory protein (StAR, STARD1) is a key factor of intracellular cholesterol transfer to mitochondria, necessary for adrenal and gonadal steroidogenesis, and is an archetypal member of the START protein family. Despite the common overall structural fold, START members differ in their binding selectivity toward various lipid ligands, but the lack of direct structural information hinders complete understanding of the binding process and cholesterol orientation in the STARD1 complex in particular. Cholesterol binding has been widely studied by commercially available fluorescent steroids, but the effect of the fluorescent group position on binding remained underexplored. Here, we dissect STARD1 interaction with cholesterol-like steroids bearing 7-nitrobenz-2 oxa-1,3-diazol-4-yl (NBD) group in different positions, namely, with 22-NBD cholesterol (22NC), 25-NBD-cholesterol (25NC), 20-((NBDamino)-pregn-5-en-3-ol (20NP) and 3-(NBDamino)-cholestane (3NC). While being able to stoichiometrically bind 22NC and 20NP with high fluorescence yield and quantitative exhaustion of fluorescence of some protein tryptophans, STARD1 binds 25NC and 3NC with much lower affinity and poor fluorescence response. In contrast to 3NC, binding of 20NP leads to STARD1 stabilization and substantially increases the NBD fluorescence lifetime. Remarkably, in terms of fluorescence response, 20NP slightly outperforms commonly used 22NC and can thus be used for screening of various potential ligands by a competition mechanism in the future. PMID- 29408457 TI - The pathogenic role of MEF2D-SS18 fusion gene in B-cell acute lymphoblastic leukemia. AB - B-cell acute lymphoblastic leukemia (B-ALL) is characterized by various fusion genes resulted from chromosome translocations, and MEF2D related fusions are recently identified in a B-ALL subtype with relatively worse survival. In this study, we investigated the pathogenic role of MEF2D-SS18 fusion in B-ALL. The recombinant retrovirus and lentivirus plasmids containing the MEF2D-SS18 transcript were constructed for functional studies. Immuno-fluorescent staining presented the nuclear localization of MEF2D-SS18. In vitro B cell differentiation assay showed MEF2D-SS18 significantly inhibited the differentiation of mouse common lymphoid progenitors into CD19 positive B cells. The data of RBMT mouse model also showed B cell developmental arrest. In REH cells overexpressing MEF2D SS18, genes related to B cell development were down-regulated, while genes related to drug sensitivity and B cell survival were up-regulated. In conclusion, MEF2D-SS18 fusion gene blocked the differentiation of B cells, thus exerted a funding role in the pathogenesis and prognosis of B-ALL. PMID- 29408458 TI - Wine and its metabolic effects. A comprehensive review of clinical trials. AB - The introduction of the term "French Paradox" motivated an extensive and in-depth research into health benefits of moderate wine consumption. The superiority of wine is thought to be attributed to its micro-constituents and consequent effort was made to isolate and identify these bioactive compounds as well as to elucidate the mechanisms of their action. Controlled trials offer more concrete answers to several raised questions than observational studies. Under this perspective, clinical trials have been implemented, mainly in healthy volunteers and rarely in patients, in order to investigate the acute or chronic effect of wine consumption on metabolism and physio-pathological systems, which are mainly associated with cardiovascular diseases. The aim of this review is to update the knowledge about the acute and long term effect of wine consumption on lipid and glucose/insulin metabolism as well as on the inflammatory and haemostatic systems, based on the reported data of controlled clinical trials. In conclusion, the most repeated result of wine consumption is on lipid metabolism, attributed mainly to ethanol, while wine micro-constituents seem to have an important role mainly in haemostatic and inflammatory/endothelial systems. PMID- 29408459 TI - Regulation of Cancer Stem Cell Self-Renewal by HOXB9 Antagonizes Endoplasmic Reticulum Stress-Induced Melanoma Cell Apoptosis via the miR-765-FOXA2 Axis. AB - Adaptation to endoplasmic reticulum (ER) stress has been indicated as a driver of malignancy and resistance to therapy in human melanoma. However, the relationship between cancer stem cells and adaptation to ER stress remains unclear. Here, we show that the ratio of cancer stem cells is increased in ER stress-resistant melanoma cells, which inhibit ER stress-induced apoptosis and promote tumorigenesis. Further mechanistic studies showed that HOXB9 triggered by ER stress favors cancer stem cell self-renewal and enhances ER stress resistance. HOXB9 directly binds to the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2, resulting in a FOXA2 decrease and cancer stem cell increase. Additionally, an increase in HOXB9 promotes melanoma growth and inhibits cell apoptosis in a mouse xenograft model. Elevated HOXB9 is found in human melanoma tissues, which is associated with microRNA-765 up regulation and FOXA2 decreases. Thus, our data showed that the HOXB9-dependent, microRNA-765-mediated FOXA2 pathway contributes to the survival of melanoma under ER stress by maintaining the properties of cancer stem cells. PMID- 29408460 TI - Prevalence of and Factors Associated With Fecal Incontinence: Results From a Population-Based Survey. AB - BACKGROUND & AIMS: Fecal incontinence (FI) is characterized by uncontrolled passage of solid or liquid stool. We aimed to determine the prevalence and severity of FI in a large sample of US residents. METHODS: We recruited a representative sample of patients in October 2015 to complete the National Gastrointestinal (GI) Survey; a mobile app called MyGiHealth was used to systematically collect data on GI symptoms. FI was defined as accidental leakage of solid or liquid stool. Severity of FI was determined by responses to the National Institutes of Health FI Patient Reported Outcomes Measurement Information System questionnaire. Multivariable regression models were used to identify factors associated with FI prevalence and severity. RESULTS: Among 71,812 individuals who completed the National GI Survey, 14.4% reported FI in the past; of these, 33.3% had FI within the past 7 days. Older age, male sex, and Hispanic ethnicity increased the likelihood of having FI within the past week. Individuals with Crohn's disease, ulcerative colitis, celiac disease, irritable bowel syndrome, or diabetes were more likely to report FI. Non-Hispanic black and Hispanic individuals and individuals with Crohn's disease, celiac disease, diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome, or chronic idiopathic constipation had more severe symptoms of FI than individuals without these features. CONCLUSIONS: In a large population-based survey, 1 in 7 people reported previous FI. FI is age-related and more prevalent among individuals with inflammatory bowel disease, celiac disease, irritable bowel syndrome, or diabetes than people without these disorders. Proactive screening for FI among these groups is warranted. PMID- 29408461 TI - Impacts of simultaneous multislice acquisition on sensitivity and specificity in fMRI. AB - Simultaneous multislice (SMS) imaging can be used to decrease the time between acquisition of fMRI volumes, which can increase sensitivity by facilitating the removal of higher-frequency artifacts and boosting effective sample size. The technique requires an additional processing step in which the slices are separated, or unaliased, to recover the whole brain volume. However, this may result in signal "leakage" between aliased locations, i.e., slice "leakage," and lead to spurious activation (decreased specificity). SMS can also lead to noise amplification, which can reduce the benefits of decreased repetition time. In this study, we evaluate the original slice-GRAPPA (no leak block) reconstruction algorithm and acceleration factor (AF = 8) used in the fMRI data in the young adult Human Connectome Project (HCP). We also evaluate split slice-GRAPPA (leak block), which can reduce slice leakage. We use simulations to disentangle higher test statistics into true positives (sensitivity) and false positives (decreased specificity). Slice leakage was greatly decreased by split slice-GRAPPA. Noise amplification was decreased by using moderate acceleration factors (AF = 4). We examined slice leakage in unprocessed fMRI motor task data from the HCP. When data were smoothed, we found evidence of slice leakage in some, but not all, subjects. We also found evidence of SMS noise amplification in unprocessed task and processed resting-state HCP data. PMID- 29408462 TI - The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy. AB - Autophagy, a virtually uniform response to external stress such as that induced by chemotherapy and radiation, is generally considered to be cytoprotective in function, providing a foundation for multiple clinical trials designed to enhance therapeutic response via autophagy inhibition. However, this cell autonomous response can also be cytotoxic or nonprotective, with the consequence that autophagy inhibition would be counterproductive or ineffective, respectively. The non-cell autonomous function of autophagy remains quite controversial, with evidence both for and against autophagy-mediated activation of the immune system. If autophagy inhibition antagonizes the immune response, this would likely interfere with the potential sensitization resulting from suppression of the cell autonomous protective function. An additional complication, which has rarely been considered, is the nature of the contribution of therapy-induced autophagy in the tumor microenvironment, particularly the tumor stroma. Taken together, it is likely that the outcome of the current clinical trials, whether positive or negative, will be difficult to interpret given the complexity of the role of autophagy relating to the tumor cell (cell autonomous), the immune system (cell non-autonomous) and the tumor microenvironment. PMID- 29408463 TI - Bupropion and naltrexone combination alters high fructose corn syrup self administration and gene expression in rats. AB - Contrave(r) is an adjunct pharmacotherapy for obesity that contains bupropion (BUP) and naltrexone (NTX). To further explore the psychopharmacology of this drug combination, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing: 40 mg/kg/day BUP, 4 mg/kg/day NTX, or 40 + 4 mg/kg/day BUP and NTX (BN). During 12 days of exposure, the animals were tested on operant intraoral self-administration (IOSA) of high fructose corn syrup (HFCS) on continuous (FR1) and progressive ratio (PR) schedules, on home cage drinking of HFCS, and on HFCS taste reactivity. Locomotion activity was also assessed. At the conclusion of the study, mRNA expression of genes involved in reward processing, appetite and mood were quantified. It was found that BN produced effects that could largely be ascribed to either BUP or NTX independently. More specifically, BN-induced reductions of HFCS IOSA on a FR1 schedule and home cage drinking, as well as alterations of MOR and POMC mRNA in the nucleus accumbens core and hypothalamus respectively, were attributable to NTX; while alterations of hippocampal BDNF mRNA was attributable to BUP. But, there was also some evidence of drug synergy: only BN caused persistent reductions of HFCS IOSA and drinking; BN produced the least gain of body weight; and only BN-treated rats displayed altered D2R mRNA in the caudate-putamen. Taken together, these observations support the use of BUP + NTX as a mean to alter consumption of sugars and reducing their impact on brain systems involved in reward, appetite and mood. PMID- 29408464 TI - Exercise reduces depression and inflammation but intensity matters. AB - BACKGROUND: Exercise may help to mitigate symptoms of depression by reducing inflammation; however, little is known about the influence of exercise intensity on depressed mood. METHODS: In the present study, sixty-one university students were assigned to six weeks of high-intensity interval training (HIT), moderate continuous training (MCT), or no exercise (CON) during their academic term. We measured changes in depression, anxiety and perceived stress along with pro inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL 6), interleukin-1 beta (IL-1beta), and C-reactive protein (CRP). RESULTS: Depression increased for CON, demonstrating how quickly mental health can decline for students during their academic term. In contrast, MCT decreased depression and pro-inflammatory cytokine TNF-alpha levels. Although HIT decreased depressive symptoms, it also increased perceived stress, TNF-alpha and IL-6 relative to MCT. This may be due to the higher level of physical stress evoked by the more strenuous exercise protocol. CONCLUSIONS: Taken together, the results suggest that moderate-intensity exercise may be an optimal intensity of exercise for the promotion of mental health by decreasing TNF-alpha. This is critical for informing the use of exercise as medicine for mental health. PMID- 29408465 TI - Prevalence of hepatitis E virus RNA and antibodies in a cohort of kidney transplant recipients in Central Brazil. AB - OBJECTIVE: To assess the prevalence of hepatitis E virus (HEV) RNA and antibodies among kidney transplant recipients (KTR) in Central Brazil. The presence of chronic HEV infection was also investigated. METHODS: A cohort study was conducted among 316 KTR treated at a referral center for kidney transplantation in Goiania, Brazil. All serum samples were tested for the presence of HEV RNA (real-time PCR) and anti-HEV IgG/IgM (ELISA). Anti-HEV-positive samples were confirmed using an immunoblot test. HEV chronicity was investigated in a subgroup of patients with elevated alanine aminotransferase (ALT >40IU/l) through HEV RNA detection in additional serum samples collected 3 and 6 months apart. RESULTS: A seroprevalence of 2.5% (95% confidence interval 1.2-5.1%) was found for anti-HEV IgG. There was no difference in characteristics between the anti-HEV IgG seropositive and seronegative KTR groups. Anti-HEV IgM was detected in only one patient (0.3%). All KTR were negative for HEV RNA. CONCLUSIONS: These results show that HEV infection is infrequent in KTR in Central Brazil, with low seroprevalence rates of past and recent infection, and also an absence of active and chronic HEV infections. PMID- 29408466 TI - Ecology shapes moral judgments towards food-wasting behavior: Evidence from the Yali of West Papua, the Ngorongoro Maasai, and Poles. AB - People judge food wasting as an immoral behavior. Although moral concerns vary widely across cultures, to this date, food wasting moral judgments were investigated only among rich and industrialized ones. This study reports first evidence of cultural variability on moral judgments of food wasting between modern and traditional cultures. We conducted our study among the Maasai - pastoralists of Ngorongoro, Yali - horticulturalists of West Papua, and among citizens of Poland. According to the results, Maasai judge food wasting as more immoral compared to Yali and Poles. What's more, Yali judge food wasting harsher than Poles. These results suggest that there are cultural differences in moral judgments of food wasting. These differences might reflect the impact of unstable ecology on food economy of a given society. We hypothesize that harsh moral judgment concerning food waste may serve as a cultural adaptation for food insecurity. PMID- 29408468 TI - Neuropeptide Y2 receptors in anteroventral BNST control remote fear memory depending on extinction training. AB - The anterior bed nucleus of stria terminalis (BNST) is involved in reinstatement of extinguished fear, and neuropeptide Y2 receptors influence local synaptic signaling. Therefore, we hypothesized that Y2 receptors in anteroventral BNST (BNSTav) interfere with remote fear memory and that previous fear extinction is an important variable. C57BL/6NCrl mice were fear-conditioned, and a Y2 receptor specific agonist (NPY3-36) or antagonist (JNJ-5207787) was applied in BNSTav before fear retrieval at the following day. Remote fear memory was tested on day 16 in two groups of mice, which had (experiment 1) or had not (experiment 2) undergone extinction training after conditioning. In the group with extinction training, tests of remote fear memory revealed partial retrieval of extinction, which was prevented after blockade of Y2 receptors in BNSTav. No such effect was observed in the group with no extinction training, but stimulation of Y2 receptors in BNSTav mimicked the influence of extinction during tests of remote fear memory. Pharmacological manipulation of Y2 receptors in BNSTav before fear acquisition (experiment 3) had no effect on fear memory retrieval, extinction or remote fear memory. Furthermore, partial retrieval of extinction during tests of remote fear memory was associated with changes in number of c-Fos expressing neurons in BNSTav, which was prevented or mimicked upon Y2 blockade or stimulation in BNSTav. These results indicate that Y2 receptor manipulation in BNSTav interferes with fear memory and extinction retrieval at remote stages, likely through controlling neuronal activity in BNSTav during extinction training. PMID- 29408469 TI - The neural crest and evolution of the head/trunk interface in vertebrates. AB - The migration and distribution patterns of neural crest (NC) cells reflect the distinct embryonic environments of the head and trunk: cephalic NC cells migrate predominantly along the dorsolateral pathway to populate the craniofacial and pharyngeal regions, whereas trunk crest cells migrate along the ventrolateral pathways to form the dorsal root ganglia. These two patterns thus reflect the branchiomeric and somitomeric architecture, respectively, of the vertebrate body plan. The so-called vagal NC occupies a postotic, intermediate level between the head and trunk NC. This level of NC gives rise to both trunk- and cephalic-type (circumpharyngeal) NC cells. The anatomical pattern of the amphioxus, a basal chordate, suggests that somites and pharyngeal gills coexist along an extensive length of the body axis, indicating that the embryonic environment is similar to that of vertebrate vagal NC cells and may have been ancestral for vertebrates. The amniote-like condition in which the cephalic and trunk domains are distinctly separated would have been brought about, in part, by anteroposterior reduction of the pharyngeal domain. PMID- 29408470 TI - The effect of sub-inhibitory concentrations of antibiotics on natural transformation in Acinetobacter baumannii. PMID- 29408471 TI - Impact of stochastic migration on species diversity in meta-food webs consisting of several patches. AB - The structure of space has an appreciable influence on the diversity and stability of ecosystems. So far, there are only few theoretical studies investigating the population dynamics of food webs consisting of many species that can migrate between several patches, and in most of these models migration is a continuous, deterministic process. However, when migration events are rare (for instance because the patches are far apart), migration is a stochastic process and should be modeled accordingly. We present computer simulations of a food web model of many species on a spatial network of several patches, combining deterministic local population dynamics with stochastic migration. We evaluate the influence of the migration rate and other model parameters on local and regional species diversity and on stability. We find that migration increases the number of surviving and coexisting populations by two effects. These are the rescue effect, which restores local populations that have gone extinct, and dynamical coexistence, which sustains local populations that could not persist in the absence of immigration. Both effects occur even when migration events are rare. Species diversity increases on local and regional scales with the frequency of migration events. Furthermore, we investigate the adiabatic limit in which population dynamics always reaches an equilibrium before the next migration event, and we investigate the possible long-term scenarios. While the final state often contains the same food web on all patches, we also find instances where two slightly different food webs coexist on different patches, even when initially each patch contained the same food web. PMID- 29408467 TI - Delta9-Tetrahydrocannabinol changes the brain lipidome and transcriptome differentially in the adolescent and the adult. AB - Exposing the adolescent brain to drugs of abuse is associated with increased risk for adult onset psychopathologies. Cannabis use peaks during adolescence, with largely unknown effects on the developing brain. Cannabis' major psychoactive component, Delta9-tetrahydrocannabinol (THC) alters neuronal, astrocytic, and microglial signaling. Therefore, multiple cellular and signaling pathways are affected with a single dose of THC. The endogenous cannabinoids (eCBs), N arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are members of an interconnected lipidome that includes an emerging class of AEA structural analogs, the lipoamines, additional 2-acyl glycerols, free fatty acids, and prostaglandins (PGs). Lipids in this lipidome share many biosynthetic and metabolic pathways, yet have diverse signaling properties. Here, we show that acute THC drives age-dependent changes in this lipidome across 8 regions of the female mouse brain. Interestingly, most changes are observed in the adult, with eCBs and related lipids predominately decreasing. Analysis of THC and metabolites reveals an unequal distribution across these brain areas; however, the highest levels of THC were measured in the hippocampus (HIPP) in all age groups. Transcriptomic analysis of the HIPP after acute THC showed that like the lipidome, the adult transcriptome demonstrated significantly more changes than the adolescent. Importantly, the regulation of 31 genes overlapped between the adolescent and the adult, suggesting a conserved transcriptomic response in the HIPP to THC exposure independent of age. Taken together these data illustrate that the first exposure to a single dose of THC has profound effects on signaling in the CNS. PMID- 29408472 TI - Tranexamic acid plus drain-clamping can reduce blood loss in total knee arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: The efficacy of tranexamic acid (TXA) plus drain-clamping in reducing blood loss after total knee arthroplasty (TKA) is controversial. This meta analysis aimed to identify whether combined tranexamic acid and drain-clamping was superior to TXA alone, drain clamping alone and control treatments. METHODS: We searched the PubMed, EMBASE, Web of Science and Google databases and the Cochrane Database of Systematic Reviews. Patients prepared for primary TKA and who underwent TXA plus drain-clamping for blood loss were included in this meta analysis. Outcomes included the need for transfusion, total blood loss, blood loss in drainage, a decrease in hemoglobin and the occurrence of deep venous thrombosis (DVT). Stata 12.0 was used for meta-analysis. RESULTS: Finally, 7 clinical studies with 839 patients were included in this meta-analysis. Compared with the control group, TXA group and drain clamping group treatments, TXA plus drain-clamping could reduce the need for transfusion, total blood loss, blood loss in drainage and the decrease in hemoglobin with statistically significance. CONCLUSIONS: TXA plus drain-clamping is an efficient method for controlling blood loss after TKA, and more studies should focus on the optimal clamping duration. PMID- 29408473 TI - Curcumin marinosomes as promising nano-drug delivery system for lung cancer. AB - Lung cancer is the major cause of cancer-related death worldwide. Curcumin attracted attention due to its promising anti-cancer properties, however its poor aqueous solubility and bioavailability have to be overcome. In the current study curcumin is encapsulated in krill lipids-based liposomes (marinosomes) to develop a potential anticancer therapy from low-cost and readily available nutraceuticals. Reflux followed by thin drug-lipid film method is used successfully to incorporate the drug into the liposomal membrane at high encapsulation efficiency (EE). The curcumin-loaded marinosomes (CURMs) showed a powerful antioxidant activity (EC50 ? 4 MUg/mL). Additionally, CURMs exhibited good physicochemical and oxidative stability after eight weeks' storage at 4 degrees C. Furthermore, CURMs exhibited sustained release of about 30% of their curcumin content under in vitro culture conditions at 37 degrees C after 72 h. Consequently, CURMs showed its maximum cytotoxic effect (IC50; 11.7 +/- 0.24 MUg/ml) after incubation for 72 h against A549 lung cancer cells. Additionally, CURMs inhibited the proliferation of HUVECs in a dose-dependent manner with IC50 of 2.64 +/- 0.21 MUg/ml after incubation for 24 h. The current study presents the CURM as a favorable in vitro drug delivery system to target cancer disease. PMID- 29408474 TI - A strategy to analyse activity-based profiling of tyrosine kinase substrates in OCT-embedded lung cancer tissue. AB - The use of optimal cutting temperature (OCT) medium has served to improve the long-term preservation of surgical tissue specimens. Unfortunately, the presence of polymers in OCT has been found to generate signal interference in proteomic based techniques. Indeed the presence of OCT medium in tissue lysates precludes the analysis of activity based proteomic profiles obtained from lung adenocarcinoma (LuAdCa) resection specimens. In order to probe this question further tissue lysates were prepared from 47 lung non-neoplastic and tumour, node, metastasis (TNM) stage 1 LuAdCa resection specimens embedded with or without OCT, and data of activity based multiplex profiles of protein tyrosine kinase peptide substrates were obtained. We found that changes in overall phosphorylation level coincided with the use of OCT and subsequently developed an OCT per peptide median correcting strategy by performing median centering on the values of each peptide. Application of this post-analytical strategy not only can identify changes in kinase activity but can also assist in identifying novel targets for therapeutic intervention against LuAdCa. PMID- 29408475 TI - Optimal route of diphtheria toxin administration to eliminate native nephron progenitor cells in vivo for kidney regeneration. AB - To address the lack of organs for transplantation, we previously developed a method for organ regeneration in which nephron progenitor cell (NPC) replacement is performed via the diphtheria toxin receptor (DTR) system. In transgenic mice with NPC-specific expression of DTR, NPCs were eliminated by DT and replaced with NPCs lacking the DTR with the ability to differentiate into nephrons. However, this method has only been verified in vitro. For applications to natural models, such as animal fetuses, it is necessary to determine the optimal administration route and dose of DT. In this study, two DT administration routes (intra peritoneal and intra-amniotic injection) were evaluated in fetal mice. The fetus was delivered by caesarean section at E18.5, and the fetal mouse kidney and RNA expression were evaluated. Additionally, the effect of the DT dose (25, 5, 0.5, and 0.05 ng/fetus-body) was studied. Intra-amniotic injection of DT led to a reduction in kidney volume, loss of glomeruli, and decreased differentiation marker expression. The intra-peritoneal route was not sufficient for NPC elimination. By establishing that intra-amniotic injection is the optimal administration route for DT, these results will facilitate studies of kidney regeneration in vivo. In addition, this method might be useful for analysis of kidney development at various time points by deleting NPCs during development. PMID- 29408476 TI - A case of giant cell arteritis associated with culture-proven Coxiella burnetii aortitis. AB - A case of proven Coxiella burnetii aortitis, possibly associated with giant cell arteritis (GCA), is reported. A 72-year-old man, who is a hunter, presented with weight loss, fever, jaw claudication, and hardened temporal arteries associated with a persistent inflammatory syndrome and arteritis of the whole aorta, including the brachiocephalic arteries, as seen on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. The diagnosis of GCA was retained, and treatment with prednisolone was started. Given the aneurysm of the abdominal aorta, the patient underwent replacement of the abdominal aorta with an allograft. Histology showed intense chronic arteritis attributed to atherosclerosis with dissection. However, Coxiella burnetii infection was confirmed by serology and then by culture and molecular biology on the surgical specimen. A combination of hydroxychloroquine and doxycycline was added to tapered prednisolone and the outcome was favourable. PMID- 29408477 TI - Development of a clinical prediction rule for the diagnosis of pleural tuberculosis in Peru. AB - OBJECTIVES: To develop a clinical prediction rule (CPR) for the diagnosis of pleural tuberculosis (PT) in patients with pleural exudates in Peru. METHODS: Clinical and laboratory information was collected from patients with exudative pleural effusion attending two reference hospitals in Lima, Peru. Predictive findings associated with PT in a multiple logistic regression model were used to develop the CPR. A definite diagnosis of PT was based on a composite reference standard including bacteriological and/or histological analysis of pleural fluid and pleural biopsy specimens. RESULTS: A total of 238 patients were included in the analysis, of whom 176 had PT. Age, sex, previous contact with a TB patient, presence of lymphadenopathy, and pleural adenosine deaminase (ADA) levels were found to be independently associated with PT. These predictive findings were used to construct a CPR, for which the area under the receiver operating characteristics curve (AUC) was 0.92. The single best cut-off point was a score of >=60 points, which had a sensitivity of 88%, specificity of 92%, a positive likelihood ratio of 10.9, and a negative likelihood ratio of 0.13. CONCLUSIONS: The CPR is accurate for the diagnosis of PT and could be useful for treatment initiation while avoiding pleural biopsy. A prospective evaluation is needed before its implementation in different settings. PMID- 29408479 TI - Neural responses during the anticipation and receipt of olfactory reward and punishment in human. AB - Pleasure experience is an important part of normal healthy life and is essential for general and mental well-being. Many neuroimaging studies have investigated the underlying neural processing of verbal and visual modalities of reward. However, how the brain processes rewards in the olfactory modality is not fully understood. This study aimed to examine the neural basis of olfactory rewards in 25 healthy participants using functional magnetic resonance imaging (fMRI). We developed an Olfactory Incentive Delay (OLID) imaging task distinguishing between the anticipation and receipt of olfactory rewards and punishments. We found that the pallidum was activated during the anticipation of both olfactory rewards and punishments. The bilateral insula was activated independently from the odours' hedonic valence during the receipt phase. In addition, right caudate activation during the anticipation of unpleasant odours was correlated with self-reported anticipatory hedonic traits, whereas bilateral insular activation during the receipt of pleasant odours was correlated with self-reported consummatory hedonic traits. These findings suggest that activity in the insula and the caudate may be biomarkers of anhedonia. These findings also highlight a useful and valid paradigm to study the neural circuitry underlying reward processing in people with anhedonia. PMID- 29408478 TI - Cluster-level statistical inference in fMRI datasets: The unexpected behavior of random fields in high dimensions. AB - Identifying regional effects of interest in MRI datasets usually entails testing a priori hypotheses across many thousands of brain voxels, requiring control for false positive findings in these multiple hypotheses testing. Recent studies have suggested that parametric statistical methods may have incorrectly modeled functional MRI data, thereby leading to higher false positive rates than their nominal rates. Nonparametric methods for statistical inference when conducting multiple statistical tests, in contrast, are thought to produce false positives at the nominal rate, which has thus led to the suggestion that previously reported studies should reanalyze their fMRI data using nonparametric tools. To understand better why parametric methods may yield excessive false positives, we assessed their performance when applied both to simulated datasets of 1D, 2D, and 3D Gaussian Random Fields (GRFs) and to 710 real-world, resting-state fMRI datasets. We showed that both the simulated 2D and 3D GRFs and the real-world data contain a small percentage (<6%) of very large clusters (on average 60 times larger than the average cluster size), which were not present in 1D GRFs. These unexpectedly large clusters were deemed statistically significant using parametric methods, leading to empirical familywise error rates (FWERs) as high as 65%: the high empirical FWERs were not a consequence of parametric methods failing to model spatial smoothness accurately, but rather of these very large clusters that are inherently present in smooth, high-dimensional random fields. In fact, when discounting these very large clusters, the empirical FWER for parametric methods was 3.24%. Furthermore, even an empirical FWER of 65% would yield on average less than one of those very large clusters in each brain-wide analysis. Nonparametric methods, in contrast, estimated distributions from those large clusters, and therefore, by construct rejected the large clusters as false positives at the nominal FWERs. Those rejected clusters were outlying values in the distribution of cluster size but cannot be distinguished from true positive findings without further analyses, including assessing whether fMRI signal in those regions correlates with other clinical, behavioral, or cognitive measures. Rejecting the large clusters, however, significantly reduced the statistical power of nonparametric methods in detecting true findings compared with parametric methods, which would have detected most true findings that are essential for making valid biological inferences in MRI data. Parametric analyses, in contrast, detected most true findings while generating relatively few false positives: on average, less than one of those very large clusters would be deemed a true finding in each brain-wide analysis. We therefore recommend the continued use of parametric methods that model nonstationary smoothness for cluster-level, familywise control of false positives, particularly when using a Cluster Defining Threshold of 2.5 or higher, and subsequently assessing rigorously the biological plausibility of the findings, even for large clusters. Finally, because nonparametric methods yielded a large reduction in statistical power to detect true positive findings, we conclude that the modest reduction in false positive findings that nonparametric analyses afford does not warrant a re analysis of previously published fMRI studies using nonparametric techniques. PMID- 29408480 TI - Understanding the Increased Aggregation Propensity of a Light-Exposed IgG1 Monoclonal Antibody Using Hydrogen Exchange Mass Spectrometry, Biophysical Characterization, and Structural Analysis. AB - This work compares the conformational stability, backbone flexibility, and aggregation propensity of monomer and dimer fractions of an IgG1 monoclonal antibody (mAb) generated on UVA light exposure for up to 72 h collected by preparative size-exclusion chromatography, compared with unstressed control. UVA light exposure induced covalent aggregation, and fragmentation as measured by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and extensive oxidation of specific methionine residues (Met 257, Met 433, and Met 109) in both size fractions identified by reverse phase chromatography coupled to mass spectrometry. Compared with unstressed mAb, both the monomer and dimer fractionated from 72 h UVA light-exposed mAb had decreased thermal melting temperatures (Tm1) by 1.4 degrees C as measured by differential scanning calorimetry, minor changes in tertiary structure as measured by near-UV CD, increased monomer loss, and aggregation on accelerated storage at 35 degrees C. Hydrogen/deuterium exchange mass spectrometry identified local segments with increased flexibility in CH2 and CH3 domains of both size fractions, and decreased flexibility in few segments of Fab and CH1 domains in the dimer fraction. Segment 247-256 in heavy chain, an established aggregation hotspot in IgG1 mAbs had large increase in flexibility in both size fractions compared with unstressed mAb. PMID- 29408482 TI - Ultrasonic extraction, structural characterization, physicochemical properties and antioxidant activities of polysaccharides from bamboo shoots (Chimonobambusa quadrangularis) processing by-products. AB - In this study, a novel polysaccharide (PCPs) was obtained from bamboo shoots (Chimonobambusa quadrangularis) processing by-products through the ultrasonic assisted extraction (UAE) and Sephadex G-100 size-exclusion chromatography purification. By using a Box-Behnken design (BBD) to optimize the parameters for extracting the crude PCPs with UAE, the maximum yield of crude PCPs (8.76%) was obtained under the optimal extraction conditions as follows: ratio of water to raw material 20.2mL/g, extraction temperature 49 degrees C, ultrasonic power 240W, and extraction time 40min. Structurally, PCPs was identified as hetero polysaccharides, which was composed of Man, Rha, GlcA, GalA, Glc, Gal, Xyl, and Ara in a molecular ratio of 1.00:2.05:2.28:2.36:15.76:49.06:16.70:39.86. The molecular weight distribution analysis showed that PCPs had three components with molecular weights of 136.1, 29.7 and 8.3kD, respectively. The glycosidic linkage analysis showed that PCPs contained 1->or 1->6 glycosidic linkages (35.1%), 1->2 or 1->4 glycosidic linkages (14.8%), and 1->3 glycosidic linkages (50.1%). conformations. The obtained results revealed that PCPs with a semi-crystalline structure exhibited important functional properties including the repose angle, swelling index (SC), water retention capacity (WRC), and oil retention capacity (ORC). The viscoelastic property of PCPs system exhibited a gel-like behavior with storage modulus G' always being higher than loss modulus G". PCPs displayed excellent thermal stability as assessed by rheology and TGA/DSC. Furthermore, PCPs exhibited good chemical antioxidant activities in DPPH, ABTS and hydroxyl radical scavenging abilities, and metal chelating activity. PMID- 29408481 TI - MiR-7-5p functions as a tumor suppressor by targeting SOX18 in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Recently, many kinds of microRNAs (miRNAs) have been found to play a significant role in development of PDAC. However, there is no investigation about expression and function of miR-7-5p in PDAC. In this study, we found that miR-7-5p was down regulated in PDAC tissues and its low expression level indicated a poor survival rate for PDAC patients. By bioinformatic analysis, we found that miR-7-5p targeted SOX18, and there was a negative correlation between them in PDAC tissues. Then luciferase reporter and western blot assays were used to verify the binding of miR-7-5p on SOX18 3'UTR. Cell function assays demonstrated that miR-7 5p inhibited proliferation, migration and invasion of PANC-1 cells by targeting SOX18. The nude mouse tumorigenicity assay further proved that miR-7-5p targeted SOX18 to inhibit pancreatic cancer growth in vivo. In order to further understand the mechanism, we applied a transcription factor prediction tool to explore the underlying targets that transcripted by SOX18, and the result indicated that SOX18 was a transcription factor for gp130 (a subunit of IL-6 receptor), and ChIP assays was performed to prove this prediction. Furthermore, we detected the suppression of gp130/JAK2/STAT3 signaling pathway after silencing SOX18 in PANC-1 cells, which demonstrated the transcriptional activation role of SOX18 on gp130. Thus, our present study revealed that miR-7-5p targeted SOX18 to inhibit gp130/JAK2/STAT3 signaling pathway to exert its suppressing role in PDAC. PMID- 29408483 TI - Comparison of Self-Report Versus Sensor-Based Methods for Measuring the Amount of Upper Limb Activity Outside the Clinic. AB - OBJECTIVE: To compare self-reported with sensor-measured upper limb (UL) performance in daily life for individuals with chronic (>=6mo) UL paresis poststroke. DESIGN: Secondary analysis of participants enrolled in a phase II randomized, parallel, dose-response UL movement trial. This analysis compared the accuracy and consistency between self-reported UL performance and sensor-measured UL performance at baseline and immediately post an 8-week intensive UL task specific intervention. SETTING: Outpatient rehabilitation. PARTICIPANTS: Community-dwelling individuals with chronic (>=6mo) UL paresis poststroke (N=64). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Motor Activity Log amount of use scale and the sensor-derived use ratio from wrist-worn accelerometers. RESULTS: There was a high degree of variability between self-reported UL performance and the sensor-derived use ratio. Using sensor-based values as a reference, 3 distinct categories were identified: accurate reporters (reporting difference +/-0.1), overreporters (difference >0.1), and underreporters (difference <-0.1). Five of 64 participants accurately self-reported UL performance at baseline and postintervention. Over half of participants (52%) switched categories from pre-to postintervention (eg, moved from underreporting preintervention to overreporting postintervention). For the consistent reporters, no participant characteristics were found to influence whether someone over- or underreported performance compared with sensor-based assessment. CONCLUSIONS: Participants did not consistently or accurately self-report UL performance when compared with the sensor-derived use ratio. Although self-report and sensor-based assessments are moderately associated and appear similar conceptually, these results suggest self-reported UL performance is often not consistent with sensor measured performance and the measures cannot be used interchangeably. PMID- 29408485 TI - Integrative Structural Investigation on the Architecture of Human Importin4_Histone H3/H4_Asf1a Complex and Its Histone H3 Tail Binding. AB - Importin4 transports histone H3/H4 in complex with Asf1a to the nucleus for chromatin assembly. Importin4 recognizes the nuclear localization sequence located at the N-terminal tail of histones. Here, we analyzed the structures and interactions of human Importin4, histones and Asf1a by cross-linking mass spectrometry, X-ray crystallography, negative-stain electron microscopy, small angle X-ray scattering and integrative modeling. The cross-linking mass spectrometry data showed that the C-terminal region of Importin4 was extensively cross-linked with the histone H3 tail. We determined the crystal structure of the C-terminal region of Importin4 bound to the histone H3 peptide, thus revealing that the acidic patch in Importin4 accommodates the histone H3 tail, and that histone H3 Lys14 contributes to the interaction with Importin4. In addition, we show that Asf1a modulates the binding of histone H3/H4 to Importin4. Furthermore, the molecular architecture of the Importin4_histone H3/H4_Asf1a complex was produced through an integrative modeling approach. Overall, this work provides structural insights into how Importin4 recognizes histones and their chaperone complex. PMID- 29408486 TI - Mutagenicity and genotoxicity studies of aspartame. AB - Two studies were conducted to further assess its mutagenic and genotoxic potential. In a bacterial reverse mutation pre-incubation study, Salmonella typhimurium strains TA100, TA1535, TA98, and TA1537 and Escherichia coli WP2 uvrA were treated with aspartame at concentrations of up to 5000 MUg/plate with or without metabolic activation and showed no mutagenic potential. Similarly, in vivo micronucleus testing of aspartame following gavage administration (500-2000 mg/kg body weight) to Crlj:CD1(ICR) strain SPF male mice showed no increase in the proportion of micronucleated polychromatic erythrocytes in bone marrow cells collected and evaluated 24 or 48 h post administration. Overall, aspartame had no potential for mutagenic or genotoxic activity. PMID- 29408488 TI - Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis. AB - Despite improved therapy, rheumatoid arthritis (RA) remains an unmet medical need. Previous efforts to validate therapeutic targets in the mitogen-activated protein kinase (MAPK) family have had minimal success. Therefore, we evaluated the potential for targeting an upstream MAPK, namely apoptosis signal-regulating kinase 1 (ASK1), as an alternative approach. ASK1 protein and gene expression were observed in RA and osteoarthritis (OA) synovium as determined by immunohistochemistry (IHC) and qPCR, respectively, particularly in the synovial intimal lining. For RA, but not OA synovium, ASK1 correlated with IL-1beta and TNF gene expression. ASK1 was also expressed by cultured fibroblast-like synoviocytes (FLS), with significantly higher levels in RA compared with OA cells. IL-1beta and TNF stimulation significantly increased ASK1 expression in a time-and concentration-dependent manner in cultured FLS. ASK1 promoter activity was significantly increased by IL-1beta and TNF and was dependent on an upstream RelA binding motif. A selective small molecule ASK1 inhibitor reduced RA FLS invasion, migration and proliferation in vitro and decreased arthritis severity in the rat collagen-induced arthritis (CIA) model. In summary, our findings demonstrate that ASK1 modulates signaling pathways relevant to RA in vitro and in vivo. It is induced by inflammatory cytokines through the activation of NF kappaB, which could provide some site- and event specificity. Thus, inhibitors of the upstream MAPK ASK1 could be a novel approach to treating inflammatory arthritis. PMID- 29408487 TI - Probing the role of ceramide hydroxylation in skin barrier lipid models by 2H solid-state NMR spectroscopy and X-ray powder diffraction. AB - In this work, we studied model stratum corneum lipid mixtures composed of the hydroxylated skin ceramides N-lignoceroyl 6-hydroxysphingosine (Cer[NH]) and alpha-hydroxylignoceroyl phytosphingosine (Cer[AP]). Two model skin lipid mixtures of the composition Cer[NH] or Cer[AP], N-lignoceroyl sphingosine (Cer[NS]), lignoceric acid (C24:0) and cholesterol in a 0.5:0.5:1:1 molar ratio were compared. Model membranes were investigated by differential scanning calorimetry and 2H solid-state NMR spectroscopy at temperatures from 25 degrees C to 80 degrees C. Each component of the model mixture was specifically deuterated for selective detection by 2H NMR. Thus, the exact phase composition of the mixture at varying temperatures could be quantified. Moreover, using X-ray powder diffraction we investigated the lamellar phase formation. From the solid state NMR and DSC studies, we found that both hydroxylated Cer[NH] and Cer[AP] exhibit a similar phase behavior. At physiological skin temperature of 32 degrees C, the lipids form a crystalline (orthorhombic) phase. With increasing temperature, most of the lipids become fluid and form a liquid-crystalline phase, which converts to the isotropic phase at higher temperatures (65-80 degrees C). Interestingly, lignoceric acid in the Cer[NH]-containing mixture has a tendency to form two types of fluid phases at 65 degrees C. This tendency was also observed in Cer[AP]-containing membranes at 80 degrees C. While Cer[AP] containing lipid models formed a short periodicity phase featuring a repeat spacing of d = 5.4 nm, in the Cer[NH]-based model skin lipid membranes, the formation of unusual long periodicity phase with a repeat spacing of d = 10.7 nm was observed. PMID- 29408489 TI - CCR5Delta32 in HCV infection, HCV/HIV co-infection, and HCV-related diseases. AB - Although a potential involvement of the CCR5Delta32 variant has already been suggested in relation to susceptibility to hepatitis C virus (HCV) infection, data from the literature is still quite controversial. Thus, our study evaluated the influence of the CCR5Delta32 allele variant in HCV infection, HCV/HIV co infection, and HCV-related diseases in individuals from southern Brazil. A total of 1352 individuals were included in this study, divided into the following groups: Control (n = 274); HCV+ (n = 674); HIV+ (n = 300); HCV+/HIV+ (n = 104). Individuals from the HCV+ group were further stratified according to clinical/histological criteria, as HCV+/control (n = 124); HCV+/fibrosis (n = 268); HCV+/cirrhosis (n = 190); HCV+/hepatocarcinoma (n = 92). Considering all individuals included in this study, the following genotype frequencies were observed: wild-type homozygous (wt/wt), 88.76%; heterozygous (wt/Delta32), 10.72%; variant homozygous (Delta32/Delta32), 0.52%. Genotypic frequencies were very similar between the groups. Of note, the frequency of the Delta32 homozygous was quite similar comparing control uninfected against the HCV+ individuals (p > 0.999). The overall Delta32 allele frequency was estimated at 5.88%. Considering the number of Delta32 allele carriers and non-carriers, no statistically significant differences (p > 0.05) between the groups were observed, suggesting that the CCR5Delta32 variant does not influence the susceptibility to HCV infection, HCV/HIV co-infection, or HCV-related diseases in individuals from southern Brazil. PMID- 29408490 TI - Gender aspects in cardiopulmonary resuscitation by schoolchildren: A systematic review. AB - AIM: Bystander CPR-rates are embarrassingly low in some European countries. To increase bystander CPR-rates, many different approaches are used; one of them is training of schoolchildren in CPR. Multiple authors investigated practical and theoretical CPR performance and demonstrated gender differences related to schoolchildren CPR. The objective was to elaborate gender aspects in practical and theoretical CPR-performance from the current literature to better address female and male students. METHODS: A systematic search in PubMed-database with different search terms was performed for controlled and uncontrolled prospective investigations. Altogether, n = 2360 articles were identified and checked for aptitude. From n = 97 appropriated articles, n = 24 met the inclusion criteria and were finally included for full review and incorporated in the manuscript. RESULTS: Female students demonstrated higher motivation to attend CPR-training (p < 0.001), to respond to cardiac arrest (CA) (p < 0.01), scored higher in a CPR questionnaire (p < 0.025), revealed better remembrance of the national emergency phone-number (p < 0.05) and showed a higher multiplier effect (p < 0.0001). Male students showed higher confidence in CPR-proficiency (p < 0.05), revealed deeper chest compressions (CC) (p < 0.001; p < 0.0015; p < 0.01), a higher CC-fraction (p < 0.01) and a higher arbitrary cardiac output simulated equivalent index (p < 0.05). Male gender could not be detected to be a predictor for higher tidal volume (p = 0.70; p = 0.0212). CONCLUSION: In context of schoolchildren CPR, gender aspects are underestimated. Female students seem to be more motivated to attend CPR-training, reach more people in the role of a multiplier and need to be individually addressed in intensified practical training. Male students achieve a more sufficient chest compression depth and -fraction and could benefit from individual motivation. PMID- 29408491 TI - NOD2-RIP2 contributes to the inflammatory responses of mice in vivo to Streptococcus pneumoniae. AB - The objectives of this study were to investigate the role of the NOD2-RIP2 pathway in host responses to the gram-positive bacteria Streptococcus pneumoniae and to evaluate the effect of the RIP2 inhibitor gefitinib in a mouse model of S. pneumoniae meningitis. Mice were randomly divided into a normal saline control group (NS group), an S. pneumoniae meningitis group (SP group), a gefitinib group and a vehicle group. Animals in the NS group were sham-infected with sterile saline. Mice in the other three groups were inoculated with S. pneumoniae and left untreated, treated with gefitinib, or treated with vehicle. The results revealed upregulation of the mRNA and protein levels of NOD2, RIP2, NF-kappaB, TNF-alpha and IL-6 within the CNS of mice with S. pneumoniae meningitis. Moreover, mice in the meningitis group were severely ill and demonstrated a significant loss of neurons. Treatment with the RIP2 inhibitor gefitinib showed less intense activation of NF-kB, decreased TNF-alpha and IL-6, attenuated neuronal injury and improved illness. These results suggest that NOD2-RIP2 is involved in the host response to the gram-positive bacteria S. pneumoniae in the CNS and that the RIP2 inhibitor gefitinib protects the brain from damage caused by S. pneumoniae. PMID- 29408484 TI - Evaluating psychosocial contributions to chronic pain outcomes. AB - The biopsychosocial model of pain dominates the scientific community's understanding of chronic pain. Indeed, the biopsychosocial approach describes pain and disability as a multidimensional, dynamic integration among physiological, psychological, and social factors that reciprocally influence one another. In this article, we review two categories of studies that evaluate the contributions of psychosocial factors to the experience of chronic pain. First, we consider general psychosocial variables including distress, trauma, and interpersonal factors. Additionally, we discuss pain-specific psychosocial variables including catastrophizing, expectations, and pain-related coping. Together, we present a diverse array of psychological, social, and contextual factors and highlight the need to consider their roles in the development, maintenance, and treatment of chronic pain conditions. PMID- 29408492 TI - Transcriptomic analyses of chemokines reveal that down-regulation of XCR1 is associated with advanced hepatocellular carcinoma. AB - Chemokines are essential coordinators of cellular migration and cell-cell interactions, therefore considerable attention has been paid to the application of chemokines to cancer immunotherapy. In this study, we screened for the expression levels of 58 human chemokines/chemokine receptors in hepatocellular carcinoma (HCC) by using samples from the TCGA LIHC cohort and found 16 consistently down-regulated and 11 up-regulated chemokine genes in HCC compared with normal samples. Furthermore, the expressions of XCR1 were verified by Western blot in liver cancer cell lines. We used CCK8, plate cloning formation, scratch-wound and transwell analysis to measure the ability of proliferation, metastasis and invasion, respectively. Protein expression was analyzed by cell immunofluorescence and western-blot. We found that silencing XCR1 promoted, while overexpressing XCR1 inhibited, HCC cell migration and invasion in vitro, its mechanism may involve in inhibition of Epithelial Mesenchymal Transition (EMT). However, the overexpression of XCR1 in HCCLM3 in vitro can restrain the growth partially due to the inhibition of MAPK and PI3K/AKT signaling pathway. Gene Set Enrichment Analysis (GSEA) showed that high expression of XCR1 is positively associated with EMT, which is closely associated with tumor migration and invasion. Our study provides the basis for further investigation of the molecular mechanism by which down-regulation of XCR1 promotes the development and progression of HCC. PMID- 29408493 TI - Blood-meal preferences and avian malaria detection in mosquitoes (Diptera: Culicidae) captured at different land use types within a neotropical montane cloud forest matrix. PMID- 29408495 TI - Multimodality Management of Vein of Galen Malformations-An Institutional Experience. AB - BACKGROUND: The vein of Galen aneurysmal malformation (VGM) is a rare intracranial arteriovenous fistula with a dramatic manifestation during infancy and 100% mortality without treatment. Therapeutic strategies for VGMs have changed over time as a result of advances in endovascular techniques. We present our experience and multimodality approach within the last 4 decades. METHODS: A retrospective analysis and angiographic review were performed of patients with VGM between 1975 and 2016 at our institution. RESULTS: Eighteen consecutive patients were identified, including 10 with choroidal and 8 with mural VGMs. In 37 endovascular interventions, a transarterial approach was mostly performed (82.8%). One patient was initially treated surgically and received 2 Gamma Knife treatments after multiple embolizations. The preferred embolization agent was histoacryl for choroidal VGMs and a combination of coils and histoacryl for mural VGMs. Total occlusion was achieved in 87.5% of mural VGMs and 11.1% of choroidal VGMs. Cerebral hemorrhages and infarction occurred only in patients younger than 1 month. At a median follow-up interval of 4.6 years, good outcome was achieved in 53.8% and poor outcome in 46.2%, with an overall mortality of 16.7%. Poor outcome was significantly associated with choroidal-type VGMs, age <1 month at first embolization, and incomplete occlusion. CONCLUSIONS: Endovascular embolization using a transarterial approach is the therapy of choice. Gamma Knife radiosurgery can be considered as second-line therapy in a multimodal approach. Whereas treatment within the first month of life is associated with the highest mortality and complications, we did not detect any severe adverse events thereafter. PMID- 29408494 TI - Ultradense Middle Cerebral Artery: Specific Sign of Cerebral Lipiodol Embolization. AB - Cerebral lipiodol embolization is a rare but known complication of lymphatic embolization for plastic bronchitis. The classic imaging finding on a noncontrast head computed tomography is multiple small areas of hyperdensity within the cerebral hemispheres, which represent lipiodol deposition in the brain. We report a case of lipiodol deposition in the middle cerebral artery following lymphatic embolization, producing an "ultradense" vessel sign on noncontrast computed tomography. PMID- 29408496 TI - Steroid Allergy: Clinical Features and the Importance of Excipient Testing in a Diagnostic Algorithm. AB - BACKGROUND: True corticosteroid (CS) allergy is rare. Instead, many patients may be allergic to excipients found in various CS preparations. Excipient testing is frequently overlooked. It might lead to unnecessary CS avoidance or dangerous re exposure. OBJECTIVE: The objective of this study was to evaluate the clinical characteristics and frequency of excipient allergy in patients with confirmed type I hypersensitivity to systemic CS preparations. METHODS: Patients with a confirmed diagnosis of allergy (positive skin test or drug provocation test [DPT]) or tolerance (negative DPT to CS) over the past 10 years were studied. Patient characteristics, index CS, route of administration, clinical indications, symptoms of index reaction, and outcomes of CS/excipient allergy testing were analyzed. RESULTS: Sixty-four patients underwent CS allergy testing. True CS allergy was confirmed in 9 of 64 (14%) patients. The majority (5/9, 56%) with positive skin tests or DPT were actually allergic to the excipients (2 to carboxymethylcellulose and 3 to polyethylene glycol) rather than the CS. Respiratory manifestations were significantly associated with confirmed allergy (odds ratio = 6.79 [95% confidence interval = 1.36-34.03], P = .02). CONCLUSIONS: Patients with respiratory manifestations were significantly more likely to be truly allergic. CS allergies are rare and may be overdiagnosed without excipient testing. We suggest the use of Carmellose eye drops as a readily available source of carboxymethylcellulose for testing and propose a comprehensive diagnostic algorithm for suspected CS allergy. PMID- 29408497 TI - A transcriptomic analysis of turmeric: Curcumin represses the expression of cholesterol biosynthetic genes and synergizes with simvastatin. AB - The spice turmeric (Curcuma longa L.) has a long history of use as an anti inflammatory agent. The active component curcumin induces a variety of diverse biological effects and forms a series of degradation and metabolic products in vivo. Our hypothesis is that the field of toxicogenomics provides tools that can be used to characterize the mode of action and toxicity of turmeric components and to predict turmeric-drug interactions. Male Sprague-Dawley rats were treated for 4 days with turmeric root containing about 3% curcumin (comparable to what people consume in the fresh or dried root) or a fraction of turmeric enriched for curcumin (~74%) and liver tissue collected for gene expression analysis. Two doses of each agent were added to the diet, corresponding to 540 and 2700 mg/kg body weight/day of turmeric. The transcriptomic effects of turmeric on rat liver tissue were examined using 3 programs, ToxFx Analysis Suite, in the context of a large drug database, Ingenuity Pathway and NextBio analyses. ToxFx analysis indicates that turmeric containing about 3% or 74% curcumin represses the expression of cholesterol biosynthetic genes. The dose of 400 mg/kg b.w./day curcumin induced the Drug Signature associated with hepatic inflammatory infiltrate. Ingenuity analysis confirmed that all 4 turmeric treatments had a significant effect on cholesterol biosynthesis, specifically the Cholesterol biosynthesis superpathway and Cholesterol biosynthesis 1 and 2. Among the top 10 up or downregulated genes, all 4 treatments downregulated PDK4; while 3 treatments downregulated ANGPTL4 or FASN. These findings suggest curcumin may enhance the anticancer effects of certain classes of statins, which we confirmed with biological assays. Given this enhancement, lower levels of statins may be required, and even be desirable. Our findings also warn of possible safety issues, such as potential inflammatory liver effects, for patients who ingest a combination of certain classes of statins and curcumin. Transcriptomic analysis suggests that turmeric is worthwhile to study to prevent and treat cancer and lipid disorders. Our approach lays new groundwork for studies of the mode of action and safety of herbal medicines and can also be used to develop a methodology to standardize herbal medicines. PMID- 29408498 TI - Dysfunctional Limbic Circuitry Underlying Freezing of Gait in Parkinson's Disease. AB - Freezing of gait (FOG) is a poorly understood symptom affecting many patients with Parkinson's disease (PD). Despite growing evidence of a behavioral link between anxiety, attention and FOG in PD, no research to date has investigated the neural mechanisms that might explain this relationship. The present study therefore examined resting-state MRI functional connectivity between the amygdala, striatum and frontoparietal attentional control network in PD patients with (freezers: n = 19) and without FOG (non-freezers: n = 21) in the dopaminergic 'off' state. Functional connectivity was subsequently correlated with an objective measure of FOG severity and a subjective scale of affective disorder within each group. Connectivity between the right amygdala and right putamen was significantly increased in freezers compared to non-freezers (p < 0.01). Furthermore, freezers showed increased anti-coupling between the frontoparietal network and left amygdala (p = 0.011), but reduced anti-coupling between this network and the right putamen (p = 0.027) as compared to non freezers. Key functional connections between the amygdala, putamen and frontoparietal network were significantly associated with FOG severity and a fear of falling. This study provides the first evidence that dysfunctional fronto striato-limbic processes may underpin the link between anxiety and FOG in PD. It is proposed that freezers have heightened striato-limbic load and reduced top down attentional control at rest, which when further challenged by the parallel processing demands of walking may precipitate FOG. PMID- 29408499 TI - Activation of AMP-activated protein kinase (AMPK) aggravated postoperative cognitive dysfunction and pathogenesis in aged rats. AB - The upstream signal molecule modulating neuro-inflammation and synaptic changes during the pathogenesis of postoperative cognitive dysfunction (POCD) is still elusive. Here, we examined the effects and mechanisms of energy sensor AMP activated protein kinase (AMPK) in the pathogenesis of POCD. Our data showed that surgery significantly increased the expression of p-AMPK in aged rats (p < 0.05), but not in adult rats (p > 0.05). Moreover, inhibiting AMPK activation via compound C during operation significantly improved surgery-induced impairment of the learning and memory of aged rats in water maze (p < 0.05). Further mechanism studies showed that corresponding to the impairment of learning and memory after surgery, surgery significantly increased the activation of microglia, decreased the expressions of NR2B and p-NR2B, and increased the expressions of Tau and p Tau, which also were obviously restored by inhibiting AMPK during operation. In contrast, Inhibiting AMPK activation during operation didn't change ATP level in the hippocampus of aged rats after surgery. These data suggest that surgery induced activation of AMPK in hippocampus in an age-dependent manner. AMPK plays important roles in POCD of aged rats via multiple mechanisms, and is a possible molecular target for the prevention and treatment of POCD. PMID- 29408500 TI - MicroRNA let-7c-5p improves neurological outcomes in a murine model of traumatic brain injury by suppressing neuroinflammation and regulating microglial activation. AB - MicroRNAs (miRNAs) are a class of non-coding small RNAs that regulate the expression of target genes. They derive from pre-miRNAs that are enzymatically processed by dicer to ~22 nucleotide mature miRNAs. Members of the pre-miRNA lethal-7 (let-7) are known to regulate cell proliferation and apoptosis. Here, we showed that the level of let-7c-5p, a key member of the let-7 family, was rapidly reduced in the traumatically injured foci in brains of adult C57BL/6J mice and gradually recovered to the pre-injury level 14 days after traumatic brain injury (TBI) induction. This finding led us to test whether upregulating let-7c-5p in murine cerebral tissue by intracerebroventricular injection (ICV) of let-7c-5p mimic could improve the outcomes of mice subjected to controlled cortical impact (CCI). We found that let-7c-5p overexpression attenuated TBI-induced neurological dysfunction and brain edema. The improvements were attributed to let-7c-5p mediated inhibiting neuroinflammation and attenuation of microglia/macrophage activation, both inhibiting M1 polarization and enhancing M2 polarization. In vitro experiments, we observed that let-7c-5p was decreased in primary microglia activated by LPS treatment or oxygen/glucose deprivation (OGD). Transfection of let-7c-5p mimic suppressed the release of inflammatory mediators in cultured activated primary microglia. In addition, the expressions of caspase-3, a let-7c 5p putative target gene, and the PKC-delta which mediates effect of caspase-3 were inhibited by let-7c-5p in a murine model of TBI. Taken together, these results define the biological activities of cerebral let-7c-5p and delineate its therapeutic potential for improving the neurological outcome of TBI. PMID- 29408501 TI - Intrinsic optical imaging study on cortical responses to electrical stimulation in ventral posterior medial nucleus of thalamus. AB - Intracortical electrical micro-stimulation has been applied widely for the attempts on reconstruction of sensory functions. More recently, thalamic electrical stimulation has been proposed as a promising target for somatosensory stimulation. However, the cortical activations and mechanisms evoked by VPM stimulation remained unclear. In this report, the cortical neural responses to electrical stimulations were recorded by optical imaging of intrinsic signals. The impact of stimulation parameters was characterized to illustrate how the VPM stimulation alter cortical activities. Significant increases were found in cortical responses with increased stimulation amplitude or pulse width. However, frequency modulation exhibited significant inhibition with higher frequency stimulation. Our results suggest that optical imaging of intrinsic signals is sensitive and reliable to deep brain stimulations. These results may not only help to understand the modulation effects through thalamocortical pathway, but also show the possibility to use VPM stimulation to evoke frequency-tuned tactile sensations in rats. PMID- 29408502 TI - GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro. AB - Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and functionally unique. Previously, we showed that transcription factor Gata4 acts as a master regulator controlling LSEC differentiation. Upon analysis of the molecular signature of LSEC, we identified GPR182 as a potential LSEC-specific orphan G-protein coupled receptor (GPCR). Here, we demonstrate that GPR182 is expressed by LSEC and by EC with sinusoidal differentiation in spleen, lymph node and bone marrow in healthy human tissues. In a tissue microarray analysis of human hepatocellular carcinoma (HCC) samples, endothelial GPR182 expression was significantly reduced in tumor samples compared to peritumoral liver tissue samples (p = 0.0105). Loss of endothelial GPR182 expression was also seen in fibrotic and cirrhotic liver tissues. In vitro, GPR182 differentially regulated canonical GPCR signaling pathways as shown using reporter luciferase assays in HEK293T cells. Whereas ERK and RhoA signaling were inhibited, CREB and Calcium signaling were activated by ectopic GPR182 overexpression. Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability. PMID- 29408503 TI - Common traffic routes for imported spermine and endosomal glypican-1-derived heparan sulfate in fibroblasts. AB - Import of the polyamine spermine from the extracellular environment depends on the presence of cell surface heparan sulfate proteoglycans, such as glypican-1. This proteoglycan is internalized by endocytosis, releases its heparan sulfate chains in endosomes by a nitric oxide-, copper- and amyloid precursor protein dependent mechanism, then penetrates the membrane and is transported to the nucleus and then to autophagosomes. This process is spontaneous or induced by ascorbate depending on the growth-state of the cell. Here, we have explored possible connections between the heparan sulfate traffic route and spermine uptake and delivery in wild-type and Tg2576 mouse fibroblasts. Cells were examined by deconvolution immunofluorescence microscopy. The antibodies used were specific for spermine, glypican-1-derived heparan sulfate, Rab7, nucleolin and a marker for autophagosomes. Endogenous immunostainable spermine was primarily associated with autophagosomes. When spermine synthesis was inhibited, imported spermine appeared in Rab7-positive endosomes. When ascorbate was added, heparan sulfate and spermine were transported to the nucleus where they colocalized with nucleolin. Spermine also appeared in autophagosomes. In a pulse-chase experiment, heparan sulfate and spermine were first arrested in late endosomes by actinomycin D treatment. During the chase, when arrest was abolished, heparan sulfate and spermine were both transported to the nucleus and targeted nucleolin. In amyloid precursor protein-/--fibroblasts, ascorbate failed to induce release of heparan sulfate and spermine remained in the endosomes. We propose that cell surface glypican-1 carries spermine to the endosomes and that the released heparan sulfate carries spermine across the membrane into the cytosol and then to the nucleus. PMID- 29408504 TI - Autocrine activation of platelet-derived growth factor receptor alpha in metastatic papillary thyroid cancer. AB - Metastatic dissemination of papillary thyroid cancer has been reported to be strongly associated with expression of platelet-derived growth factor (PDGFR) alpha and altered TTF1 function. However, the status of PDGF ligands in papillary thyroid cancer and the potential role of these ligands in metastatic disease are obscure. We assessed the prevalence of PDGF ligands in benign and malignant thyroid tumors to determine if ligand upregulation is associated with alpha isoform (PDGF-AA or PDGF-BB) or the beta-isoform (PDGF-BB or PDGF-DD) of PDGFR in individual tumors. The immunohistochemical expression of PDGFRalpha, PDGF-AA, PDGF-BB, and PDGF-DD was surveyed in follicular adenomas (n=55), papillary thyroid carcinomas (103 with and 59 without nodal metastases), and lymph node metastasis (n=12). There is an augmented tendency for PDGF-AA expression in node positive papillary thyroid cancer metastases (P<.0001). Although PDGF-BB and -DD were commonly identified, there was no relationship between the presence of these cytokines and malignant disease or metastases. Logistic regression demonstrated that PDGF-AA expression was significantly associated with the presence of PDGFRalpha (odds ratio=4.6, P=.004) and recurrent disease. When either PDGFRalpha or PDGF-AA was used to predict the presence of metastases, the sensitivity achieved was 86% and 88%, respectively, whereas specificities were lower at 71% and 61%, respectively. The augmented coexpression of PDGF-AA and PDGFRalpha in metastatic papillary thyroid cancers suggests that an autocrine signaling loop may contribute to nodal infiltration. Combined testing for the expression of PDGF AA and PDGFRalpha may identify those patients with papillary thyroid cancer at risk of metastatic disease and resistance to therapy. PMID- 29408505 TI - Mixture risk assessment of selected mainstream cigarette smoke constituents generated from low-yield cigarettes in South Korean smokers. AB - A total of 38 hazardous constituents in mainstream cigarette smoke of low-yield cigarettes sold in Korea were selected and analyzed using established methods. Risk calculations were performed using risk algorithms employed in previous studies and Korean population-based exposure parameters. The median cumulative incremental lifetime cancer risk of male smokers could vary from 828 * 10-6 to 2510 * 10-6, and that of female smokers could range from 440 * 10-6 to 1300 * 10 6, depending on the smoking regimens. The median hazard index as the sum of hazard quotients of male smokers varied from 367 to 1,225, and that of female smokers varied from 289 to 970, depending on the smoking regimens. The sensitivity analysis for this risk assessment indicated that the constituent yields in mainstream cigarette smoke, average number of cigarettes smoked per day or year, and mouth-spill rate are the main risk factors. Statistical positive correlations between the average daily dose calculated by the exposure algorithm used in this study for individual smokers and biomarkers verified the reliability of this assessment. It could be concluded that inhalation of the constituents present in the mainstream of low-yield cigarettes has significant cancer and non cancer health risks, although its effect on risk reduction is still unknown under the fixed machine-smoking conditions. PMID- 29408507 TI - Have Recent Modifications of Operating Room Attire Policies Decreased Surgical Site Infections? An American College of Surgeons NSQIP Review of 6,517 Patients. AB - BACKGROUND: After a Department of Health site visit, 2 teaching hospitals imposed strict regulations on operating room attire, including full coverage of ears and facial hair. We hypothesized that this intervention would reduce superficial surgical site infections (SSIs). STUDY DESIGN: We compared NSQIP data from all patients undergoing operations in the 9 months before implementation (n = 3,077) to time-matched data 9 months post-implementation (n = 3,440). Univariate and multivariable analyses were used to examine patient, clinical, and operative factors associated with SSIs. Power analysis was performed using pre-intervention SSI rates. RESULTS: Despite a shift toward more clean cases, there were more SSIs post-implementation (33 vs 30 [1%]; p = 0.95). There were no differences in length of stay, complications, or mortality between the 2 time periods. Overall, SSI increased with wound class: 0.6%, 0.9%, 2.3%, and 3.8% in clean, clean contaminated, contaminated, and infected cases, respectively. Limiting the review to clean or clean-contaminated cases, incisional SSIs increased from 0.7% (20 of 2,754) to 0.8% (24 of 3,115) (p = 0.85). A multivariable analysis showed that implementation of these policies was not associated with decreased SSIs (odds ratio 1.2; 95% CI 0.70 to 1.96; p = 0.56). The largest predictors of SSIs were preoperative infection, operative time >75th percentile, open wounds, and dirty/contaminated wounds. A hypothetical analysis revealed that a sample size of 485,154 patients would be required to demonstrate a 10% SSI reduction among patients with clean or clean-contaminated wounds. CONCLUSIONS: Implementation of stringent operating room attire policies do not reduce SSI rates. A study to prove this principle further would be impractical to conduct. PMID- 29408506 TI - Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume >=15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT. PMID- 29408508 TI - Role of LRRK2 in manganese-induced neuroinflammation and microglial autophagy. AB - Overexposure to manganese (Mn) leads to manganism and neurotoxicity induced by Mn is the focus of recent research. Microglia play a vital role in Mn-induced neurotoxicity, and our previous studies firstly showed that Mn could stimulate activation of microglia, leading to the neuroinflammation, and inhibition of microglial inflammation effectively attenuated Mn-induced death of dopamine neurons. However, the detailed mechanism of manganese-induced neuroinflammation is still unclear. Leucine rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of many neurodegenerative disorders. Recent studies have indicated that LRRK2, which is highly expressed in microglia, plays a specific role in microglia and autophagy process. In this paper, we try to find the effect of LRRK2 on Mn-triggered neuroinflammation and its possible mechanism in vivo and in vitro. By establishing a Mn exposure animal model, our studies found that Mn exposure could induce dopaminergic neurons damage and activate microglia. Activated microglia triggered neuroinflammation by releasing multiple inflammatory cytokines, and the expression of LRRK2 was upregulated in vivo and in vitro. We also found that Mn exposure induced autophagy dysfunction in vivo and in vitro. Next, we used LRRK2 siRNA and LRRK2-IN-1 to inhibit the expression of LRRK2, and found that inhibition of LRRK2 could not only decrease the expression of inflammatory cytokines, but also recover autophagic function of microglia. Our investigation not only reveals the role of LRRK2 in Mn-induced neuroinflammation but also sheds light on the prevention and protection of manganism. PMID- 29408509 TI - MAD2-p31comet axis deficiency reduces cell proliferation, migration and sensitivity of microtubule-interfering agents in glioma. AB - Mitotic arrest deficient-like-1 (MAD2, also known as MAD2L1) is thought to be an important spindle assembly checkpoint protein, which ensures accurate chromosome segregation and is closely associated with poor prognosis in many cancer. As a MAD2 binding protein, p31comet counteracts the function of MAD2 and leads to mitotic checkpoint silence. In this study, we explore the function of MAD2 p31comet axis in malignant glioma cells. Our results showed that disruption of MAD2-p31comet axis by MAD2 knockdown or p31comet overexpression suppressed cell proliferation, survival and migration of glioma, indicating that MAD2-p31comet axis is required for maintaining glioma cells malignancy. It is noted that MAD2 depletion or p31comet overexpression reduced the sensitivity of glioma cells to microtubule-interfering agents paclitaxel and vinblastine, providing clinical guidance for application of such drugs. Taken together, our findings suggest that MAD2-p31comet axis may serve as a potential therapeutic target for glioma. PMID- 29408510 TI - Structure-Function Relationships for Recombinant Erythropoietins: A Case Study From a Proposed Manufacturing Change With Implications for Erythropoietin Biosimilar Study Designs. AB - Comparability studies used to assess a proposed manufacturing change for a biological product include sensitive analytical studies to confirm there are no significant differences in structural or functional attributes that may contribute to clinically meaningful changes in efficacy or safety. When a proposed change is relatively complex or when clinically relevant differences between the product before and after the change cannot be ruled out based on analytical studies, nonclinical and clinical bridging studies are generally required to confirm overall comparability. In this study, we report findings from a comparability assessment of epoetin alfa before and after a proposed manufacturing process change. Although differences in glycosylation attributes were observed, these were initially believed to be irrelevant to the product's pharmacology. This assumption was initially supported via nonclinical and clinical pharmacology studies, but a clinically meaningful difference in potency was ultimately observed in a phase 3 clinical study conducted in a sensitive patient population using a sensitive study design. These results indicate that the nonclinical assessments of structure-function relationships were insufficiently sensitive to identify clinically relevant differences resulting from differences in the glycosylation profile. This case study highlights important findings that may be relevant in the development of biosimilar epoetin alfa products. PMID- 29408511 TI - Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function. AB - Unlike other antiresorptive medications, bisphosphonate molecules accumulate in the bone matrix. Previous studies of side-effects of anti-resorptive treatment focused mainly on systemic effects. We hypothesize that matrix-bound bisphosphonate molecules contribute to the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this study, we examined the effect of matrix bound bisphosphonates on osteoclast differentiation in vitro using TRAP staining and resorption assay, with and without pretreatment with EDTA. We also tested the effect of zoledronate chelation on the healing of post-extraction defect in rats. Our results confirmed that bisphosphonates bind to, and can be chelated from, mineralized matrix in vitro in a dose-dependent manner. Matrix-bound bisphosphonates impaired the differentiation of osteoclasts, evidenced by TRAP activity and resorption assay. Zoledronate-treated rats that underwent bilateral dental extraction with unilateral EDTA treatment showed significant improvement in mucosal healing and micro-CT analysis on the chelated sides. The results suggest that matrix-bound bisphosphonates are accessible to osteoclasts and chelating agents and contribute to the pathogenesis of BRONJ. The use of topical chelating agents is a promising strategy for the prevention of BRONJ following dental procedures in bisphosphonate-treated patients. PMID- 29408512 TI - Protein Kinase C-zeta stimulates colorectal cancer cell carcinogenesis via PKC zeta/Rac1/Pak1/beta-Catenin signaling cascade. AB - Colorectal cancer (CRC) is the second most common cancer in the world and death from CRC accounts for 8% of all cancer deaths both in men and women in the United States. CRC is life-threatening disease due to therapy resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter & intracellular signaling pathways involved in CRC is still a significant challenge. Hence, investigating the signaling pathways that lead to colon carcinogenesis may give insight into the therapeutic target. In this study, the role of atypical Protein Kinase C (aPKC) on CRC was investigated by using two inhibitors of that protein class: 1) zeta-Stat (8-hydroxynaphthalene-1,3,6 trisulfonic acid) is a specific inhibitor of PKC-zeta and 2) ICA-I 5-amino-1-(2,3 dihydroxy-4-hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide) is a specific inhibitor of PKC-iota. The cell lines tested were CCD18CO normal colon epithelial and LOVO metastatic CRC cells. The inhibition of aPKCs did not bring any significant toxicity on CCD18CO normal colon cell line. Although PKC-iota is an oncogene in many cancers, we found the overexpression of PKC-zeta and its direct association with Rac1. Our findings suggest that the PKC-zeta may be responsible for the abnormal growth, proliferation, and migration of metastatic LOVO colon cancer cells via PKC-zeta/Rac1/Pak1/beta-Catenin pathway. These results suggest the possibility of utilizing PKC-zeta inhibitor to block CRC cells growth, proliferation, and metastasis. PMID- 29408513 TI - Cholesterol induced asymmetry in DOPC bilayers probed by AFM force spectroscopy. AB - Cholesterol induced mechanical effects on artificial lipid bilayers are well known and have been thoroughly investigated by AFM force spectroscopy. However, dynamics of cholesterol impingement into bilayers at various cholesterol concentrations and their effects have not been clearly understood. In this paper we present, the effect of cholesterol as a function of its concentration in a simple single component dioleoylphosphatidylcholine (DOPC) bilayer. The nature of measured breakthrough forces on a bilayer with the addition of cholesterol, suggested that it is not just responsible to increase the mechanical stability but also introduces irregularities across the leaflets of the bilayer. This cholesterol induced asymmetry across the (in the inner and outer leaflets) bilayer is related to the phenomena of interleaflet coupling and is a function of cholesterol concentration probed by AFM can provide an unprecedented direction on mechanical properties of lipid membrane as it can be directly correlated to biophysical properties of a cell membrane. PMID- 29408514 TI - Real-time imaging of synaptic vesicle exocytosis by total internal reflection fluorescence (TIRF) microscopy. AB - Synaptic vesicles are one of the smallest organelle in the cell with their sizes far below the diffraction limit of the light microscopy. Exocytosis at the synapse is tightly regulated reaction which typically occurs within a millisecond after the arrival of an action potential. It has been assumed that synaptic vesicles have to be ready for immediate exocytosis upon the arrival of final trigger before exocytosis. But direct observation of the pre-exocytotic synaptic vesicle dynamics have been lacking. Total internal reflection microscopy (TIRFM) is a fluorescence microscopy which has best z-axis resolution (~100 nm) as a light microscopy, and is close to that of the ultrathin section used for electron microscopy. Although its application is limited to the objects just beneath the plasma membrane, TIRFM has revealed dynamics of various organelles and proteins. We recently managed to dissociate mammalian neuronal presynaptic terminals and let the exocytotic sites adhere tightly to the coverslip. There, TIRFM revealed the detailed dynamics of pre-exocytotic vesicles. Our work opened up the way to visualize dynamics of sub-diffraction limited sized organelle in a real time, and will be useful for direct visualization of various synaptic components in the future. PMID- 29408515 TI - Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer. AB - The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment. To this purpose, a number of databases were used to search for the cytotoxic/anticancer effects of andrographolide in pre-clinical and clinical studies. Among 1703 identified literature articles, 139 were included in this review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre clinical trials, respectively. Among the model systems, cultured cell lines appeared as the most frequently (79.14%) used, followed by in vivo models using rodents, among others. Furthermore, andrographolide was found to exert cytotoxic/anticancer effects on almost all types of cell lines with the underlying mechanisms involving oxidative stress, cell cycle arrest, anti inflammatory and immune system mediated effects, apoptosis, necrosis, autophagy, inhibition of cell adhesion, proliferation, migration, invasion, anti-angiogenic activity, and other miscellaneous actions. After careful consideration of the relevant evidence, we suggest that andrographolide can be one of the potential agents in the treatment of cancer in the near future. PMID- 29408516 TI - Alacrima, a rare cause of pediatric dry eye. AB - We report the case of a 12-year-old boy who presented with a history of 4-5 years of severe bilateral photophobia, with exacerbation and increased ocular pain for 3-4 days. There were no systemic signs, and serology tests were negative; however, parents noted crying without tears since birth. Computerized tomography of the orbits revealed bilateral hypoplasia of lacrimal glands. A clinico radiological correlation suggested a diagnosis of alacrima, a rare entity that should be considered in the differential diagnosis of severe pediatric dry eye, which is itself a commonly overlooked condition. In addition to artificial tears, permanent punctal occlusion with cautery provided symptomatic relief to the patient. PMID- 29408517 TI - Clinical features of LONP1-related infantile cataract. AB - Biallelic mutations in the nuclear gene LONP1 (LON peptidase 1, mitochondrial) cause CODAS syndrome (cerebral, ocular, dental, auricular, and skeletal anomalies), a systemic disease that can include infantile cataract. However, we have found that biallelic mutations in the gene can also underlie infantile cataract in the setting of minimal or no apparent extraocular findings. This report highlights our clinical experience with children referred for the management of infantile cataract who were found to harbor biallelic LONP1 gene mutations. Ptosis, external ear abnormalities, and joint abnormalities were accompanying findings and thus should raise suspicion for mutations in the gene when one or more are present in children with infantile cataract. PMID- 29408518 TI - A chlorogenic acid-phospholipid complex ameliorates post-myocardial infarction inflammatory response mediated by mitochondrial reactive oxygen species in SAMP8 mice. AB - Mitochondrial reactive oxygen species (mtROS) directly stimulate the inflammatory cytokines cascades and participate in age-related changes of cardiovascular diseases. Application of small molecule targeting the mtROS is significant towards development of better therapy to combat inflammatory response after myocardial infarction (MI) in the aging heart. Chlorogenic acid (CGA) is a well known natural compound while the clinical potential is largely stifled by its poor oral absorption. In the present study, we tested the protective effect of a novel chlorogenic acid-phospholipid complex (CGA-PC) against acute post-MI inflammation in aged senescence accelerated mouse model. 10-month-old SAMP8 mice were treated with CGA-PC (equivalent of CGA 10 or 20 mg/kg body weight) or phospholipid randomly by gavage on a daily basis for 2 weeks. mtROS, lipid peroxidation, H2O2 production and oxygen consumption were evaluated in hearts subjected to ischemia reperfusion (I/R) induced by left anterior descending artery ligation. CGA-PC significantly reduced pro-inflammatory cytokines and myocardial necrosis, accompanied by decreased oxidative stress and mitochondrial respiratory deficits. p-JNK, MnSOD and soluble cytochrome c were up-regulated in the necrotic heart tissue, while CGA-PC treatment increased the expression of MKP 1 and inhibited the downstream activation of JNK. Our study indicated that CGA-PC ameliorated post-MI inflammatory response in aging heart and that it might be a promising candidate for the clinical development of CGA. PMID- 29408519 TI - Using a simple equation to predict the microporation-enhanced transdermal drug flux. AB - The mathematical model describing drug flux through microporated skin was previously developed. Based on this model, two mathematical equations can be used to predict the microporatio-enhanced transdermal drug flux: the complex primal equation containing a variety of experimentally-determined variables, and the simplified straightforward equation. In this study, experimental transdermal fluxes of three corticosteroids through split-thickness human skin treated with a microneedle roller were measured, and the values of fluxes compared with those predicted using both the more complex and simplified equations. According to the results of the study, both equations demonstrated high accuracy in the prediction of the fluxes of corticosteroids. The simplified equation was validated and confirmed as robust using regression analysis of literature data. Further, its capability and ease of use was exemplified by predicting the flux of methotrexate through the skin microporated with laser and comparing with published experimental data. PMID- 29408520 TI - Development of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation. AB - Raman spectroscopy was evaluated as a process analytical technology (PAT) tool for continuous API quantification during twin-screw wet granulation. Therefore, a Raman probe was implemented in front of the granulator barrel. This setup enabled the collection of Raman spectra upon a constant granule flow. To develop an in line PLS calibration model, eight binary mixtures of the API and lactose monohydrate with API contents between 5 and 50% were pre-blended and granulated in a twin-screw granulator with a screw speed of 150 rpm and a powder feed rate of 40 g/min. Water was used as a granulation liquid with different liquid to solid ratios depending on the API content. Ibuprofen and diclofenac sodium were chosen as model drugs and separated PLS models were built for each API. The predictive performance of the developed PLS models was determined by granulating and monitoring new test samples containing different API concentrations. This evaluation showed that the models were able to predict the API concentration with an RMSEP of 0.59% for ibuprofen and 1.5% for diclofenac sodium. In a second part, the developed in-line Raman spectroscopic method was used to determine the API concentration during a split feeding process. Therefore, the API and lactose monohydrate were added by two independently adjustable feeders into the twin screw granulator barrel. The in-line spectroscopy analysis which was verified by UV-analysis indicated that the mixing ability of the twin-screw granulator was good for the used settings and all adjusted API concentrations. PMID- 29408521 TI - Intranasal oxytocin does not reduce age-related difficulties in social cognition. AB - Oxytocin is a neuropeptide that plays a key role in social processing and there are several studies suggesting that intranasally administered oxytocin may enhance social cognitive abilities and visual attention in healthy and clinical groups. However, there are very few studies to date that have investigated the potential benefits of intranasal oxytocin (iOT) on older adults' social cognitive abilities. This is a surprising omission, because relative to their younger counterparts, older adults also exhibit a range of social cognitive difficulties and also show differences in the way they visually attend to social information. Therefore, we tested the effect of iOT (24 IU) versus a placebo spray on 59 older and 61 younger adults' social cognitive abilities and visual attention using a double-blind placebo-controlled within-groups design. While iOT provided no overall age-related benefit on social cognitive abilities, the key finding to emerge was that iOT improved ToM ability in both age-groups when the task had minimal contextual information, but not when the task had enriched contextual information. Interestingly, iOT had gender specific effects during a ToM task with minimal context. For males in both age-groups, iOT reduced gazing to the social aspects of the scenes (i.e., faces & bodies), and for females, iOT eliminated age differences in gaze patterns that were observed in the placebo condition. These effects on eye-gaze were not observed in a very similar ToM task that included more enriched contextual information. Overall, these findings highlight the interactive nature of iOT with task related factors (e.g., context), and are discussed in relation to the social salience hypothesis of oxytocin. PMID- 29408523 TI - Reply. PMID- 29408522 TI - Inflammatory immune cells may impair the preBCR checkpoint, reduce new B cell production, and alter the antibody repertoire in old age. AB - Aging impairs development of new B cells and diminishes the expression of protective antibodies. Reduced numbers of B cell precursors generally occur in old (~2 yrs.) mice. At the pro-B to pre-B cell transition, the pre-B cell receptor (preBCR) checkpoint directs pre-B cell expansion and selection of the pre-B cell immunoglobulin (Ig) MU heavy chain variable region repertoire. The preBCR is comprised of Ig MU heavy chain + surrogate light chains (SLC; lambda5/VpreB). In old B cell precursors, SLC is decreased and fewer pre-B cells form the preBCR. In pro-B cells, SLC is complexed with cadherin 17 to form a "pro B cell receptor" whose signaling is postulated to increase apoptotic sensitivity. We propose that inflammation in old mice, in part mediated by the age-associated B cells (ABC), promotes apoptosis among pro-B cells, particularly those relatively high in SLC. The remaining pro-B cells, with lower SLC, now generate pre-B cells with limited capacity to form the preBCR. Ig MU heavy chains vary in their capacity to associate with SLC and form the preBCR. We speculate that limited SLC restricts formation of the preBCR to a subset of Ig MU heavy chains. This likely impacts the composition of the antibody repertoire among B cells. PMID- 29408524 TI - Dissociating neural variability related to stimulus quality and response times in perceptual decision-making. AB - According to sequential sampling models, perceptual decision-making is based on accumulation of noisy evidence towards a decision threshold. The speed with which a decision is reached is determined by both the quality of incoming sensory information and random trial-by-trial variability in the encoded stimulus representations. To investigate those decision dynamics at the neural level, participants made perceptual decisions while functional magnetic resonance imaging (fMRI) was conducted. On each trial, participants judged whether an image presented under conditions of high, medium, or low visual noise showed a piano or a chair. Higher stimulus quality (lower visual noise) was associated with increased activation in bilateral medial occipito-temporal cortex and ventral striatum. Lower stimulus quality was related to stronger activation in posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC). When stimulus quality was fixed, faster response times were associated with a positive parametric modulation of activation in medial prefrontal and orbitofrontal cortex, while slower response times were again related to more activation in PPC, DLPFC and insula. Our results suggest that distinct neural networks were sensitive to the quality of stimulus information, and to trial-to-trial variability in the encoded stimulus representations, but that reaching a decision was a consequence of their joint activity. PMID- 29408525 TI - Intentionally not imitating: Insula cortex engaged for top-down control of action mirroring. AB - Perception and action are inextricably linked, down to the level of single cells which have both visual and motor response properties - dubbed 'mirror neurons'. The mirror neuron system is generally associated with direct-matching or resonance between observed and executed actions (and goals). Yet in everyday interactions responding to another's movements with matching actions (or goals) is not always appropriate. Here we examine processes associated with intentionally not imitating, as separable from merely detecting an observed action as mismatching one's own. Using fMRI, we test how matched and mismatched stimulus-response mapping for actions is modulated depending on task-relevance. Participants were either cued to intentionally copy or oppose a presented action (intentional imitation or counter-imitation), or cued to perform a predefined action regardless of the presented action (incidental imitation or counter imitation). We found distinct cortical networks underlying imitation compared to counter-imitation, involving areas typically associated with an action observation network and widespread occipital activation. Intentionally counter imitating particularly involved frontal-parietal networks, including the insula and cingulate cortices. This task-dependent recruitment of frontal networks for the intentional selection of opposing responses supports previous evidence for the preparatory suppression of imitative responses. Sensorimotor mirroring is modulated via control processes, which complex human interactions often require. PMID- 29408526 TI - Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy is widely performed for melanoma with certain histologic parameters and offers important prognostic and staging information. Breslow thickness (BT) by itself also provides meaningful prognostic information. OBJECTIVE: To evaluate whether SLN status provides prognostic information independent from that which is already provided by BT. METHODS: We conducted a retrospective cohort study of 896 patients who underwent SLN biopsy for primary cutaneous melanoma. Stratified analysis of the impact of SLN status within BT groups (0.01-1 mm, 1.01-2.00 mm, 2.01-4.00 mm, and >4.00 mm) was performed. In addition, a Cox proportional hazard model was fit to evaluate the interaction between BT unadjusted and then adjusted for SLN status to determine whether predictive ability is improved. RESULTS: Having a negative SLN did not confer a statistically significant survival advantage for any BT subgroup (P = .54, .075, .17, and .95 for subgroups 0.01-1 mm, 1.01-2.00 mm, 2.01-4.00 mm, and >4.00 mm, respectively). In multivariate analysis, SLN status did not demonstrate independent prognostic ability over that of BT alone (P = .067). LIMITATIONS: Retrospective study, single institution. CONCLUSION: Our data suggest that SLN status does not offer better prognostic information for patients than BT alone. PMID- 29408527 TI - Crystal structure of chromo barrel domain of RBBP1. AB - RBBP1 is a retinoblastoma protein (pRb) binding protein acting as a repressor of gene transcription. RBBP1 is a multidomain protein including a chromo barrel domain, and its chromo barrel domain has been reported to recognize histone H4K20me3 weakly, and this binding is enhanced by the simultaneous binding of DNA. However, the molecular basis of this DNA-mediated histone binding by the chromo barrel domain of RBBP1 is unclear. Here we attempted to co-crystallize the chromo barrel domain of RBBP1 with either a histone H4K20me3 peptide alone or with both a histone H4K20me3 peptide and DNA, but only solved the peptide/DNA unbound crystal structure. Our structural analysis indicates that RBBP1 could interact with histone H4K20me3 similar to other histone binding chromo barrel domains, and the surface charge representation analysis of the chromo barrel domain of RBBP1 suggests that the chromo barrel domain of RBBP1 does not have a typical DNA binding surface, indicating that it might not bind to DNA. Consistently, our ITC assays also showed that DNA does not significantly enhance the histone binding ability of the chromo barrel domain of RBBP1. PMID- 29408528 TI - Structural conservation of the autoinhibitory domain in SUN proteins. AB - LINC complexes span across the nuclear envelope and are assembled by SUN and KASH proteins. SUN1 and SUN2 are the two most abundant SUN proteins in mammals. In SUN2, the predicted coiled-coil domain preceding the SUN domain forms a three helix bundle that constitutes an autoinhibitory domain (AID) to lock down the SUN domain. Here, we found that SUN1 also contains an AID preceding the SUN domain and solved the structure of the AID-SUN tandem of SUN1. SUN1 AID also adopts a three-helix bundle conformation that interacts with the SUN domain and keeps it in an autoinhibited state. Disruptions of the interaction interface in the AID SUN tandem restored the SUN domain activity for binding to the KASH peptide. Structural comparison further demonstrated that the autoinhibited conformations of the AID-SUN tandems from SUN1 and SUN2 are similar and the intramolecular interdomain packing in SUN1 is slightly more compact than that in SUN2 due to minor variations of the residues in the interaction interface. Thus, AID is a conserved functional domain in SUN proteins and this work provides the structural evidence to support the conversation of the AID-mediated autoinhibition of SUN proteins. PMID- 29408529 TI - Endovascular recanalization for chronic symptomatic intracranial vertebral artery total occlusion: Experience of a single center and review of literature. AB - OBJECTIVE: The optimal treatment of chronic symptomatic total occlusion of the intracranial vertebral artery (ICVA) remains undefined. We report a single-center experience of endovascular recanalization for patients with chronic symptomatic ICVA occlusion who were refractory to medical therapy. METHODS: From Jan 2009 to Jan 2017, we retrospectively reviewed 14 consecutive patients presenting with recurrent symptoms attributed to the chronic ICVA occlusion. We searched previous literature using PubMed databases during the same period as comparison. RESULTS: Eleven patients out of 14 presented initial symptoms to intervention less than 90days. The occlusion course was extrapolated on simultaneous two-vessel injection angiography or high-resolution MR imaging (HRMRI) in 13 cases. Nine patients had the occlusion beyond the origin of posterior inferior cerebellar artery (PICA) and 5 had the occlusion proximal to the PICA origin. The technical success rate of recanalization was 85.7% (12/14). Two patients (14.3%, 2/14) had peri-procedural complications: 1 developed TIA and 1 presented with perforator occlusion syndrome. Using the keyword-based search, we identified 6 studies at the same period. A total of 34 patients underwent recanalization with the successful recanalization rate at 94.1%, peri-procedural complication rate at 17.6% and mortality at 2.9%, respectively. CONCLUSION: Our single-center study illustrated the feasibility and safety of ICVA recanalization. Great care should be taken as revascularization is of high risk. When patient selection, occlusion course and stage as well as neuroimaging evaluation are considered, endovascular recanalization may be a useful therapeutic modality. PMID- 29408530 TI - Detailed genetic analyses of the HN gene in human respirovirus 3 detected in children with acute respiratory illness in the Iwate Prefecture, Japan. AB - We performed detailed genetic analyses of the partial hemagglutinin-neuraminidase (HN) gene in 34 human respirovirus 3 (HRV3) strains from children with acute respiratory illness during 2013-2015 in Iwate Prefecture, Japan. In addition, we performed analyses of the evolutionary timescale of the gene using the Bayesian Markov chain Monte Carlo (MCMC) method. Furthermore, we analyzed pairwise distances and performed selective pressure analyses followed by linear B-cell epitope mapping and N-glycosylation and phylodynamic analyses. A phylogenetic tree showed that the strains diversified at around 1939, and the rate of molecular evolution was 7.6 * 10-4 substitutions/site/year. Although the pairwise distances were relatively short (0.03 +/- 0.018 [mean +/- standard deviation, SD]), two positive selection sites (Cys544Trp and Leu555Ser) and no amino acid substitutions were found in the active/catalytic sites. Six epitopes were estimated in this study, and three mouse monoclonal antibody binding sites (amino acid positions 278, 281, and 461) overlapped with two epitopes belonging to subcluster C3 strains. Bayesian skyline plot analyses indicated that subcluster C3 strains have been increasing from 2004, whereas subcluster C1 strains have declined from 2004. Based on these results, Iwate strains were divided into two subclusters and each subcluster evolved independently. Moreover, our results suggested that some predicted linear epitopes (epitopes 3 and 5) are candidates for an HRV3 vaccine motif. To better understand the details of the molecular evolution of HRV, further studies are needed. PMID- 29408532 TI - Mitochondrial transgene expression via an artificial mitochondrial DNA vector in cells from a patient with a mitochondrial disease. AB - To achieve mitochondrial gene therapy, developing a mitochondrial transgene expression system that produces therapeutic proteins in mitochondria of disease cells is essential. We previously reported on the design of pCMV-mtLuc (CGG) containing a CMV promotor and a NanoLuc (Nluc) luciferase gene that records adjustments to the mitochondrial codon system, and showed that the mitochondrial transfection of pCMV-mtLuc (CGG) resulted in the efficient production of the Nluc luciferase protein in human HeLa cells. This mitochondrial transfection was achieved using a MITO-Porter, a liposome-based carrier for delivering a cargo to mitochondria via membrane fusion. We report herein that mitochondrial transfection using the MITO-Porter results in mitochondrial transgene expression in G625A fibroblasts obtained from a patient with a mitochondrial disease. We investigated the effect of promoters and the basic structure of pCMV-mtLuc (CGG) on gene expression efficiency, and were able to construct a high performance mitochondrial DNA vector, pCMV-mtLuc (CGG) [hND4] that contains a human mitochondrial endogenous gene. We also constructed an RP/KALA-MITO-Porter composed of the KALA peptide (cell-penetrating peptide) with a mitochondrial RNA aptamer to enhance cellular uptake and mitochondrial targeting. Finally, the mitochondrial transfection of pCMV-mtLuc (CGG) [hND4] in G625A fibroblasts using the RP/KALA-MITO-Porter resulted in strong mitochondrial transgene expression. PMID- 29408531 TI - The polymorphism rs671 at ALDH2 associated with serum uric acid levels in Chinese Han males: A genome-wide association study. AB - Serum uric acid (SUA) levels are highly heritable and an increased SUA level is one of important risk factors for gout, diabetes, metabolic syndrome, and cardiovascular diseases. The genetic variants underlying SUA remains largely unexplored. The aim was to explore new genetic variants underlying SUA in Chinese Han. We performed a genome-wide association study of SUA levels in Han Chinese. The discovery set contained 1634 samples and subsequent replication was comprised of 1649 females and 1169 males. 2620 subjects were recruited in the detailed analysis of rs671, alcohol drinking and SUA. We found a genome-wide significant association between SUA level and the SNP rs671 at ALDH2 (P = 1.2 * 10-10) in the merged data. In addition, we also replicated the signal from rs3733590 at SLC2A9 (P = 1.0 * 10-10). In males, about 0.21% to 1.95% of the total variance for SUA can be explained by rs671 using linear regression models in four independent cohorts. Of those, 56.75% to 93.51% might be explained by altering alcohol consumption due to rs671. No statistical association of rs671 and SUA was observed in females (P = 0.409). Furthermore, we observed a causal relationship between alcohol consumption and SUA in males using rs671 as an instrumental variable (P = 5.1 * 10-4). We replicated the previous findings in SLC2A9. Our evidence supported that rs671 was associated with SUA by affecting alcohol consumption in males. This finding strongly suggests a role for alcohol consumption in the development of hyperuricaemia and uric acid related traits. PMID- 29408533 TI - The placental immune response is dysregulated developmentally vitamin D deficient rats: Relevance to autism. AB - Emerging evidence suggests that maternal or developmental vitamin D (DVD) deficiency is a risk factor for Autism Spectrum Disorders. A well-established association has also been found between gestational infection and increased incidence of autism. Placenta mediates the maternal immune response in respect to the foetus. The placenta is also a major source of vitamin D and locally produced vitamin D is an essential regulator of immune function during pregnancy. Here we investigate the effects of DVD-deficiency on baseline placental immune status and in response to the well-known viral and bacterial immune activating agents polyriboinosinic-polyribocytidylic acid (poly(I:C) and lipopolysaccharide (LPS). We show DVD-deficiency does not affect baseline inflammatory cytokines in placenta. However, when challenged with poly(I:C) but not LPS, DVD-deficient placentas from male foetuses had higher production of IL-6 and 1L-1beta compared to control placentas. This suggests the developing DVD-deficient male foetus may be particularly vulnerable to maternal viral exposures. This in turn may have adverse implications for the developing male brain. In conclusion, a dysregulated placental immune response may provide a plausible mechanism for both the epidemiological links between DVD-deficiency and increased male incidence of developmental conditions such as autism. PMID- 29408535 TI - When Complementary and Alternative Medicine Meets Heart Failure-a Modest Proposal. PMID- 29408534 TI - Probability of Positive Genetic Testing Results in Patients with Family History of Primary Hyperparathyroidism. AB - BACKGROUND: Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. STUDY DESIGN: A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. RESULTS: Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1, 14 CDC73, and 18 GCM2). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. CONCLUSIONS: In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT. PMID- 29408536 TI - Vasoactive intestinal peptide inhibits airway smooth muscle cell proliferation in a mouse model of asthma via the ERK1/2 signaling pathway. AB - Asthma is a heterogeneous clinical syndrome characterized by airway inflammation, hyper-responsiveness and remodeling. Airway remodeling is irreversible by current antiasthmatic drugs, and it is the main cause of severe asthma. Airway smooth muscle cells (ASMCs) act as the main effector cells for airway remodeling; the proliferation and hypertrophy of which are involved in airway remodeling. Caveolin (Cav)- 1 is present on the surface of ASMCs, which is involved in cell cycle and signal transduction regulation, allowing ASMCs to change from proliferation to apoptosis. The extracellular signal-regulated kinase (ERK)1/2 signaling pathway is a common pathway regulated by various proliferative factors, which demonstrates a regulatory role in airway remodeling of asthma. There have been many studies on the correlation between vasoactive intestinal peptide (VIP) and airway reactivity and inflammation in asthma, but the functions and related mechanisms of ASMCs remain unclear. In this study, we established an airway remodeling model in asthmatic mice, and concluded that VIP inhibits airway remodeling in vivo. The in vitro effect of VIP on interleukin-13-induced proliferation of ASMCs was studied by examining the effects of VIP on expression of ERK1/2, phospho-ERK1/2 and Cav-1 in ASMCs, as well as changes in cell cycle distribution. VIP inhibited phosphorylation of the ERK1/2 signaling pathway and expression of Cav-1 on ASMCs and decreased the proportion of S phase cells in the cell cycle, thus inhibiting the proliferation of ASMCs. This study provides a novel therapeutic mechanism for the treatment of asthma. PMID- 29408537 TI - Abscisic acid: new perspectives on an ancient universal stress signaling molecule. AB - Few biological molecules have as far reaching and dynamic effects as abscisic acid (ABA). In this review, we draw together the often segregated fields of plant, animal, and human biology to highlight ABA biosynthesis, signaling and physiological effects with examples of host-pathogen interactions to emphasize the cross-kingdom biology of this ancient signaling molecule. PMID- 29408538 TI - Lower Quadriceps Rate of Force Development Is Associated With Worsening Physical Function in Adults With or at Risk for Knee Osteoarthritis: 36-Month Follow-Up Data From the Osteoarthritis Initiative. AB - OBJECTIVE: To determine the association between quadriceps rate of force development (RFD) and decline in self-reported physical function and objective measures of physical performance. DESIGN: Longitudinal cohort study. SETTING: Community-based sample from 4 urban areas. PARTICIPANTS: Osteoarthritis Initiative participants with or at risk for knee osteoarthritis, who had no history of knee/hip replacement, knee injury, or rheumatoid arthritis (N=2630). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Quadriceps RFD (N/s) was measured during isometric strength testing. Worsening physical function was defined as the minimal clinically important difference for worsening self reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale score, 20-m walk time, and repeated chair stand time over 36 months. RESULTS: Compared with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an odds ratio (OR) of .68 (95% confidence interval [CI], .51-.92) after adjustment for age, sex, body mass index, depression, history of chronic diseases, and knee pain. In women, in comparison with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an adjusted OR of .57 (95% CI, .38-.86). This decreased risk did not reach statistical significance in men (OR, 0.81; 95% CI, 0.52-1.27). No statistically significant associations were detected between baseline RFD and walk or chair stand times. CONCLUSIONS: Our results indicate that higher RFD is associated with decreased risk for worsening self-reported physical function but not with decreased risk for worsening of physical performance. PMID- 29408540 TI - Approach to Peripheral Neuropathy for the Primary Care Clinician. AB - Peripheral neuropathy is commonly encountered in the primary care setting and is associated with significant morbidity, including neuropathic pain, falls, and disability. The clinical presentation of neuropathy is diverse, with possible symptoms including weakness, sensory abnormalities, and autonomic dysfunction. Accordingly, the primary care clinician must be comfortable using the neurologic examination-including the assessment of motor function, multiple sensory modalities, and deep tendon reflexes-to recognize and characterize neuropathy. Although the causes of peripheral neuropathy are numerous and diverse, careful review of the medical and family history coupled with limited, select laboratory testing can often efficiently lead to an etiologic diagnosis. This review offers an approach for evaluating suspected neuropathy in the primary care setting. It will describe the most common causes, suggest an evidence-based workup to aid in diagnosis, and highlight recent evidence that allows for selection of symptomatic treatment of patients with neuropathy. PMID- 29408539 TI - Triple representation of language, working memory, social and emotion processing in the cerebellum: convergent evidence from task and seed-based resting-state fMRI analyses in a single large cohort. AB - Delineation of functional topography is critical to the evolving understanding of the cerebellum's role in a wide range of nervous system functions. We used data from the Human Connectome Project (n = 787) to analyze cerebellar fMRI task activation (motor, working memory, language, social and emotion processing) and resting-state functional connectivity calculated from cerebral cortical seeds corresponding to the peak Cohen's d of each task contrast. The combination of exceptional statistical power, activation from both motor and multiple non-motor tasks in the same participants, and convergent resting-state networks in the same participants revealed novel aspects of the functional topography of the human cerebellum. Consistent with prior studies there were two distinct representations of motor activation. Newly revealed were three distinct representations each for working memory, language, social, and emotional task processing that were largely separate for these four cognitive and affective domains. In most cases, the task based activations and the corresponding resting-network correlations were congruent in identifying the two motor representations and the three non-motor representations that were unique to working memory, language, social cognition, and emotion. The definitive localization and characterization of distinct triple representations for cognition and emotion task processing in the cerebellum opens up new basic science questions as to why there are triple representations (what different functions are enabled by the different representations?) and new clinical questions (what are the differing consequences of lesions to the different representations?). PMID- 29408541 TI - microRNA-210 participates in regulating RIG-I signaling pathway via targeting DUBA in miiuy croaker after poly(I:C) stimulation. AB - MicroRNAs (miRNAs) are endogenous small non-coding RNAs that participate in the regulation of various biological processes. A series of microRNAs have been shown to be important regulators of both innate and adaptive immune responses, including RIG-I signaling pathway. In this study, we evaluated the regulation role of miR-210 in the RLRs signaling pathway of miiuy croaker. Upon poly(I:C) stimulation, the expression of miR-210 in both miiuy croaker spleen tissues and macrophages were significantly upregulated. By means of the dual luciferase reporter assay, a direct interaction between miR-210 and the 3-untranslated region (UTR) of Deubiquitinating enzyme A (DUBA) was confirmed, and we found that miR-210 could reduce the luciferase levels of wild-type DUBA 3'UTR, whereas mutant-type led to a complete abrogation of the negative effect. Furthermore, the negative regulatory effects of pre-miR-210 on DUBA have been indicated in a dose- and time-dependent manners. As DUBA is an important regulator involved in the RLRs signaling pathway and could bind with and regulate TRAF3, we also examined the expression patterns of DUBA and TRAF3 in vivo and in vitro. We found that the expression of both DUBA and TRAF3 were significantly changed upon poly(I:C) stimulation in miiuy croaker. The expression patterns between miR-210 and DUBA showed a negative correlation, which indicated that miR-210 can target and downregulate the expression of DUBA. Overall, these results will enrich the knowledge of immune response related miRNAs in miiuy croaker, which will be useful for better understanding the complicated regulatory networks in fish species. PMID- 29408542 TI - Particle size distribution of selected electronic nicotine delivery system products. AB - Dosimetry models can be used to predict the dose of inhaled material, but they require several parameters including particle size distribution. The reported particle size distributions for aerosols from electronic nicotine delivery system (ENDS) products vary widely and don't always identify a specific product. A low flow cascade impactor was used to determine the particle size distribution [mass median aerodynamic diameter (MMAD); geometric standard deviation (GSD)] from 20 different cartridge based ENDS products. To assess losses and vapor phase amount, collection efficiency of the system was measured by comparing the collected mass in the impactor to the difference in ENDS product mass. The levels of nicotine, glycerin, propylene glycol, water, and menthol in the formulations of each product were also measured. Regardless of the ENDS product formulation, the MMAD of all tested products was similar and ranged from 0.9 to 1.2 MUm with a GSD ranging from 1.7 to 2.2. There was no consistent pattern of change in the MMAD and GSD as a function of number of puffs (cartridge life). The collection efficiency indicated that 9%-26% of the generated mass was deposited in the collection system or was in the vapor phase. The particle size distribution data are suitable for use in aerosol dosimetry programs. PMID- 29408543 TI - Precision medicine in cow's milk allergy: proteomics perspectives from allergens to patients. AB - : Cow's milk allergy (CMA) is one of the most common food allergies, especially during childhood. CMA is an immunological mediated adverse reaction to one or more cow's milk proteins, which are normally harmless to a non-allergic individual, as the result of a failure of oral tolerance. To make a correct diagnosis of CMA and a proper treatment is critical in clinical practice. Application of proteomics along with new bio-informatics tools in the field of food allergy is one of the hot topics presented in recent years. In the present review, we focus on recent applications of proteomics to the field of cow's milk allergy, from allergens quantification to the diagnosis, treatment and prognosis. Furthermore, we also shed a light on potential future directions and developments, that are parts of personalized medicine but also of the One Health approach. SIGNIFICANCE: The field of food allergies is becoming a milestone in public health. Food allergies, in fact, can cause life-threatening reactions and profoundly influence the quality of life. Precise, fast and reliable diagnosis of food allergies, and in particular milk allergies is essential to avoid severe allergic reactions and also to prevent dangerous and eventually unnecessary dietary restrictions; but this can be difficult also due to a complex interaction of genetic background, environment, and microbiota. In this sense, proteomics represents steps toward researching food and milk allergy integrated with the clinic to improve pathophysiology, diagnosis, therapy, and prognosis. PMID- 29408544 TI - Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications. PMID- 29408545 TI - Targeted delivery of FGF2 to subchondral bone enhanced the repair of articular cartilage defect. AB - : It is reported that growth factor (GF) is able to enhance the repair of articular cartilage (AC) defect, however underlying mechanisms of which are not fully elucidated yet. Moreover, the strategy for delivering GF needs to be optimized. The crosstalk between AC and subchondral bone (SB) play important role in the homeostasis and integrity of AC, therefore SB targeted delivery of GF represents one promising way to facilitate the repair of AC defect. In this study, we firstly investigated the effects and mechanism of FGF2 on surrounding SB and cartilage of detect defects in rabbits by using a homogenous collagen based membranes. It was found that FGF2 had a modulating effect on the defect surrounding SB via upregulation of bone morphogenetic protein (BMP)-2, BMP4 and SOX9 at the early stage. Low dose FGF2 improved the repair upon directly injected to SB. Inhibition of BMP signaling pathway compromised the beneficial effects of FGF2, which indicated the pivotal roles of BMP in the process. To facilitate SB targeted FGF2 delivery, a double-layered inhomogeneous collagen membrane was prepared and it induced increase of BMP2 and BMP4 in the synovial fluid, and subsequent successful repair of AC defect. Taken together, this targeted delivery of FGF2 to SB provides a promising strategy for AC repair owing to the relatively clear mechanism, less amount of it, and short duration of delivery. STATEMENT OF SIGNIFICANCE: Articular cartilage (AC) and subchondral bone (SB) form an integral functional unit. The homeostasis and integrity of AC depend on its crosstalk with the SB. However, the function of the SB in AC defect repair is not completely understood. The application of growth factors to promote the repair articular cartilage defect is a promising strategy, but still under the optimization. Our study demonstrate that SB plays important roles in the repair of AC defect. Particularly, SB is the effective target of fibroblast growth factor 2 (FGF2), and targeted delivery of FGF2 can modulate SB and thus significantly enhances the repair of AC defect. Therefore, targeted delivery of growth factor to SB is a novel promising strategy to improve the repair of AC defect. PMID- 29408547 TI - Acute effects of aerobic exercise on cognitive function in individuals with Parkinson's disease. AB - Deficits in executive functions are highly prevalent in Parkinson's disease (PD). Although chronic physical exercise has been shown to improve executive functions in PD, evidence of acute exercise effects is limited. This study aimed to evaluate the effects of an acute bout of exercise on cognitive processes underlying executive functions in PD. Twenty individuals with PD were assessed in both a Control and an Exercise conditions. In each condition, individuals started performing a simple and a choice reaction time (RT) task. Subsequently, participants were asked to sit on a cycle ergometer (Control) or cycle (Exercise) for 20 min in counterbalanced order. Participants were asked to repeat both reaction time tasks after 15-min rest period in both conditions. While no differences were found in simple RT, participants showed faster choice RT post Exercise as well as Control conditions (p = .012). Participants had slower choice RT for target stimulus compared to non-target stimuli irrespective of time or experimental condition (p < .001). There was no change in accuracy following experimental conditions. Results suggest that individuals with PD may not respond behaviourally to a single bout of exercise. The lack of selective effects of exercise on cognition suggests that practice effects may have influenced previous research. Future studies should assess whether neurophysiological changes might occur after an acute bout of exercise in PD. PMID- 29408548 TI - Endothelial cell dysfunction and glycocalyx - A vicious circle. AB - Dysfunctional endothelial cells are an essential contributor to the progression of diverse chronic cardiovascular, renal, and metabolic diseases. It manifests in impairment of nitric oxide-dependent vasorelaxation, vascular permeability, and leukocytes deterrent. While endothelial glycocalyx is known to regulate these functions, glycocalyx has been shown to be impaired in pathologic settings leading to endothelial dysfunction. Are these findings coincidental or are they indicative of a potential cooperation of the glycocalyx and the endothelium in inducing a dysfunctional phenotype? The main thrust of this overview is to advance a hypothesis on the existence of vicious circle relations between impaired endothelial glycocalyx and endothelial cell dysfunction. We briefly introduce physiology and pathology of blood flow-induced components of mechanotransduction in endothelial cells, as this function is dependent on glycocalyx and is critically involved in the development of endothelial dysfunction. Next, we present a series of experimental findings and arguments favoring the view on the impairment of mechanotransduction in dysfunctional endothelia. We advance the concept of feedback reinforcement between perturbed endothelial glycocalyx and progression of endothelial dysfunction and sketch therapeutic approaches to restore them. Among those we introduce our recently designed liposomal nanocarriers of preassembled glycocalyx and present evidence of their ability to expeditiously restore endothelial mechanotransduction. PMID- 29408546 TI - Two dedicated class C radical S-adenosylmethionine methyltransferases concertedly catalyse the synthesis of 7,8-dimethylmenaquinone. AB - Dimethylmenaquinone (DMMK), a prevalent menaquinone (MK) derivative of uncertain function, is characteristic for members of the class Coriobacteriia. Such bacteria are frequently present in intestinal microbiomes and comprise several pathogenic species. The coriobacterial model organism Adlercreutzia equolifaciens was used to investigate the enzymology of DMMK biosynthesis. A HemN-like class C radical S-adenosylmethionine methyltransferase (MenK2) from A. equolifaciens was produced in Wolinella succinogenes or Escherichia coli cells and found to methylate MK specifically at position C-7. In combination with a previously described MK methyltransferase (MqnK/MenK) dedicated to MK methylation at C-8, 7,8-DMMK6 was produced in W. succinogenes. The position of the two methyl groups was confirmed by two-dimensional NMR and midpoint redox potentials of 7-MMK6, 8 MMK6 and 7,8-DMMK6 were determined by cyclic voltammetry. A phylogenetic tree of MenK, MenK2 and HemN proteins revealed a Coriobacteriia-specific MenK2 clade. Using chimeric A. equolifaciens MenK/MenK2 proteins produced in E. coli it was shown that the combined linker and HemN domains determined the site-specificity of methylation. The results suggest that the use of MenK2 as a biomarker allows predicting the ability of DMMK synthesis in microbial species. PMID- 29408549 TI - Exosome-associated tau exacerbates brain functional impairments induced by traumatic brain injury in mice. AB - Traumatic brain injury (TBI) has been associated with an increased risk for neurodegenerative diseases, and Tau spread and accumulation might be one of the mechanisms underlying this process. Exosomes were speculated to be a vehicle for spreading Tau in neurodegenerative diseases. The present study sought to investigate the effect of exosome associated Tau after TBI. C57BL/6J mice were subjected to controlled cortical impact injury and the levels of total and phosphorylated Tau in exosomes were measured. Then we isolated exosomes from wildtype and Tau-knockout mice after TBI. These exosomes were either added to primary cultured neurons to evaluate the toxicity, or injected into brains of mice subjected to TBI to evaluate the effect on brain functions. The levels of total and phosphorylated Tau in exosomes after TBI were significantly elevated. TBI derived exosomes displayed toxicity in primary neuron cultures, exacerbated TBI induced LTP (long-term potentiation) impairment and exacerbated motor and cognitive impairments after TBI. The exosome-associated Tau pathology was one of the mechanisms underlying the long-term neurodegenerative effect after TBI. PMID- 29408550 TI - Expression and activation of mitogen-activated protein kinases in the optic nerve head in a rat model of ocular hypertension. AB - BACKGROUND: Glaucoma is a leading cause of irreversible blindness manifesting as an age-related, progressive optic neuropathy with associated retinal ganglion cell (RGC) loss. Mitogen-activated protein kinases (MAPKs: p42/44 MAPK, SAPK/JNK, p38 MAPK) are activated in various retinal disease models and likely contribute to the mechanisms of RGC death. Although MAPKs play roles in the development of retinal pathology, their action in the optic nerve head (ONH), where the initial insult to RGC axons likely resides in glaucoma, remains unexplored. METHODS: An experimental paradigm representing glaucoma was established by induction of chronic ocular hypertension (OHT) via laser-induced coagulation of the trabecular meshwork in Sprague-Dawley rats. MAPKs were subsequently investigated over the following days for expression and activity alterations, using RT-PCR, immunohistochemistry and Western immunoblot. RESULTS: p42/44 MAPK expression was unaltered after intraocular pressure (IOP) elevation, but there was a significant activation of this enzyme in ONH astrocytes after 6-24 h. Activated SAPK/JNK isoforms were present throughout healthy RGC axons but after IOP elevation or optic nerve crush, they both accumulated at the ONH, likely due to RGC axon transport disruption, and were subject to additional activation. p38 MAPK was expressed by a population of microglia which were significantly more populous following IOP elevation. However it was only significantly activated in microglia after 3 days, and then only in the ONH and optic nerve; in the retina it was solely activated in RGC perikarya. CONCLUSIONS: In conclusion, each of the MAPKs showed a specific spatio-temporal expression and activation pattern in the retina, ONH and optic nerve as a result of IOP elevation. These findings likely reflect the roles of the individual enzymes, and the cells in which they reside, in the developing pathology following IOP elevation. These data have implications for understanding the mechanisms of ocular pathology in diseases such as glaucoma. PMID- 29408551 TI - Dual dye in-vivo imaging of differentially charged PLGA carriers reveals antigen depot effect, leading to improved immune responses in preclinical models. AB - The present in-vivo study investigated the behavior and performance of differently charged poly(lactic-co-glycolic) acid microparticles (PLGA MP) as vaccination platform. For this purpose, particles loaded with ovalbumin (OVA) as model antigen were subcutaneously (s.c.) injected in SKH1 mice. The utilized SKH1 hairless mice exhibit a fully operative immune system and allow parallel imaging investigations due to the lack of hair. Usage of this species enabled the combination of two investigations within a single study protocol, namely noninvasive in-vivo imaging and immune responses directed towards the antigen. All treatments were well tolerated, no safety drop-outs occurred. The fate of the model antigen OVA as well as the PLGA particles was monitored using a dual dye approach (CF660C & DiR) by multispectral fluorescence imaging (msFI). A depot effect for the OVA antigen adsorbed to the MP surface could be observed for the positively charged MPs. The immune response against OVA was then analyzed. OVA alone did not induce an immune response, whereas the positively charged as well as the neutral MP induced a strong and consistent humoral immune response with a clear favor of IgG1 over IgG2a subclass antibodies. In contrast, negatively charged MP were not able to induce measurable antibody responses. Cellular immune response was weak and inconsistent for all treated groups, which verifies previous in-vitro results conducted with the herein described microparticulate antigen platform. In conclusion, the characterization of the in-vivo performance yielded valuable information about antigen and carrier fate after application. The presented adjuvant platform is capable of inducing strong TH2 dominated immune responses characterized by enhanced IgG1 subclass titers which are critical for vaccines aimed at promoting induction of neutralizing antibodies. PMID- 29408552 TI - Demographics and outcomes of stage I and II Merkel cell carcinoma treated with Mohs micrographic surgery compared with wide local excision in the National Cancer Database. AB - BACKGROUND: The optimal surgical approach (wide local excision [WLE] vs Mohs micrographic surgery [MMS]) for treating Merkel cell carcinoma (MCC) is yet to be determined. OBJECTIVE: To compare survival outcomes in patients with early-stage MCC treated with MMS versus with WLE. METHODS: A retrospective review of all cases in the National Cancer Database (NCDB) of MCC of clinical stage I or II MCC treated with WLE or MMS was performed. RESULTS: A total of 1795 cases of stage I or II MCC who underwent WLE (n = 1685) or MMS (n = 110) were identified. There was no difference in residual tumor on surgical margins between the 2 treatment groups (P = .588). On multivariate analysis, there was no difference in overall survival between the treatment modalities (adjusted hazard ratio, 1.02; 95% confidence interval, 0.72-1.45; P = .897). There was no difference in overall survival between the 2 groups on propensity score-matched analysis. LIMITATIONS: Disease-specific survival was not reported, as these data are not available in the National Cancer Database. CONCLUSIONS: MMS appears to be as effective as WLE in treating early-stage MCC. PMID- 29408553 TI - Universal serial bus dermatoscope as an oculoscopy tool. PMID- 29408554 TI - Use of sterile urine cups as sharps containers during Mohs micrographic surgery stages. PMID- 29408555 TI - Nepafenac loaded silica nanoparticles dispersed in-situ gel systems: Development and characterization. AB - This research was aimed to develop and evaluate nepafenac loaded silica nanoparticles dispersed in-situ gel system for the improved treatment of ocular diseases. The blank silica nanoparticles prepared by stober's process showed the particle size of 151 nm to 285 nm with the zeta potential of -19.6 to -31.9 mV. The nepafenac loaded silica nanoparticles were spherical in shape with smooth outer surface. The nepafenac loaded silica nanoparticles dispersed in poloxamer - chitosan in-situ gelling system showed gelling temperature of 32 degrees C with sustained release of nepafenac and higher permeation (58.79 MUg) across the goat cornea than poloxamer - poloxamer (21.18 MUg) in-situ gelling system. Hence the developed in-situ gelling system containing nepafenac loaded silica nanoparticle could be a promising tool for the topical delivery of drugs to the eye. PMID- 29408556 TI - Analysis of sialyl-Lewis x on MUC5AC and MUC1 mucins in pancreatic cancer tissues. AB - Pancreatic adenocarcinoma (PDAC) lacks efficient biomarkers. Mucins are glycoproteins that can carry aberrant glycosylation in cancer. Our objective was to identify cancer-related glycan epitopes on MUC1 and MUC5AC mucins in PDAC as potential biomarkers. We have analysed the tumour-associated carbohydrate antigens sialyl-Lewis x (SLex) and sialyl-Tn (STn) on MUC1 and MUC5AC in PDAC tissues. The selected cohort for this study consisted of twenty-one PDAC tissues positive for SLex antigen and three normal pancreas specimens as controls. STn expression was shown in 76% of the PDAC tissues. MUC1 and MUC5AC were detected in 90% of PDAC tissues. We performed in situ proximity ligation assay combining antibodies against mucins and glycan epitopes to identify specific mucin glycoforms. MUC1-SLex and MUC5AC-SLex were found in 68% and 84% respectively, of the mucin expressing PDAC tissues, while STn hardly colocalized with any of the evaluated mucins. Further analysis by Western blot of MUC5AC and SLex in eight PDAC tissue lysates showed that six out of eight cases were positive for both markers. Moreover, immunoprecipitation of MUC5AC from positive PDAC tissues and subsequent SLex immunodetection confirmed the presence of SLex on MUC5AC. Altogether, MUC5AC-SLex glycoform is present in PDAC and can be regarded as potential biomarker. PMID- 29408557 TI - Comparative transcriptomic studies identify specific expression patterns of virulence factors under the control of the master regulator PhcA in the Ralstonia solanacearum species complex. AB - The global regulator PhcA controls numerous traits associated to virulence and bacterial proliferation in strains of the plant pathogen Ralstonia solanacearum species complex. Here, we conducted a genome-wide RNA sequencing study of the GMI1000 wild-type strain and a derived phcA mutant grown in complete medium. The PhcA regulon we identified is the largest regulon described to date in the R. solanacearum species complex with 1581 regulated genes, representing about 30% of the bacterial genome. Among these genes, 166 transcription regulators were identified including known regulators controlling major cellular functions such as the Type 3 secretion system and 27 novel regulators that were not identified in previous transcriptomic studies. This study highlights that PhcA controls other functions beside pathogenicity stricto sensu which participate to the global cell homeostasis (metabolism, energy storage). We then compared the PhcA regulon identified in complete medium to the recently published PhcA regulon obtained in planta. This comparison of the set of GMI1000 genes subjected to PhcA regulation in both conditions revealed 383 common genes. Among them, 326 (85%) had a similar PhcA dependent regulation pattern in complete medium and in planta, and 57 (15%) displayed an opposite regulation pattern. A large majority of the genes repressed by PhcA in complete medium but activated in planta belong to the HrpG-HrpB regulon, which represents a set of key genes required for R. solanacearum pathogenesis. This latter class of genes appears to be specifically induced by PhcA in the plant environment whereas PhcA represses their expression in complete medium. The large set of direct and indirect targets identified in this study will contribute to enrich our knowledge of the intricate regulatory network coordinating the expression of virulence and metabolic functions in the model plant pathogen R. solanacearum. PMID- 29408558 TI - Outcomes of endoscopic intervention for overt GI bleeding in severe thrombocytopenia. AB - BACKGROUND AND AIMS: Gastrointestinal bleeding (GIB) in the setting of thrombocytopenia raises concerns about endoscopic procedure risk. We aimed to assess the safety and outcomes of endoscopy for overt GIB in the setting of severe thrombocytopenia in liver cirrhosis (LC) and non-liver cirrhosis (NLC). METHODS: This is a retrospective study on inpatients who underwent endoscopy within 24 hours of presentation for overt GIB with a platelet count (PC) of 20 to <50 * 103/mL. Outcomes included diagnostic and therapeutic yields, procedural adverse events, packed red blood cell (pRBC) and platelet transfusions, recurrent bleeding rate, and all-cause and GIB-related mortality. RESULTS: One hundred forty-four patients were identified. The median PC was 41 * 103/mL and 61% had LC. The diagnostic yield was 68% (LC = 61%, NLC = 79%, P = .04). Therapeutic yield was 60% (59% vs 60%, P = 1.00). The initial hemostasis rate was 94% with one adverse event. The median number of pRBC and platelet transfusions decreased after intervention in the entire cohort. Recurrent bleeding rates were 22% at 1 month and 30% at 1 year, with no differences between groups. An increased international normalized ratio (INR) >2 was a predictor of recurrent bleeding. All-cause mortality was 19% at 1 month and 37% at 1 year, whereas GIB-associated mortality in our cohort was only 3% at 1 month and 4% at 1 year, with no significant difference between LC and NLC. Predictors of mortality were INR >2, activated partial thromboplastin time >38 seconds, hypotension, intensive care unit admission, and pulmonary comorbidities. CONCLUSION: In this study cohort, we observed that endoscopy for overt GIB in the setting of severe thrombocytopenia in patients with LC and NLC appears safe, has moderate diagnostic and therapeutic yields with high initial hemostasis rate, and is associated with a significant decrease in pRBC and platelet transfusions. Recurrent bleeding and all-cause mortality rates remain high. PMID- 29408559 TI - In vivo therapeutic applications of cell spheroids. AB - Spheroids are increasingly being employed to answer a wide range of clinical and biomedical inquiries ranging from pharmacology to disease pathophysiology, with the ultimate goal of using spheroids for tissue engineering and regeneration. When compared to traditional two-dimensional cell culture, spheroids have the advantage of better replicating the 3D extracellular microenvironment and its associated growth factors and signaling cascades. As knowledge about the preparation and maintenance of spheroids has improved, there has been a plethora of translational experiments investigating in vivo implantation of spheroids into various animal models studying tissue regeneration. We review methods for spheroid delivery and how they have been utilized in tissue engineering experiments. We break down efforts in this field by organ systems, discussing applications of spheroids to various animal models of disease processes and their potential clinical implications. These breakthroughs have been made possible by advancements in spheroid formation, in vivo delivery and assessment. There is unexplored potential and room for further research and development in spheroid based tissue engineering approaches. Regenerative medicine and other clinical applications ensure this exciting area of research remains relevant for patient care. PMID- 29408560 TI - Plants as sources of natural and recombinant anti-cancer agents. AB - Herbal remedies were the first medicines used by humans due to the many pharmacologically active secondary metabolites produced by plants. Some of these metabolites inhibit cell division and can therefore be used for the treatment of cancer, e.g. the mitostatic drug paclitaxel (Taxol). The ability of plants to produce medicines targeting cancer has expanded due to the advent of genetic engineering, particularly in recent years because of the development of gene editing systems such as the CRISPR/Cas9 platform. These technologies allow the introduction of genetic modifications that facilitate the accumulation of native pharmaceutically-active substances, and even the production heterologous recombinant proteins, including human antibodies, lectins and vaccine candidates. Here we discuss the anti-cancer agents that are produced by plants naturally or following genetic modification, and the potential of these products to supply modern healthcare systems. Special emphasis will be put on proteinaceous anti cancer agents, which can exhibit an improved selectivity and reduced side effects compared to small molecule-based drugs. PMID- 29408561 TI - Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on Bone Structure and Architecture. AB - : Vitamin D supplements are often used to benefit skeletal health, although data on effects of daily high-dose vitamin D alone on bone density and structure are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, randomized, placebo-controlled trial testing effects of high-dose supplemental vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (FAs; 1 g/day) for the primary prevention of cancer and cardiovascular disease. The study has a mean treatment period of 5 years among 25,874 U.S. men >=50 years and women >=55 years old from all 50 states. The ancillary study, VITAL: Effects on Bone Structure and Architecture, is testing effects of vitamin D3 and/or omega-3 FAs on musculoskeletal outcomes and body composition in a subcohort of 771 participants. At in-person visits at the Harvard Catalyst Clinical and Translational Science Center (CTSC), participants completed bone density/architecture, body composition, and physical performance assessments at baseline and two-year follow-up. Baseline characteristics were evenly distributed among treatment groups, suggesting that any uninvestigated confounders will be evenly distributed; sex differences were also analyzed. Future analyses of the two-year follow-up visits will elucidate whether daily high-dose, supplemental vitamin D3 and/or omega-3 FAs improve musculoskeletal outcomes, helping to advance clinical and public health recommendations. CLINICAL TRIAL REGISTRATION NUMBER: NCT01747447. PMID- 29408563 TI - Exercise Prescription Using a Group-Normalized Rating of Perceived Exertion in Adolescents and Adults With Spina Bifida. AB - BACKGROUND: People with spina bifida (SB) face personal and environmental barriers to exercise that contribute to physical inactivity, obesity, risk of cardiovascular disease, and poor aerobic fitness. The WHEEL rating of perceived exertion (RPE) Scale was validated in people with SB to monitor exercise intensity. However, the psycho-physiological link between RPE and ventilatory breakpoint (Vpt), the group-normalized perceptual response, has not been determined and would provide a starting point for aerobic exercise in this cohort. OBJECTIVES: The primary objectives were to determine the group-normalized RPE equivalent to Vpt based on WHEEL and Borg Scale ratings and to develop a regression model to predict Borg Scale (conditional metric) from WHEEL Scale (criterion metric). The secondary objective was to create a table of interchangeable values between WHEEL and Borg Scale RPE for people with SB performing a load incremental stress test. DESIGN: Cross-sectional observational. SETTING: University laboratory. PARTICIPANTS: Twenty-nine participants with SB. METHODS: Participants completed a load incremented arm ergometer exercise stress test. WHEEL and Borg Scale ratings were recorded the last 15 seconds of each 1 minute test phase. OUTCOME MEASURES: WHEEL and Borg Scale ratings, metabolic measures (eg, oxygen consumption, carbon dioxide production). Determined Vpt via plots of oxygen consumption and carbon dioxide production against time. RESULTS: Nineteen of 29 participants achieved Vpt (Group A). The mean +/- standard deviation peak oxygen consumption at Vpt for Group A was 61.76 +/- 16.26. The WHEEL and Borg Scale RPE at Vpt were 5.74 +/- 2.58 (range 0-10) and 13.95 +/- 3.50 (range 6-19), respectively. A significant linear regression model was developed (Borg Scale rating = 1.22 * WHEEL Scale rating + 7.14) and used to create a WHEEL-to-Borg Scale RPE conversion table. CONCLUSION: A significant linear regression model and table of interchangeable values was developed for participants with SB. The group-normalized RPE (WHEEL, 5.74; Borg, 13.95) can be used to prescribe and self-regulate arm ergometer exercise intensity approximating the Vpt. LEVEL OF EVIDENCE: III. PMID- 29408562 TI - Promoting Successful Weight Loss in Primary Care in Louisiana (PROPEL): Rationale, design and baseline characteristics. AB - : Underserved and minority populations suffer from a disproportionately high prevalence of obesity and related comorbidities. Effective obesity treatment programs delivered in primary care that produce significant weight loss are currently lacking. The purpose of this trial is to test the effectiveness of a pragmatic, high intensity lifestyle-based obesity treatment program delivered within primary care among an underserved population. We hypothesize that, relative to patients who receive usual care, patients who receive a high intensity, health literacy- and culturally-appropriate lifestyle intervention will have greater percent reductions in body weight over 24 months. Eighteen clinics (N = 803 patients) serving low income populations with a high proportion of African Americans in Louisiana were randomized to the intervention or usual car. Patients in the intervention participate in a high-intensity lifestyle program delivered by health coaches employed by an academic health center and embedded in the primary care clinics. The program consists of weekly (16 in person/6 telephone) sessions in the first six months, followed by sessions held at least monthly for the remaining 18 months. Primary care practitioners in usual care receive information on weight management and the current Centers for Medicare and Medicaid Services reimbursement for obesity treatment. The primary outcome is percent weight loss at 24 months. Secondary outcomes include absolute 24-month changes in body weight, waist circumference, blood pressure, fasting glucose and lipids, health-related quality of life, and weight-related quality of life. The results will provide evidence on the effectiveness of implementing high intensity lifestyle and obesity counseling in primary care settings among underserved populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02561221. PMID- 29408564 TI - A Tale of Two Cities: Evolution of Academic Physiatry in Boston and Baltimore: Part 1: The Boston Marathon. PMID- 29408565 TI - In vitro-induced M2 type macrophages induces the resistance of prostate cancer cells to cytotoxic action of NK cells. AB - Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together. PMID- 29408566 TI - Pull-out strength of four tibial fixation devices used in anterior cruciate ligament reconstruction. AB - INTRODUCTION: In reconstructions of the anterior cruciate ligament (ACL), tibial fixation can be the weak point in the assembly during the early postoperative period. The present study sought to compare pull-out strength between four tibial fixation systems used in ACL reconstruction. HYPOTHESIS: The study hypothesis was that all four devices show >=450N pull-out strength with comparable biomechanical breakage characteristics. MATERIAL AND METHODS: An experimental study used a mechanical model to perform axial traction on a synthetic ligament (polypropylene cord folded in four) implanted in an artificial tibia (Sawbones Proximal Tibia # 1116-2: model: normal anatomy; solid foam; size: medium) using four tibial fixation systems: Ligafix(r) interference screw (SBMTM); Bio-Intrafix(r) (MitekTM); Translig(r) (SBMTM); RIGIDfix(r) (SBMTM). For each system, four models were tested using an Instron 5566(r) traction machine, allowing 100mm/min stretching up to breakage. Study parameters comprised: pull-out strength, maximal whole assembly slippage, stiffness at breaking point, and type of break. RESULTS: Mean pull-out strength was 450+/-24N (range, 421-488N) for Ligafix(r), 415+/-60N (327-454N) for Bio-Intrafix(r), 539+/-66N (449-636N) for RigidFix and 1067+/-211N (736-1301N) for Translig(r), and was significantly greater for Translig(r) than for the other devices (p=0.02), which did not significantly differ from one another. The expected maximal load of 450N was reached in 100% of cases with Translig(r) and RIGIDfix(r) and in 50% of cases with Bio-Intrafix(r) and Ligafix(r). There were no significant differences regarding stiffness. Ligafix(r) showed significantly less slippage than the others (p=0.006), with breakage caused by the ligament sliding between bone and implant. DISCUSSION: In this in vitro study, the Translig(r) fixation device showed better pull-out strength than the other three devices tested. TYPE OF STUDY AND LEVEL OF EVIDENCE: Comparative laboratory study. Level II. PMID- 29408567 TI - Influence of high-intensity interval training on ventilatory efficiency in trained athletes. AB - The aim of this study was to investigate the effects of 3 weeks high-intensity interval training (HIIT) on ventilatory efficiency (VE/VCO2 slope) in endurance athletes. Sixteen male well-trained (67.72 ml kg min-1) athletes participated in this study. Each participant performed an incremental exercise test with gas analysis (i.e. VE, VO2) and a 400 m running field test (T400m) before and after the 3 weeks intervention period. HIIT group (HIITG) performed 11 HIIT sessions consisting of four 4-min interval bouts at an exercise intensity of 90-95% of the VO2max, separated by 4-min active recovery periods (work/rest ratio = 1:1). No significant differences were found in the parameters studied. Ventilatory efficiency (up to VT2 and up to exhaustion) did not show any change in HIITG after training intervention (ES = 0.24 HIITG; ES = 0.21 CG). No significant changes were observed on ventilation (VEmax; ES = 0.38). VO2max and T400 m did not show a significant improvement after the training period (no interaction time * group, p < .05) (ES = 0.43 and ES = 0.75 respectively). These results do not support the hypothesis that 3 weeks of HIIT could modify the ventilatory efficiency response in well-trained athletes. Furthermore, they show the lack of relationship between ventilatory efficiency and sport performance. PMID- 29408568 TI - Role of Magnetic Resonance Imaging Targeted Biopsy in Detection of Prostate Cancer Harboring Adverse Pathological Features of Intraductal Carcinoma and Invasive Cribriform Carcinoma. AB - PURPOSE: The aim of this study was to compare biopsy detection of intraductal and cribriform pattern invasive prostate carcinoma in multiparametric magnetic resonance imaging positive and negative regions of the prostate. MATERIALS AND METHODS: We queried a prospectively maintained, single institution database to identify patients who underwent multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy and concurrent systematic sextant biopsy of magnetic resonance imaging negative regions between January 2013 and May 2016. All multiparametric magnetic resonance imaging targets were reviewed retrospectively by 2 readers for the PI-RADSTM (Prostate Imaging-Reporting and Data System), version 2 score, the maximum dimension, the apparent diffusion coefficient parameter and whether positive or negative on dynamic contrast enhancement sequence. Biopsy slides were reviewed by 2 urological pathologists for Gleason score/Grade Group and the presence or absence of an intraductal/cribriform pattern. RESULTS: A total of 154 patients were included in study. Multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy and systematic sextant biopsy of magnetic resonance imaging negative regions were negative for prostate carcinoma in 51 patients, leaving 103 available for the correlation of multiparametric magnetic resonance imaging and the intraductal/cribriform pattern. Prostate carcinoma was identified by multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy in 93 cases and by systematic sextant biopsy of magnetic resonance imaging negative regions in 76 (p = 0.008). Intraductal/cribriform positive tumor was detected in 23 cases, including at the multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy site in 22 and at the systematic sextant biopsy of magnetic resonance imaging negative region site in 3 (p <0.001). The intraductal/cribriform pattern was significantly associated with a PI-RADS score of 5 and a decreasing apparent diffusion coefficient value (p = 0.008 and 0.005, respectively). In 19 of the 23 cases with the intraductal/cribriform pattern prior 12-core standard systematic biopsy was negative in 8 and showed Grade Group 1 disease in 11. CONCLUSIONS: Multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy was associated with significantly increased detection of intraductal/cribriform positive prostate carcinoma compared to systematic sextant biopsy of multiparametric magnetic resonance imaging negative regions. This supports the role of magnetic resonance imaging to enhance the detection of clinically aggressive intraductal/cribriform positive prostate carcinoma. PMID- 29408570 TI - Orally administered berberine ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting activation of PPAR-gamma and subsequent expression of HGF in colons. AB - Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showed that either oral or rectal administration of berberine exhibited marked alleviation of bleomycin-induced PF in mice. In contrast, anti-PF activity of berberine disappeared when given by an intravenous injection, implying that it functioned in a gut-dependent manner. Moreover, berberine promoted both mRNA and protein levels of HGF and PTEN in colons, but only their protein levels in lungs of PF mice. In addition, SU11274 but not BPV abolished the anti-PF effect of berberine. In vitro, berberine preferentially induced expression of HGF in fibroblast cells than epithelial, preadipocyte and endothelial cells. Similarly, rosiglitazone and 15dPGJ2 also enhanced expression of HGF in fibroblasts cells, and GW9662 and siPPAR-gamma diminished induction of berberine on HGF expression. Berberine could enter into the cytoplasm, activate PPAR-gamma directly and synergistically with 15dPGJ2, as shown by an up-regulation of CD36 and aP2 mRNA expression, nuclear translocation and DNA-binding activity of PPAR-gamma both in vitro and in vivo. Additionally, GW9662 almost abolished anti-PF effect of berberine and induction of HGF expression in colons. In conclusion, oral administration of berberine displays anti-PF action probably in a colon-dependent manner, and mechanisms involve activation of PPAR-gamma and resultant promotion of HGF expression in colonic fibroblasts. The up-regulated HGF arrives in lung tissues via blood circulation to palliate PF. PMID- 29408571 TI - The use of intrapartum ultrasound to diagnose malpositions and cephalic malpresentations. PMID- 29408569 TI - Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice. AB - BACKGROUND & AIMS: Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6 ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors. METHODS: Immune competent C57BL/6 mice received intraperitoneal injections of carbon tetrachloride and intra-splenic injections of oncogenic hepatocytes. As a result, tumors resembling human hepatocellular carcinomas developed in a fibrotic liver setting. After tumors formed, mice were given an injection of LipC6 or vehicle via tail vein every other day for 2 weeks. This was followed by administration, also via tail vein, of tumor antigen specific (TAS) CD8+ T cells isolated from the spleens of line 416 mice, and subsequent immunization by intraperitoneal injection of tumor antigen-expressing B6/WT-19 cells. Tumor growth was monitored with magnetic resonance imaging. Tumor apoptosis, proliferation, and AKT expression were analyzed using immunohistochemistry and immunoblots. Cytokine production, phenotype, and function of TAS CD8+ T cells and tumor-associated macrophages (TAMs) were studied with flow cytometry, real-time polymerase chain reaction (PCR), and ELISA. Reactive oxygen species (ROS) in TAMs and bone marrow-derived macrophages, induced by colony stimulating factor 2 (GMCSF or CSF2) or colony stimulating factor 1 (MCSF or CSF1), were detected using a luminescent assay. RESULTS: Injection of LipC6 slowed tumor growth by reducing tumor cell proliferation and phosphorylation of AKT, and increasing tumor cell apoptosis, compared with vehicle. Tumors grew more slowly in mice given the combination of LipC6 injection and TAS CD8+ T cells followed by immunization compared with mice given vehicle, LipC6, the T cells, or immunization alone. LipC6 injection also reduced numbers of TAMs and their production of ROS. LipC6 induced TAMs to differentiate into an M1 phenotype, which reduced immune suppression and increased activity of CD8+ T cells. These results were validated by experiments with bone marrow-derived macrophages induced by GMCSF or MCSF. CONCLUSIONS: In mice with liver tumors, injection of LipC6 reduces the number of TAMs and the ability of TAMs to suppress the anti-tumor immune response. LipC6 also increases the anti-tumor effects of TAS CD8+ T cells. LipC6 might therefore increase the efficacy of immune therapy in patients with hepatocellular carcinoma. PMID- 29408572 TI - An integrated analysis of social stress in laying hens: The interaction between physiology, behaviour, and hierarchy. AB - Livestock is the category of animals that suffers the most severe welfare problems. Among these, physical, physiological, and behavioural distress caused by artificial grouping are some of the challenges faced by these animals. Groups whose members are frequently changed have been reported as socially unstable, which could jeopardise the welfare of animals. Here, we assessed the effect of social instability on aggression, stress, and productivity in groups of laying hens (Gallus gallus domesticus). We studied 36 females, distributed into three stable groups (without group membership change) and three unstable groups (where the dominant member was rotated every week) over the course of 10 weeks. We evaluated the frequency of agonistic interactions, glucocorticoid metabolites (GCM) concentrations, and egg production. In both treatments, dominant hens produced more eggs compared to intermediate and subordinates, and intermediate hens had the highest GCM concentrations. Socially unstable groups had lower productivity and higher frequencies of agonistic interactions than stable groups. Social instability also affected GCM of the animals: in stable groups, subordinate hens had higher concentrations than dominants; in unstable groups, this pattern was reversed. Our results point to a social destabilisation in groups whose members were alternated, and suggest the welfare of individuals in unstable groups was compromised. Our results pointed to a complex relationship between hierarchy, productivity, physiological stress and aggression in laying hens, and have implications for their husbandry and management and, consequently, for their welfare levels. PMID- 29408573 TI - Malaria, sickle cell disease, HIV, and co-trimoxazole prophylaxis: An observational study. AB - OBJECTIVES: This observational study recorded the malaria and sickle cell disease (SCD) profile of people living with HIV/AIDS (PLHA) and determined whether prophylactic co-trimoxazole (CTX) and the haemoglobin S (Hb S) allele influenced malaria episodes. METHODS: Sickling status, malaria episodes, and HIV type, as well as other data, were extracted retrospectively from the clinical records of 1001 patients attending the antiretroviral therapy clinic at Ridge Regional Hospital in Accra, Ghana between 2010 and 2015. Finger-prick capillary blood of returning patients (n=501) was tested for the haemoglobin (Hb) level and malaria, after information on malaria prevention methods was obtained through the administration of a questionnaire. RESULTS: The use of insecticide-treated mosquito nets was low (22.8%). CTX prophylaxis showed no significant influence on the overall number of malaria episodes from 2010 to 2015; however, it did show a statistically significant relationship (p=0.026) with the time elapsed since the last malaria episode. Even though 19% of participants possessed Hb S, it had no influence on malaria episodes. CONCLUSIONS: Hb S did not influence malaria in PLHA. Further studies in Hb SS and Hb SC are needed, as there are suggestions of increased frequency and severity of malaria. The impact of CTX prophylaxis on this cohort will be insightful. PMID- 29408574 TI - Clinical and Radiologic Features of 3 Reconstructive Procedures for the Surgical Management of Patients with Bilevel Cervical Degenerative Disc Disease at a Minimum Follow-Up Period of 5 Years: A Comparative Study. AB - OBJECTIVE: To assess the mid-long-term follow-up of the safety and efficacy of anterior cervical discectomy and fusion (ACDF), cervical artificial disc replacement (CADR) and hybrid surgery (HS) for bilevel cervical degenerative disc disease (cDDD). METHODS: 77 patients who underwent ACDF, HS, and CADR were retrospectively reviewed. Clinical effects were evaluated based on Neck Disability Index (NDI), Visual Analog Scale (VAS), and Japanese Orthopedic Association (JOA) scores and the Odom criteria. Radiographic outcomes were evaluated, including cervical range of motion (ROM), ROM in the operative and adjacent segments, incidence of degeneration in the adjacent segments (ASD), and heterotopic ossification (HO). RESULTS: NDI, VAS, and JOA scores significantly improved in all patients after surgery without significant differences between groups. The excellent-to-good ratio in the Odom scale was 28/30 for the HS group, 30/33 for the ACDF group, and 13/14 for the CADR group. No significant differences in clinical outcomes or complication were found between groups (P > 0.05). Furthermore, the HS and CADR groups had less decreased ROM in the cervical and operative segments and less compensatory ROM in adjacent segments (P < 0.05). By contrast, the ACDF group had decreased ROM in the cervical and operative segments and significantly increased ROM in adjacent segments (P < 0.05). Moreover, the incidence of ASD was higher in the ACDF group, but the difference was not statistically significant (P > 0.05). HO was found in 10 patients (33.3%) in the HS group and 5 patients (35.7%) in the CADR group. CONCLUSION: HS was superior to ACDF with regard to equivalent clinical outcomes in the mid-long-term follow-up. Furthermore, HS was superior in the maintenance of ROM and had less impact on its adjacent segments. The efficacy of HS is similar to that of CADR. PMID- 29408575 TI - Supratentorial Cortical Ependymomas: A Retrospective Series of 13 Cases at a Single Center. AB - OBJECTIVE: Cortical ependymomas (CEs), supratentorial ependymomas that selectively involve the cerebral cortex, are relatively rare neoplasms that have not been extensively described. The purpose of our study was to identify the clinical features, radiologic characteristics, and treatment of a series of such tumors. METHODS: Thirteen patients with CEs from our hospital were included in this study. Epidemiologic characteristics, clinical features, imaging findings, treatment methods, and clinical outcomes were reviewed retrospectively. RESULTS: The patients consisted of 7 men and 6 women with mean age of 31.1 +/- 23.2 years (range, 4-74 years). The most common clinical manifestation was seizure (n = 11; 85%), followed by headache (n = 2; 15%). None of the tumors were incidentally detected. Eight CEs were located in the right hemisphere and 5 in the left side. The 2 most common tumor locations were the frontal (n = 5; 38%) and parietal lobe (n = 5; 38%). All patients underwent surgical resection. Gross total resection was achieved in 12 patients (92%), and subtotal resection was performed in 1 patient (8%). Ten of the 11 patients who presented with seizure are seizure-free after surgery (91% seizure-free rate). According to the World Health Organization classification system, 9 tumors (69%) were Grade II (ependymoma) and 4 (31%) were Grade III (anaplastic ependymoma). The mean follow-up was 52 months (range, 20-88 months). No recurrence was observed in patients with Grade II CEs. Of 4 patients with Grade III CEs, 2 (50%) suffered from tumor recurrence after initial treatment. CONCLUSIONS: CEs are a rare subset of supratentorial ependymomas that selectively involve the cerebral cortex. Most CEs are low grade and present with seizures. Anaplastic CEs show a greater recurrence rate and a relatively poor prognosis. Gross total resection with or without adjuvant radiotherapy is currently the optimal treatment for CEs. CEs seem to have a more favorable prognosis than other supratentorial ependymomas. PMID- 29408576 TI - Neural correlates of novelty and appropriateness processing in externally induced constraint relaxation. AB - Novelty and appropriateness are considered the two fundamental features of creative thinking, including insight problem solving, which can be performed through chunk decomposition and constraint relaxation. Based on a previous study that separated the neural bases of novelty and appropriateness in chunk decomposition, in this study, we used event-related functional magnetic resonance imaging (fMRI) to further dissociate these mechanisms in constraint relaxation. Participants were guided to mentally represent the method of problem solving according to the externally provided solutions that were elaborately prepared in advance and systematically varied in their novelty and appropriateness for the given problem situation. The results showed that novelty processing was completed by the temporoparietal junction (TPJ) and regions in the executive system (dorsolateral prefrontal cortex [DLPFC]), whereas appropriateness processing was completed by the TPJ and regions in the episodic memory (hippocampus), emotion (amygdala), and reward systems (orbitofrontal cortex [OFC]). These results likely indicate that appropriateness processing can result in a more memorable and richer experience than novelty processing in constraint relaxation. The shared and distinct neural mechanisms of the features of novelty and appropriateness in constraint relaxation are discussed, enriching the representation of the change theory of insight. PMID- 29408577 TI - Diffuse Small Bowel Thickening. PMID- 29408578 TI - Novel alginate/hydroxyethyl cellulose/hydroxyapatite composite scaffold for bone regeneration: In vitro cell viability and proliferation of human mesenchymal stem cells. AB - Sodium alginate (SA)/hydroxyethylcellulose (HEC)/hydroxyapatite (HA) composite scaffolds were explored for enhanced in vitro bone regeneration. The SA/HEC/HA composites were synthesized using the lyophilization technique and further cross linked in the presence of calcium ions to form composite hydrogel networks. The physicochemical, thermal behavior and morphology properties of the prepared scaffolds were characterized through XRD, DSC/TGA, FTIR and SEM. Furthermore, the mechanical behavior of the under investigated scaffolds was determined using texture analyzer. The in vitro bioactivity in SBF and adsorption of bovine serum albumin as well as cell viability for all the prepared scaffolds were also tested. The results indicated that the higher HA concentration (40wt%) enhanced the mechanical properties (23.9MPa), bioactivity and protein adsorption. Cell viability of the tested scaffolds confirmed the non-toxicity of the fabricated systems on the human mesenchymal stem cells (hMSCs). Proliferation capability was also confirmed for the tested scaffolds after 3 and 7days, but the higher HA containing scaffold showed increased cell populations specially after 7days compared to HA-free scaffolds. This novel composite material could be used in bone tissue engineering as a scaffold material to deliver cells and biologically active molecules. PMID- 29408579 TI - Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes. AB - Nobiletin is a fully methoxylated flavone that has demonstrated anticancer activity via multiple modes of action. In the present study, the metabolism and further antiproliferative activity of nobiletin was evaluated in the CYP1 expressing human breast cancer cell line MDA-MB-468 and the normal breast cell line MCF10A. Nobiletin was metabolized in MDA-MB-468 cells to a single demethylated derivative assigned NP1. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Nobiletin exhibited submicromolar IC50 (0.1 +/ 0.04 MUM) in MDA-MB-468 cells, whereas it was considerably less active in MCF10A cells (40 MUM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 300-fold increase was noted in the IC50 (30 +/- 2.4 MUM) of nobiletin. In the presence of the CYP1 inhibitor acacetin, the conversion of nobiletin to NP1 was significantly reduced in MDA-MB-468 cells. Furthermore, a significant increase was noted in the population of the cells at the G1 phase, following treatment with nobiletin (10 MUM) for 24 h compared with the control cells treated with DMSO (0.1%) alone (55.9 +/- 0.14 vs. 45.6 +/- 1.96), whereas the cell cycle of MCF10A cells was not significantly altered under the same treatment conditions. Taken collectively, the results suggest that nobiletin is selectively bioactivated in MDA-MB-468 breast cancer cells via metabolism by the cytochrome P450 CYP1 family of enzymes. PMID- 29408580 TI - A comparative study of the antitumor efficacy of peptide-doxorubicin conjugates with different linkers. AB - The peptide-drug conjugates caused much attention currently. The purpose of present study was to elucidate the possible synergistic effect between ligand peptide and stimuli-responsive linkage in amphiphilic peptide-drug conjugates (APDCs) with different linkers. Especially, the superiority of each strategy as well as the synergistic effect between them was carefully investigated via the parallel comparisons of the three systems throughout of the whole study. Here, we synthesized three APDCs, namely, cRGD-SS-DOX (RSSDOX), cRGD-S-DOX (RSDOX) and cRGD-VC-DOX (RVCDOX), using doxorubicin (DOX) as a model cytotoxic agent, cRGDfC as a homing peptide, and reduction cleavable disulfide (SS), noncleavable single thioether (S) or cathepsin B cleavable valine-citrulline dipeptide (VC) as linker. The APDCs showed high drug loading capacity and they were evaluated in vitro in the integrin alphavbeta3-overexpressing B16 cells and in vivo in tumor bearing C57BL/6 mice. Endocytosis mechanism assay demonstrated that three types of APDCs internalized into cells through adynamin and actin depolymerizing mediated pathway following receptor-mediated endocytosis. Notably, RSDOX or RVCDOX induced stronger antitumor efficacy, which depended on their cellular uptake levels, intracellular trafficking and the colocalization rates with lysosomes. The in vivo efficacy of RSDOX or RVCDOX was 1.4-1.7 fold of free DOX and 1.7-2.0 fold of RSSDOX, respectively. In addition, RSDOX or RVCDOX demonstrated acceptable system, tissue and blood compatibility. The compromised efficacy of RSSDOX might be due to the generation of DOX-SH during degradation of prodrug, but not DOX. Taken together, our studies suggest that certain type of APDCs can significantly decrease the toxicity of free DOX and improve therapy outcome, which provides insight for the design of peptide-drug conjugates integrating ligand peptide and stimuli-responsive linkage. PMID- 29408582 TI - Unilateral optic nerve aplasia documented with optical coherence tomography-case report and literature review. AB - Optic nerve aplasia is a rare nonhereditary developmental anomaly characterized by congenital absence of the optic nerve, retinal blood vessels, retinal ganglion cells, and optic nerve fibers in a unilaterally malformed eye of an otherwise healthy individual. We report the case of a 6-year-old girl with unilateral optic nerve aplasia documented by optical coherence tomography (OCT). She had no systemic or central nervous system anomalies. Her right eye had no light perception, total afferent pupillary defect, microcornea, variable strabismus, and enophthalmos. The fundus examination showed complete absence of the optic nerve and central retinal vessels characteristic of optic nerve aplasia in the right eye. Computerized tomography and magnetic resonance imaging showed unilateral absence of the optic nerve. Spectral domain OCT showed absence of normal foveal contour, severe atrophy of the retinal layers, extremely thin choroid, and absence of the optic nerve head. PMID- 29408581 TI - The safe use of Doliocarpus dentatus in the gestational period: Absence of changes in maternal reproductive performance, embryo-fetal development and DNA integrity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Doliocarpus dentatus (Dilleniaceae) is commonly used in Brazil for the treatment of inflammatory process pain and urinary retention. Previous studies of our group have demonstrated the anti-inflammatory and antimycobacterial action of the ethanolic extract of Doliocarpus dentatus (EEDd) as well as the safety of its use. AIM OF THE STUDY: we investigated the effects of EEDd on reproductive performance, fetal development and DNA integrity in pregnant female Swiss mice. MATERIAL AND METHODS: thirty female Swiss mice were divided into three experimental groups (n = 10): control group treated with 1% tween-80 and EEDd1 and EEDd2 groups treated with EEDd at doses of 100 and 1000 mg/kg, respectively. The treatment occurred by oral gavage throughout the gestational period. At the end of pregnancy, parameters related to reproductive performance, embryofoetal development and DNA integrity was evaluated. RESULTS: both doses of the extract tested did not alter the reproductive parameters, did not present significant differences in the embryofetal development when compared to the control group and also did not induce the formation of micronuclei. CONCLUSION: the EEDd do not alter the reproductive parameters, embryofetal development and DNA integrity, ensuring its safe use during pregnancy. PMID- 29408583 TI - Long intergenic non-protein coding RNA 319 aggravates lung adenocarcinoma carcinogenesis by modulating miR-450b-5p/EZH2. AB - Growing evidence shows that long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially lung adenocarcinoma. In present study, we aim to investigate the role of lncRNA LINC00319 in the lung adenocarcinoma carcinogenesis. We observed that increased expression of LINC00319 in lung adenocarcinoma tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00319 indicated the poor prognosis of lung adenocarcinoma patients. Silence of LINC00319 was able to repress lung adenocarcinoma cell growth in vitro. Rescue assay was performed to further confirm that LINC00319 contributed to lung adenocarcinoma progression by regulating miR-450b-5p/EZH2 signal pathway. Taken together, our study discovered the oncogenic role of LINC00319 in clinical specimens and cellular experiments, showing the potential LINC00319/miR-450b-5p/EZH2 pathway. This results and findings provide a novel insight for lung adenocarcinoma tumorigenesis. PMID- 29408584 TI - Novel mitochondrial gene variants in Northwestern Chinese probands with non syndromic hearing loss by whole mitochondrial genome screening. AB - Mitochondrial DNA mutations play an important role in hereditary hearing loss. The present study aimed at identifying more novel genetic variants of mitochondrial DNA. Complete Mitochondrial genomes were detected in 97 Northwestern Chinese probands with non-syndromic hearing loss and 376 control subjects. The variants were evaluated for the pathogenicity using the following criteria: (1) present in <1% of the controls, (2) evolutional conservation, (3) potential structural and functional alterations. Mutational analysis in probands identified 706 variants, including 180 variants in the D loop region, 27 variants in the 12S rRNA gene, 29 variants in the 16S rRNA gene, 122 missense variants and 312 silent variants in the protein coding gene, 29 variants in the tRNA genes and 7 variants in the non-coding region. After further analysis assessed for the potential structural and functional significance, we identified 5 new candidate variants for hearing loss: 12S rRNA1473C>T, tRNAPhe 614A>C, tRNALys 8339A>G, ND1 3866T>C and non-coding 5656A>G. Our findings may provide the role of these genes in hearing loss development in China and valuable information for the further understanding of pathogenic mechanism of hearing loss. PMID- 29408585 TI - The Upper Esophageal Sphincter Assist Device Is Associated With Symptom Response in Reflux-Associated Laryngeal Symptoms. AB - Reflux-associated laryngeal symptoms (RALS) is the process in which chronic laryngeal symptoms are related to gastroesophagopharyngeal reflux.1 Impairment of upper esophageal sphincter (UES) reflexes may predispose to esophagopharyngeal reflux.1 The novel noninvasive nonpharmacologic UES assist device (UESAD) applies external cricoid pressure to augment intraluminal UES pressure by 20 to 30 mm Hg and reduce esophagopharyngeal reflux events.2 This study aimed to assess the therapeutic efficacy of the UESAD in a pragmatic clinical setting, and to identify factors associated with symptom response among patients with suspected RALS. PMID- 29408588 TI - Autophagy mediates the degradation of synaptic vesicles: A potential mechanism of synaptic plasticity injury induced by microwave exposure in rats. AB - : To explore how autophagy changes and whether autophagy is involved in the pathophysiological process of synaptic plasticity injury caused by microwave radiation, we established a 30 mW/cm2 microwave-exposure in vivo model, which caused reversible injuries in rat neurons. Microwave radiation induced cognitive impairment in rats and synaptic plasticity injury in rat hippocampal neurons. Autophagy in rat hippocampal neurons was activated following microwave exposure. Additionally, we observed that synaptic vesicles were encapsulated by autophagosomes, a phenomenon more evident in the microwave-exposed group. Colocation of autophagosomes and synaptic vesicles in rat hippocampal neurons increased following microwave exposure. CONCLUSION: microwave exposure led to the activation of autophagy in rat hippocampal neurons, and excessive activation of autophagy might damage synaptic plasticity by mediating synaptic vesicle degradation. PMID- 29408586 TI - A prospective cohort study of fetal heart rate monitoring: deceleration area is predictive of fetal acidemia. AB - BACKGROUND: Intrapartum electronic fetal monitoring is the most commonly used tool in obstetrics in the United States; however, which electronic fetal monitoring patterns predict acidemia remains unclear. OBJECTIVE: This study was designed to describe the frequency of patterns seen in labor using modern nomenclature, and to test the hypothesis that visually interpreted patterns are associated with acidemia and morbidities in term infants. We further identified patterns prior to delivery, alone or in combination, predictive of acidemia and neonatal morbidity. STUDY DESIGN: This was a prospective cohort study of 8580 women from 2010 through 2015. Patients were all consecutive women laboring at >=37 weeks' gestation with a singleton cephalic fetus. Electronic fetal monitoring patterns during the 120 minutes prior to delivery were interpreted in 10-minute epochs. Interpretation included the category system and individual electronic fetal monitoring patterns per the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria as well as novel patterns. The primary outcome was fetal acidemia (umbilical artery pH <=7.10); neonatal morbidities were also assessed. Final regression models for acidemia adjusted for nulliparity, pregestational diabetes, and advanced maternal age. Area under the receiver operating characteristic curves were used to assess the test characteristics of individual models for acidemia and neonatal morbidity. RESULTS: Of 8580 women, 149 (1.7%) delivered acidemic infants. Composite neonatal morbidity was diagnosed in 757 (8.8%) neonates within the total cohort. Persistent category I, and 10-minute period of category III, were significantly associated with normal pH and acidemia, respectively. Total deceleration area was most discriminative of acidemia (area under the receiver operating characteristic curves, 0.76; 95% confidence interval, 0.72-0.80), and deceleration area with any 10 minutes of tachycardia had the greatest discriminative ability for neonatal morbidity (area under the receiver operating characteristic curves, 0.77; 95% confidence interval, 0.75-0.79). Once the threshold of deceleration area is reached the number of cesareans needed-to-be performed to potentially prevent 1 case of acidemia and morbidity is 5 and 6, respectively. CONCLUSION: Deceleration area is the most predictive electronic fetal monitoring pattern for acidemia, and combined with tachycardia for significant risk of morbidity, from the electronic fetal monitoring patterns studied. It is important to acknowledge that this study was performed in patients delivering >=37 weeks, which may limit the generalizability to preterm populations. We also did not use computerized analysis of the electronic fetal monitoring patterns because human visual interpretation was the basis for the Eunice Kennedy Shriver National Institute of Child Health and Human Development categories, and importantly, it is how electronic fetal monitoring is used clinically. PMID- 29408587 TI - Fetal regional brain protein signature in FASD rat model. AB - Fetal alcohol spectrum disorders (FASD) describe neurodevelopmental deficits in children exposed to alcohol in utero. We hypothesized that gestational alcohol significantly alters fetal brain regional protein signature. Pregnant rats were binge-treated with alcohol or pair-fed and nutritionally-controlled. Mass spectrometry identified 1806, 2077, and 1456 quantifiable proteins in the fetal hippocampus, cortex, and cerebellum, respectively. A stronger effect of alcohol exposure on the hippocampal proteome was noted: over 600 hippocampal proteins were significantly (P < .05) altered, including annexin A2, nucleobindin-1, and glypican-4, regulators of cellular growth and developmental morphogenesis. In the cerebellum, cadherin-13, reticulocalbin-2, and ankyrin-2 (axonal growth regulators) were significantly (P < .05) altered; altered cortical proteins were involved in autophagy (endophilin-B1, synaptotagmin-1). Ingenuity analysis identified proteins involved in protein homeostasis, oxidative stress, mitochondrial dysfunction, and mTOR as major pathways in the cortex and hippocampus significantly (P < .05) affected by alcohol. Thus, neurodevelopmental protein changes may directly relate to FASD neuropathology. PMID- 29408589 TI - Identification of Stria Medullaris Fibers in the Massa Intermedia Using Diffusion Tensor Imaging. AB - BACKGROUND: The massa intermedia (MI) or interthalamic adhesion is an inconsistent band spanning between bilateral medial thalami that is absent in up to 20%-30% of individuals. Little is known of its significance, especially in regard to functional pathways. Probabilistic diffusion tensor imaging (DTI) has recently been used to seed the lateral habenula and define its afferent white matter pathway, the stria medullaris thalami (SM). We sought to determine whether the MI serves as a conduit for crossing of limbic fibers such as the SM. METHODS: Probabilistic DTI was performed on 10 subjects who had presence of a MI as visualized on magnetic resonance imaging. Tractography was also performed on 2 subjects without MI. Manual identification of the lateral habenula on axial T1 weighted magnetic resonance imaging was used for the initial seed region for tractography. RESULTS: In all subjects, the SM was reliably visualized. In 7 of the 10 subjects with MI, there was evidence of SM fibers that crossed to the ipsilateral hemisphere. Three subjects with small diameter MI did not have tractographic evidence of crossing SM fibers. Of the 7 subjects with crossing SM fibers within the MI, 5 showed predilection toward the right orbitofrontal cortex from both the left and right seed regions. CONCLUSIONS: Probabilistic DTI provides evidence of SM fibers within the MI. Given its anatomic location as a bridging pathway between thalami, further studies are necessary to assess its role within the limbic functional network. PMID- 29408590 TI - Brain response to food cues varying in portion size is associated with individual differences in the portion size effect in children. AB - Large portions promote intake of energy dense foods (i.e., the portion size effect--PSE), but the neurobiological drivers of this effect are not known. We tested the association between blood oxygen level dependent (BOLD) brain response to food images varied by portion size (PS) and energy density (ED) and children's intake at test-meals of high- and low-ED foods served at varying portions. Children (N = 47; age 7-10 years) participated in a within-subjects, crossover study consisting of 4 meals of increasing PS of high- and low-ED foods and 1 fMRI to evaluate food images at 2 levels of PS (Large, Small) and 2 levels of ED (High, Low). Contrast values between PS conditions (e.g., Large PS - Small PS) were calculated from BOLD signal in brain regions implicated in cognitive control and reward and input as covariates in mixed models to determine if they moderated the PSE curve. Results showed a significant effect of PS on intake. Responses to Large relative to Small PS in brain regions implicated in salience (e.g., ventromedial prefrontal cortex and orbitofrontal cortex) were positively associated with the linear slope (i.e., increase in intake from baseline) of the PSE curve, but negatively associated with the quadratic coefficient for the total meal. Responses to Large PS High ED relative to Small PS High ED cues in regions associated with cognitive control (e.g., dorsolateral prefrontal cortex) were negatively associated with the linear slope of the PSE curve for high-ED foods. Brain responses to PS cues were associated with individual differences in children's susceptibility to overeating from large portions. Responses in food salience regions positively associated with PSE susceptibility while activation in control regions negatively associated with PSE susceptibility. PMID- 29408591 TI - Continuous Acetylsalicylic Acid Treatment Does Not Influence Bleeding Pattern or Outcome of Aneurysmal Subarachnoid Hemorrhage: A Matched-Pair Analysis. AB - OBJECTIVE: Demographic changes are leading to an aging society with a growing number of patients with cardiovascular diseases, relying on antiplatelet drugs like acetylsalicylic acid (ASA). Although antiplatelet agents are suspected to be protective not only in the cardiologic but in the neurovascular field, the alteration of the coagulating process could have a major impact on the course and outcome after rupture of intracranial aneurysms. METHODS: Between June 1999 and December 2014, 1422 patients were treated for aneurysmal SAH in our institution, 144 (10.1%) with continuous ASA at the time of aneurysm rupture. A matched-pair analysis was performed. RESULTS: The rate of patients with continuous ASA treatment while rupture of the aneurysm is rising significantly (P < 0.01). Those patients were significantly older than patients without ASA (60 vs. 53 years, P < 0.001). ASA-treated patients more often had aneurysmal rebleeding (4.7% vs. 2.3%, P = 0.3) and treatment-related hemorrhagic complications (13.9% vs. 6.2%, P = 0.06). However, rates were not different in microsurgical or endovascular procedures (16.4% vs. 12.2%, P = 0.6). Favorable outcome (Modified Rankin Scale 0 2) was achieved in 49.3% of the ASA group and 52.1% of the control group (P = 0.7). CONCLUSION: Patients with continuous ASA treatment were significantly older than patients without ASA, but there was no difference in admission status or bleeding pattern. Outcome was not different in the matched-pair analysis. There was no statistical difference in treatment related-complication rates of microsurgical and endovascular procedures. Therefore, ASA use should not influence treatment decision of the ruptured aneurysm. PMID- 29408592 TI - Stereotactic Radiofrequency Thermocoagulation of Hypothalamic Hamartoma Using Robotic Guidance (ROSA) Coregistered with O-arm Guidance-Preliminary Technical Note. AB - INTRODUCTION: Treatment options for hypothalamic hamartoma (HH) include microvascular surgery, stereotactic radiofrequency thermocoagulation (SRT), laser interstitial thermal therapy, or Gamma Knife surgery. During SRT, thermographic monitoring cannot be performed and therefore highly accurate placement of electrode and confirmation of its position are required. We have used robotic guidance (ROSA) and coregistered it with O-arm for performing ablation of hamartoma. METHODS: Five patients with HH and gelastic seizures underwent SRT. Robotic guidance (ROSA) was used for placement of electrodes. An O-arm was used for coregistering and confirming the robotic trajectory with real-time intraoperative imaging. Intraoperative computed tomography was merged with preoperative magnetic resonance imaging to confirm the exact position and trajectory of the electrode. Ablation was performed using a radiofrequency generator (70 degrees C for 60 seconds). Multiple target sites were ablated to achieve proper ablation and disconnection. RESULTS: Most patients (4/5) had International League Against Epilepsy class I outcome. One patient 2 sittings of lesioning. All but 1 electrode could be placed in the planned trajectories. One electrode was detected to have a medial deviation, and it had to be revised. No permanent complication was observed. CONCLUSIONS: SRT is a cost-effective method of treating HH when compared with laser interstitial thermal therapy. With the use of a robotic arm we have demonstrated accurate placement of electrodes. Intraoperative computed tomography acquired using an O-arm can be merged with preoperative magnetic resonance imaging. This confirms electrode location and trajectory on a real-time basis by performing intraoperative imaging. This method is safe and can be used for radiofrequency ablation of HH. PMID- 29408593 TI - Acute Compartment Syndrome as a Complication of the Use of Intraoperative Neuromonitoring Needle Electrodes. AB - BACKGROUND: The use of intraoperative neurophysiologic monitoring (IOM) has become commonplace in many neurosurgical procedures as a tool to reduce the risk of complications through the early identification of reversible neurologic compromise. Although complications related to IOM itself are exceedingly rare, recognizing their clinical presentation in the postoperative neurosurgical patient is essential for the early identification and implementation of appropriate treatment. CASE DESCRIPTION: The authors present a case report of a patient who developed postoperative acute compartment syndrome in the right arm after placement of neuromonitoring needles for routine IOM during endovascular treatment of a left internal carotid artery aneurysm. Before the procedure, the patient received dual antiplatelet therapy and was noted to have a P2Y12 reaction unit value within therapeutic range. The patient had not received other anticoagulation therapy and had no family or personal history of hematologic or coagulopathic disorders. Immediately after an uncomplicated endovascular intervention, the patient began to develop symptoms of forearm swelling, tightness, and tenderness to palpation; pain with wrist flexion and extension; and paresthesias of the distal digits of the hand. She had eventual loss of a palpable radial pulse. The patient underwent emergent fasciotomies of multiple forearm compartments and had immediate return of a palpable radial pulse. CONCLUSIONS: This case represents the first report of post-procedural compartment syndrome resulting from placement of neuromonitoring needles for routine IOM. Although it is a particularly rare complication of IOM, compartment syndrome represents a surgical emergency that carries significant morbidity if not immediately recognized and treated. PMID- 29408594 TI - Effect of Tubastatin A on the Functional Recovery of Cauda Equina Injury in Rats. AB - OBJECTIVE: To explore the effect of the inhibitor of histone deacetylase (6HDAC6), tubastatin A, on the functional recovery of injured central branch of dorsal root ganglia (cauda equina). METHODS: A total of 30 Sprague-Dawley rats (n = 10 for each group) were divided randomly into sham operation (sham group), cauda equina compression control (CEC control group), and cauda equina compression plus tubastatin A treatment (tubastatin A group). The tail-flick test was performed to detect the sense of pain and warmth as well as motor function. Immunoblotting/immunofluorescence experiments, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and hematoxylin-eosin staining were performed to detect the amount of HDAC6 in dorsal root ganglion (DRG) neurons, degree of apoptosis in DRG neurons, and degree of cauda equina injury, respectively. RESULTS: The ratio of apoptotic cells in the CEC control group was greater than that in the sham group, whereas it decreased in the tubastatin A group. Hematoxylin-eosin staining revealed that the fibers of cauda equina in the tubastatin A group were more compact compared with those in the CEC control group. The expression of HDAC6 was not different between the sham and CEC control groups, whereas it decreased significantly in the tubastatin A group. Tubastatin A administration shortened tail-flick latency on the seventh day after operation compared with the CEC control group. CONCLUSIONS: Tubastatin A significantly decreased the expression of HDAC6 in DRG neurons with injured cauda equina, inhibited the apoptosis of neural cells and axonal demyelinating changes in cauda equina, and partially promoted the recovery of neural function. PMID- 29408595 TI - STX3 represses the stability of the tumor suppressor PTEN to activate the PI3K Akt-mTOR signaling and promotes the growth of breast cancer cells. AB - Syntaxin 3, also known as STX3, is a protein encoded by the STX3 gene in humans. This protein is one of the fundamental components of the exocytotic machinery required for the docking and fusion of secretory granules with the plasma membrane. The roles of STX3 in human breast cancer remains elusive. Here we report that STX3 acts as an oncogenic protein in human breast cancer. We analyzed the expression of STX3 in 148 patients with breast cancer. The mRNA and protein levels of STX3 are significantly up-regulated in human breast cancer compared with matched adjacent non-cancer tissues. The up-regulation of STX3 is correlated with high disease stage and predicts overall and disease-free survival in patients with breast cancer. Lentivirus-mediated knockdown of STX3 represses in vitro proliferation and colony formation and in vivo growth of breast cancer cells, whereas STX3 overexpression promotes the growth of breast cancer cells in vitro and in vivo. We find that STX3 promotes the proliferation of breast cancer cells by increasing the activation of the Akt-mTOR signaling, and Akt inhibitor Ipatasertib or MK-2206 represses STX3 effects on the growth of breast cancer cells. Further mechanism study shows that STX3 binds to PTEN and increases PTEN ubiquitination and degradation, thus leading to activation of the PI3K-Akt-mTOR signaling. Therefore, STX3 promotes the growth of breast cancer cells by regulating the PTEN-PI3K-Akt-mTOR signaling. PMID- 29408596 TI - Clinical and immunological profiles of anaemia in children and adolescents with Plasmodium vivax malaria in the Para state, Brazilian Amazon. AB - Children and adolescents are at great risk for developing iron deficiency anaemia worldwide. In the tropical areas, malaria and intestinal parasites may also play an important role in anaemia pathogenesis. This study aimed at evaluating clinical and immunological aspects of anaemia in children and adolescents with Plasmodium vivax malaria, in the Para State, Brazil. A longitudinal study was performed in two Reference Centers for malaria diagnosis in the Brazilian Amazon in children and adolescents with malaria (n = 81), as compared to a control group (n = 40). Patients had blood drawn three times [before treatment (D0), after treatment (D7) and at the first cure control (D30)] and hemogram, autoantibody analysis (anticardiolipin, antibodies against normal RBC membrane components) and cytokine studies (TNF and IL-10) were performed. Stool samples were collected for a parasitological examination. Malaria patients had a 2.7-fold greater chance of anaemia than the control group. At D0, 66.1% of the patients had mild anaemia, 30.5% had moderate and 3.5% had severe anaemia. Positivity to intestinal helminths and/or protozoa at stool examinations had no influence on anaemia. Patients had significantly lower levels of plasmatic TNF than control individuals at D0. Low TNF levels were more prevalent among patients with moderate/severe anaemia than in those with mild anaemia and among anaemic patients than in anaemic controls. TNF levels were positively correlated with the haemoglobin rates and negatively correlated with the interval time elapsed between the onset of symptoms and diagnosis. Both plasma TNF levels and haemoglobin rates increased during the follow-up period. The IL-10 levels were lower in patients than in the controls at day 0 and decreased thereafter up to the end of treatment. Only the anti-anticardiolipin autoantibodies were associated with moderate/severe anaemia and, possibly by reacting with the parasite glycosylphosphatidylinositol (a powerful stimulator of TNF production), may have indirectly contributed to decrease the TNF levels, which could be involved in the malarial vivax anaemia of these children and adolescents. More studies addressing this issue are necessary to confirm these findings and to add more information on the multifactorial pathogenesis of the malarial anaemia. PMID- 29408597 TI - Clostridial DivIVA and MinD interact in the absence of MinJ. AB - One of the key regulators ensuring proper Z-ring placement in rod-shaped bacteria is the Min system. It does so by creating a concentration gradient of the MinC septation inhibitor along the cell axis. In Escherichia coli, this gradient is established by a MinE-mediated pole-to-pole oscillation of the MinCDE complex. In Bacillus subtilis, the creation of an inhibitory gradient relies on the MinJ and DivIVA pair of topological determinants, which target MinCD to the newly formed cell poles. Introducing the E. coli oscillating Min system into B. subtilis leads to a sporulation defect, suggesting that oscillation is incompatible with sporulation. However, Clostridia, close endospore-forming relatives of Bacilli, do encode oscillating Min homologues in various combinations together with homologues from the less dynamic B. subtilis Min system. Here we address the questions of how these two systems could exist side-by-side and how they influence one another by studying the Clostridium beijerinckii and Clostridium difficile Min systems. The toolbox of genetic manipulations and fluorescent protein fusions in Clostridia is limited, therefore B. subtilis and E. coli were chosen as heterologous systems for studying these proteins. In B. subtilis, MinD and DivIVA interact through MinJ; here, however, we discovered that the MinD and DivIVA proteins of both C. difficile, and C. beijerinckii, interact directly, which is surprising in the latter case, since that organism also encodes a MinJ homologue. We confirm this interaction using both in vitro and in vivo methods. We also show that C. beijerinckii MinJ is probably not in direct contact with DivIVACb and, unlike B. subtilis MinJ, does not mediate the MinDCb and DivIVACb interaction. Our results suggest that the Clostridia Min system uses a new mechanism of function. PMID- 29408598 TI - Investigating the effect of supplementation on Clostridioides (Clostridium) difficile spore recovery in two solid agars. AB - BACKGROUND: A variety of supplemented solid media are used within Clostridium difficile research to optimally recover spores. Our study sought to investigate different media and additives, providing a method of optimised C. difficile spore recovery. Additionally, due to the results observed in the initial experiments, the inhibitory effects of three amino acids (glycine, l-histidine &l phenylalanine) on C. difficile spore outgrowth were investigated. METHODS: Spores of five C. difficile strains (PCR ribotypes 001,015,020,027,078) were recovered on two commonly used solid media (BHI & CCEY, or cycloserine-cefoxitin egg yolk) supplemented with various concentrations of germinants (taurocholate, glycine & lysozyme). Agar-incorporation minimum inhibitory concentration (MIC) testing was carried out for glycine and taurocholate on vegetative cells and spores of all five strains. Additionally a BHI broth microassay method was utilised to test the growth of C. difficile in the presence of increasing concentrations (0,1,2,3,4%) of three amino acids (glycine,l-histidine,l-phenyalanine). RESULTS: CCEY agar alone and BHI supplemented with taurocholate (0.1/1%) provided optimal recovery for C. difficile spores. Glycine was inhibitory to spore recovery at higher concentrations, although these varied between the two media used. In agar incorporated MIC testing, glycine concentrations higher than 2% (20 g/L) were inhibitory to both C. difficile spore and vegetative cell growth versus the control (mean absorbance = 0.33 +/- 0.02 vs 0.12 +/- 0.01) (P < 0.001). This indicates a potential mechanism whereby glycine interferes with vegetative cell growth. Further microbroth testing provided evidence of inhibition by two amino acids other than glycine, l-histidine and l-phenylalanine. CONCLUSIONS: We provide two media for optimal recovery of C. difficile spores (CCEY alone and BHI supplemented with 0.1/1% taurocholate). CCEY is preferred for isolation from faecal samples. For pure cultures, either CCEY or supplemented BHI agar are appropriate. The inhibitory nature of three amino acids (glycine,l-histidine,l phenylalanine) to C. difficile vegetative cell proliferation is also highlighted. PMID- 29408599 TI - Characterization of Fusobacterium necrophorum subsp. necrophorum outer membrane proteins. AB - Liver abscesses are of major economic importance to the cattle industry. These are mainly associated with the presence of Fusobacterium necrophorum, a non-spore forming and Gram-negative anaerobe. There are two main subspecies, F. necrophorum subspecies necrophorum and subsp. funduliforme, and they differ molecularly, morphologically, biochemically and in virulence. Previous studies have shown that the outer membrane proteins (OMP) of F. necrophorum subsp. necrophorum are important for its successful binding to immobilized bovine adrenal gland capillary endothelial (EJG) cells. In this study, a 42.4 kDa OMP of F. necrophorum subsp. necrophorum with the highest binding capacity to EJG cells was characterized. The gene was cloned into pFLAG-CTS vector and the proteins were subsequently expressed on the surface of E. coli BL21 DE3 cells. When E. coli carrying the recombinant plasmid (SM 2013) was induced using IPTG, there was significant enhancement in the binding to immobilized EJG cells compared to both uninduced SM 2013 and the E. coli carrying control vector only. When fixed EJG cells were incubated with purified native OMP, SM 2013 showed lowered levels of binding, compared to the uninduced SM 2013 and the E. coli carrying control vector only. Pre-incubation of induced SM 2013 with polyclonal antibodies made against the OMP reduced the binding to immobilized EJG cells to uninduced SM 2013 levels. This gain of function by recombinant E. coli confirms the ability of this protein to act as an adhesion to help binding of F. necrophorum subsp. necrophorum to host cells. PMID- 29408600 TI - Impact of the direct transfer to percutaneous coronary intervention-capable hospitals on survival to hospital discharge for patients with out-of-hospital cardiac arrest. AB - AIMS: Patients suffering from out-of-hospital cardiac arrest (OHCA) are frequently transported to the closest hospital. Percutaneous coronary intervention (PCI) is often indicated following OHCA. This study's primary objective was to determine the association between being transported to a PCI capable hospital and survival to discharge for patients with OHCA. The additional delay to hospital arrival which could offset a potential increase in survival associated with being transported to a PCI-capable center was also evaluated. METHODS: This study used a registry of OHCA in Montreal, Canada. Adult patients transported to a hospital following a non-traumatic OHCA were included. Hospitals were dichotomized based on whether PCI was available on-site or not. The effect of hospital type on survival to discharge was assessed using a multivariable logistic regression. The added prehospital delay which could offset the increase in survival associated with being transported to a PCI-capable center was calculated using that regression. RESULTS: A total of 4922 patients were included, of whom 2389 (48%) were transported to a PCI-capable hospital and 2533 (52%) to a non-PCI-capable hospital. There was an association between being transported to a PCI-capable center and survival to discharge (adjusted odds ratio = 1.60 [95% confidence interval 1.25-2.05], p < .001). Increasing the delay from call to hospital arrival by 14.0 min would offset the potential benefit of being transported to a PCI-capable center. CONCLUSIONS: It could be advantageous to redirect patients suffering from OHCA patients to PCI-capable centers if the resulting expected delay is of less than 14 min. PMID- 29408601 TI - Automated external defibrillators and defibrillation electrodes from major manufactures depict placement of the left apical defibrillation electrode poorly! PMID- 29408602 TI - Hepatic NAD+ levels and NAMPT abundance are unaffected during prolonged high-fat diet consumption in C57BL/6JBomTac mice. AB - Dietary supplementation of nicotinamide adenine dinucleotide (NAD+) precursors has been suggested as a treatment for non-alcoholic fatty liver disease and obesity. In the liver, NAD+ is primarily generated by nicotinamide phosphoribosyltransferase (NAMPT), and hepatic levels of NAMPT and NAD+ have been reported to be dependent on age and body composition. The aim of the present study was to identify time course-dependent changes in hepatic NAD content and NAD+ salvage capacity in mice challenged with a high-fat diet (HFD). We fed 7 week-old C57BL/6JBomTac male mice either regular chow or a 60% HFD for 6, 12, 24, and 48 weeks, and we evaluated time course-dependent changes in whole body metabolism, liver steatosis, and abundance of hepatic NAD-associated metabolites and enzymes. Mice fed a 60% HFD rapidly accumulated fat and hepatic triglycerides with associated changes in respiratory exchange ratio (RER) and a disruption of the circadian feeding pattern. The HFD did not alter hepatic NAD+ levels, but caused a decrease in NADP+ and NADPH levels. Decreased NADP+ content was not accompanied by alterations in NAD kinase (NADK) abundance in HFD-fed mice, but NADK levels increased with age regardless of diet. NAMPT protein abundance did not change with age or diet. HFD consumption caused a severe decrease in protein lysine malonylation after six weeks, which persisted throughout the experiment. This decrease was not associated with changes in SIRT5 abundance. In conclusion, hepatic NAD+ salvage capacity is resistant to long-term HFD feeding, and hepatic lipid accumulation does not compromise the hepatic NAD+ pool in HFD-challenged C57BL/6JBomTac male mice. PMID- 29408603 TI - Prostaglandin E2 (PGE2) is a testicular peritubular cell-derived factor involved in human testicular homeostasis. AB - In man, blockage of prostaglandin (PG)-production e.g. by non-steroidal anti inflammatory drug (NSAIDs) may have negative testicular side effects, implying beneficial actions of PGs in the testis. We examined human testicular samples and isolated human testicular peritubular cells (HTPCs) to explore sites of PG synthesis and targets. HTPCs express cyclooxygenase 1 (COX1) and secrete PGE2. Receptors (EP1, 2, 4) were specifically identified in peritubular cells. In HTPCs PGE2 significantly increased mRNA levels of the contractility protein calponin, but did not induce contractions. PGE2, as well as EP1 and EP4 receptor agonists, significantly increased glia cell line derived neurotrophic factor (GDNF) mRNA and/or protein levels. Importantly, the NSAID ibuprofen reduced PGE2 and this action also lowered SMA and calponin mRNA levels and levels of secreted GDNF protein. The results reveal an unknown PGE2 system in the human testis, in involving peritubular cells, which may be prone to interference by NSAIDs. PMID- 29408604 TI - Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe. AB - The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified. A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified. In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10-40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher). This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer. PMID- 29408605 TI - Nf2 Mutation in Schwann Cells Delays Functional Neural Recovery Following Injury. AB - Merlin is the protein product of the NF2 tumor suppressor gene. Germline NF2 mutation leads to neurofibromatosis type 2 (NF2), characterized by multiple intracranial and spinal schwannomas. Patients with NF2 also frequently develop peripheral neuropathies. While the role of merlin in SC neoplasia is well established, its role in SC homeostasis is less defined. Here we explore the role of merlin in SC responses to nerve injury and their ability to support axon regeneration. We performed sciatic nerve crush in wild-type (WT) and in P0SchDelta39-121 transgenic mice that express a dominant negative Nf2 isoform in SCs. Recovery of nerve function was assessed by measuring mean contact paw area on a pressure pad 7, 21, 60, and 90 days following nerve injury and by nerve conduction assays at 90 days following injury. After 90 days, the nerves were harvested and axon regeneration was quantified stereologically. Myelin ultrastructure was analyzed by electron microscopy. Functional studies showed delayed nerve regeneration in Nf2 mutant mice compared to the WT mice. Delayed neural recovery correlated with a reduced density of regenerated axons and increased endoneurial space in mutants compared to WT mice. Nevertheless, functional and nerve conduction measures ultimately recovered to similar levels in WT and Nf2 mutant mice, while there was a small (~17%) reduction in the percent of regenerated axons in the Nf2 mutant mice. The data suggest that merlin function in SCs regulates neural ultrastructure and facilitates neural regeneration, in addition to its role in SC neoplasia. PMID- 29408606 TI - Mandatory completion of a box trainer curriculum prior to laparoscopic apprenticeship in the OR for surgical residents: A Before and After study. AB - INTRODUCTION: Training on laparoscopic box trainer (BT) improves surgical skills in the operating room (OR). Despite a large consensus on the educational value of the BT, its use is currently left up to local initiatives among French residency programs. This study evaluated the impact of a requirement to complete the Fundamentals of Laparoscopic Surgery (FLS) curriculum before starting companionship in the OR. METHODS: This was a "Before and After" study conducted in two French academic hospitals in 2015-2017. Gynaecology and urology residents were given open access to a FLS BT during a six-month surgical rotation. Residents in the first group (Before group) trained on the BT while receiving classic companionship. Residents in the second group (After group) had to complete the FLS curriculum before they were allowed to participate in laparoscopic procedures as a primary operator. Outcomes measures were the time to curriculum completion and the intracorporeal suturing performances based on two validated assessment tools (FLS and GOALS scores). RESULTS: Twenty-one surgical residents were included. All but two residents in the Before group completed the curriculum. The time to curriculum completion was longer in the Before group than the After group (69.5 days versus 28 days, P=0.001). Post-curriculum performances were lower in the Before group than in the After group for the FLS scores (452.5 versus 496, P=0.01) and the GOALS scores (14.5 versus 18, P=0.01). DISCUSSION: The mandatory completion of a BT curriculum prior to receiving active companionship in the OR is beneficial to residents in reducing time to curriculum completion and in enhancing laparoscopic skills on the BT. PMID- 29408607 TI - Functional MRI in prenatally opioid-exposed children during a working memory selective attention task. AB - BACKGROUND: Opioid induced cerebral changes may contribute to neuropsychological difficulties, like attention problems, frequently reported in prenatally opioid exposed children. Reduced regional brain volumes have been shown after prenatal opioid exposure, but no study to date has explored the possible impact of prenatal opioids on brain activation patterns. MATERIALS AND METHODS: A hospital based sample of prenatally opioid-exposed school-aged children (n = 11) and unexposed controls (n = 12) underwent functional magnetic resonance imaging (fMRI) during a combined working memory-selective attention task. Within-group- and between-group analyses of blood-oxygen-level-dependent (BOLD) activation were performed using the SPM12 software package and group differences in task performance were analyzed using Cox proportional hazards modeling. RESULTS: Overall, similar patterns of task related parietal and prefrontal BOLD activations were found in both groups. The opioid-exposed group showed impaired task performance, and during the most cognitive demanding versions of the working memory-selective attention task, increased activation in prefrontal cortical areas was found in the opioid-exposed group compared to controls. CONCLUSION: Our findings suggest that prenatal opioids affect later brain function, visible through changes in BOLD activation patterns. However, results should be considered preliminary until replicated in larger samples better suited to control for potential confounding factors. PMID- 29408608 TI - Ferrous ion as a reducing agent in the generation of antibiofilm nitric oxide from a copper-based catalytic system. AB - The work found that the electron-donating properties of ferrous ions (Fe2+) can be used for the conversion of nitrite (NO2-) into the biofilm-dispersing signal nitric oxide (NO) by a copper(II) complex (CuDTTCT) catalyst, a potentially applicable biofilm control technology for the water industries. The availability of Fe2+ varied depending on the characteristics of the aqueous systems (phosphate and carbonate-containing nitrifying bacteria growth medium, NBGM and phosphate buffered saline, PBS at pH 6 to 8, to simulate conditions typically present in the water industries) and was found to affect the production of NO from nitrite by CuDTTCT (casted into PVC). Greater amounts of NO were generated from the CuDTTCT-nitrite-Fe2+ systems in PBS compared to those in NBGM, which was associated with the reduced extent of Fe2+-to-Fe3+ autoxidation by the iron precipitating moieties phosphates and carbonate in the former system. Further, acidic conditions at pH 6.0 were found to favor NO production from the catalytic system in both PBS and NBGM compared to neutral or basic pH (pH 7.0 or 8.0). Lower pH was shown to stabilize Fe2+ and reduce its autoxidation to Fe3+. These findings will be beneficial for the potential implementation of the NO-generating catalytic technology and indeed, a 'non-killing' biofilm dispersal activity of CuDTTCT-nitrite-Fe2+ was observed on nitrifying bacteria biofilms in PBS at pH 6. PMID- 29408609 TI - Microbiota-Derived Metabolic Factors Reduce Campylobacteriosis in Mice. AB - BACKGROUND & AIMS: Campylobacter jejuni, a prevalent foodborne bacterial pathogen, exploits the host innate response to induce colitis. Little is known about the roles of microbiota in C jejuni-induced intestinal inflammation. We investigated interactions between microbiota and intestinal cells during C jejuni infection of mice. METHODS: Germ-free C57BL/6 Il10-/- mice were colonized with conventional microbiota and infected with a single dose of C jejuni (109 colony forming units/mouse) via gavage. Conventional microbiota were cultured under aerobic, microaerobic, or anaerobic conditions and orally transplanted into germ free Il10-/- mice. Colon tissues were collected from mice and analyzed by histology, real-time polymerase chain reaction, and immunoblotting. Fecal microbiota and bile acids were analyzed with 16S sequencing and high-performance liquid chromatography with mass spectrometry, respectively. RESULTS: Introduction of conventional microbiota reduced C jejuni-induced colitis in previously germ free Il10-/- mice, independent of fecal load of C jejuni, accompanied by reduced activation of mammalian target of rapamycin. Microbiota transplantation and 16S ribosomal DNA sequencing experiments showed that Clostridium XI, Bifidobacterium, and Lactobacillus were enriched in fecal samples from mice colonized with microbiota cultured in anaerobic conditions (which reduce colitis) compared with mice fed microbiota cultured under aerobic conditions (susceptible to colitis). Oral administration to mice of microbiota-derived secondary bile acid sodium deoxycholate, but not ursodeoxycholic acid or lithocholic acid, reduced C jejuni induced colitis. Depletion of secondary bile acid-producing bacteria with antibiotics that kill anaerobic bacteria (clindamycin) promoted C jejuni-induced colitis in specific pathogen-free Il10-/- mice compared with the nonspecific antibiotic nalidixic acid; colitis induction by antibiotics was associated with reduced level of luminal deoxycholate. CONCLUSIONS: We identified a mechanism by which the microbiota controls susceptibility to C jejuni infection in mice, via bacteria-derived secondary bile acids. PMID- 29408611 TI - Is biofilm production a prognostic marker in adults with candidaemia? AB - OBJECTIVES: The role of biofilm production in the outcome of candidaemia remains under discussion. Current evidence relies on variable biofilm detection methods while evaluating distinct clinical end points. We aimed to determine the impact of biofilm production measured by metabolic activity (MA) and biomass (BM) on the prognosis of adults with candidaemia. METHODS: Retrospective cohort including 280 adults with candidaemia admitted from 2010 to 2016. BM was assessed using crystal violet binding stain and the XTT reduction assay was used to detect MA. Strains were classified as high and moderate-low biofilm producers according to published cut-offs. The primary outcome was overall mortality within 7 and 30 days. The secondary outcome was unfavourable prognosis defined as metastatic infection, admission to an intensive care unit due to the severity of candidaemia, or death within 30 days. RESULTS: High BM and high MA were detected in 90 (32.1%) and 114 (40.7%) of the 280 isolates, respectively. Comparison of high and moderate-low biofilm forming isolates revealed no correlation between biofilm production and 7 day mortality (BM high 15/90 (16.7%) versus moderate-low 24/190 (12.6%); MA high 12/114 (10.5%) versus moderate-low 27/166 (16.3%)), 30-day mortality (BM high 34/90 (37.8%) versus moderate-low 61/190 (32.1%); MA high 33/114 (28.9%) versus moderate-low 62/166 (37.3%)), or unfavourable prognosis (BM high 45/90 (50.0%) versus moderate-low 73/190 (38.4%); MA high 41/114 (36.0%) versus moderate-low 77/166 (46.4%)). CONCLUSIONS: Biofilm production was not a predictor of mortality or of unfavourable prognosis in adults with candidaemia. PMID- 29408612 TI - Shorter duration of antibiotic treatment for acute bacteraemic cholangitis with successful biliary drainage: a retrospective cohort study. AB - OBJECTIVES: To assess the effectiveness of short duration antimicrobial therapy for acute cholangitis with bacteraemia. METHODS: We conducted a retrospective cohort study of patients with acute bacteraemic cholangitis with successful biliary duct drainage at a single centre in Japan. We compared short-course antimicrobial therapy (SCT, <=7 days) and long-course therapy (LCT, >=8 days), with a primary outcome of 30-day mortality. We constructed logistic regression models for mortality and a composite outcome, including mortality, recurrence, recrudescence, new bacteraemia, liver abscess or other complications related to cholangitis. We also developed a propensity score for SCT with inverse probability weighting for both the primary outcome and the composite outcome. RESULTS: We identified 263 patients in our cohort; 86 (32.7%) patients received SCT and the remaining 177 (67.3%) received LCT. The median durations of SCT and LCT were 6 days (range 2-7 days) and 12 days (range 8-46 days), respectively. The 30-day mortalities of SCT and LCT were 4.7% (4/85) and 5.7% (10/176), respectively (p 1.00). Logistic regression analysis showed that the odds ratio of SCT for 30-day mortality and the composite outcome were 1.07 (95% CI 0.25-4.52, p 0.93) and 1.08 (95% CI 0.48-2.45, p 0.85), respectively. Propensity score analyses for both 30-day mortality and the composite outcome did not demonstrate a difference between SCT and LCT (p 0.65 and p 0.95, respectively). CONCLUSIONS: SCT with a median duration of 6 days did not have worse outcomes than LCT with a median duration of 12 days. Shortening the duration of antimicrobial therapy may be a reasonable option when treating acute bacteraemic cholangitis following successful biliary drainage. PMID- 29408610 TI - Efficacy and safety of fosfomycin plus imipenem versus vancomycin for complicated bacteraemia and endocarditis due to methicillin-resistant Staphylococcus aureus: a randomized clinical trial. PMID- 29408613 TI - Eudragit(r) L100-coated mannosylated chitosan nanoparticles for oral protein vaccine delivery. AB - The aim of this study was to develop a novel biodegradable polymeric carrier for the delivery of protein vaccine orally in order to target the antigen presenting cells (APCs) in the region of Peyer's patches (PPs). Here, bovine serum albumin (BSA) was chosen as a model protein vaccine and was loaded into the mannosylated chitosan nanoparticles (MCS NPs) by ionic gelation method with tripolyphosphate (TPP), followed by coating MCS NPs with Eudragit(r) L100 (Eud) by electrostatic interaction. The spherical NPs were successfully prepared with appropriate particle size around 558.2+/-35.6nm, high entrapment efficiency about 90.38+/ 9.12%, good stability and reasonable release behavior in the simulated gastrointestinal fluid, meanwhile high resistance of enzymatic and acid degradations were verified. The targeting ability of the NPs to PPs in rat was investigated by a closed ileal loop assay, where fluorescence visualization was performed. MCS NPs were accumulated more specifically into PPs after Eudragit(r) L100 dissolved in intestinal juices. Oral immunization using BSA-loaded Eudragit(r) L100-coated MCS NPs was found to elicit strong systemic IgG antibody and mucosal IgA responses. These results suggested that enteric-coated MCS NPs could serve as a promising carrier for oral protein vaccine delivery. PMID- 29408614 TI - Proteomic analyses for profiling regulated proteins/enzymes by Fucus vesiculosus fucoidan in B16 melanoma cells: A combination of enzyme kinetics functional study. AB - Fucoidans are complex sulfated polysaccharides that have a wide range of biological activities. Previously, we reported the various effects of Fucus vesiculosus fucoidan on tyrosinase and B16 melanoma cells. In this study, to identify fucoidan-targeted proteins in B16 melanoma cells, we performed a proteomics study and integrated enzyme kinetics. We detected 19 candidate proteins dysregulated by fucoidan treatment. Among the probed proteins, the enzyme kinetics of two candidate enzymes, namely lactate dehydrogenase (LDH) as an upregulated protein and superoxide dismutase (SOD) as a downregulated enzyme, were determined. The enzyme kinetics results showed that Fucus vesiculosus fucoidan significantly inhibited LDH catalytic function while it did not affect SOD activity even at a high dose, while only slightly decreased activity (up to 10%) at a low dose. Based on our previous and present observations, fucoidan could inhibit B16 melanoma cells growth via regulating proteins/enzymes expression levels such as LDH and SOD known as cell survival biomarkers. Interestingly, both expression level and enzyme catalytic activity of LDH were regulated by fucoidan, which could directly induce the apoptotic effect on B16 melanoma cells along with SOD downregulation. This study highlights how combining proteomics with enzyme kinetics can yield valuable insights into fucoidan targets. PMID- 29408615 TI - In vivo and in vitro neuroprotective effects of Panax ginseng glycoproteins. AB - The root of Panax ginseng C. A. Mey (Araliaceae) has medicinal value in complex system of Traditional Chinese medicines for its use in improving cognitive function. A glycoproteins named PGL-1 was extracted from ginseng which subjected to through a macroporous resin, hollow-fiber ultrafiltration and dialyzed. The glycoproteins has a molecular weight in the range from 0.4 to 4.4kDa, with an average molecular mass of 1.6kDa. HPLC analysis revealed that the compositions of glycoproteins included fucose, mannose, rhamnose, glucose, galacturonic acid, N acetylglucosamine and N-acetylgalactosamine. Glycan of PGL-1 has a backbone of >4)-Rha-(1->, ->4)-Fuc -(1->, ->6)-Gal-(1->, ->4)-GalA-(1->, ->4)-GlcNAc-(1-> and ->4)-GalNAc-(1->,and (->3,6)-Man-(1->) was distributed in branches. The (1->) Fuc, (1->)-Glc and (1->)-GlcNAc or (1->)-GalNAc were regarded as a terminal residue. The Morris water maze test revealed that the PGL-1 can effectively alleviate the memory impairment symptoms of rats induced by Abeta25-35. All dose groups showed significant activity of protective effect on apoptosis SH-SY5Y induced by Abeta25-35, and obviously inhibited the S phase arrest. Compared with Abeta25-35 treatment alone, a significant reduction in NO concentration and NOS activity was detected in cells co-administered with glycoproteins. Thus, glycoproteins derived from ginseng might be a promising anti-AD reagent. PMID- 29408616 TI - Risk of Venous Thromboembolism Following Peripherally Inserted Central Catheter Exchange: An Analysis of 23,000 Hospitalized Patients. AB - BACKGROUND: Catheter exchange over a guidewire is frequently performed for malfunctioning peripherally inserted central catheters (PICCs). Whether such exchanges are associated with venous thromboembolism is not known. METHODS: We performed a retrospective cohort study to assess the association between PICC exchange and risk of thromboembolism. Adult hospitalized patients that received a PICC during clinical care at one of 51 hospitals participating in the Michigan Hospital Medicine Safety consortium were included. The primary outcome was hazard of symptomatic venous thromboembolism (radiographically confirmed upper-extremity deep vein thrombosis and pulmonary embolism) in those that underwent PICC exchange vs those that did not. RESULTS: Of 23,010 patients that underwent PICC insertion in the study, 589 patients (2.6%) experienced a PICC exchange. Almost half of all exchanges were performed for catheter dislodgement or occlusion. A total of 480 patients (2.1%) experienced PICC-associated deep vein thrombosis. The incidence of deep vein thrombosis was greater in those that underwent PICC exchange vs those that did not (3.6% vs 2.0%, P < .001). Median time to thrombosis was shorter among those that underwent exchange vs those that did not (5 vs 11 days, P = .02). Following adjustment, PICC exchange was independently associated with twofold greater risk of thrombosis (hazard ratio [HR] 1.98; 95% confidence interval [CI], 1.37-2.85) vs no exchange. The effect size of PICC exchange on thrombosis was second in magnitude to device lumens (HR 2.06; 95% CI, 1.59-2.66 and HR 2.31; 95% CI, 1.6-3.33 for double- and triple-lumen devices, respectively). CONCLUSION: Guidewire exchange of PICCs may be associated with increased risk of thrombosis. As some exchanges may be preventable, consideration of risks and benefits of exchanges in clinical practice is needed. PMID- 29408618 TI - The rheological properties of native sericin. AB - : Unlike spider silk, spinning silkworm silk has the added intricacy of being both fibre and micron-thick glue-like coating. Whilst the natural flow properties of the fibre feedstock fibroin are now becoming more established, our understanding of the coating sericin is extremely limited and thus presents both a gap in our knowledge and a hindrance to successful exploitation of these materials. In this study we characterise sericin feedstock from the silkworm Bombyx mori in its native state and by employing both biochemical, rheological and spectroscopic tools, define a natural gold standard. Our results demonstrate that native sericin behaves as a viscoelastic shear thinning fluid, but that it does so at a considerably lower viscosity than its partner fibroin, and that its upper critical shear rate (onset of gelation) lies above that of fibroin. Together these findings provide the first evidence that in addition to acting as a binder in the construction of the cocoon, sericin is capable of lubricating the flow of fibroin within the silk gland, which has implications for future processing, modelling and biomimetic use of these materials. STATEMENT OF SIGNIFICANCE: This study addresses one of the major gaps in our knowledge regarding natural silk spinning by providing rigorous rheological characterisation of the other major protein involved - sericin. This allows progress in silk flow modelling, biomimetic system design, and in assessing the quality of bioinspired and waste sericin materials by providing a better understanding of the native, undegraded system. PMID- 29408617 TI - RIFM fragrance ingredient safety assessment dihydro-beta-terpinyl acetate, CAS Registry Number 26252-11-9. AB - The use of this material under current conditions is supported by existing information. The material (dihydro-beta-terpinyl acetate) was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the read across analog menthyl acetate (1alpha,2beta,5alpha) (CAS # 89-48-5) show that dihydro-beta- terpinyl acetate is not genotoxic nor does it have skin sensitization potential. The repeated dose, reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03, 0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoint was completed based on UV spectra. The environmental endpoints were evaluated, dihydro-beta-terpinyl acetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC) are <1. PMID- 29408619 TI - Long-Term Outcome of a Single Intervention Population Based Prostate Cancer Screening Study. AB - PURPOSE: We evaluated the long-term effect of screening for prostate cancer. MATERIALS AND METHODS: In 1988 we randomly selected 2,400 men from a background population of 27,464 men. The 2,400 men were invited to undergo screening, of whom 1,779 (74%) accepted and were examined with digital rectal examination, ultrasound and prostate specific antigen measurement. Biopsy was performed if there were suspicious findings on ultrasound or digital rectal examination, or prostate specific antigen was greater than 10 ng/ml. The subpopulations have now been reassessed after 20 years. RESULTS: Participants had a decreased overall mortality rate compared to the source population (IRR 0.93, 95% CI 0.86-0.98). Nonparticipants had an increased overall mortality rate (IRR 1.25, 95% CI 1.14 1.37). There was no difference between the groups in prostate cancer specific survival. The incidence of prostate cancer remained higher in the screened population throughout followup. CONCLUSIONS: A single screening intervention in men 50 to 75 years old using prostate specific antigen, digital rectal examination and transrectal ultrasound, and a prostate specific antigen cutoff of 10 ng/ml for biopsy carried a significant risk of prostate cancer detection without a concomitant reduction in prostate cancer specific mortality after 20 years. This intervention should not be considered for public screening. Nonparticipants were at greater risk for death of all causes. In addition to being a single intervention trial, the limitations of this study include an outdated prostate specific antigen cutoff for biopsy. Despite the outdated screening method the source population failed to reach the same level of prostate cancer incidence as the screened population even after 20 years. PMID- 29408620 TI - Association between SHANK3 polymorphisms and susceptibility to autism spectrum disorder. AB - Autism spectrum disorder (ASD), as one of neurodevelopmental disorders, affects about 1/160 of people worldwide. The etiology and pathogenesis of ASD remain elusive. Synapses are essential components of neurons and basic information transmission unit in the nervous system, adjusting behavior to environmental stimuli and controlling body functions, memories, and emotions. SHANK3 is one of the synapse genes which play important roles in maintaining synaptic structure and function. SHANK3 has been researched as a probably susceptibility gene for ASD. We investigated the association between polymorphisms in SHANK3 and ASD in the Northeast Han Chinese population. A total of 470 subjects (229 cases and 241 controls) were enrolled in our case-control study. Five single nucleotide polymorphisms (SNPs) (rs756638, rs4824116, rs76268556, rs9616915, and rs75767639) in SHANK3 were selected and genotyped. Our study did not identify a significant association of SHANK3 SNPs with ASD in the Northeast Han Chinese population. Future studies need to test more SHANK3 SNPs in large sample to demonstrate the association between SNPs in SHANK3 and ASD. PMID- 29408621 TI - Integrated analysis of gene expression signatures associated with colon cancer from three datasets. AB - PURPOSE: The present study aimed to elucidate the pathogenesis of colon cancer and identify genes associated with tumor development. METHODS: Three datasets, two (GSE74602 and GSE44861) from the Gene Expression Omnibus database and RNA-Seq colon cancer data from The Cancer Genome Atlas data portal, were downloaded. These three datasets were grouped using a meta-analysis approach, and differentially expressed genes (DEGs) were identified between colon tumor samples and adjacent normal samples. Functional enrichment analysis and regulatory factor predication were performed for significant genes. Additionally, small-molecule drugs associated with colon cancer were predicted, and a prognostic risk model was constructed. RESULTS: There were 251 overlapping DEGs (135 up- and 116 downregulated) between cancer samples and control samples in the three datasets. The DEGs were mainly involved in protein transport and apoptotic and neurotrophin signaling pathways. A total of 70 small-molecule drugs were predicated to be associated with colon cancer. Additionally, in the miRNA-target regulatory network, we found that SLC44A1 can be targeted by hsa-miR-183, hsa-miR-206, and hsa-miR-147, while KLF13 can be regulated by hsa-miR-182, hsa-miR-206, and hsa miR-153. Moreover, the results of the prognostic risk model showed that four genes (VAMP1, P2RX5, CACNB1, and CRY2) could divide the samples into high and low risk groups. CONCLUSION: SLC44A1 and KLF13 may be involved in tumorigenesis and the metastasis of colon cancer by miRNA regulation. In addition, a four-gene (VAMP1, P2RX5, CACNB1, and CRY2) expression signature may have prognostic and predictive value in colon cancer. PMID- 29408622 TI - Inhibition of hepatocellular carcinoma tumorigenesis by curcumin may be associated with CDKN1A and CTGF. AB - This study aimed to explore crucial genes, transcription factors (TFs), and microRNAs (miRNAs) associated with the effects of curcumin against hepatocellular carcinoma (HCC). We downloaded data (GSE59713) from Gene Expression Omnibus to analyze differentially expressed genes (DEGs) between curcumin-treated and untreated HCC cell lines. Then, we identified the disease ontology (DO) and functional enrichment analysis of these DEGs and analyzed their protein-protein interactions (PPIs). Additionally, we constructed TF-target gene and miRNA-target gene regulatory networks and explored the potential functions of these DEGs. Finally, we detected the expression of CDKN1A, CTGF, LEF1 TF and MIR-19A regulated by curcumin in PLC/PRF/5 cells using RT-PCR. In total, 345 upregulated and 212 downregulated genes were identified. The main enriched pathway of upregulated genes was the TNF signaling pathway. The downregulated genes were significantly enriched in TGF-beta signaling pathway. In addition, most DEGs were significantly enriched in DO terms such as liver cirrhosis, hepatitis, hepatitis C and cholestasis (eg., CTGF). In the constructed PPI network, CDKN1A and CTGF were the key proteins. Moreover, LEF1, CDKN1A, and miR-19A that regulated CTGF were highlighted in the regulatory networks. Furthermore, the expression of CDKN1A, CTGF, LEF1 TF and miR-19A regulated by curcumin in PLC/PRF/5 cells was consistent with the aforementioned bioinformatics analysis results. To conclude, curcumin might exert its protective effects against HCC tumorigenesis by downregulating LEF1 and downregulating CTGF regulated by MIR-19A and upregulating CDKN1A expression. PMID- 29408623 TI - Letter to the editor. PMID- 29408624 TI - Phylogenetic analysis of two goat-origin PCV2 isolates in China. AB - Complete genome characterization of non-porcine origin Porcine circovirus type 2 (PCV2) was first described in 2014 in China. In the present study, we first identified PCV2 nucleotides in goat samples and the prevalence of PCV2 in goat was 6.15%. However, only two new strains, Goat2014-4 and Goat2014-5, could be completely sequenced. The genome of the strain Goat2014-4, which collected from the goat infected with PPRV, contains 1766 nt; strain Goat2014-5, which originated from a healthy goat, is comprised of 1767 nt. The results showed that they shared the highest nucleotide identity with BDH and the lowest similarity with DK1980PMWSfree strain and they belonged only to genotype PCV2d. Meanwhile, they shared higher homology with porcine-origin PCV2 strains than others. Moreover, a detailed analysis of the capsid amino acid sequences revealed that there were distinct differences for goat2014-4 (708 bp) and goat2014-5 (705 bp); strain Goat2014-4 showed an elongation of two amino acids, and strains Goat2014-5 showed an elongation of one amino acid compared with other reference strains. This is the first report of the genetic analysis of goat-origin PCV2 isolates. It also provides an additional supported evidence for cross-species transmission of PCV2. PMID- 29408625 TI - Maternal and neonatal irisin precursor gene FNDC5 polymorphism is associated with preterm birth. AB - Irisin is a novel secreted myokine, encoded by the fibronectin type III domain containing protein 5 (FNDC5) precursor gene. Irisin plays a role in the female reproductive system in pregnancy and in embryonic development, and is associated with fetal size. It is expressed in the ovary, placenta and neonatal cord serum. We studied whether maternal and neonatal FNDC5 genetic polymorphisms are associated with preterm birth (PTB). Blood for DNA analysis was collected from Israeli mothers (n = 315) and from umbilical veins of their respected idiopathic preterm (24-36 weeks) and control term (>37 weeks) newborns (n = 161). Genotypes of maternal and neonatal FNDC5 polymorphisms (rs726344 and rs1746661) were determined by restriction fragment length polymorphism analysis. Genotype phenotype associations were analyzed using SPSS program. The Frequency of FNCD5 rs726344 G alleles in the Israeli cohort is 82%. We found significant FNCD5 rs726344 genotype frequencies control and PTB groups. Women bearing the FNDC5 rs726344 GG genotype had 2.18 fold ([CI] 1.193-4.008, p = 0.01) higher chance to deliver at term compared to both AG and AA genotypes (adjusting to age, gravidity, parity, weight percentile per gestational age and gender of newborn). Neonates carrying the FNDC5 rs726344 GG genotype had 2.24 fold ([CI] 0.979-5.134, p = 0.05) higher chance to be born at term compared to either AG or AA genotypes (adjusting to parity, previous abortions and weight percentile per gestational age). There was no significant association of the rs1746661 polymorphism with PTB. Thus, we determined FNDC5 polymorphisms frequencies in the Israeli population and demonstrated that maternal and neonatal FNDC5 rs726344 polymorphism is significantly associated with increased risk for PTB. PMID- 29408626 TI - A high-throughput and rapid computational method for screening of RNA post transcriptional modifications that can be recognized by target proteins. AB - There are over 150 currently known, highly diverse chemically modified RNAs, which are dynamic, reversible, and can modulate RNA-protein interactions. Yet, little is known about the wealth of such interactions. This can be attributed to the lack of tools that allow the rapid study of all the potential RNA modifications that might mediate RNA-protein interactions. As a promising step toward this direction, here we present a computational protocol for the characterization of interactions between proteins and RNA containing post transcriptional modifications. Given an RNA-protein complex structure, potential RNA modified ribonucleoside positions, and molecular mechanics parameters for capturing energetics of RNA modifications, our protocol operates in two stages. In the first stage, a decision-making tool, comprising short simulations and interaction energy calculations, performs a fast and efficient search in a high throughput fashion, through a list of different types of RNA modifications categorized into trees according to their structural and physicochemical properties, and selects a subset of RNA modifications prone to interact with the target protein. In the second stage, RNA modifications that are selected as recognized by the protein are examined in-detail using all-atom simulations and free energy calculations. We implement and experimentally validate this protocol in a test case involving the study of RNA modifications in complex with Escherichia coli (E. coli) protein Polynucleotide Phosphorylase (PNPase), depicting the favorable interaction between 8-oxo-7,8-dihydroguanosine (8-oxoG) RNA modification and PNPase. Further advancement of the protocol can broaden our understanding of protein interactions with all known RNA modifications in several systems. PMID- 29408627 TI - PREvaIL, an integrative approach for inferring catalytic residues using sequence, structural, and network features in a machine-learning framework. AB - Determining the catalytic residues in an enzyme is critical to our understanding the relationship between protein sequence, structure, function, and enhancing our ability to design novel enzymes and their inhibitors. Although many enzymes have been sequenced, and their primary and tertiary structures determined, experimental methods for enzyme functional characterization lag behind. Because experimental methods used for identifying catalytic residues are resource- and labor-intensive, computational approaches have considerable value and are highly desirable for their ability to complement experimental studies in identifying catalytic residues and helping to bridge the sequence-structure-function gap. In this study, we describe a new computational method called PREvaIL for predicting enzyme catalytic residues. This method was developed by leveraging a comprehensive set of informative features extracted from multiple levels, including sequence, structure, and residue-contact network, in a random forest machine-learning framework. Extensive benchmarking experiments on eight different datasets based on 10-fold cross-validation and independent tests, as well as side by-side performance comparisons with seven modern sequence- and structure-based methods, showed that PREvaIL achieved competitive predictive performance, with an area under the receiver operating characteristic curve and area under the precision-recall curve ranging from 0.896 to 0.973 and from 0.294 to 0.523, respectively. We demonstrated that this method was able to capture useful signals arising from different levels, leveraging such differential but useful types of features and allowing us to significantly improve the performance of catalytic residue prediction. We believe that this new method can be utilized as a valuable tool for both understanding the complex sequence-structure-function relationships of proteins and facilitating the characterization of novel enzymes lacking functional annotations. PMID- 29408628 TI - Effect of pulse rate variation on blood flow through axisymmetric and asymmetric stenotic artery models. AB - The present work reports numerical simulations of blood flow patterns and wall shear stress (WSS) distributions in stenotic arteries, modelled as straight tubes. Inflow waveforms have been generated for different pulse rates considering constant volumetric flow during each pulsation cycle and a two-element windkessel model has been used to specify the outlet pressure. It is noticed that the non Newtonian shear thinning rheology of blood produces more accurate and realistic predictions of the flow field as compared to the Newtonian assumption. Further, the effects of variation of pulse rates on the spatial and temporal distribution of WSS and oscillatory shear index (OSI) have also been studied for both axisymmetric and asymmetric stenosis. The changes in the mean flow features due to changes in pulsation frequencies have also been reported. PMID- 29408629 TI - Co-located hAT transposable element and 5S rDNA in an interstitial telomeric sequence suggest the formation of Robertsonian fusion in armored catfish. AB - Co-located 5S rDNA genes and interstitial telomeric sites (ITS) revealed the involvement of multiple 5S rDNA clusters in chromosome rearrangements of Loricariidae. Interstitial (TTAGGG)n vestiges, in addition to telomeric sites, can coincide with locations of chromosomal rearrangements, and they are considered to be hotspots for chromosome breaks. This study aimed the molecular characterization of 5S rDNA in two Rineloricaria latirostris populations and examination of roles of 5S rDNA in breakpoint sites and its in situ localization. Rineloricaria latirostris from Brazil's Das Pedras river (2n = 46 chromosomes) presented five pairs identified using a 5S rDNA probe, in addition to a pair bearing a co-located ITS/5S rDNA. Rineloricaria latirostris from the Piumhi river (2n = 48 chromosomes) revealed two pairs containing 5S rDNA, without ITS. A 702 bp amplified sequence, using 5S rDNA primers, revealed an insertion of the hAT transposable element (TE), referred to as a degenerate 5S rDNA. Double-FISH (fluorescence in situ hybridization) demonstrated co-localization of 5S rDNA/degenerate 5S rDNA, 5S rDNA/hAT and ITS/5S rDNA from the Das Pedras river population. Piumhi river isolates possessed only 5S rDNA sites. We suggest that the degenerate 5S rDNA was generated by unequal crossing over, which was driven by invasion of hAT, establishing a breakpoint region susceptible to chromosome breakage, non-homologous recombination and Robertsonian (Rb) fusion. Furthermore, the presence of clusters of 5S rDNA at fusion points in other armored catfish species suggests its re-use and that these regions represent hotspots for evolutionary rearrangements within Loricariidae genomes. PMID- 29408630 TI - Mechanisms and biomarkers of immune quiescence in kidney transplantation. AB - This review discusses the current understanding of biomarkers of immune quiescence based on reviews of published literature in kidney transplant operational tolerance and mechanistic studies based on a better characterization of the stable, well-functioning renal allograft. PMID- 29408632 TI - Complete elimination of a pathogenic homoplasmic mtDNA mutation in one generation. AB - Mitochondrial DNA (mtDNA) mutations have been implicated in a wide variety of neurological conditions and are maternally inherited through a complex process which is not fully understood. Genetic counselling for mitochondrial conditions secondary to a mtDNA mutation can be challenging as it is not currently possible to accurately predict the mutational load/heteroplasmy of the mutation which could be passed to the offspring. In general, one expects that the higher the level of heteroplasmy the more likely that the same mtDNA mutation will be seen in the offspring. We report here a family which places a caveat on genetic counselling for mtDNA disorders. The proband is a 63 year old woman with m.14459G>A associated dystonia/spasticity/ataxia. The m.14459G>A mutation was detected at homoplasmic/near homoplasmic levels in her muscle tissue and fibroblasts, but did not appear to have been passed on to any of her offspring. To our knowledge, this is the first report of complete selection against a homoplasmic variant within maternally transmitted mtDNA. It is not clear if this novel phenomenon occurred by random chance or by another method of mitochondrial selection. PMID- 29408631 TI - Intracellular TLR7 is activated in human oligodendrocytes in response to Borrelia burgdorferi exposure. AB - Lyme neuroborreliosis, caused by the gram-negative bacterium Borrelia burgdorferi, may affect the central and/or peripheral nervous systems. In previous studies, we showed that human oligodendrocytes exposed to the bacteria undergo apoptosis in an inflammatory environment, and that inflammatory pathways trigger cell-death pathways. We further demonstrated that several receptor tyrosine kinases were involved in triggering downstream effects, leading to inflammation and apoptosis. Toll-like receptors TLR2 and TLR5, which are commonly studied receptors in Lyme disease, only had a minimal role in inflammatory processes. To delineate the role of other TLRs, if any, real-time RT-PCR array experiments were carried out as an initial screen. Along with several inflammatory genes, TLR7 mRNA was upregulated in cells exposed to B. burgdorferi. Further analysis by immunohistochemistry showed that the TLR7 protein is present in readily detectable amounts, although no discernible differences could be seen between medium and B. burgdorferi-exposed cells by this technique. Nevertheless, use of specific inhibitors and siRNA showed that TLR7 is involved in inducing IL 6 and CCL2 in a dose dependent manner, and likely CXCL8. Triggering an intracellular receptor such as TLR7, which senses RNA, in typically non phagocytic oligodendrocytes indicates either a niche for the bacterium inside the cell or novel uptake of nucleic acids to initiate inflammatory responses. PMID- 29408633 TI - Combined lateral rectus augmented transposition and inferior rectus recession for monocular elevation deficiency. AB - We report the case of a 21-year-old woman who presented with a drooping right upper eyelid and smaller-appearing right eye, evident since birth. Her visual acuity was 20/30 in the right eye and 20/20 in the left eye. In primary gaze she had a hypotropia of 25Delta, with a marked elevation limitation and associated true upper lid ptosis of 3 mm. Under local anesthesia, the lateral rectus muscle was transposed to the superior rectus muscle and was augmented by a nonabsorbable suture attaching the superior rectus muscle and lateral rectus muscle 8 mm posterior to the insertion, accompanied by an inferior rectus recession. One year after surgery she was orthophoric in primary position and showed improvement in elevation. The surgical procedure can be performed at the same time as the inferior rectus recession and reduces the risk of anterior segment ischemia. PMID- 29408634 TI - An Unusual Cause of Cyanosis in a Child. PMID- 29408635 TI - A Rare Tumor Presenting as a Rectal Mass. PMID- 29408636 TI - Polycythemia Rubra Vera: Where Does the Truth Lie? PMID- 29408637 TI - A Case of Cryptogenic Liver Failure. PMID- 29408638 TI - A Rare Cause of Recurrent Abdominal Pain and Diarrhea. PMID- 29408639 TI - Hepatitis B Virus Does Not Interfere With Innate Immune Responses in the Human Liver. AB - BACKGROUND & AIMS: Most viruses are detected at early stages of cell infection and induce an innate immune response mediated by production of interferons (IFNs). IFNs induce expression of hundreds of IFN-stimulated genes (ISGs). Infection of chimpanzees with hepatitis C virus, but not hepatitis B virus (HBV), induces ISG expression in the liver. HBV might not induce an innate immune response because it is not detected by pattern recognition receptors (the stealth properties of HBV) or because HBV suppresses IFN production or signaling despite detection by pattern recognition receptors. We studied innate immune signaling in liver biopsies from patients with different stages of chronic HBV infection and uninfected individuals (controls). METHODS: We obtained liver within 10 minutes after collection from 30 patients with chronic HBV infection (hepatitis B e antigen-positive or -negative, with or without hepatitis) and 42 controls (most with fatty liver disease). The liver tissues were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, HBV RNA quantification, and HBV genotyping; some specimens were incubated with toll-like receptor (TLR) ligands (polyinosinic polycytidylic acid) or infected with Sendai virus and then analyzed. RESULTS: Liver specimens from patients with HBV infection were not expressing more IFN or ISGs than those from control patients, indicating that chronic HBV infection did not activate an innate immune response. However, liver specimens from patients with HBV infection did produce IFN and induce expression of ISGs following activation of TLR3 with poly(I:C) or Sendai virus infections, so the innate immune response is not suppressed in these tissues. CONCLUSION: Liver tissues from patients with chronic HBV infection do not have induction of an innate immune response, but this response can be activated by other factors (TLR3 binding, Sendai virus infection) in HBV-infected liver tissue. These findings support the hypothesis that HBV is invisible to pattern recognition receptors. PMID- 29408640 TI - Importance of frequency and morphological characteristics of nodular diabetic glomerulosclerosis in diabetic nephropathy. AB - The Renal Pathology Society proposed a pathological classification for diabetic nephropathy (DN) (RPS 2010). We retrospectively examined the renal structural functional relationships using the RPS 2010 classification in 49 DN cases. We also evaluated the importance of the percentage of glomeruli with nodular diabetic glomerulosclerosis and their morphological characteristics (cellular, cellular and extracellular matrix [ECM] or ECM types) in the pathology of DN. The classes of DN (RPS 2010) were significantly correlated with the duration of diabetes mellitus (DM), degree of proteinuria, a decreased estimated glomerular filtration rate (eGFR), and the stages of Japanese clinical DM and chronic kidney disease (CKD). When the percentage of glomeruli with nodular glomerulosclerosis (IIIA <25%, IIIB 25-50%, IIIC 50-75%, and IIID >75%) was added to class III in this classification, the classes of DN had a greater correlation with the levels of proteinuria. The morphological characteristics of nodular glomerulosclerosis such as cellular, cellular and ECM, or ECM type were associated with several clinical parameters including the duration of DM, degree of proteinuria, a decreased eGFR, and/or the stages of clinical DM and CKD. Mesangial red blood cell fragments that is indicative of microvascular injury was found in cellular or cellular and ECM types of nodular glomerulosclerosis. The RPS 2010 classification is useful as a DN pathological classification that indicates a good correlation with the clinical characteristics of DN. In addition, the frequency and morphological characteristics of nodular diabetic glomerulosclerosis is important for the evaluation of the pathology in DN. PMID- 29408641 TI - Laparoscopic versus open pancreaticoduodenectomy combined with uncinated process approach: A comparative study evaluating perioperative outcomes (Retrospective cohort study). AB - BACKGROUND: Few studies on the uncinate process-first approach in laparoscopic pancreaticoduodenectomy (LPD) have been reported. The aim of this study is to compare the perioperative outcomes of LPD to open pancreaticoduodenectomy (OPD) in terms of feasibility, safety, and efficacy using the uncinate process-first approach. MATERIALS AND METHODS: This retrospective study included 102 patients who underwent pancreaticoduodenectomy between 2013 and 2017. Patients were divided into two groups based on the surgical approach: the laparoscopic surgery group (n = 47) and open surgery group (n = 55). The clinical characteristics and intra- and postoperative data were retrospectively analysed. RESULTS: LPD was performed successfully in all 47 patients. The mean operation time was significantly longer in the LPD group (410 +/- 68 min) than in the OPD group (245 +/- 70 min; P < 0.05). LPD produced significantly less intraoperative blood loss (210 +/- 46 mL vs 420 +/- 50 mL, P < 0.05), shorter first flatus time (1.5 d vs 4 d, P < 0.05) and shorter diet start time (2 d vs 5 d, P < 0.05). The total hospital stay was significantly shorter in the LPD group, with a median of 13 +/- 4 days versus 18 +/- 5.5 days in the OPD group (P < 0.05). The postoperative complication rates of the LPD group and OPD group were 21.3% and 27.3%, respectively (P > 0.05). The rate of category I-II complications and rate of category III-IV complications did not significantly differ (P > 0.05). Pancreatic fistulae occurred in 6 patients (12.8%) in the LPD group and 8 patients (14.5%) in the OPD group (P = 0.67). Delayed gastric emptying occurred in 2 patients (4.26%) in the LPD group and 2 patients in the OPD group (3.63%; P = 0.79). Postpancreatectomy haemorrhage was not significantly different between the groups (2.13% vs 3.63%; P = 0.66). CONCLUSION: LPD with the uncinate process-first approach combines the benefits of laparoscopy with a low risk of postoperative complications and high rate of curative resection. PMID- 29408642 TI - Comparative outcomes of extracorporeal shockwave therapy for shoulder tendinitis or partial tears of the rotator cuff in athletes and non-athletes: Retrospective study. AB - BACKGROUND: Refractory shoulder tendinitis or partial thickness rotator cuff tears (PTRCTs) are common findings in overhead athletes. Previous studies have examined the effectiveness of extracorporeal shockwave therapy (ESWT) for shoulder tendinitis. MATERIALS AND METHODS: In the current study, we recruited 36 shoulders and performed a comparison between the professional athletes (13 shoulders, athletic group; AG) and the non-athletic population (23 shoulders, non athletic group, NAG) with PTRCTs or shoulder tendinitis of the shoulder after ESWT. Patients with symptomatic tendinitis of the shoulder with or without a partial tear of the rotator cuff tendon and failed oral medication and physical therapy for more than 3 months were treated with electrohydraulic mode of ESWT. All patients that met the inclusion criteria were categorized into two groups according to their pre-treatment activity level. RESULTS: We found that NAG exhibited significant aging and degenerative change around the glenohumeral joint and subacromial space. After ESWT treatment, the patients in AG were with 53.8% high satisfaction rating and patients in NAG were 52.1% by one-year followed up. CONCLUSION: The results showed ESWT was equally effective treatment in both AG and NAG. In light of its efficacy and less-invasive nature, we suggest ESWT can be used to treat athletes with refractory tendinitis or PTRCTs before proceeding to arthroscopic intervention. PMID- 29408643 TI - Open cholecystectomy: Exposure and confidence of surgical trainees and new fellows. AB - BACKGROUND: The laparoscopic approach to cholecystectomy has overtaken open procedures in terms of frequency, despite open procedures playing an important role in certain clinical situations. This study explored exposure and confidence of Australasian surgical trainees and new fellows in performing an open versus laparoscopic cholecystectomy. MATERIALS AND METHODS: An online survey was disseminated via the Royal Australasian College of Surgeons to senior general surgery trainees (years 3-5 of surgical training) and new fellows (fellowship within the previous 5 years). The survey included questions regarding level of experience and confidence in performing an open cholecystectomy and converting from a laparoscopic to an open approach. RESULTS: A total of 135 participants responded; 58 (43%) were surgical trainees, 58 (43%) were fellows and 19 (14%) did not specify their level of training. Respondents who were involved in more than 20 open cholecystectomy procedures as an assistant or independent operator compared with those less exposed were more likely to feel confident to independently perform an elective open cholecystectomy (87.8% vs. 57.3%, P = 0.001), independently convert from a laparoscopic to open cholecystectomy (87.8% vs. 58.7%, P = 0.001) and independently perform an open cholecystectomy as a surgical consultant based on their level of exposure as a trainee (73.2% vs. 45.3%, P = 0.004). CONCLUSION: This study suggests the need to ensure surgical trainees are exposed to sufficient open cholecystectomies to enable confidence and skill with performing these procedures when indicated. Greater recognition of the need for exposure during training, including meaningful simulation, may assist. PMID- 29408644 TI - MicroRNA regulation of Toll-like receptor signaling pathways in teleost fish. AB - The innate immune system is the first line defense mechanism that recognizes, responds to, controls or eliminates invading pathogens. Toll-like receptors (TLRs) are a critical family of pattern recognition receptors (PRRs) tightly regulated by complex mechanisms involving many molecules to ensure a beneficial outcome in response to foreign invaders. MicroRNAs (miRNAs), a transcriptional and posttranscriptional regulator family in a wide range of biological processes, have been identified as new molecules related to the regulation of TLR-signaling pathways in immune responses. To date, at least 22 TLR types have been identified in more than a dozen different fish species. However, the functions and underlying mechanisms of miRNAs in the regulation of inflammatory responses related to the TLR-signaling pathway in fish is lacking. In this review, we summarize the regulation of miRNA expression profiles in the presence of TLR ligands or pathogen infections in teleost fish. We focus on the effects of miRNAs in regulating TLR-signaling pathways by targeting multiple molecules, including TLRs themselves, TLR-associated signaling proteins, and TLR-induced cytokines. An understanding of the relationship between the TLR-signaling pathways and miRNAs may provide new insights for drug intervention to manipulate immune responses in fish. PMID- 29408645 TI - Novel subunit vaccine based on grass carp reovirus VP35 protein provides protective immunity against grass carp hemorrhagic disease. AB - The grass carp (Ctenopharyngodon idella) hemorrhagic disease, caused by grass carp reovirus (GCRV), is one of the most severe infectious diseases in aquaculture. Given that antiviral therapies are currently limitedly available, vaccination remains the most effective means for the prevention of viral diseases, such as GCRV. A reovirus strain, which was temporarily named GCRV-HN14, was recently isolated from grass carp in Henan province, China. The S11 gene fragment of GCRV-HN14 was speculated to encode viral structural protein VP35, which has no equivalent gene in other aquareviruses but has antigenic epitopes. In this study, the recombinant plasmid pET-32a-vp35 was constructed to express recombinant VP35 proteins in prokaryotic cells, which was used to create a novel subunit vaccine. The immune protection of recombinant VP35 protein was evaluated by a series of experiments in grass carp. Results showed that the number of white blood cells (WBC) in the peripheral blood increased significantly to 7.92 +/- 0.72 * 107/ml 5 days after vaccination (P < 0.05). The number of neutrophils and monocytes in WBC were significantly higher than those of the control 3 days after vaccination (P < 0.05) and maximally got to 12.22 +/- 1.28% and 18.70 +/- 1.78%, respectively. Owing to the significant increase in the number of lymphocytes (92.37 +/- 2.10%; P < 0.01), the percentages of neutrophils and monocytes declined significantly (14 dpi; P < 0.01). Serum antibody levels induced by recombinant VP35 protein significantly increased 7 days post immunization and continued to increase until 5 weeks post vaccination. The mRNA expression levels of type I interferon (designated as IFN1), immunoglobulin M, Toll-like receptor 22 and major histocompatibility complex class I were up-regulated significantly in the head kidneys and spleens of immunized fish (P < 0.01). Grass carp immunized by recombinant VP35 protein showed that the relative percentage of survival was about 60% after it was challenged with GCRV. Overall, the results suggested that recombinant VP35 protein can induce immunity and protect grass carp against GCRV infection. Thus, it can be used as a subunit vaccine. PMID- 29408647 TI - Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity. AB - BACKGROUND: Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. CONCLUSION: CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management. PMID- 29408646 TI - Utrophin up-regulation by artificial transcription factors induces muscle rescue and impacts the neuromuscular junction in mdx mice. AB - Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin 'A' promoter. We have previously shown that the ZF-ATF "Jazz", either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic "mdx" mice. We present the full characterization of an upgraded version of Jazz gene named "JZif1" designed to minimize any possible host immune response. JZif1 was engineered on the Zif268 gene-backbone using selective amino acid substitutions to address JZif1 to the utrophin 'A' promoter. Here, we show that JZif1 induces remarkable amelioration of the pathological phenotype in mdx mice. To investigate the molecular mechanisms underlying Jazz and JZif1 induced muscle functional rescue, we focused on utrophin related pathways. Coherently with utrophin subcellular localization and role in neuromuscular junction (NMJ) plasticity, we found that our ZF-ATFs positively impact the NMJ. We report on ZF-ATF effects on post-synaptic membranes in myogenic cell line, as well as in wild type and mdx mice. These results candidate our ZF-ATFs as novel therapeutic molecules for DMD treatment. PMID- 29408648 TI - When Are Complications After Brain Tumor Surgery Detected? AB - OBJECTIVE: To optimize follow-up and surveillance routines after intracranial surgery, knowledge about when complications occur is needed. We sought to explore when postoperative complications are detected after brain tumor surgery and assess their severity. METHODS: We performed a retrospective review of hospital records in 1291 adult patients undergoing elective craniotomy for intracranial tumors between 2008 and 2016 at our institution. Medical history, comorbidity, registered outcomes within 30 days, and time of detection of complications were registered. The severity and nature of complications were graded via the Landriel classification system. RESULTS: A total of 708 complications were registered in 465 (36.0%) operations within the first 30 days; 30.6% experienced mild or moderate complications (grade I-II), and 5.4% experienced severe or fatal complications (grade III-IV). A total of 5.7% (n = 74) developed complications within 24 hours; 45.7% of severe and fatal complications and 8.6% of mild and moderate complications were detected within 24 hours, whereas 77.1% and 57.5%, respectively, were detected within 1 week. Multivariate analysis revealed that Karnofsky Performance Status score <70 and longer duration of surgery were factors associated with developing severe or fatal complications. CONCLUSIONS: Mild and moderate complications, dominated by extracranial infections such as urinary tract infections and pneumonias, are very common after intracranial tumor surgery. Detection rates for mild and moderate complications are probably greatly affected by local routines for surveillance, screening, discharge, documentation, and follow-up, perhaps limiting their usefulness as a quality measure. Severe and fatal complications are mainly detected in the early postoperative course. PMID- 29408649 TI - Visual Outcome of an Endoscopic Endonasal Transsphenoidal Approach in Pituitary Macroadenomas: Quantitative Assessment with Diffusion Tensor Imaging Early and Long-Term Results. AB - BACKGROUND: Postoperative visual recovery in patients with pituitary adenoma can be influenced by the duration of symptoms, age, and tumor volume. Diffusion tensor imaging (DTI) allows visualization of white matter structure along with quantitative information. The aims of our study were to predict the visual recovery process in the early and long-term periods and to define the parameters affecting the recovery course. METHODS: A total of 200 patients with pituitary macroadenomas underwent endoscopic transsphenoidal surgery between January 2009 and July 2016. DTI and visual analysis including visual acuity and visual field analyses were performed for these patients at 5 periods, which included 3 years of follow-up. The effects of age, duration of symptoms, and tumor volume on visual recovery were evaluated. RESULTS: Mean tumor volume was calculated as 8871 +/- 2758 mm3 and mean symptom duration was 23.41 +/- 3.72 weeks. Mean age of the patients was 43.8 +/- 8.9 years in the full recovery group and 48.7 +/- 15.1 years in the nonrecovery group. Visual field analysis results on a Humphrey visual chart showed a significant linear strong correlation with fractional anisotropy (FA) values and a reverse strong correlation with mean diffusivity (MD) values on DTI magnetic resonance. DTI FA and MD cutoff values for each group were respectively determined as 0.373 and 1386 (*10-6 mm2/second) for the preoperative period, 0.423 and 1383 (*10-6 mm2/second) for the initial period, 0.428 and 1265 (*10-6 mm2/second) for the early period, 0.432 and 1238 (*10-6 mm2/second) for the intermediate period, and 0.437 and 1198 (*10-6 mm2/second) for the late period. CONCLUSIONS: DTI can assess and predict visual recovery after endoscopic transsphenoidal surgery of patients with pituitary macroadenomas causing chiasmal compression. FA values lower than or MD values greater than the cutoff values of the specific period reflect poor prognosis. Tumor volume was found to be the featured parameter that affects visual recovery. The postoperative first year is the most prominent interval evaluating the prognosis of visual recovery. PMID- 29408650 TI - Methane oxidation in industrial biogas plants-Insights in a novel methanotrophic environment evidenced by pmoA gene analyses and stable isotope labelling studies. AB - A broad methanotrophic community consisting of 16 different operational taxonomic units (OTUs) was detected by particulate methane monooxygenase A (pmoA) gene analyses of reactor sludge samples obtained from an industrial biogas plant. Using a cloning-sequencing approach, 75% of the OTUs were affiliated to the group of type I methanotrophs (gamma-Proteobacteria) and 25% to type II methanotrophs (alpha-Proteobacteria) with a distinct predominance of the genus Methylobacter. By database matching, half of the total OTUs may constitute entirely novel species. For evaluation of process conditions that support growth of methanotrophic bacteria, qPCR analyses of pmoA gene copy numbers were performed during a sampling period of 70 days at varying reactor feeding scenarios. During the investigation period, methanotrophic cell counts estimated by qPCR fluctuated between 3.4 * 104 and 2 * 105 cells/mL with no distinct correlation to the organic loading rate, the amount of CH4, O2 and NH4-N. Methanotrophic activity was proofed even at low O2 levels (1%) by using stable carbon isotope labelling experiments of CH4 in batch experiments inoculated with reactor sludge. Supplementation of 13C labelled CH4 in the headspace of the reaction vials unambiguously confirmed the formation of 13C labelled CO2. Thus, industrial biogas reactors can be considered as a further methanotrophic habitat that exhibits a unique methanotrophic community which is specifically adapted to high CH4 and low O2 concentrations. To the best of our knowledge, our study is the first accurate detection and quantification of methanotrophic bacteria in industrial biogas reactors. PMID- 29408652 TI - The Hippo pathway as a drug target in gastric cancer. AB - The Hippo tumor suppressor pathway is critical for balancing cellular differentiation and proliferation in response to cell-cell contact, mechanical signals and diffusible signals such as lysophosphatidic acid. Hippo pathway signaling is frequently dysregulated in gastric cancer (GC), as well as many other kinds of solid tumors, contributing to multiple aspects of malignant progression including unchecked cell division and metastasis. Considering the importance of this Hippo pathway in cancer, its pharmacological disruption may be of huge benefit in the fight against this disease. In this review, we summarize the components of the Hippo pathway, its crosstalk with other major oncogenic signaling pathways, common mechanisms of its dysregulation, as well as potential therapeutic approaches of targeting this pathway for cancer treatment, specifically in a GC context. PMID- 29408651 TI - Resistance to Bacillus thuringiensis linked with a cadherin transmembrane mutation affecting cellular trafficking in pink bollworm from China. AB - Evolution of pest resistance reduces the efficacy of insecticidal proteins from the gram-positive bacterium Bacillus thuringiensis (Bt) used widely in sprays and transgenic crops. In some previously studied strains of three major lepidopteran pests, resistance to Bt toxin Cry1Ac is associated with mutations disrupting the extracellular or cytoplasmic domains of cadherin proteins that bind Cry1Ac in the midgut of susceptible larvae. Here we report the first case of a cadherin transmembrane mutation associated with insect resistance to Bt. We discovered this mutation in a strain of the devastating global cotton pest, the pink bollworm (Pectinophora gossypiella), derived from a field population in the Yangtze River Valley of China. The mutant allele analyzed here has a 207 base pair deletion and encodes a cadherin protein lacking its transmembrane domain. Relative to a susceptible strain, a strain homozygous for this allele had 220 fold resistance to Cry1Ac and 2.1-fold cross-resistance to Cry2Ab. On transgenic cotton plants producing Cry1Ac, no susceptible larvae survived, but the resistant strain completed its life cycle. Inheritance of resistance to Cry1Ac was autosomal, recessive and tightly linked with the cadherin gene. Transportation of cadherin protein to the cell membrane and susceptibility to Cry1Ac occurred in transfected insect cells expressing the wild type cadherin allele, but not in transfected insect cells expressing the mutant cadherin allele. The results imply that the mutant allele analyzed here confers resistance to Cry1Ac by disrupting cellular trafficking of cadherin. PMID- 29408653 TI - Novel carbazole sulfonamide microtubule-destabilizing agents exert potent antitumor activity against esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide due to its chemoresistance and poor prognosis. Currently, there is a lack of effective small molecule drugs for the treatment of ESCC. Microtubules are an attractive target for cancer therapy since they play a central role in various fundamental cell functions. We investigated the anti-ESCC activity and mechanisms of the small molecule tubulin ligands, SL-3-19 and SL-1-73, which are two carbazole sulfonamide derivatives, in vitro and in vivo for the first time. These drugs were previously screened from a small molecule library with over 450 compounds and optimized for high aqueous solubility [1,2]. Here, we reveal the promising activities of these compounds against esophageal cancer. Mechanistically, both SL-3-19 and SL-1-73 inhibited ESCC cell growth by inducing cell apoptosis and arresting the cell cycle at G2/M phase in a dose-dependent manner. These drugs effectively inhibited microtubule assembly, greatly disrupted microtubule maturation by down-regulating acetylated alpha-tubulin, and significantly disrupted the vascular structure by obstructing the formation of capillary-like tubes in vitro. Consistent with their in vitro activities, SL-3-19 and SL-1-73 inhibited the growth of ESCC xenografts and inhibited the microvessel density in vivo. In summary, SL-3-19 and SL-1-73 are novel microtubule destabilizing agents that have a potential antitumor effect on ESCC both in vitro and in vivo, and SL-3-19 had a higher activity than SL-1-73, with a low IC50 value and an observable antitumor activity in vivo. These results indicate that SL-3-19 may be a new therapeutic candidate for ESCC treatment. PMID- 29408654 TI - The construction of recombinant Lactobacillus casei expressing BVDV E2 protein and its immune response in mice. AB - Bovine viral diarrhea virus (BVDV) is the etiological agent of BVD causes substantial economic losses and endemic in world-wide cattle population. Mucosal immunity plays an important role in protection against BVDV infection and Lactobacillus casei is believed as an excellent live vaccine vector for expressing foreign genes. In this study, we have constructed a novel recombinant L. casei/pELX1-E2 strain expressing the most immunogenic E2 antigen of BVDV; using growth phage dependent surface expression system pELX1. The expression of E2 protein was verified by SDS-PAGE, Western blotting, and Immunofluorescence microscopic analysis. The immune responses triggered by the E2 producing recombinant L. casei were evaluated in BALB/c mice revealed that oral and intranasal (IN) administration of the recombinant strain was able to induce a significantly higher level of specific anti-E2 mucosal IgA and serum IgG as well as the greater level of cellular response by IFN-gamma and IL-12 than those of intramuscular (IM) and control groups of mice. However, IN inoculation was found the most potent route of immunization. The ability of the recombinant strain to induce serum neutralizing antibody against BVDV and reduced viral load after viral challenge indicated better protection of BVDV infection. Therefore, this recombinant L. casei expressing E2 could be a safe and promising mucosal vaccine candidate against BVD. PMID- 29408655 TI - Nanomagnetic-mediated drug delivery for the treatment of dental disease. AB - Maintaining the vitality of the dental pulp, the highly innervated and highly vascular, innermost layer of the tooth, is a critical goal of any dental procedure. Upon injury, targeting the pulp with specific therapies is challenging because it is encased in hard tissues. This project describes a method that can effectively deliver therapeutic agents to the pulp. This method relies on the use of nanoparticles that can be actively steered using magnetic forces to the pulp, traveling through naturally occurring channels in the dentin (the middle layer of the tooth). This method can reduce the inflammation of injured pulp and improve the penetration of dental adhesives into dentin. Such a delivery method would be less expensive, and both less painful and less traumatic than existing therapeutic options available for treatment of injured dental pulp. This technique would be simple and could be readily translated to clinical use. PMID- 29408656 TI - Nanoimprinting of biomedical polymers reduces candidal physical adhesion. AB - Management of fungal biofilms represents a significant challenge to healthcare. As a preventive approach, minimizing adhesion between indwelling medical devices and microorganisms would be an important step forward. This study investigated the anti-fouling capacity of engineered nanoscale topographies to the pathogenic yeast Candida albicans. Highly ordered arrays of nano-pit topographies were shown to significantly reduce the physical adherence capacity of C. albicans. This study shows a potential of nanoscale patterns to inhibit and prevent pathogenic biofilm formation on biomedical substrates. PMID- 29408658 TI - Self-assembling toxin-based nanoparticles as self-delivered antitumoral drugs. AB - Loading capacity and drug leakage from vehicles during circulation in blood is a major concern when developing nanoparticle-based cell-targeted cytotoxics. To circumvent this potential issue it would be convenient the engineering of drugs as self-delivered nanoscale entities, devoid of any heterologous carriers. In this context, we have here engineered potent protein toxins, namely segments of the diphtheria toxin and the Pseudomonas aeruginosa exotoxin as self-assembling, self-delivered therapeutic materials targeted to CXCR4+ cancer stem cells. The systemic administration of both nanostructured drugs in a colorectal cancer xenograft mouse model promotes efficient and specific local destruction of target tumor tissues and a significant reduction of the tumor volume. This observation strongly supports the concept of intrinsically functional protein nanoparticles, which having a dual role as drug and carrier, are designed to be administered without the assistance of heterologous vehicles. PMID- 29408657 TI - Quorum sensing inhibitory potential and in silico molecular docking of flavonoids and novel terpenoids from Senegalia nigrescens. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senegalia nigrescens is used in traditional medicine for the treatment of dysentery and convulsions. AIMS OF THE STUDY: This study was aimed at identifying bioactive compounds from S. nigrescens and carrying out in vitro and in silico anti-quorum sensing studies on the compounds. MATERIALS AND METHODS: Extracts of S. nigrescens were chromatographed repeatedly. The isolated compounds were characterised using NMR spectroscopy and mass spectrometry. The anti-quorum sensing potential of S. nigrescens crude extracts and selected phytochemicals was quantified using Chromobacterium violaceum quorum sensing-controlled violacein inhibition assays. Qualitative modulation of quorum sensing activity and signal synthesis was investigated using agar diffusion double ring assays and C. violaceum. Molecular docking was conducted to explore the binding conformations of ent-kaurene diterpenes and flavonoids into the binding sites of quorum sensing regulator proteins, CviR and CviR'. RESULTS: Phytochemical investigation of S. nigrescens resulted in the isolation of a new ent-kaurene diterpenoid (ent-kaur-15-en-18,20-diol) alongside ent-kaur-15-en-18 ol, being isolated for the first time from a plant species. Other compounds isolated included 30-hydroxylup-20(29)-en-3beta-ol, 3beta-hydroxy-20(29)-en-lupan 30-al, lupeol, stigmasterol, a long chain alcohol (tetracosan-1-ol) and three flavonoids (melanoxetin, quercetin and quercetin-3-O-methyl ether). Structures of isolated compounds were elucidated using different spectroscopic techniques including 1D and 2D NMR. Inhibition of violacein production was concentration dependent, with 56.52% inhibition being obtained with 200 ug of quercetin-3-O methyl ether, while 53.38% inhibition was obtained with 600 ug of quercetin. Agar diffusion double ring assays indicated CviI synthase/CviR receptor modulation by S. nigrescens phytochemicals, suggesting that quorum signal synthesis was down regulated and/or targeting binding of signal to the receptor. The computed binding energy data suggested that the flavonoids had a stronger tendency to inhibit both CviR and CviR' with varying binding affinities. CONCLUSION: S. nigrescens crude extracts together with the novel ent-kaurenoids and flavonoids demonstrated potential anti-quorum sensing activity. S. nigrescens may thus represent a source of anti-quorum sensing therapeutic candidates for the control of existing and emerging infectious diseases. PMID- 29408660 TI - Reply. PMID- 29408659 TI - Axonal regeneration of different tracts following transplants of human glial restricted progenitors into the injured spinal cord in rats. AB - The goal of this study was to compare the efficacy of human glial restricted progenitors (hGRPs) in promoting axonal growth of different tracts. We examined the potential of hGRPs grafted into a cervical (C4) dorsal column lesion to test sensory axons, and into a C4 hemisection to test motor tracts. The hGRPs, thawed from frozen stocks, were suspended in a PureCol matrix and grafted acutely into a C4 dorsal column or hemisection lesion. Control rats received PureCol only. Five weeks after transplantation, all transplanted cells survived in rats with the dorsal column lesion but only about half of the grafts in the hemisection. In the dorsal column lesion group, few sensory axons grew short distances into the lesion site of control animals. The presence of hGRPs transplants enhanced axonal growth significantly farther into the transplants. In the hemisection group, coerulospinal axons extended similarly into both control and transplant groups with no enhancement by the presence of hGRPs. Rubrospinal axons did not grow into the lesion even in the presence of hGRPs. However, reticulospinal and raphespinal axons grew for a significantly longer distance into the transplants. These results demonstrate the differential capacity of axonal growth/regeneration of the motor and sensory tracts based on their intrinsic abilities as well as their response to the modified environment induced by the hGRPs transplants. We conclude that hGRP transplants can modify the injury site for axon growth of sensory and some motor tracts, and suggest they could be combined with other interventions to restore connectivity. PMID- 29408661 TI - A one-step multiplex real-time RT-PCR for the universal detection of all currently known CCHFV genotypes. AB - Crimean-Congo hemorrhagic fever (CCHF) is a fatal disease in humans, which is endemic in many countries of Africa, Southern Asia and Southeastern Europe. It is caused by the Crimean-Congo hemorrhagic fever virus (CCHFV), which is an arthropod-borne virus (arbovirus) transmitted by ixodid ticks, mainly of the genus Hyalomma. Animals like hares, hedgehogs, cattle, camels and small ruminants can become infected without developing clinical signs. Seroconversion occurs after a short viremia of up to two weeks, and thus seroprevalence studies in ruminants can be used to reveal risk areas for the human population. Virus detection by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) is essential to prove an actual circulation of CCHFV in a country and is also used as diagnostic method for acute human CCHFV infections. In this study, a new universal one-step multiplex real-time RT-qPCR for the sensitive and specific detection of CCHFV is presented. For this purpose, 14 new primers and 2 probes were simultaneously used to detect RNAs representing all six CCHFV genotypes. Additionally, a GC-mirrored sequence within the synthetic RNAs enables the discrimination between true positive samples and unintentional laboratory contaminations. CCHFV negative samples from different animal species and ten different members of the order Bunyavirales were eventually tested to reveal the specificity of the new RT-qPCR. PMID- 29408662 TI - Measuring and improving outcomes that matter to patients after cardiac arrest. PMID- 29408663 TI - A lytic bacteriophage of the newly emerging rainbow trout pathogen Weissella ceti. AB - This study was conducted to isolate and characterize a bacteriophage of a newly emerging pathogen, Weissella ceti, which causes weissellosis outbreaks of intensively farmed rainbow trout worldwide. The phage appeared together with the cultured Weissella ceti during isolation of pathogen from kidney of diseased rainbow trout. The morphological, physiological, proteomic and lytic spectrum were characterized. This phage, named PWc, belonged to the family Siphoviridae and possessed an isometric head (approximately 65 nm in diameter) and a flexible, non-contractile tail of 170-180 nm in length. The latent time and burst size of PWc were approximately 25 min and 16 PFU/infected cells, respectively. The PWc was relatively stable over a wide range of temperatures and pH values and possessed a broad lytic spectrum, lysing all 36 tested W. ceti strains isolated from diseased rainbow trout in Japan. The protein profile of the phage was obtained using SDS-PAGE analysis, and the potential packaging strategy was determined based on terminase large subunit sequence analysis. This is the first study to investigate a lytic bacteriophage of a newly emerging pathogen W. ceti that causes infectious disease in rainbow trout. PMID- 29408664 TI - Cytotoxicity and cellular mechanisms of toxicity of CuO NPs in mussel cells in vitro and comparative sensitivity with human cells. AB - There is a need to assess human and ecosystem health effects of copper oxide nanoparticles (CuO NPs), extensively used in many industrial products. Here, we aimed to determine the cytotoxicity and cellular mechanisms involved in the toxicity of CuO NPs in mussel cells (hemocytes and gill cells) in parallel with exposures to ionic Cu and bulk CuO, and to compare the sensitivity of mussel primary cells with a well-established human cell line (pulmonary TT1 cells). At similar doses, CuO NPs promoted dose-dependent cytotoxicity and increased reactive oxygen species (ROS) production in mussel and human cells. In mussel cells, ionic Cu was more toxic than CuO NPs and the latter more than bulk CuO. Ionic Cu and CuO NPs increased catalase and acid phosphatase activities in both mussel cells and decreased gill cells Na-K-ATPase activity. All Cu forms produced DNA damage in hemocytes, whereas in gill cells only ionic Cu and CuO NPs were genotoxic. Induction of the MXR transport activity was found in gill cells exposed to all forms of Cu and in hemocytes exposed to ionic Cu and CuO NPs. Phagocytosis increased only in hemocytes exposed to CuO NPs, indicating a nanoparticle-specific immunostimulatory effect. In conclusion, toxicity of CuO NPs is driven by ROS in human and mussel cells. Mussel cells respond to CuO NP exposure by triggering an array of defensive mechanisms. PMID- 29408665 TI - Selenium and zinc: Two key players against cadmium-induced neuronal toxicity. AB - Cadmium (Cd), a worldwide occupational pollutant, is an extremely toxic heavy metal, capable of damaging several organs, including the brain. Its toxicity has been related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neurotoxic potential of Cd has been attributed to the changes induced in the brain enzyme network involved in counteracting oxidative stress. On the other hand, it is also known that trace elements, such as zinc (Zn) and selenium (Se), required for optimal brain functions, appears to have beneficial effects on the prevention of Cd intoxication. Based on this protective effect of Zn and Se, we aimed to investigate whether these elements could protect neuronal cells from Cd-induced excitotoxicity. The experiments, firstly carried out on SH SY5Y catecholaminergic neuroblastoma cell line, demonstrated that the treatment with 10 MUM cadmium chloride (CdCl2) for 24 h caused significant modifications both in terms of oxidative stress and neuronal sprouting, triggered by endoplasmic reticulum (ER) stress. The evaluation of the effectiveness of 50 MUM of zinc chloride (ZnCl2) and 100 nM sodium selenite (Na2SeO3) treatments showed that both elements were able to attenuate the Cd-dependent neurotoxicity. However, considering that following induction with retinoic acid (RA), the neuroblastoma cell line undergoes differentiation into a cholinergic neurons, our second aim was to verify the zinc and selenium efficacy also in this neuronal phenotype. Our data clearly demonstrated that, while zinc played a crucial role on neuroprotection against Cd-induced neurotoxicity independently from the cellular phenotype, selenium is ineffective in differentiated cholinergic cells, supporting the notion that the molecular events occurring in differentiated SH SY5Y cells are critical for the response to specific stimuli. PMID- 29408666 TI - Effect of Penicillium roqueforti mycotoxins on Caco-2 cells: Acute and chronic exposure. AB - Penicillium roqueforti is a common food and feed contaminant. However, it is also worldwide renowned for its use as a technological culture responsible for the typicity of blue-veined cheese. Members of the P. roqueforti species are also known to be able to produce secondary metabolites including mycophenolic acid (MPA) and roquefortine C (ROQ C) mycotoxins. In order to more closely simulate the reality of mycotoxin exposure through contaminated food consumption, this work investigated the toxicological effects of MPA and ROQ C not only in acute but also in chronic (i.e. 21-days continuous exposure) conditions on Caco-2 cells. Acute exposure to high MPA or ROQ C concentrations induced an increase of IL-8 secretion. Effects of 21-days continuous exposure on barrier integrity, based on concentrations found in blue-veined cheese and mean of blue cheese intake by French consumers, were monitored. Concerning exposure to ROQ C, no alteration of the intestinal barrier was observed. In contrast, the highest tested MPA concentration (780 MUM) induced a decrease in the barrier function of Caco-2 cell monolayers, but no paracellular passage of bacteria was observed. This study highlighted that exposure to MPA and ROQ C average concentrations found in blue-veined cheese does not seem to induce significant toxicological effects in the tested conditions. PMID- 29408667 TI - ZnSO4 rescued vimentin from collapse in DBP-exposed Sertoli cells by attenuating ER stress and apoptosis. AB - Sertoli cells (SCs) provide physical and nutritional support for spermatogenesis. Dibutyl phthalate (DBP) is a plasticizer that has male reproductive toxicity. The collapse of vimentin in DBP-exposed SCs is thought to induce the sloughing of spermatocytes from seminiferous tubules. In this study, we explored methods to rescue vimentin from collapse in DBP-exposed SCs. DBP not only induced the hyperphosphorylation of vimentin but also triggered endoplasmic reticulum (ER) stress and apoptosis in SCs. Treatment with BAPTA-AM, an antagonist of Ca2+, significantly decreased the level of phosphorylated vimentin, while LY294002, an inhibitor of Akt1, did not. ER stress and apoptosis remained at high levels, and the distribution of vimentin was not improved. ZnSO4 treatment did not decrease the level of phosphorylated vimentin. However, after treatment, ER stress and apoptosis were obviously inhibited, and the distribution of vimentin was reconverted. These results indicated that ZnSO4 could alleviate the collapse of vimentin by attenuating ER stress and apoptosis. This study suggested that an appropriate zinc supply might be a choice to alleviate DBP-induced adverse reproductive effects. PMID- 29408668 TI - Azilsartan and its Zn(II) complex. Synthesis, anticancer mechanisms of action and binding to bovine serum albumin. AB - Azilsartan is the eighth approved member of angiotensin II receptor blockers for hypertension treatment. Considering that some drugs have additional effects when administered, we studied its effects and mechanisms of action on a human lung cancer cell line A549. We have also modified the structure of the drug by complexation with Zn(II) cation and assayed the anticancer effect. The crystal structure of the new binuclear Zn(II) complex, for short [Zn2(azil)2(H2O)4].2H2O (ZnAzil), was determined by X-ray diffraction methods. The zinc ions are bridged by azilsartan ligands through their carboxylate oxygen and oxadiazol nitrogen atoms. The compounds were examined for their cytotoxic effects against human lung fibroblast (MRC5) and human lung cancer (A549) cell lines. Azilsartan displayed low cytotoxic effects at 150 MUM concentrations in A549 human lung cancer cells but the higher effect measured for the Zn complex suggested that this compound may act as an anticancer agent. An apoptotic oxidative stress mechanism of action via the mitochondrial-dependent intrinsic pathway has been determined. Besides, the compounds exerted weak cytotoxic effects in the normal lung related cell line MRC5. Binding constants of the complex formed between each compound and bovine serum albumin (BSA) are in the intermediate range, hence suggesting that azilsartan and ZnAzil could be bonded and transported by BSA. PMID- 29408669 TI - Effect of diesel exhaust generated by a city bus engine on stress responses and innate immunity in primary bronchial epithelial cell cultures. AB - Harmful effects of diesel emissions can be investigated via exposures of human epithelial cells, but most of previous studies have largely focused on the use of diesel particles or emission sources that are poorly representative of engines used in current traffic. We studied the cellular response of primary bronchial epithelial cells (PBECs) at the air-liquid interface (ALI) to the exposure to whole diesel exhaust (DE) generated by a Euro V bus engine, followed by treatment with UV-inactivated non-typeable Haemophilus influenzae (NTHi) bacteria to mimic microbial exposure. The effect of prolonged exposures was investigated, as well as the difference in the responses of cells from COPD and control donors and the effect of emissions generated during a cold start. HMOX1 and NQO1 expression was transiently induced after DE exposure. DE inhibited the NTHi-induced expression of human beta-defensin-2 (DEFB4A) and of the chaperone HSPA5/BiP. In contrast, expression of the stress-induced PPP1R15A/GADD34 and the chemokine CXCL8 was increased in cells exposed to DE and NTHi. HMOX1 induction was significant in both COPD and controls, while inhibition of DEFB4A expression by DE was significant only in COPD cells. No significant differences were observed when comparing cellular responses to cold engine start and prewarmed engine emissions. PMID- 29408670 TI - Toxicogenomics applied to in vitro Cell Transformation Assay reveals mechanisms of early response to cadmium. AB - Cadmium is a well recognized carcinogen, primarily released into the environment by anthropogenic activities. In the effort to understand the early events responsible for cadmium carcinogenesis, we have used an in vitro biological system (the Cell Transformation Assay, CTA), that has been shown to closely model some key stages of the conversion of normal cells into malignant ones. Cadmium triggered early responses in CTA were analysed through microarray-based toxicogenomics. Metallothioneins represent the earliest cell response, together with Slc30a1 encoding for a ZnT-1 zinc exporter. Other genes were found to be up regulated in the first 24 h following Cd administration: phospatidylinositol-4 phospate 5-kinase alpha (Pip5k1a), glutathione S-transferase (Gstalpha 1-3), Gdf15 and aldolase. However, after the exposure, a number of genes expressing zinc proteins were found to be down-regulated, among which were many olfactory receptors (ORs) coding genes. Cd administration also promoted massive Zn release inside the cell that could be related to moonlighting activities of regulated genes (proteins). On the whole our data suggest that, despite the early involvement of defence mechanisms (metallothionein and GST), Cd-triggered Zn release, as well as Cd interference with different proteins, may lead to gene expression alterations which later induce metabolic changes, directing the cells towards uncontrolled growth. PMID- 29408671 TI - Impact of cell types and culture methods on the functionality of in vitro liver systems - A review of cell systems for hepatotoxicity assessment. AB - Xenobiotic safety assessment is an area that impacts a multitude of different industry sectors such as medicinal drugs, agrochemicals, industrial chemicals, cosmetics and environmental contaminants. As such there are a number of well developed in vitro, in vivo and in silico approaches to evaluate their properties and potential impact on the environment and to humans. Additionally, there is the continual investment in multidisciplinary scientists to explore non-animal surrogate technologies to predict specific toxicological outcomes and to improve our understanding of the biological processes regarding the toxic potential of xenobiotics. Here we provide a concise, critical evaluation of a number of in vitro systems utilised to assess the hepatotoxic potential of xenobiotics. PMID- 29408672 TI - Essential role of the peroxiredoxin 4 in Procambarus clarkii antioxidant defense and immune responses. AB - Peroxiredoxin (Prx) family members play a key role in host defense against oxidative stress, and modulate immune responses following microbial infection. Here, we cloned and characterized Procambarus clarkii Prx4 (Peroxiredoxin 4) cDNA, a regulator of oxidative stress and its expression analysis upon lipopolysaccharide (LPS) and polyriboinosinic polyribocytidylic acid (Poly I:C) infection. The cDNA fragment of PcPrx4 was 744 bp in length, encoding a putative protein of 248 amino acid residues. Real-time quantitative reverse transcription PCR (qRT-PCR) analysis showed that the PcPrx4 was expressed in all the examined tissues, and it was highest in the hepatopancreas followed by the hemocytes and gill. The challenge with LPS and Poly I:C significantly up-regulated the expression of PcPrx4 in hepatopancreas, hemocytes and gill when compared with the control. Recombinant PcPrx4 protein was used to investigate the antioxidant function in vitro by mixed-function oxidase assay. The results demonstrated a dose-dependent inhibition of DNA damage by rPcPrx4 protein. Altogether, our results imply that PcPrx4 is implicated in defense against microbial pathogens and oxidants in P. clarkii. PMID- 29408673 TI - Platelet-derived microparticles analysis: Techniques, challenges and recommendations. AB - Platelet-derived microparticles (PMP) are nano size fragments (100-1000 nm) released from platelets under various physiological and pathological conditions. PMP are the most abundant microparticles present in human blood. In recent past years PMP have caught attention of many clinicians as well as researchers for being associated with many diseases like cardio-vascular diseases, infections etc; and have emerged as potential biomarkers. Owing to their small size and diverse phenotype, structure and functions, microparticles including PMP render many challenges during sample handling, estimation and characterization. PMP can be analyzed for many parameters like absolute count, size distribution, functions, content, surface proteins and other phenotypic characteristics. Many techniques have been invented to analyze PMP and other extracellular vesicles for these parameters, but none of them is capable of examining all parameters alone. Apart from it, every technique has its own advantages, limitations and sets of recommendations while using it. This often leads to applying multiple techniques in combination for accurately measuring various parameters and user has to decide cautiously which technique has to be used for their selected parameter testing. This review compiles various methods, techniques, challenges during PMP analysis and recommendations based on previous studies, aimed at guiding users for selecting the most suitable techniques for their experiments with PMP. PMID- 29408674 TI - Incidence of HACEK bacteraemia in Denmark: A 6-year population-based study. AB - OBJECTIVES: Bacteria with common microbiological and clinical characteristics are often recognized as a particular group. The acronym HACEK stands for five fastidious genera associated with infective endocarditis (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella). Data on the epidemiology of HACEK are sparse. This article reports a 6-year nationwide study of HACEK bacteraemia in Denmark. METHODS: Cases of HACEK bacteraemia occurring during the years 2010-2015 were retrieved from the national Danish microbiology database, covering an average surveillance population of 5.6 million per year. RESULTS: A total of 147 cases of HACEK bacteraemia were identified, corresponding to an annual incidence of 0.44 per 100000 population. The annual incidence for males was 0.56 per 100000 and for females was 0.31 per 100000. The median age was 56 years (range 0-97 years), with variation among the genera. One hundred and forty-three isolates were identified to the species level and six to the genus level: Haemophilus spp, n=55; Aggregatibacter spp, n=37; Cardiobacterium spp, n=9; Eikenella corrodens n=21; and Kingella spp, n=27. CONCLUSIONS: This is the first study on the incidence of HACEK bacteraemia in a large surveillance population and may inspire further studies on the HACEK group. Haemophilus spp other than Haemophilus influenzae accounted for most cases of HACEK bacteraemia in Denmark, with Aggregatibacter spp in second place. PMID- 29408675 TI - Metabolomic response of a marine bacterium to 3,6-anhydro-l-galactose, the rare sugar from red macroalgae, as the sole carbon source. AB - Marine red macroalgae have received much attention as sustainable resources for producing bio-based products. Therefore, understanding the metabolic pathways of carbohydrates from red macroalgae, in fermentative microorganisms, is crucial for efficient bioconversion of the carbohydrates into bio-based products. Recently, the novel catabolic pathway of 3,6-anhydro-l-galactose (AHG), the main component of red macroalgae, was discovered in a marine bacterium, Vibrio sp. strain EJY3. However, the global metabolic network in response to AHG remains unclear. Here, the intracellular metabolites of EJY3 grown on AHG, glucose, or galactose were comparatively profiled using gas chromatography/time-of-flight mass spectrometry. The global metabolite profiling results revealed that the metabolic profile for AHG significantly differed from those for other common sugars. Specifically, the metabolic intermediate of the AHG pathway, 3,6-anhydrogalactonate, was detected during growth only in the presence of AHG; thus, the recently discovered key steps in AHG catabolism was found not to occur in the catabolism of other common sugars. Moreover, the levels of metabolic intermediates related to glycerolipid metabolism and valine biosynthesis were higher with AHG than those with other sugars. These comprehensive metabolomic analytical results for AHG in this marine bacterium can be used as the basis for having fermentative microbial strains to engineered to efficiently utilize AHG from macroalgal biomass. PMID- 29408676 TI - Distortion-free diffusion tensor imaging for evaluation of lumbar nerve roots: Utility of direct coronal single-shot turbo spin-echo diffusion sequence. AB - PURPOSE: Diffusion tensor imaging (DTI) based on a single-shot echo planer imaging (EPI-DTI) is an established method that has been used for evaluation of lumbar nerve disorders in previous studies, but EPI-DTI has problems such as a long acquisition time, due to a lot of axial slices, and geometric distortion. To solve these problems, we attempted to apply DTI based on a single-shot turbo spin echo (TSE-DTI) with direct coronal acquisition. Our purpose in this study was to investigate whether TSE-DTI may be more useful for evaluation of lumbar nerve disorders than EPI-DTI. MATERIALS AND METHODS: First, lumbar nerve roots of five healthy volunteers were evaluated for optimization of imaging parameters with TSE DTI including b-values and the number of motion proving gradient (MPG) directions. Subsequently, optimized TSE-DTI was quantitatively compared with conventional EPI-DTI by using fractional anisotropy (FA) values and visual scores in subjective visual evaluation of tractography. Lumbar nerve roots of six patients, who had unilateral neurologic symptoms in one leg, were evaluated by the optimized TSE-DTI. RESULTS: TSE-DTI with b-value of 400 s/mm2 and 32 diffusion-directions could reduce the image distortion compared with EPI-DTI, and showed that the average FA values on the symptomatic side for six patients were significantly lower than those on the non-symptomatic side (P < 0.05). CONCLUSION: Tractography with TSE-DTI might show damaged areas of lumbar nerve roots without severe image distortion. TSE-DTI might improve the reproducibility in measurements of FA values for quantification of a nerve disorder, and would become a useful tool for diagnosis of low back pain. PMID- 29408677 TI - Evaluation of shortness of breath after atrial fibrillation ablation-Is there a stiff left atrium? PMID- 29408678 TI - Pectin microgel particles as high adsorption rate material for methylene blue: Performance, equilibrium, kinetic, mechanism and regeneration studies. AB - The pectin gel has been proved to be an effective material for methylene blue (MB) removal, but it presented low adsorption rate. To get over the vice, the pectin microgel particles (PMP) was prepared. No matter high or low initial MB concentration, the PMP presented high adsorption rate with equilibrium time of 20min. The adsorption process based on monolayer adsorption and adsorbance of 284.09mg/g was obtained. What's more, the adsorption process was electrostatic adsorption with mean free energy of 74.223kJ/mol. The pseudo-second-order kinetic model fitted perfectly to the experimental data. The MB uptake was controlled by film diffusion mechanism. Furthermore, the recovery efficiency of regenerated PMP were higher than 80% after three cycles. The present study showed the PMP presented acceptable adsorbance, high adsorption rate and recovery efficiency. Thus, we believe that the PMP was a promising candidate for MB cleanup. PMID- 29408679 TI - Acid-enhanced conformation changes of yeast cytochrome c coated onto gold nanoparticles, a FT-IR spectroscopic analysis. AB - Under conditions with or without linker molecules, the effects of acidic pH on the conformation of yeast iso-1-cytochrome c coated onto gold nanoparticles (AuNPs) in correlation with color changes of a Cyt c-coated AuNPs solution/suspension were examined by Fourier transform infrared (FT-IR) spectroscopy and correlated to color change. The results of detailed secondary structural analysis revealed that although the color changes coincide with acid induced conformational changes in Cyt c coated onto AuNPs, the pH-related conformational unfolding of Cyt c coated onto AuNPs differed dramatically from that of its counterpart in solution. For Cyt c free in solution, the acid-induced unfolding did not occur until the pH was below 3.0, whereas for Cyt c coated onto AuNPs via C102 coordination near the C-terminal, a partial unfolding was observed even at near neutral pH which continuously intensified as pH decreased. Insertion of a short alkanethiol (3-mercaptoproprionic acid, 3-MPA) molecule between Cyt c and AuNP, which changes the interaction mode from a thiol coordination between Cyt c and AuNP to an electrostatic interaction between Cyt c and 3-MPA, which stabilized the conformation of Cyt c significantly, but did not prevent the acid induced aggregation of Cyt c-3MPA-AuNPs. PMID- 29408680 TI - Tools for Learning About the Referral and Consultation Process for Pediatric Residents. AB - Management of referral and consultation is an entrustable professional activity for pediatric residents; however, few tools exist to teach these skills. We designed and implemented tools to prompt discussion, feedback, and reflection about the process of referral, notably including the family's perspective. PMID- 29408681 TI - Housing environment influences stress-related hippocampal substrates and depression-like behavior. AB - Rats are widely used animal models for biological psychiatry and neuroscience. Laboratory rats are typically housed in impoverished sensory environments. The lack of species-typical sensory environment might radically change the response of individual animals to stressful and/or threatening episodes. In this report, we demonstrate that behavioral and neural sequelae of chronic stress were modified by sensory environment of adult male rats. This includes effects of stress on the density of spines on CA3 hippocampal neurons, hippocampal neurogenesis and abundance of glucocorticoid or mineralocorticoid receptors. Enrichment also reduced depression-like behavior in a forced swim task. Stress and sensory enrichment evoked opposing effects on all the above endpoints. The sensory enrichment used in this report is of a relatively short duration provided during adulthood. This period excludes critical windows of greater plasticity during pre- and peripubertal stages. Our results suggest that standard housing practices for laboratory rats remain austere concerning sensory requirements of this species. Thus, even a moderate sensory enrichment is capable of reducing high stress-sensitivity and depressive-like behavior in standard laboratory rats. PMID- 29408682 TI - Neurochemical changes in unilateral cerebral hemisphere during the subacute stage of focal cerebral ischemia-reperfusion in rats: An ex vivo 1H magnetic resonance spectroscopy study. AB - Understanding the subacute may shed light on the mechanism of cerebral ischemia. The present study aimed to explore metabolic features underlying subacute stage of ischemia-reperfusion injury and developing effective treatments. Rats were divided into three groups: the permanent middle cerebral artery occlusion (pMCAO), transient cerebral focal ischemia (tMCAO) and sham group. Evaluation of animal models was performed by the neurological deficit, MR images and pathological morphological abnormality. To elucidate metabolic changes, we conducted a comparative analysis of metabolic composition of unilateral brain tissue using 1H nuclear magnetic resonance spectroscopy. The successful model was observed low signal on T1WI and high signal on T2WI lesions in the left cerebral. Histopathological results confirmed the formation of apparent lesions in the left striatum, hippocampus CA1 and cortex tissues of subacute cerebral ischemia rats and showed that rats with focal cerebral ischemia-reperfusion could alleviate the extent of pathological damage degree. In pMCAO rats 7 days after surgery, decreased levels of N-acetyl aspartate (NAA), gamma-aminobutyric acid (GABA), glutamate (Glu) and succinate (Suc) concomitantly with increased levels of glutamine (Gln), myo-inositol (m-Ins) and lactate (Lac) were observed compared to the control. Whereas, increased level of Lac with decreased levels of NAA, GABA, Glu, Suc, creatine (Cre) were observed in the tMCAO rats. This demonstrated that experimental subacute ischemic stroke in rats caused extensive perturbation in energy metabolism, the tricarboxylic acid cycle and GABA shunt, which provided essential information for understanding the pathogenesis of subacute cerebral ischemia-reperfusion and provided guidance in choosing the suitable therapeutic schedule. PMID- 29408683 TI - Aberrant apolipoprotein C-III glycosylation in glycogen storage disease type III and IX. PMID- 29408684 TI - A novel dexamethasone-loaded liposome alleviates rheumatoid arthritis in rats. AB - In this study, an inflammation-targeted delivery system based on a liposomal carrier was developed to deliver hydrophobic dexamethasone against arthritis. Using two FDA-approved excipients for intravenous injection, dexamethasone loaded liposome (Dex-Lip) was prepared by a thin-film hydration method. The biodistribution of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine loaded liposomes (DiD-Lips) were performed in rats with adjuvant-induced arthritis and demonstrated specific targeting efficacy in the disease site. DiD Lips showed prolonged retention time in the inflammatory joint tissues compared with free DiD. Dex-Lips effectively suppressed the joint swelling in arthritis rats and significantly down-regulated serum pro-inflammatory cytokines including tumor necrosis factor-alpha and interleukin-1beta when compared to free dexamethasone. Furthermore, Dex-Lips had no significantly impact on the body weight, alleviated the hyperglycemia and improved haematological profiles of rheumatoid arthritis rats during the treatment process. Taken together, a safe liposomal delivery system was developed to achieve inflammation targeted therapy against arthritis. PMID- 29408685 TI - Perspectives on diagnostic strategies for hyperglycemia in pregnancy - Dealing with the barriers and challenges in South Asia. AB - Estimates indicate that south Asia accounts for over two fifths of the global burden of hyperglycemia in pregnancy (HIP) and the ongoing nutritional and epidemiological transition may make the situation worse. Given their higher risk, all women of south Asian decent require to be tested for HIP. With approximately 37 million births annually in the region requires that 37 million women be tested annually; thereby placing a huge burden on the fragile inadequately resourced health systems in the region with poor awareness and lack of trained manpower. Recommendation for testing must therefore be pragmatic, feasible, convenient and cost effective. Diabetes in pregnancy study group India (DIPSI) has proposed a simple testing protocol that is endorsed by the Indian National Guideline on GDM, and by the FIGO guideline on HIP for use in South Asia. This testing protocol has received widespread support in the region. Despite the many challenges it is encouraging to note that in the four large countries in the region - Bangladesh, India, Pakistan and Sri Lanka which account for over 80% of the estimated burden of HIP in south Asia, large scale credible programs have been initiated to address the identified barriers. PMID- 29408686 TI - The Urology Applicant: An Analysis of Contemporary Urology Residency Candidates. AB - OBJECTIVE: To better understand today's urology applicant. METHODS: All 2016 Urology Residency Match applicants to the study-participating institutions were provided a survey via email inquiring about their paths to urology, their career aspirations, how they evaluate a training program, and how they perceive residency programs evaluate them. RESULTS: Of a possible 468 applicants registered for the match, 346 applicants completed the survey. Only 8.7% had a mandatory urology rotation, yet 58.4% believed that a mandatory urology rotation would influence their career decision. Most applicants (62.1%) spent more than 8 weeks on urology rotations, and 79.2% completed 2 or more away rotations. Applicants were attracted to urology by the diversity of procedures, prior exposure to the field, and the mix of medicine and surgery, with mean importance scores of 4.70, 4.52, and 4.45 of 5, respectively. Female applicants were more likely to be interested in pediatric urology, trauma or reconstructive urology, and female pelvic medicine and reconstructive surgery. Significant differences in survey results were noted when applicants were separated by gender. Three-fourths of respondents (75.7%) applied to more than 50 residency programs. Applicants ranked operative experience, interactions with current residents, and relationships between faculty and residents as the most important criteria when evaluating training programs. Of the subspecialties, 62.1% of applicants expressed most interest in urologic oncology. At this stage in their career, a significant majority (83.5%) expressed interest in becoming academic faculty. CONCLUSION: This study provides new information that facilitates a more comprehensive understanding of today's urology applicants. PMID- 29408687 TI - Clinical and radiological outcomes of a cohort of 9 patients with anatomical fractures of the cuboid treated by locking plate fixation. AB - INTRODUCTION: Cuboid fractures are very rare. Hence, their treatment has not been standardized. Advances in imaging techniques, particularly three-dimensional computed tomography (3D CT), and the introduction of cuboid-specific plates has improved the care of these injuries. The aim of this study was to determine the radiological and clinical outcomes of anatomical reconstruction of comminuted cuboid fractures with a locking plate. HYPOTHESIS: Fixation of comminuted cuboid fractures with a cuboid-specific locking plate leads to stable anatomical reduction and good functional outcomes. MATERIAL AND METHODS: This was a retrospective study of 9 consecutive cases of comminuted cuboid fracture treated at a single hospital between January 2009 and December 2015. A 3D CT scan was performed preoperatively with subtraction of the posterior tarsal bone to allow the articular facets to be viewed and analyzed. Fracture fixation was done with a Locking Cuboid Plate (DePuy SynthesTM). Associated lesions in the foot were treated during the same procedure. The patients were reviewed by an independent observer who performed a clinical examination, and determined the AOFAS and Maryland Foot Score. The success of the reconstruction was determined by comparing the parameters on weight-bearing X-rays views between the fixed and non operated cuboid. RESULTS: The mean follow-up was 4.1 years (range 1-6). The Maryland Foot Score was 93.1 [86-100] and the AOFAS was 91.9 [82-100]. The reconstruction was anatomical and long lasting in all 9 cases. There was no foot misalignment in the frontal plane, based on the radiographs (hindfoot axis 5.5 degrees [0-9]). The mean Djian-Annonier angle was 123.9 degrees [108-130]. CONCLUSION: Cuboid fractures can be treated effectively through appropriate imaging and with a cuboid-specific locking plate as evidenced by very good midterm clinical and radiological outcomes in this study. LEVEL OF EVIDENCE: IV Retrospective study. PMID- 29408688 TI - Nomenclature for factors of the HLA system, update October 2017. PMID- 29408689 TI - Updated follow-up of a tolerance protocol in HLA-identical renal transplant pairs given donor hematopoietic stem cells. AB - Kidney transplant recipients given donor hematopoietic stem cells from their HLA identical living related donors have now been followed between 5 and 91/2 years post-operatively. Recipients who were designated as tolerant (Tol) have remained so since the last report when the 5 year (biopsy associated) milestone was reached. There has been 1 mortality of a Tol patient, unrelated to the study protocol, while 5 (of 15) have remained Tol between 7 and 81/2 years post operatively. There has been continuing elevated T-regulatory (CD4+CD25HighCD127 FOXP3+) cells in PBMC previously reported on. Ten year renal transplant biopsies are tentatively planned. PMID- 29408690 TI - Female sexual attractiveness and sex recognition in leopard gecko: Males are indiscriminate courters. AB - The nature and hormonal control of cues used for recognition of sex and reproductive status of conspecifics remain largely unstudied in reptiles. It has been proposed that production of a female attractiveness pheromone controlled by female ovarian hormones (and which is suppressed by male gonadal androgens) is necessary to elicit courtship in males. In the case of leopard gecko (Eublepharis macularius), it has been suggested that an individual is recognized as a male and attacked unless it produces female-specific stimuli in its skin and that females are attacked, not courted, while shedding. We tested the reactions of males to control males and control shedding and non-shedding females, castrated males, females treated with exogenous androgens (testosterone and dihydrotestosterone), and prepubertal individuals. The individuals with high androgen levels (i.e., control males and hormone-treated females) were attacked while animals in all the other groups were courted. Our results indicate that in leopard gecko hormonally controlled pheromones advertising female attractiveness are not required and that sex discrimination is based on the presence or absence of cues dependent on masculinization by male gonadal steroids. PMID- 29408691 TI - How does school size affect tail beat frequency in turbulent water? AB - : The energy savings experienced by fish swimming in a school have so far been investigated in an near-idealised experimental context including a relatively laminar water flow. The effects of explicitly turbulent flows and different group sizes are yet to be considered. Our repeated-measures study is a first step in addressing both of these issues: whether schooling is more energetically economical for fish when swimming in a quantified non-laminar flow and how this might be moderated by group size. We measured tail beat frequency (tbf) in sea bass swimming in a group of 3 or 6, or singly. Video data enabled us to approximately track the movements of the fish during the experiments and in turn ascertain the water flow rates and turbulence levels experienced for each target individual. Although the fish exhibited reductions in tbf during group swimming, which may indicate some energy savings, these savings appear to be attenuated, presumably due to the water turbulence and the movement of the fish relative to each other. Surprisingly, tbf was unrelated to flow rate when the fish were swimming singly or in a group of three, and decreased with increasing flow rates when swimming in a group of six. However, the fish increased tbf in greater turbulence at all group sizes. Our study demonstrates that under the challenging and complex conditions of turbulent flow and short-term changes in school structure, group size can moderate the influences of water flow on a fish's swimming kinematics, and in turn perhaps their energy costs. SUMMARY STATEMENT: The energy savings that sea bass experience from schooling are affected by flow speed or turbulence, moderated by group size. PMID- 29408692 TI - Proteomic analysis of the sarcolemma-enriched fraction from dystrophic mdx-4cv skeletal muscle. AB - : The highly progressive neuromuscular disorder dystrophinopathy is triggered by primary abnormalities in the Dmd gene, which causes cytoskeletal instability and loss of sarcolemmal integrity. Comparative organellar proteomics was employed to identify sarcolemma-associated proteins with an altered concentration in dystrophic muscle tissue from the mdx-4cv mouse model of dystrophinopathy. A lectin agglutination method was used to prepare a sarcolemma-enriched fraction and resulted in the identification of 190 significantly changed protein species. Proteomics established differential expression patterns for key components of the muscle plasma membrane, cytoskeletal network, extracellular matrix, metabolic pathways, cellular stress response, protein synthesis, immune response and neuromuscular junction. The deficiency in dystrophin and drastic reduction in dystrophin-associated proteins appears to trigger (i) enhanced membrane repair involving myoferlin, dysferlin and annexins, (ii) increased protein synthesis and the compensatory up-regulation of cytoskeletal proteins, (iii) the decrease in the scaffolding protein periaxin and myelin PO involved in myelination of motor neurons, (iv) complex changes in bioenergetic pathways, (v) elevated levels of molecular chaperones to prevent proteotoxic effects, (vi) increased collagen deposition causing reactive myofibrosis, (vii) disturbed ion homeostasis at the sarcolemma and associated membrane systems, and (viii) a robust inflammatory response by the innate immune system in response to chronic muscle damage. SIGNIFICANCE: Duchenne muscular dystrophy is a devastating muscle wasting disease and represents the most frequently inherited neuromuscular disorder in humans. Genetic abnormalities in the Dmd gene cause a loss of sarcolemmal integrity and highly progressive muscle fibre degeneration. Changes in the neuromuscular system are associated with necrosis, fibrosis and inflammation. In order to evaluate secondary changes in the sarcolemma membrane system due to the lack of the membrane cytoskeletal protein dystrophin, comparative organellar proteomics was used to study the mdx-4cv mouse model of dystrophinopathy. Mass spectrometric analyses identified a variety of altered components of the extracellular matrix sarcolemma-cytoskeleton axis in dystrophic muscles. This included proteins involved in membrane repair, cytoskeletal restoration, calcium homeostasis, cellular signalling, stress response, neuromuscular transmission and reactive myofibrosis, as well as immune cell infiltration. These pathobiochemical alterations agree with the idea of highly complex secondary changes in X-linked muscular dystrophy and support the concept that micro-rupturing of the dystrophin deficient plasma membrane is at the core of muscle wasting pathology. PMID- 29408693 TI - Identification and sequence analysis of putative Sulla species nod factor receptor. AB - In legumes, LysM domains of receptors-like kinases (RLKs) mediate rhizobial NFs perception; which are required for infection and establishment of symbiosis without triggering the host immune response. In this study, we identify the LysM extracellular domain sequences of putative Sulla species Nod factor receptors (S. pallida, S. capitata and S. coronaria). The Blast search displayed high identity percentages with genes encoding LjNFR5-like of several legumes. Phylogenetic trees were built using the partial nod factor receptor and predicted amino acid sequences, which grouped Sulla in a separate clade. The multiple alignments of the LysM2 domains revealed that amino acids found to be important in other legume species are not conserved in Sulla species. Further examination of the predicted proteins sequences (LysM2 domain) showed that the three species were different in the two crucial sites for Nod factor perception. PMID- 29408695 TI - Irrigation after Laparoscopic Power Morcellation and the Dispersal of Leiomyoma Cells: A Pilot Study. AB - STUDY OBJECTIVE: To evaluate if copious irrigation and suctioning after electromechanical power morcellation will reduce myoma cell dissemination and if there is a difference between sterile water and normal saline. DESIGN: Prospective single-center cohort pilot study (Canadian Task Force classification II-2). SETTING: Academic tertiary referral center. PATIENTS: Sixteen women undergoing laparoscopic myomectomy with 1 surgeon between January 1, 2017 and August 31, 2017. INTERVENTIONS: Peritoneal washings were collected 3 specific times during surgery: after dissection of myoma(s) and hysterotomy repair but before morcellation, after morcellation, and after irrigation with 3 L normal saline or sterile water. The primary outcome was the detection of benign spindle cells (BSCs) in peritoneal washings. MEASUREMENTS AND MAIN RESULTS: Sixteen patients were enrolled in the study. Eight were randomized to the normal saline group and 8 to the sterile water group. In the normal saline group BSCs were detected in 3 of 8 patients (37.5%) after closure of the hysterotomy but before morcellation, in 3 of 8 (37.5%) after morcellation, and in 0 of 8 (0%) after irrigation and suctioning of the peritoneal cavity with 3 L normal saline. In the sterile water group BSCs were detected in 3 of 8 patients (37.5%) after closure of the hysterotomy but before morcellation, 2 of 8 (25%) after morcellation, and in 0 of 8 (0%) after irrigation and suctioning with 3 L sterile water. Thus, no differences were found between the normal saline and sterile water groups. CONCLUSION: In this pilot study myoma cells were disseminated before electromechanical morcellation. Irrigation and suctioning with 3 L normal saline or sterile water after morcellation may reduce myoma cell dissemination. PMID- 29408696 TI - Stop-and-watch strategy after cessation of nucleos(t)ide analogue therapy in HBeAg-negative patients. PMID- 29408697 TI - Strong androgen receptor expression can aid in distinguishing GATA3+ metastases. AB - GATA3 is a transcription factor used clinically as a marker of breast or urothelial differentiation. A marker is yet needed to distinguish this in the case of the GATA3-positive tumor of unknown origin. We tested classical markers of breast differentiation and hormonal signaling to see which correlated strongest with GATA3 expression in breast cancer and thus which could help correctly identify breast origin in the case of the GATA3-positive tumor of unknown origin. GATA3, estrogen receptor, progesterone receptor, androgen receptor (AR), HER2, GCDFP15, and mammaglobin expression was intercorrelated in a histologically diverse 259-case breast cancer tissue microarray. We show herein a uniquely high level of correlation between GATA3 and AR expression (r=0.61; 95% confidence interval 0.52-0.68) that was strongest among lobular carcinomas (r=1; 95% confidence interval 0.73-1) and stronger than any other correlation studied. Separate AR staining of 10 metastatic GATA3+ carcinomas of urothelial origin and 13 metastatic GATA3+ carcinomas of breast origin showed that strong AR staining (>60% of tumor cells) has a sensitivity of 54% and a specificity of 100% for correctly distinguishing GATA3+ carcinoma of mammary origin from urothelial origin in the metastatic setting. Androgen receptor expression is strongly correlated with GATA3 in breast cancer, particularly in tumors with lobular morphology. Strong AR expression (>60% of tumor cells) is an excellent test to rule out urothelial carcinoma in the GATA3+ metastatic setting (specificity 100%) and will effectively identify breast origin in approximately 50% of cases. PMID- 29408694 TI - Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease. PMID- 29408698 TI - Visualization of T Cell-Regulated Monocyte Clusters Mediating Keratinocyte Death in Acquired Cutaneous Immunity. AB - It remains unclear how monocytes are mobilized to amplify inflammatory reactions in T cell-mediated adaptive immunity. Here, we investigate dynamic cellular events in the cascade of inflammatory responses through intravital imaging of a multicolor-labeled murine contact hypersensitivity model. We found that monocytes formed clusters around hair follicles in the contact hypersensitivity model. In this process, effector T cells encountered dendritic cells under regions of monocyte clusters and secreted IFN-gamma, which mobilizes CCR2-dependent monocyte interstitial migration and CXCR2-dependent monocyte cluster formation. We showed that hair follicles shaped the inflammatory microenvironment for communication among the monocytes, keratinocytes, and effector T cells. After disrupting the T cell-mobilized monocyte clusters through CXCR2 antagonization, monocyte activation and keratinocyte apoptosis were significantly inhibited. Our study provides a new perspective on effector T cell-regulated monocyte behavior, which amplifies the inflammatory reaction in acquired cutaneous immunity. PMID- 29408700 TI - A prospective study comparing patients with early and late relapsing pemphigus treated with rituximab. AB - BACKGROUND: Rituximab (RTX) is an effective therapy for patients with pemphigus; however, the therapy does not prevent relapse. OBJECTIVES: To compare early relapsing patients (before 12 months) and late relapsing patients (after 24 months) following RTX therapy. METHOD: In this prospective study, 19 patients were enrolled (14 with pemphigus vulgaris and 5 with pemphigus foliaceus). The baseline disease score, autoantibody levels, and percentage of CD20+ cells of patients with pemphigus were measured. Patients received 1 cycle of RTX and were followed for 26 months. RESULTS: Among early relapsing patients (n = 5), the time to relapse was 6 to 11 months. Among late relapsing patients (n = 6), the time to relapse was 24 to 26 months. A significant difference was observed in the mean baseline anti-desmoglein 1 (DSG1) index between early relapsing (705.72) and late relapsing patients (210.4) (P = .0014). A significant negative correlation was found between the baseline anti-DSG1 index and time to relapse (r = -0.777, P = .00009). LIMITATIONS: The small number of patients with pemphigus foliaceus. CONCLUSIONS: Because patients with high baseline anti-DSG1 indices relapsed earlier, it may be important to follow these patients closely for the initial 12 months after RTX therapy. These patients may require a maintenance RTX dose during the first 12 months after RTX therapy. PMID- 29408699 TI - Accumulation of carboxymethyl-lysine (CML) in human cortical bone. AB - Advanced glycation end-products (AGEs) are a category of post translational modification associated with the degradation of the structural properties of multiple different types of tissues. Typically, AGEs are the result of a series of post-translational modification reactions between sugars and proteins through a process known as non-enzymatic glycation (NEG). Increases in the rate of NEG of bone tissue are associated with type 2 diabetes and skeletal fragility. Current methods of assessing NEG and its impact on bone fracture risk involve measurement of pentosidine or total fluorescent AGEs (fAGEs). However, pentosidine represents only a small fraction of possible fAGEs present in bone, and neither pentosidine nor total fAGE measurement accounts for non-fluorescent AGEs, which are known to form in significant amounts in skin and other collagenous tissues. Carboxymethyl lysine (CML) is a non-fluorescent AGE that is often measured and has been shown to accumulate in tissues such as skin, heart, arteries, and intervertebral disks, but is currently not assessed in bone. Here we show the localization of CML to collagen I using mass spectrometry for the first time in human bone. We then present a new method using demineralization followed by heating and trypsin digestion to measure CML content in human bone and demonstrate that CML in bone is 40-100 times greater than pentosidine (the current most commonly used marker of AGEs in bone). We then establish the viability of CML as a measurable AGE in bone by showing that levels of CML, obtained from bone using this technique, increase with age (p<0.05) and are correlated with previously reported measures of bone toughness. Thus, CML is a viable non-fluorescent AGE target to assess AGE accumulation and fragility in bone. The method developed here to extract and measure CML from human bone could facilitate the development of a new diagnostic assay to evaluate fracture risk and potentially lead to new therapeutic approaches to address bone fragility. PMID- 29408702 TI - Comparison of 3D cellular imaging techniques based on scanned electron probes: Serial block face SEM vs. Axial bright-field STEM tomography. AB - Microscopies based on focused electron probes allow the cell biologist to image the 3D ultrastructure of eukaryotic cells and tissues extending over large volumes, thus providing new insight into the relationship between cellular architecture and function of organelles. Here we compare two such techniques: electron tomography in conjunction with axial bright-field scanning transmission electron microscopy (BF-STEM), and serial block face scanning electron microscopy (SBF-SEM). The advantages and limitations of each technique are illustrated by their application to determining the 3D ultrastructure of human blood platelets, by considering specimen geometry, specimen preparation, beam damage and image processing methods. Many features of the complex membranes composing the platelet organelles can be determined from both approaches, although STEM tomography offers a higher ~3 nm isotropic pixel size, compared with ~5 nm for SBF-SEM in the plane of the block face and ~30 nm in the perpendicular direction. In this regard, we demonstrate that STEM tomography is advantageous for visualizing the platelet canalicular system, which consists of an interconnected network of narrow (~50-100 nm) membranous cisternae. In contrast, SBF-SEM enables visualization of complete platelets, each of which extends ~2 um in minimum dimension, whereas BF-STEM tomography can typically only visualize approximately half of the platelet volume due to a rapid non-linear loss of signal in specimens of thickness greater than ~1.5 um. We also show that the limitations of each approach can be ameliorated by combining 3D and 2D measurements using a stereological approach. PMID- 29408701 TI - yVDAC2, the second mitochondrial porin isoform of Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae genome is endowed with two distinct isoforms of Voltage-Dependent Anion Channel (VDAC). The isoform yVDAC2 is currently understudied with respect to the best known yVDAC1. Yet, since the discovery, the function of yVDAC2 was unclear, leading to the hypothesis that it might be devoid of a channel function. In this work we have elucidated, by bioinformatics modeling and electrophysiological analysis, the functional activity of yVDAC2. The conformation of yVDAC2 and, for comparison, of yVDAC1 were modeled using a multiple template approach involving mouse, human and zebrafish structures and both showed to arrange the sequences as the typical 19-stranded VDAC beta-barrel. Molecular dynamics simulations showed that yVDAC2, in comparison with yVDAC1, has a different number of permeation paths of potassium and chloride ions. yVDAC2 protein was over-expressed in the S. cerevisiae cells depleted of functional yVDAC1 (Deltapor1 mutant) and, after purification, it was reconstituted in artificial membranes (planar lipid bilayer (PLB) system). The protein displayed channel-forming activity and the calculated conductance, voltage-dependence and ion selectivity values were similar to those of yVDAC1 and other members of VDAC family. This is the first time that yVDAC2 channel features are detected and characterized. PMID- 29408703 TI - Structural characterization of 14-3-3zeta in complex with the human Son of sevenless homolog 1 (SOS1). AB - The deviant Ras activation machinery is found in approximately 30% of all human cancers. SOS1 is an important protagonist of this pathway that plays a key-role in aberrant cell proliferation and differentiation. Interaction of SOS1 with 14-3 3 proteins modulates SOS1 activity in Ras-MAPK signaling. In the present study, we analyze the 14-3-3/SOS1 protein-protein interaction (PPI) by different biochemical assays and report the high resolution crystal structure of a 13-mer motif of SOS1 bound to 14-3-3zeta. These structural and functional insights are important for the evaluation of this PPI interface for small-molecule stabilization as a new starting point for modulating the Ras-Raf-MAPK pathway. PMID- 29408704 TI - The effects of short-term continuous subcutaneous insulin infusion treatment on fasting glucagon-like peptide-1 concentrations in newly diagnosed type 2 diabetes. AB - OBJECTIVE: Early short-term intensive insulin therapy in newly diagnosed type 2 diabetes patients shows benefit in glycemic control and beta-cell function. Glucagon-like peptide-1 (GLP-1) plays an important role in glucose metabolism and development of type 2 diabetes. We did a study to observe the changes of GLP-1 and beta-cell function after short-term continuous subcutaneous insulin infusion (CSII) treatment. METHODS: A total of 66 subjects were enrolled, including 30 normal glucose tolerance controls (NGT) and 36 patients with newly diagnosed type 2 diabetes between October 2015 and July 2016. Fasting plasma glucose (FPG), insulin, and GLP-1 were measured in each subject. The patients underwent CSII treatment for 2 weeks, and then FBG, insulin, and GLP-1 were measured. HOMA-IR and HOMA-B were then calculated. RESULTS: All patients achieved target glycemic control in two weeks. HOMA-IR and HOMA-B improved significantly after intensive interventions (p < 0.05). The GLP-1 concentration increased significantly in patients after treatment (p < 0.05). When grouped according to bodyweight and age in all patients, the HOMA-IR changed significantly in overweight and old age subgroups, the HOMA-B increased significantly in normal weight, overweight and middle age subgroups, and the GLP-1 concentration also increased significantly in overweight and middle age subgroups respectively (p < 0.05). CONCLUSION: Short term CSII treatment can obtain glycemic control target and recover beta-cell function and GLP-1 secretion in newly diagnosed type 2 diabetes patients. The overweight and middle-aged patients may get more benefit from this treatment. PMID- 29408705 TI - The potential long-term neurological improvement of early hyperbaric oxygen therapy on hemorrhagic stroke in the diabetics. AB - AIMS: Although Hyperbaric oxygen therapy (HyperBOT) attract our attention successfully these days, it is still full of controversy on the treatment of acute stroke. The aim of this study is to assess the potential long-term neurological consequences and safety of using HyperBOT on intracerebral hemorrhage (ICH) in the diabetics. METHODS: In this prospective, randomized controlled trial, 79 diabetes patients suffering from acute ICH were randomized to treat for 60 min in a monoplace hyperbaric chamber pressurized with pure oxygen to 2.5-atm absolute (ATA) in the HyperBOT group or 1.5 ATA in the normobaric oxygen therapy (NormBOT) group, which was performed as control. Both short-term and long-term neurological consequences were studied and compared in each group on National Institutes of Health Stroke Scale [NIHSS], Barthel Index, modified Rankin Scale [mRS] and Glasgow Outcome Scale [GOS]. The related complications or side-events of all patients were recorded as well at the final follow-up of six months after onset. RESULTS: No distinct difference was observed between each group at one month follow-up. However, in the long-term follow-up of six months, a higher frequency of patients in the HyperBOT group resulted into good outcome with a relative high neurological consequence compared with the NormBOT group (Barthel Index: 85.1% versus 65.6%, P = 0.080; mRS: 89.4% versus 68.8%, P = 0.045; GOS: 83.0% versus 62.5%, P = 0.073; NIHSS: 80.9% versus 56.2%, P = 0.035). CONCLUSIONS: Early HyperBOT was found to be safe and effective with regards to the long-term neurological outcome of diabetic patients suffering from ICH. PMID- 29408706 TI - Population-based cohort study suggesting a significantly increased risk of developing chronic obstructive pulmonary disease in people with type 2 diabetes mellitus. AB - AIMS: To investigate whether type 2 diabetes mellitus (T2DM) increases the risk of developing chronic obstructive pulmonary disease (COPD). METHODS: This population-based cohort study used Taiwan's National Health insurance claim data to investigate the association of T2DM with the risk of COPD. A total of 716,623 pairs of people (patients with T2DM and their age-, sex-, and calendar year matched controls) were identified in 2002-2003 and were followed until the occurrence of newly-diagnosed COPD or the end of 2011. Cox proportional hazard models were used to relate COPD incidence to T2DM. RESULTS: People with T2DM experienced a higher incidence rate of COPD than controls (159.6 vs 122.7 per 104 person-years). After controlling for confounders, T2DM significantly increased the hazard of COPD (hazard ratio [HR] = 1.15, 95% confidence interval = 1.14 1.16). Stratified analysis indicated that the association between T2DM and COPD was slightly greater in women than in men (HR, 1.15 vs. 1.11) and in people aged <65 years than in people aged >=65 years (HR, 1.17 vs. 1.05 in men; 1.16 vs. 1.13 in women). CONCLUSIONS: Our findings demonstrated a modest association of T2DM with the risk of developing COPD, possibly shedding light into the adverse effects of hyperglycemia on pulmonary function. PMID- 29408707 TI - Precision-cut human liver slice cultures as an immunological platform. AB - The liver is the central metabolic organ in the human body, and also plays an essential role in innate and adaptive immunity. While mouse models offer significant insights into immune-inflammatory liver disease, human immunology differs in important respects. It is not easy to address those differences experimentally. Therefore, to improve the understanding of human liver immunobiology and pathology, we have established precision-cut human liver slices to study innate immunity in human tissue. Human liver slices collected from resected livers could be maintained in ex vivo culture over a two-week period. Although an acute inflammatory response accompanied by signs of tissue repair was observed in liver tissue following slicing, the expression of many immune genes stabilized after day 4 and remained stable until day 15. Remarkably, histological evidence of pre-existing liver diseases was preserved in the slices for up to 7 days. Following 7 days of culture, exposure of liver slices to the toll-like receptor (TLR) ligands, TLR3 ligand Poly-I:C and TLR4 ligand LPS, resulted in a robust activation of acute inflammation and cytokine genes. Moreover, Poly-I:C treatment induced a marked antiviral response including increases of interferons IFNB, IL-28B and a group of interferon-stimulated genes. Therefore, precision-cut liver slices emerge as a valuable tool to study human innate immunity. PMID- 29408708 TI - Excavating differentially expressed antimicrobial peptides from transcriptome of Larimichthys crocea liver in response to Cryptocaryon irritans. AB - Larimichthys crocea, the special marine economy fish, owns the largest annual yield for a single species in China. One of the most significant factors affecting large yellow croaker culture is the diseases, especially the threat of marine white spot disease which caused by a protozoan Cryptocaryon irritans. Antimicrobial peptides (AMPs) have been demonstrated to be active against bacterium, fungi and parasites, showing their potential usefulness in aquaculture as substitutes for antibiotics. Many researches have been carried out about the AMPs concentrating on the activity resist on C. irritans, and piscidin-like of L. crocea owning widely antibacterial spectrum and strong activity against C. irritans was screened in our team. In the paper, taking advantage of the large yellow croaker hepatic comparison transcriptome in response to C. irritans at 3d post infection, seven kinds of AMPs have been excavated from the differently expressed genes, including LEAP2 like, LEAP-2A, hepcidin, hepcidin-like, piscidin 5-like, piscidin-5-like type 4 and bactericidal permeability increasing protein (BPI). Hepcidin, hepcidin-like, piscidin-5-like, piscidin-5-like type4 and BPI were up-regulated to protect large yellow croaker from being damaged by C. irritans infection; while LEAP2 like and LEAP-2A were down-regulated, they might be as a negative-feedback regulation factor or some other regulatory mechanisms to adjust the immune response in the process of C. irritans infection. The differential expression changes were verified with quantitative real-time PCR (qRT-PCR) to illustrate the reliability of the sequenced data. Hearteningly, piscidin-5-like type 4 was a novel type which was high similar to other piscidin 5-like types. Interestingly, the infection may well cause alternative splicing of LEAP-2A mRNA, which was a surprised phenomenon and finding after C. irritans infection, but more further study was needed to be conducted. Therefore, the data showed that these AMPs were involved in the immune response to the C. irritans infection. In all, these results implied that the immune response of AMPs to C. irritans infection was a complex and sophisticated regulatory process. PMID- 29408709 TI - Venoms of Neotropical wasps lack cross-reactive carbohydrate determinants enabling reliable protein-based specific IgE determination. PMID- 29408710 TI - Delayed release of chemokine CCL25 with bioresorbable microparticles for mobilization of human mesenchymal stem cells. AB - : Chemokines are guiding cues for directional trafficking of mesenchymal stem cells (MSC) upon injury and local chemokine delivery at injury sites is an up-to date strategy to potentiate and prolong recruitment of MSC. In this study we present the chemokine CCL25, also referred to as thymus-expressed chemokine, to mobilize human MSC along positive but not along negative gradients. We hence proceeded to design a biodegradable and injectable release device for CCL25 on the basis of poly(lactic-co-glycolic acid) (PLGA). The conducted studies had the objective to optimize PLGA microparticle fabrication by varying selected formulation parameters, such as polymer type, microparticle size and interior phase composition. We found that microparticles of DV,50~75 um and fabricated using end-capped polymers, BSA as carrier protein and vortex mixing to produce the primary emulsion yielded high chemokine loading and delayed CCL25 release. To determine bioactivity, we investigated CCL25 released during the microparticle erosion phase and showed that deacidification of the release medium was required to induce significant MSC mobilization. The designed PLGA microparticles represent an effective and convenient off-the-shelf delivery tool for the delayed release of CCL25. However, continuative in vivo proof-of-concept studies are required to demonstrate enhanced recruitment of MSC and/or therapeutical effects in response to CCL25 release microparticles. STATEMENT OF SIGNIFICANCE: With the discovery of chemokines, particularly CXCL12, as stimulators of stem cell migration, the development of devices that release CXCL12 has proceeded quickly in the last few years. In this manuscript we introduce CCL25 as chemokine to induce mobilization of human MSC. This study proceeds to demonstrate how selection of key formulation parameters of CCL25 loading into PLGA microparticles exerts considerable influence on CCL25 release. This is important for a broad range of efforts in in situ tissue engineering where the candidate chemokine and the delivery device need to be selected carefully. The use of such a cell-free CCL25 release device may provide a new therapeutic option in regenerative medicine. PMID- 29408711 TI - Phenotypic plasticity, canalization, and the origins of novelty: evidence and mechanisms from amphibians. AB - A growing number of biologists have begun asking whether environmentally induced phenotypic change--'phenotypic plasticity'--precedes and facilitates the origin and canalization of novel, complex phenotypes. However, such 'plasticity-first evolution' (PFE) remains controversial. Here, we summarize the PFE hypothesis and describe how it can be evaluated in natural systems. We then review the evidence for PFE from amphibians (a group in which phenotypic plasticity is especially widespread) and describe how phenotypic plasticity might have facilitated macroevolutionary change. Finally, we discuss what is known about the proximate mechanisms of PFE in amphibians. We close with suggestions for future research. As we describe, amphibians offer some of the best support for plasticity's role in the origin of evolutionary novelties. PMID- 29408712 TI - Protective effect of polysaccharides from Celluclast-assisted extract of Hizikia fusiforme against hydrogen peroxide-induced oxidative stress in vitro in Vero cells and in vivo in zebrafish. AB - Polysaccharides were extracted by Celluclast-assisted hydrolysis and ethanol precipitation from Hizikia fusiforme (HFPS), and their in vitro antioxidant effects were evaluated in Vero cells. HFPS contains 63.56+/-0.32% sulfate polysaccharides, which comprise fucose (53.53%), galactose (23.15%), glucose (5.95%), and xylose (17.37%). HFPS scavenged DPPH, alkyl, and hydroxyl radicals at IC50 values of 0.81+/-0.02, 0.25+/-0.02, and 0.21+/-0.03mg/mL, respectively. HFPS significantly reduced H2O2-induced cytotoxicity in Vero cells. Furthermore, HFPS reduced intracellular ROS levels, and H2O2-induced apoptosis. HFPS has a strong protective effect against H2O2-stimulated oxidative stress in vivo in zebrafish, and showed improved survival rate, decreased heart rate, and reduced ROS generation and cell death. These results suggest that HFPS may be useful as an antioxidant in medical and cosmetic industries. PMID- 29408713 TI - Synthesis, characterization, and in vitro cytotoxicity of fatty acyl-CGKRK chitosan oligosaccharides conjugates for siRNA delivery. AB - In this studies, three fatty acyl derivatives of CGKRK homing peptides were coupled successfully to chitosan oligosaccharides (COS) using sulfosuccinimidyl-4 (N-maleimidomethyl)cyclohexane-1-carboxylate sodium salt (sulfo-SMCC). The COS SMCC was prepared by direct coupling between COS and sulfo-SMCC in PBS (pH7.5) at RT for 48h. The structure of COS-SMCC and the three fatty acyl-CGKRK-SMCC-COS conjugates were characterized by FT-IR, 13C NMR, and SEM. The ability of three conjugates to condense siRNA into nanosized polyplexes and their efficacy in protecting siRNA from serum nucleases degradation were investigated. Among the investigated derivatives, S-CGKRK-COS showed higher siRNA binding affinity as compared to the P-CGKRK-COS and O-CGKRK-COS, respectively. At a ratio of 10:1, complete protection for siRNA from early enzymatic degradation was achieved. The polymers and the polymer/siRNA polyplexes showed negligible cytotoxicity on human breast cancer cell line MDA-MB-231 at all investigated ratios. However, the polyplexes prepared with palmitoyl and oleoyl derivatives at polymer concentration 10MUg/mL reduced the cell viability by 21.5% and 35%, respectively. The results of this study revealed the potential use of fatty acyl-CGKRK-COS as a siRNA carrier and confirmed the importance of incorporating a hydrophobic moiety into chitosan to improve its capacity in complexing with siRNA and protection from degradation. PMID- 29408714 TI - Effect of exercise training on left ventricular mechanics after acute myocardial infarction-an exploratory study. AB - BACKGROUND: Cardiac rehabilitation (CR) exercise training is beneficial after myocardial infarction (MI). Whilst the peripheral adaptations to training are well defined, little is known regarding the effect on left ventricular (LV) remodelling, particularly LV function. Efficient LV ejection and filling is achieved through deformation and rotation of the myocardium in systole and diastole - LV mechanics. The response of LV mechanics to CR exercise training in MI patients is unknown. METHODS: In this observational exploratory study, 36 (of 40 enrolled) male, MI patients completed either 10-weeks of twice-weekly gym based cardiovascular exercise at 60-80% VO2peak (n=18), or a non-exercise control period (n=18). Cardiopulmonary exercise testing and speckle tracking echocardiography were performed at baseline and 10 weeks. RESULTS: Compared to the non-exercise group, VO2peak improved with CR exercise training (Difference: +4.28 [95% CI: 1.34 to 7.23] ml.kg-1.min-1, P=0.01). Neither conventional LV structural or functional indices, nor LV global longitudinal strain, significantly changed in either group. In contrast, LV twist and twist velocity decreased in the exercise group and increased in the non-exercise group (Difference: -3.95 degrees [95% CI: -7.92 to 0.03 degrees ], P=0.05 and -19.2 degrees .s-1 [95% CI: -35.9 to -2.7 degrees .s-1], P=0.02, respectively). CONCLUSION: In MI patients who completed CR exercise training, LV twist and twist velocity decreased, whereas these parameters increased in patients who did not exercise. These preliminary data may indicate reverse LV functional remodelling and improved functional reserve. The assessment of LV twist may serve as an indicator of the therapeutic benefit of CR exercise training and should be investigated in larger trials. PMID- 29408715 TI - Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets. AB - BACKGROUND: The contribution of phenotypic variation of peanut-specific T cells to clinical allergy or tolerance to peanut is not well understood. OBJECTIVES: Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of subjects with and without peanut allergy (PA). METHODS: We obtained samples from patients with PA, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (Consortium of Food Allergy Research [CoFAR] 6). Subjects were confirmed as having PA, or if they passed a 1-g peanut challenge, they were termed high-threshold subjects. Healthy control (HC) subjects were also recruited. Peanut-responsive T cells were identified based on CD154 expression after 6 to 18 hours of stimulation with peanut extract. Cells were analyzed by using flow cytometry and single-cell RNA sequencing. RESULTS: Patients with PA had tissue- and follicle-homing peanut-responsive CD4+ T cells with a heterogeneous pattern of TH2 differentiation, whereas control subjects had undetectable T-cell responses to peanut. The PA group had a delayed and IL-2 dependent upregulation of CD154 on cells expressing regulatory T (Treg) cell markers, which was absent in HC or high-threshold subjects. Depletion of Treg cells enhanced cytokine production in HC subjects and patients with PA in vitro, but cytokines associated with highly differentiated TH2 cells were more resistant to Treg cell suppression in patients with PA. Analysis of gene expression by means of single-cell RNA sequencing identified T cells with highly correlated expression of IL4, IL5, IL9, IL13, and the IL-25 receptor IL17RB. CONCLUSIONS: These results demonstrate the presence of highly differentiated TH2 cells producing TH2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional TH2 response was more evident than a Treg cell deficit among peanut-responsive T cells. PMID- 29408717 TI - A smartphone application for dispatch of lay responders to out-of-hospital cardiac arrests. AB - BACKGROUND: Dispatch of lay volunteers trained in cardiopulmonary resuscitation (CPR) and equipped with automated external defibrillators (AEDs) may improve survival in cases of out-of-hospital cardiac arrest (OHCA). The aim of this study was to investigate the functionality and performance of a smartphone application for locating and alerting nearby trained laymen/women in cases of OHCA. METHODS: A system using a smartphone application activated by Emergency Dispatch Centres was used to locate and alert laymen/women to nearby suspected OHCAs. Lay responders were instructed either to perform CPR or collect a nearby AED. An online survey was carried out among the responders. RESULTS: From February to August 2016, the system was activated in 685 cases of suspected OHCA. Among these, 224 cases were Emergency Medical Services (EMSs)-treated OHCAs (33%). EMS witnessed cases (n = 11) and cases with missing survey data (n = 15) were excluded. In the remaining 198 OHCAs, lay responders arrived at the scene in 116 cases (58%), and prior to EMSs in 51 cases (26%). An AED was attached in 17 cases (9%) and 4 (2%) were defibrillated. Lay responders performed CPR in 54 cases (27%). Median distance to the OHCA was 560 m (IQR 332-860 m), and 1280 m (IQR 748 1776 m) via AED pick-up. The survey-answering rate was 82%. CONCLUSION: A smartphone application can be used to alert CPR-trained lay volunteers to OHCAs for CPR. Further improvements are needed to shorten the time to defibrillation before EMS arrival. PMID- 29408718 TI - Detection of delta-9-tetrahydrocannabinol (THC) in oral fluid, blood and urine following oral consumption of low-content THC hemp oil. AB - Hemp-derivative (Cannabis sativa L.) food products containing trace levels of Delta-9-tetrahydrocannabinol (THC) are proposed for consumption in Australia and New Zealand; however, it is unclear whether use of these products will negatively affect existing drug screening protocols. This double-blind, within-subjects, cross-over trial assessed 35 adults (17 male; 18 female), aged 22-52 years [Mean=30.7, Standard Deviation (S.D)+/-7.6]. Low dose THC oil [5mL bearer sesame oil containing 10mg/kg THC (0.046mg THC per 5mL dose)]; high dose THC oil [5mL bearer sesame oil containing 20mg/kg THC (0.092mg THC per 5mL dose)]; and a placebo oil (THC negative) was consumed during a three-week protocol. The Securetec Drugwipe(r) II Twin device assessed THC presence (cut-off 20ng/mL) in oral fluid at baseline, at 5, 30, 60, 120 and 240min post-treatment. Blood was drawn at baseline, 30, 120 and 240min post-treatment, and urine at baseline and 240min post-treatment. No THC was detected in oral fluid, blood or urine samples at any time-point following consumption of the low or high THC dose. Trace concentrations of 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid (THCa) were detected in blood 4-h after consumption of the high THC treatment (M=0.0001mg/L) and in urine at 4-h post consumption of both low and high THC treatments (M=0.0001mg/L and 0.0004mg/L, respectively). Consumption of low content THC oil does not result in positive biological assessments. It is therefore highly unlikely that ingestion of products containing these levels of THC will negatively impact existing region-specific drug driving enforcement protocols. PMID- 29408716 TI - Scanning Fiber Endoscope Improves Detection of 5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence at the Boundary of Infiltrative Glioma. AB - OBJECTIVE: Fluorescence-guided surgery with protoporphyrin IX (PpIX) as a photodiagnostic marker is gaining acceptance for resection of malignant gliomas. Current wide-field imaging technologies do not have sufficient sensitivity to detect low PpIX concentrations. We evaluated a scanning fiber endoscope (SFE) for detection of PpIX fluorescence in gliomas and compared it to an operating microscope (OPMI) equipped with a fluorescence module and to a benchtop confocal laser scanning microscope (CLSM). METHODS: 5-Aminolevulinic acid-induced PpIX fluorescence was assessed in GL261-Luc2 cells in vitro and in vivo after implantation in mouse brains, at an invading glioma growth stage, simulating residual tumor. Intraoperative fluorescence of high and low PpIX concentrations in normal brain and tumor regions with SFE, OPMI, CLSM, and histopathology were compared. RESULTS: SFE imaging of PpIX correlated to CLSM at the cellular level. PpIX accumulated in normal brain cells but significantly less than in glioma cells. SFE was more sensitive to accumulated PpIX in fluorescent brain areas than OPMI (P < 0.01) and dramatically increased imaging time (>6*) before tumor-to background contrast was diminished because of photobleaching. CONCLUSIONS: SFE provides new endoscopic capabilities to view PpIX-fluorescing tumor regions at cellular resolution. SFE may allow accurate imaging of 5-aminolevulinic acid labeling of gliomas and other tumor types when current detection techniques have failed to provide reliable visualization. SFE was significantly more sensitive than OPMI to low PpIX concentrations, which is relevant to identifying the leading edge or metastasizing cells of malignant glioma or to treating low-grade gliomas. This new application has the potential to benefit surgical outcomes. PMID- 29408719 TI - Diagnosis of electrocution: The application of scanning electron microscope and energy-dispersive X-ray spectroscopy in five cases. AB - INTRODUCTION: Deaths from electricity, generally, do not have specific findings at the autopsy. The diagnosis is commonly based on the circumstances of the death and the morphologic findings, above all the current mark. Yet, the skin injury due to an electrocution and other kinds of thermal injuries often cannot be differentiated with certainty. Therefore, there is a great interest in finding specific markers of electrocution. The search for the metallization of the skin through Scanning Electron Microscope equipped with Energy Dispersive X-Ray Spectroscopy (EDS) probe is of special importance in order to achieve a definite diagnosis in case of suspected electrocution. MATERIALS AND METHODS: We selected five cases in which the electrocution was extremely likely considering the circumstances of the death. In each case a forensic autopsy was performed. Then, the skin specimens were stained with Hematoxylin Eosin and Perls. On the other hand, the skin lesions were examined with a scanning electron microscope equipped with EDS probe in order to evaluate the morphological ultrastructural features and the presence of deposits on the surface of the skin. RESULTS: The typical skin injury of the electrocution (current mark) were macroscopically detected in all of the cases. The microscopic examination of the skin lesions revealed the typical spherical vacuoles in the horny layer and, in the epidermis, the elongation of the cell nuclei as well as necrosis. Perls staining was negative in 4 out 6 cases. Ultrastructural morphology revealed the evident vacuolization of the horny layer, elongation of epidermic cells, coagulation of the elastic fibers. EDS-MICROANALYSIS: In the specimens collected from the site of contact with the conductor of case 1 and 2, the presence of the Kalpha peaks of iron was detected. In the corresponding specimens taken from cases 2, 4, 5 the microanalysis showed the Kalpha peaks of titanium. In case 3, titanium and carbon were found. CONCLUSIONS: In the suspicion of electrocution, the integrated use of different tools is recommended, including macroscopic observation, H&E staining, iron-specific staining, scanning electron microscopy and EDS microanalysis. Only the careful interpretation of the results provided by all these methods can allow the pathologist to correctly identify the cause of the death. Particularly, the present study suggests that the microanalysis (SEM-EDS) represents a very useful tool for the diagnosis of electrocution, allowing the detection and the identification of the metals embedded in the skin and their evaluation in the context of the ultrastructural morphology. PMID- 29408720 TI - Development and validation of rapid and simultaneous method for determination of 12 hair-growth compounds in adulterated products by UHPLC-MS/MS. AB - Synthetic hair-growth compounds have been illegally used in diverse products to enhance the short-term efficacy of these products. In this study, a rapid and simultaneous method for the determination of hair-growth compounds in adulterated products based on ultra high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed and validated. The limit of detection (LOD) and limit of quantitation (LOQs) of the method were 0.08-43.6ng/mL and 0.27 145ng/mL for the solid-, liquid-, and cream-type samples, respectively. Good calibration linearity for all compounds was demonstrated with a correlation coefficient (r2) higher than 0.997. The intra- and inter-assay precisions were within 11%. The corresponding accuracies were 86-117% and 81-113%, respectively. The mean recoveries obtained for the solid-, liquid, and cream-type samples ranged from 87 to 114%, with a relative standard deviation (RSD) within 6%. The RSD of the stability evaluated at 4 degrees C for 48h was less than 6%. The established method was used to screen 76 samples advertised as hair-growth treatments, from online and offline markets, over the course of two years. In 10% of the samples, four compounds, including triaminodil, minoxidil, finasteride, methyltestosterone, and testosterone-propionate were detected. The concentrations were in the range of 0.5-16.4mg/g. This technique provides a reliable platform for technical analysis for continuous monitoring of adulterated products to protect public health. PMID- 29408721 TI - Fit for purpose quality management system for military forensic exploitation. AB - In a previous publication we described a systems approach to forensic science applied in the military domain. The forensic science 'system of systems' describes forensic science as a sub-system in the larger criminal justice, law enforcement, intelligence, and military systems, with quality management being an important supporting system. Quality management systems help to ensure that organisations achieve their objective and continually improve their capability. Components of forensic science quality management systems can include standardisation of processes, accreditation of facilities to national/international standards, and certification of personnel. A fit for purpose quality management system should be balanced to allow organisations to meet objectives, provide continuous improvement; mitigate risk; and impart a positive quality culture. Considerable attention over the last decades has been given to the need for forensic science quality management systems to meet criminal justice and law enforcement objectives. More recently, the need for the forensic quality management systems to meet forensic intelligence objectives has been considered. This paper, for the first time, discusses the need for a fit for purpose quality management system for military forensic exploitation. PMID- 29408722 TI - Is LSD toxic? AB - LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD's potential to cause psychological disturbance (bad trips) has been long understood, and has rarely been associated with accidental deaths and suicide. From a physiological perspective, however, LSD is known to be non-toxic and medically safe when taken at standard dosages (50-200MUg). The scientific literature, along with recent media reports, have unfortunately implicated "LSD toxicity" in five cases of sudden death. On close examination, however, two of these fatalities were associated with ingestion of massive overdoses, two were evidently in individuals with psychological agitation after taking standard doses of LSD who were then placed in maximal physical restraint positions (hogtied) by police, following which they suffered fatal cardiovascular collapse, and one case of extreme hyperthermia leading to death that was likely caused by a drug substituted for LSD with strong effects on central nervous system temperature regulation (e.g. 25i-NBOMe). Given the renewed interest in the therapeutic potential of LSD and other psychedelic drugs, it is important that an accurate understanding be established of the true causes of such fatalities that had been erroneously attributed to LSD toxicity, including massive overdoses, excessive physical restraints, and psychoactive drugs other than LSD. PMID- 29408723 TI - The distribution and redistribution of fentanyl & norfentanyl in post mortem samples. AB - This article compares 249 post mortem case reports that were positive for fentanyl/norfentanyl. All the cases were submitted to, and analyzed by, the toxicology department of the Office of the Chief Medical Examiner, Edmonton, Alberta, Canada. This study highlights the varied distribution of fentanyl in the body after death as a result of misadventure, i.e., these are accidental drug overdose cases as opposed to a study of analytical data resulting from fentanyl use/administration in a clinical environment and/or death as a result of suicide. Post mortem samples were collected from more than one anatomical site and analyzed for fentanyl and norfentanyl using liquid chromatography-tandem mass spectrometry. Ante-mortem samples were available in 4 of these cases and were also analyzed. Post mortem mean blood fentanyl concentrations were found to be 13.2ng/mL (femoral), 19.1ng/mL (iliac) and 42.0ng/mL (subclavian). For norfentanyl the mean concentrations were 4.6ng/mL (femoral), 4.6ng/mL (iliac) and 7.4ng/mL (subclavian). Mean vitreous fentanyl and norfentanyl concentrations were 10.8ng/mL and 3.5ng/mL respectively. Mean liver fentanyl and norfentanyl concentrations were found to be 185.5ng/g and 18.8ng/g respectively. This study demonstrates the importance of multi-site sample collection and subsequent analysis for a thorough post mortem toxicological investigation. The study also highlights the risks and limitations associated with the interpretation of post mortem analytical results concerning fentanyl. PMID- 29408724 TI - Disappearance of R/S-methamphetamine and R/S-amphetamine from human scalp hair after discontinuation of methamphetamine abuse. AB - Methamphetamine (MA) and amphetamine (AM) are widely abused drugs. These compounds contain a chiral center, and their enantiomers exhibit different pharmacologic, pharmacokinetic, and metabolic properties due to differences in binding affinities to their receptor sites. Until now, there was a lack of information on the decline in the concentration of drugs in hair after abstinence. A simple procedure for the chiral separation and determination of methamphetamine (MA) and its metabolite amphetamine (AM) enantiomers by LC-MS/MS in hair samples has been developed and fully validated. The LODs and LLOQs were 0.02ng/mg and 0.05ng/mg for all analytes, respectively. This method was successfully applied to both real hair specimens from chronic MA users and after the discontinuation of MA. The concentration of total MA, and total AM in fifty eight authentic hair specimens ranged from 7.8ng/mg to 521.0ng/mg, and from 0.3ng/mg to 84.0ng/mg, respectively. Both enantiomers of MA and/or AM were detected in seven of fifty-eight authentic hair specimens. Hair specimens were from thirteen women with a known history of MA abuse, who went to a rehabilitation center and ceased consuming MA (for 4-5 months). The S-isomers of MA and AM were detected in all the 5-6cm segments. Both enantiomers of MA were detected in nine of the 5-6cm segments and the enantiomers of AM were found in only five of the nine samples. Assuming a hair growth rate of 1cm/month, the mean hair elimination half-lives of S-MA, R-MA, S-AM, and R-AM were 0.64(95% CI, 0.46 0.96), 0.58(95% CI, 0.41-0.93), 0.62(0.49-0.88), and 0.50 months (95% CI, 0.42 0.56), respectively. With the developed method, R/S-MA and R/S-AM could be detected in the hair of former drug users for approximately 4 months after abstinence. S-MA is the most commonly found analyte in hair segments and is principally used by abusers. Our results suggest that to evaluate the discontinuation of MA abuse after a 6-month period of abstinence, a 3-cm proximal hair segment should be free of MA at the SOHT proposed cut-off level. PMID- 29408725 TI - Assessment of adulthood in the living Spanish population based on ossification of the medial clavicle epiphysis using ultrasound methods. AB - It is a fact that in recent years requests have greatly increased to obtain estimates of the legal age of undocumented individuals alleged to be minors who have been forced to enter different European Community countries for socioeconomic reasons or due to war. Spain is one of the countries most affected by this illegal immigration because of its proximity to North Africa. Therefore, it has become necessary to develop new standards which help provide a response to the demands of the justice administration. In recent years, the Superior Justice Court has rejected several pieces of expert evidence on the grounds that the age intervals therein were not sufficiently reliable and that the radiographic techniques used to determine age were invasive, potentially causing harm to the alleged minor. These sentences have caused interest in this field of work to increase within the scientific community. As a result, in order to improve age predictions and, above all, reduce minors' exposure to radiation, this study was created for completion on the Spanish population, using the ultrasound scan as a diagnostic technique. Used as a study sample were the ultrasound images of the proximal sternal epiphysis of the clavicle among 221 individuals of both sexes, of ages ranging from 5 to 30 years. All of the images were classified into 4 stages of fusion, in accordance with the development of metaphyseal closure proposed by Schulz et al. in 2008. The results show differences among the 4 proposed groups for each of the stages of fusion, with the results found in Stage II being especially important because, for both sexes, they would imply that the patient studied has reached an age of over 18 years, which is the legal age of adulthood in Spain, as established by the Spanish Constitution of 1978. Though further research is still recommended, these results, coupled with the use of ultrasound as a non-invasive diagnostic technique, could help solve some of the problems currently arising in justice courts. PMID- 29408726 TI - Forensic genetic analysis of bone remain samples. AB - DNA typing from degraded human remains is still challenging forensic DNA scientists not only in the prospective of DNA purification but also in the interpretation of established DNA profiles and data manipulation, especially in mass fatalities. In this report, we presented DNA typing protocol to investigate many skeletal remains in different degrees of decomposing. In addition, we established the grading system aiming for prior determination of the association between levels of decomposing and overall STR amplification efficacy. A total of 80 bone samples were subjected to DNA isolation using the modified DNA IQTM System (Promega, USA) for bone extraction following with STR analysis using the AmpFLSTR Identifiler(r) (Thermo Fisher Scientific, USA). In low destruction group, complete STR profiles were observed as 84.4% whereas partial profiles and non-amplified were found as 9.4% and 6.2%, respectively. Moreover, in medium destruction group, both complete and partial STR profiles were observed as 31.2% while 37.5% of this group was unable to amplify. Nevertheless, we could not purify DNA and were unable to generate STR profile in any sample from the high destroyed bone samples. Compact bones such as femur and humerus have high successful amplification rate superior than loose/spongy bones. Furthermore, costal cartilage could be a designate specimen for DNA isolation in a case of the body that was discovered approximately to 3 days after death which enabled to isolate high quality and quantity of DNA, reduce time and cost, and do not require special tools such as freezer mill. PMID- 29408728 TI - Impact of carpet construction on fluid penetration: The case of blood. AB - Bloodstains and bloodstain patterns are often observed at crime scenes and their analysis through bloodstain pattern analysis (BPA) can assist in reconstructing crime scenes. However, most published work related to BPA only deals with hard, non-porous surfaces and none of the studies have carefully characterized carpets. Soft and porous carpets are often encountered at crime scenes since they are common in American homes accounting for 51% of total U.S. flooring market; this has motivated the research described herein. To assess fluid penetration into tufted carpers, a new method for determining porosity and pore size distribution in tufted carpets has been developed for bloodstains on carpet. In this study, three kinds of nylon carpet were used: a low, a medium and a high face-weight carpet. Each carpet had an antistain treatment, which was removed from half of each carpet by steam-cleaning with a pH 12 NaOH solution. This resulted in six carpet samples. Yarn twist, carpet weight, pile height, water contact angles on carpets, water contact angles on individual fibers, and fiber cross-sectional shapes were characterized. Porosity and pore size distribution were analyzed using confocal laser scanning microscopy (CLSM). Porcine blood was used as a human blood substitute at three liquid volumes (30MUL, 10MUL, and 2MUL). Analysis showed that porous carpet construction and antistain finishing both affected penetration. The depth of blood penetration decreased with the increase of carpet face-weight but increased with increased drop height. The removal of antistain treatment increased blood penetration into the carpets and changed the pore size distribution. Effects of antistain treatment, porosity and pore size distribution of tufted carpet, and blood wicking behaviors on carpets were found to strongly affect blood penetration into the carpets. PMID- 29408727 TI - Establishing state of motion through two-dimensional foot and shoe print analysis: A pilot study. AB - According to the College of Podiatry, footprints rank among the most frequent forms of evidence found at crime scenes, and the recent ascension of forensic podiatry reflects the importance of footwear and barefoot traces in contemporary forensic practice. In this context, this pilot study focused on whether it is possible to distinguish between walking and running states using parameters derived from two-dimensional foot or shoe prints. Eleven subjects moved along four tracks (barefoot walking; barefoot running; footwear walking; footwear running) while having their bare feet or footwear stained with artificial blood and their footstep patterns recorded. Contact stains and associated bloodstain patterns were collected, and body movements were recorded through three dimensional motion capture. Barefoot walking prints were found to be larger than barefoot static prints (1.789+/-0.481cm; p<0.001) and barefoot running prints (0.635+/-0.405cm; p=0.006). No correlation was observed for footwear prints. Running trials were more associated with the presence of both passive and cast off stains than walking trials, and the quantity of additional associated stains surrounding individual foot and shoe prints was also higher in running states. Furthermore, a previously proposed equation predicted speed with a high degree of accuracy (within 6%) and may be used for clinical assessment of walking speed. Contact stains, associated bloodstain patterns and stride length measurements may serve to ascertain state of motion in real crime scene scenarios, and future studies may be capable of designing statistical frameworks which could be used in courts of law. PMID- 29408729 TI - Analysis of illicit drugs seized in the Province of Florence from 2006 to 2016. AB - Comprehension of illicit drug market's features at local level is useful to plan and to correctly set-up specific informative and contrast activities. In this paper we report trends, purities and consumption estimations of illicit substances available on the Florentine territory from 2006 to 2016. These data were obtained by the analysis of 10,451 samples seized by the Law Enforcement Agencies in case of personal use offence. Analytical procedures consisted in targeted and untargeted analyses by gas chromatography-flame ionization detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. The most detected substances were: cannabis (78.0%; resin: 51.7%; herb: 26.3%), cocaine (10.4%), opiates (6.6%; heroin: 6.5%; morphine: 0.1%), ketamine (1.4%), amphetamines (1.3%; 3,4-methylenedioxymethamphetamine - MDMA -: 0.7%; methamphetamine: 0.6%; amphetamine: <0.1%) and methadone (1.3%). Cocaine, heroin and methamphetamine purities were higher than their mean values estimated for the Italian and European market, while THC content in cannabis seizures was unexpectedly below the European mean values. Starting from 2015, a total of 5 new psychoactive substances (NPS) were detected in seized material, mainly composed of white powders (pentedrone, 3-methylmethcathinone, 4-fluoroamphetamine, methoxethamine and AB-FUBINACA). Most of the seizures (75.5%) were from young male adults (14-34 years old). These data contribute to highlight new trends in the illicit drug market in the Tuscany area, but also to verify the persistence of old habits of drug consumption, confirming the need for more effective counteraction and prevention plans, especially among young people, where the diffusion of the legal highs is worrisome, also in consideration of the young age and the unconsciousness of the possible health effects. PMID- 29408730 TI - Potential effects of ionizing radiation on the evidentiary value of DNA, latent fingerprints, hair, and fibers: A comprehensive review and new results. AB - An extensive literature review and new post-irradiation experimental results are presented of genotyping blood stains and hair, and physical examinations of latent fingerprints, hairs, and fibers. Results indicate that successful development of nuclear short tandem repeat (STR) and mitochondrial DNA sequence profiles from human blood and hair evidence is possible-up to a point-following exposure to gamma, neutron, beta, and alpha radiation at several levels that would most likely be present at this type of crime scene (i.e., a "dirty bomb," etc.). Commencing at gamma radiation levels between 90 and 900kGy, DNA analysis using conventional DNA techniques was unsuccessful. In general, irradiation negatively affected the quality of latent fingerprints. All four radiation types degraded most fingerprint samples at all doses; nevertheless, many fingerprints remained of value for potential use in comparison. Although variable from one hair to another, microscopic changes observed for all types and levels of irradiation could potentially result in false exclusions. Negligible microscopic changes were observed in papers and fibers (used as substrates for fingerprints and bloodstains) up to 90kGy gamma, but fluorescence of fibers began to change above that dose. Paper and fibers, as well as plastic evidence enclosures, became extremely brittle leading to breakage after a gamma dose of 900kGy. PMID- 29408731 TI - Neuronal-specific impairment of heparan sulfate degradation in Drosophila reveals pathogenic mechanisms for Mucopolysaccharidosis type IIIA. AB - Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder resulting from the deficit of the N-sulfoglucosamine sulfohydrolase (SGSH) enzyme that leads to accumulation of partially-degraded heparan sulfate. MPS IIIA is characterized by severe neurological symptoms, clinically presenting as Sanfilippo syndrome, for which no effective therapy is available. The lysosomal SGSH enzyme is conserved in Drosophila and we have identified increased levels of heparan sulfate in flies with ubiquitous knockdown of SGSH/CG14291. Using neuronal specific knockdown of SGSH/CG14291 we have also observed a higher abundance of Lysotracker-positive puncta as well as increased expression of GFP tagged Ref(2)P supporting disruption to lysosomal function. We have also observed a progressive defect in climbing ability, a hallmark of neurological dysfunction. Genetic screens indicate proteins and pathways that can functionally modify the climbing phenotype, including autophagy-related proteins (Atg1 and Atg18), superoxide dismutase enzymes (Sod1 and Sod2) and heat shock protein (HSPA1). In addition, reducing heparan sulfate biosynthesis by knocking down sulfateless or slalom expression significantly worsens the phenotype; an important observation given that substrate inhibition is being evaluated clinically as a treatment for MPS IIIA. Identifying the cellular pathways that can modify MPS IIIA neuropathology is an essential step in the development of novel therapeutic approaches to prevent and/or ameliorate symptoms in children with Sanfilippo syndrome. PMID- 29408732 TI - Polymorphism rs2476601 in the PTPN22 gene is associated with type 1 diabetes in children from the South Region of Brazil. PMID- 29408733 TI - Bioinformatics analysis of non-synonymous variants in the KLF genes related to cardiac diseases. AB - Kruppel-like Factors (KLF) are responsible for regulating many genes involved in physiological and pathological processes. They are characterized by three conserved zinc-fingers in the DNA-binding domain, wherein mutations could affect the binding efficiency and transcription regulation. This study aimed to perform bioinformatics analysis to determine the most deleterious non-synonymous variants in KLFs involved in cardiac development and diseases, and their effects over the protein structure and stability. Eight hundred and fifty non-synonymous variants were found in seven KLFs related to cardiac diseases. Seventeen algorithms were used to predict the effect of selected variants over the structure and function of seven KLFs. The Top3 variants were selected in each category of conserved and non-conserved residues in the zinc-finger (ZF) domain. KLF5 p.Cys410Phe was the only variant predicted as deleterious in all algorithms, occurring in a conserved residue of zinc ion interaction. KLF15 p.Arg364Pro was the only variant predicted to affect the DNA-binding, and also occurs in a conserved ZF-domain. Our bioinformatics analysis determined potential variants that may lead to development of cardiac diseases, as well as reinforced the importance of KLF analysis in vitro and in vivo. PMID- 29408734 TI - Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats. AB - Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI. PMID- 29408735 TI - Lithium doped silica nanospheres/poly(dopamine) composite coating on polyetheretherketone to stimulate cell responses, improve bone formation and osseointegration. AB - Osseointegration is crucial for early fixation as well as long-term success of orthopedic implants. Bioactive composite containing lithium doping silica nanospheres (LSNs) and poly(dopamine) (PDA) were coated on polyetheretherketone (PK) surface (LPPK), and effects of the LSNs/PDA composite (LPC) coating on the biological properties of LPPK were assessed both in vitro and in vivo. Results showed that LPPK with improved bioactivity remarkably promoted apatite mineralization in simulated body fluid (SBF) compared with PDA coated on PK (PPK) and PK. Moreover, the LPPK remarkably stimulated rat bone marrow stromal cells (rBMSCs) responses compared with PPK and PK. Furthermore, the LPPK significantly promoted bone tissues responses in vivo compared with PPK and PK. It could be suggested that the improvements of cells and bone tissues responses were attributed to the surface characteristics of the bioactive LPC coating on LPPK. The LPPK would be a great candidate for orthopedic and dental applications. PMID- 29408736 TI - Diagnostic Evaluation, Comorbidity Screening, and Treatment of Polycystic Ovary Syndrome in Adolescents in 3 Specialty Clinics. AB - STUDY OBJECTIVE: A polycystic ovary syndrome (PCOS) diagnosis in adolescence can have significant long-term health implications. The criteria for its diagnosis in adolescents have been subject to much debate. In this study we aimed to characterize the variability in diagnosis and management among different pediatric specialties. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: This was a retrospective review of electronic medical records of female patients (11-21 years old) who presented to 3 specialties (adolescent medicine [ADO], pediatric endocrinology [ENDO], and gynecology [GYN]), with a postvisit diagnosis of PCOS, menstrual disorders, or hirsutism, at a large tertiary care center, from November 1, 2011 to October 31, 2012. Demographic, clinical, laboratory, and treatment data were abstracted. MAIN OUTCOME MEASURES: Testing for diagnosis of PCOS and its comorbidities, and treatment strategies in the 3 pediatric specialties. RESULTS: One hundred forty-one patients (50 ADO, 48 ENDO, and 43 GYN) were eligible. Testing for hyperandrogenemia (17-hydroxy-progesterone, dehydroepiandrosterone, estradiol), thyroxine, and use of pelvic ultrasound differed among specialties. Providers failed to document weight concerns in 28.3% (29 of 101) of overweight or obese patients. Patients seen by ENDO were most likely, and GYN least likely, to be identified as having elevated weight, and to be tested for glucose abnormalities, dyslipidemia, and liver disease. ENDO providers prescribed metformin more often and hormonal therapy less often than ADO and GYN. CONCLUSION: There is considerable variability across pediatric specialties in the evaluation of PCOS, with significant underassessment of comorbidities. Use of unified guidelines, including for the evaluation of comorbidities, would improve evidence-based management of adolescent PCOS. PMID- 29408738 TI - Prevalence and genotypes of human papillomavirus in saliva and tumor samples of head and neck cancer patients in Hungary. AB - In addition to traditional risk factors such as smoking, alcohol consumption and betel nut use, human papillomavirus (HPV) infection also plays a role in the development of head and neck squamous cell carcinomas (HNSCCs). Although among European countries the highest incidence and mortality rates of head and neck cancer types were recorded in Hungary, data regarding HPV prevalence in HNSCCs is scarce. We collected biopsy and saliva samples from patients diagnosed with HNSCC or oral potentially malignant disorders (OPMDs) and tested them for the presence of HPV using the PCR consensus primer set MY09/11 and the GP5+/6+ primer pair. HPV genotypes were assessed by sequencing of the amplified PCR fragments. Oral mucosa and saliva samples from tumor- and OPMD-free individuals were also analysed. HPV was detected in 11 out of 60 HNSCC samples (18%). All of the HPV positive tumors carried HPV type 16. 5 out of the 57 saliva samples collected from HNSCC patients was HPV positive (8.8%); among them, in addition to HPV16, HPV13 was also detected. Tumors located to the oropharynx had the highest HPV positivity rate with 50% (7 out of 14), which was significantly higher than the HPV prevalence in oral mucosa samples collected from controls (0 out of 20; p > 0.001) or in OPMD biopsies (0 out of 21, p > 0.001). 2 out of 57 control saliva samples (3.5%, subtype HPV13 and 11) and 3 out of 39 saliva samples from OPMD patients (7.7%, subtype HPV18, 81 and 10) were HPV positive. Our data suggested that HPV16 infection may contribute, in concert with cigarette smoking, to the development of a subset of head and neck cancers in Hungary. HPV16 infection per se does not account, however, for the high HNSCC incidence rate recorded in this country. PMID- 29408737 TI - A nationwide survey of intravenous antimicrobial use in intensive care units in Japan. AB - Although most patients in the intensive care unit (ICU) receive antibiotics, little is known about patterns of antibiotic use in ICUs in Japan. The objective of this study was to evaluate the pattern of antibiotic use in ICUs. A nationwide one-day cross-sectional surveillance of antibiotic use in the ICU was conducted three times between January 2011 and December 2011. All patients aged at least16 years were included. Data from 52 ICUs and 1148 patients were reviewed. There were 1028 prescriptions for intravenous antibiotics. Of 1148 patients, 834 (73%) received at least one intravenous antibiotic, and 575 had at least one known site of infection. Respiratory and intra-abdominal infections were the two most common types. Of 1028 prescriptions, 331 (34%) were for surgical or medical prophylaxis. Excluding prophylaxis, carbapenems were the most commonly prescribed agent. Infectious disease consultations, pre- and post-prescription antimicrobial stewardship, and ICU-dedicated antibiograms were available in 44%, 52%, 77%, and 21% of the ICUs, respectively. In logistic regression analysis adjusting for patient characteristics, treatment in a university hospital (adjusted odds ratio, 1.72; 95% CI, 1.05-2.84; P = 0.033) and an open ICU (adjusted odds ratio, 2.30; 95% CI, 1.02-5.17; P = 0.044) were significantly associated with greater likelihood of carbapenem use. An increase in the number of closed ICUs and more intensive care specialists may reduce carbapenem use in Japanese ICUs. Large scale epidemiological studies of antimicrobial resistance in the ICU are needed. PMID- 29408739 TI - Planned home versus planned hospital births in women at low-risk pregnancy: A systematic review with meta-analysis. AB - New interest in home birth have recently arisen in women at low risk pregnancy. Maternal and neonatal morbidity of women planning delivery at home has yet to be comprehensively quantified. We aimed to quantify pregnancy outcomes following planned home (PHB) versus planned hospital birth (PHos). We did a systematic review of maternal and neonatal morbidity following planned home (PHB) versus planned hospital birth (PHos). We included prospective, retrospective, cohort and case-control studies of low risk pregnancy outcomes according to planning place of birth, identified from January 2000 to June 2017. We excluded studies in which high-risk pregnancy and composite morbidity were included. Outcomes of interest were: maternal and neonatal morbidity/mortality, medical interventions, and delivery mode. We pooled estimates of the association between outcomes and planning place of birth using meta-analyses. The study protocol is registered with PROSPERO, protocol number CRD42017058016. We included 8 studies of the 4294 records identified, consisting in 14,637 (32.6%) in PHB and 30,177 (67.4%) in PHos group. Spontaneous delivery was significantly higher in PHB than PHos group (OR: 2.075; 95%CI:1.654-2.063) group. Women in PHB group were less likely to undergo cesarean section compared with women in PHos (OR:0.607; 95%CI:0.553 0.667) group. PHB group was less likely to receive medical interventions than PHos group. The risk of fetal dystocia was lower in PHB than PHos group (OR:0.287; 95%CI:0.133-0.618). The risk of post-partum hemorrhage was lower in PHB than PHos group (OR:0.692; 95% CI.0.634-0.755). The two groups were similar with regard to neonatal morbidity and mortality. Births assisted at hospital are more likely to receive medical interventions, fetal monitoring and prompt delivery in case of obstetrical complications. Further studies are needed in order to clarify whether home births are as safe as hospital births. PMID- 29408740 TI - Responsiveness of the Golombok Rust Inventory of Sexual Satisfaction in couples with incontinent partners. AB - OBJECTIVE: In order for a measure to reliably evaluate treatment efficacy, it is important that the measure used has adequate responsiveness. However, the responsiveness of the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire, a highly recommended questionnaire by the International Consultation of Incontinence to assess sexual function in patients with incontinence, has not been established. To enable the use of GRISS to measure change in sexual function following incontinence treatment, we evaluated the short- and long-term responsiveness of the GRISS in couples with female stress urinary incontinence partners. STUDY DESIGN: Forty-eight couples with female stress urinary incontinence partners were included in the study. The GRISS, a 28 item multidimensional measure, comprises two sets of questionnaires to assess sexual function in both male and female partners. Responsiveness was investigated using data from our recent randomized controlled trials evaluating efficacy of pulsed magnetic stimulation for treatment of female patients with stress urinary incontinence. Effect size index and standardized response mean were used to measure responsiveness of the English and Chinese versions of GRISS. RESULTS: For short-term responsiveness, the overall female and male GRISS scores had effect sizes and standardized response means ranging from 0.60 to 0.83 and 0.44 to 0.78 respectively. For long-term responsiveness, the overall female and male GRISS scores had effect sizes and standardized response means ranging from 0.59 to 0.77 and 0.48 to 0.79 respectively. CONCLUSION: In conclusion, the English and Chinese versions of GRISS had adequate responsiveness for use in couples with incontinent partners. The GRISS can be a useful measure to detect change in sexual function of couples following treatment of females with stress urinary incontinence. PMID- 29408741 TI - A Swedish population-based evaluation of benign hysterectomy, comparing minimally invasive and abdominal surgery. AB - OBJECTIVE: The aim was to evaluate surgical routes for benign hysterectomy in a Swedish population, including abdominal and minimally invasive surgery. STUDY DESIGN: Prospectively collected data from the Swedish National GynOp Registry 2009-2015: 13 806 hysterectomy cases were included: abdominal (AH, n = 7485), vaginal (VH, n = 3767), conventional laparoscopic (LH, n = 1539) and robotically assisted (RAH, n = 1015). RESULTS: The VH group had the shortest operation time at 75 min, AH 97 min and RAH 104 min. LH was longest at 127 min (p < 0.005). The mean estimated blood loss was higher in the AH group (250 ml) compared to all minimally invasive surgery (MIS, 65-172 ml); p < 0.005). Conversion rates were 10% for LH, 4.8% for VH and 1.6% for RAH (p < 0.005). Hospitalization and patient reported time to normal activities of daily living (ADL) were longer for AH compared to MIS (p < 0.005). Time to return to work was eight days longer in the AH group (35 days) compared with the MIS groups (p < 0.005). Complications were fewest in the VH group at 5.4% compared with AH 7.6% and RAH 8.7% (both p < 0.001), but did not significantly differ from the LH group at 6.6%. Overall patient satisfaction was reported to be 86-94% one year after surgery. CONCLUSION: Women operated on for benign hysterectomy with minimally invasive methods in Sweden 2009-2015 had reduced length of hospitalization, as well as time to resuming normal ADL and return to work, compared to AH. Postoperative outcome measures were improved by minimally invasive methods and MIS should preferably be used. PMID- 29408742 TI - Role of Lh polymorphisms and r-hLh supplementation in GnRh agonist treated ART cycles: A cross sectional study. AB - STUDY OBJECTIVES: To investigate the effect of N312S polymorphism in the LHCGR gene as a predictive pharmacogenetic marker on clinical and embryological parameters and determining the need of r-hLH supplementation combine with r-hFSH in patients undergoing ART treatment. STUDY DESIGN: In a cross-sectional study, a retrospective analysis of women (n = 553), who underwent controlled ovarian stimulation treatment protocol was conducted during the years 2012-2014. R-hFSH (Gonal-F, Merck Serono) was administered to all patients undergoing ART cycle after initiating long luteal gonadotrophin-releasing hormone (GnRH) agonist down regulation. R-hLH was supplemented based on P.C. Wong criteria. N312S genotype was determined using sequencing methodology. The mean r-hFSH, r-hLH doses, total number of oocytes, cleavage rates of embryos and clinical pregnancy were recorded. The association between the r-hLH supplementation and LHCGR N312S polymorphism and clinical pregnancy rates was determined using regression analysis by SPSS. RESULTS: 19.7% of women were homozygous for A allele encoding asparagine (N/N), 45.7% were heterozygous (N/S) and 34.6% were homozygous (S/S) for G allele encoding serine. Women heterozygous (N/S) or homozygous (S/S) for serine showed a higher requirement for r-hLH (OR, 95% p-trend = <0.0001) compared to those homozygous for asparagine (N/N). Homozygous G allele was also associated with higher daily and total r-hLH dose per treatment cycle p-trend = <0.0001. Though, the total no of oocytes (14.87 +/- 4.95 vs 12.98 +/- 5.39 and 13.58 +/- 5.45), Gr-I quality embryos (2.61 +/- 1.81 vs 2.18 +/- 1.96 and 1.98 +/- 2.05) were significantly higher in women homozygous for A allele compared to women with heterozygous and homozygous for G allele, clinical pregnancy rates were significantly more in women with for G allele after excluding patients with PCOS and endometriosis conditions (P < 0.04). CONCLUSION: The present findings reveal that women heterozygous and homozygous for G allele required higher doses of r hLH supplementation and these women were shown to have higher clinical pregnancy rates. PMID- 29408743 TI - Tumor necrosis factor alpha versus LH and androstendione as a reliable predictor of spontaneous ovulation after laparoscopic ovarian drilling for women with clomiphene citrate resistance polycystic ovarian disease. AB - OBJECTIVE: Laparoscopic ovarian drilling (LOD) is still a controversial decision; due to the long term hazards; so short and long term predictors after the procedure should be taken in consideration. The aim of this work was to investigate the role of the serum level of tumor necrosis factor alpha (TNF alpha) and other polycystic ovarian disease (PCOD) relevant clinical and biochemical factors as a predictor of spontaneous ovulation after laparoscopic ovarian drilling (LOD) in women with clomiphene citrate resistant polycystic ovarian disease (CCR-PCOD). METHODS: It was a prospective research work, where 150 infertile women with CCR-PCOD had been recruited. TNF-alpha serum level, which is an inflammatory biomarker, was investigated in addition to other PCOD relevant clinical and biochemical parameters as possible predictors of successful spontaneous ovulation and subsequent pregnancy after LOD. RESULTS: Recruited women with higher preoperative levels of TNF-alpha, LH, and androstenedione had significantly higher rates of spontaneous ovulation within the first three months follow up after LOD, in contrast to obese women with BMI >= 25 kg/m2, long duration of infertility >=3 years, marked biochemical hyperandrogenism (testosterone levels >=4.5 nmol/L, free androgen index >=15), and high insulin resistance (IR). Ninty five (95 = 63.3%) women in between women regularly menstruated (105 = 70%) had spontaneous ovulation, and of those spontaneously ovulated, 35(36.8%) women got pregnant spontaneously during the first 3 months follow up. Extended follow up for 12 months period revealed that 61 women got pregnant, with cumulative pregnancy rate of 58%. Logistic regression showed that the best cut-off values for spontaneous ovulation after LOD were 65.1 pg/ml, 11.5 IU/l, and 3.1 ng/ml and with a sensitivity of 91%, 88%, 55%, and with a specificity of 85%, 79%, 78%, for TNF-alpha, LH, androstenedione serum level respectively. CONCLUSION: TNF-alpha, LH, and Androstenedione could be considered as reliable predictors to depend on for recruiting the ideal women candidates with CCR-PCOD; to have the maximum benefits after LOD treatment option. PMID- 29408744 TI - The use of antenatal fetal magnetic resonance imaging in the assessment of patients at high risk of preterm birth. AB - Preterm birth, defined as birth occurring prior to 37 weeks gestation is a common obstetric complication affecting 8% of pregnancies and is associated with significant morbidity and mortality. Infection/inflammation has been implicated in both the aetiology of preterm birth itself and associated neonatal pulmonary and neurological morbidity. Treatment options are currently limited to prolongation of the pregnancy using cervical cerclage, pessaries or progesterone or administration of drugs including steroids to promote lung maturity and neuroprotective agents such as magnesium sulphate, the timing of which are highly critical. Although delivery is expedited in cases of overt infection, decisions regarding timing and mode of delivery in subclinical infection are not clear-cut. This review aims to explore the use of magnetic resonance imaging (MRI) in the antenatal assessment of pregnancies at high risk of preterm birth and its potential to guide management decisions in the future. PMID- 29408745 TI - Should the visceral peritoneum be closed over mesh in abdominal sacrocolpopexy? AB - INTRODUCTION AND HYPOTHESIS: Peritonisation of mesh during Abdominal sacrocolpopexy is generally advocated to prevent adhesions to the viscera; however, randomized clinical trials are lacking. In this study; we aimed to investigate whether the mesh peritonisation is clinically significant or not. MATERIAL METHOD: Thirty-four patients who were operated for the reason of pelvic organ prolapse were included in the study. Patients were divided into two groups by retrospective scanning from the files and surgical reports. Group 1 patients consisted of those who underwent peritonisation and group 2 patients consisted of those who did not in abdominal sacrocolpopexy. RESULTS: Operative time and the amount of blood lost were statistically less in the group 2. Postoperative pain and analgesic drug requirements were obviously higher in the group 1. Postoperative De novo dyspareunia and urinary urgency were higher in the group 1. There were no statistical differences between the groups in terms of other complications. CONCLUSION: We noticed that there was no difference between the patients who were peritonized and those who were not in terms of postoperative complications. PMID- 29408746 TI - Prevalence and risk factors for urinary tract infection up to one year following midurethral sling incontinence surgery. AB - OBJECTIVE: To investigate the prevalence and risk factors of urinary tract infection (UTI) one year following sub-midurethral sling (SMUS) incontinence surgery in a university affiliated medical center in southern Israel. METHODS: A retrospective cohort study was conducted to identify and characterize patients who suffered UTI within a year following SMUS surgery. The study population comprised of all patients who underwent a SMUS surgery between the years 2014 and 2015. Demographic and clinical data were retrieved from the patients' medical records, and a comparison between patients with and without a positive urine culture was performed. RESULTS: During the study period, there were 178 SMUS surgeries. Urine culture positive UTI was noted in 21% (38 patients) within the first year following surgery. The mean age and BMI of patients complicated with UTI was 64.8 and 29.1, respectively. The most common pathogen found in urine culture was E. coli that accounted for 55% of all UTIs. When comparing patients with and without UTI, no significant difference was noted in the pre- and intra operative characteristics. However, duration of hospitalization and readmissions in the first year following surgery, were significantly associated with the risk of UTI (p < 0.026 and p < 0.003, respectively). CONCLUSIONS: Approximately one in every five women undergoing a SMUS operation in our population will suffer from UTI within a year from surgery. A significant association was found between the duration of hospitalization and readmissions in the first postoperative year and suffering from UTI. PMID- 29408747 TI - Risk factors for ovarian involvement in young and premenopausal endometrioid endometrial cancer patients. AB - OBJECTIVE: This study aimed to investigate the incidence of ovarian malignant involvement in young and premenopausal endometrioid endometrial cancer and study the possible risk factors. METHODS: Premenopausal patients 45 years of age or younger with endometrioid endometrial cancer treated at the OB/GYN Hospital of Fudan University between 2009 and 2013 were identified. The incidence of ovarian malignant involvement in young and premenopausal endometrioid endometrial cancer patients were calculated and the possible risk factors were investigated. RESULTS: A total of 144 younger (age <= 45, premenopausal) patients with endometrioid endometrial cancer were identified and coexisting malignant ovarian neoplasms were detected in 6 patients. Univariate analysis revealed that deeper myometrial invasion, positive lymphonode metastasis, positive LVSI, and high histologic grade (G2-G3) were associated with ovarian involvement in younger endometrial cancer patients. However, multivariate analysis revealed that only deep myometrial invasion was an independent risk factors for ovarian involvement (OR = 12.81, P = 0.046). CONCLUSION: In conclusions, the incidence of coexisting ovarian malignant neoplasms in young and premenopausal patients with endometrioid endometrial cancer is low, and these findings may facilitate preoperative counseling of patients and decision making at the time of surgery. PMID- 29408748 TI - Comparison of outcomes between induction of labor and spontaneous labor for term breech - A systemic review and meta analysis. AB - OBJECTIVES: Few studies have assessed the impact of induction of labor on breech presentation. This study aims to summarize the effect of induction of labor of breech presentation on perinatal morbidity. METHODS: Literature review was done in Medline, Embase, Web of science and Cochrane Library up to 20 October 2017. Randomized control studies, cohort studies, and case control publishing studies comparing induction of labor versus spontaneous labor of singleton live breech birth were included. Perinatal morbidity was calculated by RevMan 5 and presented by pooled odds ratio with 95% confidence intervals. RESULTS: Cesarean section rate and neonatal intensive care unit admission were increased in induction of breech labor as compared with spontaneous breech labor. No significant difference in umbilical cord blood base excess <= -12 mmol/L, Apgar 5 min < 7, Apgar 5 min < 4, umbilical cord blood PH < 7, neonatology unit admission, maternal fever, and intrapartum stillbirth between the two groups was found. CONCLUSIONS: Induction of breech labor has higher cesarean section rate and NICU perinatal morbidity compared to spontaneous breech labor. The neonatal outcomes were otherwise similar across both groups. Eligibility for induction of breech labor needs to be assessed carefully according to individual situation. PMID- 29408749 TI - Comparison of maternal and neonatal outcomes for patients with placenta accreta spectrum between online-to-offline management model with standard care model. AB - OBJECTIVE: Online-to-offline is a new model for emergent medical service with the ability to connect care providers with patients on instant basis. This study aims to evaluate maternal and neonatal outcomes in patients with placenta accreta spectrum managed by an online-to-offline care model. METHODS: Starting from January 1, 2015, management of patients with placenta accreta spectrum was changed from standard care model into an online-to-offline care model through "Wechat" in Guangzhou Medical Centre for Critical Obstetrical Care. This study compared maternal and neonatal outcomes in patients affected by placenta accreta spectrum between 2015 (online-to-offline model) and 2014 (standard care model). RESULTS: A total of 209 cases of placenta accrete spectrum were treated in our center in 2015 and 218 such cases were treated in 2014. Patients treated in 2015 had lower rate of hysterectomy (14.83% versus 20.64%) and shorter hospital stay (7 days versus 8 days). The average interval from admission to emergency cesarean section for critically ill patients was 38.5 min in 2015 versus 50.7 min in 2014. CONCLUSION: Patients affected by placenta accreta spectrum managed by online-to offline care model have reduced risk of hysterectomy, shorter hospital stay, and shorter response time from admission to emergency cesarean section. PMID- 29408750 TI - Diurnal rhythm of follicle-stimulating hormone is associated with nonalcoholic fatty liver disease in a Chinese elderly population. AB - OBJECTIVE: Previous studies have found that impairment of the circadian clock appears to contribute to the development of nonalcoholic fatty liver disease (NAFLD) and the circulating follicle-stimulating hormone (FSH) level showed a diurnal cycle. A recent study reported that a lower FSH level was associated with NAFLD. However, the effects of the diurnal rhythm of FSH on NAFLD have not been reported. The aim of this study was to evaluate whether the diurnal rhythm of FSH was associated with NAFLD in an elderly population. STUDY DESIGN: We performed a cross-sectional study among 71 elderly patients between August 2015 and November 2015 at Fujian Provincial Hospital. Anthropometrics and tests for laboratory were performed for each patient. FSH was determined by radioimmunoassay. The FSH receptor (FSHR) expression was identified in liver and ovary tissue by immunohistochemical staining. NAFLD was diagnosed by sonographic features. RESULTS: Of the 71 patients, 33 (42.9%) had NAFLD on their ultrasound. There were no significant differences between subjects with NAFLD and those without NAFLD in terms of age, sex, body mass index, waist-to-hip ratio, fasting plasma glucose, postload plasma glucose, liver enzyme, triglycerides, total cholesterol, high density lipoprotein-cholesterol and low-density lipoprotein-cholesterol. Both the serum FSH levels of 8AM and 0AM showed no differences between the groups. The proportion of the 'normal' diurnal rhythm of FSH was higher among the patients with NAFLD (78.1% vs. 52.6%, P = .027). After adjusting for all potential confounders, the fully adjusted odds ratios (OR) of diurnal rhythm of FSH for NAFLD was 3.86 (95%CI: 1.01, 14.81, P = .049). Immunohistochemical staining showed that the FSHR protein was detected in human ovarian and hepatic tissues. CONCLUSIONS: These results suggest that the 'normal' diurnal rhythm of FSH was independently associated with NAFLD in an elderly population. This study provides a novel insight into the diurnal rhythm of FSH in the pathogenesis of NAFLD. PMID- 29408751 TI - Placental pathology and neonatal outcome in small for gestational age pregnancies with and without abnormal umbilical artery Doppler flow. AB - OBJECTIVE: To compare neonatal outcome and placental pathology in cases of small for gestational age (SGA) according to umbilical artery (UA) Doppler flow. STUDY DESIGN: Pregnancy and placental reports of SGA neonates (birth-weight <10th), born between 2008 and 2017 were compared between cases with normal and abnormal UA Doppler indices. Placental lesions were classified to malperfusion lesions and inflammatory responses. RESULTS: The abnormal Doppler group (n = 66) delivered at an earlier gestational age, compared to the normal Doppler group (n = 92). Placentas from the abnormal Doppler group were characterized by a higher rate of maternal malperfusion lesions, while placentas from the normal Doppler group exhibited a higher rate of chronic villitis. Neonatal outcome was independently associated with abnormal Doppler, gestational age and birth weight <5th percentile. CONCLUSION: SGA may involve a vascular mechanism, associated with abnormal Doppler flow and placental malperfusion, and an inflammatory mechanism, with normal Doppler flow and chronic villitis. PMID- 29408752 TI - Ulipristal acetate for pre-operative management of uterine fibroids: Modeling outcomes and costs. AB - OBJECTIVES: The aim of this study was to evaluate the pharmacoeconomic profile in Italy of preoperative treatment with ulipristal acetate at the dose of 5 mg/day for 13 weeks in comparison with placebo prior to surgical management of symptomatic uterine fibroids. STUDY DESIGN: The pharmacoeconomic analysis was based on the calculation of incremental cost-effectiveness ratio (ICER). Effectiveness data were derived from the randomized-controlled trial PEARL-1, whilst costs data were retrieved from the published literature. A Markov model was employed to simulate the pattern of costs and two univariate sensitivity analyses tested the robustness of the results. RESULTS: In comparison with placebo, ulipristal acetate 5 mg for presurgical therapy was estimated to be associated with an incremental cost of ?351 per patient. Costs per patient were ?3836 for ulipristal acetate vs ?3485 for placebo. The incremental effectiveness was 0.01931 QALYs per patient (around 7 quality-adjusted days per patient). Hence, the cost effectiveness ratio was calculated to be ?18,177 per QALY gained. CONCLUSIONS: Preoperative use of ulipristal acetate 5 mg in patients with uterine fibroids has a favourable pharmacoeconomic profile. PMID- 29408753 TI - Norethindrone acetate versus extended-cycle oral contraceptive (Seasonique(r)) in the treatment of endometriosis symptoms: A prospective open-label comparative study. AB - INTRODUCTION: This patient preference prospective study was designed to compare patients' satisfaction in women with endometriosis treated either by an extended cycle oral contraception (OC) or by norethindrone acetate (NETA). METHODS: This patient preference prospective study included women of reproductive age with endometriosis. Patients were submitted to one of the following 12 months' treatments: Group A, continuous oral treatment with NETA (2.5 mg/day) and Group B, a 91-day extended-cycle OC (LNG/EE 150/30 mcg for 84 days and EE 10 mcg for 7 days). Patient satisfaction was the primary endpoint. RESULTS: There was no statistically significant difference in the rate of satisfied patients at 12 month follow up between the two study groups, 82.2% and 68.4% in Group A and Group B respectively (p = 0.143). At 6 and 12-months, there was a significant amelioration in the intensity of all pain in both groups. The median number of days of unscheduled bleeding during the first cycle was significantly higher in Group B compared to Group A. CONCLUSION: Both NETA and extended-cycle OC are effective in treating pain symptoms related to endometriosis. Extended-cycle OC may cause more unscheduled bleeding, but the rate of satisfaction for those who completed the treatment was similar in the two groups. PMID- 29408755 TI - Excellent antitumor effects for gastrointestinal cancers using photodynamic therapy with a novel glucose conjugated chlorin e6. AB - BACKGROUND: Photodynamic therapy (PDT) exploits the reaction between photosensitizer and irradiated light to generate potentially therapeutic reactive oxygen species such as singlet oxygen in cancer cells. We have reported several sugar-conjugated chlorins that express stronger antitumor effects in PDT than talaporfin sodium (TS), a second-generation photosensitizer clinically used in Japan. In this study, we developed a novel glucose-conjugated chlorin e6 (G chlorin e6) and evaluated its antitumor effects. METHODS: G-chlorin e6 was synthesized with a core photosensitizer chlorin e6 conjugated to glucose. We measured the half maximal inhibitory concentration (IC50) to compare the PDT effects of G-chlorin e6 and TS, and flow cytometry was performed to examine the accumulation of G-chlorin e6 in cancer cells. We also compared the accumulation of G-chlorin e6 between normal immortalized esophageal epithelial cells and esophageal cancer cells. Antitumor effects of G-chlorin e6 PDT were finally analyzed in allograft tumor mouse models. RESULTS: PDT in vitro using G-chlorin e6 elicited 9, 000-34,000 times stronger antitumor effects than TS, and there was 70-190 times more G-chlorin e6 accumulated than TS by flow cytometry. G-chlorin e6 accumulated more selectively in esophageal cancer cells than in esophageal immortalized epithelial cells, and in an allograft model, PDT with G-chlorin e6 showed very strong antitumor effects and a 40% complete response (CR) rate. CONCLUSIONS: G-chlorin e6 showed excellent tumor selectivity, and PDT using G chlorin e6 revealed the strongest anti-tumor effects among all sugar-conjugated chlorins that we have studied. G-chlorin e6 is considered to be the best photosensitizer for next-generation PDT. PMID- 29408754 TI - Elective abortion: Clinical practice guidelines from the French College of Gynecologists and Obstetricians (CNGOF). AB - The number of elective abortions has been stable for several decades. Many factors explain women's choice of abortion in cases of unplanned pregnancies. Early initiation of contraceptive use and a choice of contraceptive choices appropriate to the woman's life are associated with lower rates of unplanned pregnancies. Reversible long-acting contraceptives should be favored as first line methods for adolescents because of their effectiveness (grade C). Ultrasound scan before an elective abortion must be encouraged but should not be obligatory (professional consensus). As soon as the embryo appears on the ultrasound scan, the date of pregnancy is estimated by measuring the crown-rump length (CRL) or, from 11 weeks on, by measuring the biparietal diameter (BPD) (grade A). Because reliability of these parameters is +/-5 days, the abortion may be done if measurements are respectively less than 90 mm for CRL and less than 30 mm for BPD (professional consensus). A medically induced abortion, performed with a dose of 200 mg mifepristone combined with misoprostol, is effective at any gestational age (Level of Evidence (LE) 1). Before 7 weeks, mifepristone should be followed 24-48 h later by misoprostol, administered orally, buccally, sublingually, or even vaginally followed if needed by a further dose of 400 MUg after 3 h, to be renewed if needed after 3 h (LE 1, grade A). After 7 weeks, administration of misoprostol by the vaginal, sublingual, or buccal routes is more effective and better tolerated than by the oral route (LE 1). Cervical preparation is recommended for systematic use in surgical abortions (professional consensus). Misoprostol is a first-line agent for cervical preparation at a dose of 400 MUg (grade A). Vacuum aspiration is preferable to curettage (grade B). A uterus perforated during surgical aspiration should not routinely be considered to be scarred (professional consensus). An elective abortion is not associated with a higher risk of subsequent infertility or ectopic pregnancy (LE 2). The medical consultation before an elective abortion generally does not affect the decision to end or continue the pregnancy, and most women are sufficiently certain about their choice at this time. Women appear to find the method used most acceptable and to be most satisfied when they were able to choose the method (grade B). Elective abortions are not associated with an increased rate of psychiatric disorders (LE 2). However, women with psychiatric histories are at a higher risk of psychological disorders after the occurrence of an unplanned pregnancy than women with such a history (LE 2). For surgical abortions, combined hormonal contraceptives - oral or transdermal - should be started on the day of the abortion, while the vaginal ring should be inserted 5 days afterwards (grade B). For medical abortions, the vaginal ring should be inserted in the week after mifepristone administration, while the combined contraceptives should begin the same day as the misoprostol or the day after (grade C). Contraceptive implants should be inserted on the same day as a surgical abortion, and may be inserted the day the mifepristone is administered for medical abortions (grade B and C respectively). In case of medical abortion, the implant can be inserted the same day the mifepristone is administered (grade C). Both the copper IUDs and levonorgestrel intrauterine system should be inserted on the day of the surgical abortion (grade A). After medical abortions, an IUD can be inserted in 10 days after mifepristone administration, after ultrasound scan verification of the absence of an intrauterine pregnancy (grade C). PMID- 29408756 TI - Plasma metabolic profile reveals PGF2alpha protecting against non-proliferative diabetic retinopathy in patients with type 2 diabetes. AB - Diabetic retinopathy (DR) is the most frequent microvascular complications of diabetes and the leading cause of blindness in adults worldwide. Non proliferative DR (NPDR) is the first stage of DR but currently has few recommended intervention. Eicosanoids play important roles in maintaining vessel homeostasis. However, the functions of eicosanoids in NPDR are still unknown. In this study, we investigated the eicosanoids profile difference in plasma between type 2 diabetes with NPDR or not. A total of 50 patients with type 2 diabetes were recruited and divided into non-DR (NDR) group and NPDR group based on fundus photographs. The eicosanoids profiles in plasma were determined by LC-MS/MS. Adhesion and transwell assay were used to detect the adhesion and migration effects of metabolites on primary bovine retinal pericyte cells (BRPC), respectively. Streptomycin (STZ)-induced diabetic mouse model was used to test the protective effects of selected metabolites according to retinal immunofluorescence staining and fluorescence confocal microscopy. Prostaglandin 2alpha (PGF2alpha) was decreased significantly in NPDR group compared to NDR group and negatively correlated with NPDR. In vitro, PGF2alpha was found to accelerate adhesion and migration by activating prostaglandin F receptor (FP receptor) and subsequent increasing RhoA activity in primary bovine retinal pericyte. Administration of PGF2alpha analogue diminished the damage on retinal capillary in an STZ-induced diabetic mouse model. Our results suggested that PGF2alpha may be a protective factor in the progression of NPDR in T2D patients. The protective mechanism of PGF2alpha was to increase pericyte mobility through FP receptor/RhoA pathway. PMID- 29408757 TI - Therapeutic administration of inhaled INS1009, a treprostinil prodrug formulation, inhibits bleomycin-induced pulmonary fibrosis in rats. AB - Idiopathic pulmonary fibrosis is a progressive and lethal disease and while there are now two approved drugs (Esbriet(r) and Ofev(r)) additional effective treatments are still needed. Recently, prostacyclin analogs such as iloprost and treprostinil (TRE) have been shown to exert some protection against bleomycin induced pulmonary fibrosis in mice when administered in a prophylactic regimen. In this study, we evaluated the effect of the inhaled treprostinil prodrug hexadecyl-treprostinil (C16TR) formulated in a lipid nanoparticle (INS1009) administered therapeutically in a fibrotic rat model. Male Fischer 344 rats challenged with intra-tracheal saline instillation were then treated with daily inhaled phosphate buffered saline (PBS) while rats challenged with bleomycin sulfate (3.5-4.0 mg/kg) instillation were treated with either daily inhaled PBS, daily inhaled INS1009 (10, 30, or 100 MUg/kg), or twice-daily orally with the anti-fibrotic compound pirfenidone (100 mg/kg). Dosing started on day 10 post bleomycin challenge and continued until day 27 after bleomycin. Lungs were harvested 24 h after the last dose of treatment for evaluation of lung hydroxyproline content and pulmonary histology. Lung hydroxyproline content increased from 421 MUg/lung lobe in saline challenged and PBS treated animals to 673 MUg/lung lobe in bleomycin challenged and PBS treated rats. Treatment of bleomycin challenged rats with 10, 30, or 100 MUg/kg INS1009 dose-dependently reduced lung hydroxyproline content to 563, 501, and 451 MUg/lung lobe, respectively, and pirfenidone decreased hydroxyproline content to 522 MUg/lung lobe. Histologically, both INS1009 (100 MUg/kg) and pirfenidone (100 mg/kg) reduced the severity of subepithelial fibrosis. Single dose pharmacokinetic (PK) studies of inhaled INS1009 in bleomycin challenged rats showed dose-dependent increases in lung C16TR concentration and plasma TRE on day 10 post-bleomycin challenge. Multiple dose PK studies of inhaled INS1009 showed dose-dependent increases only in lung C16TR concentration on day 27 post-bleomycin challenge. We also investigated the effects of TRE on the cytokine transforming growth factor beta1 (TGF-beta1)-stimulated collagen gene and protein expressions in cultured human lung fibroblasts, assessed by real-time PCR and Sirius Red staining, respectively. In human fibroblasts, TRE (0.001-10 MUM) inhibited TGF-beta1 (20 ng/mL)-induced expression of collagen mRNA and protein in a concentration dependent manner. These results demonstrated that inhaled INS1009, administered in a therapeutic dosing paradigm, dose-dependently (10-100 MUg/kg) inhibited bleomycin-induced pulmonary fibrosis in rats. This effect may involve direct actions of TRE in suppressing collagen expression in lung fibroblasts. PMID- 29408758 TI - Methodology for exposing avian embryos to quantified levels of airborne aromatic compounds associated with crude oil spills. AB - Oil spills on birds and other organisms have focused primarily on direct effects of oil exposure through ingestion or direct body fouling. Little is known of indirect effects of airborne volatiles from spilled oil, especially on vulnerable developing embryos within the bird egg. Here a technique is described for exposing bird embryos in the egg to quantifiable amounts of airborne volatile toxicants from Deepwater Horizon crude oil. A novel membrane inlet mass spectrometry system was used to measure major classes of airborne oil-derived toxicants and correlate these exposures with biological endpoints. Exposure induced a reduction in platelet number and increase in osmolality of the blood of embryos of the chicken (Gallus gallus). Additionally, expression of cytochrome P4501A, a protein biomarker of oil exposure, occurred in renal, pulmonary, hepatic and vascular tissues. These data confirm that this system for generating and measuring airborne volatiles can be used for future in-depth analysis of the toxicity of volatile organic compounds in birds and potentially other terrestrial organisms. PMID- 29408760 TI - The effect of Zataria multiflora on pulmonary function tests, hematological and oxidant/antioxidant parameters in sulfur mustard exposed veterans, a randomized doubled-blind clinical trial. AB - BACKGROUND: Sulfur mustard is an alkylating agent which cause to short and long term incapacitations on various organs including lung. There is no definite treatment for lung disorders induced by SM exposure. In the present study, the preventive effect of Zataria multiflora (Z. multiflora) on hematological parameters, oxidant/antioxidant markers and pulmonary function tests (PFT) in veterans, 27-30 years after exposed to SM were studied. MATERIALS AND METHODS: Forty seven veterans allocated to three groups included: placebo group (P) and two groups treated with 5 and 10 mg/kg/day of Z. multiflora (Zat 5 and Zat 10). Drugs were prescribed in a double-blind manner for two months. Total and different WBC, hematological indices, oxidant/antioxidant markers and PFT values included; force vital capacity (FVC) and peak expiratory flow (PEF) were assessed at the beginning (step 0), one and two month (step I and II, respectively) after starting treatment. RESULTS: Total and different white blood cell in Zat 5 and 10 mg/kg treated groups in Step I and II were significantly decreased compared to Step 0 (p < 0.05 to p < 0.001). The levels of thiol, superoxide dismutase (SOD) and catalase (CAT) in Zat 5 and 10 mg/kg treated groups in step I and II were significantly increased (p < 0.05 to p < 0.001) but the level of malondialdehyde (MDA) significantly decreased in two treatment groups compared to Step 0 (p < 0.05 and p < 0.001 respectively). FVC and PEF values were significant increase in Zat 5 and 10 mg/kg treated groups in step I and II compared to step 0 (p < 0.05 to p < 0.001). Furthermore, FVC and PEF values in Zat 5 mg/kg were also increased in step II compared to step I (p < 0.01 for both). The percentage improvement of total and differential WBC, oxidant/antioxidant markers, FVC and PEF values during two moth treatment period significantly improved in the treated groups compared to the placebo group. CONCLUSION: Z. multiflora reduces inflammatory cells and oxidant biomarkers, while increase antioxidant biomarkers and improved PFT tests in SM exposed patients in a two moth treatment period. PMID- 29408759 TI - Changes in intermediate metabolism and oxidative balance parameters in sexually matured three-barbeled catfishes exposed to herbicides from rice crops (Roundup(r), Primoleo(r) and Facet(r)). AB - This study analyzed the effect of different concentrations of herbicides (Facet(r), Primoleo(r), and Roundup(r)) on metabolism and oxidative balance (superoxide dismutase and catalase activity, lipid peroxidation) in the gills, liver, kidneys, and tail muscle of adult catfish. All herbicides caused protein depletion in gills, increased glycogen and triacylglycerol consumption in the liver, and changes in muscle glycogen. Roundup(r) and Primoleo(r) stimulated lipid deposition in the liver, while Roundup(r) and Facet(r) stimulated lipid consumption in gills. In kidneys, protein content increased after Roundup(r) and Primoleo(r) exposure, glycogen increased after Facet(r), and lipids increased after Roundup(r). Primoleo(r) had the strongest effect on muscle, with changes in all metabolites. Regarding oxidative stress, the liver and kidneys were the organs most affected by exposure to herbicides, and catalase was the main enzyme involved in the detoxification of these herbicides. A hierarchy of toxicity was established for the tested chemicals: Facet(r) > Primoleo(r) > Roundup(r). PMID- 29408761 TI - Hepatoprotective effects of capping protein gelsolin against hyperoxia-induced hepatotoxicity, oxidative stress and DNA damage in neonatal rats. AB - Tissues and organs get exposed to high oxygen (O2) supply in hyperoxia conditions. The goal of this research was to investigate the protective effect of actin binding protein gelsolin on hyperoxia-induced hepatotoxicity through histopathology and measurement of oxidative stress parameters and DNA damage in a neonatal Wistar albino rats. The pups were randomly separated to four equal groups such as: normoxia control group (NC), normoxia plus gelsolin group (NG, 10 ng/kg bw/day gelsolin), hyperoxia (>=85% O2) group (HC), hyperoxia plus gelsolin group (HG, >=85% O2; 10 ng/kg bw/day gelsolin). Histopathological changes of pups in hyperoxia condition were revealed in the form of severe leukocyte infiltration, vascular congestion, necrosis, vacuolar degeneration, binucleated hepatocytes and hemorrhage in the liver tissue. SOD, CAT, GPx and GST activities decreased and MDA level increased in the hyperoxia-induced group in liver tissue (P < 0.05). Tail DNA%, tail length and moment indicating DNA damage statistically increased in hyperoxia treatment groups when compared to controls. Treatment of rats with hyperoxia plus gelsolin prevented hyperoxia-induced changes in tissue structure, antioxidant enzyme activities and MDA level, mean tail DNA% and length. Based on these findings, gelsolin restored these changing to near normal levels but it does not protect completely in the hyperoxia conditions. PMID- 29408763 TI - Multiple pharmacological activities of Caesalpinia crista against aluminium induced neurodegeneration in rats: Relevance for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia and mainly affects cognitive function of the aged populations. Aluminium, a neurotoxic metal, has been suggested as a contributing factor of AD. Caesalpinia crista is a medicinal plant known for its anti-microbial, anti-inflammatory and anti-oxidant properties. The present study was conducted in order to evaluate the neuroprotective effects of methanolic extracts of C. crista (MECC) on aluminium induced neurodegeneration in rats. Co-administration with MECC significantly and dose dependently ameliorated the aluminium-dependent cognitive impairment, AChE hyperactivity and oxidative stress in the hippocampus and in the frontal cortex of rat brain. Moreover, MECC reduced the neuronal injury induced by aluminium as shown by the diminution of neuron loss and pyknosis in the CA1 and CA3 regions of the hippocampus. From this study, it is inferred that MECC protect against aluminium-induced behavioral alterations, cognitive function, oxidative stress and neuroinflammation in vivo. Therefore, this plant may serve as a source of natural products having multiple functions and could be utilized as an anti-AD preparation. PMID- 29408762 TI - Hydroxylated and sulfated metabolites of commonly occurring airborne polychlorinated biphenyls inhibit human steroid sulfotransferases SULT1E1 and SULT2A1. AB - Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that are associated with varied adverse health effects. Lower chlorinated PCBs are prevalent in indoor and outdoor air and can be metabolized to their hydroxylated derivatives (OH-PCBs) followed by sulfation to form PCB sulfates. Sulfation is also a means of signal termination for steroid hormones. The human estrogen sulfotransferase (SULT1E1) and alcohol/hydroxysteroid sulfotransferase (SULT2A1) catalyze the formation of steroid sulfates that are inactive at steroid hormone receptors. We investigated the inhibition of SULT1E1 (IC50s ranging from 7.2 nM to greater than 10 MUM) and SULT2A1 (IC50s from 1.3 MUM to over 100 MUM) by five lower-chlorinated OH-PCBs and their corresponding PCB sulfates relevant to airborne PCB-exposure. Several congeners of lower chlorinated OH-PCBs relevant to airborne PCB exposures were potent inhibitors of SULT1E1 and SULT2A1 and thus have the potential to disrupt regulation of intracellular concentrations of the receptor-active steroid substrates for these enzymes. PMID- 29408764 TI - Protective role of nebivolol in cadmium-induced hepatotoxicity via downregulation of oxidative stress, apoptosis and inflammatory pathways. AB - Cadmium (Cd) intoxication in human occurs through inhalation of cigarette smoke and ingestion of contaminated water and food. We investigated the role of nebivolol (NEB) in Cd induced hepatotoxicity. In our study; NEB was given as (10 mg/kg/d) orally to rats for 6 weeks, in the presence or absence of hepatotoxicity induced by oral administration of Cd (7 mg/kg/d) for 6 weeks. Levels of serum liver enzyme biomarkers; alanine transaminase (ALT), aspartate transaminase (AST) and serum total antioxidant capacity (TAC) were measured. In addition; mean arterial pressure and total cholesterol levels were measured. Hepatic superoxide dismutase (SOD) and malondialdehyde (MDA) were detected. Hepatic histopathological features, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) immunoexpressions were evaluated. Tumor necrosis factor alpha (TNF-alpha) and B-cell lymphoma-2 (Bcl-2) mRNA gene expressions were detected using real time-PCR (rt-PCR). Our results showed marked increase in all measured parameters except SOD, TAC, eNOS immunoexpression and Bcl2 mRNA gene expression which decreased in Cd induced hepatotoxicity group. NEB showed marvelous protective effect against Cd induced changes. NEB decreased liver enzymes (ALT and AST), mean arterial pressure, total cholesterol levels, MDA, iNOS immunoexpression and TNF-alpha gene expression but significantly increased SOD, TAC, eNOS immunoexpression and Bcl-2 gene expression. Moreover; NEB markedly improved the histopathological changes induced by Cd. These findings prove the antioxidant, anti-apoptotic and anti-inflammatory properties of NEB and its protective role in Cd induced hepatotoxicity. PMID- 29408765 TI - Suppression of gluconeogenic gene transcription by SIK1-induced ubiquitination and degradation of CRTC1. AB - CRTCs are a group of three transcriptional coactivators required for CREB dependent transcription. CREB and CRTCs are critically involved in the regulation of various biological processes such as cell proliferation, metabolism, learning and memory. However, whether CRTC1 efficiently induces gluconeogenic gene expression and how CRTC1 is regulated by upstream kinase SIK1 remain to be understood. In this work, we demonstrated SIK1-induced phosphorylation, ubiquitination and degradation of CRTC1 in the context of the regulation of gluconeogenesis. CRTC1 protein was destabilized by SIK1 but not SIK2 or SIK3. This effect was likely mediated by phosphorylation at S155, S167, S188 and S346 residues of CRTC1 followed by K48-linked polyubiquitination and proteasomal degradation. Expression of gluconeogenic genes such as that coding for phosphoenolpyruvate carboxykinase was stimulated by CRTC1, but suppressed by SIK1. Depletion of CRTC1 protein also blocked forskolin-induced gluconeogenic gene expression, knockdown or pharmaceutical inhibition of SIK1 had the opposite effect. Finally, SIK1-induced ubiquitination of CRTC1 was mediated by RFWD2 ubiquitin ligase at a site not equivalent to K628 in CRTC2. Taken together, our work reveals a regulatory circuit in which SIK1 suppresses gluconeogenic gene transcription by inducing ubiquitination and degradation of CRTC1. Our findings have implications in the development of new antihyperglycemic agents. PMID- 29408766 TI - SUNCT like syndrome preceding acute ophthalmic- distribution zoster: A case report and review of the literature. AB - BACKGROUND: SUNCT like syndrome has been observed as a post zoster condition, as a syndrome associated with overt ophthalmic zoster after appearance of herpetic lesions and in varicella zoster virus meningoencephalitis without rash. However, SUNCT like syndrome fully consistent and congruent with the criteria of the ICHD immediately before onset of an ophthalmic-distribution zoster has not been reported. CASE PRESENTATION: We report 73-year-old patient with a SUNCT like syndrome as the first presentation of an acute ophthalmic-distribution zoster. Symptomatic treatment was highly effective, after antiviral treatment with acyclovir no further medication was required. CONCLUSIONS: SUNCT like syndrome can be the initial clinical presentation immediately preceding an acute ophthalmic-distribution zoster. This is congruent with previous observations of zoster - related SUNCT like syndromes with different temporal relationship to zoster. Zoster - related SUNCT like syndromes seem to respond well to symptomatic treatment. Clinicians should ask and look for history and signs of ophthalmic zoster in SUNCT like headaches. PMID- 29408767 TI - The Woven EndoBridge (WEB) for endovascular therapy of intracranial aneurysms: Update of a systematic review with meta-analysis. AB - OBJECTIVES: Endovascular treatment of wide-neck intracranial aneurysms (IAs) is challenging, especially in bifurcation location. The intra-saccular flow disruptor Woven EndoBridge (WEB) offers a new concept of endovascular therapy for wide-neck IAs. We performed an update of a systematic review aimed to report the feasibility, effectiveness and safety of WEB device therapy. PATIENTS AND METHODS: A systematic review was conducted using several electronic databases (including PUBMED and EMBASE), searching for studies published between October 2015 and December 2017 (those published between January 2010 and September 2015 were included in our initial systematic review). Outcomes were: success of implantation, peri-procedural complications, mortality, and adequate occlusion (complete occlusion or neck remnant). RESULTS: In total (initial review + update), 12 uncontrolled case-series studies were included, reporting outcomes for 940 patients (68.6% female; mean age, 57 years) harboring 962 IAs. Most IAs were wide-neck bifurcation aneurysms (75%-100%), mainly at middle cerebral artery (37%) and anterior communicating artery (24.6%). Feasibility was 97% (95% confidence interval [CI], 95%-99%), and 9% (95%CI, 5%-14%) of cases required additional treatment. There were 14% (95%CI, 9%-19%) peri-procedural complications. After a median clinical follow-up of 7 months, mortality was 5% (95%CI, 1%-10%) and was higher in series with larger proportions of ruptured IAs. At last angiographic follow-up (median, 7 months; range, 3-27.9 months), adequate occlusion rate was 81% (95%CI, 73%-88%). CONCLUSION: Although WEB showed high rates of adequate aneurysm occlusion at mid-term, procedure-related complications and mortality rates were not negligible. Future studies should compare the WEB device with other treatment options. PMID- 29408768 TI - Craniopharyngiomas: A systematic review and evaluation of the current intratumoral treatment landscape. AB - Cushing once described craniopharyngiomas as the most forbidding tumor; and, despite surgical advances decades later, craniopharyngioma resection is still extremely complex due to its location and infiltration into local structures, making gross total resection challenging. Adjuvant treatments include radiation and chemotherapy, but intratumoral therapy may emerge as an adjuvant treatment for craniopharyngiomas. Here, we present a review of the literature on this treatment modality; and, summarize the available reported cases to underline usefulness and effectiveness of this treatment method. Our review of the literature included all articles from MEDLINE/PubMed and Ovid from 1974 to 2017. All articles were assessed for relevancy before inclusion into this review. Although the role for intratumoral therapy is unclear, multiple studies have reported efficacy in the treatment of craniopharyngiomas, and current results are promising. Out of the intratumoral agents utilized, intratumoral alpha interferon seems to provide the best response and least side effects for the treatment of craniopharyngiomas. The use of intratumoral therapy has led to delay in treatment with definitive surgery or radiation, both of which are associated with significant morbidities, detrimental in developmental years of childhood. Out of the intratumoral agents utilized, intratumoral alpha interferon seems to provide the best response and least side effects for the treatment of craniopharyngiomas. These findings need to be explored further with randomized controlled trials, outlining a standard dosing regimen. Furthermore, trials in craniopharyngioma patients with these combination therapies must be performed to determine the optimal therapeutic regimen for the successful treatment of these patients. PMID- 29408769 TI - Posterior surgery versus combined laminectomy and thoracoscopic surgery for treatment of dumbbell-type thoracic cord tumor: A long-term follow-up. AB - OBJECTIVE: The goal of this study was to compare the clinical outcomes of posterior surgery with combined laminectomy and thoracoscopic surgery for treating dumbbell-type thoracic cord tumors. PATIENTS AND METHODS: We retrospectively analyzed 32 cases of dumbbell-type thoracic cord tumors treated by two surgical procedures in our center from February 2003 to July 2013. CASES WERE DIVIDED INTO TWO GROUPS DEPENDING ON THE TYPE OF SURGERY: Group A cases (n = 12) underwent posterior surgery followed by laminectomy, costotransversectomy and instrumentation; Group B cases (n = 20) underwent posterior laminectomy and anterior video-assisted thoracoscopic surgery in a single-stage procedure. Operation time, blood loss, hospitalization, recovery of neurological function, and complications were compared between the two groups. RESULTS: Complete surgical excision was achieved in both groups. All patients were followed up for an average of 7.4 +/- 2.8 years (range, 3-13). At the final follow-up visit, there was no tumor recurrence and no differences in neurological results between the two groups (P > 0.05). However, the average operative duration, blood loss, hospitalization, and rate of complications were significantly lower in Group A compared to Group B (P < 0.05). CONCLUSION: Both posterior surgery and the posterior surgery combined with anterior thoracoscopic surgery were effective for removing dumbbell-type thoracic cord tumors. However, posterior surgery alone was associated with reduced operative duration and rate of complications compared to the combined surgical approach. PMID- 29408770 TI - Factors of influence upon the SF-36-based health related quality of life of patients following surgery for petroclival and lateral posterior surface of pyramid meningiomas. AB - OBJECTIVE: To describe the patient's self assessed health related quality of life (saHRQoL) based upon the medical outcome study 36-item short form health survey (SF-36) as well as the factors of influence upon the saHRQoL following surgery for petroclival (PCM) and lateral posterior surface of the pyramid (LPPM) meningiomas. PATIENTS AND METHODS: In a series of 78 patients operated consecutively for PCM (n = 46) or LPPM (n = 32) the preoperative, intraoperative and postoperative data were collected retrospectively. The saHRQoL was obtained by mailing the SF-36 questionnaire to the patients. The SF-36 data of the whole patients group was compared with a healthy population. The SF-36 data of the PCM- and LPPM were compared to each other. The influence of pre-, intra- and postoperative findings upon the SF-36 was assessed by uni- and multifactorial analysis. RESULTS: 58 (69%) out of the 78 patients answered the SF-36 questionnaire at a median postoperative follow-up of 59 months. The patients, who answered the SF-36 questionnaire, had a significant lower perioperative complication rate than those who did not (46% vs. 75%, p = 0.019). The saHRQoL of the LPPM and PCM was reduced on several sub-scales, when compared to the German reference population. The outcome of PCM is, assessed by saHRQoL as well as by conventional neurosurgical grading scales, inferior to that of LPPM. The saHRQoL of LPPM correlated in the uni- and multivariate analysis with the early postoperative KPI on the sub-scales SF1 (physical functioning) and SF5 (vitality). Accordingly, the sub-scale SF2 (role-physical) of PCM correlated with the change of the KPI from preoperative to the last follow up. CONCLUSIONS: The saHRQoL of the evaluable patients was lower than that of the normal population. The saHRQoL score of PCM-patients was lower than that of LPPM-patients. For the future the saHRQol should be assessed routinely; It reflects the patients' perspective upon postoperative outcome and enables the comparison with other treatment modalities of these difficult to treat tumors. PMID- 29408771 TI - Headache in mitochondrial disorders. AB - Headache is a prominent feature in mitochondrial disorders (MIDs) but no comprehensive overview is currently available. This review aims at summarising and discussing findings concerning type, frequency, pathogenesis, and treatment of headache in MIDs. The most frequent headache types in MIDs are migraine and migraine-like headache (MLH). MLH is classified as secondary headache. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine or MLH may manifest with or without aura. MLH is frequently associated with an ongoing or previous stroke-like episode (SLE) or a seizure but may also occur independently of other neurological features. MLH may be associated with prolonged aura or visual phenomena after headache. Except for MLH, treatment of headache in MIDs is not at variance from other causes of headache. Beyond the broadly accepted subtype-related headache treatment, diet, cofactors, vitamins, and antioxidants may provide a supplementary benefit. Midazolam, l-arginine, or l-citrulline may be beneficial for MLH. The pathogenesis of headache in MIDs largely remains unsolved. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely. In conclusion, migraine and MLH are the prominent headache types in MIDs. MLH may or may not be associated with current or previous SLEs. MLH is pathophysiologically different from migraine and requires treatment at variance from that of migraine with aura. PMID- 29408772 TI - Cervical spine surgery for tandem spinal stenosis: The impact on low back pain. AB - STUDY DESIGN: Retrospective Cohort. OBJECTIVE: Tandem spinal stenosis (TSS) can present similarly to cervical myelopathy, but often has a worse prognosis. Few studies have investigated outcomes and compared treatment approaches for patients with TSS. We sought to determine the impact of cervical spine surgery on cervical and lumbar spine symptoms in patients with symptomatic tandem spinal stenosis. PATIENTS METHODS: 84 patients with TSS were identified over 5 years. 48 underwent cervical spine surgery alone, 20 underwent both cervical and lumbar spine surgery, and 16 received conservative treatment alone (conservative cohort). Quality of life (QOL) measures included the Visual Analogue Scale (VAS) for arm, neck, and back pain, and EuroQOL-5 Dimensions (EQ-5D). QOL data were acquired at baseline (pre-operative) and 1 year postoperatively via an institutional prospectively collected database. RESULTS: Both surgical cohorts showed significant (p < 0.01) pre- to postoperative improvement for VAS neck and arm scores at 1-year post-op and significantly (p < 0.01) greater improvements than the conservative cohort. In addition, the cohort undergoing cervical spine surgery alone experienced significant improvement in the EQ-5D score whereas those undergoing both cervical and lumbar spine surgery did not. CONCLUSIONS: Cervical spine surgery with or without follow-up lumbar spine surgery significantly improves neck pain in patients with TSS. In contrast, cervical spine surgery in these patients does not improve lumbar symptoms. Lumbar surgery also did not improve low back pain or quality of life. Future prospective studies are necessary to examine the impact of lumbar decompression alone on cervical spine symptoms in patients with TSS. PMID- 29408773 TI - Dopaminergic involvement in a drummer with focal dystonia: A case study. AB - Musician's Dystonia (MD) represents an intriguing disorder with rich phenomenology and unclear pathophysiology. We observed a MD affecting left upper limb in a professional drummer. DaT-Scan revealed slight reduced uptake in the right putamen; no extrapyramidal or other neurological signs emerged in 2.5 years of follow up. The case offers insight on dopaminergic involvement in MD. PMID- 29408774 TI - Postoperative pneumocephalus increases the recurrence rate of chronic subdural hematoma. AB - OBJECTIVES: Pneumocephalus is a common operative complication of chronic subdural hematoma. This study is to analyze the relationship between postoperative pneumocephalus and the recurrence and surgical outcomes. PATIENTS AND METHODS: This is a retrospective case-cohort study, including a pneumocephalus group (n = 46) and a control group (n = 181). Their recurrence rates, CT attenuation values, hospital stay, healing time and the neurological status were recorded and analyzed. RESULTS: The pneumocephalus group had a recurrence rate of 32.6%, significantly higher than the control (17.7%). In addition, the pneumocephalus group had a higher rate of postoperative epilepsy (21.7% vs 3.3%), longer hospital stay (11.5 +/- 2.8 vs 7.8 +/- 1.2 days), longer healing time (10.8 +/- 5.4 vs 6.5 +/- 2.3 months), and worse neurological scores than the control. CONCLUSION: Pneumocephalus increases the recurrence rate of chronic subdural hematoma, and it not only prolongs the hospital stay and healing time, but also leads to deterioration of the neurological status. PMID- 29408775 TI - Value-based procurement of medical devices: Application to devices for mechanical thrombectomy in ischemic stroke. AB - OBJECTIVES: In the acute ischemic stroke, endovascular devices have shown promising clinical results and are also likely to represent value for money, as several modeling studies have shown. Pharmacoeconomic evaluations in this field, however, have little impact on the procurement of these devices. The present study explored how complex pharmacoeconomic models that evaluate effectiveness and cost can be incorporated into the in-hospital procurement of thrombectomy devices. PATIENTS AND METHODS: As regards clinical modeling, we extracted outcomes at three months from randomized trials conducted for four thrombectomy devices, and we projected long-term results using standard Markov modeling. In estimating QALYs, the same model was run for the four devices. As regards economic modeling, we firstly estimated for each device the net monetary benefit (NMB) per patient (threshold = $60,000 per QALY); then, we simulated a competitive tender across the four products by determining the tender-based score (on a 0-to-100 scale). Prices of individual devices were obtained from manufacturers. Extensive sensitivity testing was applied to our analyses. RESULTS: For the four devices (Solitaire, Trevo, Penumbra, Solumbra), QALYs were 1.86, 1.52, 1,79, 1.35, NMB was $101,824, $83,546, $101,923, $69,440, and tender based scores were 99.70, 43.43, 100, 0, respectively. Sensitivity analysis confirmed findings from base-case. CONCLUSION: Our results indicate that, in the field of thrombectomy devices, incorporating the typical tools of cost effectiveness into the processes of tenders and procurement is feasible. Bridging the methodology of cost-effectiveness with the every-day practice of in-hospital procurement can contribute to maximizing the health returns that are generated by in-hospital expenditures for medical devices. PMID- 29408776 TI - Readability and quality of wikipedia pages on neurosurgical topics. AB - OBJECTIVES: Wikipedia is the largest online encyclopedia with over 40 million articles, and generating 500 million visits per month. The aim of this study is to assess the readability and quality of Wikipedia pages on neurosurgical related topics. PATIENTS AND METHODS: We selected the neurosurgical related Wikipedia pages based on the series of online patient information articles that are published by the American Association of Neurological Surgeons (AANS). We assessed readability of Wikipedia pages using five different readability scales (Flesch Reading Ease, Flesch Kincaid Grade Level, Gunning Fog Index, SMOG) Grade level, and Coleman-Liau Index). We used the Center for Disease Control (CDC) Clear Communication Index as well as the DISCERN Instrument to evaluate the quality of each Wikipedia article. RESULTS: We identified a total of fifty-five Wikipedia articles that corresponded with patient information articles published by the AANS. This constitutes 77.46% of the AANS topics. The mean Flesch Kincaid reading ease score for all of the Wikipedia articles we analyzed is 31.10, which indicates that a college-level education is necessary to understand them. In comparison to the readability analysis for the AANS articles, the Wikipedia articles were more difficult to read across every scale. None of the Wikipedia articles meet the CDC criterion for clear communications. CONCLUSION: Our analyses demonstrated that Wikipedia articles related to neurosurgical topics are associated with higher grade levels for reading and also below the expected levels of clear communications for patients. Collaborative efforts from the neurosurgical community are needed to enhance the readability and quality of Wikipedia pages related to neurosurgery. PMID- 29408777 TI - Streamlined triage and transfer protocols improve door-to-puncture time for endovascular thrombectomy in acute ischemic stroke. AB - OBJECTIVE: Shorter time from symptom onset to treatment is associated with improved outcomes in patients who undergo mechanical thrombectomy for treatment of acute ischemic stroke due to emergent large vessel occlusion. In this work, we detail pre-thrombectomy process improvements in a multi-hospital network and report the effect on door-to-puncture time in patients undergoing mechanical thrombectomy. PATIENTS AND METHODS: A streamlined workflow was adopted to minimize door-to-puncture time. Key features of this workflow included rapid and concurrent clinical and radiological evaluation with point-of-care image interpretation, pre-transfer IV thrombolysis and CTA for transferred patients, immediate transport to the angiography suite potentially before neurointerventional radiology team arrival, and minimalist room setup. Door-to puncture time was measured prospectively and analyzed retrospectively for 78 consecutive patients treated between January 2015 and December 2015. Statistical analysis was performed using the F-test on individual coefficients of a linear regression model. RESULTS: From quarter 1 to quarter 4, the number of thrombectomies performed increased by 173% (11 patients to 30 patients, p = 0.002), and there was a significant increase in the proportion of transferred patients that underwent pre-transfer CTA (p = 0.04). During this interval, overall median door-to-puncture time decreased by 74% (147 min to 39 min, p < 0.001); this decrease was greatest in transferred patients with pre-transfer CTA (81% decrease, 129 min to 25 min, p < 0.001) and smallest in patients presenting directly to the emergency department (52% decrease, 167 min to 87 min, p < 0.001). CONCLUSION: Simple workflow improvements to streamline in-hospital triage and perform critical workup at transferring hospitals can produce reductions in door-to-puncture time. PMID- 29408778 TI - Increased serum levels of TNF-alpha and decreased serum levels of IL-27 in patients with Parkinson disease and their correlation with disease severity. AB - OBJECTIVES: Immunological basis of neurodegenerative diseases including Alzheimer and Parkinson disease (PD) has some important roles in their pathogenesis. There are conflicting studies to serum level of TNF-alpha in PD. Also, according to our finding there is no report evaluating serum level of IL-27 in PD. This study correlates the serum level of those factors with severity of PD. PATIENTS AND METHODS: In this case-control study, 83 patients with PD and 83 healthy volunteers were enrolled. The diagnosis was fulfilled in accordance with clinical diagnostic criteria of the UK Parkinson's Disease Society Brain Bank by two neurologists. The modified Hoehn and Yahr (H and Y) scale was used to evaluate the severity of PD. Serum levels of TNF-alpha and IL-27 were measured by Elisa. Correlation of H and Y scale with serum levels of these cytokines was evaluated. RESULTS: The serum levels of TNF-alpha were increased and serum levels of IL-27 were decreased in patients with PD compared to those in healthy subjects (P < 0.0001). There was a significant correlation between serum levels of TNF-alpha and IL-27 with H and Y scale. CONCLUSION: Our study showed that the serum levels of TNF-alpha and IL-27 may be important prognostic biomarkers of PD. PMID- 29408779 TI - Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: Improving diagnosis with targeted sequencing for variants by in silico analysis. AB - OBJECTIVES: Genetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis. PATIENTS AND METHODS: A 36-gene-panel next generation sequencing was applied for IEE in two Iranian families. A literature search was performed using keywords to identify reported splicing mutations in SCN1A and perform genotype-phenotype correlation. RESULTS: An update of splicing mutations revealed 147 variants with 65.75% of them de novo mutations. Most of the familial variants were of parental origin. The structure of the protein was often affected in the linker and transmembrane segments. 92% of intronic variants were pathogenic. A de novo heterozygous mutation was found in the first patient, but not in her sibling and parents. In the second family, a novel de novo heterozygous mutation was found at position c.1210insT leading to a truncated protein. CONCLUSION: Gene-panel sequencing is helpful for reducing the time and cost, guiding early treatment, and estimating the recurrence risks. The importance of characterization of intronic variants was noticed; though bioinformatics analysis of novel intronic variants should be of concern for rapid reporting the pathogenic effect of variants. PMID- 29408780 TI - Role of radiotherapy in residual pineal parenchymal tumors. AB - OBJECTIVES: Surgical excision of pineal parenchymal tumors(PPT), though desirable for good long term outcome, may not always be possible. Role of adjuvant radiotherapy (RT) in residual PPT's is not well delineated. The purpose of this single institutional retrospective study is to assess the role of radiotherapy in residual PPT's. PATIENTS AND METHODS: Between 2006-2016, fourteen patients with residual PPT's were treated with adjuvant radiotherapy (12 with 3D conformal RT). Eight had pineocytomas (PC), 4 pineal parenchymal tumors with intermediate differentiation (PPID) and 2 pineoblastomas (PB). Doses of 45-54 Gy was delivered in 1.8-2 Gy per fraction. Cranio-spinal irradiation(CSI) was given to one case of PB and PPID each, with drop lesions at presentation. Patients were followed up at regular intervals. RESULTS: The average Planning Target Volume (PTV) was 279.4cc. Clinico-radiological response was noted in all with complete disappearance of tumor in 4 patients with PC and 2 with PPID. Delayed recurrence (36-72 months later, median 42.5 months) was seen in 3 patients with PC and early recurrence in both with PB (median 28 months). Overall median follow-up for PC and PB was 54 and 31.5 months respectively. Two patients with PC and 2 with PB expired. The median follow-up for PPID was 21.5 months with no deaths or recurrences. CONCLUSIONS: Some PC and PPID may behave aggressively and recur or spread along neural axes requiring close follow up. Radiotherapy appears to be effective in patients with residual PC, PPID. Re-irradiation or radiosurgery may help in recurrences. PMID- 29408781 TI - Extradural petromastoid calcifying pseudoneoplasm of the neuraxis (CAPNON): Case report and literature review. AB - BACKGROUND: Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a very rare tumor with fewer than 70 cases reported in the literature. In general, this tumor occurs intracranially either within the brain parenchyma or in an extra-axial location, but it has also been described within the spine as an extra-axial lesion. CASE DESCRIPTION: We describe an unusual case of intracranial-extradural CAPNON involving the mastoid region. This may be only the second such case reported in the literature, as one patient with CAPNON has been reported involving the sinonasal region. Our patient was managed with surgical resection through a translabyrinthine approach with good early result. CONCLUSIONS: We describe an unusual case of extradural CAPNON involving the mastoid bone. It appears that when located extradurally, this tumor may have a predilection for the bony sinuses. This little-known, generally benign entity can mimic more common lesions such as meningiomas, and should be considered in the differential diagnosis of skull base tumors, particularly when associated with heavy calcification. PMID- 29408782 TI - Changes of cerebrospinal fluid protein concentrations and gait patterns in geriatric normal pressure hydrocephalus patients after ventriculoperitoneal shunting surgery. AB - Normal pressure hydrocephalus (NPH) was the first type of dementia ever described that can be treated using ventriculoperitoneal shunting surgery. Three typical clinical symptoms of NPH include gait disturbance, progressive cognitive dysfunction, and urinary incontinence. Although there are articles that have discovered several cerebrospinal fluid (CSF) protein biomarkers associated with NPH; however, studies examining individual and total protein concentrations from the ventricular CSF before and after shunting surgery are lacking. This study used proteomics to calculate the CSF individual and total protein concentrations before, and one week, one month and three months after the shunting surgery. Parameters of cadence, step length, walking speed, and percentages of single- and double-limb support in a gait cycle were measured. Protein concentrations associated with anti-oxidation, aging, and in the prevention of neurotoxic agent production increased by at least 2-folds after the surgery, indicating that the brain may become less susceptible to neurodegeneration. These proteins were alpha 1B-glycoprotein, apolipoproteins A-1 & A-IV, prostaglandin-H2 D-isomerase, alpha 1-antitrypsin, and serotransferrin. In gait analysis, lower cadence, decreased double-limb support, longer step length, and increased single-limb support were observed after the surgery, indicating a more stable walking balance. These changes lasted for a period of at least 3 months. As a result, shunting surgery may be recommended for geriatric patients with confirmed diagnosis of normal pressure hydrocephalus. PMID- 29408783 TI - Incorporation of Prior Knowledge of Signal Behavior Into the Reconstruction to Accelerate the Acquisition of Diffusion MRI Data. AB - Diffusion MRI data are generally acquired using hyperpolarized gases during patient breath-hold, which yields a compromise between achievable image resolution, lung coverage, and number of -values. In this paper, we propose a novel method that accelerates the acquisition of diffusion MRI data by undersampling in both the spatial and -value dimensions and incorporating knowledge about signal decay into the reconstruction (SIDER). SIDER is compared with total variation (TV) reconstruction by assessing its effect on both the recovery of ventilation images and the estimated mean alveolar dimensions (MADs). Both methods are assessed by retrospectively undersampling diffusion data sets ( =8) of healthy volunteers and patients with Chronic Obstructive Pulmonary Disease (COPD) for acceleration factors between x2 and x10. TV led to large errors and artifacts for acceleration factors equal to or larger than x5. SIDER improved TV, with a lower solution error and MAD histograms closer to those obtained from fully sampled data for acceleration factors up to x10. SIDER preserved image quality at all acceleration factors, although images were slightly smoothed and some details were lost at x10. In conclusion, we developed and validated a novel compressed sensing method for lung MRI imaging and achieved high acceleration factors, which can be used to increase the amount of data acquired during breath hold. This methodology is expected to improve the accuracy of estimated lung microstructure dimensions and provide more options in the study of lung diseases with MRI. PMID- 29408784 TI - On-the-Fly Adaptive ${k}$ -Space Sampling for Linear MRI Reconstruction Using Moment-Based Spectral Analysis. AB - In high-dimensional magnetic resonance imaging applications, time-consuming, sequential acquisition of data samples in the spatial frequency domain ( -space) can often be accelerated by accounting for dependencies in linear reconstruction, at the cost of noise amplification that depends on the sampling pattern. Common examples are support-constrained, parallel, and dynamic MRI, and -space sampling strategies are primarily driven by image-domain metrics that are expensive to compute for arbitrary sampling patterns. It remains challenging to provide systematic and computationally efficient automatic designs of arbitrary multidimensional Cartesian sampling patterns that mitigate noise amplification, given the subspace to which the object is confined. To address this problem, this paper introduces a theoretical framework that describes local geometric properties of the sampling pattern and relates them to the spread in the eigenvalues of the information matrix described by its first two spectral moments. This new criterion is then used for very efficient optimization of complex multidimensional sampling patterns that does not require reconstructing images or explicitly mapping noise amplification. Experiments with in vivo data show strong agreement between this criterion and traditional, comprehensive image domain- and -space-based metrics, indicating the potential of the approach for computationally efficient (on-the-fly), automatic, and adaptive design of sampling patterns. PMID- 29408785 TI - Cyclic Continuous Max-Flow: A Third Paradigm in Generating Local Phase Shift Maps in MRI. AB - Sensitivity to phase deviations in MRI forms the basis of a variety of techniques, including magnetic susceptibility weighted imaging and chemical shift imaging. Current phase processing techniques fall into two families: those which process the complex image data with magnitude and phase coupled, and phase unwrapping-based techniques that first linearize the phase topology across the image. However, issues, such as low signal and the existence of phase poles, can lead both methods to experience error. Cyclic continuous max-flow (CCMF) phase processing uses primal-dual-variational optimization over a cylindrical manifold, which represent the inherent topology of phase images, increasing its robustness to these issues. CCMF represents a third distinct paradigm in phase processing, being the only technique equipped with the inherent topology of phase. CCMF is robust and efficient with at least comparable accuracy as the prior paradigms. PMID- 29408786 TI - Multi-Scale Segmentation and Surface Fitting for Measuring 3-D Macular Holes. AB - Macular holes are blinding conditions, where a hole develops in the central part of retina, resulting in reduced central vision. The prognosis and treatment options are related to a number of variables, including the macular hole size and shape. High-resolution spectral domain optical coherence tomography allows precise imaging of the macular hole geometry in three dimensions, but the measurement of these by human observers is time-consuming and prone to high inter and intra-observer variability, being characteristically measured in 2-D rather than 3-D. We introduce several novel techniques to automatically retrieve accurate 3-D measurements of the macular hole, including: surface area, base area, base diameter, top area, top diameter, height, and minimum diameter. Specifically, we introduce a multi-scale 3-D level set segmentation approach based on a state-of-the-art level set method, and we introduce novel curvature based cutting and 3-D measurement procedures. The algorithm is fully automatic, and we validate our extracted measurements both qualitatively and quantitatively, where our results show the method to be robust across a variety of scenarios. Our automated processes are considered a significant contribution for clinical applications. PMID- 29408787 TI - Evaluation of Parallel Level Sets and Bowsher's Method as Segmentation-Free Anatomical Priors for Time-of-Flight PET Reconstruction. AB - In this article, we evaluate Parallel Level Sets (PLS) and Bowsher's method as segmentation-free anatomical priors for regularized brain positron emission tomography (PET) reconstruction. We derive the proximity operators for two PLS priors and use the EM-TV algorithm in combination with the first order primal dual algorithm by Chambolle and Pock to solve the non-smooth optimization problem for PET reconstruction with PLS regularization. In addition, we compare the performance of two PLS versions against the symmetric and asymmetric Bowsher priors with quadratic and relative difference penalty function. For this aim, we first evaluate reconstructions of 30 noise realizations of simulated PET data derived from a real hybrid positron emission tomography/magnetic resonance imaging (PET/MR) acquisition in terms of regional bias and noise. Second, we evaluate reconstructions of a real brain PET/MR data set acquired on a GE Signa time-of-flight PET/MR in a similar way. The reconstructions of simulated and real 3D PET/MR data show that all priors were superior to post-smoothed maximum likelihood expectation maximization with ordered subsets (OSEM) in terms of bias noise characteristics in different regions of interest where the PET uptake follows anatomical boundaries. Our implementation of the asymmetric Bowsher prior showed slightly superior performance compared with the two versions of PLS and the symmetric Bowsher prior. At very high regularization weights, all investigated anatomical priors suffer from the transfer of non-shared gradients. PMID- 29408788 TI - Fast Spatial Resolution Analysis of Quadratic Penalized Least-Squares Image Reconstruction With Separate Real and Imaginary Roughness Penalty: Application to fMRI. AB - Penalized least-squares iterative image reconstruction algorithms used for spatial resolution-limited imaging, such as functional magnetic resonance imaging (fMRI), commonly use a quadratic roughness penalty to regularize the reconstructed images. When used for complex-valued images, the conventional roughness penalty regularizes the real and imaginary parts equally. However, these imaging methods sometimes benefit from separate penalties for each part. The spatial smoothness from the roughness penalty on the reconstructed image is dictated by the regularization parameter(s). One method to set the parameter to a desired smoothness level is to evaluate the full width at half maximum of the reconstruction method's local impulse response. Previous work has shown that when using the conventional quadratic roughness penalty, one can approximate the local impulse response using an FFT-based calculation. However, that acceleration method cannot be applied directly for separate real and imaginary regularization. This paper proposes a fast and stable calculation for this case that also uses FFT-based calculations to approximate the local impulse responses of the real and imaginary parts. This approach is demonstrated with a quadratic image reconstruction of fMRI data that uses separate roughness penalties for the real and imaginary parts. PMID- 29408789 TI - Automatic Calcium Scoring in Low-Dose Chest CT Using Deep Neural Networks With Dilated Convolutions. AB - Heavy smokers undergoing screening with low-dose chest CT are affected by cardiovascular disease as much as by lung cancer. Low-dose chest CT scans acquired in screening enable quantification of atherosclerotic calcifications and thus enable identification of subjects at increased cardiovascular risk. This paper presents a method for automatic detection of coronary artery, thoracic aorta, and cardiac valve calcifications in low-dose chest CT using two consecutive convolutional neural networks. The first network identifies and labels potential calcifications according to their anatomical location and the second network identifies true calcifications among the detected candidates. This method was trained and evaluated on a set of 1744 CT scans from the National Lung Screening Trial. To determine whether any reconstruction or only images reconstructed with soft tissue filters can be used for calcification detection, we evaluated the method on soft and medium/sharp filter reconstructions separately. On soft filter reconstructions, the method achieved F1 scores of 0.89, 0.89, 0.67, and 0.55 for coronary artery, thoracic aorta, aortic valve, and mitral valve calcifications, respectively. On sharp filter reconstructions, the F1 scores were 0.84, 0.81, 0.64, and 0.66, respectively. Linearly weighted kappa coefficients for risk category assignment based on per subject coronary artery calcium were 0.91 and 0.90 for soft and sharp filter reconstructions, respectively. These results demonstrate that the presented method enables reliable automatic cardiovascular risk assessment in all low-dose chest CT scans acquired for lung cancer screening. PMID- 29408790 TI - Accelerated Parameter Mapping of Multiple-Echo Gradient-Echo Data Using Model Based Iterative Reconstruction. AB - A new reconstruction method, coined MIRAGE, is presented for accurate, fast, and robust parameter mapping of multiple-echo gradient-echo (MEGE) imaging, the basis sequence of novel quantitative magnetic resonance imaging techniques such as water content and susceptibility mapping. Assuming that the temporal signal can be modeled as a sum of damped complex exponentials, MIRAGE performs model-based reconstruction of undersampled data by minimizing the rank of local Hankel matrices. It further incorporates multi-channel information and spatial prior knowledge. Finally, the parameter maps are estimated using nonlinear regression. Simulations and retrospective undersampling of phantom and in vivo data affirm robustness, e.g., to strong inhomogeneity of the static magnetic field and partial volume effects. MIRAGE is compared with a state-of-the-art compressed sensing method, -ESPIRiT. Parameter maps estimated from reconstructed data using MIRAGE are shown to be accurate, with the mean absolute error reduced by up to 50% for in vivo results. The proposed method has the potential to improve the diagnostic utility of quantitative imaging techniques that rely on MEGE data. PMID- 29408791 TI - Convolutional Invasion and Expansion Networks for Tumor Growth Prediction. AB - Tumor growth is associated with cell invasion and mass-effect, which are traditionally formulated by mathematical models, namely reaction-diffusion equations and biomechanics. Such models can be personalized based on clinical measurements to build the predictive models for tumor growth. In this paper, we investigate the possibility of using deep convolutional neural networks to directly represent and learn the cell invasion and mass-effect, and to predict the subsequent involvement regions of a tumor. The invasion network learns the cell invasion from information related to metabolic rate, cell density, and tumor boundary derived from multimodal imaging data. The expansion network models the mass-effect from the growing motion of tumor mass. We also study different architectures that fuse the invasion and expansion networks, in order to exploit the inherent correlations among them. Our network can easily be trained on population data and personalized to a target patient, unlike most previous mathematical modeling methods that fail to incorporate population data. Quantitative experiments on a pancreatic tumor data set show that the proposed method substantially outperforms a state-of-the-art mathematical model-based approach in both accuracy and efficiency, and that the information captured by each of the two subnetworks is complementary. PMID- 29408792 TI - On the Reliability of Individual Brain Activity Networks. AB - There is intense interest in fMRI research on whole-brain functional connectivity, and however, two fundamental issues are still unresolved: the impact of spatiotemporal data resolution (spatial parcellation and temporal sampling) and the impact of the network construction method on the reliability of functional brain networks. In particular, the impact of spatiotemporal data resolution on the resulting connectivity findings has not been sufficiently investigated. In fact, a number of studies have already observed that functional networks often give different conclusions across different parcellation scales. If the interpretations from functional networks are inconsistent across spatiotemporal scales, then the whole validity of the functional network paradigm is called into question. This paper investigates the consistency of resting state network structure when using different temporal sampling or spatial parcellation, or different methods for constructing the networks. To pursue this, we develop a novel network comparison framework based on persistent homology from a topological data analysis. We use the new network comparison tools to characterize the spatial and temporal scales under which consistent functional networks can be constructed. The methods are illustrated on Human Connectome Project data, showing that the DISCOH2 network construction method outperforms other approaches at most data spatiotemporal resolutions. PMID- 29408793 TI - Imaging Corneal Biomechanical Responses to Ocular Pulse Using High-Frequency Ultrasound. AB - Imaging corneal biomechanical changes or abnormalities is important for better clinical diagnosis and treatment of corneal diseases. We propose a novel ultrasound-based method, called ocular pulse elastography (OPE), to image corneal deformation during the naturally occurring ocular pulse. Experiments on animal and human donor eyes, as well as synthetic radiofrequency (RF) data, were used to evaluate the efficacy of the OPE method. Using very high-frequency ultrasound (center frequency = 55 MHz), correlation-based speckle tracking yielded an accuracy of less than 10% error for axial tissue displacements of or above. Satisfactory speckle tracking was achieved for out-of-plane displacements up to . Using synthetic RF data with or without a pre-defined uniform strain, the OPE method detected strains down to 0.0001 axially and 0.00025 laterally with an error less than 10%. Experiments in human donor eyes showed excellent repeatability with an intraclass correlation of 0.98. The measurement outcome from OPE was also shown to be highly correlated with that of standard inflation. These results suggest the feasibility of OPE as a potential clinical tool for evaluating corneal biomechanics in vivo. PMID- 29408794 TI - Determination of selenium during pathogenesis of hepatic fibrosis employing hydride generation and inductively coupled plasma mass spectrometry. AB - Serum and liver selenium levels were studied during the pathogenesis of N nitrosodimethylamine (NDMA) induced hepatic fibrosis in rats. The degree of fibrosis was assessed with Masson's trichrome staining and quantifying collagen content in the liver. Lipid peroxides were measured in blood and liver samples and total glutathione and glutathione peroxidase were assayed in the liver tissue to evaluate oxidative stress. Interleukin-6 (IL-6) and transforming growth factor beta1 (TGF-beta1) were measured in the serum. Selenium levels were determined using inductively coupled plasma-mass spectrometry (ICP-MS) after acid digestion and hydride generation of selenium. Serial administrations of NDMA produced well developed fibrosis and early cirrhosis in the liver with 4-fold increase of total collagen content and deposition of collagen fibers. Blood and hepatic lipid peroxides, serum IL-6 and TGF-beta1 were significantly increased. There was significant reduction in hepatic glutathione and glutathione peroxidase levels. Serum and liver selenium were remarkably decreased on all the days studied. The results suggest that decreased selenium and glutathione peroxidase contribute to the impairment of cellular antioxidant defense, which in turn results in oxidative stress and trigger pathogenesis of hepatic fibrosis. The study further demonstrated that ICP-MS with hydride generation technique is a reliable and sensitive method for determination of selenium in biological samples. PMID- 29408795 TI - Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation. AB - GABAA receptors are ligand-gated anion channels that form pentameric arrangements of various subunits. Positive allosteric modulators of GABAA receptors have been reported as being isolated either from plants or synthesized analogs of known GABAA receptor targeting drugs. Recently, we identified monoterpenes, e.g. myrtenol as a positive allosteric modulator at alpha1beta2 GABAA receptors. Here, along with pharmacophore-based virtual screening studies, we demonstrate that scaffold modifications of myrtenol resulted in the loss of modulatory activity. Two independent approaches, fluorescence-based compound analysis and electrophysiological recordings in whole-cell configurations were used for analysis of transfected cells. C-atoms 1 and 2 of the myrtenol backbone were identified as crucial to preserve positive allosteric potential. A modification at C-atom 2 and lack of the hydroxyl group at C-atom 1 exhibited significantly reduced GABAergic currents at alpha1beta2, alpha1beta2gamma, alpha2beta3, alpha2beta3gamma and alpha4beta3delta receptors. This effect was independent of the gamma2 subunit. A sub-screen with side chain length and volume differences at the C-atom 1 identified two compounds that inhibited GABAergic responses but without receptor subtype specificity. Our combined approach of pharmacophore based virtual screening and functional readouts reveals that side chain modifications of the bridged six-membered ring structure of myrtenol are crucial for its modulatory potential at GABAA receptors. PMID- 29408796 TI - Search for new biomarkers of pediatric multiple sclerosis: application of immunoglobulin free light chain analysis. AB - BACKGROUND: Identifying new biomarkers is needed to overcome the diagnostic difficulties of pediatric multiple sclerosis (MS). Recently, we developed a new technique including CSF analysis of free light chain (FLC) monomers and dimers, which can improve diagnosis of adult MS. The present study has been designed to evaluate the utility of our technique for MS diagnosis in children. METHODS: Patients with MS (n=21) and non-MS demyelinating or inflammatory neurological disorders (n=35) participated in the study. MS diagnosis was based on clinical and magnetic resonance imaging (MRI) findings. Western blot analysis was applied to examine FLC in the patients' CSF and serum. FLC indices for FLC monomer and dimer levels and kappa/lambda ratios were estimated. The samples were also analyzed by oligoclonality test. RESULTS: The study revealed abnormally elevated levels of kappa-FLC monomers and dimers in the CSF of 10 MS patients ("kappa-type MS"). Increased amounts of lambda dimers were found in six MS cases ("lambda-type MS"), while high levels of both kappa and lambda FLC ("mixed type MS") were documented in three MS cases. MRI and clinical assessment showed a more aggressive disease form for the "mixed" and "lambda-type" cases. Our method demonstrated higher sensitivity (90.5%) and specificity (91.4%) for discrimination between MS and non-MS patients, as compared to oligoclonality test (81% and 65.7%, respectively). CONCLUSIONS: The proposed method may significantly contribute to diagnosis and prognosis of pediatric MS. PMID- 29408798 TI - Conservative treatment of postoperative chylothorax: a case report. AB - Background Chylothorax is a well-documented complication of thoracic trauma and is associated with high rates of morbidity and mortality. Treatment for chylothorax includes conservative measures (total parenteral nutrition, pleural drainage, and pleurodesis) and surgery (thoracic duct ligation). Case presentation We present the case of a 65-year-old man who developed chylothorax after an elective surgical procedure. In this report conservative treatment aims to reduce chyle flow, to drain the pleural cavity in an effective manner, and to prevent chronic sequelae. Optimal conservative treatment, started immediately upon diagnosis, effectively reduces the need for reoperation and long-term hospitalization, and it might prevent further sequelae of chylothorax. Conclusions The chylothorax was successfully treated conservatively, which may reduce the need for reoperation. PMID- 29408797 TI - Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy. AB - BACKGROUND: Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel. METHODS: We performed a cross sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measured ex vivo using the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19, ABCB1, PON1 and P2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute). RESULTS: Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207+/-53 (range, 78-325) with higher P2Y12 reaction units in the non-cilostazol group, 224+/-45 vs. 191+/-55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity. CONCLUSIONS: In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR. PMID- 29408799 TI - The case for a distinctive philosophy of physiology and pathophysiology. AB - What is an organ and what is an organ system? According to the 'standard' hierarchical model of physiology, each living organism comprises of organ systems including those that offer sensory and control functions (nervous system), energy accumulation (gastrointestinal system), internal dissipation (circulatory system) and mobility (musculoskeletal system). Each organ system in turn is comprised of individual organs. This taxonomy has conceptual flaws as not every organ has a single organ system function but may participate in a myriad of physiological functions. To answer this philosophical question, several principles are applied. At one level, the assessment of physiological function and organ system can be considered to have some relation to the broader issue of the species problem in the philosophy of biology. Additionally, however, there is a relationship to the more fundamental issue of the biochemistry of each organ that can be considered through the philosophy of chemistry. The philosophy of physiology can therefore be considered to occupy a position somewhere between these two strata of thought on the path of science reductionism. A distinctive philosophy of physiology and pathophysiology may ultimately offer a myriad of new pathways through which to better explore the metaphysical elements of medicine and science. PMID- 29408800 TI - Body composition in preterm infants with intrauterine growth restriction: a cohort study. PMID- 29408801 TI - Pt decorated MoS2 nanoflakes for ultrasensitive resistive humidity sensor. AB - In this work, we report the fabrication of a low power, humidity sensor where platinum nanoparticles (NPs) decorated few-layered molybdenum disulphide (MoS2) nanoflakes have been used as the sensing layer. A mixed solvent was used to exfoliate the nanoflakes from the bulk powder. Then the Pt/MoS2 composites were prepared by reducing Pt NPs from chloroplatinic acid hexahydrate using a novel reduction technique using sulphide salt. The successful reduction and composite preparation were confirmed using various material characterization tools like scanning electron microscopy, atomic force microscopy, transmission electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy, Raman spectroscopy and UV-visible spectroscopy. The humidity sensors were prepared by drop-coating the Pt-decorated MoS2 on gold interdigitated electrodes and then exposed to various levels of relative humidity (RH). Composites with different weight ratios of Pt were tested and the best response was shown by the Pt/MoS2 (0.25:1) sample with a record high response of ~4000 times at 85% RH. The response and recovery times were ~92 s and ~154 s respectively with repeatable behaviour. The sensor performance was found to be stable when tested over a few months. The underlying sensing mechanisms along with detailed characterization of the various composites have been discussed. PMID- 29408802 TI - Analysis of volatile organic compounds: an innovative approach to heart failure characterization in older patients. AB - BACKGROUND: Analysis of exhaled volatile organic compounds (VOCs) may be applied for diagnostic purposes in some chronic diseases, but there are no data on their role for discriminating people with congestive heart failure (CHF), particularly in older patients where natriuretic peptides have lower accuracy. We evaluated whether VOCs analysis can discriminate patients with or without CHF, stratify CHF severity and predict the response to therapy of decompensated CHF. METHODS AND RESULTS: We recruited 89 subjects admitted to an acute care ward with acutely decompensated CHF, 117 healthy controls and 103 chronic obstructive pulmonary disease (COPD) controls. CHF patients performed echocardiography. VOCs were collected using the Pneumopipe(r) and analyzed with the BIONOTE electronic nose. Partial least square analysis was used to evaluate the discriminative capacity of VOCs. Accuracy in discrimination of CHF versus healthy and COPD controls was 81% and 69%, respectively; accuracy did not decrease in a sensitivity analysis excluding subjects younger than 65 and older than 80 years. In CHF patients VOCs pattern could predict with fair precision ejection fraction and systolic pulmonary arterial pressure, but not changes in weight due to therapy. CONCLUSIONS: VOCs pattern is able to discriminate older CHF patients from healthy people and COPD patients and correlates with cardiac function markers. PMID- 29408803 TI - PET attenuation correction for rigid MR Tx/Rx coils from 176Lu background activity. AB - One challenge for PET-MR hybrid imaging is the correction for attenuation of the 511 keV annihilation radiation by the required RF transmit and/or RF receive coils. Although there are strategies for building PET transparent Tx/Rx coils, such optimised coils still cause significant attenuation of the annihilation radiation leading to artefacts and biases in the reconstructed activity concentrations. We present a straightforward method to measure the attenuation of Tx/Rx coils in simultaneous MR-PET imaging based on the natural 176Lu background contained in the scintillator of the PET detector without the requirement of an external CT scanner or PET scanner with transmission source. The method was evaluated on a prototype 3T MR-BrainPET produced by Siemens Healthcare GmbH, both with phantom studies and with true emission images from patient/volunteer examinations. Furthermore, the count rate stability of the PET scanner and the x ray properties of the Tx/Rx head coil were investigated. Even without energy extrapolation from the two dominant gamma energies of 176Lu to 511 keV, the presented method for attenuation correction, based on the measurement of 176Lu background attenuation, shows slightly better performance than the coil attenuation correction currently used. The coil attenuation correction currently used is based on an external transmission scan with rotating 68Ge sources acquired on a Siemens ECAT HR + PET scanner. However, the main advantage of the presented approach is its straightforwardness and ready availability without the need for additional accessories. PMID- 29408804 TI - A simple way to synthesize large-scale Cu2O/Ag nanoflowers for ultrasensitive surface-enhanced Raman scattering detection. AB - Here, we report a simple strategy to prepare highly sensitive surface-enhanced Raman spectroscopy (SERS) substrates based on Ag decorated Cu2O nanoparticles by combining two common techniques, viz, thermal oxidation growth of Cu2O nanoparticles and magnetron sputtering fabrication of a Ag nanoparticle film. Methylene blue is used as the Raman analyte for the SERS study, and the substrates fabricated under optimized conditions have very good sensitivity (analytical enhancement factor ~108), stability, and reproducibility. A linear dependence of the SERS intensities with the concentration was obtained with an R 2 value >0.9. These excellent properties indicate that the substrate has great potential in the detection of biological and chemical substances. PMID- 29408805 TI - Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation. AB - Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anemia and 5q- syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal-associated factors in this process. Ribonuclease inhibitor 1 (RNH1) is a ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases. Here, we report that RNH1 binds to ribosomes and regulates erythropoiesis by controlling translation of the erythroid transcription factor GATA1. Rnh1-deficient mice die between embryonic days E8.5 and E10 due to impaired production of mature erythroid cells from progenitor cells. In Rnh1-deficient embryos, mRNA levels of Gata1 are normal, but GATA1 protein levels are decreased. At the molecular level, we found that RNH1 binds to the 40S subunit of ribosomes and facilitates polysome formation on Gata1 mRNA to confer transcript-specific translation. Further, RNH1 knockdown in human CD34+ progenitor cells decreased erythroid differentiation without affecting myelopoiesis. Our results reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis. PMID- 29408806 TI - Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn's disease. AB - In these studies, we evaluated the contribution of the NLRP3 inflammasome to Crohn's disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified the affected individuals as having a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL 1beta in the affected individuals were increased compared with those in healthy controls, and their peripheral monocytes produced increased amounts of IL-1beta when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 failed to downregulate the NLRP3 inflammasome because it did not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerted a dominant-negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impeded their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevented NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti-TNF-alpha, but did respond to IL-1beta inhibitors. Thus, patients with anti-TNF-alpha-resistant CD may respond to this treatment option. PMID- 29408807 TI - Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. AB - A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1 associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications. PMID- 29408810 TI - Is Parenteral Thiamin a Super Antibiotic? PMID- 29408808 TI - Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons. AB - Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control. PMID- 29408811 TI - Two for One: B-Cell Lymphomas with Features of Marginal and Follicular Lymphomas. AB - Low-grade follicular lymphomas are genetically characterized by the translocation t(14; 18)(q32;q21) with BCL2 gene rearrangements. Marginal zone lymphomas are often associated with translocations or transcriptional deregulations of the MALT gene. We report 2 cases of lymphomas which harbor both the t(14;18)(q32;q21) translocation and MALT gene upregulation. Patients presented with numerous circulating atypical lymphocytes. Lymph node biopsy in both cases on HE staining demonstrated vague nodularity readily highlighted by CD10, CD23, or BCL6. Staining with CD20 and BCL2 demonstrated monotonous diffuse effacement of normal architecture with tumor cells without obvious follicular structures. Morphologically, tumor cells were consistent with centrocytes. Bone marrow biopsy demonstrated a combined peritrabecular and interstitial distribution of the tumor cells. These cases present substantial difficulties for diagnosis and classification. Clinical and morphological features were mostly consistent with follicular lymphoma, with a few features more often seen in marginal zone lymphomas (leukemic presentation, no CD10 in circulating cells, interstitial location of tumor cells in bone marrow); therefore, these cases were finally classified as follicular lymphoma grade I. Both patients were treated with standard chemotherapy regimens for follicular and nongastric MALT lymphomas with a good response to date. PMID- 29408812 TI - High Expression of Human Cathepsin S by Recombinant Pichia pastoris with Cod Skin as an Organic Co-Nitrogen Source. AB - Human cathepsin S production by recombinant Pichia pastoris using cod skin as the co-nitrogen source was investigated in this study. The addition of carbon sources of glycerol in the fed-batch phase and of methanol in the induction stage was also investigated. A new approach to the highly expression of human cathepsin S was developed using 90 g/L of cod skin (wet weight). After 24 h of the initial fermentation, 4% glycerol (v/v, glycerol/culture) was added once to enhance the cell density (OD600) in the cultivation. Then, adding and maintaining methanol at 0.5% (v/v, methanol/cultivation) after about 48 h of fermentation achieved a high expression of human cathepsin S in a 5-L bioreactor. The results demonstrate that the maximum activity of human cathepsin S in the fermentation supernatant reached 7,152 U/L after 96 h of methanol induction. The methylotrophic yeast P. pastoris grown in the medium containing cod skin (90 g/L) as the co-nitrogen source provided a 21% higher cell density (OD600) and 18.3% higher human cathepsin S yield than P. pastoris grown in BMGY medium. For the first time, human cathepsin S was successfully expressed by P. pastoris with cod skin as the co-nitrogen source. The glycerol fed-batch controlling strategy and method of maintaining methanol at a constant concentration of 0.5% (v/v, methanol/cultivation) in the induction stage was efficient for P. pastoris growth and the expression of human cathepsin S. PMID- 29408809 TI - FoxO transcription factors are required for hepatic HDL cholesterol clearance. AB - Insulin resistance and type 2 diabetes are associated with low levels of high density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver. PMID- 29408813 TI - GTPBP4 Promotes Gastric Cancer Progression via Regulating P53 Activity. AB - BACKGROUND/AIMS: gastric cancer is a serious health concern with high morbidity and mortality. Therefore, it is urgent to find novel targets for gastric cancer diagnosis and treatment. METHODS: qRT-PCR and immunohistochemistry assays were used to detect GTPBP4 expression in gastric cancer tissues, and gastric cancer and gastric epithelial cells. Lentivirus infection was used to construct GTPBP4 stable knockdown cells. Annexin V/PI apoptosis, CCK8, EdU incorporation and cell clone formation analysis were performed to evaluate the effects of GTPBP4 on gastric cancer cell proliferation and apoptosis. Further RNA-based high throughput sequencing and co-IP assays were constructed to explore the related mechanisms contributing to GTPBP4-mediated effects. RESULTS: GTPBP4 expression was significantly increased in gastric cancer tissues compared with that in adjacent normal tissues, and positively correlated with gastric cancer stages. Meanwhile, GTPBP4 level was markedly upregulated in gastric cancer cells than in gastric epithelial cells. Additionaly, stable knockdown of GTPBP4 inhibited cell proliferation and promoted cell apoptosis. Mechanistically, p53 and its related signaling were significantly activated in GTPBP4 stable knockdown cells. And GTPBP4 interacted with p53 in gastric cancer cells. CONCLUSIONS: our results provide insights into mechanistic regulation and linkage of the GTPBP4-p53 in gastric cancer, and also a valuable potential target for gastric cancer. PMID- 29408814 TI - Magnesium as a Neuroprotective Agent: A Review of Its Use in the Fetus, Term Infant with Neonatal Encephalopathy, and the Adult Stroke Patient. AB - Magnesium is an intracellular cation essential for many en-zymatic processes and cellular functions. Magnesium sulfate acts as an endogenous calcium channel antagonist at neuronal synapses, thought to prevent excessive activation of N methyl-D-aspartate receptors by excitatory amino acids, such as glutamate, and by downregulation of proinflammatory pathways. Early intervention is essential in the prevention of the secondary phase of neuronal injury. The immature brain is particularly prone to excitotoxicity, and inflammation has been strongly implicated in the pathogenesis of cerebral palsy. This article explores the current status of magnesium being used as an adjunct to hypothermia in term neonatal encephalopathy (NE) against a background of its use in other populations. There is some evidence for magnesium sulfate as a neuroprotective agent, however animal studies of NE at term equivalent age have been confounded by concomitant hypothermia induced by magnesium itself. Nevertheless, the combination of magnesium and cooling has been shown to be more effective than either treatment alone in adult rodents. In the preterm baby, magnesium sulfate given antenatally in threatened preterm labor has demonstrated a significant reduction in the risk of cerebral palsy at 2 years of age, though the benefit is not clear at school age. In adult clinical studies of ischemic and hemorrhagic stroke, there have been disappointing results for magnesium sulfate as a neuroprotective strategy. Importantly, clinical neurological scores may be affected by the increased hypotonia observed. We suggest that magnesium sulfate should be carefully re-evaluated as a neuroprotective agent given its favorable safety profile, relative low cost, and widespread availability. PMID- 29408815 TI - Virtual Networks for Exchanging Information and Biomaterials: Future Directions. AB - Clinical and research networks for rare conditions are increasingly common nowadays. Given the rarity of many such conditions, there is a need to cover more conditions, yet there is also a need to sustain and improve the quality and effectiveness of existing networks. This review will discuss the qualities that are required by a virtual network using some international clinical and research networks that are currently active in the field of rare endocrine conditions affecting sex and adrenal development as exemplars. PMID- 29408816 TI - Study Time after School and Habitual Eating Are Associated with Risk for Obesity among Overweight Korean Children: A Prospective Study. AB - OBJECTIVE: To investigate behavioral factors that contribute to the development of obesity among overweight children. METHODS: Among a community sample of 884 children aged 9-13 years, 833 children completed a baseline and 1-year follow-up examination that included anthropometrics, physical fitness, and behavioral factors. RESULTS: During the follow-up period, BMI for most children with normal weight or obesity did not change. However, among overweight children (n = 100), about one-third developed obesity (n = 26), while the others were categorized as normal weight (n = 32) or overweight (n = 42) after 1 year. Characteristics of overweight children at baseline and follow-up were analyzed. Those who developed obesity showed a notable increase in blood pressure as well as in BMI, waist circumference, and body fat over 1 year. At baseline, this group spent more time studying after school compared to overweight children who did not develop obesity, while there were no differences in time spent viewing television or engaging in vigorous physical activity. Eating outside the home, fast food consumption, and habitual eating in the absence of hunger were more common at baseline in those who did versus those who did not develop obesity. After adjusting for age, sex, and BMI, spending more time studying after school and habitual eating without hunger were associated with the development of obesity. CONCLUSION: Among Korean overweight children, study time after school and habitual eating without hunger were associated with an increased risk for development of obesity. PMID- 29408817 TI - Prelemniscal Lesion for Selective Improvement of Parkinson Disease Tremor. AB - BACKGROUND: Selective improvement of symptoms may be required when treating Parkinson disease (PD) patients with a predominantly monosymptomatic clinical picture. OBJECTIVE: To define a target in prelemniscal radiation fibers (Raprl) related to the physiopathology of tremor evidenced by tractography. CASE REPORT: We report a patient with predominant unilateral rest and postural tremor, diagnosed as PD based on 80% improvement induced by the administration of L DOPA/carbidopa, subsequently complicated by motor fluctuations, L-DOPA dyskinesia, and a reduced ON period. A stereotactic radiofrequency lesion was made for tremor control, and postoperative diffusion-weighted imaging (DWI) demonstrated the precise location and extension of the lesioned tract. RESULTS: Perfect control of the tremor was achieved with the patient OFF medication; this has lasted for 5 years, without hypotonia in the treated extremities. DWI revealed a 3.0-mm lesion at the base of the nucleus ventralis intermedius (Vim) interrupting cerebellar-Vim fibers sparing the cerebellar ventralis oralis posterior nucleus component. CONCLUSION: Selective improvement of symptoms is feasible in patients with a predominantly monosymptomatic PD clinical presentation. PMID- 29408818 TI - Microcomputed Tomography Evaluation of Dentine Mineral Concentration in Primary Molars Managed by Three Treatment Protocols. AB - The objectives of the study were to quantify the dentine mineral concentration (DMC) in teeth restored conventionally, according to the atraumatic restorative treatment (ART) and ultraconservative (UCT) protocols (open cavities and small ART restorations), and the DMC underneath the open cavities of teeth managed by UCT versus nontreated, open cavities. We studied 50 teeth with restorations/open cavities, 39 restored teeth (9 by conventional restorative treatment [CRT], 17 by ART, and 13 by UCT) and 16 teeth with open cavities. Each restoration/open cavity was scanned using microcomputed tomography, with 3 hydroxyapatite disks with respective densities of 1.24, 1.33, and 1.57 g/cm3 as a reference. Images were reconstructed and the greyscale images were converted into DMC values. For each restoration/open cavity, 15 measurements of dentine immediately underneath and from the corresponding area in sound dentine were taken. DMC was expressed as a percentage of the DMC of sound dentine. ANOVA and the Student t test were used for statistical analysis. The mean DMC underneath restorations of the ART protocol group (98.93%) was statistically significantly higher than that of the UCT protocol group (91.98%), but not of the CRT protocol group (91.33%). On multiple surfaces, mean DMC in the axial area (94.32%) was statistically significantly higher than in the gingival area (92.80%). The mean DMC of open cavities managed by UCT protocol (89.05%) was statistically significantly higher than in nontreated open cavities (83.90%). In conclusion, a dentine hypermineralized area underneath ART restorations was observed. Managing open cavities with a toothbrush and fluoride toothpaste (the UCT protocol) resulted in higher mineralized dentine underneath the cavity than in nontreated open cavities. PMID- 29408819 TI - Placenta-Derived Decidua Stromal Cells for Hemorrhagic Cystitis after Stem Cell Transplantation. AB - BACKGROUND/AIMS: Hemorrhagic cystitis (HC) is a serious complication after hematopoietic stem cell transplantation (HSCT). Stromal cells have been tested as therapy for HC. Decidua stromal cells (DSCs) protect the fetus from the mother's immune system. METHODS: Eleven patients with HC of grades 3-4 were treated with DSCs after HSCT. The median age was 33 years (range 8-50), and the median dose of DSCs was 1.5 * 106/kg (range 0.7-2.5). The patients were given 1 dose (1-4). RESULTS: In 5 patients, HC disappeared within 5 days after DSC infusion. Patients who received DSCs within 3 days after the start of HC had a duration of HC of 5 days and a shorter duration of pain than patients who were given DSCs later (p = 0.02). Three patients received DSCs prepared in albumin instead of AB-plasma and tended to have a shorter duration of pain (p = 0.07). There was no infusion toxicity. Adverse events were those often seen after HSCT. Nine of the 11 patients (82%) were alive 1 year after HSCT. CONCLUSIONS: Based on this pilot study, we started a randomized, placebo-controlled double-blind study using 2 doses of 1 * 106 DSCs/kg suspended in albumin for treatment of early HC. PMID- 29408820 TI - Heterogeneity of Thyroid Cancer. AB - There are 5 main histological types of thyroid cancers (TCs): papillary, follicular (also known as differentiated), poorly differentiated, anaplastic (the most aggressive form), and medullary TC, and only the latter arises from thyroid C cells. These different forms of TCs show significant variability, both among and within tumours. This great variation is particularly notable among the first 4 types, which all originate from thyroid follicular cells. Importantly, this heterogeneity is not limited to histopathological diversity only but is also manifested as variation in several genetic and/or epigenetic alterations, the numbers of interactions between the tumour and surrounding microenvironment, and interpatient differences, for example. All these factors contribute to the great complexity in the development of a tumour from cancer cells. In the present review, we summarise the knowledge accumulated about the heterogeneity of TCs. Further research in this direction should help to gain a better understanding of the underlying mechanisms contributing to the development and diversity of TCs, paving the way toward more effective treatment strategies. PMID- 29408821 TI - A Time-Series Study of the Effect of Air Pollution on Outpatient Visits for Acne Vulgaris in Beijing. AB - BACKGROUND/AIMS: There is increasing evidence that exposure to air pollutants, including particulate matter (PM2.5, PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2), might aggravate preexisting skin diseases such as eczema and urticaria. Here we investigated if a possible link exists between air pollution and acne vulgaris. We assessed the association between ambient air pollutant concentrations and the number of visits of patients for acne vulgaris to a dermatological outpatient clinic in Beijing, China, from April 1, 2012 to April 30, 2014. METHODS: In this time period, 59,325 outpatient visits were recorded because of acne vulgaris. Daily air pollution parameters for PM10, PM2.5, SO2, and NO2 were obtained from the Beijing Municipal Environmental Monitoring Center. RESULTS: Increased concentrations of ambient PM2.5, PM10, and NO2 were significantly associated with increased numbers of outpatient visits for acne vulgaris over the 2 years. These effects could be observed for NO2 in a single pollutant model and for PM2.5, PM10, and NO2 in 2-pollutant models, which are closer to real-life exposure. Of note, these effects were specific because they were not observed for increased SO2 concentrations, which even showed negative correlations in all test models. CONCLUSION: This study provides indirect evidence for a link between acne vulgaris and air pollution. PMID- 29408822 TI - Identifying Signalling Pathways Regulated by GPRC5B in beta-Cells by CRISPR-Cas9 Mediated Genome Editing. AB - BACKGROUND/AIMS: CRISPR-Cas9, a RNA-guided targeted genome editing tool, has revolutionized genetic engineering by offering the ability to precisely modify DNA. GPRC5B is an orphan receptor belonging to the group C family of G protein coupled receptors (GPCRs). In this study, we analysed the functional roles of the Gprc5b receptor in MIN6 beta-cells using CRISPR-Cas9 and transient over expression of Gprc5b. METHODS: The optimal transfection reagent for use in MIN6 beta-cells was determined by analysing efficiency of GFP plasmid delivery by cell sorting. A MIN6 beta-cell line in which Gprc5b expression was knocked down (Gprc5b KD) was generated using CRISPR-Cas9 technology. Gprc5b receptor mRNA expression, proliferation, apoptosis, Cignal 45-Pathway Reporter Array signalling and western blot assays were carried out using Gpcr5b KD MIN6 beta-cells that had been transiently transfected with different concentrations of mouse Gprc5b plasmid to over-express Gprc5b. RESULTS: JetPRIME(r) was the best candidate for MIN6 beta-cell transfection, providing approximately 30% transfection efficiency. CRISPR-Cas9 technology targeting Gprc5b led to stable knock-down of this receptor in MIN6 beta-cells and its re-expression induced proliferation and potentiated cytokine- and palmitate-induced apoptosis. The Cignal 45 Reporter analysis indicated Gprc5b-dependent regulation of apoptotic and proliferative pathways, and western blotting confirmed activation of signalling via TGF-beta and IFNgamma. CONCLUSION: This study provides evidence of CRISPR-Cas9 technology being used to down-regulate Gprc5b expression in MIN6 beta-cells. This strategy allowed us to identify signalling pathways linking GPRC5B receptor expression to beta-cell proliferation and apoptosis. PMID- 29408823 TI - Torsion Mechanics as an Indicator of More Advanced Left Ventricular Systolic Dysfunction in Secondary Mitral Regurgitation in Patients with Dilated Cardiomyopathy: A 2D Speckle-Tracking Analysis. AB - : Left ventricular (LV) twist serves as a compensatory mechanism in systolic dysfunction and its degree of reduction may reflect a more advanced stage of disease. AIM: The aim was to investigate twist alterations depending on the degree of functional mitral regurgitation (MR) by speckle-tracking echocardiography. METHODS: Sixty-three patients with symptomatic dilated cardiomyopathy (DCM) were included. Patients were divided according to MR vena contracta width (VCW): group 1 with VCW <7 mm (mild/moderate MR) and group 2 with VCW >=7 mm (severe MR). RESULTS: There were no differences in LV geometry and function between groups. Group 2 showed lower endocardial basal rotation (BR) ( 2.04 degrees +/- 1.83 degrees vs. -3.23 degrees +/- 1.83 degrees , p = 0.012); epicardial BR (-1.54 degrees +/- 1.18 degrees vs. -2.31 degrees +/- 1.22 degrees , p = 0.015); endocardial torsion (0.41 degrees /cm +/- 0.36 degrees /cm vs. 0.63 degrees /cm +/- 0.44 degrees /cm, p = 0.033) and mid-level circumferential strain (CSmid) (-6.12% +/- 2.64% vs. -7.75% +/- 2.90%, p = 0.028), when compared with group 1. Multivariable linear regression analysis identified endocardial BR, torsion and CSmid, as the best predictors of larger VCW. In the ROC curve analysis, endocardial BR and CSmid values greater than or equal to -3.63 degrees and -9.35%, respectively, can differentiate patients with severe MR. CONCLUSIONS: In DCM patients, torsional profile was more altered in severe MR. Endocardial BR, endocardial torsion, and CSmid, can be used as indicators of advanced structural wall architecture damage. PMID- 29408824 TI - Craniofacial Distraction in the Management of Anterior Plagiocephaly: A Novel Idea and a Systematic Review of the Literature. AB - BACKGROUND: The objective of this work is to present a review of all reports involving the management of unicoronal synostosis with distraction osteogenesis (DO). Also, we have innovated a new method in the treatment of cases of anterior plagiocephaly at a young age using DO. METHODS: We present a case in which anterior plagiocephaly was treated by DO of both metopic and hemicoronal sutures in a 4-month-old female patient. A comprehensive systematic literature review was completed using the search terms "distraction osteogenesis," "unicoronal synostosis," "anterior plagiocephaly," and "craniosynostosis." We excluded all experimental articles and reviewed clinical reports detailing the use of DO in the management of unicoronal synostosis. RESULTS: The study sample of this review consisted of 16 reports published over a period of 17 years that were analyzed in detail. The total number of patients treated by DO was 120, and the mean age at operation was 12 months. In the case presented, successful correction of the unicoronal synostosis was achieved. CONCLUSION: Hemicoronal and metopic suture distraction in anterior plagiocephaly achieves considerable improvement in the midline shift of the anterior cranial base and naso-orbital complex. PMID- 29408825 TI - Ligand-Activated Peroxisome Proliferator-Activated Receptor delta Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression. AB - Thrombospondin-1 (TSP-1) is implicated in vascular diseases associated with oxidative stress, such as abdominal aortic aneurysms, ischemia-reperfusion injury, and atherosclerosis. However, the regulatory mechanisms underlying TSP-1 expression are not fully elucidated. In this study, we found that peroxisome proliferator-activated receptor delta (PPARdelta) inhibited oxidative stress induced TSP-1 expression and migration in vascular smooth muscle cells (VSMCs). Activation of PPARdelta by GW501516, a specific ligand for PPARdelta, significantly attenuated hydrogen peroxide (H2O2)-induced expression of TSP-1 in VSMCs. Small interfering RNA-mediated knockdown of PPARdelta and treatment with GSK0660, a selective PPARdelta antagonist, reversed the effect of GW501516 on H2O2-induced expression of TSP-1, suggesting that PPARdelta is associated with GW501516 activity. Furthermore, JNK (c-Jun N-terminal kinase), but not p38 and ERK (extracellular signal-regulated kinase), mediated PPARdelta-dependent inhibition of TSP-1 expression in VSMCs exposed to H2O2. GW501516- activated PPARdelta also reduced the H2O2-induced generation of reactive oxygen species, concomitant with inhibition of VSMC migration. In particular, TSP-1 contributed to the action of PPARdelta in the regulation of H2O2-induced interleukin-1beta expression. These results suggest that PPARdelta-modulated downregulation of TSP 1 is associated with reduced cellular oxidative stress, thereby inhibiting H2O2 induced pheno-typic changes in vascular cells. PMID- 29408826 TI - The Effect of Chemically Modified Tetracycline-3 on the Progression of Dental Caries in Rats. AB - OBJECTIVE: Matrix metalloproteinases (MMPs) exist in human saliva and dentin and play an important role in the degradation of organic matrix in teeth. Chemically modified tetracycline-3 (CMT-3) is an inhibitor of MMPs. CMT-3 has been used experimentally to treat caries since 1999, but no distinction between dental caries prevalence and dentin caries prevalence has been described. METHODS: A total of 65 Sprague-Dawley rats were randomly divided into three groups. The positive control group (25 rats) was inoculated with Streptococcus mutans (ATCC700610) and fed the cariogenic feed of improved Keyes Diet 2000. The CMT-3 group (25 rats) was also inoculated with S. mutans and fed the cariogenic feed of improved Keyes Diet 2000; the surfaces of rats' molars were daily treated with 0.02% CMT-3. The negative control group (15 rats) was only fed the standard rodent chow. At the end of the 10th week, the dental caries prevalence and dentin caries prevalence of each group were calculated, and the regions of caries were assessed. RESULTS: No caries was found in the negative control group. The dental caries prevalence of the CMT-3 and the positive control group was 75.0 and 83.3%, respectively (p > 0.05, Table 2). The dentin caries prevalence of the CMT-3 and the positive control group was 33.3 and 70.8%, respectively (p < 0.05, Table 2). The Keyes scoring of dentin caries in the CMT-3 group was significantly lower than that in the positive control group (p < 0.05, Table 3). CONCLUSIONS: CMT-3 had no effect on the prevalence of dental caries, but could lower the prevalence and slow down the progression of dentin caries. PMID- 29408827 TI - Corneal Optical Changes Associated with Induced Edema in Fuchs Endothelial Corneal Dystrophy. AB - PURPOSE: Patients with Fuchs endothelial corneal dystrophy (FECD) often notice poor vision in the morning that improves as the day progresses. In this study, we determined changes in corneal optical properties associated with induced corneal edema. METHODS: Twenty-three phakic eyes (23 participants) with FECD (grades 1-6, modified Krachmer scale) and 8 normal eyes (8 participants) were examined by Scheimpflug photography. Central corneal thickness, high-order aberrations from anterior and posterior corneal surfaces, and backscatter from the anterior, mid-, and posterior cornea were determined from the Scheimpflug images. A low-oxygen permeable contact lens was placed on the eye, and eyes were closed for 2 hours, after which the lens was removed and Scheimpflug photography was repeated for up to 5 hours to determine changes in backscatter and high-order aberrations. RESULTS: Corneas swelled by 10% [95% confidence interval (CI), 9-10]. Backscatter from the anterior cornea increased by 416 scatter units (SU, 95% CI, 344-488; P < 0.001), independent of the presence and severity of FECD. Recovery of anterior backscatter was slower in advanced FECD (81 SU/h, 95% CI, 60-120) compared with normal (123 SU/h, 95% CI, 95-150; P = 0.019). Anterior and posterior corneal high order aberrations, and mid and posterior backscatter, did not increase with induced swelling. CONCLUSIONS: Inducing corneal edema increases anterior corneal backscatter but not high-order aberrations. Subjective poor vision in the morning in FECD is probably caused by scattered light rather than by high-order aberrations, suggesting that these patients experience more disability glare than decreased visual acuity. PMID- 29408829 TI - Femtosecond Laser-Assisted Small Incision Endokeratophakia Using a Xenogeneic Lenticule in Rhesus Monkeys. AB - PURPOSE: To evaluate the feasibility and safety of xenogeneic endokeratophakia in rhesus monkeys and to explore the effects of a concave lenticule on refractive power. METHODS: Three adult New Zealand white rabbits and 6 healthy rhesus monkeys were used. The xenogenic concave grafts were created from the rabbits using a modified small incision lenticule extraction technique; after being cryopreserved in glycerol for 1 week, the grafts were implanted into the monkey recipient corneas. Spherical equivalent (SE), central corneal thickness, and keratometry curvature were assessed preoperatively, 1 week, 1, 4 and 6 months postoperatively. The quality of the xenogenic graft was also assessed by slit lamp microscopy, in vivo confocal microscopy, and optical coherence tomography with anterior segment imaging. RESULTS: The graft appeared to be swollen a day after the operation but reduced considerably after a week. A trend of a lower refractive power (hyperopic shift) was demonstrated in relation to the SE after concave graft implantation. The mean SE increased from -0.60 +/- 1.31 (median 0.69, interquartile range -1.00 to 0.50) preoperatively to 0.75 +/- 1.27 (median 1.38, interquartile range -0.25 to 1.63) at 1 month postoperatively (P = 0.01). Central corneal thickness was significantly thicker each time after surgery compared with that recorded preoperatively (P < 0.01). The anterior and posterior interface between the graft and stroma was visible during the study. Corneal nerve regeneration was evident at 6 months postoperatively. The xenogeneic concave graft was stable and transparent at follow-up. Severe adverse events or evidence of a rejection response were not observed. CONCLUSIONS: Femtosecond laser-assisted small incision endokeratophakia using a xenogeneic corneal lenticule seems to be feasible and safe, which may provide a new method for myopia correction and keratoconus treatment. PMID- 29408828 TI - Clinical Features, Antibiotic Susceptibility Profile, and Outcomes of Infectious Keratitis Caused by Stenotrophomonas maltophilia. AB - PURPOSE: Stenotrophomonas maltophilia, an uncommon cause of infectious keratitis, is difficult to treat because of its resistance to multiple antibiotics. The purpose of this study is to describe the clinical features, antibiotic susceptibility profile, and outcomes of S. maltophilia keratitis. METHODS: A retrospective review of records from 1987 to 2016 identified 26 eyes of 26 patients who were treated at the Bascom Palmer Eye Institute for an S. maltophilia corneal ulcer. Clinical data were analyzed as to predisposing factors, clinical presentation, antibiotic susceptibility, treatment selection, and clinical outcomes. RESULTS: Median age at presentation was 65 years (range, 16-98). Twelve patients were using topical corticosteroids, 8 patients had a history of penetrating keratoplasty, and 9 were contact lens wearers. All patients received topical antibiotics, 2 required therapeutic penetrating keratoplasty, and 1 was enucleated. At presentation, 57.7% (15/26) of the patients had visual acuity of 20/400 or worse. At the final visit, only 30.4% (7/23) of the patients had visual acuity worse than 20/400, whereas 65.2% (15/23) of the patients had 20/100 or better. Almost all isolates (25/26, 96.2%) were susceptible to fluoroquinolones and 77.3% (17/22) of them to polymyxin B/trimethoprim. Only 33.3% (5/15) of the tested isolates were susceptible to aminoglycosides and 58.3% (7/12) to cephalosporins. CONCLUSIONS: Infectious keratitis due to S. maltophilia presents a treatment challenge because of its resistance to aminoglycosides and cephalosporins, which are typically used for empiric broad-spectrum gram-negative coverage as fortified solutions. Fluoroquinolones and polymyxin B/trimethoprim should be considered instead in cases of S. maltophilia infection. PMID- 29408830 TI - Selective Endothelial Removal for Peters Anomaly. AB - PURPOSE: Peters anomaly is the most common cause of congenital corneal opacities. Although conservative management is often ineffective except in mild cases, surgical intervention in the form of penetrating keratoplasty is fraught with unpredictability and often has unacceptable postoperative outcomes. As such, there is a need to explore alternative surgical interventions that may possibly improve the postoperative visual prognosis in these patients. In this report, we present a case of type 1 Peters anomaly treated by selective endothelial removal without corneal tissue transplantation. METHODS: A case report with literature review. RESULTS: A 21-month-old child, who presented with unilateral type 1 Peters anomaly, underwent selective endothelial removal without corneal tissue transplantation for the treatment of her condition. The patient demonstrated excellent anatomical and visual recovery after the procedure over a 1-year period. Her visual acuity had improved from 20/960 preoperatively to 20/30 during the latest review. Postoperative recovery was not complicated by the development of any sight-threatening complications, and she has been successfully weaned off all topical and systemic medications. CONCLUSIONS: Selective endothelial removal can potentially be used to treat cases of type 1 Peters anomaly. PMID- 29408831 TI - Reply. PMID- 29408832 TI - Quantitative Primary Tumor Indocyanine Green Measurements Predict Osteosarcoma Metastatic Lung Burden in a Mouse Model. AB - BACKGROUND: Current preclinical osteosarcoma (OS) models largely focus on quantifying primary tumor burden. However, most fatalities from OS are caused by metastatic disease. The quantification of metastatic OS currently relies on CT, which is limited by motion artifact, requires intravenous contrast, and can be technically demanding in the preclinical setting. We describe the ability for indocyanine green (ICG) fluorescence angiography to quantify primary and metastatic OS in a previously validated orthotopic, immunocompetent mouse model. QUESTIONS/PURPOSES: (1) Can near-infrared ICG fluorescence be used to attach a comparable, quantitative value to the primary OS tumor in our experimental mouse model? (2) Will primary tumor fluorescence differ in mice that go on to develop metastatic lung disease? (3) Does primary tumor fluorescence correlate with tumor volume measured with CT? METHODS: Six groups of 4- to 6-week-old immunocompetent Balb/c mice (n = 6 per group) received paraphyseal injections into their left hindlimb proximal tibia consisting of variable numbers of K7M2 mouse OS cells. A hindlimb transfemoral amputation was performed 4 weeks after injection with euthanasia and lung extraction performed 10 weeks after injection. Histologic examination of lung and primary tumor specimens confirmed ICG localization only within the tumor bed. RESULTS: Mice with visible or palpable tumor growth had greater hindlimb fluorescence (3.5 +/- 2.3 arbitrary perfusion units [APU], defined as the fluorescence pixel return normalized by the detector) compared with those with a negative examination (0.71 +/- 0.38 APU, -2.7 +/- 0.5 mean difference, 95% confidence interval -3.7 to -1.8, p < 0.001). A strong linear trend (r = 0.81, p < 0.01) was observed between primary tumor and lung fluorescence, suggesting that quantitative ICG tumor fluorescence is directly related to eventual metastatic burden. We did not find a correlation (r = 0.04, p = 0.45) between normalized primary tumor fluorescence and CT volumetric measurements. CONCLUSIONS: We demonstrate a novel methodology for quantifying primary and metastatic OS in a previously validated, immunocompetent, orthotopic mouse model. Quantitative fluorescence of the primary tumor with ICG angiography is linearly related to metastatic burden, a relationship that does not exist with respect to clinical tumor size. This highlights the potential utility of ICG near infrared fluorescence imaging as a valuable preclinical proof-of-concept modality. Future experimental work will use this model to evaluate the efficacy of novel OS small molecule inhibitors. CLINICAL RELEVANCE: Given the histologic localization of ICG to only the tumor bed, we envision the clinical use of ICG angiography as an intraoperative margin and tumor detector. Such a tool may be used as an alternative to intraoperative histology to confirm negative primary tumor margins or as a valuable tool for debulking surgeries in vulnerable anatomic locations. Because we have demonstrated the successful preservation of ICG in frozen tumor samples, future work will focus on blinded validation of this modality in observational human trials, comparing the ICG fluorescence of harvested tissue samples with fresh frozen pathology. PMID- 29408833 TI - Many Shoulder MRI Findings in Elite Professional Throwing Athletes Resolve After Retirement: A Clinical and Radiographic Study. AB - BACKGROUND: Anatomic findings on MRI scans of the shoulder likely affect patients differently based on their physical demands and fitness levels. The natural history of these anatomic findings once professional overhead athletes retire remains unclear. A better understanding of what happens with these findings after retirement may influence how we manage shoulder problems in athletes. PURPOSE: (1) What is the natural history of MRI-observed findings in the throwing and nonthrowing shoulders of professional European handball players after retirement from the sport? What proportion of these individuals have diagnosable findings on MRI, and do these findings disappear after retirement? (2) Do clinical findings such as Constant and Murley score and shoulder ROM change after retirement in these professional overhead athletes? METHODS: The inception cohort of this series consisted of the entire Swiss National European handball team except the goalkeepers. These 30 professional players also played in the highest Swiss handball league in 2001. None of these players previously had shoulder surgery. During their career, they had a clinical assessment and bilateral shoulder MRI as part of an earlier study. We sought to evaluate the players who had retired and did not have a history of shoulder surgery, to evaluate the natural history of MRI-observed findings made in the initial study during their professional career. Of the 30 players, 10 were excluded (four continued to play professionally, four declined participation, and two had surgery after the initial study), leaving 20 (66%) for analysis at a mean of 6 years (SD, 3 years) after retirement. To gain a better understanding of the evolution of these MRI findings in the longer-term, we also evaluated 18 additional former professional European handball players who did not have any history of shoulder surgery, had all played in the highest Swiss league and for the National Team, and had terminated their career at a mean of 15 years (SD, 3 years) ago. All the subjects in both study groups (those at 6 and 15 years after retirement) underwent a detailed interview, standardized clinical examination including ROM measurements, collection of the Constant and Murley scores and the subjective shoulder value of both shoulders, and bilateral shoulder MRI. MRI findings (consisting of abnormalities and normal variations) were reported as radiographic diagnoses, independent of the potential that these findings could be considered normal variations in people in this age group. RESULTS: At the initial MRI evaluation, the proportion of active professional European handballers with diagnosable MRI findings in the throwing shoulder was 19 of 20 (95%) and for the handballers with nonthrowing shoulders was 17 of 20 (85%), while 15 years after retirement, both shoulders of all subjects showed MRI findings. None of the rotator cuff tears progressed to full-thickness tears after retirement. In the throwing shoulders, we observed fewer individuals with ganglion cysts larger than 5 mm (initial followup: six of 20 [30%] versus 6 years after retirement: 0 of 20 (0%); odds ratio, 14.5; [95% CI, 0.7-283]; p = 0.044). The Constant and Murley score increased in the throwing shoulder from 93 points (SD, 6 points) at initial followup to 98 points (SD, 3 points) at a mean of 6 years after retirement (mean difference, 5 points; SD, 5 points; 95% CI, 2.5-7.4; p < 0.001), and to 97 points (SD, 3 points) at a mean of 15 years after retirement. However these differences are below the typically reported minimum clinically important difference for the Constant and Murley score, and so are unlikely to be clinically relevant. External rotation in 90 degrees abduction remained increased in the throwing shoulder compared with the nonthrowing shoulder up to 15 years after retirement (initial followup: mean difference, 8 degrees ; p = 0.014; 15 years after retirement: mean difference, 4 degrees ; SD, 15; p = 0.026). Internal rotation remained decreased in the throwing compared with the nonthrowing shoulders (during the career: mean difference, 5 degrees [SD, 10 degrees ], p = 0.036; 15 years after retirement: mean difference, 3 degrees [SD, 4 degrees ], p = 0.021). CONCLUSIONS: Our data suggest that findings of the throwing shoulder like partial rotator cuff tears, bony cysts and ganglions do not progress after retirement, and sometimes they resolve. Because of this and because many MRI changes correlate poorly with clinical symptoms, the indication for surgical treatment of these findings should be questioned very carefully. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29408835 TI - Incidence and Factors Correlating With Incisional Hernia Following Open Bowel Resection in Patients With Inflammatory Bowel Disease: A Review of 1000 Patients. AB - OBJECTIVE: The aim of this study was to identify the incidence and factors associated with the development of incisional hernia (IH) in patients with inflammatory bowel disease (IBD) undergoing open bowel resections. BACKGROUND: Predisposing factors for IH have not been well studied in patients with IBD undergoing open bowel resection. The role of duration of the disease, nutritional factors, anti-inflammatory treatment, previous operative procedures, wound infection, and other complicating factors remains unclear. METHODS: One thousand patients with ulcerative colitis and Crohn's disease were followed for a mean of 8 years after open bowel resection. The incidence of IH was recorded as well as correlating factors with the development of IH. RESULTS: The overall incidence of IH in this series was 20% (21% for ulcerative colitis and 20% for Crohn's disease). Statistically significant risk factors for development of IH were wound infection (HR 3.66, P <0.001), hypoalbuminemia (HR 2.02, P = 0.002), history of previous bowel resection (HR 1.60, P = 0.003), creation of ileostomy at the time of procedure (HR 1.53, P = 0.01), history of smoking (HR 1.52, P = 0.013), body mass index at surgery (1.036, P = 0.009), age at surgery (HR 1.021, P <0.001), and age at the onset of disease (HR 1.018, P <0.001). CONCLUSIONS: Patients with IBD have a high incidence of incisional hernia after open bowel resection. Wound infection had the strongest correlation with the development of IH. The other factors were age at onset of IBD, age at surgery, body mass index, serum albumin, presence of ileostomy, previous surgical procedures, and history of smoking. Duration of disease, preoperative steroids, immunosuppressive therapy, and blood transfusion were not found to correlate with IH. PMID- 29408834 TI - Longitudinal profiles of back pain across adulthood and their relationship with childhood factors: evidence from the 1946 British birth cohort. AB - This study aimed to (1) characterise long-term profiles of back pain across adulthood and (2) examine whether childhood risk factors were associated with these profiles, using data from 3271 participants in the Medical Research Council National Survey of Health and Development. A longitudinal latent class analysis was conducted on binary outcomes of back pain at ages 31, 36, 43, 53, 60 to 64, and 68 years. Multinomial logistic regression models were used to examine associations between selected childhood risk factors and class membership; adjusted for sex, adult body size, health status and behaviours, socioeconomic position, and family history of back pain. Four profiles of back pain were identified: no or occasional pain (57.7%), early-adulthood only (16.1%), mid adulthood onset (16.9%), and persistent (9.4%). The "no or occasional" profile was treated as the referent category in subsequent analyses. After adjustment, taller height at age 7 years was associated with a higher likelihood of early adulthood only (relative risk ratio per 1 SD increase in height = 1.31 [95% confidence interval: 1.05-1.65]) and persistent pain (relative risk ratio = 1.33 [95% confidence interval: 1.01-1.74]) in women (P for sex interaction = 0.01). Factors associated with an increased risk of persistent pain in both sexes were abdominal pain, poorest care in childhood, and poorer maternal health. Abdominal pain and poorest housing quality were also associated with an increased likelihood of mid-adulthood onset pain. These findings suggest that there are different long-term profiles of back pain, each of which is associated with different early life risk factors. This highlights the potential importance of early life interventions for the prevention and management of back pain. PMID- 29408836 TI - Pathophysiological Response to Burn Injury in Adults. AB - OBJECTIVE: The aim of this study was to compare the hypermetabolic, and inflammatory trajectories in burned adults to gain insight into the pathophysiological alterations and outcomes after injury. SUMMARY OF BACKGROUND DATA: Burn injury leads to a complex response that is associated with hypermetabolism, morbidity, and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated in adult burn patients. METHODS: Burned adult patients (n = 1288) admitted to our center from 2006 to 2016 were enrolled in this prospective study. Demographics, clinical data, metabolic and inflammatory markers, hypermetabolism, organ function, and clinical outcomes were obtained throughout acute hospitalization. We then stratified patients according to burn size (<20%, 20% to 40%, and >40% total body surface area [TBSA]) and compared biomedical profiles and clinical outcomes for these patients. RESULTS: Burn patients were hypermetabolic with elevated resting energy expenditure (REE) associated with increased browning of white adipose tissue from weeks 2 to 4. Hyperglycemia and hyperinsulinemia peaked 7 to 14 days after injury. Oral glucose tolerance and insulin resistance (QUICKI, HOMA2) tests further confirmed these findings with similar areas under the curve for moderate (20% to 40% TBSA) and severe burn (>40% TBSA). Lipid metabolism in sera revealed elevated pro-inflammatory stearic and linoleic acid, with complementary increases in anti-inflammatory free fatty acids. Similar increases were observed for inflammatory cytokines, chemokines, and metabolic hormones. White adipose tissue from the site of injury had increased ER stress, mitochondrial damage, and inflammasome activity, which was exacerbated with increasing burn severity. CONCLUSIONS: In this large prospective trial, we delineated the complexity of the pathophysiologic responses postburn in adults and concluded that these profound responses are time and burn size dependent. Patients with medium-size (20% to 40% TBSA) burn demonstrated a very robust response that is similar to large burns. PMID- 29408837 TI - Reply: The Important Role for Intravenous Iron in Perioperative Patient Blood Management in Major Abdominal Surgery: A Randomized Controlled Trial. PMID- 29408838 TI - Drain After Pancreatoduodenectomy: Methodological Issues. PMID- 29408839 TI - Moving From Faculty Development to Faculty Identity, Growth, and Empowerment. PMID- 29408840 TI - Medical Schools' Competition for Clinical Training Sites. PMID- 29408841 TI - More About Offshore Medical Schools Buying Clerkships in U.S. Hospitals. PMID- 29408842 TI - More About Offshore Medical Schools Buying Clerkships in U.S. Hospitals. PMID- 29408843 TI - More About Offshore Medical Schools Buying Clerkships in U.S. Hospitals. PMID- 29408844 TI - In Reply to Balon and Morreale, to Flaherty, and to Olds. PMID- 29408845 TI - A Health Professions Education Research-Specific Ethical Review Board. PMID- 29408847 TI - Artist's Statement: Reflection. PMID- 29408846 TI - In Reply to van den Broek et al. PMID- 29408848 TI - I Brought My Father With Me. PMID- 29408849 TI - Commentary on "I Brought My Father With Me". PMID- 29408850 TI - The Gold-Hope Tang, MD 2016 Humanism in Medicine Essay Contest: First Place: Your Soul Is Not Concrete (Survive, Anyway). PMID- 29408851 TI - Taking Time. PMID- 29408852 TI - High EVI1 Expression Predicts Poor Outcomes in Adult Acute Myeloid Leukemia Patients with Intermediate Cytogenetic Risk Receiving Chemotherapy. AB - BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold. RESULTS The normal upper limit of EVI1 transcript levels was 8.0%. Receiver operating characteristic curve analysis showed that 1.0% (a 0.9-log reduction from the normal limit) was the EVI1 optimal cutoff value for significantly differentiating relapse (P=0.049). A total of 23 patients (12%) had EVI1 levels >=1.0%. EVI1 >=1.0% had no effect on CR achievement, whereas it was significantly associated with lower 2 year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates in the entire cohort (P=0.0003, 0.0017, and 0.0009, respectively), patients with normal karyotypes (P=0.0032, 0.0047, and 0.0007, respectively), and FLT3-ITD (-) patients (all P<0.0001). Multivariate analysis showed that EVI1 >=1.0% was an independent adverse prognostic factor for RFS, DFS, and OS in the entire cohort. In addition, patients with EVI1 transcript levels between 1.0% and 8.0% had 2-year RFS rates similar to those with EVI1 >=8.0%, and they both had significantly lower RFS rates than those with EVI1 <1.0% (P=0.0005 and 0.027). CONCLUSIONS High EVI1 expression predicts poor outcome in ICR-AML patients receiving chemotherapy. The optimal cutoff value for patient stratification is different from the normal limit. PMID- 29408854 TI - Path analysis of phenotypic traits in young cacao plants under drought conditions. AB - Drought is worldwide considered one of the most limiting factors of Theobroma cacao production, which can be intensified by global climate changes. In this study, we aimed to investigate the phenotypic correlation among morphological characteristics of cacao progenies submitted to irrigation and drought conditions and their partitions into direct and indirect effects. Path analysis with phenotypic plasticity index was used as criteria for estimation of basic and explanatory variables. The experiment was conducted in a greenhouse at the Cacao Research Center (CEPEC), Ilheus, Bahia, Brazil, in a randomized block 21 x 2 factorial arrangement [21 cacao progenies obtained from complete diallel crosses and two water regimes (control and drought)] and six replications. In general, drought conditions influenced biomass production in most progenies, causing significant reductions in total leaf area, leaf number, leaf biomass, fine-roots length (diameter <1 mm), root volume and root area for considered drought intolerant. All progenies showed alterations in growth due to drought. Phenotypic plasticity was most strongly pronounced in root volume. Stem and root diameters, as well as stem dry biomass were the growth variables with the greatest direct effects on root volume under drought conditions, these characters being indicated in screening of cacao progenies drought tolerant. PMID- 29408853 TI - Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC. AB - The aberrant activation of Wnt signal transduction initiates the development of 90% of colorectal cancers, the majority of which arise from inactivation of the tumor suppressor Adenomatous polyposis coli (APC). In the classical model for Wnt signaling, the primary role of APC is to act, together with the concentration limiting scaffold protein Axin, in a "destruction complex" that directs the phosphorylation and consequent proteasomal degradation of the transcriptional activator beta-catenin, thereby preventing signaling in the Wnt-off state. Following Wnt stimulation, Axin is recruited to a multiprotein "signalosome" required for pathway activation. Whereas it is well-documented that APC is essential in the destruction complex, APC's role in this complex remains elusive. Here, we demonstrate in Drosophila that Axin exists in two distinct phosphorylation states in Wnt-off and Wnt-on conditions, respectively, that underlie its roles in the destruction complex and signalosome. These two Axin phosphorylation states are catalyzed by glycogen synthase kinase 3 (GSK3), and unexpectedly, completely dependent on APC in both unstimulated and Wnt-stimulated conditions. In a major revision of the classical model, we show that APC is essential not only in the destruction complex, but also for the rapid transition in Axin that occurs after Wnt stimulation and Axin's subsequent association with the Wnt co-receptor LRP6/Arrow, one of the earliest steps in pathway activation. We propose that this novel requirement for APC in Axin regulation through phosphorylation both prevents signaling in the Wnt-off state and promotes signaling immediately following Wnt stimulation. PMID- 29408855 TI - Ensilage of oats and wheatgrass under natural alpine climatic conditions by indigenous lactic acid bacteria species isolated from high-cold areas. AB - Five different species of selected broad-spectrum antibiotic lactic acid bacteria isolated from extremely high-cold areas were used as starters to ferment indigenous forage oats and wheatgrass under rigid alpine climatic conditions. The five isolates were Lactobacillus plantarum QZ227, Enterococcus mundtii QZ251, Pediococcus cellicola QZ311, Leuconostoc mesenteroides QZ1137 and Lactococcus lactis QZ613, and commercial Lactobacillus plantarum FG1 was used as the positive control and sterile water as the negative control. The minimum and maximum temperatures were -22 degrees C and 23 degrees C during the fermentation process, respectively. The pH of wheatgrass silage fermented by the QZ227 and FG1 inocula reached the expected values (<=4.15) although the pathogens detected in the silage should be further investigated. All of the inocula additives used in this study were effective in improving the fermentation quality of oat silage as indicated by the higher content of lactic acid, lower pH values (<=4.17) and significant inhibition of pathogens. QZ227 exhibited a fermentation ability that was comparable with the commercial inoculum FG1 for the whole process, and the deterioration rate was significantly lower than for FG1 after storage for 7 months. The pathogens Escherichia coli, mold and yeast were counted and isolated from the deteriorated silage. E. coli were the main NH3-N producer while F. fungi and yeast produced very little. PMID- 29408856 TI - Quick and easy sample preparation without resin embedding for the bone quality assessment of fresh calcified bone using fourier transform infrared imaging. AB - Fourier transform infrared (FTIR) imaging is a powerful tool for the assessment of bone quality; however, it requires the preparation of thin bone sections. Conventional poly(methyl methacrylate) (PMMA) embedding for the preparation of sections takes more than two weeks and causes denaturation of the bone. Development of a quick and easy sample preparation technique without denaturation is needed for accurate clinical evaluation of fresh calcified bone using FTIR imaging. Frozen sectioning allows the quick and easy preparation of thin sections without denaturation, but it requires a substrate with good chemical resistance and improved heat shock resistance. Polypropylene (PP) film afforded both good chemical resistance and greater heat shock resistance, and the 4-MUm-thick PP film coated with glue was thin enough for the IR beam to pass through it, while the optical anisotropy of infrared bands overlapping with PO43- band was negligible. The bone quality of femoral thin sections prepared by the conventional PMMA embedding and sectioning procedure (RESIN-S) or the newly developed frozen sectioning procedure (FROZEN-S) was evaluated by FTIR imaging. The mineral-to-matrix ratio and crystallinity in the RESIN-S sections were higher than those in the FROZEN-S sections, whereas the carbonate-to-phosphate ratio in the RESIN-S sections was lower than that in the FROZEN-S sections. In RESIN-S, the increased mineral-to-matrix ratio could be caused by dehydration, and the increased crystallinity and decreased carbonate-to-phosphate ratio might be consequence of dissolution of bone mineral during PMMA embedding. Therefore, the combined use of PP film coated with glue and the frozen sectioning procedure without denaturation appears well suited to the assessment of the bone quality of fresh calcified bone using FTIR imaging. PMID- 29408857 TI - Intra-aneurysmal flow disruption after implantation of the Medina(r) Embolization Device depends on aneurysm neck coverage. AB - BACKGROUND AND PURPOSE: Flow disruption achieved by braided intrasaccular implants is a novel treatment strategy for cerebrovascular aneurysms. We hypothesized that the degree of intra-aneurysmal flow disruption can be quantified in vitro and is influenced by device position across the aneurysm neck. We tested this hypothesis using the Medina(r) Embolization Device (MED). METHODS: Ten different patient-specific elastic vascular models were manufactured. Models were connected to a pulsatile flow circuit, filled with a blood-mimicking fluid and treated by two operators using a single MED. Intra aneurysmal flow velocity was measured using conventional and high-frequency digital subtraction angiography (HF-DSA) before and after each deployment. Aneurysm neck coverage by the implanted devices was assessed with flat detector computed tomography on a three-point Likert scale. RESULTS: A total of 80 individual MED deployments were performed by the two operators. The mean intra aneurysmal flow velocity reduction after MED implantation was 33.6% (27.5-39.7%). No significant differences in neck coverage (p = 0.99) or flow disruption (p = 0.84) were observed between operators. The degree of flow disruption significantly correlated with neck coverage (rho = 0.42, 95% CI: 0.21-0.59, p = 0.002) as well as with neck area (rho = -0,35, 95% CI: -0.54 --0.13, p = 0.024). On multiple regression analysis, both neck coverage and total neck area were independent predictors of flow disruption. CONCLUSIONS: The degree of intra aneurysmal flow disruption after MED implantation can be quantified in vitro and varies considerably between different aneurysms and different device configurations. Optimal device coverage across the aneurysm neck improves flow disruption and may thus contribute to aneurysm occlusion. PMID- 29408858 TI - Efficacy of PI3K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: A literature-based meta-analysis of 46 randomised control trials. AB - BACKGROUND: The phosphatidylinositol-3- kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) plays a key role in cancer. We performed this meta-analysis to assess the clinical effect of using PI3K/AKT/mTOR pathway inhibitors on advanced solid tumours. METHODS: All the randomised controlled trials (RCT) that compared the therapy with PI3K/AKT/mTOR pathway inhibitors with other therapies were included. The main end-point was progression free survival (PFS); other end-points included overall survival (OS) and objective response rate (ORR). A subgroup analysis was performed mainly for PFS. RESULTS: In total, 46 eligible RCT were included. The pooled results showed that PI3K/AKT/mTOR pathway inhibitor-based regimens significantly improved the PFS of patients with advanced solid tumours (hazard ratios (HR) = 0.79; 95% confidence intervals (CI): 0.71-0.88) and PI3K pathway mutations (HR = 0.69; 95% CI: 0.56 0.85). All single PI3K/AKT/mTOR pathway inhibitor therapies were compared with other targeted therapies (HR = 0.99; 95% CI: 0.93-1.06) and dual targeted therapies, including PI3K/AKT/mTOR pathway inhibitors and other targeted therapies (HR = 1.04; 95% CI: 0.62-1.74), which showed no significant differences in the PFS. Additional PI3K/AKT/mTOR pathway inhibitors showed no advantage with respect to the OS (HR = 0.98; 95% CI: 0.90-1.07) or ORR (risk ratio (RR) = 1.02; 95% CI: 0.87-1.20). CONCLUSION: Our meta-analysis results suggest that the addition of the PI3K pathway inhibitors to the therapy regiment for advanced solid tumours significantly improves PFS. The way that patients are selected to receive the PI3K pathway inhibitors might be more meaningful in the future. PMID- 29408859 TI - Transcriptome analysis revealed the possible regulatory pathways initiating female geese broodiness within the hypothalamic-pituitary-gonadal axis. AB - Geese have the strongest tendency toward broodiness among all poultry. The mechanisms initiating broodiness within the goose hypothalamic-pituitary-gonadal axis (HPGA) are still unclear. Here, we reported the transcriptome differences between laying and initial nesting within the HPGA tissues of geese. We constructed a unigene database based on HPGA tissues and identified 128,148 unigenes, 100% of which have been annotated. By using Digital Gene Expression (DGE) sequencing, we screened 19, 110, 289, and 211 differentially expressed genes (DEGs) in the hypothalamus, pituitary gland, stroma ovarii, and follicles, respectively, between laying and nesting geese. Expression changes of hypocretin (HCRT) and pro-opiomelanocortin (POMC) in the hypothalamus of nesting geese may cause appetite reduction, which is possibly the first step and a prerequisite to initiate broodiness. In addition to prolactin (PRL), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), genes including oxytocin-neurophysin (OXT), chordin-like protein 1 (CHRDL1) and growth hormone (GH), expressed in the pituitary gland, are new candidate molecules that may be involved in broodiness in geese. Heme oxygenase 1 (HMOX1) in the pituitary gland, the proto-oncogene c Fos (FOS), heat shock protein 90-alpha (HSP90AA), and cyclin-dependent kinase 1 (CDK1) in the ovary that may consolidate and transduce signals regulating the HPGA during broodiness in geese. PMID- 29408860 TI - Human cytomegalovirus epidemiology and relationship to tuberculosis and cardiovascular disease risk factors in a rural Ugandan cohort. AB - Human cytomegalovirus (HCMV) infection has been associated with increased mortality, specifically cardiovascular disease (CVD), in high-income countries (HICs). There is a paucity of data in low- and middle-income countries (LMICs) where HCMV seropositivity is higher. Serum samples from 2,174 Ugandan individuals were investigated for HCMV antibodies and data linked to demographic information, co-infections and a variety of CVD measurements. HCMV seropositivity was 83% by one year of age, increasing to 95% by five years. Female sex, HIV positivity and active pulmonary tuberculosis (TB) were associated with an increase in HCMV IgG levels in adjusted analyses. There was no evidence of any associations with risk factors for CVD after adjusting for age and sex. HCMV infection is ubiquitous in this rural Ugandan cohort from a young age. The association between TB disease and high HCMV IgG levels merits further research. Known CVD risk factors do not appear to be associated with higher HCMV antibody levels in this Ugandan cohort. PMID- 29408861 TI - MicroRNA-10b expression in breast cancer and its clinical association. AB - MicroRNAs (miRNAs) are short non-coding RNA molecules that play a significant role in many types of cancers including breast cancer. In the current study, we evaluated the expression levels of microR-10b (miR-10b) in 115 breast cancer patients from Sichuan Cancer Center. Real time reverse transcription-PCR was used to assess miR-10b expression. Clinical data including disease stage, survival status, age, ER/PR/HER2 status, molecular subtypes, tumor size, lymph node status and Ki-67 expression levels were correlated with miR-10b expression levels. Our data showed that the miR-10b expression is correlated with disease stage, living status and tumor sizes. We also found that miR-10b expression levels are higher in the lymph node positive group and the Ki-67 higher scoring group (score > 20). No statistically significant differences were observed based on age or molecular sub-type grouping. In conclusion, miR-10b may be a biomarker for breast cancer and is a potential treatment target. PMID- 29408863 TI - Peers at work: Evidence from the lab. AB - This paper reports the results of a lab experiment designed to study the role of observability for peer effects in the setting of a simple production task. In our experiment, participants in the role of workers engage in a team real-effort task. We vary whether they can observe, or be observed by, one of their co workers. In contrast to earlier findings from the field, we find no evidence that low-productivity workers perform better when they are observed by high productivity co-workers. Instead, our results imply that peer effects in our experiment are heterogeneous, with some workers reciprocating a high-productivity co-worker but others taking the opportunity to free ride. PMID- 29408862 TI - Shared and unshared exposure measurement error in occupational cohort studies and their effects on statistical inference in proportional hazards models. AB - Exposure measurement error represents one of the most important sources of uncertainty in epidemiology. When exposure uncertainty is not or only poorly accounted for, it can lead to biased risk estimates and a distortion of the shape of the exposure-response relationship. In occupational cohort studies, the time dependent nature of exposure and changes in the method of exposure assessment may create complex error structures. When a method of group-level exposure assessment is used, individual worker practices and the imprecision of the instrument used to measure the average exposure for a group of workers may give rise to errors that are shared between workers, within workers or both. In contrast to unshared measurement error, the effects of shared errors remain largely unknown. Moreover, exposure uncertainty and magnitude of exposure are typically highest for the earliest years of exposure. We conduct a simulation study based on exposure data of the French cohort of uranium miners to compare the effects of shared and unshared exposure uncertainty on risk estimation and on the shape of the exposure response curve in proportional hazards models. Our results indicate that uncertainty components shared within workers cause more bias in risk estimation and a more severe attenuation of the exposure-response relationship than unshared exposure uncertainty or exposure uncertainty shared between individuals. These findings underline the importance of careful characterisation and modeling of exposure uncertainty in observational studies. PMID- 29408864 TI - In vitro characterization of PlyE146, a novel phage lysin that targets Gram negative bacteria. AB - The recent rise of multidrug-resistant Gram-negative bacteria represents a serious threat to public health and makes the search for novel effective alternatives to antibiotics a compelling need. Bacteriophage (Phage) lysins are enzymes that hydrolyze the cell wall of bacteria and represent a promising alternative to tackle this ever-increasing problem. Despite their use is believed to be restricted to Gram-positive bacteria, recent findings have shown that they can also be used against Gram-negative bacteria. By using a phage genome-based screening approach, we identified and characterized a novel lysin, PlyE146, encoded by an Escherichia coli prophage and with a predicted molecular mass of ca. 17 kDa. PlyE146 is composed of a C-terminal cationic peptide and a N-terminal N-acetylmuramidase domain. Histidine-tagged PlyE146 was overexpressed from a plasmid in Lactococcus lactis NZ9000 and purified by NI-NTA chromatography. PlyE146 exhibited in vitro optimal bactericidal activity against E. coli K12 (3.6 log10 CFU/mL decrease) after 2 h of incubation at 37 degrees C at a concentration of 400 MUg/mL in the absence of NaCl and at pH 6.0. Under these conditions, PlyE146 displayed antimicrobial activity towards several other E. coli, Pseudomonas aeruginosa (3 to 3.8-log10 CFU/mL decrease) and Acinetobacter baumannii (4.9 to >5-log10 CFU/mL decrease) strains. Therefore, PlyE146 represents a promising therapeutic agent against E. coli, P. aeruginosa and A. baumannii infections. However, further studies are required to improve the efficacy of PlyE146 under physiological conditions. PMID- 29408865 TI - A new pathological scoring system by the Japanese classification to predict renal outcome in diabetic nephropathy. AB - BACKGROUND AND OBJECTIVES: The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor-Tervaert' and JRPS classifications-and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated. RESULTS: The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0-19). Renal survival curves, when dividing into four J-score grades (0-5, 6-10, 11-15, and 16-19), were significantly different from each other (p<0.01, log-rank test). After adjusting clinical factors, the J-score was a significant predictor of renal outcome. Ability to predict 10-year renal outcome was improved when the J-score was added to the basic model: c-statistics from 0.661 to 0.685; category-free net reclassification improvement, 0.154 (-0.040, 0.349, p = 0.12); and integrated discrimination improvement, 0.015 (0.003, 0.028, p = 0.02). CONCLUSIONS: Mesangiolysis, polar vasculosis, and doubling of GBM-features of the JRPS system were significantly associated with renal outcome. Prediction of DN patients' renal outcome was better with the J-score than without it. PMID- 29408866 TI - Oral paracetamol and/or ibuprofen for treating pain after soft tissue injuries: Single centre double-blind, randomised controlled clinical trial. AB - BACKGROUND: Soft tissue injuries commonly present to the emergency department (ED), often with acute pain. They cause significant suffering and morbidity if not adequately treated. Paracetamol and ibuprofen are commonly used analgesics, but it remains unknown if either one or the combination of both is superior for pain control. OBJECTIVES: To investigate the analgesic effect of paracetamol, ibuprofen and the combination of both in the treatment of soft tissue injury in an ED, and the side effect profile of these drugs. METHODS: Double-blind, double dummy, placebo-controlled randomised controlled trial. 782 adult patients presenting with soft tissue injury without obvious fractures attending the ED of a university hospital in the New Territories of Hong Kong were recruited. Patients were randomised using a random number table into three parallel arms of paracetamol only, ibuprofen only and a combination of paracetamol and ibuprofen in a 1:1:1 ratio. The primary outcome measure was pain score at rest and on activity in the first 2 hours and first 3 days. Data was analysed on an intention to treat basis. RESULTS: There was no statistically significant difference in pain score in the initial two hours between the three groups, and no clinically significant difference in pain score in the first three days. CONCLUSION: There was no difference in analgesic effects or side effects observed using oral paracetamol, ibuprofen or a combination of both in patients with mild to moderate pain after soft tissue injuries attending the ED. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (no. NCT00528658). PMID- 29408868 TI - Witnessing extinction in real time. PMID- 29408867 TI - Genome-wide profiling reveals functional diversification of ?FosB gene targets in the hippocampus of an Alzheimer's disease mouse model. AB - The activity-induced transcription factor ?FosB has been implicated in Alzheimer's disease (AD) as a critical regulator of hippocampal function and cognition downstream of seizures and network hyperexcitability. With its long half-life (> 1 week), ?FosB is well-poised to modulate hippocampal gene expression over extended periods of time, enabling effects to persist even during seizure-free periods. However, the transcriptional mechanisms by which ?FosB regulates hippocampal function are poorly understood due to lack of identified hippocampal gene targets. To identify putative ?FosB gene targets, we employed high-throughput sequencing of genomic DNA bound to ?FosB after chromatin immunoprecipitation (ChIP-sequencing). We compared ChIP-sequencing results from hippocampi of transgenic mice expressing mutant human amyloid precursor protein (APP) and nontransgenic (NTG) wild-type littermates. Surprisingly, only 52 ?FosB gene targets were shared between NTG and APP mice; the vast majority of targets were unique to one genotype or the other. We also found a functional shift in the repertoire of ?FosB gene targets between NTG and APP mice. A large number of targets in NTG mice are involved in neurodevelopment and/or cell morphogenesis, whereas in APP mice there is an enrichment of targets involved in regulation of membrane potential and neuronal excitability. RNA-sequencing and quantitative PCR experiments confirmed that expression of putative ?FosB gene targets were altered in the hippocampus of APP mice. This study provides key insights into functional domains regulated by ?FosB in the hippocampus, emphasizing remarkably different programs of gene regulation under physiological and pathological conditions. PMID- 29408869 TI - Computed tomography in adult patients with primary ciliary dyskinesia: Typical imaging findings. AB - OBJECTIVES: Among patients with non-cystic fibrosis bronchiectasis, 1-18% have an underlying diagnosis of primary ciliary dyskinesia (PCD) and it is suspected that there is under-recognition of this disease. Our intention was to evaluate the specific features of PCD seen on computed tomography (CT) in the cohort of bronchiectasis in order to facilitate the diagnosis. MATERIALS AND METHODS: One hundred and twenty-one CTs performed in patients with bronchiectasis were scored for the involvement, type, and lobar distribution of bronchiectasis, bronchial dilatation, and bronchial wall thickening. Later, associated findings such as mucus plugging, tree in bud, consolidations, ground glass opacities, interlobular thickening, intralobular lines, situs inversus, emphysema, mosaic attenuation, and atelectasis were registered. Patients with PCD (n = 46) were compared to patients with other underlying diseases (n = 75). RESULTS: In patients with PCD, the extent and severity of the bronchiectasis and bronchial wall thickness were significantly lower in the upper lung lobes (p<0.001-p = 0.011). The lobar distribution differed significantly with a predominance in the middle and lower lobes in patients with PCD (<0.001). Significantly more common in patients with PCD were mucous plugging (p = 0.001), tree in bud (p <0.001), atelectasis (p = 0.009), and a history of resection of a middle or lower lobe (p = 0.047). Less common were emphysematous (p = 0.003) and fibrotic (p<0.001) changes. A situs inversus (Kartagener's Syndrome) was only seen in patients with PCD (17%, p <0.001). CONCLUSION: Typical imaging features in PCD include a predominance of bronchiectasis in the middle and lower lobes, severe tree in bud pattern, mucous plugging, and atelectasis. These findings may help practitioners to identify patients with bronchiectasis in whom further work-up for PCD is called for. PMID- 29408870 TI - Mid-term outcomes of biventricular obstruction and left ventricular outflow tract obstruction after surgery correction in child and adolescent patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Data on the outcomes of hypertrophic cardiomyopathy (HCM) with biventricular obstruction are limited. OBJECTIVE: Our aim is to compare mid-term outcomes of biventricular outflow tract obstruction (BVOTO) HCM, left ventricular outflow tract obstruction (LVOTO) HCM and nonobstructive hypertrophic cardiomyopathy (NO-HCM) in children and adolescents who were treated with standard medication or surgical resection. METHODS: This retrospective study identified 21 BVOTO patients and recruited 27 LVOTO and 24 NO-HCM patients younger than 18 years presenting at our institution. The primary endpoint was all cause death, and secondary endpoints were cardiovascular events. RESULTS: More BVOTO patients (61.9%) than LVOTO (19.2%) and NO-HCM patients (25%) exhibited New York Heart Association (NYHA) III/IV status (p < 0.01). Fourteen BVOTO and 16 LVOTO patients obtained a significant reduction of outflow tract pressure gradients after surgery (vs. preoperative baseline, p < 0.001). One of the 14 BVOTO patients died, whereas no deaths occurred among LVOTO patients. Three of 14 BVOTO surgery patients had complete heart block (CHB) and 4 had new right bundle branch block (RBBB), while no CHB or RBBB occurred in the LVOTO surgery patients. The BVOTO patients had a longer duration of aortic cross-clamping and postoperative hospital days than the LVOTO patients (p < 0.05). During a median 42-month follow-up, no deaths occurred among the remaining patients. The primary and secondary endpoint-free survival rates of the BVOTO group were comparable to those of the LVOTO and NO-HCM groups. CONCLUSIONS: In children and adolescents, BVOTO patients were associated with more severe symptoms than LVOTO and NO-HCM patients; however, good mid-term outcomes similar to those of the LVOTO and NO HCM groups can be achieved with the application of contemporary cardiovascular treatment strategies. Notably, BVOTO surgery was associated with an increased risk of CHB and RBBB compared to LVOTO surgery. PMID- 29408871 TI - Association of cancer-related mortality, age and gonadectomy in golden retriever dogs at a veterinary academic center (1989-2016). AB - Golden retriever dogs have been reported to have an increased prevalence of cancer compared to other breeds. There is also controversy over the effect spay or neuter status might have on longevity and the risk for developing cancer. The electronic medical records system at an academic center was searched for all dogs who had a necropsy exam from 1989-2016. 9,677 canine necropsy examinations were completed of which 655 were golden retrievers. Age was known for 652 with a median age of death 9.15 years. 424 of the 652 (65.0%) were determined to have died because of cancer. The median age for dying of a cause other than cancer was 6.93 years while those dying of cancer had a median age of 9.83 years (p<0.0001). There was no significant difference in the proportion of intact males and castrated males dying of cancer (p = 0.43) but a greater proportion of spayed females died of cancer compared to intact females (p = 0.001). Intact female dogs had shorter life spans than spayed female dogs (p<0.0001), but there were no differences between intact and castrated males. Intriguingly, being spayed or neutered did not affect the risk of a cancer related death but increasing age did. The most common histologic diagnosis found in golden retrievers dying of cancer was hemangiosarcoma (22.64%) followed by lymphoid neoplasia (18.40%). Overall golden retriever dogs have a substantial risk of cancer related mortality in a referral population and age appears to have a larger effect on cancer related mortality than reproductive status. PMID- 29408872 TI - Vicilin-A major storage protein of mungbean exhibits antioxidative potential, antiproliferative effects and ACE inhibitory activity. AB - Enzymatic hydrolysates of different food proteins demonstrate health benefits. Search for diet related food protein hydrolysates is therefore of interest within the scope of functional foods. Mungbean is one of the popular foods in India because of rich protein source. In this study, mungbean vicilin protein (MBVP) was enzymatically hydrolysed by alcalase and trypsin under optimal conditions. We have studied the antioxidant, antiproliferative and angiotensin-converting enzyme (ACE) inhibitory activities of mungbean vicilin protein hydrolysate (MBVPH) vis-a vis alcalase-generated mungbean vicilin protein hydrolysate (AMBVPH) and trypsin generated mungbean vicilin protein hydrolysate (TMBVPH). The results showed that MBVPH exhibited higher antioxidant potential, ACE inhibitory and antiproliferative activities than MBVP. The alcalase treated hydrolysate displayed highest ACE inhibitory activity with IC50 value of 0.32 mg protein/ml. The MBVP showed significant antiproliferative activity against both MCF-7 and MDA MB-231 breast cancer cells at the doses between 0.2-1.0 mg/ml. The data suggested that MBVPH can be utilized as physiologically active functional foods with sufficient antihypertensive activity. The results indicate that mungbean can be utilized as a rich resource of functional foods. PMID- 29408873 TI - Mouse IgG2c Fc loop residues promote greater receptor-binding affinity than mouse IgG2b or human IgG1. AB - The structures of non-human antibodies are largely unstudied despite the potential for the identification of alternative structural motifs and physical properties that will benefit a basic understanding of protein and immune system evolution as well as highlight unexplored motifs to improve therapeutic monoclonal antibody. Here we probe the structure and receptor-binding properties of the mouse IgG2c crystallizable fragment (Fc) to compare to mouse IgG2b and human IgG1 Fcs. Models of mIgG2c Fc determined by x-ray crystallography with a complex-type biantennary (to 2.05 A) or a truncated (1)GlcNAc asparagine-linked (N)-glycan attached (to 2.04 A) show differences in key regions related to mouse Fc gamma receptor IV (mFcgammaRIV) binding. Mouse IgG2c forms different non bonded interactions between the BC, DE and FG loops than the highly-conserved mIgG2b and binds to FcgammaRIV with 4.7-fold greater affinity in the complex-type glycoform. Secondary structural elements surrounding the Asn297 site of glycosylation form longer beta strands in the truncated mIgG2c Fc glycoform when compared to mIgG2c with the complex-type N-glycan. Solution NMR spectroscopy of the N-linked (1)GlcNAc residues show differences between mIgG2b, 2c and hIgG1 Fc that correlate to receptor binding affinity. Mutations targeting differences in mIgG2 DE and FG loops decreased affinity of mIgG2c for FcgammaRIV and increased affinity of mIgG2b. Changes in NMR spectra of the mutant Fc proteins mirrored these changes in affinity. Our studies identified structural and functional differences in highly conserved molecules that were not predicted from primary sequence comparison. PMID- 29408874 TI - A mathematical model of multisite phosphorylation of tau protein. AB - Abnormal tau metabolism followed by formation of tau deposits causes a number of neurodegenerative diseases called tauopathies including Alzheimer's disease. Hyperphosphorylation of tau protein precedes tau aggregation and is a topic of interest for the development of pharmacological interventions to prevent pathology progression at early stages. The development of a mathematical model of multisite phosphorylation of tau would be helpful for searching for the targets of pharmacological interventions and candidates for biomarkers of pathology progression. In the present study, we for the first time developed a model of multisite phosphorylation of tau protein and elucidated the relative contribution of kinases to phosphorylation of distinct sites. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3beta and CDK5 and dephosphorylation by PP2A, accurately reproducing the data for short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may more specifically prevent tau hyperphosphorylation, e.g., on PHF sites, which are key biomarkers of pathological changes in Alzheimer's disease. The main features of our model are partial phosphorylation of tau residues and merging of random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events. PMID- 29408875 TI - Semi-automated digital measurement as the method of choice for beta cell mass analysis. AB - Pancreas injury by partial duct ligation (PDL) activates beta cell differentiation and proliferation in adult mouse pancreas but remains controversial regarding the anticipated increase in beta cell volume. Several reports unable to show beta cell volume augmentation in PDL pancreas used automated digital image analysis software. We hypothesized that fully automatic beta cell morphometry without manual micrograph artifact remediation introduces bias and therefore might be responsible for reported discrepancies and controversy. However, our present results prove that standard digital image processing with automatic thresholding is sufficiently robust albeit less sensitive and less adequate to demonstrate a significant increase in beta cell volume in PDL versus Sham-operated pancreas. We therefore conclude that other confounding factors such as quality of surgery, selection of samples based on relative abundance of the transcription factor Neurogenin 3 (Ngn3) and tissue processing give rise to inter-laboratory inconsistencies in beta cell volume quantification in PDL pancreas. PMID- 29408877 TI - Combining radar and direct observation to estimate pelican collision risk at a proposed wind farm on the Cape west coast, South Africa. AB - Pre-construction assessments of bird collision risk at proposed wind farms are often confounded by insufficient or poor quality data describing avian flight paths through the development area. These limitations can compromise the practical value of wind farm impact studies. We used radar- and observer-based methods to quantify great white pelican flights in the vicinity of a planned wind farm on the Cape west coast, South Africa, and modelled turbine collision risk under various scenarios. Model outputs were combined with pre-existing demographic data to evaluate the possible influence of the wind farm on the pelican population, and to examine impact mitigation options. We recorded high volumes of great white pelican movement through the wind farm area, coincident with the breeding cycle of the nearby colony and associated with flights to feeding areas located about 50 km away. Pelicans were exposed to collision risk at a mean rate of 2.02 High Risk flights.h-1. Risk was confined to daylight hours, highest during the middle of the day and in conditions of strong north westerly winds, and 82% of High Risk flights were focused on only five of the proposed 35 turbine placements. Predicted mean mortality rates (22 fatalities.yr 1, 95% Cl, 16-29, with average bird and blade speeds and 95% avoidance rates) were not sustainable, resulting in a negative population growth rate (lambda = 0.991). Models suggested that removal of the five highest risk turbines from the project, or institution of a curtailment regimen that shuts down at least these turbines at peak traffic times, could theoretically reduce impacts to manageable levels. However, in spite of the large quantities of high quality data used in our analyses, our collision risk model remains compromised by untested assumptions about pelican avoidance rates and uncertainties about the existing dynamics of the pelican population, and our findings are probably not reliable enough to ensure sustainable development. PMID- 29408876 TI - Cloning and expression analysis of the DEAD-box/RNA helicase Oslaf-1 in Ovomermis sinensis. AB - Ovomermis sinensis is a potentially-valuable nematode for controlling insect pests. The parasitic stage of the nematode absorbs nutrients in its host's hemolymph to maintain its growth development and then kills the host when it emerges. At present, little known about its reproductive development, particularly the responsible molecular mechanism. More detailed research on the genes of reproductive development will not only help us understand the mechanisms underlying sex differentiation in the nematode, but would also be valuable for successfully cultivating them in vitro and using them for biocontrol. In this study, we used the homology cloning method to clone the full-length cDNA of a DEAD-box family gene (Oslaf-1) from O. sinensis. Then, using qRT-PCR technology to detect the expression pattern of the Oslaf-1 gene at different development stages and tissues, the gene was found to be highly expressed in the post parasitic stage (P < 0.01) and ovarian (P < 0.05) of O. sinensis. Western blot analysis showed the same result that the gene is associated with gonadal development and function, but is not gonad-specific. In situ hybridization further demonstrated that the gene is widely expressed in early embryos and is mainly distributed in the gonadal area. However, the signal was mainly concentrated in the reproductive primordia in pre-parasitic juveniles. RNA interference (RNAi) studies revealed that the sex ratio of O. sinensis soaked in dsRNA of Oslaf-1 was not statistically different than the gfp dsRNA treated groups. Our results suggest that Oslaf-1 may play a vital role in the reproductive systems of the nematode. In addition, we speculate that the Oslaf-1 gene plays an important role during embryonic development and that it occurs and develops in the gonads of pre-parasitic juveniles of O. sinensis. PMID- 29408879 TI - Shared trauma reality in war: Mental health therapists' experience. AB - INTRODUCTION: Shared traumatic reality occurs when therapists are doubly exposed to a traumatic event, both through their clients' experience, along with their own direct exposure. Studies have shown that a shared traumatic reality can lead to both positive and negative outcomes for therapists. Most studies have examined these reactions sometime after the end of the traumatic event, and less is known about reactions that occur during a traumatic event. In addition, most studies have assumed, rather than examined, indirect exposure. In this study, we extend this literature by examining direct and indirect exposure of therapists during a war situation, and their psychological reactions. METHOD: Over a period of two months in 2014, 70% of the Israeli population was exposed to rocket fire. Geographical areas differed in terms of amount of exposure, and its potential danger. 151 therapists living throughout Israel were assessed via an Internet based survey in the middle of the war, and were assessed for the effects on their professional and personal lives, degree of burnout, ways of coping and symptoms levels of PTSD and psychological distress. RESULTS: These indicate that significant differences in direct exposure occurred depending on place of residence. PTSD levels were related to higher direct exposure, as well as prior trauma exposure, but not to indirect exposure. Indirect exposure, as measured by increased workload, was related to increased distress and emotional exhaustion. DISCUSSION: These data shed light on the effects of direct and indirect exposure to a shared traumatic experience of war amongst therapists. The data support previous studies showing a greater effect of direct exposure on PTSD. Since indirect exposure appears to negatively impact burnout and psychological distress, rather than PTSD, this study shows that symptoms other than PTSD should be the result of in a shared traumatic reality. PMID- 29408878 TI - The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis. AB - Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of infiltrating leukocytes (i.e. neutrophils, eosinophils, lymphocytes, plasma cells, and macrophages) at lesion sites. The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases. PMID- 29408880 TI - Daily visual stimulation in the critical period enhances multiple aspects of vision through BDNF-mediated pathways in the mouse retina. AB - Visual experience during the critical period modulates visual development such that deprivation causes visual impairments while stimulation induces enhancements. This study aimed to determine whether visual stimulation in the form of daily optomotor response (OMR) testing during the mouse critical period (1) improves aspects of visual function, (2) involves retinal mechanisms and (3) is mediated by brain derived neurotrophic factor (BDNF) and dopamine (DA) signaling pathways. We tested spatial frequency thresholds in C57BL/6J mice daily from postnatal days 16 to 23 (P16 to P23) using OMR testing. Daily OMR-treated mice were compared to littermate controls that were placed in the OMR chamber without moving gratings. Contrast sensitivity thresholds, electroretinograms (ERGs), visual evoked potentials, and pattern ERGs were acquired at P21. To determine the role of BDNF signaling, a TrkB receptor antagonist (ANA-12) was systemically injected 2 hours prior to OMR testing in another cohort of mice. BDNF immunohistochemistry was performed on retina and brain sections. Retinal DA levels were measured using high-performance liquid chromatography. Daily OMR testing enhanced spatial frequency thresholds and contrast sensitivity compared to controls. OMR-treated mice also had improved rod-driven ERG oscillatory potential response times, greater BDNF immunoreactivity in the retinal ganglion cell layer, and increased retinal DA content compared to controls. VEPs and pattern ERGs were unchanged. Systemic delivery of ANA-12 attenuated OMR-induced visual enhancements. Daily OMR testing during the critical period leads to general visual function improvements accompanied by increased DA and BDNF in the retina, with this process being requisitely mediated by TrkB activation. These results suggest that novel combination therapies involving visual stimulation and using both behavioral and molecular approaches may benefit degenerative retinal diseases or amblyopia. PMID- 29408882 TI - Modeling for influenza vaccines and adjuvants profile for safety prediction system using gene expression profiling and statistical tools. AB - Historically, vaccine safety assessments have been conducted by animal testing (e.g., quality control tests and adjuvant development). However, classical evaluation methods do not provide sufficient information to make treatment decisions. We previously identified biomarker genes as novel safety markers. Here, we developed a practical safety assessment system used to evaluate the intramuscular, intraperitoneal, and nasal inoculation routes to provide robust and comprehensive safety data. Influenza vaccines were used as model vaccines. A toxicity reference vaccine (RE) and poly I:C-adjuvanted hemagglutinin split vaccine were used as toxicity controls, while a non-adjuvanted hemagglutinin split vaccine and AddaVax (squalene-based oil-in-water nano-emulsion with a formulation similar to MF59)-adjuvanted hemagglutinin split vaccine were used as safety controls. Body weight changes, number of white blood cells, and lung biomarker gene expression profiles were determined in mice. In addition, vaccines were inoculated into mice by three different administration routes. Logistic regression analyses were carried out to determine the expression changes of each biomarker. The results showed that the regression equations clearly classified each vaccine according to its toxic potential and inoculation amount by biomarker expression levels. Interestingly, lung biomarker expression was nearly equivalent for the various inoculation routes. The results of the present safety evaluation were confirmed by the approximation rate for the toxicity control. This method may contribute to toxicity evaluation such as quality control tests and adjuvant development. PMID- 29408881 TI - Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016. AB - BACKGROUND: Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. METHODS AND FINDINGS: In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC >= 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC >= 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%-19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%-2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. CONCLUSIONS: To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China. PMID- 29408883 TI - Draft genome sequence of the New Jersey aster yellows strain of 'Candidatus Phytoplasma asteris'. AB - The NJAY (New Jersey aster yellows) strain of 'Candidatus Phytoplasma asteris' is a significant plant pathogen responsible for causing severe lettuce yellows in the U.S. state of New Jersey. A draft genome sequence was prepared for this organism. A total of 177,847 reads were assembled into 75 contigs > 518 bp with a total base value of 652,092 and an overall [G+C] content of 27.1%. A total of 733 protein coding genes were identified. This Whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBank under the accession MAPF00000000. This draft genome was used for genome- and gene-based comparative phylogenetic analyses with other phytoplasmas, including the closely related 'Ca. Phytoplasma asteris' strain, aster yellows witches'- broom (AY-WB). NJAY and AY-WB exhibit approximately 0.5% dissimilarity at the nucleotide level among their shared genomic segments. Evidence indicated that NJAY harbors four plasmids homologous to those known to encode pathogenicity determinants in AY-WB, as well as a chromosome-encoded mobile unit. Apparent NJAY orthologs to the important AY-WB virulence factors, SAP11 and SAP54, were identified. A number of secreted proteins, both membrane bound and soluble, were encoded, with many bearing similarity to known AY-WB effector molecules and others representing possible secreted proteins that may be novel to the NJAY lineage. PMID- 29408884 TI - Using NMR in saliva to identify possible biomarkers of glioblastoma and chronic periodontitis. AB - Nowadays there is increasing interest in identifying-and using-metabolites that can be employed as biomarkers for diagnosing, treating and monitoring diseases. Saliva and NMR have been widely used for this purpose as they are fast and inexpensive methods. This case-control study aimed to find biomarkers that could be related to glioblastoma (GBL) and periodontal disease (PD) and studied a possible association between GBL and periodontal status. The participants numbered 130, of whom 10 were diagnosed with GBL and were assigned to the cases group, while the remaining 120 did not present any pathology and were assigned to the control group. On one hand, significantly increased (p < 0.05) metabolites were found in GBL group: leucine, valine, isoleucine, propionate, alanine, acetate, ethanolamine and sucrose. Moreover, a good tendency to separation between the two groups was observed on the scatterplot of the NMR. On the other hand, the distribution of the groups attending to the periodontal status was very similar and we didn't find any association between GBL and periodontal status (Chi-Square 0.1968, p = 0.91). Subsequently, the sample as a whole (130 individuals) was divided into three groups by periodontal status in order to identify biomarkers for PD. Group 1 was composed of periodontally healthy individuals, group 2 had gingivitis or early periodontitis and group 3 had moderate to advanced periodontitis. On comparing periodontal status, a significant increase (p < 0.05) in certain metabolites was observed. These findings along with previous reports suggest that these could be used as biomarkers of a PD: caproate, isocaproate+butyrate, isovalerate, isopropanol+methanol, 4 aminobutyrate, choline, sucrose, sucrose-glucose-lysine, lactate-proline, lactate and proline. The scatter plot showed a good tendency to wards separation between group 1 and 3. PMID- 29408885 TI - Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury. AB - Epigenetic predisposition is thought to critically contribute to adult-onset disorders, such as retinal neurodegeneration. The histone methyltransferase, enhancer of zeste homolog 2 (Ezh2), is transiently expressed in the perinatal retina, particularly enriched in retinal ganglion cells (RGCs). We previously showed that embryonic deletion of Ezh2 from retinal progenitors led to progressive photoreceptor degeneration throughout life, demonstrating a role for embryonic predisposition of Ezh2-mediated repressive mark in maintaining the survival and function of photoreceptors in the adult. Enrichment of Ezh2 in RGCs leads to the question if Ezh2 also mediates gene expression and function in postnatal RGCs, and if its deficiency changes RGC susceptibility to cell death under injury or disease in the adult. To test this, we generated mice carrying targeted deletion of Ezh2 from RGC progenitors driven by Math5-Cre (mKO). mKO mice showed no detectable defect in RGC development, survival, or cell homeostasis as determined by physiological analysis, live imaging, histology, and immunohistochemistry. Moreover, RGCs of Ezh2 deficient mice revealed similar susceptibility against glaucomatous and acute optic nerve trauma-induced neurodegeneration compared to littermate floxed or wild-type control mice. In agreement with the above findings, analysis of RNA sequencing of RGCs purified from Ezh2 deficient mice revealed few gene changes that were related to RGC development, survival and function. These results, together with our previous report, support a cell lineage-specific mechanism of Ezh2-mediated gene repression, especially those critically involved in cellular function and homeostasis. PMID- 29408887 TI - Improving working equine welfare in 'hard-win' situations, where gains are difficult, expensive or marginal. AB - PURPOSE: Brooke is a non-government organisation with working equine welfare programmes across Africa, Asia and Latin America. In 2014, staff from ten country programmes were asked to identify 'no-win' situations (subsequently reframed as 'hard-wins')-where improving equine welfare is proving difficult, expensive and/or marginal-in order to inform strategic decisions on how to approach, manage and mitigate for such situations. METHODS: The Delphi-type consultation process had three phases. Round 1 posed five questions in the form of a workshop, survey and semi-structured interviews. Round 2 re-presented key themes and sense-checked initial conclusions. Round 3 reviewed the nature and prevalence of hard-win situations at an international meeting of all participants. RESULTS: Reasons given for hard-win situations included: no economic or social benefit from caring for working animals; poor resource availability; lack of empathy for working equids or their owners among wider stakeholders; deep-seated social issues, such as addiction or illegal working; areas with a high animal turnover or migratory human population; lack of community cooperation or cohesion; unsafe areas where welfare interventions cannot be adequately supported. Participants estimated the prevalence of hard-win situations as 40-70% of their work. They suggested some current ways of working that may be contributing to the problem, and opportunities to tackle hard-wins more effectively. CONCLUSION AND ANIMAL WELFARE IMPLICATIONS: Respondents agreed that if equine welfare improvements are to span generations of animals, interventions cannot rely on relatively simple, technical knowledge-transfer strategies and quick-wins alone. Programmes need to be more flexible and iterative and less risk-averse in their approaches to embedding good equine welfare practices in all relevant actors. Consultation recommendations informed development of Brooke's new global strategy, a revised organisational structure and redefinition of roles and responsibilities to streamline ways to approach hard-wins in the complex environments and socio-economic contexts in which working equids are found. PMID- 29408886 TI - Contribution of bacterial pathogens to evoking serological disease markers and aggravating disease activity in rheumatoid arthritis. AB - : Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes. TRIAL REGISTRATION: UMIN CTR UMIN000012200. PMID- 29408888 TI - Structural validation of the Self-Compassion Scale with a German general population sample. AB - BACKGROUND: Published validation studies have reported different factor structures for the Self-Compassion Scale (SCS). The objective of this study was to assess the factor structure of the SCS in a large general population sample representative of the German population. METHODS: A German population sample completed the SCS and other self-report measures. Confirmatory factor analysis (CFA) in MPlus was used to test six models previously found in factor analytic studies (unifactorial model, two-factor model, three-factor model, six-factor model, a hierarchical (second order) model with six first-order factors and two second-order factors, and a model with arbitrarily assigned items to six factors). In addition, three bifactor models were also tested: bifactor model #1 with two group factors (SCS positive items, called SCS positive) and SCS negative items, called SCS negative) and one general factor (overall SCS); bifactor model #2, which is a two-tier model with six group factors, three (SCS positive subscales) corresponding to one general dimension (SCS positive) and three (SCS negative subscales) corresponding to the second general dimension (SCS negative); bifactor model #3 with six group factors (six SCS subscales) and one general factor (overall SCS). RESULTS: The two-factor model, the six-factor model, and the hierarchical model showed less than ideal, but acceptable fit. The model fit indices for these models were comparable, with no apparent advantage of the six factor model over the two-factor model. The one-factor model, the three-factor model, and bifactor model #3 showed poor fit. The other two bifactor models showed strong support for two factors: SCS positive and SCS negative. CONCLUSION: The main results of this study are that, among the German general population, six SCS factors and two SCS factors fit the data reasonably well. While six factors can be modelled, the three negative factors and the three positive factors, respectively, did not reflect reliable or meaningful variance beyond the two summative positive and negative item factors. As such, we recommend the use of two subscale scores to capture a positive factor and a negative factor when administering the German SCS to general population samples and we strongly advise against the use of a total score across all SCS items. PMID- 29408889 TI - Kruppel-like factor 15 is required for the cardiac adaptive response to fasting. AB - Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARalpha. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization. PMID- 29408890 TI - Electron spin resonance (ESR) dose measurement in bone of Hiroshima A-bomb victim. AB - Explosion of the bombs in Hiroshima and Nagasaki corresponds to the only historical moment when atomic bombs were used against civilians. This event triggered countless investigations into the effects and dosimetry of ionizing radiation. However, none of the investigations has used the victims' bones as dosimeter. Here, we assess samples of bones obtained from fatal victims of the explosion by Electron Spin Resonance (ESR). In 1973, one of the authors of the present study (SM) traveled to Japan and conducted a preliminary experiment on the victims' bone samples. The idea was to use the paramagnetism induced in bone after irradiation to measure the radiation dose. Technological advances involved in the construction of spectrometers, better knowledge of the paramagnetic center, and improvement in signal processing techniques have allowed us to resume the investigation. We obtained a reconstructed dose of 9.46 +/- 3.4 Gy from the jawbone, which was compatible with the dose distribution in different locations as measured in non-biological materials such as wall bricks and roof tiles. PMID- 29408891 TI - Neutrophils kill the parasite Trichomonas vaginalis using trogocytosis. AB - T. vaginalis, a human-infective parasite, causes the most common nonviral sexually transmitted infection (STI) worldwide and contributes to adverse inflammatory disorders. The immune response to T. vaginalis is poorly understood. Neutrophils (polymorphonuclear cells [PMNs]) are the major immune cell present at the T. vaginalis-host interface and are thought to clear T. vaginalis. However, the mechanism of PMN clearance of T. vaginalis has not been characterized. We demonstrate that human PMNs rapidly kill T. vaginalis in a dose-dependent, contact-dependent, and neutrophil extracellular trap (NET)-independent manner. In contrast to phagocytosis, we observed that PMN killing of T. vaginalis involves taking "bites" of T. vaginalis prior to parasite death, using trogocytosis to achieve pathogen killing. Both trogocytosis and parasite killing are dependent on the presence of PMN serine proteases and human serum factors. Our analyses provide the first demonstration, to our knowledge, of a mammalian phagocyte using trogocytosis for pathogen clearance and reveal a novel mechanism used by PMNs to kill a large, highly motile target. PMID- 29408893 TI - Long-term exposure to acidification disrupts reproduction in a marine invertebrate. AB - Climate change research is advancing to more complex and more comprehensive studies that include long-term experiments, multiple life-history stages, multi population, and multi-trait approaches. We used a population of the barnacle Balanus improvisus known to be sensitive to short-term acidification to determine its potential for long-term acclimation to acidification. We reared laboratory bred individuals (as singles or pairs), and field-collected assemblages of barnacles, at pH 8.1 and 7.5 (~ 400 and 1600 MUatm pCO2 respectively) for up to 16 months. Acidification caused strong mortality and reduced growth rates. Acidification suppressed respiration rates and induced a higher feeding activity of barnacles after 6 months, but this suppression of respiration rate was absent after 15 months. Laboratory-bred barnacles developed mature gonads only when they were held in pairs, but nonetheless failed to produce fertilized embryos. Field collected barnacles reared in the laboratory for 8 months at the same pH's developed mature gonads, but only those in pH 8.1 produced viable embryos and larvae. Because survivors of long-term acidification were not capable of reproducing, this demonstrates that B. improvisus can only partially acclimate to long-term acidification. This represents a clear and significant bottleneck in the ontogeny of this barnacle population that may limit its potential to persist in a future ocean. PMID- 29408892 TI - Novel technique for repairing posterior medial meniscus root tears using porcine knees and biomechanical study. AB - Transtibial pullout suture (TPS) repair of posterior medial meniscus root (PMMR) tears was shown to achieve good clinical outcomes. The purpose of this study was to compare biomechanically, a novel technique designed to repair PMMR tears using tendon graft (TG) and conventional TPS repair. Twelve porcine tibiae (n = 6 each) TG group: flexor digitorum profundus tendon was passed through an incision in the root area, created 5 mm postero-medially along the edge of the attachment area. TPS group: a modified Mason-Allen suture was created using no. 2 FiberWire. The tendon grafts and sutures were threaded through the bone tunnel and then fixed to the anterolateral cortex of the tibia. The two groups underwent cyclic loading followed by a load-to-failure test. Displacements of the constructs after 100, 500, and 1000 loading cycles, and the maximum load, stiffness, and elongation at failure were recorded. The TG technique had significantly lower elongation and higher stiffness compared with the TPS. The maximum load of the TG group was significantly lower than that of the TPS group. Failure modes for all specimens were caused by the suture or graft cutting through the meniscus. Lesser elongation and higher stiffness of the constructs in TG technique over those in the standard TPS technique might be beneficial for postoperative biological healing between the meniscus and tibial plateau. However, a slower rehabilitation program might be necessary due to its relatively lower maximum failure load. PMID- 29408894 TI - Emotions surrounding friendships of adolescents with autism spectrum disorder in Japan: A qualitative interview study. AB - Emotions are embedded in culture and play a pivotal role in making friends and interacting with peers. To support the social participation of students with autism spectrum disorders (ASD) it is essential to understand their emotional life in the context of ethnic and school cultures. We are particularly interested in how anxiety and loneliness are experienced in developing and maintaining friendships in the daily encounters of adolescents with ASD in the specific context of Japanese schools, because these emotions could serve either as facilitators or barriers to social interaction, depending on how individuals manage them. The present qualitative study investigated perceptions of emotions related to friendship in the everyday school life of 11 adolescents with ASD in Japan. Data were collected by means of semi-structured individual interviews, which revealed a wide range of motivations for socialization, limited future prospects to deepen friendships, robust self-awareness of one's own social challenges, and conscious efforts to cope with these challenges. An inductive approach to data analysis resulted in four themes: social motivation, loneliness, anxiety, and distress. To our knowledge this is the first study to uncover the rich emotional life of adolescents with ASD in the context of their friendships in an Asian culture. PMID- 29408895 TI - Systematic review of school tobacco prevention programs in African countries from 2000 to 2016. AB - BACKGROUND: The World Bank has reported that global smoking rates declined from 2000 to 2012, with the only exception found in males in Sub-Saharan Africa. Sub Saharan Africa is considered to be in stage one of the tobacco epidemic continuum. To address this problem, school-based programs for smoking prevention are considered cost-effective and promising. Since tobacco prevention programs are influenced by social competence or customs of each country, tobacco prevention programs that have success in Western countries are not always effective in African countries. Therefore, the current study systematically reviewed relevant literature to examine the effects of these types of programs in African countries. METHOD: Online bibliographic databases and a hand search were used. We included the studies that examined the impact of school-based programs on preventing tobacco use in Africa from 2000 to 2016. RESULTS: Six articles were selected. Four were conducted in South Africa and two were performed in Nigeria. Four programs were systematically incorporated into annual curriculums, targeting 8th to 9th graders, while the other two were temporary programs. All programs were based on the hypothesis that providing knowledge and/or social skills against smoking would be helpful. All studies utilized smoking or polydrug use rates to compare outcomes before/after intervention. There were no significant differences between intervention and control groups in three studies, with the other three demonstrating only partial effectiveness. Additionally, three studies also examined change of knowledge/attitudes towards smoking as an outcome. Two of these showed significant differences between groups. CONCLUSION: All RCTs studies showed no significant change of smoking-rate by the intervention. The effectiveness of intervention was observed only in some sub-group. The cohort studies showed school-based interventions may be effective in improving knowledge and attitudes about smoking. However, they reported no significant change of smoking-rate by the intervention. PMID- 29408896 TI - Comparison of SNP-based subtyping workflows for bacterial isolates using WGS data, applied to Salmonella enterica serotype Typhimurium and serotype 1,4,[5],12:i:. AB - Whole genome sequencing represents a promising new technology for subtyping of bacterial pathogens. Besides the technological advances which have pushed the approach forward, the last years have been marked by considerable evolution of the whole genome sequencing data analysis methods. Prior to application of the technology as a routine epidemiological typing tool, however, reliable and efficient data analysis strategies need to be identified among the wide variety of the emerged methodologies. In this work, we have compared three existing SNP based subtyping workflows using a benchmark dataset of 32 Salmonella enterica subsp. enterica serovar Typhimurium and serovar 1,4,[5],12:i:- isolates including five isolates from a confirmed outbreak and three isolates obtained from the same patient at different time points. The analysis was carried out using the original (high-coverage) and a down-sampled (low-coverage) datasets and two different reference genomes. All three tested workflows, namely CSI Phylogeny-based workflow, CFSAN-based workflow and PHEnix-based workflow, were able to correctly group the confirmed outbreak isolates and isolates from the same patient with all combinations of reference genomes and datasets. However, the workflows differed strongly with respect to the SNP distances between isolates and sensitivity towards sequencing coverage, which could be linked to the specific data analysis strategies used therein. To demonstrate the effect of particular data analysis steps, several modifications of the existing workflows were also tested. This allowed us to propose data analysis schemes most suitable for routine SNP-based subtyping applied to S. Typhimurium and S. 1,4,[5],12:i:-. Results presented in this study illustrate the importance of using correct data analysis strategies and to define benchmark and fine-tune parameters applied within routine data analysis pipelines to obtain optimal results. PMID- 29408897 TI - Rates and predictors of attrition among children on antiretroviral therapy in Ethiopia: A prospective cohort study. AB - INTRODUCTION: Attrition from antiretroviral therapy (ART) programmes is a critical challenge among children receiving care in resource-limited settings. Our objective was to determine the rates and predictors of attrition among children on ART in Ethiopia. METHODS: Between December 2014 and September 2016, we conducted a prospective cohort study in eight health facilities in Ethiopia. Eligibility criteria included age 3 months-14 years; being on ART for not more than a month. Outcome was attrition due to death and/or loss to follow-up. Predictor variables were child clinical and socio-demographic characteristics, and caregiver socio-demographic characteristics. We used Cox Regression analyses to examine the association between predictors and outcome. RESULTS: Of 309 children, 304 were included, 52% were male. Their median age was 9 years (Inter quartile range, IQR, 6-12). At ART initiation, their median CD4 was 362 cells/mm3 (IQR 231-499); and 74.3% had WHO stage 1 or 2 disease. During 287.7 person-years of observation (PYO), 24 attritions were recorded, yielding an attrition rate of 8.3 per 100 PYO (95% CI 5.4-12.1). Of these, six children were reported dead, leading to a mortality rate of 2.1 per 100 PYO (95% CI 0.8-4.3). Eighteen were lost to follow-up (LTFU) leading to LTFU rate of 6.26 per 100 PYO (95% CI: 3.83 9.70). The majority, 14 (58%) of attrition occurred during the first six months of treatment. Age below three years [aHR] = 5.14 (95% CI: 2.07-12.96), rural residence (aHR = 3.97, 95% CI: 1.34-11.78) and baseline Hgb in g/dl < 10 g/dl [aHR] = 5.68 (95% CI: 2.03-6.23) predicted higher risk of attrition. Baseline Hgb < 10 g/dl (aHR = 16.63, 95% CI: 1.64-168.4) and WHO stage III or IV (aHR = 12.25, 95% CI: 1.26-119.05) predicted the death of the child. Higher attrition was documented among children of both biological parents alive and biologically related close family caregivers. CONCLUSION: Younger children, those from rural areas, and children with anaemia were at higher risk of attrition, especially during the early months of treatment, and therefore should be prioritized during treatment follow-up. Further studies should examine underlying reasons for higher attrition. PMID- 29408898 TI - Therapeutic effects of percutaneous endoscopic gastrostomy on survival in patients with amyotrophic lateral sclerosis: A meta-analysis. AB - Percutaneous endoscopic gastrostomy (PEG) is a method widely used for patients with amyotrophic lateral sclerosis (ALS); nevertheless, its effect on survival remains unclear. The purpose of this meta-analysis study was to determine the effects of PEG on survival in ALS patients. Relevant studies were retrieved from PubMed, EmBase, and the Cochrane Library databases, from inception to June 2017. Studies comparing PEG with other procedures in ALS patients were included. Odds ratios (ORs) in a random-effects model were used to assess the survival at different follow-up periods. Briefly, ten studies involving a total of 996 ALS patients were included. Summary ORs indicated that PEG administration was not associated with 30-day (OR = 1.59; 95%CI 0.93-2.71; P = 0.092), 10-month (OR = 1.25; 95%CI 0.72-2.17; P = 0.436), and 30-month (OR = 1.28; 95% CI 0.77-2.11; P = 0.338) survival rates, while they showed a beneficial effect in 20-month survival rate (OR = 1.97; 95%CI 1.21-3.21; P = 0.007). The survival rate was significantly prominent in reports published before 2005, and in studies with a retrospective design, sample size <100, mean age <60.0 years, and percentage male >=50.0%. To sum up, these findings suggested that ALS patients administered with PEG had an increased 20-month survival rates, while there was no significant effect in 30 day, 10-month, and 30-month survival rates. PMID- 29408899 TI - Correction: Total flavonoid concentrations of bryophytes from Tianmu Mountain, Zhejiang Province (China): Phylogeny and ecological factors. AB - [This corrects the article DOI: 10.1371/journal.pone.0179837.]. PMID- 29408901 TI - Impact of person-centred care training and person-centred activities on quality of life, agitation, and antipsychotic use in people with dementia living in nursing homes: A cluster-randomised controlled trial. AB - BACKGROUND: Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed to evaluate the efficacy of a person-centred care and psychosocial intervention incorporating an antipsychotic review, WHELD, on QoL, agitation, and antipsychotic use in people with dementia living in nursing homes, and to determine its cost. METHODS AND FINDINGS: This was a randomised controlled cluster trial conducted between 1 January 2013 and 30 September 2015 that compared the WHELD intervention with treatment as usual (TAU) in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person centred care and social interaction and education regarding antipsychotic medications (antipsychotic review), followed by ongoing delivery through a care staff champion model. The primary outcome measure was QoL (DEMQOL-Proxy). Secondary outcomes were agitation (Cohen-Mansfield Agitation Inventory [CMAI]), neuropsychiatric symptoms (Neuropsychiatric Inventory-Nursing Home Version [NPI NH]), antipsychotic use, global deterioration (Clinical Dementia Rating), mood (Cornell Scale for Depression in Dementia), unmet needs (Camberwell Assessment of Need for the Elderly), mortality, quality of interactions (Quality of Interactions Scale [QUIS]), pain (Abbey Pain Scale), and cost. Costs were calculated using cost function figures compared with usual costs. In all, 847 people were randomised to WHELD or TAU, of whom 553 completed the 9-month randomised controlled trial. The intervention conferred a statistically significant improvement in QoL (DEMQOL-Proxy Z score 2.82, p = 0.0042; mean difference 2.54, SEM 0.88; 95% CI 0.81, 4.28; Cohen's D effect size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68, p = 0.0076; mean difference 4.27, SEM 1.59; 95% CI -7.39, -1.15; Cohen's D 0.23) and overall neuropsychiatric symptoms (NPI-NH Z score 3.52, p < 0.001; mean difference 4.55, SEM 1.28; 95% CI -7.07,-2.02; Cohen's D 0.30). Benefits were greatest in people with moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94; 95% CI 2.12, 37.16, p = 0.03; Cohen's D 0.55). There were no statistically significant differences between WHELD and TAU for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL-Proxy, CMAI, and NPI-NH outcomes with the WHELD intervention. Antipsychotic drug use was at a low stable level in both treatment groups, and the intervention did not reduce use. The WHELD intervention reduced cost compared to TAU, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group. CONCLUSIONS: These findings suggest that the WHELD intervention confers benefits in terms of QoL, agitation, and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented in nursing homes. Future work should consider how to facilitate sustainability of the intervention in this setting. TRIAL REGISTRATION: ISRCTN Registry ISRCTN62237498. PMID- 29408900 TI - Phosphoproteomic analysis reveals Smad protein family activation following Rift Valley fever virus infection. AB - Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-beta superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results. Gene promoter analysis of transcripts altered after RVFV infection identified 913 genes that contained a Smad-response element. Functional annotation of these potential Smad regulated genes clustered in axonal guidance, hepatic fibrosis and cell signaling pathways involved in cellular adhesion/migration, calcium influx, and cytoskeletal reorganization. Furthermore, chromatin immunoprecipitation confirmed the presence of a Smad complex on the interleukin 1 receptor type 2 (IL1R2) promoter, which acts as a decoy receptor for IL-1 activation. PMID- 29408902 TI - Imaging of neural oscillations with embedded inferential and group prevalence statistics. AB - Magnetoencephalography and electroencephalography (MEG, EEG) are essential techniques for studying distributed signal dynamics in the human brain. In particular, the functional role of neural oscillations remains to be clarified. For that reason, imaging methods need to identify distinct brain regions that concurrently generate oscillatory activity, with adequate separation in space and time. Yet, spatial smearing and inhomogeneous signal-to-noise are challenging factors to source reconstruction from external sensor data. The detection of weak sources in the presence of stronger regional activity nearby is a typical complication of MEG/EEG source imaging. We propose a novel, hypothesis-driven source reconstruction approach to address these methodological challenges. The imaging with embedded statistics (iES) method is a subspace scanning technique that constrains the mapping problem to the actual experimental design. A major benefit is that, regardless of signal strength, the contributions from all oscillatory sources, which activity is consistent with the tested hypothesis, are equalized in the statistical maps produced. We present extensive evaluations of iES on group MEG data, for mapping 1) induced oscillations using experimental contrasts, 2) ongoing narrow-band oscillations in the resting-state, 3) co modulation of brain-wide oscillatory power with a seed region, and 4) co modulation of oscillatory power with peripheral signals (pupil dilation). Along the way, we demonstrate several advantages of iES over standard source imaging approaches. These include the detection of oscillatory coupling without rejection of zero-phase coupling, and detection of ongoing oscillations in deeper brain regions, where signal-to-noise conditions are unfavorable. We also show that iES provides a separate evaluation of oscillatory synchronization and desynchronization in experimental contrasts, which has important statistical advantages. The flexibility of iES allows it to be adjusted to many experimental questions in systems neuroscience. PMID- 29408904 TI - Sequence-based multiscale modeling for high-throughput chromosome conformation capture (Hi-C) data analysis. AB - In this paper, we introduce sequence-based multiscale modeling for biomolecular data analysis. We employ spectral clustering method in our modeling and reveal the difference between sequence-based global scale clustering and local scale clustering. Essentially, two types of distances, i.e., Euclidean (or spatial) distance and genomic (or sequential) distance, can be used in data clustering. Clusters from sequence-based global scale models optimize spatial distances, meaning spatially adjacent loci are more likely to be assigned into the same cluster. Sequence-based local scale models, on the other hand, result in clusters that optimize genomic distances. That is to say, in these models, sequentially adjoining loci tend to be cluster together. We propose two sequence-based multiscale models (SeqMMs) for the study of chromosome hierarchical structures, including genomic compartments and topological associated domains (TADs). We find that genomic compartments are determined only by global scale information in the Hi-C data. The removal of all the local interactions within a band region as large as 10 Mb in genomic distance has almost no significant influence on the final compartment results. Further, in TAD analysis, we find that when the sequential scale is small, a tiny variation of diagonal band region in a contact map will result in a great change in the predicted TAD boundaries. When the scale value is larger than a threshold value, the TAD boundaries become very consistent. This threshold value is highly related to TAD sizes. By the comparison of our results with those previously obtained using a spectral clustering model, we find that our method is more robust and reliable. Finally, we demonstrate that almost all TAD boundaries from both clustering methods are local minimum of a TAD summation function. PMID- 29408903 TI - Vitamin D deficiency causes inward hypertrophic remodeling and alters vascular reactivity of rat cerebral arterioles. AB - BACKGROUND AND PURPOSE: Vitamin D deficiency (VDD) is a global health problem, which can lead to several pathophysiological consequences including cardiovascular diseases. Its impact on the cerebrovascular system is not well understood. The goal of the present work was to examine the effects of VDD on the morphological, biomechanical and functional properties of cerebral arterioles. METHODS: Four-week-old male Wistar rats (n = 11 per group) were either fed with vitamin D deficient diet or received conventional rat chow with per os vitamin D supplementation. Cardiovascular parameters and hormone levels (testosterone, androstenedione, progesterone and 25-hydroxyvitamin D) were measured during the study. After 8 weeks of treatment anterior cerebral artery segments were prepared and their morphological, biomechanical and functional properties were examined using pressure microangiometry. Resorcin-fuchsin and smooth muscle actin staining were used to detect elastic fiber density and smooth muscle cell counts in the vessel wall, respectively. Sections were immunostained for eNOS and COX-2 as well. RESULTS: VDD markedly increased the wall thickness, the wall-to-lumen ratio and the wall cross-sectional area of arterioles as well as the number of smooth muscle cells in the tunica media. As a consequence, tangential wall stress was significantly lower in the VDD group. In addition, VDD increased the myogenic as well as the uridine 5'-triphosphate-induced tone and impaired bradykinin-induced relaxation. Decreased eNOS and increased COX-2 expression were also observed in the endothelium of VDD animals. CONCLUSIONS: VDD causes inward hypertrophic remodeling due to vascular smooth muscle cell proliferation and enhances the vessel tone probably because of increased vasoconstrictor prostanoid levels in young adult rats. In addition, the decreased eNOS expression results in endothelial dysfunction. These morphological and functional alterations can potentially compromise the cerebral circulation and lead to cerebrovascular disorders in VDD. PMID- 29408905 TI - Splenic macrophages are required for protective innate immunity against West Nile virus. AB - Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (MPhis) were necessary for control of WNV infection. We selectively depleted splenic MPhis, but not draining lymph node MPhis, by injecting mice intravenously with clodronate liposomes several days prior to infecting them with WNV. Mice missing splenic MPhis succumbed to WNV infection after an increased and accelerated spread of virus to the spleen and the brain. WNV-specific Ab and CTL responses were normal in splenic MPhi-depleted mice; however, numbers of NK cells and CD4 and CD8 T cells were significantly increased in the brains of infected mice. Splenic MPhi deficiency led to increased WNV in other splenic innate immune cells including CD11b- DCs, newly formed MPhis and monocytes. Unlike other splenic myeloid subsets, splenic MPhis express high levels of mRNAs encoding the complement protein C1q, the apoptotic cell clearance protein Mertk, the IL-18 cytokine and the FcgammaR1 receptor. Splenic MPhi-deficient mice may be highly susceptible to WNV infection in part to a deficiency in C1q, Mertk, IL-18 or Caspase 12 expression. PMID- 29408906 TI - Efficacy and safety of Modified Tongxie Yaofang in diarrhea-predominant irritable bowel syndrome management: A meta-analysis of randomized, positive medicine controlled trials. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of Modified Tongxie Yaofang (M-TXYF) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). METHOD: Electronic databases including PubMed, Springer Link, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang, and Chinese Scientific Journals Database (VIP) were conducted from their inception through May 11, 2017 without language restrictions. Primary and secondary outcomes were estimated by 95% confidence intervals (CI). RevMan 5.3 and the Cochrane Collaboration's risk of bias tool were analyzed for this meta-analysis. RESULTS: Twenty-three literatures with a total of 1972 patients were included for the meta-analysis. The overall risk of bias evaluation was low. The pooled odds ratio showed that M-TXYF was significantly superior to routine pharmacotherapies (RP) in clinical therapeutic efficacy (OR 4.04, 95% CI 3.09, 5.27, P < 0.00001, therapeutic gain = 17.6%, number needed to treat (NNT) = 5.7). Moreover, compared with RP, M-TXYF showed that it can significantly reduce the scores of abdominal pain (standardized mean difference (SMD) -1.27; 95% CI -1.99, -0.56; P = 0.0005), abdominal distention (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09), diarrhea (SMD -1.10; 95% CI -1.95, 0.25; P = 0.01), and frequency of defecation (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003). The differences of the adverse events between experiment and control groups had no statistical significance. CONCLUSION: This meta-analysis indicated that M-TXYF could be a promising Chinese herbal formula in treating IBS-D. However, considering the lack of higher quality of randomized controlled trials (RCTs), highly believable evidences should be required. PMID- 29408907 TI - Five year outcomes of Boston type I keratoprosthesis as primary versus secondary penetrating corneal procedure in a matched case control study. AB - Despite improved retention and reduced complication rates paving the way for the current expansion of applications and surge in prevalence for the Boston type I Keratoprosthesis (KPro), the most frequent indication for its implantation today remains prior graft failure. The purpose of this study is to evaluate the long term outcomes of primary KPro and compare to secondary implantation in a matched cohort study. This study included patients who underwent KPro implantation in a single center by two surgeons between July 2008 and October 2014. All eyes with KPro implantation as the primary procedure with a minimum follow up of 12 months were matched with eyes with same preoperative diagnoses that underwent secondary KPro implantation. Main outcomes included visual acuity and device retention. A total of 56 eyes were included with 28 eyes in each group. Mean follow up was 5.0 years for both groups. Twenty-nine percent (8) of the eyes in the primary group had a diagnosis of chemical or thermal injuries, 25% (7) aniridia, 18% (5) autoimmune disease, 4% (1) infectious keratitis/neurotrophic cornea, 7% (2) gelatinous corneal dystrophy, 7% (2) ectrodactyly ectodermal dysplasia/limbal stem cell deficiency, and 11% (3) uveitis/hypotony. Sixty-one percent (17) of the eyes in the primary group and 39% (11) in the secondary group maintained a final best-corrected visual acuity of 20/200 or better at a mean follow up of 5.0 years; the probability of maintaining best-corrected vision is 0.83 and 0.49 for primary and secondary groups at 5.0 years (p = 0.02). There is no statistically significant difference between groups in device retention (p = 0.22) or postoperative complication rates (p >0.05). This study demonstrates that Boston KPro implantation may be successful as a primary procedure in patients at high risk of failure with traditional penetrating keratoplasty. The device has a good long-term retention rate and visual outcomes are promising however a larger study is needed for more definitive results. PMID- 29408908 TI - Resurrection and resilience of the rarest butterflies. PMID- 29408909 TI - Dynamical analysis of the global business-cycle synchronization. AB - This paper reports the dynamical analysis of the business cycles of 12 (developed and developing) countries over the last 56 years by applying computational techniques used for tackling complex systems. They reveal long-term convergence and country-level interconnections because of close contagion effects caused by bilateral networking exposure. Interconnectivity determines the magnitude of cross-border impacts. Local features and shock propagation complexity also may be true engines for local configuration of cycles. The algorithmic modeling proves to represent a solid approach to study the complex dynamics involved in the world economies. PMID- 29408910 TI - Pervasive, hard-wired and male: Qualitative study of how UK adolescents view alcohol-related aggression. AB - Laboratory studies of alcohol-inexperienced adolescents show that aggression can be primed by alcohol-related stimuli, suggesting that alcohol-related aggression is partly socially learned. Script theory proposes that alcohol-related aggression 'scripts' for social behaviors are culturally-available and learned by individuals. The purpose of the study was to understand the content and origins of alcohol-related aggression scripts learned by adolescents. This qualitative focus group study of 40 adolescents (ages 14-16 years) examined alcohol-related aggression scripts. Participants believed aggression and severe injury to be pervasive when young people drink. Viewed through a biological lens, participants described aggression as an 'instinctive' and 'hard-wired' male trait facilitated by intoxication. As such, alcohol-related aggression was not seen as intended or personally controllable and participants did not see it in moral terms. Females were largely viewed as either bystanders of inter-male aggression or potential victims of male sexual aggression. Participants attributed their views on the frequency and nature of alcohol-related aggression to current affairs and reality television, which they felt portrayed a reality of which they had little experience. The origins of the explicitly biological frameworks that participants used seemed to lie in pre-existing beliefs about the nature of gender differences. Perceptions of the pervasiveness of male alcohol-related aggression, and the consequent failure to view alcohol-related aggression in moral terms, could dispose some young people to alcohol-related aggression. Interventions could target (1) the beliefs that alcohol-related aggression is pervasive and uncontrollable in males, and (2) participants' dysfunctional views of masculinity that underpin those beliefs. PMID- 29408911 TI - Effect of repeated-sprints on the reliability of short-term parasympathetic reactivation. AB - This study determined the reliability of post-exercise heart rate recovery (HRR) and vagal-related HR variability (HRV) after repeated-sprints (RSs), and contrasted it with the smallest worthwhile change (SWC) of these indices. Fourteen healthy male participants performed on four occasions, separated by 7 days, five 30-m sprints interspersed by 25-s of recovery. Post-exercise HR during 10 min of seated rest was measured. HRR during the first 60-s of recovery was computed (HRR60s). HRV indices were calculated in time and frequency domains during the last 5-min of the recovery. Absolute and relative reliability were assessed by typical error of measurement expressed as coefficient of variation (CV) and intraclass correlation coefficients (ICCs), respectively. Sensitivity was assessed comparing SWC to the typical error of measurement. CV ranged from 3.6% to 13.5% and from 6.3% to 109.2% for the HRR and HRV indices, respectively. ICCs were from 0.78 to 0.96 and from 0.76 to 0.92, respectively. HRR and HRV indices showed large discrepancies reliability. HRR60s and the square root of the mean sum of the squared differences between R-R intervals presented the highest levels of both absolute and relative reliability. However, SWC was lower than the typical error of measurement, indicating insufficient sensitivity to confidently detect small, but meaningful, changes in HRR and HRV indices. PMID- 29408913 TI - Correction: Consensus Analysis of Whole Transcriptome Profiles from Two Breast Cancer Patient Cohorts Reveals Long Non-Coding RNAs Associated with Intrinsic Subtype and the Tumour Microenvironment. AB - [This corrects the article DOI: 10.1371/journal.pone.0163238.]. PMID- 29408912 TI - Effect of maternal height on caesarean section and neonatal mortality rates in sub-Saharan Africa: An analysis of 34 national datasets. AB - RATIONALE: The lifecycle perspective reminds us that the roots of adult ill health may start in-utero or in early childhood. Nutritional and infectious disease insults in early life, the critical first 1000 days, are associated with stunting in childhood, and subsequent short adult stature. There is limited or no opportunity for stunted children above 2 years of age to experience catch-up growth. Some previous research has shown short maternal height to lead to adverse birth outcomes. In this paper, we document the association between maternal height and caesarean section, and between maternal height and neonatal mortality in 34 sub-Saharan African countries. We also explore the appropriate height cut offs to use. Our paper contributes arguments to support a focus on preventing non communicable risk factors, namely early childhood under-nutrition, as part of the fight to reduce caesarean section rates and other adverse maternal and newborn health outcomes, particularly neonatal mortality. We focus on the Sub-Saharan Africa region because it carries the highest burden of maternal and neonatal ill health. METHODS: We used the most recent Demographic and Health Survey for 34 sub Saharan African countries. The distribution of heights of women who had given birth in the 5 years before the survey was explored. We adopted the following cut offs: Very Short (<145.0cm), Short (145.0-149.9cm), Short-average (150.0 154.9cm), Average (155.0-159.9cm), Average-tall (160.0-169.9cm) and Tall (>=170.0cm). Multivariate logistic regression was used to assess the contribution of maternal stature to the odds ratio of caesarean section delivery, adjusting for other exposures, such as age at index birth, residence, maternal BMI, maternal education, wealth index quintile, previous caesarean section, multiple birth, birth order and country of survey. We also look at its contribution to neonatal mortality adjusting for age at index birth, residence, maternal BMI, maternal education, wealth index quintile, multiple birth, birth order and country of survey. RESULTS: There was a gradual increase in the rate of caesarean section with decreasing maternal height. Compared to women of Average height (155.0-159.9cm), taller women were protected. The adjusted odds ratio (aOR) for Tall women was 0.67 (95% CI:0.52-0.87) and for Average-tall women was 0.78 (95% CI:0.69-0.89). Compared to women of Average height, shorter women were at increased risk. The aOR for Short-average women was 1.19 (95% CI:1.03-1.37), for Short women was 2.06 (95% CI:1.71-2.48), and for Very Short women was 2.50 (95% CI:1.85-3.38). There was evidence that compared to Average height women, Very Short and Short women had increased odds of experiencing a neonatal death aOR = 1.95 (95% CI 1.17-3.25) and aOR = 1.66 (95% CI 1.20-2.28) respectively. When we focused on the period of highest risk, the day of delivery and first postnatal day, these aORs increased to 2.36 (95% CI 1.57-3.55) and 2.34 (95% CI 1.19-4.60) respectively. The aORs for the first week of life (early neonatal mortality) were 1.90 (95% CI 1.07-3.36) and 1.83 (95% CI 1.30-2.59) respectively. CONCLUSIONS: Short stature is associated with an increased prevalence of caesarean section and neonatal mortality, particularly on the newborn's first days. These results are even more striking because we know that caesarean section rates tend to be higher among wealthier and more educated women, who are often taller and that the same patterns may hold for neonatal survival; in such cases, adjusting for wealth, education and urban residence would attenuate these associations. Caesarean sections can be lifesaving operations; however, they cost the health system and families more, and are associated with worse health outcomes. We suggest that our findings be used to argue for policies targeting stunting in infant girls and potential catch-up growth in adolescence and early adulthood, aiming to increase their adult height and thus decrease their subsequent risk of experiencing caesarean section and adverse birth outcomes. PMID- 29408914 TI - Tracking of body adiposity indicators from childhood to adolescence: Mediation by BMI. AB - Our aim was to verify the tracking of body adiposity indicators from childhood to adolescence and analyze the mediation effects of BMI on the stability of body adiposity. Our sample was composed by 375 children (197 boys). The children were followed-up over 3 years. Body mass and stature were measured as anthropometric indicators. Body adiposity was estimated through the subcutaneous skinfold method, with measures of triceps (TRSF) and subscapular skinfolds (SSSF). Skinfolds were analyzed singly and agglutinated through the sum of skinfolds (?SF). The sample was categorized into tertiles, and thereafter, the kappa coefficient and McNemar test were adopted to verify stability. For continuous measures, the Intra-Class Correlation coefficient (ICC) was used. Moreover, mediation analyzes were used according to Baron and Kenny with the Sobel test to verify mediation effects. The significance level adopted was 5%. Adiposity indicators increased during the 3 years of follow-up in both sexes (p<0.05). ICCs in all indicators of adiposity were between 0.84 and 0.94 for boys and 0.86 and 0.94 for girls, indicating high tracking. Moreover, 70% of subjects remained in the highest tertile of body adiposity. However, no differences were observed in tertile changes (p>0.05). BMI at the age of adiposity rebound partially mediated all indicators of adiposity from childhood (baseline) to adolescence (3 years later) in both sexes (p<0.001). Thus, moderate to high tracking of body adiposity indicators between childhood and adolescence was verified. Moreover, BMI at the age of adiposity rebound partially mediated the relationship between adiposity in childhood (baseline) and in adolescence (3 years of follow-up). PMID- 29408915 TI - Comorbidity profiles of psoriasis in Taiwan: A latent class analysis. AB - BACKGROUND: Psoriasis is associated with many comorbidities. An understanding of these comorbidity patterns can help foster better care of patients with psoriasis. OBJECTIVE: To identify the heterogeneity of psoriasis comorbidities using latent class analysis (LCA). METHODS: LCA was used to empirically identify psoriasis comorbidity patterns in a nationwide sample of 110,729 incident cases of psoriasis (2002-2012) from the National Health Insurance database in Taiwan. RESULTS: The mean age of incident psoriasis was 46.1 years. Hypertension (28.8%), dyslipidemia (18.9%), and chronic liver disease/cirrhosis/hepatitis (18.1%) were the top three comorbidities in patients with psoriasis. LCA identified four distinct comorbidity classes among these patients, including 9.9% of patients in the "multi-comorbidity" class, 17.9% in the "metabolic syndrome" class, 11.3% in the "hypertension and chronic obstructive pulmonary disease (COPD)" class, and 60.9% in the "relatively healthy" class. Psoriatic arthritis was evenly distributed among each class. Relative to membership in the "relative healthy" class, an increase of one year of age had a higher probability of membership in the "multi-comorbidity" (odds ratio [OR], 1.25), "metabolic syndrome" (OR, 1.11), or "hypertension and COPD" (OR, 1.34) classes. Relative to membership in the "relative healthy" class, compared to women, men had a higher probability of membership in the "multi-comorbidity" (OR, 1.39), "metabolic syndrome" (OR, 1.77), or "hypertension and COPD" (OR, 1.22) classes. CONCLUSION: We observed four distinct classes of psoriasis comorbidities, including the "multi comorbidity", "metabolic syndrome", "hypertension and COPD", and "relatively healthy" classes, as well as the clustering of liver diseases with metabolic syndrome and clustering of COPD with hypertension. PMID- 29408916 TI - Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer. AB - Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13-2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51-0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pair wise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T-NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1 based immunotherapy in CRC. PMID- 29408917 TI - Adaptive evolution of benzoxazinoids in wild emmer wheat, Triticum dicoccoides, at "Evolution Canyon", Mount Carmel, Israel. AB - BACKGROUND: "Evolution Canyon" (ECI) at Lower Nahal Oren, Mount Carmel, Israel, is an optimal natural microscale model for unraveling evolution-in-action, highlighting the evolutionary processes of biodiversity evolution, adaptation, and incipient sympatric speciation. A major model organism in ECI is the tetraploid wild emmer wheat, Triticum dicoccoides (TD), the progenitor of cultivated emmer and durum wheat. TD displays dramatic interslope adaptive evolutionary divergence on the tropical, savannoid-hot and dry south-facing, "African" slope (AS), and on the temperate, forested, cool and humid, north facing, "European" slope (ES), separated on average by 250 m. From the perspective of chemical evolution and metabolomics, it is important to unravel interslope divergence in biologically relevant secondary metabolites between the abutting slope populations. Here, in TD we examined hydroxamic acid (Hx), which is a family of secondary cereal metabolites, and plays a major role in defending the plant against fungi, insects and weeds. RESULTS: Our examination revealed that higher concentrations of DIBOA and DIMBOA were found in seedlings growing in the same greenhouse from seeds collected from the cool and humid forested ES, whereas the seedlings of seeds collected from the savannoid AS (both in root and shoot tissues), showed no DIMBOA. Remarkably, only DIBOA appears in both shoots and roots of the AS seedlings. It rises to a peak and then decreases in both organs and in seedlings from both slopes. The DIMBOA, which appears only in the ES seedlings, rises to a peak and decreases in the shoot, but increased and remained in a plateau in the root, till the end of the experiment. CONCULSIONS/SIGNIFICANCE: The results suggest stronger genetic resistance of defense compounds DIBOA and DIMBOA against biotic stresses (fungi and other pathogens) by ES seedlings. However, AS seedlings responded earlier but were to the same biotic stresses. The genetic difference found in AS seedlings was caused by the main adaptive selection in AS, which was against climatic, abiotic stresses, and was weaker, or not at all, against biotic stresses. The distinct genetic interslope differences appear important and is very significant and are elaborated in the discussion. PMID- 29408918 TI - Effects of an EPSPS-transgenic soybean line ZUTS31 on root-associated bacterial communities during field growth. AB - The increased worldwide commercial cultivation of transgenic crops during the past 20 years is accompanied with potential effects on the soil microbial communities, because many rhizosphere and endosphere bacteria play important roles in promoting plant health and growth. Previous studies reported that transgenic plants exert differential effects on soil microbial communities, especially rhizobacteria. Thus, this study compared the soybean root-associated bacterial communities between a 5-enolpyruvylshikimate-3-phosphate synthase transgenic soybean line (ZUTS31 or simply Z31) and its recipient cultivar (Huachun3 or simply HC3) at the vegetative, flowering, and seed-filling stages. High-throughput sequencing of 16S rRNA gene (16S rDNA) V4 hypervariable region amplicons via Illumina MiSeq and real-time quantitative PCR (qPCR) were performed. Our results revealed no significant differences in the overall alpha diversity of root-associated bacterial communities at the three developmental stages and in the beta diversity of root-associated bacterial communities at the flowering stage between Z31 and HC3 under field growth. However, significant differences in the beta diversity of rhizosphere bacterial communities were found at the vegetative and seed-filling stages between the two groups. Furthermore, the results of next generation sequencing and qPCR showed that the relative abundances of root-associated main nitrogen-fixing bacterial genera, especially Bradyrhizobium in the roots, evidently changed from the flowering stage to the seed-filling stage. In conclusion, Z31 exerts transitory effects on the taxonomic diversity of rhizosphere bacterial communities at the vegetative and seed-filling stages compared to the control under field conditions. In addition, soybean developmental change evidently influences the main symbiotic nitrogen-fixing bacterial genera in the roots from the flowering stage to the seed-filling stage. PMID- 29408919 TI - UPLC-QTOF-MS metabolomics analysis revealed the contributions of metabolites to the pathogenesis of Rhizoctonia solani strain AG-1-IA. AB - To explore the pathogenesis of Rhizoctonia solani and its phytotoxin phenylacetic acid (PAA) on maize leaves and sheaths, treated leaf and sheath tissues were analyzed and interpreted by ultra-performance liquid chromatography-mass spectrometry combined with chemometrics. The PAA treatment had similar effects to those of R. solani on maize leaves regarding the metabolism of traumatin, phytosphingosine, vitexin 2'' O-beta-D-glucoside, rutin and DIBOA-glucoside, which were up-regulated, while the synthesis of OPC-8:0 and 12-OPDA, precursors for the synthesis of jasmonic acid, a plant defense signaling molecule, was down regulated under both treatments. However, there were also discrepancies in the influences exhibited by R. solani and PAA as the metabolic concentration of zeaxanthin diglucoside in the R. solani infected leaf group decreased. Conversely, in the PAA-treated leaf group, the synthesis of zeaxanthin diglucoside was enhanced. Moreover, although the synthesis of 12 metabolites were suppressed in both the R. solani- and PAA-treated leaf tissues, the inhibitory effect of R. solani was stronger than that of PAA. An increased expression of quercitrin and quercetin 3-O-glucoside was observed in maize sheaths treated by R. solani, while their concentrations were not changed significantly in the PAA treated sheaths. Furthermore, a significant decrease in the concentration of L Glutamate, which plays important roles in plant resistance to necrotrophic pathogens, only occurred in the R. solani-treated sheath tissues. The differentiated metabolite levels may be the partial reason of why maize sheaths were more susceptible to R. solani than leaves and may explain the underlying mechanisms of R. solani pathogenesis. PMID- 29408920 TI - Examining the association between livestock ownership typologies and child nutrition in the Luangwa Valley, Zambia. AB - OBJECTIVE: To investigate the association between livestock ownership and dietary diversity, animal-source food consumption, height-for-age z-score, and stunting among children living in wildlife "buffer zones" of Zambia's Luangwa Valley using a novel livestock typology approach. METHODS: We conducted a cross-sectional study of 838 children aged 6-36 months. Households were categorized into typologies based on the types and numbers of animals owned, ranging from no livestock to large numbers of mixed livestock. We used multilevel mixed-effects linear and logistic regression to examine the association between livestock typologies and four nutrition-related outcomes of interest. Results were compared with analyses using more common binary and count measures of livestock ownership. RESULTS: No measure of livestock ownership was significantly associated with children's odds of animal-source food consumption, child height-for-age z-score, or stunting odds. Livestock ownership Type 2 (having a small number of poultry) was surprisingly associated with decreased child dietary diversity (beta = 0.477; p<0.01) relative to owning no livestock. Similarly, in comparison models, chicken ownership was negatively associated with dietary diversity (beta = 0.320; p<0.01), but increasing numbers of chickens were positively associated with dietary diversity (beta = 0.022; p<0.01). Notably, neither child dietary diversity nor animal-source food consumption was significantly associated with height, perhaps due to unusually high prevalences of morbidities. CONCLUSIONS: Our novel typologies methodology allowed for an efficient and a more in-depth examination of the differential impact of livestock ownership patterns compared to typical binary or count measures of livestock ownership. We found that these patterns were not positively associated with child nutrition outcomes in this context. Development and conservation programs focusing on livestock must carefully consider the complex, context-specific relationship between livestock ownership and nutrition outcomes-including how livestock are utilized by the target population-when attempting to use livestock as a means of improving child nutrition. PMID- 29408921 TI - The relationship between famine exposure during early life and body mass index in adulthood: A systematic review and meta-analysis. AB - BACKGROUND: Previous epidemiologic studies have reported famine exposure during early life association with overweight or obesity in adulthood, but a consistent perspective has not been established to date. PURPOSE: To determine, by conducting a systematic review and meta-analysis, whether exposure to famine could increase body mass index (BMI) in adult or not, and assess the association between famine exposure and the risk of overweight or obesity. METHODS: Published articles were systematically searched (until August, 2017) from PubMed, ScienceDirect, Cochrane, and China National Knowledge Infrastructure. Initially, comparing differences in BMI between exposed and non-exposed groups that weight mean difference (WMD) were used. Subsequently, the effect of famine exposure on overweight or obesity risk, which pooled relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULT: Twenty studies were included in this systematic review and meta-analysis. Compared with non-exposed group, famine exposure group significantly increased the risk of overweight (OR = 1.10, 95% CI: 1.04-1.16) and obesity (OR = 1.15, 95% CI: 1.05-1.24). Sensitivity analyses revealed no significant change in the famine exposure and BMI, the risk of overweight and obesity study when any one study was excluded. Subgroup analyses showed that age, gender, exposure type, study type, continent, famine cause and paper publication date were associated with BMI, the risk of overweight and obesity. Meta regression analyses suggested that continent, famine cause could partially explain heterogeneity for famine exposure and BMI studies. CONCLUSION: The systematic review and meta-analysis indicates that famine exposure during early life may increase BMI, the risk of overweight and obesity, especially for female, fetal famine exposure or subject age less than 50. Furthermore, famine exposure group the risk of overweight and obesity in cross-sectional studies, Asian studies, famine cause by natural disaster or paper published from 2015 to the present studies are higher than that of non-exposed group. PMID- 29408922 TI - The effect of metal pollution on the life history and insecticide resistance phenotype of the major malaria vector Anopheles arabiensis (Diptera: Culicidae). AB - Metal exposure is one of the commonest anthropogenic pollutants mosquito larvae are exposed to, both in agricultural and urban settings. As members of the Anopheles gambiae complex, which contains several major malaria vector species including An. arabiensis, are increasingly adapting to polluted environments, this study examined the effects of larval metal exposure on various life history traits of epidemiological importance. Two laboratory strains of An. arabiensis, SENN (insecticide susceptible) and SENN DDT (insecticide resistant), were reared in maximum acceptable toxicity concentrations, (MATC-the highest legally accepted concentration) of cadmium chloride, lead nitrate and copper nitrate. Following these exposures, time to pupation, adult size and longevity were determined. Larvae reared in double the MATC were assessed for changes in malathion and deltamethrin tolerance, measured by lethal time bottle bioassay, as well as changes in detoxification enzyme activity. As defence against oxidative stress has previously been demonstrated to affect the expression of insecticide resistance, catalase, glutathione peroxidase and superoxide dismutase activity was assessed. The relative metal toxicity to metal naive larvae was also assessed. SENN DDT larvae were more tolerant of metal pollution than SENN larvae. Pupation in SENN larvae was significantly reduced by metal exposure, while adult longevity was not affected. SENN DDT showed decreased adult size after larval metal exposure. Adult insecticide tolerance was increased after larval metal exposure, and this effect appeared to be mediated by increased beta-esterase, cytochrome P450 and superoxide dismutase activity. These data suggest an enzyme mediated positive link between tolerance to metal pollutants and insecticide resistance in adult mosquitoes. Furthermore, exposure of larvae to metal pollutants may have operational consequences under an insecticide-based vector control scenario by increasing the expression of insecticide resistance in adults. PMID- 29408923 TI - Analytic method for evaluating players' decisions in team sports: Applications to the soccer goalkeeper. AB - The aim of this study was to define a method for evaluating a player's decisions during a game based on the success probability of his actions and for analyzing the player strategy inferred from game actions. There were developed formal definitions of i) the stochastic process of player decisions in game situations and ii) the inference process of player strategy based on his game decisions. The method was applied to the context of soccer goalkeepers. A model of goalkeeper positioning, with geometric parameters and solutions to optimize his position based on the ball position and trajectory, was developed. The model was tested with a sample of 65 professional goalkeepers (28.8 +/- 4.1 years old) playing for their national teams in 2010 and 2014 World Cups. The goalkeeper's decisions were compared to decisions from a large dataset of other goalkeepers, defining the probability of success in each game circumstance. There were assessed i) performance in a defined set of classes of game plays; ii) entropy of goalkeepers' decisions; and iii) the effect of goalkeepers' positioning updates on the outcome (save or goal). Goalkeepers' decisions were similar to the ones with the lowest probability of goal on the dataset. Goalkeepers' entropy varied between 24% and 71% of the maximum possible entropy. Positioning dynamics in the instants that preceded the shot indicated that, in goals and saves, goalkeepers optimized their position before the shot in 21.87% and 83.33% of the situations, respectively. These results validate a method to discriminate successful performance. In conclusion, this method enables a more precise assessment of a player's decision-making ability by consulting a representative dataset of equivalent actions to define the probability of his success. Therefore, it supports the evaluation of the player's decision separately from his technical skill execution, which overcomes the scientific challenge of discriminating the evaluation of a player's decision performance from the action result. PMID- 29408924 TI - A particle filter for ammonia coverage ratio and input simultaneous estimations in Diesel-engine SCR system. AB - As NOx emissions legislation for Diesel-engines is becoming more stringent than ever before, an aftertreatment system has been widely used in many countries. Specifically, to reduce the NOx emissions, a selective catalytic reduction(SCR) system has become one of the most promising techniques for Diesel-engine vehicle applications. In the SCR system, input ammonia concentration and ammonia coverage ratio are regarded as essential states in the control-oriental model. Currently, an ammonia sensor placed before the SCR Can is a good strategy for the input ammonia concentration value. However, physical sensor would increase the SCR system cost and the ammonia coverage ratio information cannot be directly measured by physical sensor. Aiming to tackle this problem, an observer based on particle filter(PF) is investigated to estimate the input ammonia concentration and ammonia coverage ratio. Simulation results through the experimentally validated full vehicle simulator cX-Emission show that the performance of observer based on PF is outstanding, and the estimation error is very small. PMID- 29408925 TI - Outcome of medial hamstring lengthening in children with spastic paresis: A biomechanical and morphological observational study. AB - To improve gait in children with spastic paresis due to cerebral palsy or hereditary spastic paresis, the semitendinosus muscle is frequently lengthened amongst other medial hamstring muscles by orthopaedic surgery. Side effects on gait due to weakening of the hamstring muscles and overcorrections have been reported. How these side effects relate to semitendinosus morphology is unknown. This study assessed the effects of bilateral medial hamstring lengthening as part of single-event multilevel surgery (SEMLS) on (1) knee joint mechanics (2) semitendinosus muscle morphology and (3) gait kinematics. All variables were assessed for the right side only. Six children with spastic paresis selected for surgery to counteract limited knee range of motion were measured before and about a year after surgery. After surgery, in most subjects popliteal angle decreased and knee moment-angle curves were shifted towards a more extended knee joint, semitendinosus muscle belly length was approximately 30% decreased, while at all assessed knee angles tendon length was increased by about 80%. In the majority of children muscle volume of the semitendinosus muscle decreased substantially suggesting a reduction of physiological cross-sectional area. Gait kinematics showed more knee extension during stance (mean change +/- standard deviation: 34+/-13 degrees ), but also increased pelvic anterior tilt (mean change +/- standard deviation: 23+/-5 degrees ). In most subjects, surgical lengthening of semitendinosus tendon contributed to more extended knee joint angle during static measurements as well as during gait, whereas extensibility of semitendinosus muscle belly was decreased. Post-surgical treatment to maintain muscle belly length and physiological cross-sectional area may improve treatment outcome of medial hamstring lengthening. PMID- 29408926 TI - Mid-to-long term mortality following surgical versus percutaneous coronary revascularization stratified according to stent subtype: An analysis of 6,682 patients with multivessel disease. AB - BACKGROUND: Studies comparing coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) have largely been performed in the bare metal stent (BMS) and first-generation drug eluting stent (F-DES) era. Second generation DES (S-DES) have shown improved outcomes when compared to F-DES, but data comparing CABG with PCI using S-DES is limited. We compared mortality following CABG versus PCI for patients with multivessel disease and analyzed different stent types. METHODS: A total of 6,682 patients underwent multivessel revascularization at Harefield Hospital, UK. We stratified CABG patients into single arterial graft (SAG) or multiple arterial grafts (MAG); and PCI patients into BMS, F-DES or S-DES groups. We analyzed all-cause mortality at 5 years. RESULTS: 4,388 patients had CABG (n[SAG] = 3,358; n[MAG] = 1,030) and 2,294 patients had PCI (n[BMS] = 416; n[F-DES] = 752; n[S-DES] = 1,126). PCI had higher 5-year mortality with BMS (HR = 2.27, 95% CI:1.70-3.05, p<0.001); F-DES (HR = 1.52, 95% CI:1.14-2.01, p = 0.003); and S-DES (HR = 1.84, 95% CI:1.42-2.38, p<0.001). This was confirmed in inverse probability treatment weighted analyses. When adjusting for both measured and unmeasured factors using instrumental variable analyses, PCI had higher 5-year mortality with BMS (Delta = 15.5, 95% CI:3.6,27.5, p = 0.011) and FDES (Delta = 16.5, 95% CI:6.6,26.4, p<0.001), but had comparable mortality with CABG for PCI with SDES (Delta = 0.9, 95% CI: 9.6,7.9, p = 0.844), and when exclusively compared to CABG patients with SAG (Delta = 0.4, 95% CI: -8.0,8.7, p = 0.931) or MAG (Delta = 4.6, 95% CI: -0.4,9.6, p = 0.931). CONCLUSIONS: In this real-world analysis, when adjusting for measured and unmeasured confounding, PCI with SDES had comparable 5-year mortality when compared to CABG. This warrants evaluation in adequately-powered randomized controlled trials. PMID- 29408927 TI - Transcriptional profiling of liver tissues in chicken embryo at day 16 and 20 using RNA sequencing reveals differential antioxidant enzyme activity. AB - Considering the high proportion of polyunsaturated fatty acids, the antioxidant defense of chick embryo tissues is vital during the oxidative stress experienced at hatching. In order to better understand the mechanisms of the defense system during chicken embryo development, we detected the activity of antioxidant enzymes during the incubation of chicken embryo. Results showed that the activity of superoxide dismutase (SOD) and (GSH-PX) in livers were higher than those in hearts. Based on these results, liver tissues were used as the follow-up study materials, which were obtained from chicken embryo at day 16 and day 20. Thus, we used RNA sequencing (RNA-Seq) analysis to identify the transcriptome from 6 liver tissues. In total, we obtained 45,552,777-45,462,856 uniquely mapped reads and 18,837 mRNA transcripts, across the 6 liver samples. Among these, 1,154 differentially expressed genes (p<0.05, foldchange>=1) were identified between the high and low groups, and 1,069 GO terms were significantly enriched (p<0.05). Of these, 10 GO terms were related to active oxygen defense and antioxidant enzyme activity. GO enrichment and KEGG pathway analysis indicated that GSTA2, GSTA4, MGST1, GPX3, and HAO2 participated in glutathione metabolism, and were considered as the most promising candidate genes affecting the antioxidant enzyme activity of chicken embryo at day 16 and day 20. Using RNA-Seq and differential gene expression, our study here investigated the complexity of the liver transcriptome in chick embryos and analyzed the key genes associated with the antioxidant enzyme. PMID- 29408928 TI - Validation of the Patient Health Questionnaire (PHQ-9) as a screening tool for depression in pregnant women: Afaan Oromo version. AB - BACKGROUND: Semantic, technical, content, criterion and conceptual equivalence must be examined in order to validate a psychological rating scale in a new cultural setting. Few validation studies have been conducted in sub-Saharan Africa for scales seeking to detect depression in pregnant women. The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression among Afaan Oromo speaking pregnant Ethiopian women. METHODS: A random sample of 246 pregnant women were recruited in Seka Chekorsa District, Ethiopia during their first, second or third trimester. One week later, 29 participants were selected to answer the questionnaire for a second time to evaluate test retest reliability. The Mini International Neuropsychiatric Interview (MINI-Plus) scale was used as a gold standard to evaluate validity. PHQ-9 was compared with MINI-Plus and sensitivity, specificity, accuracy, positive likelihood ratio, negative likelihood ratio and Receiver Operating Characteristic Curves (ROC) for PHQ-9 were calculated. Rasch analysis was also carried out using Winsteps version 3.81.0. RESULTS: The reliability coefficient, Cronbach's alpha, for the PHQ-9 total score was 0.84. Both the agreement and consistency Intra-class Correlation coefficients (ICC) for the one-week test-retest reliability were 0.98. The cut-off point of a summed score of eight resulted in a sensitivity of 80.8% and a specificity of 79.5%. The calculated area under the curve (AUC) for the PHQ-9 score versus the MINI-Plus was excellent, 0.88 (SE = 0.04; CI = 0.81-0.95). The PHQ-9 meets the criteria established by Linacre for rating scale effectiveness. CONCLUSIONS: The PHQ-9 proved to be a reliable and valid instrument that may be used to screen major depressive disorders among Afaan Oromo speaking Ethiopian pregnant women. PMID- 29408929 TI - Cytokine-mediated inflammation mediates painful neuropathy from metabolic syndrome. AB - Painful neuropathy (PN) is a prevalent condition in patients with metabolic syndrome (MetS). However, the pathogenic mechanisms of metabolic syndrome associated painful neuropathy (MetSPN) remain unclear. In the current study, high fat-fed mice (HF mice) were used to study MetSPN. HF mice developed MetS phenotypes, including increased body weight, elevated plasma cholesterol levels, and insulin resistance in comparison with control-fat-fed (CF) mice. Subsequently, HF mice developed mechanical allodynia and thermal hyperalgesia in hind paws after 8 wk of diet treatment. These pain behaviors coincided with increased densities of nociceptive epidermal nerve fibers and inflammatory cells such as Langerhans cells and macrophages in hind paw skin. To study the effect of MetS on profiles of cytokine expression in HF mice, we used a multiplex cytokine assay to study the protein expression of 12 pro-inflammatory and anti inflammatory cytokines in dorsal root ganglion and serum samples. This method detected the elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6, IL-1beta as well as reduced anti-inflammatory IL-10 in lumbar dorsal root ganglia (LDRG) of HF mice. Intraperitoneal administration of IL-10 reduced the upregulation of pro inflammatory cytokines and alleviated pain behaviors in HF mice without affecting MetS phenotypes. Our findings suggested targeting HF-induced cytokine dysregulation could be an effective strategy for treating MetSPN. PMID- 29408930 TI - Interpretation of correlated neural variability from models of feed-forward and recurrent circuits. AB - Neural populations respond to the repeated presentations of a sensory stimulus with correlated variability. These correlations have been studied in detail, with respect to their mechanistic origin, as well as their influence on stimulus discrimination and on the performance of population codes. A number of theoretical studies have endeavored to link network architecture to the nature of the correlations in neural activity. Here, we contribute to this effort: in models of circuits of stochastic neurons, we elucidate the implications of various network architectures-recurrent connections, shared feed-forward projections, and shared gain fluctuations-on the stimulus dependence in correlations. Specifically, we derive mathematical relations that specify the dependence of population-averaged covariances on firing rates, for different network architectures. In turn, these relations can be used to analyze data on population activity. We examine recordings from neural populations in mouse auditory cortex. We find that a recurrent network model with random effective connections captures the observed statistics. Furthermore, using our circuit model, we investigate the relation between network parameters, correlations, and how well different stimuli can be discriminated from one another based on the population activity. As such, our approach allows us to relate properties of the neural circuit to information processing. PMID- 29408931 TI - Inhibition of experimental autoimmune encephalomyelitis by tolerance-promoting DNA vaccination focused to dendritic cells. AB - In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-beta1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG). For comparison, the strong and ubiquitously active CMV promoter was employed (pCMV-MOG), which allows MOG expression in all transfected cells. Expression of IL-10 and TGF-beta1 was controlled by the CMV promoter to yield maximal synthesis (pCMV-IL10, pCMV-TGFbeta). Co-application of pFscn-MOG and pCMV IL10 significantly ameliorated EAE pathology, while vaccination with pCMV-MOG plus pCMV-IL10 did not affect EAE outcome. In contrast, vaccination with either of the two MOG-encoding plasmids in combination with pCMV-TGFbeta significantly attenuated the clinical EAE symptoms. Mechanistically, we observed diminished infiltration of Th17 and Th1 cells as well as macrophages/DCs into the CNS, which correlated with decreased MOGp35-55-specific production of IL-17 and IFN-? by spleen cells and reduced peptide-specific T cell proliferation. Our findings suggest deletion of or anergy induction in MOG-specific CD4+ T cells by the suppressive vaccination platform employed. MOG expression driven by the DC specific fascin1 promoter yielded similar inhibitory effects on EAE progression as the ubiquitously active viral CMV promoter, when coapplying pCMV-TGFbeta. Our finding that pCMV-IL10 promoted tolerogenic effects only, when coapplied with pFscn-MOG, but not pCMV-MOG suggests that IL-10 affected only directly transfected DCs (pFscn-MOG), but not neighbouring DCs that engulfed MOG containing vesicles derived from transfected keratinocytes (pCMV-MOG). Thus, due to its DC-restricted expression, the fascin1 promoter might be an interesting alternative to ubiquitously expressed promoters for vaccination strategies. PMID- 29408933 TI - Inducible transgenic expression of tripeptidyl peptidase 1 in a mouse model of late-infantile neuronal ceroid lipofuscinosis. AB - Late-infantile neuronal ceroid lipofuscinosis is a fatal neurodegenerative disease of children caused by mutations resulting in loss of activity of the lysosomal protease, tripeptidyl peptidase 1 (TPP1). While Tpp1-targeted mouse models of LINCL exist, the goal of this study was to create a transgenic mouse with inducible TPP1 to benchmark treatment approaches, evaluate efficacy of treatment at different stages of disease, and to provide insights into the pathobiology of disease. A construct containing a loxP-flanked stop cassette inserted between the chicken-actin promoter and a sequence encoding murine TPP1 (TgLSL-TPP1) was integrated into the ROSA26 locus in mice by homologous recombination. Tested in both transfected CHO cells and in transgenic mice, the TgLSL-TPP1 did not express TPP1 until cre-mediated removal of the LSL cassette, which resulted in supraphysiological levels of TPP1 activity. We tested four cre/ERT2 transgenes to allow tamoxifen-inducible removal of the LSL cassette and subsequent TPP1 expression at any stage of disease. However, two of the cre/ERT2 driver transgenes had significant cre activity in the absence of tamoxifen, while cre-mediated recombination could not be induced by tamoxifen by two others. These results highlight potential problems with the use of cre/ERT2 transgenes in applications that are sensitive to low levels of basal cre expression. However, the germline-recombined mouse transgenic that constitutively overexpresses TPP1 will allow long-term evaluation of overexposure to the enzyme and in cell culture, the inducible transgene may be a useful tool in biomarker discovery projects. PMID- 29408934 TI - The effect of bio-irrigation by the polychaete Lanice conchilega on active denitrifiers: Distribution, diversity and composition of nosZ gene. AB - The presence of large densities of the piston-pumping polychaete Lanice conchilega can have important consequences for the functioning of marine sediments. It is considered both an allogenic and an autogenic ecosystem engineer, affecting spatial and temporal biogeochemical gradients (oxygen concentrations, oxygen penetration depth and nutrient concentrations) and physical properties (grain size) of marine sediments, which could affect functional properties of sediment-inhabiting microbial communities. Here we investigated whether density-dependent effects of L. conchilega affected horizontal (m-scale) and vertical (cm-scale) patterns in the distribution, diversity and composition of the typical nosZ gene in the active denitrifying organisms. This gene plays a major role in N2O reduction in coastal ecosystems as the last step completing the denitrification pathway. We showed that both vertical and horizontal composition and richness of nosZ gene were indeed significantly affected when large densities of the bio-irrigator were present. This could be directly related to allogenic ecosystem engineering effects on the environment, reflected in increased oxygen penetration depth and oxygen concentrations in the upper cm of the sediment in high densities of L. conchilega. A higher diversity (Shannon diversity and inverse Simpson) of nosZ observed in patches with high L. conchilega densities (3,185-3,440 ind. m-2) at deeper sediment layers could suggest a downward transport of NO3- to deeper layers resulting from bio-irrigation as well. Hence, our results show the effect of L. conchilega bio-irrigation activity on denitrifying organisms in L. conchilega reefs. PMID- 29408932 TI - Peripheral TNFalpha elevations in abstinent alcoholics are associated with hepatitis C infection. AB - Substantial evidence supports the view that inflammatory processes contribute to brain alterations in HIV infection. Mechanisms recently proposed to underlie neuropathology in Alcohol Use Disorder (AUD) include elevations in peripheral cytokines that sensitize the brain to the damaging effects of alcohol. This study included 4 groups: healthy controls, individuals with AUD (abstinent from alcohol at examination), those infected with HIV, and those comorbid for HIV and AUD. The aim was to determine whether inflammatory cytokines are elevated in AUD as they are in HIV infection. Cytokines showing group differences included interferon gamma-induced protein 10 (IP-10) and tumor necrosis factor alpha (TNFalpha). Follow-up t-tests revealed that TNFalpha and IP-10 were higher in AUD than controls but only in AUD patients who were seropositive for Hepatitis C virus (HCV). Specificity of TNFalpha and IP-10 elevations to HCV infection status was provided by correlations between cytokine levels and HCV viral load and indices of liver integrity including albumin/globulin ratio, fibrosis scores, and AST/platelet count ratio. Because TNFalpha levels were mediated by HCV infection, this study provides no evidence for elevations in peripheral cytokines in "uncomplicated", abstinent alcoholics, independent of liver disease or HCV infection. Nonetheless, these results corroborate evidence for elevations in IP 10 and TNFalpha in HIV and for IP-10 levels in HIV+HCV co-infection. PMID- 29408936 TI - Forecasting short-term data center network traffic load with convolutional neural networks. AB - Efficient resource management in data centers is of central importance to content service providers as 90 percent of the network traffic is expected to go through them in the coming years. In this context we propose the use of convolutional neural networks (CNNs) to forecast short-term changes in the amount of traffic crossing a data center network. This value is an indicator of virtual machine activity and can be utilized to shape the data center infrastructure accordingly. The behaviour of network traffic at the seconds scale is highly chaotic and therefore traditional time-series-analysis approaches such as ARIMA fail to obtain accurate forecasts. We show that our convolutional neural network approach can exploit the non-linear regularities of network traffic, providing significant improvements with respect to the mean absolute and standard deviation of the data, and outperforming ARIMA by an increasingly significant margin as the forecasting granularity is above the 16-second resolution. In order to increase the accuracy of the forecasting model, we exploit the architecture of the CNNs using multiresolution input distributed among separate channels of the first convolutional layer. We validate our approach with an extensive set of experiments using a data set collected at the core network of an Internet Service Provider over a period of 5 months, totalling 70 days of traffic at the one second resolution. PMID- 29408935 TI - Depression and smoking characteristics among HIV-positive smokers in Russia: A cross-sectional study. AB - INTRODUCTION: Globally, persons with HIV infection, depression and substance use disorders have a higher smoking prevalence and smoke more heavily than other populations. These associations have not been explored among Russian smokers with HIV infection and substance use disorders. The purpose of this study was to examine the relationship between the presence of depressive symptoms and smoking outcomes in an HIV-positive cohort of Russian smokers with a history of substance use disorders (alcohol and/or drug use disorders). METHODS: We performed a cross sectional secondary data analysis of a cohort of HIV-positive regular smokers with a history of substance use disorders recruited in St. Petersburg, Russia in 2012-2015. The primary outcome was heavy smoking, defined as smoking > 20 cigarettes per day. Nicotine dependence (moderate-very high) was a secondary outcome. The main independent variable was a high level of depressive symptoms in the past 7 days (defined as CES-D > = 24). We used multivariable logistic regression to examine associations between depressive symptoms and the outcomes, controlling for age, sex, education, income, running out of money for housing/food, injection drug use, and alcohol use measured by the AUDIT. RESULTS: Among 309 regular smokers, 79 participants (25.6%) had high levels of depressive symptoms, and 65 participants (21.0%) were heavy smokers. High levels of depressive symptoms were not significantly associated with heavy smoking (adjusted odds ratio [aOR] 1.50, 95% CI 0.78-2.89) or with moderate-very high levels of nicotine dependence (aOR 1.35, 95% CI 0.75-2.41). CONCLUSIONS: This study did not detect an association between depressive symptoms and smoking outcomes among HIV-positive regular smokers in Russia. PMID- 29408937 TI - Comparison of secretory signal peptides for heterologous protein expression in microalgae: Expanding the secretion portfolio for Chlamydomonas reinhardtii. AB - Efficient protein secretion is a desirable trait for any recombinant protein expression system, together with simple, low-cost, and defined media, such as the typical media used for photosynthetic cultures of microalgae. However, low titers of secreted heterologous proteins are usually obtained, even with the most extensively studied microalga Chlamydomonas reinhardtii, preventing their industrial application. In this study, we aimed to expand and evaluate secretory signal peptides (SP) for heterologous protein secretion in C. reinhardtii by comparing previously described SP with untested sequences. We compared the SPs from arylsulfatase 1 and carbonic anhydrase 1, with those of untried SPs from binding protein 1, an ice-binding protein, and six sequences identified in silico. We identified over 2000 unique SPs using the SignalP 4.0 software. mCherry fluorescence was used to compare the protein secretion of up to 96 colonies for each construct, non-secretion construct, and parental wild-type cc1690 cells. Supernatant fluorescence varied according to the SP used, with a 10 fold difference observed between the highest and lowest secretors. Moreover, two SPs identified in silico secreted the highest amount of mCherry. Our results demonstrate that the SP should be carefully selected and that efficient sequences can be coded in the C. reinhardtii genome. The SPs described here expand the portfolio available for research on heterologous protein secretion and for biomanufacturing applications. PMID- 29408938 TI - Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes. AB - BACKGROUND: We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 MUg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. METHODS: The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. RESULTS: From the ITC, decreases in HbA1c were 1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20MUg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. CONCLUSIONS: The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 MUg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving. PMID- 29408939 TI - A structural equation modeling approach to understanding pathways that connect socioeconomic status and smoking. AB - The inverse association between socioeconomic status and smoking is well established, yet the mechanisms that drive this relationship are unclear. We developed and tested four theoretical models of the pathways that link socioeconomic status to current smoking prevalence using a structural equation modeling (SEM) approach. Using data from the 2013 National Health Interview Survey, we selected four indicator variables (poverty ratio, personal earnings, educational attainment, and employment status) that we hypothesize underlie a latent variable, socioeconomic status. We measured direct, indirect, and total effects of socioeconomic status on smoking on four pathways through four latent variables representing social cohesion, financial strain, sleep disturbance, and psychological distress. Results of the model indicated that the probability of being a smoker decreased by 26% of a standard deviation for every one standard deviation increase in socioeconomic status. The direct effects of socioeconomic status on smoking accounted for the majority of the total effects, but the overall model also included significant indirect effects. Of the four mediators, sleep disturbance and psychological distress had the largest total effects on current smoking. We explored the use of structural equation modeling in epidemiology to quantify effects of socioeconomic status on smoking through four social and psychological factors to identify potential targets for interventions. A better understanding of the complex relationship between socioeconomic status and smoking is critical as we continue to reduce the burden of tobacco and eliminate health disparities related to smoking. PMID- 29408940 TI - Regulation of neuritogenesis in hippocampal neurons using stiffness of extracellular microenvironment. AB - The mechanosensitivity of neurons in the central nervous system (CNS) is an interesting issue as regards understanding neuronal development and designing compliant materials as neural interfaces between neurons and external devices for treating CNS injuries and disorders. Although neurite initiation from a cell body is known to be the first step towards forming a functional nervous network during development or regeneration, less is known about how the mechanical properties of the extracellular microenvironment affect neuritogenesis. Here, we investigated the filamentous actin (F-actin) cytoskeletal structures of neurons, which are a key factor in neuritogenesis, on gel substrates with a stiffness-controlled substrate, to reveal the relationship between substrate stiffness and neuritogenesis. We found that neuritogenesis was significantly suppressed on a gel substrate with an elastic modulus higher than the stiffness of in vivo brain. Fluorescent images of the F-actin cytoskeletal structures showed that the F-actin organization depended on the substrate stiffness. Circumferential actin meshworks and arcs were formed at the edge of the cell body on the stiff gel substrates unlike with soft substrates. The suppression of F-actin cytoskeleton formation improved neuritogenesis. The results indicate that the organization of neuronal F actin cytoskeletons is strongly regulated by the mechanical properties of the surrounding environment, and the mechanically-induced F-actin cytoskeletons regulate neuritogenesis. PMID- 29408942 TI - Carbon nanofiber-filled conductive silicone elastomers as soft, dry bioelectronic interfaces. AB - Soft and pliable conductive polymer composites hold promise for application as bioelectronic interfaces such as for electroencephalography (EEG). In clinical, laboratory, and real-world EEG there is a desire for dry, soft, and comfortable interfaces to the scalp that are capable of relaying the MUV-level scalp potentials to signal processing electronics. A key challenge is that most material approaches are sensitive to deformation-induced shifts in electrical impedance associated with decreased signal-to-noise ratio. This is a particular concern in real-world environments where human motion is present. The entire set of brain information outside of tightly controlled laboratory or clinical settings are currently unobtainable due to this challenge. Here we explore the performance of an elastomeric material solution purposefully designed for dry, soft, comfortable scalp contact electrodes for EEG that is specifically targeted to have flat electrical impedance response to deformation to enable utilization in real world environments. A conductive carbon nanofiber filled polydimethylsiloxane (CNF-PDMS) elastomer was evaluated at three fill ratios (3, 4 and 7 volume percent). Electromechanical testing data is presented showing the influence of large compressive deformations on electrical impedance as well as the impact of filler loading on the elastomer stiffness. To evaluate usability for EEG, pre-recorded human EEG signals were replayed through the contact electrodes subjected to quasi-static compressive strains between zero and 35%. These tests show that conductive filler ratios well above the electrical percolation threshold are desirable in order to maximize signal-to-noise ratio and signal correlation with an ideal baseline. Increasing fill ratios yield increasingly flat electrical impedance response to large applied compressive deformations with a trade in increased material stiffness, and with nominal electrical impedance tunable over greater than 4 orders of magnitude. EEG performance was independent of filler loading above 4 vol % CNF (< 103 ohms). PMID- 29408941 TI - Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression. AB - ALC1 (amplified in liver cancer 1), an SNF2 superfamily chromatin-remodeling factor also known as CHD1L (chromodomain helicase/ATPase DNA binding protein 1 like), is implicated in base-excision repair, where PARP (Poly(ADP-ribose) polymerase) mediated Poly(ADP-ribose) signaling facilitates the recruitment of this protein to damage sites. We here demonstrate the critical role played by ALC1 in the regulation of replication-fork progression in cleaved template strands. To analyze the role played by ALC1 as well as its functional relationship with PARP1, we generated ALC1-/-, PARP1-/-, and ALC1-/-/PARP1-/- cells from chicken DT40 cells. We then exposed these cells to camptothecin (CPT), a topoisomerase I poison that generates single-strand breaks and causes the collapse of replication forks. The ALC1-/- and PARP1-/- cells exhibited both higher sensitivity to CPT and an increased number of chromosome aberrations, compared with wild-type cells. Moreover, phenotypes were very similar across all three mutants, indicating that the role played by ALC1 in CPT tolerance is dependent upon the PARP pathway. Remarkably, inactivation of ALC1 resulted in a failure to slow replication-fork progression after CPT exposure, indicating that ALC1 regulates replication-fork progression at DNA-damage sites. We disrupted ATPase activity by inserting the E165Q mutation into the ALC1 gene, and found that the resulting ALC1-/E165Q cells displayed a CPT sensitivity indistinguishable from that of the null-mutant cells. This observation suggests that ALC1 contributes to cellular tolerance to CPT, possibly as a chromatin remodeler. This idea is supported by the fact that CPT exposure induced chromatin relaxation in the vicinity of newly synthesized DNA in wild-type but not in ALC1 /- cells. This implies a previously unappreciated role for ALC1 in DNA replication, in which ALC1 may regulate replication-fork slowing at CPT-induced DNA-damage sites. PMID- 29408943 TI - Analysis of HBV basal core promoter/precore gene variability in patients with HBV drug resistance and HIV co-infection in Northwest Ethiopia. AB - BACKGROUND: We recently reported complex hepatitis B virus (HBV) drug resistant and concomitant vaccine escape hepatitis B surface antigen (HBsAg) variants during human immunodeficiency virus (HIV) co-infection and antiretroviral therapy (ART) exposure in Ethiopia. As a continuation of this report using the HBV positive sera from the same study participants, the current study further analyzed the HBV basal core promoter (BCP)/precore (PC) genes variability in patients with HBV drug resistance (at tyrosine-methionine-aspartate-aspartate (YMDD) reverse transcriptase (RT) motifs) and HIV co-infection in comparison with HBV mono-infected counterparts with no HBV drug resistant gene variants. MATERIALS AND METHODS: A total of 143 participants of HBV-HIV co-infected (n = 48), HBV mono-infected blood donors (n = 43) and chronic liver disease (CLD) patients (n = 52) were included in the study. The BCP/PC genome regions responsible for HBeAg expression from the EcoRI site (nucleotides 1653-1959) were sequenced and analyzed for the BCP/PC mutant variants. RESULTS: Among the major mutant variants detected, double BCP mutations (A1762T/G1764A) (25.9%), Kozak sequences mutations (nt1809-1812) (51.7%) and the classical PC mutations such as A1814C/C1816T (15.4%), G1896A (25.2%) and G1862T (44.8%) were predominant mutant variants. The prevalence of the double BCP mutations was significantly lower in HIV co-infected patients (8.3%) compared with HBV mono-infected blood donors (32.6%) and CLD patients (36.5%). However, the Kozak sequences BCP mutations and the majority of PC mutations showed no significant differences among the study groups. Moreover, except for the overall BCP/PC mutant variants, co-prevalence rates of each major BCP/PC mutations and YMDDRT motif associated lamivudine (3TC)/entecavir (ETV) resistance mutations showed no significant differences when compared with the rates of BCP/PC mutations without YMDD RT motif drug resistance gene mutations. Unlike HIV co-infected group, no similar comparison made among HBV mono-infected blood donors and CLD patients since none of them developed the YMDD RT motif associated 3TC/ETV resistance mutations. However, HBV mono-infected blood donors and CLD patients who had no any drug resistance gene variants developed comparable G1862T (60.6% vs. 65.1%) and G1896A (24.2% vs. 11.6%) PC gene mutations. CONCLUSION: No correlation observed between the BCP/PC genome variability and the YMDD RT motif associated HBV drug resistance gene variants during HIV co-infection. Nevertheless, irrespective of HIV co-infection status, the higher records of the BCP/PC gene variability in this study setting indicate a high risk of potential HBeAg negative chronic HBV infection in Northwest Ethiopia. PMID- 29408945 TI - Collaborations with Pediatric Hospitalists: National Surveys of Pediatric Surgeons and Orthopedic Surgeons. AB - To understand characteristics of pediatric hospitalist (PH) involvement in the care of children admitted to surgical services and explore surgeons' perspectives of PH effectiveness, we conducted a cross-sectional, web-based survey of pediatric surgical (PS) and pediatric orthopedic subspecialists (OS) from professional organizations. We used basic analyses to compare responses between the 2 surgical groups. The initial response rate was 48% (291/606) for PS and 59% (415/706) for OS. Among 185 PS and 212 OS unique programs, PH were routinely engaged (69% and 75%) in the care of surgical patients, particularly in patients with medical complexity (64% PS vs 81% OS; P = .003). PS and OS perceived positive PH impact on care coordination and comorbidity management but little on pain management or length of stay. OS were more likely than PS to view PH involvement positively (64% vs 42%; P < .001). Further research on care models, especially for children with medical complexity, is needed. PMID- 29408944 TI - Production of fluorescent antibody-labeling proteins in plants using a viral vector and the application in the detection of Acidovorax citrulli and Bamboo mosaic virus. AB - Serological methods are relatively convenient and simple for the detection of pathogens for front-line workers. On-site visualization of the test results plays a pivotal role in the process. However, an efficient, universal labeling agent for antibodies is needed for the development of efficient serological detection tools. In this study, a Bamboo mosaic virus (BaMV)-based viral vector was employed to express recombinant proteins, collectively designated GfED, consisting of Staphylococcus aureus Protein A domain ED (SpaED) fused to either the N- or C-terminal of an improved green florescent protein (GFP) with or without the coat protein (CP) of BaMV, efficiently in Chenopodium quinoa. The GfED in crude leaf extracts could specifically attach to IgG molecules of rabbits and mice, effectively labeling IgG with GFP, emitting green light at 506 nm when excited at 450 nm using simple, handheld equipment. To demonstrate the applicability of GfED in serological assays, we have developed a fluorescent dot blot assay for the rapid detection of Acidovorax citrulli (Ac), a bacterial pathogen of cucurbits, and BaMV, a viral pathogen of bamboos. By using the crude extracts of inoculated C. quinoa leaves expressing GfED as an IgG-labeling agent, the pathogens were easily and quickly detected through uncomplicated operations using simple equipment, with results observable by the naked eye. Examination using fluorescent microscopy and transmission electron microscopy revealed that the GfED subunits may assemble into virus-like particles, which were further involved in the formation of aggregates of GfED-antibody-antigen complexes with the potential for fluorescence signal enhancement. The results suggested that plant-expressed GfED may serve as a promising alternative of IgG-labeling agent for current serological assays. PMID- 29408946 TI - Poor Adherence to Risk Stratification Guidelines Results in Overuse of Venous Thromboembolism Prophylaxis in Hospitalized Older Adults. PMID- 29408952 TI - Predictive Value of Malignancy of Thyroid Nodule Ultrasound Classification Systems: A Prospective Study. AB - Context: British Thyroid Association (BTA), American Thyroid Association (ATA), and American Association of Clinical Endocrinologists (AACE/ACE/AME) recommend for thyroid nodules an ultrasound (US)-based stratification of risk of malignancy. Aim of our study was to assess the diagnostic accuracy of US classification systems and their reliability for indication to fine-needle aspiration (FNA). Design: Prospective study on 987 thyroid nodules consecutively referred for FNA. US images were independently reviewed by four experts for assignment of malignancy risk. Cytologically benign nodules had confirmation with a second FNA, whereas Bethesda class IV, V, and VI nodules were operated upon. Class III nodules had surgery or follow-up on the basis of clinical, immunocytochemical, and US features. Results: BTA: Malignancy rate was 2.8% in benign, 10.0% in indeterminate, 51.3% in suspicion, and 80.9% in malignant US class. Sensitivity was 0.74, specificity was 0.92, and accuracy was 0.89. ATA: Malignancy rate was 0.0% in benign, 2.2% in very low suspicion, 3.0% in low suspicion, 5.8% in intermediate, and 55.0% in high suspicion US class. Sensitivity was 0.81, specificity was 0.87, and accuracy was 0.86. AACE/ACE/AME: Malignancy rate was 1.1% in low-risk, 4.4% in intermediate-risk, and 54.9% in high-risk US class. Sensitivity was 0.82, specificity was 0.87, and accuracy was 0.86. K correlation coefficient was 78.9%, 76.9%, and 82.0% for BTA, ATA, and AACE/ACE/AME classifications. Conclusions: Classification systems had elevated predictive value of malignancy in high-risk classes. ATA and AACE/ACE/AME systems were effective for ruling out indication to FNA in low-US-risk nodules. A similar diagnostic accuracy and a substantial interobserver agreement was provided by the three- and the five-category classifications. PMID- 29408951 TI - Malaria Coinfections in Febrile Pediatric Inpatients: A Hospital-Based Study From Ghana. AB - Background: The epidemiology of pediatric febrile illness is shifting in sub Saharan Africa, but malaria remains a major cause of childhood morbidity and mortality. The present study describes causes of febrile illness in hospitalized children in Ghana and aims to determine the burden of malaria coinfections and their association with parasite densities. Methods: In a prospective study, children (aged >=30 days and <=15 years) with fever >=38.0 degrees C were recruited after admission to the pediatric ward of a primary hospital in Ghana. Malaria parasitemia was determined and blood, stool, urine, respiratory, and cerebrospinal fluid specimens were screened for parasitic, bacterial, and viral pathogens. Associations of Plasmodium densities with other pathogens were calculated. Results: From November 2013 to April 2015, 1238 children were enrolled from 4169 admissions. A clinical/microbiological diagnosis could be made in 1109/1238 (90%) patients, with Plasmodium parasitemia (n = 728/1238 [59%]) being predominant. This was followed by lower respiratory tract infections/pneumonia (n = 411/1238 [34%]; among detected pathogens most frequently Streptococcus pneumoniae, n = 192/299 [64%]), urinary tract infections (n = 218/1238 [18%]; Escherichia coli, n = 21/32 [66%]), gastrointestinal infections (n = 210 [17%]; rotavirus, n = 32/97 [33%]), and invasive bloodstream infections (n = 62 [5%]; Salmonella species, n = 47 [76%]). In Plasmodium infected children the frequency of lower respiratory tract, gastrointestinal, and bloodstream infections increased with decreasing parasite densities. Conclusions: In a hospital setting, the likelihood of comorbidity with a nonmalarial disease is inversely correlated with increasing blood levels of malaria parasites. Hence, parasite densities provide important information as an indicator for the probability of coinfection, in particular to guide antimicrobial medication. PMID- 29408953 TI - Skin Biopsy Findings in Patients With CMT1A: Baseline Data From the CLN-PXT3003 01 Study Provide New Insights Into the Pathophysiology of the Disorder. AB - Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot Marie-Tooth diseases, is a demyelinating neuropathy caused by a deletion encompassing the gene coding for PMP22, a myelin protein of the peripheral nervous system. Although myelinated fibers are mostly involved in CMT1A, some patients experience neuropathic pain. We thus investigated whether unmyelinated fibers are lost in CMT1A. Skin biopsies were taken from the distal portion of the leg of 80 patients with CMT1A as part of the PXT30003-01 study and processed for quantification of intraepidermal nerve fiber density (IENFD). Mean IENFD was significantly lower in CMT1A patients than in healthy controls. Although the data were highly dispersed, IENFD tended to decrease with age and was higher overall in female patients and controls than male patients and controls. This study shows that small nerve fibers are affected in CMT1A and that this correlates with pin sensitivity. The density of epidermal Langerhans cells (LCs) was also significantly reduced in CMT1A patients, suggesting the involvement of LCs in neuropathic pain processes. These findings raise several questions concerning the interactions of Schwann cells and LCs with unmyelinated fibers in CMT1A. Moreover, they suggest that factors other than PMP22 gene dosage are involved in small fiber pathology in CMT1A. PMID- 29408954 TI - ARGs-OAP v2.0 with an expanded SARG database and Hidden Markov Models for enhancement characterization and quantification of antibiotic resistance genes in environmental metagenomes. AB - Motivation: Much global attention has been paid to antibiotic resistance in monitoring its emergence, accumulation and dissemination. For rapid characterization and quantification of antibiotic resistance genes (ARGs) in metagenomic datasets, an online analysis pipeline, ARGs-OAP has been developed consisting of a database termed Structured Antibiotic Resistance Genes (the SARG) with a hierarchical structure (ARGs type-subtype-reference sequence). Results: The new release of the database, termed SARG version 2.0, contains sequences not only from CARD and ARDB databases, but also carefully selected and curated sequences from the latest protein collection of the NCBI-NR database, to keep up to date with the increasing number of ARG deposited sequences. SARG v2.0 has tripled the sequences of the first version and demonstrated improved coverage of ARGs detection in metagenomes from various environmental samples. In addition to annotation of high-throughput raw reads using a similarity search strategy, ARGs OAP v2.0 now provides model-based identification of assembled sequences using SARGfam, a high-quality profile Hidden Markov Model (HMM), containing profiles of ARG subtypes. Additionally, ARGs-OAP v2.0 improves cell number quantification by using the average coverage of essential single copy marker genes, as an option in addition to the previous method based on the 16S rRNA gene. Availability and implementation: ARGs-OAP can be accessed through http://smile.hku.hk/SARGs. The database could be downloaded from the same site. Source codes for this study can be downloaded from https://github.com/xiaole99/ARGs-OAP-v2.0. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29408955 TI - High Androgens in Postmenopausal Women and the Risk for Atherosclerosis and Cardiovascular Disease: The Rotterdam Study. AB - Context: Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD). Objective: To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. Design: The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years. Setting: General community. Participants: A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62). Intervention: None. Main Outcomes and Measures: Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone-binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD. Results: Mean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (beta [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [beta (95% CI), -0.008 (-0.015 to -0.001)] and androstenedione [beta (95% CI), -0.010 ( 0.017 to -0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD. Conclusion: Postmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated. PMID- 29408956 TI - The structure of an elongation factor G-ribosome complex captured in the absence of inhibitors. AB - During translation's elongation cycle, elongation factor G (EF-G) promotes messenger and transfer RNA translocation through the ribosome. Until now, the structures reported for EF-G-ribosome complexes have been obtained by trapping EF G in the ribosome. These results were based on use of non-hydrolyzable guanosine 5'-triphosphate (GTP) analogs, specific inhibitors or a mutated EF-G form. Here, we present the first cryo-electron microscopy structure of EF-G bound to ribosome in the absence of an inhibitor. The structure reveals a natural conformation of EF-G.GDP in the ribosome, with a previously unseen conformation of its third domain. These data show how EF-G must affect translocation, and suggest the molecular mechanism by which fusidic acid antibiotic prevents the release of EF-G after GTP hydrolysis. PMID- 29408958 TI - Erratum. PMID- 29408957 TI - Disability Prior to Death Among the Oldest-Old in China. AB - Background: To estimate the prevalence of disability during the last 3 years prior to death among the oldest-old (>=80 years) in China. Methods: We used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a nationally representative study of the oldest-old in China. The analytic sample included 23,934 decedents who died between 1998 and 2014 and had at least one interview within the last 3 years of life. Disability was defined as being incontinent or needing assistance in performing one or more of five other essential activities (bathing, transferring, dressing, eating, and toileting). Results: About 57.8% (weighted) of the study decedents were female. The prevalence of disability increased modestly from 36 months to 24 months prior to death (20% to 23%), more rapidly from 24-months to 12-months before death (23% to 31%), and substantially from 12 months before death to the last month of life (31% to 48%). The disability rates were lowest for participants who died between 80 and 89 years, intermediate for those who died between 90 and 99 years, and highest for those who died at age 100 or older, although the patterns over the 3-year period were comparable for the three age groups. At each time point prior to death, a higher percentage of women was disabled than men. Conclusions: In this large nationally representative sample of the oldest-old in China, the prevalence of disability during the 3 years prior to death is high and is greater in women than men and those who die at the oldest ages. PMID- 29408960 TI - Helping Your Partner with Chronic Pain: The Importance of Helping Motivation, Received Social Support, and Its Timeliness. AB - Objective: Like all intentional acts, social support provision varies with respect to its underlying motives. Greater autonomous or volitional motives (e.g., enjoyment, full commitment) to help individuals with chronic pain (ICPs) are associated with greater well-being benefits for the latter, as indexed by improved satisfaction of their psychological needs for autonomy, competence, and relatedness. The present study investigates the processes explaining why partners' autonomous or volitional helping motivation yields these benefits. Methods: A total of 134 couples, where at least one partner had chronic pain, completed a 14-day diary. Partners reported on their daily helping motives, whereas ICPs reported on their daily received support, timing of help, need-based experiences, and pain. Results: On days when partners provided help for volitional motives, ICPs indicated receiving more help, which partially accounted for the effect of autonomous helping motivation on ICP need-based experiences. Timing of help moderated the effects of daily received support on ICP need-based experiences. Conclusions: Findings highlight the importance of ICPs of receiving support in general and the role of timing in particular, which especially matters when there is little support being received. PMID- 29408959 TI - A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia. AB - Context: The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available. Objective: To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation. Design, Setting, and Patients: An adult cohort of unrelated patients referred to a lipid clinic for genetic testing. Main Outcome Measures: Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity. Results: A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation. Conclusions: The DLCN, SB, and MEDPED criteria are valid predictors of an FH causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH. PMID- 29408961 TI - Evidence for the Domains Supporting the Construct of Intrinsic Capacity. AB - Healthy ageing can be defined as "the process of developing and maintaining the functional ability that enables wellbeing in older age". Functional ability (i.e., the health-related attributes that enable people to be and to do what they have reason to value) is determined by intrinsic capacity (i.e., the composite of all the physical and mental capacities of an individual), the environment (i.e., all the factors in the extrinsic world that form the context of an individual's life), and the interactions between the two. This innovative model recently proposed by the World Health Organization has the potential to substantially modify the way in which clinical practice is currently conducted, shifting from disease-centered toward function-centered paradigms. By overcoming the multiple limitations affecting the construct of disease, this novel framework may allow the worldwide dissemination of a more proactive and function-based approach toward achieving optimal health status. In order to facilitate the translation of the current theoretical model into practice, it is important to identify the inner nature of its constituting constructs. In this article, we consider intrinsic capacity. Using the International Classification of Functioning, Disability and Health (ICF) framework as background and taking into account available evidence, five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual's intrinsic capacity (and therefore also reserves) and, through this, pave the way for its objective measurement. PMID- 29408962 TI - Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo. AB - STUDY QUESTION: Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? SUMMARY ANSWER: In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. WHAT IS KNOWN ALREADY: In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. STUDY DESIGN, SIZE, DURATION: Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 MUM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: Human ovarian explants exposed to 10 and 100 MUM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 MUM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development. PMID- 29408963 TI - Novel concepts for the role of smooth muscle cells in vascular disease: towards a new smooth muscle cell classification. PMID- 29408964 TI - A Homozygous RET K666N Genotype With an MEN2A Phenotype. AB - Context: Germline RET K666N mutation has been described as a pathogenic mutation with low disease penetrance for medullary thyroid cancer (MTC) without other features of multiple endocrine neoplasia type 2A. We describe a patient with homozygous RET K666N mutation with MTC and bilateral pheochromocytoma (PHEO). Case Description: A 59-year-old woman received a diagnosis of MTC after biopsy of two thyroid nodules. Coincident biochemical and radiologic testing was suspicious for bilateral PHEO, confirmed after bilateral adrenalectomy. There was no evidence of primary hyperparathyroidism (PHPT). She had a total thyroidectomy with neck dissection revealing bilateral MTC with lymph node metastases. Germline RET testing identified homozygous K666N mutations. Genetic testing of family members showed that both adult children harbor a heterozygous K666N mutation. Her 32-year-old son had an elevated calcitonin level and underwent thyroidectomy, which identified MTC. Her 30-year-old daughter had a normal calcitonin level. Prophylactic thyroidectomy showed C-cell hyperplasia only. Three of seven other family members were tested and found to carry the mutation. All had normal calcitonin levels, and none had biochemical evidence of PHEO or PHPT. Given the absence of PHEO in reported RET K666N families, our proband underwent genetic testing for causes of hereditary paragangliomas or PHEO. No additional mutations were identified. Conclusions: Here we report a case of a homozygous RET K666N mutation leading to coincident MTC and PHEO. Heterozygous presentations of RET K666N mutations have low penetrance for isolated MTC. We believe that the gene dosage associated with the homozygosity of this variant contributed to the occurrence of bilateral PHEO. PMID- 29408966 TI - Sustained Cross-protection of the Bivalent Human Papillomavirus Vaccine. PMID- 29408965 TI - Impacts of estrus expression and intensity during a timed-AI protocol on variables associated with fertility and pregnancy success in Bos indicus influenced beef cows. AB - This experiment evaluated the impacts of estrus expression and intensity, estimated by physical activity during a timed-AI protocol, on reproductive performance of Bos indicus-influenced beef cows. A total of 290 lactating, primiparous, and multiparous nonpregnant Nelore * Angus cows received a 2 mg injection of estradiol benzoate and an intravaginal progesterone (P4) releasing device (CIDR) on d -11, a 12.5 mg injection of PGF2alpha on d -4, CIDR removal in addition to 0.6 mg injection of estradiol cypionate and 300 IU injection of eCG on d -2, and timed-AI on d 0. Cows were fitted with a pedometer behind their left shoulder on d -4. An estrus detection patch was attached to the tail-head of each cow on d -2. Pedometer results were recorded on d -2 and 0. Estrus expression was defined as removal of >50% of the rub-off coating from the patch on d 0. Net physical activity during estrus was calculated by subtracting total steps from d 4 to -2 (nonestrus basal activity) from total steps from d -2 to 0 (proestrus + estrus period) of each cow. Cows that did not express estrus were classified as NOESTR. Cows that expressed estrus were ranked by net physical activity; those above the median were classified as HIESTR and the remaining cows as LWESTR. Ovarian ultrasonography was performed on d 0 and 7. Blood was collected on d 0, 7, 20, and 30. Pregnancy status was verified by ultrasonography on d 30. Only data from cows responsive to the estrus synchronization protocol were utilized (NOESTR, n = 59; LWESTR, n = 100; HIESTR, n = 98). Diameter of dominant follicle on d 0, corpus luteum volume on d 7, and plasma P4 concentrations on d 7 were greater (P <= 0.05) in HIESTR vs. LWESTR and NOESTR and also greater (P <= 0.05) for LWESTR vs. NOESTR. Plasma P4 concentrations on d 0 were greater (P < 0.01) in NOESTR vs. HIESTR and LWESTR and similar (P = 0.93) between HIESTR and LWESTR. Whole blood mRNA expression of myxovirus resistance 2 on d 20 was greater (P <= 0.05) in HIESTR vs. LWESTR and NOESTR, and similar (P = 0.72) between LWESTR and NOESTR. Pregnancy rates were less (P <= 0.04) in NOESTR vs. HIESTR and LWESTR (52.4%, 68.9%, and 73.5%, SEM = 7.2), and similar (P = 0.57) between HIESTR and LWESTR. Hence, expression of estrus during a timed-AI protocol improved ovarian dynamics and pregnancy success, whereas estrus intensity modulated key biological markers associated with fertility but not pregnancy rates in B. indicus influenced cows beef cows. PMID- 29408967 TI - Effects of Stellate Ganglion Block on Analgesia Produced by Cervical Paravertebral Block as Established by Quantitative Sensory Testing: A Randomized Controlled Trial. AB - Objective: To use quantitative sensory testing (QST) to assess whether a stellate ganglion block (SGB) modulates the analgesia induced by cervical paravertebral block (CPVB). Design: A prospective double-blind randomized controlled trial. Setting: Department of Anesthesia, Antwerp University Hospital, October 2011 to December 2015. Subjects: Twenty-eight adults scheduled for arthroscopy of a nonfractured shoulder were enrolled. Methods: Participants were randomly assigned to receive either single CPVB (5 mL of levobupivacaine 0.5%) or combined CPVB + SGB (5 mL and 3 mL of levobubivacaine 0.5%, respectively). The detection thresholds for cold/warm sensations and cold/heat pain were established using thermal QST on the C4-C7 dermatomes before local anesthetic infiltration and at 0.5, 6, 10, and 24 hours thereafter. Our primary outcome was the time course of QST thresholds for the different neurosensitive/nociceptive modalities. As secondary and tertiary outcomes, we evaluated the degree of motor block and the time to first administration of rescue analgesics. Results: We randomized 20 patients. There were no significant differences in the detection thresholds for the neurosensitive/nociceptive modalities, motor block, or timing for rescue analgesics between the groups (P = 0.15-0.94). All patients with CPVB + SGB exhibited Horner's signs, whereas patients in the CPVB group did not exhibit these signs; however, this does not exclude sympathetic block. Conclusions: We were unable to demonstrate any analgesic benefit of CPVB + SGB in arthroscopic shoulder surgery. It is therefore not unreasonable to suppose that pain from soft tissue injuries without bony lesions is transmitted mainly by somatic nerves with no or only minimal involvement of the sympathetic nervous system. PMID- 29408969 TI - Geographical Variation and Social Work Students' Job Intentions in China: A Geographic Information Systems Approach. AB - Social work education in China is undergoing far-reaching development. However, an important issue, low professional commitment, has been identified. Why do social work graduates-especially master's level graduates-take jobs unrelated to social work? To answer this question, it is important to take into account that the professionalization of social work is happening unevenly across China as a result of uneven social and economic development. Models used in past research do not consider the possibility that the low intention for social work jobs and its potential predictors may vary across regions. To address this problem, Geographic Information Systems software is being adopted to explore the varying degrees of social work graduates' job intention, its predictors across China, and the association between job intention and predictors at both national and regional levels. Authors of this study found substantial geographic variation in predictors of social work graduates' job intention across regions. Their findings also suggest some heterogeneity in the association between job intention and specific correlates that would be masked in the traditional nationwide model. Policymakers aiming to improve the job intention of social work graduates should consider regional variation as part of their approach. PMID- 29408968 TI - MicroRNA132 associated multimodal neuroimaging patterns in unmedicated major depressive disorder. AB - There is compelling evidence that epigenetic factors contribute to the manifestation of depression, in which microRNA132 (miR-132) is suggested to play a pivotal role in the pathogenesis and neuronal mechanisms underlying the symptoms of depression. Additionally, several depression-associated genes [MECP2, ARHGAP32 (p250GAP), CREB, and period genes] were experimentally validated as miR 132 targets. However, most studies regarding miR-132 in major depressive disorder are based on post-mortem, animal models or genetic comparisons. This work will be the first attempt to investigate how miR-132 dysregulation may impact covariation of multimodal brain imaging data in 81 unmedicated major depressive patients and 123 demographically-matched healthy controls, as well as in a medication-naive subset of major depressive patients. MiR-132 values in blood (patients > controls) was used as a prior reference to guide fusion of three MRI features: fractional amplitude of low frequency fluctuations, grey matter volume, and fractional anisotropy. The multimodal components correlated with miR-132 also show significant group difference in loadings. Results indicate that (i) higher miR-132 levels in major depressive disorder are associated with both lower fractional amplitude of low frequency fluctuations and lower grey matter volume in fronto-limbic network; and (ii) the identified brain regions linked with increased miR-132 levels were also associated with poorer cognitive performance in attention and executive function. Using a data-driven, supervised-learning method, we determined that miR-132 dysregulation in major depressive disorder is associated with multi-facets of brain function and structure in fronto-limbic network (the key network for emotional regulation and memory), which deepens our understanding of how miR-132 dysregulation in major depressive disorders contribute to the loss of specific brain areas and is linked to relevant cognitive impairments. PMID- 29408970 TI - Assessing quality of health services with the SERVQUAL model in Iran. A systematic review and meta-analysis. AB - Purpose: The five-dimension service quality (SERVQUAL) scale is one of the most common tools for evaluating gaps between clients' perceptions and expectations. This study aimed to assess the quality of health services in Iran through a meta analysis of all Iranian studies which used the SERVQUAL tool. Data sources: A systematic literature review has been performed in Web of Science, PubMed, Scopus, Google Scholar, Iran Medex, Magiran and Scientific Information Database. Study selection: All relevant English or Persian studies published between January 2009 and April 2016 were have been selected. Papers were considered if they regarded all five dimensions of the SERVQUAL tool for assessing the quality of health care services. Data extraction: Two reviewer independently extracted mean and standard deviation of five dimensions and characteristics of studies. The quality of studies included in meta-analysis using STROBE checklist. Results of data synthesis: Of 315 studies initially identified, 12 were included in our meta-analysis. All analyses were performed in Stata MP v. 14. Patients' perceptions were lower than their expectations (gap = -1.64). Responsibility ( 1.22) and reliability (-1.15) had the lowest gaps, and tangibility and empathy ( 1.03) had the largest gaps. Except gender, other variables had no significant associations with gaps. Patients in the cities of Arak (-3.47) and Shiraz (-3.02) had the largest gaps. Conclusions: All dimensions of service quality were negative, which implies that the quality of health services in Iran has not been satisfying to patients and needs to be improved. PMID- 29408971 TI - The Education of American Surgeons and the Rise of Surgical Residencies, 1930 1960. AB - In the first half of the twentieth century, the training of American surgeons changed from an idiosyncratic, often isolated venture to a standardized, regulated, and mandated regimen in the form of the surgical residency. Over the three critical decades between 1930 and 1960, these residencies developed from an extraordinary, unique opportunity for a few leading practitioners to a widespread, uniform requirement. This article explores the transformation of surgical education in the United States, focusing on the standardization and dissemination of residencies during this key period. Utilizing the archives of professional organizations, it shows how surgical societies initiated and forced reform in the 1930s. It demonstrates the seminal and early role taken by the federal government in the expansion of surgical residencies through incentivized policies and, especially, the growth of the Veterans Administration health system after World War II. Finally, an examination of intra-professional debates over this process illustrates both the deeper struggles to control the nature of surgical training and the importance of residency education in defining the midcentury American surgeon. PMID- 29408972 TI - Subclinical Hypothyroidism and Incident Depression in Young and Middle-Age Adults. AB - Background: The role of subclinical hypothyroidism in the development of depression remains controversial. We examined the prospective association between subclinical hypothyroidism and incident depressive symptoms. Methods: We conducted a prospective cohort study of 220,545 middle-age adults without depression who had undergone at least two comprehensive health examinations between 1 January 2011 and 31 December 2014. Thyroid-stimulating hormone, free triiodothyronine (FT3), and free thyroxine (FT4) levels were measured using an electrochemiluminescent immunoassay. The study outcome was incident depressive symptoms, defined as a Center for Epidemiologic Studies-Depression score >16. Results: During a median follow-up period of 2 years, incident depressive symptoms occurred in 7323 participants. The multivariable-adjusted hazard ratio for incident depressive symptoms comparing subclinical hypothyroid and euthyroid participants was 0.97 (95% confidence interval, 0.87 to 1.09). Similarly, among euthyroid participants (n = 87,822), no apparent association was found between thyroid hormone levels and an increased risk of incident depressive symptoms. Conclusions: No apparent association was found between subclinical hypothyroidism and incident depressive symptoms in a large prospective cohort of middle-age men and women. PMID- 29408973 TI - Analyzing Analgesic Medications in Community-Dwelling Older Adults. AB - Objectives: Analyzing medication data for research purposes is complex, and methods are rarely described in the literature. Our objective was to describe methods of quantifying opioid and nonopioid analgesics and to compare the utility of five different analgesic coding methods when analyzing relationships between pain, analgesic use, and clinical outcomes. In this study, we used physical function as the outcome variable for its clinical relevance and its relationship to pain in older adults. Design: Secondary analyses of baseline cross-sectional data from the Advanced Cognitive Training Interventions for Vital Elders (ACTIVE) study. Setting: Community settings in six regions of the United States. Subjects: A total of 2,802 community-residing adults older than age 65 years. Methods: A medication audit was conducted. Analgesics were coded as any pain medication, counts (total analgesics, number of opioids and nonopioids), equianalgesics (oral morphine equivalents, oral acetaminophen equivalents), and dose categories. Adjuvant medications used to treat pain (e.g., tricyclic antidepressants and anticonvulsants) and low-dose aspirin typically used for cardiovascular conditions were excluded from these analyses. To examine the utility of these various approaches, a series of hierarchical regression models were conducted with pain and analgesics as predictors and physical functioning as the dependent variable. Results: Eighty-one point nine percent of participants reported experiencing recent pain, but 26% reported analgesic use. Nonopioids were the most common drug class used. Models revealed that pain was significantly associated with worse physical function (beta = -0.45, P = 0.001), after controlling for demographic and analgesic variables. Two basic drug coding methods (e.g., any pain medication, number of pain medications) were equivalent in their explanatory power (beta = -0.12, P = 0.001) and were slightly stronger predictors of function than the more complex coding procedures. Conclusions: Analgesic medications are important variables to consider in community-based studies of older adults. We illustrate several methods of quantifying analgesic medications for research purposes. In this community-based sample, we found no advantage of complex equianalgesic coding methods over simple counts in predicting physical functioning. The results may differ depending on the research question or clinical outcome studied. Thus, methods of analyzing analgesic drug data warrant further research. PMID- 29408974 TI - The impact of sleep disorders on driving safety-findings from the Second Strategic Highway Research Program naturalistic driving study. AB - Study Objectives: This study investigated the association between driving safety and seven sleep disorders amongst 3541 participants of the Second Strategic Highway Research Program (SHRP 2) naturalistic driving study. Methods: SHRP 2 collected naturalistic driving data from participants between 16 and 98 years old by instrumenting participants' vehicles. The analyses used logistic regression to determine the likelihood of crash or near-crash involvement, Poisson log-linear regression to assess crash or near-crash rate, and ordinal logistic regression to assess driver maneuver appropriateness and crash or near-crash severity. These analyses did not account for any medical treatments for the sleep disorders. Results: Females with restless legs syndrome/Willis-Ekbom disease (RLS/WED), drivers with insomnia or narcolepsy, are associated with significantly higher risk of crash or near-crash. Drivers with shift work sleep disorder (SWSD) are associated with significantly increased crash or near-crash rate. Females with RLS/WED or sleep apnea and drivers with SWSD are associated with less safe driver maneuver and drivers with periodic limb movement disorder are associated with more severe events. The four analyses provide no evidence of safety decrements associated with migraine. Conclusions: This study is the first examination on the association between seven sleep disorders and different measures of driving risk using large-scale naturalistic driving study data. The results corroborate much of the existing simulator and epidemiological research related to sleep-disorder patients and their driving safety, but add ecological validity to those findings. These results contribute to the empirical basis for medical professionals, policy makers, and employers in making decisions to aid individuals with sleep disorders in balancing safety and personal mobility. PMID- 29408975 TI - Sitting Time and Physical Function in Australian Retirees: An Analysis of Bidirectional Relationships. AB - Background: There is limited evidence on the directionality of the associations of sitting time with physical function. This study examined the longitudinal associations of sitting time with changes in physical function, and physical function with changes in sitting time. Methos: Data from 10,027 retirees in the Social, Economic, and Environmental Factor (SEEF) population-based cohort were collected in 2006-20008 and in 2010-2011. Daily sitting time was assessed by a single-item question. Physical function was measured with the Medical Outcomes Study Physical Functioning Scale (range 0-100) with participants categorized as: no; minor; moderate; or severe limitation. General linear regression models, adjusted for covariates, were used to assess associations of sitting time with physical function for all participants and in subgroups according to sex, and categories of body mass index, physical activity, and physical function limitations. Results: Each hour of baseline sitting was associated with declines in physical function for women (0.20 units [95% confidence interval {CI} 0.04 0.37]) and those with severe functional limitations (0.65 units [95% CI 0.20 1.12]). Each unit of baseline physical function was associated with declines in sitting time for all participants (0.009 hours/day [95% CI 0.005-0.013]) and for all subgroups. Conclusions: There was limited evidence of a bidirectional association of sitting time with physical function except in women and people with severe functional limitations. Health promotion efforts are needed to address the impact of poor physical function on increases in sitting time which result in further functional declines for these subgroups of the population. PMID- 29408976 TI - Host immune responses to Toxoplasma gondii. AB - Toxoplasma gondii can infect homoeothermic animals including humans and cause lethal toxoplasmosis in immunocompromised individuals. When hosts are infected with T. gondii, the cells induce immune responses against T. gondii. The pathogen infection is recognized by immune sensors that directly detect T. gondii structural components, leading to production of pro-inflammatory cytokines and chemokines. Antigen-presenting cells such as macrophages and dendritic cells strongly activate T cells and induce development of Th1 cells and antigen specific killer CD8 T cells. These T cells and Group 1 innate lymphoid cells are main producers of IFN-gamma, which robustly stimulates cell-autonomous immunity in cells infected with T. gondii. IFN-gamma-inducible effectors such as IFN inducible GTPases, inducible nitric oxide synthase and indoleamine-2,3 dioxygenase differentially play important roles in suppression of T. gondii growth and its direct killing in anti-T. gondii cell-autonomous immune responses. In this review, we will describe our current knowledge of innate, adaptive and IFN-gamma-mediated cell-autonomous immunity against T. gondii infection. PMID- 29408977 TI - Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02). AB - Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number: UMIN000010507. PMID- 29408978 TI - Effects of Temperature on the Development and Reproduction of Thrips hawaiiensis (Thysanoptera: Thripidae). AB - Environmental temperature has a significant impact on insect behavior. The present study aimed to determine the effects of temperature on the development, survival, and reproduction of Thrips hawaiiensis (Thysanoptera: Thripidae), an important flower-inhabiting thrips. These effects were evaluated at five constant temperatures (18, 21, 24, 27, and 30 degrees C) on thrips reared in the laboratory on excised Gardenia jasminoides flowers. The developmental durations of egg, first instar, second instar, prepupa, pupa, and the entire immature stages were shortened in response to a temperature increase from 18 to 30 degrees C. The highest generational survival rate was at 27 degrees C (75.00%), whereas the lowest was at 18 degrees C (46.00%). The minimum threshold and effective accumulated temperatures for completing a generation of T. hawaiiensis were 7.62 degrees C and 171.26 degree-days, respectively. The highest fecundity (95.80) was at 27 degrees C, but it was not significantly different than at 24 degrees C (84.72) or 30 degrees C (84.32). The highest oviposition rate of 5.57 eggs per female per day occurred at 27 degrees C, which was significantly higher than at any other temperature. Both the highest intrinsic rate of increase, at 0.200, and net reproduction rate, at 44.97, for T. hawaiiensis were observed at 27 degrees C, whereas the lowest values of 0.114 and 25.56, respectively, were observed at 18 degrees C. These results suggest that T. hawaiiensis is well adapted to temperate conditions, with an optimal temperature range for development of 24 to 30 degrees C, with the most suitable temperature for both development and reproduction being 27 degrees C. PMID- 29408979 TI - The provision of seven day multidisciplinary staffing in Scottish acute medical units: a cross-sectional study. AB - Background: Acute medical units (AMUs) are a central component of the admission pathway for the majority of medical patients presenting to hospital in the United Kingdom and other international settings. Detail on multidisciplinary staffing provision on weekdays and weekends is lacking. Equity of staffing across 7 days is a strategic priority for national health services in the United Kingdom. Aim: To evaluate weekday compared with weekend multidisciplinary staffing in a national set of AMUs. Design: Cross-sectional survey. Methods: Twenty-nine Scottish AMUs were identified and all were included in the study population. Data were collected by semi-structured interviews with nursing, pharmacy, therapy, non consultant medical and consultant staff. Staffing was quantified in staff hours. A correction factor of 0.5 was applied to non-dedicated staff. The percentage of weekend/weekday staffing was calculated for each unit and the mean of these percentages was calculated to give a summary measure for each professional group. Results: As a percentage of weekday staffing levels, weekend staffing across the units was 93.8% for nursing staff; 2.2% for pharmacy staff; 13.1% for therapy staff; 69.6% for non-consultant staff and 65.0% for consultant staff. Conclusions: There is a contrast between weekday and weekend staffing on the AMU, with reductions at weekends in total staff hours, the proportion of dedicated vs. undedicated staff and the seniority of nursing staff. The weekday/weekend difference was far more pronounced for allied healthcare professional staff than any other group. These findings have potential implications for patient outcomes, quality of care, hospital flow and workforce planning. PMID- 29408980 TI - Detecting persons at risk for diabetes mellitus type 2 using FINDRISC: results from a community pharmacy-based study. AB - Background: This cross-sectional study has been developed within the framework of the Italian project 'We love your heart' ('Ci sta a cuore il tuo cuore') and reports the results of the initial type 2 diabetes mellitus (T2DM) risk assessment carried out in a big network of community pharmacies in Italy and Spain. Methods: In total 4002 pharmacists from 854pharmacies were specifically trained to collect data and perform the evaluation of the probability of developing T2DM among pharmacy customers. The risk of developing T2DM within 10 years was evaluated using the FINDRISC. Results: Overall, 7234 (22.1%) subjects were at low risk to develop the disease, whereas 43.3% were at slightly elevated risk (scores 7-11), 19.3% were at moderate (scores 12-14), 13.9% were at high (scores 15-20), and 1.4% were at very high risk (scores > 20). Spanish participants showed higher levels of risk than Italian (16.7 vs. 14.7%) taking the cut-off FINDRISC >= 15. Conclusion: This study shows that considerable percentage of persons is likely to develop diabetes in the next 10 years. Analyses of the risk factors indicate that men were more susceptible to develop this disease, as well as the Spanish participants respect to Italian. PMID- 29408981 TI - Excessive Adiposity and Metabolic Dysfunction Relate to Reduced Natriuretic Peptide During RAAS Activation in HIV. AB - Purpose: Natriuretic peptides (NPs) negatively feedback on the renin-angiotensin aldosterone system (RAAS) and play a critical role in preserving cardiac structure and maintaining metabolic homeostasis. Well-treated HIV-infected individuals are at risk for fat redistribution and demonstrate evidence of RAAS dysregulation, which relates to metabolic dysfunction. We investigated circulating NPs in relation to RAAS physiology and metrics of body composition in HIV. Methods: We assessed atrial natriuretic peptide, brain natriuretic peptide (BNP), and amino terminal pro B-type natriuretic peptide (NT-proBNP) during acute activation of the RAAS using a low-sodium controlled diet among 20 HIV-infected and 10 non-HIV-infected individuals well phenotyped for body composition. Results: BNP was significantly lower [median, 60 (interquartile range, 44, 152) pg/mL vs 196 (91, 251) pg/mL, respectively; P = 0.04], and serum aldosterone was higher, among HIV-infected than among non-HIV-infected individuals. BNP was significantly and inversely associated with body composition [waist circumference: r = -0.46 (P = 0.04); BMI: r = -0.55 (P = 0.01); body adiposity index: r = -0.49 (P = 0.03)], metabolic indices [total cholesterol: r = -0.44 (P = 0.05), insulin resistance calculated by using homeostatic model assessment: r = -0.44 (P = 0.05); mean arterial pressure: r = -0.44 (P = 0.05)], and serum aldosterone (r = -0.49; P = 0.03) among the HIV-infected group. These relationships were not demonstrated in the non-HIV-infected group. In a four group comparison stratifying by HIV serostatus and above or below a body mass index (BMI) of 25 kg/m2, BNP decreased significantly across groups; it was highest in non-HIV-infected patients with a BMI <25 kg/m2 and lowest in HIV infected patients with a BMI >=25 kg/m2 (overall P = 0.01). Conclusion: Relatively reduced NP, particularly BNP, among HIV-infected individuals with excess adiposity may contribute to reduced suppression of aldosterone and potentially drive aldosterone-mediated metabolic complications. Strategies that target RAAS blockade and/or augment NPs may be useful to reduce cardiometabolic disease among HIV-infected individuals in whom these systems are perturbed. PMID- 29408982 TI - Embryo selection and democratic control. AB - Recently, American colleagues called for a systematic collection of anonymized data on how many embryos and foetuses are deselected per institution per year, and for which conditions. These authors argued that if this information would be reported to a government agency or international body, the information would provide a baseline against which jurisdiction-specific trends in selection could be assessed. People who have disabilities, together with other key stakeholders, laypeople and experts, would then be in a position to assess the social impact of human selecting technologies and to make recommendations for action to mitigate negative effects as appropriate. However, such a systematic data collection does already exist in the Netherlands and has been in place for more than 30 years. It was first introduced to monitor the practise of prenatal diagnosis by the eight licence holders sending in all data to the Minister of Public Health, Welfare and Sports. Later, the same method was expanded to preimplantation genetic diagnosis. For 8 years, these data have been discussed in the parliament, which shows that the practice of embryo selection can indeed be kept under democratic control, albeit retrospectively. PMID- 29408983 TI - Extended sleeve lobectomy for centrally located non-small-cell lung cancer: a 20 year single-centre experience. AB - OBJECTIVES: Extended sleeve lobectomy (ESL), an atypical bronchoplasty with resection of more than 1 lobe, might be technically demanding but has certain theoretical advantages, including the avoidance of pneumonectomy. However, clinical outcomes after ESL are not well known. METHODS: Between March 1995 and December 2015, 540 patients with centrally located non-small-cell lung cancer underwent sleeve resection. Among them, 63 patients underwent an ESL procedure. We retrospectively analysed those patients in terms of hospital mortality, postoperative complications and local recurrence and compared clinical outcomes with patients who underwent simple sleeve lobectomy in the same period. RESULTS: The 63 patients were classified into 4 groups: anastomosis between the right main and lower bronchi (n = 14), anastomosis between the right main and upper bronchi (n = 37), anastomosis between the left main and basal segmental bronchi (n = 4) and anastomosis between the left main and upper divisional bronchi (n = 8). No operative deaths occurred within 30 days, but there were 2 in-hospital deaths from postoperative acute lung injury. Ten (16%) patients had anastomosis-related complications including 3 strictures, 5 bronchopleural fistulas and 2 pulmonary vein thromboses. There were no significant differences in in-hospital mortality (3% vs 3%, P = 0.67), anastomosis-related complications (16% vs 9%, P = 0.07) and loco-regional recurrence rate (8% vs 10%, P = 0.63) between ESL and simple sleeve lobectomy. CONCLUSIONS: According to our findings, ESL is a safe and feasible procedure that does not compromise oncological principles. It can be considered an appropriate alternative to pneumonectomy and should be considered in patients with centrally located tumours. PMID- 29408985 TI - Cleaved beta-Actin May Contribute to DNA Fragmentation Following Very Brief Focal Cerebral Ischemia. AB - Our previous study demonstrated caspase independent DNA fragmentation after very brief cerebral ischemia, the mechanism of which was unclear. In this study, we explore whether actin is cleaved following focal cerebral ischemia, and whether these structural changes of actin might modulate DNA fragmentation observed following focal ischemia. Results showed that a cleaved beta-actin fragment was identified in brains of rats 24 hours following 10-minute and 2-hour focal ischemia. Though granzyme B and caspase-3 cleaved beta-actin in vitro, the fragment size of beta-actin cleaved by granzyme B was the same as those found after 10-minute and 2-hour focal ischemia. This was consistent with increases of granzyme B activity after 10-minute and 2-hour ischemia compared with controls. Cerebral extracts from 10-minute and 2-hour ischemic brains degraded DNA in vitro. Adding intact beta-actin to these samples completely abolished DNA degradation from the 10-minute ischemia group but not from the 2-hour ischemia group. We concluded that beta-actin is likely cleaved by granzyme B by 24 hours following 10-minute and 2-hour focal cerebral ischemia. Intact beta-actin inhibits DNase, and cleavage of beta-actin activates DNase, which leads to DNA fragmentation observed in the brain following very brief focal ischemia. PMID- 29408984 TI - Postnatal Changes in Testicular Position Are Associated With IGF-I and Function of Sertoli and Leydig Cells. AB - Context: Despite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it. Objective: To assess changes in and factors associated with testicular position during childhood. Design: Testicular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, and 7 years and reproductive hormones at 3 months were measured. Setting: Prenatally recruited, prospective longitudinal birth cohort. Participants: A total of 2545 boys were recruited prenatally in a Danish-Finnish birth cohort and had a testicular position examination available. A subset of 680 Danish and 362 Finnish boys had serum reproductive hormone concentrations and insulin-like growth factor I (IGF-I) determined at 3 months. Main Outcome Measures: Testicular distance to pubic bone (TDP), serum reproductive hormone, and IGF-I concentrations. Results: TDP increased from birth to 3 months and decreased thereafter. Length, gestational age, weight for gestational age, and penile length were positively associated with larger TDP and thus lower testicular position in a linear mixed effect model. Furthermore, IGF-I concentration, inhibin B/follicle-stimulating hormone ratio, and testosterone/luteinizing hormone ratio were all independently and positively associated with longer TDP. Conclusions: We provide longitudinal data on postnatal changes in TDP. TDP is dynamic and associated with Leydig and Sertoli cell function as well as with IGF-I levels during the first months of life at mini-puberty of infancy. TDP may thus be a useful biomarker of postnatal testicular function. PMID- 29408986 TI - Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. AB - Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from >=3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867. PMID- 29408987 TI - Mg2+ reduces biofilm quantity in Acidithiobacillus ferrooxidans through inhibiting Type IV pili formation. AB - Bioleaching is a promising process for 350 million tons of Jinchuan low-grade pentlandite. But high concentration of Mg2+ is harmful to bioleaching microorganisms. Interestingly, biofilm formation can improve leaching rate. Thus, it is actually necessary to investigate the effect of Mg2+ stress on Acidithiobacillus ferrooxidans biofilms formation. In this study, we found that 0.1 and 0.5 M Mg2+ stress significantly reduced the total biomass of biofilm in a dose-dependent manner. The observation results of extracellular polymeric substances and bacteria using confocal laser scanning microscopy showed that the biofilm became thinner and looser under Mg2+ stress. Whereas 0.1 and 0.5 M Mg2+ stress had no remarkable effect on the bacterial viability, the attachment rate of Acidithiobacillus ferrooxidans to pentlandite was reduced by Mg2+ stress. Furthermore, sliding motility, twitching motility and the gene expression level of pilV and pilW were inhibited under Mg2+ stress. These results suggested that Mg2+ reduced biofilm formation through inhibiting pilV and pilW gene expression, decreasing Type IV pili formation and then attenuating the ability of attachment, subduing the active expansion of biofilms mediated by twitching motility. This study provided more information about the effect of Mg2+ stress on biofilm formation and may be useful for increasing the leaching rate in low-grade pentlandit. PMID- 29408988 TI - Matrix Metalloproteinase Activity Correlates With Uterine Myoma Volume Reduction After Ulipristal Acetate Treatment. AB - Context: Ulipristal acetate (UPA), a selective progesterone receptor modulator, clinically reduces uterine myoma size in 80% of cases. However, the molecular mechanism of action is still poorly understood, as is the reason why 20% of myomas do not respond to treatment. Objective: To elucidate whether matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are associated with myoma volume shrinkage after UPA therapy. Design: Prospective study. Setting: Academic research unit of a university hospital. Patients: Uterine biopsies were obtained from 59 patients with symptomatic myomas undergoing myomectomy, 45 of whom were treated preoperatively with either one or greater than or equal to two, 3-month courses of UPA and 14 not given any hormone therapy to serve as controls. Myoma volume was individually monitored during UPA therapy to determine any substantial clinical response (defined as a reduction in volume of >25%). Three groups were established based on the response to treatment: responsive (R) after one course (n = 12); R after two to four courses (n = 15); and nonresponsive (NR; n = 18). Interventions: UPA treatment given as preoperative management for symptomatic myomas. Main Outcome Measures: MMP and TIMP expression assessed by zymography and immunohistochemistry. Results: Compared with controls and NR myomas, responders showed significantly higher expression levels for MMP-1 (P < 0.0001) and MMP-2 (P = 0.009) and significantly lower expression levels for TIMP-1 (P = 0.040). Conclusions: The correlation found between MMP expression and volume fold change supports the notion that MMPs play a key role in UPA-induced myoma shrinkage. PMID- 29408989 TI - Modified predictive score based on frailty for mid-term outcomes in open total aortic arch surgery. AB - OBJECTIVES: The aim of this study was to seek a new predictor of mid-term survival of surgical total aortic arch replacement (SAR) by evaluating indices relevant to frailty. METHODS: Between October 2012 and March 2017, 113 consecutive patients underwent elective surgical total aortic arch replacement with antegrade cerebral perfusion under circulatory arrest at a single cardiovascular institute. In addition to common parameters, Katz index of activities of daily living, nutritional status, skeletal muscle mass volume, swallowing and motor functions were used to evaluate patients' frailty. RESULTS: The associated variables with mid-term all-cause death include the following: age >=79 years was assigned 4 points; 68 years <=age <79 years, 1 point; age <68 years, 0 point; Canadian Study of Health and Aging (CSHA) scale >=4, 1 point; serum albumin level <3.7 g/dl, 2 points; 3.7 g/dl <= serum albumin level <4.25 g/dl, 1 point; serum albumin level >=4.25 g/dl, 0 point or Katz index of activities of daily living index <6, 2 points each, according to the hazard ratio. The total score was reclassified into the low-risk (0-5) (n = 96) and high risk (6-9) (n = 17) groups. Percentage of complicated patients was as follows: aided walking (11.5% and 47.1%; P = 0.001), dysphagia (13.5% and 41.2%; P = 0.012) and no discharge to home (13.5% and 47.1%; P = 0.003) in the low- and high risk groups, respectively. The Kaplan-Meier curve revealed a significant decrease of 3-year survival according to the risk grades (96.2% and 33.9%; P < 0.001). CONCLUSIONS: Risk stratification for mid-term mortality of elective surgical total aortic arch replacement was achieved by simple score relevant to frailty. The risk classification was correlated with postoperative waning of physical functions. PMID- 29408990 TI - Leydig cell genes change their expression and association with polysomes in a stage-specific manner in the adult mouse testis. AB - Spermatogenesis in mammals occurs in a very highly organized manner within the seminiferous epithelium regulated by different cell types in the testis. Testosterone produced by Leydig cells regulates blood-testis barrier formation, meiosis, spermiogenesis, and spermiation. However, it is unknown whether Leydig cell function changes with the different stages of the seminiferous epithelium. This study utilized the WIN 18,446 and retinoic acid (RA) treatment regime combined with the RiboTag mouse methodology to synchronize male germ cell development and allow for the in vivo mapping of the Leydig cell translatome across the different stages of one cycle of the seminiferous epithelium. Using microarrays analysis, we identified 11 Leydig cell-enriched genes that were expressed in stage-specific manner such as the glucocorticoid synthesis and transport genes, Cyp21a1 and Serpina6. In addition, there were nine Leydig cell transcripts that change their association with polysomes in correlation with the different stages of the spermatogenic cycle including Egr1. Interestingly, the signal intensity of EGR1 and CYP21 varied among Leydig cells in the adult asynchronous testis. However, testosterone levels across the different stages of germ cell development did not cycle. These data show, for the first time, that Leydig cell gene expression changes in a stage-specific manner during the cycle of the seminiferous epithelium and indicate that a heterogeneous Leydig cell population exists in the adult mouse testis. PMID- 29408991 TI - Astrocytes: new players in progressive myoclonus epilepsy of Lafora type. AB - Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy characterized by the accumulation of insoluble poorly branched glycogen-like inclusions named Lafora bodies (LBs) in the brain and peripheral tissues. In the brain, since its first discovery in 1911, it was assumed that these glycogen inclusions were only present in affected neurons. Mouse models of LD have been obtained recently, and we and others have been able to report the accumulation of glycogen inclusions in the brain of LD animals, what recapitulates the hallmark of the disease. In this work we present evidence indicating that, although in mouse models of LD glycogen inclusions co-localize with neurons, as originally established, most of them co-localize with astrocytic markers such as glial fibrillary acidic protein (GFAP) and glutamine synthase. In addition, we have observed that primary cultures of astrocytes from LD mouse models accumulate higher levels of glycogen than controls. These results suggest that astrocytes may play a crucial role in the pathophysiology of Lafora disease, as the accumulation of glycogen inclusions in these cells may affect their regular functionality leading them to a possible neuronal dysfunction. PMID- 29408993 TI - Effects of histone methyltransferase inhibition in endometriosis. AB - Although the histone methyltransferase EZH2 and its product H3K27me3 are well studied in cancer, little is known about their role and potential as therapeutic targets in endometriosis. We have previously reported that endometriotic lesions are characterized by global enrichment of H3K27me3. Therefore, we aimed to (1) characterize the expression levels of EZH2 in endometriotic tissues; (2) assess H3K27me3 enrichment in candidate genes promoter regions; and (3) determine if pharmacological inhibition of EZH2 impacts migration, proliferation, and invasion of endometriotic cells. Immunohistochemistry of an endometriosis-focused tissue microarray was used to assess the EZH2 protein levels in tissues. Chromatin immunoprecipitation-qPCR was conducted to assess enrichment of H3K27me3 in candidate gene promoter regions in tissues. Immunofluorescence was performed to assess the effect of an EZH2-specific pharmacological inhibitor on H3K27me3 global enrichment in cell lines. To measure effects of the inhibitor in migration, proliferation, and invasion in vitro we used Scratch, BrdU, and Matrigel assays, respectively. Endometriotic lesions had significantly higher EZH2alpha nuclear immunostaining levels compared to eutopic endometrium from patients (glands, stroma) and controls (glands). H3K27me3 was enriched within promoter regions of candidate genes in some but not all of the endometriotic lesions. Inhibition of EZH2 reduced H3K27me3 levels in the endometriotic cells specifically, and also reduced migration, proliferation but not invasion of endometriotic epithelial cells (12Z). These findings support future preclinical studies to determine in vivo efficacy of EZH2 inhibitors as promising nonhormonal treatments for endometriosis, still an incurable gynecological disease. PMID- 29408992 TI - Reconstructing spatial organizations of chromosomes through manifold learning. AB - Decoding the spatial organizations of chromosomes has crucial implications for studying eukaryotic gene regulation. Recently, chromosomal conformation capture based technologies, such as Hi-C, have been widely used to uncover the interaction frequencies of genomic loci in a high-throughput and genome-wide manner and provide new insights into the folding of three-dimensional (3D) genome structure. In this paper, we develop a novel manifold learning based framework, called GEM (Genomic organization reconstructor based on conformational Energy and Manifold learning), to reconstruct the three-dimensional organizations of chromosomes by integrating Hi-C data with biophysical feasibility. Unlike previous methods, which explicitly assume specific relationships between Hi-C interaction frequencies and spatial distances, our model directly embeds the neighboring affinities from Hi-C space into 3D Euclidean space. Extensive validations demonstrated that GEM not only greatly outperformed other state-of art modeling methods but also provided a physically and physiologically valid 3D representations of the organizations of chromosomes. Furthermore, we for the first time apply the modeled chromatin structures to recover long-range genomic interactions missing from original Hi-C data. PMID- 29408995 TI - CORRIGENDUM FOR "Assessment of beta Cell Mass and Function by AIRmax and Intravenous Glucose in High-Risk Subjects for Type 1 Diabetes". PMID- 29408994 TI - Impact of C-Peptide Status on the Response of Glucagon and Endogenous Glucose Production to Induced Hypoglycemia in T1DM. AB - Context: Complete loss of beta-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia. Objective: We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM. Design and Setting: We conducted an open, comparative trial. Patients: Ten C peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled. Intervention: Plasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique. Main Outcome Measure: Impact of C-peptide status on glucagon response and EGP during hypoglycemia. Results: Glucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 +/- 4.6 vs 4.19 +/- 2.4 pmol/L, P = 0.016, mean +/- standard deviation) but comparable EGP rates (2.13 +/- 0.2 vs 2.04 +/- 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients. Conclusions: Glucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved beta-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM. PMID- 29408996 TI - Re-assessing the Validity of the Opioid Risk Tool in a Tertiary Academic Pain Management Center Population. AB - Objective: To analyze the validity of the Opioid Risk Tool (ORT) in a large. diverse population. Design: A cross-sectional descriptive study. Setting: Academic tertiary pain management center. Subjects: A total of 225 consecutive new patients, aged 18 years or older. Methods: Data collection included demographics, ORT scores, aberrant behaviors, pain intensity scores, opioid type and dose, smoking status, employment, and marital status. Results: In this population, we were not able to replicate the findings of the initial ORT study. Self-report was no better than chance in predicting those who would have an opioid aberrant behavior. The ORT risk variables did not predict aberrant behaviors in either gender group. There was significant disparity in the scores between self-reported ORT and the ORT supplemented with medical record data (enhanced ORT). Using the enhanced ORT, high-risk patients were 2.5 times more likely to have an aberrant behavior than the low-risk group. The only risk variable associated with aberrant behavior was personal history of prescription drug misuse. Conclusions: The self-report ORT was not a valid test for the prediction of future aberrant behaviors in this academic pain management population. The original risk categories (low, medium, high) were not supported in the either the self-reported version or the enhanced version; however, the enhanced data were able to differentiate between high- and low-risk patients. Unfortunately, without technological automation, the enhanced ORT suffers from practical limitations. The self-report ORT may not be a valid tool in current pain populations; however, modification into a binary (high/low) score system needs further study. PMID- 29408997 TI - AbDesigner3D: a structure-guided tool for peptide-based antibody production. AB - Summary: We present AbDesigner3D, a new tool for identification of optimal immunizing peptides for antibody production using a peptide-based strategy. AbDesigner3D integrates 3D structural data from the Protein Data Bank (PDB) with UniProt data, which includes basic sequence data, post-translational modification sites, SNP occurrences and more. Other features, such as uniqueness and conservation scores, are calculated based on sequences from UniProt. The 3D visualization capabilities allow an intuitive interface, while an abundance of quantitative output simplifies the process of comparing immunogen peptides. Important quantitative features added in this tool include calculation and display of accessible surface area (ASA) and protein-protein interacting residues (PPIR). The specialized data visualization features of AbDesigner3D will greatly assist users to optimize their choice of immunizing peptides. Availability and implementation: AbDesigner3D is freely available at http://sysbio.chula.ac.th/AbDesigner3D or https://hpcwebapps.cit.nih.gov/AbDesigner3D/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29408999 TI - Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease. AB - The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Abeta) in 12-month-old APP transgenic mice. Using rotarod and Morris water maze tests, immunoblotting and immunofluorescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2 and quantified dendritic spines and mitochondrial number and length in 12-month-old APP mice that express Swedish mutation. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Morris water maze and rotarod tests revealed that hippocampal learning and memory and motor learning and coordination were impaired in APP mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels of fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1alpha, NRF1, NRF2 and TFAM), autophagy (ATG5 and LC3BI, LC3BII), mitophagy (PINK1 and TERT), synaptic (synaptophysin and PSD95) and dendritic (MAP2) proteins were found in 12-month-old APP mice relative to age-matched non-transgenic WT mice. Golgi-cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice. These findings suggest that hippocampal accumulation of mutant APP and Abeta is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins and reduced dendritic spines and hippocampal-based learning and memory impairments, and mitochondrial structural and functional changes in 12-month-old APP mice. PMID- 29409000 TI - The Standardized Antimicrobial Administration Ratio: A New Metric for Measuring and Comparing Antibiotic Use. AB - Background: To provide a standardized, risk-adjusted method for summarizing antibiotic use (AU), enable hospitals to track their AU over time and compare their AU data to national benchmarks, the Centers for Disease Control and Prevention developed the Standardized Antimicrobial Administration Ratio (SAAR). Methods: Hospitals reporting to the National Healthcare Safety Network (NHSN) AU Option collect and submit aggregated AU data electronically as antimicrobial days of therapy per patient days present. SAARs were developed for specific NHSN adult and pediatric patient care locations and cover five antimicrobial agent categories: (1) broad-spectrum agents predominantly used for hospital-onset/multi drug resistant bacteria; (2) broad-spectrum agents predominantly used for community-acquired infections; (3) anti-methicillin-resistant Staphylococcus aureus agents; (4) agents predominantly used for surgical site infection prophylaxis; and (5) all antibiotic agents. The SAAR is an observed-to-predicted use ratio where predicted use is estimated from a statistical model; a SAAR of 1 indicates that observed use and predicted use are equal. Results: Most location level SAARs were statistically significantly different than 1: adult locations up to 52% lower than 1 and up to 41% higher than 1. Median SAARs in adult and pediatric ICUs had a range of 0.667-1.119. SAAR distributions serve as an external comparison to national SAARs. Conclusions: This is the first aggregate AU metric that uses point-of-care, antimicrobial administration data electronically reported to a national surveillance system to enable risk adjusted, AU comparisons across multiple hospitals. Endorsed by the National Quality Forum, SAARs provide AU benchmarks that stewardship programs can use to help drive improvements. PMID- 29408998 TI - Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice. AB - X-linked myotubular myopathy (XLMTM) is a severe congenital disorder in male infants that leads to generalized skeletal muscle weakness and is frequently associated with fatal respiratory failure. XLMTM is caused by loss-of-function mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals. We recently demonstrated the therapeutic efficacy of intravenous delivery of rAAV vectors expressing MTM1 in animal models of myotubular myopathy. Here, we tested whether the closest homologues of MTM1, MTMR1, and MTMR2 (the latter being implicated in Charcot Marie-Tooth neuropathy type 4B1) are functionally redundant and could represent a therapeutic target for XLMTM. Serotype 9 recombinant AAV vectors encoding either MTM1, MTMR1, or MTMR2 were injected into the tibialis anterior muscle of Mtm1 deficient knockout mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtm1 and Mtmr2, but not Mtmr1; with Mtm1 being the most efficacious transgene. Furthermore, intravenous administration of a single dose of the rAAV9-Mtmr2 vector in XLMTM mice improved the motor activity and muscle strength and prolonged survival throughout a 3-month study. These results indicate that strategies aiming at increasing MTMR2 expression levels in skeletal muscle may be beneficial in the treatment of myotubular myopathy. PMID- 29409001 TI - Glucose and acetate metabolism in bovine intramuscular and subcutaneous adipose tissues from steers infused with glucose, propionate, or acetate. AB - We hypothesized that abomasal infusion of glucose would promote de novo fatty acid biosynthesis from glucose in vitro in bovine intramuscular (i.m.) and subcutaneous (s.c.) adipose tissues to a greater extent than ruminal infusion of acetate, propionate, or glucose. Angus crossbred steers (n = 24), 22 mo of age, were fitted with ruminal cannulas, and steers were adapted to another corn/sorghum finishing diet over a 2-wk period while recovering from the placement of the cannulas. After the adaptation period, the steers were fed the second finishing diet at 130% of their voluntary intake and were infused with isocaloric amounts (3.76 Mcal/d) of glucose, propionate, or acetate for 35 d. Glucose was infused either into the rumen or into the abomasum, whereas propionate and acetate were infused into the rumen. Acetate infusion decreased DM and DE intakes (P < 0.05). The 5th to 8th longissimus muscle section was removed immediately and transported to the laboratory within 10 min post-exsanguination in 38 degrees C, oxygenated Krebs Henseleit buffer containing 5 mM glucose and 5 mM acetate. Intramuscular and s.c. adipose tissues were dissected from the muscle and incubated in vitro in 5 mM glucose plus 5 mM acetate (containing [U 14C]glucose or [1-14C]acetate). Lipid content was lower (P = 0.04) in i.m. adipose tissue of the acetate-infused steers than in the other treatment groups, and i.m. adipocytes from acetate-infused steers were smaller (P = 0.01) than those from propionate-infused steers. The rate of incorporation of acetate into glyceride-fatty acids (GFA) in i.m. and s.c. adipose tissues was greater (P < 0.03) in steers receiving ruminal or abomasal infusions of glucose than in adipose tissues from steers infused with acetate. The greatest rates of GFA synthesis were observed in s.c. adipose tissue from steers infused ruminally with propionate or abomasally infused with glucose (P < 0.001). In i.m. and s.c. adipose tissues, the proportion of acetyl units from acetate incorporated into GFA was greater in steers receiving glucose infusion in the rumen or abomasum than in steers receiving acetate or propionate infusion (P < 0.05). Contrary to our hypothesis, abomasal glucose infusion did not promote greater fatty acid biosynthesis from glucose in i.m. adipose tissue than ruminal glucose infusion. However, glucose infusion caused the greatest production of acetyl units from acetate in i.m. and s.c. adipose tissues. PMID- 29409002 TI - PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity. AB - Context: Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce. Objective: Evaluate potential associations of eight SNPs with APSs. Setting: Academic referral endocrine clinic. Patients: A total of 543 patients with APS and monoglandular autoimmunity and controls. Intervention: The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor alpha rs1800630 (-863); and interleukin-2 receptor alpha rs10795791 were tested by single-base extension in all subjects. Results: The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P = 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001). T-allele carriers' risk for APS was increased (OR: 3.76; 95% CI: 1.97 to 7.14; P < 0.001). T-allele frequency was higher among APS than controls (OR: 3.25; 95% CI: 1.82 to 5.82; P < 0.001), T1D (OR: 2.54; 95% CI: 1.48 to 4.36; P = 0.001), or GD (OR: 1.89; 95% CI: 1.15 to 3.11; P = 0.012). The SNP CTLA-4 CT60 G allele carriers were more frequent in APS (85%) than controls (78%) (OR: 1.55; 95% CI: 0.81 to 2.99). Combined analysis of CTLA-4 AG49 and CT60 revealed OR 4.89; 95% CI: 1.86 to13.59; P = 0.00018 of the genotype combination AG/GG for APS vs controls. VDR polymorphisms Bsm I, Apa I, and Taq I did not, but the haplotypes differed between APS and controls (P = 0.0011). Conclusions: PTPN22 and CTLA-4 polymorphisms are associated with APS and differentiate between polyglandular and monoglandular autoimmunity. PMID- 29409003 TI - Experimental Leprosy Granulomas. PMID- 29409004 TI - Acceleration of nucleation of prion protein during continuous ultrasonication. AB - Although pulsatile irradiation of ultrasonication is frequently used for generating amyloid fibrils in vitro, the potential for inducing amyloid fibrillation of proteins during continuous ultrasonication is unknown. In this study, we implemented a continuous irradiation system and measured far ultraviolet circular dichroism in a real-time manner. During the continuous ultrasonication, the conformation of full-length mouse prion protein (mPrP) was rapidly altered without a lag time and electron microscopy revealed that distorted fibrils, beta-oligomers and amorphous aggregates were formed at pH 2.2, 4.0 and 9.1, respectively. Similarly, hen egg white lysozyme formed distorted fibrils and small and large amorphous aggregates at pH 2.2 and 7.1 and 11.9, respectively, without a lag time. The concentration dependencies of the initial rates were different between the two systems. The aggregate formation of mPrP followed a first-order reaction, whereas that of lysozyme followed the zeroth order reaction. Importantly, the reactions were immediately stopped by switching off ultrasonication, and restarted instantaneously when ultrasonication was restarted. Thus, the continuous ultrasonication significantly accelerates the nucleations of mPrP and lysozyme aggregates by the interaction between monomer and cavitation bubble. These cavitation bubbles may act as catalysts that decrease the activation free energy for nucleation, which is low in mPrP and high in lysozyme. PMID- 29409005 TI - Environmental and Dietary Exposure to Copper and Its Cellular Mechanisms Linking to Alzheimer's Disease. AB - Metals are commonly found in the environment, household, and workplaces in various forms, and a significant segment of the population is routinely exposed to the trace amount of metals from variety of sources. Exposure to metals, such as aluminum, lead, iron, and copper, from environment has long been debated as a potential environmental risk factor for Alzheimer's disease (AD) for decades, yet results from in vitro, in vivo, and human population remain controversial. In the case of copper, the neurotoxic mechanism of action was classically viewed as its strong affinity to amyloid-beta (Abeta) to help its aggregation and increase oxidative stress via Fenton reaction. Thus, it has been thought that accumulation of copper mediates neurotoxicity, and removing it from the brain prevents or reverse Abeta plaque burden. Recent evidence, however, suggests dyshomeostasis of copper and its valency in the body, instead of the accumulation and interaction with Abeta, are major determinants of its beneficial effects as an essential metal or its neurotoxic counterpart. This notion is also supported by the fact that genetic loss-of-function mutations on copper transporters lead to severe neurological symptoms. Along with its altered distribution, recent studies have also proposed novel mechanisms of copper neurotoxicity mediated by nonneuronal cell lineages in the brain, such as capillary endothelial cells, leading to development of AD neuropathology. This review covers recent findings of multifactorial toxic mechanisms of copper and discusses the risk of environmental exposure as a potential factor in accounting for the variability of AD incidence. PMID- 29409007 TI - Highly biocompatible super-resolution fluorescence imaging using the fast photoswitching fluorescent protein Kohinoor and SPoD-ExPAN with Lp-regularized image reconstruction. AB - Far-field super-resolution fluorescence microscopy has enabled us to visualize live cells in great detail and with an unprecedented resolution. However, the techniques developed thus far have required high-power illumination (102-106 W/cm2), which leads to considerable phototoxicity to live cells and hampers time lapse observation of the cells. In this study we show a highly biocompatible super-resolution microscopy technique that requires a very low-power illumination. The present technique combines a fast photoswitchable fluorescent protein, Kohinoor, with SPoD-ExPAN (super-resolution by polarization demodulation/excitation polarization angle narrowing). With this technique, we successfully observed Kohinoor-fusion proteins involving vimentin, paxillin, histone and clathrin expressed in HeLa cells at a spatial resolution of 70-80 nm with illumination power densities as low as ~1 W/cm2 for both excitation and photoswitching. Furthermore, although the previous SPoD-ExPAN technique used L1 regularized maximum-likelihood calculations to reconstruct super-resolved images, we devised an extension to the Lp-regularization to obtain super-resolved images that more accurately describe objects at the specimen plane. Thus, the present technique would significantly extend the applicability of super-resolution fluorescence microscopy for live-cell imaging. PMID- 29409006 TI - Vitamin D Status and Intakes and Their Association With Cognitive Trajectory in a Longitudinal Study of Urban Adults. AB - Context: Serum 25-hydroxyvitamin D [25(OH)D], and dietary and supplemental vitamin D may influence cognitive outcomes. Objectives: Sex-, age-, and race specific associations of vitamin D status and intake with longitudinal change in various cognitive domains were examined in a large sample of ethnically and socioeconomically diverse US urban adults. Design: Two prospective waves of data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study were used. Participants: Adults in Baltimore, Maryland, aged 30 to 64 years at baseline (n = 1231 to 1803), were followed for a mean (+/- standard deviation) of 4.64 +/- 0.93 years. Visit 1 occurred between 2004 and 2009; visit 2, between 2009 and 2013; there were 1.5 to 2.0 visits per participant. Main outcome and exposure measures: Cognitive performance was assessed using 11 test scores covering domains of global cognition, attention, learning/memory, executive function, visuospatial/visuoconstruction ability, psychomotor speed, and language/verbal. Serum 25(OH)D, vitamin D intake, and use of supplements containing vitamin D were the key exposures. Results: A consistent relationship was found between vitamin D status (overall) and supplemental intake (older women and black adults), with a slower rate of decline in the domain of verbal fluency. Higher dietary intake of vitamin D was linked to slower rate of decline in verbal memory among younger women, and a slower rate of decline in visual memory/visuoconstructive abilities among white adults. All other associations were inconsistent. Conclusions: Vitamin D status and intakes were inversely related to domain-specific cognitive decline in US urban adults. PMID- 29409008 TI - Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. AB - Background: Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis. Methods: We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated. Results: A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (~32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (~8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients. Conclusions: Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients. PMID- 29409009 TI - A method for inferring regional origins of neurodegeneration. AB - Alzheimer's disease, the most common form of dementia, is characterized by the emergence and spread of senile plaques and neurofibrillary tangles, causing widespread neurodegeneration. Though the progression of Alzheimer's disease is considered to be stereotyped, the significant variability within clinical populations obscures this interpretation on the individual level. Of particular clinical importance is understanding where exactly pathology, e.g. tau, emerges in each patient and how the incipient atrophy pattern relates to future spread of disease. Here we demonstrate a newly developed graph theoretical method of inferring prior disease states in patients with Alzheimer's disease and mild cognitive impairment using an established network diffusion model and an L1 penalized optimization algorithm. Although the 'seeds' of origin using our inference method successfully reproduce known trends in Alzheimer's disease staging on a population level, we observed that the high degree of heterogeneity between patients at baseline is also reflected in their seeds. Additionally, the individualized seeds are significantly more predictive of future atrophy than a single seed placed at the hippocampus. Our findings illustrate that understanding where disease originates in individuals is critical to determining how it progresses and that our method allows us to infer early stages of disease from atrophy patterns observed at diagnosis. PMID- 29409010 TI - Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. AB - Background: Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and tumor initiating cell maintenance. The rate-limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in glioblastoma (GBM; grade IV astrocytoma) is guanosine triphosphate (GTP) cyclohydrolase 1 (GCH1). We sought to define the role of GCH1 in the regulation of GBM growth and brain tumor initiating cell (BTIC) maintenance. Methods: We examined GCH1 mRNA and protein expression in patient-derived xenografts, clinical samples, and glioma gene expression datasets. GCH1 levels were modulated using lentiviral expression systems, and effects on cell growth, self-renewal, reactive species production, and survival in orthotopic patient-derived xenograft models were determined. Results: GCH1 was expressed in GBMs with elevated but not exclusive RNA and protein levels in BTICs in comparison to non-BTICs. Overexpression of GCH1 in GBM cells increased cell growth in vitro and decreased survival in an intracranial GBM mouse model. In converse experiments, GCH1 knockdown with short hairpin RNA led to GBM cell growth inhibition and reduced self-renewal in association with decreased CD44 expression. GCH1 was critical for controlling reactive species balance, including suppressing reactive oxygen species production, which mediated GCH1 cell growth effects. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence, and worse survival. Conclusions: GCH1 expression in established GBMs is pro-tumorigenic, causing increased growth due, in part, to promotion of BTIC maintenance and suppression of reactive oxygen species. PMID- 29409012 TI - Tool for filtering PubMed search results by sample size. AB - Objective: The most used search engine for scientific literature, PubMed, provides tools to filter results by several fields. When searching for reports on clinical trials, sample size can be among the most important factors to consider. However, PubMed does not currently provide any means of filtering search results by sample size. Such a filtering tool would be useful in a variety of situations, including meta-analyses or state-of-the-art analyses to support experimental therapies. In this work, a tool was developed to filter articles identified by PubMed based on their reported sample sizes. Materials and Methods: A search engine was designed to send queries to PubMed, retrieve results, and compute estimates of reported sample sizes using a combination of syntactical and machine learning methods. The sample size search tool is publicly available for download at http://ihealth.uemc.es. Its accuracy was assessed against a manually annotated database of 750 random clinical trials returned by PubMed. Results: Validation tests show that the sample size search tool is able to accurately (1) estimate sample size for 70% of abstracts and (2) classify 85% of abstracts into sample size quartiles. Conclusions: The proposed tool was validated as useful for advanced PubMed searches of clinical trials when the user is interested in identifying trials of a given sample size. PMID- 29409011 TI - Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. AB - Aims: A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Methods and results: Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. The cardiac functions by echocardiography show no difference in young wild-type C57BL/6 J (WT, 4-6 months), aged WT C57BL/6 J (24 26 months), and young inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 KO) (4-6 months) mice under physiological conditions. However, after 45 mins ischaemia and 24-h reperfusion, the ejection fraction of aged WT and icSIRT1 KO mice was impaired. The aged WT and icSIRT1 KO hearts vs. young WT hearts also show an impaired post-ischemic contractile function in a Langendorff perfusion system. The infarct size of aged WT and icSIRT1 KO hearts was larger than that of young WT hearts. The immunoblotting data demonstrated that aged WT and icSIRT1 KO hearts vs. young WT hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischaemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged WT and icSIRT1 KO hearts; this could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impaired substrate metabolism in the hearts; fatty acid oxidation is augmented and glucose oxidation is blunted during ischaemia and reperfusion. Adeno-associated virus (AAV9)-Sirt1 was delivered into the aged hearts via a coronary delivery approach, which significantly rescued the protein level of SIRT1 and the ischemic tolerance of aged hearts. Furthermore, AMPK agonist can rescue the tolerance of aged heart and icSIRT1 KO heart to ischemic insults. Conclusions: Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease. PMID- 29409013 TI - Effects of spent mushroom Cordyceps militaris supplementation on apparent digestibility, rumen fermentation, and blood metabolite parameters of goats. AB - The objective of this experiment was to study the effects of dried spent mushroom Cordyceps militaris (SMCM) supplementation on digestibility, rumen fermentation, and blood metabolite parameters in goats. When the mushroom production and harvesting was complete, SMCM was collected fresh from a mushroom farm. Four 18 mo-old male crossbred (Thai Native * Anglo Nubian) goats with initial BW of 26.0 +/- 1.40 kg were randomly assigned according to a 4 * 4 Latin square design to receive four different levels of SMCM at 0, 100, 200, and 300 g/d. There were quadratic effects (P < 0.06) on apparent digestibility of DM, OM, CP, NDF, and ADF among treatment groups, and greater values for the goats fed SMCM at 100 g/d were observed. A quadratic effect in energy intake (ME, Mcal/kg DM) (P = 0.02), with greater values for the goats fed SMCM at 100 g/d, was also observed. Rumen temperature was similar among groups (P = 0.23), whereas feeding of SMCM linearly decreased (P = 0.001) ruminal pH with increasing SMCM supplementation. Supplementing SMCM linearly decreased plasma concentration of cholesterol (P = 0.01), and there was also a tendency of reduction in plasma concentration of triglyceride (P = 0.10), with greater values for the goats fed SMCM at 100 g/d. There were quadratic effects on plasma of total protein, HgB, and MCHC among treatment groups. However, there were quadratic effects on fecal N (P = 0.04) and nitrogen retention (P = 0.07) based on g/d/animal or percentage of nitrogen retained (P = 0.01) among treatment groups, and greater values for the goats fed SMCM at 100 g/d were observed. Based on this experiment, it could be concluded that supplementing goat diets with SMCM at 100 to 200 g/d results in improved apparent digestibility of nutrients and blood metabolites, suggesting that SMCM has positive functions as a feed additive to improve energy substance metabolism and contribute to glyconeogenesis. PMID- 29409014 TI - LncRNA SNHG5/miR-26a/SOX2 signal axis enhances proliferation of chondrocyte in osteoarthritis. AB - Chondrocyte is involved in the destruction of joints in osteoarthritis (OA) patients. The aim of this study was to explore the expression level of small nucleolar RNA host gene 5 (SNHG5) and evaluate its function in chondrocyte. In our current study, the expression levels of SNHG5, miR-26a, and SOX2 in 17 pairs of articular cartilage tissues and in the non-OA group were assessed by real-time quantitative reverse-transcription polymerase chain reaction. Results showed that the levels of SNHG5 and SOX2 were significantly downregulated in OA tissues, while the level of miR-26a was upregulated. MTT, colony formation and cell transwell assays were performed to assess the function of SNHG5 on the cell viability, growth ability, and migration capacity in CHON-001 cells. It was found that SNHG5 could promote chondrocyte cell proliferation and migration. The relationship between SNHG5 and miR-26a was confirmed by RIP and the luciferase reporter assays. SOX2 was identified as a target gene of miR-26a by the luciferase reporter assay. Rescue assay was applied to verify the relationship among SNHG5, miR-26a, and SOX2. Our current study demonstrated that SNHG5 is involved in the mechanism of OA through functioning as a ceRNA to competitively sponge miR-26a, therefore, regulating the expression of SOX2. PMID- 29409015 TI - Juvenile-Specific Burst Firing of Terminal Nerve GnRH3 Neurons Suggests Novel Functions in Addition to Neuromodulation. AB - Peptidergic neurons are suggested to play a key role in neuromodulation of animal behaviors in response to sensory cues in the environment. Terminal nerve gonadotropin-releasing hormone 3 (TN-GnRH3) neurons are thought to be one of the peptidergic neurons important for such neuromodulation in adult vertebrates. On the other hand, it has been reported that TN-GnRH3 neurons are labeled by a specific GnRH3 antibody from early developmental stages to adulthood and are thus suggested to produce mature GnRH3 peptide even in the early developmental stages. However, it remains unknown when TN-GnRH3 neurons show spontaneous burst firing, which is suggested to be involved in neuropeptide release. Using a whole-brain in vitro preparation of gnrh3:enhanced green fluorescent protein (EGFP) medaka fish, we first recorded spontaneous firings of TN-GnRH3 neurons after hatching to adulthood. Contrary to what one would expect from their neuromodulatory functions that TN-GnRH3 neurons are more active in adulthood-TN-GnRH3 neurons in juveniles showed spontaneous burst firing more frequently than in adulthood (juvenile specific burst firing). Ca2+ imaging of TN-GnRH3 neurons in juveniles may further suggest that juvenile-specific burst firing triggers neuropeptide release. Furthermore, juvenile-specific burst firing was suggested to be induced by blocking persistent GABAergic inhibition to the glutamatergic neurons, which leads to an increase in glutamatergic synaptic inputs to TN-GnRH3 neurons. The present study reports that peptidergic neurons show juvenile-specific burst firing involved in triggering peptide release and suggests that juvenile TN-GnRH3 neurons have novel functions, in addition to neuromodulation. PMID- 29409016 TI - Social Work Educational Debt and Salary Survey: A Snapshot from Ohio. AB - Educational debt is on the rise, and social work salaries remain low compared with salaries of other similarly educated and trained professionals. To better understand the implications of educational debt for social workers, an online survey was sent to social workers in Ohio. More than 700 respondents provided information concerning educational debt and social work wages. It was found that educational attainment levels were correlated with educational debt burden but did not affect the length of the payback period. In contrast, type of practice setting did not affect educational debt burden but did affect payback period. Regarding social work wages, educational levels affected salaries; specifically, more time spent earning a degree resulted in higher starting and current salaries. Those with an MSW earned more than those with only a bachelor's degree in the field, both in starting and current salaries. Practice setting did not have an impact on starting salary but did affect current salary. This study has implications for social work education and advocacy work related to student debt forgiveness. PMID- 29409018 TI - Intimate Partner Violence, Traumatic Brain Injury, and Social Work: Moving Forward. PMID- 29409017 TI - Varicella-Zoster Virus DNA in Blood After Administration of Herpes Zoster Vaccine. AB - We studied the relationship between varicella-zoster virus (VZV) DNAemia and development of VZV-specific immunity after administration of live-attenuated zoster vaccine. VZV-DNAemia, detected by polymerase chain reaction (PCR), and VZV specific effector (Teff) and memory (Tmem) T cells, was measured in 67 vaccinees. PCR was positive in 56% (9 direct, 28 nested) on day 1 and in 16% (1 direct, 10 nested) on day 14. Teff progressively increased in direct-PCR-positive vaccinees up to day 30, but Tmem did not. Conversely, Tmem, but not Teff, increased in direct-PCR-negative vaccinees on day 7. The kinetics of these immune responses and VZV DNAemia suggested that direct-PCR sample positive represented viremia. PMID- 29409019 TI - Altered Expression of miR-181a-5p and miR-23a-3p Is Associated With Obesity and TNFalpha-Induced Insulin Resistance. AB - Context: The proinflammatory cytokine TNFalpha is a key player in insulin resistance (IR). The role of miRNAs in inflammation associated with IR is poorly understood. Objective: To investigate miR-181a-5p and miR-23a-3p expression profiles in obesity and to study their role in TNFalpha-induced IR in adipocytes. Design: Two separate cohorts were used. Cohort 1 was used in adipose tissue (AT) expression studies and included 28 subjects with body mass index (BMI) <30 kg/m2 and 30 with BMI >=30 kg/m2. Cohort 2 was used in circulating serum miRNA studies and included 101 subjects with 4 years of follow-up (48 case subjects and 53 control subjects). miR-181a-5p and miR-23a-3p expression was assessed in subcutaneous and visceral AT. Functional analysis was performed in adipocytes, using miRNA mimics and inhibitors. Key molecules of the insulin pathway, AKT, PTEN, AS160, and S6K, were analyzed. Results: Expression of miR-181a-5p and miR 23a-3p was reduced in adipose tissue from obese and diabetic subjects and was inversely correlated to adiposity and homeostasis model assessment of IR index. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin stimulated AKT activation and reduced TNFalpha-induced IR, regulating PTEN and S6K expression. Serum levels of miR-181a-5p were reduced in case vs control subjects at baseline, suggesting a prognostic value. Variable importance in projection scores revealed miR-181a-5p had more effect on the model than insulin or glucose at 120 minutes. Conclusion: miR-181a-5p and miR-23a-3p may prevent TNFalpha-induced IR in adipocytes through modulation of PTEN and S6K expression. PMID- 29409020 TI - Follicular localization of growth differentiation factor 8 and its receptors in normal and polycystic ovary syndrome ovaries. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor beta superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS. PMID- 29409021 TI - Epidemiological trends and risk factors for tobacco, alcohol and drug use among adolescents in Scotland, 2002-13. AB - Background: This study estimates trends in prevalence, and patterns, of individual and multiple substance use between 2002 and 2013 amongst adolescents in Scotland. Methods: The study uses data from 134 387 participants of the biennial national 'Scottish Schools Adolescent Lifestyle and Substance Use Survey' on smoking, alcohol and illicit drug use. Current regular use and current heavy use of smoking, alcohol, illicit drugs and multiple substances was measured. Time trends in the prevalence of each outcome were estimated using univariate and multivariate logistic regression. Results: Regular smoking, alcohol, illicit drug and multiple substance use declined significantly amongst adolescents in Scotland. However, multivariate analyses that focussed upon high risk levels of these behaviours revealed an upward linear trend in heavy alcohol (OR = 1.06; 95% CI: 1.04, 1.07) and heavy illicit drug (OR = 1.04; 95% CI: 1.00, 1.08) use (P < 0.05). Non-white pupils were more likely to be involved in individual and multiple substance use than ethnically white British pupils. In comparison to pupils from the least deprived socioeconomic quintile, pupils from the most deprived quintile had increased odds of 1.41 (95% CI: 1.02, 1.97; P < 0.05) and 1.62 (95% CI: 1.14, 2.29; P < 0.05) of being regular and heavy multiple substance users, respectively. Conclusions: Further effort is required to tackle heavy alcohol and heavy illicit drug use amongst adolescents in Scotland. Prevention strategies should be informed by the risk profiles of substance misusers and evidence around the clinical and cost-effectiveness of preventive interventions. PMID- 29409022 TI - Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRalpha Knockout Male Mice. AB - Liver X receptor (LXR) alpha expression is mainly localized to metabolic tissues, such as the liver, whereas LXRbeta is ubiquitously expressed. LXRalpha is activated by oxysterols and plays an important role in the regulation of lipid metabolism in metabolic tissues. In macrophages, LXRs stimulate reverse cholesterol transport and regulate immune responses. Although a high-cholesterol diet induces severe steatohepatitis in LXRalpha-knockout (KO) mice, the underlying mechanisms linking lipid metabolism and immune responses remain largely unknown. In this study, we investigated the role of LXRalpha in the pathogenesis of steatohepatitis by assessing the effects of a high-fat and high cholesterol diet (HFCD) on hepatic immune cell proportion and function as well as lipid metabolism in wild-type (WT) and LXRalpha-KO mice. HFCD feeding induced severe steatohepatitis in LXRalpha-KO mice compared with WT mice. These mice had higher cholesterol levels in the plasma and the liver and dysregulated expression of LXR target and proinflammatory genes in both whole liver samples and isolated hepatic mononuclear cells. Flow cytometry showed an increase in CD68+CD11b+ Kupffer cells/macrophages and a decrease in invariant natural killer T cells in the liver of HFCD-fed LXRalpha-KO mice. These mice were more susceptible to lipopolysaccharide-induced liver injury and resistant to inflammatory responses against alpha-galactosylceramide or concanavalin-A treatment. The findings provide evidence for activation of bone marrow-derived Kupffer cells/macrophages and dysfunction of invariant natural killer T cells in LXRalpha-KO mouse liver. These findings indicate that LXRalpha regulates hepatic immune function along with lipid metabolism and protects against the pathogenesis of nonalcoholic steatohepatitis. PMID- 29409023 TI - ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially co-localized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins. PMID- 29409024 TI - Postprandial Saturated Fatty Acids Increase the Risk of Type 2 Diabetes: A Cohort Study in a Chinese Population. AB - Context: Experimental evidence suggests saturated fatty acids (SFAs) are associated with insulin resistance, but results from epidemiological studies on fasting SFAs-diabetes risk are inconsistent. Objective: We investigated SFA (fasting and 2-hour postprandial) profiles and diabetes risk. Design Setting: A total of 8940 participants were recruited for the Harbin People's Health Study in 2008. Serum SFAs (fasting and 2-hour postprandial) at baseline in Chinese men and women without diabetes were profiled, and type 2 diabetes was ascertained using World Health Organization criteria after 4 to 7 years of follow-up. Outcome: Associations between 2-hour postprandial SFA (2h-SFA) and diabetes. Results: At baseline, incident cases of diabetes were older with a higher body mass index and waist circumference. After a mean follow-up of 6.7 years, 658 incident cases of diabetes occurred. After propensity score computation and inverse probability of treatment weighting (IPTW) estimation, fasting SFAs were unrelated to diabetes risk but IPTW-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the highest tertile of 2-hour postprandial stearic acid (2h-SA), 2-hour postprandial palmitic acid (2h-PA), and 2h-SFA for diabetes risk were 2.50 (2.08 to 3.16), 1.56 (1.23 to 2.02), and 1.70 (1.34 to 2.17), respectively (P-trend < 0.0001). Similarly, 2h-SA/fasting SA, 2h-PA/fasting PA, and 2h-SFA/fasting SFA ratios [IPTW-adjusted OR (95% CI): 2.94 (2.39 to 3.58), 2.31 (1.80 to 2.93), and 2.42 (1.91 to 3.11), respectively; P-trend < 0.0001] predicted the diabetes risk. Conclusions: Higher serum 2h-SFA (but not fasting SFA) independently predicted diabetes risk. PMID- 29409025 TI - Effects of a Lifestyle Intervention During Pregnancy and First Postpartum Year: Findings From the RADIEL Study. AB - Context: Women with a history of gestational diabetes (GDM) have a sevenfold risk of developing type 2 diabetes. Objective: To assess the effects of a lifestyle intervention during pregnancy and first postpartum year on glucose regulation, weight retention, and metabolic characteristics among women at high GDM risk. Design: In the Finnish Gestational Diabetes Prevention study, trained study nurses provided lifestyle counseling in each trimester and 6 weeks, 6 months, and 12 months postpartum. Setting: Three maternity hospitals in the Helsinki area and one in Lappeenranta. Patients: In total, 269 women with previous GDM and/or a prepregnancy body mass index >=30 kg/m2 were enrolled before 20 gestational weeks and allocated to either a control or an intervention group. This study includes the 200 participants who attended study visits 6 weeks and/or 12 months postpartum. Intervention: The lifestyle intervention followed Nordic diet recommendations and at least 150 minutes of moderate exercise was recommended weekly. Main Outcome Measure: The incidence of impaired glucose regulation (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) during the first postpartum year. Results: Impaired glucose regulation was present in 13.3% of the women in the control and in 2.7% in the intervention group [age adjusted odds ratio, 0.18 (95% confidence interval, 0.05 to 0.65), P = 0.009] during the first postpartum year. There were no differences between the groups in weight retention, physical activity, or diet at 12 months postpartum. Conclusions: A lifestyle intervention during pregnancy and the first postpartum year successfully reduced the incidence of postpartum impairment in glucose regulation. PMID- 29409026 TI - Health-Care Utilization Patterns of Maltreated Youth. AB - To examine in detail the health-care utilization patterns of maltreated children, we studied electronic health records (EHRs) of children assigned maltreatment related codes in a large medical system. We compared youth with maltreatment related diagnoses (N = 406) with those of well-matched youth (N = 406). Data were based on EHRs during a 4-year period from the University of Minnesota's Clinical Data Repository, which covers eight hospitals and over 40 clinics across Minnesota. A primary care provider (PCP) was assigned to over 80% of youth in both groups. As expected, however, the odds of not having a PCP were twice as high in the maltreated as in the comparison group. Also as expected, maltreated youth had higher rates of emergency department visits. We ruled out differences in age, gender, race, public insurance, duration in the medical system, type of specialty department, and clinic location as potential explanations for these differences. On the other hand, there were no significant differences between maltreated and comparison youth in hospitalizations, preventive visits, or office visits. Contrary to expectations, maltreated youth were not in the medical system for just a brief period of time and were not more likely to cancel or miss appointments. The current study adds to the research literature by providing more detailed information about the nature of health-care services used by children with maltreatment-related diagnoses. PMID- 29409028 TI - A snapshot of health information exchange across five nations: an investigation of frontline clinician experiences in emergency care. AB - Objective: Ensuring the ability to exchange patient information among disparate electronic health records systems is a top priority and a domain of substantial public investment across countries. However, we know little about the extent to which current capabilities meet the needs of frontline clinicians. Materials and Methods: We conducted in-person, semistructured interviews with emergency care physicians and nurses in select hospitals in Canada, Denmark, Finland, Germany, and the USA. We characterized the state of health information exchange (HIE) by country and used thematic analysis to identify the perceived benefits of access to complete past medical history (PMH), the conditions under which PMH is sought, and the challenges to accessing and using HIE capabilities. Results: HIE approaches, and the information electronically accessible to clinicians, differed by country. Benefits of access to PMH included safer care, reduced patient length of stay, and fewer lab and imaging orders. Conditions under which PMH was sought included moderate-acuity patients, patients with chronic conditions, and instances where accessing PMH was convenient. Challenges to HIE access and use included difficulty knowing where information is located, delay in receiving information, and difficulty finding information within documents. Discussion: Even with different HIE approaches across countries, all clinicians reported shortcomings in their country's approach. Notably, challenges were similar and shaped the conditions under which PMH was sought. Conclusion: As countries continue to pursue broad-based HIE, they appear to be facing similar challenges in realizing HIE value and therefore have an opportunity to learn from one another. PMID- 29409027 TI - Transcriptional and post-transcriptional upregulation of p27 mediates growth inhibition of isorhapontigenin (ISO) on human bladder cancer cells. AB - There are few approved drugs available for the treatment of muscle-invasive bladder cancer (MIBC). Recently, we have demonstrated that isorhapontigenin (ISO), a new derivative isolated from the Chinese herb Gnetum cleistostachyum, effectively induces cell-cycle arrest at the G0/G1 phase and inhibits anchorage independent cell growth through the miR-137/Sp1/cyclin D1 axis in human MIBC cells. Herein, we found that treatment of bladder cancer (BC) cells with ISO resulted in a significant upregulation of p27, which was also observed in ISO treated mouse BCs that were induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Importantly, knockdown of p27 caused a decline in the ISO-induced G0-G1 growth arrest and reversed ISO suppression of anchorage-independent growth in BC cells. Mechanistic studies revealed that ISO promoted p27 expression at mRNA transcription level through increasing direct binding of forkhead box class O1 (FOXO1) to its promoter, while knockdown of FOXO1 attenuated ISO inhibition of BC cell growth. On the other hand, ISO upregulated the 3'-untranslated region (3' UTR) activity of p27, which was accompanied by a reduction of miR-182 expression. In line with these observations, ectopic expression of miR-182 significantly blocked p27 3'-UTR activity, whereas mutation of the miR-182-binding site at p27 mRNA 3'-UTR effectively reversed this inhibition. Accordingly, ectopic expression of miR-182 also attenuated ISO upregulation of p27 expression and impaired ISO inhibition of BC cell growth. Our results not only provide novel insight into understanding of the underlying mechanism related to regulation of MIBC cell growth but also identify new roles and mechanisms underlying ISO inhibition of BC cell growth. PMID- 29409030 TI - Genetic Variability of the Noncoding Control Region of Cutaneous Merkel Cell Polyomavirus: Identification of Geographically Related Genotypes. AB - Background: Merkel cell polyomavirus (MCPyV) is a ubiquitous cutaneous virus that causes Merkel cell carcinoma, which develops preferentially in white populations from Europe and North America. However, the genomic variations of MCPyV among ethnic groups have not been well delineated, and even less is known regarding alterations in the noncoding control region (NCCR) in the general population. Methods: MCPyV strains recovered from skin swab specimens from 250 healthy participants with distinct ethnicities and geographic origins were subjected to sequencing analysis of the NCCR. Results: A 25-base pair tandem repeat caused by a 25-base pair insertion within the NCCR was found predominantly in Japanese and East Asian individuals. Based on the presence of 2 other insertions and a deletion, the NCCR could be classified further into 5 genotypes. This tandem repeat was also found exclusively in the NCCR from Japanese patients with Merkel cell carcinoma, while other genotypes were detected in white patients from Europe and North America. Conclusions: Our results suggest that the MCPyV NCCR varies according to ethnicity and that assessing the short NCCR sequence provides a rapid and simple means for identification of the Japanese and East Asian variant genotype. It remains to be established whether these NCCR variations are associated differentially with the pathogenesis of MCPyV-driven Merkel cell carcinoma between regions with varying endemicity. PMID- 29409029 TI - The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors. AB - Background: Neurofibromatosis 1 (NF1) leads to the development of benign and malignant peripheral nerve sheath tumors (MPNST). MPNST have been described to develop in preexisting benign plexiform neurofibromas (PN) and have a poor prognosis. Atypical neurofibromas (ANF) were recently described as precursor lesions for MPNST, making early detection and management of ANF a possible strategy to prevent MPNST. We aimed to clinically characterize ANF and identify management approaches. Methods: We analyzed clinical, imaging, and pathology findings of all patients with NF1 and ANF at 3 institutions. Results: Sixty-three patients had 76 ANF (32M/31F; median age 27.1 y). On MRI, most ANF appeared as distinct nodular lesions and were 18F-fluorodeoxyglucose (FDG) avid. Forty-six ANF were associated with pain, 19 with motor weakness, 45 were palpable or visible, and 13 had no clinical signs. Completely resected ANF (N = 57) have not recurred (median follow-up, 4.1 y; range, 0-14 y). Four ANF transformed into MPNST and 17 patients had a history of MPNST in a different location than was their ANF. Conclusions: Growth of distinct nodular lesions, pain, and FDG-PET avidity should raise concern for ANF in NF1. Patients with ANF are at greater risk for development of MPNST. Complete resection of ANF may prevent development of MPNST. PMID- 29409031 TI - A Typology of Social Workers in Long-Term Care Facilities in Israel. AB - This article explores moral distress among long-term care facility (LTCF) social workers by examining the relationships between moral distress and environmental and personal features. Based on these features, authors identified a typology of LTCF social workers and how they handle moral distress. Such a typology can assist in the identification of social workers who are in a particular need for assistance. Overall, 216 LTCF social workers took part in the study. A two-step cluster analysis was conducted to identify a typology of LTCF social workers based on features such as ethical environment, support in workplace, mastery, and resilience. The variance of the identified clusters and their associations with moral distress were examined, and four clusters of LTCF social workers were identified. The clusters varied from each other in relation to their personal and environmental features and in relation to their experience of moral distress. The article concludes with a discussion of the importance of developing programs for LTCF social workers that provide support and enhancement of personal resources and an adequate and ethical environment for practice. PMID- 29409032 TI - Critical role of phosphodiesterase 2A in mouse congenital heart defects. AB - Aims: Phosphodiesterase 2 A (Pde2A), a cAMP-hydrolysing enzyme, is essential for mouse development; however, the cause of Pde2A knockout embryonic lethality is unknown. To understand whether Pde2A plays a role in cardiac development, hearts of Pde2A deficient embryos were analysed at different stage of development. Methods and results: At the stage of four chambers, Pde2A deficient hearts were enlarged compared to the hearts of Pde2A heterozygous and wild-type. Pde2A knockout embryos revealed cardiac defects such as absence of atrial trabeculation, interventricular septum (IVS) defects, hypertrabeculation and thinning of the myocardial wall and in rare cases they had overriding aorta and valves defects. E14.5 Pde2A knockouts showed reduced cardiomyocyte proliferation and increased apoptosis in the IVS and increased proliferation in the ventricular trabeculae. Analyses of E9.5 Pde2A knockout embryos revealed defects in cardiac progenitor and neural crest markers, increase of Islet1 positive and AP2 positive apoptotic cells. The expression of early cTnI and late Mef2c cardiomyocyte differentiation markers was strongly reduced in Pde2A knockout hearts. The master transcription factors of cardiac development, Tbx, were down-regulated in E14.5 Pde2A knockout hearts. Absence of Pde2A caused an increase of intracellular cAMP level, followed by an up-regulation of the inducible cAMP early repressor, Icer in fetal hearts. In vitro experiments on wild-type fetal cardiomyocytes showed that Tbx gene expression is down-regulated by cAMP inducers. Furthermore, Pde2A inhibition in vivo recapitulated the heart defects observed in Pde2A knockout embryos, affecting cardiac progenitor cells. Interestingly, the expression of Pde2A itself was dramatically affected by Pde2A inhibition, suggesting a potential autoregulatory loop. Conclusions: We demonstrated for the first time a direct relationship between Pde2A impairment and the onset of mouse congenital heart defects, highlighting a novel role for cAMP in cardiac development regulation. PMID- 29409033 TI - A dashboard-based system for supporting diabetes care. AB - Objective: To describe the development, as part of the European Union MOSAIC (Models and Simulation Techniques for Discovering Diabetes Influence Factors) project, of a dashboard-based system for the management of type 2 diabetes and assess its impact on clinical practice. Methods: The MOSAIC dashboard system is based on predictive modeling, longitudinal data analytics, and the reuse and integration of data from hospitals and public health repositories. Data are merged into an i2b2 data warehouse, which feeds a set of advanced temporal analytic models, including temporal abstractions, care-flow mining, drug exposure pattern detection, and risk-prediction models for type 2 diabetes complications. The dashboard has 2 components, designed for (1) clinical decision support during follow-up consultations and (2) outcome assessment on populations of interest. To assess the impact of the clinical decision support component, a pre-post study was conducted considering visit duration, number of screening examinations, and lifestyle interventions. A pilot sample of 700 Italian patients was investigated. Judgments on the outcome assessment component were obtained via focus groups with clinicians and health care managers. Results: The use of the decision support component in clinical activities produced a reduction in visit duration (P ? .01) and an increase in the number of screening exams for complications (P < .01). We also observed a relevant, although nonstatistically significant, increase in the proportion of patients receiving lifestyle interventions (from 69% to 77%). Regarding the outcome assessment component, focus groups highlighted the system's capability of identifying and understanding the characteristics of patient subgroups treated at the center. Conclusion: Our study demonstrates that decision support tools based on the integration of multiple-source data and visual and predictive analytics do improve the management of a chronic disease such as type 2 diabetes by enacting a successful implementation of the learning health care system cycle. PMID- 29409035 TI - Personal Reflections of a Social Justice Warrior. PMID- 29409034 TI - High Effectiveness of the Bivalent Human Papillomavirus (HPV) Vaccine Against Incident and Persistent HPV Infections up to 6 Years After Vaccination in Young Dutch Women. AB - Background: Monitoring vaccine effectiveness (VE) in vaccination programs is of importance for assessing the impact of immunization. This study aimed to estimate the VE of the bivalent human papillomavirus (HPV) vaccine against incident and 12 month persistent infections up to 6 years after vaccination. Methods: In 2009 2010, girls eligible for the vaccination catch-up campaign (ie, those aged 14-16 years) were enrolled into a prospective cohort. Annually, participants completed a questionnaire and submitted a self-collected vaginal swab sample for HPV testing by the SPF10-LiPA25 assay. We compared sociodemographic characteristics and infection rates between vaccinated and unvaccinated girls. The VE was adjusted for characteristics related to HPV vaccination status. We used combined end points for VE estimation. Results: In total, 1635 women, of whom 54% were fully vaccinated, were included for VE estimation. The adjusted VE against HPV16 and 18 persistent infections amounted to 97.7% (95% confidence interval [CI], 83.5%-99.7%). We found a VE against HPV31, 33, and 45 persistent infections of 61.8% (95% CI, 16.7%-82.5%). We found no indications that the protection against vaccine or cross-protective types changes over time. Conclusion: Our findings of nearly full protection against vaccine-type persistent infections and significant cross-protection to nonvaccine types in a population-based cohort study confirm the effectiveness of the bivalent HPV vaccine as estimated in trials. We found no indications for waning protection up to 6 years after vaccination. PMID- 29409036 TI - Simultaneous Quantitation of Amlodipine Besylate and Olmesartan Medoxomil in Fixed-Dose Combination Tablets: HPLC-DAD Versus UHPLC-DAD. AB - Association of amlodipine besylate and olmesartan medoxomil in fixed-dose combination tablets is effective, safe and well tolerated for the treatment of hypertension. The aim of this study was to optimize and validate a novel and fast UHPLC-DAD method for simultaneous quantification of these antihypertensive drugs in tablets, using a transfer procedure from a conventional HPLC-DAD method. The HPLC separation was carried out using a C18 column (150 * 4.6 mm2; 5 MUm) and a mobile phase composed of acetonitrile, methanol and 0.3% trimethylamine pH 2.75 (30:30:40), at 1.0 mL/min. UV detection was performed at 238 nm and injection volume was 10 MUL. Then, the analytical method was transferred to UHPLC, using a BEH C18 column (50 * 2.1 mm2; 1.7 MUm). Mathematical equations were applied to calculate the UHPLC mobile phase flow rate and injection volume, which were 0.613 mL/min and 0.7 MUL, respectively. UHPLC method was fully validated and showed to be selective, linear (r2 > 0.99), precise (RSD < 2.0%), accurate and robust. UHPLC method was statistically equivalent to the HPLC method after analysis of three batches of BenicarAnlo(r) tablets. However, UHPLC method promoted faster analyses, better chromatographic performance and lower solvent consumption. PMID- 29409037 TI - Metabolites of Heroin in Several Different Post-mortem Matrices. AB - In some forensic autopsies blood is not available, and other matrices are sampled for toxicological analysis. The aims of the present study were to examine whether heroin metabolites can be detected in different post-mortem matrices, and investigate whether analyses in other matrices can give useful information about concentrations in peripheral blood. Effects of ethanol on the metabolism and distribution of heroin metabolites were also investigated. We included 45 forensic autopsies where morphine was detected in peripheral blood, concomitantly with 6-acetylmorphine (6-AM) detected in any matrix. Samples were collected from peripheral blood, cardiac blood, pericardial fluid, psoas muscle, lateral vastus muscle, vitreous humor and urine. Opioid analysis included 6-AM, morphine, codeine, and morphine glucuronides. The 6-AM was most often detected in urine (n = 39) and vitreous humor (n = 38). The median morphine concentration ratio relative to peripheral blood was 1.3 (range 0-3.6) for cardiac blood, 1.4 (range 0.07-5.3) for pericardial fluid, 1.2 (range 0-19.2) for psoas muscle, 1.1 (range 0-1.7) for lateral vastus muscle and 0.4 (range 0.2-3.2) for vitreous humor. The number of 6-AM positive cases was significantly higher (P = 0.03) in the ethanol positive group (n = 6; 86%) compared to the ethanol negative group (n = 14; 37%) in peripheral blood. The distribution of heroin metabolites to the different matrices was not significantly different between the ethanol positive and the ethanol negative group. This study shows that toxicological analyses of several matrices could be useful in heroin-related deaths. Urine and vitreous humor are superior for detection of 6-AM, while concentrations of morphine could be assessed from peripheral or cardiac blood, pericardial fluid, psoas muscle and lateral vastus muscle. PMID- 29409038 TI - Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery. AB - The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60 15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC. PMID- 29409039 TI - The Affinity of Brominated Phenolic Compounds for Human and Zebrafish Thyroid Receptor beta: Influence of Chemical Structure. AB - Brominated phenolic compounds (BPCs) are found in the environment, and in human and wildlife tissues, and some are considered to have endocrine disrupting activities. The goal of this study was to determine how structural differences of 3 BPC classes impact binding affinities for the thyroid receptor beta (TRbeta) in humans and zebrafish. BPC classes included halogenated bisphenol A derivatives, halogenated oxidative transformation products of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), and brominated phenols. Affinities were assessed using recombinant TRbeta protein in competitive binding assays with 125I triiodothyronine (125I-T3) as the radioligand. Zebrafish and human TRbeta displayed similar binding affinities for T3 (Ki = 0.40 and 0.49 nM) and thyroxine (T4, Ki = 6.7 and 6.8 nM). TRbeta affinity increased with increasing halogen mass and atomic radius for both species, with the iodinated compounds having the highest affinity within their compound classes. Increasing halogen mass and radius increases the molecular weight, volume, and hydrophobicity of a compound, which are all highly correlated with increasing affinity. TRbeta affinity also increased with the degree of halogenation for both species. Human TRbeta displayed higher binding affinities for the halogenate bisphenol A compounds, whereas zebrafish TRbeta displayed higher affinities for 2,4,6-trichlorophenol and 2,4,6-trifluorophenol. Observed species differences may be related to amino acid differences within the ligand binding domains. Overall, structural variations impact TRbeta affinities in a similar manner, supporting the use of zebrafish as a model for TRbeta disruption. Further studies are necessary to investigate how the identified structural modifications impact downstream receptor activities and potential in vivo effects. PMID- 29409042 TI - Corrigendum to "Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients". PMID- 29409041 TI - The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population. AB - Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (+/- standard deviation) age was 33.2 +/- 1.0 years. Compared with age , sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 +/- 1.2 mmol/L vs control, 4.9 +/- 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 +/- 17.0 pmol/L vs control, 14.2 +/- 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 +/- 1.2 mmol/L) compared with control subjects (1.3 +/- 0.8 mmol/L; P < 0.001), but total cholesterol, high density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 +/- 18 mm Hg vs control subjects, 129 +/- 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 +/- 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation. PMID- 29409043 TI - Education and Training for Clinical Neuropsychologists in Integrated Care Settings. AB - The increasing importance of integrated care necessitates that education and training experiences prepare clinical neuropsychologists for competent practice in integrated care settings, which includes (a) general competence related to an integrated/interdisciplinary approach and (b) competence specific to the setting. Formal neuropsychology training prepares neuropsychologists with a wide range of knowledge and skills in assessment, intervention, teaching/supervision, and research that are relevant to such settings. However, less attention has been paid to the knowledge and skills that directly address functioning within integrated teams, such as the ability to develop, maintain, and expand collaboration across disciplines, bidirectional clinical-research translation and implementation in integrated team settings, and how such collaboration contributes to clinical and research activities. Foundational knowledge and skills relevant to interdisciplinary systems have been articulated as part of competencies for entry into clinical neuropsychology, but their emphasis in education and training programs is unclear. Recommendations and resources are provided regarding how competencies relevant to integrated care can be provided across the continuum of education and training (i.e., doctoral, internship, postdoctoral, and post-licensure). PMID- 29409044 TI - Intensive Care Unit Wastewater Interventions to Prevent Transmission of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Organisms. AB - Background: The increasing prevalence of nosocomial carbapenemase-producing Enterobacteriaceae is a concern. However, the role of the environment in multispecies outbreaks remains poorly understood. There is increasing recognition that hospital wastewater plumbing may play a role. Methods: Covers were installed on all hoppers (a "toilet-like" waste disposal system) in adult intensive care units (ICUs) of a university hospital; additionally in the surgical ICU, sink trap heating and vibration devices were also installed. Patient acquisitions of Klebsiella pneumoniae carbapenemase-producing organisms (KPCOs) for patients who were admitted to an intervention unit were compared for 18-month preintervention and intervention periods. Results: Sixty hopper covers and 23 sink trap devices were installed. Fifty-six new multispecies KPCO acquisitions occurred preintervention compared to 30 during the intervention. Decreases for all KPCO acquisitions (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.31-0.81; P = .003) and KPCO-positive clinical cultures (OR, 0.29; 95% CI, 0.17-0.48; P < .001) per admission in patients exposed to an intervention unit were observed. The incidence rate ratio was 0.51-fold (95% CI, 0.43-0.61) lower for all KPCO acquisitions during the intervention. The effect of the sink trap devices alone could not be determined, although the proportion of sink drain cultures positive for KPCO decreased (12/15 [80%] sites sampled preintervention vs 40/840 [5%] sampled during the intervention; P = .001). Conclusions: An intervention targeting wastewater plumbing fixtures, by installation of hopper covers, demonstrated a decrease in patient KPCO acquisitions. Considering wastewater reservoirs in nosocomial transmission of multispecies carbapenemase-producing Enterobacteriaceae may be critical. PMID- 29409046 TI - Evaluation of Drager DrugTest 5000 in a Naturalistic Setting. AB - Reliable field testing devices for psychoactive drugs would be useful tools for the police for detecting drug-impaired drivers. The Norwegian Mobile Police Service (NMPS) started using Drager DrugTest 5000 (DDT5000) in 2015 as an on-site screening instrument for drugs in samples of oral fluid. The aim of this study was to compare the results of field testing of DDT5000 with drug findings in blood and oral fluid samples taken from drivers suspected for driving under the influence of drugs (DUID). In total, 369 drivers were included in this field testing; blood samples were obtained from all of them, while oral fluid samples were collected with the Intercept device from 301 of them. The median time from field testing with DDT5000 and collection of blood and oral fluid samples was 50 min. The proportions of false positive results with DDT5000 compared to findings in blood samples above the Norwegian legal per se limits were for cannabis 14.5%, amphetamine 23.2%, methamphetamine 38.4%, cocaine 87.1%, opiates 65.9% and benzodiazepines 36.4%. The proportions of false negatives were for cannabis 13.4%, amphetamine 4.9%, methamphetamine 6.1%, cocaine 0.0%, opiates 0.0% and benzodiazepines 18.8%. Among drivers who had drug concentrations above the legal limits in blood, the proportion who tested positive using DDT5000 was 82.9% for THC, 90.8% for amphetamine, 75.7% for methamphetamine, 100.0% for cocaine, 100.0% for opiates and 37.2% for benzodiazepines. In cases with false-positive DDT5000 results compared to blood, traces of drugs were most often found in oral fluid. The DDT5000 did not absolutely correctly identify DUID offenders due to fairly large proportions of false-positive or false-negative results compared to drug concentrations in blood. The police reported that DDT5000 was still a valuable tool in identifying possible DUID offenders, resulting in more than doubling the number of apprehended DUID offenders. PMID- 29409045 TI - GnRH Receptor Expression and Reproductive Function Depend on JUN in GnRH Receptor Expressing Cells. AB - Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. LH and FSH are heterodimers composed of a common alpha-subunit and unique beta-subunits, which provide biological specificity and are limiting components of mature hormone synthesis. Gonadotrope cells respond to GnRH via specific expression of the GnRH receptor (Gnrhr). GnRH induces the expression of gonadotropin genes and of the Gnrhr by activation of specific transcription factors. The JUN (c-Jun) transcription factor binds to AP 1 sites in the promoters of target genes and mediates induction of the FSHbeta gene and of the Gnrhr in gonadotrope-derived cell lines. To analyze the role of JUN in reproductive function in vivo, we generated a mouse model that lacks JUN specifically in GnRH receptor-expressing cells (conditional JUN knockout; JUN cKO). JUN-cKO mice displayed profound reproductive anomalies such as reduced LH levels resulting in lower gonadal steroid levels, longer estrous cycles in females, and diminished sperm numbers in males. Unexpectedly, FSH levels were unchanged in these animals, whereas Gnrhr expression in the pituitary was reduced. Steroidogenic enzyme expression was reduced in the gonads of JUN-cKO mice, likely as a consequence of reduced LH levels. GnRH receptor-driven Cre activity was detected in the hypothalamus but not in the GnRH neuron. Female, but not male, JUN-cKO mice exhibited reduced GnRH expression. Taken together, our results demonstrate that GnRH receptor-expression levels depend on JUN and are critical for reproductive function. PMID- 29409047 TI - Nonthyroidal Illness Syndrome and Thyroid Hormone Actions at Integrin alphavbeta3. AB - Context: The nonthyroidal illness syndrome (NTIS) is a constellation of changes in circulating thyroid hormone levels that occur in euthyroid patients with acute or chronic systemic diseases. The changes that occur include a reduction in serum T3, an increase in serum rT3, and variable changes in circulating T4 levels. No consensus exists regarding therapeutic intervention for NTIS. Methods: We briefly review the published literature on the physiological actions of T4 and of rT3 hormones that until recently have been seen to have little or no bioactivity-and analyze the apparent significance of changes in circulating T4 and T3 encountered in the setting of NTIS in patients with cancer. In the case of T4, these actions may be initiated at a cancer or endothelial cell plasma membrane receptor on integrin alphavbeta3 or at the cytoskeleton. Results: This review examines possible therapeutic intervention in NTIS in patients with cancer in terms of T4 reduction and T3 support. Evidence also exists that rT3 may support cancer. Conclusions: Prospective study is proposed of pharmacological reduction of normal or elevated T4 in cancer-associated NTIS. We also support investigation of normally circulating levels of T3 in such patients. PMID- 29409048 TI - The public health evidence-base on novel psychoactive substance use: scoping review with narrative synthesis of selected bodies of evidence. AB - Background: This review aimed to address what was known about the public health burden associated with novel psychoactive substances (NPS) use, and the effectiveness of responses targeting NPS use and/or associated problems. Methods: Relevant literature was identified through a range of searches covering the period from January 2006 to June 2016. Data synthesis was undertaken in three stages. Firstly we mapped the evidence available in order to characterize the literature according to a set of analytic categories developed a priori. Secondly, we identified evidence gaps from a set of a priori research questions. Finally, we then undertook a narrative synthesis of selected bodies of evidence, interpreting data using a conceptual framework specifically designed for use in this review. Results: A total of 995 articles were included in the scoping review with the majority being case reports/series on individual level adverse effects due to NPS use. We synthesized UK data from 29 surveys and 7 qualitative studies, and international data in 10 systematic reviews on harms associated with NPS use, and 17 evaluations of policy responses. We found little data on risk factors, harms associated with long-term NPS use, and interventions. Conclusion: In all cases we found the available evidence to be at an early stage of development. PMID- 29409049 TI - Theory and practice of electron diffraction from single atoms and extended objects using an EMPAD. AB - What does the diffraction pattern from a single atom look like? How does it differ from the scattering from long-range potential? With the development of new high-dynamic range pixel array detectors to measure the complete momentum distribution, these questions have immediate relevance for designing and understanding momentum-resolved imaging modes. We explore the asymptotic limits of long-range and short-range potentials. We use a simple quantum mechanical model to explain the general and asymptotic limits for the probability distribution in both real and reciprocal space. Features in the scattering potential much larger than the probe size cause the bright field (BF) disk to deflect uniformly, while features much smaller than the probe size, instead of a deflection, cause a redistribution of intensity within the BF disk. Because long range and short-range features are encoded differently in the diffraction pattern, it is possible to separate their contributions in differential phase contrast (DPC) or center-of-mass (CoM) imaging. The shape profiles for atomic resolution CoM imaging are dominated by the shape of the probe gradient and not the highly singular atomic potentials or their local fields. Instead, only the peak height shows an atomic number sensitivity, whose precise dependence is determined by the convergence angle. At lower convergence angles, the contrast oscillates with increasing atomic number, similar to BF imaging. The range of collection angles impacts DPC and CoM imaging differently, with CoM being more sensitive to the upper cutoff limit, while DPC is more sensitive to the lower cutoff. PMID- 29409050 TI - Small Heterodimer Partner Deficiency Increases Inflammatory Liver Injury Through C-X-C motif chemokine ligand 2-Driven Neutrophil Recruitment in Mice. AB - Although detailed pathophysiological mechanisms of fulminant hepatitis remain elusive, immune cell recruitment with excessive cytokine production is a well recognized hallmark of the disease. We determined the function of orphan nuclear receptor small heterodimer partner (SHP) in concanavalin A (ConA)-induced hepatitis model. Male C57BL/6 J mice were injected intravenously with either a lethal dose (25 mg/kg) or a sub-lethal dose (15 mg/kg) of ConA. For the C-X-C motif chemokine ligand (CXCL) 2 neutralization study, mice were intravenously administered anti-mouse CXCL2 antibody (100 MUg/mouse). Thirty-six hours following lethal dose of ConA administration, 47% wild type (WT) mice were alive, whereas >85% of Shp knockout (KO) were dead. Shp KO mice were highly susceptible to ConA-induced liver injury and exhibited increased liver necrosis upon sub lethal dose of ConA administration. FACS analysis and immunohistochemical staining showed significantly higher neutrophil infiltration in Shp KO mice, as compared with WT mice. We found that also in the WT situation, Shp expression gradually decreased, while Cxcl2 expression increased until 6 h, and vice versa at 24 h upon ConA-treatment, indicating an inverse correlation between Shp and Cxcl2 expression during ConA-induced hepatitis. Furthermore, in vivo neutralization of CXCL2 with neutralizing antibody reduces ConA-induced plasma ALT and AST levels, hepatocyte death and neutrophil infiltration in Shp KO mice. Collectively, these results confirm that lacking of SHP results in CXCL2 dependent neutrophil infiltration in ConA-induced liver damage. SHP plays a protective, anti-inflammatory role in liver during acute liver inflammation. PMID- 29409052 TI - A heart-stopping diagnosis. PMID- 29409051 TI - Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients. AB - Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy. PMID- 29409053 TI - CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications. AB - Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC 0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed. Results: We found that GDC-0575 abrogated DNA damage induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. Conclusion: We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting. PMID- 29409054 TI - Connection Between BMI-Related Plasma Metabolite Profile and Gut Microbiota. AB - Context: Emerging evidence has related the gut microbiome and circulating metabolites to human obesity. Gut microbiota is responsible for several metabolic functions, and altered plasma metabolome might reflect differences in the gut microbiome. Objective: To identify a plasma metabolite profile associated with body mass index (BMI) in a general population and investigate whether such metabolite profile is associated with distinct composition of the gut microbiota. Design: Targeted profiling of 48 plasma metabolites was performed in a population of 920 Swedish adults (mean age, 39 years; 53% women) from the ongoing Malmo Offspring Study using targeted liquid chromatography-mass spectrometry. Gut microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region) in fecal samples of 674 study participants. Results: BMI was associated with 19 metabolites (P < 0.001 for all), of which glutamate provided the strongest direct association (P = 5.2e-53). By orthogonal partial least squares regression, a metabolite principal component predictive of BMI was constructed (PCBMI). In addition to glutamate, PCBMI was dominated by branched-chain amino acids (BCAAs) and related metabolites. Four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) were associated with both BMI and PCBMI (P < 8.0e-4 for all). When simultaneously regressing PCBMI and metabolite-associated gut bacteria against BMI, only PCBMI remained statistically significant. Conclusions: We discovered associations between four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) and BMI-predictive plasma metabolites, including glutamate and BCAAs. Thus, these metabolites could be mediators between gut microbiota and obesity, pointing to potential future opportunities for targeting the gut microbiota in prevention of obesity. PMID- 29409055 TI - Effectiveness of additional lead shielding to protect staff from scattering radiation during endoscopic retrograde cholangiopancreatography procedures. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is often complex and involves long fluoroscopic times, with significant radiation exposure to medical staff. We investigated protective effects of an additional attached lead shielding device. The lead shielding device covered with the X-ray tube table (0.125 mm lead equivalent) during ERCP procedures. Fluoroscopy scatter radiation, with or without the lead shielding device, was measured using an acrylic phantom and a radiation survey meter. Measurements (25 points) were made at 50 cm intervals, at both 90 and 150 cm above the floor. We created radiation maps, with and without the additional lead shielding device. Moreover, we monitored annual staff exposure to radiation, before and after inclusion of the shielding device. Without additional shielding, exposure doses at the physician's position, 90 and 150 cm above the floor, were 1940 and 4040 (MUSv/h) respectively. In contrast, with the shielding device, corresponding exposures were 270 and 450 (MUSv/h) at 90 and 150 cm, respectively. Scattered radiation was decreased by 86.1% at 90 cm or 88.9% at 150 cm. However, with additional lead shielding in the middle, rather than hung over the operating table, scattered radiation was decreased by only ~10%. The staff's annual dose equivalents (DEs) were 12.2-29.8 mSv/year without and 3.8-8.4 mSv/year with lead shielding. With lead shielding, dose equivalent values for the staff were decreased by 41.0-76.5%. Thus, with additional lead shielding, properly used, scattered radiation would be decreased by ~90%, thus decreasing exposure doses to medical staff during ERCPs. PMID- 29409057 TI - Endothelial shear stress 5 years after implantation of a coronary bioresorbable scaffold. AB - Aims: As a sine qua non for arterial wall physiology, local hemodynamic forces such as endothelial shear stress (ESS) may influence long-term vessel changes as bioabsorbable scaffolds dissolve. The aim of this study was to perform serial computational fluid dynamic (CFD) simulations to examine immediate and long-term haemodynamic and vascular changes following bioresorbable scaffold placement. Methods and results: Coronary arterial models with long-term serial assessment (baseline and 5 years) were reconstructed through fusion of intravascular optical coherence tomography and angiography. Pulsatile non-Newtonian CFD simulations were performed to calculate the ESS and relative blood viscosity. Time-averaged, systolic, and diastolic results were compared between follow-ups. Seven patients (seven lesions) were included in this analysis. A marked heterogeneity in ESS and localised regions of high blood viscosity were observed post-implantation. Percent vessel area exposed to low averaged ESS (<1 Pa) significantly decreased over 5 years (15.92% vs. 4.99%, P < 0.0001) whereas moderate (1-7 Pa) and high ESS (>7 Pa) did not significantly change (moderate ESS: 76.93% vs. 80.7%, P = 0.546; high ESS: 7.15% vs. 14.31%, P = 0.281), leading to higher ESS at follow up. A positive correlation was observed between baseline ESS and change in lumen area at 5 years (P < 0.0001). Maximum blood viscosity significantly decreased over 5 years (4.30 +/- 1.54 vs. 3.21+/- 0.57, P = 0.028). Conclusion: Immediately after scaffold implantation, coronary arteries demonstrate an alternans of extremely low and high ESS values and localized areas of high blood viscosity. These initial local haemodynamic disturbances may trigger fibrin deposition and thrombosis. Also, low ESS can promote neointimal hyperplasia, but may also contribute to appropriate scaffold healing with normalisation of ESS and reduction in peak blood viscosity by 5 years. PMID- 29409056 TI - Short-Term Blood Pressure Responses to Ambient Fine Particulate Matter Exposures at the Extremes of Global Air Pollution Concentrations. AB - BACKGROUND: Fine particulate matter (PM2.5) air pollution is a leading cause of global cardiovascular mortality. A key mechanism may be PM2.5-induced blood pressure (BP) elevations. Whether consistent prohypertensive responses persist across the breadth of worldwide pollution concentrations has never been investigated. METHODS: We evaluated the hemodynamic impact of short-term exposures to ambient PM2.5 in harmonized studies of healthy normotensive adults (4 BP measurements per participant) living in both a highly polluted (Beijing) and clean (Michigan) location. RESULTS: Prior 7-day outdoor-ambient and 24-hour personal-level PM2.5 concentration averages were much higher in Beijing (86.7 +/- 52.1 and 52.4 +/- 79.2 ug/m3) compared to Michigan (9.1 +/- 1.8 and 12.2 +/- 17.0 ug/m3). In Beijing (n = 73), increased outdoor-ambient exposures (per 10 ug/m3) during the prior 1-7 days were associated with significant elevations in diastolic BP (0.15-0.17 mm Hg). In overweight adults (body mass index >=25 kg/m2), significant increases in both systolic (0.34-0.44 mm Hg) and diastolic (0.22-0.66 mm Hg) BP levels were observed. Prior 24-hour personal-level exposures also significantly increased BP (0.41/0.61 mm Hg) in overweight participants. Conversely, low PM2.5 concentrations in Michigan (n = 50), on average within Air Quality Guidelines, were not associated with BP elevations. CONCLUSIONS: Our findings demonstrate that short-term exposures to ambient PM2.5 in a highly polluted environment can promote elevations in BP even among healthy adults. The fact that no adverse hemodynamic responses were observed in a clean location supports the key public health importance of international efforts to improve air quality as part of the global battle against hypertension. PMID- 29409058 TI - Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus. AB - Context: The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and caspase-8, a marker of apoptotic activity, have both been implicated in beta-cell function. Objective: To investigate the associations between sleep duration and plasma caspase-8 and incident DM, respectively. Design: Prospective cohort study. Setting: The Malmo Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmo, Sweden. Participants: A total of 4023 individuals from the MDC Study aged 45 to 68 years at baseline without a history of prevalent DM and with information on habitual sleep duration. Main Outcomes: Incident DM. Results: Mean follow-up time was 17.8 years. Sleep duration was the only behavioral variable significantly associated with plasma caspase-8. Plasma caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form [hazard ratio (HR) = 1.24; 95% confidence interval (CI), 1.13 to 1.36] and when dichotomized into high (quartile 4) (HR = 1.44; 95% CI, 1.19 to 1.74) compared with low (quartiles 1 to 3) concentrations. Caspase-8 interacted with sleep duration; compared with individuals who had 7 to 8 hours of sleep and low plasma caspase-8, those with high plasma caspase-8 and sleep duration <6 hours (HR = 3.54; 95% CI, 2.12 to 5.90), 6 to 7 hours (HR = 1.81; 95% CI, 1.24 to 2.65), and 8 to 9 hours (HR = 1.54; 95% CI, 1.09 to 2.18) were at significantly increased risks of incident DM. Conclusions: Sleep duration is associated with plasma caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of caspase-8. PMID- 29409059 TI - Darwin Assembly: fast, efficient, multi-site bespoke mutagenesis. AB - Engineering proteins for designer functions and biotechnological applications almost invariably requires (or at least benefits from) multiple mutations to non contiguous residues. Several methods for multiple site-directed mutagenesis exist, but there remains a need for fast and simple methods to efficiently introduce such mutations - particularly for generating large, high quality libraries for directed evolution. Here, we present Darwin Assembly, which can deliver high quality libraries of >108 transformants, targeting multiple (>10) distal sites with minimal wild-type contamination (<0.25% of total population) and which takes a single working day from purified plasmid to library transformation. We demonstrate its efficacy with whole gene codon reassignment of chloramphenicol acetyl transferase, mutating 19 codons in a single reaction in KOD DNA polymerase and generating high quality, multiple-site libraries in T7 RNA polymerase and Tgo DNA polymerase. Darwin Assembly uses commercially available enzymes, can be readily automated, and offers a cost-effective route to highly complex and customizable library generation. PMID- 29409060 TI - Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism. AB - Context: Pheochromocytomas (PCCs) are tumors that are derived from the chromaffin cells of the adrenal medulla. Extra-adrenal PCCs called paragangliomas (PGLs) are derived from the sympathetic and parasympathetic chain ganglia. PCCs secrete catecholamines, which cause hypertension and have adverse cardiovascular consequences as a result of catecholamine excess. PGLs may or may not produce catecholamines depending on their genetic type and anatomical location. The most worrisome aspect of these tumors is their ability to become aggressive and metastasize; there are no known cures for metastasized PGLs. Methods: Original articles and reviews indexed in PubMed were identified by querying with specific PCC/PGL- and Krebs cycle pathway-related terms. Additional references were selected through the in-depth analysis of the relevant publications. Results: We primarily discuss Krebs cycle mutations that can be instrumental in helping investigators identify key biological pathways and molecules that may serve as biomarkers of or treatment targets for PCC/PGL. Conclusion: The mainstay of treatment of patients with PCC/PGLs is surgical. However, the tide may be turning with the discovery of new genes associated with PCC/PGLs that may shed light on oncometabolites used by these tumors. PMID- 29409062 TI - Novel overlapping subgraph clustering for the detection of antigen epitopes. AB - Motivation: Antigens that contain overlapping epitopes have been occasionally reported. As current algorithms mainly take a one-antigen-one-epitope approach to the prediction of epitopes, they are not capable of detecting these multiple and overlapping epitopes accurately, or even those multiple and separated epitopes existing in some other antigens. Results: We introduce a novel subgraph clustering algorithm for more accurate detection of epitopes. This algorithm takes graph partitions as seeds, and expands the seeds to merge overlapping subgraphs based on the term frequency-inverse document frequency (TF-IDF) featured similarity. Then, the merged subgraphs are each classified as an epitope or non-epitope. Tests of our algorithm were conducted on three newly collected datasets of antigens. In the first dataset, each antigen contains only a single epitope; in the second, each antigen contains only multiple and separated epitopes; and in the third, each antigen contains overlapping epitopes. The prediction performance of our algorithm is significantly better than the state-of art methods. The lifts of the averaged f-scores on top of the best existing methods are 60, 75 and 22% for the single epitope detection, the multiple and separated epitopes detection, and the overlapping epitopes detection, respectively. Availability and implementation: The source code is available at github.com/lzhlab/glep/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29409061 TI - Child labor and health: a systematic literature review of the impacts of child labor on child's health in low- and middle-income countries. AB - Objective: To summarize current evidence on the impacts of child labor on physical and mental health. Methods: We searched PubMed and ScienceDirect for studies that included participants aged 18 years or less, conducted in low- and middle-income countries (LMICs), and reported quantitative data. Two independent reviewers conducted data extraction and assessment of study quality. Results: A total of 25 studies were identified, the majority of which were cross-sectional. Child labor was found to be associated with a number of adverse health outcomes, including but not limited to poor growth, malnutrition, higher incidence of infectious and system-specific diseases, behavioral and emotional disorders, and decreased coping efficacy. Quality of included studies was rated as fair to good. Conclusion and recommendations: Child labor remains a major public health concern in LMICs, being associated with adverse physical and mental health outcomes. Current efforts against child labor need to be revisited, at least in LMICs. Further studies following a longitudinal design, and using common methods to assess the health impact of child labor in different country contexts would inform policy making. PMID- 29409063 TI - Recovery of the Paracoccidioides brasiliensis virulence after animal passage promotes changes in the antioxidant repertoire of the fungus. AB - Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis (PCM), a cause of disease in healthy and immunocompromised persons in Latin America. The infection begins after inhalation of the fungal propagules and their thermo dimorphic shift to yeast form. The development of the disease depends on factors associated with the host immune response and the infectious agent's characteristics, especially virulence. The oxidative stress response is an important virulence attribute in several fungi. In this study, we assessed the enzymatic repertoire of responses to oxidative stress in the Pb18 isolate with different degrees of virulence. The virulence of attenuated Pb18 (aPb18) strain was recovered after several animal passages. Virulent strain (vPb18) showed an effective fungal oxidative stress response and several genes involved in response to oxidative stress were up-regulated in this isolate. These genes expressed the same profile when we recovered the phenotypic virulence in attenuated strain aPb18. Our study demonstrated that attenuated P. brasiliensis recovered their virulence after serial animal passages (vPb18), and this process positively modulated the fungus's antioxidant repertoire. PMID- 29409064 TI - Randomized Trial of CPAP and Vardenafil on Erectile and Arterial Function in Men With Obstructive Sleep Apnea and Erectile Dysfunction. AB - Context: Erectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first line therapy for erectile dysfunction (ED), but may worsen OSA. Objective: To assess the effects of CPAP and vardenafil on ED. Design: Sixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design. Main Outcome Measures: International Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep disordered breathing. Results: CPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality. Conclusion: CPAP improves overall sexual satisfaction, sleep related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life. PMID- 29409066 TI - Extensor Mechanism Injury in the Pediatric Population-A Clinical Review. AB - The extensor mechanism of the knee-consisting of the four muscles of the quadriceps, the quadriceps tendon, the patella, and the patellar ligament-is essential for lower extremity function during both standing and ambulation. The presence of articular cartilage and growing physes in the pediatric knee, coupled with the generation of significant tensile force, creates an opportunity for pathology unique to the pediatric population.Tibial tubercle fractures and patella injuries are quite rare, and even pediatric-trained orthopaedic surgeons may not be exposed to these injuries on a regular basis. It is the intent of this article to discuss the current literature regarding the mechanism of injury, diagnostic workup, classification, indications for surgical versus non-surgical management, and techniques for operative management for both tibial tubercle and patella (transverse and sleeve) fractures. PMID- 29409065 TI - An unexpected RNA distal interaction mode found in an essential region of the hepatitis C virus genome. AB - The 3'X tail is a functionally essential 98-nt sequence located at the 3'-end of the hepatitis C virus (HCV) RNA genome. The domain contains two absolutely conserved dimer linkage sequence (DLS) and k nucleotide segments involved in viral RNA dimerization and in a distal base-pairing interaction with stem-loop 5BSL3.2, respectively. We have previously shown that domain 3'X forms an elongated structure comprising two coaxially stacked SL1' and SL2' stem-loops. This conformation favors RNA dimerization by exposing a palindromic DLS segment in an apical loop, but buries in the upper stem of hairpin SL2' the k nucleotides involved in the distal contact with 5BSL3.2. Using nuclear magnetic resonance spectroscopy and gel electrophoresis experiments, here we show that the establishment of the complex between domain 3'X and stem-loop 5BSL3.2 only requires a rearrangement of the nucleotides forming the upper region of subdomain SL2'. The results indicate that the interaction does not occur through a canonical kissing loop mechanism involving the unpaired nucleotides of two terminal loops, but rather involves a base-paired stem and an apical loop and may result in a kissing three-way junction. On the basis of this information we suggest how the 3'X tail switches between monomer, homodimer and heterodimer states to regulate the HCV viral cycle. PMID- 29409067 TI - Meta-analysis of randomized controlled trials challenging the usefulness of purgative preparation before small-bowel video capsule endoscopy. AB - BACKGROUND: The usefulness of purgative preparation before small-bowel video capsule endoscopy is controversial. We aimed to examine the effect of purgative preparation on small-bowel video capsule endoscopy outcomes. METHODS: We performed literature searches in MEDLINE and the Cochrane library for randomized controlled trials evaluating the effect of purgative preparation (polyethylene glycol, sodium phosphate, others) vs. clear-liquid diet/fasting in patients undergoing small-bowel capsule endoscopy. Meta-analysis outcomes included the examination's diagnostic yield, small-bowel mucosal visualization quality, the examination's completion rate, and gastric and small-bowel transit times. The effect size on study outcomes was calculated using a fixed- or random-effect model, as appropriate, and is shown as the risk ratio (RR) with 95 % confidence interval (CI). RESULTS: We identified 12 eligible trials with 17 sets of data including 1221 subjects. Significant heterogeneity was detected with no evidence of publication bias. As compared with clear-liquid diet, purgative bowel preparation did not increase capsule endoscopy diagnostic yield (RR 1.17 [95 %CI 0.97 to 1.40]; P = 0.11). Neither the small-bowel mucosal visualization quality (RR 1.14 [95 %CI 0.96 to 1.35]; P = 0.15) nor completion rate for the examination (RR 0.99 [95 %CI 0.95 to 1.04]; P = 0.76) significantly improved after purgative preparation. Purgatives also had no effect on video capsule endoscopy gastric and small-bowel transit times. CONCLUSIONS: Our analysis challenges the usefulness of purgative preparation for improving the diagnostic yield of small-bowel video capsule endoscopy and the quality of small-bowel mucosal visualization. PMID- 29409068 TI - Musculoskeletal Imaging in Children: Prologue. PMID- 29409069 TI - Percutaneous Image-Guided Treatment of Benign Musculoskeletal Tumors in Children. AB - Percutaneous ablation of benign musculoskeletal tumors in children has become an area of significant clinical growth over the last decade. With growing research interest, the technologies available and techniques used are becoming increasingly safe and effective. We review some of the more common ablation technologies and their utility in several common benign bone and soft tissue tumors that occur in children and young adults. PMID- 29409070 TI - Orthopaedic Fixation Devices Used in Children: A Radiologist's Guide. AB - Fractures are common in children with some requiring surgical reduction and fixation to maintain anatomical alignment. Although various surgical techniques and principles are shared between children and adults, certain unique considerations in children can influence the surgical approach and device selection. In particular, for skeletally immature children, it is of utmost importance to protect certain critical open growth plates because permanent injury can produce severe growth disturbances. The often robust healing response and potential limited patient compliance can also influence the treatment algorithm and decision making. Commonly encountered orthopaedic fixation devices, including screws, intramedullary devices, and plates, are reviewed with an emphasis on their mechanism and application in children. Additional miscellaneous devices that are commonly used to treat malalignment and guide bone growth including epiphysiodesis plates, proximal femur osteotomy plates, and spinal magnetic growing rods are also reviewed. The goal of this article is to provide a basic understanding of the principles and mechanisms of different types of pediatric orthopaedic devices and thereby improve the radiologist's diagnostic confidence and allow better anticipation of complications. PMID- 29409071 TI - Nuclear Medicine Applications in Pediatric Musculoskeletal Diseases: The Added Value of Hybrid Imaging. AB - The introduction of diphosphonates in the 1970s revolutionized not only nuclear medicine but musculoskeletal imaging as well, providing functional assessment of entities such as osteomyelitis, trauma, and osseous metastatic disease. Although rarely the first-line imaging modality used today, nuclear medicine procedures continue to play a pivotal role in the evaluation of musculoskeletal diseases in children, providing whole-body assessment of disease involvement. More recently, the introduction of technologies such as single-photon emission computed tomography/computed tomography (SPECT/CT), as well as newer positron-emitting tracers such as 18fluorine-fluorodeoxyglucose and sodium 18F-fluorine, particularly when combined with CT (positron emission tomography/CT), have injected new life into the older established techniques and expanded the application of nuclear medicine imaging into new arenas. This article discusses the utility of standard nuclear medicine procedures as they apply to children with musculoskeletal disorders, focusing on the added value of and indications for SPECT/CT. Subsequently, we discuss the expanding role of positron-emitting agents in infection, trauma, and for the diagnosis, staging, and therapeutic response monitoring of children with malignant bone and soft tissue tumors. Differences between disease processes encountered in children as compared with adults are discussed; developmental variants that can, but should not, be confused with disease are illustrated. The need for pediatric-specific protocols is addressed. PMID- 29409072 TI - The Acutely Limping Preschool and School-Age Child: An Imaging Perspective. AB - Acute limp in a child presents a diagnostic conundrum and can result from a variety of causes. The underlying etiology is often referable to the hip, but the spine, abdomen, pelvis, or knee can be alternatively implicated. An adequate clinical history and satisfactory physical examination are often difficult in younger children. Consequently, there is disproportionate reliance on imaging to arrive at the correct diagnosis. The potential for rapid clinical deterioration and long-term sequelae is a risk with some of the conditions presenting with acute hip (septic hip, osteomyelitis). This review article describes the imaging appearance of common etiologies for acute limp in the ambulatory preschool (1-5 years) and school-age child (5-12 years). The ultimate goal is to familiarize the interpreting radiologist with the imaging appearance of specific clinical entities that lead to acute limp while providing a readily accessible resource on how to image the patient most appropriately and judiciously. PMID- 29409073 TI - Pediatric Osteochondral Lesions. AB - Osteochondral lesions are common in children and may arise from a variety of etiologies. Although they most frequently occur in the knee, other joints may be involved including the ankle and elbow. We describe the typical imaging appearance of osteochondral lesions with a focus on radiographs and magnetic resonance imaging. Assessment of the stability of these lesions is of paramount importance in directing management. As such, we describe staging schemes as well as imaging features differentiating stable from unstable lesions. Finally, we briefly discuss management strategies as they correlate to imaging findings. PMID- 29409074 TI - Skeletal Dysplasias: Radiologic Approach with Common and Notable Entities. AB - Skeletal dysplasia is a heterogeneous group of abnormalities affecting growth and development of bone and cartilage characterized by disproportionate shortening of the limbs and/or spine. A systematic radiographic approach combined with pertinent clinical details can help guide specific genetic testing and treatment. We provide a discussion and examples of a few common and notable skeletal dysplasias to help familiarize general, pediatric, and musculoskeletal radiologists who do not commonly encounter children with these entities in their daily practices. PMID- 29409075 TI - The Pediatric Patella: Normal Development, Anatomical Variants and Malformations, Stability, Imaging, and Injury Patterns. AB - We discuss the pediatric patella, with an emphasis on diagnostic imaging. Topics include normal patellar development, anatomical variants and their physiologic significance, genetic syndromes that alter the appearance of the patella, physiology of patellar tracking and stability, patellofemoral instability, and injury patterns and classification. Recognition of appropriate development on imaging prevents diagnostic error and unnecessary evaluation. Knowledge of the pertinent features of syndromes associated with morphological patellar abnormalities can aid in generating a succinct and relevant differential diagnosis. In patellofemoral instability, the patient's baseline anatomy, factors that predispose to instability, and the specific injuries that occur as a result are critical considerations for determining the course of treatment. Patellar sleeve fractures are unique to pediatric patients, and timely identification is critical to achieving an optimal treatment outcome. PMID- 29409076 TI - The Primary Physis. AB - The primary physis is responsible for long bone growth in children and adolescents. Injury and physiologic or metabolic stress to the primary physis present unique radiologic findings that are important for radiologists to recognize and diagnose. Appreciation of the anatomy and histology of the primary physis forms the basis for understanding the imaging findings associated with pathologic conditions affecting the primary physis. Salter-Harris injuries, physeal bars, growth arrest lines, rickets, and focal periphyseal edema zones are common conditions with recognizable radiologic presentations. Proper diagnosis of these primary physeal conditions will aid in the treatment of affected pediatric patients. PMID- 29409077 TI - Ankle and Foot Injuries in the Young Athlete. AB - Injuries to the ankle and foot are common in the young athlete, especially with increasing participation and high levels of competitiveness in youth sports programs. Knowledge of the normal development of the foot and ankle is crucial to understand age-specific injury patterns because acute or chronic/repetitive stress to the developing skeleton results in injuries that differ from those seen in adults. Congenital abnormalities may also predispose children to increased risk of injury and pain. Radiologists must be aware of these distinctions to diagnose and classify injuries correctly for optimum treatment. We describe common and unique foot and ankle injuries in the young athlete. Throughout the article we focus not only on imaging findings but also on the mechanism of injury. PMID- 29409078 TI - Osteochondroses. AB - The osteochondroses are a group of disorders that affect the epiphysis or epiphyseal equivalent segments of the immature skeleton. These disorders are believed to be primarily the result of traumatic or vascular pathology, often in the setting of overuse, and are usually self-limited. Their imaging findings are based on the time of the study within the natural course of the disease process. Early findings may best be demonstrated by magnetic resonance imaging or may be recognized radiographically as sclerosis of the involved segment. Later disease demonstrates bone fragmentation and collapse, followed by healing where bone architecture is restored with variable reconstitution of the normal morphology. PMID- 29409079 TI - [Internal Medicine in Europe - One Joint Strategy for the Future?] PMID- 29409080 TI - [Prolonged Secondary Prevention After Venous Thromboembolism]. AB - Recent studies: Shortly after discontinuation of the oral anticoagulation (OAC) there is a 2- to 3 fold increase in VTE recurrences. The risk for recurrence is particularly high in VTE events that occurred without provoking risk factor, with minor provoking factors and in cases with persistent risk factors such as active cancer.Guidance document for the categorization of risk factors for VTE: A recent guidance document defined underlying risk factors for the occurrence of VTE and categorized them into three groups. Direct oral anticoagulants (DOACs): For long term secondary prevention, a reduced dosing regimen of DOACs was found to be effective with a low bleeding risk. Aspirin should no longer be used for secondary prevention of VTE because the efficacy to prevent recurrent events is lower, while there was no difference in the risk of major bleeding.A Traffic light system helps to select the appropriate duration of anticoagulation. Patients are risk stratified into three groups according to their presumed risk of recurrence. For the majority of the patients this leads to a clear decision to stop or continue OAC (green or red traffic light, respectively). In case of prolonged anticoagulation, the use of a reduced dose DOAC regimen may be considered in view of risk-benefit-balancing. PMID- 29409081 TI - [Conn's syndrome - more than just aldosterone excess?] AB - ?? Englischen Text bitte erganzen! ??. PMID- 29409082 TI - [Orophagyngeal Dysphagia in Older Persons - Evaluation and Therapeutic Options]. AB - The prevalence of oropharyngeal dysphagia in older persons is high. Because it is frequently undetected, screening tests should be applied in risk groups. If the screening test is positive or typical risk factors are present, an instrumental assessment should be utilized. Objective diagnostic tools such as endoscopic evaluation and videofluoroscopy allow the description of the individual dysphagia pattern, which is the basis for an individualized treatment. The endoscopic evaluation of swallowing is increasingly used because it includes several advantages. Potential therapeutic strategies are multifaceted. The evidence for the effectiveness of adaptive, compensatory and rehabilitative strategies is growing, supporting the evolution of dysphagia therapy to an evidence based treatment. PMID- 29409083 TI - [Acute Promyelocytic Leukemia - A Rare, Life-Threatening Disease with High Healing Chance]. AB - The acute promyelocytic leukemia (APL) is a rare disease. However, if diagnosed early and treated immediately high cure rates can be achieved. Signs of hematopoietic insufficiency such as cytopenias or leucocytosis can be present at first presentation of the patients. Moreover, hemorrhagic diatheses due to coagulpathy are present in approximately 80 % of cases and contribute substatially to the high early death rate in APL patients, which has been reported as high as 30 % in population based studies. In case of initial suspicion of APL treatment with all-trans retinoic acid (ATRA) should be initated immediately to reduce the risk of fatal bleeding events and confirmation or exclusion of the PML-RARA transcript should not be awaited before start of ATRA treatment. While patients with a low or intermediate risk of relapse are treated with a combination of ATRA and arsenic trioxide (ATO), those with high risk of relapse still receive a combination regimen consisting of ATRA, anthracyclines and cytosine-arabinosid. However, treatment strategies are under clinical investigation aiming at reducing the administration of conventional chemotherapy in high risk APL patients. With the current treatment approaches cure rates of approximately 90 % of the patients with low or intermeditae risk APL can be achieved. Nevertheless, particularly the high initial death rate warrants further clinical and pathiobiologic studies to identify targets and means to decrease hemorrhagic complications in patients with APL. PMID- 29409084 TI - [Infectiological Rapid Tests in Practices and at Home]. AB - Bedside laboratory procedures so called "point of care testing - POCT" plays an emerging role in clinical routine practice. While glucose or urine protein screening has been established since a while, newer lateral flow assays (LFID), mostly as rapid diagnostic tests (RDT), play and upcoming role, as well as nucleic amplification based and micro carrier based systems. Hereby an accurate and precise diagnostic allows clinical decisions; in infectious diseases as well as other disciplines in medicine. All test are limited by sensitivity and specifity. Moreover, pre- and post-analytic handling also influences the test results. All results need to be assessed by a trained medical doctor. PMID- 29409085 TI - [Point-of-Care Sonography in Emergency and Intensive Care Medicine]. AB - The use of Point-of-care ultrasonography (POC Ultrasonography) is getting more and more important in the bedside care of patients, especially in emergency- and intensive care units. In addition to the focused sonography of the heart, lungs and abdomen, the POC Ultrasonography recently includes also cases in prehospital care. Increasingly special applications in intensive care, e.g. the assessment of weaning from mechanical ventilation or evaluation of the hemodynamics of a patient by means of sonographic control, gain meaning.The German Society for Internistic Intensive Care and Emergency Medicine e. V. (DGIIN), the German society for Ultrasound in Medicine e. V. (DEGUM) and the German Society of Cardiology e. V. (DGK) recently published a common recommendation for a training concept in POC Ultrasonography. The aim is quality assurance and accordingly the improvement of patient care in emergency- and intensive care. PMID- 29409086 TI - [Update Ventricular Tachycardia]. AB - Idiopathic ventricular tachycardia: Frequent monomorphic premature ventricular contractions or non-sustained ventricular tachycardia without underlying structural heart disease is not a rare condition and may cause significant symptoms. A subgroup of patients develops IVT-associated cardiomyopathy. Current ESC guidelines recommend primary catheter ablation in symptomatic patients with right ventricular outflow tract IVT. Catheter ablation is also recommended in symptomatic patients with a left ventricular outflow tract (or other rare) origin, if antiarrhythmic drugs are ineffective or not desired.Ventricular tachycardia associated with structural heart disease: Scar-associated ventricular arrhythmias may cause sudden cardiac death in a variety of heart diseases. While ICD implantation has been shown to reduce mortality, repetitive ICD shocks impact on survival and quality of life. In a recent meta-analysis, both amiodarone and catheter ablation reduce the incidence of recurrent ICD shocks. Discontinuation of amiodarone due to side effects is common. Current ESC guidelines recommend both strategies (class 1 indication). Catheter ablation is also recommended in drug-resistant VT or electrical storm. A totally subcutaneous ICD is a novel option in patients not requiring pacing. PMID- 29409087 TI - [Chronic Kidney Disease - Update 2018]. AB - : SGLT2-INHIBITION IN DIABETIC AND NON-DIABETIC KIDNEY DISEASE: The CANVAS Program Collaborative Group study confirmed nephroprotective actions by canagliflocin comparable to empagliflozin as published in the EMPA-REG Outcome study. Treatment with Liraglutide (LEADER study) also suggests nephroprotection via albuminuria reduction a decreased eGFR decline in subgroups and depending on stages of diabetic nephropathy. KDIGO CKD-MBD GUIDELINE UPDATE 2017: In July 2017, an update of the KDIGO (Kidney Disease: Improving Global Outcomes) 2009 guideline on diagnostic and treatment chronic kidney disease - mineral and bone disorders (CKD-MBD) was published. Changes focused on the judgement of bone mineral density measurements, therapy of hyperphosphatemia and secondary hyperparathyroidism in CKD patients not on dialysis and on advising caution concerning excess calcium exposition. A NOVEL PARENTERAL CALCIMIMETIC: Two phase 3 studies on the use of a new parenteral calcimimetic drug (etelcalcitide) were published in 2017. PMID- 29409088 TI - [News about COPD - the Current GOLD Recommendations 2017]. PMID- 29409089 TI - [Psoriatic Arthritis - Update 2018]. PMID- 29409090 TI - ? PMID- 29409091 TI - [60-Year Old Woman with Dyspnea in Cardiogenic Shock]. PMID- 29409093 TI - ? PMID- 29409092 TI - [Gallop in the Routineergometrie: Only Chore or Diagnostic Challenge?] AB - ANAMNESIS: A 47-year-old recreational sportsman showed in a routine ergometry polymorphic ventricular extrasystoles with good physical performance. INVESTIGATIONS: In resting ECG impressed ventricular extrasystoles (VES) predominantly right-hand-block-like with superior axis, a long-term ECG yielded up to 100 VES per hour. Echocardiographically imposing 4 - 5 trabeculae, feathered, reticular structures apically in the left and lower in the right ventricle. The cardio-MRT revealed a wall dilation laterally and apically with increased trabecularization, no late enhancement. DIAGNOSIS: mild form of NCCM, currently asymptomatic THERAPY: Cardiac insufficiency treatment is based on the guidelines, including ICD-CRT therapy. We recommended ramipril and decided against transvenous ICD implantation. At the time of the presentation, subcutaneous ICD systems were not available. Family screening and genotyping of affected persons are recommended. CONCLUSION: Most patients have cardiac insufficiency, rhythmic symptoms, or thrombi formation in the noncompact portions of the left ventricular wall. Ventricular tachycardias are frequent and sudden cardiac death is the leading cause of death. Arrythmias are accessible to medication or ablation treatment. Endurance sports lead to favorable adaptations of the cardiovascular system in spite of increased risk of sudden cardiac death. The example shows that asymptomatic boundary findings also exist. Whether a sporting activity has a protective influence must be further investigated. PMID- 29409094 TI - ? PMID- 29409095 TI - [From the History of the German Society of Internal Medicine (DGIM) - Part 2: The DGIM in the Post-War Period]. AB - Although times were difficult in 1947/48 - with war damage, travel restrictions and the East-West conflict - the German Society for Internal Medicine not only managed to re-organise itself but also hosted its first scientific congress in that year. The DGIM members Franz Volhard and Paul Martini, who rather disapproved of the Nazi regime, played a decisive role in this process. However, a critical discussion of the NS medical crimes, which occurred just a few years ago, remained the exception. It is interesting to note that members who were persecuted by the NS regime were nevertheless willing to attend a congress that obviously provided a forum for the protagonists of the Nazi era.This work presents - for the first time - an overview of the specific conditions of the reconstitution of the German Society for Internal Medicine and enriches our knowledge about the actions of the medical societies in the years between the fall of the Nazi regime and the founding of the two German states. PMID- 29409096 TI - Managing the Thick Skin in Facial Plastic Surgery. PMID- 29409097 TI - Integrated Management of the Thick-Skinned Rhinoplasty Patient. AB - Patients with thick skin are a challenge in facial plastic surgery. Rhinoplasty is still the most frequently performed facial plastic procedure worldwide and it becomes very difficult to obtain optimal consistent results in these patients. A systematic presurgical skin evaluation is performed dividing skin into type I-III depending on the elasticity, oiliness, presence of skin alterations, size of skin pores, and laxity. Depending on the skin type, presurgical, surgical, and postsurgical management of the epidermis and dermis is defined. Preconditioning and treating thick skin can improve postsurgical results and reduce postsurgical unwanted results. PMID- 29409098 TI - Use of 5-Fluorouracil for Management of the Thick-Skinned Nose. AB - Patients with a thick nasal skin and soft tissue envelope can have unpredictable results and irregular scarring after rhinoplasty surgery. These patients typically have sebaceous tissue over the nasal tip and are particularly susceptible to soft tissue polly beak formation and excess scar tissue in the radix, tip, and septum. Targeted injections of 5-fluorouracil alone or mixed with low concentrations of steroid can be useful to prevent and treat excess postoperative scar tissue deposition. Ideally, four to six injections are performed every 1 to 4 weeks beginning 1 week postoperatively. The injections are most beneficial when performed within the first 3 months after surgery. Even a single injection may improve outcomes with minimal side effects. PMID- 29409099 TI - Reducing Periorbital Edema and Ecchymosis after Rhinoplasty: Literature Review and Personal Approach. AB - Postoperative periorbital edema and ecchymosis are most bothersome to rhinoplasty patients. The degree of swelling and bruising is influenced by several factors, and numerous prophylactic and therapeutic measures have been described in the literature. This article reviews the current literature and concludes with the author's suggestions on how to best minimize postoperative periorbital edema and ecchymosis. PMID- 29409101 TI - Surgical Tips for the Management of the Wide Nasal Base. AB - Alar base reduction (ABR) was first described by Weir in 1892, but continues to be a controversial topic in rhinoplasty in terms of optimal techniques. The authors describe the techniques for ABR including internal, external and combined ABR, flare excisions, and alar hooding reductions. The techniques described have resulted in consistent outcomes with acceptable scarring and high patient satisfaction. PMID- 29409100 TI - Surgical Management of the Thick-Skinned Nose. AB - When executed properly, open structure rhinoplasty can dramatically improve the consistency, durability, and quality of the cosmetic surgical outcome. Moreover, in expert hands, dramatic transformations in skeletal architecture can be accomplished with minimal risk and unparalleled control, all while preserving nasal airway function. While skeletal enhancements have become increasingly more controlled and precise, the outer skin-soft tissue envelope (SSTE) often presents a formidable obstacle to a satisfactory cosmetic result. In noses with unusually thick skin, excessive skin volume and characteristically hostile healing responses frequently combine to obscure or sometimes even negate cosmetic skeletal modifications and taint the surgical outcome. For this challenging patient subgroup, care must be taken to optimize the SSTE using a graduated treatment strategy directed at minimizing skin thickness and controlling unfavorable healing responses. When appropriate efforts are implemented to manage thick nasal skin, cosmetic outcomes are often substantially improved, sometimes even negating the ill-effects of thick skin altogether. PMID- 29409102 TI - Management of the Heavy Brows: Long-Term Surgical Options. AB - One of the first signs of aging belongs to the upper third of the face. With the aging process, mestizo facial features become more prominent. The thicker skin soft tissue envelope (S-STE) has a tendency to sag more, hooding of the eyelids tends to be more pronounced, and there is a tendency for eyebrows to droop, specifically the tail of the brows, because of the loss of support. A "tired" or "sad" look implies that the complex eyebrow-upper eyelid is showing one or more of these signs. Different surgical as well as non-surgical techniques have been described to treat this area, every one of them aiming at making the patient look rested and natural. The objective of this study is to describe a technique for endoscopic brow lifting, consisting on minimal incisions, a biplanar dissection, and a different fixation technique designed for helping reshape the brow. This particular surgical technique has shown the advantage of being minimally invasive and effective. Careful analysis of the patient should be made to decide both the technique and the changes desired by the patient and the surgeon. The authors believe the technique described is another option for approaching and fixating the heavy eyebrows in mestizo patients. PMID- 29409103 TI - Upper Lid Thick Skin Blepharoplasty. AB - While many of the basic tenants of upper lid blepharoplasty remain constant regardless of skin type, the thick-skinned eyelid patient requires special consideration. The brow may be naturally lower in the thick-skinned patient. These patients are more prone to having the brow pulled downward while attempting to remove redundant skin. There may also be more fat in the medial and central compartments. There may be fat in a lateral compartment overlying the lacrimal gland. Patient's expectations for a deep lid sulcus and complete excision of redundant skin may not be possible. They are more prone to an observable scar, a small dog ear at the lateral wound edge, and prolonged postoperative lid edema. Patients with lifelong upper lid fullness must get some input from significant others because their upper face aesthetic will change. In these patients, the eyelid surgery is not a rejuvenation, but a creation. PMID- 29409104 TI - Managing the Lower Eyelid Complex in the Thick-Skinned Patient. AB - Thick skin presents a unique set of challenges within the realm of facial plastic surgery, and addressing the lower lid complex is no exception. There are several procedures for addressing the lower lids, the first and foremost being lower lid blepharoplasty. However, the remaining procedures combined with surgical techniques have exclusive implications in thick skin. Understanding the anatomy and various techniques that can be applied to thick skin can help achieve aesthetically more pleasing results in comparison to those of thin skin. As will be discussed in this article, patients with skin color of Fitzpatrick's grade III or higher have several characteristics associated with their skin, including thicker dermis as well as different patterns of aging, which have implications for addressing the lower lid complex. The senior author has extensive experience performing lower lid procedures and seeks to impart how best to understand and adapt for these differences to allow for the best aesthetic result. PMID- 29409105 TI - Surgical Approach to the Thick Nasolabial Folds, Jowls and Heavy Neck-How to Approach and Suspend the Facial Ligaments. AB - Patients with thick skin typically present with a redundant, baggy, lax skin envelope together with prominent nasolabial folds, jowls, and a heavy neck. Durable and natural-appearing rejuvenation is not possible unless the deformities are addressed adequately and harmoniously in these patients. Traditional superficial musculoaponeurotic system techniques do not include surgical release of the zygomatic cutaneous ligaments and repositioning of descendent malar fat pad, and may lead to an unbalanced, unnatural appearance and the lateral sweep phenomenon. Additional attempts to improve unopposed nasolabial folds such as fat grafting to malar region are more likely to result with a "stuffed" look, far from a natural and rejuvenated appearance, and must therefore be avoided. The facelift techniques including true release of the anchoring ligaments of the midface and allowing adequate repositioning of saggy tissues are ideal for these patients to obtain harmonious, natural result. Despite the extensive dissections, maximal release, and maximal lateral pull, additional maneuvers, e.g., platysmaplasty, subplatysmal fat removal, or partial resection of submandibular glands may be required for satisfying result in patients with heavy neck. In this article, the authors outline the relevant anatomy of the facial retaining ligaments and their implications to surgical management of patients with heavy skin are discussed. PMID- 29409106 TI - Cool Atmospheric Plasma (J-Plasma) and New Options for Facial Contouring and Skin Rejuvenation of the Heavy Face and Neck. AB - Treating patients with heavy or thick features comes with challenges not present in those patients lacking these physical characteristics. The authors report our experience with cool atmospheric plasma for facial contouring and skin rejuvenation of the heavy face and neck including rhinophyma. Cool atmospheric plasma is generated by running helium gas over radiofrequency energy. The resulting plasma is a fourth state of matter and has enhanced clinical effects for ablation and thinning of skin and soft tissues as well of contouring and tightening of deeper soft tissues and fascia. Cool helium plasma has been a very effective tool for skin rejuvenation and skin tightening as well as using it as a tool for nonexcisional microinvasive face and neck rejuvenation. Future research may indicate that it can help treat primary or recurrent superficial cutaneous malignancies. PMID- 29409107 TI - Indications and Use of Isotretinoin in Facial Plastic Surgery. AB - Isotretinoin is a first generation retinoid with pleiotropic effects on keratinocyte differentiation, proliferation, and activity of sebaceous glands. For years, there has been intense debate on whether the use of isotretinoin combined with cosmetic or surgical procedures is safe and potentially more efficient than either therapy alone. Due to delays in wound healing and keloid formation, conservative recommendations were not to combine isotretinoin with any plastic surgery or local treatment at 6 to 12 months after discontinuation of the drug. However, there is increasing evidence that a combination approach is not only safe, but may also provide excellent cosmetic outcomes in acne scars, sebaceous gland hyperplasia, and thick-skinned patients undergoing facial plastic surgery. In particular, low-dose regimens of isotretinoin may offer advantages over standard dosage treatments because of better tolerability and safety in long term use adjunct with surgical interventions. In this article, the authors aim to summarize the current evidence on the use of isotretinoin in facial plastic surgery and to share their experience from selected patients. PMID- 29409109 TI - Paraparesis Revealing Tophaceous Gout. PMID- 29409108 TI - Psychometric evaluation and adaptation of the Spine Oncology Study Group Outcomes Questionnaire to evaluate health-related quality of life in patients with spinal metastases. AB - BACKGROUND: The Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology-specific health-related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases. METHODS: An international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) at baseline and fixed follow-up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF-36 and NRS pain score. Test-retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later. RESULTS: A total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF-36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains. CONCLUSIONS: The SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018;124:1828-38. (c) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 29409111 TI - Pre-operative core muscle index in combination with hypoalbuminemia is associated with poor prognosis in advanced ovarian cancer. AB - BACKGROUND AND OBJECTIVES: Age and frailty have been correlated with poor clinical outcomes in cancer. Core muscle index (CMI) and nutritional status are integral in assessing frailty. We explored the effect of pre-operative serum albumin and body composition on clinical outcomes in patients with epithelial ovarian cancer (EOC). METHODS: We identified stage III-IV EOC patients undergoing primary cytoreductive surgery from 2007 to 2015. Data were abstracted from medical records. Body composition measurements were obtained from pre-operative imaging. Psoas muscle cross-sectional area was normalized to height2 to determine CMI. Sarcopenia was defined as CMI below the population mean. The influence of sarcopenia on short-term morbidity was evaluated. Relationships among body composition measurements and albumin were assessed with Spearman correlations. Patient characteristics and body composition measurements between patients with and without sarcopenia were compared with parametric and non-parametric statistical methods. Kaplan-Meier survival curves were compared using log-rank. RESULTS: 102 women met inclusion criteria. Sarcopenia correlated with albumin (P = 0.0002). Sarcopenia was not associated with short-term morbidity or time to recurrence. Sarcopenia was associated with nearly a fourfold increased risk of death when hypoalbuminemia was present (P = 0.02). CONCLUSIONS: Pre-operative sarcopenia in combination with hypoalbuminemia was associated with significantly worse survival. PMID- 29409110 TI - Mixed-Methods Study Identifying Key Intervention Targets to Improve Participation in Daily Living Activities in Primary Sjogren's Syndrome Patients. AB - OBJECTIVE: Functional ability and participation in life situations are compromised in many primary Sjogren's syndrome (SS) patients. This study aimed to identify the key barriers and priorities to participation in daily living activities, in order to develop potential future interventions. METHODS: Group concept mapping, a semiquantitative, mixed-methods approach was used to identify and structure ideas from UK primary SS patients, adult household members living with a primary SS patient, and health care professionals. Brainstorming generated ideas, which were summarized into a final set of statements. Participants individually arranged these statements into themes and rated each statement for importance. Multidimensional scaling and hierarchical cluster analysis were applied to sorted and rated data to produce visual representations of the ideas (concept maps), enabling identification of agreed priority areas for interventions. RESULTS: A total of 121 patients, 43 adult household members, and 67 health care professionals took part. In sum, 463 ideas were distilled down to 94 statements. These statements were grouped into 7 clusters: Patient Empowerment, Symptoms, Wellbeing, Access and Coordination of Health Care, Knowledge and Support, Public Awareness and Support, and Friends and Family. Patient Empowerment and Symptoms were rated as priority conceptual themes. Important statements within priority clusters indicate patients should be taken seriously and supported to self-manage symptoms of oral and ocular dryness, fatigue, pain, and poor sleep. CONCLUSION: Our data highlighted the fact that in addition to managing primary SS symptoms, interventions aiming to improve patient empowerment, general wellbeing, access to health care, patient education, and social support are important to facilitate improved participation in daily living activities. PMID- 29409112 TI - Prognostic factors for resected non-small cell lung cancer in patients with type 2 diabetes mellitus. AB - BACKGROUND: For diabetic patients with lung cancer, blood glucose levels and medications such as metformin and statins may influence survival. OBJECTIVES: This study aimed to determine prognostic survival factors for diabetic patients with resected non-small cell lung cancer. PATIENTS AND METHODS: Between January 2005 and December 2013, 301 patients with type 2 diabetes mellitus who underwent curative resection for non-small cell lung cancer were identified and reviewed retrospectively. RESULTS: The median follow-up period was 48 months. In multivariate analysis for lung cancer-specific survival, older age, forced expiratory volume in 1 s (FEV1) <80% predicted, and advanced pathologic stage were significant negative prognostic factors; statin use was a positive prognostic factor (hazard ratio (HR), 0.468). In multivariate analysis for overall survival, male sex, older age, comorbidity index, and advanced pathologic stage were significant negative prognostic factors and proper glycemic control (HR, 0.621) and statin use (HR, 0.585) were positive prognostic factors. CONCLUSIONS: Proper glycemic control (glycated hemoglobin A1c <7%) is recommended for diabetic patients undergoing lung cancer operations. Further studies are required to elucidate associations between type 2 diabetes mellitus and antineoplastic effects of statins and to evaluate statins as a novel adjuvant treatment for lung cancer. PMID- 29409113 TI - Structure-Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors. AB - The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small-molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the "northern region" of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C4 hydroxy group and C3alpha proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 ((1R,3aR,4R,7aR)-1-[(R)-1,5-dimethylhexyl]-4-(4-aminophenoxy)-7a methyloctahydro-1H-indene) demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway. PMID- 29409114 TI - Is BMI associated with post-operative complication risk among patients undergoing major abdominal surgery for cancer? A systematic review. AB - We systematically reviewed 118 studies comparing peri-operative outcomes among obese and non-obese patients. Obesity was associated with longer operative time in 60% of available studies. Just 35.8% of studies that evaluated overall morbidity identified high morbidity in obese patients. Lymph node yield or surgical margin status, was only affected by obesity in 19.6% of studies. In this review obesity was frequently found to have no effect on peri-operative and oncologic outcomes. PMID- 29409115 TI - Expression of nerve growth factor carried by pseudotyped lentivirus improves neuron survival and cognitive functional recovery of post-ischemia in rats. AB - AIMS: Nerve growth factor (NGF) has been reported to prevent neuronal damage and contributes to the functional recovery in animal brain injury models and human ischemic disease as well. We aimed to investigate a potential therapeutic effect of NGF gene treatment in ischemic stroke and to estimate the functional recovery both at the cellular and cognitive levels in an ischemia rat model. METHODS: After microinjection of pseudolentivirus-delivered beta-NGF into an established ischemic stroke model in rats (tMCAO), we estimated neuronal cell apoptosis with TUNEL labeling and neurogenesis by cell proliferation marker Ki67 staining in both ischemic core and penumbra of striatum. Furthermore, we used behavioral functional tests, Morris water maze performance, to evaluate cognitive functional recovery in vivo and propose a potential underlying mechanism. RESULTS: We found that pseudolentivirus-mediated delivery of beta-NGF gene into the brain induced high expression in striatum of the infarct core area after ischemia in rats. The beta-NGF overexpression in the striatal infarction core after ischemia not only improved neuronal survival by reducing cell apoptosis and increasing cell proliferation, but also rescued cognitive functional impairment through upregulation of GAP-43 protein expression in tMCAO rat model of ischemia. CONCLUSION: This study demonstrates a potential beta-NGF gene therapy by utilization of pseudolentivirus in ischemia and indicates future applications of NGF gene treatment in ischemic patients. PMID- 29409117 TI - Comparison of Secretome Profile of Pathogenic and Non-Pathogenic Entamoeba histolytica. AB - The obligatory intracellular protozoan parasite Entamoeba histolytica causes amebic dysentery and liver abscess. E. histolytica adheres to the host tissues in a contact-dependent manner. E. histolytica excretory-secretory products (ESP) might play critical roles during invasion. We comparatively analyzed the secretome profile of E. histolytica pathogenic HM-1:IMSS and non-pathogenic Rahman strains. The two ESP revealed similar but distinct spotting patterns. In both ESP, alcohol dehydrogenase, enolase 1, and transketolase, which control classical carbohydrate metabolism and other moonlighting effects, constituted the most abundant fractions. We recognized differently secreted molecules. Secretion of cytoskeletal organization proteins (actin, actin binding protein, and EHI_068510), protein remodeling amino peptidase, and multifunctional elongation factor 1-alpha were increased in Rahman. Conversely, carbohydrate metabolizing enolase 1, alcohol dehydrogenase, transketolase, calponin, phosphoglucose mutase, malic enzyme and EHI_156420, xenobiotic scavenging superoxide dismutase and EHI_140740, and pyruvate:ferredoxin oxidoreductase and coronin (carbohydrate metabolism/detoxification) showed reduced secretion. Transcription levels of some genes involved in these processes also decreased. Changes of secretory behavior, especially decreased secretion of multifunctional carbohydrate metabolizing enzymes and detoxifying proteins that importantly participated in amoeba pathogenesis might reflect avirulent nature of Rahman strain in the host. PMID- 29409116 TI - Long-term quality of life after esophagectomy with gastric pull-up. AB - BACKGROUND AND OBJECTIVES: Data on long-term health-related quality of life (HRQL) after esophagectomy for cancer show contradictory results. The aim was to analyze long-term HRQL at 3 or more years after esophagectomy. METHODS: Survivors were identified among patients who had undergone esophagectomy during 2007-2013 using the local clinic database. Quality of life was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and OG25 questionnaires. Specific aspects were selected a priori and compared with published scores from European healthy subjects (mean difference, MD). RESULTS: Sixty-five long-term survivors (median follow-up 4 years) were identified. All functional scales and most symptom scales were clinically similar between EC long term survivors and European healthy subjects. Survivors reported more problems concerning eating (MD 13.1, 95% C.I. 10.6-15.6) and reflux (MD 19.7, 95% C.I. 15.9-23.5). HQRL variation from discharge to long term was available in 27 participants who reported improvements in role functioning (MD 40.1, 95%C.I. 24.3 56.0) and dysphagia (MD -41.9, 95% C.I. -51.7 to 32.0). CONCLUSIONS: Long-term HRQL after esophagectomy is similar between EC survivors and European healthy subjects, despite persisting reflux and eating problems. Further research may focus on improvements of postoperative alimentary habits. PMID- 29409118 TI - Evaluation of a Methodologic Approach to Define an Inception Cohort of Rheumatoid Arthritis Patients Using Administrative Data. AB - OBJECTIVE: Identifying incident rheumatoid arthritis (RA) is desirable in order to create inception cohorts. We evaluated an approach to identify incident RA in health plan claims data. METHODS: Both Medicare and commercial claims data were linked to Corrona, a US RA registry. We evaluated the accuracy of year of RA onset in the registry (gold standard) versus different claims algorithms, varying International Classification of Diseases, Ninth Revision codes for RA/arthritis, duration of health plan enrollment preceding diagnosis (minimum of 1 versus 2 years), and use of RA medications. Results were reported as positive predictive values (PPVs) of the claims-based algorithm for incident RA. RESULTS: Depending on the algorithm tested and whether patients were enrolled in Medicare or the commercial health plan, the PPVs for incident RA ranged from 68-81%. A 2-year clean period free of all RA-related diagnoses and medications was somewhat more optimal although, by comparison, a 1-year clean period yielded similar PPVs and retained approximately 90% more RA patients for analysis. CONCLUSION: Claims based algorithms can accurately identify incident RA. PMID- 29409119 TI - Treatment and survival vary by race/ethnicity in patients with anaplastic thyroid cancer. AB - BACKGROUND: Anaplastic thyroid cancer (ATC) is the rarest type of thyroid cancer and has the lowest overall survival. To the authors' knowledge, the impact of socioeconomic status and race/ethnicity has not yet been described. METHODS: Data regarding 719 patients diagnosed with their first primary malignant ATC from January 1, 1998 to December 31, 2011 in the Surveillance, Epidemiology, and End Results program registries were examined. Differences in receipt of thyroidectomy, radiotherapy, and lymph node examination were examined by race/ethnicity. Survival also was examined by race/ethnicity. RESULTS: Nearly 70% of patients were non-Hispanic white, and 55.4% of patients received treatment. Tumor size (P = .13), lymph node involvement (P = .60), and residence in high poverty neighborhoods (P = .08) did not vary by race/ethnicity. Nonwhite patients were more likely to receive no treatment (adjusted odds ratio, 0.29; 95% confidence interval [95% CI], 0.16-0.54). When receipt of radiotherapy was adjusted for, nonwhite patients had a higher risk of overall death (adjusted hazards ratio [aHR], 1.24; 95% CI, 1.01-1.54), although not disease-specific death (aHR, 1.14; 95% CI, 0.92-1.42). Patients living in areas of high poverty had lower overall survival (aHR, 1.54; 95% CI, 1.09-2.18) and disease-specific survival (aHR, 1.68; 95% CI, 1.19-2.36). CONCLUSIONS: In this population-based study of patients with ATC, nonwhite patients were found to be less likely to receive treatment. Furthermore, nonwhite patients had poorer overall survival, and patients living in areas of high poverty had both worse overall and disease specific survival. Racial/ethnic and socioeconomic disparities appear to exist in the treatment and survival of patients with ATC. Cancer 2018;124:1780-90. (c) 2018 American Cancer Society. PMID- 29409120 TI - Transforming Growth Factor beta Activation Primes Canonical Wnt Signaling Through Down-Regulation of Axin-2. AB - OBJECTIVE: Aberrant activation of Wnt signaling has been observed in tissues from patients with systemic sclerosis (SSc). This study aimed to determine the role of transforming growth factor beta (TGFbeta) in driving the increased Wnt signaling, through modulation of axis inhibition protein 2 (Axin-2), a critical regulator of the Wnt canonical pathway. METHODS: Canonical Wnt signaling activation was analyzed by TOPflash T cell factor/lymphoid enhancer factor promoter assays. Axin 2 was evaluated in vitro by analysis of Axin-2 primary/mature transcript expression and decay, TGFbeta receptor type I (TGFbetaRI) blockade, small interfering RNA-mediated depletion of tristetraprolin 1, and XAV-939-mediated Axin-2 stabilization. In vivo, Axin-2 messenger RNA (mRNA) and protein expression was determined in skin and lung biopsy samples from mice that express a kinase deficient TGFbetaRII specifically on fibroblasts (TbetaRIIDeltak-fib-transgenic mice) and from littermate controls. RESULTS: SSc fibroblasts displayed an increased response to canonical Wnt ligands despite basal levels of Wnt signaling that were comparable to those in healthy control fibroblasts in vitro. Notably, we showed that SSc fibroblasts had reduced basal expression of Axin-2, which was caused by an endogenous TGFbeta-dependent increase in Axin-2 mRNA decay. Accordingly, we observed that TGFbeta decreased Axin-2 expression both in vitro in healthy control fibroblasts and in vivo in TbetaRIIDeltak-fib-transgenic mice. Additionally, using Axin-2 gain- and loss-of-function experiments, we demonstrated that the TGFbeta-induced increased response to Wnt activation characteristic of SSc fibroblasts depended on reduced bioavailability of Axin-2. CONCLUSION: This study highlights the importance of reduced bioavailability of Axin-2 in mediating the increased canonical Wnt response observed in SSc fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt/beta-catenin-driven pathology and supports the rationale for targeting the TGFbeta pathway to regulate the aberrant Wnt signaling observed during fibrosis. PMID- 29409121 TI - Novel aspects of live intestinal epithelial cell function revealed using a custom time-lapse video microscopy apparatus. AB - Many aspects of cell physiology, including migration, membrane function, and cell division, are best understood by observing live cell dynamics over time using video microscopy. To probe these phenomena in colon epithelial cells using simple components with a limited budget, we have constructed an inexpensive (<$410) self contained apparatus, consisting of a closed-loop, feedback-controlled system regulated by a PID (proportional-integrative-derivative) controller contained within a 0.077 m3 insulated acrylic box. Temperature, humidity, pH, and proliferative capacity of colon epithelial cells in this system mimic those in a standard tissue culture incubator for over four days. Our system offers significant advantages over existing cost-prohibitive commercially available and custom-made devices because of its very low cost, use of PID temperature control, lack of reliance on constant infusion of external humidified, heated air or carbon dioxide, ability to directly measure cell culture medium temperature, and combination of exquisite cellular detail with minimal focus drift under physiological conditions for extended periods of time. Using this apparatus, coupled with an inverted microscope equipped with phase contrast optics and a programmable digital camera, we have observed many events in colon epithelial cells not visible by static imaging, including kinetics of normal and abnormal mitoses, dynamic membrane structures, intracellular vesicle movements, and cell migration. (c) 2018 International Society for Advancement of Cytometry. PMID- 29409122 TI - Postmetastasis survival in high-grade extremity osteosarcoma: A retrospective analysis of prognostic factors in 126 patients. AB - BACKGROUND AND OBJECTIVES: Prognostic factors predictive of postmetastasis survival (PMS) in metastatic osteosarcoma are poorly understood. Our aims were to evaluate PMS in patients with high-grade osteosarcoma in extremities, and to identify prognostic factors related to PMS. METHODS: A retrospective review of data for 126 patients with metastatic osteosarcoma was conducted. The study population consisted of 70 men and 56 women, with a mean age of 21 years (range: 4-75 years). The mean postmetastasis follow-up period was 37 months (range: 1-245 months). RESULTS: The 5-year PMS rate was 31% and median PMS duration was 22 months. In the multivariate analyses, no metastasectomy (P < 0.001), local recurrence prior to metastasis (P = 0.016), extrapulmonary metastasis (P = 0.006), and poor histologic response to preoperative chemotherapy (P = 0.047) were significant poor prognostic factors. The 5-year PMS without any negative prognostic factor was 60.2%; with one factor, 31.6%; and with more than two factors, 3.6%. CONCLUSIONS: PMS in osteosarcoma patients was influenced by primary tumor-related factors such as histologic response to chemotherapy, as well as metastasis-related factors such as complete metastasectomy and metastasis site. A certain group of patients without such poor prognostic factors could be cured even after the development of metastasis. PMID- 29409123 TI - Characterization of Patients With Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis in the US-Based Corrona Registry. AB - OBJECTIVE: To describe the characteristics of patients with ankylosing spondylitis (AS) and patients with nonradiographic axial spondyloarthritis (SpA) in the US. METHODS: Demographics, clinical characteristics, patient-reported outcomes, and treatment characteristics of patients with AS and those with nonradiographic axial SpA were assessed at the time of enrollment in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Patients with AS were defined as those who fulfilled the 1984 modified New York criteria for AS; patients with nonradiographic axial SpA were defined as all other patients with axial SpA who did not fulfill the radiology criterion. RESULTS: Of the 407 patients with a diagnosis of axial SpA who were included in this study, 310 had AS, and 97 had nonradiographic axial SpA. Although patients with nonradiographic axial SpA were younger and showed a trend toward a shorter symptom duration, the nonradiographic axial SpA and AS groups shared a similar disease burden, as reflected by comparisons of disease activity and function, quality of life, pain, fatigue, job absenteeism, and loss of work productivity (all P > 0.05). The proportions of patients with nonradiographic axial SpA and patients with AS who received prior biologic disease-modifying drugs (DMARDs) (74.2% and 64.8%, respectively) or were currently receiving biologic DMARDs (63.9% and 61.3%, respectively) were also similar (P > 0.05). CONCLUSION: This was the first nationwide study to characterize patients with AS and nonradiographic axial SpA in the US. Consistent with studies published outside of the US, this study showed that patients with nonradiographic axial SpA and patients with AS shared a comparable degree of disease burden and had similar treatment patterns in clinical practice. PMID- 29409124 TI - Current developments in immunotherapy in the treatment of multiple myeloma. AB - Multiple myeloma (MM) is the second most common hematologic malignancy and represents approximately 10% of all hematological neoplasms. Standard therapy consists of induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) or, if ASCT cannot be performed, standard doublet, triplet, or quadruplet, novel agent-containing induction treatment until progression. Although MM is still regarded as mostly incurable by current standards, the development of several novel compounds, combination therapies, and immunotherapy approaches has raised great hopes about transforming MM into an indolent, chronic disease and possibly achieving a cure for individual patients. Several new inhibitory and immunological agents have been approved or are under intensive investigation and may lead to new therapeutic options for patients with relapsed/refractory MM, for patients ineligible for ASCT, and for patients after ASCT. Especially in the field of immunotherapy, including monoclonal antibodies, checkpoint inhibition, and chimeric antigen receptor T cells, current advances are rapid and highly promising. This review aims to summarize the newest and most promising immunotherapeutic agents for MM, their clinical efficacy, their adverse event (AE) profiles, and the ways in which these AEs can best be overcome or avoided. Cancer 2018;124:2075-85. (c) 2018 American Cancer Society. PMID- 29409125 TI - Editorial: Marginal Jawbone Loss Is Associated With the Onset of Rheumatoid Arthritis and Is Related to the Plasma Level of RANKL. PMID- 29409126 TI - WITHDRAWN: Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission. AB - BACKGROUND: Prophylactic cranial irradiation halves the rate of brain metastases in patients with small cell lung cancer. Individual randomized trials conducted on patients in complete remission were unable to clarify whether this treatment improves survival. OBJECTIVES: This study aims to test whether prophylactic cranial irradiation prolongs survival of patients with small cell lung cancer in complete remission. SEARCH METHODS: Published and unpublished trials were eligible. Electronic databases (Medline, Cancerlit, Excerpta Medica, Biosis from 1965 to 1998), reference lists of trial publications, review articles and relevant books were used to identify potentially eligible trials. The search was also guided by discussions with investigators and experts, and the examination of meeting proceedings and of the Physician Data Query clinical trial registry. SELECTION CRITERIA: Randomized trials comparing prophylactic cranial irradiation with no prophylactic cranial irradiation in patients with small cell lung cancer in complete remission. DATA COLLECTION AND ANALYSIS: Meta-analysis based on updated individual data. The main endpoint was survival. MAIN RESULTS: Seven trials with a total of 987 participants were included. The relative risk of death in the treatment group compared to the control group was 0.84 (95% confidence interval=0.73 to 0.97, P=0.01), corresponding to a 5.4 percent increase in the 3 year survival rate (from 15.3 percent in the control group to 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased disease-free survival (relative risk=0.75, 95% confidence interval=0.65 to 0.86, P<0.001) and decreased the risk of brain metastases (relative risk=0.46, 95% confidence interval=0.38 to 0.57, P<0.001). Increasing doses of irradiation decreased the risk of brain metastases when four groups (8 Gy, 24-25 Gy, 30 Gy, 36-40 Gy) were analyzed [trend test, P=0.02], but the effect on survival did not differ significantly according to the dose. We found a trend (P=0.01) for a decrease in the brain metastasis risk in favour of earlier administration of cranial irradiation after the initiation of induction treatment. AUTHORS' CONCLUSIONS: Prophylactic cranial irradiation significantly improves survival and disease-free survival for patients with small cell lung cancer in complete remission. Further clinical trials are needed to confirm the potential greater benefit on brain metastasis rate suggested when cranial irradiation is given earlier or at higher doses. PMID- 29409127 TI - The use of surgical Apgar score to predict perioperative adverse outcomes following esophagectomy. PMID- 29409128 TI - Acceptability and satisfaction of project MOVE: A pragmatic feasibility trial aimed at increasing physical activity in female breast cancer survivors. AB - OBJECTIVE: Despite the physical and psychological health benefits associated with physical activity (PA) for breast cancer (BC) survivors, up to 70% of female BC survivors are not meeting minimum recommended PA guidelines. The objective of this study was to evaluate acceptability and satisfaction with Project MOVE, an innovative approach to increase PA among BC survivors through the combination of microgrants and financial incentives. METHODS: A mixed-methods design was used. Participants were BC survivors and support individuals with a mean age of 58.5 years. At 6-month follow-up, participants completed a program evaluation questionnaire (n = 72) and participated in focus groups (n = 52) to explore their experience with Project MOVE. RESULTS: Participants reported that they were satisfied with Project MOVE (86.6%) and that the program was appropriate for BC survivors (96.3%). Four main themes emerged from focus groups: (1) acceptability and satisfaction of Project MOVE, detailing the value of the model in developing tailored group-base PA programs; (2) the importance of Project MOVE leaders, highlighting the value of a leader that was organized and a good communicator; (3) breaking down barriers with Project MOVE, describing how the program helped to address common BC related barriers; and (4) motivation to MOVE, outlining how the microgrants enabled survivors to be active, while the financial incentive motivated them to increase and maintain their PA. CONCLUSION: The findings provide support for the acceptability of Project MOVE as a strategy for increasing PA among BC survivors. PMID- 29409129 TI - Successful management of a rare type of complex myxofibrosarcoma which affected right lung and invading into the left atrium under the guidance of multimode image. AB - Myxofibrosarcoma is a rare type of highly malignant sarcoma which easily occur lung metastasis. We report a rare metastatic myxofibrosarcoma which generated from the upper and middle lobe of the lung, invading the right superior pulmonary vein, extending to the left atrium. A single imaging examination may lead to misdiagnosis, so the combination of computed tomography imaging, magnetic resonance imaging, as well as positron emission tomographic scan are necessary for perioperative diagnosis and surgical planning. PMID- 29409130 TI - Response: Cardiac magnetic resonance in cardiac angiosarcoma-Which contrast enhancement pattern is typical? PMID- 29409131 TI - Cardiac magnetic resonance in cardiac angiosarcoma-Which contrast-enhancement pattern is typical? PMID- 29409132 TI - Leydig cell insufficiency in hypospermatogenesis: a paracrine effect of activin inhibin signaling? AB - Clinical findings and a variety of experimental models indicate that Leydig cell dysfunction accompanies damage to the seminiferous tubules with increasing severity. Most studies support the idea that intratesticular signaling from the seminiferous tubules to Leydig cells regulates steroidogenesis, which is disrupted when hypospermatogenesis occurs. Sertoli cells seem to play a pivotal role in this process. In this review, we summarize relevant clinical and experimental observations and present evidence to support the hypothesis that testicular activin signaling and its regulation by testicular inhibin may link seminiferous tubular dysfunction to reduced testosterone biosynthesis. PMID- 29409133 TI - Minimal Disease Activity Among Active Psoriatic Arthritis Patients Treated With Secukinumab: 2-Year Results From a Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase III Study. AB - OBJECTIVE: To evaluate minimal disease activity (MDA) among psoriatic arthritis (PsA) patients receiving secukinumab through 2 years in the FUTURE 2 study. METHODS: Patients with active PsA were randomized to receive subcutaneous secukinumab 300, 150, or 75 mg or placebo. MDA was assessed in the overall population (anti-tumor necrosis factor [anti-TNF]-naive and inadequate responders [anti-TNF-IR]) and in patients stratified by prior anti-TNF exposure and by time since diagnosis at weeks 16, 24, 52, and 104. Function and patient-reported outcomes (PROs), including health-related quality of life (QoL) and work productivity, were assessed in MDA responders versus nonresponders. RESULTS: Overall, 28% of patients (27 of 98) and 23% (23 of 100) achieved MDA at week 16 with secukinumab 300 and 150 mg, respectively, versus 10% (9 of 94) with placebo. In the anti-TNF-naive cohort, a higher proportion of patients achieved MDA at week 16 with secukinumab 300 and 150 mg (34% and 32%, respectively) versus placebo (13%). The corresponding value in the anti-TNF-IR cohort was 15% and 8% with secukinumab 300 and 150 mg, respectively, versus with placebo (3%). At week 16, 27.1% of MDA responders (16 of 59) achieved a very low disease activity (VLDA) response, with the percentage being numerically greater with secukinumab 300 and 150 mg (30% [8 of 27] and 26% [6 of 23], respectively) versus placebo (22% [2 of 9]). The MDA and VLDA responses with secukinumab 300 and 150 mg were sustained through 2 years. MDA responders showed greater improvements in QoL outcomes compared to nonresponders through 2 years. CONCLUSION: A greater proportion of patients achieved MDA with secukinumab versus placebo at week 16, with response rates sustained through 2 years. MDA was associated with improved PROs, including QoL, through 2 years. PMID- 29409134 TI - Musculoskeletal mechanobiology: A new era for MechanoMedicine. PMID- 29409135 TI - Reassessing the value of high-volume cancer care in the era of precision medicine. AB - The ethical and economic discussions regarding the extreme costs of many new cancer therapies are familiar. The authors have long held that changes in cancer care delivery also are an important strategy, yielding large benefits at potentially far lower costs. To put this into context, the authors performed an analysis to compare the overall survival of patients receiving a complex oncologic surgery, radical cystectomy, at high-volume and low-volume centers. Propensity score weighting was performed to simulate random allocation into high volume versus low-volume centers, as would be the case in a prospective trial. On average, patients undergoing surgery at high-volume centers survived 15 months longer than those treated at low-volume centers (57.0 months vs 41.8 months). Although there certainly are caveats in contrasting the survival benefit of different care settings with anticancer agents, this differential clearly rivals or exceeds the benefit of many expensive, recently approved agents. As the debate regarding the costs of cancer therapies continues, it is worth remembering that investments in simple systems-based changes to improve cancer care delivery remain an important and likely cost-effective strategy with which to improve the survival of patients with cancer. Cancer 2018;124:1319-21. (c) 2018 American Cancer Society. PMID- 29409136 TI - Brief Report: Novel UNC13D Intronic Variant Disrupting an NF-kappaB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (JIA) and has pathologic similarity to hemophagocytic lymphohistiocytosis (HLH). Intronic variants in UNC13D are found in patients with familial HLH type 3 (FHLH3), but the role of noncoding variants in MAS is unknown. The objective of this study was to identify deep intronic UNC13D variants in patients with MAS. METHODS: A custom enrichment library was constructed to sequence a genomic region of ~1 Mb flanking UNC13D in 24 patients with systemic JIA, recurrent MAS, and negative results of prior genetic (exon/coding) testing. The functional consequences of intronic variants were assessed using quantitative polymerase chain reaction in patient-derived peripheral blood mononuclear cells (PBMCs), electromobility shift assay, in vitro transcriptional enhancer assays, and natural killer (NK) cell degranulation assays. RESULTS: We evaluated a patient with systemic JIA and recurrent MAS in whom a novel functional intronic variant in UNC13D, c.117+143A>G, was observed. This variant occurred in a proposed regulatory region that drives lymphocyte specific UNC13D expression and is associated with reduced transcript levels in patient PBMCs. This variant also disrupted NF-kappaB binding to a functional transcriptional enhancer, leading to reduced enhancer activity in vitro. Partial knockdown of UNC13D expression also led to impaired NK cell degranulation. An additional patient was identified with a previously described UNC13D intronic variant, for a total noncoding variant hit rate of 8.3% (2 of 24). CONCLUSION: These findings highlight the notion that intronic variants in key regulatory regions may be associated with MAS in patients with systemic JIA and support deep sequencing approaches when causative coding variants are not identified. PMID- 29409137 TI - Mortality in Patients With Giant Cell Arteritis: A Cohort Study in UK Primary Care. AB - OBJECTIVE: To examine whether giant cell arteritis (GCA) is associated with increased all-cause mortality and whether mortality differs according to age, sex, and calendar year of cohort entry. METHODS: Using the UK-based Clinical Practice Research Datalink, we identified 9,778 newly diagnosed GCA patients from 1990-2014, and up to 10 nonvasculitis patients randomly matched to each case on age, sex, practice, and years of history before cohort entry. We used Cox regression to estimate adjusted hazard ratios (HRs) for mortality of GCA patients in comparison to nonvasculitis patients, then stratified by age, sex, and calendar year of cohort entry. RESULTS: Compared with nonvasculitis patients, GCA patients had increased mortality during the first year following diagnosis (adjusted HR 1.51, 95% confidence interval [95% CI] 1.40-1.64), and marginally increased mortality between 1 and 5 years after the diagnosis (adjusted HR 1.16, 95% CI 1.09-1.23), but not >5 years after the diagnosis (adjusted HR 1.06, 95% CI 1.00-1.12). GCA patients diagnosed before age 65 years had the highest mortality risk during the first year following diagnosis (adjusted HR 2.32, 95% CI 1.60 3.35). The mortality risk did not differ substantially by sex or calendar year of cohort entry. CONCLUSION: GCA patients had an increased risk of mortality during the period shortly after the GCA diagnosis, in particular during the first year, but no increased risk after 5 years postdiagnosis. The mortality risk differed by age with an even greater increased 1-year mortality in those age <65 years at diagnosis, but not by sex or calendar year of cohort entry. PMID- 29409138 TI - Treatment of semen samples with alpha-chymotrypsin alters the expression pattern of sperm functional proteins-a pilot study. AB - Semen hyperviscosity delays the liquefaction of semen sample and is subjected to limited proteolysis by addition of alpha-chymotrypsin to reduce the viscosity. alpha-Chymotrypsin is a proteolytic enzyme involved in degradation of the proteins and polypeptides. Even though alpha-chymotrypsin improves the handling of hyperviscous samples, its effect on the sperm proteins is not clear. This study was aimed to evaluate the alteration in the expression of sperm functional proteins in samples treated with alpha-chymotrypsin. Among all the proteins examined in both donor and patient samples, HSPA2 (70 KDa), BAG6 (150 KDa), HIST1H2BA (14 KDa), SPA17 (17 KDa formed after cleavage of C-terminal calmodulin binding domain), and OXPHOS complexes were undetectable in alpha-chymotrypsin treated samples, while the expression of the native SPA17 (20 KDa) was significantly decreased in the alpha-chymotrypsin-treated samples in comparison with controls. The use of alpha-chymotrypsin for liquefaction of hyperviscous samples degrades functional proteins of spermatozoa. Intracellular proteins, such as OXPHOS complexes and HIST1H2BA, and sperm surface proteins (HSPA2, BAG6, and SPA17) were degraded in all treated samples. Whether treatment of samples with alpha-chymotrypsin affects the global proteomic outcome is unclear. More in-depth calibration studies are required to determine the appropriate concentration of alpha-chymotrypsin for processing hyperviscous semen samples without compromising its protein expression and function. Similarly, the effects of altered protein function on assisted reproductive techniques (ART), such as intrauterine insemination (IUI) and in vitro fertilization (IVF) outcome, are not known and require further research. PMID- 29409139 TI - WITHDRAWN: Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. AB - BACKGROUND: Malignant melanoma, one of the most aggressive of all skin cancers, is increasing in incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most affected people, because melanoma does not respond to most systemic treatments. A number of novel approaches are under evaluation and have shown promising results, but they are usually associated with increased toxicity and cost. The combination of chemotherapy and immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone. No language restrictions were imposed. OBJECTIVES: To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in people with metastatic malignant melanoma. SEARCH METHODS: We searched the Cochrane Skin Group Specialised Register (14 February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to 30 January 2006 ), EMBASE (2003 to 20 July 2005) and LILACS (1982 to 20 February 2006). References, conference proceedings, and databases of ongoing trials were also used to locate trials. SELECTION CRITERIA: All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age, diagnosed with metastatic melanoma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed each study to determine whether it met the pre defined selection criteria, with differences being resolved through discussion with the review team. Two authors independently extracted the data from the articles using data extraction forms. Quality assessment included an evaluation of various components associated with biased estimates of treatment effect. Whenever possible, a meta-analysis was performed on the extracted data, in order to calculate a weighed treatment effect across trials. MAIN RESULTS: Eighteen studies met our criteria and were included in the meta-analysis, with a total of 2625 participants. We found evidence of an increase of objective response rates in people treated with chemoimmunotherapy, in comparison with people treated with chemotherapy. Nevertheless, the impact of these increased response rates was not translated into a survival benefit. We found no difference in survival to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma, with a hazard ratio of 0.89 (95% CI 0.72 to 1.11, P = 0.31). Additionally, we found increased hematological and non-hematological toxicities in people treated with chemoimmunotherapy. AUTHORS' CONCLUSIONS: We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma. Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials. PMID- 29409140 TI - A Multicenter Retrospective Analysis Evaluating Performance of Synovial Biopsy Techniques in Patients With Inflammatory Arthritis: Arthroscopic Versus Ultrasound-Guided Versus Blind Needle Biopsy. AB - OBJECTIVE: To evaluate whether the choice of synovial biopsy technique (arthroscopy, blind needle [BN] biopsy, ultrasound [US]-guided portal and forceps [P&F], or US-guided needle biopsy [NB]) translates to significant variation in synovial tissue quality and quantity, with the aim of informing recommendations for the choice of synovial sampling technique within clinical trials. METHODS: In total, 159 procedures from 5 academic rheumatology centers were evaluated. Hematoxylin and eosin-stained, paraffin-embedded synovial tissue sections from patients with inflammatory arthritis were assessed in order to determine the proportion of graded synovial fragments, total area of graded synovial tissue, and synovitis score per procedure. RNA quantity (MUg of RNA) and quality (RNA integrity number) per procedure were also assessed in the synovial samples. RESULTS: In this study, 84 of the 159 procedures performed on large joints at baseline (25 arthroscopic, 35 US-P&F, 11 US-NB, and 13 BN biopsies), 41 of the 159 procedures performed on small joints at baseline (11 US-P&F, 20 US-NB, and 10 BN biopsies), and 34 sequential biopsy procedures were evaluated. Compared to all other techniques evaluated in the small and large joints, fewer small joint BN biopsies and a significantly lower proportion of large joint BN biopsies yielded graded synovial tissue. No significant difference in either the proportion of graded tissue samples or total graded synovial tissue area between the US-NB and arthroscopic large joint procedures was demonstrated. Among the sequential biopsy procedures evaluated (small joint US-NB, large joint arthroscopy, US-P&F biopsy, and BN biopsy), no significant difference in the proportion of graded synovial tissue or total graded synovial tissue area was demonstrated. All procedures yielded RNA of significant quality and quantity for subsequent transcriptomic analysis. CONCLUSION: These data support the integration of US-guided methods along with arthroscopic biopsy for clinical trial protocols in which sequential sampling of synovium from the large and small joints is needed for both histologic and molecular analysis. BN biopsy may be considered if graded synovial tissue is not required for subsequent analyses. PMID- 29409141 TI - Synthesis of Macromolecules Containing Phenylalanine and Aliphatic Building Blocks. AB - Aiming at developing efficient interfacial agents for fiber-reinforced composite materials, macromolecules are designed to have different components able to stick to the fiber and be compatible with the polymer matrix, respectively. Herein, macromolecules are prepared by solid-phase synthesis considering phenylalanine residues to promote adsorption of the macromolecule on aramid fibers and aliphatic building blocks to interact with a hydrophobic polymer matrix. Using phenylalanine as building block for the preparation of macromolecules by iterative synthesis has been shown to be challenging. Thus, the screening of various parameters for the optimization of the synthesis of these macromolecules is discussed in this communication. A preliminary thermal study by thermal gravimetric analysis is conducted to evaluate their thermal stability. PMID- 29409142 TI - Baseline Retinal Examinations in Patients With Systemic Lupus Erythematosus Newly Initiating Hydroxychloroquine Treatment in a US Medicaid Systemic Lupus Erythematosus Population, 2000-2010. AB - OBJECTIVE: Baseline retinal examinations have long been recommended for patients beginning treatment with hydroxychloroquine (HCQ), but it is unknown how well this guideline is followed. We investigated baseline eye examinations among US SLE patients enrolled in Medicaid in whom HCQ treatment was newly initiated. METHODS: Using billing codes, we identified SLE patients ages 18-65 years who were enrolled in Medicaid and residing in the 29 most populated US states, from 2000 to 2010. New users of HCQ were identified by filled prescriptions, with none filled in the preceding 12 months. Retinal examinations that were performed within 30 days before to 1 year after the index prescription were identified. We examined the proportions of patients receiving retinal examinations over the study years and compared the characteristics of those who did and those who did not receive examinations, using bivariable and multivariable logistic regression models. RESULTS: Among 12,755 SLE patients newly starting HCQ treatment, 32.5% received baseline dilated eye examinations. The proportions of patients receiving baseline eye examinations did not significantly change from 2000 to 2010 (31.0 34.4%; P for linear trend = 0.12). Factors associated with an increased likelihood of having an examination included female sex, Asian versus white race, and a higher number of laboratory tests performed during the preceding year. Compared with white patients, lower proportions of black and Native American patients with SLE had baseline retinal examinations. CONCLUSION: Only one-third of patients with SLE enrolled in Medicaid and in whom HCQ was newly initiated received the recommended baseline retinal examinations, and this proportion did not significantly increase from 2000 to 2010. The sociodemographic variation in this recommended care has been observed for other recommended medical care in SLE and requires both further investigation and interventions to address it. PMID- 29409143 TI - Long-Term Safety and Efficacy of Belimumab in Patients With Systemic Lupus Erythematosus: A Continuation of a Seventy-Six-Week Phase III Parent Study in the United States. AB - OBJECTIVE: We undertook this US multicenter continuation study (GlaxoSmithKline study BEL112233; ClinicalTrials.gov identifier: NCT00724867) to assess long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) who completed the Study of Belimumab in Subjects with SLE 76-week trial (ClinicalTrials.gov identifier: NCT00410384). METHODS: Patients continued to receive the same belimumab dose plus standard therapy; patients previously receiving placebo received 10 mg/kg belimumab. The primary outcome measure was long-term safety of belimumab (frequency of adverse events [AEs] and damage assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI], evaluated every 48 weeks [1 study year]). Other assessments included the SLE Responder Index (SRI), flare rates (using the modified SLE Flare Index [SFI]), prednisone use, and B cell levels. RESULTS: Of 268 patients, 140 completed the study and 128 withdrew. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) at baseline was 7.8 +/- 3.86. The mean +/- SD SDI score increased by 0.4 +/- 0.68 from its value at baseline (1.2 +/- 1.51). The overall incidence of treatment-related and serious AEs remained stable or declined through study year 7. An SRI response was achieved by 41.9% and 75.6% of patients at the study year 1 and study year 7 midpoints, respectively. At the study year 7 midpoint, relative to baseline, 78.2% had achieved a >=4-point reduction in the SELENA-SLEDAI score, 98.4% had no new British Isles Lupus Assessment Group (BILAG) A organ domain score and no more than 1 new BILAG B organ domain score, 93.7% had no worsening in the physician's global assessment of disease activity, 20.6% had experienced >=1 severe SFI flare, the mean decrease in prednisone dose was 31.4%, and the median change in CD20+ B cell numbers was -83.2%. CONCLUSION: These long-term exposure results confirm the previously observed safety and efficacy profiles of belimumab in patients with SLE. PMID- 29409144 TI - Structural and Hydrogeological Controls on Hydrocarbon and Brine Migration into Drinking Water Aquifers in Southern New York. AB - Environmental concerns regarding the potential for drinking water contamination in shallow aquifers have accompanied unconventional energy development in the northern Appalachian Basin. These activities have also raised several critical questions about the hydrogeological parameters that control the naturally occurring presence and migration of hydrocarbon gases in shallow aquifers within petroliferous basins. To interrogate these factors, we analyzed the noble gas, dissolved ion, and hydrocarbon gas (molecular and isotopic composition) geochemistry of 98 groundwater samples from south-central New York. All samples were collected ?1km from unconventional drilling activities and sample locations were intentionally targeted based on their proximity to various types of documented fault systems. In agreement with studies from other petroliferous basins, our results show significant correlations between elevated levels of radiogenic [4 He], thermogenic [CH4 ], and dissolved ions (e.g., Cl, Br, Sr, Ba). In combination, our data suggest that faults have facilitated the transport of exogenous hydrocarbon-rich brines from Devonian source rocks into overlying Upper Devonian aquifer lithologies over geologic time. These data conflict with previous reports, which conclude that hydrodynamic focusing regulates the occurrence of methane and salt in shallow aquifers and leads to elevated levels of these species in restricted flow zones within valley bottoms. Instead, our data suggest that faults in Paleozoic rocks play a fundamental role in gas and brine transport from depth, regulate the distribution of their occurrence in shallow aquifers, and influence the geochemistry of shallow groundwater in this petroliferous basin. PMID- 29409145 TI - Evaluation of the Catalytic Relevance of the CO-Bound States of V-Nitrogenase. AB - Binding and activation of CO by nitrogenase is a topic of interest because CO is isoelectronic to N2 , the physiological substrate of this enzyme. The catalytic relevance of one- and multi-CO-bound states (the lo-CO and hi-CO states) of V nitrogenase to C-C coupling and N2 reduction was examined. Enzymatic and spectroscopic studies demonstrate that the multiple CO moieties in the hi-CO state cannot be coupled as they are, suggesting that C-C coupling requires further activation and/or reduction of the bound CO entity. Moreover, these studies reveal an interesting correlation between decreased activity of N2 reduction and increased population of the lo-CO state, pointing to the catalytic relevance of the belt Fe atoms that are bridged by the single CO moiety in the lo CO state. Together, these results provide a useful framework for gaining insights into the nitrogenase-catalyzed reaction via further exploration of the utility of the lo-CO conformation of V-nitrogenase. PMID- 29409147 TI - Uncovering the Rab5-Independent Autophagic Trafficking of Influenza A Virus by Quantum-Dot-Based Single-Virus Tracking. AB - Autophagy is closely related to virus-induced disease and a comprehensive understanding of the autophagy-associated infection process of virus will be significant for developing more effective antiviral strategies. However, many critical issues and the underlying mechanism of autophagy in virus entry still need further investigation. Here, this study unveils the involvement of autophagy in influenza A virus entry. The quantum-dot-based single-virus tracking technique assists in real-time, prolonged, and multicolor visualization of the transport process of individual viruses and provides unambiguous dissection of the autophagic trafficking of viruses. These results reveal that roughly one-fifth of viruses are ferried into cells for infection by autophagic machineries, while the remaining are not. A comprehensive overview of the endocytic- and autophagic trafficking process indicates two distinct trafficking pathway of viruses, either dependent on Rab5-positive endosomes or autophagosomes, with striking similarities. Expressing dominant-negative mutant of Rab5 suggests that the autophagic trafficking of viruses is independent on Rab5. The present study provides dynamic, precise, and mechanistic insights into the involvement of autophagy in virus entry, which contributes to a better understanding of the relationship between autophagy and virus entry. The quantum-dot-based single virus tracking is proven to hold promise for autophagy-related fundamental research. PMID- 29409146 TI - Reliability and Validity of Three Versions of the Brief Fear of Negative Evaluation Scale in Patients With Systemic Sclerosis: A Scleroderma Patient Centered Intervention Network Cohort Study. AB - OBJECTIVE: Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently 3 versions of the BFNE with strong demonstrated measurement properties: two 8-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients. METHODS: Participants were 1,010 patients with SSc enrolled in the Scleroderma Patient Centered Intervention Network cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson's product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively. RESULTS: Confirmatory factor analysis demonstrated that 1-factor models fit acceptably well for the 12-item BFNE-II, the 8-item BFNE-S, and the 8-item BFNE-8. Additionally, all Cronbach's alphas demonstrated excellent internal consistency reliability (BFNE-II = 0.98, BFNE-S = 0.97, BFNE-8 = 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education. CONCLUSION: Psychometric support was found for all 3 versions of the BFNE, although the longer 12-item BFNE-II did not improve measurement compared to the shorter 8-item versions (BFNE-S and BFNE-8). Of these 2, the BFNE-S has been more widely studied, with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc. PMID- 29409148 TI - Hydrocarbon-Rich Groundwater above Shale-Gas Formations: A Karoo Basin Case Study. AB - Horizontal drilling and hydraulic fracturing have enhanced unconventional hydrocarbon recovery but raised environmental concerns related to water quality. Because most basins targeted for shale-gas development in the USA have histories of both active and legacy petroleum extraction, confusion about the hydrogeological context of naturally occurring methane in shallow aquifers overlying shales remains. The Karoo Basin, located in South Africa, provides a near-pristine setting to evaluate these processes, without a history of conventional or unconventional energy extraction. We conducted a comprehensive pre-industrial evaluation of water quality and gas geochemistry in 22 groundwater samples across the Karoo Basin, including dissolved ions, water isotopes, hydrocarbon molecular and isotopic composition, and noble gases. Methane-rich samples were associated with high-salinity, NaCl-type groundwater and elevated levels of ethane, 4 He, and other noble gases produced by radioactive decay. This endmember displayed less negative delta13 C-CH4 and evidence of mixing between thermogenic natural gases and hydrogenotrophic methane. Atmospheric noble gases in the methane-rich samples record a history of fractionation during gas-phase migration from source rocks to shallow aquifers. Conversely, methane-poor samples have a paucity of ethane and 4 He, near saturation levels of atmospheric noble gases, and more negative delta13 C-CH4 ; methane in these samples is biogenic and produced by a mixture of hydrogenotrophic and acetoclastic sources. These geochemical observations are consistent with other basins targeted for unconventional energy extraction in the USA and contribute to a growing data base of naturally occurring methane in shallow aquifers globally, which provide a framework for evaluating environmental concerns related to unconventional energy development (e.g., stray gas). PMID- 29409149 TI - Absolute Configuration of Pharmaceutical Research Compounds Determined by X-ray Powder Diffraction. AB - The absolute configuration of active pharmaceutical ingredients (APIs) was determined by generating salts of the active pharmaceutical ingredient (API) with counterions of known chirality, and determining the crystal structures by X-ray powder diffraction. This approach avoids the (often tedious) growth of single crystals, and is successful with very limited quantities of material (less than 1 mg). The feasibility of the method is demonstrated on five examples, and its limitations are discussed as well. PMID- 29409150 TI - Measuring Disease Damage and Its Severity in Childhood-Onset Systemic Lupus Erythematosus. AB - OBJECTIVE: To describe the frequency and types of disease damage occurring with childhood-onset systemic lupus erythematosus (SLE) as measured by the 41-item Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and to assess the SDI's ability to reflect damage severity. METHODS: Information for the SDI was prospectively collected from 1,048 childhood-onset SLE patients. For a subset of 559 patients, physician rated damage severity measured by visual analog scale (MD VAS damage) was also available. Frequency of SDI items and the association between SDI summary scores and MD VAS damage were estimated. Finally, an international consensus conference, using nominal group technique, considered the SDI's capture of childhood-onset SLE-associated damage and its severity. RESULTS: After a mean disease duration of 3.8 years, 44.2% of patients (463 of 1,048) already had an SDI summary score >0 (maximum 14). The most common SDI items scored were proteinuria, scarring alopecia, and cognitive impairment. Although there was a moderately strong association between SDI summary scores and MD VAS damage (Spearman's r = 0.49, P < 0.0001) in patients with damage (SDI summary score >0), mixed-effects analysis showed that only 4 SDI items, each occurring in <2% of patients overall, were significantly associated with MD VAS damage. There was consensus among childhood onset SLE experts that the SDI in its current form is inadequate for estimating the severity of childhood-onset SLE-associated damage. CONCLUSION: Disease damage as measured by the SDI is common in childhood-onset SLE, even with relatively short disease durations. Given the shortcomings of the SDI, there is a need to develop new tools to estimate the impact of childhood-onset SLE-associated damage. PMID- 29409151 TI - Facile Synthesis of Porous Pd3 Pt Half-Shells with Rich "Active Sites" as Efficient Catalysts for Formic Acid Oxidation. AB - Exploring highly efficient electrocatalysts is greatly important for the widespread uptake of the fuel cells. However, many newly generated nanocrystals with attractive nanostructures often have extremely limited surface area or large particle-size, which leads them to display limited electrocatalytic performance. Herein, a novel anode catalyst of hollow and porous Pd3 Pt half-shells with rich "active sites" is synthesized by using urea as a guiding surfactant. It is identified that the formation of Pd3 Pt half-shells involves the combination of bubble guiding, in situ deposition of particles and bubble burst. The obtained Pd3 Pt half-shells demonstrate a rich edge area with abundant exposed active sites and surface defects, indicating great potential for the electrocatalysis. When used as an electrocatalyst, the Pd3 Pt half-shells exhibit remarkably improved electrocatalytic performance for formic acid oxidation (FAO), where it promotes the dehydrogenation process of FAO by suppressing the formation of poisonous species COads via the electronic effect and ensemble effect. PMID- 29409152 TI - Is Rheumatoid Arthritis a Cardiovascular Risk-Equivalent to Diabetes Mellitus? AB - OBJECTIVE: The 2013 American College of Cardiology/American Heart Association cholesterol treatment guidelines recommend statins for patients with diabetes mellitus ages 40-75 years due to their elevated cardiovascular disease (CVD) risk. We compared the incidence of hospitalized acute myocardial infarction (MI), stroke, and coronary revascularization according to whether patients had diabetes mellitus, rheumatoid arthritis (RA), both, or neither. METHODS: Using 2006-2010 private and public health plan claims, we identified 4 mutually exclusive retrospective cohorts ages >40 years: patients with RA and diabetes mellitus, RA only, diabetes mellitus only, or neither condition. Patients with prevalent CVD were excluded. Outcomes included acute MI and stroke, identified from inpatient discharge diagnosis codes, and coronary revascularization from procedure codes. Across the 4 cohorts, we calculated incidence rates (IRs) of the outcomes, standardized to the 2010 US census age and sex distribution. RESULTS: We identified 920,772 eligible participants. The age- and sex-standardized IRs (per 1,000 person-years) for MI were highest among patients with RA and diabetes mellitus (IR 12.6 [95% confidence interval (95% CI) 10.7-14.7]), followed by patients with diabetes mellitus only (IR 10.7 [95% CI 10.3-11.0]), RA only (IR 5.7 [95% CI 5.2-6.3]), and with neither condition (IR 4.2 [95% CI 4.1-4.3]). CONCLUSION: Findings from the present study suggest that while CVD risk in RA is elevated, it is lower in magnitude compared to the CVD risk associated with diabetes mellitus. Therefore, considering RA a diabetes mellitus risk-equivalent with respect to hyperlipidemia management may not be appropriate. PMID- 29409153 TI - Quality of life and its contributing factors in an elderly community-dwelling population in Shanghai, China. AB - BACKGROUND: We aimed to investigate the relationship between quality of life and the factors that may influence it in an elderly community-dwelling population in Shanghai. METHODS: From August to October 2014, elderly individuals were enrolled from three randomly selected communities in Shanghai. Participant information was collected from responses to a general questionnaire and to the Lubben Social Network Scale-6, Cumulative Illness Rating Scale for Geriatrics, Patient Health Questionnaire, and the 12-item Short Form Health Survey. The factors influencing quality of life were explored in a multivariate stepwise linear regression model. RESULTS: Physical and mental component summary scores for the elderly in Shanghai communities were 50.1 +/- 10.1 and 47.3 +/- 7.9, respectively. Physical component summary scores in the rural area were higher than those in the urban-rural intersection area (a place where urban and rural transitions are taking place) (52.32 +/- 9.81 vs 49.63 +/- 9.33, P < 0.05) and the urban area (52.32 +/- 9.81 vs 47.34 +/- 10.18, P < 0.05). Additionally, mental component summary scores in the rural area were higher than those in the urban-rural intersection area (52.63 +/- 9.28 vs 48.43 +/- 9.42, P < 0.05) and the urban area (52.63 +/- 9.28 vs 48.13 +/- 10.69, P < 0.05). CONCLUSIONS: Depression, self-care ability, and medical care burden were found to be significantly associated with the quality of life of elderly individuals in Shanghai, China. Therefore, more attention should be paid to the mental health of this elderly population. PMID- 29409155 TI - Using virtual reality to distinguish subjects with multiple- but not single domain amnestic mild cognitive impairment from normal elderly subjects. AB - AIM: Spatial disorientation is a hallmark of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. Our aim was to use virtual reality to determine the allocentric and egocentric memory deficits of subjects with single-domain aMCI (aMCIsd) and multiple-domain aMCI (aMCImd). For this purpose, we introduced an advanced virtual reality navigation task (VRNT) to distinguish these deficits in mild Alzheimer's disease (miAD), aMCIsd, and aMCImd. METHODS: The VRNT performance of 110 subjects, including 20 with miAD, 30 with pure aMCIsd, 30 with pure aMCImd, and 30 cognitively normal controls was compared. Our newly developed VRNT consists of a virtual neighbourhood (allocentric memory) and virtual maze (egocentric memory). Verbal and visuospatial memory impairments were also examined with Rey Auditory-Verbal Learning Test and Rey-Osterrieth Complex Figure Test, respectively. RESULTS: We found that miAD and aMCImd subjects were impaired in both allocentric and egocentric memory, but aMCIsd subjects performed similarly to the normal controls on both tasks. The miAD, aMCImd, and aMCIsd subjects performed worse on finding the target or required more time in the virtual environment than the aMCImd, aMCIsd, and normal controls, respectively. Our findings indicated the aMCImd and miAD subjects, as well as the aMCIsd subjects, were more impaired in egocentric orientation than allocentric orientation. CONCLUSION: We concluded that VRNT can distinguish aMCImd subjects, but not aMCIsd subjects, from normal elderly subjects. The VRNT, along with the Rey Auditory-Verbal Learning Test and Rey-Osterrieth Complex Figure Test, can be used as a valid diagnostic tool for properly distinguishing different forms of aMCI. PMID- 29409154 TI - Anosognosia in mild Alzheimer's disease is correlated with not only neural dysfunction but also compensation. AB - BACKGROUND: Anosognosia in Alzheimer's disease (AD) is a complicated, non-unitary phenomenon. In a clinical setting, patients with mild AD often preserve their awareness partially. We hypothesized that compensation, as well as neural dysfunction, could be correlated with anosognosia in mild AD. METHODS: The severity of anosognosia was evaluated using the Anosognosia Questionnaire for Dementia in 37 subjects with mild AD or mild cognitive impairment due to AD. The subjects also underwent single-photon emission computed tomography with N isopropyl-p-[123 I]iodoamphetamine. Correlation between the severity of anosognosia and perfusion was assessed, and anosognosia (+) and (-) groups were compared. RESULTS: The severity of anosognosia was relatively mild; the mean Anosognosia Questionnaire for Dementia score was 6.76 +/- 14.16. Subjects were divided into two groups: anosognosia (+) (n = 11) and anosognosia (-) (n = 26). In the single-photon emission computed tomography data analysis, the severity of anosognosia was correlated with both lower regional cerebral blood flows of the right prefrontal cortex and higher regional cerebral blood flows of the parietal cortex, especially the left temporo-parietal junction. CONCLUSIONS: Our results suggest that anosognosia in mild AD could be correlated with compensation as well as neural dysfunction. We speculate that this compensation may be related to the retrieval of outdated autobiographical memory. PMID- 29409156 TI - Fatigue in Parkinson's disease: concepts and clinical approach. AB - Parkinson's disease (PD) is a progressive neurological disorder characterized by a large number of motor and non-motor features. Fatigue is one of the most common and most disabling symptoms among patients with PD, and it has a significant impact on their quality of life. Although fatigue has been recognized for a long time, its pathophysiology remains poorly understood, and there is no evidence to support any therapeutic approach in PD patients. Expert consensus on case definition and diagnostic criteria for PD-related fatigue have been recently published, and although they still need to be adequately validated, they provide a great step forward in the study of fatigue. The goal of this article is to provide relevant information for the identification and management of patients with fatigue. PMID- 29409157 TI - Sentence composition ability in two patients with non-fluent/agrammatic variant primary progressive aphasia. AB - Agrammatism is one of the core clinical features of non-fluent/agrammatic variant primary progressive aphasia, and it has traditionally been considered the hallmark of non-fluent aphasia in Western countries. However, agrammatic speech may remain undetected in Japanese patients because of the agglutinative structure of the language and high flexibility in word order. In the present study, we aimed to analyze agrammatism in the speech production of Japanese patients with aphasia due to neurodegenerative disease using an anagram test generated by our laboratory. Four patients were recruited from the dementia clinic at Tohoku University Hospital between December 2014 and August 2015: two patients with non fluent/agrammatic variant primary progressive aphasia, one with semantic variant primary progressive aphasia, and one with probable Alzheimer's disease experiencing episodic memory impairment accompanied by transcortical sensory aphasia. All patients underwent thorough neurological and neuropsychological testing before performing a Japanese anagram task based on the Northwestern Anagram Test. Our findings indicated that the two patients with non fluent/agrammatic variant primary progressive aphasia exhibited poorer performance on the anagram task than the remaining two patients. Therefore, the anagram test used in the present study may aid in detecting output aspects of agrammatism in Japanese patients with aphasia, although future studies are required to develop a standardized version of test. PMID- 29409158 TI - Usefulness of carer-held records to support informal caregivers of patients with dementia who live at home. AB - AIM: It is unclear whether carer-held records (CHR) are useful for patients with dementia. In this study, we evaluated the usefulness of the CHR for patients with dementia at the municipal level. METHODS: Candidates for CHR use in this study were informal caregivers of patients with dementia who lived at home in Kawanishi, Japan. CHR users were those who are involved in the patient's care and treatment, such as informal caregivers, family physicians, dementia specialists, care professionals, and care service coordinators, known as 'care managers' in Japan. Collaborative meetings were held every month mainly to help users, especially care managers, learn how to effectively use CHR. We surveyed informal caregivers before and 1.5 years after the start of CHR use to evaluate whether CHR improved collaboration and information provision. The Zarit Caregiver Burden Interview and Dementia Behaviour Disturbance Scale were also administered. We divided the informal caregivers who continued CHR use for 1.5 years into two subgroups based on whether their care manager attended the collaborative meetings at least twice. In addition, we divided informal caregivers into three subgroups depending on their relationship to the patient: spouse, child, or daughter-in law. RESULTS: The study initially consisted of 201 informal caregivers. Among them, 74 informal caregivers continued CHR use for 1.5 years. The information provision score significantly improved after CHR use for all informal caregivers. The collaboration score significantly improved after CHR use only for informal caregivers whose care managers attended at least two collaborative meetings. The Zarit Caregiver Burden Interview score significantly improved after CHR use for daughter-in-law caregivers. The Dementia Behaviour Disturbance Scale scores did not significantly improve after CHR use. CONCLUSIONS: CHR were useful for informal caregivers of patients with dementia. However, care managers need to teach informal caregivers how to properly use CHR. PMID- 29409159 TI - Prevalence of hyperphagia in Alzheimer's disease: a meta-analysis. AB - BACKGROUND: Unlike other behavioural and psychological symptoms of dementia, hyperphagia is less recognized among patients with Alzheimer's disease (AD). The prevalence of hyperphagia varies among studies, but there has been no systematic review or meta-analysis. METHODS: An extensive search on the literature on hyperphagia in AD published between 1 January 1980 and 30 October 2017 was conducted. Data on the prevalence were retrieved. Meta-analysis with a random effect model was performed to determine the pooled estimate of prevalence. Meta regression analysis was performed based on study characteristics, population demographics, or condition information. RESULTS: Results from 20 studies were extracted. Twenty-six reported cases of hyperphagia were identified. The mean age of onset was 70.7 +/- 8.9 years, with a male predominance (68.4%). Hyperphagia occurred in all stages of AD. Only eight studies reported the prevalence of hyperphagia. Meta-analysis showed a pooled prevalence of hyperphagia of 18.6%. Publication bias may have been present. Meta-regression showed that ethnicity accounted for the variance among studies (coefficient: -1.247 (95% confidence interval: -1.978 to -0.516), R2 analogue: 0.77, P < 0.001). CONCLUSIONS: Hyperphagia occurs in all stages of AD. In this meta-analysis of eight published studies, the prevalence of hyperphagia was 18.6%. In view of the possible publication bias, a large-scale study on hyperphagia is recommended in the future. PMID- 29409160 TI - Decreasing hospitalizations in patients on hemodialysis: Time for a paradigm shift. AB - Hospitalizations drive up to 35% of the astronomical costs of care for patients on hemodialysis and are associated with poor outcomes. We describe outpatient care-sensitive categories of hospitalization risks in an effort to engage stakeholders and patients, as stakeholders, in mitigating hospitalizations. These categories include: (1) fluid (interdialytic weight gain (IDWG) and chronic volume status), (2) infection (vascular access and malnutrition/inflammation resilience), and c) psychosocial (poor social support, poor self-efficacy, and mood disorders) risks. Barriers to improving hospitalization outcomes, especially as they relate to above risk categories, exist at multiple stakeholder levels and include: (1) dialysis facilities (strict shift changes, personnel challenges), (2) nephrologists (static dialysis prescriptions and protocols based on dialysis facility metrics), and (3) patients (lack of engagement and self-efficacy). System-level elements, such as payment models, help to propagate these barriers. In this article, we seek to shift the care paradigm discussion to patient trajectories and long-term outcomes, and to active engagement of patients as self managers, through which we hope to impact on high inpatient resource utilization. We will also focus attention on the complex interplay of practices that have become acceptable care structures, but that may be deleterious to outcomes. Only after thorough consideration of these topics can we hope to impact on this important problem. PMID- 29409161 TI - Triple test, a diagnostic observation, can detect cognitive impairment in older adults. AB - BACKGROUND: A simple, quick, and efficient screening tool for detecting mild cognitive impairment (MCI) and Alzheimer's disease (AD) is essential, especially in the primary care setting. In this study, we examined the neuropsychological profiles of elderly patients and aimed to assess the diagnostic value of the triple test, comprised of the attended alone sign (AAS), head-turning sign, and applause sign (AS), for detecting MCI and AD. METHOD: Comprehensive geriatric assessment was performed in 354 elderly outpatients, and the presence or absence of AS, AAS and HTS was investigated. RESULTS: Of the 354 patients, 93 patients were considered to be cognitively impaired (MCI: 30; AD: 63); the remaining 261 were cognitively healthy. Relative to those without AS, patients with AS had significantly lower scores on the Mini-Mental State Examination, the clock drawing test, Instrumental Activities of Daily Living Scale, and Basic Activities of Daily Living Scale (P < 0.001, for each). Similar significant differences were found between patients who were positive and negative for the HTS (P < 0.001) and between those who attended the clinic alone and those who were accompanied (P < 0.001). The sensitivity of the triple test for identifying cognitively impairment (CI), MCI, and AD was 0.61, 0.30, and 0.72, respectively; the specificity was 0.85, 0.68, and 0.83, respectively; and the positive and negative predictive values were 0.69, 0.09, and 0.59, respectively, and 0.79, 0.90, and 0.89, respectively. CONCLUSIONS: The present study suggests that the triple test is a simple, quick, and efficient screening tool for detecting cognitive impairment, and the results may reflect deterioration in patients' activities of daily living. Additionally, it could be advantageous in clinical practice because educational level does not affect the test outcome. Therefore, it may be an appropriate test to screen for cognitive impairment in the elderly, both as a bedside diagnostic test and in daily clinical practice, especially in the primary care setting. PMID- 29409162 TI - Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia. AB - BACKGROUND: Since the 1950s antipsychotic medication has been extensively used to treat people with chronic mental illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. OBJECTIVES: To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other chronic mental illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. SEARCH METHODS: We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other chronic mental illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. MAIN RESULTS: We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. AUTHORS' CONCLUSIONS: Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area. PMID- 29409163 TI - Clinical characteristics and quality of life of older adults with cognitive impairment in Macao. AB - BACKGROUND: Little is known about the characteristics of older adults with cognitive impairment in Macao. This study aimed to determine the prevalence of cognitive impairment and the quality of life (QOL) of older adults living in the community and nursing homes. METHODS: A consecutive sample of 413 subjects (199 from the community; 214 from nursing homes) was recruited and interviewed using standardized instruments. Cognition was measured with the Repeatable Battery for the Assessment of Neuropsychological Status and QOL with the brief version of the World Health Organization Quality of Life instrument. RESULTS: Altogether 87 subjects (21.0%) had cognitive impairment. On multivariate analyses, advanced age (P < 0.001, OR = 1.06, 95%CI: 1.03-1.1) and depressive symptoms (P = 0.03, OR = 1.07, 95%CI: 0.005-1.1) were positively associated with cognitive impairment. Married marital status (P = 0.01, OR = 0.3, 95%CI: 0.1-0.7) and higher education level (P < 0.001, OR = 0.1, 95%CI: 0.06-0.3) were negatively associated with cognitive impairment. After the confounders were controlled for, cognitive impairment was significantly associated with the lower psychological (F (11,412) = 6.3, P = 0.01) and social relationship domains of QOL (F (11,412) = 4.0, P = 0.04). CONCLUSION: Cognitive impairment was found to be common in community dwelling and nursing home resident older adults in Macao. Given cognitive impairment's negative impact on QOL, appropriate strategies should be implemented to improve access to treatment in this population. PMID- 29409164 TI - Reliability and structural validity of the Chinese version of the Neuropsychiatric Inventory, Nursing Home version. AB - BACKGROUND: With the increasing number of dementia patients in China, there is a pressing need for a reliable and valid Chinese instrument that can measure neuropsychiatric symptoms in institutionalized dementia patients. This study examined the reliability and structural validity of the Chinese version of the Neuropsychiatric Inventory, Nursing Home version (NPI-NH), in a sample of institutionalized dementia patients in China. METHODS: A total of 112 residents with dementia (Clinical Dementia Rating = 1: 10.7%; Clinical Dementia Rating = 2: 39.3%; Clinical Dementia Rating = 3: 50.0%) and 30 informants participated in this cross-sectional study. Reliability was tested using Cronbach's alpha and intra-class correlation coefficient. Principal component analysis was used to evaluate the factor structure of the inventory. RESULTS: Of the patients, 92.9% had at least one neuropsychiatric symptom. Apathy (57%) was the most common symptom. The Chinese version of the Neuropsychiatric Inventory, Nursing Home version, showed acceptable internal consistency (Cronbach's alpha for the total scale, frequency, severity, and disturbance subscales were 0.64, 0.70, 0.73, and 0.80, respectively) and test-retest reliability (intra-class correlation coefficient for the total scale, frequency, severity, and disturbance subscales were 0.93, 0.92, 0.89, and 0.91, respectively). Five factors-psychomotor behaviour, affective symptoms, psychosis, sleep disorders, and eating disorders were identified for the total scale. The cluster symptoms aggression and irritability, depression and anxiety, and delusions and hallucinations were three of the optimally stable groups of symptoms. CONCLUSIONS: This study demonstrated that the Chinese version of the Neuropsychiatric Inventory, Nursing Home version, is a valid and reliable instrument for evaluating neuropsychiatric symptoms in institutionalized dementia patients. PMID- 29409165 TI - Frequency of an accessory popliteal efferent lymphatic pathway in dogs. AB - Staging and therapeutic planning for dogs with malignant disease in the popliteal lymph node are based on the expected patterns of lymphatic drainage from the lymph node. The medial iliac lymph nodes are known to receive efferent lymph from the popliteal lymph node; however, an accessory popliteal efferent pathway with direct connection to the sacral lymph nodes has also been less frequently reported. The primary objective of this prospective, anatomic study was to describe the frequency of various patterns of lymphatic drainage of the popliteal lymph node. With informed client consent, 50 adult dogs with no known disease of the lymphatic system underwent computed tomographic lymphography after ultrasound guided, percutaneous injection of 350 mg/ml iohexol into a popliteal lymph node. In all 50 dogs, the popliteal lymph node drained directly to the ipsilateral medial iliac lymph node through multiple lymphatic vessels that coursed along the medial thigh. In 26% (13/50) of dogs, efferent vessels also drained from the popliteal lymph node directly to the internal iliac and/or sacral lymph nodes, coursing laterally through the gluteal region and passing over the dorsal aspect of the pelvis. Lymphatic connections between the right and left medial iliac and right and left internal iliac lymph nodes were found. Based on our findings, the internal iliac and sacral lymph nodes should be considered when staging or planning therapy for dogs with malignant disease in the popliteal lymph node. PMID- 29409166 TI - Development of the Japanese version of the Quality of Life in Late-stage Dementia Scale. AB - AIM: Until now, there has been no instrument to measure the quality of life (QoL) of patients with severe dementia in Japan. The purpose of this study was to translate the Quality of Life in Late-stage Dementia Scale and to evaluate the reliability and validity of the Japanese version (QUALID-J). METHODS: We translated the Quality of Life in Late-stage Dementia into Japanese with permission from the original authors. We assessed a total of 70 dementia patients (14 men, 56 women; mean age: 87.4 +/- 7.9 years) with the QUALID-J. RESULTS: The test-retest and inter-rater reliability of the QUALID-J was significant. With regard to the criterion-related validity, the correlation coefficient for the total score between the QUALID-J and Quality of Life for Alzheimer's Disease was 0.287 (P < 0.05). With regard to the construct validity, the QUALID-J total score was significantly correlated with the Mini-Mental State Examination (rho = 0.346, P < 0.01), the Cognitive Test for Severe Dementia (rho = -0.323, P < 0.01), the Neuropsychiatry Inventory-Nursing Home version (rho = 0.386, P < 0.01), the Cornell Scale for Depression in Dementia (rho = 0.262, P < 0.05), the Physical Self-Maintenance Scale (rho = -0.283, P < 0.05), and the Pain Assessment in Advanced Dementia (rho = 0.530, P < 0.01). CONCLUSION: The results of this study showed that the QUALID-J is a reliable and valid quality of life scale for severe dementia. This scale finally enables an adequate assessment of the quality of life of patients with severe dementia in Japan, which has not been possible until now. PMID- 29409167 TI - Three-dimensional printing enhances preparation for repair of double outlet right ventricular surgery. AB - OBJECTIVE: To assess the clinical value of three-dimensional (3D) printing technology for treatment strategies for complex double outlet right ventricle (DORV). METHODS: Twenty-five patients with complex double outlet right ventricle were enrolled in this study. The patients were divided into two groups: 3D printing group (eight patients) and a non-3-D printing control group (17 patients). The cardiac images of patients in the 3D printing group were transformed to Digital Imaging and Communications and were segmented and reconstructed to create a heart model. No cardiac models were created in the control group. A Pearson coefficient analysis was used to assess the correlation between measurements of 3D printed models and computed tomography angiography (CTA) data. Pre-operative assessment and planning were performed with 3D printed models, and then operative time and recovery time were compared between the two groups. RESULTS: There was good correlation (r = 0.977) between 3D printed models and CTA data. Patients in the 3D printing group had shorter aortic cross-clamp time (102.88 vs 127.76 min, P = 0.094) and cardiopulmonary bypass time (151.63 vs 184.24 min; P = 0.152) than patients in the control group. Patients with 3D printed models had significantly lower mechanical ventilation time (56.43 vs 96.76 h, P = 0.040) and significantly shorter intensive care unit time (99.04 vs 166.94 h, P = 0.008) than patients in the control group. CONCLUSIONS: 3D printed models can accurately demonstrate anatomic structures and are useful for pre operative treatment strategies in DORV. PMID- 29409168 TI - Three-dimensional printing in cardiac surgery: Enhanced imagery results in enhanced outcomes. PMID- 29409169 TI - Coronary artery revascularization in infants, children, and adolescents: The internal mammary artery is still the conduit of choice. PMID- 29409170 TI - Virtual Issue Highlighting Selected Women Analytical Chemists. PMID- 29409171 TI - Comparing 30-day all-cause readmission rates between tibiotalar fusion and total ankle replacement. AB - BACKGROUND: End-stage ankle arthritis is a debilitating condition that negatively impacts patient quality of life. Tibiotalar fusion and total ankle replacement are treatment options for managing ankle arthritis. Few studies have examined short term readmission rates of these two procedures. The objective of this study was compare all-cause 30-day readmission rates between patients undergoing tibiotalar fusion vs. total ankle replacement. METHODS: This study queried the Nationwide Readmission Database (NRD) from 2013-2014 and used international classification of disease, 9th revision (ICD-9) procedure codes to identify all patients who underwent a tibiotalar fusion or a total ankle replacement. Comorbidities, insurance status, hospital characteristics, and readmission rates were statistically compared between the two cohorts. Risk factors were then identified for 30-day readmission. RESULTS: A total of 5660 patients were analyzed with 2667 in the tibiotalar fusion cohort and 2993 in the total ankle replacement cohort. Univariate analysis revealed that the readmission rate after tibiotalar fusion (4.4%) was statistically greater than after total ankle replacement (1.4%). Multivariable regression analysis indicated that deficiency anemia (OR 2.18), coagulopathy (OR 3.51), renal failure (OR 2.83), other insurance relative to private (OR 3.40), and tibiotalar fusion (OR 2.51) were all statistically significant independent risk factors for having a readmission within 30-days. CONCLUSIONS: These findings suggest that during the short-term period following discharge from the hospital, patients who received a tibiotalar fusion are more likely to experience a 30-day readmission. These findings are important for decision making when a surgeon encounters a patient with end stage ankle arthritis. LEVEL OF EVIDENCE: Level III, cohort study. PMID- 29409172 TI - Minimally invasive distal first metatarsal osteotomy can be an option for recurrent hallux valgus. AB - BACKGROUND: Recurrence rate of surgical treatment of hallux valgus ranges in the literature from 2.7% to 16%, regardless of used procedure. In this study, long term results of a minimally invasive distal osteotomy of the first metatarsal bone for treatment of recurrent hallux valgus are described. METHODS: 32 consecutive percutaneous distal osteotomies of the first metatarsal were performed in 26 patients for treatment of recurrent hallux valgus. Primary surgery had been soft tissue procedures in 8 cases (25%), first metatarsal or phalangeal osteotomies in 19 cases (59.4%) and Keller procedures in 5 cases (15.6%). RESULTS: Patients were assessed with a mean follow-up of 9.8+/-4.3 years. All patients reported the disappearance or reduction of the pain. The mean overall AOFAS score improved from 46.9+/-17.8 points to 85.2+/-14.9 at final follow-up. The mean hallux valgus angle decreased from 26.1+/-9.1 to 9.7+/-5.4 degrees , the intermetatarsal angle decreased from 11.5+/-4.5 to 6.7+/-4.0 degrees . No major complications were recorded with a re-recurrence rate of 3.1% (1 case). CONCLUSIONS: Percutaneous distal osteotomy of the first metatarsal can be a reliable and safe surgical option in the recurrent hallux valgus with low complication rate and the advantages of a minimally invasive surgery. LEVELS OF EVIDENCE: IV, Retrospective Case Series. PMID- 29409173 TI - Characteristics of anterior inferior calcaneal cortex. AB - BACKGROUND: Minimal invasive surgery of calcaneal fracture provided satisfactory outcomes. In tongue type calcaneal fracture, percutaneous screw usually purchases in anterior inferior calcaneal cortex. However, there was no detail about the cortex of anterior inferior calcaneus so the surface anatomy and cortical thickness of this area were studied. METHODS: 88 calcaneus from embalmed cadavers were enrolled. Anterior part of the inferior cortex was identified. Surface anatomy was examined. Length, anterior and posterior widths were measured. Anterior inferior calcaneal cortex was divided into anterior, middle and posterior segments. The cortical thickness at middle, medial most and lateral most of 3 segments were measured. RESULTS: Anterior inferior calcaneal cortex was a long trapezoidal shape with well-defined borders as a dense and thick cortical bone, convex relief from medial and lateral walls. Mean(SD) length was 33.40(3.46) millimeters (mm). Median(min,max) of anterior and posterior width were 10.50(8.21,19.26) mm and 14.00(10.05,20.42) mm, respectively. Mean(SD) of middle cortical thickness of anterior and middle segment were 3.12(0.76) and 3.72(0.74). Median(min,max) middle cortical thickness of posterior segment was 3.13(1.62,6.51) mm. Whereas, of the medial most were 1.31(0.78,3.11), 1.31(0.90,2.57) and 1.26(0.85,2.61) mm and of the lateral most were 1.17(0.67,2.64), 1.38(0.80,2.55) and 1.31(0.84,2.61) mm, respectively. Inter intraobserver reliabilities of the measurements were >0.79. The statistical analysis showed the middle cortex is significantly the thickest (P<0.001) and posterior width is significant wider than the anterior (P<0.001). CONCLUSIONS: Anterior inferior calcaneal cortex has special characteristics in term of surface anatomy, width and thickness. For the percutaneous screw insertion from posterosuperior to anterior inferior calcaneus in tongue type calcaneal fracture, we recommend that screw should purchase in middle cortex due to maximal cortical thickness as well as its cortical width could accept 6.5 or 7.0mm screw without screw extrusion. PMID- 29409174 TI - All-inside arthroscopic allograft reconstruction of the anterior talo-fibular ligament using an accesory transfibular portal. AB - BACKGROUND: Anatomic graft reconstruction of the anterior talo-fibular ligament is an alternative for patients who are bad candidates for standard procedures such as a Brostrom-Gould reconstruction (high-demand athletes, obesity, hyperlaxity or collagen disorders, capsular insufficiency or talar avulsions). The purpose of this study is to describe an all-inside arthroscopic technique for ATFL reconstruction, and the results in a series of patients with chronic ankle instability. METHODS: We reviewed patients with chronic ATFL ruptures treated with an all-inside arthroscopic allograft reconstruction of the ATFL, with a minimum 2-year follow-up. Twenty-two patients with lateral ankle instability were included. Mean follow-up was 34+/-2.5 months. RESULTS: The mean AOFAS score improved from 62.3+/-6.7 points preoperatively to 97.2+/-3.2 points at final follow-up. Three patients suffered complications: one case each of ankle rigidity, superficial peroneal nerve injury and fibular fracture. CONCLUSIONS: Chronic ATFL injuries are amenable to all-inside arthroscopic allograft reconstruction fixed with tenodesis screws. This procedure simplifies other reported techniques in that it facilitates identification and bone tunnel placement of the talar ATFL insertion. PMID- 29409175 TI - Vitamin D levels in 577 consecutive elective foot & ankle surgery patients. AB - BACKGROUND: Vitamin D deficiency is a global concern impacting upon large communities and certain disease populations. It can adversely affect the outcome of orthopaedic operations. We aimed to perform an audit of the Vitamin D status of patients in two centres in the United Kingdom undergoing elective foot and ankle surgery. METHODS: Serum 25-hydroxyvitamin-D (vitamin D) levels were obtained prospectively in 577 consecutive elective patients undergoing elective foot and ankle surgery between October 2014 and March 2017 (29 months). Variables including age, gender, ethnicity, location, season, month and procedure type were recorded. RESULTS: 577 patients were included over the study period. 62.0% were female. Mean age was 53.2 (median 54.5, range 16.7-86.6). 300 patients were treated in Northampton and 277 in Leicester. The serum 25-hydroxyvitamin-D levels for the patient group were normally distributed. The mean was 52.3nmol/L (SD 28.0; range 7.5-175) and the median 47.5nmol/L. 21.7% were grossly deficient, 31.9% deficient, 28.9% insufficient and 17.5% within normal range. Age, gender and procedure type did not statistically affect vitamin D levels (p=0.5, t-test). Ethnicity, location and Winter season did affect Vitamin D levels (p<0.05). August was the most significant month with levels significantly higher than January, February, March, April, June, November and December (p<0.05, one-way ANOVA). CONCLUSIONS: Only 1 in 5.7 patients had a normal Vitamin D level and 1 in 4.6 were grossly deficient. Ethnicity and patient location significantly affected Vitamin D results. Summer months were noted to demonstrate significantly the highest levels and August the highest. We did not find that age or gender affected Vitamin D levels in our cohort. PMID- 29409176 TI - Minimally invasive surgery for young female patients with mild-to-moderate juvenile hallux valgus deformity. AB - BACKGROUND: We aimed to compare the clinical and radiographic outcomes of minimally invasive surgery (MIS) and distal chevron metatarsal osteotomy (DCMO) for young female patients with mild-to-moderate juvenile hallux valgus deformity. METHODS: We retrospectively reviewed the radiographs and clinical findings of young female patients with mild-to-moderate juvenile hallux valgus who underwent MIS (25 feet) or DCMO (30 feet). In 12 of 25 MIS feet, 2.0-mm bio-absorbable pins were used as an additional fixation device crossing the osteotomy site, and 1.4 mm Kirschner wires were used in the remaining 13 feet. RESULTS: Radiographic and clinical parameters preoperatively and at the final follow-up were not significantly different between the 2 groups. There were no significant differences in the increments of hallux valgus angle (HVA), distal metatarsal articular angle, medial sesamoid position, first metatarsal length, metatarsal length index, or relative second metatarsal length. Two MIS subgroups according to the additional fixation device showed no significant differences in HVA, the first to second intermetatarsal angle lateral translation ratio, or plantar offset at the final follow-up. CONCLUSIONS: MIS for young female patients with mild-to-moderate juvenile hallux valgus deformity had similar radiographic and clinical outcomes compared to DCMO. Regarding additional fixation crossing the osteotomy site, both temporary Kirschner wires and absorbable pins showed no radiographic differences in terms of correction maintenance. LEVEL OF EVIDENCE: 3. PMID- 29409177 TI - Can the introduction of Enhanced Recovery After Surgery (ERAS) reduce the variation in length of stay after total ankle replacement surgery? AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been successfully adopted across a range of procedures. This study explores whether there is scope to improve length of stay (LOS) for total ankle replacement surgery (TAR) in the UK by implementing ERAS pathways. METHODS: Hospital Episode Statistics (HES) data (April 2015/March 2016) on LOS for TAR were analysed. A literature search was then carried out to examine whether there were any publications on outpatient TAR and/or the use of ERAS protocols. RESULTS: Mean observed LOS was 3.3days (range 0 17.3) days. Case mix-adjusted expected LOS range was 2.0-5.7 days. It is likely that the wide observed LOS range is due to differences in local processes and pathways. Two papers were found by the literature search. CONCLUSIONS: TAR should aim to be outpatient surgery as the literature, and data demonstrating scope for improvement in LOS, suggest this should be possible. PMID- 29409178 TI - Outcomes of flexor digitorum longus (FDL) tendon transfer in the treatment of Achilles tendon disorders. AB - BACKGROUND: In patients with chronic Achilles tendon disorders, Achilles tendon debridement can be supplemented with a tendon transfer, with the flexor hallucis longus tendon (FHL) transfer representing the most common used technique. Our study describes clinical and functional results of patients treated with flexor digitorum longus (FDL) tendon transfer in the treatment of patients with chronic Achilles tendon disorders. METHODS: Retrospective study of prospectively collected data of thirteen patients (15 feet) that underwent FDL tendon transfer as part of the treatment of chronic Achilles tendon disorders. Preoperative and postoperative assessment included visual analogue score (VAS) for pain, SF-36 survey and lower extremity functional scale (LEFS). The average follow-up was 26.4 (range, 14-56) months. Patients were also assessed for ability to perform single leg heel rise test, muscle power for plantar flexion of the lesser toes, surgical scar condition and associated complications. RESULTS: At final follow up, we found significant postoperative improvement in VAS score (6.6 +/- 2.99 vs 1.06 +/- 1.43; p < .0001), SF-36 physical component summary (PCS) (28.20 +/- 10.71 vs 45.04 +/- 11.19; p < .0001) and LEFS (36.13 +/- 20.49 vs 58.73 +/- 18.19; p < .0001). Twelve patients (92%) could perform a single leg heel rise test in the operated extremity, although there was significant difference when comparing operated and uninvolved sides (4.86 +/- 3.36 cm vs 7.18 +/- 3.40 cm; p = .0002). One patient reported weakness for plantar flexion of the lesser toes, without balance or gait disturbances. Two patients (2 feet, 13.3%) had superficial infections and one patient (one foot, 6.6%) needed operative debridement for a deep infection. CONCLUSIONS: FDL tendon transfer represent an operative alternative in the treatment of chronic Achilles tendon disorders. Our study showed good clinical outcomes with low complications and donor site morbidity. LEVEL OF EVIDENCE: Observational study, case series - level IV. PMID- 29409179 TI - Limb salvage for malignant bone tumours of distal tibia with dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array with ankle arthrodesis and preserving subtalar joint. AB - BACKGROUND: The treatment of malignant tumours of the distal tibia is a challenging surgical problem due to the scarce soft tissue coverage and the instability of the ankle joint that often occurs after resection. However, there is no consensus on the ideal treatment for malignant tumours of the distal tibia. METHODS: We report a new reconstruction for five patients with high-grade osteosarcoma of distal tibia, using dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array and external fixator, with ankle arthrodesis and preserving subtalar joints. The patients were examined clinically and radiographically. RESULTS: The average follow-up duration was 88 months. The mean wound healing time was 14 days. Bone healing was achieved for all the five patients at an average time of 7 months. There were no complications of mal union, skin necrosis, post-operative infection, loss of internal fixation, peroneal nerve injury. One patient had a local recurrence, which required amputation 15 months postoperatively. The remaining four patients were able to walk with an average functional score of 81.25% according to MSTS. CONCLUSIONS: Our study shows that this technique is safe and effective to perform implantation of dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array and preserving subtalar joints in terms of the distal tibial reconstruction for malignant bone tumour of the distal tibia. This reconstruction represents a biological alternative protocol for limb salvage in cases of malignant bone tumour of the distal tibia, with encouraging results and with the advantages of lower complications and accelerating recovery. LEVEL OF EVIDENCE: Level IV. PMID- 29409180 TI - Conversion of painful tibiotalocalcaneal arthrodesis to total ankle replacement using a 3-component mobile bearing prosthesis. AB - BACKGROUND: The aim of this study was to assess the short-term clinical and radiographic outcomes in patients who underwent conversion of a painful tibiotalocalcaneal arthrodesis to a total ankle replacement. METHODS: Six patients with painful ankle arthrodesis after tibiotalocalcaneal arthrodesis were included in this study. In all patients, conversion to total ankle replacement was performed using a 3rd-generation, non-constrained, cementless three-component prosthesis. The outcomes were analyzed at a mean follow-up of 3.4+/-1.9years (range 1.0-6.5). RESULTS: One patient with painful arthrofibrosis underwent two open arthrolysis procedures at 1.2 and 5.6 years post index surgery, respectively. No revision of tibial or talar prosthesis components was necessary in this study. All patients reported significant pain relief and significant improvement in functional status. CONCLUSION: In the present study, the conversion of a painful ankle arthrodesis following tibiotalocalcaneal arthrodesis to a total ankle replacement was a reliable surgical treatment. PMID- 29409181 TI - Technique tip: EDL-to-EHL double loop transfer for extensor hallucis longus reconstruction. AB - BACKGROUND: Extensor hallucis longus (EHL) tendon injuries often occur in the setting of lacerations to the dorsum of the foot. End-to-end repair is advocated in acute lacerations, or in chronic cases when the tendon edges are suitable for tension free repair. Reconstruction with allograft or autograft is advocated for cases not amenable to a primary direct repair. This is often seen in cases with tendon retraction and more commonly in the chronic setting. In many countries the use of allograft is very limited or unavailable making reconstruction with autograft and tendon transfers the primary choice of treatment. Tendon diameter mismatch and diminished resistance are common issues in other previously described tendon transfers. METHODS: We present the results of a new technique for reconstruction of non-reparable EHL lacerations in three patients using a dynamic double loop transfer of the extensor digitorum longus (EDL) of the second toe that addresses these issues. RESULTS: At one-year follow up, all patients recovered active/passive hallux extension with good functional (AOFAS Score) and satisfaction results. No reruptures or other complications were reported in this group of patients. No second toe deformities or dysfunction were reported. CONCLUSIONS: Second EDL-to-EHL Double Loop Transfer for Extensor Hallucis Longus reconstruction is a safe, reproducible and low-cost technique to address EHL ruptures when primary repair is not possible. LEVEL OF EVIDENCE: IV (Case Series). PMID- 29409182 TI - Matrix-associated stem cell transplantation (MAST) in chondral lesions at the ankle as part of a complex surgical approach- 5-year-follow-up in 100 patients. AB - BACKGROUND: The aim of the study was to assess the 5-year-follow-up after matrix associated stem cell transplantation (MAST) in chondral lesions at the ankle as part of a complex surgical approach. METHODS: In a prospective consecutive non controlled clinical follow-up study, all patients with chondral lesion at the ankle that were treated with MAST from April 1, 2009 to May 31, 2012 were included. Size and location of the chondral lesions, method-associated problems and the Visual-Analogue-Scale Foot and Ankle (VAS FA) before treatment and at follow-up were analysed. Stem cell-rich blood was harvested from the ipsilateral pelvic bone marrow and centrifuged (10min, 1500RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Gide) that was fixed into the chondral lesion with fibrin glue. RESULTS: One hundred and twenty patients with 124 chondral lesions were included in the study. Age at the time of surgery was 35 years on average (range, 12-65 years), 74 (62%) were male. VAS FA before surgery was 45.2 on average (range, 16.4-73.5). Lesions were located at medial talar shoulder, n=55; lateral talar shoulder, n=58 (medial and lateral, n=4); tibia, n=11. Lesion size was 1.7cm2 on average (range, .8-6cm2). One hundred patients (83%) completed 5-year-follow-up after. VAS FA improved to 84.4 (range, 54.1-100; t-test, p<0.01). CONCLUSIONS: MAST as part of a complex surgical approach led to improved and high validated outcome scores in the mid-term-follow up. No method related complications were registered. Even though a control group is missing, we conclude that MAST as part of a complex surgical approach is an effective method for the treatment of chondral lesions of the ankle for at least five years. PMID- 29409183 TI - Long-term results after triple arthrodesis: Influence of alignment on ankle osteoarthritis and clinical outcome. AB - BACKGROUND: Pain, deformity and instability are the main reasons for fusion of the tarsal joints, a triple arthrodesis. The short and midterm results show that mobility, function and satisfaction increase postoperatively. However, osteoarthritis (OA) of the adjacent ankle joint is described as a long-term complication. Alignment of the foot could be an influencing factor. The aim of this study was to examine whether malalignment after triple arthrodesis leads to a higher grade of OA at long-term follow-up. METHODS: Between 1991 and 2002, 81 patients underwent a triple arthrodesis. Preoperatively, postoperatively, 3, 7.5 and 15 years after surgery, dorsoplantar (DP) and lateral X-rays were taken and used to evaluate the degree of OA and the geometry of the foot. The degree of OA was estimated using the Kellgren and Lawrence score. The geometry of the foot was assessed using Meary's angle; a Meary's angle exceeding 15 degrees in DP and/or greater than -5 to 5 degrees from the lateral view was defined as malalignment. In addition to the radiological evaluation, clinical scores (FFI and AOFAS) were recorded. RESULTS: Thirty-five patients (40 feet) were available for analysis 15 years after surgery. In 19 cases there was an increase in ankle OA following the operation. Eight feet showed malalignment on the lateral view and 28 on the DP view. There was no difference in both an increase of ankle OA or clinical outcome between correct aligned feet and feet classified as malaligned. Thirty-three patients with 38 treated feet stated that they would decide to undergo the treatment again. Two patients would not want to undergo the same surgery again. The patients were satisfied with the result of surgery, clinical scores improved after surgery and remained stable in the long-term. CONCLUSIONS: Triple arthrodesis is a salvage procedure in patients with a painful and deformed hindfoot and results in a clinically beneficial outcome, even 15 years after surgery. The present study did not show that malalignment after triple arthrodesis results in a higher grade of OA of the ankle joint in the long-term. The cause of the aggravation of OA is still not fully understood and needs further research. Nevertheless, clinical results are satisfying 15 years postoperatively. PMID- 29409184 TI - Peri-prosthetic bone cysts after total ankle replacement. A systematic review and meta-analysis. AB - BACKGROUND: Periprosthetic cystic osteolysis is a well-known complication of total ankle replacement. Several theories have been proposed for its aetiology, based on individual biomechanical, radiological, histopathology and outcome studies. METHODS: Studies that met predefined inclusion/exclusion criteria were analysed to identify literature describing the presence of peri-prosthetic ankle cystic osteolysis. Quantitative data from the selected articles were combined and statistically tested in order to analyse possible relations between ankle peri prosthetic bone cysts and specific implant characteristics. RESULTS: Twenty-one articles were elected, totalizing 2430 total ankle replacements, where 430 developed peri-prosthetic cystic osteolysis. A statistically significant association (P<.001) was found between the presence of bone cysts and non anatomic implant configuration, hydroxyapatite-coating, mobile-bearing and non tibial-stemmed implants. No significant association existed between the type of constraining and the presence of cysts (P>.05). CONCLUSIONS: Non-anatomic, mobile bearing, hydroxyapatite-coated and non tibial-stemmed total ankle replacements are positively associated with more periprosthetic bone cysts. PMID- 29409185 TI - Reconstruction of the lateral ankle ligaments using the anterior half of peroneus longus tendon graft. AB - BACKGROUND: This study aimed to report our institution's experience in the treatment of chronic lateral ankle instability using the anterior half of the peroneus longus tendon (AHPLT) to reconstruct the lateral ligament. METHODS: This retrospective study included 32 consecutive patients with chronic lateral ankle instability who underwent surgery from January 2013 to December 2014. All patients had failed to resolve with conservative treatment. A total of 32 ankles underwent AHPLT transfer. Patients returned for a clinical and radiologic follow up evaluation at an average of 28 (range, 24-35) months postoperatively. Outcomes were assessed by comparison of pre- and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores, visual analog scale pain scores, and Karlsson scores, and the radiographic assessment including talar tilt and anterior talar translation. RESULTS: Thirty-two patients (32 ankles) (100%) returned for final evaluation. All patients had an excellent or good outcome on patient subjective self-assessment, pain scores, AOFAS scores, and Karlsson scores at final follow up. Ankle range of motion was not affected by lateral ankle reconstruction. The talar tilt was significantly reduced from a preoperative mean of 14.1+/-4.2 degrees to 3.4+/-1.3 degrees postoperatively (P<.001), and the anterior drawer was significantly reduced from a preoperative mean of 13.8+/-3.4mm to 3.6+/-1.5mm after lateral ankle ligamentous reconstruction (P<.001). CONCLUSIONS: AHPLT transfer to reconstruct the lateral ligament resulted in a high percentage of successful results, with excellent ankle stability and not affected of ankle motion. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 29409186 TI - Medial and lateral exostoses of the distal phalanx of the hallux: A potentially painful bunion-like structure. Part 1: Incidence and clinical application. AB - BACKGROUND: Exostoses at the base of the distal phalanx of the great toe are usually asymptomatic. The literature has not generally considered them as the origin of a possible problem resulting from a pressure conflict between hallux and shoe (medial aspect) or second toe (lateral aspect) nor a potential complication of surgical correction of hallux valgus deformity. No studies, to our knowledge, have evaluated its possible correlation with other foot disorders. When one of these neglected exostoses became painful after surgical correction of hallux valgus, we decided to start a study to determine their possible origin, prevalence in daily practice and histo-pathological morphology. METHODS: Two hundred and fifty-four feet of patients (average age 41.7y.) were enrolled in the study from January 2007 to June 2009. Dorsoplantar weight-bearing radiographs were used to analyze the presence of exostoses and their correlation with the distal phalanx morphology, metatarsal formula (or transverse plane orientation of the metatarsal heads parabola) and hallux valgus angles. Patients were classified according to their age and main symptom for consultation. Four exostoses removed from cadaver feet were also analyzed microscopically. RESULTS: Osseous excrescences arising on the medial or lateral aspect at the proximal part of the terminal phalanx of the hallux were observed in 132 feet (51.9%). Thirty-five feet out of these 132 (13.7%) had exostoses on both sides of the phalanx.A statistically significant positive correlation was found between the presence of a medial exostosis of the phalanx and the severity of HVA. Patients with higher IPH and asymmetry angles have a lower prevalence of medial exostoses (p<0.05). Amongst the different morphologies of the second phalanx, exostoses were most likely found in the standard form. CONCLUSIONS: Prevalence of exostoses at the base of the distal phalanx is high (51.9% of the studied feet). Histological findings would suggest that these exostoses could be considered a mechanical reactive process, produced by a chronic irritation by shoes. We encourage surgeons to be aware of its potential clinical implications. Direct resection is very simple and the most appropriate treatment for symptomatic cases. PMID- 29409187 TI - Flexor hallucis longus transfer versus turndown flaps augmented with flexor hallucis longus transfer in the repair of chronic Achilles tendon rupture. AB - BACKGROUND: Repairs of chronic Achilles tendon ruptures are technically challenging due to large defects after scar excision. Multiple techniques for repair have been proposed but little consensus on best practice established. This study aims to compare flexor hallucis longus (FHL) transfers versus turndown flaps augmented by FHL transfers. METHODS: Between 2005 and 2015, 49 unilateral repairs of chronic Achilles tendon ruptures were performed. We retrospectively compared the outcomes of 20 patients who underwent FHL transfer with 19 patients who underwent turndown flaps augmented with FHL transfer before surgery and at three time points after surgery (three, six and twelve months). Visual Analogue Scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale and the 36-Item Short Form Health Survey (SF-36) were used to evaluate outcome. RESULTS: Both techniques demonstrated significant improvement in their outcome scores and were comparable to one another. At one year, the mean VAS score was 0 for both groups. The mean AOFAS Ankle-Hindfoot score was 90+/-11 (FHL) and 95+/-10 (FHL with turndown flaps); and SF-36 scores showed significant improvements in physical, role and social function scores. Turndown flaps augmented with FHL transfer however required significantly longer operative time (100+/-21min) compared to FHL transfer alone (73+/-23min). CONCLUSIONS: FHL transfer required significantly less operative time compared to turndown flaps augmented with FHL transfer, with comparable outcomes. FHL transfer is a reliable and effective technique in the repair of chronic Achilles tendon ruptures. PMID- 29409188 TI - Reliability of hindfoot alignment measurements from standard radiographs using the methods of Meary and Saltzman. AB - BACKGROUND: Few methods have been described for measuring hindfoot alignment from an anteroposterior view. The objective of this study was to compare two methods of angular measurement based on the views of Meary and Saltzman. METHODS: Thirty asymptomatic volunteers were included. Four radiographs were performed: the views of Meary and Saltzman with parallel feet and with the Fick correction. The reproducibility was determined by the inter- and intraobserver variability (ICC). RESULTS: Meary's method revealed a mean valgus angulation of 3.9 degrees (SD 3.47 degrees ). The reliability was extremely variable with a mean ICC of 0.59. The best reproducibility was obtained with Meary's method with and without Fick correction. CONCLUSION: The results of this study show that the reliability of the angular measurements depends on the radiographic view and measurement method chosen. The lateral Fick correction did not counteract the influence of tibial rotation. The same method should be used consistently. PMID- 29409189 TI - The peroneal strength deficits in patients with chronic ankle instability compared to ankle sprain copers and normal individuals. AB - BACKGROUND: Despite a consensus regarding the correlation of peroneal strength deficit with chronic ankle instability (CAI), there are conflicting reports in regards to peroneal strength as assessed by isokinetic dynamometer in patients with CAI. The purpose of this study was to evaluate the changes of isokinetic strength in patients with CAI compared to ankle sprain copers and normal individuals. METHODS: Forty-two patients (CAI group) with chronic ankle instability who were scheduled for the modified Brostrom procedure met inclusion criteria. Thirty-one ankle sprain copers (ASC group) who were eligible at 6 months after acute injury and 30 controls were recruited. The muscle strength associated with four motions of the ankle were evaluated using isokinetic dynamometer. RESULTS: Peak torque for inversion and eversion at 60 degrees /s angular velocity were significantly lower in the CAI group compared to the ASC and control group (P=.004, P<.001, respectively). Deficit ratio of peak torque for eversion at 60 degrees /s and 120 degrees /s in the CAI group were 33.8% and 19.8%, respectively, which indicated significant side to side differences (both P<.001). The evertor/invertor strength ratio (0.59) for eversion at 60 degrees /s was significantly lower in the CAI group (P<.001). CONCLUSION: As compared to the ankle sprain copers and normal individuals, patients with chronic ankle instability who were scheduled for modified Brostrom procedure demonstrated a significant weakness of isokinetic peroneal strength. Isokinetic muscular assessment can provide the useful preoperative informations regarding functional ankle instability focusing on peroneal weakness. PMID- 29409190 TI - Clinical presentation and surgical management of chronic Achilles tendon disorders - A retrospective observation on a set of consecutive patients being operated by the same orthopedic surgeon. AB - BACKGROUND: Non-invasive treatment is not always successful in patients with Achilles tendon disorders, and surgical treatment is instituted as the next step. There is sparse knowledge about the diagnoses, pain levels before surgery, surgically confirmed pathologies and postoperative complications in large patient groups. AIMS: To study the diagnoses, pain scores before surgery, macroscopic surgical findings and postoperative complications in a series of patients treated for Achilles disorders. MATERIAL AND METHODS: One surgeon operated on 771 Achilles tendons of 481 men and 290 women during a 10-year period. The clinically and ultrasound confirmed diagnoses, pre-operative pain and functional scores (Visual Analogue Scale, VAS, range 0-100; Victorian Institute Sports Tendon Assessment - Achilles questionnaire, VISA-A), macroscopic findings during surgery and postoperative complications, were retrospectively collected from a database. RESULTS: Clinically, by ultrasound and during surgery midportion Achilles tendinopathy was confirmed in 519 (67%) patients, 41% of them had a thickened plantaris tendon located close the Achilles tendon. Partial midportion rupture was found in 31 (4%) patients, chronic midportion rupture in 12 (2%) patients and insertional Achilles tendinopathy, including superficial and retro-calcaneal bursitis, Haglund deformity, distal Achilles tendinopathy, plantaris tendon pathology, and bone spurs, in 209 (27%) patients. The mean pre-operative pain scores for midportion Achilles tendinopathy were 73 (VAS) and 45 (VISA-A), and for insertional Achilles tendinopathy 77 (VAS) and 39 (VISA-A). For midportion Achilles tendinopathy there were 14 (3%), and for insertional Achilles tendinopathy 10 (5%), postoperative complications. CONCLUSIONS: Patients presenting high pain scores from midportion Achilles tendinopathy were the most common. Plantaris tendon involvement is a frequent observation. For insertional Achilles tendinopathy the combination of pathology in the subcutaneous and retrocalcaneal bursa, a Haglund deformity and distal Achilles tendinopathy/tendinosis was most frequent. SERIES STUDY, LEVEL OF EVIDENCE: 4. PMID- 29409191 TI - Evaluation of peritalar subluxation in adult acquired flatfoot deformity using computed tomography and weightbearing multiplanar imaging. AB - BACKGROUND: The aim of this study was to assess the inferior talus-superior talus (inf-tal-sup-tal) angle (previously proven reliable in multiplanar-weight bearing imaging (MP-WB)) on both computed tomography (CT) and MP-WB scans. We sought to compare the angle between the two modalities in both AAFD and control groups, as well as to compare the groups to each other. METHODS: Inf-tal-sup-tal angles were compared between a stage II AAFD group (n=38) with routine MP-WB and CT scans and a control group (n=20) with preoperative CT scans for lisfranc injuries and normal hindfoot alignment after healing. RESULTS: The CT inf-tal-sup-tal angle was significantly greater in AAFD compared to control (AAFD, 12+/-6; control, 5+/ 4; p<0.001), but was even greater with MP-WB. There was no significant correlation between inf-tal-sup-tal angles on MP-WB and CT (Pearson's=0.29, p=0.08). CONCLUSIONS: MP-WB imaging proved to be correlated more strongly with AAFD than CT by revealing greater hindfoot valgus. This confirmed that CT scans are useful in predicting AAFD, but cannot be used as a surrogate for MP-WB scans. PMID- 29409192 TI - Reliability and validity of the Finnish version of the Visual Analogue Scale Foot and Ankle (VAS-FA). AB - BACKGROUND: There have previously been no validated foot and ankle-specific patient-reported outcome measures in Finnish. METHODS: The Visual Analogue Scale Foot and Ankle (VAS-FA) was translated and adapted into Finnish. Thereafter, 165 patients who had undergone foot and ankle surgery completed a questionnaire set on two separate occasions. Analyses included testing of floor-ceiling effect, internal consistency, reproducibility, and validity. RESULTS: Minor linguistic differences emerged during the translation. Some structural adjustments were made. The mean (SD) total VAS-FA score was 74 (23). In the three subscales, maximum scores were noted in 2-5% of the responses, and internal consistency ranged from 0.81 to 0.94. Reproducibility was excellent (ICC, 0.97). The total VAS-FA score correlated significantly with the Lower Extremity Functional Scale (r=0.84) and the 15D Mobility dimension (r=0.79). The VAS-FA loaded on two factors (pain/movement and problems/limitations). CONCLUSIONS: The Finnish version of the VAS-FA has high reliability and strong validity. PMID- 29409193 TI - Gastrocnemius recession for recalcitrant plantar fasciitis in overweight and obese patients. AB - BACKGROUND: Plantar fasciitis is a common foot pathology that is typically treated non-operatively. However, a minority of patients fail non-operative management, develop chronic symptoms, and request a surgical option. Gastrocnemius recession has recently been shown to be effective for the treatment of chronic plantar fasciitis. The purpose of this paper is to present evidence that gastrocnemius recession is safe and effective in the subset of chronic plantar fasciitis patients who are overweight and obese. METHODS: We retrospectively reviewed 18 cases (17 patients) of chronic plantar fasciitis in overweight or obese patients who underwent gastrocnemius recession (mean age=46years, mean body mass index=34.7kg/m2, mean follow-up=20months). Data was gathered regarding pre-operative and post-operative pain (visual analog scale, 0 10), Foot Function Index score, and complications. RESULTS: Mean Foot Function Index score improved from 66.4 (range, 32.3-97.7) preoperatively to 26.5 (range, 0-89.4) postoperatively (p<0.01). Mean pain score improved from 8.3 (range, 5-10) preoperatively to 2.4 (range, 0-7) at final follow-up (p<0.01). CONCLUSIONS: Gastrocnemius recession improved foot function and pain symptoms in overweight and obese patients with chronic plantar fasciitis. PMID- 29409194 TI - Reliability, validity and responsiveness of the German Manchester-Oxford Foot Questionnaire (MOXFQ) in patients with foot or ankle surgery. AB - BACKGROUND: Patient-reported outcome measures are a critical tool in evaluating the efficacy of orthopaedic procedures. The intention of this study was to develop and culturally adapt a German version of the Manchester-Oxford Foot Questionnaire (MOXFQ) and to evaluate reliability, validity and responsiveness. METHODS: According to guidelines forward and backward translation has been performed. The German MOXFQ was investigated in 177 consecutive patients before and 6 months after foot or ankle surgery. All patients completed MOXFQ, Foot and Ankle Outcome Score (FAOS), Short form 36 and numeric scales for pain and disability (NRS). Test-Retest reliability, internal consistency, floor and ceiling effects, construct validity and minimal important change were analyzed. RESULTS: The German MOXFQ demonstrated excellent test-retest reliability with ICC values >0.9 Cronbach's alpha (alpha) values demonstrated strong internal consistency. No floor or ceiling effects were observed. As hypothesized MOXFQ subscales correlated strongly with corresponding FAOS and SF-36 domains. All subscales showed excellent (ES/SRM >0.8) responsiveness between preoperative assessment and postoperative follow-up. CONCLUSIONS: The German version of the MOXFQ demonstrated good psychometric properties. It proofed to be a valid and reliable instrument for use in foot and ankle patients. PMID- 29409195 TI - Anterolateral talar palpation: A complementary test for ankle instability. AB - BACKGROUND: The anterior drawer test is traditionally used to assess ankle instability, but we believe that there is room for a small but effective improvement by adding digital palpation of the talus. We aimed to determine the accuracy of anterolateral talar palpation (ATP) in the diagnosis of ankle instability by comparing it with the traditional anterior drawer test. METHODS: Fourteen symptomatic and 10 asymptomatic patients were examined for excessive mobility through comparison of both ankles by two blinded orthopedic surgeons, each one using one of the above-mentioned tests. Symptomatic patients were also referred for stress radiography and magnetic resonance imaging (MRI). RESULTS: ATP was the most sensitive test, but also the least specific, yielding more positive results than the other tests, including tests with negative MRI. ATP and radiography had the highest accuracy and highest level of agreement with MRI. CONCLUSIONS: ATP significantly improved diagnostic accuracy in detecting ankle instability. LEVEL OF EVIDENCE: IV: cross-sectional study. PMID- 29409196 TI - Postoperative CT-scan 3D reconstruction of the calcaneus following lateral calcaneal lengthening osteotomy for flatfoot deformity in children. Is the surgical procedure potentially associated with subtalar joint damage? AB - BACKGROUND: Several anatomical studies have shown that the articular facets of the calcaneus can present with different anatomy. This study assessed the 3D anatomy of lateral calcaneal lengthening (LCL) osteotomy in relation to the anterior and middle facet of the calcaneus in a group of skeletally immature patients treated for symptomatic flatfoot deformity. METHODS: During the study period, 14 consecutive patients (10 males, 4 females) presenting symptomatic flatfoot (20 feet) with different aetiologies underwent LCL osteotomy and CT scan with 3D reconstruction of the operated feet. Anatomy of articular factes of the calcaneus were graded according to Bunning & Barnett's classification. In order to assess clinical and functional outcome, all patients were evaluated according to Yoo et al.'s, Mosca's and AOFAS clinical criteria before surgery and at last follow-up visit. RESULTS: Despite proving difficult to assess (10 out of 20 feet), dimensions of bone and joint structures revealed significant anatomical variations. In particular, working to Bunning & Barnett's classification, anatomy of the articular facet varied significantly among patients, and in Bunning & Barnett type-B1 or B2 the LCL osteotomy necessarily violates the articular surface of the anterior and middle facet of the calcaneus due to the fact that the two facets are fused together (single articular surface). CONCLUSIONS: These biometric notions allow a better understanding of the impact on articular facets of the calcaneus of the osteotomy procedure suggested by Evans and Mosca. We anticipate that the findings reported here should lead to improved techniques for assessing all bone structures of the hindfoot, support logical classifications of the different pathological situations, and ultimately lead to improved treatment strategies. PMID- 29409197 TI - Location and direction of the nutrient artery to the first metatarsal at risk in osteotomy for hallux valgus. AB - BACKGROUND: Osteotomy for hallux valgus interrupts intraosseous blood supply to the first metatarsal, presumably causing non-union, delayed union, or osteonecrosis of the head of the first metatarsal. We investigated the first metatarsal nutrient artery, arising from the first dorsal metatarsal artery, and identified aspects of surgical technique contributing to nutrient artery injury. METHODS: Enhanced computed tomography scans of 8 feet of 8 fresh cadavers were assessed. Barium was injected through the external iliac artery; location and direction of the first metatarsal nutrient artery was recorded. RESULTS: Mostly, the nutrient artery entered the first metatarsal at the distal third or junction of the middle and distal thirds obliquely from a proximal direction coronally; entry point and direction varied axially. Saw blade overpenetration alone or with extensive capsular stripping might damage the artery. CONCLUSIONS: Location and direction of the first metatarsal nutrient artery was established. PMID- 29409198 TI - Result of IOFIX (Intra Osseous FIXation) device for first metatarsophalangeal joint arthrodesis: A single surgeon's series. AB - BACKGROUND: Arthrodesis of the first metatarsophalangeal joint (MTPJ) is a common procedure to treat significant first MTPJ arthritis. However, dorsal plates used for this have been associated with high incidence of metalwork removal. The IOFIX (Intra-Osseous FIXation) is a fixed angle device that is noted to provide a more uniform compression over a larger aspect of the fusion surfaces than a screw construct alone with the advantage of minimizing soft tissue irritation which can reduce the need for subsequent implant removal. METHODS: Twenty one consecutive patients who underwent primary first MTPJ fusion with the IOFIX were reviewed. The mean age of the cohort was 63 years (range 47-81), with 80% female. The ratio of left to right was 9:12. The mean follow up of was 28 months (range 13.4-48.2 months). Outcomes analyzed were rate of fusion, Manchester-Oxford foot questionnaire (MOXFQ) score, patient satisfaction, improvement in the intermetatarsal angle and complications. RESULTS: Complete fusion of the first MTPJ was achieved in twenty (95%) patients. One patient had a non union and another patient developed a delayed union. The mean preoperative MOXFQ score improved from 49.7 (95% confidence interval: 46-52) to 17.9 (95% confidence interval: 12-22), p<0.05.Improvement gained in all the domains of the MOXFQ score (walking/standing, pain and social) was statistically significant (p<0.05). Eighteen out of 21 patients (85%) were very pleased or fairly pleased with the procedure. CONCLUSION: Early results show that the rate of fusion achieved by using the IOFIX device for the first MTPJ arthrodesis in our series was found to be comparable to other devices quoted in the literature. PMID- 29409199 TI - Treatment of first metatarsophalangeal joint arthritis using hemiarthroplasty with a synthetic cartilage implant or arthrodesis: A comparison of operative and recovery time. AB - BACKGROUND: First metatarsophalangeal joint (MTPJ1) hemiarthroplasty using a novel synthetic cartilage implant was as effective and safe as MTPJ1 arthrodesis in a randomized clinical trial. We retrospectively evaluated operative time and recovery period for implant hemiarthroplasty (n=152) and MTPJ1 arthrodesis (n=50). METHODS: Perioperative data were assessed for operative and anaesthesia times. Recovery and return to function were prospectively assessed with the Foot and Ankle Ability Measure (FAAM) Sports and Activities of Daily Living (ADL) subscales and SF-36 Physical Functioning (PF) subscore. RESULTS: Mean operative time for hemiarthroplasty was 35+/-12.3min and 58+/-21.5min for arthrodesis (p<0.001). Anaesthesia duration was 28min shorter with hemiarthroplasty (p<0.001). At weeks 2 and 6 postoperative, hemiarthroplasty patients demonstrated clinically and statistically significantly higher FAAM Sport, FAAM ADL, and SF-36 PF subscores versus arthrodesis patients. CONCLUSION: MTPJ1 hemiarthroplasty with a synthetic cartilage implant took less operative time and resulted in faster recovery than arthrodesis. LEVEL OF EVIDENCE: III, Retrospective case control study. PMID- 29409200 TI - The results of Scarf osteotomy combined with distal soft tissue procedure are mostly satisfactory in surgical management of moderate to severe hallux valgus. AB - BACKGROUND: Intrinsically stable diaphyseal osteotomy gained popularity in recent years for symptomatic hallux valgus deformities. In this study, Scarf osteotomy results, in surgical management of moderate to severe hallux valgus, are presented. METHODS AND PATIENTS: Study group consisted of 40 feet of 32 (28 females, four males) patients surgically managed by Scarf osteotomy between September 2009 and 2011, with a mean age of 52,98 (range, 31-75) years at the time of surgery. Patient satisfaction and VAS were used for subjective evaluation while for objective measures AOFAS score, first metatarsophalangeal joint ROM and radiological measurements (intermetatarsal, hallux valgus and distal metatarsal articular angles) were evaluated. RESULTS: Mean follow-up period was 38 (range, 24-60) months. Sixteen feet (40%) were reported as very satisfied, 19 (47,5%) as satisfied and the remaining five (12,5%) as unsatisfied resulting with a total of 35 (87,5%) satisfaction. The mean preoperative VAS and AOFAS forefoot scores improved from 8,13+/-0,791 to 2,68+/-1,228 (p=0,0001) and from 58,25+/-6,15 to 78,25+/-8,13 (p=0,0001) on the final follow-up, respectively. The postoperative change of first metatarsophalangeal joint ROM was not statistically significant (p=0,281). On the radiological evaluation; intermetatarsal and hallux valgus angles improved from a mean value of 14,77+/-1,76 to 8,13+/-1,52 degrees (p=0,0001) and from 35,28+/-5,86 to 20,10+/-5,55 degrees (p=0,0001), respectively. Distal metatarsal articular angle did not show any statistically significant change (p=0,195). CONCLUSION: Scarf osteotomy combined with distal soft tissue procedure is a technically demanding procedure. The osteotomy is intrinsically stable and the correction power is high and the results are mostly satisfactory. PMID- 29409201 TI - Quantitative relationship of first metatarsophalangeal head morphology to hallux rigidus and hallux valgus. AB - BACKGROUND: Previous qualitative studies have linked first metatarsal head morphology with hallux valgus (HV) and hallux rigidus (HR). This study used a quantitative measurement of 1st MT radius of curvature to assess if HR MT heads were flatter than HV heads. METHODS: Weight bearing foot films were used in HV, HR, and normal patients (no forefoot complaints) to measure the metatarsal head radius of curvature (normalized by dividing the radius of curvature by the first metatarsal length to adjust for magnification and foot size). RESULTS: Radiographs from 299 feet were analyzed (105 normal, 57 HR, and 137 HV). The mean normalized radius of curvature was smaller in HV than HR, with normal feet in between (p<.05 for all comparisons). Metatarsal head curvature did not vary with age, weight, or BMI. CONCLUSION: These quantitative measurements are consistent with qualitative observations, validating the use of subjective metatarsal head morphology assessments. PMID- 29409202 TI - Achillon versus open surgery in acute Achilles tendon repair. AB - BACKGROUND: Open Achilles tendon repairs (OATR) are associated with high complication rates. Minimally invasive surgery (MIS) techniques like the Achillon Achilles tendon repair (AATR) were developed to reduce this. We performed a systematic review and meta-analysis to compare OATR with AATR. METHODS: We performed an extensive literature search including all studies that compared the two techniques. Outcomes assessed included overall complication rate, re-rupture rate, sural nerve injury, wound length, The American Orthopaedic Foot and Ankle Scores (AOFAS) scores and return to sports. RESULTS: Eight studies were suitable for inclusion totalling 210 patients in the AATR group vs 233 patients in the OATR group. Total complication rates were significantly reduced in the Achillon patients with odd ratio of 0.14 (CI 95%, 0.08-0.27, P<0.00001) in favour. There were no significant differences in re-rupture rate, sural nerve injury, return to sports and AOFAS scores following repair between the two groups. CONCLUSIONS: AATR has fewer overall complications compared with OATR. It should be considered as an alternative to open surgical repair. PMID- 29409203 TI - Intramedullary fixation of lateral malleolus using Fibula Rod System in ankle fractures in the elderly. AB - BACKGROUND: Operative management of ever increasing ankle fractures in the elderly need a reliable system of internal fixation. We present results of one such fixation, Fibula Rod System. METHODS: Patients who underwent Fibula Rod System were included. Fracture union rate, complications, time to weight bearing and patient satisfaction using FAAM score were studied. RESULTS: The mean age of the fifteen patients included was 74 years. Satisfactory reduction was achieved and maintained in all. All fractures united. There were no infections. Complications included lack of purchase of distal AP screw (n=1), fracture of fibula shaft (n=1), failure to insert syndesmotic screws through zig (n=2), delayed secondary wound healing (n=1) and removal of metal ware (n=2). At a mean follow-up of 12 months (n=10 responses), median FAAM score was 91% (Interquartile range of 62%-99%). CONCLUSION: Fibula Rod System providing good stability and union, is a reliable operation for ankle fractures in the elderly. PMID- 29409204 TI - Correction of ankle and hind foot deformity in Charcot neuroarthropathy using a retrograde hind foot nail-The Kings' Experience. AB - BACKGROUND: Corrective fusion for the unstable deformed hind foot and mid foot in Charcot Neuroarthropathy (CN) is quite challenging and is best done in tertiary centres under the supervision of multidisciplinary teams. METHODS: We present a follow up to our initial report with a series of 42 hind foot corrections in 40 patients from a tertiary level teaching hospital in the United Kingdom. The mean patient age was 59 (33-82). 17 patients had type1diabetes mellitus, 23 had type 2. 23 feet in 22 patients had chronic ulceration despite offloading. 17 patients were ASA 2 and 23 were ASA grade 3. All patients had hind foot nail fusion performed through a standard technique by the senior author and managed perioperatively by the multidisciplinary team. RESULTS: At a mean follow up of 42 months (12-99) we achieved 100% limb salvage initially and a 97% fusion rate. One patient with persisting non-union of ankle and subtalar joint with difficulty in bracing has been offered below-knee amputation. We achieved deformity correction in 100% and ulcer healing in 83%. 83% patients are able to mobilize and manage independent activities of daily living. There were 11 patients with one or more complications including metal work failure, infection and ulcer reactivation. There have been nine repeat procedures including one revision fixation and one vascular procedure. CONCLUSION: Single stage corrective fusion for hind foot deformity in CN is an effective procedure when delivered by a skilled multidisciplinary team. PMID- 29409205 TI - Clinical characteristics and surgical experience of Type III Wagstaffe fractures: Pay attention to concomitant chondral injury of the talus. AB - BACKGROUND: The purpose of this study was to investigate clinical characteristics and surgical management of Type III Wagstaffe fracture. METHODS: From August 2012 to July 2015, 13 patients with Type III Wagstaffe fractures were surgically treated. During operation, the cartilage of joint surface was explored. Wagstaffe fragment was fixed with cannulated screw or suture, Chaput fragment was fixed with cannulated screw or plate, and Cotton test was performed to evaluate the stability of syndesmosis during the operation. All the patients were followed up for 14.3 months in average. Clinical outcome was assessed with Olerud-Molander score and American Orthopedic Foot and Ankle Society (AOFAS) score. The traumatic arthritis was evaluated with osteoarthritis-score (OA-score). RESULTS: During the operation, chondral injury was found on the lateral top of the talus in 8 cases, as "kissing lesion" of Chaput fragment. The fractures healed uneventfully and all the patients recovered satisfactorily except two had moderate restriction in ankle movement. The average Olerud-Molander score and AOFAS score were 82.3 and 86.1, respectively. CONCLUSION: Type III Wagstaffe is a rare and often missed fracture. 61% are associated with a chondral lesion on the lateral top of the talus. Anatomical reduction and rigid fixation of both fragments are mandatory to obtain ankle stability and good results. PMID- 29409206 TI - Percutaneous distal osteotomy of lesser metatarsals (DMMO) for treatment of metatarsalgia with metatarsophalangeal instability. AB - BACKGROUND: Clinical and radiological results of percutaneous distal metatarsal minimally invasive osteotomy (DMMO) of the lesser rays for surgical treatment of primary metatarsalgia due to plantar overpressure with metatarsophalangeal instability are described. The aim of this prospective study was to assess the efficacy, feasibility and safety of this minimally invasive surgical (MIS) technique, verifying the possibility to lower the complication rate related to surgical exposures, to reduce operating times with comparable functional and cosmetic results to those reported with traditional open procedures. METHODS: Hundred and six consecutive percutaneous distal osteotomies without fixation (DMMO) of the second, third or fourth metatarsal bones were performed in 57 patients (70ft) with a mean age at the surgery of 60.2 years (30-81) for treatment of metatarsalgia with metatarsophalangeal instability. Patients were clinically assessed with the AOFAS and Coughlin's Scores, the latter classifying the results in relation to the patient's subjective satisfaction. RESULTS: The mean follow-up was of 45.0+/-13.3months (24-68). All patients reported the disappearance or reduction of the pain that they had experienced prior to the operation around the metatarsal heads. The mean overall AOFAS score improved from 42.7+/-13.4 points (9-77) to 92.8+/-8.6 points (44-100) at the time of final follow-up. Patient subjective satisfaction according to Coughlin's classification was excellent in 62ft (88.6%), good in 7ft (10.0%), fair in 0ft and poor in one foot (1.4%). CONCLUSIONS: We consider the percutaneous distal lesser metatarsal osteotomy without fixation (DMMO) a reliable surgical option in metatarsalgia due to metatarsophalangeal instability in early stages as in grade I and II according to Coughlin classification. PMID- 29409207 TI - Relationship between symptomatic osteochondral lesions of the talus and quality of life, body mass index, age, size and anatomic location. AB - INTRODUCTION: The aim of the study was to assess the relationship between symptomatic osteochondral lesions of the talus (OLTs) and age, body mass index (BMI), quality of life (QOL), size and anatomic location. METHODS: Fifty-two patients with chronic OLTs were analyzed including BMI, Visual Analogue Scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS), Short-Form Health Survey (SF-12 divided into Mental (MCS) and Physical (PCS) score) and the 12-Item General Health Questionnaire (GHQ-12). Every patient underwent magnetic resonance imaging (MRI) and computed tomography (CT) examinations. We carried out a sub analysis by dividing the talus into 6 areas, 3 vertical (medial, central and lateral group) and 3 horizontal (anterior, middle and posterior group). RESULTS: There were 31 (60%) male and 21 (40%) female patients. Mean MCS and PCS resulted respectively 43.9 and 35.2. OLTs were located as follows: medial 20 (38.50%); central 13 (24.0%); and lateral 19 (36.50%); anterior 24 (46.15%); middle 16 (30.77%); and posterior 12 (23.08%). No significant differences were found among different groups with the exception of the anterior and posterior group for MCS (p=0.021). In the central group we identified a negative correlation (R=-0.672) between aging and AOFAS and a positive correlation between BMI and lesion size. We found a positive correlation between CT and MRI in each group. CONCLUSIONS: OLTs impact patients' quality of life particularly in the physical component. Additionally, in patients with central lesions we found a positive linear correlation between lesion size and BMI and a worsening of the ankle with increasing age. PMID- 29409208 TI - Increased rates of delayed union after percutaneous Akin osteotomy. AB - BACKGROUND: Akin osteotomy is a well-known surgical procedure in forefoot surgery. When performing percutaneously, we have found a lot of delayed unions on follow up X-rays. The objective of this study was to assess the incidence of delayed union when performing a percutaneous Akin osteotomy. METHODS: We report a series of 26 cases who underwent minimally invasive (percutaneous) Akin osteotomy. The mean follow-up duration was 17.6 (range 12 to 24) months. We analys-24) months. We analyzed the time to fusion using standard weight bearing radiographs. All the procedures were uneventful and we had only two skin burns that healed without sequelae. RESULTS: All the procedures were uneventful and we had only two skin burns that healed without sequelae. The average time to fusion in our series was 4.69 months (2-11): seventeen of the 26 osteotomies (65.4%) were considered radiographically healed at an average time of 2,94 months (2-5), whereas 9 patients (34.6%) sustained a delayed-union and healed at an average of 8 months (7-11). CONCLUSIONS: Despite few intraoperative complications and satisfactory clinical and radiological outcomes, our data suggest that a delayed union after Akin osteotomy is very common in the daily practice when performing it through a minimally invasive technique. PMID- 29409209 TI - Preliminary results of a plantar plate for Lapidus arthrodesis. AB - The TMT I arthrodesis is an established procedure for the correction of hallux valgus deformity associated with the instability of the TMT-I joint. A risk of transfer metatarsalgia is reported in the literature associated with persistant elevation of MT-I. Detailed information for ideal positioning of the arthrodesis is missing so far. Clinical, radiological and padobarografical results and their correlations were analyzed with special consideration of the elevation position of the MT-I in a TMT-I arthrodesis using the plantar plate osteosynthesis. Postoperative changes in plantar pressure and force distribution occured after TMT-I arthrodesis. A postoperative increase of the load under the medial forefoot and the dependence on the positioning of MT-I in the sagittal plane has been shown. The authors suggest, that increased load of the medial forefoot and constant pressures and forces under the central forefoot may lead to a relative relief of the area, which might explain the postoperative reduction of metatarsalgia. PMID- 29409210 TI - Fractures of the talus: Current concepts and new developments. AB - Fractures of the talus are challenging to manage, with historically poor outcomes and a high rate of complications. The rare nature of this injury limits the number of studies available to guide treatment. Fortunately, a number of advancements have been made in the last decade. There is increased recognition regarding the importance of anatomic reconstruction of the osseous injury. Advanced imaging is used to assess the subtalar joint, where even slight displacement may predispose to arthritis. Increasing use of dual anteromedial and anterolateral approaches, along with plate fixation, has improved our ability to accurately restore the anatomy of the talus. Modification of the original Hawkins classification can both guide treatment and allow us to better predict which patients will develop avascular necrosis. Lastly, improved reconstructive techniques help address the most common complications after talus fracture, including arthritis, avascular necrosis, and malunion. PMID- 29409211 TI - The dowel technique for first metatarso-phalangeal joint arthrodesis in revision surgery with bone loss. AB - BACKGROUND: The operative management of failed first metatarso-phalangeal joint (MTPJ) surgery is often complicated by bone loss and shortening of the hallux. Restoration of first ray length and alignment often cannot be achieved with in situ fusion and reconstruction techniques with bone graft are therefore required. We present a novel technique of longitudinal (proximo-distal) bone dowel arthrodesis for first MTPJ arthrodesis with bone loss. METHODS: Between August 2007 and February 2015, eight patients have been treated by the senior author with this technique. The mean age at surgery was 60.5 years (range 45-80) with seven females and one male. Index surgery was MTPJ arthrodesis (three patients), Keller excision arthroplasty (two patients), MTPJ hemiarthroplasty (two patients) and silastic arthroplasty (one patient). Clinical and radiological fusion was assessed and other radiological measurements included hallux valgus angle (HVA) and length of the hallux (LOH). RESULTS: All patients achieved fusion at a mean of 9.3 weeks (range 6-12) from surgery and only one patient required removal of metalwork. There were no major complications. The HVA improved in all cases from 21.4+/-2.8 pre-operatively to 11.6+/-3.5 post-operatively (p>0.05). The LOH also increased in all cases from 82.1+/-8.3mm to 86.7+/-8.2mm (p>0.05). The subgroup of patients who were revised from an arthroplasty, where maintenance of length rather than increase in length was desirable (hemiarthroplasty, silastic) had significantly lower increase in LOH than those revised from a non-arthroplasty index surgery (arthrodesis, Keller) (p=0.029). CONCLUSION: The dowel technique is successful for first MTPJ arthrodesis revision surgery with optimal union rates and satisfactory radiographic and clinical outcomes. It is an effective and versatile option for managing bone loss and deformity of the hallux. PMID- 29409212 TI - American Orthopaedic Foot and Ankle Society ankle-hindfoot scale: A cross cultural adaptation and validation study from Iran. AB - BACKGROUND: The use of valid and reliable outcome rating scales is essential for evaluating the result of different treatments and interventions. The purposes of this study were to translate and culturally adapt the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale (AOFAS-AHFS) into Persian languages and evaluate its psychometric properties. METHODS: Forward-backward translation and cultural adaptation method were used to develop Persian version of AOFAS-AHFS. From March to July 2016, one hundred consecutive patients with ankle and hindfoot injuries were included. Internal consistency and reproducibility were evaluated using Cronbach's alpha, Spearman's rank correlation coefficient and Intraclass correlation coefficient (ICC) respectively. Construct validity reported which compare the outcome rating scale measurements with Short Form-36 (SF-36), also convergent and discriminant validity evaluated using Spearman's rank correlation coefficient. RESULTS: Mean age (SD) of the patients was 41.95+/-13.45years. Cronbach's alpha coefficient, Spearman's rho and ICC values were 0.71, 0.89 and 0.90 respectively. Total score of AOFAS-AHFS and SF-36 domains has a correlation ranged between 0.17-0.55. Spearman's rank correlation coefficient of 0.4 was exceeded by all items with the exception of stability. The Spearman's rank correlation between each item in functional subscales with its own subscales was higher than the correlation between these items and other subscales. CONCLUSIONS: Persian version of AOFAS-AHFS provides additional reliable and valid instrument which can be used to assess broad range of patients with foot and ankle disorders that speaking in Persian. However, it seems that the original version of AOFAS AHFS needs some revisions. PMID- 29409213 TI - Weightbearing CT in normal hindfoot alignment - Presence of a constitutional valgus? AB - BACKGROUND: The normal hindfoot angle is estimated between 2 degrees and 6 degrees of valgus in the general population. These results are solely based on clinical findings and plain radiographs. The purpose of this study is to assess the hindfoot alignment using weightbear CT. METHODS: Forty-eight patients, mean age of 39.6+/-13.2 years, with clinical and radiological absence of hindfoot pathology were included. A weightbear CT was obtained and allowed to measure the anatomical tibia axis (TAx) and the hindfoot alignment (HA). The HA was firstly determined using the inferior point of the calcaneus (HAIC). A density measurement of this area was subsequently performed to analyze if this point concurred with an increased ossification, indicating a higher load exposure. Secondly the HA was determined by dividing the calcaneus in the long axial view (HALA) and compared to the (HAIC) to point out any possible differences attributed to the measurement method. Reliability was assessed using an intra class correlation coefficient (ICC). RESULTS: The mean HAIC equaled 0.79 degrees of valgus+/-3.2 (ICCHA IC=0.73) with a mean TAx of 2.7 degrees varus+/-2.1 (ICCTA=0.76). The HALA equaled 9.1 degrees of valgus+/-4.8 (ICCHA LA=0.71) and differed significantly by a P<0.001 from the HAIC, which showed a more neutral alignment. Correlation between both was shown to be good by a Spearman's correlation coefficient of 0.74. The mean density of the inferior calcaneal area equaled 271.3+/-84.1 and was significantly higher than the regional calcaneal area (P<0.001). CONCLUSIONS: These results show a more neutral alignment of the hindfoot in this group of non-symptomatic feet as opposed to the generally accepted constitutional valgus. This could have repercussion on hindfoot position during fusion or in quantifying the correction of a malalignment. The inferior calcaneus point in this can be used during pre-operative planning of a hindfoot correction as an anatomical landmark due to its shown influence on load transfer. PMID- 29409214 TI - Posterolateral plate fixation with Talarlock(r) is more stable than screw fixation in ankle arthrodesis in a biomechanical cadaver study. AB - BACKGROUND: A number of studies report on limitations of the screw arthrodesis in severe malalignment of the hindfoot, neuropathic deformity, poor bone quality and osteoporosis. METHODS: Fourteen anatomically correct polyurethane foam models of the right leg (Sawbones Europe, Malmo, Sweden) and eighteen fresh-frozen human lower leg specimens (9 pairs) were used for the comparative biomechanical testing. RESULTS: The statistical analysis of the stiffness of the fixation developed a significant difference in favor of the plate in all test directions. CONCLUSIONS: The excellent biomechanical results are very promising and we hope for a reduction of the pseudarthrosis rate and shorten the postoperative treatment phase. PMID- 29409215 TI - Syndesmotic stability: Is there a radiological normal?-A systematic review. AB - BACKGROUND: Syndesmotic injury and instability poses a diagnostic challenge with unreliable clinical tests and inconsistent radiologic measures. Thus, used widely in clinical practice, there is huge debate pertaining to the reliability and validity of the radiologic parameters used for syndesmotic instability. OBJECTIVE: Hence the purpose of the review was to explore the normal radiologic measures and morphometrics of distal tibiofibular syndesmosis and its relationships, which can aid in diagnosing syndesmotic instability. METHOD: Computerised literature searches was performed for articles published in English using Pubmed, from inception through June 2016. All published articles reporting the normal anatomic and morphometric measures of distal tibiofibular syndesmosis with the use of any radiological modality individually or in combination, either in cadaveric or in live subjects were included. Studies done on or reporting of measures in healthy ankles or radiologically normal ankles were only included. RESULTS: In this review wide anatomic and morphologic variability was observed amidst the landmarks used commonly for assessing syndesmotic instability and hence the normal measures. Further age and gender based variations were seen across the most commonly used radiologic measures for syndesmotic instability diagnosis, demanding the modification of existing radiologic criteria. PMID- 29409216 TI - Distal Akin osteotomy for hallux valgus interphalangeus. AB - BACKGROUND: The aim of this study was to assess clinical and radiological outcomes in patients who underwent distal Akin osteotomy for hallux valgus interphalangeus (HVI). METHODS: A series of 15 consecutive patients (17 feet) was retrospectively reviewed. All the patients were preoperatively and post operatively evaluated with a physical and radiographic assessment (HVI angle). Satisfaction has been assessed through a satisfaction survey, the scale used consisted in three possible choice: very satisfied, satisfied, not satisfied. RESULTS: Among 15 patients the 52.9% (9 patients) stated to be "very satisfied", the 41.2% (7 patients) "satisfied" and just a 5.9% (one patient) was "not satisfied". The mean HVI value decreased from 24.9 degrees +/-7.8 degrees preoperatively to 13.1 degrees +/-5.8 degrees postoperatively at last follow up (p<0.05). CONCLUSIONS: Based on these findings we can conclude that the distal Akin osteotomy can be considered safe and effective in the surgical correction of symptomatic HVI deformities. PMID- 29409217 TI - Surgical management of chronic Achilles tendon ruptures using less invasive techniques. AB - BACKGROUND: Surgical management of chronic Tendo Achillis (TA) ruptures usually requires tendon grafting procedures. Several techniques have been described. We examined the outcome of three different less invasive (incisions length less than 3 cm) tendon transfer techniques in the management of patients with a chronic rupture of the TA. METHODS: Of 62 patients (39 males and 23 females; mean age 44.8 years; range 29.3-62 years) with chronic TA ruptures managed operatively, 21 patients had a >=6cm gap and underwent free ipsilateral semitendinosus (ST) graft (21 patients), whereas patients with smaller gaps had either ipsilateral peroneus brevis (PB) (20 patients) or ipsilateral flexor hallucis longus (FHL) transfer (21 patients). Outcome measures included maximum calf circumference, isometric plantar flexion strength, and the Achilles tendon total rupture score (ATRS), preoperatively and at the last follow up. We also recorded the time to return to activities of daily living (ADL) and sports, and the number of single-leg heel lifts on the affected leg at the last follow up, at an average of 35.4 months. RESULTS: Patient characteristics between groups were similar. All outcome measures significantly improved after surgery (p<0.001), without differences between the three groups. Return to ADL was possible at an average of 4.5 months. Patients undergoing PB transfer had a slower return to sports compared to the other groups, at 6.9+/-0.5months versus 6.1+/-0.8 for the FHL and 5.8+/-0.6 for the ST groups (t-test p=0.005 and p<0.001, respectively). However, 13/14 patients (90%) in the PB group returned to high impact sports, compared to 9/12 (75%) in the FHL and 6/11 (55%) in the ST groups (Fisher's test, p=0.31 and p=0.056, respectively). CONCLUSION: All three techniques produced significant functional improvement, and return to sports was possible in most patients. This study does not demonstrate a clear advantage of one technique over the others. PMID- 29409218 TI - Use of Masquelet's technique for treating the first metatarsophalangeal joint in cases of gout combined with a massive bone defect. AB - BACKGROUND: To examine the safety and efficacy of Masquelet's technique as a surgical method for treating the first metatarsophalangeal joint in cases of gout accompanied by a massive bone defect. METHODS: From January 2010 to January 2016, eleven patients (7 males and 4 females; mean age 33.1 years; range, 23-43 years) received surgical treatment for a first metatarsophalangeal joint tophus which caused a serious bone defect. The first metatarsophalangeal bone defects ranged from 3-6cm, or nearly 50% of the length of normal bone. During the first stage of Masquelet's technique, we removed the tophus and infused that area with bone cement that contained antibiotics. Two months later, we performed the second stage, in which the prosthesis was replaced with iliac cancellous bone, and the operated area was stabilized via locking plate fixation. RESULTS: All of the surgeries were successful, and the 11 patients were followed up for an average of 10.9 months. Postoperative evaluations showed that 10 of the 11 patients healed between 9 and 14 days after the initial surgery. Bone fusion occurred between 2.3 and 3.6 months after the operation, and the average healing time was 3.0 months. One foot wound became infected, but healed after vacuum aspiration. When the American Association of Foot and Ankle Surgery Maryland Foot scoring system was used to evaluate the foot function of the 11 patients prior to surgery, all 11 patients were graded as "failures." Following surgery, 2 patients were graded excellent, 5 were good, 3 were fair, and only 1 patient failed. The total combined excellent and good rate was 63.6%. The total mean Maryland scores pre- and post-surgery were 27.8 points and 74.1 points, respectively; thus the average patient score increased by 46.3 points. CONCLUSIONS: Joints with advanced tophus nodules develop segmental bone defects. Masquelet's technique is an effective method for treating such nodules and their associated bone defects. PMID- 29409219 TI - ?Diagnostic and therapeutic injections of the foot and ankle-An overview. AB - Foot and ankle injections are useful diagnostic and therapeutic tools, particularly when the pain etiology is uncertain. A variety of foot and ankle injuries and pathologies, including degenerative joint disease, plantar fasciitis and different tendinopathies are amenable to injections. Understanding the foot and ankle anatomical landmarks, a thorough physical exam and knowledge of the different injection techniques is key for a successful approach to different pathologies. The objective of this study is to review the use of foot and ankle injections in the orthopaedic literature, present the readers with the senior author's experience and provide a comprehensive clinical guideline to the most common foot and ankle diagnostic and therapeutic injections. PMID- 29409220 TI - Safe aftercare following foot ankle surgery: Doing less is more: The Jones dressing cast, part 2. AB - BACKGROUND: There is no universal approach to surgery aftercare among foot and ankle surgeons. Although infections following foot and ankle surgery are rare, soft tissue healing can be jeopardized after extensive and multiple approaches. METHODS: We defined a precise fixation technique of the foot and ankle in the immediate post-operative phase using what we call "the Jones dressing cast". This technique is a modification of the Jones dressing bandage. In a previous study we compared two groups of patients (N=20/23) who underwent similar reconstructive surgery with the application of the described cast for one week and without. At the two-month follow-up we observed that the group treated with the cast required less pain relief, spent less time in hospital and achieved faster autonomy using crutches (Gottlieb and Klaue, 2013). In this study we considered a group of 45 patients who underwent similar reconstructive procedures to those in the first study and who were treated with the cast for two weeks post-operatively. There was no visual check of the soft tissues before removal of the cast. RESULTS: Unlike the earlier study, the results from this second study were more significant. Revision surgery occurred far less frequently in the group wearing the cast for two weeks. CONCLUSIONS: The reduced strain to the soft tissue around the foot due to the cast and less manipulation of the wound dressing decrease complications in the post-operative period. PMID- 29409221 TI - Morton's interdigital neuroma of the foot: A literature review. AB - Morton's neuroma is one of the most common causes of metatarsalgia. Despite this, it remains little studied, as the diagnosis is clinical with no reliable instrumental diagnostics, and each study may deal with incorrect diagnosis or inappropriate treatment, which are difficult to verify. The present literature review crosses all key points, from diagnosis to surgical and nonoperative treatment, and recurrences. Nonoperative treatment is successful in a limited percentage of cases, but it can be adequate in those who want to delay or avoid surgery. Dorsal or plantar approaches were described for surgical treatment, both with strengths and weaknesses that will be scanned. Failures are related to wrong diagnosis, wrong interspace, failure to divide the transverse metatarsal ligament, too distal resection of common plantar digital nerve, an association of tarsal tunnel syndrome and incomplete removal. A deep knowledge of the causes and presentation of failures is needed to surgically face recurrences. PMID- 29409222 TI - Reconstruction of bone defect with allograft and retrograde intramedullary nail for distal tibia osteosarcoma. AB - BACKGROUND: To investigate the effectiveness of tibiotalocalcaneal arthrodesis with a retrograde nail and allograft in limb salvage surgery for patients with distal tibia osteosarcoma. METHODS: 5 patients diagnosed as distal tibia osteosarcoma underwent ankle arthrodesis with a retrograde nail in our hospital. During the follow-up, radiographic views of the ankle joint were taken in two planes to assess bone healing and axis alignment. Other measurements of outcomes included procedure-related complications, local recurrence, and metastasis. Functional outcomes were evaluated with the Musculoskeletal Tumor Society (MSTS) scoring system. RESULTS: Postoperative complications occurred in 4 patients, including 4 cases of mild subcutaneous fluid and 1 case of screw breakage. All patients showed stable ankle and could stand or walk with the assistance of crutch before the complete union between allograft and host bone. One patient died due to multiple bone and pulmonary metastasis at 1 year after surgery. As for the other 4 patients, they were followed-up regularly for a mean period of 42 months. No local recurrence or distant metastasis occurred in any of these four patients. All the 4 patients expressed satisfaction with the outcome. According to MSTS scale, the mean postoperative functional score was 74.3%+/-4.4% (range, 70%-81%). CONCLUSIONS: Intramedullary retrograde nail for distal tibia osteosarcoma could produce a satisfactory outcome in terms of functional results and complications. Excellent stabilization of the ankle joint can be achieved through this technique, as it allows patients to perform much earlier postoperative weight-bearing exercise. PMID- 29409223 TI - An anatomical study about the arthroscopic repair of the lateral ligament of the ankle. AB - BACKGROUND: The purpose of this anatomical study to was to determine the relationship of the structures involved in the arthroscopic repair of the anterior talofibular ligament. METHODS: Dissection of fifteen lower leg cadaveric specimens was made and distances in the anterior direction from the reference point at the lateral malleolus origin of the anterior talofibular ligament were measured, to the talar insertion of the ligament, to the superficial peroneal nerve at 60 degrees and 90 degrees in relation to the lateral malleolus axis in the sagittal plane, and to the inferior extensor retinaculum. RESULTS: The mean+/ SD distance to superficial peroneal nerve from the reference-point was 25+/-6 (range 17-35) mm at 60 degrees , and 32+/-9 (range 24-48) mm at 90 degrees in relation to the lateral malleolus axis. The mean+/-SD distance to the inferior extensor retinaculum was 20+/-5 (range 14-29) mm. The mean+/-SD length of the anterior talofibular ligament was 21+/-4 (range 13-29) mm. CONCLUSIONS: The superficial peroneal nerve demonstrated the greatest variance in its anatomy. An accessory incision to include the inferior extensor retinaculum in the repair should not surpass the 22mm distance from the lateral malleolus in the anterior direction, due to the risk of damaging the nerve. PMID- 29409224 TI - Arthroscopic versus open ankle arthrodesis. AB - BACKGROUND: It is thought that arthroscopic ankle fusion offers improved outcomes over open fusion in terms of functional outcomes, time to fusion, length of stay and fewer complications. However, there are doubts about whether correction of established severe deformity can be achieved using the arthroscopic approach. METHODS: A retrospective review of medical records and radiographs at our hospital identified consecutive tibio-talar ankle fusions between April 2009 and March 2014 with minimum 1 year follow up. Records were scrutinised for type of arthrodesis, demographics, length of stay (LOS), time to fusion (TTF), pre- and postoperative deformity, complications and unplanned procedures. Significant factors in the complication group were then compared, using multivariate binary logistic backward stepwise regression to see if any factors were predictive. RESULTS: There were 29 open and 50 arthroscopic ankle fusions (2 converted to open). Mean LOS was 1.93 versus 2.52 days (p=0.590). TTF was shorter after arthroscopic fusion 196d versus 146d (p=0.083). Severe deformity (>10 degrees ) was correctable to within 5 degrees of neutral in the majority of cases (97% versus 96%, p=0.903). Union occurred in 83% versus 98% (p=0.0134). The open arthrodesis group had 9 (31%) complications (1 death-PE, 1 SPN injury, 5 non unions, 1 delayed union and 1 wound infection) and 6 (25%) screw removals. The arthroscopic arthrodesis group had 4 (8%) complications (1 non-union, 1 reactivation of osteomyelitis and subsequent BKA, 1 wound infection, 1 delayed union) with 11 (24%) screw removals. After multi-variant regression analysis of all ankle fusions, low BMI was shown to be associated with complications (p=0.064). CONCLUSIONS: Open arthrodesis was associated with a higher rate of complications and a lower rate of fusion. However, there was no significant difference in terms of LOS and ability to correct deformity compared to arthroscopic arthrodesis. Overall, low BMI was also associated with more complications. PMID- 29409225 TI - Osteochondral lesions of the ankle: The current evidence supporting scaffold based techniques and biological adjuncts. AB - BACKGROUND: Talar osteochondral lesions are more common than has been previously recognized. Optimal treatment remains unclear and the subject of much debate in the literature. Although reparative techniques such as microfracture have produced initial good results and remain the gold standard in the management of these lesions, the literature is deficient in long-term data. Recently, techniques focused on enhancing the local biological environment have been developed which have demonstrated promising outcomes. METHODS: We reviewed the available evidence concerning scaffold-based techniques and biological adjuncts in the management of talar osteochondral lesions published in the English language on PubMed. RESULTS: An update is provided on the current evidence concerning the role of biological adjuncts in the management of osteochondral lesions of the talus. CONCLUSIONS: There has been an explosion of interest among the orthopaedic community in the role of biologics in the management of complex talar osteochondral lesions. A number of exciting new techniques have been developed which show promise. Robust randomized control trials are required to identify the optimal surgical strategy. PMID- 29409226 TI - Surgical management of large talar osteochondral defects using autologous chondrocyte implantation. AB - BACKGROUND: Talar osteochondral lesions (OLT) occur frequently in ankle sprains and fractures. We hypothesize that matrix-induced autologous chondrocyte implantation (MACI) will have a low reoperation rate and high patient satisfaction rate in treating OLT less than 2.5cm2. METHODS: A systematic review was registered with PROSPERO and performed with PRISMA guidelines using three publicly available free databases. Clinical outcome investigations reporting OLT outcomes with levels of evidence I-IV were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared. Statistics were calculated using Student's t-tests, one-way ANOVA, chi-squared, and two-proportion Z-tests. RESULTS: Nineteen articles met our inclusion criteria, which resulted in a total of 343 patients. Six studies pertained to arthroscopic MACI, 8 to open MACI, and 5 studies to open periosteal ACI (PACI). All studies were Level IV evidence. Due to study quality, imprecise and sparse data, and potential for reporting bias, the quality of evidence is low. In comparison of open and arthroscopic MACI, we found both advantages favoring open MACI. However, open MACI had higher complication rates. CONCLUSIONS: No procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5cm2. Ultimately, well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment options. PMID- 29409227 TI - Are two incisions necessary for hallux valgus correction? AB - BACKGROUND: Soft tissue release for hallux valgus correction is traditionally performed through a dorsal first web space incision. We performed a single surgeon series review of hallux valgus correction with Scarf+/-Akin osteotomy and lateral release using a single medial incision. METHODS: 192 feet were included. Patient satisfaction survey was conducted at the time of study. Pre-operative and final post-operative radiographic data obtained. RESULTS: All radiological parameters had statistically significant improvement [p<0.05 for each variable]. Response rate was 71% (completely satisfied 69%, satisfied with minor reservation 14%, satisfied with major reservation 11%, dissatisfied 6%). There was no correlation of any preoperative or postoperative radiographic measure with satisfaction grade. No patient required revision procedure. CONCLUSIONS: Single medial incision surgery for hallux valgus correction is a simple, safe and effective technique with very high satisfaction. The results are comparable to traditional two-incision surgery. PMID- 29409228 TI - Closing the gap on Achilles tendon rupture: A cadaveric study quantifying the tendon apposition achieved with commonly used immobilisation practices. AB - The relative benefits of surgical and conservative treatment of Achilles tendon rupture are widely debated. With modern conservative management protocols, the re rupture risk appears to fall to one similar to surgical repair with negligible loss of function. Conservative management typically employs a period of time in an equinus cast with sequential ankle dorsiflexion in a functional orthosis. The optimal duration of immobilisation and rate of dorsiflexion is unknown. We aimed to quantify the change in Achilles tendon approximation achieved in common immobilisation techniques to assist the design of rehabilitation protocols. Twelve fresh-frozen cadaveric specimens had 2.5cm of Achilles tendon excised. The gap between the tendon ends were measured via windowed full equinus casts and compared with functional boots with successively removed heel wedges. The greatest tendon apposition was achieved with the equinus cast. Each wedge removed decreased the reapproximation by approximately 5mm. This paper supports the early use of maximal equinus casting in early management of acute Achilles tendon ruptures. PMID- 29409229 TI - Utility outcome assessment of pes planus deformity. AB - BACKGROUND: Despite being a common condition, there are no objective measures in the literature to reflect the burden of pes planus on affected individuals. Our primary objective was to evaluate this burden by recruiting a sample from the general population using validated utility outcome measures. METHODS: Participants were recruited online and filled a questionnaire to help measure the health burden of pes planus. Three recognized utility outcome scores were used to compare the health burden of monocular blindness, binocular blindness, and pes planus. These included the standard gamble (SG), time trade-off (TTO), and visual analogue score (VAS). Paired t test, independent t test, and linear regression were used for statistical analysis. RESULTS: Ninety-two participants were included in the final analysis. The utility outcome scores (VAS, TTO, SG) for pes planus were 73+/-17, 0.90+/-0.08, and 0.88+/-0.12, respectively. The linear regression analysis showed that age was inversely proportional to the time trade off. However, race, educational level, and income were not significant predictors of utility outcome score for pes planus. CONCLUSIONS: This study shows that the perceived burden of living with pes planus is comparable to living with some debilitating conditions. Our participants were willing to sacrifice 3.6 years of life, and have a procedure with a theoretical 12% mortality risk to attain perfect health. PMID- 29409230 TI - Dorsal closing wedge calcaneal osteotomy for the treatment of Insertional Achilles Tendinopathy: A technical tip to optimize its results and reduce complications. AB - BACKGROUND: Dorsal closing wedge calcaneal osteotomy is a technique for the treatment of Haglund's triad, which is considered a safe procedure with good results. However, one of the complications that could lead to revision operation is the nonunion of the osteotomy and failure of osteosynthesis. This is attributed to instability of the osteotomy site and proximal migration of the posterior calcaneal process due to breakage of plantar bone-bridge at the apex of the wedge osteotomy. METHODS: This study presents a technical tip that helps the surgeon to avoid the breakage of the plantar hinge of the os calcis which is believed that causes instability of the osteotomy. RESULTS: After the utilization of that technical tip, no proximal migration of posterior calcaneal process or subsequent nonunion and failure of the osteosynthesis was noted. CONCLUSION: Dorsal closing wedge osteotomy is a technique for the treatment of IAT, which is considered a safe procedure with good results. The proposed technical tip helps to avoid the breakage of the plantar hinge which is believed that causes instability of the osteotomy with proximal migration of the posterior calcaneal process and subsequent nonunion and failure of the osteosynthesis. PMID- 29409231 TI - Outcome after operative treatment for chronic versus acute Achilles tendon rupture - A comparative analysis. AB - BACKGROUND: This study compared outcomes after treatment of acute Achilles tendon (AT) rupture via percutaneous suturing, with those after chronic AT rupture treated via open reconstruction. METHODS: This retrospective study included 30 patients who underwent either percutaneous suturing for acute AT rupture (group AR, n=16) or open reconstruction for chronic AT rupture (group CR, n=14). Function was evaluated by calf muscle circumference, and endurance through isokinetic measurement and single-leg heel-rise test. Score evaluation included AT Total Rupture Score, Victorian Institute of Sports Assessment-Achilles questionnaire, and visual analogue scale pain score. Postoperative tendon thickness was measured using ultrasonography and MRI. RESULTS: Follow-up was conducted 4.97+/-1.79 years postoperatively. The groups were similar in age and body mass index. There was no significant difference between groups in calf circumference, isokinetic measurement, heel-rise test, and score evaluation. There was significantly less mediolateral tendon thickening in group AR compared with group CR on ultrasonography (p=0.01) and MRI (p=0.001). CONCLUSIONS: Open reconstruction for chronic AT rupture may result in comparable clinical and functional outcomes, but a thicker tendon compared with percutaneous suturing after acute AT rupture. PMID- 29409232 TI - A comparison of surgical exposures for posterolateral osteochondral lesions of the talar dome. AB - BACKGROUND: Perpendicular access to the posterolateral talar dome for the management of osteochondral defects is difficult. We examined exposure available from each of four surgical approaches. MATERIALS AND METHODS: Four surgical approaches were performed on 9 Thiel-embalmed cadavers: anterolateral approach with arthrotomy; anterolateral approach with anterior talo-fibular ligament (ATFL) release; anterolateral approach with antero-lateral tibial osteotomy; and anterolateral approach with lateral malleolus osteotomy. The furthest distance posteriorly allowing perpendicular access with a 2mm k-wire was measured. RESULTS: An anterolateral approach with arthrotomy provided a mean exposure of the anterior third of the lateral talar dome. A lateral malleolus osteotomy provided superior exposure (81.5% vs 58.8%) compared to an anterolateral tibial osteotomy. CONCLUSIONS: Only the anterior half of the lateral border of the talar dome could be accessed with an anterolateral approach without osteotomy. A fibular osteotomy provided best exposure to the posterolateral aspect of the talar dome. PMID- 29409233 TI - A 24-month follow-up after treatment of hallux rigidus with resection arthroplasty in combination with a resorbable polymer-based implant and platelet rich plasma. AB - BACKGROUND: Aim of this study was to analyze the clinical outcome after treatment of hallux rigidus with implantation of a resorbable polymer-based implant immersed with autologous platelet-rich plasma (PRP). METHODS: Forty-five patients with hallux rigidus were treated with three-stage resection arthroplasty and subsequent covering of the metatarsal head with a polyglycolic acid-hyaluronan implant immersed with autologous PRP. Patients were clinically assessed using the AOFAS rating scale preoperatively and at 12 and 24 month follow-up. Alignment and range of motion in the metatarsophalangeal joint was measured using a goniometer. RESULTS: The AOFAS rating scale and ROM showed significant (p<.01) improvement in all subcategories one and two years after surgery compared to the preoperative situation. CONCLUSIONS: Covering of the metatarsal head after resection arthroplasty with the PGA-hyaluronan implant immersed with autologous PRP is safe and leads to a notable improvement of the symptoms in patients with hallux rigidus. PMID- 29409234 TI - Arthroscopic subtalar arthrodesis through the sinus tarsi portal approach: A series of 77 cases. AB - BACKGROUND: Subtalar arthrodesis through an open approach carries significant risk of complications. An arthroscopic approach aims to minimise damage to the soft tissue envelope to improve recovery, union and complication rates. A two portal approach through the sinus tarsi was used. METHODS: A retrospective review of all patients undergoing isolated arthroscopic arthrodesis was performed. RESULTS: Seventy-seven procedures were performed. Successful arthrodesis was achieved in 75 (97.4%). Two patients underwent successful revision arthrodesis for aseptic nonunion. There was one (1.3%) superficial infection and one (1.3%) partial sural nerve injury. CONCLUSIONS: Two-portal sinus tarsi arthroscopic subtalar arthrodesis is safe and effective. Advantages over other arthroscopic approaches are the access to all three facets of the joint, avoidance of a posterolateral portal in order to minimise risk to the sural nerve, and the ability to use the same approach to arthrodese the entire triple hindfoot joint complex. Technical tips and pitfalls are discussed. PMID- 29409235 TI - The arthroereisis procedure in adult flexible flatfoot grade IIA due to insufficiency of posterior tibial tendon. AB - BACKGROUND: To report on the functional, biomechanical, and radiographic results of patients who had undergone arthroereisis plus tensioning of the posterior tibial tendon for flexible flatfoot. The hypothesis is that arthroereisis associated to a tensioning of the posterior tibial tendon give a good correction with great satisfaction in patients with flexible flatfoot in grade IIA. METHODS: We evaluated 29 patients (31 feet), mean age of 46.4 years, who had been surgically treated for adult flatfoot grade IIA according to Myerson. Mean follow up was 34.15 months. For clinical evaluation, the AOFAS hindfoot and VAS-FA scores were used. RESULTS: Postoperative results showed significant increases in both AOFAS and VAS-FA scores: 54.2-81.9 and 61.5-83.2 points, respectively. For the X-ray parameters, we observed a significant variation in the talo-first metatarsal angle, from 13.8 degrees in pre-op to 7.4 degrees in post-op. In lateral view, Djian Annonier angle was improved from 146.6 degrees to 134.1 degrees . The Meary's angle, compared to an average of 8.8 degrees in pre operative stage improved to 4.3 degrees in the post-operative stage. Postoperative satisfaction was excellent-good according to 23 patients (79.4%). Pain in the tarsal sinus was reported in 5 out of 31 feet (16.1%) for the first three months after surgery. CONCLUSIONS: Arthroereisis and tensioning of the posterior tibial tendon provided good functional outcomes for patients under 60 years of age having stage IIA flexible flatfoot without arthritic manifestations. PMID- 29409236 TI - Tibiotalocalcaneal nail fixation and soft tissue coverage of Gustilo-Anderson grade 3B open unstable ankle fractures in a frail population; a case series in a major trauma centre. AB - BACKGROUND: Gustilo-Anderson grade 3B open ankle fracture-dislocations requiring stable fixation and soft tissue coverage are increasingly common in frail populations. METHODS: We identified all patients with open ankle fracture dislocations treated with a tibiotalocalcaneal nail and soft tissue coverage over a five-year period. We retrospectively recorded pre-morbid status, fracture and soft tissue injury pattern, surgical details, post-operative mobility, length of hospital stay, complication and re-operation rate and survival. RESULTS: 21 ankles (20 patients) are included, all grade 3B open fractures. All patients were permitted to mobilise by one to six weeks post-surgery. One patient required further soft tissue surgery. Six patients had superficial wound colonization/infection, none developed deep infections. None of the nails have required removal. We observed a 15% three-month mortality rate. CONCLUSION: Tibiotalocalcaneal nail fixation and soft tissue coverage of unstable open ankle fractures in frail patients facilitates early return to ambulation with a low complication and re-operation rate. PMID- 29409237 TI - Does timing of surgery influence the long-term results of foot polydactyly treatment? AB - BACKGROUND: There is an evident lack of research on timing of polydactyly surgery and its effects on treatment results. METHODS: Retrospective comparative study on foot polydactyly patients treated at our department from 1995 to 2009. Patients were divided into 2 groups, group A - under the age of 5 at surgery, and group B 5 years and older. RESULTS: There were 24 patients (8 male, 16 female), 30 feet. Median age at surgery was 1 year (range, 9 months-4.5 years) for group A, and 8.5 years (range, 6-37 years) for group B. Median follow-up was 16.2 years (range, 7 21 years). There were 16 postaxial and 8 preaxial cases. At the last follow-up 12 patients' feet were "excellent" and 12 "good". No significant differences were identified between the two groups at final follow-up. CONCLUSIONS: Timing of surgery for foot polydactyly is not crucial for final results. PMID- 29409238 TI - Gastrocnemius recession leads to medial shift of gait line, impairment of muscle strength and improved dorsal extension in forefoot overload syndrome. AB - BACKGROUND: Gastrocnemius recession (GR) has been introduced for treatment of forefoot overload syndrome (FOS). We questioned if GR leads to an altered forefoot load and weakness of plantarflexors in those patients. METHODS: 26 patients suffering from FOS and gastrocnemius tightness underwent GR. A strength power analysis of plantar flexors and a pedobarography was performed. Clinical outcome was measured by Foot Function Index (FFI). RESULTS: Plantarflexors are impaired about 40% six weeks and around 10% 24 weeks following GR compared to the contralateral side. Patients experienced a pain relief and an improvement of ankle dorsiflexion from 2 degrees to 15 degrees . An increased contact time of the heel (15%) and a shift of metatarsal plantar pressure from lateral to medial could be demonstrated. CONCLUSIONS: This study suggests that GR leads to pain reduction by an increase in heel contact time and a shift of gait line to medial in patients with a FOS. Despite, a temporary impairment of muscle strength has to be considered. PMID- 29409239 TI - Effects of wearing shoes on the feet: Radiographic comparison of middle-aged partially shod Maasai women's feet and regularly shod Maasai and Korean women's feet. AB - BACKGROUND: Maasai tribe members walk long distances daily either barefoot or wearing traditional shoes made from recycled car tires, without any foot ailments. To figure out the characteristic of their feet, we designed a radiographic comparative study of middle-aged partially shod Maasai women's feet and regularly shod Maasai and Korean women's feet. METHODS: Weight bearing radiographs of bilateral foot and ankle joints from 20 healthy middle-aged bush living partially shod (PS) Maasai women were obtained. Same number of radiographs from 20 urban-living regularly shod (RS) Maasai and 20 Korean women were obtained and compared. The hallux valgus angle, the first to second intermetatarsal angle, talonavicular coverage angle, talo-first metatarsal angle, Meary angle, naviculo cuboidal overlap, and the medial cuneiform height were measured to establish the degree of pes plano-valgus and hallux valgus deformity. RESULTS: On comparing PS and RS Maasai groups radiographically, the talonavicular coverage angle, talo first metatarsal angle, and naviculo-cuboidal overlap were significantly greater in the PS Maasai group, whereas hallux valgus angle, the first and second intermetatarsal angle, Meary angle, and the medial cuneiform height were greater in the RS Maasai and Korean group. CONCLUSIONS: Regularly wearing shoes would protect the feet from pes plano-valgus deformity, despite potentially contributing to hallux valgus deformity. PMID- 29409240 TI - Treatment of Morton's neuroma: A systematic review. AB - BACKGROUND: The treatment of Morton's neuroma (MN) can be operative, conservative and infiltrative. Our aim was the evaluation of evidence on outcomes with different types of conservative, infiltrative and surgical treatment in patients affected by primary MN. METHODS: The bibliographic search was conducted in MEDLINE, Cochrane Library, DARE. Only studies in English were collected. The last search was in August 2015. Case series and randomized controlled trials (RCTs) assessing patients' satisfaction or pain improvement at an average follow-up of at least 6 months after treatment of primary MN were included. Two reviewers selected the studies, evaluated their methodological quality, and retrieved data independently. RESULTS: Of 283 titles found, only 29 met the inclusion criteria. Data showed better outcomes with operative treatment. CONCLUSIONS: The evaluated case series and few RCTs showed better results with invasive treatment. More and better RCTs which evaluate risk-benefit ratio are required to confirm these results. PMID- 29409241 TI - Biomechanical analysis of polyaxial locking vs. non-locking plate fixation of unstable fractures of the distal fibula: A cadaver study with a bone only model. AB - BACKGROUND: Open reduction and internal fixation is the current standard of treatment of displaced distal fibula fractures, whereupon using a lag screw often is impossible because of a multifragmantary fracturezone. This study investigates in what extend polyaxial-locking plating is superior to non-locking constructs in unstable distal fibula fractures. METHODS: Seven pairs of human cadaver fibulae were double osteotomized in standardized fashion with a 5mm gap. This gap simulated an area of comminution, where both main fragments were no longer in direct contact. One fibula of the pair was managed using a 3.5-mm screw in a polyaxial-locking construct and the other fibula in a non-locking construct. PMID- 29409242 TI - Predictors of functional outcome in non-operatively managed Achilles tendon ruptures. AB - BACKGROUND: Acute Achilles tendon (AT) rupture management remains debatable but non-operative functional regimes are beginning to gain popularity. The aim of this study was to identify predictors of functional outcome in patients with AT ruptures treated non-operatively with an immediate weight bearing functional regime in an orthosis. METHODS: Analysis of prospectively gathered data from a local database of all patients treated non-operatively at our institution with an AT rupture was performed. For inclusion in the study patients required a completed Achilles Tendon Rupture Score (ATRS) at a minimum of 6 months post injury. The ATRS score was correlated against age, gender, time following rupture, duration (8 or 11 weeks) of treatment in a functional orthoses and complications were recorded. RESULTS: 236 patients of average age 49.5 years were included. The mean ATRS on completion of rehabilitation was 74 points. The mean ATRS was significantly lower in the 37 females (65.8) as compared to the 199 males (75.6) (p=0.013). Age inversely affected ATRS with a Pearsons correlation of -0.2. There was no significant difference in the ATRS score when comparing the two different treatment regime durations. There were 12 episodes of VTE and 4 episodes of re-rupture. The ATRS does not change significantly after 6 months following rupture treatment completion. CONCLUSION: Patients with AT ruptures treated non-operatively with a functional rehabilitation regime demonstrate comparable function to other non-surgical regimes with low re-rupture rates. Increasing age and female gender demonstrate inferior functional outcomes. CLINICAL RELEVANCE: Females and increasing age predict poorer functional outcome in acute Achilles tendon ruptures managed in a dynamic full-weight bearing treatment regime. PMID- 29409243 TI - High resolution real time ultrasonography of the sural nerve after percutaneous repair of the Achilles tendon. AB - BACKGROUND: Percutaneous Achilles tendon repair has been developed to minimise soft tissue complications following treatment of tendon ruptures. However, there are concerns because of the risk of sural nerve injury. Few studies have investigated the relationship between the Achilles tendon, the sural nerve and its several anatomical course variants. METHODS: We studied 7 cadaveric limbs (7 Achilles tendons) in which a percutaneous repair of the Achilles tendon was performed. On each tendon, high resolution real time ultrasonography examination was performed by an experienced musculoskeletal radiologist before and after the procedure, with the surgeons blind to the results of the scan both before and after surgery. RESULTS: In two instances, high resolution real time ultrasonography examination revealed nerve entrapment at the level of most proximal lateral suture. CONCLUSIONS: Since the sural nerve can be easily visualised using high-frequency high resolution real time ultrasonography, intraoperative ultrasound can be of assistance during percutaneous repair of Achilles tendon rupture. CLINICAL RELEVANCE: The sural nerve can be readily visualised by high-frequency high resolution real time ultrasonography probes. It could be beneficial to use high resolution real time ultrasonography intraoperatively or perioperatively to minimise the risks of sural nerve injury when undertaking percutaneous repair of Achilles tendon tears. PMID- 29409244 TI - Is Achillon repair safe and reliable in delayed presentation Achilles tendon rupture? A five-year follow-up. AB - BACKGROUND: To assess the outcome of delayed repair of ruptured Achilles tendon using the Achillon mini-open technique. METHODS: A review of all patients who underwent delayed repair (>10 days post injury) of ruptured Achilles tendon with mini invasive technique was compared to acute repairs carried out at the same unit. Leppilahti Score and Achilles Tendon Total Rupture Score (ATRS) were utilised. Complication rates including re-rupture were also reviewed. RESULTS: 14 patients were identified as having delayed repair (11-31 days). The mean follow up period was 71 months (range: 58-92). There were no statistically significant difference in the Leppilahti Score and ATRS compared to patients treated acutely (<10 days post injury) in the same time period. 79% of patients with delayed repair reported good to excellent, comparable to 80% of patients having undergone acute repair. CONCLUSIONS: For those patients who would benefit from surgical repair, a mini-open technique using the Achillon suture-passing device remains a safe and reliable option for delayed presentation of 11-31 days. PMID- 29409245 TI - Evaluation of the 1st metatarso-sesamoid joint using standing CT - The Stanmore classification. AB - BACKGROUND: Little is understood about the role that relative sesamoid displacement and chondral wear have on outcome after hallux valgus (HV) surgery. All existing methods to evaluate relative sesamoid displacement have limitations and furthermore, there have been no radiographic studies evaluating metatarso sesamoid joint wear. Standing CT scan circumvents many of the existing problems in evaluation of relative sesamoid displacement, and also enables the first radiographic study assessing metatarso-sesamoid joint wear. METHODS: Fifty feet (in 43 patients) with symptomatic HV (Group A) were compared with a control group of 50 feet (50 patients) (Group B). All images were standardised to enable reproducible measurements. The hallux valgus angle, Intermetatarsal angle, sesamoid rotation angle, sesamoid position and metatarso-sesamoid joint space were measured in all patients. RESULTS: The intra and inter-observer reliability correlation showed that the standing CT assessment of sesamoid position (1.000), rotation (0.991) and metatarso-sesamoid joint space (0.960) were highly reproducible. There was a highly significant difference (p<0.0001) in sesamoid position, sesamoid rotation and metatarso-sesamoid joint space between Group A and Group B. CONCLUSIONS: Standing CT has been shown to be a reproducible and accurate method of assessing the relative sesamoid displacement and metatarso sesamoid joint space narrowing. The results have been used to propose a novel standing CT based classification of hallucal sesamoids, considering the degree of displacement and wear. This classification may ultimately facilitate research to provide new insight into the effect relative sesamoid displacement and chondral wear have on outcomes from hallux valgus surgery. PMID- 29409246 TI - Prospective study of the " Inside-Out" arthroscopic ankle ligament technique: Preliminary result. AB - BACKGROUND: Lateral ankle ligament injury is among the most common orthopedic injuries. The objective of this study is to present the preliminary prospective results of treatment using the "Inside-Out" variant of the fully arthroscopic Brostrom-Gould technique. METHODS: Twenty six patients were included: 20 male and 6 female, aged 19-60 years, mean 41 years. All patients had positive "anterior drawer" and "talar tilt" tests. When necessary, cartilage injuries were treated with microfracture and arthroscopic resection for anterior impingement; three patients had hindfoot varus, on whom Dwyer osteotomy was performed; one patient had peroneal tendinopathy and was treated with tendoscopic debridement and another one had partial injury of the deltoid ligament, which was treated by direct repair. Two arthroscopic surgery portals were used; the anteromedial and anterolateral. After careful inspection of the joint, the anterior surface of the fibula was cleaned to resect the remains of the anterior talo-fibular ligament. An anchor with two sutures was placed on the anterior aspect of the fibula, 1cm from the distal apex of the malleolus. The sutures were passed through the remnant of the anterior talo-fibular ligament as well as the extensor retinaculum using special curved needles. Duncan knots were used to tie the ligament and the inferior extensor retinaculum while the ankle was kept in a neutral position. Patients were kept immobilized non-weight bearing for 2 weeks and were then allowed to start weight bearing in a removable protective boot for 4 weeks. The patients were able to return to sporting activities 6 months after surgery. RESULTS: After a mean follow-up of 27 months (range 21-36 months), patients were functionally evaluated using the American Orthopedics Foot and Ankle Society (AOFAS) ankle score. The mean preoperative value was 58 points, while the mean postoperative value increased to 90 points. One patient had paresthesia in the superficial fibular nerve area, which resolved spontaneously. CONCLUSION: Despite the limited cohort and the relatively short follow-up period, the use of the "inside-out" arthroscopic technique may be considered as a valid option for the treatment of chronic ankle instability. PMID- 29409247 TI - Clinical and radiological outcomes of concomitant endoscopic gastrocnemius release with scarf osteotomy. AB - BACKGROUND: Studies showed patients with hallux valgus also have tight gastrocnemius concomitantly. This study aims to investigate (1) prevalence of tight gastrocnemius in symptomatic hallux valgus (2) clinical and radiological outcomes of concomitant endoscopic gastrocnemius release with scarf osteotomy. METHODS: Between January 2011 to December 2013, 224 patients underwent hallux valgus surgery were evaluated. They were categorized into 2 groups: scarf osteotomy (n=195), scarf and endoscopic gastrocnemius release (combine, n=29). Clinical outcome measures assessed included VAS, AOFAS Hallux MTP-IP and SF-36 scores. Radiological outcomes included HVA, IMA, HVI and TSP. All patients were prospectively followed up for 6 and 24 months. RESULTS: The prevalence of ipsilateral gastrocnemius tightness in symptomatic hallux valgus is 12.9%. No significant difference in preoperative clinical outcomes between the two groups (all p>.05). Although AOFAS was 6+/-2 points poorer in the combine group compared to the scarf group at 6 months follow up (p=0.021), at 24 months, all clinical outcomes were comparable between the two groups (all p>0.05). Significant difference in the HVA change between the groups were observed but comparable radiological outcomes in IMA, TSP and HVI at 24 months follow up. CONCLUSIONS: We conclude clinical and radiological outcomes of concomitant endoscopic gastrocnemius release and scarf osteotomy are comparable with scarf osteotomy alone at 24 months. PMID- 29409248 TI - The lateral malleolar bony fleck classified by size and pathoanatomy: The IOFAS classification. AB - BACKGROUND: This study analyzes position of the peroneal tendons and status of the superior peroneal retinaculum (SPR) whenever a lateral malleolar bony flake fracture occurs. METHODS: Twenty-four patients had a lateral malleolar bony fleck on anteroposterior ankle radiographs, either in isolation or associated with other hindfoot injuries. We studied size of the bony flecks, presence or absence of peroneal tendon dislocation and pathoanatomy on CT scans. RESULTS: In 11 patients, a small bony fleck lies within the superior peroneal retinaculum and contiguous periosteum, which are stripped off the lateral fibula (Class II lesions). Tendons dislocate into the subperiosteal pouch thus formed, resembling Class I lesions without associated bony avulsion. Treatment for Class II is same as for Class I injuries. In 8 patients with a big bony fleck, tendons dislocate into the fracture site and SPR is intact (Class III lesions). In Class IV lesions, observed in 5 patients with 2-part calcaneal fracture/dislocation, SPR remains intact and peroneal tendons are not dislocated. The invariably large fleck results from the displacing lateral calcaneal fragment abutting against the fibula, whereas the dislocating tendons cause the bony avulsions in Classes II and III. CONCLUSIONS: Due to pathoanatomical differences, surgical approach and natural history of neglected lesions differ depending on size of the bony fleck. The SPR must not be incised in case of big Class III flecks. PMID- 29409249 TI - Evaluation of different shape-memory staple configurations against crossed screws for first metatarsophalangeal joint arthrodesis: A biomechanical study. AB - BACKGROUND: The first metatarsophalangeal joint may be fused in order to treat arthritis or instability. The use of shape-memory staples for fixation is well recognised, but little work has been done into the optimal configuration of staples. METHODS: The structural behaviour of first metatarsophalangeal joint (MTPJ) arthrodeses using shape-memory staples or crossed screws was studied using cadaveric porcine joints. Five fixation configurations were tested: single vertical or horizontal staple, paired staples in dorsal-medial configuration (0 90 degrees to the sagittal plane), paired staples in oblique orthogonal configuration (45-135 degrees ); or two crossed screws. Specimens were loaded in cyclical dorsiflexion for 1000 cycles. Plantar gapping and shearing were measured. Specimens were then loaded to failure. RESULTS: Cyclic testing caused more shear in the 45-135 degrees staples than the crossed screws (1.0mm+/-0.5mm compared to 0.14mm+/-0.4mm, p<0.01). No significant difference was found in plantar gap formation. Single vertical and horizontal single staples failed at 15N and 19. CONCLUSIONS: N, respectively. Paired 0-90 degrees staples failed at 43N+/-9N, significantly lower than the 45-135 degrees staples (141N+/-25N; p<0.001) and crossed screws (180N+/-67N; p<0.001). There was no significant difference between the 45-135 degrees staples and crossed screws. Screws failed by sudden cortical fracture; staples displayed gradual pull-out and shearing. First MTPJ arthrodeses fixed with single staples are not recommended. Arthrodeses fixed with staples at 0-90 degrees to the sagittal plane were significantly less strong than two crossed screws. However, positioning oblique staples at 45-135 degrees significantly improved stability, creating a construct as strong as, crossed screws. None of the constructs was strong enough for immediate weight bearing. PMID- 29409250 TI - Scarf osteotomy without internal fixation for correction of hallux valgus: A clinical and radiographic review of 148 cases. AB - BACKGROUND: Hallux valgus is a common condition with in excess of 120 procedures described in the literature for its correction. Traditionally, distal metatarsal osteotomies have been employed in the treatment of mild deformities, with proximal osteotomies being reserved for more severe presentations. The Scarf osteotomy without internal fixation allows large translations which can successfully correct severe hallux valgus deformities, without limitations related to screw placement. METHODS: This is a retrospective single surgeon case series performed over a three year period. One hundred and forty-eight cases were identified, with an average follow up time of 16.5 months. Visual analogue scales were used to obtain preoperative and postoperative pain and cosmetic scores, with the Foot and Ankle Disability Index (FADI) index used to assess functional status. The hallux valgus angle (HVA) and intermetatarsal angle (IMA) were assessed on preoperative and postoperative AP weight-bearing foot X-rays. RESULTS: The mean pain score improved from 7.04/10 preoperatively to 0.29/10 postoperatively. The mean cosmetic score improved from 2.1/10 to 9.1/10 postoperatively. The mean preoperative HVA and IMA were 35.04 degrees and 15.04 degrees , respectively. The mean postoperative HVA and IMA were 11.54 degrees and 4.83 degrees , respectively. The mean postoperative FADI score was 103.4/104. We report a loss of correction in two cases. One revision surgery was performed. CONCLUSIONS: We report a large series of cases of the modified Scarf osteotomy as described by Maestro-a versatile, cost-effective, safe and reliable technique with the potential for three dimensional correction. Whilst this is a technically demanding procedure, we recommend the use of the modified Scarf osteotomy in the treatment of a wide range of hallux valgus deformities. PMID- 29409252 TI - Arthroscopic approach to the spring (calcaneonavicular) ligament. AB - BACKGROUND: This research studied the safety and efficacy of a new portal to the spring ligament. This portal is located just plantar to the insertion of the posterior tibial tendon and above the fibrous septum between the posterior tibial and the flexor digitorum longus tendons. METHODS: Twelve fresh frozen foot and ankle specimens were used. The distance between the accessory medial portal and the medial plantar nerve was measured. The relation between the medial plantar nerve and the spring ligament was studied. The depth that can be reached through the portal was also assessed. RESULTS: The average distance between the insertion point of the 3mm diameter metal rod and the medial plantar nerve was 20(6-27)mm. The medial plantar nerve located at lateral third of the ligament in 8 specimens (67%), middle third in 2 specimens (17%) and medial third in 2 specimens (17%). The tip of rod can reach Zone A in all specimens. CONCLUSION: This study demonstrated that arthroscopic approach and repair of the spring ligament can injure the medial plantar nerve. CLINICAL RELEVANCE: The clinical relevance of this cadaver study is that it confirmed the feasibility of arthroscopic approach to the whole span of the spring ligament and alerted the potential risk of injury to the medial plantar nerve during arthroscopic assisted repair of the ligament. PMID- 29409253 TI - Functional pedal construct achieved by combined operative treatment in peritalar complex Charcot arthropathy: A prospective study of 38 feet. AB - BACKGROUND: Charcot arthropathy of the peritalar complex carries a high risk of amputation if not properly managed. Our aim is to assess the functional outcome of severe Charcot arthropathy of the peritalar complex following enblock resection of the ulcer, massive debridement and stabilizing all the elements of the peritalar complex. METHODS: We prospectively studied 38 feet in 35 patients with peritalar complex Charcot arthropathy. All Feet underwent intense debridement and fusion using a combination of (Ilizarov) external fixation, and (plate and locked nail) internal fixation. Thirty two feet were graded as Eichenholtz 2, and six feet were graded as Eichenholtz 3. The mean follow up was 35.9months. RESULTS: The mean AOFAS score was significantly elevated from 25.4+/ 9.1 preoperatively to 67.6+/-5.7 at the most recent follow-up (p<0.001). Complete bony fusion was achieved in 28 feet. Unsound bony fusion occurred in 8 feet. Two feet required below knee amputation. CONCLUSION: Peritalar complex Charcot arthropathy is not uncommon variety. Such cases carry high risk of complications and amputation is not excluded. The proper timing of surgery is crucial. Massive debridement and rigid fixation with strict follow up is mandatory to achieve the ultimate goal of obtaining a plantigrade, stable, mechanically sound, painless and infection free pedal construct. PMID- 29409251 TI - Large variation in use of patient-reported outcome measures: A survey of 188 foot and ankle surgeons. AB - BACKGROUND: There is an increasing interest in the use of patient reported outcome measures (PROMs). However, there is a large variety of PROMs and a lack of consensus regarding preference for their use. Aim of this study is to determine how often PROMS are used for foot and ankle disorders, for what purpose PROMs are used, and what the preferences of the foot and ankle surgeons are, when choosing a PROM to use. METHODS: Members of the Ankleplatform Study Group-Science of Variation Collaborative were invited to participate in this survey by email. The online survey consisted of six questions on the use and preferences regarding foot and ankle PROMs. RESULTS: 188 participants completed the questionnaire. Of the respondents 17% reported not to use PROMs, 72% stated to use PROMS for research, 39% routinely for patient care and 34% for registration or quality assessment. The respondents were familiar with 30 different outcome measures, of which 20 were PROMs. One of the excluded outcome measures, the AOFAS Hindfoot scale was most commonly reported as preferred outcome measure. FAOS and MOXFQ were the preferred PROMs, reported by 9.7% of the surgeons. Subsequently followed by the FFI (4.3%), the FAAM (3.7%) and the VAS-FA (3.7%). CONCLUSIONS: A large majority of the foot and ankle surgeons uses PROMs. The AOFAS hindfoot scale is mentioned as the most preferred outcome measure, while in fact this is not a PROM. Of the twenty different PROMs mentioned in this study, most reported were the FAOS and MOXFQ both supported by only 9.7% of the surgeons. For proper comparison between patients in clinical practice and research, consensus is needed on which easy-to-use PROM with adequate clinimetric properties should be used. Therefore more evidence in the field of clinimetrics of foot and ankle outcome measures is needed. PMID- 29409254 TI - The role of bone marrow edema on osteochondral lesions of the talus. AB - BACKGROUND: To assess the functional and radiological outcomes after arthroscopic talus autologous matrix-induced chondrogenesis (AT-AMIC(r)) in 2 groups: patients with and without bone marrow edema (BME). METHODS: Thirty-seven patients of which 24 without edema (GNE) and 13 with edema (GE) were evaluated. All patients were treated with AT-AMIC(r) repair for symptomatic osteochondral talar lesion. Clinical and radiological parameters were evaluated with VAS score for pain, AOFAS and SF-12 at T0 (preoperatively), T1 (6 months), T2 (12 months), T3 (24 months) and MRI and CT-scan at T0, T1, T2 and T3. RESULTS: No patients were lost to the final follow-up. In both groups we found a significant difference for clinical and radiological parameters with ANOVA for repeated measures through four time points (p<0.001). In GNE, AOFAS improved significantly at each follow up (p<0.05); while CT and MRI showed a significant reduction in lesion size between T1 and T2 and T2 and T3 (p<0.05). In GE, AOFAS improved significantly between T0 and T1 and T2 and T3 (p<0.05); lesion size, measured with CT, decreased between T1 and T2 (p<0.05), while with MRI the lesion showed a reduction at each follow-up (p<0.05). Lesion size was significantly higher both in MRI and CT in GE compared to GNE (p<0.05). In GNE no patients presented edema at T3, while in GE only 23.08% of the patients presented edema at T3. CONCLUSIONS: The study revealed that osteochondral lesions of the talus were characterized by bigger size both in MRI and CT in patients with edema. We conclude that AT-AMIC(r) can be considered a safe and reliable procedure that allows effective healing, regardless of edema and more than half of patients did not present edema six months after surgery. PMID- 29409255 TI - Non-anatomical or direct anatomical repair of chronic lateral instability of the ankle: A systematic review of the literature after at least 10 years of follow up. AB - INTRODUCTION: A lateral ankle sprain is one of the most frequent reasons for consultation at the emergency trauma unit. Numerous surgical procedures have been described with long-term outcomes that differ. HYPOTHESIS: The long-term results of anatomical repair of the anterior talofibular ligament (ATFL) and the calcaneofibular (CFL) ligament are better, with less secondary radiological osteoarthritis than non-anatomical repair. MATERIALS AND METHODS: A review of the literature after a minimum follow-up of 10 years was performed to analyze the clinical and radiological results of direct anatomical repair (Brostrom, Duquennoy) and non-anatomical repair (Watson Jones, Evans, Castaing). Thirteen articles were selected. RESULTS: Eight hundred and one ankles were evaluated after a mean follow-up of 15.3 years. The functional outcome was better after anatomical repair but with recurrent instability. Loss of range of motion and secondary osteoarthritis was more frequent after non-anatomical repair. CONCLUSION: Anatomical repair of the lateral collateral ligament of the ankle resulted in a better functional outcome and less secondary osteoarthritis than non-anatomical repair. STUDY DESIGN: Review of the literature; level of proof IV. PMID- 29409256 TI - Biomechanical comparison of fixation stability using a Lisfranc plate versus transarticular screws. AB - BACKGROUND: To obtain adequate fixation in treating Lisfranc soft tissue injuries, the joint is commonly stabilized using multiple transarticular screws; however iatrogenic injury is a concern. Alternatively, two parallel, longitudinally placed plates, can be used to stabilize the 1st and 2nd tarsometatarsal joints; however this may not provide adequate stability along the Lisfranc ligament. Several biomechanical studies have compared earlier methods of fixation using plates to the standard transarticular screw fixation method, highlighting the potential issue of transverse stability using plates. A novel dorsal plate is introduced, intended to provide transverse and longitudinal stability, without injury to the articular cartilage. METHODS: A biomechanical cadaver model was developed to compare the fixation stability of a novel Lisfranc plate to that of traditional fixation, using transarticular screws. Thirteen pairs of cadaveric specimens were tested intact, after a simulated Lisfranc injury, and then following implant fixation, using one method of fixation randomly assigned, on either side of each pair. Optical motion tracking was used to measure the motion between each of the following four bones: 1st metatarsal, 2nd metatarsal, 1st cuneiform, and 2nd cuneiform. Testing included both cyclic abduction loading and cyclic axial loading. RESULTS: Both the Lisfranc plate and screw fixation method provided stability such that the average 3D motions across the Lisfranc joint (between 2nd metatarsal and 1st cuneiform), were between 0.2 and 0.4mm under cyclic abduction loading, and between 0.4 and 0.5mm under cyclic axial loading. Comparing the stability of fixation between the Lisfranc plate and the screws, the differences in motion were all 0.3mm or lower, with no clinically significant differences (p>0.16). CONCLUSIONS: Diastasis at the Lisfranc joint following fixation with a novel plate or transarticular screw fixation were comparable. Therefore, the Lisfranc plate may provide adequate support without risk of iatrogenic injury to the articular cartilage. PMID- 29409257 TI - Anatomy of the tibial incisura as a risk factor for syndesmotic injury. AB - BACKGROUND: The study aims at comparing the bony anatomy of the syndesmosis in patients who sustained a high fibular fracture with syndesmosis disruption and that of the non-injured population. We hypothesised that there are certain anatomical features making the syndesmosis susceptible to injury. METHODS: The CT examinations of 75 patients who sustained a high fibular fracture with syndesmosis disruption and control group of 75 patients with unrelated foot problems were compared. The depth, fibular engagement and rotational orientation of the tibial incisura were analyzed. RESULTS: With the median values of the control group as cutoff there were 71% shallow, 71% disengaged and 77% retroverted syndesmoses in the injury group. The differences between the groups were statistically significant for every measure (P<.002 to P>.0001). CONCLUSIONS: Patients with a shallow, disengaged and retroverted bony configuration of the syndesmosis are overrepresented among patients with syndesmosis disruption. PMID- 29409258 TI - Can we use biomarkers of coagulation to predict which patients with foot and ankle injury will develop deep vein thrombosis? AB - BACKGROUND: Our aim was to determine whether plasma levels of Tissue Factor (TF), Vascular Cell Adhesion Molecule 1 (VCAM-1), Interleukin 6 (IL-6) or D-dimer after foot and ankle injury could predict which patients would develop deep vein thrombosis (DVT). METHODS: Patients aged 18-60 years with acute foot and ankle injury had venous blood sample to measure TF, VCAM-1, IL-6 and D-dimer within 3 days of injury. Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. RESULTS: 21 of 77 patients were found to have DVT (27%). There was no statistically significant association between levels of TF, VCAM-1, IL-6 or D-dimer and subsequent development of DVT. CONCLUSION: Tissue Factor (TF), Vascular Cell Adhesion Molecule-1 (VCAM-1), Interleukin-6 (IL-6) and D-dimer levels were not associated with development deep vein thrombosis in patients with acute foot and ankle injury. PMID- 29409259 TI - To compare the efficacy between fixation with tightrope and screw in the treatment of syndesmotic injuries: A meta-analysis. AB - BACKGROUND: To compare the efficacy between fixation with suture-button and screw in the treatment of syndesmotic injuries: a meta-analysis. METHODS: We comprehensively searched PubMed, Embase, and the Cochrane Library and performed a meta-analysis of randomized controlled trials (RCTs) and retrospective comparative studies (RTCs). We performed using Review Manager 5.2. RESULTS: Three RCTs and six retrospective studies were conducted, including a total of 397 patients. The significant differences of the fixation of suture-button were reported for AOFAS scores (at 3, 6 and 12 months follow-up), full-weight time, reoperation, malreduction and the rate of failure of fixation. There were no significant differences between the groups regarding complications of infection, VAS, OMAS, range of motion, TFCS, TFO and MCS. CONCLUSIONS: Neither the functional outcome nor complications significantly differed between the fixation methods, but suture-button might lead to a quicker return to work. This analysis needs to be confirmed and updated by larger sample data and rigorously designed RCTs. PMID- 29409260 TI - Resection or preservation of the metatarsal heads in rheumatoid forefoot surgery? A randomised clinical trial. AB - BACKGROUND: Despite impressive results of the pharmacological management of rheumatoid arthritis, still certain patients suffer from rheumatoid forefoot problems. Surgical treatment of these forefoot deformities can be an option. In literature no high-quality studies on this topic can be found. The goal of present study is to compare the results of a metatarsal head (MTH) resecting technique with a MTH preserving technique in the operative treatment of severe rheumatoid forefoot deformity. METHODS: Patients suffering from well-defined rheumatoid forefoot deformity were prospectively enrolled in three institutions. This non-blinded study had a randomised clinical design and eligible patients were randomly assigned to undergo either resection of preservation of the MTH. The primary outcome measure consisted of the AOFAS score. Secondary outcome measures were: the FFI, the VAS for pain and the SF-36. RESULTS: Twenty-three patients (10 in MTH preservation group) were included and analysed. After one year follow-up no significant differences in AOFAS score and additional outcome factors were found. A total of 10 complications in 23 patients were reported. CONCLUSIONS: This randomised clinical study did not show significant clinical difference between a MTH resecting and a preserving procedure in patients suffering from rheumatoid forefoot deformity. Both procedures resulted in considerable improvement of pain and activity scores. PMID- 29409261 TI - Non-contact ulcer area calculation system for neuropathic foot ulcer. AB - BACKGROUND: Around 125,785 new cases in year 2013-14 of leprosy were detected in India as per WHO report on leprosy in September 2015 which accounts to approximately 62% of the total new cases. Anaesthetic foot caused by leprosy leads to uneven loading of foot leading to ulcer in approximately 20% of the cases. Much efforts have gone in identifying newer techniques to efficiently monitor the progress of ulcer healing. Current techniques followed in measuring the size of ulcers, have not been found to be so accurate but are still is followed by clinicians across the globe. Quantification of prognosis of the condition would be required to understand the efficacy of current treatment methods and plan for further treatment. This study aims at developing a non contact technique to precisely measure the size of ulcer in patients affected by leprosy. METHODS: Using MATLAB software, GUI was designed to process the acquired ulcer image by segmenting and calculating the pixel area of the image. The image was further converted to a standard measurement using a reference object. The developed technique was tested on 16 ulcer images acquired from 10 leprosy patients with plantar ulcers. Statistical analysis was done using MedCalc analysis software to find the reliability of the system. RESULTS: The analysis showed a very high correlation coefficient (r=0.9882) between the ulcer area measurements done using traditional technique and the newly developed technique, The reliability of the newly developed technique was significant with a significance level of 99.9%. CONCLUSIONS: The designed non-contact ulcer area calculating system using MATLAB is found to be a reliable system in calculating the size of ulcers. The technique would help clinicians have a reliable tool to monitor the progress of ulcer healing and help modify the treatment protocol if needed. PMID- 29409262 TI - Foot and ankle infections: Debridement, early fixation and rifampicin provide earlier recovery of function and quality of life. AB - BACKGROUND: Infection after foot and ankle fractures is a major concern for orthopedic surgeons. It is widely believed that final osteosynthesis should be delayed until the infection is cured. However, there is no literature that supports this practice. In addition, the delay impairs patient function and quality of life (QoL). METHODS: In the present study, four cases of ankle infection treated with aggressive debridement, early fixation and antibiofilm antibiotics are described. It is thought that, like other implant related infections, ankle infections can be rapidly treated with the definitive fixation and by curing the infection to make for a fast recovery of QoL and function. RESULTS: The infections were caused by MSSA and Pseudomonas aeruginosa in case 1, MSSA in case 2 and MRSA as well as K. pneumonia in case 3. Case 4 was a culture negative infection. They were susceptible to antibiofilm antibiotics (the gram negative bacilli susceptible to ciprofloxacin and the gram-positive cocci susceptible to rifampicin). Cases 1, 3 and 4 were treated with a tibio-talo calcaneal arthrodesis and case 2 was treated with a de-rotational fibular osteotomy and a medial closing wedge supramalleolar osteotomy. All cases improved at a median time of 4 weeks in terms of quality of life (SF-36) and function (AOFAS). At 2-years follow-up, no recurrence of infection was observed in any of the cases. All the cases achieved fusion or osteotomy healing at final follow-up. CONCLUSIONS: Early fixation after debridement combined with antibiofilm antibiotics can be performed in foot and ankle inflections to provide early recovery of QoL and function in patients. PMID- 29409263 TI - Infections in primary total ankle replacement: Anterior approach versus lateral transfibular approach. AB - BACKGROUND: Total ankle replacement (TAR) represents an alternative to fusion for the treatment of end-stage ankle osteoarthritis. The aim of the present study was to retrospectively assess the frequency of infections between TARs with anterior and lateral transfibular approach at 12-months follow-up. METHODS: 81 TARs through an anterior approach and 69 TARs through a lateral approach were performed between May 2011 and July 2015. We compared surgical time and tourniquet time, as well as superficial and deep infections frequency during the first 12 postoperative months. RESULTS: In the anterior approach group, there were 3 (3.7%) deep infections and 4 (4.9%) superficial wound infections. In the lateral approach group, there were 1 (1.4%) deep infection and 2 superficial wound infections (2.9%). There were not statistically significant differences between the groups. There was a significant difference between anterior approach (115minutes) and lateral approach group (179minutes) in terms of surgical time (P<0.001). CONCLUSIONS: The frequency of superficial and deep periprosthetic infections during the first postoperative year was not significantly different in the lateral approach group compared to the anterior approach group, despite the significantly longer surgical time in the lateral transfibular approach group. PMID- 29409264 TI - A comparison of the "All-Inside" arthroscopic Brostrom procedure with the traditional open modified Brostrom-Gould technique: A review of 62 patients. AB - BACKGROUND: The open Brostrom-Gould lateral ankle stabilization procedure has been the gold standard for primary lateral ankle stabilization. A new minimally invasive all-inside arthroscopic technique has been described for the correction of lateral ankle instability. METHODS: We performed a review of patients who underwent lateral ankle stabilization by either the traditional open Brostrom Gould (BG) or the All-Inside Brostrom (AIB) technique to compare and identify any discrepancies between functional and/or patient satisfaction outcomes. A total of 62 patients underwent a lateral ankle stabilization. Of those 62 patients, 32 received a traditional open Brostrom-Gould procedure and 30 patients underwent an All-Inside Brostrom type procedure. The two groups were compared preoperatively with AOFAS ankle-hindfoot scoring system and Visual Analog Score (VAS) for pain. Postoperatively, AOFAS, Karlsson Peterson and VAS scores were compared. RESULTS: The mean preoperative VAS pain score for the open Brostrom-Gould was 7.28, the All-Inside Brostrom was 8.18. The mean postoperative VAS pain score for the open Brostrom-Gould was 1.2, the All-Inside Brostrom was 1.5. The mean preoperative AOFAS score for the Brostrom-Gould was 35.44, the All-Inside Brostrom was 35.07. The mean postoperative AOFAS score for the open Brostrom-Gould was 93.53, the All Inside Brostrom was 95.33. The mean postoperative Karlsson Peterson score for the open Brostrom-Gould was 93.41, the All-Inside Brostrom was 91.80. The mean time to weight bearing for the Brostrom-Gould was 22 days, the All-Inside Brostrom was 12 days. CONCLUSION: There were no statistically significant differences identified in any of the functional or patient satisfaction outcome scores using either technique. This review suggests the minimally invasive arthroscopic technique using bone anchors for lateral ankle stabilization may be comparable to the traditional open Brostrom-Gould with the added advantage of earlier time to weight bearing. PMID- 29409265 TI - Use of intramedullary carbon fiber nail in hindfoot fusion: A small cohort study. AB - BACKGROUND: Current literature on carbon fiber implant use in foot and ankle surgery is scant. The purpose of this paper is to report medium-term outcomes of hindfoot fusion using a carbon fiber intramedullary nail. METHODS: We retrospectively reviewed 30 cases of hindfoot fusion using carbon fiber intramedullary nail fixation between 2014 and 2017. We excluded revisions and cases with bulk allograft or ankle infection prior to surgery. We reviewed charts for length of followup, radiographic union, and complications. RESULTS: Eleven patients were included (6 females, 5 males; mean age=52+/-15years; mean BMI=29.0+/-6.4kg/m2). Mean followup was 20 (range, 1.5-107) months. Nine of eleven cases achieved radiographic union while one case developed a complication requiring surgery. The mean time to union was 3 (range, 1.5-6) months. CONCLUSIONS: Carbon fiber implants offer several theoretical advantages over traditional metallic implants. They can be used safely in foot and ankle surgery without concern for high failure or complication rate. Larger scale studies with longer followup are needed on this topic. PMID- 29409266 TI - Validation and cross-cultural adaptation of Greek version of Achilles tendon Total Rupture Score. AB - BACKGROUND: The purpose of this study was the translation, cross-cultural adaptation and validation of the Achilles Tendon Total Rupture Score (ATRS) in Greek population. METHODS: The translation and cross-cultural adaptation of the original version of ATRS in Greek language was performed according to the methodology described by Beaton et al. Validation and test-retest reliability were evaluated in forty-six patients, treated surgically for acute Achilles tendon rupture. Validity was evaluated by correlation of total and all subscale scores of Greek version of Manchester Foot Pain and Disability Index (MFPDI). Test-retest reliability evaluated with interclass correlation coefficient and Crombach's alpha coefficient was used for internal consistency. RESULTS: The internal consistency (alpha=0.96) and test-retest reliability (ICC=0.97) were excellent. There were no ceiling and floor effects during test-retest assessment. The Greek version of ATRS showed strong correlation with all subscales and overall score of MFPDI (pain subscale: R=-0.954, p<0.01, function subscale: R= 0.811, p<0.01, appearance subscale: R=-0.763, p<0.01, overall: R=-0.914, p<0.01). CONCLUSIONS: Greek version of ATRS was successfully adapted in Greek population and it appears to be a valid and reliable instrument to evaluate outcomes in Greek speaking patients after Achilles tendon rupture. LEVEL OF EVIDENCE: Level III. PMID- 29409267 TI - Uncontrolled diabetes as a potential risk factor in tibiotalocalcaneal fusion using a retrograde intramedullary nail. AB - BACKGROUND: Tibiotalocalcaneal (TTC) fusion using a retrograde intramedullary (IM) nail is an effective salvage option for terminal-stage hindfoot problems. However, as many patients who receive TTC fusion bear unfavorable medical comorbidities, the risk of nonunion, infection and other complications increases. This study was performed to identify the factors influencing outcomes after TTC fusion using a retrograde IM nail. METHODS: Between September 2008 and February 2012, 34 consecutive patients received TTC fusion using a retrograde IM nail for limb salvage. All patients had a minimum follow-up of two years. Throughout follow-up, standard ankle radiography was performed along with clinical outcome assessment using a visual analog scale (VAS) for pain, the American Orthopaedic Foot and Ankle Society Ankle-Hind Foot Scale (AOFAS A/H scale) and the Foot and Ankle Outcome Score (FAOS). For the retrospective analysis, demographic factors, preoperative medical status, laboratory markers, and etiology were comprehensively reviewed using medical records. The success of the index operation was determined using clinical and radiological outcomes. Finally, the effect of each factor on failure after the operation was analyzed using univariate logistic regression. RESULTS: In a mean of seven months, 82% (28/34) achieved union, as evaluated by standard radiography. All clinical outcome parameters improved significantly after the operation, including VAS, AOFAS A/H scale, and FAOS (P<0.001). At the last follow-up, five cases of nonunion with less than AOFAS A/H scale of 80 and two cases of below knee amputation due to uncontrolled infection were determined to be failures. None of the factors (etiology, demographics, laboratory markers and medical status) significantly influenced failures. However, uncontrolled DM significantly increased the failure rate with an odds ratio of 10 (P=0.029). CONCLUSIONS: TTC fusion with a retrograde intramedullary nail is a successful treatment for complicated hindfoot problems such as traumatic osteoarthritis, Charcot arthropathy and failed TAA. However, it should be used judiciously in patients with uncontrolled DM, as the risk of failure increases. DESIGN: Retrospective cohort study. PMID- 29409268 TI - Clinical and radiographic outcomes of the Kramer osteotomy in the treatment of bunionette deformity. AB - BACKGROUND: Bunionette deformity is a painful bony prominence of the 5th metatarsal. We evaluated outcomes of using a Kramer osteotomy to treat this condition. METHODS: Retrospective study of patients treated with a Kramer osteotomy from 2003 and 2016. Outcome measures included Foot Functional Index (FFI) and radiographic measurements. RESULTS: 38 patients (43 feet) with an average follow-up of 55 months. Mean postoperative FFI1 was 19.4. Mean 4-5 IMA2 improved 3.9 degrees , from 8.3 degrees preoperatively to 4.4 degrees on final postoperative films (p<0.01). Mean MTP-53 angle improved 13.2 degrees from 13.6 degrees preoperatively to 0.4 degrees at final follow-up (p<0.01). There were 5 delayed unions (11.6%) and 1 non-union (2.3%). CONCLUSIONS: The Kramer osteotomy is an effective treatment option in patients with bunionette deformity, with significant correction of the 4-5 IM2 and MTP-53 angles and few complications. PMID- 29409269 TI - Gait analysis and functional outcome in patients after Lisfranc injury treatment. AB - INTRODUCTION: Lisfranc injuries involve any bony or ligamentous disruption of the tarsometatarsal joint. Outcome results after treatment are mainly evaluated using patient-reported outcome measures (PROM), physical examination and radiographic findings. Less is known about the kinematics during gait. METHODS: Nineteen patients (19 feet) treated for Lisfranc injury were recruited. Patients with conservative treatment and surgical treatment consisting of open reduction and internal fixation (ORIF) or primary arthrodesis were included. PROM, radiographic findings and gait analysis using the Oxford Foot Model (OFM) were analysed. Results were compared with twenty-one healthy subjects (31 feet). Multivariable logistic regression was used to determine factors influencing outcome. RESULTS: Patients treated for Lisfranc injury had a significantly lower walking speed than healthy subjects (P<0.001). There was a significant difference between the two groups regarding the range of motion (ROM) in the sagittal plane (flexion extension) in the midfoot during the push-off phase (p<0.001). The ROM in the sagittal plane was significantly correlated with the AOFAS midfoot score (r2=0.56, p=0.012), FADI (r2=0.47, p=0.043) and the SF-36-physical impairment score (r2=0.60, p=0.007) but not with radiographic parameters for quality of reduction. In a multivariable analysis, the best explanatory factors were ROM in the sagittal plane during the push-off phase (beta=0.707, p=0.001), stability (beta=0.423, p=0.028) and BMI (beta=-0.727 p=<0.001). This prediction model explained 87% of patient satisfaction. CONCLUSIONS: This study showed that patients treated for Lisfranc injury had significantly lower walking speed and significantly lower flexion/extension in the midfoot than healthy subjects. The ROM in these patients was significantly correlated with PROM, but not with radiographic quality of reduction. Most important satisfaction predictors were BMI, ROM in the sagittal plane during the push-off phase and fracture stability. PMID- 29409270 TI - Full text publication rates of papers presented at the British Foot and Ankle Society. AB - BACKGROUND: Techniques in foot and ankle surgery have expanded rapidly in recent years, often presented at national society meetings. It is important that research is published to guide evidence based practice. Many abstracts however do not go on to full text publication. METHODS: A database was created of all abstracts presented at BOFAS meetings from 2009 to 2013. Computerised searches were performed using PubMed and Google search engines. RESULTS: In total 341 papers were presented, with an overall publication rate of 31.7%. Of 251 clinical papers, 200 were case series (79.6%). Factors associated with publication success included basic science studies, papers related to arthroscopic surgery and research performed outside the UK. CONCLUSION: A relatively low conversion rate from presentation to publication could be as a result of papers failing to pass the scrutiny of peer review, or that the work is never formally submitted for publication. The information from this study could be used to prioritise future research and promote higher quality research. PMID- 29409271 TI - Comparison of postoperative pain control methods after bony surgery in the foot and ankle. AB - BACKGROUND: We performed a prospective study to evaluate and compare the effectiveness of postoperative pain control methods after bone surgery in the foot and ankle. METHODS: Among the patients who underwent foot and ankle surgery from June 2014 to September 2015 with an ultrasound-guided nerve block, 84 patients who fully completed a postoperative pain survey were enrolled. An opioid patch (fentanyl patch, 25mg) was applied in group A (30 patients). Diluted anesthetic (0.2% ropivacaine, 30ml) was injected into the sciatic nerve once, about 12h after the preoperative nerve block, in group B (27 patients). Periodic intramuscular injection of an analgesic (ketorolac [Tarasyn], 30mg) was performed in group C (27 patients). The visual analogue scale (VAS) pain scores at 6, 12, 18, 24, and 48h after surgery were checked, and the complications of all methods were monitored. RESULTS: The mean VAS pain score was lower in group B, with a statistically significant difference (P<.05) between groups A, B, and C at 12 and 18h after surgery. Four patients in group A experienced nausea and vomiting; however, no other patients complained of any complications or adverse effects. CONCLUSION: The ultrasound-guided injection of a diluted anesthetic into the sciatic nerve seemed to be the most useful method for controlling pain in the acute phase after bone surgery in the foot and ankle. The injection of the diluted anesthetic once on the evening of the day of surgery resulted in less postoperative pain in the patients. LEVEL OF EVIDENCE: II. PMID- 29409272 TI - Surgical approaches to the calcaneus and the sural nerve: There is no safe zone. AB - BACKGROUND: Sural nerve related symptoms following the extensile lateral approach to the calcaneus (ELA) and the sinus tarsi approach (STA) are a known postoperative complication despite awareness of the course the sural nerve. While the main trunk of the sural nerve and its location relative to the approaches have been previously described, the nerve gives rise to lateral calcaneal branches (LCBs) and an anastomotic branch (AB) that may be at risk of injury. The purpose of this study was to describe the course of the sural nerve, its LCBs and the AB in relation to the ELA and STA. METHODS: 17 cadaveric foot specimens were dissected, exposing the sural nerve, the LCBs and the AB. A line representing the ELA and STA incision was then created. It was noted if the line crossed the sural nerve trunk, any of the LCBs, and the AB, and at what distance they were crossed using the distal tip of the fibula as a reference. RESULTS: The sural nerve was identified in all specimens, and the main trunk was noted to cross the path of the ELA in no specimens and the path of the STA in 2 (12%) specimens. At least one LCB of the sural nerve was identified in all specimens. The ELA crossed the path of at least one LCB in 15 specimens (88%). An AB was present in 9 specimens (53%). If an AB was present, this was crossed by the STA in every instance. CONCLUSIONS: The ELA and the STA traverses the path of either the main trunk of the sural nerve, the LCBs, or the AB in the majority of specimens, potentially accounting for the presence of sural nerve postoperative symptoms regardless of the approach used. PMID- 29409273 TI - Tendoscopy of Achilles, peroneal and tibialis posterior tendons: An evidence based update. AB - BACKGROUND: Tendoscopy has been proposed in treating several conditions affecting tendons around the ankle. We reviewed literature to investigate the efficacy of Achilles, peroneal and tibialis posterior tendoscopy. METHODS: Following the PRISMA checklist, the Medline, Scopus and EMBASE databases were searched, including studies reporting patients affected by disorders of Achilles, peroneal and tibialis posterior tendons and treated by tendoscopy (or tendoscopic-assisted procedures). The tendoscopic technique, rehabilitation protocol, clinical scores, patient satisfaction, success and failure rates and complications were evaluated. RESULTS: Sixteen studies (319 procedures) dealt with Achilles tendoscopy, nine (108) and six (78) about peroneal and tibialis posterior, respectively. Wound healing, cosmetic results, complication rate, work and sport resumption delay were satisfactory. Clinical scores, classification methods and rehabilitation protocols adopted were heterogeneous. CONCLUSIONS: The recent scientific evidence suggests that tendoscopy and endoscopic-assisted percutaneous procedures are a safe and effective treatment in chronic and acute disorders of tendons around the ankle. PMID- 29409274 TI - Proximal oblique metatarsal osteotomy for hallux valgus using a plantar locking plate. AB - BACKGROUND: The purpose of this retrospective study was to evaluate the clinical and radiological results of hallux valgus surgery using a plantar locking plate. METHODS: Proximal oblique metatarsal osteotomy combined with distal soft tissue treatment was performed in 59 adult patients (68 feet) with hallux valgus, using an anatomically pre-contoured plantar locking plate for fixation of the osteotomy. The median age was 64.0 years and the median follow-up period was 16.5 months. RESULTS: The mean JSSF scale improved significantly from 56.0 points preoperatively to 95.8 points postoperatively. The mean intermetatarsal angle and hallux valgus angle decreased from 16.4 degrees and 41.8 degrees preoperatively to 4.2 degrees and 10.8 degrees postoperatively, respectively. The mean inclination angle was 19.9 degrees preoperatively and 20.5 degrees postoperatively. Removal of hardware was needed in 2 feet (2.9%). CONCLUSIONS: Proximal oblique metatarsal osteotomy is an effective method for relief of pain and improvement of function in correction of hallux valgus deformity. Use of a plantar locking plate provides sufficient maintenance of the correction, and complications associated with the hardware are rare. PMID- 29409275 TI - Early radiographic risk factors for rigid relapse in idiopathic clubfoot treated with the Ponseti method. AB - BACKGROUND: This study aimed at identifying early risk factors for rigid relapse in idiopathic clubfoot using foot radiographs. METHODS: Thirty-four patients with 43 idiopathic clubfeet treated with the Ponseti method were retrospectively reviewed. RESULTS: There were seven rigid relapse recalcitrant to manipulation and requiring extensive soft-tissue release. Three radiograabphic measurements on the maximum dorsiflexion lateral (MD-Lat) radiograph, talocalcaneal (TaloCalc Lat), tibiocalcaneal (TibCalc-Lat), and calcaneus-first metatarsal (CalcMT1-Lat) angles, showed significant differences between patients with and without rigid relapse. The TaloCalc-Lat and CalcMT1-Lat angles showed significant hazard ratio for rigid relapse by multivariate survival analysis. Clubfeet demonstrating TibCalc-Lat>90 degrees and CalcMT1-Lat<5 degrees have a 24.9-fold odds ratio to develop rigid relapse compared to those demonstrating TibCalc-Lat<=90 degrees or CalcMT1-Lat>=5 degrees . CONCLUSIONS: The TaloCalc-Lat, TibCalc-Lat, and CalcMT1 Lat angles on the MD-Lat radiograph immediately before the tenotomy, probably representing intrinsic tightness of the midfoot and/or hindfoot, are significant risk factors for rigid relapse in patients treated with the Ponseti method. PMID- 29409276 TI - Ultrasonographic evaluation of the ankle after unilateral traumatic lower limb amputations. AB - BACKGROUND: Unilateral lower limb amputation can alter the tissue morphology leading to increase future risk of degenerative secondary disorders. METHODS: Thirty-four consecutive male patients with unilateral lower limb amputations of different levels and 34 well matched male controls were included. To explore whether the ankles of traumatic lower limb amputees were undergoing morphological changes, three different tissue types i.e. talar cartilage, plantar fascia and Achilles tendon thicknesses in the intact limb of the lower limb amputee and healthy controls were measured by using ultrasound. RESULTS: Plantar fascia was found to be thicker (p=0.013) and talar cartilage was thinner (p<0.001) on the intact sides of the patients than those of the controls. Achilles tendon thickness was found to be similar. In patients group, plantar fascia thickness was positively correlated with age (r=0.601, p<0.001), BMI (r=0.454, p=0.007) and durations of amputation (r=0.443, p=0.009) and prosthetic use (r=0.429, p=0.011). Achilles tendon thickness was positively correlated with durations of amputation (r=0.338, p=0.05) and prosthetic use (r=0.468, p=0.005). In controls group, talar cartilage thickness was negatively correlated with age (r=-0.640, p<0.001) and BMI (r=-0.401, p=0.019). CONCLUSIONS: The talar cartilage seemed to be thinner and the plantar fascia to be thicker on the intact sides of the unilateral limb amputees. PMID- 29409277 TI - The current standard of Foot and Ankle Fellowship in the UK. AB - BACKGROUND: The aim of this study was to evaluate the current standards of Fellowship training in Foot and Ankle Surgery Fellowship in the UK. METHODS: Thirteen UK post-FRCS (Tr&Orth) or equivalent Fellows completed a questionnaire detailing their outpatient, surgical, teaching and research experience, along with documenting their supervision and terms of employment. RESULTS: A Fellow attended a mean of 2.5 (0.5-4) clinics and 3.84 (2-7) theatre sessions per week. 62% of Fellows had independent clinics. The three largest sub-specialty areas experienced were forefoot surgery, mid or/hindfoot arthritis and deformity correction. 82% of Fellows had a regular MDT meeting. All were involved in both teaching and research, but only 64% had timetabled research sessions. All Fellows were satisfied with their experience and would recommended the Fellowship. CONCLUSIONS: The current standard of a post FRCS (Tr&Orth) Fellowship in Foot & Ankle surgery in the UK has been defined. Further improvement will require all Fellows to be involved in a regular MDT meetings, work in an independent clinic, have guaranteed timetabled research time and a ring fenced study leave budget. PMID- 29409278 TI - Involvement of foot in patients with spondyloarthritis: Prevalence and clinical features. AB - BACKGROUND: The purpose of this study was to evaluate the foot involvement in a group of patients with spondyloarthritis in regard to symptoms, type and frequency of deformities, location and radiological changes. METHODS: We conducted a cross sectional study including 60 patients with spondyloarthritis over a period of six months. Anamnesis, clinical examination, podoscopic examination, biological tests and X-rays of feet were done for each patient. RESULTS: Foot involvement was found in 31 patients (52%). It was symptomatic in 35% of cases and inaugural in 42% of cases. The most frequent site was the hindfoot (22 patients/31). Radiological findings were: erosion (17%), reconstruction (33%), erosion and reconstruction (50%). Forefoot involvement was found in 18/31 patients. Forefoot deformities were found in 9 patients. Two patients had sausage toe and feet skin abnormalities were observed in 12 patients. At podoscopic examination, 23 patients had abnormal footprints. Foot involvement was more frequent in peripheral spondyloarthritis (p=0.008). Patients with foot involvement had an advanced age of disease onset (p=0.05), a shorter disease duration (p=0.038) and more comorbidities (p=0.039). Foot involvement was correlated with C Reactive protein (p=0.043). CONCLUSION: In our study, foot involvement and foot symptoms were seen frequently in spondyloarthritis and it is associated with late onset of the disease and with higher inflammation in blood tests. PMID- 29409279 TI - A prospective comparison of wide-awake local anesthesia and general anesthesia for forefoot surgery. AB - BACKGROUND: A recent case series suggested that surgery with wide-awake local anesthesia is tolerated well by most foot and ankle patients. However, patients were assessed retrospectively and there was no comparison group to show the relative efficacy of this approach. The present study was conducted to address these concerns. METHODS: Perioperative pain and anxiety were assessed in 40 patients receiving forefoot surgery using either wide-awake local anesthesia or general anesthesia. Ratings were collected on the day of surgery using 11-point (0-10) numerical rating scales. RESULTS: Patients in the two anesthesia groups reported no differences in preoperative pain (p=0.500) or anxiety (p=0.820). Patients who received wide-awake local anesthesia reported lower levels of postoperative pain (p<0.001) and anxiety (p<0.001) than patients who received general anesthesia. They also reported little pain (M=0.17, SD=0.32) or anxiety (M=1.33, SD=1.74) during the operation. CONCLUSIONS: Results indicate that surgery with wide-awake local anesthesia is tolerated well by most patients, and that it may have some benefit compared to surgery with general anesthesia. PMID- 29409280 TI - The value of axial loading three dimensional (3D) CT as a substitute for full weightbearing (standing) 3D CT: Comparison of reproducibility according to degree of load. AB - BACKGROUND: Full weightbearing (WB) three dimensional computed tomography (3D CT) is an excellent imaging tool. However, due to its high cost, it is only used in a few hospitals. We evaluated the usefulness and cost-effectiveness of axial loading (AL) 3D CT by comparing bony alignments with standing radiographs, and assessed reproducibility according to the degree of AL. METHODS: Eighty patients (156 feet), who underwent standing radiographs and 3D CT with an AL device from January 2016 to May 2017, were investigated. According to the degree of AL (AL force*100/body weight), the patients were randomly assigned to three groups: Group A (30-50%; n=21, 40 feet), Group B (50-70%; n=32, 63 feet), and Group C (70 100%; n=27, 53 feet). The following angles were measured three times by two orthopedists: hallux valgus (HVA), 1st-2nd intermetatarsal (IMA1-2), and talo navicular coverage (TNCA), calcaneal pitch (CPA), talo-1st metatarsal (T1MA), and talo-calcaneal angle (TCA). Agreements between the two imaging methods were analyzed and compared according to the degree of axial loading in each group. RESULTS: Intra- and interobserver reliability was excellent (>0.75). In Group A (30-50% AL), all of the angles except HVA and IMA1-2 differed (p<.05). In Group B (50-70%), TNCA (p=.023), T1MA (p=.017), and TCA (p=.035) differed. In Group C (70 100%), none of the angles differed between the two imaging methods (p>.05). Higher agreement between the two imaging methods was realized when 70% or more(>70%) AL was applied. CONCLUSIONS: AL 3D CT with >70% axial load has full WB effects and can be substituted for expensive full WB 3D CT. PMID- 29409281 TI - The Dutch version of the Oxford Ankle and Foot Questionnaire for Children: Useful for evaluation of pediatric foot problems in groups. AB - BACKGROUND: The purpose of this study is to develop a Dutch version of the Oxford Ankle and Foot Questionnaire for Children (OxAFQ-c) to allow evaluation of pediatric foot care. METHODS: The OxAFQ-c was translated into Dutch, according to the ISPOR-guidelines. Children with different foot and ankle complaints completed the OxAFQ-c at baseline, after two weeks, and after 4-6 months. Measurement properties were assessed in terms of reliability, responsiveness, and construct validity. RESULTS: Test-retest reliability showed moderate intraclass correlation coefficients. Bland-Altman plots showed wide limits of agreement. After 4-6 months, the group that experienced improvement also showed improved questionnaire outcomes, indicating responsiveness. Moderate correlation between the OxAFQ-c and the Kidscreen and foot-specific VAS-scores were observed, indicating moderate construct validity. CONCLUSIONS: The Dutch OxAFQ-c showed moderate to good measurement properties. However, because we observed limited sensitivity to changes and wide limits of agreement in individual patients, we think the questionnaire should only be used in groups. PMID- 29409282 TI - Stair-shaped Achilles tendon lengthening in continuity - A new method to treat equinus deformity in patients with spastic cerebral palsy. AB - BACKGROUND: Equinus of the ankle is a common deformity in spastic cerebral palsy. Achilles tendon lengthening is one of the effective options for the treatment of equinus deformity. METHODS: In the study, a new stair-shaped Achilles tendon lengthening (ATL) procedure that preserves of the tendon continuity was performed in 28 tendons with equinus deformity (20 patients, mean age=10.5+/-2.6 years). The results were compared with a group of patients treated with the Z-lengthening procedure. During the latest follow-up visit, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot scale score was much higher in the stair shaped ATL group than in the Z-lengthening group (p<0.05). RESULTS: The two groups showed similar surgical correction angle after ATL(37.2+/-3.5 degrees for stair-shaped ATL and 36.1+/-4.5 degrees for Z-lengthening). During the latest follow-up visit, the correction angle in the Z-lengthening group decreased to 21.6+/-4.3 degrees , which was lower than in the stair-shaped ATL group (29.0+/ 3.1 degrees ; p<0.05). In addition, the data regarding the time required by each patient before being able to start rehabilitation and walking as well as gaining better stability for running indicated that the stair-shaped ATL group recovered significantly quicker than the Z-lengthening group. CONCLUSIONS: The stair-shaped ATL procedure resulted in a successful correction of the equinus deformity in spastic cerebral palsy, with the advantage of preserving a degree of continuity without a complete section of the tendon. This confers greater antigravity stability and quicker recovery in patients. PMID- 29409283 TI - Relationship of vitamin D receptor gene polymorphisms with susceptibility, surgical outcome and prognosis of hallux valgus in a Chinese Han population. AB - BACKGROUND: This study aimed to identify the relationship between the vitamin D receptor (VDR) BsmI gene polymorphism and risk factors, surgical outcome and prognosis of hallux valgus (HV). METHODS: A case-control study was performed on a cohort of 236 HV patients and 236 controls in a Chinese Han population. Detection of the VDR BsmI/G2A polymorphism was performed using restriction fragment length polymorphism-polymerase chain reaction. RESULTS: We detected a statistically significant difference in the allele distribution of the BsmI polymorphism between cases and controls (p<0.01). Significant loss of hallux valgus angle (HVA) and intermetatarsal angle (IMA) correction was only noted in patients with the bb genotype during the 2-year follow-up period (p<0.01). The average American Orthopaedic Foot and Ankle Society (AOFAS) scores at the 2-year follow-up were decreased in both groups when compared with those at the 6 month follow-up, and 1.45 points more decrease in patients with the bb genotype was observed as compared to those with the BB and Bb genotypes (p<0.0001). The average visual analogue scales (VAS) also had the tendency with more pains in the bb genotype group (p<0.0001). Furthermore, larger numbers of transfer metatarsalgia were found in patients with the bb genotype upon 2-year follow-up (p=0.049). CONCLUSIONS: We report the first candidate gene polymorphism associated with susceptibility, surgical outcome and prognosis of HV in a Chinese Han population. Moreover, development of genetically-based method to predict the surgical outcome accurately and individualized therapy for HV are warranted. PMID- 29409284 TI - Reliability of the Phi angle to assess rotational alignment of the talar component in total ankle replacement. AB - BACKGROUND: The purpose of this study was to investigate the test-retest reliability of the Phi angle in patients undergoing total ankle replacement (TAR) for end stage ankle osteoarthritis (OA) to assess the rotational alignment of the talar component. METHODS: Retrospective observational cross-sectional study of prospectively collected data. Post-operative anteroposterior radiographs of the foot of 170 patients who underwent TAR for the ankle OA were evaluated. Three physicians measured Phi on the 170 randomly sorted and anonymized radiographs on two occasions, one week apart (test and retest conditions), inter and intra observer agreement were evaluated. RESULTS: Test-retest reliability of Phi angle measurement was excellent for patients with Hintegra TAR (ICC=0.995; p<0.001) and Zimmer TAR (ICC=0.995; p<0.001) on radiographs of subjects with ankle OA. There were no significant differences in the reliability of the Phi angle measurement between patients with Hintegra vs. Zimmer implants (p>0.05). CONCLUSIONS: Measurement of Phi angle on weight-bearing dorsoplantar radiograph showed an excellent reliability among orthopaedic surgeons in determining the position of the talar component in the axial plane. LEVEL OF EVIDENCE: Level II, cross sectional study. PMID- 29409285 TI - The physiological range of the Bohler's angle in the adult Croatian population. AB - BACKGROUND: To examine the relationship of the Bohler's angle with age, sex, and laterality, and to analyze the interrater agreement. METHODS: After 248 digital lateral radiographs of the foot were submitted to exclusion criteria, three raters independently measured the Bohler's angle on the remaining 130 X-rays in PACS. The variables were analyzed with correlation coefficients, and one-way ANOVA. The repeated measures of ANOVA were computed across age groups (30-39, 40 49, 50-59, and 60-69 years). The interrater agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: The mean value of the Bohler's angle was 34+/-5 degrees (21-46 degrees ). It was not related to age (in general [p=0.057], and across groups [p from 0.107 to 0.122]), sex (p=0.344; p=0.342), and laterality (p=0.618; p=0.617). The interrater reliability was almost perfect (ICC=0.94). CONCLUSIONS: The Bohler's angle was not related to age, sex, and laterality, whereas the interrater agreement was almost perfect. PMID- 29409286 TI - Percutaneous soft tissue release performed using a blunt cannula in rabbits with chronic collagenase-induced Achilles tendinopathy. AB - BACKGROUND: This study investigated the effects of percutaneous soft tissue release (PSTR) performed using a blunt cannula on (1) the inflammatory cells count, (2) expressions of calcitonin gene-related peptide (CGRP) and (3) substance P (SP) in rabbits with chronic phase of collagenase-induced Achilles tendinopathy. METHODS: Thirty-two adult male New Zealand rabbits were randomly divided into four groups: (1) collagenase and PSTR treatment; (2) collagenase and sham-operated PSTR treatment; (3) vehicle-only injection and PSTR treatment; and (4) vehicle-only injection and sham-operated PSTR treatment. Achilles tendon of adult male rabbits was injected with 10MUl of collagenase under ultrasonography localization. After 30 days, PSTR was performed using an 18G beauty cosmetic blunt tip micro cannula needle to release the soft tissue and paratenon above the inflamed Achilles tendon. The treated tendons and spinal cords of L5-S2 were harvested 5days after treatment for histological assessment and immunohistochemical analysis. RESULTS: Histopathological examination revealed that PSTR achieved significant reduction in hypercellularity with pronounced infiltration of immune cells at the site of paratenon in tendons injected with collagenase compared with sham operation (p<0.05). Immunohistochemical analysis also showed marked decrease in expression of CGRP in tendon and SP in dorsal horns after PSTR (p<0.05). CONCLUSIONS: This study showed positive effects in an animal model of chronic tendinopathy, and can be considered a treatment option, but that further research is necessary to determine its role in clinical practice. PMID- 29409287 TI - Direction and location of the nutrient artery to the fifth metatarsal at risk in osteotomy for bunionette. AB - BACKGROUND: The aims of this study were to identify the artery feeding the fifth metatarsal and determine how bunionette osteotomy could injure this vessel. METHODS: The nutrient artery entering the fifth metatarsal was investigated in 10 adult cadaveric lower limbs by barium injection and enhanced computed tomography. RESULTS: The nutrient artery entered the medial aspect of the fifth metatarsal around the junction of the middle and proximal thirds obliquely from a distal direction (mean angle 36 degrees ) in the coronal plane in all cases; in the axial plane, the point of entry and direction of the artery was medial-plantar (mean angle 49 degrees ). CONCLUSIONS: This report revealed direction and location of the nutrient artery entering the fifth metatarsal. PMID- 29409288 TI - Ankle fractures with syndesmotic stabilisation are associated with a high rate of secondary osteoarthritis. AB - BACKGROUND: The primary aim of this study was to present the incidence of clinically significant end stage osteoarthritis (cOA) after syndesmotic fixation of ankle fractures. The secondary aim was to and identify independent predictors of cOA. METHODS: A retrospective review of consecutive patients presenting to a single University affiliated institution between March 2008 and May 2010 was undertaken. Inclusion criteria were ankle fractures with syndesmotic stabilisation. Patients were excluded if pre or postoperative radiographs were missing or were lost to follow up. Data were gathered regarding demographics, fracture pattern, fixation methods, reduction parameters, screw removal, revision surgery, complications and cOA up to seven years post injury. RESULTS: Data were available for 120 patients (86%). In total, 13 patients (11%) developed cOA. Univariate analysis showed that increasing age, open fracture, malreduction of the syndesmosis, removal of symptomatic screws, revision surgery and complications were predictors of developing cOA. Cox regression analysis revealed increasing age (hazard ratio (HR) 1.09, p=0.006), and malreduction (HR 45.5, p=0.001) were independent predictors of developing cOA. CONCLUSIONS: Ankle fractures with syndesmotic stabilisation represent a severe injury with a high rate of cOA. The only modifiable risk factor for developing cOA in this large series of patients was radiological malalignment. When syndesmotic stabilisation is required, careful intraoperative assessment should be undertaken to ensure the syndesmosis is reduced. PMID- 29409289 TI - A randomized comparison between lateral ligaments augmentation using suture-tape and modified Brostrom repair in young female patients with chronic ankle instability. AB - BACKGROUND: Although various minimally invasive procedures for chronic ankle instability are increasingly being used, a question regarding whether these procedures can be a viable alternative of the modified Brostrom procedure remains controversial. This study was conducted to compare the intermediate-term clinical outcomes between lateral ligaments augmentation using suture-tape and modified Brostrom repair in a selected cohort of patients. METHODS: Sixty female patients with chronic lateral ankle instability were randomly assigned and underwent surgical treatments by one surgeon. Twenty-eight patients with suture-tape augmentation and 27 modified Brostrom procedures were followed >=2 years and analysed in this comparative study. The clinical evaluation included the Foot and Ankle Outcome Score (FAOS), Foot and Ankle Ability Measure (FAAM), and stress radiographs. Medical expense related with operation was analysed to evaluate the cost-effectiveness. RESULTS: There were no statistically significant differences in the clinical outcomes between two procedures based on FAOS, FAAM, recurrence rate of instability, and stress radiographs. Total medical expense was approximately 1.3 times more in the suture-tape group (P<0.001), despite shorter operation time. CONCLUSIONS: Lateral ankle ligaments augmentation using suture tape showed the similar clinical outcomes but low cost-effectiveness, as compared to modified Brostrom repair for young female patients with chronic ankle instability. PMID- 29409290 TI - Subtalar joint alignment in ankle osteoarthritis. AB - BACKGROUND: Although it has been proposed that in mid-stage ankle osteoarthritis, the subtalar joint can compensate for deformities above the ankle joint, the evidence is weak. We thus investigated subtalar joint alignment in different stages of ankle osteoarthritis using weightbearing computed tomography (CT) scans. METHODS: The subtalar joint of 88 patients with osteoarthritis of the ankle joint and a control group of 27 healthy volunteers were assessed. Subgroups were performed according to the ankle deformity (varus and valgus) and stage of ankle joint osteoarthritis. Subtalar joint alignment was assessed on weightbearing CT scans. RESULTS: A more valgus subtalar joint alignment was found in patients with varus ankle osteoarthritis. No significant difference of the subtalar joint alignment was evident when comparing different stages of ankle osteoarthritis. CONCLUSIONS: Varus ankles compensate in the subtalar joint for deformities above the ankle joint. Compensation does not correlate with the stage of ankle osteoarthritis. PMID- 29409291 TI - Response to the Letter to the Editor on "The arthroereisis procedure in adult flexible flatfoot grade IIA due to insufficiency of posterior tibial tendon". PMID- 29409292 TI - Structural interaction between bone and implants due to arthroplasty of the first metatarsophalangeal joint. AB - BACKGROUND: Currently, the metatarsophalangeal joint replacement through a restorative arthroplasty, where implants are used, is a viable invasive surgical medical procedure in the treatment of severe cases of osteoarthritis in this joint, better known as hallux rigidus. However, few things are known about the postoperative complications that implants can cause on the joint, like Swanson and Tornier implants.Research in this field can provide a valuable information that would help the specialist surgeon in the decision-making during the selection of the more suitable joint implant in each patient, as well as the redesign of the devices, to make them more efficient, durable and biocompatible with the human body. METHODS: The aim of this work is to perform a structural biomechanical analysis of a restorative arthroplasty of the first metatarsophalangeal joint, and to analyze the interaction between bone and medical grade silicone implants. For that, a simulation of a foot with Swanson and Tornier joint implants were performed to evaluate the stress/strain distribution during a critical stage (toe-off). RESULTS AND CONCLUSIONS: Principal stresses obtained for the first metatarsal with both implants suggest that failure is induced in this bone because, values exceed (up to 136.84% for Swanson model) the tensile strength reported for phalange trabecular bone, which may be related to osteolysis. Stress and strain values obtained in this work suggest that arthroplasty surgery with Swanson implant is more likely to cause postoperative complications versus Tornier implant. PMID- 29409293 TI - Two year outcomes of minimally invasive hallux valgus surgery. AB - BACKGROUND: We report our experience with the Minimally Invasive Chevron Akin (MICA) technique for correcting hallux valgus, and evaluate its effectiveness and associated complications. METHODS: Case series of 13 feet with mild to moderate symptomatic hallux valgus treated surgically from July 2013 to December 2014, with at least 48-months follow-up. Patients were assessed pre-operatively and post-operatively with radiographical measurements (Hallux Valgus Angle (HVA) and Intermetatarsal Angle (IMA)) and clinical scores (American Orthopaedic Foot and Ankle Society (AOFAS), 36-Item Short Form Health Survery (SF-36), Visual Analog Scale (VAS)). RESULTS: Mean HVA and IMA decreased from 30.4 degrees and 13.9 degrees -10.9 degrees and 10.2 degrees respectively (p<0.05). The mean AOFAS score improved from an average of 59.0-93.7 (p<0.05). All patients reported a VAS score of 0 post-operatively, and the 4 SF-36 domains improved significantly (p<0.05). CONCLUSIONS: The MICA technique is a safe and effective method in the surgical correction of mild to moderate hallux valgus deformity, and continued use is justified. PMID- 29409294 TI - Is generalized ligamentous laxity a prognostic factor for recurred hallux valgus deformity? AB - BACKGROUND: This study was performed to evaluate the intermediate-term clinical outcomes after proximal chevron osteotomy for hallux valgus in patients with generalized ligamentous laxity, and to determine the effect on postoperative recurrence of deformity. METHODS: There were 23 cases in laxity group (Beighton score >=5 points) and 175 in non-laxity group with a mean followup of 46.3 months. Clinical evaluation consisted of the AOFAS score, Foot and Ankle Ability Measure (FAAM), and radiographic measurement of hallux alignment. Risk factors associated with postoperative recurrence were evaluated using univariate analysis. RESULTS: Recurrence rates were 21.7% in the laxity group and 17.1% in non-laxity group (P=.218). There were no significant differences in clinical and radiographic measurements at final followup between the 2 groups. Preoperative HVA and IMA were found to be predictive factors of recurrence (OR=6.3, 4.2; P=.001, .018, respectively). CONCLUSION: There were no statistical differences in the clinical and radiographic outcomes between hallux valgus with and without generalized ligamentous laxity. Generalized ligamentous laxity demonstrated no definitive effects on postoperative recurrence of hallux valgus deformity. PMID- 29409295 TI - The arthroereisis procedure in adult flexible flatfoot grade IIA due to insufficiency of posterior tibial tendon. PMID- 29409296 TI - First metatarsophalangeal fusion using joint specific dorsal plate with interfragmentary screw augmentation: Clinical and radiological outcomes. AB - BACKGROUND: This study reports the outcome of a plating system for arthrodesis of the first metatarsophalangeal joint (1st MTPJ) that incorporates a lag compression screw within a low profile titanium plate with a predetermined contour. This is the first report of the outcomes of this implant from a non affiliated centre. PATIENT AND METHODS: This is a prospective cohort study of 40 consecutive primary 1st MTPJ arthrodesis procedures. The mean age of the cohort was 56 years (range, 20-74 years). The diagnosis was hallux rigidus in 31 patients and inflammatory arthropathy in 7 patients. RESULTS: All patients achieved clinical union at 6 weeks and radiological union was confirmed on plain radiographs between 6-16 weeks. One case of hardware removal was reported. CONCLUSION: The cohort achieved consistently satisfactory results with a reliable and reproducible MTPJ position and a 100% union rate. There was a low rate of hardware removal. LEVEL OF EVIDENCE: Level IV evidence. Prospective cohort study. PMID- 29409297 TI - Complications of distraction osteogenesis in brachymetatarsia: Comparison between the first and fourth brachymetatarsia. AB - BackgroundRecently, distraction osteogenesis has been widely used to treat brachymetatarsia. However, few papers have compared complications associated with this treatment. The purpose of the present study was to compare the complications between the first and fourth brachymetatarsia treated by distraction osteogenesis. MethodsWe performed distraction osteogenesis to 83 metatarsals in 41 patients between 1999 and 2012. A total of 30 metatarsals received treatment for the first metatarsal (Group A) while 53 metatarsals received treatment with the fourth metatarsal (Group B). ResultsThe complication rate in Group A (40%) was higher than that in Group B (18.9%). Those who had high percentage of lengthening gain were more likely to have complications. A cut-off value for lengthening gain developing complication was 41.3%. ConclusionComplication incidence after distraction osteogenesis was increased when lengthening gain was more than 41.3% for brachymetatarsia. In the 1st metatarsal lengthening, the most common complication was stiffness. In contrast, complications of the 4th metatarsal lengthening were pin-track infection and angular deformity. PMID- 29409298 TI - Use of a percutaneous osteotomy with plate fixation in hallux valgus correction. AB - BACKGROUND: With hundreds of operative methods described for correction of hallux valgus we can state that the ideal surgical treatment is still controversial. The Bosch technique has been used as a percutaneous way of correcting hallux valgus deformities with the use of a pin fixation. The aim of this study is to evaluate a new method of fixation by using a percutaneous locking plate. METHODS: Between June 2013 and January 2015, 24 consecutive percutaneous subcapital osteotomies of the first metatarsal bone were performed for the treatment of painful hallux valgus deformities in 24 patients. Additional surgical procedures included DMMO's (Distal Metatarsal Minimally-Invasive Osteotomies) in 12 of the operated feet (44.44%); minor digits were corrected in 7 cases (25.9%). An Akin procedure was performed in 81% of cases and all cases underwent an adductor hallucis tenotomy. All patients were clinically assessed using the AOFAS score. Radiographic measures included the preoperative and postoperative values of the Hallux Valgus Angle (HVA), Intermetatarsal Angle (IMA), and the Distal Metatarsal Articular Angle (DMAA). RESULTS: The mean correction achieved improved for AHV from 36.57+/ 7.1 to 12.22+/-8.69 degrees , for IMA from 13.8+/-1.59 to 7.08+/-2.72 and for DMAA from 13.98+/-7.38 to 6.07+/-4.99. Clinically, scores on the AOFAS scale improved from a 45.8+/-9.6 to 91.29+/-9.8. Although healing of the osteotomies was observed radiographically within 6 to 12 weeks, two cases (8.3%) exhibited delayed healing. There were no cases of nonunion. There were no superficial or deep infections or wound healing problems. Plate had to be removed in 3 cases (12.5%). CONCLUSION: This technique modification is an acceptable procedure to correct hallux valgus in patients with a moderate level of deformity. LEVEL OF EVIDENCE: Level IV. CASE SERIES: PMID- 29409299 TI - Distal fibular malrotation and lateral ankle contact characteristics. AB - BACKGROUND: Any amount of malreduction of the syndesmotic joint compared with the uninjured syndesmosis has been associated with an adverse effect on functional outcome. The amount of malrotation that may lead to clinically relevant pressure change in this joint has not been reported. Our purpose was to determine whether small degrees of external and internal malrotation would be associated with statistically significant changes in contact pressure in the tibiofibular and talofibular articulations. METHODS: Twelve cadaveric ankles were osteotomized above the syndesmosis and instrumented with a rotatable distal fibula plate. Sensors at the distal tibiofibular and talofibular articulations recorded contact pressure and area at neutral position and at 5 and 10 degrees of external and internal malrotation through a full range of ankle motion. RESULTS: Compared with neutral rotation, there was a significant decrease in contact pressure at the talofibular articulation with external rotation of 5 degrees (103+/-113kPa versus 52+/-69kPa; P=0.01) and 10 degrees (43+/-62kPa; P=0.01) in plantarflexion.Contact pressure at the tibiofibular articulation in plantarflexion increased with 10 degrees of internal malrotation compared with neutral rotation (56+/-30kPa versus 74+/-38kPa; P=0.05) in plantarflexion. Contact area decreased significantly with plantarflexion and 10 degrees of external rotation and increased significantly in plantarflexion and after cyclic loading with 10 degrees of internal rotation (P<=0.05). CONCLUSION: Any degree of distal fibular external rotation significantly reduced contact pressure in the talofibular articulation with plantarflexion. A minimal increase in contact pressure was found in the tibiofibular and talofibular joints with plantarflexion and mild internal rotation of 5 degrees , but pressure increased significantly in both articulations with 10 degrees of internal rotation. The findings support clinical findings that subtle degrees of fibular malrotation may be associated with alteration of lateral ankle mechanics. LEVEL OF EVIDENCE: Controlled biomechanical study. PMID- 29409300 TI - Lateral malleolus closed reduction and internal fixation with intramedullary fibular rod using minimal invasive approach for the treatment of ankle fractures. AB - BACKGROUND: Ankle fractures are extremely common and represent nearly one quarter of all lower-limb fractures. Techniques for fixation of displaced fractures of the lateral malleolus have remained essentially unchanged in recent decades. The current gold standard of treating unstable fractures is with open reduction and internal fixation (ORIF), using plates and screws construct. This study evaluates the use of fibula intramedullary nailing based on minimal invasive surgical approach. METHODS: Thirty-nine cases treated with fibula intramedullary nailing between the years 2014-2016 were retrospectively studied. A fibular nail was utilized for the treatment of various ankle fractures either as the sole method of fixation or combined with another method. Patient charts were reviewed for fracture patterns, comorbidities, quality of reduction, complications and additional surgeries. RESULTS: Out of 39 cases in the study cohort, 37 were closed fractures while 2 had an associated medial malleolus open injury. According to Weber classification of lateral malleolus fractures, 20 cases were type B, 18 cases type C, and one case of a pathologic fracture type B like fracture. Quality of reduction was based on previously published criteria. It was determined to be good in 32 cases, fair in 5 cases and poor in 2 cases that were revised intraoperatively to plate fixation. Overall no systemic complications occurred. Eight patients have undergone additional surgeries, namely hardware removals. In two cases, the nail was later revised to a different fixation method: one case to a plate, due to secondary displacement at 2 weeks, and one to an intramedullary tibiotalocalcaneal arthrodesis secondary to hardware failure and Charcot neuroarthropathy. CONCLUSION: Intramedullary fibular nail offers a satisfactory and safe procedure to establish good reduction and fixation of lateral malleoli fractures. It may be considered as treatment of choice for patients with soft tissue problems due to its minimal invasive approach. The current study shows that while good fracture reduction can be achieved, without major complications, more than fifth of patients, required secondary procedures, mainly hardware removals. LEVEL OF EVIDENCE: Level IV. PMID- 29409301 TI - A comparison of union rates and complications between single screw and double screw fixation of sliding calcaneal osteotomy. AB - BACKGROUND: The number of screws used for sliding calcaneal osteotomy fixation has not been examined in the literature. The purpose of this paper is to examine this topic. METHODS: Retrospective chart review was performed on 190 patients who met selection criteria. We compared complication risk for single versus double screw, headed versus headless screw, and short versus longitudinal incision cases. RESULTS: The mean age was 48.4 (18-83) years and average follow up was 28 (12-150) weeks. All cases achieved radiographic union. Overall complication rate was 19.5% (37/190). Risk of complication did not differ significantly between single and double screw (RR: 1.170; 95% CI: 0.66-2.09; p=0.594) or short and extended incision groups (RR: 0.868; 95% CI: 0.42-1.80; p=0.704). Risk of complication differed significantly between headed and headless screw fixation (RR: 5.558; 95% CI: 2.69-11.50; p<0.0001). CONCLUSIONS: Single screw fixation of sliding calcaneal osteotomy achieves similar outcomes as double screw fixation. Headless screws are advantageous for minimizing hardware pain and subsequent hardware removal. PMID- 29409302 TI - Factors Associated with Rebleeding in Patients with Peptic Ulcer Bleeding: Analysis of the Korean Peptic Ulcer Bleeding (K-PUB) Study. AB - Background/Aims: Rebleeding is associated with mortality in patients with peptic ulcer bleeding (PUB), and risk stratification is important for the management of these patients. The purpose of our study was to examine the risk factors associated with rebleeding in patients with PUB. Methods: The Korean Peptic Ulcer Bleeding registry is a large prospectively collected database of patients with PUB who were hospitalized between 2014 and 2015 at 28 medical centers in Korea. We examined the basic characteristics and clinical outcomes of patients in this registry. Univariate and multivariate analyses were performed to identify the factors associated with rebleeding. Results: In total, 904 patients with PUB were registered, and 897 patients were analyzed. Rebleeding occurred in 7.1% of the patients (64), and the 30-day mortality was 1.0% (nine patients). According to the multivariate analysis, the risk factors for rebleeding were the presence of co-morbidities, use of multiple drugs, albumin levels, and hematemesis/hematochezia as initial presentations. Conclusions: The presence of co-morbidities, use of multiple drugs, albumin levels, and initial presentations with hematemesis/hematochezia can be indicators of rebleeding in patients with PUB. The wide use of proton pump inhibitors and prompt endoscopic interventions may explain the low incidence of rebleeding and low mortality rates in Korea. PMID- 29409303 TI - Slow-Pull Using a Fanning Technique Is More Useful Than the Standard Suction Technique in EUS-Guided Fine Needle Aspiration in Pancreatic Masses. AB - Background/Aims: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful for obtaining pancreatic mass samples. The combination of modified techniques (i.e., slow-pull technique and fanning technique) may improve the quality of the sample obtained by EUS-FNA. We investigated the effectiveness of a combined slow-pull fanning technique in EUS-FNA for pancreatic mass. Methods: This prospective comparative study investigated EUS-FNA performed for pancreatic solid masses between August 2015 and July 2016. Pairwise specimens were alternately obtained using the following two techniques for targeted pancreatic lesions: standard suction or slow-pull with fanning. We compared the specimen quality, blood contamination, and diagnostic accuracy of these techniques. Results: Forty-eight consecutive patients were included (29 men; mean age, 68.1+/ 11.9 years), and 96 pancreatic mass specimens were obtained. The slow-pull with fanning technique had a significantly superior diagnostic accuracy than the suction technique (88% vs 71%, p=0.044). Furthermore, blood contamination was significantly reduced using the slow-pull with fanning technique (ratio of no or slight contamination, 77% vs 56%, p=0.041). No difference was observed in the acquisition of adequate cellularity between the groups. In the subgroup analysis, the tumor size and sampling technique were related to the EUS-FNA diagnostic accuracy. Conclusions: The slow-pull with needle fanning technique showed a good diagnostic yield for EUS-FNA for pancreatic mass. This technique can be useful for performing EUS-guided sampling for diagnosing pancreatic disease. PMID- 29409304 TI - Gastric Cancer Caused by Adenoma: Predictive Factors Associated with Lesions Other Than the Expanded Indications. AB - Background/Aims: We aimed to investigate whether the current indications for curative endoscopic resection (ER) of gastric cancer (GC) can be applied to GC caused by adenoma. Additionally, we attempted to identify factors predictive of lesions subsequently found in addition to the expanded indications for ER. Methods: We retrospectively analyzed 342 patients diagnosed with GC caused by adenoma who underwent ER at a single tertiary center between February 2011 and December 2014. The gross whole tumor size was measured using the endoscopically resected specimen. The microscopic whole tumor size was measured using mapping paper. The estimated cancer size was calculated using the microscopic whole tumor size and the square root of the carcinoma component. Results: A gross whole tumor size >=3 cm, carcinoma component >=35%, and gross ulceration were predictive of lesions other than the expanded indications for ER. The overall rate of lymph node metastasis was 0.3% (1/327), which only occurred in one patient with a lesion other than the expanded indications (4.5%, 1/22). Conclusions: The current indications for curative ER in GC can be applied to GC caused by adenoma. In cases suspected of having lesions other than the expanded indications, patients should be cautiously selected for ER to reduce the risk of an inappropriate procedure. PMID- 29409305 TI - Prospective Comparison of Intraductal Ultrasonography-Guided Transpapillary Biopsy and Conventional Biopsy on Fluoroscopy in Suspected Malignant Biliary Strictures. AB - Background/Aims: In suspected malignant biliary strictures (MBSs), the diagnostic yield of endoscopic retrograde cholangiopancreatography (ERCP)-based tissue sampling is limited. Transpapillary forceps biopsy (TPB) under intraductal ultrasonography (IDUS) guidance is expected to improve the diagnostic accuracy in patients with indeterminate biliary strictures. We evaluated the usefulness of IDUS-guided TPB in patients with suspected MBS. Methods: Consecutive patients with suspected MBS were prospectively enrolled in the study. ERCP with IDUS was performed in all patients. Both conventional TPB and IDUS-guided TPB on fluoroscopy were performed in each patient. The primary outcome was the diagnostic accuracy of conventional TPB and IDUS-guided TPB. Results: The technical success rate of IDUS-guided TPB was 97.0% (65/67 patients). Of these 65 patients, the final diagnosis was malignancy in 61 patients (93.8%). On IDUS, the most common finding of IDUS was an intraductal infiltrating lesion in 29 patients (47.5%). The overall diagnostic accuracy was significantly higher using IDUS guided TPB than that using conventional TPB (90.8% vs 76.9%, p=0.027). According to the subgroup analysis based on the tumor morphology, IDUS-guided TPB had a significantly higher cancer detection rate than conventional TPB for intraductal infiltrating lesions (89.6% vs 65.5%, p=0.028). Conclusions: IDUS-guided TPB appears to improve the accuracy of histological diagnosis in patients with MBS. PMID- 29409306 TI - The Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio Are Prognostic Factors in Patients with Locally Advanced Pancreatic Cancer Treated with Chemoradiotherapy. AB - Background/Aims: We investigated whether inflammatory markers such as neutrophil lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) independently and in combination would be significant prognostic factors for survival in patients with locally advanced pancreatic cancer. Methods: A total of 497 patients with locally advanced pancreatic cancer who received neoadjuvant or definitive chemoradiotherapy from 2005 to 2015 were evaluated. We divided the patients into groups according to the median values of NLR and PLR: NLR<1.89 (n=156), NLR>=1.89 (n=341), PLR <149 (n=248) and PLR >=149 (n=249). Results: For NLR <1.89 and >=1.89 groups, respectively, the 1-year overall survival (OS) rates were 73.2% and 60.8% (p<0.001) and 1-year progression-free survival (PFS) rates were 43.9% and 31.3% (p<0.001). For PLR <149 and >=149 groups, respectively, the 1-year OS rates were 68.1% and 61.3% (p=0.029) and 1-year PFS rates were 37.9% and 32.5% (p=0.027). Patients with both high NLR and high PLR showed the worst OS and PFS rates compared with those with both lower NLR and lower PLR. Conclusions: Elevated pretreatment NLR and PLR independently and in combination significantly predicted poor OS and PFS. PMID- 29409307 TI - Prevalence and Implications of Bone Marrow Involvement in Patients with Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. AB - Background/Aims: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is an uncommon disease. Bone marrow involvement is reported even in patients with only a mucosal lesion. We evaluated the prevalence and risk factors of marrow involvement and its implications for diagnosis and treatment. Methods: In total, 132 patients who were diagnosed with gastric MALT lymphoma at the National Cancer Center in Korea between January 2001 and December 2016 were enrolled in the study. The patient data were collected and analyzed retrospectively. Results: Of the 132 patients, 47 (35.6%) were male, with a median age of 52 years (range, 17 to 81 years). The median follow-up duration was 48.8 months (range, 0.5 to 169.9 months). Helicobacter pylori infection was detected in 82 patients (62.1%). Most patients (80.3%) had stage IE1 according to the modified Ann Arbor staging system. Ninety-two patients underwent bone marrow evaluation, and four patients (4.3%) had marrow involvement. Of these patients, one presented with abdominal lymph node involvement, while the other three had stage IE1 disease if marrow involvement was disregarded. All three patients had no significant symptoms and were monitored after local treatment without evidence of disease aggravation. Conclusions: Bone marrow involvement was found in 4.3% of the patients with gastric MALT lymphoma. Bone marrow examination may be deferred because marrow involvement does not change the treatment options or outcome in gastric MALT lymphoma confined to the stomach wall. PMID- 29409308 TI - A Prospective Multicenter Study Evaluating Bleeding Risk after Endoscopic Ultrasound-Guided Fine Needle Aspiration in Patients Prescribed Antithrombotic Agents. AB - Background/Aims: Although the risk of bleeding after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is low, the safety of EUS-FNA in patients prescribed antithrombotic agents is unclear. Therefore, this study evaluated the incidence of bleeding after EUS-FNA in those patients. Methods: Between September 2012 and September 2015, patients who were prescribed antithrombotic agents underwent EUS-FNA at 13 institutions in Japan were prospectively enrolled in the study. The antithrombotic agents were managed according to the guidelines of the Japanese Gastrointestinal Endoscopy Society. The rate of bleeding events, thromboembolic events and other complications within 2 weeks after EUS-FNA were analyzed. Results: Of the 2,629 patients who underwent EUS-FNA during the study period, 85 (62 males; median age, 74 years) patients were included in this stduy. Two patients (2.4%; 95% confidence interval [CI], 0.6% to 8.3%) experienced bleeding events. One patient required surgical intervention for hemothorax 5 hours after EUS-FNA, and the other experienced melena 8 days after EUS-FNA and required red blood cell transfusions. No thromboembolic events occurred (0%; 95% CI, 0.0% to 4.4%). Three patients (3.5%; 95% CI, 1.2% to 10.0%) experienced peri puncture abscess formation. Conclusions: The rate of bleeding after EUS-FNA in patients prescribed antithrombotic agents might be considerable. PMID- 29409309 TI - Daclatasvir Plus Asunaprevir for the Treatment of Patients with Hepatitis C Virus Genotype 1b Infection: Real-World Efficacy, Changes in Liver Stiffness and Fibrosis Markers, and Safety. AB - Background/Aims: The treatment with daclatasvir plus asunaprevir (DCV+ASV) is associated with potent antiviral effects in patients with genotype 1b hepatitis C virus (HCV) infection. We investigated the real-world efficacy, changes in liver stiffness and noninvasive fibrosis markers, and the safety of DCV+ASV treatment in Korean patients. Methods: In total, 363 patients with chronic hepatitis C were treated with DCV+ASV between August 2015 and January 2017. Finally, we analyzed the data of 270 patients who were monitored for at least 12 weeks after the end of treatment. Results: The mean age was 60.7 years, and females predominated (60.4%). Most patients (64.8%) were treatment-naive, and 56 patients (20.7%) had cirrhosis. Two hundred fifty-seven (95.2%) and 251 (93.0%) patients achieved end of-treatment responses and sustained virological responses at 12 weeks posttreatment (SVR12), respectively. The SVR12 rates were higher in patients who were <65 years of age, males, without cirrhosis and had lower HCV RNA levels. All LS values and fibrosis-4 and aspartate aminotransferase-to-platelet ratio index values declined from baseline to the time of assessment of SVR12. Conclusions: The DCV+ASV therapy resulted in a high SVR12 and improved liver fibrosis; the treatment was well tolerated in patients with genotype 1b HCV infections. PMID- 29409310 TI - Electrohydraulic Lithotripsy for Difficult Bile Duct Stones under Endoscopic Retrograde Cholangiopancreatography and Peroral Transluminal Cholangioscopy Guidance. AB - Background/Aims: Electrohydraulic lithotripsy (EHL) under endoscopic retrograde cholangiopancreatography (ERCP) guidance can be an option to treat difficult stones. Recently, a digital, single-operator cholangioscope (SPY-DS) has become available. Peroral transluminal cholangioscopy (PTLC) using SPY-DS has also been reported. In this retrospective study, the technical feasibility and clinical effectiveness of EHL for difficult bile duct stones under ERCP guidance and under PTLC guidance was examined. Methods: In this pilot study, patients with difficult bile duct stones between July 2016 and July 2017 were retrospectively enrolled. Results: Forty-two consecutive patients underwent EHL using a SPY-DS; 34 patients underwent EHL under ERCP guidance, and the other 8 patients underwent EHL under PTLC guidance. Median procedure time was 31 minutes (range, 19 to 66 minutes). The median number of EHL sessions was 1 (range, 1 to 2), and that of ERCP sessions was also 1 (range, 1 to 3). The rate of complete stone clearance was 98% (41/42). Adverse events such as cholangitis and acute pancreatitis were seen in 14% (6/42), which could be treated conservatively. Conclusions: EHL using SPY-DS was technically feasible, not only under ERCP guidance, but also PTLC guidance. A prospective clinical study of EHL using SPY-DS is needed. PMID- 29409311 TI - Effect of Multiple Intraperitoneal Injections of Human Bone Marrow Mesenchymal Stem Cells on Cuprizone Model of Multiple Sclerosis AB - Background: Bone marrow mesenchymal stem cells (BM-MSCs) elicit neuroprotective effects, and their repair ability has been investigated in different experimental models. We aimed to investigate the effect of multiple i.p. BM-MSCs injections in the cuprizone model of multiple sclerosis in mice. Methods: Adult male C57BL/6 mice (n = 40) were fed a regular diet or a diet containing cuprizone (0.2% w/w) for 6 six weeks. Bone marrow samples were taken from patients with spinal cord injury. BM-MSCs (2 * 106 in 1 milliliter medium) were administered intraperitoneally for two consecutive weeks at the end of the forth weeks of cuprizone administration. Animals (n = 12) were perfused with 10% paraformaldehyde at the end of sixth week. The brains were sectioned coronally in 6-8-MUm thickness (-2.3 to 1.8 mm from bregma). The sections were stained by luxol fast blue-cresyl violet, and images were captured via a microscope. Demyelination ratio was estimated in corpus callosum in a blind manner. A quantitative real-time PCR was used to measure the myelin basic protein gene expression at sixth week. Results: Histologically, cuprizone induced demyelination in the corpus callosum. Demyelinated area was diminished in the corpus callosum of cell-administered group. Cuprizone could decrease myelin binding protein mRNAs expression in corpus callosum, which was significantly recovered after BM-MSCs injections. Conclusion: Our data indicated a remyelination potency of multiple i.p. BM-MSCs in the cuprizone model of multiple sclerosis in mice. PMID- 29409312 TI - Impact and Modulations of Peripheral and Edaphic B Cell Subpopulations in Chronic Rhinosinusitis With Nasal Polyposis. AB - OBJECTIVES: The pathophysiological mechanisms of chronic rhinosinusitis with nasal polyposis (CRSwNP) still are discussed controversially. Regulatory B cells (Breg) are responsible for the suppression of T cell activity: deficiencies for Breg have been demonstrated to contribute to autoimmune disorders, e.g., systemic lupus erythematosus. In order to evaluate the influence of B cell subpopulations, especially Breg, on the etiology of this disease, the aim of this study was to characterize subpopulations of peripheral and edaphic B cells in CRSwNP. METHODS: Polypoid tissue and blood samples were collected from 10 patients undergoing paranasal sinus surgery and lymphocytes were analyzed by multicolor flow cytometry. RESULTS: There was a significantly lower frequency of B cells in nasal polyps compared to peripheral blood mononuclear cells (PBMC) in patients with CRSwNP. Mature resting B cells were the main population within B cells in PBMC, and memory B cells in nasal polyps. Remarkably, Breg and mature B cells significantly decreased in nasal polyps compared to PBMC. Memory B cells significantly increased and represented the main subpopulation in nasal polyps in patients with CRSwNP. CONCLUSION: In this study a detailed contemporary characterization of B cell subpopulations in patients with CRSwNP is presented. The influence of edaphic B cells could play a key role in the maintenance of this chronic infectious disease. PMID- 29409313 TI - The Characteristics and Survival Outcomes in Patients Aged 70 Years and Older with Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era. AB - Purpose: We aim to examine nasopharyngeal carcinoma (NPC) characteristics and survival outcomes in patients aged 70 years and older in the intensity-modulated radiotherapy (IMRT) era. Methods and Materials: From 2006 to 2013, 126 non metastatic NPC patients aged >= 70 years who were treated with IMRT +/- chemotherapy were included. Adult Comorbidity Evaluation 27 (ACE-27) was used to measure patient comorbidities. The overall survival (OS) and cancer-specific survival (CSS) were calculated with the Kaplan-Meier method, and differences were compared using the log-rank test. The Cox proportional hazards model was used to carry out multivariate analyses. Results: For the entire group, only two patients (1.6%) presented stage I disease, and up to 84.1% patients had stage III-IVB disease. All patients had a comorbidity score of 0 in 24 (19.0%), 1 in 45 (35.7%), 2 in 42 (33.3%), and 3 in 15 (11.9%) patients. The main acute grade during radiotherapy was 3-4 adverse events consisting of mucositis (25.4%), bone marrow suppression (16.7%), and dermatitis (8.7%). After treatment, 4 patients (3.2%) developed temporal lobe injury. Five-year CSS and OS rates were 67.3% (95% confidence interval [CI], 58.6% to 77.4%) and 54.0% (95% CI, 45.6% to 63.9%), respectively. Five-year OS was significantly higher for ACE-27 score 0-1 than ACE 27 score 2-3 (72.9% and 39.9%, respectively; p<0.001). Multivariate analyses showed ACE-27 score 0-1 was significantly associated with superior OS (hazard ratio [HR], 3.02; 95% CI, 1.64 to 5.55; p < 0.001). In addition, the rate of OS was higher for stage I-III than that of stage IV, with borderline significance (HR, 1.67; 95% CI, 0.99 to 2.82; p=0.053). But no significant advantage was observed in OS when chemotherapy was used (p > 0.05). Conclusion: Our findings suggest IMRT +/- chemotherapy has a manageable toxicity and provides an acceptable survival in patients aged >= 70 years with NPC. ACE-27 score was significantly associated with survival outcomes in this group population. PMID- 29409314 TI - Data-driven respiratory gating for ventilation/perfusion lung scan. AB - BACKGROUND: Ventilation/perfusion lung scan is subject to blur due to respiratory motion whether with planar acquisition or single photon emission computed tomography (SPECT). We propose a data- driven gating method for extracting different respiratory phases from lung scan list-mode or dynamic data. METHODS: The algorithm derives a surrogate respiratory signal from an automatically detected diaphragmatic region of interest. The time activity curve generated is then filtered using a Savitzky- Golay filter. We tested this method on an oscillating phantom in order to evaluate motion blur decrease and on one lung SPECT. RESULTS: Our algorithm reduced motion blur on phantom acquisition: mean full width at half maximum 8.1 pixels on non-gated acquisition versus 5.3 pixels on gated acquisition and 4.1 pixels on reference image. Automated detection of the diaphragmatic region and time-activity curves generation were successful on patient acquisition. CONCLUSIONS: This algorithm is compatible with a clinical use considering its runtime. Further studies will be needed in order to validate this method. PMID- 29409315 TI - Prognostic impact of postoperative 123I-metaiodobenzylguanidine scintigraphy: added value of SPECT/CT and semiquantification of the uptake at the surgical site. AB - BACKGROUND: The aim of this study was to assess the prognostic value of postoperative 123I-MIBG scintigraphy, including systematic SPECT/CT and semiquantification of the uptake at the surgical site, in a prospective series of NB patients. METHODS: Patients operated for neuroblastoma and who had benefited from postoperative 123I-MIBG scintigraphy were prospectively and consecutively included. Completeness of surgery was assessed on operative report. One month postoperative 123I-MIBG scintigraphy included planar acquisition and SPECT/CT. Semi-quantification of the 123I-MIBG SPECT/CT uptake at the surgical site was performed and ratios to reference (liver and mediastinum) areas were calculated. RESULTS: Thirty patients were included between August 2012 and July 2015. Median follow-up was 36 months (range 10-98). Surgery was considered as complete in 23 patients and incomplete in 7 patients. Eight patients (26.7%) presented progressive disease (1 progression and 7 recurrences). Seven patients died (23.3%), all from NB. Six (20%) patients had positive 123I-MIBG scintigraphy (3 on planar acquisitions and 6 on SPECT/CT) and 24 patients had negative 123I-MIBG scintigraphy. Five of the 6 patients (83%) with positive 123I-MIBG scintigraphy presented progressive disease. Ratio of the uptake at the surgical site to mediastinum was strongly and independently correlated with disease-free interval and overall survival (p=0.02 and 0.01 respectively). The amplified MYCN status was also confirmed as correlated with poorer outcomes. CONCLUSIONS: Postoperative 123I-MIBG scintigraphy including SPECT/CT and semiquantification of the uptake at the surgical site appeared to be a valuable prognostic tool in neuroblastoma. PMID- 29409316 TI - Injectable Hexapeptide Hydrogel for Localized Chemotherapy Prevents Breast Cancer Recurrence. AB - Although postsurgical chemotherapy is frequently used for the treatment of breast cancer, tumor recurrence is still a frequent event. Enhancing the efficacy of chemotherapy via localized drug delivery may help to prevent breast cancer recurrence. To achieve this goal, we designed a hydrogel nanocarrier that could be injected at the tumor site by coassembly of tailor-made hexapeptide and doxorubicin. Evidently, on the basis of our findings, the sustained release of drug from the hydrogel led to a reduction in cancer recurrence, including the suppression of primary regrowth and distant metastasis. This localized chemotherapy strategy did not show any obvious side effects in vivo and represents a promising adjuvant therapeutic strategy for breast cancer recurrence. PMID- 29409318 TI - Two-Photon DNAzyme-Gold Nanoparticle Probe for Imaging Intracellular Metal Ions. AB - RNA-cleaving DNAzymes have been demonstrated as a promising platform for sensing metal ions. However, the poor biological imaging performance of RNA-cleaving DNAzyme-based fluorescent probes has limited their intracellular applications. Compared with traditional one-photon fluorescence imaging, two-photon (TP) fluorescent probes have shown advantages such as increased penetration depth, lower tissue autofluorescence, and reduced photodamage. Herein, for the first time, we developed an RNA-cleaving DNAzyme-based TP imaging probe (TP-8-17ES AuNP) for Zn2+ detection in living cells by modifying a Zn2+-specific DNAzyme (8 17) with a TP fluorophore (TP-8-17ES) and using gold nanoparticles (AuNPs) for intracellular delivery. The modified TP-8-17ES exhibits good two-photon properties and excellent photostability. For the TP-8-17ES-AuNP, in the absence of Zn2+, the TP fluorophore is quenched by both AuNPs and the molecular quencher. Only in the presence of Zn2+ does the DNAzyme cleave the TP fluorophore-labeled substrate strand, resulting in fluorescence enhancement and TP imaging. Such probe shows remarkable selectivity of Zn2+ over other metal ions existing in the biological environment. Benefiting from the labeled TP fluorophore, the near infrared (NIR) excited probe has the capability of TP imaging of Zn2+ in living cells and tissue with a deep tissue penetration up to 160 MUm. This method can be generally applied to detect other metal ions in biological systems under TP imaging with higher tissue penetration ability and lower phototoxicity. PMID- 29409319 TI - Retraction of "Chemoselective Reactions of (E)-1,3-Dienes: Cobalt-Mediated Isomerization to (Z)-1,3-Dienes and Reactions with Ethylene". PMID- 29409317 TI - Intracellular GPCRs Play Key Roles in Synaptic Plasticity. AB - The trillions of synaptic connections within the human brain are shaped by experience and neuronal activity, both of which underlie synaptic plasticity and ultimately learning and memory. G protein-coupled receptors (GPCRs) play key roles in synaptic plasticity by strengthening or weakening synapses and/or shaping dendritic spines. While most studies of synaptic plasticity have focused on cell surface receptors and their downstream signaling partners, emerging data point to a critical new role for the very same receptors to signal from inside the cell. Intracellular receptors have been localized to the nucleus, endoplasmic reticulum, lysosome, and mitochondria. From these intracellular positions, such receptors may couple to different signaling systems, display unique desensitization patterns, and/or show distinct patterns of subcellular distribution. Intracellular GPCRs can be activated at the cell surface, endocytosed, and transported to an intracellular site or simply activated in situ by de novo ligand synthesis, diffusion of permeable ligands, or active transport of non-permeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in synaptic plasticity and learning and memory. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools. PMID- 29409320 TI - Boosting Formate Production in Electrocatalytic CO2 Reduction over Wide Potential Window on Pd Surfaces. AB - Facile interconversion between CO2 and formate/formic acid (FA) is of broad interest in energy storage and conversion and neutral carbon emission. Historically, electrochemical CO2 reduction reaction to formate on Pd surfaces was limited to a narrow potential range positive of -0.25 V (vs RHE). Herein, a boron-doped Pd catalyst (Pd-B/C), with a high CO tolerance to facilitate dehydrogenation of FA/formate to CO2, is initially explored for electrochemical CO2 reduction over the potential range of -0.2 V to -1.0 V (vs RHE), with reference to Pd/C. The experimental results demonstrate that the faradaic efficiency for formate (etaHCOO-) reaches ca. 70% over 2 h of electrolysis in CO2 saturated 0.1 M KHCO3 at -0.5 V (vs RHE) on Pd-B/C, that is ca. 12 times as high as that on homemade or commercial Pd/C, leading to a formate concentration of ca. 234 mM mg-1 Pd, or ca. 18 times as high as that on Pd/C, without optimization of the catalyst layer and the electrolyte. Furthermore, the competitive selectivity etaHCOO-/etaCO on Pd-B/C is always significantly higher than that on Pd/C despite a decreases of etaHCOO- and an increases of the CO faradaic efficiency (etaCO) at potentials negative of -0.5 V. The density functional theory (DFT) calculations on energetic aspects of CO2 reduction reaction on modeled Pd(111) surfaces with and without H-adsorbate reveal that the B-doping in the Pd subsurface favors the formation of the adsorbed HCOO*, an intermediate for the FA pathway, more than that of *COOH, an intermediate for the CO pathway. The present study confers Pd B/C a unique dual functional catalyst for the HCOOH <-> CO2 interconversion. PMID- 29409321 TI - Electron Pair Repulsion Responsible for the Peculiar Edge Effects and Surface Chemistry of Black Phosphorus. AB - The electronic and optical properties of black phosphorus (black-P) are significantly modulated by fabricating the edges of this two-dimensional material. Electron lone pairs (ELPs) are ubiquitous in black-P, but their role in creating the edge effects of black-P is poorly understood. Using first-principle calculations, we report ELPs of black-P experience severe Coulomb repulsion and play a central role in creating the edge effects of black-P. We discover the outermost P atoms of the zigzag edges of black-PQDs are free of the Coulomb repulsion, but the P atoms of the armchair edges do experience the Coulomb repulsion. The Coulomb repulsion serves as a new chemical driving force to make electron donor-acceptor bonds with chemical groups bearing vacant orbitals. Our results provide insights into the mechanism responsible for the peculiar edge effects of black-P and highlight the opportunity to use the ELPs of black-P for their damage-free surface functionalization. PMID- 29409322 TI - Diverse Metabolite Variations in Tea (Camellia sinensis L.) Leaves Grown Under Various Shade Conditions Revisited: A Metabolomics Study. AB - With the increase of tea (Camellia sinensis) consumption, its chemical or metabolite compositions play a crucial role in the determination of tea quality. In general, metabolite compositions of fresh tea leaves including shoots depend on plucking seasons and tea cultivators. Therefore, choosing a specific plucking time of tea leaves can provide use-specified tea products. Artificial control of tea growing, typically shade treatments, can lead to significant changes of the tea metabolite compositions. However, metabolic characteristics of tea grown under various shade treatment conditions remain unclear. Therefore, the objective of the current study was to explore effects of various shade conditions on metabolite compositions of tea through a 1H NMR-based metabolomics approach. It was noteworthy that the levels of catechins and their derivatives were only influenced at the initial time of shade treatments while most amino acids were upregulated as amounts of shade and periods were increased: that is, the levels of alanine, asparagine, aspartate, isoleucine, threonine, leucine, and valine in fresh tea leaves were conspicuously elevated when shade levels were raised from 90% to 100% and when period of shade treatments was increased by 20 days. Such increased synthesis of amino acids along with large reductions of glucose level reflected carbon starvation under the dark conditions, indicating remarkable proteolysis in the chloroplast of tea leaves. This study provides important information about making amino acid-enhanced tea products based on global characteristics of diverse tea leaf metabolites induced by various shade treatment conditions. PMID- 29409323 TI - Impact of Small Phonon Energies on the Charge-Carrier Lifetimes in Metal-Halide Perovskites. AB - Metal-halide perovskite (MHP) solar cells exhibit long nonradiative lifetimes as a crucial feature enabling high efficiencies. Long nonradiative lifetimes occur if the transfer of electronic into vibrational energy is slow due to, e.g., a low trap density, weak electron-phonon coupling, or the requirement to release many phonons in the electronic transition. Here, we combine known material properties of MHPs with basic models for electron-phonon coupling and multiphonon-transition rates in polar semiconductors. We find that the low phonon energies of MAPbI3 lead to a strong dependence of recombination rates on trap position, which we deduce from the underlying physical effects determining nonradiative transitions. This is important for nonradiative recombination in MHPs, as it implies that they are rather insensitive to defects that are not at midgap energy, which can lead to long lifetimes. Therefore, the low phonon energies of MHPs are likely an important factor for their optoelectronic performance. PMID- 29409325 TI - Dermatology ECHO - an innovative solution to address limited access to dermatology expertise. AB - INTRODUCTION: The present maldistribution of dermatologists in the USA may make it difficult for patients to access timely and quality care. Access to specialty care may be even more challenging for rural and underserved patients due to geographical limitations and other socioeconomic hardships. With over one-third of primary care patients seeking care for at least one skin problem, it is important to follow the American Academy of Dermatology Special Positioning Workgroup?'s core areas of impact regarding treatment of conditions that affect millions of patients by using a team-based approach and telemedicine technologies. The objective of this study was to demonstrate the Dermatology Extension for Community Healthcare Outcomes (ECHO) project approach in multidisciplinary telementoring and education of primary care providers (PCPs) in treatment and management of complex, costly, and common skin diseases via live interactive video technologies. METHODS: Dermatology ECHO is a distance education telementoring platform that uses a multidisciplinary case-based approach in a non judgemental environment. A team of specialists, including general dermatologists, pediatric dermatologists, a dermatopathologist, a clinical psychologist, and a nurse practitioner, meets via video with a number of PCPs from isolated, rural, or underserved areas to discuss de-identified patient cases and present dermatology-specific continuing medical education (CME)-approved didactic presentations. The University of Missouri, Department of Dermatology, leads the first Dermatology ECHO in the USA. They partner with various primary care clinics across Missouri to provide mentoring in the treatment of skin conditions. Missouri Telehealth Network provides operational support through the Show-Me ECHO project. The network also assists with provider recruitment activities. RESULTS: The authors describe a patient case to illustrate the effect of ECHO on provider distance learning and patient outcomes. A 69-year-old woman from rural Missouri was spurred by a rooster. She presented to her primary care clinic six times over a 2-month period. She was prescribed several different medications and underwent tests and one procedure, including vaccination. After the patient?'s case was presented during the Dermatology ECHO session, she was correctly diagnosed with a Mycobacterium skin infection, and new recommendations were made. The patient improved significantly within 2 weeks. CONCLUSIONS: As specialty medical evidence based recommendations continue to increase, providers practicing in isolated rural and underserved areas may find it challenging to keep up with the new knowledge. Dermatology ECHO creates a community of practice that allows participating providers to discuss complex cases, receive specific guidance and mentoring, and participate in CME presentations. The case presented here supports the authors?' observations that Dermatology ECHO is an appropriate platform for learning evidence-based medical knowledge via videoconferencing technology. PMID- 29409326 TI - Five-year outcome after pelvic floor reconstructive surgery: evaluation using dynamic magnetic resonance imaging compared to clinical examination and quality of-life questionnaire. AB - Background Dynamic magnetic resonance imaging (dMRI) captures the entire pelvis during Valsalva maneuver and helps diagnosing pelvic floor changes after reconstructive surgery. Purpose To evaluate therapeutic outcome five years after reconstructive surgery using clinical examination, dMRI, and quality-of-life (QOL) questionnaire. Material and Methods Clinical examination, dMRI, and QOL questionnaire were conducted before surgery and in the follow-ups at 12 weeks, one year, and five years in women with pelvic organ prolapse (POP) stage >=2. dMRI was performed at 1.5-T using a predefined protocol including sagittal T2 weighted (T2W) sequence at rest and sagittal T2W true-FISP sequence at maximum strain for metric POP measurements (reference points = bladder, cervix, pouch, rectum). Pelvic organ mobility (POM) was defined as the difference of the metric measurement at maximum strain and at rest. Results Twenty-six women with 104 MRI examinations were available for analysis. dMRI results mostly differ to clinical examination regarding the overall five-year outcome and the posterior compartment in particular. dMRI diagnosed substantially more patients with recurrent or de novo POP in the posterior compartment (n = 17) compared to clinical examination (n = 4). POM after five years aligns to preoperative status except for the bladder. POM reflects best the QOL results regarding defecation disorders. Conclusion A tendency for recurrent and de novo POP was seen in all diagnostic modalities applied. dMRI objectively visualizes the interaction of the pelvic organs and the pelvic floor after reconstructive surgery and POM correlated best with the women's personal impression on pelvic floor complaints. PMID- 29409327 TI - Pilot Randomized Phase II Trial of the Enhancing Quality of Life in Patients (EQUIP) Intervention for Patients With Advanced Lung Cancer. AB - CONTEXT: New models of care that are effective and feasible for widespread implementation need to be developed for the delivery of early palliative care to patients with advanced cancer. OBJECTIVES: The objectives were to determine the feasibility and acceptability of the Enhancing Quality of Life in Patients (EQUIP) intervention, data completion rate of patient-reported outcome measures in the context of the EQUIP trial, and the estimated effect of the EQUIP intervention on quality of life and mood. METHODS: In this pilot randomized phase II trial, eligible patients had newly diagnosed advanced lung cancer and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Randomization was to the control group that received standard oncology care or to the intervention group where patients individually received the EQUIP intervention, comprising 4 face-to-face educational sessions with a nurse. RESULTS: A total of 69 patients were recruited. In the intervention group, 30 (85.7%) of 35 patients completed all 4 EQUIP sessions. All patients were satisfied with the topics shared and felt they were useful. However, there was no significant difference between intervention and control groups in terms of quality of life and mood at 12 weeks after baseline. CONCLUSION: This pilot study showed that nurse-directed face-to-face educational sessions were feasible and acceptable to patients with advanced lung cancer. However, there was no indication of benefit of the EQUIP intervention on quality of life and mood. This could be due in part to a low prevalence of targeted symptoms. PMID- 29409328 TI - Parental reactions to parent- and sibling-directed aggression within a domestic violence context. AB - Parent- and sibling-directed aggression by minor children are two forms of family violence that often co-occur and have strong relations to prior exposure to domestic violence, yet are often overlooked in intervention efforts. In addition, current research does not examine these forms of family violence in tandem, and there is very limited research with samples exposed to domestic violence. To better understand how these forms of aggression operate within a domestic violence context, we interviewed 44 women residing in a domestic violence shelter with at least one child over 3.5 years of age who was aggressive toward them and/or siblings. Caregivers reported on their emotional reactions to children's parent-directed aggression and the types of and effectiveness of help they sought for parent- and/or sibling-directed aggression. In line with previous literature, caregivers endorsed a complex mix of emotional reactions to their children's parent-directed aggression, including anger, sadness, guilt, forgiveness, and worthlessness. In contrast to other studies, most caregivers (89%) had sought help for children's parent- and/or sibling-directed aggression and found it effective. Findings contribute to the literature on parent- and sibling-directed aggression and provide implications for how to effectively intervene. PMID- 29409329 TI - Downregulation of MicroRNA 29a/b exacerbated diabetic retinopathy by impairing the function of Muller cells via Forkhead box protein O4. AB - BACKGROUND: Diabetic retinopathy is a neurological disease, which can lead to blindness in severe cases. The pathogenesis underlying diabetic retinopathy is unclear. The aim of this study was to explore the role of dysregulated microRNA 29a/b in the onset and progression of diabetic retinopathy. METHODS: Diabetes mellitus was induced in rats using 60 mg/kg of streptozotocin. Glucose (5.5 and 25 mM) was used to stimulate rat retinal Muller cells. Real-time polymerase chain reaction and Western blot analyses were used to determine gene expression. A luciferase reporter assay was conducted to validate the relationship of microRNA 29a/b with glioma-associated oncogene homolog 1 and Forkhead box protein O4. RESULTS: The expression of microRNA 29a/b and glutamine synthetase decreased in both diabetes mellitus rats and rat retinal Muller cells stimulated with high glucose, whereas the expression of sonic hedgehog, glioma-associated oncogene homolog 1, glial fibrillary acidic protein, and vascular endothelial growth factor, as well as the content of glutamate, increased. Dysregulated microRNA 29a/b was directly regulated by the sonic hedgehog-glioma-associated oncogene homolog 1 signalling pathway, and microRNA 29a and microRNA 29b targeted Forkhead box protein O4 and regulated its expression. CONCLUSION: Downregulation of microRNA 29a/b, mediated by the sonic hedgehog-glioma-associated oncogene homolog 1 signalling pathway, exacerbated diabetic retinopathy by upregulating Forkhead box protein O4. PMID- 29409330 TI - Bifidobacteria and its rice fermented products on diet induced obese mice: analysis of physical status, serum profile and gene expressions. AB - Obesity is highly correlated with the dysbiosis of intestinal microbiota, and bifidobacteria are one of the soft targets of this metabolic syndrome. The aim of this study is to evaluate the efficacy of Bifidobacterium sp. MKK4 and rice-based fermented foods on physical, haematological, gut microbiota and lypogenic lypolytic marker genes in diet-induced obese mice. Adult male mice (21+/-0.7 g) were randomly divided into four groups (n=10) according to the type of diet: normal diet (ND), high fat diet (HFD), HFD supplemented with Bifidobacterium sp. MKK4 and HFD supplemented with MKK4 associated rice-fermented food. 8 weeks of bacterial therapy in the obese mice resulted in significant reduction of body and organ weights, improved serum levels of glucose, triglyceride and cholesterol, the histological structure of the liver (steatosis), and re-establishment of gut Lactobacillus, Bifidobacterium and Bacteroides species. The bacterial therapy led to up-regulation of lipolytic transcription factors, such as peroxisome proliferator-activated receptor (PPAR)-alpha, PPAR-delta, and their regulated gene products in fatty acid metabolism and glucose uptake, such as acyl-CoA oxidase, carnitine palmitoyl-transferase-1, uncoupling protein-3 and glucose transporter-4. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol regulatory element binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase and tumour necrosis factor alpha genes. The effectiveness of the fermented product was more profound than the single bacterium. These data provide experimental support with regard to the use of Bifidobacterium sp. MKK4 as a natural therapeutic agent to control obesity. PMID- 29409331 TI - Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice. AB - Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13 acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1beta, IL-6, tumour necrosis factor alpha (TNF-alpha), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1*109 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1beta, IL-6, TNF-alpha, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that their use could be beneficial in dermatological conditions such as AD. PMID- 29409332 TI - Radial artery calcification in a young coronary bypass patient: a caution. PMID- 29409333 TI - Inconsistent Condom Use Among Male University Students in Northern Thailand. AB - University students are at increased risk of HIV infection, but little is known about the determinants of inconsistent condom use among them. The study aims to assess the association of sociodemographic, individual, dyadic, and social factors with inconsistent condom use among male university students. Of 1091 participants, 67.0% had sexual intercourse, though 64.4% had inconsistent condom use. It was found that "did not use a condom at first sexual intercourse" (adjusted odds ratio [AOR] 6.1; CI, 3.7-10.1), "history of STIs" (AOR, 2.1; CI, 1.0-4.2), low "self-efficacy" (AOR, 2.4; CI, 1.3-4.7), "perception that condom use reduces pleasure" (AOR, 1.4; CI, 1.0-2.1), and "high subjective norm" (AOR, 1.9; CI, 1.3-2.8) were associated with increased odds of inconsistent condom use. Condom use should be promoted from the onset of sexual activity to establish a habit of safe sex practices and for improvement in self-efficacy of condom use. Emphasis must be laid on pleasure-enhancing benefits of condom use and changing social norms. PMID- 29409334 TI - Geographic Clustering of Admissions to Inpatient Psychiatry among Adults with Cognitive Disorders in Ontario, Canada: Does Distance to Hospital Matter? AB - OBJECTIVE: This study examined relationships among hospital accessibility, socio economic context, and geographic clustering of inpatient psychiatry admissions for adults with cognitive disorders in Ontario, Canada. METHOD: A retrospective cross-sectional analysis was conducted using admissions data from 71 hospitals with inpatient psychiatry beds in Ontario, Canada between 2011 and 2014. Data included 7,637 unique admissions for 4,550 adults with a DSM-IV diagnosis of Delirium, Dementia, Amnestic and other Cognitive Disorders. Bayesian spatial Poisson regression was employed to examine the relationship between accessibility of general hospitals with psychiatric beds and psychiatric hospitals, area-level marginalization, and hospitalization rate with the risk of admission to inpatient psychiatry among adults with cognitive disorders across 516 Forward Sortation Areas (FSA) in Ontario. RESULTS: Residential instability and the overall hospitalization rate were significantly associated with an increase in the relative risk of admissions to inpatient psychiatry. Accessibility to general hospitals and psychiatric hospitals were marginally insignificant at the 95% credible interval in the final model. Significant geographic clustering of admissions was identified where individuals residing in FSA's with the highest relative risk were 2.0 to 7.1 times more likely to be admitted to inpatient psychiatry compared to the average. CONCLUSIONS: Geographic clustering of inpatient psychiatry admissions for adults with cognitive disorders exists across the Province of Ontario, Canada. At the geographic level, the risk of admission was positively associated with residential instability and the overall hospitalization rate, but not distance to the closest general or psychiatric hospital. PMID- 29409335 TI - Can interpersonal psychotherapy be delivered by a community agency? AB - OBJECTIVES: There are limited options for depressed patients to have access to evidence-based psychotherapies in the community. This pilot study explored the feasibility of delivering interpersonal psychotherapy (IPT) to clients in a community support agency. METHOD: A total of 18 clients with depression completed at least eight sessions of IPT (range 8-13) and 17 completed a range of pre- and post-treatment measures. RESULTS: Clients had a high level of depression and were functioning poorly. All found the delivery of IPT in the community useful and would recommend therapy to others. There was a significant reduction in self report and clinician-rated depression, and improvement in social functioning. CONCLUSIONS: This study supports the notion that therapy can be delivered by appropriately trained non-mental-health clinicians in the community with good effect and adds to the range of options for delivery of psychiatric care. PMID- 29409336 TI - Hypolipidemic Drugs and Diabetes Mellitus-Mechanisms and Data From Genetic Trials. AB - Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on target" and "off-target" effects of these drugs. PMID- 29409337 TI - Management of multiple sclerosis: the role of coping self-efficacy and self esteem. AB - Patients with multiple sclerosis (MS) engage in various coping behaviours in order to manage their disease. The aim of this study is to find out if the self esteem of patients is associated with coping strategies - problem-focused (e.g. making a plan of action when confronted with a problem); emotion focused (e.g. get emotional support from community); and focused on stopping unpleasant emotions and thoughts (e.g. keeping oneself from feeling sad), and if it can enhance or hinder coping efforts in the disease management. We collected data from 155 consecutive MS patients who completed the Coping Self-Efficacy Scale (CSE) and the Rosenberg Self-esteem Scale (RSE). Explained variance for problem focused coping, emotion-focused coping, and coping focused on stopping unpleasant emotions and thoughts was 33, 24, and 31%, respectively. Self-esteem seems to be associated with coping strategies indicating that feelings of self-worth are linked with the ability to handle difficult life situations and can be helpful in chronic disease management. PMID- 29409338 TI - Ambiguous loss and incomplete abduction narratives in Kosovo. AB - Ten mothers of men and boys who were abducted and listed as missing during the war in Kosovo in 1998/1999 were interviewed in Kosovo in the spring of 2012. Although the missing are presumed dead by the authorities, the mothers continue to live in a state of emotional ambiguity where a presumption of death is balanced with the hope of being reunited. In the absence of absolute proof, finding the remains of their loved ones becomes a major preoccupation. Using a social phenomenological approach, this study explored the social and political complexities existing within the life-world of these women. The findings suggest that they live in a continual state of psychological distress, and even when remains are returned, the unknown elements of the narrative of their abduction and murder only add to their distress and force many into self-imposed emotional exile away from community and close family. PMID- 29409339 TI - Ten myths about work addiction. AB - Background and aims Research into work addiction has steadily grown over the past decade. However, the literature is far from unified and there has been much debate on many different issues. Aim and methods This paper comprises a narrative review and focuses on 10 myths about work addiction that have permeated the psychological literature and beyond. The 10 myths examined are (a) work addiction is a new behavioral addiction, (b) work addiction is similar to other behavioral addictions, (c) there are only psychosocial consequences of work addiction, (d) work addiction and workaholism are the same thing, (e) work addiction exclusively occurs as a consequence of individual personality factors, (f) work addiction only occurs in adulthood, (g) some types of work addiction are positive, (h) work addiction is a transient behavioral pattern related to situational factors, (i) work addiction is a function of the time spent engaging in work, and (j) work addiction is an example of overpathogizing everyday behavior and it will never be classed as a mental disorder in the DSM. Results Using the empirical literature to date, it is demonstrated that there is evidence to counter each of the 10 myths. Conclusion It appears that the field is far from unified and that there are different theoretical constructs underpinning different strands of research. PMID- 29409341 TI - Quality of care reported by proxies - Does resident cognition count? AB - Resident self-reports are considered the primary source of quality of care information, but proxy reports by family or staff can also be used to supplement or substitute resident reports. This study analyses how the results of proxy reports vary according to residents' cognition level. The data set used covers proxy reports of family ( n = 558) and staff ( n = 801), divided by the availability of resident self-reports (family yes n = 289, no n = 269; staff yes 393, no = 408). Family and staff proxies assessed residents' quality of care as better when resident self-reports were also available, and quality of care tended to be assessed as poorer among those with higher cognitive decline. The results of this methodological study indicate the importance of using several proxy evaluations; however, these can only supplement resident self-reports, not replace them. The interpretation rules acknowledging dependency between residents' cognition and proxy assessments could be used as a basis for future comparisons of quality improvement in long-term care and for painting a more comprehensive picture of service quality. PMID- 29409340 TI - Exercise addiction in adolescents and emerging adults - Validation of a youth version of the Exercise Addiction Inventory. AB - Background Behavioral addictions often onset in adolescence and increase the risk of psychological and social problems later in life. The core symptoms of addiction are tolerance, withdrawal symptoms, lack of control, and compulsive occupation with the behavior. Psychometrically validated tools are required for detection and early intervention. Adolescent screening instruments exist for several behavioral addictions including gambling and video gaming addiction but not for exercise addiction. Given recent empirical and clinical evidence that a minority of teenagers appear to be experiencing exercise addiction, a psychometrically robust screening instrument is required. Aims The aim of this study was to develop and test the psychometric properties of a youth version of the Exercise Addiction Inventory (EAI) - a robust screening instrument that has been used across different countries and cultures - and to assess the prevalence of exercise addiction and associated disturbed eating. Methods A cross-sectional survey was administered to three high-risk samples (n = 471) aged 11-20 years (mean age: 16.3 years): sport school students, fitness center attendees, and patients with eating disorder diagnoses. A youth version of the EAI (EAI-Y) was developed and distributed. Participants were also screened for disordered eating with the SCOFF Questionnaire. Results Overall, the EAI-Y demonstrated good reliability and construct validity. The prevalence rate of exercise addiction was 4.0% in school athletes, 8.7% in fitness attendees, and 21% in patients with eating disorders. Exercise addiction was associated with feelings of guilt when not exercising, ignoring pain and injury, and higher levels of body dissatisfaction. PMID- 29409342 TI - Chitosan nanoparticles for the oral delivery of tenofovir disoproxil fumarate: formulation optimization, characterization and ex vivo and in vivo evaluation for uptake mechanism in rats. AB - OBJECTIVE: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption. SIGNIFICANCE: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption. METHODS: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles. RESULTS: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156 +/- 5 nm with an entrapment efficiency of 48.2 +/- 1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin mediated uptake played a key role in increasing the oral absorption of tenofovir. CONCLUSIONS: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways. PMID- 29409343 TI - The Effects of Enriched Environmental Intervention on the Parturition Outcome and Filial Health of Pregnant Mice With Chronic Pain. AB - Chronic pain (CP) adversely impacts people's health. However, the influence of CP on pregnant women and their fetuses remains unclear. Few reasonable interventions have been offered to these women. This study aimed to examine the effects of enriched environmental intervention (EEI) on the delivery outcome and offspring health of pregnant mice with CP. Forty pregnant mice were equally and randomly divided into four groups (control, sham, CP, and CP + EEI). Monoarthritis was induced by subcutaneous injection of the complete Freund's adjuvant (100 MUg/100 MUl) into the left hind paw of mice on Day 0 of gestation. Sham mice received 100 ul of sterile phosphate-buffered saline subcutaneously. General health status and delivery outcomes of pregnant mice and general physical status, growth, and development of offspring were observed and compared between groups. CP mice exhibited less weight gain, higher rate of premature delivery, smaller litter size, lower live birth rate, lower filial birth weight, shorter filial tail length, and lower filial rates of achieving righting reflex and crawling compared to mice in the control/sham/CP + EEI groups. There were no significant differences between mice in the CP + EEI group and those in the control and sham groups. CP during pregnancy led to serious adverse impacts on both the mother and fetus mice in this study, and EEI was an effective treatment for these effects. PMID- 29409344 TI - Experiences of stigma and discrimination in social and healthcare settings among trans people living with HIV in the UK. AB - The People Living with HIV StigmaSurvey UK 2015 was a community led national survey investigating experiences of people living with HIV in the UK in the past 12 months. Participants aged 18 and over were recruited through over 120 cross sector community organisations and 46 HIV clinics to complete an anonymous online survey. Trans is an umbrella term which refers to individuals whose current gender identity is different to the gender they were assigned at birth. Trans participants self-identified via gender identity and gender at birth questions. Descriptive analyses of reported experiences in social and health care settings were conducted and multivariate logistic regression analyses were used to identify sociodemographic predictors of reporting being treated differently to non-HIV patients, and being delayed or refused healthcare treatment in the past 12 months. 31 out of 1576 participants (2%) identified as trans (19 trans women, 5 trans men, 2 gender queer/non-binary, 5 other). High levels of social stigma were reported for all participants, with trans participants significantly more likely to report worrying about verbal harassment (39% vs. 23%), and exclusion from family gatherings (23% vs. 9%) in the last 12 months, compared to cisgender participants. Furthermore, 10% of trans participants reported physical assault in the last 12 months, compared to 4% of cisgender participants. Identifying as trans was a predictor of reporting being treated differently to non-HIV patients (48% vs. 30%; aOR 2.61, CI 1.06, 6.42) and being delayed or refused healthcare (41% vs. 16%; aOR 4.58, CI 1.83, 11.44). Trans people living with HIV in the UK experience high levels of stigma and discrimination, including within healthcare settings, which is likely to impact upon health outcomes. Trans-specific education and awareness within healthcare settings could help to improve service provision for this demographic. PMID- 29409345 TI - A three-dimensional topology optimization model for tooth-root morphology. AB - To obtain the root of a lower incisor through structural optimization, we used two methods: optimization with Solid Isotropic Material with Penalization (SIMP) and Soft-Kill Option (SKO). The optimization was carried out in combination with a finite element analysis in Abaqus/Standard. The model geometry was based on cone-beam tomography scans of 10 adult males with healthy bone-tooth interface. Our results demonstrate that the optimization method using SIMP for minimum compliance could not adequately predict the actual root shape. The SKO method, however, provided optimization results that were comparable to the natural root form and is therefore suitable to set up the basic topology of a dental root. PMID- 29409346 TI - The kinetics of thermal degradation of polyphenolic compounds from elderberry ( Sambucus nigra L.) extract. AB - This main focus of this study was to evaluate the thermal degradation kinetics and the phytochemical characterization of the elderberries extract. Pelargonidin 3-sophoroside and delphinidin-3-glucoside were identified as the major anthocyanin compounds and catechin hydrate as the major flavonoid compound. In order to further understand the action of the heat treatment on the bioactive compounds from elderberry extract, fluorescence studies were also carried out. In general, heating at temperatures ranging from 100 to 150 C for up to 90 min caused a decrease in fluorescence intensity, simultaneously with significant redshifts in lambdamax suggesting important molecular changes inside the anthocyanins structure, affecting the antioxidant activity. Increasing the heating time up to 120 min, the elderberry extract peaked at about 88 nm shifted toward higher wavelengths with respect to that of untreated solutions (peak at 442 nm). The kinetics studies of anthocyanins, fluorescence intensity, and antioxidant activity evidenced a decrease of the degradation rate constants with increased temperature while the activation energies for heat-induced fluorescence intensity, monomeric anthocyanins, and antioxidant activity were 39.62 +/- 9.60, 49.97 +/- 5.61, and 31.04 +/- 19.92 kJ/mol, respectively. Our results can be valuable in terms of establishing the appropriate processing and formulation protocols that could lead to a more efficient utilization of these pigments in actual food products and/or nutraceuticals. PMID- 29409347 TI - Fryl deficiency is associated with defective kidney development and function in mice. AB - FRY like transcription coactivator ( Fryl) gene located on chromosome 5 is a paralog of FRY microtubule binding protein ( Fry) in vertebrates. It encodes a protein with unknown functions. Fryl gene is conserved in various species ranging from eukaryotes to human. Although there are several reports on functions of Fry gene, functions of Fryl gene remain unclear. A mouse line containing null mutation in Fryl gene by gene trapping was produced in this study for the first time. The survival and growth of Fryl-/- mice were observed. Fryl gene expression levels in mouse tissues were determined and histopathologic analyses were conducted. Most Fryl-/- mice died soon after birth. Rare Fryl-/- survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl-/- survivors died of hydronephrosis before age 1. No abnormal histopathologic lesion was apparent in full-term embryo or adult tissues except the kidney. Abnormal lining cell layer detachments from walls of collecting and convoluted tubules in kidneys were apparent in Fryl-/- neonates and full-term embryos. Fryl gene was expressed in renal tubular tissues including the glomeruli and convoluted and collecting tubules. This indicates that defects in tubular systems are associated with Fryl functions and death of Fryl-/- neonates. Fryl protein is required for normal development and functional maintenance of kidney in mice. This is the first report of in vivo Fryl gene functions. Impact statement FRY like transcription coactivator ( Fryl) gene is conserved in various species ranging from eukaryotes to human. It expresses a protein with unknown function. We generated a Fryl gene mutant mouse line and found that most homozygous mice died soon after their birth. Rare Fryl-/- survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl-/- survivors died of hydronephrosis before age 1. Full-term mutant embryos showed abnormal collecting and convoluted tubules in kidneys where Fryl gene was expressed. Collectively, these results indicate that Fryl protein is required for normal development and functional maintenance of kidney in mice. To the best of our knowledge, this is the first report on in vivo Fryl gene functions. PMID- 29409349 TI - A new cadinane sesquiterpenoid glucoside with cytotoxicity from Abelmoschus sagittifolius. AB - A new cadinane sesquiterpenoid glucoside, 2beta,7,3-trihydroxycalamenene 3-O-beta d-glucoside (1) together with six known compounds, N-(p-trans-coumaroyl)-N-methyl tyramine (2), Cleomiscosin A (3), 9,12,13-trihydroxy-10,15-heptadecadienoic acid (4), Cytochalasin B (5), Marmesinin (6) and N-(p-trans-coumaroyl) tyramine (7) were obtained from the stem bark of Abelmoschus sagittifolius. The new structure of compound 1 was elucidated by analysing its 1H and 13C-NMR, 1H-1H COSY, HSQC, HMBC, NOESY and HR-ESI-MS spectra. Compounds 1-7 showed moderate cytotoxicity against Hela and HepG-2 human cancer cell lines. PMID- 29409348 TI - Better living through chemistry: Addressing emerging antibiotic resistance. AB - The increasing emergence of multidrug-resistant bacteria is recognized as a major threat to human health worldwide. While the use of small molecule antibiotics has enabled many modern medical advances, it has also facilitated the development of resistant organisms. This minireview provides an overview of current small molecule drugs approved by the US Food and Drug Administration (FDA) for use in humans, the unintended consequences of antibiotic use, and the mechanisms that underlie the development of drug resistance. Promising new approaches and strategies to counter antibiotic-resistant bacteria with small molecules are highlighted. However, continued public investment in this area is critical to maintain an edge in our evolutionary "arms race" against antibiotic-resistant microorganisms. Impact statement The alarming increase in antibiotic-resistant microorganisms is a rapidly emerging threat to human health throughout the world. Historically, small molecule drugs have played a major role in controlling bacterial infections and they continue to offer tremendous potential in countering resistant organisms. This minireview provides a broad overview of the relevant issues, including the diversity of FDA-approved small molecule drugs and mechanisms of drug resistance, unintended consequences of antibiotic use, the current state of development for small molecule antibacterials and financial challenges that impact progress towards novel therapies. The content will be informative to diverse stakeholders, including clinicians, basic scientists, translational scientists and policy makers, and may be used as a bridge between these key players to advance the development of much-needed therapeutics. PMID- 29409350 TI - Scrutiny of 13C-phenylalanine breath test reproducibility. AB - We evaluated the reproducibility of the 13C-phenylalanine breath test (13C PheBT). On three separate days, 21 healthy volunteers (11 F and 10 M) underwent 13C-PheBT with 100 mg l-[1-13C]phenylalanine taken orally. Short-term reproducibility was evaluated with paired examinations taken 3 days apart; paired examinations separated by 23 days (median) served for the medium-term reproducibility assessment. Expiratory air was sampled at 19 points throughout 3 h. Determined limited reproducibility of the 13C-PheBT must be taken into consideration while interpreting the results of this diagnostic tool. The results of this study imply the following conclusions: (i) From among the three parameters examined, the cumulative 13C recovery area under the curve (AUC) offers much better reproducibility than the maximum momentary 13C recovery in the expiratory air (Dmax) or the time to reach the maximum momentary 13C recovery (Tmax) (ii) Collection of the breath air samples for 2 h results in a much better reproducibility of AUC, than for 1 h only; (iii) Reproducibility of 13C-PheBT is affected neither by the duration of the time gap between repeated tests nor by gender; (iv) Comparison with data obtained formerly reveals that reproducibility of the 13C-PheBT is worse than either that of of the 13C-methacetin (13C-MBT) or the 13C-alpha-ketoisocaproic acic (13C-KICA-BT) breath tests. This finding will have to be taken into consideration while interpreting the results of this diagnostic tool. PMID- 29409351 TI - CD33-Specific Chimeric Antigen Receptor T Cells with Different Co-Stimulators Showed Potent Anti-Leukemia Efficacy and Different Phenotype. AB - Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. In particular, relapsed and refractory AML still have a poor prognosis. T cells modified by chimeric antigen receptor (CAR) was an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different co-stimulators (CD28, 4 1BB, or both, referred to as CD33 28z.CAR-T cells, CD33 BBz.CAR-T cells, or CD33 28BBz.CAR-T cells, respectively) were developed to evaluate their efficacy against AML. The effectiveness of three types of CD33 CAR-T cells against AML was verified by specific killing effect to AML cells and prolonged survival of a xenograft mouse model. In terms of CAR-T cell efficacy, especially when transfused into human bodies, the persistence of T cells is also an important index, as it is closely associated with the long-term effect of CAR-T cells. Therefore, the characteristics of three types of CD33 CAR-T cells related to the persistence of T cells were examined. It was found that during expansion, CD33 BBz.CAR-T cells had an increased central memory compartment, while CD33 28z.CAR-T cells were predominantly effector memory T cells. In addition, CD33 28z.CAR-T cells were more inclined to become exhausted. The study suggests that incorporation of 4-1BB in CARs may endow T cells with long-lasting survival ability, thus improving the long-term anti-leukemia effect of CAR-T cells, especially when transfused to the human body. PMID- 29409352 TI - Hepatocyte Growth Factor Gene Therapy for Ischemic Diseases. AB - Stem cells and gene therapy have become promising strategies for treating ischemic diseases and regenerating tissue. Hepatocyte growth factor (HGF) is an angiogenic growth factor with multiple functions, including promoting angiogenesis, regulating inflammation, inhibiting fibrosis, and activating tissue regeneration. Numerous preclinical experiments and clinical trials have demonstrated the feasibility and efficacy of HGF gene therapy in the treatment of ischemic diseases and tissue regeneration. This review summarizes the current advances of therapeutic angiogenesis using HGF gene transfer and modified stem cells. The physiological roles of HGF in angiogenesis and tissue regeneration are revisited. The current advances of clinical trials of plasmid and adenovirus HGF in the treatment of critical limb ischemia and coronary heart disease in China are introduced. Furthermore, valuable insight is provided into the prospective future of novel regenerative strategies using HGF-modified mesenchymal stem cells. HGF gene therapy is presented as a promising therapeutic approach in the treatment of ischemic diseases and regenerative medicine. PMID- 29409353 TI - Serum creatine is not a reliable marker of muscular fitness in young adults. AB - PURPOSE: Elevated serum creatine and higher handgrip strength are individually associated with better health profiles yet the link between two variables remains unknown. In this cross-sectional study, we evaluated serum creatine levels in relation to handgrip strength in a cohort of 130 young healthy adults (61 women and 69 men; age 23.3 +/- 2.6 years), while controlling for age, gender, fat-free mass and biomarkers of creatine metabolism as effect modifiers. MATERIALS AND METHODS: Serum creatine, creatinine and guanidinoacetic acid (GAA) levels were measured with liquid chromatography-tandem mass spectroscopy, while handgrip strength was assessed with a hydraulic hand dynamometer. RESULTS: Hierarchical multiple regression revealed that our model as a whole explained 79.9% of the variance in handgrip strength (p < 0.001). However, the evaluation of the contribution of each independent variable revealed that gender and free-fat mass make significant contributions (45.4 and 31.8%, respectively) to our model (p < 0.05), while neither age (0.9%) nor serum creatine (4.5%) or any other lab markers made significant contributions to the model (p > 0.05). CONCLUSIONS: Having higher blood creatine appears to be unrelated with better physical performance in young healthy adults. Serum creatine was not a reliable marker of muscular fitness in this population. PMID- 29409354 TI - Discrimination as a social determinant of stress and health among New York City taxi drivers. AB - Discrimination is associated with poorer mental and physical health outcomes. Taxi drivers have a higher risk of exposure to discrimination and higher rates of chronic conditions. A cross-sectional needs assessment was conducted with a multilingual group of 535 male taxi drivers in New York City. Drivers reporting higher discrimination were more likely to have higher perceived stress and were more likely to have anxiety/depression and chronic pain, adjusting for confounders. Workplace-based interventions designed to help drivers cope with discrimination, stress, and chronic health conditions, interventions to educate the taxi-riding public, and greater attention to these issues from administrative agencies are warranted. PMID- 29409355 TI - It is time to close the book on device-guided slow breathing. PMID- 29409356 TI - Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes. AB - Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM. PMID- 29409357 TI - Macrolides for KCNJ5-mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism. AB - PURPOSE: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. METHODS AND DESIGN: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. DISCUSSION: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations. PMID- 29409359 TI - Corrigendum. PMID- 29409358 TI - AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS. PMID- 29409360 TI - British Columbia Ministry of Health Patients as Partners: A transformational approach. AB - Patients as Partners is a quality improvement initiative of the British Columbia Ministry of Health (the Ministry) that aims to bring patient voice, choice, and representation to the forefront of healthcare through collaboration with patients, families, non-governmental organizations, funded partners, regional health authorities, and healthcare providers. A spectrum of patient engagement activities, including capacity building and self-management support, occur through partnerships at the individual patient and provider, community, and system levels. These activities ensure patient priorities are identified and embed a patient-centred care approach into provincial policies and projects. Multi-/interdisciplinary collaborations in the healthcare sector occur through participation in working groups, advisory committees, and engagement events. Ongoing improvements include enhancing measurement strategies and leveraging opportunities around gaps. The Ministry was honoured with the International Association of Public Participation Award as the 2016 Canadian Organization of the Year in recognition of improving healthcare through patient and public education. PMID- 29409361 TI - Association between age at asthma diagnosis and tooth loss. AB - OBJECTIVES: This study aimed to investigate the association between age at asthma diagnosis and tooth loss due to caries using data obtained from the Korean National Health and Nutrition Examination Survey. MATERIALS AND METHODS: A complex sample multivariable linear regression was used, and the results were analysed. Age at diagnosis and the number of teeth lost were set as independent and dependent variables, respectively. Among the total 65,973 subjects, 10,056 aged <12 years and 11,714 with missing values in dependent and independent variables were excluded. Asthmatic subjects were divided into the following age groups based on the age at diagnosis: 0-6 years, 7-12 years, 13-18 years, 19-28 years, and 29-64 years. In each analysis, the calibration was performed by adding covariates to each model. RESULTS: Compared with the no asthma group (beta = 0), the values of beta in asthmatic subjects belonging to the age groups 0-6 years (beta = 0.794, 0.521, 0.560) and 7-12 years (beta = 0.527, 0.407, 0.437) were high in all models. CONCLUSIONS: Our findings revealed significant increase in tooth loss due to caries after early asthma diagnosis at 0-6 years (beta = 0.560, p < .001) and 7-12 years (beta = 0.437, p < .001). Clinicians need to shift their perception of dental risks in young asthmatic patients and provide active oral health care to them. PMID- 29409362 TI - Why Research Design and Methods Is So Crucial to Understanding Drug Use/Abuse: Introduction to the Special Issue. AB - The collection of articles in this special issue both raise the bar and inspire new thinking with regard to both design and methodology concerns that influence drug use/abuse research. Thematically speaking, the articles focus on issues related to missing data, response formats, strategies for data harmonization, propensity scoring methods as an alternative to randomized control trials, integrative data analysis, statistical corrections to reduce bias from attrition, challenges faced from conducting large-scale evaluations, and employing abductive theory of method as an alternative to the more traditional hypothetico-deductive reasoning. Collectively, these issues are of paramount importance as they provide specific means to improve our investigative tools and refine the logical framework we employ to examine the problem of drug use/abuse. Each of the authors addresses a specific challenge outlining how it affects our current research efforts and then outlines remedies that can advance the field. To their credit, they have included issues that affect both etiology and prevention, thus broadening our horizons as we learn more about developmental processes causally related to drug use/abuse and intervention strategies that can mitigate developmental vulnerability. This is the essential dialogue required to advance our intellectual tool kit and improve the research skills we bring to bear on the important questions facing the field of drug use/abuse. Ultimately, the goal is to increase our ability to identify the causes and consequences of drug use/abuse and find ways to ameliorate these problems as we engage the public health agenda. PMID- 29409363 TI - Comparison of clinical outcomes among dual ovarian stimulation, mild stimulation and luteal phase stimulation protocols in women with poor ovarian response. AB - This study aimed to determine whether consecutive ovarian stimulation in follicular and luteal phases within a single menstrual cycle (dual stimulation) is achievable and superior to conventional stimulation for poor ovarian responders (PORs). Data of 260 PORs were retrospectively collected and divided into three groups. Group A comprised of cycles with dual ovarian stimulation (n = 76), which were divided into two subgroups (follicular [group A-F] and luteal phase stimulation [group A-L]); group B comprised of cycles with ovarian stimulation that was performed only in the luteal phase (n = 52). Group C comprised of mild ovarian stimulation cycles (n = 132). Baseline parameters were not different among the three groups. The numbers of oocytes and embryo obtained were less in group A-F than group B and C, while group A overall had significantly more oocytes and viable embryo retrieved than did group B and C. Group A-L consumed significantly less gonadotropin than group B, without compromising the number of retrieved oocytes and embryo. The pregnancy outcomes of transfer of embryo from different stimulation phases were similar. We conclude that dual ovarian stimulation protocol is effective and potentially optimal for PORs. PMID- 29409364 TI - Graphene onto medical grade titanium: an atom-thick multimodal coating that promotes osteoblast maturation and inhibits biofilm formation from distinct species. AB - The time needed for the osseointegration of titanium implants is deemed too long. Moreover, the bacterial colonization of their surfaces is a major cause of failure. Graphene can overcome these issues but its wet transfer onto substrates employs hazardous chemicals limiting the clinical applications. Alternatively, dry transfer technique has been developed, but the biological properties of this technique remain unexplored. Here, a dry transfer technique based on a hot pressing method allowed to coat titanium substrates with high-quality graphene and coverage area >90% with a single transfer. The graphene-coated titanium is cytocompatible, did not induce cell membrane damage, induced human osteoblast maturation (gene and protein level), and increased the deposition of mineralized matrix compared to titanium alone. Moreover, graphene decreased the formation of biofilms from Streptococcus mutans, Enterococcus faecalis and even from whole saliva on titanium without killing the bacteria. These findings confirm that coating of titanium with graphene via a dry transfer technique is a promising strategy to improve osseointegration and prevent biofilm formation on implants and devices. PMID- 29409365 TI - A single session of laser ablation for toxic thyroid nodules: three-year follow up results. AB - PURPOSE: To confirm the effectiveness of laser ablation on toxic nodules in a large population with three years of follow-up. MATERIAL AND METHODS: Between 2009 and 2014, we treated 82 patients with hyperthyroidism related to the presence of a toxic nodular goitre. Patients were pre-treated pharmacologically with methimazole prior to single session of laser ablation (LA) and then followed up every 3 months with FT4 and TSH blood tests as well as ultrasound examination of the nodules treated. RESULTS: All patients responded to the treatment. The median nodule volume decreased from 12 ml (range 5-118 ml) to 5 ml (range 1.2-40 ml) after three years (p < 0.001). The percentage of patients who discontinued methimazole therapy was reduced by increasing the initial volume of the toxic nodule. In nodules with a volume less than 5 ml, all patients were able to suspend methimazole; this percentage was reduced to 90.2% in nodules with a volume between 5 and 15 ml, 61.1% in those with volume 15-25 ml and only 28.5% in nodules larger than 25 ml. We had no major complications but only moderate pain and fever in the evening, a few hours after ablation therapy in 10% of treated patients. CONCLUSIONS: Single session of LA of toxic thyroid nodules is effective and safe, especially in nodules with a volume under 15 ml. PMID- 29409366 TI - Oral shedding of HSV-1 and EBV and oral manifestations in paediatric chronic kidney disease patients and renal transplant recipients. AB - OBJECTIVE: Previous research demonstrated that salivary shedding of HSV-1 and EBV occurs often in adult renal transplant recipients, but there is a lack of studies on the presence of them in the saliva of paediatric population. Therefore, the objective of this study is to describe oral characteristics and to compare the shedding profile of HSV-1 and EBV in the saliva of children with renal transplant to that of chronic kidney disease patients and controls. METHODS: This is a cross sectional study involving 100 children, being 25 renal transplant recipients, 25 chronic kidney disease patients and 50 healthy children. Demographic and oral clinical characteristics were assessed. Saliva samples were collected and submitted to screening for EBV and HSV-1 by using nested polymerase chain reaction technique. Fisher's exact, Pearson's chi-square and Kruskal-Wallis tests were used for statistical analysis at a significance level of 5%. RESULTS: Oral shedding of HSV-1 (28%) and EBV (60%) were significantly higher in renal transplant recipients compared to the other groups. Single vesicles in the oral mucosa were statistically associated with the presence of HSV-1 (p = .035). In children with chronic kidney disease, there was a higher prevalence of pale oral mucosa (32%) and enamel hypoplasia (40%) compared to paediatric renal transplant recipients and controls. Dental calculus (36%), candidiasis (8%), drug-induced gingival overgrowth (16%), mouth blisters (8%), xerostomia (12%) and salivary gland enlargement (20%) were more common in paediatric renal transplant recipients. CONCLUSIONS: Therefore, it can be concluded that salivary shedding of HSV-1 and EBV in paediatric patients was more often found in renal transplant recipients than in the renal failure and control children. Transplanted recipients showed more oral manifestations than renal failure and control children did. PMID- 29409367 TI - Sustainability of exercise intervention outcomes among people with disabilities: a secondary review. AB - BACKGROUND: This review explored the sustainability of health and physical activity-based outcomes following exercise trials that were conducted for people with disabilities, and characterised the influence of technology and behaviour change strategies. METHODS: A total of 132 studies were screened from an existing database. RESULTS: Only 22 studies featured follow-up periods and met eligibility criteria. At follow-up, studies typically reported at least one significant health outcome that was maintained (n = 18/21; 86%). However, significant health outcomes accounted for only 32% of the total volume of outcomes that were measured at follow-up. For physical activity-based outcomes, six studies (n = 6/8; 75%) reported that intervention gains were maintained throughout follow-up. The incorporation of technology or behaviour change strategies appeared to be linked with sustainable intervention effects. CONCLUSIONS: Overall, some evidence demonstrated that post-intervention effects were sustainable. However, the strength of the evidence was weak and several existing gaps in knowledge were identified. Moreover, most studies did not focus on sustainability, but instead emphasised short-term effects of exercise participation on health and physical activity outcomes. Study findings call for greater research and programme efforts to maintain health, function, and physical activity behaviour after supports provided by research studies are removed. Implications for rehabilitation Short term exercise programmes may require additional strategies designed specifically to enhance the sustainability of exercise outcomes and physical activity participation. Incorporating technology within exercise interventions may enhance the likelihood of sustaining health and function outcomes. Exercise programmes framed within behaviour change theory can equip individuals with the appropriate strategies necessary to maintain their physical activity participation. PMID- 29409368 TI - Reference centiles for the middle cerebral artery and umbilical artery pulsatility index and cerebro-placental ratio from a low-risk population - a Generalised Additive Model for Location, Shape and Scale (GAMLSS) approach. AB - OBJECTIVE: The primary aim of this study was to create reference ranges for the fetal Middle Cerebral artery Pulsatility Index (MCA PI), Umbilical Artery Pulsatility Index (UA PI) and the Cerebro-Placental Ratio (CPR) in a clearly defined low-risk cohort using the Generalised Additive Model for Location, Shape and Scale (GAMLSS) method. METHODS: Prospectively collected cross-sectional biometry and Doppler data from low-risk women attending the Mater Mother's Hospital, Maternal and Fetal Medicine Department in Brisbane, Australia between January 2010 and April 2017 were used to derive gestation specific centiles for the MCA PI, UA PI and CPR. All ultrasound scans were performed between 18 + 0 and 41 + 6 weeks gestation with recorded data for the MCA PI and/or UA PI. The GAMLSS method was used for the calculation of gestational age-adjusted centiles. Distributions and additive terms were assessed and the final model was chosen on the basis of the Global Deviance, Akaike information criterion (AIC) and Schwartz bayesian criterion (SBC), along with the results of the model and residual diagnostics as well as visual assessment of the centiles themselves. RESULTS: Over the study period 6013 women met the inclusion criteria. The MCA PI was recorded in 4473 fetuses, the UA PI in 6008 fetuses and the CPR was able to be calculated in 4464 cases. The centiles for the MCA PI used a fractional polynomial additive term and Box-Cox t (BCT) distribution. Centiles for the UA PI used a cubic spline additive term with BCT distribution and the CPR used a fractional polynomial additive term and a BCT distribution. CONCLUSION: We have created gestational centile reference ranges for the MCA PI, UA PI and CPR from a large low-risk cohort that supports their applicability and generalisability. PMID- 29409369 TI - Adverse perinatal outcome in teenage pregnancies: an analysis of a 5-year period in Southeastern Hungary. AB - OBJECTIVE: To determine the risks of adverse perinatal outcomes of teenage mothers. MATERIAL AND METHODS: A retrospective analysis was performed on teenage mothers (under 20 years of age) who delivered in the period of 2010-2014 at the Department of Obstetrics and Gynecology, University of Szeged (study group). All mothers who delivered in Hungary during the same period were studied as a control group. The following parameters were analyzed: demographic data of the mothers, maternal complications, perinatal outcome and congenital malformations of the newborns. The binominal test, Student's t-test and Poisson's regression were applied using STATA 9.0 (StataCorp, College Station, TX, USA) statistical software (p < .05 was considered to be statistically significant). RESULTS: During this 5-year period, 12,845 births were recorded at the Department, of these 274 (2.1%) were teenage pregnancies with 275 newborns. The offsprings of teenage mothers had significantly lower mean birth weight (3110.2 +/- 564.03 g versus 3247 g), higher rate of congenital malformations (8.0 versus 5.0%) and higher admission to neonatal intensive care unit (12.4 versus 8.0%) than the infants in the control group. CONCLUSIONS: Younger maternal age was significantly associated with lower mean birth weight, higher risk of congenital malformations, and increased admission rate to neonatal intensive care unit. PMID- 29409370 TI - Clinical practice guideline for Sjogren's syndrome 2017. AB - OBJECTIVES: The objective of this study is to develop clinical practice guideline (CPG) for Sjogren's syndrome (SS) based on recently available clinical and therapeutic evidences. METHODS: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. RESULTS: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. CONCLUSION: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS. PMID- 29409371 TI - Partial cage division significantly reduces aggressive behavior in male laboratory mice. AB - Aggression in mice often results in injury leading to unplanned euthanasia or the initiation of protocols to isolate animals, thereby increasing research costs and straining resources. Here, we tested if adding a partial cage divider into existing mouse cages affected aggressive-like behavior in group-housed male mice (18 mice; 3 per cage). Mice were randomly assigned to one of two groups upon arrival to the vivarium: (1) standard cage; (2) cage with a partial cage divider. Behavioral observation over 12 hours were conducted at day one, two, and seven after receipt at the facility in order to assess aggression during the course of establishing dominance hierarchies. Observers blinded to study design and hypothesis scored each video for the number and type of aggressive behaviors, which were summed for each hour and analyzed. Results indicated a statistically significant decrease in aggressive behaviors of mice in cages with dividers compared to mice in standard cages. We conclude that cage dividers, which resemble burrows and provide access to common food/water, may promote rigorous research by reducing the number of animals used in a study and refining housing, thus, improving animal welfare. PMID- 29409372 TI - Is iguratimod effective in refractory axial spondyloarthritis? PMID- 29409373 TI - Epidemiology of primary systemic vasculitis in children: a population-based study from southern Sweden. AB - OBJECTIVES: To estimate the annual incidence rate of paediatric primary systemic vasculitis (PSV) in a defined geographical area in southern Sweden. METHODS: Potential cases of PSV [IgA vasculitis (IgAV, Henoch-Schonlein purpura), Kawasaki disease (KD), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), polyarteritis nodosa (PAN), and Takayasu's arteritis (TAK)] were identified in a comprehensive regional healthcare register. The study area is Skane, the southernmost county of Sweden (population 1.29 million; 21.4% aged <18 years). Case records for children (0-17 years) assigned a diagnosis code between M300 and M319 and/or D690 were reviewed to ascertain diagnosis. Only patients diagnosed between 2004 and 2014 were included. RESULTS: In total, 556 patients with PSV were identified. The annual incidence rate per million children (95% confidence interval) was estimated to be 200 (183-217) for all PSV, 175.5 for IgAV (160-191), 20.1 for KD (14.9-25.4), 1.4 (0-2.8) for each of GPA and MPA, 0.7 (0-1.7) for PAN, and 0.4 (0 1.1) for each of EGPA and TAK. Among children aged <10 years, 99.5% of cases were either IgAV or KD, both exhibiting a seasonal pattern paralleling infections. There were no deaths, but three cases of end-stage renal disease were noted, all in MPA. CONCLUSIONS: Vasculitis is relatively common during childhood. Mild cases associated with the infection season are most common in the youngest age groups, while during adolescence a substantial proportion has more severe forms of vasculitis. PMID- 29409375 TI - Films based on soy protein-agar blends for wound dressing: Effect of different biopolymer proportions on the drug release rate and the physical and antibacterial properties of the films. AB - No single material can provide all requirements for wound dressings. Here, we evaluated the influence of different soy protein isolate and agar proportions (3:1, 1:1, and 1:3) in blend films on some of their physical-chemical and antibacterial properties to elucidate their potential as wound dressings. The films were synthesized by the gel casting method and ciprofloxacin hydrochloride was incorporated into the films. Films were characterized based on their surface morphology, water uptake ability, and weight loss profile. Also, the ciprofloxacin hydrochloride release kinetics was quantified spectrophotometrically. The antibacterial effect was evaluated against Staphylococcus aureus and Pseudomonas aeruginosa strains. The soy protein isolate agar ratio affected the water uptake of the films and the release profile of ciprofloxacin hydrochloride but not the weight loss profile. The amount of drug released decreased near 80% because of the decrease in agar content in the films. The release kinetics of ciprofloxacin hydrochloride data best fitted to the Korsmeyer-Peppas model, suggesting that the mechanism of drug release was mainly of the diffusion type. All ciprofloxacin hydrochloride-releasing soy protein isolate-agar films strongly inhibited the cell viability of the bacterial strains studied. We concluded that water uptake and ciprofloxacin hydrochloride release can be controlled by changing the soy protein isolate-agar proportion. The proportions did not lead to changes in the antibacterial strength of the films. PMID- 29409374 TI - Selenium-loaded cellulose film derived from Styela clava tunic accelerates the healing process of cutaneous wounds in streptozotocin-induced diabetic Sprague Dawley rats. AB - PURPOSE: Aims of this study is to evaluate the therapeutic effects and toxicity of Se-loaded cellulose film originated from Styela clava tunic (SeSCTF) on cutaneous wounds during diabetic conditions. MATERIALS AND METHODS: Alterations in skin regeneration, angiogenesis and toxicity were examined using streptozotocine (STZ)-induced diabetic Sprague Dawley(r) (SD) rats with surgical skin wounds after application of SeSCTF for 12 days. RESULTS: SCTF showed high tensile strength (1.64 MPa), low elongation (28.59%), low water vapor transmission rate (WVTR) and outstanding porous structure. Although SeSCTF application did not induce any significant alterations in glucose concentration or toxicity, wound morphology was rapidly recovered in the SeSCTF treated group relative to the gauze (GZ) and SCTF treated group. Moreover, recovery of re epithelization, wound contraction and number of blood vessel was observed in SeSCTF treated groups when compared with all other groups. Furthermore, the SeSCTF treated group showed complete recovery of key protein expressions of the downstream signaling pathway of vascular endothelial growth factor (VEGF), angiopoietin-2/1 (Ang-2/1), the signaling pathway of insulin receptors and anti oxidative status. CONCLUSIONS: Overall, the results of this study suggest that SeSCTF accelerates the healing process of cutaneous wounds in STZ-induced diabetic SD rats through stimulation of angiogenesis and the glucose receptor signaling pathway. PMID- 29409376 TI - Suitability of a PLCL fibrous scaffold for soft tissue engineering applications: A combined biological and mechanical characterisation. AB - Poly(lactide-co-epsilon-caprolactone) (PLCL) has been reported to be a good candidate for tissue engineering because of its good biocompatibility. Particularly, a braided PLCL scaffold (PLL/PCL ratio = 85/15) has been recently designed and partially validated for ligament tissue engineering. In the present study, we assessed the in vivo biocompatibility of acellular and cellularised scaffolds in a rat model. We then determined its in vitro biocompatibility using stem cells issued from both bone marrow and Wharton Jelly. From a biological point of view, the scaffold was shown to be suitable for tissue engineering in all these cases. Secondly, while the initial mechanical properties of this scaffold have been previously reported to be adapted to load-bearing applications, we studied the evolution in time of the mechanical properties of PLCL fibres due to hydrolytic degradation. Results for isolated PLCL fibres were extrapolated to the fibrous scaffold using a previously developed numerical model. It was shown that no accumulation of plastic strain was to be expected for a load-bearing application such as anterior cruciate ligament tissue engineering. However, PLCL fibres exhibited a non-expected brittle behaviour after two months. This may involve a potential risk of premature failure of the scaffold, unless tissue growth compensates this change in mechanical properties. This combined study emphasises the need to characterise the properties of biomaterials in a pluridisciplinary approach, since biological and mechanical characterisations led in this case to different conclusions concerning the suitability of this scaffold for load-bearing applications. PMID- 29409379 TI - Extrinsic Compression of the Ovation Stent-Graft Following Glue Embolization for Type II Endoleak: An Unusual Complication. AB - PURPOSE: To describe a case of extrinsic compression of the Ovation stent-graft following glue embolization for type II endoleak. CASE REPORT: A 75-year-old man with a past history of ischemic heart disease and endovascular aneurysm repair with an Ovation stent-graft was admitted for treatment of type II endoleaks from the right L2 and left L4 lumbar arteries with egress via the inferior mesenteric and right L4 lumbar arteries, respectively. Successful embolization was performed via a translumbar sac puncture with a combination of coils and histoacryl glue. On final angiography severe lumen narrowing of the unsupported portion of the Ovation stent-graft was seen owing to extrinsic compression by the glue. This was successfully salvaged with percutaneous transarterial kissing balloon angioplasty. CONCLUSION: Aortic lumen narrowing caused by extrinsic compression of an Ovation stent-graft following glue embolization of type II endoleak is an unusual and potentially problematic complication. PMID- 29409377 TI - The role of artichoke leaf tincture (Cynara scolymus) in the suppression of DNA damage and atherosclerosis in rats fed an atherogenic diet. AB - CONTEXT: Polyphenols and flavonoids in artichoke leaf tincture (ALT) protect cells against oxidative damage. OBJECTIVES: We examined ALT effects on deoxyribonucleic acid (DNA) damage and lipid profiles in rat plasma and gene expression in rat aorta [haemeoxygenase-1 (HO1), haemeoxygenase-2 (HO2), NADPH oxidase 4 (NOX-4), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. MATERIALS AND METHODS: Eighteen male Wistar albino rats were divided into three groups (n = 6/group): The control group (CG) was fed with standard pellet chow for 11 weeks; the AD group was fed for a similar period of time with pellet chow supplemented with 2% cholesterol, 3% sunflower oil and 1% sodium cholate. The ADA group was fed with pellet chow (for 1 week), the atherogenic diet (see above) for the following 4 weeks and then with ALT (0.1 mL/kg body weight) and atherogenic diet for 6 weeks. According to HPLC analysis, the isolated main compounds in ALT were chlorogenic acid, caffeic acid, isoquercitrin and rutin. RESULTS: Normalized HO-1 [0.11 (0.04-0.24)] and MCP-1 [0.29 (0.21-0.47)] mRNA levels and DNA scores [12.50 (4.50-36.50)] were significantly lower in the ADA group than in the AD group [0.84 (0.35-2.51)], p = 0.021 for HO-1 [0.85 (0.61-3.45)], p = 0.047 for MCP-1 and [176.5 (66.50 221.25)], p = 0.020 for DNA scores. HO-1 mRNA was lower in the ADA group than in the CG group [0.30 (0.21-0.71), p = 0.049]. CONCLUSIONS: Supplementation with ALT limited the effects of the atherogenic diet through reduced MCP-1 expression, thereby preventing oxidative damage. PMID- 29409380 TI - Ultrasound-Guided Percutaneous Dilational Tracheostomy: A Systematic Review of Randomized Controlled Trials and Meta-Analysis. AB - INTRODUCTION: Percutaneous dilational tracheostomy (PDT) is a common and increasingly used procedure in the intensive care unit (ICU). It is usually performed with bronchoscopy guidance. Ultrasound has emerged as a useful tool in order to assist PDT, potentially improving its success rate and reducing procedural-related complications. OBJECTIVE: To investigate whether the ultrasound-guided PDT is equivalent or superior to the bronchoscopy-guided or anatomical landmarks-guided PDT with regard to procedural-related and clinical complications. METHODS: A systematic review of randomized clinical trials was conducted comparing an ultrasound-guided PDT to the control groups (either a bronchoscopy-guided PDT or an anatomical landmark-guided PDT) in patients undergoing a PDT in the ICU. The primary outcome was the incidence of major procedural-related and clinical complication rates. The secondary outcome was the incidence of minor complication rates. Random-effect meta-analyzes were used to pool the results. RESULTS: Four studies fulfilled the inclusion criteria and they were analyzed. The studies included 588 participants. There were no differences in the major complication rates between the patients who were assigned to the ultrasound-guided PDT when compared to the control groups (pooled risk ratio [RR]: 0.48; 95% confidence interval [CI]: 0.13-1.71, I2 = 0%). The minor complication rates were not different between the groups, but they had a high heterogeneity (pooled RR: 0.49; 95% CI 0.16-1.50; I2 = 85%). The sensitivity analyzes that only included the randomized controlled trials that used a landmark guided PDT as the control group showed lower rates of minor complications in the ultrasound-guided PDT group (pooled RR: 0.55; 95% CI: 0.31-0.98, I2 = 0%). CONCLUSION: The ultrasound-guided PDT seems to be safe and it is comparable to the bronchoscopy-guided PDT regarding the major and minor procedural-related or clinical complications. It also seems to reduce the minor complications when compared to the anatomical landmark-guided PDT. PMID- 29409381 TI - Moving towards novel multidisciplinary approaches for improving elderly quality of life: The emerging role of telemedicine in Sicily. AB - Introduction Elderly care is a worldwide social and economic challenge for the public health system, and it requires the development of new management strategies. Telemedicine provides an innovative approach towards elderly care, especially for those with chronic diseases. In this study, we aimed to evaluate the potential role of a multidisciplinary telemedicine approach for improving elderly quality of life. Methods Twenty-two participants received weekly vital parameter monitoring and nutritional counselling, biweekly psychological counselling and a monthly consultation with a neurologist. The neuropsychological assessment included the Mini Mental State Examination, the Activities of Daily Living, the Instrumental Activities of Daily Living, the Geriatric Depression Scale and the Short-Form Health Survey, and was administered at enrolment (T0) and at the end of the study (T3). The nutritional evaluation included haematochemical examinations of glycaemia, total cholesterol, and triglycerides at baseline (T0) and every four months (T1, T2, T3). Results Significant differences in Activities of Daily Living, Geriatric Depression Scale and all domains of the Short-Form Health Survey were observed between baseline and the end of the study. The haematochemical parameters showed obvious changes over time, especially in cholesterol values, and the patients with hypercholesterolaemia and hypertriglyceridaemia showed a reduction in body mass index. Moreover, we found that the haematochemical values were moderately correlated with the Activities of Daily Living, Geriatric Depression Scale and Short-Form Health Survey scores. Conclusion Telemedicine can be a suitable tool for caring for elderly people more efficiently by promoting the remission of depressive symptoms and improving social functioning, cognitive levels and nutritional habits to prevent vascular diseases and exacerbations of pre-existing chronic illness. PMID- 29409382 TI - Distal Placement of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to Restore Hemodynamic Stability in a Patient With Proximal Aortic Rupture. AB - PURPOSE: To report unconventional use of the resuscitative endovascular balloon occlusion of the aorta (REBOA) technique to restore hemodynamic stability in a patient who was hemorrhaging from aortic injury proximal to the target zone of occlusion. CASE REPORT: A 72-year-old woman underwent urgent thoracic stent-graft repair of a ruptured 8*8-cm mycotic pseudoaneurysm. Two months later, follow-up imaging revealed that the proximal aortic stent seal zone had degenerated, so a percutaneous procedure was performed 2 months later to preemptively reinforce the segment of stented aorta. Shortly after obtaining femoral access, the patient's condition abruptly deteriorated with profound hypotension, presumably a result of an access complication. REBOA was established in the supraceliac aorta, which sustained the mean arterial pressure while the anesthesiologist resuscitated the patient. Unexpectedly, angiography showed a rupture of the descending thoracic aorta immediately proximal to the upper stent-graft. Balloon inflation distal to the rupture site was maintained while the patient's hypotension was treated. Another stent-graft was quickly placed over the area of concern, overlapping proximal to the prior grafts. Once the aortic perforation was sealed, the patient stabilized hemodynamically. Inotropic support was weaned, and the REBOA occlusion catheter was deflated. Final angiograms of the arch and thoracic aorta confirmed no extravasation; angiograms of the infrarenal aorta and iliac arteries showed no evidence of injury. CONCLUSION: This case illustrates that applying REBOA distal to the injury site in certain clinical scenarios may sufficiently increase peripheral resistance to compensate temporarily for cardiovascular collapse secondary to aortic injury. PMID- 29409383 TI - Variance in State Protection from Exposure to NORM and TENORM Wastes Generated During Unconventional Oil and Gas Operations: Where We Are and Where We Need to Go. AB - Radioactive materials for the medical, technological, and industrial sectors have been effectively regulated in the United States since as early as 1962. The steady increase in the exploration and production of shale gas in recent years has led to concerns about exposures to Naturally Occurring Radioactive Materials (NORM) and Technologically Enhanced Naturally Occurring Radioactive Materials (TENORM) in oil and gas waste streams. This study applied policy surveillance methods to conduct a cross-sectional fifty-state survey of law and regulations of NORM and TENORM waste from oil and gas operations. Results indicated that seventeen states drafted express regulations to reduce exposure to oil and gas NORM and TENORM waste. States with active oil and gas drilling that lack regulations controlling exposure to NORM and TENORM may leave the public and workers susceptible to adverse health effects from radiation. The study concludes with recommendations in regard to regulating oil and gas NORM and TENORM waste. PMID- 29409384 TI - Circular Ribonucleic Acid Expression Alteration in Exosomes from the Brain Extracellular Space after Traumatic Brain Injury in Mice. AB - Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying TBI are unclear and may include the change in biological material in exosomes. Circular ribonucleic acids (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain. We first isolated exosomes from the brain extracellular space in mice with TBI by digestion. We then investigated the alterations in circRNA expression in exosomes by high throughput whole transcriptome sequencing, analyzed the data by gene ontology (GO) and pathway analysis, and constructed the circRNA-miRNA network. In this study, we identified 231 significantly and differentially expressed circRNAs, including 155 that were upregulated and 76 that were downregulated. GO analysis showed that these differentially expressed circRNAs might be related to the growth and repair of neurons, the development of the nervous system, and the transmission of nerve signals. The most highly correlated pathways that we identified were involved primarily with glutamatergic synapse and the cyclic guanosine monophosphate-protein kinase G signaling pathway. The circRNA-miRNA network predicted the potential roles of these differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our study broadens the horizon of research on gene regulation in exosomes from the brain extracellular space after TBI and provides novel targets for further research on both the molecular mechanisms of TBI and the potential intervention therapy targets. PMID- 29409385 TI - Evidence for increase in finger blood flow, evaluated by laser Doppler flowmetry, following iloprost infusion in patients with systemic sclerosis: a week-long observational longitudinal study. AB - OBJECTIVES: Iloprost plays an important role in the treatment of Raynaud's phenomenon (RP), but has transient vasodilatory effects owing to its very short half-time. We aimed to evaluate short- and medium-term haemodynamic effects of iloprost by measuring dorsal finger microvessel blood flow using laser Doppler flowmetry (LDF), in patients with RP associated with systemic sclerosis (SSc). METHOD: In 24 consecutive SSc patients with RP (disease duration 10.5 +/- 1.3 years), LDF with heating probes was used to measure blood flow in four fingers by occlusive and heating tests, at baseline, after 3 consecutive days of iloprost infusion, and at 24 h and 7 days after last iloprost infusion. Nailfold videocapillaroscopy (NVC) patterns of microvascular damage were investigated. Sixteen healthy controls were studied to compare baseline flows. RESULTS: Compared to controls, SSc patients showed significantly impaired axon reflex vasoregulation and nitric oxide responses at baseline (p = 0.001 and p = 0.03, respectively). After iloprost, a prompt but transient significant improvement in endothelial-dependent vasodilation (occlusive test) was seen only in SSc patients with an 'active' NVC pattern (p <= 0.05). The iloprost effects vanished within 7 days after the last infusion. No significant differences were found, in the whole study, between patients with and without digital ulcers. CONCLUSIONS: Microcirculatory blood flow increases following 3 days of iloprost infusion but fades shortly after treatment. Although iloprost is effective in reducing the severity of RP in SSc, the most suitable regimen and timing to obtain longer lasting vasodilatory benefits remain to be established. PMID- 29409386 TI - Applying user-centred research design and evidence to develop and guide the use of technologies, including robots, in aged care. PMID- 29409387 TI - Relations between emotion, memory encoding, and time perception. AB - This study examined duration judgments for taboo and neutral words in prospective and retrospective timing tasks. In the prospective task, participants attended to time from the beginning and generated shorter duration estimates for taboo than neutral words and for words that they subsequently recalled in a surprise free recall task. These findings suggested that memory encoding took priority over estimating durations, directing attention away from time and causing better recall but shorter perceived durations for taboo than neutral words. However, in the retrospective task, participants only judged durations in a surprise test at the end, and their duration estimates were longer for taboo than neutral words. Present findings therefore suggest that the same emotion-linked memory encoding processes can cause underestimation of durations in prospective tasks but overestimation in retrospective tasks, as if emotion enhances recall of ongoing events but causes overestimation of the durations of those events in retrospect. PMID- 29409388 TI - Are previous episodes of bacterial vaginosis a predictor for vaginal symptoms in breast cancer patients treated with aromatase inhibitors? AB - Objective To estimate the prevalence of vaginal symptoms in postmenopausal women with breast cancer exposed to aromatase inhibitors, and to investigate if the risk of vaginal symptoms is associated with previous episodes of bacterial vaginosis. Methods Patients from Rigshospitalet and Herlev University Hospital, Denmark, were identified through the register of Danish Breast Cancer Cooperation Group and 78 patients participated in the study. Semiquantitave questionnaires and telephone interview were used to assess the prevalence of vaginal symptoms and previous episode(s) of bacterial vaginosis. Multivariable logistic regression models were used to assess the association between vaginal symptoms and previous episodes of bacterial vaginosis. Results Moderate to severe symptoms due to vaginal itching/irritation were experienced by 6.4% (95% CI: 2.8-14.1%), vaginal dryness by 28.4% (95% CI: 19.4-39.5%), and dyspareunia by 23.1% (95% CI: 11.0 42.1%). Patients with earlier episodes of bacterial vaginosis had an increased risk of vaginal dryness when exposed to a treatment with an aromatase inhibitor, adjusted OR 5.5 (95% CI 1.3-21.6). Conclusion A considerable number of patients exposed to aromatase inhibitor have vaginal symptoms and the risk is highest among patients with earlier episodes of bacterial vaginosis. PMID- 29409389 TI - Weaning adult patients with cardiogenic shock on veno-arterial extracorporeal membrane oxygenation by pump-controlled retrograde trial off. AB - BACKGROUND: There is a lack of consensus on the timing of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) liberation. VA-ECMO weaning usually consists of serial decrements until an idling flow is achieved, supported by echocardiographic and haemodynamic assessments. Even with minimal idling flow, right ventricular (RV) preload is reduced and, hence, right heart function is not fully tested under adequate loading conditions. Following the use of a novel technique called Pump Controlled Retrograde Trial Off (PCRTO) in neonate VA-ECMO weaning, we report the use of this technique in seven adult patients on VA-ECMO. METHODS: We retrospectively reviewed all adult VA-ECMO patients treated at a tertiary teaching hospital in Hong Kong since 2010. Clinical data, including diagnosis, echocardiography findings, ECMO configuration, PCRTO settings, survival after veno-arterial ECMO (SAVE) score and outcomes, were collected. Mortality and death due to cardiac failure was compared between PCRTO and conventional weaning. RESULTS: Seven patients underwent PCRTO, with a mean SAVE score of -4.4 +/- 5.9. All seven patients were successfully decannulated without haemodynamic deterioration. In all cases, no clots or fibrin deposits were found in the circuit after the trial. There was no difference in mean SAVE scores among the seven patients in PCRTO and the 23 patients in the conventional group (-3.6, 95% CI -8.8 to 1.5). The number of deaths due to cardiac failure in the PCRTO group and the conventional group were 0 and 3, respectively (0% vs. 13%, p=0.99). Mortality after decannulation for PCRTO was 42.9% vs. conventional weaning 34.8% (p=0.99). CONCLUSION: Our study suggests that PCRTO is a simple, safe and reversible alternative weaning method. It may have a particular role in the assessment of patients who have marginal recovery and right heart failure. Prospective controlled studies are needed to establish the potential role of PCRTO in the liberation of patients from VA-ECMO support. PMID- 29409390 TI - Survival Analysis-Based Human Head Injury Risk Curves: Focus on Skull Fracture. AB - Head contact-induced loads can result in skull fractures and/or brain injuries. While skull fractures have been produced from post-mortem human cadaver surrogates (PMHS), injury probability curves describing their structural responses have not been developed. The objectives of this study were to develop skull fracture-based injury risk curves and describe human tolerances using survival analysis. Published PMHS data in this journal were used. Mean age, stature, and weight of 12 PMHS were: 66.6 +/- 2.3 years, 1.71 +/- 2.9 m, and 76.4 +/- 4.6 kg. A testing device applied contact loading to the head. Failure force, deflection, energy, and linear and secant stiffness variables were used to develop probability curves. Parametrical survival analysis included identifying most optimal distribution, ensuring that the chosen distribution is not significantly different from the nonparametrical model, determining +/-95% confidence interval bounds and Normalized Confidence Interval Sizes (NICS), obtaining quality indices for each risk curve, and determining their hierarchical sequence using the Brier score metric (BSM). Lognormal distribution was the most optimal distribution for all variables, except failure force, for which Weibull distribution was optimal. Tightness-of-fit of risk curves for failure force, energy, and deflection were better than linear and secant stiffness variables. Force best represented skull fracture response based on BSM and NCIS, followed by deflection and energy, while two stiffness variables were least preferred metrics. These structural response-based set of risk curves, hitherto not reported, form a fundamental dataset for validating/assessing accuracy of outputs from computational models and serve as hierarchical skull fracture injury criteria under head contact loads. PMID- 29409391 TI - Adverse events associated with aprepitant pediatric bone cancer patients. AB - An eight-year long case series follow-up study with pediatric bone cancer patients was conducted to compare the occurrence of adverse events associated with aprepitant with official sources of drug information (manufacturer's leaflet, clinical trials, and European Medicines Agency leaflet). All patients admitted were analyzed, representing 192 aprepitant cycles. Anorexia, febrile neutropenia, and headache were observed in frequencies over 43.8 per 100 patients, which was higher than previous estimates. Adverse events were classified as probable or possible, by using Naranjo score. The increased rates of adverse events, especially on the risk febrile neutropenia, warrant further safety studies on this population. PMID- 29409392 TI - HIV/AIDS and older adults in Cameroon: Emerging issues and implications for caregiving and policy-making. AB - The burden of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) on the elderly population in three divisions within the Northwest Region of Cameroon was examined. Data for this paper were extracted from a larger study which had been conducted concerning the burden of HIV infection and AIDS on the older adults in the Northwest Region of Cameroon. Using in-depth interviews (IDIs) and focus group discussions (FGDs), data were collected from 36 participants who were purposively selected from the three divisions which had been chosen randomly. 6 FGD sessions were held with 30 women aged 60 years and above and who were affected by HIV infection and AIDS, while IDIs sessions were held with 6 male community leaders. The results revealed that HIV infection and AIDS has added another dimension to the role of older persons. HIV infection and AIDS affects older people in diverse ways, as they have to look after themselves, their sick children and are often also left to look after their grandchildren orphaned by HIV infection and AIDS. These emerging issues in their lives make them vulnerable to health, social, economic and psychological challenges, and place a burden on them as caregivers instead of being cared for in their old age. Apart from increased direct expenditures, taking care of victims of HIV infection and AIDS requires older people to stay away from social, religious and community activities. The results showed that the loss of a child to HIV infection and AIDS affects the economic/financial well-being, participation in social/religious interactions as well as the community activities of older people participants. The implications of these findings for caregiving and social policy are discussed. PMID- 29409394 TI - Major developments in methods addressing for whom psychotherapy may work and why. AB - Significant progress has been achieved in the last decades in studying two central questions in psychotherapy research: what treatment works for which patient and why does treatment work. This paper delineates central developments in the methods used to study each of these questions. Through targeted examples, the paper discusses several phenomena and trends in psychotherapy research. Regarding the question of what works for whom, the discussion focuses on the progress from the search for one moderator to guide clinical decision-making to the search for a set of such moderators and their interactive effects, to best answer this question. To answer the question why treatment is effective, the paper reviews the progress from a single snapshot of a process variable to approaching causality, that is, temporal relationships, higher dependability, and closer attention to the dynamics of change in process variables. Finally, methodological developments made it possible to combine these two questions so as to better capture the richness and complexity of therapeutic work. Two central products of this integration are discussed and demonstrated through the case of the working alliance. Clinical or methodological significance of this article: Progress achieved in research regarding the methods used to examine which treatments work for which patients and why is reviewed, and some of the most promising paths toward personalized treatment integrating research on these two questions are suggested. PMID- 29409393 TI - Detecting stent geometry changes after venous recanalization using duplex ultrasound. AB - Background Patients with post-thrombotic syndrome due to chronic venous obstruction and resistant to conservative management can benefit from endovenous revascularization. The current study investigated the usefulness of duplex ultrasound in monitoring the stent changes over the time. Method All duplex ultrasound images of treated patients were reviewed retrospectively. The stent diameter and area during the follow-up visits have been analyzed. Result A total of 210 stents were placed in 137 limbs. Duplex ultrasound findings showed a decrease in area of stent in all patients (mean: 0.69 cm2). Reduction of stent area over the time was a predictor of stent patency (odds ratio: 0.910; confidence interval: 0.832-0.997). Conclusion Duplex ultrasound has sufficient accuracy in detection of stent changes and its patency. There is a discrepancy between diameter of the stent lumen in vitro and after deployment in all patients. Stent occlusion is related to reduction of stent lumen over the time rather than the percent of the stenosis. PMID- 29409395 TI - Like Mother, Like Child: The Influences of Maternal Attitudes and Behaviors on Weight-Related Health Behaviors in Their Children. AB - BACKGROUND: Childhood obesity has become a global health issue, yet little is known about the influence of maternal factors on children's weight-related health behaviors (dietary habits and physical activity), especially in China. The purpose of this study was to examine the influence of maternal factors on children's eating behaviors and physical activity in Chinese preschool-age children. METHOD: A cross-sectional study was utilized to describe weight-related health behaviors among preschool-aged children and identify maternal factors that are associated with children's weight-related health behaviors in China. Mothers completed questionnaires regarding family eating and activity habits, child feeding practices, and maternal self-efficacy regarding their child's health related health behaviors. RESULTS: A total of 222 mother-child dyads participated in this study. Maternal health-related behavior and attitudes regarding feeding practices and self-efficacy were associated with children's health-related behaviors, including eating behaviors and physical and sedentary activities. The influence of maternal behaviors and attitudes were domain specific. DISCUSSION: Improvement of children's health behaviors, promoting a healthy lifestyle of the mother and self-efficacy, and providing health home environment for the child are critical in obesity prevention. IMPLICATIONS FOR PRACTICE: Because children's health is critical to the health of the nation and to global development, understanding the factors related to children's health-related behaviors is an important first step toward development of tailored, culturally sensitive interventions for promoting a healthy lifestyle and preventing obesity. PMID- 29409396 TI - Analysis of Iliac Artery Geometric Properties in Fenestrated Aortic Stent Graft Rotation. AB - INTRODUCTION: A complication of fenestrated endovascular aneurysm repair is the potential for stent graft rotation during deployment causing fenestration misalignment and branch artery occlusion. The objective of this study is to demonstrate that this rotation is caused by a buildup of rotational energy as the device is delivered through the iliac arteries and to quantify iliac artery geometric properties associated with device rotation. METHODS: A retrospective clinical study was undertaken in which iliac artery geometric properties were assessed from preoperative imaging for 42 cases divided into 2 groups: 27 in the nonrotation group and 15 in the rotation group. Preoperative computed tomography scans were segmented, and the iliac artery centerlines were determined. Iliac artery tortuosity, curvature, torsion, and diameter were calculated from the centerline and the segmented vessel geometry. RESULTS: The total iliac artery net torsion was found to be higher in the rotation group compared to the nonrotation group (23.5 +/- 14.7 vs 14.6 +/- 12.8 mm-1; P = .05). No statistically significant differences were found for the mean values of tortuosity, curvature, torsion, or diameter between the 2 groups. CONCLUSION: Stent graft rotation occurred in 36% of the cases considered in this study. Cases with high iliac artery total net torsion were found to be more likely to have stent graft rotation upon deployment. This retrospective study provides a framework for prospectively studying the influence of iliac artery geometric properties on fenestrated stent graft rotation. PMID- 29409397 TI - Long-term MBR performance of polymeric membrane modified with Bismuth-BAL chelate (BisBAL). AB - An ultrafiltration membrane prepared by polyethersulfone (PES) was modified with Bismuth-BAL chelate (BisBAL) and was used in submerged membrane bioreactor system. Moreover, a control membrane reactor was also tasked to evaluate the effect of BisBAL on the membrane performance. The flux profile, transmembrane pressure, the effect of chemical treatment, cake layer formation, anti-fouling properties against extracellular polymeric substances (EPS) and soluble microbial products (SMP) were studied. The UF modified membrane demonstrated a sustained permeability, low cleaning frequency, and longer filtration time. In terms of anti-EPS and SMP accumulation, the modified membrane showed a lower membrane resistance. It can be illustrated from scanning electron microscopy and confocal laser scanning microscope images that the modified membrane had presented better properties than bare PES membrane, as it was looser and thinner. Thus, the UF membrane proved to be more efficient in terms of permeability and lifetime. PMID- 29409398 TI - Immune dysregulation in primary immune thrombocytopenia patients. AB - OBJECTIVES: To explore the immunological abnormalities in patients with primary immune thrombocytopenia (ITP), and analyze its relationship with treatment. METHODS: Proportion of different immune cell subsets were detected in the peripheral blood of 124 ITP patients at different time points and 45 normal controls by flow cytometry. The treatments included glucocorticoids, intravenous IgG as first-line treatment and second-line drugs. RESULTS: Elevated CD4/CD8 ratio and decreased the proportion of NK and CD4 + CD25 + CD127low regulatory T cells (Tregs) were found in pre-treated ITP patients than healthy controls. The newly diagnosed group had a significantly higher CD4/CD8 ratio than the relapsed group, but no differences in the proportion of B cells, NK cells and Tregs. No relationships were found between the curative effect and the pre-treated cell subsets within both the effective and ineffective groups. Furthermore, compared with the ineffective group, the effective group had higher Tregs and lower CD4/CD8 ratio post-treatment, but no significant differences in NK and B cells. CONCLUSION: ITP patients presented with a high CD4/CD8 ratio and low levels of Tregs and NK cells, suggesting that immune deregulation was involved in the pathogenesis of ITP. The pre-treated immune status of ITP patients may not be related to the curative effect. Tregs significantly increased in the effective group post-treatment, highlighting that the mechanism of restoring Tregs may be involved in the treatment of ITP. However, whether or not the targeted regulation of Tregs is an effective treatment for ITP still requires further studies. PMID- 29409400 TI - Barriers to and Methods of Help Seeking for Domestic Violence Victimization: A Comparison of Hispanic and Non-Hispanic White Women Residing in the United States. AB - This study examined strategies Hispanic and non-Hispanic White victims of domestic violence use to manage violence and leave their relationships. Participants ( N = 76, 41% Hispanic) completed self-report questionnaires and a semistructured interview with a language-congruent research assistant. Hispanics reported child care needs and fears of social embarrassment as barriers to leaving, while non-Hispanic Whites reported fewer social supports as a barrier. Hispanics were more likely to use legal resources for help, while non-Hispanic Whites used more informal resources. Recognizing unique barriers to leaving abusive relationships and accessing help can guide service providers and others to target vulnerable populations more effectively. PMID- 29409399 TI - The implications of women's activity limitations and role disruptions during breast cancer survivorship. AB - Early survivorship is a time of critical transition for women survivors of breast cancer as they attempt to resume functional activities and important life roles. This study aimed to explore the challenges of women and their partners as they attempted to resume activities and roles, identify unmet needs and make recommendations regarding a suitable framework to support women and partners to recommence valued activities and important roles during early survivorship. Qualitative methods utilising in-depth interviews of women (n = 18) and their partners (n = 8), and two focus groups (n = 10) were completed in Perth, Western Australia, between June 2014 and April 2015. These methods were used to facilitate women and partners' views regarding the resumption of previously meaningful activities and important life roles during early survivorship. Questions addressed their individual and shared experiences concerning self-care, leisure, social and productive activities and important roles. Thematic analysis was employed to determine themes. Women and partners reported significant impact on their ability to engage in valued activities, resulting in changes to participation in meaningful roles. Three themes were determined: (1) ambiguity regarding survivorship prevents resumption of activities and previous roles, (2) breast cancer continues to impact a couples' relationship during survivorship, and (3) support is needed to assist women and partners to resume activities and important roles. This research provides evidence suggesting that the ongoing symptoms of breast cancer treatment continue to impact many women and their partners, as they attempt to resume functional activities and important life roles during early survivorship. Disruption to these valued activities and roles may influence women and their partner's health and well-being during early survivorship and extend beyond this period. Rehabilitation following cessation of treatment could be offered as required to facilitate access to multi-disciplinary services and supports for both individuals and couples. PMID- 29409401 TI - A review: Motor rehabilitation after stroke with control based on human intent. AB - Strokes are a leading cause of acquired disability worldwide, and there is a significant need for novel interventions and further research to facilitate functional motor recovery in stroke patients. This article reviews motor rehabilitation methods for stroke survivors with a focus on rehabilitation controlled by human motor intent. The review begins with the neurodevelopmental principles of motor rehabilitation that provide the neuroscientific basis for intuitively controlled rehabilitation, followed by a review of methods allowing human motor intent detection, biofeedback approaches, and quantitative motor rehabilitation assessment. Challenges for future advances in motor rehabilitation after stroke using intuitively controlled approaches are addressed. PMID- 29409402 TI - Exploring Fatal and Non-Fatal Violence Against Parents: Challenging the Orthodoxy of Abused Adolescent Perpetrators. AB - An examination of scholarly literature concerning fatal violence (i.e., parricide) and non-fatal violence toward parents reveals dominant themes of mental illness, child abuse, and pathology based on a research paradigm that focuses on adolescent perpetrators and, to a lesser extent, elderly victims. This article presents a critical analysis of this literature and argues for a more contextualized approach to the study of violence against parents. It is argued that criminologists should widen their methodological lens to examine this issue from a life course perspective and draw on conceptual tools such as developmental pathways, sources of conflict, and intersectionality to allow for an analysis that can offer new ways of thinking about violence toward parents. PMID- 29409403 TI - Exploring Differences in Criminogenic Risk Factors and Criminal Behavior Between Young Adult Violent Offenders With and Without Mild to Borderline Intellectual Disability. AB - The relation between mild to borderline intellectual disability (MBID) and violent offense behavior was studied among a group of former juvenile delinquents currently in a diversion program for persistent young adult violent offenders from Amsterdam ( N = 146). Offenders were considered MBID if they had received juvenile probation from the local youth care agency specialized in intellectual disability (21%). A file study was used to estimate prevalence rates of criminogenic risk factors. Police data were used to depict recent criminal behavior. Nearly all offenders grew up in large and unstable multi-problem households and had psychosocial problems. More MBID offenders displayed externalizing behavior before the age of 12, were susceptible to peer pressure, and had low social-relational skills. MBID offenders committed more violent property crimes than offenders without MBID. Youth care interventions for MBID offenders should focus on the acquisition of social-relational skills and on the pedagogical skills of parents. PMID- 29409404 TI - Infant sitting postural control appears robust across changes in surface context. AB - AIM OF THE STUDY: Independent sitting requires the control of the involved body segments over the base of support using information obtained from the three sensory systems (visual, vestibular, and somatosensory). The contribution of somatosensory information in infant sitting has not been explored. To address this gap, we altered the context of the sitting support surface and examined the infants' immediate postural responses. MATERIALS AND METHODS: Ten 7-month-old typically developing infants sat on compliant and firm surfaces in one session. Spatial, frequency, and temporal measures of postural control were obtained using center of pressure data. Results Our results suggest that infants' postural sway is not immediately affected by the different types of foam surface while sitting. CONCLUSIONS: It seems that mature sitter infants are able to adapt to different environmental constraints by disregarding the distorted somatosensory information from the support surface and relying more on their remaining senses (visual and vestibular) to control their sitting posture. PMID- 29409405 TI - Complex Regional Pain Syndrome Type 1: Diagnosis and Management. AB - Diagnosis of Complex regional pain syndrome (CRPS) is made primarily on a clinical basis, and no specific test is known to confirm or exclude CRPS diagnosis. That is, there aren't specific diagnostic tools and instrumental tests are made only for identifying an etiology at the basis of the CRPS. Numerous therapeutic methods have been introduced, but none have shown definitive results. When symptoms persist, patients experience permanent impairment and disability. Therefore, early recognition of CRPS, along with proper treatment, is important for minimizing permanent loss of function. As there is no gold standard test for CRPS, several clinical diagnostic criteria have been introduced and applied in various studies. However, to date, no formal or standardized diagnostic criteria for CRPS have been widely accepted. However, the Budapest diagnostic criteria have recently increased in popularity and are frequently used in scientific studies. The goal for management of CRPS is the return of normal limb function. No specific technique has been shown to prevent CRPS following surgery, but avoidance of prolonged immobilization may be important. Therefore, initiating early post-surgical rehabilitation, where possible, is important. A multidisciplinary approach would seem to be optimal, above all things objectives of physical and occupational therapy are fulfilled with combination pharmacotherapy due to provide pain relief to facilitate physical rehabilitation. Future research using large randomized controlled trials should focus on collecting strong evidence for the etiology of CRPS, testing pharmacological effects, and determining appropriate combination treatment strategies. PMID- 29409406 TI - The Bilobed Racquet Flap or Extended Seagull Flap for Thumb Reconstruction: A Case Report. AB - The treatment of extensive soft tissue defects in the thumb with dorsal metacarpal artery flaps has been previously reported in the literature. Island flaps from the dorsum of the index and long fingers have been the subject of many reports and studies. However, when the defect involves the whole thumb, a 360 degrees circumferential defect, standard first or second dorsal metacarpal artery flaps are usually insufficient. There are fewer reports on the use of bilobed flaps for this application and we have found no reports on the use of bilobed racquet flaps or extended seagull flaps as treatment for this condition. We report the salvage of a thumb degloving injury with use of a bilobed racquet flap. PMID- 29409407 TI - Complications of Intramedullary Fixation for Distal Radius Fractures in Elderly Patients: A Retrospective Analysis Using McKay's Complication Checklist. AB - BACKGROUND: Intramedullary fixation for distal radius fractures is reported to be free of hardware irritation and less invasive than other fixation methods. Some specific complications associated with intramedullary fixation, such as radial nerve sensory neuritis, have been reported, but no study has focused on the complication rates of intramedullary fixation for distal radius fractures in the elderly population. Furthermore, no studies have analyzed common complications, such as carpal tunnel syndrome and flexor tenosynovitis including trigger finger, among patients with distal radius fractures treated by intramedullary fixation based on a comprehensive complication checklist. METHODS: We reviewed the medical records of 52 elderly patients with distal radius fractures treated with intramedullary nail fixation. We investigated the postoperative complications in these patients using McKay's complication checklist. RESULTS: 5 patients experienced radial nerve sensory disorder, and one patients developed carpal tunnel syndrome. All neurological symptoms resolved spontaneously, and these neurological complications were categorized as mild. Further, 3 patients developed trigger finger at the A1 pulley and needed triamcinolone injections for symptomatic relief. There were no tendinous complications around the implanted hardware. All tendinous complications were categorized as moderate complications and resolved with steroid injection therapy. Among skeletal complications, 1 case of postoperative volar displacement resolved with good functional outcome without the need for corrective osteotomy. This was considered a mild complication. The total complication rate was 19.2%. All complications were categorized as mild or moderate, and no patients experienced severe complications that needed further surgery such as hardware removal. CONCLUSIONS: Intramedullary fixation for distal radius fractures was free from tendinous complications such as tenosynovitis and tendon ruptures around the implant, which are frequently caused by volar locking plate fixation. However, this less invasive technique could not avoid common complications such as trigger finger and carpal tunnel syndrome associated with distal radius fractures. PMID- 29409408 TI - Superficial Ulnar Artery Crossing Over the Palmaris Longus Tendon at the Wrist in a Cadaver: A Case Report. AB - Superficial ulnar artery (SUA) is defined as arterial variation of an ulnar artery of high origin that lies superficially in the forearm. Because an SUA may be mistaken for a superficial vein, there is a risk of arterial damage. During routine dissection of the cadaver, we incidentally detected a case of unilateral SUA in the left arm. SUA arose from the axillary artery and descended superficial to the axillary artery and median nerve. At the wrist, the SUA crossed over palmaris longus (PL) tendon from the radial side to the ulnar side. In this cadaver, the PL tendon was located on the ulnar side and was thicker than the flexor carpi radialis tendon. Clinicians should check for the presence of SUA before any technical procedure, because lack of awareness of its presence can have serious consequences. PMID- 29409409 TI - Use of Computed Tomography in Determining the Occurrence of Dorsal and Intra articular Screw Penetration in Volar Locking Plate Osteosynthesis of Distal Radius Fracture. AB - BACKGROUND: The use of volar locking plate in distal radius fracture can lead to extensor tendon rupture due to dorsal screw penetration. The aim of our study was to investigate the occurrence of dorsal and intra-articular screw penetration using CT scan after volar distal radius osteosynthesis for distal radius fractures. METHODS: Thirty patients who underwent distal volar locking plate for distal radius fracture were included in a retrospective study. In all 30 patients no dorsal and intra-articular screw penetration were detected on standard AP and lateral views of a plain radiograph. CT scan of the operated wrist was performed to determine the number of intra-articular and dorsal screw penetrations. Clinical examination was performed to determine the wrist functions in comparison to the normal wrist. RESULTS: Nineteen wrists were noted to have screw penetration either dorsally or intraarticularly. The highest incidence is in the 2nd extensor compartment where 13 screws had penetrated with a mean of 2.46 mm. Six screws penetrated into the distal radial ulnar joint and five screws into the wrist joint with a mean of 2.83 mm and 2.6 mm, respectively. However, there was no incidence of tendon irritation or rupture. CONCLUSIONS: This study demonstrated a high incidence of dorsal and intra-articular screw penetration detected by CT scan which was not apparent in plain radiograph. We recommend that surgeons adhere to the principle of only near cortex fixation and downsizing the locking screw length by 2 mm. PMID- 29409410 TI - Are Carpal Tunnel Syndrome and Regional Degenerative Osteoarthritis Linked? Results of a Case-Control Study. AB - BACKGROUND: Causality has not been formally demonstrated between carpal tunnel syndrome and osteoarthritis of the wrist or at the base of the thumb. The purpose of this study was to assess the relationship between carpal tunnel syndrome and concomitant degenerative osteoarthritis of the wrist or basal thumb joint. We hypothesised that wrist osteoarthritis by reducing the free volume of the carpal tunnel would be associated with carpal tunnel syndrome, while basal thumb osteoarthritis would show no direct correlation with carpal tunnel syndrome. METHODS: A case-control study including 95 cases and 99 control subjects, has been carried out. Sixty-eight per group were matched for age and sex. Posterior anterior and lateral plain wrist radiographs for the two matched groups were analysed. RESULTS: Except for scaphotrapeziotrapezoid location, degenerative osteoarthritis of the wrist was significantly linked with carpal tunnel syndrome, whereas there was no significant difference between case and control groups for prevalence of basal osteoarthritis of the thumb. CONCLUSIONS: These results suggest that basal osteoarthritis of the thumb is not a causal factor in carpal tunnel syndrome. In contrast, degenerative osteoarthritis of the wrist was strongly associated with carpal tunnel syndrome, suggesting a causal relation. PMID- 29409411 TI - Irreducible Volar Rotatory Subluxation of the Proximal Interphalangeal Joint of the Finger. AB - We describe 4 cases of irreducible volar rotatory subluxation of the proximal interphalangeal (PIP) joint of the finger that required open reduction. All of the patients had radiographically proven (in lateral-view radiographs) volar rotatory subluxation of the PIP joint, without fracture. The causes of irreducibility were interposition of the lateral band about the condyle of the middle phalanx in 2 cases, interposition of the collateral ligament in 1 case, and scarring of the injured central slip in 1 case. Rupture of the collateral ligament of one side was found in all cases. Acceptable results were provided with all cases after restoration of the collateral ligaments and the damaged parts. Accurate early diagnosis by careful physical examination and obtaining true lateral radiographs of the PIP joint is important. PMID- 29409412 TI - Metacarpophalangeal Joint Arthroplasty Using Flexible Hinge Toe Implant with Grommets for Boutonniere Deformity of Rheumatoid Thumb. AB - BACKGROUND: MP joint arthroplasty is one of the treatment options for the rheumatoid thumb with boutonniere deformity. The use of flexible hinge toe implant for MP joint reconstruction was introduced; however, the outcome of flexible toe implantation for the reconstruction of the MP joint has not as yet been reported in detail. Therefore, in this study, we retrospectively investigated the clinical outcome and radiological findings. METHODS: We assessed 56 Swanson implant arthroplasties that used flexible hinge toe implants with grommets to address boutonniere deformity of the thumb MP joint. The minimum follow-up period was 6 months. Pain, the range of motion, grip strength, pinch strength, General health Visual analogue scale and DASH (Disabilities of Hand, Shoulder and Hand) were assessed. RESULTS: For most of the patients, the procedure provided painless motion and stability to the thumb. In the radiological assessments, the preoperative flexion angles at the MP joint were 45 degrees improved to 17 degrees . The origin of arc was shifted toward the extended position and the average arc of motion was 21 degrees , with a flexion arc from 23 degrees to 44 degrees . The severity of boutonniere deformity was improved in most cases. The average grip strength changed from 110 to 121 mmHg and the average side pinch power changed from 1.5 to 2.2 kgf. General health VAS improved from 40 to 29 (p = 0.019), and the DAS28-CRP decreased from 3.3 to 2.4 (p < 0.001). Infection occurred in one case, and there were no implant fractures. CONCLUSIONS: Swanson flexible hinge toe implant arthroplasty with grommets applied to the MP joint of the thumb was one of the recommended procedures for the reconstruction of boutonniere deformity of the thumb. PMID- 29409413 TI - "Silent Ruptures" of the Flexor Digitorum Profundus of the Little Finger due to Pisotriquetral Arthroses. AB - Asymptomatic pisotriquetral arthroses caused ruptures of the flexor digitorum profundus tendon of the little finger in 2 elderly patients. Ruptures occurred with unnoticeable onset, and bilateral ruptures separately occurred with interval of several years in one patient. The tendon was ruptured in zone IV with perforation of the gliding floor through which the degenerative pisiform was visible. The gliding floor was repaired followed with excision of the pisiform, and the ruptured tendon was then transferred to the profundus tendon of the ring finger. Asymptomatic pisotriquetral arthrosis in old age can be an aspect of the pathological background of flexor tendon ruptures of the little finger that occur unnoticed. PMID- 29409414 TI - Postoperative Infection Related with the Total Elbow Arthroplasty (Kudo's Prosthesis) in Rheumatoid Arthritis. AB - BACKGROUND: Total Elbow Arthroplasty (TEA) for the rheumatoid arthritis (RA) has been popularized since 1980s. The outcomes of TEA using any type of implant design for RA has been satisfactory. On the other hand, many orthopedicians experience several postoperative complications. Among them, postoperative infection has still being the most troublesome and difficult to treat. This study is to clarify the causes of postoperative infection of TEA using Kudo's prosthesis for RA and discuss how to manage and prevent infection. METHODS: 421 TEAs were performed for 405 cases with RA at the authors' institute during the period between 1982 and 2007. They were followed up for 1~25 years (Av. 12.3 years). The authors examined pain, the range of motion, roentgenograms and complications postoperatively. We were able to start treatment within 4 weeks after occurrence of infection. For surgical management of infected TEAs, debridement of the synovium and removal of the prosthesis with loosening were performed for all cases. In addition, all cases have been regularly and strictly followed-up with the elbow protector to prevent recurrence of infection since 2008. RESULTS: There were 98 TEAs with the postoperative complications (23.3%). Eight out of 98 TEAs were infected (1.9%). Five of eight infected TEAs were primarily at the surgical scar site infection (SSSI) (60%), unknown causes in two, hematogenous course in 1. It's obvious that surgical scar site infection (SSSI) was the leading cause of postoperative infection in this study. Thus, the authors made the elbow proctor to avoid injuries of the skin around surgical scar site (SSS). Since 2008, all of the TEAs and revised TEAs have been applied with this protector. CONCLUSIONS: The authors reported 8 infected TEAs: 5 cases were revised, 2 with the brace, 1 had above the elbow amputated. The regular and meticulous follow up and application of the elbow protector were useful to prevent infection of post-TEAs using Kudo's prosthesis in RA. Since 2008, there have been no infection of post TEAs and revised TEAs. PMID- 29409415 TI - Cylinder-Shaped Bone Graft for Scaphoid Nonunion. AB - BACKGROUND: Wedge-shaped bone grafts that are internally fixed by a Herbert-type screw are a well-established surgical treatment for scaphoid nonunion. A procedure using cylinder-shaped bone grafts was also reported, but preoperative wrist functions were not assessed. In addition, it was not reported whether the humpback deformity of the scaphoid nonunion was corrected. The purpose of the current study was to compare preoperative wrist functions in cases of scaphoid nonunion with those observed at final follow-up, using cylinder-shaped bone grafts The humpback deformity of the scaphoid nonunion was also evaluated. METHODS: We conducted a retrospective study to examine operative outcomes from 2008 to 2015. Twelve wrists in 12 patients (average age, 41 years; range, 17-67), with a mean follow-up of 19 months, were included in the current study. Cylinder shaped bone grafts were obtained from the iliac crest with a newly designed trephine and fixed with a Herbert-type screw. We reviewed both the preoperative wrist functions and those obtained at final follow-up. RESULTS: Union was achieved in 11 of 12 nonunion cases. Preoperative wrist functions, except for the range of wrist motion, significantly improved by final follow-up. CONCLUSIONS: We conclude that the use of cylinder-shaped bone grafts improves preoperative wrist functions in cases of scaphoid nonunion. PMID- 29409416 TI - Attrition of the Extensor Tendon of the Index Finger Following an Avulsion Fracture of the Third Metacarpal. AB - We report an avulsion fracture at the base of the third metacarpal involving the extensor carpi radialis brevis insertion and a resulting complication of attritional rupture of the extensor indicis proprius tendon and the extensor digitorum communis to the index finger, in a 67-year-old man. PMID- 29409417 TI - The Hand Surgeon Consultation Improves Patient Knowledge in a Hand Surgery Mission to Honduras. AB - BACKGROUND: The purpose of this study was to assess impact of the surgeon consultation and informed consent process on patient education in an international hand surgery mission compared with a US academic hand surgery practice. These two groups were selected to evaluate communication difficulties in a surgical mission setting compared with standard of care in a high-income country. METHODS: A multi-part survey was administered to patients presenting to a hand surgery mission during March 2012 and new patients of a university hand center in a 3-month period during 2011. Surveys were administered prior to and following surgeon consultation with one fellowship-trained hand surgeon. The survey assessed knowledge of basic hand anatomy, physiology, disease, individual diagnosis, and surgical risks. RESULTS: 71 patients participated in the study (university n=36, mission n=35). Pre-consultation quiz score averaged 58% in the university group versus 27% in the mission group. Post-consultation quiz scores averaged 62% in the university group versus 40% in the mission group. Only the mission group's quiz score increase was statistically significant. 93% of the university group reported learning about their condition and diagnosis, but only 40% demonstrated correct insight into their diagnosis. In the mission group, 73% reported learning about their condition and diagnosis while 53% demonstrated correct insight into their diagnosis. Although all consultations involved discussion of surgical risks, only 62% of the university group and 52% of the mission group recalled discussing surgical risks. CONCLUSIONS: The hand surgeon consultation was more effective in improving hand knowledge in the surgery mission group compared to in a university hand practice. This suggests that the surgeon consultation should be pursued despite communication barriers in surgical missions. However, the discrepancy between patient perception of knowledge gains and correct insight into diagnosis, and the deficit of patient retention of surgical risks need to be improved. PMID- 29409418 TI - Soft-Tissue Distraction Prior to Single Bone Forearm Surgery in Ulnar Longitudinal Deficiency: A Report of Two Cases. AB - Ulnar longitudinal deficiency (ULD) is a rare congenital disease of the upper limb. The deformities caused by ULD can be very challenging and may compromise hand function during daily activities. Although the first surgical intervention dates back to the year 1952 there is still no gold standard for treating this uncommon disorder. Two children aged 16 and 3 years with ULD Bayne Type II (partial ulna aplasia) were diagnosed and treated at our department with single bone forearm surgery to achieve stability and improve function using a modified surgical method. For the purpose of an additional gain in limb length and improved cosmesis we used an Ilizarov external fixator for soft tissue distraction including radius distalization prior to the creation of the single bone forearm. This new technique and results are presented and discussed. PMID- 29409419 TI - Endoscopic Trigger Finger Release: Surgical Technique. AB - Numerous surgical approaches have been described for treating patients suffering with stenosing tenosynovitis. The usual surgical descriptions differ mainly by the type of skin incision utilized. The goal of surgery is to completely release the A1 pulley, thereby allowing unimpeded motion of the flexor tendons. We describe a minimally invasive endoscopic technique to address this condition in the fingers. PMID- 29409420 TI - Failed Reconstruction of the Extensor Pollicis Longus in a Patient with a Major Variation of the Extensor Indicis Proprius Tendon: A Case Report. AB - Tendon transfer with extensor indicis proprius (EIP) has been performed widely for reconstructing ruptures of the extensor pollicis longus because of its simplicity and clinical outcome. We experienced a rerupture of the extensor pollicis longus restored by incorrect tendon transfer because of a major unrecognized variation in the anatomy of the EIP. Surgeons should perform such transfer with a detailed knowledge of the possible anatomical variations to avoid such serious complications. PMID- 29409421 TI - Treatment of Hand Allodynia Resulting from Wrist Cutting with Radial and Ulnar Artery Perforator Adipofascial Flaps. AB - In this article, we report two cases in which recurrent adhesive hand neuropathy with allodynia were successfully treated with radial and ulnar artery adipofascial perforator flap coverage. Treatment of recurrent neuropathy, such as recurrent carpal tunnel syndrome and re-adhesion after neurolysis using free and pedicle flaps to cover the nerves, has been reported to show good results. However, for severe painful nerve disorders, such as complex regional pain syndrome, the efficacy of this treatment was unclear. We present two cases diagnosed with recurrent adhesive hand neuropathy with allodynia, resulting from wrist cutting; these cases were treated with neurolysis and flap coverage with good results and no recurrence. This suggests that neurolysis and flap coverage are effective methods for treating complex regional pain syndrome. PMID- 29409422 TI - Results of the Volar Approach in Proximal Interphalangeal Joint Arthroplasty. AB - BACKGROUND: Most hand surgeons use a dorsal approach for proximal interphalangeal (PIP) joint implant arthroplasty. However, a volar approach offers the advantage of no disturbance to the extensor mechanism, thus allowing early initiation of active range of motion. We examined our results in patients who underwent PIP joint arthroplasty via a volar approach. METHODS: Using a retrospective chart review, we evaluated the outcomes of patients undergoing PIP joint arthroplasty through a volar approach between 2001 and 2005 by 3 fellowship-trained hand surgeons at our institution. The indication for surgery was PIP joint pain with radiographic evidence of joint destruction. Variables included implant type, diagnosis, affected digit(s), preoperative and postoperative range of motion, and complications. Hand therapy was initiated on postoperative day 3 or 4. RESULTS: Over the 5 years, 25 PIP joints were replaced in 18 women and 2 men with the volar approach. Replacements consisted of 14 surface replacement prostheses, 9 pyrocarbon prostheses, and 2 silicone prostheses. The average age of patients at prosthesis implantation was 64 years (range, 39-75 years). Prostheses were placed in 1 index, 12 long, 7 ring, and 5 small digits. Average follow-up period was 33 months (range, 24-69 months). Preoperative diagnoses were osteoarthritis (14), rheumatoid arthritis (4), and posttraumatic arthritis (2). Preoperative total arc of motion averaged 42 degrees (range, 0 degrees extension to 80 degrees flexion); postoperative total arc of motion averaged 56 degrees (range, -10 degrees extension to 90 degrees flexion). Complications comprised 1 swan neck deformity, 1 deep infection, 1 dislocation (early), and 2 loose implants with flexion contractures. Seventeen patients had minimal or no pain at their last follow-up visit. CONCLUSIONS: PIP joint arthroplasty can be successfully implemented through a volar approach with various implant types and has outcomes similiar to the published results of the dorsal approach. PMID- 29409423 TI - Isolated Salter-Harris Type III Physeal Fracture of the Distal Ulna. AB - We describe a case of isolated physeal fracture of ulna distal end in a 13-year old boy. This fracture type is uncommon, especially Salter-Harris type III of this injury has not been reported. Plain radiographs showed a small vertical fracture line at the ulnar distal end and an enlargement of epiphyseal plate at the base of ulnar styloid process. The present case was successfully managed with conservative treatment because of its minimal displacement. PMID- 29409424 TI - Subcutaneous and Intramuscular Injection of Petrol (Hydrocarbon): A Case Report and Review of the Literature. AB - Deliberate injection of hydrocarbon remains an uncommon method of self harm. There is a paucity of information pertaining to soft tissue toxicity throughout the literature. Prompt recognition of the potential ramifications is needed to try salvage limb function. Hydrocarbon toxicity can result in multi organ failure. This case report demonstrates the recommended diagnostic approach, work up and treatment involved in such a case. A 26 year old male deliberately injected petrol into the anterior compartment of his non dominant forearm in a suicide attempt. Multidisciplinary involvement from surgeons, psychiatrists and hand therapists was needed to maximize functional outcome. He avoided systemic toxicity but required an urgent fasciotomy. He required significant follow up with hand therapy to regain usage of the limb. However his long term outcomes were poor with a power grading 3/5 in the anterior compartment muscles. PMID- 29409425 TI - A Median Nerve Anterior Transposition Procedure for Multi-Recurrent Hemodialysis Related Carpal Tunnel Syndrome. AB - BACKGROUND: Some long-term hemodialysis patients suffer from multi-recurrent carpal tunnel syndrome because amyloid originating from beta2-microglobulin continues to be deposited mainly in the flexor tendons, tendon sheaths and flexor retinaculum during maintenance hemodialysis. These amyloid deposits inside carpal canal (tunnel) tissues increase carpal canal pressure and this leads to compression of the median nerve. When multi-recurrent carpal tunnel syndrome occurs, previous operative scarring of soft tissue may prohibit further enlargement of the carpal canal even if any carpal canal decompression procedure is used. For this reason, we developed a median nerve anterior transposition procedure, as a new approach in the treatment of multi-recurrent hemodialysis related carpal tunnel syndrome. METHODS: Median nerve anterior transposition procedures were performed on seven hands in six patients with multi-recurrent carpal tunnel syndrome. The mean age of the patients was 68.3 years and the mean hemodialysis duration was 35.3 years. Mean follow-up period was 9.9 months. The median nerve is transposed from inside to outside of the carpal canal under local and infiltration anesthesia without a pneumatic tourniquet on an outpatient basis. This procedure is based on the same principles applied in ulnar nerve anterior transposition procedures for cubital tunnel syndrome. RESULTS: Main preoperative patient complaints were intolerable tingling and/or pain in the diseased hands throughout the day. Following the surgeries, preoperative clinical symptoms began to subside and eventually improved in all hands. Postoperative abductor pollicis brevis muscle power using manual muscle testing improved except in one hand. Abnormal preoperative distal motor and sensory latency were improved except in two hands following the surgeries. CONCLUSIONS: The median nerve anterior transposition procedure is a beneficial treatment for patients suffering from hemodialysis-related multi-recurrent carpal tunnel syndrome. PMID- 29409426 TI - Ex-vivo Tendon Repair Augmented with Bone Marrow Derived Mesenchymal Stem Cells Stimulated with Myostatin for Tenogenesis. AB - BACKGROUND: To investigate the effect of myostatin (GDF-8) stimulation of bone marrow derived mesenchymal stem cells (BMSCs) on tenogenesis in the setting of tendon repair. GDF-8 has demonstrated the ability to augment tenogenesis and we sought to identify if this effect could lead to the focused differentiation of pluripotential stem cells down a tenocyte lineage ex vivo. METHODS: Cadaveric upper limb flexor tendons were harvested, decellularized and divided into 1 cm segments. Sutures seeded with stem cells were passed through tendon segments to simulate repair. The repaired tendons were then cultured either with or without myostatin for 3, 5, and 7 days. The experiment was also repeated with non decellularized tendons for a total of 4 groups. The tendons were then evaluated for the expression of scleraxis and tenomodulin, two biomarkers for tendon. RESULTS: Myostatin stimulation led to an increase in expression of tenomodulin and scleraxis at 5 and 7 days in both the decellularized and non-decellularized tendons. Myostatin increased the differentiation of BMSCs into tenocytes and/or led to the upregulation of tenomodulin and scleraxis production by the native tenocytes present within the non-decellularized tendons. CONCLUSIONS: The addition of myostatin to BMSCs leads to tenocyte differentiation as evidenced by the expression of tenocyte biomarkers, scleraxis and tenomodulin. This effect is maintained in an ex vivo tendon repair model suggestive that these cells survive the passage through tendon tissue and remain metabolically active. PMID- 29409427 TI - The Role of the Muscle Brachioradialis in Elbow Flexion: An Electromyographic Study. AB - BACKGROUND: In the classical conception, the brachioradialis is a forearm supinator. The hypothesis of this study was that, at least in certain positions of elbow flexion and forearm rotation, the brachioradialis is, along with the biceps and brachialis, one of the main elbow flexors. METHODS: Fifteen young healthy male volunteers participated in this research. The activities of the biceps, brachialis and brachioradialis muscles were studied using surface electromyography, while the subjects were performing elbow flexions/extensions with as much strength as possible, forearm in neutral position, then in full pronation, then in full supination. The elbow flexion torques were isokinetically measured at 60 degrees /sec for an arc of 120 degrees . RESULTS: The biceps, brachialis and brachioradialis muscles were electromyographically very active throughout resisted elbow flexion, in all three investigated positions of forearm rotation. At certain positions, the electromyographic activities were much higher than the maximal voluntary contraction signal. For what concerns specifically the brachioradialis, in all three forearm rotation investigated positions, the activity curve demonstrated a slow increase during the first part of elbow flexion, reaching in 73.3% of subjects its peak at the end of flexion; in the remaining 26.7%, the brachioradialis had a flat activity without significant peak. The activity was slightly higher in supination. CONCLUSIONS: This study indirectly supports the idea that the brachioradialis is one of the main elbow flexors, especially when the elbow flexion is done with the forearm in supination. This observation could be important in clinical elbow and wrist surgical practice. PMID- 29409428 TI - Pyrolytic Carbon Hemiarthroplasty for Avascular Necrosis of the Metacarpal Head: A Case Report. AB - Avascular necrosis of the metacarpal head is a rare entity. Surgical interventions, such as curettage, bone-grafting, and osteotomy, have been reported in symptomatic patients. We present a patient who underwent pyrolytic carbon hemiarthroplasty of the metacarpal head and had satisfactory outcomes at 1 year follow-up. PMID- 29409429 TI - A Prospective Study of Acute Undisplaced and Minimally Displaced Scaphoid Fractures Managed by Aggressive Conservative Approach. AB - BACKGROUND: To identify acute un-displaced and minimally displaced scaphoid fractures which are unlikely to unite with non-operative treatment at six weeks with CT scan and stabilize them with percutaneous screw fixation with the aim of preventing non-union. METHODS: A scaphoid series radiographs of wrist were obtained for patients with undisplaced or minimally displaced fractures and were immobilized in a thumb spica cast for six weeks. At six weeks, CT scan was done for patients showing doubtful signs of clinical and radiographic union. Patients with a gap less than 2 mm were continued on cast for an additional two to four weeks. Those with gap more than 2 mm underwent percutaneous screw fixation. In both cases the immobilisation was discontinued when the fracture was considered to be united and mobilization was initiated. RESULTS: 21 out of 39 patients managed initially with cast for six weeks showed clinical and radiological evidence of union. 18 patients showed persistent tenderness of which eight showed a clear gap in radiographs and 10 patients had doubtful union. Eight of these 10 patients on CT scan showed fracture gap of more than 2 mm while two patients showed fracture gap of less than 2 mm. Hence, 16 patients underwent percutaneous fixation. Repeat radiographs showed progression to union at an average of 3.8 weeks from surgery. Remaining two eventually united on continuing the cast. All patients showed confirmed union at one year on follow up. CONCLUSIONS: An objective measurement of fracture gap by CT scan at six weeks is useful in predicting cases with tendency for delayed union. Early percutaneous fixation of fractures would not further jeopardize the blood supply of fracture site. This aggressive conservative management also avoids unnecessary surgery in all acute scaphoid fractures. PMID- 29409430 TI - Outcomes of Ulnar Shortening for Ulnar Impaction Syndrome Using the 2.7 mm AO Ulna Shortening Osteotomy System. AB - BACKGROUND: Ulnar shortening osteotomy is a well-established treatment for ulnar impaction syndrome. Controversy remains regarding the most effective system to achieve efficient bony union, whilst minimising incidence of complications, particularly hardware irritation. We present outcomes at 2 years using the recently released low profile AO osteotomy system. METHODS: 32 consecutive patients with significant pain from ulnar impaction syndrome (idiopathic or post traumatic), without degenerative changes of the distal radio-ulnar joint, were included. Time to union, range of motion, grip strength, pain and complications were recorded. RESULTS: Median time to union was 10.14 weeks (9.27-11.01, 95%CI), with one nonunion. Visual Analogue Pain score, grip strength and range of motion improved significantly. No patient experienced hardware irritation. No plate required removal. Positive ulnar variance was reduced by 3.8 mm (mean). CONCLUSIONS: The low profile AO system appears effective in achieving bony union whilst minimising incidence of hardware irritation, at a follow up of 2 years. PMID- 29409431 TI - The Predictive Value of Ultrasound Scanning in Certain Hand and Wrist Conditions. AB - BACKGROUND: Fast and accurate diagnosis of conditions of the hand and wrist is essential in guiding management. We aimed to analyse the predictive value of ultrasound in identifying different pathologies in the hand and wrist by correlating pre-operative ultrasound findings with per-operative surgical findings. METHODS: We retrospectively reviewed the case notes of all patients under the care of the senior author on whom a hand/wrist ultrasound had been performed between January 2007-May 2013. Of these only patients who proceeded to surgery were included as this was the correlating endpoint. Positive and negative predictive values (PPV/NPV) and sensitivity and specificity were calculated for ultrasound in identifying (i) post-repair complete tendon ruptures (versus intact repairs with scar adherence), (ii) ganglionic cysts, (iii) soft tissue masses and (iv) nerve injuries. RESULTS: Of 70 patients who underwent ultrasound, 36 proceeded to surgery. Fifteen patients were post traumatic and the remaining 21 were elective presentations. The median age was 38 (range 14-87) with a 1.25:1 male to female ratio. All results had a 95% confidence interval. Ultrasound had a 100% PPV for identifying post-repair complete tendon ruptures and for ganglionic cysts (sensitivities 75% and 87% respectively). Of our 6 soft tissue masses ultrasound also showed a 100% PPV. For the two nerve injury patients, PPV was 100%. CONCLUSIONS: Our study shows that ultrasound is diagnostic for post-repair tendon ruptures and ganglionic cysts, and shows promising results for benign soft tissue masses and nerve injuries. We propose the use of ultrasound as an extension to physical examination in a dynamic clinic setting. PMID- 29409432 TI - People diagnosed with dementia in Sweden: What type of home care services and housing are they granted? A cross-sectional study. AB - AIMS: This study aims to examine what types of home care services and housing are granted to people with a dementia diagnosis and how these types are associated with socio-demographic factors (sex, age, marital status, native or foreign born, and regional area). METHODS: A cross-sectional study of all people diagnosed with dementia in three Swedish counties was conducted from the medical records in 2012. Logistic regression analysis was carried out to investigate associations between home care services and housing and socio-demographic variables. RESULTS: In total, 17,405 people had a dementia diagnosis, and the majority were women, aged 80+ years, and unmarried. Some 72% were living in ordinary housing and 28% lived in special housing. Of those who lived in ordinary housing, 50% did not receive any home care service. Not receiving any type of home care services was less common for older people and was also associated with being married and living in rural municipalities. The most common home care services granted were home help and personal care. Special housing was more common for older people, unmarried persons, and those living in rural municipalities. CONCLUSIONS: Most people with a dementia diagnosis were living in ordinary housing, and, surprisingly, half of those did not receive any type of home care service. This knowledge is essential for making the living conditions and needs of people living with dementia more visible and to provide good home care services for people with dementia and their families. PMID- 29409433 TI - Widening the Lens: An Ecological Review of Campus Sexual Assault. AB - Varying prevalence rates of sexual violence across colleges and universities indicate the need to understand institutional factors underlying such variation; however, research often focuses exclusively on individual risk and protective factors, which both under theorizes and under explains the phenomenon of campus sexual assault. In this review, we propose that broadening to include campus- and contextual-level factors is necessary to fully explain campus sexual assault. Using an ecological approach, we identify and synthesize research related to campus-level variation in sexual violence, including availability of campus services and resources for survivors, institutional risk factors such as alcohol and party culture, athletics, and fraternities, and the impact of policies at the state and federal levels. Suggestions are made for conducting additional research at the campus level and implications of reframing campus sexual assault from an institutional lens are discussed, including the importance of this approach for practice, evaluation, and policy. PMID- 29409434 TI - Challenges in the management of syphilis in pregnancy: completing a multicentre audit cycle with mixed outcomes. PMID- 29409435 TI - Simulation for competency assessment in vascular and cardiac ultrasound. AB - Healthcare providers who use peripheral vascular and cardiac ultrasound require specialized training to develop the technical and interpretive skills necessary to perform accurate diagnostic tests. Assessment of competence is a critical component of training that documents a learner's progress and is a requirement for competency-based medical education (CBME) as well as specialty certification or credentialing. The use of simulation for CBME in diagnostic ultrasound is particularly appealing since it incorporates both the psychomotor and cognitive domains while eliminating dependency on the availability of live patients with a range of pathology. However, successful application of simulation in this setting requires realistic, full-featured simulators and appropriate standardized metrics for competency testing. The principal diagnostic parameter in peripheral vascular ultrasound is measurement of peak systolic velocity (PSV) on Doppler spectral waveforms, and simulation of Doppler flow detection presents unique challenges. The computer-based duplex ultrasound simulator developed at the University of Washington uses computational fluid dynamics modeling and presents real-time color-flow Doppler images and Doppler spectral waveforms along with the corresponding B-mode images. This simulator provides a realistic scanning experience that includes measuring PSV in various arterial segments and applying actual diagnostic criteria. Simulators for echocardiography have been available since the 1990s and are currently more advanced than those for peripheral vascular ultrasound. Echocardiography simulators are now offered for both transesophageal echo and transthoracic echo. These computer-based simulators have 3D graphic displays that provide feedback to the learner and metrics for assessment of technical skill that are based on transducer tracking data. Such metrics provide a motion-based or kinematic analysis of skill in performing cardiac ultrasound. The use of simulation in peripheral vascular and cardiac ultrasound can provide a standardized and readily available method for training and competency assessment. PMID- 29409436 TI - Technique of Ileobladder and Kidney Transplant in Rats and Pigs. AB - OBJECTIVES: Kidney transplant is the best choice for treatment of patients with advanced chronic renal disease. However, small, poorly compliant, and unstable bladders can result in major problems for patients. Here, we aimed to develop and evaluate a new ileobladder model. MATERIALS AND METHODS: Fifteen rats (250-300 g) and 5 pigs (~100 kg) were cared for according to institutional and published guidelines. After general anesthesia, laparotomy was done through midline incision. Ileal loops were prepared for ileobladder. After cystectomy (0.5 cm above the trigone in rats, 1 cm above the trigone in pigs), anastomoses were done between antimesenteric sides of ileal loops and bladder remnant with 6/0 Prolene suture. Three other pigs received simultaneous renal transplant. RESULTS: One rat died on day 1 postsurgery from multiorgan hemorrhage. Two rats survived for 5 days, 3 rats for 7 days, and 3 rats for 11 days; 6 rats were killed for pathologic evaluation after 3 months. One pig survived for 22 days and 1 for 9 days. Of the 3 pigs that received a simultaneous renal transplant, 2 pigs were alive and doing well 80 and 72 days after surgery with normal urinary discharge (1 pig was killed for pathologic evaluation after 3 days). When ileobladder was opened, complete recovery of the anastomosis line was observed. Pathologic examination of the anastomosis sites reported a normal healing process with moderate inflammation and the muscular wall of the intestine showed hypertrophia that nearly reached the size of the bladder muscularis propria. CONCLUSIONS: Although we had some complications because no draining procedure was used, in terms of technique, our new ileobladder model is promising for providing functional bladder volume. A larger scale series in the clinical setting is planned. This technique can be useful for small bladders and bladder physiology disorders. PMID- 29409437 TI - Urine Leak After Kidney Transplant: A Review of the Literature. AB - Although they are not common, urologic complications after renal transplant are associated with risk of graft loss. Fluid collection during the postoperative period can be caused by urine leak or lymph leak of seroma. Biochemical analysis of the drained liquid is essential and should be compared with a concomitant serum sample. Surgical exploration is indicated if suspected urine leak is significant. Reimplantation of the ureter to the bladder can be challenging if there is extensive ureteral necrosis due to compromised vascularization. PMID- 29409438 TI - Impact of Race and Gender on Cardiovascular Morbidity and Mortality after Orthotopic Liver Transplant. PMID- 29409439 TI - Hematopoietic Stem Cell Transplant in Facilities Without Intensive Care Units in Japan. AB - OBJECTIVES: Substantial numbers of patients after hematopoietic stem cell transplant need critical care. In Japan, however, data regarding the availability of an intensive care unit and intensivists at hospitals performing hematopoietic stem cell transplant are lacking. We aimed to investigate this issue using data from the 2014 Hematopoietic Cell Transplantation in Japan Annual Report of Nationwide Survey. MATERIALS AND METHODS: We examined whether hospitals have intensive care unit facilities and whether these hospitals are authorized by the Japanese Society of Intensive Care Medicine to provide intensivist training. The number of hematopoietic cell transplantations at each hospital was collected from the Transplant Registry Unified Management Program by the Japanese Data Center for Hematopoietic Cell Transplantation. RESULTS: Among 236 hospitals that perform hematopoietic stem cell transplants, 106 hospitals did not have intensive care units certified by the Japanese Society of Intensive Care Medicine. In patients who receive hematopoietic stem cell transplants with the highest mortality rate, 947 allogeneic transplants were performed at hospitals without this certification and 73 were performed at hospitals without intensive care units. CONCLUSIONS: We found that a considerable number of hematopoietic stem cell transplants are performed at hospitals with insufficient availability of critical care facilities or physicians. PMID- 29409440 TI - Macroevolutionary diversification with limited niche disparity in a species-rich lineage of cold-climate lizards. AB - BACKGROUND: Life diversifies via adaptive radiation when natural selection drives the evolution of ecologically distinct species mediated by their access to novel niche space, or via non-adaptive radiation when new species diversify while retaining ancestral niches. However, while cases of adaptive radiation are widely documented, examples of non-adaptively radiating lineages remain rarely observed. A prolific cold-climate lizard radiation from South America (Phymaturus), sister to a hyper-diverse adaptive radiation (Liolaemus), has extensively diversified phylogenetically and geographically, but with exceptionally minimal ecological and life-history diversification. This lineage, therefore, may offer unique opportunities to investigate the non-adaptive basis of diversification, and in combination with Liolaemus, to cover the whole spectrum of modes of diversification predicted by theory, from adaptive to non-adaptive. Using phylogenetic macroevolutionary modelling performed on a newly created 58-species molecular tree, we establish the tempo and mode of diversification in the Phymaturus radiation. RESULTS: Lineage accumulation in Phymaturus opposes a density-dependent (or 'niche-filling') process of diversification. Concurrently, we found that body size diversification is better described by an Ornstein Uhlenbeck evolutionary model, suggesting stabilizing selection as the mechanism underlying niche conservatism (i.e., maintaining two fundamental size peaks), and which has predominantly evolved around two major adaptive peaks on a 'Simpsonian' adaptive landscape. CONCLUSIONS: Lineage diversification of the Phymaturus genus does not conform to an adaptive radiation, as it is characterised by a constant rate of species accumulation during the clade's history. Their strict habitat requirements (rocky outcrops), predominantly invariant herbivory, and especially the constant viviparous reproduction across species have likely limited their opportunities for adaptive diversifications throughout novel environments. This mode of diversification contrasts dramatically with its sister lineage Liolaemus, which geographically overlaps with Phymaturus, but exploits all possible microhabitats in these and other bioclimatic areas. Our study contributes importantly to consolidate these lizards (liolaemids) as promising model systems to investigate the entire spectrum of modes of species formations, from the adaptive to the non-adaptive extremes of the continuum. PMID- 29409441 TI - G4PromFinder: an algorithm for predicting transcription promoters in GC-rich bacterial genomes based on AT-rich elements and G-quadruplex motifs. AB - BACKGROUND: Over the last few decades, computational genomics has tremendously contributed to decipher biology from genome sequences and related data. Considerable effort has been devoted to the prediction of transcription promoter and terminator sites that represent the essential "punctuation marks" for DNA transcription. Computational prediction of promoters in prokaryotes is a problem whose solution is far from being determined in computational genomics. The majority of published bacterial promoter prediction tools are based on a consensus-sequences search and they were designed specifically for vegetative sigma70 promoters and, therefore, not suitable for promoter prediction in bacteria encoding a lot of sigma factors, like actinomycetes. RESULTS: In this study we investigated the possibility to identify putative promoters in prokaryotes based on evolutionarily conserved motifs, and focused our attention on GC-rich bacteria in which promoter prediction with conventional, consensus based algorithms is often not-exhaustive. Here, we introduce G4PromFinder, a novel algorithm that predicts putative promoters based on AT-rich elements and G quadruplex DNA motifs. We tested its performances by using available genomic and transcriptomic data of the model microorganisms Streptomyces coelicolor A3(2) and Pseudomonas aeruginosa PA14. We compared our results with those obtained by three currently available promoter predicting algorithms: the sigma70consensus-based PePPER, the sigma factors consensus-based bTSSfinder, and PromPredict which is based on double-helix DNA stability. Our results demonstrated that G4PromFinder is more suitable than the three reference tools for both the genomes. In fact our algorithm achieved the higher accuracy (F1-scores 0.61 and 0.53 in the two genomes) as compared to the next best tool that is PromPredict (F1-scores 0.46 and 0.48). Consensus-based algorithms produced lower performances with the analyzed GC-rich genomes. CONCLUSIONS: Our analysis shows that G4PromFinder is a powerful tool for promoter search in GC-rich bacteria, especially for bacteria coding for a lot of sigma factors, such as the model microorganism S. coelicolor A3(2). Moreover consensus-based tools and, in general, tools that are based on specific features of bacterial sigma factors seem to be less performing for promoter prediction in these types of bacterial genomes. PMID- 29409442 TI - Semantic annotation of consumer health questions. AB - BACKGROUND: Consumers increasingly use online resources for their health information needs. While current search engines can address these needs to some extent, they generally do not take into account that most health information needs are complex and can only fully be expressed in natural language. Consumer health question answering (QA) systems aim to fill this gap. A major challenge in developing consumer health QA systems is extracting relevant semantic content from the natural language questions (question understanding). To develop effective question understanding tools, question corpora semantically annotated for relevant question elements are needed. In this paper, we present a two-part consumer health question corpus annotated with several semantic categories: named entities, question triggers/types, question frames, and question topic. The first part (CHQA-email) consists of relatively long email requests received by the U.S. National Library of Medicine (NLM) customer service, while the second part (CHQA web) consists of shorter questions posed to MedlinePlus search engine as queries. Each question has been annotated by two annotators. The annotation methodology is largely the same between the two parts of the corpus; however, we also explain and justify the differences between them. Additionally, we provide information about corpus characteristics, inter-annotator agreement, and our attempts to measure annotation confidence in the absence of adjudication of annotations. RESULTS: The resulting corpus consists of 2614 questions (CHQA-email: 1740, CHQA web: 874). Problems are the most frequent named entities, while treatment and general information questions are the most common question types. Inter-annotator agreement was generally modest: question types and topics yielded highest agreement, while the agreement for more complex frame annotations was lower. Agreement in CHQA-web was consistently higher than that in CHQA-email. Pairwise inter-annotator agreement proved most useful in estimating annotation confidence. CONCLUSIONS: To our knowledge, our corpus is the first focusing on annotation of uncurated consumer health questions. It is currently used to develop machine learning-based methods for question understanding. We make the corpus publicly available to stimulate further research on consumer health QA. PMID- 29409443 TI - Experiences of fear of falling in persons with Parkinson's disease - a qualitative study. AB - BACKGROUND: Fear of falling is common among persons with Parkinson's disease and is negatively associated with quality of life. However a lack of in-depth understanding of fear of falling as a phenomenon persists. This qualitative study aimed to explore the experiences of fear of falling in persons with Parkinson's disease. METHODS: Individual interviews were performed with twelve persons with Parkinson's disease (median age 70 years, median Parkinson duration 9 years, 50% women). The interviews were semi-structured and followed a study-specific interview guide. The transcribed interviews were analyzed using qualitative content analysis. RESULTS: Fear of falling was experienced as a disturbing factor in everyday life. It generated a feeling of vulnerability and made daily activities and everyday environments seem potentially hazardous. Persons also missed performing previous activities. The fear of falling was a varying experience, fueled by an awareness of falls and near falls, Parkinson-related symptoms and disabilities, and by others in their environment. The persons adopted different strategies to handle their fear of falling. Activities were adapted, avoided, performed with help, or carried out despite their fear of falling. CONCLUSIONS: The experiences of fear of falling were complex, multifaceted and varied over time and in relation to different activities and environments. This indicates that interventions targeting fear of falling need to be individually tailored for persons with Parkinson's disease and should focus on several aspects, such as Parkinson-related symptoms and disabilities, activities and environmental factors. This study provides new information that increases the understanding of fear of falling, which has implications for researchers as well as clinicians working with persons with Parkinson's disease and fear of falling. PMID- 29409444 TI - Should heart age calculators be used alongside absolute cardiovascular disease risk assessment? AB - BACKGROUND: National estimates of 'heart age' by government health organisations in the US, UK and China show most people have an older heart age than current age. While most heart age calculators are promoted as a communication tool for lifestyle change, they may also be used to justify medication when clinical guidelines advocate their use alongside absolute risk assessment. However, only those at high absolute risk of a heart attack or stroke are likely to benefit from medication, and it is not always clear how heart age relates to absolute risk. This article aims to: 1) explain how heart age calculation methods relate to absolute risk guidelines; 2) summarise research investigating whether heart age improves risk communication; and 3) discuss implications for the use of medication and shared decision making in clinical practice. MAIN BODY: There is a large and growing number of heart age models and online calculators, but the clinical meaning of an older heart age result is highly variable. An older heart age result may indicate low, moderate or high absolute risk of a heart attack or stroke in the next 5-10 years, and the same individual may receive a younger or older heart age result depending on which calculator is used. Heart age may help doctors convey the need to change lifestyle, but it cannot help patients make an informed choice about medication to reduce CVD risk. CONCLUSION: Interactive heart age tools may be helpful as a communication tool to initiate lifestyle change to reduce risk factors. However, absolute risk should be used instead of heart age to enable informed decision making about medication, to avoid unnecessary treatment of low risk people. Evidence-based decision aids that improve patient understanding of absolute risk should be considered as alternatives to heart age calculators for lifestyle and medication decisions. PMID- 29409445 TI - Integrative analysis of methylomic and transcriptomic data in fetal sheep muscle tissues in response to maternal diet during pregnancy. AB - BACKGROUND: Numerous studies have established a link between maternal diet and the physiological and metabolic phenotypes of their offspring. In previous studies in sheep, we demonstrated that different maternal diets altered the transcriptome of fetal tissues. However, the mechanisms underlying transcriptomic changes are poorly understood. DNA methylation is an epigenetic mark regulating transcription and is largely influenced by dietary components of the one-carbon cycle that generate the methyl group donor, SAM. Therefore, in the present study, we tested whether different maternal diets during pregnancy would alter the DNA methylation and gene expression patterns in fetal tissues. RESULTS: Pregnant ewes were randomly divided into two groups which received either hay or corn diet from mid-gestation (day 67 +/- 5) until day 131 +/- 1 when fetuses were collected by necropsy. A total of 1516 fetal longissimus dorsi (LD) tissues were used for DNA methylation analysis and gene expression profiling. Whole genome DNA methylation using methyl-binding domain enrichment analysis revealed 60 differentially methylated regions (DMRs) between hay and corn fetuses with 39 DMRs more highly methylated in the hay fetuses vs. 21 DMRs more highly methylated in the corn fetuses. Three DMRs (LPAR3, PLIN5-PLIN4, and the differential methylation of a novel lincRNA) were validated using bisulfite sequencing. These DMRs were associated with differential gene expression. Additionally, significant DNA methylation differences were found at the single CpG level. Integrative methylome and transcriptome analysis revealed an association between gene expression and inter-/intragenic methylated regions. Furthermore, intragenic DMRs were found to be associated with expression of neighboring genes. CONCLUSIONS: The findings of this study imply that maternal diet from mid- to late-gestation can shape the epigenome and the transcriptome of fetal tissues, and putatively affect phenotypes of the lambs. PMID- 29409446 TI - Exploring the potential of 3D Zernike descriptors and SVM for protein-protein interface prediction. AB - BACKGROUND: The correct determination of protein-protein interaction interfaces is important for understanding disease mechanisms and for rational drug design. To date, several computational methods for the prediction of protein interfaces have been developed, but the interface prediction problem is still not fully understood. Experimental evidence suggests that the location of binding sites is imprinted in the protein structure, but there are major differences among the interfaces of the various protein types: the characterising properties can vary a lot depending on the interaction type and function. The selection of an optimal set of features characterising the protein interface and the development of an effective method to represent and capture the complex protein recognition patterns are of paramount importance for this task. RESULTS: In this work we investigate the potential of a novel local surface descriptor based on 3D Zernike moments for the interface prediction task. Descriptors invariant to roto translations are extracted from circular patches of the protein surface enriched with physico-chemical properties from the HQI8 amino acid index set, and are used as samples for a binary classification problem. Support Vector Machines are used as a classifier to distinguish interface local surface patches from non-interface ones. The proposed method was validated on 16 classes of proteins extracted from the Protein-Protein Docking Benchmark 5.0 and compared to other state-of-the-art protein interface predictors (SPPIDER, PrISE and NPS-HomPPI). CONCLUSIONS: The 3D Zernike descriptors are able to capture the similarity among patterns of physico chemical and biochemical properties mapped on the protein surface arising from the various spatial arrangements of the underlying residues, and their usage can be easily extended to other sets of amino acid properties. The results suggest that the choice of a proper set of features characterising the protein interface is crucial for the interface prediction task, and that optimality strongly depends on the class of proteins whose interface we want to characterise. We postulate that different protein classes should be treated separately and that it is necessary to identify an optimal set of features for each protein class. PMID- 29409447 TI - Microbial contaminants isolated from items and work surfaces in the post- operative ward at Kawolo general hospital, Uganda. AB - BACKGROUND: Nosocomial infections are a major setback in the healthcare delivery system especially in developing countries due to the limited resources. The roles played by medical care equipment and work surfaces in the transmission of such organisms have inevitably contributed to the elevated mortality, morbidity and antibiotic resistances. METHODS: A total 138 samples were collected during the study from Kawolo general hospital. Swab samples were collected from various work surfaces and fomites which consisted of; beds, sink taps, infusion stands, switches, work tables and scissors. Cultures were done and the susceptibility patterns of the isolates were determined using Kirby Bauer disc diffusion method. Data was analyzed using Stata 13 and Microsoft Excel 2013 packages. RESULTS: A total of 44.2% (61/138) of the collected swab specimens represented the overall bacterial contamination of the sampled articles. Staphylococcus aureus and Klebsiella pneumoniae accounted for the highest bacterial contaminants constituting of 75.4% (46/61) and 11.5% (7/61) respectively. Infusion stands and patient beds were found to have the highest bacterial contamination levels both constituting 19.67% (12/61). The highest degree of transmission of organisms to patients was found to be statistically significant for patient beds with OR: 20.1 and P-value 8X10- 4. Vancomycin, ceftriaxone and ciprofloxacin were the most effective antibiotics with 100%, 80% and 80% sensitivity patterns among the isolates respectively. Multi-drug resistant (MDR) Staphylococcus aureus accounted for 52% (24/46) with 4% (1/24) classified as a possible extensively drug resistant (XDR) whereas Gram negative isolates had 27% (4/15) MDR strains out of which 50%(2/4) were classified as possible pan-drug resistant (PDR). CONCLUSION: The high prevalence of bacterial contaminants in the hospital work environment is an indicator of poor or ineffective decontamination. The study findings reiterate the necessity to formulate drug usage policies and re-examine effectiveness of decontamination and sterilization practices within Kawolo general hospital. We also recommend installation of a sound Microbiology unit at the hospital to take on susceptibility testing to check on the empirical use of antibiotics as a way of reducing the rampant elevations in drug resistances. PMID- 29409448 TI - An exploration of the subjective social status construct in patients with acute coronary syndrome. AB - BACKGROUND: Perception of low subjective social status (SSS) relative to others in society or in the community has been associated with increased risk of cardiovascular disease. Our objectives were to determine whether low SSS in society was associated with barriers to access to care or hospital readmission in patients with established cardiovascular disease, and whether perceptions of discordantly high SSS in the community modified this association. METHODS: We conducted a prospective cohort study from 2009 to 2013 in Canada, United States, and Switzerland in patients admitted to hospital with acute coronary syndrome (ACS). Data on access to care and SSS variables were obtained at baseline. Readmission data were obtained 12 months post-discharge. We conducted multivariable logistic regression to model the odds of access to care and readmission outcomes in those with low versus high societal SSS. RESULTS: One thousand ninety patients admitted with ACS provided both societal and community SSS rankings. The low societal SSS cohort had greater odds of reporting that their health was affected by lack of health care access (OR 1.48, 95% CI 1.11, 1.97) and of experiencing cardiac readmissions (1.88, 95% CI 1.15, 3.06). Within the low societal SSS cohort, there was a trend toward fewer access to care barriers for those with discordantly high community SSS though findings varied based on the outcome variable. There were no statistically significant differences in readmissions based on community SSS rankings. CONCLUSION: Low societal SSS is associated with increased barriers to access to care and cardiac readmissions. Though attenuated, these trends remained even when adjusting for clinical and sociodemographic factors, suggesting that perceived low societal SSS has health effects above and beyond objective socioeconomic factors. Furthermore, high community SSS may potentially mitigate the risk of experiencing barriers to access to health care in those with low societal SSS, though these associations were not statistically significant. Subjective social status relative to society versus relative to the community seem to represent distinct concepts. Insight into the differences between these two SSS constructs is imperative in the understanding of cardiovascular health and future development of public health policies. PMID- 29409449 TI - Enhancing delivery of osteoarthritis care in the general practice consultation: evaluation of a behaviour change intervention. AB - BACKGROUND: Professionally-focussed behaviour change intervention (BCI) workshops were utilised in the Management of OsteoArthritis in Consultations (MOSAICS) trial investigating the feasibility of implementing the National Institute for Health and Care Excellence (NICE) Osteoarthritis (OA) Guideline in general practice. The workshops aimed to implement the general practitioner (GP) component of the trial intervention: an enhanced consultation for patients presenting with possible OA. This study presents an evaluation of the BCI workshops on GP competency in conducting these enhanced consultations. METHODS: A before-and-after evaluation of the workshops, delivered to GPs participating in the intervention arm of the MOSAICS trial, using video-recorded GP consultations with simulated OA patients. GPs attended four workshops, which had been developed using an implementation framework. Videos were undertaken at three time-points (before workshops and at one- and five-months after) and were assessed by independent observers, blinded to time points, for GP competency in undertaking 14 predetermined consultation tasks. RESULTS: Videos of 15 GPs were assessed. GP competency increased from a median of seven consultation tasks undertaken by each GP at baseline to 11 at both time-points after the workshops. Specific tasks which were undertaken more frequently after the workshops related to explaining that OA is treatable and not inevitably progressive, eliciting and addressing patient expectations of the consultation, and providing written OA information. However, the use of the word "osteoarthritis" in giving the diagnosis of OA was not enhanced by the workshops. CONCLUSIONS: BCI workshops can enhance GP competency in undertaking consultations for OA. Further initiatives to implement the NICE OA Guideline and enhance the care of people with OA in primary care can be informed by the content and delivery of the workshops evaluated in this study. PMID- 29409450 TI - Using an onset-anchored Bayesian hierarchical model to improve predictions for amyotrophic lateral sclerosis disease progression. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a rare disease with extreme between-subject variability, especially with respect to rate of disease progression. This makes modelling a subject's disease progression, which is measured by the ALS Functional Rating Scale (ALSFRS), very difficult. Consider the problem of predicting a subject's ALSFRS score at 9 or 12 months after a given time-point. METHODS: We obtained ALS subject data from the Pooled Resource Open-Access ALS Clinical Trials Database, a collection of data from various ALS clinical trials. Due to the typical linearity of the ALSFRS, we consider several Bayesian hierarchical linear models. These include a mixture model (to account for the two potential classes of "fast" and "slow" ALS progressors) as well as an onset-anchored model, in which an additional artificial data-point, using time of disease onset, is utilized to improve predictive performance. RESULTS: The onset-anchored model had a drastically reduced posterior predictive mean-square-error distributions, when compared to the Bayesian hierarchical linear model or the mixture model under a cross-validation approach. No covariates, other than time of disease onset, consistently improved predictive performance in either the Bayesian hierarchical linear model or the onset-anchored model. CONCLUSIONS: Augmenting patient data with an additional artificial data-point, or onset anchor, can drastically improve predictive modelling in ALS by reducing the variability of estimated parameters at the cost of a slight increase in bias. This onset-anchored model is extremely useful if predictions are desired directly after a single baseline measure (such as at the first day of a clinical trial), a feat that would be very difficult without the onset-anchor. This approach could be useful in modelling other diseases that have bounded progression scales (e.g. Parkinson's disease, Huntington's disease, or inclusion-body myositis). It is our hope that this model can be used by clinicians and statisticians to improve the efficacy of clinical trials and aid in finding treatments for ALS. PMID- 29409451 TI - Plant vigour QTLs co-map with an earlier reported QTL hotspot for drought tolerance while water saving QTLs map in other regions of the chickpea genome. AB - BACKGROUND: Terminal drought stress leads to substantial annual yield losses in chickpea (Cicer arietinum L.). Adaptation to water limitation is a matter of matching water supply to water demand by the crop. Therefore, harnessing the genetics of traits contributing to plant water use, i.e. transpiration rate and canopy development dynamics, is important to design crop ideotypes suited to a varying range of water limited environments. With an aim of identifying genomic regions for plant vigour (growth and canopy size) and canopy conductance traits, 232 recombinant inbred lines derived from a cross between ICC 4958 and ICC 1882, were phenotyped at vegetative stage under well-watered conditions using a high throughput phenotyping platform (LeasyScan). RESULTS: Twenty one major quantitative trait loci (M-QTLs) were identified for plant vigour and canopy conductance traits using an ultra-high density bin map. Plant vigour traits had 13 M-QTLs on CaLG04, with favourable alleles from high vigour parent ICC 4958. Most of them co-mapped with a previously fine mapped major drought tolerance "QTL hotspot" region on CaLG04. One M-QTL was found for canopy conductance on CaLG03 with the ultra-high density bin map. Comparative analysis of the QTLs found across different density genetic maps revealed that QTL size reduced considerably and % of phenotypic variation increased as marker density increased. CONCLUSION: Earlier reported drought tolerance hotspot is a vigour locus. The fact that canopy conductance traits, i.e. the other important determinant of plant water use, mapped on CaLG03 provides an opportunity to manipulate these loci to tailor recombinants having low/high transpiration rate and plant vigour, fitted to specific drought stress scenarios in chickpea. PMID- 29409452 TI - Whole blood microRNAs as potential biomarkers in post-operative early breast cancer patients. AB - BACKGROUND: microRNAs (miRNAs) are considered promising cancer biomarkers, showing high reliability, sensitivity and stability. Our study aimed to identify associations between whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-operative early breast cancer patients (EBC) to assess the utility of miRNAs as prognostic markers in this setting. METHOD: A total of 48 post-operative patients, recruited in frame of the SUCCESS A trial, were included in this retrospective study and tested with a panel of 8 miRNAs (miR-10b, -19a, - 21, - 22, -20a, - 127, - 155, -200b). Additional 17 female healthy donors with no previous history of cancer were included in the study as negative controls. Blood samples were collected at different time points (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up), total RNA was extracted and the relative concentration of each miRNA was measured by quantitative PCR and compared in patients stratified on blood collection time or CTC detection. Furthermore, we compared miRNA profiles of patients, for each time point separately, and healthy donors. CTCs were visualized and quantified with immunocytochemistry analysis. Data were analyzed using non-parametric statistical tests. RESULTS: In our experimental system, miR-19a, miR-22 and miR-127 showed the most promising results, differentiating patients at different time points and from healthy controls, while miR-20a, miR-21 and miR-200b did not show any difference among the different groups. miR-10b and miR-155 were never detectable in our experimental system. With respect to patients' clinical characteristics, we found a significant correlation between miR-200b and lymph node status and between miR-20a and tumor type. Furthermore, miR-127 correlated with the presence of CTCs. Finally, we found a borderline significance between Progression Free Survival and miR-19a levels. CONCLUSIONS: This pilot study suggests that profiling whole blood miRNAs could help to better stratify post-operative EBC patients without any sign of metastasis to prevent later relapse or metastatic events. PMID- 29409453 TI - Factors associated with carotid Intima media thickness and carotid plaque score in community-dwelling and non-diabetic individuals. AB - BACKGROUND: The carotid intima media thickness (cIMT) and carotid plaque score (cPS) are respective markers of early and late stage subclinical atherosclerosis. Relationships between some laboratory parameters and subclinical atherosclerosis are not yet clear in community dwelling individuals and non-diabetic subjects, so we try to elucidate these relationships and find a model to predict early and late stage subclinical atherosclerosis. METHODS: We examined relationships of the cIMT and cPS with different laboratory and demographic data of 331 subjects from a community-based prospective cohort study, using univariate and multivariate analyses. RESULTS: In regression models and after multiple adjustments, only systolic blood pressure (SBP), age, glycated hemoglobin (HBA1c), and waist circumference (WC) were determinants of the cIMT, and only age, SBP, HBA1c, and blood urea nitrogen (BUN) were determinants of a cPS of > 2 in all individuals. Only HBA1c lost its association with regard to predicting the cIMT in non diabetic subjects. CONCLUSIONS: HBA1c at > 5.9% can determine early and late stage subclinical atherosclerosis in community dwelling individuals, but only late stage subclinical atherosclerosis in non-diabetic subjects. PMID- 29409454 TI - Gene loss and genome rearrangement in the plastids of five Hemiparasites in the family Orobanchaceae. AB - BACKGROUND: The chloroplast genomes (plastome) of most plants are highly conserved in structure, gene content, and gene order. Parasitic plants, including those that are fully photosynthetic, often contain plastome rearrangements. These most notably include gene deletions that result in a smaller plastome size. The nature of gene loss and genome structural rearrangement has been investigated in several parasitic plants, but their timing and contributions to the adaptation of these parasites requires further investigation, especially among the under studied hemi-parasites. RESULTS: De novo sequencing, assembly and annotation of the chloroplast genomes of five photosynthetic parasites from the family Orobanchaceae were employed to investigate plastome dynamics. Four had major structural rearrangements, including gene duplications and gene losses, that differentiated the taxa. The facultative parasite Aureolaria virginica had the most similar genome content to its close non-parasitic relative, Lindenbergia philippensis, with similar genome size and organization, and no differences in gene content. In contrast, the facultative parasite Buchnera americana and three obligate parasites in the genus Striga all had enlargements of their plastomes, primarily caused by expansion within the large inverted repeats (IRs) that are a standard plastome feature. Some of these IR increases were shared by multiple investigated species, but others were unique to particular lineages. Gene deletions and pseudogenization were also both shared and lineage-specific, with particularly frequent and independent loss of the ndh genes involved in electron recycling. CONCLUSIONS: Five new plastid genomes were fully assembled and compared. The results indicate that plastome instability is common in parasitic plants, even those that retain the need to perform essential plastid functions like photosynthesis. Gene losses were slow and not identical across taxa, suggesting that different lineages had different uses or needs for some of their plastome gene content, including genes involved in some aspects of photosynthesis. Recent repeat region extensions, some unique to terminal species branches, were observed after the divergence of the Buchnera/Striga clade, suggesting that this otherwise rare event has some special value in this lineage. PMID- 29409455 TI - Association between brain-derived neurotrophic factor and von Willebrand factor levels in patients with stable coronary artery disease. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in angiogenesis and maintenance of endothelial integrity. Whether circulating BDNF levels are associated with von Willebrand factor (vWF) levels, which are indicators of endothelial dysfunction is not known. This study investigated the association between plasma BNDF and vWF levels and whether these biomarkers could predict cardiovascular events at a 12-month follow-up in patients with stable coronary artery disease (CAD). METHODS: We recruited 234 patients with suspected angina pectoris. Subjects were divided into CAD (n = 143) and control (n = 91) groups based on coronary angiography. Plasma BDNF and vWF levels were measured using ELISA. Patients were followed-up for one year, and information on adverse cardiac events was collected. RESULTS: CAD patients exhibited significantly lower plasma BDNF and higher vWF levels than those of control patients. High vWF levels were associated with low BDNF levels even after adjustment for age, gender, low density lipoprotein (LDL) levels, and the presence of diabetes mellitus. A receiver operating characteristic curve was used to determine whether low BDNF and high vWF levels could predict adverse cardiovascular events. The area under the curve for vWF and the inverse of BDNF were 0.774 and 0.804, respectively. CONCLUSIONS: These findings suggest that endothelial dysfunction is an important determinant of the impaired circulating BDNF levels, and they further reflected cardiovascular prognosis in stable CAD patients. PMID- 29409456 TI - Task shifting in active management of the third stage of labor: a systematic review. AB - BACKGROUND: Active management of the third stage of labor (AMTSL) describes interventions with the common goal to prevent postpartum hemorrhage (PPH). In low and middle-income countries, implementation of AMTSL is hampered by shortage of skilled birth attendants and a high percentage of home deliveries. Task shifting of specific AMTSL components to unskilled birth attendants or self-administration could be a strategy to increase access to potentially life-saving interventions. This study was designed to evaluate the effect, acceptance and safety of task shifting of specific aspects of AMTSL to unskilled birth attendants. METHODS: A systematic search was conducted in five databases in September 2015 to identify intervention studies of AMTSL implemented by unskilled birth attendants or pregnant women themselves. Quality of studies was evaluated with an adapted Cochrane Collaboration assessment tool. RESULTS: Of 2469 studies screened, 21 were included. All studies assessed implementation of uterotonics (misoprostol tablets or oxytocin injections), administered by community health workers (CHWs), auxiliary midwives, traditional birth attendants (TBAs) or self-administration at antenatal (home) visits or delivery. Task shifting for none of the other AMTSL components was reported. Task shifting of provision of uterotonics reduced the risk of PPH (RR 0.16 to 1) compared to standard care (13 studies, n = 15.197). The correct dose and timing was reported for 83.4 to 99.8% (5 studies, n = 6083) and 63 to 100% (9 studies, n = 8378) women respectively. Uterotonics were recommended to others by 80 to 99.7% (7 studies, n = 6445); 80 to 99.4% (5 studies, n = 2677) would use the drug at next delivery. Willingness to pay for uterotonics varied from 54.6 to 100% (7 studies, n = 6090). CONCLUSION: Task shifting of AMTSL has thus far been evaluated for administration of uterotonics (misoprostol tablets and oxytocin injected by CHWs and auxiliary midwives) and resulted in reduction of PPH, high rates of appropriate use and satisfaction among users. In order to increase AMTSL coverage in low-staffed health facilities, task shifting of uterine massage or postpartum tonus assessment to unskilled attendants or delivered women could be considered. Task shifting of controlled cord traction is currently not recommended. PMID- 29409457 TI - The potential predictive value of DEK expression for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer. AB - BACKGROUND: Limited data are available regarding the ability of biomarkers to predict complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Complete response translates to better patient survival. DEK is a transcription factor involved not only in development and progression of different types of cancer, but is also associated with treatment response. This study aims to analyze the role of DEK in complete pathological response following chemoradiotherapy for locally advanced rectal cancer. METHODS: Pre-treated tumour samples from 74 locally advanced rectal-cancer patients who received chemoradiation therapy prior to total mesorectal excision were recruited for construction of a tissue microarray. DEK immunoreactivity from all samples was quantified by immunohistochemistry. Then, association between positive stained tumour cells and pathologic response to neoadjuvant treatment was measured to determine optimal predictive power. RESULTS: DEK expression was limited to tumour cells located in the rectum. Interestingly, high percentage of tumour cells with DEK positiveness was statistically associated with complete pathological response to neoadjuvant treatment based on radiotherapy and fluoropyrimidine-based chemotherapy and a marked trend toward significance between DEK positiveness and absence of treatment toxicity. Further analysis revealed an association between DEK and the pro-apoptotic factor P38 in the pre treated rectal cancer biopsies. CONCLUSIONS: These data suggest DEK as a potential biomarker of complete pathological response to treatment in locally advanced rectal cancer. PMID- 29409458 TI - It is no longer the time to disregard thyroid metastases from breast cancer: a case report and review of the literature. AB - BACKGROUND: Metastases to the thyroid gland are more frequent than previously thought, although most of them are occult or not clinically relevant. Overall, only 42 cases of metastases to thyroid from breast cancer have been reported thus far. Here we report the case of a patient with breast cancer metastatic to the thyroid. We also review the 42 previously reported cases (published between 1962 and 2012). This is the first review about metastases to thyroid gland from breast cancer. CASE PRESENTATION: A 64-year-old woman of Caucasian origin was diagnosed with a lobular invasive carcinoma of the breast (luminal A, stage II). She received adjuvant chemotherapy, followed by endocrine therapy. During follow-up, fine-needle cytology of a thyroid nodule revealed malignant cells that were estrogen-positive, which suggested a diagnosis of metastases to the thyroid. Imaging did not reveal any other metastatic site and showed only enlargement of the left thyroid lobe and an inhomogeneous pattern of colloid and cystic degeneration and calcifications. The patient underwent left hemithyroidectomy. Histology of thyroid tissue showed a colloid goitre containing dispersed small atypical neoplastic cells with eccentric nuclei. Immunohistochemistry showed cytokeratin-19 and oestrogen receptor, but not tireoglobulin, e-cadherin or cytokeratin-7, thereby confirming metastases from a lobular breast carcinoma. Hormonal treatment is ongoing. CONCLUSION: This case report and first review of the literature on metastases to thyroid from breast cancer highlight the importance of a correct early diagnostic work-up in such cases. Indeed, a primary lesion should be distinguished from metastases given the different treatment protocol related to primary cancer and the clinical impact on prognosis. PMID- 29409459 TI - A three-lncRNA signature predicts overall survival and disease-free survival in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Increasing evidence shows that dysregulated long non-coding RNAs (lncRNAs) can serve as potential biomarkers for cancer prognosis. However, lncRNA signatures, as potential prognostic biomarkers for esophageal squamous cell carcinoma (ESCC), have been seldom reported. METHODS: Based on our previous transcriptome RNA sequencing analysis from 15 paired ESCC tissues and adjacent normal tissues, we selected 10 lncRNAs with high score rank and characterized the expression of those lncRNAs, by qRT-PCR, in 138 ESCC and paired adjacent normal samples. These 138 patients were divided randomly into training (n = 77) and test (n = 59) groups. A prognostic signature of lncRNAs was identified in the training group and validated in the test group and in an independent cohort (n = 119). Multivariable Cox regression analysis evaluated the independence of the signature in overall survival (OS) and disease-free survival (DFS) prediction. GO and KEGG pathway analysis, combined with cell transwell and proliferation assays, are applied to explore the function of the three lncRNAs. RESULTS: A novel three lncRNA signature, comprised of RP11-366H4.1.1 (ENSG00000248370), LINC00460 (ENSG00000233532) and AC093850.2 (ENSG00000230838), was identified. The signature classified patients into high-risk and low-risk groups with different overall survival (OS) and disease-free survival (DFS). For the training group, median OS: 23.1 months vs. 39.1 months, P < 0.001; median DFS: 15.2 months vs. 33.3 months, P < 0.001. For the test group, median OS: 23 months vs. 59 months, P < 0.001; median DFS: 16.4 months vs. 50.8 months, P < 0.001. For the independent cohort, median OS: 22.4 months vs. 60.4 months, P < 0.001). The signature indicates that patients in the high-risk group show poor OS and DFS, whereas patients with a low risk group show significantly better outcome. The independence of the signature was validated by multivariable Cox regression analysis. GO and KEGG pathway analysis for 588 protein-coding genes-associated with the three lncRNAs indicated that the three lncRNAs were involved in tumorigenesis. In vitro assays further demonstrated that the three lncRNAs promoted the migration and proliferation of ESCC cells. CONCLUSIONS: The three-lncRNA signature is a novel and potential predictor of OS and DFS for patients with ESCC. PMID- 29409460 TI - HtrA1 as a promising tissue marker in cancer: a meta-analysis. AB - BACKGROUND: HtrA1 is expressed in a variety of normal human tissues and seems to be involved in numerous physiological processes as well as tumorigenesis. This study reports the results of a meta-analysis that was performed: to compare HtrA1 expression as mRNA and protein, in cancer tissue versus non-cancer tissue and to assess overall survival in relation to low or medium-high HtrA1 tissue expression. METHODS: The PRISMA method was used for study selection. OR and HR with 95% confidence interval was used as a measure of effect size as appropriate. A random-effects model was applied to account for different sources of variation among studies. Heterogeneity across studies was assessed using Q statistic. Sensitivity analysis was conducted to check the stability of study findings. Egger's regression method was applied to test funnel plot asymmetry. RESULTS: Sensitivity analysis indicated the stability of meta-analytic findings in each meta-analysis. The study found a significantly different HtrA1 expression in cancer and non-cancer tissue. The meta-analysis of the prognostic studies showed a different survival according to HtrA1 expression. CONCLUSIONS: The present data may provide a contribution to future work directed at exploring the role of HtrA1 in tumor development and progression and at establishing whether it may be used as a promising tissue marker for some tumors. PMID- 29409461 TI - Factor structure and psychometric properties of the english version of the trier inventory for chronic stress (TICS-E). AB - BACKGROUND: Demands placed on individuals in occupational and social settings, as well as imbalances in personal traits and resources, can lead to chronic stress. The Trier Inventory for Chronic Stress (TICS) measures chronic stress while incorporating domain-specific aspects, and has been found to be a highly reliable and valid research tool. The aims of the present study were to confirm the German version TICS factorial structure in an English translation of the instrument (TICS-E) and to report its psychometric properties. METHODS: A random route sample of healthy participants (N = 483) aged 18-30 years completed the TICS-E. The robust maximum likelihood estimation with a mean-adjusted chi-square test statistic was applied due to the sample's significant deviation from the multivariate normal distribution. Goodness of fit, absolute model fit, and relative model fit were assessed by means of the root mean square error of approximation (RMSEA), the Comparative Fit Index (CFI) and the Tucker Lewis Index (TLI). RESULTS: Reliability estimates (Cronbach's alpha and adjusted split-half reliability) ranged from .84 to .92. Item-scale correlations ranged from .50 to .85. Measures of fit showed values of .052 for RMSEA (Cl = 0.50-.054) and .067 for SRMR for absolute model fit, and values of .846 (TLI) and .855 (CFI) for relative model-fit. Factor loadings ranged from .55 to .91. CONCLUSION: The psychometric properties and factor structure of the TICS-E are comparable to the German version of the TICS. The instrument therefore meets quality standards for an adequate measurement of chronic stress. PMID- 29409462 TI - The FREGAT biobank: a clinico-biological database dedicated to esophageal and gastric cancers. AB - BACKGROUND: While the incidence of esophageal and gastric cancers is increasing, the prognosis of these cancers remains bleak. Endoscopy and surgery are the standard treatments for localized tumors, but multimodal treatments, associated chemotherapy, targeted therapies, immunotherapy, radiotherapy, and surgery are needed for the vast majority of patients who present with locally advanced or metastatic disease at diagnosis. Although survival has improved, most patients still present with advanced disease at diagnosis. In addition, most patients exhibit a poor or incomplete response to treatment, experience early recurrence and have an impaired quality of life. Compared with several other cancers, the therapeutic approach is not personalized, and research is much less developed. It is, therefore, urgent to hasten the development of research protocols, and consequently, develop a large, ambitious and innovative tool through which future scientific questions may be answered. This research must be patient-related so that rapid feedback to the bedside is achieved and should aim to identify clinical-, biological- and tumor-related factors that are associated with treatment resistance. Finally, this research should also seek to explain epidemiological and social facets of disease behavior. METHODS: The prospective FREGAT database, established by the French National Cancer Institute, is focused on adult patients with carcinomas of the esophagus and stomach and on whatever might be the tumor stage or therapeutic strategy. The database includes epidemiological, clinical, and tumor characteristics data as well as follow-up, human and social sciences quality of life data, along with a tumor and serum bank. DISCUSSION: This innovative method of research will allow for the banking of millions of data for the development of excellent basic, translational and clinical research programs for esophageal and gastric cancer. This will ultimately improve general knowledge of these diseases, therapeutic strategies and patient survival. This database was initially developed in France on a nationwide basis, but currently, the database is available for worldwide contributions with respect to the input of patient data or the request for data for scientific projects. TRIAL REGISTRATION: The FREGAT database has a dedicated website ( www.fregat-database.org ) and is registered on the Clinicaltrials.gov site, number NCT 02526095 , since August 8, 2015. PMID- 29409463 TI - Overweight or obese BMI is associated with earlier, but not later survival after common acute illnesses. AB - BACKGROUND: Obesity has been associated with improved short-term mortality following common acute illness, but its relationship with longer-term mortality is unknown. METHODS: Observational study of U.S. Health and Retirement Study (HRS) participants with federal health insurance (fee-for-service Medicare) coverage, hospitalized with congestive heart failure (N = 4287), pneumonia (N = 4182), or acute myocardial infarction (N = 2001), 1996-2012. Using cox proportional hazards models, we examined the association between overweight or obese BMI (BMI >= 25.0 kg/m2) and mortality to 5 years after hospital admission, adjusted for potential confounders measured at the same time as BMI, including age, race, sex, education, partnership status, income, wealth, and smoking status. Body mass index (BMI) was calculated from self-reported height and weight collected at the HRS survey prior to hospitalization (a median 1.1 year prior to hospitalization). The referent group was patients with a normal BMI (18.5 to < 25.0 kg/m2). RESULTS: Patients were a median of 79 years old (IQR 71-85 years). The majority of patients were overweight or obese: 60.3% hospitalized for heart failure, 51.5% for pneumonia, and 61.6% for acute myocardial infarction. Overweight or obese BMI was associated with lower mortality at 1 year after hospitalization for congestive heart failure, pneumonia, and acute myocardial infarction-with adjusted hazard ratios of 0.68 (95% CI 0.59-0.79), 0.74 (95% CI: 0.64-0.84), and 0.65 (95%CI: 0.53-0.80), respectively. Among participants who lived to one year, however, subsequent survival was similar between patients with normal versus overweight/obese BMI. CONCLUSIONS: In older Americans, overweight or obese BMI was associated with improved survival following hospitalization for congestive heart failure, pneumonia, and acute myocardial infarction. This association, however, is limited to the shorter-term. Conditional on surviving to one year, we did not observe a survival advantage associated with excess weight. PMID- 29409464 TI - CK1alpha overexpression correlates with poor survival in colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1alpha might have the potential to serve as prognostic marker. METHODS: CK1alpha RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1alpha expression levels with patients' survival rate generating Kaplan-Meier survival plots. RESULTS: It could be shown that CK1alpha is overexpressed in colorectal tumor tissue compared to normal tissue and CK1alpha overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1alpha is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side. CONCLUSION: In summary, this study provides evidence for the first time that CK1alpha RNA levels might serve as prognostic marker for CRC. PMID- 29409466 TI - Frequency of the acquired resistant mutation T790 M in non-small cell lung cancer patients with active exon 19Del and exon 21 L858R: a systematic review and meta analysis. AB - BACKGROUND: Although EGFR-TKI is the preferred treatment for NSCLC patients with sensitive mutations, subsequent drug resistance is almost inevitable. The specific mechanisms of EGFR-TKI drug resistance can be identified through repeat biopsy. METHODS: To better understand the clinical characteristics of TKI resistance in NSCLC patients, we retrospectively reviewed studies of acquired TKI drug resistance using repeat biopsy from the last decade. The relevant literature was retrieved from January 2005 to August 2015 in the databases Medline and Embase. The search terms were NSCLC or non-small cell lung cancer and T790 M. RESULTS: A total of 478 patients with NSCLC tested by repeated biopsy were confirmed to have acquired TKI resistance. Analysis indicated that 240 patients (50.21%) of the 478 patients with acquired TKI drug resistance had the T790 M mutation. The detection rate of T790 M in different repeat biopsy sites was also different, with the highest positive rate in the lymph nodes (60%) and the lowest detection rate in cerebrospinal fluid (less than 5%). In addition, patients with T790 M had longer overall survival compared to those without the mutation (P < 0.05). Of the 240 patients with T790 M mutations, 213 patients showed results consistent with the mutation analysis before TKI treatment, and the rate of patients with the L858R point mutation along with the T790 M mutation was lower than that of patients with the exon 19 deletion (36.42% to 58.30%). CONCLUSIONS: T790 M occurred more frequently in patients with the exon 19 deletion than in those with exon 21 L858R, which gave the survival benefit of the T790 M mutation and may explain why patients with the exon 19 deletion had an improved overall survival. PMID- 29409467 TI - Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells. AB - BACKGROUND: We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain containing phosphatase-1 (SHP-1) during this process. METHODS: We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route. RESULTS: Treatment of ATO 5 and 10 MUM significantly decreased cellular migration and invasion in a dose dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate. CONCLUSION: Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells. PMID- 29409465 TI - Association of rs2282679 A>C polymorphism in vitamin D binding protein gene with colorectal cancer risk and survival: effect modification by dietary vitamin D intake. AB - BACKGROUND: The rs2282679 A>C polymorphism in the vitamin D binding protein gene is associated with lower circulating levels of vitamin D. We investigated associations of this SNP with colorectal cancer (CRC) risk and survival and whether the associations vary by dietary vitamin D intake and tumor molecular phenotype. METHODS: A population-based case-control study identified 637 incident CRC cases (including 489 participants with follow-up data on mortality end points) and 489 matched controls. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom(r) myDesignTM Array in controls. Logistic regression examined the association between the rs2282679 polymorphism and CRC risk with inclusion of potential confounders. Kaplan-Meier curves and multivariable Cox models assessed the polymorphism relative to overall survival (OS) and disease-free survival (DFS). RESULTS: The rs2282679 polymorphism was not associated with overall CRC risk; there was evidence, however, of effect modification by total vitamin D intake (Pinteraction = 0.019). Survival analyses showed that the C allele was correlated with poor DFS (per-allele HR, 1.36; 95%CI, 1.05-1.77). The association of rs2282679 on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95%CI, 1.12-2.23). For OS, the C allele was associated with higher all-cause mortality among patients with higher levels of dietary vitamin D (HR, 2.11; 95%CI, 1.29-3.74), calcium (HR, 1.93; 95%CI, 1.08-3.46), milk (HR, 2.36; 95%CI, 1.26-4.44), and total dairy product intakes (HR, 2.03; 95%CI, 1.11-3.72). CONCLUSION: The rs2282679 SNP was not associated with overall CRC risk, but may be associated with survival after cancer diagnosis. The association of this SNP on survival among CRC patients may differ according to dietary vitamin D and calcium intakes and according to tumor BRAF mutation status. PMID- 29409468 TI - Delirium in older hospitalized patients-signs and actions: a retrospective patient record review. AB - BACKGROUND: Delirium is common in older hospitalized patients, and is associated with negative consequences for the patients, next of kin, healthcare professionals and healthcare costs. It is important to understand its clinical features, as almost 40% of all cases in hospitals may be preventable. Yet, delirium in hospitalized patients is often unrecognized and untreated. Few studies describe thoroughly how delirium manifests itself in older hospitalized patients and what actions healthcare professionals take in relation to these signs. Therefore, the aim of this study was to describe signs of delirium in older hospitalized patients and action taken by healthcare professionals, as reported in patient records. METHODS: Patient records from patients aged >=65 (n = 286) were retrospectively reviewed for signs of delirium, which was found in 78 patient records (27%). Additionally, these records were reviewed for action taken by healthcare professionals in relation to the patients' signs of delirium. The identified text was analyzed with qualitative content analysis in two steps. RESULTS: Healthcare professionals responded only in part to older hospitalized patients' needs of care in relation to their signs of delirium. The patients displayed various signs of delirium that led to a reduced ability to participate in their own care and to keep themselves free from harm. Healthcare professionals met these signs with a variation of actions and the care was adapted, deficient and beyond the usual care. A systematic and holistic perspective in the care of older hospitalized patients with signs of delirium was missing. CONCLUSION: Improved knowledge about delirium in hospitals is needed in order to reduce human suffering, healthcare utilization and costs. It is important to enable older hospitalized patients with signs of delirium to participate in their own care and to protect them from harm. Delirium has to be seen as a preventable adverse event in all hospitals units. To improve the prevention and management of older hospitalized patients with signs of delirium, person-centered care and patient safety may be important issues. PMID- 29409471 TI - PD-L1 expression in malignant salivary gland tumors. AB - BACKGROUND: Programmed death-1 ligand-1 (PD-L1) an important cancer biomarker that can suppress the immune system and its high expression is often reported to be related with increased tumor aggressiveness in some cancers. Here, we examined and evaluated PD-L1 expression in patients with malignant salivary gland tumor. Moreover, the relationship between PD-L1 immunolocalization and clinical pathological features, as well as the prognosis of malignant salivary gland tumors was investigated. METHODS: We examined PD-L1expression in 47 patients with malignant salivary gland tumor by immunohistochemical staining. PD-L1 positivity was defined as >=5% in tumor cell membrane and evaluated according to three categories (0% = 0, < 5% = 1, >=5% = 2) in tumor-infiltrating mononuclear cells (TIMCs). Fisher's exact test was used to compare between PD-L1 expression and clinico-pathological features, and Kaplan-Meier method was used to estimate the distribution of OS by PD-L1 positivity. RESULTS: PD-L1 expression was detected in 51.1% of malignant salivary gland tumor tissues. No association was observed between PD-L1 immunolocalization in tumor and patient gender, or age. However, PD L1 immunodetection of tumor cell membranes was significantly associated to stage, recurrence or metastasis after surgery, and patient outcome. On the other hand, PD-L1 immunodetection of tumor-infiltrating mononuclear cells (TIMCs) was significantly associated to recurrence or metastasis after surgery, and patient outcome. PD-L1 positivity in both tumor cell membrane and TIMCs was associated with shorter overall survival (OS) (p = 0.002 and p = 0.016, respectively). CONCLUSION: These findings suggested that patients with PD-L1 positive tumors or TIMCs appear to have poor clinical outcomes in malignant salivary gland tumors. PMID- 29409470 TI - Identifying the social and environmental determinants of plague endemicity in Peru: insights from a case study in Ascope, La Libertad. AB - BACKGROUND: Plague remains a public health problem in specific areas located in Bolivia, Brazil, Ecuador and Peru. Its prevention and control encompasses adequate clinical management and timely laboratory diagnosis. However, understanding communities' interaction with its surrounding ecosystem as well as the differences between community members and institutional stakeholders regarding the root causes of plague might contribute to understand its endemicity. We aim at bridging the traditionally separate biological and social sciences by elucidating communities' risk perception and identifying knowledge gaps between communities and stakeholders. This approach has been used in other areas but never in understanding plague endemicity, nor applied in the Latin American plague context. The objectives were to identify (i) plague risk perception at community level, (ii) perceived social and environmental determinants of plague endemicity, and (iii) institutions that need to be involved and actions needed to be taken as proposed by stakeholders and community members. The study was performed in 2015 and took place in Ascope rural province, La Libertad Region, in Peru, where the study areas are surrounded by intensive private sugarcane production. METHODS: We propose using a multi-level discourse analysis. Community households were randomly selected (n = 68). Structured and semi-structured questionnaires were applied. A stakeholder analysis was used to identify policy makers (n = 34). In-depth interviews were performed, recorded and transcribed. Descriptive variables were analyzed with SPSS(r). Answers were coded following variables adapted from the Commission on Social Determinants of Health and analyzed with the assistance of ATLAS.ti(r). RESULTS: Results showed that risk perception was low within the community. Policy-makers identified agriculture and sugarcane production as the root cause while community answers ranked the hygiene situation as the main cause. Stakeholders first ranked governmental sectors (education, housing, agriculture and transport) and the community prioritized the health sector. Social surveillance and improving prevention and control were first cited by policy-makers and community members, respectively. CONCLUSIONS: The determinants of plague endemicity identified by the two groups differed. Similarly, actions and sectors needed to be involved in solving the problem varied. The gaps in understanding plague root causes between these two groups might hinder the efficiency of current plague prevention and control strategies. PMID- 29409469 TI - Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. METHODS: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided alpha 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. DISCUSSION: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care. PMID- 29409472 TI - Dietary flexibility of Bale monkeys (Chlorocebus djamdjamensis) in southern Ethiopia: effects of habitat degradation and life in fragments. AB - BACKGROUND: Understanding the effects of habitat modification on the feeding strategies of threatened species is essential to designing effective conservation management plans. Bale monkeys (Chlorocebus djamdjamensis) are endemic to the rapidly shrinking montane forests of the southern Ethiopian Highlands. Most populations inhabit continuous bamboo forest subsisting largely on the young leaves and shoots of a single species of bamboo. Because of habitat disturbance in recent decades, however, there are now also several dozen small populations inhabiting isolated forest fragments where bamboo has been degraded. During 12 months, we assessed Bale monkey responses to habitat degradation by comparing habitat composition, phenological patterns, and feeding ecology in a largely undisturbed continuous forest (Continuous groups A and B) and in two fragments (Patchy and Hilltop groups). RESULTS: We found that habitat quality and food availability were much lower in fragments than in continuous forest. In response to the relative scarcity of bamboo in fragments, Bale monkeys spent significantly less time feeding on the young leaves and shoots of bamboo and significantly more time feeding on non-bamboo young leaves, fruits, seeds, stems, petioles, and insects in fragments than in continuous forest. Groups in fragments also broadened their diets to incorporate many more plant species (Patchy: >= 47 and Hilltop: >= 35 species)-including several forbs, graminoids and cultivated crops than groups in continuous forest (Continuous A: 12 and Continuous B: 8 species). Nevertheless, bamboo was still the top food species for Patchy group (30% of diet) as well as for both continuous forest groups (mean = 81%). However, in Hilltop group, for which bamboo was especially scarce, Bothriochloa radicans (Poaceae), a grass, was the top dietary species (15% of diet) and bamboo ranked 10th (2%). CONCLUSIONS: We demonstrate that Bale monkeys are more dietarily flexible than previously thought and able to cope with some degradation of their primary bamboo forest habitat. However, crop raiding and other terrestrial foraging habits more common among fragment groups may place them at greater risk of hunting by humans. Thus, longitudinal monitoring is necessary to evaluate the long-term viability of Bale monkey populations in fragmented habitats. PMID- 29409473 TI - Attention-deficit hyperactivity disorder and nonsuicidal self-injury in a clinical sample of adolescents: the role of comorbidities and gender. AB - BACKGROUND: The aim of the present study was to investigate the possible association between attention-deficit hyperactivity disorder (ADHD) and non suicidal self-injury (NSSI) with special focus on the role of comorbidities and gender in a clinical sample of adolescents with both a dimensional and a categorical approach to psychopathology. METHODS: Using a structured interview, the Mini International Neuropsychiatric Interview Kid and a self-rated questionnaire, the Deliberate Self-Harm Inventory, the authors examined 202 inpatient adolescents (aged: 13-18 years) in the Vadaskert Child and Adolescent Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary. Descriptive statistics, Mann-Whitney U test, chi-square test and mediator model were used. RESULTS: Fifty-two adolescents met full criteria for ADHD and a further 77 showed symptoms of ADHD at the subthreshold level. From the 52 adolescents diagnosed with ADHD, 35 (67.30%) had NSSI, of whom there were significantly more girls than boys, boys: n = 10 (28.60%), girls: n = 25 (71.40%) ((chi2(1) = 10.643 p < .001 phi = .452). Multiple mediation analyses resulted in a moderated mediation model in which the relationship between symptoms of ADHD and the prevalence of current NSSI was fully mediated by the symptoms of comorbid conditions in both sex. Significant mediators were the symptoms of affective and psychotic disorders and suicidality in both sexes and the symptoms of alcohol abuse/dependence disorders in girls. CONCLUSIONS: ADHD symptoms are associated with an increased risk of NSSI in adolescents, especially in the case of girls. Our findings suggest that clinicians should routinely screen for the symptoms of ADHD and comorbidity, with a special focus on the symptoms of affective disorders and alcohol abuse/dependence psychotic symptoms to prevent NSSI. PMID- 29409474 TI - Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target? AB - BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment. METHODS: Data from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells. RESULTS: By bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer. CONCLUSIONS: ETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients. PMID- 29409475 TI - Impact of body mass index on surgical outcomes of gastric cancer. AB - BACKGROUND: The association between body mass index (BMI) and clinical outcomes of gastric cancer were still under debate. The aim of the present study was to investigate the impact of BMI on intraoperative conditions, postoperative complications and prognosis of gastric cancer. METHODS: From October 2008 to March 2015, 1210 gastric cancer patients treated with D2 gastrectomy were enrolled in the present study. Patients were divided into three groups: low BMI group (BMI < 18.5 Kg/m2), normal BMI group (18.5 Kg/m2 <= BMI < 25.0 Kg/m2) and high BMI group (BMI >= 25.0 Kg/m2). Clinicopathological characteristics and prognosis of patients were recorded and analyzed. Propensity score matching was used to match patients in the three groups. RESULTS: There were 107 patients in low BMI group (8.9%), 862 patients in normal BMI group (71.2%) and 241 patients in high BMI group (19.95%). Before matching, BMI was inversely associated with tumor size, tumor depth, lymph node metastasis (LNM) and tumor stage (all P < 0.05). After matching, the clinicopathological features were all comparable among the three groups (all P > 0.05). High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes (all P < 0.05). For postoperative complications, low BMI was associated with decreased rate of postoperative fever (P = 0.025). Age, BMI, tumor size, Borrmann type, pathological type, type of gastrectomy, tumor depth, LNM and tumor stage were risk factors for the prognosis of gastric cancer. Multivariate analysis showed that only BMI, tumor size, tumor depth and LNM were independent prognostic factors. The overall survival of patients with low BMI was significantly worse than patients with normal (P < 0.05) or high BMI (P < 0.05). However, the overall survival was comparable between patients with normal and high BMI (P > 0.05). CONCLUSIONS: BMI was inversely associated with tumor size, tumor depth, LNM and tumor stage. High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes. Low BMI was associated with decreased rate of postoperative fever and decreased survival. PMID- 29409476 TI - Germline BRCA1/BRCA2 mutations among high risk breast cancer patients in Jordan. AB - BACKGROUND: Breast cancer is the most common malignancy and the leading cause of cancer-related deaths among Jordanian women. With a median age of 50 years at diagnosis, a higher prevalence of hereditary breast cancer may be expected. The objective of this pilot study is to evaluate, for the first time, the contribution of germline mutations in BRCA1/2 to breast cancer among Jordanian patients. METHODS: Jordanian breast cancer women with a selected high risk profile were invited to participate. Peripheral blood samples were obtained for DNA extraction. A detailed 3-generation family history was also collected. BRCA sequencing was performed at a reference laboratory. Mutations were classified as deleterious, suspected deleterious, variant of uncertain significance or favor polymorphisms. Patients' medical records were reviewed for extraction of clinical and tumor pathology data. RESULTS: One hundred patients were enrolled to the study. Median age was 40 (22-75) years. In total, 20 patients had deleterious and 7 suspected deleterious mutations in BRCA1 or BRCA2 genes. Seven variants of uncertain significance were also detected. After excluding patients tested subsequent to the index case in their families, highest mutation rates were observed among triple negatives (9/16, 56.3%) especially among those with positive family history of breast and/or ovarian cancer (9/13, 69.2%), patients with bilateral or second primary breast cancer (10/15, 66.7%) and those with family history of male breast cancer (2/5, 40.0%). CONCLUSIONS: BRCA1/2 mutations are not uncommon among selected Jordanian females with breast cancer. The contribution of these findings to much younger age at diagnosis is debatable. Although small, our selected patient cohort shows an important incidence of deleterious and suspected deleterious BRCA1/2 mutations suggesting that genetic testing should be offered to patients with certain high risk features. PMID- 29409477 TI - Clinical and radiological outcomes of arthroscopically assisted cannulated screw fixation for tibial eminence fracture in children and adolescents. AB - BACKGROUND: The purpose of this study was to determine the efficacy and complications of arthroscopically assisted reduction and fixation with cannulated screws for tibial eminence fracture in skeletally immature patients. METHODS: This was a retrospective case series study. Forty-eight patients who were skeletally immature at the time of tibial eminence fracture were treated in a tertiary children's hospital between May 2004 and August 2015. Twenty-one patients were excluded due to non-operative treatment (n = 10), other surgical treatments (n = 9), multiple fracture (n = 1), and follow-up < 1 year (n = 1). Twenty-seven knees of 27 patients were analyzed. Avulsed fragment was reduced arthroscopically. One to three cannulated screws (4.0 mm or 5.0 mm in diameter) were used for fixation. Passive knee motion was started in 3-4 weeks. Clinical outcomes were evaluated by Lysholm score, instability of the knee, and complications. Radiological outcomes including nonunion and malunion of the avulsed fragment and physeal growth disturbance were evaluated. RESULTS: Mean age at the time of surgery was 10.1 years (range, 6.2 to 13.8 years). Patients were followed up for a mean of 3.9 years (range, 1.0 to 7.6 years). Fracture types included type III (n = 13), type II (n = 12), and type IV (n = 2) according to Zaricznyj modification of Meyers and McKeever classification. Meniscus was entrapped in five patients. Six patients showed concomitant meniscal tear. Mean Lysholm score at the latest follow-up was 95 (range, 78 to 100). Joint instability was not observed in any patient except one (instability of 5-10 mm). All patients showed full range of knee motion except one (10 degrees of flexion contracture). Screw head impingement against intercondylar notch of the femur was observed in two patients during screw removal procedure. Five knees showed prominent tibial eminence without symptoms. The injured lower limb was longer than the contralateral normal side by a mean of 6.2 mm (range, - 4 to 18 mm). CONCLUSIONS: Arthroscopically assisted reduction and fixation with cannulated screws is an effective and safe surgical option for treating tibial eminence fracture with few complications. PMID- 29409478 TI - Parathyroid cysts: experience of a rare phenomenon at a single institution. AB - BACKGROUND: Parathyroid cysts are relatively uncommon lesions and are often misdiagnosed. We evaluate our experience in the diagnosis of and therapy to correct parathyroid cystic lesions. METHODS: We retrospectively reviewed a series of 32 patients with parathyroid cysts who were admitted to our department between July 2011 and November 2016. Clinical pathological features of the patients, including age, gender, location, size, ultrasonography, histopathology, surgery, and follow-up, were analyzed. RESULTS: There were 22 female and 10 male participants with a median age of 46.7 years old (27-76 years old). Only two cysts were found in the superior mediastinum. The rest were located under the lower pole of the thyroid. All of the patients underwent ultrasonography scans and serum parathyroid hormone (PTH) assays. Three patients had elevated serum PTH levels, and they were further scanned with Tc99m sestamibi as functional cysts. In 29 cases of nonfunctional cysts, 3 cases were preoperatively diagnosed by cystic aspiration with PTH detection. The rest were diagnosed by postoperative immunopathology. All of the patients underwent cystectomy, and 24 patients also underwent thyroidectomy. There was a significant difference in cyst diameter size between the cystectomy alone and cystectomy with thyroidectomy groups (4.0 +/- 2.0 vs 1.5 +/- 1.0 cm; p < 0.05). No participant experienced recurrence during the median 36 months of follow-up. CONCLUSIONS: Cystic lesions located under the lower pole of the thyroid gland should be considered to have originated at the parathyroid gland. Cystic aspiration with PTH detection or postoperative immunopathology can lead to a definitive diagnosis. Cystectomy is still a commonly used and effective treatment. PMID- 29409479 TI - Orbital radiotherapy plus three-wall orbital decompression in a patient with rare ocular manifestations of thyroid eye disease: case report. AB - BACKGROUND: Thyroid eye disease (TED) is a debilitating autoimmune orbital disease that is often a result of Graves' disease. Dysthyroid optic neuropathy (DON) is a rare but sight-threatening manifestation of TED with therapeutic challenges that can potentially lead to visual loss. CASE PRESENTATION: A 74-year old man experienced active TED with extremely severe redness and swelling of the conjunctiva, loss of visual acuity and exacerbation of disfiguring proptosis. Computed tomography revealed the involvement of extraocular muscles resulting in optic nerve compression. He was in poor general condition and was intolerant to steroids. To achieve the optimal operating conditions for orbital decompression surgery, the patient was initially treated with orbital radiotherapy. The patient responded well, with improvements in clinical activity score and visual acuity. CONCLUSION: This case demonstrates a rare and severe case of DON with therapeutic challenges. To date, no cases has been reported of a patient with such severe and unusual ocular manifestations. Early awareness of the occurrence of optic nerve compression and prompt treatment are important to prevent irreversible outcomes. Orbital radiotherapy should be considered as a useful surgery-delaying alternative for DON, especially in patients who have contraindications to steroids. PMID- 29409481 TI - How the study of online collaborative learning can guide teachers and predict students' performance in a medical course. AB - BACKGROUND: Collaborative learning facilitates reflection, diversifies understanding and stimulates skills of critical and higher-order thinking. Although the benefits of collaborative learning have long been recognized, it is still rarely studied by social network analysis (SNA) in medical education, and the relationship of parameters that can be obtained via SNA with students' performance remains largely unknown. The aim of this work was to assess the potential of SNA for studying online collaborative clinical case discussions in a medical course and to find out which activities correlate with better performance and help predict final grade or explain variance in performance. METHODS: Interaction data were extracted from the learning management system (LMS) forum module of the Surgery course in Qassim University, College of Medicine. The data were analyzed using social network analysis. The analysis included visual as well as a statistical analysis. Correlation with students' performance was calculated, and automatic linear regression was used to predict students' performance. RESULTS: By using social network analysis, we were able to analyze a large number of interactions in online collaborative discussions and gain an overall insight of the course social structure, track the knowledge flow and the interaction patterns, as well as identify the active participants and the prominent discussion moderators. When augmented with calculated network parameters, SNA offered an accurate view of the course network, each user's position, and level of connectedness. Results from correlation coefficients, linear regression, and logistic regression indicated that a student's position and role in information relay in online case discussions, combined with the strength of that student's network (social capital), can be used as predictors of performance in relevant settings. CONCLUSION: By using social network analysis, researchers can analyze the social structure of an online course and reveal important information about students' and teachers' interactions that can be valuable in guiding teachers, improve students' engagement, and contribute to learning analytics insights. PMID- 29409480 TI - Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells. AB - BACKGROUND: Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves. The aim of this study is to test the hypothesis that epigenetic dysregulation of apoptosis mediators underlies PDAC resistance to gemcitabine, the standard chemotherapy for human PDAC. METHODS: PDAC cells were analyzed for apoptosis sensitivity in the presence of a selective epigenetic inhibitor. The epigenetic regulation of apoptosis regulators was determined by Western Blotting and quantitative PCR. The specific epigenetic modification of apoptosis regulator promoter chromatin was determined by chromatin immunoprecipitation in PDAC cells. RESULTS: Inhibition of histone methyltransferase (HMTase) by a selective HMTase inhibitor, verticillin A, significantly increased human PDAC cell sensitivity to gemcitabine-induced growth suppression. Verticillin A treatment decreased FLIP, Mcl-1, Bcl-x and increased Bak, Bax and Bim protein level in the tumor cells, resulting in activation of caspases, elevated cytochrome C release and increased apoptosis as determined by upregulated PARP cleavage in tumor cells. Analysis of human PDAC specimens indicated that the expression levels of anti-apoptotic mediators Bcl-x, Mcl-1, and FLIP were significantly higher, whereas the expression levels of pro apoptotic mediators Bim, Bak and Bax were dramatically lower in human PDAC tissues as compared to normal pancreas. Verticillin A downregulated H3K4me3 levels at the BCL2L1, CFLAR and MCL-1 promoter to decrease Bcl-x, FLIP and Mcl-1 expression level, and inhibited H3K9me3 levels at the BAK1, BAX and BCL2L11 promoter to upregulate Bak, Bax and Bim expression level. CONCLUSION: We determined that PDAC cells use H3K4me3 to activate Bcl-x, FLIP and Mcl-1, and H3K9me3 to silence Bak, Bax and Bim to acquire an apoptosis-resistant phenotype. Therefore, selective inhibition of H3K4me3 and H3K9me3 is potentially an effective approach to overcome PDAC cells resistance to gemcitabine. PMID- 29409482 TI - Cross-cultural adaptation and validation of the child perceptions questionnaire (CPQ11-14) among children in Lebanon. PMID- 29409483 TI - Real-world refractive outcomes of toric intraocular lens implantation in a United Kingdom National Health Service setting. AB - BACKGROUND: With increasing availability of toric intraocular lenses (IOL) for cataract surgery, real-world refractive outcome data is needed to aid the counselling of patients regarding lens choice. We aim to assess the outcomes of toric intraocular lens use in the non-specialist environment of a typical United Kingdom NHS cataract service. METHODS: A retrospective cohort study conducted at the Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, UK. All patients who received a toric IOL implant over a 10 months period. Patients underwent pre-operative corneal marking, phacoemulsification and toric IOL implantation. Biometry was obtained using a Zeiss IOLMaster 500 and the toric IOLs were selected using the manufacturers' online calculators. Post-operative refractions were obtained from optometrist's manifest refraction or by autorefraction. The outcome measures were post-operative unaided visual acuity (UVA), spherical equivalent refraction, cylindrical correction and all complications. RESULTS: Thirty-two eyes of 24 patients aged 21-86 years (mean 66.4, SD 14.5) were included. UVA was superior to pre-operative best-corrected visual acuity (BCVA) in 81% of eyes, same in 16% and inferior in 3%, resulting in a median improvement of 0.20 LogMAR (IQR 0.10 to 0.30). 56%, 81%, 94% and 100% of eyes were within +/-0.5, +/-1.0, +/-1.5 and +/-2.0 D of predicted spherical equivalent, respectively. Three (9%) eyes required further surgery to rectify significant IOL rotation. CONCLUSIONS: Reduced cylindrical correction and improved UVA could be expected in the majority of patients undergoing toric IOL implantation. Patients should be counselled about the risk of lens rotation. PMID- 29409484 TI - The UDP-glucose ceramide glycosyltransferase (UGCG) and the link to multidrug resistance protein 1 (MDR1). AB - The UDP-glucose ceramide glycosyltransferase (UGCG) is a key enzyme in the sphingolipid metabolism by generating glucosylceramide (GlcCer), the precursor for all glycosphingolipids (GSL), which are essential for proper cell function. Interestingly, the UGCG is also overexpressed in several cancer types and correlates with multidrug resistance protein 1 (MDR1) gene expression. This membrane protein is responsible for efflux of toxic substances and protects cancer cells from cell damage through chemotherapeutic agents. Studies showed a connection between UGCG and MDR1 overexpression and multidrug resistance development, but the precise underlying mechanisms are unknown. Here, we give an overview about the UGCG and its connection to MDR1 in multidrug resistant cells. Furthermore, we focus on UGCG transcriptional regulation, the impact of UGCG on cellular signaling pathways and the effect of UGCG and MDR1 on the lipid composition of membranes and how this could influence multidrug resistance development. To our knowledge, this is the first review presenting an overview about UGCG with focus on the relationship to MDR1 in the process of multidrug resistance development. PMID- 29409485 TI - Unearthing new genomic markers of drug response by improved measurement of discriminative power. AB - BACKGROUND: Oncology drugs are only effective in a small proportion of cancer patients. Our current ability to identify these responsive patients before treatment is still poor in most cases. Thus, there is a pressing need to discover response markers for marketed and research oncology drugs. Screening these drugs against a large panel of cancer cell lines has led to the discovery of new genomic markers of in vitro drug response. However, while the identification of such markers among thousands of candidate drug-gene associations in the data is error-prone, an appraisal of the effectiveness of such detection task is currently lacking. METHODS: Here we present a new non-parametric method to measuring the discriminative power of a drug-gene association. Unlike parametric statistical tests, the adopted non-parametric test has the advantage of not making strong assumptions about the data distorting the identification of genomic markers. Furthermore, we introduce a new benchmark to further validate these markers in vitro using more recent data not used to identify the markers. RESULTS: The application of this new methodology has led to the identification of 128 new genomic markers distributed across 61% of the analysed drugs, including 5 drugs without previously known markers, which were missed by the MANOVA test initially applied to analyse data from the Genomics of Drug Sensitivity in Cancer consortium. CONCLUSIONS: Discovering markers using more than one statistical test and testing them on independent data is unusual. We found this helpful to discard statistically significant drug-gene associations that were actually spurious correlations. This approach also revealed new, independently validated, in vitro markers of drug response such as Temsirolimus-CDKN2A (resistance) and Gemcitabine EWS_FLI1 (sensitivity). PMID- 29409486 TI - Antidepressants use and risk of cataract development: a systematic review and meta-analysis. AB - BACKGROUND: Epidemiological studies suggest that antidepressants use may increase the risk of cataract, but the results are inconclusive. We aimed to examine this association by performing a systematic review and meta-analysis. METHODS: Relevant studies were identified by searching PubMed and Web of Science databases through June 2017. We included studies that reported risk estimates for the association between antidepressants use and cataract risk. A random-effects model was used to calculate the summary odds ratio (OR) with its 95% confidence interval (CI). RESULTS: We identified seven studies of antidepressants use and risk of cataract involving 447,672 cases and 1,510,391 controls. Overall, the combined ORs (95% CIs) of cataract for selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenalin reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) were 1.12 (1.06-1.19), 1.13 (1.04-1.24), and 1.19 (1.11 1.28), respectively. A certain degree of heterogeneity was observed across studies (P < 0.001, I 2 = 92.2% for SSRIs, P = 0.026, I 2 = 67.5% for SNRIs, and P = 0.092, I 2 = 58.0% for TCAs). CONCLUSION: This meta-analysis provides evidence of a significant positive association between antidepressants use and risk of cataract. Because of the heterogeneity and limited eligible studies, further prospective studies are warranted to confirm the preliminary findings of our study. PMID- 29409487 TI - Heterogeneous pattern of differences in respiratory parameters between elderly with either good or poor FEV1. AB - BACKGROUND: The relationship of spirometric values to other respiratory and functional parameters in advanced age is not well studied. We assessed this relationship in elderly subjects with either good or poor spirometric parameters to reveal whether different domains of lung function show comparable differences between the two groups. METHODS: Among subjects of the population-based KORA-Age cohort (n = 935, 65-90y; 51% male) two groups were selected from either the lower (LED; n = 51) or the upper (UED; n = 72) end of the FEV1 distribution. All subjects did not have a history of lung disease and were non-smokers at the time of the study. Measurements included spirometry, body plethysmography, diffusing capacity for NO and CO, respiratory pump function and exhaled NO (FeNO). In addition, 6-min walking distance as a functional overall measure, as well as telomere length of blood leukocytes and serum 8-hydroxydeoxyguanosine (8-OHdG) as potential markers of overall biological ageing and stress were determined. RESULTS: In the majority of parameters, LED subjects showed significantly impaired values compared to UED subjects. Differences in spirometric parameters, airway resistance and respiratory pump function ranged between 10% and more than 90% in terms of predicted values. In contrast, volume-related CO and NO diffusing capacity showed differences between groups of lower than 5%, while telomere length, 8-OHdG and FeNO were similar. This was reflected in the differences in "functional age" as derived from prediction equations. CONCLUSIONS: In elderly subjects without a history of lung disease differences in spirometric parameters were associated with differences in other lung-mechanical parameters including body plethysmography but not with differences in volume-corrected gas exchange measures. Thus, the concept of a general "lung age" as suggested by the widespread use of this term in connection with spirometry should be considered with caution. PMID- 29409488 TI - The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis. AB - BACKGROUND: Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). METHODS: The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99mTechnetium-labelled monodisperse salbutamol (1.5 MUm or 6 MUm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 MUg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). RESULTS: Small monodisperse particles (1.5 MUm) achieved significantly better total lung deposition (TLD, mean % +/- SD) than larger particles (6 MUm), where polydisperse nebulisation was poor; (TLD, 64.93 +/- 10.72; 50.46 +/- 17.04; 8.19 +/- 7.72, respectively). Small monodisperse particles (1.5 MUm) achieved significantly better lung penetration (mean % +/- SD) than larger particles (6 MUm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean +/- SD) 0.8 +/- 0.16, 0.49 +/- 0.21, and 0.73 +/- 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 MUm and 6 MUm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. CONCLUSION: Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. TRIAL REGISTRATION: This trial was registered on clinicaltrials.gov ( NCT01457261 ). PMID- 29409489 TI - Intimate partner sexual violence and risk for femicide, suicidality and substance use among women in antenatal care and general out-patients in Thailand. AB - BACKGROUND: Little is known about the occurrence and health consequences of intimate partner sexual assault. The aim of this study was to assess the prevalence and correlates of sexual assault in the context of intimate partner violence (IPV) in Thailand. METHODS: In a cross-sectional survey adult female participants were systematically screened (self-administered or interview administered) for IPV in antenatal care and general outpatient clinics in nine randomly selected hospitals in two provinces in the central region. Measures included the Abuse Assessment Screen, Severity of Violence Against Women Scale, Danger assessment and suicidal behaviour. RESULTS: From 14,288 women screened, 1.5% were positive for IPV and 207 participated in the study. The mean age of the study participants was 26.8 years (SD = 9.3). Fifty-seven women, 27.5% of the sample, reported sexual assault, one or more times, during the relationship in the past 12 months. Most reported some form of psychological abuse (82.1%), physical violence (67.1%) and danger (72.0%). In all, 21.3% reported psychological, physical and sexual violence. Bivariate analyses found that older age, being recruited in the general out-patient department, greater number of children, high psychological abuse, high physical violence, danger and suicidal behaviour in the past 12 months were associated with sexual assault. In multivariable backward conditional logistic regression physical violence (OR = 5.32, CI = 2.52-11.24) and suicidal behaviour (OR = 3.28, CI = 1.37-7.83) were found to be associated with sexual assault. CONCLUSIONS: The study found a moderate rate of sexual assault in intimate violent partner relationships and those sexual assaults are more likely to co-occur with physical intimate partner violence and suicidal behaviour. This knowledge may be helpful in the detection and management of sexual assault in intimate violent partner relationships of women in health care settings in Thailand. PMID- 29409490 TI - Unilateral pedal lymphangiography plus computed tomography angiography for location of persistent idiopathic chyle leakage not detectable by ordinary contrast computed tomography. AB - BACKGROUND: To identify the value of unilateral pedal lymphangiography (LPG) plus computed tomography angiography (CTA) in accurate depiction of persistent idiopathic chyluria undetectable by ordinary contrast CT. METHODS: Eighteen patients 44-63 years of age with persistent idiopathic chyluria who failed conservative management were included. Ordinary CT had not revealed a chyle leak. Cystoscopy, unilateral LPG, and post-LPG CT angiography (CTA) were sequentially performed. Ligation and stripping of the perirenal lymphatics were subsequently performed guided by lymphangiography and CTA. RESULTS: LPG and post-LPG CTA detected 17 unilateral and one bilateral chyle leaks in the 18 patients, with clear images of the communication of lymphatic vessels and the renal collecting or vascular system. The success rate was significantly better than cystoscopy (100% vs 50.0%, P = 0.005) or LPG alone (100% vs. 72.2%, P = 0.016). Chyluria resolved after surgery in all patients; no relapses were found. CONCLUSIONS: LPG plus post-LPG CTA accurately characterized perirenal lymphangiectasia that was not demonstrated by routine contrast-enhanced CT or not suitable for magnetic resonance imaging. Despite of its invasiveness, this method is a good diagnostic alternative to LPG in patients with persistent chyluria requiring surgery. PMID- 29409491 TI - Does the Stockholm Syndrome affect female sex workers? The case for a "Sonagachi Syndrome". AB - Female sex workers are subjected to intense physical, sexual, and mental abuses that are well documented in the medical and public health literature. However, less well-studied are the mental coping mechanisms that are employed by women in this population to survive. The Stockholm Syndrome has been discussed in the news media as a potential phenomenon in this vulnerable population, but has not been formally studied. From a previous retrospective qualitative analysis reviewing interviews with women in sex work throughout India, we found that the four main criteria for Stockholm Syndrome (perceived threat to survival; showing of kindness from a captor; isolation from other perspectives; perceived inability to escape) are present in narrative accounts from this population. Thus, we propose that Stockholm Syndrome should be considered as a contributing phenomenon with regard to the psychological challenges faced by female sex workers, and can likely help guide interventions accordingly. PMID- 29409492 TI - Epidemiology of paediatric presentations with musculoskeletal problems in primary care. AB - BACKGROUND: Musculoskeletal disease is a common cause of morbidity, but there is a paucity of musculoskeletal research focusing on paediatric populations, particularly in primary care settings. In particular, there is limited information on population consultation frequency in paediatric populations, and frequency varies by age and sex. Few studies have examined paediatric musculoskeletal consultation frequency for different body regions. The objective was to determine the annual consultation prevalence of regional musculoskeletal problems in children in primary care. METHODS: Musculoskeletal codes within the Read morbidity Code system were identified and grouped into body regions. Consultations for children aged three to seventeen in 2006 containing these codes were extracted from recorded consultations at twelve general practices contributing to a general practice consultation database (CiPCA). Annual consultation prevalence per 10,000 registered persons for the year 2006 was determined, stratified by age and sex, for problems in individual body regions. RESULTS: Over 8 % (8.27%, 95% CI 7.86 to 8.68%) of the 16,862 children consulted with a musculoskeletal problem during 2006. Annual consultation prevalence for any musculoskeletal problem was significantly higher in males than females (male: female prevalence ratio 1.18, 95% CI 1.06 to 1.31). Annual consultation prevalence increased with age and the most common body regions consulted for were the foot, knee and back all of which had over 100 consultations (109, 104 and 101 respectively) per 10,000 persons per year. CONCLUSIONS: This study provides new and detailed information on patterns of paediatric musculoskeletal consultations in primary care. Musculoskeletal problems in children are varied and form a significant part of the paediatric primary care workload. The findings of this study may be used as a resource for planning future studies. PMID- 29409493 TI - Scrotal hemorrhage after testicular sperm aspiration may be associated with phosphodiesterase-5 inhibitor administration: a retrospective study. AB - BACKGROUND: Scrotal hemorrhage after testicular sperm aspiration (TESA) is uncommon in clinical operation. Phosphodiesterase-5 inhibitors (PDE5i) are commonly given to men who have difficulty providing a sperm sample for assisted reproductive technique such as in vitro fertilization. In this study, we examine the incidence of scrotal hemorrhage after TESA in men who received a PDE5i. METHODS: In this retrospective study, 504 men with TESA operation in Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University were collected. Men in the drug group had taken orally PDE5i before TESA. Men in the control group only operated TESA. The testis volume, coagulation function were measured. Sonographic examination with Doppler imaging was performed when scrotal hemorrhage appeared. RESULTS: A total of 504 men with a mean age of 28.63 +/- 4.22 years were included in the analysis. Of these, 428 did not receive a PDE5i prior to TESA and 76 received a PDE5i prior to TESA. Measures of coagulation function were not different between the groups. The incidence of hemorrhage was 0.0% in the control group and the drug group was 5.3%. The incidence of hemorrhage between two groups was different significantly (P = 0.000). CONCLUSION: In summary, the results of this study suggest that a PDE5i administration increases the risk of scrotal hemorrhage in men undergoing TESA, although the study design does not allow drawing a conclusion of cause and effect. Given the potential risk of scrotal hemorrhage after the ingestion of PDE5i, it may be wise not to administer it to men in whom a TESA may be performed. PMID- 29409494 TI - Efficacy of Chinese herbal medicine Zengru Gao to promote breastfeeding: a multicenter randomized controlled trial. AB - BACKGROUND: Breastfeeding is recommended worldwide but not fully practiced. The first week after childbirth is regarded as a critical period for increasing breast milk production. The aim of the study was to investigate whether Chinese herbal medicine Zengru Gao would result in more women breastfeeding in the first week after childbirth. METHODS: A multicenter randomized controlled trial was conducted of 588 mothers considering breastfeeding in China. Among the mothers of the intervention group, the intervention included Chinese herbal medicine Zengru Gao; among those of the control group, it did not. Primary outcomes were the percentages of fully and partially breastfeeding mothers. Secondary outcome was baby's daily formula intake. RESULTS: At 3 d and 7 d after delivery, significant differences were found in favour of Zengru Gao group on the percentage of full/ partial breastfeeding (Z = - 3.0037, p = 0.0027). At day 7, the percentage of full/ partial breastfeeding of the active group increased to 71.48%/20.70% versus 58.67%/30.26% in the control group, the differences remained significant (Z = - 3.0037, p = 0.0027). No statistically significant differences were detected on primary measures at 1 d. While intake of formula differed between groups at 1 d and 3 d, this difference did not achieve statistical significance, but this difference was apparent by 7 d (55.45 +/- 115.39 ml/day vs 90.66 +/- 153.89 ml/day). CONCLUSION: In conclusion, Chinese Herbal medicine Zengru Gao enhanced breastfeeding success during one week postpartum. The approach is acceptable to participants and merits further evaluation. TRIAL REGISTRATION: ChiCTR-IPR 15007376 , December 11, 2015. PMID- 29409495 TI - PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. AB - BACKGROUND: Immune checkpoint inhibitors have led to a breakthrough in solid tumor immunotherapy, but related studies on musculoskeletal tumors are few, especially for PD-L2. METHODS: We examined expression of three molecular effectors of the PD-1 axis in 234 patients with musculoskeletal tumors, including osteosarcoma, chondrosarcoma, synovial sarcoma, and giant cell tumor. Survival analyses and potential mechanisms were investigated in osteosarcoma per the Gene Expression Omnibus (GEO) and immunohistochemistry analyses. In vivo, humanized mice were used to evaluate the effect of nivolumab on osteosarcoma. RESULTS: PD L1, PD-L2, and PD-1 expression levels were significantly different between the histologic types of the musculoskeletal tumors. For osteosarcoma, PD-L1 was negatively correlated with prognosis, while PD-1 had a negative correlation tendency with overall survival (OS). Meanwhile, PD-L2 had a positive correlation trend with OS. Nivolumab inhibited osteosarcoma metastasis in humanized mice by increasing CD4+ and CD8+ lymphocytes and the cytolytic activity of CD8 lymphocytes in the lung but did not affect primary osteosarcoma growth. CONCLUSION: We systematically detected the expression patterns of PD-L1, PD-L2, and PD-1 in musculoskeletal tumors for the first time and demonstrated the prognostic roles and underlying mechanisms of PD-1 axis in osteosarcoma. Furthermore, PD-1 blockade could effectively control osteosarcoma pulmonary metastasis in vivo. Therefore, the PD-1 axis may be a potential immunotherapeutic target for metastatic osteosarcoma. PMID- 29409497 TI - Langerian mindfulness, quality of life and psychological symptoms in a sample of Italian students. AB - BACKGROUND: Noticing new things, accepting the continuously changing nature of circumstances, and flexibly shifting perspectives in concert with changing contexts constitute the essential features of Langerian mindfulness. This contrasts with a "mindless" approach in which one remains fixed in a singular mindset and is closed off to new possibilities. Despite potentially important clinical applications for this construct, few studies have explored them. The instrument developed to measure Langerian mindfulness is the Langer Mindfulness Scale (LMS), although this tool has been limited primarily to English-speaking populations. The study aimed to test LMS validity in the Italian language and to analyze the relationships between Langerian mindfulness and well-being. METHODS: We translated the LMS into Italian, analyzed its factor structure, and investigated the correlation between mindfulness and quality of life and psychological well-being in a sample of 248 Italian students (88.7% females, mean age 20.05). A confirmatory factor analysis confirmed the tri-dimensional structure of the English LMS in the Italian version. RESULTS: The primary analysis found a significant negative correlation between mindfulness and psychological symptoms including obsessive-compulsive tendencies, depression, anxiety, and paranoid ideation. There was also a positive correlation between mindfulness and reports of quality of life. CONCLUSIONS: The Italian LMS appears reliable and it shows relevant correlations with well-being. PMID- 29409496 TI - Gold nanoparticles improve metabolic profile of mice fed a high-fat diet. AB - BACKGROUND: Obesity is a high risk for multiple metabolic disorders due to excessive influx of energy, glucose and lipid, often from a western based diet. Low-grade inflammation plays a key role in the progression of such metabolic disorders. The anti-inflammatory property of gold compounds has been used in treating rheumatoid arthritis in the clinic. Previously we found that pure gold nanoparticles (AuNPs, 21 nm) also possess anti-inflammatory effects on the retroperitoneal fat tissue following intraperitoneal injection, by downregulating tumor necrosis factor (TNF) alpha. However, whether such an effect can change the risk of metabolic disorders in the obese has not been well studied. The study employed C57BL/6 mice fed a pellet high fat diet (HFD, 43% as fat) that were treated daily with AuNPs [low (HFD-LAu) or high (HFD-HAu) dose] via intraperitoneal injection for 9 weeks. In the in vitro study, RAW264.7 macrophages and 3T3-L1 adipocytes were cultured with low and high concentrations of AuNPs alone or together. RESULTS: The HFD-fed mice showed a significant increase in fat mass, glucose intolerance, dyslipidemia, and liver steatosis. The HFD-LAu group showed an 8% reduction in body weight, ameliorated hyperlipidemia, and normal glucose tolerance; while the HFD-HAu group had a 5% reduction in body weight with significant improvement in their glucose intolerance and hyperlipidemia. The underlying mechanism may be attributed to a reduction in adipose and hepatic local proinflammatory cytokine production, e.g. TNFalpha. In vitro studies of co-cultured murine RAW264.7 macrophage and 3T3-L1 adipocytes supported this proposed mechanism. CONCLUSION: AuNPs demonstrate a promising profile for potential management of obesity related glucose and lipid disorders and are useful as a research tool for the study of biological mechanisms. PMID- 29409498 TI - DNA methylome profiling at single-base resolution through bisulfite sequencing of 5mC-immunoprecipitated DNA. AB - BACKGROUND: Detection of DNA methylome at single-base resolution is a significant challenge but promises to shed considerable light on human disease etiology. Current technologies could not detect DNA methylation genome-wide at single-base resolution with small amount of sequencing data and could not avoid detecting the methylation of repetitive elements which are considered as "junk DNA". METHODS: In this study, we have developed a novel DNA methylome profiling technology named MB-seq with its ability to identify genome-wide 5mC and quantify DNA methylation levels by introduced an assistant adapter AluI-linker This linker can be ligated to sonicated DNA and then be digested after the bisulfite treatment and amplification, which has no effect of MeDIP enrichment. Because many researchers are interested in investigating the methylation of functional regions such as promoters and gene bodies, we have also developed a novel alternative method named MRB-seq, which can be used to investigate the DNA methylation of functional regions by removing the repeats with Cot-1 DNA. RESULTS: In this study, we have developed MB-seq, a novel DNA methylome profiling technology combining MeDIP-seq with bisulfite conversion, which can precisely detect the 5mC sites and determine their DNA methylation level at single-base resolution in a cost-effective way. In addition, we have developed a new alternative method, MRB-seq (MeDIP-repetitive elements removal-bisulfite sequencing), which interrogates 5mCs in functional regions by depleting nearly half of repeat fragments enriched by MeDIP. Comparing MB-seq and MRB-seq to whole-genome BS-seq using the same batch of DNA from YH peripheral blood mononuclear cells. We found that the sequencing data of MB-seq and MRB-seq almost reaches saturation after generating 7-8 Gbp data, whereas BS seq requires about 100 Gbp data to achieve the same effect. In comparison to MeDIP-seq and BS-seq, MB-seq offers several key advantages, including single-base resolution, discriminating the methylated sites within a CpG and non-CpG pattern and overcoming the false positive of MeDIP-seq due to the non-specific binding of 5-methylcytidine antibody to genomic fragments. CONCLUSION: Our novel developed method MB-seq can accelerate the decoding process of DNA methylation mechanism in human diseases because it requires 7-8 Gbp data to measure human methylome with enough coverage and sequencing depth, affording it a direct and practical application in the study of multiple samples. In addition, we have also provided a novel alternative MRB-seq method, which removes most repetitive sequences and allows researchers to genome-wide characterize DNA methylation of functional regions. PMID- 29409500 TI - Autoimmune comorbidities in patients with metastatic melanoma: a retrospective analysis of us claims data. AB - BACKGROUND: Immunotherapies have advanced the treatment of metastatic melanoma; however, they are associated with immune-related toxicities. Patients with pre existing autoimmune comorbidities are commonly excluded from clinical trials investigating immunotherapies in metastatic melanoma. Since information on pre existing autoimmune comorbidities in "real-world" patients with newly diagnosed metastatic melanoma is limited, we sought to estimate the prevalence of autoimmune comorbidities and its change over time. METHODS: Data were obtained from a large US claims database, MarketScan(r), from 2004 to 2014. Records of patients with newly diagnosed metastatic or non-metastatic melanoma and of general population were analyzed. Autoimmune comorbidities were defined as presence of autoimmune disorders, which were obtained from the list of diseases at the American Autoimmune-Related Diseases Association web portal ( www.aarda.org ). The prevalence of pre-existing autoimmune comorbidities and its change over the 11-year period were calculated. Logistic regression analyses were performed to evaluate the relationship between clinical and demographic factors and pre-existing autoimmune comorbidities in patients with metastatic melanoma. RESULTS: This study assessed the prevalence and change of prevalence over a period of 11 years of 147 autoimmune comorbidities. Among 12,028 patients with newly diagnosed metastatic melanoma, the prevalence rate of pre-existing autoimmune comorbidities increased from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates of autoimmune comorbidities increased from 11.7% in 2004 to 19.8% in 2014 in patients with non-metastatic melanoma and 7.9% in 2004 to 9.2% in 2014 in the general population. In addition, patients with bone or gastrointestinal melanoma metastases, those with more comorbid diseases, or female patients, were found to have a higher risk of autoimmune comorbidities. CONCLUSIONS: The prevalence of pre-existing autoimmune comorbidities in patients with newly diagnosed metastatic melanoma was high, and increased over 11 years. In comparison, a lower prevalence of autoimmune comorbidities was seen in patients with newly diagnosed non-metastatic melanoma and in the general population. Increases in prevalence for these population groups were also observed over 11 years. Impact of autoimmune comorbidities on treatment decisions in patients with metastatic melanoma should be explored. PMID- 29409499 TI - Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia. AB - BACKGROUND: Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. METHODS: Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight. There was a control group containing rats fed a standard laboratory rodent chow diet (CD); a hypercholesterolemic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil - this is also called a CCT diet) group; a positive group (CCT + F) fed CCT, supplemented with 10 mg.kg.bw- 1.d- 1 fluvastatin sodium by gastric perfusion; and lycopene groups at five dose levels (CCT + LYCO) fed with CCT and supplied lycopene at doses of 5, 25, 45, 65, and 85 mg.kg.bw- 1.d- 1. The levels of TC, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha), oxidized low density lipoprotein (ox-LDL), low-density lipoprotein receptor (LDLR), nerve growth factor (NGF), glutamic acid (Glu), Gamma aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), N-methyl-D aspartate (NMDA1R), GABAA, 5-HT1, D1, and apoptosis-related proteins Caspase3, bax, and bcl-2 were measured after the experiment. Nissl staining was adopted to observe the morphological changes in neurons. RESULTS: At the end of the experiment, the levels of TC, TG, LDL-C, IL-1, TNF-alpha, and ox-LDL in the serum and brain as well as the content of Glu, DA, NMDA, and D1 in the brain of rats in the CCT group were higher than those in the control group (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABAA, 5-HT1, and neuron quantities in the hippocampal CA1 and CA3 areas were lower than those in the control group (P<0.05). Compared to the CCT group, levels of TC, TG, LDL-C, IL-1, TNF-alpha, and ox-LDL in the serum and brain, as well as the content of Glu, DA and the expression of pro-apoptotic Caspase3 in the brain decreased in the rats with lycopene (25 mg to 85 mg) added to the diet (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABAA, and 5-HT1 as well as the expression of anti-apoptotic bcl-2 and the neuron quantity in hippocampal CA1 and CA3 areas increased (P<0.05); further, the hippocampal cells were closely arranged. Lycopene dose was negatively correlated with the levels of TC, TG, and LDL-C in the serum and brain as well as levels of IL-1, TNF-alpha, ox LDL, Glu/GABA, NMDA1R, and Caspase3 (P<0.05); it was positively correlated with the levels of LDLR, NGF, 5-HT, 5-HT1, GABAA, bcl-2, and the neuron quantity in hippocampal CA1 and CA3 areas (P<0.05). CONCLUSIONS: Lycopene exerts anti-injury effects in the brain as-induced by hyperlipidemia. It can inhibit the elevation of serum TC, TG, and LDL-C in rats with hyperlipidemia while indirectly affecting the levels of TC, TG, and LDL-C in the brain, leading to a reduction in ox-LDL, IL-1, and TNF-alpha in the brain. This inhibits the release of Glu, which weakens nerve toxicity and downregulates pro-apoptotic Caspase3. Lycopene also plays an anti-injury role by promoting the release of the inhibitory neurotransmitter GABA and 5-HT, which enhances the protective effect, and by upregulating the anti apoptotic bcl-2. PMID- 29409501 TI - Development and psychometric evaluation of a women shift workers' reproductive health questionnaire: study protocol for a sequential exploratory mixed-method study. AB - BACKGROUND: Although shift works is a certain treat for female reproductive health, but currently, there is no standardized instrument for measuring reproductive health among female shift workers. This study aims to develop and evaluate the psychometric properties of a Women Shift Workers' Reproductive Health Questionnaire (WSW-RHQ). METHODS: This is a sequential exploratory mixed method study with a qualitative and a quantitative phase. In the qualitative phase, semi-structured interviews will be held with female shift workers who live in Mazandaran Province, Iran, additionally, the literature review will be performed by searching electronic databases. Sampling will be done in different workplaces and with maximum variation respecting female shift workers' age and job and educational and different economic situation. Interview data will be analyzed using conventional content analysis and then, the primary item pool for the questionnaire will be developed. In the quantitative phase, we will evaluate the psychometric properties of the questionnaire, i.e. its face, content, construct as well as reliability via the internal consistency, stability. Finally, a scoring system will be developed for the questionnaire. DISCUSSION: The development of WSW-RHQ will facilitate the promotion and implementation of reproductive health interventions and assessment of their effectiveness. Other scholars can cross-culturally adapt and use the questionnaire according to their immediate contexts. PMID- 29409503 TI - Perceptions of counsellors and youth-serving professionals about sexual and reproductive health services for adolescents in Soweto, South Africa. AB - BACKGROUND: Adolescents in South Africa remain vulnerable to HIV. Therefore, it is crucial to provide accessible adolescent-friendly HIV prevention interventions that are sensitive to their needs. This study aimed to investigate the perceptions of HIV counsellors and other youth-serving professionals about the barriers to providing adolescent youth-friendly sexual and reproductive health services to adolescents in Soweto, South Africa. The study also explored how sexual and reproductive health services in South Africa could be improved to become more accessible to adolescents. METHODS: The research team conducted two focus group discussions with HIV counsellors, and 19 semi-structured interviews with youth-serving professionals from organisations working with adolescents. Audio-recorded data were transcribed verbatim and analysed using thematic analysis. RESULTS: The results of the study reveal that counsellors were expected to give adolescents HIV counselling and testing (HCT) but felt restricted by what they perceived as inflexible standard operating procedures. Counsellors reported inadequate training to address adolescent psychosocial issues during HCT. Healthcare provider attitudes were perceived as a barrier to adolescents using sexual and reproductive health services. Participants strongly recommended augmenting adolescent sexual and reproductive health services to include counsellors and adolescents in developing age- and context-specific HIV prevention services for adolescents. CONCLUSION: Continuous upskilling of HIV counsellors is a critical step in providing adolescent-friendly services. Input from all relevant stakeholders, including counsellors and adolescents, is essential in designing adolescent-friendly services. PMID- 29409502 TI - Private sector malaria RDT initiative in Nigeria: lessons from an end-of-project stakeholder engagement meeting. AB - The malaria rapid diagnosis testing (RDT) landscape is rapidly evolving in health care delivery in Nigeria with many stakeholders playing or having potential for critical roles. A recent UNITAID grant supported a pilot project on the deployment of quality-assured RDTs among formal and informal private service outlets in three states in Nigeria. This paper describes findings from a series of stakeholder engagement meetings held at the conclusion of the project. The agreed meeting structure was a combination of plenary presentations, structured facilitated discussions, and nominal group techniques to achieve consensus. Rapporteurs recorded the meeting proceeding and summaries of the major areas of discussion and consensus points through a retrospective thematic analysis of the submitted meeting reports. Key findings indicate that private providers were confident in the use of RDTs for malaria diagnosis and believed it has improved the quality of their services. However, concerns were raised about continued access to quality-assured RDT kits. Going forward, stakeholders recommended increasing client-driven demand, and continuous training and supervision of providers through integration with existing monitoring and supervision mechanisms. PMID- 29409504 TI - Unusual progression of renal cell carcinoma with carcinomatosis peritoneii and Krukenberg tumour and alopecia with sunitinib therapy in young female. AB - BACKGROUND: Sunitinib is a multiple receptor tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma (RCC). It increases the median survival considerably with minimum side effects. Alopecia is one of the rare side effects. Metastasis to the ovary is also rare. We report a case of RCC metastasizing to the ovary developing alopecia early on starting sunitinib. CASE PRESENTATION: A 22-year-old hypothyroid girl underwent right radical nephrectomy for T2N0 RCC. Histopathology was clear cell carcinoma. Six months later, she presented with right iliac fossa pain, imaging revealed metastasis to the ileocolic junction and the ovary, an exploratory laparotomy was carried out and, after debulking, the patient was started on sunitinib. Four weeks after the start of the treatment, she developed alopecia. She was continued with sunitinib therapy till progression. CONCLUSIONS: The present case shows a rare metastasis to the ovary and early onset of rare adverse event of alopecia on starting sunitinib therapy. In the presence of confounding factors like hypothyroidism and dandruff, establishing this as an adverse reaction of sunitinib is difficult. This case had a unique metastatic spread with involvement of the bowel, ovary and peritoneal carcinomatosis. Use of adjuvant TKI's after resection of primary tumour in nonmetastatic setting may reduce metastatic rates and increase progression-free survival. PMID- 29409505 TI - Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. AB - BACKGROUND: Preliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of D-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS. METHODS: An open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 * 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4 week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (D-lactate free multistrain probiotic, 5 * 1010 cfu twice daily). 2 * 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post intervention for microbial, lactate and clinical outcomes. Ancillary non parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes. RESULTS: Large treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine D:L lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females. CONCLUSIONS: Results support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of D-lactate. Further investigation of lactate concentrations are needed to elucidate any role of D-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment. Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview= rue. PMID- 29409506 TI - The molecular mechanism of ovarian granulosa cell tumors. AB - Over these years, more and more sex cord-stromal tumors have been reported. Granulosa cell tumor (GCT) is a rare tumor in ovaries, accounts for 2% to 5% of ovarian cancers. The main different feature of GCTs from other ovarian cancers is that GCTs can lead to abnormally secreted hormones (estrogen, inhibin and Mullerian inhibiting substance). The GCT is divided into two categories according to the age of patients, namely AGCT (adult granulosa cell tumor) and JGCT (Juvenile granulosa cell tumor). AGCT patients accounts for 95%. Although the pathogenesis is not clear, FOXL2 (Forkhead box L2) mutation was considered as the most critical factor in AGCT development. The current treatment is dominated by surgery. Target therapy remains in the adjuvant therapy stage, such as hormone therapy. During these years, other pathogenic factors were also explored, such as PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-beta (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor). These factors and signaling pathway play important roles in GCT cell proliferation, apoptosis, or angiogenesis. The purpose of this review is to summarize the possible pathogenic factors and signaling pathways, which may shed lights on developing potential therapeutic targets for GCT. PMID- 29409507 TI - Fate of Antibody-Drug Conjugates in Cancer Cells. AB - Antibody-Drug Conjugates (ADCs) are a class of cancer therapeutics that combines antigen specificity and potent cytotoxicity in a single molecule as they are comprised of an engineered antibody linked chemically to a cytotoxic drug. Four ADCs have received approval by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and can be prescribed for metastatic conditions while around 60 ADCs are currently enrolled in clinical trials. The efficacy of an ADC greatly relies on its intracellular trafficking and processing of its components to trigger tumor cell death. A limited number of studies have addressed these critical processes that both challenge and help foster the design of ADCs. This review highlights those mechanisms and their relevance for future development of ADCs as cancer therapeutics. PMID- 29409509 TI - "Cross-border collaboration in onchocerciasis elimination in Uganda: progress, challenges and opportunities from 2008 to 2013". AB - BACKGROUND: Until recently onchocerciasis was prevalent in 37 out of 112 districts of Uganda with at least 3.8 million people at risk of contracting the disease, but following the launching of community-directed treatment with ivermectin (CDTI) in 1996 and the adoption of an onchocerciasis elimination policy in 2007, the country has made significant progress in combating the disease. By 2015, interruption of transmission had been achieved in ten of the 17 onchocerciasis foci, but cross-border foci remained particularly problematic, and therefore within the onchocerciasis elimination framework, Uganda embarked upon addressing these issues with its neighbouring countries, namely the Democratic Republic of Congo (DRC) and South Sudan. This paper summarises the experience of Uganda in addressing cross-border issues on onchocerciasis elimination with DRC. MAIN ACHIEVEMENTS AND LESSONS LEARNED: The key achievements comprise of the adoption of an elimination policy by the Government of Uganda, cross-border meetings, training DRC technical staff and entomological/ epidemiological surveys. The first strategy meeting was held in Kampala in 2008, but the second strategy meeting was not held in Kinshasa until 2013. The involvement of the high level officials from the Ministry of Health of DRC was critical for the success of the second strategy meeting, and was precipitated by collaboration to control an outbreak of Ebola Virus. Both meetings demonstrated the political commitment of endemic countries and allowed the implementation of a joint action plan. Important steps in establishing a mutually respected elimination targets was agreed on during cross border meetings. The African Programme for Onchocerciasis Control facilitated and funded these initial meetings, thus overcoming some political and financial challenges faced by both countries. This highlighted the need for multilateral organisations such as the Expanded Special Project for the Elimination of Neglected Tropical Diseases in cross-border activities for other Neglected Tropical Diseases. The collaboration between both countries facilitated the training of technical staff from DRC in entomology which facilitated joint cross-border activities to update the epidemiological understanding of onchocerciasis in Beni and Mahagi districts in North Kivu and Ituri Provinces respectively. In Nebbi district, Uganda, 23.7% of crabs were infested by the vector Simulium neavei compared with 6.3% in Mahagi district, DRC. Rapid Epidemiological Assessment (REA) revealed nodule prevalence of 3.2% and onchodermatitis at 26.4% from five villages in DRC. CONCLUSION: Political commitment of both countries and the support from APOC allowed two cross-border meetings which were critical for the implementation of initial cross border activities for onchocerciasis elimination. PMID- 29409508 TI - Human cytomegalovirus infection and coronary heart disease: a systematic review. AB - BACKGROUND: Human cytomegalovirus (HCMV) infection is closely associated with coronary heart disease. In 1987, Adam et al. were the first to report an association between HCMV infection and atherosclerosis (AS), and later, many serum epidemiology and molecular biology studies showed that HCMV-infected endothelial cells play an important role in the development of AS. As patients with HCMV are generally susceptible to coronary heart disease, and with the increasing elderly population, a review of recent studies focusing on the relationships of HCMV infection and coronary heart disease is timely and necessary. SHORT CONCLUSION: The role of HCMV infection in the development of AS needs further study, since many remaining issues need to be explored and resolved. For example, whether HCMV promotes the development of coronary AS, and what the independent factors that lead to coronary artery AS by viral infection are. A comprehensive understanding of HCMV infection is needed in order to develop better strategies for preventing AS. PMID- 29409510 TI - Comparing fiberoptic bronchoscopy- and a tracheal tube-mounted camera-guided percutaneous dilatational tracheostomy. PMID- 29409511 TI - A qualitative study of use of long-lasting insecticidal nets (LLINs) for intended and unintended purposes in Adami Tullu, East Shewa Zone, Ethiopia. AB - BACKGROUND: Malaria poses a significant public health threat globally, across Africa and in Ethiopia. The use of long-lasting insecticidal nets (LLINs) is currently a proven prevention mechanism. Evidence is building on what happens to LLINs following mass distribution campaigns, with mixed results from different studies, some reporting very low use for intended purposes, others an encouraging level of using for intended purposes. In Ethiopia, between 2005 and 2015, about 64 million LLINs were distributed through periodic mass campaigns with the aims to achieve 100% coverage and 80% utilization. However, studies from rural Ethiopia showed variable LLINs coverage and utilization rate. The MalTrial Project, a collaborative venture between Hawassa University, Ethiopia and NROAID, Norway, has started a trial project in 2014 in Adami Tullu District of central Ethiopia. Quantitative surveys have established evidence on LLINs ownership and utilization, but the behavioural, sociocultural and socioeconomic dynamics of why LLINs' use for intended purposes is low or why they are employed for other purposes remained elusive. The present qualitative study, building on the quantitative findings and framework, therefore, attempted to fill gaps in these areas using qualitative methods in selected localities of the district. METHODS: The study employed 7 focus groups, 16 individual interviews and observation to undertake data collection in January 2017. The data were analysed using NVivo Version 11 (QSR International) to transcribe, code and identify themes using thematic analysis approach. RESULTS: The study found out that certain households were more likely to use nets for intended needs in proper ways; a range of factors, notably socio-cultural and poverty, highly influence users' ideas about the right ways and decisions to use and care for the nets; knowledge gaps and wrong perception exist regarding the purposes and life cycle of the nets; LLINs are employed for repurposed uses once they are considered non-viable, old, or lose their physical integrity; existence of misuse was acknowledged and understood as wrong; and values about gender roles further shape uses, misuses and repurposed use of the nets. CONCLUSIONS: Behavioural, socio-cultural, economic and ecological conditions coupled with deficiencies in perceived bed net design and distribution policies; weak education, communication and social support structures were important in understanding and accounting for why a low level of intended use and a rampant misuse and repurposed use in Adami Tullu community of Ethiopia. A major nexus to address in order to improve intended use of LLINs lies, first and foremost, in economic poverty and socio-cultural factors that underlie much of the misuse and repurposed use of the nets. PMID- 29409512 TI - A quasi-placebo may have a role in some randomised controlled trials. PMID- 29409513 TI - Efficient differentially private learning improves drug sensitivity prediction. AB - BACKGROUND: Users of a personalised recommendation system face a dilemma: recommendations can be improved by learning from data, but only if other users are willing to share their private information. Good personalised predictions are vitally important in precision medicine, but genomic information on which the predictions are based is also particularly sensitive, as it directly identifies the patients and hence cannot easily be anonymised. Differential privacy has emerged as a potentially promising solution: privacy is considered sufficient if presence of individual patients cannot be distinguished. However, differentially private learning with current methods does not improve predictions with feasible data sizes and dimensionalities. RESULTS: We show that useful predictors can be learned under powerful differential privacy guarantees, and even from moderately sized data sets, by demonstrating significant improvements in the accuracy of private drug sensitivity prediction with a new robust private regression method. Our method matches the predictive accuracy of the state-of-the-art non-private lasso regression using only 4x more samples under relatively strong differential privacy guarantees. Good performance with limited data is achieved by limiting the sharing of private information by decreasing the dimensionality and by projecting outliers to fit tighter bounds, therefore needing to add less noise for equal privacy. CONCLUSIONS: The proposed differentially private regression method combines theoretical appeal and asymptotic efficiency with good prediction accuracy even with moderate-sized data. As already the simple-to-implement method shows promise on the challenging genomic data, we anticipate rapid progress towards practical applications in many fields. REVIEWERS: This article was reviewed by Zoltan Gaspari and David Kreil. PMID- 29409514 TI - Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines: a case report. AB - BACKGROUND: Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing. METHODS: Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN gamma+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-gamma-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization. RESULTS: A peptide specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRValpha chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now. CONCLUSIONS: Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial. PMID- 29409515 TI - Correction to: AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity. AB - After publication of the article [1], it has been brought to our attention that the caption for Figure 2 has been mistakenly replaced with a reproduction of the Figure 4 caption. PMID- 29409516 TI - Cerebral cortex dose sparing for glioblastoma patients: IMRT versus robust treatment planning. AB - BACKGROUND: To date, patients with glioblastoma still have a bad median overall survival rate despite radiation dose-escalation and combined modality treatment. Neurocognitive decline is a crucial adverse event which may be linked to high doses to the cortex. In a planning study, we investigated the impact of dose constraints to the cerebral cortex and its relation to the organs at risk for glioblastoma patients. METHODS: Cortical sparing was implemented into the optimization process for two planning approaches: classical intensity-modulated radiotherapy (IMRT) and robust treatment planning. The plans with and without objectives for cortex sparing where compared based on dose-volume histograms (DVH) data of the main organs at risk. Additionally the cortex volume above a critical threshold of 28.6 Gy was elaborated. Furthermore, IMRT plans were compared with robust treatment plans regarding potential cortex sparing. RESULTS: Cortical dose constraints result in a statistically significant reduced cerebral cortex volume above 28.6 Gy without negative effects to the surrounding organs at risk independently of the optimization technique. For IMRT we found a mean volume reduction of doses beyond the threshold of 19%, and 16% for robust treatment planning, respectively. Robust plans delivered sharper dose gradients around the target volume in an order of 3 - 6%. Aside from that the integration of cortical sparing into the optimization process has the potential to reduce the dose around the target volume (4 - 8%). CONCLUSIONS: We were able to show that dose to the cerebral cortex can be significantly reduced both with robust treatment planning and IMRT while maintaining clinically adequate target coverage and without corrupting any organ at risk. Robust treatment plans delivered more conformal plans compared to IMRT and were superior in regards to cortical sparing. PMID- 29409518 TI - Performance of the quick Sequential (sepsis-related) Organ Failure Assessment score as a prognostic tool in infected patients outside the intensive care unit: a systematic review and meta-analysis. AB - BACKGROUND: The usefulness of the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) score in providing bedside criteria for early prediction of poor outcomes in patients with suspected infection remains controversial. We investigated the prognostic performance of a positive qSOFA score outside the intensive care unit (ICU) compared with positive systemic inflammatory response syndrome (SIRS) criteria. METHODS: A systematic literature search was performed using MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Data were pooled on the basis of sensitivity, specificity, and diagnostic OR. Overall test performance was summarized using a hierarchical summary ROC and the AUC. Meta-regression analysis was used to identify potential sources of bias. RESULTS: We identified 23 studies with a total of 146,551 patients. When predicting in-hospital mortality in our meta-analysis, we identified pooled sensitivities of 0.51 for a positive qSOFA score and 0.86 for positive SIRS criteria, as well as pooled specificities of 0.83 for a positive qSOFA score and 0.29 for positive SIRS criteria. Discrimination for in-hospital mortality had similar AUCs between the two tools (0.74 vs. 0.71; P = 0.816). Using meta regression analysis, an overall mortality rate >= 10% and timing of qSOFA score measurement could be significant sources of heterogeneity. For predicting acute organ dysfunction, although the AUC for a positive qSOFA score was higher than that for positive SIRS criteria (0.87 vs. 0.76; P < 0.001), the pooled sensitivity of positive qSOFA score was very low (0.47). In addition, a positive qSOFA score tended to be inferior to positive SIRS criteria in predicting ICU admission (0.63 vs. 0.78; P = 0.121). CONCLUSIONS: A positive qSOFA score had high specificity outside the ICU in early detection of in-hospital mortality, acute organ dysfunction, and ICU admission, but low sensitivity may have limitations as a predictive tool for adverse outcomes. Because between-study heterogeneity was highly represented among the studies, our results should be interpreted with caution. PMID- 29409517 TI - Isolation and purification of glycosylphosphatidylinositols (GPIs) in the schizont stage of Theileria annulata and determination of antibody response to GPI anchors in vaccinated and infected animals. AB - BACKGROUND: Tropical theileriosis is widely distributed from North Africa to East Asia. It is a tick-borne disease caused by Theileria annulata, an obligate two host intracellular protozoan parasite of cattle. Theileria annulata use leukocytes and red blood cells for completion of the life-cycle in mammalian hosts. The stage of Theileria annulata in monocytes and B lymphocytes of cattle is an important step in pathogenicity and diagnosis of the disease. Glycosylphosphatidylinositols (GPIs) are a distinct class of glycolipid structures found in eukaryotic cells and are implicated in several biological functions. GPIs are particularly abundant in protozoan parasites, where they are found as free glycolipids or attached to proteins in the plasma membrane. RESULTS: In this study we first isolated and purified schizonts of Theileria annulata from infected leukocytes in Theileria annulata vaccine cell line (S15) by aerolysin-percoll technique. Then, the free GPIs of schizont stage and isolated GPI from cell membrane glycoproteins were purified by high performance liquid chromatography (HPLC) and confirmed by gas chromatography-mass spectrometry (GC-MS). Furthermore, enzyme linked immunosorbent assay (ELISA) on the serum samples obtained from naturally infected, as well as Theileria annulata vaccinated animals, confirmed a significant (P < 0.01) high level of anti-GPI antibody in their serum. CONCLUSIONS: The results presented in this study show, to our knowledge for the first time, the isolation of GPI from the schizont stage of Theileria annulata and demonstrate the presence of anti-GPI antibody in the serum of naturally infected as well as vaccinated animals. This finding is likely to be valuable in studies aimed at the evaluation of chemically structures of GPIs in the schizont stage of Theileria annulata and also for pathogenicity and immunogenicity studies with the aim to develop GPI-based therapies or vaccines. PMID- 29409519 TI - Effectiveness of respectful care policies for women using routine intrapartum services: a systematic review. AB - BACKGROUND: Several studies have identified how mistreatment during labour and childbirth can act as a barrier to the use of health facilities. Despite general agreement that respectful maternity care (RMC) is a fundamental human right, and an important component of quality intrapartum care that every pregnant woman should receive, the effectiveness of proposed policies remains uncertain. We performed a systematic review to assess the effectiveness of introducing RMC policies into health facilities providing intrapartum services. METHODS: We included randomized and non-randomized controlled studies evaluating the effectiveness of introducing RMC policies into health facilities. We searched PubMed, CINAHL, LILACS, AJOL, WHO RHL, and Popline, along with ongoing trials registers (ISRCT register, ICTRP register), and the White Ribbon Respectful Maternity Care Repository. Included studies were assessed for risk of bias. Certainty of evidence was assessed using GRADE criteria. FINDINGS: Five studies were included. All were undertaken in Africa (Kenya, Tanzania, Sudan, South Africa), and involved a range of components. Two were cluster RCTs, and three were before/after studies. In total, over 8000 women were included at baseline and over 7500 at the endpoints. Moderate certainty evidence suggested that RMC interventions increases women's experiences of respectful care (one cRCT, approx. 3000 participants; adjusted odds ratio (aOR) 3.44, 95% CI 2.45-4.84); two observational studies also reported positive changes. Reports of good quality care increased. Experiences of disrespectful or abusive care, and, specifically, physical abuse, were reduced. Low certainty evidence indicated fewer accounts of non-dignified care, lack of privacy, verbal abuse, neglect and abandonment with RMC interventions, but no difference in satisfaction rates. Other than low certainty evidence of reduced episiotomy rates, there were no data on the pre specified clinical outcomes. CONCLUSION: Multi-component RMC policies appear to reduce women's overall experiences of disrespect and abuse, and some components of this experience. However, the sustainability of the demonstrated effect over time is unclear, and the elements of the programmes that have most effect have not been examined. While the tested RMC policies show promising results, there is a need for rigorous research to refine the optimum approach to deliver and achieve RMC in all settings. PMID- 29409520 TI - Factors associated with menstrual cycle irregularity and menopause. AB - BACKGROUND: A regular menstrual cycle is an important indicator of a healthy reproductive system. Previous studies reported obesity, stress, and smoking as the factors that are associated with irregular menstruation and early menopause. However, the integrative effects of these modifiable risk factors have not been fully understood. This study aimed to investigate the modifiable risk factors of menstrual cycle irregularity and premature menopause, as well as their individual and combined effects among adult women in Korea. METHOD: This study selected adult women aged 19 years and above who had been included in the 2007-2014 Korean National Health and Nutrition Examination Survey. We used a separate dataset to analyze the risk factors of menstrual cycle irregularity and menopause (pre- and postmenopausal women: n = 4788 and n = 10,697, respectively). Univariate and multiple logistic regression analyses were conducted to evaluate the effects of smoking, drinking, obesity, and perceived level of stress on the menstrual cycle and menopause. Both logit and linear models were used in the analyses of the association between smoking and menopausal age. Equivalized household income, marital status, and educational level were considered as covariates. The modifiable risk factor scores were also calculated to integrate the effect of smoking, drinking, and obesity in the analysis. RESULT: Results showed that smoking status, pack-year, obesity, and perceived level of stress were significantly associated with irregular menstruation among premenopausal women. Especially, women demonstrating > 3 modifiable risk factor scores had 1.7 times higher risk of having irregular menstruation than those who had a 0 score. Meanwhile, early initiation of smoking (<=19 years) and high pack-year (>=5) were also significantly associated with premature menopause among postmenopausal women. CONCLUSION: This study demonstrated that modifiable risk factors, such as smoking, obesity, and stress, were significantly associated with menstrual cycle irregularity. Lifetime smoking was also correlated with early menopause. Our results suggested that healthier lifestyle practices, including, cessation of smoking, weight control, and stress management, were important factors in improving the reproductive health of women throughout life. PMID- 29409521 TI - Role in virulence of phospholipases, listeriolysin O and listeriolysin S from epidemic Listeria monocytogenes using the chicken embryo infection model. AB - Most human listeriosis outbreaks are caused by Listeria monocytogenes evolutionary lineage I strains which possess four exotoxins: a phosphatidylinositol-specific phospholipase C (PlcA), a broad-range phospholipase C (PlcB), listeriolysin O (LLO) and listeriolysin S (LLS). The simultaneous contribution of these molecules to virulence has never been explored. Here, the importance of these four exotoxins of an epidemic lineage I L. monocytogenes strain (F2365) in virulence was assessed in chicken embryos infected in the allantoic cavity. We show that LLS does not play a role in virulence while LLO is required to infect and kill chicken embryos both in wild type transcriptional regulator of virulence PrfA (PrfAWT) and constitutively active PrfA (PrfA*) backgrounds. We demonstrate that PlcA, a toxin previously considered as a minor virulence factor, played a major role in virulence in a PrfA* background. Interestingly, GFP transcriptional fusions show that the plcA promoter is less active than the hly promoter in vitro, explaining why the contribution of PlcA to virulence could be observed more importantly in a PrfA* background. Together, our results suggest that PlcA might play a more important role in the infectious lifecycle of L. monocytogenes than previously thought, explaining why all the strains of L. monocytogenes have conserved an intact copy of plcA in their genomes. PMID- 29409522 TI - Systematic prediction of DNA shape changes due to CpG methylation explains epigenetic effects on protein-DNA binding. AB - BACKGROUND: DNA shape analysis has demonstrated the potential to reveal structure based mechanisms of protein-DNA binding. However, information about the influence of chemical modification of DNA is limited. Cytosine methylation, the most frequent modification, represents the addition of a methyl group at the major groove edge of the cytosine base. In mammalian genomes, cytosine methylation most frequently occurs at CpG dinucleotides. In addition to changing the chemical signature of C/G base pairs, cytosine methylation can affect DNA structure. Since the original discovery of DNA methylation, major efforts have been made to understand its effect from a sequence perspective. Compared to unmethylated DNA, however, little structural information is available for methylated DNA, due to the limited number of experimentally determined structures. To achieve a better mechanistic understanding of the effect of CpG methylation on local DNA structure, we developed a high-throughput method, methyl-DNAshape, for predicting the effect of cytosine methylation on DNA shape. RESULTS: Using our new method, we found that CpG methylation significantly altered local DNA shape. Four DNA shape features-helix twist, minor groove width, propeller twist, and roll-were considered in this analysis. Distinct distributions of effect size were observed for different features. Roll and propeller twist were the DNA shape features most strongly affected by CpG methylation with an effect size depending on the local sequence context. Methylation-induced changes in DNA shape were predictive of the measured rate of cleavage by DNase I and suggest a possible mechanism for some of the methylation sensitivities that were recently observed for human Pbx-Hox complexes. CONCLUSIONS: CpG methylation is an important epigenetic mark in the mammalian genome. Understanding its role in protein-DNA recognition can further our knowledge of gene regulation. Our high-throughput methyl-DNAshape method can be used to predict the effect of cytosine methylation on DNA shape and its subsequent influence on protein-DNA interactions. This approach overcomes the limited availability of experimental DNA structures that contain 5 methylcytosine. PMID- 29409523 TI - Prevalence survey on lungworm (Angiostrongylus vasorum, Crenosoma vulpis, Eucoleus aerophilus) infections of wild red foxes (Vulpes vulpes) in central Germany. AB - BACKGROUND: Angiostrongylus vasorum, Crenosoma vulpis and Eucoleus aerophilus are a source of increasing concern, potentially causing significant pulmonary and severe cardiac/systemic diseases in domestic dogs and wild canids, especially red foxes (Vulpes vulpes). To investigate the prevalence and geographical distribution of these parasites in central Germany, a total of 569 foxes were examined by dissection. METHODS: Pluck (heart and lung) and faecal samples of red foxes were collected from three regions of Germany. Lungs, hearts and adjacent vessels were processed for adult nematode detection. Parasitological diagnoses of faecal samples were performed by SAF technique, Giardia- and Cryptosporidium Coproantigen-ELISAs and by a duplex copro-PCR for the detection of A. vasorum and C. vulpis DNA. RESULTS: Foxes originated from three Federal States of central Germany: Thuringia (n = 359); Rhineland-Palatinate (n = 121) and Hesse (n = 89). High prevalences for all three nematodes were detected, with E. aerophilus (69.4%; 395/569), followed by C. vulpis (32.3%; 184/569) and A. vasorum (14.1%; 80/569). In case of A. vasorum, prevalences varied significantly between Federal States, with the highest prevalence of 27.3% in Rhineland-Palatinate, followed by 19.1% and 8.4% in Hesse and Thuringia, respectively. The presence of A. vasorum in fox populations showed a rather patchy distribution, increasing from north eastern to south-western regions. Analyses on C. vulpis revealed prevalences of 35.1%, 30.3% and 25.6% (Thuringia, Hesse and Rhineland-Palatinate, respectively). The most prevalent lungworm nematode was E. aerophilus, with a prevalence of 75.2%, 71.9% and 66.9% (Rhineland-Palatinate, Hesse and Thuringia, respectively) and an almost area-wide equal distribution. Significant differences for single parasite prevalences within geographical regions of the Federal States could be detected whilst no correlation between age or gender and parasite occurrence was estimated. Weak seasonality for the winter months for A. vasorum, stronger correlation to spring and late summer for C. vulpis and no correlation to any season for E. aerophilus were detected. The method of dissection revealed a significantly higher sensitivity for C. vulpis when compared with the results of the duplex copro-PCR. CONCLUSIONS: A sylvatic cycle was confirmed for all three lungworm nematodes in the examined area. The prevalences for all three lungworm nematodes are some of the highest recorded so far in German foxes. The data suggest that A. vasorum might be spreading from south-western to north-eastern parts of Germany. PMID- 29409524 TI - Bacterial and parasitic contaminants of salad vegetables sold in markets in Fako Division, Cameroon and evaluation of hygiene and handling practices of vendors. AB - OBJECTIVE: Increase in awareness of the health benefits of vegetables has resulted in an increase in consumption. Many vegetables are consumed raw to retain the natural taste and heat labile nutrients. The safety of raw vegetables is a great concern. We investigated the bacteriological and parasitological quality of salad vegetables sold in three major markets in Fako Division Cameroon, the hygiene and preservation practices of vendors and determined the antimicrobial sensitivity of bacterial isolates, to provide data that could be used to improve food safety and safeguard public health. RESULTS: Bacterial contamination was high. Mean aerobic bacteria counts ranged from 2.5 * 106 to 15 * 106 cfu/g, total coliform counts from 4 to > 2400/g and fecal coliforms < 3 to 1100/g. Six bacterial species were isolated among which Staphylococcus aureus (35.4%) predominated while Serratia marcescens (8.5%) was the least. Bacteria showed high resistance to erythromycin (87.6%). Ten parasitic organisms were detected. Balantidium coli (25.6%) and Entamoeba spp. (21.7%) predominated. Contamination was highest in lettuce and lowest in green pepper. Hygiene and vegetable preservation practices of vendors were poor and could aggravate contamination. Contamination of fresh salad vegetables with pathogenic bacteria and parasites could be a food safety concern in study area. PMID- 29409525 TI - Pre-hospital transthoracic echocardiography for early identification of non-ST elevation myocardial infarction in patients with acute coronary syndrome. AB - BACKGROUND: Non-ST elevation myocardial infarction (NSTEMI) is a common manifestation of acute coronary syndrome (ACS), but delayed diagnosis can increase mortality. In this proof of principle study, the emergency physician performed transthoracic echocardiography (TTE) on scene to determine whether NSTEMI could be correctly diagnosed pre-hospitalization. This could expedite admission to the appropriate facility and reduce the delay until initiation of correct therapy. METHODS: Pre-hospital TTE was performed on scene by the emergency physician in patients presenting with ACS but without ST-elevation in the initial 12-lead electrocardiography (ECG) (NSTE-ACS). A presumptive NSTEMI diagnosis was made if regional wall motion abnormalities (RWMA) were detected. These patients were admitted directly to a specialist cardiac facility. Patient characteristics and pre-admission and post-admission clinical, pre-hospital TTE data, and therapeutic measures were recorded. RESULTS: Patients with NSTE-ACS (n = 53; 72.5 +/- 13.4 years of age; 23 female) were studied. The 20 patients with pre-hospital RWMA and presumptive NSTEMI, and two without RWMA were conclusively diagnosed with NSTEMI in hospital. Percutaneous coronary intervention was performed in 50% of the patients presumed to have NSTEMI immediately after admission. The RWMA seen before hospital TTE corresponded with the in-hospital ECG findings and/or the supply regions of the occluded coronary vessels seen during PCI in 85% of the cases. The diagnostic sensitivity of pre-hospital TTE for NSTEMI was 90.9% with 100% specificity. CONCLUSIONS: Pre-hospital transthoracic echocardiography by the emergency physician can correctly diagnose NSTEMI in more than 90% of cases. This can expedite the initiation of appropriate therapy and could thereby conceivably reduce morbidity and mortality. TRIAL REGISTRATION: Deutsche Register klinischer Studien, DRKS00004919 . Registered on 29 April 2013. PMID- 29409527 TI - Bystro: rapid online variant annotation and natural-language filtering at whole genome scale. AB - Accurately selecting relevant alleles in large sequencing experiments remains technically challenging. Bystro ( https://bystro.io/ ) is the first online, cloud based application that makes variant annotation and filtering accessible to all researchers for terabyte-sized whole-genome experiments containing thousands of samples. Its key innovation is a general-purpose, natural-language search engine that enables users to identify and export alleles and samples of interest in milliseconds. The search engine dramatically simplifies complex filtering tasks that previously required programming experience or specialty command-line programs. Critically, Bystro's annotation and filtering capabilities are orders of magnitude faster than previous solutions, saving weeks of processing time for large experiments. PMID- 29409526 TI - Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. AB - BACKGROUND: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and other tauopathies. METHODS: To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease. RESULTS: We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP 43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls. CONCLUSIONS: Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration. PMID- 29409528 TI - Approaches towards improving the quality of maternal and newborn health services in South Asia: challenges and opportunities for healthcare systems. AB - BACKGROUND: South Asia is experiencing a dismal state of maternal and newborn health (MNH) as the region has been falling behind in reducing the levels of maternal and neonatal mortality. Most of the efforts are focused on enhancing coverage of MNH services; however, quality remains a serious concern if the region is to achieve expected outcomes in terms of standardised MNH services within healthcare delivery systems. This research consists of a review of South Asian quality improvement (QI) approaches/interventions, specifically implemented for MNH improvement. METHODS: A literature review of QI approaches/interventions was conducted using the PRISMA guidelines. Online databases, including PubMed, the Cochrane Library and Google Scholar, were searched. Primary studies published between 1998 and 2013 were considered. Studies were initially screened and selected based upon the selection criteria for data extraction. A thematic synthesis/analysis was performed to organise, group and interpret the key findings according to prominent themes. RESULTS: Thirty studies from six South Asian countries were included in the review. Findings from these selected studies were grouped under eight broad, cross-cutting themes, which emerged from a deductive approach, representing the most commonly employed QI approaches for improving MNH services within different geographical settings. These consist of capacity building of healthcare providers on clinical quality, clinical audits and feedback, financial incentives to beneficiaries, pay-for-performance, supportive supervision, community engagement, collaborative efforts and multidimensional interventions. CONCLUSIONS: Employing and documenting QI approaches is essential in order to measure the potential of an intervention, considering its cost-effectiveness, feasibility and acceptability to communities. This research concluded that QI approaches are very diverse and cross-cutting, because they are subject to the varied requirements of regional health systems. This high level of variability leads to implementation and knowledge-management challenges for MNH programme planners and managers in the countries of the South Asia region. PMID- 29409529 TI - The JAK2 pathway is activated in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. METHODS AND RESULTS: JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti apoptosis. CONCLUSIONS: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease. PMID- 29409530 TI - Frequency of breast cancer subtypes among African American women in the AMBER consortium. AB - BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women. PMID- 29409531 TI - Development and characterization of serotype-specific monoclonal antibodies against the dengue virus-4 (DENV-4) non-structural protein (NS1). AB - BACKGROUND: Dengue, caused by one of the four serologically distinct dengue viruses (DENV-1 to - 4), is a mosquito-borne disease of serious global health significance. Reliable and cost-effective diagnostic tests, along with effective vaccines and vector-control strategies, are highly required to reduce dengue morbidity and mortality. Evaluation studies revealed that many commercially available NS1 antigen (Ag) tests have limited sensitivity to DENV-4 serotype compared to the other three serotypes. These studies indicated the need for development of new NS1 Ag detection test with improved sensitivity to DENV-4. An NS1 capture enzyme linked immunoassay (ELISA) specific to DENV-4 may improve the detection of DENV-4 cases worldwide. In addition, a serotype-specific NS1 Ag test identifies both DENV and the infecting serotype. METHODS: In this study, we used a small-ubiquitin-like modifier (SUMO*) cloning vector to express a SUMO*-DENV-4 rNS1 fusion protein to develop NS1 DENV-4 specific monoclonal antibodies (MAbs). These newly developed MAbs were then optimized for use in an anti-NS1 DENV-4 capture ELISA. The serotype specificity and sensitivity of this ELISA was evaluated using (i) supernatants from DENV (1-4)-infected Vero cell cultures, (ii) rNS1s from all the four DENV (1-4) and, (iii) rNS1s of related flaviviruses (yellow fever virus; YFV and West Nile virus; WNV). RESULTS: From the evaluation studies of the newly developed MAbs, we identified three DENV-4 specific anti-NS1 MAbs: 3H7A9, 8A6F2 and 6D4B10. Two of these MAbs were optimal for use in a DENV-4 serotype-specific NS1 capture ELISA: MAb 8A6F2 as the capture antibody and 6D4B10 as a detection antibody. CONCLUSION: This ELISA was sensitive and specific to DENV-4 with no cross-reactivity to other three DENV (1-3) serotypes and other heterologous flaviviruses. Taken together these data indicated that our MAbs are useful reagents for the development of DENV-4 immunodiagnostic tests. PMID- 29409532 TI - SCANPY: large-scale single-cell gene expression data analysis. AB - SCANPY is a scalable toolkit for analyzing single-cell gene expression data. It includes methods for preprocessing, visualization, clustering, pseudotime and trajectory inference, differential expression testing, and simulation of gene regulatory networks. Its Python-based implementation efficiently deals with data sets of more than one million cells ( https://github.com/theislab/Scanpy ). Along with SCANPY, we present ANNDATA, a generic class for handling annotated data matrices ( https://github.com/theislab/anndata ). PMID- 29409533 TI - Isolation of three novel reassortant phleboviruses, Ponticelli I, II, III, and of Toscana virus from field-collected sand flies in Italy. AB - BACKGROUND: Different phleboviruses are important pathogens for humans; most of these viruses are transmitted by sand flies. An increasing number of new phleboviruses have been reported over the past decade, especially in Mediterranean countries, mainly via their detection in sand flies. RESULTS: At least five different phleboviruses co-circulated in sand flies that were collected in three sites in Emilia-Romagna (Italy) in the summer of 2013. The well-known Toscana virus (TOSV) was isolated; three new, closely related phleboviruses differing in their M segments and tentatively named Ponticelli I, Ponticelli II and Ponticelli III virus, respectively, were isolated; a fifth putative phlebovirus, related to the sand fly fever Naples phlebovirus species, was also detected. The co-circulation, in a restricted area, of three viruses characterized by different M segments, likely resulted from reassortment events. According to the phylogenetic analysis of complete genome sequences, the TOSV belongs to clade A, together with other Italian isolates, while the Ponticelli viruses fall within the Salehabad phlebovirus species. CONCLUSIONS: Results highlight an unexpected diversity of phleboviruses that co-circulate in the same area, suggesting that interactions likely occur amongst them, that can present challenges for their correct identification. The co-circulation of different phleboviruses appears to be common, and the bionomics of sand fly populations seem to play a relevant role. Such a complex situation emphasizes the need for detailed investigations of the biology of these viruses to better characterize their pathogenic potential for mammals, including humans. PMID- 29409534 TI - The implausible "in vivo" role of hydrogen peroxide as an antimicrobial factor produced by vaginal microbiota. AB - In the cervicovaginal environment, the production of hydrogen peroxide (H2O2) by vaginal Lactobacillus spp. is often mentioned as a critical factor to the in vivo vaginal microbiota antimicrobial properties. We present several lines of evidence that support the implausibility of H2O2 as an "in vivo" contributor to the cervicovaginal milieu antimicrobial properties. An alternative explanation is proposed, supported by previous reports ascribing protective and antimicrobial properties to other factors produced by Lactobacillus spp. capable of generating H2O2. Under this proposal, lactic acid rather than H2O2 plays an important role in the antimicrobial properties of protective vaginal Lactobacillus spp. We hope this commentary will help future research focus on more plausible mechanisms by which vaginal Lactobacillus spp. exert their antimicrobial and beneficial properties, and which have in vivo and translational relevance. PMID- 29409535 TI - DMTO: a realistic ontology for standard diabetes mellitus treatment. AB - BACKGROUND: Treatment of type 2 diabetes mellitus (T2DM) is a complex problem. A clinical decision support system (CDSS) based on massive and distributed electronic health record data can facilitate the automation of this process and enhance its accuracy. The most important component of any CDSS is its knowledge base. This knowledge base can be formulated using ontologies. The formal description logic of ontology supports the inference of hidden knowledge. Building a complete, coherent, consistent, interoperable, and sharable ontology is a challenge. RESULTS: This paper introduces the first version of the newly constructed Diabetes Mellitus Treatment Ontology (DMTO) as a basis for shared semantics, domain-specific, standard, machine-readable, and interoperable knowledge relevant to T2DM treatment. It is a comprehensive ontology and provides the highest coverage and the most complete picture of coded knowledge about T2DM patients' current conditions, previous profiles, and T2DM-related aspects, including complications, symptoms, lab tests, interactions, treatment plan (TP) frameworks, and glucose-related diseases and medications. It adheres to the design principles recommended by the Open Biomedical Ontologies Foundry and is based on ontological realism that follows the principles of the Basic Formal Ontology and the Ontology for General Medical Science. DMTO is implemented under Protege 5.0 in Web Ontology Language (OWL) 2 format and is publicly available through the National Center for Biomedical Ontology's BioPortal at http://bioportal.bioontology.org/ontologies/DMTO . The current version of DMTO includes more than 10,700 classes, 277 relations, 39,425 annotations, 214 semantic rules, and 62,974 axioms. We provide proof of concept for this approach to modeling TPs. CONCLUSION: The ontology is able to collect and analyze most features of T2DM as well as customize chronic TPs with the most appropriate drugs, foods, and physical exercises. DMTO is ready to be used as a knowledge base for semantically intelligent and distributed CDSS systems. PMID- 29409537 TI - Complete resection of a rectus abdominis muscle invaded by desmoid tumors and subsequent management with an abdominal binder: a case report. AB - BACKGROUND: Desmoid-type fibromatosis is characterized by desmoid tumors, which are benign soft tissue tumors that can be locally aggressive but typically do not metastasize. Desmoid tumors can manifest anywhere in the body, and those in the abdominal cavity account for approximately 30 to 50% of all such tumors. Complete resection with free margins has been the standard treatment, but non-surgical therapies have been implemented recently. However, if tumors are strongly invasive and/or persistently recur, radical surgical resection with free margins remains the primary treatment. Unfortunately, radical resection may cause large abdominal defects and hinder reconstruction. Several reports and recommendations have addressed this issue; however, to the best of our knowledge, few reports have described complete resection and the subsequent reconstruction of the rectus abdominis muscle. CASE PRESENTATION: A 35-year-old Asian woman presented at our hospital with a chief complaint of abdominal pain. She had abdominal desmoid tumors that required complete resection of her rectus abdominis muscle. Due to necrosis in her own reconstructed tissue, we failed to cover her anterior abdominal wall; thus, we used an abdominal binder as a substitute material to avoid exacerbating the incisional hernia and help her generate intra-abdominal pressure. CONCLUSIONS: This case report may be informative and helpful for the treatment of patients with desmoid tumors, as managing desmoid-type fibromatosis is difficult. PMID- 29409536 TI - Pharmacological and immunological effects of praziquantel against Schistosoma japonicum: a scoping review of experimental studies. AB - BACKGROUND: Chemotherapy for schistosomiasis has been around for 100 years. During the past century, great efforts have been made to develop new antischistosomal drugs from antimonials to nonantimonials, and some of these have been used extensively in clinical treatment. With the exception of a few drugs, such as oxamniquine and metrifonate, most of the antischistosomals developed in the pre-praziquantel period have variable limitations with respect to safety and efficacy. Although oxamniquine and metrifonate have been used for schistosomiasis control, they are only effective against Schistosoma mansoni and S. haematobium, respectively. Currently, praziquantel is the only drug used for treatment of all five species of human schistosomes. In this review, the pharmacological and immunological effects of praziquantel against S. japonicum are summarized and discussed. MAIN TEXT: From the end of the 1970s until the 2000s, scientists have conducted a series of experimental studies on the effects of praziquantel against S. japonicum. These have included examining its unique pharmacological action on schistosomes, the characteristics in susceptibility of the different developmental stages of schistosomes to the drug, the relationship between plasma concentration of the drug and efficacy, the impact of host factors on cidal action of the drug, prevention and early treatment of schistosomal infection, as well as praziquantel-resistant schistosomiasis. CONCLUSION: The effects of praziquantel against S. japonicum, as elucidated by the experimental studies that are reviewed in this paper, may have some reference significance for the development of new antischistosomals. PMID- 29409538 TI - Laboratory parameters in lean NAFLD: comparison of subjects with lean NAFLD with obese subjects without hepatic steatosis. AB - OBJECTIVE: Search for meaningful laboratory and anthropometric parameters in lean non-alcoholic fatty liver disease (lean NAFLD) in the general population. Out of 2445 subjects in a random population sample, we compared those who had a body mass index (BMI) < 25 and a fatty liver [lean NAFLD (LN), n = 5] with obese subjects who had a BMI > 30 but no fatty liver [non-NAFLD (NN), n = 27] in a follow-up examination. Ultrasonic, anthropometric and laboratory parameters were collected. RESULTS: There were significant differences (p < 0.05) between the LN and the NN groups with respect to serum ferritin (199.2 +/- 72.1 LN vs 106.0 +/- 89.6 NN), haemoglobin (14.9 +/- 0.8 LN vs 13.5 +/- 1.2 NN), haematocrit (0.438 +/ 0.019 LN vs 0.407 +/- 0.035 NN) and Mean corpuscular haemoglobin concentration (34 +/- 0.6 LN vs 33.2 +/- 0.8 NN). Significantly lower values of soluble transferrin receptor were measured in the LN group (2.8 +/- 0.4 LN vs 3.8 +/- 1.5 NN). In both groups, the measured HOMA-IR index (homeostatic model assessment of insulin resistance index) (2.3; normal range <= 1) was abnormal. Mean cholesterol (6.2 +/- 1.4 LN and 5.6 +/- 1.1 NN) and low-density lipoprotein levels (3.8 +/- 1.0 LN 3.4 +/- 0.9 NN) were above the upper limit of normal in both groups, as was the mean triglycerides level in the LN group (2.6 +/- 2.0). In summary, there are differences in parameters of iron and fat metabolism between subjects with LN and overweight subjects without fatty liver infiltration. PMID- 29409539 TI - Eligibility for heroin-assisted treatment (HAT) among people who inject opioids and are living with HIV in a Canadian setting. AB - OBJECTIVES: A growing body of evidence supports the effectiveness of injectable diacetylmorphine (i.e., heroin) for individuals with treatment-refractory opioid use disorder. Despite this evidence, and the increasing toll of opioid-associated morbidity and mortality, it remains controversial in some settings. To investigate the possible contribution of heroin-assisted treatment (HAT) to HIV treatment-related outcomes, we sought to estimate the proportion and characteristics of HIV-positive people who inject opioids that might be eligible for HAT in Vancouver, Canada. METHODS: We used data from a prospective cohort of people living with HIV who use illicit drugs in Vancouver, Canada. Using generalized estimating equations (GEE), we assessed the longitudinal relationships between eligibility for HAT, using criteria from previous clinical trials and guidelines, with behavioural, social, and clinical characteristics. RESULTS: Between 2005 and 2014, 478 participants were included in these analyses, contributing 1927 person-years of observation. Of those, 94 (19.7%) met eligibility for HAT at least once during the study period. In a multivariable GEE model, after adjusting for clinical characteristics, being eligible for HAT was positively associated with homelessness, female gender, high-intensity illicit drug use, drug dealing and higher CD4 count. CONCLUSIONS: In our study of HIV positive people with a history of injection drug use, approximately 20% of participants were eligible for HAT at >= 1 follow-up period. Eligibility was linked to risk factors for sub-optimal HIV/AIDS treatment outcomes, such as homelessness and involvement in the local illicit drug trade, suggesting that scaling-up access to HAT might contribute to achieving optimal HIV treatment in this setting. PMID- 29409540 TI - Mesenchymal stromal cell-derived exosome-rich fractionated secretome confers a hepatoprotective effect in liver injury. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are an attractive therapeutic agent in regenerative medicine. Recently, there has been a paradigm shift from differentiation of MSCs to their paracrine effects at the injury site. Several reports elucidate the role of trophic factors secreted by MSCs toward the repair of injured tissues. We hypothesize that fractionating the MSC secretome will enrich exosomes containing soluble bioactive molecules, improving its therapeutic potential for liver failure. METHODS: Rat bone marrow MSCs were isolated and the conditioned media filtered, concentrated and ultracentrifuged to generate fractionated secretome. This secretome was characterized for the presence of exosomes and recovery from liver injury assessed in in-vitro liver injury models. The results were further validated in vivo. RESULTS: Studies on in-vitro liver injury models using acetaminophen and hydrogen peroxide show better cell recovery and reduced cytotoxicity in the presence of fractionated as opposed to unfractionated secretome. Further, the cells showed reduced oxidative stress in the presence of fractionated secretome, suggesting a potential antioxidative effect. These results were further validated in vivo in liver failure models, wherein improved liver regeneration in the presence of fractionated secretome (0.819 +/- 0.035) was observed as compared to unfractionated secretome (0.718 +/- 0.042). CONCLUSIONS: The work presented is a proof of concept that fractionating the secretome enriches certain bioactive molecules involved in the repair and recovery of injured liver tissue. Exosome enriched mesenchymal stromal cell derived fractionated secretome potentiates recovery upon injection in injured liver. PMID- 29409541 TI - Comparative genomics reveals a widespread distribution of an exopolysaccharide biosynthesis gene cluster among Vibrionaceae. AB - OBJECTIVES: The eps locus in Vibrio diabolicus is involved in the production of the biotechnologically valuable HE800 EPS. In this study, the distribution and diversity of similar eps gene clusters across Vibrionaceae and its variability in relation to phylogenetic relationship were investigated. The aim was to provide a better knowledge of the eps gene cluster importance and to facilitate discovery of new EPS with potent interesting bioactivities. RESULTS: Seventy percent of the 103 genome sequences examined display such an eps locus with a high level of synteny. However, genetic divergence was found inside some monophyletic clades or even between some strains of the same species. It includes gene insertions, truncations, and deletions. Comparative analysis also reveals some variations in glycosyltransferase and export systems genes. Phylogenetic analysis of the Vibrionaceae eps gene clusters within Vibrionaceae suggests a vertical transfer by speciation but also pinpoints rearrangement events independent of the speciation. PMID- 29409542 TI - To eat or to breathe? The answer is both! Nutritional management during noninvasive ventilation. AB - Treating respiratory distress is a priority when managing critically ill patients. Non-invasive ventilation (NIV) is increasingly used as a tool to prevent endotracheal intubation. Providing oral or enteral nutritional support during NIV may be perceived as unsafe because of the possible risk of aspiration so that these patients are frequently denied adequate caloric and protein intake. Newly available therapies, such as high-flow nasal oxygen (HFNO) may allow for more appropriate oral feeding. PMID- 29409543 TI - Effects of predation stress and food ration on perch gut microbiota. AB - BACKGROUND: Gut microbiota provide functions of importance to influence hosts' food digestion, metabolism, and protection against pathogens. Factors that affect the composition and functions of gut microbial communities are well studied in humans and other animals; however, we have limited knowledge of how natural food web factors such as stress from predators and food resource rations could affect hosts' gut microbiota and how it interacts with host sex. In this study, we designed a two-factorial experiment exposing perch (Perca fluviatilis) to a predator (pike, Esox lucius), and different food ratios, to examine the compositional and functional changes of perch gut microbiota based on 16S rRNA amplicon sequencing. We also investigated if those changes are host sex dependent. RESULTS: We showed that overall gut microbiota composition among individual perch significantly responded to food ration and predator presence. We found that species richness decreased with predator presence, and we identified 23 taxa from a diverse set of phyla that were over-represented when a predator was present. For example, Fusobacteria increased both at the lowest food ration and at predation stress conditions, suggesting that Fusobacteria are favored by stressful situations for the host. In concordance, both food ration and predation stress seemed to influence the metabolic repertoire of the gut microbiota, such as biosynthesis of other secondary metabolites, metabolism of cofactors, and vitamins. In addition, the identified interaction between food ration and sex emphasizes sex-specific responses to diet quantity in gut microbiota. CONCLUSIONS: Collectively, our findings emphasize an alternative state in gut microbiota with responses to changes in natural food webs depending on host sex. The obtained knowledge from this study provided us with an important perspective on gut microbiota in a food web context. PMID- 29409545 TI - Monogenoidean parasites of Acestrorhynchus falcatus (Characiformes: Acestrorhynchidae) from Para, Brazil: species of Diaphorocleidus and Rhinoxenoides n. gen. (Monogenoidea: Dactylogyridae). AB - Two new species of Diaphorocleidus and one new species of Rhinoxenoides n. gen. are described from the gills of Acestrorhynchus falcatus (Bloch) from rivers of north-eastern Para, Brazil. Diaphorocleidus jaymedeloyolai n. sp. is characterized by a male copulatory organ (MCO) possessing three counterclockwise coils; similar anchors with subtriangular superficial roots; a ventral bar with posteromedial projection; and hooks of pairs 1, 4 and 7 approximately three times longer than hook pair 5. Diaphorocleidus sclerocolpus n. sp. differs from its congeners by a dual-branched accessory piece articulated with the MCO and a sclerotized tubular vagina with a bottle-shaped vestibule. Rhinoxenoides n. gen. is proposed and is characterized by possessing: MCO sclerotized with clockwise coils; an accessory piece articulated to the base of MCO; a sinistroventral vaginal aperture; ventral anchor with conspicuous roots; dorsal anchor with superficial root five times longer than deep root; and absence of dorsal bar. The proposal of Rhinoxenoides n. gen. is also supported by its phylogenetic relationship with Protorhinoxenus prochilodi and species of Rhinoxenus, using 16 morphological characters, which resulted in the following hypothesis of sister group relationships: Rhinoxenoides n. gen. [Protorhinoxenus (Rhinoxenus curimatae (R. nyttus (R. bulbovaginatus (R. guianensis, R. piranhus, R. euryxenus (R. arietinus, R. anaclaudiae)))))]. PMID- 29409544 TI - Revisiting the Trypanosoma cruzi metacyclogenesis: morphological and ultrastructural analyses during cell differentiation. AB - BACKGROUND: Trypanosoma cruzi uses several strategies to survive in different hosts. A key step in the life-cycle of this parasite is metacyclogenesis, which involves various morphological, biochemical, and genetic changes that induce the differentiation of non-pathogenic epimastigotes into pathogenic metacyclic trypomastigotes. During metacyclogenesis, T. cruzi displays distinct morphologies and ultrastructural features, which have not been fully characterized. RESULTS: We performed a temporal description of metacyclogenesis using different microscopy techniques that resulted in the identification of three intermediate forms of T. cruzi: intermediates I, II and III. Such classification was based on morphological and ultrastructural aspects as the location of the kinetoplast in relation to the nucleus, kinetoplast shape and kDNA topology. Furthermore, we suggested that metacyclic trypomastigotes derived from intermediate forms that had already detached from the substrate. We also found that changes in the kinetoplast morphology and kDNA arrangement occurred only after the repositioning of this structure toward the posterior region of the cell body. These changes occurred during the later stages of differentiation. In contrast, changes in the nucleus shape began as soon as metacyclogenesis was initiated, while changes in nuclear ultrastructure, such as the loss of the nucleolus, were only observed during later stages of differentiation. Finally, we found that kDNA networks of distinct T. cruzi forms present different patterns of DNA topology. CONCLUSIONS: Our study of T. cruzi metacyclogenesis revealed important aspects of the morphology and ultrastructure of this intriguing cell differentiation process. This research expands our understanding of this parasite's fascinating life cycle. It also highlights the study of T. cruzi as an important and exciting model system for investigating diverse aspects of cellular, molecular, and evolutionary biology. PMID- 29409546 TI - Suspected necrotising enterocolitis after surgery for CHD: an opportunity to improve practice and outcomes. AB - Infants with CHD are at increased risk of necrotising enterocolitis, which can interfere with the achievement of adequate nutrition and, ultimately, growth and development. Necrotising enterocolitis is classified by severity as suspected, confirmed, and advanced. We sought to quantify the incidence of all types of necrotising enterocolitis among infants who underwent surgery, with a particular focus on suspected necrotising enterocolitis. This is a retrospective review of all infants <6 months of age who underwent cardiac surgery during 2012 and 2013 at Children's Hospital Colorado. We examined the hospital course of 265 hospitalisations (n=251 patients) and found 18 patients (19 hospitalisations) with suspected necrotising enterocolitis and 16 patients (16 hospitalisations) with confirmed or advanced necrotising enterocolitis. Single-ventricle physiology, lower weight, and younger age were associated with necrotising enterocolitis. Patients with all types of necrotising enterocolitis experienced prolonged length of hospital stay. We found suspected necrotising enterocolitis to be as common as confirmed necrotising enterocolitis, and it frequently occurred early in the post-operative course. We speculate that suspected necrotising enterocolitis may often be overlooked in research owing to a reliance on billing codes. Nevertheless, suspected necrotising enterocolitis poses a substantial barrier to post-operative progression of the CHD patient, as does confirmed necrotising enterocolitis. Following the diagnosis of all types of necrotising enterocolitis, there was wide variability in practice patterns. In response to this variability, we developed care guidelines for the diagnosis and treatment of necrotising enterocolitis in this population. PMID- 29409547 TI - Using MALDI-TOF MS to identify mosquitoes collected in Mali and their blood meals. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been recently described as an innovative and effective tool for identifying arthropods and mosquito blood meal sources. To test this approach in the context of an entomological survey in the field, mosquitoes were collected from five ecologically distinct areas of Mali. We successfully analysed the blood meals from 651 mosquito abdomens crushed on Whatman filter paper (WFPs) in the field using MALDI-TOF MS. The legs of 826 mosquitoes were then submitted for MALDI-TOF MS analysis in order to identify the different mosquito species. Eight mosquito species were identified, including Anopheles gambiae Giles, Anopheles coluzzii, Anopheles arabiensis, Culex quinquefasciatus, Culex neavei, Culex perexiguus, Aedes aegypti and Aedes fowleri in Mali. The field mosquitoes for which MALDI-TOF MS did not provide successful identification were not previously available in our database. These specimens were subsequently molecularly identified. The WFP blood meal sources found in this study were matched against human blood (n = 619), chicken blood (n = 9), cow blood (n = 9), donkey blood (n = 6), dog blood (n = 5) and sheep blood (n = 3). This study reinforces the fact that MALDI-TOF MS is a promising tool for entomological surveys. PMID- 29409548 TI - A clinimetric analysis of a BPRS-6 scale for schizophrenia severity. AB - OBJECTIVE: A restricted Brief Psychiatric Rating Scale (BPRS-6) with the six schizophrenia specific items from the Positive and Negative Syndrome Scale (PANSS) has been investigated. These six items from the PANSS have recently been found to have both clinical validity and 'unidimensionality' in measuring the severity of schizophrenic states. The primary objective of this study was to evaluate the clinical validity of the BPRS-6. The secondary objective was to evaluate the 'unidimensionality' of the BPRS-6 by an 'item response theory' model. METHODS: The BPRS-6 was scored independently by two psychiatrists and two psychologists while viewing six open-ended videotaped interviews in patients with a DSM-III diagnosis of schizophrenia. The interviews were conducted by Heinz E. Lehmann, an experienced psychiatrist. They were focused on the psychopathology that contributed most to the 'severity' of the patient's clinical state. RESULTS: The BPRS-6 with three positive symptoms (delusions, conceptual disorganisation, hallucinations) and three negative symptoms (blunted affect, emotional withdrawal, poverty of speech) was found to be clinically valid and captured the variables that contribute most to the severity of schizophrenia. The BPRS-6 was also found to have acceptable 'unidimensionality' (coefficient of homogeneity 0.45) and inter-rater reliability (inter-class-coefficient 0.81). CONCLUSION: The BPRS-6 was found to capture the information that translates into the severity of schizophrenia. It has also acceptable psychometric validity. PMID- 29409549 TI - Sclerocollum saudii Al-Jahdali, 2010 (Acanthocephala: Cavisomidae) as a sentinel for heavy-metal pollution in the Red Sea. AB - Currently, fish helminth parasites, especially cestodes and acanthocephalans, are regarded as sentinel organisms to elucidate metal pollution in aquatic ecosystems. Here, 34 specimens of the fish Siganus rivulatus were collected in the Red Sea, from a seriously polluted, small lagoon named Sharm-Elmaya Bay, at Sharm El-Sheikh, South Sinai, Egypt; 22 (64.7%) were infected by Sclerocollum saudii (Acanthocephala: Cavisomidae). Thus, 22 natural infrapopulations (26-245 individuals) of this parasite were collected from infected fish. Samples of water and sediments from the bay, samples of muscle, intestine and liver from each fish, and samples from the parasite were taken for analysis of heavy metals (cadmium (Cd) and lead (Pb)). Both Cd and Pb concentrations in sediments were higher than those in water. The concentration of these metals were significantly higher in tissues (intestine, liver and muscle) of non-infected fish than those in infected fish, with Pb concentrations consistently higher than those of Cd, and both were drastically decreased in the order: liver > intestine > muscle. Metal concentrations in this acanthocephalan were much higher than those in its fish host. There were strong negative relationships between metal concentrations in tissues (intestine, liver and muscle) of infected fish and infrapopulation size, and between metal concentrations in the acanthocephalan and its infrapopulation size. These relationships strongly suggest competition for these metals between the fish host and its acanthocephalan parasite, and intraspecific competition among acanthocephalan individuals for available metals in the fish intestine. Bioconcentration factors were relatively high, since the mean Cd concentration in S. saudii was 239, 68 and 329 times higher than those in intestine, liver and muscle tissues, respectively, of its fish host. Also, mean Pb concentration was 55, 13 and 289 times higher than those in these tissues, respectively. The host-parasite system described here seems to be promising for biomonitoring of metal pollution in the Red Sea. PMID- 29409550 TI - Clinical and haematological characteristics of human trichostrongyliasis. AB - Trichostrongylus spp. are primarily parasites of ruminants, but humans can become infected as accidental hosts. Information about the clinical aspects of human trichostrongyliasis is limited. This study investigated the clinical and haematological characteristics of a large number of trichostrongyliasis patients. In the Fouman district of Guilan Province in northern Iran, during 2015-2016, 60 patients were identified as positive for Trichostrongylus spp., using stool examination methods. The clinical manifestations and demographic data of all patients were recorded and further analysed. Twenty-three patients (38.3%) were male and 37 (61.7%) were female. Among the individuals infected only with Trichostrongylus, only nine patients (16.4%) were asymptomatic. Forty-six patients (83.6%) presented with gastrointestinal (76.3%), pulmonary (30.9%) and cutaneous (12.7%) symptoms. No statistically significant relationship was found between clinical manifestations and sex or age groups. Ten patients (18.1%) revealed eosinophilia and five (9.1%) presented with hypochromic microcytic anaemia. The relationship between eosinophilia and age group, sex and clinical manifestations showed no statistical significance. Our study indicated that trichostrongyliasis may be a major parasitic aetiology for gastrointestinal symptoms and eosinophilia in rural residents of endemic areas. PMID- 29409551 TI - Impact of prenatal diagnosis on the management and early outcome of critical duct dependent cardiac lesions. AB - OBJECTIVE: The objective of this study was to compare the preoperative management and outcome of neonates with duct-dependent critical CHD with fetal versus postnatal diagnosis. METHODS: Patients referred with CHD to our centre from January 1, 2009 to December 31, 2010 were enrolled prospectively. Live births with a critical form of CHD, a gestational age ?36 weeks and a weight ?2 kg at birth, and the intention-to-treat were included in this sub-study. Excluded were neonates with lethal non-cardiac and/or genetic anomalies. RESULTS: In total, 129, 63 fetal and 66 postnatal, cases met the study inclusion criteria. All had received appropriate antenatal care, including a routine fetal anatomy scan. Both cohorts were comparable in weight, gestational age, and APGAR scores at birth. Unlike the postnatal cases, there were no deaths (0/63 versus 5/66; p=0.06) and no cardiac arrests (0/63 versus 9/63; p=0.003) before surgery or catheter intervention in those cases with a prenatal diagnosis of critical CHD. Moreover, newborns with fetal diagnoses were admitted earlier (median 0 (range 0-3) versus 2 (0-25) days; p<0.001) and were less likely to require preoperative ventilation (19/63 versus 31/61, p=0.03) and vasoactive medication (4/63 versus 15/61, p=0.006) than the postnatal cases. CONCLUSIONS: Prenatal diagnosis of critical CHD in this study was associated with significantly shorter time intervals from birth to neonatal admission and the absence of life-threatening or fatal preoperative cardiac events. Increased efforts should be made to improve rates of prenatal diagnosis. PMID- 29409552 TI - Dying for the group: Towards a general theory of extreme self-sacrifice. AB - Whether upheld as heroic or reviled as terrorism, throughout history people have been willing to lay down their lives for the sake of their groups. Why? Previous theories of extreme self-sacrifice have highlighted a range of seemingly disparate factors such as collective identity, outgroup hostility, and kin psychology. This paper attempts to integrate many of these factors into a single overarching theory based on several decades of collaborative research with a range of special populations, from tribes in Papua New Guinea to Libyan insurgents, and from Muslim fundamentalists in Indonesia to Brazilian football hooligans. These studies suggest that extreme self-sacrifice is motivated by 'identity fusion', a visceral sense of oneness with the group resulting from intense collective experiences (e.g. painful rituals or the horrors of frontline combat) or from perceptions of shared biology. In ancient foraging societies, fusion would have enabled warlike bands to stand united despite strong temptations to scatter and flee. The fusion mechanism has often been exploited in cultural rituals, not only by tribal societies but also in specialized cells embedded in armies, cults, and terrorist organizations. With the rise of social complexity and the spread of states and empires, fusion has also been extended to much larger groups, including doctrinal religions, ethnicities, and ideological movements. Explaining extreme self-sacrifice is not only a scientific priority but also a practical challenge as we seek a collective response to suicide terrorism and other extreme expressions of outgroup hostility that continue to bedevil humanity today. PMID- 29409553 TI - Diagnostic errors in paediatric cardiac intensive care. AB - : IntroductionDiagnostic errors cause significant patient harm and increase costs. Data characterising such errors in the paediatric cardiac intensive care population are limited. We sought to understand the perceived frequency and types of diagnostic errors in the paediatric cardiac ICU. METHODS: Paediatric cardiac ICU practitioners including attending and trainee physicians, nurse practitioners, physician assistants, and registered nurses at three North American tertiary cardiac centres were surveyed between October 2014 and January 2015. RESULTS: The response rate was 46% (N=200). Most respondents (81%) perceived that diagnostic errors harm patients more than five times per year. More than half (65%) reported that errors permanently harm patients, and up to 18% perceived that diagnostic errors contributed to death or severe permanent harm more than five times per year. Medication side effects and psychiatric conditions were thought to be most commonly misdiagnosed. Physician groups also ranked pulmonary overcirculation and viral illness to be commonly misdiagnosed as bacterial illness. Inadequate care coordination, data assessment, and high clinician workload were cited as contributory factors. Delayed diagnostic studies and interventions related to the severity of the patient's condition were thought to be the most commonly reported process breakdowns. All surveyed groups ranked improving teamwork and feedback pathways as strategies to explore for preventing future diagnostic errors. CONCLUSIONS: Paediatric cardiac intensive care practitioners perceive that diagnostic errors causing permanent harm are common and associated more with systematic and process breakdowns than with cognitive limitations. PMID- 29409554 TI - Redescription of Macrolaimus canadensis Sanwal, 1960 and M. ruehmi Andrassy, 1966 (Nematoda, Rhabditida, Chambersiellidae), and new data on M. crucis Maupas, 1900. AB - Three species belonging to the genus Macrolaimus, namely M. canadensis, M. crucis and M. ruehmi, have been obtained from areas of natural vegetation in Bosnia and Herzegovina, Corsica (France), the Czech Republic and Spain. These three species are characterized by the body length of males and females, stomatal proportion of the gymnostom and cheilostom, excretory pore position, postvulval uterine sac length, male and female tail length and morphology, and the length and morphology of the spicules and gubernacula. The occurrence of M. crucis in Spain has, as a result of this study, now also been expanded to a larger area of the southern Iberian Peninsula. Morphological and morphometrical analyses showed that M. canadensis and M. ruehmi are very similar, sharing apomorphic characters. In contrast, M. crucis has plesiomorphic characters. Description, measurements and illustrations are provided for these three species. PMID- 29409555 TI - Seattle's minimum wage ordinance did not affect supermarket food prices by food processing category. AB - OBJECTIVE: To examine the impacts of Seattle's minimum wage ordinance on food prices by food processing category. DESIGN: Supermarket food prices were collected for 106 items using a University of Washington Center for Public Health Nutrition market basket at affected and unaffected supermarket chain stores at three times: March 2015 (1-month pre-policy enactment), May 2015 (1-month post policy enactment) and May 2016 (1-year post-policy enactment). Food items were categorized into four food processing groups, from minimally to ultra-processed. Data were analysed across time using a multilevel, linear difference-in differences model at the store and price level stratified by level of food processing. SETTING: Six large supermarket chain stores located in Seattle ('intervention') affected by the policy and six same-chain but unaffected stores in King County ('control'), Washington, USA. SUBJECTS: One hundred and six food and beverage items. RESULTS: The largest change in average price by food item was +$US 0.53 for 'processed foods' in King County between 1-month post-policy and 1 year post-policy enactment (P < 0.01). The smallest change was $US 0.00 for 'unprocessed or minimally processed foods' in Seattle between 1-month post-policy and 1-year post-policy enactment (P = 0.94). No significant changes in averaged chain prices were observed across food processing level strata in Seattle v. King County stores at 1-month or 1-year post-policy enactment. CONCLUSIONS: Supermarket food prices do not appear to be differentially impacted by Seattle's minimum wage ordinance by level of the food's processing. These results suggest that the early implementation of a city-level minimum wage policy does not alter supermarket food prices by level of food processing. PMID- 29409556 TI - Effect of default menus on food selection and consumption in a college dining hall simulation study. AB - OBJECTIVE: To test an obesity prevention strategy derived from behavioural economics (optimal defaults plus delay), focused on changing the college dining hall service method. DESIGN: After a uniform pre-load, participants attended an experimental lunch in groups randomized to one of three conditions: a nutrient dense, lower-fat/energy lunch as an optimal default (OD); a less-nutrient-dense, higher-fat/energy lunch as a suboptimal default (SD); or a free array (FA) lunch. In the OD condition, students were presented a menu depicting healthier vegetarian and omnivore foods as default, with opt-out alternatives (SD menu) available on request with a 15 min wait. In the SD condition, the same menu format was used with the positioning of food items switched. In the FA condition, all choices were presented in uniform fonts and were available immediately. SETTING: Private rooms designed to provide a small version of a college dining hall, on two campuses of a Northeastern US university. SUBJECTS: First-year college students (n 129). RESULTS: There was a significant main effect for condition on percentage of optimal choices selected, with 94 % of food choices in the OD condition optimal, 47 % in the FA condition optimal and none in the SD condition optimal. Similarly, energy intake for those in the SD condition significantly exceeded that in the FA condition, which exceeded that in the OD condition. CONCLUSIONS: Presenting menu items as optimal defaults with a delay had a significant impact on choice and consumption, suggesting that further research into its long-term applicability is warranted. PMID- 29409557 TI - Incubation period for outbreak-associated, non-typhoidal salmonellosis cases, Minnesota, 2000-2015. AB - Incubation period for non-typhoidal Salmonella (NTS) infections is generally reported as 6-72 h despite numerous reports of foodborne NTS outbreaks with median incubation periods >3 days. We summarised 16 years of Minnesota foodborne NTS outbreaks to better estimate the expected range of incubation periods for NTS infections. Of the 1517 NTS outbreak cases, 725 had enough data to calculate a precise incubation period. The median incubation period was 45 h; 77 (11%) cases had incubations ?12 h and 211 (29%) cases had incubations >72 h. Incubation period length varied by outbreak vehicle type, Salmonella serotype and outbreak setting. Based on our data, a more accurate description would be that the incubation of NTS infection is usually from 12 to 96 h, that incubations in >96 to 144 h (>4 to 6-day) range are not unusual and that incubations from 7 to 9 days and occasionally longer also occur. PMID- 29409558 TI - Echinococcus multilocularis in a Eurasian lynx (Lynx lynx) in Turkey. AB - Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most threatening zoonoses in Eurasia. Human AE is widespread in the Erzurum region of Turkey, but the situation of the disease in intermediate and definitive hosts is unknown. A Eurasian lynx (Lynx lynx) was killed in a traffic accident in the north of Erzurum, and was taken to our laboratory. Sedimentation and counting technique (SCT), DNA isolation and polymerase chain reaction (PCR) analysis were performed. The SCT results showed that the lynx was infected with E. multilocularis with a medium (745 worms) worm burden. The DNA of adult worms obtained from the lynx was analyzed with a species-specific PCR, and the worms were confirmed to be E. multilocularis by 12S rRNA gene sequence analysis. This is the first report of E. multilocularis from Eurasian lynx in Turkey. PMID- 29409560 TI - The nutritional content of supermarket beverages: a cross-sectional analysis of New Zealand, Australia, Canada and the UK. AB - OBJECTIVE: To compare the nutritional content, serving size and taxation potential of supermarket beverages from four different Western countries. DESIGN: Cross-sectional analysis. Multivariate regression analysis and chi 2 comparisons were used to detect differences between countries. SETTING: Supermarkets in New Zealand (NZ), Australia, Canada and the UK. SUBJECTS: Supermarket beverages in the following categories: fruit juices, fruit-based drinks, carbonated soda, waters and sports/energy drinks. RESULTS: A total of 4157 products were analysed, including 749 from NZ, 1738 from Australia, 740 from Canada and 930 from the UK. NZ had the highest percentage of beverages with sugar added to them (52 %), while the UK had the lowest (9 %, P8 % sugar) categories. CONCLUSIONS: There is substantial difference between countries in the mean energy, serving size and proportion of products eligible for fiscal sugar taxation. Current self regulatory approaches used in these countries may not be effective to reduce the availability, marketing and consumption of sugar-sweetened beverages and subsequent intake of free sugars. PMID- 29409559 TI - Comparison of trace element levels after cardiopulmonary bypass between cyanotic and acyanotic patients. AB - Trace elements are essential micronutrients for the human body. In this study, we evaluated the alterations in copper, chromium, manganese, selenium, magnesium, zinc, iron, arsenic, boron, and silicon levels in children with cyanotic and acyanotic CHD who underwent cardiac surgery with cardiopulmonary bypass. Participants were divided into the following three groups: patients acyanotic CHDs (n=34), patients with cyanotic CHDs (n=30), and healthy controls (n=30). Blood samples were collected before the surgery and 1 hour after the sternum was closed. Serum trace elements were determined by Inductively Coupled Plasma Optical Emission Spectrometer-ICAP 6000. The baseline serum arsenic, manganese, and zinc levels of both patient groups were lower compared with controls, but there was no significant difference between baseline serum trace element levels of cyanotic and acyanotic patients. In both the patient groups, there was a significant decrease in postoperative serum arsenic, boron, copper, and zinc levels, and a significant increase in postoperative serum iron and magnesium levels. Silicon levels increased in cyanotic patients. Alterations in trace element levels were in the same direction in cyanotic and acyanotic patients. Copper, zinc, and manganase replacement may be needed after on-pump cardiac surgery. PMID- 29409561 TI - Validation of the register-based lifetime antimicrobial usage measurement for finisher batches based on comparison with recorded antimicrobial usage at farm level. AB - Assessing the relationship between antimicrobial usage (AMU) and antimicrobial resistance (AMR) requires the accurate and precise utilisation of register data. Therefore, validation of register-based data is essential for evaluating the quality and, subsequently, the internal validity of studies based on the data. In this study, different smoothing methods for Veterinary Medicine Statistic Program database (VetStat)-records were validated by comparing these with farm-records. Comparison between measurements included accuracy as; completeness and correctness, and precision as; a relative difference of the error, correlation with Fisher's z transformation and reliability coefficient. The most valid methods of those examined were then used in re-analyses of the abundance of AMR genes in 10 finisher batches from a previous study. Improved accuracy was found when detailed smoothing methods were applied. Although the precision also increased, the effect was not as pronounced, as the usage estimate of all smoothing methods deviated moderately compared with the farm-registrations. Applying the most valid methods to the 10 finisher batches increased estimates of statistical model fit for aminoglycosides, lincosamides, tetracyclines and decreased estimates of statistical model fit for macrolides. The estimates of statistical model fit for sulfonamides and broad-spectrum penicillins remained the same. Through refined data transformation, VetStat-records can be used to calculate a daily amount of AMU per pig reflecting the true usage accurately and moderately precisely, which is the foundation for calculating lifetime AMU. PMID- 29409562 TI - Birth weight is associated with dietary factors at the age of 6-8 years: the Physical Activity and Nutrition in Children (PANIC) study. AB - OBJECTIVE: Low and high birth weight have been associated with increased risk of type 2 diabetes and CVD. Diet could partly mediate this association, e.g. by intra-uterine programming of unhealthy food preferences. We examined the association of birth weight with diet in Finnish children. DESIGN: Birth weight standard deviation score (SDS) was calculated using national birth register data and Finnish references. Dietary factors were assessed using 4 d food records. Diet quality was defined by the Finnish Children Healthy Eating Index (FCHEI). SETTING: The Physical Activity and Nutrition in Children (PANIC) study. SUBJECTS: Singleton, full-term children (179 girls, 188 boys) aged 6-8 years. RESULTS: Birth weight was inversely associated (standardized regression coefficient beta; 95 % CI) with FCHEI (-0.15; -0.28, -0.03) in all children and in boys (-0.27; 0.45, -0.09) but not in girls (-0.01; -0.21, 0.18) after adjusting for potential confounders (P=0.044 for interaction). Moreover, higher birth weight was associated with lower fruit and berries consumption (-0.13; -0.25, 0.00), higher energy intake (0.17; 0.05, 0.29), higher sucrose intake (0.19; 0.06, 0.32) and lower fibre intake (-0.14; -0.26, -0.01). These associations were statistically non-significant after correction for multiple testing. Children with birth weight >1 SDS had higher sucrose intake (mean; 95 % CI) as a percentage of energy intake (14.3 E%; 12.6, 16.0 E%) than children with birth weight of -1 to 1 SDS (12.8 E%; 11.6, 14.0 E%) or <-1 SDS (12.4 E%; 10.8, 13.9 E%; P=0.036). CONCLUSIONS: Higher birth weight may be associated with unhealthy diet in childhood. PMID- 29409563 TI - Dignity in cancer patients with a life expectancy of a few weeks. Implementation of the factor structure of the Patient Dignity Inventory and dignity assessment for a patient-centered clinical intervention: A cross-sectional study. AB - OBJECTIVE: Hospice is a favored setting for dignity care. Studies on dignity dimension in end-of-life patients are growing. The Patient Dignity Inventory (PDI) is a tool that can lead to interesting information on dignity-related aspects of suffering. The study aimed to investigate dignity among end-of-life cancer patients, by examining the Italian version of the PDI factor structure and assessing the relationship between dignity and other patients' psychosocial and spiritual variables to improve a patient-centered clinical practice. METHOD: This is a cross-sectional study. Data were collected using a battery of self administered validated rating scales. The sample included 127 hospice patients with a life expectancy of a few weeks and a Karnofsky Performance Status <=40. Factor structure and concurrent validity of PDI and correlations between dignity and anxious and depressive symptomatology, quality of life, demoralization, personal coping styles, spiritual well-being, and spiritual daily experience were analyzed. Result Factor analysis highlighted a five-factor solution, accounting for 60% of the overall variance. The factors were labeled Psychological Distress, Social Support, Physical Symptoms and Dependency, Existential Distress, and Loss of Purpose/Meaning. Dignity assessment evidenced that self-blame coping style, emotional and physical well-being, and depression were the loss of dignity significant predictors (R 2 = 0.605; p < 0.01). Significance of results The results point out the intercultural validity of the PDI and empower an accurate detection of dignity-related distress sources in the daily clinical practice. Personality traits seem to have an active role in the loss of dignity, whereas spirituality is confirmed to be positively involved in dignity enhancement. PMID- 29409564 TI - Post-Patent Ductus Arteriosus ligation syndrome with hypertension and masking of renal artery stenosis in an infant. AB - Post-patent ductus arteriosus ligation syndrome is common, but rarely has hypertension been described following ductal ligation with an unclear mechanism. We report a case of an infant who exhibited features of post-patent ductus arteriosus ligation syndrome and hypertension, but was found to have bilateral renal artery stenosis. Increased systemic vascular resistance can be masked by the parallel circuit physiology of a patent ductus arteriosus. PMID- 29409565 TI - The Management of the Khan Al-Assal Chemical Attack in Aleppo University Hospital (AUH). AB - On March 19, 2013, Khan al-Assal was attacked with chemical weapons. In total, 20 people were killed and an additional 124 were injured; 63 people were cared for at Aleppo University Hospital on that day, where 14 died, all of them were civilians; 7 men, 6 women, and 1 child. This is a brief first hand report, for what has now become a more frequent, more deadly and horrific event in the lives of many Syrians. (Disaster Med Public Health Preparedness. 2018;12:663-665). PMID- 29409566 TI - Brain-behavior patterns define a dimensional biotype in medication-naive adults with attention-deficit hyperactivity disorder. AB - BACKGROUND: Childhood-onset attention-deficit hyperactivity disorder (ADHD) in adults is clinically heterogeneous and commonly presents with different patterns of cognitive deficits. It is unclear if this clinical heterogeneity expresses a dimensional or categorical difference in ADHD. METHODS: We first studied differences in functional connectivity in multi-echo resting-state functional magnetic resonance imaging (rs-fMRI) acquired from 80 medication-naive adults with ADHD and 123 matched healthy controls. We then used canonical correlation analysis (CCA) to identify latent relationships between symptoms and patterns of altered functional connectivity (dimensional biotype) in patients. Clustering methods were implemented to test if the individual associations between resting state brain connectivity and symptoms reflected a non-overlapping categorical biotype. RESULTS: Adults with ADHD showed stronger functional connectivity compared to healthy controls, predominantly between the default-mode, cingulo opercular and subcortical networks. CCA identified a single mode of brain-symptom co-variation, corresponding to an ADHD dimensional biotype. This dimensional biotype is characterized by a unique combination of altered connectivity correlating with symptoms of hyperactivity-impulsivity, inattention, and intelligence. Clustering analyses did not support the existence of distinct categorical biotypes of adult ADHD. CONCLUSIONS: Overall, our data advance a novel finding that the reduced functional segregation between default-mode and cognitive control networks supports a clinically important dimensional biotype of childhood-onset adult ADHD. Despite the heterogeneity of its presentation, our work suggests that childhood-onset adult ADHD is a single disorder characterized by dimensional brain-symptom mediators. PMID- 29409567 TI - Percutaneous retrieval of a partially flared Melody valve. AB - We report on successful endovascular retrieval of an accidentally flared Melody valve in an adult patient with an indication for percutaneous pulmonary valve implantation. The Melody valve was removed through a 24 F sheath, introduced via the right jugular vein, and the urgent open-heart surgery was avoided. PMID- 29409568 TI - The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET Active, beta-Catenin-Mutated Mouse Model. AB - Simultaneous mutations in CTNNB1 and activation of c-MET occur in 9%-12.5% of patients with hepatocellular carcinoma (HCC). Coexpression of c-MET-V5 and mutant beta-catenin-Myc in mouse liver by sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HTVI) led to the development of HCC with 70% molecular identity to the clinical subset. Using this model, we investigated the effect of EMD1214063, a highly selective c-MET inhibitor. Five weeks after SB HTVI when tumors were established, EMD1214063 (10 mg/kg) was administered by gastric gavage as a single agent on 5-day-on/3-day-off schedule, compared to vehicle only control. Mice were harvested at 8 or 11 weeks posttreatment. Decreased p-MET, p-AKT, p-STAT3, and p-ERK proved in vivo efficacy of EMD1214063. We observed lower Ki-67, PCNA, V5-tag, and cyclin D1 after EMD1214063 treatment only at 8 weeks. Overall, no significant differences were observed in tumor burden between the groups, although EMD1214063 marginally but significantly improved overall survival by 1.5-2 weeks. Tumors remained alpha-fetoprotein+, did not show any differences in inflammation, and lacked fibrosis in either group. In conclusion, c-MET inhibition alone had a minor effect on Met-beta-catenin HCC at the early stages of HCC development. Thus, a single therapy with the c-MET inhibitor will be insufficient for sustained response in Met-beta-catenin HCC requiring assessment of additional combinations. PMID- 29409569 TI - Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016. AB - Respiratory syncytial virus (RSV) is considered the most common pathogen causing severe lower respiratory tract infections among infants and young children. We describe the seasonality and geographical spread of RSV infection in 15 countries of the European Union and European Economic Area. We performed a retrospective descriptive study of weekly laboratory-confirmed RSV detections between weeks 40/2010 and 20/2016, in patients investigated for influenza-like illness, acute respiratory infection or following the clinician's judgment. Six countries reported 4,230 sentinel RSV laboratory diagnoses from primary care and 14 countries reported 156,188 non-sentinel laboratory diagnoses from primary care or hospitals. The median length of the RSV season based on sentinel and non-sentinel surveillance was 16 (range: 9-24) and 18 (range: 8-24) weeks, respectively. The median peak weeks for sentinel and non-sentinel detections were week 4 (range: 48 to 11) and week 4.5 (range: 49 to 17), respectively. RSV detections peaked later (r = 0.56; p = 0.0360) and seasons lasted longer with increasing latitude (r = 0.57; p = 0.0329). Our data demonstrated regular seasonality with moderate correlation between timing of the epidemic and increasing latitude of the country. This study supports the use of RSV diagnostics within influenza or other surveillance systems to monitor RSV seasonality and geographical spread. PMID- 29409571 TI - Resolve to Be Better. PMID- 29409570 TI - Early season co-circulation of influenza A(H3N2) and B(Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018. AB - Using a test-negative design, we assessed interim vaccine effectiveness (VE) for the 2017/18 epidemic of co-circulating influenza A(H3N2) and B(Yamagata) viruses. Adjusted VE for influenza A(H3N2), driven by a predominant subgroup of clade 3C.2a viruses with T131K + R142K + R261Q substitutions, was low at 17% (95% confidence interval (CI): -14 to 40). Adjusted VE for influenza B was higher at 55% (95% CI: 38 to 68) despite prominent use of trivalent vaccine containing lineage-mismatched influenza B(Victoria) antigen, suggesting cross-lineage protection. PMID- 29409572 TI - Medical-Legal Partnerships: A Healing Collaboration. AB - Medical providers know that there are some conditions they can't treat because the condition is caused or exacerbated by social conditions and are known as "social determinants of health." ThIs classic example-a patient has asthma, lives in a moldor cockroach-infested apartment, has no resources to move, and has a landlord who refuses to clean or exterminate bugs- exemplifies why patients need legal advocates to improve their health. This article discusses medical-legal partnerships (MLPs), models in which medical providers refer patients to attorneys to represent them to resolve such problems. MLPs recognize social determinants of health and foster collaboration between attorneys and health care providers. Originally developed to advocate for children, many MLPs now focus on the vulnerable elderly, individuals at the end of life, and veterans. As these collaborations grow, it's important to spread the word among health care providers and to engage all collaborators. Today, more than 300 MLPs across the nation have documented remarkable achievements. The authors hope that in the future, pharmacists will become MLP team members and help patients address many of their medication-related problems. PMID- 29409573 TI - Pharmacists Catch the Wave. PMID- 29409574 TI - Atypical Antipsychotics in Late-Life and Treatment-Resistant Depression. AB - As persons age, their risk of developing late-life depression increases. Older adults not only have an increased risk of late-life depression, but they also have an increased risk of suicidal ideation. Because of these increased risks, it is vital that clinicians be aware of the options available to assist these persons to achieve remission of their symptoms, as well as prevent relapse. Atypical antipsychotics have been considered an augmentation option in younger adults with depression. However, because of the black box warning associated with atypical antipsychotics in older adults with dementia, clinicians often exercise caution when using these agents to help treat late-life depression. This article explores the various studies conducted for the use of atypical antipsychotics in older adults and their safety and efficacy in this population. PMID- 29409575 TI - Bezlotoxumab for the Prevention of Clostridium difficile Recurrence. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosing, and administration of bezlotoxumab (BEZ), as well as its place in the prevention of Clostridium difficile infection (CDI) recurrence. DATA SOURCES: A search of PubMed and Google Scholar using the terms "bezlotoxumab," "CDB1," "MDX-1388," and "MK-6072" was performed. The manufacturer's website was also reviewed to further identify relevant information. STUDY SELCTION: All English-language articles from 2006 to May 2017 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches. DATA SYNTHESIS: BEZ is a human monoclonal antibody that binds to Clostridium difficile toxin B. It is approved by the Food and Drug Administration to reduce CDI recurrence in adult patients who are receiving antibiotic therapy for CDI and are at high risk for CDI recurrence. It is given as a single dose of 10 mg/kg via an intravenous infusion. It is eliminated by catabolism. Phase III clinical trials demonstrated that BEZ was associated with significantly lower rates of CDI recurrence, compared with placebo. The most common adverse events reported during clinical trials were diarrhea and nausea. There is a warning regarding the use of BEZ in patients with a history of congestive heart failure. The most common adverse reactions associated with BEZ are nausea, pyrexia, and headache. CONCLUSION: BEZ has been proven safe and effective in preventing CDI recurrence. Given its high cost, it should be reserved for patients at high risk for CDI recurrence. PMID- 29409576 TI - Naloxone for Opioid Overdose and the Role of the Pharmacist. AB - With the rise of the opioid epidemic in the United States and increased mortality as a result of opioid overdoses, there have been many national and statewide initiatives to combat this health crisis. Many states have expanded accessibility to naloxone, an opioid-reversal agent. Naloxone is safe, cost-effective, and nonaddictive. In addition, simple administration allows naloxone to be used by patients, family members, caregivers, and bystanders in the event of an opioid overdose. While a great emphasis has been placed on the prescribing practices of health care providers as it pertains to opioid therapy for chronic pain, a new focus has been placed on coprescribing naloxone with opioids for high-risk patients. Naloxone standing orders have allowed health care providers, including pharmacists, to prescribe, dispense, and/ or administer the medication in an attempt to save lives. In addition, pharmacists play a role in counseling and educating patients, family members, caregivers, and bystanders on the safe administration of naloxone in the event of an emergency. PMID- 29409577 TI - Proper Antibiotic Use in a Home-Based Primary Care Population Treated for Urinary Tract Infections. AB - OBJECTIVE: To evaluate the trends associated with diagnosis and treatment of urinary tract infections (UTI) in a home-based primary care population of Veterans Health System patients from 2006 to 2015. DESIGN: Retrospective cohort study. SETTING: Veterans Healthcare System. PARTICIPANTS: Home-based primary care patients treated for UTI from 2006 to 2015. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Appropriate therapy was determined based on the McGeer criteria. Multivariate logistic regression was used to determine factors leading to appropriate UTI treatment. RESULTS: Of 366 available patients, 68 (18.6%) were tested for a UTI. Appropriate therapy occurred in 26% of patients. Allergy to any antibiotic increased the odds of appropriate treatment (odds ratio [OR] = 5.6, 95% confidence interval [CI] 1.5-23.2). Flank pain and increased urinary frequency also increased the likelihood of being treated appropriately (OR = 25.9, 95% CI 2.9-584.0 and OR = 4.49, 95% CI 0.99-21.2, respectively). CONCLUSION: Antibiotics were overused for treating UTIs in the homebound population. Patients with flank pain, increased urinary frequency, and antibiotic allergy were more likely to receive appropriate treatment. Pharmacists, therefore, have a viable opportunity to increase appropriate antibiotic prescribing in the home-based primary care population. PMID- 29409578 TI - What's Ahead for Health Care in 2018. PMID- 29409580 TI - Gender Differences in the Prevalence of Overweight and Obesity, Associated Behaviors, and Weight-related Perceptions in a National Survey of Primary School Children in China. AB - OBJECTIVE: To in vestigate potential gender differences in the odds of overweight/obese, weight-related perceptions, and behaviors among Chinese school children. METHODS: Height, weight, and a survey of weight-related perceptions and behaviors were measured in a nationally representative survey of 12,811 children in primary schools in China. Logistic regression analyses were used to assess gender differences, adjusting for confounders. RESULTS: Boys had higher odds of being overweight/obese compared to girls within both urban [adjusted odds ratio (OR) 2.30, 95% CI 2.00 to 2.65] and rural areas (OR = 1.85, 95% CI 1.55 to 2.20). Girls reported healthier diets (e.g., daily vegetables OR = 0.79, 95% CI 0.73 to 0.85) whereas boys consumed fried food (OR = 1.21, 95% CI 1.06 to 1.38) and sugar sweetened drinks more often (OR = 1.49, 95% CI 1.34 to 1.65). Gender differences included higher odds of boys perceiving themselves as overweight if they had more highly educated mothers (OR = 1.35, 95% CI 1.09 to 1.68), less educated fathers (OR = 0.79, 95% CI 0.63 to 0.99), and if they frequently consumed carbonated drinks (OR = 1.48, 95% CI 1.07 to 2.05). CONCLUSION: Childhood obesity prevention in China should be gender-focused, particularly for boys who reported an unhealthier diet but were less likely to see they were fat, even though more boys were overweight or obese than girls. PMID- 29409581 TI - Endocrine Disruption Activity of 30-day Dietary Exposure to Decabromodiphenyl Ethane in Balb/C Mouse. AB - OBJECTIVE: This study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane (DBDPE). METHODS: In this study, Balb/C mice were treated orally by gavage with various doses of DBDPE. After 30 days of treatment, mice were sacrificed; blood, livers and thyroid glands were obtained, and hepatic microsomes were isolated. Biochemical parameters including 8 clinical chemistry parameters, blood glucose and hormone levels including insulin and thyroid hormone were assayed. The effects of DBDPE on hepatic cytochrome P450 (CYP) levels and activities and uridinediphosphate-glucuronosyltransferase (UDPGT) activities were investigated. Liver and thyroid glands were observed. RESULTS: There were no obvious signs of toxicity and no significant treatment effect on body weight, or liver-to-body weight ratios between treatment groups. The levels of ALT and AST of higher dose treatment groups were markedly increased. Blood glucose levels of treatment groups were higher than those of control group. There was also an induction in TSH, T3, and fT3. UDPGT, PROD, and EROD activities were found to have been increased significantly in the high dose group. Histopathologic liver changes were characterized by hepatocyte hypertrophy and cytoplasmic vacuolization. Our findings suggest that DBDPE can cause a certain degree of mouse liver damage and insufficiency. CONCLUSION: DBDPE has the activity of endocrine disruptors in Bal/C mice, which may induce drug-metabolizing enzymes including CYPs and UDPGT, and interfere with thyroid hormone levels mediated by AhR and CAR signaling pathways. Endocrine disrupting activity of DBDPE could also affect the glucose metabolism homeostasis. PMID- 29409583 TI - Repeat HIV Testing and Incident Rates among Individuals Attending Voluntary Counseling and Testing Clinics in Wuxi, China: A Retrospective Study. AB - OBJECTIVE: We aimed to elucidate the rates of repeat HIV testing and incident HIV diagnosis, and baseline CD4+ T cell count among individuals attending HIV voluntary counseling and testing (VCT) clinics in Wuxi, China. METHODS: A repeat HIV testing within 12 months was recorded if individuals had their first test with negative results, during 2013-2014 and retested within 12 months. An incident HIV diagnosis was recorded if individuals had their first test with negative results, during 2013-2015 and had a subsequent positive result at any point by the end of 2015. Data on HIV testing and diagnosis among individuals attending 32 VCT clinics from 2013 to 2015 and HIV diagnosis from other clinical services in Wuxi, China, were retrieved. A multivariate logistic regression model was used to analyze factors associated with repeat HIV testing. Cox regression was used to evaluate factors associated with incident HIV diagnosis. RESULTS: From 2013 to 2014, 11,504 individuals tested HIV negative at their first recorded test, with 655 (5.7%) retesting within 12 months. Higher repeat HIV testing within 12 months was associated with male gender [adjusted odds ratio (aOR) = 1.7, 95% confidence interval (CI): 1.4-2.2], risk behaviors [commercial heterosexual behaviors (aOR = 1.4, CI: 1.1-1.6), male-male sexual behaviors (aOR = 3.7, CI: 2.7-4.9)], injection drug use (aOR = 9.9, CI: 6.5-15.1), and having taken HIV tests previously (aOR = 2.0, CI: 1.6-2.4). From 2013 to 2015, 1,088 individuals tested negative on HIV test at their visit and at ? 2 subsequent tests; of them 30 had incident HIV diagnosis. The overall rate of incident HIV diagnosis among all VCT individuals was 1.6 (95% CI: 1.1-2.1) per 100 person years. Incident HIV diagnosis was associated with male gender [adjusted hazard ratio (aHR) = 8.5, 95% CI: 1.9-38.1], attending hospital-based VCT clinics (aHR = 7.8, 95% CI: 1.1-58.3), and male-male sexual behavior (aHR = 8.4, 95% CI: 1.5 46.7). Individuals diagnosed at VCT clinics had higher CD4+ T cell count compared with those diagnosed at other clinical services (median 407 vs. 326 copies/mm3, P = 0.003). CONCLUSION: VCT individuals in Wuxi, China, had a low repeat HIV testing rate and high HIV incidence. VCT-clinic-based interventions aimed at increasing repeat HIV testing are needed to detect more cases at an earlier stage, especially among individuals at high risk for HIV infection such as men who have sex with men. PMID- 29409582 TI - Health Risk Impacts of Exposure to Airborne Metals and Benzo(a)Pyrene during Episodes of High PM10 Concentrations in Poland. AB - OBJECTIVE: To check whether health risk impacts of exposure to airborne metals and Benzo(a) Pyrene during episodes of high PM10 concentrations lead to an increased number of lung cancer cases in Poland. METHODS: In this work, we gathered data from 2002 to 2014 concerning the ambient concentrations of PM10 and PM10-bound carcinogenic Benzo(a)pyrene [B(a)P] and As, Cd, Pb, and Ni. With the use of the criterion of the exceedance in the daily PM10 mass concentration on at least 50% of all the analyzed stations, the PM10 maxima's were selected. Lung cancer occurrences in periods with and without the episodes were further compared. RESULTS: During a 12-year period, 348 large-scale smog episodes occurred in Poland. A total of 307 of these episodes occurred in the winter season, which is characterized by increased emissions from residential heating. The occurrence of episodes significantly (P < 0.05) increased the concentrations of PM10-bound carcinogenic As, Cd, Pb, Ni, and B(a)P. During these events, a significant increase in the overall health risk from those PM10-related compounds was also observed. The highest probability of lung cancer occurrences was found in cities, and the smallest probability was found in the remaining areas outside the cities and agglomerations. CONCLUSION: The link between PM pollution and cancer risk in Poland is a serious public health threat that needs further investigation. PMID- 29409584 TI - Rapid Identification and Subtyping of Enterobacter cloacae Clinical Isolates Using Peptide Mass Fingerprinting. AB - OBJECTIVE: To establish a domestic database of Enterobacteria cloacae (E. cloacae), and improve the identification efficiency using peptide mass fingerprinting. METHODS: Peptide mass fingerprinting was used for the identification and subtyping of E. cloacae. Eighty-seven strains, identified based on hsp60 genotyping, were used to construct and evaluate a new reference database. RESULTS: Compared with the original reference database, the identification efficiency and accuracy of the new reference database was greatly improved at the species level. The first super reference database for E. cloacae identification was also constructed and evaluated. Based on the super reference database and the main spectra projection dendrogram, E. cloacae strains were divided into two clades. CONCLUSION: Peptide mass fingerprinting is a powerful method to identify and subtype E. cloacae, and the use of this method will allow us to obtain more information to understand the heterogeneous organism E. cloacae. PMID- 29409585 TI - Effects of Electromagnetic Radiation on Autophagy and its Regulation. PMID- 29409586 TI - Circulating Neutrophil Counts Decrease in Response to Mitigated Air Quality in Stable COPD Patients. AB - This three-year study, based on the Guangzhou Institute of Respiratory Disease (GRID), chronic obstructive pulmonary disease (COPD) Biobank, was conducted in 36 COPD patients to estimate whether changes in levels of leukocytes, erythrocytes, hemoglobin, and platelets were related to changes in air pollutant concentration. Daily NO2 levels exhibited significant differences between baseline years and the 2010 Asian Game period. We observed significant reductions in leukocyte and neutrophils counts levels, by 15.51% and 23.01%, from pre-Asian Games to during Asian Games, respectively. In the post-Asian Game period, most pollutants approximated pre-Asian Game period levels, and similar effects were demonstrated in leukocyte and neutrophil counts. For both items, we identified significant increases resulting from elevated NO2 at lag days 0-2/5-6. We concluded that reductions in pollutants during the intervention period were associated with inactivation of hematological events in COPD. PMID- 29409587 TI - Comparative Analysis of the Multi-Frequency Bio-impedance and Dual-energy X-ray Absorptiometry on Body Composition in Obese Subjects. AB - To examine accuracy of body composition predicted by the Multi-Frequency Bioelectric Impedance Analysis (MF-BIA) compared with the Dual-energy X-ray Absorptiometry (DXA) in adults with obese. We measured body composition of 749 adults with obese both by the MF-BIA and DXA. The Lin's concordance correlation and the Bland-Altman plots were used to examine the consistency. The concordance correlation coefficient of %BF between the MF-BIA and DXA in men and women was 0.560, and 0.669, respectively. Compared with the DXA, the MF-BIA significantly underestimated %BF by 4.33% in men (P < 0.001), however overestimated %BF by 0.50% in women (P < 0.001). After corrected by the correction equations established in this study, the differences were significantly decreased. Therefore, the MF-BIA (TANITA MC-180) may need to be corrected in estimating body composition for adults with obese. PMID- 29409588 TI - Serum Metabonomics of Articular Cartilage Destruction Induced by T-2 Toxin in Wistar Rats. AB - The molecular pathogenesis of T-2 toxin-induced cartilage destruction has not been fully unraveled yet. The aim of this study was to detect changes in serum metabolites in a rat anomaly model with articular cartilage destruction. Thirty healthy male Wistar rats were fed a diet containing T-2 toxin (300 ng/kg chow) for 3 months. Histopathological changes in femorotibial cartilage were characterized in terms of chondrocyte degeneration/necrosis and superficial cartilage defect, and the endogenous metabolite profile of serum was determined by UPLC/Q-TOF MS. Treated rats showed extensive areas of chondrocyte necrosis and superficial cartilage defect in the articular cartilage. In addition, 8 metabolites were found to change significantly in these rats compared to the control group, including lysoPE (18:0/0:0), lysoPC(14:0), lysoPC[18:4 (6Z,9Z,12Z,15Z)], lysoPC[(16:1(9Z)], lysoPC(16:0), L-valine, hippuric acid, and asparaginyl-glycine. These 8 metabolites associated with cartilage injury are mainly involved in phospholipid and amino acid metabolic pathways. PMID- 29409589 TI - Intestinal Microbial Community Differs between Acute Pancreatitis Patients and Healthy Volunteers. AB - A case control study including 45 acute pancreatitis and 44 healthy volunteers was performed to investigate the association between intestinal microbial community and acute pancreatitis. High-throughput 16S rRNA gene amplicon sequencing was used to profile the microbiological composition of the samples. In total, 27 microbial phyla were detected and the samples of pancreatitis patients contained fewer phyla. Samples from acute pancreatitis patients contained more Bacteroidetes and Proteobacteria and fewer Firmicutes and Actinobacteria than those from healthy volunteers. PCoA analyses distinguished the fecal microbial communities of acute pancreatitis patients from those of healthy volunteers. The intestinal microbes of acute pancreatitis patients are different from those of healthy volunteers. Modulation of the intestinal microbiome may serve as an alternative strategy for treating acute pancreatitis. PMID- 29409591 TI - Optimal supplementary frequency controller design using the wind farm frequency model and controller parameters stability region. AB - In most of the existing studies, the frequency response in the variable speed wind turbines (VSWTs) is simply realized by changing the torque set-point via appropriate inputs such as frequency deviations signal. However, effective dynamics and systematic process design have not been comprehensively discussed yet. Accordingly, this paper proposes a proportional-derivative frequency controller and investigates its performance in a wind farm consisting of several VSWTs. A band-pass filter is deployed before the proposed controller to avoid responding to either steady state frequency deviations or high rate of change of frequency. To design the controller, the frequency model of the wind farm is first characterized. The proposed controller is then designed based on the obtained open loop system. The stability region associated with the controller parameters is analytically determined by decomposing the closed-loop system's characteristic polynomial into the odd and even parts. The performance of the proposed controller is evaluated through extensive simulations in MATLAB/Simulink environment in a power system comprising a high penetration of VSWTs equipped with the proposed controller. Finally, based on the obtained feasible area and appropriate objective function, the optimal values associated with the controller parameters are determined using the genetic algorithm (GA). PMID- 29409590 TI - Base deficit is superior to lactate in trauma. AB - BACKGROUND: Base Deficit (BD) and lactate have been used as indicators of shock and resuscitation. This study was done to determine the association of BD and lactate and to determine if one is superior. METHODS: A retrospective review from 3/2014-12/2016 was performed. Data included demographics, systolic BP, ISS, BD, lactate, blood transfusion, and outcomes. BD and lactate were modeled continuously and categorically and compared. RESULTS: 1191 patients were included. BD and lactate correlated strongly (r = -0.76 p < 0.001). Higher lactate and more negative BD were associated with transfusion and mortality. On multivariate regression, only BD was associated with transfusion (OR = 0.8, p < 0.001). As a categorical variable, worsening BD was associated with decreased BP, higher ISS, increased transfusions and worse outcomes. CONCLUSIONS: BD and lactate are strongly related. BD was superior to lactate in assessing the need for transfusion. The BD categories discriminate high risk trauma patients better than lactate. PMID- 29409592 TI - What Are the Causes for Discrepancies of Antidepressant Actions of (2R,6R) Hydroxynorketamine? PMID- 29409593 TI - Roles of insulin-like growth factors in metamorphic development of turbot (Scophthalmus maximus). AB - Larval turbot (Scophthalmus maximus) undergo metamorphosis, a late post-embryonic developmental event that precedes juvenile transition. Insulin-like growth factors (IGFs) are important endocrine/autocrine/paracrine factors that provide essential signals to control of the embryonic and postnatal development of vertebrate species, including fish. Accumulating evidence suggests that IGFs are involved in regulating the metamorphic development of flatfish. This mini review focus on the functions of all known IGFs (IGF-I and IGF-II) during the metamorphic development of turbot. Information about IGFs and insulin-like growth factors binding proteins (IGFBPs) from other teleosts is also included in this review to provide an overview of IGFs functions in the metamorphic development of turbot. These findings may enhance our understanding of the potential roles of the IGFs system in controlling of flatfish metamorphosis and contributing to the improvement of broodstock management strategies for larval turbot. PMID- 29409594 TI - [Horner's syndrome and paresthesia in the trigeminal nerve territory secondary to epidural analgesia for labor]. AB - Currently, epidural analgesia is a common procedure for labor analgesia. Although it is considered a safe technique, it is not without complications. Horner's syndrome and paresthesia within the trigeminal nerve distribution are rare complications of epidural analgesia. We report a case of a pregnant woman who developed Horner's syndrome and paresthesia within the distribution of the trigeminal nerve following epidural analgesia for the relief of labor pain. PMID- 29409595 TI - The pediatric resuscitative thoracotomy during combat operations in Iraq and Afghanistan - A retrospective cohort study. AB - BACKGROUND: Combat zone trauma poses a unique set of challenges and injury patterns not seen in the civilian setting. The role of the pediatric resuscitative thoracotomy in combat zones remains unclear given a paucity of data regarding procedure outcomes in this setting. We compare outcomes among children in traumatic arrest undergoing resuscitative thoracotomy versus cardiopulmonary (CPR) resuscitation only. METHODS: We queried the Department of Defense Trauma Registry (DODTR) from 2007 to 2016 for all pediatric subjects that underwent a resuscitative thoracotomy or CPR in the prehospital or emergency department setting during operations in Iraq or Afghanistan. We removed CPR subjects with mechanisms of injury not matched in the thoracotomy cohort. RESULTS: During the study period, there were 3439 pediatric encounters. We identified 13 subjects who underwent a resuscitative thoracotomy and 66 subjects who underwent CPR without thoracotomy with matching mechanisms of injury. When comparing the two cohorts those in the thoracotomy group had higher median thorax body region scores (median 3 versus 0, p = .001), but a trend towards higher rates of survival to discharge (31% versus 9%, p = .108). The youngest survivor in the thoracotomy cohort was less than 1 year old. CONCLUSIONS: We observed a trend towards higher survival among subjects that underwent a resuscitative thoracotomy survived to hospital discharge compared to subjects undergoing CPR without thoracotomy. The literature will benefit from further data to confirm an association between this procedure and a survival benefit among pediatric subjects in the resource limited setting. Furthermore, improvements in documentation will guide equipping and training providers expected to care for pediatric trauma patients. PMID- 29409596 TI - Thermodynamics of acid-base dissociation of several cathinones and 1 phenylethylamine, studied by an accurate capillary electrophoresis method free from the Joule heating impact. AB - Capillary electrophoresis is often used to the determination of the acid-base dissociation/deprotonation constant (pKa), and the more advanced thermodynamic quantities describing this process (DeltaH degrees , -TDeltaS degrees ). Remarkably, it is commonly overlooked that due to insufficient dissipation of Joule heating the accuracy of parameters determined using a standard approach may be questionable. In this work we show an effective method allowing to enhance reliability of these parameters, and to estimate the magnitude of errors. It relies on finding a relationship between electrophoretic mobility and actual temperature, and performing pKa determination with the corrected mobility values. It has been employed to accurately examine the thermodynamics of acid-base dissociation of several amine compounds - known for their strong dependency of pKa on temperature: six cathinones (2-methylmethcathinone, 3-methylmethcathinone, 4-methylmethcathinone, alpha-pyrrolidinovalerophenone, methylenedioxypyrovalerone, and ephedrone); and structurally similar 1 phenylethylamine. The average pKa error caused by Joule heating noted at 25 degrees C was relatively small - 0.04-0.05 pH unit, however, a more significant inaccuracy was observed in the enthalpic and, in particular, entropic terms. An alternative correction method has also been proposed, simpler and faster, but not such effective in correcting DeltaH degrees /-TDeltaS degrees terms. The corrected thermodynamic data have been interpreted with the aid of theoretical calculations, on a ground of the enthalpy-entropy relationships and the most probable structural effects accounting for them. Finally, we have demonstrated that the thermal dependencies of electrophoretic mobility, modelled during the correction procedure, may be directly used to find optimal temperature providing a maximal separation efficiency. PMID- 29409598 TI - Comment: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. PMID- 29409597 TI - The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults. AB - BACKGROUND: While common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. METHODS: Genotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. RESULTS: For pediatric subjects, 408 relapses were captured over 622 patient years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18 2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05-3.03, p = 0.026). CONCLUSIONS: Our results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility. PMID- 29409599 TI - Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. PMID- 29409600 TI - Editors' Welcome. PMID- 29409601 TI - Infusion of butyrate affects plasma glucose, butyrate, and beta-hydroxybutyrate but not plasma insulin in lactating dairy cows. AB - The objective of this study was to investigate the effects on plasma metabolites and rumen traits when butyrate was infused into the rumen or abomasum of lactating cows. Jugular catheters were inserted into 5 ruminally fistulated Holstein cows [94.2 +/- 26.3 DIM; 717 +/- 45 kg of body weight (BW); mean +/- SD] in a 5 * 5 Latin square with 3-d periods. Cows were infused for 24 h with 1 of 5 treatments: water (CON), 1 g/kg of BW of butyrate infused into either the abomasum (A1) or rumen (R1), or 2 g/kg of BW of butyrate infused into either the abomasum or rumen. Sodium butyrate was the source of butyrate and NaCl was added to the CON, A1, and R1 treatments to provide the same amount of sodium as supplied by the sodium butyrate treatment in the 2-g treatments. Plastisol flanges were inserted into the abomasum to allow infusion to the abomasum and peristaltic pumps provided continuous infusion at 9.3 mL/min for all treatments. The concentration of NaCl and sodium butyrate was varied in the infusate to provide the correct infusion amount. Rumen fluid samples were collected at -2, 1, 0, 1, 2, 3, 4, 6, 8, 12, 18, 24, 28, and 32 h relative to start of infusion. Serial blood samples were collected at -2, -1, 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 26, 28, and 32 h relative to start of infusion. Compared with CON, infusing butyrate increased both plasma butyrate and plasma beta-hydroxybutyrate (BHB), whereas plasma glucose decreased. Increasing butyrate infusion from 1 to 2 g increased plasma butyrate, tended to decrease plasma glucose, and tended to increase plasma BHB. Compared with abomasal infusion, rumen infusion of butyrate increased rumen butyrate, did not affect plasma glucose, and tended to increase plasma BHB. Treatment had no effect on plasma insulin. Results demonstrated that site of infusion and amount of butyrate affected several plasma metabolites when butyrate was infused in lactating dairy cows over a period of 24 h. PMID- 29409602 TI - Attachment disorder in thoracoabdominal surgery. PMID- 29409603 TI - Redefining tricuspid valve anatomy: Acknowledging the "forgotten valve". PMID- 29409604 TI - Pretreatment with diazoxide and erythropoietin: A novel strategy to prevent paraplegia after aortic surgery. PMID- 29409605 TI - Left ventricular assist device outcomes and preoperative kidney dysfunction: The truth be told. PMID- 29409606 TI - Repetition is the mother of skill. PMID- 29409607 TI - Conventional mitral surgery in octogenarians: The "MUiotasigmaomicron" study against skepticism. PMID- 29409608 TI - Body mass index in lung transplantation: Every unit counts. PMID- 29409609 TI - Where have all the mentors gone? PMID- 29409610 TI - There and back again: An immunotherapy tale. PMID- 29409611 TI - Bespoke surgery: We're virtually there. PMID- 29409612 TI - Does nature provide the clues for future heart failure treatments? PMID- 29409613 TI - We don't know what we need to know about atrial fibrillation. PMID- 29409614 TI - Take a deep breath but don't relax: Anesthesia for thymectomy in myasthenia gravis. PMID- 29409615 TI - Who is not comfortable with the term "palliative care"-patient, family, or surgeon? PMID- 29409616 TI - The matrix revisited. PMID- 29409617 TI - Translocation of intramural coronary artery in the arterial switch operation: Divide and conquer? PMID- 29409618 TI - Outcome of tricuspid valve surgery in the presence of permanent pacemaker. AB - OBJECTIVES: Given the paucity of available literature, we sought to evaluate the mechanisms of tricuspid regurgitation and the outcomes of tricuspid valve surgery in the presence of permanent pacemakers. METHODS: We retrospectively reviewed the records of 622 adult patients who underwent tricuspid valve surgery in the presence of permanent pacemakers between January 1993 and December 2013. Those with prosthetic tricuspid valve or tricuspid valve endocarditis and those undergoing concomitant heart transplant were excluded (n = 23). Patients were divided into 2 etiologic groups: pacemaker-associated tricuspid regurgitation (n = 349, 58%) and pacemaker-induced tricuspid regurgitation (n = 249, 42%). One patient was not categorized, because permanent pacemaker involvement was unknown. RESULTS: Mean age was 69.5 +/- 12.0 years; 312 patients (52%) were female. In pacemaker-associated tricuspid regurgitation, the most common cause was functional (n = 304, 87%). The most common mechanism leading to pacemaker-induced tricuspid regurgitation was restricted leaflet mobility (n = 101, 41%), followed by adherent leaflet to the leads (n = 93, 37%), leaflet perforation (n = 30, 12%), scarring of leaflets (n = 19, 8%), and chordal entrapment (n = 18, 7%). The most common leaflet involved was septal leaflet (n = 182, 73%). Tricuspid valve repair (n = 215, 62%) was higher in the pacemaker-associated tricuspid regurgitation group. In multivariable analysis, pacemaker-induced tricuspid regurgitation was found to be protective with improved survival (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.68-0.98). Other independent risk factors of mortality included tricuspid valve replacement (HR, 1.50; 95% CI, 1.20 1.87), nonelective surgery (HR, 1.66; 95% CI, 1.33-2.08), diabetes (HR, 1.37; 95% CI, 1.09-1.73), severe tricuspid regurgitation (HR, 1.42; 95% CI, 1.04-1.95), and older age when there was a concomitant aortic valve surgery (HR, 1.44; 95% CI, 1.15-1.79). CONCLUSIONS: Several mechanisms lead to pacemaker-induced tricuspid regurgitation. Pacemaker-induced tricuspid regurgitation when compared with pacemaker-associated tricuspid regurgitation carries a better prognosis with improved survival. PMID- 29409619 TI - Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia. AB - BACKGROUND: Lung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model. METHODS: Olive oil or nitrofen was administered alone or in combination with RA or imatinib to pregnant rats. Pups were assessed for PA blood flow by ultrasound and pulmonary function/morphology following delivery, intubation, and short-term ventilation. RESULTS: Neither RA nor imatinib had a negative effect on lung and body growth. RA accelerated lung maturation indicated by increased alveoli number and thinner interalveolar septa and was associated with decreased PA resistance and improved oxygenation. With the exception of a decreased PA pulsatility index, no significant changes in morphology and pulmonary function were noted following imatinib. CONCLUSION: Prenatal treatment with RA but not imatinib was associated with improved pulmonary morphology and function, and decreased pulmonary vascular resistance. This study highlights the potential of prenatal pharmacologic therapies, such as RA, for management of CDH. PMID- 29409620 TI - Necrotizing enterocolitis as a prognostic factor for the neurodevelopmental outcome of preterm infants - match control study after 2years. AB - PURPOSE: Necrotizing enterocolitis (NEC) in very low birth weight infants is a risk factor for developmental delay. To our knowledge, there are no studies published investigating the neurodevelopmental outcome of patients with NEC comparing surgically treated and conservatively treated patients versus match paired controls. The aim of this retrospective case control study was to measure the neurodevelopmental outcome of patients with NEC who were treated surgically or conservatively METHODS: All patients were identified, who have been diagnosed with NEC (ICD-10 code, P77) born between 2006 and 2013. Patients with NEC received antibiotic therapy, nasogastric decompression and fasting. Surgical treatment was indicated for patients with Bell stages IIIb. We excluded patients suffering from other relevant diseases with a possible impact on their neurodevelopmental outcome (e.g., intraventricular hemorrhage, associated malformations, asphyxia, focal intestinal perforation, short bowel syndrome). Patients were tested at the corrected gestational age of 24months according to the Bayley Scales of Infant Development II. Each participant was compared to a child of the same sex, gestational age at birth (+/-two days), birth weight (+/ 10%), and age at neurodevelopmental testing (IRB approval, No. 14/2014). The outcome measures were the psychomotor index (PDI) and the mental developmental index (MDI). RESULTS: We included 13 conservatively and 24 surgically treated patients. The patients in group A (without surgery) achieved a mean PDI of 106, and those in group B (with surgery) a mean PDI of 90. These values were significantly higher in the conservative group A. The mean MDIs were 99 in the patient group A and 85 in patient group B. This difference was also significant. CONCLUSION: We found significantly lower MDIs and PDIs in children with surgical treatment of NEC. Further systematic prospective research on the prevention of NEC and systematic follow-ups at later stages in the patients' development are necessary in order to implement early intervention. TYPE OF STUDY: case control study. LEVEL OF EVIDENCE: III. PMID- 29409621 TI - An analysis of the suitability of a low-cost eye tracker for assessing the cognitive load of drivers. AB - This paper presents a driving simulator study in which we investigated whether the Eye Tribe eye tracker (ET) is capable of assessing changes in the cognitive load of drivers through oculography and pupillometry. In the study, participants were asked to drive a simulated vehicle and simultaneously perform a set of secondary tasks with different cognitive complexity levels. We measured changes in eye properties, such as the pupil size, blink rate and fixation time. We also performed a measurement with a Detection Response Task (DRT) to validate the results and to prove a steady increase of cognitive load with increasing secondary task difficulty. The results showed that the ET precisely recognizes an increasing pupil diameter with increasing secondary task difficulty. In addition, the ET shows increasing blink rates, decreasing fixation time and narrowing of the attention field with increasing secondary task difficulty. The results were validated with the DRT method and the secondary task performance. We conclude that the Eye Tribe ET is a suitable device for assessing a driver's cognitive load. PMID- 29409623 TI - Objective assessment of knife sharpness over a working day cutting meat. AB - Knife sharpness is one of multiple factors involved in musculoskeletal disorders in industrial meat cutting. The aim of this study was to objectively evaluate, in real working situations, how knife sharpness changed over a working day cutting meat, and to analyse the impact of sharpening, steeling and meat-cutting activities on these variations. Twenty-two meat-cutting workers from three different companies participated in the study. The methods included measurements of knife sharpness in relation to real work situations and consideration of the way meat-cutting and sharpening operations were organised. Results showed that the type of meat-cutting activities, the steeling strategy adopted by the worker, including the types of tool used, and the overall organisation of the sharpening task all had a significant influence on how knife sharpness evolved over a 2-h period and over an entire working day. To improve MSD prevention, sharpening and steeling operations should not be considered as independent activities, but taken into account as a continuity of working actions. Appropriate assessment of knife sharpness by meat cutters affects how they organise meat-cutting and sharpening tasks. PMID- 29409622 TI - Biomechanical evaluation of exoskeleton use on loading of the lumbar spine. AB - The objective of this study was to investigate biomechanical loading to the low back as a result of wearing an exoskeletal intervention designed to assist in occupational work. Twelve subjects simulated the use of two powered hand tools with and without the use of a Steadicam vest with an articulation tool support arm in a laboratory environment. Dependent measures of peak and mean muscle forces in ten trunk muscles and peak and mean spinal loads were examined utilizing a dynamic electromyography-assisted spine model. The exoskeletal device increased both peak and mean muscle forces in the torso extensor muscles (p < 0.001). Peak and mean compressive spinal loads were also increased up to 52.5% and 56.8%, respectively, for the exoskeleton condition relative to the control condition (p < 0.001). The results of this study highlight the need to design exoskeletal interventions while anticipating how mechanical loads might be shifted or transferred with their use. PMID- 29409624 TI - Relationship among several measurements of slipperiness obtained in a laboratory environment. AB - Multiple sensing mechanisms could be used in forming responses to avoid slips, but previous studies, correlating only two parameters, revealed a limited picture of this complex system. In this study, the participants walked as fast as possible without a slip under 15 conditions of different degrees of slipperiness. The relationships among various response parameters, including perceived slipperiness rating, utilized coefficient of friction (UCOF), slipmeter measurement and kinematic parameters, were evaluated. The results showed that the UCOF, perceived rating and heel angle had higher adjusted R2 values as dependent variables in the multiple linear regressions with the remaining variables in the final pool as independent variables. Although each variable in the final data pool could reflect some measurement of slipperiness, these three variables are more inclusive than others in representing the other variables and were bigger predictors of other variables, so they could be better candidates for measurements of slipperiness. PMID- 29409625 TI - Symptoms associated with reading from a smartphone in conditions of light and dark. AB - Asthenopia symptoms were investigated in visually-normal subjects without computer-related vision symptoms after prolonged reading from: smartphone versus hardcopy under photopic conditions, and smartphone in conditions of ambient versus dark room illumination. After reading from the smartphone, total symptom scores and nine out of ten questionnaire symptoms were significantly worse than for the hardcopy ("blurred vision while viewing the text, "blurred distance vision after the task", "difficulty in refocusing from one distance to another", "irritated or burning eyes", "dry eyes", "eyestrain", "tired eyes", "sensitivity to bright lights" and "eye discomfort"). Mean total symptom scores and scores for "irritated or burning eyes" and "dry eyes" were significantly higher for the dark versus photopic conditions. In conclusion, prolonged smartphone reading could cause worse asthenopic symptoms than reading from a hardcopy under similar conditions. Symptoms could be even worse when reading from a smartphone in the dark. PMID- 29409626 TI - Assessment of an active industrial exoskeleton to aid dynamic lifting and lowering manual handling tasks. AB - The aim of this study was to evaluate the effect of an industrial exoskeleton on muscle activity, perceived musculoskeletal effort, measured and perceived contact pressure at the trunk, thighs and shoulders, and subjective usability for simple sagittal plane lifting and lowering conditions. Twelve male participants lifted and lowered a box of 7.5 kg and 15 kg, respectively, from mid-shin height to waist height, five times, both with and without the exoskeleton. The device significantly reduced muscle activity of the Erector Spinae (12%-15%) and Biceps Femoris (5%). Ratings of perceived musculoskeletal effort in the trunk region were significantly less with the device (9.5%-11.4%). The measured contact pressure was highest on the trunk (91.7 kPa-93.8 kPa) and least on shoulders (47.6 kPa-51.7 kPa), whereas pressure was perceived highest on the thighs (35-44% of Max LPP). Six of the users rated the device usability as acceptable. The exoskeleton reduced musculoskeletal loading on the lower back and assisted with hip extensor torque during lifting and lowering. Contact pressures fell below the Pain Pressure Threshold. Perceived pressure was not exceptionally high, but sufficiently high to cause discomfort if used for long durations. PMID- 29409627 TI - Social Network Analysis of peer-specific safety support and ergonomic behaviors: An application to safe patient handling. AB - This study applied Social Network Analysis (SNA) to test whether advice-seeking interactions among peers about safe patient handling correlate with a higher frequency of equipment use. Patient-care workers (n=38) at a community hospital in Oregon nominated peers they would consult for advice regarding safe patient handling. Results show a positive correlation between identifying more peers for safe patient handling advice and using equipment more frequently. Moreover, nurses with more reciprocal advice seeking nominations used safe patient handling equipment more frequently. However, employees who would be more consulted about safe patient handling by their peers did not use equipment more frequently than nurses with fewer nominations. Despite the small sample size, the magnitude of the adjusted regressions coefficients ranged between 3 to 4 standard deviations. These results suggest that having more or reciprocal sources of peer-based support may trigger ergonomic related behaviors such as frequent utilization of equipment. PMID- 29409628 TI - Is partially automated driving a bad idea? Observations from an on-road study. AB - The automation of longitudinal and lateral control has enabled drivers to become "hands and feet free" but they are required to remain in an active monitoring state with a requirement to resume manual control if required. This represents the single largest allocation of system function problem with vehicle automation as the literature suggests that humans are notoriously inefficient at completing prolonged monitoring tasks. To further explore whether partially automated driving solutions can appropriately support the driver in completing their new monitoring role, video observations were collected as part of an on-road study using a Tesla Model S being operated in Autopilot mode. A thematic analysis of video data suggests that drivers are not being properly supported in adhering to their new monitoring responsibilities and instead demonstrate behaviour indicative of complacency and over-trust. These attributes may encourage drivers to take more risks whilst out on the road. PMID- 29409629 TI - The impact of team characteristics and context on team communication: An integrative literature review. AB - Many studies on teams report measures of team communication; however, these studies vary widely in terms of the team characteristics, situations, and tasks studied making it difficult to understand impacts on team communication more generally. The objective of this review is systematically summarize relationships between measures of team communication and team characteristics and situational contexts. A literature review was conducted searching in four electronic databases (PsycINFO, MEDLINE, Ergonomics Abstracts, and SocINDEX). Additional studies were identified by cross-referencing. Articles included for final review had reported at least one team communication measure associated with some team and/or context dimension. Ninety-nine of 727 articles met the inclusion criteria. Data extracted from articles included characteristics of the studies and teams and the nature of each of the reported team and/or context dimensions-team communication properties relationships. Some dimensions (job role, situational stressors, training strategies, cognitive artifacts, and communication media) were found to be consistently linked to changes in team communication. A synthesized diagram that describes the possible associations between eleven team and context dimensions and nine team communication measures is provided along with research needs. PMID- 29409630 TI - Spinal kinematics during smartphone texting - A comparison between young adults with and without chronic neck-shoulder pain. AB - To advance our understanding about the association between smartphone use and chronic neck-shoulder pain, the objective of this study was to compare spinal kinematics between different text-entry methods in smartphone users with and without chronic neck-shoulder pain. Symptomatic (n = 19) and healthy participants (n = 18) were recruited and they performed three tasks: texting on a smartphone with one hand, with two hands, and typing on a desktop computer. Three dimensional kinematics were examined in the cervical, thoracic and lumbar regions for each task. This study suggests that altered kinematics may be associated with pain since significantly increased angles of cervical right side flexion during smartphone texting and greater postural changes in cervical rotation were found during all text-entry tasks in the symptomatic group. Two-handed texting was associated with increased cervical flexion while one-handed texting was correlated with an asymmetric neck posture, indicating both text-entry methods are not favorable in terms of spinal postures. PMID- 29409631 TI - Looking forward: In-vehicle auxiliary display positioning affects carsickness. AB - Carsickness is associated with a mismatch between actual and anticipated sensory signals. Occupants of automated vehicles, especially when using a display, are at higher risk of becoming carsick than drivers of conventional vehicles. This study aimed to evaluate the impact of positioning of in-vehicle displays, and subsequent available peripheral vision, on carsickness of passengers. We hypothesized that increased peripheral vision during display use would reduce carsickness. Seated in the front passenger seat 18 participants were driven a 15 min long slalom on two occasions while performing a continuous visual search task. The display was positioned either at 1) eye-height in front of the windscreen, allowing peripheral view on the outside world, and 2) the height of the glove compartment, allowing only limited view on the outside world. Motion sickness was reported at 1-min intervals. Using a display at windscreen height resulted in less carsickness compared to a display at glove compartment height. PMID- 29409632 TI - Predictors of disability and absenteeism in workers with non-specific low back pain: A longitudinal 15-month study. AB - OBJECTIVES: The objective of this study was to identify baseline predictors of disability and absenteeism in workers with a history of non-specific low back pain (LBP). METHODS: One hundred workers with a history of non-specific LBP participated in three evaluations (baseline, 7 and 15 months follow-up). Current and past history of LBP, clinical pain intensity, disability, absenteeism, fear avoidance beliefs, pain catastrophizing, pain hypervigilance, work satisfaction and patient stratification based on "risk of poor clinical outcome assessment" (RPCO) were evaluated using questionnaires and interviews. In addition, cutaneous heat pain thresholds, cutaneous heat pain tolerance thresholds, conditioned pain modulation (CPM), trunk kinematics and muscle activity were measured during each evaluation. Logistic regression models were used to determine predictors of LBP disability and absenteeism at 15-months. RESULTS: Sixty-eight workers returned for the 15-month follow-up and among this sample, 49% reported disability and 16% reported absenteeism at follow-up. Baseline clinical pain intensity predicted disability (OR = 1.08, 95%CI: 1.03-1.13) at 15-month while work satisfaction (OR = 0.93, 95%CI: 0.87-0.99) and RPCO (OR = 1.51, 95%CI: 1.05-2.16) predicted absenteeism. These results remained significant after adjustments for age, gender as well as type of work and intervention. CONCLUSION: This study highlights the importance of clinical pain and psychological factors in the prediction and potentially the prevention of future disability. Screening tools assessing these risk factors can be useful to evaluate workers with past history of low back pain. PMID- 29409633 TI - Factors influencing experience in crowds - The organiser perspective. AB - Crowds are a commonplace encounter but the experience for participants can be highly variable. Crowds are complex sociotechnical phenomenon, affected by many interacting factors. Little is known, however, about how those responsible for organising crowd situations approach their responsibilities. This study conducted semi-structured interviews (n = 41) with organisers responsible for different aspects of the design, planning, management and operations of events and other crowd situations. The objective was to understand organisers' priorities, along with the consideration given to the experience of crowd participants. The interviews revealed that organisers generally prioritised finance, security and health and safety aspects, whilst giving limited explicit attention to other important factors that affect participant experience. Organisers tended to approach their planning and decisions on the basis of their own experience and judgement, without accessing training or reference to guidance. It is suggested that the non-use of guidance is in part due to problems with the guidance currently available, both its content and its form. The organisers of infrequent or small-scale events have the greatest knowledge and experience gap. It is concluded that in order to achieve a consistent, high quality experience for crowd participants, there needs to be improved understanding among organisers of the complexity of crowds and the multiple factors influencing participant experience. Guidance and tools need to be usable and tailored to organisers' requirements. Organisers of infrequent or small-scale events are especially in need of support. PMID- 29409634 TI - Manual work in cold environments and its impact on selection of materials for protective gloves based on workplace observations. AB - This article presents a workplace observations on manual work in cold environments and its impact on the selection of materials for protective gloves. The workplace observations was conducted on 107 workers in 7 companies and involved measurements of the temperature of air and objects in the workplaces; in addition the type of surface and shape of the objects was determined. Laboratory tests were also carried out on 11 materials for protective gloves to be used in cold environments. Protective characteristics, including mechanical properties (wear, cut, tear, and puncture resistance), insulation properties (thermal resistance), functional parameters, and hygienic properties (resistance to surface wetting, material stiffness) were evaluated. Appropriate levels of performance and quality, corresponding to the protective and functional properties of the materials, were determined. Based on the results of manual work and laboratory tests, directions for the selection of materials for the construction of protective gloves were formulated with a view to improving work ergonomics. PMID- 29409635 TI - Identifying and characterising the physical demands for an Australian specialist policing unit. AB - Many police organisations incorporate specialist policing roles where incumbents are tasked with providing operational response capabilities above and beyond the general duties policing role. The current research utilised subjective job task analysis methods to identify and characterise the physically demanding, frequently occurring, and operationally important tasks, as well as the dominant fitness component for each task, inherent to specialist policing roles in an Australian policing organisation. This was achieved through engagement with subject matter experts and online survey responses from specialist police incumbents. In total, 11 criterion tasks were identified, which covered a range of physical capacities including muscular strength, muscular endurance, and aerobic power. The most physically demanding tasks included those with an arrest component, requiring high muscular strength and power capacities. Having identified the criterion tasks, three operational scenarios were constructed, which incorporated each of the 11 tasks in different operational contexts. The criterion tasks and composite scenarios will allow practitioners within specialised police units to develop evidence-based strategies, including physical selection procedures and physical training programs, specific to the demands of their work. PMID- 29409636 TI - Evaluation of physical workload affected by mass and center of mass of head mounted display. AB - A head-mounted display (HMD) with inappropriate mass and center of mass (COM) increases the physical workload of HMD users. The aim of this study was to investigate the effects of mass and COM of HMD on physical workload. Twelve subjects participated in this study. The mass and posteroanterior COM position were 0.8, 1.2, or 1.6 kg and -7.0, 0.0, or 7.0 cm, respectively. The subjects gazed at the target objects in four test postures: the neutral, look-up, body bending, and look-down postures. The normalized joint torques for the neck and the lumbar region were calculated based on the measured segment angles. The results showed that the neck joint torque was significantly affected by mass and COM and it increased as the HMD mass increased for all test postures. The COM position that minimized the neck joint torque varied depending on the test postures, and the recommended ranges of COM were identified. PMID- 29409637 TI - Creating the environment for driver distraction: A thematic framework of sociotechnical factors. AB - As modern society becomes more reliant on technology, its use within the vehicle is becoming a concern for road safety due to both portable and built-in devices offering sources of distraction. While the effects of distracting technologies are well documented, little is known about the causal factors that lead to the drivers' engagement with technological devices. The relevance of the sociotechnical system within which the behaviour occurs requires further research. This paper presents two experiments, the first aims to assess the drivers self-reported decision to engage with technological tasks while driving and their reasoning for doing so with respect to the wider sociotechnical system. This utilised a semi-structured interview method, conducted with 30 drivers to initiate a discussion on their likelihood of engaging with 22 different tasks across 7 different road types. Inductive thematic analysis provided a hierarchical thematic framework that detailed the self-reported causal factors that influence the drivers' use of technology whilst driving. The second experiment assessed the relevance of the hierarchical framework to a model of distraction that was established from within the literature on the drivers use of distracting technologies while driving. The findings provide validation for some relationships studied in the literature, as well as providing insights into relationships that require further study. The role of the sociotechnical system in the engagement of distractions while driving is highlighted, with the causal factors reported by drivers suggesting the importance of considering the wider system within which the behaviour is occurring and how it may be creating the conditions for distraction to occur. This supports previous claims made within the literature based model. Recommendations are proposed that encourage a movement away from individual focused countermeasures towards systemic actors. PMID- 29409638 TI - Erratum to human factors in mental healthcare: A work system analysis of a community-based program for older adults with depression and dementia applied ergonomics 64 (2017) 27e40. PMID- 29409639 TI - The effects of breaks on low back pain, discomfort, and work productivity in office workers: A systematic review of randomized and non-randomized controlled trials. AB - The purpose of this study was to evaluate the effectiveness of breaks on low back pain, discomfort, and work productivity in office workers. Publications were systematically searched in several databases from 1980 to December 2016. Relevant randomized and non-randomized controlled trials were retrieved and assessed for methodological quality by two independent reviewers. Quality of evidence was assessed and rated according to GRADE guidelines. Eight randomized controlled trials and three non-randomized controlled trials were included in this review, of which 10 were rated as high-quality studies. The break programs were highly heterogeneous with work duration ranging from 5 min to 2 h and break duration ranging from 20 s to 30 min. The results showed low-quality evidence for the conflicting effect of breaks on pain and low-quality evidence for the positive effect of breaks on discomfort. When stratified by type of breaks, moderate quality evidence was found for the positive effect of active breaks with postural change for pain and discomfort. Moderate-quality evidence indicated that the use of breaks had no detrimental effect on work productivity. More high-quality studies are needed before recommendations can be given. Within a number of methodological limitations that are present in the published studies, active breaks with postural change may be effective in reducing pain in workers with acute low back pain and to prevent discomfort in healthy subjects. PMID- 29409640 TI - Fit, stability and comfort assessment of custom-fitted bicycle helmet inner liner designs, based on 3D anthropometric data. AB - Research has demonstrated that a better-fitted bicycle helmet offers improved protection to the rider during an impact. Nowadays, bicycle helmets in the market that range in size from small/medium to medium/large might not fit the diverse range of human head shapes and dimensions. 3D scanning was used to create 3D head shape databases of 20 participants who volunteered for the study. We developed new custom-fitted helmet inner liners, based on the 3D head shape of two sub groups of participants, to map their head sizes and contours closely to the conventional Medium (M) and Large (L) sizes as described in from AS/NZS 2512.1: 2009. The new custom-fitted helmet was compared with the helmet available in the market place in a dynamics stability test and from participants' subjective feedback. A significant reduction in the angle of helmet rotation on the headform in the lateral direction was recorded for the custom-fitted helmet. A Wilcoxon signed-rank test was conducted to evaluate participants' feedback on the helmets according to different area definitions. The overall fit and comfort and the top region of the new helmet were significantly improved. However, no difference was found at the significant level of 0.05 for the front and rear region of the new helmet. PMID- 29409641 TI - Health care clinicians' engagement in organizational redesign of care processes: The importance of work and organizational conditions. AB - The Swedish health care system is reorienting towards horizontal organization for care processes. A main challenge is to engage health care clinicians in the process. The aim of this study was to assess engagement (i.e. attitudes and beliefs, the cognitive state and clinical engagement behaviour) among health care clinicians, and to investigate how engagement was related to work resources and demands during organizational redesign. A cohort study was conducted, using a questionnaire distributed to clinicians at five hospitals working with care process improvement approaches, two of them having implemented Lean production. The results show that kinds of engagement are interlinked and contribute to clinical engagement behaviour in quality of care and patient safety. Increased work resources have importance for engagements in organizational improvements, especially in top-down implementations. An extended work engagement model during organizational improvements in health care was supported. The model contributes to knowledge about how and when clinicians are mobilized to engage in organizational changes. PMID- 29409642 TI - Distributed Cognition on the road: Using EAST to explore future road transportation systems. AB - Connected and Autonomous Vehicles (CAV) are set to revolutionise the way in which we use our transportation system. However, we do not fully understand how the integration of wireless and autonomous technology into the road transportation network affects overall network dynamism. This paper uses the theoretical principles underlying Distributed Cognition to explore the dependencies and interdependencies that exist between system agents located within the road environment, traffic management centres and other external agencies in both non connected and connected transportation systems. This represents a significant step forward in modelling complex sociotechnical systems as it shows that the principles underlying Distributed Cognition can be applied to macro-level systems using the visual representations afforded by the Event Analysis of Systemic Teamwork (EAST) method. PMID- 29409643 TI - Further analysis of the unintentional discharge of firearms in law enforcement. AB - Empirical analysis of the contexts in which UDs occur in law enforcement have only recently begun to emerge. We analyzed a novel sample of UD reports (N = 171) that occurred between 1992 and 2016, collected from one non-U.S. and three U.S. law enforcement entities. Using an established antecedent-behavior-consequence (A B-C) taxonomy, reports were analyzed by context, officer behavior, type of firearm, injuries, deaths, and property damages. This study is the first to empirically document reports of UDs caused by the startle response and the first to analyze a substantial sample of UDs that involved handguns with a double action only trigger mechanism. An expanded analysis of UD consequences suggested that deaths and injuries might be more prevalent than previously reported. PMID- 29409644 TI - The Low-Event Task Subjective Situation Awareness (LETSSA) technique: Development and evaluation of a new subjective measure of situation awareness. AB - Situation awareness (SA) is an important component of an individual's ability to function in a complex environment. As such, it is essential to have effective measures of an individual's SA. The most widely used subjective measure of SA is the Situation Awareness Rating Technique [SART]. However, SART has been criticised for not predicting performance or objective SA, and being highly correlated with workload. This paper describes the development and testing of a new subjective measure of SA, the Low-Event Task Subjective Situation Awareness (LETSSA) measure. To evaluate LETSSA a train simulator study was conducted with 23 novice and 26 expert freight train drivers. LETSSA was able to detect differences in manipulated SA and was comparable to an established objective SA measure (SAGAT). LETSSA was significantly associated with performance but not significantly associated with workload. While further validation is required, LETSSA shows promise as an effective subjective measure of SA. PMID- 29409645 TI - Reflections on work as done (WAD) and work as imagined (WAI) in an emergency response organization: A study on firefighters training exercises. AB - Emergency response organizations need to be resilient to cope with escalating events resulting from dynamic, unexpected, or complex situations. In Brazil, the Firefighter Corps are military hierarchal organizations with a culture based on fixed structures, well defined norms and procedures. These push against innovations which are necessary to be resilient. This research describes how firefighter captains in the 30-35-year age range managed an emergency response escalation in light of standard operating procedures (SOPs) during a training exercise. The study used ethnographic methods to find and discuss gaps between the instructions and the activities carried out during the exercise, highlighting the differences between work as done (WAD) and work as imagined (WAI), as it was instantiated in the SOP prescriptions. The aim was to produce reflections on WAI and WAD as a way to raise awareness of the need for a cultural change toward resilience in firefighter organizations. This was achieved through firefighter engagement with a comprehensive visualization of the analysis results which afforded easy interaction between the experts, the data, and the researchers. PMID- 29409646 TI - Design-validation of a hand exoskeleton using musculoskeletal modeling. AB - Exoskeletons are progressively reaching homes and workplaces, allowing interaction with virtual environments, remote control of robots, or assisting human operators in carrying heavy loads. Their design is however still a challenge as these robots, being mechanically linked to the operators who wear them, have to meet ergonomic constraints besides usual robotic requirements in terms of workspace, speed, or efforts. They have in particular to fit the anthropometry and mobility of their users. This traditionally results in numerous prototypes which are progressively fitted to each individual person. In this paper, we propose instead to validate the design of a hand exoskeleton in a fully digital environment, without the need for a physical prototype. The purpose of this study is thus to examine whether finger kinematics are altered when using a given hand exoskeleton. Therefore, user specific musculoskeletal models were created and driven by a motion capture system to evaluate the fingers' joint kinematics when performing two industrial related tasks. The kinematic chain of the exoskeleton was added to the musculoskeletal models and its compliance with the hand movements was evaluated. Our results show that the proposed exoskeleton design does not influence fingers' joints angles, the coefficient of determination between the model with and without exoskeleton being consistently high (R2-=0.93) and the nRMSE consistently low (nRMSE- = 5.42 degrees ). These results are promising and this approach combining musculoskeletal and robotic modeling driven by motion capture data could be a key factor in the ergonomics validation of the design of orthotic devices and exoskeletons prior to manufacturing. PMID- 29409647 TI - Participatory ergonomics: Evidence and implementation lessons. AB - Participatory ergonomics programs have been proposed as the most effective means of eliminating, or redesigning, manual tasks with the aim of reducing the incidence of occupational musculoskeletal disorders. This review assesses the evidentiary basis for this claim; describes the range of approaches which have been taken under the banner of participatory ergonomics in diverse industries; and collates the lessons learned about the implementation of such programs. PMID- 29409648 TI - A systems approach using the functional resonance analysis method to support fluoride varnish application for children attending general dental practice. AB - BACKGROUND: All children attending General Dental Practice in Scotland are recommended to receive twice-yearly applications of sodium fluoride varnish to prevent childhood caries, yet application is variable. Development of complex interventions requires theorizing and modelling to understand context. This study applies the Functional Resonance Analysis Method (FRAM) to produce a sociotechnical systems model and identify opportunities for intervention to support application. METHODS: The FRAM was used to synthesise data which were: routine monitoring of fluoride varnish application in 2015/16; a longitudinal survey with practitioners (n = 1090); in-depth practitioner and key informant interviews (n = 43); and a 'world cafe' workshop (n = 56). RESULTS: We describe a detailed model of functions linked to application, and use this to make recommendations for system-wide intervention. CONCLUSIONS: Rigorous research is required to produce accessible models of complex systems in healthcare. This novel paper shows how careful articulation of the functions associated with fluoride varnish application can support future improvement efforts. PMID- 29409649 TI - Performance testing of work shoes labeled as slip resistant. AB - The variability in friction and slip propensity across slip resistant (SR) shoes is poorly understood. This study aimed to quantify the impact of shoe design features on the available coefficient of friction (ACOF) across shoes labeled as SR. Differences in ACOF and the slipping rate across SR shoes were also quantified. Twelve shoes were tested across five types of flooring and three contaminant conditions using a whole shoe mechanical slip tester. Geometric and hardness parameters were measured to determine the effect of heel outsole design on ACOF. The rate of slipping was evaluated for three of the shoes on vinyl tile with canola oil using human subjects. Differences in ACOF were significant across shoe outsole designs (p < .001). ACOF was correlated with geometrical and hardness parameters. Rate of slipping was lower for the highest ACOF shoe (p < .001). This information can be used to guide SR shoe selection and design. PMID- 29409650 TI - Influence of work clothing on physiological responses and performance during treadmill exercise and the Wildland Firefighter Pack Test. AB - This study investigated physiological responses and performance during three separate exercise challenges (Parts I, II, and III) with wildland firefighting work clothing ensemble (boots and coveralls) and a 20.4 kg backpack in four conditions: U-EX (no pack, exercise clothing); L-EX (pack, exercise clothing); U W (no pack, work clothing); and, L-W (pack and work clothing). Part I consisted of randomly-ordered graded exercise tests, on separate days, in U-EX, L-EX and L W conditions. Part II consisted of randomly-ordered bouts of sub-maximal treadmill exercise in the four conditions. In Part III, subjects completed, in random-order on separate days, 4.83 km Pack Tests in L-EX or L-W conditions. In Part I, peak oxygen uptake was reduced (p < .05) in L-W. In Part II, mass specific oxygen uptake was significantly higher in both work clothing conditions. In Part III, Pack Test time was slower (p < .05) in L-W. These results demonstrate the negative impact of work clothing and load carriage on physiological responses to exercise and performance. PMID- 29409651 TI - A group-level approach to analyzing participative ergonomics (PE) effectiveness: The relationship between PE dimensions and employee exposure to injuries. AB - Most studies concerned with participative ergonomic (PE) interventions, focus on organizational rather than group level analysis. By implementing an intervention at a manufacturing plant, the current study, utilizing advanced information systems, measured the effect of line-supervisor leadership on employee exposure to risks. The study evaluated which PE dimensions (i.e., extent of workforce involvement, diversity of reporter role types and scope of analysis) are related to such exposure at the group level. The data for the study was extracted from two separate computerized systems (workforce medical records of 791 employees and an intranet reporting system) during a two-year period. While the results did not confirm the effect of line-supervisor leadership on subordinates' exposure to risks, they did demonstrate relationships between PE dimensions and the employees' exposure to risks. The results support the suggested level of analysis and demonstrate that group-based analysis facilitates the assimilation of preventive interventions. PMID- 29409652 TI - Modelling interactions between procedures and resilience skills. AB - Although work in complex socio-technical systems needs support from several "resources for action", the interactions between these are not usually managed systematically. This study introduces a six-step framework for analyzing the interactions between two key resources for action, namely the use of standardized operating procedures and resilience skills (RSs). The main steps for applying the framework involve: (i) a content analysis of the procedure, which allows for the identification of underspecified rules and situations that could be emphasized in scenario-based training focused on developing RSs; and (ii) the identification of factors that set the stage for the emergence of RSs, which could be accounted for by procedures and the broader work system design. An application of the framework is presented in the preparation and administration of intravenous medications in an emergency department. Data collection involved 98 h of observations, 14 interviews, and document analysis. Based on this field study, a model of the interactions between procedures and RSs is proposed as well as the lessons learned from applying the framework are discussed. PMID- 29409653 TI - Classification scheme and prevention measures for caught-in-between occupational fatalities. AB - The current study analyzed 312 caught-in-between fatalities caused by machinery and vehicles. A comprehensive and mutually exclusive coding scheme was developed to analyze and code each caught-in-between fatality in terms of age, gender, experience of the victim, type of industry, source of injury, and causes for these accidents. Boolean algebra analysis was applied on these 312 caught-in between fatalities to derive minimal cut set (MCS) causes associated with each source of injury. Eventually, contributing factors and common accident patterns associated with (1) special process machinery including textile, printing, packaging machinery, (2) metal, woodworking, and special material machinery, (3) conveyor, (4) vehicle, (5) crane, (6) construction machinery, and (7) elevator can be divided into three major groups through Boolean algebra and MCS analysis. The MCS causes associated with conveyor share the same primary causes as those of the special process machinery including textile, printing, packaging and metal, woodworking, and special material machinery. These fatalities can be eliminated by focusing on the prevention measures associated with lack of safeguards, working on a running machine or process, unintentional activation, unsafe posture or position, unsafe clothing, and defective safeguards. Other precise and effective intervention can be developed based on the identified groups of accident causes associated with each source of injury. PMID- 29409654 TI - Process evaluation of a participatory organizational change program to reduce musculoskeletal and slip, trip and fall injuries. AB - BACKGROUND: Long-term care (LTC) workers are at significant risk for occupational related injuries. Our objective was to evaluate the implementation process of a participatory change program to reduce risk. METHODS: A process evaluation was conducted in three LTC sites using a qualitative approach employing structured interviews, consultant logs and a focus group. RESULTS: Findings revealed recruitment/reach themes of being "voluntold", using established methods, and challenges related to work schedules. Additional themes about dose were related to communication, iterative solution development, participation and engagement. For program fidelity and satisfaction, themes emerged around engagement, capacity building and time demands. CONCLUSION: Process evaluation revealed idiosyncratic approaches to recruitment and related challenges of reaching staff. Solutions to prioritized hazards were developed and implemented, despite time challenges. The iterative solution development approach was embraced. Program fidelity was considered good despite early program time demands. Post implementation reports revealed sustained hazard identification and solution development. PMID- 29409655 TI - Extended Fitts' model of pointing time in eye-gaze input system - Incorporating effects of target shape and movement direction into modeling. AB - This study attempted to investigate the effects of the target shape and the movement direction on the pointing time using an eye-gaze input system and extend Fitts' model so that these factors are incorporated into the model and the predictive power of Fitts' model is enhanced. The target shape, the target size, the movement distance, and the direction of target presentation were set as within-subject experimental variables. The target shape included: a circle, and rectangles with an aspect ratio of 1:1, 1:2, 1:3, and 1:4. The movement direction included eight directions: upper, lower, left, right, upper left, upper right, lower left, and lower right. On the basis of the data for identifying the effects of the target shape and the movement direction on the pointing time, an attempt was made to develop a generalized and extended Fitts' model that took into account the movement direction and the target shape. As a result, the generalized and extended model was found to fit better to the experimental data, and be more effective for predicting the pointing time for a variety of human-computer interaction (HCI) task using an eye-gaze input system. PMID- 29409656 TI - User Systems Architectures - Two studies in design and assessment. AB - The concept of User System Architectures (USA) is introduced as part of the overall systems architecture. A USA is defined as a set of ergonomics information and knowledge assembled to represent system structure and content. It is described in the context of the system development lifecycle. The characteristics associated with a USA are outlined. These include layers of description, viewpoints, coherency and traceability. The concept of coherency between layers and the techniques for tracing the design characteristics back to the requirements (i.e. traceability) are discussed with their implications for ergonomics. Two studies (one design and one assessment) are used to demonstrate the use of USA techniques. The benefits, shortfalls and costs of using the USA technique are outlined for each case, and in a more general range of applications. The validity and reliability of the representations are discussed. PMID- 29409657 TI - Assessing the effects of slippery steel beam coatings to ironworkers' gait stability. AB - Since ironworkers walk and perform their tasks on steel beams, identifying the effects of slippery steel beam surfaces on ironworkers' gait stability-which can be related to safety risk-is critical. However, there is no accepted or validated standard for measuring the slipperiness of coated steel beams, which makes evaluating and controlling for slipperiness a challenge. In this context, this study investigated the effect of the slipperiness of steel beam coatings on ironworkers' gait stability. Accordingly, to identify the relationships between coefficient of friction, perceived slipperiness, and gait stability-represented as the Maximum Lyaponuv exponent (Max LE)-an experiment was conducted with eight different surfaces and sixteen subjects with varying experience as ironworkers. The experiment's results indicate that the slipperiness of the various surfaces greatly affect ironworkers' gait stability while they walk on coated steel beam surfaces. In detail, the Max LE of two subject groups-experienced and inexperienced ironworkers-highly correlated with both the dynamic coefficient of friction values measured by following ANSI B101.3 and with the subjective rating scores of the inexperienced subject group. Unlike subjective rating scores-which were particularly incongruent among experienced workers-the Max LE of inexperienced and experienced subjects has a consistent pattern. This study result highlights an opportunity for using gait stability measurements to quantify and differentiate the safety risks caused by slippery coated steel beams in the future. PMID- 29409658 TI - The effect of a multi-axis suspension on whole body vibration exposures and physical stress in the neck and low back in agricultural tractor applications. AB - Whole body vibration (WBV) exposures are often predominant in the fore-aft (x) or lateral (y) axis among off-road agricultural vehicles. However, as the current industry standard seats are designed to reduce mainly vertical (z) axis WBV exposures, they may be less effective in reducing drivers' exposure to multi axial WBV. Therefore, this laboratory-based study aimed to determine the differences between a single-axial (vertical) and multi-axial (vertical + lateral) suspension seat in reducing WBV exposures, head acceleration, self reported discomfort, and muscle activity (electromyography) of the major muscle of the low back, neck and shoulders. The results showed that the multi-axial suspension seat had significantly lower WBV exposures compared to the single axial suspension seats (p' < 0.04). Similarly, the multi-axial suspension seat had lower head acceleration and muscle activity of the neck, shoulder, and low back compared to the single-axial suspension seat; some but not all of the differences were statistically significant. These results indicate that the multi axial suspension seat may reduce the lateral WBV exposures and associated muscular loading in the neck and low back in agricultural vehicle operators. PMID- 29409659 TI - Development of a positioning aid to reduce postural variability and errors in 3D whole body scan measurements. AB - Three-dimensional (3D) body scanners have the potential to evaluate changes to the human form through different clothing configurations, the use of protective equipment, or the effects of medical interventions. To achieve this, scans of an individual need to be superimposed for each experimental condition. The literature highlights that one of the limiting factors is postural variability. This paper describes a newly developed 'positioning aid' that stabilises the posture during the scanning process and is invisible on scans. The results of a study evaluating the efficacy of the positioning aid showed that it reduces postural variability for all body parts in lateral and longitudinal directions. A reference test with a rigid mannequin indicated that the 'technical' variability due to the scanner hardware and software significantly contributes to the residual variability. Furthermore, the study showed that the newly developed positioning aid overall increased the precision of the software-assisted extraction of body dimensions. PMID- 29409660 TI - Reply-Letter to the Editor-Different dietary approaches and coronary plaque morphology. PMID- 29409661 TI - Through Sex, Nature Is Telling Us Something Important. AB - Theoretically, a variety of mechanisms can make amphimixis advantageous due to reshuffling of offspring genotypes. Recently, it has been shown experimentally that some of these mechanisms can indeed work in artificial populations. However, we still do not know which of them, if any, are relevant in nature, and the available indirect estimates seem to suggest that neither negative nor positive selection in natural populations is strong enough to provide evolutionary protection for obligate amphimixis. Thus, progress in understanding the evolution of amphimixis will depend on direct measurements of the strength of natural selection. PMID- 29409663 TI - Penta-therapy for severe acute hyperlipidemic pancreatitis. AB - INTRODUCTION: The purpose of our study is to evaluate the efficacy of penta therapy for HL-SAP in a retrospective study. METHODS: Retrospective study between January 2007 and December 2016 in a hospital intensive care unit. HL-SAP patients were assigned to conventional treatment alone (the control group) or conventional treatment with the experimental protocol (the penta-therapy group) consists of blood purification, antihyperlipidemic agents, low-molecular weight heparin, insulin, covering the whole abdomen with Pixiao (a traditional Chinese medicine). Serum triglyceride, serum calcium, APACHE II score, SOFA score, Ranson score, and other serum biomarkers were evaluated. The hospital length of stay, local complications, systematic complications, rate of recurrence, overall mortality, and operation rate were considered clinical outcomes. RESULTS: 63 HL-SAP patients received conventional treatment alone (the control group) and 25 patients underwent penta- therapy combined with conventional treatment (the penta-therapy group). Serum amylase, serum triglyceride, white blood cell count, C-reactive protein, and blood sugar were significantly reduced, while serum calcium was significantly increased with penta-therapy. The changes in serum amylase, serum calcium were significantly different between the penta-therapy and control group on 7th day after the initiation of treatment. The reduction in serum triglyceride in the penta-therapy group on the second day and 7th day were greater than the control group. Patients in the penta-therapy group had a significantly shorter length of hospital stay. CONCLUSION: This study suggests that the addition of penta-therapy to conventional treatment for HL-SAP may be superior to conventional treatment alone for improvement of serum biomarkers and clinical outcomes. PMID- 29409662 TI - The DISCOVER Study 3-Year Results: Feasibility and Usefulness of Microscope Integrated Intraoperative OCT during Ophthalmic Surgery. AB - PURPOSE: To report the 3-year assessment of feasibility and usefulness of microscope-integrated intraoperative OCT (iOCT) during ophthalmic surgery. DESIGN: Prospective, consecutive case series. PARTICIPANTS: Adult participants undergoing incisional ophthalmic surgery with iOCT imaging who consented to be enrolled in the Determination of Feasibility of Intraoperative Spectral-Domain Microscope Combined/Integrated OCT Visualization during En Face Retinal and Ophthalmic Surgery (DISCOVER) study. METHODS: The DISCOVER study is a single site, multisurgeon, institutional review board-approved investigational device prospective study. Participants included patients undergoing anterior or posterior segment surgery who underwent iOCT imaging with 1 of 3 prototype microscope-integrated iOCT systems (i.e., Zeiss Rescan 700, Leica EnFocus, or Cole Eye iOCT systems). Clinical characteristics were documented, iOCT was directed by the operating surgeon at predetermined surgical time points, and each surgeon completed a questionnaire after surgery to evaluate the usefulness of iOCT during surgery. MAIN OUTCOME MEASURES: Feasibility of iOCT based ability to obtain an OCT image during surgery and usefulness of iOCT based on surgeon reporting during surgery. RESULTS: Eight hundred thirty-seven eyes (244 anterior segment cases and 593 posterior segment cases) were enrolled in the DISCOVER study. Intraoperative OCT demonstrated feasibility with successful image acquisition in 820 eyes (98.0%; 95% confidence interval [CI], 96.8%-98.8%). In 106 anterior segment cases (43.4%; 95% CI, 37.1%-49.9%), the surgeons indicated that the iOCT information impacted their surgical decision making and altered the procedure. In posterior segment procedures, surgeons reported that iOCT enabled altered surgical decision making during the procedure in 173 cases (29.2%; 95% CI, 25.5%-33.0%). CONCLUSIONS: The DISCOVER iOCT study demonstrated both generalized feasibility and usefulness based on the surgeon-reported impact on surgical decision making. This large-scale study confirmed similar findings from other studies on the potential value and impact of iOCT on ophthalmic surgery. PMID- 29409664 TI - Spontaneous methicillin-resistant Staphylococcus aureus (MRSA) meningitis. AB - Spontaneous methicillin-resistant Staphylococcus aureus (MRSA) meningitis is extremely rare and has a high mortality rate. We report a case of MRSA meningitis in an otherwise healthy young adult female with no recent trauma or neurosurgical interventions. Despite antibiotics she suffered a vasculitis-induced cerebral vascular ischemic event. PMID- 29409665 TI - Public knowledge and perceptions about cardiopulmonary resuscitation (CPR): Results of a multicenter survey. PMID- 29409666 TI - Growth factors FGF8 and FGF2 and their receptor FGFR1, transcriptional factors Msx-1 and MSX-2, and apoptotic factors p19 and RIP5 participate in the early human limb development. AB - The expression pattern of fibroblast growth factors FGF8 and FGF2 and their receptor FGFR1, transcription factors MSX-1 and MSX-2, as well as cell proliferation (Ki-67) and cell death associated caspase-3, p19 and RIP5 factors were analyzed in histological sections of eight 4th-9th-weeks developing human limbs by immunohistochemistry and semi-thin sectioning. Increasing expression of all analyzed factors (except FGF8) characterized both the multilayered human apical ectodermal ridge (AER), sub-ridge mesenchyme (progress zone) and chondrocytes in developing human limbs. While cytoplasmic co-expression of MSX-1 and MSX-2 was observed in both limb epithelium and mesenchyme, p19 displayed strong cytoplasmic expression in non-proliferating cells. Nuclear expression of Ki-67 proliferating cells, and partly of MSX-1 and MSX-2 was detected in the whole limb primordium. Strong expression of factors p19 and RIP5, both in the AER and mesenchyme of human developing limbs indicates their possible involvement in control of cell senescence and cell death. In contrast to animal studies, expression of FGFR1 in the surface ectoderm and p19 in the whole limb primordium might reflect interspecies differences in limb morphology. Expression of FGF2 and downstream RIP5 gene, and transcription factors Msx-1 and MSX-2 did not show human-specific changes in expression pattern. Based on their spatio-temporal expression during human limb development, our study indicates role of FGFs and Msx genes in stimulation of cell proliferation, limb outgrowth, digit elongation and separation, and additionally MSX-2 in control of vasculogenesis. The cascade of orchestrated gene expressions, including the analyzed developmental factors, jointly contribute to the complex human limb development. PMID- 29409667 TI - Pathologists - The watchpersons for hereditary tumor syndromes. PMID- 29409668 TI - How Should a Man with Prostate Cancer Choose his Surgeon? PMID- 29409669 TI - Oral Pain and Morbidity with Buccal Mucosa Grafts for Substitution Urethroplasty: Closure or Not. PMID- 29409670 TI - Downstream effects of a large reservoir on the reproductive activity of Prochilodus hartii (Pisces: Prochilodontidae). AB - To analyze the effect of the Irape reservoir on the reproduction of "curimba", Prochilodus hartii, a migratory species, 503 specimens were collected during the reproductive period from February 2012 to January 2013. Specimens were collected from two river sections within the Jequitinhonha River Basin: Site 1 - a section of the Itacambirucu River, a tributary of the Jequitinhonha River upstream of the Irape reservoir; and Site 2 - a section of the Jequitinhonha River immediately downstream from the Irape dam. Specimens (n = 270) were captured at Site 1 (160 males and 110 females), and 233 specimens at Site 2 (136 males and 97 females). The following were determined for each specimen: gonadosomatic index (GSI), hepatosomatic index (HSI), stomach repletion index (SRI), coelomic fat index (CFI) and condition factor (K). Both male and female fish were captured at all stages of gonadal maturation at Site 1, whereas only fish in the inactive and initial maturation stages were captured at Site 2. Length and mean GSI were greater (P < .05) at Site 1. Mean HSI and SRI of females was less in the advanced maturation stage. There were lesser values for temperature and dissolved oxygen at Site 2 than 1. It is possible that the lesser values for the physical and chemical characteristics of the water at Site 2 failed to promote advanced gonadal maturation, spawning, and spermiation of P. hartii, thus there are associations that are indicative of a negative effect of the Irape reservoir on the reproduction of this migratory species. PMID- 29409671 TI - Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer. AB - OBJECTIVES: To determine the prognostic significance of spatial proximity of lung cancer cells and specific immune cells in the tumor microenvironment. MATERIALS AND METHODS: We probed formalin-fixed, paraffin-embedded (FFPE) tissue microarrays using a novel tyramide signal amplification multiplexing technique labelling CD8, CD4, Foxp3, and CD68+ cells. Each multiplex stained immunohistochemistry slide was digitally processed by Vectra INFORMS software, and an X- and Y-coordinate assigned to each labeled cell type. The abundance and spatial location of each cell type and their proximity to one another was analyzed using a novel application of the G-cross spatial distance distribution method which computes the probability of finding at least one immune cell of any given type within a rMUm radius of a tumor cell. Cox proportional hazards multiple regression was used for multivariate analysis of the influence of proximity of lymphocyte types. RESULTS: Pathologic tumor specimens from 120 NSCLC patients with pathologic tumor stage I-III disease were analyzed. On univariate analysis, age (P = .0007) and number of positive nodes (P = .0014) were associated with overall survival. Greater area under the curve (AUC) of the G cross function for tumor cell-Treg interactions was significantly associated with worse survival adjusting for age and number of positive nodes (HR 1.52 (1.11 2.07), P = .009). Greater G-cross AUC for T-reg-CD8 was significantly associated with better survival adjusting for age and number of positive lymph nodes (HR 0.96 (0.92-0.99), P = .042). CONCLUSION: Increased infiltration of regulatory T cells into core tumor regions is an independent predictor of worse overall survival in NSCLC. However, increased infiltration of CD8+ cytotoxic T cells among regulatory T cells seems to mitigate this effect and was significantly associated with better survival. Validation of the G-cross method of measuring spatial proximity between tumor and immune cell types and exploration of its use as a prognostic factor in lung cancer treatment is warranted. PMID- 29409672 TI - Autonomic nerve activity indexed using 24-h heart rate variability in patients with burns. AB - BACKGROUND: Heart rate variability (HRV) is a noninvasive method used to quantify fluctuations in the time interval between normal heart beats. The purpose of this study was to compare the autonomic nervous system functioning of patients with burns to healthy participants after their burn scars had been re-epithelialized. MATERIALS AND METHODS: The authors prospectively performed 24-h HRV monitoring in 60 patients with electrical burns, those with other major burns, those with other minor burns, and 10 healthy participants. Analysis of HRV in the time and frequency domain was performed. RESULTS: The difference in sympathetic nerve measures (standard deviation of NN intervals [SDNN], total power [TP] and a low frequency [LF] band) and parasympathetic nerve measures (Root mean square successive difference [RMSSD], the number of interval differences of successive NN intervals greater than 50ms [NN50], the percentage of differences between following RR intervals greater than 50ms [pNN50] and a high frequency [HF] band) in patients with burns was significantly decreased during the daytime and the nighttime. the difference in parasympathetic nerve measures were more significantly decreased during the nighttime compared with measures of HRV in healthy participants. The groups of other burns showed significantly lower HRV than the electrical burn group indexed by a very low frequency (VLF) measure and TP during the daytime. CONCLUSION: We hypothesized that HRV is a surrogate for autonomic nervous system dysfunction in patients with burns. The patients with burns were observed a sympathetic predominance during daytime and a decreased parasympathetic activity during nighttime. These results of patients with other major burns were more predominant compared with the results of patients with other groups. PMID- 29409673 TI - OGG1 regulates the level of symmetric dimethylation of histone H4 arginine-3 by interacting with PRMT5. AB - OGG1 is the first enzyme in the base excision repair pathway (BER) responsible for repairing 8-oxoguanine DNA lesions. Recent studies found that OGG1 may also be involved in epigenetic regulation. In this study, we focused on the roles of OGG1 in histone modification. First, to study the effects of OGG1 on histone modification, the protein levels of symmetric dimethylation of histone H4 arginine-3 (H4R3me2s) were determined by western blot analysis following the knockdown or overexpression of OGG1. Second, the molecular mechanisms by which OGG1 regulates H4R3me2s were assessed by co-immunoprecipitation (CO-IP) assays in mouse embryonic fibroblast (MEF) wild-type (WT) and Ogg-/- cells. Finally, to verify the regulation of H4R3me2s by OGG1 on specific genes, chromatin immunoprecipitation (CHIP) was performed on MEF WT and Ogg-/- cells. We found that OGG1 affects PRMT5 binding on histone H4 and the formation of H4R3me2s via PRMT5. The methylation level of H4R3me2s was dramatically decreased in MEF Ogg-/- cells compared to WT cells. Knockdown of OGG1 by siRNA led to a decrease in H4R3me2s, while overexpression of OGG1 increased the level of H4R3me2s. OGG1 also interacted with PRMT5 and histone H4, and the interaction between PRMT5 and histone H4 was reduced in MEF Ogg-/- cells. Our data not only illustrate the important roles of OGG1 in histone modification, but also reveal the mechanism by which OGG1 affects PRMT5 binding on H4R3 resulting in the symmetrical dimethylation of histone H4 arginine-3. PMID- 29409675 TI - Features of fracture of prosthetic tooth-endocrown constructions by means of acoustic emission analysis. AB - OBJECTIVE: The study aims at comparing the fracture resistance of different restorative materials used in dental endocrown restorations and respective endocrown restorations under a quasi-static compressive load using acoustic emission (AE) method. METHODS: Five restorative materials were used in this study. The restorative materials were manufactured into discs 13mm in diameter and 5mm thick, which were then divided into 5 groups and included into Type 1: Group B: zirconium dioxide (Prettau zirconia); Group C: ceramics (IPS e.max Press); Group D: metal ceramics (GC Initial MC+Nicrallium N2 BCS); Group E: composite resin (Nano Q); Group F: luting cement (RelyXTM U200). Twenty-five extracted human molars were divided into 5 groups and included into Type 2: Group A: control, no restoration; Group BE: restored by zirconium dioxide endocrowns; Group CE: restored by ceramic endocrowns; Group DE: restored by metal ceramic endocrowns; Group EE: restored by composite resin endocrowns. An increasing load was applied to the center of the samples with a hard steel ball until a fracture occurred. The loading rate was 0.12mm/min. An AE system was used to monitor the fracture of the samples. The load corresponding to the first AE event and the final fracture load were used to evaluate the fracture resistance of the restored teeth. The data were analyzed using ANOVA and Tukey's post hot test (alpha=0.05). RESULTS: A lower threshold of 220MUV was selected to exclude spurious background signals. For the initial fracture load of Type 1 samples, Group F (0.029kN)65 years (n = 8875) were included. RESULTS: 1839 residents (20.7%) were in total need of help in feeding on a daily basis. At the multilevel analysis, predictors were moderate/severe dementia (OR 4.044, CI 95% 3.213-5.090); dysphagia (OR 4.003 CI 95% 3.155-5.079); pressure sores (OR 2.317 CI 95% 1.803-2.978); unintentional weigh loss (OR 2.197 CI 95% 1.493-3.233); unsociability (OR 1.561 CI 95% 1.060 2.299); and clinical instability (OR 1.363 CI 95% 1.109-1.677). CONCLUSIONS: The feeding dependence prevalence emerged seem to be unique compared to that documented at the international levels. Modifiable and unmodifiable predictors found require new policies regarding workforce skills-mix and shifts schedules; as well as alliances with families, associations and communities' stakeholders. According to the complexity of the resident profile emerged, staff education and training is also recommended. PMID- 29409684 TI - Ongoing strategies and updates on pain management in gynecologic oncology patients. AB - The opioid crisis in the United States has been declared a public health emergency. Various governmental agencies, cancer care organizations and the Centers for Disease Control and Prevention have issued guidelines in hopes of managing this crisis. Curbing over-prescription of opioids by medical professionals has been a central theme in many of these guidelines. Gynecologic oncologists encounter patients with a variety of pain sources, including acute pain secondary to the underlying malignancy or surgical procedures as well as chronic pain related to the malignancy and the sequelae of treatments rendered. In this review, we discuss the various etiologies of pain experienced by gynecologic oncology patients and discuss modalities frequently used to treat this pain. We highlight strategies to reduce the number of opioids prescribed and focus on incorporating non-opioid pain relief management principles in this review. We also discuss the mechanisms and etiology of various types of pain, with a focus on multimodal treatment strategies including preoperative counseling, strategies to identify individuals at risk of developing opioid dependence, and the role of symptom management and palliative care teams. Finally, we provide a blueprint for gynecologic oncology practices to develop their practice-specific pain management contracts to engage patients in a meaningful conversation around the addictive potential of opioids. PMID- 29409683 TI - Neural Correlates of Unconsciousness in Large-Scale Brain Networks. AB - The biological basis of consciousness is one of the most challenging and fundamental questions in 21st century science. A related pursuit aims to identify the neural correlates and causes of unconsciousness. We review current trends in the investigation of physiological, pharmacological, and pathological states of unconsciousness at the level of large-scale functional brain networks. We focus on the roles of brain connectivity, repertoire, graph-theoretical techniques, and neural dynamics in understanding the functional brain disconnections and reduced complexity that appear to characterize these states. Persistent questions in the field, such as distinguishing true correlates, linking neural scales, and understanding differential recovery patterns, are also addressed. PMID- 29409685 TI - Starved viable but non-culturable (VBNC) Legionella strains can infect and replicate in amoebae and human macrophages. AB - Legionella infections are among the most important waterborne infections with constantly increasing numbers of cases in industrialized countries, as a result of aging populations, rising numbers of immunocompromised individuals and increased need for conditioned water due to climate change. Surveillance of water systems is based on microbiological culture-based techniques; however, it has been shown that high percentages of the Legionella populations in water systems are not culturable. In the past two decades, the relevance of such viable but non culturable (VBNC) legionellae has been controversially discussed, and whether VBNC legionellae can directly infect human macrophages, the primary targets of Legionella infections, remains unclear. In this study, it was demonstrated for the first time that several starved VBNC Legionella strains (four L. pneumophila serogroup 1 strains, a serogroup 6 strain and a L. micdadei strain) can directly infect different types of human macrophages and amoebae even after one year of starvation in ultrapure water. However, under these conditions, the strains caused infection with reduced efficacy, as represented by the lower percentages of infected cells, prolonged time in co-culture and higher multiplicities of infection required. Interestingly, the VBNC cells remained mostly non-culturable even after multiplication within the host cells. Amoebal infection by starved VBNC Legionella, which likely occurs in oligotrophic biofilms, would result in an increase in the bacterial concentration in drinking-water systems. If cells remain in the VBNC state, the real number of active legionellae will be underestimated by the use of culture-based standard techniques. Thus, further quantitative research is needed in order to determine, whether and how many starved VBNC Legionella cells are able to cause disease in humans. PMID- 29409686 TI - LPA5 signaling is involved in multiple sclerosis-mediated neuropathic pain in the cuprizone mouse model. AB - Lysophosphatidic acid (LPA) and LPA1 receptor signaling play a crucial role in the initiation of peripheral nerve injury-induced neuropathic pain through the alternation of pain-related genes/proteins expression and demyelination. However, LPA and its signaling in the brain are still poorly understood. In the present study, we revealed that the LPA5 receptor expression in corpus callosum elevated after the initiation of demyelination, and the hyperalgesia through Adelta-fibers following cuprizone-induced demyelination was mediated by LPA5 signaling. These data suggest that LPA5 signaling may play a key role in the mechanisms underlying neuropathic pain following demyelination in the brain. PMID- 29409687 TI - Cardiac imaging in Ebstein anomaly. AB - Ebstein anomaly is a congenital disorder of right ventricular myocardial development, which affects the tricuspid valve in addition to the right ventricular myocardium. Cardiac imaging by transthoracic echocardiography and cardiac magnetic resonance imaging are the key modalities used to assess timing and type of surgery. In this article, we review the current standards of echocardiographic and magnetic resonance imaging in Ebstein anomaly. PMID- 29409688 TI - Classification and molecular pathogenesis of NBIA syndromes. AB - Brain iron accumulation is the hallmark of a group of seriously invalidating and progressive rare diseases collectively denominated Neurodegeneration with Brain Iron Accumulation (NBIA), characterized by movement disorder, painful dystonia, parkinsonism, mental disability and early death. Currently there is no established therapy available to slow down or reverse the progression of these conditions. Several genes have been identified as responsible for NBIA but only two encode for proteins playing a direct role in iron metabolism. The other genes encode for proteins either with various functions in lipid metabolism, lysosomal activity and autophagic processes or with still unknown roles. The different NBIA subtypes have been classified and denominated on the basis of the mutated genes and, despite genetic heterogeneity, some of them code for proteins, which share or converge on common metabolic pathways. In the last ten years, the implementation of genetic screening based on Whole Exome Sequencing has greatly accelerated gene discovery, nevertheless our knowledge of the pathogenic mechanisms underlying the NBIA syndromes is still largely incomplete. PMID- 29409690 TI - Prevalence of nasolacrimal canal obstruction and epiphora following maxillary orthognathic surgery. AB - Acquired injuries of the nasolacrimal apparatus may be the result of craniomaxillofacial surgical procedures, facial trauma, or inflammation. Injury to the nasolacrimal duct system following maxillary orthognathic surgery is rarely reported. This study evaluated the importance of early diagnosis and treatment of epiphora developing after Le Fort I surgery. The records of 83 patients who underwent maxillary orthognathic surgery over a 2-year period were reviewed. The prevalence of postoperative epiphora was 3.6% and it persisted for a mean of 32.7 days. No patient required further surgical treatment of the nasolacrimal duct obstruction. Clinicians should evaluate the lacrimal canal position and schedule close postoperative follow-up of injuries to the nasolacrimal apparatus. These may become permanent, necessitating additional surgery. PMID- 29409689 TI - Hacking an Algal Transcription Factor for Lipid Biosynthesis. AB - Transcriptional engineering is a viable means for engineering microalgae to produce lipid, but it often results in a trade-off between production and growth. A recent study shows that engineering a single transcriptional regulator enables efficient carbon partitioning to lipid biosynthesis with high biomass productivity. PMID- 29409691 TI - Biohydrogen production from space crew's waste simulants using thermophilic consolidated bioprocessing. AB - Human waste simulants were for the first time converted into biohydrogen by a newly developed anaerobic microbial consortium via thermophilic consolidated bioprocessing. Four different BioH2-producing consortia (denoted as C1, C2, C3 and C4) were isolated, and developed using human waste simulants as substrate. The thermophilic consortium C3, which contained Thermoanaerobacterium, Caloribacterium, and Caldanaerobius species as the main constituents, showed the highest BioH2 production (3.999 mmol/g) from human waste simulants under optimized conditions (pH 7.0 and 60 degrees C). The consortium C3 also produced significant amounts of BioH2 (5.732 mmol/g and 2.186 mmol/g) using wastewater and activated sludge, respectively. The developed consortium in this study is a promising candidate for H2 production in space applications as in situ resource utilization. PMID- 29409692 TI - Bacteremia due to Moraxella osloensis: a case report and literature review. AB - Herein we report the case of a 10-year-old boy with an autosomal mosaic mutation who developed bacteremia. The causative agent was identified as Moraxella osloensis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene sequencing. In the pediatric population, there have been 13 case reports of infection attributed to M. osloensis and this is the fifth reported case of pediatric bacteremia due to M. osloensis. After Moraxella species infection was confirmed, the patient recovered with appropriate antimicrobial therapy. It is important to consider that M. osloensis can cause serious infections, such as bacteremia, in otherwise healthy children. PMID- 29409693 TI - Pulmonary Mycobacterium heckeshornense infection in a healthy woman. AB - Pulmonary infection due to Mycobacterium heckeshornense (M. heckeshornense) in healthy adults without underlying diseases is very rare and optimal treatments have not yet been established. A 39-year-old woman was admitted to our hospital for further examinations following the identification of a pulmonary cavitary nodule. Acid-fast bacilli were cultured from specimens obtained by bronchofiberscopy, and identified with M. heckeshornense using nucleotide sequencing. Antimycobacterial chemotherapy was effective temporarily, while the nodular lesion subsequently worsened. The patient underwent lobectomy and has not relapsed thus far. A lung specimen showed marked granulomatous inflammation with extensive caseous necrosis and the preservation of some parts of alveolar septa within caseous necrosis, indicating an exudative process and resistance to chemotherapy. M. heckeshornense is strongly pathogenic and switching to surgical intervention needs to be considered when chemotherapy is insufficient. PMID- 29409694 TI - Effective concentration of intravenous immunoglobulin for neutralizing Panton Valentine leukocidin in human blood. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infects healthy individuals, although the precise cause remains unclear. CA-MRSA produces Panton-Valentine leukocidin (PVL), which often causes severe invasive infection; however, antitoxin drugs against PVL are limited. Intravenous immunoglobulin (IVIg) possesses antitoxin activity, but unfortunately, the optimal dose is unknown. Here, we measured the PVL neutralizing antibody titer in the plasma of Japanese individuals and sera of American donors. Next, we compared the cytotoxic effects of PVL on neutrophils in phosphate buffered saline (PBS) or whole blood to determine the effect of the neutralizing antibody. Finally, we evaluated the effective concentration of IVIg required to neutralize PVL in PBS and whole blood. We observed that the titer of PVL neutralizing antibody in healthy individuals polarized as high and low/none group. Additionally, the PVL neutralizing antibody titer considerably affected the concentration at which IVIg elicited its effect. This suggests that PVL-producing CA-MRSA might be involved in determining the severity of infection in healthy individuals without neutralizing antibody against PVL. The neutralizing effect of IVIg was observed in both PBS and whole blood. However, the optimal concentration of IVIg required for neutralizing PVL varied between PBS and whole blood. In addition, since the PVL-neutralizing activity of IVIg also largely depends on blood composition, such as neutralizing antibody concentration, the optimal dosage of IVIg as an antitoxin drug should be decided in a timely manner after considering the patient's medical background. PMID- 29409695 TI - Haemoglobin variants, iron status and anaemia in Sri Lankan adolescents with low red cell indices: A cross sectional survey. AB - Iron deficiency complicates the use of red cell indices to screen for carriers of haemoglobin variants in many populations. In a cross sectional survey of 7526 secondary school students from 25 districts of Sri Lanka, 1963 (26.0%) students had low red cell indices. Iron deficiency, identified by low serum ferritin, was the major identifiable cause occurring in 550/1806 (30.5%) students. Low red cell indices occurred in iron-replete students with alpha-thalassaemia including those with single alpha-globin gene deletions. Anaemia and low red cell indices were also common in beta-thalassaemia trait. An unexpected finding was that low red cell indices occurred in 713 iron-replete students with a normal haemoglobin genotype. It is common practice to prescribe iron supplements to individuals with low red cell indices. Since low red cell indices were a feature of all forms of alpha thalassaemia and also of iron deficiency, in areas where both conditions are common, such as Sri Lanka, it is imperative to differentiate between the two, to allow targeted administration of iron supplements and avoid the possible deleterious effects of increased iron availability in iron replete individuals with low red cell indices due to other causes such as alpha thalassaemia. PMID- 29409696 TI - Fur regulation of Staphylococcus aureus heme oxygenases is required for heme homeostasis. AB - Heme is a cofactor that is essential for cellular respiration and for the function of many enzymes. If heme levels become too low within the cell, S. aureus switches from producing energy via respiration to producing energy by fermentation. S. aureus encodes two heme oxygenases, IsdI and IsdG, which cleave the porphyrin heme ring releasing iron for use as a nutrient source. Both isdI and isdG are only expressed under low iron conditions and are regulated by the canonical Ferric Uptake Regulator (Fur). Here we demonstrate that unregulated expression of isdI and isdG within S. aureus leads to reduced growth under low iron conditions. Additionally, the constitutive expression of these enzymes leads to decreased heme abundance in S. aureus, an increase in the fermentation product lactate, and increased resistance to gentamicin. This work demonstrates that S. aureus has developed tuning mechanisms, such as Fur regulation, to ensure that the cell has sufficient quantities of heme for efficient ATP production through aerobic respiration. PMID- 29409697 TI - Heterologous expression, purification and characterization of human beta-1,2-N acetylglucosaminyltransferase II using a silkworm-based Bombyx mori nucleopolyhedrovirus bacmid expression system. AB - beta-1,2-N-Acetylglucosaminyltransferase II (GnTII, EC 2.4.1.143) is a Golgi localized type II transmembrane enzyme that catalyzes the transfer of N acetylglucosamine to the 6-arm of the trimanosyl core of N-glycans, an essential step in the conversion of oligomannose-type to complex-type N-glycans. Despite its physiological importance, there have been only a few reports on the heterologous expression and structure-function relationship of this enzyme. Here, we constructed a silkworm-based Bombyx mori nucleopolyhedrovirus bacmid expression system and expressed human GnTII (hGnTII) lacking the N-terminal cytosolic tail and transmembrane region. The recombinant hGnTII was purified from silkworm larval hemolymph in two steps by using tandem affinity purification tags, with a yield of approximately 120 MUg from 10 mL hemolymph, and exhibited glycosyltransferase activity and strict substrate specificity. The enzyme was found to be N-glycosylated by the enzymatic cleavage of glycans, while hGnTII expressed in insect cells had not been reported to be glycosylated. Although insects typically produce pauci-mannosidic-type glycans, the structure of N glycans in the recombinant hGnTII was suggested to be of the complex type, and the removal of the glycans did not affect the enzymatic activity. PMID- 29409698 TI - Determination of trigger levels for groundwater quality in landfills located in historically human-impacted areas. AB - Landfills are one of the most recurrent sources of groundwater contamination worldwide. In order to limit their impacts on groundwater resources, current environmental regulations impose the adoption of proper measures for the protection of groundwater quality. For instance, in the EU member countries, the calculation of trigger levels for identifying significant adverse environmental effects on groundwater generated by landfills is required by the Landfill Directive 99/31/EC. Although the derivation of trigger levels could be relatively easy when groundwater quality data prior to the construction of a landfill are available, it becomes challenging when these data are missing and landfills are located in areas that are already impacted by historical contamination. This work presents a methodology for calculating trigger levels for groundwater quality in landfills located in areas where historical contaminations have deteriorated groundwater quality prior to their construction. This method is based on multivariate statistical analysis and involves 4 steps: (a) implementation of the conceptual model, (b) landfill monitoring data collection, (c) hydrochemical data clustering and (d) calculation of the trigger levels. The proposed methodology was applied on a case study in northern Italy, where a currently used lined landfill is located downstream of an old unlined landfill and others old unmapped waste deposits. The developed conceptual model stated that groundwater quality deterioration observed downstream of the lined landfill is due to a degrading leachate plume fed by the upgradient unlined landfill. The methodology led to the determination of two trigger levels for COD and NH4-N, the former for a zone representing the background hydrochemistry (28 and 9 mg/L for COD and NH4-N, respectively), the latter for the zone impacted by the degrading leachate plume from the upgradient unlined landfill (89 and 83 mg/L for COD and NH4-N, respectively). PMID- 29409699 TI - Calcium Dynamics as a Machine for Decoding Signals. AB - Calcium (Ca2+) is considered one of the most-important biological cations, because it is implicated in cell physiopathology and cell fate through a finely tuned signaling system. In support of this notion, Ca2+ is the primary driver of cell proliferation and cell growth; however, it is also intimately linked to cell death. Functional abnormalities or mutations in proteins that mediate Ca2+ homeostasis usually lead to a plethora of diseases and pathogenic states, including cancer, heart failure, diabetes, and neurodegenerative disease. In this review, we examine recent discoveries in the highly localized nature of Ca2+ dependent signal transduction and its roles in cell fate, inflammasome activation, and synaptic transmission. PMID- 29409700 TI - Commentary on "An Updated Systematic Review and Meta-analysis of Outcomes Following Eversion vs. Conventional Carotid Endarterectomy in Randomised Controlled Trials and Observational Studies". PMID- 29409701 TI - Aortoiliac Dissection After Blunt Abdominal Trauma. PMID- 29409702 TI - Telangiectatic Matting is Associated with Hypersensitivity and a Bleeding Tendency. AB - OBJECTIVE: The aim was to investigate the pathogenesis of telangiectatic matting (TM) and identify possible risk factors. METHODS: This study had two parts. The clinical records of consecutive patients were retrospectively analysed to identify risk factors for TM. In the second part, the haemostatic and coagulation profile of the subset of patients with TM were analysed and compared with controls using standard coagulation tests, platelet function and a global assay of coagulation (rotational thromboelastometry, ROTEM). RESULTS: In 352 consecutive patients presenting to a phlebology practice, 25 patients had TM (7.1%). All 25 patients were female with the median age of 45 (27-57) years. A comprehensive medical history was taken. Among 27 possible risk factors assessed, statistically significant associations included recurrent epistaxis, easy bruising, hypersensitivity (eczema, hives, hay fever, and rhinitis), previous treatment with sclerotherapy or endovenous laser for lower limb veins, and a family history of telangiectasias. Variables not associated with TM included oral contraceptive intake, hormone replacement therapy, and age. The haemostatic and coagulation profile of 12 patients (6 male and 6 female) with TM did not differ significantly from those without TM. CONCLUSION: TM is associated with both hypersensitivity and a bleeding tendency. This study revealed no significant increase in the incidence of haemostatic abnormalities in patients with TM compared with the control group. Given the significant association with hypersensitivity disorders, the underlying mast cell hyper-reactivity may contribute to both hypersensitivity and a bleeding tendency and predispose patients to TM. PMID- 29409703 TI - Advancements of two dimensional correlation spectroscopy in protein researches. AB - The developments of two-dimensional correlation spectroscopy (2DCOS) applications in protein studies are discussed, especially for the past two decades. The powerful utilities of 2DCOS combined with various analytical techniques in protein studies are summarized. The emphasis is on the vibration spectroscopic techniques including IR, NIR, Raman and optical activity (ROA), as well as vibration circular dichroism (VCD) and fluorescence spectroscopy. In addition, some new developments, such as hetero-spectral 2DCOS, moving-window correlation, and model based correlation, are also reviewed for their utility in the investigation of the secondary structure, denaturation, folding and unfolding changes of protein. Finally, the new possibility and challenges of 2DCOS in protein research are highlighted as well. PMID- 29409704 TI - Evolution of cerebrospinal fluid total alpha-synuclein in Parkinson's disease. AB - INTRODUCTION: Cerebrospinal fluid (CSF) total alpha-synuclein is considered a potential biomarker for Parkinson's disease (PD), but little is known about the evolution of this marker during the course of the disease. Our objective was to investigate whether CSF total alpha-synuclein concentrations change over time and are associated with motor and cognitive function in PD. METHODS: CSF total alpha synuclein concentrations were quantified in 56 longitudinally followed PD patients, 27 of whom provided CSF repeatedly 2 and/or 4 years later. Another 18 subjects were included as controls. The samples were analyzed using two independent, validated ELISA methods: our recently developed and validated in house ELISA and a commercial kit from BioLegend. RESULTS: CSF total alpha synuclein levels did not distinguish PD patients from controls, displayed no substantial changes during a period of up to 4 years, and did not predict subsequent motor or cognitive decline. These findings were consistent for both analytical methods. CONCLUSION: Our findings do not support the clinical utility of total alpha-synuclein as a single diagnostic or prognostic biomarker in PD. PMID- 29409706 TI - Blocking Ras inhibition as an antitumor strategy. AB - Ras proteins are among the most frequently mutated drivers in human cancer and remain an elusive pharmaceutical targeting. Previous studies have improved the understanding of Ras structure, processing, and signaling pathways in cancer cells and have opened new possibilities for inhibiting Ras function. In this review we discuss the most recent advances towards inhibiting Ras activity with small molecules, highlighting the two approaches: (i) compounds that bind directly to Ras protein and (ii) inhibitors of the enzymes involved in the post translational modifications of Ras. In the former, we analyze the most recent contributions in each of the main classes of Ras direct binders, including the different types of nucleotide exchange inhibitors, allosteric compounds, and molecules that interfere with the interaction between Ras and its effectors. In the latter, we examine the compounds that inhibit Ras activation by blocking any of its post-translational modifications. Also, a special focus is made on those molecules that have progressed the farthest from medicinal chemistry and drug development points of view. Finally, the current scene regarding the clinical trials of Ras inhibitors, together with the future promising avenues for further development of the challenging Ras field are reviewed. PMID- 29409705 TI - Genetic status of KRAS influences Transforming Growth Factor-beta (TGF-beta) signaling: An insight into Neuropilin-1 (NRP1) mediated tumorigenesis. AB - Oncogenic RAS and deregulated transforming growth factor-beta (TGF)-beta signaling have been implicated in several cancers. So far, attempts to target either one of them therapeutically have been futile as both of them are involved in multiple fundamental cellular processes and the normal forms are expressed by almost all cells. Hence, their inhibition would disrupt several physiological processes. Besides, their downregulation stimulates the tumor cells to develop adaptive mechanisms and would most likely be ineffective as therapeutic targets. Furthermore, growing literature suggests that both of these signaling pathways converge to enhance tumor development. Therefore, a lot of interest has been generated to explore the areas where these pathways interface that might identify new molecules that could potentially serve as novel therapeutic targets. In this review, we focus on such convergent signaling and cross-interaction that is mediated by neuropilin-1 (NRP1), a receptor that can interact with multiple growth factors including TGF-beta for promoting tumorigenesis process. PMID- 29409707 TI - Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment. AB - A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Abeta1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Abeta1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD. PMID- 29409708 TI - Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic tetrasaccharide as a high-affinity FGF-2 and midkine ligand. AB - Here, we present the preparation of a sulfated, fully protected tetrasaccharide derivative following the glycosaminoglycan (GAG)-related sequence GlcNAc-beta(1 > 4)-Glc-beta(1 -> 3). The tetramer was efficiently assembled via an iterative glycosylation strategy using monosaccharide building blocks. A fluorous tag was attached at position 6 of the reducing end unit enabling the purification of reaction intermediates by simple fluorous solid phase extraction. Fluorescence polarization competition experiments revealed that the synthesized tetrasaccharide strongly interacts with two heparin-binding growth factors, midkine and FGF-2 (IC50 of 270 nM and 2.4 uM, respectively). Our data indicate that this type of oligosaccharide derivatives, displaying sulfates, hydrophobic protecting groups and a fluorinated tail can be considered as interesting GAG mimetics for the regulation of relevant carbohydrate-protein interactions. PMID- 29409709 TI - Systolic Anterior Motion of the Mitral Valve Causing Dynamic Left Ventricular Outflow Tract Obstruction: An Underappreciated Complication During Lung Transplantation. PMID- 29409710 TI - Anesthetic Management of a Crossbow Bolt Injury to the Heart. PMID- 29409711 TI - Phosphocreatine in Cardiac Surgery Patients: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: There is experimental evidence that phosphocreatine (PCr) can decrease ischemia/reperfusion injury of the heart. The authors investigated if PCr would improve heart performance as compared with standard treatment in cardiac surgery. DESIGN: Meta-analysis of randomized controlled trials. SETTING: Hospitals. PARTICIPANTS: Adult and pediatric patients undergoing cardiac surgery. INTERVENTIONS: The ability of PCr to improve cardiac outcomes as compared with standard treatment was investigated. MEASUREMENTS AND MAIN RESULTS: PubMed/Medline, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, WANGFANG DATA, and VIP Paper Check System were searched to March 1 2017. The authors included 26 randomized controlled trials comprising 1,948 patients. Random and fixed-effects models were used to estimate odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI). PCr use was associated with reduced rates of intraoperative inotropic support (27% v 44%; OR 0.47, 95% CI 0.35-0.61; p < 0.001), major arrhythmias (16% v 28%; OR 0.44, 95% CI 0.27-0.69; p < 0.001), as well as increased spontaneous recovery of the cardiac rhythm immediately after aortic declamping (50% v 34%; OR 2.45, 95% CI 1.82-3.30; p < 0.001) as compared with standard treatment. The use of PCr decreased myocardial damage and augmented left ventricular ejection fraction in the postoperative period; however, MD for these outcomes were small and do not seem to be clinically significant. CONCLUSIONS: In randomized trials, PCr administration was associated with reduced rates of intraoperative inotropic support and major arrhythmias, and increased spontaneous recovery of the cardiac rhythm after aortic declamping. Large multicenter evidence is needed to validate these findings. PMID- 29409712 TI - Squeezing Flux Out of Fat. AB - Merging transcriptomics or metabolomics data remains insufficient for metabolic flux estimation. Ramirez et al. integrate a genome-scale metabolic model with extracellular flux data to predict and validate metabolic differences between white and brown adipose tissue. This method allows both metabolic phenotyping and the identification of potential therapeutic targets for obesity. PMID- 29409714 TI - Reply to "is it significant? Is it relevant?" PMID- 29409713 TI - Bilirubin in the Liver-Gut Signaling Axis. AB - Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes. PMID- 29409715 TI - Hydration-dependent dynamics of water in calcium-silicate-hydrate: A QENS study by global model. AB - HYPOTHESIS: In a saturated cement paste, there are three different types of water: the structural water chemically reacted with cement, the constrained water absorbed to the surface of the pores, and the free water in the center of the pores. Each type has different physicochemical state and unique relation to cement porosity. The different water types have different dynamics which can be detected using quasi-elastic neutron scattering (QENS). Since the porosity of a hardened cement paste is impacted strongly by the water to cement ratio (w/c), it should be possible to extract the hydration dependence of the pores by exploiting the dynamical parameters of the confined water. EXPERIMENTS: Three C-S-H samples with different water levels, 8%, 17% and 30% were measured using QENS. The measurements were carried out in the scattering vector, Q, range from 0.5 A-1 to 1.3 A-1, and in the temperature interval from 230 K to 280 K. The data were analyzed using a novel global model developed for cement QENS spectra. FINDINGS: The results show that while increasing the water content, the structural water index (SWI) decreases and the confining radius, a, increases. Both SWI and a have a linear relationship with the water content. The Arrhenius plot of the translational relaxation time shows that the constrained water dominates the non structural water at water contents lower than 17%. The rotational activation energy is smaller for lower water content. The analysis demonstrated that our newly proposed global model is practical and useful for analyzing cement QENS data. PMID- 29409716 TI - Efficient deep learning model for mitosis detection using breast histopathology images. AB - Mitosis detection is one of the critical factors of cancer prognosis, carrying significant diagnostic information required for breast cancer grading. It provides vital clues to estimate the aggressiveness and the proliferation rate of the tumour. The manual mitosis quantification from whole slide images is a very labor-intensive and challenging task. The aim of this study is to propose a supervised model to detect mitosis signature from breast histopathology WSI images. The model has been designed using deep learning architecture with handcrafted features. We used handcrafted features issued from previous medical challenges MITOS @ ICPR 2012, AMIDA-13 and projects (MICO ANR TecSan) expertise. The deep learning architecture mainly consists of five convolution layers, four max-pooling layers, four rectified linear units (ReLU), and two fully connected layers. ReLU has been used after each convolution layer as an activation function. Dropout layer has been included after first fully connected layer to avoid overfitting. Handcrafted features mainly consist of morphological, textural and intensity features. The proposed architecture has shown to have an improved 92% precision, 88% recall and 90% F-score. Prospectively, the proposed model will be very beneficial in routine exam, providing pathologists with efficient and - as we will prove - effective second opinion for breast cancer grading from whole slide images. Last but not the least, this model could lead junior and senior pathologists, as medical researchers, to a superior understanding and evaluation of breast cancer stage and genesis. PMID- 29409717 TI - Comparison of invasively measured FFR with FFR derived from coronary CT angiography for detection of lesion-specific ischemia: Results from a PC-based prototype algorithm. AB - BACKGROUND: We evaluated the diagnostic accuracy of a novel prototype for on-site determination of CT-based FFR (cFFR) on a standard personal computer (PC) compared to invasively measured FFR in patients with suspected coronary artery disease. METHODS: A total of 91 vessels in 71 patients (mean age 65 +/- 9 years) in whom coronary CT angiography had been performed due to suspicion of coronary artery disease, and who subsequently underwent invasive coronary angiography with FFR measurement were analyzed. For both cFFR and FFR, a threshold of <=0.80 was used to indicate a hemodynamically relevant stenosis. The mean time needed to calculate cFFR was 12.4 +/- 3.4 min. A very close correlation between cFFR and FFR could be shown (r = 0.85; p < 0.0001) with Bland-Altman analysis showing moderate agreement between FFR and cFFR with mild systematic overestimation of FFR values in CT (mean difference 0.0049, 95% limits of agreement +/-2SD -0.007 to 0.008). Compared to FFR, the sensitivity of cFFR to detect hemodynamically significant lesions was 91% (19/21, 95% CI: 70%-99%), specificity was 96% (67/70, 95% CI: 88%-99%), positive predictive value 86% (95% CI: 65%-97%) and negative predictive value was 97% (95% CI: 90%-100%) with an accuracy of 93%. CONCLUSION: cFFR obtained using an on-site algorithm implemented on a standard PC shows high diagnostic accuracy to detect lesions causing ischemia as compared to FFR. Importantly, the time needed for analysis is short which may be useful for improving clinical workflow. PMID- 29409718 TI - Transient influence of blood meal and natural environment on blacklegged tick bacterial communities. AB - Blacklegged ticks (Ixodes scapularis) spend the majority of their life cycle off host, typically in woodland habitat, but require a blood meal at each of three life stages (larva, nymph, adult) to reach maturity and reproduce. Blood feeding usually lasts for several days each time and as blood is imbibed, a range of known pathogens from the host may also be acquired. Using next generation sequencing of 16S rRNA gene amplicons, we examined the influence of host blood meal on the internal bacterial community within nymphal blacklegged ticks across host-seeking, feeding, blood meal digestion, and after molting into the adult stage. Results demonstrate bacterial community structuring across host and ticks with 287 taxa found exclusively in ticks, suggesting the field environment plays a significant role in shaping the internal tick microbiome. A decrease in bacterial diversity was noted from unfed nymphs through feeding/digestion and after molting into adults, suggesting that bacterial species are lost during the corresponding physiological changes. The similarity in biochemical pathways across the different tick categories suggests that the loss of bacterial taxa does not mirror a large change in microbial function. Ticks likely lose bacterial taxa after feeding, but continual exposure to bacteria from the field environment counters this loss. PMID- 29409720 TI - Automated cortical auditory evoked potentials threshold estimation in neonates. AB - INTRODUCTION: The evaluation of Cortical Auditory Evoked Potential has been the focus of scientific studies in infants. Some authors have reported that automated response detection is effective in exploring these potentials in infants, but few have reported their efficacy in the search for thresholds. OBJECTIVE: To analyze the latency, amplitude and thresholds of Cortical Auditory Evoked Potential using an automatic response detection device in a neonatal population. METHODS: This is a cross-sectional, observational study. Cortical Auditory Evoked Potentials were recorded in response to pure-tone stimuli of the frequencies 500, 1000, 2000 and 4000Hz presented in an intensity range between 0 and 80dB HL using a single channel recording. P1 was performed in an exclusively automated fashion, using Hotelling's T2 statistical test. The latency and amplitude were obtained manually by three examiners. The study comprised 39 neonates up to 28 days old of both sexes with presence of otoacoustic emissions and no risk factors for hearing loss. RESULTS: With the protocol used, Cortical Auditory Evoked Potential responses were detected in all subjects at high intensity and thresholds. The mean thresholds were 24.8+/-10.4dB NA, 25+/-9.0dB NA, 28+/-7.8dB NA and 29.4+/ 6.6dB HL for 500, 1000, 2000 and 4000Hz, respectively. CONCLUSION: Reliable responses were obtained in the assessment of cortical auditory potentials in the neonates assessed with a device for automatic response detection. PMID- 29409719 TI - Comparison of heat shock protein 70 kDa and 18S rDNA genes for molecular detection and phylogenetic analysis of Babesia vogeli from whole blood of naturally infected dogs. AB - A total of 300 blood samples of domiciliated dogs in rural and urban areas of southeast Rio de Janeiro State, Brazil, were used to compare the 18S ribosomal DNA region (18S rDNA) and the heat shock protein 70 kDa (hsp70) gene for molecular detection of Babesia vogeli and to perform a phylogenetic study comparing the two genes for B. vogeli classification. Using conventional polymerase chain reaction (cPCR) of 18S rDNA and hsp70 sequences, we were able to detect B. vogeli with the same sensitivity (96.15%) and specificity (99.63%). However, sequencing revealed one false positive (Rangelia sp.) for 18S rDNA that was not detected by hsp70. This is the first report of an organism closely related to the Rangelia vitalii parasite of dogs in Brazil. In the hsp70-cPCR and hsp70-qPCR comparison, 15.66% of samples were considered positive by quantitative (q)PCR, significantly more than was detected by cPCR (8.66%). In addition to the high conservation of the 18S rDNA, phylogenetic analysis showed that the hsp70 gene can be used to describe phylogenetic relationships between canine piroplasmids with more accuracy than 18S rDNA. According to these findings, the qPCR method has greater sensitivity than cPCR for detection of B. vogeli in naturally infected dogs. The hsp70-qPCR detection limit was 10 copies, with an efficiency of 100.30% and a determination coefficient (R2) of 0.998. The development of this qPCR method provides a highly sensitive approach for B. vogeli molecular detection and a tool that is capable of quantifying parasitemia levels in whole blood samples from dogs. The primers and probes were designed to be specific for B. vogeli, though analytical specificity of the assay has not been tested in vitro with DNA of certain Babesia species that infect dogs. The hsp70 gene is a precise molecular marker for Babesia phylogeny, especially species that infect dogs. PMID- 29409721 TI - The Chronic Knee Pain Program: A self-management model. AB - BACKGROUND: It is vital that patients take an active role in self-management of their chronic knee pain condition. The Chronic Knee Pain Program was developed to assist patients in managing their chronic condition and to improve their overall well-being. PURPOSE: The purpose of this pilot study was to determine the feasibility of a six-week self-management program and to explore whether it may assist in decreasing body mass index (BMI) and depression symptom severity and increase physical activity levels in obese adults with chronic knee pain. DESIGN: A one group, pre-test/post-test pilot study. SETTING: A pain management clinic in the northeastern United States. SAMPLE: Convenience sample of twelve adult patients with chronic knee pain and a BMI of 30 or greater were recruited, however, six participants completed the full program. RESULTS: This type of intervention has potential value to improve the lifestyles of those individuals with chronic knee pain, including improvements in BMI, depression symptom severity and physical activity levels. In this study there was a decrease in mean BMI overtime; 41.2 (at week 1), 40.8 (at week 6), and 40.7 (at week 10). CONCLUSIONS: The Chronic Knee Pain Program had a small sample size and high attrition rate, though yielded positive outcomes for some participants. Future research could focus on depression management, using conservative measures to help manage pain, and increasing pain coping skills. Implementing this program with a larger sample size is recommended to see if BMI, depression symptom severity and physical activity levels reach statistical significance. PMID- 29409722 TI - Smoking behaviors of adults with developmental disabilities and their direct support professional providers. AB - BACKGROUND: People with developmental disabilities are not immune from the addictive effects and poor health outcomes associated with cigarette use. Direct support professionals often play a large role in the social environments of people with developmental disabilities and the literature suggests that one's environment can influence behavior. OBJECTIVES: To examine the relationship between the smoking behaviors of people with developmental disabilities and their direct support professional providers. Two exploratory aims of the study were to assess how direct support professionals facilitate smoking behaviors and to describe the use of home smoking policies. METHODS: The Ohio Department of Disabilities' online provider search database was used to randomly select participants. A total of 398 direct support professionals completed an online survey about smoking. Direct support professionals served as proxy reporters for the smoking behaviors of those with developmental disabilities. Descriptive statistics were calculated and Chi-Square tests were used. RESULTS: Findings suggest that there was no significant relationship (chi12 = 0.300, p = 0.584) between the current smoking behaviors of people with developmental disabilities and their direct support providers. Direct support professionals were most likely to facilitate smoking behaviors by allowing people with developmental disabilities to smoke in front of them and waiting for them to finish smoking before moving on to a new activity. Approximately 46% of people with developmental disabilities were reported to have some type of home smoking policy. CONCLUSIONS: Future research is needed to better understand the reasons why people with developmental disabilities initially start smoking and continue to smoke. PMID- 29409723 TI - CaMKII in Vascular Signalling: "Friend or Foe"? AB - Signalling mechanisms within and between cells of the vasculature enable function and maintain homeostasis. However, a number of these mechanisms also contribute to the pathophysiology of vascular disease states. The multifunctional signalling molecule calcium/calmodulin-dependent kinase II (CaMKII) has been shown to have critical functional effects in many tissue types. For example, CaMKII is known to have a dual role in cardiac physiology and pathology. The function of CaMKII within the vasculature is incompletely understood, but emerging evidence points to potential physiological and pathological roles. This review discusses the evidence for CaMKII signalling within the vasculature, with the aim to better understand both positive and potentially deleterious effects of CaMKII activation in vascular tissue. PMID- 29409724 TI - Survival After MI in a Community Cohort Study: Contribution of Comorbidities in NSTEMI. AB - BACKGROUND: Non-ST-segment elevation myocardial infarction (NSTEMI) comprises the majority of MI worldwide, yet mortality remains high. Management of NSTEMI is relatively delayed and heterogeneous compared with the "time is muscle" approach to ST-segment elevation MI, though it is unknown to what extent comorbid conditions drive NSTEMI mortality. OBJECTIVES: We sought to quantify mortality due to MI versus comorbid conditions in patients with NSTEMI. METHODS: Participants of the ARIC (Atherosclerosis Risk in Communities) study cohort ages 45 to 64 years, who developed incident NSTEMI were identified and incidence density matched to participants who did not experience an MI by age group, sex, race, and study community. We estimated hazard ratios for all-cause mortality, comparing those who developed NSTEMI to those who did not experience an MI. RESULTS: ARIC participants with incident NSTEMI were more likely at baseline to be smokers, have diabetes and renal dysfunction, and take blood pressure or cholesterol-lowering medications than were participants who did not have an MI. Over one-half of participants experiencing NSTEMI died over a median follow-up of 8.4 years; incident NSTEMI was associated with 30% higher risk of mortality after adjusting for comorbid conditions (hazard ratio: 1.30; 95% confidence interval: 1.11 to 1.53). CONCLUSIONS: NSTEMI confers a significantly higher mortality hazard beyond what can be attributed to comorbid conditions. More consistent and effective strategies are needed to reduce mortality in NSTEMI amid comorbid conditions. PMID- 29409725 TI - Treatment of rheumatoid arthritis with biologic agents lowers the risk of incident chronic kidney disease. AB - Rheumatoid arthritis is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. However, little is known about the effects of using the newer novel non-nephrotoxic biologic agents on the risk of incident chronic kidney disease (CKD). To study this we used a cohort of 20,757 United States veterans diagnosed with rheumatoid arthritis with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m2 or more, recruited between October 2004 and September 2006, and followed through 2013. The associations of biologic use with incident CKD (eGFR under 60 with a decrease of at least 25% from baseline, and eGFR under 45 mL/min/1.73m2) and change in eGFR (<-3, -3 to <0 [reference], and >=0 mL/min/1.73m2/year) were examined in propensity-matched patients based on their likelihood to initiate biologic treatment, using Cox models and multinomial logistic regression models, respectively. Among 20,757 patients, 4,617 started biologic therapy. In the propensity-matched cohort, patients treated (versus not treated) with biologic agents had a lower risk of incident CKD (hazard ratios 0.95, 95% confidence interval [0.82-1.10] and 0.71 [0.53-0.94] for decrease in eGFR under 60 and under 45 mL/min/1.73m2, respectively) and progressive eGFR decline (multinomial odds ratios [95% CI] for eGFR slopes <-3 and >=0 [versus -3 to <0] mL/min/1.73m2/year, 0.67 [0.58-0.79] and 0.76 [0.69-0.83], respectively). A significant deceleration of eGFR decline was also observed after biologic administration in patients treated with biologics (-1.0 versus -0.4 [mL/min/1.73m2/year] before and after biologic use). Thus, biologic agent administration was independently associated with lower risk of incident CKD and progressive eGFR decline. PMID- 29409726 TI - Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. AB - Excessive expression of Tbet and IFNgamma is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall proinflammatory microenvironment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases. PMID- 29409727 TI - Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family. AB - Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A>C [p.Ile154Leu], c.541G>A [p.Ala181Thr], c.2036G>C [p.Arg679Pro] and c.2059A>G [p.Lys687Glu]) result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of gammaA3-PCDH and gammaA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading. PMID- 29409729 TI - Acquired amegakaryocytic thrombocytopenia and red cell aplasia in a patient with thymoma progressing to aplastic anemia successfully treated with allogenic stem cell transplantation. AB - Association of pure red-cell aplasia with thymoma is well documented. However, acquired amegakaryocytic thrombocytopenia (AAMT) has been rarely associated with thymoma with only five reported cases in literature. We report a patient with thymoma complicated by pure red cell aplasia (PRCA) and AAMT who progressed to develop aplastic anemia (AA). The patient was refractory to 10-months of immunosuppressive therapy with cyclosporine, prednisone, and antithymocyte globulin. She was eventually treated with allogeneic stem cell transplantation (allo-SCT). On Day +323 the patient continues to be transfusion-independent. This case illustrates how in patients with thymoma and AAMT may herald development of AA. This is also the first report of a patient with AAMT progressing to thymoma associated AA being successfully treated with allo-SCT. The successful outcome suggests allo-SCT as a feasible option similar to other AA patients. PMID- 29409728 TI - Relations of GlycA and lipoprotein particle subspecies with cardiovascular events and mortality: A post hoc analysis of the AIM-HIGH trial. AB - BACKGROUND: The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial showed no incremental benefit of extended-release niacin (ERN) therapy added to simvastatin in subjects with cardiovascular disease (CVD). OBJECTIVES: To examine the effects of ERN treatment on lipoprotein particles and GlycA, a new marker of systemic inflammation, and their relations with incident CVD events including mortality. METHODS: GlycA and very low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle subclasses were quantified by nuclear magnetic resonance spectroscopy using available stored baseline (n = 2754) and 1 year in-trial (n = 2581) samples. Associations with CVD events and all-cause mortality were assessed using multivariable Cox proportional hazards regression adjusted for age, sex, diabetes, treatment assignment, and lipoproteins. RESULTS: Compared to placebo, ERN treatment lowered very low-density lipoprotein and LDL and increased HDL particle concentrations, increased LDL and HDL particle sizes (all P < .0001), but did not affect GlycA. Baseline and in-trial GlycA levels were associated with increased risk of CVD events: hazard ratio (HR) per SD increment, 1.17 (95% confidence interval [CI], 1.06-1.28) and 1.13 (1.02-1.26), respectively. However, none of the lipoprotein particle classes or subclasses was associated with incident CVD. By contrast, all-cause mortality was significantly associated with both GlycA (baseline HR: 1.46 [1.22-1.75]; in-trial HR: 1.41 [1.24-1.60]) and low levels of small HDL particles (baseline HR: 0.69 [0.56 0.86]; in-trial HR: 0.69 [0.56-0.86]). CONCLUSIONS: This Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial post hoc substudy indicates that inflammation, as indexed by GlycA, is unaffected by ERN treatment but is significantly associated with the residual risk of CVD and death in patients treated to low levels of LDL cholesterol. PMID- 29409730 TI - Incidence of filled antidepressant prescriptions among people with newly diagnosed diabetes and its interaction with occupational status within the working population of Denmark 1996-2010. AB - AIMS: People with diabetes have heightened levels of depressive symptoms, but less is known about the development of these symptoms in relation to diabetes duration. In this study, we examined the use of prescribed antidepressants in the first five years after diagnosis of diabetes among the working-age population in Denmark. METHODS: All Danish adults aged 18-54 years, diagnosed with diabetes in the study period were included. Diabetes status and purchase of prescription antidepressants were obtained from validated population registers. Data analysis focused on filled antidepressant prescriptions at <=1 and <=5years from diagnosis with diabetes. RESULTS: 35,677 people diagnosed with diabetes were included in the study. At <=1 year post-diagnosis, 2.6% had filled antidepressant prescriptions. At <=5years, this figure rose to 10.4%. Overall, both female gender and lower socioeconomic status were associated with higher incidence of filled antidepressant prescriptions. Diabetes duration modified the degree of differences between men and women and socioeconomic strata. CONCLUSION: Diagnosis with diabetes immediately impacts mental wellbeing, with higher rates of filled antidepressant prescriptions in the first year after diagnosis. People of working age diagnosed with diabetes face specific challenges and addressing such challenges would enhance patient experiences. Focus on mental health in the clinical encounter with people newly diagnosed with diabetes is warranted and important. PMID- 29409731 TI - Comparison between open and laparoscopic gastrectomy for gastric cancer: A monocentric retrospective study from a western country. AB - BACKGROUND: The majority of laparoscopic gastrectomy (LG) reports arise from Asia and the benefit of this approach in western countries remains unclear. The objective of this study was to compare the postoperative outcomes between LG and open gastrectomy (OG) for gastric cancer in a western center. METHODS: Between 2005 and 2015, all consecutive patients with gastric cancer who underwent either LG or OG were enrolled. Postoperative morbimortality was evaluated according to Dindo-Clavien classification. RESULTS: Over 164 patients, 60 had LG and 104 OG with a mean age of 62 and 65 years, respectively. Total gastrectomy represented 58% of LG and 54% of OG (P=0.749). Operative time was not different in the two groups (160.8 vs. 174.2min, P=0.780) so as intraoperative blood loss (111 vs. 173mL, P=0.057). The rate of severe complications (including postoperative bleeding) was significantly higher in the LG group (40% vs. 23%, P=0.012) so as reoperation rate (27% vs. 6%, P<0.001). There was no statistical difference in terms of postoperative mortality (0 vs. 3%, P=0.252) or length of hospital stay (20 vs. 16 days, P=0.116). CONCLUSION: Laparoscopic gastrectomy for the treatment of gastric cancer in western countries appears to be feasible but with a higher rate of severe complications compared to open gastrectomy. PMID- 29409732 TI - Application of n-dodecane as an oxygen vector to enhance the activity of fumarase in recombinant Escherichia coli: role of intracellular microenvironment. AB - The effect of the intracellular microenvironment in the presence of an oxygen vector during expression of a fusion protein in Escherichia coli was studied. Three organic solutions at different concentration were chosen as oxygen vectors for fumarase expression. The addition of n-dodecane did not induce a significant change in the expression of fumarase, while the activity of fumarase increased significantly to 124% at 2.5% n-dodecane added after 9h induction. The concentration of ATP increased sharply during the first 6h of induction, to a value 7600% higher than that in the absence of an oxygen-vector. NAD/NADH and NADP/NADPH ratios were positively correlated with fumarase activity. n-Dodecane can be used to increase the concentration of ATP and change the energy metabolic pathway, providing sufficient energy for fumarase folding. PMID- 29409733 TI - Nutrition and Bone Density in Boys with Autism Spectrum Disorder. AB - BACKGROUND: Boys with autism spectrum disorder (ASD) have lower bone mineral density (BMD) than typically developing controls. Differences in diet and exercise may contribute to low BMD. OBJECTIVE: Our aim was to examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC and the relationship of these variables with BMD. DESIGN/METHODS: We conducted a cross-sectional study of 49 boys (25 ASD, 24 typically developing controls) assessed for 3-day food records and physical activity records, and BMD of the whole body less head, hip, and spine using dual-energy x-ray absorptiometry. Fasting levels of 25(OH) vitamin D and calcium were obtained. PARTICIPANTS: Participants were adolescent boys, aged 8 to 17 years, recruited from a clinic population (ASD) or community advertisements (ASD and typically developing controls) matched for age. RESULTS: ASD participants were approximately 9 months younger than typically developing control participants on average. Body mass index and serum vitamin D and calcium levels were similar. Boys with ASD consumed 16% fewer calories, with a larger percentage obtained from carbohydrates, and 37% less animal protein and 20% less fat than typically developing controls. A lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P<0.001). BMD z scores were 0.7 to 1.2 standard deviations lower in ASD than typically developing controls at all locations. Higher animal protein, calcium, and phosphorus intakes were associated positively with bone density measures in boys with ASD. CONCLUSIONS: Compared to typically developing controls, boys with ASD had lower protein, calcium, and phosphorus intakes, activity levels, and BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head. Protein, calcium, and phosphorus intakes were associated positively with BMD. PMID- 29409734 TI - Development and psychometric properties of the stressor scale for emergency nurses. AB - INTRODUCTION: Emergency department nurses are exposed to specific stressors and report higher stress levels than nurses in other hospital departments. This study aimed to develop and test the psychometric properties of a questionnaire-based instrument for identifying stressors for emergency department nurses. METHODS: The instrument's content and face validities were examined by five experts and nurses in emergency nursing field. The test-retest reliability was examined on 30 emergency department nurses. The construct validity, including an exploratory and a confirmatory factor analysis, was tested on 405 emergency department nurses. Cronbach's alpha values and intra-class coefficients were calculated. RESULTS: The instrument's content and face validities were satisfactory. The exploratory factor analysis provided a five-factor solution, whereas the confirmatory factor analysis provided a final four-factor solution with 25 items distributed among the factors Life and death situations, Patients' and families' actions and reactions, Technical and formal support, and Conflicts. The Cronbach's alpha values ranged from 0.89 to 0.93 per factor, and the intra-class correlation coefficient was 0.89, indicating good homogeneity and stability. CONCLUSIONS: The instrument's content, face, and construct validities were satisfactory, and the internal consistency and test-retest reliability were good. This instrument can be useful in the management of emergency departments. PMID- 29409735 TI - Population analysis of 27 Y-chromosomal STRs in the Li ethnic minority from Hainan province, southernmost China. PMID- 29409737 TI - Impact of a classroom standing desk intervention on daily objectively measured sedentary behavior and physical activity in youth. AB - OBJECTIVES: We investigated the impact of a standing desk intervention on daily objectively monitored sedentary behavior and physical activity in 6th grade school students. DESIGN: Cluster non-randomised controlled trial. METHOD: Two classes (intervention students: n=22 [aged 11.8+/-0.4years]; control students: n=27 [11.6+/-0.5years]) from a public school in Lisbon were selected. The intervention involved replacing traditional seated classroom desks for standing desks, for a total duration of 16 weeks, in addition to performing teacher training and holding education/motivation sessions with students and parents. Sedentary behavior (ActivPAL inclinometer) and physical activity (Actigraph GT3X+ accelerometer) were measured for seven days immediately before and after the intervention. RESULTS: There were no differences in baseline behaviors between intervention and control groups (p>0.05). At follow-up (16 weeks), it was observed that the intervention group had decreased time spent sitting (total week: -6.8% and at school: -13.0% relative to baseline) and increased standing (total week: 16.5% and at school: 31.0%) based on inclinometer values (p-value for interaction group*time <0.05). No significant differences in activity outcomes were observed outside school time (week or weekend) between groups. CONCLUSION: We conclude that a 16 week classroom standing desk intervention successfully reduced sitting time and increase standing time at school, with no observed compensatory effects outside of school time. PMID- 29409736 TI - Biosignature Discovery for Substance Use Disorders Using Statistical Learning. AB - There are limited biomarkers for substance use disorders (SUDs). Traditional statistical approaches are identifying simple biomarkers in large samples, but clinical use cases are still being established. High-throughput clinical, imaging, and 'omic' technologies are generating data from SUD studies and may lead to more sophisticated and clinically useful models. However, analytic strategies suited for high-dimensional data are not regularly used. We review strategies for identifying biomarkers and biosignatures from high-dimensional data types. Focusing on penalized regression and Bayesian approaches, we address how to leverage evidence from existing studies and knowledge bases, using nicotine metabolism as an example. We posit that big data and machine learning approaches will considerably advance SUD biomarker discovery. However, translation to clinical practice, will require integrated scientific efforts. PMID- 29409738 TI - OCA2 rs4778137 polymorphism predicts survival of breast cancer patients receiving neoadjuvant chemotherapy. AB - BACKGROUND: Genome-wide association study (GWAS) studies have showed that single nucleotide polymorphisms (SNPs) in OCA2 gene were associated with the survival of breast cancer patients treated with adjuvant chemotherapy. To further explain the association between OCA2 SNPs and breast cancer survival, we investigated the predictive value of rs4778137 located in OCA2 in local advanced breast cancer patients receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: A case-cohort with 150 breast cancer patients was performed to evaluate the effects of the OCA2 rs4778137 on breast cancer survival. The association between rs4778137 genotypes and pathological complete response (pCR, defined that the postoperative pathology indicating no residual invasive breast cancer in the breast or the axillary lymph node) were analyzed. Logistic regression analysis was performed to identify the independent predictors of pCR. Survival was assessed by Kaplan-Meier method and Cox regression analysis according to the rs4778137 genotypes. RESULTS: The differences between pCR and the rs4778137 genotypes were statistically significant (p < 0.05). The patients with genotype GG harbored a better disease free survival (HR: 2.358, p = 0.000) and overall survival (HR: 1.578, p = 0.008) than the patients with genotype CC in rs4778137. The further Univariate and Multivariate survival analysis revealed that SNP rs4778137 was an independent predictive factor of disease-free survival (p = 0.000/p = 0.001) and overall survival (p = 0.006/p = 0.045). CONCLUSION: The OCA2 rs4778137 may be a predictor for the clinical response and survival in local advanced breast cancer patients who received neoadjuvant chemotherapy. PMID- 29409739 TI - Expansion of circulating T follicular helper cells is associated with disease progression in HIV-infected individuals. AB - BACKGROUND: T follicular helper (Tfh) cells within germinal centers (GC) of lymphoid tissue play an important role in HIV infection. Recently, circulating Tfh cells have been described, which share phenotypic and functional characteristics with GC Tfh cells. This study aimed to investigate the effect of HIV infection on four circulating Tfh subsets, including CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+PD-1+ cells. PATIENTS AND METHODS: Peripheral blood samples were collected from 33 HIV-infected individuals and 21 healthy controls. The frequency and absolute number of CD3, CD4 and CD8 cells were detected by flow cytometry. The frequency of circulating Tfh cell subsets was also determined by flow cytometry. The correlation between the frequency of Tfh subsets and CD4 T cells counts was assessed by Pearson correlation analysis. RESULTS: There was no significant difference in the frequency of peripheral CD4+CXCR5+ Tfh cells between HIV-infected individuals and healthy controls. However, the percentages of circulating CD4+CXCR5+ICOS+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+PD-1+ Tfh cells were significantly higher in individuals with HIV infection than those of healthy controls. Furthermore, the percentage of CD4+CXCR5+PD-1+ Tfh cells showed negative correlation with CD4 T cell counts in HIV-infected individuals. CONCLUSION: Our results suggested the potential involvement of circulating CD4+CXCR5+PD-1+ Tfh cells during the development of HIV infection. PMID- 29409740 TI - Regulation of threat in post-traumatic stress disorder: Associations between inhibitory control and dissociative symptoms. AB - The current study investigated links between trauma exposure, Post-traumatic Stress Disorder (PTSD) symptoms, and inhibitory control assessed using a modified version of the visual flanker task. The study had three aims: (1) specifically confirm general non-affective deficits in sustained attention in PTSD; (2) probe the influence of threatening and trauma-related stimuli on inhibitory control; and (3) explore neural correlates connecting PTSD, facets of dissociation, and inhibitory control. Participants with PTSD (n = 16), trauma-exposed individuals without PTSD (TE; n = 14), and healthy controls (n = 15) discriminated line orientations while ignoring temporally flanking lines and images depicting threatening or non-threatening scenes or faces. Electrophysiological recordings were made during task performance. Relative to TE participants, PTSD participants had poor sustained non-affective attention, but nevertheless exhibited greater inhibition of distractors (i.e., high event-related potential [ERP] Rejection Positivity [RP]) to threatening (versus non-threatening) stimuli. RP was associated with greater self-reported depersonalization in PTSD participants, but with less depersonalization in TE participants. Dipole source analysis localized RP to the posterior cingulate cortex in both PTSD and TE (and healthy controls), but with an additional source in the ventromedial prefrontal cortex in TE, components of the default mode network. Results suggest a paradox in the executive control of distraction in PTSD: Whereas individuals with PTSD experience a general impairment in non-affective inhibitory control, their enhanced control of threat is associated with more severe symptoms of dissociation. PMID- 29409741 TI - Lipoic acid metabolism in Trypanosoma cruzi as putative target for chemotherapy. AB - Lipoic acid (LA) is a cofactor of relevant enzymatic complexes including the glycine cleave system and 2-ketoacid dehydrogenases. Intervention on LA de novo synthesis or salvage could have pleiotropic deleterious effect in cells, making both pathways attractive for chemotherapy. We show that Trypanosoma cruzi was susceptible to treatment with LA analogues. 8-Bromo-octanic acid (BrO) inhibited the growth of epimastigote forms of both Dm28c and CL Brener strains, although only at high (chemotherapeutically irrelevant) concentrations. The methyl ester derivative MBrO, was much more effective, with EC50 values one order of magnitude lower (62-66 MUM). LA did not bypass the toxic effect of its analogues. Small monocarboxylic acids appear to be poorly internalized by T. cruzi: [14C]-octanoic acid was taken up 12 fold less efficiently than [14C]-palmitic acid. Western blot analysis of lipoylated proteins allowed the detection of the E2 subunits of pyruvate dehydrogenase (PDH), branched chain 2-ketoacid dehydrogenase and 2 ketoglutarate dehydrogenase complexes. Growth of parasites in medium with 10 fold lower glucose content, notably increased PDH activity and the level of its lipoylated E2 subunit. Treatment with BrO (1 mM) and MBrO (0.1 mM) completely inhibited E2 lipoylation and all three dehydrogenases activities. These observations indicate the lack of specific transporters for octanoic acid and most probably also for BrO and LA, which is in agreement with the lack of a LA salvage pathway, as previously suggested for T. brucei. They also indicate that the LA synthesis/protein lipoylation pathway could be a valid target for drug intervention. Moreover, the free LA available in the host would not interfere with such chemotherapeutic treatments. PMID- 29409742 TI - Reply to: "Stop-and-watch strategy after cessation of nucleos(t)ide analogue therapy in HBeAg-negative patients". PMID- 29409743 TI - Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: The importance of durable chimerism. AB - Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system in order to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for anti-rejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for anti-rejection drugs. Establishment of durable hematopoietic chimerism through hematopoietic stem cell transplantation (HSCT) has been shown in preclinical models and patients to lead to donor specific tolerance. However, the application HSCT is limited by the potential toxicity of conditioning regimens, the risk of graft versus host disease (GVHD) and the challenge of HLA mismatching. In this review we describe the clinical outcomes and science behind a CD8+/TCR- facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to mismatched renal allografts while minimizing the risk of graft-versus-host GVHD and achieving avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. PMID- 29409744 TI - Prognostic implications of a negative echocardiography in patients with infective endocarditis. AB - BACKGROUND: Echocardiography plays an important role in infective endocarditis (IE) diagnosis according with the modified Duke criteria. We evaluated the implications of a positive echocardiography in the prognosis of a cohort of patients with IE. METHODS: Prospective multicentre study in 31 Spanish centres. From January 2008 to September 2016, 3467 patients were included (2765 definite IE, 702 possible IE). The main outcome was in-hospital mortality. Echocardiography diagnosis was based on modified Duke criteria for the diagnosis of IE. RESULTS: Median age was 69 years (interquartile range: 57-77 years). Comorbidity was high (mean Charlson index 4.7 +/- 2.8). Transoesophageal echocardiography was performed in 2680 (77.3%). The overall inhospital mortality rate was 26.7%. Univariate analysis showed that, in patients with definite IE, inhospital mortality was similar in patients with positive and negative echocardiography (27.7% vs. 24.6%, respectively, p = 0.121). In possible IE these figures were 27.5% vs. 16.7%, respectively, p < 0.001. Complications (cardiac and extracardiac [embolic, immunological, and septic shock]) were more frequent with positive than with negative echocardiography, regardless of clinical suspicion (definite IE 35.5% vs. 16.8%, respectively, p < 0.001; possible IE 20.8% vs. 7.6%, respectively, p < 0.001). Positive echocardiography was a predictor of inhospital death by logistic regression modelling, after adjusting for confounders, definite IE (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.02 1.76, p = 0.036), possible IE (OR 1.59, 95% CI 1.02-2.45, p = 0.036). CONCLUSIONS: A positive echocardiography in patients with IE is associated with increased inhospital mortality, in addition to other clinical factors and comorbidities. PMID- 29409745 TI - Association of non-immediate drug hypersensitivity with drug exposure: A case control analysis of spontaneous reports from a Tunisian pharmacovigilance database. AB - PURPOSE: To assess delayed-type cutaneous reactions (DTCRs) related to drugs, using a case-control approach to qualify drug risks. METHODS: The study used the Tunisian pharmacovigilance database of Monastir. The association between drugs and DTCRs was assessed using a case/non-case method. Drugs were grouped according to the ATC Classification System. Patients were defined as "cases" if they have developed DTCRs regardless of the causality assessment. All other reports were "non-cases". Association between reactions and drugs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals (CIs). A p value < 0.05 was considered significant. RESULTS: The analysis was carried out on 1798 reports, of which 867 concerned DTCRs (cases) and 931 concerned non-cases. The calculated risk estimates were significant for cefotaxime (ROR 2.1; 95% CI 1.5 to 3), pristinamycin (ROR 4; 95% CI 2 to 7.9), sulfamethoxazole (ROR 4.4; 95% CI 1.6 to 11.7), oxacillin (ROR 2.2; 95% CI 1.2 to 3.8), doxycycline (ROR 10.8; 95% CI 1.4 to 84.9), carbamazepine (ROR 3.3; 95% CI 1.7 to 6.2), phenobarbital (ROR 2.3; 95% CI 1.03 to 5.1), allopurinol (ROR 3.6; 95% CI 1.8 to 7.2), furosemide (ROR 2.4; 95% CI 1.3 to 6.3), hydrochlorothiazide(ROR 2.9; 95% CI 1.3 to 6.3) and candesartan (ROR 4.7; 95% CI 1.3 to 16.6). CONCLUSION: Our findings corroborate risks for a number of drugs, such as antibacterials, antiepileptics and allopurinol in inducing DTCRs. Given the widespread use of these drug classes, awareness should be raised among patients and prescribers about these risks. PMID- 29409746 TI - In vitro and in silico attenuation of quorum sensing mediated pathogenicity in Pseudomonas aeruginosa using Spirulina platensis. AB - Biofilm forming pathogenic bacteria showing resistance towards antimicrobial agents has increased the urge to find an alternative treatment strategy. Among the biofilm forming pathogenic bacteria, Pseudomonas aeruginosa is a well recognised Gram negative biofilm former causing nosocomial infection and other disease among immunocompromised patients. The aim of the current study is to evaluate the antipathogenic potentials of S. platensis against P. aeruginosa. S. platensis methanolic extract (SME) inhibited the biofilm (89%), extracellular polymeric substances (EPS), cell surface hydrophobicity (CSH) (44%), pyocyanin, pyoveridin and swarming motility of P. aeruginosa. Partial purification of SME using thin layer chromatography (TLC), column chromatography and gas chromatography mass spectroscopy (GCMS) revealed the major component as hexadecanoic acid (HxD). Further analysis through in silico approach showed the efficient binding of HxD with the biofilm regulatory proteins (Las R and salidase enzyme) of P. aeruginosa. The coating of HxD over different material surfaces efficiently prevented the adhesion of P. aeruginosa biofilm. The results of the toxicity assay revealed that the SME is non-toxic towards Artemia salina at the given concentration. Hence the overall work proves the potential non-toxic effects of SME against P. aeruginosa pathogenicity. PMID- 29409747 TI - The impact of the injection mold temperature upon polymer crystallization and resulting drug release from immediate and sustained release tablets. AB - It was the aim of this study to elucidate the impact of the injection mold temperature upon the polymer crystallinity, its microstructure and the resulting drug release from immediate and sustained release tablets containing semi crystalline polymers. The immediate release formulation contained 20% (w/w) ketoprofen (KETO) in poly (ethylene oxide) (PEO) and the sustained release formulation contained 20-40% (w/w) metoprolol tartrate (MPT) in polycaprolactone (PCL). Physical mixtures of drug-polymer were characterized via isothermal crystallization experiments using DSC and rheological measurements to elucidate the impact of the drug solid-state upon the crystallization kinetics. Tablets were prepared using various thermal histories (extrusion barrel temperature and injection mold temperatures). Polymer crystallinity and microstructure in the tablets was characterized via DSC and polarized optical microscopy. The polymer microstructure was altered by the various applied thermal histories. The differences in PEO crystallinity induced by the various mold temperatures did not affect the KETO dissolution from the tablets. On the other hand, MPT (20-40% w/w) dissolution from the PCL matrix when extruded at 80 degrees C and injection molded at 25 and 35 degrees C was significantly different due to the changes in the polymer microstructure. More perfect polymer crystals are obtained with higher mold temperatures, decreasing the drug diffusion rate through the PCL matrix. The results presented in this study imply that the injection mold temperature should be carefully controlled for sustained release formulations containing hydrophobic semi-crystalline polymers. PMID- 29409748 TI - Lower light intensity reduces larval aggression in matrinxa, Brycon amazonicus. AB - Brycon amazonicus shows a high frequency of aggressive behavior, which can be a limiting factor in intensive farming systems. Environmental changes can modulate the social interactions of fish and reduce aggression during the different stages of production. Groups of three larvae at 12 h after hatching (HAH) were subjected to different levels of light intensity: low (17 +/- 3 lx), intermediate (204 +/- 12.17 lx) and high (1,613.33 +/- 499.03 lx), with eight replicates for each level. The lower light intensity reduced the frequency of aggressive interactions and locomotor activity exhibited by the animals. Based on these results, light intensity modulates aggression in B. amazonicus larvae. Manipulation of this factor could improve the social conditions of this species during farming and contribute to the development of new production technologies. PMID- 29409749 TI - Travellers' diarrhoea: Impact of TD definition and control group design on study results. AB - BACKGROUND: Travellers' diarrhoea (TD) is a common health problem among visitors to the (sub)tropics. Much research deals with aetiology, prevention, and post infection sequalae, yet the data may not allow comparisons due to incompatible definitions of TD and No TD control groups. METHOD: The impact of defining TD and No TD control groups was explored by revisiting our recent data. We set up two TD groups: classical TD i.e. >=3 loose or liquid stools/day and WHO TD (diarrhoea as defined by the WHO) i.e. any diarrhoea, and four No TD groups by TD definition and timing (no classical/WHO TD during travel, no ongoing classical/WHO TD). RESULTS: TD was recorded for 37% versus 65% of subjects when using classical versus WHO definitions, respectively; the proportions of the various pathogens proved similar. The strictest criterion for the No TD control group (no WHO TD during travel) yielded pathogens among 61% and the least strict (no ongoing classical TD) among 73% of the travellers; the differences were greatest for enteroaggregative Escherichia coli and Campylobacter. CONCLUSIONS: Definition of TD and control group design substantially impact on TD study results. The WHO definition yields more cases, but the pathogen selection is similar by both definitions. Design of the No TD control group was found critical: only those remaining asymptomatic throughout the journey should be included. PMID- 29409750 TI - Modeling individual differences: A case study of the application of system identification for personalizing a physical activity intervention. AB - BACKGROUND: Control systems engineering methods, particularly, system identification (system ID), offer an idiographic (i.e., person-specific) approach to develop dynamic models of physical activity (PA) that can be used to personalize interventions in a systematic, scalable way. The purpose of this work is to: (1) apply system ID to develop individual dynamical models of PA (steps/day measured using Fitbit Zip) in the context of a goal setting and positive reinforcement intervention informed by Social Cognitive Theory; and (2) compare insights on potential tailoring variables (i.e., predictors expected to influence steps and thus moderate the suggested step goal and points for goal achievement) selected using the idiographic models to those selected via a nomothetic (i.e., aggregated across individuals) approach. METHOD: A personalized goal setting and positive reinforcement intervention was deployed for 14 weeks. Baseline PA measured in weeks 1-2 was used to inform personalized daily step goals delivered in weeks 3-14. Goals and expected reward points (granted upon goal achievement) were pseudo-randomly assigned using techniques from system ID, with goals ranging from their baseline median steps/day up to 2.5* baseline median steps/day, and points ranging from 100 to 500 (i.e., $0.20-$1.00). Participants completed a series of daily self-report measures. Auto Regressive with eXogenous Input (ARX) modeling and multilevel modeling (MLM) were used as the idiographic and nomothetic approaches, respectively. RESULTS: Participants (N = 20, mean age = 47.25 +/- 6.16 years, 90% female) were insufficiently active, overweight (mean BMI = 33.79 +/- 6.82 kg/m2) adults. Results from ARX modeling suggest that individuals differ in the factors (e.g., perceived stress, weekday/weekend) that influence their observed steps/day. In contrast, the nomothetic model from MLM suggested that goals and weekday/weekend were the key variables that were predictive of steps. Assuming the ARX models are more personalized, the obtained nomothetic model would have led to the identification of the same predictors for 5 of the 20 participants, suggesting a mismatch of plausible tailoring variables to use for 75% of the sample. CONCLUSION: The idiographic approach revealed person-specific predictors beyond traditional MLM analyses and unpacked the inherent complexity of PA; namely that people are different and context matters. System ID provides a feasible approach to develop personalized dynamical models of PA and inform person-specific tailoring variable selection for use in adaptive behavioral interventions. PMID- 29409751 TI - The role of gut microbiota and IL-23/IL-17 pathway in ankylosing spondylitis immunopathogenesis: New insights and updates. AB - Ankylosing spondylitis (AS) is a type of arthritis that is referred to a group of chronic immune-mediated inflammatory diseases termed as seronegative spondyloarthropathies or spondyloarthritides. It typically affects the joints of the spinal and axial skeleton and exhibits common clinical features and genetic factors such as human leukocyte antigen class I allele HLA-B27, the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), and environmental factors such as microbial triggers. Although the precise etiopathogenic mechanisms that implicate the pathogenesis of AS have still remained to be clarified, the IL-23/IL-17 immune axis has been detected as an important factor in the immunopathogenesis of AS. Moreover, therapeutic options targeting this signaling pathway have been demonstrated to be effective in various other inflammatory diseases that share similar genetic etiology and pathogenetic pathways. In mammalian intestinal, there are trillions of commensal microbes that create the intricate symbiotic relationship with host well-known as the microbiota and play the major role in human health and disease. Several publications have appeared in recent years documenting the pivotal role of the gut microbiota and the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritides. In this review, several points are discussed and summarized including recent advances on the role of the IL-17/IL-23 immune pathway in the pathogenesis of AS, HLA-B27, and ERAP 1 and 2 mediated pathogenesis, AS-related microbiota compositions, and new potential therapies for AS. PMID- 29409752 TI - Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors. AB - Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10 fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. PMID- 29409753 TI - Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents. AB - A novel series of substituted pyrazolo-quinoline derivatives 7pa-7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on 1H NMR, 13C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC50 values of 3.76, 3.87 and 3.83 uM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC50 values of 2.43 and 6.01 uM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti proliferative evaluation of pyrazolo-quinoline derivatives. PMID- 29409754 TI - Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells. AB - In a search of small molecules active against apoptosis-resistant cancer cells, a skeletal rearrangement of alkaloid haemanthamine was utilized to generate a series of compounds possessing the alkaloid montanine ring system. The synthesized compounds were found to inhibit proliferation of cancer cells resistant to apoptosis at micromolar concentrations. Selected compounds were also active against patient-derived glioblastoma cells expressing stem-cell markers. This is the first report describing the preparation of synthetic analogues of the montanine-type alkaloids with antiproliferative activity. The compounds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with poor prognoses. PMID- 29409755 TI - Chemical and genetic rescue of an ep300 knockdown model for Rubinstein Taybi Syndrome in zebrafish. AB - EP300 is a member of the EP300/CBP family of lysine acetyltransferases (KATs) with multiple roles in development and physiology. Loss of EP300/CBP activity in humans causes a very rare congenital disorder called Rubinstein Taybi Syndrome (RSTS). The zebrafish genome has two co-orthologs of lysine acetyltransferase EP300 (KAT3B) in zebrafish viz. ep300a and ep300b. Chemical inhibition of Ep300 with C646, a competitive inhibitor and morpholino-based genetic knockdown of ep300a and ep300b cause defects in embryonic development reminiscent of the human RSTS syndrome. Remarkably, overexpression of Ep300a KAT domain results in near complete rescue of the jaw development defects, a characteristic feature of RSTS in human suggesting the dispensability of the protein-interaction and DNA-binding domains for at least some developmental roles of Ep300. We also perform a chemical screen and identify two inhibitors of deacetylases, CHIC35 and HDACi III, that can partially rescue the RSTS-like phenotypes. Thus, modeling rare human genetic disorders in zebrafish allows for functional understanding of the genes involved and can also yield small molecule candidates towards therapeutic goals. PMID- 29409757 TI - Polygenic risk for schizophrenia affects working memory and its neural correlates in healthy subjects. AB - Schizophrenia is a disorder with a high heritability. Patients as well as their first degree relatives display lower levels of performance in a number of cognitive domains compared to subjects without genetic risk. Several studies could link these aberrations to single genetic variants, however, only recently, polygenic risk scores as proxies for genetic risk have been associated with cognitive domains and their neural correlates. In the present study, a sample of healthy subjects (n=137) performed a letter version of the n-back task while scanned with 3-T fMRI. All subjects were genotyped with the PsychChip and polygenic risk scores were calculated based on the PGC2 schizophrenia GWAS results. Polygenic risk for schizophrenia was associated with a lower degree of brain activation in prefrontal areas during the 3-back compared to the 0-back baseline condition. Furthermore, polygenic risk was associated with lower levels of brain activation in the right inferior frontal gyrus during the 3-back compared to a 2-back condition. Polygenic risk leads to a shift in the underlying activation pattern to the left side, thus resembling results reported in patients with schizophrenia. The data may point to polygenic risk for schizophrenia being associated with brain function in a cognitive task known to be impaired in patients and their relatives. PMID- 29409758 TI - Regulation of natriuretic peptides postprandially in vivo and of their receptors in adipocytes by fatty acids in vitro. AB - BACKGROUND AND AIM: Natriuretic peptides (NPs) and their receptors gain attention regarding adipocyte function. It was the aim to investigate the expression of natriuretic peptide receptors NPR-A, NPR-B and NPR-C during adipocyte differentiation (AD), upon stimulation with fatty acids (FA), and in murine and human adipose tissue depots (AT) of patients undergoing bariatric surgery (n = 44). PATIENTS, MATERIAL AND METHODS: The postprandial regulation of NT-proANP and NT-proBNP levels was measured by ELISA and was studied in two cohorts of healthy individuals undergoing an oral glucose tolerance test (OGTT) (n = 100) and an oral lipid tolerance test (OLTT) (n = 100). Adipocyte mRNA expression was investigated by quantitative real-time PCR. RESULTS: During AD, an early expression pattern could be described for NPR-C, a bimodal expression for NPR-B and a late expression pattern for NPR-A. NPR-A and NPR-B expression was high in epididymal and subcutaneous AT but low in peri-renal AT of mice. NPR-C showed a differential expression profile. FA stimulation caused a significant and differential regulation of NPRs in adipocytes. Serum NT-proANP and NT-proBNP concentrations did not change during OGTT, whereas NT-proANP significantly declined during OLTT. Basal NT-proANP and NT-proBNP concentrations were positively correlated with each other and with FGF-19 and FGF-21 levels. CONCLUSION: Adipocytes and AT show a characteristic expression of NPRs. FA are able to regulate NPR expression differentially. There is a postprandial and negative regulation of serum NT-proANP concentrations after OLTT and of NPR-A after FA stimulation. Both effects could represent a novel hypothetical negative feedback mechanism on adipocyte lipolysis. PMID- 29409756 TI - VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function. AB - Mutations in VPS33B and VIPAS39 cause the severe multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome. Amongst other symptoms, patients with ARC syndrome suffer from severe ichthyosis. Roles for VPS33B and VIPAR have been reported in lysosome-related organelle biogenesis, integrin recycling, collagen homeostasis and maintenance of cell polarity. Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype. We demonstrate that the skin manifestations in Vps33b and Vipar deficient mice are histologically similar to those of patients with ARC syndrome. Histological, immunofluorescent and electron microscopic analysis of Vps33b and Vipar deficient mouse skin biopsies and isolated primary cells showed that epidermal lamellar bodies, which are essential for skin barrier function, had abnormal morphology and the localisation of lamellar body cargo was disrupted. Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids. These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome. PMID- 29409759 TI - Prevalence of Chlamydia Trachomatis, Neisseria Gonorrhoeae, and Trichomonas Vaginalis Infection in Chilean Adolescents and Young Adults. AB - STUDY OBJECTIVE: To determine the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis infection in sexually active Chilean adolescents and young adults. A comparative analysis was performed between genders to identify demographic, clinical, and sexual behavior characteristics to predict the occurrence of C trachomatis. DESIGN: Analytical observational study. SETTING: Santiago, Chile. PARTICIPANTS: Two hundred eighty-six sexually active volunteers aged 24 years or younger (171 female and 115 male); 82.9% (237/286) of them were classified as having high socioeconomic status. INTERVENTIONS: Confidential survey and self-collected samples (urine for men and vaginal swabs for women). MAIN OUTCOME MEASURES: Prevalence, demographic characteristics, symptoms, and sexual behavior characteristics. RESULTS: The prevalence rate of C trachomatis was 8.7% (10/115) in men and 8.8% (15/171) in women (P = .58). N gonorrhoeae was detected in 1 subject, whereas no T vaginalis cases were detected. In multivariate analysis, having some college education was protective (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.09-0.89), whereas having a higher number of sexual partners was a risk factor (OR, 1.19; 95% CI, 1.1-1.3) for C trachomatis infection. The latter was also predicted by postcoital bleeding (OR, 4.6; 95% CI, 1.30-16.23) in the female model. CONCLUSION: C trachomatis infection rates were similar between both genders. Protective characteristics for the occurrence of this infection were having some college education, lower number of sexual partners, and if female, the absence of postcoital bleeding. This study highlights the importance of C trachomatis screening among the Chilean affluent population younger than 25 years. However, further studies are needed in a more diverse and representative sample to recommend universal screening in Chilean adolescents and young adults. PMID- 29409760 TI - American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. PMID- 29409761 TI - Sunscreen use in schools: A content analysis of US state laws. PMID- 29409763 TI - Knockout of the CCCH zinc finger protein TcZC3H31 blocks Trypanosoma cruzi differentiation into the infective metacyclic form. AB - In the protozoan parasite Trypanosoma cruzi - the causative agent of Chagas disease - gene expression control is mainly post-transcriptional, where RNA binding proteins (RBPs) play a central role, by controlling mRNA stability, distribution and translation. A large variety of RBPs are encoded in the T. cruzi genome, including the CCCH-type zinc finger (CCCH ZnF) protein family, which is characterized by the presence of the C-X7/8-C-X5-C-X3-H (CCCH) motif. In the related parasite T. brucei, CCCH ZnF proteins have been shown to control key differentiation steps in the parasite's life cycle. However, little is known about the CCCH ZnF proteins in T. cruzi. We have worked on the generation of T. cruzi mutants for CCCH ZnF proteins in an effort to shed light on the functions of these proteins in this parasite. Here, we characterize the expression and function of the CCCH ZnF protein TcZC3H31 of T. cruzi. TcZC3H31 is almost exclusively expressed in epimastigotes and metacyclic trypomastigotes, the parasite forms found in the invertebrate host. Importantly, we show that the epimastigote form of the T. cruzi knockout for the TcZC3H31 gene (TcZC3H31 KO) is incapable, both in vitro and in vivo (in infected triatomine insects), to differentiate into the metacyclic trypomastigote form, which is responsible for infection transmission from vectors to humans. The epimastigote forms recovered from the excreta of insects infected with TcZC3H31 KO parasites do not have the typical epimastigote morphology, suggesting that parasites are arrested in a mid differentiation step. Also, epimastigotes overexpressing TcZC3H31 differentiate into metacyclics more efficiently than wild-type epimastigotes, in vitro. These data suggest that TcZC3H31 is an essential positive regulator of T. cruzi differentiation into the human-infective metacyclic form. PMID- 29409762 TI - Effects of antihistamines on the H295R steroidogenesis - Autocrine up-regulation following 3beta-HSD inhibition. AB - Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Delta5 steroids and significant decreases in Delta4-steroids were observed, indicating an inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in significant up-regulation of 3beta-HSD and 17beta-HSD, whereas CET only resulted in up-regulation of 3beta-HSD. This indicated that the decrease in steroids downstream from 3beta-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3beta-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded. PMID- 29409764 TI - Unsaturated aldehyde, 4-hydroxynonenal (HNE) alters the structural integrity of HSA with consequences in the immuno-pathology of rheumatoid arthritis. AB - Human serum albumin (HSA) - the most abundant plasma protein plays an important role in the transport of endogenous and exogenous molecules in the body. Its modifications have been implicated in a variety of pathological disorders. We have studied the interaction of HNE with HSA at a molecular level by docking experiment and the results suggest a strong interaction between HNE and HSA. Immunological studies revealed that the circulating auto-antibodies in rheumatoid arthritis (RA) patients have a stronger affinity towards HNE-modified HSA. The HSA isolated from RA patients (RA-HSA) exhibited HNE mediated damage in its secondary and tertiary structure when compared to HSA derived from healthy human subjects (NH-HSA). RA patients presented a significant rise in carbonyls and a considerable decline in free thiol content. Preferential binding of experimentally induced anti-HNE-HSA antibodies to RA-HSA over NH-HSA was observed by ELISA. The results suggest HNE induced structural perturbations in HSA with neoepitopes that generate anti-HNE-HSA antibodies in RA. Hence, HNE-HSA may provide lead towards the development of a biomarker for the disease. PMID- 29409765 TI - Structural characterization and immunomodulatory activity of a pectic polysaccharide (CALB-4) from Fructus aurantii. AB - A purified polysaccharide, designated CALB-4, was acquired from Fructus aurantii that is the traditional edible/medicina plant in China. The present study was performed to characterize the CALB-4 and to evaluate its immunomodulatory activities on human peripheral blood mononuclear cells (PBMCs). The structure of CALB-4 was characterized by partial acid hydrolysis, periodate oxidation, Smith degradation, and methylation analysis combined with gas chromatography-mass spectrometry (GC-MS), Infrared Spectroscopy (IR) and scanning electron microscopy (SEM). The results indicated that CALB-4 was elucidated as a pectic polysaccharide and its main chain is composed of Man, Gal UA and Gal, interspersed with Ara, Rha, Man and Gal. Furthermore, immunological tests showed that CALB-4 exhibits the immunoenhancement effects. The mechanism for this action might be attributed to the increase of the cytoplasmic concentration of pro-IL-1 via the up-regulation of several mitogen-activated protein kinases (MAPKs) and the nuclear translocation of p65. This study clarified that CALB-4 could be as an efficacious biological response modifier in immunotherapy. PMID- 29409766 TI - An Event-Related Potential study of letter spacing during visual word recognition. AB - Increasing spacing between letters in words (e.g., s p a c e vs. space) helps children and adults read more fluidly and with fewer errors. This effect has been demonstrated behaviorally, chiefly through lexical decision reaction time and total paragraph reading time. To date, however, no electrophysiological work has examined the letter spacing effect, resulting in little insight regarding how letter spacing impacts "hidden" levels of processing between apprehension of the word form and the final behavioral outcome. Here, we examined how varying levels of interletter spacing (crowded, standard, and increased) impact ERPs elicited by words and other item types (pseudowords, illegal strings, and a false font). Results indicate that letter spacing does not impact the ERP within the first second after viewing a wordform, but that it does have downstream effects as indicated by data collected using a priming design. Further, the facilitation of downstream processing afforded by increased spacing seems to be greater for more word-like stimuli (e.g., greater for words than for consonant strings, etc). Results are discussed as being somewhat inconsistent with prevalent views of the mechanism of the letter spacing effect (i.e., crowding). PMID- 29409767 TI - Association of hyperglycemic crisis with an increased risk of end-stage renal disease: A nationwide population-based cohort study. AB - BACKGROUND: A hyperglycemic crisis episode (HCE) is associated with poor management of diabetes, which is a risk factor for end-stage renal disease (ESRD); however, the association between an HCE and ESRD has not been clarified. We conducted a nationwide population-based cohort study with the purpose of delineating this issue. METHODS: We identified 9208 diabetic patients with an HCE and an identical number of diabetic patients with matched age, sex, and index date without an HCE between 2000 and 2002. A comparison of the risk of ESRD between the diabetic patients with and without an HCE was achieved by a follow-up until 2014. RESULTS: A Cox proportional hazard regression analysis showed that the diabetic patients with an HCE were at a higher risk of ESRD than those without an HCE (the adjusted hazard ratio [AHR]: 1.47; 95% confidence interval [CI]: 1.34-1.62) by adjusting for renal disease, hypertension, hyperlipidemia, coronary artery disease, hyperuricemia, anemia, chronic obstructive pulmonary disease, liver disease, malignancy, connective tissue disease, non-steroid anti inflammatory drug use, and monthly income. The increased risk of ESRD was more prominent in the age subgroup of 15-25 years (AHR: 4.91; 95% CI: 1.92-12.56); 25 35 years (AHR: 2.42; 95% CI: 1.51-3.86); 35-45 years (AHR: 3.01; 95% CI: 2.21 4.09); and 45-55 years (AHR: 1.75; 95% CI: 1.41-2.19). CONCLUSIONS: An HCE was associated with an increased risk of ESRD, especially in the younger diabetic patients (15-55 years). A close follow-up for the control of diabetes and for monitoring renal function is proposed. PMID- 29409768 TI - Cooling methods of targeted temperature management and neurological recovery after out-of-hospital cardiac arrest: A nationwide multicenter multi-level analysis. AB - OBJECTIVE: The purpose of this study was to determine whether the cooling method used for target temperature management (TTM) was associated with neurological recovery after out-of-hospital cardiac arrest (OHCA). METHODS: From January 2008 to December 2016, adult OHCA patients who survived to hospitalization without any traumatic etiology and who received TTM were included. Patients who did not have information about neurological status at hospital discharge or who did not have information on target temperature management were excluded. Cooling methods were classified into four groups: (1) external device cooling (EDC) using a pad with cooling device, (2) external conventional cooling (ECC) such as ice water, fans, and simple blankets, (3) Intravascular cooling (IVC) using an intravascular cooling catheter, and (4) intracavitary cooling (ICC) using ice water for washing cavitary organ. The outcomes were good cerebral performance scale (CPC) score 1 or 2 and survival to discharge. In multivariate logistic regression analysis, the adjusted odds ratios (AORs) and the 95% confidence intervals (CIs) were calculated (reference = ECC). Finally, we used a GLIMMIX procedure with group level variables (hospitals) to create a multilevel model for adjusting the clustering factor of patients being treated in the same hospital. RESULTS: The final analysis included a total of 4246 eligible patients (ECC 1386, EDC 2107, IVC 376, ICC 377). Good neurologic recovery was 20.7% for all (ECC 17.4, EDC 23.1%, IVC 26.9%, and ICC 13.3%, p < .001). The survival rate was 46.4% for all (ECC 45.4%, EDC 48.5%, IVC 50.5%, ICC 34.2%, p < .001). There were no significant differences (AOR and 95% CI) in the multi-level analysis for good neurological recovery between cooling methods compared with ECC; EDC 1.20 (0.95-1.52), IVC 1.43 (0.90-2.27), and ICC 0.71 (0.46-1.10). The ICC group had a lower survival to discharge rate compared with ECC; EDC 0.97 (0.83-1.15), IVC 0.96 (0.78-1.19), and ICC 0.63 (0.43-0.85). CONCLUSION: The cooling methods for TTM did not show any significant difference in neurological recovery in multi-level logistic regression analysis. Only intracavitary cooling resulted in a lower survival to discharge than external surface cooling. PMID- 29409769 TI - Zebrafish sp7 mutants show tooth cycling independent of attachment, eruption and poor differentiation of teeth. AB - The capacity to fully replace teeth continuously makes zebrafish an attractive model to explore regeneration and tooth development. The requirement of attachment bone for the appearance of replacement teeth has been hypothesized but not yet investigated. The transcription factor sp7 (osterix) is known in mammals to play an important role during odontoblast differentiation and root formation. Here we study tooth replacement in the absence of attachment bone using sp7 zebrafish mutants. We analysed the pattern of tooth replacement at different stages of development and demonstrated that in zebrafish lacking sp7, attachment bone is never present, independent of the stage of tooth development or fish age, yet replacement is not interrupted. Without bone of attachment we observed abnormal orientation of teeth, and abnormal connection of pulp cavities of predecessor and replacement teeth. Mutants lacking sp7 show arrested dentinogenesis, with non-polarization of odontoblasts and only a thin layer of dentin deposited. Osteoclast activity was observed in sp7 mutants; due to the lack of bone of attachment, remodelling was diminished but nevertheless present along the pharyngeal bone. We conclude that tooth replacement is ongoing in the sp7 mutant despite poor differentiation and defective attachment. Without bone of attachment tooth orientation and pulp organization are compromised. PMID- 29409770 TI - International migration and dietary change in Mexican women from a social practice framework. AB - Migration from lower- and middle-income to high-income countries is associated with dietary change, and especially with the adoption of a modern, less healthy diet. In this article we analyze the dietary changes experienced by Mexican migrants, employing as a theoretical framework the concept of social practice. According to this framework, practices integrate material elements, meanings and competences that provide their conditions of possibility. Practices are shared by members of social groups, and interact with other competing or reinforcing practices. Between 2014 and 2015, we conducted semi-structured interviews with 27 women, international return migrants living in Tijuana, Mexico. The interview guide asked about history of migration and dietary change. We found three main areas of dietary change: from subsistence farming to ready meals, abundance vs. restriction, and adoption of new food items. The first one was associated with changes in food procurement and female work: when moving from rural to urban areas, participants substituted self-produced for purchased food; and as migrant women joined the labor force, consumption of ready meals increased. The second was the result of changes in income: participants of lower socioeconomic position modified the logic of food acquisition from restriction to abundance and back, depending on the available resources. The third change was relatively minor, with occasional consumption of new dishes or food items, and was associated with exposure to different cuisines and with learning how to cook them. Public health efforts to improve the migrants' diets should take into account the constitutive elements of dietary practices, instead of isolating individuals from their social contexts. PMID- 29409771 TI - Development of low molecular weight heparin based nanoparticles for metastatic breast cancer therapy. AB - Tumor metastasis is the primary obstacle in cancer treatment and is always the leading cause of human death. And heparin and its derivatives are potential anti metastatic agents with good biocompatibility. In this work, low molecular weight heparin (LMWH) based LMWH-Cholesterol (LHC) conjugates were prepared for intravenous delivery of doxorubicin (DOX). The DOX/LHC nanoparticles (DOX/LHC NPs) exhibited a spherical shape with a mean diameter of 135.5+/-2.2nm and had a longer circulation time than that of DOX. The in vitro results confirmed that the DOX/LHC NPs was more effectively taken up by 4T1 cells and showed a stronger anti metastatic effect by cell invasion and cell migration compared with DOX. Meanwhile, DOX/LHC NPs also exhibited superior anti-metastatic effects in the pulmonary metastasis model compared with other groups. The reason may be account for the synergistic effect between the cytotoxic drug of DOX and its drug carrier of LMWH based nanoparticles, which is capable of anti-metastatic and anti angiogenic efficiency. Thus DOX/LHC nanoparticles could be a promising anti metastatic drug delivery system for postoperative chemotherapy. PMID- 29409773 TI - Editorial Comment. PMID- 29409772 TI - Two complement fixing pectic polysaccharides from pedicel of Lycium barbarum L. promote cellular antioxidant defense. AB - Purification, characterization and biological activities of polysaccharides from Lycium barbarum pedicel were investigated in this study. Two polysaccharides, PLBP-I-I and PLBP-II-I, were obtained from water extracts by anion exchange chromatography and gel filtration. Structural elucidation based on IR, 1H NMR, and 13C NMR spectra indicated that these two fractions were typical pectic polysaccharides, with homogalacturonan and rhamnogalacturonan type I regions and arabinogalactan side chains, and some of the galacturonic acid units were methyl esterified. Both fractions exhibited potent complement fixating activity and pro antioxidant defense capacity, and those two fractions showed different activities. The higher complement fixation activity was obtained in fraction PLBP I-I, while the higher pro-antioxidant defense capacity was obtained in fraction PLBP-II-I, which may be due to the structural differences between those two fractions. Thus, the pedicel of L. barbarum could be used as a potential source for natural immunomodulator and antioxidant. PMID- 29409774 TI - Adult Tethered Cord Syndrome Following Chiari Decompression. AB - BACKGROUND: Adult tethered cord syndrome is a rare neurologic disorder that classically presents with back or leg pain, weakness, and urinary dysfunction. Spinal cord tethering has been associated with acquired Chiari malformations. Whereas the effects of tethered cord release on Chiari malformation symptoms have been described previously, we report an unusual case of acquired tethered cord syndrome following Chiari decompression. CASE DESCRIPTION: We report a 68-year old man with a history of distant T12-level spinal cord injury and 2 weeks of progressive bilateral lower extremity weakness. The patient underwent a T12-L1 laminectomy in 1977, complicated by arachnoiditis and syringomyelia, with eventual placement of a syringopleural shunt. He remained neurologically stable until 2012, when he underwent a suboccipital craniectomy for Chiari decompression for new-onset headache and dysphagia. Ten days later, the patient noted progressive leg weakness and radiographic evidence of spinal cord tethering at the T11-T12 level. A T10-L1 laminectomy and medical facetectomy was undertaken for detethering with postoperative recovery of ambulatory function with assistance. CONCLUSIONS: Our patient exhibited an unusual acquisition of tethered cord syndrome. The tethering of the spinal cord may have been triggered by arachnoid adhesions from initial lumbar surgery 35 years before presentation and subsequently exacerbated by alterations of cerebrospinal fluid dynamics after Chiari decompression. Given the potentially devastating sequelae of tethered cord syndrome, investigation of cerebrospinal fluid flow dynamics may be beneficial before operative intervention in patients with risk factors for a tethered cord who exhibit adult-onset Chiari malformation. PMID- 29409775 TI - Atmospheric Pressure Variation is a Delayed Trigger for Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: There is an ongoing search for conditions that induce spontaneous subarachnoid hemorrhage (SAH). The seasonal pattern of SAH is shown in a large meta-analysis of the literature, but its explanation remains undecided. There is a clear need for sound meteorologic data to further elucidate the seasonal influence on SAH. Because of the stable and densely monitored atmospheric situation in the north of the Netherlands, we reviewed our unique cohort on the seasonal incidence of SAH and the association between SAH and local atmospheric changes. METHODS: Our observational cohort study included 1535 patients with spontaneous SAH admitted to our neurovascular center in the north of the Netherlands between 2000 and 2015. Meteorologic data could be linked to the day of the ictus. To compare SAH incidences over the year and to test the association with meteorologic conditions, incidence rate ratios (IRRs) with corresponding 95% confidence intervals (CIs) were used, calculated by Poisson regression analyses. RESULTS: Atmospheric pressure variations were significantly associated with aneurysmal SAH. In particular, the pressure change on the second and third day before the ictus was independently correlated to a higher incidence of aneurysmal SAH (IRR, 1.11; 95% CI, 1.00-1.23). The IRR for aneurysmal SAH in July was calculated 0.67 (95% CI, 0.49-0.92) after adjustment for temperature and atmospheric pressure changes. CONCLUSIONS: Atmospheric pressure variations are a delayed trigger for aneurysmal SAH. Also, a significantly decreased incidence of aneurysmal SAH was noted in July. PMID- 29409777 TI - The Egyptian hepatitis C programme: a model of HCV treatment intervention? PMID- 29409776 TI - The validation of simplified EEG derived from the bispectral index monitor in post-cardiac arrest patients. AB - AIMS: We aimed to validate retrospectively the accuracy of simplified electroencephalography (EEG) monitoring derived from the bispectral index (BIS) monitor in post-cardiac arrest (CA) patients. METHODS: Successfully resuscitated CA patients were transferred to the Catherization Lab followed by percutaneous coronary intervention when indicated. On arrival at the coronary care unit, bilateral BIS monitoring was started and continued up to 72 h. Raw simplified EEG tracings were extracted from the BIS monitor at a time point coinciding with the registration of standard EEG monitoring. BIS EEG tracings were reviewed by two neurophysiologists, who were asked to indicate the presence of following patterns: diffuse slowing rhythm, burst suppression pattern, cerebral inactivity, periodic epileptiform discharges and status epilepticus (SE). Additionally, these simplified BIS EEG tracings were analysed by two inexperienced investigators, who were asked to indicate the presence of SE only. RESULTS: Thirty-two simplified BIS EEG samples were analysed. Compared to standard EEG, neurophysiologists interpreted all simplified EEG samples with a sensitivity of 86%, a specificity of 100% and an interobserver variability of 0.843. Furthermore, SE was identified with a sensitivity of 80% and a specificity of 94% by two unexperienced physicians. CONCLUSION: Using a simple classification system, raw simplified EEG derived from a BIS monitoring device is comparable to standard EEG monitoring. Moreover, investigators without EEG experience were capable to identify SE in post-CA patients. Future studies will be warranted to confirm our results and to determine the added value of using simplified BIS EEG in terms of prognostic and therapeutic implications. PMID- 29409779 TI - A rare cause of occult gastrointestinal bleeding. PMID- 29409778 TI - Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study). AB - INTRODUCTION: In advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75 mg/m2 q3w) to cisplatin (75 mg/m2 q3w) and 5 fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated. AIM: GASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50 mg/m2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity. MATERIALS AND METHODS: Main eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions. RESULTS: The primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HR = 0.73) Based on a two-sided alpha risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index. CONCLUSION: This study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432). PMID- 29409780 TI - Radiotherapy of rectal cancer in elderly patients: Real-world data assessment in a decade. AB - BACKGROUND AND PURPOSE: There is paucity of data on the efficacy and toxicity of radiotherapy in rectal cancer (RC) elderly patients. The objective was to identify management strategies and resulting outcomes in RC patients >=70 years undergoing radiotherapy. MATERIAL AND METHODS: A retrospective study included consecutive RC patients >=70 years undergoing rectal radiotherapy. RESULTS: From 2004-2015, 340 RC patients underwent pre-operative (n = 238; 70%), post-operative (n = 41, 12%), or exclusive (n = 61, 18%) radiotherapy, with a median age of 78.5 years old (range: 70-96). Radiotherapy protocols were tailored, with 54 different radiotherapy programs (alteration of the total dose, and/or fractionation, and/or volume). Median follow-up was 27.1 months. Acute and late grade 3-4 radio-induced toxicities were reported in 3.5% and 0.9% of patients. Metastatic setting (OR = 6.60, CI95% 1.47-46.03, p = 0.02), exclusive radiotherapy (OR = 5.08, CI95% 1.48 18.21, p = 0.009), and intensity-modulated radiotherapy (OR = 6.42, CI95% 1.31 24.73, p = 0.01) were associated with grade >=3 acute toxicities in univariate analysis. Exclusive radiotherapy (OR = 9.79, CI95% 2.49-43.18, p = 0.001) and intensity-modulated radiotherapy (OR = 12.62, CI95% 2.05-71.26, p = 0.003) were independent predictive factors of grade >=3 acute toxicities in multivariate analysis. A complete pathological response was achieved in 12 out of 221 pre operative patients (5.4%). Age, tumor stage, and surgery were independent predictive factors of survival in multivariate analysis. At end of follow-up, 7.1% of patients experienced local relapse. CONCLUSION: Radiotherapy for RC in elderly patients appeared safe and manageable, perhaps due to the tailoring of radiotherapy protocols. Tailored management resulted in acceptable rate of local tumor control. PMID- 29409781 TI - Clinical association of anti-glutathione S-transferase T1 antibodies and de novo immune hepatitis after hematopoietic cell transplantation. PMID- 29409782 TI - Intrinsic EEG and task-related changes in EEG affect Go/NoGo task performance. AB - Substantial research into the brain dynamics underlying cognitive functioning during tasks links the brain's EEG activity to the stimulus-evoked ERP activity. This study focused on examining how the resting state intrinsic EEG, and the change from rest to the task, affect these stimulus-response processes. Forty young adults (aged 20.3 +/- 2.3 years) had EEG recorded during eyes-closed (EC) and eyes-open (EO) resting states, and then during an auditory Go/NoGo task. Amplitude in the delta to beta bands was analyzed for the overall resting state EEG, the reactive change from EC to EO, and for the change from EO to the task (termed task-related change here). The relationships between these EEG measures and Go/NoGo behavioral outcomes and ERPs were assessed. Greater resting state delta and theta amplitudes were linked to Go N1-1 enhancements, but only resting state delta correlated with the NoGo N1-1. These relationships replicate previous data and highlight the functional relevance of low frequency intrinsic activity in attentional processes. However, delta increases from EO to the task predicted poorer Go response accuracy and variability, and enhanced Go Slow Wave (SW) positivity. This increase in delta, and smaller alpha-1 increments, were associated with longer mean RTs. Theta increases predicted larger Go N1-1 amplitudes, but lower NoGo accuracy rates, while beta-1 increments were predictive of NoGo SW negativity. These novel effects suggest that task-related EEG changes impact decision-making and cognitive control processes, and subsequent behavioral performance. PMID- 29409784 TI - Bacterial type III secretion system as a protein delivery tool for a broad range of biomedical applications. AB - A protein delivery tool based on bacterial type III secretion system (T3SS) has been broadly applied in biomedical researches. In this review, we summarize various applications of the T3SS-mediate protein delivery which enables translocation of proteins directly into mammalian cells without protein purification. Some of the remarkable advancements include delivery of antigens for therapeutic vaccines, nucleases for genome editing, transcription factors for cellular reprogramming and stem cells differentiation, and signaling molecules for post-translational proteomics studies. With continued improvement of the T3SS mediated protein delivery tools, even wider application of the technology is anticipated. PMID- 29409783 TI - Analysis of solute-protein interactions and solute-solute competition by zonal elution affinity chromatography. AB - Many biological processes involve solute-protein interactions and solute-solute competition for protein binding. One method that has been developed to examine these interactions is zonal elution affinity chromatography. This review discusses the theory and principles of zonal elution affinity chromatography, along with its general applications. Examples of applications that are examined include the use of this method to estimate the relative extent of solute-protein binding, to examine solute-solute competition and displacement from proteins, and to measure the strength of these interactions. It is also shown how zonal elution affinity chromatography can be used in solvent and temperature studies and to characterize the binding sites for solutes on proteins. In addition, several alternative applications of zonal elution affinity chromatography are discussed, which include the analysis of binding by a solute with a soluble binding agent and studies of allosteric effects. Other recent applications that are considered are the combined use of immunoextraction and zonal elution for drug-protein binding studies, and binding studies that are based on immobilized receptors or small targets. PMID- 29409785 TI - High hydrostatic pressure in cancer immunotherapy and biomedicine. AB - High hydrostatic pressure (HHP) has been known to affect biological systems for >100 years. In this review, we describe the technology of HHP and its effect macromolecules and physiology of eukaryotic cells. We discuss the use of HHP in cancer immunotherapy to kill tumor cells for generation of whole cell and dendritic cell-based vaccines. We further summarize the current use and perspectives of HHP application in biomedicine, specifically in orthopedic surgery and for the viral, microbial and protozoan inactivation to develop vaccines against infectious diseases. PMID- 29409786 TI - Cine MRI during spontaneous cramps in women with menstrual pain. AB - BACKGROUND: The lack of noninvasive methods to study dysmenorrhea has resulted in poor understanding of the mechanisms underlying pain, insufficient diagnostic tests, and limited treatment options. To address this knowledge gap, we have developed a magnetic resonance imaging-based strategy for continuously monitoring the uterus in relationship to participants' spontaneous pain perception. OBJECTIVE: The study objective was to evaluate whether magnetic resonance imaging can detect real-time changes in myometrial activity during cramping episodes in women with dysmenorrhea, with a handheld squeeze bulb for pain reporting. STUDY DESIGN: Sixteen women with dysmenorrhea and 10 healthy control women both on and off their menses were evaluated with magnetic resonance imaging while not taking analgesic medication. Continuous magnetic resonance imaging was acquired using half-Fourier acquisition single-shot turbo spin echo sequence along with simultaneous reporting of pain severity with a squeeze bulb. Pearson's coefficient was used to compare results between reviewers. Proportional differences between women with dysmenorrhea and controls on/off menses were evaluated with a Fisher exact test. The temporal relationships between signal changes were evaluated with Monte Carlo simulations. RESULTS: Spontaneous progressive decreases in myometrial signal intensity were more frequently observed in women on their menses than in the absence of pain in the same women off their menses or participants without dysmenorrhea (P < .01). Women without reductions in myometrial signal intensity on their menses either had a history of endometriosis or were not in pain. Observations of myometrial events were consistently reported between 2 raters blinded to menstrual pain or day status (r = 0.97, P < .001). Episodes of cramping occurred either immediately before or 32 70 seconds after myometrial signal change onset (P < .05). CONCLUSION: Transient decreases in myometrial uterine T2-weighted signal intensity can be reliably measured in women with menstrual pain. The directionality of signal change and temporal relationship to pain onset suggest that cramping pain may be caused by a combination of uterine pressure and hemodynamic dysfunction. PMID- 29409787 TI - Structural, functional, and symptomatic differences between women with rectocele versus cystocele and normal support. AB - BACKGROUND: Prolapse of the anterior and posterior vaginal walls has been generally associated with apical descent and levator ani muscle defects. However, the relative contributions of these factors to the pathophysiology of descent in the different vaginal compartments is not well understood. Furthermore, symptoms uniquely associated with prolapse in these compartments have not been well characterized. OBJECTIVES: The objectives of the study were to compare the associations between the following: (1) apical support, (2) levator ani muscles, and (3) pelvic floor symptoms in women with posterior-predominant prolapse, anterior-predominant prolapse, and normal support. STUDY DESIGN: This is a cross sectional study with 2 case arms: 60 women with posterior prolapse, 90 with anterior prolapse, and a referent control arm with 103 asymptomatic subjects with normal support, determined from pelvic organ prolapse quantification examinations. Levator muscle defects were graded from magnetic resonance imaging. Vaginal closure forces above resting were measured with an instrumented speculum during maximal contraction. Pelvic floor symptoms were measured via the Pelvic Floor Distress Inventory-Short Form. RESULTS: Mean point C location in controls was -6.9 cm [1.5] (mean [standard deviation]); and was higher in posterior prolapse (-4.7 cm [2.7], 2.2 cm below controls) than the anterior prolapse group (-1.2 cm [4.1]; 5.6 cm below controls, P < .001 for all comparisons). Normal appearing muscles (ie, muscle without a visible defect) occurred at similar frequencies in posterior prolapse (45%) and controls (51%, P = .43) but less often in anterior prolapse (28%, P <= .03 for pairwise comparisons). Major levator ani defects occurred at similar rates in women with posterior (33%) and anterior prolapse (42%, P = .27) but less often in controls (16%, P <= .012 for both pairwise comparisons). Similarly, there were significant differences in generated vaginal closure forces across the 3 groups, with the prolapse groups generating weaker closure forces than the control group (P = .004), but the differences between the 2 prolapse groups were not significant after controlling for prolapse size (P = .43). Pelvic floor symptoms were more severe for the posterior (mean Pelvic Floor Distress Inventory score, 129) and anterior prolapse groups (score, 128) than the controls (score, 40.2, P < .001 for both comparisons); the difference between the 2 prolapse groups was not significant (P = .83). CONCLUSION: Posterior-predominant prolapse involves an almost 3-fold less apical descent below normal than anterior-predominant vaginal prolapse. Levator ani defects and muscle impairment also have a lower impact. Pelvic floor symptoms reflect the presence and size of prolapse more than the predominant lax vaginal compartment. PMID- 29409788 TI - Pharmacist delegation: An approach to pharmacy technician regulation. PMID- 29409789 TI - Newly identified type II crustin (SpCrus2) in Scylla paramamosain contains a distinct cysteine distribution pattern exhibiting broad antimicrobial activity. AB - Type II crustins are the most abundant type of crustins in shrimps that exhibit remarkable sequence diversities and broad antibacterial activities. This study characterized a novel type II crustin, SpCrus2, in the mud crab Scylla paramamosain. The SpCrus2 cDNA sequence is 620-bp long with a 495-bp open reading frame encoding a 164-amino acid protein. In the deduced protein, a 17-amino acid signal peptide, a glycine-rich hydrophobic region (GRR), and a cysteine-rich region (CRR) containing a whey acidic protein domain were predicted. SpCrus2 shares high similarity with most type II crustins (types IIa and IIb crustins) in shrimps but has a novel distribution pattern of cysteine residues that is distinct from most crustins. SpCrus2 and PlCrus3 from Pacifastacus leniusculus share high similarity and the same distribution pattern of cysteine residues. Thus, we proposed them as type IIc crustins. SpCrus2 is mainly distributed in the gills and can be up-regulated through Vibrio parahemolyticus or Staphylococcus aureus challenge. To investigate the biological functions of SpCrus2 and the underlying mechanisms, SpCrus2, GRR, CRR, and the mutant of CRR (CRR-M, the cysteine distribution pattern is mutated into that in most conventional crustins) were all overexpressed and purified. SpCrus2 GRR itself, as a glycine-rich amphiphilic peptide, exhibited evident antibacterial ability against Gram negative bacteria, whereas CRR possessed potent antibacterial activity against Gram-positive bacteria. Either GRR or CRR exhibited weaker antibacterial activity than the whole protein of SpCrus2, indicating that GRR and CRR synergized to exert their potential antibacterial functions. In addition, CRR exhibited slightly stronger antimicrobial activity than CRR-M, suggesting that SpCrus2 containing this novel cysteine distribution pattern may exhibit stronger antimicrobial activity than most type II crustins with the conventional distribution pattern of cysteine residues. The likely antimicrobial ability of SpCrus2 may result from its microbial polysaccharide-binding and agglutination activities. Overall, this study characterized the first type II crustin in crabs and provided new insights into understanding the sequence and functional diversity of crustins and their immune functions in crustaceans. PMID- 29409790 TI - Hallmarks of cancer- focus on RNA metabolism and regulatory noncoding RNAs. PMID- 29409791 TI - Minimally invasive surgery in the era of step-up approach for treatment of severe acute pancreatitis. AB - OBJECTIVES: To assess the minimally invasive surgery into the step-up approach procedures as a standard treatment for severe acute pancreatitis and comparing its results with those obtained by classical management. METHODS: Retrospective cohort study comparative with two groups treated over two consecutive, equal periods of time were defined: group A, classic management with open necrosectomy from January 2006 to June 2010; and group B, management with the step-up approach with minimally invasive surgery from July 2010 to December 2014. RESULTS: In group A, 83 patients with severe acute pancreatitis were treated, of whom 19 underwent at least one laparotomy, and in 5 any minimally invasive surgery. In group B, 81 patients were treated: minimally invasive surgery was necessary in 17 cases and laparotomy in 3. Among operated patients, the time from admission to first interventional procedures was significantly longer in group B (9 days vs. 18.5 days; p = 0.042). There were no significant differences in Intensive Care Unit stay or overall stay: 9.5 and 27 days (group A) vs. 8.5 and 21 days (group B). Mortality in operated patients and mortality overall were 50% and 18.1% in group A vs 0% and 6.2% in group B (p < 0.001 and p = 0.030). CONCLUSIONS: The combination of the step-up approach and minimally invasive surgery algorithm is feasible and could be considered as the standard of treatment for severe acute pancreatitis. The mortality rate deliberately descends when it is used. PMID- 29409792 TI - Role of scavenger receptor from Octopus ocellatus as a co-receptor of Toll-like receptor in initiation of TLR-NF-kappaB signaling during anti-bacterial response. AB - Scavenger receptors are crucial for innate immunity owing to their prominent role in clearance of harmful endogenous factors, immune recognition, and more importantly, as co-receptors of Toll-like receptors (TLRs) to initiate downstream responses. At present, invertebrate scavenger receptors, especially their role in immune mechanisms, are largely unknown. We report here that scavenger receptors form a diverse superfamily in Octopus ocellatus, including at least five different members with distinct tissue expression patterns. Two members, OoSR-B and OoSR-I, are grouped into class B and I scavenger receptors, respectively. OoSR-B and OoSR-I are located on the hemocyte membrane, and both recombinant scavenger receptors could serve as pattern recognition receptors to bind a broad range of pathogen-associated molecular patterns. Although OoSR-B and OoSR-I expression was induced by bacterial stimulation, only OoSR-B promoted hemocyte phagocytosis. Moreover, OoSR-B, but not OoSR-I, could act as a co-receptor of TLR to activate TLR-NF-kappaB signaling and initiate TNF-alpha production during anti bacterial response. As the first report on an invertebrate scavenger receptor acting as a co-receptor of TLR, our study reveals the immune mechanism mediated by scavenger receptors in O. ocellatus, and provides new insight into the evolution of this important receptor family. PMID- 29409793 TI - Brain mechanisms underlying cue-based memorizing during free viewing of movie Memento. AB - How does the human brain recall and connect relevant memories with unfolding events? To study this, we presented 25 healthy subjects, during functional magnetic resonance imaging, the movie 'Memento' (director C. Nolan). In this movie, scenes are presented in chronologically reverse order with certain scenes briefly overlapping previously presented scenes. Such overlapping "key-frames" serve as effective memory cues for the viewers, prompting recall of relevant memories of the previously seen scene and connecting them with the concurrent scene. We hypothesized that these repeating key-frames serve as immediate recall cues and would facilitate reconstruction of the story piece-by-piece. The chronological version of Memento, shown in a separate experiment for another group of subjects, served as a control condition. Using multivariate event related pattern analysis method and representational similarity analysis, focal fingerprint patterns of hemodynamic activity were found to emerge during presentation of key-frame scenes. This effect was present in higher-order cortical network with regions including precuneus, angular gyrus, cingulate gyrus, as well as lateral, superior, and middle frontal gyri within frontal poles. This network was right hemispheric dominant. These distributed patterns of brain activity appear to underlie ability to recall relevant memories and connect them with ongoing events, i.e., "what goes with what" in a complex story. Given the real-life likeness of cinematic experience, these results provide new insight into how the human brain recalls, given proper cues, relevant memories to facilitate understanding and prediction of everyday life events. PMID- 29409794 TI - Management of Complications Caused by a Massive Left Ventricle Tumor in a Neonate. AB - We report the case of a neonate born with a giant fibroma occupying the entirety of her left ventricle. Owing to the extensive resection, her postoperative course was complicated by severely diminished left ventricular function and complete heart block necessitating extracorporeal support. Ultimately, cardiac resynchronization therapy was used, after which the infant's ventricular function gradually improved and she was successfully discharged to home. PMID- 29409795 TI - Medicinal foods and beverages among Maasai agro-pastoralists in northern Tanzania. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pastoralist Maasai populations of east Africa use several different wild plants as dietary and medicinal additives in beverages (soups and teas), yet little is known about how the plants used and the rationales for use compare and contrast across different Maasai beverages, including how gender specific dietary and health concerns structure patterns of intake. AIM OF THE STUDY: We investigated three Maasai beverages: almajani (tea or herbal infusion); motori (traditional soup); and okiti (psychoactive herbal tea). In order to build knowledge about the cultural functions of these Maasai food-medicines and their incidence of use we also investigated use rationales and self-reported frequencies of use. We conclude by examining gender differences and the possible pharmacological antimicrobial activity of the most frequently used plants. MATERIALS AND METHODS: Research was conducted in 2015, with a population of semi-nomadic agropastoralist Maasai residing in northern Tanzania. Data were collected using key informant interviews, plant collections, n = 32 structured surveys, and n = 40 freelist interviews followed by a literature review to determine the known antimicrobial activity of the most used plants. RESULTS: We identified 20 plants that Maasai add to soup, 11 in tea, and 11 in the psychoactive tea, for a total of 24 herbal additives. Seven plant species were used in all three Maasai beverages, and these clustered with 10 common ailments. Based on self-reports, women use the beverages less frequently and in smaller amounts than men. There were also several gender differences in the plants that Maasai add to motori and their associated use rationales. CONCLUSIONS: There are several intersections concerning the plant species used and their associated rationales for use in almajani, motori, and okiti. Moving outward, Maasai beverages and their additives increasingly involve gender specific concerns. Female use of food-medicines, relative to men, is structured by concerns over pregnancy, birth, and lactation. The frequent consumption of herbal additives, many of which contain antimicrobial compounds, potentially helps modulate infections, but could have other unintentional effects as well. PMID- 29409797 TI - Cognitive performance under motor demands - On the influence of task difficulty and postural control. AB - We often walk around when we have to think about something, but suddenly stop when we are confronted with a demanding cognitive task, such as calculating 1540*24. While previous neurophysiological research investigated cognitive and motor performance separately, findings that combine both are rare. To get a deeper understanding of the influence of motor demands as well as the difficulty of a simultaneously performed cognitive task, we investigated 20 healthy individuals. Participants performed two cognitive tasks with different levels of difficulty while sitting or standing on one leg. In addition to behavioral data, we recorded the electroencephalogram from 26Ag/AgCI scalp electrodes. The critical time-windows, predefined by visual inspection, yielded an early (200-300 ms, P2) and a subsequent positivity (350-500 ms, P3). Statistical analysis of the early time window registered a motor * cognition interaction. Resolution of this interaction revealed an effect of the cognitive task in the one-legged stance motor condition, with a more pronounced positivity for the difficult task. No significant differences between cognitive tasks emerged for the simple motor condition. The time-window between 350 and 500 ms registered main effects of the motor task and a trend for the cognitive task. While the influence of cognitive task difficulty (in the P3) is in accordance with previous studies, the motor task effect is specific to one-legged stance (cf. no effects for running in previous research). The motor-cognition interaction found in the P2 indicates that the more difficult motor task (one-legged stance) facilitates cognitive task performance. PMID- 29409796 TI - The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. AB - AIM: Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings. MATERIAL AND METHODS: Arterial tone measurement was performed in aortic smooth muscle. KEY FINDINGS: Application of dapagliflozin induced vasodilation in a concentration-dependent manner. Pre-treatment with the BKCa channel inhibitor paxilline, the KATP channel inhibitor glibenclamide, and the Kir channel inhibitor Ba2+ did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca2+ channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin did not alter the vasodilatory effect of dapagliflozin. Moreover, the adenylyl cyclase inhibitor SQ 22536 and the protein kinase A (PKA) inhibitor KT 5720 had no effect on dapagliflozin-induced vasodilation. Although guanylyl cyclase inhibitors, NS 2028 and ODQ, did not reduce the vasodilatory effect of dapagliflozin, the protein kinase G (PKG) inhibitor KT 5823 effectively inhibited dapagliflozin-induced vasodilation. The vasodilatory effect of dapagliflozin was not affected by elimination of the endothelium. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or the small-conductance Ca2+ activated K (SKCa) channel inhibitor apamin did not change the vasodilatory effect of dapagliflozin. SIGNIFICANCE: We concluded that dapagliflozin induced vasodilation via the activation of Kv channels and PKG, and was independent of other K+ channels, Ca2+ channels, intracellular Ca2+, and the endothelium. PMID- 29409798 TI - Are laboratory tests always needed? Frequency and causes of laboratory overuse in a hospital setting. AB - BACKGROUND: Inappropriate utilization of laboratory resources is an increasing concern especially in high-throughput facilities. Until now, no reliable information has been published addressing to which extent laboratory results are actually used for clinical decision-making. Therefore, we aimed to close this gap using a novel retrospective approach including a survey of clinicians and nurses. METHODS: We retrospectively evaluated the number of re-orders for potassium (K), lactate dehydrogenase (LD), aspartate-aminotransferase (AST), activated partial thromboplastin-time (APTT) and prothrombin-time/INR (PT/INR), after the initial order had to be cancelled due to preanalytical non-conformities. We analyzed subgroups regarding time to re-order, ward and sample priority (urgent vs. routine). Subsequently, we surveyed clinicians and nurses, asking for their estimate of the amount of failed re-orders as well as for possible reasons. RESULTS: From initially cancelled tests, only ~20% of K, LD, AST and ~30% of APTT and PT/INR tests were re-ordered within 24 h. 70% of the investigated clinical chemistry and 60% of coagulation tests were re-ordered one week after cancellation or not at all. Survey participants quite accurately estimated these numbers. Routine laboratory panels, short stay of out-patients, obsolete test results and avoiding additional phlebotomies were the main reasons for not re ordering cancelled tests. CONCLUSIONS: Overall, 60-70% of test results in the investigated assays ordered in a high throughput laboratory are potentially inappropriate or of doubtful clinically importance. Although clinicians and nurses are aware of this situation, it is the duty of laboratory specialists to overcome overutilization in close collaboration with all involved healthcare workers. PMID- 29409799 TI - Self-organization in aggregating robot swarms: A DW-KNN topological approach. AB - In certain swarm applications, where the inter-agent distance is not the only factor in the collective behaviours of the swarm, additional properties such as density could have a crucial effect. In this paper, we propose applying a Distance-Weighted K-Nearest Neighbouring (DW-KNN) topology to the behaviour of robot swarms performing self-organized aggregation, in combination with a virtual physics approach to keep the robots together. A distance-weighted function based on a Smoothed Particle Hydrodynamic (SPH) interpolation approach, which is used to evaluate the robot density in the swarm, is applied as the key factor for identifying the K-nearest neighbours taken into account when aggregating the robots. The intra virtual physical connectivity among these neighbours is achieved using a virtual viscoelastic-based proximity model. With the ARGoS based simulator, we model and evaluate the proposed approach, showing various self organized aggregations performed by a swarm of N foot-bot robots. Also, we compared the aggregation quality of DW-KNN aggregation approach to that of the conventional KNN approach and found better performance. PMID- 29409800 TI - Infectious bursal disease virus in Algeria: Detection of highly pathogenic reassortant viruses. AB - Infectious bursal disease (IBD) is an immunosuppressive viral disease, present worldwide, which causes mortality and immunosuppression in young chickens. The causative agent, the Avibirnavirus IBDV, is a non-enveloped virus whose genome consists of two segments (A and B) of double-stranded RNA. Different pathotypes of IBDV exist, ranging from attenuated vaccine strains to very virulent viruses (vvIBDV). In Algeria, despite the prophylactic measures implemented, cases of IBD are still often diagnosed clinically and the current molecular epidemiology of IBDV remains unknown. The presence of the virus and especially of strains genetically close to vvIBDV was confirmed in 2000 by an unpublished OIE report. In this study, nineteen IBDV isolates were collected in Algeria between September 2014 and September 2015 during clinical outbreaks. These isolates were analyzed at the genetic, antigenic and pathogenic levels. Our results reveal a broad genetic and phenotypic diversity of pathogenic IBDV strains in Algeria, with, i) the circulation of viruses with both genome segments related to European vvIBDV, which proved as pathogenic for specific pathogen-free chickens as vvIBDV reference strain, ii) the circulation of viruses closely related - yet with a specific segment B - to European vvIBDV, their pathogenicity being lower than reference vvIBDV, iii) the detection of reassortant viruses whose segment A was related to vvIBDV whereas their segment B did not appear closely related to any reference sequence. Interestingly, the pathogenicity of these potentially reassortant strains was comparable to that of reference vvIBDV. All strains characterized in this study exhibited an antigenicity similar to the cognate reference IBDV strains. These data reveal the continuous genetic evolution of IBDV strains in Algerian poultry through reassortment and acquisition of genetic material of unidentified origin. Continuous surveillance of the situation as well as good vaccination practice associated with appropriate biosecurity measures are necessary for disease control. PMID- 29409801 TI - The minimum infusion rate of alfaxalone during its co-administration with lidocaine at three different doses by constant rate infusion in goats. AB - OBJECTIVE: To determine the minimum infusion rate (MIR) of alfaxalone required to prevent purposeful movement in response to standardized stimulation while co administered with lidocaine at three different doses by constant infusion rate infusion (CRI) in goats. STUDY DESIGN: Prospective, blinded, randomized crossover, experimental. ANIMALS: A total of eight healthy goats: four does and four wethers. METHODS: Anaesthetic induction was with lidocaine at 1 mg kg-1 [low dose of lidocaine (L-Lid)], 2 mg kg-1 [moderate dose (M-Lid)] or 4 mg kg-1 [high dose (H-Lid)] and alfaxalone at 2 mg kg-1. Anaesthetic maintenance was with alfaxalone initially at 9.6 mg kg-1 hour-1 combined with one of three lidocaine treatments: 3 mg kg-1 hour-1 (L-Lid), 6 mg kg-1 hour-1 (M-Lid) or 12 mg kg-1 hour 1 (H-Lid). The MIR of alfaxalone was determined by testing for responses to a stimulation in the form of clamping on a digit with a Vulsellum forceps every 30 minutes during lidocaine CRI. Basic cardiopulmonary parameters were measured. RESULTS: The alfaxalone MIRs were 8.64 (6.72-10.56), 6.72 (6.72-8.64) and 6.72 (6.72-6.72) mg kg-1 hour-1 during L-Lid, M-Lid and H-Lid, respectively, without any significant differences among treatments. Compared to the initial rate of 9.6 mg kg-1 hour-1, these reductions in MIR are equivalent to 10, 30 and 30%, respectively. Significant increases in heart rate (HR) and arterial carbon dioxide partial pressure (PaCO2) and decreases in arterial haemoglobin saturation (SaO2), arterial oxygen partial pressure (PaO2) and respiratory frequency (fR) immediately after induction were observed during all lidocaine treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine reduces the alfaxalone MIR by up to 30% with a tendency towards a plateauing in this effect at high CRIs. Immediate oxygen supplementation might be required to prevent hypoxaemia. PMID- 29409802 TI - Corneal abrasion and microbial contamination in horses following general anaesthesia for non-ocular surgery. AB - OBJECTIVE: To evaluate the incidence of corneal abrasions/ulceration and microbial contamination in horses undergoing general anaesthesia. STUDY DESIGN: Prospective, observational, clinical study. ANIMALS: A total of 40 client-owned healthy horses scheduled for elective non-ophthalmic procedures. METHODS: Conjunctival sac swabs were taken, fluorescein dye applied and digital images recorded from both eyes of the horses after preanaesthetic medication and 24 hours after recovery from general anaesthesia. A paraffin-based bland ophthalmic ointment was applied on the ocular surface intraoperatively following collection of a sample into a sterile container. All samples underwent aerobic, anaerobic and fungal culture. Subject demographics, chronology of ophthalmic ointment use, anaesthesia duration, recumbency after induction, during surgery and recovery, fluorescein uptake and culture results were recorded. Descriptive statistics were performed. RESULTS: Complete data were collected from 34 horses; six (17.6%) developed mild unilateral generalized fluorescein uptake consistent with corneal abrasions. Recumbency on the operating table was the only risk factor significantly associated with corneal abrasions. A total of 11 bacterial species were identified; Staphylococcus spp. (15 eyes) and Micrococcus spp. (eight eyes) were the most frequently isolated bacteria. Two fungal species were isolated postoperatively (Aspergillus spp., Saccharomyces spp.) in two eyes. Ointment contamination was recorded in two cases (5%) but cross-contamination was not recognized. CONCLUSIONSAND CLINICAL RELEVANCE: Incidence of corneal abrasion/ulceration in horses undergoing general anaesthesia and contamination rate of ophthalmic solutions are similar to those previously reported in dogs. PMID- 29409803 TI - Effect of metoclopramide on nausea and emesis in dogs premedicated with morphine and dexmedetomidine. AB - OBJECTIVE: To evaluate whether subcutaneous (SC) metoclopramide (0.2 mg kg-1) administered 30 minutes prior to (T30) or simultaneously with (T0) intramuscular (IM) morphine (0.2 mg kg-1) and dexmedetomidine (0.003 mg kg-1) reduces the incidence of nausea and emesis in healthy dogs. STUDY DESIGN: Prospective, randomized and blinded study. ANIMALS: A total of 45 dogs scheduled for elective procedures. METHODS: Dogs were assigned randomly to three groups to be administered SC metoclopramide (0.2 mg kg-1) 30 minutes before (group M30) or simultaneously (group M0) to IM morphine (0.2 mg kg-1) and dexmedetomidine (0.003 mg kg-1). Dogs in the control group (group C) were administered SC saline at T30 and T0. Dogs were observed for 30 minutes after premedication to evaluate signs of nausea (continuous lip-licking and sialorrhoea) and emesis. Signs of pain or discomfort caused by SC injections were also recorded. RESULTS: There were no statistical differences amongst groups for age, body weight and sex. More dogs developed continuous lip-licking in group C (12/15, 80.0%) compared to dogs in group M30 (1/15, 6.7%) and dogs in group M0 (5/15, 33.3%; p = 0.0001 and p = 0.01, respectively). More dogs developed sialorrhoea in group M0 (8/15, 53.3%) and in group C (10/15, 66.7%) compared to dogs in group M30 (2/15, 13.3%; p = 0.03 and p = 0.004, respectively). More dogs vomited in group M0 (4/15, 26.7%) and in group C (9/15, 60.0%) compared to dogs in group M30 (0/15, 0.0%; p = 0.05 and p = 0.0003, respectively). None of the dogs demonstrated signs of pain or discomfort during SC metoclopramide injection. CONCLUSIONS AND CLINICAL RELEVANCE: Subcutaneous metoclopramide at 0.2 mg kg-1 may reduce IM morphine and dexmedetomidine-induced nausea and emesis if administered 30 minutes in advance. It is effective in reducing lip-licking even when administered concurrently with IM morphine-dexmedetomidine. PMID- 29409804 TI - Stress-related biomarkers in dogs administered regional anaesthesia or fentanyl for analgesia during stifle surgery: a comment. PMID- 29409805 TI - PROMises Made, PROMises To Be Kept: Patient-Reported Outcome Measures in Inflammatory Bowel Diseases. PMID- 29409806 TI - Vitamin A deficiency induces endoplasmic reticulum stress and apoptosis in pancreatic islet cells: Implications of stearoyl-CoA desaturase 1-mediated oleic acid synthesis. AB - Previously, we reported that vitamin A deficiency resulted in the reduction of stearoyl-CoA desaturase 1 (SCD1) and monounsaturated fatty acid (MUFA) levels, which corroborated with attenuation of high fructose-induced hepatic steatosis. Here, we aimed at assessing the effect of vitamin A deficiency on SCD1, MUFA levels and their impact on pancreas' structure and functions. Male weanling Wistar rats fed one of the four diets, namely control (Con), vitamin A-deficient (VAD), highfructose (HFr) and vitamin A-deficient diet with highfructose (VADHFr) for 16 weeks period. Compared to the control, feeding of VAD diet (alone or with HFr) resulted in pancreatic intra-islet vessel dilation and reduced plasma insulin, glucagon and C-peptide levels, however, glucose levels decreased only in VADHFr group. In line with plasma levels, VAD diet-fed animals displayed lower immunostaining for insulin and glucagon, which corroborated with increased apoptotic staining observed in the islet regions, possibly due to increased cellular stress, as indicated by high immunostaining for endothelial nitric oxide synthase (eNOS) and CCAAT/Enhancer-binding protein homologues protein (CHOP). On the other hand, it significantly decreased the SCD1 protein, which corroborated with reduced MUFA levels, particularly, oleic acid (C18:1), when compared to the control and HFr groups. In conclusion, chronic vitamin A deficiency altered the structure and functions of pancreas by diminishing the islet cells, possibly by inducing cellular stress-mediated apoptosis and decreasing SCD1-mediated oleic acid (C18:1) synthesis. Thus, the data suggest that unlike liver, the reduction in SCD1 and MUFA levels in the pancreas exerts deleterious effects on its functions and perturb the overall cellular metabolism. PMID- 29409808 TI - Long non-coding RNA linc00460 promotes epithelial-mesenchymal transition and cell migration in lung cancer cells. AB - Long non-coding RNAs (lncRNAs) function as critical regulators to participate in tumor progression and metastasis. However, their roles in non-small cell lung cancer (NSCLC) are poorly understood. In this study, we found that the expression of the lncRNA linc00460 is significantly upregulated in NSCLC tumors and associated with poor prognosis for NSCLC patients, implying that linc00460 is important for lung cancer development. The accurate transcription initiation and termination sites of linc00460 were then identified by rapid-amplification of cDNA ends (RACE) technologies, and the sequencing data demonstrated that linc00460, predominantly located in the cytoplasm of lung cancer cells, is a novel transcript variant. Functional studies through gain- and loss-of-function strategies showed that linc00460 promotes cell migration and invasion through inducing epithelial-mesenchymal transition in lung cancer cells, whereas it has no effect on cell proliferation. The mechanism investigations through RNA pull down assay and mass spectrometry identified that hnRNP K physically interacts with linc00460, and it also participates in cell migration and invasion. Therefore, our findings suggest that linc00460 acts as an oncogene in NSCLC to promote cell migration and highlight the potential prognostic and therapeutic values of linc00460 for NSCLC patients. PMID- 29409807 TI - Locomotor activity does not predict individual differences in morphine self administration in rats. AB - Understanding factors contributing to individual differences in opioid addiction vulnerability is essential for developing more effective preventions and treatments. Sensation seeking has been implicated in addiction to several drugs of abuse, yet its relationship with individual differences in opioid addiction vulnerability has not been well established. The primary goal of this study was to evaluate the relationship between locomotor activity in a novel environment, a preclinical model of sensation-seeking, and individual differences in acquisition of i.v. morphine self-administration (SA) in rats. A secondary goal was to evaluate the relationship between activity and elasticity of demand (reinforcing efficacy) for morphine measured using a behavioral economic approach. Following an initial locomotor activity screen, animals were allowed to acquire morphine SA at a unit dose of 0.5 mg/kg/infusion in 4 hour/day sessions (Experiment 1) or 0.2 mg/kg/infusion in 2 hour/day sessions (Experiment 2) until infusion rates were stable. Unit price was subsequently manipulated via progressive reductions in unit dose (Experiment 1) or increases in response requirement per infusion (Experiment 2). Activity levels were not correlated with acquisition of morphine SA in either experiment. Morphine consumption was generally well described by an exponential demand function in both experiments (R2 values > 0.95 for rats as a group), but activity did not correlate with behavioral economic measures. Locomotor activity in a novel environment did not predict individual differences in acquisition of morphine SA. These data complement findings from some human studies and suggest that the role of sensation seeking in individual differences in opioid addiction vulnerability may be limited. PMID- 29409809 TI - Crosstalk between the Notch signaling pathway and long non-coding RNAs. AB - The Notch signaling pathway has a key role in cellular development and is involved in initiation and progression of cancer by fundamentally influencing cellular processes such as differentiation, proliferation or migration. The pathway is regulated on many stages, generating diverse outcomes depending on cellular context or signaling dose. Recent studies suggest that long non-coding RNAs (lncRNAs), a class of non-coding RNAs deregulated in many cancers, are involved in regulating the Notch pathway activity by modulating the expression of receptors or ligands on transcriptional or posttranscriptional levels. LncRNAs are also downstream targets of Notch signaling and some of these Notch-induced lncRNAs have been reported to be inducers of its oncogenic effects. This cross talk between Notch signaling and lncRNAs makes those molecules potential biomarkers for Notch signaling activity and interesting therapeutic RNA-based targets in the future. PMID- 29409810 TI - FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway. AB - Lymphatic metastasis is the main route of breast cancer metastasis. It is known that lymphangiogenesis facilitates lymphatic metastasis through vascular endothelial growth factor-C (VEGF-C)/VEGF receptor 3 (VEGFR3) pathway-linked interactions between the tumor and its microenvironment. Here, we report a novel mechanism of lymphatic metastasis by which aggressive basal-like breast cancer (BLBC) cells form lymphatic vessel-like structures that are identified by the positive expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin, and VEGFR3, and termed as lymphangiogenic mimicry (LM), for the first time. Our clinical evidence and experimental data in vivo and in vitro revealed that forkhead box F2 (FOXF2) deficiency promotes the lymphatic metastasis of BLBC by conferring a lymphangiogenic mimetic feature upon cancer cells through directly activating VEGFR3 transcription. The fact that FOXF2 controls the activation of the VEGF C/VEGFR3 signaling pathway in BLBC cells provides potential molecular diagnostic and therapeutic strategies for lymphatic metastasis in BLBC patients. PMID- 29409811 TI - Serum Albumin's Protective Inhibition of Amyloid-beta Fiber Formation Is Suppressed by Cholesterol, Fatty Acids and Warfarin. AB - Central to Alzheimer's disease (AD) pathology is the assembly of monomeric amyloid-beta peptide (Abeta) into oligomers and fibers. The most abundant protein in the blood plasma and cerebrospinal fluid is human serum albumin. Albumin can bind to Abeta and is capable of inhibiting the fibrillization of Abeta at physiological (MUM) concentrations. The ability of albumin to bind Abeta has recently been exploited in a phase II clinical trial, which showed a reduction in cognitive decline in AD patients undergoing albumin-plasma exchange. Here we explore the equilibrium between Abeta monomer, oligomer and fiber in the presence of albumin. Using transmission electron microscopy and thioflavin-T fluorescent dye, we have shown that albumin traps Abeta as oligomers, 9 nm in diameter. We show that albumin-trapped Abeta oligomeric assemblies are not capable of forming ion channels, which suggests a mechanism by which albumin is protective in Abeta exposed neuronal cells. In vivo albumin binds a variety of endogenous and therapeutic exogenous hydrophobic molecules, including cholesterol, fatty acids and warfarin. We show that these molecules bind to albumin and suppress its ability to inhibit Abeta fiber formation. The interplay between Abeta, albumin and endogenous hydrophobic molecules impacts Abeta assembly; thus, changes in cholesterol and fatty acid levels in vivo may impact Abeta fibrillization, by altering the capacity of albumin to bind Abeta. These observations are particularly intriguing given that high cholesterol or fatty acid diets are well established risk factors for late-onset AD. PMID- 29409812 TI - Effects of obesity therapies on sleep disorders. AB - Obesity is a significant risk factor for obstructive sleep apnea syndrome (OSAS), and has also been linked to reductions in sleep quality and quantity. Weight loss has been shown to be an effective treatment for improving OSAS; however, there is a high degree of variability in improvements of OSAS in response to weight loss. There are three modalities of obesity therapies: 1) lifestyle modification, which includes changes in dietary intake and physical activity, along with behavioral interventions; 2) pharmacologic agents; and 3) bariatric surgery. Individuals have a highly variable response to the various obesity interventions, and maintenance of weight loss can be especially challenging. These factors influence the effect of weight loss on sleep disorders. There is still a need for large, well-controlled studies examining short- and long-term efficacy of weight loss modalities and their impact on long-term treatment of OSAS and other sleep parameters, particularly in youth. Nonetheless, given our current knowledge, weight reduction should always be encouraged for people coping with obesity, OSAS, and/or sleep disruptions and resources identified to assist patients in choosing a weight loss approach that will benefit them the most. PMID- 29409813 TI - Duration of Dual Antiplatelet Therapy for Stented Patients: An Update for the Clinician. AB - Determining the optimal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention is a complex decision. Randomized controlled trials have shown that while shorter durations of DAPT may lower the risk of bleeding, longer durations of DAPT can reduce the risk of late stent thrombosis and ischemia-related events. In this review article, we will discuss the current guidelines, review contemporary trial data that have evaluated short and extended durations of DAPT, and address common clinical questions. Ultimately, the determination of the optimal duration of DAPT is an individualized decision that requires clinicians to assess each patient's risk for bleeding and recurrent ischemic events. PMID- 29409814 TI - SMARCAD1 Haploinsufficiency Underlies Huriez Syndrome and Associated Skin Cancer Susceptibility. PMID- 29409815 TI - Fusobacterium nucleatum and adverse pregnancy outcomes: Epidemiological and mechanistic evidence. AB - Fusobacterium nucleatum is a Gram-negative anaerobic oral commensal associated with periodontal disease. F. nucleatum has been implicated in a wide spectrum of systemic diseases, including oral, gastro-intestinal, rheumatologic, and vascular pathologies. As pregnancy risk has been linked to periodontal disease, there has also been significant research into the effects of periodontal disease on adverse pregnancy outcomes. This article reviews the epidemiological and mechanistic evidence of the role of F. nucleatum in adverse pregnancy outcomes. PMID- 29409816 TI - Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). AB - RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome. PMID- 29409817 TI - Botulinum toxin treatment of pain syndromes -an evidence based review. AB - This review evaluates the existing level of evidence for efficacy of BoNTs in different pain syndromes using the recommended efficacy criteria from the Assessment and Therapeutic Subcommittee of the American Academy of Neurology. There is a level A evidence (effective) for BoNT therapy in post-herpetic neuralgia, trigeminal neuralgia, and posttraumatic neuralgia. There is a level B evidence (probably effective) for diabetic neuropathy, plantar fasciitis, piriformis syndrome, pain associated with total knee arthroplasty, male pelvic pain syndrome, chronic low back pain, male pelvic pain, and neuropathic pain secondary to traumatic spinal cord injury. BoNTs are possibly effective (Level C one class II study) for female pelvic pain, painful knee osteoarthritis, post operative pain in children with cerebral palsy after adductor release surgery, anterior knee pain with vastus lateralis imbalance. There is a level B evidence (one class I study) that BoNT treatment is probably ineffective in carpal tunnel syndrome. For myofascial pain syndrome, the level of evidence is U (undetermined) due to contradicting results. More high quality (Class I) studies and studies with different types of BoNTs are needed for better understanding of the role of BoNTs in pain syndromes. PMID- 29409818 TI - Effect of N-linked glycosylation on the activity and stability of a beta glucosidase from Putranjiva roxburghii. AB - In this study, the effect of N-glycosylation on the conformational and functional stability of Putranjiva roxburghii family 1 beta-glucosidase (PRGH1) enzyme was investigated. The deglycosylation of PRGH1 was carried out by using PNGase F enzyme and confirmed by SDS-PAGE and carbohydrate estimation. Comparative analysis with respect to enzyme activity, stability and aggregation behaviour was carried out for the glycosylated and deglycosylated PRGH1. The deglycosylation of PRGH1 affected enzyme activity to a certain extent only where Km was not affected but a slight reduction in Vmax for various substrates was observed. Circular dichroism, fluorescence studies and differential scanning calorimetry (DSC) analysis demonstrated the possible effect of glycosylation on local and/or global conformational dynamics of protein and its effect on the thermostability of PRGH1. DSC results showed deglycosylated form had lower Tm as compared to the glycosylated form of PRGH1. The PRGH1 was found to be more sensitive to proteolysis after deglycosylation suggesting that the glycosylated PRGH1 was quite compact and rigid. Mutagenesis studies revealed that out of seven potential N-linked glycosylation sites, only three were glycosylated. The results demonstrated that N-linked glycosylation played an important role in conformational stability of PRGH1; however, it did not affect the enzyme function drastically. PMID- 29409819 TI - Referenced MR thermometry using three-echo phase-based fat water separation method. AB - A three-point image reconstruction method for internally referenced MR thermometry was developed. The technique exploits the fact that temperature induced changes in the water resonance frequency are small relative to the chemical shift difference between water and fat signals. This property enabled the use of small angle approximations to derive an analytic phase-based fat-water separation method for MR thermometry. Ethylene glycol and cream cool-down experiments were performed to validate measurement technique. Over a cool-down temperature range of 20 degrees C, maximum deviation between probe and MR measurement (averaged over 1.3 cm3 region surrounding probe) was 0.6 degrees C and 1.1 degrees C for ethylene glycol and cream samples, respectively. PMID- 29409820 TI - Versatile redox-sensitive pullulan nanoparticles for enhanced liver targeting and efficient cancer therapy. AB - A reversibly disulfide-crosslinked pullulan nanoparticle with folic acid (FA) decoration (FA-Pull-LA CLNPs) was fabricated for dual-targeted and reduction responsive anti-tumoral liver drug delivery based on the specific affinity of pullulan and FA to overexpress asialoglycoprtein receptors (ASGPR) and folate receptors (FR), respectively. Paclitaxel (PTX)-loaded FA-Pull-LA nanoparticles (NPs) with satisfactory size, polydispersity index (PDI), and zeta potential exhibited much faster PTX release in the presence of 10mM glutathione (GSH) rather than physiological conditions. In vitro cellular assays confirmed the dual targetability and endosomal accumulation of FA-Pull-LA NPs. In SMMC-7721 tumor bearing mice, FA-Pull-LA-PTX CLNPs showed the strongest anti-tumor efficiency as well as the lowest toxicity among all three groups. Conclusively, the present study implied that reversibly crosslinked FA-Pull-LA NPs with dual-targeting capacity provided a stable and intelligent platform for efficient liver cancer therapy, which should be further studied for a wide range of anti-cancer applications. PMID- 29409821 TI - Ether-linked lipids: Spin-label EPR and spin echoes. AB - Electron spin echo envelope modulation (ESEEM) and conventional electron paramagnetic resonance (EPR) of site-specifically spin-labelled phospholipids are used to investigate the effect of ether-linked chains on the water-penetration and polarity profiles, as well as the phase behaviour and chain flexibility profiles, of phospholipid membranes. D2O-ESEEM reveals that water exposure of the terminal methyl groups in the interdigitated phase of dihexadecyl phosphatidylcholine (DHPC) is comparable to that of the methylene groups at the polar head-group end of the chains. Similarly, an uniform transmembrane polarity profile is obtained from the dependence of the outer 14N-hyperfine splitting on the spin-label position along the chain in frozen interdigitated DHPC dispersions. Two-component conventional EPR spectra of spin labels at the terminal methyl end of the chain reveal that the intermediate gel phase above the pretransition of DHPC contains components in which the lipid chains are interdigitated. The polarity and chain-flexibility profiles in the fluid Lalpha phase of DHPC with ether-linked chains are shifted outwards, towards the polar apolar interface, as compared with that of dihexadecanoyl phosphatidylcholine (DPPC) with ester-linked chains. Also, the polarity profile of DHPC is shifted upwards, to higher polarities. These differences reflect those in hydrocarbon thickness and area/lipid molecule reported by x-ray diffraction for the Lalpha phases of the two lipids. PMID- 29409822 TI - Serum levels of advanced glycation end-products (AGEs) and the decoy soluble receptor for AGEs (sRAGE) can identify non-alcoholic fatty liver disease in age-, sex- and BMI-matched normo-glycemic adults. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a serious health problem affecting ~25% of the global population. While NAFLD pathogenesis is still unclear, multiple NAFLD parameters, including reduced insulin sensitivity, impaired glucose metabolism and increased oxidative stress are hypothesised to foster the formation of advanced glycation end-products (AGEs). Given the link of AGEs with end organ damage, there is scope to examine the role of the AGE/RAGE axis activation in liver injury and NAFLD. METHODS: Age, sex and body mass index matched normo-glycemic NAFLD adults (n = 58) and healthy controls (n = 58) were enrolled in the study. AGEs were analysed by liquid chromatography-mass spectrometry (CML, CEL), fluorescence (pentosidine, AGE fluorescence), colorimetry (fructosamine) and ELISA (sRAGE). Their association with liver function, inflammation, fibrosis and stage of NAFLD was examined. RESULTS: Early and advanced glycation end-products, except Nepsilon-carboxymethyl-L-lysine (CML), were 10-30% higher, sRAGE levels 1.7-fold lower, and glycation/sRAGE ratios 4-fold higher in the NAFLD cases compared to controls. While AGEs presented weak to moderate correlations with indices of liver function and damage (AST/ALT, HOMA-IR, TNF-alpha and TGF-beta1), including sRAGE to characterize the AGEs/sRAGE axis strengthened the associations observed. High glycation/sRAGE ratios were associated with 1.3 to 14-fold likelihood of lower AST/ALT ratios. The sum of AGEs/sRAGE ratios accurately distinguished between healthy controls and NAFLD patients (area under the curve of 0.85). Elevated AGEs/sRAGE (>7.8 mmol/pmol) was associated with a 12-fold likelihood of the presence of NAFLD. CONCLUSION: These findings strengthen the involvement of AGEs-RAGE axis in liver injury and the pathogenesis of NAFLD. PMID- 29409823 TI - Polymerase chain reaction (PCR) in ocular and ganglionar toxoplasmosis and the effect of therapeutics for prevention of ocular involvement in South American setting. AB - INTRODUCTION: Cases of toxoplasmosis present in South America tend to be more severe than that found in other continents. Here, we present our clinical experience of ocular and ganglionar toxoplasmosis in the use of PCR, and of the treatment to prevent ocular involvement. METHODOLOGY: Retrospective analysis of clinical charts of patients with ocular and lymphadenitic toxoplasmosis at the parasitology and tropical medicine consultation in the "Universidad del Quindio" in Colombia. In total, 91 records of cases with ocular toxoplasmosis and 17 with lymphadenitis that underwent PCR analysis for B1 repeated sequence in blood, were compared to the results of 104 people with chronic asymptomatic toxoplasmosis. In addition, 41 clinical records were included from patients with confirmed toxoplasmic lymphadenitis: 10 untreated, 6 that begun treatment after four months of symptoms, and 25 that were treated during the first four months of symptoms and had a follow-up during at least one year. RESULTS: Patients with ocular toxoplasmosis or lymphadenitis had a higher probability of PCR positivity in peripheral blood than chronic asymptomatic people. There were no cases of retinochoroiditis in 25 patients with toxoplasmic lymphadenitis treated before 4 months of symptoms and followed during at least 12 months. In four out of ten untreated cases, new lesions of retinochoroiditis presented after the symptoms of lymphadenitis. CONCLUSIONS: Toxoplasmosisin South America exhibits different clinical behavior and this influences the laboratory results as well as the need for treatment in the case of lymphadenitis. Clinicians should be aware of the geographical origin of the infection in order to adopt different therapeutic and diagnostic approaches. PMID- 29409824 TI - 68Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study. AB - PURPOSE: 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography may represent the most promising imaging modality to identify and risk stratify prostate cancer in patients with contraindications to or negative multiparametric magnetic resonance imaging. MATERIALS AND METHODS: In this prospective observational study we analyzed 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography in a select group of patients with persistently elevated prostate specific antigen and/or Prostate Health Index suspicious for prostate cancer, negative digital rectal examination and at least 1 negative biopsy. The cohort comprised men with equivocal multiparametric magnetic resonance imaging (Prostate Imaging-Reporting and Data System, version 2 score of 2 or less), or an absolute or relative contraindication to multiparametric magnetic resonance imaging. Sensitivity, specificity and CIs were calculated compared to histopathology findings. ROC analysis was applied to determine the optimal cutoff values of 68Ga labeled prostate specific membrane antigen uptake to identify clinically significant prostate cancer (Gleason score 7 or greater). RESULTS: A total of 45 patients with a median age of 64 years were referred for 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography between January and August 2017. The 25 patients (55.5%) considered to have positive positron emission tomography results underwent software assisted fusion biopsy. We determined the uptake values of regions of interest, including a median maximum standardized uptake value of 5.34 (range 2.25 to 30.41) and a maximum-to-background standardized uptake value ratio of 1.99 (range 1.06 to 14.42). Mean and median uptake values on 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography (ie the maximum standardized uptake value or the maximum-to-background standardized uptake value ratio) were significantly higher for Gleason score 7 lesions than for Gleason score 6 or benign lesions (p <0.001). On ROC analysis a maximum standardized uptake value of 5.4 and a maximum-to-background standardized uptake value ratio of 2 discriminated clinically relevant prostate cancer with 100% overall sensitivity in each case, and 76% and 88% specificity, respectively. CONCLUSIONS: Our findings support the use of 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography for primary detection of prostate cancer in a specific subset of men. PMID- 29409825 TI - The impact of air pollutants, UV exposure and geographic location on vitamin D deficiency. AB - Vitamin D (VD) is an important nutrient for preventing several chronic diseases, and vitamin D deficiency (VDD) causes many diseases. Air pollution has been reported as one of the most significant factors that causes VDD. Some epidemiological studies have evaluated VDD prevalence, and presented air pollution as a potential cause of VDD. In addition, recent case studies have found that VDD is associated with air pollutants. Nearly all reports agree that air pollution affects VD levels by reducing sun exposure, especially UVB radiation. Sun exposure accounts for >90% of VD production in humans. Recent studies have demonstrated that tropospheric ozone and particulate matter are independent risks to VD levels and cause deficiency. However, obtaining comprehensive conclusions on the impact of air pollution on VDD is necessary. This study aims to review all related papers to determine how air pollution can affect VD levels. PMID- 29409826 TI - Capsule Endoscopy for Refractory Iron Deficiency Anemia in Crohn's Disease: Captivating Pathology, Hybrid Therapy. PMID- 29409827 TI - High Fever After Radiofrequency Ablation of Hepatocellular Carcinoma. PMID- 29409828 TI - Don't Mess With the Pancreas (Wherever It May Be): Acute Pancreatic Rest"itis" Presenting as a Submucosal Mass With Gastric Outlet Obstruction. PMID- 29409829 TI - An Emerging Cause for Liver Abscesses With Poor Prognosis. PMID- 29409831 TI - Serum uric acid in Friedreich Ataxia. AB - Serum uric acid (UA) is a circulating antioxidant whose levels are typically lower in patients with idiopathic neurodegenerative diseases than healthy controls, reflecting a higher oxidative stress. Here we provided the first assessment of serum UA in Friedreich Ataxia (FRDA), an inherited neurodegenerative disorder, aimed at exploring novel disease biomarkers. Serum UA was measured in 19 FRDA patients and compared to 26 healthy controls (CTL). Multivariate analysis was conducted to eliminate main confounding factors (age, gender and BMI). Diagnostic accuracy was tested with ROC curve analysis and cut off point calculation. Clinical predictive value was quantified by means Spearman's correlation with SARA score and other clinical parameters. Serum UA levels resulted significantly higher in FRDA than CTL (p = .016), independently from age, gender and BMI. At the cut-off value of 4.45 mg/dl, serum UA discriminates FRDA from CTL with >70% of sensitivity and >60% of specificity. No correlations emerged with clinical data. Contrarily to other neurodegenerative diseases, in FRDA, we observed an independent increase of serum UA content. Taking in account previous experimental findings, we hypothesize that such a finding may result from biochemical impairment induced by the genetic defect, acting as a sort of compensatory antioxidant defense although proper dedicated studies are mandatory. This preliminary report focuses UA as a potential biomarker for FRDA and encourages further studies on novel therapeutic strategies. PMID- 29409830 TI - HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas. AB - We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-gamma dimer (Fib-gammaD) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-gammaD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-gammaD formation. Cerulein administration resulted in activation and stabilization of hypoxia inducible factor-1alpha (HIF1alpha) in pancreata of oxygen-dependent degradation domain-luciferase HIF1alpha reporter mice. Cerulein also led to induction of genes regulated by HIF1alpha, including Vegfa and Ero1a, before evidence of Fib gammaD deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1aAc-/-) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-gammaD following administration of cerulein. Feeding mice increased pancreatic expression of HIF1alpha, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1alpha has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation. PMID- 29409832 TI - The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers. AB - Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6alpha-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo cholestan-3beta,5alpha-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors. Importantly, by binding the liver X receptor (LXR), DDA activates the expression of genes controlling autophagy. These genes include NR4A1, NR4A3, LC3 and TFEB. The canonical LXR ligands 22(R)hydroxycholesterol, TO901317 and GW3965 did not induce these effects indicating that DDA delineates a new class of selective LXR modulator (SLiM). The induction of lethal autophagy by DDA was associated with the accumulation in cancer cells of lysosomes and of the pro-lysosomal cholesterol precursor zymostenol due to the inhibition of the 3beta-hydroxysteroid-Delta8Delta7 isomerase enzyme (D8D7I). The anti-cancer efficacy of DDA was established on different mouse and human cancers such as breast cancers, melanoma and acute myeloid leukemia, including patient derived xenografts, and did not discriminate bulk cancer cells from cancer cell progenitors. Together these data highlight that the mammalian metabolite DDA is a promising anticancer compound with a broad range of anticancer applications. In addition, DDA and LXR are new actors in the transcriptional control of autophagy and DDA being a "first in line" driver of lethal autophagy in cancers via the LXR. PMID- 29409833 TI - A randomized comparison of intravenous sedation using a dosing algorithm compared to standard care during first-trimester surgical abortion. AB - OBJECTIVE: The objective was to compare the safety and efficacy of an algorithm for abortion intravenous sedation dosing (AAID) to standard dosing during first trimester surgical abortion. STUDY DESIGN: This was a randomized, single-blinded, controlled trial in which women undergoing first-trimester surgical abortion received fentanyl and midazolam dosed per either an algorithm or clinic standard. Patient-level factors including weight, airway risk, anxiety, and drug and alcohol use determined AAID doses. The primary outcome was pain with suction curettage measured immediately on a 21-point verbal numerical rating scale ranging from 0 to 100. Secondary outcomes included pain with cervical dilation and postprocedure, intraoperative pain as recalled postprocedure, need for additional doses of medication, oxygen saturation<93%, sedation level, adverse events, side effects and patient satisfaction. RESULTS: We enrolled 196 women and randomized 98 to the AAID and 98 to standard care. Baseline factors were similar between groups. Median intraoperative pain scores did not differ between groups when measured immediately (47.5 vs. 50, p=.81) or on recall (30 in both arms, p=.68). There were no significant differences in other secondary outcomes. Women with a body mass index (BMI) 30-35 trended toward improved pain control with the algorithm (60 vs. 27.5, p=.07). CONCLUSIONS: Intravenous sedation determined by an algorithm did not produce differences in pain scores in a setting with highly experienced providers. IMPLICATIONS: An intravenous sedation algorithm did not demonstrate significant benefit for the general population of surgical abortion patients. Providers with less experience titrating intravenous sedation might find it a helpful tool to guide sedation dosing. A possible benefit in obese patients warrants further study. PMID- 29409834 TI - Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone(r) and estradiol: pharmacokinetics from a dose-finding study. AB - BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone(r) (NES)) combined with one of three different estradiol (E2) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E2, the Cmax occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to<=50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. CONCLUSION: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS: While these novel estradiol releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed. PMID- 29409835 TI - Reactive oxygen species-responsive nanoprodrug with quinone methides-mediated GSH depletion for improved chlorambucil breast cancers therapy. AB - Prodrug-based stimuli-responsive vectors have emerged as highly promising platform. Inspired by the fact that antioxidant systems including glutathione (GSH) make cancer cells adapt to oxidative stress and play a role in the inactivation of alkylating agents like chlorambucil (CHL) inside tumor cells, while arylboronic acid could transform into GSH depleting agent quinone methide (QM) upon degradation by reactive oxygen species (ROS) over-expressed in tumor cells, a ROS-responsive nanoprodrug (denoted by PPAHC) of CHL was established by integrating CHL into diols-containing hydrophilic polymer with self-immolative linker 4-(hydroxymethyl)phenylboronic acid (HPBA). The prodrug could form core shell nanoparticle and possess high stability during storage. Drug release profile of PPAHC nanoprodrug demonstrated that nature CHL could be quickly released from PPAHC nanoprodrug in the presence of hydrogen peroxide (H2O2). Moreover, PPAHC nanoprodrug showed improved therapeutic efficiency compared to CHL via anti-proliferative study and cell apoptosis assay. Further measurement of GSH content and ROS levels in tumor cells suggested that the synergistic impact resulted from QM-mediated GSH reduction and CHL-induced further oxidative stress insults to tumor cells. In vivo tumor suppression effect and biocompatibility indicated the superiorities of PPAHC nanoprodrug. Accordingly, PPAHC provides a new approach as a ROS-responsive CHL delivery system and has a great potential for cancer therapy. PMID- 29409837 TI - Cell of origin markers identify different prognostic subgroups of lung adenocarcinoma. AB - Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic "cell of origin," allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003-2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of "hotspot" mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: "alveolar," "bronchiolar," "mixed" and "null type." Alveolar-differentiated ADC were more common in young (P=.065), female (P=.083) patients, frequently harboring EGFR mutated (P=.003) tumors with acinar pattern (P<.001). Bronchiolar-differentiated ADC were more associated with mucinous and solid pattern (P<.001), higher degree of vascular invasion (P=.01) and KRAS gene mutations (P=.07). Bronchiolar, mixed, and null types were independent negative predictors for overall survival, and the latter two had a shorter time to recurrence. This "Cell of Origin" classifier is more predictable than morphology and genetics and is an independent predictor of survival on a multivariate analysis. PMID- 29409838 TI - Deciphering the microstructure of hippocampal subfields with in vivo DTI and NODDI: Applications to experimental multiple sclerosis. AB - The hippocampus contains distinct populations of neurons organized into separate anatomical subfields and layers with differential vulnerability to pathological mechanisms. The ability of in vivo neuroimaging to pinpoint regional vulnerability is especially important for better understanding of hippocampal pathology at the early stage of neurodegenerative disorders and for monitoring future therapeutic strategies. This is the case for instance in multiple sclerosis whose neurodegenerative component can affect the hippocampus from the early stage. We challenged the capacity of two models, i.e. the classical diffusion tensor imaging (DTI) model and the neurite orientation dispersion and density imaging (NODDI) model, to compute quantitative diffusion MRI that could capture microstructural alterations in the individual hippocampal layers of experimental-autoimmune encephalomyelitis (EAE) mice, the animal model of multiple sclerosis. To achieve this, the hippocampal anatomy of a healthy mouse brain was first explored ex vivo with high resolution DTI and NODDI. Then, 18 EAE mice and 18 control mice were explored 20 days after immunization with in vivo diffusion MRI prior to sacrifice for the histological quantification of neurites and glial markers in each hippocampal layer. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) maps were computed from the DTI model while the orientation dispersion index (ODI), the neurite density index (NDI) and the volume fraction of isotropic diffusivity (isoVF) maps were computed from the NODDI model. We first showed in control mice that color-coded FA and ODI maps can delineate three main hippocampal layers. The quantification of FA, AD, RD, MD, ODI, NDI and isoVF presented differences within these 3 layers, especially within the molecular layer of the dentate gyrus which displayed a specific signature based on a combination of AD (or MD), ODI and NDI. Then, the comparison between EAE and control mice showed a decrease of AD (p = 0.036) and of MD (p = 0.033) selectively within the molecular layer of EAE mice while NODDI indices did not present any difference between EAE and control mice in any layer. Histological analyses confirmed the differential vulnerability of the molecular layer of EAE mice that exhibited decreased dendritic length and decreased dendritic complexity together with activated microglia. Dendritic length and intersections within the molecular layer were independent contributors to the observed decrease of AD (R2 = 0.37 and R2 = 0.40, p < 0.0001) and MD (R2 = 0.41 and R2 = 0.42, p < 0.0001). We therefore identified that NODDI maps can help to highlight the internal microanatomy of the hippocampus but NODDI still presents limitations in grey matter as it failed to capture selective dendritic alterations occurring at early stages of a neurodegenerative disease such as multiple sclerosis, whereas DTI maps were significantly altered. PMID- 29409839 TI - Renewable resources-based approach to biantennary glycolipids. AB - A new synthesis approach towards biantennary lipids of Guerbet glycoside type was developed based on oleic acid as sustainable resource. Functionalization of the double bond provided access to primary alcohols with alpha-branched C19-skeleton. Formulation studies with corresponding lactosides indicated formation of vesicles with high assembly stability. A relatively narrow bimodal size distribution of the latter, which turns into a narrow unimodal distribution of small vesicles upon addition of an ionic cosurfactant, suggests potential for a vesicular drug delivery system. PMID- 29409836 TI - Immunological effects of iron oxide nanoparticles and iron-based complex drug formulations: Therapeutic benefits, toxicity, mechanistic insights, and translational considerations. AB - Nanotechnology offers several advantages for drug delivery. However, there is the need for addressing potential safety concerns regarding the adverse health effects of these unique materials. Some such effects may occur due to undesirable interactions between nanoparticles and the immune system, and they may include hypersensitivity reactions, immunosuppression, and immunostimulation. While strategies, models, and approaches for studying the immunological safety of various engineered nanoparticles, including metal oxides, have been covered in the current literature, little attention has been given to the interactions between iron oxide-based nanomaterials and various components of the immune system. Here we provide a comprehensive review of studies investigating the effects of iron oxides and iron-based nanoparticles on various types of immune cells, highlight current gaps in the understanding of the structure-activity relationships of these materials, and propose a framework for capturing their immunotoxicity to streamline comparative studies between various types of iron based formulations. PMID- 29409840 TI - Flow Microscopy Imaging Is Sensitive to Characteristics of Subvisible Particles in Peginesatide Formulations Associated With Severe Adverse Reactions. AB - The presence of subvisible particles in formulations of therapeutic proteins is a risk factor for adverse immune responses. Although the immunogenic potential of particulate contaminants likely depends on particle structural characteristics (e.g., composition, size, and shape), exact structure-immunogenicity relationships are unknown. Images recorded by flow imaging microscopy reflect information about particle morphology, but flow microscopy is typically used to determine only particle size distributions, neglecting information on particle morphological features that may be immunologically relevant. We recently developed computational techniques that utilize the Kullback-Leibler divergence and multidimensional scaling to compare the morphological properties of particles in sets of flow microscopy images. In the current work, we combined these techniques with expectation maximization cluster analyses and used them to compare flow imaging microscopy data sets that had been collected by the U.S. Food and Drug Administration after severe adverse drug reactions (including 7 fatalities) were observed in patients who had been administered some lots of peginesatide formulations. Flow microscopy images of particle populations found in the peginesatide lots associated with severe adverse reactions in patients were readily distinguishable from images of particles in lots where severe adverse reactions did not occur. PMID- 29409841 TI - Measurement of Average Aggregate Density by Sedimentation and Brownian Motion Analysis. AB - The spatially averaged density of protein aggregates is an important parameter that can be used to relate size distributions measured by orthogonal methods, to characterize protein particles, and perhaps to estimate the amount of protein in aggregate form in a sample. We obtained a series of images of protein aggregates exhibiting Brownian diffusion while settling under the influence of gravity in a sealed capillary. The aggregates were formed by stir-stressing a monoclonal antibody (NISTmAb). Image processing yielded particle tracks, which were then examined to determine settling velocity and hydrodynamic diameter down to 1 MUm based on mean square displacement analysis. Measurements on polystyrene calibration microspheres ranging in size from 1 to 5 MUm showed that the mean square displacement diameter had improved accuracy over the diameter derived from imaged particle area, suggesting a future method for correcting size distributions based on imaging. Stokes' law was used to estimate the density of each particle. It was found that the aggregates were highly porous with density decreasing from 1.080 to 1.028 g/cm3 as the size increased from 1.37 to 4.9 MUm. PMID- 29409843 TI - T cell dysfunction and patient age are associated with poor outcomes after mechanical circulatory support device implantation. AB - Immunologic impairment may contribute to poor outcomes after implantation of mechanical circulatory support device (MCSD), with infection often as a terminal event. The study of immune dysfunction is of special relevance given the growing numbers of older patients with heart disease. The aim of the study was to define which immunologic characteristics are associated with development of adverse clinical outcomes after MCSD implantation. We isolated peripheral blood mononuclear cells (PBMC) from patients pre- and up to 20 days post-MCSD implantation and analyzed them by multiparameter flow cytometry for T cell dysfunction, including terminal differentiation, exhaustion, and senescence. We used MELD-XI and SOFA scores measured at each time point as surrogate markers of clinical outcome. Older patients demonstrated increased frequencies of terminally differentiated T cells as well as NKT cells. Increased frequency of terminally differentiated and immune senescent T cells were associated with worse clinical outcome as measured by MELD-XI and SOFA scores, and with progression to infection and death. In conclusion, our data suggest that T cell dysfunction, independently from age, is associated with poor outcomes after MCSD implantation, providing a potential immunologic mechanism behind patient vulnerability to multiorgan dysfunction and death. This noninvasive approach to PBMC evaluation holds promise for candidate evaluation and patient monitoring. PMID- 29409842 TI - Disturbed sleep and diabetes: A potential nexus of dementia risk. AB - Type 2 diabetes (T2D) and sleep disturbance (e.g., insomnia, sleep-disordered breathing) are prevalent conditions among older adults that are associated with cognitive decline and dementia, including Alzheimer's disease (AD). Importantly, disturbed sleep is associated with alterations in insulin sensitivity and glucose metabolism, and may increase the risk of T2D, and T2D-related complications (e.g., pain, nocturia) can negatively affect sleep. Despite these associations, little is known about how interactions between T2D and sleep disturbance might alter cognitive trajectories or the pathological changes that underlie dementia. Here, we review links among T2D, sleep disturbance, cognitive decline and dementia-including preclinical and clinical AD-and identify gaps in the literature, that if addressed, could have significant implications for the prevention of poor cognitive outcomes. PMID- 29409844 TI - Association of paraoxonase-1 gene polymorphisms with insulin resistance in South Indian population. AB - BACKGROUND AND AIM: Insulin resistance plays a crucial role in the pathogenesis of type 2 diabetes and cardiovascular diseases. Recently, paraoxonase-1(PON1) is reported to have an ability to reduce insulin resistance by promoting glucose transporter-4 (GLUT-4) expression in vitro. Single nucleotide polymorphism (SNP) in PON1 is associated with variability in enzyme activity and concentration. Based on this we aimed to investigate the association of PON1 (Q192R and L55M) polymorphisms with the risk of developing insulin resistance in adult South Indian population. METHODS: Two hundred and eighty seven (287) Type 2 diabetes patients and 293 healthy controls were enrolled in this study. All the study subjects were genotyped for PON1 (Q192R and L55M) missense polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) method. Fasting serum insulin level was measured by ELISA. RESULTS: The distribution of QR/RR and LM/MM genotypes were significantly higher in type 2 diabetes patients compared with healthy controls. Moreover, the R and M alleles were significantly associated with type 2 diabetes with an Odds Ratio of 1.68 (P < 0.005) and 2.24 (P < 0.005) respectively. SNP 192 Q > R genotypes were found to be significantly associated with higher BMI, cholesterol, triglycerides, LDL, fasting serum insulin and HOMA-IR. Further, the mutant allele or genotypes of PON1 L55M were associated with higher BMI, triglycerides, VLDL, fasting serum insulin and HOMA-IR among adult type 2 diabetes patients. CONCLUSION: PON1 (Q192R and L55M) polymorphisms may play a crucial role in pathogenesis and susceptibility of insulin resistance thus leads to the development of type 2 diabetes in South Indian population. PMID- 29409845 TI - Initial Experience Performing In-office Ultrasound-guided Transperineal Prostate Biopsy Under Local Anesthesia Using the PrecisionPoint Transperineal Access System. AB - OBJECTIVE: To describe our procedural technique and initial outcomes performing in-office transperineal prostate biopsies using the PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD). PATIENTS AND METHODS: Following institutional review board approval, we retrospectively reviewed the records of men who underwent an in-office transperineal prostate biopsy using the PrecisionPoint device. Records were reviewed for baseline characteristics, biopsy results, and postbiopsy complications. RESULTS: Between January 4, 2017 and August 23, 2017, 43 men underwent an in-office transperineal prostate biopsy using the PrecisionPoint Transperineal Access System. Patients had a median serum prostate specific antigen level of 6.1 ng/mL (range 0.8-32.9). Of the 43 biopsies, 12 (27.9%) were performed for active surveillance of low-risk prostate cancer and 31 (72.1%) were performed for cancer screening. Overall, 21 (48.8%) men were found to have prostate cancer. Among those on active surveillance, cancer was detected in 8 of 12 (66.7%) patients, with 2 of 12 (16.7%) found to have Gleason >=3 + 4 = 7 prostate cancer. Additionally, cancer was detected in 13 of 31 (41.9%) patients undergoing a biopsy for prostate cancer screening, with 5 (16.1%) found to have Gleason >=3 + 4 = 7 disease. In total, 3 (7.0%) patients experienced a postbiopsy complication: 2 (4.7%) with urinary retention and 1 (2.3%) with gross hematuria requiring catheterization. No patient experienced an infectious complication despite omission of periprocedural antibiotics in all cases. CONCLUSION: The PrecisionPoint device allowed for the successful performance of in-office transperineal prostate biopsies under local anesthesia without the need for periprocedural antibiotics. We observed an acceptable cancer detection rate with no infectious complications. PMID- 29409846 TI - Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome). AB - Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome-a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose-is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome >=9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children. PMID- 29409848 TI - SMFM Statement: Pharmacological treatment of gestational diabetes. PMID- 29409847 TI - Cost-effectiveness of emergency contraception options over 1 year. AB - BACKGROUND: The copper intrauterine device is the most effective form of emergency contraception and can also provide long-term contraception. The levonorgestrel intrauterine device has also been studied in combination with oral levonorgestrel for women seeking emergency contraception. However, intrauterine devices have higher up-front costs than oral methods, such as ulipristal acetate and levonorgestrel. Health care payers and decision makers (eg, health care insurers, government programs) with financial constraints must determine if the increased effectiveness of intrauterine device emergency contraception methods are worth the additional costs. OBJECTIVE: We sought to compare the cost effectiveness of 4 emergency contraception strategies-ulipristal acetate, oral levonorgestrel, copper intrauterine device, and oral levonorgestrel plus same-day levonorgestrel intrauterine device-over 1 year from a US payer perspective. STUDY DESIGN: Costs (2017 US dollars) and pregnancies were estimated over 1 year using a Markov model of 1000 women seeking emergency contraception. Every 28-day cycle, the model estimated the predicted number of pregnancy outcomes (ie, live birth, ectopic pregnancy, spontaneous abortion, or induced abortion) resulting from emergency contraception failure and subsequent contraception use. Model inputs were derived from published literature and national sources. An emergency contraception strategy was considered cost-effective if the incremental cost effectiveness ratio (ie, the cost to prevent 1 additional pregnancy) was less than the weighted average cost of pregnancy outcomes in the United States ($5167). The incremental cost-effectiveness ratios and probability of being the most cost-effective emergency contraception strategy were calculated from 1000 probabilistic model iterations. One-way sensitivity analyses were used to examine uncertainty in the cost of emergency contraception, subsequent contraception, and pregnancy outcomes as well as the model probabilities. RESULTS: In 1000 women seeking emergency contraception, the model estimated direct medical costs of $1,228,000 and 137 unintended pregnancies with ulipristal acetate, compared to $1,279,000 and 150 unintended pregnancies with oral levonorgestrel, $1,376,000 and 61 unintended pregnancies with copper intrauterine devices, and $1,558,000 and 63 unintended pregnancies with oral levonorgestrel plus same-day levonorgestrel intrauterine device. The copper intrauterine device was the most cost-effective emergency contraception strategy in the majority (63.9%) of model iterations and, compared to ulipristal acetate, cost $1957 per additional pregnancy prevented. Model estimates were most sensitive to changes in the cost of the copper intrauterine device (with higher copper intrauterine device costs, oral levonorgestrel plus same-day levonorgestrel intrauterine device became the most cost-effective option) and the cost of a live birth (with lower-cost births, ulipristal acetate became the most cost-effective option). When the proportion of obese women in the population increased, the copper intrauterine device became even more most cost-effective. CONCLUSION: Over 1 year, the copper intrauterine device is currently the most cost-effective emergency contraception option. Policy makers and health care insurance companies should consider the potential for long-term savings when women seeking emergency contraception can promptly obtain whatever contraceptive best meets their personal preferences and needs; this will require removing barriers and promoting access to intrauterine devices at emergency contraception visits. PMID- 29409849 TI - Combination antimicrobial prophylaxis for hysterectomy: harm without the benefit? PMID- 29409850 TI - Efficacy and safety of Pueraria candollei var. mirifica (Airy Shaw & Suvat.) Niyomdham for menopausal women: A systematic review of clinical trials and the way forward. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pueraria candollei var. mirifica (Airy Shaw & Suvat.) Niyomdham (commonly termed P. mirifica, PM) growing in upland Thailand has a long history as a postmenopausal rejuvenant therapy for indigenants. Its amelioration of menopause symptoms in clinical trials was assessed. MATERIALS AND METHODS: International and Thai databases were searched from inception to February 2017. Clinical trials investigating effects of PM menopausal or postmenopausal women were included. Outcomes were self-reported menopausal symptoms, serum reproductive hormones, urino-genital tract function, and bone surrogates. Methodological quality was assessed by Cochrane risk-of-bias v2.0, and a 22-parameter quality score based on the CONSORT checklist for herbal medicines. RESULTS: Eight studies (9 articles) used data from 309 menopausal patients. Five-studies demonstrated that PM was associated with climacteric scores reduced by ~50% compared to baseline. Other PM studies using limited numbers of placebo participants suggested improved vaginal and other urogenital tract symptoms. Bone alkaline phosphatase halved (suggesting lowered bone turnover). Variable serum reproductive hormone levels suggested menopausal status differed between studies. PM active ingredients and sources were not defined. Adverse event rates (mastodynia, vaginal spotting, dizziness) were similar in all groups (PM, conjugated equine estrogen, and placebos) but serum C-reactive protein doubled. These studies had design and reporting deficiencies, high risks of biases, and low quality scores. CONCLUSIONS: The efficacy of PM on menopausal symptoms remains inconclusive because of methodological short-comings especially placebo effects inherent in self-assessment/recall questionnaires and no PM standardization. PM efficacy and safety need a fundamental re-appraisal by: (i) cohort (retro- and prospective) studies on current users to define its traditional use for rejuvenation; (ii) tightly coupling long-term efficacy to safety of well-defined PM and multiple end-points; (iii) using study design related to current understanding of menopause progression and estrogen pharmacology (iv) robust pharmacovigilance. PMID- 29409852 TI - Recent advances in food allergy prevention and treatment. PMID- 29409851 TI - Identification and expression analysis of the IPT and CKX gene families during axillary bud outgrowth in apple (Malus domestica Borkh.). AB - Cytokinins (CKs) play a crucial role in promoting axillary bud outgrowth and targeting the control of CK metabolism can be used to enhance branching in plants. CK levels are maintained mainly by CK biosynthesis (isopentenyl transferase, IPT) and degradation (dehydrogenase, CKX) genes in plants. A systematic study of the IPT and CKX gene families in apple, however, has not been conducted. In the present study, 12 MdIPTs and 12 MdCKXs were identified in the apple genome. Systematic phylogenetic, structural, and synteny analyses were performed. Expression analysis of these genes in different tissues was also assessed. MdIPT and MdCKX genes exhibit distinct expression patterns in different tissues. The response of MdIPT, MdCKX, and MdPIN1 genes to various treatments (6 BA, decapitation and Lovastatin, an inhibitor of CKs synthesis) that impact branching were also investigated. Results indicated that most of the MdIPT and MdCKX, and MdPIN1 genes were upregulated by 6-BA and decapitation treatment, but inhibited by Lovastatin, a compound that effectively suppresses axillary bud outgrowth induced by decapitation. These findings suggest that cytokinin biosynthesis is required for the activation of bud break and the export of auxin from buds in apple tree with intact primary shoot apex or decapitated apple tree. MdCKX8 and MdCKX10, however, exhibited little response to decapitation, but were significantly up-regulated by 6-BA and Lovastatin, a finding that warrants further investigation in order to understand their function in bud-outgrowth. PMID- 29409853 TI - Liver resection for BCLC 0-A stage hepatocellular carcinoma: Does the time to surgery not impact the prognosis? PMID- 29409854 TI - Genetic and haplotype analyses targeting cytochrome b gene of Plasmodium knowlesi isolates of Malaysian Borneo and Peninsular Malaysia. AB - Malaria is a notorious disease which causes major global morbidity and mortality. This study aims to investigate the genetic and haplotype differences of Plasmodium knowlesi (P. knowlesi) isolates in Malaysian Borneo and Peninsular Malaysia based on the molecular analysis of the cytochrome b (cyt b) gene. The cyt b gene of 49 P. knowlesi isolates collected from Sabah, Malaysian Borneo and Peninsular Malaysia was amplified using PCR, cloned into a commercialized vector and sequenced. In addition, 45 cyt b sequences were retrieved from humans and macaques bringing to a total of 94 cyt b gene nucleotide sequences for phylogenetic analysis. Genetic and haplotype analyses of the cyt b were analyzed using MEGA6 and DnaSP ver. 5.10.01. The haplotype genealogical linkage of cyt b was generated using NETWORK ver. 4.6.1.3. Our phylogenetic tree revealed the conservation of the cyt b coding sequences with no distinct cluster across different geographic regions. Nucleotide analysis of cyt b showed that the P. knowlesi isolates underwent purifying selection with population expansion, which was further supported by extensive haplotype sharing between the macaques and humans from Malaysian Borneo and Peninsular Malaysia in the median-joining network analysis. This study expands knowledge on conservation of the zoonotic P. knowlesi cyt b gene between Malaysian Borneo and Peninsular Malaysia. PMID- 29409856 TI - Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. AB - Diabetic Nephropathy (DN) is one of the main complications associated with diabetes mellitus. Persistently elevated blood glucose level drives histopathological changes in renal tissues that hinder normal kidney functions. In the current study, crocin; the main bioactive constituent of Crocus sativus was investigated as a reno-protective agent against DN by virtue of its numerous pharmacological activities. Diabetes was induced in male Sprague-Dawely rats through intravenous injection of streptozocin (STZ) (50 mg/kg), DN was confirmed eight weeks post diabetes induction. Daily oral crocin for eight weeks (20 mg/kg) significantly reduced blood glucose level with a significant increase in insulin level. Moreover, crocin improved impaired kidney functions as manifested in reduction of serum creatinine levels, blood urea nitrogen and proteinuria with concomitant increase in urinary creatinine clearance. Furthermore, biomarkers of cell injury and tissue necrosis like LDH activity was significantly reduced, kidney content of NOS significantly declined likewise. In addition, renal antioxidants such as SOD, GSH and serum catalase activity significantly increased with concomitant reduction of kidney MDA; biomarker of oxidative load. Kidney content of toll-like receptors 4 and IL-6 significantly declined with simultaneous suppression of nuclear factor kappa-B (NF-kappaB/p65) protein expression and immuno-staining in rat renal cortex. Furthermore, crocin inhibited progression of renal fibrosis as seen with reduction of renal hydroxyproline and collagen content, TGF-beta immuno-staining and Masson's Trichrome positive tissue. Histopathologically, crocin pretreatment was associated with minimal renal damage with fewer fibrotic lesions. There was a concomitant restoration of renal tubules integrity with preservation of glomerular space area. In conclusion, crocin's ameliorative impact on DN may be attributed to its free radicals scavenging properties, its ability to enhance host antioxidant defense system and its ability to inhibit inflammatory and fibrotic cascades activation. PMID- 29409857 TI - Early choriocapillaris changes after half-fluence photodynamic therapy in chronic central serous chorioretinopathy evaluated by optical coherence tomography angiography: Preliminary results. AB - BACKGROUND: The purpose of this study is to examine the choridal perfusion in patients with chronic central serous chorioretinopathy (CSC) after half-fluence photodynamic therapy (PDT) in the early post-treatment period. METHODS: This retrospective study included patients with chronic CSC. Indocyanine green angiography (ICGA) guided half-fluence PDT was applied to the all eyes. Best corrected visual acuity (BCVA) was assessed by Snellen chart and central retinal thickness (CRT) and subfoveal choroidal thickness (SFCT) was measured by spectral domain optical coherence tomography (SD-OCT) before PDT and at 3 and 30 days following the therapy. Optical coherence tomography angiography (OCTA) was performed to evaluate choriocapillaris perfusion in all patients before PDT and 3 and 30 days of therapy. RESULTS: Of the patients participating in this study, the mean age was 49.8 +/- 14.1 years. BCVA remained stable in all eyes during follow up period. CRT was 360 +/- 148 MUm at baseline, 327 +/- 133 MUm at day 3 and 203 +/- 40 MUm at day 30 after treatment. Subretinal fluid totally resolved at day 30 in all eyes. The mean SFCT was 493 +/- 67 MUm at baseline, 498 +/- 71 MUm at day 3 and 450 +/- 63 MUm at day 30. At day 3, OCTA revealed markedly decreased choriocapillaris flow limited to the site of PDT spot. The choriocapillaris perfusion appeared to be normal in all eyes in OCTA images at day 30. CONCLUSIONS: OCTA is a noninvasive imaging tool for detecting choroidal vascular changes after PDT in CSC. In this preliminary study of a limited number of CSC patients, choroiocapillaris perfusion seemed to decreased in very early period following half-fluence PDT and then returned to normal until 30 days of therapy. PMID- 29409855 TI - PDGF/PDGFR axis in the neural systems. AB - Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are expressed in several cell types including the brain cells such as neuronal progenitors, neurons, astrocytes, and oligodendrocytes. Emerging evidence shows that PDGF-mediated signaling regulates diverse functions in the central nervous system (CNS) such as neurogenesis, cell survival, synaptogenesis, modulation of ligand-gated ion channels, and development of specific types of neurons. Interestingly, PDGF/PDFGR signaling can elicit paradoxical roles in the CNS, depending on the cell type and the activation stimuli and is implicated in the pathogenesis of various neurodegenerative diseases. This review summarizes the role of PDGFs/PDGFRs in several neurodegenerative diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, brain cancer, cerebral ischemia, HIV-1 and drug abuse. Understanding PDGF/PDGFR signaling may lead to novel approaches for the future development of therapeutic strategies for combating CNS pathologies. PMID- 29409858 TI - Cost of unintended pregnancy in Sweden - a possibility to lower costs by increasing LARC usage. AB - OBJECTIVES: The objective of this study was to determine the cost of unintended pregnancy (UP) in Sweden and savings generated by a switch of 5% of women from short-acting reversible contraception (SARC) and other methods to long-acting reversible contraceptives (LARCs). STUDY DESIGN: We constructed an economic model to estimate the number and costs of UPs and contraceptive use over a 1-year period. The population consisted of all women aged 15-44years requiring reversible contraception and at risk of UP. UPs could result in birth, spontaneous abortion, induced abortion, and ectopic pregnancy. The model included costs incurred by the healthcare payer or out-of-pocket expenses by women, and indirect costs, i.e., foregone wages from time away from work. RESULTS: We estimated 73,989 unintended pregnancies yearly, amounting to costs of almost ?158 million. A 5% switch from non-LARCs to LARCs would generate more than 3500 fewer UPs yearly with savings of nearly ?7.7 million. The majority of these savings would arise from reduced costs for UPs. CONCLUSIONS: UPs are costly for society and women. A small change in the proportion of women using the most effective methods generates substantial cost savings due to fewer UPs and thus fewer abortions. A switch in 5% of women using non-LARCs could prevent more than 3500 UPs yearly, generating savings of more than SEK 70 million (?7.7 million) or of 2.4% of costs for UPs. PMID- 29409860 TI - Feeding the developing brain: Juvenile rats fed diet rich in prebiotics and bioactive milk fractions exhibit reduced anxiety-related behavior and modified gene expression in emotion circuits. AB - Early life nutrition is critical for brain development. Dietary prebiotics and bioactive milk fractions support brain development by increasing plasticity and altering activity in brain regions important for cognition and emotion regulation, perhaps through the gut-microbiome-brain axis. Here we examined the impact of a diet containing prebiotics, lactoferrin, and milk fat globule membrane (test diet) on beneficial gut bacteria, basal gene expression for activity and plasticity markers within brain circuits important for cognition and anxiety, and anxiety-related behavior in the open field. Juvenile male F344 rats were fed the test diet or a calorically matched control diet beginning postnatal day 24. After 4 weeks on diets, rats were sacrificed and brains were removed. Test diet significantly increased mRNA expression for cfos, brain derived neurotropic factor, and the GluN1 subunit of the NMDA receptor in the prefrontal cortex and reduced cfos mRNA within the amygdala. Diet-induced increases in fecal Lactobacillus spp., measured using selective bacterial culture, positively correlated with altered gene expression for cfos and serotonin receptors within multiple brain regions. In a separate cohort of juvenile rats, 4 weeks of the test diet increased time spent in the center of the open field, a behavior indicative of reduced anxiety. These data demonstrate that early life diets containing prebiotics and bioactive milk fractions can adaptively alter genes in neural circuits underlying emotion regulation and impact anxiety-related behavior. PMID- 29409859 TI - Rice In Vivo RNA Structurome Reveals RNA Secondary Structure Conservation and Divergence in Plants. AB - RNA secondary structure plays a critical role in gene regulation. Rice (Oryza sativa) is one of the most important food crops in the world. However, RNA structure in rice has scarcely been studied. Here, we have successfully generated in vivo Structure-seq libraries in rice. We found that the structural flexibility of mRNAs might associate with the dynamics of biological function. Higher N6 methyladenosine (m6A) modification tends to have less RNA structure in 3' UTR, whereas GC content does not significantly affect in vivo mRNA structure to maintain efficient biological processes such as translation. Comparative analysis of RNA structurome between rice and Arabidopsis revealed that higher GC content does not lead to stronger structure and less RNA structural flexibility. Moreover, we found a weak correlation between sequence and structure conservation of the orthologs between rice and Arabidopsis. The conservation and divergence of both sequence and in vivo RNA structure corresponds to diverse and specific biological processes. Our results indicate that RNA secondary structure might offer a separate layer of selection to the sequence between monocot and dicot. Therefore, our study implies that RNA structure evolves differently in various biological processes to maintain robustness in development and adaptational flexibility during angiosperm evolution. PMID- 29409861 TI - Mathematical modeling of antibody drug conjugates with the target and tubulin dynamics to predict AUC. AB - Antibody drug conjugates (ADCs)are one of the most recently developed chemotherapeutics to treat some types of tumor cells. They consist of monoclonal antibodies (mAbs), linkers, and potent cytotoxic drugs. Unlike common chemotherapies, ADCs combine selectively with a target at the surface of the tumor cell, and a potent cytotoxic drug (payload) effectively prevents microtubule polymerization. In this work, we construct an ADC model that considers both the target of antibodies and the receptor (tubulin) of the cytotoxic payloads. The model is simulated with brentuximab vedotin, one of ADCs, and used to investigate the pharmacokinetic (PK) characteristics of ADCs in vivo. It also predicts area under the curve (AUC) of ADCs and the payloads by identifying the half-life. The results show that dynamical behaviors fairly coincide with the observed data and half-life and capture AUC. Thus, the model can be used for estimating some parameters, fitting experimental observations, predicting AUC, and exploring various dynamical behaviors of the target and the receptor. PMID- 29409862 TI - The antimicrobial cathelicidin peptide hlF(1-11) attenuates alveolar macrophage pyroptosis induced by Acinetobacter baumannii in vivo. AB - Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections, including bacterial pneumonia. The hLF(1-11) peptide comprising the first 11 N-terminal residues of human lactoferrin exerts antimicrobial activity in vivo and was highly effective against multidrug-resistant A. baumannii strains in vitro and in vivo. Pyroptosis is a caspase-1-dependent inflammatory cell death process and is induced by various microbial infections. In the present study, we investigated the molecular mechanisms that regulate pyroptosis induced by A. baumannii in macrophages. Our results revealed that A. baumannii induced pyroptosis through caspase-1 activation and IL-1beta production. We also found that caspase-1 activation and IL-1beta maturation in A. baumannii-triggered pyroptotic cell death were reduced by hLF(1-11) treatment. Moreover, hLF(1-11) inhibited the A. baumannii-induced caspase-1 activation and pyroptosis of pulmonary alveolar macrophages in vivo. PMID- 29409863 TI - Cellulomonas fimi secretomes: In vivo and in silico approaches for the lignocellulose bioconversion. AB - Lignocellulose degradation is a challenging step for value added products and biofuels production. Cellulomonas fimi secretes complex mixtures of carbohydrate active enzymes (CAZymes) which synergistically degrade cellulose and hemicelluloses. Their characterization may provide new insights for enzymatic cocktails implementation. Bioinformatic analysis highlighted 1127 secreted proteins, constituting the in silico secretome, graphically represented in a 2DE map. According to Blast2GO functional annotation, many of these are involved in carbohydrates metabolism. In vivo secretomes were obtained, growing C. fimi on glucose, CMC or wheat straw for 24 h. Zymography revealed degradative activity on carbohydrates and proteomic analysis identified some CAZymes, only in secretomes obtained with CMC and wheat straw. An interaction between cellobiohydrolases is proposed as a strategy adopted by soluble multimodular cellulases. Such approach can be crucial for a better characterization and industrial exploitation of the synergism among C. fimi enzymes. PMID- 29409864 TI - Starch nanocapsules containing a novel neutrophil elastase inhibitor with improved pharmaceutical performance. AB - Psoriasis and atopic dermatitis patients show an excessive amount of elastase in peripheral blood neutrophils due to an imbalance between this proteolytic enzyme and its endogenous inhibitors, the search for new human neutrophil elastase (HNE) inhibitors are required. The HNE is an attractive therapeutic target and inhibitors with new molecular architectures have been extensively investigated. In this context a promising novel synthetic human neutrophil elastase inhibitor (ER143) was associated to a starch-based nanoparticulate system (StNC) with improved pharmaceutical performance, using a quality by design approach to support product development and optimization. The resulting formulation was characterized in terms of and in vitro release, permeation and retention studies in newborn pig skin, using Franz diffusion cells revealing the StNC have the ability to control the drug release rate and contribute to a high skin retention and/or permeation profiles. The anti-inflammatory activity accessed in vivo using the croton oil-induced ear inflammation model in mice showed that erythema and edema were attenuated in 98% following local application. These observations suggest the association of ER143 to the StNC promotes a deeper skin penetration and retention, also confirming StNC as a potential topical delivery system. PMID- 29409865 TI - Identification and evaluation of Galleria mellonella peptides with antileishmanial activity. AB - Leishmaniasis is a neglected disease, World Health Organization (WHO) declared it as high priority worldwide. Colombia is one of the 98 countries in which the disease caused more than 17.000 cases per year. There is a need to explore novel therapies to reduce the side effects of the current treatments. For this reason, this study was aimed to evaluate Galleria mellonella hemolymph for potential peptides with anti-parasitic activity. Larvae were challenged with Leishmania (V) panamensis promastigotes and hemolymph was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), reversed-phase chromatography (RP HPLC), two-dimensional gel electrophoresis and liquid chromatography-mass spectroscopy (LC/MS). The immunological response of Galleria mellonella was followed by SDS-PAGE, immunized hemolymph was fractionated by RP-HPLC where fractions 5 and 11 showed the highest antileishmanial activity. From these fractions 15 spots were isolated by 2D gel electrophoresis and evaluated by LC/MS to identify the peptides present in the spots. After the analysis Moricin-B, Moricin-C4, Cecropin-D and Anionic Peptide 2 were identified due to the immune challenge with Leishmania promastigotes. Anionic peptide 2 and Cecropin-D were synthesized and evaluated for antileishmanial activity. The results showed that Anionic peptide 2 presented more anti-parasitic activity. This study showed for the first time the anti-parasitic potential of peptides derived from hemolymph of Galleria mellonella. PMID- 29409866 TI - Introduction of sacrificial bonds to hydrogels to increase defect tolerance during suturing of multilayer vascular grafts. AB - : Small-caliber vascular grafts used in coronary artery bypass procedures typically fail due to the development of intimal hyperplasia or thrombosis. Our laboratory has developed a multilayered vascular graft with an electrospun polyurethane outer layer with improved compliance matching and a hydrogel inner layer that is both thromboresistant and promotes endothelialization. Initial in vivo studies showed that hydrogel particulates were dislodged from the hydrogel layer of the grafts during suturing. To address this problem, we developed and characterized a new hydrogel formulation that resists damage during suturing. Introduction of sacrificial, hydrogen bonds to poly(ethylene glycol)-based hydrogels via co-polymerization with n-vinyl pyrrolidone (NVP) increased the fracture energy as determined by single edge notch testing. This enhanced defect tolerance resulted in a hydrogel layer that was resistant to suture-induced damage with no dislodged particles observed. Importantly, the incorporation of NVP did not affect the thromboresistance, bioactivity, or biostability of the hydrogel layer. In addition to eliminating complications due to hydrogel particle generation in our multilayer graft design, this defect tolerant hydrogel formulation has broad potential use in many cardiovascular and soft tissue applications. STATEMENT OF SIGNIFICANCE: Small-caliber vascular grafts used in coronary artery bypass procedures typically fail due to development of intimal hyperplasia or thrombosis. Our laboratory has developed a multilayered vascular graft with an electrospun polyurethane outer layer with improved compliance matching and a hydrogel inner layer that is both thromboresistant and promotes endothelialization. However, hydrogel particulates were dislodged from the hydrogel layer during suturing in vivo. This work describes a hydrogel formulation based on poly(ethylene glycol) that is resistant to suture-induced damage. The introduction of sacrificial, hydrogen bonds by co-polymerization with n-vinyl pyrrolidone (NVP) resulted in an increase fracture energy without affecting the thromboresistance, bioactivity, or biostability. This defect tolerant hydrogel formulation and the methodology to assess hydrogel defect tolerance has broad potential use in cardiovascular and soft tissue applications. PMID- 29409867 TI - Bone regeneration capacity of magnesium phosphate cements in a large animal model. AB - : Magnesium phosphate minerals have captured increasing attention during the past years as suitable alternatives for calcium phosphate bone replacement materials. Here, we investigated the degradation and bone regeneration capacity of experimental struvite (MgNH4PO4.6H2O) forming magnesium phosphate cements in two different orthotopic ovine implantation models. Cements formed at powder to liquid ratios (PLR) of 2.0 and 3.0 g ml-1 were implanted into trabecular bone using a non-load-bearing femoral drill-hole model and a load-bearing tibial defect model. After 4, 7 and 10 months the implants were retrieved and cement degradation and new bone formation was analyzed by micro-computed tomography (uCT) and histomorphometry. The results showed cement degradation in concert with new bone formation at both defect locations. Both cements were almost completely degraded after 10 months. The struvite cement formed with a PLR of 2.0 g ml-1 exhibited a slightly accelerated degradation kinetics compared to the cement with a PLR of 3.0 g ml-1. Tartrat-resistant acid phosphatase (TRAP) staining indicated osteoclastic resorption at the cement surface. Energy dispersive X-ray analysis (EDX) revealed that small residual cement particles were mostly accumulated in the bone marrow in between newly formed bone trabeculae. Mechanical loading did not significantly increase bone formation associated with cement degradation. Concluding, struvite-forming cements might be promising bone replacement materials due to their good degradation which is coupled with new bone formation. STATEMENT OF SIGNIFICANCE: Recently, the interest in magnesium phosphate cements (MPC) for bone substitution increased, as they exhibit high initial strength, comparably elevated degradation potential and the release of valuable magnesium ions. However, only few in vivo studies, mostly including non-load-bearing defects in small animals, have been performed to analyze the degradation and regeneration capability of MPC derived compounds. The present study examined the in vivo behavior of magnesiumammoniumphosphate hexahydrate (struvite) implants with different porosity in both mechanically loaded and non-loaded defects of merino sheep. For the first time, the effect of mechanical stimuli on the biological outcome of this clinically relevant replacement material is shown and directly compared to the conventional unloaded defect situation in a large animal model. PMID- 29409868 TI - Structure and collagen crimp patterns of functionally distinct equine tendons, revealed by quantitative polarised light microscopy (qPLM). AB - : Structure-function relationships in tendons are directly influenced by the arrangement of collagen fibres. However, the details of such arrangements in functionally distinct tendons remain obscure. This study demonstrates the use of quantitative polarised light microscopy (qPLM) to identify structural differences in two major tendon compartments at the mesoscale: fascicles and interfascicular matrix (IFM). It contrasts functionally distinct positional and energy storing tendons, and considers changes with age. Of particular note, the technique facilitates the analysis of crimp parameters, in which cutting direction artefact can be accounted for and eliminated, enabling the first detailed analysis of crimp parameters across functionally distinct tendons. IFM shows lower birefringence (0.0013 +/- 0.0001 [-]), as compared to fascicles (0.0044 +/- 0.0005 [-]), indicating that the volume fraction of fibres must be substantially lower in the IFM. Interestingly, no evidence of distinct fibre directional dispersions between equine energy storing superficial digital flexor tendons (SDFTs) and positional common digital extensor tendons (CDETs) were noted, suggesting either more subtle structural differences between tendon types or changes focused in the non-collagenous components. By contrast, collagen crimp characteristics are strongly tendon type specific, indicating crimp specialisation is crucial in the respective mechanical function. SDFTs showed much finer crimp (21.1 +/- 5.5 um) than positional CDETs (135.4 +/- 20.1 um). Further, tendon crimp was finer in injured tendon, as compared to its healthy equivalents. Crimp angle differed strongly between tendon types as well, with average of 6.5 +/- 1.4 degrees in SDFTs and 13.1 +/- 2.0 degrees in CDETs, highlighting a substantially tighter crimp in the SDFT, likely contributing to its effective recoil capacity. STATEMENT OF SIGNIFICANCE: This is the first study to quantify birefringence in fascicles and interfascicular matrix of functionally distinct energy storing and positional tendons. It adopts a novel method - quantitative polarised light microscopy (qPLM) to measure collagen crimp angle, avoiding artefacts related to the direction of histological sectioning, and provides the first direct comparison of crimp characteristics of functionally distinct tendons of various ages. A comparison of matched picrosirius red stained and unstained tendons sections identified non-homogenous staining effects, and leads us to recommend that only unstained sections are analysed in the quantitative manner. qPLM is successfully used to assess birefringence in soft tissue sections, offering a promising tool for investigating the structural arrangements of fibres in (soft) tissues and other composite materials. PMID- 29409869 TI - The role of hippocampal brain-derived neurotrophic factor in age-related differences in neuropathic pain behavior in rats. AB - AIMS: This study was aimed to explore the contribution of central brain-derived neurotrophic factor (BDNF) in the neuropathic pain pathogenesis using an aged rodent model. MAIN METHODS: Adult and aged rats were randomly assigned to either a sciatic nerve ligation (SNL) group or a control skin sham surgery group. Sensory behavioral testing were performed on the day before surgery and on the 3rd, 7th, 14th, and 21st days after surgery, followed by measurement of BDNF protein levels in different brain regions. In another experiment, the hippocampal BDNF gene expression after SNL surgery was assessed at different time-points. Furthermore, the analgesic effects of intranasal BDNF administration were tested in SNL animals. KEY FINDINGS: Our behavioral results demonstrated that the hyperalgesia-like behavior after painful nerve injury has a higher incidence in aged rats compared with in adult animals. In particular, the hippocampal BDNF levels were inversely correlated with the probability of hyperalgesia-type behavior, in both brain-region specific and age-dependent manner. Time-course analysis showed that the hippocampal levels of BDNF mRNA in aged and adult rats started to decrease 7 and 14 days after surgery, respectively. However, the decrease was more pronounced in aged animals. Moreover, the repeated intranasal BDNF treatment could restore the central BDNF signaling, counteracting the age related exacerbation of hyperalgesic behavior. SIGNIFICANCE: Our findings imply that hippocampal BDNF may be related with the pathogenesis of elderly neuropathic pain. Pharmacological data further suggest that brain BDNF may be modifiable in aged neuropathic animals, and therefore, represent a promising target for intervention. PMID- 29409870 TI - Factors Affecting Palliative Care Development in Africa: In-Country Experts' Perceptions in Seven Countries. AB - CONTEXT: Factors contributing to and impeding palliative care (PC) development in Africa can provide insights into current strategies for advancing PC. OBJECTIVES: To identify key factors affecting PC development in African countries from in country PC experts' perspectives. METHODS: About 16 PC experts from seven African countries undertook semistructured interviews on PC development in their respective countries. An interpretive description approach was adopted, with data analyzed using constant comparison. RESULTS: Emerged themes included drivers, strengths, challenges, and aspirations for PC development in Africa. Drivers included advocates and pioneering organizations, HIV/AIDS, culture of caregiving, and the World Health Assembly PC resolution. Strengths included community health workers, the special role of nurses, diversity of services, and short training courses. Challenges included lack of PC education; lack of standardization in implementation; limited availability of and/or accessibility to morphine; poverty and disease burden; and lack of funding for PC. Aspirations included integration of PC, specialization in PC, nurse prescribing, and strong partnerships with Ministries of Health. Factors already highlighted in the literature were only briefly discussed. CONCLUSION: The key factors underpinning PC development in the seven countries contributed to the beginnings of PC in Africa, fueled by advocates who built on existing strengths to maximize opportunities. However, the current approach is at high risk in terms of its sustainability, and strategies for maximizing existing resources and growing infrastructure support are needed moving forward. PMID- 29409871 TI - Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. METHODS: We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. RESULTS: Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 MUg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. CONCLUSIONS: In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI). PMID- 29409872 TI - An Unusual Cause of Large Bowel Obstruction. PMID- 29409873 TI - A 7-Year-Old Boy With Alport Syndrome and Vomiting. PMID- 29409874 TI - Vanishing Pancreas. PMID- 29409875 TI - An Unlikely Lesion to Be Identified in the Cervical Esophagus. PMID- 29409876 TI - Abdominal Septated Mass in a 19-Year-Old Man. PMID- 29409877 TI - An Unusual, But Potentially Life-Threatening Lesion in the Cecum. PMID- 29409878 TI - Abnormal Gastrointestinal Imaging in a Patient With Dyspepsia. PMID- 29409879 TI - Soluble FLT-1 rules placental destiny. AB - INTRODUCTION: Placenta previa is an abnormality in which the placenta covers the internal uterine os, and it can cause serious morbidity and mortality in both mother and fetus due to catastrophic hemorrhage. Some pregnant women recover from placenta previa due to a phenomenon called "migration." However, the mechanism of "migration" of the placenta has not been elucidated. METHODS: Human placentas were collected from patients with placenta previa and those with no abnormal placentation (control). A microarray analysis was performed to detect the genes up- or down-regulated only in the caudal part in the previa group. Specific mRNA expression was evaluated using real-time quantitative reverse transcription PCR (qRT-PCR). Unilateral uterine artery ablation of 8.5 dpc mice was performed to reproduce the reduction of placental blood supply, and weights of the placentas and fetuses were evaluated in 18.5 dpc. Specific mRNA expression was also evaluated in mice placentas. RESULTS: According to the result of the microarray analysis, we focused on soluble fms-like tyrosine kinase-1 (sFLT-1) and hypoxia inducible factor-1 (HIF-1) alpha. The sFLT-1 expression level is locally high in the caudal part of the human placenta in patients with placenta previa. In mice experiments, the weights of the placentas and fetuses were significantly smaller in the ablation side than those in the control side, and the sFlt-1 expression level was significantly higher in the ablation side than in the control side. DISCUSSION: Our study suggests that "migration" of the placenta is derived from placental degeneration at the caudal part of the placenta, and sFlt-1 plays a role in this placental degeneration. PMID- 29409882 TI - Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: A Nationwide Survey in Japan. AB - POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, lambda-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose >= 200 mg/m2. The median CD34 cell dose was 2.47 * 106/kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P < .0001). Over a median follow-up of 46.6 months 10 patients died, and 5-year overall survival was 88.8% (n = 95). Progression-free survival at 3 years was 78.3% (n = 70; median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving quality of life. However, disease recurrence remains a major issue for long-term survivors. PMID- 29409881 TI - Preparation of irritant polymer samples for an in vitro round robin study. AB - A round robin study using reconstructed human epidermis (RhE) tissues was conducted to test medical device polymer extracts for skin irritation potential. Test samples were four irritant and three non-irritant medical device polymers. Five of these polymer samples were developed and two were obtained commercially. The three non-irritant samples were comprised of 100% 80A polyurethane, one-part silicone, and polyvinyl chloride (PVC). The polyurethane samples were made using a hot-melt process, while the silicone samples were created by mixing and casting. The PVC samples were commercially produced sheets. The four irritant samples were comprised of one-part silicone and 25% heptanoic acid (HA), two-part silicone and 15% sodium dodecyl sulfate (SDS), PVC and 4% Genapol(r) X-100, and PVC and 5.8% Genapol(r) X-080. The HA, SDS, and Genapol(r) X-100 samples were produced using the mixing and casting method, while the Genapol(r) X-080 sheet samples were obtained commercially. During development, irritant polymer samples were extracted using polar and non-polar solvents that were subsequently analyzed chemically. Samples with sufficient levels of extracted irritants were tested on RhE tissues to confirm their irritation potential. Polymers that passed this screening test were used in the round robin study described elsewhere in this special edition. PMID- 29409880 TI - The effects of graded intraocular pressure challenge on the optic nerve head. AB - Intraocular pressure (IOP) is an important risk factor for glaucoma, and the response of the ONH and surrounding tissues to elevated IOP are often investigated to better understand pathophysiology. In vivo structure including that of the optic nerve head (ONH) and surrounding tissue of the eye are often assessed using optical coherence tomography (OCT). With advances in OCT technology, both large vessels and capillaries can be imaged non-invasively (OCT Angiography). Because a significant portion of retinal thickness is comprised of vasculature, the purpose of the current study was to investigate OCT structural and vascular changes in healthy non-human primate eyes with systematic graded increases and decreases in IOP. Six healthy animals with no previous experimental intervention were used. The pressure in the anterior chamber was adjusted from 10 mmHg to 60 mmHg and back to 10 mmHg in 10 mmHg steps every 10 min. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, minimum rim width (MRW), Bruch's membrane opening (BMO) size and relative height, anterior lamina cribrosa surface (ALCS) depth, choroidal thickness, and angiography (OCTA) were quantified. With IOP challenge there were significant changes in all morphological measures quantified (p < 0.01) other than BMO size (p = 0.30) and RNFL thickness (p = 0.29). Specifically, the position of the BMO was sensitive to both an increase and decease in IOP. The inner retinal capillary density gradually decreased with increasing IOP, reaching statistical significance when pressure exceeded 50 mmHg, but returned when IOP was reduced. The average choroidal thickness around the ONH decreased for elliptical annuli 500-1000 MUm and 1000-1500 MUm, from the BMO, with increasing IOP (p < 0.01). For the 1000-1500 MUm annulus, choroid thickness did not return to baseline with IOP reduction. Similarly, the MRW decreased with increase in IOP, but with pressure reduction did not return, and at the final 10 mmHg time point was thinner than at baseline (p < 0.01). The results from this experiment illustrate differences in ONH neural rim tissue, RNFL and vessel density changes with acute IOP challenge. Overall, vessel collapse could not completely account for changes in RNFL or ONH MRW thickness. The study supports the hypothesis neural rim compression may be an important part of IOP-induced damage. PMID- 29409883 TI - Long non-coding RNA MEG3 silencing protects against light-induced retinal degeneration. AB - Excessive light exposure leads to retinal degeneration and accelerates the progression and severity of several ocular diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa. Long non-coding RNAs (LncRNAs) have emerged as important regulators of photoreceptor development and ocular diseases. In this study, we investigated the role of lncRNA-MEG3 in light-induced retinal degeneration. MEG3 expression was significantly up-regulated after light insult in vivo and in vitro. MEG3 silencing protected against light-induced retinal degeneration in vivo and light-induced photoreceptor cell apoptosis in vitro. Mechanistically, MEG3 regulated retinal photoreceptor cell function by acting as p53 decoy. MEG3 silencing decreased caspase 3/7 activity, up-regulated anti apoptotic protein (Bcl-2) expression, and down-regulated pro-apoptotic protein (Bax) expression. Taken together, this study provides a promising method of MEG3 silencing for treating light-induced retinal degeneration. PMID- 29409884 TI - Identification of Toll-like receptor family members in Oncomelania hupensis and their role in defense against Schistosoma japonicum. AB - The amphibious snail, Oncomelania hupensis, primarily distributed in the Far East, is the only intermediate host of Schistosoma japonicum, which causes the most virulent form of schistosomiasis. Obligatory parasitism of snails is the main vehicle for human and livestock infection and depends primarily on parasite infectivity, snail defense capacity and specificity, and parasite-snail compatibility. Therefore, the schistosome-snail interaction is biomedically significant, particularly the molecular mechanisms involved in the innate immune response against S. japonicum. Several immune effectors and signaling pathways have been successfully identified in mollusks, especially in Biomphalaria glabrata, the intermediate snail host of S. mansoni; however, limited information is available for O. hupensis. Here, we identified 16 Toll-like receptors (TLRs) in O. hupensis. These O. hupensis TLRs (OhTLRs) are highly expressed in haemocytes, the primary immune cell of mollusks. Most of the OhTLRs were more highly expressed in female gonads than in other tissues, which may suggest maternal immune transfer in O. hupensis. After S. japonicum challenge, the expression levels of all of the OhTLRs were significantly up-regulated at 6 h post-challenge; many of the OhTLR expression levels were inhibited at later time points in haemocytes, while they were inhibited and fluctuated to varying degrees in other tissues. Additionally, we further determined the tissue-specific expression and dynamic response against S. japonicum of one of the TLR signaling adaptors, myeloid differentiation factor 88 (MyD88), from O. hupensis. Three OhMyD88 genes were highly expressed in haemocytes, and were up-regulated in haemocytes and inhibited in the head-foot muscle at the early time-point after S. japonicum challenge; however, these had slower changes and longer durations compared to OhTLRs. These results provide evidence suggesting that immune effectors are involved in innate immune responses of O. hupensis against S. japonicum and may play a role in the activation of different haemocytes, and not limited for the early response to S. japonicum invasion. Further investigation into the varied expression of OhTLRs in other tissues after S. japonicum challenge will improve our understanding of TLR function in innate immunity of O. hupensis. PMID- 29409885 TI - Propionibacterium acnes-Derived Extracellular Vesicles Promote Acne-Like Phenotypes in Human Epidermis. AB - Acne vulgaris is an inflammatory disease occurring in the pilosebaceous unit and is the most common skin condition in young people. A gram-positive bacterium, Propionibacterium acnes, has been suspected to contribute to the development of acne. Here, we report that P. acnes constitutively releases extracellular vesicles (EVs) exhibiting typical EV morphology and size. Moreover, the P. acnes derived EVs (PEVs) can induce acne-like phenotypes in human epidermal keratinocytes and a reconstituted human skin model. PEVs significantly induced inflammatory cytokines IL-8 and GM-CSF and dysregulated epidermal differentiation by increasing proliferating keratinocytes and decreasing epidermal keratin 10 and desmocollin 1 levels. PEVs showed strong effects, evoking these responses at earlier time points compared with P. acnes extract at the same protein concentration. We verified that PEVs were internalized via clathrin-dependent endocytosis into keratinocytes and that PEV-induced cellular responses occurred via Toll-like receptor 2-dependent signal cascades. Furthermore, PEVs showed a stronger effect than keratinocytes in inducing inflammatory cytokines in myeloid cells. Collectively, our study suggests that PEVs induce acne-like phenotypes in a unique way; therefore, inhibiting the release of EVs from P. acnes or targeting PEV-mediated signaling pathways could represent an alternative method for alleviating acne occurrence and phenotypes. PMID- 29409886 TI - Changes in the morphology and gene expression of developing zebrafish gonads. AB - Zebrafish gonadal sexual differentiation is an important but poorly understood subject. The difficulty in investigating zebrafish sexual development lies in its sex determination plasticity, the lack of morphological tools to distinguish juvenile females from males, and the lack of sex chromosomes in laboratory strains. Zebrafish sexual differentiation starts at around 8 days post fertilization when germ cells start to proliferate. The number of germ cells determines the future sex of the gonad. Gonads with more germ cells differentiate into ovaries, whereas a reduced germ cell number leads to male-biased sexual differentiation. Genes controlling sexual differentiation in pre-meiotic gonads encode proteins such as transcription factors, the transforming growth factor (TGF)-beta family of signaling proteins, and RNA-binding proteins. These proteins coordinately control germ cell proliferation/meiosis/maintenance and gonadal somatic cell differentiation, leading to stepwise differentiation of gonads. Morphological changes in differentiating gonads are characterized by the appearance of oocytes containing condensed chromatin, followed by incorporation of vitellogenin and oocyte maturation. Marker genes and morphological characteristics help distinguish the steps in zebrafish gonadal differentiation during this important sex-determining stage. PMID- 29409887 TI - Do children with obesity have worse table manners? Associations between child table manners, weight status and weight gain. AB - BACKGROUND: Children with obesity experience stigma stemming from stereotypes, one such stereotype is that people with obesity are "sloppy" or have poor manners. Teaching children "proper table manners" has been proposed as an obesity prevention strategy. Little is known about the association between children's weight status and table manners. OBJECTIVES: To examine correlates of child table manners and to examine the association of child table manners with child obese weight status and prospective change in child body mass index z-score (BMIz). METHODS: Mother-child dyads (N = 228) participated in a videotaped laboratory eating task with cupcakes. Coding schemes to capture child table manners (making crumbs, chewing with mouth open, getting food on face, shoving food in mouth, slouching, and getting out of seat), and maternal attentiveness to child table manners, were reliably applied. Anthropometrics were measured at baseline and at follow-up two years later. Regression analyses examined the association of participant characteristics with child table manners, as well as the associations of child table manners with child obese weight status, and prospective change in BMIz/year. RESULTS: Predictors of poorer child table manners were younger child age, greater cupcake consumption, and greater maternal attentiveness to child table manners. Poorer child table manners were not associated with child obese (vs. not) weight status, but were associated with a prospective decrease in BMIz/year in children with overweight/obesity. CONCLUSIONS: Obesity interventions to improve table manners may be perpetuating unfavorable stereotypes and stigma. Future work investigating these associations is warranted to inform childhood obesity guidelines around table manners. PMID- 29409888 TI - Comparison of Adjuvant Radiation Therapy Alone and Chemotherapy Alone in Surgically Resected Low-Grade Gliomas: Survival Analyses of 2253 Cases from the National Cancer Data Base. AB - BACKGROUND: It is becoming increasingly common to incorporate chemotherapy (CT) with radiotherapy (RT) in the treatment of low-grade gliomas (LGGs) after surgical resection. However, there is a lack of literature comparing survival of patients who underwent RT or CT alone. METHODS: The U.S. National Cancer Data Base was used to identify patients with histologically confirmed, World Health Organization grade 2 gliomas who received either RT alone or CT alone after surgery from 2004 to 2013. Overall survival (OS) was evaluated by Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and propensity-score matched analysis. RESULTS: In total, 2253 patients with World Health Organization grade 2 gliomas were included, of whom 1466 (65.1%) received RT alone and 787 (34.9%) CT alone. The median OS was 98.9 months for the RT alone group and 125.8 months for the CT alone group. On multivariable analysis, CT alone was associated with a significant OS benefit compared with RT alone (hazard ratio [HR], 0.405; 95% confidence interval, 0.277-0.592; P < 0.001). On subgroup analyses, the survival advantage of CT alone over RT alone persisted across all age groups, and for the subtotal resection and biopsy groups, but not in the gross total resection group. In propensity-score-matched analysis, CT alone still showed significantly improved OS compared with RT alone (HR, 0.612; 95% confidence interval, 0.506-0.741; P < 0.001). CONCLUSIONS: Our results suggest that CT alone was independently associated with longer OS compared with RT alone in patients with LGGs who underwent surgery. PMID- 29409889 TI - Analysis of Four Scoring Systems for the Prognosis of Patients with Metastasis of the Vertebral Column. AB - OBJECTIVE: Metastatic spinal diseases are common health problems and there is no consensus on the appropriate treatment of metastases in several conditions. Using clinical measures (e.g., survival time and functional status), prognosis prediction systems advise on the appropriate interventions. The aim of this article is to assess and compare 4 widely used scoring systems (revised Tokuhashi, Tomita, van der Linden, and modified Bauer scores) on a single-center cohort. METHODS: A retrospective study was designed of 329 patients who were subjected to surgery because of metastatic spinal diseases. Subpopulations according to the classifications of the 4 scoring systems were identified. The overall survival was calculated with the Kaplan-Meier formula. The difference between the survival curves of subpopulations was analyzed with log-rank tests. The consistency rates for the 4 scoring systems are calculated as well. RESULTS: The follow-up period was 8 years. The median survival time was 222 days. The overall survival of prognostic categories in 3 scoring systems was significantly different from each other, but we found no differences between the categories of the van der Linden system. In this cohort, the revised Tokuhashi system gave the best approximation for survival, with a mean predictive capability 60.5%. CONCLUSIONS: The evaluation of 4 standard scoring systems showed that 3 were self consistent, although none of systems was able to predict the survival in our cohort. Based on the predictive capability, the revised Tokuhashi system may provide the best predictions with careful examination of individual cases. PMID- 29409890 TI - Regarding "Laparoscopic Sterilization Under Local Anesthesia with Conscious Sedation Versus General Anesthesia: A Systematic Review of the Literature". PMID- 29409891 TI - Hereditary galactosemia. AB - Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1 phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved. PMID- 29409892 TI - Invited Commentary. PMID- 29409893 TI - Rice Functional Genomics Research: Past Decade and Future. AB - Rice (Oryza sativa) is a major staple food crop for more than 3.5 billion people worldwide. Understanding the regulatory mechanisms of complex agronomic traits in rice is critical for global food security. Rice is also a model plant for genomics research of monocotyledons. Thanks to the rapid development of functional genomic technologies, over 2000 genes controlling important agronomic traits have been cloned, and their molecular biological mechanisms have also been partially characterized. Here, we briefly review the advances in rice functional genomics research during the past 10 years, including a summary of functional genomics platforms, genes and molecular regulatory networks that regulate important agronomic traits, and newly developed tools for gene identification. These achievements made in functional genomics research will greatly facilitate the development of green super rice. We also discuss future challenges and prospects of rice functional genomics research. PMID- 29409894 TI - Trimming of N-Glycans by the Golgi-Localized alpha-1,2-Mannosidases, MNS1 and MNS2, Is Crucial for Maintaining RSW2 Protein Abundance during Salt Stress in Arabidopsis. AB - Asparagine (Asn/N)-linked glycans are important for protein folding, trafficking, and endoplasmic reticulum-associated degradation in eukaryotes. The maturation of glycoproteins involves the trimming of mannosyl residues by mannosidases and addition of other sugar molecules to three-branched N-glycans in the Golgi. However, the biological importance of Golgi-mediated mannose trimming is not fully understood. Here, we show that abolishment of two functionally redundant mannosidases, MNS1 and MNS2, responsible for alpha-1,2-mannose trimming on the A and C branches of plant N-glycans lead to severe root growth inhibition under salt stress conditions in Arabidopsis. In contrast, mutants with defects in the biosynthesis of the oligosaccharide precursor displayed enhanced salt tolerance in the absence of mannose trimming. However, mutation in EBS3, which is required for the formation of the branched N-glycan precursor, suppressed the salt sensitive phenotype of mns1 mns2 double mutant. Interestingly, we observed that cellulose biosynthesis was compromised in mns1 mns2 roots under high salinity. Consistently, abundance of a membrane anchored endo-beta-1,4-endoglucanase (RSW2/KOR) that plays a key role in cellulose biosynthesis and its mutant variant rsw2-1 were modulated by alpha-1,2-mannose trimming under salt stress. Overexpression of RSW2 could partially rescue the salt-sensitive phenotype of mns1 mns2. Taken together, these results suggest that MNS1/2-mediated mannose trimming of N-glycans is crucial in modulating glycoprotein abundance to withstand salt stress in plants. PMID- 29409895 TI - Bcl-2-associated athanogene 3 (BAG3) is an enhancer of small heat shock protein turnover via activation of autophagy in the heart. AB - Bcl-2-associated athanogene 3 (BAG3) is strongly expressed in both cardiac and skeletal muscle. A recent study showed that BAG3 may play a protective role in muscles. Little is known, however, regarding the detailed role of BAG3 in cardiac muscle. To better understand the functional role of cardiac BAG3 in the heart, we generated transgenic (TG) mice that overexpress BAG3. A decrease in fractional shortening, and the induction of cardiac atrial natriuretic peptide, were observed in BAG3 TG mice. Moreover, a marked reduction in the protein level of small HSPs was detected in BAG3 TG mouse hearts. We analyzed the cardiac small HSP levels when either the ubiquitin-proteasome system (UPS) or the autophagy system (AS) was inhibited in BAG3 TG mice. The protein turnovers of small HSPs by the AS were activated in BAG3 TG mouse hearts. Thus, BAG3 is critical for the protein turnover of small HSPs via activation of autophagy in the heart. PMID- 29409896 TI - Pol I DNA polymerases stimulate DNA end-joining by Escherichia coli DNA ligase. AB - Klenow and Klentaq are the large fragment domains of the Pol I DNA polymerases from Escherichia coli and Thermus aquaticus, respectively. Herein, we show that both polymerases can significantly stimulate complementary intermolecular end joining ligations by E.coli DNA ligase when the polymerases are present at concentrations lower than that of the DNA substrates. In contrast, high polymerase concentrations relative to the DNA substrates inhibit the intermolecular ligation activity of DNA ligase. Neither polymerase was able to stimulate the DNA ligase from T4 bacteriophage. Additionally, nick-closure by E. coli DNA ligase (but not T4 ligase) is slightly stimulated by both polymerases, but only at about 10% of the magnitude seen for end-joining enhancement. The data represent one of the first observations of direct polymerase-ligase interactions in prokaryotes, and suggest that the polymerases stabilize the associated DNA ends during intermolecular ligation, and that such a complex can be taken advantage of by some, but not all, DNA ligases. PMID- 29409897 TI - Comparison of the antimicrobial efficacy of photodynamic therapy with two mediators against Lactobacillus acidophilus in vitro. AB - BACKGROUND AND OBJECTIVES: Lactobacillus is a cariogenic microorganism. Different therapeutic approaches including photodynamic therapy (PDT) have been suggested for treatment of bacterial infection. The purpose of the current study was to compare the effects of PDT with Indocyanine green (ICG) and Methylene blue (MB) photosensitizers (PSs) on Lactobacillus acidophilus (L. acidophilus). MATERIALS AND METHODS: In this in-vitro experimental study, 84 samples of L. acidophilus (1 McFarland standard) were compared in 14 experimental groups including: MB, ICG, 660-nm laser, 808-nm laser (pulsed, 74s/continuous-wave, 37s), different combinations of lasers and PSs, Chlorhexidine (CHX) 0.2%, sodium hypochlorite (NaOCl) 2.5%, penicillin 6.3.3 and control groups. The samples were cultured in microplates containing blood agar culture medium. After incubation at 37 degrees C for 48 h, the colony forming units (CFUs) of L. acidophilus were counted and compared before and after therapeutic interventions. Data were analyzed using SPSS19 software program according to one-way ANOVA test. RESULTS: This study showed that the separate use of ICG, 660- and 808-nm lasers (pulsed, 74s/continuous-wave, 37s), and the combined use of 808-nm laser (pulsed, 74s/continuous-wave, 37s) and ICG have no significant inhibitory effect on L. acidophilus colonies (P > 0.05), whereas the separate use of MB and the combined use of 660-nm laser (continuous-wave, 37s/pulsed, 74s) and MB significantly inhibited the growth of L. acidophilus in comparison with the control group (p < 0.05). Likewise, CHX 0.2%, NaOCl 2.5% and penicillin 6.3.3 significantly inhibited the bacterial growth (p < 0.05). CONCLUSION: The results showed that separate use of MB and combined use of 660-nm laser and MB have a significant inhibitory effect on L. acidophilus growth. PMID- 29409898 TI - Phenotypic heterogeneity: a bacterial virulence strategy. AB - Growing knowledge of the complexity of the host-pathogen interactions during the course of an infection revealed an amazing variability of bacterial pathogens within the same host tissue site. This heterogeneity in bacterial populations is either the result of a different bacterial response to a slightly divergent tissue microenvironment or is caused by a genetic circuit in which small endogenous fluctuations in a small number of transcription factors drive gene expression in combination with a positive feedback loop. As a result host pathogen encounters can have different outcomes in individual cells, which enables bet-hedging and/or a co-operative behavior that enhance bacterial fitness and virulence, drive different host responses and promote resistance of small subpopulations to antibiotic treatment. This has a strong impact on the progression and control of the infection, which must be considered for the development of successful antimicrobial therapies. PMID- 29409899 TI - A 12-Year Study of Slotted Palladium-103 Plaque Radiation Therapy for Choroidal Melanoma: Near, Touching, or Surrounding the Optic Nerve. AB - PURPOSE: To present our 12-year experience with low-energy-photon, slotted eye plaque radiation therapy. DESIGN: Retrospective interventional case series. METHODS: Setting: The New York Eye Cancer Center. STUDY POPULATION: Fifty-two consecutive patients with uveal melanomas near, touching, or surrounding the optic disc. INTERVENTION: Slotted eye plaque radiation therapy. MAIN OUTCOME MEASURES: Change in visual acuity, local tumor control, radiation side effects, eye salvage, and systemic metastases. RESULTS: Tumors were peripapillary within 1.5 mm of the optic disc (n = 8, 15%), juxtapapillary touching <=180 degrees (n = 23, 44%), or circumpapillary >180 degrees and encircling the disc (n = 21, 41%). Mean follow-up was 47 months (median 34 months, range 6-146 months). Radiation induced a mean 41.2% reduction in tumor thickness. Life table analysis showed that 69% of patients retained their visual acuities >= 20/40 and had a vision loss-free survival 84 months after treatment. Also, 90% of patients retained their visual acuity between 20/50 and 20/200 and had a vision loss-free survival 36 months after treatment. Slotted plaque brachytherapy was associated with 4% secondary cataract, 11% neovascular glaucoma, and no dry eye or eyelash loss. Local tumor control (no recurrence) was achieved in 98.1% of patients. Life table analysis showed an overall enucleation-free survival of 93% and metastasis-free survival of 94%. CONCLUSIONS: Slotted plaque radiation therapy provided a normalized plaque-tumor position, such that the entire choroidal melanoma plus a 2- to 3-mm free margin of normal-appearing tissue was included in the targeted zone. At 12 years, slotted plaque radiation therapy resulted in high rates of local tumor control and vision and eye retention. PMID- 29409900 TI - Both the PH domain and N-terminal region of oxysterol-binding protein related protein 8S are required for localization to PM-ER contact sites. AB - Oxysterol-binding protein-related proteins are implicated in the sensing and transporting lipids at the membrane contact sites. One of the members of the mammalian ORP family, ORP8, is thought to transport lipids through directly tethering both ER and PM membranes. Targeting to PM is thought to be mediated by N-terminal pleckstrin homology domain via binding to phosphoinositides. Sequence alignments and NMR structural determination revealed that the PH domain of ORP8 is atypical and contains an insertion of 20 amino acids in an unstructured loop region that may potentially block interactions with ligands. Using standard lipid protein overlay assays or liposomal binding assays we could not detect binding of a recombinant version of the PH domain. Examination of a series of deletion constructs demonstrated that both the N-terminal polybasic region and the PH domain are required for proper targeting of the short splice variant ORP8S to the PM-ER contact site in Chinese hamster ovary cells. PMID- 29409901 TI - ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis. AB - OBJECTIVE: Adenomyosis is a benign gynecological disease, characterized by the malignant biological behaviors of invasion and metastasis. ILK plays an important role in intercellular adhesion and triggers the process of EMT. In this study, we investigated the role of ILK-induced EMT in the pathogenesis of adenomyosis. METHODS: ILK and EMT markers including E-cadherin, N-cadherin and Vimentin have been detected with Immunohistochemistry(IHC), RT-PCR and Western Blot, in normal endometrium, matched eutopic and ectopic endometrium respectively. Primary endometrial cells were isolated in order to observed the morphology features, as well as the change of invasiveness. RESULTS: Hyper-activation of ILK were detected in the adenomyosis lesions, along with the typical aberrant expression of EMT markers. Furthermore, comparing with ESCs, the EuSCs showed a more invasive and dynamic phenotype. CONCLUSIONS: ILK-induced EMT is a novel mechanism in the pathogenesis of adenomyosis and may be a potential therapeutic agent for adenomyosis. PMID- 29409902 TI - Predicting ligand binding poses for low-resolution membrane protein models: Perspectives from multiscale simulations. AB - Membrane receptors constitute major targets for pharmaceutical intervention. Drug design efforts rely on the identification of ligand binding poses. However, the limited experimental structural information available may make this extremely challenging, especially when only low-resolution homology models are accessible. In these cases, the predictions may be improved by molecular dynamics simulation approaches. Here we review recent developments of multiscale, hybrid molecular mechanics/coarse-grained (MM/CG) methods applied to membrane proteins. In particular, we focus on our in-house MM/CG approach. It is especially tailored for G-protein coupled receptors, the largest membrane receptor family in humans. We show that our MM/CG approach is able to capture the atomistic details of the receptor/ligand binding interactions, while keeping the computational cost low by representing the protein frame and the membrane environment in a highly simplified manner. We close this review by discussing ongoing improvements and challenges of the current implementation of our MM/CG code. PMID- 29409904 TI - Early Assessment of Burn Depth with Far Infrared Time-Lapse Thermography. AB - BACKGROUND: Diagnosing the extremes of superficial burns and full-thickness burns is straightforward. It is in the middle ground of partial-thickness burns where the diagnostic difficulties emerge; it can take up to 3 to 5 days for signs of healing to appear. We hypothesize that cooling partial-thickness burns and tracking the rate of rewarming will immediately reflect the condition of the burn: shallow partial-thickness burns that retain cell health and blood flow will rewarm rapidly, and deeper burns with damaged microvessels will rewarm slowly. STUDY DESIGN: We enrolled 16 patients with isolated, partial-thickness burns on their extremities who were diagnosed as indeterminate by our burn surgeon. Within 24 hours after presentation, room-temperature saline was poured over the burn as a cooling challenge. An infrared camera that was sensitive to body temperature produced false-color images showing pixel-by-pixel temperatures. A time-lapse recording from the infrared camera images taken as the burn rewarmed produced a time-temperature curve that reflected the kinetics of rewarming. The outcomes variable was whether or not the patient received a skin graft, which was determined 72 hours after presentation. RESULTS: The method correctly predicted whether or not the patient required a skin graft. CONCLUSIONS: Here we report a new technique that permits determination of wound viability much earlier than clinical examination. Due to the simplicity of the method, non-experts can successfully perform the technique on the first day of the burn and make the correct diagnosis and decision to graft or not to graft. PMID- 29409903 TI - Cholinesterases and the fine line between poison and remedy. AB - Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) are related enzymes found across the animal kingdom. The critical role of acetylcholinesterase in neurotransmission has been known for almost a century, but a physiological role for butyrylcholinesterase is just now emerging. The cholinesterases have been deliberately targeted for both therapy and toxicity, with cholinesterase inhibitors being used in the clinic for a variety of disorders and conversely for their toxic potential as pesticides and chemical weapons. Non-catalytic functions of the cholinesterases (ChEs) participate in both neurodevelopment and disease. Manipulating either the catalytic activities or the structure of these enzymes can potentially shift the balance between beneficial and adverse effect in a wide number of physiological processes. PMID- 29409905 TI - CTCF-Induced Circular DNA Complexes Observed by Atomic Force Microscopy. AB - The CTCF protein has emerged as a key architectural protein involved in genome organization. Although hypothesized to initiate DNA looping, direct evidence of CTCF-induced DNA loop formation is still missing. Several studies have shown that the 11 zinc finger (11 ZF) domain of CTCF is actively involved in DNA binding. We here use atomic force microscopy to examine the effect of the 11 ZF domain comprising residues 266-579 (11 ZF CTCF) and the 3 ZF domain comprising residues 402-494 (6-8 ZF CTCF) of human CTCF on the DNA morphology. Our results show that both domains alter the DNA architecture from the relaxed morphology observed in control DNA samples to compact circular complexes, meshes, and networks, offering important insights into the multivalent character of the 11 ZF CTCF domain. Atomic force microscopy images reveal quasi-circular DNA/CTCF complexes, which are destabilized upon replacing the 11 ZF CTCF by the 6-8 ZF CTCF domain, highlighting the role of the 11 ZF motif in loop formation. Intriguingly, the formation of circular DNA/CTCF complexes is dominated by non-specific binding, whereby contour length and height profiles suggest a single DNA molecule twice wrapped around the protein. PMID- 29409906 TI - Phylogenetic position of the enigmatic deep-sea nematode order Rhaptothyreida: A molecular analysis. AB - The placement of the rare deep-sea nematode order Rhaptothyreida remains unclear due to the unique morphology of this group, an unknown life cycle with morphologically distinct juvenile stages which may or may not be parasitic, and lack of molecular sequences. Here, we investigate the phylogenetic placement and status of the Rhaptothyreida based on SSU and D2-D3 of LSU rDNA sequences of Rhaptothyerus typicus specimens obtained from the continental slope of New Zealand. Molecular sequences of three adults and a late stage juvenile were identical, confirming that they belong to the same species despite pronounced morphological differences. We observed the presence of the rare nucleotide transition A -> G and transversion G -> Y in the loops of Hairpin 35 and 48 regions, which is consistent with the placement of R. typicus within the order Enoplida. Rhaptothyreus typicus was consistently recovered as a long branch clade in SSU and D2-D3 of LSU analyses, which can have a destabilising effect on tree topology. After Gblocks were used to remove sites of questionable alignment, R. typicus was placed in a clade comprising Trissonchulus, Dolicholaimus and Ironus sequences (family Ironidae, order Enoplida) in both Bayesian and Maximum Likelihood SSU topologies. Depending on which alignment algorithm was used, analyses of LSU sequences focusing on enoplid taxa either suggested a relationship between R. typicus and Halalaimus (family Oxystominidae) or did not identify any clear relationships. Overall, our results provide strong evidence for placing R. typicus and the family Rhaptothyreidae within the order Enoplida, although further work is required to clarify relationships between rhaptothyreids and other enoplid taxa. A parasitic lifestyle could explain the unique morphology of this group, their highly divergent SSU and LSU rDNA molecular sequences, and the marked morphological differences between late juveniles and adults. Further molecular investigations targeting both free-living and parasitic early juvenile life stages in potential deep-sea hosts are needed to better understand the evolution of this unusual nematode taxon. PMID- 29409907 TI - National Imaging Trends after Percutaneous Nephrolithotomy. AB - PURPOSE: Followup imaging after percutaneous nephrolithotomy serves to detect postoperative complications, residual fragments and silent hydronephrosis. However, the timing and optimal imaging modality remain poorly defined. We describe imaging use patterns after percutaneous nephrolithotomy. MATERIALS AND METHODS: In the MarketScan(r) database we identified patients 17 to 64 years old who underwent percutaneous nephrolithotomy between 2007 and 2014. Imaging modalities were identified by CPT, and ICD-9 and 10 codes, and tracked for 1 year after percutaneous nephrolithotomy. The modalities included computerized tomography, renal ultrasound, abdominal x-ray and intravenous pyelogram. Cumulative longitudinal use patterns were characterized and the association with demographic factors was assessed by the chi-square test. RESULTS: Of the 6,495 patients included in analysis 29% and 15% had undergone no postoperative imaging by 3 and 12 months, respectively. While abdominal x-ray was the most common modality at 3, 6 and 12 months, performed in 46%, 53% and 62% patients, respectively, nearly 50% underwent computerized tomography by 1 year. Of these patients 34% underwent computerized tomography within 3 months, which was done within the first 3 days in 69%. During the study period renal ultrasound use increased by 13% while computerized tomography and abdominal x-ray use remained relatively stable. Female gender, residence in the Northeast, no health maintenance organization status and treatment in a metropolitan statistical area were independently associated with higher rates of renal ultrasound on multivariate analyses (p <0.05). CONCLUSIONS: Among insured adults national imaging patterns vary following percutaneous nephrolithotomy. Many patients do not receive any followup imaging while approximately half undergo computerized tomography within a year. Imaging patterns may be evolving with the increased use of ultrasound. PMID- 29409908 TI - Biocompatibility of pristine graphene monolayer: Scaffold for fibroblasts. AB - The aim of the present study was to evaluate the cytotoxicity of pristine graphene monolayer and its utility as a scaffold for murine fibroblast L929 cell line. Cell viability, morphology, cytoskeleton architecture (microfilaments and microtubules), cell adhesion and migration into the scratch-wound area were determined using pristine graphene-coated microscopic slides. We found that fibroblasts cultured on pristine graphene monolayer exhibited changes in cell attachment, motility and cytoskeleton organization. Graphene was found to have no cytotoxicity on L929 fibroblasts and increased cell adhesion and proliferation within 24 h of culture. The area of cells growing on graphene was comparable to the area of fibroblasts cultured on glass. Migration of cells on the surface of graphene substrate appeared to be more regular in comparison to uncoated glass surface, however in both control (glass) and experimental (graphene) groups the scratch wound was closed after 48 h of culture. Taken together, our results indicate that pristine graphene monolayer is non-toxic for murine subcutaneous connective tissue fibroblasts and could be beneficial for recovery of damaged tissues after injury. These studies could be helpful in evaluating biocompatibility of graphene, which still remains ambiguous. PMID- 29409909 TI - Threonine 67 is a key component in the coupling of the NSS amino acid transporter KAAT1. PMID- 29409911 TI - Inhibition of gingipains prevents Porphyromonas gingivalis-induced preterm birth and fetal death in pregnant mice. AB - Accumulating epidemiological evidence indicates that infection with Porphyromonas gingivalis which is a major periodontal pathogen, causes preterm birth and low birth weight. However, virulence factors of P. gingivalis responsible for preterm birth/low birth weight remain to be elucidated. In this study, using P. gingivalis-infected pregnant mice as an in vivo model, we investigated whether gingipains-cysteine proteinases produced by P. gingivalis-affect preterm birth and low birth weight. We found that intravenous infection of pregnant mice with P. gingivalis induced higher accumulation of the bacterium in the placenta than that in other organs. Compared to infection with P. gingivalis wild-type, infection with a gingipain-deficient P. gingivalis mutant KDP136 led to significant reduction in preterm birth and pregnancy loss. Although repetitive low-level infections of P. gingivalis failed to induce preterm birth and fetal death, it induced suppressive effects on IFN-gamma production. Therapeutically, treatment with ginginpain inhibitors prevented fetal death and preterm birth caused by P. gingivalis infection and resulted in recovery of IFN-gamma suppression caused by repetitive chronic P. gingivalis infection. These results indicate that gingipains are major virulence factors of P. gingivalis responsible for preterm birth/low birth, and gingipain inhibitors may be useful not only as a therapeutic agent for periodontal diseases, but also as a preventive medicine for preterm birth/low birth weight. PMID- 29409912 TI - Crush injury to motor nerves in the G93A transgenic mouse model of amyotrophic lateral sclerosis promotes muscle reinnervation and survival of functionally intact nerve-muscle contacts. AB - Selective survival of small motor nerve fibers and their neuromuscular contacts in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS) suggests that smaller regenerated nerve fibers are more able to sustain reformed nerve-muscle connections as functionally intact motor units (MUs). The sciatic nerve was crushed unilaterally in SOD1G93A transgenic mice at 40 days of age and contractile forces of reinnervated muscles and their MUs were recorded at 90 days in order to determine the capacities of the nerves to regenerate and to form and retain functional neuromuscular connections. Reduced MU numbers in fast-twitch tibialis anterior, extensor digitorum longus and medial gastrocnemius muscles and the lesser reductions in slow-twitch soleus muscle of SOD1G93A transgenic mice were reversed in reinnervated muscles: there were more reinnervated MUs and their contractile forces and the muscle forces and weights increased. In line with the contrasting ability of only small not large nerve fibers to sprout to form enlarged MUs in the SOD1G93A transgenic mouse, the smaller regenerating nerve fibers formed enlarged MUs that were better able to survive. Because nerve fibers with and without muscle contacts were severed by the sciatic nerve crush injury, the conditioning lesion is untenable as the explanation for improved maintenance of reinnervated neuromuscular junctions. Elevated neurotrophic factor expression in axotomized motoneurons and/or denervated Schwann cells and the synapse withdrawal from axotomized motoneurons are other factors that, in addition to reduced size of nerve fibers reinnervating muscles, may account for increased survival and size of reinnervated MUs in ALS. PMID- 29409910 TI - SP600125 blocks the proteolysis of cytoskeletal proteins in apoptosis induced by gas signaling molecule (NO) via decreasing the activation of caspase-3 in rabbit chondrocytes. AB - NO plays a key role in the pathological mechanisms of articular diseases. As cytoskeletal proteins are responsible for the polymerization, stabilization, and dynamics of the cytoskeleton network, we investigated whether cytoskeletal proteins are the intracellular pathological targets of NO. We aimed at clarifying whether the cytoskeleton perturbations involved in apoptosis are induced in rabbit articular chondrocytes by NO, which can be liberated by sodium nitroprusside (SNP) treatment. The first passage rabbit articular chondrocytes were cultured as monolayer for the experiments, and the effects of NO were tested in the presence of JNK-specific inhibitor, SP600125. SNP treatment of cultured chondrocytes caused significant apoptosis in a concentration-dependent manner (time and dose), as evaluated by TUNEL assay and Annexin V flow cytometry, while the apoptosis was reduced by the SP600125 addition 30 min before SNP treatment. Besides, SP600125 decreased significantly the protein expression of total caspase 3 and the intracellular gene expression of caspase-3, measured by Western blot analysis and PCR. SP600125 also increased the cytoskeletal protein expressions. These results suggested that JNK pathway plays a critical role in the NO-induced chondrocyte apoptosis, and SP600125 treatment blocks the dissolution of the cytoskeletal proteins via activation of caspase-3 pathways. PMID- 29409913 TI - Agency for Healthcare Research and Quality Evidence-based Practice Center methods provide guidance on prioritization and selection of harms in systematic reviews. AB - OBJECTIVES: Systematic reviews should provide balanced assessments of benefits and harms, while focusing on the most important outcomes. Selection of harms to be reviewed can be a challenge due to the potential for large numbers of diverse harms. STUDY DESIGN AND SETTING: A workgroup of methodologists from Evidence based Practice Centers (EPCs) developed consensus-based guidance on selection and prioritization of harms in systematic reviews. Recommendations were informed by a literature scan, review of Evidence-based Practice Center reports, and interviews with experts in conducting reviews or assessing harms and persons representing organizations that commission or use systematic reviews. RESULTS: Ten recommendations were developed on selection and prioritization of harms, including routinely focusing on serious as well as less serious but frequent or bothersome harms; routinely engaging stakeholders and using literature searches and other data sources to identify important harms; using a prioritization process (formal or less formal) to inform selection decisions; and describing the methods used to select and prioritize harms. CONCLUSION: We provide preliminary guidance for a more structured approach to selection and prioritization of harms in systematic reviews. PMID- 29409914 TI - Efficacy and safety of oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: Findings from the 52-week open label REVEAL trial. AB - BACKGROUND: Limited treatments are available for persistent erythema of rosacea. OBJECTIVE: To examine the long-term safety and efficacy of oxymetazoline cream 1.0% in patients with rosacea with moderate-to-severe persistent erythema. METHODS: Patients applied oxymetazoline once daily for 52 weeks. Safety assessments included treatment-emergent adverse events (TEAEs), skin blanching, inflammatory lesion counts, telangiectasia, disease severity, and rebound effect. Efficacy was assessed by the Clinician Erythema Assessment and Subject Self Assessment composite score at 3 and 6 hours after the dose on day 1 and at weeks 4, 26, and 52. RESULTS: Among 440 patients, 8.2% reported treatment-related TEAEs; the most common were application-site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation due to adverse events (mostly application site TEAEs) was 3.2%. No clinically meaningful changes were observed in skin blanching, inflammatory lesions, or telangiectasia. At week 52, 36.7%, and 43.4% of patients achieved a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment 3 and 6 hours after a dose, respectively. Less than 1% of patients experienced a rebound effect following treatment cessation. LIMITATIONS: A vehicle-control group was not included. CONCLUSION: This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea. PMID- 29409915 TI - WITHDRAWN: Efficacy and safety of topical oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: findings from the 2 phase 3, 29-day, randomized, controlled REVEAL trials. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29409916 TI - Consultative teledermatology in the emergency department and inpatient wards: A survey of potential referring providers. PMID- 29409917 TI - Skin in the game: Existing and upcoming physician payment models in dermatology. PMID- 29409918 TI - Horizontal and vertical sections of scalp biopsy specimens from dermatomyositis patients with scalp involvement. AB - BACKGROUND: The histologic findings of scalp involvement in dermatomyositis are not well characterized on account of a lack of large series. OBJECTIVE: To systematize the histologic features of scalp involvement in dermatomyositis on horizontal and vertical sections. METHODS: A descriptive, prospective, cross sectional study recruited 31 patients with pathologically and serologically confirmed dermatomyositis in Mexico City, Mexico, from June 2014 to June 2015. A total of 36 scalp biopsy specimens from 20 patients with scalp involvement in dermatomyositis were processed as 20 vertical and 16 horizontal sections. RESULTS: Dilated capillaries and diffuse mucin deposition were detected in all biopsy specimens, followed by interface dermatitis. Partial or segmental thickening of the basement membrane, hyperkeratosis, atrophic epidermis, and acrosyringeal hypergranulosis with hyperkeratosis were other very common findings. Preserved follicular architecture, with intact or slightly atrophic sebaceous glands, was present in most horizontal sections. There was decreased follicular density, with a terminal-to-vellus ratio of 4:1 and telogen count of 10.3%. Eosinophils were present in 15% and 25% of horizontal and vertical sections, respectively. LIMITATIONS: No special stains performed. CONCLUSION: Scalp involvement in dermatomyositis shows nonscarring pattern on horizontal sections that is consistent with chronic telogen effluvium. Telangiectasia and mucin are universal histologic features; eosinophils and acrosyringeal hypergranulosis with hyperkeratosis are new findings. PMID- 29409919 TI - sst2-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing. AB - This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle aged (10-12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level). A re-evaluation was performed 6 months later (i.e. with 18-month-old mice). UCMS reproduced neuroendocrine and behavioral features of stress-related disorders such as elevated circulating CORT levels, physical deteriorations, increased anxiety- and depressive-like behaviors and working memory impairments. sst2KO mice displayed behavioral alterations which were similar to stressed WT and exhibited exacerbated changes following UCMS exposure. The evaluations performed in the older mice showed significant long-term effects of UCMS exposure. Old sst2KO mice previously exposed to UCMS exhibited spatial learning and memory accuracy impairments and high levels of anxiety-like behaviors which drastically added to the effects of normal ageing. Spatial abilities and emotionality scores (mean z scores) measured both at the UCMS outcome and 6 months later were correlated with the initially measured CORT levels in middle-age. The present findings indicate that the deletion of the sst2 receptor gene produces chronic hypercorticosteronemia and exacerbates sensitivity to stressors which over time, have consequences on ageing brain function processes. PMID- 29409920 TI - The effects of serotonin modulation on medial prefrontal connectivity strength and stability: A pharmacological fMRI study with citalopram. AB - BACKGROUND: Static and dynamic functional connectivity are being increasingly used to measure the effects of disease and a range of different interventions on brain networks. While preliminary evidence suggests that static connectivity can be modulated by chronic antidepressants administration in healthy individuals and in major depression, much less is known about the acute effects of antidepressants especially on dynamic functional connectivity changes. Here we examine acute effects of antidepressants on dynamic functional connectivity within the default mode network. The default mode network is a well described network with many functions in which the role of serotonin is not clear. METHODS: In this work we measured acute pharmacological effects of an infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) in a sample of thirteen healthy volunteers randomised to receive on two occasions the active compound or placebo in a cross over dosing. RESULTS: Acute citalopram administration relative to placebo increased static connectivity between the medial prefrontal cortex and right dorsolateral prefrontal cortex and posterior cingulate cortex. The SSRI also induced a reduction in variability of connectivity with the medial prefrontal cortex in the precuneus and posterior cingulate cortex. DISCUSSION: The measured changes are compatible with modified serotonin cortical availability. PMID- 29409921 TI - A Rationally Designed Multifunctional Antibiotic for the Treatment of Drug Resistant Acne. AB - Acne is a multifactorial skin disease, underpinned by colonization of Propionibacterium acnes and inflammation. The emergence of resistant P. acnes strains has affected the current acne treatment algorithm. This setback served as an impetus for rationally designing a library of next-generation antibiotics that exhibit a bactericidal effect on resistant P. acnes and exert an immunomodulatory function to reduce inflammation. In silico screening showed that one of the molecules, VCD-004, exhibits improved mode of binding to bacterial DNA gyrase. VCD-004 shows high potency against clinical isolates of resistant P. acnes and excellent efficacy in vivo. Furthermore, VCD-004 exhibits a superior mutant prevention index, suggesting that it impedes the development of resistance better than clindamycin. Additionally, it shows optimal skin penetration and has a potent anti-inflammatory effect via reduction of proinflammatory cytokines (IL-6) independent of its antibacterial action. VCD-004 affects P. acnes-induced nuclear accumulation of NF-kappaB in THP-1 cells. The in vitro viability of human keratinocytes in the presence of VCD-004 indicates a desirable therapeutic window for topical use. Such rationally designed bactericidal and immunomodulatory dual pharmacophore-based lipophilic molecule(s) can emerge as the next-generation topical therapy for acne with underlying resistant P. acnes etiology. PMID- 29409922 TI - Effectiveness of Botulinum Toxin A for Persistent Upper Limb Pain After Breast Cancer Treatment: A Double-Blinded Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effect of a single botulinum toxin A (BTX-A) infiltration in the pectoralis major muscle in addition to a standard physical therapy program for treatment of persistent upper limb pain in breast cancer survivors. DESIGN: Double-blinded (patient and assessor) randomized controlled trial. SETTING: A university hospital. PARTICIPANTS: Breast cancer patients (N=50) with pain. INTERVENTION: The intervention group received a single BTX-A infiltration. The control group received a placebo (saline) infiltration. Within 1 week after the infiltration, all patients attended an individual physical therapy program (12 sessions) during the first 3 months and a home exercise program up to 6 months after infiltration. MAIN OUTCOME MEASURES: The primary outcome was change in pain intensity at the upper limb (visual analog scale, 0 100) after 3 months. Secondary outcomes were prevalence rate of pain, pressure hypersensitivity, pain quality, shoulder function, and quality of life. Measures were taken before the intervention and at 1, 3, and 6 months' follow-up. RESULTS: No significant difference in change in pain intensity after 3 months was found (mean difference in change, 3/100; 95% confidence interval [CI], -13 to 19). From baseline up to 6 months, a significantly different change in upper limb pain intensity was found between groups in favor of the intervention group (mean difference in change, 16/100; 95% CI, 1-31). CONCLUSIONS: A single BTX-A infiltration in combination with an individual physical therapy program significantly decreased pain intensity at the upper limb in breast cancer survivors up to 6 months. However, the effect size was not clinically relevant, and no other beneficial effects were found. PMID- 29409923 TI - Hot snare polypectomy with or without saline solution/epinephrine lift for the complete resection of small colorectal polyps. AB - BACKGROUND AND AIMS: The criteria for a standard polypectomy technique for complete removal of small colorectal polyps has not yet been established. This study aimed to compare the complete resection rate of hot snare polypectomy (HSP) with that of EMR for small, sessile, or flat polyps. METHODS: Patients with 5- to 9-mm non-pedunculated colorectal polyps were prospectively randomized to the HSP or EMR group. The presence of residual polyps was assessed by performing histologic assessment of 4-quadrant forceps biopsy specimens taken from the edges of the polypectomy site. The primary outcome was the complete resection rate after HSP or EMR; the secondary outcomes were the proportion of procedure-related adverse events and specimen-loss rate. Sample size was estimated using a superiority trial design. We assumed that the complete resection rate of the EMR group would be at least 8% higher than that of the HSP group. RESULTS: A total of 382 polyps in 269 patients were assessed and randomly assigned to each method using 4 * 4 block randomization. Of these, 353 polyps were finally analyzed based on the pathology results. The mean polyp size was 6.3 +/- 1.3 mm. The complete resection rate did not differ between the HSP and EMR groups (88.4% [152/172] vs 92.8% [168/181], respectively; P = .2). The intraprocedural bleeding rate, immediately after polypectomy, was significantly higher in the HSP group than in the EMR group (5.2% vs 0.6%, respectively; P = .009). However, clinically significant bleeding and tissue retrieval failure rates did not differ between the groups. In the multivariate logistic regression analysis, sessile serrated adenoma/polyps or hyperplastic polyps were almost 3 times (odds ratio, 2.824; 95% confidence interval, 1.03-7.75; P = .044) more likely to be incompletely resected compared with other conventional adenomatous polyps. Except for pathology, we found no significant independent predictors for incomplete resection. CONCLUSION: EMR for small non-pedunculated colorectal polyps is not superior to HSP in terms of complete resection or safety. Both methods can be performed according to the endoscopist's preference. (Clinical trial registration number: KCT0001640; cris.nih.go.kr.). PMID- 29409924 TI - Current and future challenges of subcutaneous and sublingual allergy immunotherapy for allergists in the United States. PMID- 29409925 TI - Investigations on the role of hemoglobin in sulfide metabolism by intact human red blood cells. AB - In addition to their role as oxygen transporters, red blood cells (RBCs) contribute to cardiovascular homeostasis by regulating nitric oxide (NO) metabolism via interaction of hemoglobin (Hb) with nitrite and NO itself. RBCs were proposed to also participate in sulfide metabolism. Although Hb is known to react with sulfide, sulfide metabolism by intact RBCs has not been characterized so far. Therefore we explored the role of Hb in sulfide metabolism in intact human RBCs. We find that upon exposure of washed RBCs to sulfide, no changes in oxy/deoxyhemoglobin (oxy/deoxyHb) are observed by UV-vis and EPR spectroscopy. However, sulfide reacts with methemoglobin (metHb), forming a methemoglobin sulfide (metHb-SH) complex. Moreover, while metHb-SH is stable in cell-free systems even in the presence of biologically relevant thiols, it gradually decomposes to produce oxyHb, inorganic polysulfides and thiosulfate in intact cells, as detected by EPR and mass spectrometry. Taken together, our results demonstrate that under physiological conditions RBCs are able to metabolize sulfide via intermediate formation of a metHb-SH complex, which subsequently decomposes to oxyHb. We speculate that decomposition of metHb-SH is preceded by an inner-sphere electron transfer, forming reduced Hb (which binds oxygen to form oxyHb) and thiyl radical (a process we here define as "reductive sulfhydration"), which upon release, gives rise to the oxidized products, thiosulfate and polysulfides. Thus, not only is metHb an efficient scavenger and regulator of sulfide in blood, intracellular sulfide itself may play a role in keeping Hb in the reduced oxygen-binding form and, therefore, be involved in RBC physiology and function. PMID- 29409926 TI - Rapid Intraoperative in Situ Synthetic Cranioplasty. AB - Craniectomy is a frequently performed neurosurgical procedure, and coverage of the cranial defect is necessary for protection of the underlying brain, cosmesis, and patient satisfaction. We report a new technique for intraoperative in situ synthetic cranioplasty that provides one-step resection of skull osteomas and reconstruction of cranial defects. Strategies of intraoperative cranioplasty are reviewed. A 48-year-old man who presented with a suspected benign osteoma over his forehead was offered surgical excision and primary cranioplasty in a one-step procedure using hydroxyapatite bone cement, a dural prosthetic, and a resorbable plate. Following craniectomy around the lesion, there was evidence of dural and bone involvement. The craniectomy was enlarged, and the involved dura was resected. SYNTHECEL dura repair was used to repair the dural defect and at the same time fashioned to form a receptacle for the cranioplasty by fixation of the dural substrate to the cut vertical bone edges. DirectInject hydroxyapatite bone cement was used to fill the receptacle and contoured to the curvature of the adjacent skull. A Delta resorbable plate was then placed over the bone cement and fixed to the skull. This technique provided a satisfactory cosmetic outcome following craniectomy for benign skull tumor excision. When possible, one-step surgery with primary cranioplasty should be considered. PMID- 29409927 TI - Endoscope Holders in Cranial Neurosurgery. Perspective Statement. PMID- 29409928 TI - The Most-Cited Works in Severe Traumatic Brain Injury: A Bibliometric Analysis of the 100 Most-Cited Articles. AB - BACKGROUND: There is an abundance of works published on severe traumatic brain injury (sTBI). Bibliometric analyses aim to provide a macroscopic view of research activities regarding sTBI and are helpful in determining the most impactful studies within this field. METHODS: We performed a generalized search using the database of Web of Science, organized the references by the number of citations, and reviewed full length-articles for the top-100 most-cited articles on sTBI. The articles were classified according to focus. RESULTS: The top-100 articles were cited on average 326.4 times per paper. The Journal of Neurosurgery published the greatest number of top-100 cited articles (9 of 100). Authors from the United States published the majority (67%) of the most-cited articles. The most popular categories were "reviews and guidelines" and "etiology and epidemiology." CONCLUSIONS: The present study provides a cross-sectional summary of the 100 most-cited articles on sTBI, highlighting areas of research needing further investigation and development. PMID- 29409929 TI - Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. AB - Cysteine cathepsins have been for a long time considered to execute mainly nonspecific bulk proteolysis in the endolysosomal system. However, this view has been changing profoundly over the last decade as cathepsins were found in the cytoplasm, nucleus and in the extracellular milieu. Cathepsins are currently gaining increased attention largely because of their extracellular roles associated with disease development and progression. While kept under tight control under physiological conditions, their dysregulated and elevated activity in the extracellular milieu are distinctive hallmarks of numerous diseases such as various cancers, inflammatory disorders, rheumatoid arthritis, bone disorders and heart diseases. In this review, we discuss cysteine cathepsins with a major focus on their extracellular roles and extracellular proteolytic targets beyond degradation of the extracellular matrix. We further highlight the perspectives of cathepsin research and novel avenues in cathepsin-based diagnostic and therapeutic applications. PMID- 29409930 TI - The importance of EGFR as a biomarker in molecular apocrine breast cancer. AB - Molecular apocrine breast cancer (MABC) is a molecular subtype with a poor prognosis, and there is urgent need to find new therapeutic targets. Epidermal growth factor receptor (EGFR) plays an important part in regulating the biological behavior of tumor cells, and EGFR-targeted drugs have already been used in therapy for lung and colorectal cancers. The purpose of this study was to analyze the significance of EGFR expression in MABC. A total of 400 patients with invasive breast cancer were analyzed, including 200 MABC and 200 non-MABC cases. Immunohistochemistry and immunofluorescence were carried out to evaluate the expression of estrogen receptor, progesterone receptor, androgen receptor (AR), EGFR, epidermal growth factor receptor 2 (HER2), and other biomarkers. Two hundred twelve (53%) cases were positive for EGFR expression, including 173 MABC and 39 non-MABC cases. EGFR expression was positively associated with AR expression in MABC, as well as with more advanced tumor stage and high Ki67 expression. Patients with EGFR expression had worse outcomes than those without. As a prognosis biomarker, EGFR was significantly associated with poorer clinical outcomes, and the co-expression of EGFR and HER2 often predicted worse outcomes in MABC. This study suggests that the identification of new targets such as HER2 and EGFR may help with assessing the prognosis of patients with MABC. Using both AR and EGFR as therapeutic targets may be especially important in MABC and may help to guide the choice of suitable treatments for individual breast cancer patients. PMID- 29409931 TI - Bentonite clay supplemented diet on immunity in stinging catfish, Heteropneustes fossilis against Aeromonas hydrophila. AB - The effect of Sodium Bentonite (SB) enriched diet on growth performance, innate immune response, and disease resistance in stinging catfish, Heteropneustes fossilis against Aeromonas hydrophila is reported. The infected fish fed with 5% SB had the maximum weight gain diet (PWG %) and specific growth rate (SGR %) were 26% and 29% when compared to 14% and 17% with 10% diet. Similarly the phagocytic activity increased significantly when infected fish were fed with 5% or 10% SB diets during the experimental period; the complement, respiratory burst and lysozyme activities were also significantly enhanced on weeks 2 and 4. The lower cumulative mortality (10% and 15%) was observed when the infected fish were fed with 5% and 10% SB diets for 30 days. The results suggest that the infected H. fossilis after administration of 5% and 10% SB enriched diets for 30 days had significantly improved growth performance, innate immunity, and disease resistance against A. hydrophilla. Hence, sodium bentonite can be used as a feed additive to stimulate immunity and for disease resistance in the effective production of economically valuable freshwater catfish, H. fossilis. PMID- 29409932 TI - Comparative study of the immunoprotective effect of two DNA vaccines against grass carp reovirus. AB - Grass carp reovirus II (GCRV II) causes severe hemorrhagic disease with high mortality in grass carp, Cyenopharyngodon idellus. DNA vaccination has been proven to be a very effective method in conferring protection against fish viruses. However, DNA vaccines for GCRV II have not yet been conducted on grass carp. In the current work, we vaccinated grass carp with a DNA vaccine consisting of the segment 6 (pC-S6; encoding VP4) or 10 (pC-S10; encoding NS38) of GCRV II and comparatively analyzed the immune responses induced by these two vaccines. The protective efficacy of pC-S6 and pC-S10, in terms of relative percentage survival (RPS), was 59.9% and 23.1% respectively. This suggests that pC-S6 and pC S10 DNA vaccines could increase the survival rate of grass carp against GCRV, albeit with variations in immunoprotective effect. Immunological analyses indicated the following. First, post-vaccination (pv), both pC-S6 and pC-S10 up regulated the expression of interferon (IFN-1), Mx1, IL-1beta, and TNF-alpha. However, CD4 and CD8alpha were up-regulated in the case of pC-S6 but not pC-S10. Second, comparing non-vaccinated and pC-S10-vaccinated fish, the T cell response related genes, such as CD4, CD8alpha, and GATA3, were elevated in pC-S6 vaccinated fish at 48 h post-challenge (pc). Third, pC-S6 and pC-S10 induced similar patterns of specific antibody response pv. However, only anti-VP4 IgM in the sera of surviving fish infected with GCRV was significantly increased pc compared with that pre-challenge. Taken together, these results indicate that pC S6 promotes both innate (IFN-1 and Mx1 induction) and adaptive (T cell and specific antibody response) immunity pv and that the induction of a memory state promptly primes the immune response upon later encounters with the virus, whereas pC-S10 only induces the type I IFN-related response pv and a lower inflammatory response pc. PMID- 29409933 TI - Signs and Symptoms in 1,043 Patients with Complex Regional Pain Syndrome. AB - : Complex regional pain syndrome (CRPS) is a complex pain disorder that can emerge after limb trauma or a lesion in the peripheral nervous system. Typical features include continuing pain, sensory, vasomotor, sudomotor, motor, and trophic changes as well as edema. These signs provide the basis of CRPS diagnosis. A detailed description of the signs, symptoms, and medical history of CRPS could potentially facilitate an earlier and more accurate diagnosis. The aim of this study was to provide such a description, on the basis of epidemiological measures, clinical presentation, and a thorough description of pain sensations. Some signs (eg, differences of skin temperature >1 degrees C), which have been thought to be crucial for diagnosis, were less common than assumed. We identified 11 distinct etiological triggers, which cover more than 99% of the study participants. We developed a weighted score on the basis of the most decisive data, which achieved a sensitivity of .869 and a specificity of .829, compared with .819 and .679 for the Budapest criteria. The weighted diagnostic criteria may help to better aid in distinguishing CRPS from other pain disorders. PERSPECTIVE: This article provides a retrospective epidemiological analysis of 1,043 CRPS patients compared with 421 patients with other pain disorders. The findings could potentially facilitate a more reliable and earlier diagnosis of CRPS, a better differentiation from other pain disorders, and ultimately in a more targeted and effective therapy. PMID- 29409934 TI - Huge Prolapsed Pedunculated Necrotizing Submucosal Leiomyoma. PMID- 29409935 TI - Comparison between cervical disc arthroplasty and conservative treatment for patients with single level cervical radiculopathy at C5/6. AB - BACKGROUND: Cervical radiculopathy is a common disease that affects millions of people. Patients usually are managed by conservative therapy and surgical treatments. OBJECTIVE: To compare the clinical outcomes between cervical disc arthroplasty (CDA) and conservative management for patients with single level cervical radiculopathy at C5/6. METHODS: Seventy-two patients with cervical radiculopathy that only affect C5/6 joints were included and thirty-two of them received CDA surgery, and forty patients were treated with conservative management. All the patients were followed up around 4 years. Cervical curvature, cervical range of motion (CROM), horizontal displacement of cervical spine, and intervertebral gap were measured by radiological examination. RESULTS: All the patients have comparable disease severity based on pre-surgical radiological assessments. At the 4-year follow-up examination, patients with CDA surgery had less CROM at C5/6 level, while greater CROM at C4/5 level, than control group. Similarly, the horizontal displacement in CDA group decreased at C5/6 vertebrae, and increased at C4/5 level at the 4-year follow-up examination. The intervertebral gaps of patients in CDA group were larger than control group at one-year and last follow-up examination. CONCLUSION: CDA surgery stabilized C5/6 vertebrae and increased the CROM and horizontal displacement of upper adjacent C4/5 vertebrae. PMID- 29409936 TI - Epigenetic regulation by CpG methylation splits strong from retarded IFNgamma induced IL-18BP in epithelial versus monocytic cells. AB - Interferon (IFN)-gamma-inducing interleukin (IL)-18 is a crucial inflammatory cytokine systemically provided by monocytes. It is counteracted by IL-18 binding protein (IL-18BP), a decoy receptor that displays IFNgamma-inducibility thus curbing inflammation by negative feedback. Since IL18BP inducibility is pronounced in human epithelial cells but diminished in monocytes, differential IL18BP regulation was investigated herein in both types of cells. Interestingly, DNA-demethylating 5-aza-2'-deoxycytidine enhanced IFNgamma-induced IL-18BP only in monocytic but not in epithelial cells. Subsequent promoter analysis brought into focus a specific CpG (coined CpG2) neighboring a gamma-activated site responsible for IL18BP induction. CpG2 was consistently methylated in monocytic but unmethylated in epithelial cells. Notably, demethylation by 5-aza-2' deoxycytidine treatment of monocytic cells impeded methyl-CpG-binding protein-2 (MeCP2) interaction with CpG2, increased adjacent histone H3K9-acetylation, and enhanced RNA-polymerase-II recruitment to the nearby IL18BP transcriptional start. Both latter observations are indicative of a gene locus displaying augmented transcriptional activity. Data suggest that epigenetic silencing by single CpG methylation determines differential IL18BP inducibility in monocytic versus epithelial cells. This regulatory principle should serve and control pivotal IL-18-related cell type-specific (patho)-physiological functions. Whereas epithelial IL-18BP evidently counteracts pathological inflammation at biological barriers, retarded IL18BP inducibility in monocytes may be key to combat blood borne infections in IL-18-dependent manner. PMID- 29409937 TI - The genetic and phylogenetic analysis of a highly pathogenic influenza A H5N6 virus from a heron, southern China, 2013. AB - The H5N6 highly pathogenic avian influenza viruses (HPAIVs) have circulated within poultry in China since 2013. Infections of H5N6 in wild birds were reported since 2014. In order to investigate the infection history of H5N6 in wild birds, we conducted a retrospective analysis of H5 positive wild bird samples collected in 2013, the year H5N6 was discovered in poultry. We isolated a new HPAI H5N6 virus from a dead heron collected in 2013. The virus had high identity in all eight gene sequences to those collected from poultry in 2013 (for example, A/chicken/Shenzhen/1845/2013, 99.1%-99.7%). Our findings revealed that H5N6 HPAIVs infected wild birds in southern China since the emergence of H5N6 in poultry in 2013. The co-circulation of H5N6 between wild birds and poultry is very close, and should raise our attention more. PMID- 29409938 TI - An Uncommon Mimic of Acute Coronary Syndrome: Infiltrating Non-Hodgkins Lymphoma. PMID- 29409939 TI - A new soluble and bioactive polymorph of praziquantel. AB - Praziquantel is the only available drug to treat Schistosomiasis. However, its utilization is limited by many drawbacks, including the high therapeutic dose needed, resulting in large tablets and capsules difficult to be swallowed, especially from pediatric patients. In this study, an alternative option to overcome these disadvantages is proposed: to switch to a novel crystalline polymorph of racemic compound praziquantel. The preparation of the crystalline polymorph was realized via a neat grinding process in a vibrational mill. The new phase (Form B) was chemically identical to the starting material (as proved by HPLC, 1H NMR, and polarimetry), but showed different physical properties (as evaluated by SEM, differential scanning calorimetry, thermogravimetry, ATR-FTIR spectroscopy, X-ray powder diffraction, and solid-state NMR). Furthermore, the crystal structure of the new phase was solved from the powder synchrotron X-ray diffraction pattern, resulting in a monoclinic C2/c cell and validated by DFT-D calculation. Moreover the simulated solid-state NMR 13C chemical shifts were in excellent agreement with the experimental data. The conversion of original praziquantel into Form B showed to affect positively the water solubility and the intrinsic dissolution rate of praziquantel. Both the in vitro and in vivo activity against Schistosoma mansoni were maintained. Our findings suggest that the new phase, that proved to be physically stable for at least one year, is a promising product for designing a new praziquantel formulation. PMID- 29409940 TI - Nomenclature for factors of the HLA system, update December 2017. PMID- 29409941 TI - An Unusual Cause of Skin Rash in Crohn's Disease. PMID- 29409942 TI - Black Smoke Arising in the Duodenum After Liver Biopsy: What Does the Smoke Signal Mean? PMID- 29409943 TI - Pediatricians' Knowledge and Practices Related to Long-Acting Reversible Contraceptives for Adolescent Girls. AB - STUDY OBJECTIVE: A 2014 American Academy of Pediatrics (AAP) policy statement identified long-acting reversible contraceptives (LARCs) as first-line choices for adolescents, but pediatricians' current knowledge and practices about intrauterine devices (IUDs) and subdermal contraceptive implants (Implants) is unknown. We aimed to characterize pediatricians' knowledge and practices about LARCs for adolescents. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional online survey emailed to a convenience sample of AAP member pediatricians in New York, Utah, Illinois, and Kansas in 2015 and 2016. The study included 561 practicing pediatricians. MAIN OUTCOME MEASURES: We measured knowledge about the suitability of IUDs and Implants for adolescents using two 7-item scales; a score of 7 indicates all correct. We dichotomized participants' scores as high and low knowledge if they scored >=85% correct or <85%, respectively. RESULTS: Mean age was 47.4 (+/-11) years; 73% were female; and 72% general pediatricians. Almost all, 88%, counsel about contraception; 64% counsel about IUDs, and Implants, but only 4.1% insert them; 72% prescribe short-acting hormonal contraceptives; 44% had read the AAP policy statement. Mean score on the knowledge scale was lower for IUDs than for Implants (4.2 vs 5.1, respectively; P < .001). Multivariable regression analysis indicated that female pediatricians, adolescent medicine subspecialists, agreeing that pregnancy is a serious problem for adolescents in their practice, and having read the AAP policy statement predicted high knowledge about IUDs as well as Implants for adolescents. CONCLUSION: Most pediatrician respondents provided reproductive health care for adolescents and counseled about LARCs, but few inserted the devices. We identified knowledge deficits about suitability of IUDs for adolescents. PMID- 29409944 TI - Comparative study between spatio-temporal models for brain tumor growth. AB - Modeling of brain tumor growth simulator can estimate life expectancy for individual patients, estimate future effect of brain damages toward human senses and attitude and help in evaluating the efficiency of applied treatments. Brain tumor growth can be calculated based on Spatio-Temporal mathematical models namely the isotropic reaction-diffusion model and the anisotropic reaction diffusion model where the second model produces more realistic results. Tumor normally grows in White Matter (WM) five times faster than in Gray Matter (GM) which makes brain tissues modeled as inhomogeneous-anisotropic material to assign different parameters to each tissue. In this research a comparative study between several tumor growth models has been achieved to clarify the effect of different algorithms on modeling tumor grow. PMID- 29409945 TI - Billion-scale production of hepatocyte-like cells from human induced pluripotent stem cells. AB - Human induced pluripotent stem (iPS) cell-derived hepatocyte-like cells are expected to be utilized in drug screening and regenerative medicine. However, hepatocyte-like cells have not been fully used in such applications because it is difficult to produce such cells on a large scale. In this study, we tried to establish a method to mass produce hepatocyte-like cells using a three dimensional (3D) cell culture bioreactor called the Rotary Cell Culture System (RCCS). RCCS enabled us to obtain homogenous hepatocyte-like cells on a billion scale (>109 cells). The gene expression levels of some hepatocyte markers (alpha 1 antitrypsin, cytochrome (CYP) 1A2, CYP2D6, and hepatocyte nuclear factor 4alpha) were higher in 3D-cultured hepatocyte-like cells than in 2D-cultured hepatocyte-like cells. This result suggests that RCCS could provide more suitable conditions for hepatocyte maturation than the conventional 2D cell culture conditions. In addition, more than 90% of hepatocyte-like cells were positive for albumin and could uptake low-density lipoprotein in the culture medium. We succeeded in the large-scale production of homogenous and functional hepatocyte like cells from human iPS cells. This technology will be useful in drug screening and regenerative medicine, which require enormous numbers of hepatocyte-like cells. PMID- 29409946 TI - FABP4 inhibitors suppress inflammation and oxidative stress in murine and cell models of acute lung injury. AB - Acute lung injury (ALI) is a severe disease with high morbidity and mortality, and is characterized by devastating inflammation of the lung and increased production of reactive oxygen species (ROS). Recent studies have indicated that fatty acid binding protein (FABP4) is important in the regulation of inflammation. However, the role of FABP4 in sepsis-related ALI, and the specific mechanism of action have not been examined. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) and recombinant FABP4 (hrFABP4) resulted in the production of pro-inflammatory cytokines, inflammatory cytokines, and ROS, while these changes were ameliorated by pretreatment with the FABP4 inhibitor BMS309403 and FABP4 siRNA. Sequentially, treatment of A549 cells with N-acetylcysteine (NAC) significantly attenuated LPS and hrFABP4-induced the generation of ROS and the release of inflammatory cytokines. In vivo, a cecal ligation and puncture (CLP)-induced ALI murine model was successfully established. Then, the mice were treated with FABP4 inhibitor BMS309403. The results showed treatment with BMS309403 improved the survival rate of CLP-induced ALI mice, and prevented lung inflammation, histopathological changes, and increase of FABP4 induced by CLP. These data indicate that FABP4 plays an important role in lung inflammation of sepsis-induced ALI. Blockade of FABP4 signaling exhibits a protective effect in a CLP-induced ALI mouse model, and in A549 cell LPS specifically induces enhanced expression of FABP4, which then causes inflammatory cytokine production by elevating the ROS level. PMID- 29409947 TI - De-escalating systemic therapy in triple negative breast cancer: The example of secretory carcinoma. AB - Triple negative breast cancers have the highest relapse risk and the least favourable prognosis of all breast cancer subtypes, leading to an escalation of chemotherapy, substantially during recent years. Secretory carcinoma of the breast is a rare triple negative neoplasm, first described in children but more often presenting in adults. We report a case of a 70-years-old woman, initially diagnosed on the biopsy with a triple negative infiltrating Not Otherwise Specified (NOS) carcinoma of the breast, before it was later correctly identified as a secretory carcinoma, notably because of an abundant intra and extracellular secretory material. This new diagnosis, confirmed by fluorescence in-situ hybridization analysis showing ETS variant 6 (ETV6) gene rearrangement, allowed the de-escalation of chemotherapy therapy. Four years later, the patient is free of recurrences. PMID- 29409948 TI - Intracranial Pressure: A Comparison of the Noninvasive HeadSense Monitor versus Lumbar Pressure Measurement. AB - OBJECTIVE: To compare a new method of noninvasive intracranial pressure (nICP) measurement with conventional lumbar puncture (LP) opening pressure. METHODS: In a prospective multicenter study, patients undergoing LP for diagnostic purposes underwent intracranial pressure measurements with HeadSense, a noninvasive transcranial acoustic device, and indirectly with LP. Noninvasive measurements were conducted with the head in a 30 degrees tilt and in supine position before and after LP. The primary endpoint was the correlation between nICP measurement in supine position before LP and the LP opening pressure. RESULTS: There was no correlation between supine nICPs before LP and the LP opening pressures (r = 0.211, P = 0.358). The 30 degrees head-tilt nICPs correlated with the supine nICPs before LP (r = 0.830, P < 0.01). There was no correlation between supine nICPs before and after LP (r = 0.056, P = 0.831) or between 30 degrees head-tilt nICPs and LP opening pressures (r = -0.038, P = 0.861). CONCLUSIONS: There was no correlation between nICPs and LP opening pressures. Further development is warranted before transcranial acoustic HeadSense can become a clinical tool for investigating patients with neurologic conditions. PMID- 29409949 TI - Fighting antibiotic resistance in Portuguese hospitals: Understanding antibiotic prescription behaviours to better design antibiotic stewardship programmes. AB - OBJECTIVES: Since physicians play an important role in antibiotic usage, it is vital to understand their antibiotic-prescribing behaviour and knowledge on antimicrobial resistance in order to develop and implement effective antibiotic stewardship interventions. The aim of this study was to evaluate Portuguese physicians' knowledge and to understand prescription behaviours, difficulties and barriers in their antibiotic prescription process in order to promote better and well-adapted antibiotic stewardship policies. METHODS: This study was conducted in 2016 using a self-administered questionnaire to physicians in two tertiary public hospitals from two different regions in Portugal. RESULTS: Participating physicians [response rate 47.6% (30/63)] identified antibiotic resistance as a global problem; however, one-third did not recognise antibiotic resistance as a major problem on their own hospital. Factors that most influenced antibiotic prescription were 'microbiology laboratory results', 'patient clinical situation' and patient 'co-morbidities'. On the other hand, 'colleagues' opinion' and 'costs control' were considered as less determining factors. Regarding difficulties and bottlenecks in the antibiotic prescription process, participant physicians reported 'lack of (or delayed) microbiological results' and 'no access to antibiotic susceptibility patterns' as major barriers. 'Education and training' was considered the most effective intervention to improve antibiotic prescription. CONCLUSION: These results suggest that the design and implementation of antibiotic stewardship interventions should provide better data management and sharing tools between physicians and the microbiology laboratory, especially through the creation of antimicrobial prescribing guidelines according to hospital epidemiology, and easy access to hospital antibiotic susceptibility patterns and epidemiological data. PMID- 29409951 TI - Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. AB - BACKGROUND: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. OBJECTIVE: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations. METHODS: We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting beta2-agonists received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (>=150 kU/L) or low serum IgE (<150 kU/L) and as having atopy or no atopy. Efficacy outcomes were for all patients and by blood eosinophil counts and included annual exacerbation rate ratio and pre bronchodilator forced expiratory volume in 1 second change at treatment end vs placebo. RESULTS: Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26-61, P = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018-0.232, P = .0218) vs placebo for patients with at least 300 eosinophils/MUL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate (P <= .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second (P <= .0041) vs placebo, respectively. CONCLUSION: Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status. PMID- 29409950 TI - Tamoxifen activates hypothalamic l-dopa synthesis to stimulate ovarian estrogen production in chicken. AB - Estrogen is the primary sex hormone responsible for the development and modulation of the female reproductive system in all vertebrates including avian species. The actions of estrogen are mediated by the estrogen receptor, which could be modulated by the selective estrogen receptor modulator tamoxifen (TAM). In this study, we administered TAM into the actively laying chicken to investigate the ovarian and hypothalamic responses to the estrogen action blockage. The laying was disrupted and the development of the pre-ovulatory hierarchical follicles was arrested. However, the TAM treatment caused an increase of estrogen level in both serum and ovary. Among the main estrogen targeted tissues, the hypothalamus showed specific dopaminergic activation as indicated by gene expression analysis. In the ovary, l-dopa, the precursor of dopamine, could stimulate the estrogen synthesis in undifferentiated follicles but not in the differentiated pre-ovulatory follicles. Thus, we established a feedback loop links ovarian estrogen production with hypothalamic l-dopa synthesis and we propose that the dopamine is involved in estrogen action to regulate the ovarian follicle development and ovulation. PMID- 29409952 TI - Adenosine has two faces: Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders. AB - OBJECTIVE: Adenosine participates in maintaining the excitatory/inhibitory balance in neuronal circuits. Studies indicate that adenosine levels in the cortex and hippocampus increase and exert sleep pressure in sleep-deprived and control animals, whereas in epilepsy reduced adenosine tone promotes hyperexcitability. To date, the role of adenosine in pathological conditions that result in both seizures and sleep disorders is unknown. Here, we determined adenosine tone in sleep and seizure regulating brain regions of Kv1.1 knockout (KO) mice, a model of temporal epilepsy with comorbid sleep disorders. METHODS: 1) Reverse phase-high performance liquid chromatography (RP-HPLC) was performed on brain tissue to determine levels of adenosine and adenine nucleotides. 2) Multi-electrode array extracellular electrophysiology was used to determine adenosine tone in the hippocampal CA1 region and the lateral hypothalamus (LH). RESULTS: RP-HPLC indicated a non-significant decrease in adenosine (~50%, p = 0.23) in whole brain homogenates of KO mice. Regional examination of relative levels of adenine nucleotides indicated decreased ATP and increased AMP in the cortex and hippocampus and increased adenosine in cortical tissue. Using electrophysiological and pharmacological techniques, estimated adenosine levels were ~35% lower in the KO hippocampal CA1 region, and 1-2 fold higher in the KO LH. Moreover, the increased adenosine in KO LH contributed to lower spontaneous firing rates of putative wake-promoting orexin/hypocretin neurons. INTERPRETATION: This is the first study to demonstrate a direct correlation of regionally distinct dichotomous adenosine levels in a single model with both epilepsy and comorbid sleep disorders. The weaker inhibitory tone in the dorsal hippocampus is consistent with lower seizure threshold, whereas increased adenosine in the LH is consistent with chronic partial sleep deprivation. This work furthers our understanding of how adenosine may contribute to pathological conditions that underlie sleep disorders within the epileptic brain. PMID- 29409953 TI - Reply. PMID- 29409954 TI - Effect of Waon Therapy in Individuals With Heart Failure: A Systematic Review. PMID- 29409955 TI - KRAS and 2 rare PI3KCA mutations coexisting in a metastatic colorectal cancer patient with aggressive and resistant disease. AB - We describe a metastatic colorectal cancer patient, treated with first-line 5 fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS, NRAS, BRAF, and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-AktSer473, phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-AktSer473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2-mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies. PMID- 29409956 TI - The interaction between calcineurin and alpha-synuclein is regulated by calcium and calmodulin. AB - Calcineurin (CN) is a protein phosphatase and widely distributed in eukaryotes, with an extremely high level of expression in mammalian brain. Alpha-synuclein (alpha-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. In our present study, we explored the interactions between CN and alpha-syn in vitro. Based on the data from microscale thermophoresis, GST pull-down assays, and co-immunoprecipitation, we found that CN binds alpha-syn. Furthermore, this interaction is mediated by calcium/calmodulin (Ca2+/CaM) signaling. Additionally, thapsigargin (TG) triggered an increase in CN activity and alpha-syn aggregation in HEK293 cells stably transfected with alpha-syn. Our previous study in vivo suggest that overexpression of alpha-syn in transgenic mice significantly promoted CN activity and subsequent nuclear translocation of nuclear factor of activated T-cells (NFAT) in the midbrain dopaminergic (mDA) neurons. These in vivo and in vitro studies have been complementary with each other, representing the changes in the CN-dependent pathway affected by overexpression of alpha-syn. PMID- 29409957 TI - DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes. AB - It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-betaH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-betaH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-betaH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival. PMID- 29409958 TI - Expression, purification, and electrophysiological characterization of a recombinant, fluorescent Kir6.2 in mammalian cells. AB - The inwardly rectifying K+ (Kir) channel, Kir6.2, plays critical roles in physiological processes in the brain, heart, and pancreas. Although Kir6.2 has been extensively studied in numerous expression systems, a comprehensive description of an expression and purification protocol has not been reported. We expressed and characterized a recombinant Kir6.2, with an N-terminal decahistidine tag, enhanced green fluorescent protein (eGFP) and deletion of C terminal 26 amino acids, in succession, denoted eGFP-Kir6.2Delta26. eGFP Kir6.2Delta26 was expressed in HEK293 cells and a purification protocol developed. Electrophysiological characterization showed that eGFP-Kir6.2Delta26 retains native single channel conductance (64 +/- 3.3 pS), mean open times (tau1 = 0.72 ms, tau2 = 15.3 ms) and ATP affinity (IC50 = 115 +/- 25 MUM) when expressed in HEK293 cells. Detergent screening using size exclusion chromatography (SEC) identified Fos-choline-14 (FC-14) as the most suitable surfactant for protein solubilization, as evidenced by maintenance of the native tetrameric structure in SDS-PAGE and western blot analysis. A two-step scheme using Co2+-metal affinity chromatography and SEC was implemented for purification. Purified protein activity was assessed by reconstituting eGFP Kir6.2Delta26 in black lipid membranes (BLMs) composed of 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1' rac-glycerol) (POPG), l-alpha-phosphatidylinositol-4,5-bisphosphate (PIP2) in a 89.5:10:0.5 mol ratio. Reconstituted eGFP-Kir6.2Delta26 displayed similar single channel conductance (61.8 +/- 0.54 pS) compared to eGFP-Kir6.2Delta26 expressed in HEK293 membranes; however, channel mean open times increased (tau1 = 7.9 ms, tau2 = 61.9 ms) and ATP inhibition was significantly reduced for eGFP Kir6.2Delta26 reconstituted into BLMs (IC50 = 3.14 +/- 0.4 mM). Overall, this protocol should be foundational for the production of purified Kir6.2 for future structural and biochemical studies. PMID- 29409961 TI - Evaluation of hibergene loop-mediated isothermal amplification assay for detection of group B streptococcus in recto-vaginal swabs: a prospective diagnostic accuracy study. AB - OBJECTIVES: To prospectively evaluate HiberGene's loop-mediated isothermal amplification (LAMP) assay for detection of group B streptococcus (GBS) in maternal recto-vaginal swabs and compare it with enrichment culture. METHODS: Following ethical approval and informed written consent, two low vaginal and rectal swabs were obtained from 400 pregnant women. One swab was tested for GBS using the rapid LAMP assay (index test), the second swab was tested using enrichment culture (reference standard). Antimicrobial susceptibility testing was performed according to EUCAST guidelines. RESULTS: There were 376 concordant results, 20 discordant and four invalid LAMP results. Among discordant results, six were LAMP negative/culture positive and 14 were LAMP positive/culture negative. The sensitivity was 92.2%, specificity 95.6%, positive predictive value 83.5% and negative predictive value 98.1%. The prevalence of GBS carriage was 19.25% (77/400). Forty-eight of 77 GBS-positive women were colonized vaginally (62.3%) and 70 were colonized rectally (90.9%). Erythromycin resistance was 22.4% (17/76) and clindamycin resistance was 17.1% (13/76). CONCLUSIONS: The LAMP assay is a rapid and simple test with results available in approximately 1 h compared with 48 h for culture. The test has good sensitivity and specificity compared with enrichment culture. This test can be used for rapid antenatal GBS screening. PMID- 29409962 TI - Occupational asthma caused by high- and low-molecular weight agents in an auto body worker. PMID- 29409960 TI - The developing human connectome project: A minimal processing pipeline for neonatal cortical surface reconstruction. AB - The Developing Human Connectome Project (dHCP) seeks to create the first 4 dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity. PMID- 29409959 TI - Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls. AB - Polychlorinated biphenyls (PCBs) are persistent organic pollutants known to cause adverse health effects and linked to neurological deficits in both human and animal studies. Children born to exposed mothers are at highest risk of learning and memory and motor deficits. We developed a mouse model that mimics human variation in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) to determine if genetic variation increases susceptibility to developmental PCB exposure. In our previous studies, we found that high-affinity AhrbCyp1a2(-/-) and poor-affinity AhrdCyp1a2(-/-) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with AhrbCyp1a2(+/+) wild type mice (C57BL/6J strain). Our follow-up studies focused on motor deficits, because human studies have identified PCBs as a potential risk factor for Parkinson's disease. Dams were treated with an environmentally relevant PCB mixture at gestational day 10 and postnatal day 5. We used a motor battery that included tests of nigrostriatal function as well as cerebellar function, because PCBs deplete thyroid hormone, which is essential to normal cerebellar development. There was a significant effect of PCB treatment in the rotarod test with impaired performance in all three genotypes, but decreased motor learning as well in the two Cyp1a2(-/-) knockout lines. Interestingly, we found a main effect of genotype with corn oil-treated control Cyp1a2(-/-) mice performing significantly worse than Cyp1a2(+/+) wild type mice. In contrast, we found that PCB-treated high-affinity Ahrb mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in AhrbCyp1a2(-/ ) mice. We conclude that differences in AHR affinity combined with the absence of CYP1A2 protein affect susceptibility to motor deficits following developmental PCB exposure. PMID- 29409963 TI - Web-based longitudinal remote assessment of dry eye symptoms. AB - PURPOSE: To investigate the feasibility of remote assessment and follow-up of dry eye symptoms using electronic versions of two validated questionnaires. METHODS: We conducted a prospective study of consecutive patients with dry eye disease (DED). Patients were enrolled during a clinical visit and were explained how to respond electronic versions of the Ocular surface Disease Index (OSDI) and the Symptom Assessment in Dry Eye (SANDE) questionnaires using a computer in the presence of investigators. A secure link to both questionnaires was sent to each patient every 2 weeks in order to respond and submit their symptoms over a 3 month period. We analyzed the number of patients who responded to both questionnaires, the recurrence, and the symptoms scores reported. RESULTS: A total of 1121 questionnaires were collected; 103 patients (85%) reported their symptoms at least once during the 3-month study duration. The majority of participants who completed the study (71.6%) responded remotely at least once per month during the 3-month duration of the study. The mean OSDI and SANDE scores from the total of remote evaluations were 34.9 +/- 21.9 (range 0-97.5) and 50.3 +/- 24.9 (range 0-100), respectively. There was a statistically significant correlation between the total scores collected with the two questionnaires (R = 0.67, P < 0.001). CONCLUSIONS: Patients are motivated to report DED symptoms while away from the clinic. Distance-based evaluation of DED symptoms is both feasible and convenient, and can be implemented to follow symptoms in large populations with chronic dry eye. PMID- 29409964 TI - Unexpected placement of the MAT1-1-2 gene in the MAT1-2 idiomorph of Thielaviopsis. AB - Sexual reproduction in the Ascomycota is controlled by genes encoded at the mating-type or MAT1 locus. The two allelic versions of this locus in heterothallic species, referred to as idiomorphs, are defined by the MAT1-1-1 (for the MAT1-1 idiomorph) and MAT1-2-1 (for the MAT1-2 idiomorph) genes. Both idiomorphs can contain additional genes, although the contents of each is typically specific to and conserved within particular Pezizomycotina lineages. Using full genome sequences, complemented with conventional PCR and Sanger sequencing, we compared the mating-type idiomorphs in heterothallic species of Thielaviopsis (Ceratocystidaceae). The analyses showed that the MAT1-1 idiomorph of T. punctulata, T. paradoxa, T. euricoi, T. ethacetica and T. musarum harboured only the expected MAT1-1-1 gene. In contrast, the MAT1-2 idiomorph of T. punctulata, T. paradoxa and T. euricoi encoded the MAT1-2-1, MAT1-2-7 and MAT1-1 2 genes. Of these, MAT1-2-1 and MAT1-2-7 are genes previously reported in this idiomorph, while MAT1-1-2 is known only in the MAT1-1 idiomorph. Phylogenetic analysis showed that the Thielaviopsis MAT1-1-2 groups with the known homologues of this gene in other Microascales, thus confirming its annotation. Previous work suggests that MAT1-1-2 is involved in fruiting body development, a role that would be unaffected by its idiomorphic position. This notion is supported by our findings for the MAT1 locus structure in Thielaviopsis species. This also serves as the first example of a MAT1-1-specific gene restricted to only the MAT1-2 idiomorph. PMID- 29409965 TI - Optimal Dose of Vaginal Misoprostol for Cervical Ripening before Hysteroscopy: A Randomized Double-Blind Study. AB - STUDY OBJECTIVE: To evaluate the optimal dose of vaginal misoprostol (200 and 400 ug) for cervical priming before operative hysteroscopy. DESIGN: A randomized, controlled, double-blind trial (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Sixty-eight patients undergoing operative hysteroscopy. INTERVENTIONS: Patients were randomized to receive a low (200 ug) or high (400 ug) dose of misoprostol administered vaginally 8 hours before operative hysteroscopy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was perioperative dilatation time, and the secondary outcome measurements included the subjective difficulty of cervical dilatation assessed by the surgeon, operative time, self-reported adverse events after vaginal administration and before the start of the operation, and complications during the procedure. A comparison of the 200-ug (n = 34) and 400-ug (n = 34) misoprostol cohorts revealed similarities when comparing time with cervical dilatation, operative difficulty, result, and time. Misoprostol-related adverse events were significantly lower in the 200-ug cohort than the 400-ug cohort (58.8% vs 85.3%, p = .015). Abdominal pain was the most common adverse event and was higher in the 400-ug cohort compared with the 200-ug cohort (73.5% vs 50.0%, p = .046). However, there were no operative delays resulting from adverse events, and all individuals reported the procedure to be tolerable and recovered without medication or treatment. CONCLUSION: Both 200 ug and 400 ug vaginally administered misoprostol are effective for cervical dilatation, and we recommend vaginal administration of 200 ug misoprostol for cervical dilatation 8 hours before operative hysteroscopy because of lower adverse events in the 200-ug group as well as similar efficacy between cohorts. PMID- 29409966 TI - Fasciola hepatica - Convoluted life forms and names. PMID- 29409967 TI - Community-acquired urinary tract infections due to extended-spectrum beta lactamase-producing organisms in United Arab Emirates. AB - BACKGROUND: The epidemiology of extended-spectrum beta-lactamase (ESBL)-producing bacteria is fast evolving with increasing global trend towards community-acquired infections. Limited information available about ESBLs therapy outcomes and control strategies, especially in the Middle Eastern countries. METHODS: We studied 399 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates from urinary tract infections (UTIs) occurred between 2014 and 2016 in University Hospital Sharjah. We included 124 ESBL-negative E. coli and K. pneumoniae isolates from UTIs as controls. Pearson Chi squares test and independent t-test were used to compare difference between ESBL positives and negatives. Multivariate logistic regression analysis was also performed. RESULTS: Approximately 75% of the E. coli and K. pneumoniae isolates causing UTIs were community-acquired. We found that recurrent UTIs, old age, and catheterization among other risk factors for community-acquired ESBL-positive UTIs. Majority of these ESBL-positive isolates were resistant to antibiotics such as ciprofloxacin (74%) and trimethoprim-sulphamethoxazole (73%) that are commonly used for treatment of community-acquired urinary tract infections. CONCLUSIONS: ESBL producing E. coli and K. pneumoniae have become major etiological pathogens of community-acquired UTIs in the United Arab Emirates. Healthcare providers should implement better infection control strategies and careful use of antimicrobials especially in out-patient and community settings. PMID- 29409968 TI - Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells: Implications for co-ordinated airway and vascular branching in lung development. AB - Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3' sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de methylation, hypoxia inducible factor-1alpha activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung. PMID- 29409969 TI - Challenges, pitfalls and surprises: development and validation of a monoclonal antibody for enzyme immunoassay of the steroid 1alpha-hydroxycorticosterone in elasmobranch species. AB - Sharks and rays are popular species used in wildlife ecotourism and aquariums to educate the public on the behavior, ecology and conservation challenges of elasmobranchs. To understand long-term physiological health and welfare under varying social and husbandry conditions, we developed and validated an enzyme immunoassay (EIA) to measure stress/ionoregulatory hormones in managed and semi free range southern rays (Hypanus americanus). Banked serum and interrenal samples from 27 female rays managed at Disney's The Seas with Nemo and Friends(r) and Castaway Cay were used to evaluate measurement of 1alpha hydroxycorticosterone (1alphaOHB) relative to corticosterone (B). Although commercial EIAs are available for B, those tested exhibit only low relative cross reactivity to 1alphaOHB (3-5%). To improve measurement of 1alphaOHB, we developed a monoclonal antibody using a synthesized 1alphaOHB-derivative for evaluation using high-performance liquid chromatography (HPLC) and EIA. Relative displacements of cross-reactant compounds showed that the antibody had good sensitivity for the target antigen 1alphaOHB, and low sensitivity to related steroids (desoxycorticosterone and B), but greater sensitivity to 11 dehydrocorticosterone. Tests of competitive vs. noncompetitive EIA formats, reagent titration, and incubation times of the antibody and conjugate were used to optimize sensitivity, repeatability and precision of measured 1alphaOHB in standards and samples (4 ng/ml, 90% binding). Tests of sample pre-treatment (pH adjustment) and extraction with varying solvent polarity were used to optimize measurement of 1alphaOHB in <1 ml (serum) or 1 g (interrenal) samples. HPLC analysis revealed the 1alphaOHB EIA to be superior for measurement of 1alphaOHB compared to use of a B EIA with or without HPLC fractioning. Results may prove useful for extrapolation to guide best practices for 1alphaOHB measurement in other elasmobranch species. Improved measurement of stress/ionoregulatory hormones in sharks and rays will be important for many aspects of collection, transport, medical treatment in aquaria and conservation management of these charismatic and ecologically important species. PMID- 29409970 TI - Evaluation of the safety of a protocol for switching venom immunotherapy products. PMID- 29409972 TI - Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2. AB - Obesity is a major risk factor for hepatocellular carcinoma (HCC) and is typically accompanied by higher levels of serum dipeptidyl peptidase 4 (DPP4). However, the role of DPP4 in obesity-promoted HCC is unclear. Here, we found that consumption of a high-fat diet (HFD) promoted HCC cell proliferation and metastasis and led to poor survival in a carcinogen-induced model of HCC in rats. Notably, genetic ablation of DPP4 or treatment with a DPP4 inhibitor (vildagliptin) prevented HFD-induced HCC. Moreover, HFD-induced DPP4 activity facilitated angiogenesis and cancer cell metastasis in vitro and in vivo, and vildagliptin prevented tumor progression by mediating the pro-angiogenic role of chemokine ligand 2 (CCL2). Loss of DPP4 effectively reversed HFD-induced CCL2 production and angiogenesis, indicating that the DPP4/CCL2/angiogenesis cascade had key roles in HFD-associated HCC progression. Furthermore, concomitant changes in serum DPP4 and CCL2 were observed in 210 patients with HCC, and high serum DPP4 activity was associated with poor clinical prognosis. These results revealed a link between obesity-related high serum DPP4 activity and HCC progression. Inhibition of DPP4 may represent a novel therapeutic intervention for patients with HCC. PMID- 29409973 TI - LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85. AB - Phosphoinositide 3-kinase (PI3K) activity is aberrantly activated in nasopharyngeal carcinoma. However, the underlying mechanisms remain unclear. Here, we found that Leucine zipper tumor suppressor 2 (LZTS2) was downregulated and predicted poor prognosis in nasopharyngeal carcinoma patients. Furthermore, we identified the PI3K subunit p85 as a novel LZTS2-interacting protein using an unbiased proteomics approach. Moreover, we demonstrated that LZTS2 competes with p110 for p85 binding and inhibits activation of the PI3K/AKT signaling pathway. Functionally, we showed that LZTS2 suppresses tumorigenesis and radioresistance in nasopharyngeal carcinoma in a p85-dependent manner. Taken together, our results not only provide understanding of the molecular mechanisms by which PI3K/AKT signaling is activated but also suggest that targeting the LZTS2/PI3K/AKT signaling axis is a promising therapeutic strategy for radiosensitization of nasopharyngeal carcinoma. PMID- 29409971 TI - Stem cells and heterotopic ossification: Lessons from animal models. AB - Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and acquired. Acquired HO is a common complication of major connective tissue injury, traumatic central nervous system injury, and surgical interventions, where it can cause significant pain and postoperative disability. A particularly devastating form of HO is manifested in the rare genetic disorder, fibrodysplasia ossificans progressiva (FOP), in which progressive heterotopic bone formation occurs throughout life, resulting in painful and disabling cumulative immobility. While the central role of stem/progenitor cell populations in HO is firmly established, the identity of the offending cell type(s) remains to be conclusively determined, and little is known of the mechanisms that direct these progenitor cells to initiate cartilage and bone formation. In this review, we summarize current knowledge of the cells responsible for acquired HO and FOP, highlighting the strengths and weaknesses of animal models used to interrogate the cellular origins of HO. PMID- 29409974 TI - Survivin-targeting miR-542-3p overcomes HER3 signaling-induced chemoresistance and enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer. AB - Elevated expression of HER3, which interacts with HER2 in breast cancer cells, confers chemoresistance via phosphoinositide 3-kinase (PI-3K)/Akt-dependent upregulation of Survivin. However, the underlying mechanism is not clear. Ectopic expression or specific knockdown of HER3 in HER2-overexpressing breast cancer cells did not alter Survivin mRNA levels and Survivin protein stability, supporting the notion that HER3 signaling may regulate specific miRNAs that target Survivin to alter its protein translation. Here we showed that overexpression and specific knockdown of HER3 reduced and enhanced expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p, in breast cancer cells, respectively. While the specific inhibitor of either miR-203 or miR-542-3p attenuated an anti-HER3 antibody-induced downregulation of Survivin, inhibition of miR-542-3p exhibited a better efficacy than miR-203 inhibition did. Consistently, miR-542-3p mimic was much more effective than miR-203 mimic not only in inhibition of Survivin, but also in enhancement of paclitaxel-induced apoptosis in HER2-overexpressing breast cancer cells. Moreover, the combination of miR-542-3p mimic and paclitaxel, as compared with either agent alone, significantly inhibited in vivo tumor growth of HER2-overexpressing breast cancer cells. Collectively, our data indicated that the HER3/PI-3K/Akt signaling upregulates Survivin via suppression of miR-203 and miR-542-3p. Because miR-542 3p has three binding sites on the 3'-UTR of Survivin mRNA, its mimic was able to effectively downregulate Survivin in vitro and in vivo. Thus, miR-542-3p replacement therapy is an excellent approach to overcome HER3-mediated paclitaxel resistance and significantly enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer. PMID- 29409975 TI - Transformation of Chlamydia: current approaches and impact on our understanding of chlamydial infection biology. AB - The intonation "The king is dead, long live the king" aptly describes the state of Chlamydia research. Genetic-based approaches are rapidly replacing correlative strategies to provide new insights. We describe how current transformation technologies are enhancing progress in understanding Chlamydia infection biology and present key opportunities for further development. PMID- 29409977 TI - Extending the analysis of zebrafish behavioral endophenotypes for modeling psychiatric disorders: Fear conditioning to conspecific alarm response. AB - Anxiety, trauma- and stressor-related disorders are severe psychiatric conditions that affect human population worldwide. Given their genetic tractability, evolutionarily conserved neurotransmitter systems, and extensive behavioral repertoire, zebrafish have become an emergent model organism in translational neuroscience. Here, we investigate whether a single exposure to conspecific alarm substance (CAS) produces fear conditioning in zebrafish using a conditioned place aversion (CPA) paradigm, as well as the persistence of aversive responses at different time intervals. While CAS elicited freezing and erratic movements at conditioning phase, zebrafish showed a robust avoidance for the CAS-paired compartment and increased risk assessment up to 7 days postconditioning. Additionally, we observed the existence of two behavioral phenotypes (high- and low-avoider fish) that present different fear-like responses at conditioning phase and evasion of the conditioning side at postconditioning trials. Collectively, we show a prolonged conditioned place aversion in zebrafish after a single CAS conditioning session, reinforcing the use of fear conditioning protocols as valuable strategies for modeling psychiatric disorders-related phenotypes in zebrafish. PMID- 29409976 TI - A Randomized, Double-Blind, Placebo-Controlled Trial of Escitalopram in Patients with Asthma and Major Depressive Disorder. AB - BACKGROUND: Depression is common in asthma and is associated with poor outcomes. However, antidepressant therapy in depressed patients with asthma has been the topic of little research. OBJECTIVE: This study examined the impact of antidepressant treatment with escitalopram versus placebo on the Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self Report (IDS-SR), Asthma Control Questionnaire (ACQ), and oral corticosteroid use in patients with asthma and major depressive disorder (MDD). METHODS: Single-site 12 week, randomized, double-blind, placebo-controlled, parallel-group trial of escitalopram (10 mg/d) was conducted in 139 outpatients with asthma and MDD. Randomization was stratified by oral corticosteroid use (>=3 bursts in past 12 months, yes or no) and baseline depressive symptom severity (HRSD score >= 20) (higher severity, n = 42) versus less than 3 bursts, HRSD score less than 20, or both (lower severity, n = 97). The primary data analysis was conducted using hierarchical linear modeling Version 7.01 on the higher and lower severity samples and post hoc was conducted on the combined sample. RESULTS: Among the higher severity completers (n = 21), a significant reduction in the ACQ score (P = .04) and oral corticosteroid use (P = .04) was observed with escitalopram. In the combined sample, no significant differences were observed, but a trend toward greater reduction in the IDS-SR score was observed with escitalopram (P = .07). Side effects were comparable across groups. CONCLUSIONS: The findings suggest that patients with more severe asthma and depression symptomatology may have a positive response, in terms of both asthma and depressive symptom reduction, to antidepressant treatment. PMID- 29409978 TI - Effect of chlorhexidine skin disinfection and retrosternal gentamicin sponge on post-sternotomy mediastinitis: results from a prospective controlled registry of 2340 patients. AB - BACKGROUND: Reducing post-sternotomy mediastinitis (PSM) requires incorporating multiple methods. However, the independent effects of these measures are not well studied. AIM: To evaluate the independent effect of preoperative disinfection using isopropyl alcohol (IPA)-chlorhexidine gluconate (CHG) and the topical application of a retrosternal gentamicin collagen sponge at wound closure on reducing PSM. METHODS: From October 2012 to August 2014, 2340 patients were included in this prospective, controlled registry. Patients were divided into four groups. In groups 1 and 2, the skin was disinfected with IPA, and in groups 3 and 4, the skin was disinfected with IPA-CHG. A retrosternal gentamicin collagen sponge was used in groups 2 and 4. Freedom from PSM up to the 30th postoperative day was the primary endpoint. The secondary endpoint was freedom from any surgical site dehiscence. A stepwise regression model was made to reveal the independent factors associated with lower incidence of PSM. FINDINGS: There were significant differences in outcome among the groups (P < 0.0001). Primary healing was highest in group 4 (91.4%), which showed the lowest rate for mediastinitis (0.9%). Multivariate analysis showed that the use of CHG and a gentamicin sponge was statistically significant (P = 0.026 and 0.013, respectively). The other significant independent factors were valve operation (P = 0.001), body mass index >30 kg/m2 (P = 0.001), preoperative stroke (P = 0.005), and blood transfusion (P = 0.022). CONCLUSION: Preoperative skin disinfection with IPA-CHG is superior to only IPA, and it should be recommended. The addition of a retrosternal gentamicin-releasing sponge further reduces the rate of mediastinitis. PMID- 29409980 TI - Potential Impact of the Proposed Revised UNOS Thoracic Organ Allocation System. AB - The current United States heart allocation system faces 2 main challenges: an evolving landscape of device therapy in advanced heart failure and a rapidly increasing transplant waiting list. The proposed new heart allocation system involves expansion of the 3 tiers and enables greater distinction between different types of mechanical circulatory support devices. In this review, we discuss how the proposed revision reconciles key concerns of the current system to create a more fair and equitable allocation of hearts in the United States. PMID- 29409979 TI - Legionella indianapolisensis sp. nov., isolated from a patient with pulmonary abscess. AB - BACKGROUND: To date, at least 50 species of Legionella have been described. These organisms are ubiquitous in nature and have been isolated from diverse ecological environments, including man-made structures such as cooling towers and spas. Legionellae have also been isolated from human and veterinary clinical specimens, and their roles in disease are well-established. This report describes the isolation of a novel Legionella species from a respiratory specimen from a patient with influenza and suspected pulmonary embolus. CASE: A 68-year-old male presented to an Indianapolis-area hospital with pulmonary disease; upon workup, he was found to have influenza A. Bronchoalveolar lavage fluid was also submitted for conventional bacterial culture and Legionella culture. The patient was prescribed a broad-spectrum antibiotic and recovered. RESULTS: A Legionella-like bacterium was isolated on buffered charcoal yeast extract agar, and mass spectrometry and comparative 16S rRNA gene sequencing inconclusively identified the isolate as a Legionella sp. Further analysis of the 16S rRNA gene confirmed the strain to be a new species, related to Legionella hackeliae. Physiochemical and morphological testing were used to confirm the discovery of a novel species, Legionella indianapolisensis sp. nov., type strain SMNF-IS. PMID- 29409981 TI - Liver Transplantation for Severe Alcoholic Hepatitis, Updated Lessons from the World's Largest Series. AB - BACKGROUND: Six-month sobriety before transplantation for alcoholic liver disease is typically required but poorly supported by data. We initiated a pilot program after a report of liver transplantation for severe alcoholic hepatitis (SAH) in which the 6-month rule was waived. We previously reported early outcomes; we now provide longer follow-up in the largest cohort of early liver transplantation for SAH in the literature to date. STUDY DESIGN: Forty-six carefully selected patients with SAH underwent liver transplantation from October 2012 through July 2017; none had been abstinent for 6 months. We also examined 34 patients with alcoholic cirrhosis who received liver transplants under standard protocols with at least 6 months sobriety. We identified patient characteristics and primary outcomes of patient and graft survival, as well as alcohol recidivism. Secondary outcomes included post-transplantation infection, malignancy, and rejection. RESULTS: Compared with patients with alcoholic cirrhosis, SAH patients were younger and with shorter drinking history and higher Model for End-Stage Liver Disease scores at listing and at transplantation. Of these patients, 46% received preoperative steroids; all were nonresponders by Lille score. At a median follow up time of 532 days (interquartile range 281 to 998 days), there were no significant differences between groups by log-rank testing of Kaplan-Meier estimates for patient and graft survival or alcohol recidivism. CONCLUSIONS: In the largest cohort of patients reported, outcomes after liver transplantation for SAH had excellent 1-year outcomes, similar to those seen in patients who received transplants with 6 months of sobriety. Recidivism was similar in the 2 groups. Early liver transplantation for SAH represents life-saving therapy for patients with otherwise high mortality, calling into question the utility of the 6-month rule in predicting outcomes in patients receiving transplants for alcoholic liver disease. PMID- 29409982 TI - Understanding cancer and its treatment in Thai traditional medicine: An ethnopharmacological-anthropological investigation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thai traditional medicine (TTM) is widely practiced in Thailand and continues to gain importance in cancer management, but little is known about the TTM practitioners' emic concepts and practice. AIM OF THE STUDY: With this study we firstly aim to document the practice of cancer treatment and prevention by TTM practitioners and, secondly, to evaluate how such traditional concepts and practices are correlated with biomedical ones. This in turn can form the basis for developing novel strategies for designing pharmacological experiments and longer term strategies to develop TTM practice. METHODS: Semi-structured interviews with 33 TTM practitioners were performed in five provinces in different regions of Thailand. The following information were recorded; basic information of informants, descriptions of cancer (mareng in Thai), causes, diagnosis, treatment, and prevention. Plants used in the treatment and prevention of mareng were also collected. RESULTS: Using an in depth ethnographic approach four representative case studies to assist in a better understanding of the characteristics of mareng, its diagnosis, treatment, and prevention are reported here. Five characteristics of mareng - waste accumulation (khong sia), chronic illnesses (krasai), inflammation (kan aksep), bad blood (luead) and lymph (namlueang), and the imbalance of four basic elements (dhatu si) - have been identified. Explanatory models of cancer in TTM were linked with biomedical concepts and relevant pharmacological actions. Traditional uses and available scientific evidence of medicinal plants mentioned in the case studies for the treatment or prevention of mareng are presented and discussed. CONCLUSION: Here for the first time five main characteristics of cancer based on Thai traditional medical concepts are analysed. Our findings are relevant not only for the planning of clinical studies or pharmacological experiment in the search for novel compounds for cancer treatment and prevention, but also for the integration of Thai traditional medicine in cancer care. PMID- 29409984 TI - Molecular phylogeny of Neotropical rock frogs reveals a long history of vicariant diversification in the Atlantic forest. AB - The Brazilian Atlantic coastal forest is one of the most heterogeneous morphoclimatic domains on earth and is thus an excellent region in which to examine the role that habitat heterogeneity plays in shaping diversification of lineages and species. Here we present a molecular phylogeny of the rock frogs of the genus Thoropa Cope, 1865, native to the Atlantic forest and extending to adjacent campo rupestre of Brazil. The goal of this study is to reconstruct the evolutionary history of the genus using multilocus molecular phylogenetic analyses. Our topology reveals 12 highly supported lineages among the four nominal species included in the study. Species T. saxatilis and T. megatympanum are monophyletic. Thoropa taophora is also monophyletic, but nested within T. miliaris. Populations of T. miliaris cluster in five geographically distinct lineages, with low support for relationships among them. Although all 12 lineages are geographically structured, some T. miliaris lineages have syntopic distributions with others, likely reflecting a secondary contact zone between divergent lineages. We discuss a biogeographic scenario that best explains the order of divergence and the distribution of species in Atlantic forest and adjacent areas, and outline the implications of our findings for the taxonomy of Thoropa. PMID- 29409983 TI - Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram-negative pathogens. AB - The proteobacterial antimicrobial compound efflux (PACE) family of transport proteins was only recently described. PACE family transport proteins can confer resistance to a range of biocides used as disinfectants and antiseptics, and are encoded by many important Gram-negative human pathogens. However, we are only just beginning to appreciate the range of functions and the mechanism(s) of transport operating in these proteins. Genes encoding PACE family proteins are typically conserved in the core genomes of bacterial species rather than on recently acquired mobile genetic elements, suggesting that they confer important core functions in addition to biocide resistance. Three-dimensional structural information is not yet available for PACE family proteins. However, PACE proteins have several very highly conserved amino acid sequence motifs that are likely to be important for substrate transport. PACE proteins also display strong amino acid sequence conservation between their N and C-terminal halves, suggesting that they evolved by duplication of an ancestral protein comprised of two transmembrane helices. In light of their drug resistance functions in Gram negative pathogens, PACE proteins should be the subject of detailed future investigation. PMID- 29409986 TI - Application of the Eighth AJCC TNM Staging System in Patients With Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The eighth edition of the American Joint Committee on Cancer Tumor Node-Metastasis staging system separates classifications for the clinical (c), pathologic (p), and postneoadjuvant pathologic (yp) stages. We aimed to evaluate its application in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Patient data were obtained from the Taiwan Cancer Registry database. Patients who underwent esophagectomy for c stage I to III ESCC were included for survival analysis. RESULTS: Data of 3,399, 1,805, and 1,594 patients were included for c, p, and yp staging, respectively. The 3-year overall survival (OS) rates for c stage I, II, and III were 67.4%, 46.7%, and 38.4%, respectively. The 3-year OS rates for p stage I, II, III, and IV were 70.7%, 49.8%, 30.8%, and 10.6%, respectively. The 3-year OS rates for yp stage I, II, III, and IV were 59.4%, 37.8%, 27.6%, and 3.7%, respectively. Survival curve analysis demonstrated a robust discriminatory capability and monotonicity of gradients of the new system. However, yp stage I was observed in a heterogeneous group of patients with substantial survival differences. Meanwhile, patients in the ypT0 N0 stage had a 5-year OS rate of 52.1%, which was equivalent to that of patients with p stage I (54.5%). The 5-year OS rate of patients in the ypTis-2N0 was 39.1%, which was equivalent to that of patients in p stage II (40.1%). CONCLUSIONS: The present study serves as an external validation of the newly released staging system in the prognostication of patients with ESCC and suggests subgrouping of the yp stage I into ypT0 N0 and non-ypT0 N0 in the future. PMID- 29409985 TI - Transforming growth factor beta superfamily regulation of adipose tissue biology in obesity. AB - Accumulation of dysfunctional white adipose tissues increases risks for cardiometabolic diseases in obesity. In addition to white, brown or brite adipose tissues are also present in adult humans and increasing their amount may be protective. Therefore, understanding factors regulating the amount and function of each adipose depot is crucial for developing therapeutic targets for obesity and its associated metabolic diseases. The transforming growth factor beta (TGFbeta) superfamily, which consists of TGFbeta, BMPs, GDFs, and activins, controls multiple aspects of adipose biology. This review focuses on the recent development in understanding the role of TGFbeta superfamily in the regulation of white, brite and brown adipocyte differentiation, adipose tissue fibrosis, and adipocyte metabolic and endocrine functions. TGFbeta family and their antagonists are produced locally within adipose tissues and their expression levels are altered in obesity. We also discuss their potential contribution to adipose tissue dysfunction in obesity. PMID- 29409987 TI - Decreased ATP production and myocardial contractile reserve in metabolic heart disease. AB - Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) 'Western' diet to recapitulate the MHD phenotype. In isolated beating hearts, we used 31P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (?G~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ?G~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ?G~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca2+-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ?G~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux. PMID- 29409988 TI - Species-specific developmental toxicity in rats and rabbits: Generation of a reference compound list for development of alternative testing approaches. AB - For regulatory information requirements, developmental toxicity testing is often conducted in two mammalian species. In order to provide a set of reference compounds that could be used to explore alternative approaches to supersede testing in a second species, a retrospective data analysis was conducted. The aim was to identify compounds for which species sensitivity differences between rats and rabbits are not caused by maternal toxicity or toxicokinetic differences. A total of 330 compounds were analysed and classified according to their species specific differences. A lack of concordance between rat and rabbit was observed in 24% of the compounds, of which 10% were found to be selective developmental toxicants in one of the species. In contrast to previously published analyses the presented comparison is based entirely on publically data allowing validating and comparing alternative approaches for developmental toxicity testing. Furthermore, this list could be useful to identify mechanisms leading to species differences. PMID- 29409989 TI - Combined inhibition of PI3Kdelta and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia. AB - PI3Kdelta and FLT3 are frequently activated in acute myeloid leukemia (AML) and have been implicated as potential therapeutic targets. In this report, we demonstrate that combined inhibition of PI3Kdelta and FLT3 exerts synergistic antitumor activity in FLT3-activated AML. Synergistic antiproliferative effects were observed in FLT3-activated MV-4-11 and EOL-1 AML cell lines, but not in FLT3 independent RS4;11 and HEL cells, as demonstrated by both pharmacological inhibition and silencing of PI3Kdelta/FLT3. Combined treatment with PI3Kdelta and FLT3 inhibitors more effectively inhibited AKT and ERK phosphorylation, and induced apoptosis more efficiently than either agent alone. This synergistic effect was confirmed in hematopoietic 32D cells transfected with an FLT3-ITD mutant, but not FLT3 wild type. In in vivo FLT3-activated AML xenografts, a PI3Kdelta inhibitor CAL101 combined with FLT3 inhibitor led to significantly enhanced antitumor activity compared with either agent alone, in association with simultaneous inhibition of AKT and ERK. Importantly, CAL101 combined with FLT3 inhibitors overcame acquired drug resistance in FLT3-ITD AML cells. Thus, combined inhibition of PI3Kdelta and FLT3 may be a promising strategy in FLT3 activated AML, particularly for patients with FLT3-inhibitor-resistant mutations. PMID- 29409990 TI - A Rare Cause of Esophageal Stenosis in an Infant. PMID- 29409991 TI - A Multicystic, Malrotated Pancreas in a Patient With Wandering Spleen. PMID- 29409992 TI - The expression profiling and ontology analysis of non-coding RNAs in dexamethasone induced steatosis in hepatoma cell. AB - Increasing amounts of evidence have indicated that non-coding RNAs (ncRNAs) have important regulatory potential in various biological processes. However, the contribution of ncRNAs, especially long non-coding RNAs (lncRNAs) to drug induced steatosis remain largely unknown. The aim of this study is to investigate miRNA, lncRNA and mRNA expression profiles and their potential roles in the process of drug induced steatosis. Microarray expression profiles of miRNAs, lncRNAs and mRNAs were determined in dexamethasone treated HepG2 cell as well as control cell. Differential expression, pathway and gene network analyses were developed to identify possible functional RNA molecules in dexamethasone induced steatosis. Compared with control HepG2 cell, 652 lncRNAs (528 up-regulated and 124 down regulated), 655 mRNAs (527 upregulated and 128 down-regulated) and 114 miRNAs (55 miRNAs up-regulated and 59 down-regulated) were differentially expressed in dexamethasone treated HepG2 cell. Pathway analysis showed that the fatty acid biosynthesis, insulin resistance, PPAR signaling pathway, regulation of lipolysis in adipocytes, carbohydrate digestion and absorption, steroid hormone biosynthesis signaling pathways had a close relationship with dexamethasone induced steatosis. 10 highly dysregulated mRNAs and 20 miRNAs, which are closely related to lipid metabolism, were identified and validated by PCR, which followed by ceRNA analysis. CeRNA network analysis identified 5 lipid metabolism related genes, including CYP7A1, CYP11A1, PDK4, ABHD5, ACSL1. It also identified 12 miRNAs (miR-23a-3p, miR-519d-3p, miR-4328, miR-15b-5p etc.) and 177 lncRNAs (ENST00000508884, ENST00000608794, ENST00000568457 etc.). Our results provide a foundation and an expansive view of the roles and mechanisms of ncRNAs in dexamethasone induced steatosis. PMID- 29409993 TI - The prevalence of colistin resistance in Escherichia coli and Klebsiella pneumoniae isolated from food animals in China: coexistence of mcr-1 and blaNDM with low fitness cost. AB - Increasing colistin resistance is a global concern because colistin is used as a last resort for the treatment of carbapenem-resistant Enterobacteriaceae infections. The plasmid-mediated colistin resistance gene, mcr-1 was found in distinct bacterial species isolated from humans, animals, and the environment. In this study, farms in four different agricultural provinces in China were investigated to determine the occurrence of the antimicrobial resistance and related genes. A total of 373 Escherichia coli and 54 Klebsiella pneumoniae were isolated from 510 non-duplicated samples. Of the E. coli and K. pneumoniae isolates, 72.7% and 66.7%, respectively, were susceptible to colistin. Isolates resistant to colistin comprised 46.6% of the samples isolated from Shandong, and 17.8% and 16.4% of the samples from Jilin and Henan, respectively. Twenty-six carbapenem-resistant E. coli isolates were resistant to colistin, in which both mcr-1 and blaNDM were present. Specifically, the co-existence was found in isolates from animals and sewage. Most of the resistance genes were located on plasmids and were 40-244 kilobases. Growth curves of transconjugants carrying mcr 1, blaNDM-1, blaNDM-4, blaNDM-5, and blaNDM-9 showed a low fitness cost compared with the recipient. In conclusion, mcr-1 was widespread in E. coli and K. pneumoniae isolated from farms in China. Co-existence of mcr-1 and blaNDM-9 was identified in different sequence types of E. coli with low fitness cost from various origins, indicating an urgent need to take measures for decreasing dissemination. PMID- 29409994 TI - Infectious meningitis and encephalitis in adults in Denmark: a prospective nationwide observational cohort study (DASGIB). AB - OBJECTIVES: To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark. METHODS: Nationwide prospective observational study of all cases of proven community-acquired infectious meningitis and encephalitis in adults treated in all infectious diseases departments in Denmark from 1 January 2015 to 30 June 2016. We included data on symptoms, aetiology, treatment and outcome assessed by the Glasgow Outcome Scale (GOS) 30 days after discharge. GOS 1-4 was categorized as unfavourable outcome. RESULTS: During 18 months of observation, we identified 252 cases of viral meningitis (3.6/100 000/year), 214 cases of bacterial meningitis (3.1/100 000/year) and 96 cases of infectious encephalitis (1.4/100 000/year). In bacterial meningitis, Streptococcus pneumoniae was the most frequent infectious agent (n = 101) followed by Staphylococcus aureus (n = 24) and beta-haemolytic streptococci (n = 14). Meningococcal meningitis was rare (n = 11). In encephalitis, herpes simplex virus type 1 was most common (n = 37) followed by varicella zoster virus (n = 20), whereas varicella zoster virus (n = 61) was most common in viral meningitis followed by enterovirus (n = 50) and herpes simplex virus type 2 (n = 46). Case fatality and unfavourable outcome occurred in 31/214 (15%) and 96/214 (45%) with bacterial meningitis and in 5/96 (5%) and 55/89 (62%) with encephalitis. For viral meningitis, unfavourable outcome occurred in 41/252 (17%). CONCLUSIONS: The epidemiology and clinical presentation of the examined central nervous system infections differed considerably and bacterial meningitis was more frequent than previously estimated. Overall prognosis remains poor for bacterial meningitis and encephalitis. Prospective nationwide clinical databases of central nervous system infections may be superior to epidemiological monitoring based on notifications or laboratory systems. PMID- 29409995 TI - The Scribble Cell Polarity Module in the Regulation of Cell Signaling in Tissue Development and Tumorigenesis. AB - The Scribble cell polarity module, comprising Scribbled (Scrib), Discs-large (Dlg) and Lethal-2-giant larvae (Lgl), has a tumor suppressive role in mammalian epithelial cancers. The Scribble module proteins play key functions in the establishment and maintenance of different modes of cell polarity, as well as in the control of tissue growth, differentiation and directed cell migration, and therefore are major regulators of tissue development and homeostasis. Whilst molecular details are known regarding the roles of Scribble module proteins in cell polarity regulation, their precise mode of action in the regulation of other key cellular processes remains enigmatic. An accumulating body of evidence indicates that Scribble module proteins play scaffolding roles in the control of various signaling pathways, which are linked to the control of tissue growth, differentiation and cell migration. Multiple Scrib, Dlg and Lgl interacting proteins have been discovered, which are involved in diverse processes, however many function in the regulation of cellular signaling. Herein, we review the components of the Scrib, Dlg and Lgl protein interactomes, and focus on the mechanism by which they regulate cellular signaling pathways in metazoans, and how their disruption leads to cancer. PMID- 29409996 TI - Fatty acid composition in native bees: Associations with thermal and feeding ecology. AB - Fatty acid (FA) composition of lipids plays a crucial role in the functioning of lipid-containing structures in organisms and may be affected by the temperature an organism experiences, as well as its diet. We compared FA composition among four bee genera: Andrena, Bombus, Megachile, and Osmia which differ in their thermal ecology and diet. Fatty acid methyl esters (FAME) were prepared by direct transesterification with KOH and analyzed using gas-liquid chromatography with a flame ionization detector. Sixteen total FAs ranging in chain length from eight to 22 carbon atoms were identified. Linear discriminant analysis separated the bees based on their FA composition. Andrena was characterized by relatively high concentrations of polyunsaturated FAs, Bombus by high monounsaturated FAs and Megachilids (Megachile and Osmia) by relatively high amounts of saturated FAs. These differences in FA composition may in part be explained by variation in the diets of these bees. Because tongue (proboscis) length may be used as a proxy for the types of flowers bees may visit for nectar and pollen, we compared FA composition among Bombus that differed in proboscis length (but have similar thermal ecology). A clear separation in FA composition within Bombus with varying proboscis lengths was found using linear discriminant analysis. Further, comparing the relationship between each genus by cluster analysis revealed aggregations by genus that were not completely separated, suggesting potential overlap in dietary acquisition of FAs. PMID- 29409997 TI - Improved TaqMan real-time assays for detecting hepatitis A virus. AB - Rapid advancement in genomics and bioinformatics in recent years holds great promise for research and development in many disciplines including public health. For the detection of pathogens, methods based on nucleic acid amplification need to be re-evaluated periodically to ensure the validity of signature primers and probes as more and more outbreak strains are sequenced and collected into databases in public domains. In this study, a previous assay designed computationally for detecting hepatitis A virus (HAV) was re-examined. Alignment of 57 complete or near complete HAV genomes allowed identification of conserved sequences for developing new primers and TaqMan probes. Two sets of real-time reverse transcription PCR reagents were developed by targeting highly conserved regions with primers and probes having optimal melting temperatures and minimum secondary structures. These two assays had 10 to 1000 fold lower detection limits than the previous assay when tested using representative human HAV genotypes IA, IB, and IIIA. The better of the two improved assays had a detection limit of 3.7 * 10-2 to 6.6 * 10-2 TCID50 or less. The improved detection sensitivity was likely due to improvement in the following four areas: 1) The Gardner1 probe has a single nucleotide mismatch at the 5' end in all 19 strains of genotypes IIIA and IIIB. 2) For the Gardner1 forward primer, there is a mismatch corresponding to the 3' end of the oligonucleotides in two strains belonging to genotype IA. 3) The Gardner1 probe had a melting temperature of 66.2 degrees C, which is less than the optimum of 68-70 degrees C (Dorak, 2006). 4) The Gardner1 forward and reverse primers had high potential of forming primer dimers. The improved HAV detection assays developed in this study would support better food safety surveillance initiatives and response to disease outbreaks of viral food-borne illness. PMID- 29409998 TI - Motivational effects on the processing of delayed intentions in the anterior prefrontal cortex. AB - Delaying intentions bears the risk of interference from distracting activities during the delay interval. Motivation can increase intention retrieval success but little is known about the underlying brain mechanisms. Here, we investigated whether motivational incentives (monetary reward) modulate the processing of delayed intentions in the anterior prefrontal cortex (aPFC), known to be crucial for intention processing. Using a mixed blocked and event-related functional Magnetic Resonance Imaging design, we specifically tested whether reward affects intention processing in the aPFC in a transient or in a sustained manner and whether this is related to individual differences in retrieval success. We found a generalized effect of reward on both correct intention retrieval and ongoing task performance. Fronto-parietal regions including bilateral lateral aPFC showed sustained activity increases in rewarded compared to non-rewarded blocks as well as transient reward-related activity during the storage phase. Additionally, individual differences in reward-related performance benefits were related to the degree of transient signal increases in right lateral aPFC, specifically during intention encoding. This suggests that the ability to integrate motivational relevance into the encoding of future intentions is crucial for successful intention retrieval in addition to general increases in processing effort. Bilateral aPFC is central to these motivation-cognition interactions. PMID- 29409999 TI - Errors can elicit an error positivity in the absence of an error negativity: Evidence for independent systems of human error monitoring. AB - Errors in human behavior elicit a cascade of brain activity related to performance monitoring and error detection. Whereas the early error-related negativity (Ne/ERN) has been assumed to reflect a fast mismatch or prediction error signal in the medial frontal cortex, the later error positivity (Pe) is viewed as a correlate of conscious error processing. A still open question is whether these components represent two independent systems of error monitoring that rely on different types of information to detect an error. Here, we investigated the prediction that the Ne/ERN but not the Pe requires a representation of the correct response to emerge. To this end, we created a condition in which no information about the correct response was available while error detection was still possible. We hypothesized that a Pe, but no Ne/ERN should be obtained in this case. Participants had to classify targets but ignore flankers that were always associated with an incorrect response. Targets but not flankers were masked with varying target-masking intervals. Crucially, on some trials no target at all was presented, thus preventing the representation of a correct response and the emergence of an Ne/ERN. However, because flankers were easily visible and responses to the flankers were always incorrect, detection of these flanker errors was still possible. In line with predictions of a multiple systems account, we observed a robust Pe in the absence of an Ne/ERN for these errors. Moreover, this Pe relied on the same neural activity as that on trials with a visible target, as revealed by multivariate pattern analysis. These findings demonstrate that the mechanisms reflected by the two components use different types of information to detect errors, providing evidence for independent systems of human error monitoring. PMID- 29410000 TI - Meta regression: Relationship between antipsychotic receptor binding profiles and side-effects. AB - Our objective was to examine the association between antipsychotic receptor binding profiles and the magnitude of common side-effects. We used regression analysis to examine the association between the receptor binding affinities of antipsychotic agents (log Ki) and degree of specific antipsychotic side-effects. Data on magnitude of weight gain, prolactin increase and QTc prolongation (in Standardized Mean Difference) and risk of sedation and extrapyramidal symptoms (in Odds Ratio) between individual antipsychotic medications as compared to placebo was based on a recent network meta-analysis examining the treatment of schizophrenia. Receptor affinities (in log Ki) were examined for the D2, 5-HT1A, 5-HT2A, 5-HT2C, H1, alpha1, alpha2, M1, M3 and M4 receptors. Medications were weighted in the analysis using the generic inverse variance method utilizing variance estimates from the previous meta-analysis. Magnitude of weight gain was significantly associated with the affinity of antipsychotic medications to M1, M3, 5-HT2C and H1 receptors. Risk of sedation was significantly associated with the affinity to the M1 and M4 receptors. Magnitude of hyperprolactinemia was significantly associated with the affinity to M1 and M4 receptors. Risk of extrapyramidal side effects was associated with the affinity to 5-HT2C and M1 receptors. QT prolongation was not significantly associated with antipsychotic receptor affinities. Our meta-analysis demonstrated that increased affinity of antipsychotics for certain receptors are significantly associated with higher risk of sedation, hyperprolactinemia, extrapyramidal side effects and weight gain. PMID- 29410001 TI - Preparation, characterization and efficacy of lysostaphin-chitosan gel against Staphylococcus aureus. AB - Lysostaphin (LST) is a bacteriocin that cleaves within the pentaglycine cross bridge of Staphylococcus aureus peptidoglycan. Previous studies have reported the high efficiency of LST even against multi drug resistant S. aureus including methicillin resistant S. aureus (MRSA). In this study, we have developed a new chitosan based hydrogel formulation of LST to exploit its anti-staphylococcal activity. The atomic interactions of LST with chitosan were studied by molecular docking studies. The rheology and the antibacterial properties of the developed LSTC gel were evaluated. The developed LST containing chitosan hydrogel (LSTC gel) was flexible, flows smoothly and remains stable at physiological temperature. The in vitro studies by agar well diffusion and ex vivo studies in porcine skin model exhibited a reduction in S. aureus survival by ~3 Log10CFU/mL in the presence of LSTC gel. The cytocompatibility of the gel was tested in vitro using macrophage RAW 264.7 cell line and in vivo in Drosophila melanogaster. A gradual disruption of S. aureus biofilms with the increase of LST concentrations in the LSTC gel was observed which was confirmed by SEM analysis. We conclude that LSTC gel could be highly effectual and advantageous over antibiotics in treating staphylococcal-topical and biofilm infections. PMID- 29410002 TI - A Schwannoma of the Small Bowel. PMID- 29410003 TI - Pig KDM5B: mRNA expression profiles of different tissues and testicular cells and association analyses with testicular morphology traits. AB - Lysine specific demethylase 5B gene (KDM5B, also known as JARID1B or PLU-1), encoding an enzyme of the lysine-specific histone demethylase family, has been reported to regulate androgen receptor transcriptional activity and male reproduction. To fully study the expression characteristics and genetic effects of pig KDM5B gene, the objective of this study was to investigate the mRNA expression profiles of KDM5B among different tissues and testicular cells (spermatogonia stem cells, SSCs; sertoli cells, SCs; leydig cells, LCs), as well as to explore the insertion/deletion (indel) variations of this gene. Expression analysis results revealed that the KDM5B gene was highly expressed in testis than other tissues in 7-day-old piglet (P < 0.01). In particular, this gene was highest expressed in testis of adult boar (P < 0.01). Furthermore, the KDM5B mRNA expression level in SSCs was significantly higher than those in LCs and SCs (P < 0.01). Besides, a 35-bp indel was first verified in the intron 11 of pig KDM5B gene, and the animals with insertion/insertion genotype exhibited superior testicular weight and testicular short perimeter than those with other genotypes (P < 0.05) in 40-day-old Landrace pigs. Together, these findings suggest that KDM5B plays a crucial role in male fertility and the 35-bp indel can be used for marker-assisted selection of boar. PMID- 29410004 TI - A case-control study and meta-analysis confirm glucokinase regulatory gene rs780094 is a risk factor for gestational diabetes mellitus. AB - BACKGROUND: Although the influence of a common variant in the glucokinase regulatory gene (GCKR rs780094) in type 2 diabetes mellitus has been well documented, less data however, is available of its role in gestational diabetes mellitus (GDM). We carried out a case control study to assess the association between GCKR rs780094 and GDM in the Asian, and also a meta-analysis to further assess the strength of the association. METHODS: Demographic, clinical and genotype data were determined for 1122 women (267 cases and 855 controls) recruited from the University of Malaya Medical Centre in the Klang Valley, Kuala Lumpur. Relevant articles were identified from Pubmed, Embase, MEDLINE, and Web of Science. Extraction of data was carried out and summary estimates of the association between rs780094 and GDM were examined. RESULTS: The frequency of risk allele C was significantly higher in the cases than controls (OR 1.34, 95% CI 1.09-1.66, P = 0.006). The C allele was also associated with increased level of random 2-hour fasting plasma glucose and pregravid body mass index. Meta analysis further confirmed the association of the GCKR rs780094 with GDM (OR 1.32, 95% CI 1.14-1.52, P = 0.0001). CONCLUSION: This study strongly suggests that GCKR rs780094-C is associated with increased risk of GDM. PMID- 29410005 TI - Viral infections and breast cancer - A current perspective. AB - Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer. PMID- 29410006 TI - Non-apoptotic cell death in malignant tumor cells and natural compounds. AB - Traditional cancer therapy is mainly targeting on enhancing cell apoptosis, however, it is well established that many cancer cells are chemo-resistant and defective in apoptosis induction. Therefore, it may have important therapeutic implications to exploit some novel natural compounds based on non-apoptotic programmed cell death. Currently, accumulating evidence shows that the compounds from nature source can induce non-apoptotic programmed cell death in cancer cells, and therefore these natural compounds have gained a great promise for the future anticancer therapeutics. In this review, we will concentrate our efforts on the latest developments regarding major forms of non-apoptotic programmed cell death--autophagic cell death, necroptosis, ferroptosis, pyroptosis, glutamoptosis and exosome-associated cell death. Our increased understanding of the role of natural compounds in regulating non-apoptotic programmed cell death will hopefully provide prospective strategies for cancer therapy. PMID- 29410007 TI - Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish children and adolescents at risk of congenital adrenal hyperplasia. AB - Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but potential long-term adverse effects are largely unknown. In this report we intended to explore potential side effects of DEX therapy to enhance the adequacy of future risk benefit analyses of DEX treatment. We investigated the long-term effects of first trimester prenatal DEX treatment on behavioral problems and temperament in children and adolescents aged 7-17 years. The study included 34 children and adolescents, without CAH, who had been exposed to DEX during the first trimester and 67 untreated controls. Standardized parent-completed questionnaires were used to evaluate adaptive functioning and behavioral/emotional problems (CBCL), social anxiety (SPAI-C-P), and temperament (EAS) in the child. Self-reports were used to assess the children's perception of social anxiety (SASC-R). No statistically significant differences were found between DEX-treated and control children and adolescents, suggesting that, in general, healthy children treated with DEX during early fetal life are well adjusted. PMID- 29410008 TI - Changes in eating behavior and plasma leptin in children with obesity participating in a family-centered lifestyle intervention. AB - The goal of childhood obesity lifestyle interventions are to positively change body composition, however it is unknown if interventions also modulate factors that are related to energy intake. This study aimed to examine changes in eating behaviors and plasma leptin concentrations in overweight and obese children participating in a 1-year family-centered lifestyle intervention. Interventions were based on Canadian diet and physical activity (PA) guidelines. Children were randomized to 1 of 3 groups: Control (Ctrl; no intervention), Standard treatment (StnTx: 2 servings milk and alternatives/day (d), 3x/wk weight-bearing PA), or Modified treatment (ModTx: 4 servings milk and alternatives/day; daily weight bearing PA). Study visits occurred every 3-months for 1-y; interventions were held once a month for 6-months with one follow-up visit at 8-months. Ctrl received counselling after 1-y. Caregivers completed the Children's Eating Behavior Questionnaire (CEBQ) and reported on diet and activity. Plasma leptin were measured from morning fasted blood samples. Seventy-eight children (mean age 7.8 +/- 0.8 y; mean BMI 24.4 +/- 3.3 kg/m2) participated; 94% completed the study. Compared to baseline, at 6-months StnTx reduced Emotional Overeating and Desire to Drink scores (p < 0.05) while Food Responsiveness scores were reduced in both StnTx and ModTx (p < 0.05). At 1-year, scores for Desire to Drink in StnTx remained reduced compared to baseline (p < 0.05). Plasma leptin concentrations were significantly lower in ModTx at 6-months compared to baseline (p < 0.05). This study resulted in intervention groups favorably changing eating behaviors, supporting the use family-centered lifestyle interventions using Canadian diet and PA recommendations for children with obesity. PMID- 29410009 TI - Serum IL-1ra, a novel biomarker predicting olanzapine-induced hypercholesterolemia and hyperleptinemia in schizophrenia. AB - Olanzapine (OLZ) is efficacious whereas leads to adverse metabolic effects thus lead to higher risk of cardiovascular diseases (CVD) on schizophrenia. Cytokines have been found associated with metabolic disorders. Therefore, pretreatment prediction of OLZ-induced adverse metabolic effects is urgently needed. To investigate if baseline cytokine levels could become biomarkers for pathogenesis of schizophrenia or prediction for OLZ-induced adverse metabolic effects, we recruited 75 participants, including 23 schizophrenia inpatients, who were antipsychotic-free over the past 6 months or first episode and drug-naive and 52 matched health controls, in our prospective cohort study and cross-sectional study. We simultaneously examined 7 serum cytokine levels (IFN-gamma, IL-1ra, IL 1beta, IL-8, TNF-alpha, MCP-1, VEGF) before OLZ treatment by using liquid suspension array technique and obtained clinical correlates at 4-week intervals in total 8 weeks. The psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). The metabolic parameters were BMI, TG, total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein a, fasting glucose, HbA1c, insulin, and leptin. At baseline, IL-1ra and MCP-1 levels in schizophrenia were significantly higher than health controls (t = 4.55, P = 0.0001, t = 3.08 P = 0.003). BMI, fasting insulin, cholesterol, triglyceride, LDL, ApoB and leptin were significantly increased in patients with schizophrenia after 8 weeks of olanzapine treatment. Correlation analysis showed that the baseline IL-1ra level were significantly correlated with the increased levels of cholesterol (P = 0.004), LDL (P = 0.005), ApoB (P = 0.018) and leptin (P = 0.010), but not with the increased BMI, insulin or triglycerides. Further stepwise multiple linear regression analysis indicated that IL-1ra levels prior to treatment remained significantly associated with increased levels of cholesterol, LDL, ApoB and leptin. Above all, higher IL-1ra and MCP-1 levels may be biomarkers indicating pathogenesis of schizophrenia. Higher serum levels of IL-1ra may predict subsequent higher possibility of hypercholesterolemia and hyperleptinemia following OLZ treatment in schizophrenia patients. PMID- 29410010 TI - Notch1 knockdown disturbed neural oscillations in the hippocampus of C57BL mice. AB - Neural oscillations and their interactions are associated with the coordination of neural groups, which provide a mechanism underlying information processing of brain functions. Notch1 receptor is involved in the neurological and psychiatric disorders, such as neurodevelopmental deficits, cerebral ischemia, Alzheimer's disease and depression. Here, we investigated the dynamics of neural oscillations in hippocampus of Notch1+/- mice in urethane-anesthetized state. Notch1 knockdown altered the distribution of power in the hippocampal DG areas, reduced theta (3-8 Hz) power and enhanced low gamma (LG, 30-50 Hz) and high gamma (HG, 50-100 Hz) power. Moreover, theta-gamma phase-amplitude coupling in the hippocampal DG area was markedly impaired in the Notch1+/- mice. The data further showed that the expression of NR2B was decreased, and the expressions of GABAARalpha1, GAD67 and parvalbumin were considerably increased after Notch1 knockdown. Taken together, our results suggest that Notch1 genetic deficiency significantly impaired the corss-frequency coupling of neural oscillations, and their interactions in the hippocampal DG region by means of disrupting the balance of excitatory and inhibitory receptors, which could be an underlying mechanism of cognitive impairment in neuropsychiatric disorders. PMID- 29410012 TI - Community-acquired Clostridium difficile: epidemiology, ribotype, risk factors, hospital and intensive care unit outcomes, and current and emerging therapies. AB - BACKGROUND: The epidemiological landscape of Clostridium difficile infection (CDI) has changed over the past 30 years. AIM: To review studies of CDI in the community setting. METHODS: Electronic databases including PubMed, MEDLINE, Embase, Google Scholar, Scopus, ClinicalTrials.gov and Cochrane Databases were searched for human studies performed between 2000 and 2017 that assessed the epidemiology, risk factors, ribotypes, hospital and intensive care unit (ICU) outcomes, and management of community-acquired CDI. In addition, references were searched manually to identify other relevant studies. FINDINGS: In total, 39 articles met the inclusion criteria. The incidence of community-acquired CDI has almost doubled in the past decade. Approximately half of all cases of CDI are attributed to community origin. Individuals who are younger, female, in the presence of infants, frequently use proton pump inhibitors or specific classes of antibiotics, or live near farms and livestock are at higher risk for community acquired CDI. Additionally, approximately 40% of all community-acquired cases require hospitalization, where severity has been linked to hypervirulent ribotypes 027 and 078 with poor outcomes. Emerging data on treatment paradigms have led to the revision of clinical guidelines and two potential vaccines in phase three clinical trials. However, ribotype-specific responses to current treatment strategies are lacking. CONCLUSION: Community-acquired CDI represents a growing public health threat and burden on healthcare systems. A multi disciplinary approach will be required to stem the tides. PMID- 29410013 TI - Neuroimaging with ultra-high field MRI: Present and future. PMID- 29410011 TI - Presumed structural and functional neural recovery after long-term abstinence from cocaine in male military veterans. AB - Cumulative evidence suggests that cocaine use could alter the structure and function of different brain systems. However, the extent to which the altered brain structure and function possibly recover over time after cocaine abstinence remains less clear. The present study examines 39 male military veterans with different stages of cocaine addiction and long-term abstinence (from 1 year up to 30 years) and evaluates plausible changes in brain structure and function of specific brain regions that sub-serve addictions. These include the striatum that is involved in cocaine reward; the lateral prefrontal cortex (especially the dorsolateral PFC) that plays a major role in inhibitory control; the insula, which has been implicated in craving; and the medial orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) shown to play key roles in foresight and decision-making. The results suggest that there are differences in both brain structure (gray matter volume, GMV) and function between cocaine USERS and CONTROLS, with USERS showing plausible relative strengthening in neural systems for processing reward and craving, and relative weakening in neural systems involved in inhibitory control and decision-making. Examination of possible neural changes after abstinence suggests that presumed recovery occurs mostly in neural systems related to reward, craving, and inhibitory control, but to a lesser extent in neural systems related to decision-making. Given the limitations of the data in terms of a small sample size, as well as the lack of certainty about occasional use in the abstinent group, these results may be considered as preliminary. However, they are compelling in that they suggest that male military veterans cocaine USERS are indefinitely at a higher risk compared to CONTROLS for making lapses in judgment and decision-making leading to possible relapse, if reward salience and craving become more intense. Understanding the neurobiology of long-term cocaine abstinence in vulnerable populations and beyond could help devising better therapeutic strategies that prevent relapse. PMID- 29410014 TI - Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. AB - BACKGROUND: Baricitinib, an oral selective inhibitor of Janus kinase (JAK)1 and JAK2, modulates pro-inflammatory cytokine signaling. OBJECTIVES: The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 2, randomized, double-blind, placebo controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCS) for 4 weeks before randomization to once daily placebo, baricitinib 2 mg, or baricitinib 4 mg for 16 weeks. Use of TCS was permitted during the study. Primary outcome was the proportion of patients achieving >=50% reduction in the Eczema Area and Severity Index (EASI-50) compared to placebo. RESULTS: Significantly more baricitinib 4-mg patients achieved EASI-50 compared to placebo (61% vs 37%; P=0.027) at 16 weeks. The proportion of baricitinib 2- and 4-mg patients achieving EASI-50 compared to placebo was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 (49%) placebo, 17 (46%) baricitinib 2-mg, and 27 (71%) baricitinib 4-mg patients. LIMITATIONS: A TCS standardization period prior to randomization reduced disease severity, limiting the ability to compare results to baricitinib monotherapy. Longer studies are required to confirm baricitinib efficacy and safety in AD patients. CONCLUSIONS: Baricitinib used with TCS reduced inflammation and pruritus in patients with moderate-to-severe atopic dermatitis (AD). PMID- 29410015 TI - Quack: A quality assurance tool for high throughput sequence data. AB - The quality of data generated by high-throughput DNA sequencing tools must be rapidly assessed in order to determine how useful the data may be in making biological discoveries; higher quality data leads to more confident results and conclusions. Due to the ever-increasing size of data sets and the importance of rapid quality assessment, tools that analyze sequencing data should quickly produce easily interpretable graphics. Quack addresses these issues by generating information-dense visualizations from FASTQ files at a speed far surpassing other publicly available quality assurance tools in a manner independent of sequencing technology. PMID- 29410016 TI - A coupled fluorescence-based assay for the detection of protein arginine N methyltransferase 6 (PRMT6) enzymatic activity. AB - The protein arginine N-methyltransferase 6 (PRMT6) is overexpressed in a variety of different cancer types and plays a role in human immunodeficiency virus (HIV) infections. Furthermore, the PRMT6 activity might also influence the pathogenesis of neurodegenerative, inflammatory, and cardiovascular diseases, whereby it becomes an interesting target for drug development. Previously reported activity assays for PRMT6 activity are either expensive, time-consuming or use radioactive substrates. To overcome these challenges, we developed a coupled fluorescence based activity assay using recombinant PRMT6 expressed in E. coli. In the first step of the assay, the fluorogenic substrate Nalpha-Benzoyl-L-arginine-7-amido-4 methylcoumarin (Bz-Arg-AMC) is methylated by PRMT6, while in a second step the remaining un-methylated substrate is cleaved by trypsin, producing the fluorescent 7-amino-4-methylcoumarin. PMID- 29410017 TI - Differential response to caloric restriction of retroperitoneal, epididymal, and subcutaneous adipose tissue depots in rats. AB - The beneficial actions of caloric restriction (CR) are partially mediated by metabolic remodeling of white adipose tissue (WAT). Recently, we showed that CR enhances de novo fatty acid (FA) biosynthesis and mitochondrial biogenesis, particularly in WAT. Here, to better understand the response of WAT to CR, we compare the effects of CR on three WAT depots in rats: retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous (sWAT). Computed tomography and histological analysis showed that CR reduced the volume and average size of rWAT adipocytes. In all WAT depots, CR markedly upregulated the expression of proteins involved in FA biosynthesis in fed rats. In visceral WAT (rWAT and eWAT), hormone-sensitive lipase (lipolytic form) phosphorylation was increased by CR under fed conditions, and decreased by CR under fasted conditions. Conversely, in sWAT, hormone sensitive lipase phosphorylation was increased by CR under fasted conditions. CR enhanced the effect of feeding on AKT activity in sWAT (indicative of a positive effect on insulin sensitivity) but not in rWAT or eWAT. These data suggest that CR improves lipid metabolism in an insulin signaling-dependent manner in sWAT only. The effects of CR on adipokine (adiponectin and leptin) expression were also different among rWAT, eWAT and sWAT, and CR reduced the gene expression of M2 macrophage markers in rWAT and sWAT, but not in eWAT. We conclude that CR differentially affects the characteristics of WAT depots in rats, including adipocyte size, lipid metabolism, insulin signaling, adipocytokine profile and macrophage infiltration. PMID- 29410018 TI - Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll like receptor 4, TGF-beta1, NF-kappaB and glucagon-like peptide 1. AB - OBJECTIVE: Our aim was to assess the effect of different doses of linagliptin with or without l-dopa/Carbidopa on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. METHODS: Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + l-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + l-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + l-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF alpha), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-beta1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO 1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination. RESULTS: The combination of l-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-beta1, TNF-alpha, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either l-dopa/Carbidopa or linagliptin alone. CONCLUSION: The combination of l-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism. PMID- 29410019 TI - Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors. AB - Cabotegravir (CAB, S/GSK1265744) is an investigational second-generation integrase strand transfer inhibitor (INSTI) with a chemical structure similar to dolutegravir. CAB is under development as a long-acting injectable formulation for treatment of HIV-1 infection and for pre-exposure prophylaxis. We conducted an in vitro passage study of raltegravir- or elvitegravir-resistant signature mutants in the presence of CAB to characterize the resistance profile of this drug. During passage with Q148H virus, G140S arose by day 14, followed by G149A and C56S. Using site-directed mutagenesis, we obtained HIV molecular clones containing mutations encoding C56S and G149A in the integrase-coding region. Those substitutions were characterized in vitro as INSTI-resistance-associated secondary resistance mutations. Signature mutant viruses G140S/Q148H in which C56S and G149A were added acquired further INSTI resistance in conjunction with diminished integration activity, which yielded slower growth under drug-free conditions. PMID- 29410020 TI - Impact of 2 generational improvements in colonoscopes on adenoma miss rates: results of a prospective randomized multicenter tandem study. AB - BACKGROUND AND AIMS: Numerous randomized studies have shown that changing certain features of colonoscopes, usually incorporated when switching from one endoscope generation to the next, mostly do not increase adenoma yield. There is, however, indirect evidence that it may be necessary to skip one instrument generation (ie, changing from one generation to the next but one) to achieve this effect. METHODS: We compared the latest-generation colonoscopes from one company (Olympus Exera III, 190-C) with the next to last one (Olympus 160/5-C) in a prospective multicenter study randomized for the order of colonoscopes in a tandem fashion, involving 2 different examiners. Patients with increased risk for colorectal neoplasia undergoing colonoscopy (positive fecal occult blood test, personal/familial history of colorectal cancer/adenoma, rectal bleeding, recent change in bowel movements) were included. The primary outcome was the adenoma miss rate with the 190 (190-C) colonoscope in comparison with the 160/5 colonoscope (160/5-C). RESULTS: A total of 856 patients (48.8% male; mean age, 58.3 years) with a personal (41%) or family (38%) history of colorectal neoplasia, rectal bleeding (19%), and other indications were included. Of the 429 patients in the 190-C first group, 16.6% (95% confidence interval [CI], 13.0% 20.1%) had at least one adenoma missed during the first procedure, compared with 30.2% (95% CI, 25.9%-34.6%) in the group with 160/5-C first (P < .001). Similarly, the adenoma detection rate during the first colonoscopy was 43.8% versus 36.5% (P = .030) for 190-C versus 160/5-C, respectively. CONCLUSIONS: This randomized tandem trial showed lower adenoma miss rates and higher adenoma detection rates for the newer 190 colonoscopes compared with the 160/5 series. These results suggest that it takes multiple improvements, such as those implemented over 2 instrument generations, before an effect on adenoma (miss) rate can be observed. (Study registration number: ISRCTN 2010-A01256-33.). PMID- 29410021 TI - A rare presentation of cytomegalovirus infection in an immunocompetent patient. PMID- 29410022 TI - Efficacy and safety of endoscopic submucosal dissection for gastric neoplasms in patients with compensated liver cirrhosis: a propensity score-matched case control study. AB - BACKGROUND AND AIMS: The clinical outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms in liver cirrhosis patients have not been adequately reported, leading to clinician concerns about adverse events, including bleeding and the deterioration of liver function. We compared the efficacy and safety of ESD between cirrhosis and noncirrhosis patients. METHODS: Between January 2005 and December 2014, 158 cirrhosis patients underwent ESD for gastric neoplasms at a tertiary medical institution. Their clinical outcomes were compared with those of a propensity score-matched control group (158 patients) selected from noncirrhosis patients, using age, sex, histology, tumor location, and lesion size as variables. RESULTS: En bloc resection (96.8%), curative resection (89.9%), and adverse event (bleeding [10.1%] and perforation [1.9%]) rates in the cirrhosis group did not differ significantly from those in the noncirrhosis group. The median procedure time (25.0 vs 23.0 minutes) was also comparable between the groups. In a survival analysis cirrhosis patients exhibited a significantly higher mortality risk than noncirrhosis patients (hazard ratio [HR], 3.52; 95% confidence interval [CI], 1.35-9.23; P = .01). Cirrhosis patients without hepatocellular carcinoma (HCC) showed no statistically significant difference in mortality compared with the noncirrhosis group (HR, 2.14; 95% CI, .72-6.39; P = .171). Three of 153 patients (2%) exhibited a deterioration of prognosis from Child-Pugh class A to B. CONCLUSIONS: In compensated cirrhosis patients, especially those without HCC, ESD for gastric epithelial neoplasms can be performed with safety and efficacy comparable with that in noncirrhosis patients, without deterioration in liver function. PMID- 29410023 TI - Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells. AB - Hepatocellular carcinoma (HCC) remains the third most common cause of cancer related mortality. Resection and transplantation are the only curative treatments available, but are greatly hampered by high recurrence rates. Histone deacetylase inhibitors (HDACIs) are considered to be promising anticancer agents in drug development. Currently, four HDACIs have been granted Food and Drug Administration (FDA) approval for cancer. HDACIs have shown significant efficacy in hematological malignancies. However, they have limited effects in epithelial cell-derived cancers, including HCC, and the mechanisms of these are not elucidated. In this study, our results demonstrated that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) in hepatoma cells which are believed to trigger tumor cell invasion and metastasis. We found that HDACIs promoted the expression of Snail and Snail-induced EMT was critical for HDACI initiated invasion and metastasis. We indicated that HDACIs upregulated Snail in two ways. Firstly, HDACIs upregulated Snail at the transcriptional level by promoting Smad2/3 phosphorylation and nuclear translocation, then combined with the promoter to activate the transcription of Snail. Secondly, we showed that HDACIs regulated the stabilization of Snail via upregulating the expression of COP9 signalosome 2 (CSN2), which combined with Snail and exposed its acetylation site, then promoted acetylation of Snail, thereby inhibiting its phosphorylation and ubiquitination to repress the degradation of Snail. All these results highlighted that HDACIs have limited effects in HCC, and the use of HDACIs combined with other targeted strategies to inhibit EMT, which explored in this study is a promising treatment method for treating HCC. PMID- 29410024 TI - DNA methylation profiling in nonfunctioning pituitary adenomas. AB - Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors. PMID- 29410025 TI - Whole-genome shotgun sequences of seven colistin-resistant Acinetobacter baumannii isolates from bacteraemia. AB - OBJECTIVES: Acinetobacter baumannii is a nosocomial pathogen responsible for various infections, including bloodstream infections, meningitis and ventilator associated pneumonia. It is resistant to most antimicrobial agents, including colistin, and the development of colistin-resistant A. baumannii is of serious concern in the hospital setting. In this study, the whole-genome shotgun sequences of seven colistin-resistant A. baumannii isolates from bloodstream infections were characterised. METHODS: Colistin susceptibility testing was performed by broth microdilution. Whole genomes of all seven isolates were sequenced using an Ion TorrentTM PGM platform with 400-bp chemistry. RESULTS: All seven isolates were confirmed to be resistant to colistin, with minimum inhibitory concentrations (MICs) ranging from 8MUg/mL to 64MUg/mL. Various antimicrobial resistance genes were present. The mcr1-5 genes were absent in all seven isolates. Chromosomal mutations that could be responsible for colistin resistance were observed. Six isolates belonged to ST848 and one isolate belonged to ST451. CONCLUSION: Increased colistin resistance among clinical isolates of A. baumannii is alarming. Several mutations that could be responsible for colistin resistance were observed in all seven isolates. However, the significant contribution of these mutations requires further confirmation. However, genome information for these colistin-resistant A. baumannii isolates will be helpful for further comparative analysis. PMID- 29410026 TI - W1038 near D-loop of NBD2 is a focal point for inter-domain communication in multidrug transporter Cdr1 of Candida albicans. AB - Candida drug resistance 1 (Cdr1), a PDR subfamily ABC transporter mediates efflux of xenobiotics in Candida albicans. It is one of the prime factors contributing to multidrug resistance in the fungal pathogen. One hallmark of this transporter is its asymmetric nature, characterized by peculiar alterations in its nucleotide binding domains. As a consequence, there exists only one canonical ATP-binding site while the other is atypical. Here, we report suppressor analysis on the drug susceptible transmembrane domain mutant V532D that identified the suppressor mutation W1038S, close to the D-loop of the non-catalytic ATP-binding site. Introduction of the W1038S mutation in the background of V532D mutant conferred resistance for most of the substrates to the latter. Such restoration is accompanied by a severe reduction of ATPase activity, of about 85%, while that of the V532D mutant is half-reduced. Conversely, alanine substitution of the highly conserved aspartate D1033A in that D-loop rendered cells selectively hyper susceptible to miconazole without an impact on steady-state ATPase activity, suggesting altogether that ATP hydrolysis may not hold the key to restoration mechanism. Analysis of the ABCG5/ABCG8-based 3D-model of Cdr1p suggested that the W1038S substitution leads to the loss of hydrophobic interactions and H-bond with residues of the neighbor NBD1, in the non-catalytic ATP-binding site area. The compensatory effect within TMDs accounting for transport restoration in the V532D W1038S variant may, therefore, be mainly due to an increase in NBDs mobility at the non-catalytic interface. PMID- 29410027 TI - Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappaB pathway. AB - Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues. Secreted AGR2 was defined to enhance VEGFR2 activity as evidenced by physical interaction of purified recombinant human AGR2 (rhAGR2) with rhVEGFA through the formation of a disulfide bond. Mutant or deleted thioredoxin motif in rhAGR2 was also unable to bind to rhVEGFA that led to the significant abolishment in the vessel formation, but partially affecting the aggressive process, implicating alternative mechanisms are required for AGR2-conferring metastasis. Cytosolic AGR2 contributed to cell metastasis ascribed to its stabilizing effect on p65 protein, which subsequently activated the NF-kappaB and facilitated epithelial to mesenchymal transition (EMT). Importantly, GSH and cabozantinib, but not bevacizumab, effectively blocked the pro-angiogenic effect of rhAGR2 in vitro and in vivo, providing evidence that secreted AGR2 acts as a predictive biomarker for selection of angiogenesis-targeting therapeutic drugs based on its levels in the circular system. PMID- 29410028 TI - Mechanistic insights into the inhibition of quercetin on xanthine oxidase. AB - Quercetin, one of the most abundant flavonoid in the daily diet, was found to reversibly inhibit the generation of uric acid and superoxide radicals (O2 )catalyzed by xanthine oxidase (XOD) in a mixed-type manner with IC50 values of (2.74+/-0.04)*10-6 and (2.90+/-0.03)*10-6molL-1, respectively, and the inhibition of quercetin on O2- generation may be ascribed to the reduced form of XOD by a ping-pong mechanism. XOD had one high affinity binding site for quercetin with a binding constant of 4.28*104Lmol-1 at 298K, and the binding process was predominately driven by van der Waals forces and hydrogen bonds on account of the negative enthalpy and entropy changes. Moreover, molecular docking confirmed that the binding site for quercetin located in the isoalloxazine ring of the flavin adenine dinucleotide (FAD) domain of XOD, then the diffusion of O2- out of the FAD site was blocked in favor of another electron transferred from FADH2 to O2- to form hydrogen peroxide (H2O2). This study may clarify the role of quercetin on inhibiting XOD catalysis and provide a potential nutritional supplement for preventing gout and peroxidative damage. PMID- 29410029 TI - Sustained multimodal antimicrobial stewardship in an Australian tertiary intensive care unit from 2008-2015: an interrupted time-series analysis. AB - The long-term outcomes and sustainability of antimicrobial stewardship (AMS) in the intensive care unit (ICU) require evaluation. This study analysed the effect of a multimodal ICU AMS introduced in a 15-bed medical-surgical tertiary Australian adult ICU in November 2008, using interrupted time-series analysis of antibiotic usage, Gram-negative resistance and cost from November 2005 to October 2015, including national ICU average usage as a control. Overall ICU mortality, 30-day blood stream infection (BSI) mortality and length of stay (LOS) were compared over the same period. There were 2512 patients admitted to ICU before and 6435 after AMS intervention. Post-AMS there was a reduction in the trend of aminoglycoside usage both absolute from 63.3 DDD/1000 occupied bed days (OBD)/month (-1.1; 95% confidence interval [CI] -2.2, -0.1; P = 0.033) and relative to the national trend (-1.3; 95%CI -2.4, -0.3; P = 0.016). Vancomycin usage increased both absolute from 161.2 DDD/1000 OBD/month (1.8; 95%CI 0.03, 3.6; P = 0.046) and relative to the national trend (1.8; 95%CI -0.3, 3.9; P = 0.092). There were sustained post-AMS downward trends in carbapenem, antipseudomonal penicillin, third-generation cephalosporin and fluoroquinolone use that did not reach statistical significance. Post-AMS, antipseudomonal penicillin resistance declined (-12.8%; 95%CI -24.9, -0.6; P = 0.040). Antimicrobial acquisition costs declined by AUD$0.5/OBD/month (95%CI -1.1, 0.1; P = 0.096). Over the study period, severity-adjusted ICU mortality declined from 12.9% to 10.4%; risk ratio (RR) 0.92 (95%CI 0.82, 1.03) and BSI 30-day mortality from 37.9% to 26.3%; RR, 0.76 (95%CI 0.56, 1.03). Median ICU LOS for ICU survivors increased from 2.3 to 2.6 days. Multimodal AMS sustainably embedded in ICU was associated with reductions in broad-spectrum Gram-negative antibiotic use, overall antibiotic costs and Gram-negative resistance, without adverse clinical impact. PMID- 29410030 TI - LmrBPP9: A synthetic bradykinin-potentiating peptide from Lachesis muta rhombeata venom that inhibits the angiotensin-converting enzyme activity in vitro and reduces the blood pressure of hypertensive rats. AB - Bradykinin-potentiating peptides (BPPs) are an important group of toxins present in Lachesis muta rhombeata venom. They act directly at renin-angiotensin aldosterone system, through the inhibition of angiotensin-converting enzyme (ACE). This action may contribute to the hypotensive shock observed during the envenoming by this species. Thus, the main goal of this study was the solid-phase synthesis of a BPP found in L. m. rhombeata venom and its in vitro and in vivo characterization in relation to ACE inhibition and hypotensive activity, respectively. The LmrBPP9 peptide was synthesized using an automated solid-phase peptide synthesizer and purified by reversed-phase fast protein liquid chromatography (FPLC). The in vitro IC50 of the synthetic peptide is 4.25 +/- 0.10 MUM, showing a great capacity of ACE inhibition. The in vivo studies showed that LmrBPP9 induces blood pressure reduction, both in normotensive and hypertensive rats, being more pronounced in the last ones. These results agree with the in vitro results, showing that the synthetic peptide LmrBPP9 is a potential molecule to the development of a new antihypertensive drug. PMID- 29410031 TI - Intraperitoneal administration of aluminium-based adjuvants produces severe transient systemic adverse events in mice. AB - Vaccines typically come with adjuvants that trigger the innate immune system in order to prepare best possible inflammatory conditions as to allow the adaptive immune system to become activated, generally for the induction of antibodies. The oldest approved and most abundant immunological adjuvants are salts of aluminium, which are also frequently used in animal models of immunisation and allergy desensitization. In rodents, the intraperitoneal administration of aluminium adjuvants is commonly performed and considered safe. In the current investigation, we show that intraperitoneal administration of aluminium adjuvants is associated with a dose-dependent hypothermic reaction within 10 min of the injection. The body temperature of mice dropped as much as 4 degrees C, and the clinical symptoms included apathy, hunched posture, and piloerection. The temperature normalised and other clinical manifestations disappeared within 60-80 min of the intraperitoneal aluminium injection, which caused strong infiltration of neutrophil and eosinophil granulocytes into the peritoneal cavity, a clinical manifestations typically associated with inflammasome activation. However, the observed reactions to aluminium adjuvants were independent of NALP3, caspase-1, and interleukin-1beta, but dependent on histamine. Hence, aluminium adjuvants may have potential local and systemic side effects, which warrants further investigations into the nature of these side effects, but also into the possible implications on health in man. PMID- 29410032 TI - The synthetic cannabinoid XLR-11 induces in vitro nephrotoxicity by impairment of endocannabinoid-mediated regulation of mitochondrial function homeostasis and triggering of apoptosis. AB - Synthetic cannabinoids (SCBs)-related intoxications and deaths have been increasingly reported, turning its widespread recreational use into a major public health concern. Specifically, a direct link between SCBs and acute kidney injury (AKI) has been established. XLR-11 is an SCB commonly found in the toxicological analysis of patients with SCB-associated AKI. However, the pathophysiology of AKI among SCB consumers remains unknown. This work thus represents the first in vitro assessment of SCB nephrotoxicity, as a first approach to identify its cellular targets. We demonstrate that XLR-11, at biologically relevant concentrations (in the nanomolar range), primarily targets mitochondrial function in human proximal tubule (HK-2) cells, inducing a transient hyperpolarization of the mitochondrial membrane and increasing ATP production, accompanied by Bax translocation from cytosol into mitochondria. These phenomena further triggered energy-dependent apoptotic cell death pathways, indicated by increased caspase-3 activity and chromatin condensation. Experiments using SR141716A and SR144258, specific antagonists for CB1 and CB2 receptors, respectively, as well as HEK293T cells (which do not express CBRs) highlighted these processes' dependence on CBR activation. Nevertheless, ATP formation seemed to follow a CBR-independent pathway. Our findings using specific inhibitors of endogenous cannabinoids biosynthesis (i.e. MAFP and THL) further evidenced the involvement of the endocannabinoid system in the regulation of these processes, as XLR-11 binding to CBRs seemed to compromise endocannabinoid-mediated preservation of mitochondrial function. Nevertheless, the exact mechanisms involved require further clarification. PMID- 29410033 TI - Local Spinal Cord Decompression Through a Full Endoscopic Percutaneous Transcorporeal Approach for Cervicothoracic Ossification of the Posterior Longitudinal Ligament at the T1-T2 Level. AB - OBJECTIVE: To describe a percutaneous full endoscopic transcorporeal procedure to excise local ossification of the posterior longitudinal ligament (OPLL) lesions and decompress the spinal cord at the cervicothoracic transitional segment is safe and effective with respect to surgical complications. METHODS: A 67-year-old woman presented with nuchal pain and numbness below the T2 dermatome for 3 months and a 2-week history of paraplegia. T1-T2 myelopathy and paraplegia caused by OPLL was diagnosed based on clinical presentation, computed tomography, and magnetic resonance imaging. An anterior percutaneous full endoscopic transcorporeal procedure addressed local OPLL and achieved local spinal cord decompression at T1-T2. After surgery, magnetic resonance imaging was repeated to evaluate degree of spinal cord decompression. Visual analog scale, Neck Disability Index, and Japanese Orthopaedic Association scores were evaluated at each follow-up. RESULTS: The patient tolerated the full endoscopic operation successfully. Operative time was 225 minutes. On postoperative day 6, muscle strength of the bilateral lower extremities had progressed from grade 0/5 preoperatively to grade 2-/5 on the right and grade 2+/5 on the left. No surgery related complications were discovered. CONCLUSIONS: The percutaneous full endoscopic transcorporeal procedure is an alternative to previously described surgical methods of local spinal cord decompression for T1-T2 OPLL with fewer complications, effective spinal cord decompression, and a satisfactory cosmetic result. Successful cases confirm that treatment of spinal cord-limited compression by endoscopic technology is feasible. PMID- 29410034 TI - Repeated Endovascular Treatments in Patients with Recurrent Cerebral Vasospasms After Subarachnoid Hemorrhage: A Worthwhile Strategy? AB - OBJECTIVE: Endovascular interventions in patients with subarachnoid hemorrhage (SAH) and symptomatic cerebral vasospasm (sCVS) are commonly performed, but the potential benefits of repeated interventions have not been proven. The aim of this study was to show the potential burden and opportunities of repeated endovascular interventions in cases of recurrent sCVS. METHODS: We reviewed 15 patients with SAH who underwent more than 2 endovascular treatments of recurrent sCVS (CVS group) regarding the radiation doses, their clinical course, and their functional outcome. A case-control group of SAH patients without sCVS individually matched for age, World Federation of Neurosurgical Societies score, Fisher grade, and treatment modality was used as control group (non-CVS group). RESULTS: A total of 70 endovascular treatments were performed in the CVS group. CVS group patients received longer mechanical ventilation (585 days vs. 439 days) and showed a higher rate of tracheostomy (12/15 vs. 7/15) and shunt-dependent hydrocephalus (6/15 vs. 2/15) than did the non-CVS patients. Moreover, patients from the CVS group underwent significantly (P < 0.001) more angiographies (median, 5 vs. 2) and CTP/CTA scans (median, 4 vs. 1) and consequently received significantly (P < 0.001) higher radiation doses. The rate of unfavorable outcomes (mRS 3-6) after 3 months was nonsignificantly higher in the CVS group (6/15 vs. 2/15), but after 6 months at least 5/14 patients from the CVS group showed a favorable outcome. CONCLUSION: Repeated endovascular treatments of SAH patients with recurrent CVS are complex and expose the patients to high radiation doses. Nevertheless, favorable results could be achieved in patients in otherwise poor condition. PMID- 29410035 TI - Cerebellar Vermian Epidermoid Tumor: A Report of 2 Cases. AB - BACKGROUND: Epidermoid tumors are rare, benign slow-growing congenital tumors, most frequently located in the cerebellopontine angle of the intracranial cavity. They usually grow to a large size before patients become symptomatic. Although these tumors are amenable to surgery, their adherence to neurovascular structures poses a surgical challenge that results in subtotal resection, thus increasing the risk of recurrence. CASE DESCRIPTION: We report 2 adult patients whose imaging studies revealed epidermoid tumors located in the cerebellar vermis, an uncommon site for such tumors. The patients presented with variable symptomatology. We highlight the imaging features and challenges of surgery. Both patients had good outcomes, with resolution of symptoms and neurologic deficits. CONCLUSIONS: A safe complete excision of epidermoid tumor and its capsule is possible with a good understanding of their clinical and radiologic features and a high index of suspicion. To the best of our knowledge, this is the first report of cerebellar vermian epidermoid tumors from sub-Saharan Africa. PMID- 29410036 TI - Management of Penetrating Brain Injury Caused by a Nail Gun: Three Case Reports and Literature Review. AB - BACKGROUND: Penetrating brain injury (PBI) caused by a nail gun is an extremely rare neurosurgical emergency that poses a challenge for neurosurgeons because of its rarity and complexity. CASE DESCRIPTION: Here we present 3 cases of PBI caused by a nail gun. In the first case, the nail entered through the right parietal bone and lodged in the right parietal lobe and basal ganglia. In the second case, the nail entered through the right occipital bone and lodged in the right occipital lobe. In the third case, the nail entered through the right parietal bone and lodged in the right frontal and parietal lobes. All patients underwent surgical removal of the nail. The first patient presented with reduced left-side strength, whereas the second and third patients were neurologically intact on presentation. CONCLUSIONS: PBI caused by a nail gun can present with differing clinical manifestations, and most cases require immediate surgery. A rational management strategy should provide a good postoperative prognosis with minimal neurologic deficits in these patients. PMID- 29410037 TI - Investigation of Ethylene Oxide-co-propylene Oxide for Dissolution Enhancement of Hot-Melt Extruded Solid Dispersions. AB - The optimal design of amorphous solid dispersion formulations requires the use of excipients to maintain supersaturation and improve physical stability to ensure shelf-life stability and better absorption during intestinal transit, respectively. Blends of excipients (surfactants and polymers) are often used within pharmaceutical products to improve the oral delivery of Biopharmaceutical Classification System class II drugs. Therefore, in this study, a dissolution enhancer, poloxamer 407 (P407), was investigated to determine its effect on the dissolution properties and on the amorphous nature of the active pharmaceutical ingredient contained in the formulation. Phase solubility studies of indomethacin (INM) in aqueous solutions of P407 and poly(vinylpyrrolidone-vinyl acetate copolymer) showed an increase in the kinetic solubility of INM compared with the pure drug at 37 degrees C with a Ka value of 0.041 MUg/mL. The solid dispersions showed a higher dissolution rate when compared to pure and amorphous drugs when performed in pH buffer 1.2 with a kinetic solubility of 21 MUg/mL. The stability data showed that the amorphous drug in solid solutions with poly(vinylpyrrolidone vinyl acetate copolymer) and P407 remained amorphous, and the %P407 loading had no effect on the amorphous stability of INM. This study concluded that the amorphous solid dispersion contributed to the increased solubility of INM. PMID- 29410038 TI - Influence of Niobium Pentoxide Particulates on the Properties of Brushite/Gelatin/Alginate Membranes. AB - Novel nonporous membranes were prepared by impregnating brushite and niobium pentoxide (Nb2O5) into a gelatin/alginate matrix. The physicochemical properties, morphology, and mechanical properties of the prepared membranes were characterized using X-ray diffractometer, FTIR spectroscopy, scanning electron microscopy, transmission electron microscopy, and universal testing machine, respectively. Swelling ability of the prepared membranes was determined in distilled water. The surfaces of the membranes were characterized by means of FTIR spectroscopy and scanning electron microscopy coupled with energy dispersive x-ray spectroscopy after submersion in simulated body fluid up to 15 days. Moreover, the calcium and phosphorus ion concentrations in the simulated body fluid were measured using an UV spectrophotometer. The in vitro drug release and the release mechanism of a model antibiotic, namely, ciprofloxacin (CFX), were tested in phosphate-buffered saline for 15 days. The antibacterial activities of the CFX-loaded membranes were tested against known microorganisms. The physicochemical properties, morphology, mechanical properties, and swelling ability of the prepared membranes were found to be dependent on the presence of Nb2O5 allowing control of their properties. For example, the Nb2O5-loaded membranes exhibited a higher in vitro bioactivity and slower drug release compared to those of Nb2O5-free membranes. The CFX-loaded membranes also exhibited an excellent inhibition zones against the selected microorganisms. Overall, the prepared membranes have been found to be very promising for use in bone substitute applications. PMID- 29410039 TI - Autophagic dysfunction in patients with Papillon-Lefevre syndrome is restored by recombinant cathepsin C treatment. AB - BACKGROUND: Cathepsin C (CatC) is a lysosomal enzyme involved in activation of serine proteases from immune and inflammatory cells. Several loss-of-function mutations in the CatC gene have been shown to be the genetic mark of Papillon Lefevre syndrome (PLS), a rare autosomal recessive disease characterized by severe early-onset periodontitis, palmoplantar hyperkeratosis, and increased susceptibility to infections. Deficiencies or dysfunction in other cathepsin family proteins, such as cathepsin B or D, have been associated with autophagic and lysosomal disorders. OBJECTIVES: Here we characterized the basis for autophagic dysfunction in patients with PLS by analyzing skin fibroblasts derived from patients with several mutations in the CatC gene and reduced enzymatic activity. METHODS: Skin fibroblasts were isolated from patients with PLS assessed by using genetic analysis. Authophagic flux dysfunction was evaluated by examining accumulation of p62/SQSTM1 and a bafilomycin assay. Ultrastructural analysis further confirmed abnormal accumulation of autophagic vesicles in mutant cells. A recombinant CatC protein was produced by a baculovirus system in insect cell cultures. RESULTS: Mutant fibroblasts from patients with PLS showed alterations in oxidative/antioxidative status, reduced oxygen consumption, and a marked autophagic dysfunction associated with autophagosome accumulation. These alterations were accompanied by lysosomal permeabilization, cathepsin B release, and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Treatment of mutant fibroblasts with recombinant CatC improved cell growth and autophagic flux and partially restored lysosomal permeabilization. CONCLUSIONS: Our data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for PLS. PMID- 29410040 TI - Hereditary angioedema with normal C1 inhibitor: Four types and counting. PMID- 29410041 TI - PCR-based evidence showing the presence of Vibrio vulnificus in wound infection cases in Mangaluru, India. AB - Vibrio vulnificus is a Gram-negative, opportunistic human pathogen capable of causing life-threatening septicaemia, wound infections, and gastroenteritis, especially in immunocompromised individuals. Two cases of V. vulnificus associated wound infection occurring in diabetic patients are reported here. The pathogen was detected by PCR targeting species-specific marker gyrB and virulence markers, including repeats in toxin (rtxA) and hemolysin (vvhA), but the causative agent could not be cultured. Genotyping based on the virulence correlated gene revealed that the V. vulnificus detected in this study belonged to the vcg-C type, which is commonly associated with clinical cases. This report highlights the clinical applicability of PCR-based methods in the detection of V. vulnificus in culture-negative cases. Such methods may add a very useful clinical dimension to currently used diagnostic practices. PMID- 29410042 TI - Similar in Size But Different in Detail. PMID- 29410043 TI - Pancreatic Mass in a Patient With an Increased Serum Level of IgG4. PMID- 29410044 TI - Biomarkers in obese asthma: Age of asthma onset matters! PMID- 29410045 TI - Lifetime air pollution exposure and asthma in a pediatric birth cohort. PMID- 29410047 TI - A treat for the eyes. An eye-tracking study on children's attention to unhealthy and healthy food cues in media content. AB - Based on cue reactivity theory, food cues embedded in media content can lead to physiological and psychological responses in children. Research suggests that unhealthy food cues are represented more extensively and interactively in children's media environments than healthy ones. However, it is not clear to this date whether children react differently to unhealthy compared to healthy food cues. In an experimental study with 56 children (55.4% girls; Mage = 8.00, SD = 1.58), we used eye-tracking to determine children's attention to unhealthy and healthy food cues embedded in a narrative cartoon movie. Besides varying the food type (i.e., healthy vs. unhealthy), we also manipulated the integration levels of food cues with characters (i.e., level of food integration; no interaction vs. handling vs. consumption), and we assessed children's individual susceptibility factors by measuring the impact of their hunger level. Our results indicated that unhealthy food cues attract children's visual attention to a larger extent than healthy cues. However, their initial visual interest did not differ between unhealthy and healthy food cues. Furthermore, an increase in the level of food integration led to an increase in visual attention. Our findings showed no moderating impact of hunger. We conclude that especially unhealthy food cues with an interactive connection trigger cue reactivity in children. PMID- 29410046 TI - Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator. AB - BACKGROUND: Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids, presents a serious challenge in asthma management, particularly for steroid-resistant patients with little or no response to treatment. OBJECTIVE: We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children. METHODS: We selected 104 inhaled corticosteroid-treated asthmatic non-Hispanic white children and determined a steroid responsiveness endophenotype (SRE) using observations of 6 clinical measures over 4 years. We modeled each subject's cellular steroid response using data from a previously published study of immortalized lymphoblastoid cell lines under dexamethasone (DEX) and sham treatment. We integrated SRE with immortalized lymphoblastoid cell line DEX responses and genotypes to build a genome-scale network using the Reverse Engineering, Forward Simulation modeling framework, identifying 7 genes modulating SRE. RESULTS: Three of these genes were functionally validated by using a stable nuclear factor kappa-light-chain enhancer of activated B cells luciferase reporter in A549 human lung epithelial cells, IL-1beta cytokine stimulation, and DEX treatment. By using small interfering RNA transfection, knockdown of family with sequence similarity 129 member A (FAM129A) produced a reduction in steroid treatment response (P < .001). CONCLUSION: With this systems-based approach, we have shown that FAM129A is associated with variation in clinical asthma steroid responsiveness and that FAM129A modulates steroid responsiveness in lung epithelial cells. PMID- 29410048 TI - A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval. AB - Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 MUM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions. PMID- 29410049 TI - Sine wave electropermeabilization reveals the frequency-dependent response of the biological membranes. AB - The permeabilization of biological membranes by electric fields, known as electroporation, has been traditionally performed with square electric pulses. These signals distribute the energy applied to cells in a wide frequency band. This paper investigates the use of sine waves, which are narrow band signals, to provoke electropermeabilization and the frequency dependence of this phenomenon. Single bursts of sine waves at different frequencies in the range from 8 kHz-130 kHz were applied to cells in vitro. Electroporation was studied in the plasma membrane and the internal organelles membrane using calcium as a permeabilization marker. Additionally, a double-shell electrical model was simulated to give a theoretical framework to our results. The electroporation efficiency shows a low pass filter frequency dependence for both the plasma membrane and the internal organelles membrane. The mismatch between the theoretical response and the observed behavior for the internal organelles membrane is explained by a two-step permeabilization process: first the permeabilization of the external membrane and afterwards that of the internal membranes. The simulations in the model confirm this two-step hypothesis when a variable plasma membrane conductivity is considered in the analysis. This study demonstrates how the use of narrow-band signals as sine waves is a suitable method to perform electroporation in a controlled manner. We suggest that the use of this type of signals could bring a simplification in the investigations of the very complex phenomenon of electroporation, thus representing an interesting option in future fundamental studies. PMID- 29410051 TI - Positive Predictive Value of International Classification of Diseases, 10th Revision, Codes for Cirrhosis and Its Related Complications. AB - Large administrative databases using International Classification of Diseases (ICD) codes are useful for epidemiologic, health services, and outcomes research.1,2 However, coding accuracy of disease conditions could be a limiting factor. Cirrhosis prevalence is increasing because of an aging hepatitis C cohort and an increase in nonalcoholic steatohepatitis.3 We previously examined the validity of ICD, 9th revision (ICD-9), codes for cirrhosis in US Department of Veterans Affairs (VA) administrative databases.4,5 This work has formed the basis for many clinical, epidemiologic, and health services research studies. However, with transition from the ICD-9 to ICD, 10th revision (ICD-10), coding system, it is important to determine the validity of these new cirrhosis codes in administrative databases. Although the greater number of codes in the ICD-10 system may be associated with greater specificity and coding accuracy than with the ICD-9 system, this hypothesis remains untested. PMID- 29410050 TI - High-throughput single-cell fate potential assay of murine hematopoietic progenitors in vitro. AB - The advent of single-cell transcriptomics has led to the proposal of a number of novel high-resolution models for the hematopoietic system. Testing the predictions generated by such models requires cell fate potential assays of matching, single-cell resolution. Here we detail the development of an in vitro high-throughput single-cell culture assay using flow cytometrically sorted single murine bone marrow progenitors, which measures their differentiation into any of five myeloid lineages. We identify critical parameters for single-cell culture outcome, including the choice of sorter nozzle size and pressure, culture media, and the coating of culture dishes with extracellular matrix proteins. Further, we find that accurate assay readout requires the titration of antibodies specifically for their use under low-cell-number conditions. Our approach may be used as a template for the development of single-cell fate potential assays for a variety of blood cell progenitors. PMID- 29410052 TI - A Unique Finding of Small Intestinal Leiomyoma. PMID- 29410053 TI - An Unusual Cause of Gastric Outlet Obstruction. PMID- 29410054 TI - The influence of microsporidian pathogens from commercially available lady beetles on larval development of the green lacewing, Chrysoperla carnea, in the absence of infection. AB - In North America, more than 70 species of natural enemies are available for pest control, including the aphid predators, Adalia bipunctata L. (two-spotted lady beetle) and Hippodamia convergens Guerin-Meneville (convergent lady beetle), and the generalist predator Chrysoperla carnea Stephens (green lacewing). The two lady beetle species are known to host microsporidian pathogens: Nosema adaliae was originally described from Adalia bipunctata and Tubulinosema hippodamiae from H. convergens. Microsporidia are spore-forming pathogens that typically produce chronic, debilitating disease. Because the spores of both pathogens are transovarially transmitted through beetle eggs, the predation behavior of lacewing larvae provides an opportunity for the transmission of these pathogens when infected lady beetles and lacewings share the same local environment. In this study, uninfected and microsporidia-infected eggs from A. bipunctata and H. convergens were offered to C. carnea larvae. The development of larvae that consumed N. adaliae-infected eggs was not affected, but larval development was prolonged by almost 3 days for those that consumed two or more T. hippodamiae infected eggs. Prolonged larval development is considered to be costly because larvae remain vulnerable to cannibalization by sibling larvae or other predators. Longevity did not differ significantly between sexes of C. carnea, and the sex ratio of newly eclosed adults did not differ from the previously reported sex ratio of 1?: 1?. Upon examination by light microscopy at the end of the trial, two C. carnea larvae were infected with N. adaliae and none were infected with T. hippodamiae, suggesting that T. hippodamiae influenced lacewing larval development without establishing an infection. PMID- 29410055 TI - Jellyfish collagen: A new allergen in the beach. PMID- 29410056 TI - Evaluation of monoclonal antibodies that detect conserved proteins from Respiratory Syncytial Virus, Metapneumovirus and Adenovirus in human samples. AB - Human Respiratory Syncytial Virus (hRSV), human Metapneumovirus (hMPV) and Adenovirus (ADV), are three of the most prevalent viruses responsible for pneumonia and bronchiolitis in children and elderly worldwide, accounting for a high number of hospitalizations annually. Diagnosis of these viruses is required to take clinical actions that allow an appropriate patient management. Thereby, new strategies to design fast diagnostic methods are highly required. In the present work, six monoclonal antibodies (mAbs, two for each virus) specific for conserved proteins from hRSV, hMPV and ADV were generated and evaluated through different immunological techniques, based on detection of purified protein, viral particles and human samples. In vitro evaluation of these antibodies showed higher specificity and sensitivity than commercial antibodies tested in this study. These antibodies were used to design a sandwich ELISA tests that allowed the detection of hRSV, hMPV, and ADV in human nasopharyngeal swabs. We observed that hRSV and ADV were detected with sensitivity and specificity equivalent to a current Direct Fluorescence Assay (DFA) methodology. However, hMPV was detected with more sensitivity than DFA. Our data suggest that these new mAbs can efficiently identify infected samples and discriminate from patients infected with other respiratory pathogens. PMID- 29410057 TI - A pivotal role for NF-kappaB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid. AB - Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1beta. At high oxidant concentrations (>200 MUM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking. PMID- 29410058 TI - UPLC/Q-TOF-MS-based metabolomics study of the anti-osteoporosis effects of Achyranthes bidentata polysaccharides in ovariectomized rats. AB - Osteoporosis is a frequent disease among the elderly especially in postmenopausal women. Achyranthes bidentata is a traditional Chinese medicine used to strengthen bones. Here, A. bidentata polysaccharides (ABPs) were confirmed to have anti osteoporosis effects. This study discovered biomarkers by comparing normal and osteoporosis rats and evaluated the effects of ABPs on osteoporosis based on the UPLC/Q-TOF-MS-based metabolomics analysis. We could then predict the underlying mechanisms from the perspective of metabolomics. Osteoporotic rats were treated with ABPs, and serum was then sampled for metabolic analysis. Glutarylcarnitine, lysoPC (18:1) and 9-cis-retinoic acid were identified as biomarkers. The ABPs could significantly increase these biomarkers, and this indicated that ABPs curing osteoporosis regulated lipid metabolism. The UPLC/Q-TOF-MS-based metabolomics analysis offered a potential strategy to evaluate the anti osteoporosis effects of ABPs and to explain the relative mechanisms. Furthermore, the ABPs have good potential for treating osteoporosis. PMID- 29410060 TI - Pharmacy-level barriers to implementing expedited partner therapy in Baltimore, Maryland. AB - BACKGROUND: Addressing record high rates of Chlamydia trachomatis incidence in the United States requires the utilization of effective strategies, such as expedited partner therapy, to reduce reinfection and further transmission. Expedited partner therapy, which can be given as a prescription or medication, is a strategy to treat the sexual partners of index patients diagnosed with a sexually transmitted infection without prior medical evaluation of the partners. OBJECTIVE: There are multiple steps in the prescription-expedited partner therapy cascade, and we sought to identify pharmacy-level barriers to implementing prescription-expedited partner therapy for Chlamydia trachomatis treatment. STUDY DESIGN: We used spatial analysis and ArcGIS, a geographic information system, to map and assess geospatial access to pharmacies within Baltimore, MD, neighborhoods with the highest rates of Chlamydia trachomatis (1180.25-4255.31 per 100,000 persons). Expedited partner therapy knowledge and practices were collected via a telephone survey of pharmacists employed at retail pharmacies located in these same neighborhoods. Cost of antibiotic medication in US dollars was collected. RESULTS: Census tracts with the highest Chlamydia trachomatis incidence rates had lower median pharmacy density than other census tracts (26.9 per 100,000 vs 31.4 per 100,000, P < .001). We identified 25 pharmacy deserts. Areas defined as pharmacy deserts had larger proportions of black and Hispanic or Latino populations compared with non-Hispanic whites (93.1% vs 6.3%, P < .001) and trended toward higher median Chlamydia trachomatis incidence rates (1170.0 per 100,000 vs 1094.5 per 100,000, P = .110) than non-pharmacy desert areas. Of the 52 pharmacies identified, 96% (50 of 52) responded to our survey. Less than a fifth of pharmacists (18%, 9 of 50) were aware of expedited partner therapy for Chlamydia trachomatis. Most pharmacists (59%, 27 of 46) confirmed they would fill an expedited partner therapy prescription. The cost of a single dose of azithromycin (1 g) ranged from 5.00 to 39.99 US dollars (median, 30 US dollars). CONCLUSION: Limited geographic access to pharmacies, lack of pharmacist awareness of expedited partner therapy, and wide variation in expedited partner therapy medication cost are potential barriers to implementing prescription-expedited partner therapy. Although most Baltimore pharmacists were unaware of expedited partner therapy, they were generally receptive to learning about and filling expedited partner therapy prescriptions. This finding suggests the need for wide dissemination of educational material targeted to pharmacists. In areas with limited geographic access to pharmacies, expedited partner therapy strategies that do not depend on partners physically accessing a pharmacy merit consideration. PMID- 29410059 TI - Protective effect of low molecular-weight seleno-aminopolysaccharides against H2O2-induecd oxidative stress in intestinal epithelial cells. AB - Organoselemium compounds possess strong antioxidant activity as well as protecting cells from DNA damage, mitochondrial injury, lipid peroxidation, protein denaturation and cell death. Herein, we used an in vitro oxidative model to further investigate the antioxidant effects of a novel organoselemium compound, low molecular-weight seleno-aminopolysaccharides (LSA) in intestinal porcine epithelial cells (IPEC-1), and the molecular mechanisms of these effects. Analysis by MTT assay showed that LSA could significantly increase the viability of IPEC-1 cells compared to cells exposed to H2O2. We found that the levels of different antioxidant enzymes could dramatically increase in LSA pretreatment group compared to H2O2 treatment group. Furthermore, LSA significantly increased the gene expression of antioxidant enzymes and phase 2 detoxifying enzymes in IPEC-1 cells, as measured by qRT-PCR. In addition, LSA up-regulated the expression level of intracellular transcription factor NF-E2-related factor 2 (Nrf2) and inhibited the level of kelch-like ECH-associated protein 1 (Keap1) with western blot analysis. Collectively, the present study suggested that LSA has the protective effect of IPEC-1 cells against H2O2-induecd oxidative stress, and its mechanism may be related to activation of Keap1/Nrf2 signaling pathway in intestinal epithelial cells. PMID- 29410061 TI - US-CAB protocol for ultrasonographic evaluation during cardiopulmonary resuscitation: Validation and potential impact. AB - BACKGROUND: We previously developed a US-CAB protocol for evaluation of circulatory-airway-breathing status during cardiopulmonary resuscitation (CPR). This study aimed at validating its application in real CPR scenarios and the potential impact on CPR outcomes. METHODS: The US-CAB protocol was implemented at the emergency department of National Taiwan University Hospital since January 2016. The US images, initiation time and operation duration of each US-CAB procedure, and relevant CPR information were recorded for analysis. RESULTS: From January 2016 to March 2017, 177 cardiac arrest patients receiving US-CAB were included. The durations of US-C-A-B procedure were 9.0 +/- 1.4, 7.5 +/- 1.5, and 16.0 +/- 1.9 s, respectively. Cardiac activity was identified in 47 cases (26.6%), with higher rates of return of spontaneous circulation (ROSC) (95.7% vs. 21.5%, p < .0001) and survival to hospital discharge (25.5% vs. 10.0%, p < .01). Detection of cardiac activity after 10 min of CPR exhibited 100% sensitivity, specificity, positive and negative predictive value for ROSC. Cardiac tamponade was noted in eight patients. ROSC was achieved in two (25.0%) after pericardiocentesis, and aortic dissection was diagnosed in one (12.5%). Confirmation of correct intubation was significantly faster by US than by capnography (7.4 +/- 1.4 vs. 38.3 +/- 110.2 s, p < .001). US detected 21 (11.9%) esophageal intubations and 3 (1.7%) one-lung intubations. All were promptly corrected. CONCLUSION: The US-CAB protocol is feasible in real CPR scenarios. It confers diagnostic value and prognostic implications which potentially impact the efficacy and outcomes of CPR. However, a future prospective multi-center study to validate its feasibility and indicate the need of structured training is mandated. PMID- 29410062 TI - Micro and nanotechnologies for bone regeneration: Recent advances and emerging designs. AB - Treatment of critical-size bone defects is a major medical challenge since neither the bone tissue can regenerate nor current regenerative approaches are effective. Emerging progresses in the field of nanotechnology have resulted in the development of new materials, scaffolds and drug delivery strategies to improve or restore the damaged tissues. The current article reviews promising nanomaterials and emerging micro/nano fabrication techniques for targeted delivery of biomolecules for bone tissue regeneration. In addition, recent advances in fabrication of bone graft substitutes with similar properties to normal tissue along with a brief summary of current commercialized bone grafts have been discussed. PMID- 29410063 TI - Meningioma assessment: Kinetic parameters in dynamic contrast-enhanced MRI appear independent from microvascular anatomy and VEGF expression. AB - BACKGROUND AND PURPOSE: Kinetic parameters of T1-weighted dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) are considered to be influenced by microvessel environment. This study was performed to explore the extent of this association for meningiomas. MATERIALS AND METHODS: DCE-MRI kinetic parameters (contrast agent transfer constants Ktrans and kep, volume fractions vp and ve) were determined in pre-operative 3T MRI of meningioma patients for later biopsy sites (19 patients; 15 WHO Io, no previous radiation, and 4 WHO IIIo pre-radiated recurrent tumors). Sixty-three navigated biopsies were consecutively retrieved. Biopsies were immunohistochemically investigated with endothelial marker CD34 and VEGF antibodies, stratified in a total of 4383 analysis units and computationally assessed for VEGF expression and vascular parameters (vessel density, vessel quantity, vascular fraction within tissue [vascular area ratio], vessel wall thickness). Derivability of kinetic parameters from VEGF expression or microvascularization was determined by mixed linear regression analysis. Tissue kinetic and microvascular parameters were tested for their capacity to identify the radiation status in a subanalysis. RESULTS: Kinetic parameters were neither significantly related to the corresponding microvascular parameters nor to tissue VEGF expression. There was no significant association between microvessel density and its presumed correlate vp (P=0.07). The subgroup analysis of high-grade radiated meningiomas showed a significantly reduced microvascular density (AUC 0.91; P<0.0001) and smaller total vascular fraction (AUC 0.73; P=0.01). CONCLUSIONS: In meningioma, DCE-MRI kinetic parameters neither allow for a reliable prediction of tumor microvascularization, nor for a prediction of VEGF expression. Kinetic parameters seem to be determined from different independent factors. PMID- 29410064 TI - ICAM-1 upregulation is not required for retinoic acid-induced human eosinophil survival. AB - Active metabolites of vitamin A, retinoic acids (RAs), are known to play critical roles in mucosal immune responses and dramatically inhibit human eosinophil apoptosis, but the detailed mechanisms have not been elucidated. We previously screened for ICAM-1 (CD54) upregulation in RA-stimulated human eosinophils by gene microarray analysis. As ICAM-1 induction and activation were observed to have a role in maintenance of eosinophil survival, we tested the hypothesis that RAs prolong eosinophil survival through ICAM-1 outside-in signaling. Blood derived isolated eosinophils cultured with 9-cis RA and all-trans RA showed significant upregulation of ICAM-1 mRNA and cell surface expression. TTNPB, a retinoic acid receptor agonist, also induced ICAM-1 expression, while HX630, a retinoid X receptor agonist, did not. Furthermore, an RAR antagonist, HX531, completely inhibited the effect of RAs. Upregulated ICAM-1 was associated with altered kinetics of Akt, ERK, and p38 MAP kinase phosphorylation through ICAM-1 cross-linking, but an ICAM-1-blocking antibody did not affect RA-mediated cell survival. These findings indicate that RAs induce functional ICAM-1 expression through RARs, but the induced ICAM-1 does not contribute to prolongation of eosinophil survival. PMID- 29410065 TI - Reply to: "Liver resection for BCLC 0-A stage hepatocellular carcinoma: Does the time to surgery not impact the prognosis". PMID- 29410066 TI - Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis. AB - Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease. PMID- 29410067 TI - Single-cell Transcriptome Analyses Reveal Molecular Signals to Intrinsic and Acquired Paclitaxel Resistance in Esophageal Squamous Cancer Cells. AB - Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel. Gene expression profiles were measured utilizing population RNA-seq and single-cell RNA-seq (scRNA-seq). 37 single cells from KYSE-30 cells and 73 single cells from paclitaxel resistant KYSE-30 cells (Taxol-R) were subjected to scRNA-seq. Weighted gene co-expression network analysis (WGCNA) of scRNA-seq data revealed two major subpopulations in both KYSE-30 and Taxol-R cancer cells. Two subpopulations based on the KRT19 expression levels in KYSE-30 cells exhibited different paclitaxel sensitivity, suggesting the existence of an intrinsic paclitaxel resistance in KYSE-30 cells. In addition, the Taxol-R cells that acquired the resistance to paclitaxel through induction were characterized with higher expressions of proteasomes but a lower expression of HIF-1 signaling genes. Furthermore, we showed that carfilzomib (CFZ), a proteasome inhibitor, could attenuate the paclitaxel resistance in Taxol-R cancer cells through activating the HIF-1 signaling. Our new finding may pave a way leading to an improvement in the treatment on cancers including ESCC by combining CFZ with paclitaxel as a novel approach for cancer therapy. PMID- 29410068 TI - Thermal behavior remains engaged following exercise despite autonomic thermoeffector withdrawal. AB - We tested the hypothesis that thermal behavior during the exercise recovery compensates for elevated core temperatures despite autonomic thermoeffector withdrawal. In a thermoneutral environment, 6 females and 6 males (22 +/- 1 y) cycled for 60 min (225 +/- 46 W metabolic heat production), followed by 60 min passive recovery. Mean skin and core temperatures, skin blood flow, and local sweat rate were measured continually. Subjects controlled the temperature of their dorsal neck to perceived thermal comfort using a custom-made neck device. Neck device temperature provided an index of thermal behavior. Mean body temperature, calculated as the average of mean skin and core temperatures, provided an index of the stimulus for thermal behavior. To isolate the independent effect of exercise on thermal behavior during recovery, data were analyzed post-exercise the exact minute mean body temperature recovered to pre exercise levels within a subject. Mean body temperature returned to pre-exercise levels 28 +/- 20 min into recovery (Pre: 33.5 +/- 0.2, Post: 33.5 +/- 0.2 degrees C, P = 0.20), at which point, mean skin temperature had recovered (Pre: 29.6 +/- 0.4, Post: 29.5 +/- 0.5 degrees C, P = 0.20) and core temperature (Pre: 37.3 +/- 0.2, Post: 37.5 +/- 0.3 degrees C, P = 0.01) remained elevated. Post exercise, skin blood flow (Pre: 59 +/- 78, Post: 26 +/- 25 PU, P = 0.10) and local sweat rate (Pre: 0.05 +/- 0.25, Post: 0.13 +/- 0.14 mg/cm2 min-1, P = 0.09) returned to pre-exercise levels, while neck device temperature was depressed (Pre: 27.4 +/- 1.1, Post: 21.6 +/- 7.4 degrees C, P = 0.03). These findings suggest that thermal behavior compensates for autonomic thermoeffector withdrawal in the presence of elevated core temperatures post-exercise. PMID- 29410070 TI - The neuroimaging basis of apathy: Empirical findings and conceptual challenges. AB - Apathy, usually defined as loss of motivation, is common in both neurodegenerative conditions such as Alzheimer's disease, and acute neurological disorders such as stroke. Neuroradiological studies on the imaging correlates of apathy have used a variety of methods such as structural and functional magnetic resonance imaging, diffusion tensor imaging, and single photon and positron emission tomography to assess brain metabolic activity and specific synaptic receptors. Dysfunction of the anterior cingulate cortex (ACC) is the strongest anatomical correlate of apathy in Alzheimer's disease, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders. These findings should be considered in the context of important conceptual and empirical limitations. There are diverging definitions of apathy, and this behavioural disorder has not yet been validated in most neurological conditions. Moreover, apathy may be related not only to specific brain dysfunction, but to relevant contextual confounders which deserve further study. PMID- 29410069 TI - In vitro identification of mitochondrial oxidative stress production by time resolved fluorescence imaging of glioma cells. AB - Oxidative phosphorylation and glycolysis are important features, by which cells could bypass oxidative stress. The level of oxidative stress, and the ability of cells to promote oxidative phosphorylation or glycolysis, significantly determined proliferation or cell demise. In the present work, we have employed selective mitochondrial probe MitoTrackerTM Orange CMTM/Ros (MTO) to estimate the level of oxidative stress in cancer cells at different stressed conditions. MTO is partially sensitive to decrease of mitochondrial membrane potential and to reactive oxygen species (ROS) generated in mitochondria. We have demonstrated, that fluorescence lifetime of MTO is much more sensitive to oxidative stress than intensity-based approaches. This method was validated in different cancer cell lines. Our approach revealed, at relatively low ROS levels, that Go 6976, a protein kinase C (PKC) alpha inhibitor, and rottlerin, an indirect PKCdelta inhibitor, increased mitochondrial ROS level in glioma cell. Their involvement in oxidative phosphorylation and apoptosis was investigated with oxygen consumption rate estimation, western blot and flow-cytometric analysis. Our study brings new insight to identify feeble differences in ROS production in living cells. PMID- 29410071 TI - The Growing Demand for Hospice and Palliative Medicine Physicians: Will the Supply Keep Up? AB - CONTEXT: The need for hospice and palliative care is growing rapidly as the population increases and ages and as both hospice and palliative care become more accepted. Hospice and palliative medicine (HPM) is a relatively new physician specialty, currently training 325 new fellows annually. Given the time needed to increase the supply of specialty-trained physicians, it is important to assess future needs to guide planning for future training capacity. OBJECTIVES: We modeled the need for and supply of specialist HPM physicians through the year 2040 to determine whether training capacity should continue growing. METHODS: To create a benchmark for need, we used a population-based approach to look at the current geographic distribution of the HPM physician supply. To model future supply, we calculated the annual change in current supply by adding newly trained physicians and subtracting physicians leaving the labor force. RESULTS: The current U.S. supply of HPM specialists is 13.35 per 100,000 adults 65 and older. This ratio varies greatly across the country. Using alternate assumptions for future supply and demand, we project that need in 2040 will range from 10,640 to almost 24,000 HPM specialist physicians. Supply will range from 8100 to 19,000. CONCLUSION: Current training capacity is insufficient to keep up with population growth and demand for services. HPM fellowships would need to grow from the current 325 graduates annually to between 500 and 600 per year by 2030 to assure sufficient physician workforce for hospice and palliative care services given current service provision patterns. PMID- 29410072 TI - Effect of alkanol surface grafting on the hydrophobicity of starch-based films. AB - The surface hydrophobicity of starch-based films could be regulated using a two step surface modification method. Such modification was realized by grafting with alkanols of different chain lengths (hexanol, dodecanol and octadecanol) on the surface of starch-based films. The grafting of alkanol increased the mobility of glycerol as the plasticizer within the film surface. Also, this grafting increased the mass ratio of carbon to oxygen on the film surface but reduced the mass ratio of carbon to nitrogen. Under the same reaction conditions, there were fewer dodecyl chains grafted onto the film surface than hexyl or octadecyl chains. Furthermore, the results revealed that the surface hydrophobicity of starch-based films could be enhanced by simply increasing the alkyl chain length. Also, fewer alkyl chains tended to reduce the surface hydrophobicity of the films. These results are valuable for the rational design of starch-based materials with demanded hydrophobic properties. PMID- 29410073 TI - The receptor tyrosine kinase ERBB4 is expressed in skin keratinocytes and influences epidermal proliferation. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) and associated receptors ERBB2 and ERBB3 are important for skin development and homeostasis. To date, ERBB4 could not be unambiguously identified in the epidermis. The aim of this study was to analyze the ERBB-receptor family with a special focus on ERBB4 in vitro in human keratinocytes and in vivo in human and murine epidermis. METHODS: We compared the transcript levels of all ERBB-receptors and the seven EGFR ligands in HaCaT and A431 cells. ERBB-receptor activity was analyzed after epidermal growth factor (EGF) stimulation by Western blot analysis. The location of the receptors was investigated by immunofluorescence in human keratinocytes and skin. Finally, we investigated the function of ERBB4 in the epidermis of skin specific ERBB4-knockout mice. RESULTS: After EGF stimulation, all ligands were upregulated except for epigen. Expression levels of EGFR were unchanged, but all other ERBB-receptors were down-regulated after EGF stimulation, although all ERBB receptors were phosphorylated. We detected ERBB4 at mRNA and protein levels in both human epidermal cell lines and in the basal layer of human and murine epidermis. Skin-specific ERBB4-knockout mice revealed a significantly reduced epidermal thickness with a decreased proliferation rate. CONCLUSIONS: ERBB4 is expressed in the basal layer of human epidermis and cultured keratinocytes as well as in murine epidermis. Moreover, ERBB4 is phosphorylated in HaCaT cells due to EGF stimulation, and its deletion in murine epidermis affects skin thickness by decreasing proliferation. GENERAL SIGNIFICANCE: ERBB4 is expressed in human keratinocytes and plays a role in murine skin homeostasis. PMID- 29410074 TI - The relative composition of actin isoforms regulates cell surface biophysical features and cellular behaviors. AB - BACKGROUND: Cell surface mechanics is able to physically and biomechanically affect cell shape and motility, vesicle trafficking and actin dynamics. The biophysical properties of cell surface are strongly influenced by cytoskeletal elements. In mammals, tissue-specific expression of six actin isoforms is thought to confer differential biomechanical properties. However, the relative contribution of actin isoforms to cell surface properties is not well understood. Here, we sought to investigate whether and how the composition of endogenous actin isoforms directly affects the biomechanical features of cell surface and cellular behavior. METHODS: We used fibroblasts isolated from wild type (WT), heterozygous (HET) and from knockout (KO) mouse embryos where both beta-actin alleles are not functional. We applied a combination of genome-wide analysis and biophysical methods such as RNA-seq and atomic force microscopy. RESULTS: We found that endogenous beta-actin levels are essential in controlling cell surface stiffness and pull-off force, which was not compensated by the up-regulation of other actin isoforms. The variations of surface biophysical features and actin contents were associated with distinct cell behaviors in 2D and 3D WT, HET and KO cell cultures. Since beta-actin in WT cells and smooth muscle alpha-actin up regulated in KO cells showed different organization patterns, our data support the differential localization and organization as a mechanism to regulate the biophysical properties of cell surface by actin isoforms. CONCLUSIONS: We propose that variations in actin isoforms composition impact on the biophysical features of cell surface and cause the changes in cell behavior. PMID- 29410075 TI - The small molecule CS1 inhibits mitosis and sister chromatid resolution in HeLa cells. AB - BACKGROUND: Mitosis, the most dramatic event in the cell cycle, involves the reorganization of virtually all cellular components. Antimitotic agents are useful for dissecting the mechanism of this reorganization. Previously, we found that the small molecule CS1 accumulates cells in G2/M phase [1], but the mechanism of its action remains unknown. METHODS: Cell cycle analysis, live cell imaging and nuclear staining were used. Chromosomal morphology was detected by chromosome spreading. The effects of CS1 on microtubules were confirmed by tubulin polymerization, colchicine tubulin-binding, cellular tubulin polymerization and immunofluorescence assays and by analysis of microtubule dynamics and molecular modeling. Histone phosphoproteomics was performed using mass spectrometry. Cell signaling cascades were analyzed using immunofluorescence, immunoprecipitation, immunoblotting, siRNA knockdown and chemical inhibition of specific proteins. RESULTS: The small molecule CS1 was shown to be an antimitotic agent. CS1 potently inhibited microtubule polymerization via interaction with the colchicine-binding pocket of tubulin in vitro and inhibited the formation of the spindle apparatus by reducing the bulk of growing microtubules in HeLa cells, which led to activation of the spindle assembly checkpoint (SAC) and mitotic arrest of HeLa cells. Compared with colchicine, CS1 impaired the progression of sister chromatid resolution independent of cohesin dissociation, and this was reversed by the removal of CS1. Additionally, CS1 induced unique histone phosphorylation patterns distinct from those induced by colchicine. CONCLUSIONS AND SIGNIFICANCE: CS1 is a unique antimitotic small molecule and a powerful tool with unprecedented value over colchicine that makes it possible to specifically and conditionally perturb mitotic progression. PMID- 29410076 TI - A kinetic-based safety assessment of consumer exposure to salicylic acid from cosmetic products demonstrates no evidence of a health risk from developmental toxicity. AB - Salicylic acid (SA) has a long history of safe use as ingredient in topical cosmetic products. In 2016, the Committee for Risk Assessment of the European Chemicals Agency proposed to classify SA as a Category 2 reproductive toxicant based on adverse developmental effects in animal toxicity studies. This hazard based classification (based on mg/kg doses) requires a reassessment of the safety of the current SA concentrations in cosmetic consumer products. Herein, a safety reassessment was performed in which margins of safety were calculated based on literature data on the NOAEL plasma exposure levels from animal reproductive toxicity studies with ASA (rapidly converts to SA in plasma), human SA plasma levels from oral exposure to ASA and human dermal exposure to SA-containing cosmetic products. In addition, a literature review was performed, which shows that there are no adverse developmental effects despite extensive human clinical oral use of ASA up to the maximum recommended therapeutic doses. The plasma exposure-based safety assessment for SA combined with an absence of any clinical health risk with oral ASA use in the literature supports that there is an acceptable margin of safety for the consumer exposure to SA as authorized in the current EU cosmetic regulation. PMID- 29410077 TI - Simplified internal fixation of fifth metacarpal neck fractures. AB - BACKGROUND: Fifth metacarpal neck fractures (boxer's fractures) are common injuries that contribute 20% of all hand fractures. Divergent percutaneous pinning (bouquet fixation) as described by Foucher has gained popularity but is challenging and at times arduous, as it requires the insertion of several slender K-wires into a narrow medullary canal. Here, we report on a simplified technique in which a single thick K-wire is inserted. TECHNIQUE: An 18/10 K-wire is bent at one end then mounted on a drill chuck. The incision is performed and the entry hole created using the K-wire, which is then advanced along the medullary canal. After reduction of the metacarpal head using the Jahss manoeuvre, the K-wire is inserted across the fracture site into the subchondral bone. Any persistent rotational malalignment is corrected by rotating the metacarpal around the K wire. Immobilisation is by buddy taping covered by a resin guard. METHODS: We collected follow-up data for 30 patients treated using our technique, at a mean age of 32 years. RESULTS: 90 days after surgery, the fracture was healed in all patients. No patients had rotational malalignment. Mean operative time was 14minutes. No complications were recorded. DISCUSSION: The use of a single thick K-wire proved simple, effective, reproducible, and rapid. No rotational malalignment occurred. This technique is faster and easier to perform than divergent pinning with multiple K-wires. CONCLUSION: This technique can be used to treat fifth metacarpal neck fractures. PMID- 29410078 TI - A common brain network among state, trait, and pathological anxiety from whole brain functional connectivity. AB - Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a brain network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related brain network derived from whole brain. We first conducted the anxiety provocation task with healthy participants who tended to feel anxiety related to obsessive-compulsive disorder (OCD) in their daily life. We found a common state anxiety brain network across participants (1585 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants' behavioral trait anxiety scale scores (879 participants from the Human Connectome Project), we demonstrated that trait anxiety shared the same brain network as state anxiety. Furthermore, the brain network between common to state and trait anxiety could detect patients with OCD, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety. PMID- 29410079 TI - The Marburg-Munster Affective Disorders Cohort Study (MACS): A quality assurance protocol for MR neuroimaging data. AB - Large, longitudinal, multi-center MR neuroimaging studies require comprehensive quality assurance (QA) protocols for assessing the general quality of the compiled data, indicating potential malfunctions in the scanning equipment, and evaluating inter-site differences that need to be accounted for in subsequent analyses. We describe the implementation of a QA protocol for functional magnet resonance imaging (fMRI) data based on the regular measurement of an MRI phantom and an extensive variety of currently published QA statistics. The protocol is implemented in the MACS (Marburg-Munster Affective Disorders Cohort Study, http://for2107.de/), a two-center research consortium studying the neurobiological foundations of affective disorders. Between February 2015 and October 2016, 1214 phantom measurements have been acquired using a standard fMRI protocol. Using 444 healthy control subjects which have been measured between 2014 and 2016 in the cohort, we investigate the extent of between-site differences in contrast to the dependence on subject-specific covariates (age and sex) for structural MRI, fMRI, and diffusion tensor imaging (DTI) data. We show that most of the presented QA statistics differ severely not only between the two scanners used for the cohort but also between experimental settings (e.g. hardware and software changes), demonstrate that some of these statistics depend on external variables (e.g. time of day, temperature), highlight their strong dependence on proper handling of the MRI phantom, and show how the use of a phantom holder may balance this dependence. Site effects, however, do not only exist for the phantom data, but also for human MRI data. Using T1-weighted structural images, we show that total intracranial (TIV), grey matter (GMV), and white matter (WMV) volumes significantly differ between the MR scanners, showing large effect sizes. Voxel-based morphometry (VBM) analyses show that these structural differences observed between scanners are most pronounced in the bilateral basal ganglia, thalamus, and posterior regions. Using DTI data, we also show that fractional anisotropy (FA) differs between sites in almost all regions assessed. When pooling data from multiple centers, our data show that it is a necessity to account not only for inter-site differences but also for hardware and software changes of the scanning equipment. Also, the strong dependence of the QA statistics on the reliable placement of the MRI phantom shows that the use of a phantom holder is recommended to reduce the variance of the QA statistics and thus to increase the probability of detecting potential scanner malfunctions. PMID- 29410080 TI - Incremental yield of dysplasia detection in Barrett's esophagus using volumetric laser endomicroscopy with and without laser marking compared with a standardized random biopsy protocol. AB - BACKGROUND AND AIMS: Volumetric laser endomicroscopy (VLE) is a new wide-field advanced imaging technology for Barrett's esophagus (BE). No data exist on incremental yield of dysplasia detection. Our aim is to report the incremental yield of dysplasia detection in BE using VLE. METHODS: This is a retrospective study from a prospectively maintained database from 2011 to 2017 comparing the dysplasia yield of 4 different surveillance strategies in an academic BE tertiary care referral center. The groups were (1) random biopsies (RB), (2) Seattle protocol random biopsies (SP), (3) VLE without laser marking (VLE), and (4) VLE with laser marking (VLEL). RESULTS: A total of 448 consecutive patients (79 RB, 95 SP, 168 VLE, and 106 VLEL) met the inclusion criteria. After adjusting for visible lesions, the total dysplasia yield was 5.7%, 19.6%, 24.8%, and 33.7%, respectively. When compared with just the SP group, the VLEL group had statistically higher rates of overall dysplasia yield (19.6% vs 33.7%, P = .03; odds ratio, 2.1, P = .03). Both the VLEL and VLE groups had statistically significant differences in neoplasia (high-grade dysplasia and intramucosal cancer) detection compared with the SP group (14% vs 1%, P = .001 and 11% vs 1%, P = .003). CONCLUSION: A surveillance strategy involving VLEL led to a statistically significant higher yield of dysplasia and neoplasia detection compared with a standard random biopsy protocol. These results support the use of VLEL for surveillance in BE in academic centers. PMID- 29410081 TI - The Impact of Preoperative alpha-Adrenergic Antagonists on Ureteral Access Sheath Insertion Force and the Upper Limit of Force Required to Avoid Ureteral Mucosal Injury: A Randomized Controlled Study. AB - PURPOSE: Excessive bulking force during primary access of the ureteral access sheath may induce ureteral injury. We investigated the efficacy of preoperative alpha-blockade to reduce ureteral access sheath insertion force and determine the upper limit required to avoid ureteral injury. MATERIALS AND METHODS: In this randomized controlled trial 135 patients from a single institution who had ureteropelvic junction or renal pelvis stones and were scheduled to undergo retrograde intrarenal surgery were prospectively enrolled from December 2015 to January 2017. Of the patients 41 and 42 were randomly assigned to the control and experimental groups, respectively. The experimental group received alpha-blockade preoperatively. The 21 patients who were pre-stented were assessed separately. We developed a homemade device to measure maximal ureteral access sheath insertion force. RESULTS: Our ureteral access sheath insertion force measurement device showed excellent reproducibility. Higher insertion velocity resulted in greater maximal sheath insertion force. Maximal insertion force in the alpha-blockade group was significantly lower than in the control group at the ureterovesical junction (p = 0.008) and the proximal ureter (p = 0.036). Maximal insertion force in the alpha-blockade group was comparable to that in pre-stented patients. Female patients and patients 70 years old or older showed a lower maximal ureteral access sheath insertion force than their counterparts. The rate of grade 2 or greater ureteral injury was lower in the alpha-blockade group than in controls (p = 0.038). No injury occurred in any case in which ureteral access sheath insertion force did not exceed 600 G. CONCLUSIONS: Preoperative alpha blockade and slow sheath placement may reduce maximal ureteral access sheath insertion force. If the force exceeds 600 G, a smaller diameter sheath may be an alternative. Alternatively the procedure can be terminated and followed later by pre-stented retrograde intrarenal surgery. PMID- 29410082 TI - Cholesterol internalization and metabolism in insect prothoracic gland, a steroidogenic organ, via lipoproteins. AB - Dietary sterols including cholesterol and phytosterols are essential substrates for insect steroid hormone (ecdysteroid) synthesis in the prothoracic glands (PGs). In the silkworm Bombyx mori, one of the model species of insects, the steroidogenesis has been well demonstrated that cholesterol biotransformation into ecdysone in the PG cells. Because insects lack the ability to synthesize cellular sterol de novo, lipoprotein, lipophorin (Lp), has been thought to be the major cholesterol supply source; however, details of cholesterol behavior from Lp to the PG cells has not been analyzed till date. In this report, we developed Lp incorporation method using labeled cholesterols such as 22-NBD-cholesterol and cholesterol-25,26,26,26,27,27,27-d7 (cholesterol-d7), and analyzed the internalization and metabolism of cholesterol in PGs in vitro using the silkworm Bombyx mori. The internalization of cholesterol was visualized using 22-NBD cholesterol. PGs showed an enriched cellular 22-NBD-cholesterol signal, which dissociated from the Lp localizing at the close area of cell membrane. The distribution pattern observed in the PGs was different from other tissues such as the brain, fat body, and Malpighian tubules, suggesting that the internalization of cholesterol in the PGs was distinct from other tissues. The metabolism of cholesterol was traced using LC-MS/MS methods to detect cholesterol-d7, 7 dehydrocholesterol-d7 (an expected intermediate metabolite), and the final product ecdysone-d6. 7-Dehydrocholesterol-d7 and ecdysone-d6 were detected in the PG culture incubated with labeled Lp, showing that the cholesterol of Lp was utilized for ecdysone synthesis in the PGs. Our results reveal the distinct behavior of cholesterol in the PGs, with the first direct evidence of biochemical fate of lipoprotein cholesterol in insect steroidogenic organ. This will aid in the understanding of the involvement of lipoprotein cholesterol in steroid hormone synthesis in insects. PMID- 29410083 TI - Transient expression of a bovine leukemia virus envelope glycoprotein in plants by a recombinant TBSV vector. AB - Plants offer a unique combination of advantages for the production of valuable recombinant proteins in a relatively short time. For instance, a variety of diagnostic tests have been developed that use recombinant antigens expressed in plants. The envelope glycoprotein gp51 encoded by Bovine leukemia virus (BLV) is one of the essential subunits for viral infectivity. It was indicated that the recombinant gp51 (rgp51) of BLV san be used as an synthetic alternative antigen useful in the diagnosis of BLV infection in cattle. Here we evaluate the potential for using a viral vector based on the genome of Tomato bushy stunt virus (TBSV) for the efficient expression of BLV envelope glycoprotein rgp51 in Nicotiana benthamiana plants. The codon-optimized gene encoding rgp51 was synthesized by the de novo DNA synthesis to replace the GFP gene in the TBSV derived viral vector that was then delivered into 4-5 week old N. benthamiana plants by agroinfiltration. Expression of recombinant his-tagged rgp51 was verified by protein extraction followed by western blot procedures, and by purification using Ni2+-affinity chromatography. The molecular weight of this plant-expressed rgp51 ranged from 43 to 55 kDa and it was shown to be glycosylated. Important for potential use in diagnostic tests, purified rgp51 specifically reacted with BLV infected bovine sera while no reaction was observed with the negative serum samples. PMID- 29410085 TI - Journal of Structural Biology - Paper of the year 2017. PMID- 29410084 TI - Measles-derived vaccines to prevent emerging viral diseases. AB - Infectious disease epidemics match wars and natural disasters in their capacity to threaten lives and damage economies. Like SARS previously and Zika recently, the Ebola crisis in 2015 showed how vulnerable the world is to these epidemics, with over 11,000 people dying in the outbreak. In addition to causing immense human suffering, these epidemics particularly affect low- and middle-income countries. Many of these deadly infectious diseases that have epidemic potential can become global health emergencies in the absence of effective vaccines. But very few vaccines against these threats have been developed to create proven medical products. The measles vaccine is an efficient, live attenuated, replicating virus that has been safely administered to 2 billion children over the last 40 years, affording life-long protection after a single dose. Taking advantage of these characteristics, this attenuated virus was transformed into a versatile chimeric or recombinant vaccine vector with demonstrated proof-of principle in humans and a preclinical track record of rapid adaptability and effectiveness for a variety of pathogens. Clinical trials have shown the safety and immunogenicity of this vaccine platform in individuals with preexisting immunity to measles. This review describes the potential of this platform to develop new vaccines against emerging viral diseases. PMID- 29410086 TI - Apoptosome formation upon overexpression of native and truncated Apaf-1 in cell free and cell-based systems. AB - Apaf-1 is a cytosolic multi-domain protein in the apoptosis regulatory network. When cytochrome c releases from mitochondria; it binds to WD-40 repeats of Apaf-1 molecule and induces oligomerization of Apaf-1. Here in, a split luciferase assay was used to compare apoptosome formation in cell-free and cell-based systems. This assay uses Apaf-1 tagged with either N-terminal fragment or C-terminal fragment of P. pyralis luciferase. In cell based-system, the apoptosome formation is induced inside the cells which express Apaf-1 tagged with complementary fragments of luciferase while in cell-free system, the apoptosome formation is induced in extracts of the cells. In cell-free system, cytochrome c dependent luciferase activity was observed with full length Apaf-1. However, luciferase activity due to apoptosome formation was much higher in cell based system compared to cell-free system. The truncated Apaf-1 which lacks WD-40 repeats (DeltaApaf-1) interacted with endogenous Apaf-1 in a different fashion compared to native form as confirmed by different retention time of eluate in gel filtration and binding to affinity column. The interactions between endogenous Apaf-1 and DeltaApaf-1 is stronger than its interaction with native exogenous Apaf-1 as indicated by dominant negative effect of DeltaApaf-1 on caspase-3 processing. PMID- 29410087 TI - Characteristics of Unscheduled and Scheduled Outpatient Palliative Care Clinic Patients at a Comprehensive Cancer Center. AB - CONTEXT: There is limited literature regarding outpatient palliative care and factors associated with unscheduled clinic visits. OBJECTIVES: To compare characteristics of patients with unscheduled vs. scheduled outpatient palliative care clinic visits. METHODS: Medical records of 183 unscheduled cancer new outpatients and 104 unscheduled follow-up (FU) patients were compared with random samples of 361 and 314 scheduled new patients and FU patients, respectively. We gathered data on demographics, symptoms, daily opioid usage, and performance status. RESULTS: Compared with scheduled new patients, unscheduled new patients had worse Edmonton Symptom Assessment Scale subscores for pain (P < 0.001), fatigue (P = 0.002), nausea (P = 0.016), depression (P = 0.003), anxiety (P = 0.038), drowsiness (P = 0.002), sleep (P < 0.001), and overall feeling of well being (P = 0.001); had a higher morphine equivalent daily dose of opioids (median of 45 mg for unscheduled vs. 30 mg for scheduled; P < 0.001); and were more likely to be from outside the greater Houston area (P < 0.001). Most unscheduled and scheduled new and FU visits were for uncontrolled physical symptoms. Unscheduled FU patients, compared with scheduled FU patients, had worse Edmonton Symptom Assessment Scale subscores for pain (P < 0.001), fatigue (P < 0.001), depression (P = 0.002), anxiety (P = 0.004), drowsiness (P = 0.010), appetite (P = 0.023), sleep (P = 0.022), overall feeling of well-being (P < 0.001), and higher morphine equivalent daily dose of opioid (median of 58 mg for unscheduled FU visits vs. 40 mg for scheduled FU visits; P = 0.054). CONCLUSION: Unscheduled new FU patients have higher levels of physical and psychosocial distress and higher opioid intake. Outpatient palliative care centers should consider providing opportunities for walk-in visits for timely management and close monitoring of such patients. PMID- 29410088 TI - Mapping Interactions between p27 and RhoA that Stimulate Cell Migration. AB - p27 mediates cell cycle arrest by binding to and inhibiting cyclin-dependent kinase/cyclin complexes, but p27 can also contribute to pro-oncogenic signaling upon mislocalization to the cytoplasm. Cytoplasmic p27 stimulates cell migration by associating with RhoA and interfering with the exchange of GDP from RhoA stimulated by guanine nucleotide exchange factors. We used biophysical methods to show that the N-terminus of p27 directly interacts with RhoA in vitro. The affinity of p27 for RhoA is low, with an equilibrium dissociation constant of hundreds of micromolar; however, at high concentrations, p27 interfered with guanine nucleotide exchange factor-mediated nucleotide exchange from RhoA. We also show that promotion of cell migration in scratch wound cell healing assays requires full-length p27 despite the C-terminus being dispensable for the direct interaction between p27 and RhoA in vitro. These results suggest that there may be an unidentified factor(s) that associates with the C-terminus of p27 to enhance its interactions with RhoA and promote cell migration. PMID- 29410089 TI - Linking multiscale deformation to microstructure in cortical bone using in situ loading, digital image correlation and synchrotron X-ray scattering. AB - : The incidence of fragility fractures is expected to increase in the near future due to an aging population. Therefore, improved tools for fracture prediction are required to treat and prevent these injuries efficiently. For such tools to succeed, a better understanding of the deformation mechanisms in bone over different length scales is needed. In this study, an experimental setup including mechanical tensile testing in combination with digital image correlation (DIC) and small/wide angle X-ray scattering (SAXS/WAXS) was used to study deformation at multiple length scales in bovine cortical bone. Furthermore, micro-CT imaging provided detailed information about tissue microstructure. The combination of these techniques enabled measurements of local deformations at the tissue- and nanoscales. The orientation of the microstructure relative to the tensile loading was found to influence the strain magnitude on all length scales. Strains in the collagen fibers were 2-3 times as high as the strains found in the mineral crystals for samples with microstructure oriented parallel to the loading. The local tissue strain at fracture was found to be around 0.5%, independent of tissue orientation. However, the maximum force and the irregularity of the crack path were higher when the load was applied parallel to the tissue orientation. This study clearly shows the potential of combining these different experimental techniques concurrently with mechanical testing to gain a better understanding of bone damage and fracture over multiple length scales in cortical bone. STATEMENT OF SIGNIFICANCE: To understand the pathophysiology of bone, it is important to improve our knowledge about the deformation and fracture mechanisms in bone. In this study, we combine several recently available experimental techniques with mechanical loading to investigate the deformation mechanisms in compact bone tissue on several length scales simultaneously. The experimental setup included mechanical tensile testing in combination with digital image correlation, microCT imaging, and small/wide angle X-ray scattering. The combination of techniques enabled measurements of local deformations at the tissue- and nanoscales. The study clearly shows the potential of combining different experimental techniques concurrently with mechanical testing to gain a better understanding of structure property-function relationships in bone tissue. PMID- 29410091 TI - Nocebo and pseudo-neglect: Paradoxical effects detected with eye-tracking. AB - The knowledge about effects of placebos and nocebos on specific visual attention processes is still very limited. In the present eye-tracking study, it was analyzed if a nocebo (sham transcranial magnetic stimulation) is able to elicit left-sided attentional deficits (pseudo-neglect). Fifty-two healthy participants performed a search task on the computer, once with and once without the nocebo. Indicators of left-biased search behavior (e.g. fixation count, reaction times for left vs. right-sided target detection) and affective state (e.g., valence, arousal) were assessed. The sample was divided into two groups (nocebo responder, non-responder) based on the experienced effectiveness of the nocebo. The nocebo treatment was associated with a positive and calm affective state. Contrary to the verbal suggestion, the nocebo increased the number of fixations and the dwell time on the left side of the computer screen. Moreover, the nocebo decreased the detection time for targets on the left side. These paradoxical nocebo effects were restricted to nocebo responders. Possible implications of nocebo-related compensatory behaviors for neuropsychological therapy are discussed. PMID- 29410092 TI - PDGF-C and PDGF-D signaling in vascular diseases and animal models. AB - Members of the platelet-derived growth factor (PDGF) family are well known to be involved in different pathological conditions. The cellular and molecular mechanisms induced by the PDGF signaling have been well studied. Nevertheless, there is much more to discover about their functions and some important questions to be answered. This review summarizes the known roles of two of the PDGFs, PDGF C and PDGF-D, in vascular diseases. There are clear implications for these growth factors in several vascular diseases, such as atherosclerosis and stroke. The PDGF receptors are broadly expressed in the cardiovascular system in cells such as fibroblasts, smooth muscle cells and pericytes. Altered expression of the receptors and the ligands have been found in various cardiovascular diseases and current studies have shown important implications of PDGF-C and PDGF-D signaling in fibrosis, neovascularization, atherosclerosis and restenosis. PMID- 29410090 TI - Temporal partitioning of adaptive responses of the murine heart to fasting. AB - Recent studies suggest that the time of day at which food is consumed dramatically influences clinically-relevant cardiometabolic parameters (e.g., adiposity, insulin sensitivity, and cardiac function). Meal feeding benefits may be the result of daily periods of feeding and/or fasting, highlighting the need for improved understanding of the temporal adaptation of cardiometabolic tissues (e.g., heart) to fasting. Such studies may provide mechanistic insight regarding how time-of-day-dependent feeding/fasting cycles influence cardiac function. We hypothesized that fasting during the sleep period elicits beneficial adaptation of the heart at transcriptional, translational, and metabolic levels. To test this hypothesis, temporal adaptation was investigated in wild-type mice fasted for 24-h, or for either the 12-h light/sleep phase or the 12-h dark/awake phase. Fasting maximally induced fatty acid responsive genes (e.g., Pdk4) during the dark/active phase; transcriptional changes were mirrored at translational (e.g., PDK4) and metabolic flux (e.g., glucose/oleate oxidation) levels. Similarly, maximal repression of myocardial p-mTOR and protein synthesis rates occurred during the dark phase; both parameters remained elevated in the heart of fasted mice during the light phase. In contrast, markers of autophagy (e.g., LC3II) exhibited peak responses to fasting during the light phase. Collectively, these data show that responsiveness of the heart to fasting is temporally partitioned. Autophagy peaks during the light/sleep phase, while repression of glucose utilization and protein synthesis is maximized during the dark/active phase. We speculate that sleep phase fasting may benefit cardiac function through augmentation of protein/cellular constituent turnover. PMID- 29410093 TI - What could be the mechanisms of immunological memory in fish? AB - Vaccination is the most effective strategy to control infectious diseases in species with adaptive immunity. In human and in mouse, vaccination typically induces specific memory cells, which can mediate a fast anamnestic response upon infection by the targeted pathogen. In these species, successful vaccination induces a long-lasting protection, long after the titres of specific antibodies and the frequency of specific T cells have returned to steady state. Vaccination is also an important challenge in aquaculture, since alternative treatments are either too costly, or, in the case of antibiotics, are harmful for the environment or may result in dangerous resistances. However, the mechanisms of the long-term protection elicited by vaccines in fish remain poorly understood. Although fish possess typical B- and T-cells expressing diverse repertoires of immunoglobulins and T-cell receptors, many features of antigen specific responses are different from what is known in mouse and in human. Memory is one of the most elusive properties of fish adaptive immunity, and its basis is widely unknown. In this opinion article, we discuss the concept of immune memory in the context of the fish immunity. We illustrate the complexity of this question by discussing the results of experiments showing that protection can be passed through adoptive transfer of leukocytes from vaccinated donor fish to naive histocompatible recipients. Combined with tools developed in Targetfish and in previous projects, such as monoclonal antibodies against B- and T-cell markers, we propose that such models of protection transfer provide excellent systems to dissect the mechanisms of B- and T-cell memory in the future. PMID- 29410095 TI - Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice. AB - The importance of toll-like receptor (TLR) 4 in the pathogenesis of steatohepatitis has been well documented; however, little is known about the role of TLR3. In this study, we determined whether the depletion of TLR3 modulated hepatic injury in mice and further aimed to provide mechanistic insights into the TLR3-mediated modulation of diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were induced by feeding wild-type (WT) or TLR3 knockout mice a high-fat diet for 8 weeks. Primary liver resident cells, including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs), were treated with palmitic acid. TLR3 knockout mice fed a high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-kappaB and IRF3 activation, which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells in TLR3 knockout mice compared to that in the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that the selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis. PMID- 29410096 TI - Surface modifications for antimicrobial effects in the healthcare setting: a critical overview. AB - The spread of infections in healthcare environments is a persistent and growing problem in most countries, aggravated by the development of microbial resistance to antibiotics and disinfectants. In addition to indwelling medical devices (e.g. implants, catheters), such infections may also result from adhesion of microbes either to external solid-water interfaces such as shower caps, taps, drains, etc., or to external solid-gas interfaces such as door handles, clothes, curtains, computer keyboards, etc. The latter are the main focus of the present work, where an overview of antimicrobial coatings for such applications is presented. This review addresses well-established and novel methodologies, including chemical and physical functional modification of surfaces to reduce microbial contamination, as well as the potential risks associated with the implementation of such anticontamination measures. Different chemistry-based approaches are discussed, for instance anti-adhesive surfaces (e.g. superhydrophobic, zwitterions), contact-killing surfaces (e.g. polymer brushes, phages), and biocide-releasing surfaces (e.g. triggered release, quorum sensing based systems). The review also assesses the impact of topographical modifications at distinct dimensions (micrometre and nanometre orders of magnitude) and the importance of applying safe-by-design criteria (e.g. toxicity, contribution for unwanted acquisition of antimicrobial resistance, long-term stability) when developing and implementing antimicrobial surfaces. PMID- 29410097 TI - HBV Bypasses the Innate Immune Response and Does Not Protect HCV From Antiviral Activity of Interferon. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy, whereas hepatitis B virus (HBV) infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in coinfected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level. METHODS: PHHs were isolated from liver resection tissues from HBV-, HCV-, and human immunodeficiency virus-negative patients. Differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate cotransporting polypeptide (dHepaRGNTCP) and PHHs were infected with HBV. Huh7.5 cells were transfected with circular HBV DNA genomes resembling viral covalently closed circular DNA (cccDNA), and subsequently infected with HCV; this served as a model of HBV and HCV coinfection. Cells were incubated with IFN inducers, or IFNs, and antiviral response and viral replication were analyzed by immune fluorescence, reverse-transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, and flow cytometry. RESULTS: HBV infection of dHepaRGNTCP cells and PHHs neither activated nor inhibited signaling via pattern recognition receptors. Incubation of dHepaRGNTCP cells and PHHs with IFN had little effect on HBV replication or levels of cccDNA. HBV infection of these cells did not inhibit JAK-STAT signaling or up-regulation of IFN-stimulated genes. In coinfected cells, HBV did not prevent IFN-induced suppression of HCV replication. CONCLUSIONS: In dHepaRGNTCP cells and PHHs, HBV evades the induction of IFN and IFN-induced antiviral effects. HBV infection does not rescue HCV from the IFN-mediated response. PMID- 29410094 TI - Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals. AB - OBJECTIVES: To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals. METHODS: Cross sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions. RESULTS: Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%-100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence. CONCLUSIONS: Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking. PMID- 29410098 TI - An Unusual Cause of Recurrent Gastric Bleeding. PMID- 29410099 TI - Repeat Robotic Endoscopic Mitral Valve Operation: A Safe and Effective Strategy. AB - BACKGROUND: Mitral valve reoperation is necessary in a finite percentage of patients. With growth in robotic mitral valve operations, reoperative strategies need to be developed. A review of institutional mitral valve reoperations after a previous robotic approach was undertaken. METHODS: From January 2006 through April 2017, 1,853 patients underwent an initial robotic mitral valve operation by a dedicated robotic team. During this interval, 54 of these patients (2.9%) required mitral reoperation at our institution. The prospectively collected operative, echocardiographic, videoscopic, and outcome data for these patients were retrospectively reviewed to assess the feasibility, efficacy, and safety of a repeat robotic mitral valve operation. RESULTS: Reoperative mitral operation after a previous robotic procedure was completed robotically in 50 patients (92.6%). Robotic mitral re-repair was achieved in 36 of the 50 patients (72%), including 33 of the 39 patients (85%) with degenerative disease. Conversion of a previous repair to a replacement was performed in 12 patients (24%) and re replacement in 2 patients (4%). No patients were converted from a robotic approach to a thoracotomy or sternotomy approach. There were no deaths or strokes in this series. Major morbidity occurred in 1 patient (2%) in the repeat robotic group. Sternotomy for reoperation was required in 4 patients (7%) due to right chest access or peripheral perfusion limitations. CONCLUSIONS: Repeat robotic mitral operation after a previous robotic approach is feasible and appears to be an effective and safe strategy in a high percentage of patients when performed by an experienced robotic team. PMID- 29410100 TI - Association Between Neurological Outcomes Related to Aneurysmal Subarachnoid Hemorrhage and Onsite Access to Neurointerventional Radiology. AB - OBJECTIVE: An onsite access to neurointerventional radiology (NIR) may be useful for managing patients with aneurysmal subarachnoid hemorrhage (aSAH) after the aneurysm-securing procedure. We aimed to assess the association between neurological outcomes related to aSAH and onsite access to NIR service. METHODS: This was a sequential period study of 47 patients with aSAH admitted consecutively during the pre-NIR period (January 2010 to June 2012) compared with 81 patients with aSAH admitted consecutively during the post-NIR period (January 2013 to June 2015) at an academic tertiary referral intensive care unit (ICU). The primary end point was the incidence of poor neurological outcome, defined as modified Rankin scale of >=3 at 6 months from ictus. Secondary outcomes included incidence of symptomatic vasospasm (SV) and length of stay in ICU/hospital. RESULTS: The primary end point was observed in 18 of 47 (38%) patients during the pre-NIR period versus 25 of 81 (31%) patients during the post-NIR period (P = 0.39). The post-NIR period did not have an independent impact on neurological outcomes (adjusted odds ratio = 0.8, 95% confidence interval 0.3-2.1; P = 0.66). Of the patients who developed SV, 10 of 47 (21%) were during the pre-NIR period versus 33 of 81 (41%) during the post-NIR period (P = 0.02). The post-NIR period and higher Fisher grade were independent predictors of SV. Patients with SV had similar outcomes, but with longer stay in ICU during the post-NIR period compared with the pre-NIR period. CONCLUSIONS: Among patients with aSAH, the post-NIR period was associated with more frequent detection of SV, more endovascular procedures, longer hospital stay, but with no appreciable improvement in neurological outcomes either overall or in the subset of patients with SV. STUDY REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000201471. PMID- 29410101 TI - Adjustable Polyurethane Foam as Filling Material for a Novel Spondyloplasty: Biomechanics and Biocompatibility. AB - OBJECTIVE: To investigate the biomechanics and biocompatibility of polyurethane (PU) foam with adjustable stiffness as a filling material for a novel spondyloplasty that is designed to reduce the risk of postoperative adjacent level fractures. METHODS: Sixty individual porcine lumbar vertebrae were randomly split into 4 groups: A, B, C, and D. Group A served as unmodified vertebral body controls. Groups B, C, and D consisted of hollowed vertebral bodies. Vertebrae of groups C and D were filled with adjustable PU foams of different stiffness. The compressive strength and stiffness of vertebrae from groups A-D were recorded and analyzed. 3T3 mouse fibroblasts were cultured with preformed PU foams for 4 days to test biocompatibility. RESULTS: The strength and stiffness of the hollowed groups were lower than in group A. However, the differences were not statistically significant between group A and group C (P > 0.05), and were obviously different between group A and group B or group D (P < 0.01 and <0.05, respectively). Moreover, the strength and stiffness after filling foams in group C or group D were significantly greater than in group B (P < 0.01 and <0.05, respectively). Live/dead staining of 3T3 cells confirmed the biocompatibility of the PU foam. CONCLUSIONS: The new PU foam shows adaptability regarding its stiffness and excellent cytocompatibility in vitro. The results support the clinical translation of the new PU foams as augmentation material in the development of a novel spondyloplasty. PMID- 29410102 TI - Laser-Induced Thermal Therapy in Neuro-Oncology: A Review. AB - OBJECTIVES: Laser therapy has become an appealing treatment modality in neurosurgery. In this review, we report on the history, physics, surgical steps, indications and uses, and complications that have been reported to date. METHODS: An extensive literature search was performed for laser interstitial thermal therapy (LITT) and laser therapy in the context of glial tumors, metastatic lesions, pediatric brain tumors, and radiation necrosis. Reported complications in each series also were reviewed. RESULTS: In the past decade, multiple studies have demonstrated the use, outcomes, and complications associated with LITT in neurosurgery. These same studies have consistently reported an overall benefit of LITT in cases in which traditional surgical approaches may be limited by the patient's clinical status, tumor location, or overall prognosis. However, there have been complications reported from local effects of thermal damage, technical error, and edema development. Increased experience has reduced complications and brought more promising results. CONCLUSIONS: With the advent of real-time monitoring and damage estimation, LITT has gained ground in the management of intracranial tumors. Larger scale trials must be performed to develop standard protocols to define specific indications for use. Further large clinical studies for LITT in non-oncologic cases are also of interest. PMID- 29410103 TI - Frontoparietal areas link impairments of large-scale intrinsic brain networks with aberrant fronto-striatal interactions in OCD: a meta-analysis of resting state functional connectivity. AB - Neuroimaging studies report evidence for two distinct pathophysiological models of obsessive-compulsive disorder (OCD): disrupted fronto-striatal circuits and impaired large-scale fronto-parietal-limbic intrinsic brain networks, defined by functionally connected (FC) infra-slow oscillations in ongoing brain activity. To synthesize this literature and overcome inconsistencies, we conducted a coordinate-based meta-analysis of 18 whole-brain resting-state functional magnetic resonance imaging (fMRI) studies (541 patients, 572 healthy controls) comparing seed-based FC between OCD patients and healthy controls. In patients, the meta-analysis revealed (1) consistent hypoconnectivity within frontoparietal and salience network, and between salience, frontoparietal and default-mode network, and (2) consistent general dysconnectivity (no specific direction of connectivity change) within default-mode and frontoparietal network, as well as between frontoparietal, default-mode, and salience networks. Between-network hypoconnectivity provides evidence for the triple-network model in OCD, while aberrant within-network connectivity of frontoparietal and striatal regions supports reports of aberrant fronto-striatal circuitry. Therefore, results corroborate both models of OCD pathophysiology and link them by underlining the importance of intrinsic connectivity of frontoparietal regions which are common to both models. PMID- 29410104 TI - Evaluation of a novel optical assay for rapid detection of methicillin-resistant Staphylococcus aureus in liquid culture. AB - Valid detection of methicillin-resistant Staphylococcus aureus (MRSA) is a precondition for MRSA prevention measures. Most of the available MRSA screening tests are based either on the identification of colony material grown on solid agar media or on direct molecular approaches. The HB&L MRSA KIT (Alifax, Polverara, Italy) is designed to screen for MRSA in liquid cultures applying the light scattering technology. Here, the assay was evaluated with pure culture isolates from solid agar media on a representative subset of 29 MRSA and 171 methicillin-susceptible S. aureus clinical strains from a German multicenter study reflecting the ratio of MRSA to MSSA in Germany. Additionally, 53 mecA/mecC MRSA comprising hospital-, community and livestock-associated MRSA as well as 20 clinical coagulase-negative staphylococci (CoNS) challenge strains were tested. Including the results of the assay-immanent confirmatory tests for positively tested strains, the sensitivity, specificity and the positive and negative predictive values were 100%. The methicillin-resistance was also correctly identified for all challenge strains. PMID- 29410105 TI - The Catch Mini stent retriever for mechanical thrombectomy in distal intracranial occlusions. AB - OBJECTIVE: Mechanical thrombectomy (MTB) is a treatment of reference for acute ischemic stroke due to large brain vessel occlusion but some concerns remain about its use in small distal branches. In the present study, we assessed the efficacy and the safety of distal MTB using the Catch Mini (CM) stent retriever. METHODS: We retrospectively reviewed a prospectively maintained database of all consecutive patients who underwent MTB for a distal intracranial occlusion with the Catch Mini device at our hospital. RESULTS: Forty-one patient underwent MTB for distal intracranial occlusions using the CM stent retriever. Good capillary reperfusion (TICT>=2b) was observed in 32 out of 41 patients (78%). Focal ischemia within the territory vascularized by the artery addressed by the CM was observed in 8 patients (19.5%). Post-procedural vasospasm was observed in 8 patients, all responding rapidly to vasodilatator administration. Two asymptomatic hemorrhages (4.9%) were noted on follow-up imaging (one patechial hemorrhage and one parenchymal hematoma) in patients with M2 occlusions. No vessel rupture were observed. Overall, good neurological outcome at three months (mRS<=2) was observed in 28 (out of 34 patients followed; 82.4%) of patients. CONCLUSIONS: Our single-center experience shows that the CM stent retriever is safe and effective for the recanalization of small diameter distal branches feeding eloquent brain areas. PMID- 29410106 TI - Thermodynamic and conformational analysis of the interaction between antibody binding proteins and IgG. AB - Studying interaction of IgG with bacterial proteins such as proA (Protein A) and proG is essential for development in the areas of drug discovery and biotechnology. Some solution studies in the past have hinted at the possibility of variable binding ratios for IgG with proA and proG. Since earlier crystallographic studies focussed mostly on monomeric complexes, the knowledge about the binding interfaces and protein conformational changes involved in multimeric complexes is scarce. In this paper, we observed that single proA molecule was able to bind to three IgG molecules (1:3, proA:IgG) in ITC accentuating the presence of conformational flexibility in proA, corroborated also by CD results. By contrast, proG binds with 1:1 stoichiometry to IgG, which also involves key structural rearrangement within the binding interface of IgG proG complex, confirmed by fluorescence KI quenching study. It is implicit from CD and fluorescence results that IgG does not undergo any significant conformational changes, which further suggests that proA and proG dictate the phenomenon of recognition in antibody complexes. ANS as a hydrophobic probe helped in revealing the distinctive antibody binding mechanism of proA and proG. Additionally, the binding competition experiments using ITC established that proA and proG cannot bind IgG concurrently. PMID- 29410107 TI - Laparoscopic vs transvaginal cuff closure after total laparoscopic hysterectomy: a randomized trial by the Italian Society of Gynecologic Endoscopy. AB - BACKGROUND: Vaginal cuff dehiscence following hysterectomy is considered an infrequent but potentially devastating complication. Different possible techniques for cuff closure have been proposed to reduce this threatening adverse event. OBJECTIVE: The aim of the present randomized study was to compare laparoscopic and transvaginal suture of the vaginal vault at the end of a total laparoscopic hysterectomy, in terms of incidence of vaginal dehiscence and vaginal cuff complications. Factors associated with vaginal dehiscence were also analyzed. This article presents the results of the interim analysis of the trial. STUDY DESIGN: Patients undergoing total laparoscopic hysterectomy for benign indications were randomized at the time of colpotomy to receive vaginal closure through transvaginal vs laparoscopic approach using a 1:1 ratio. Allocation concealment was obtained using a password-protected randomization database. Monopolar energy for colpotomy was set at 60W. Vaginal closure was performed with a single-layer running braided and coated 0-polyglactin suture. In all cases an attempt was performed to include the posterior peritoneum in the suture. Laparoscopic knots were tied intracorporeally. All patients were scheduled for a postoperative follow-up visit 3 months after surgery, to detect possible vaginal cuff complications. Univariate and multivariable analyses were performed to identify independent predictors of vaginal cuff dehiscence after total laparoscopic hysterectomy. RESULTS: After enrollment of 1408 patients, a prespecified interim analysis was conducted. Thirteen (0.9%) women did not undergo the postoperative assessment and were excluded. Baseline characteristics of the 1395 patients included (695 in the transvaginal group and 700 in the laparoscopic group) were similar between groups. Patients in the transvaginal group had a significantly higher incidence of vaginal dehiscence (2.7% vs 1%; odds ratio, 2.78; 95% confidence interval, 1.16-6.63; P = .01) and of any cuff complication (9.8% vs 4.7%; odds ratio, 2.19; 95% confidence interval, 1.43-3.37; P = .0003). Based on these findings, the data monitoring committee recommended that the trial be terminated early. After multivariable analysis, transvaginal closure of the vault was independently associated with a higher incidence of vaginal dehiscence and any vaginal complication; premenopausal status and smoking habit were independently associated with a higher risk of dehiscence. CONCLUSION: Laparoscopic closure of the vaginal cuff at the end of total laparoscopic hysterectomy is associated with a significant reduction of vaginal dehiscence, any cuff complication, vaginal bleeding, vaginal cuff hematoma, postoperative infection, need for vaginal resuture, and reintervention. PMID- 29410108 TI - Postmortem microfocus computed tomography for early gestation fetuses: a validation study against conventional autopsy. AB - BACKGROUND: Perinatal autopsy provides useful clinical information in up to 40% of cases. However, there is a substantial unmet clinical need with regards to postmortem investigation of early gestation fetal loss for parents for whom standard autopsy is either not available or not acceptable. Parents dislike the invasive nature of autopsy, but current clinical imaging techniques do not provide high-enough imaging resolution in small fetuses. We hypothesized that microfocus computed tomography, which is a rapid high-resolution imaging technique, could give accurate diagnostic imaging after early gestation fetal loss. OBJECTIVE: The objective of the study was to evaluate the diagnostic accuracy of microfocus computed tomography for noninvasive human fetal autopsy for early gestation fetuses, with the use of conventional autopsy as the reference standard. STUDY DESIGN: We compared iodinated whole body microfocus computed tomography in 20 prospectively recruited fetuses (11-21 weeks gestation from 2 centers) with conventional autopsy in a double-blinded manner for a main diagnosis and findings in specific body organs. Fetuses were prepared with 10% formalin/potassium tri-iodide. Images were acquired with a microfocus computed tomography scanner with size-appropriate parameters. Images were evaluated independently by 2 pediatric radiologists, who were blinded to formal perinatal autopsy results, across 40 individual indices to reach consensus. The primary outcome was agreement between microfocus computed tomography and conventional autopsy for overall diagnosis. RESULTS: Postmortem whole body fetal microfocus computed tomography gave noninvasive autopsy in minutes, at a mean resolution of 27MUm, with high diagnostic accuracy in fetuses at <22 weeks gestation. Autopsy demonstrated that 13 of 20 fetuses had structural abnormalities, 12 of which were also identified by microfocus computed tomography (92.3%). Overall, microfocus computed tomography agreed with overall autopsy findings in 35 of 38 diagnoses (15 true positive, 18 true negative; sensitivity 93.8% [95% confidence interval, 71.7-98.9%], specificity 100% [95% confidence interval, 82.4-100%]), with 100% agreement for body imaging diagnoses. Furthermore, after removal of nondiagnostic indices, there was agreement for 700 of 718 individual body organ indices that were assessed on microfocus computed tomography and autopsy (agreement, 97.5%; 95% confidence interval, 96.1-98.4%), with no overall differences between fetuses at <=14 or >14 weeks gestation (agreement, 97.2% and 97.9%, respectively). Within first-trimester fetal loss cases (<14 weeks gestation), microfocus computed tomography analysis yielded significantly fewer nondiagnostic indices than autopsy examination (22/440 vs 48/348, respectively; P<.001). CONCLUSION: Postmortem whole-body fetal microfocus computed tomography gives noninvasive, detailed anatomic examinations that are achieved in minutes at high resolution. Microfocus computed tomography may be preferable to magnetic resonance imaging in early gestation fetuses and may offer an acceptable method of examination after fetal loss for parents who decline invasive autopsy. This will facilitate autopsy and subsequent discussions between medical professionals who are involved in patient care and counselling for future pregnancies. PMID- 29410111 TI - An aptamer-enabled DNA nanobox for protein sensing. AB - DNA nanostructures can show dynamic responses to molecular triggers for a wide variety of applications. While DNA sequence signal triggers are now well established, there is a critical need for a broader diversity of molecular triggers to drive dynamic responses in DNA nanostructures. DNA aptamers are ideal; they can both seamlessly integrate into DNA nanostructure scaffolds and transduce molecular recognition into functional responses. Here, we report construction and optimization of a DNA origami nanobox locked by a pair of DNA double strands where one strand is a DNA aptamer targeting the malaria biomarker protein Plasmodium falciparum lactate dehydrogenase. The protein acts as the key which enables box opening. We observe highly specific protein-mediated box opening by both transmission electron microscopy and fluorescence. Aptamer enabled DNA boxes have significant potential for enabling direct responses to proteins and other biomolecules in nanoscale diagnostics, drug delivery and sensing devices. PMID- 29410110 TI - Selective liposome targeting of folate receptor positive immune cells in inflammatory diseases. AB - Activated macrophages play a key role in the development and maintenance of inflammatory diseases such as atherosclerosis, lupus, psoriasis, rheumatoid arthritis, ulcerative colitis, and many others. These activated macrophages, but not resting or quiescent macrophages highly up-regulate folate receptor beta (FR beta). This differential expression of FR-beta provides a mechanism to selectively deliver imaging and therapeutic agents utilizing folate as a targeting molecule. In an effort to determine whether inflammatory diseases can be targeted utilizing a folate-linked nanosize carrier, a PEG-coated liposome was prepared that incorporated a folate conjugated PEG that also could transport imaging or therapeutic cargo. We demonstrate that these folate-liposomes specifically bind to folate receptor positive cells and accumulate at sites of inflammation in mouse models of colitis and atherosclerosis. These two animal models show that folate-targeted liposomes could be successfully utilized to deliver fluorescent molecules and an anti-inflammatory drug (betamethasone) for diagnostic and therapeutic applications. PMID- 29410109 TI - In vivo Raman spectroscopy for biochemical monitoring of the human cervix throughout pregnancy. AB - BACKGROUND: The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications. OBJECTIVE: The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair. STUDY DESIGN: In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6-week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses. RESULTS: Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm-1) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm-1) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm-1) and cholesterol (1447 cm-1) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals. CONCLUSION: Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth. PMID- 29410112 TI - One-step sonochemical fabrication and embedding of gentamicin nanoparticles into parylene C implant coating: towards controlled drug delivery. AB - A facile one-step sonochemical method was employed for the first time for gentamicin nanoparticles (GNPs) fabrication and embedding into the surface of parylene C implant coating. The developed system was thoroughly characterized in terms of particle size (NTA, STEM/EDX), surface dispersion (IR-image) and drug release kinetics (UV-Vis). It was revealed that the optimization of the applied ultrasound conditions resulted in the formation of GNPs with an average size in the narrow range of 30-70 nm and their docking into the parylene C nanopores, while the molecular structure of the antibiotic was preserved as confirmed by the FTIR spectra. The obtained surface morphology resulted in controlled elution of the drug up to 7 days, and the kinetics followed the Korsmeyer-Peppas model. The apparent benefits of the proposed sonochemical approach (short preparation time, direct drug accessibility, lack of chemical wastes) are pointed out. PMID- 29410115 TI - Marijuana and stoned fruit. PMID- 29410113 TI - Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies. PMID- 29410114 TI - Differences in Physical Performance Measures Among Patients With Unilateral Lower Limb Amputations Classified as Functional Level K3 Versus K4. AB - OBJECTIVE: To determine whether differences in physical function, assessed via self-report questionnaires and physical performance tests, exist between individuals with lower-limb loss using a prosthetic device classified as a K3 versus a K4 functional level. DESIGN: Cross-sectional study. SETTING: A university physical therapy amputee clinic. PARTICIPANTS: Participants (N=55) were included if they (1) were aged >=18 years with a unilateral transfemoral or transtibial amputation; (2) were classified as K3 or K4 functional level; (3) completed all relevant outcome measures; and (4) were currently using a prosthesis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Locomotor Capabilities Index (LCI), Prosthetic Evaluation Questionnaire-Mobility Section (PEQ-MS), Timed Up and Go (TUG), 10-Meter Walk Test (10MWT), Amputee Mobility Predictor (AMPPRO), and 6-Minute Walk Test (6MWT). K level was determined by group consensus based on a standardized clinical evaluation. RESULTS: After controlling for covariates, patients classified as K3 had slower TUG times (P=.002) and self-selected and fast gait speeds (P<.001), lower AMPPRO scores (P<.001), and walked shorter distances during the 6MWT (P=.003) when compared with patients classified as K4. No significant between-group differences for the LCI or PEQ-MS were found. CONCLUSIONS: Clinicians involved in prosthetic prescription may consider including the TUG, 10MWT, AMPPRO, and 6MWT during their clinical evaluations to help differentiate between individuals of higher functional mobility. The LCI and PEQ-MS may be less useful in classifying individuals as K3 versus K4 because of a ceiling effect. PMID- 29410116 TI - FOXO family in regulating cancer and metabolism. AB - FOXO proteins are a sub-group of a superfamily of forkhead box (FOX)-containing transcription factors (TFs). FOXOs play an important role in regulating a plethora of biological activities ranging from development, cell signaling, and tumorigenesis to cell metabolism. Here we mainly focus on reviewing the role of FOXOs in regulating tumor and metabolism. Moreover, how crosstalk among various pathways influences the function of FOXOs will be reviewed. Further, the paradoxical role for FOXOs in controlling the fate of cancer and especially resistance/sensitivity of cancer to the class of drugs that target PI3K/AKT will also be reviewed. Finally, how FOXOs regulate crosstalk between common cancer pathways and cell metabolism pathways, and how these crosstalks affect the fate of the cancer will be discussed. PMID- 29410118 TI - Esophageal Cytology: A Tale of Shish Kebab and Roman Legionaries. PMID- 29410117 TI - Best Practice Update: Incorporating Psychogastroenterology Into Management of Digestive Disorders. AB - Chronic digestive diseases, including irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychological context-the substantial burden of these diseases is co determined by symptom and disease severity and the ability of patients to cope with their symptoms without significant interruption to daily life. The growing field of psychogastroenterology focuses on the application of scientifically based psychological principles and techniques to the alleviation of digestive symptoms. In this Clinical Practice Update, we describe the structure and efficacy of 2 major classes of psychotherapy-cognitive behavior therapy and gut directed hypnotherapy. We focus on the impact of these brain-gut psychotherapies on gastrointestinal symptoms, as well as their ability to facilitate improved coping, resilience, and self-regulation. The importance of the gastroenterologist in the promotion of integrated psychological care cannot be overstated, and recommendations are provided on how to address psychological issues and make an effective referral for brain-gut psychotherapy in routine practice. PMID- 29410119 TI - A Rare Cause of a Left Abdominal Liver Mass. PMID- 29410120 TI - A Young Patient With Diabetes and Liver Tumors. PMID- 29410121 TI - Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained beta-adrenergic receptor stimulation. AB - BACKGROUND: Sustained beta-adrenergic receptor (beta-AR) stimulation causes pathophysiological changes during heart failure (HF), including inhibition of the slow component of the delayed rectifier potassium current (IKs). Aberrant calcium handling, including increased activation of calcium/calmodulin-dependent protein kinase II (CaMKII), contributes to arrhythmia development during HF. OBJECTIVE: The purpose of this study was to investigate CaMKII regulation of KCNQ1 (pore forming subunit of IKs) during sustained beta-AR stimulation and associated functional implications on IKs. METHODS: KCNQ1 phosphorylation was assessed using liquid chromatography-tandem mass spectrometry after sustained beta-AR stimulation with isoproterenol (ISO). Peptide fragments corresponding to KCNQ1 residues were synthesized to identify CaMKII phosphorylation at the identified sites. Dephosphorylated (alanine) and phosphorylated (aspartic acid) mimics were introduced at identified residues. Whole-cell, voltage-clamp experiments were performed in human endothelial kidney 293 cells coexpressing wild-type or mutant KCNQ1 and KCNE1 (auxiliary subunit) during ISO treatment or lentiviral deltaCaMKII overexpression. RESULTS: Novel KCNQ1 carboxy-terminal sites were identified with enhanced phosphorylation during sustained beta-AR stimulation at T482 and S484. S484 peptides demonstrated the strongest deltaCaMKII phosphorylation. Sustained beta-AR stimulation reduced IKs activation (P = .02 vs control) similar to the phosphorylated mimic (P = .62 vs sustained beta-AR). Individual phosphorylated mimics at S484 (P = .04) but not at T482 (P = .17) reduced IKs function. Treatment with CN21 (CaMKII inhibitor) reversed the reductions in IKs vs CN21-Alanine control (P < .01). deltaCaMKII overexpression reduced IKs similar to ISO treatment in wild type (P < .01) but not in the dephosphorylated S484 mimic (P = .99). CONCLUSION: CaMKII regulates KCNQ1 at S484 during sustained beta-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF. PMID- 29410122 TI - Virulence factors, antibiotic resistance genes and genetic relatedness of commensal Escherichia coli isolates from dogs and their owners. AB - Escherichia coli (E. coli) is a normal flora of gastrointestinal tracts of humans and warm-blooded animals including dogs that has close vicinity with humans. Because the inter-species transmission of E. coli between pets and human beings, within a household, obtaining more information about the epidemiology, genetics, virulence factors, and antibiotic resistance of E. coli from dogs and their owners will help to control the inter-species transmission and treatment of E. coli infections. In this study we characterize and compare the antibiotic resistance and virulence profiles of fecal E. coli isolates from dogs and their owners. A total of 149 commensal E. coli isolates comprised 62 isolates from dogs, 56 isolates from their owners and 31 isolates from humans with no pet as control were collected. Extracted DNA was assessed for the presence of antibiotic resistance genes cmlA (chloramphenicol), sulI (sulfamethoxazole), floR (florfenicol) and blaCTX-M1 (cefotaxime) and virulence genes (papA, ompT, hlyD, traT, tsh and cnf1). To determine the extent of genetic relatedness of isolates, RAPD-PCR was performed. sulI and traT genes were the most dominant resistance profile and the most prevalent virulence gene in all groups, respectively, while hlyD had the lowest frequency among investigated virulence genes. Based on RAPD PCR analysis clonal sharing between dogs and their owners were observed in 2/28 (7.1%) potential within-household clone-sharing pairs. Allowing dog to lick on owner's face, dog sex (female dogs), dog's sexual status (intact dogs) and times of disposing the feces (>=twice a day) were associated with a higher percentage of RAPD profile similarity (P < 0.05). The current study did not show an obvious evidence to prove considerable transmission of fecal E. coli from dogs to their owners. But in two households, there were relationship between isolates from dogs and their owners. PMID- 29410124 TI - Outcome of acute staphylococcal prosthetic joint infection treated with debridement, implant retention and antimicrobial treatment with short duration of rifampicin. PMID- 29410123 TI - Cognitive control and midline theta adjust across multiple timescales. AB - Cognitive control of attention in conflict situations is a basic skill that is vital for goal-oriented behavior. Behavioral evidence shows that conflict control occurs over successive trials as well as longer time scales of trial blocks, but the relation among time scales as well as their neural mechanisms are unclear. This study used measures of behavior, EEG, and a simple quantitative model to test the hypothesis that conflict control at the block level is not exclusively driven by control adjustments over successive trials. Young adults performed an auditory Simon task, and the base rate of compatible vs. incompatible trials was manipulated in separate blocks (25, 50, 75% compatible). EEG data were analyzed using independent component analysis (ICA) to define cortical mechanisms of any base rate and trial-by-trial sequence effects. Reaction time measures had both sequence and base rate effects. Two fronto-medial ICA components indexed sequence and base rate effects, with specific profiles for evoked potentials and oscillations in the theta and alpha frequency bands. Predictive modeling showed that sequence effects accounted for a minority of the variance on behavioral and ICA measures (all < 36%). The results strongly suggest that the base rate manipulation affected behavior and many neural measures beyond the influence of sequence effects. PMID- 29410125 TI - Predicting a New Reality. PMID- 29410126 TI - Heart Transplant in Patient With Isolated Left Superior Vena Cava by Atrial Appendage Rotation. AB - Orthotopic heart transplantation in patients with an isolated persistent left superior vena cava is extremely rare, and the anastomotic connection between a right-sided donor superior vena cava and left-sided recipient superior vena cava can be challenging to perform. We present a novel technique used in an infant female, using the left atrial appendage to extend the superior vena cava anastomosis. PMID- 29410127 TI - Early Mortality in Patients Undergoing Adjuvant Chemotherapy for Non-Small Cell Lung Cancer. AB - BACKGROUND: Although adjuvant chemotherapy improves survival in patients with completely resected NSCLC, it is also associated with potentially disabling or lethal adverse events. Because there is limited information on the early mortality among patients undergoing adjuvant chemotherapy, we used the National Cancer Database to calculate the percentage of deaths within the first 6 months of starting chemotherapy. METHODS: The National Cancer Database was queried for patients age 18 or older in whom stage IB to IIIA NSCLC had been diagnosed between 2004 and 2012 and who had received multiagent adjuvant chemotherapy starting within 120 days from the surgical resection with negative surgical margins. Age groups were divided as follows: younger than 50, 51 to 60, 61 to 70, 71 to 80, and older than 80 years. RESULTS: A total of 19,691 patients met the eligibility criteria, 19,398 of whom had a known 6-month mortality status. The median age was 65 years (range 19-89). The 1-, 2-, 3-, 4-, 5-, and 6-month cumulative mortality rates from initiation of chemotherapy were 0.7%, 1.3%, 1.9%, 2.6%, 3.2%, and 4.1% respectively. The 6-month mortality rates for each age group (<= 50 years, 51-60, 61-70, 71-80, and >80) were 2.6%, 3.1%, 4.1%, 5.3%, and 7.6%, respectively (p < 0.001). Independent factors associated with increased 6 month mortality included age 71 to 80 versus younger than 50 (OR = 1.72, 95% confidence interval [CI]: 1.16-2.55, p = 0.007), age older than 80 versus younger than 50 (OR = 2.43, 95% CI: 1.40-4.20, p = 0.002), male sex (OR = 1.42; 95% CI: 1.21-1.67, p < 0.001), Charlson-Deyo comorbidity score of 2 versus 0 (OR = 1.52, 95% CI 1.22-1.89, p < 0.001), pneumonectomy (OR = 1.38, 95% CI: 1.11-1.73, p = 0.004), length of postopertive stay longer than 6 days after surgery (OR = 1.21, 95% CI: 1.03-1.41, p = 0.02), and readmission within 30 days from surgery (OR = 1.48, 95% CI: 1.15-1.90, p = 0.02). CONCLUSIONS: Early mortality with the use of adjuvant chemotherapy after complete resection of NSCLC is a clinical concern. The risk is higher in patients older than 70 years, with higher comorbidity scores and a prolonged length of stay postoperatively. PMID- 29410128 TI - Pseudomonas aeruginosa zinc homeostasis: Key issues for an opportunistic pathogen. AB - Zinc is an essential trace element for almost all living organisms. In the opportunistic bacterial pathogen Pseudomonas aeruginosa, zinc has been shown to play an important role in virulence, in colonization of the host organism and has also been shown to be involved in antibiotic resistance. P. aeruginosa possesses numerous systems enabling it to thrive in zinc-depleted conditions as well as high-zinc situations, two environments that are encountered during human infection. These capabilities account for its pathogenic strength. The main aim of this review is to focus on zinc homeostasis in P. aeruginosa and the genetic regulation of the systems involved. The interconnection with virulence, as well as the mechanism of co-regulation between metal and antibiotic resistance, are of prime interest for understanding the molecular mechanisms allowing P. aeruginosa to switch from its existence as a common environmental bacterium to a severe opportunistic pathogen. This article is part of a Special Issue entitled: Dynamic gene expression, edited by Prof. Patrick Viollier. PMID- 29410129 TI - Non-small cell lung carcinoma with diffuse coexpression of thyroid transcription factor-1 and DeltaNp63/p40. AB - Here, we present a case of non-small cell lung carcinoma (NSCLC) with widespread and strong nuclear immunopositivity for both thyroid transcription factor-1 (TTF 1) and DeltaNp63/p40 (p40). Double immunofluorescence for TTF-1 and p40 showed coexpression of both markers in the tumor cells. Furthermore, PTEN (pHis123Asp) and TP53 (pVal272Leu) mutations were identified as possible mitogenic driver mutations by next-generation sequencing. To the best of our knowledge, this is the first case of NSCLC harboring concurrent PTEN and TP53 mutations with widespread and strong coexpression of TTF-1 and p40, which has been confirmed in the resected specimen, and only the second documented case of NSCLC with TTF-1 and p40 diffuse coexpression in the carcinoma cells from the same individual. Our case illustrates the possibility that poorly differentiated NSCLCs with widespread and strong nuclear positivity for TTF-1 and p40 may be an underrecognized and new entity. PMID- 29410131 TI - Invitation to the 54th Congress of the French Society of Stomatology, Oral and Maxillofacial Surgery, Marseille, 3-6 October 2018. PMID- 29410130 TI - Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome. AB - Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration. PMID- 29410132 TI - Use of a prescription opioid registry to examine opioid misuse and overdose in an integrated health system. AB - Strategies are needed to identify at-risk patients for adverse events associated with prescription opioids. This study identified prescription opioid misuse in an integrated health system using electronic health record (EHR) data, and examined predictors of misuse and overdose. The sample included patients from an EHR-based registry of adults who used prescription opioids in 2011 in Kaiser Permanente Northern California, a large integrated health care system. We characterized time at-risk for opioid misuse and overdose, and used Cox proportional hazard models to model predictors of these events from 2011 to 2014. Among 396,452 patients, 2.7% were identified with opioid misuse and 1044 had an overdose event. Older patients were less likely to meet misuse criteria or have an overdose. Whites were more likely to be identified with misuse, but not to have an overdose. Alcohol and drug disorders were related to higher risk of misuse and overdose, with the exception that marijuana disorder was not related to opioid misuse. Higher daily opioid dosages and benzodiazepine use increased the risk of both opioid misuse and overdose. We characterized several risk factors associated with misuse and overdose using EHR-based data, which can be leveraged relatively quickly to inform preventive strategies to address the opioid crisis. PMID- 29410133 TI - The EMT-related transcription factor snail up-regulates FAPalpha in malignant melanoma cells. AB - FAPalpha is a cell surface serine protease, mainly expressed in tumor stromal fibroblasts in more than 90% of human epithelial carcinomas. Due to its almost no expression in normal tissues and its tumor-promoting effects, FAPalpha has been studied as a novel potential target for antitumor therapy. However, the regulation mechanism on FAPalpha expression is poorly understood. In this study, we found that overexpression of snail significantly increased the mRNA and protein expression levels of FAPalpha in malignant melanoma B16 and SK-MEL-28 cells. Overexpression of snail increased FAPalpha promoter activity remarkably. Snail could directly bind to FAPalpha promoter to regulate FAPalpha expression. Moreover, snail expression was positively correlated to FAPalpha expression in human cutaneous malignant melanoma. Furthermore, knockdown of FAPalpha markedly reduced snail-induced cell migration. Overall, our findings provide a novel regulation mechanism on FAPalpha expression and highlight the role of snail/FAPalpha axis as a novel target for melanoma treatment. PMID- 29410134 TI - Behavioral phenotype relates to physiological differences in immunological and stress responsiveness in reactive and proactive birds. AB - It has now been demonstrated in many species that individuals display substantial variation in coping styles, generally separating into two major behavioral phenotypes that appear to be linked to the degree of physiological stress responsiveness. Laying hens are perfect examples of these dichotomous phenotypes; white laying hens are reactive, flighty, and exhibit large hormonal and behavioral responses to both acute and chronic stress, while brown laying hens are proactive, exploratory, and exhibit low hormonal and behavioral responses to stress. Given the linkages between stress physiology and many other body systems, we hypothesized that behavioral phenotype would correspond to additional physiological responses beyond the stress response, in this case, immunological responses. Because corticosterone is widely known to be immunosuppressive, we predicted that the reactive white hens would show more dampened immune responses than the proactive brown hens due to their exposure to higher levels of corticosterone throughout life. To assess immune function in white and brown hens, we compared febrile responses, corticosterone elevations, feed consumption, and egg production that occurred in response an injection of lipopolysaccharide (LPS) or saline, inflammatory responses to phytohemagglutinin (PHA) injection in the toe web, innate phagocytic activity in whole blood, and antibody responses to an injection of Sheep Red Blood Cells (SRBCs). Contrary to our predictions, white hens had significantly greater swelling of the toe web in response to PHA and showed a greater inhibition of feeding and reproductive output in response to LPS. These results indicated that reactive individuals are more reactive in both stress and immunological responsiveness. PMID- 29410135 TI - Risk Factors of Recurrence of Atrial Fibrillation (AF) After AF Surgery in Patients With AF and Mitral Valve Disease. AB - The purpose of this study was to determine the 22-year experience of the relationship between preoperative left atrial diameter (LAD) and atrial fibrillation (AF) recurrence after AF surgery. Between November 1993 and April 2015, 244 patients underwent AF surgery concomitant with mitral valve surgery, and were completely followed up in our institute. The full-maze procedure was performed in 231 patients and pulmonary vein isolation in 13. Three quartiles divided the list of sorted LAD data into 4 groups: group Q1: LAD = 40.5 +/- 4.3 (n = 55), group Q2: LAD = 47.9 +/- 2.0 (n = 61), group Q3: LAD = 54.2 +/- 1.6 (n = 66), and group Q4: LAD = 64.2 +/- 5.6 (n = 62). The AF cure rates for 22 years were verified between the groups. Although the AF cure rate of the full-maze procedure was 94%, 80%, 63%, and 51% at 1, 5, 10, and 20 years after AF surgery, respectively, it was 100% at 5 and 10 years after the pulmonary vein isolation (P = 0.088). Although there were no significant differences in the AF cure rate between groups Q1-Q3, the AF cure rate was significantly lower in group Q4 than the other groups (P < 0.001). A multivariate Cox proportional hazard model revealed that the preoperative LAD and cardiothoracic ratio were significant risk factors of AF recurrence (hazard ratio 1.063 per 1-mm increase, P = 0.003, and hazard ratio 1.064 per 1% increase, P = 0.043, respectively). AF surgery was effective for 22 years after surgery for AF concomitant with mitral valve disease. A preoperative LAD of >=58.0 mm and the cardiothoracic ratio were risk factors of AF recurrence after AF surgery. PMID- 29410136 TI - Pretherapeutic Functional Imaging Allows Prediction of Head Tremor Arrest After Thalamotomy for Essential Tremor: The Role of Altered Interconnectivity Between Thalamolimbic and Supplementary Motor Circuits. AB - OBJECTIVE: To correlate pretherapeutic resting-state functional magnetic resonance imaging (rs-fMRI) measures with pretherapeutic head tremor presence and/or further improvement 1 year after stereotactic radiosurgical thalamotomy (SRS-T) for essential tremor (ET). METHODS: We prospectively collected head tremor scores (range, 0-3) and rs-fMRI data for a cohort of 17 consecutive ET patients in pretherapeutic and 1 year after SRS-T states. We additionally acquired rs-fMRI data for a healthy control (HC) group (n = 12). Group-level independent component analysis (n = 17 for pretherapeutic rs-fMRI) was applied to decompose neuroimaging data into 20 large-scale brain networks using a standard approach. Through spatial regression, we projected 1 year after SRS-T and HC rs fMRI time points, on the same 20 brain networks. RESULTS: Pretherapeutic interconnectivity (IC) strength between the network including bilateral thalamus and limbic system with left supplementary motor area predicted head tremor improvement at 1 year after SRS-T (family-wise corrected P < 0.001, cluster size Kc = 146). For the statistically significant cluster, IC strength was strongest in HCs (mean, 4.6; median, 3.8) compared with pre- (mean, 0.1; median, 0.2) or posttherapeutic (mean, -0.2; median, 0.09) states. CONCLUSIONS: Baseline measures of IC between bilateral thalamus and limbic system with left supplementary motor area may predict head tremor arrest after thalamotomy. However, procedures such as SRS-T, for this particular clinical feature, do not align patients to HCs in terms of functional brain connectivity. We postulate that supplementary motor area is modulating head tremor appearance, by abnormal connectivity with the thalamolimbic system. PMID- 29410137 TI - Fibrin glue versus staple mesh fixation in single-port laparoscopic totally extraperitoneal inguinal hernia repair: A propensity score-matched analysis. AB - BACKGROUND: Mesh fixation minimizes the risk of recurrence following laparoscopic inguinal hernia repair. Mesh fixation using staples has been implicated as a cause of chronic inguinal pain. We investigated whether fibrin glue mesh fixation reduces acute or chronic postoperative pain in patients undergoing single-port laparoscopic totally extraperitoneal inguinal hernia repair (SP TEP). METHODS: Inguinal hernia patients undergoing SP TEP between October 2013 and September 2016 were evaluated. Propensity score matching was performed to compare short term and chronic pain in patients undergoing mesh fixation involving either staples or fibrin glue. RESULTS: Stapling was performed in 82 patients and 78 underwent fibrin glue mesh fixation; these individuals were balanced into 50 pairs. Immediately after surgery, the fibrin glue group required significantly less analgesia than did the staple group (p = 0.023). Otherwise, no significant between-group differences in postoperative pain scores or analgesia requirements were noted during the initial 7 postoperative days. Activities of daily living (ADLs) resumed earlier in patients undergoing fibrin glue mesh fixation, compared with staples (p = 0.016). At 6 months, no significant differences in the incidence of chronic pain were observed. CONCLUSIONS: The short-term outcomes of SP TEP were comparable regardless of the mesh fixation method, but the immediate postoperative analgesia requirement was significantly less for those in the fibrin glue group. The time to resume ADLs was shorter for the fibrin glue group. Fibrin glue for mesh fixation during SP TEP may be an efficacious alternative to stapling during minimally invasive inguinal hernia repair. PMID- 29410138 TI - Lamprey immune protein-1 (LIP-1) from Lampetra japonica induces cell cycle arrest and cell death in HeLa cells. AB - The lamprey (Lampetra japonica), a representative of the jawless vertebrates, is the oldest extant species in the world. LIP-1, which has a jacalin-like domain and an aerolysin pore-forming domain, has previously been identified in Lampetra japonica. However, the structure and function of the LIP-1 protein have not been described. In this study, the LIP-1 gene was overexpressed in HeLa cells and H293T cells. The results showed that the overexpression of LIP-1 in HeLa cells significantly elevated LDH release (P < 0.05), phosphatidylserine exposure and ROS accumulation. The overexpression of LIP-1 also had remarkable effects on the organelles in HeLa cells, while it had no effect on H293T cell organelles. Array data indicated that overexpression of LIP-1 primarily upregulated P53 signaling pathways in HeLa cells. Cell cycle assay results confirmed that LIP-1 caused arrest in the G2/M phase of the cell cycle in HeLa cells. In summary, our findings provide insights into the function and characterization of LIP-1 genes in vertebrates and establish the foundation for further research into the biological function of LIP-1. Our observations suggest that this lamprey protein has the potential for use in new applications in the medical field. PMID- 29410139 TI - Significance of microcystic, elongated, and fragmented glandular-like features in intraductal papillary mucinous neoplasm of the pancreas. AB - Microcystic, elongated, and fragmented (MELF) glandular features are associated with epithelial-mesenchymal transition, invasion, and progression in endometrioid adenocarcinoma of the uterus. Similar histological features are also observed at the periphery of pancreatic intraductal papillary mucinous neoplasms (IPMNs). However, the clinicopathological significance of MELF-like features-particularly whether they represent regenerative or truly neoplastic conditions-in IPMNs remains unclear. We assessed a total of 152 surgically resected IPMNs. Fifty cases exhibited MELF-like features, including 26 cases of IPMNs with accompanying adenocarcinomas and 24 cases of IPMNs without accompanying adenocarcinomas. MELF like features were more frequently observed in IPMN cases with accompanying adenocarcinomas, larger tumors, main-duct type, and non-gastric histologic subtype. A positive correlation between the presence of MELF-like features and high-grade dysplasia was observed in IPMNs without accompanying adenocarcinomas. Moreover, DPC4 loss and p53 overexpression in MELF-like glands were more commonly observed in IPMNs with high-grade dysplasia. IPMN patients with MELF-like features had worse overall and disease-specific survival by univariate analyses. Our observations suggest that MELF-like features in some IPMNs with high-grade dysplasia could be related to stromal invasion. Hence, when MELF-like features are observed in IPMNs, pathologists should carefully evaluate the results of microscopic examinations to identify the invasive components; and, immunohistochemical staining for DPC4 and p53 could help clarify its clinicopathological significance. PMID- 29410140 TI - Nonaccidental injury presenting as unilateral retinal detachment in two infants. AB - The association between abusive head trauma and retinal hemorrhages is well documented. As such, ophthalmic review in suspected nonaccidental injury has become routine. However, there is a paucity of reports focusing on ocular trauma and retinal detachment presenting as unilateral findings in nonaccidental injury and in the absence of other signs of physical abuse. This report identifies 2 suspected cases of nonaccidental injury in infants presenting to a tertiary care center with retinal detachment presumed secondary to severe unilateral direct ocular trauma. The fellow eye was normal in both cases. Findings were inconsistent with the reported histories from parents. PMID- 29410141 TI - Development of polymorphic microsatellites for the invasive Asian fish tapeworm Schyzocotyle acheilognathi. AB - We describe the development of ready-to-use set of fifteen polymorphic microsatellite markers to benefit future population biology and phylogeographic studies on the invasive Asian fish tapeworm Schyzocotyle acheilognathi. The microsatellite loci were selected from partial Illumina shotgun genome sequences of three parasite specimens and their universality tested on a set of 12 geographically distant populations of the parasite. Particularly low levels of heterozygosity have been detected in the Chinese population pointing towards possible hidden population structure that deserves further attention in future population genetic studies. PMID- 29410142 TI - A Randomized Multicenter Study Assessing the Educational Impact of a Computerized Interactive Hysterectomy Trainer on Gynecology Residents. AB - STUDY OBJECTIVE: To assess the improvement of cognitive surgical knowledge of laparoscopic hysterectomy in postgraduate year (PGY) 1 and 2 gynecology residents who used an interactive computer-based Laparoscopic Hysterectomy Trainer (Red Llama, Inc., Seattle, WA). DESIGN: A multicenter, randomized, controlled study (Canadian Task Force classification I). SETTING: Five departments of obstetrics and gynecology: Keck School of Medicine of the University of Southern California, Los Angeles, CA; University of California, Los Angeles, Los Angeles, CA; University of Washington, Seattle, WA; University of British Columbia, Vancouver, British Columbia, Canada; and University of Toronto, Toronto, Ontario, Canada. PARTICIPANTS: Gynecology residents, fellows, faculty, and minimally invasive surgeons. INTERVENTIONS: The use of an interactive computer-based Laparoscopic Hysterectomy Trainer. MEASUREMENTS AND MAIN RESULTS: In phase 1 of this 3-phase multicenter study, 2 hysterectomy knowledge assessment tests (A and B) were developed using a modified Delphi technique. Phase 2 administered these 2 online tests to PGY 3 and 4 gynecology residents, gynecology surgical fellows, faculty, and minimally invasive surgeons (n = 60). In phase 3, PGY 1 and 2 gynecology residents (n = 128) were recruited, and 101 chose to participate, were pretested (test A), and then randomized to the control or intervention group. Both groups continued site-specific training while the intervention group additionally used the Laparoscopic Hysterectomy Trainer. Participant residents were subsequently posttested (test B). Phase 2 results showed no differences between cognitive tests A and B when assessed for equivalence, internal consistency, and reliability. Construct validity was shown for both tests (p < .001). In phase 3, the pretest mean score for the control group was 242 (standard deviation [SD] = 56.5), and for the intervention group it was 217 (SD = 57.6) (nonsignificant difference, p = .089). The t test comparing the posttest control group (mean = 297, SD = 53.6) and the posttest intervention group (mean = 343, SD = 50.9) yielded a significant difference (p < .001, 95% confidence interval, 48.4-108.8). Posttest scores for the intervention group were significantly better than for the control group (p < .001). CONCLUSION: Using the Laparoscopic Hysterectomy Trainer significantly increased knowledge of the hysterectomy procedure in PGY 1 and 2 gynecology residents. PMID- 29410143 TI - Transvaginal Natural Orifice Transluminal Endoscopic Surgery Myomectomy: A Novel Route for Uterine Myoma Removal. AB - STUDY OBJECTIVE: Transvaginal surgery is the most minimally invasive surgery for a gynecologic procedure, but it has the limitation of lack of exposure and limited surgical space when using traditional vaginal surgical instrumentation, such as in a hysterectomy for a uterus without descent or for a myomectomy. Transvaginal natural orifice transluminal endoscopic surgery (NOTES) offers similar benefits of traditional vaginal surgery but also expands the horizon of transvaginal surgery by allowing the surgeon to perform procedures that are typically limited to an abdominal approach. The advantages of NOTES may include no incisional pain as well as a better cosmetic outcome. These benefits help outweigh the obstacle of learning this novel approach. Our objective is to demonstrate the transvaginal NOTES technique as a combination of traditional vaginal surgical skill with single-site surgical skill. DESIGN: Stepwise demonstration of the transvaginal NOTES technique for myomectomy with narrated video footage (Canadian Task Force classification III). SETTING: Academic tertiary care hospital. PATIENT: A 42-year-old woman. INTERVENTIONS: Transvaginal NOTES myomectomy with combined transvaginal surgical and single-site surgical skills. MEASUREMENTS AND MAIN RESULTS: A 42-year-old woman (gravida 2 para 2) with a preoperative transvaginal ultrasound diagnosis of a 6-cm left anterior myoma requested myoma removal with uterine preservation. She presented with a 2 year history of left pelvic pain and menorrhagia. The myoma was removed with minimal blood loss, and pathology revealed a necrotic myoma. The patient had resolution of her left-sided pelvic pain. CONCLUSIONS: Combined with traditional transvaginal anterior colpotomy, single-site surgical skills allow the surgeon to access the entire abdomen and perform myomectomy through a transvaginal single port. Transvaginal NOTES myomectomy is not only possible but allows myomectomy to be performed with no abdominal incision. PMID- 29410145 TI - Response to 'The start of another infection prevention learning curve: reducing healthcare-associated Gram-negative bloodstream infections'. PMID- 29410144 TI - Endoscopic Endonasal Transrotundum Middle Fossa Exposure: Technique of Transpterygoid Maxillary Nerve Transposition. AB - OBJECTIVE: Middle fossa floor access can be challenging. Open skull base approaches have associated morbidity and yield suboptimal working angles around the temporal lobe. Endoscopic endonasal approaches to the middle fossa are poorly described, but provide an improved angle. I hypothesized that the length of the maxillary nerve can be transposed out of the foramen rotundum to provide a path to expose the full width of the middle fossa floor through the anterolateral and anteromedial triangle. METHODS: Endoscopic endonasal transpterygoid dissections to expose the middle fossa were performed bilaterally on 2 silicone-injected cadaveric heads (4 sides). Transposition of V2 was then performed on all sides, and additional middle fossa exposure was achieved. High-resolution computed tomography imaging was obtained to quantify the extent of exposure. A transzygomatic approach was also performed for comparison. RESULTS: The maxillary nerve was successfully transposed in each dissection. A periosteal fold was identified to assist in the mobilization of the infraorbital nerve. The average middle fossa exposure achieved without transposition was 50% (of the medial to lateral width). Transposition increased that to 95%. Comparison with the open transzygomatic approach demonstrated superior surgical trajectory (inferior to superior) with the endonasal route. CONCLUSIONS: Endoscopic endonasal transpterygoid approaches with or without transposition of the maxillary nerve provide a reasonable option for sequentially exposing the entire medial to lateral extent of the anterolateral triangle. It provides an advantageous inferior to superior surgical angle and can be considered for treatment of select middle fossa floor pathology. PMID- 29410146 TI - A method for the analysis and visualization of clinical workflow in dynamic environments. AB - The analysis of clinical workflow offers many challenges, especially in settings characterized by rapid dynamic change. Typically, some combination of approaches drawn from ethnography and grounded theory-based qualitative methods are used to develop relevant metrics. Medical institutions have recently attempted to introduce technological interventions to develop quantifiable quality metrics to supplement existing purely qualitative analyses. These interventions range from automated location tracking to repositories of clinical data (e.g., electronics health record (EHR) data, medical equipment logs). Our goal in this paper is to present a cohesive framework that combines a set of analytic techniques that can potentially complement traditional human observations to derive a deeper understanding of clinical workflow and thereby to enhance the quality, safety, and efficiency of care offered in that environment. We present a series of theoretically-guided techniques to perform analysis and visualization of data developed using location tracking, with illustrations using the Emergency Department (ED) as an example. Our framework is divided into three modules: (i) transformation, (ii) analysis, and (iii) visualization. We describe the methods used in each of these modules, and provide a series of visualizations developed using location-tracking data collected at the Mayo Clinic ED (Phoenix, AZ). Our innovative analytics go beyond qualitative study, and includes user data collected from a relatively modern but increasingly ubiquitous technique of location tracking, with the goal of creating quantitative workflow metrics. Although we believe that the methods we have developed will generalize well to other settings, additional work will be required to demonstrate their broad utility beyond our single study environment. PMID- 29410147 TI - Evaluation of Mycobacterium tuberculosis-specific antibody responses for the discrimination of active and latent tuberculosis infection. AB - OBJECTIVES: The serological antibody detection tests offer several advantages for the rapid diagnosis of tuberculosis (TB). The Mycobacterium tuberculosis-specific antibody responses associated with different stages of TB infection remain to be investigated. METHODS: The Pathozyme-Myco IgG (Myco G), Pathozyme TB Complex Plus (TB Complex), IBL M. tuberculosis IgG ELISA (IBL), Anda Biologicals TB IgG (Anda TB), and T-SPOT.TB (T-SPOT) tests were performed for 133 active TB patients (ATB group), 131 controls (CON group), and 95 subjects with latent TB infection (LTBI group). RESULTS: The four serological tests all showed relatively low sensitivity in the ATB group but high specificity in the LTBI and CON groups. The antibody levels of the four serological tests were significantly higher in the ATB group than in the LTBI group. The same trend was observed between the LTBI and CON groups. The four serological tests demonstrated potential diagnostic value in discriminating ATB from LTBI. A combination of the Anda-TB and TB Complex tests exhibited the best diagnostic potential in discriminating ATB from LTBI, with a sensitivity of 89.4% and a specificity of 94.7%. Further, the diagnostic value of Anda-TB and TB Complex were validated in a prospective cohort including 106 patients with suspected ATB. Combined with the T-SPOT test, the tests showed a sensitivity of 87.2% and a specificity of 92.5% for discriminating ATB patients from all ATB suspected cases in the validation group. CONCLUSIONS: The antibody responses of the serological tests all showed significant differences between the ATB and LTBI groups. A combination of Anda-TB and the TB Complex test demonstrated high diagnostic potential in discriminating ATB from LTBI and may be an additional diagnostic tool in the diagnosis of M. tuberculosis infection. PMID- 29410148 TI - Cryo-tomography tilt-series alignment with consideration of the beam-induced sample motion. AB - Recent evidence suggests that the beam-induced motion of the sample during tilt series acquisition is a major resolution-limiting factor in electron cryo tomography (cryoET). It causes suboptimal tilt-series alignment and thus deterioration of the reconstruction quality. Here we present a novel approach to tilt-series alignment and tomographic reconstruction that considers the beam induced sample motion through the tilt-series. It extends the standard fiducial based alignment approach in cryoET by introducing quadratic polynomials to model the sample motion. The model can be used during reconstruction to yield a motion compensated tomogram. We evaluated our method on various datasets with different sample sizes. The results demonstrate that our method could be a useful tool to improve the quality of tomograms and the resolution in cryoET. PMID- 29410149 TI - Cost calculation for a flash glucose monitoring system for UK adults with type 1 diabetes mellitus receiving intensive insulin treatment. AB - AIMS: To estimate the costs associated with a flash glucose monitoring system as a replacement for routine self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes mellitus (T1DM) using intensive insulin, from a UK National Health Service (NHS) perspective. METHODS: The base-case cost calculation was created using the maximum frequency of glucose monitoring recommended by the 2015 National Institute for Health and Care Excellence guidelines (4-10 tests per day). Scenario analyses considered SMBG at the frequency observed in the IMPACT clinical trial (5.6 tests per day) and at the frequency of flash monitoring observed in a real-world analysis (16 tests per day). A further scenario included potential costs associated with severe hypoglycaemia. RESULTS: In the base case, the annual cost per patient using flash monitoring was L234 (19%) lower compared with routine SMBG (10 tests per day). In scenario analyses, the annual cost per patient of flash monitoring compared with 5.6 and 16 SMBG tests per day was L296 higher and L957 lower, respectively. The annual cost of severe hypoglycaemia for flash monitoring users was estimated to be L221 per patient, compared with L428 for routine SMBG users (based on 5.6 tests/day), corresponding to a reduction in costs of L207. CONCLUSIONS: The flash monitoring system has a modest impact on glucose monitoring costs for the UK NHS for patients with T1DM using intensive insulin. For people requiring frequent tests, flash monitoring may be cost saving, especially when taking into account potential reductions in the rate of severe hypoglycaemia. PMID- 29410150 TI - High performance of maternal characteristics and assessment of uterine artery Doppler waveform for the prediction of early-onset preeclampsia. PMID- 29410151 TI - Placenta increta after high-intensity-focused ultrasound for the treatment of a uterine leiomyoma. PMID- 29410153 TI - A reconstitution method for integral membrane proteins in hybrid lipid-polymer vesicles for enhanced functional durability. AB - Hybrid vesicles composed of lipids and block copolymers hold promise for increasing liposome stability and providing a stable environment for membrane proteins. Recently we reported the successful functional reconstitution of the integral membrane protein cytochrome bo3 (ubiquinol oxidase) into hybrid vesicles composed of a blend of phospholipids and a block copolymer (PBd-PEO). We demonstrated that these novel membrane environments stabilise the enzymes' activity, prolonging their functional lifetime [Chem. Commun. 52 (2016) 11020 11023]. This approach holds great promise for applications of membrane proteins where enhanced durability, stability and shelf-life will be essential to creating a viable technology. Here we present a detailed account of our methods for membrane protein reconstitution into hybrid vesicles and discuss tips and challenges when using block copolymers compared to pure phospholipid systems that are more common materials for this purpose. We also extend the characterisation of these hybrid vesicles beyond what we have previously reported and show: (i) hybrid membranes are less permeable to protons than phospholipid bilayers; (ii) extended enzyme activity data is presented over a period of 500 days, which fully reveals the truly remarkable enhancement in functional lifetime that hybrid vesicles facilitate. PMID- 29410152 TI - Quantitative analysis in peritumoral volumes of brain metastases treated with stereotactic radiotherapy. AB - PURPOSE: The purpose of this study was to verify changes in diffusion tensor imaging (DTI) factors in patients with brain metastases treated with stereotactic radiotherapy (SRT). We also investigated the impact of SRT on peritumoral volumes though the use of DTI. METHODS: A total of 28 patients with brain metastases who had undergone SRT between March 2014 and December 2015 were enrolled. Magnetic resonance imaging with DTI factors, such as fractional anisotropy (FA) and apparent diffusion tensor (ADC) value, was performed 1 day before the procedure and 3 months after the procedure. DTI data from tumor lesions, edema volumes, and the volumes that received 12Gy were measured. RESULTS: Tumor volume (P=0.001) and ADC values in the volumes that received 12Gy (P=0.018) and the edema volumes (P=0.003) significantly decreased after the procedure. Decreases in tumor volume were only correlated with decreases in edema volumes (P<0.001). Decreases in edema volumes were correlated with increases in FA values and decreases in ADC values of the volumes that received 12Gy [P=0.019 (FA)/0.002 (ADC)] and the edema volumes [P=0.011 (FA)/0.002 (ADC)]. CONCLUSIONS: It was possible to quantify changes in peritumoral volumes in patients with brain metastases after SRT by using DTI. ADC values of peritumoral volumes decreased significantly after SRT. Therefore, it was confirmed through DTI that performing SRT on tumor lesions has a positive effect on the structure and function of peritumoral volumes. PMID- 29410154 TI - Antinociceptive and anti-inflammatory activities of a standardizedextract of bis iridoids from Pterocephalus hookeri. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pterocephalus hookeri (C.B. Clarke) Hoeck, one of the most popular Tibetan herbs, has been widely applied in Tibetan medicine prescriptions. Chemical investigations have led to the isolation of many bis iridoids. However, the pharmacological activities of bis-iridoid constituents of this plant have never been reported before. AIM OF THE STUDY: This study evaluated the anti-inflammatory and analgesic activities of afraction of bis iridoid constituents of P. hookeri (BCPH) in order to provide experimental evidence for its traditional use, such as for cold, flu, and rheumatoid arthritis. MATERIALS AND METHODS: The analgesic effects of BCPH were investigated using the hot-plate test and acetic acid-induced writhing test. The anti inflammatory activities were observed using the following models: carrageenin induced edema of the hind paw of rats and xylene-induced ear edema in mice. The effects of dexamethasone administration were also studied. RESULTS: BCPH significantly increased the hot-platepain threshold and reduced acetic acid induced writhing response in mice. Moreover, BCPH remarkably inhibited xylene induced ear edema and reduced the carrageenin-induced rat paw edema perimeter. CONCLUSION: The results reveal that BCPH has central, peripheral analgesic activities as well as anti-inflammatory effects, supporting the traditional application of this herb in treating various diseases associated with inflammation and pain. PMID- 29410155 TI - Best Practices for Physician-Scientist Training Programs: Recommendations from the Alliance for Academic Internal Medicine. PMID- 29410156 TI - Backstories on the US Opioid Epidemic. Good Intentions Gone Bad, an Industry Gone Rogue, and Watch Dogs Gone to Sleep. AB - Epidemics of opioid use are old news in the United States, but an epidemic that kills over 200,000 Americans is not. A multiplicity of intertwined factors have brought us to this place. From 30,000 feet, it is the story of good intentions gone bad, a drug industry gone rogue, and government watch dog agencies gone to sleep. At ground level, it is the story of physicians unfamiliar with addictive drugs and drug addiction, new long-acting opioids deceptively marketed, cheap black tar heroin, encouragement to use opioids for chronic noncancer pain by professional organizations with conflicts of interest and without science, a culture intolerant to pain and tolerant to drug use, and the greedy response of the pharmaceutical industry and drug cartels to an expanding market opportunity. These factors are among those that have joined to form a tsunami of addiction and deaths that keeps on coming. A better understanding of them could speed the end of the present cycle of opioid abuse, perhaps prevent others, and inform future decisions about pain management. PMID- 29410157 TI - Regulatory-accepted drug development tools are needed to accelerate innovative CNS disease treatments. AB - Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics. PMID- 29410159 TI - Sinus tarsi approach (STA) versus extensile lateral approach (ELA) for treatment of closed displaced intra-articular calcaneal fractures (DIACF): A meta-analysis. AB - INTRODUCTION: Our aim was to compare the effect of sinus tarsi approach (STA) vs extensile lateral approach (ELA) for treatment of closed displaced intra articular calcaneal fractures (DIACF) is still being debated. MATERIALS AND METHODS: A thorough research was carried out in the MEDLINE, EMBASE and Cochrane library databases from inception to December 2016. Only prospective or retrospective comparative studies were selected in this meta-analysis. Two independent reviewers conducted literature search, data extraction and quality assessment. The primary outcomes were anatomical restoration and prevalence of complications. Secondary outcomes included operation time and functional recovery. RESULTS: Four randomized controlled trials involving 326 patients and three cohort studies involving 206 patients were included. STA technique for DIACFs led to a decline in both operation time and incidence of complications. There were no significant differences between the groups in American Orthopedic Foot and Ankle Society scores, nor changes in Bohler angle. CONCLUSIONS: This meta-analysis suggests that STA technique may reduce the operation time and incidence of complications. In conclusion, STA technique is reasonably an optimal choice for DIACF. PMID- 29410160 TI - Sensing adhesion forces between erythrocytes and gamma' fibrinogen, modulating fibrin clot architecture and function. AB - Plasma fibrinogen includes an alternatively spliced gamma-chain variant (gamma'), which mainly exists as a heterodimer (gammaAgamma') and has been associated with thrombosis. We tested gammaAgamma' fibrinogen-red blood cells (RBCs) interaction using atomic force microscopy-based force spectroscopy, magnetic tweezers, fibrin clot permeability, scanning electron microscopy and laser scanning confocal microscopy. Data reveal higher work necessary for RBC-RBC detachment in the presence of gammaAgamma' rather than gammaAgammaA fibrinogen. gammaAgamma' fibrinogen-RBCs interaction is followed by changes in fibrin network structure, which forms an heterogeneous clot structure with areas of denser and highly branched fibrin fibers. The presence of RBCs also increased the stiffness of gammaAgamma' fibrin clots, which are less permeable and more resistant to lysis than gammaAgammaA clots. The modifications on clots promoted by RBCs-gammaAgamma' fibrinogen interaction could alter the risk of thrombotic disorders. PMID- 29410161 TI - Trace amounts of pyroglutaminated Abeta-(3-42) enhance aggregation of Abeta-(1 42) on neuronal membranes at physiological concentrations: FCS analysis of cell surface. AB - Minor species of amyloid beta-peptide (Abeta), such as Abeta-(1-43) and pyroglutaminated Abeta-(3-42) (Abeta-(3pE-42)), have been suggested to be involved in the initiation of the Abeta aggregation process, which is closely associated with the etiology of Alzheimer's disease. They can play important roles in aggregation not only in the aqueous phase but also on neuroral membranes; however, the latter behaviors remain mostly unexplored. Here, initial aggregation processes of Abeta on living cells were monitored at physiological nanomolar concentrations by fluorescence correlation spectroscopy. Membrane-bound Abeta-(1-42) and Abeta-(1-40) formed oligomers composed of ~4 Abeta molecules during 48-h incubation, whereas the peptides remained monomeric in the culture medium, indicating that the membranes facilitated Abeta aggregation. The presence of 5 mol% Abeta-(3pE-42), but not Abeta-(1-43), significantly enhanced the aggregation of Abeta-(1-42) up to ~10-mers. On the other hand, neither trace amounts of Abeta-(1-42) nor Abeta-(3pE-42) enhanced the aggregation of Abeta-(1 40). The observed small Abeta oligomers are expected to act as pathogenic seeds for amyloid fibrils responsible for neurotoxicity. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29410162 TI - Microbiologic Outcome of Interventions Against Mycobacterium avium Complex Pulmonary Disease: A Systematic Review. AB - OBJECTIVE: Pulmonary disease (PD) caused by Mycobacterium avium complex (MAC) is increasing worldwide. We conducted a systematic review of studies that include microbiologic outcomes to evaluate current macrolide-based treatment regimens. METHODS: We searched literature published before April 2017 by using the MEDLINE, Cochrane, and Embase databases. Risk of bias in randomized trials was assessed using the Cochrane tool. RESULTS: We retrieved 333 citations and evaluated 42 studies including 2,748 patients: 18 studies were retrospective chart reviews, 18 were prospective, and six were randomized. The weighted average proportion of sputum culture conversions in macrolide-containing regimens after subtracting posttreatment microbiologic recurrences was 52.3% (95% CI, 44.7%-59.9%). Using the triple-drug regimens recommended by the American Thoracic Society (ATS) achieved treatment success in 61.4% (95% CI, 49.7%-72.5%), which further increased to 65.7% (95% CI, 53.3%-77.4%) when drugs were taken for at least 1 year by patients who were macrolide susceptible and had previously untreated MAC. The overall risk of bias was low in five of the six randomized trials. However, selective outcome reporting because of a posteriori exclusion of initially included patients (14.0%), uncompleted treatment (17.6%), and inconsistent use of outcome parameters (17 definitions of treatment success) hampered the comparison of nonrandomized trials. CONCLUSIONS: To date, randomized studies on treatment outcome in patients with MAC PD are scarce. Long-term treatments with ATS recommended regimens for patients who are macrolide susceptible are superior to other macrolide-based therapies. A standardized definition of treatment success and genotypic distinction between reinfection and relapse by means of pretreatment and posttreatment identification of MAC species in cases of microbiologic recurrences may help to optimize evaluation of treatment regimens in the future. PMID- 29410158 TI - Fluorescence anisotropy imaging in drug discovery. AB - Non-invasive measurement of drug-target engagement can provide critical insights in the molecular pharmacology of small molecule drugs. Fluorescence polarization/fluorescence anisotropy measurements are commonly employed in protein/cell screening assays. However, the expansion of such measurements to the in vivo setting has proven difficult until recently. With the advent of high resolution fluorescence anisotropy microscopy it is now possible to perform kinetic measurements of intracellular drug distribution and target engagement in commonly used mouse models. In this review we discuss the background, current advances and future perspectives in intravital fluorescence anisotropy measurements to derive pharmacokinetic and pharmacodynamic measurements in single cells and whole organs. PMID- 29410163 TI - Management of Low-Risk Pulmonary Embolism Patients Without Hospitalization: The Low-Risk Pulmonary Embolism Prospective Management Study. AB - BACKGROUND: The efficacy and safety of managing patients with low-risk pulmonary embolism (PE) without hospitalization requires objective data from US medical centers. We sought to determine the 90-day composite rate of recurrent symptomatic VTE, major bleeding events, and all-cause mortality among consecutive patients diagnosed with acute low-risk PE managed without inpatient hospitalization; and to measure patient satisfaction. METHODS: We performed a prospective cohort single-arm management study conducted from January 2013 to October 2016 in five EDs. We enrolled 200 consecutive adults diagnosed with objectively confirmed acute PE and assessed to have a low risk for mortality using the Pulmonary Embolism Severity Index (PESI) score (< 86), echocardiography, and whole-leg compression ultrasound (CUS). The primary intervention was observation in the ED or hospital (observation status) for > 12 to < 24 h, followed by outpatient management with Food and Drug Administration approved therapeutic anticoagulation. Patients were excluded for a PESI >= 86, echocardiographic signs of right heart strain, DVT proximal to the popliteal vein, hypoxia, hypotension, hepatic or renal failure, contraindication to therapeutic anticoagulation, or another condition requiring hospital admission. The primary outcome was 90-day composite rate of all-cause mortality, recurrent symptomatic VTE, and major bleeding. RESULTS: The composite outcome occurred in one of 200 patients (90-day composite rate = 0.5%; 95% CI, 0.02%-2.36%). No patient suffered recurrent VTE or died during the 90-day follow-up period. A major bleed occurred in one patient. Patients indicated a high level of satisfaction with their care. CONCLUSIONS: Treatment of carefully selected patients with acute PE and low risk by PESI < 86, echocardiography, and CUS without inpatient hospitalization is safe and acceptable to patients. Results must be viewed with caution because of the small sample size relative to the end point and the generalizability surrounding availability of emergent echocardiography. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02355548; URL: www.clinicaltrials.gov. PMID- 29410164 TI - Rebuttal From Dr Weiner. PMID- 29410166 TI - Silk fibroin/collagen protein hybrid cell-encapsulating hydrogels with tunable gelation and improved physical and biological properties. AB - : Cell encapsulating hydrogels with tunable mechanical and biological properties are of special importance for cell delivery and tissue engineering. Silk fibroin and collagen, two typical important biological proteins, are considered potential as cell culture hydrogels. However, both have been used individually, with limited properties (e.g., collagen has poor mechanical properties and cell mediated shrinkage, and silk fibroin from Bombyx mori (mulberry) lacks cell adhesion motifs). Therefore, the combination of them is considered to achieve improved mechanical and biological properties with respect to individual hydrogels. Here, we show that the cell-encapsulating hydrogels of mulberry silk fibroin / collagen are implementable over a wide range of compositions, enabled simply by combining the different gelation mechanisms. Not only the gelation reaction but also the structural characteristics, consequently, the mechanical properties and cellular behaviors are accelerated significantly by the silk fibroin / collagen hybrid hydrogel approach. Of note, the mechanical and biological properties are tunable to represent the combined merits of individual proteins. The shear storage modulus is tailored to range from 0.1 to 20 kPa along the iso-compositional line, which is considered to cover the matrix stiffness of soft-to-hard tissues. In particular, the silk fibroin / collagen hydrogels are highly elastic, exhibiting excellent resistance to permanent deformation under different modes of stress; without being collapsed or water-squeezed out (vs. not possible in individual proteins) - which results from the mechanical synergism of interpenetrating networks of both proteins. Furthermore, the role of collagen protein component in the hybrid hydrogels provides adhesive sites to cells, stimulating anchorage and spreading significantly with respect to mulberry silk fibroin gel, which lacks cell adhesion motifs. The silk fibroin / collagen hydrogels can encapsulate cells while preserving the viability and growth over a long 3D culture period. Our findings demonstrate that the silk / collagen hydrogels possess physical and biological properties tunable and significantly improved (vs. the individual protein gels), implying their potential uses for cell delivery and tissue engineering. STATEMENT OF SIGNIFICANCE: Development of cell encapsulating hydrogels with excellent physical and biological properties is important for the cell delivery and cell-based tissue engineering. Here we communicate for the first time the novel protein composite hydrogels comprised of 'Silk' and 'Collagen' and report their outstanding physical, mechanical and biological properties that are not readily achievable with individual protein hydrogels. The properties include i) gelation accelerated over a wide range of compositions, ii) stiffness levels covering 0.1 kPa to 20 kPa that mimic those of soft-to-hard tissues, iii) excellent elastic behaviors under various stress modes (bending, twisting, stretching, and compression), iv) high resistance to cell mediated gel contraction, v) rapid anchorage and spreading of cells, and vi) cell encapsulation ability with a long-term survivability. These results come from the synergism of individual proteins of alpha-helix and beta-sheet structured networks. We consider the current elastic cell-encapsulating hydrogels of silk collagen can be potentially useful for the cell delivery and tissue engineering in a wide spectrum of soft-to-hard tissues. PMID- 29410165 TI - Mid-gestational sevoflurane exposure inhibits fetal neural stem cell proliferation and impairs postnatal learning and memory function in a dose dependent manner. AB - Advancements in fetal intervention procedures have led to increases in the number of pregnant women undergoing general anesthesia during the second trimester-a period characterized by extensive proliferation of fetal neural stem cells (NSCs). However, few studies have investigated the effects of mid-gestational sevoflurane exposure on fetal NSC proliferation or postnatal learning and memory function. In the present study, pregnant rats were randomly assigned to a control group (C group), a low sevoflurane concentration group (2%; L group), a high sevoflurane concentration group (3.5%; H group), a high sevoflurane concentration plus lithium chloride group (H + Li group), and a lithium chloride group (Li group) at gestational day 14. Rats received different concentrations of sevoflurane anesthesia for 2 h. The offspring rats were weaned at 28 days for behavioral testing (i.e., Morris Water Maze [MWM]), and fetal brains or postnatal hippocampal tissues were harvested for immunofluorescence staining, real-time PCR, and Western blotting analyses in order to determine the effect of sevoflurane exposure on NSC proliferation and the Wnt/beta-catenin signaling pathway. Our results indicated that maternal exposure to 3.5% sevoflurane (H group) during the mid-gestational period impaired the performance of offspring rats in the MWM test, reduced NSC proliferation, and increased protein levels of fetal glycogen synthase kinase-3 beta (GSK-3beta). Such treatment also decreased levels of beta-catenin protein, CD44 RNA, and Cyclin D1 RNA relative to those observed in the C group. However, these effects were transiently attenuated by treatment with lithium chloride. Conversely, maternal exposure to 2% sevoflurane (L group) did not influence NSC proliferation or the Wnt signaling pathway. Our results suggest that sevoflurane exposure during the second trimester inhibits fetal NSC proliferation via the Wnt/beta-catenin pathway and impairs postnatal learning and memory function in a dose-dependent manner. PMID- 29410167 TI - Post-exposure prevention of toxicodendron dermatitis with early forceful unidirectional washing. PMID- 29410168 TI - Pullulan as a potent green inhibitor for corrosion mitigation of aluminum composite: Electrochemical and surface studies. AB - This work emphasizes the corrosion inhibition ability of pullulan, an environmentally benign fungal polysaccharide on acid corrosion of 6061Aluminum 15%(v) SiC(P) composite material (Al-CM). The electrochemical measurements such as potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) studies were carried out for the corrosion inhibition studies. Conditions were optimized to obtain maximum inhibition efficiency, by performing the experiment at varying concentrations of inhibitor, in the temperature range of 308K- 323K. Surface morphology studies were done to reaffirm the adsorption of inhibitor on the surface of composite material. Pullulan acted as mixed type of inhibitor with a maximum efficiency of 89% at 303K for the addition of 1.0 gL-1 of inhibitor. Evaluation of kinetic and thermodynamic parameters revealed that inhibitor underwent physical adsorption onto the surface of Al-CM and obeyed Freundlich adsorption isotherm. The surface characterization like SEM-EDX, AFM confirmed the adsorption of pullulan molecule. Pullulan can be considered as effective, eco friendly green inhibitor for the corrosion control of Al-CM. PMID- 29410169 TI - Telemedicine for Neurotrauma in Albania: Initial Results from Case Series of 146 Patients. AB - BACKGROUND: Use of telemedicine for neurotrauma when performed by neurosurgeons is an innovative care option for traumatic brain injury patients, particularly in countries with limited neurosurgery expertise resources. In recent years, Albania has developed a robust telemedicine program and teleneurotrauma is the flagship of the program. We aimed to evaluate the outcomes of the first neurotrauma patients managed via telemedicine in Albania. METHODS: A retrospective analysis of prospectively collected data on all telemedicine consultations for isolated neurotrauma was performed from 2014 through 2016. Patient demographics, mechanism of injury, modes of teleneurotrauma consultation (store-and-forward vs. live video consultation), outcomes of teleconsultation (whether the patient was transferred or kept at the regional hospital), operative procedures for those transferred, length of hospital stay, and discharge status were analyzed. RESULTS: Of the 146 teleconsultations for neurotrauma, asynchronous technology (store-and-forward) accounted for the majority of teleconsultations (84%), while the live plus store-and-forward technique was employed in 15% of cases. Median time of response to teleconsultation was 20 minutes. Sixty-six percent of patients remained at the referring hospital for further observation and did not require transfer to a trauma center. Of the patients transferred to the tertiary care, 91% were treated nonoperatively, 85% percent were discharged to home, 9% were transferred to another hospital, and 6% died in the hospital. CONCLUSION: Telemedicine for neurotrauma, when structured appropriately and led by neurosurgeons, is a valuable service for the entire country, prevents unnecessary transfers to trauma center, and saves resources, particularly in low- and middle income countries. PMID- 29410171 TI - How Fragile Are Clinical Trial Outcomes That Support the CHEST Clinical Practice Guidelines for VTE? AB - BACKGROUND: VTE remains a health concern for global populations. Clinical practice guidelines are necessary to guide physicians in the prophylaxis and treatment of VTE. METHODS: Our investigation assessed the robustness of the underlying evidence in 21 randomized controlled trials (RCTs) used to support treatment recommendations in the 2016 update of the CHEST Guideline and Expert Panel Report on Antithrombotic Therapy for VTE Disease. We calculated the fragility index and fragility quotient for qualifying outcomes within RCTs. RESULTS: The median fragility index for all studies was 5 (interquartile range, 1 9), with a median fragility quotient of 0.012 (interquartile range, 0.002-0.032). CONCLUSIONS: Our conclusions parallel those of previous investigations of the fragility of RCT outcomes; we found that some outcomes used to support recommendations in AT10 are fragile. We recommend that the fragility index and fragility quotient be adopted as measures of robustness of clinical trial outcomes. PMID- 29410170 TI - Intracellular acidification reduces l-arginine transport via system y+L but not via system y+/CATs and nitric oxide synthase activity in human umbilical vein endothelial cells. AB - l-Arginine is taken up via the cationic amino acid transporters (system y+/CATs) and system y+L in human umbilical vein endothelial cells (HUVECs). l-Arginine is the substrate for endothelial NO synthase (eNOS) which is activated by intracellular alkalization, but nothing is known regarding modulation of system y+/CATs and system y+L activity, and eNOS activity by the pHi in HUVECs. We studied whether an acidic pHi modulates l-arginine transport and eNOS activity in HUVECs. Cells loaded with a pH-sensitive probe were subjected to 0.1-20 mmol/L NH4Cl pulse assay to generate pHi 7.13-6.55. Before pHi started to recover, l arginine transport (0-20 or 0-1000 MUmol/L, 10 s, 37 degrees C) in the absence or presence of 200 MUmol/L N-ethylmaleimide (NEM) (system y+/CATs inhibitor) or 2 mmol/L l-leucine (systemy+L substrate) was measured. Protein abundance for eNOS and serine1177 or threonine495 phosphorylated eNOS was determined. The results show that intracellular acidification reduced system y+L but not system y+/CATs mediated l-arginine maximal transport capacity due to reduced maximal velocity. Acidic pHi reduced NO synthesis and eNOS serine1177 phosphorylation. Thus, system y+L activity is downregulated by an acidic pHi, a phenomenon that may result in reduced NO synthesis in HUVECs. PMID- 29410172 TI - Impact of Additional Treatment of Paralumbar Spine and Peripheral Nerve Diseases After Lumbar Spine Surgery. AB - OBJECTIVE: Some patients experience failed back surgery syndrome after lumbar spine surgery. We report the effect of additional treatments for paralumbar spine and peripheral nerve diseases addressing residual symptoms after surgery. METHODS: We enrolled 74 patients (59 men and 15 women; mean age 62.9 years) who had undergone lumbar posterior decompression surgery. Mean follow-up after initial surgery was 26.2 months (range, 13-48 months). We subsequently diagnosed paralumbar spine diseases, including superior cluneal nerve entrapment neuropathy with (n = 3) or without gluteus medius muscle pain (n = 4) and gluteus medius muscle pain alone (n = 5), and peripheral nerve diseases, including peroneal nerve entrapment neuropathy (n = 4) and tarsal tunnel syndrome (n = 1), based on persistent or recurring clinical symptoms and nerve block effects. Treatment outcomes were analyzed by comparing Roland-Morris Disability Questionnaire and Japanese Orthopaedic Association scores. RESULTS: Of 74 patients, 54 (73.0%) improved after initial lumbar surgery (group A), and 20 (27.0%) continued to experience symptoms or experienced symptom recurrence during follow-up (group B). In group B, 4 patients improved with conservative therapy, 11 underwent 1 additional surgical procedure, and 5 underwent >1 additional surgical procedures. After these additional treatments, clinical outcomes were recorded as good. At the last follow-up visit, there was no difference between group A and group B. CONCLUSIONS: Of 74 patients who underwent lumbar spine surgery, 16 (21.6%) required additional surgery. To reduce the incidence of failed back surgery syndrome, concurrent diseases that may be masked by symptoms resulting from severe lumbar spine disease must be ruled out, as these diseases may become apparent after initial lumbar spine surgery. PMID- 29410173 TI - Knowledge and Attitude Regarding Radiation Exposure Among Spine Surgeons in Latin America. AB - BACKGROUND: Spine surgeons are exposed to high amounts of radiation from fluoroscopic procedures during their lifetime. In this study, we evaluated spine surgeons' knowledge of and attitude regarding radiation exposure during spine surgery. METHODS: We developed a questionnaire including questions about surgeons' characteristics and knowledge of and attitude regarding radiation exposure during spine surgery. A survey was performed with the members of AOSpine Latin America. The main variables studied were specialty, years of experience, surgeon's position during fluoroscopy, and practices to reduce the patient's and surgeon's radiation exposure during surgery. The results were analyzed and compared among different specialties, levels of experience, and countries of origin. RESULTS: The questionnaire was answered by 371 members of AOSpine Latin America from different countries. The sample was mostly from orthopedic surgeons (57.1%) and surgeons in practice for longer than 10 years (54.2%). Thyroid lead protection was used by 64.2% of the spine surgeons, lead glasses by 20.2%, and lead gloves by 7%. A dosimeter badge was never or only rarely used by 75.7%. The correct answer for surgeon position during lateral lumbar fluoroscopy was reported by only one-third of the surgeons. The reported rate of thyroid protector use was higher in surgeons from Brazil and Colombia compared with surgeons from Mexico and Argentina (P < 0.001), whereas the use of pulsed-mode fluoroscopy was higher in Mexico and Argentina compared with Brazil and Colombia (P < 0.0001). CONCLUSIONS: Future efforts toward implementing educational programs in Latin America focused on safety strategies are needed to minimize intraoperative radiation exposure. PMID- 29410174 TI - Mortality after Spontaneous Subarachnoid Hemorrhage: Causality and Validation of a Prediction Model. AB - OBJECTIVE: To evaluate primary causes of death after spontaneous subarachnoid hemorrhage (SAH) and externally validate the HAIR score, a prognostication tool, in a single academic institution. METHODS: We reviewed all patients with SAH admitted to our neuro-intensive care unit between 2010 and 2016. Univariate and multivariate logistic regressions were performed to identify predictors of in hospital mortality. The HAIR score predictors were Hunt and Hess grade at treatment decision, age, intraventricular hemorrhage, and rebleeding within 24 hours. Validation of the HAIR score was characterized with the receiver operating curve, the area under the curve, and a calibration plot. RESULTS: Among 434 patients with SAH, in-hospital mortality was 14.1%. Of the 61 mortalities, 54 (88.5%) had a neurologic cause of death or withdrawal of care and 7 (11.5%) had cardiac death. Median time from SAH to death was 6 days. The main causes of death were effect of the initial hemorrhage (26.2%), rebleeding (23%) and refractory cerebral edema (19.7%). Factors significantly associated with in-hospital mortality in the multivariate analysis were age, Hunt and Hess grade, and intracerebral hemorrhage. Maximum lumen size was also a significant risk factor after aneurysmal SAH. The HAIR score had a satisfactory discriminative ability, with an area under the curve of 0.89. CONCLUSIONS: The in-hospital mortality is lower than in previous reports, attesting to the continuing improvement of our institutional SAH care. The major causes are the same as in previous reports. Despite a different therapeutic protocol, the HAIR score showed good discrimination and could be a useful tool for predicting mortality. PMID- 29410175 TI - Everolimus as cancer therapy: Cardiotoxic or an unexpected antiatherogenic agent? A narrative review. AB - Everolimus (EVE) is now approved by many agencies for the treatment of variable neoplasms. The risk for adverse events with this agent is not adequately defined. The purpose of this review is to summarize the EVE-induced cardiotoxic effect as an antineoplastic factor on patients who received the specific drug and to evaluate any possible antiatherogenic effects due to systemic use of the drug. Articles were searched on PubMed until August 2017. Articles included an expanded access clinical trial, as well as phase 2 or 3 clinical trials (most of them were randomized). Three experimental studies that provided evidence for the possible antiatherogenic action of EVE were also included. In addition, only studies that evaluated the systemic use of the drug were included. To be eligible for inclusion, trials should have evaluated patients with malignancy, treated by EVE, or assessed the antiatherogenic effect of the systemic use of EVE through clinical or experimental studies. Only articles written in English language were included. No direct cardiotoxic adverse effects (arrhythmia, acute coronary event, heart failure, and echocardiography pathologic findings) were reported. Patients appeared to have a risk of developing adverse events that could be associated with the risk factors of cardiovascular disease. In all clinical studies, patients suffered hyperglycemia, and in most of them, hyperlipidemia was observed. Fewer studies have reported the incidence of hypertension. Finally, there is evidence claiming that EVE has an antiatherogenic action. Three experimental studies have shown that the systemic use of EVE in mice or rabbits with atherosclerotic lesions led to the reduction in atheromatous plaque growth. However, we could not find any clinical study that showed similar results in patients with cancer. To sum up, the only reported cardiac adverse event of EVE treatment in patients with cancer is indirect. They are associated with the risk factors of cardiovascular disease (hyperglycemia, hyperlipidemia, and hypertension), which are mainly mild and easily manageable. Further research and data that support the antiatherogenic action of EVE are needed. PMID- 29410177 TI - Mutation in fission yeast phosphatidylinositol 4-kinase Pik1 is synthetically lethal with defect in telomere protection protein Pot1. AB - Fission yeast Pik1p is one of three phosphatidylinositol 4-kinases associated with the Golgi complex, but its function is not fully understood. Deletion of pot1+ causes telomere degradation and chromosome circularization. We searched for the gene which becomes synthetically lethal with pot1Delta. We obtained a novel pik1 mutant, pik1-1, which is synthetically lethal with pot1Delta. We found phosphoinositol 4-phosphate in the Golgi was reduced in pik1-1. To investigate the mechanism of the lethality of the pot1Delta pik1-1 double mutant, we constructed the nmt-pot1-aid pik1-1 strain, where Pot1 function becomes low by drugs, which leads to telomere loss and chromosome circularization, and found pik1-1 mutation does not affect telomere resection and chromosome circularization. Thus, our results suggest that pik1+ is required for the maintenance of circular chromosomes. PMID- 29410178 TI - Overexpression of histone methyltransferase NSD in Drosophila induces apoptotic cell death via the Jun-N-terminal kinase pathway. AB - The nuclear receptor-binding SET domain protein gene (NSD) family encodes a group of highly conserved SET domain-containing histone lysine methyltransferases that are important in multiple aspects of development in various organisms. The association of NSD1 duplications has been reported with growth retardation diseases in humans. In this study, to gain insight into the molecular mechanisms by which the overexpression of NSD1 influences the disease progression, we analyzed the gain-of-function mutant phenotypes of the Drosophila NSD using the GAL4/UAS system. Ubiquitous overexpression of NSD in the fly caused developmental delay and reduced body size at the larval stage, resulting in pupal lethality. Moreover, targeted overexpression in various developing tissues led to significant phenotype alterations, and the gain-of-function phenotypes were rescued by NSD RNAi knockdown. We also demonstrated that NSD overexpression not only enhanced the transcription of pro-apoptotic genes but also activated caspase. The atrophied phenotype of NSD-overexpressing wing was strongly suppressed by a loss-of-function mutation in hemipterous, which encodes a Drosophila Jun N-terminal kinase. Taken together, our findings suggest that NSD induces apoptosis via the activation of JNK, and thus contributes to the understanding of the molecular mechanisms involved in NSD1-related diseases in humans. PMID- 29410176 TI - Transient activation of Wnt/beta-catenin signaling reporter in fibrotic scar formation after compression spinal cord injury in adult mice. AB - After traumatic spinal cord injury (SCI), a scar may form with a fibrotic core (fibrotic scar) and surrounding reactive astrocytes (glial scar) at the lesion site. The scar tissue is considered a major obstacle preventing regeneration both as a physical barrier and as a source for secretion of inhibitors of axonal regeneration. Understanding the mechanism of scar formation and how to control it may lead to effective SCI therapies. Using a compression-SCI model on adult transgenic mice, we demonstrate that the canonical Wnt/beta-catenin signaling reporter TOPgal (TCF/Lef1-lacZ) positive cells appeared at the lesion site by 5 days, peaked on 7 days, and diminished by 14 days post injury. Using various representative cell lineage markers, we demonstrate that, these transiently TOPgal positive cells are a group of Fibronectin(+);GFAP(-) fibroblast-like cells in the core scar region. Some of them are proliferative. These results indicate that Wnt/beta-catenin signaling may play a key role in fibrotic scar formation after traumatic spinal cord injury. PMID- 29410179 TI - Envelope analysis links oscillatory and arrhythmic EEG activities to two types of neuronal synchronization. AB - Traditionally, EEG is understood as originating from the synchronous activation of neuronal populations that generate rhythmic oscillations in specific frequency bands. Recently, new neuronal dynamics regimes have been identified (e.g. neuronal avalanches) characterized by irregular or arrhythmic activity. In addition, it is starting to be acknowledged that broadband properties of EEG spectrum (following a 1/f law) are tightly linked to brain function. Nevertheless, there is still no theoretical framework accommodating the coexistence of these two EEG phenomenologies: rhythmic/narrowband and arrhythmic/broadband. To address this problem, we present a new framework for EEG analysis based on the relation between the Gaussianity and the envelope of a given signal. EEG Gaussianity is a relevant assessment because if EEG emerges from the superposition of uncorrelated sources, it should exhibit properties of a Gaussian process, otherwise, as in the case of neural synchronization, deviations from Gaussianity should be observed. We use analytical results demonstrating that the coefficient of variation of the envelope (CVE) of Gaussian noise (or any of its filtered sub-bands) is the constant 4pi-1~0.523, thus enabling CVE to be a useful metric to assess EEG Gaussianity. Furthermore, a new and highly informative analysis space (envelope characterization space) is generated by combining the CVE and the envelope average amplitude. We use this space to analyze rat EEG recordings during sleep-wake cycles. Our results show that delta, theta and sigma bands approach Gaussianity at the lowest EEG amplitudes while exhibiting significant deviations at high EEG amplitudes. Deviations to low-CVE appeared prominently during REM sleep, associated with theta rhythm, a regime consistent with the dynamics shown by the synchronization of weakly coupled oscillators. On the other hand, deviations to high-CVE, appearing mostly during NREM sleep associated with EEG phasic activity and high-amplitude Gaussian waves, can be interpreted as the arrhythmic superposition of transient neural synchronization events. These two different manifestations of neural synchrony (low-CVE/high-CVE) explain the well-known spectral differences between REM and NREM sleep, while also illuminating the origin of the EEG 1/f spectrum. PMID- 29410180 TI - Plerixafor Plus Granulocyte Colony-Stimulating Factor for Patients with Non Hodgkin Lymphoma and Multiple Myeloma: Long-Term Follow-Up Report. AB - The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 ug/kg plerixafor plus 10 ug/kg G-CSF, or placebo plus 10 ug/kg G-CSF to mobilize and collect CD34+ cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5 year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM. PMID- 29410181 TI - Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy. AB - We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft. PMID- 29410182 TI - A cooperative transition from the semi-flexible to the flexible regime of polymer elasticity: Mitoxantrone-induced DNA condensation. AB - We report a high cooperative transition from the semi-flexible to the flexible regime of polymer elasticity during the interaction of the DNA molecule with the chemotherapeutic drug Mitoxantrone (MTX). By using single molecule force spectroscopy, we show that the force-extension curves of the DNA-MTX complexes deviate from the typical worm-like chain behavior as the MTX concentration in the sample increases, becoming straight lines for sufficiently high drug concentrations. The behavior of the radius of gyration of the complexes as a function of the bound MTX concentration was used to quantitatively investigate the cooperativity of the condensation process. The present methodology can be promptly applied to other ligands that condense the DNA molecule upon binding, opening new possibilities in the investigation of this type of process and, more generally, in the investigation of phase transitions in polymer physics. PMID- 29410183 TI - Direct visualization of nucleolar G-quadruplexes in live cells by using a fluorescent light-up probe. AB - BACKGROUND: Direct detection of G-quadruplexes in human cells has become an important issue due to the vital role of G-quadruplex related to biological functions. Despite several probes have been developed for detection of the G quadruplexes in cytoplasm or whole cells, the probe being used to monitor the nucleolar G-quadruplexes is still lacking. METHODS: Formation of the nucleolar G quadruplex structures was confirmed by using circular dichroism (CD) spectroscopy. The binding affinity and selectivity of Thioflavin T (ThT) towards various DNA/RNA motifs in solution and gel system were measured by using fluorescence spectroscopy and polyacrylamide gel electrophoresis (PAGE), respectively. G-quadruplex imaging in live cells was directly captured by using confocal laser scanning microscopy (CLSM). RESULTS: Formation of the rDNA and rRNA G-quadruplex structures is demonstrated in vitro. ThT is found to show much higher affinity and selectivity towards these G-quadruplex structures versus other nucleic acid motifs either in solution or in gel system. The nucleolar G quadruplexes in living cells are visualized by using ThT as a fluorescent probe. G-quadruplex-ligand treatments in live cells lead to sharp decrease of ThT signal. CONCLUSIONS: The natural existence of the G-quadruplexes structure in the nucleoli of living cells is directly visualized by using ThT as an indicator. GENERAL SIGNIFICANCE: The research provides substantive evidence for formation of the rRNA G-quadruplex structures, and also offers an effective probe for direct visualization of the nucleolar G-quadruplexes in living cells. PMID- 29410185 TI - Evaluation of the Adult Congenital Heart Surgery Mortality Score at Two European Centers. AB - BACKGROUND: The adult congenital heart surgery (ACHS) score was derived from The Society of Thoracic Surgeons Congenital Heart Surgery Database. The score was validated with data for 1,603 operations and reached a good predictive power. We sought to evaluate its predictive power for 1,654 operations performed in two European centers. METHODS: Data of all consecutive patients aged 18 years or more who underwent surgery for congenital heart disease between 2004 and 2013 at center 1 (n = 830) and between 2005 and 2016 at center 2 (n = 824) were collected. Mortality was defined as hospital mortality or mortality within 30 days after surgery. The discriminatory power of the ACHS score was assessed using the area under the receiver-operating characteristics curve (c-index). RESULTS: During the examined 13-year period, 1,639 operations of 43 different procedural groups were eligible for scoring. The most frequent procedures were closure of atrial septal defect (n = 175, 10.7%), repair of partial anomalous pulmonary venous connection (n = 117, 7.1%), and aortic valve replacement (n = 112, 6.8%). Hospital mortality was 3.1%. The procedures with the highest mortality were heart transplantation (3 of 11, 27.3%), mitral valve replacement (9 of 39, 23.1%), and systemic venous stenosis repair (2 of 9, 22.2%). The c-index for the ACHS mortality score was 0.760 (0.750 in center 1 and 0.772 in center 2). CONCLUSIONS: The ACHS score reached similar, good predictive power in two different centers. The score is a useful tool to analyze surgical outcomes and to support individual decision making. PMID- 29410186 TI - Optimal Approach for Repair of Left Atrial-Esophageal Fistula Complicating Radiofrequency Ablation. AB - Left atrial-esophageal fistula after endovascular radiofrequency ablation for cardiac arrhythmias is a life-threatening complication. Immediate surgical repair offers the best chance for survival. The optimal surgical technique is unknown. We describe our recommended surgical approach. PMID- 29410184 TI - Interleukin-6 potentiates FcepsilonRI-induced PGD2 biosynthesis and induces VEGF from human in situ-matured skin mast cells. AB - BACKGROUND: Interleukin-6 is a gp130 utilizing cytokine that is consistently associated with allergic diseases like asthma and urticaria in humans where mast cells are known to play a critical role. However, the role of IL-6 in allergic disease in not known. IL-6 was reported to enhance degranulation of in vitro derived mast cells, but the effect of IL-6 on mediator release from human in situ matured tissue-isolated mast cells had not been reported. METHODS: Human mature mast cells were isolated and purified from normal skin tissue from different donors. The expression of surface-expressed IL-6 receptors was demonstrated by flow cytometry. The effect of IL-6 on FcepsilonRI-induced degranulation, PGD2 biosynthesis, and cytokine production was determined with beta-hexosaminidase release assay, Western blotting, quantitative real-time PCR, and ELISA. The small molecule inhibitor of STAT-3, C188-9, was used to demonstrate STAT3 dependency. RESULTS: IL-6 significantly potentiated FcepsilonRI-induced PGD2 biosynthesis, but had no effect on degranulation. IL-6 also induced VEGF gene expression and protein secretion, and enhanced FcepsilonRI-induced IL-8 production. Mechanistically, IL-6 enhanced FcepsilonRI-induced COX-2 expression, PGD2 biosynthesis, and VEGF production in a STAT3 dependent manner. CONCLUSION: Here, we demonstrate that IL-6 is a potentiator of FcepsilonRI-induced PGD2 biosynthesis, and can induce or enhance production of pro-angiogenesis factors VEGF and IL-8 from human in situ-matured skin mast cells. GENERAL SIGNIFICANCE: These findings from this study indicate that IL-6 contributes to human allergic disease by enhancing the production of inflammatory PGD2 from tissue-resident mast cells. Moreover, the data suggest a novel role for IL-6 in mast cell mediated angiogenesis. PMID- 29410187 TI - Development of a Risk Prediction Model and Clinical Risk Score for Isolated Tricuspid Valve Surgery. AB - BACKGROUND: Although tricuspid valve operations remain associated with high mortality (approximately 8% to 10%), no robust prediction models exist to support clinical decision making. We developed a preoperative clinical risk model with an easily calculable clinical risk score (CRS) to predict mortality and major morbidity after isolated tricuspid valve surgery. METHODS: The Society of Thoracic Surgeons database records were evaluated for 2,050 isolated TV repair and replacement operations for any etiology performed at 50 hospitals (2002 to 2014) in a number of states. Parsimonious preoperative risk prediction models were developed using multiple-level mixed effects regression to estimate mortality and composite major morbidity risk. Model results were utilized to establish a novel CRS for patients undergoing tricuspid valve operations. Models were evaluated for discrimination and calibration. RESULTS: Operative mortality and composite major morbidity rates were 9% and 42%, respectively. Final regression models performed well (both p < 0.001; areas under the receiver operating characteristics curve 0.74 and 0.76) and included preoperative factors: age, sex, stroke, hemodialysis, ejection fraction, lung disease, New York Heart Association class, reoperation, and urgent or emergency status (all p < 0.05). A simple CRS from 0 to 10+ was highly associated (p < 0.001) with incremental increases in predicted mortality and major morbidity. Predicted mortality risk ranged from 2% to 34% across CRS categories, and predicted major morbidity risk ranged from 13% to 71%. CONCLUSIONS: Mortality and major morbidity after isolated tricuspid valve surgery can be predicted using preoperative patient data from The Society of Thoracic Surgeons National Adult Cardiac Database. A simple clinical risk score predicts mortality and major morbidity after isolated tricuspid valve surgery. This score may facilitate perioperative counseling and identification of suitable patients for tricuspid valve surgery. PMID- 29410188 TI - Blunted cerebral oxygenation during exercise in women with gestational diabetes mellitus: associations with macrovascular function and cardiovascular risk factors. AB - AIM/HYPOTHESIS: This cross-sectional, observational, controlled study examined cerebral oxygenation during exercise, an index of cerebrovascular function and cortical activation, in pregnancies complicated by gestational diabetes mellitus (GDM) and unaffected pregnancies. The association of cerebral oxygenation with macrovascular and cardiovascular function indices was also evaluated. MATERIAL AND METHODS: Vascular function and structure [aortic pulse-wave-velocity (PWV), augmentation index (AI), carotid intima-media thickness], as well as 24-hour ambulatory blood pressure (BP) were assessed in women with GDM (n = 21) and uncomplicated pregnancies (n = 16), at 26-32 gestational weeks. Changes in cerebral oxygenation [oxy- (O2Hb), deoxy- (HHb) and total- (tHb) hemoglobin] were continuously recorded by near-infrared spectroscopy (NIRS) during intermittent handgrip exercise. Beat-by-beat BP and systemic vascular resistance (SVR) were assessed (Finapres). RESULTS: Women with GDM had higher AI than controls. During exercise, women with GDM maintained a smaller force (p < 0.05), despite similar ratings of perceived exertion. Despite similar increases in BP during exercise, the GDM group exhibited a lower average and total (AUC) increase in cerebral-O2Hb than controls (p < 0.05). In addition, GDM exhibited a slower rate of cerebral O2Hb decay during recovery (p < 0.05). SVR was lower in GDM compared to controls throughout the protocol (p < 0.01). Cerebral oxygenation indices were correlated with PWV and AI (p < 0.05). CONCLUSIONS: This study provided novel evidence for blunted cerebral oxygenation during exercise in women with GDM compared to uncomplicated pregnancies, suggesting a link between reduced cerebrovascular function with exercise intolerance in GDM. Cerebral oxygenation during physical stress was correlated with macrovascular function and cardiovascular risk factors. More studies are needed to examine whether this impaired cerebral oxygenation reflects early cerebrovascular disease. PMID- 29410189 TI - Maternal allocation of carotenoids to eggs in an Anolis lizard. AB - The maternal allocation of carotenoids to eggs has been widely documented and manipulated. However, it is often assumed that the sole adaptive value of this allocation is to increase offspring fitness. Because carotenoids can be pro oxidants or antioxidants depending on their concentrations and their chemical environment (i.e. presence of other antioxidants), dams may need to dispose of excess carotenoids upon depletion of other antioxidants to prevent oxidative damage. Additionally, the amount of carotenoids deposited in eggs may be dependent on male traits such as quality and coloration. We evaluated these two non-mutually exclusive hypotheses for carotenoid allocation to eggs and assessed paternal effects by supplementing male and female brown anole lizards, Anolis sagrei, with dietary carotenoids or with a combination of carotenoids and vitamin C. We found significant differences in the antioxidant capacities of fertilized and unfertilized eggs produced by female lizards, but the treatment did not affect the antioxidant capacity or carotenoid content of eggs. However, the carotenoid concentration of unfertilized eggs from carotenoid-supplemented females was significantly higher than eggs from the control group. Male coloration and body size did not affect the antioxidant capacity or carotenoid content of the eggs. Carotenoids may be allocated to unfertilized eggs to offset oxidative damage to the dam, with a neutral effect on offspring, rather than to solely provide antioxidant benefits to offspring as has been widely assumed. PMID- 29410192 TI - Patient perceptions and clinical efficacy of labial frenectomies using diode laser versus conventional techniques. AB - INTRODUCTION: The aim of present study was to compare the keratinized gingival tissue measurements, degree of subjective complaints and functional complications of using an 980nm diode laser versus a scalpel for labial frenectomies. MATERIAL AND METHODS: Thirty-six patients requiring labial frenectomies, between 14 and 51 years old, were randomly assigned to either scalpel or diode laser treatments. The soft tissue measurements, including the keratinized gingiva width (KGW), attached gingiva width (AGW) and attached gingiva thickness (AGT), were recorded before surgery, immediately after, one week later and one, three and six months after surgery. In addition, the functional complications and the morbidity (level of pain, swelling and redness) were evaluated during the first postoperative week using a visual analog scale (VAS). RESULTS: We determined statistically significant gains in the KGW, AGW and AGT after surgery in both groups; however, there was no significant difference between the study groups. The VAS scores indicated that the patients treated with a diode laser had less discomfort and functional complications compare with scalpel surgery. DISCUSSION: The results described above show that diode laser surgery offers a safe, impressive alternative for labial frenectomies that are comfortable for the patients. PMID- 29410191 TI - Regional cerebral oxygen saturation during cardiopulmonary resuscitation as a predictor of return of spontaneous circulation and favourable neurological outcome - A review of the current literature. AB - INTRODUCTION: Regional cerebral oxygen saturation (rSO2) can be measured non invasively even at no- or low-flow states. It thus allows assessment of brain oxygenation during CPR. Certain rSO2 values had been associated with return of spontaneous circulation (ROSC) and neurological outcome in the past. Clear-cut thresholds for the prediction of beneficial outcome, however, are still lacking. METHODS: We conducted a database search to extract all available investigations on rSO2 measurement during CPR. Mean, median, and DeltarSO2 values were either taken from the studies or calculated. Thresholds for the outcome "ROSC" and "neurological outcome" were sought. RESULTS: We retrieved 26 publications for the final review. The averaged mean rSO2 for patients achieving ROSC was 41 +/- 12% vs. 30 +/- 12% for non-ROSC (p = .009). ROSC was not observed when mean rSO2 remained <26%. In ROSC patients, DeltarSO2 was 22 +/- 16% vs. 7 +/- 10% in non ROSC patients (p = .009). A rSO2 threshold of 36% predicted ROSC with a sensitivity of 67% and specificity of 69% while DeltarSO2 of 7% showed a sensitivity of 100% and a specificity of 86% (AUC = 0.733 and 0.893, respectively). Mean rSO2 of 47 +/- 11% was associated with favourable and 38 +/- 12% with poor neurological outcome. There was, however, a great overlap between groups due to scarce data. CONCLUSION: Higher rSO2 consistently correlated with increased rates of ROSC. The discriminatory power of rSO2 to prognosticate favourable neurological outcome remains unclear. Measuring rSO2 during CPR could potentially facilitate clinical decision-making. PMID- 29410193 TI - Inflammation-Associated Cytokines IGFBP1 and RANTES Impair the Megakaryocytic Potential of HSCs in PT Patients after Allo-HSCT. AB - Prolonged isolated thrombocytopenia (PT) is a severe complication in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether the megakaryoctic potential of hematopoietic stem cells (HSCs) in bone marrow is intact and what factors drive the pathological process of PT remain elusive. A retrospective study in patients (n = 285) receiving HSCT revealed that the occurrence of PT was approximately 8% and the number of platelets and megakaryocytes in PT patients is much lower compared with control subjects. To test whether the deficiency of thrombopoiesis was caused by the activities of HSCs, the megakaryocytic differentiation potential of HSCs before or after transplantation was assessed. Interestingly, a substantial decrease of megakaryocytic differentiation was observed 2 weeks after transplantation of HSCs in all of the allo-HSCT recipients. However, 4 weeks after transplantation, the ability of HSCs to generate CD41+CD42b+ megakaryocytes in successful platelet engraftment patients recovered to the same level as those of HSCs before implantation. In contrast, HSCs derived from PT patients throughout the postimplantation period exhibited poor survival and failed to differentiate properly. A protein array analysis demonstrated that multiple inflammation associated cytokines were elevated in allo-HSCT recipients with PT. Among them, insulin-like growth factor-binding protein 1 and regulated on activation, normal T cell expressed and secreted were found to significantly suppress the proliferation and megakaryocytic differentiation of HSCs in vitro. Our results suggested that the occurrence of PT may be attributed, at least partially, to the damage to HSC function caused by inflammation-associated cytokines after HSCT. These findings shed light on the mechanism underlying HSC megakaryocytic differentiation in PT patients and may provide potential new strategies for treating PT patients after HSCT. PMID- 29410194 TI - Human serine racemase is nitrosylated at multiple sites. AB - Serine racemase is a pyridoxal 5'-phosphate dependent enzyme responsible for the synthesis of d-serine, a neuromodulator of the NMDA receptors. Its activity is modulated by several ligands, including ATP, divalent cations and protein interactors. The murine orthologue is inhibited by S-nitrosylation at Cys113, a residue adjacent to the ATP binding site. We found that the time course of inhibition of human serine racemase by S-nitrosylation is markedly biphasic, with a fast phase associated with the reaction of Cys113. Unlike the murine enzyme, two additional cysteine residues, Cys269, unique to the human orthologue, and Cys128 were also recognized as S-nitrosylation sites through mass spectrometry and site-directed mutagenesis. The effect of S-nitrosylation on the fluorescence of tryptophan residues and on that of the pyridoxal phosphate cofactor indicated that S-nitrosylation produces a partial interruption of the cross-talk between the ATP binding site and the active site. Overall, it appears that the inhibition results from a conformational change rather than the direct displacement of ATP. PMID- 29410195 TI - Optic disk contractility in morning glory disk anomaly. AB - Morning glory disk anomaly is a nonhereditary, congenital optic disk dysplasia characterized by conical excavation of the posterior fundus with a central glial tuft and radial retinal vessels. We report the case of a 4-year-old girl who presented with esotropia, enophthalmos, no light perception, and afferent pupillary defect in her left eye; fundus examination revealed morning glory disk anomaly. Ultrasound B-scan showed axial length increasing in the left eye on consensual light exposure. Magnetic resonance imaging/angiogram of the brain and orbits were within normal limits except for globe elongation posteriorly in the left eye. On examination under anesthesia with video indirect ophthalmoscopy, the left optic disk showed contraction and expansion when stimulated by strong light to the fellow eye and no spontaneous contraction on direct light stimulation. Morning glory disk contractility with increasing axial length on consensual light exposure in a child has not been reported previously. PMID- 29410196 TI - Mechanoreceptors distribution in the human medial collateral ligament of the elbow. AB - BACKGROUND: The human elbow maintains its stability mainly through its bony structure. Stability is enhanced by ligamentous structures. To allow the ligamento-muscular reflex, which protects against strain and stress, mechanoreceptors are embedded in the ligament. This report describes the existence and the distribution of the elbow medial collateral ligaments (MCLs) mechanoreceptors. HYPOTHESIS: The bony attachment site has the highest density of mechanoreceptors, and the anterior part has the highest density of mechanoreceptors. MATERIALS AND METHODS: Eight MCLs of elbow from fresh frozen cadavers were used. The MCLs were harvested deep to the periosteum from the medial epicondyle to the ulna. The fan-shaped ligaments were divided into six regions of interest (ROI) and stained with modified gold chloride stain. Specimens were evaluated under a light microscope. Golgi, Ruffini, and Pacinian corpuscles were found in every specimen. The number and the distribution of each mechanoreceptor in each ROI were recorded. The density of each mechanoreceptor was calculated in regards to its volume. RESULTS: Golgi, Ruffini, and Pacinian corpuscles were seen in the ligament with small nerve fibers. Ruffini corpuscles had the highest median density of all three corpuscles. The median corpuscle density was higher in the anterior than in the posterior part and higher in the bony attachment than in the mid-substance site except for Golgi corpuscle. CONCLUSION: The three typical types of mechanoreceptors were identified in human MCL with the anterior part and bony attachment as the dominant distribution site. LEVEL OF EVIDENCE: Basic Science Study. PMID- 29410197 TI - Patellofemoral reconstruction for patellar instability with patella alta in middle-aged patients: Clinical outcomes. AB - INTRODUCTION: Although several surgical treatments for patellar instability with patella alta have been reported, the clinical outcomes and optimal surgical procedures for patellar instability with patella alta in middle-aged patients are still controversial. We hypothesized that optimal surgical procedures for patellar instability with patella alta in middle-aged patients may induce good clinical outcomes with better patellofemoral geometry. MATERIALS AND METHODS: Twelve middle-aged patients with a mean age of 44 years (range: 40-55 years), who presented with patellar instability and patella alta, were treated with a combination of several surgeries, such as medial patellofemoral ligament (MPFL) reconstruction, trochleoplasty, lateral release, and three-dimensional transfer of the tibial tuberosity, based on a surgical algorithm. Patellar position and clinical outcomes were evaluated postoperatively. The mean follow-up time was 41.5 months (range: 24-72 months). RESULTS: Patellar position altered from 1.31 (1.21-1.53) preoperatively to 0.88 (0.69-1.06) postoperatively on the Caton Deschamps Index (p<0.01). The tibial tuberosity-trochlear groove (TT-TG) distance altered from 21.8mm (20.1-25.8mm) to 10.3mm (5.1-14.7mm), and patellar tilt ranged from 28.1 degrees (21-40 degrees ) to 14.6 degrees (5-28 degrees ), respectively (p<0.01). Clinical outcomes on the Lysholm and Kujala scales improved from 43.1 and 38.4 to 86.7 and 78.3, respectively, at final follow-up (p<0.01). Surgical treatment that included trochleoplasty resulted in better outcomes than other surgical combinations without trochleoplasty (p<0.05). Sulcus angle and postoperative patellar tilt improved more in those who underwent trochleoplasty than in those who did not (p<0.05). DISCUSSION: Surgical treatment for patellar instability with patella alta in middle-aged patients resulted in improved clinical outcomes. In particular, a combination surgery including trochleoplasty resulted in the greatest improvement in case of severe trochlear dysplasia. LEVEL OF EVIDENCE: IV. Retrospective case series study. PMID- 29410190 TI - Hyaluronan interactions with innate immunity in lung biology. AB - Lung disease is a leading cause of morbidity and mortality worldwide. Innate immune responses in the lung play a central role in the pathogenesis of lung disease and the maintenance of lung health, and thus it is crucial to understand factors that regulate them. Hyaluronan is ubiquitous in the lung, and its expression is increased following lung injury and in disease states. Furthermore, hyaladherins like inter-alpha-inhibitor, tumor necrosis factor-stimulated gene 6, pentraxin 3 and versican are also induced and help form a dynamic hyaluronan matrix in injured lung. This review synthesizes present knowledge about the interactions of hyaluronan and its associated hyaladherins with the lung immune system, and the implications of these interactions for lung biology and disease. PMID- 29410198 TI - Elongated Mitral Valve Vegetation. PMID- 29410199 TI - Effect of distress on transient network dynamics and topological equilibrium in phantom sound perception. AB - Distress is a domain-general behavioral symptom whose neural correlates have been under investigation for a long time now. Although some studies suggest that distress is encoded by changes in alpha activity and functional connectivity between specific brain regions, no study that we know has delved into the whole brain temporal dynamics of the distress component. In the current study, we compare the changes in the mean and variance of functional connectivity and small worldness parameter over 3 min of resting state EEG to analyze the fluctuation in transient stable states, and network structure. On comparing these measures between healthy controls and patients experiencing low and high levels of distress due to a continuous ringing in the ear (tinnitus), we observe an increase in fluctuation between transient stable states characterized by an increase in both variance of functional connectivity and the small-worldness parameter. This results in a possible increase in degrees of freedom leading to a paradoxical equilibrium of the network structure in highly distressed patients. This may also be interpreted as a maladaptive compensation to look for information in order to reduce the hyper-salience in highly distressed individuals. In addition, this is correlated with the amount of distress only in the high distress tinnitus group, suggesting a catastrophic breakdown of the brain's resilience. Distress not only accompanies tinnitus, but other disorders such as somatic disorders, fibromyalgia, post-traumatic stress disorder, etc. Since the current study focuses on a disorder-general distress symptom, the methods and results of the current study have a wide application in different neuropathologies. PMID- 29410200 TI - A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy. AB - Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients. PMID- 29410201 TI - Cerebrospinal fluid features in adults with enteroviral nervous system infection. AB - OBJECTIVES: The aim of this study was to investigate the clinical and laboratory features of adults with nervous system infections caused by enteroviruses, with special emphasis on cerebrospinal fluid (CSF). METHODS: The data of 46 patients who were PCR-positive for enteroviruses in the CSF between 2002 and 2017 were evaluated. RESULTS: Meningitis was the most common clinical manifestation (89%), followed by encephalitis (7%) and isolated cranial nerve involvement (4%). Twenty percent of patients reported a sudden onset of severe headache that led to the initial suspected diagnosis of subarachnoid haemorrhage. General signs of infection, such as fever, elevated C-reactive protein, and an elevated white blood cell count, were found in only 61%. Most patients exhibited consistent inflammatory CSF changes, with elevated cell counts (85%) and blood-CSF barrier dysfunction (83%). Patients with normal CSF cell counts were significantly older, less frequently presented with meningitis, and exhibited lower peripheral white blood cell counts. Sequencing revealed species Enterovirus B in all patients, with most sequences related to echovirus 30. CONCLUSIONS: The absence of CSF pleocytosis, isolated cranial nerve involvement, and only infrequent general signs of infection may impede the diagnosis of enteroviral nervous system infections. A thorough CSF analysis including PCR is essential for a reliable diagnosis. PMID- 29410202 TI - Evolving Use of Prebiopsy Prostate Magnetic Resonance Imaging in the Medicare Population. AB - PURPOSE: We assessed the changing use of prebiopsy prostate magnetic resonance imaging in Medicare beneficiaries. MATERIALS AND METHODS: Men who underwent prostate biopsy were identified in 5% Medicare RIFs (Research Identifiable Files) from October 2010 through September 2015. We evaluated the rate of prebiopsy prostate magnetic resonance imaging, defined as any pelvic MRI 6 months or less before biopsy with a prostate indication diagnosis code. Temporal changes were determined as well as variation by geography and among populations. RESULTS: In male Medicare beneficiaries the prebiopsy magnetic resonance imaging use rate increased from 0.1% in 2010 to 0.7% in 2011, to 1.2% in 2012, to 2.9% in 2013, to 4.7% in 2014 and to 10.3% in 2015. In 2015 the prebiopsy prostate magnetic resonance imaging rate varied significantly by patient age, including 5.7% for greater than 80 years vs 8.4% to 9.3% for other age ranges (p = 0.040) as well as by race, including 5.8% in African American vs 10.1% in Caucasian men (p = 0.009) and geographic region, including 6.3% in the Midwest to 12.5% in the Northeast (p <0.001). The rate was highest in Wyoming at 25.0%, New York at 23.7% and Minnesota at 20.5% but it was less than 1% in 10 states. CONCLUSIONS: Historical Medicare claims provide novel insights into the dramatically increasing adoption of magnetic resonance imaging prior to prostate biopsy. Following earlier minimal use the performance increased sharply beginning in 2013, exceeding 10% in 2015. However, substantial racial and geographic variation exists in adoption. Continued educational, research and policy efforts are warranted to optimize the role of prebiopsy magnetic resonance imaging and minimize sociodemographic and geographic disparities. PMID- 29410203 TI - POINT: Is ICD-10 Diagnosis Coding Important in the Era of Big Data? Yes. PMID- 29410204 TI - Simulating the gamma-secretase enzyme: Recent advances and future directions. AB - gamma-secretase is an intra-membrane aspartyl protease involved in the production of amyloid-beta peptides. Aberrant cleavage of the 99-residue C-terminal fragment of the amyloid precursor protein leads to the formation of a 42-amino-acid isoform (Abeta42). Further oligomerization and aggregation of this isoform is implicated in the onset and progression of Alzheimer's disease. Recent elucidation of gamma-secretase by cryo-electron microscopy techniques have opened a new horizon in the structural and dynamic characterization of the enzyme. Currently, only a few molecular dynamics studies have been carried out to explore the mechanism of substrate recognition and entry, or the transition between active and inactive states of the catalytic subunit. Herein, we briefly review the computational approaches and their most relevant findings. The general picture of the current GS simulation studies will open new questions to understand the behavior of the enzyme dynamics and explain the modulation mechanisms for the treatment of Alzheimer's disease. PMID- 29410205 TI - Spatial coherence of oriented white matter microstructure: Applications to white matter regions associated with genetic similarity. AB - We present a method to discover differences between populations with respect to the spatial coherence of their oriented white matter microstructure in arbitrarily shaped white matter regions. This method is applied to diffusion MRI scans of a subset of the Human Connectome Project dataset: 57 pairs of monozygotic and 52 pairs of dizygotic twins. After controlling for morphological similarity between twins, we identify 3.7% of all white matter as being associated with genetic similarity (35.1 k voxels, p<10-4, false discovery rate 1.5%), 75% of which spatially clusters into twenty-two contiguous white matter regions. Furthermore, we show that the orientation similarity within these regions generalizes to a subset of 47 pairs of non-twin siblings, and show that these siblings are on average as similar as dizygotic twins. The regions are located in deep white matter including the superior longitudinal fasciculus, the optic radiations, the middle cerebellar peduncle, the corticospinal tract, and within the anterior temporal lobe, as well as the cerebellum, brain stem, and amygdalae. These results extend previous work using undirected fractional anisotrophy for measuring putative heritable influences in white matter. Our multidirectional extension better accounts for crossing fiber connections within voxels. This bottom up approach has at its basis a novel measurement of coherence within neighboring voxel dyads between subjects, and avoids some of the fundamental ambiguities encountered with tractographic approaches to white matter analysis that estimate global connectivity. PMID- 29410207 TI - Male X-chromosome mosaicism leading to carrier phenotype and inheritance of chronic granulomatous disease. PMID- 29410208 TI - Trends in insect repellent formulations: A review. AB - The use of natural and synthetic repellents, marketed in different pharmaceutical forms, is growing in the world due to the emerging vector-borne viral diseases as Dengue, Zika, Chikungunya, Yellow Fever and Malaria. The choice of the ideal formulation will depend on a series of factors to be analyzed: type of repellent active (natural or synthetic), pharmaceutical forms (spray, lotion, cream, gel), action time duration (short or long), environment of exposure and the user (adult, pregnant women, children, newborn). The most used repellents are DEET, IR3535 (Ethyl Butylacetylaminopropionate) (EB), Icaridin (Picaridin) and essential oils, each of them presenting advantages and disadvantages. DEET is the oldest and the most powerful repellent available in the market, thus being the reference standard. For this reason, there are many classic formulations available in the market containing the chemical component DEET in spray forms and lotions. However, due to its toxicity, DEET is not recommended for children up to 6 months and pregnant women. DEET has been an option along with other market shared products as IR3535 and Icaridin (Picaridin), which present less toxicity in their composition. IR3535 is the less toxic and may be prescribed for children over 6 months of age and pregnant women so that they have been the best option because of the lower toxicity levels presented. IR3535 is the one that has the lowest toxicity level among the three options and may be prescribed for children above 6 months of age and pregnant women. Icaridin is as potent as DEET, but less toxic, and has the advantage of having the long-lasting action among the aforementioned repellents. The new formulations have been based on controlled release systems (CRS). The CRSs for repellents comprise polymer micro/nanocapsules, micro/solid lipid nanoparticles, nanoemulsions/microemulsions, liposomes/niosomes, nanostructured hydrogels and cyclodextrins. There are many formulations based on micro and nanocapsules containing DEET and essential oils to increase repellent action time duration and decrease permeation and consequently, systemic toxicity. The development of new formulations for the IR3535 and Icaridin is a research field yet to be explored. The current trend is the use of natural repellent actives such as essential oils, which present low toxicity, do not harm the environment, but present reduced repellent action time due to rapid evaporation after skin application. CRSs have been used as vehicle of natural repellents to improve long-lasting repellent action, reduce skin permeation and systemic effects. PMID- 29410206 TI - Regulation of spermatid polarity by the actin- and microtubule (MT)-based cytoskeletons. AB - It is conceivable that spermatid apico-basal polarity and spermatid planar cell polarity (PCP) are utmost important to support spermatogenesis. The orderly arrangement of developing germ cells in particular spermatids during spermiogenesis are essential to obtain structural and nutrient supports from the fixed number of Sertoli cells across the limited space of seminiferous epithelium in the tubules following Sertoli cell differentiation by ~17 day postpartum (dpp) in rodents and ~12 years of age at puberty in humans. Yet few studies are found in the literature to investigate the role of these proteins to support spermatogenesis. Herein, we briefly summarize recent findings in the field, in particular emerging evidence that supports the concept that apico-basal polarity and PCP are conferred by the corresponding polarity proteins through their effects on the actin- and microtubule (MT)-based cytoskeletons. While much research is needed to bridge our gaps of understanding cell polarity, cytoskeletal function, and signaling proteins, a critical evaluation of some latest findings as summarized herein provides some important and also thought provoking concepts to design better functional experiments to address this important, yet largely expored, research topic. PMID- 29410209 TI - GRP78 protects CHO cells from ribosylation. AB - d-Ribose (Rib), a reactive glycation compound that exists in organisms, abnormally increases in the urine of diabetic patients and can yield large amounts of advanced glycation end products (AGEs), leading to cell dysfunction. However, whether cellular proteins are sensitive to this type of glycation is unknown. In this study, we found that cellular AGEs accumulate in Chinese hamster ovary (CHO) cells with increased Rib concentration and administration time. Mass spectrum analysis of isolated AGE-modified proteins from cell lysates showed that glucose-regulated protein 78 kD (GRP78) is one of the main ribosylated proteins. Co-immunoprecipitation assays further confirmed the interaction between AGEs and GRP78. Compared with d-glucose (Glc), Rib produced much more AGEs in cells. In kinetic studies, the first order rate constant of LDH released from CHO cells incubated with Rib was nearly 8-fold higher than that of Glc, suggesting that Rib is highly cytotoxic. Immunofluorescent co-localization analysis manifested partial superimposition of AGEs and GRP78, which were distributed throughout the endoplasmic reticulum. Western blotting showed that the expression of GRP78 is up regulated and then down-regulated in CHO cells during Rib treatment. In the presence of Rib, the suppression of GRP78 expression either with transfected siRNA or with the inhibitor (-)-epigallocatechin gallate (EGCG) dramatically increased AGE levels and decreased cell viability compared with these parameters in the control groups. GRP78 overexpression decreased AGE levels and rescued the cells from Rib-induced cytotoxicity. These data indicate that GRP78 plays a role in preventing Rib-induced CHO cell cytotoxicity. PMID- 29410210 TI - Characterization of three mitogen-activated protein kinase kinase-like proteins in Beauveria bassiana. AB - Pbs2, Mkk1 and Ste7 orthologs are three mitogen-activated protein kinase (MAPK) kinases (MAPKKs) acting as checkpoints of the Hog1, Slt2 and Fus3 MAPK cascades that constitute major parts of fungal signaling network. Here, we show that three other MAPKK-like proteins (Mkk4/5/6) exist in Beauveria bassiana and other entomopathogenic or non-entomopathogenic fungi but lack in yeasts and aspergilli, and elucidate how they function in the fungal insect pathogen. Based on phenotypic defects of single-, double- and triple-deletion mutants, Mkk4, Mkk5 and Mkk6 played collaborative or independent roles in sustaining radial growth on various media, conidiation capacity, conidial germination, conidial UV-B resistance, and/or virulence. In stress assays, three single-deletion Deltamkk mutants showed increased tolerance to cell wall stress but null response to a 3-h heat shock at 40 degrees C during normal incubation. Only did Deltamkk6 exhibit increased sensitivity to either menadione or H2O2 oxidation. Intriguingly, Deltamkk5 and Deltamkk6 displayed a remarkable increase in cellular sensitivity to a high osmolarity of NaCl or KCl instead of non-salt sorbitol, suggesting a link of their increased sensitivity to the toxicity of a high Na+/K+ concentration rather than to the plausible osmotic stress of either salt. However, all of the deletion mutants showed no resistance to fludioxonil, a phenylpyrrole-type fungicide. A discussion is provided on whether Mkk4, Mkk5 and Mkk6 could be likely associated with or without the MAPK cascades in B. bassiana. PMID- 29410211 TI - Standardization, Pump Position and the Unloading Paradox. PMID- 29410212 TI - Orthopedic injuries associated with jet-skis (personal watercrafts): A review of 127 inpatients. AB - BACKGROUND: Personal watercrafts (PWC) account for a disproportionate amount of water based injuries. Current literature suggests those with less PWC experience are more at risk for injury. Previous studies have not specifically evaluated the orthopedic implications of PWC usage or how various mechanisms of injury (MOI) contribute to different injury patterns. HYPOTHESIS: PWC injuries will frequently require orthopedic intervention. The presence of an orthopedic injury will result in increased injury severity score (ISS), hospital and intensive care unit (ICU) length of stay (LOS). Patients visiting our region will have less PWC experience and so are more prone to serious injuries. MATERIALS AND METHODS: Retrospective cohort study at a single Level 1 trauma center of admitted patients sustaining PWC injuries from 02/2004-03/2017. The following were studied: demographics, mechanism, season, ISS, hospital and ICU LOS, follow-up, fracture characteristics and management. RESULTS: Hundred and twenty-seven patients were admitted due to PWC injury, 66 (52.0%) sustained an orthopedic injury, totaling 103 fractures (48 [46.6%] lower extremity, 26 [25.2%] upper extremity, 14 [13.6%] vertebral, 11 [10.7%] pelvic ring and 4 [3.9%] acetabulum). The mean age of orthopedic patients was 29 years (range 8-62). Handle bar injuries were significantly associated with open fractures, (13 of 25 open fractures, 3 of which became infected). Injuries occurring during the winter were associated with a higher ISS, yet more injuries occurred in the summer. A patient being a "visitor" to the region did not influence ISS. The mean LOS was 12.6 days for orthopedic patients. Eighteen orthopedic patients (27.3%) required ICU admission and 36 (54.5%) patients required orthopedic surgery (mean 2.11 operations). DISCUSSION: A majority of PWC injuries resulted in extremity fractures with a moderate percentage requiring orthopedic surgery. Correlations between PWC experience and injury incidence can provide information for increased safety. LEVEL OF EVIDENCE: IV; retrospective. PMID- 29410213 TI - Subcutaneous immunoglobulin treatment and thromboembolic risk. PMID- 29410214 TI - The environment and food allergy. PMID- 29410215 TI - Cytokine-targeting biologics for allergic diseases. AB - OBJECTIVE: Asthma and allergic diseases continue to increase in prevalence, creating a financial burden on the health care system and affecting the quality of life for those who have these diseases. Many intrinsic and extrinsic factors are involved in the initiation and maintenance of the allergic response. Cytokines are proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses. DATA SOURCES: clinicaltrials.gov and PubMed. STUDY SELECTIONS: Relevant clinical trials and recent basic science studies were chosen for discussion. RESULTS: Many cytokines have been implicated in the development and perpetuation of the allergic response. Biologics have been and are continuing to be developed that target these molecules for use in patients with asthma and atopic dermatitis where standard treatment options fail. The current state of cytokine-targeting therapies is discussed. CONCLUSION: This review focused on cytokines involved in the allergic response with an emphasis on those for which therapies are being or have been developed. PMID- 29410218 TI - Cholinergic neurons in medial septum maintain anxiety-like behaviors induced by chronic inflammatory pain. AB - Cholinergic neurons in the medial septum (MS) participate in various cognitive and emotional behaviors, including innate anxiety. Chronic pain involves perceptual, cognitive and emotional components. Whether MS cholinergic system modulates pain-induced anxiety and the underlying neural circuits are involved remain unclear. In the present study, we showed that chemogenetic (DREADD) inhibition of MS cholinergic neurons relieved pain-induced anxiety-like behaviors in open field and elevated plus maze tests. Inhibiting the MS-rostral anterior cingulate cortex (rACC), but not the MS-ventral hippocampal CA1 pathway, achieved anxiolysis. These findings indicate the involvement of MS cholinergic system in modulating pain-induced anxiety-like behaviors. PMID- 29410219 TI - Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance. AB - Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance. PMID- 29410217 TI - Is carbonic anhydrase activity of photosystem II required for its maximum electron transport rate? AB - It is known, that the multi-subunit complex of photosystem II (PSII) and some of its single proteins exhibit carbonic anhydrase activity. Previously, we have shown that PSII depletion of HCO3-/CO2 as well as the suppression of carbonic anhydrase activity of PSII by a known inhibitor of alpha-carbonic anhydrases, acetazolamide (AZM), was accompanied by a decrease of electron transport rate on the PSII donor side. It was concluded that carbonic anhydrase activity was required for maximum photosynthetic activity of PSII but it was not excluded that AZM may have two independent mechanisms of action on PSII: specific and nonspecific. To investigate directly the specific influence of carbonic anhydrase inhibition on the photosynthetic activity in PSII we used another known inhibitor of alpha-carbonic anhydrase, trifluoromethanesulfonamide (TFMSA), which molecular structure and physicochemical properties are quite different from those of AZM. In this work, we show for the first time that TFMSA inhibits PSII carbonic anhydrase activity and decreases rates of both the photo-induced changes of chlorophyll fluorescence yield and the photosynthetic oxygen evolution. The inhibitory effect of TFMSA on PSII photosynthetic activity was revealed only in the medium depleted of HCO3-/CO2. Addition of exogenous HCO3- or PSII electron donors led to disappearance of the TFMSA inhibitory effect on the electron transport in PSII, indicating that TFMSA inhibition site was located on the PSII donor side. These results show the specificity of TFMSA action on carbonic anhydrase and photosynthetic activities of PSII. In this work, we discuss the necessity of carbonic anhydrase activity for the maximum effectiveness of electron transport on the donor side of PSII. PMID- 29410216 TI - Hormones, sex, and asthma. AB - OBJECTIVE: To summarize the current literature on the sex disparity in asthma and the role of sex hormone signaling in allergic and neutrophilic airway inflammation. DATA SOURCES: PubMed and Centers for Disease Control and Prevention health surveys were searched. STUDY SELECTIONS: Clinical and epidemiologic studies in children and adults as well as animal models of asthma were included in this review. RESULTS: Compared with males, females have an increase in asthma prevalence starting around puberty, and fluctuations in hormones during menstruation, pregnancy, and menopause are associated with changes in asthma symptoms. Animal studies using genetic deletions of estrogen receptors or androgen receptors have shown that estrogen signaling promotes and androgen signaling attenuates allergen-mediated type 2 airway inflammation. Furthermore, animal studies have found that ovarian hormones are important for interleukin 17A mediated airway inflammation. CONCLUSION: Sex hormones are important in regulating asthma pathogenesis. However, additional studies need to be conducted to further elucidate how sex hormones are initiating and driving the inflammatory response(s) in asthma. Determining these pathways will provide the foundation necessary for the development of treatment strategies and potentially new therapeutics for patients, in particular females, with asthma. PMID- 29410220 TI - Rasmussen aneurysm: A rare but not gone complication of tuberculosis. AB - This report describes the case of a 30-year-old homeless man from Pereira, Colombia with tuberculosis, who presented with massive hemoptysis and associated aneurysm of the left upper lobe (Rasmussen aneurysm). Computed tomography angiography with three-dimensional reconstruction confirmed the aneurysm, and embolization was performed successfully. PMID- 29410221 TI - Reply. PMID- 29410222 TI - Effective light-triggered contents release from helper lipid-incorporated liposomes co-encapsulating gemcitabine and a water-soluble photosensitizer. AB - Triggered drug release is a promising strategy for delivering anticancer drugs to cancer cells and tissues. We found that liposomes co-encapsulating calcein (a water-soluble model drug and fluorescence marker) and talaporfin sodium (TPS, a water-soluble photosensitizer) released the drug upon irradiation with a near infrared (NIR)-laser. The liposomes were composed of phospholipid (DSPC)/helper lipid (DOPE)/cholesterol/PEG-lipid (PEG2000-DSPE) at a molar ratio of 85/10/5/5 and released a large amount of drug (70%<, within 10 min) upon irradiation, but no drug in the absence of NIR-laser irradiation and/or TPS. NIR-laser-triggered drug release was facilitated by the incorporation of DOPE into the liposomes, and the amount of DOPE incorporated affected drug leakage in the absence of NIR-laser irradiation at 37 degrees C (body temperature). Drug leakage was tuned by incorporating cholesterol into the liposomes. NIR-laser-triggered drug release from the liposomes was confirmed using the anticancer drug gemcitabine. NIR-laser treatment of liposomes co-encapsulating gemcitabine and TPS provided the maximum cytotoxic effect towards EMT6/P cells. These results suggest that these novel light sensitive liposomes may be useful for drug delivery to cancer cells. PMID- 29410223 TI - Spatio-temporal image correlation spectroscopy and super-resolution microscopy to quantify molecular dynamics in T cells. AB - Many cellular processes are regulated by the spatio-temporal organisation of signalling complexes, cytoskeletal components and membranes. One such example is at the T cell immunological synapse where the retrograde flow of cortical filamentous (F)-actin from the synapse periphery drives signalling protein microclusters towards the synapse centre. The density of this mesh however, makes visualisation and analysis of individual actin fibres difficult due to the resolution limit of conventional microscopy. Recently, super-resolution methods such as structured illumination microscopy (SIM) have surpassed this resolution limit. Here, we apply SIM to better visualise the dense cortical actin meshwork in T cell synapses formed against activating, antibody-coated surfaces and image under total-internal reflection fluorescence (TIRF) illumination. To analyse the observed molecular flows, and the relationship between them, we apply spatio temporal image correlation spectroscopy (STICS) and its cross-correlation variant (STICCS). We show that the dynamic cortical actin mesh can be visualised with unprecedented detail and that STICS/STICCS can output accurate, quantitative maps of molecular flow velocity and directionality from such data. We find that the actin flow can be disrupted using small molecule inhibitors of actin polymerisation. This combination of imaging and quantitative analysis may provide an important new tool for researchers to investigate the molecular dynamics at cellular length scales. Here we demonstrate the retrograde flow of F-actin which may be important for the clustering and dynamics of key signalling proteins within the plasma membrane, a phenomenon which is vital to correct T cell activation and therefore the mounting of an effective immune response. PMID- 29410224 TI - Re: "Comparison of antipseudomonal betalactams for febrile neutropenia empiric therapy: systematic review and network metaanalysis" by Horita et al. PMID- 29410225 TI - Evaluation of an S-system root-finding method for estimating parameters in a metabolic reaction model. AB - In a mathematical model, estimation of parameters from time-series data of metabolic concentrations in cells is a challenging task. However, it seems that a promising approach for such estimation has not yet been established. Biochemical Systems Theory (BST) is a powerful methodology to construct a power-law type model for a given metabolic reaction system and to then characterize it efficiently. In this paper, we discuss the use of an S-system root-finding method (S-system method) to estimate parameters from time-series data of metabolite concentrations. We demonstrate that the S-system method is superior to the Newton Raphson method in terms of the convergence region and iteration number. We also investigate the usefulness of a translocation technique and a complex-step differentiation method toward the practical application of the S-system method. The results indicate that the S-system method is useful to construct mathematical models for a variety of metabolic reaction networks. PMID- 29410226 TI - Genetic diversity of Giardia duodenalis circulating in three Brazilian biomes. AB - Giardia duodenalis has a wide genetic variety, and its characterization helps in the understanding of its transmission dynamics and in the development control strategies. This study aimed to assess the genetic diversity of G. duodenalis obtained in different Brazilian biomes and estimate their phylogenetic relationships. Three surveys including 944 participants were carried out in the municipalities of Russas (RSS, Caatinga semiarid biome), Santa Isabel do Rio Negro (SIRN, Amazon rainforest biome) and Nossa Senhora de Nazare (NSN, Cerrado Caatinga transition biome). G. duodenalis-positive fecal samples were submitted to amplification of gene fragments encoding beta-giardin (betaG, N = 71), glutamate dehydrogenase (GDH, N = 42), and triosephosphate isomerase (TPI, N = 27). Overall detection rates of assemblage A in G. duodenalis-positive samples through betaG, GDH and TPI were 22/71 (31%), 13/42 (31%), and 13/27 (48.1%), respectively. Concerning assemblage B, rates with distinct genetic markers were 49/71 (69%), 29/42 (69%), and 14/27 (51.9%), respectively. In the Amazon, assemblage B was more prevalent (77.8%, 71.8% and 65% through betaG, GDH and TPI, respectively), while in the Cerrado biome assemblage A predominated (50%, 66.6%, and 85.7%, through betaG, GDH and TPI, respectively). In Caatinga biome assemblage A also predominated (71.4%, through betaG). Thirty new sub-assemblages are described for assemblage B (24 betaG and six TPI), as well as three new sub assemblages are described for assemblage A (one GDH and 2 TPI). Higher genetic diversity of assemblage B in the Amazon may be related to demographic concentration leading to a more complex transmission network within a poorer sanitation background. The high genetic divergence between assemblages A and B (5.5-6.3%) support the proposal of taxon separation in distinct species. PMID- 29410227 TI - Spot Urine Sodium as Triage for Effective Diuretic Infusion in an Ambulatory Heart Failure Unit. AB - BACKGROUND: Admission for diuresis remains a common and costly event in patients with advanced heart failure (HF). We tested whether spot urine sodium could identify patients likely to respond to ambulatory diuretic infusion without hospitalization. METHODS AND RESULTS: We prospectively followed 176 consecutive patients with advanced heart failure receiving intravenous furosemide for congestion in an ambulatory clinic. Spot urine sodium was measured in 1st voided urine after diuretic infusion and compared with 3-hour urine output and subsequent risk of 30-day hospitalization or emergency department (ED) visit. Spot urine sodium was significantly associated with urine output in a model adjusted for age, renal function, and blood urea nitrogen (P = .02). Higher urine sodium was associated with lower risk of hospitalization or ED visit within 30 days (odds ratio [OR] 0.82 [95% confidence interval 0.72-0.94] per 10 mmol/L increase; P < .001), in a model adjusted for hemoglobin (OR 0.80 [0.66-0.97]; P = .02) and systolic blood pressure (OR 0.82 [0.67-1.0]; P = .05). Spot urine sodium >=65 mmol/L and urine output >=1200 mL identified a lower-risk group for outpatient management. CONCLUSION: High spot urine sodium after diuretic administration identifies HF patients likely to respond to an ambulatory diuretic infusion with lower rates of hospitalization or ED visits at 30 days. PMID- 29410229 TI - Preliminary evaluation of the impact of a Web-based HIV testing programme in Abruzzo Region on the prevention of late HIV presentation and associated mortality. AB - OBJECTIVE: This study aimed to analyze the efficacy of a Web-based testing programme in terms of the prevention of late HIV presentation. The clinical characteristics of patients diagnosed with HIV via the Web-based testing programme were compared to those of patients diagnosed in parallel via standard diagnostic care procedures. METHODS: This study included the clinical and demographic data of newly diagnosed HIV patients enrolled at the study clinic between February 2014 and June 2017. These patients were diagnosed either via standard diagnostic procedures or as a result of the Web-based testing programme. RESULTS: Eighty-eight new cases of HIV were consecutively enrolled; their mean age was 39.1+/-13.0 years. Fifty-nine patients (67%) were diagnosed through standard diagnostic procedures and 29 (33%) patients came from the Web-based testing programme. Late presentation (62% vs. 34%, p=0.01) and AIDS-defining conditions at presentation (13 vs. 1, p=0.02) were significantly more frequent in the standard care group than in the Web-based group; four of 13 patients with AIDS diagnosed under standard diagnostic procedures died, versus none in the Web based testing group (p<0.001). CONCLUSIONS: Web-based recruitment for voluntary and free HIV testing helped to diagnose patients with less advanced HIV disease and no risk of death, from all at-risk groups, in comparison with standard care testing. PMID- 29410228 TI - Facile metabolic glycan labeling strategy for exosome tracking. AB - BACKGROUND: Exosomes are nano-sized vesicles derived from the fusion of multivesicular bodies with the surrounding plasma membrane. Exosomes have various diagnostic and therapeutic potentials in cancer and other diseases, thus tracking exosomes is an important issue. METHODS: Here, we report a facile exosome labeling strategy using a natural metabolic incorporation of an azido-sugar into the glycan, and a strain-promoted azide-alkyne click reaction. In culture, tetra acetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) was spontaneously incorporated into glycans within the cells and later redistributed onto their exosomes. These azido-containing exosomes were then labeled with azadibenzylcyclooctyne (ADIBO) fluorescent dyes by a bioorthogonal click reaction. RESULTS: Cellular uptake and the in vivo tracking of fluorescent labeled exosomes were evaluated in various cells and tumor bearing mice. Highly metastatic cancer-derived exosomes showed an increased self-homing in vitro and selective organ distribution in vivo. CONCLUSION: Our metabolic exosome labeling strategy could be a promising tool in studying the biology and distribution of exosomes, and optimizing exosome based therapeutic approaches. GENERAL SIGNIFICANT: A facile and effective exosome labeling strategy was introduced by presenting azido moiety on the surface of exosome through metabolic glycan synthesis, and then conjugating a strain promoted fluorescent dye. PMID- 29410231 TI - Using smooth forceps for assisting incision and drainage of an infected epidermoid cyst. PMID- 29410230 TI - Risk factors for pertussis among hospitalized children in a high HIV prevalence setting, South Africa. AB - BACKGROUND: In low- and middle-income countries, including South Africa, the epidemiology of pertussis in relation to immunization, nutritional, and HIV status is poorly described. This article reports on risk factors in South African children hospitalized with pertussis. METHODS: A prospective, hospital-based, sentinel surveillance programme for pertussis was conducted in Gauteng Province, South Africa. Hospitalized children (<=10 years) meeting the surveillance criteria for clinically suspected pertussis were screened and enrolled. Nasopharyngeal specimens were collected for real-time multiplex PCR and culture of Bordetella species. RESULTS: Bordetella pertussis was detected in 6.2% (61/992) of children. Pertussis was significantly more prevalent in infants younger than 3 months (9.8%; 38/392) and in young children between the ages of 5 and 9 years (12%; 4/34) (p=0.0013). Of the 61 confirmed pertussis cases, 17 were too young for vaccination. Of the remaining 44 infants, vaccination DTP1 was administered in 73% (32/44) of pertussis-confirmed patients who were eligible, DTP2 in 50% (16/32), DTP3 in 54% (14/26), and DTP4 in 56% (5/9) of vaccine eligible cases at 18 months of age. B. pertussis infection was less likely in children immunized at least once (5%, 32/692) than in unvaccinated children (10%, 24/230) (p=0.0001). HIV exposure and infection status were determined in 978 (99%) patients: 69% (678/978) were HIV-unexposed and uninfected and 31% (300/978) were HIV-exposed. Of these HIV-exposed patients, 218 (22%) were proven HIV exposed and uninfected and 82 patients were HIV-infected (8.4%, 82/978). HIV prevalence was similar in pertussis-positive (6%, 5/82) and pertussis-negative (6%, 55/896) children (p=0.90). B. pertussis infection was unrelated to poor nutritional status. CONCLUSIONS: In South Africa, B. pertussis poses a greater risk to infants who are too young for the first vaccine dose, those who are not vaccinated in a timely manner, and those who do not receive all three primary doses. HIV infection and HIV exposure were not associated with pertussis infection. PMID- 29410232 TI - Tip to protect the tip: An inexpensive alternative to protect damage to fine instruments during sterilization. PMID- 29410233 TI - Predominance of non-fumigatus Aspergillus species among patients suspected to pulmonary aspergillosis in a tropical and subtropical region of the Middle East. AB - Non-fumigatus Aspergillus species are the leading cause of Aspergillus infections in the tropical and subtropical regions of the world. In a prospective study between 2015 and 2016, a total of 150 bronchoalveolar (BAL) specimens was collected from patients suspected to pulmonary aspergillosis (PA) underlying immunodeficiencies in Mashhad, Northeastern Iran, located in the Middle East. All Aspergillus strains were phylogenetically identified at the species level by PCR sequencing of partial beta-tubulin gene. Overall, Aspergillus species were isolated from 20 specimens originating from 10 (50%) patients with cancer, 5 (25%) patients receiving corticosteroid therapy, 3 (15%) organ transplant recipients and 2 (10%) patients admitted to intensive care unit (ICU). A. flavus complex was the predominant 15 (75%) cause of probable invasive pulmonary aspergillosis (IPA), followed by A. tubingensis 3 (15%), and 2 (10%) A. fumigates complex. In conclusion, distribution of clinical Aspergillus species in the tropical region of the Middle East shows predominance of the non-fumigatus Aspergillus spp., which warrants further attention by health care professionals. PMID- 29410234 TI - The physical capabilities underlying timed "Up and Go" test are time-dependent in community-dwelling older women. AB - Timed 'Up and Go' (TUG) has been widely used in research and clinical practice to evaluate physical function and mobility in older adults. However, the physical capabilities underlying TUG performance are not well elucidated. Therefore, the present study aimed at investigating a selection of physical capacities underlying TUG performance in community-dwelling older women. Four hundred and sixty-eight apparently healthy older women independent to perform the activities of daily living (mean age: 65.8 +/- 6.0 years) were recruited from two specialized healthcare centers for older adults to participate in the study. Volunteers had their medical books reviewed and underwent evaluations of anthropometric data as well as physical and functional capacities. Pearson's correlation results indicate that TUG performance was significantly associated with upper (i.e., handgrip strength) and lower (i.e., sit-to-stand) limb muscle strength, balance (i.e., one-leg stand), lower limb muscle power (i.e., countermovement jump), aerobic capacity (i.e., 6-minute walk test), and mobility (i.e., usual and maximal walking speeds). When the analyses were performed based on TUG quartiles, a larger number of physical capabilities were associated with TUG >75% in comparison with TUG <25%. Multiple linear regression results indicate that the variability in TUG (~20%) was explained by lower limb muscle strength (13%) and power (1%), balance (4%), mobility (2%), and aerobic capacity (<1%), even after adjusted by age and age plus body mass index (BMI). However, when TUG results were added as quartiles, a decrease in the impact of physical capacities on TUG performance was determined. As a whole, our findings indicate that the contribution of physical capabilities to TUG performance is altered according to the time taken to perform the test, so that older women in the lower quartiles - indicating a higher performance - have an important contribution of lower limb muscle strength, while volunteers in the highest quartile demonstrate a decreased dependence on lower limb muscle strength and an increased contribution of other physical capabilities, such as lower limb muscle power and balance. PMID- 29410235 TI - Variation in thermally induced taste response across thermal tasters. AB - Thermal tasters (TTs) perceive thermally induced taste (thermal taste) sensations when the tongue is stimulated with temperature in the absence of gustatory stimuli, while thermal non tasters (TnTs) only perceive temperature. This is the first study to explore detailed differences in thermal taste responses across TTs. Using thermal taster status phenotyping, 37 TTs were recruited, and the temporal characteristics of thermal taste responses collected during repeat exposure to temperature stimulation. Phenotyping found sweet most frequently reported during warming stimulation, and bitter and sour when cooling, but a range of other sensations were stated. The taste quality, intensity, and number of tastes reported greatly varied. Furthermore, the temperature range when thermal taste was perceived differed across TTs and taste qualities, with some TTs perceiving a taste for a small temperature range, and others the whole trial. The onset of thermal sweet taste ranged between 22 and 38 degrees C during temperature increase. This supports the hypothesis that TRPM5 may be involved in thermal sweet taste perception as TRPM5 is temperature activated between 15 and 35 degrees C, and involved in sweet taste transduction. These findings also raised questions concerning the phenotyping protocol and classification currently used, thus indicating the need to review practices for future testing. This study has highlighted the hitherto unknown variation that exists in thermal taste response across TTs, provides some insights into possible mechanisms, and importantly emphasises the need for more research into this sensory phenomenon. PMID- 29410236 TI - Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? AB - The gut microbiota plays an important role in host metabolism and its dysregulation have been related to cardiometabolic disorders (CMD), such as type 2 diabetes mellitus (T2D), dyslipidemia and arterial hypertension, as well as to chronic kidney diseases (CKD). The implication of the gut microbiota on systemic disorders has been associated with changes in its composition (dysbiosis) as a result of the oxidative unbalance in the body. This alteration may be the result of the adoption of unhealthy lifestyle behavior, including lack of physical activity and fat- or sugar-rich diets, which are largely associated with increased incidence of CMD and CKD. In last years, a number of clinical trials and experimental studies have demonstrated that probiotics can modulate the host metabolism, resulting in amelioration of systemic disease phenotypes by the improvement of dyslipidemia, glycemic profile and blood pressure or CKD parameters. The beneficial effects of probiotics consumption have been associated with their anti-inflammatory, antioxidant and gut-modulating properties. Despite of some mechanistic evidence, these effects are not totally elucidated. The present review summarizes and clarifies the effects of probiotics administration on CMD and CKD using combined evidence from clinical and experimental studies. Considering that the microbiota dysregulation has been associated with inflammation and oxidative stress and consequently with CMD and CKD, supplementation with probiotics is discussed as a strategy for management of CMD and CKD. PMID- 29410237 TI - A Traveler's Disease Without Leaving Home: Typhoid Fever. PMID- 29410238 TI - Selective hemangioma cell dysfunction and apoptosis triggered by in vitro treatment with imiquimod. AB - Infantile hemangiomas are the most common benign tumors of infancy, characterized by unregulated angiogenesis and endothelial cells with high mitotic rate. Although spontaneous regression occurs, sometimes treatment is required and alternatives to corticosteroids should be considered to reduce side effects. Imiquimod is an imidazoquinoline, approved for some skin pathologies other than hemangioma. It is proposed that the effectiveness of imiquimod comes from the activation of immune cells at tumor microenvironment. However, the possibility to selectively kill different cell types and to directly impede angiogenesis has been scarcely explored in vitro for endothelial cells. In this work we showed a dramatic cytotoxicity on hemangioma cell, with a significant lower IC50 value in hemangioma compared to normal endothelial cells and melanoma (employed as a non endothelial tumor cell line). Nuclear morphometric and flow-cytometry assays revealed imiquimod-induced apoptosis on hemangioma and melanoma cells but a small percentage of senescence on normal endothelial cells. At sub-lethal conditions, cell migration, a key step in angiogenesis turned out to be inhibited in a tumor selective manner along with actin cytoskeleton disorganization on hemangioma cells. Altogether, these findings pointed out the selective cytotoxic effects of imiquimod on transformed endothelial cells, evidencing the potential for imiquimod to be a therapeutic alternative to reduce extensive superficial hemangioma lesions. PMID- 29410239 TI - What the oncologist can learn from diabetes studies: Epidemiology, prevention, management, cure. AB - Notwithstanding massive efforts and investment in improving cancer therapy, the limited progress made in reducing overall mortality has mostly been achieved through early diagnosis. Mortality rates for cardiovascular disease are in decline, a success attributable in large part to an active prevention approach coupled with identification of risk factors and biomarkers. Promising natural and synthetic molecules including numerous flavonoids have the potential to be used in diabetes care and in prevention of cardiovascular pathologies. These concepts should also be applied to cancer, the incidence of which continues to increase. In cancer chemoprevention low toxicity drugs or dietary constituents are used to prevent or delay onset of malignancy. Evidence is accumulating that cancer chemoprevention is a valuable weapon against human cancer. For example, doubling of fruit and fiber intake is associated with reduction of colorectal cancer whereas fat food consumption appears to increase malignant progression of certain tumors. Breast, colorectal and prostate cancer are the most suitable cancers for dietary prevention and scientists have strong data in these cancers at basic, translational, clinical and epidemiological levels, due to experimental evidence and the large EPIC study. Physical activity is also crucial. Yet, cancer chemoprevention research in oncology is largely underrepresented and lags far behind the efforts dedicated to therapy; it is important to close this gap. Few European phase III clinical trials are ongoing and systematic development of novel agents for cancer prevention is rare in Europe. PMID- 29410240 TI - The use of omics profiling to improve outcomes of bone regeneration and osseointegration. How far are we from personalized medicine in dentistry? AB - : Increased life expectancy and broader restorative dental treatment alternatives for missing teeth have resulted in an increasing request of bone regeneration/augmentation procedures not only in healthy patients, but also in elderly and medically compromised ones. This is also combined with a growing demand for short implant loading protocols and for optimal aesthetic results. In order to meet these new dental needs, personalized treatment strategies tailored on each individual's characteristics and healing profile are warranted. Omics technologies are emerging as powerful tools to uncover molecules and signalling pathways involved in bone formation and osseointegration and to investigate differences in the molecular mechanisms between health and systemic diseases that could be targeted by future therapies. This review critically appraises the available knowledge on the application of omics technologies in the field of bone regeneration and osseointegration and explores their potential use for personalized medicine in the dento-maxillo-facial field. SIGNIFICANCE: The use of omics in personalising dental maxillo-facial treatments emerges as a desirable diagnostic and treatment strategy. Omics represent, in fact, powerful tools not only to shade light on the cascade of events taking place during bone formation/osseointegration, but also to identify specific signalling pathways and molecules that can be targeted by future therapies with the aim to enhance clinical outcomes in patients with compromised healing conditions. PMID- 29410241 TI - Independent control of matrix adhesiveness and stiffness within a 3D self assembling peptide hydrogel. AB - : A cell's insoluble microenvironment has increasingly been shown to exert influence on its function. In particular, matrix stiffness and adhesiveness strongly impact behaviors such as cell spreading and differentiation, but materials that allow for independent control of these parameters within a fibrous, stromal-like microenvironment are very limited. In the current work, we devise a self-assembling peptide (SAP) system that facilitates user-friendly control of matrix stiffness and RGD (Arg-Gly-Asp) concentration within a hydrogel possessing a microarchitecture similar to stromal extracellular matrix. In this system, the RGD-modified SAP sequence KFE-RGD and the scrambled sequence KFE-RDG can be directly swapped for one another to change RGD concentration at a given matrix stiffness and total peptide concentration. Stiffness is controlled by altering total peptide concentration, and the unmodified base peptide KFE-8 can be included to further increase this stiffness range due to its higher modulus. With this tunable system, we demonstrate that human mesenchymal stem cell morphology and differentiation are influenced by both gel stiffness and the presence of functional cell binding sites in 3D culture. Specifically, cells 24 hours after encapsulation were only able to spread out in stiffer matrices containing KFE-RGD. Upon addition of soluble adipogenic factors, soft gels facilitated the greatest adipogenesis as determined by the presence of lipid vacuoles and PPARgamma-2 expression, while increasing KFE-RGD concentration at a given stiffness had a negative effect on adipogenesis. This three-component hydrogel system thus allows for systematic investigation of matrix stiffness and RGD concentration on cell behavior within a fibrous, three-dimensional matrix. STATEMENT OF SIGNIFICANCE: Physical cues from a cell's surrounding environment such as the density of cell binding sites and the stiffness of the surrounding material-are increasingly being recognized as key regulators of cell function. Currently, most synthetic biomaterials used to independently tune these parameters lack the fibrous structure characteristic of stromal extracellular matrix, which can be important to cells naturally residing within stromal tissues. In this manuscript, we describe a 3D hydrogel encapsulation system that provides user-friendly control over matrix stiffness and binding site concentration within the context of a stromal-like microarchitecture. Binding site concentration and gel stiffness both influenced cell spreading and differentiation, highlighting the utility of this system to study the independent effects of these material properties on cell function. PMID- 29410242 TI - SR Ca2+-leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure. AB - AIMS: Ethanol has acute negative inotropic and arrhythmogenic effects. The underlying mechanisms, however, are largely unknown. Sarcoplasmic reticulum Ca2+ leak is an important mechanism for reduced contractility and arrhythmias. Ca2+ leak can be induced by oxidative stress and Ca2+/Calmodulin-dependent protein kinase II (CaMKII). Therefore, we investigated the influence of acute ethanol exposure on excitation-contraction coupling in atrial and ventricular cardiomyocytes. METHODS AND RESULTS: Isolated human atrial and murine atrial or ventricular cardiomyocytes were preincubated for 30 min and then superfused with control solution or solution containing ethanol. Ethanol had acute negative inotropic and positive lusitropic effects in human atrial muscle strips and murine ventricular cardiomyocytes. Accordingly, Ca2+-imaging indicated lower Ca2+ transient amplitudes and increased SERCA2a activity, while myofilament Ca2+ sensitivity was reduced. SR Ca2+-leak was assessed by measuring Ca2+-sparks. Ethanol induced severe SR Ca2+-leak in human atrial cardiomyocytes (calculated leak: 4.60 +/- 0.45 mF/F0 vs 1.86 +/- 0.26 in control, n >= 80). This effect was dose-dependent, while spontaneous arrhythmogenic Ca2+-waves increased ~5-fold, as investigated in murine cardiomyocytes. Delayed afterdepolarizations, which can result from increased SR Ca2+-leak, were significantly increased by ethanol. Measurements using the reactive oxygen species (ROS) sensor CM-H2DCFDA showed increased ROS-stress in ethanol treated cells. ROS-scavenging with N acetylcysteine prevented negative inotropic and positive lusitropic effects in human muscle strips. Ethanol-induced Ca2+-leak was abolished in mice with knockout of NOX2 (the main source for ROS in cardiomyocytes). Importantly, mice with oxidation-resistant CaMKII (Met281/282Val mutation) were protected from ethanol-induced Ca2+-leak. CONCLUSION: We show for the first time that ethanol acutely induces strong SR Ca2+-leak, also altering excitation-contraction coupling. Acute negative inotropic effects of ethanol can be explained by reduced systolic Ca2+-release. Mechanistically, ROS-production via NOX2 and oxidative activation of CaMKII appear to play central roles. This provides a mechanism for the arrhythmogenic and negative inotropic effects of ethanol and suggests a druggable target (CaMKII). PMID- 29410243 TI - SVCV impairs mitochondria complex III resulting in accumulation of hydrogen peroxide. AB - Spring viraemia of carp virus (SVCV) is a deadly pathogen of common carp. SVCV infection is found to be associated with excess reactive oxygen species (ROS) generation and induces oxidative stress in EPC and FHM cells, which contributes to its pathogenesis. In this study, ROS production and mitochondria function as well as antioxidant enzymes in mitochondria were investigated during SVCV infection in EPC cells. Dysfunction of mitochondria and inactivation of mitochondria electron transport chain complex III to augment O2-? and H2O2 accumulation were observed in SVCV infected EPC cells. Treatment of Antimycin A reduced the activity of mitochondria complex III in EPC cells, which also inhibited the transcription of SVCV glycoprotein gene (SVCV-G) and production of SVCV. Our studies explain the production of ROS following SVCV infection and also suggest that integrate mitochondrial function is important for SVCV infection. PMID- 29410244 TI - A new host for Hematodinium infection among lithodid crabs from the Sea of Okhotsk. AB - A disease caused by parasitic dinoflagellates of the genus Hematodinium has been found in the soft crab Hapalogaster grebnitzkii from the Sea of Okhotsk, which is considered a new host for this agent among lithodid crabs. This report provides macro- and micromorphological descriptions (using light and transmission electron microscopy) of the disease, as well as molecular identification of Hematodinium sp. from soft crabs, based on 18S RNA sequence data. PMID- 29410245 TI - Engineered humanized bone organs maintain human hematopoiesis in vivo. AB - Hematopoietic stem cells (HSCs) are maintained in a specialized bone marrow (BM) environment, the so-called HSC niche, that provides pivotal factors for their maintenance. Although the cellular and molecular components of the mouse BM HSC niche have been extensively studied using genetically modified animals, relatively little is known about the counterpart human BM niche components. We previously illustrated, with a developmental tissue engineering approach, that human adult BM-derived mesenchymal stromal cells (MSCs) can develop into human bone organs (so-called ossicles) through endochondral ossification in vivo and that these human ossicles are able to maintain functional mouse HSCs. We here report that human ossicles in immunodeficient mice maintain human immature and mature hematopoiesis in vivo. Moreover, a higher percentage of human stem and progenitor cells are kept in quiescence in human ossicles as compared with mouse BM. These findings indicate that the human MSC-derived ossicles function as a hematopoietic niche and may potentially serve as a re-engineerable platform to study normal and diseased human hematopoiesis in a physiologically optimized environment. PMID- 29410246 TI - How to: accreditation of blood cultures' proceedings. A clinical microbiology approach for adding value to patient care. AB - BACKGROUND: Quality assurance and quality management are driving forces for controlling blood culture best practices but should not be disconnected from the end-point target, i.e. patient value. AIMS: This article is intended to help microbiologists implement blood culture accreditation that is actually beneficial to patient management. SOURCES: Experience from a nationwide taskforce for promoting quality assurance and competence in clinical microbiology laboratories, guidelines on blood culture. CONTENT: Experience in blood culture accreditation according to International standard ISO 15189 standards is provided in this review, with a particular focus on critical points that are specific to blood culture (e.g. excluding strain identification or antimicrobial susceptibility testing). Blood culture test method verification is based on risk analysis, and evaluation of the test method's performance is based on the literature review and suppliers' data. In addition, blood culture performance relies largely on the quality of its pre-analytical phase, and the test method should be monitored based on key performance indicators such as the volume of blood cultured, the contamination rate and time to transportation. Other critical key indicators include the rate of false-positive signals, the rate of positive blood cultures, the ecology associated with positive results, and the timely communication of the results to the ward during the post-analytical phase. Finally, a critical analysis of quality controls and of the tools needed to improve blood culture monitoring in the future is provided. IMPLICATION: Appropriate quality assurance should focus on patient value rather than technical details to provide an appropriate clinical service. PMID- 29410248 TI - TFCP2/TFCP2L1/UBP1 transcription factors in cancer. AB - The TFCP2/Grainyhead family of transcription factors is divided into two distinct subfamilies, one of which includes the Grainyhead-like 1-3 (GRHL1-3) proteins and the other consists of TFCP2 (synonyms: CP2, LSF, LBP-1c), TFCP2L1 (synonyms: CRTR 1, LBP-9) and UBP1 (synonyms: LBP-1a, NF2d9). Transcription factors from the TFCP2/TFCP2L1/UBP1 subfamily are involved in various aspects of cancer development. TFCP2 is a pro-oncogenic factor in hepatocellular carcinoma, pancreatic cancer and breast cancer, may be important in cervical carcinogenesis and in colorectal cancer. TFCP2 can also act as a tumor suppressor, for example, it inhibits melanoma growth. Furthermore, TFCP2 is involved in epithelial mesenchymal transition and enhances angiogenesis. TFCP2L1 maintains pluripotency and self-renewal of embryonic stem cells and was implicated in a wide variety of cancers, including clear cell renal cell carcinoma, breast cancer and thyroid cancer. Here we present a systematic review of current knowledge of this protein subfamily in the context of cancer. We also discuss potential challenges in investigating this family of transcription factors. These challenges include redundancies between these factors as well as their interactions with each other and their ability to modulate each other's activity. PMID- 29410247 TI - Cocaine use may induce telomere shortening in individuals with HIV infection. AB - BACKGROUND: Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection. METHODS: Between June 2010 and December 2016, 147 HIV infected participants in Baltimore, Maryland, were enrolled in a cross-sectional study investigating factor(s) associated with telomere length. Of these 147, 93 participated in a follow-up study to examine factor(s) associated with telomere shortening. Robust regression model was used to analyze cross-sectional data and the generalized estimating equation approach was used to analyze follow-up data. RESULTS: Cross-sectional analyses demonstrated that (1) both daily alcohol consumption and use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were independently associated with telomere length, and cocaine use modified the associations of daily alcohol use and NNRTI use with telomere length. Longitudinal analyses suggested that both daily alcohol consumption and duration of NNRTI use were independently associated with telomere shortening, and (2) cocaine use induced/accelerated telomere shortening in HIV-infected individuals. CONCLUSIONS: Our findings suggest that cocaine use may promote premature aging in HIV-infected individuals who are on ART. Our results emphasize the importance of cocaine abstinence/reduced use, which may retard HIV-associated premature aging. PMID- 29410249 TI - Biphasic effect of sumatriptan on PTZ-induced seizures in mice: Modulation by 5 HT1B/D receptors and NOS/NO pathway. AB - Sumatriptan has been among the top choices in the management of migraine headaches. The association between migraine and epilepsy highlights the possible effect of sumatriptan on seizures. In this regard, we investigated sumatriptan effects on PTZ-induced seizures thresholds and delineated the modulatory role of 5-HT1B/D receptors and NOS/NO pathway. Our data revealed the anti-convulsant effects of lower doses of sumatriptan, and pro-convulsant effects of higher doses of sumatriptan. GR 127935, a selective 5-HT1B/D antagonist, could abolish the sumatriptan anti-convulsant effects, but it was ineffective against the sumatriptan pro-convulsant effects. Serotonin depletion by consecutive administration of p-CPA, a selective irreversible inhibitor of tryptophan hydroxylase, could not affect the anti-convulsant effects of sumatriptan. The anti-convulsant effects of sumatriptan was potentiated by L-NAME, a non-selective NOS inhibitor, 7-NI, a selective nNOS inhibitor, but not AG, an iNOS inhibitor. It was also neutralized by L-ARG, a NO precursor. The pro-convulsant effects of sumatriptan were blocked by L-NAME and AG, but not 7-NI. It was also potentiated by L-ARG. Our data revealed that anti-convulsive effects of sumatriptan is mediated by interaction between non-serotonergic 5-HT1B/D receptors and nNOS/NO pathway. Besides, the pro-convulsive effect of sumatriptan is mediated by iNOS/NO pathway independent of 5-HT1B/D receptors. For the first time, this study reported the biphasic effect of sumatriptan on an animal model of GCS and its modulatory pathways. PMID- 29410251 TI - Rebuttal From Dr Pavord. PMID- 29410252 TI - Allergy skin testing: Methodologic issues on reliability and validity. PMID- 29410250 TI - Differences in the rate of carbapenem-resistant Enterobacteriaceae colonisation or Clostridium difficile infection following frontline treatment with tigecycline vs. meropenem for intra-abdominal infections. AB - OBJECTIVES: We hypothesised that treatment with a tigecycline-based antimicrobial regimen for intra-abdominal infection (IAI) could be associated with lower rates of subsequent carbapenem-resistant Enterobacteriaceae (CRE) colonisation or Clostridium difficile infection (CDI) compared with a meropenem-based regimen. METHODS: We performed a retrospective, single-centre, matched (1:1) cohort analysis of all patients who received at least 5 days of empirical or targeted tigecycline (TIG)- or meropenem (MER)-based treatment regimens for IAI over a 50 month period. Patients with previous CRE colonisation and CDI were excluded. Risk factors for CRE and CDI were assessed with a Cox regression model that included treatment duration as a time-dependent variable. Thirty-day mortality was assessed with Kaplan-Meier curves. RESULTS: We identified 168 TIG-treated and 168 MER-treated patients. The cumulative incidence rate ratio of CDI was 10-fold lower in TIG-treated vs. MER-treated patients (incidence rate ratio [IRR] 0.10/1000 patient-days, 95%CI 0.002-0.72, P = 0.007), but similar incidence rates were found for CRE colonisation (IRR 1.39/1000 patient-days, 95%CI 0.68-2.78, P = 0.36). In a multivariate Cox regression model, the receipt of a TIG- vs. MER based regimen was associated with significantly lower rates of CDI (HR 0.07, 95%CI 0.03-0.71, P = 0.02), but not CRE (HR 1.12, 95% CI 0.45-2.83, P = 0.80). All-cause 30-day mortality was similar in the two groups (P = 0.46). CONCLUSION: TIG-based regimens for IAI were associated with a 10-fold lower incidence of CDI compared with MER-based regimens, but there was no difference in the incidence of CRE colonisation. PMID- 29410253 TI - Global forecast of antimicrobial resistance in invasive isolates of Escherichia coli and Klebsiella pneumoniae. AB - OBJECTIVES: To project future antimicrobial resistance (AMR) in Escherichia coli and Klebsiella pneumoniae. METHODS: Mixed linear models were constructed from a sample of countries with AMR data in the ResistanceMap database. Inverse probability weighting methods were used to account for countries without AMR data. RESULTS: The estimated prevalence of AMR in 2015 was 64.5% (95% confidence interval (CI) 42-87%) for third-generation cephalosporin-resistant (3GCR) Escherichia coli, 5.8% (95% CI 1.8-9.7%) for carbapenem-resistant (CR) E. coli, 66.9% (95% CI 47.1-86.8%) for 3GCR Klebsiella pneumoniae, and 23.4% (95% CI 7.4 39.4%) for CR K. pneumoniae. The projected AMR prevalence in 2030 was 77% (95% CI 55-99.1%) for 3GCR E. coli, 11.8% (95% CI 3.7-19.9%) for CR E. coli, 58.2% (95% CI 50.2-66.1%) for 3GCR K. pneumoniae, and 52.8% (95% CI 16.3-89.3%) for CR K. pneumoniae. CONCLUSIONS: The models suggest that third-generation cephalosporins and carbapenems could be ineffective against a sizeable proportion of infections by E. coli and K. pneumoniae in most parts of the world by 2030, supporting both the need to enhance stewardship efforts and to prioritize research and development of new antibiotics for resistant Enterobacteriaceae. PMID- 29410254 TI - Successful drug desensitization in patients with delayed-type allergic reactions to anti-tuberculosis drugs. AB - OBJECTIVE: To evaluate the outcomes of anti-tuberculosis drug desensitization. METHODS: This was a retrospective study. Inclusion criteria were as follows: age >18years, documented tuberculosis infection, a previous cutaneous allergic reaction to anti-tuberculosis drugs, and having undergone drug desensitization between January 2003 and March 2014. The definition of allergic reaction to anti tuberculosis drugs included (1) a temporal relationship between drug use and the allergic reaction; (2) improvement in the allergic reaction after drug withdrawal; (3) recurrence of the allergic reaction after reintroduction of only the offending drug; and (4) absence of other causes. RESULTS: A total of 19 desensitization procedures were performed. The drugs used for these procedures were isoniazid (n=7), rifampicin (n=6), or ethambutol (n=6). Of note, severe allergic reactions (Stevens-Johnson syndrome (n=4), erythema multiforme (n=3), and drug rash with eosinophilia and systemic syndrome (n=1)) were included. All patients underwent resolution of the previous allergic reactions before desensitization. The median duration of desensitization was 18 days. The success rate was 78.9%. The allergic reactions following failed desensitization were not severe; most were maculopapular rashes. CONCLUSIONS: The desensitization protocol for anti-tuberculosis drugs was associated with a high success rate, and the individuals who failed desensitization experienced mild allergic reactions. PMID- 29410256 TI - A high throughput methodology for susceptibility testing of Mycobacterium tuberculosis isolates. AB - MICs for eleven anti-TB drugs with M. tuberculosis isolates were obtained by means of agar dilution with multi-point inoculation. The results were compared with classic agar dilution and the MTT assay. The multi-point inoculation method was reproducible with all drugs and correlated with classic agar dilution and MTT assay. This methodology can be used for routine breakpoint drug susceptibility testing (DST) and for MIC determination. PMID- 29410255 TI - Antimicrobial efficacy of photodynamic therapy and light-activated disinfection on contaminated zirconia implants: An in vitro study. AB - BACKGROUND: We aimed to evaluate the antimicrobial efficacy of photodynamic therapy (PDT) and light-activated disinfection (LAD) on zirconia dental implants contaminated with three bacterial species and investigate if the PDT and LAD cause implant surface alterations. METHODS: Seventy-two zirconia dental implants were contaminated with a bacterial suspension of Prevotella intermedia, Actinomyces actinomycetemcomitans, and Porphyromonas gingivalis. The implants were subsequently randomly divided into four groups (n = 12 dental implants/each) according to the decontamination protocol: Group 1 (PDT1) - PDT (660 nm, 100 mW) with toluidine blue; Group 2 (PDT2) - PDT (660 nm, 100 mW) with phenothiazine chloride dye; Group 3 (LAD) - light emitting diode (LED) with toluidine blue; and Group 4 (TB) - toluidine blue without the application of light. Implants in the positive control (PC) group were treated with a 0.2% chlorhexidine-based solution, and implants assigned to the negative control (NC) group did not undergo any treatment. Each implant was then placed in tubes containing phosphate buffered saline (PBS) and vortexed for 60 s to remove the remaining bacteria from the implant surface. After 10-fold serial dilutions, 30 MUl of the suspension was plated on Brucella agar plates. After 72 h, the colony forming units (CFU) were counted. Distinctive colonies were confirmed with MALDI Biotyper. The implants were analyzed using scanning electron microscope (SEM) to evaluate the possible surface alterations due to PDT or LAD. RESULTS: All study groups had significant reductions in the number of CFUs compared with the NC (p < 0.05). PDT1, the PDT2, and the LAD groups had the largest bacterial reduction with respect to each bacterial species separately and the total bacterial count, and they were more efficient compared with the TB group (p < 0.05). SEM analysis did not reveal any alterations of the implant surface after the treatment procedures. CONCLUSION: Both PDT protocols and LAD showed high and equal effectiveness in decontamination of zirconia dental implants. PMID- 29410258 TI - Comprehensive analysis of immune, extracellular matrices and pathogens profile in lung granulomatosis of unexplained etiology. AB - This study analyzed the type 1 and type 2T helper (Th1/Th2) cytokines (including interleukins), immune cellular, matrix profile, and pathogens in granulomas with unexplained etiology compared to those with infectious and noninfectious etiology. Surgical lung biopsies from 108 patients were retrospectively reviewed. Histochemistry, immunohistochemistry, immunofluorescence, morphometry and polymerase chain reaction were used, respectively, to evaluate total collagen and elastin fibers, collagen I and III, immune cells, cytokines, matrix metalloproteinase-9, myofibroblasts, and multiple usual and unusual pathogens. No relevant polymerase chain reaction expression was found in unexplained granulomas. A significant difference was found between the absolute number of eosinophils, macrophages, and lymphocytes within granulomas compared to uninvolved lung tissue. Granulomas with unexplained etiology (UEG) presented increased number of eosinophils and high expression of interleukins (ILs) IL-4/IL 5 and transforming growth factor-beta. In sarcoidosis, CD4/CD8 cell number was significantly higher within and outside granulomas, respectively; the opposite was detected in hypersensitivity pneumonitis. Again, a significant difference was found between the high number of myofibroblasts and matrix metalloproteinase-9 in UEG, hypersensitivity pneumonitis, and sarcoidosis compared to granulomas of tuberculosis. Granulomas of paracoccidioisis exhibited increased type I collagen and elastic fibers. Th1 immune cellular profile was similar among granulomas with unexplained, infectious, and noninfectious etiology. In contrast, modulation of Th2 and matrix remodeling was associated with more fibroelastogenesis and scarring of lung tissue in UEG compared to infectious and noninfectious. We concluded that IL-4/IL-5 and transforming growth factor-beta might be used as surrogate markers of early fibrosis, reducing the need for genotyping, and promise therapeutic target in unexplained granulomas. PMID- 29410259 TI - Estimated versus measured blood loss during dilation and evacuation: an observational study. AB - OBJECTIVE: To compare estimated versus measured blood loss at the time of dilation and evacuation (D&E). STUDY DESIGN: We measured blood loss for all D&E procedures between 16 and 24 weeks at one abortion clinic over 9 months. We weighed all blood-containing items and measured blood captured in the D&E tray. Providers recorded estimated blood loss before weighing or measuring blood. We compared median measured blood loss (MBL) and estimated blood loss (EBL) for each gestational week. RESULTS: We measured blood loss in 371 of the 534 D&Es in the study period; we excluded 163 procedures because of failure to measure blood loss or contamination with amniotic fluid. Included and excluded procedures had similar median EBLs. Median EBL differed significantly from MBL for each week gestation from 16 to 24 weeks (p<=.001 for all comparisons); MBL was approximately twice as high as EBL for each gestational week. EBL and MBL increased with increasing gestation, as did the difference between EBL and MBL. CONCLUSION: Providers consistently and significantly underestimate blood loss at the time of D&E. D&E providers may want to consider using a new heuristic for estimating blood loss. IMPLICATIONS: Providers significantly underestimate blood loss at the time of D&E. Future research should confirm these findings (particularly at 22-24 weeks gestation), evaluate the efficacy of interventions to improve estimations of blood loss, and determine best practices for decreasing blood loss. PMID- 29410257 TI - Plasticizers used in food-contact materials affect adipogenesis in 3T3-L1 cells. AB - Recent studies suggest that exposure to some plasticizers, such as Bisphenol A (BPA), play a role in endocrine/metabolic dispruption and can affect lipid accumulation in adipocytes. Here, we investigated the adipogenic activity and nuclear receptor interactions of four plasticizers approved for the manufacturing of food-contact materials (FCMs) and currently considered safer alternatives. Differentiating 3T3-L1 mouse preadipocytes were exposed to scalar concentrations (0.01-25 MUM) of DiNP (Di-iso-nonyl-phthalate), DiDP (Di-iso-decyl-phthalate), DEGDB (Diethylene glycol dibenzoate), or TMCP (Tri-m-cresyl phosphate). Rosiglitazone, a well-known pro-adipogenic peroxisome proliferator activated receptor gamma (PPARgamma) agonist, and the plasticizer BPA were included as reference compounds. All concentrations of plasticizers were able to enhance lipid accumulation, with TMCP being the most effective one. Accordingly, when comparing in silico the ligand binding efficiencies to the nuclear receptors PPARgamma and retinoid-X-receptor-alpha (RXRalpha), TMPC displayed the highest affinity to both receptors. Differently from BPA, the four plasticizers were most effective in enhancing lipid accumulation when added in the mid-late phase of differentiation, thus suggesting the involvement of different intracellular signalling pathways. In line with this, TMCP, DiDP, DiNP and DEGDB were able to activate PPARgamma in transient transfection assays, while previous studies demonstrated that BPA acts mainly through other nuclear receptors. qRT-PCR studies showed that all plasticizers were able to increase the expression of CCAAT/enhancer binding protein beta (Cebpbeta) in the early steps of adipogenesis, and the adipogenesis master gene Ppargamma2 in the middle phase, with very similar efficacy to that of Rosiglitazone. In addition, TMCP was able to modulate the expression of both Fatty Acid Binding Protein 4/Adipocyte Protein 2 (Fabp4/Ap2) and Lipoprotein Lipase (Lpl) transcripts in the late phase of adipogenesis. DEGDB increased the expression of Lpl only, while the phthalate DiDP did not change the expression of either late-phase marker genes Fabp4 and Lpl. Taken together, our results suggest that exposure to low, environmentally relevant doses of the plasticizers DiNP, DiDP, DEGDB and TMCP increase lipid accumulation in 3T3-L1 adipocytes, an effect likely mediated through activation of PPARgamma and interference at different levels with the transcriptional cascade driving adipogenesis. PMID- 29410260 TI - Protein expression pattern and analysis of differentially expressed peptides during various stages of tail regeneration in Hemidactylus flaviviridis. AB - Epimorphic regeneration is a process allowing the animal to regain its lost structure which depends on the resident pluripotent stem cells as well as de differentiation of existing cells to form multi-potent stem cells. Many studies have been done to understand the appendage regeneration mechanism. The animal model used since decades is an urodele amphibian the axolotl. However, this ability is also seen in some members of reptiles, mainly lizards which on autotomy of tail regain the same by forming a replica of its lost tail. Lizards being closer to mammals are of greater interest and cannot be neglected. Hence, a stage specific protein profiling was undertaken in order to find the peptides playing a major role in epimorphosis. 2-DGE being basic tool for creating a protein profile was used. With advent of newer modern technology, label-free analysis which uses MS/MS was also performed. The study reports the peptides involved in apoptosis, inflammation and ECM remodelling across the stages of lizard tail regeneration for the first time. Apart from these peptides, structural protein, enzymes involved in metabolism have also been highlighted in the current study to give a bigger picture of the processes and the specific peptides required for tail regeneration. PMID- 29410261 TI - Quantitative lipidomic insights in the inhibitory response of Pichia stipitis to vanillin, 5-hydroxymethylfurfural, and acetic acid. AB - To obtain a global view of the dynamic phospholipids in Pichia stipitis during the ethanol fermentation in the presence of three representative inhibitors (vanillin, 5-hydroxymethylfurfural, and acetic acid). Considerable efforts have been expended to elucidate the biochemical mechanisms of inhibitors interaction with phospholipids. In this study, a comparative lipidomic analysis was performed using liquid chromatography-mass/mass spectrometry (LC-MS/MS) on P. stipitis. Partial least squares-discriminate analysis (PLS-DA) was used to deal with the large quantity of data generated using the systematic methods. PLS-DA revealed that phosphatidylinositol (PI) (PI34:1, PI34:2 and PI34:6), phosphatidylserine (PS) (PS34:1 and PS34:2), phosphatidylethanolamine (PE) (PE34:1 and PE34:2), and phosphatidylcholine (PC) (PC34:1, PC34:2, and PC34:3) were the predominant biomarkers. Further analysis of different classes of phospholipids indicated that: (a) the samples from three combined inhibitors condition during the lag phase possessed the lowest PI/PS value 1.4%, (b) alterations in PC/PE ratios with changes in inhibitors were coincident with the changes in xylose utilization rates, and (c) the levels of unsaturated and the relatively long chain phospholipids increased in the inhibitor-plus condition. These findings suggest that regulation of membrane properties with inhibitors might offer a way of self protection of yeast to inhibitors stress. PMID- 29410262 TI - Laparoscopic Heller Myotomy vs Per Oral Endoscopic Myotomy: Patient-Reported Outcomes at a Single Institution. AB - BACKGROUND: Although laparoscopic Heller myotomy (LHM) has been the standard of care for achalasia, per oral endoscopic myotomy (POEM) has gained popularity as a viable alternative. This retrospective study aimed to compare patient-reported outcomes between LHM and POEM in a consecutive series of achalasia patients with more than 1 year of follow-up. STUDY DESIGN: We reviewed demographic and procedure-related data for patients who underwent either LHM or POEM for achalasia between January 2011 and May 2016. Phone interviews were conducted assessing post-procedure achalasia symptoms via the Eckardt score and achalasia severity questionnaire (ASQ). Demographics, disease factors, and survey results were compared between LHM and POEM patients using univariate analysis. Significant predictors of procedure failure were analyzed using univariate and multivariate analysis. RESULTS: There were no serious complications in 110 consecutive patients who underwent LHM or POEM during the study period, and 96 (87%) patients completed phone surveys. There was a nonsignificant trend toward better patient-reported outcomes with POEM. There were significant differences in patient characteristics including sex, achalasia type, mean residual lower esophageal pressure (rLESP), and follow-up time. The only univariate predictors of an unsatisfactory Eckardt score or ASQ were longer follow-up and lower rLESP, with follow-up length being the only predictor on multivariate analysis. CONCLUSIONS: There were significant demographic and clinical differences in patient selection for POEM vs LHM in our group. Although the 2 procedures have similar patient-reported effectiveness, subjective outcomes seem to decline as a result of time rather than procedure type. PMID- 29410263 TI - Modified Ravitch Procedure or Nuss Procedure? PMID- 29410264 TI - Early Outcome of Bilateral Versus Single Internal Mammary Artery Grafting in the Elderly. AB - BACKGROUND: Bilateral internal mammary artery (BIMA) grafting is increasingly used in elderly patients without evidence of its risks or benefits compared with single internal mammary artery (SIMA) grafting. METHODS: In all, 2,899 patients aged 70 years or older (855 [29.5%] underwent BIMA grafting) operated on from January 2015 to December 2016 and included in the prospective multicenter Outcome After Coronary Artery Bypass Grafting (E-CABG) study were considered in this analysis. RESULTS: One-to-one propensity matching resulted in 804 pairs with similar preoperative risk profile. Propensity score matched analysis showed that BIMA grafting was associated with a nonstatistically significant increased risk of inhospital death (2.7% versus 1.6%, p = 0.117). The BIMA grafting cohort had a significantly increased risk of any sternal wound infection (7.7% versus 5.1%, p = 0.031) as well as higher risk of deep sternal wound infection/mediastinitis (4.0% versus 2.2%, p = 0.048). The BIMA grafting cohort required more frequently extracorporeal membrane oxygenation (1.0% versus 0.1%, p = 0.02), and the intensive care unit stay (mean 3.6 versus 2.6 days, p < 0.001) and inhospital stay (mean 11.3 versus 10.0 days, p < 0.001) were significantly longer compared with the SIMA grafting cohort. Test for interaction showed that urgent operation in patients undergoing BIMA grafting was associated with higher risk of inhospital death (5.6% versus 1.3%, p = 0.009). CONCLUSIONS: Bilateral internal mammary artery grafting in elderly patients seems to be associated with a worse early outcome compared with SIMA grafting, particularly in patients undergoing urgent operation. Until more conclusive results are gathered, BIMA grafting should be reserved only for elderly patients with stable coronary artery disease, without significant baseline comorbidities and with long life expectancy. PMID- 29410265 TI - Radiofrequency Ablation Effectively Treated Focal Recurrence of Mesothelioma. AB - A 55-year-old man with malignant pleural mesothelioma underwent multimodality treatment comprising induction chemotherapy followed by extrapleural pneumonectomy and radiation therapy. After 2.5 years, focal recurrence occurred, with computed tomography revealing a tumor in the left cardiophrenic angle. Surgery was considered a problem for the patient because of the previous extrapleural pneumonectomy and difficult tumor location. Radiofrequency ablation was therefore performed; the course was uneventful, and there was no recurrence. Radiofrequency ablation should be considered an option to treat recurrence of malignant pleural mesothelioma. PMID- 29410266 TI - Visual, sensorimotor and cognitive routes to understanding others' enjoyment: An individual differences rTMS approach to empathic accuracy. AB - Functional imaging studies suggest that accurate understanding of others' emotional feelings (i.e., empathic accuracy, EA) recruits high-order visual, sensorimotor and mentalizing brain networks. However, the behavioral relevance of these findings is unclear. To fill in this gap, we used repetitive transcranial magnetic stimulation (rTMS) to interfere with the right superior temporal sulcus (STS), inferior frontal gyrus (IFG) and temporoparietal junction (TPJ) during an EA task requiring participants to infer the enjoyment felt by a social target while smiling/laughing. Relative to a baseline condition (sham rTMS), active rTMS of STS, IFG and TPJ (but not of a control site) disrupted the efficiency of EA task performance, mainly by lowering task accuracy; rTMS of IFG and TPJ also slowed down response speeds. Importantly, the effects of rTMS on EA task efficiency were predicted by baseline EA performance, with high-performers showing a performance decrease when the TPJ was targeted, and low-performers showing a performance decrease when the STS or the IFG was targeted. The double dissociation in the effect of rTMS between low- and high-performers suggests distinct roles of STS, IFG and TPJ in efficient understanding of the enjoyment felt by others. These findings provide causal evidence of distinct visual, sensorimotor and cognitive routes to EA and suggest that individual differences in EA are underpinned by differential recruitment of these routes. PMID- 29410267 TI - Development of Enteromorpha prolifera polysaccharide-based nanoparticles for delivery of curcumin to cancer cells. AB - Polyelectrolyte complex nanoparticles were fabricated via electrostatic complexation between Enteromorpha prolifera polysaccharide (EP) and chitosan (CS). The monodisperse EP/CS NPs with negatively charge were prepared at pH4.0 and mixing ratio of 3.0:1.0. Curcumin loaded nanoparticles (CUR-NPs) showed spherical morphology with negatively charge of -16.27+/-0.97mV and average diameter range of 230 to 330nm. The results of spectroscopic analysis, XRD and DSC confirmed that there were hydrogen-bonding interaction and hydrophobic interaction between curcumin and EP/CS NPs. The CUR-NPs improved storage, thermal and photo stability of curcumin and exhibited sustained release of curcumin in vitro. Moreover, the CUR-NPs showed higher cellular uptake than free CUR with incubation for 3h by CLSM visualization and fluorescence quantitative assay. Furthermore, MTT assay results demonstrated that the CUR-NPs possessed good anticancer activity against B16F10 cells. Therefore, the EP-based nanoparticles are promising candidates for carriers in controllable hydrophobic anti-tumor drug delivery. PMID- 29410268 TI - Preparation and characterization of thermoplastic starch and cellulose nanofibers as green nanocomposites: Extrusion processing. AB - This research was aimed at studying the preparation of thermoplastic starch (TPS) from cornstarch flour using twin screw extrusion. Also, the effects of the addition of cellulose nanofibers (CNFs) as reinforcement, on TPS nanocomposite films properties were evaluated. Nanocomposites with 0.5, 1.0 and 1.5wt% of CNFs content were prepared. The chemical structure of starch, TPS and TPS/CNFs were characterized by Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction. The mechanical properties, morphological structure, and thermal stability of neat thermoplastic starch and their nanocomposites were investigated by scanning electron microscopy (SEM), dynamic mechanical thermal analysis (DMTA), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and water absorption (WA) test. Results showed that it was possible to improve the WA, thermal, and mechanical properties of TPS with the addition of CNFs due to its good dispersion and the interaction of CNFs with the TPS matrix. The storage modulus, loss modulus, and the tan delta peak position of TPS/CNF nanocomposites improved in comparison with the TPS matrix. These findings confirmed the enhancement of mechanical properties of TPS/CNF nanocomposites. In addition, TGA and DSC results showed that increasing CNF content improves the thermal stability of TPS-based nanocomposites. SEM images showed that CNFs dispersion within the TPS matrix was uniform and the surfaces of TPS/CNF films were smooth. The WA of the TPS/CNF composites moderately decreased with the addition of CNFs. Finally, the results obtained clearly showed the advantages of reinforcing TPS with CNFs, a natural, cheap and abundant green nanocomposite. PMID- 29410269 TI - Pullulan-alginate fibers produced using free surface electrospinning. AB - Pullulan-alginate ultrafine fibers, with and without CaCl2, were electrospun from aqueous polymer solutions using a free-surface electrospinning method, without the use of synthetic spinning aid polymer. Aqueous pullulan solution (10%, w/w) could be electrospun into beaded fibers of 110 nm in diameter with a board diameter distribution. By contrast, continuous and smooth fibers were formed when 0.8 to 1.6% (w/w) alginate was added to the 10% (w/w) pullulan solutions, producing smaller fibers ranging from 87 to 57 nm in diameter. The positive effect of alginate can be attributed to the increase in polymer chain entanglement, as well as enhanced hydrogen bonding interaction between pullulan and alginate. The addition of trace amount of CaCl2 (up to 0.045%, w/w) resulted in smooth and ultrafine fibers that were significantly smaller in diameter and greater thermal stability than those prepared without the addition of CaCl2. The production of typical electrospun fibers involves the use of undesirable organic solvents and/or non-food grade synthetic spinning aid polymer. The water-based edible biopolymer systems presented in this study can be useful for the preparation of nano-scale fibers that are more conducive for food, nutraceutical, and pharmaceutical applications. PMID- 29410270 TI - Molecular mechanisms of immunomodulatory activity by polysaccharide isolated from the peels of Citrus unshiu. AB - The extracts of the Citrus unshiu fruit induce numerous biological activities such as anticancer, anti-adipogenic, and antimicrobial effects. Furthermore, its peel has been used as a Chinese medicine for centuries and is consumed as a tea in China, Japan, and Korea. We investigated the effects of the polysaccharide isolated from C. unshiu peel (CPE-II) on cytokine and inflammatory mediator production in RAW 264.7 macrophages and performed signal transduction experiments to identify the pathways involved in its actions. CPE-II exhibited macrophage stimulatory activity by inducing the production of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and nitric oxide (NO) in RAW 264.7 macrophages. Signal transduction experiments showed that CPE-II phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB in RAW 264.7 cells in a concentration-dependent manner. The effects of CPE-II on IL-6/IL-12 and TNF-alpha production were completely suppressed by a specific inhibitor of c Jun N-terminal kinase (JNK). Moreover, experiments with neutralizing antibodies showed that Toll-like receptor 2 (TLR2) and TLR4 were involved in the stimulation of IL-6 and NO production by CPE-II in RAW 264.7 cells. Collectively, these results suggest that the TLR2/4 and JNK pathways are essential for the CPE-II immune activity in RAW 264.7 cells. PMID- 29410271 TI - Prdx1 alleviates cardiomyocyte apoptosis through ROS-activated MAPK pathway during myocardial ischemia/reperfusion injury. AB - Apoptosis induced by oxidative stress blocks the recovery of heart function in myocardial ischemia reperfusion injury (MIRI). Peroxiredoxin 1 (Prdx1) inhibits oxidative stress. However, the expression and function of Prdx1 in MIRI are unclear. In present study, Prdx1 protein level increased in rat MIRI model, associated with cardiomyocyte apoptosis. Cultured rat embryonic ventricular myocardial H9c2 cells with hypoxia/reoxygenation (H/R) treatment was utilized to mimic MIRI in vitro, showing that H/R treatment increased the ratio of p-p38/p38, p-JNK/JNK and apoptosis index. But Prdx1 ameliorate the up-regulation of p p38/p38 ratio and p-JNK/JNK ratio, as well as decreased H9c2 cell apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) inhibited H9c2 cell apoptosis, and at the same time Prdx1 down-regulated the activation of p38 MAPK and JNK during H/R treatment. In addition, a ROS scavenger N-acetyl-l-cysteine (NAC) down-regulated the protein level of p-p38, p-JNK and Prdx1, and H9c2 cell apoptosis. In summary, these findings indicated that Prdx1 inhibited MAPK pathway induced cells apoptosis, and ROS is the upstream regulator of H/R induced apoptosis. PMID- 29410273 TI - The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption. AB - Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC. PMID- 29410272 TI - Epigenetic regulation of male fate commitment from an initially bipotential system. AB - A fundamental goal in biology is to understand how distinct cell types containing the same genetic information arise from a single stem cell throughout development. Sex determination is a key developmental process that requires a unidirectional commitment of an initially bipotential gonad towards either the male or female fate. This makes sex determination a unique model to study cell fate commitment and differentiation in vivo. We have focused this review on the accumulating evidence that epigenetic mechanisms contribute to the bipotential state of the fetal gonad and to the regulation of chromatin accessibility during and immediately downstream of the primary sex-determining switch that establishes the male fate. PMID- 29410274 TI - Polycyclic aromatic hydrocarbons (PAHs) skin permeation rates change with simultaneous exposures to solar ultraviolet radiation (UV-S). AB - Road construction workers are simultaneously exposed to two carcinogens; solar ultraviolet (UV-S) radiation and polycyclic aromatic hydrocarbons (PAHs) in bitumen emissions. The combined exposure may lead to photogenotoxicity and enhanced PAH skin permeation rates. Skin permeation rates (J) for selected PAHs in a mixture (PAH-mix) or in bitumen fume condensate (BFC) with and without UV-S co-exposures were measured with in vitro flow-through diffusion cells mounted with human viable skin and results compared. Possible biomarkers were explored. Js were greater with UV-S for naphthalene, anthracene, and pyrene in BFC (0.08 0.1 ng/cm2/h) compared to without (0.02-0.26 ng/cm2/h). This was true for anthracene, pyrene, and chrysene in the PAH-mix. Naphthalene and benzo(a)pyrene (BaP) in the PAH-mix had greater Js without (0.97-13.01 ng/cm2/h) compared to with UV-S (0.40-6.35 ng/cm2/h). Time until permeation (Tlags) in the PAH-mix were generally shorter compared to the BFC, and they ranged from 1 to 13 h. The vehicle matrix could potentially be the reason for this discrepancy as BFC contains additional not identified substances. Qualitative interpretation of p53 suggested a dose-response with UV-S, and somewhat with the co-exposures. MMP1, p65 and cKIT were not exploitable. Although not statistically different, PAHs permeate human viable skin faster with simultaneous exposures to UV. PMID- 29410275 TI - The comprehensive expression analysis of the G protein-coupled receptor from Penaeus monodon indicating it participates in innate immunity and anti-ammonia nitrogen stress. AB - The G protein-coupled receptors (GPCRs) composed a superfamily that played an important role in physiological processes of crustaceans, with multiple functions such as growth and development, acting as a defense against stimulations from external factors. In this paper, one kind of GPCRs were identified from Penaeus monodon, called PmGPCR, included an open reading frame (ORF) of 1113 bp. Bioinformatic analysis showed that PmGPCR protein had the typical structure of seven transmembrane domains (7TM), especially the special Asp-Arg-Try motif (DRY motif) between the third transmembrane structures (TM3) and the second intracellular loops (IL-2) which can prove that PmGPCR belongs to the rhodopsin like family. The analyses of phylogenetic tree indicated that the amino acid sequence of PmGPCR should be merged into Procambarus clarkiic with high identity (98%). Quantitative real-time PCR (q RT-PCR) revealed that PmGPCR mRNA was highly expressed in hepatopancreas, abdominal ganglia and lymph, in which it was significantly higher than that of other tissues (P < 0.05). In addition, the expression of PmGPCR was analyzed during three days post-stimulation with the gram-positive/negative bacteria, the mRNA expression level increased after challenged with gram - positive bacteria in hepatopancreas, lymph and intestines. During the development stages, PmGPCR showed significantly higher expression in nauplius, zoea III, mysis III and post larvae stages than that in other development stages. Meanwhile, the highest transcripts expression of PmGPCR in abdominal ganglia, hepatopancreas, lymph and intestines respectively appeared at D0, D1, D2 and D3/D4 stages of molting. High or low concentration of ammonia nitrogen up-regulated the expression level of PmGPCR at the initial stage in hepatopancreas and gill, and then down-regulated at 48 h. These results indicated PmGPCR may mediate the pathways that involved in growth and development process, survival in the adversity, in addition, provided the useful data to research GPCR mediated physiological and biological process and explain the mechanisms to defense pathogens and anti-stress in shrimp. PMID- 29410276 TI - The potential benefits of repeated measure experiments for fish disease-challenge host-pathogen investigations. AB - The utility of molecular response data arising from in-vivo single and repeated measure fish disease-challenge experiments is compared. An in-silico 'experiment' involving the generation of two imaginary immune-molecule quantity response profiles over time for individual animals was carried out. Daily 'observed' molecule quantities were drawn from the 'known' individual response profiles to mimic the results of single and repeated measurement. The results indicate that repeated measure experiments are required to infer individual level response profiles, and that these experiments also provide more accurate summary statistics and data more suited to inferring the dependent ordering of the molecular response. Additionally repeated measure experiments utilise fewer animals than single measure experiments. These results are described alongside a discussion of experimental methodological issues pertinent to the adoption of aquatic animal repeated measure experimental designs. We conclude that investigators need to take particular care when making inferences from single measure experiments and that serious consideration should be given to using repeated measure experiments for in-vivo fish disease-challenge investigations. PMID- 29410277 TI - Measurement uncertainty: Friend or foe? AB - The definition and enforcement of a reference measurement system, based on the implementation of metrological traceability of patients' results to higher order reference methods and materials, together with a clinically acceptable level of measurement uncertainty, are fundamental requirements to produce accurate and equivalent laboratory results. The uncertainty associated with each step of the traceability chain should be governed to obtain a final combined uncertainty on clinical samples fulfilling the requested performance specifications. It is important that end-users (i.e., clinical laboratory) may know and verify how in vitro diagnostics (IVD) manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. However, full information about traceability and combined uncertainty of calibrators is currently very difficult to obtain. Laboratory professionals should investigate the need to reduce the uncertainty of the higher order metrological references and/or to increase the precision of commercial measuring systems. Accordingly, the measurement uncertainty should not be considered a parameter to be calculated by clinical laboratories just to fulfil the accreditation standards, but it must become a key quality indicator to describe both the performance of an IVD measuring system and the laboratory itself. PMID- 29410279 TI - StructureFold2: Bringing chemical probing data into the computational fold of RNA structural analysis. AB - The secondary structure of an RNA is often implicit to its function. Recently, various high-throughput RNA structure probing techniques have been developed to elucidate important RNA structure-function relationships genome-wide. These techniques produce unwieldy experimental data sets that require evaluation with unique computational pipelines. Herein, we present StructureFold2, a user friendly set of analysis tools that makes precise data processing and detailed downstream analyses of such data sets both available and practical. StructureFold2 processes high-throughput reads sequenced from libraries prepared after experimental probing for reverse transcription (RT) stops generated by chemical modification of RNA at solvent accessible residues. This pipeline is able to analyze reads generated from a variety of structure-probing chemicals (e.g. DMS, glyoxal, SHAPE). Notably, StructureFold2 offers a new fully featured suite of utilities and tools to guide a user through multiple types of analyses. A particular emphasis is placed on analyzing the reactivity patterns of transcripts, complementing their use as folding restraints for predicting RNA secondary structure. StructureFold2 is hosted as a Github repository and is available at (https://github.com/StructureFold2/StructureFold2). PMID- 29410278 TI - Use of BMI as the marker of adiposity in a metabolic syndrome severity score: Derivation and validation in predicting long-term disease outcomes. AB - BACKGROUND: Estimates of adiposity in evaluating the metabolic syndrome (MetS) have traditionally utilized measures of waist circumference (WC), whereas body mass index (BMI) is more commonly used clinically. Our objective was to determine if a MetS severity Z-score employing BMI as its measure of adiposity (MetS-Z-BMI) would perform similarly to a WC-based score (MetS-Z-WC) in predicting future disease. METHODS: To formulate the MetS-Z-BMI, we performed confirmatory factor analysis on a sex- and race/ethnicity-specific basis on MetS-related data for 6870 adult participants of the National Health and Nutrition Survey 1999-2010. We then validated this score and compared it to MetS-Z-WC in assessing correlations with future coronary heart disease (CHD) and Type 2 diabetes mellitus (T2DM) using Cox proportional hazard analysis of 13,094 participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study. RESULTS: Loading factors, which represent the relative contribution of each component to the latent MetS factor, were lower for BMI than for WC in formulating the two respective scores (MetS-Z-BMI and MetS-Z-WC). Nevertheless, MetS-Z-BMI and MetS-Z WC exhibited similar hazard ratios (HR) toward future disease. For each one standard-deviation-unit increase in MetS-Z-BMI, HR for CHD was 1.76 (95% confidence interval [CI]: 1.65, 1.88) and HR for T2DM was 3.39 (CI 3.16, 3.63) (both p < 0.0001). There were no meaningful differences between the MetS-Z-WC and MetS-Z-BMI scores in their associations with future CHD and T2DM. CONCLUSIONS: A MetS severity Z-score utilizing BMI as its measure of adiposity operated similarly to a WC-based score in predicting future CHD and T2DM, suggesting overall similarity in MetS-based risk as estimated by both measures of adiposity. This indicates potential clinical usefulness of MetS-Z-BMI in assessing and following MetS-related risk over time. PMID- 29410280 TI - Should International Classification of Diseases codes be used to survey hospital acquired pneumonia? AB - As surveillance of hospital-acquired pneumonia (HAP) is very resource intensive, alternatives for HAP surveillance are needed urgently. This study compared HAP rates according to routine discharge diagnostic codes of the International Classification of Diseases, 10th Revision (ICD-10; ICD-HAP) with HAP rates according to the validated surveillance definitions of the Hospitals in Europe Link for Infection Control through Surveillance (HELICS/IPSE; HELICS-HAP) by manual retrospective re-evaluation of patient records. The positive predictive value of ICD-HAP for HELICS-HAP was 0.35, and sensitivity was 0.59. Therefore, the currently available ICD-10-based routine discharge data do not allow reliable identification of patients with HAP. PMID- 29410281 TI - Minimizing microbial contamination risk simultaneously from multiple hospital washbasins by automated cleaning and disinfection of U-bends with electrochemically activated solutions. AB - BACKGROUND: Outbreaks of infection associated with microbial biofilm in hospital hand washbasin U-bends are being reported increasingly. In a previous study, the efficacy of a prototype automated U-bend decontamination method was demonstrated for a single non-hospital pattern washbasin. It used two electrochemically activated solutions (ECA) generated from brine: catholyte with detergent properties and anolyte with disinfectant properties. AIM: To develop and test a large-scale automated ECA treatment system to decontaminate 10 hospital pattern washbasin U-bends simultaneously in a busy hospital clinic. METHODS: A programmable system was developed whereby the washbasin drain outlets, U-bends and proximal wastewater pipework automatically underwent 10-min treatments with catholyte followed by anolyte, three times weekly, over five months. Six untreated washbasins served as controls. Quantitative bacterial counts from U bends were determined on Columbia blood agar, Reasoner's 2A agar and Pseudomonas aeruginosa selective agar following treatment and 24 h later. FINDINGS: The average bacterial densities in colony-forming units/swab from treated U-bends showed a >3 log reduction compared with controls, and reductions were highly significant (P<0.0001) on all media. There was no significant increase in average bacterial counts from treated U-bends 24 h later on all media (P>0.1). P. aeruginosa was the most prevalent organism recovered throughout the study. Internal examination of untreated U-bends using electron microscopy showed dense biofilm extending to the washbasin drain outlet junction, whereas treated U-bends were free from biofilm. CONCLUSION: Simultaneous automated treatment of multiple hospital washbasin U-bends with ECA consistently minimizes microbial contamination and thus the associated risk of infection. PMID- 29410282 TI - Osmotic stress induced toxicity exacerbates Parkinson's associated effects via dysregulation of autophagy in transgenic C. elegans model. AB - The accumulation of aggregate-prone proteins is a major representative of many neurological disorders, including Parkinson's disease (PD) wherein the cellular clearance mechanisms, such as the ubiquitin-proteasome and autophagy pathways are impaired. PD, known to be associated with multiple genetic and environmental factors, is characterized by the aggregation of alpha-synuclein protein and loss of dopaminergic neurons in midbrain. This disease is also associated with other cardiovascular ailments. Herein, we report our findings from studies on the effect of hyper and hypo-osmotic induced toxicity representing hyper and hypotensive condition as an extrinsic epigenetic factor towards modulation of Parkinsonism, using a genetic model Caenorhabditis elegans (C. elegans). Our studies showed that osmotic toxicity had an adverse effect on alpha-synuclein aggregation, autophagic puncta, lipid content and oxidative stress. Further, we figure that reduced autophagic activity may cause the inefficient clearance of alpha-synuclein aggregates in osmotic stress toxicity, thereby promoting alpha synuclein deposition. Pharmacological induction of autophagy by spermidine proved to be a useful mechanism for protecting cells against the toxic effects of these proteins in such stress conditions. Our studies provide evidence that autophagy is required for the removal of aggregated proteins in these conditions. Studying specific autophagy pathways, we observe that the osmotic stress induced toxicity was largely associated with atg-7 and lgg-1 dependent autophagy pathway, brought together by involvement of mTOR pathway. This represents a unifying pathway to disease in hyper- and hypo-osmotic conditions within PD model of C. elegans. PMID- 29410283 TI - New insights into the Vav1 activation cycle in lymphocytes. AB - Vav1 is a hematopoietic-specific Rho GDP/GTP exchange factor and signaling adaptor. Although these activities are known to be stimulated by direct Vav1 phosphorylation, little information still exists regarding the regulatory layers that influence the overall Vav1 activation cycle. Using a collection of cell models and activation-mimetic Vav1 mutants, we show here that the dephosphorylated state of Vav1 in nonstimulated T cells requires the presence of a noncatalytic, phospholipase Cgamma1-Slp76-mediated inhibitory pathway. Upon T cell stimulation, Vav1 becomes rapidly phosphorylated via the engagement of Lck and, to a much lesser extent, other Src family kinases and Zap70. In this process, Lck, Zap70 and the adaptor protein Lat contribute differently to the dynamics and amplitude of the Vav1 phosphorylated pool. Consistent with a multiphosphosite activation mechanism, the optimal stimulation of Vav1 can only be recapitulated by the combination of several activation-mimetic phosphosite mutants. The analysis of these mutants has also unveiled the presence of different Vav1 signaling competent states that are influenced by phosphosites present in the N- and C-terminal domains of the protein. PMID- 29410284 TI - Coronary angiographic findings and outcomes in patients with sudden cardiac arrest without ST-elevation myocardial infarction: A SWEDEHEART study. AB - BACKGROUND/AIM: Sudden cardiac arrest (SCA) has a substantial mortality rate and the acute coronary syndrome constitutes the major cause. Post-resuscitation electrocardiogram ST-elevation SCA (STE-SCA) is a strong indication for emergency coronary angiography, but the role of early angiography and PCI in patients without ST-elevation (NSTE-SCA) remains to be established. This paper aimed to describe this patient group and evaluate the prognostic effect of early PCI in a large nationwide cohort of NSTE-SCA patients undergoing coronary angiography. METHODS: Data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) and RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) on 4308 SCA patients in Sweden between 2005 and 2016 were descriptively analyzed and related to mortality within 30-days in both unadjusted and adjusted analyses using Cox proportional hazard models. RESULTS: NSTE-SCA patients had more often serious comorbidities than STE-SCA patients. Among NSTE SCA patients, 36.4% had no significant coronary artery stenosis while severe coronary stenosis (>=90%) was present in 43.9% (1271/2896). In NSTE-SCA patients with significant stenosis (>=90%), PCI was performed in 59.2% (753/1271) with an increased unadjusted 30-day mortality (40.9% vs. 32.7%; p = .011). However, after adjustments for confounders, no difference in mortality was observed (hazard ratio 1.07; 95% CI 0.84-1.36; p = .57). CONCLUSION: In resuscitated SCA patients without ST-elevation who underwent coronary angiography, this large retrospective study found severe coronary artery stenosis in 43.9% but found no clear benefit of early PCI. Prospective randomized controlled trials are needed to accurately define the role of coronary angiography and PCI in post-resuscitation care. PMID- 29410285 TI - Comparison of allergy immunotherapy medication persistence with a sublingual immunotherapy tablet versus subcutaneous immunotherapy in Germany. PMID- 29410286 TI - Drug-induced thrombocytopenia: Focus on platelet apoptosis. AB - Thrombocytopenia is a serious and potentially fatal complication of drug therapy that results either from a decrease in bone marrow platelet production or the excessive destruction of circulating platelets. Although multiple mechanisms are responsible for deregulated platelet clearance, the role of programmed platelet death (apoptosis) in drug-induced thrombocytopenia has been relatively under investigated until recently. Here we review apoptotic signaling pathways in platelets, with a focus on current data that provide mechanistic insights into drug-induced apoptosis and thrombocytopenia. PMID- 29410287 TI - No-touch multibipolar radiofrequency ablation vs. surgical resection for solitary hepatocellular carcinoma ranging from 2 to 5 cm. AB - BACKGROUND & AIMS: No-touch multibipolar radiofrequency ablation (NTM-RFA) represents a novel therapy that surpasses standard RFA for hepatocellular carcinoma (HCC), but it has not been compared to surgical resection (SR). We aimed to compare the outcomes of NTM-RFA and SR for intermediate-sized HCC. METHODS: Between 2012 and 2016, 141 patients with solitary HCC ranging from 2 to 5 cm were treated by NTM-RFA or SR at a single-center. The outcomes of 128 patients were compared after using inverse probability of treatment weighting (IPTW). RESULTS: Seventy-nine patients had NTM-RFA and 62 had SR. After IPTW, the two groups were well-balanced for most baseline characteristics including tumor size, location, etiology, severity of underlying liver disease and alpha fetoprotein level. Morbidity was higher (67.9% vs. 50.0%, p = 0.042) and hospital stay was longer (12 [IQR 8-13] vs. 7 [IQR 5-9] days, p <0.001) after SR. Local recurrence rates at one and three years were 5.5% and 10.0% after NTM-RFA and 1.9% and 1.9% after SR, respectively (p = 0.065). The rates of systematized recurrence (within the treated segment or in an adjacent segment within a 2 cm distance from treatment site) were higher after NTM-RFA (7.4% vs. 1.9% at one year, 27.8% vs. 3.3% at three years, p = 0.008). Most patients with recurrence were eligible for rescue treatment, resulting in similar overall survival (86.7% after NTM-RFA, 91.4% after SR at three years, p = 0.954) and disease-free survival (40.8% after NTM-RFA, 56.4% after SR at three years, p = 0.119). CONCLUSION: Compared to SR, NTM-RFA for solitary intermediate-sized HCC was associated with less morbidity and more systematized recurrence, while the rate of local recurrence was not significantly different. Most patients with intrahepatic recurrence remained eligible for rescue therapies, resulting in equivalent long-term oncological results after both treatments. LAY SUMMARY: Outcomes of patients treated for intermediate-sized hepatocellular carcinoma by surgical resection or no-touch multibipolar radiofrequency ablation were compared. No-touch multibipolar radiofrequency ablation was associated with a lower overall morbidity and a higher rate of systematized recurrence within the treated segment or in an adjacent segment within a 2 cm distance from the initial tumor site. Most patients with intrahepatic recurrence remained eligible for rescue curative therapy, enabling them to achieve similar long-term oncological results after both treatments. PMID- 29410288 TI - Identification of key microRNAs, transcription factors and genes associated with congenital obstructive nephropathy in a mouse model of megabladder. AB - OBJECTIVE: The present study aimed to investigate the molecular mechanism underlying congenital obstructive nephropathy (CON). METHODS: The microarray dataset GSE70879 was downloaded from the Gene Expression Omnibus, including 3 kidney samples of megabladder mice and 4 control kidneys. Using this dataset, differentially expressed miRNAs (DEMs) were identified between the kidney samples from megabladder mice and controls, followed by identification of the target genes for these DEMs and construction of a DEM and target gene interaction network. Additionally, the target genes were subjected to Gene Ontology and pathway enrichment analyses, and were used for construction of a protein-protein interaction (PPI) network. Finally, regulatory networks were constructed to analyze transcription factors for the key miRNAs. RESULTS: From 17 DEMs identified between kidney samples of megabladder mice and controls, 3 key miRNAs were screened, including mmu-miR-150-5p, mmu-miR-374b-5p and mmu-miR-126a-5p. The regulatory networks identified vascular endothelial growth factor A (Vegfa) as the common target gene of mmu-miR-150-5p and five transcription factors, including nuclear receptor subfamily 4, group A, member 2 (Nr4a2), Jun dimerisation protein 2 (Jdp2), Kruppel-like factor 6 (Klf6), Neurexophilin-3 (Nxph3) and RNA binding motif protein 17 (Rbm17). The gene encoding phosphatase and tensin homolog (Pten) was found to be co-regulated by mmu-miR-374b-5p and high mobility group protein A1 (Hmga1), whereas the kirsten rat sarcoma viral oncogene (Kras) was identified as a common target gene of mmu-miR-126a-5p and paired box 6 (Pax6). CONCLUSIONS: In summary, the above-listed key miRNAs, transcription factors and key genes may be involved in the development of CON. PMID- 29410289 TI - Association between variations in the disrupted in schizophrenia 1 gene and schizophrenia: A meta-analysis. AB - Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations. PMID- 29410290 TI - One Thousand Pediatric Liver Transplants During Thirty Years: Lessons Learned. AB - BACKGROUND: Pediatric liver transplantation (pLTx) has been the standard of care for children with liver failure since the 1980s. This study examined the world's largest single-center experience and aimed to identify unique preoperative predictors of early graft and patient survival for primary transplantation (1 degrees -pLTx) and retransplantation (Re-pLTx). STUDY DESIGN: We conducted an IRB approved, retrospective study of all consecutive, isolated pLTx patients 18 years of age or younger. Twenty-eight demographic, laboratory, and perioperative variables were analyzed as potential outcome predictors. Univariate and multivariate analyses were performed using log-rank test and Cox's proportional hazards model. RESULTS: There were 806 children who received 1,016 isolated pLTx between February1984 and June 2017. Median follow-up was 12 years. Leading indications for pLTx were cholestatic liver disease (40%), re-pLTx (21%), and fulminant hepatic failure (14%). Seventy-three percent received cadaveric whole grafts. Overall graft and patient survival rates at 0.5, 1, 5, 10, and 20 years were: 76%, 73%, 67%, 63%, 53%, and 87%, 86%, 81%, 78%, 69%, respectively. Relative to 1 degrees -pLTx, re-pLTx recipients were significantly older, larger, with worse renal function, and more likely to be awaiting pLTx in an ICU. Independent significant predictors of graft survival for 1 degrees -pLTx included weight, transplantation era, and renal replacement therapy; for re-pLTx, warm ischemia time and time between 1 degrees -pLTx and re-pLTx. Independent significant predictors of patient survival were renal function, mechanical ventilation, and etiology of liver disease. CONCLUSIONS: This is the largest reported single-center experience of pLTx with substantial follow-up time and a large re-pLTx experience. Important transplant predictors of graft survival include weight, renal function, modern era, warm ischemia time, and time between primary transplantation and re-pLTx. Renal function, mechanical ventilation, and underlying cause of liver disease affect patient survival. Awareness of these factors can help in the decision making for children requiring pLTx. PMID- 29410291 TI - Orienting toward threat: Contributions of a subcortical pathway transmitting retinal afferents to the amygdala via the superior colliculus and pulvinar. AB - Probabilistic diffusion tractography was used to provide the first direct evidence for a subcortical pathway from the retina to the amygdala, via the superior colliculus and pulvinar, that transmits visual stimuli signaling threat. A bias to orient toward threat was measured in a temporal order judgement saccade decision task, under monocular viewing, in a group of 19 healthy participants who also underwent diffusion weighted MR imaging. On each trial of the behavioural task a picture depicting threat was presented in one visual field and a competing non-threatening stimulus in the other. The onset interval between the two pictures was randomly varied and participants made a saccade toward the stimulus that they judged to have appeared first. The bias to orient toward threat was stronger when the threatening stimulus was in the temporal visual hemifield, suggesting that afferents via the retinotectal tract contributed to the bias. Probabalistic tractography was used to virtually dissect connections between the superior colliculus and the amygdala traversing the pulvinar. Individual differences in microstructure (fractional anisotropy) of the streamline predicted the magnitude of the bias to orient toward threat, providing supporting evidence for a functional role of the subcortical SC-amygdala pathway in processing threat in healthy humans. PMID- 29410292 TI - Hemispheric asymmetries in rapid temporal processing at age 7 predict subsequent phonemic decoding 2 years later: A longitudinal event-related potential (ERP) study. AB - The asymmetric sampling in time hypothesis (AST) suggests that the left and right secondary auditory areas process auditory stimuli according to different sampling rates (Poeppel, 2003). We investigated whether asymmetries consistent with the AST are observable in children at age 7 and whether they become more pronounced at age 9. Data were collected from 50 children who attended a 2-day research program at age 7 and were followed up 2 years later. At both time points, children were presented with tone-pairs, each composed of two 50 ms, 1000 Hz, sinusoidal tones separated by inter-stimulus intervals (ISIs) of 25, 50, 100, or 200 ms. Stimuli were presented binaurally whilst the EEG was recorded. The Ta and Tb, which are components of the auditory event-related potential (ERP), were used as electrophysiological indices of auditory processing. There was no significant effect of age on Ta or Tb responses. Tb responses to the second tone of tone pairs indicated a left-hemisphere preference for rapidly presented stimuli (50 ms ISI) and a right hemisphere preference for more slowly presented stimuli (100 and 200 ms ISI). The results provide evidence that auditory areas of the left hemisphere preferentially respond to fast temporal rates, and those of the right hemisphere preferentially respond to slow temporal rates in children at age 7 and 9. In 7-year-old children, leftward lateralisation of responses to rapidly presented tones predicted better phonemic decoding ability 2 years later, which suggests that hemispheric specialisation may be a precursor for subsequent phonemic decoding skills. PMID- 29410293 TI - Rule activation and ventromedial prefrontal engagement support accurate stopping in self-paced learning. AB - When weighing evidence for a decision, individuals are continually faced with the choice of whether to gather more information or act on what has already been learned. The present experiment employed a self-paced category learning task and fMRI to examine the neural mechanisms underlying stopping of information search and how they contribute to choice accuracy. Participants learned to classify triads of face, object, and scene cues into one of two categories using a rule based on one of the stimulus dimensions. After each trial, participants were given the option to explicitly solve the rule or continue learning. Representational similarity analysis (RSA) was used to examine activation of rule relevant information on trials leading up to a decision to solve the rule. We found that activation of rule-relevant information increased leading up to participants' stopping decisions. Stopping was associated with widespread activation that included medial prefrontal cortex and visual association areas. Engagement of ventromedial prefrontal cortex (vmPFC) was associated with accurate stopping, and activation in this region was functionally coupled with signal in dorsolateral prefrontal cortex (dlPFC). Results suggest that activating rule information when deciding whether to stop an information search increases choice accuracy, and that the response profile of vmPFC during such decisions may provide an index of effective learning. PMID- 29410294 TI - Cognitive Impairment in Men with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review and Meta-Analysis. AB - PURPOSE: Use of androgen deprivation therapy may increase the risk of cognitive impairment in men with prostate cancer. We performed a systematic review of the risk of overall cognitive impairment as an outcome in men receiving androgen deprivation therapy for prostate cancer. MATERIALS AND METHODS: Studies were identified through PubMed(r), MEDLINE(r), PsycINFO(r), Cochrane Library and Web of Knowledge/ScienceTM. Articles were included if they 1) were published in English, 2) had subjects treated for prostate cancer with androgen deprivation therapy, 3) incorporated longitudinal comparisons and 4) used control groups. In addition, prospective studies were required to assess an established cognitive related end point using International Cognition and Cancer Task Force criteria defining impaired cognitive performance as scoring 1.5 or more standard deviations below published norms on 2 or more tests, or scoring 2.0 or more standard deviations below published norms on at least 1 test. The effect of androgen deprivation therapy on cognitive impairment was pooled using a random effects model. RESULTS: Of 221 abstracts 26 were selected for full text review, and 2 prospective and 4 retrospective studies were analyzed. Androgen deprivation therapy was not associated with overall cognitive impairment when the prospective cohort studies were pooled (OR 1.57, 95% CI 0.50 to 4.92, p = 0.44) with significant heterogeneity between estimates (I2 = 83%). In retrospective data the relative risk of any cognitive impairment, including senile dementia and Alzheimer disease, was increased in men receiving androgen deprivation therapy, although the difference was not statistically significant (HR 1.28, 95% CI 0.93 to 1.76, p = 0.13) with moderate heterogeneity between estimates (I2 = 67%). CONCLUSIONS: Analyses between overall cognitive impairment and use of androgen deprivation therapy defined according to International Cognition and Cancer Task Force criteria in a pooled analysis were inconclusive. In retrospective cohort studies the risk of overall cognitive impairment after androgen deprivation therapy was not significant. Better prospective studies need to be designed for the assessment of this end point. PMID- 29410295 TI - Donor Cell-Derived Hematologic Neoplasms after Hematopoietic Stem Cell Transplantation: A Systematic Review. AB - Development of de novo hematologic malignancies in donor cells after allogeneic stem cell transplantation (allo-SCT) provides a useful in vivo model to study the process of leukemogenesis. A systematic analysis of the cases reported in the literature was performed to identify risk factors and mechanisms involved in the pathogenesis of donor cell-derived hematologic neoplasms (DCHN) and leukemogenic transformation. Relevant data were extracted from 137 cases. Cases of DCHN show a wide heterogeneity with regard to recipient/donor age, sex mismatch, and conditioning regimen. Some characteristics, such as the type of primary disease, the type of hematologic malignancy of the DCHN, and the stem cell source used in the transplant procedure, differ from those expected. Mechanisms involved in the pathogenesis of DCHN are complex, and several hypotheses have been proposed, such as pre-existing hematologic neoplasms or premalignant clones in the donor, decreased immune surveillance, and damage to bone marrow microenvironment in the recipient. Most likely several if not all these mechanisms play a role in DCHN development. Novel approaches, such as next-generation sequencing to study consecutive samples after allo-SCT in these patients, appear to be promising to decipher the mechanisms of leukemogenesis. PMID- 29410296 TI - Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors. AB - Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 * 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 * 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 * 106/kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 * 106/kg; Q2, 2.0 to 2.9 * 106/kg; Q3, 3.0 to 4.1 * 106/kg; and Q4, 4.2 to 16.0 * 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P <.001) and platelet recovery (P <.001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P <.001), fewer days of filgrastim (P <.001), i.v. antibiotic (P = .012) and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P <.001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartile. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed. PMID- 29410297 TI - Trends in Corneal Transplantation from 2001 to 2016 in Germany: A Report of the DOG-Section Cornea and its Keratoplasty Registry. AB - PURPOSE: The purpose of this retrospective panel study was to provide an overview of absolute numbers and of trends in the types of and indications for corneal transplantation in Germany from 2001 to 2016. METHODS: A questionnaire about absolute numbers, types of transplantation, and indications was sent to 111 ophthalmologic departments in Germany, out of which 94 (85%) provided their data. RESULTS: Since the year 2001, the number of corneal transplantations has increased by 1.5-fold, from 4730 penetrating keratoplasties (PKPs) in 2001 to 7325 penetrating and lamellar keratoplasties in 2016. The shift from penetrating to lamellar procedures began in 2006. In 2014, lamellar procedures (231 [4%] anterior and 2883 [49%] posterior lamellar keratoplasties) surpassed PKPs (2721, 47%) for the first time. Main indications for keratoplasty in Germany (2016) are Fuchs endothelial corneal dystrophy (46%), pseudophakic corneal decompensation (bullous keratopathy, 13%), repeated keratoplasty after graft failure (11%), keratoconus (8%), and corneal scarring (6%; others: 16%). The number of Descemet membrane endothelial keratoplasties (DMEKs) was 12 times higher (3850, 53%) than Descemet stripping automated endothelial keratoplasties (DSAEKs, 319, 4.4%) in 2016. The proportion of deep anterior lamellar keratoplasties (DALKs) never exceeded 6% (269 in 2011). CONCLUSIONS: The number of keratoplasties in Germany has increased from 2001 to 2016. Since 2014, posterior lamellar keratoplasties have surpassed PKPs. There was a constant increase of DMEKs, with a 12-fold higher number compared to DSAEKs in 2016. The shorter recovery time after DMEK seems to contribute to the trend toward earlier operative intervention in corneal endothelial diseases. PMID- 29410298 TI - Renal outcomes in primary IgA nephropathy patients with segmental glomerular necrosis: a case-control study. AB - The renal prognosis and treatment of primary IgA nephropathy (IgAN) patients with segmental glomerular necrosis (SGN) remain controversial. Patients with primary IgAN confirmed by renal biopsy were enrolled. Patients with SGN on renal biopsy were selected as the necrosis group, and a propensity score matching method was used to match a control group according to age, gender, weight, height and follow up time. A total of 825 IgAN patients were enrolled in the present study. Seventy three (8.8%) patients with SGN were selected as the necrosis group, and 292 patients without SGN were matched as the control group. Compared to the control group, a significantly increased serum fibrinogen level (3.97 g/L vs 3.54 g/L, P=.002) and proportion of patients with macroscopic hematuria (35.6% vs 14.7%, P<.001) was observed in the necrosis group. According to the new IgA pathological classification system, crescent formation was more pronounced in the necrosis group (P=.001). The average estimated glomerular filtration rate was obviously higher in the necrosis group and decreased more slowly during follow-up. However, the time-averaged urine protein-to-creatinine ratio remained low in the necrotic group, whereas it gradually increased in the control group. SGN suggests an active renal inflammatory state, but it was not an independent risk factor for a poor renal outcome in patients treated with immunosuppressive therapy. Furthermore, patients with SGN had a more stable renal function and low urinary protein excretion during follow-up, which may be attributable to aggressive immunotherapy. PMID- 29410299 TI - The impact of the difference in O-C2 angle in the development of dysphagia after occipitocervical fusion: a simulation study in normal volunteers combined with a case-control study. AB - BACKGROUND CONTEXT: Dysphagia has been recognized as one of the most serious complications after occipitocervical fusion (OCF), and the difference between postoperative and preoperative O-C2 angle (dO-C2A) was proposed to be an indicator in predicting and preventing dysphagia. Therefore, to prevent postoperative dysphagia, previous studies recommend that surgeons should correct the O-C2 angle (O-C2A) during surgery if the occipitocervical alignment was in an excessively flexed position. However, until now, there was no explicit indicator of the condition in which surgeons should adjust the patient's O-C2A during surgery. PURPOSE: One of the purposes of this study was to explore the threshold of dO-C2A between dysphagia and normal swallowing by a simulation study. The other aim was to evaluate the validity of the threshold of dO-C2A in predicting dysphagia after OCF via a case-control study. STUDY DESIGN: This is a simulation study combined with a retrospective case-control study. PATIENT SAMPLE: Thirty volunteers were enrolled in the simulation study. Thirty-four consecutive patients who underwent OCF between September 2011 and September 2016 were included in the case-control study. OUTCOME MEASURES: The outcome measures included O-C2A, C2-7 angle (C2-7A), atlantodental interval (ADI), the narrowest oropharyngeal airway space (nPAS), the rate of change in dnPAS (%dnPAS), and the prevalence of postoperative dysphagia. MATERIALS AND METHODS: In the simulation study, each volunteer received two lateral x-rays of their cervical spine in neutral position and dysphagia position, respectively. We compared the radiographic parameters in neutral and dysphagia positions. The cumulative frequency diagram of dO-C2A in the dysphagia position was analyzed to identify the threshold of dO-C2A in the development of dysphagia. In the case-control study, these 34 patients were divided into two groups according to the threshold of dO-C2A identified in the simulation study. The impact of radiographic parameters on nPAS was analyzed. The prevalence of postoperative dysphagia between the two groups was compared to evaluate the validity of the threshold of dO-C2A in predicting dysphagia after OCF. RESULTS: In the simulation study, the mean O-C2A and nPAS in the dysphagia position were significantly smaller than in the neutral position (p<.05). There was no significant difference between the mean C2-7A in the neutral and dysphagia positions (p>.05). There was a significant positive correlation between dO-C2A and dnPAS (p<.05). A dO-C2A of -5 degrees delineated the threshold between normal swallowing and dysphagia. In the case-control study, multiple regression analysis showed that dO-C2A was the only significant variable correlated with dnPAS (beta=0.769, p<.001). Among the reviewed 34 patients, the incidence of dysphagia was 17.6% (6/34) at 2 weeks after surgery and decreased over time to 11.8% (4 of 34) at the last follow-up. There was also a significant positive correlation between the dO-C2A and dnPAS (p<.05). The prevalence of dysphagia after OCF in patients with dO-C2A<-5 degrees was as high as 66.7% (6/9). However, there was no patient suffering from dysphagia in patients with dO-C2A>=-5 degrees . CONCLUSION: The present study showed that the dO-C2A should be a key factor in the development of postoperative dysphagia after OCF. A dO-C2A of -5 degrees could be the threshold between dysphagia and normal swallowing. Furthermore, to avoid dysphagia, surgeons should correct the O-C2A just before the final occipitocervical fixation if the checked dO-C2A during surgery is less than -5 degrees . PMID- 29410300 TI - Median Supraorbital Keyhole Approach for Clipping Ruptured Distal Anterior Cerebral Artery Aneurysm: Technical Report with Review of Literature. AB - BACKGROUND: The minimally invasive approach to distal anterior cerebral artery (DACA) aneurysms has not gained much acceptance due to difficulties associated with the conventional frontal paramedian approach. The more proximal basal interhemispheric approach, however, necessitates extensive dissection of soft tissues. We describe a novel minimally invasive median supraorbital keyhole craniotomy with a basal interhemispheric approach for clipping a ruptured DACA aneurysm. METHODS: A 62-year-old patient presented with subarachnoid hemorrhage. Computed tomography angiography revealed a DACA aneurysm. The surgical technique involved a keyhole craniotomy made via an eyebrow incision extending between the supraorbital notches, and flush with the anterior cranial fossa. The dura was opened at the anterior part, the falx was cut, an interhemispheric dissection was carried out, adequate proximal control was obtained, and the aneurysm neck was dissected and clipped. A relevant review of the literature was carried out. RESULTS: The patient recovered well, with no residual aneurysm or forehead numbness, with good cosmesis. Compared with the previously described "keyhole unilateral interhemispheric" approaches, our technique has less likelihood of encountering bridging veins; easier cisternal cerebrospinal fluid release, making it feasible even in swollen brain; better proximal vascular control; and trajectory toward the neck rather than dome. CONCLUSION: The median supraorbital keyhole approach is a minimally invasive technique sufficient for clipping most DACA aneurysms, with easier access, better proximal control, and good cosmesis. PMID- 29410301 TI - Phase 1/2 Trial of Carfilzomib Plus High-Dose Melphalan Preparative Regimen for Salvage Autologous Hematopoietic Cell Transplantation Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. AB - We performed a phase 1/2 trial to investigate the safety and activity of the second-generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2 (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36 mg/m2 days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). The patients had received a median of 3 previous lines of therapy, 56% had undergone previous AHCT, and 51% had received previous K therapy. During phase 1 (n = 15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27 mg/m2 (on day -3) and 56 mg/m2 (on day -2) was used in phase 2. The rate of very good partial response after K-MEL therapy (n = 44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n = 27), 12-month progression-free survival was 66.7% and 12 month overall survival was 88.1%. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in patients with MM. PMID- 29410302 TI - The blackfly vectors and transmission of Onchocerca volvulus in Mahenge, south eastern Tanzania. AB - The Mahenge Mountains onchocerciasis focus in south eastern Tanzania was historically one of the most heavily infected areas in the country. The vectors of Onchocerca volvulus are mainly Simulium damnosum complex blackflies, but a species of the Simulium neavei group may also contribute to transmission in some areas. The only detailed studies of parasite transmission in Mahenge were conducted in the late 1960s. The taxonomy of the S. damnosum complex has since been revised and onchocerciasis control through annual community directed treatment with ivermectin (CDTI) commenced in 1997. This study aimed to provide a cytogenetic and molecular update of the S. damnosum complex cytoforms present in Mahenge, and to evaluate the current status of O. volvulus transmission by blackflies following 19 years of annual CDTI. Rivers were surveyed to identify sites of S. damnosum s.l. breeding among the eastern slopes of the mountains, and human landing collections of adult female blackflies were made close to breeding sites. Identification of S. damnosum complex cytoforms was by cytotaxonomy of late-instar larvae and ITS1 amplicon size polymorphisms of larvae and adults. Adult blackflies were pool screened for O. volvulus infection using a triplex real-time PCR. The cytoforms 'Nkusi', Simulium kilibanum and 'Turiani' were found breeding in perennial rivers. 'Nkusi' and S. kilibanum were collected on human bait at 7/7 catch sites and possessed ITS1 profiles most closely resembling the molecular forms 'Nkusi J' and S. kilibanum 'T'. Whereas 'Turiani' was present in rivers, it was not collected on human bait and appears to be zoophilic. Simulium nyasalandicum was collected in low numbers on human bait at 3/7 catch sites. In total, 12,452 S. damnosum s.l. were pool screened and O. volvulus infection was detected in 97/104 pools of bodies and 51/104 pools of heads. The estimated percentage of S. damnosum s.l. carrying infective L3 stage parasites was 0.57% (95% CI 0.43%-0.74%). Onchocerca volvulus transmission by S. damnosum s.l. is continuing in the Mahenge Mountains after 19 years of annual CDTI. Infection rates appear similar to those reported in the 1960s, but a more detailed study is required to fully understand the epidemiological significance of the ongoing transmission. These results provide further evidence that annual CDTI may be insufficient to eliminate the parasite in formerly hyperendemic foci. PMID- 29410303 TI - Association of Leptin: Adiponectin ratio and metabolic risk markers in postmenopausal women. AB - Leptin and adiponectin play an important role in the regulation of body weight and energy homeostasis. The purpose of the present study was to ascertain the relationship between leptin to adiponectin ratio (L:A) and metabolic risk factors in postmenopausal women.This is a cross sectional case-control study. A total of 523 postmenopausal women were recruited for the study 270 postmenopausal women with metabolic syndrome and 253 apparently healthy control postmenopausal women without metabolic syndrome. Biochemical and Anthropometrical parameters were measured. Leptin and adiponectin levels were determined by sandwich enzyme-linked immunosorbent assay, insulin resistance was determined by homeostasis model assessment for insulin resistance (HOMA-IR). Results of this study indicate that leptin (15.92 +/- 10.50 vs.9.43 +/- 4.39 pg/ml, p < 0.001), L:A ratio (1.08 +/- 1.06 vs.0.42 +/- 0.38 pg/ml, p < 0.001), HOMA-IR, the lipid profile, and other metabolic risk factors (waist circumference (WC), waist-to-hip ratio(WHR), body mass index((BMI)), fasting plasma glucose (FPG) level and fasting plasma insulin(FPI)) were significantly higher but HDL, HDL/LDL and adiponectin level (20.55 +/- 10.76 vs.30.08 +/- 13.08 pg/ml, p < 0.001)were significantly lower in postmenopausal women with metabolic syndrome than in women without the syndrome (p < 0.001). Further, in postmenopausal women with metabolic syndrome, L: A ratio was significantly positive (p < 0.05 or p < 0.001) correlated with WC, BMI, WHR, TG, FPG, TC/HDL, LDL/HDL, FPI and HOMA-IR (p < 0.01), and negatively correlated with HDL and HDL/LDL (p < 0.001). Conclusively L: A ratio was found to be significantly associated with central obesity and other metabolic risk factors so that high L:A ratio may act as a diagnostic marker for metabolic syndrome in postmenopausal women. PMID- 29410304 TI - Life after per-oral endoscopic myotomy: long-term outcomes of quality of life and their association with Eckardt scores. AB - BACKGROUND AND AIMS: The clinical efficacy of per-oral endoscopic myotomy (POEM) has been commonly established by reduction in the Eckardt score (<3) after the procedure. However, achalasia can lead to significant impairment in the patient's quality of life that may go beyond the 4 classic achalasia symptoms as measured by the Eckardt score. The aims of our study were to evaluate the effect of POEM on short-term and long-term health-related quality of life (HRQOL) and to assess the association between HRQOL and Eckardt scores. METHODS: Single-center, prospective, cohort study of consecutive POEMs during a 3-year period. Eckardt and HRQOL scores as measured by the short-form survey questionnaire (SF-36) were obtained at baseline and at various intervals after POEM. Comparison of the mean scores was described by using univariate linear regression. The association between Eckardt scores and HRQOL were calculated by using a linear, mixed-model analysis. RESULTS: POEM was performed in 143 consecutive patients (54% male; mean +/- standard deviation [SD] age, 56.9 +/- 17.9 years). At long-term follow-up (mean 16.4 months, range 12-40), both the HRQOL baseline mental and physical component scores improved significantly from 61.5 +/- 2.2 to 71.2 +/- 3.6; (P < .021) and from 55.8 +/- 2.2 to 63.6 +/- 3.3; (P = < .034), respectively. Mixed model analysis showed a significant association between Eckardt and all HRQOL scores (P < .001). CONCLUSION: POEM improved all dimensions of HRQOL as measured by the SF-36 survey at both short-term and long-term follow-up. A strong association was seen between Eckardt scores and all HRQOL domains. Further studies with the use of disease-specific HRQOL instruments are warranted. (Clinical trial registration number: NCT01832779.). PMID- 29410305 TI - Ara h 2 basophil activation test does not predict clinical reactivity to peanut. PMID- 29410306 TI - Two-week intervals during omalizumab treatment may provide better symptom control in selected patients with chronic urticaria. PMID- 29410307 TI - Determination of the preferred tongue position for optimal inhaler use. PMID- 29410308 TI - What provides a better value for your time? The use of relative value units to compare posterior segmental instrumentation of vertebral segments. AB - BACKGROUND CONTEXT: Relative value units (RVUs) are a compensation model based on the effort required to provide a procedure or service to a patient. Thus, procedures that are more complex and require greater technical skill and aftercare, such as multilevel spine surgery, should provide greater physician compensation. However, there are limited data comparing RVUs with operative time. Therefore, this study aims to compare mean (1) operative times; (2) RVUs; and (3) RVU/min between posterior segmental instrumentation of 3-6, 7-12, and >=13 vertebral segments, and to perform annual cost difference analysis. METHODS: A total of 437 patients who underwent instrumentation of 3-6 segments (Cohort 1, current procedural terminology [CPT] code: 22842), 67 patients who had instrumentation of 7-12 segments (Cohort 2, CPT code: 22843), and 16 patients who had instrumentation of >=13 segments (Cohort 3, CPT code: 22844) were identified from the National Surgical Quality Improvement Program (NSQIP) database. Mean operative times, RVUs, and RVU/min, as well as an annualized cost difference analysis, were calculated and compared using Student t test. This study received no funding from any party or entity. RESULTS: Cohort 1 had shorter mean operative times than Cohorts 2 and 3 (217 minutes vs. 325 minutes vs. 426 minutes, p<.05). Cohort 1 had a lower mean RVU than Cohorts 2 and 3 (12.6 vs. 13.4 vs. 16.4). Cohort 1 had a greater RVU/min than Cohorts 2 and 3 (0.08 vs. 0.05, p<.05; vs. 0.08 vs. 0.05, p>.05). A $112,432.12 annualized cost difference between Cohorts 1 and 2, a $176,744.76 difference between Cohorts 1 and 3, and a $64,312.55 difference between Cohorts 2 and 3 were calculated. CONCLUSION: The RVU/min takes into account not just the value provided but also the operative times required for highly complex cases. The RVU/min for fewer vertebral level instrumentation being greater (0.08 vs. 0.05), as well as the $177,000 annualized cost difference, indicates that compensation is not proportional to the added time, effort, and skill for more complex cases. PMID- 29410309 TI - Gastroprotective effects of Hwanglyeonhaedok-tang against Helicobacter pylori induced gastric cell injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Helicobacter pylori, which is found in the stomachs of approximately half of the world's population, has been associated with the development of chronic gastritis and gastric cancer. Hwanglyeonhaedok tang (HHT) is a popular traditional medicine for the therapies of gastric ulcers and gastritis. AIM OF THE STUDY: The emerging resistance of H. pylori to antibiotics arouses requirement on alternative nonantibiotic-based therapies. In the present study, we investigated the anti-inflammatory activity and anti microbial activity of HHT against H. pylori in vitro and in an H. pylori-infected mouse model. MATERIALS AND METHODS: H. pylori were treated with various concentrations of HHT and then incubated with human gastric carcinoma AGS cells. For the in vivo study, mice were orally infected with H. pylori three times over the course of 1 week, and then subjected to daily administration of HHT (120 or 600 mg/kg) for 4 weeks or standard triple therapy for 1 week. At the scheduled termination of the experiment, all mice were killed and their stomachs were collected for histological examination, quantitative real-time PCR, and Western blot analysis. RESULTS: Our in vitro studies showed that HHT treatment inhibited the adhesion of H. pylori to AGS cells and suppressed the H. pylori-induced increases of inflammatory regulators, such as interleukin (IL)-8, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). In the mouse model, HHT treatment significantly reduced H. pylori colonization, inflammation, and the levels of IL-1beta, IL-6, C-X-C motif chemokine ligand 1 (CXCL1), tumor necrosis factor alpha (TNF-alpha), COX-2, and iNOS in gastric mucosa. Further investigation showed that HHT treatment reduced the H. pylori-induced phosphorylations of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and nuclear factor-kappa B (NF-kappaB). CONCLUSIONS: Our findings collectively suggest that HHT has anti-inflammatory activity and antibacterial activity against H. pylori and could be an alternative to antibiotics for preventing H. pylori infection. PMID- 29410311 TI - Clinical Outcome of Retroperitoneal Lymph Node Dissection after Chemotherapy in Patients with Pure Embryonal Carcinoma in the Orchiectomy Specimen. AB - OBJECTIVE: To determine the pathologic findings and clinical outcome of patients with pure embryonal carcinoma (EC) of the testis who were diagnosed with testis cancer from January 1989 to January 2013 who underwent an orchiectomy, cisplatin based chemotherapy and a postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). METHODS: We compared those patients with 100% EC with those with mixed nonseminomatous germ cell tumor pathology who underwent a PC-RPLND. RESULTS: Of 1105 patients who underwent a PC-RPLND, 145 had pure EC. Twenty-six percent of patients presented with metastatic disease outside the retroperitoneum. Patients with mixed histologies tended to have worse International Germ Cell Cancer Collaborative Group risk compared to those with EC at orchiectomy (P = .037). Histology at PC-RPLND revealed fibrosis or necrosis in 76%, mature teratoma in 19% and viable cancer in 4%. Over one-third of the patients had a residual mass of <1 cm prior to RPLND; of whom 15% harbored mature teratoma in PC-RPLND histology. The Kaplan-Meier estimated probability of recurrence at 5 years of follow-up was 3.1% (95% CI 1.2%, 8.0%) for EC histology, 7.3% lower than mixed histology. For cancer-specific mortality, the Kaplan-Meier estimated probability at 5 years was 4.6% (95% CI 3.3%, 6.3%) and 1.7% (95% CI 0.4%, 6.8%) for mixed and pure EC histologies, respectively. CONCLUSION: Approximately 20% of patients with pure EC had teratoma at PC-RPLND. We have shown that those with a maximum node size of <1 cm should not be precluded from RPLND. PMID- 29410310 TI - Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood. AB - The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships. PMID- 29410312 TI - Ethylene signaling triggered by low concentrations of ascorbic acid regulates biomass accumulation in Arabidopsis thaliana. AB - Ascorbic acid (AA) is a major redox buffer in plant cells. The role of ethylene in the redox signaling pathways that influence photosynthesis and growth was explored in two independent AA deficient Arabidopsis thaliana mutants (vtc2-1 and vtc2-4). Both mutants, which are defective in the AA biosynthesis gene GDP-L galactose phosphorylase, produce higher amounts of ethylene than wt plants. In contrast to the wt, the inhibition of ethylene signaling increased leaf conductance, photosynthesis and dry weight in both vtc2 mutant lines. The AA deficient mutants showed altered expression of genes encoding proteins involved in the synthesis/responses to phytohormones that control growth, particularly auxin, cytokinins, abscisic acid, brassinosterioids, ethylene and salicylic acid. These results demonstrate that AA deficiency modifies hormone signaling in plants, redox-ethylene interactions providing a regulatory node controlling shoot biomass accumulation. PMID- 29410313 TI - Motor dysfunction as research domain in the period preceding manifest schizophrenia: A systematic review. AB - Schizophrenia is a severe behavioral syndrome of neurodevelopmental nature marked by primary or genuine motor abnormalities (GMA), which refer to spontaneous and medication-independent motor phenomena. Since motor dysfunction thus might be a consequence of events occurring during early childhood and adolescence, GMA can be detected in the period preceding manifest schizophrenia. However, the question whether motor system dysfunction might be a promising motor intermediate phenotype for schizophrenia remains unanswered. In this review, we systematically evaluate the evidence on GMA in healthy persons, individuals with schizotypal personality traits, persons at ultra-high risk for psychosis, and unaffected first-degree relatives of schizophrenia patients. What becomes evident is a continuum of GMA expression, which appears to be linked to abnormalities of cerebello-thalamo-cortical, fronto-parietal, and cortico-subcortical motor circuits. According to current evidence, motor dysfunction is a key aspect of the neurodevelopmental risk factor model of schizophrenia. Insights provided by this research will help promoting the RDoC Motor System construct and expand the clinical relevance of the motor domain in the period preceding manifest schizophrenia. PMID- 29410314 TI - Serum biomarker profiles suggest that atopic dermatitis is a systemic disease. PMID- 29410315 TI - Lung cancer risk perception biases. AB - This paper provides new evidence on biased perceptions about the risks of smoking. It studies predictors of lung cancer risk perceptions. Lung cancer is one of the deadliest and most aggressive cancer types with 5-year survival rates of only up to 15%. A cross-sectional online survey in Berlin assessed lung cancer risk perceptions among smokers (n = 664), never smokers (n = 703), and former smokers (n = 501) in 2013. In addition to lung cancer risk perceptions, the survey measured many respondent characteristics, such as intention to quit smoking and a self-assessment of the likelihood of success in quitting. The findings show that 80% of all respondents overestimated lung cancer survival rates and suggest significant room for public health campaigns to educate smokers and nonsmokers about the deadliness of lung cancer. Multivariate linear regressions show that smokers who do not plan to quit estimate the 5-Year Lung Cancer Survival Rate to be 11% (p = 0.044) higher than other smokers. A reduction in risk perception biases may induce some smokers to alter their quitting intentions and others to successfully quit. PMID- 29410316 TI - A Catalytically Disabled Double Mutant of Src Tyrosine Kinase Can Be Stabilized into an Active-Like Conformation. AB - Tyrosine kinases are enzymes playing a critical role in cellular signaling. Molecular dynamics umbrella sampling potential of mean force computations are used to quantify the impact of activating and inactivating mutations of c-Src kinase. The potential of mean force computations predict that a specific double mutant can stabilize c-Src kinase into an active-like conformation while disabling the binding of ATP in the catalytic active site. The active-like conformational equilibrium of this catalytically dead kinase is affected by a hydrophobic unit that connects to the hydrophobic spine network via the C-helix. The alphaC-helix plays a crucial role in integrating the hydrophobic residues, making it a hub for allosteric regulation of kinase activity and the active conformation. The computational free-energy landscapes reported here illustrate novel design principles focusing on the important role of the hydrophobic spines. The relative stability of the spines could be exploited in future efforts to artificially engineer active-like but catalytically dead forms of protein kinases. PMID- 29410317 TI - Secreted amyloid precursor protein alpha activates neuronal insulin receptors and prevents diabetes-induced encephalopathy. AB - Secreted amyloid precursor protein alpha (sAPPalpha) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Abeta), a peptide cleaved from the same parent peptide as sAPPalpha, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPalpha increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPalpha bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals. To further examine the effects of sAPPalpha on the diabetic brain, we next rendered sAPPalpha overexpressing mice insulin depleted and found that sAPPalpha blocked aberrant tau phosphorylation (T231) in cortical tissue after 16 weeks diabetes. sAPPalpha overexpression also prevented hyperphosphorylation of AKT/GSK3 and activation of the unfolded protein response (UPR). In total, these data show sAPPalpha binds and activates neuronal IRs and that sAPPalpha has a protective effect on diabetic brain tissue. PMID- 29410318 TI - Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial. AB - BACKGROUND: Epidermolysis bullosa simplex (EBS) is a rare genetic, blistering skin disease for which there is no cure. Treatments that address the pathophysiology of EBS are needed. OBJECTIVE: Compare the impact of 1% diacerein cream with placebo in reducing the number of blisters in EBS. METHODS: In a randomized, placebo-controlled, phase 2/3 trial we used a 1% diacerein topical formulation to treat defined skin areas in 17 patients. In a 2-period crossover trial, patients were randomized to either placebo or diacerein for a 4-week treatment and a 3-month follow-up in period 1. After a washout, patients were crossed over during period 2. The prespecified primary end point was the proportion of patients with a reduction of number of blisters by more than 40% from baseline in selected areas over the treatment episode. RESULTS: Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up. Changes in absolute blister numbers were significant for the diacerein group only. No adverse effects were observed. LIMITATIONS: Low patient numbers and no invasive data acquisition because of clinical burden in children. CONCLUSION: This trial provides evidence of the impact of 1% diacerein cream in the treatment of EBS. PMID- 29410321 TI - Soft, adhesive (+) alpha tocopherol phosphate planar bilayers that control oral biofilm growth through a substantive antimicrobial effect. AB - 'Soft' nanomaterials have the potential to produce substantive antibiofilm effects. The aim of this study was to understand the oral antimicrobial activity of soft nanomaterials generated from alpha-tocopherol (alpha-T) and alpha tocopherol phosphate (alpha-TP). (+) alpha-TP formed planar bilayer islands (175 +/- 21 nm, -14.9 +/- 3.5 mV) in a Trizma(r) buffer, whereas (+) alpha-T formed spherical liposomes (563 +/- 1 nm, -10.5 +/- 0.2 mV). The (+) alpha-TP bilayers displayed superior Streptococcus oralis biofilm growth retardation, a more substantive action, generated a superior adsorption to hydroxyapatite and showed an enhanced inhibition of multi-species bacterial saliva biofilm growth (38 +/- 7MUm vs 58 +/- 18 MUm, P ? 0.05) compared to (+) alpha-T. Atomic force microscopy data indicated that the ability of the 'soft' alpha-TP nanomaterials to transition into planar bilayer structures upon contact with interfaces facilitated their adhesive properties and substantive antimicrobial effects. PMID- 29410320 TI - A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3. AB - Human bombesin receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-receptor, because of homology is classified as a bombesin receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer. PMID- 29410322 TI - Characterizing Clinically Meaningful Changes in Lower Urinary Tract Symptoms Using the American Urological Association Symptom Index. AB - OBJECTIVE: To correlate patients' perception of changes in their lower urinary tract symptoms with changes in their American Urological Association Symptom Index (AUA-SI) scores with the goal of improving the ability of patients and clinicians to assess the clinical meaningfulness of changes in the AUA-SI score. MATERIALS AND METHODS: Men were asked to complete an AUA-SI survey and answer a symmetrical response framework question to evaluate their global perception of change in lower urinary tract symptoms at each interval, namely, "Are your urinary symptoms much better, slightly better, the same, slightly worse, or much worse compared to your prior visit?" Median changes and interquartile ranges (IQRs) in the AUA-SI scores were compared with the global evaluation response for the entire cohort. Additionally, outcomes were stratified by baseline AUA-SI severity classification (mild, moderate, or severe). RESULTS: The median changes and IQRs in AUA-SI scores of patients rating themselves as much better, slightly better, the same, slightly worse, and much worse compared with their symptoms at the time of their last AUA-SI were -2 (IQR -6 to 0), -1 (IQR -5 to 1), 0 (IQR -2 to 2), 5 (IQR 0-9), and 11 (IQR 5-18), respectively. There was a significant difference in AUA-SI score change between each rating category (P <.001). CONCLUSION: These results demonstrate that the patients require only a small decrease in their AUA-SI scores to report they are slightly better or much better, whereas a larger increase in their AUA-SI scores is required for patients to report their symptoms are slightly worse or much worse. PMID- 29410323 TI - EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib. AB - INTRODUCTION: Dacomitinib was superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. METHODS: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib by using N-ethyl-N-nitrosourea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells by using retroviral vectors. RESULTS: Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% of L858R-mutant clones (four of 35) and in 24% of G719A-mutant clones (12 of 38) established by using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p = 0.93) and G719A clones (p = 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R plus C797S mutations were sensitive to gefitinib or erlotinib. CONCLUSIONS: These in vitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers. PMID- 29410324 TI - Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent. AB - Chronic granulomatous disease (CGD) is a phagocytic disorder characterized by a defective production of reactive oxygen species (ROSs). Although infections and granuloma formation are the most common manifestations in CGD patients, a significant number of patients experienced autoimmunity and inflammatory diseases suggesting that adaptive immune abnormalities might be involved. Here we investigated T-cell compartment and showed that CGD patients had a skewed TCRV beta distribution in CD8+ T cells, particularly in older patients, and a reduced proliferative responses toward mitogens compared to healthy donors (HD). Afterwards we studied the role of gp91phox protein in causing these alterations and demonstrated that human T cells do not express gp91phox and TCR-stimulated ROS generation is gp91phox-NADPH oxidase independent. Finally, we proved that the NADPH oxidase is not active in the T cell compartment even when forcing gp91phox expression transducing T cells from X-CGD and HD with a SIN lentiviral vector (LVV) encoding the gp91phox cDNA. PMID- 29410319 TI - Genetic cartography of longevity in humans and mice: Current landscape and horizons. AB - Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA variants that modulate aging. We argue that the problem in mapping longevity genes is mainly one of low power and the genetic and environmental complexity of aging. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40 years of linkage studies using murine cohorts and 15 years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan. PMID- 29410325 TI - Effects of co-existing autoimmune diseases on serum lipids and lipoprotein subclasses profile in paediatric patients with type 1 diabetes mellitus. AB - OBJECTIVE: Paediatric patients with type 1 diabetes mellitus (T1DM) frequently develop other autoimmune disorders; most commonly autoimmune thyroiditis (ATD) and celiac disease (CD). In this study we evaluated whether co-existing autoimmune diseases had significant impact on lipid and lipoprotein subclasses, as known cardiovascular risk factors in T1DM. DESIGN AND METHODS: Study included 201 subjects with T1DM (14.1 +/- 2.9 years) and 141 age- and gender-matched controls. ATD was presented in 30 and CD in 15 T1DM patients. Serum lipid parameters were determined by routine laboratory methods and plasma low-density (LDL) and high-density lipoprotein (HDL) subclasses by gradient-gel electrophoresis method. RESULTS: Both groups of T1DM patients with concomitant autoimmune disease had significantly lower HDL-C levels (P < 0.05) than the patients with T1DM only, but comparable to control group (P = 0.436). T1DM patients had significantly higher (P < 0.001) proportion of small HDL subclasses than controls. Mean value of atherosclerosis index in patients with T1DM + CD was the highest (1.75 +/- 0.86) and it was significantly higher than the index in patients with T1DM only (1.33 +/- 0.51; P < 0.05). LDL size did not differ between the groups of T1DM patients and control group (P = 0.619). The size of HDL particles was significantly reduced (P < 0.05) in the groups with associated autoimmune diseases. The patients with co-existing autoimmune diseases had higher risk of low HDL-C level (OR: 2.96; P < 0.05). CONCLUSIONS: The results have shown significant impact of co-existing autoimmune diseases on lipid profile in patients with T1DM. The most prominent changes were found in HDL lipoprotein characteristics in T1DM + CD group. PMID- 29410326 TI - Is gentamicin safe and effective for severe community-acquired pneumonia? An 8 year retrospective cohort study. AB - Gram-negative bacilli are the causative organisms in a significant proportion of patients with severe community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU). Clinical guidelines recommend broad-spectrum antimicrobials for empirical treatment despite alarming global trends in antimicrobial resistance. In this study, we aimed to assess the safety and efficacy of gentamicin, an aminoglycoside with potent bactericidal activity, for empirical Gram-negative coverage of severe CAP in patients admitted to the ICU. A retrospective cohort study was performed at a university teaching hospital where the severe CAP guideline recommends penicillin, azithromycin and gentamicin as empirical cover. Ceftriaxone plus azithromycin is used as an alternative. Adults with radiologically-confirmed severe CAP were included, comparing those who received gentamicin in the first 72 h of admission with those who did not. Participants were identified using ICD-10 codes for bacterial pneumonia and data manually extracted from electronic medical records. Of 148 patients admitted with severe pneumonia, 117 were given at least one dose of gentamicin whereas the remaining 31 were not. The two groups were well matched in terms of demographics, co morbidities and disease severity. There were no significant differences between the gentamicin and no-gentamicin groups in the incidence of acute kidney injury [60/117 (51%) vs. 16/31 (52%), respectively], hospital mortality [20/117 (17%) vs. 7/31 (23%)] and secondary outcomes including relapse and length of hospital stay. In conclusion, gentamicin is safe and has similar outcomes to alternative Gram-negative antimicrobial regimens for empirical coverage in severe CAP patients admitted to the ICU. PMID- 29410327 TI - The importance of species: Pygmy rattlesnake venom toxicity differs between native prey and related non-native species. AB - Venom toxicity assessments are often based upon non-native surrogate prey species that are not consumed in the wild by the venomous predator. This raises questions about the relevance of toxicity results on these "model" prey in addressing ecological or evolutionary questions about venom effects on native prey. We explore this issue by comparing the toxicity of venom from pygmy rattlesnakes (Sistrurus miliarius) on taxonomically-diverse sets of model (non-native) and native prey. Specifically, we compared rattlesnake venom toxicity for nine species from three broad taxonomic groups of prey (reptiles, mammals, and amphibians) to determine whether estimates of venom toxicity for the non-native model species of each group was representative of species which were native prey. In all three groups, model species (Anolis sagrei, Mus musculus, and Lithobates pipiens) had a significantly different mortality response from one or more of the native prey species (Anolis carolinensis, Peromyscus gossypinus, Lithobates sphenocephalus, Hyla cinerea, and Hyla squirella) that the models were meant to represent. Two features of our results suggest an importance of evolutionary history in understanding these differences. First, there was a phylogenetic component to prey responses to venom in that in each group, non-native models and congeneric native prey showed more similar responses than prey from other genera suggesting that venom may act on common prey targets that result from common ancestry. Second, native prey generally showed higher LD50 values than their non native counterparts, suggesting greater resistance to venom from a predator with which they interact in nature. Our results suggest that researchers should use native prey to generate measures of venom toxicity that are ecologically and evolutionarily relevant. If this is not possible using "model" prey species that are close taxonomic relatives to natural prey may be a reasonable alternative. PMID- 29410328 TI - Modified Coronary Reimplantation for Small Aortic Root Replacement Mismatch. AB - Coronary reimplantation is a key step of aortic root replacement and may present special challenges under specific circumstances. Particularly in reoperations, mobilization of the coronary ostia can be hazardous and reattachment may require one or more interposition grafts to avoid tension, as originally described by Cabrol. We report a modified reimplantation technique of the coronary arteries that allows the creation of wide neo-ostia with minimal prosthetic material in case of a small aortic root. PMID- 29410329 TI - Comparison of 2 Kinds of Methods for the Treatment of Bladder Calculi. AB - OBJECTIVE: To evaluate the safety and efficacy of sheath (JQL sheath) in the treatment of bladder calculi. MATERIALS AND METHODS: We used the novel sheath that we have invented. The water sealing cap can only be passed through the ureteroscope without water leakage, and the diameters of the side hole and the sheath are sufficiently large. The clinical data of the 2 groups of patients include 45 cases of the novel sheath group and 41 cases in the control group. RESULT: The overall success rate of the 2 groups was 94.79%. The success rate of the new stone sheath group was 97.78% and that of the control group was 90.24%. The operation times were 25.8 +/- 12.5 and 46.6 +/- 26.3 minutes for the new stone sheath and control groups, respectively. The stones were divided into 3 groups according to their sizes: less than 1.5, 1.5-2.5, and greater than 2.5 cm. The durations of the novel sheath groups were 12.5 +/- 6.5, 24.5 +/- 9.5, and 37.5 +/- 11.5 minutes, whereas those of the control groups were 17.6 +/- 6.5, 39.5 +/- 18.5, and 49.5 +/- 20.5 minutes. Five patients with unsuccessful endovascular treatment were treated with open surgery. Among the 5 cases, 1 case belongs to the novel sheath group and 4 cases to the control group. CONCLUSION: The novel sheath, whose production is simple and low cost, improves the efficiency of transurethral treatment of bladder calculi and shortens the operation time; furthermore, it involves skills that can be easily mastered and presents clinical application value. PMID- 29410330 TI - Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains. AB - Seasonal influenza vaccines elicit antibody responses that can prevent infection, but their efficacy is reduced in the elderly. While a subset of elderly individuals can still mount sufficient vaccine-induced antibody responses, little is known about the properties of the vaccine-induced antibody repertoires in elderly as compared to young responders. To gain insights into the effects of aging on influenza vaccine-induced antibody responses, we used flow cytometry and a cell-barcoding method to sequence antibody heavy and light chain gene pairs expressed by individual blood plasmablasts generated in response to influenza vaccination in elderly (aged 70-89) and young (aged 20-29) responders. We found similar blood plasmablast levels in the elderly and young responders seven days post vaccination. Informatics analysis revealed increased clonality, but similar heavy chain V(D)J gene usage in the elderly as compared to young vaccine responders. Although the elderly responders exhibited decreased antibody sequence diversity and fewer consequential mutations relative to young responders, recombinant antibodies from elderly responders bound a broader range of influenza strain HAs. Thus elderly influenza vaccine responders mount plasmablast responses with restricted diversity but with an increased breadth of binding across influenza strains. Our results suggest that the ability to generate plasmablast responses encoding cross-strain binding antibodies likely represents a mechanism important to vaccine responses in the elderly. PMID- 29410331 TI - Cisplatin inhibits the progression of bladder cancer by selectively depleting G MDSCs: A novel chemoimmunomodulating strategy. AB - Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs. PMID- 29410332 TI - Adverse Effects of Delayed Transplant Listing Among Patients With Implantable Left Ventricular Assist Devices. AB - BACKGROUND: The timing of transplant listing after implantation of a left ventricular assist device (LVAD) remains uncertain, given high device complication rates and apparent stability of some LVAD-supported patients. This investigation quantifies the effect of delayed transplant listing and transplantation rates on medium-term survival and LVAD complications. METHODS AND RESULTS: A Markov model was used to simulate the effects of delaying initial transplant listing after LVAD implantation. Modeled parameters were derived from the Standard Transplant Analysis and Research file. When transplant listing was delayed and 5-year results were examined, fewer persons underwent transplantation (53% in base model vs 51% in 180-day-delay model) and the fraction of deaths while waiting increased (17% in base model vs 21% in 180-day delay model). Life expectancy changed minimally from the base model (3.50 y) when initial listing was delayed by 180 days (3.51 y). CONCLUSIONS: Delaying initial transplant listing increased the likelihood of death while waiting for a transplant and decreased the likelihood of transplantation. In aggregate, life expectancy was unchanged by delays in listing. This study suggests that delaying transplant listing with the expectation of providing additional life expectancy is not likely with current LVAD technology. PMID- 29410333 TI - Effect of pollution on allergy/immunology. PMID- 29410334 TI - Epidemiology of traumatic upper limb amputations. AB - INTRODUCTION: While published data on functional outcomes after upper limb amputations are plentiful, epidemiology data are relatively rare. This led us to performing an epidemiology study of traumatic upper limb amputations at our facility. MATERIAL AND METHODS: This retrospective study spanned a 10-year period of cases seen at the SOS Main (Hand emergency center) of the Nancy University Hospital in France. Patients who suffered traumatic amputation of the upper limb were identified and divided into two groups: replantation and surgical amputation. All anatomical amputation levels were retained. Non-traumatic amputations were excluded. Epidemiology data (sex, age, dominant side, injured side) was collected along with the specific anatomical level of the injury, the injury mechanism and whether it was work-related. We also looked at the success rate of microsurgery and whether multi-finger amputations were partial or complete. In parallel, the annual incidence of amputations seen at the SOS Main over this period was calculated. RESULTS: Over the 10-year period, 1715 traumatic upper-limb amputations were identified, which was 3% of all cases seen at the SOS Main. Most of the cases involved middle-aged men. Revascularization was attempted in one-third of cases and microsurgery was successful in 70% of cases. The surgical amputation group consisted of 1132 patients with a mean age of 59 years, while the replantation group consisted of 583 patients with a mean age of 48 years. The primary mechanism of injury was a table saw. DISCUSSION: This injury, which must be addressed urgently, is not very common in everyday practice. This is contrary to lower limb amputations, which are more common and occur in the context of micro- and macroangiopathy in older patients. The success rate of microsurgery in this cohort must be placed in the context of age, amputation level and mechanism. The functional outcomes are not always as good as the vascular outcomes. This data is invaluable as it fills a gap in our knowledge about amputations. LEVEL OF EVIDENCE: IV. PMID- 29410335 TI - Lung cancer specific and reduction-responsive chimaeric polymersomes for highly efficient loading of pemetrexed and targeted suppression of lung tumor in vivo. AB - : Lung cancer is one of the worldwide leading and fast-growing malignancies. Pemetrexed disodium (PEM, Alimta(r)), a small hydrophilic drug, is currently used for treating lung cancer patients. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Here, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lung cancer cells in vitro and in vivo. PEM-loaded CC9-RCPs (PEM-CC9-RCPs) was obtained from co-self assembly of poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) and CC9 functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self crosslinking. PEM-CC9-RCPs displayed an optimal CC9 density of 9.0% in targeting H460 cells, a high PEM loading content of 14.2 wt%, a small hydrodynamic size of ca. 60 nm and glutathione-triggered PEM release. MTT assays showed that PEM-CC9 RCPs was 2.6- and 10- fold more potent to H460 cells than the non-targeting PEM RCPs and free PEM controls, respectively. Interestingly, PEM-CC9-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta(r). Moreover, CC9-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC9-RCPs at 12.5 mg PEM equiv./kg effectively suppressed growth of H460 xenografts and significantly prolonged mouse survival time as compared to PEM-RCPs and Alimta(r) controls. These lung cancer specific and reduction-responsive chimaeric polymersomes provide a unique pemetrexed nanoformulation for targeted lung cancer therapy. STATEMENT OF SIGNIFICANCE: Multitargeted antifolate agent pemetrexed (PEM, Alimta(r)) is currently used for treating lung cancer patients and has low side-effects. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Scarce work on targeted delivery of PEM has been reported, partly because most conventional nanocarriers show a low and instable loading for hydrophilic, negatively charged drugs like PEM. Herewith, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction responsive chimaeric polymersomes (CC9-RCPs) which showed efficient PEM encapsulation (14.2 wt%, 60 nm) and targeted delivery of PEM to H460 human lung cancer cells, leading to effective suppression of H460 tumor xenografts and significantly prolonged survival rates of mice than Alimta(r). To the best of our knowledge, this represents a first report on targeted nanosystems that are capable of efficient loading and targeted delivery of PEM to lung tumors. PMID- 29410336 TI - Initial Attempt to Select Patients for Mechanical Thrombectomy Using Noncontrast Computed Tomography and Symptom-Based Criteria: Single-Center Experience. AB - BACKGROUND: In the treatment of acute ischemic stroke (AIS), patients need to be selected for mechanical thrombectomy (MT) in the acute phase. Selection criteria vary, however, depending on the patient's situation. This study investigated the effectiveness of a noncontrast computed tomography and symptom-based protocol for selecting patients for MT. METHODS: This retrospective study included 20 patients with AIS. The first 8 patients (earlier group) were screened by magnetic resonance imaging (MRI). Among the later 12 patients, MRI was deliberately skipped in 9, and major vessel occlusion was confirmed by digital subtraction angiography after meeting 4 criteria: 1) hospital arrival within 90 minutes from onset; 2) National Institutes of Health Stroke Scale score 9-25; 3) history or presence of atrial fibrillation; and 4) Alberta Stroke Program Early CT Score of 9-10. The clinical outcomes and time course were compared. RESULTS: Among the later period group, 9 of 12 patients skipped MRI-based confirmation of large vessel occlusion. They underwent the direct angiography protocol, which had a 78% (7/9) positive predictive value for identifying large-vessel occlusion. In this group, National Institutes of Health Stroke Scale scores on the next day had significantly improved (median -8 points) compared with those at admission. Good functional outcome did not differ between the groups at 3 months. CONCLUSIONS: Noncontrast computed tomography and symptom-based selection of MT to treat AIS can be useful for achieving better neurologic recovery in a subgroup of patients. This approach could broaden the use of MT. PMID- 29410337 TI - Use of Pipeline Embolization Device for Posterior Circulation Aneurysms: Single Center Experiences with Comparison with Anterior Circulation Aneurysms. AB - OBJECTIVE: To evaluate the performance of the Pipeline embolization device (PED) for posterior circulation aneurysms. METHODS: From November 2015 to November 2016, 35 patients with 38 posterior circulation aneurysms were treated with the PED in this retrospective study. We evaluated the angiographic and clinical outcomes of these aneurysms at last follow-up, and made a comparison between anterior (n = 163) and posterior circulation (n = 38) aneurysms regarding the technical nuances, occlusion rate, complications rate, and time to occlusion to explore whether we should rationalize the use of the PED for these aneurysms. RESULTS: With a median follow-up time of 5.5 months, complete occlusion was achieved in 33 aneurysms (91.7%). Aneurysms with stenosis parent artery tended to have lower occlusion rate (P = 0.064; odds ratio, 0.074; 90% confidence interval, 0.001-1.781), and V4 segment aneurysms tended to occlude themselves much faster than vertebrobasilar junction aneurysms (median, 148 vs. 246 days, respectively; P = 0.076). The periprocedural complication rate was 10.8%, and no major adverse events occurred. Compared with anterior circulation aneurysms, shorter procedure time (116.0 vs. 135.4 minutes, P = 0.012) and higher occlusion rate (91.4% vs. 72.8%, P = 0.023) were achieved for posterior circulation aneurysms. Besides, technical event rate (8.1% vs. 14.1%, P = 0.424) and complication rate (10.8% vs. 18.4%, P = 0.338) tended to be lower. Survival analysis indicated a shorter interval to complete occlusion for V4 segment aneurysms compared with anterior circulation (148 vs. 191 days, respectively; P = 0.047). CONCLUSIONS: PED has a favorable performance at posterior circulation, and it is rational to expand the indication to include these aneurysms. However, a case-control study is still needed to further expatiate whether the PED has advantages over traditional endovascular treatment. PMID- 29410338 TI - Diffusion Tensor Imaging of Axonal and Myelin Changes in Classical Trigeminal Neuralgia. AB - OBJECTIVE: Trigeminal neuralgia (TN) is commonly associated with pathologic factors of axonopathy and demyelination resulting from neurovascular compression at the trigeminal root entry zone (REZ). Decompression surgery can relieve TN pain, likely by resolving such structural abnormalities. To test this hypothesis, we used diffusion tensor imaging (DTI) to capture the full extent of trigeminal microarchitecture changes in vivo in patients with TN. METHODS: Twenty-four patients with TN were compared with 28 controls. DTI metrics of fractional anisotropy (FA) and mean, parallel, and perpendicular diffusivities (MD, lambda||, and lambda?, respectively) were calculated in isolation at each trigeminal REZ. In 6 patients with pain relief following decompression surgery, repeated studies were performed 2 times (1 week and 4-6 months) after surgery to detect dynamic changes in FA, MD, lambda||, and lambda?. RESULTS: We observed significant FA reductions and increased diffusivity at the affected trigeminal REZ, corresponding to known underlying pathologic changes, including axonal edema and demyelination. Specifically, our results showed that these DTI-derived metrics are discriminating features for patients with TN according to the support vector machine approach. After effective treatment, diffusion recovery at 1 week was mainly due to the decrease in lambda|| (consistent with axonal membrane stabilization), whereas at 4-6 months it was due to the predominant reduction in lambda? (consistent with remyelination). CONCLUSIONS: Together, these results support that DTI permits the noninvasive detection of the trigeminal microstructural abnormalities underlying TN in vivo, and DTI-derived metrics could be considered surrogate markers of the axonal and myelin states for monitoring patients. PMID- 29410339 TI - Comparison of 4 Different Methods for Direct Hypoglossal-Facial Nerve Anastomosis in Rats. AB - BACKGROUND: Classic hypoglossal-facial nerve anastomosis inevitably causes hemitongue atrophy and dysfunction. Thus, many variants have been developed to reduce tongue-related morbidities. A comparative study concerning these techniques was conducted in rats to systematically evaluate long-term functional and histologic outcomes of the recipient and donor systems. METHODS: Rats (8 per group) were treated by end-to-end neurorrhaphy (EEN), EEN using the hemisectioned and longitudinally split donor nerve (EEN-Hemi), end-to-side neurorrhaphy through a perineurial window (ESN-PW), or 30% to 40% partial neurotomy (ESN-PN). Four additional rats were left intact. At 8 months postoperatively, behavioral, electrophysiologic, and morphologic studies were carried out to compare the groups. RESULTS: All techniques resulted in partial functional recovery, but complete restoration was not obtained. There were no significant differences between the experimental groups in axon diameter or myelin thickness. The facial nerve fiber count after ESN-PN, but not after EEN-Hemi or ESN-PW, was comparable with that after EEN, which agreed with the behavioral and electrophysiologic results. The hypoglossal nerve fiber count after ESN-PN was slightly less than that after ESN-PW, but markedly more than that after EEN-Hemi, corresponding to the electrophysiologic examination. Quantitative measures of muscle fiber cross sectional area and connective tissue area density of the tongue demonstrated severe muscle atrophy on the operated side after EEN and EEN-Hemi when compared with ESN-PW and ESN-PN. CONCLUSIONS: ESN with 30% to 40% partial donor neurotomy offers the best balance between motor reinnervation and donor deficits. The method of nerve split for provision of hemihypoglossal nerve stump may not effectively preserve the tongue function. PMID- 29410340 TI - Survival of Lymphoma Patients Experiencing Relapse or Progression after an Allogeneic Hematopoietic Cell Transplantation. AB - Outcome and management of patients who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has evolved in the recent decade. Using a multi institutional retrospective database we report the predictive factors and survival of lymphoma patients who relapse after allo-HCT. We evaluated 495 allo HCT recipients transplanted between 2000 and 2015 at 3 academic US medical centers. Landmark analysis evaluating predictive factors was performed at 1 month after allo-HCT relapse with a primary endpoint of postrelapse overall survival (PR-OS). A total of 175 lymphoma patients (35%) experienced relapse after allo HCT. Of these, 126 patients, median age 46 years (range, 19 to 71), were assessable. Most patients (86%) received subsequent therapy; 80 patients received targeted agents and 19 donor lymphocyte infusion. On univariate analysis median PR-OS for patients with Hodgkin lymphoma was 47.9 months compared with 11.3 months in patients with indolent and 10.1 months in aggressive non-Hodgkin lymphoma (P = .04). On multivariate analysis postrelapse therapy administration (no therapy versus targeted therapy: hazard ratio, .21 [95% confidence interval, .10 to .45]; no therapy versus nontargeted therapy: hazard ratio, .26 [95% confidence interval, .11 to .57]), late relapse 130 days after allo-HCT (relative to early relapse: hazard ratio, .25; P < .001), and Eastern Cooperative Oncology Group performance status of 0 to 1 (versus Eastern Cooperative Oncology Group performance status >= 2: hazard ratio, .49; P = .003) were associated with a significantly reduced risk of mortality. Patients relapsing >= 130 days from the time of allo-HCT yielded PR-OS of 48.8 months compared with 6.5 months in patients with early relapse (P < .001). Our data suggest that in the modern era, therapies used for patients experiencing lymphoma relapse after allo-HCT can extend survival. PMID- 29410342 TI - Diagnostic Utility of Endoscopy and Biopsy in Suspected Acute Gastrointestinal Graft-versus-Host Disease after Hematopoietic Progenitor Cell Transplantation. AB - Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies. PMID- 29410341 TI - Evaluation of a Machine Learning-Based Prognostic Model for Unrelated Hematopoietic Cell Transplantation Donor Selection. AB - The survival of patients undergoing hematopoietic cell transplantation (HCT) from unrelated donors for acute leukemia exhibits considerable variation, even after stringent genetic matching. To improve the donor selection process, we attempted to create an algorithm to quantify the likelihood of survival to 5 years after unrelated donor HCT for acute leukemia, based on the clinical characteristics of the donor selected. All standard clinical variables were included in the model, which also included average leukocyte telomere length of the donor based on its association with recipient survival in severe aplastic anemia, and links to multiple malignancies. We developed a multivariate classifier that assigned a Preferred or NotPreferred label to each prospective donor based on the survival of the recipient. In a previous analysis using a resampling method, recipients with donors labeled Preferred experienced clinically compelling better survival compared with those labeled NotPreferred by the test. However, in a pivotal validation study in an independent cohort of 522 patients, the overall survival of the Preferred and NotPreferred donor groups was not significantly different. Although machine learning approaches have successfully modeled other biological phenomena and have led to accurate predictive models, our attempt to predict HCT outcomes after unrelated donor transplantation was not successful. PMID- 29410343 TI - Single Antigen-Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide Is a Suitable Alternative for Patients Lacking HLA-Matched Donors. AB - The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing 2 contemporaneous groups: PTCy MMUD (n = 26) versus matched unrelated donor (MUD) (n = 60). Graft source was primarily peripheral blood (92%). All PTCy MMUD were HLA 7/8 (differences in HLA class I loci in 92% of patients) and received PTCy plus tacrolimus +/- mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCy MMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II to IV (31% versus 22%, respectively; P = .59) and III to IV (8% versus 10%, P = .67). There was a trend for a lower incidence of moderate to severe chronic GVHD at 1 year after PTCy MMUD in comparison with MUD (22% versus 41%, P = .098). No differences between PTCy MMUD and MUD were found regarding nonrelapse mortality (25% versus 18%, P = .52) or relapse rate (11% versus 19%, P = .18). Progression-free survival and overall survival at 2 years were similar in both cohorts (67% versus 54% [HR, .84; 95% CI, .38 to 1.88; P = .68] and 72% versus 57% [HR, .71; 95% CI, .31 to 1.67; P = .44], respectively). The 2-year cumulative incidence of survival free of moderate to severe chronic GVHD and relapse tended to be higher in the PTCy MMUD group (47% versus 24%; HR, .60; 95% CI, .31 to 1.14; P = .12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD. PMID- 29410344 TI - Real-world evidence-What is it and does it matter for approval of drugs? PMID- 29410345 TI - Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women. AB - CONTEXT: Toll-like receptor 4 (TLR4) activation contributes to obesity-associated insulin resistance in skeletal muscles (SM). TLR4 signaling involves two pathways: the myeloid differentiation primary response gene 88 (MyD88) leading to inflammatory cytokines production and the toll/interleukin-1 receptor domain containing adapter-inducing interferon (IFN) I (TRIF)-dependent pathways leading to type 1 interferon (IFNI) and interferon stimulated genes (ISG) expression. The E3 ubiquitin ligase RNF41 allows the preferential activation of the TRIF-IFNI pathway; however, its role in insulin response has not been reported. METHODS: We measured RNF41 level and IFNI pathway activation (ISG expression) in SM biopsies of obese insulin sensitive (OIS) and obese insulin resistant (OIR) women. Then we isolated and differentiated in myotubes, primary human SM cell progenitors from OIS and OIR SM biopsies. We modulated RNF41 and ISG expression in these myotubes and investigated their effects on insulin response. RESULTS: RNF41 expression is down-regulated in vivo in OIR SM and myotubes compared to OIS SM and myotubes. TLR4 activation with palmitate induces TRIF-IFNI pathway and ISG in OIS myotubes but not in OIR myotubes. Inhibition of RNF41 expression with siRNF41 in OIS myotubes treated with palmitate attenuates insulin response, IFNI pathway activation and ISG induction, mimicking OIR phenotype. Further, overexpression of RNF41 in OIR myotubes increases insulin response and ISG expression. Exposure to IFNI or to its inducer polyinosinic-polycytidylic acid, restores ISG expression and insulin sensitivity in OIR myotubes and OIS myotubes transfected with siRNF41. CONCLUSION: Our results identify RNF41 as essential to IFNI pathway activation in order to maintain muscle insulin sensitivity during human obesity. PMID- 29410346 TI - Pathologic Upgrade Rates of High-Risk Breast Lesions on Digital Two-Dimensional vs Tomosynthesis Mammography. AB - BACKGROUND: Our aim was to compare the pathologic upgrade rates of high-risk breast lesions (HRLs) on digital two-dimensional mammography (DM) vs digital breast tomosynthesis (DBT). STUDY DESIGN: The study cohort was composed of patients with HRLs diagnosed by image-guided core needle biopsy from December 2007 to February 2011 (DM group, before DBT integration) and from January 2013 to March 2016 (DBT group, after complete DBT integration). Medical records were reviewed for surgical outcomes and follow-up imaging. RESULTS: Eight hundred and ninety-three patients with 900 biopsy-proven HRLs underwent surgical excision (97.0% [873 of 900]) or had at least 2 years of imaging follow-up (3.0% [27 of 900]). The most common HRL was atypical ductal hyperplasia in the DM and DBT groups (37.4% [337 of 900]). The overall upgrade rate of HRLs to malignancy was 11.3% (102 of 900). There were no statistically significant differences in overall upgrades rates of HRLs on DM vs DBT (11.4% [54 of 475] vs 11.3% [48 of 425]; p = 0.97) or in upgrade rates of HRL subtypes. However, HRLs that upgraded on DBT were more likely to be invasive rather than in situ carcinoma compared with HRLs that upgraded on DM (39.6% [19 of 48] vs 20.4% [11 of 54]; p = 0.03). Overall, the most common HRL to upgrade was atypical ductal hyperplasia (18.4% [62 of 337]). The least common HRLs to upgrade in the DBT group were biphasic neoplasms (0% [0 of 22]), flat epithelial atypia (1.6% [1 of 62]), and papillomas without atypia (4.5% [2 of 44]). CONCLUSIONS: There is no difference in the upgrade rates of HRLs on DM vs DBT, but the proportion of HRL upgrades that are invasive rather than in situ carcinoma is higher with DBT. PMID- 29410348 TI - Caloric restriction improves glucose homeostasis, yet increases cardiometabolic risk in caveolin-1-deficient mice. AB - BACKGROUND AND PURPOSE: The plasma membrane protein caveolin-1 (CAV-1) has been shown to be involved in modulating glucose homeostasis and the actions of the renin-angiotensin-aldosterone system (RAAS). Caloric restriction (CR) is widely accepted as an effective therapeutic approach to improve insulin sensitivity and reduce the severity of diabetes. Recent data indicate that polymorphisms of the CAV-1 gene are strongly associated with insulin resistance, hypertension and metabolic abnormalities in non-obese individuals. Therefore, we sought to determine whether CR improves the metabolic and cardiovascular (CV) risk factors in the lean CAV-1 KO mice. MATERIALS/METHODS: Twelve- to fourteen-week-old CAV-1 knockout (KO) and genetically matched wild-type (WT) male mice were randomized by genotype to one of two dietary regimens: ad libitum (ad lib) food intake or 40% CR for 4 weeks. Three weeks following the onset of dietary restriction, all groups were assessed for insulin sensitivity. At the end of the study, all groups were assessed for fasting glucose, insulin, HOMA-IR, lipids, corticosterone levels and blood pressure (BP). Aldosterone secretion was determined from acutely isolated Zona Glomerulosa cells. RESULTS: We confirmed that the CAV-1 KO mice on the ad lib diet display a phenotype consistent with the cardiometabolic syndrome, as shown by higher systolic BP (SBP), plasma glucose, HOMA-IR and aldosterone levels despite lower body weight compared with WT mice on the ad lib diet. CAV-1 KO mice maintained their body weight on the ad lib diet, but had substantially greater weight loss with CR, as compared to caloric restricted WT mice. CR mediated changes in weight were associated with dramatic improvements in glucose and insulin tolerance in both genotypes. These responses to CR, however, were more robust in CAV-1KO vs. WT mice and were accompanied by reductions in plasma glucose, insulin and HOMA-IR in CAV-1KO but not WT mice. Surprisingly, in the CAV 1 KO, but not in WT mice, CR was associated with increased SBP and aldosterone levels, suggesting that in CAV-1 KO mice CR induced an increase in some CV risk factors. CONCLUSIONS: CR improved the metabolic phenotype in CAV-1 KO mice by increasing insulin sensitivity; nevertheless, this intervention also increased CV risk by inappropriate adaptive responses in the RAAS and BP. PMID- 29410347 TI - A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways. AB - OBJECTIVE: As the leading risk factor for the development of liver cancer, chronic infection with hepatitis B virus (HBV) represents a significant global health concern. Although an effective HBV vaccine exists, at least 240 million people are chronically infected with HBV worldwide. Therapeutic options for the treatment of chronic HBV remain limited, and none achieve an absolute cure. To develop novel therapeutic targets, a better understanding of the complex network of virus-host interactions is needed. Because of the central metabolic role of the liver, we assessed the metabolic impact of HBV infection as a means to identify viral dependency factors and metabolic pathways that could serve as novel points of therapeutic intervention. METHODS: Primary rat hepatocytes were infected with a control adenovirus, an adenovirus expressing a greater-than-unit length copy of the HBV genome, or an adenovirus expressing the HBV X protein (HBx). A panel of 369 metabolites was analyzed for HBV- or HBx-induced changes 24 and 48 h post infection. Pathway analysis was used to identify key metabolic pathways altered in the presence of HBV or HBx expression, and these findings were further supported through integration of publically available gene expression data. RESULTS: We observed distinct changes to multiple metabolites in the context of HBV replication or HBx expression. Interestingly, a panel of 7 metabolites (maltotriose, maltose, myristate [14:0], arachidate [20:0], 3 hydroxybutyrate [BHBA], myo-inositol, and 2-palmitoylglycerol [16,0]) were altered by both HBV and HBx at both time points. In addition, incorporation of data from a transcriptome-based dataset allowed us to identify metabolic pathways, including long chain fatty acid metabolism, glycolysis, and glycogen metabolism, that were significantly altered by HBV and HBx. CONCLUSIONS: Because the liver is a central regulator of metabolic processes, it is important to understand how HBV replication and HBV protein expression affects the metabolic function of hepatocytes. Through analysis of a broad panel of metabolites we investigated this metabolic impact. The results of these studies have defined metabolic consequences of an HBV infection of hepatocytes and will help to lay the groundwork for novel research directions and, potentially, development of novel anti-HBV therapeutics. PMID- 29410349 TI - Non-targeted profiling of circulating microRNAs in women with polycystic ovary syndrome (PCOS): effects of obesity and sex hormones. AB - PURPOSE: Circulating micro-ribonucleic acids (miRNAs) are small noncoding RNA molecules that influence gene transcription. We conducted the present profiling study to characterize the expression of circulating miRNAs in lean and obese patients with polycystic ovary syndrome (PCOS), the most common endocrine and metabolic disorder in premenopausal women. BASIC PROCEDURES: We selected 11 control women, 12 patients with PCOS and 12 men so that they were similar in terms of body mass index. Five control women, 6 men and 6 patients with PCOS had normal weight whereas 6 subjects per group were obese. We used miRCURY LNATM Universal RT microRNA PCR for miRNA profiling. MAIN FINDINGS: The expression of 38 miRNAs and was different between subjects with PCOS and male and female controls. The differences in 15 miRNAs followed a pattern suggestive of androgenization characterized by expression levels that were similar in patients with PCOS and men but were different compared with those of control women. The expression of 13 miRNAs in women with PCOS was similar to that of control women and different compared with the expression observed in men, suggesting sexual dimorphism and, lastly, we observed 5 miRNAs that were expressed differently in women with PCOS compared with both men and control women, suggesting a specific abnormality in expression associated with the syndrome. Obesity interacted with the differences in several of these miRNAs, and the expression levels of many of them correlated with the hirsutism score, sex hormones and/or indexes of obesity, adiposity and metabolic dysfunction. PRINCIPAL CONCLUSIONS: The present results suggest that several serum miRNAs are influenced by PCOS, sex hormones and obesity. Our findings may guide the targeted search of miRNAs as clinically relevant markers for PCOS and its association with obesity and metabolic dysfunction in future studies. PMID- 29410350 TI - Novel phytopeptide osmotin mimics preventive effects of adiponectin on vascular inflammation and atherosclerosis. AB - INTRODUCTION: The novel phytohormone, osmotin, has been reported to act like mammalian adiponectin through PHO36/AdipoR1 in various in vitro and in vivo models. However, there have been no reports regarding the precise effects of osmotin on atherosclerosis. METHODS: We assessed the atheroprotective effects of osmotin on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), human leukemic monocyte (THP-1) adhesion, inflammatory responses, and foam cell formation in THP-1-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs). We examined whether 4-week infusion of osmotin could suppress the development of aortic atherosclerotic lesions in apolipoprotein E-deficient (ApoE /-) mice. RESULTS: AdipoR1 was abundantly expressed in HUVECs, HASMCs, THP-1, and derived macrophages. Osmotin suppressed lipopolysaccharide-induced upregulation of tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E selectin in HUVECs, and TNF-alpha-induced THP-1-HUVEC adhesion. In THP-1-derived macrophages, osmotin suppressed the inflammatory M1 phenotype, lipopolysaccharide induced secretion of interleukin-6 and TNF-alpha, and oxidized low-density lipoprotein-induced foam cell formation associated with CD36 and acyl CoA:cholesterol acyltransferase 1 downregulation and ATP-binding cassette transporter A1 upregulation. In HASMCs, osmotin suppressed angiotensin II-induced migration, proliferation, collagen-1 and fibronectin expression, and matrix metalloproteinase-2 activity without inducing apoptosis. Infusion of osmotin into ApoE-/- mice prevented the development of aortic atherosclerotic lesions with reductions of intraplaque pentraxin-3 expression, fasting plasma glucose, and insulin resistance. CONCLUSIONS: This study provided the first evidence that osmotin exerts preventive effects on vascular inflammation and atherosclerosis, which may facilitate the development of new therapeutic modalities for combating atherosclerosis and related diseases. PMID- 29410351 TI - Fibroblast growth factor 21 in cardio-metabolic disorders: a systematic review and meta-analysis. AB - BACKGROUND: Fibroblast growth factor 21 is a signalling protein involved in cell differentiation, morphogenesis, proliferation and metabolism. Recent studies have associated increased levels of FGF21 in the development of cardiovascular diseases, whereas others have reported no significant associations. Therefore, this systematic review and meta-analysis evaluated the value in predicting the risk of cardio-metabolic disorders and mortality. METHODS: PubMed and EMBASE were searched until 5th September 2017 for studies that evaluated the roles of FGF21 levels in cardio-metabolic disorders. RESULTS: A total of 183 and 301 entries were retrieved; 24 studies met the inclusion criteria. Four studies were identified by an additional search. Therefore, 28 studies were included in the final meta-analysis. High FGF21 levels significantly predicted the incidence of coronary artery disease (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.06-1.55; P < 0. 01; I2 = 48%) and the risk of metabolic syndrome (HR: 1.70, 95% CI: 1.35-2.15; P < 0.0001 I2 = 24%). In diabetes mellitus, FGF21 predicted disease incidence or progression (HR: 1.35, 95% CI: 1.06-1.72, P < 0.05, I2 = 69%) and worsening renal failure (HR: 1.06, 95% CI: 1.03-1.09, P < 0.0001, I2 = 47%). FGF21 also predicted all-cause mortality (HR: 3.00, 95% CI: 1.23-7.33; P < 0.05; I2 = 51%), and cardiovascular mortality (HR: 2.33, 95% CI: 1.08-4.99, P < 0.05, I2 = 75%). CONCLUSION: FGF21 significantly predicts the incidence of coronary artery disease, the risks of metabolic syndrome, diabetes mellitus and renal progression in diabetes. It also predicted all-cause and cardiovascular mortality. PMID- 29410352 TI - Differential effects of saturated fatty acids on the risk of metabolic syndrome: a matched case-control and meta-analysis study. AB - BACKGROUND: We investigated the association between plasma saturated fatty acids (SFAs) and the risk of metabolic syndrome among ethnic Chinese adults in Taiwan who attended a health check-up center. METHODS: A case-control study based on 1000 cases of metabolic syndrome and 1:1 matched control participants (mean age, 54.9 +/- 10.7 y; 36% females) were recruited. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation. Gas chromatography was used to measure the distribution of fatty acids in plasma (% of total fatty acids). RESULTS: Even-chain SFAs, including 14:0, 16:0, and 18:0, were associated with metabolic syndrome; the adjusted odds ratio [OR] and 95% confidence interval [CI] per standard deviation [SD] difference was 3.32, [1.98 5.59]; however, very-long-chain SFAs, including 20:0, 21:0, 22:0, 23:0, and 24:0, were inversely associated with metabolic syndrome. The adjusted OR [95% CI] per SD difference was 0.67 [0.58-0.78]. The area under the receiver operative characteristic curve increased from 0.814 in the basic model to 0.815 (p = 0.54, compared with the basic model), 0.818 (p < 0.0001), and 0.820 (p < 0.0001) after adding odd-chain, even-chain, and very-long chain SFAs. A meta-analysis based on 12 studies showed that the summarized OR for type 2 diabetes mellitus was 1.16 [0.96-1.41] for the top versus bottom SFAs. CONCLUSIONS: Different carbon numbers of SFAs have been shown to have differential effects on the status of metabolic syndrome, implying that SFAs are not homogenous for the effects. PMID- 29410353 TI - Phylogeny, historical biogeography, and diversification of angiosperm order Ericales suggest ancient Neotropical and East Asian connections. AB - Inferring interfamilial relationships within the eudicot order Ericales has remained one of the more recalcitrant problems in angiosperm phylogenetics, likely due to a rapid, ancient radiation. As a result, no comprehensive time calibrated tree or biogeographical analysis of the order has been published. Here, we elucidate phylogenetic relationships within the order and then conduct time-dependent biogeographical and diversification analyses by using a taxon and locus-rich supermatrix approach on one-third of the extant species diversity calibrated with 23 macrofossils and two secondary calibration points. Our results corroborate previous studies and also suggest several new but poorly supported relationships. Newly suggested relationships are: (1) holoparasitic Mitrastemonaceae is sister to Lecythidaceae, (2) the clade formed by Mitrastemonaceae + Lecythidaceae is sister to Ericales excluding balsaminoids, (3) Theaceae is sister to the styracoids + sarracenioids + ericoids, and (4) subfamilial relationships with Ericaceae suggest that Arbutoideae is sister to Monotropoideae and Pyroloideae is sister to all subfamilies excluding Arbutoideae, Enkianthoideae, and Monotropoideae. Our results indicate Ericales began to diversify 110 Mya, within Indo-Malaysia and the Neotropics, with exchange between the two areas and expansion out of Indo-Malaysia becoming an important area in shaping the extant diversity of many families. Rapid cladogenesis occurred along the backbone of the order between 104 and 106 Mya. Jump dispersal is important within the order in the last 30 My, but vicariance is the most important cladogenetic driver of disjunctions at deeper levels of the phylogeny. We detect between 69 and 81 shifts in speciation rate throughout the order, the vast majority of which occurred within the last 30 My. We propose that range shifting may be responsible for older shifts in speciation rate, but more recent shifts may be better explained by morphological innovation. PMID- 29410354 TI - Two Types of Gastric Cancer Caused by the Same Underlying Condition. PMID- 29410356 TI - A shared latent space matrix factorisation method for recommending new trial evidence for systematic review updates. AB - BACKGROUND: Clinical trial registries can be used to monitor the production of trial evidence and signal when systematic reviews become out of date. However, this use has been limited to date due to the extensive manual review required to search for and screen relevant trial registrations. Our aim was to evaluate a new method that could partially automate the identification of trial registrations that may be relevant for systematic review updates. MATERIALS AND METHODS: We identified 179 systematic reviews of drug interventions for type 2 diabetes, which included 537 clinical trials that had registrations in ClinicalTrials.gov. Text from the trial registrations were used as features directly, or transformed using Latent Dirichlet Allocation (LDA) or Principal Component Analysis (PCA). We tested a novel matrix factorisation approach that uses a shared latent space to learn how to rank relevant trial registrations for each systematic review, comparing the performance to document similarity to rank relevant trial registrations. The two approaches were tested on a holdout set of the newest trials from the set of type 2 diabetes systematic reviews and an unseen set of 141 clinical trial registrations from 17 updated systematic reviews published in the Cochrane Database of Systematic Reviews. The performance was measured by the number of relevant registrations found after examining 100 candidates (recall@100) and the median rank of relevant registrations in the ranked candidate lists. RESULTS: The matrix factorisation approach outperformed the document similarity approach with a median rank of 59 (of 128,392 candidate registrations in ClinicalTrials.gov) and recall@100 of 60.9% using LDA feature representation, compared to a median rank of 138 and recall@100 of 42.8% in the document similarity baseline. In the second set of systematic reviews and their updates, the highest performing approach used document similarity and gave a median rank of 67 (recall@100 of 62.9%). CONCLUSIONS: A shared latent space matrix factorisation method was useful for ranking trial registrations to reduce the manual workload associated with finding relevant trials for systematic review updates. The results suggest that the approach could be used as part of a semi automated pipeline for monitoring potentially new evidence for inclusion in a review update. PMID- 29410355 TI - An Unusual Cause of a Liver Mass in a Woman. PMID- 29410357 TI - The macro-structural variability of the human neocortex. AB - The human neocortex shows a considerable individual structural variability. While primary gyri and sulci are found in all normally developed brains and bear clear cut gross structural descriptions, secondary structures are highly variable and not present in all brains. The blend of common and individual structures poses challenges when comparing structural and functional results from quantitative neuroimaging studies across individuals, and sets limits on the precision of location information much above the spatial resolution of current neuroimaging methods. This work aimed at quantifying structural variability on the neocortex, and at assessing the spatial relationship between regions common to all brains and their individual structural variants. Based on structural MRI data provided as the "900 Subjects Release" of the Human Connectome Project, a data-driven analytic approach was employed here from which the definition of seven cortical "communities" emerged. Apparently, these communities comprise common regions of structural features, while the individual variability is confined within a community. Similarities between the community structure and the state of the brain development at gestation week 32 lead suggest that communities are segregated early. Subdividing the neocortex into communities is suggested as anatomically more meaningful than the traditional lobar structure. PMID- 29410360 TI - Basic fibroblast growth factor enhances cell proliferation in the dentate gyrus of neonatal rats following hypoxic-ischemic brain damage. AB - BACKGROUND: Perinatal hypoxic-ischemic insult is considered a major contributor to child mortality and morbidity and leads to neurological deficits in newborn infants. There has been a lack of promising neurotherapeutic interventions for hypoxic-ischemic brain damage (HIBD) for clinical application in infants. The present study aimed to investigate the correlation between neurogenesis and basic fibroblast growth factor (bFGF) in the hippocampal dentate gyrus (DG) region in neonatal rats following HIBD. MATERIAL AND METHODS: Cell proliferation was examined by detecting BrdU signals, and the role of bFGF in cell proliferation in the DG region following neonatal HIBD was investigated. RESULTS: Cell proliferation was induced by HIBD in the hippocampal DG of neonatal rats. Furthermore, bFGF gene expression was upregulated in the hippocampus in neonatal rats, particularly between 7 and 14 days after HIBD. Moreover, intraperitoneal injection of exogenous bFGF enhanced cell proliferation in the hippocampal DG following neonatal HIBD. CONCLUSIONS: Taken together, these data indicate that cell proliferation in the DG could be induced by neonatal HIBD, and bFGF promotes proliferation following neonatal HIBD. PMID- 29410359 TI - Modulation of the zebrafish optokinetic reflex by pharmacologic agents targeting GABAA receptors. AB - Optokinetic reflex (OKR) responses provide a convenient means to evaluate visual, integrative and oculomotor function in larval zebrafish. We measured multiple aspects of the OKR response in zebrafish exposed systemically to compounds altering signaling at GABAA receptors in order to derive quantitative concentration-response relationships. The GABAA antagonist picrotoxin caused concentration-dependent decreases in reflex gain, saccade velocity, saccade amplitude, interocular concordance and interocular gain. Conversely, the GABAA agonist gaboxadol provoked increases in reflex gain, saccade velocity, saccade amplitude and ocular range at low concentrations, and decreases in some of these parameters at higher concentrations. These data show that GABAA signaling influences multiple aspects of the OKR (including gain, generation of saccades, and coordination between the two eyes) and provide proof of concept that quantitative OKR analysis can be used as a tool for chemical biology and neuropharmacology applications. PMID- 29410358 TI - Hypoglossal nerve stimulation in a pre-clinical anesthetized rabbit model relevant to OSA. AB - We tested the functional effects of hypoglossal (CNXII) stimulation in the anesthetized rabbit before and after injections of saline into the tongue base to obstruct the airway. Data (n = 6) show little or no effect of CN XII trunk stimulation; however, medial branch stimulation (20-100 Hz; 50-500 MUs pulse width, and incremental increases from 10 MUA) reduced upper airway resistance. Medial branch stimulation was less effective in reducing resistance than anterior advancement of the hyoid. Endoscopic viewing (n-3) of the retropalate showed this region as the narrowest and dynamically changed by anterior hyoid displacement, with less evident effects than CNXII stimulation. We conclude that under these conditions CNXII medial branch stimulation reduces airway resistance, especially after induced obstruction. PMID- 29410361 TI - Caspase-8 function, and phosphorylation, in cell migration. AB - Caspase-8 is involved in a number of cellular functions, with the most well established being the control of cell death. Yet caspase-8 is unique among the caspases in that it acts as an environmental sensor, transducing a range of signals to cells, modulating responses that extend far beyond simple survival. Ranging from the control of apoptosis and necroptosis and gene regulation to cell adhesion and migration, caspase-8 uses proteolytic and non-proteolytic functions to alter cell behavior. Novel interacting partners provide mechanisms for caspase 8 to position itself at signaling nodes that affect a variety of signaling pathways. Here, we examine the catalytic and noncatalytic modes of action by which caspase-8 influences cell adhesion and migration. The mechanisms vary from post-cleavage remodeling of the cytoskeleton to signaling elements that control focal adhesion turnover. This is facilitated by caspase-8 interaction with a host of cell proteins ranging from the proteases caspase-3 and calpain-2 to adaptor proteins such as p85 and Crk, to the Src family of tyrosine kinases. PMID- 29410362 TI - Tetracaine derivatives for catecholaminergic polymorphic ventricular tachycardia: New drugs for correction of diastolic Ca2+ leak? PMID- 29410363 TI - ROS-dependent signalling pathways in plants and algae exposed to high light: Comparisons with other eukaryotes. AB - Like all aerobic organisms, plants and algae co-opt reactive oxygen species (ROS) as signalling molecules to drive cellular responses to changes in their environment. In this respect, there is considerable commonality between all eukaryotes imposed by the constraints of ROS chemistry, similar metabolism in many subcellular compartments, the requirement for a high degree of signal specificity and the deployment of thiol peroxidases as transducers of oxidising equivalents to regulatory proteins. Nevertheless, plants and algae carry out specialised signalling arising from oxygenic photosynthesis in chloroplasts and photoautotropism, which often induce an imbalance between absorption of light energy and the capacity to use it productively. A key means of responding to this imbalance is through communication of chloroplasts with the nucleus to adjust cellular metabolism. Two ROS, singlet oxygen (1O2) and hydrogen peroxide (H2O2), initiate distinct signalling pathways when photosynthesis is perturbed. 1O2, because of its potent reactivity means that it initiates but does not transduce signalling. In contrast, the lower reactivity of H2O2 means that it can also be a mobile messenger in a spatially-defined signalling pathway. How plants translate a H2O2 message to bring about changes in gene expression is unknown and therefore, we draw on information from other eukaryotes to propose a working hypothesis. The role of these ROS generated in other subcellular compartments of plant cells in response to HL is critically considered alongside other eukaryotes. Finally, the responses of animal cells to oxidative stress upon high irradiance exposure is considered for new comparisons between plant and animal cells. PMID- 29410364 TI - COUNTERPOINT: Should an Attempt Be Made to Withdraw Inhaled Corticosteroids in All Patients With Stable GOLD 3 (30% <= FEV1 < 50% Predicted) COPD? No. PMID- 29410365 TI - Asp133 Residue in NhaA Na+/H+ Antiporter Is Required for Stability Cation Binding and Transport. AB - Na+/H+ antiporters have a crucial role in pH and Na+ homeostasis in cells. The crystal structure of NhaA, the main antiporter of Escherichia coli, has provided general insights into antiporter mechanisms and revealed a previously unknown structural fold, which has since been identified in several secondary active transporters. This unique structural fold is very delicately electrostatically balanced. Asp133 and Lys 300 have been ascribed essential roles in this balance and, more generally, in the structure and function of the antiporter. In this work, we show the multiple roles of Asp133 in NhaA: (i) The residue's negative charge is critical for the stability of the NhaA structure. (ii) Its main chain is part of the active site. (iii) Its side chain functions as an alkaline-pH dependent gate, changing the protein's conformation from an inward-facing conformation at acidic pH to an outward-open conformation at alkaline pH, opening the periplasm funnel. On the basis of the experimental data, we propose a tentative mechanism integrating the structural and functional roles of Asp133. PMID- 29410366 TI - Performance of the TB-LAMP diagnostic assay in reference laboratories: Results from a multicentre study. AB - OBJECTIVE: To evaluate the diagnostic performance of TB-LAMP, a manual molecular tuberculosis (TB) detection method, and provide comparison to the Xpert MTB/RIF assay. METHODS: In a large multicentre study, two sputum samples were collected from participants with TB symptoms in reference laboratories in Peru, South Africa, Brazil, and Vietnam. Each sample was tested with TB-LAMP. The reference standard consisted of four direct smears, four cultures, and clinical and radiological findings. Individuals negative on conventional tests were followed up after 8 weeks. The Xpert MTB/RIF assay was performed on fresh or frozen samples as a molecular test comparison. RESULTS: A total of 1036 adults with suspected TB were enrolled. Among 375 culture-confirmed TB cases with 750 sputum samples, TB-LAMP detected 75.6% (95% confidence interval (CI) 71.8-79.4%), including 97.9% (95% CI 96.4-99.4%) of smear-positive TB samples and 46.6% (95% CI 40.6-52.7%) of smear-negative TB samples. Specificity in 477 culture-negative participants not treated for TB (954 sputum samples) was 98.7% (95% CI 97.9 99.6%). TB-LAMP test results were indeterminate in 0.3% of cases. CONCLUSIONS: TB LAMP detects nearly all smear-positive and half of smear-negative TB cases and has a high specificity when performed in reference laboratories. Performance was similar to the Xpert MTB/RIF assay. PMID- 29410367 TI - Identification of a small molecule inhibitor of the aminoglycoside 6'-N acetyltransferase type Ib [AAC(6')-Ib] using mixture-based combinatorial libraries. AB - The aminoglycoside, 6'-N-acetyltransferase type Ib [AAC(6')-Ib] is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides, including amikacin. This enzyme is therefore an ideal target for enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R-group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin it potentiated the inhibition of growth of three resistant bacteria in culture, and it improved survival when used as treatment of Galleria mellonella infected with aac(6')-Ib-harboring Klebsiella pneumoniae and Acinetobacter baumannii strains. PMID- 29410368 TI - Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016). AB - Tigecycline and comparators were tested by the reference broth microdilution method against 33 348 non-duplicate bacterial isolates collected prospectively in 2016 from medical centres in the Asia-Pacific (3443 isolates), Europe (13 530 isolates), Latin America (3327 isolates) and the USA (13 048 isolates). Among 7098 Staphylococcus aureus isolates tested, >99.9% were inhibited by <=0.5 mg/L tigecycline (MIC50/90, 0.06/0.12 mg/L), including >99.9% of methicillin-resistant S. aureus and 100.0% of methicillin-susceptible S. aureus. Tigecycline was slightly more active against Enterococcus faecium (MIC50/90, 0.03/0.06 mg/L) compared with Enterococcus faecalis (MIC50/90, 0.06/0.12 mg/L) and its activity was not adversely affected by vancomycin resistance when tested against these organisms. Tigecycline potency was comparable for Streptococcus pneumoniae (MIC50/90, 0.03/0.06 mg/L), viridans group streptococci (MIC50/90, 0.03/0.06 mg/L) and beta-haemolytic streptococci (MIC50/90, 0.06/0.06 mg/L) regardless of species and penicillin susceptibility. Tigecycline was active against Enterobacteriaceae (MIC50/90, 0.25/1 mg/L; 97.8% inhibited at <=2 mg/L) but was slightly less active against Enterobacteriaceae isolates expressing resistant phenotypes: carbapenem-resistant Enterobacteriaceae (MIC50/90, 0.5/2 mg/L; 98.0% susceptible); multidrug-resistant (MIC50/90, 0.5/2 mg/L; 93.1% susceptible); and extensively drug-resistant (MIC50/90, 0.5/4 mg/L; 87.8% susceptible). Tigecycline inhibited 74.4% of 888 Acinetobacter baumannii isolates at <=2 mg/L (MIC50/90, 2/4 mg/L) and demonstrated good in vitro activity against Stenotrophomonas maltophilia (MIC50/90, 1/2 mg/L; 90.6% inhibited at <=2 mg/L) Tigecycline was active against Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/L) regardless of beta-lactamase status. Tigecycline represents an important treatment option for resistant Gram-negative and Gram-positive bacterial infections. PMID- 29410369 TI - Active packaging from chitosan-titanium dioxide nanocomposite film for prolonging storage life of tomato fruit. AB - The feasibility of active packaging from chitosan (CS) and chitosan containing nanosized titanium dioxide (CT) to maintain quality and extend storage life of climacteric fruit was investigated. The CT nanocomposite film and CS film were fabricated using a solution casting method and used as active packaging to delay ripening process of cherry tomatoes. Changes in firmness, weight loss, a*/b* color, lycopene content, total soluble solid, ascorbic acid, and concentration of ethylene and carbon dioxide of the tomatoes packaged in CT film, CS film, and control (without CT or CS films) were monitored during storage at 20 degrees C. Classification of fruit quality as a function of different packaging treatments was visualized using linear discriminant analysis. Tomatoes packaged in the CT film evolved lower quality changes than those in the CS film and control. The results suggested that the CT film exhibited ethylene photodegradation activity when exposed to UV light and consequently delayed the ripening process and changes in the quality of the tomatoes. PMID- 29410370 TI - Characterization of soluble soybean (SSPS) polysaccharide and development of eco friendly SSPS/TiO2 nanoparticle bionanocomposites. AB - This research aims to characterization of soluble soybean polysaccharide (SSPS) and development of a biodegradable SSPS nanocomposites prepared using various concentrations of TiO2 nanoparticles. 13C NMR suggested that backbone of SSPS is rhamnogalacturonan [1->4)-alpha-GalAp-(1/2)-alpha Rhap(1->]. Weight average molecular weight, number average molecular weight (Mn) and polydispersity index (PDI) of SSPS were found to be 2.54*106g/mol, 5.54*106g/mol, and 4.5, respectively. The intrinsic viscosity of SSPS (0.33) was lower than most of hydrocolloids. With increasing TiO2 concentration, the water solubility, moisture content and water-vapor permeability (WVP) of SSPS-based nanocomposite films decreased. TiO2 addition led to an increase in the melting temperature to a maximum of 132 degrees C for the SSPS nanocomposite with 5wt% TiO2. With increasing TiO2 concentrations from 5 to 15wt%, the melting temperature declined from 24 to 19 degrees C. There were no significant agglomerates when the TiO2 concentrations were increased to 5wt%; however, when the concentration reached 15wt%, agglomerations were observed. With addition of TiO2 nanoparticles, tensile strength increased but elongation at break decreased. SSPS-based nanocomposite films demonstrated a promising range of antimicrobial activity. The current research clearly introduces a new antimicrobial composite which is potentially useful to prevent and treat infections. PMID- 29410371 TI - Trans-venous embolization of a basal ganglia ruptured arteriovenous malformation with open surgical arterial control: A hybrid technique. AB - Treatment of ruptured deep-seated arteriovenous malformations is challenging and associated with elevated risks. This is due to the proximity or involvement of critical brain structures and the specifically fine and delicate angioarchitecture of these lesions, making both endovascular and surgical access technically complicated. We present the advantages of a true combined, open surgical and endovascular transvenous approach in a hybrid operating room. The technique may overcome in part the difficulties and may improve safety and risk related concerns. PMID- 29410372 TI - Addressing Ethical and Procedural Principles for Unrelated Allogeneic Hematopoietic Progenitor Cell Donation in a Changing Medical Environment. PMID- 29410374 TI - A novel combination of astilbin and low-dose methotrexate respectively targeting A2AAR and its ligand adenosine for the treatment of collagen-induced arthritis. AB - Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment with frequently serious adverse effects. Therefore, combination of low-dose MTX with other drugs is often used in clinic. In this study, we investigated the improvement of astilbin and low-dose MTX combination on collagen-induced arthritis in DBA/1J mice. Results showed that the clinic score, incidence rate, paw swelling, pathological changes of joints and rheumatoid factors were more alleviated in combination therapy than MTX or astilbin alone group. Elevated antibodies (IgG, IgG1, IgG2a, IgM and anti-collagen IgG) and pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, IFN-gamma and IL-17A) in serum were significantly inhibited, while anti-inflammatory cytokine, IL-10, was enhanced by combination therapy. Further studies indicated that combination therapy significantly decreased Th1 and Th17 cell differentiation and increased Treg cell differentiation. Mechanisms analysis demonstrated combination therapy greatly inhibited Con A-activated MAPK and inflammatory transcriptional signals. Moreover, MTX activated adenosine release and astilbin specifically up-regulated A2A adenosine receptor (A2AAR) expression simultaneously, which most probably contributed to the synergistic efficacy of combination therapy. ZM241385, a specific antagonist of A2AAR, greatly blocked the effects of combination therapy on T cell functions and downstream pathways. All these findings suggest that astilbin is a valuable candidate for low-dose MTX combined therapy in RA via increasing A2AAR/adenosine system and decreasing ERK/NFkappaB/STATs signals. PMID- 29410373 TI - Integration of Real-Time Intraoperative Contrast-Enhanced Ultrasound and Color Doppler Ultrasound in the Surgical Treatment of Spinal Cord Dural Arteriovenous Fistulas. AB - BACKGROUND: In the surgical treatment of spinal dural arteriovenous fistulas (DAVFs), intraoperative definition of anatomic characteristics of the DAVF and identification of the fistulous point is mandatory to effectively exclude the DAVF. CASE DESCRIPTION: Intraoperative ultrasound and contrast-enhanced ultrasound integrated with color Doppler ultrasound was applied in the surgical setting for a cervical DAVF to identify the fistulous point and evaluate correct occlusion of the fistula. CONCLUSIONS: Integration of intraoperative ultrasound and contrast-enhanced ultrasound is a simple, cost-effective technique that provides an opportunity for real-time dynamic visualization of DAVF vascular patterns, identification of the fistulous point, and assessment of correct exclusion. Compared with other intraoperative tools, such as indocyanine green videoangiography, it allows the surgeon to visualize hidden anatomic and vascular structures, minimizing surgical manipulation and guiding the surgeon during resection. PMID- 29410376 TI - Hemorrhagic Complications of Arachnoid Cysts: When, Why, and Who? PMID- 29410375 TI - Efficacy of Caudal Epidural Steroid Injection with Targeted Indwelling Catheter and Manipulation in Managing Patients with Lumbar Disk Herniation and Radiculopathy: A Prospective, Randomized, Single-Blind Controlled Trial. AB - BACKGROUND: Lumbar disk herniation (LDH) is considered a common cause of lumbosacral radiculopathy. Epidural steroid injection is a common method to treat inflammation associated with low back-related leg pain. Spinal manipulations are widely used, and systematic reviews have also shown that these manipulations are more effective than placebos. OBJECTIVE: Due to the absence of clinical evidence, we designed a prospective, randomized, single-blind controlled trial in patients with LDH with radiculopathy, aiming to detect the safety and clinical efficacy of targeted indwelling catheter combined with "4-step" manipulative therapy in patients with LDH. METHODS: Patient visits were performed at baseline and days 1, 3, 7, and 28 after treatment. Clinical outcomes were measured using visual analog scale for back and leg pain, Oswestry Disability Index (ODI), and clinical symptom scores of the Japanese Orthopedic Association (JAO). RESULTS: The study included 85 eligible patients. They were categorized with a randomization schedule into a Catheter Group (N = 43) and No-Catheter Group (N = 42). Between the measurement points, there was a statistically significant difference in the visual analog scale (back) at days 1, 3, and 7 of follow-up after treatment between the 2 groups. The change was statistically different at days 1 and 3, and a higher change was observed in the Catheter Group compared with the No-Catheter Group. There was a statistically significant difference in change of JOA and ODI scores at day 1 of follow-up after treatment between the 2 groups, and a greater change was seen in the Catheter Group at days 1 and 3 compared with the No Catheter Group. LIMITATIONS: The small sample size was small, and the follow-up time was short. The study also lacked documents of adjuvant therapies, like individual patient exercise routines and analgesic drug therapy. CONCLUSION: Both methods were effective in reducing pain intensity and functional disability compared with pretreatment. The Catheter Group showed a more significant decrease in visual analog scale and greater changes in JOA and ODI scores of short/term follow-up, compared with the No-Catheter Group. The therapy project was safe. PMID- 29410377 TI - Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatobiliary magnetic resonance imaging (MRI) provides additional information beyond the size and number of tumours, and may have prognostic implications. We examined whether pretransplant radiological features on MRI could be used to stratify the risk of tumour recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS: A total of 100 patients who had received a liver transplant and who had undergone preoperative gadoxetic acid-enhanced MRI, including the hepatobiliary phase (HBP), were reviewed for tumour size, number, and morphological type (e.g. nodular, nodular with perinodular extension, or confluent multinodular), satellite nodules, non smooth tumour margins, peritumoural enhancement in arterial phase, peritumoural hypointensity on HBP, and apparent diffusion coefficients. The primary endpoint was time to recurrence. RESULTS: In a multivariable adjusted model, the presence of satellite nodules [hazard ratio (HR) 3.07; 95% confidence interval (CI) 1.14 8.24] and peritumoural hypointensity on HBP (HR 4.53; 95% CI 1.52-13.4) were identified as independent factors associated with tumour recurrence. Having either of these radiological findings was associated with a higher tumour recurrence rate (72.5% vs. 15.4% at three years, p <0.001). When patients were stratified according to the Milan criteria, the presence of these two high-risk radiological findings was associated with a higher tumour recurrence rate in both patients transplanted within the Milan criteria (66.7% vs. 11.6% at three years, p <0.001, n = 68) and those who were transplanted outside the Milan criteria (75.5% vs. 28.6% at three years, p <0.001, n = 32). CONCLUSIONS: Radiological features on preoperative hepatobiliary MRI can stratify the risk of tumour recurrence in patients who were transplanted either within or outside the Milan criteria. Therefore, hepatobiliary MRI can be a useful way to select potential candidates for LT. LAY SUMMARY: High-risk radiological findings on preoperative hepatobiliary magnetic resonance imaging (either one of the following features: satellite nodule and peritumoural hypointensity on hepatobiliary phase) were associated with a higher tumour recurrence rate in patients transplanted either within or outside the Milan criteria. PMID- 29410378 TI - New insights into NAFLD and subclinical coronary atherosclerosis. PMID- 29410379 TI - Methicillin-Resistant Staphylococcus aureus Colonization Is Associated with Decreased Skin Commensal Bacteria in Atopic Dermatitis. PMID- 29410380 TI - One signal stimulates different transcriptional activation mechanisms. AB - Transcriptional activation is often represented as a "one-step process" that involves the simultaneous recruitment of co-activator proteins, leading to a change in gene status. Using Drosophila developmental ecdysone-dependent genes as a model, we demonstrated that activation of transcription is instead a continuous process that consists of a number of steps at which different phases of transcription (initiation or elongation) are stimulated. Thorough evaluation of the behaviour of multiple transcriptional complexes during the early activation process has shown that the pathways by which activation proceeds for different genes may vary considerably, even in response to the same induction signal. RNA polymerase II recruitment is an important step that is involved in one of the pathways. RNA polymerase II recruitment is accompanied by the recruitment of a significant number of transcriptional coactivators as well as slight changes in the chromatin structure. The second pathway involves the stimulation of transcriptional elongation as its key step. The level of coactivator binding to the promoter shows almost no increase, whereas chromatin modification levels change significantly. PMID- 29410381 TI - Optimal Timing and Recommended Route of Delivery after Hysteroscopic Management of Isthmocele? A Consensus Statement From the Global Congress on Hysteroscopy Scientific Committee. PMID- 29410382 TI - Long-term Air Pollution Exposure, Genome-wide DNA Methylation and Lung Function in the LifeLines Cohort Study. AB - BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5, fine particulate matter with aerodynamic diameter <=2.5 MUm; PM10, particulate matter with aerodynamic diameter <=10 MUm) and PM2.5absorbance, indicator of elemental carbon content (estimated with land-use regression models) with DNA methylation in whole blood (Illumina(r) HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA). RESULTS: Depending on the p-value threshold used, we found significant associations between NO2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p<1.19*10-7) or for 4,980 CpG sites (False Discovery Rate<0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure. CONCLUSIONS: Long-term NO2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO2-exposure-related respiratory disease. https://doi.org/10.1289/EHP2045. PMID- 29410384 TI - Ambient Air Pollution and Chronic Bronchitis in a Cohort of U.S. Women. AB - BACKGROUND: Limited evidence links air pollution exposure to chronic cough and sputum production. Few reports have investigated the association between long term exposure to air pollution and classically defined chronic bronchitis. OBJECTIVES: Our objective was to estimate the association between long-term exposure to particulate matter (diameter <10 MUm, PM10; <2.5MUm, PM2.5), nitrogen dioxide (NO2), and both incident and prevalent chronic bronchitis. METHODS: We estimated annual average PM2.5, PM10, and NO2 concentrations using a national land-use regression model with spatial smoothing at home addresses of participants in a prospective nationwide U.S. cohort study of sisters of women with breast cancer. Incident chronic bronchitis and prevalent chronic bronchitis, cough and phlegm, were assessed by questionnaires. RESULTS: Among 47,357 individuals with complete data, 1,383 had prevalent chronic bronchitis at baseline, and 647 incident cases occurred over 5.7-y average follow-up. No associations with incident chronic bronchitis were observed. Prevalent chronic bronchitis was associated with PM10 [adjusted odds ratio (aOR) per interquartile range (IQR) difference (5.8 MUg/m3)=1.07; 95% confidence interval (CI): 1.01, 1.13]. In never-smokers, PM2.5 was associated with prevalent chronic bronchitis (aOR=1.18 per IQR difference; 95% CI: 1.04, 1.34), and NO2 was associated with prevalent chronic bronchitis (aOR=1.10; 95% CI=1.01, 1.20), cough (aOR=1.10; 95% CI: 1.05, 1.16), and phlegm (aOR=1.07; 95% CI: 1.01, 1.14); interaction p-values (nonsmokers vs. smokers) <0.05. CONCLUSIONS: PM10 exposure was related to chronic bronchitis prevalence. Among never-smokers, PM2.5 and NO2 exposure was associated with chronic bronchitis and component symptoms. Results may have policy ramifications for PM10 regulation by providing evidence for respiratory health effects related to long-term PM10 exposure. https://doi.org/10.1289/EHP2199. PMID- 29410385 TI - Functional Magnetic Resonance Imaging Evaluation of Auricular Percutaneous Electrical Neural Field Stimulation for Fibromyalgia: Protocol for a Feasibility Study. AB - BACKGROUND: Fibromyalgia is a chronic pain state that includes widespread musculoskeletal pain, fatigue, psychiatric symptoms, cognitive and sleep disturbances, and multiple somatic symptoms. Current therapies are often insufficient or come with significant risks, and while there is an increasing demand for non-pharmacologic and especially non-opioid pain management such as that offered through complementary and alternative medicine therapies, there is currently insufficient evidence to recommend these therapies. Percutaneous electrical neural stimulation (PENS) is an evidence-based treatment option for pain conditions that involves electrical current stimulation through needles inserted into the skin. Percutaneous electrical neural field stimulation (PENFS) of the auricle is similar to PENS, but instead of targeting a single neurovascular bundle, PENFS stimulates the entire ear, covering all auricular branches of the cranial nerves, including the vagus nerve. The neural mechanisms of PENFS for fibromyalgia symptom relief are unknown. OBJECTIVE: We hypothesize that PENFS treatment will decrease functional brain connectivity between the default mode network (DMN) and right posterior insula in fibromyalgia patients. We expect that the decrease in functional connectivity between the DMN and insula will correlate with patient-reported analgesic improvements as indicated by the Defense and Veterans Pain Rating Scale (DVPRS) and will be anti-correlated with patient-reported analgesic medication consumption. Exploratory analyses will be performed for further hypothesis generation. METHODS: A total of 20 adults from the Atlanta Veterans Affairs Medical Center diagnosed with fibromyalgia will be randomized into 2 groups: 10 subjects to a control (standard therapy) group and 10 subjects to a PENFS treatment group. The pragmatic, standard therapy group will include pharmacologic treatments such as anticonvulsants, non-steroidal anti inflammatory drugs, topical agents and physical therapy individualized to patient comorbidities and preferences, prescribed by a pain management practitioner. The PENFS group will include the above therapies in addition to the PENFS treatments. The PENFS subject group will have the Neuro-Stim System placed on the ear for 5 days then removed and replaced once per week for 4 weeks. The primary outcome will be resting functional magnetic resonance imaging connectivity between DMN and insula, which will also be correlated with pain relief and functional improvements. This connectivity will be analyzed utilizing functional connectivity magnetic resonance imaging (fcMRI) and will be compared with patient reported analgesic improvements as indicated by the DVPRS and patient-reported analgesic medication consumption. Pain and function will be further evaluated using Patient-Reported Outcomes Measurement Information System measures and measures describing a person's functional status from Activity and Participation section of the International Classification of Functioning Disability and Health. RESULTS: This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017. CONCLUSIONS: This is a feasibility study that is meant to demonstrate the practicality of using fcMRI to study the neural correlates of PENFS outcomes and provide information regarding power calculations in order to design and execute a larger randomized controlled clinical trial to determine the efficacy of PENFS for improving pain and function. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008837; https://clinicaltrials.gov/ct2/show/NCT03008837 (Archived by WebCite at http://www.webcitation.org/6wrY3NmaQ). PMID- 29410383 TI - Concentrated Ambient PM2.5-Induced Inflammation and Endothelial Dysfunction in a Murine Model of Neural IKK2 Deficiency. AB - BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2/NF-kappaB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM2.5 (CAP). OBJECTIVES: In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM2.5. METHODS: We assessed inflammatory and vascular responses in Nestin-creIKK2flox/flox (IKK2Neu-KO) and littermate Nestin-creIKK2flox/+ (control) mice after 4 mo of exposure to filtered air (FA) or CAP. RESULTS: CAP exposure was associated with significantly higher tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2Neu-KO mice. In addition, CAP exposure-induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFalpha and IL-1beta levels, adipose macrophage infiltration and IL-1beta expression, and endothelial dysfunction were reduced or absent in IKK2Neu-KO mice compared with controls. CONCLUSIONS: Our findings support a role of neural IKK2 in CAP exposure-induced local and systemic pro inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM2.5 exposure. https://doi.org/10.1289/EHP2311. PMID- 29410386 TI - Patterns in Patient Access and Utilization of Online Medical Records: Analysis of MyChart. AB - BACKGROUND: Electronic patient portals provide a new method for sharing personal medical information with individual patients. OBJECTIVE: Our aim was to review utilization patterns of the largest online patient portal in Canada's largest city. METHODS: We conducted a 4-year time-trend analysis of aggregated anonymous utilization data of the MyChart patient portal at Sunnybrook Health Sciences Centre in Ontario, Canada, from January 1, 2012, through December 31, 2015. Prespecified analyses examined trends related to day (weekend vs weekday), season (July vs January), year (2012 vs 2015), and an extreme adverse weather event (ice storm of December 20-26, 2013). Primary endpoints included three measures of patient portal activity: registrations, logins, and pageviews. RESULTS: We identified 32,325 patients who registered for a MyChart account during the study interval. Time-trend analysis showed no sign of attenuating registrations over time. Logins were frequent, averaged 734 total per day, and showed an increasing trend over time. Pageviews mirrored logins, averaged about 3029 total per day, and equated to about 5 pageviews during the average login. The most popular pageviews were clinical notes, followed by laboratory results and medical imaging reports. All measures of patient activity were lower on weekends compared to weekdays (P<.001) yet showed no significant changes related to seasons or extreme weather. No major security breach, malware attack, or software failure occurred during the study. CONCLUSIONS: Online patient portals can provide a popular and reliable system for distributing personal medical information to active patients and may merit consideration for hospitals. PMID- 29410387 TI - Text-Based Program Addressing the Mental Health of Soon-to-be and New Fathers (SMS4dads): Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Recent estimates indicating that approximately 10% of fathers experience Paternal Perinatal Depression (PPND) and the increasing evidence of the impact of PPND on child development suggest that identifying and assisting distressed fathers is justified on public health grounds. However, addressing new fathers' mental health needs requires overcoming men's infrequent contact with perinatal health services and their reluctance to seek help. Text-based interventions delivering information and support have the potential to reach such groups in order to reduce the impact of paternal perinatal distress and to improve the wellbeing of their children. While programs utilising mobile phone technology have been developed for mothers, fathers have not been targeted. Since text messages can be delivered to individual mobile phones to be accessed at a time that is convenient, it may provide a novel channel for engaging with "hard to-reach" fathers in a critical period of their parenting. OBJECTIVE: The study will test the efficacy of SMS4dads, a text messaging program designed specifically for fathers including embedded links to online information and regular invitations (Mood Tracker) to monitor their mood, in order to reduce self reported depression, anxiety and stress over the perinatal period. METHODS: A total of 800 fathers-to-be or new fathers from within Australia will be recruited via the SMS4dads website and randomized to the intervention or control arm. The intervention arm will receive 14 texts per month addressing fathers' physical and mental health, their relationship with their child, and coparenting with their partner. The control, SMS4health, delivers generic health promotion messages twice per month. Messages are timed according to the babies' expected or actual date of birth and fathers can enroll from 16 weeks into the pregnancy until their infant is 12 weeks of age. Participants complete questionnaires assessing depression, anxiety, stress, and alcohol at baseline and 24 weeks postenrolment. Measures of coparenting and parenting confidence are also completed at baseline and 24 weeks for postbirth enrolments. RESULTS: Participant were recruited between October 2016 and September 2017. Follow-up data collection has commenced and will be completed in March 2018 with results expected in June 2018. CONCLUSIONS: This study's findings will assess the efficacy of a novel text-based program specifically targeting fathers in the perinatal period to improve their depression, anxiety and distress symptoms, coparenting quality, and parenting self-confidence. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000261415; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx?id=370085 (Archived by WebCite at http://www.webcitation.org/6wav55wII). PMID- 29410388 TI - Reducing Misses and Near Misses Related to Multitasking on the Electronic Health Record: Observational Study and Qualitative Analysis. AB - BACKGROUND: Clinicians' use of electronic health record (EHR) systems while multitasking may increase the risk of making errors, but silent EHR system use may lower patient satisfaction. Delaying EHR system use until after patient visits may increase clinicians' EHR workload, stress, and burnout. OBJECTIVE: We aimed to describe the perspectives of clinicians, educators, administrators, and researchers about misses and near misses that they felt were related to clinician multitasking while using EHR systems. METHODS: This observational study was a thematic analysis of perspectives elicited from 63 continuing medical education (CME) participants during 2 workshops and 1 interactive lecture about challenges and strategies for relationship-centered communication during clinician EHR system use. The workshop elicited reflection about memorable times when multitasking EHR use was associated with "misses" (errors that were not caught at the time) or "near misses" (mistakes that were caught before leading to errors). We conducted qualitative analysis using an editing analysis style to identify codes and then select representative themes and quotes. RESULTS: All workshop participants shared stories of misses or near misses in EHR system ordering and documentation or patient-clinician communication, wondering about "misses we don't even know about." Risk factors included the computer's position, EHR system usability, note content and style, information overload, problematic workflows, systems issues, and provider and patient communication behaviors and expectations. Strategies to reduce multitasking EHR system misses included clinician transparency when needing silent EHR system use (eg, for prescribing), narrating EHR system use, patient activation during EHR system use, adapting visit organization and workflow, improving EHR system design, and improving team support and systems. CONCLUSIONS: CME participants shared numerous stories of errors and near misses in EHR tasks and communication that they felt related to EHR multitasking. However, they brainstormed diverse strategies for using EHR systems safely while preserving patient relationships. PMID- 29410389 TI - Estrogen regulates muscle bioenergetic signaling. PMID- 29410390 TI - Genes associated with Type 2 Diabetes and vascular complications. AB - Type 2 Diabetes (T2D) is a chronic disease associated with a number of micro- and macrovascular complications that increase the morbidity and mortality of patients. The risk of diabetic complications has a strong genetic component. To this end, we sought to evaluate the association of 40 single nucleotide polymorphisms (SNPs) in 21 candidate genes with T2D and its vascular complications in 503 T2D patients and 580 healthy controls. The genes were chosen because previously reported to be associated with T2D complications and/or with the aging process. We replicated the association of T2D risk with IGF2BP rs4402960 and detected novel associations with TERT rs2735940 and rs2736098. The addition of these SNPs to a model including traditional risk factors slightly improved risk prediction. After stratification of patients according to the presence/absence of vascular complications, we found significant associations of variants in the CAT, FTO, and UCP1 genes with diabetic retinopathy and nephropathy. Additionally, a variant in the ADIPOQ gene was found associated with macrovascular complications. Notably, these genes are involved in some way in mitochondrial biology and reactive oxygen species regulation. Hence, our findings strongly suggest a potential link between mitochondrial oxidative homeostasis and individual predisposition to diabetic vascular complications. PMID- 29410391 TI - The role of autophagy during murine primordial follicle assembly. AB - It is generally accepted that significant germ cell loss occurs during the establishment of the primordial follicle pool in most mammalian ovaries around the time of birth. However, the underlying mechanisms responsible for these processes remain largely unknown. In this investigation, we explored the role of autophagy during the establishment of the primordial follicle pool and found that autophagy was active in this process. Our data suggested that 17.5 dpc ovaries treated with rapamycin displayed a delay in germ cell cyst breakdown resulting in more oocytes at day 5 of treatment, while, ovaries that treated with 3-MA showed the opposite effect. We found that rapamycin treatment promoted autophagy and depressed cell apoptosis increasing the number of NOBOX positive oocytes. Furthermore, our results also revealed that epigenetic regulator, Sirt1, plays a role in germ cell loss. An epigenetic inhibitor or RNAi treatment of Sirt1, showed an increased level of H4K16ac and a decreased level of autophagy. Thus, these data indicate that autophagy prevents germ cell over loss during the establishment of primordial follicle pool, and this process may be influenced by Sirt1-invovled epigenetic regulation. PMID- 29410392 TI - Mammalian oogenesis and female reproductive aging. PMID- 29410393 TI - Intentional Modulation of Portal Venous Pressure by Splenectomy Saves the Patient with Liver Failure and Portal Hypertension After Major Hepatectomy: Is Delayed Splenectomy an Acceptable Therapeutic Option for Secondary Portal Hypertension? AB - BACKGROUND Major or aggressively-extended hepatectomy (MAEH) may cause secondary portal hypertension (PH), and postoperative liver failure (POLF) and is often fatal. Challenges to prevent secondary PH and subsequent POLF, such as shunt creation and splenic arterial ligation, have been reported. However, these procedures have been performed simultaneously only during the initial MAEH. CASE REPORT A 58-year-old female with chronic hepatitis C developed a solitary hepatic cellular carcinoma with portal tumor thrombosis. Blood examination and imaging revealed a decreased platelet count and splenomegaly. Her liver viability was preserved, and collaterals did not develop, and her tumor thrombosis forced us to perform a right hepatectomy from an oncological standpoint. The estimated volume of her liver remnant was 51.8%. A large volume of ascites and pleural effusion were observed on post-operative day (POD) 3, and ascetic infection occurred on POD 14. Hepatic encephalopathy was observed on POD 16. According to the post operative development of collaterals due to secondary PH, submucosal bleeding in the stomach occurred on POD 37. Though it is unclear whether delayed portal venous pressure (PVP) modulation after MAEH is effective, a therapeutic strategy for recovery from POLF may involve PVP modulation to resolve intractable PH. We performed a splenectomy on POD 41 to reduce PVP. The initial PVP value was 32 mm Hg, and splenectomy decreased PVP to 23 mm Hg. Thereafter, she had a complete recovery from POLF. CONCLUSIONS Our thought-provoking case is the first successfully-treated case of secondary PH and POLF after MAEH, achieved by delayed splenectomy for PVP modulation. PMID- 29410394 TI - Silencing Ras-Related C3 Botulinum Toxin Substrate 1 Inhibits Growth and Migration of Hypopharyngeal Squamous Cell Carcinoma via the P38 Mitogen-Activated Protein Kinase Signaling Pathway. AB - BACKGROUND Ras-related C3 botulinum toxin substrate 1 (Rac1) is implicated in a variety of cellular functions and is related to tumor growth and metastasis. This study aimed to explore the role of Rac1 in hypopharyngeal squamous cell carcinoma (HSCC). MATERIAL AND METHODS The Rac1 expression in HSCC tissues was determined by quantitative real-time polymerase chain reaction and Western blot analysis. The level of Rac1 in HSCC cells was downregulated by a Rac1-specific shRNA. Then, the growth and metastasis of HSCC cells were assessed in vitro by 3-(4,5-dimethyl 2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, Hoechst staining, and Transwell assay. Moreover, cells transfected with Rac1 shRNA or negative control were injected subcutaneously into the right axilla of mice, and then the effects of Rac1 silencing on the growth of HSCC were also explored in vivo. Additionally, activation of the P38 mitogen-activated protein kinase (MAPK) signaling pathway was assessed by Western blot. RESULTS Rac1 was highly expressed in HSCC tissues. Silencing Rac1 inhibited the proliferation and cell cycle progress of HSCC cells, and induced their apoptosis. Rac1 silencing also suppressed the migration and invasion of HSCC cells. In vivo study showed that silencing Rac1 suppressed the growth of tumor bodies. Moreover, the P38 MAPK signaling pathway was implicated in the tumor-suppressing effect of Rac1 silencing in vitro and in vivo. CONCLUSIONS Silencing Rac1 suppressed the growth and migration of HSCC through the P38 MAPK signaling pathway. Due to its contribution in HSCC, Rac1 has the potential to become a promising antitumor therapeutic target for HSCC. PMID- 29410395 TI - Two reassortant types of highly pathogenic H5N8 avian influenza virus from wild birds in Central China in 2016. AB - Since 2016, the highly pathogenic avian influenza H5N8 virus has emerged in the Central Asian flyway and Europe, causing massive deaths in poultry and wild birds. In this study, we isolated and identified three H5N8 viruses from swan goose and black swans in Hubei province during the 2016/2017 winter season. Whole genome sequencing and phylogenetic analysis revealed that the three viruses clustered into a group of H5N8 viruses from Qinghai Lake and Europe. A novel reassortment virus from swan goose was distinguished from that of black swans, in that its PA and NP genes were distinct from those of Qinghai Lake viruses. Molecular dating revealed that the ancestral strain of these H5N8 viruses emerged around July 2015. From sequence comparison, we discovered eight amino acid substitutions in HA and NA during the adaption process from poultry to wild birds. The three viruses were isolated from wild birds in the East Asian Australasian flyway; however, the viral genomes were similar to H5N8 viruses circulating along the Central Asian flyway. From these data, we conclude that wetlands and lakes in Central China may play a key role in disseminating H5N8 viruses between the East Asian-Australasian and Central Asian flyways. PMID- 29410397 TI - Tackling imported tropical diseases in China. PMID- 29410396 TI - Notch1 is a prognostic factor that is distinctly activated in the classical and proneural subtype of glioblastoma and that promotes glioma cell survival via the NF-kappaB(p65) pathway. AB - Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and have extensive heterogeneity. Notch1 signaling is a more complex process in the development of numerous cell and tissue types, including gliomagenesis and progression, and is upregulated in glioma-initiating cells. However, the contradictory expression of Notch1 among lower grade gliomas and GBMs confounds our understanding of GBM biology and has made identifying effective therapies difficult. In this study, we validated that Notch1 and NF kappaB(p65) are highly expressed in the classical and proneural subtypes of GBM using the data set from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). DAPT and shRNA targeting Notch1 decreased NF-kappaB(p65) expression, suppressed cell proliferation, and induced apoptosis of GBM cells in vitro and in vivo. Furthermore, we illustrated that the intracellular Notch could bind with NF-kappaB(p65) in GBM cells. These findings suggest that the cross-talk between Notch1 signaling and NF-kappaB(p65) could contribute to the proliferation and apoptosis of glioma, and this discovery could help drive the design of more effective therapies in Notch1-targeted clinical trials. PMID- 29410398 TI - Evidence of a one-dimensional thermodynamic phase diagram for simple glass formers. AB - Glass formers show motional processes over an extremely broad range of timescales, covering more than ten orders of magnitude, meaning that a full understanding of the glass transition needs to comprise this tremendous range in timescales. Here we report simultaneous dielectric and neutron spectroscopy investigations of three glass-forming liquids, probing in a single experiment the full range of dynamics. For two van der Waals liquids, we locate in the pressure temperature phase diagram lines of identical dynamics of the molecules on both second and picosecond timescales. This confirms predictions of the isomorph theory and effectively reduces the phase diagram from two to one dimension. The implication is that dynamics on widely different timescales are governed by the same underlying mechanisms. PMID- 29410399 TI - Selective control of fcc and hcp crystal structures in Au-Ru solid-solution alloy nanoparticles. AB - Binary solid-solution alloys generally adopt one of three principal crystal lattices-body-centred cubic (bcc), hexagonal close-packed (hcp) or face-centred cubic (fcc) structures-in which the structure is dominated by constituent elements and compositions. Therefore, it is a significant challenge to selectively control the crystal structure in alloys with a certain composition. Here, we propose an approach for the selective control of the crystal structure in solid-solution alloys by using a chemical reduction method. By precisely tuning the reduction speed of the metal precursors, we selectively control the crystal structure of alloy nanoparticles, and are able to selectively synthesize fcc and hcp AuRu3 alloy nanoparticles at ambient conditions. This approach enables us to design alloy nanomaterials with the desired crystal structures to create innovative chemical and physical properties. PMID- 29410400 TI - Biochemical mechanisms determine the functional compatibility of heterologous genes. AB - Elucidating the factors governing the functional compatibility of horizontally transferred genes is important to understand bacterial evolution, including the emergence and spread of antibiotic resistance, and to successfully engineer biological systems. In silico efforts and work using single-gene libraries have suggested that sequence composition is a strong barrier for the successful integration of heterologous genes. Here we sample 200 diverse genes, representing >80% of sequenced antibiotic resistance genes, to interrogate the factors governing genetic compatibility in new hosts. In contrast to previous work, we find that GC content, codon usage, and mRNA-folding energy are of minor importance for the compatibility of mechanistically diverse gene products at moderate expression. Instead, we identify the phylogenetic origin, and the dependence of a resistance mechanism on host physiology, as major factors governing the functionality and fitness of antibiotic resistance genes. These findings emphasize the importance of biochemical mechanism for heterologous gene compatibility, and suggest physiological constraints as a pivotal feature orienting the evolution of antibiotic resistance. PMID- 29410401 TI - Ub-ProT reveals global length and composition of protein ubiquitylation in cells. AB - Protein ubiquitylation regulates diverse cellular processes via distinct ubiquitin chains that differ by linkage type and length. However, a comprehensive method for measuring these properties has not been developed. Here we describe a method for assessing the length of substrate-attached polyubiquitin chains, "ubiquitin chain protection from trypsinization (Ub-ProT)." Using Ub-ProT, we found that most ubiquitylated substrates in yeast-soluble lysate are attached to chains of up to seven ubiquitin molecules. Inactivation of the ubiquitin selective chaperone Cdc48 caused a dramatic increase in chain lengths on substrate proteins, suggesting that Cdc48 complex terminates chain elongation by substrate extraction. In mammalian cells, we found that ligand-activated epidermal growth factor receptor (EGFR) is rapidly modified with K63-linked tetra to hexa-ubiquitin chains following EGF treatment in human cells. Thus, the Ub ProT method can contribute to our understanding of mechanisms regulating physiological ubiquitin chain lengths and composition. PMID- 29410402 TI - Genomic analysis of a large set of currently-and historically-important human adenovirus pathogens. AB - Human adenoviruses (HAdVs) are uniquely important "model organisms" as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to "one-time" appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population. PMID- 29410403 TI - Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo. AB - Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. In the present study, we investigated the anticancer effect of honokiol (HNK), an active component isolated and purified from the magnolia officinalis on human osteosarcoma cells. Our results showed that honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells. The types of cell death induced by honokiol were primarily autophagy and apoptosis. Furthermore, honokiol induced G0/G1 phase arrest, elevated the levels of glucose-regulated protein (GRP)-78, an endoplasmic reticular stress (ERS)-associated protein, and increased the production of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Furthermore, pretreatment of osteosarcoma cells with PD98059, an inhibitor of ERK1/2, inhibited honokiol induced apoptosis and autophagy. Finally, honokiol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that honokiol caused G0/G1 phase arrest, induced apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells. Honokiol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma. PMID- 29410404 TI - A microengineered vascularized bleeding model that integrates the principal components of hemostasis. AB - Hemostasis encompasses an ensemble of interactions among platelets, coagulation factors, blood cells, endothelium, and hemodynamic forces, but current assays assess only isolated aspects of this complex process. Accordingly, here we develop a comprehensive in vitro mechanical injury bleeding model comprising an "endothelialized" microfluidic system coupled with a microengineered pneumatic valve that induces a vascular "injury". With perfusion of whole blood, hemostatic plug formation is visualized and "in vitro bleeding time" is measured. We investigate the interaction of different components of hemostasis, gaining insight into several unresolved hematologic issues. Specifically, we visualize and quantitatively demonstrate: the effect of anti-platelet agent on clot contraction and hemostatic plug formation, that von Willebrand factor is essential for hemostasis at high shear, that hemophilia A blood confers unstable hemostatic plug formation and altered fibrin architecture, and the importance of endothelial phosphatidylserine in hemostasis. These results establish the versatility and clinical utility of our microfluidic bleeding model. PMID- 29410405 TI - Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. AB - Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo 2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3. PMID- 29410406 TI - Cryo-EM structure of 5-HT3A receptor in its resting conformation. AB - Serotonin receptors (5-HT3AR) directly regulate gut movement, and drugs that inhibit 5-HT3AR function are used to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. The 5-HT3AR function involves a finely tuned orchestration of three domain movements that include the ligand binding domain, the pore domain, and the intracellular domain. Here, we present the structure from the full-length 5-HT3AR channel in the apo-state determined by single-particle cryo-electron microscopy at a nominal resolution of 4.3 A. In this conformation, the ligand-binding domain adopts a conformation reminiscent of the unliganded state with the pore domain captured in a closed conformation. In comparison to the 5-HT3AR crystal structure, the full-length channel in the apo conformation adopts a more expanded conformation of all the three domains with a characteristic twist that is implicated in gating. PMID- 29410407 TI - Differential Impact of Interference on Internally- and Externally-Directed Attention. AB - Attention can be oriented externally to the environment or internally to the mind, and can be derailed by interference from irrelevant information originating from either external or internal sources. However, few studies have explored the nature and underlying mechanisms of the interaction between different attentional orientations and different sources of interference. We investigated how externally- and internally-directed attention was impacted by external distraction, how this modulated internal distraction, and whether these interactions were affected by healthy aging. Healthy younger and older adults performed both an externally-oriented visual detection task and an internally oriented mental rotation task, performed with and without auditory sound delivered through headphones. We found that the addition of auditory sound induced a significant decrease in task performance in both younger and older adults on the visual discrimination task, and this was accompanied by a shift in the type of distractions reported (from internal to external). On the internally oriented task, auditory sound only affected performance in older adults. These results suggest that the impact of external distractions differentially impacts performance on tasks with internal, as opposed to external, attentional orientations. Further, internal distractibility is affected by the presence of external sound and increased suppression of internal distraction. PMID- 29410409 TI - Exosome-Mimetic Nanovesicles from Hepatocytes promote hepatocyte proliferation in vitro and liver regeneration in vivo. AB - The liver has great regenerative capacity after functional mass loss caused by injury or disease. Many studies have shown that primary hepatocyte-derived exosomes, which can deliver biological information between cells, promote the regenerative process of the liver. However, the yield of exosomes is very limited. Recent studies have demonstrated that exosome-mimetic nanovesicles (NVs) can be prepared from cells with almost 100 times the production yield compared with exosomes. Thus, this study investigated the therapeutic capacity of exosome mimetic NVs from primary hepatocytes in liver regeneration. Exosome-mimetic NVs were prepared by serial extrusions of cells through polycarbonate membranes, and the yield of these NVs was more than 100 times that of exosomes. The data indicated that the NVs could promote hepatocyte proliferation and liver regeneration by significantly enhancing the content of sphingosine kinase 2 in recipient cells. To the best of our knowledge, this is the first time that exosome-mimetic NVs from primary hepatocytes have been prepared, and these NVs have components similar to exosomes from primary hepatocytes and, in some respects, biofunctions similar to exosomes. Strategies inspired by this study may lead to substitution of exosomes with exosome-mimetic NVs for biofunctional purposes, including utilization in tissue repair and regeneration. PMID- 29410408 TI - A chiral selectivity relaxed paralog of DTD for proofreading tRNA mischarging in Animalia. AB - D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes D-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNAAla. An invariant cross-subunit Gly-cisPro motif forms the mechanistic basis of L-amino acid rejection from the catalytic site. Here, we present the identification of a DTD variant, named ATD (Animalia-specific tRNA deacylase), that harbors a Gly-transPro motif. The cis-to-trans switch causes a "gain of function" through L-chiral selectivity in ATD resulting in the clearing of L alanine mischarged on tRNAThr(G4*U69) by eukaryotic AlaRS. The proofreading activity of ATD is conserved across diverse classes of phylum Chordata. Animalia genomes enriched in tRNAThr(G4*U69) genes are in strict association with the presence of ATD, underlining the mandatory requirement of a dedicated factor to proofread tRNA misaminoacylation. The study highlights the emergence of ATD during genome expansion as a key event associated with the evolution of Animalia. PMID- 29410411 TI - Amorphous martensite in beta-Ti alloys. AB - Martensitic transformations originate from a rigidity instability, which causes a crystal to change its lattice in a displacive manner. Here, we report that the martensitic transformation on cooling in Ti-Zr-Cu-Fe alloys yields an amorphous phase instead. Metastable beta-Ti partially transforms into an intragranular amorphous phase due to local lattice shear and distortion. The lenticular amorphous plates, which very much resemble alpha'/alpha" martensite in conventional Ti alloys, have a well-defined orientation relationship with the surrounding beta-Ti crystal. The present solid-state amorphization process is reversible, largely cooling rate independent and constitutes a rare case of congruent inverse melting. The observed combination of elastic softening and local lattice shear, thus, is the unifying mechanism underlying both martensitic transformations and catastrophic (inverse) melting. Not only do we reveal an alternative mechanism for solid-state amorphization but also establish an explicit experimental link between martensitic transformations and catastrophic melting. PMID- 29410410 TI - The reunion of two lineages of the Neotropical brown stink bug on soybean lands in the heart of Brazil. AB - The rapid pace of conversion of natural areas to agricultural systems is highly concerning, and the consequences for conservation and pest management are not yet fully understood. We examined mitochondrial (COI and Cytb) and nuclear (ITS1) gene regions of 21 populations of the stink bug Euschistus heros, to investigate the genetic diversity, genetic structure, and demographic history of this emerging soybean pest in South America. Two deep lineages that diverged in the Pliocene (4.5 Myr) occur over wide areas of Brazil. Historical changes during the Plio-Pleistocene led to significant genetic differences between E. heros populations, which differentiated further in several biomes. The northern lineage is older, more diverse, and prevalent in the Amazon and Caatinga, while the southern lineage is younger, less diverse, and prevalent in the Atlantic Forest and Chaco biomes. Euschistus heros populations are expanding in size and range but at different rates, strongly affected by environmental variables. Secondary contact between the main lineages is now occurring, mainly in areas of intensive farming and particularly in the Cerrado, an important agricultural frontier. Individuals adapted to different environmental conditions and to large monocultures might currently be combining into a panmictic and hard-to-control pest population. PMID- 29410412 TI - Bacterial capture efficiency in fluid bloodstream improved by bendable nanowires. AB - Bacterial infectious diseases, such as sepsis, can lead to impaired function in the lungs, kidneys, and other vital organs. Although established technologies have been designed for the extracorporeal removal of bacteria, a high flow velocity of the true bloodstream might result in low capture efficiency and prevent the realization of their full clinical potential. Here, we develop a dialyzer made by three-dimensional carbon foam pre-grafted with nanowires to isolate bacteria from unprocessed blood. The tip region of polycrystalline nanowires is bent readily to form three-dimensional nanoclaws when dragged by the molecular force of ligand-receptor, because of a decreasing Young's moduli from the bottom to the tip. The bacterial capture efficiency was improved from ~10% on carbon foam and ~40% on unbendable single-crystalline nanowires/carbon foam to 97% on bendable polycrystalline nanowires/carbon foam in a fluid bloodstream of 10 cm s-1 velocity. PMID- 29410413 TI - Crystal structure reveals vaccine elicited bactericidal human antibody targeting a conserved epitope on meningococcal fHbp. AB - Data obtained recently in the United Kingdom following a nationwide infant immunization program against serogroup B Neisseria meningitidis (MenB) reported >80% 4CMenB vaccine-mediated protection. Factor H-binding protein (fHbp) is a meningococcal virulence factor and a component of two new MenB vaccines. Here, we investigated the structural bases underlying the fHbp-dependent protective antibody response in humans, which might inform future antigen design efforts. We present the co-crystal structure of a human antibody Fab targeting fHbp. The vaccine-elicited Fab 1A12 is cross-reactive and targets an epitope highly conserved across the repertoire of three naturally occurring fHbp variants. The free Fab structure highlights conformational rearrangements occurring upon antigen binding. Importantly, 1A12 is bactericidal against MenB strains expressing fHbp from all three variants. Our results reveal important immunological features potentially contributing to the broad protection conferred by fHbp vaccination. Our studies fuel the rationale of presenting conserved protein epitopes when developing broadly protective vaccines. PMID- 29410415 TI - Selenide-catalyzed enantioselective synthesis of trifluoromethylthiolated tetrahydronaphthalenes by merging desymmetrization and trifluoromethylthiolation. AB - Trifluoromethylthiolated molecules are an important class of biologically active compounds and potential drug candidates. Because of the lack of efficient synthetic methods, catalytic enantioselective construction of these molecules is rare and remains a challenge. To expand this field, we herein disclose a bifunctional selenide-catalyzed approach for the synthesis of various chiral trifluoromethylthiolated tetrahydronaphthalenes bearing an all-carbon quaternary stereocenter with gem-diaryl-tethered alkenes and alkynes by merging desymmetrization and trifluoromethylthiolation strategy. The products are obtained in high yields with excellent enantio- and diastereo-selectivities. This method can be applied to the desymmetrization and sulfenylation of diols as well. Computational studies reveal that selenide can activate the electrophilic reagent better than sulfide, confirming the higher efficiency of selenide catalysis in these reactions. On the basis of the theoretical calculations, an acid-derived anion-binding interaction is suggested to exist in the whole pathway and accounts for the observed high selectivities. PMID- 29410414 TI - Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. AB - Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction. PMID- 29410416 TI - Broad and long-lasting immune protection against various Chikungunya genotypes demonstrated by participants in a cross-sectional study in a Cambodian rural community. AB - Chikungunya virus (CHIKV) is an alphavirus circulating worldwide. Its presence in Asia has been reported since the 1950s, constituting the Asian genotype. Since 2005, strains from the Eastern, Central, and Southern African (ECSA) genotype have caused several outbreaks across Asia. Viruses from the ECSA genotype were also detected in Cambodia in late 2011 and led to an outbreak in a rural community in 2012. A former investigation from 2012 found a higher risk of infection in people younger than 40 years, suggesting a pre-existing herd immunity in the older Cambodian population due to infection with an Asian genotype. In 2016, we collected serum from equivalent numbers of individuals born before 1975 and born after 1980 that were also part of the 2012 study. We analyzed the 154 serum samples from 2016 for neutralization against the Cambodian ECSA isolate and three strains belonging to the Asian genotype. This experiment revealed that 22.5% (18/80) of the younger study participants had no CHIKV antibodies, whereas 5.4% (4/74) of the older population remained naive. Study participants infected during the ECSA outbreak had twofold neutralizing titers against the ECSA and the most ancient Asian genotype virus (Thailand 1958) compared to the other two Asian genotype viruses. The neutralization data also support the older population's exposure to an Asian genotype virus during the 1960s. The observed cross-reactivity confirms that the investigated CHIKV strains belong to a single serotype despite the emergence of novel ECSA genotype viruses and supports the importance of the development of a Chikungunya vaccine. PMID- 29410417 TI - Ultrafast current imaging by Bayesian inversion. AB - Spectroscopic measurements of current-voltage curves in scanning probe microscopy is the earliest and one of the most common methods for characterizing local energy-dependent electronic properties, providing insight into superconductive, semiconductor, and memristive behaviors. However, the quasistatic nature of these measurements renders them extremely slow. Here, we demonstrate a fundamentally new approach for dynamic spectroscopic current imaging via full information capture and Bayesian inference. This general-mode I-V method allows three orders of magnitude faster measurement rates than presently possible. The technique is demonstrated by acquiring I-V curves in ferroelectric nanocapacitors, yielding >100,000 I-V curves in <20 min. This allows detection of switching currents in the nanoscale capacitors, as well as determination of the dielectric constant. These experiments show the potential for the use of full information capture and Bayesian inference toward extracting physics from rapid I-V measurements, and can be used for transport measurements in both atomic force and scanning tunneling microscopy. PMID- 29410418 TI - Samarium hexaboride is a trivial surface conductor. AB - SmB6 is predicted to be the first member of the intersection of topological insulators and Kondo insulators, strongly correlated materials in which the Fermi level lies in the gap of a many-body resonance that forms by hybridization between localized and itinerant states. While robust, surface-only conductivity at low temperature and the observation of surface states at the expected high symmetry points appear to confirm this prediction, we find both surface states at the (100) surface to be topologically trivial. We find the [Formula: see text] state to appear Rashba split and explain the prominent [Formula: see text] state by a surface shift of the many-body resonance. We propose that the latter mechanism, which applies to several crystal terminations, can explain the unusual surface conductivity. While additional, as yet unobserved topological surface states cannot be excluded, our results show that a firm connection between the two material classes is still outstanding. PMID- 29410420 TI - Novel non-periodic spoof surface plasmon polaritons with H-shaped cells and its application to high selectivity wideband bandpass filter. AB - In this paper, one kind of novel non-periodic spoof surface plasmon polaritons (SSPPs) with H-shaped cells is proposed. As we all know, the cutoff frequency exists inherently for the conventional comb-shaped SSPPs, which is a kind of periodic groove shape structures and fed by a conventional coplanar waveguide (CPW). In this work, instead of increasing the depth of all the grooves, two H shaped cells are introduced to effectively reduce the cutoff frequency of the conventional comb-shaped SSPPs (about 12 GHz) for compact design. More importantly, the guide waves can be gradually transformed to SSPP waves with high efficiency, and better impedance matching from 50 Omega to the novel SSPP strip is achieved. Based on the proposed non-periodic SSPPs with H-shaped cells, a wideband bandpass filter (the 3-dB fractional bandwidths 68%) is realized by integrating the spiral-shaped defected ground structure (DGS) etched on CPW. Specifically, the filter shows high passband selectivity (Deltaf3 dB/Deltaf20 dB = 0.91) and wide upper stopband with -20 dB rejection. A prototype is fabricated for demonstration. Good agreements can be observed between the measured and simulated results, indicating potential applications in the integrated plasmonic devices and circuits at microwave and even THz frequencies. PMID- 29410419 TI - Methane utilization in Methylomicrobium alcaliphilum 20ZR: a systems approach. AB - Biological methane utilization, one of the main sinks of the greenhouse gas in nature, represents an attractive platform for production of fuels and value-added chemicals. Despite the progress made in our understanding of the individual parts of methane utilization, our knowledge of how the whole-cell metabolic network is organized and coordinated is limited. Attractive growth and methane-conversion rates, a complete and expert-annotated genome sequence, as well as large enzymatic, 13C-labeling, and transcriptomic datasets make Methylomicrobium alcaliphilum 20ZR an exceptional model system for investigating methane utilization networks. Here we present a comprehensive metabolic framework of methane and methanol utilization in M. alcaliphilum 20ZR. A set of novel metabolic reactions governing carbon distribution across central pathways in methanotrophic bacteria was predicted by in-silico simulations and confirmed by global non-targeted metabolomics and enzymatic evidences. Our data highlight the importance of substitution of ATP-linked steps with PPi-dependent reactions and support the presence of a carbon shunt from acetyl-CoA to the pentose-phosphate pathway and highly branched TCA cycle. The diverged TCA reactions promote balance between anabolic reactions and redox demands. The computational framework of C1 metabolism in methanotrophic bacteria can represent an efficient tool for metabolic engineering or ecosystem modeling. PMID- 29410421 TI - Distractor displacements during saccades are reflected in the time-course of saccade curvature. AB - Every time we make a saccade we form a prediction about where objects are going to be when the eye lands. This is crucial since the oculomotor system is retinotopically organized and every saccade drastically changes the projection of objects on the retina. We investigated how quickly the oculomotor system accommodates new spatial information when a distractor is displaced during a saccade. Participants performed sequences of horizontal and vertical saccades and oculomotor competition was induced by presenting a task-irrelevant distractor before the first saccade. On half of the trials the distractor remained in the same location after the first saccade and on the other half the distractor moved during the first saccade. Curvature of the second saccade was used to track target-distractor competition. At short intersaccadic intervals, saccades curved away from the original distractor location, confirming that in the oculomotor system spatiotopic representations emerge rapidly and automatically. Approximately 190 ms after the first saccade, second saccades curved away from the new distractor location. These results show that after a saccade the oculomotor system is initially driven by the spatial prediction made before the saccade, but it is able to quickly update these spatial predictions based on new visual information. PMID- 29410423 TI - Double blind microarray-based polysaccharide profiling enables parallel identification of uncharacterized polysaccharides and carbohydrate-binding proteins with unknown specificities. AB - Marine algae are one of the largest sources of carbon on the planet. The microbial degradation of algal polysaccharides to their constitutive sugars is a cornerstone in the global carbon cycle in oceans. Marine polysaccharides are highly complex and heterogeneous, and poorly understood. This is also true for marine microbial proteins that specifically degrade these substrates and when characterized, they are frequently ascribed to new protein families. Marine (meta)genomic datasets contain large numbers of genes with functions putatively assigned to carbohydrate processing, but for which empirical biochemical activity is lacking. There is a paucity of knowledge on both sides of this protein/carbohydrate relationship. Addressing this 'double blind' problem requires high throughput strategies that allow large scale screening of protein activities, and polysaccharide occurrence. Glycan microarrays, in particular the Comprehensive Microarray Polymer Profiling (CoMPP) method, are powerful in screening large collections of glycans and we described the integration of this technology to a medium throughput protein expression system focused on marine genes. This methodology (Double Blind CoMPP or DB-CoMPP) enables us to characterize novel polysaccharide-binding proteins and to relate their ligands to algal clades. This data further indicate the potential of the DB-CoMPP technique to accommodate samples of all biological sources. PMID- 29410422 TI - A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. AB - Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand targeted anti-integrin therapy to prevent inflammatory conditions. PMID- 29410424 TI - B-site ordering and strain-induced phase transition in double-perovskite La2NiMnO6 films. AB - The magnetic and electrical properties of complex oxide thin films are closely related to the phase stability and cation ordering, which demands that we understand the process-structure-property relationships microscopically in functional materials research. Here we study multiferroic thin films of double perovskite La2NiMnO6 epitaxially grown on SrTiO3, KTaO3, LaAlO3 and DyScO3 substrates by pulsed laser deposition. The effect of epitaxial strains imposed by the substrate on the microstructural properties of La2NiMnO6 has been systematically investigated by means of advanced electron microscopy. It is found that La2NiMnO6 films under tensile strain exhibit a monoclinic structure, while under compressive strain the crystal structure of La2NiMnO6 films is rhombohedral. In addition, by optimizing the film deposition conditions a long range ordering of B-site cations in La2NiMnO6 films has been obtained in both monoclinic and rhombohedral phases. Our results not only provide a strategy for tailoring phase stability by strain engineering, but also shed light on tuning B site ordering by controlling film growth temperature in double-perovskite La2NiMnO6 films. PMID- 29410425 TI - Lymphocyte-specific protein 1 regulates mechanosensory oscillation of podosomes and actin isoform-based actomyosin symmetry breaking. AB - Subcellular fine-tuning of the actomyosin cytoskeleton is a prerequisite for polarized cell migration. We identify LSP (lymphocyte-specific protein) 1 as a critical regulator of actomyosin contractility in primary macrophages. LSP1 regulates adhesion and migration, including the parameters cell area and speed, and also podosome turnover, oscillation and protrusive force. LSP1 recruits myosin IIA and its regulators, including myosin light chain kinase and calmodulin, and competes with supervillin, a myosin hyperactivator, for myosin regulators, and for actin isoforms, notably beta-actin. Actin isoforms are anisotropically distributed in myosin IIA-expressing macrophages, and contribute to the differential recruitment of LSP1 and supervillin, thus enabling an actomyosin symmetry break, analogous to the situation in cells expressing two myosin II isoforms. Collectively, these results show that the cellular pattern of actin isoforms builds the basis for the differential distribution of two actomyosin machineries with distinct properties, leading to the establishment of discrete zones of actomyosin contractility. PMID- 29410426 TI - Lateral epitaxial heterojunctions in single nanowires fabricated by masked cation exchange. AB - Cation exchange is a versatile tool to control the composition of nanocrystals, and recently deterministic patterning could be achieved by combining it with lithography techniques. Regarding single nanocrystal structures, such spatial control of cation exchange enables the design of heterostructures, which can be integrated in functional optoelectronic elements. In this work, we fabricate nanowire CdSe/Cu2Se heterojunctions by masking cation exchange via electron-beam irradiation, such that cation exchange proceeds only in the non-irradiated sections. Interestingly, the heterojunction interfaces are almost atomically sharp, and the adjacent CdSe and Cu2Se domains exhibit epitaxial relationships. We show that the cation exchange at the CdSe/Cu2Se interface is only possible if the displaced Cd2+ ions can radially out-diffuse to the solution phase. If this exit pathway is blocked, the cation exchange cannot occur. Our technique allows one to transform already contacted single nanowires, and the obtained heterojunction nanowires manifest a noticeable gain in conductance. PMID- 29410427 TI - Legionella DotM structure reveals a role in effector recruiting to the Type 4B secretion system. AB - Legionella pneumophila, a causative agent of pneumonia, utilizes the Type 4B secretion (T4BS) system to translocate over 300 effectors into the host cell during infection. T4BS systems are encoded by a large gene cluster termed dot/icm, three components of which, DotL, DotM, and DotN, form the "coupling complex", which serves as a platform for recruitment of effector proteins. One class of effectors includes proteins containing Glu-rich/E-block sequences at their C terminus. However, the protein or region of the coupling complex mediating recruitment of such effectors is unknown. Here we present the crystal structure of DotM. This all alpha-helical structure exhibits patches of positively charged residues. We show that these regions form binding sites for acidic Glu-rich peptides and that mutants targeting these patches are defective in vivo in the translocation of acidic Glu-rich motif-containing effectors. We conclude that DotM forms the interacting surface for recruitment of acidic Glu rich motif-containing Legionella effectors. PMID- 29410428 TI - Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials. AB - Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed. PMID- 29410429 TI - Transcriptome of Porcine PBMCs over Two Generations Reveals Key Genes and Pathways Associated with Variable Antibody Responses post PRRSV Vaccination. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a virus susceptible to antibody dependent enhancement, causing reproductive failures in sows and preweaning mortality of piglets. Modified-live virus (MLV) vaccines are used to control PRRS in swine herds. However, immunized sows and piglets often generate variable antibody levels. This study aimed to detect significant genes and pathways involved in antibody responsiveness of pregnant sows and their offspring post-PRRSV vaccination. RNA sequencing was conducted on peripheral blood-mononuclear cells (PBMCs), which were isolated from pregnant sows and their piglets with high (HA), median (MA), and low (LA) PRRS antibody levels following vaccination. 401 differentially expressed genes (DEGs) were identified in three comparisons (HA versus MA, HA versus LA, and MA versus LA) of sow PBMCs. Two novel pathways (complement and coagulation cascade pathway; and epithelial cell signaling in H. pylori infection pathway) revealed by DEGs in HA versus LA and MA versus LA were involved in chemotactic and proinflammatory responses. TNF-alpha, CCL4, and NFKBIA genes displayed the same expression trends in subsequent generation post-PRRS-MLV vaccination. Findings of the study suggest that two pathways and TNF-alpha, CCL4, and NFKBIA could be considered as key pathways and potential candidate genes for PRRSV vaccine responsiveness, respectively. PMID- 29410430 TI - Novel global effector mining from the transcriptome of early life stages of the soybean cyst nematode Heterodera glycines. AB - Soybean cyst nematode (SCN) Heterodera glycines is an obligate parasite that relies on the secretion of effector proteins to manipulate host cellular processes that favor the formation of a feeding site within host roots to ensure its survival. The sequence complexity and co-evolutionary forces acting upon these effectors remain unknown. Here we generated a de novo transcriptome assembly representing the early life stages of SCN in both a compatible and an incompatible host interaction to facilitate global effector mining efforts in the absence of an available annotated SCN genome. We then employed a dual effector prediction strategy coupling a newly developed nematode effector prediction tool, N-Preffector, with a traditional secreted protein prediction pipeline to uncover a suite of novel effector candidates. Our analysis distinguished between effectors that co-evolve with the host genotype and those conserved by the pathogen to maintain a core function in parasitism and demonstrated that alternative splicing is one mechanism used to diversify the effector pool. In addition, we confirmed the presence of viral and microbial inhabitants with molecular sequence information. This transcriptome represents the most comprehensive whole-nematode sequence currently available for SCN and can be used as a tool for annotation of expected genome assemblies. PMID- 29410431 TI - A general soft-enveloping strategy in the templating synthesis of mesoporous metal nanostructures. AB - Metal species have a relatively high mobility inside mesoporous silica; thus, it is difficult to introduce the metal precursors into silica mesopores and suppress the migration of metal species during a reduction process. Therefore, until now, the controlled growth of metal nanocrystals in a confined space, i.e., mesoporous channels, has been very challenging. Here, by using a soft-enveloping reaction at the interfaces of the solid, liquid, and solution phases, we successfully control the growth of metallic nanocrystals inside a mesoporous silica template. Diverse monodispersed nanostructures with well-defined sizes and shapes, including Ag nanowires, 3D mesoporous Au, AuAg alloys, Pt networks, and Au nanoparticle superlattices are successfully obtained. The 3D mesoporous AuAg networks exhibit enhanced catalytic activities in an electrochemical methanol oxidation reaction. The current soft-enveloping synthetic strategy offers a robust approach to synthesize diverse mesoporous metal nanostructures that can be utilized in catalysis, optics, and biomedicine applications. PMID- 29410433 TI - Multidimensional correlation of nuclear relaxation rates and diffusion tensors for model-free investigations of heterogeneous anisotropic porous materials. AB - Despite their widespread use in non-invasive studies of porous materials, conventional MRI methods yield ambiguous results for microscopically heterogeneous materials such as brain tissue. While the forward link between microstructure and MRI observables is well understood, the inverse problem of separating the signal contributions from different microscopic pores is notoriously difficult. Here, we introduce an experimental protocol where heterogeneity is resolved by establishing 6D correlations between the individual values of isotropic diffusivity, diffusion anisotropy, orientation of the diffusion tensor, and relaxation rates of distinct populations. Such procedure renders the acquired signal highly specific to the sample's microstructure, and allows characterization of the underlying pore space without prior assumptions on the number and nature of distinct microscopic environments. The experimental feasibility of the suggested method is demonstrated on a sample designed to mimic the properties of nerve tissue. If matched to the constraints of whole body scanners, this protocol could allow for the unconstrained determination of the different types of tissue that compose the living human brain. PMID- 29410434 TI - Simultaneous electroporation and dielectrophoresis in non-electrolytic micro/nano electroporation. AB - It was recently shown that electrolysis may play a substantial detrimental role in microfluidic electroporation. To overcome this problem, we have developed a non-electrolytic micro/nano electroporation (NEME) electrode surface, in which the metal electrodes are coated with a dielectric. A COMSOL based numerical scheme was used to simultaneously calculate the excitation frequency and dielectric material properties dependent electric field delivered across the dielectric, fluid flow, electroporation field and Clausius-Mossotti factor for yeast and E. coli cells flowing in a channel flow across a NEME surface. A two layer model for yeast and a three-layer model for E. coli was used. The numerical analysis shows that in NEME electroporation, the electric fields could induce electroporation and dielectrophoresis simultaneously. The simultaneous occurrence of electroporation and dielectrophoresis gives rise to several interesting phenomena. For example, we found that a certain frequency exists for which an intact yeast cell is drawn to the NEME electrode, and once electroporated, the yeast cell is pushed back in the bulk fluid. The results suggest that developing electroporation technologies that combine, simultaneously, electroporation and dielectrophoresis could lead to new applications. Obviously, this is an early stage numerical study and much more theoretical and experimental research is needed. PMID- 29410432 TI - Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space. AB - Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination. PMID- 29410435 TI - Diesel engine performance and emissions with fuels derived from waste tyres. AB - The disposal of waste rubber and scrap tyres is a significant issue globally; disposal into stockpiles and landfill poses a serious threat to the environment, in addition to creating ecological problems. Fuel production from tyre waste could form part of the solution to this global issue. Therefore, this paper studies the potential of fuels derived from waste tyres as alternatives to diesel. Production methods and the influence of reactor operating parameters (such as reactor temperature and catalyst type) on oil yield are outlined. These have a major effect on the performance and emission characteristics of diesel engines when using tyre derived fuels. In general, tyre derived fuels increase the brake specific fuel consumption and decrease the brake thermal efficiency. The majority of studies indicate that NOx emissions increase with waste tyre derived fuels; however, a few studies have reported the opposite trend. A similar increasing trend has been observed for CO and CO2 emissions. Although most studies reported an increase in HC emission owing to lower cetane number and higher density, some studies have reported reduced HC emissions. It has been found that the higher aromatic content in such fuels can lead to increased particulate matter emissions. PMID- 29410436 TI - Plant probiotic bacteria Bacillus and Paraburkholderia improve growth, yield and content of antioxidants in strawberry fruit. AB - Strawberry is an excellent source of natural antioxidants with high capacity of scavenging free radicals. This study evaluated the effects of two plant probiotic bacteria, Bacillus amylolequefaciens BChi1 and Paraburkholderia fungorum BRRh-4 on growth, fruit yield and antioxidant contents in strawberry fruits. Root dipping of seedlings (plug plants) followed by spray applications of both probiotic bacteria in the field on foliage significantly increased fruit yield (up to 48%) over non-treated control. Enhanced fruit yield likely to be linked with higher root and shoot growth, individual and total fruit weight/plant and production of phytohormone by the probiotic bacteria applied on plants. Interestingly, the fruits from plants inoculated with the isolates BChi1 and BRRh 4 had significantly higher contents of phenolics, carotenoids, flavonoids and anthocyanins over non-treated control. Total antioxidant activities were also significantly higher (p < 0.05) in fruits of strawberry plants treated with both probiotic bacteria. To the best of our knowledge, this is the first report of significant improvement of both yield and quality of strawberry fruits by the application of plant probiotic bacteria BChi1 and BRRh-4 in a field condition. Further study is needed to elucidate underlying mechanism of growth and quality improvement of strawberry fruits by probiotic bacteria. PMID- 29410437 TI - Unraveling the determinants of microRNA mediated regulation using a massively parallel reporter assay. AB - Despite extensive research, the sequence features affecting microRNA-mediated regulation are not well understood, limiting our ability to predict gene expression levels in both native and synthetic sequences. Here we employed a massively parallel reporter assay to investigate the effect of over 14,000 rationally designed 3' UTR sequences on reporter construct repression. We found that multiple factors, including microRNA identity, hybridization energy, target accessibility, and target multiplicity, can be manipulated to achieve a predictable, up to 57-fold, change in protein repression. Moreover, we predict protein repression and RNA levels with high accuracy (R = 0.84 and R = 0.80, respectively) using only 3' UTR sequence, as well as the effect of mutation in native 3' UTRs on protein repression (R = 0.63). Taken together, our results elucidate the effect of different sequence features on miRNA-mediated regulation and demonstrate the predictability of their effect on gene expression with applications in regulatory genomics and synthetic biology. PMID- 29410438 TI - Chitosan nanoparticles having higher degree of acetylation induce resistance against pearl millet downy mildew through nitric oxide generation. AB - Downy mildew of pearl millet caused by the biotrophic oomycete Sclerospora graminicola is the most devastating disease which impairs pearl millet production causing huge yield and monetary losses. Chitosan nanoparticles (CNP) were synthesized from low molecular weight chitosan having higher degree of acetylation was evaluated for their efficacy against downy mildew disease of pearl millet caused by Sclerospora graminicola. Laboratory studies showed that CNP seed treatment significantly enhanced pearl millet seed germination percentage and seedling vigor compared to the control. Seed treatment with CNP induced systemic and durable resistance and showed significant downy mildew protection under greenhouse conditions in comparison to the untreated control. Seed treatment with CNP showed changes in gene expression profiles wherein expression of genes of phenylalanine ammonia lyase, peroxidase, polyphenoloxidase, catalase and superoxide dismutase were highly upregulated. CNP treatment resulted in earlier and higher expression of the pathogenesis related proteins PR1 and PR5. Downy mildew protective effect offered by CNP was found to be modulated by nitric oxide and treatment with CNP along with NO inhibitors cPTIO completely abolished the gene expression of defense enzymes and PR proteins. Further, comparative analysis of CNP with Chitosan revealed that the very small dosage of CNP performed at par with recommended dose of Chitosan for downy mildew management. PMID- 29410439 TI - Efficient communication dynamics on macro-connectome, and the propagation speed. AB - Global communication dynamics in the brain can be captured using fMRI, MEG, or electrocorticography (ECoG), and the global slow dynamics often represent anatomical constraints. Complementary single-/multi-unit recordings have described local fast temporal dynamics. However, global fast temporal dynamics remain incompletely understood with considering of anatomical constraints. Therefore, we compared temporal aspects of cross-area propagations of single-unit recordings and ECoG, and investigated their anatomical bases. First, we demonstrated how both evoked and spontaneous ECoGs can accurately predict latencies of single-unit recordings. Next, we estimated the propagation velocity (1.0-1.5 m/s) from brain-wide data and found that it was fairly stable among different conscious levels. We also found that the shortest paths in anatomical topology strongly predicted the latencies. Finally, we demonstrated that Communicability, a novel graph-theoretic measure, is able to quantify that more than 90% of paths should use shortest paths and the remaining are non-shortest walks. These results revealed that macro-connectome is efficiently wired for detailed communication dynamics in the brain. PMID- 29410440 TI - The Charging Events in Contact-Separation Electrification. AB - Contact electrification (CE)-charging of surfaces that are contacted and separated, is a common phenomenon, however it is not completely understood yet. Recent studies using surface imaging techniques and chemical analysis revealed a 'spatial' bipolar distribution of charges at the nano dimension, which made a paradigm shift in the field. However, such analyses can only provide information about the charges that remained on the surface after the separation, providing limited information about the actual course of the CE event. Tapping common polymers and metal surfaces to each other and detecting the electrical potential produced on these surfaces 'in-situ' in individual events of contact and separation, we show that, charges are generated and transferred between the surfaces in both events; the measured potential is bipolar in contact and unipolar in separation. We show, the 'contact-charges' on the surfaces are indeed the net charges that results after the separation process, and a large contribution to tribocharge harvesting comes, in fact, from the electrostatic induction resulting from the generated CE charges. Our results refine the mechanism of CE providing information for rethinking the conventional ranking of materials' charging abilities, charge harvesting, and charge prevention. PMID- 29410441 TI - Involvement of PKA/DARPP-32/PP1alpha and beta- arrestin/Akt/GSK-3beta Signaling in Cadmium-Induced DA-D2 Receptor-Mediated Motor Dysfunctions: Protective Role of Quercetin. AB - Given increasing risk of cadmium-induced neurotoxicity, the study was conducted to delineate the molecular mechanisms associated with cadmium-induced motor dysfunctions and identify targets that govern dopaminergic signaling in the brain involving in vivo, in vitro, and in silico approaches. Selective decrease in dopamine (DA)-D2 receptors on cadmium exposure was evident which affected the post-synaptic PKA/DARPP-32/PP1alpha and beta-arrestin/Akt/GSK-3beta signaling concurrently in rat corpus striatum and PC12 cells. Pharmacological inhibition of PKA and Akt in vitro demonstrates that both pathways are independently modulated by DA-D2 receptors and associated with cadmium-induced motor deficits. Ultrastructural changes in the corpus striatum demonstrated neuronal degeneration and loss of synapse on cadmium exposure. Further, molecular docking provided interesting evidence that decrease in DA-D2 receptors may be due to direct binding of cadmium at the competitive site of dopamine on DA-D2 receptors. Treatment with quercetin resulted in the alleviation of cadmium-induced behavioral and neurochemical alterations. This is the first report demonstrating that cadmium-induced motor deficits are associated with alteration in postsynaptic dopaminergic signaling due to a decrease in DA-D2 receptors in the corpus striatum. The results further demonstrate that quercetin has the potential to alleviate cadmium-induced dopaminergic dysfunctions. PMID- 29410442 TI - Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity. AB - Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNgamma+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNgamma+ T cells. IL 6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNgamma+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes. PMID- 29410443 TI - Evolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade. AB - In this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for blaOXA 24/40 beta-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1phi (63 proteins) and Ab105-2phi (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1phi and Ab105-2phi) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade. PMID- 29410445 TI - The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus. AB - In Staphylococcus aureus, an important Gram-positive human pathogen, the SaeRS two-component system is essential for the virulence and a good target for the development of anti-virulence drugs. In this study, we screened 12,200 small molecules for Sae inhibitors and identified two anti-cancer drugs, streptozotocin (STZ) and floxuridine (FU), as lead candidates for anti-virulence drug development against staphylococcal infections. As compared with STZ, FU was more efficient in repressing Sae-regulated promoters and protecting human neutrophils from S. aureus-mediated killing. FU inhibited S. aureus growth effectively whereas STZ did not. Intriguingly, RNA-seq analysis suggests that both compounds inhibit other virulence-regulatory systems such as Agr, ArlRS, and SarA more efficiently than they inhibit the Sae system. Both compounds induced prophages from S. aureus, indicating that they cause DNA damages. Surprisingly, a single administration of the drugs was sufficient to protect mice from staphylococcal intraperitoneal infection. Both compounds showed in vivo efficacy in a murine model of blood infection too. Finally, at the experimental dosage, neither compound showed any noticeable side effects on blood glucose level or blood cell counts. Based on these results, we concluded that STZ and FU are promising candidates for anti-virulence drug development against S. aureus infection. PMID- 29410446 TI - Publisher Correction: Influence of intermixing at the Ta/CoFeB interface on spin Hall angle in Ta/CoFeB/MgO heterostructures. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29410444 TI - Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+ binding. AB - Collagen lysyl hydroxylases (LH1-3) are Fe2+- and 2-oxoglutarate (2-OG)-dependent oxygenases that maintain extracellular matrix homeostasis. High LH2 levels cause stable collagen cross-link accumulations that promote fibrosis and cancer progression. However, developing LH antagonists will require structural insights. Here, we report a 2 A crystal structure and X-ray scattering on dimer assemblies for the LH domain of L230 in Acanthamoeba polyphaga mimivirus. Loop residues in the double-stranded beta-helix core generate a tail-to-tail dimer. A stabilizing hydrophobic leucine locks into an aromatic tyrosine-pocket on the opposite subunit. An active site triad coordinates Fe2+. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe2+-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase Km and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer. PMID- 29410447 TI - Attention Gates the Selective Encoding of Duration. AB - The abundance of temporal information in our environment calls for the effective selection and utilization of temporal information that is relevant for our behavior. Here we investigated whether visual attention gates the selective encoding of relevant duration information when multiple sources of duration information are present. We probed the encoding of duration by using a duration adaptation paradigm. Participants adapted to two concurrently presented streams of stimuli with different durations, while detecting oddballs in one of the streams. We measured the resulting duration after-effect (DAE) and found that the DAE reflects stronger relative adaptation to attended durations, compared to unattended durations. Additionally, we demonstrate that unattended durations do not contribute to the measured DAE. These results suggest that attention plays a crucial role in the selective encoding of duration: attended durations are encoded, while encoding of unattended durations is either weak or absent. PMID- 29410448 TI - Intestinal microbiota development and gestational age in preterm neonates. AB - The intestinal microbiota is an important contributor to the health of preterm infants, and may be destabilized by a number of environmental factors and treatment modalities. How to promote the development of a healthy microbiota in preterm infants is largely unknown. We collected fecal samples from 45 breastfed preterm very low birth weight (birth weight < 1500 g) infants from birth until 60 days postnatal age to characterize the intestinal microbiota development during the first weeks of life in preterm infants. Fecal microbiota composition was determined by 16S rRNA amplicon sequencing. The main driver of microbiota development was gestational age; antibiotic use had strong but temporary effects and birth mode had little influence. Microbiota development proceeded in four phases indicated by the dominance of Staphylococcus, Enterococcus, Enterobacter, and finally Bifidobacterium. The Enterococcus phase was only observed among the extremely premature infants and appeared to delay the microbiota succession. The results indicate that hospitalized preterm infants receiving breast milk may develop a normal microbiota resembling that of term infants. PMID- 29410449 TI - Origin and dispersal of Hepatitis E virus. AB - Hepatitis E virus (HEV, genus Orthohepevirus) is a common cause of hepatitis worldwide. Human-infecting HEV strains (Orthohepevirus A) include human restricted and enzootic genotypes. Viruses in the Orthohepevirus A species also infect rabbits (HEV-3ra), camels, and swine. Using a selection-informed method, we dated the origin of the Orthohepevirus genus at least 21 million years ago, whereas the Orthohepevirus A species originated in Asia, most likely from a human infecting ancestor that existed ~4500 to 6800 years ago. In this period, the appearance of large human settlements probably facilitated HEV emergence and spread. The earliest events in Orthohepevirus A evolutionary history involved the separation of the enzootic and human-restricted genotypes, as well as the split of the camel-infecting genotypes, which occurred during the time-frame of camel domestication. The place and timing of HEV-3ra divergence also correspond to the circumstances of rabbit domestication. This study clarifies the origin and historical events underlying HEV dispersal. PMID- 29410450 TI - Tunable Open Circuit Voltage by Engineering Inorganic Cesium Lead Bromide/Iodide Perovskite Solar Cells. AB - Perovskite solar cells based on series of inorganic cesium lead bromide and iodide mixture, CsPbBr3-xI x , where x varies between 0, 0.1, 0.2, and 0.3 molar ratio were synthesized by two step-sequential deposition at ambient condition to design the variations of wide band gap light absorbers. A device with high overall photoconversion efficiency of 3.98 % was obtained when small amount of iodide (CsPbBr2.9I0.1) was used as the perovskite and spiro-OMeTAD as the hole transport material (HTM). We investigated the origin of variation in open circuit voltage, Voc which was shown to be mainly dependent on two factors, which are the band gap of the perovskite and the work function of the HTM. An increment in Voc was observed for the device with larger perovskite band gap, while keeping the electron and hole extraction contacts the same. Besides, the usage of bilayer P3HT/MoO3 with deeper HOMO level as HTM instead of spiro-OMeTAD, thus increased the Voc from 1.16 V to 1.3 V for CsPbBr3 solar cell, although the photocurrent is lowered due to charge extraction issues. The stability studies confirmed that the addition of small amount of iodide into the CsPbBr3 is necessarily to stabilize the cell performance over time. PMID- 29410451 TI - Non-knee-spanning muscles contribute to tibiofemoral shear as well as valgus and rotational joint reaction moments during unanticipated sidestep cutting. AB - Anterior cruciate ligament (ACL) injuries are a burdensome condition due to potential surgical requirements and increased risk of long term debilitation. Previous studies indicate that muscle forces play an important role in the development of ligamentous loading, yet these studies have typically used cadaveric models considering only the knee-spanning quadriceps, hamstrings and gastrocnemius muscle groups. Using a musculoskeletal modelling approach, we investigated how lower-limb muscles produce and oppose key tibiofemoral reaction forces and moments during the weight acceptance phase of unanticipated sidestep cutting. Muscles capable of opposing (or controlling the magnitude of) the anterior shear force and the external valgus moment at the knee are thought to be have the greatest potential for protecting the anterior cruciate ligament from injury. We found the best muscles for generating posterior shear to be the soleus, biceps femoris long head and medial hamstrings, providing up to 173N, 111N and 77N of force directly opposing the anterior shear force. The valgus moment was primarily opposed by the gluteus medius, gluteus maximus and piriformis, with these muscles providing contributions of up to 32 Nm, 19 Nm and 21 Nm towards a knee varus moment, respectively. Our findings highlight key muscle targets for ACL preventative and rehabilitative interventions. PMID- 29410452 TI - Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Elevated Cancer Incidence in Firefighters. AB - Cancer incidence appears to be higher amongst firefighters compared to the general population. Given that many cancers have an environmental component, their occupational exposure to products of carbon combustion such as polycyclic aromatic hydrocarbons (PAHs) is of concern. This is the first UK study identifying firefighters exposure to PAH carcinogens. Wipe samples were collected from skin (jaw, neck, hands), personal protective equipment of firefighters, and work environment (offices, fire stations and engines) in two UK Fire and Rescue Service Stations. Levels of 16 US Environmental Protection Agency (EPA) PAHs were quantified together with more potent carcinogens: 7,12 dimethylbenzo[a]anthracene, and 3-methylcholanthrene (3-MCA) (12 months post initial testing). Cancer slope factors, used to estimate cancer risk, indicate a markedly elevated risk. PAH carcinogens including benzo[a]pyrene (B[a]P), 3-MCA, and 7,12-dimethylbenz[a]anthracene PAHs were determined on body surfaces (e.g., hands, throat), on PPE including helmets and clothing, and on work surfaces. The main exposure route would appear to be via skin absorption. These results suggest an urgent need to monitor exposures to firefighters in their occupational setting and conduct long-term follow-up regarding their health status. PMID- 29410453 TI - Flip-flop Converter of Dual-bistability Using Cavity and Parametric Amplified Four-Wave Mixing. AB - We study the realization of dual-bistability flip-flop converter in cavity and parametrically amplified four-wave mixing (FWM) process at a four-level cavity atomic system. Using the effect of nonreciprocity optical dual-bistability, we can obtain different output multi-mode states of probe transmission signal and FWM signal. We find the channel equalization ratio and optical contrast between multi-mode states is related to the degree of dual-bistability. Besides, the degree of dual-bistability can be controlled by the input parameters (frequency detuning and powers of the dressing beams). More, using electro-optical modulator and acoustic optical modulator to modulate the powers and frequency detuning, respectively, we can realize the fast conversion between different output states. And the switch speed of this flip-flop converter is about 16 ns. These outcomes may provide foundation for the development of all-optical devices and quantum information processing. PMID- 29410454 TI - Sugar-sweetened beverages and school students' hypertension in urban areas of Nanjing, China. AB - Literature showed that sugar-sweetened beverages (SSBs) could increase the risk of developing hypertension in school students, but there is no reported evidence from China yet, so this study aims to investigate the association of the SSBs consumption and school students' hypertension in urban areas of Nanjing, China. A cross-sectional survey was conducted among primary and junior high school students selected from 32 primary schools and 16 junior high schools using a multi-stage random sampling method, with a total number of 10,091 participants involved. The mean age of Grade 4 is 9.04 +/- 0.38, while the mean age of Grade 7 is 12.03 +/- 0.41. Blood pressure was measured and SSBs consumption was reported using a validated questionnaire. The overall prevalence of hypertension was 4.5% among the participants. After adjustment for school, parental education, physical activity, diet intake including meat and snacks, participants who had an experience of SSBs intake were at a higher risk of developing hypertension (odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.15, 1.70) compared with those who had no experience of SSBs intake. A significant association between the consumption of SSBs and hypertension was observed among the students who were at a healthy weight (OR = 1.78, 95% CI = 1.20, 2.65), as well as who were overweight or obese (OR = 1.28, 95% CI = 1.01, 1.61). SSBs may play a contributing role in developing childhood hypertension in this population in China, which is of important implications for future population-based childhood hypertension intervention in China and other countries. PMID- 29410455 TI - Anthropometric cut-off values identifying Greek children at risk of hypertension: the Healthy Growth Study. AB - Excess body weight and fat mass levels in children have previously been associated with childhood hypertension. The aim of the current study was to identify anthropometric and body composition indices most strongly associated with hypertension and to propose relevant cut-off values for these indices, above which the likelihood of hypertension in schoolchildren aged 9-13 years old is increased. A sample of 2,665 children participated in a cross-sectional epidemiological study, the Healthy Growth Study. The current study enrolled 1,315 children with full data on blood pressure, anthropometric, and body composition indices. Increased blood pressure in children was associated with body mass index (BMI) (odds ratio (OR) 1.188), waist circumference (OR 1.062), waist-to-height ratio (OR 1.101), total body fat mass (OR 1.063), and trunk fat mass levels (OR 1.083). Also, BMI, waist circumference, waist-to-height ratio, trunk fat mass, and total body fat mass levels above the age-specific and gender-specific cut-off values identified in the present study were associated with a higher likelihood of hypertension. Anthropometric and body composition indices and the relevant cut off values proposed by the current study can be used for identifying children with higher likelihood of presence of hypertension, as the available BMI thresholds for identifying overweight and obese children may underestimate those at increased risk of hypertension. It is essential for future studies to confirm these findings. PMID- 29410456 TI - Spiroplasma affects host aphid proteomics feeding on two nutritional resources. AB - Bacterial symbionts are broadly distributed among insects, influencing their bioecology to different degrees. Aphids carry a number of secondary symbionts that can influence aphid physiology and fitness attributes. Spiroplasma is seldom reported as an aphid symbiont, but a high level of infection has been observed in one population of the tropical aphid Aphis citricidus. We used sister isolines of Spiroplasma-infected (Ac-BS) and Spiroplasma-free (Ac-B) aphids reared on sweet orange (optimum host) and orange jasmine (suboptimum host) to demonstrate the effects of Spiroplasma infection in the aphid proteome profile. A higher number of proteins were differently abundant in aphids feeding on orange jasmine, indicating an impact of host plant quality. In both host plants, the majority of proteins affected by Spiroplasma infection were heat shock proteins, proteins linked to cell function and structure, and energy metabolism. Spiroplasma also induced changes in proteins involved in antimicrobial activity, carbohydrate processing and metabolism, amino acid synthesis and metabolism in aphids feeding on orange jasmine. We discuss on how the aphid host proteome is differentially affected by Spiroplasma infection when the host is exploiting host plants with different nutritional values. PMID- 29410457 TI - Sensory deprivation in Staphylococcus aureus. AB - Bacteria use two-component systems (TCSs) to sense and respond to environmental changes. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Here we show that S. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. Characterization of S. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches. PMID- 29410459 TI - Publisher Correction: Evaluating agroclimatic constraints and yield gaps for winter oilseed rape (Brassica napus L.) - A case study. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29410458 TI - Heme interaction of the intrinsically disordered N-terminal peptide segment of human cystathionine-beta-synthase. AB - Cystathionine-beta-synthase (CBS) belongs to a large family of pyridoxal 5' phosphate (PLP)-dependent enzymes, responsible for the sulfur metabolism. The heme-dependent protein CBS is part of regulatory pathways also involving the gasotransmitter hydrogen sulfide. Malfunction of CBS can lead to pathologic conditions like cancer, cardiovascular and neurodegenerative disorders. Truncation of residues 1-40, absent in X-ray structures of CBS, reduces but does not abolish the activity of the enzyme. Here we report the NMR resonance assignment and heme interaction studies for the N-terminal peptide stretch of CBS. We present NMR-spectral evidence that residues 1-40 constitute an intrinsically disordered region in CBS and interact with heme via a cysteine proline based motif. PMID- 29410460 TI - Escaping the Ashby limit for mechanical damping/stiffness trade-off using a constrained high internal friction interfacial layer. AB - The development of new materials with reduced noise and vibration levels is an active area of research due to concerns in various aspects of environmental noise pollution and its effects on health. Excessive vibrations also reduce the service live of the structures and limit the fields of their utilization. In oscillations, the viscoelastic moduli of a material are complex and it is their loss part - the product of the stiffness part and loss tangent - that is commonly viewed as a figure of merit in noise and vibration damping applications. The stiffness modulus and loss tangent are usually mutually exclusive properties so it is a technological challenge to develop materials that simultaneously combine high stiffness and high loss. Here we achieve this rare balance of properties by filling a solid polymer matrix with rigid inorganic spheres coated by a sub micron layer of a viscoelastic material with a high level of internal friction. We demonstrate that this combination can be experimentally realised and that the analytically predicted behaviour is closely reproduced, thereby escaping the often termed 'Ashby' limit for mechanical stiffness/damping trade-off and offering a new route for manufacturing advanced composite structures with markedly reduced noise and vibration levels. PMID- 29410461 TI - In silico clinical trials for pediatric orphan diseases. AB - To date poor treatment options are available for patients with congenital pseudarthrosis of the tibia (CPT), a pediatric orphan disease. In this study we have performed an in silico clinical trial on 200 virtual subjects, generated from a previously established model of murine bone regeneration, to tackle the challenges associated with the small, pediatric patient population. Each virtual subject was simulated to receive no treatment and bone morphogenetic protein (BMP) treatment. We have shown that the degree of severity of CPT is significantly reduced with BMP treatment, although the effect is highly subject specific. Using machine learning techniques we were also able to stratify the virtual subject population in adverse responders, non-responders, responders and asymptomatic. In summary, this study shows the potential of in silico medicine technologies as well as their implications for other orphan diseases. PMID- 29410462 TI - Structural, microstructural and magnetic evolution in cryo milled carbon doped MnAl. AB - The low cost, rare earth free tau-phase of MnAl has high potential to partially replace bonded Nd2Fe14B rare earth permanent magnets. However, the tau-phase is metastable and it is experimentally difficult to obtain powders suitable for the permanent magnet alignment process, which requires the fine powders to have an appropriate microstructure and high tau-phase purity. In this work, a new method to make high purity tau-phase fine powders is presented. A high purity tau-phase Mn0.55Al0.45C0.02 alloy was synthesized by the drop synthesis method. The drop synthesized material was subjected to cryo milling and followed by a flash heating process. The crystal structure and microstructure of the drop synthesized, cryo milled and flash heated samples were studied by X-ray in situ powder diffraction, scanning electron microscopy, X-ray energy dispersive spectroscopy and electron backscatter diffraction. Magnetic properties and magnetic structure of the drop synthesized, cryo milled, flash heated samples were characterized by magnetometry and neutron powder diffraction, respectively. The results reveal that the 2 and 4 hours cryo milled and flash heated samples both exhibit high tau-phase purity and micron-sized round particle shapes. Moreover, the flash heated samples display high saturation magnetization as well as increased coercivity. PMID- 29410463 TI - OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model. AB - Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients. PMID- 29410464 TI - Female dispersion and sex ratios interact in the evolution of mating behavior: a computational model. AB - The evolution of mating strategies is not well understood. Several hypotheses have been proposed to explain the variation in mating strategies, with varying levels of support. Specifically, female dispersion, adult sex ratio and mate guarding have been proposed as drivers of the evolution of monogamous strategies. In this study, we used an agent-based model (ABM) to examine how different mating behaviors evolve in a population under different conditions related to these putative drivers, looking to understand the interaction between them. We found an interaction among different factors in the evolution of social monogamy, and their impact is in this order: adult sex ratio (ASR), female dispersion and extra pair copulation. Thus, when the adult sex ratio is male-biased, monogamous strategies are strongly favored. However, this is only the case if mate guarding is fully efficient, i.e., if there is no extra-pair copulation. On the other hand, in scenarios where the population is female-biased, or mate guarding is not efficient, we find that polygamous strategies are favored but proportionally to the dispersion of females. These results confirm previous findings regarding mate guarding and sex ratios, while also showing how female dispersion enters the dynamics. PMID- 29410465 TI - Effect of tetramethylpyrazine on tibial dyschondroplasia incidence, tibial angiogenesis, performance and characteristics via HIF-1alpha/VEGF signaling pathway in chickens. AB - Tibial dyschodroplasia (TD) is a most common pathological condition in many avian species that is characterized by failure of growth plate (GP) modeling that leads to the persistence of avascular lesion in the GP. Tetramethylpyrazine (TMP) is widely used to treat neurovascular disorders and pulmonary hypertension, but no report is available about promoting effect of TMP against TD. Therefore, a total of 210 broiler chicks were equally divided into three groups; Control, TD and TMP. During the experiment mortality rate, chicken performance indicators (daily weight, average daily feed intake, average daily weight gain and feed conversion ratio), tibia bone indicators (weight, length, width of tibial and the size of GP) in addition to gene expression of HIF-1alpha and VEGF were examined. The results showed that TMP administration restore the GP width, increase growth performance, and mitigated the lameness in broiler chickens. The expression of HIF-1alpha and VEGF increased significantly in TD affected thiram induced chicks. Whereas, TMP treatment down-regulated HIF-1alpha and VEGF genes and proteins expressions. The present study demonstrates that the TMP plays an important role in angiogenesis during the impairment and recovery of GP in TD via regulation of the HIF-1alpha/VEGF signaling pathway in chickens. PMID- 29410466 TI - Influence of chromium hyperdoping on the electronic structure of CH3NH3PbI3 perovskite: a first-principles insight. AB - Organic-inorganic hybrid halide perovskites compounds are emerging as new materials with great potential for efficient solar cells. This paper explores the possibility of increasing their photovoltaic efficiency through sub-bandgap absorption by way of the in gap band (IGB) concept. Thus, we assess the formation of an in gap band as well as its effect on the absorption features of Organic inorganic hybrid halide perovskites CH3NH3PbI3 (MAPI). For this task, we use density functional theory (DFT) as well as many-body perturbation methods along to spin-orbit coupling (SOC) to study structural, energetic and electronic properties of partially Cr-substituted MAPI perovskites (CH3NH3Pb1-xCrxI3). Our results reveal that Cr replacement does not lead to an important cell distortion, while the energetic of the substitution process evidences the possibility of obtaining Cr-substituted perovskite. The analysis of the electronic structure shows that Cr 3d-orbitals induce new electronic states in the host semiconductor bandgap, which fulfill the requirements to be considered as an IGB. Precise many body perturbation methods in G0W0 approach provided an accurate description on the electronic structures as well as the position of the IGB. In short, Pb replacement by Cr could be useful for improved absorption features through new sub-bandgap transitions across the in gap band. PMID- 29410467 TI - Data-driven Modeling of Hemodynamics and its Role on Thrombus Size and Shape in Aortic Dissections. AB - Aortic dissection is a pathology that manifests due to microstructural defects in the aortic wall. Blood enters the damaged wall through an intimal tear, thereby creating a so-called false lumen and exposing the blood to thrombogenic intramural constituents such as collagen. The natural history of this acute vascular injury thus depends, in part, on thrombus formation, maturation, and possible healing within the false lumen. A key question is: Why do some false lumens thrombose completely while others thrombose partially or little at all? An ability to predict the location and extent of thrombus in subjects with dissection could contribute significantly to clinical decision-making, including interventional design. We develop, for the first time, a data-driven particle continuum model for thrombus formation in a murine model of aortic dissection. In the proposed model, we simulate a final-value problem in lieu of the original initial-value problem with significantly fewer particles that may grow in size upon activation, thus representing the local concentration of blood-borne species. Numerical results confirm that geometry and local hemodynamics play significant roles in the acute progression of thrombus. Despite geometrical differences between murine and human dissections, mouse models can provide considerable insight and have gained popularity owing to their reproducibility. Our results for three classes of geometrically different false lumens show that thrombus forms and extends to a greater extent in regions with lower bulk shear rates. Dense thrombi are less likely to form in high-shear zones and in the presence of strong vortices. The present data-driven study suggests that the proposed model is robust and can be employed to assess thrombus formation in human aortic dissections. PMID- 29410468 TI - Realization of a thermal cloak-concentrator using a metamaterial transformer. AB - By combining rotating squares with auxetic properties, we developed a metamaterial transformer capable of realizing metamaterials with tunable functionalities. We investigated the use of a metamaterial transformer-based thermal cloak-concentrator that can change from a cloak to a concentrator when the device configuration is transformed. We established that the proposed dual functional metamaterial can either thermally protect a region (cloak) or focus heat flux in a small region (concentrator). The dual functionality was verified by finite element simulations and validated by experiments with a specimen composed of copper, epoxy, and rotating squares. This work provides an effective and efficient method for controlling the gradient of heat, in addition to providing a reference for other thermal metamaterials to possess such controllable functionalities by adapting the concept of a metamaterial transformer. PMID- 29410469 TI - Quantitative Magnetization Transfer in Monitoring Glioblastoma (GBM) Response to Therapy. AB - Quantitative magnetization transfer (qMT) was used as a biomarker to monitor glioblastoma (GBM) response to chemo-radiation and identify the earliest time point qMT could differentiate progressors from non-progressors. Nineteen GBM patients were recruited and MRI-scanned before (Day0), two weeks (Day14), and four weeks (Day28) into the treatment, and one month after the end of the treatment (Day70). Comprehensive qMT data was acquired, and a two-pool MT model was fit to the data. Response was determined at 3-8 months following the end of chemo-radiation. The amount of magnetization transfer ([Formula: see text]) was significantly lower in GBM compared to normal appearing white matter (p < 0.001). Statistically significant difference was observed in [Formula: see text] at Day0 between non-progressors (1.06 +/- 0.24) and progressors (1.64 +/- 0.48), with p = 0.006. Changes in several qMT parameters between Day14 and Day0 were able to differentiate the two cohorts with [Formula: see text] providing the best separation (relative [Formula: see text] = 1.34 +/- 0.21, relative [Formula: see text] = 1.07 +/- 0.08, p = 0.031). Thus, qMT characteristics of GBM are more sensitive to treatment effects compared to clinically used metrics. qMT could assess tumor aggressiveness and identify early progressors even before the treatment. Changes in qMT parameters within the first 14 days of the treatment were capable of separating early progressors from non-progressors, making qMT a promising biomarker to guide adaptive radiotherapy for GBM. PMID- 29410470 TI - Optical imaging of strain in two-dimensional crystals. AB - Strain engineering is widely used in material science to tune the (opto )electronic properties of materials and enhance the performance of devices. Two dimensional atomic crystals are a versatile playground to study the influence of strain, as they can sustain very large deformations without breaking. Various optical techniques have been employed to probe strain in two-dimensional materials, including micro-Raman and photoluminescence spectroscopy. Here we demonstrate that optical second harmonic generation constitutes an even more powerful technique, as it allows extraction of the full strain tensor with a spatial resolution below the optical diffraction limit. Our method is based on the strain-induced modification of the nonlinear susceptibility tensor due to a photoelastic effect. Using a two-point bending technique, we determine the photoelastic tensor elements of molybdenum disulfide. Once identified, these parameters allow us to spatially image the two-dimensional strain field in an inhomogeneously strained sample. PMID- 29410471 TI - Effect of nanopatterning on mechanical properties of Lithium anode. AB - One of the challenges in developing Lithium anodes for Lithium ion batteries (LIB) is controlling the formation of Li dendrites during cycling of the battery. Nanostructuring and nanopatterning of electrodes shows a promising way to suppress the growth of Li dendrites. However, in order to control this behavior, a fundamental understanding of the effect of nanopatterning on the electro mechanical properties of Li metal is necessary. In this paper, we have investigated the mechanical and wear properties of Li metal using Atomic Force Microscopy (AFM) in an airtight cell. By using different load regimes, we determined the mechanical properties of Li metal. We show that as a result of nanopatterning, Li metal surface underwent work hardening due to residual compressive stress. The presence of such stresses can help to improve cycle lifetime of LIBs with Li anodes and obtain very high energy densities. PMID- 29410472 TI - Afforestation neutralizes soil pH. AB - Soil pH regulates soil biogeochemical processes and has cascading effects on terrestrial ecosystem structure and functions. Afforestation has been widely adopted to increase terrestrial carbon sequestration and enhance water and soil preservation. However, the effect of afforestation on soil pH is still poorly understood and inconclusive. Here we investigate the afforestation-caused soil pH changes with pairwise samplings from 549 afforested and 148 control plots in northern China. We find significant soil pH neutralization by afforestation afforestation lowers pH in relatively alkaline soil but raises pH in relatively acid soil. The soil pH thresholds (TpH), the point when afforestation changes from increasing to decreasing soil pH, are species-specific, ranging from 5.5 (Pinus koraiensis) to 7.3 (Populus spp.) with a mean of 6.3. These findings indicate that afforestation can modify soil pH if tree species and initial pH are properly matched, which may potentially improve soil fertility and promote ecosystem productivity. PMID- 29410473 TI - Offering pregnant women different levels of genetic information from prenatal chromosome microarray: a prospective study. AB - This study aimed to examine the choice pregnant women make about the amount of fetal genetic information they want from chromosome microarray. Women having invasive prenatal testing in the absence of fetal structural abnormality were recruited in Victoria, Australia. A decision aid for women described 'targeted' analysis as reporting only copy number variants implicated in a highly penetrant and well-described phenotype and 'extended' as additionally reporting variants of uncertain or unknown significance. Participant's choice and demographics were collected by survey before chorionic villus sampling or amniocentesis; psychological data were also collected then and again about 10 days after receiving results. High-resolution single-nucleotide polymorphism array analysis was performed, and a clinical review committee assessed variants for reporting before returning results to participants. Sixty-six participants (59.5%) chose extended analysis and 45 (40.5%) targeted. Choosing extended information was associated with (1) indication for prenatal diagnosis: maternal age alone (adjusted odds ratio (adjOR) 9.6, 95% confidence interval (CI): 1.4-66.0, p= 0.02), or 'other' indication (adjOR 7.1, 95% CI: 1.5-33.1, p= 0.01)); (2) >12 months to conceive (adjOR 4.1, 95% CI: 1.0-17.7, p= 0.05); and (3) Asian background (adjOR 4.67, 95% CI: 1.0-21.0, p= 0.04). No adverse psychological impact occurred in either group. We conclude that offering pregnant women different levels of fetal genetic analysis is warranted, alongside decision support. PMID- 29410474 TI - Anthropometry-based estimation of body heat capacity in individuals aged 7-69 years: the Size Korea Survey 2010. AB - Although our previously developed anthropometry-based calculation of heat capacity (HC) for adults appeared to be precise and valid, its use in children and adolescents may be associated with bias. This study investigated a large dataset from the Size Korea survey, a national anthropometric survey conducted in 2010, to revalidate our previous HC equation and to develop another one that is appropriate for children and adolescents. We enrolled 12,766 participants aged 7 69 years with body composition data measured by multi-frequency bioelectrical impedance analysis. Age was associated with HC in children aged 7-19 years (R2 = 0.58) but not in adults (R2 = 0.007). Linear regression was appropriate to describe the relationship between HC and body surface area (BSA) in adults, whereas the regression in children and adolescent was quadratic. The previously developed HC equation had high reliability (intra-class correlation coefficient = 0.995) and predictive power (accurate prediction rate = 86.1%) in the >20 age group. The model composed of sex, body weight, BSA, and BSA2 was appropriate for the prediction of HC in young individuals aged 7-19 years. In conclusion, anthropometric-based modelling is a simple, reliable, and useful method for the calculation of HC. PMID- 29410476 TI - Microkinetics of alcohol reforming for H2 production from a FAIR density functional theory database. AB - The large-scale production of hydrogen from biomass under industrial conditions is fundamental for a sustainable future. Here we present a multiscale study of the available reforming technologies based on a density functional theory open database that allows the formulation of linear scaling relationships and microkinetics. The database fulfills the FAIR criteria: findability, accessibility, interoperability and reusability. Moreover, it contains more than 1000 transition states for the decomposition of C2 alcohols on close-packed Cu, Ru, Pd, and Pt surfaces. The microkinetic results for activity, selectivity toward H2, and stability can be directly mapped to experiments, and the catalytic performance is controlled by various types of poisoning. Linear scaling relationships provide valid quantitative results that allow the extrapolation to larger compounds like glycerol. Our database presents a robust roadmap to investigate the complexity of biomass transformations through the use of small fragments as surrogates when investigated under different reaction conditions. PMID- 29410475 TI - Cleaner fuels for ships provide public health benefits with climate tradeoffs. AB - We evaluate public health and climate impacts of low-sulphur fuels in global shipping. Using high-resolution emissions inventories, integrated atmospheric models, and health risk functions, we assess ship-related PM2.5 pollution impacts in 2020 with and without the use of low-sulphur fuels. Cleaner marine fuels will reduce ship-related premature mortality and morbidity by 34 and 54%, respectively, representing a ~ 2.6% global reduction in PM2.5 cardiovascular and lung cancer deaths and a ~3.6% global reduction in childhood asthma. Despite these reductions, low-sulphur marine fuels will still account for ~250k deaths and ~6.4 M childhood asthma cases annually, and more stringent standards beyond 2020 may provide additional health benefits. Lower sulphur fuels also reduce radiative cooling from ship aerosols by ~80%, equating to a ~3% increase in current estimates of total anthropogenic forcing. Therefore, stronger international shipping policies may need to achieve climate and health targets by jointly reducing greenhouse gases and air pollution. PMID- 29410477 TI - Author Correction: Conjugation of wildtype and hypoallergenic mugwort allergen Art v 1 to flagellin induces IL-10-DC and suppresses allergen-specific TH2 responses in vivo. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29410478 TI - Confessions of a thin-fat Indian. PMID- 29410479 TI - The efficacy of a high protein/low glycemic index diet intervention in non-obese patients with asthma. AB - BACKGROUND/OBJECTIVES: EFFORT Asthma study is a randomized controlled trial designed to assess the effects of diet and exercise in non-obese, untrained patients with asthma. We here present results from a subgroup of participants in the diet and control group to assess the feasibility of a high protein and low glycemic index (GI) diet and the effects on body composition. SUBJECTS/METHODS: Of the 149 subjects who were included in the study, 76 subjects (30 males) were randomized into either a diet group (n = 38) or a control group (n = 38) and included in the present analysis. The 8 week intervention consisted of a high protein and low GI diet whilst the control group continued habitual diet. RESULTS: Thirty-three patients in the diet and 34 in the control group completed the study. The diet group reduced their energy intake by ~20% and had high dietary compliance. Intake of fatty fish doubled and GI was reduced by 8.4 units. The diet group reduced their weight by 2.3 +/- 2.2 kg vs. 0.5 +/- 1.8 (p < 0.001), fat mass by 2.2 +/- 2.0 kg vs. 0.3 +/- 1.6 kg (p < 0.001) and preserved lean body mass (-0.02 +/- 1.1 kg). The control group had no changes in body composition. CONCLUSIONS: The ad libitum high protein-low GI diet resulted in a greater loss of fat mass among non-obese patients with asthma. The subjects were satisfactory and highly compliant with the dietary regimen. PMID- 29410480 TI - Cognitive and affective factors linking mothers' perceived weight history to child feeding. AB - BACKGROUND/OBJECTIVES: To explore whether mothers' lifetime experiences with their own weight status and related cognitive and affective factors influence child feeding behavior. SUBJECTS/METHODS: Overweight mothers (N = 221) of 4-5 year olds recalled their weight at four time points, and were grouped into weight history trajectories: recently overweight, always overweight, and steady-gain obese. Objective food choice behavior was assessed in a virtual reality buffet and subjective food restriction for the index child was assessed using a psychometric measure. RESULTS: Mothers' observed food choice was not associated with weight trajectory, but mothers who spent more time being overweight and who weighed more at present were more restrictive of their child's eating. Mothers' concern about child weight increased with more time spent being overweight. Concern for child weight and mothers' body guilt differentially mediated the relationships between weight trajectories and perceived feeding restriction. CONCLUSIONS: Considering mothers' lifetime weight experiences may suggest that parental influences on child feeding are amenable to intervention that would otherwise be obscured by static weight measures. PMID- 29410481 TI - Body fat percentage cutoffs for risk of cardiometabolic abnormalities in the Chinese adult population: a nationwide study. AB - BACKGROUND/OBJECTIVES: The direct assessment of body fat (BF) by using simple methods might be an alternative index of obesity. We aim to investigate the optimal cutoffs of the %BF relating to metabolic disorders and cardiovascular risks in China. SUBJECTS/METHODS: The data were from the 2007-2008 China National Diabetes and Metabolic Disorders Study. Participants with age of 20-75 years and with a BF measurement record were included. The %BF was measured using a foot-to foot bioelectrical impedance analysis. Receiver operating characteristic curve was used to decide the optimal %BF cutoffs for predicting the risk of diabetes, hypertension, metabolic syndrome (MetS), and 10-year cardiovascular events (estimated by Framingham risk score (FRS)). RESULTS: A total of 23,769 participants were enrolled with the mean age of 44.88 years, the male percentage of 40.59%, and the mean %BF of 25.22%. The mean %BFs of subjects who had diabetes, hypertension, metabolic syndrome, and FRS >= 10% were higher than those without diabetes, hypertension, metabolic syndrome, and FRS >= 10%, respectively. In men, the optimal %BF cutoffs for these four endpoints were 24.50%, 24.90%, 24.21%, and 22.10%, respectively. In women, they were 35.69%, 32.50%, 32.60%, and 32.31%, respectively. On the basis of the weights of these endpoints, the pooled optimal %BF cutoff was 23.67% and 32.88% in men and women, respectively. CONCLUSIONS: We suggest the optimal foot-to-foot BIA-measured %BF cutoffs for predicting risk of cardiometabolic abnormalities to be 24% and 33% in Chinese men and women, respectively. PMID- 29410482 TI - A mosaic genetic structure of the human population living in the South Baltic region during the Iron Age. AB - Despite the increase in our knowledge about the factors that shaped the genetic structure of the human population in Europe, the demographic processes that occurred during and after the Early Bronze Age (EBA) in Central-East Europe remain unclear. To fill the gap, we isolated and sequenced DNAs of 60 individuals from Kowalewko, a bi-ritual cemetery of the Iron Age (IA) Wielbark culture, located between the Oder and Vistula rivers (Kow-OVIA population). The collected data revealed high genetic diversity of Kow-OVIA, suggesting that it was not a small isolated population. Analyses of mtDNA haplogroup frequencies and genetic distances performed for Kow-OVIA and other ancient European populations showed that Kow-OVIA was most closely linked to the Jutland Iron Age (JIA) population. However, the relationship of both populations to the preceding Late Neolithic (LN) and EBA populations were different. We found that this phenomenon is most likely the consequence of the distinct genetic history observed for Kow-OVIA women and men. Females were related to the Early-Middle Neolithic farmers, whereas males were related to JIA and LN Bell Beakers. In general, our findings disclose the mechanisms that could underlie the formation of the local genetic substructures in the South Baltic region during the IA. PMID- 29410483 TI - Transparent Displays Utilizing Nanopatterned Quantum Dot Films. AB - We report the realization of a transparent display using glass covered by a nanopatterned quantum dot (QD) film with good transmittance. The film was fabricated by nanoimprint lithography (NIL) and spin coating of colloidal QDs with specificexcitation maxima. The produced nanopatterned QD film was attached to transparent glass, enabling active image generation using a laser light source of a specific wavelength. Selective light emission was induced by strongly exciting the laser-exposed film surface, creating desired images, with color modulationenabled by controlling the QD layer (dozens of nanometers in size) via nanopatterning. The nanopatterned QD film used for image generation exhibits excellent transmittance (>80%), and can be used for transparent displays, with image realization in both bright and dark spaces. The fabricated displays have wide viewing anglesowing to their good light emission characteristics, and the fabrication through spin coating renders the fabrication process simple and applicable to large areas. PMID- 29410484 TI - A Longitudinal Investigation of Preferential Attention to Biological Motion in 2- to 24-Month-Old Infants. AB - Preferential attention to biological motion is an early-emerging mechanism of adaptive action that plays a critical role in social development. The present study provides a comprehensive longitudinal mapping of developmental change in preferential attention to biological motion in 116 infants at 7 longitudinal time points. Tested repeatedly from 2 until 24 months of age, results reveal that preferential attention to biological motion changes considerably during the first months of life. Previously reported preferences in both neonates and older infants are absent in the second month but do reemerge by month 3 and become increasingly pronounced during the subsequent two years. These results highlight the second month of life as a potentially critical transition period in social visual engagement. PMID- 29410485 TI - Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer. AB - We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs. QC treatment selectively upregulated cell cycle inhibitor p21, and downregulated F box protein Skp2 and p62/SQSTM1 expression independent of p53 status. Genetic downregulation of key autophagy protein ATG5 abolished QC mediated effects on both cell cycle protein p21/Skp2 as well as autophagic cargo protein p62. Furthermore, genetic silencing of p62/SQSTM1 resulted in increased sensitivity to QC-mediated apoptosis, downregulated Skp2 mRNA and increased accumulation of p21 expression. Likewise, genetic knockdown of Skp2 resulted in the upregulation of p21 and p27 and increased sensitivity of OC cells to QC treatment. In contrast, transient overexpression of exogenous p62-HA plasmid rescued the QC-mediated Skp2 downregulation indicating the positive regulation of Skp2 by p62. Collectively, these data indicate that QC-mediated effects on cell cycle proteins p21/Skp2is autophagy-dependent and p53-independent in high grade serious OC cells. PMID- 29410486 TI - The Energy Landscape of Neurophysiological Activity Implicit in Brain Network Structure. AB - A critical mystery in neuroscience lies in determining how anatomical structure impacts the complex functional dynamics of the brain. How does large-scale brain circuitry constrain states of neuronal activity and transitions between those states? We address these questions using a maximum entropy model of brain dynamics informed by white matter tractography. We demonstrate that the most probable brain states - characterized by minimal energy - display common activation profiles across brain areas: local spatially-contiguous sets of brain regions reminiscent of cognitive systems are co-activated frequently. The predicted activation rate of these systems is highly correlated with the observed activation rate measured in a separate resting state fMRI data set, validating the utility of the maximum entropy model in describing neurophysiological dynamics. This approach also offers a formal notion of the energy of activity within a system, and the energy of activity shared between systems. We observe that within- and between-system energies cleanly separate cognitive systems into distinct categories, optimized for differential contributions to integrated versus segregated function. These results support the notion that energetic and structural constraints circumscribe brain dynamics, offering insights into the roles that cognitive systems play in driving whole-brain activation patterns. PMID- 29410488 TI - Multiregion gene expression profiling reveals heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer. AB - Intra-tumor heterogeneity may be present at all molecular levels. Genomic intra tumor heterogeneity at the exome level has been reported in many cancer types, but comprehensive gene expression intra-tumor heterogeneity has not been well studied. Here, we delineated the gene expression intra-tumor heterogeneity by exploring gene expression profiles of 35 tumor regions from 10 non-small cell lung cancer tumors (three or four regions/tumor), including adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, and pleomorphic carcinoma of the lung. Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for every sample. Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of intra-tumor heterogeneity. The analysis of various clinically relevant gene expression signatures including molecular subtype, epithelial-to-mesenchymal transition, and anti-PD-1 resistance signatures also revealed heterogeneity between different regions of the same tumor. The gene expression intra-tumor heterogeneity we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression intra-tumor heterogeneity. PMID- 29410489 TI - Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration. AB - Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino) cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing. PMID- 29410487 TI - Solar-panel and parasol strategies shape the proteorhodopsin distribution pattern in marine Flavobacteriia. AB - Proteorhodopsin (PR) is a light-driven proton pump that is found in diverse bacteria and archaea species, and is widespread in marine microbial ecosystems. To date, many studies have suggested the advantage of PR for microorganisms in sunlit environments. The ecophysiological significance of PR is still not fully understood however, including the drivers of PR gene gain, retention, and loss in different marine microbial species. To explore this question we sequenced 21 marine Flavobacteriia genomes of polyphyletic origin, which encompassed both PR possessing as well as PR-lacking strains. Here, we show that the possession or alternatively the lack of PR genes reflects one of two fundamental adaptive strategies in marine bacteria. Specifically, while PR-possessing bacteria utilize light energy ("solar-panel strategy"), PR-lacking bacteria exclusively possess UV screening pigment synthesis genes to avoid UV damage and would adapt to microaerobic environment ("parasol strategy"), which also helps explain why PR possessing bacteria have smaller genomes than those of PR-lacking bacteria. Collectively, our results highlight the different strategies of dealing with light, DNA repair, and oxygen availability that relate to the presence or absence of PR phototrophy. PMID- 29410490 TI - MYB and MYBL1 in adenoid cystic carcinoma: diversity in the mode of genomic rearrangement and transcripts. AB - MYB-NFIB and MYBL1-NFIB have been reported in ~60% of adenoid cystic carcinoma cases, but driver alterations in the remaining ~40% of adenoid cystic carcinoma remain unclear. We examined 100 adenoid cystic carcinoma cases for MYB and MYBL1 locus rearrangements by fluorescence in situ hybridization (FISH) with originally designed probe sets using formalin-fixed paraffin-embedded materials. Approximately one-third of samples were also analyzed by fusion transcript specific RT-PCR and capture RNA sequencing. In the 27 cases with frozen materials, MYB-NFIB and MYBL1-NFIB fusion transcripts were detected in 9 (33%) and 6 cases (22%) by RT-PCR, respectively. Meanwhile, high expression of MYB (18 cases, 67%) or MYBL1 (9 cases, 33%) was detected in all 27 cases in a mutually exclusive manner, regardless of its form (full-length, truncation, or fusion transcript). Interestingly, genomic rearrangements around the corresponding highly-expressed gene were observed in all 27 cases by FISH, suggesting a causative relationship between genomic rearrangements and gene expression. Among the 100 cases, including additional 73 cases, 97 harbored genomic rearrangements in the MYB (73 cases) or MYBL1 locus (24 cases) including 10 cases with atypical FISH patterns undetectable through ordinary split FISH approaches: breakpoints far distant from MYB (5 cases) and a small NFIB locus insertion into the MYB (3 cases) or MYBL1 locus (2 cases). In clinicopathological analyses, histological grade, primary tumor size, and lymph node metastasis were identified as prognostic factors, whereas MYB/MYBL1 rearrangements were not, but were associated with histological grade. In the present study, MYB or MYBL1 locus rearrangement was detected in nearly all adenoid cystic carcinoma cases, and therefore it would be a good diagnostic marker for adenoid cystic carcinoma. However, fusion transcript-specific RT-PCR for MYB-NFIB and MYBL1-NFIB and ordinary split FISH assays for MYB and MYBL1 were less sensitive, and thus detection methods should be judiciously designed because of the diversity of rearrangement modes in adenoid cystic carcinoma. PMID- 29410491 TI - An expanded immunohistochemical profile of osteoclast-rich undifferentiated carcinoma of the urinary tract. AB - Osteoclast-rich undifferentiated carcinoma of the urinary tract (ORUCUT) is a rare tumor composed of ovoid to spindle-shaped mononuclear cells with intermixed or focally clustered osteoclast-like giant cells. Previous studies have demonstrated that the mononuclear cells are neoplastic cells, while the giant cells are reactive cells of histiocytic lineage. The association between these tumors and classic urothelial carcinomas suggest that the mononuclear cells are derived from urothelial cells; however, no studies have been conducted to assess the immunohistochemical profile of ORUCUT with more specific urothelial markers. This study identified 21 cases of ORUCUT and performed immunohistochemistry for GATA3, uroplakin II, and thrombomodulin along with pancytokeratin (AE1/3) on all cases. Mononuclear cells stained positive in 20 cases (95%) for GATA3 and 19 cases (90%) for thrombomodulin. None of the mononuclear cells were positive for uroplakin II and only three cases showed focal positivity for AE1/3. The osteoclast-like giant cells were negative for GATA3, uroplakin II, thrombomodulin, and AE1/3, providing additional support to a reactive origin for these cells. Additionally, 15 cases (71%) were associated with either in situ or invasive urothelial carcinoma. This study provides an expanded immunohistochemical profile for ORUCUT and more definitively supports a urothelial origin for this tumor. PMID- 29410492 TI - Cellular recovery from exposure to sub-optimal concentrations of AB toxins that inhibit protein synthesis. AB - Ricin, Shiga toxin, exotoxin A, and diphtheria toxin are AB-type protein toxins that act within the host cytosol and kill the host cell through pathways involving the inhibition of protein synthesis. It is thought that a single molecule of cytosolic toxin is sufficient to kill the host cell. Intoxication is therefore viewed as an irreversible process. Using flow cytometry and a fluorescent reporter system to monitor protein synthesis, we show a single molecule of cytosolic toxin is not sufficient for complete inhibition of protein synthesis or cell death. Furthermore, cells can recover from intoxication: cells with a partial loss of protein synthesis will, upon removal of the toxin, increase the level of protein production and survive the toxin challenge. Thus, in contrast to the prevailing model, ongoing toxin delivery to the cytosol appears to be required for the death of cells exposed to sub-optimal toxin concentrations. PMID- 29410493 TI - Virtual acoustics in inhomogeneous media with single-sided access. AB - A virtual acoustic source inside a medium can be created by emitting a time reversed point-source response from the enclosing boundary into the medium. However, in many practical situations the medium can be accessed from one side only. In those cases the time-reversal approach is not exact. Here, we demonstrate the experimental design and use of complex focusing functions to create virtual acoustic sources and virtual receivers inside an inhomogeneous medium with single-sided access. The retrieved virtual acoustic responses between those sources and receivers mimic the complex propagation and multiple scattering paths of waves that would be ignited by physical sources and recorded by physical receivers inside the medium. The possibility to predict complex virtual acoustic responses between any two points inside an inhomogeneous medium, without needing a detailed model of the medium, has large potential for holographic imaging and monitoring of objects with single-sided access, ranging from photoacoustic medical imaging to the monitoring of induced-earthquake waves all the way from the source to the earth's surface. PMID- 29410494 TI - Diversity and metabolic potential of the microbiota associated with a soil arthropod. AB - Springtails are important members of the soil fauna and play a key role in plant litter decomposition, for example through stimulation of the microbial activity. However, their interaction with soil microorganisms remains poorly understood and it is unclear which microorganisms are associated to the springtail (endo) microbiota. Therefore, we assessed the structure of the microbiota of the springtail Orchesella cincta (L.) using 16S rRNA gene amplicon sequencing. Individuals were sampled across sites in the field and the microbiota and in particular the endomicrobiota were investigated. The microbiota was dominated by the families of Rickettsiaceae, Enterobacteriaceae and Comamonadaceae and at the genus level the most abundant genera included Rickettsia, Chryseobacterium, Pseudomonas, and Stenotrophomonas. Microbial communities were distinct for the interior of the springtails for measures of community diversity and exhibited structure according to collection sites. Functional analysis of the springtail bacterial community suggests that abundant members of the microbiota may be associated with metabolism including decomposition processes. Together these results add to the understanding of the microbiota of springtails and interaction with soil microorganisms including their putative functional roles. PMID- 29410495 TI - Leisure time physical activity participation in individuals with spinal cord injury in Malaysia: barriers to exercise. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: An epidemiological study describing leisure time physical activities (LTPA) and the associations of barriers, sociodemographic and injury characteristics to moderate-vigorous aerobic exercise participation among individuals with spinal cord injury (SCI) in a developing Southeast Asian country. SETTING: SCI community in Malaysia. METHODS: The study sample consisted of 70 participants with SCI. Questionnaires were distributed containing an abbreviated Physical Activity Scale for Individuals with Physical Disabilities (items 2-6) and the Barriers to Exercise Scale using a 5-tier Likert format. Statistical analyses were chi2 tests, odds ratios, and binary forward stepwise logistic regression to assess the association and to predict factors related to participation in moderate-vigorous intensity aerobic exercise (items 4 and 5). RESULTS: Seventy-three percent of the study sample did not participate in any form of moderate or vigorous LTPA. The top three barriers to undertaking LTPA (strongly agree and agree descriptors) were expensive exercise equipment (54%), pain (37%) and inaccessible facilities (36%). Participants over the age of 35 years, ethnicity, health concerns, perceiving exercise as difficult and indicating lack of transport were significantly different (p < 0.05) between participation and non-participation in moderate-vigorous aerobic exercise type of LTPA. Age, ethnicity, indicated health concerns and lack of transport were the significant predictors in likelihood of participating in moderate-vigorous LTPA (p < 0.1). CONCLUSION: The issues raised depicted barriers within the intrapersonal (health concerns, exercising is too difficult, pain while exercising, age more than 35), interpersonal (different ethnicity), community (expensive exercise equipment), and policy levels (lack of or poor access to transportation, inaccessible facilities) that prevent LTPA participation. PMID- 29410496 TI - Identification of a novel Na+-coupled Fe3+-citrate transport system, distinct from mammalian INDY, for uptake of citrate in mammalian cells. AB - NaCT is a Na+-coupled transporter for citrate expressed in hepatocytes and neurons. It is the mammalian ortholog of INDY (I'm Not Dead Yet), a transporter which modifies lifespan in Drosophila. Here we describe a hitherto unknown transport system for citrate in mammalian cells. When liver and mammary epithelial cells were pretreated with the iron supplement ferric ammonium citrate (FAC), uptake of citrate increased >10-fold. Iron chelators abrogated the stimulation of citrate uptake in FAC-treated cells. The iron exporter ferroportin had no role in this process. The stimulation of citrate uptake also occurred when Fe3+ was added during uptake without pretreatment. Similarly, uptake of Fe3+ was enhanced by citrate. The Fe3+-citrate uptake was coupled to Na+. This transport system was detectable in primary hepatocytes and neuronal cell lines. The functional features of this citrate transport system distinguish it from NaCT. Loss-of-function mutations in NaCT cause early-onset epilepsy and encephalopathy; the newly discovered Na+-coupled Fe3+-citrate transport system might offer a novel treatment strategy for these patients to deliver citrate into affected neurons independent of NaCT. It also has implications to iron-overload conditions where circulating free iron increases, which would stimulate cellular uptake of citrate and consequently affect multiple metabolic pathways. PMID- 29410497 TI - The Neuroprotective Effect of Thalidomide against Ischemia through the Cereblon mediated Repression of AMPK Activity. AB - Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide's neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain. We used a cerebral ischemia rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Thalidomide treatment significantly decreased the infarct volume and neurological deficits of MCAO/R rats. AMPK was the key signalling protein in this mechanism. Furthermore, we considered that the AMPK-CRBN interaction was altered when neuroprotective action by thalidomide occurred in cells under ischemic conditions. Binding was strong between AMPK and CRBN in normal SH-SY5Y cells, but was weakened by the addition of H2O2. However, when thalidomide was administered at the same time as H2O2, the binding of AMPK and CRBN was partly restored. These results suggest that thalidomide inhibits the activity of AMPK via CRBN under oxidative stress and suppresses nerve cell death. PMID- 29410498 TI - Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours. AB - Testicular germ cell tumour (TGCT) is the most common cancer in young men in large parts of the world, but the aetiology is mainly unknown. Genome-wide association studies have so far identified about 50 susceptibility loci associated with TGCT, including SPRY4. SPRY4 has shown tumour suppressor activity in several cancer cells, such as lung and prostate, while it was found to act as an oncogene in ovarian cancer. An intronic region within the SPRY4 gene produces a long non-coding RNA, SPRY4-IT1, which has been reported to act as an oncogene in melanoma, breast cancer, and colorectal cancer, and as a tumour suppressor in lung cancer. The roles of SPRY4 and SPRY4-IT1 in TGCT development are yet unknown. We found higher expression levels of SPRY4, both mRNA and protein, and of SPRY4-IT1 in human TGCT than in normal adult testis. Small-interfering RNA (siRNA)-mediated transient knockdown of SPRY4 and SPRY4-IT1 in two TGCT cell lines 833 K and NT2-D1 resulted in decreased cell growth, migration, and invasion. Knockdown of SPRY4 and SPRY4-IT1 also led to a significant reduction in the phosphorylation of Akt. Our findings indicate that SPRY4 and SPRY4-IT1 may act as oncogenes in TGCTs via activation of the PI3K / Akt signalling pathway. PMID- 29410499 TI - Two-dimensional materials from high-throughput computational exfoliation of experimentally known compounds. AB - Two-dimensional (2D) materials have emerged as promising candidates for next generation electronic and optoelectronic applications. Yet, only a few dozen 2D materials have been successfully synthesized or exfoliated. Here, we search for 2D materials that can be easily exfoliated from their parent compounds. Starting from 108,423 unique, experimentally known 3D compounds, we identify a subset of 5,619 compounds that appear layered according to robust geometric and bonding criteria. High-throughput calculations using van der Waals density functional theory, validated against experimental structural data and calculated random phase approximation binding energies, further allowed the identification of 1,825 compounds that are either easily or potentially exfoliable. In particular, the subset of 1,036 easily exfoliable cases provides novel structural prototypes and simple ternary compounds as well as a large portfolio of materials to search from for optimal properties. For a subset of 258 compounds, we explore vibrational, electronic, magnetic and topological properties, identifying 56 ferromagnetic and antiferromagnetic systems, including half-metals and half-semiconductors. PMID- 29410500 TI - Optimal donor for severe aplastic anemia patient requiring allogeneic hematopoietic stem cell transplantation: A large-sample study from China. AB - HLA-haploidentical hematopoietic stem cell transplantation (HSCT) may be an option for severe aplastic anemia (SAA) patients. However, to date, no large sample studies have been performed to determine which types of SAA patients are suitable for HLA-haploidentical HSCT. We retrospectively studied 189 consecutive patients with SAA who underwent HLA-identical or HLA-haploidentical HSCT at seven transplant centers in China. Propensity score matching (PSM) was applied in this study to reduce the influence of potential confounders. The 5-year overall survival (OS) rate was 72.0% in the HLA-haploidentical group and 76.5% in the HLA identical group. The median time to achieve engraftment and the incidence of acute GVHD/chronic GVHD were not significantly different between the two groups. In the subgroup analysis, the outcome of patients older than 40 years in the HLA haploidentical group was significantly poorer than that of patients younger than 40 years in the same group and that of patients older than 40 years in the HLA identical group. Based on the above results, we suggest that HLA-haploidentical relative HSCT should be considered as a valid alternative option for patients younger than 40 years with SAA for whom no matched sibling donor is available. PMID- 29410501 TI - Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve. AB - Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRalpha and beta) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2 dependant antioxidant response. Interestingly, the reactive oxygen species scavenger N-acetylcysteine counteracts behavioral, electrophysical, ultrastructural and biochemical alterations in LXRdKO mice. Furthermore, Schwann cells in culture pretreated with LXR agonist, TO901317, exhibit improved defenses against oxidative stress generated by tert-butyl hydroperoxide, implying that LXRs play an important role in maintaining the redox homeostasis in the peripheral nervous system. Thus, LXR activation could be a promising strategy to protect from alteration of peripheral myelin resulting from a disturbance of redox homeostasis in Schwann cell. PMID- 29410502 TI - Controlling motile disclinations in a thick nematogenic material with an electric field. AB - Manipulating topological disclination networks that arise in a symmetry-breaking phase transformation in widely varied systems including anisotropic materials can potentially lead to the design of novel materials like conductive microwires, self-assembled resonators, and active anisotropic matter. However, progress in this direction is hindered by a lack of control of the kinetics and microstructure due to inherent complexity arising from competing energy and topology. We have studied thermal and electrokinetic effects on disclinations in a three-dimensional nonabsorbing nematic material with a positive and negative sign of the dielectric anisotropy. The electric flux lines are highly nonuniform in uniaxial media after an electric field below the Freedericksz threshold is switched on, and the kinetics of the disclination lines is slowed down. In biaxial media, depending on the sign of the dielectric anisotropy, apart from the slowing down of the disclination kinetics, a nonuniform electric field filters out disclinations of different topology by inducing a kinetic asymmetry. These results enhance the current understanding of forced disclination networks and establish the presented method, which we call fluctuating electronematics, as a potentially useful tool for designing materials with novel properties in silico. PMID- 29410503 TI - Differential responses of Miocene rodent metacommunities to global climatic changes were mediated by environmental context. AB - The study of how long-term changes affect metacommunities is a relevant topic, that involves the evaluation of connections among biological assemblages across different spatio-temporal scales, in order to fully understand links between global changes and macroevolutionary patterns. We applied multivariate statistical analyses and diversity tests using a large data matrix of rodent fossil sites in order to analyse long-term faunal changes. Late Miocene rodent faunas from southwestern Europe were classified into metacommunities, presumably sharing ecological affinities, which followed temporal and environmental non random assembly and disassembly patterns. Metacommunity dynamics of these faunas were driven by environmental changes associated with temperature variability, but there was also some influence from the aridity shifts described for this region during the late Miocene. Additionally, while variations in the structure of rodent assemblages were directly influenced by global climatic changes in the southern province, the northern sites showed a pattern of climatic influence mediated by diversity-dependent processes. PMID- 29410504 TI - Fast and accurate detection of spread source in large complex networks. AB - Spread over complex networks is a ubiquitous process with increasingly wide applications. Locating spread sources is often important, e.g. finding the patient one in epidemics, or source of rumor spreading in social network. Pinto, Thiran and Vetterli introduced an algorithm (PTVA) to solve the important case of this problem in which a limited set of nodes act as observers and report times at which the spread reached them. PTVA uses all observers to find a solution. Here we propose a new approach in which observers with low quality information (i.e. with large spread encounter times) are ignored and potential sources are selected based on the likelihood gradient from high quality observers. The original complexity of PTVA is O(N alpha ), where alpha ? (3,4) depends on the network topology and number of observers (N denotes the number of nodes in the network). Our Gradient Maximum Likelihood Algorithm (GMLA) reduces this complexity to O (N2log (N)). Extensive numerical tests performed on synthetic networks and real Gnutella network with limitation that id's of spreaders are unknown to observers demonstrate that for scale-free networks with such limitation GMLA yields higher quality localization results than PTVA does. PMID- 29410505 TI - Sudden emergence of human infections with H7N9 avian influenza A virus in Hubei province, central China. AB - There have been five waves of H7N9 avian influenza virus (AIV) infection in humans since its initial emergence in China in 2013, posing a significant threat to public health. Hubei province was free local transmission during the first four waves of H7N9 AIV. However, multiple cases of human H7N9 infection were reported in Hubei during January 2017. To understand the molecular epidemiology that underlies this sudden emergence, we collected samples from 14 human cases of H7N9 influenza virus from Hubei province, along with environmental samples from different locations in Hubei. Our analysis revealed that the newly emerged human H7N9 viruses were all from persons exposed to poultry and shared the same origin as the environmental sampled viruses in the Yangtze River lineage of H7N9. Notably, we also documented an earlier and distinct importation from Jiangsu province that may have established a local environmental reservoir. Our study highlights the need for continued surveillance of H7N9 in both human and avian populations in central China. PMID- 29410506 TI - Publisher Correction: Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29410507 TI - Polymerisation force of a rigid filament bundle: diffusive interaction leads to sublinear force-number scaling. AB - Polymerising filaments generate force against an obstacle, as in, e.g., microtubule-kinetochore interactions in the eukaryotic cell. Earlier studies of this problem have not included explicit three-dimensional monomer diffusion, and consequently, missed out on two important aspects: (i) the barrier, even when it is far from the polymers, affects free diffusion of monomers and reduces their adsorption at the tips, while (ii) parallel filaments could interact through the monomer density field ("diffusive coupling"), leading to negative interference between them. In our study, both these effects are included and their consequences investigated in detail. A mathematical treatment based on a set of continuum Fokker-Planck equations for combined filament-wall dynamics suggests that the barrier-induced monomer depletion reduces the growth velocity and also the stall force, while the total force produced by many filaments remains additive. However, Brownian dynamics simulations show that the linear force number scaling holds only when the filaments are far apart; when they are arranged close together, forming a bundle, sublinear scaling of force with number appears, which could be attributed to diffusive interaction between the growing polymer tips. PMID- 29410508 TI - Visible to near-IR fluorescence from single-digit detonation nanodiamonds: excitation wavelength and pH dependence. AB - Detonation nanodiamonds are of vital significance to many areas of science and technology. However, their fluorescence properties have rarely been explored for applications and remain poorly understood. We demonstrate significant fluorescence from the visible to near-infrared spectral regions from deaggregated, single-digit detonation nanodiamonds dispersed in water produced via post-synthesis oxidation. The excitation wavelength dependence of this fluorescence is analyzed in the spectral region from 400 nm to 700 nm as well as the particles' absorption characteristics. We report a strong pH dependence of the fluorescence and compare our results to the pH dependent fluorescence of aromatic hydrocarbons. Our results significantly contribute to the current understanding of the fluorescence of carbon-based nanomaterials in general and detonation nanodiamonds in particular. PMID- 29410509 TI - A 1000 Arab genome project to study the Emirati population. AB - Discoveries from the human genome, HapMap, and 1000 genome projects have collectively contributed toward the creation of a catalog of human genetic variations that has improved our understanding of human diversity. Despite the collegial nature of many of these genome study consortiums, which has led to the cataloging of genetic variations of different ethnic groups from around the world, genome data on the Arab population remains overwhelmingly underrepresented. The National Arab Genome project in the United Arab Emirates (UAE) aims to address this deficiency by using Next Generation Sequencing (NGS) technology to provide data to improve our understanding of the Arab genome and catalog variants that are unique to the Arab population of the UAE. The project was conceived to shed light on the similarities and differences between the Arab genome and those of the other ethnic groups. PMID- 29410510 TI - Mitochondrial involvement in a Bosch-Boonstra-Schaaf optic atrophy syndrome patient with a novel de novo NR2F1 gene mutation. AB - We report the clinical and biochemical findings from a patient who presented with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), an autosomal-dominant disorder characterized by optic atrophy, developmental delay and intellectual disability. In addition, the patient also displays hypotonia, stroke-like episodes, and complex IV deficiency of the mitochondrial respiratory chain. Whole exome sequencing (WES) uncovered a novel heterozygous mutation in the NR2F1 gene (NM_005654:c.286A>G:p.Lys96Glu) that encodes for the COUP transcription factor 1 protein (COUP-TF1). Loss-of-function mutations in this protein have been associated with BBSOAS, and a luciferase reporter assay showed that this variant, in the zinc-finger DNA-binding domain (DBD) of COUP-TF1 protein, impairs its transcriptional activity. The additional features of this patient are more related with mitochondrial diseases that with BBSOAS, indicating a mitochondrial involvement. Finally, our data expand both the genetic and phenotypic spectrum associated with NR2F1 gene mutations. PMID- 29410511 TI - Novel de novo mutation affecting two adjacent aminoacids in the EED gene in a patient with Weaver syndrome. AB - Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome, a rare condition caused by mutations in EZH2 gene. Recently, in four patients with Weaver-like symptoms without mutations in EZH2 gene, pathogenic variants in EED were described. We present another patient clinically diagnosed with Weaver syndrome in whom WES revealed an EED de novo mutation affecting two neighboring aminoacids, NM_003797.3:c.917_919delinsCGG/p.(Arg306_Asn307delinsThrAsp) located in one allele (in cis). Our observation, together with previous reports suggests that EED gene testing is warranted in patients with the overgrowth syndrome features and suspicion of Weaver syndrome with normal results of EZH2 gene sequencing. PMID- 29410512 TI - Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations. AB - Most of the 19 mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) involved in mitochondrial protein synthesis are already linked to specific entities, one of the exceptions being PARS2 mutations for which pathogenic significance is not finally validated. The aim of the study was to characterize the PARS2- related phenotype.Three siblings with biallelic PARS2 mutations presented from birth with infantile spasms, secondary microcephaly, and similar facial dysmorphy. Mental development was deeply impaired with speech absence and no eye contact. A dilated cardiomyopathy and multiorgan failure developed in childhood at the terminal stage, together with mitochondrial dysfunction triggered by valproate administration.Brain MRI showed progressive volume loss of the frontal lobes, both cortical and subcortical, with widening of the cortical sulci and frontal horns of the lateral ventricles. Hypoplasia of the corpus callosum and progressive demyelination were additional findings. Similar brain features were seen in three already reported PARS2 patients and seemed specific for this defect when compared with other mt-aaRSs defects (DARS2, EARS2, IARS2, and RARS2).Striking resemblance of the phenotype and Alpers-like brain MRI changes with predominance of frontal cerebral volume loss (FCVL-AS) in six patients from three families of different ethnicity with PARS2 mutations, justifies to distinguish the condition as a new disease entity. PMID- 29410513 TI - A novel homozygous DPH1 mutation causes intellectual disability and unique craniofacial features. AB - Biallelic mutations of the gene encoding diphthamide biosynthesis 1 (DPH1, NM_001383.3) cause developmental delay, dysmorphic features, sparse hair, and short stature (MIM *603527). Only two missense DPH1 mutations have been reported to date. Here, we describe a consanguineous family with two siblings both showing developmental delay, agenesis of the corpus callosum, dysmorphic facial features, sparse hair, brachycephaly, and short stature. By wholeexome sequencing, a homozygous frameshift mutation in DPH1 (c.1227delG, p.[Ala411Argfs*91]) was identified, which is likely responsible for the familial condition. The unique clinical features of the affected siblings are cleft palate and absent renal findings. PMID- 29410514 TI - Buccal mucosa cell damage in individuals following dental X-ray examinations. AB - The aim of the present study was to monitor genotoxic and cytotoxic effect of X ray on exfoliated buccal mucosa cells and investigate the association between the effects and the accumulated absorbed doses of oral mucosa. 98 participants' buccal mucosa cells were collected before and 10 days after different series of dental radiographs performed. Cytological preparations were successively dyed with the methods of Feulgen and fast-green, and analyzed under a light microscope. Micronuclei (MN)and other cells were scored. Accumulated absorbed dose of buccal mucosa was estimated with the method of anthropomorphic phantom and dosimeter chips. The dose rang was 0.18-3.54 mGy. A significant difference in the rate of MN cell was found before and after X-ray examinations (P = 0.008) as well as in the rates of Pyknotic (p < 0.001) and Karyolytic cell (p = 0.0021). When only the patients whose mucosa absorbed dose is lower than 1 mGy was analyzed, significant differences were not found except for Karyolytic cells (p = 0.0313). There was a correlation between the accumulated does and the change rate (rho = 0.25, p = 0.0118). The frequency of micronuclei cells in buccal mucosa may be increased when a series of dental radiographs including a CBCT examination was performed. PMID- 29410515 TI - The PKA-C3 catalytic subunit is required in two pairs of interneurons for successful mating of Drosophila. AB - Protein kinase A (PKA) has been shown to play a role in a plethora of cellular processes ranging from development to memory formation. Its activity is mediated by the catalytic subunits whereby many species express several paralogs. Drosophila encodes three catalytic subunits (PKA-C1-3) and whereas PKA-C1 has been well studied, the functions of the other two subunits were unknown. PKA-C3 is the orthologue of mammalian PRKX/Pkare and they are structurally more closely related to each other than to other catalytic subunits within their species. PRKX is expressed in the nervous system in mice but its function is also unknown. We now show that the loss of PKA-C3 in Drosophila causes copulation defects, though the flies are active and show no defects in other courtship behaviours. This phenotype is specifically due to the loss of PKA-C3 because PKA-C1 cannot replace PKA-C3. PKA-C3 is expressed in two pairs of interneurons that send projections to the ventro-lateral protocerebrum and the mushroom bodies and that synapse onto motor neurons in the ventral nerve cord. Rescue experiments show that expression of PKA-C3 in these interneurons is sufficient for copulation, suggesting a role in relaying information from the sensory system to motor neurons to initiate copulation. PMID- 29410517 TI - Kinanthraquinone, a new anthraquinone carboxamide isolated from Streptomyces reveromyceticus SN-593-44. AB - A new anthraquinone derivative, kinanthraquinone (1) was isolated from Streptomyces reveromyceticus SN-593-44. Its structure was determined by the combination of spectroscopic methods including NMR and MS. Kinanthraquinone had a characteristic carboxamide group and was a rare class of metabolite as an anthraquinone derivative isolated from microbes. It showed moderate cytotoxocity against HL-60 and srcts-NRK cell with IC50 value of 7.9 and 10 MUM, respectively. PMID- 29410516 TI - Anti-adipogenic effects of KD025 (SLx-2119), a ROCK2-specific inhibitor, in 3T3 L1 cells. AB - Adipose tissue is a specialized organ that synthesizes and stores fat. During adipogenesis, Rho and Rho-associated kinase (ROCK) 2 are inactivated, which enhances the expression of pro-adipogenic genes and induces the loss of actin stress fibers. Furthermore, pan ROCK inhibitors enhance adipogenesis in 3T3-L1 cells. Here, we show that KD025 (formerly known as SLx-2119), a ROCK2-specific inhibitor, suppresses adipogenesis in 3T3-L1 cells partially through a ROCK2 independent mechanism. KD025 downregulated the expression of key adipogenic transcription factors PPARgamma and C/EBPalpha during adipogenesis in addition to lipogenic factors FABP4 and Glut4. Interestingly, adipogenesis was blocked by KD025 during days 1~3 of differentiation; after differentiation terminated, lipid accumulation was unaffected. Clonal expansion occurred normally in KD025-treated cells. These results suggest that KD025 could function during the intermediate stage after clonal expansion. Data from depletion of ROCKs showed that KD025 suppressed cell differentiation partially independent of ROCK's activity. Furthermore, no further loss of actin stress fibers emerged in KD025-treated cells during and after differentiation compared to control cells. These results indicate that in contrast to the pro-adipogenic effect of pan-inhibitors, KD025 suppresses adipogenesis in 3T3-L1 cells by regulating key pro-adipogenic factors. This outcome further implies that KD025 could be a potential anti adipogenic/obesity agent. PMID- 29410518 TI - Rifaximin decreases virulence of Crohn's disease-associated Escherichia coli and epithelial inflammatory responses. AB - Escherichia coli with an adherent and invasive pathotype (AIEC) is implicated in the pathogenesis of Crohn's disease (CD). Rifaximin improves symptoms in mild-to moderate CD. It is unclear if this outcome is due to its effects on bacteria or intestinal epithelial inflammatory responses. We examined the effects of rifaximin on the growth and virulence of CD-associated E. coli and intestinal epithelial inflammatory responses. Seven well-characterized CD-associated E. coli strains (six AIEC, one non-AIEC; four rifaximin-resistant, three sensitive) were evaluated. We assessed the effects of rifaximin on CD-associated E. coli growth, adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and survival in macrophages. Additionally, we determined the effects of rifaximin on intestinal epithelial inflammatory responses. In vitro rifaximin exerted a dose-dependent effect on the growth of sensitive strains but did not affect the growth of resistant strains. Rifaximin reduced adhesion, invasion, virulence gene expression and motility of CD-associated E. coli in a manner that was independent of its antimicrobial effect. Furthermore, rifaximin reduced IL-8 secretion from pregnane X receptor-expressing T84 colonic epithelial cells. The effect of rifaximin on adhesion was largely attributable to its action on bacteria, whereas decreases in invasion and cytokine secretion were due to its effect on the epithelium. In conclusion, our results show that rifaximin interferes with multiple steps implicated in host-AIEC interactions related to CD, including adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and pro-inflammatory cytokine secretion. Further study is required to determine the relationship of these effects to clinical responses in CD patients. PMID- 29410519 TI - Rationale and design of an inhibitor of RecA protein as an inhibitor of Acinetobacter baumannii. AB - Acinetobacter baumannii is one of the ESKAPE pathogen, which causes pneumonia, urinary tract infections, and is linked to high degree of morbidity and mortality. One-way antibiotic and disinfectant resistance is acquired by the activation of RecA-mediated DNA repair (SOS-response) that maintain ROS-dependent DNA damage caused by these anti-bacterial molecules. To increase the efficacy of different anti-microbial, there is a need to design an inhibitor against RecA of A. baumannii. We have performed homology modeling to generate the structure of RecA, followed by model refinement and validation. High-throughput virtual screening of 1,80,313 primary and secondary metabolites against RecA was performed in HTVS, SP, and XP docking modes. The selected 195 compounds were further analyzed for binding free energy by molecular mechanics approach. The selected top two molecules from molecular mechanics approach were further validated by molecular dynamics simulation (MDS). In-silico high-throughput virtual screening and MDS validation identified ZINC01530654 or (+-)-2-((4-((7 Chloro-4-quinolyl)amino)pentyl)ethylamino)ethanol sulfate (or hydroxychloroquine sulfate) as a possible lead molecule binding to RecA protein. We have experimentally determined the mechanism of ZINC01530654 to RecA protein. These findings suggest a strategy to chemically inhibit the vital process controlled by RecA that could be helpful for the development of new antibacterial agents. PMID- 29410520 TI - High dietary salt intake correlates with modulated Th17-Treg cell balance resulting in enhanced bone loss and impaired bone-microarchitecture in male mice. AB - Osteoporosis is associated with reduced density and quality of bone leading to weakened skeleton thereby increasing the risk of fractures responsible for increased morbidity and mortality. Due to preference for western food style the consumption of salt intake in our diets has increased many folds. High dietary salt intake has recently been linked with induction of Th17 cells along with impairment of Treg cells. Also, Th17 cells have been one of major players in the pathophysiology of various bone pathologies including osteoporosis. We thus hypothesized that high salt diet (HSD) intake would lead to enhanced bone loss by modulating Th17-Treg cell balance. In the present study, we report for the first time that HSD intake in male mice impairs both trabecular and cortical bone microarchitecture along with decreasing the mineral density and heterogeneity of bones. The HSD modulates host immune system and skews Treg-Th17 balance by promoting osteoclastogenic Th17 cells and inhibiting development of anti osteoclastogenic Treg cells in mice. HSD also enhanced expression of proinflammatory cytokines (IL-6, TNF-alpha, RANKL and IL-17) and decreased the expression of anti-inflammatory cytokines (IL-10, IFN-gamma). Taken together the present study for the first time establishes a strong correlation between high dietary salt intake and bone health via interplay between Th17-Treg cells. PMID- 29410522 TI - Molecular mechanisms of detection and discrimination of dynamic signals. AB - Many molecules decode not only the concentration of cellular signals, but also their temporal dynamics. However, little is known about the mechanisms that underlie the detection and discrimination of dynamic signals. We used computational modelling of the interaction of a ligand with multiple targets to investigate how kinetic and thermodynamic parameters regulate their capabilities to respond to dynamic signals. Our results demonstrated that the detection and discrimination of temporal features of signal inputs occur for reactions proceeding outside mass-action equilibrium. For these reactions, thermodynamic parameters such as affinity do not predict their outcomes. Additionally, we showed that, at non-equilibrium, the association rate constants determine the amount of product formed in reversible reactions. In contrast, the dissociation rate constants regulate the time interval required for reversible reactions to achieve equilibrium and, consequently, control their ability to detect and discriminate dynamic features of cellular signals. PMID- 29410521 TI - The role of transposable elements in functional evolution of amphioxus genome: the case of opsin gene family. AB - Transposable elements (TEs) are able to jump to new locations (transposition) in the genome, usually after replication. They constitute the so-called selfish or junk DNA and take over large proportions of some genomes. Due to their ability to move around they can change the DNA landscape of genomes and are therefore a rich source of innovation in genes and gene regulation. Surge of sequence data in the past years has significantly facilitated large scale comparative studies. Cephalochordates have been regarded as a useful proxy to ancestral chordate condition partially due to the comparatively slow evolutionary rate at morphological and genomic level. In this study, we used opsin gene family from three Branchiostoma species as a window into cephalochordate genome evolution. We compared opsin complements in terms of family size, gene structure and sequence allowing us to identify gene duplication and gene loss events. Furthermore, analysis of the opsin containing genomic loci showed that they are populated by TEs. In summary, we provide evidence of the way transposable elements may have contributed to the evolution of opsin gene family and to the shaping of cephalochordate genomes in general. PMID- 29410523 TI - Oxidized Carbon Black: Preparation, Characterization and Application in Antibody Delivery across Cell Membrane. AB - Modulating biomolecular networks in cells with peptides and proteins has become a promising therapeutic strategy and effective biological tools. A simple and effective reagent that can bring functional proteins into cells can increase efficacy and allow more investigations. Here we show that the relatively non toxic and non-immunogenic oxidized carbon black particles (OCBs) prepared from commercially available carbon black can deliver a 300 kDa protein directly into cells, without an involvement of a cellular endocytosis. Experiments with cell sized liposomes indicate that OCBs directly interact with phospholipids and induce membrane leakages. Delivery of human monoclonal antibodies (HuMAbs, 150 kDa) with specific affinity towards dengue viruses (DENV) into DENV-infected Vero cells by OCBs results in HuMAbs distribution all over cells' interior and effective viral neutralization. An ability of OCBs to deliver big functional/therapeutic proteins into cells should open doors for more protein drug investigations and new levels of antibody therapies and biological studies. PMID- 29410525 TI - Time- & Load-Dependence of Triboelectric Effect. AB - Time- and load-dependent friction behavior is considered as important for a long time, due to its time-evolution and force-driving characteristics. However, its electronic behavior, mainly considered in triboelectric effect, has almost never been given the full attention and analyses from the above point of view. In this paper, by experimenting with fcc-latticed aluminum and copper friction pairs, the mechanical and electronic behaviors of friction contacts are correlated by time and load analyses, and the behind physical understanding is provided. Most importantly, the difference of "response lag" in force and electricity is discussed, the extreme points of coefficient of friction with the increasing normal loads are observed and explained with the surface properties and dynamical behaviors (i.e. wear), and the micro and macro theories linking tribo-electricity to normal load and wear (i.e. the physical explanation between coupled electrical and mechanical phenomena) are successfully developed and tested. PMID- 29410524 TI - Transcriptome-wide survey of gene expression changes and alternative splicing in Trichophyton rubrum in response to undecanoic acid. AB - While fatty acids are known to be toxic to dermatophytes, key physiological aspects of the Trichophyton rubrum response to undecanoic acid (UDA), a medium chain saturated fatty acid (C11:0), are not well understood. Thus, we analysed RNA-seq data from T. rubrum exposed to sub-lethal doses of UDA for 3 and 12 h. Three putative pathways were primarily involved in UDA detoxification: lipid metabolism and cellular membrane composition, oxidative stress, and pathogenesis. Biochemical assays showed cell membrane impairment, reductions in ergosterol content, and an increase in keratinolytic activity following UDA exposure. Moreover, we assessed differential exon usage and intron retention following UDA exposure. A key enzyme supplying guanine nucleotides to cells, inosine monophosphate dehydrogenase (IMPDH), showed high levels of intron 2 retention. Additionally, phosphoglucomutase (PGM), which is involved in the glycogen synthesis and degradation as well as cell wall biosynthesis, exhibited a significant difference in exon 4 usage following UDA exposure. Owing to the roles of these enzymes in fungal cells, both have emerged as promising antifungal targets. We showed that intron 2 retention in impdh and exon 4 skipping in pgm might be related to an adaptive strategy to combat fatty acid toxicity. Thus, the general effect of UDA fungal toxicity involves changes to fungal metabolism and mechanisms for regulating pre-mRNA processing events. PMID- 29410526 TI - Impact of mid-season sulphur deficiency on wheat nitrogen metabolism and biosynthesis of grain protein. AB - Wheat (Triticum aestivum) quality is mainly determined by grain storage protein compositions. Sulphur availability is essential for the biosynthesis of the main wheat storage proteins. In this study, the impact of different sulphur fertilizer regimes on a range of agronomically important traits and associated gene networks was studied. High-performance liquid chromatography was used to analyse the protein compositions of grains grown under four different sulphur treatments. Results revealed that sulphur supplementation had a significant effect on grain yield, harvest index, and storage protein compositions. Consequently, two comparative sulphur fertilizer treatments (0 and 30 kg ha-1 sulphur, with 50 kg ha-1 nitrogen) at seven days post-anthesis were selected for a transcriptomics analysis to screen for differentially expressed genes (DEGs) involved in the regulation of sulphur metabolic pathways. The International Wheat Genome Sequencing Consortium chromosome survey sequence was used as reference. Higher sulphur supply led to one up-regulated DEG and sixty-three down-regulated DEGs. Gene ontology enrichment showed that four down-regulated DEGs were significantly enriched in nitrogen metabolic pathway related annotation, three of which were annotated as glutamine synthetase. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment identified three significantly enriched pathways involved in nitrogen and amino acid metabolism. PMID- 29410527 TI - RNA metabolism: Interfering with interferon by RNA editing. PMID- 29410528 TI - Stem cells: A balancing act of lipids. PMID- 29410530 TI - Ubiquitin chains as second messengers. PMID- 29410529 TI - Understanding the diversity of membrane lipid composition. AB - Cellular membranes are formed from a chemically diverse set of lipids present in various amounts and proportions. A high lipid diversity is universal in eukaryotes and is seen from the scale of a membrane leaflet to that of a whole organism, highlighting its importance and suggesting that membrane lipids fulfil many functions. Indeed, alterations of membrane lipid homeostasis are linked to various diseases. While many of their functions remain unknown, interdisciplinary approaches have begun to reveal novel functions of lipids and their interactions. We are beginning to understand why even small changes in lipid structures and in composition can have profound effects on crucial biological functions. PMID- 29410532 TI - Pancreatic cancer: KRAS dosage key in PDAC. PMID- 29410533 TI - Diagnosis: Biomarkers and balloons for the detection of Barrett oesophagus. PMID- 29410534 TI - Reimagining the diagnostic pathway for gastrointestinal cancer. AB - A crisis is looming for the diagnosis of gastrointestinal cancers, one grounded only partly in the steady increase in their overall incidence. Public demand for diagnostic tests to be undertaken early and at lower levels of risk is reflected in early diagnosis being a widely held policy objective for reasons of both clinical outcome and patient experience. In the UK, urgent referrals for suspected lower gastrointestinal cancer have increased by 78% in the past 6 years, with parallel increases in endoscopy and imaging activity. Such growth in demand is unsustainable with current models of care. If gastrointestinal cancer diagnosis is to be affordable, the roles of professionals and their interactions with each other will need to be reframed while retaining public confidence in the process. In this Perspective, we consider how the relationship between medical specialists and generalists could be redefined to make better use of the skills of each while delivering optimal clinical outcomes and a good patient experience. PMID- 29410531 TI - Mechanisms of clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis is a key process in vesicular trafficking that transports a wide range of cargo molecules from the cell surface to the interior. Clathrin-mediated endocytosis was first described over 5 decades ago. Since its discovery, over 50 proteins have been shown to be part of the molecular machinery that generates the clathrin-coated endocytic vesicles. These proteins and the different steps of the endocytic process that they mediate have been studied in detail. However, we still lack a good understanding of how all these different components work together in a highly coordinated manner to drive vesicle formation. Nevertheless, studies in recent years have provided several important insights into how endocytic vesicles are built, starting from initiation, cargo loading and the mechanisms governing membrane bending to membrane scission and the release of the vesicle into the cytoplasm. PMID- 29410535 TI - Corrigendum: Disease status is a more reliable predictive factor than histology in lymphoma patients after reduced-intensity conditioning regimen and allo-SCT. AB - This corrects the article DOI: 10.1038/bmt.2012.225. PMID- 29410536 TI - Acute appendicitis in leukaemia patients undergoing haematopoietic stem cell transplantation during the neutropaenic phase: a case series from a single BMT centre in China. PMID- 29410537 TI - Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats. AB - Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA sequencing data showed that suppression of cell mitosis, response to hypoxia, inflammation, and angiogenesis were the top genetic changes in 3D UC-MSCs compared with 2D UC-MSCs. Although both pro-inflammatory and anti inflammatory genes were upregulated in the 3D UC-MSCs, the mRNA and protein of an RNase (ZC3H12A), which turnovers the mRNA of pro-inflammatory genes at the post transcript level, were significantly upregulated in 3D UC-MSCs. 3D UC-MSCs reduced the secretion of many chemokines and growth factors, but increased the secretion of vascular endothelial growth factor. Compared with the vehicle and 2D UC-MSCs, 3D UC-MSCs significantly reduced hepatic IRI in rats, based on the plasma aminotransferase levels, liver damage scores, neutrophil infiltration, hepatocyte apoptosis and expression of inflammation-associated genes. These findings suggest that 3D UC-MSCs therapy is a promising treatment for hepatic IRI. PMID- 29410538 TI - Theoretical Study of Sesterfisherol Biosynthesis: Computational Prediction of Key Amino Acid Residue in Terpene Synthase. AB - The cyclization mechanisms involved in the biosynthesis of sesterterpenes are not fully understood. For example, there are two plausible reaction pathways for sesterfisherol biosynthesis, which differ in the order of ring cyclization: A-D B/C (Path a) and A-B-C/D (Path b). It is difficult to capture intermediates of terpene cyclization, which is a complex, domino-type reaction, and so here we employed a combination of experimental and computational methods. Density functional theory calculations revealed unexpected intermediates and transition states, and implied that C-H...pi interaction between a carbocation intermediate and an aromatic residue of sesterfisherol synthase (NfSS) plays a critical role, serving to accelerate the 1,2-H shift (thereby preventing triquinane carbocation formation) and to protect reactive carbocation intermediates from bases such as pyrophosphate or water in the active site. Site-directed mutagenesis of NfSS guided by docking simulations confirmed that phenylalanine F191 is a critical amino acid residue for sesterfisherol synthase, as the F191A mutant of NfSS produces novel sesterterpenes, but not sesterfisherol. Although both pathways are energetically viable, on the basis of our computational and experimental results, NfSS-mediated sesterfisherol biosynthesis appears to proceed via Path a. These findings may also provide new insight into the cyclization mechanisms in related sesterterpene synthases. PMID- 29410539 TI - Risk factors and prognostic significance of altered left ventricular geometry in preterm infants. AB - OBJECTIVE: Left ventricular (LV) hypertrophy (LVH) predicts adverse cardiac events in adults. We sought to determine the risk factors and prognostic significance of altered LV geometry in preterm infants. STUDY DESIGN: In an echocardiographic, single-center, retrospective case-control study we investigated the risk factors and outcomes in patients with altered LV geometry (either increased left ventricular mass index (LVMI) or increased relative wall thickness (RWT)) from a cohort of 503 preterm infants <=2 kg. RESULT: Altered LV geometry was seen in 180 patients and was predicted by postnatal steroids and small for gestational age. Hospital stay was longer in the elevated RWT cases. Altered LV geometry resolved in 129 of the 131 cases with follow-up echocardiogram. Fifteen of 94 patients with elevated RWT died compared to 3/90 controls (P = 0.004). CONCLUSION: Altered LV geometry in preterm infants is associated with postnatal steroid use and small for gestational age. Elevated RWT is associated with longer hospital stay and increased mortality. PMID- 29410540 TI - ABO hemolytic disease of the fetus and newborn: thirteen years of data after implementing a universal bilirubin screening and management program. AB - OBJECTIVE: ABO hemolytic disease occurs among neonates with blood groups A or B delivered to group O women. Extreme neonatal hyperbilirubinemia due to ABO disease has been reported, but its frequency is not well known. We sought to determine the odds of developing severe ABO hemolytic disease in the 13 years since adopting universal bilirubin screening/management in the Intermountain Healthcare system. STUDY DESIGN: We conducted a retrospective analysis of neonates born between 2004 and 2016, defining "severe hemolytic disease" as; (1) total serum bilirubin (TSB) >25 mg/dL, or (2) hospital readmission for jaundice, or (3) bilirubin encephalopathy. Neonates born to group O (+) mothers were included and considered either; (1) Controls (not at risk for ABO disease because they were group O), (2) Study subjects (at risk for ABO disease because they were group A or B). RESULTS: Of 400,531 live births, 47% were to group O women; 86% of whom were group O (+). Overall, 42,529 (27%) neonates born to group O (+) women had their blood group determined; 29,729 (68%) were O, 10,682 (25%) A, and 3109 (7%) B. Peak TSBs during the first 10 days were higher in group A (11.0 +/- 4.2 mg/dL) and B (11.5 +/- 4.3) than group O neonates (10.3 +/- 4.1). However the relative risks of a TSB >=25 mg/dL, readmission for jaundice, or kernicterus, were the same in the control vs. study groups. CONCLUSIONS: In our health system, severe hemolytic disease in neonates born to group O (+) woman is not more likely in group A or B neonates than in controls (group O). We recognize that in other practices, particularly those who do not have a universal bilirubin screening/management program, ABO hemolytic disease severity might be different than in our system. PMID- 29410541 TI - Implementation of safe sleep practices in Massachusetts NICUs: a state-wide QI collaborative. AB - OBJECTIVE: To increase the use of safe sleep practices (SSP) among high-risk infants discharged from Massachusetts (MA) NICUs to 90% in 2 years. DESIGN/METHODS: The Neonatal Quality Improvement Collaborative of MA (NeoQIC) is a consortium of neonatal providers that provides infrastructure to lead and manage state-wide quality improvement initiatives. The safe sleep initiative was started in July 2015 with participation of all 10 MA level III NICUs. Based upon the project algorithm, infants are eligible for two sleep practices: SSP or NICU therapeutic positioning (NTP) depending on their gestational age, weight, and clinical illness. Compliance with SSP is defined as: (1) supine positioning, (2) in a flat crib with no incline, (3) without positioning devices, and (4) without soft objects. NTP comprised usual NICU care. Local improvement teams devise intervention strategies, perform weekly crib audits for all NICU infants, and submit data on overall compliance and compliance with each SSP component on a monthly basis to NeoQIC. RESULTS: From July 2015 to June 2017, 7261 cribs were audited. Statistical process control charts showed significant improvement in the primary outcome of interest, overall compliance with SSP, for all participating NICUs. Compliance increased from 47.7% at the start of the project to 75.5% by the end of year 1 and to 81.0% by June 2017. CONCLUSIONS: This state-wide collaborative has improved SSP compliance in all level III MA NICUs and demonstrated that on a state-wide level, SSPs can be routinely integrated into the care of high-risk infants. PMID- 29410542 TI - Utility of prenatal Doppler ultrasound to predict neonatal impaired cerebral autoregulation. AB - OBJECTIVE: Determine if abnormal prenatal Doppler ultrasound indices are predictive of postnatal impaired cerebral autoregulation. STUDY DESIGN: Prospective cohort study of 46 subjects, 240-296 weeks' gestation. Utilizing near infrared spectroscopy and receiver-operating characteristic analysis, impaired cerebral autoregulation was defined as >16.5% time spent in a dysregulated state within 96 h of life. Normal and abnormal Doppler indices were compared for perinatal outcomes. RESULTS: Subjects with abnormal cerebroplacental ratio (n = 12) and abnormal umbilical artery pulsatility index (n = 13) were likely to develop postnatal impaired cerebral autoregulation (p <= 0.02). Abnormal cerebroplacental ratio was associated with impaired cerebral autoregulation between 24 and 48 h of life (p = 0.016). These subjects have increased risk for fetal growth restriction, lower birth weight, lower Apgar scores, acidosis, and severe intraventricular hemorrhage and/or death (p < 0.05). CONCLUSION: Abnormal cerebroplacental ratio and umbilical artery pulsatility index are associated with postnatal impairment in cerebral autoregulation and adverse outcome. PMID- 29410543 TI - Efficacy of modified Tochen's formula for optimum endotracheal tube placement in low birth weight neonates: an RCT. AB - OBJECTIVE: To assess the efficacy of modified Tochen's formula (birth weight + 5 cm) when compared to Tochen's formula for optimum placement of endotracheal tubes (ET) in low birth weight (LBW) neonates. STUDY DESIGN: In the NICU of a tertiary care hospital, LBW babies requiring intubation were randomized to Tochen's formula or modified Tochen's formula. The incidence of inadequate placement and optimum length of ET insertion were estimated. Analysis was done by the Chi square and 't'-tests. RESULTS: Sixty-seven babies were included: 34 in Tochen's group and 33 in modified Tochen's group. Baseline characteristics were similar. Modified Tochen's formula was significantly (p = 0.006) closer to the optimum position when compared to Tochen's formula. The percentages of optimum and adequate placements of the ET tube was higher in the modified Tochen's group, though not statistically significant. CONCLUSION: Modified Tochen's formula in LBW babies may enable more optimum placement of ETs. PMID- 29410544 TI - Prenatal microarray analysis in right aortic arch-a retrospective cohort study and review of the literature. AB - OBJECTIVE: To examine the risk for clinically significant chromosomal microarray analysis (CMA) findings in fetal right aortic arch (RAA). METHODS: Data from all CMA analyses performed owing to isolated RAA reported to the Israeli Ministry of Health between January 2013 and September 2016 were evaluated retrospectively. Risk for abnormal CMA findings was compared with two control populations, based on both previously described 9272 pregnancies with normal ultrasound, and on a local cohort of 5541 pregnancies undergoing CMA testing owing to maternal request. In addition, Pubmed database search was conducted for original researches examining this issue. RESULTS: Of 94 CMA analyses performed owing to isolated RAA, six (6.4%) pathogenic findings were detected (47,XX + 21; 45,X; two 22q11.2 microdeletions; 10p15.3 microdeletion and 16p11.2 duplication). Compared with control groups, an isolated RAA yielded a significantly increased relative risk for abnormal CMA results. Literature search yielded two additional retrospective studies describing microarray testing in RAA and encompassing 57 cases. The overall risk for clinically significant CMA findings was 6.62% (10/151). CONCLUSIONS: CMA testing is indicated in cases of prenatal isolated RAA, even in the era of advanced sonographic equipment, routine biochemical screening for Down syndrome and available non-invasive prenatal testing. PMID- 29410545 TI - Placental transfusion in preterm neonates of 30-33 weeks' gestation: a randomized controlled trial. AB - OBJECTIVES: To compare effect of placental transfusion by delayed cord clamping (DCC) or cord milking (CM) with early cord clamping (ECC) on a composite of mortality or abnormal neurological status at 40 weeks' post-menstrual age (PMA) and 24-30 months' chronological age in neonates of 30-33 weeks' gestation. STUDY DESIGN: Randomized, controlled trial. OUTCOMES: A composite of mortality or abnormal neurological status at 40 weeks PMA and survival free of neurodevelopmental abnormalities at 24-30 months' chronological age. RESULTS: A total of 461 neonates were randomized to placental transfusion (n = 233) or to ECC (n = 228). Among those assigned to placental transfusion group, 173 underwent DCC while in the remaining 60, CM was done. Incidence of mortality or abnormal neurological status at 40 weeks PMA (43 (18%) vs 35 (15%), RR (95% CI) 1.2 (0.8, 1.8), p = 0.4) and survival free of neurodevelopmental impairment at 24-30 months of chronological age (99 (47%) vs. 100 (50%); RR (95% CI): 0.9 (0.8, 1.2); P = 0.9) was similar between the study groups. The placental transfusion group showed a trend towards lower incidence of necrotizing enterocolitis. CONCLUSION: In 30 33 weeks' gestation preterm neonates, placental transfusion as compared to early cord clamping resulted in similar mortality or abnormal neurological status at 40 weeks PMA and at 24-30 months of chronological age. PMID- 29410546 TI - HLA mismatches that are identical for the antigen recognition domain are less immunogenic. AB - For hematopoietic stem cell transplantation (HCT) HLA 10/10 (HLA-A, B, C, DRB1, DQB1) matched donors are optimal, but are not available for all patients. The identification of permissive/non-immunogenic mismatches may improve the outcome of HLA mismatched transplants. We hypothesize that HLA alleles identical within the antigen recognition domain (ARD), but mismatched outside the peptide binding groove or alpha-helices are often permissive mismatches. We evaluated the functional impact of non-ARD mismatches by performing in vitro functional T cell assays. Cytotoxic T Lymphocyte precursor assays were performed for 23 HLA class I mismatches and 96% (22 out of 23) were negative. Mixed lymphocyte reaction assays were conducted on 10 HLA class II mismatches and all were negative. However, 4 out of 10 combinations were positive in the Elispot and all involved one direction: a DRB1*14:01/DRB3*02:01 responder against a DRB1*14:54/DRB3*02:02 stimulator. These positive responses were confirmed by Primed Lymphocyte Testing and the DRB1* mismatch seemed to be responsible for the response. In conclusion, HLA mismatches with amino-acid differences outside the ARD are not very immunogenic. However, in some cases weak T cell reactivity in vitro can be observed. The impact of these responses on clinical outcome of HCT remains to be established. PMID- 29410550 TI - The role of peritoneal drainage in veno-occlusive disease in pediatric patients post hematopoietic stem cell transplant. PMID- 29410547 TI - Thyroid dysfunction in adult hematopoietic cell transplant survivors: risks and outcomes. AB - The incidence and risk factors for thyroid disorders among adult survivors of allogeneic hematopoietic stem cell transplantation (alloHCT) is not well known. This study evaluated incidence and risk factors of thyroid dysfunction in 259 adult alloHCT recipients who had survived for 2 years or more after transplant. Median follow-up was 4.6 years (range; 2.3 to 15.4 years). The 5-year cumulative incidence of thyroid dysfunction was 30.5% (79 of 259 patients). Majority of thyroid abnormalities were observed beyond 2 years after alloHCT. Subclinical hypothyroidism was the most common thyroid abnormalities accounting for 89% of cases (71 patients). Among these, treatment with thyroid replacement was eventually started in 44% (31 patients). Based on the multivariate analysis, thyroid abnormality was more likely in patients who received high-dose (>=12 Gy) total body irradiation (TBI)-based conditioning regimen compare to low-dose TBI based (<=500 cGy) and non-TBI-conditioning regimen (p = 0.032). This risk was further augmented directly proportional with the time from alloHCT. These data identify high-dose TBI-conditioning regimen as a risk factor for thyroid dysfunction in adult recipients of alloHCT. PMID- 29410548 TI - Analysis of the Spanish CCR5-?32 inventory of cord blood units: lower cell counts in homozygous donors. AB - The possibility to use CCR5-?32 umbilical cord blood to cure HIV infection in patients in need of a hematopoietic transplant has been suggested. The less stringent HLA compatibility needed in this type of transplant facilitates the search of a suitable donor having the CCR5-?32 mutation. To achieve an inventory of CCR5-?32 cord blood units, the 20,236 best cell quality units of the Spanish Registry were genotyped. Furthermore, their CD34+ and total nucleated cells counts, blood type, gender, HLA and donor's geographical and ancestral origin were analyzed. The results showed 130 (0.64%) units homozygous for the deletion, 2,646 (13.08%) heterozygous and 17,460 (86.28%) did not present the mutation. Interestingly, a significant lower amount of CD34+ cells was found in the CCR5 ?32 homozygous units. In addition, a significant association was found among donor's ancestral origin and the mutation, with a higher percentage of CCR5-?32 units with a European ancestry. In summary, identification of a relatively high number of CCR5-?32 units is feasible and will facilitate the development of clinical trials for HIV cure in patients requiring hematopoietic transplantation. Further studies are required to understand the significance of lower cell counts within the CCR5-?32 homozygous group and its clinical impact. PMID- 29410551 TI - Association between occupational lead exposure and plasma levels of selected oxidative stress related parameters in Jordanian automobile workers. AB - OBJECTIVES: To study any possible correlation between blood lead levels and some oxidative stress parameters of selected groups of lead-exposed automobile occupational Jordanian workers. MATERIAL AND METHODS: Blood lead levels were determined for a total of 90 male automobile workers aged within the range of 25 45 years old along with the group of 20 agematched healthy males control. To get an idea about the antioxidant status of controls and lead-exposed workers, and to estimate the oxidative stress caused by exposure to lead, we measured the hydrogen peroxide (H2O2) concentration, superoxide dismutase (SOD) activity, lipid peroxidation as malondialdehyde (MDA) and total antioxidant capacity of controls and workers. RESULTS: The study showed that lead levels in the case of workers were approximately 4-5 times as high as in controls 14.5-21 MUg*dl-1 vs. 4.3 MUg*dl-1, respectively. There was a significant decrease (16-25%) in the level of plasma reduced glutathione and 21 33% decrease in total antioxidant capacity (TAOC) in all worker groups, as compared to controls. The results showed that the concentration of malondialdehyde (MDA) in plasma was higher (120-333%) in the case of workers than controls being the highest in automobile electronics and the lowest - in mechanics. Furthermore, there was 149-221% increase in hydrogen peroxide (H2O2) concentration, and 26-38% increase in SOD activity in the case of workers compared to the control group. CONCLUSIONS: There is a strong evidence for the associations between occupational lead exposure and various markers of oxidative stress in Jordanian automobile occupational workers. Thus, there is an urgent need to raise awareness and to initiate suitable protection guidelines for workers. Int J Occup Med Environ Health 2018;31(4):517 525. PMID- 29410549 TI - Chronic graft versus host disease presenting as lichen planus pigmentosus. PMID- 29410552 TI - Letter to the Editor (June 10, 2017) concerning the paper "Trends in smoking among secondary school and high school students in Poland, 2009 and 2011". PMID- 29410553 TI - Authors' response (December 7, 2017) to the letter to the Editor concerning the paper "Trends in smoking among secondary school and high school students in Poland, 2009 and 2011". PMID- 29410554 TI - Job autonomy in relation to work engagement and workaholism: Mediation of autonomous and controlled work motivation. AB - OBJECTIVES: This study integrates the Self Determination Theory and the Job Demands-Resource model in explaining motivational antecedents of 2 forms of excessive work: work engagement and workaholism. It specifically examines the relationship between job autonomy, situational work motivation, work engagement, and workaholism. MATERIAL AND METHODS: The sample comprised 318 full-time employees of an international outsourcing company located in Poland. The mediation analysis was used for testing hypotheses about the mediation of autonomous and controlled motivation in the relationship between job autonomy, work engagement, and workaholism. RESULTS: The results have confirmed that autonomous motivation mediates the relationship between job autonomy and work engagement. The assumption about the mediation role of controlled motivation in the relationship between job autonomy and workaholism has not been confirmed; however, external regulation (i.e., controlled motivation) is a significant predictor of workaholism. CONCLUSIONS: Giving employees more job autonomy might increase their intrinsic and identified regulation and may therefore lead to more energetic, enthusiastic, and dedicated engagement with their jobs. Workaholism may be predicted by external regulation, and work characteristics other than job autonomy may play an important role in enhancing this controlled type of motivation. Int J Occup Med Environ Health 2018;31(4):445-458. PMID- 29410555 TI - Reliability analysis of the Korean version of the trunk control measurement scale in cerebral palsy. AB - [Purpose] The purpose of this study was to translate the Trunk Control Measurement Scale into a Korean version and to analyze the intra- and inter-rater reliability. [Subjects and Methods] Fifteen children with spastic cerebral palsy and four physical therapists with over 10 years of clinical experience participated in this study. A Korean-American physical therapist translated the trunk control measurement scale from English into a Korean version. Four physical therapists viewed the video data of 15 children and scored each child's trunk control measurement scale performance on seven separate days. Four testers analyzed the test-retest reliability and inter-rater reliability using the intra class correlation coefficient. [Results] Intra-class correlation coefficients for test-retest and inter-rater reliability for the Korean trunk control measurement scale showed significantly high reliability in all testers and sublevels. [Conclusion] The Korean version of the measurement scale is a reliable and suitable instrument for assessing trunk control in individuals with cerebral palsy in Korea. PMID- 29410556 TI - Survey report on awareness and participation behavior in disabled sports and disability understanding after Tokyo's bid for the 2020 Olympics and Paralympics. AB - [Purpose] This study analyzes awareness and participation behavior in disabled sports and disability understanding after Tokyo's bid for the 2020 Olympics and Paralympics. [Subjects and Methods] The study conducted a cross survey on 220 registrants of an Internet research firm. It analyzed: the awareness of citizens and their behavioral changes, in the aftermath of the allocation of Olympic and Paralympic Games; subject attributes and education level; recognition of disabled sports; and the awareness and behavior of participants, with regard to disabled sports. The analysis was conducted using SPSS Ver. 21 (IBM). [Results] The subjects were not interested in watching (72.2%), participating (76.8%), or volunteering (71.8%) in disabled sports. In addition, 76.8% of the subjects exhibited no behavioral changes-such as by watching, participating, or volunteering in disabled sports-after the Olympics and Paralympics bid decision. [Conclusion] This study's subjects had no confidence in their disability knowledge and no opportunities to interact with disabled persons. Furthermore, the bids for mega-events such as the Olympic and Paralympic Games did not lead to behavioral changes concerning disabled sports. Therefore, disability understanding should promote and deepen participation behavior in disabled sports. PMID- 29410557 TI - Effect of limbering up of the muscles attached to the pelvis on the strength of upper and lower extremity and trunk muscles through the transitional network. AB - [Purpose] To study the effect that limbering up of the muscles attached to the pelvis has on muscle strength of the trunk and upper and lower extremities, which are not being exercised, and to investigate the possibilities for clinical application. [Subjects and Methods] A total of 152 healthy adult men. Sthenometry was conducted using a handheld dynamometer to assess the effect of limbering up of the upper gluteus maximus, hamstrings, and internal abdominal oblique muscles attached to thoracolumbar fascia on the trunk and upper and lower extremities. The exercises were slowly performed 20 repetitions. Subjects were divided into AB group (n=49) measuring abdominal and back muscle strength, K group (n=42) measuring knee flexor and extensor strength, and S group (n=61) measuring shoulder flexor and external rotator strength and compared to non-exercising controls. [Results] In the exercise groups, exercising either gluteus maximus or hamstrings significantly increased the strength of abdominal and back muscles; exercising gluteus maximus increased knee extensor strength, and exercising the abdominal internal oblique muscle significantly increased knee flexor strength; and shoulder flexor strength significantly increased after exercising gluteus maximus versus controls. [Conclusion] This may be useful in rehabilitation of injuries to the trunk and upper and lower extremities. PMID- 29410558 TI - Effects of 12-week lumbar stabilization exercise and sling exercise on lumbosacral region angle, lumbar muscle strength, and pain scale of patients with chronic low back pain. AB - [Purpose] The purpose of this study is to investigate the effects of lumbar stabilization exercise and sling exercise on lumbosacral region angle, lumbar muscle strength, pain scale of patients with chronic low back pain. [Subjects and Methods] The subjects of this study were 29 chronic low back pain patient women who were selected among participants in exercise class at K Region Health Promotion Center in South Korea and were randomly assigned to the lumbar stabilization exercise group (n=10), sling exercise group (n=10), and the control group (n=9). Both lumbar stabilization and sling exercise programs were executed for 60 minutes, three times a week, for 12 weeks. Before and after exercise we measured lumbosacral region angle (lumbar lordosis angle, lumbosacral angle, sacral inclination angle), lumbar muscle strength, and pain scale in all subjects. Two-way analysis of variance was conducted to analyze experimental data. In order to analyze the interaction effect, we conducted paired t-test before and after treatment. [Results] Lumbar stabilization exercise group and sling exercises group did not affect lumbar lordosis angle, lumbosacral angle and sacral inclination angle. Whereas the lumbar flexion muscle strength and lumbar extension muscle strength significantly increased in the lumbar stabilization exercise group and sling exercise group. The flexibility increased in the lumbar stabilization exercise group and sling exercise group. The pain scale decreased in the lumbar stabilization exercise group and sling exercise group. [Conclusion] Both lumbar stabilization exercise and sling exercises are useful therapeutic approaches to chronic back pain. PMID- 29410559 TI - The effect of actively induced vibration using shoulder joint on pain and dysfunction in patients with low back pain. AB - [Purpose] This study aimed to determine the effect of a Flexi-Bar exercise program with vibration stimulation on pain and dysfunction in patients with low back pain. [Subjects and Methods] This study included 30 patients with low back pain. The participants were divided into a control (n=15) group and an experimental group (n=15). General physical therapy was used in both groups. A Flexi-Bar exercise program with vibration stimulation was used in the experimental group. The Visual Analog Scale was used to measure pain severity. The Oswestry Disability Index was used to measure the extent of dysfunction due to low back pain. [Results] The VAS and ODI of the experimental group showed a significant difference compared to that of the control group. [Conclusion] The results show that a Flexi-Bar exercise program with vibration stimulation is effective in alleviating pain and dysfunction in patients with low back pain. PMID- 29410560 TI - The relationship between anterior pelvic tilt and gait, balance in patient with chronic stroke. AB - [Purpose] The aim of this study is to find out the association between anterior pelvic tilt and gait and balance in chronic stroke. [Subjects and Methods] Fourteen chronic stroke patients were included in this study. A palpation meter was employed to measure the anterior inclination of the pelvis. A GAITRite system automates measuring temporal and spatial gait parameters. A 10-Meter Walk test was used to measure gait speed. The Timed Up and Go test was used to measure the dynamic balance ability and gait ability of the participants. A BioRescue was used to assess balance by measuring the moving distance and area of the center of pressure. [Results] There were significant negative correlations between pelvic anterior tilt and velocity, step length, and stride. There were significant positive correlations between velocity and cadence, step length, and stride length. There were significant negative correlations between velocity and cycle time, H-H base, TUG, and 10MWT. There was significant negative correlation between cadence and cycle time and H-H base. [Conclusion] This study showed a negative correlation between pelvic anterior tilt and gait function including gait speed and step length. PMID- 29410561 TI - Rater reliability and construct validity of a mobile application for posture analysis. AB - [Purpose] Measurement of posture is important for those with a clinical diagnosis as well as researchers aiming to understand the impact of faulty postures on the development of musculoskeletal disorders. A reliable, cost-effective and low tech posture measure may be beneficial for research and clinical applications. The purpose of this study was to determine rater reliability and construct validity of a posture screening mobile application in healthy young adults. [Subjects and Methods] Pictures of subjects were taken in three standing positions. Two raters independently digitized the static standing posture image twice. The app calculated posture variables, including sagittal and coronal plane translations and angulations. Intra- and inter-rater reliability were calculated using the appropriate ICC models for complete agreement. Construct validity was determined through comparison of known groups using repeated measures ANOVA. [Results] Intra rater reliability ranged from 0.71 to 0.99. Inter-rater reliability was good to excellent for all translations. ICCs were stronger for translations versus angulations. The construct validity analysis found that the app was able to detect the change in the four variables selected. [Conclusion] The posture mobile application has demonstrated strong rater reliability and preliminary evidence of construct validity. This application may have utility in clinical and research settings. PMID- 29410562 TI - Effects of microcurrent and cryotherapy on C-reactive protein levels and muscle tone of patients with rotator cuff reconstruction. AB - [Purpose] The purpose of the present study was to apply early intervention via microcurrent and cryotherapy in patients who underwent rotator cuff reconstruction surgery, and to investigate the effects of such interventions on pain and inflammation levels based on the analysis of C-reactive protein (CRP) levels, and on changes in muscle tone. [Subjects and Methods] The study population consisted of 30 patients who had undergone rotator cuff reconstruction surgery, with 10 patients each assigned to the control, experimental I (E-1), and experimental II (E-II) groups. On the day after surgery, muscle tone, blood CRP level, and pain were measured. For the following two weeks, continues passive motion (CPM), icing, cryotherapy, and microcurrent were applied to the each group. After the respective interventions, CRP levels, pain, and muscle tone near the shoulder area were measured again. [Results] In the post-hoc test of between group comparison, a statistically significant difference in CRP level was found in the cryotherapy group. A difference in shoulder muscle tone appeared only in the supraspinatus muscle, with post-hoc test results showing that the biggest change occurred in the cryotherapy group. [Conclusion] Cryotherapy may be able to help stabilize inflammation as well as reduce pain and muscle tension when applied in patients following rotator cuff reconstruction. PMID- 29410563 TI - Changes in oxidative stress severity and antioxidant potential during muscle atrophy and reloading in mice. AB - [Purpose] Changes in oxidative stress severity and antioxidant potential are routinely used as oxidative stress markers. While several studies have reported the relationship between these markers and exercise, little is known about the dynamic nature of these markers during muscle atrophy and reloading. Therefore, we examined changes in oxidative stress severity and antioxidant potential during muscle atrophy and reloading. [Subjects and Methods] Muscle atrophy was induced in mice by casting the limb for 2 weeks. Mice were then subjected to reloading for 2 weeks. The severity of oxidative stress (hydroperoxide) and antioxidant potential (degree of reduction) were quantified. [Results] Muscle atrophy was induced by cast immobilization. The muscle mass of mice recovered to similar levels as the control group following 2 weeks of reloading. The degree of oxidative stress was within the normal range throughout the experimental period. The antioxidant potential decreased to the clinical borderline level 2 weeks after immobilization, further decreased after 1 day of reloading, and then recovered to within the normal range. [Conclusion] Performing d-ROMs and BAP tests may contribute to the understanding to atrophic process of skeletal muscle in clinical practice of physical therapy. PMID- 29410564 TI - Correlations between measurement time and different expansibility of the elastic tape on the rectus femoris and body sway index with plyometric exercise. AB - [Purpose] The purpose of this study was to examine correlations between measurement time and different expansibility of the elastic tape on the rectus femoris and body sway index with plyometric exercise. [Subjects and Methods] The subjects of this study were 24 healthy men. C90 area, C90 angle, trace length, sway average velocity for body sway index were measured using a force plate by BT4. The collected data were analyzed using Kendall's coefficient of concordance. [Results] All of body sway index on measuring follow up 24 hours after removing tape were significantly decreased than before and right after plyometric exercise. No significant correlations were found between body sway index and different expansibility of the elastic tape. [Conclusion] It appears that different expansibility of the elastic tape does not affect the ability to body sway index. Carry over effect of taping was verified on measuring follow up 24 hours after removing tape through the decreasing body sway index. PMID- 29410565 TI - The reliability and validity of the Korean version of the lower limb functional index. AB - [Purpose] The purpose of this study was to establish the reliability and validity of the Korean-translated version of the Lower Limb Functional Index (LLFI) in the assessment of patients with lower-limb disorders. [Subjects and Methods] Fifty six subjects with lower-limb disorders, 24 men and 32 women, participated in this study. Reliability was determined by using the intra-class correlation coefficient and Cronbach's alpha for internal consistency. Validity was examined by correlating the LLFI scores with the Lower Extremity Functional Scale (LEFS) and Short Form 36 (SF-36) scores. [Results] The test-retest reliability was 0.95. The criterion-related validity was established through a comparison with the Korean versions of the LEFS and SF-36. [Conclusion] The Korean version of the LLFI was shown to be a reliable and valid instrument for assessing lower-limb complaints. PMID- 29410566 TI - Study on change of rat soleus extensibility caused by reduction in joint movement with unweighting of the hind limbs. AB - [Purpose] The purpose of this study was to investigate the change in soleus extensibility from a joint contracture caused by a reduction in joint movement with unweighted lower limbs and to interpret the results to aid in the treatment of human joint contractures. [Subjects and Methods] The subjects of this study were twenty-one 10-weeks-old male Wistar rats. Twenty-one rats were divided into one control (C) and two experimental groups. The first experimental group included fixed right ankle joints in full plantar flexion (F). The second experimental group's hind limbs were suspended and the right ankle joints were fixed in full plantar flexion (FS). The period of this study was one week. On the first and last day of this study, all of the rats' ankle dorsiflexion angles were measured. On the last day of this study, all of the rats' soleus extensibilities were measured. [Results] On the last day of this study, the ankle dorsiflexion angles and the soleus extensibility in the FS group were significantly more decreased than those of the F group. [Conclusion] It was shown that the skeletal muscle extensibility from joint contracture caused by reduction of joint movement with unweighted lower limbs was more markedly decreased than that from joint contracture caused by reduction of joint movement. PMID- 29410567 TI - Side-to-side difference in dynamic unilateral balance ability and pitching performance in Japanese collegiate baseball pitchers. AB - [Purpose] To evaluate the side-to-side difference in dynamic unilateral balance ability and to determine the correlation of the balance ability with pitching performance in collegiate baseball pitchers. [Subjects and Methods] Twenty-five Japanese collegiate baseball pitchers participated in this study. Dynamic balance ability during a unilateral stance was bilaterally evaluated using the star excursion balance test (SEBT). The pitchers threw 20 fastballs at an official pitching distance; the maximal ball velocity and pitching accuracy (the number of strike/20 pitches * 100) were assessed. Side-to-side difference in scores of SEBT was assessed using a paired t-test. Correlations between SEBT scores and pitching performance were evaluated for both legs using a Pearson's correlation analysis. [Results] The pivot side showed significantly higher score of the SEBT in the anteromedial direction than the stride side. On the other hand, the SEBT scores in the pivot and stride legs did not have significant correlations with maximal ball velocity and pitching accuracy. [Conclusion] These findings suggest that marked side-to-side difference does not exist in the dynamic unilateral balance ability of collegiate baseball pitchers and that the dynamic unilateral balance ability of each leg is not directly related to maximal ball velocity and pitching accuracy. PMID- 29410568 TI - Comparison of sleep status among three Japanese national wheelchair basketball teams. AB - [Purpose] Sufficient sleep is required for maximal performance and good mood. Japan has three national wheelchair basketball teams: Top male, Top female, and Under-23 (U23) male teams. Using these team members as model, this study investigated the difference of sleep status of wheelchair basketball players by age and gender. [Subjects and Methods] There were 44 participants: 14 in the Top male team (29.5 +/- 5.2 years), 18 in the Top female team (30.6 +/- 9.2 years), and 12 in the U23 team (19.1 +/- 2.0 years). Sleep status was assessed with the Pittsburgh Sleep Quality Index (PSQI); higher scores indicate poor sleep quality. [Results] PSQI scores in the Top male and female teams were higher than in the U23 team. The Top teams showed shorter sleep duration and worse sleep efficacy than the U23 team. Time spent in bed and sleep duration in the female team were shorter than in the Top male and U23 teams. More male players reported "feel too hot" as the reason for sleep disturbance than female players. [Conclusion] Players in the Top Japanese national wheelchair basketball teams had poorer sleep status than U23 players. Among female players, the reason for insomnia was less sleep duration. For males, the reason for insomnia was "feel too hot." PMID- 29410569 TI - Electrophysiological assessment of piano players' back extensor muscles on a regular piano bench and chair with back rest. AB - [Purpose] Sitting position is the dominant position for a professional pianist. There are many static and dynamic forces which affect musculoskeletal system during sitting. In prolonged sitting, these forces are harmful. The aim of this study was to compare pianists' back extensor muscles activity during playing piano while sitting on a regular piano bench and a chair with back rest. [Subjects and Methods] Ten professional piano players (mean age 25.4 +/- 5.28, 60% male, 40% female) performed similar tasks for 5 hours in two sessions: one session sitting on a regular piano bench and the other sitting on a chair with back rest. In each session, muscular activity was assessed in 3 ways: 1) recording surface electromyography of the back-extensor muscles at the beginning and end of each session, 2) isometric back extension test, and 3) musculoskeletal discomfort questionnaire. [Results] There were significantly lesser muscular activity, more ability to perform isometric back extension and better personal comfort while sitting on a chair with back rest. [Conclusion] Decreased muscular activity and perhaps fatigue during prolonged piano playing on a chair with back rest may reduce acquired musculoskeletal disorders amongst professional pianists. PMID- 29410570 TI - The effects of a client-centered leisure activity program on satisfaction, self esteem, and depression in elderly residents of a long-term care facility. AB - [Purpose] This study aimed to examine the effects of a client-centered leisure activity program on satisfaction, upper limb function, self-esteem, and depression in elderly residents of a long-term care facility. [Subjects and Methods] This study included 12 elderly subjects, aged 65 or older, residing in a nursing home. The subjects were divided into an experimental and a control group. Subjects in the control group received leisure activities already provided by the facility. The experimental group participated in a client-centered leisure activity program. The subjects conducted individual activities three times per week, 30 minutes per session. The group activity was conducted three times per week for eight weeks. Each subject's performance of and satisfaction with the leisure activity programs, upper limb function, self-esteem, and depression were measured before and after the intervention. [Results] After participating in a program, significant improvements were seen in both the Canadian Occupational Performance Measure and upper limb function in the experimental group. Also after the intervention, the subjects' self-esteem significantly increased and their depression significantly decreased. [Conclusion] A client-centered leisure activity program motivates elderly people residing in a long-term care facility and induces their voluntary participation. Such customized programs are therefore effective for enhancing physical and psychological functioning in this population. PMID- 29410571 TI - The effects of modified constraint-induced movement therapy and mirror therapy on upper extremity function and its influence on activities of daily living. AB - [Purpose] Modified constraint-induced movement therapy and mirror therapy are recognized as stroke rehabilitation methods. The aim of the present study was to determine whether these therapies influence upper extremity function and whether upper extremity function influences the ability to perform activities of daily living in further. [Subjects and Methods] Twenty-eight stroke patients participated in the study. Interventions were administered five times per week for 3 weeks. Activities of daily living or self-exercise were performed after modified constraint-induced movement therapy or mirror therapy, respectively. Analyses were performed on the results of the Manual Function Test and the Korean version of the Modified Barthel Index to determine the factors influencing activities of daily living. [Results] Both groups showed improvement in upper extremity function, but only the modified constraint-induced movement therapy group showed a correlation between upper extremity function and performance in the hygiene, eating, and dressing. The improved hand manipulation function found in the modified constraint-induced movement therapy had statistically significant influences on eating and dressing. [Conclusion] Our results suggest that a patient's attempts to move the affected side result in improved performance in activities of daily living as well as physical function. PMID- 29410572 TI - Effects of pelvic tilt angles and forced vital capacity in healthy individuals. AB - [Purpose] The purpose of this study was to investigate the effect of pelvic tilt angles and lung function in participants performing pelvic tilts on a ball. [Subjects and Methods] Eighteen subjects participated in this study. While they performed pelvic tilt on sitting at a ball, the peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) were measured at 10 degrees of anterior and posterior pelvic tilt, respectively, and neutral position. The repeated measure ANOVA was performed, and the Bonferroni correction was used for post-hoc analysis. [Results] The PEF of the participants was significantly higher at neutral position, compared with an anterior pelvic tilt at 10 degrees. The FEV1 was also higher in neutral position, compared with anterior and posterior pelvic tilt. [Conclusion] This study underlines the need for the standardization of the FVC testing protocol for positioning the pelvic angle in a neutral position in patients with respiratory disorders to promote reliable interpretation of intervention outcomes. PMID- 29410573 TI - Age-dependent changes in dynamic standing-balance ability evaluated quantitatively using a stabilometer. AB - [Purpose] The efficacy of a stabilometer-based index of postural stability (IPS) as an indicator of dynamic balance ability was investigated. [Subjects and Methods] Using a stabilometer, we calculated the IPS in 583 healthy subjects (178 males, 405 females) under two conditions (open eyes/hard surface, OE/HS; closed eyes/soft surface, CE/SS). [Results] Results revealed a negative relation between IPS and age. IPS (OE/HS) began to decrease at middle-age (40-60 years old), and then decreased more rapidly during elderly ages (>60 years old). On the other hand, IPS (CE/SS) decreased linearly with increasing age. There was no gender difference between the two IPSs. [Conclusion] These results suggest that IPS can evaluate balance ability quantitatively and without a ceiling effect. It was concluded that IPS (OE/HS) indicates comprehensive balance ability, while IPS (CE/SS) reveals balance ability without compensation by visual acuity and plantar superficial sense. PMID- 29410574 TI - The tactile detection threshold changes when a visual stimulus is presented with a short temporal gap. AB - [Purpose] The interaction between the visual and tactile modalities influences on different levels from neural activity, perception, higher cognition to behavior. The aim of this study was to examine how a visual stimulus influences tactile sensitivity depending on temporal asynchrony. [Subjects and Methods] In total, 15 participants took part in this study. They were required to perform a two alternative forced-choice task regarding whether a tactile pulse was felt. The individual participants' tactile thresholds were estimated using a repetitive stepwise method. Visual stimuli were simultaneously presented with various temporal gaps (0 ms, +/- 50 ms, +/- 100 ms, and +/- 300 ms), whereas no visual stimulus was presented in the tactile only condition. The tactile thresholds in eight conditions were compared using analysis of variance. [Results] Of the participants, 53.5% showed the most sensitive tactile threshold when presented with a visual stimulus with a short temporal gap, especially when the visual stimulus preceded the tactile one by 50 ms. [Conclusion] The preceding visual stimulus facilitates the perceptual sensitivity of the tactile sensation. Providing sensory stimuli in a multisensory mode benefits perceptual encoding. A pre-attentional mechanism led by a particular sensory modality might work as a perceptual advantage for another modality. PMID- 29410575 TI - The effectiveness of manual therapy in treating cervicogenic dizziness: a systematic review. AB - [Purpose] This review provides an evaluation of the evidence for the effectiveness of using manual therapy to treat cervicogenic dizziness. [Subjects and Methods] The literature was systematically searched on the May 2, 2016 using the following online databases: Medline, EMBASE, CINAHL and PEDro. This review included randomised controlled trials and compared the efficacy of manual therapy for the treatment of cervicogenic dizziness, compared to other types of intervention. This study measured changes based on dizziness intensity and frequency. [Results] The primary search found 30 articles, but only four articles met the inclusion criteria. Assessment of methodological quality was performed by two researchers using the PEDro scale. The level of evidence was determined using a recognised grading scale. Three out of the four articles were deemed to have high methodological quality, while the fourth was rated as moderate quality. The attributed level of evidence was moderate (level 2). [Conclusion] Manual therapy is potentially effective for managing cervicogenic dizziness. However, due to the heterogeneity of the results and techniques and the low number of studies, further research is recommended to provide conclusive evidence. PMID- 29410576 TI - Resolution of temporomandibular joint dysfunction (TMJD) by correcting a lateral head translation posture following previous failed traditional chiropractic therapy: a CBP(r) case report. AB - [Purpose] To present the case of the resolution of right temporomandibular joint dysfunction (TMJD) following the correction of a right lateral head translation posture. [Subject and Methods] A 24 year old female reported facial pain and jaw clicking in the right TMJ. Radiography revealed a 19 mm right head (shift) translation posture. TMJ vibration analysis showed characteristic abnormalities for the right TMJ. The patient was treated with CBP(r) technique mirror image(r) left sided exercises, and traction methods as well as spinal manipulative therapy (SMT). [Results] After 36 treatments over a 12-week time period, a complete correction of the lateral head posture was achieved corresponding with a complete resolution of jaw pain and clicking. TMJ vibration analysis demonstrated normal right side TMJ characteristics following treatment. [Conclusion] Abnormal head/neck postures, such as lateral head translation, may be an unrealized source of TMJD and may be explained through the 'regional interdependence' model or by how seemingly unrelated anatomy may be associated with a primary complaint. PMID- 29410577 TI - Non-surgical improvement of cervical lordosis is possible in advanced spinal osteoarthritis: a CBP(r) case report. AB - [Purpose] To present a case of the non-surgical improvement in cervical kyphosis in a patient with history of cervical spine trauma and advanced osteoarthritis. [Subject and Methods] A 38 year old male presented with a chief complaint of chronic neck pain that was not substantially relieved by recent previous traditional physiotherapy and chiropractic manipulation. The cervical radiograph demonstrated a cervical hypolordosis of 5 degrees as measured by the Harrison posterior tangent method from C2-C7. There was a 15 degrees kyphosis at C4-C6 with advanced degenerative changes consistent with previous spine trauma. The patient was treated by CBP(r) methods incorporating cervical extension traction, extension exercises, and spinal manipulation for 30 sessions over an 18 week period. [Results] After the treatment sessions, there was a substantial (27 degrees ) increase in global C2-C7 lordosis, and 5 degrees decrease in C4-C6 degenerative kyphosis corresponding to the reduction in neck pain and disability, and an improvement in overall health status as indicated on the SF-36 health questionnaire. [Conclusion] Although degenerative spondylosis of the cervical spine will have physical limitations to non-surgical correction, this case serves as an example that it is possible to reduce degenerative kyphosis and increase global cervical lordosis corresponding to health improvements in these patients. PMID- 29410578 TI - Effects of visual feedback balance training on the balance and ankle instability in adult men with functional ankle instability. AB - [Purpose] This study examined the effects of visual feedback balance training on the balance and ankle instability in adult men with functional ankle instability. [Subjects and Methods] Twenty eight adults with functional ankle instability, divided randomly into an experimental group, which performed visual feedback balance training for 20 minutes and ankle joint exercises for 10 minutes, and a control group, which performed ankle joint exercise for 30 minutes. Exercises were completed three times a week for 8 weeks. Bio rescue was used for balance ability. It measured limit of stability at one minute. For ankle instability was measured using Cumberland ankle instability tool (CAIT). This measure was performed before and after the experiments in each group. [Results] The experimental group had significant increase in the Limit of Stability and CAIT score. The control group had significant increase in CAIT score. While the Limit of Stability increased without significance. [Conclusion] In conclusion, visual feedback balance training can be recommended as a treatment method for patients with functional ankle instability. PMID- 29410579 TI - Relationship between hamstring length and gluteus maximus strength with and without normalization. AB - [Purpose] This study assessed the relationship between hamstring length and gluteus maximus (GM) strength with and without normalization by body weight and height. [Subjects and Methods] In total, 34 healthy male subjects volunteered for this study. To measure GM strength, subjects performed maximal hip joint extension with the knee joints flexed to 90 degrees in the prone position. GM strength was normalized for body weight and height. [Results] GM strength with normalization was positively correlated with hamstring length, whereas GM strength without normalization was negatively correlated with hamstring length. [Conclusion] The normalization of GM strength by body weight and height has the potential to lead to more appropriate conclusions and interpretations about its correlation with hamstring length. Hamstring length may be related to GM strength. PMID- 29410580 TI - Changes in thickness of the transversus abdominis during the abdominal drawing-in manoeuvre and expiratory muscle training in elderly people. AB - [Purpose] It has been reported that exercises focusing upon the transversus abdominis (TrA) ameliorate low back pain (LBP). We investigated whether expiratory muscle training (EMT) can promote activity of the TrA to the same degree as the abdominal drawing-in manoeuvre (ADIM) in elderly individuals. [Subjects and Methods] Twenty-one elderly subjects (9 males, 12 females; mean age, 84.9 +/- 6.6 years) without LBP symptoms were included. Using ultrasound imaging we measured changes in thickness of the lateral abdominal muscles, TrA, internal oblique muscle (IO), and external oblique muscle (EO) during ADIM and EMT. The load in EMT was set to 15% of maximal expiratory pressure. [Results] TrA showed a significant increase in muscle thickness during ADIM and EMT compared with at rest. A significant increase in muscle thickness was noted for EMT in comparison with ADIM. No significant differences were found for IO and EO. [Conclusion] In elderly people, EMT may be an effective alternative to ADIM for promoting activity of the TrA and can be used as an exercise to maintain TrA function. PMID- 29410581 TI - The effects of proprioception exercise with and without visual feedback on the pain and balance in patients after total knee arthroplasty. AB - [Purpose] The aim of this study was to determine the effects of proprioception exercise to decrease pain and increase the ability to balance by implementing visual feedback during early rehabilitation after total knee arthroplasty. [Subjects and Methods] In this study, 24 patients who receive a total knee arthroplasty were randomly and equally assigned to a visual feedback training group (VFT group) and a visual disuse group (Control group). They performed visual feedback training using the My Fitness Trainer (MFT, Austria) for 20 minutes, three times per week for eight weeks. The patients' balance ability and pain was measured before and after the exercises. Pain was measured by the visual analogue scale (VAS). To assess balance ability, the anteroposterior and mediolateral directions on unstable ground was measured by using the MFT measurement system. [Results] The VFT group showed a significant decrease in VAS and an increase in balance ability within the group, as well as a significant increase in balance ability between groups when compared with the control group. [Conclusion] Visual feedback training during the rehabilitation of patients who received a total knee arthroplasty will be useful in reducing pain and improving balance. PMID- 29410583 TI - Correlation between pulmonary functions and respiratory muscle activity in patients with forward head posture. AB - [Purpose] The purpose of this study is to determine the effect that secondary postural deformities and chronic postural abnormalities have on lung capacity, as well as correlate the activity of the respiratory muscles. The results provide basic objective data about the forward head posture and respiratory muscle activity that can be used in clinical situations. [Subjects and Methods] The subjects used in this study were 24 patients aged 25 to 35 years old who visited a hospital in Jeollanam-do Province, Korea, between September 2015 and January 2016. The patients were diagnosed with forward head posture because the vertical line between the acromion process and the external acoustic meatus was at least 5 cm. We measured the craniovertebral angle, pulmonary functions, and respiratory muscle activity of the subjects for correlation analysis. [Results] A positive correlation was found between the craniovertebral angle and the forced vital capacity (r=0.63), while a negative correlation was found between the craniovertebral angle and the sternocleidomastoid muscle (r=-0.77). The craniovertebral angle and the anterior scalene muscle showed a negative correlation (r=-0.65). There were positive correlations between the forced vital capacity and the sternocleidomastoid muscle (r=0.71), and between the forced vital capacity and the anterior scalene muscle (r=0.59). [Conclusion] Severe forward head posture increased the activities of the sternocleidomastoid muscles and the anterior scalene muscles, and decreased the forced vital capacity. Thus, it is necessary to develop more efficient interventions for managing forward head posture based on pulmonary function and the activity of the respiratory synergist muscles. PMID- 29410582 TI - Comparison of pain, disorder, back performance, and psychological factors in patients with low back pain and radicular pain. AB - [Purpose] This study investigated the relationship between pain intensity, lumber disability, and psychological factors in patients with low back pain. [Subjects and Methods] A total of 166 outpatients (116 female, 50 male) with chronic low back pain presenting for physical therapy participated in this study. Patients were divided into two groups: those with low back pain alone and those with both low back pain and radicular pain. Pain intensity and lumbar disability were measured using a visual analogue scale and the Roland-Morris Disability Questionnaire. Psychological factors, such as self-efficiency, fear avoidance, and depression were measured using the Chronic Pain Self-efficacy Scale, Fear Avoidance Beliefs Questionnaire, and Beck Depression Index, respectively. [Results] Patients with low back pain with radicular pain had greater pain and lumber disability and lower psychological factors compared with patients with chronic low back pain alone. [Conclusion] Our findings indicate the presence of low back pain with radicular pain is more related to pain, LBP disability index, Back performance, Self-efficiency (Pain, Function, Symptom), Fear-avoidance (body, work) and depression factors than low back pain. Considering the relationships between in pain, LBP disability index, Back performance, Self efficiency (Pain, Function, Symptom), Fear-avoidance (body, work) and depression factors in patients with low back pain, therapeutic intervention for not only pain and dysfunction, but also psychological factors is needed. PMID- 29410584 TI - Relationships between motives to become a physical therapist, delayed graduation, and perceptions of school and internship learning among physical therapy students. AB - [Purpose] The purpose of this study is to reveal the relationships between physical therapy students' motives to become physical therapists and their academic performance. This was investigated by their experience of delayed or non delayed graduation, and their perceptions of learning in school and internship. [Subjects and Methods] Subjects were 245 physical therapists participating in a newcomer orientation by the Hiroshima Prefectural Physical Therapy Association in May, 2017. Subjects' basic attributes and their responses to specially created questionnaires were investigated. [Results] Seventeen of 193 physical therapists in their first year experienced delayed graduation. There were differences between the delayed graduation group and the non-delayed graduation group about motives for becoming a physical therapist. Moreover, there were significant relationships between motives for becoming a physical therapist and perceptions of learning in school as opposed to internship. [Conclusion] We conclude that motives for becoming a physical therapist are related to academic performance. PMID- 29410585 TI - Extension of knee immobilization delays recovery of histological damages in the anterior cruciate ligament insertion and articular cartilage in rabbits. AB - [Purpose] To investigate the influence of knee immobilization period on recovery of histological damages in the anterior cruciate ligament (ACL) insertion and articular cartilage in rabbits. This knowledge is important for determining the appropriate rehabilitation approach for patients with ligament injuries, fracture, disuse atrophy, and degenerative joint disease. [Materials and Methods] Forty-eight male Japanese white rabbits were divided equally into the remobilization and control groups. The remobilization group had the right knee surgically immobilized, and was divided equally into four subgroups according to the duration of immobilization (1, 2, 4 and 8 weeks). After the immobilization was removed, the rabbits moved freely for 8 weeks. The control group underwent sham operation and followed the same time course as the remobilization group. The chondrocyte apoptosis rate and chondrocyte proliferation rate in the ACL insertion and articular cartilage were analyzed after remobilization. [Results] In the ACL insertion, the remobilization group had a higher chondrocyte apoptosis rate than the control group after 8 weeks of immobilization, and a lower chondrocyte proliferation rate than the control group after 4 and 8 weeks of immobilization. In the articular cartilage, the remobilization group had a lower chondrocyte proliferation rate than the control group after 8 weeks of immobilization. After 8 weeks of remobilization, the ACL insertion and articular cartilage are not completely recovered after 4 and 8 weeks of immobilization, respectively. [Conclusion] Our results suggest that 8 weeks of remobilization will result in recovery of the ACL insertion after 2 weeks of knee immobilization, and recovery of the articular cartilage after 4 weeks of knee immobilization. If 8 weeks of immobilization occurs, a remobilization duration of more than 8 weeks may be necessary. PMID- 29410586 TI - Identifying elderly people at risk for cognitive decline by using the 2-step test. AB - [Purpose] The purpose is to verify the effectiveness of the 2-step test in predicting cognitive decline in elderly individuals. [Subjects and Methods] One hundred eighty-two participants aged over 65 years underwent the 2-step test, cognitive function tests and higher level competence testing. Participants were classified as Robust, <1.3, and <1.1 using criteria regarding the locomotive syndrome risk stage for the 2-step test, variables were compared between groups. In addition, ordered logistic analysis was used to analyze cognitive functions as independent variables in the three groups, using the 2-step test results as the dependent variable, with age, gender, etc. as adjustment factors. [Results] In the crude data, the <1.3 and <1.1 groups were older and displayed lower motor and cognitive functions than did the Robust group. Furthermore, the <1.3 group exhibited significantly lower memory retention than did the Robust group. The 2 step test was related to the Stroop test (beta: 0.06, 95% confidence interval: 0.01-0.12). [Conclusion] The finding is that the risk stage of the 2-step test is related to cognitive functions, even at an initial risk stage. The 2-step test may help with earlier detection and implementation of prevention measures for locomotive syndrome and mild cognitive impairment. PMID- 29410587 TI - Correlation between diaphragm thickness and respiratory synergist muscle activity according to severity of chronic obstructive pulmonary disease. AB - [Purpose] This study aims to analyze the effect that moderate to severe chronic obstructive pulmonary disease (COPD) has on the respiratory synergist muscles. The results will provide basic data that can be used in the clinical management of COPD. [Subjects and Methods] The subjects in the study were 47 male patients with COPD between 55 and 70 years old who were treated in a medical institution located in Jeollanam-do Province, South Korea, from October 2015 to December 2016. Measurements were analyzed to determine the correlation between the diaphragm thickness and the respiratory synergist muscle activity in patients with mild COPD. [Results] The results showed that there was a negative correlation between the diaphragm thickness and the sternocleidomastoid muscle and between the diaphragm thickness and the scalene muscle; however, there was a positive correlation between the diaphragm thickness and the external intercostal. For patients with severe COPD, negative correlations were found between the diaphragm thickness and the sternocleidomastoid muscle and between the diaphragm thickness and the scalene muscle. [Conclusion] The mechanical deformation of the thoracic cage caused by severe COPD reduces the lung capacity of patients and, thus, increases the difficulty in breathing. As the disease worsens, the patients tend to maintain ventilation using the respiratory synergist muscles. Thus, offering early and aggressive treatment and a respiration rehabilitation program to patients with COPD can help to reduce the actions of the respiratory synergist muscles to ensure normal breathing. PMID- 29410588 TI - Piriformis electromyography activity during prone and side-lying hip joint movement. AB - [Purpose] To measure electromyographic activity of the piriformis using fine-wire electrodes during 7 hip movements. [Subjects and Methods] Eleven healthy men, without severe low back pain or lower limb injury, participated in this study. Fine-wire electrodes were inserted into the piriformis and surface electrodes were attached to the muscles in the hip region and the trunk muscles on the dominant arm side. Electromyographic signal amplitude was measured during 7 hip movements: side-lying external rotation in hip neutral position, side-lying abduction in hip neutral position, side-lying abduction in hip external rotation, side-lying abduction in hip internal rotation, prone extension in hip neutral position, prone extension in hip external rotation, and prone extension in hip internal rotation. Repeated-measures one-way analysis of variance was used to examine electromyographic activity in each of the 7 hip movements. [Results] Piriformis electromyographic activity was highest during prone hip extension in external rotation. Both the superior and inferior portions of the gluteus maximus were also highly activated during prone hip extension in external rotation. [Conclusion] Prone hip extension in external rotation induced high electromyographic activity in the piriformis and superior and inferior gluteus maximus muscles. PMID- 29410590 TI - Effect of musculoskeletal pain of care workers on job satisfaction. AB - [Purpose] The purpose of this study was to examine the musculoskeletal pain of care workers and investigate its effect on their job satisfaction. [Subjects and Methods] Subjects were 87 care workers working at C elderly care service center in P region. The average age of men was 62.5 +/- 3.4 years and that of women was 57.3 +/- 2.7 years. The 'Guidelines for Risk Factor Survey on Tasks with Musculoskeletal Burden' of the KOSHA CODE (H-30-2003) of the Korea Occupational Safety and Health Agency (KOSHA) was used for measurement of musculoskeletal pain. This survey tool for job satisfaction consisted of 12 questions including the areas of wage satisfaction, professional satisfaction, job performance satisfaction, and relationship satisfaction. [Results] Study results showed that musculoskeletal pain varied depending on professional satisfaction, job performance satisfaction, and relationship satisfaction. The correlation between the areas of musculoskeletal pain and job satisfaction was examined and the following was revealed. Professional satisfaction was correlated with arm/elbow pain and lower back pain, job performance satisfaction with lower back pain, and relationship satisfaction with shoulder pain and lower back pain. [Conclusion] In this study, subjects were older and could have been easily exposed to diseases because of their age. To improve job efficiency among care workers, continuing education related to the job should take precedence. In addition, social support is required that can alleviate the heavy workload related to physical activity support, which is among the responsibilities of care workers. Moreover, application standards and coverage of industrial insurance for the treatment of musculoskeletal disorders of care workers should be extended further to relieve the burden of medical costs. A series of such measures will have a positive effect on improving the job satisfaction of care workers. PMID- 29410589 TI - The modulation of motor control by imitating non-biological motions: a study about motor resonance. AB - [Purpose] Sensorimotor experience modulates motor resonance, such as motor interference, which occurs when observing others' movements; however, it is unclear how motor resonance is modulated by intentionally imitating others' movements. This study examined the effects of imitation experience on subsequent motor resonance. [Subjects and Methods] Twenty-seven healthy participants performed horizontal arm movements while observing non-biological, incongruent (vertical) movements of a visual stimulus (triangle object) in pre- and post-test procedures. Thirteen participants in the imitation group imitated vertical movements (non-biological motion) of the triangle object between pre- and post test procedures and fourteen participants in the non-imitation group observed that. [Results] Variance in the executed movements was measured as an index of motor resonance. Although there was no significant difference in the non imitation group, there was a significantly smaller variance for post-test compared to pre-test in the imitation group. [Conclusion] Motor resonance was inhibited by intentionally imitating non-biological motions. Imitating movements different from one's own motor property might inhibit subsequent motor resonance. This finding might be applied to selectively using motor resonance as a form of rehabilitation. PMID- 29410591 TI - Effects of 12-week circuit exercise program on obesity index, appetite regulating hormones, and insulin resistance in middle-aged obese females. AB - [Purpose] The purpose of this study is to investigate the effects of circuit exercise on obesity index, appetite regulating hormones and insulin resistance in middle-aged obese women. [Subjects and Methods] The subjects of this study were 26 obese middle-aged women who were selected among participants in exercise class at K Region Health Promotion Center in South Korea and were randomly assigned to the exercise group (n=13; age 50.15 +/- 3.82, % body fat 38.79 +/- 3.28) and the control group (n=13; age 49.84 +/- 2.96, % body fat 37.46 +/- 2.51). Circuit exercise consisted of aerobic exercise and resistance exercise for 5 weeks and 50 minutes for 12 weeks. Before and after exercise we measured obesity index, leptin, ghrelin, fasting blood glucose, insulin, and insulin resistance in all subjects. A repeated-measured two-way of variance was performed for comparison of the treatment effects between the exercise and control groups. [Results] Body weight, BMI, and body fat percentage of obese index decreased significantly. Leptin of dietary regulation hormone was significantly decreased and ghrelin was significantly increased. Insulin and insulin resistance was significantly decreased. [Conclusion] Circuit exercise can be viewed as an effective exercise program to induce changes in appetite regulating hormones and to improve insulin resistance by mechanisms of energy homeostasis by weight loss. PMID- 29410592 TI - The relationships between cognitive function and hearing loss among the elderly. AB - [Purpose] Research related to dementia has gained momentum in South Korea and studies have found that the auditory sense affects dementia. This study aims to examine the relationship between the decline in hearing function and the overall cognitive function among the elderly. [Subjects and Methods] Eighty-two older adults aged 65-90 years (mean age: 79.3, SD: 5.2) participated. The Korean Mini Mental State Examination was used to assess cognitive function. Further, to assess the hearing function, pure-tone audiometry was performed prior to the cognitive function test. We used a paired t-test and Pearson's correlation test for the analysis. [Results] Generally, the higher the frequency band, the more hearing loss was identified among the elderly. In addition, the difference in hearing between both ears was significant; particularly, hearing loss in the right ear was significantly higher than that in the left. Cognitive function was not related to age, however, the correlation between cognitive function and hearing loss in the right ear was statistically significant. [Conclusion] Hearing loss influences cognitive function among the elderly. PMID- 29410593 TI - Cross-cultural adaptation and construct validity of the Korean version of a physical activity measure for community-dwelling elderly. AB - [Purpose] This study aimed to cross-cultural adapt and validate the Korean version of an physical activity measure (K-PAM) for community-dwelling elderly. [Subjects and Methods] One hundred and thirty eight community-dwelling elderlies, 32 males and 106 female, participated in the study. All participants were asked to fill out a fifty-one item questionnaire measuring perceived difficulty in the activities of daily living (ADL) for the elderly. One-parameter model of item response theory (Rasch analysis) was applied to determine the construct validity and to inspect item-level psychometric properties of 51 ADL items of the K-PAM. [Results] Person separation reliability (analogous to Cronbach's alpha) for internal consistency was ranging 0.93 to 0.94. A total of 16 items was misfit to the Rasch model. After misfit item deletion, 35 ADL items of the K-PAM were placed in an empirically meaningful hierarchy from easy to hard. The item-person map analysis delineated that the item difficulty was well matched for the elderlies with moderate and low ability except for high ceilings. [Conclusion] Cross-cultural adapted K-PAM was shown to be sufficient for establishing construct validity and stable psychometric properties confirmed by person separation reliability and fit statistics. PMID- 29410594 TI - Acute effects of accumulated aerobic exercise on aortic and peripheral pulse wave velocity in young males. AB - [Purpose] The present study investigates the acute effects of accumulated aerobic exercise on aortic and peripheral pulse wave velocity (PWV) in healthy young males. [Subjects and Methods] We gathered data from 9 healthy young males (age, 23.4 +/- 0.6 years) performed aerobic exercise group (AE, 65% peak oxygen uptake; two 15 min bouts of cycling performed with 20 min rest) and control group (CON, seated and resting in a quiet room) on separate days in a randomized, controlled crossover fashion. Carotid-femoral (aortic) and femoral-ankle (peripheral) PWV, carotid augmentation index, carotid, brachial and ankle blood pressure and heart rate were measured before (baseline) and 20 min for both groups. [Results] Aortic and peripheral PWV decreased from baseline at 20 min for the AE group, but not in the CON group. [Conclusion] The present findings indicate that acute accumulated aerobic exercise decreases aortic and peripheral PWV in healthy young males. PMID- 29410595 TI - Relief of exertional dyspnea and spinal pains by increasing the thoracic kyphosis in straight back syndrome (thoracic hypo-kyphosis) using CBP(r) methods: a case report with long-term follow-up. AB - [Purpose] To present the clinically significant improvement of straight back syndrome (SBS) in a patient with spinal pain and exertional dyspnea. [Subject and Methods] A 19 year old presented with excessive thoracic hypokyphosis and other postural deviations. A multimodal CBP(r) mirror image(r) protocol of corrective exercises, traction procedures and spine/posture adjusting were given over an initial 12-week course of intensive treatment followed by a 2.75 year follow-up with minimal supportive treatment. [Results] The patient had significant postural improvements in all postural measures and specifically a 14 degrees increase in the thoracic kyphosis that was maintained at long-term follow-up. The postural improvements were consistent with relief of exertional dyspnea and pain, as well as increases in both antero-posterior thoracic diameter and the ratio of antero posterior to transthoracic diameter, measurements critical to the wellbeing of patients with SBS. [Conclusion] Long-term follow-up confirmed stable improvement in physiologic thoracic kyphosis in this patient. Nonsurgical correction in thoracic hypokyphosis/SBS can be achieved by mirror image traction procedures configured to flex the thoracic spine into hyperkyphosis as well as corrective exercise and manipulation as a part of CBP technique protocols. PMID- 29410596 TI - Immediate effects of scapular stabilizing exercise in chronic stroke patient with winging and elevated scapula: a case study. AB - [Purpose] The purpose of this study was to investigate the effect of scapular stabilizing exercise in a stroke patient with winging and elevated scapula. [Subject and Methods] The subject was a 46-year-old female with a history of stroke. She had right side hemiplegia with winging and elevated scapula on the right side, and had compensatory motions of the neck and shoulder when using the paretic upper extremity. The subject participated in scapular stabilizing exercises for four days. This exercise program consisted of scapular protraction retraction in an upright seated position. Scapular position was measured as distance between scapular medial border and thoracic vertebrae 3, 4. Upper extremity function was measured as time required for lifting and lowering a cup with the affected arm. [Results] After intervention, distance between scapular medial border and spinouse process of T3, 4 decreased. Time required for lifting and lowering a cup with the affected arm decreased. Compensatory motions of the neck and shoulder joint decreased. [Conclusion] Despite the short period, scapular stabilizing exercises had a positive effect on scapular position and upper extremity function. PMID- 29410597 TI - Comparison of a retraction exercise and passive scapular lifting for acute scapular medial pain. AB - [Purpose] This study developed an effective self-relaxation exercise for acute scapular medial pain and investigated its pain relief effects. [Subject and Methods] The subject was a 41-year-old male with scapular medial pain. During session 1, the subject performed a retraction exercise. During session 2, the subject performed a passive scapular lifting exercise. [Results] After session 2, the frequency of the pain decreased to about once a month, and the patient's VAS score for acute scapular medial pain was 2/10. After session 1, there was no change compared to the initial values. [Conclusion] Therefore, the results of this study suggest that the passive scapular lifting exercise offers effective control of acute scapular medial pain. PMID- 29410598 TI - Administration of FTY720 during Tourniquet-Induced Limb Ischemia Reperfusion Injury Attenuates Systemic Inflammation. AB - Acute ischemia-reperfusion injury (IRI) of the extremities leads to local and systemic inflammatory changes which can hinder limb function and can be life threatening. This study examined whether the administration of the T-cell sequestration agent, FTY720, following hind limb tourniquet-induced skeletal muscle IRI in a rat model would attenuate systemic inflammation and multiple end organ injury. Sprague-Dawley rats were subjected to 1 hr of ischemia via application of a rubber band tourniquet. Animals were randomized to receive an intravenous bolus of either vehicle control or FTY720 15 min after band placement. Rats (n = 10/time point) were euthanized at 6, 24, and 72 hr post-IRI. Peripheral blood as well as lung, liver, kidney, and ischemic muscle tissue was analyzed and compared between groups. FTY720 treatment markedly decreased the number of peripheral blood T cells (p < 0.05) resulting in a decreased systemic inflammatory response and lower serum creatinine levels and had a modest but significant effect in decreasing the transcription of injury-associated target genes in multiple end organs. These findings suggest that early intervention with FTY720 may benefit the treatment of IRI of the limb. Further preclinical studies are necessary to characterize the short-term and long-term beneficial effects of FTY720 following tourniquet-induced IRI. PMID- 29410600 TI - Additive Manufacturing Techniques for the Reconstruction of 3D Fetal Faces. AB - This paper deals with additive manufacturing techniques for the creation of 3D fetal face models starting from routine 3D ultrasound data. In particular, two distinct themes are addressed. First, a method for processing and building 3D models based on the use of medical image processing techniques is proposed. Second, the preliminary results of a questionnaire distributed to future parents consider the use of these reconstructions both from an emotional and an affective point of view. In particular, the study focuses on the enhancement of the perception of maternity or paternity and the improvement in the relationship between parents and physicians in case of fetal malformations, in particular facial or cleft lip diseases. PMID- 29410601 TI - Application of the GRADE Approach in the Development of Guidelines and Recommendations in Genomic Medicine. AB - A great deal of ambiguity exists in the development of guidelines for genomic applications used in clinical practice. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach has the potential to be applied in the guidelines and recommendations development process in genomics. Here, we discuss whether and how GRADE can be applied to address the challenges posed by the evidence-based guidelines and recommendations development process in genomics. To see how GRADE can complement to the current guidelines development in genomics, we compare and contrast GRADE with other approaches. GRADE differed from other methods by incorporating patient values and preferences and balance of consequences. We conclude that the groups trying to implement genomics into practice may gleam more information from applying the GRADE framework. However, it is not clear yet whether GRADE can address the issue of timeliness in terms of the differences between the time required for guidelines development and the rapid pace of genomics. PMID- 29410599 TI - Geographic distribution of rare variants associated with age-related macular degeneration. AB - Purpose: A recent genome-wide association study by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) identified seven rare variants that are individually associated with age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. In literature, several of these rare variants have been reported with different frequencies and odds ratios across populations of Europe and North America. Here, we aim to describe the representation of these seven AMD-associated rare variants in different geographic regions based on 24 AMD studies. Methods: We explored the occurrence of seven rare variants independently associated with AMD (CFH rs121913059 (p.Arg1210Cys), CFI rs141853578 (p.Gly119Arg), C3 rs147859257 (p.Lys155Gln), and C9 rs34882957 (p.Pro167Ser)) and three non-coding variants in or near the CFH gene (rs148553336, rs35292876, and rs191281603) in 24 AMD case-control studies. We studied the difference in distribution, interaction, and effect size for each of the rare variants based on the minor allele frequency within the different geographic regions. Results: We demonstrate that two rare AMD-associated variants in the CFH gene (rs121913059 [p.Arg1210Cys] and rs35292876) deviate in frequency among different geographic regions (p=0.004 and p=0.001, respectively). The risk estimates of each of the seven rare variants were comparable across the geographic regions. Conclusions: The results emphasize the importance of identifying population-specific rare variants, for example, by performing sequencing studies in case-control studies of various populations, because their identification may have implications for diagnostic screening and personalized treatment. PMID- 29410602 TI - Exploration of the administrative aspects of the delivery of home health care services: a qualitative study. AB - Background: Because of the variety of services and resources offered in the delivery of home health care, its management is a challenging and difficult task. Objectives: The purpose of this study was to explore the administrative aspects of the delivery of home health care services. Methods: This qualitative study was conducted based on the traditional content analysis approach in 2015 in Iran. The participants were selected using the purposeful sampling method and data were collected through in-depth semi-structured personal interviews and from discussions in a focus group. The collected data were analyzed using the Lundman and Graneheim method. Results: 23 individuals participated in individual interviews, and the collected data were categorized into the two main themes of policymaking and infrastructures, each of which consisted of some subcategories. Conclusion: Health policymakers could utilize the results of this study as baseline information in making decisions about the delivery of home health care services, taking into account the contextual dimensions of home care services, leading to improvements in home health care services. PMID- 29410603 TI - The expression of MDM2 in gastrointestinal stromal tumors: immunohistochemical analysis of 35 cases. AB - Background: Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the digestive system. The assessment of their biological behavior still remains a scientific challenge. To date, there are no well established biological prognostic markers of GIST. Our aim is to study the expression of the MDM2 oncoprotein in GIST through an immunohistochemical analysis. Methods: It was a retrospective study of 35 cases of GIST diagnosed from 2009 to 2012 in the department of pathology of Hassan II university hospital, Fes, Morocco. MDM2 immunohistochemical staining was performed on archival paraffin-embedded and formalin-fixed specimens (with a threshold of nuclear positivity > 10%). Analysis of correlations between MDM2 immunoexpression and clinicopathological features of GIST has been performed. Results: The mean age was 55.23 years (range 25-84 years) with a male predominance (sex ratio = 1.5). The stomach was the main site of GIST, with 17 cases (48.57%) followed by the small bowel (9 cases, 25.71%). The spindle cell type GIST was the most frequent morphological variant (29 cases, 82.85%). Tumor necrosis was present in 8 cases (22.85%). Two patients (5.71%) had very low risk GIST, 5 (14.28%) had low risk GIST, 7 patients (20%) had intermediate risk tumors. The remaining 21 cases (60%) had high risk GIST. At the time of diagnosis, 9 patients (25.71%) had metastatic tumors. At immunohistochemical analysis, 40% of cases (14 patients) stained positive for MDM2. Of these MDMD2-positive tumors, 11/14 (78.57%) had high risk tumors and 8/14 cases (57.14%) presented with metastatic GIST. MDM2 positivity was significantly associated with the metastatic status (p = 0.001). Conclusion: The current study suggests that MDM2 immunohistochemical expression is a negative histoprognostic factor in GIST with a statistically significant correlation with metastasis. PMID- 29410604 TI - Exosomal lncRNA 91H is associated with poor development in colorectal cancer by modifying HNRNPK expression. AB - Background: Exosomes mediated transfer of lncRNA 91H may play a critical role in the development of CRC. However, few studies have proved the mechanism. So we performed this study to deeply explore the biological functions of exosomal 91H in the development and progression of CRC. Methods: The association between lncRNA 91H and exosomes was detected in vitro and vivo. Then RNA pulldown and RIP were used to detect how lncRNA 91H affect CRC IGF2 express. At last, clinic pathological significance of exosomal 91H was evaluated by Cox proportional hazards model. Results: We found that serum lncRNA 91H expression was closely related to cancer exosomes in vitro and vivo which may enhance tumor-cell migration and invasion in tumor development by modifying HNRNPK expression. Then the clinic pathological significance of exosomal 91H was evaluated which demonstrated that CRC patients with high lncRNA 91H expression usually showed a higher risk in tumor recurrence and metastasis than patients with low lncRNA 91H expression (P < 0.05). Conclusion: All these data suggested that exosomal lncRNA 91H enhancing CRC metastasis by modifying HNRNPK expression might be an early plasma-based biomarker for CRC recurrence or metastasis. Further large-scale studies are needed to confirm our findings. PMID- 29410605 TI - BARKER-CODED NODE-PORE RESISTIVE PULSE SENSING WITH BUILT-IN COINCIDENCE CORRECTION. AB - A resistive pulse sensing device is able to extract quantities such as concentration and size distribution of particles, e.g. cells or microspheres, as they flow through the device's sensor region, i.e. channel, in an electrolyte solution. The dynamic range of detectable particle sizes is limited by the channel dimensions. In addition, signal interference from multiple particles transiting the channel simultaneously, i.e. coincidence event, further hinder the dynamic range. Coincidence data is often considered unusable and is discarded, reducing the throughput and introducing possible biases and errors into the distributions. Here, we propose a two-step solution. We code the channel such that the system response results in a Manchester encoded Barker-Code sequence, allowing us to take advantage of the code's pulse compression properties. We pose the parameter estimation problem as a sparse inverse problem, which enables estimation of particle sizes and velocities while resolving coincidences, and solve it with a successive interference cancellation algorithm. We introduce modifications to the algorithm to account for device fabrication variations and natural stochastic variations in flow. We demonstrate the ability to resolve coincidences and possible increases in the device's dynamic range by screening particles of different size through a Barker encoded device. PMID- 29410606 TI - Effects of lemon verbena extract (Recoverben(r)) supplementation on muscle strength and recovery after exhaustive exercise: a randomized, placebo-controlled trial. AB - Background: Exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation leading to muscle fatigue and muscle soreness. Lemon verbena leaves, commonly used as tea and refreshing beverage, demonstrated antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of a proprietary lemon verbena extract (Recoverben(r)) on muscle strength and recovery after exhaustive exercise in comparison to a placebo product. Methods: The study was performed as a randomized, placebo-controlled, double-blind study with parallel design. Forty-four healthy males and females, which were 22-50 years old and active in sports, were randomized to 400 mg lemon verbena extract once daily or placebo. The 15 days intervention was divided into 10 days supplementation prior to the exhaustive exercise day (intensive jump protocol), one day during the test and four days after. Muscle strength (MVC), muscle damage (CK), oxidative stress (GPx), inflammation (IL6) and volunteer reported muscle soreness intensity were assessed pre and post exercise. Results: Participants in the lemon verbena group benefited from less muscle damage as well as faster and full recovery. Compared to placebo, lemon verbena extract receiving participants had significantly less exercise-related loss of muscle strength (p = 0.0311) over all timepoints, improved glutathione peroxidase activity by trend (p = 0.0681) and less movement induced pain (p = 0.0788) by trend. Creatine kinase and IL-6 didn't show significant discrimmination between groups. Conclusion: Lemon verbena extract (Recoverben(r)) has been shown to be a safe and well tolerated natural sports ingredient, by reducing muscle damage after exhaustive exercise. Trial registration: The trial was registered in the clinical trials registry (clinical trial.gov NCT02923102). Registered 28 September 2016. PMID- 29410607 TI - Music Intervention Leads to Increased Insular Connectivity and Improved Clinical Symptoms in Schizophrenia. AB - Schizophrenia is a syndrome that is typically accompanied by delusions and hallucinations that might be associated with insular pathology. Music intervention, as a complementary therapy, is commonly used to improve psychiatric symptoms in the maintenance stage of schizophrenia. In this study, we employed a longitudinal design to assess the effects of listening to Mozart music on the insular functional connectivity (FC) in patients with schizophrenia. Thirty-six schizophrenia patients were randomly divided into two equal groups as follows: the music intervention (MTSZ) group, which received a 1-month music intervention series combined with antipsychotic drugs, and the no-music intervention (UMTSZ) group, which was treated solely with antipsychotic drugs. Resting-state functional magnetic resonance imaging (fMRI) scans were performed at the following three timepoints: baseline, 1 month after baseline and 6 months after baseline. Nineteen healthy participants were recruited as controls. An FC analysis seeded in the insular subregions and machine learning techniques were used to examine intervention-related changes. After 1 month of listening to Mozart music, the MTSZ showed increased FC in the dorsal anterior insula (dAI) and posterior insular (PI) networks, including the dAI-ACC, PI-pre/postcentral cortices, and PI-ACC connectivity. However, these enhanced FCs had vanished in follow-up visits after 6 months. Additionally, a support vector regression on the FC of the dAI-ACC at baseline yielded a significant prediction of relative symptom remission in response to music intervention. Furthermore, the validation analyses revealed that 1 month of music intervention could facilitate improvement of the insular FC in schizophrenia. Together, these findings revealed that the insular cortex could potentially be an important region in music intervention for patients with schizophrenia, thus improving the patients' psychiatric symptoms through normalizing the salience and sensorimotor networks. PMID- 29410608 TI - Toward a Neuroscience of Adult Cognitive Developmental Theory. AB - Piaget's genetic epistemology has provided the constructivist approach upon which child developmental theories were founded, in that infants are thought to progress through distinct cognitive stages until they reach maturity in their early 20's. However, it is now well established that cognition continues to develop after early adulthood, and several "neo-Piagetian" theories have emerged in an attempt to better characterize adult cognitive development. For example, Kegan's Constructive Developmental Theory (CDT) argues that the thought processes used by adults to construct their reality change over time, and reaching higher stages of cognitive development entails becoming objectively aware of emotions and beliefs that were previously in the realm of the subconscious. In recent years, neuroscience has shown a growing interest in the biological substrates and neural mechanisms encompassing adult cognitive development, because psychological and psychiatric disorders can arise from deficiencies therein. In this article, we will use Kegan's CDT as a framework to discuss adult cognitive development in relation to closely correlated existing constructs underlying social processing, such as the perception of self and others. We will review the functional imaging and electrophysiologic evidence behind two key concepts relating to these posited developmental changes. These include self-related processing, a field that distinguishes between having conscious experiences ("being a self") and being aware of oneself having conscious experiences ("being aware of being a self"); and theory of mind, which is the objective awareness of possessing mental states such as beliefs and desires (i.e., having a "mind") and the understanding that others possess mental states that can be different from one's own. We shall see that cortical midline structures, including the medial prefrontal cortex and cingulate gyrus, as well as the temporal lobe, are associated with psychological tasks that test these models. In addition, we will review computational modeling approaches to cognitive development, and show how mathematical modeling can provide insights into how sometimes continuous changes in the neural processing substrate can give rise to relatively discrete developmental stages. Because deficiencies in adult cognitive development can result in disorders such as autism and depression, bridging the gaps between developmental psychology, neuroscience, and modeling has potential implications for clinical practice. As neuromodulation techniques such as deep brain and transcranial stimulation continue to advance, interfacing with these systems may lead to the emergence of novel investigational methods and therapeutic strategies in adults suffering from developmental disorders. PMID- 29410609 TI - Abnormal Resting-State Functional Connectivity of the Anterior Cingulate Cortex in Unilateral Chronic Tinnitus Patients. AB - Purpose: The anterior cingulate cortex (ACC) has been suggested to be involved in chronic subjective tinnitus. Tinnitus may arise from aberrant functional coupling between the ACC and cerebral cortex. To explore this hypothesis, we used resting state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity (FC) network of the ACC subregions in chronic tinnitus patients. Methods: Resting-state fMRI scans were obtained from 31 chronic right-sided tinnitus patients and 40 healthy controls (age, sex, and education well-matched) in this study. Rostral ACC and dorsal ACC were selected as seed regions to investigate the intrinsic FC with the whole brain. The resulting FC patterns were correlated with clinical tinnitus characteristics including the tinnitus duration and tinnitus distress. Results: Compared with healthy controls, chronic tinnitus patients showed disrupted FC patterns of ACC within several brain networks, including the auditory cortex, prefrontal cortex, visual cortex, and default mode network (DMN). The Tinnitus Handicap Questionnaires (THQ) scores showed positive correlations with increased FC between the rostral ACC and left precuneus (r = 0.507, p = 0.008) as well as the dorsal ACC and right inferior parietal lobe (r = 0.447, p = 0.022). Conclusions: Chronic tinnitus patients have abnormal FC networks originating from ACC to other selected brain regions that are associated with specific tinnitus characteristics. Resting-state ACC-cortical FC disturbances may play an important role in neuropathological features underlying chronic tinnitus. PMID- 29410610 TI - Disruption of Intracellular ATP Generation and Tight Junction Protein Expression during the Course of Brain Edema Induced by Subacute Poisoning of 1,2 Dichloroethane. AB - The aim of this study was to explore changes in intracellular ATP generation and tight junction protein expression during the course of brain edema induced by subacute poisoning of 1,2-dichloroethane (1,2-DCE). Mice were exposed to 1.2 g/m3 1,2-DCE for 3.5 h per day for 1, 2, or 3 days, namely group A, B, and C. Na+-K+ ATPase and Ca2+-ATPase activity, ATP and lactic acid content, intracellular free Ca2+ concentration and ZO-1 and occludin expression in the brain were measured. Results of present study disclosed that Ca2+-ATPase activities in group B and C, and Na+/K+-ATPase activity in group C decreased, whereas intracellular free Ca2+ concentrations in group B and C increased significantly compared with control. Moreover, ATP content decreased, whereas lactic acid content increased significantly in group C compared with control. On the other hand, expressions of ZO-1 and occludin at both the protein and gene levels in group B and C decreased significantly compared with control. In conclusion, findings from this study suggest that calcium overload and depressed expression of tight junction associated proteins, such as ZO-1 and occludin might play an important role in the early phase of brain edema formation induced by subacute poisoning of 1,2 DCE. PMID- 29410611 TI - Optimizing Within-Subject Experimental Designs for jICA of Multi-Channel ERP and fMRI. AB - Joint independent component analysis (jICA) can be applied within subject for fusion of multi-channel event-related potentials (ERP) and functional magnetic resonance imaging (fMRI), to measure brain function at high spatiotemporal resolution (Mangalathu-Arumana et al., 2012). However, the impact of experimental design choices on jICA performance has not been systematically studied. Here, the sensitivity of jICA for recovering neural sources in individual data was evaluated as a function of imaging SNR, number of independent representations of the ERP/fMRI data, relationship between instantiations of the joint ERP/fMRI activity (linear, non-linear, uncoupled), and type of sources (varying parametrically and non-parametrically across representations of the data), using computer simulations. Neural sources were simulated with spatiotemporal and noise attributes derived from experimental data. The best performance, maximizing both cross-modal data fusion and the separation of brain sources, occurred with a moderate number of representations of the ERP/fMRI data (10-30), as in a mixed block/event related experimental design. Importantly, the type of relationship between instantiations of the ERP/fMRI activity, whether linear, non-linear or uncoupled, did not in itself impact jICA performance, and was accurately recovered in the common profiles (i.e., mixing coefficients). Thus, jICA provides an unbiased way to characterize the relationship between ERP and fMRI activity across brain regions, in individual data, rendering it potentially useful for characterizing pathological conditions in which neurovascular coupling is adversely affected. PMID- 29410612 TI - NaV1.9 Potentiates Oxidized Phospholipid-Induced TRP Responses Only under Inflammatory Conditions. AB - Oxidized phospholipids (OxPL) like oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero 3-phosphocholine (OxPAPC) were recently identified as novel proalgesic targets in acute and chronic inflammatory pain. These endogenous chemical irritants are generated in inflamed tissue and mediate their pain-inducing function by activating the transient receptor potential channels TRPA1 and TRPV1 expressed in sensory neurons. Notably, prototypical therapeutics interfering with OxPL were shown to inhibit TRP channel activation and pain behavior. Here, we asked how OxPL excite primary sensory neurons of dorsal root ganglia (DRG neurons from mice of either sex). Acute stimulation of sensory neurons with the prototypical OxPL 1 palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) evoked repetitive calcium spikes in small-diameter neurons. As NaV1.9, a voltage-gated sodium channel involved in nociceptor excitability, was previously shown to be essential for the generation of calcium spikes in motoneurons, we asked if this channel is also important for OxPL mediated calcium spike and action potential generation in nociceptors. In wild-type and NaV1.9-deficient neurons, the action potential firing rate and the calcium spike frequency to an acute PGPC stimulus was similar. When preincubated with inflammatory mediators, both, the action potential firing rate and the calcium spike frequency were markedly increased in response to an acute PGPC stimulus. However, this potentiating effect was completely lost in NaV1.9-deficient small-diameter neurons. After treatment with inflammatory mediators, the resting membrane potential of NaV1.9 KO neurons was slightly more negative than that of wild-type control neurons. This suggests that NaV1.9 channels are active under this condition and therefore increases the ease with which action potentials are elicited after OxPL stimulation. In summary, our data suggest that NaV1.9 has a switch function to potentiate the receptor potentials induced by OxPL under inflammatory conditions. Since human NaV1.9 has been shown to mediate painful and painless channelopathies, this study provides new insights into the mechanism by which NaV1.9 amplifies stimuli of endogenous irritants under inflammatory conditions. PMID- 29410614 TI - Farnesylation of the Transducin G Protein Gamma Subunit Is a Prerequisite for Its Ciliary Targeting in Rod Photoreceptors. AB - Primary cilia are microtubule-based organelles, which protrude from the plasma membrane and receive a wide range of extracellular signals. Various cilia use G protein-coupled receptors (GPCRs) for the detection of these signals. For instance, vertebrate rod photoreceptors use their cilia (also called outer segments) as antennae detecting photons by GPCR rhodopsin. Rhodopsin recognizes incoming light and activates its G protein, transducin, which is composed of three subunits alpha, beta, and gamma. Similar to all G protein gamma subunits, the transducin Ggamma1 subunit undergoes C-terminal prenylation resulting in the addition of an isoprenoid farnesyl; however, the significance of this posttranslational modification is unclear. To study the role of the farnesyl group, we genetically introduced a mutant Ggamma1 that lacked the prenylation site into the retinal photoreceptors of mice. The biochemical and physiological analyses of these mice revealed that mutant Ggamma1 dimerizes with the endogenous transducin Gbeta1 subunit and that the resulting Gbetagamma dimers display reduced hydrophobicity. Although mutant Gbetagamma dimers could form a heterotrimeric G protein, they could not mediate phototransduction. This deficiency was due to a strong exclusion of non-farnesylated Gbetagamma complexes from the cilia (rod outer segments). Our results provide the first evidence that farnesylation is required for trafficking of G-protein betagamma subunits to the cilium of rod photoreceptors. PMID- 29410615 TI - Leptin Receptor Expression in Mouse Intracranial Perivascular Cells. AB - Past studies have suggested that non-neuronal brain cells express the leptin receptor. However, the identity and distribution of these leptin receptor expressing non-neuronal brain cells remain debated. This study assessed the distribution of the long form of the leptin receptor (LepRb) in non-neuronal brain cells using a reporter mouse model in which LepRb-expressing cells are permanently marked by tdTomato fluorescent protein (LepRb-CretdTomato). Double immunohistochemistry revealed that, in agreement with the literature, the vast majority of tdTomato-tagged cells across the mouse brain were neurons (i.e., based on immunoreactivity for NeuN). Non-neuronal structures also contained tdTomato-positive cells, including the choroid plexus and the perivascular space of the meninges and, to a lesser extent, the brain. Based on morphological criteria and immunohistochemistry, perivascular cells were deduced to be mainly pericytes. Notably, tdTomato-positive cells were immunoreactive for vitronectin and platelet derived growth factor receptor beta (PDGFBR). In situ hybridization studies confirmed that most tdTomato-tagged perivascular cells were enriched in leptin receptor mRNA (all isoforms). Using qPCR studies, we confirmed that the mouse meninges were enriched in Leprb and, to a greater extent, the short isoforms of the leptin receptor. Interestingly, qPCR studies further demonstrated significantly altered expression for Vtn and Pdgfrb in the meninges and hypothalamus of LepRb-deficient mice. Collectively, our data demonstrate that the only intracranial non-neuronal cells that express LepRb in the adult mouse are cells that form the blood-brain barrier, including, most notably, meningeal perivascular cells. Our data suggest that pericytic leptin signaling plays a role in the integrity of the intracranial perivascular space and, consequently, may provide a link between obesity and numerous brain diseases. PMID- 29410616 TI - Bilateral Pathways from the Basal Forebrain to Sensory Cortices May Contribute to Synchronous Sensory Processing. AB - Sensory processing in the cortex should integrate inputs arriving from receptive fields located on both sides of the body. This role could be played by the corpus callosum through precise projections between both hemispheres. However, different studies suggest that cholinergic projections from the basal forebrain (BF) could also contribute to the synchronization and integration of cortical activities. Using tracer injections and optogenetic techniques in transgenic mice, we investigated whether the BF cells project bilaterally to sensory cortical areas, and have provided anatomical evidence to support a modulatory role for the cholinergic projections in sensory integration. Application of the retrograde tracer Fluor-Gold or Fast Blue in both hemispheres of the primary somatosensory (S1), auditory or visual cortical areas showed labeled neurons in the ipsi- and contralateral areas of the diagonal band of Broca and substantia innominata. The nucleus basalis magnocellularis only showed ipsilateral projections to the cortex. Optogenetic stimulation of the horizontal limb of the diagonal band of Broca facilitated whisker responses in the S1 cortex of both hemispheres through activation of muscarinic cholinergic receptors and this effect was diminished by atropine injection. In conclusion, our findings have revealed that specific areas of the BF project bilaterally to sensory cortices and may contribute to the coordination of neuronal activity on both hemispheres. PMID- 29410617 TI - Long-term Potentiation Decay and Poor Long-lasting Memory Process in the Wild Rodents Proechimys from Brazil's Amazon Rainforest. AB - Proechimys are small terrestrial rodents from Amazon rainforest. Each animal species is adapted to a specific environment in which the animal evolved therefore without comparative approaches unique characteristics of distinct species cannot be fully recognized. Laboratory rodents are exceedingly inbred strains dissociated from their native habitats and their fundamental ecological aspects are abstracted. Thus, the employment of exotic non-model species can be informative and complement conventional animal models. With the aim of promoting comparative studies between the exotic wildlife populations in the laboratory and traditional rodent model, we surveyed a type of synaptic plasticity intimately related to memory encoding in animals. Using theta-burst paradigm, in vitro long term potentiation (LTP) in the CA1 subfield of hippocampal slices was assessed in the Amazon rodents Proechimys and Wistar rats. Memory, learning and anxiety were investigated through the plus-maze discriminative avoidance task (PM-DAT) and object recognition test. In PM-DAT, both animal species were submitted to two test sessions (3-h and 24-h) after the conditioning training. Proechimys exhibited higher anxiety-like behavior in the training session but during test sessions both species exhibited similar patterns of anxiety-related behavior. After 3-h of the training, Proechimys and Wistar spent significantly less time in the aversive enclosed arm than in the non-aversive arm. But, at 24-h after training, Wistar rats remained less time in the aversive closed arm in comparison with the non-aversive one, while Proechimys rodents spent the same amount of time in both enclosed arms. In the object recognition test, both species were evaluated at 24-h after the acquisition session and similar findings than those of the PM-DAT (24-h) were obtained, suggesting that long-term memory duration did not persist for 24-h in the Amazon rodent. Field excitatory post-synaptic potentials recordings revealed that LTP decays rapidly over time reaching basal levels at 90 min after theta-burst stimulation in Proechimys, contrasting to the stable LTP found in the Wistar rats which was observed throughout 3-h recording period. These findings suggest a link between the LTP decay and the lack of 24-h long-lasting memory process in Proechimys. Nevertheless, why early-phase LTP in Proechimys decays very rapidly remains to be elucidated. PMID- 29410613 TI - Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease. AB - Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS. PMID- 29410619 TI - Implicit and Explicit Motivational Tendencies to Faces Varying in Trustworthiness and Dominance in Men. AB - Motivational tendencies to happy and angry faces are well-established, e.g., in the form of aggression. Approach-avoidance reactions are not only elicited by emotional expressions, but also linked to the evaluation of stable, social characteristics of faces. Grounded in the two fundamental dimensions of face based evaluations proposed by Oosterhof and Todorov (2008), the current study tested whether emotionally neutral faces varying in trustworthiness and dominance potentiate approach-avoidance in 50 healthy male participants. Given that evaluations of social traits are influenced by testosterone, we further tested for associations of approach-avoidance tendencies with endogenous and prenatal indicators of testosterone. Computer-generated faces signaling high and low trustworthiness and dominance were used to elicit motivational reactions in three approach-avoidance tasks, i.e., one implicit and one explicit joystick-based paradigm, and an additional rating task. When participants rated their behavioral tendencies, highly trustworthy faces evoked approach, and highly dominant faces evoked avoidance. This pattern, however, did not translate to faster initiation times of corresponding approach-avoidance movements. Instead, the joystick tasks revealed general effects, such as faster reactions to faces signaling high trustworthiness or high dominance. These findings partially support the framework of Oosterhof and Todorov (2008) in guiding approach-avoidance decisions, but not behavioral tendencies. Contrary to our expectations, neither endogenous nor prenatal indicators of testosterone were associated with motivational tendencies. Future studies should investigate the contexts in which testosterone influences social motivation. PMID- 29410618 TI - Biological Clocks and Rhythms of Anger and Aggression. AB - The body's internal timekeeping system is an under-recognized but highly influential force in behaviors and emotions including anger and reactive aggression. Predictable cycles or rhythms in behavior are expressed on several different time scales such as circadian (circa diem, or approximately 24-h rhythms) and infradian (exceeding 24 h, such as monthly or seasonal cycles). The circadian timekeeping system underlying rhythmic behaviors in mammals is constituted by a network of clocks distributed throughout the brain and body, the activity of which synchronizes to a central pacemaker, or master clock. Our daily experiences with the external environment including social activity strongly influence the exact timing of this network. In the present review, we examine evidence from a number of species and propose that anger and reactive aggression interact in multiple ways with circadian clocks. Specifically, we argue that: (i) there are predictable rhythms in the expression of aggression and anger; (ii) disruptions of the normal functioning of the circadian system increase the likelihood of aggressive behaviors; and (iii) conversely, chronic expression of anger can disrupt normal rhythmic cycles of physiological activities and create conditions for pathologies such as cardiovascular disease to develop. Taken together, these observations suggest that a comprehensive perspective on anger and reactive aggression must incorporate an understanding of the role of the circadian timing system in these intense affective states. PMID- 29410621 TI - Effects of Firing Variability on Network Structures with Spike-Timing-Dependent Plasticity. AB - Synaptic plasticity is believed to be the biological substrate underlying learning and memory. One of the most widespread forms of synaptic plasticity, spike-timing-dependent plasticity (STDP), uses the spike timing information of presynaptic and postsynaptic neurons to induce synaptic potentiation or depression. An open question is how STDP organizes the connectivity patterns in neuronal circuits. Previous studies have placed much emphasis on the role of firing rate in shaping connectivity patterns. Here, we go beyond the firing rate description to develop a self-consistent linear response theory that incorporates the information of both firing rate and firing variability. By decomposing the pairwise spike correlation into one component associated with local direct connections and the other associated with indirect connections, we identify two distinct regimes regarding the network structures learned through STDP. In one regime, the contribution of the direct-connection correlations dominates over that of the indirect-connection correlations in the learning dynamics; this gives rise to a network structure consistent with the firing rate description. In the other regime, the contribution of the indirect-connection correlations dominates in the learning dynamics, leading to a network structure different from the firing rate description. We demonstrate that the heterogeneity of firing variability across neuronal populations induces a temporally asymmetric structure of indirect-connection correlations. This temporally asymmetric structure underlies the emergence of the second regime. Our study provides a new perspective that emphasizes the role of high-order statistics of spiking activity in the spike-correlation-sensitive learning dynamics. PMID- 29410620 TI - Neural Correlates of Drug-Related Attentional Bias in Heroin Dependence. AB - The attention of drug-dependent persons tends to be captured by stimuli associated with drug consumption. This involuntary cognitive process is considered as attentional bias (AB). AB has been hypothesized to have causal effects on drug abuse and drug relapse, but its underlying neural mechanisms are still unclear. This study investigated the neural basis of AB in abstinent heroin addicts (AHAs), combining event-related potential (ERP) analysis and source localization techniques. Electroencephalography data were collected in 21 abstinent heroin addicts and 24 age- and gender-matched healthy controls (HCs) during a dot-probe task. In the task, a pair of drug-related image and neutral image was presented randomly in left and right side of the cross fixation, followed by a dot probe replacing one of the images. Behaviorally, AHAs had shorter reaction times (RTs) for the congruent condition compared to the incongruent condition, whereas this was not the case in the HCs. This finding demonstrated the presence of AB towards drug cues in AHAs. Furthermore, the image evoked ERPs in AHAs had significant shorter P1 latency compared to HCs, as well as larger N1, N2, and P2 amplitude, suggesting that drug-related stimuli might capture attention early and overall require more attentional resources in AHAs. The target-related P3 had significantly shorter latency and lower amplitude in the congruent than incongruent condition in AHAs compared to HCs. Moreover, source localization of ERP components revealed increased activity for AHAs as compared to HCs in the dorsal posterior cingulate cortex (dPCC), superior parietal lobule and inferior frontal gyrus (IFG) for image-elicited responses, and decreased activity in the occipital and the medial parietal lobes for target elicited responses. Overall, the results of our study confirmed that AHAs may exhibit AB in drug-related contexts, and suggested that the bias might be related to an abnormal neural activity, both in early and late attention processing stages. PMID- 29410622 TI - Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer's Dementia. AB - Background: While hepatocyte growth factor (HGF) is known to exert cell growth, migration and morphogenic effects in various organs, recent studies suggest that HGF may also play a role in synaptic maintenance and cerebrovascular integrity. Although increased levels of HGF have been reported in brain and cerebrospinal fluid (CSF) samples of patients with Alzheimer's disease (AD), it is unclear whether peripheral HGF may be associated with cerebrovascular disease (CeVD) and dementia. In this study, we examined the association of baseline serum HGF with neuroimaging markers of CeVD in a cohort of pre-dementia (cognitive impaired no dementia, CIND) and AD patients. Methods: Serum samples from aged, Non cognitively impaired (NCI) controls, CIND and AD subjects were measured for HGF levels. CeVD (cortical infarcts, microinfarcts, lacunes, white matter hyperintensities (WMH) and microbleeds) were assessed by magnetic resonance imaging (MRI). Results: After controlling for covariates, higher levels of HGF were associated with both CIND and AD. Among the different CeVD MRI markers in CIND and AD, only small vessel disease, but not large vessel disease markers were associated with higher HGF levels. Conclusion: Serum HGF may be a useful peripheral biomarker for small vessel disease in subjects with cognitive impairment and AD. PMID- 29410623 TI - Changes in Prescribing Symptomatic and Preventive Medications in the Last Year of Life in Older Nursing Home Residents. AB - Background: At the end of life goals of care change from disease prevention to symptomatic control, however, little is known about the patterns of medication prescribing at this stage. Objectives: To explore changes in prescribing of symptomatic and preventive medication in the last year of life in older nursing home residents. Methods: A retrospective cohort study was conducted using pharmacy medication supply data of 553 residents from 16 nursing home facilities around Sydney, Australia. Residents received 24-h nursing care, were aged >= 65 years, died between June 2008 and June 2010 and were using at least one medication 1 year before death. Medications were classified as symptomatic, preventive, or other. A linear mixed model was used to compare changes in prescribing in the last year of life. Results: 68.1% of residents were female, mean age was 88.0 (SD: 7.5) years and residents used a mean of 9.1 (SD: 4.1) medications 1 year before death. The mean number of symptomatic medications per resident increased from 4.6 medications 1 year before death to 5.1 medications at death [95% CI 4.4-4.7 to 5.9-5.2, P = 0.000], while preventive medication decreased from 2.0 to 1.4 medications [95% CI 1.9-2.1 to 1.3-1.5, P = 0.000]. Symptomatic medications were used longer in the last year of life, compared to preventive medications (336.3 days [95% CI 331.8-340.8] versus 310.9 days [95% CI 305.2-316.7], P = 0.000). Conclusion: Use of medications for symptom relief increased throughout the last year of life, while medications for prevention of long-term complications decreased. But changes were slight and clinical relevance can be questioned. PMID- 29410624 TI - CP-25 Attenuates the Activation of CD4+ T Cells Stimulated with Immunoglobulin D in Human. AB - Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck. Human CD4+ T cells were purified from peripheral blood mononuclear cells using microbeads. T cell viability and proliferation were detected by Cell Counting Kit-8 and CFSE Cell Proliferation Kit. Cytokines secreted by T cells were assessed with the Quantibody Human Inflammation Array. The binding affinity and expression of IgDR on T cells were detected by flow cytometry, and protein expression of IgDR, Lck, and P-Lck were analyzed by western blot. IgD was shown to bind to IgDR on CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394). CP-25 inhibited the IgD-stimulated activation and proliferation of CD4+ T cells, as well as the production of inflammatory cytokines; it was thus suggested that this process might be related to the downregulation of Lck (Tyr394) phosphorylation. These results demonstrate that IgD amplifies the activation of CD4+ T cells, which could be mediated by Lck phosphorylation. Further, CP-25, via its ability to modulate Lck, is a novel potential therapeutic agent for the treatment of human autoimmune diseases. PMID- 29410626 TI - Hydrazone-Containing Triblock Copolymeric Micelles for pH-Controlled Drug Delivery. AB - In this study, the structure-activity relationship of amphiphilic block copolymer micelles as nanosized drug delivery system was revealed. Firstly, a biodegradable triblock polymers PEG-DiHyd-PLA containing hydrazone bond was synthesized through the ring-opening polymerization. In this method, PEG-DiHyd-Phenol was used as the initiator and L-lactide as the monomer. Then, the polymeric micelles were formed and used as nano-drug carriers with pH sensitivity. The structure and composition of the polymer were characterized by infrared (IR), nuclear magnetic resonance (1H-NMR), and gel permeation chromatography (GPC), we characterized the self assembling process of the triblock polymers and the pH sensitivity of the micelles by the means of transmission electron microscopy (TEM), dynamic light scattering method (DLS). Doxorubicin (DOX) acts as the model drug, and we researched the capacities of drug loading and release in vitro of the micelles. MTT experiments showed that the blank micelles of PEG-DiHyd-PLA were not cytotoxic to tumor cells (HepG-2, MCF-7) and normal cell (L-02 cells), but the DOX loaded ones displayed more toxicity than the ones without hydrazone, which was consistent to the further confocal laser scanning microscopy and flow cytometry study. PMID- 29410625 TI - Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. AB - Drug development is a lengthy and costly process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation and clinical trials culminating in approval for clinical use. An important step in this process is high-throughput screening (HTS) of small compound libraries for lead identification. Currently, the majority of cell-based HTS is being carried out on cultured cells propagated in two-dimensions (2D) on plastic surfaces optimized for tissue culture. At the same time, compelling evidence suggests that cells cultured in these non-physiological conditions are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to be a significant contributor to the high failure rate in drug discovery, where only a low percentage of drugs investigated ever make it through the gamut of testing and approval to the market. Thus, three dimensional (3D) cell culture technologies that more closely resemble in vivo cell environments are now being pursued with intensity as they are expected to accommodate better precision in drug discovery. Here we will review common approaches to 3D culture, discuss the significance of 3D cultures in drug resistance and drug repositioning and address some of the challenges of applying 3D cell cultures to high-throughput drug discovery. PMID- 29410627 TI - Mechanisms of Anesthetic Action and Neurotoxicity: Lessons from Molluscs. AB - Anesthesia is a prerequisite for most surgical procedures in both animals and humans. Significant strides have been made in search of effective and safer compounds that elicit rapid induction and recovery from anesthesia. However, recent studies have highlighted possible negative effects of several anesthetic agents on the developing brain. The precise nature of this cytotoxicity remains to be determined mainly due to the complexity and the intricacies of the mammalian brain. Various invertebrates have contributed significantly toward our understanding of how both local and general anesthetics affect intrinsic membrane and synaptic properties. Moreover, the ability to reconstruct in vitro synapses between individually identifiable pre- and postsynaptic neurons is a unique characteristic of molluscan neurons allowing us to ask fundamental questions vis a-vis the long-term effects of anesthetics on neuronal viability and synaptic connectivity. Here, we highlight some of the salient aspects of various molluscan organisms and their contributions toward our understanding of the fundamental mechanisms underlying the actions of anesthetic agents as well as their potential detrimental effects on neuronal growth and synaptic connectivity. We also present some novel preliminary data regarding a newer anesthetic agent, dexmedetomidine, and its effects on synaptic transmission between Lymnaea neurons. The findings presented here underscore the importance of invertebrates for research in the field of anesthesiology while highlighting their relevance to both vertebrates and humans. PMID- 29410629 TI - Discovery of Phosphatidic Acid, Phosphatidylcholine, and Phosphatidylserine as Biomarkers for Early Diagnosis of Endometriosis. AB - The sensitivity and specificity of clinical diagnostic indicators and non invasive diagnostic methods for endometriosis at early stage is not optimal. Previous studies demonstrated that abnormal lipid metabolism was involved in the pathological development of endometriosis. Our cross-sectional study included 21 patients with laparoscopically confirmed endometriosis at stage I-II and 20 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium was collected by pipelle endometrial biopsy. Lipid metabolites were quantified by ultra-high performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS). Lipid profiles of endometriosis patients at early stage (I-II) was characterized by a decreased concentration of phosphatidylcholine (18:1/22:6), (20:1/14:1), (20:3/20:4), and phosphatidylserine (20:3/23:1) and an increased concentration of phosphatidic acid (25:5/22:6) compared with control. The synthesized predicting strategy with 5 biomarkers has a specificity of 75.0% and a sensitivity of 90.5%. Lipid profile of eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS based metabolomics. Our study demonstrated the alteration of phosphatidic acid, phosphatidylcholine, phosphatidylserine metabolites in endometriosis and provided potential biomarkers for semi-invasive diagnose of endometriosis at early stage. PMID- 29410628 TI - Reticuloendotheliosis Virus Inhibits the Immune Response Acting on Lymphocytes from Peripheral Blood of Chicken. AB - Chicken reticuloendotheliosis virus (REV) causes the atrophy of immune organs and immuno-suppression. The pathogenic mechanisms of REV are poorly understood. The aim of this study was to use RNA sequencing to analyse the effect of REV on immunity and cell proliferation in chicken lymphocytes from peripheral blood in vitro. Overall, 2977 differentially expressed genes (DEGs) were examined from cells between infected with REV or no; 56 DEGs related to cell proliferation and 130 DEGs related to immunity were identified. MTT, Q-PCR, and FCM indicated that REV reduced the number of lymphocytes by inhibiting the transition of S/G1 phase through FOXO and p53 pathways. Similarly, REV infection would destroy the immune defense of lymphocytes through MAPK-AP1 via Toll-like receptor-, NOD-like receptor-, and salmonella infection pathways to reduce the secretion of IL8 and IL18. In addition, the reduction of lymphocytes also might be responsible for the lower levels of IL8 and IL18, and the rescue of lymphocytes would been activated still through FOXO and p53 pathways. Moreover, the immune response for REV in lymphocytes would activate by up-regulating the expression of NOD1, MYD88, and AP1 through Toll-like receptor-/NOD-like receptor/salmonella-MAPK-AP1 pathways. These results indicate that REV could affect lymphocytes from peripheral blood by inhibit the cell proliferation and the immune system. It also was revealed that NOD1, MYD88, and AP1 were the key genes to activate the immune response through Toll-like receptor-/NOD-like receptor/salmonella-MAPK-AP1 pathways. These findings establish the groundwork and provide new clues for deciphering the molecular mechanism underlying REV infection in chickens. PMID- 29410630 TI - Astragaloside IV Inhibits Adipose Lipolysis and Reduces Hepatic Glucose Production via Akt Dependent PDE3B Expression in HFD-Fed Mice. AB - Objective: This study aims to investigate the effect of astragaloside IV on adipose lipolysis and hepatic gluconeogenesis. Methods: High-fat diet (HFD) feeding induced adipose dysfunction with enhanced endogenous glucose production in mice. The effects of Astragaloside IV on lipolysis and hepatic glucose production were investigated. Results: HFD feeding induced cAMP accumulation through reducing PDE3B expression and activity in adipose tissue. As a result, HFD feeding increased adipose lipolysis in mice. Astragaloside IV enhanced Akt phosphorylation and promoted Akt binding to PDE3B to preserve PDE3B content, resultantly reducing adipose cAMP accumulation. Knockdown of Akt1/2 diminished the effect of astragaloside IV on PDE3B induction, indicative of the role of Akt in astragaloside IV action. As a result from blocking of cAMP/PKA signaling, astragaloside IV suppressed hormone-sensitive lipase (HSL) activation and inhibited inflammation-associated adipose lipolysis. Moreover, astragaloside IV reduced ectopic fat deposition in the liver and inhibited FoxO1 activation via regulation of Akt, resultantly restraining excess hepatic glucose production. Conclusion: We showed that preserving PDE3B content by Akt is a key regulation to prevent lipolysis. Astragaloside IV inhibited lipolysis by reducing cAMP accumulation via regulation of Akt/PDE3B, contributing to limiting hepatic lipid deposition and restraining excessive hepatic glucose production. PMID- 29410631 TI - Sympathetic Nervous Regulation of Calcium and Action Potential Alternans in the Intact Heart. AB - Rationale: Arrhythmogenic cardiac alternans are thought to be an important determinant for the initiation of ventricular fibrillation. There is limited information on the effects of sympathetic nerve stimulation (SNS) on alternans in the intact heart and the conclusions of existing studies, focused on investigating electrical alternans, are conflicted. Meanwhile, several lines of evidence implicate instabilities in Ca handling, not electrical restitution, as the primary mechanism underpinning alternans. Despite this, there have been no studies on Ca alternans and SNS in the intact heart. The present study sought to address this, by application of voltage and Ca optical mapping for the simultaneous study of APD and Ca alternans in the intact guinea pig heart during direct SNS. Objective: To determine the effects of SNS on APD and Ca alternans in the intact guinea pig heart and to examine the mechanism(s) by which the effects of SNS are mediated. Methods and Results: Studies utilized simultaneous voltage and Ca optical mapping in isolated guinea pig hearts with intact innervation. Alternans were induced using a rapid dynamic pacing protocol. SNS was associated with rate-independent shortening of action potential duration (APD) and the suppression of APD and Ca alternans, as indicated by a shift in the alternans threshold to faster pacing rates. Qualitatively similar results were observed with exogenous noradrenaline perfusion. In contrast with previous reports, both SNS and noradrenaline acted to flatten the slope of the electrical restitution curve. Pharmacological block of the slow delayed rectifying potassium current (IKs), sufficient to abolish IKs-mediated APD-adaptation, partially reversed the effects of SNS on pacing-induced alternans. Treatment with cyclopiazonic acid, an inhibitor of the sarco(endo)plasmic reticulum ATPase, had opposite effects to that of SNS, acting to increase susceptibility to alternans, and suggesting that accelerated Ca reuptake into the sarcoplasmic reticulum is a major mechanism by which SNS suppresses alternans in the guinea pig heart. Conclusions: SNS suppresses calcium and action potential alternans in the intact guinea pig heart by an action mediated through accelerated Ca handling and via increased IKs. PMID- 29410632 TI - Correlations among Psychological Resilience, Self-Efficacy, and Negative Emotion in Acute Myocardial Infarction Patients after Percutaneous Coronary Intervention. AB - Objective: We investigated the influencing factors of the psychological resilience and self-efficacy of acute myocardial infarction (AMI) patients after percutaneous coronary intervention (PCI) and the relationships of psychological resilience and self-efficacy with negative emotion. Methods: Eighty-eight participants were enrolled. Psychological resilience, self-efficacy, and negative emotion were assessed with the Psychological Resilience Scale, Self-Efficacy Scale, Zung Self-Rating Anxiety Scale (SAS), and Zung Self-Rating Depression Scale (SDS), respectively. Furthermore, the relationships of psychological resilience and self-efficacy with negative emotion were investigated. Results: The average scores of psychological resilience, self-efficacy, anxiety, and depression were 70.08 +/- 13.26, 21.56 +/- 9.66, 53.68 +/- 13.10, and 56.12 +/- 12.37, respectively. The incidences of anxiety and depression were 23.90% (21/88) and 28.40% (25/88), respectively. The psychological resilience and self-efficacy scores of AMI patients after PCI varied significantly with age and economic status. SAS scores and SDS scores were significantly negatively correlated with psychological resilience and self-efficacy. Conclusion: Negative emotions in AMI patients after PCI are closely related to psychological resilience and self efficacy. Therefore, anxiety and depression could be alleviated by improving the psychological resilience and self-efficacy of patients undergoing PCI, thus improving patients' quality of life. PMID- 29410633 TI - The Limited Role of Number of Nested Syntactic Dependencies in Accounting for Processing Cost: Evidence from German Simplex and Complex Verbal Clusters. AB - This paper presents three acceptability experiments investigating German verb final clauses in order to explore possible sources of sentence complexity during human parsing. The point of departure was De Vries et al.'s (2011) generalization that sentences with three or more crossed or nested dependencies are too complex for being processed by the human parsing mechanism without difficulties. This generalization is partially based on findings from Bach et al. (1986) concerning the acceptability of complex verb clusters in German and Dutch. The first experiment tests this generalization by comparing two sentence types: (i) sentences with three nested dependencies within a single clause that contains three verbs in a complex verb cluster; (ii) sentences with four nested dependencies distributed across two embedded clauses, one center-embedded within the other, each containing a two-verb cluster. The results show that sentences with four nested dependencies are judged as acceptable as control sentences with only two nested dependencies, whereas sentences with three nested dependencies are judged as only marginally acceptable. This argues against De Vries et al.'s (2011) claim that the human parser can process no more than two nested dependencies. The results are used to refine the Verb-Cluster Complexity Hypothesis of Bader and Schmid (2009a). The second and the third experiment investigate sentences with four nested dependencies in more detail in order to explore alternative sources of sentence complexity: the number of predicted heads to be held in working memory (storage cost in terms of the Dependency Locality Theory [DLT], Gibson, 2000) and the length of the involved dependencies (integration cost in terms of the DLT). Experiment 2 investigates sentences for which storage cost and integration cost make conflicting predictions. The results show that storage cost outweighs integration cost. Experiment 3 shows that increasing integration cost in sentences with two degrees of center embedding leads to decreased acceptability. Taken together, the results argue in favor of a multifactorial account of the limitations on center embedding in natural languages. PMID- 29410634 TI - Urban Adolescents' Physical Activity Experience, Physical Activity Levels, and Use of Screen-Based Media during Leisure Time: A Structural Model. AB - There is limited understanding of the relationship between physical activity and use of screen-based media, two important behaviors associated with adolescents' health outcomes. To understand this relationship, researchers may need to consider not only physical activity level but also physical activity experience (i.e., affective experience obtained from doing physical activity). Using a sample predominantly consisting of African and Latino American urban adolescents, this study examined the interrelationships between physical activity experience, physical activity level, and use of screen-based media during leisure time. Data collected using self-report, paper and pencil surveys was analyzed using structural equation modeling. Results showed that physical activity experience was positively associated with physical activity level and had a direct negative relationship with use of non-active video games for males and a direct negative relationship with use of computer/Internet for both genders, after controlling for physical activity level. Physical activity level did not have a direct relationship with use of non-active video games or computer/Internet. However, physical activity level had a direct negative association with use of TV/movies. This study suggests that physical activity experience may play an important role in promoting physical activity and thwarting use of screen-based media among adolescents. PMID- 29410635 TI - Experiencing Nature through Immersive Virtual Environments: Environmental Perceptions, Physical Engagement, and Affective Responses during a Simulated Nature Walk. AB - By combining physical activity and exposure to nature, green exercise can provide additional health benefits compared to physical activity alone. Immersive Virtual Environments (IVE) have emerged as a potentially valuable supplement to environmental and behavioral research, and might also provide new approaches to green exercise promotion. However, it is unknown to what extent green exercise in IVE can provide psychophysiological responses similar to those experienced in real natural environments. In this study, 26 healthy adults underwent three experimental conditions: nature walk, sitting-IVE, and treadmill-IVE. The nature walk took place on a paved trail along a large river. In the IVE conditions, the participants wore a head-mounted display with headphones reproducing a 360 degrees video and audio of the nature walk, either sitting on a chair or walking on a manually driven treadmill. Measurements included environmental perceptions (presence and perceived environmental restorativeness - PER), physical engagement (walking speed, heart rate, and perceived exertion), and affective responses (enjoyment and affect). Additionally, qualitative information was collected through open-ended questions. The participants rated the IVEs with satisfactory levels of 'being there' and 'sense of reality,' but also reported discomforts such as 'flatness,' 'movement lag' and 'cyber sickness.' With equivalent heart rate and walking speed, participants reported higher perceived exertion in the IVEs than in the nature walk. The nature walk was associated with high enjoyment and enhanced affect. However, despite equivalent ratings of PER in the nature walk and in the IVEs, the latter were perceived as less enjoyable and gave rise to a poorer affect. Presence and PER did not differ between the two IVEs, although in the treadmill-IVE the negative affective responses had slightly smaller magnitude than in the sitting-IVE. In both the IVEs, the negative affective responses were mainly associated with cyber sickness, whereas PER was positively associated with enjoyment. From the qualitative analysis, it emerged that poor postural control and lack of a holistic sensory experience can also hinder immersion in the IVE. The results indicate that IVE technology might in future be a useful instrument in green exercise research and promotion, but only if image quality and cyber sickness can be addressed. PMID- 29410636 TI - Non-linguistic Conditions for Causativization as a Linguistic Attractor. AB - An attractor, in complex systems theory, is any state that is more easily or more often entered or acquired than departed or lost; attractor states therefore accumulate more members than non-attractors, other things being equal. In the context of language evolution, linguistic attractors include sounds, forms, and grammatical structures that are prone to be selected when sociolinguistics and language contact make it possible for speakers to choose between competing forms. The reasons why an element is an attractor are linguistic (auditory salience, ease of processing, paradigm structure, etc.), but the factors that make selection possible and propagate selected items through the speech community are non-linguistic. This paper uses the consonants in personal pronouns to show what makes for an attractor and how selection and diffusion work, then presents a survey of several language families and areas showing that the derivational morphology of pairs of verbs like fear and frighten, or Turkish korkmak 'fear, be afraid' and korkutmak 'frighten, scare', or Finnish istua 'sit' and istutta 'seat (someone)', or Spanish sentarse 'sit down' and sentar 'seat (someone)' is susceptible to selection. Specifically, the Turkish and Finnish pattern, where 'seat' is derived from 'sit' by addition of a suffix-is an attractor and a favored target of selection. This selection occurs chiefly in sociolinguistic contexts of what is defined here as linguistic symbiosis, where languages mingle in speech, which in turn is favored by certain demographic, sociocultural, and environmental factors here termed frontier conditions. Evidence is surveyed from northern Eurasia, the Caucasus, North and Central America, and the Pacific and from both modern and ancient languages to raise the hypothesis that frontier conditions and symbiosis favor causativization. PMID- 29410637 TI - Editorial: Psychological Responses to Violations of Expectations. PMID- 29410638 TI - Types of Anxiety and Depression: Theoretical Assumptions and Development of the Anxiety and Depression Questionnaire. AB - The present paper is addressed to (1) the validation of a recently proposed typology of anxiety and depression, and (2) the presentation of a new tool-the Anxiety and Depression Questionnaire (ADQ)-based on this typology. Empirical data collected across two stages-construction and validation-allowed us to offer the final form of the ADQ, designed to measure arousal anxiety, apprehension anxiety, valence depression, anhedonic depression, and mixed types of anxiety and depression. The results support the proposed typology of anxiety and depression and provide evidence that the ADQ is a reliable and valid self-rating measure of affective types, and accordingly its use in scientific research is recommended. PMID- 29410640 TI - Fear of Being Laughed at in Borderline Personality Disorder. AB - Building on the assumption of a possible link between biases in social information processing frequently associated with borderline personality disorder (BPD) and the occurrence of gelotophobia (i.e., a fear of being laughed at), the present study aimed at evaluating the prevalence rate of gelotophobia among BPD patients. Using the Geloph<15> , a questionnaire that allows a standardized assessment of the presence and severity of gelotophobia symptoms, rates of gelotophobia were assessed in a group of 30 female BPD patients and compared to data gathered in clinical and non-clinical reference groups. Results indicate a high prevalence of gelotophobia among BPD patients with 87% of BPD patients meeting the Geloph<15> criterion for being classified as gelotophobic. Compared to other clinical and non-clinical reference groups, the rate of gelotophobia among BPD patients appears to be remarkably high, far exceeding the numbers reported for other groups in the literature to date, with 30% of BPD patients reaching extreme levels, 37% pronounced levels, and 20% slight levels of gelotophobia. PMID- 29410639 TI - What Can Lexical Tone Training Studies in Adults Tell Us about Tone Processing in Children? AB - A growing number of studies on the acquisition of lexical tone by adult learners have revealed that factors such as language background, musical experience, cognitive abilities, and neuroanatomy all play a role in determining tone learning success. On the basis of these findings, it has been argued that the effectiveness of tone learning in adulthood depends on individual differences in these factors. However, it is not clear whether similar individual differences play an analogous role in tone learning in childhood. Indeed, relatively few studies have made comparisons between how adults and children learn lexical tones. Here, we review recent developments for tone learning in both adults and children. The review covers tone training in a range of contexts, including in naive listeners, in native speakers of other tone languages, in listeners with varying levels of musical experience, and in individuals with speech and hearing disorders. Finally, we discuss the parallels between adult and child tone learning, and provide recommendations concerning how findings in adult tone training can provide insights into tone learning for children by accommodating the needs of individual learners. PMID- 29410641 TI - Rapid Adaptation of Night Vision. AB - Apart from the well-known loss of color vision and of foveal acuity that characterizes human rod-mediated vision, it has also been thought that night vision is very slow (taking up to 40 min) to adapt to changes in light levels. Even cone-mediated, daylight, vision has been thought to take 2 min to recover from light adaptation. Here, we show that most, though not all adaptation is rapid, taking less than 0.6 s. Thus, monochrome (black-white-gray) images can be presented at mesopic light levels and be visible within a few 10th of a second, even if the overall light level, or level of glare (as with passing headlamps while driving), changes abruptly. PMID- 29410642 TI - Shopping versus Nature? An Exploratory Study of Everyday Experiences. AB - Although a growing volume of empirical research shows that being in nature is important for human wellbeing, the definition of what constitutes an 'experience in nature,' and how this is different from other types of experiences, is very often left implied. In this paper we contrast everyday experiences involving nature with a category of everyday experience in which most people regularly partake. We present an exploratory study in which people (N = 357) were explicitly asked to describe a memory they had of an everyday 'experience which involved nature,' as well as an everyday 'experience which involved shopping.' The open-ended responses to these questions were analyzed both quantitatively and qualitatively. Nature experiences were generally found to be more positive than shopping experiences, and they were more likely to be rated as 'peaceful' and 'active' compared to shopping experiences. Follow-up analyses indicate a significant interaction between experience category (nature or shopping), and the relationship between connectedness to nature and the amount of pleasure associated with that experience: The more strongly connected to nature a respondent was, the larger the disparity between the pleasantness of the shopping experience and that of the experience in nature tended to be. PMID- 29410643 TI - Psychopathological Processes Involved in Social Comparison, Depression, and Envy on Facebook. AB - Is Facebook utilization beneficial or detrimental for psychological well-being? I draw on outstanding research (e.g., Chou and Edge, 2012; Lin and Utz, 2015; Appel et al., 2016; Ehrenreich and Underwood, 2016; Vogel and Rose, 2016; Hu et al., 2017) to substantiate that examining other individuals' positively presented material on Facebook may have detrimental consequences. Increasing comparisons on Facebook may generate feelings of envy, the latter being a significant process determining the effect of growing social comparison on psychological well-being. To date, there is an increasing body of literature investigating the psychological consequences of Facebook usage, the function of relationship closeness in producing the feelings of contentment and envy, the impacts of exposure to positive content on Facebook, the link between envy and depression on Facebook, and the function of tie strength in expecting the emotional results of browsing Facebook. I am specifically interested in how previous research explored the consequences of Facebook use on psychological outcomes, the moderating function of envy in the link between Facebook use and reduced affective wellbeing, the psychological results of non-interactive Facebook conduct, and the role of relationship closeness in anticipating user's contentment and envy after inspecting a post. A synthesis of the extant literature suggests that inspecting other individuals' positive news on Facebook brings about contentment through emotional contagion, whereas negative news causes discomfort as a consequence of mood contagion, the transmissible effect being more powerful when the news is associated with a strong tie. The outcomes of this research back the argument that self-confidence and dispositional envy are instrumental in producing Facebook envy. These findings highlight that the emotional results of browsing Facebook are considerably affected by the substance of the comment, the personal attributes of the Facebook user, and link between the reader and the poster. As limitations in the current review, more hypotheses need to be tested and future directions for subsequent multilevel research on the behavioral and cognitive outcomes of Facebook should illuminate why when individuals achieve belongingness demands on Facebook, they feel in a superior way about themselves and their reputation in social circles. PMID- 29410644 TI - Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis. AB - Introduction: Plasma factor VIII (FVIII) and von Willebrand factor (VWF) levels have been associated with the rate and severity of arterial thrombus formation and have been linked to outcomes following thrombolytic therapy in acute myocardial infarction patients. Here, we aimed to investigate FVIII and VWF levels during the course of thrombolysis in acute ischemic stroke (AIS) patients and to find out whether they predict long-term outcomes. Materials and methods: Study population included 131 consecutive AIS patients (median age: 69 years, 60.3% men) who underwent i.v. thrombolysis with recombinant tissue plasminogen activator (rt-PA). Blood samples were taken on admission, 1 and 24 h after rt-PA administration to measure FVIII activity and VWF antigen levels. Neurological deficit of patients was determined according to the National Institutes of Health Stroke Scale (NIHSS). ASPECT scores were assessed using computer tomography images taken before and 24 h after thrombolysis. Intracranial hemorrhage was classified according to the European Cooperative Acute Stroke Study (ECASS) II criteria. Long-term functional outcome was determined at 90 days after the event by the modified Rankin scale (mRS). Results: VWF levels on admission were significantly elevated in case of more severe AIS [median and IQR values: NIHSS <6:189.6% (151.9-233.2%); NIHSS 6-16: 199.6% (176.4-250.8%); NIHSS >16: 247.8% (199.9-353.8%), p = 0.013]; similar, but non-significant trend was observed for FVIII levels. FVIII and VWF levels correlated well on admission (r = 0.748, p < 0.001) but no significant correlation was found immediately after thrombolysis (r = 0.093, p = 0.299), most probably due to plasmin-mediated FVIII degradation. VWF levels at all investigated occasions and FVIII activity before and 24 h after thrombolysis were associated with worse 24 h post-lysis ASPECT scores. In a binary backward logistic regression analysis including age, gender, high sensitivity C-reactive protein, active smoking, diabetes, and NIHSS >5 on admission, elevated FVIII and VWF levels after thrombolysis were independently associated with poor functional outcomes (mRS >= 3) at 90 days (immediately after thrombolysis: FVIII: OR: 7.10, 95% CI: 1.77-28.38, p = 0.006, VWF: OR: 6.31, 95% CI: 1.83-21.73, p = 0.003; 24 h after thrombolysis: FVIII: OR: 4.67, 95% CI: 1.42 15.38, p = 0.011, VWF: OR: 19.02, 95% CI: 1.94-186.99, p = 0.012). Conclusion: Elevated FVIII activity and VWF antigen levels immediately after lysis and at 24 h post-therapy were shown to have independent prognostic values regarding poor functional outcomes at 90 days. PMID- 29410645 TI - Common Misconceptions Regarding Pediatric Auditory Processing Disorder. AB - Pediatric hearing evaluation based on pure tone audiometry does not always reflect how a child hears in everyday life. This practice is inappropriate when evaluating the difficulties children experiencing auditory processing disorder (APD) in school or on the playground. Despite the marked increase in research on pediatric APD, there remains limited access to proper evaluation worldwide. This perspective article presents five common misconceptions of APD that contribute to inappropriate or limited management in children experiencing these deficits. The misconceptions discussed are (1) the disorder cannot be diagnosed due to the lack of a gold standard diagnostic test; (2) making generalizations based on profiles of children suspected of APD and not diagnosed with the disorder; (3) it is best to discard an APD diagnosis when another disorder is present; (4) arguing that the known link between auditory perception and higher cognition function precludes the validity of APD as a clinical entity; and (5) APD is not a clinical entity. These five misconceptions are described and rebutted using published data as well as critical thinking on current available knowledge on APD. PMID- 29410646 TI - Intramuscular EMG Decomposition Basing on Motor Unit Action Potentials Detection and Superposition Resolution. AB - A novel electromyography (EMG) signal decomposition framework is presented for the thorough and precise analysis of intramuscular EMG signals. This framework first detects all of the active motor unit action potentials (MUAPs) and assigns single MUAP segments to their corresponding motor units. MUAP waveforms that are found to be superimposed are then resolved into their constituent single MUAPs using a peel-off approach and similarly assigned. The method is composed of six stages of analytical procedures: preprocessing, segmentation, alignment and feature extraction, clustering and refinement, supervised classification, and superimposed waveform resolution. The performance of the proposed decomposition framework was evaluated using both synthetic EMG signals and real recordings obtained from healthy and stroke participants. The overall detection rate of MUAPs was 100% for both synthetic and real signals. The average accuracy for synthetic EMG signals was 87.23%. Average assignment accuracies of 88.63 and 94.45% were achieved for the real EMG signals obtained from healthy and stroke participants, respectively. Results demonstrated the ability of the developed framework to decompose intramuscular EMG signals with improved accuracy and efficiency, which we believe will greatly benefit the clinical utility of EMG for the diagnosis and rehabilitation of motor impairments in stroke patients. PMID- 29410647 TI - Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. AB - Dimethyl fumarate (DMF) is an effective treatment option for relapsing-remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models. DMF decreases absolute lymphocyte counts, but does not affect all subsets uniformly. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets. Similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory state. In vitro and animal models demonstrate a role for DMF within the central nervous system (CNS) in promoting neuronal survival in an Nrf2 pathway-dependent manner. However, the impact of DMF directly within the CNS of MS patients remains largely unknown. PMID- 29410648 TI - Status Epilepticus: Behavioral and Electroencephalography Seizure Correlates in Kainate Experimental Models. AB - Various etiological factors, such as head injury, chemical intoxication, tumors, and gene mutation, can induce epileptogenesis. In animal models, status epilepticus (SE) triggers epileptogenesis. In humans, convulsive SE for >30 min can be a life-threatening medical emergency. The duration and severity of convulsive SE are highly variable in chemoconvulsant animal models. A continuous video-electroencephalography (EEG) recording, and/or diligent direct observation, facilitates quantification of exact duration of different stages of convulsive seizures (Racine stages 3-5) to determine the severity of SE. A continuous convulsive SE for >30 min usually causes high mortality in some rodents and results in widespread brain damage in the surviving animals, in spite of treating with antiepileptic drugs (AEDs). AEDs control behavioral seizures but not EEG seizures. The severity of initial SE impacts epileptogenesis and cognitive function; therefore, quantitative assessment of behavioral SE and EEG in animal models will help to understand the impact of SE severity on epileptogenesis. There are several excellent reviews on experimental models of seizure/SE/epilepsy. This review focusses on the comparison of induction and characterization of behavioral SE and EEG correlates in mice and rats induced by kainate. We also discuss the advantages of repeated low dose of kainate (i.p. route), which minimizes variability in the initial SE severity between animals and reduces mortality rate. A refined approach to induce SE with kainate also addresses the two of the 3Rs (i.e., refinement and reduction), the guiding principles for ethical and scientific standpoint of animal research. PMID- 29410650 TI - Olfactory Receptors in Semen and in the Male Tract: From Proteome to Proteins. AB - The estimated number of testicular olfactory receptors (ORs) in mammals range between 20 and 66. Previous data reported the role of hOR17-4 and mOR23 in sperm oocyte chemiotaxis. Proteomic analysis was performed to understand which are the ORs expressed in seminal plasma. Seminal samples by four fertile men were analyzed by an Ultimate 3000Nano/Micro-HPLC apparatus coupled with an LTQ Orbitrap XL hybrid mass spectrometer. Western blot analysis confirmed the expression of three identified ORs. The expression of ORs in sperm cells, testis, and epididymis was evaluated by confocal microscopy analysis. In seminal plasma eight different ORs were identified by proteomics and three ORs have been confirmed by western blot. Confocal microscopy analysis revealed that OR4S1, OR4C13, and OR1I1 are expressed on the surface of sperm cells. In testicular tissue, OR4S1 and OR1I1 are expressed in spermatocytes and spermatids and OR4C13 is expressed throughout all the tubules. In patients with spermatocyte maturation arrest OR4S1 and OR1I1 expression was reduced and a weak positivity for OR4C13 was detected in the spermatogonia. OR4S1, OR4C13, and OR1I1 had intense and diffuse staining in the epididymis. This study initiated a new methodology for screening OR repertoire in sperms, testis and epididymis. Our results open new insights into OR involvement in sperm maturation and migration. PMID- 29410651 TI - The Development of Microbiota and Metabolome in Small Intestine of Sika Deer (Cervus nippon) from Birth to Weaning. AB - The dense and diverse community of microorganisms inhabiting the gastrointestinal tract of ruminant animals plays critical roles in the metabolism and absorption of nutrients, and gut associated immune function. Understanding microbial colonization in the small intestine of new born ruminants is a vital first step toward manipulating gut function through interventions during early life to produce long-term positive effects on host productivity and health. Yet the knowledge of microbiota colonization and its induced metabolites of small intestine during early life is still limited. In the present study, we examined the microbiota and metabolome in the jejunum and ileum of neonatal sika deer (Cervus nippon) from birth to weaning at days 1, 42, and 70. The microbial data showed that diversity and richness were increased with age, but a highly individual variation was observed at day 1. Principal coordinate analysis revealed significant differences in microbial community composition across three time points in the jejunum and ileum. The abundance of Halomonas spp., Lactobacillus spp., Escherichia-Shigella, and Bacteroides spp. tended to be decreased, while the proportion of Intestinibacter spp., Cellulosilyticum spp., Turicibacter spp., Clostridium sensu stricto 1 and Romboutsia spp. was significantly increased with age. For metabolome, metabolites separated from each other across the three time points in both jejunum and ileum. Moreover, the amounts of methionine, threonine, and putrescine were increased, while the amounts of myristic acid and pentadecanoic acid were decreased with age, respectively. The present study demonstrated that microbiota colonization and the metabolome becomes more developed in the small intestine with age. This may shed new light on the microbiota-metabolome-immune interaction during development. PMID- 29410649 TI - Microglia and CNS Interleukin-1: Beyond Immunological Concepts. AB - Activation of microglia and expression of the inflammatory cytokine interleukin-1 (IL-1) in the CNS have become almost synonymous with neuroinflammation. In numerous studies, increased CNS IL-1 expression and altered microglial morphology have been used as hallmarks of CNS inflammation. A central concept of how CNS IL 1 and microglia influence functions of the nervous system was derived from the notion initially generated in the peripheral immune system: IL-1 stimulates monocyte/macrophage (the peripheral counterparts of microglia) to amplify inflammation. It is increasingly clear, however, CNS IL-1 acts on other targets in the CNS and microglia participates in many neural functions that are not related to immunological activities. Further, CNS exhibits immunological privilege (although not as absolute as previously thought), rendering amplification of inflammation within CNS under stringent control. This review will analyze current literature to evaluate the contribution of immunological and non-immunological aspects of microglia/IL-1 interaction in the CNS to gain insights for how these aspects might affect health and disease in the nervous tissue. PMID- 29410652 TI - Distribution of Archaeal Communities along the Coast of the Gulf of Finland and Their Response to Oil Contamination. AB - The Baltic Sea is vulnerable to environmental changes. With the increasing shipping activities, the risk of oil spills remains high. Archaea are widely distributed in many environments. However, the distribution and the response of archaeal communities to oil contamination have rarely been investigated in brackish habitats. Hence, we conducted a survey to investigate the distribution, diversity, composition, and species interactions of indigenous archaeal communities at oil-contaminated sites along the coast of the Gulf of Finland (GoF) using high-throughput sequencing. Surface water and littoral sediment samples were collected at presumably oil-contaminated (oil distribution facilities) and clean sites along the coastline of the GoF in the winter 2015 and the summer 2016. Another three samples of open sea surface water were taken as offshore references. Of Archaea, Euryarchaeota dominated in the surface water and the littoral sediment of the coast of the GoF, followed by Crenarchaeota (including Thaumarchaeota, Thermoprotei, and Korarchaeota based on the Greengenes database used). The unclassified sequences accounted for 5.62% of the total archaeal sequences. Our study revealed a strong dependence of the archaeal community composition on environmental variables (e.g., salinity, pH, oil concentration, TOM, electrical conductivity, and total DNA concentration) in both littoral sediment and coastal water in the GoF. The composition of archaeal communities was season and ecosystem dependent. Archaea was highly diverse in the three ecosystems (littoral sediment, coastal water, and open sea water). Littoral sediment harbored the highest diversity of archaea. Oil was often detected in the littoral sediment but rarely detected in water at those presumably contaminated sites. Although the composition of archaeal community in the littoral sediment was sensitive to low-input oil contamination, the unchanged putative functional profiles and increased interconnectivity of the archaeal core species network plausibly revealed resilience and the potential for oil degradation. Halobacteriaceae and putative cytochrome P450 pathways were significantly enriched in the oil-contaminated littoral sediment. The archaeal taxa formed highly interconnected and interactive networks, in which Halobacteriaceae, Thermococcus, and methanogens were the main components, implying a potential relevant trophic connection between hydrocarbon degradation, methanogenesis, sulfate reduction, and/or fermentative growth. PMID- 29410653 TI - The Risk of Chronic Gastrointestinal Disorders Following Acute Infection with Intestinal Parasites. AB - Background: Infectious gastroenteritis (IGE) is caused by numerous bacterial, viral, and parasitic pathogens. A history of IGE has been shown in previous studies to increase the risk of developing chronic gastrointestinal disorders and other chronic conditions. As bacteria and viruses represent the majority of pathogen-specific causes of IGE, post-infectious studies have primarily focused on these organisms. The objective of this study was to investigate an association between a history of parasite-associated IGE and the subsequent development of chronic post-infectious gastrointestinal and non-gastrointestinal disorders in a military population. Methods: International Classification of Diseases, 9th Revision Clinical Modification (ICD-9-CM) diagnostic coding data for primary exposures and outcomes were obtained for a retrospective cohort study of active component military personnel from 1998 to 2013. Exposed subjects consisted of individuals with documented infection with one of ten parasitic pathogens. Unexposed subjects were matched to exposed subjects on demographic and operational deployment history parameters. Adjusted odds ratios (aORs) were estimated using logistic regression for several chronic disorders previously shown to be associated with a history of IGE. Results: A total of 896 subjects with a parasitic exposure were matched to 3681 unexposed subjects for multivariate regression analysis. Individuals infected with Balantidium coli, Ascaris lumbricoides, Strongyloides stercoralis, Necator americanus/Ancylostoma duodenale, and Taenia spp. had higher aOR for development of several chronic gastrointestinal disorders when compared with unexposed subjects after controlling for various covariates. Conclusion: We found that parasite-associated enteric infection increases the risk of development of post-infectious chronic gastrointestinal disorders in a military population. These results require confirmation in similar populations and in the developing world where infection with these parasites is endemic. Further understanding of disease burden and causal mechanisms should direct primary prevention and potential disease interception strategies. PMID- 29410654 TI - Stress Tolerance-Related Genetic Traits of Fish Pathogen Flavobacterium psychrophilum in a Mature Biofilm. AB - Flavobacterium psychrophilum is the causative agent of bacterial cold-water disease and rainbow trout fry syndrome, and hence this bacterium is placed among the most important salmonid pathogens in the freshwater aquaculture industry. Since bacteria in biofilms differ substantially from free-living counterparts, this study sought to find the main differences in gene expression between sessile and planktonic states of F. psychrophilum LM-02-Fp and NCMB1947T, with focus on stress-related changes in gene expression occurring during biofilm formation. To this end, biofilm and planktonic samples were analyzed by RNA sequencing to detect differentially expressed candidate genes (DECGs) between the two growth states, and decreasing the effects of interstrain variation by considering only genes with log2-fold changes <= -2 and >= 2 at Padj-values <= 0.001 as DECGs. Overall, 349 genes accounting for ~15% of total number of genes expressed in transcriptomes of F. psychrophilum LM-02-Fp and NCMB1947T (n = 2327) were DECGs between biofilm and planktonic states. Approximately 83 and 81% of all up- and down-regulated candidate genes in mature biofilms, respectively, were assigned to at least one gene ontology term; these were primarily associated with the molecular function term "catalytic activity." We detected a potential stress response in mature biofilms, characterized by a generalized down-regulation of DECGs with roles in the protein synthesis machinery (n = 63, primarily ribosomal proteins) and energy conservation (seven ATP synthase subunit genes), as well as an up-regulation of DECGs involved in DNA repair (ruvC, recO, phrB1, smf, and dnaQ) and oxidative stress response (cytochrome C peroxidase, probable peroxiredoxin, and a probable thioredoxin). These results support the idea of a strategic trade-off between growth-related processes and cell homeostasis to preserve biofilm structure and metabolic functioning. In addition, LDH-based cytotoxicity assays and an intraperitoneal challenge model for rainbow trout fry agreed with the transcriptomic evidence that the ability of F. psychrophilum to form biofilms could contribute to the virulence. Finally, the reported changes in gene expression, as induced by the plankton-to-biofilm transition, represent the first transcriptomic guideline to obtain insights into the F. psychrophilum biofilm lifestyle that could help understand the prevalence of this bacterium in aquaculture settings. PMID- 29410655 TI - MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria. AB - MacroD1 is a macrodomain containing protein that has mono-ADP-ribose hydrolase enzymatic activity toward several ADP-ribose adducts. Dysregulation of MacroD1 expression has been shown to be associated with the pathogenesis of several forms of cancer. To date, the physiological functions and sub-cellular localization of MacroD1 are unclear. Previous studies have described nuclear and cytosolic functions of MacroD1. However, in this study we show that endogenous MacroD1 protein is highly enriched within mitochondria. We also show that MacroD1 is highly expressed in human and mouse skeletal muscle. Furthermore, we show that MacroD1 can efficiently remove ADP-ribose from 5' and 3'-phosphorylated double stranded DNA adducts in vitro. Overall, we have shown that MacroD1 is a mitochondrial protein with promiscuous enzymatic activity that can target the ester bonds of ADP-ribosylated phosphorylated double-stranded DNA ends. These findings have exciting implications for MacroD1 and ADP-ribosylation within the regulation of mitochondrial function and DNA-damage in vivo. PMID- 29410656 TI - Biogeographic Differences in the Microbiome and Pathobiome of the Coral Cladocora caespitosa in the Western Mediterranean Sea. AB - The endemic Mediterranean zooxanthellate scleractinian reef-builder Cladocora caespitosa is among the organisms most affected by warming-related mass mortality events in the Mediterranean Sea. Corals are known to contain a diverse microbiota that plays a key role in their physiology and health. Here we report the first study that examines the microbiome and pathobiome associated with C. caespitosa in three different Mediterranean locations (i.e., Genova, Columbretes Islands, and Tabarca Island). The microbial communities associated with this species showed biogeographical differences, but shared a common core microbiome that probably plays a key role in the coral holobiont. The putatively pathogenic microbial assemblage (i.e., pathobiome) of C. caespitosa also seemed to depend on geographic location and the human footprint. In locations near the coast and with higher human influence, the pathobiome was entirely constituted by Vibrio species, including the well-known coral pathogens Vibrio coralliilyticus and V. mediterranei. However, in the Columbretes Islands, located off the coast and the most pristine of the analyzed locations, no changes among microbial communities associated to healthy and necrosed samples were detected. Hence, our results provide new insights into the microbiome of the temperate corals and its role in coral health status, highlighting its dependence on the local environmental conditions and the human footprint. PMID- 29410657 TI - Multiple Food-Animal-Borne Route in Transmission of Antibiotic-Resistant Salmonella Newport to Humans. AB - Characterization of transmission routes of Salmonella among various food-animal reservoirs and their antibiogram is crucial for appropriate intervention and medical treatment. Here, we analyzed 3728 Salmonella enterica serovar Newport (S. Newport) isolates collected from various food-animals, retail meats and humans in the United States between 1996 and 2015, based on their minimum inhibitory concentration (MIC) toward 27 antibiotics. Random Forest and Hierarchical Clustering statistic was used to group the isolates according to their MICs. Classification and Regression Tree (CART) analysis was used to identify the appropriate antibiotic and its cut-off value between human- and animal population. Two distinct populations were revealed based on the MICs of individual strain by both methods, with the animal population having significantly higher MICs which correlates to antibiotic-resistance (AR) phenotype. Only ~9.7% (267/2763) human isolates could be attributed to food animal origins. Furthermore, the isolates of animal origin had less diverse antibiogram than human isolates (P < 0.001), suggesting multiple sources involved in human infections. CART identified trimethoprim-sulfamethoxazole to be the best classifier for differentiating the animal and human isolates. Additionally, two typical AR patterns, MDR-Amp and Tet-SDR dominant in bovine- or turkey population, were identified, indicating that distinct food-animal sources could be involved in human infections. The AR analysis suggested fluoroquinolones (i.e., ciprofloxacin), but not extended-spectrum cephalosporins (i.e., ceftriaxone, cefoxitin), is the adaptive choice for empirical therapy. Antibiotic resistant S. Newport from humans has multiple origins, with distinct food-animal borne route contributing to a significant proportion of heterogeneous isolates. PMID- 29410658 TI - Spatiotemporal Dynamics of Ammonia-Oxidizing Thaumarchaeota in Distinct Arctic Water Masses. AB - One of the most abundant archaeal groups on Earth is the Thaumarchaeota. They are recognized as major contributors to marine ammonia oxidation, a crucial step in the biogeochemical cycling of nitrogen. Their universal success is attributed to a high genomic flexibility and niche adaptability. Based on differences in the gene coding for ammonia monooxygenase subunit A (amoA), two different ecotypes with distinct distribution patterns in the water column have been identified. We used high-throughput sequencing of 16S rRNA genes combined with archaeal amoA functional gene clone libraries to investigate which environmental factors are driving the distribution of Thaumarchaeota ecotypes in the Atlantic gateway to the Arctic Ocean through an annual cycle in 2014. We observed the characteristic vertical pattern of Thaumarchaeota abundance with high values in the mesopelagic (>200 m) water throughout the entire year, but also in the epipelagic (<200 m) water during the dark winter months (January, March and November). The Thaumarchaeota community was dominated by three OTUs which on average comprised 76% +/- 11 and varied in relative abundance according to water mass characteristics and not to depth or ammonium concentration, as suggested in previous studies. The ratios of the abundance of the different OTU types were similar to that of the functional amoA water cluster types. Together, this suggests a strong selection of ecotypes within different water masses, supporting the general idea of water mass characteristics as an important factor in defining microbial community structure. If indeed, as suggested in this study, Thaumarchaeota population dynamics are controlled by a set of factors, described here as water mass characteristics and not just depth alone, then changes in water mass flow will inevitably affect the distribution of the different ecotypes. PMID- 29410659 TI - Gut Microbiota Mediate Insecticide Resistance in the Diamondback Moth, Plutella xylostella (L.). AB - The development of insecticide resistance in insect pests is a worldwide concern and elucidating the underlying mechanisms is critical for effective crop protection. Recent studies have indicated potential links between insect gut microbiota and insecticide resistance and these may apply to the diamondback moth, Plutella xylostella (L.), a globally and economically important pest of cruciferous crops. We isolated Enterococcus sp. (Firmicutes), Enterobacter sp. (Proteobacteria), and Serratia sp. (Proteobacteria) from the guts of P. xylostella and analyzed the effects on, and underlying mechanisms of insecticide resistance. Enterococcus sp. enhanced resistance to the widely used insecticide, chlorpyrifos, in P. xylostella, while in contrast, Serratia sp. decreased resistance and Enterobacter sp. and all strains of heat-killed bacteria had no effect. Importantly, the direct degradation of chlorpyrifos in vitro was consistent among the three strains of bacteria. We found that Enterococcus sp., vitamin C, and acetylsalicylic acid enhanced insecticide resistance in P. xylostella and had similar effects on expression of P. xylostella antimicrobial peptides. Expression of cecropin was down-regulated by the two compounds, while gloverin was up-regulated. Bacteria that were not associated with insecticide resistance induced contrasting gene expression profiles to Enterococcus sp. and the compounds. Our studies confirmed that gut bacteria play an important role in P. xylostella insecticide resistance, but the main mechanism is not direct detoxification of insecticides by gut bacteria. We also suggest that the influence of gut bacteria on insecticide resistance may depend on effects on the immune system. Our work advances understanding of the evolution of insecticide resistance in this key pest and highlights directions for research into insecticide resistance in other insect pest species. PMID- 29410660 TI - Drivers of Macrofungi Community Structure Differ between Soil and Rotten-Wood Substrates in a Temperate Mountain Forest in China. AB - The effects of environmental and dispersal processes on macrofungi community assembly remain unclear. Further, it is not well understood if community assembly differs for different functional guilds of macrofungi, e.g., soil and rotten-wood macrofungi. In this study, using 2433 macrofungi sporocarps belonging to 217 species located within a forest dynamics plot in temperate mountain forest (China), we examined the explanatory power of topography, spatial eigenvectors (representing unknown spatial processes, e.g., dispersal), plant community, and light availability for local spatial variation in the macrofungi community through variance partitioning and partial least squares path modeling. We found spatial eigenvectors and light as the most important factors for explaining species richness and composition of macrofungi. Light was negatively correlated with species richness of macrofungi. Furthermore, species richness and composition of soil macrofungi were best explained by light, and species richness and composition of rotten-wood macrofungi were best explained by spatial eigenvectors. Woody plant community structure was not an important factor for species richness and composition of macrofungi. Our findings suggest that spatial processes, perhaps dispersal limitation, and light availability were the most important factors affecting macrofungi community in temperate deciduous broad leaved forest. Major differences in influencing factors between soil and rotten wood macrofungi were observed, with light as the major driver for soil macrofungi and unknown spatial processes as the major driver for rotten-wood macrofungi. These findings shed new light to the processes shaping community assembly in macrofungi in temperate deciduous broad-leaved forest and point to the potential importance of both intrinsic dynamics, such as dispersal, and external forcing, such as forest dynamics, via its effect on light availability. PMID- 29410662 TI - Editorial: Radiation and the Immune System: Current Knowledge and Future Perspectives. PMID- 29410661 TI - Metatranscriptome Sequencing Reveals Insights into the Gene Expression and Functional Potential of Rumen Wall Bacteria. AB - Microbiota of the rumen wall constitute an important niche of rumen microbial ecology and their composition has been elucidated in different ruminants during the last years. However, the knowledge about the function of rumen wall microbes is still limited. Rumen wall biopsies were taken from three fistulated dairy cows under a standard forage-based diet and after 4 weeks of high concentrate feeding inducing a subacute rumen acidosis (SARA). Extracted RNA was used for metatranscriptome sequencing using Illumina HiSeq sequencing technology. The gene expression of the rumen wall microbial community was analyzed by mapping 35 million sequences against the Kyoto Encyclopedia for Genes and Genomes (KEGG) database and determining differentially expressed genes. A total of 1,607 functional features were assigned with high expression of genes involved in central metabolism, galactose, starch and sucrose metabolism. The glycogen phosphorylase (EC:2.4.1.1) which degrades (1->4)-alpha-D-glucans was among the highest expressed genes being transcribed by 115 bacterial genera. Energy metabolism genes were also highly expressed, including the pyruvate orthophosphate dikinase (EC:2.7.9.1) involved in pyruvate metabolism, which was covered by 177 genera. Nitrogen metabolism genes, in particular glutamate dehydrogenase (EC:1.4.1.4), glutamine synthetase (EC:6.3.1.2) and glutamate synthase (EC:1.4.1.13, EC:1.4.1.14) were also found to be highly expressed and prove rumen wall microbiota to be actively involved in providing host-relevant metabolites for exchange across the rumen wall. In addition, we found all four urease subunits (EC:3.5.1.5) transcribed by members of the genera Flavobacterium, Corynebacterium, Helicobacter, Clostridium, and Bacillus, and the dissimilatory sulfate reductase (EC 1.8.99.5) dsrABC, which is responsible for the reduction of sulfite to sulfide. We also provide in situ evidence for cellulose and cellobiose degradation, a key step in fiber-rich feed digestion, as well as oxidative stress response and oxygen scavenging at the rumen wall. Archaea, mainly Methanocaldococcus and Methanobrevibacter, were found to be metabolically active with a high number of transcripts matching to methane and carbohydrate metabolism. These findings enhance our understanding of the metabolic function of the bovine rumen wall microbiota. PMID- 29410663 TI - A cDNA Immunization Strategy to Generate Nanobodies against Membrane Proteins in Native Conformation. AB - Nanobodies (Nbs) are soluble, versatile, single-domain binding modules derived from the VHH variable domain of heavy-chain antibodies naturally occurring in camelids. Nbs hold huge promise as novel therapeutic biologics. Membrane proteins are among the most interesting targets for therapeutic Nbs because they are accessible to systemically injected biologics. In order to be effective, therapeutic Nbs must recognize their target membrane protein in native conformation. However, raising Nbs against membrane proteins in native conformation can pose a formidable challenge since membrane proteins typically contain one or more hydrophobic transmembrane regions and, therefore, are difficult to purify in native conformation. Here, we describe a highly efficient genetic immunization strategy that circumvents these difficulties by driving expression of the target membrane protein in native conformation by cells of the immunized camelid. The strategy encompasses ballistic transfection of skin cells with cDNA expression plasmids encoding one or more orthologs of the membrane protein of interest and, optionally, other costimulatory proteins. The plasmid is coated onto 1 um gold particles that are then injected into the shaved and depilated skin of the camelid. A gene gun delivers a helium pulse that accelerates the DNA-coated particles to a velocity sufficient to penetrate through multiple layers of cells in the skin. This results in the exposure of the extracellular domains of the membrane protein on the cell surface of transfected cells. Repeated immunization drives somatic hypermutation and affinity maturation of target-specific heavy-chain antibodies. The VHH/Nb coding region is PCR amplified from B cells obtained from peripheral blood or a lymph node biopsy. Specific Nbs are selected by phage display or by screening of Nb-based heavy chain antibodies expressed as secretory proteins in transfected HEK cells. Using this strategy, we have successfully generated agonistic and antagonistic Nbs against several cell surface ecto-enzymes and ligand-gated ion channels. PMID- 29410664 TI - MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development. AB - MicroRNAs play crucial roles in modulating immune system. miR-146a, a potent feedback suppressor of NF-kappaB signaling, was shown to limit the innate immune response and myelopoiesis in a knockout mouse model. Here, we observed high lymphopoiesis demonstrated as mild splenomegaly and severe lymphadenopathy in a miR-146a transgenic mouse model. Overexpression of miR-146a resulted in enhanced proliferation and reduced apoptosis of T cells. More activated CD4+ T cells or effector memory T cells were observed in transgenic mice even under physiological conditions. Importantly, as one of the key steps to generate central tolerance, the positive selection of thymocytes is impaired in transgenic mice, resulting in more CD4+CD8+ double-positive thymocytes but fewer CD4+CD8- and CD4-CD8+ single positive thymocytes. The maturation of selected CD4-CD8+ thymocytes was also impaired, leading to more severe loss of CD4-CD8+ than CD4+CD8- thymocytes in thymus of transgenic mice. Gene expression profiling analysis identified nine positive selection-associated genes, which were downregulated in transgenic mice, including genes encoding major histocompatibility complex class I/II molecules, IL-7 receptor alpha chain, and Gimap4, whose downregulation may contribute to the impairment of positive selection. Gimap4 was verified as a novel target of miR 146a. These findings further extend our understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development. PMID- 29410665 TI - The Role of MicroRNAs in Myeloid Cells during Graft-versus-Host Disease. AB - The successful treatment of various hematologic diseases with allogeneic hematopoietic cell transplantation is often limited by the occurrence of graft versus-host disease (GvHD). Several microRNAs (miRs) have recently been shown to impact the biology of GvHD by regulating pro- as well as anti-inflammatory target genes. There is increasing evidence that a single miR can have different effects by preferentially targeting certain genes depending on the cell type that the miR is analyzed in. This review will focus on the role of miRs in myeloid cells during the development of acute and chronic GvHD and autoimmune diseases. Because miRs act on the expression of multiple target genes and may thereby influence the immune system at different functional levels, they are potentially attractive targets for the modification of allogeneic immune responses using miR mimics and inhibitors. PMID- 29410666 TI - Salmonella Immunotherapy Improves the Outcome of CHOP Chemotherapy in Non-Hodgkin Lymphoma-Bearing Mice. AB - We have previously shown that Salmonella immunotherapy is effective to treat B cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients' conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP-Salmonella combined therapy showed increased numbers of tumor infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting. PMID- 29410667 TI - Double-Stranded RNA Derived from Lactic Acid Bacteria Augments Th1 Immunity via Interferon-beta from Human Dendritic Cells. AB - Lactic acid bacteria (LAB) are one of the major commensal species in the small intestine and known for contributing to maintenance of protective immunity and immune homeostasis. However, currently there has been no evidence regarding the cellular mechanisms involved in the probiotic effects of LAB on human immune cells. Here, we demonstrated that LAB double-stranded RNA (dsRNA) triggered interferon-beta (IFN-beta) production by human dendritic cells (DCs), which activated IFN-gamma-producing T cells. Interleukin-12 (IL-12) secretion from human DCs in response to LAB was abrogated by depletion of bacterial dsRNA, and was attenuated by neutralizing IFN-beta, indicating LAB dsRNA primarily activated the IFN-beta/IL-12 pathway. Moreover, the induction of IL-12 secretion from DCs by LAB was abolished by the inhibition of endosomal acidification, confirming the critical role of the endosomal digestion of LAB. In a coculture of human naive CD4+ T cells and BDCA1+ DCs, DCs stimulated with LAB containing dsRNA induced IFN gamma-producing T cells. These results indicate that human DCs activated by LAB enhance Th1 immunity depending on IFN-beta secretion in response to bacterial dsRNA. PMID- 29410668 TI - Sulforaphane Inhibits Lipopolysaccharide-Induced Inflammation, Cytotoxicity, Oxidative Stress, and miR-155 Expression and Switches to Mox Phenotype through Activating Extracellular Signal-Regulated Kinase 1/2-Nuclear Factor Erythroid 2 Related Factor 2/Antioxidant Response Element Pathway in Murine Microglial Cells. AB - Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant effects. In this study, we evaluated the mechanisms of its effects on lipopolysaccharide (LPS)-induced cell death, inflammation, oxidative stress, and polarization in murine microglia. We found that SFN protects N9 microglial cells upon LPS-induced cell death and suppresses LPS-induced levels of secreted pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. SFN is also a potent inducer of redox sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which is responsible for the transcription of antioxidant, cytoprotective, and anti inflammatory genes. SFN induced translocation of Nrf2 to the nucleus via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation. siRNA mediated knockdown study showed that the effects of SFN on LPS-induced reactive oxygen species, reactive nitrogen species, and pro-inflammatory cytokine production and cell death are partly Nrf2 dependent. Mox phenotype is a novel microglial phenotype that has roles in oxidative stress responses. Our results suggested that SFN induced the Mox phenotype in murine microglia through Nrf2 pathway. SFN also alleviated LPS-induced expression of inflammatory microRNA, miR 155. Finally, SFN inhibits microglia-mediated neurotoxicity as demonstrated by conditioned medium and co-culture experiments. In conclusion, SFN exerts protective effects on microglia and modulates the microglial activation state. PMID- 29410670 TI - Editorial: Single-Domain Antibodies-Biology, Engineering and Emerging Applications. PMID- 29410669 TI - Lactoferrin-Containing Immunocomplexes Drive the Conversion of Human Macrophages from M2- into M1-like Phenotype. AB - Macrophages are multifunctional cells that perform diverse roles in health and disease and considered the main source of inflammatory cytokines in affected joints of patients with rheumatoid arthritis (RA). M2 macrophages are well known as anti-inflammation and wound-healing cells; however, recent evidence suggests that they can also promote inflammation in RA, although the underlying mechanism remains to be clarified. Based upon our recent finding that lactoferrin (LTF) containing IgG immunocomplex (LTF-IC), found elevated in RA sera, potent activators of human monocytes/macrophages, we herein demonstrate that LTF-IC was able to elicit immediate proinflammatory cytokine production by M2-polarized human macrophages through coligation with CD14/toll-like receptor (TLR) 4 and FcgammaRIIa (CD32a). The LTF-IC-treated M2 cells adopted surface maker expression profile similar to that of M1 phenotype and became functionally hyperactive to subsequent stimuli such as lipopolysaccharide, zymosan and IL-1beta, which could provide a positive feedback signal to promote excessive inflammation in RA. They also acquired the ability to facilitate activation of Th17 cells that are known to play critical roles in RA pathology. We propose that IgG ICs containing TLR agonizing autoantigens are able to directly switch human macrophages from M2 into M1-like phenotype, thereby promoting excessive inflammation in autoimmune diseases such as RA. PMID- 29410671 TI - Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults. AB - Background: Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Methods: Blood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax) at middle age (N = 53, 50-65 years of age). VZV-specific IFNgamma-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Results: Robust short-term enhancement of the VZV-specific IFNgamma-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFNgamma-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFNgamma producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV specific CD8 T-cells in participants with high numbers of VZV-specific pre vaccination IFNgamma-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFNgamma-producing cells. Conclusion: These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFNgamma producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age. PMID- 29410672 TI - BoALMT1, an Al-Induced Malate Transporter in Cabbage, Enhances Aluminum Tolerance in Arabidopsis thaliana. AB - Aluminum (Al) is present in approximately 50% of the arable land worldwide and is regarded as the main limiting factor of crop yield on acidic soil. Al-induced root malate efflux plays an important role in the Al tolerance of plants. Here, the aluminum induced malate transporter BoALMT1 (KF322104) was cloned from cabbage (Brassica oleracea). BoALMT1 showed higher expression in roots than in shoots. The expression of BoALMT1 was specifically induced by Al treatment, but not the trivalent cations lanthanum (La), cadmium (Cd), zinc (Zn), or copper (Cu). Subcellular localization studies were performed in onion epidermal cells and revealed that BoALMT1 was localized at the plasma membrane. Scanning Ion selective Electrode Technique was used to analyze H+ flux. Xenopus oocytes and Arabidopsis thaliana expressing BoALMT1 excreted more H+ under Al treatment. Overexpressing BoALMT1 in transgenic Arabidopsis resulted in enhanced Al tolerance and increased malate secretion. The results suggested that BoALMT1 functions as an Al-resistant gene and encodes a malate transporter. Expressing BoALMT1 in Xenopus oocytes or A. thaliana indicated that BoALMT1 could increase malate secretion and H+ efflux to resist Al tolerance. PMID- 29410673 TI - Defense Enzyme Responses in Dormant Wild Oat and Wheat Caryopses Challenged with a Seed Decay Pathogen. AB - Seeds have well-established passive physical and chemical defense mechanisms that protect their food reserves from decay-inducing organisms and herbivores. However, there are few studies evaluating potential biochemical defenses of dormant seeds against pathogens. Caryopsis decay by the pathogenic Fusarium avenaceum strain F.a.1 was relatively rapid in wild oat (Avena fatua L.) isoline "M73," with >50% decay after 8 days with almost no decay in wheat (Triticum aestivum L.) var. RL4137. Thus, this fungal strain has potential for selective decay of wild oat relative to wheat. To study defense enzyme activities, wild oat and wheat caryopses were incubated with F.a.1 for 2-3 days. Whole caryopses were incubated in assay reagents to measure extrinsic defense enzyme activities. Polyphenol oxidase, exochitinase, and peroxidase were induced in whole caryopses, but oxalate oxidase was reduced, in response to F.a.1 in both species. To evaluate whether defense enzyme activities were released from the caryopsis surface, caryopses were washed with buffer and enzyme activity was measured in the leachate. Significant activities of polyphenol oxidase, exochitinase, and peroxidase, but not oxalate oxidase, were leached from caryopses. Defense enzyme responses were qualitatively similar in the wild oat and wheat genotypes evaluated. Although the absolute enzyme activities were generally greater in whole caryopses than in leachates, the relative degree of induction of polyphenol oxidase, exochitinase, and peroxidase by F.a.1 was greater in caryopsis leachates, indicating that a disproportionate quantity of the induced activity was released into the environment from the caryopsis surface, consistent with their assumed role in defense. It is unlikely that the specific defense enzymes studied here play a key role in the differential susceptibility to decay by F.a.1 in these two genotypes since defense enzyme activities were greater in the more susceptible wild oat, compared to wheat. Results are consistent with the hypotheses that (1) dormant seeds are capable of mounting complex responses to pathogens, (2) a diversity of defense enzymes are involved in responses in multiple plant species, and (3) it is possible to identify fungi capable of selective decay of weed seeds without damaging crop seeds, a concept that may be applicable to weed management in the field. While earlier work on seed defenses demonstrated the presence of passive defenses, this work shows that dormant seeds are also quite responsive and capable of activating and releasing defense enzymes in response to a pathogen. PMID- 29410674 TI - Metarhizium brunneum (Ascomycota; Hypocreales) Treatments Targeting Olive Fly in the Soil for Sustainable Crop Production. AB - Soil treatments with Metarhizium brunneum EAMa 01/58-Su strain conducted in both Northern and Southern Spain reduced the olive fly (Bactrocera oleae) population density emerging from the soil during spring up to 70% in treated plots compared with controls. A model to determine the influence of rainfall on the conidial wash into different soil types was developed, with most of the conidia retained at the first 5 cm, regardless of soil type, with relative percentages of conidia recovered ranging between 56 and 95%. Furthermore, the possible effect of UV-B exposure time on the pathogenicity of this strain against B. oleae adults coming from surviving preimaginals and carrying conidia from the soil at adult emergence was also evaluated. The UV-B irradiance has no significant effect on M. brunneum EAMa 01/58-Su pathogenicity with B. oleae adult mortalities of 93, 90, 79, and 77% after 0, 2, 4, and 6 of UV-B irradiance exposure, respectively. In a next step for the use of these M. brunneum EAMa 01/58-Sun soil treatments within a B. oleae IPM strategy, its possible effect of on the B. oleae cosmopolitan parasitoid Psyttalia concolor, its compatibility with the herbicide oxyfluorfen 24% commonly used in olive orchards and the possible presence of the fungus in the olive oil resulting from olives previously placed in contact with the fungus were investigated. Only the highest conidial concentration (1 * 108 conidia ml-) caused significant P. concolor adult mortality (22%) with enduing mycosis in 13% of the cadavers. There were no fungal propagules in olive oil samples resulting from olives previously contaminated by EAMa 01/58-Su conidia. Finally, the strain was demonstrated to be compatible with herbicide since the soil application of the fungus reduced the B. oleae population density up to 50% even when it was mixed with the herbicide in the same tank. The fungal inoculum reached basal levels 4 months after treatments (1.6 * 103 conidia g soil-1). These results reveal both the efficacy and environmental and food safety of this B. oleae control method, protecting olive groves and improving olive oil quality without negative effects on the natural enemy P. concolor. PMID- 29410675 TI - What Is There in Seeds? Vertically Transmitted Endophytic Resources for Sustainable Improvement in Plant Growth. AB - Phytobeneficial microbes, particularly endophytes, such as fungi and bacteria, are concomitant partners of plants throughout its developmental stages, including seed germination, root and stem growth, and fruiting. Endophytic microbes have been identified in plants that grow in a wide array of habitats; however, seed borne endophytic microbes have not been fully explored yet. Seed-borne endophytes are of great interest because of their vertical transmission; their potential to produce various phytohormones, enzymes, antimicrobial compounds, and other secondary metabolites; and improve plant biomass and yield under biotic and abiotic stresses. This review addresses the current knowledge on endophytes, their ability to produce metabolites, and their influence on plant growth and stress mitigation. PMID- 29410676 TI - The Geographic Origins of Ethnic Groups in the Indian Subcontinent: Exploring Ancient Footprints with Y-DNA Haplogroups. AB - Several studies have evaluated the movements of large populations to the Indian subcontinent; however, the ancient geographic origins of smaller ethnic communities are not clear. Although historians have attempted to identify the origins of some ethnic groups, the evidence is typically anecdotal and based upon what others have written before. In this study, recent developments in DNA science were assessed to provide a contemporary perspective by analyzing the Y chromosome haplogroups of some key ethnic groups and tracing their ancient geographical origins from genetic markers on the Y-DNA haplogroup tree. A total of 2,504 Y-DNA haplotypes, representing 50 different ethnic groups in the Indian subcontinent, were analyzed. The results identified 14 different haplogroups with 14 geographic origins for these people. Moreover, every ethnic group had representation in more than one haplogroup, indicating multiple geographic origins for these communities. The results also showed that despite their varied languages and cultural differences, most ethnic groups shared some common ancestors because of admixture in the past. These findings provide new insights into the ancient geographic origins of ethnic groups in the Indian subcontinent. With about 2,000 other ethnic groups and tribes in the region, it is expected that more scientific discoveries will follow, providing insights into how, from where, and when the ancestors of these people arrived in the subcontinent to create so many different communities. PMID- 29410677 TI - Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model. AB - The goal of this study was to develop a method for whole genome cell-free DNA (cfDNA) methylation analysis in humans and mice with the ultimate goal to facilitate the identification of tumor derived DNA methylation changes in the blood. Plasma or serum from patients with pancreatic neuroendocrine tumors or lung cancer, and plasma from a murine model of pancreatic adenocarcinoma was used to develop a protocol for cfDNA isolation, library preparation and whole-genome bisulfite sequencing of ultra low quantities of cfDNA, including tumor-specific DNA. The protocol developed produced high quality libraries consistently generating a conversion rate >98% that will be applicable for the analysis of human and mouse plasma or serum to detect tumor-derived changes in DNA methylation. PMID- 29410678 TI - Actiflagelin, a new sperm activator isolated from Walterinnesia aegyptia venom using phenotypic screening. AB - Background: Sperm contains a wealth of cell surface receptors and ion channels that are required for most of its basic functions such as motility and acrosome reaction. Conversely, animal venoms are enriched in bioactive compounds that primarily target those ion channels and cell surface receptors. We hypothesized, therefore, that animal venoms should be rich enough in sperm-modulating compounds for a drug discovery program. Our objective was to demonstrate this fact by using a sperm-based phenotypic screening to identify positive modulators from the venom of Walterinnesia aegyptia. Methods: Herein, as proof of concept that venoms contain interesting compounds for sperm physiology, we fractionated Walterinnesia aegyptia snake venom by RP-HPLC and screened for bioactive fractions capable of accelerating mouse sperm motility (primary screening). Next, we purified each compound from the positive fraction by cation exchange and identified the bioactive peptide by secondary screening. The peptide sequence was established by Edman sequencing of the reduced/alkylated compound combined to LC-ESI-QTOF MS/MS analyses of reduced/alkylated fragment peptides following trypsin or V8 protease digestion. Results: Using this two-step purification protocol combined to cell phenotypic screening, we identified a new toxin of 7329.38 Da (actiflagelin) that activates sperm motility in vitro from OF1 male mice. Actiflagelin is 63 amino acids in length and contains five disulfide bridges along the proposed pattern of disulfide connectivity C1-C5, C2-C3, C4-C6, C7-C8 and C9-C10. Modeling of its structure suggests that it belongs to the family of three finger toxins with a noticeable homology with bucandin, a peptide from Bungarus candidus venom. Conclusions: This report demonstrates the feasibility of identifying profertility compounds that may be of therapeutic potential for infertility cases where motility is an issue. PMID- 29410680 TI - Neural-Based Compensation of Nonlinearities in an Airplane Longitudinal Model with Dynamic-Inversion Control. AB - The inversion design approach is a very useful tool for the complex multiple input-multiple-output nonlinear systems to implement the decoupling control goal, such as the airplane model and spacecraft model. In this work, the flight control law is proposed using the neural-based inversion design method associated with the nonlinear compensation for a general longitudinal model of the airplane. First, the nonlinear mathematic model is converted to the equivalent linear model based on the feedback linearization theory. Then, the flight control law integrated with this inversion model is developed to stabilize the nonlinear system and relieve the coupling effect. Afterwards, the inversion control combined with the neural network and nonlinear portion is presented to improve the transient performance and attenuate the uncertain effects on both external disturbances and model errors. Finally, the simulation results demonstrate the effectiveness of this controller. PMID- 29410679 TI - Effects of Brazilian scorpion venoms on the central nervous system. AB - In Brazil, the scorpion species responsible for most severe incidents belong to the Tityus genus and, among this group, T. serrulatus, T. bahiensis, T. stigmurus and T. obscurus are the most dangerous ones. Other species such as T. metuendus, T. silvestres, T. brazilae, T. confluens, T. costatus, T. fasciolatus and T. neglectus are also found in the country, but the incidence and severity of accidents caused by them are lower. The main effects caused by scorpion venoms - such as myocardial damage, cardiac arrhythmias, pulmonary edema and shock - are mainly due to the release of mediators from the autonomic nervous system. On the other hand, some evidence show the participation of the central nervous system and inflammatory response in the process. The participation of the central nervous system in envenoming has always been questioned. Some authors claim that the central effects would be a consequence of peripheral stimulation and would be the result, not the cause, of the envenoming process. Because, they say, at least in adult individuals, the venom would be unable to cross the blood-brain barrier. In contrast, there is some evidence showing the direct participation of the central nervous system in the envenoming process. This review summarizes the major findings on the effects of Brazilian scorpion venoms on the central nervous system, both clinically and experimentally. Most of the studies have been performed with T. serrulatus and T. bahiensis. Little information is available regarding the other Brazilian Tityus species. PMID- 29410681 TI - Postpartum Vaginal Blood Loss following Two Different Methods of Cervical Ripening. AB - Eighty women undergoing induction of labor at the University of Calabar Teaching Hospital were recruited and randomly allocated into two treatment groups (40 each), to receive either serial 50 ug doses of misoprostol or intracervical Foley catheter. Vaginal blood loss was collected and measured using an under buttocks plastic collection bag and by perineal pad weighing up to 6 hours postpartum. There were no significant differences between the two groups with respect to sociodemographic and obstetric characteristics. Comparison of blood loss in vaginal deliveries between the two groups revealed that subjects in the misoprostol group had significantly higher blood loss than subjects in the Foley catheter group (488 +/- 222 versus 326 +/- 106, p<0.05). In both groups, there was strong and statistically significant positive correlation between postpartum blood loss and induction delivery interval (r=0.75, p<0.0001; r=0.77, p<0.0001). There were no significant differences in maternal outcomes. In view of this, further study is required to ascertain if lower doses of misoprostol for induction of labor may result in lesser blood loss. This trial is registered with ISRCTN14479515. PMID- 29410682 TI - Focus on Mesenchymal Stem Cell-Derived Exosomes: Opportunities and Challenges in Cell-Free Therapy. AB - Mesenchymal stem cells have been at the forefront of regenerative medicine for many years. Exosomes, which are nanovesicles involved in intercellular communication and the transportation of genetic material transportation that can be released by mesenchymal stem cells, have been recently reported to play a role in cell-free therapy of many diseases, including myocardial infarction, drug addiction, and status epilepticus. They are also thought to help ameliorate inflammation-induced preterm brain injury, liver injury, and various types of cancer. This review highlights recent advances in the exploration of mesenchymal stem cell-derived exosomes in therapeutic applications. The natural contents, drug delivery potency, modification methods, and drug loading methods of exosomes are also discussed. PMID- 29410683 TI - Knowledge and Acceptability of Human Papillomavirus Vaccination among Women Attending the Gynaecological Outpatient Clinics of a University Teaching Hospital in Lagos, Nigeria. AB - Objectives: This study was aimed at determining the knowledge and acceptability of HPV vaccine among women attending the gynaecology clinics of the Lagos University Teaching Hospital (LUTH). Methods: This was a descriptive cross sectional study involving 148 consecutively selected women attending the gynaecology clinic of LUTH. Relevant information was obtained from these women using an interviewer-administered questionnaire. The data was analysed and then presented by simple descriptive statistics using tables and charts. Chi-square statistics were used to test the association between the sociodemographical variables and acceptance of HPV vaccination. All significance values were reported at P < 0.05. Results: The mean age of the respondents was 35.7 +/- 9.7 years. The study showed that 36.5% of the respondents had heard about HPV infection while only 18.9% had knowledge about the existence of HPV vaccines. Overall, 81.8% of the respondents accepted that the vaccines could be administered to their teenage girls with the level of education of the mothers being the major determinant of their acceptability (P = 0.013). Conclusions: Awareness of HPV infections and existence of HPV vaccines is low. However, the acceptance of HPV vaccines is generally high. Efforts should be made to increase the awareness about cervical cancer, its aetiologies, and prevention via HPV vaccination. PMID- 29410684 TI - The Incidence of Acute Gastrointestinal Illness in Canada, Foodbook Survey 2014 2015. AB - Acute gastrointestinal illness (AGI) is an important public health issue, with many pathogen sources and modes of transmission. A one-year telephone survey was conducted in Canada (2014-2015) to estimate the incidence of self-reported AGI in the previous 28 days and to describe health care seeking behaviour, using a symptom-based case definition. Excluding cases with respiratory symptoms, it is estimated that there are 0.57 self-reported AGI episodes per person-year, almost 19.5 million episodes in Canada each year. The proportion of cases seeking medical care was nearly 9%, of which 17% reported being requested to submit a sample for laboratory testing, and 49% of those requested complied and provided a sample. Results can be used to inform burden of illness and source attribution studies and indicate that AGI continues to be an important public health issue in Canada. PMID- 29410685 TI - Lipocrinology - the relationship between lipids and endocrine function. AB - While lipids are an integral part of the endocrine clinic, the opposite is not necessarily true. The lipocrinology framework addresses this lacuna, by highlighting the similarities and multiple relationships between lipid and endocrine function. It reinforces the need to screen (clinically or biochemically) all dyslipidemic patients for endocrine disease and appropriate endocrine patients for dyslipidemia. Thus, it aims to improve clinical care for persons with lipid abnormalities as well as endocrine disease. PMID- 29410686 TI - Thunbergia laurifolia Exhibits Antifibrotic Effects in Human Hepatic Stellate Cells. AB - Leaves of Thunbergia laurifolia (TL) have been reported to have antioxidation, anti-inflammatory, detoxifying, and hepatoprotective effects. However, studies relating to antifibrotic activity have not been reported. Currently, there is no standard treatment for hepatic fibrosis. This study aimed to investigate the antifibrotic activity of TL in human hepatic stellate LX-2 cells. Results from cell viability and cell death assays showed that the extract at high concentrations was toxic to LX-2 cells. TL extract reversed the transformation of LX-2 cells to myofibroblast-like characteristics in response to stimulation by transforming growth factor-beta 1. This action may be associated with the effect of TL in suppressing alpha-SMA and collagen-I production observed by immunofluorescence study and western blot analysis. Additionally, TL extract significantly decreased MMP-9 activity which is consistent with the reduction of MMP-9, MMP-2, and TIMP-1 gene expression. The effect of TL in suppressing fibrosis may be associated with its ability to inhibit the activation of p38 MAPK and Erk1/2 kinases as examined by western blot analysis. Our study provides convincing evidence that TL possesses antifibrotic activity which may be through the suppression of TGF-beta1-mediated production of MMPs, collagen-1, and alpha SMA in hepatic stellate cells. PMID- 29410687 TI - Editorial. PMID- 29410688 TI - Management and outcome of heterotopic interstitial pregnancy: Case report and review of literature. AB - Objective: To report a case of heterotopic interstitial pregnancy after in vitro fertilization-embryo transfer (IVF-ET), presenting with a second trimester uterine rupture. To review the clinical presentations, risk factors, treatment options, and outcome of heterotopic interstitial pregnancies. Methods: We describe the clinical presentation, management, and outcome of a patient with a heterotopic interstitial pregnancy, diagnosed following second trimester rupture of the interstitial pregnancy. We reviewed all published cases of heterotopic interstitial pregnancies. Results: A 35-year-old pregnant woman with a past history of right adnexectomy and 16 weeks pregnant with dichorionic diamniotic twins following IVF-ET, was admitted to our department with unexplained recurrent abdominal pain and anemia. Further investigation showed a hemoperitoneum and because of hypovolemic shock an emergency laparotomy was performed, with diagnosis of a ruptured heterotopic interstitial pregnancy. The uterine defect was sutured using simple interrupted sutures. The intrauterine pregnancy progressed uneventful afterwards.We found 86 cases in the published literature, reporting on heterotopic interstitial pregnancies. 80.2% (69/86) occurred after IVF-ET. History of uni- or bilateral salpingectomy is a major risk factor, present in 39.5% (34/86). 37.2% (32/86) presented with cornual rupture. Surgery was performed in 53.5% (46/86) of cases. Medical management was possible in case of unruptured, early diagnosed heterotopic interstitial pregnancy (32.6% (28/86)). Watchful waiting was only possible when the interstitial pregnancy miscarried (5.8% (5/86)). The live birth rate of the intrauterine pregnancy, when viable at presentation, was 70.0% (56/80). The live birth rate of the interstitial pregnancy was only 4.7% (4/86). Conclusions: The majority of cases are diagnosed by detailed ultrasound in the setting of early follow-up after IVF ET and are asymptomatic at diagnosis. Yet, a substantial number of patients present with cornual rupture. Risk factors are IVF-ET and a history of salpingectomy. Depending on clinical presentation, treatment options include watchful waiting, medical treatment, or surgery. Unfortunately, the interstitial pregnancy is generally lost, and only has a chance of survival in case of presentation at a viable gestational age. The outcome of the coexisting intrauterine pregnancy is generally good. PMID- 29410689 TI - Comparison of longitudinal excursion of a nerve-phantom model using quantitative ultrasound imaging and motion analysis system methods: A convergent validity study. AB - Background: Quantitative ultrasound imaging is gaining popularity in research and clinical settings to measure the neuromechanical properties of the peripheral nerves such as their capability to glide in response to body segment movement. Increasing evidence suggests that impaired median nerve longitudinal excursion is associated with carpal tunnel syndrome. To date, psychometric properties of longitudinal nerve excursion measurements using quantitative ultrasound imaging have not been extensively investigated. Methods: This study investigates the convergent validity of the longitudinal nerve excursion by comparing measures obtained using quantitative ultrasound imaging with those determined with a motion analysis system. A 38-cm long rigid nerve-phantom model was used to assess the longitudinal excursion in a laboratory environment. The nerve-phantom model, immersed in a 20-cm deep container filled with a gelatin-based solution, was moved 20 times using a linear forward and backward motion. Three light-emitting diodes were used to record nerve-phantom excursion with a motion analysis system, while a 5-cm linear transducer allowed simultaneous recording via ultrasound imaging. Results: Both measurement techniques yielded excellent association (r = 0.99) and agreement (mean absolute difference between methods = 0.85 mm; mean relative difference between methods = 7.48 %). Small discrepancies were largely found when larger excursions (i.e. > 10 mm) were performed, revealing slight underestimation of the excursion by the ultrasound imaging analysis software. Conclusion: Quantitative ultrasound imaging is an accurate method to assess the longitudinal excursion of an in vitro nerve-phantom model and appears relevant for future research protocols investigating the neuromechanical properties of the peripheral nerves. PMID- 29410690 TI - Shear wave elastography: Can it be a new radiologic approach for the diagnosis of erectile dysfunction? AB - Introduction: Erectile dysfunction (ED) is a common health problem among males, and radiology has limited use in its diagnosis and treatment. Shear wave elastography (SWE) is a new sonographic technique. In this study, we examined the significance of SWE in the diagnosis of ED. Methods: The study included a total number of 70 participants. The mean age of the participants was 54.14 +/- 8.03 years (range: 39 and 71 years old). We composed two groups. Group 1 had 35 patients who presented to the urology clinic in our hospital complaining of ED, and had a score of 17 or lower from the International Index of Erectile Function (IIEF) questionnaire. Group 2 consisted of 35 healthy volunteers who did not have ED. SWE measurements were performed from corpus cavernosum penis in both groups, and the results were noted. Differences between the groups were evaluated statistically. Results: The difference between the mean SWE measurements of two groups (Group 1: 20.94 +/- 6.23 kPa and group 2: 24.63 +/- 7.58 kPa) was found to be statistically significant (p = 0.027; p < 0.05). For a cut-off value of 17.1 kPa, the SWE method has specificity, sensitivity, positive predictive value, and negative predictive value regarding diagnosis of ED as 94.29%, 34.29%, 85.71%, and 58.93%, respectively. The mean age of the groups did not show a statistically significant difference (p = 0.287; p > 0.05). Conclusions: Due to its high specificity and positive predictive value, SWE can offer useful data in the radiologic evaluation of ED cases. PMID- 29410691 TI - Intra-observer repeatability when assessing the foetal urinary bladder volume by the Virtual Organ Computer-aided AnaLysis and SUM-OF-CYLINDERS methods: A pilot study. AB - Introduction: The aim of this study was to compare the intra-observer repeatability when using two different methods for estimating the volume of foetal urinary bladders. Method: The urinary bladders of 20 foetuses were documented by three-dimensional ultrasound. Standard deviation was compared when the volumes of identical bladder images were repeatedly estimated using the Virtual Organ Computer-aided AnaLysis and the experimental SUM-OF-CYLINDERS methods. Results: No systematic deviation was found between the estimated volumes when using these two methods. Standard deviation was smaller for the SUM-OF CYLINDERS compared to the Virtual Organ Computer-aided AnaLysis method (p < 0.0001). In relation to bladder volumes of 5-25 ml, standard deviation was 11-14% for the Virtual Organ Computer-aided AnaLysis and 4-5% for the SUM-OF-CYLINDERS method. Conclusions: Using three-dimensional ultrasound images adapted for the Virtual Organ Computer-aided AnaLysis method, foetal urinary bladder volumes can also be estimated using the SUM-OF-CYLINDERS method. The SUM-OF-CYLINDERS method employs technical advances which may result in a lower standard deviation and therefore higher intra-observer repeatability. PMID- 29410692 TI - Evaluating the risk of appendiceal perforation when using ultrasound as the initial diagnostic imaging modality in children with suspected appendicitis. AB - Background: Ultrasound scan has gained attention for diagnosing appendicitis due to its avoidance of ionizing radiation. However, studies show that ultrasound scan carries inferior sensitivity to computed tomography scan. A non-diagnostic ultrasound scan could increase the time to diagnosis and appendicectomy, particularly if follow-up computed tomography scan is needed. Some studies suggest that delaying appendicectomy increases the risk of perforation. Objective: To investigate the risk of appendiceal perforation when using ultrasound scan as the initial diagnostic imaging modality in children with suspected appendicitis. Methods: We retrospectively reviewed 1411 charts of children <=17 years old diagnosed with appendicitis at two urban academic medical centers. Patients who underwent ultrasound scan first were compared to those who underwent computed tomography scan first. In the sub-group analysis, patients who only received ultrasound scan were compared to those who received initial ultrasound scan followed by computed tomography scan. Main outcome measures were appendiceal perforation rate and time from triage to appendicectomy. Results: In 720 children eligible for analysis, there was no significant difference in perforation rate between those who had initial ultrasound scan and those who had initial computed tomography scan (7.3% vs. 8.9%, p = 0.44), nor in those who had ultrasound scan only and those who had initial ultrasound scan followed by computed tomography scan (8.0% vs. 5.6%, p = 0.42). Those patients who had ultrasound scan first had a shorter triage-to-incision time than those who had computed tomography scan first (9.2 (IQR: 5.9, 14.0) vs. 10.2 (IQR: 7.3, 14.3) hours, p = 0.03), whereas those who had ultrasound scan followed by computed tomography scan took longer than those who had ultrasound scan only (7.8 (IQR: 5.3, 11.6) vs. 15.1 (IQR: 10.6, 20.6), p < 0.001). Children < 12 years old receiving ultrasound scan first had lower perforation rate (p = 0.01) and shorter triage-to-incision time (p = 0.003). Conclusion: Children with suspected appendicitis receiving ultrasound scan as the initial diagnostic imaging modality do not have increased risk of perforation compared to those receiving computed tomography scan first. We recommend that children <12 years of age receive ultrasound scan first. PMID- 29410693 TI - Intra-renal splenosis mimicking a solid renal mass. AB - We present the case of a young woman found to have an exophytic solid renal mass who was referred to our institution for ablation of said mass versus partial nephrectomy. The patient had a history of splenectomy. Ultrasound demonstrated a homogeneous solid left renal mass, and the diagnosis of intra-renal splenosis was considered based on the patient's history. The diagnosis was confirmed using Tc 99 m heat-damaged red blood cell scintigraphy, obviating the need for an invasive procedure. The diagnosis of intra-renal splenosis should be considered for a solid renal mass with an appropriate history of prior splenic trauma or splenectomy. PMID- 29410694 TI - Multiparametric ultrasound findings in a patient with polyorchidism. AB - Polyorchidism is a rare condition usually incidentally discovered in young patients investigated with ultrasound for unrelated reasons. It is characterized by the presence of unilateral or, rarely, bilateral supernumerary testes which, depending on the type of polyorchidism, may have their own epididymis and vas deferens. Ultrasound, including B-mode and color Doppler technique, represents the primary imaging modality for the evaluation of scrotal diseases, including the characterization of supernumerary testes, which normally appear identical to the ipsilateral testicular parenchyma on every ultrasonographic technique performed. The role of MRI is thus limited to confirming ultrasonographic findings and excluding the presence of malignancy. Contrast-enhanced ultrasound is a recently introduced ultrasonographic technique providing detailed and sensitive visualization of the perfusion pattern of structures. It can thus be added to the conventional ultrasonographic examination in order to establish the diagnosis, negating the use of more expensive and time-consuming imaging modalities. We present a young patient with an incidentally found supernumerary testis, where new distinctive ultrasonographic findings, like the identification of transmediastinal vessels and a cystic appendage along with the perfusion pattern on contrast-enhanced ultrasound, established the diagnosis of polyorchidism. PMID- 29410696 TI - The interaction of selenoprotein F (SELENOF) with retinol dehydrogenase 11 (RDH11) implied a role of SELENOF in vitamin A metabolism. AB - Background: Selenoprotein F (SELENOF, was named as 15-kDa selenoprotein) has been reported to play important roles in oxidative stress, endoplasmic reticulum (ER) stress and carcinogenesis. However, the biological function of SELENOF is still unclear. Methods: A yeast two-hybrid system was used to screen the interactive protein of SELENOF in a human fetal brain cDNA library. The interaction between SELENOF and interactive protein was validated by fluorescence resonance energy transfer (FRET), co-immunoprecipitation (co-IP) and pull-down assays. The production of retinol was detected by high performance liquid chromatograph (HPLC). Results: Retinol dehydrogenase 11 (RDH11) was found to interact with SELENOF. RDH11 is an enzyme for the reduction of all-trans-retinaldehyde to all trans-retinol (vitamin A). The production of retinol was decreased by SELENOF overexpression, resulting in more retinaldehyde. Conclusions: SELENOF interacts with RDH11 and blocks its enzyme activity to reduce all-trans-retinaldehyde. PMID- 29410697 TI - Metabolomics insights into the modulatory effects of long-term compound polysaccharide intake in high-fat diet-induced obese rats. AB - Background: Polysaccharides can alleviate obesity in mammals; however, studies on mechanism of this alleviation are limited. A few studies have indicated that polysaccharides improve obesity by regulating the metabolism of the body. Therefore, a metabolomics approach, consisting of high resolution nuclear magnetic resonance (NMR) spectroscopy and a multivariate statistical technique, was applied to explore the mechanism of the protective effects of lentinan and Flos Lonicera polysaccharides (LF) on high-fat diet (HFD) induced obesity. Methods: In this study, rats were randomly divided into three groups: control diet (CD), HFD, and HFD supplemented with a mixture of lentinan and Flos Lonicera polysaccharide. Histopathological and clinical biochemical assessments were also conducted. A combination of a NMR metabolomics study and a multivariable statistical analysis method to distinguish urinary and fecal metabolites was applied. Results: Significant obesity symptoms appeared in HFD rats (for example, significant weight gain, epididymal adipose accumulation and lipid deposition in hepatocytes), which was attenuated in the LF group. Additionally, the HFD induced a reduction of choline, citrate, pyruvate and glycerol and increased the levels of trimethylamine oxide (TMAO) and taurine. Of note, these metabolic disorders were reversed by LF intervention mainly through pathways of energy metabolism, choline metabolism and gut microbiota metabolism. Conclusions: LF supplementation had a re-balancing effect on the disturbed metabolic pathways in the obese body. The results of this study validate the therapeutic effect of the compound polysaccharide--LF in obesity and described the biochemical and metabolic mechanisms involved. PMID- 29410698 TI - Suicide ideation and attempts among people with epilepsy in Addis Ababa, Ethiopia. AB - Background: Suicidal ideation and attempts are more frequent in people with epilepsy than in general population and suicide attempt increases the chance of later completed suicide. The aim of this study was to assess the prevalence and associated factors of suicidal ideation and attempt among people with epilepsy in Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia. Methods: Institution based cross-sectional study was conducted from May to June 2014 at Amanuel Mental Specialized Hospital among people with epilepsy. The pre-tested semi-structured questionnaire was used for interviewing the study participants. Logistic regression analysis was used to assess predictors of suicidal ideation and attempt. Results: The study indicated that the prevalence of suicidal ideation and attempt among people with epilepsy were 29.8 and 14.1%, respectively. Poor social support, drug treatment for mental illness, had co-morbid depression, no seizure free within 1 year and family history committed suicide were significantly associated with suicidal ideation and attempt. Conclusion: The prevalence of suicidal ideation and attempt in people with epilepsy found to be higher when compared to general population. Therefore, screening all epilepsy patients should be done for early diagnosis and treatment. PMID- 29410699 TI - Initiation of breastfeeding within one hour of birth among mothers with infants younger than or equal to 6 months of age attending public health institutions in Addis Ababa, Ethiopia. AB - Background: Breast milk is comprised of the essential nutrients that an infant needs in the first six months of life. Timely initiation of breastfeeding guarantees that infants receive the colostrum, 'the first breastmilk', which contains antibodies that protect the newborn against diseases. Breastfeeding within the first hour of life prevents newborn death due to sepsis, pneumonia, diarrhea and hypothermia. Although breastfeeding is a common practice in sub Saharan Africa, evidence show that early initiation of breastfeeding is low. Methods: We conducted a cross-sectional study of 583 mothers with infants younger than or equal to 6 months of age attending Maternal and Child Health (MCH) clinics of public health institutions in Addis Ababa, Ethiopia from April to May 2012. A simple random sampling design was used to select the institutions included in this study. Data from mothers of infants were collected using interviewer-administered questionnaire. We analyzed the data to examine factors associated with initiation of breastfeeding within one hour of birth using logistic regression models. Results: Of 564 (96.7%, 564/583) mothers who breastfed their infants, 58.3% (329/564) initiated breastfeeding within one hour of birth. In the adjusted analysis, mothers who had three or more infants had about twice higher odds of timely initiation of breastfeeding within one hour of birth (Adjusted Odds Ratio [aOR] 2.10; 95% Confidence Interval [CI]1.04, 4.30) compared with mothers who had one infant. Furthermore, women who started antenatal care at their fourth month of pregnancy or later had a 49.0% higher odds of initiation of breastfeeding within one hour of birth (aOR 1.49; 95% CI 1.01, 2.19) compared to mothers who started antenatal care before their fourth month of pregnancy. Conclusions: Initiation of breastfeeding within one hour of birth was low. Initiation of breastfeeding within one hour of birth was highest among multiparous women, mothers aged 30-34 years, and women who began antenatal care at their fourth month of pregnancy or later. Public health officials and health care providers should consider interventions to promote and support early initiation of breastfeeding. PMID- 29410700 TI - Epileptic Seizures Prediction Using Machine Learning Methods. AB - Epileptic seizures occur due to disorder in brain functionality which can affect patient's health. Prediction of epileptic seizures before the beginning of the onset is quite useful for preventing the seizure by medication. Machine learning techniques and computational methods are used for predicting epileptic seizures from Electroencephalograms (EEG) signals. However, preprocessing of EEG signals for noise removal and features extraction are two major issues that have an adverse effect on both anticipation time and true positive prediction rate. Therefore, we propose a model that provides reliable methods of both preprocessing and feature extraction. Our model predicts epileptic seizures' sufficient time before the onset of seizure starts and provides a better true positive rate. We have applied empirical mode decomposition (EMD) for preprocessing and have extracted time and frequency domain features for training a prediction model. The proposed model detects the start of the preictal state, which is the state that starts few minutes before the onset of the seizure, with a higher true positive rate compared to traditional methods, 92.23%, and maximum anticipation time of 33 minutes and average prediction time of 23.6 minutes on scalp EEG CHB-MIT dataset of 22 subjects. PMID- 29410701 TI - Is case triaging a useful tool for emergency surgeries? A review of 106 trauma surgery cases at a level 1 trauma center in South Africa. AB - Background: The optimal timing for emergency surgical interventions and implementation of protocols for trauma surgery is insufficient in the literature. The Groote Schuur emergency surgery triage (GSEST) system, based on Cape Triaging Score (CTS), is followed at Groote Schuur Hospital (GSH) for triaging emergency surgical cases including trauma cases. The study aimed to look at the effect of delay in surgery after scheduling based on the GSEST system has an impact on outcome in terms of postoperative complications and death. Methods: Prospective audit of patients presenting to GSH trauma center following penetrating or blunt chest, abdominal, neck and peripheral vascular trauma who underwent surgery over a 4-month period was performed. Post-operative complications were graded according to Clavien-Dindo classification of surgical complications. Results: One hundred six patients underwent surgery during the study period. One-hundred two (96.2%) cases were related to penetrating trauma. Stab wounds comprised 71 (67%) and gunshot wounds (GSW) 31 (29.2%) cases. Of the 106 cases, 6, 47, 40, and 13 patients were booked as red, orange, yellow, and green, respectively. The median delay for green, yellow, and orange cases was within the expected time. The red patients took unexpectedly longer (median delay 48 min, IQR 35-60 min). Thirty one (29.3%) patients developed postoperative complications. Among the booked red, orange, yellow, and green cases, postoperative complications developed in 3, 18, 9, and 1 cases, respectively. Only two (1.9%) postoperative deaths were documented during the study period. There was no statistically significant association between operative triage and post-operative complications (p = 0.074). Conclusion: Surgical case categorization has been shown to be useful in prioritizing emergency trauma surgical cases in a resource constraint high-volume trauma center. PMID- 29410702 TI - The impact of the Boko Haram insurgency in Northeast Nigeria on childhood wasting: a double-difference study. AB - Background: This research examines the relationship between violent conflict and childhood wasting in Northeast Nigeria, where residents have been subjected to fighting between the Nigerian government and Boko Haram - an extremist Islamist movement - since 2009. Methods: Using two Demographic and Health Surveys from before and after the Boko Haram insurgency started, a double-difference (difference-in-difference) approach is used to assess the impact of the conflict on mean weight-for-height z-scores and the likelihood of wasting. Results: Results suggest that if children exposed to the conflict had not been exposed, their mean weight-for-height z-score would be 0.49 standard deviations higher (p < 0.001) than it is, increasing from - 0.74 to - 0.25. Additionally, the likelihood of wasting would be 13 percentage points lower (mean z-statistic - 4.2), bringing the proportion down from 23% to 10%. Conclusion: Descriptive evidence suggests that poor child health outcomes in the conflict areas of Northeast Nigeria may be due to disruptions to social services and increased food insecurity in an already resource poor area. Although other unidentified factors may contribute to both conflict and wasting, the findings underscore the importance of appropriate programs and policies to support children in conflict zones. PMID- 29410703 TI - Mental health in primary health care in a rural district of Cambodia: a situational analysis. AB - Background: While mental and substance use disorders are common worldwide, the treatment gap is enormous in low and middle income countries. Primary health care is considered to be the most important way for people to get mental health care. Cambodia is a country with a long history of war and has poor mental health and limited resources for care. The aim of this study was to conduct a situational analysis of the mental health services in the rural district of Lvea Em, Kandal Province, Cambodia. Methods: A cross-sectional situational analysis was done to understand the mental health situation in Lvea Em District comparing it with the national one. The Programme for improving mental health care (PRIME) tool was used to collect systematic information about mental health care from 14 key informants in Cambodia. In addition, a separate questionnaire based on the PRIME tool was developed for the district health care centres (12 respondents). Ethical approval was obtained from the National Ethics Committee for Health Research in Cambodia. Results: Mental health care is limited both in Lvea Em District and the country. Though national documents containing guidelines for mental health care exist, the resources available and health care infrastructure are below what is recommended. There is no budget allocated for mental health in the district; there are no mental health specialists and the mental health training of health care workers is insufficient. Based on the limited knowledge from the respondents in the district, mental health disorders do exist but no documentation of these patients is available. Respondents discussed how community aspects such as culture, history and religion were related to mental health. Though there have been improvements in understanding mental health, discrimination and abuse against people with mental health disorders seems still to be present. Conclusions: There are very limited mental health care services with hardly any budget allocated to them in Lvea Em District and Cambodia overall. There is dire need for scaling up and integrating mental health into primary health care to improve the population's access to and quality service of Cambodian mental care. PMID- 29410704 TI - Association between attempted suicide and academic performance indicators among middle and high school students in Mexico: results from a national survey. AB - Background: Students' mental health is associated to academic performance. In high income countries, higher students' grades are related to lower odds of suicidal behaviors, but studies on other indicators of academic performance are more limited, specially in middle income countries. Methods: Data from 28,519 middle and high school students selected with multistage clustered sampling in the Mexican National Survey of Student's Drug Use. Using a self-administered questionnaire, lifetime suicidal attempt and four indicators of academic performance were assessed: age inconsistency with grade level, not being a student in the last year, perceived academic performance and number of failed courses. Multiple logistic regression models were used to control for sociodemographic and school characteristics. Results: The lifetime prevalence of attempted suicide was 3.0% for middle school students and 4.2% for high school students. Among middle school students, statistically adjusted significant associations of suicide attempt with academic performance indicators were: not being a student the year before, worse self-perceived performance and a higher number of failed courses; among high school students, predictors were failed courses and self-perceived academic performance, with ORs of 1.65 and 1.96 for the categories of good and fair/poor respectively, compared to those who reported very good performance. Conclusion: Self-perceived academic performance was the main indicator for suicide in both school levels. Suicide prevention efforts in Mexico's schools should include asking students about the perception they have about their own academic performance. PMID- 29410705 TI - Body image perceptions and symptoms of disturbed eating behavior among children and adolescents in Germany. AB - Theoretical background: Body image distortions such as perception biases are assumed to be precursors of eating disorders (ED). This study aims to investigate body image perceptions and symptoms of disturbed eating behavior among a sample of 11-17 year-old students in Germany. Methods: A cross-sectional survey study was carried out among 1524 students of twelve secondary schools from all school types in North Rhine-Westphalia (Germany). A naturalistic photograph-rating consisting of photographs of young women's bodies was used to examine children's perceptions of female bodies (i.e., perceived average body size and perceived ideal body size of young women). Also, symptoms of disturbed eating behavior were examined. Results: Compared to statistical data, children and adolescents underestimated the average body size of young women by more than two BMI-points (estimated average BMI = 20), with no differences between boys and girls. Also, girls and boys generally held a slim female thin-ideal (perceived ideal BMI = 19.5), which is nearly three BMI-points below the average body size in the young female population. Girls showed a slightly stronger female thin-ideal than boys. Among all subgroups, early-adolescent girls (13-14 years) displayed the strongest thin-ideal internalization. Nearly one-third of this group perceived a BMI below 18 as ideal female body size. Symptoms of disturbed eating behavior were common among youth and most frequent among adolescent girls (15-17 years). Girls who displayed a bias towards underestimation of female body size and girls who displayed an underweight female thin-ideal were more likely to report harmful dieting behaviors and psychological distress associated with eating, body, and weight. Conclusions: This study found that 11-17 year-old girls and boys do not show accurate judgements regarding the average body size of young women. Instead, there is systematic and significant underestimation, indicating considerable perception biases, which may constitute a risk factor for the development and maintenance of ED. Symptoms of disturbed eating behavior were common, especially among girls, and associated with body-related perceptions. Future research will need to clarify the severity and course of these symptoms. PMID- 29410706 TI - Enhanced isopropanol-butanol-ethanol mixture production through manipulation of intracellular NAD(P)H level in the recombinant Clostridium acetobutylicum XY16. AB - Background: The formation of by-products, mainly acetone in acetone-butanol ethanol (ABE) fermentation, significantly affects the solvent yield and downstream separation process. In this study, we genetically engineered Clostridium acetobutylicum XY16 isolated by our lab to eliminate acetone production and altered ABE to isopropanol-butanol-ethanol (IBE). Meanwhile, process optimization under pH control strategies and supplementation of calcium carbonate were adopted to investigate the interaction between the reducing force of the metabolic networks and IBE production. Results: After successful introduction of secondary alcohol dehydrogenase into C. acetobutylicum XY16, the recombinant XY16 harboring pSADH could completely eliminate acetone production and convert it into isopropanol, indicating great potential for large-scale production of IBE mixtures. Especially, pH could significantly improve final solvent titer through regulation of NADH and NADPH levels in vivo. Under the optimal pH level of 4.8, the total IBE production was significantly increased from 3.88 to 16.09 g/L with final 9.97, 4.98 and 1.14 g/L of butanol, isopropanol, and ethanol. Meanwhile, NADH and NADPH levels were maintained at optimal levels for IBE formation compared to the control one without pH adjustment. Furthermore, calcium carbonate could play dual roles as both buffering agency and activator for NAD kinase (NADK), and supplementation of 10 g/L calcium carbonate could finally improve the IBE production to 17.77 g/L with 10.51, 6.02, and 1.24 g/L of butanol, isopropanol, and ethanol. Conclusion: The complete conversion of acetone into isopropanol in the recombinant C. acetobutylicum XY16 harboring pSADH could alter ABE to IBE. pH control strategies and supplementation of calcium carbonate were effective in obtaining high IBE titer with high isopropanol production. The analysis of redox cofactor perturbation indicates that the availability of NAD(P)H is the main driving force for the improvement of IBE production. PMID- 29410707 TI - A novel proximal 3q29 chromosome microdeletion in a Chinese patient with Chiari malformation type II and Sprengel's deformity. AB - Background: Chiari malformation type II (CM-II) is mainly characterized by elongation and descent of the cerebellum through the foramen magnum into the spinal canal. Moreover, CM-II is uniquely associated with myelomeningocele. Sprengel's deformity refers to the malposition of the scapula, i.e. scapular elevation which is sometimes accompanied with scapula dysplasia. Although few familial cases of CM-II and Sprengel's deformity have been previously reported, both of these defects are considered to be sporadic, thus the exact etiology and causative genes have largely remained unknown. Case presentation: The patient was diagnosed with CM-II accompanied with Sprengel's deformity. Further genetic investigation revealed a novel 666 kb microdeletion located in 3q29 (chr3:194,532,035-195,198,585; Hg19). Subsequently, genes within the affected region were summarized, and XXYLT1 and ACAP2 were identified as the candidate genes. Conclusion: We reported a case of a patient with CM-II and Sprengel's deformity harboring a microdeletion in 3q29. This case highlights the importance of 3q29 in early neural and skeletal development, as well as expands the phenotype spectrum of this rare disorder. PMID- 29410709 TI - Genomic 5-mC contents in peripheral blood leukocytes were independent protective factors for coronary artery disease with a specific profile in different leukocyte subtypes. AB - Background: Alterations in DNA methylation are demonstrated in atherosclerosis pathogenesis. However, changing rules of global DNA methylation and hydroxymethylation in peripheral blood leukocytes (PBLs) and different blood cell subtypes of coronary artery disease (CAD) patients are still inconclusive, and much less is known about mechanisms underlying. Results: We recruited 265 CAD patients and 270 healthy controls with genomic DNA from PBLs, of which 50 patients and 50 controls were randomly chosen with DNA from isolated neutrophils, lymphocytes and monocytes, and RNA from PBLs. Genomic 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) contents were quantified by liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) assay. Genomic 5 mC contents were negatively associated with the serum total cholesterol (TC) level (P = 0.010), age (P = 0.016), and PBL classifications (P = 0.023), explaining 6.8% individual variation in controls. Furthermore, genomic 5-mC contents were inversely associated with an increased risk of CAD (odds ratio (OR) = 0.325, 95% confidence interval (CI) = 0.237~0.445, P = 2.62 * 10- 12), independent of PBL counts and classifications, age, sex, histories of hyperlipidemia, hypertension, and diabetes. Within-individual analysis showed a general 5-mC decrease in PBL subtypes, but significant difference was found in monocytes only (P = 0.001), accompanied by increased 5-hmC (P = 3.212 * 10- 4). In addition, coincident to the reduced DNMT1 expression in patients' PBLs, the expression level of DNMT1 was significantly lower (P = 0.022) in oxidized low density lipoprotein (ox-LDL) stimulated THP-1-derived foam cells compared to THP 1 monocytes, with decreased genomic 5-mdC content (P = 0.038). Conclusions: Global hypomethylation of blood cells defined dominantly by the monocyte DNA hypomethylation is independently associated with the risk of CAD in Chinese Han population. The importance of monocytes in atherosclerosis pathophysiology may demonstrate via an epigenetic pathway, but prospective studies are still needed to test the causality. PMID- 29410708 TI - Dietary fat stimulates development of NAFLD more potently than dietary fructose in Sprague-Dawley rats. AB - Background: In humans and animal models, excessive intake of dietary fat, fructose and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD). However, the individual roles of the dietary components remain unclear. To investigate this further, we compared the effects of a high-fat diet, a high-fructose diet and a combination diet with added cholesterol on the development of NAFLD in rats. Methods: Forty male Sprague Dawley rats were randomized into four groups receiving either a control-diet (Control: 10% fat); a high-fat diet (HFD: 60% fat, 20% carbohydrate), a high fructose diet [HFr: 10% fat, 70% carbohydrate (mainly fructose)] or a high fat/high-fructose/high-cholesterol-diet (NASH: 40% fat, 40% carbohydrate (mainly fructose), 2% cholesterol) for 16 weeks. Results: After 16 weeks, liver histology revealed extensive steatosis and inflammation in both NASH- and HFD-fed rats, while hepatic changes in HFr-rats were much more subtle. These findings were corroborated by significantly elevated hepatic triglyceride content in both NASH- (p < 0.01) and HFD-fed rats (p < 0.0001), elevated hepatic cholesterol levels in NASH-fed rats (p < 0.0001), but no changes in HFr-fed rats, compared to Control. On the contrary, only HFr-fed rats developed dyslipidemia as characterized by higher levels of plasma triglycerides compared to all other groups (p < 0.0001). Hepatic dysfunction and inflammation was confirmed in HFD-fed rats by elevated levels of hepatic MCP-1 (p < 0.0001), TNF-alpha (p < 0.001) and plasma beta hydroxybutyrate (p < 0.0001), and in NASH-fed rats by elevated levels of hepatic MCP-1 (p < 0.01), increased hepatic macrophage infiltration (p < 0.001), and higher plasma levels of alanine aminotransferase (p < 0.0001) aspartate aminotransferase (p < 0.05), haptoglobin (p < 0.001) and TIMP-1 (p < 0.01) compared to Control. Conclusion: These findings show that dietary fat and cholesterol are the primary drivers of NAFLD development and progression in rats, while fructose mostly exerts its effect on the circulating lipid pool. PMID- 29410711 TI - Serum miR-122-5p and miR-206 expression: non-invasive prognostic biomarkers for renal cell carcinoma. AB - Background: MicroRNAs (miRNA) play a relevant role in carcinogenesis, cancer progression, invasion, and metastasis. Thus, they can serve as diagnostic/prognostic biomarkers. The knowledge on circulating miRNAs for clear cell renal cell carcinomas (ccRCC) is limited. Our study was designed to identify novel biomarkers for ccRCC patients. Results: The serum small RNA expression profile was determined in 18 ccRCC and 8 patients with benign renal tumors (BRT) using small RNA sequencing. We detected 29 differentially expressed miRNAs (17 upregulated and 12 downregulated in ccRCC) in the expression profiling cohort. Based on the expression levels, we next validated serum miR-122-5p, miR-193a-5p, and miR-206 levels in an independent cohort (68 ccRCC, 47 BRT, and 28 healthy individuals) using quantitative real-time PCR. Serum expression levels of miR-122 5p and miR-206 were significantly decreased in ccRCC compared to healthy individuals. Both miRNAs were circulating at similar levels in ccRCC and BRT patients. miR-193a-5p expression levels were not different within the study cohort. High serum miR-122-5p and miR-206 levels were associated with adverse clinicopathological parameters: miR-122-5p levels were correlated with metastatic RCC and grade, and miR-206 with pT-stage and metastasis. Furthermore, high miR 122-5p and miR-206 serum levels were associated with a shorter period of progression-free, cancer-specific, and overall survival in patients with ccRCC. Conclusion: We identified serum miR-122-5p and miR-206 as novel non-invasive prognostic biomarkers for patients with ccRCC. PMID- 29410710 TI - Identification of reliable biomarkers of human papillomavirus 16 methylation in cervical lesions based on integration status using high-resolution melting analysis. AB - Background: The dynamic methylation of human papillomavirus (HPV) 16 DNA is thought to be associated with the progression of cervical lesions. Previous studies that did not consider the physical status of HPV 16 may have incorrectly mapped HPV 16 methylomes. In order to identify reliable biomarkers for squamous cervical cancer (SCC), we comprehensively evaluated the methylation of HPV 16 depending on the integration incidence of each sample. Methods: Based on the integration status of 115 HPV 16-infected patients (50 SCC, 30 high-grade squamous intraepithelial lesion [HSIL], and 35 low-grade squamous intraepithelial lesion [LSIL]) and HPV 16-infected Caski cell lines by PCR detection of integrated papillomavirus sequences, we designed a series of primers that would not be influenced by breakpoints for a high-resolution melting (HRM) PCR method to detect the genome methylation. Results: A few regions with recurrent interruptions were identified in E1, E2/E4, L1, and L2 despite scattering of breakpoints throughout all eight genes of HPV 16. Frequent integration sites often occurred concomitantly with methylated CpG sites. The HRM PCR method showed 100% agreement with pyrosequencing when 3% was set as the cutoff value. A panel of CpG sites such as nt5606, nt5609, nt5615, and nt5378 can be combined in reweighing calculations to distinguish SCC from HSIL and LSIL patients which have high sensitivity and specificity (88% and 92.31%, respectively). Conclusions: Our research shows that combination of CpG sites nt5606, nt5609, nt5615, and nt5378 can be used as potential diagnosis biomarkers for SCC, and the HRM PCR method is suitable for clinical methylation analysis. PMID- 29410712 TI - Mechanistic insights into water adsorption and dissociation on amorphous -based catalysts. AB - Despite having defects, amorphous titanium dioxide ([Formula: see text]) have attracted significant scientific attention recently. Pristine, as well as various doped [Formula: see text] catalysts, have been proposed as the potential photocatalysts for hydrogen production. Taking one step further, in this work, the author investigated the molecular and dissociative adsorption of water on the surfaces of pristine and [Formula: see text] doped [Formula: see text] catalysts by using density functional theory with Hubbard energy correction (DFT+U). The adsorption energy calculations indicate that even though there is a relatively higher spatial distance between the adsorbed water molecule and the [Formula: see text] surface, pristine [Formula: see text] surface is capable of anchoring [Formula: see text] molecule more strongly than the doped [Formula: see text] as well as the rutile (1 1 0) surface. Further, it was found that unlike water dissociation on crystalline [Formula: see text] surfaces, water on pristine [Formula: see text] catalyst experience the dissociation barrier. However, this barrier reduces significantly when [Formula: see text] is doped with [Formula: see text], providing an alternative route for the development of an inexpensive and more abundant catalyst for water splitting. PMID- 29410713 TI - Chemical modification of group IV graphene analogs. AB - Mono-elemental two-dimensional (2D) crystals (graphene, silicene, germanene, stanene, and so on), termed 2D-Xenes, have been brought to the forefront of scientific research. The stability and electronic properties of 2D-Xenes are main challenges in developing practical devices. Therefore, in this review, we focus on 2D free-standing group-IV graphene analogs (graphene quantum dots, silicane, and germanane) and the functionalization of these sheets with organic moieties, which could be handled under ambient conditions. We highlight the present results and future opportunities, functions and applications, and novel device concepts. PMID- 29410714 TI - Extracting Cross-Sectional Clinical Images Based on Their Principal Axes of Inertia. AB - Cross-sectional imaging is considered the gold standard in diagnosing a range of diseases. However, despite its widespread use in clinical practice and research, no widely accepted method is available to reliably match cross-sectional planes in several consecutive scans. This deficiency can impede comparison between cross sectional images and ultimately lead to misdiagnosis. Here, we propose and demonstrate a method for finding the same imaging plane in images obtained during separate scanning sessions. Our method is based on the reconstruction of a "virtual organ" from which arbitrary cross-sectional images can be extracted, independent of the axis orientation in the original scan or cut; the key is to establish unique body coordinates of the organ from its principal axes of inertia. To verify our method a series of tests were performed, and the same cross-sectional plane was successfully extracted. This new approach offers clinicians access, after just a single scanning session, to the morphology and structure of a lesion through cross-sectional images reconstructed along arbitrary axes. It also aids comparable detection of morphological and structural changes in the same imaging plane from scans of the same patient taken at different times-thus potentially reducing the misdiagnosis rate when cross sectional images are interpreted. PMID- 29410715 TI - Non-Duality, Simplicity and the Chong Mai. AB - Chinese Medicine (CM) suggests that the root of all disease lies in separation from the Tao, which occurs when Yin and Yang differentiate. Chong Mai-focused acupuncture can theoretically address this level, but an adjusted therapeutic approach could be necessary to produce the best results. In this article, the author explores some context and needling strategies used to work effectively with the Chong Mai in a unique way. PMID- 29410716 TI - Cellular Reorganization Plays a Vital Role in Acupuncture Analgesia. AB - Background: Acupuncture has a long history of relieving many forms of pain. However, many of acupuncture's mechanisms are still unknown and/or misunderstood. Objective: This review looks at past research on many different methods and targets of study related to acupuncture. The main focus is upon the importance of connective-tissue planes in and around acupuncture points. Method: Relevant articles from journals as well as books on the topic were searched manually for information related to the topic. Results: Various studies offered different (and sometimes interrelated) mechanisms for how acupuncture needling results in analgesia among other effects. Emerging evidence, however, has shown the increasing importance of extracellular matrix rearrangements that result in lower mechanical stress states of surrounding tissues. This leads to lower constant stimulation of regional mechanoreceptors, in turn, reducing chronic pain and discomfort. Conclusions: The extracellular matrix has emerged as an important area of study on the effects of acupuncture needling. PMID- 29410717 TI - Single-Point Acupuncture for Treatment of Urge Incontinence in Women: A Pilot Nonrandomized Trial. AB - Objectives: Urinary incontinence (UI) is common in middle- and old-age. Previous studies have shown that multiple-point and multiple-frequency acupuncture are efficacious treatment modalities for UI. This study investigated the efficacy of single-point acupuncture for the treatment of UI in women. Materials and Methods: Twelve female subjects, ages 40-75, participated in the trial. Acupuncture at CV 2 was performed. Before needle insertion, each subject completed the Revised Urinary Incontinence Scale (RUIS). After treatment, subjects were contacted at 2 and 8 weeks to assess treatment effects using the RUIS questionnaire again. Results: Statistically significant improvements were seen with respect to symptoms of urgency, stress incontinence, impact of urine leakage, quantity of urine leakage, and the total score at 2 weeks postintervention. A statistically significant increase in impact of urine leakage was found at the 8-week follow up, compared to the 2-week results. Conclusions: In this pilot trial, single point acupuncture was associated with significant but short-term improvements in UI symptoms. Future trials should include a control group and an increased sample size for a more-rigorous examination of this potential adjunctive treatment for UI. PMID- 29410718 TI - Effects of Noninvasive Skin Stimulation with Microcones on Constipation: A Double Blinded Controlled Study. AB - Objective: The use of noninvasive skin stimulation with microcones for constipation is promising. However, no double-blinded study has assessed the effects of this approach on constipation. The goal of this research was to assess the effects on constipation when using noninvasive skin stimulation with microcones. Materials and Methods: This double-blinded, controlled study included 44 subjects, each with a score of 5 points or higher on the Japanese version of the Constipation Assessment Scale (CAS-J). The subjects were randomly divided into 2 groups: (1) a stimulation group (skin-stimulation device with microcones; n = 23; group S) and (2) a placebo group (identical device without microcones; n = 21; group P). The subjects were required to attach the skin-stimulation devices to both cavum conchae with dedicated bandages every day for 2 months by themselves. Main Outcome Measures: This study assessed the severity of constipation, total mood disturbance (TMD) score, and salivary amylase activity (SAA) in each subject. Measurements were obtained before, during, and after the intervention. Results: With regard to the CAS-J score, significant differences were observed in both groups; however, no significant differences were observed between the groups. With regard to the TMD score, significant differences were observed in group S but not in group P. With regard to SAA, there were no significant differences in both groups; however, significant differences were noted after the intervention between the groups. Conclusions: Noninvasive skin stimulation with microcones could relieve constipation and improve TMD scores and SAA activity. This procedure may be used as a self-care option. PMID- 29410719 TI - Use of Acupuncture in the United States Military Healthcare System. AB - Objectives: The Military Healthcare System (MHS) shows increasing interest in acupuncture as an alternative to opioids for pain control. However, specific factors associated with this procedure in the MHS are not well-described in literature. This study examines usage within the MHS to determine patterns among the diagnoses, provider types, and facilities associated with acupuncture. Materials and Methods: Acupuncture-treated patients were identified from TRICARE claims data in the MHS Data Repository as having at least one acupuncture treatment in fiscal year (FY) 2014. Bivariate analysis was performed to determine demographics, diagnoses, and number of visits, for both active-duty and nonactive duty personnel. Descriptive statistics were used to show associated provider and facility types. Results: A total of 15,761 people received acupuncture in the MHS in FY 2014. Use of acupuncture was greater for Army service, white race, and senior enlisted rank overall, and for males ages 26-35 among active-duty and females ages 46-64 among nonactive-duty beneficiaries. A cumulative 76% of diagnoses were for musculoskeletal or nerve and system issues. Approximately 60% of patients received acupuncture from physicians, 16% from physical therapists or chiropractors, and 9.7% from physician extenders. Specific acupuncture techniques (traditional, auricular, etc.) could not be determined from the data set. Conclusions: The most common diagnoses associated with acupuncture are consistent with pain management. However, full analysis is hampered by inconsistent coding and lack of granularity regarding specific techniques. Given the popularity of acupuncture in the MHS, further research is necessary to explore the full scope of this intervention. PMID- 29410720 TI - Auricular Acupuncture and Skin-Cancer Detection: An Opportunity. AB - Background: Auricular acupuncture is effective for many patients with pain. Many skin malignancies and precancerous lesions are found on the head and neck. Practitioners of acupuncture are in a unique situation to detect cutaneous malignancy at an early state. Case: An 83-year-old man referred for Battlefield Acupuncture was found to have a scalp lesion suspicious for malignancy as well as several precancerous lesions. Results: Referral to a dermatologist led to excision of a basal-cell cancer and treatment of actinic keratoses. Conclusions: Practitioners of auricular acupuncture should be familiar with common skin cancers and precancerous lesions; these practitioners are in a unique situation to detect these common skin lesions. PMID- 29410721 TI - I Ching Balance Acupuncture Treatment of Migraines, Insomnia, and Depression in a Post-Ovariectomy Patient Receiving Hormone Replacement Therapy. AB - Introduction: Surgical menopause is associated with symptoms that can affect a woman's quality of life (QoL) significantly. These symptoms include migraines, insomnia, and depression. Case: A 45-year-old Caucasian female presented at an acupuncture clinic. Fourteen years prior, she had been diagnosed with ovarian carcinoma, underwent ovariectomy, and was prescribed hormone replacement therapy. Deteriorating QoL caused her to seek acupuncture for migraines, insomnia, and depression. The outcomes sought for treatment of this case included intensity, duration, and frequency of migraines, insomnia, and depression, as well as her QoL. The outcome measures were estimated monthly throughout her treatment. Each was rated on a numeric scale of 0-10 (0 = "the lowest possible" and 10 = "the worst imaginable"). At baseline, the patient rated the intensity, duration, and frequency of each complaint as 10. She was treated with 60-minute, I Ching Balance Acupuncture (ICBA) sessions once per week for 7 months. Results: This acupuncture treatment did not cause any adverse events, pain, or discomfort. Her migraines, insomnia, and depression decreased to a great extent. In addition, this patient reported considerable improvement in her QoL. The improvement in her QoL was inversely related to the intensity, duration, and frequency of her complaints throughout her acupuncture treatment. Conclusions: This patient reported a considerable improvement in all the outcome measures. She completed the treatment after experiencing great improvement in her QoL. Additional, larger scale studies are warranted to investigate the effects of ICBA. PMID- 29410722 TI - Topical 5-aminolevulinic photodynamic therapy with red light vs intense pulsed light for the treatment of acne vulgaris: A spilit face, randomized, prospective study. AB - 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) has been an effective method for treating acne vulgaris. Red light is the most widely used light source while Intense pulsed lights (IPL) is reported effective and well-tolerated. The purpose of this study was to evaluate the efficacy and adverse reactions of ALA-PDT with red light on acne compared with ALA-PDT with IPL.12 patients were recruited in the randomized, prospective and split-face study. 5% ALA cream were applied on the whole face with 2 hours' incubation before narrow band LED(633 +/- 10 nm, 36 ~ 108J/cm2) on one side of face and IPL(590~1200 nm, 15~17J/cm2) on the other side. Three treatment sessions were administered with 2-week interval each time and 8 weeks' follow up. The number of the total acne lesions and inflammatory lesions of the side treated by red light-PDT showed a relatively higher reduction rate that that by IPL-PDT (P < 0.05). Significant PpIX fluorescence decrease was observed only for the group of red light (P < 0.05). Lower pain intensity numeric rating scale values and Investigator's Global Severity Assessment (IGA) grading for erythema of the IPL side were observed (P<0.05).The results suggested that both red light and IPL are effective for ALA-PDT on acne vulgaris. ALA-PDT with red light may achieve better efficacy by more effective photobleaching of protoporphyrin IX (PpIX), whereas IPL may accomplish less adverse reactions and better tolerance. PMID- 29410724 TI - Chronic Skin Fragility of Aging: Current Concepts in the Pathogenesis, Recognition, and Management of Dermatoporosis. AB - Thin skin and the appearance of bruises, seemingly unprovoked, are frequent complaints of elderly patients. Chronic cutaneous insufficiencies such as these are termed dermatoporosis. Although it is seldom the primary reason for consultation, dermatoporosis is associated with bleeding and healing complications and presents an opportunity for patient education and prevention. In this review, the authors explore the risk factors, pathogenetic mechanisms, clinical expression, and evidence-based therapies reported for chronic skin fragility due to aging. PMID- 29410725 TI - A Retrospective Review of New-onset Dermatitis in Patients Aged 60 Years or Older. AB - Background: New-onset dermatitis in the elderly can be attributed to a variety of disease processes. We defined new-onset dermatitis in which the etiology is attributed solely to age-related processes as "dermatitis of immune senescence"-a diagnosis of exclusion based on clinical presentation and further diagnostic testing. Objective: Retrospective cohort of elderly patients with new-onset dermatitis to examine the differences in demographics, work-up, and treatments between patients with dermatitis of immune senescence and those patients ultimately given more specific diagnoses. Methods: Four hundred and thirty-three patients aged 60 years and older with new-onset dermatitis from 2011 to 2016 at Ohio State University were identified by chart review and categorized as "dermatitis of immune senescence" or "alternate diagnosis" based on patch testing, biopsy, and physician documentation. Results: In this subset of patients, 10.2 percent (44/433) underwent patch testing and 16.2 percent (70/433) underwent biopsy. Furthermore, 86.4 percent of patients who underwent patch testing (38/44) and 57.1 percent who underwent biopsy (40/70) were given a more specific diagnosis following their test. Use of intramuscular steroids (p<.001), oral steroids (p=.004), and antihistamines (p=.002) were significantly higher in the alternate diagnosis group. Conclusion: The low rate of patch testing and biopsy and the high rate of diagnosis change post-procedure demonstrate an underutilization of diagnostic testing in this population. PMID- 29410723 TI - Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2017 MauiDerm Meeting. PMID- 29410726 TI - Adult Acne Versus Adolescent Acne: A Retrospective Study of 1,167 Patients. AB - Background: Acne is predominantly known as a skin disorder of the adolescent population. However, current research indicates that the prevalence of adult patients with acne, especially among women, is increasing. Objective: The objective of this study was to evaluate differences between adults and teenagers with regard to acne prevalence, patient sex, acne severity, and quality of life. In adult patients, we considered differences in family history of acne, onset, and smoking habits. Design: We performed a retrospective study of a total of 1,167 patients with acne who attended our outpatient clinic from January 2008 to March 2015. Participants: The study population was divided into two groups: adolescent acne and adult acne. Among the adult subjects, 385 were female and 69 were male; among the adolescent subjects, 378 were female and 335 were male. Measurements: The severity of acne was recorded using the Global Acne Grading System. The impact of acne on quality of life was investigated using the Assessment of Quality of Life questionnaire. Results: Study results show that acne in female patients was more prevalent than in male patients. The evaluation of acne severity showed that "mild acne" is the most frequent form. With regard to smoking habits, time of onset, and family history of acne, we did not find any statistically significant differences between the sexes. Conclusion: In both sexes, there are some differences in adult acne versus the adolescent form. Treating adult acne demands a different approach to diagnosis and a tailored management plan that considers all of the variables involved. PMID- 29410728 TI - Granuloma Annulare and Radial Pulse Therapy: Preliminary Findings. AB - In this case report, the authors describe a first-time trial of a variation of extracorporeal shockwave therapy in a patient with disseminated granuloma annulare. Radial pulse therapy was administered in an outpatient clinic of a university hospital to a 72-year-old woman with a 14-year history of disseminated granuloma annulare. The authors describe changes in clinical appearance and results of histological evaluation, reporting observable positive changes in all four treated plaques. The authors conclude that radial pulse therapy was well tolerated and seemed to influence the course of disseminated granuloma annulare plaques positively. PMID- 29410727 TI - Scalp Seborrheic Dermatitis and Dandruff Therapy Using a Herbal and Zinc Pyrithione-based Therapy of Shampoo and Scalp Lotion. AB - Objective: The aim of this study was to evaluate the safety and efficacy of an herbal and zinc pyrithione shampoo and a scalp lotion (Kamedis Derma-Scalp Dandruff Therapy, Kamedis Ltd., Tel Aviv, Israel) for the treatment of scalp seborrheic dermatitis and dandruff. Design: This was an interventional, open label, safety and efficacy study. Setting: This open-label study was conducted at Consumer Product Testing Company Inc. in Fairfield, New Jersey. At the baseline visit (Day 0), an examination of the scalp was conducted by a board-certified dermatologist. The entire scalp was evaluated for evidence of seborrheic dermatitis using the Adherent Scalp Flaking Score with a 10-point scale. Only subjects with evidence of moderate-to-greater seborrheic dermatitis or moderate to-greater dandruff were deemed qualified for inclusion in the study. Participants: Fifty subjects were recruited and included in the study. Measurements: Study subjects were evaluated by the same dermatologist for erythema and flaking at Days 0, 14, 28, and 42 using a five-point scale for each parameter. At each time point, a total severity score was calculated based on the findings of the evaluations. Following the scalp evaluation, each subject had a standardized digital photograph taken of his or her scalp. Each subject was also asked to answer a satisfaction questionnaire regarding the product treatment enhancement and characteristics. Results: A reduction in both parameters evaluated was seen at all time points. Statistical significance was achieved at each time point when compared with the baseline visit. In addition, the subjects expressed a high degree of satisfaction with the treatment. No adverse events were reported during this study. Conclusion: The study showed that the herbal zinc pyrithione shampoo and scalp lotion provided improvement in the main symptoms of seborrheic dermatitis. PMID- 29410729 TI - Patient Knowledge of Sunscreen Guidelines and Frequency of Physician Counseling: A Cross-sectional Study. AB - : Background: Skin cancer and photodamage are problems commonly addressed by dermatologists. Despite the opportunities for chemoprevention with broad-spectrum sunscreen, there is little research investigating patient knowledge of proper sunscreen guidelines, or patient perception of physician counseling. Objective: The author sought to determine patient knowledge of the American Academy of Dermatology guidelines for proper sunscreen use and to obtain patient-reported rates of physician counseling regarding sunscreen. Design: We used a 12-question, multiple choice, anonymous survey to collect data. Setting: The study setting was a private dermatology clinic near Detroit, Michigan. PARTICIPANTS: Two hundred ninety- four adult patients presenting for routine office visits were included in the study. Results: About 59 percent of the subjects selected the recommended frequency of proper sunscreen use and 60 percent selected the recommended minimum sun protection factor. The minimum amount of sunscreen to cover the body, time of application before sun exposure, and time between reapplications of sunscreen did not receive a majority response. Differences in knowledge were seen between the sexes and skin types. Forty-four percent of patients previously received sunscreen counseling. Patients older than 40 years of age (39.3% vs. 18.4%, p=0.04), those who were fair skinned (62.5% vs. 23.8%), established patients (40.7% vs. 8.3%, p <0.0001), and those with a skin cancer (58.3% vs. 28%, p<0.0001) were more likely to report previous counseling. Conclusions: The majority of the study subjects never received counseling and lacked adequate knowledge of sunscreen guidelines. In order to obtain adequate primary prevention of skin cancer, it is essential to provide patients with further counseling and education on proper sunscreen use. PMID- 29410730 TI - NRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib. AB - NF-E2-related factor 2 (NRF2) regulates the transcription of a battery of metabolic and cytoprotective genes. NRF2 and epidermal growth factor receptors (EGFRs/HERs) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents. Nevertheless, there is limited understanding of the regulation of HER expression and activation and the link between NRF2 and HER signalling pathways. We show that NRF2 regulates both basal and inducible expression of HER1, as treatment of ovarian cancer cells (PEO1, OVCAR3, and SKOV3) with NRF2 activator tBHQ inducing HER1, while inhibition of NRF2 by siRNA knockdown or with retinoid represses HER1. Furthermore, treatment of cells with tBHQ increased total and phosphorylated NRF2, HER1, and AKT levels and compromised the cytotoxic effect of lapatinib or erlotinib. Treatment with siRNA or retinoid antagonised the effect of tBHQ on NRF2 and HER1 levels and enhanced the sensitivity of ovarian cancer cells to lapatinib or erlotinib. Pharmacological or genetic inhibition of NRF2 and/or treatment with lapatinib or erlotinib elevated cellular ROS and depleted glutathione. This extends the understanding of NRF2 and its regulation of HER family receptors and opens a strategic target for improving cancer therapy. PMID- 29410731 TI - Chrysin Administration Protects against Oxidative Damage in Varicocele-Induced Adult Rats. AB - Oxidative stress is known as the leading factor responsible for varicocele related infertility and for that reason, many antioxidant therapies have been proposed. Considering that, we evaluated the reproductive outcomes and fertility of varicocelized rats and the impact of chrysin within these parameters. The animals were allocated into three groups: sham (control), varicocele treated via gavage with 50 mg/kg/day of chrysin (V1), or vehicle (V2) for 56 days. Chrysin treatment prevented oxidative damage resulting from varicocele by decreasing testicular concentrations of malondialdehyde and sperm DNA fragmentation. It also improved histological aspect of the testis and maintained morphometric parameters similar to the sham group. Furthermore, there were no differences in body and reproductive organ weights, histopathological analysis of epididymis, sperm counts and morphology, testosterone levels, sexual behavior, and fertility parameters among experimental groups. Our results reinforce the idea that injuries provoked by experimental varicocele are related, at least in part, to oxidative stress. Moreover, varicocele showed bilateral deleterious effects without interfering with fertility. Chrysin administration significantly ameliorated sperm parameters, protecting the reproductive system against varicocele damages. For that reason, chrysin might be an alternative adjuvant therapy to improve sperm quality in men presenting this condition. PMID- 29410734 TI - Change of the State of the Natural Antioxidant Barrier of a Body and Psychological Parameters in Patients Aged above 60. AB - Background: The goal of this study is to assess the natural antioxidant barrier of the organism and selected psychological aspects of the aging process in patients above 60 years old. Methods: The study included a total of 52 patients aged above 60 (mean age 67 +/- 3.4) and 32 healthy subjects (mean age 22 +/- 3.4) as a control group. All patients underwent psychological assessment using Test of Attentional Performance version 2.3 (TAP 2.3, four subtests: alertness, cross modal integration, neglect with central task, and working memory) and biochemical analysis of venous blood concerning values of the selected parameters of oxidative stress (HT, GSH, GPXOS, GPXRBC, GRRBC1, SODRBC1, MDARBC1, NO2-/NO3-, and CP). Results: Disorders of attention were observed mainly in elderly people, but an assumption that elderly people have developed more efficient ways of working memory use than younger people may be true. Results showed the reduced effectiveness of the body's natural antioxidant barrier in elderly people. Moderate positive and negative correlations among parameters of oxidative stress and psychological parameters were observed in the control group. Discussion: Intensification of the attention deficits and oxidative stress may be observed as one of the pathogenic factors of age-dependent diseases. PMID- 29410733 TI - Antidepressant Flavonoids and Their Relationship with Oxidative Stress. AB - Depression is a serious disorder that affects hundreds of millions of people around the world and causes poor quality of life, problem behaviors, and limitations in activities of daily living. Therefore, the search for new therapeutic options is of high interest and growth. Research on the relationship between depression and oxidative stress has shown important biochemical aspects in the development of this disease. Flavonoids are a class of natural products that exhibit several pharmacological properties, including antidepressant-like activity, and affects various physiological and biochemical functions in the body. Studies show the clinical potential of antioxidant flavonoids in treating depressive disorders and strongly suggest that these natural products are interesting prototype compounds in the study of new antidepressant drugs. So, this review will summarize the chemical and pharmacological perspectives related to the discovery of flavonoids with antidepressant activity. The mechanisms of action of these compounds are also discussed, including their actions on oxidative stress relating to depression. PMID- 29410732 TI - Ischemic Retinopathies: Oxidative Stress and Inflammation. AB - Ischemic retinopathies (IRs), such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and (in many cases) age-related macular degeneration (AMD), are ocular disorders characterized by an initial phase of microvascular changes that results in ischemia, followed by a second phase of abnormal neovascularization that may culminate into retinal detachment and blindness. IRs are complex retinal conditions in which several factors play a key role during the development of the different pathological stages of the disease. Increasing evidence reveals that oxidative stress and inflammatory processes are important contributors to the pathogenesis of IRs. Despite the beneficial effects of the photocoagulation and anti-VEGF therapy during neovascularization phase, the need to identify novel targets to prevent initial phases of these ocular pathologies is still needed. In this review, we provide an update on the involvement of oxidative stress and inflammation in the progression of IRs and address some therapeutic interventions by using antioxidants and anti-inflammatory agents. PMID- 29410736 TI - Cytotoxicity Study of Cyclopentapeptide Analogues of Marine Natural Product Galaxamide towards Human Breast Cancer Cells. AB - Herein, we report the cytotoxicity of cyclopentapeptide analogues of marine natural product galaxamide towards breast carcinoma cells and the underlying mechanisms. We examined the effect of the novel galaxamide analogues on cancer cell proliferation by MTT assay and also further examined the most active compound for morphological changes using Hoechst33342 staining technique, induction of apoptosis, cell cycle phases, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) generation using flow cytometry in human breast cancer MCF-7 cells in vitro. Galaxamide and its analogues effectively induced toxicity in human hepatocellular carcinoma HepG2, human breast carcinoma MCF-7, human epitheloid cervix carcinoma HeLa, and human breast carcinoma MB-MDA 231 cell lines. Amongst them, compound 3 exhibited excellent toxicity towards MCF 7 cells. This galaxamide analogue significantly induced apoptosis in a dose dependent manner in MCF-7 cells involves cell cycle arrest in the G1 phase, a reduction of MMP, and a marked increase in generation of ROS. Particularly, compound 3 of galaxamide analogues might be a potential candidate for the treatment of breast cancer. PMID- 29410735 TI - The Crosstalk between ROS and Autophagy in the Field of Transplantation Medicine. AB - Many factors during the transplantation process influence posttransplant graft function and survival, including donor type and age, graft preservation methods (cold storage, machine perfusion), and ischemia-reperfusion injury. Successively, they will lead to cellular and molecular alterations that determine cell and ultimately organ fate. Oxidative stress and autophagy are implicated in posttransplant outcome since they are both affected by the stress responses triggered in each step (donor, preservation, and recipient) of the transplantation process. Furthermore, oxidative stress influences autophagy and vice versa. Interestingly, both processes have positive as well as negative effects on graft outcome, suggesting they are tightly linked during the transplantation process. In this review, we discuss the importance, regulation and crosstalk of oxidative signals, and autophagy in the field of transplantation medicine. PMID- 29410738 TI - Effect of a medicinal plant (Passiflora incarnata L) on sleep. AB - INTRODUCTION: Extracts of the plant Passiflora incarnata L. (Passifloraceae) were administered intraperitoneally in order to test its effects on sleep. METHOD: Experiments were carried out on chronically implanted male adult wistar rats to obtain cerebral (EEG), ocular (EOG) and muscular (EMG) activities throughout their states of vigilance. Polygraphic recordings were taken during 9 continuous hours before and after the extract administration (500 mg/kg). RESULTS: Passiflora incarnata induced a significant increment in the total sleep time (p<0.05). This increment was due to an increase in the time spent by animals in slow wave sleep (SWS). Concomitantly, a significant decrement in wakefulness (W) was observed (p<0.05). In contrast, time spent in rapid eye movement (REM) sleep showed a decreasing tendency, since both its frequency and mean duration were reduced. CONCLUSIONS: The extracts obtained from Passiflora incarnata can be considered as appropriated sleep inducers. PMID- 29410737 TI - Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2 expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 MUg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2 as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future. PMID- 29410739 TI - Retrospectively reported month-to-month variation in sleeping problems of people naturally exposed to high-amplitude annual variation in daylength and/or temperature. AB - Compared to literature on seasonal variation in mood and well-being, reports on seasonality of trouble sleeping are scarce and contradictive. To extend geography of such reports on example of people naturally exposed to high-amplitude annual variation in daylength and/or temperature. Participants were the residents of Turkmenia, West Siberia, South and North Yakutia, Chukotka, and Alaska. Health and sleep-wake adaptabilities, month-to-month variation in sleeping problems, well-being and behaviors were self-assessed. More than a half of 2398 respondents acknowledged seasonality of sleeping problems. Four of the assessed sleeping problems demonstrated three different patterns of seasonal variation. Rate of the problems significantly increased in winter months with long nights and cold days (daytime sleepiness and difficulties falling and staying asleep) as well as in summer months with either long days (premature awakening and difficulties falling and staying asleep) or hot nights and days (all 4 sleeping problems). Individual differences between respondents in pattern and level of seasonality of sleeping problems were significantly associated with differences in several other domains of individual variation, such as gender, age, ethnicity, physical health, morning evening preference, sleep quality, and adaptability of the sleep-wake cycle. These results have practical relevance to understanding of the roles playing by natural environmental factors in seasonality of sleeping problems as well as to research on prevalence of sleep disorders and methods of their prevention and treatment in regions with large seasonal differences in temperature and daylength. PMID- 29410740 TI - Crude and Adjusted Prevalence of Sleep Complaints in Mexico City. AB - OBJECTIVE: To estimate the crude prevalence rates of several sleep complaints and the prevalence for each one adjusted for the coexistence of symptoms in other sleep domains in a representative sample of adult individuals from Mexico City. METHODS: A probabilistic sample of 1933 adult individuals living in Mexico City was surveyed using fourteen questions of the Sleep Disorders Questionnaire to assess sleep-related symptoms and sleep complaints. Estimates of crude prevalence rates for each sleep disturbance and adjusted for a score >= the 80th. percentile in the questionnaire were calculated. RESULTS: The following prevalence rates were found: insomnia 39.7%; excessive diurnal sleepiness (EDS) 20.9%; obstructive sleep apnea syndrome (EDS plus snoring) 7.7%; habitual snoring 9.9%; restless legs syndrome (RLS) 4.4%; narcolepsy 0.9%; sleep paralysis (SP) 13.2%; and hypnotic use 1.2%. When prevalence rates were calculated accounting for symptoms in other sleep domains, notable reductions were observed in complaints of insomnia (17.3%), EDS (10.3%), and SP (8.7%), while minor decreases were observed for complaints of snoring (7.4%), OSAS (5%), and RLS (3.8%); narcolepsy prevalence practically did not change (0.9%). CONCLUSIONS: Sleep complaints are highly prevalent in Mexican adult population. More than a half of the individuals with a given sleep disturbance have a global sleep deterioration associated to psychosocial and health impairments. PMID- 29410741 TI - Validation of midsagittal jaw movements to measure sleep in healthy adults by comparison with actigraphy and polysomnography. AB - OBJECTIVE: In a device based on midsagittal jaw movements analysis, we assessed a sleep-wake automatic detector as an objective method to measure sleep in healthy adults by comparison with wrist actigraphy against polysomnography (PSG). METHODS: Simultaneous and synchronized in-lab PSG, wrist actigraphy and jaw movements were carried out in 38 healthy participants. Epoch by epoch analysis was realized to assess the ability to sleep-wake distinction. Sleep parameters as measured by the three devices were compared. This included three regularly reported parameters: total sleep time, sleep onset latency, and wake after sleep onset. Also, two supplementary parameters, wake during sleep period and latency time, were added to measure quiet wakefulness state. RESULTS: The jaw movements showed sensitivity level equal to actigraphy 96% and higher specificity level (64% and 48% respectively). The level of agreement between the two devices was high (87%). The analysis of their disagreement by discrepant resolution analysis used PSG as resolver revealed that jaw movements was right (58.9%) more often than actigraphy (41%). In sleep parameters comparison, the coefficient correlation of jaw movements was higher than actigraphy in all parameters. Moreover, its ability to distinct sleep-wake state allowed for a more effective estimation of the parameters that measured the quiet wakefulness state. CONCLUSIONS: Midsagittal jaw movements analysis is a reliable method to measure sleep. In healthy adults, this device proved to be superior to actigraphy in terms of estimation of all sleep parameters and distinction of sleep-wake status. PMID- 29410742 TI - Lip muscle training improves obstructive sleep apnea and objective sleep: a case report. AB - The present study assessed the potential of lip muscle training for improving sleep. A patient with heavy snoring, daytime sleepiness and dry mouth underwent lip muscle training. Lip closure force LCFmax increased by 67.3% and LCFmin by 152% post-training. AHI decreased from 12.2 to 3.9 events/h by reducing hypopneic episodes. TST, sleep stage N3 and REM sleep increased, and WASO, sleep stage N1, and AI decreased. The patient switched from mouth to nose breathing during sleep and stopped snoring. Improved LCF, by moving the tongue into the anterior superior oral cavity, may increase upper airway space and reduce the hypopnea index. PMID- 29410743 TI - What wrist should you wear your actigraphy device on? Analysis of dominant vs. non-dominant wrist actigraphy for measuring sleep in healthy adults. AB - OBJECTIVE: Differences in sleep results due to the placement of actigraphy devices (non-dominant vs. dominant wrist) are yet to be determined. METHODS: 65 nights of data from 13 adult participants was collected while participants wore two actigraphy devices, one on each wrist. Sleep indices including total sleep time (TST), total time in bed (TTB), sleep efficiency (SE%), sleep latency (SL), wake after sleep onset (WASO), sleep onset time (SOT) and wake time (WT) were assessed between the two devices. RESULTS: There were no significant differences between devices for any of the measured sleep variables (p>0.05). SE%, SL and WASO resulted in high correlations between devices (0.89, 0.89 and 0.76, respectively), with all other sleep variables resulting in very high correlations (>0.90) between devices. CONCLUSIONS: Based on our results, it does not seem critical which wrist the actigraphy device is worn on for measuring key sleep variables. PMID- 29410744 TI - Sleep Architecture in Night Shift Workers Police Officers with Obstructive Sleep Apnea-hypopnea Syndrome. AB - Introduction: Reduced sleep to increase work hours is common among police officers, when this situation is combined with Obstructive sleep apnea/hypopnea syndrome (OSAHS), health consequences are greater, therefore we believe there is a need of research for these alterations. The aim of this study was to measure the changes in sleep architecture (SA) in police officers who currently have Night shift work (NSW) and OSAHS. Methods: We compared SA in 107 subjects divided in three groups: the first group included police officers with NSW and severe OSAHS (n = 48); the second group were non-police officers with diurnal work time and severe OSAHS (n = 48) and the third group was formed by healthy controls (n = 11). Polysomnography (PSG) variables and Epworth sleepiness scale (ESS) scores were compared. Results: SA was more disrupted in the group of police officers with NSW and OSAHS than in patients with OSAHS only and in the control group. Police officers with NSW and OSAHS presented an increased number of electroencephalographic activations, apnea/hypopnea index, and sleep latency, and showed lower scores of oxygen saturation, and in the ESS. Multivariate analysis revealed significant influence of age and Body mass index (BMI). Conclusions: Data suggested with caution an additive detrimental effect of NSW and OSAHS in SA and ESS of police officers. However age and BMI must be also taken into account in future studies. PMID- 29410745 TI - Prevalence and Predictors of Arrhythmia in Patients with Obstructive Sleep Apnea. AB - Objectives: To assess the prevalence and types of arrhythmias in Saudi OSA patients and to identify predictors of arrhythmia in this group of patients. Methods: This case-control study included all patients who underwent level I attended overnight polysomnography between 2009 and 2012. Electrocardiographic data collected during sleep studies of patients with and without OSA were manually reviewed. Results: The study comprised 498 patients (394 OSA patients and 104 non-OSA patients (controls). The prevalence of arrhythmia in OSA patients was higher than that in the controls (26.9% vs. 11.5%; p=0.001). Comparing OSA patients and controls showed: premature atrial contraction (10.2%vs.2.9%;p=0.019), premature ventricular contraction (PVC) (19.3%vs.9.6%;p=0.02), non-isolated PVC (bi/tri/qua) 10.8%vs.2.3%;p=0.04) and atrial fibrillation (1.6%vs.0%;p=0.001). Multiple logistic regression analysis revealed that, patients with OSA had twice the odds of having any cardiac arrhythmia (OR 1.91; CI 95% 1.27-3.11; p <0.05). Conclusions: Patients with OSA had a higher prevalence of arrhythmia compared to controls, and OSA is a predictor of arrhythmia during sleep. PMID- 29410746 TI - Subjective sleep quality, unstimulated sexual arousal, and sexual frequency. AB - Introduction: REM sleep deprivation increases unstimulated erections in rats, and total sleep deprivation increases erections during audiovisual sexual stimulation in men, but the effects of sleep problems on human unstimulated sexual arousal are unknown. Objective: We examined the associations of subjective sleep quality with unstimulated sexual arousal, satisfaction with sex life, and sexual frequency and desire over the past month. Methods: 275 Portuguese (169 women) reported their anxiety, sexual arousal and sexual desire during a resting state, and completed the Pittsburgh Sleep Quality Index, the sexual satisfaction subscale of the LiSat scale, the Desire dimensions of the Female Sexual Function Index (women only) and International Index of Erectile Function (men only). They additionally reported how many days in the past month they engaged in penile vaginal intercourse, noncoital sex, and masturbation. Salivary testosterone (T) was assayed by luminescence immunoassays. Results: Poorer sleep quality correlated with greater unstimulated sexual arousal in men with higher T levels and in women with higher T levels not taking oral contraceptives. In women with lower T, poorer subjective sleep quality correlated with greater sexual dissatisfaction. In both sexes, sleep quality was uncorrelated with sexual desire and sexual frequency over the past month. Discussion: Consistently with other studies in humans and animals, the findings are congruent with the notion that lack of sleep can increase sexual arousal, but not sexual frequency. T might play a role in the sexual arousal caused by lack of appropriate sleep. PMID- 29410747 TI - Sleep quality in children: questionnaires available in Brazil. AB - Introduction: The purpose of this paper was to evaluate and compare the questionnaires regarding sleep quality among children aged up to 12 years old, used in the Portuguese language in Brazil. Material and methods: A search at the literature databases of Lilacs, Scielo and Pubmed was performed using keywords "sleep quality" and "children". Selected Articles were analysed for age of the studied population, the number of questions and the issues addressed thereby, who realized the application, the analysis of the results, and content. Results: Out of 9377 titles, 11 studies were included, performing 7 different questionnaires: Questionnaire to measure quality of life among children with enlarged palatine and pharyngeal tonsils (translation of OSD-6) (1); Inventory of Sleep Habits for Preschool Children (2); the Questionnaire on Obstructive Sleep Apnoea-18 (OSA-18) (3), Sleep Questionnaire by Reimao and Lefevre - QRL (4); the Questionnaire on Sleep Behaviour Patterns (5) and the translation of the Sleep Disturbance Scale for Children (6); Brief Infant Sleep Questionnaire - BISQ (7) . Six of the questionnaires have covered the following issues: snoring and daytime sleepiness. Conclusions: A total of 7 protocols were found to be available in Brazil, the most commonly mentioned being OSA-18 and OSD-6. The use of protocols as a guided interview helps to define diagnosis and treatment among the paediatric population, but its large variability makes it difficult to compare a standardised monitoring process. PMID- 29410748 TI - Polysomnographic Aspects of Sleep Architecture on Self-limited Epilepsy with Centrotemporal Spikes: A Systematic Review and Meta-analysis. AB - Self-limited epilepsy with centrotemporal spikes is the most common paediatric epileptic syndrome, with growing evidence linking it to various degrees and presentations of neuropsychological dysfunction. The objective of this study is to evaluate the possible sleep macro and microstructural alterations in children with this diagnosis. A systematic review of published manuscripts was carried out in Medline, LILACS and Scielo databases, using the MeSH terms epilepsy, sleep and polysomnography. From 753 retrieved references, 5 were selected, and data from macro and, when available, microstructure of sleep were extracted. Meta-analysis was performed with data from 4 studies using standardized mean difference. Findings were heterogeneous between studies, being the most frequent macrostructural findings a smaller proportion and greater latency of REM sleep in two studies and, in meta-analysis, a longer sleep latency was the most significant finding among epileptic patients. Only one study evaluated sleep microstructure, suggesting possible alterations in cyclic alternating pattern in diagnosed children. Studies evaluating macro and microstructure of sleep in children with self-limited epilepsy with centrotemporal spikes are necessary to a better understanding of mechanisms of the neuropsychologic disturbances that are frequently seen in children with this diagnosis. PMID- 29410749 TI - Surgical treatment of a Pattern I Obstructive Sleep Apnea Syndrome individual - clinical case report. AB - Obstructive Sleep Apnea Syndrome (OSA) is a multifactorial disease that highly alters a persons quality of life. It is characterized by the repeated interruption of breathing during sleep, due to an obstruction or the collapse of the upper airways. Since it is a multifactorial etiological disorder, it requires a thorough diagnosis and treatment with an interdisciplinary team, which comprises several professionals such as a surgical dentist, phonoaudiologist, otorhinolaryngologist, sleep doctor, neurologist and physiotherapist. The diagnosis and the degree of severity of the syndrome is determined through a polysomnography examination. After that, the best form of treatment is devised depending on the gravity of the case. In cases of moderate to severe apnea, invasive treatment through surgical procedures such as maxillomandibular advancement remains the preferred option as it increases the posterior air space, reducing and/or eliminating the obstruction. Thus, improving the patients respiratory function and, consequently, his quality of life as it is shown in the clinical case at hand. In which the male patient, facial pattern type I, 41 years of age, diagnosed with moderate OSA (Apnea-Hypopnea Index - AHI of 23.19), decided to have a surgical treatment instead of a conservative one, resulting in the cure of apnea (AHI of 0.3). PMID- 29410751 TI - Michel Jouvet and his Importance for Brazilian Preclinical Sleep Research. PMID- 29410750 TI - Women's Sleep Disorders: Integrative Care. AB - The integrative care model is rooted in a biopsychosocial approach. Integrative is a term which refers to increasing the harmony and coherence of your whole being, and integrative care is therefore focused on the person, not on either the disease or a therapy. It is provided collaboratively by a health team comprising physicians, psychologists, physiotherapists, acupuncturists, and meditation, nutrition, and floral therapy. Previous studies have demonstrated that interventions based on the integrative care model improved womens lifestyle and quality of life. Our aim was to describe the use of complementary and alternative medicine (CAM) alongside traditional medicine among women with sleep conditions in our Womens Sleep Disorders Integrative Treatment Outpatient Clinic. We are sharing our experiences and clinical practice as the model we developed seems to have both physical and psychological benefits for women with sleep problems. We discuss the wide range of benefits that result from this type of complex intervention, and the contextual factors that may influence these benefits. This will inform future practitioners and we hope to contribute to quantitative research in the clinical setting. The study highlights the importance of treating sleep complaints with a caring relationship and a CAM approach, alongside conventional medicine. Exploration of the lived experience of CAM and its meaning enables healthcare professionals to gain insights into the patients needs, preferences, and values. Gynecologists, clinicians, and health care providers should support and guide patients in their decision to use CAM by providing evidence-based and comprehensive advice on the potential benefits, risks and related safety issues of this approach. PMID- 29410752 TI - Immediate prosthesis over implants retained using abutments with flexible screws: A preliminary study. AB - Background: Immediate loading protocols for the rehabilitation of edentulous or partially edentulous patients have become very popular, due to the conveniences they afford in comparison with conventional loading techniques. Material and Methods: A preliminary study was carried out with 8 patients subjected to dental implant treatment with an immediate loading protocol involving a novel system of abutments with flexible screws. Implant survival was analyzed, together with marginal bone loss and patient and dentist satisfaction. Results: A total of 35 implants were subjected to immediate loading using the abutments with flexible screws. The mean patient and dentist satisfaction score was 9.1 and 8.5, respectively. After 12 months the dental implant survival rate was 95.8%, with a mean marginal bone loss of 0.51 +/- 0.12 mm. Conclusions: The novel system of abutments with flexible screws offers a good alternative to conventional immediate loading, since it allows rapid and simple manufacture of a reliable passive fit, fixed interim prosthesis after surgery. Key words:Dental implants, Flexafit(r), Immediate loading, Immediate prosthesis. PMID- 29410753 TI - The effects of fractional CO2 laser, Nano-hydroxyapatite and MI paste on mechanical properties of bovine enamel after bleaching. AB - Background: This study investigated the effect of post bleaching treatments to the change of enamel elastic modulus and microhardness after dental bleaching in- vitro. Material and Methods: Fifty bovine incisor slab were randomly assigned into five groups (n=10). The samples were bleached for three times; 20 minutes each time, by 40% hydrogen peroxide. Next it was applied fractional CO2 laser for two minutes, Nano- hydroxy apatite (N-HA) and MI-paste for 7 days and 2 minutes per day. The sound enamel and bleached teeth without post treatment remained as control groups. The elastic modulus and microhardness were measured at three times; 24 hours, 1 and 2 months. Data were statistically analyzed by two-way analysis of variance with 95% confidence level. Results: Different methods of enamel treatment caused a significant increase in elastic modulus compared to bleached group (P<0.05). Modulus was significantly increased in 1 and 2 months (P<0/001: bleach, P= 0/015: laser, P= 0/008: NHA, P=0/010: MI paste) but there were no significantly difference between 1 and 2 months (P>0.05). There was any significance difference for hardness among treated and control groups, but hardness increased significantly by increasing storage time (P<0.05). Conclusions: The use of the protective tested agents can be useful in clinical practice to reduce negative changes of enamel surface after whitening procedures. Key words:Bleaching enamel, CO2 laser, MI pastes, Nano-hydroxy apatite, Microhardness, Elastic modulus. PMID- 29410754 TI - The Discoloration effect of White Mineral Trioxide Aggregate (WMTA), Calcium Enriched Mixture (CEM), and Portland Cement (PC) on Human Teeth. AB - Background: The aim of this study was to evaluate the discoloration induced by CEM cement, Portland cement (PC) and MTA mixed with propylene glycol (MTA-PG) in comparison to White MTA. Material and Methods: Ninety extracted premolar and canine teeth were resected 2 mm below the CEJ. The coronal part of crown was prepared with peeso reamer and Gates-Glidden drills, and the specimens were randomly divided into 4 experimental (n=20) and one control (n=10) groups. The tooth crowns in experimental groups 1 to 4 were filled with White MTA, PC, CEM cement and MTA-PG, respectively; and in group 5, the teeth were kept empty. After incubation, digital photographs of teeth were acquired at 4 time points (before, immediately after placing the materials, 3 and 6 months afterwards). Images were transferred to Adobe Photoshop CS4 and CIE L*a*b color space was used for tooth shade assessment. One-Way ANOVA and One-Sample t-test were used to compare discoloration of teeth between groups. Results: Significant statistical discoloration was only observed in the cervical one third of all groups at each time points (except between 3 and 6 months). Tooth discoloration was greatest in PC and lower in MTA and MTA-PG at the end of 6 months. The tooth discoloration between immediately and 3 months after placing the materials had significant difference only between MTA and PC; and also the tooth discoloration between immediately and 6 months after placing the materials was observed only between PC and MTA, and PC and MTA-PG. Conclusions: All of the experimental biomaterials caused tooth discoloration after 6 months, of those, PC had the most and MTA and MTA-PG had the least discoloration effect. Key words:Mineral trioxide aggregate (MTA). Calcium enriched mixture (CEM). Propylene glycol. Portland cement. PMID- 29410755 TI - Influence of the teaching program on the learning in knowledge and practice of osteonecrosis of the jaws produced by antireasorptives in dental students of the Principality of Asturias (Spain). AB - Background: This study aims to evaluate the influence of changes in the teaching contents on medication-related osteonecrosis of the jaw may have on the knowledge and the capacity for practical case resolution about this pathology. Material and Methods: A cross-sectional descriptive study was conducted through a survey divided into four sections: degree of means of knowledge acquisition, habitual practice and ability to solve clinical cases. The total number of respondents (n = 225) was divided into two groups: Group A (Year 2015-2016) and Group B (Year 2016-2017). The students in Group B received more teaching content on the subject than group A. Results: A total of 175 survey responses were collected. The internet was the preferred tool for continuing education in both groups. The best known bisphosphonates (BPs) were Alendronate (Fosamax(r): 56.9% Group A, 67.5% Group B) and Zoledronic Acid (Zometa(r): 56.9% Group A, 51.8% Group B). A low percentage of students (37.9% Group A, 43.4% Group B) acknowledged the existence of other drugs that could also cause osteonecrosis of the jaws. Regarding the correct resolution of practical cases, the respondents of Group B reached a significantly higher score (5.67) than the score observed in Group A (4.04). Conclusions: Training on medication-related osteonecrosis among dental students is susceptible to improvement. Introducing minor changes in the teachings allows this goal to be successfully achieved. Key words:Osteonecrosis of the jaw (ONJ), bisphosphonate-related osteonecrosis of the jaws (BRONJ), medication-related osteonecrosis of the jaw (MRONJ), dental education. PMID- 29410756 TI - Comparative evaluation between glass and polyethylene fiber reinforced composites: A review of the current literature. AB - Background: Fiber reinforced composite (FRC) is a promising class of material that gives clinicians alternative treatment options. There are many FRC products available in the market based on either glass or polyethylene fiber type. The aim of this study was to present a comparison between glass and polyethylene fiber reinforced composites based on available literature review. Material and Methods: A thorough literature search, with no limitation, was done up to June 2017. The range of relevant publications was surveyed using PubMed and Google Scholar. From the search results, articles related to our search terms were only considered. An assessment of these articles was done by two individuals in order to include only articles directly compare between glass and polyethylene FRCs. The search terms used were "fiber reinforced dental composites" and "glass and polyethylene fibers in dentistry". Results: The search provided 276 titles. Full-text analysis was performed for 29 articles that met the inclusion criteria. Most were laboratory based research with various test specimen designs prepared according to ISO standard or with extracted teeth and only three articles were clinical studies. Most of studies (n=23) found superior characteristics of glass FRCs over polyethylene FRCs. Conclusions: Significant reinforcement differences between commercial glass and polyethylene fiber reinforced composites were found. Key words:Fiber reinforced composite, glass fiber, polyethylene fiber. PMID- 29410757 TI - Podoplanin expression in oral potentially malignant disorders and oral squamous cell carcinoma. AB - Background: Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is specifically expressed in lymphatic endothelial cells. Studies have shown that assessment of podoplanin expression in the epithelial cells can be used to predict the malignant transformation of potentially malignant disorders and the metastatic tendency of primary head and neck squamous cell carcinoma. The aim of our study was to compare the expression of podoplanin in oral leukoplakia, oral submucous fibrosis and oral squamous cell carcinoma with that in normal buccal mucosa by immunohistochemical methods. Material and Methods: Immunohistochemical expression of podoplanin was analyzed in 20 cases each of oral leukoplakia, oral submucous fibrosis, oral squamous cell carcinoma and normal buccal mucosa, with monoclonal antibody D2-40. The expression of podoplanin was graded from grade 0 4. Results: There was a statistically significant upregulation of the grades of podoplanin expression in oral squamous cell carcinoma(100%), oral submucous fibrosis (90%) and oral leukoplakia (65%) when compared to that in normal mucosa(35%). Podoplanin expression increased with decrease in grades of differentiation in oral squamous cell carcinoma . Podoplanin expression in the samples of oral submucous fibrosis was higher than that in oral leukoplakia. Conclusions: Evaluation of podoplanin expression in the epithelial cells of oral dysplastic lesions may provide valuable information to predict their risk of malignant transformation. Key words:Immunohistochemistry, Oral leukoplakia, Oral submucous fibrosis, Podoplanin, Squamous cell carcinoma. PMID- 29410758 TI - Post-orthodontic position of lower incisors and gingival recession: A retrospective study. AB - Background: To evaluate if changes in lower incisor position following orthodontic treatment are correlated with development of gingival recessions. Material and Methods: Pre- and post-treatment digital models and lateral cephalograms of 22 subjects were collected retrospectively. The clinical crown length, gingival scallop, and papilla height of the central lower incisor were measured along with the cephalometric incisor's inclination, the distance from the mandibular plane, and the distance between the Infradentale and Menton points. Statistical correlations between gingival and cephalometric variables were studied. In addition, two groups were defined based on the post-treatment incisor inclination value ('normal' or 'proclined') and compared. Results: The incisor inclination was correlated with the change in gingival scallop and papilla height. Moreover, there was a statistically significant difference in clinical crown height and gingival scallop between the 'normal' group and the 'proclined' group. Conclusions: Changes in lower incisor position, especially an excessive proclination, after orthodontic treatment may play a role in the development of gingival recession. Key words:Orthodontic treatment, Incisor inclination, IMPA, Gingival recession, Alveolar bone. PMID- 29410759 TI - A controlled clinical study of periodontal health in anticoagulated patients: Assessment of bleeding on probing. AB - Background: According to the Spanish Society of Cardiology, 700,000 patients receive oral anticoagulants, and in these cases bleeding on probing (BOP) could be altered. However, no studies have analyzed the periodontal status of these patients and the effects anticoagulants may have upon BOP. A study was made of the possible relationship between plaque index, probing depth, INR (International Normalized Ratio) and acenocoumarol dose versus the clinical signs of BOP in a sample of anticoagulated patients. Likewise, an analysis was made of oral hygiene habits and attitude towards bleeding in these patients. Material and Methods: A controlled observational clinical study was made in La Ribera Hospital (Valencia, Spain) involving 44 anticoagulated patients treated with Sintrom(r) (acenocoumarol) and a homogeneous control group of 44 non-anticoagulated patients. A survey on oral hygiene habits and attitude towards bleeding was carried out, and the main periodontal parameters were recorded. Results: Probing depth was the parameter with the strongest correlation to BOP (p<0.001), followed by the plaque index (p<0.002). In contrast, no relationship was observed between acenocoumarol dose or INR and BOP. Mean BOP was greater in the control group than in the anticoagulated group (p<0.001). Oral hygiene habits and attitude towards bleeding differed significantly between groups. Conclusions: We have found no explanation why BOP was greater in the control group. What seems clear is that in the presence of the same plaque index and probing depth, anticoagulated patients did not bleed more than non-anticoagulated patients. A lack of knowledge of health and oral hygiene habits was observed in these subjects. Key words:Anticoagulant therapy, bleeding on probing, periodontal health. PMID- 29410760 TI - Complications of harvesting a connective tissue graft from the palate. A retrospective study and description of a new technique. AB - Background: Connective tissue graft (CTG) is considered as the gold standard for the treatment of gingival recessions (GR). There are few studies assessing the complications that can arise in the donor site when harvesting a connective tissue graft (CTG) and how the harvesting technique can influence those complications. Material and Methods: A retrospective clinical study was carried out in order to compare the complications observed in 40 patients with Miller class I, II and III GR >= 3 mm, after using the trap-door technique (TD) in the control group and a newly described technique, the "UPV/EHU technique", in the test group. Patients were consecutively allocated to each treatment group. Patients were monitored 14 days after surgery in order to evaluate post-operative complications in the donor site: presence of pain (P), bleeding (B), infection (I) and necrosis > 30%. Results: Although morbidity was observed in both groups, it was less important in the test group (no pain and minimal pain in 30% and 35% of the cases, respectively, and absence of bleeding or infection and necrosis >30% in only 5% of the cases). Conclusions: Within the limits of this study, this newly described "UPV/EHU technique" should be considered as a treatment option when harvesting a CTG, with minimal morbidity for patients. Key words:Connective tissue graft, pain, gingival recessions, wound healing, cosmetic periodontal plastic surgery, trap-door technique, "UPV/EHU technique". PMID- 29410761 TI - Elongated styloid process: An epidemiological study on digital panoramic radiographs. AB - Background: The styloid process is a projecton of the temporal bone, its lenght is between 20 to 30 mm, when it is longer than 30 mm it is defined elongated styloid process. The aim of this study is an epidemiological evaluation of 1003 digital panoramic radiographs in an Italian population between 5 and 90 years old. Material and Methods: This is a retrospective analysis and the radiographs were selected from the Complex Operating Unit of Dentistry of Padua University Hospital database. The radiographs were performed using a Sirona Ortophos XG and the styloid process length was measured using the measuring tool of Sidexis Software. It was measured from the point where it left the temporal bone plate to its tip. Styloid processes measuring more than 30 mm were considered elongated. Chi-squared test, Fligner-Killeen test, Shapiro-Wilk test and t-test with Welch correction were performed. Results: In the study 33.40% of the patients showed an elongated styloid process. Conclusions: The number of patients with elongated styloid process and the mean length of the process increase with the age confirming the chronic development of the calcification described in literature. No statistically significant correlation is found between the presence of elongated styloid process and the gender and affected side (bilateral or unilateral). Key words:Elongated styloid process, panoramic radiograph, epidemiological study, Eagle's syndrome. PMID- 29410763 TI - Oral peripheral nerve sheath tumors: A clinicopathological and immunohistochemical study of 32 cases in a Brazilian population. AB - Background: Oral peripheral nerve sheath tumors (OPNSTs) are reactive or neoplastic diseases that develop from proliferation of the nerve itself or their limiting sheaths. Here we describe the clinicopathologic data of OPNSTs observed in a sample of the Brazilian population and evaluate the expression of molecules associated with neural biology to determine their usefulness in the diagnosis. Material and Methods: Descriptive study of cases diagnosed as OPNSTs, from the Pathology Laboratory at the School of Dentistry/ Federal University of Uberlandia, followed by an immunohistochemical study of S-100, CD57, neurofilament protein (NFP) and epithelial membrane antigen (EMA). Results: OPNSTs comprised 0.27% of all biopsies. There were eight patients with neurofibromas, eight with traumatic neuromas, seven with schwannomas, five with granular cell tumor (GCT), and four with palisaded encapsulated neuromas (PEN). Women were more frequently affected (60.6% of the cases). Tongue and lips prevailed as the most frequent sites. S-100 was reactive in 100% of the cases. Neural fibers evidenced by CD57 reactivity of their Schwann cells were always nested in bundles within neurofibromas and GCT, absent within schwannomas and dispersed within PEN. Reactivity for NFP was limited to axons and then followed the same pattern of CD57, though much less evident. Reactivity for EMA was observed in the capsular tissues and perineurium of nerve fascicles, and absent in parenchymal cells of GCT. Conclusions: This study showed that OPNSTs are rare, widely benign and often found in tongue and lips. OPNSTs evolve from a common origin to distinct histological patterns, with eventual overlapping in their clinical and morphologic features. The arrangement of reactive residual neural fibers for CD57 can be a useful staining in the differential diagnosis of OPNSTs. Key words:Peripheral nerve sheath tumors. Oral cavity. Differential diagnosis. Immunohistochemistry. CD57 antigens. PMID- 29410762 TI - Relationship between the psychosocial impact of dental aesthetics and perfectionism and self-esteem. AB - Background: Awareness of the influence of personality traits such as self-esteem and perfectionism on the aesthetic self-image can help clinicians to improve their patients' satisfaction and quality of life. The main objective of this study was to examine the relationship between self-esteem, perfectionism and the psychosocial impact of dental aesthetics, and their association with gender. Material and Methods: A descriptive-analytical cross-sectional study was conducted in a sample of 301 students of the Faculty of Medicine and Dentistry of the University of Valencia, aged between 18 and 30 years. Each participant was asked to complete a survey comprising three questionnaires: PIDAQ (Psychosocial Impact of Dental Aesthetics Questionnaire), MPS (Multidimensional Perfectionism Scale) and RSS (Rosenberg Self-esteem Scale). The response rate was 79%. Results: The mean age was 20.8 years; 226 were women (75 %) and 75 were men (25 %). A negative correlation (Pearson = -0.387) was found between the total PIDAQ score and self-esteem. The correlation with perfectionism was found to be positive (Pearson = 0.281). On comparing the questionnaire and subscale scores by gender, the only statistically significant differences were in perfectionism (men 97.4, women 89.1) and self-confidence (men 22.1, women 23.5). Conclusions: The students most affected by poor dental aesthetics had lower self-esteem and higher levels of perfectionism. The men presented higher levels of perfectionism than the women, while the latter displayed greater self-confidence in their dental aesthetics. Clinicians should pay greater attention to these traits and to their implications for treating these patients. Key words:Psychosocial impact of dental aesthetics questionnaire, multidimensional perfectionism scale, rosenberg self esteem scale, students. PMID- 29410764 TI - Dental measurements and Bolton index reliability and accuracy obtained from 2D digital, 3D segmented CBCT, and 3d intraoral laser scanner. AB - Background: To compare the reliability and accuracy of direct and indirect dental measurements derived from two types of 3D virtual models: generated by intraoral laser scanning (ILS) and segmented cone beam computed tomography (CBCT), comparing these with a 2D digital model. Material and Methods: One hundred patients were selected. All patients' records included initial plaster models, an intraoral scan and a CBCT. Patients' dental arches were scanned with the iTero(r) intraoral scanner while the CBCTs were segmented to create three-dimensional models. To obtain 2D digital models, plaster models were scanned using a conventional 2D scanner. When digital models had been obtained using these three methods, direct dental measurements were measured and indirect measurements were calculated. Differences between methods were assessed by means of paired t-tests and regression models. Intra and inter-observer error were analyzed using Dahlberg's d and coefficients of variation. Results: Intraobserver and interobserver error for the ILS model was less than 0.44 mm while for segmented CBCT models, the error was less than 0.97 mm. ILS models provided statistically and clinically acceptable accuracy for all dental measurements, while CBCT models showed a tendency to underestimate measurements in the lower arch, although within the limits of clinical acceptability. Conclusions: ILS and CBCT segmented models are both reliable and accurate for dental measurements. Integration of ILS with CBCT scans would get dental and skeletal information altogether. Key words:CBCT, intraoral laser scanner, 2D digital models, 3D models, dental measurements, reliability. PMID- 29410766 TI - Implant-supported fixed prostheses in a Patient with Osteogenesis Imperfecta: A 4 year follow-up. AB - Osteogenesis Imperfecta (OI) is a rare autosomal dominant connective tissue disorder in wich, the bone quality and density is affected. OI includes some metabolic disorders and have a wide range of clinical presentations. In Osteogenesis Imperfecta bone has a very low density and it is a disorder currently treated with bisphosphonates. Quality and quantity of bone is important for establishment of osseointegration in dental implants. There are few reported cases in the literature. This is a case report of a 61 year-old man with grade IV OI, rehabilitated with implant-supported fixed prostheses in the posterior right and left mandible, whithout bone grafts. At the 4-year follow-up, clinical and imaging study showed no evidence of pathology in the peri-implant tissues. The final outcome is a correct occlusion and masticatory function. This case shows that dental implants may be a treatment option in this patients, however there is still quite limited scientific evidence. Key words:Osteogenesis imperfecta, osteoporotic bone, dental implants, bone fragility, bisphosphonates, drilling technique. PMID- 29410765 TI - Alternative intraoral donor sites to the chin and mandibular body-ramus. AB - Background: Provide a review of alternative intraoral donor sites to the chin and body-ramus of the mandible that bring fewer complications and that may be used to regenerate small and medium defects. Material and Methods: A review was conducted using the search engine PUBMED and looking manually into scientific journals. Results: From the 35 articles included, 6 corresponded to the coronoids, 3 corresponded to the zygomatic body, 5 corresponded to the anterior maxillary sinus wall, 3 corresponded to the zygomatic alveolar process, 2 corresponded to the incisive fossa, 2 corresponded to the anterior nasal spine, 2 corresponded to the palatal region, 5 corresponded to the tuberosity, and 7 corresponded to the palatal and mandibular tori. Conclusions: Although there are few complications described when using alternative intraoral donor sites, the main problem with these types of grafts is their scarce bone volume, with only the zygomatic body, anterior sinus wall, and palate sites being able to be used in medium defects. More clinical trials are necessary in order to evaluate the behavior of the alternative donor sites over time. Key words:Grafting, autologous bone, autografts, mandible, maxilla, palate hard, zygoma. PMID- 29410767 TI - Hyperpigmentation of hard palate induced by chloroquine therapy. AB - The antimalarials are one of the most commonly prescribed drugs for conditions such as lupus erythematosus and rheumatoid arthritis, and the side effects, though infrequent, are well known. The antimalarial agent chloroquine diphosphate usually causes pigmentary changes in the oral mucosa characterized by a bluish grey to black discolorations mainly in the hard palate. Considering only the hard palate hyperpigmentation caused by chloroquine, to the best of our knowledge, only 13 cases have been reported in the English language literature. We described an additional case of palate hyperpigmentation related to the chronic use of chloroquine diphosphate in a 60-year-old Mexican woman. Although the diagnosis is usually made based on medication history and clinical presentation, a biopsy specimen may be helpful to confirm the diagnosis. Clinicians must be aware of these drugs and their adverse effects in order to make the correct diagnosis and decide on the optimal treatment for the condition. Key words:Oral cavity, hard palate, hyperpigmentation, chloroquine, antimalarials. PMID- 29410768 TI - Recurrence in a patient with a 10-year history of sinonasal mucosal melanoma manifesting as facial swelling. AB - Sinonasal mucosal melanoma is a rare tumor that develops slowly and may manifest with non specific signs and symptoms, causing significant delay in diagnosis. Local recurrence is common and usually occurs within the first two years after the initial treatment. Prognosis of recurrent lesions is poor and 5-year survival ranges between 10-47%. We report the clinical, radiographic, histopathological and immunohistochemical findings of a recurrent sinonasal mucosal melanoma which was diagnosed 10 years after the initial treatment, in a patient who presented with unilateral facial swelling and one-sided difficulty in breathing of two years duration. We discuss the causes of late diagnosis and review the negative predictive factors for recurrence and survival. As early diagnosis is of paramount importance for prognosis, we emphasize the signs and symptoms of patients with a history of sinonasal mucosal melanoma which should raise the suspicion for recurrence, in spite of a long time interval since diagnosis. Key words: Mucosal melanoma, nasal cavity, sinus, recurrence. PMID- 29410769 TI - Dental-gingival remodeling with BOPT no-prep veneers. AB - : Recent years have seen increasing demand for treatments aimed at improving dental esthetics. In this context, both patients and dentists prefer to preserve dental structures as far as possible; thanks to technological advances, especially in adhesive dentistry, new materials and minimally invasive techniques such as "no-prep" (no preparation) veneers have made this possible. Nevertheless, no-prep veneers have specific indications and suffer certain disadvantages. OBJECTIVES: This clinical case describes the rehabilitation of the upper anterior region by means of no-prep veneers, with BOPT (Biologically Oriented Preparation Technique) cervical margins. The patient had requested an aesthetic treatment to improve irregularities of the gingival margins associated with the presence of diastemata resulting from microdontia. Key words:BOPT, micro-veneers, hybrid ceramic, ultra-fine veneers, diastemata, without prosthetic finish line, no-prep. PMID- 29410770 TI - Comparative analysis of Salivette(r) and paraffin gum preparations for establishment of a metaproteomics analysis pipeline for stimulated human saliva. AB - The value of saliva as a diagnostic tool can be increased by taxonomic and functional analyses of the microbiota as recently demonstrated. In this proof-of principle study, we compare two collection methods (Salivette(r) (SV) and paraffin gum (PG)) for stimulated saliva from five healthy participants and present a workflow including PG preparation which is suitable for metaproteomics. PMID- 29410771 TI - Inhibition of Steptococcus mutans biofilm formation by extracts of Tenacibaculum sp. 20J, a bacterium with wide-spectrum quorum quenching activity. AB - Background: Previous studies have suggested the quorum sensing signal AI-2 as a potential target to prevent the biofilm formation by Streptococcus mutans, a pathogen involved in tooth decay. Objective: To obtain inhibition of biofilm formation by S. mutans by extracts obtained from the marine bacterium Tenacibaculum sp. 20J interfering with the AI-2 quorum sensing system. Design: The AI-2 inhibitory activity was tested with the biosensors Vibrio harveyi BB170 and JMH597. S. mutans ATCC25175 biofilm formation was monitored using impedance real-time measurements with the xCELLigence system(r), confocal laser microscopy, and the crystal violet quantification method. Results: The addition of the cell extract from Tenacibaculum sp. 20J reduced biofilm formation in S. mutans ATCC25175 by 40-50% compared to the control without significantly affecting growth. A decrease of almost 40% was also observed in S. oralis DSM20627 and S. dentisani 7747 biofilms. Conclusions: The ability of Tenacibaculum sp. 20J to interfere with AI-2 and inhibit biofilm formation in S. mutans was demonstrated. The results indicate that the inhibition of quorum sensing processes may constitute a suitable strategy for inhibiting dental plaque formation, although additional experiments using mixed biofilm models would be required. PMID- 29410772 TI - The abrupt temperature changes in the plantar skin thermogram of the diabetic patient: looking in to prevent the insidious ulcers. AB - Background: One of the complications of the diabetes mellitus is the amputation of the lower limbs. This complication may be developed after an insidious ulcer, that may be raised by the peripheral neuropathy or the ischaemic limb, and that the ulcer get infected. That is, to develop an ulcer, in the diabetic patient, three factors should be taken into the account, the autonomic nervous system, the blood supply and the inmune system. Methods: In this work, the thermogram is used to identify regions on the plantar skin with blood supply deficiencies and the behaviour of the thermoregulation process. Within the thermogram of the plantar skin, it can be identify local regions with low and high temperatures that corresponds to ischemic or inflammatory process on that part of the skin. Results: The findings within the 186 thermograms of diabetic patients, obtained from three hospitals and from INAOE facilities, showed, first, the thermograms of the plantar skin of two diabetic patients, acquired in two different times show that the temperature distribution and the average temperatures, vary slightly for a period of weeks. Second, the thermograms of two patients, who both developed insidious ulcers which evolved favourable, demonstrated the importance of the immune system and the drug therapy. These patients are, one who has a Charcot foot, and in the second one, the patient had loss the sensibility of the feet. Finally, the thermograms of two patients, showing abrupt temperature change within small regions in the plantar skin, are discussed. Conclusion: A diabetic patient, with an asymmetric thermogram, as physiological interpretation of the thermoregulation, may indicate a decrease of the blood supply, which may be corroborated by vascular ultrasound. The regions of abrupt temperature change, cold or hot spots, may correspond to ischaemic or inflammatory processes. PMID- 29410773 TI - Affect dysregulation, psychoform dissociation, and adult relational fears mediate the relationship between childhood trauma and complex posttraumatic stress disorder independent of the symptoms of borderline personality disorder. AB - Objective: Complex posttraumatic stress disorder (CPTSD) as defined by the Disorders of Extreme Stress Not Otherwise Specified (DESNOS) formulation is associated with childhood relational trauma and involves relational impairment, affect dysregulation, and identity alterations. However, the distinct contributions of relational impairment (operationalized in the form fears of closeness or abandonment), affect dysregulation (operationalized in the form of overregulation and under-regulation of affect), and identity alterations (operationalized in the form of positive or negative psychoform or somatoform dissociation) to the relationship between childhood trauma and CPTSD/DESNOS have not been systematically tested. Method and Results: In a clinical sample of adults diagnosed with severe and chronic psychiatric and personality disorders (n = 472; M = 34.7 years, SD = 10.1), structural equation modelling with bootstrap 95% confidence intervals demonstrated that the association between childhood trauma and CPTSD/DESNOS symptoms in adulthood was partially mediated by under regulation of affect, negative psychoform dissociation, and adult relational fears of closeness and of abandonment. These results also were independent of the effects of borderline personality disorder (BPD) symptoms. Conclusions: Some, but not all, hypothesized components of the DESNOS formulation of CPTSD statistically mediate the relationship between childhood trauma and adult CPTSD/DESNOS. These relationships appear specific to CPTSD/DESNOS and not to the effects of another potential sequelae of childhood trauma BPD. Replication with prospective longitudinal studies is needed. PMID- 29410774 TI - Peritraumatic distress fully mediates the relationship between posttraumatic stress symptoms preoperative and three months postoperative in patients undergoing spine surgery. AB - Background: Growing evidence shows the significance of illness and surgical procedures as traumatizing stressors. Risk factors are widely investigated in various settings and samples, using numerous measures of posttraumatic stress and posttraumatic stress disorder (PTSD). While pretrauma psychological distress is acknowledged as an influential factor, peritraumatic experiences are controversially still being discussed as relevant to the development of PTSD. Objective: In a group of patients consecutively undergoing elective spine surgery (N = 89) in a German hospital, this longitudinal study addressed the question of how pretrauma PTSD symptoms and peritrauma distress interact with one another in regard to the amount of posttrauma symptoms of PTSD. Methods: Pre- and posttrauma symptoms of PTSD as well as peritrauma distress were assessed through questionnaires one week before, one week after or three months after surgery. Results: Even though all three variables showed significant correlations with one another, mediation analysis revealed that peritrauma distress fully mediated the relationship between pre- and posttrauma PTSD symptoms. Conclusions: These results add new insights to the controversial discussion on the role peritraumatic experiences play in the development of PTSD, especially in medical settings. PMID- 29410775 TI - Posttraumatic stress symptoms among Polish World War II survivors: the role of social acknowledgement. AB - Background: There is growing evidence of the important role played by socio interpersonal variables on the maintenance of PTSD. Many World War II survivors in Poland could, as a result of political circumstances during the aftermath of the war, have experienced a lack of social recognition of their war-related trauma. Objective: The main aim of the study was to examine the association between perceived social reactions and the level of posttraumatic stress symptoms (PTSD) and depression. Method: Participants (N = 120) were aged 71-97 years (M = 82.44; SD = 6.14). They completed a WWII trauma-related questionnaire, the Posttraumatic Diagnostic Scale (PDS), the Impact of Events Scale (IES) and Beck's Depression Inventory (BDI). The Social Acknowledgement Questionnaire (SAQ) was used to measure participants' perception of others' acknowledgement and disapproval of their war trauma. Results: The rate of probable PTSD, diagnosed according to DSM-IV, was 38.3%. PTSD symptoms and General Disapproval were significantly correlated for all three PTSD symptom groups (Pearson's r ranged from .25 to .41). The structural equation modelling results also demonstrated the importance of General Disapproval with regard to the level of PTSD symptoms. It explained both the intensity of PTSD symptoms (13.4% of variance) and the level of depression (12.0% of variance). Conclusion: In addition to confirming the high rate of PTSD among WWII survivors in Poland, the results indicate the importance of social reactions to survivors' traumatic experiences. PMID- 29410776 TI - Intensive prolonged exposure therapy for chronic PTSD patients following multiple trauma and multiple treatment attempts. AB - Background: Suboptimal response and high dropout rates leave room for improvement of trauma-focused treatment (TFT) effectiveness in ameliorating posttraumatic stress disorder (PTSD) symptoms. Objective: To explore the effectiveness and safety of intensive prolonged exposure (iPE) targeting chronic PTSD patients with a likely diagnosis of ICD-11 Complex PTSD following multiple interpersonal trauma and a history of multiple treatment attempts. Method: Participants (N = 73) received iPE in 12 * 90-minute sessions over four days (intensive phase) followed by four weekly 90-minute booster prolonged exposure (PE) sessions (booster phase). The primary outcomes, clinician-rated severity of PTSD symptoms, and diagnostic status (Clinician-Administered PTSD Scale; CAPS-IV) were assessed at baseline, post-treatment, and at three and six months. Treatment response trajectories were identified and predictors of these trajectories explored. Results: Mixed model repeated measures analysis of CAPS-IV scores showed a baseline-to-posttreatment decrease in PTSD symptom severity (p < .001) that persisted during the three- and six-month follow-ups with large effect sizes (Cohen's d > 1.2); 71% of the participants responded. None of the participants dropped out during the intensive phase and only 5% during the booster phase. Adverse events were extremely low and only a minority showed symptom exacerbation. Cluster analysis demonstrated four treatment response trajectories: Fast responders (13%), Slow responders (26%), Partial responders (32%), and Non responders (29%). Living condition and between-session fear habituation were found to predict outcome. Participants living alone were more likely to belong to the Partial responders than to the Non-responders cluster, and participants showing more between-session fear habituation were more likely to belong to the Fast responders than to the Non-responders cluster. Conclusions: The results of this open study suggest that iPE can be effective in PTSD patients with multiple interpersonal trauma and after multiple previous treatment attempts. In addition, in this chronic PTSD population iPE was safe. PMID- 29410777 TI - A socio-interpersonal approach to adjustment disorder: the example of involuntary job loss. AB - Background: Adjustment disorder (AjD) was redefined for ICD-11 with core symptoms of preoccupation with a stressor and failure to adapt. The socio-interpersonal framework model for stress-response syndromes suggests that interpersonal factors, besides intrapersonal processes, substantially contribute to the development of AjD. Objective: The current study aimed to identify predictive factors in the development of AjD symptoms by the application of a framework model for stress-response syndromes. Method: N = 321 recently laid-off participants (47.7% female) were assessed with a newly developed standardized clinical diagnostic interview section on ICD-11 AjD. Self-report questionnaires measured AjD symptom severity, and interpersonal and intrapersonal predictors. Path analysis was used to model the associations between AjD symptom severity and the predictor variables. We conducted logistic regression to identify associated characteristics of diagnostic status. Results: AjD symptoms were highly prevalent and 25.6% of participants met the diagnostic criteria. Higher loneliness, higher dysfunctional disclosure, and lower self-efficacy were associated with both higher symptom severity and higher likelihood of meeting the diagnostic criteria for AjD. Higher perceived social support was associated with higher likelihood for AjD diagnosis. Conclusions: Research on risk factors for AjD is still sparse. This study provided empirical evidence on the role of interpersonal factors supporting the socio-interpersonal model for stress-response syndromes. PMID- 29410778 TI - Efficient ultrafiltration-based protocol to deplete extracellular vesicles from fetal bovine serum. AB - Fetal bovine serum (FBS) is the most commonly used supplement in studies involving cell-culture experiments. However, FBS contains large numbers of bovine extracellular vesicles (EVs), which hamper the analyses of secreted EVs from the cell type of preference and, thus, also the downstream analyses. Therefore, a prior elimination of EVs from FBS is crucial. However, the current methods of EV depletion by ultracentrifugation are cumbersome and the commercial alternatives expensive. In this study, our aim was to develop a protocol to completely deplete EVs from FBS, which may have wide applicability in cell-culture applications. We investigated different EV-depleted FBS prepared by our novel ultrafiltration based protocol, by conventionally used overnight ultracentrifugation, or commercially available depleted FBS, and compared them with regular FBS. All sera were characterized by nanoparticle tracking analysis, electron microscopy, Western blotting and RNA quantification. Next, adipose-tissue mesenchymal stem cells (AT-MSCs) and cancer cells were grown in the media supplemented with the three different EV-depleted FBS and compared with cells grown in regular FBS media to assess the effects on cell proliferation, stress, differentiation and EV production. The novel ultrafiltration-based protocol depleted EVs from FBS clearly more efficiently than ultracentrifugation and commercial methods. Cell proliferation, stress, differentiation and EV production of AT-MSCs and cancer cell lines were similarly maintained in all three EV-depleted FBS media up to 96 h. In summary, our ultrafiltration protocol efficiently depletes EVs, is easy to use and maintains cell growth and metabolism. Since the method is also cost effective and easy to standardize, it could be used in a wide range of cell culture applications helping to increase comparability of EV research results between laboratories. PMID- 29410779 TI - Exosomes as secondary inductive signals involved in kidney organogenesis. AB - The subfraction of extracellular vesicles, called exosomes, transfers biological molecular information not only between cells but also between tissues and organs as nanolevel signals. Owing to their unique properties such that they contain several RNA species and proteins implicated in kidney development, exosomes are putative candidates to serve as developmental programming units in embryonic induction and tissue interactions. We used the mammalian metanephric kidney and its nephron-forming mesenchyme containing the nephron progenitor/stem cells as a model to investigate if secreted exosomes could serve as a novel type of inductive signal in a process defined as embryonic induction that controls organogenesis. As judged by several characteristic criteria, exosomes were enriched and purified from a cell line derived from embryonic kidney ureteric bud (UB) and from primary embryonic kidney UB cells, respectively. The cargo of the UB-derived exosomes was analysed by qPCR and proteomics. Several miRNA species that play a role in Wnt pathways and enrichment of proteins involved in pathways regulating the organization of the extracellular matrix as well as tissue homeostasis were identified. When labelled with fluorescent dyes, the uptake of the exosomes by metanephric mesenchyme (MM) cells and the transfer of their cargo to the cells can be observed. Closer inspection revealed that besides entering the cytoplasm, the exosomes were competent to also reach the nucleus. Furthermore, fluorescently labelled exosomal RNA enters into the cytoplasm of the MM cells. Exposure of the embryonic kidney-derived exosomes to the whole MM in an ex vivo organ culture setting did not lead to an induction of nephrogenesis but had an impact on the overall organization of the tissue. We conclude that the exosomes provide a novel signalling system with an apparent role in secondary embryonic induction regulating organogenesis. PMID- 29410781 TI - Career perspective: Kenneth J. Collins. AB - A career interest in thermoregulation research has included wide contrasts in the subjects of enquiry, extending from heat stroke to hypothermia, special investigations in many different purpose-built climatic chambers, laboratory based biomedical studies together with hospital practice, and field work in tropical climates to physiological surveys on urban populations in temperate environments. The scientific process and need to focus on careful planning of experiments, using the most appropriate methods, selecting the right controls and eventually applying correct statistical analysis do not always follow a smooth transition, as illustrated in this account. The result of endeavour to resolve a human environmental problem, however, is greatly satisfying, and sometimes becomes a unique experience when the solution reveals new fundamental facts. PMID- 29410780 TI - Characterization of Trichuris muris secreted proteins and extracellular vesicles provides new insights into host-parasite communication. AB - Whipworms are parasitic nematodes that live in the gut of more than 500 million people worldwide. Owing to the difficulty in obtaining parasite material, the mouse whipworm Trichuris muris has been extensively used as a model to study human whipworm infections. These nematodes secrete a multitude of compounds that interact with host tissues where they orchestrate a parasitic existence. Herein we provide the first comprehensive characterization of the excretory/secretory products of T. muris. We identify 148 proteins secreted by T. muris and show for the first time that the mouse whipworm secretes exosome-like extracellular vesicles (EVs) that can interact with host cells. We use an Optiprep(r) gradient to purify the EVs, highlighting the suitability of this method for purifying EVs secreted by a parasitic nematode. We also characterize the proteomic and genomic content of the EVs, identifying >350 proteins, 56 miRNAs (22 novel) and 475 full length mRNA transcripts mapping to T. muris gene models. Many of the miRNAs putatively mapped to mouse genes are involved in regulation of inflammation, implying a role in parasite-driven immunomodulation. In addition, for the first time to our knowledge, colonic organoids have been used to demonstrate the internalization of parasite EVs by host cells. Understanding how parasites interact with their host is crucial to develop new control measures. This first characterization of the proteins and EVs secreted by T. muris provides important information on whipworm-host communication and forms the basis for future studies. PMID- 29410782 TI - In vitro studies of the antibacterial activity of Copaifera spp. oleoresins, sodium hypochlorite, and peracetic acid against clinical and environmental isolates recovered from a hemodialysis unit. AB - Background: Patients submitted to hemodialysis therapy are more susceptible to infection, especially to infection by Gram-positive bacteria. Various research works have attempted to discover new antimicrobial agents from plant extracts and other natural products. Methods: The present study aimed to assess the antibacterial activities of Copaifera duckei, C. reticulata, and C. oblongifolia oleoresins; sodium hypochlorite; and peracetic acid against clinical and environmental isolates recovered from a Hemodialysis Unit. The Minimum Inhibitory Concentration and the Fractionated Inhibitory Concentration Index were determined; the ability of the tested compounds/extracts to inhibit biofilm formation was evaluated by calculating the MICB50 and IC50. Results: C. duckei was the most efficient among the assayed Copaifera species, and its oleoresin was more effective than peracetic acid and sodium hypochlorite. Copaifera oleoresins and disinfectants did not act synergistically at any of the tested combinations. Certain of C. duckei oleoresin, peracetic acid, and sodium hypochlorite concentrations inhibited biofilm formation and eradicated 50% of the biofilm population. Conclusion: C. duckei oleoresin is a potential candidate for disinfectant formulations. Based on these results and given the high incidence of multi-resistant bacteria in hemodialysis patients, it is imperative that new potential antibacterial agents like C. duckei oleoresin, which is active against Staphylococcus, be included in disinfectant formulations. PMID- 29410785 TI - Cooperation between cancer cells. PMID- 29410784 TI - Self-reported changes in alcohol use behavior among people living with HIV in China after receiving HIV positive diagnosis. AB - Background: Alcohol use remains a significant challenge for treating people living with HIV (people living with HIV). We aimed to examine current use and retrospective self-reported changes in drinking behavior after HIV+ diagnosis in people living with HIV. Method: Survey data were collected from a large random sample of people living with HIV (N = 2964, mean age = 42.5, standard deviation = 12.8) in Guangxi, China. Results: The estimated prevalence rate of current alcohol use was 42.8%. Among current drinkers, 41.7% reported binge drinking and 10.4% reported hazardous drinking. Among the ever drinkers, 45.4% reported reductions in drinking and 19.5% reported quitting after HIV+ diagnosis. Older age, female gender, higher income, being employed, if currently on antiretroviral therapy, and having received an HIV+ diagnosis within a year were positively associated with quitting; and more education, lower income, currently on antiretroviral therapy, and having received an HIV+ diagnosis more than one year were associated with reduced drinking. Conclusion: The time period immediately following receiving an HIV+ diagnosis may represent a window of opportunity for alcohol use intervention in people living with HIV. PMID- 29410783 TI - Functional roles of ornithine decarboxylase and arginine decarboxylase during the peri-implantation period of pregnancy in sheep. AB - Background: Polyamines stimulate DNA transcription and mRNA translation for protein synthesis in trophectoderm cells, as well as proliferation and migration of cells; therefore, they are essential for development and survival of conceptuses (embryo/fetus and placenta). The ovine conceptus produces polyamines via classical and non-classical pathways. In the classical pathway, arginine (Arg) is transformed into ornithine, which is then decarboxylated by ornithine decarboxylase (ODC1) to produce putrescine which is the substrate for the production of spermidine and spermine. In the non-classical pathway, Arg is converted to agmatine (Agm) by arginine decarboxylase (ADC), and Agm is converted to putrescine by agmatinase (AGMAT). Methods: Morpholino antisense oligonucleotides (MAOs) were designed and synthesized to inhibit translational initiation of the mRNAs for ODC1 and ADC, in ovine conceptuses. Results: The morphologies of MAO control, MAO-ODC1, and MAO-ADC conceptuses were normal. Double knockdown of ODC1 and ADC (MAO-ODC1:ADC) resulted in two phenotypes of conceptuses; 33% of conceptuses appeared to be morphologically and functionally normal (phenotype a) and 67% of the conceptuses presented an abnormal morphology and functionality (phenotype b). Furthermore, MAO-ODC1:ADC (a) conceptuses had greater tissue concentrations of Agm, putrescine, and spermidine than MAO control conceptuses, while MAO-ODC1:ADC (b) conceptuses only had greater tissue concentrations of Agm . Uterine flushes from ewes with MAO-ODC1:ADC (a) had greater amounts of arginine, aspartate, tyrosine, citrulline, lysine, phenylalanine, isoleucine, leucine, and glutamine, while uterine flushes of ewes with MAO-ODC1:ADC (b) conceptuses had lower amount of putrescine, spermidine, spermine, alanine, aspartate, glutamine, tyrosine, phenylalanine, isoleucine, leucine, and lysine. Conclusions: The double-knockdown of translation of ODC1 and ADC mRNAs was most detrimental to conceptus development and their production of interferon tau (IFNT). Agm, polyamines, amino acids, and adequate secretion of IFNT are critical for establishment and maintenance of pregnancy during the peri implantation period of gestation in sheep. PMID- 29410786 TI - The effect of mere measurement from a cardiovascular examination program on physical activity and sedentary time in an adult population. AB - Background: Measuring physical activity (PA) and sedentary time (ST) by self report or device as well as assessing related health factors may alter those behaviors. Thus, in intervention trials assessments may bias intervention effects. The aim of our study was to examine whether leisure-time PA, transport related PA, and overall ST measured via self-report vary after assessments and whether a brief tailored letter intervention has an additional effect. Methods: Among a sample of subjects with no history of myocardial infarction, stroke, or vascular intervention, a number of 175 individuals participated in a study comprising multiple repeated assessments. Of those, 153 were analyzed (mean age 54.5 years, standard deviation = 6.2; 64% women). At baseline, participants attended a cardiovascular examination (standardized measurement of blood pressure and waist circumference, blood sample taking) and wore an accelerometer for seven days. At baseline and after 1, 6, and 12 months, participants completed the International Physical Activity Questionnaire. A random subsample received a tailored counseling letter intervention at month 1, 3, and 4. Changes in PA and ST from baseline to 12-month follow-up were analyzed using random-effects modelling. Results: From baseline to 1-month assessment, leisure-time PA did not change (Incidence rate ratio = 1.13, p = .432), transport-related PA increased (Incidence rate ratio = 1.45, p = .023), and overall ST tended to decrease (b = - 1.96, p = .060). Further, overall ST decreased from month 6 to month 12 (b = - 0.52, p = .037). Time trends of the intervention group did not differ significantly from those of the assessment-only group. Conclusions: Results suggest an effect of measurements on PA and ST. Data of random-effects modelling results revealed an increase of transport-related PA after baseline to 1-month assessment. Decreases in overall ST may result from repeated assessments. A brief tailored letter intervention seemed to have no additional effect. Thus, measurement effects should be considered when planning intervention studies and interpreting intervention effects. Trial registration: ClinicalTrials.gov NCT02990039. Registered 7 December 2016. Retrospectively registered. PMID- 29410787 TI - A secondary syphilis rash with scaly target lesions. AB - A 40-year-old man reported a 5-day history of fever and malaise, followed by a pruritic generalized rash. He had well-demarcated erythematous papules and plaques with scaling. The patient was diagnosed with secondary syphilis. The skin biopsy showed a psoriasiform lichenoid dermatitis with plasma cells. The anti-T. pallidum antibody confirmed the presence of spirochetes. He was also found to be hepatitis C virus and human immunodeficiency virus positive. The characteristic rash of secondary syphilis may appear as maculopapular, evolving initially from macules to small reddish-brown papules with minor scaling later. When the scaling is prominent, lesions can be difficult to differentiate from guttate psoriasis. Typical target lesions are most often associated with erythema multiforme, but they can rarely occur in secondary and congenital syphilis. Syphilis should be suspected in high-risk patients presenting a variety of atypical syndromes such as neurologic symptoms, uveitis or cholestatic hepatitis, especially if palmoplantar lesions are present. PMID- 29410788 TI - Experiencing El Nino conditions during early life reduces recruiting probabilities but not adult survival. AB - In wild long-lived animals, analysis of impacts of stressful natal conditions on adult performance has rarely embraced the entire age span, and the possibility that costs are expressed late in life has seldom been examined. Using 26 years of data from 8541 fledglings and 1310 adults of the blue-footed booby (Sula nebouxii), a marine bird that can live up to 23 years, we tested whether experiencing the warm waters and food scarcity associated with El Nino in the natal year reduces recruitment or survival over the adult lifetime. Warm water in the natal year reduced the probability of recruiting; each additional degree ( degrees C) of water temperature meant a reduction of roughly 50% in fledglings' probability of returning to the natal colony as breeders. Warm water in the current year impacted adult survival, with greater effect at the oldest ages than during early adulthood. However, warm water in the natal year did not affect survival at any age over the adult lifespan. A previous study showed that early recruitment and widely spaced breeding allow boobies that experience warm waters in the natal year to achieve normal fledgling production over the first 10 years; our results now show that this reproductive effort incurs no survival penalty, not even late in life. This pattern is additional evidence of buffering against stressful natal conditions via life-history adjustments. PMID- 29410789 TI - Fine-scale movement responses of free-ranging harbour porpoises to capture, tagging and short-term noise pulses from a single airgun. AB - Knowledge about the impact of anthropogenic disturbances on the behavioural responses of cetaceans is constrained by lack of data on fine-scale movements of individuals. We equipped five free-ranging harbour porpoises (Phocoena phocoena) with high-resolution location and dive loggers and exposed them to a single 10 inch3 underwater airgun producing high-intensity noise pulses (2-3 s intervals) for 1 min. All five porpoises responded to capture and tagging with longer, faster and more directed movements as well as with shorter, shallower, less wiggly dives immediately after release, with natural behaviour resumed in less than or equal to 24 h. When we exposed porpoises to airgun pulses at ranges of 420-690 m with noise level estimates of 135-147 dB re 1 uPa2s (sound exposure level), one individual displayed rapid and directed movements away from the exposure site and two individuals used shorter and shallower dives compared to natural behaviour immediately after exposure. Noise-induced movement typically lasted for less than or equal to 8 h with an additional 24 h recovery period until natural behaviour was resumed. The remaining individuals did not show any quantifiable responses to the noise exposure. Changes in natural behaviour following anthropogenic disturbances may reduce feeding opportunities, and evaluating potential population-level consequences should be a priority research area. PMID- 29410790 TI - Pre-linguistic infants employ complex communicative loops to engage mothers in social exchanges and repair interaction ruptures. AB - Language has long been identified as a powerful communicative tool among humans. Yet, pre-linguistic communication, which is common in many species, is also used by human infants prior to the acquisition of language. The potential communicational value of pre-linguistic vocal interactions between human infants and mothers has been studied in the past decades. With 120 dyads (mothers and three- or six-month-old infants), we used the classical Still Face Paradigm (SFP) in which mothers interact freely with their infants, then refrain from communication (Still Face, SF), and finally resume play. We employed innovative automated techniques to measure infant and maternal vocalization and pause, and dyadic parameters (infant response to mother, joint silence and overlap) and the emotional component of Infant Directed Speech (e-IDS) throughout the interaction. We showed that: (i) during the initial free play mothers use longer vocalizations and more e-IDS when they interact with older infants and (ii) infant boys exhibit longer vocalizations and shorter pauses than girls. (iii) During the SF and reunion phases, infants show marked and sustained changes in vocalizations but their mothers do not and (iv) mother-infant dyadic parameters increase in the reunion phase. Our quantitative results show that infants, from the age of three months, actively participate to restore the interactive loop after communicative ruptures long before vocalizations show clear linguistic meaning. Thus, auditory signals provide from early in life a channel by which infants co-create interactions, enhancing the mother-infant bond. PMID- 29410791 TI - Colonization of weakened trees by mass-attacking bark beetles: no penalty for pioneers, scattered initial distributions and final regular patterns. AB - Bark beetles use aggregation pheromones to promote group foraging, thus increasing the chances of an individual to find a host and, when relevant, to overwhelm the defences of healthy trees. When a male beetle finds a suitable host, it releases pheromones that attract potential mates as well as other 'spying' males, which result in aggregations on the new host. To date, most studies have been concerned with the use of aggregation pheromones by bark beetles to overcome the defences of living, well-protected trees. How insects behave when facing undefended or poorly defended hosts remains largely unknown. The spatio-temporal pattern of resource colonization by the European eight toothed spruce bark beetle, Ips typographus, was quantified when weakly defended hosts (fallen trees) were attacked. In many of the replicates, colonization began with the insects rapidly scattering over the available surface and then randomly filling the gaps until a regular distribution was established, which resulted in a constant decrease in nearest-neighbour distances to a minimum below which attacks were not initiated. The scattered distribution of the first attacks suggested that the trees were only weakly defended. A minimal theoretical distance of 2.5 cm to the earlier settlers (corresponding to a density of 3.13 attacks dm-2) was calculated, but the attack density always remained lower, between 0.4 and 1.2 holes dm-2, according to our observations. PMID- 29410792 TI - Exploring the difference in xerogels and organogels through in situ observation. AB - Solvent-gelator interactions play a key role in mediating organogel formation and ultimately determine the physico-chemical properties of the organogels and xerogels. The ethanol organogels of 1,4-bis[(3,4,5-trihexyloxy phenyl)hydrazide]phenylene (TC6) were investigated in situ by FT-IR, Raman and fluorescence spectra, and XRD, and it was confirmed that the intermolecular interaction and aggregation structure of TC6 ethanol organogels were quite different from those of xerogels. Simultaneously, unprecedented phase transition from organogel to suspension upon heating was observed in ethanol organogel, and the suspension phase exhibited lytropic liquid crystalline behaviour with a rectangular columnar structure. This study may open the possibility to design new gelators with a new dimension of versatility. PMID- 29410793 TI - Investigation of nitrogen and phosphorus contents in water in the tributaries of Danjiangkou Reservoir. AB - As part of the efforts to ensure adequate supply of quality water from Danjiangkou Reservoir to Beijing, surface water samples were taken from the tributaries of Danjiangkou Reservoir in the normal (May), flood (August) and dry (December) seasons of 2014, and characterized for nitrogen and phosphorus contents as specified in the applicable standards. Test results indicated that (i) the organic pollution in the Sihe and Shendinghe rivers was more serious than those in other tributaries, and the concentrations of nitrogen and phosphorus favoured the growth of most algae; (ii) total phosphorus (TP), total nitrogen (TN) and dissolved inorganic nitrogen (DIN) were in the forms of dissolved phosphorus (DTP), dissolved nitrogen (DTN) and nitrate nitrogen [Formula: see text], respectively, in these seasons; (iii) compared with nitrogen, phosphorus was more likely to block an overrun of phytoplankton; (iv) TN, TP, permanganate index (CODMn) and other ions were positively correlated. These findings are helpful for the government to develop effective measures to protect the source water in Danjingkou Reservoir from pollution. PMID- 29410794 TI - Survival of adult Steller sea lions in Alaska: senescence, annual variation and covariation with male reproductive success. AB - Population dynamics of long-lived vertebrates depend critically on adult survival, yet factors affecting survival and covariation between survival and other vital rates in adults remain poorly examined for many taxonomic groups of long-lived mammals (e.g. actuarial senescence has been examined for only 9 of 34 extant pinniped species using longitudinal data). We used mark-recapture models and data from 2795 Steller sea lion (Eumetopias jubatus) pups individually marked at four of five rookeries in southeastern Alaska (SEAK) and resighted for 21 years to examine senescence, annual variability and covariation among life history traits in this long-lived, sexually dimorphic pinniped. Sexes differed in age of onset (approx. 16-17 and approx. 8-9 years for females and males, respectively), but not rate (-0.047 and -0.046/year of age for females and males) of senescence. Survival of adult males from northern SEAK had greatest annual variability (approx. +/-0.30 among years), whereas survival of adult females ranged approximately +/-0.10 annually. Positive covariation between male survival and reproductive success was observed. Survival of territorial males was 0.20 higher than that of non-territorial males, resulting in the majority of males alive at oldest ages being territorial. PMID- 29410796 TI - Environmental and social factors impacting on epidemic and endemic tuberculosis: a modelling analysis. AB - Tuberculosis (TB) transmission results from the interaction between infective sources and susceptible individuals within enabling socio-environmental conditions. As TB is an airborne pathogen, the transmission probability is determined by the volume of air inhaled from an infected source and the concentration of Mycobacterium tuberculosis containing respirable particles (doses) per volume of air. In this study, we model the contributions of infectious dose production, prevalence of infectious cases and daily rebreathed air volume (RAV) for defining the boundary conditions necessary to sustain endemic TB transmission at the population level. Results suggest that in areas with high RAV (range 300-1000 l d-1), such as prisons, TB transmission is contributed by both super-spreaders (exhaling >=10 infectious doses hr-1) and lower infectivity individuals (exhaling less than 10 infectious doses hr-1). In settings with a low quantity of RAV (less than 100 l d-1), TB transmission occurs only from super-spreaders. Point-source epidemics occur in low rebreathed environments when super-spreaders infect a number of susceptibles but subsequent transmission is limited by the mean infectivity of secondary cases. By contrast, endemic TB occurs in poor socio-environmental conditions where mean infectivity cases are able to maintain a sufficiently high effective contact number. PMID- 29410795 TI - Non-destructive geographical traceability of sea cucumber (Apostichopus japonicus) using near infrared spectroscopy combined with chemometric methods. AB - Sea cucumber is the major tonic seafood worldwide, and geographical origin traceability is an important part of its quality and safety control. In this work, a non-destructive method for origin traceability of sea cucumber (Apostichopus japonicus) from northern China Sea and East China Sea using near infrared spectroscopy (NIRS) and multivariate analysis methods was proposed. Total fat contents of 189 fresh sea cucumber samples were determined and partial least-squares (PLS) regression was used to establish the quantitative NIRS model. The ordered predictor selection algorithm was performed to select feasible wavelength regions for the construction of PLS and identification models. The identification model was developed by principal component analysis combined with Mahalanobis distance and scaling to the first range algorithms. In the test set of the optimum PLS models, the root mean square error of prediction was 0.45, and correlation coefficient was 0.90. The correct classification rates of 100% were obtained in both identification calibration model and test model. The overall results indicated that NIRS method combined with chemometric analysis was a suitable tool for origin traceability and identification of fresh sea cucumber samples from nine origins in China. PMID- 29410797 TI - In situ formation of surface-functionalized ionic calcium carbonate nanoparticles with liquid-like behaviours and their electrical properties. AB - This paper reports a new route to synthesize calcium carbonate (CaCO3)-based nanoscale ionic materials (NIMs) via an in situ formation method to form the CaCO3 nanoparticles with a polysiloxane quaternary ammonium salt (PQAC) corona (PQAC-CaCO3 nanoparticles), followed by an ionic exchange reaction to fabricate a poly(ethylene glycol)-tailed sulfonate anion (NPEP) canopy. The chemical compositions and structures of the CaCO3-based NIMs synthesized in this work were confirmed by Fourier-transform infrared spectroscopy and solid-state 13C NMR spectroscopy. Transmission electron microscopic observation indicated that the CaCO3-based NIMs presented a rhombohedral shape with a well-defined core-shell structure, and they also obtained an NPEP canopy with a thickness of 4-6 nm. X ray powder diffraction investigation confirmed that the CaCO3 inner core had a calcite crystalline structure, whereas the NPEP canopy was amorphous. The NPEP canopy was found to show a characteristic crystallization-melting behaviour in the presence of the ion bonding with PQAC-CaCO3 nanoparticles according to the characterization of differential scanning calorimetry. Thermogravimetric analysis indicated that the CaCO3-based NIMs achieved a high content of NPEP canopy as well as an improvement in thermal stability owing to the ion-bonding effect. Most of all, the CaCO3-based NIMs demonstrated a liquid-like behaviour above the critical temperature in the absence of solvent. Moreover, the CaCO3-based NIMs also showed a relatively high electrical conductivity with a temperature dependency due to the ionic conductive effect. This work will provide a more feasible and energy-saving methodology for the preparation of CaCO3-based NIMs to promote their industrialization and extensive applications. PMID- 29410798 TI - Pleistocene glaciation of Fenland, England, and its implications for evolution of the region. AB - Detailed investigation of landforms and their underlying deposits on the eastern margin of Fenland, East Anglia, demonstrated that they represent a series of glaciofluvial delta-fan and related sediments. Associated with these deposits are glacially dislocated sediments including tills, meltwater and pre-existing fluvial sediments. These 'Skertchly Line' deposits occur in the context of a substantial ice lobe that entered Fenland from the N to NE, dammed the streams entering the basin and caused glacial lakes to form in the valleys on the margins. Bulldozing by the ice lobe caused a series of ice-pushed ridges to form at the dynamic margin, especially at the ice maximum and during its retreat phases. Meltwater formed a series of marginal fans that coalesced into marginal accumulations in the SE of the basin. The ice lobe is named the Tottenhill glaciation. Further investigations of the Fenland margin have revealed the extent of the Tottenhill glaciation in the Fenland Basin, to the south and west, in sufficient detail to demonstrate the nature of the Tottenhill ice lobe and the landscape left on deglaciation. The ice lobe is likely to have been prone to surging. This is indicated by the low gradient of the ice lobe, the presence of underlying ductile Mesozoic clays, the evidence of ice-marginal flooding and the presence of arcuate glaciotectonic push moraines. Regional correlation, supported by independent numerical geochronology, indicates that the glaciation occurred ca 160 ka, i.e. during the late Middle Pleistocene, Marine Isotope Stage (MIS) 6, the Wolstonian Stage. Comparison and correlation across the southern North Sea Basin confirms that the glaciation is the equivalent of that during the Late Saalian Drenthe Stadial in The Netherlands. The implications of this correlation are presented. Before the glaciation occurred, the Fenland Basin did not exist. It appears to have been initiated by a subglacial tunnel valley system beneath the Anglian (=Elsterian, MIS 12) ice sheet. During the subsequent Hoxnian (=Holsteinian; approx. MIS 11) interglacial, the sea invaded the drainage system inherited following the glacial retreat. The evolution through the subsequent ca 200 ka Early to Middle Wolstonian substages, the interval between the Hoxnian (Holsteinian) temperate Stage and the Wolstonian glaciation, represents a period during which fluvial and periglacial activity modified the landscape under cold climates, and organic sediments were laid down during a warmer event. Palaeolithic humans were also periodically present during this interval, their artefacts having been reworked by the subsequent glaciation. The deglaciation was followed by re-establishment of the rivers associated with the deposition of Late Wolstonian (Warthe Stadial) gravels and sands, and later, deposits of the Ipswichian interglacial (=Eemian, approx. MIS 5e) including freshwater, then estuarine sediments. Subsequent evolution of the basin occurred during the Devensian Stage (=Weichselian, MIS 5d-2) under predominantly cold, periglacial conditions. PMID- 29410799 TI - Quantification of plasma cell dynamics using mathematical modelling. AB - Plasma cells (PCs) are the main antibody-producing cells in humans. They are long lived so that specific antibodies against either pathogens or vaccines are produced for decades. PC longevity is attributed to specific areas within the bone marrow micro-environment, the so-called 'niche', providing the cells with required growth and survival factors. With antigen encounters, e.g. infection or vaccination, new PCs are generated and home to the bone marrow where they compete with resident PCs for the niche. We propose a parametrized mathematical model describing healthy PC dynamics in the bone marrow. The model accounts for competition for the niche between newly produced PCs owing to vaccination and resident PCs. Mathematical analysis and numerical simulations of the model allow explanation of the recovery of PC homoeostasis after a vaccine-induced perturbation, and the fraction of vaccine-specific PCs inside the niche. The model enables quantification of the niche-related dynamics of PCs, i.e. the duration of PC transition into the niche and the impact of different rates for PC transitions into and out of the niche on the observed cell dynamics. Ultimately, it provides a potential basis for further investigations in health and disease. PMID- 29410800 TI - Deletion/loss of bone morphogenetic protein 7 changes tooth morphology and function in Mus musculus: implications for dental evolution in mammals. AB - Quantifying regulatory gene effects on dental morphology and function has implications for the underlying mechanisms that generated dental diversity in mammals. We tested the hypothesis that regulatory gene expression changes lead to differences in molars using a neural crest knockout of bone morphogenetic protein 7 (BMP7) in Mus musculus. Three-dimensional geometric morphometric methods were used to quantify the shape of the molar toothrow. BMP7 mutants have extra cusps on the first upper and lower molars, and alterations in cusp orientation and morphology. Furthermore, significant shape differences between control and mutant were found for upper and lower toothrows. Mutant mice also exhibited differences in attrition facets, indicating functional changes that could lead to advantages in chewing new food resources and eventually niche diversification. The size ratio of the molars in the toothrow remained unchanged, implying that BMP7 induced changes in molar size ratio are a result of knocking out epithelial, rather than neural crest, expression of BMP7. Our results indicate that changes in BMP7 expression are sufficient to alter the morphology and function of the toothrow, suggesting that BMP7 or genes affecting its function could have played a role in structuring the dental diversity of extinct and extant mammals. PMID- 29410801 TI - Reference values of gait using APDM movement monitoring inertial sensor system. AB - Normal gait data reported show variability depending on specific equipment and techniques. Reference values of initial contact angle (ICA) and toe-off angle (TOA) are still lacking. We present a normative gait database of 292 healthy adults using the APDM Movement Monitoring inertial sensor system across a large age span of adulthood. Data were collected as participants completed a walk test for 2 min. Normalization was conducted and two factors were extracted by a factor analysis. Six reference gait variables under each factor were presented and the impacts of age, gender and BMI were evaluated by MANOVA and ANCOVA. ICA and TOA were highly correlated with speed and stride length. ICA was significantly larger in men, whereas larger TOA could be observed in women in all age groups but could not achieve significant difference. Overweight and obese adults walked at significantly lower speed, shorter stride length, reduced cadence and longer gait cycle duration. TOA was smaller in the obese group. However, the differences in ICA were not significant. Reference gait values described herein were valuable for identifying and interpreting gait phenomena using APDM(r), contributing to rehabilitation of gait dysfunction. PMID- 29410802 TI - Repartitioning of glycerol between levitated and surrounding deposited glycerol/NaNO3/H2O droplets. AB - Repartitioning of semi-volatile organic compounds (SVOCs) between particles is an important process to understand the particle growth and shrinkage in the atmosphere environment. Here, by using optical tweezers coupled with cavity enhanced Raman spectroscopy, we report the repartitioning of glycerol between a levitated glycerol/NaNO3/H2O droplet and surrounding glycerol/NaNO3/H2O droplets deposited on the inner wall of a chamber with different organic to inorganic molar ratios (OIRs). For the high OIR with 3 : 1, no NaNO3 crystallization occurs both for levitated and deposited droplets in the whole relative humidity (RH) range, the radius of the levitated droplet decreases slowly due to the evaporation of glycerol from the levitated droplet at constant RHs. The levitated droplets radii with OIR of 1 : 1 and 1 : 3 increase with constant RHs that are lower than 45.3% and 55.7%, respectively, indicating that the repartitioning of glycerol occurs. The reason is that NaNO3 in the deposited droplets is crystallized when RH is lower than 45.3% for 1 : 1 or 55.7% for 1 : 3. So the vapour pressure of glycerol at the surface of deposited droplets is higher than that of the levitated droplet which always remains as liquid droplet without NaNO3 crystallization, resulting in the transfer of glycerol from the deposited ones to the levitated one. The process of the glycerol repartitioning we discussed herein is a useful model to interpret the repartitioning of SVOCs between the externally mixed particles with different phase states. PMID- 29410803 TI - Development of bioabsorbable polylactide membrane with controllable hydrophilicity for adjustment of cell behaviours. AB - Cell functions can be mediated through their interactions with the microenvironments, which highly depend on the surface state of the substrate. However, how to finely adjust the surface of biomaterials is still very challenging. In this study, poly(d,l-lactide) (PDLLA) with high molecular weight was synthesized via ring opening polymerization, which was hot-pressed into PDLLA membrane. In order to modify the hydrophobicity of the membrane (a limiting factor for its biomedical application), an amphiphilic monomethoxyl poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) was selected to improve its surface hydrophilicity through a simple self-assembly approach. It was found that the contact angles of the modified membrane can be well controlled by variation of PEG-PDLLA concentrations. In vitro cell biological study indicates that optimized cell adhesion can be achieved on the modified membrane with a contact angle of around 50 degrees via its self-assembly with an ethanol/water solution of PEG PDLA (35 mg ml-1). The surface modification of the membrane also changed its biodegradation property in the process of its incubation period up to 240 days. The surface modification method may afford an effective way for adjustment of the surface (interface) of membrane (scaffolds) of different biomaterials, beyond polylactide. PMID- 29410805 TI - Transcriptomic inspection revealed a possible pathway regulating the formation of the high-quality brush hair in Chinese Haimen goat (Capra hircus). AB - The high-quality brush hair, or Type III brush hair, is coarse hair but with a tip and little medulla, which uniquely grows in the cervical carina of Chinese Haimen goat (Capra hircus). To unveil the mechanism of the formation of Type III brush hair in Haimen goats, transcriptomic RNAseq technology was used for screening of differentially expressed genes (DEGs) in the skin samples of the Type III and the non-Type III hair goats, and these DEGs were analysed by KEGG pathway analysis. The results showed that a total of 295 DEGs were obtained, mainly from three main functional types: cellular component, molecular function and biological process. These DEGs were mainly enriched in three KEGG pathways, such as protein processing in endoplasmic reticulum, MAPK, and complement and coagulation cascades. These DEGs gave hints to a possible mechanism, under which heat stress possibly initiated the formation. The study provided some useful biological information, which could give a new view about the roles of certain factors in hair growth and give hints on the mechanism of the formation of the Type III brush hair in Chinese Haimen goat. PMID- 29410804 TI - The genomic ancestry, landscape genetics and invasion history of introduced mice in New Zealand. AB - The house mouse (Mus musculus) provides a fascinating system for studying both the genomic basis of reproductive isolation, and the patterns of human-mediated dispersal. New Zealand has a complex history of mouse invasions, and the living descendants of these invaders have genetic ancestry from all three subspecies, although most are primarily descended from M. m. domesticus. We used the GigaMUGA genotyping array (approximately 135 000 loci) to describe the genomic ancestry of 161 mice, sampled from 34 locations from across New Zealand (and one Australian city-Sydney). Of these, two populations, one in the south of the South Island, and one on Chatham Island, showed complete mitochondrial lineage capture, featuring two different lineages of M. m. castaneus mitochondrial DNA but with only M. m. domesticus nuclear ancestry detectable. Mice in the northern and southern parts of the North Island had small traces (approx. 2-3%) of M. m. castaneus nuclear ancestry, and mice in the upper South Island had approximately 7-8% M. m. musculus nuclear ancestry including some Y-chromosomal ancestry-though no detectable M. m. musculus mitochondrial ancestry. This is the most thorough genomic study of introduced populations of house mice yet conducted, and will have relevance to studies of the isolation mechanisms separating subspecies of mice. PMID- 29410806 TI - From conservation genetics to conservation genomics: a genome-wide assessment of blue whales (Balaenoptera musculus) in Australian feeding aggregations. AB - Genetic datasets of tens of markers have been superseded through next-generation sequencing technology with genome-wide datasets of thousands of markers. Genomic datasets improve our power to detect low population structure and identify adaptive divergence. The increased population-level knowledge can inform the conservation management of endangered species, such as the blue whale (Balaenoptera musculus). In Australia, there are two known feeding aggregations of the pygmy blue whale (B. m. brevicauda) which have shown no evidence of genetic structure based on a small dataset of 10 microsatellites and mtDNA. Here, we develop and implement a high-resolution dataset of 8294 genome-wide filtered single nucleotide polymorphisms, the first of its kind for blue whales. We use these data to assess whether the Australian feeding aggregations constitute one population and to test for the first time whether there is adaptive divergence between the feeding aggregations. We found no evidence of neutral population structure and negligible evidence of adaptive divergence. We propose that individuals likely travel widely between feeding areas and to breeding areas, which would require them to be adapted to a wide range of environmental conditions. This has important implications for their conservation as this blue whale population is likely vulnerable to a range of anthropogenic threats both off Australia and elsewhere. PMID- 29410807 TI - Degradation of folic acid wastewater by electro-Fenton with three-dimensional electrode and its kinetic study. AB - The three-dimensional electro-Fenton method was used in the folic acid wastewater pretreatment process. In this study, we researched the degradation of folic acid and the effects of different parameters such as the air sparging rate, current density, pH and reaction time on chemical oxygen demand (COD) removal in folic acid wastewater. A four-level and four-factor orthogonal test was designed and optimal reaction conditions to pretreat folic acid wastewater by three dimensional electrode were determined: air sparge rate 0.75 l min-1, current density 10.26 mA cm-2, pH 5 and reaction time 90 min. Under these conditions, the removal of COD reached 94.87%. LC-MS results showed that the electro-Fenton method led to an initial folic acid decomposition into p-aminobenzoyl-glutamic acid (PGA) and xanthopterin (XA); then part of the XA was oxidized to pterine-6 carboxylic acid (PCA) and the remaining part of XA was converted to pterin and carbon dioxide. The kinetics analysis of the folic acid degradation process during pretreatment was carried out by using simulated folic acid wastewater, and it could be proved that the degradation of folic acid by using the three dimensional electro-Fenton method was a second-order reaction process. This study provided a reference for industrial folic acid treatment. PMID- 29410808 TI - The role of maternal age and context-dependent maternal effects in the offspring provisioning of a long-lived marine teleost. AB - Despite evidence of maternal age effects in a number of teleost species, there have been challenges to the assertion that maternal age intrinsically influences offspring quality. From an evolutionary perspective, maternal age effects result in young females paradoxically investing in less fit offspring despite a greater potential fitness benefit that might be gained by allocating this energy to individual somatic growth. Although a narrow range of conditions could lead to a maternal fitness benefit via the production of lower quality offspring, evolutionary theorists suggest these conditions are seldom met and that the reported maternal age effects are more likely products of the environmental context. Our goal was to determine if maternal effects operated on offspring provisioning in a long-lived rockfish (genus Sebastes), and to evaluate any such effects as an intrinsic function of maternal age or a context-dependent effect of the offspring release environment. We found that offspring provisioning is a function of both maternal age and the timing of offspring release; older females exhibit increased provisioning over younger females throughout the spawning season despite a decrease in provisioning across all maternal ages as the season progresses. These findings suggest a role for both maternal age effects and a potential context-dependent maternal effect in population productivity, carrying important implications when modelling population persistence and resilience. PMID- 29410809 TI - Population, sex and body size: determinants of behavioural variations and behavioural correlations among wild zebrafish Danio rerio. AB - This study (1) investigated variation among populations and the effects of sex and body size on boldness, activity and shoal-association tendency among wild zebrafish, and (2) tested for existence of correlations between behaviours, controlling for sex and body size. Individuals across four natural populations were tested for general activity in a novel situation, number of predator inspections undertaken and tendency to associate with a conspecific shoal in the presence of predators. Results showed a significant effect of population on boldness with a population from high-predation habitat being bolder than populations from low-predation habitats. Males showed significantly higher tendencies than females to associate with a conspecific shoal in the presence of predators. Further, a negative relationship was found between activity and boldness only within two low-predation populations. Individual body size had a strong effect on the activity-boldness relationship within the low-predation population from flowing water habitat. Smaller fish were bolder and less active while larger fish were more cautious and active. Overall, the results indicated that while population-level behavioural responses might be shaped by predation pressure, state-dependent factors could determine behavioural correlations among individuals within populations. PMID- 29410810 TI - Ferromagnetically filled carbon nano-onions: the key role of sulfur in dimensional, structural and electric control. AB - A key challenge in the fabrication of ferromagnetically filled carbon nano-onions (CNOs) is the control of their thickness, dimensions and electric properties. Up to now literature works have mainly focused on the encapsulation of different types of ferromagnetic materials including alpha-Fe, Fe3C, Co, FeCo, FePd3 and others within CNOs. However, no report has yet shown a suitable method for controlling both the number of shells, diameter and electric properties of the produced CNOs. Here, we demonstrate an advanced chemical vapour deposition approach in which the use of small quantities of sulfur during the pyrolysis of ferrocene allows for the control of (i) the diameter of the CNOs, (ii) the number of shells and (iii) the electric properties. We demonstrate the morphological, structural, electric and magnetic properties of these new types of CNOs by using SEM, XRD, TEM, HRTEM, EIS and VSM techniques. PMID- 29410811 TI - Mesoporous silica nanoparticle-based intelligent drug delivery system for bienzyme-responsive tumour targeting and controlled release. AB - This paper proposes a novel type of multifunctional envelope-type mesoporous silica nanoparticle (MSN) to achieve cancer cell targeting and drug-controlled release. In this system, MSNs were first modified by active targeting moiety hyaluronic acid (HA) for breast cancer cell targeting and hyaluronidases (Hyal) induced intracellular drug release. Then gelatin, a proteinaceous biopolymer, was grafted onto the MSNs to form a capping layer via glutaraldehyde-mediated cross linking. To shield against unspecific uptake of cells and prolong circulation time, the nanoparticles were further decorated with poly(ethylene glycol) polymers (PEG) to obtain MSN@HA-gelatin-PEG (MHGP). Doxorubicin (DOX), as a model drug, was loaded into PEMSN to assess the breast cancer cell targeting and drug release behaviours. In vitro study revealed that PEG chains protect the targeting ligand and shield against normal cells. After reaching the breast cancer cells, MMP-2 overpressed by cells hydrolyses gelatin layer to deshield PEG and switch on the function of HA. As a result, DOX-loaded MHGP was selectively trapped by cancer cells through HA receptor-mediated endocytosis and subsequently release DOX due to Hyal-catalysed degradation of HA. This system presents successful bienzyme-responsive targeting drug delivery in an optimal fashion and provides potential applications for targeted cancer therapy. PMID- 29410812 TI - Paternity and kin structure among neighbouring groups in wild bonobos at Wamba. AB - Although both bonobos and chimpanzees are male-philopatric species, outcomes of male-male reproductive competition seem to be more closely associated with mating success in chimpanzees. This suggests that the extent of male reproductive skew is lower in bonobos. In addition, between-group male-male reproductive competition is more lethal in chimpanzees. This suggests that between-group differentiation in male kinship is lower in bonobos. We analysed the paternity of 17 offspring in two bonobo groups and estimated the relatedness of individuals among three neighbouring groups by using DNA extracted from non-invasive samples at Wamba, in the Democratic Republic of the Congo. The alpha males sired at least nine of 17 offspring. This supports a previous finding that the male reproductive skew is higher in bonobos than that in chimpanzees. Average relatedness among males within groups was significantly higher than that among males across groups, whereas there was no significant difference among females between within and across groups. These results are consistent with male philopatry, highly skewed reproductive success of males and female dispersal. Higher average relatedness among males within groups suggest that the differences in hostility towards males of different groups between bonobos and chimpanzees may be explained by factors other than kinship. PMID- 29410814 TI - Network analysis of the Viking Age in Ireland as portrayed in Cogadh Gaedhel re Gallaibh. AB - Cogadh Gaedhel re Gallaibh ('The War of the Gaedhil with the Gaill') is a medieval Irish text, telling how an army under the leadership of Brian Boru challenged Viking invaders and their allies in Ireland, culminating with the Battle of Clontarf in 1014. Brian's victory is widely remembered for breaking Viking power in Ireland, although much modern scholarship disputes traditional perceptions. Instead of an international conflict between Irish and Viking, interpretations based on revisionist scholarship consider it a domestic feud or civil war. Counter-revisionists challenge this view and a long-standing and lively debate continues. Here, we introduce quantitative measures to the discussions. We present statistical analyses of network data embedded in the text to position its sets of interactions on a spectrum from the domestic to the international. This delivers a picture that lies between antipodal traditional and revisionist extremes; hostilities recorded in the text are mostly between Irish and Viking-but internal conflict forms a significant proportion of the negative interactions too. PMID- 29410813 TI - Stabilization of golden cages by encapsulation of a single transition metal atom. AB - Golden cage-doped nanoclusters have attracted great attention in the past decade due to their remarkable electronic, optical and catalytic properties. However, the structures of large golden cage doped with Mo and Tc are still not well known because of the challenges in global structural searches. Here, we report anionic and neutral golden cage doped with a transition metal atom MAu16 (M = Mo and Tc) using Saunders 'Kick' stochastic automation search method associated with density functional theory (DFT) calculation (SK-DFT). The geometric structures and electronic properties of the doped clusters, MAu16q (M = Mo and Tc; q = 0 and 1), are investigated by means of DFT theoretical calculations. Our calculations confirm that the 4d transition metals Mo and Tc can be stably encapsulated in the Au16- cage, forming three different configurations, i.e. endohedral cages, planar structures and exohedral derivatives. The ground-state structures of endohedral cages C2v Mo@Au16--(a) and C1 Tc@Au16--(b) exhibit a marked stability, as judged by their high binding energy per atom (greater than 2.46 eV), doping energy (0.29 eV) as well as a large HOMO-LUMO gap (greater than 0.40 eV). The predicted photoelectron spectra should aid in future experimental characterization of MAu16 (M = Mo and Tc). PMID- 29410815 TI - A novel adenine-based metal organic framework derived nitrogen-doped nanoporous carbon for flexible solid-state supercapacitor. AB - In this article, we have synthesized a series of nitrogen-doped nanoporous carbon (NPC) from metal organic framework of UiO-66 with different ratios of adenine and 1,4-benzendicarboxylate (H2BDC) coated on carbon nanotube film (CNTF) to obtain a flexible porous electrode (NPC/CNTF). It is worth noting that the introduction of adenine at different ratios did not change the structure of UiO-66. We also investigated the effect of carbonization temperature from 800 to 1000 degrees C on the electrochemical properties of the NPC. The ratio (H2BDC:adenine) 9 : 1 and the NPC carbonized at 900 degrees C (denoted as NPC-1-900) exhibits better electrochemical properties. The results show that NPC-1-900/CNTF electrode exhibits an exceptional areal capacitance of 121.5 mF cm-2 compared to that of PC 900/CNTF electrode (22.8 mF cm-2) at 5 mV s-1 in a three-electrode system, indicating that the incorporation of nitrogen is beneficial to the electrochemical properties of nanoporous carbon. A symmetric flexible solid-state supercapacitor of NPC-1-900/CNTF has also been assembled and tested. Electrochemical data show that the device exhibited superior areal capacitance (43.2 mF cm-2) at the scan rate of 5 mV s-1; the volumetric energy density is 57.3 uWh cm-3 and the volumetric power density is 2.4 mW cm-3 at the current density of 0.5 mA cm-2 based on poly(vinyl alcohol)/H3PO4 gel electrolyte. For practical application, we have also studied the bending tests of the device, which show that the device exhibits outstanding mechanical stability under different bending angles. Furthermore, the flexible device shows excellent cyclic stability, which can retain 91.5% of the initial capacitance after 2000 cycles. PMID- 29410816 TI - Parenting behaviour is highly heritable in male stickleback. AB - Parental care is critical for fitness, yet little is known about its genetic basis. Here, we estimate the heritability of parenting behaviour in a species famous for its diversity and its behavioural repertoire: three-spined stickleback (Gasterosteus aculeatus). Male three-spined stickleback are the sole providers of parental care that is necessary for offspring survival; therefore, this system offers the opportunity to study the inheritance of parental behaviour when selection is primarily acting on males. Fanning behaviour is a conspicuous parental behaviour that is readily quantified in this species. We show that the heritability of fanning behaviour is >=0.9 and significantly different from zero within a freshwater population. Moreover, there was abundant genetic variation for fanning behaviour, indicating that it could readily evolve. These results suggest that parenting behaviour is tractable for further genetic dissection in this system. PMID- 29410817 TI - Control of the mixing time in vessels agitated by submerged recirculating jets. AB - Submerged recirculating jet mixing systems are an efficient and economical method of agitating large tanks with a high hydraulic residence time. Much work has been carried out in developing design correlations to aid the predictions of the mixing time in such systems, with the first such correlation being developed nearly 70 years ago. In most of these correlations, the mixing time depends directly on the volume of the vessel and inversely on the injection velocity of the submerged jet. This work demonstrates, for the first time, that the distance between the injection and suction nozzles also significantly affects the mixing time and can be used to control this time scale. The study introduces a non dimensional quantity that can be used as an adjustable parameter in systems where such control is desired. PMID- 29410818 TI - Beyond 'significance': principles and practice of the Analysis of Credibility. AB - The inferential inadequacies of statistical significance testing are now widely recognized. There is, however, no consensus on how to move research into a 'post p < 0.05' era. We present a potential route forward via the Analysis of Credibility, a novel methodology that allows researchers to go beyond the simplistic dichotomy of significance testing and extract more insight from new findings. Using standard summary statistics, AnCred assesses the credibility of significant and non-significant findings on the basis of their evidential weight, and in the context of existing knowledge. The outcome is expressed in quantitative terms of direct relevance to the substantive research question, providing greater protection against misinterpretation. Worked examples are given to illustrate how AnCred extracts additional insight from the outcome of typical research study designs. Its ability to cast light on the use of p-values, the interpretation of non-significant findings and the so-called 'replication crisis' is also discussed. PMID- 29410819 TI - Preparation of polypropylene/Mg-Al layered double hydroxides nanocomposites through wet pan-milling: non-isothermal crystallization behaviour. AB - Differential scanning calorimeter was used to extensively investigate the non isothermal crystallization of polypropylene (PP)/layered double hydroxides (LDHs) nanocomposites prepared through wet solid-state shear milling. The corresponding crystallization kinetics was further investigated by using Ozawa, modified Avrami and combined Avrami-Ozawa method, respectively. The results showed that the Ozawa method could not well describe the crystallization kinetics of pure PP and its nanocomposites. Comparatively, the modified Avrami method as well as the combined Avrami-Ozawa method gives the satisfactory results. Under the effect of pan milling, the produced LDH nano intercalated/exfoliated particles exhibit the inhibitive effect on the PP nucleation but more remarkable promotion effect on the spherulite growth, leading to enhancement in the overall crystallization rate. This is reflected in increase of the calculated fold surface free energy sigmae and also the supercooling degree DeltaT required for crystallization nucleation. In addition, the polarized optical microscopy observation also verifies the higher spherulite growth rate of PP/LDHs nanocomposites than that of pure PP. PMID- 29410820 TI - How water availability influences morphological and biomechanical properties in the one-leaf plant Monophyllaea horsfieldii. AB - In its natural habitat, the one-leaf plant Monophyllaea horsfieldii (Gesneriaceae) shows striking postural changes and dramatic loss of stability in response to intermittently occurring droughts. As the morphological, anatomical and biomechanical bases of these alterations are as yet unclear, we examined the influence of varying water contents on M. horsfieldii by conducting dehydration rehydration experiments together with various imaging techniques as well as quantitative bending and turgor pressure measurements. As long as only moderate water stress was applied, gradual reductions in hypocotyl diameters and structural bending moduli during dehydration were almost always rapidly recovered in acropetal direction upon rehydration. On an anatomical scale, M. horsfieldii hypocotyls revealed substantial water stress-induced alterations in parenchymatous tissues, whereas the cell form and structure of epidermal and vascular tissues hardly changed. In summary, the functional morphology and biomechanics of M. horsfieldii hypocotyls directly correlated with water status alterations and associated physiological parameters (i.e. turgor pressure). Moreover, M. horsfieldii showed only little passive structural-functional adaptations to dehydration in comparison with poikilohydrous Ramonda myconi. PMID- 29410821 TI - Emission characteristics and vapour/particulate phase distributions of PCDD/F in a hazardous waste incinerator under transient conditions. AB - Polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (PCDD/F) emission characteristics and vapour/particulate phase partitions under three continued operation conditions, i.e. shut-down, start-up and after start-up, were investigated by sampling stack gas. The results indicated that the PCDD/F emission levels were 0.40-18.03 ng I-TEQ Nm-3, much higher than the annual monitoring level (0.016 ng I-TEQ Nm-3). Additionally, the PCDD/F emission levels in start-up were higher than the other two conditions. Furthermore, the PCDD/F congener profiles differed markedly between shut-down and start-up, and the chlorination degree of PCDD/F increased in shut-down and decreased evidently in start-up. Moreover, PCDD/F vapour/particulate phase distributions varied significantly under three transient conditions. The PCDD/F vapour phase proportion decreased as the shut-down process continued, then increased as the start-up process proceeded, finally more than 98% of the PCDD/F congeners were distributed in the vapour phase after start-up. The correlations between log(Cv/Cs ) versus [Formula: see text] of each PCDD/F congener in stack gas were disorganized in shut-down, and trend to a linear distribution after start-up. Besides, polychlorinated biphenyl emissions show behaviour similar to that of PCDD/F, and the lower chlorinated congeners have a stronger relationship with 2,3,7,8-PCDD/Fs, such as M1CB and D2CB. PMID- 29410822 TI - Frequency doubling by active in vivo motility of mechanosensory neurons in the mosquito ear. AB - Across vertebrate and invertebrate species, nonlinear active mechanisms are employed to increase the sensitivity and acuity of hearing. In mosquitoes, the antennal hearing organs are known to use active force feedback to enhance auditory acuity to female generated sounds. This sophisticated form of signal processing involves active nonlinear events that are proposed to rely on the motile properties of mechanoreceptor neurons. The fundamental physical mechanism for active auditory mechanics is theorized to rely on a synchronization of motile neurons, with a characteristic frequency doubling of the force generated by an ensemble of motile mechanoreceptors. There is however no direct biomechanical evidence at the mechanoreceptor level, hindering further understanding of the fundamental mechanisms of sensitive hearing. Here, using in situ and in vivo atomic force microscopy, we measure and characterize the mechanical response of mechanosensory neuron units during forced oscillations of the hearing organ. Mechanoreceptor responses exhibit the hallmark of nonlinear feedback for force generation, with movements at twice the stimulus frequency, associated with auditory amplification. Simultaneous electrophysiological recordings exhibit similar response features, notably a frequency doubling of the firing rate. This evidence points to the nature of the mechanism, whereby active hearing in mosquitoes emerges from the double-frequency response of the auditory neurons. These results open up the opportunity to directly investigate active cellular mechanics in auditory systems, and they also reveal a pathway to study the nanoscale biomechanics and its dynamics of cells beyond the sense of hearing. PMID- 29410823 TI - Ghosts of infections past: using archival samples to understand a century of monkeypox virus prevalence among host communities across space and time. AB - Infectious diseases that originate from multiple wildlife hosts can be complex and problematic to manage. A full understanding is further limited by large temporal and spatial gaps in sampling. However, these limitations can be overcome, in part, by using historical samples, such as those derived from museum collections. Here, we screened over 1000 museum specimens collected over the past 120 years to examine the historical distribution and prevalence of monkeypox virus (MPXV) in five species of African rope squirrel (Funisciurus sp.) collected across Central Africa. We found evidence of MPXV infections in host species as early as 1899, half a century earlier than the first recognized case of MPXV in 1958, supporting the suggestion that historic pox-like outbreaks in humans and non-human primates may have been caused by MPXV rather than smallpox as originally thought. MPX viral DNA was found in 93 of 1038 (9.0%) specimens from five Funisciurus species (F. anerythrus, F. carruthersi, F. congicus, F. lemniscatus and F. pyrropus), of which F. carruthersi and pyrropus had not previously been identified as potential MPXV hosts. We additionally documented relative prevalence rates of infection in museum specimens of Funisciurus and examined the spatial and temporal distribution of MPXV in these potential host species across nearly a hundred years (1899-1993). PMID- 29410824 TI - Substrate specificity of healthy human sera IgG antibodies with peroxidase and oxydoreductase activities. AB - We have carried out an analysis of whether blood IgG antibodies can protect humans from oxidative stress by oxidizing different harmful compounds. A somewhat unexpected result was obtained. We show here for the first time that healthy human sera IgGs with the peroxidase (in the presence H2O2) efficiently oxidize different compounds: 3,3'-diaminobenzidine (1; DAB), 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (2; ATBS), o phenylenediamine (3; OPD), homovanillic acid (4; HVA), alpha-naphthol (5), 5 aminosalicylic acid (6; 5-ASA) and 3-amino-9-ethylcarbazole (7; AEC), but seven of nine IgG preparations from different volunteers cannot oxidize p-hydroquinone (8: pHQ). The average apparent kcat values in the H2O2-dependent oxidation by human IgGs decreased in the following order (min-1): ATBS (73.7) >= DAB (66.3) > AEC (38.0) >= HVA (19.8) >= alpha-naphthol (8.6) > OPD (0.62) >= 5-ASA (0.48) > pHQ (0.24). In the absence of H2O2 (oxidoreductase activity), the relative average kcat values decreased in the following order (min-1): DAB (52.1) >= ATBS (50.5) > OPD (0.25). The peroxidase average activity of human IgGs was higher than the oxidoreductase one: 1.2-, 1.5- and 2.5-fold for DAB, ATBS and OPD, respectively. It should be assumed that antibodies can oxidize in addition to the large number of other different compounds analysed by us. As a whole, the specific wide repertoire of polyclonal human IgGs oxidizing various compounds could play an important role in protecting humans from oxidative stress and serve as an additional natural system destroying H2O2 and different toxic mutagenic and carcinogenic compounds. PMID- 29410825 TI - A functional evaluation of feeding in the surgeonfish Ctenochaetus striatus: the role of soft tissues. AB - Ctenochaetus striatus is one of the most abundant surgeonfishes on Indo-Pacific coral reefs, yet the functional role and feeding ecology of this species remain unclear. This species is reported to possess a rigid structure in its palate that is used for scraping, but some authors have reported that this element is comprised of soft tissue. To resolve the nature and role of this structure in the feeding ecology of C. striatus we examined evidence from anatomical observations, scanning electron microscopy, histology, X-ray micro-computed tomography scanning, high-speed video and field observations. We found that C. striatus from the Great Barrier Reef possess a retention plate (RP) on their palates immediately posterior to the premaxillary teeth which is soft, covered in a thin veneer of keratin with a papillate surface. This RP appears to be used during feeding, but does not appear to be responsible for the removal of material, which is achieved primarily by a fast closure of the lower jaw. We infer that the RP acts primarily as a 'dustpan', in a 'dustpan and brush' feeding mechanism, to facilitate the collection of particulate material from algal turfs. PMID- 29410827 TI - Eco-dyeing with biocolourant based on natural compounds. AB - Biomass pigments have been regarded as promising alternatives to conventional synthetic dyestuffs for the development of sustainable and clean dyeing. This investigation focused on in situ dyeing of fabrics with biopigments derived from tea polyphenols via non-enzymatic browning reaction. The average particle size of dyed residual liquor with natural tea polyphenol was 717.0 nm (ranging from 615.5 to 811.2 nm), and the Integ value of dyed wool fabrics was the greatest compared to those of counterparts. In addition, the Integ values of dyed fabrics with residual liquor were much bigger than those with the first reaction solutions when dyed by identical dyeing liquor. As a result, the dyeing process could be carried out many times because the concentration of the residual liquor was relatively superior. All dyed fabrics acquired admirable rubbing as well as washing fastness, and the relevant dyeing mechanism has been analysed in the paper. PMID- 29410826 TI - Silver nanoparticles as a medical device in healthcare settings: a five-step approach for candidate screening of coating agents. AB - Silver nanoparticle-based antimicrobials can promote a long lasting bactericidal effect without detrimental toxic side effects. However, there is not a clear and complete protocol to define and relate the properties of the particles (size, shape, surface charge, ionic content) with their specific activity. In this paper, we propose an effective multi-step approach for the identification of a 'purpose-specific active applicability window' to maximize the antimicrobial activity of medical devices containing silver nanoparticles (Ag NPs) (such as surface coaters), minimizing any consequent risk for human health (safety by design strategy). The antimicrobial activity and the cellular toxicity of four types of Ag NPs, differing in their coating composition and concentration have been quantified. Through the implementation of flow-field flow fractionation, Ag NPs have been characterized in terms of metal release, size and shape. The particles are fractionated in the process while being left unmodified, allowing for the identification of biological particle-specific contribution. Toxicity and inflammatory response in vitro have been assessed on human skin models, while antimicrobial activity has been monitored with both non-pathogenic and pathogenic Escherichia coli. The main benefit associated with such approach is the comprehensive assessment of the maximal effectiveness of candidate nanomaterials, while simultaneously indexing their properties against their safety. PMID- 29410828 TI - Twinning ferroelasticity facilitated by the partial flipping of phenyl rings in single crystals of 4,4'-dicarboxydiphenyl ether. AB - Evidence of ferroelasticity in a non-planar organic molecular crystal is presented for 4,4'-dicarboxydiphenyl ether. Ferroelasticity has been demonstrated by the micro- and macroscopic mechanical characterization of single crystals, including recording of a full hysteretic stress-strain cycle. The underlying mechanism involves the partial flipping of phenyl rings. PMID- 29410829 TI - Efficiency enhancement of Cu2ZnSnS4 solar cells via surface treatment engineering. AB - Pure-sulphide Cu2ZnSnS4 (CZTS) thin film solar cells were prepared by a low-cost, non-toxic and high-throughput method based on the thermal decomposition and reaction of sol-gel precursor solution, followed by a high temperature sulfurization process in sulphur atmosphere, which usually gave rise to the unexpected Cu-poor and Zn-rich phase after sulfurization. In order to remove the formation of detrimental secondary phases, e.g. ZnS, a novel method with hydrochloric acid solution treatment to the CZTS absorber layer surface was employed. By using this method, a competitive power conversion efficiency as high as 4.73% was obtained, which is a factor of 4.8 of that of the control CZTS solar cell without surface treatment. This presents a customized process for CZTS photovoltaic technologies that is more environmentally friendly and considerably less toxic than the widely used KCN etching approach. PMID- 29410830 TI - Nanostructure selenium compounds as pseudocapacitive electrodes for high performance asymmetric supercapacitor. AB - The electrochemical performance of an energy conversion and storage device like the supercapacitor mainly depends on the microstructure and morphology of the electrodes. In this paper, to improve the capacitance performance of the supercapacitor, the all-pseudocapacitive electrodes of lamella-like Bi18SeO29/BiSe as the negative electrode and flower-like Co0.85Se nanosheets as the positive electrode are synthesized by using a facile low-temperature one-step hydrothermal method. The microstructures and morphology of the electrode materials are carefully characterized, and the capacitance performances are also tested. The Bi18SeO29/BiSe and Co0.85Se have high specific capacitance (471.3 F g 1 and 255 F g-1 at 0.5 A g-1), high conductivity, outstanding cycling stability, as well as good rate capability. The assembled asymmetric supercapacitor completely based on the pseudocapacitive electrodes exhibits outstanding cycling stability (about 93% capacitance retention after 5000 cycles). Moreover, the devices exhibit high energy density of 24.2 Wh kg-1 at a power density of 871.2 W kg-1 in the voltage window of 0-1.6 V with 2 M KOH solution. PMID- 29410831 TI - Signatures of natural selection in abiotic stress-responsive genes of Solanum chilense. AB - Environmental conditions are strong selective forces, which may influence adaptation and speciation. The wild tomato species Solanum chilense, native to South America, is exposed to a range of abiotic stress factors. To identify signatures of natural selection and local adaptation, we analysed 16 genes involved in the abiotic stress response and compared the results to a set of reference genes in 23 populations across the entire species range. The abiotic stress-responsive genes are characterized by elevated nonsynonymous nucleotide diversity and divergence. We detected signatures of positive selection in several abiotic stress-responsive genes on both the population and species levels. Local adaptation to abiotic stresses is particularly apparent at the boundary of the species distribution in populations from coastal low-altitude and mountainous high-altitude regions. PMID- 29410832 TI - Prediction of cholesterol ratios within a Korean population. AB - Cholesterol ratios (total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-c) and triglyceride (TG)/HDL-c) have been suggested as better indicators to predict various clinical features such as insulin resistance and heart disease. Therefore, we aimed to build a single nucleotide polymorphism (SNP) set to predict constitutional lipid metabolism. The genotype data of 7795 samples were obtained from the Korea Association Resource. Among the total of 7795 samples, 7016 subjects were used to perform 10-fold cross-validation. We selected the SNPs that showed significance constantly throughout all 10 cross-validation sets; another 779 samples were used as the final validation set. After performing the 10-fold cross-validation, the six SNPs (rs4420638 (APOC1), rs12421652 (BUD13), rs17411126 (LPL), rs6589566 (ZPR1), rs16940212 (LOC101928635) and rs10852765 (ABCA8)) were finally selected for predicting cholesterol ratios. The weighted genetic risk scores (wGRS) were calculated based on the regression slopes of the six selected SNPs. Our results showed upward trends of wGRS for both the TC/HDL-c and TG/HDL-c ratios within the 10-fold cross-validation. Similarly, the wGRS of the six SNPs also showed upward trends in analyses using the SNP selection set and final validation set. The selected six SNPs can be used to explain both the TC/HDL-c and TG/HDL-c ratios. Our results may be useful for the prospective predictions of cholesterol-related diseases. PMID- 29410833 TI - The contextual separation of lateral white line patterns in chameleons. AB - While many animals display different colour patterns that signal different messages, some species use various tactics to separate between colour and pattern displays. The common chameleon (Chamaeleo chamaeleon) is capable of rapidly changing and separating among displays of colour patterns and ornaments. We used chameleons to study the contextual role of separation among colour and pattern displays. Specifically, we studied the predominant white badge, which is composed of multiple parts, during different seasons and in different social contexts. We hypothesized that the badge contains important information about the sender and, therefore, would be present during important social contexts. We carried out a series of trials to document the presence/absence of the badge and found that the badge is individually specific and reflects body size. We also revealed that the badge remained fixed throughout other body colour changes, but was replaced by other colour patterns during mating behaviour. During social encounters, additional dark patches delineating the badge appeared, presumably amplifying its signal. Thus, we suggest that the badge constitutes an important feature in intraspecific communication, and is possibly employed to display quality. However, the replacement of the badge by other displays during courtship suggests that during important social events like mating, chameleons transmit exclusive information that is not broadcast by the badge. Our findings demonstrate the importance of separation between colour patterns, and the alternative use of intraspecific colour patterns for specific social contexts in chameleons. PMID- 29410834 TI - Effect of curvature on wetting and dewetting of proboscises of butterflies and moths. AB - Proboscises of butterflies are modelled as elliptical hollow fibres that can be bent into coils. The behaviour of coating films on such complex fibres is investigated to explain the remarkable ability of these insects to control liquid collection after dipping the proboscis into a flower or pressing and mopping it over a food source. By using a thin-film approximation with the air-liquid interface positioned almost parallel to the fibre surface, capillary pressure was estimated from the profile of the fibre surfaces supporting the films. The film is always unstable and the proboscis shape and movements have adaptive value in collecting fluid: coiling and bending of proboscises of butterflies and moths facilitate fluid collection. Some practical applications of this effect are discussed with regard to fibre engineering. PMID- 29410835 TI - In vitro evaluation of the effect of C-4 substitution on methylation of 7,8 dihydroxycoumarin: metabolic profile and catalytic kinetics. AB - Daphnetin (7,8-dihydroxycoumarin (7,8-DHC)) and its C-4 derivatives have multiple pharmacological activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Methylation plays important roles in catechol elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of human catechol-O-methyltransferase (COMT) remain unclear. This study was aimed at exploring the structure-methylation relationship of daphnetin and its C-4 derivatives, including 4-methyl, 4-phenyl and 4-acetic acid daphnetin. It was achieved by identifying the methylated products generated and by careful characterization of the reaction kinetics. These catechols are selectively metabolized to the corresponding 8-O-methyl conjugates, and this regioselective methylation could be elucidated by flexible docking, in which all the 8-OH groups of these catechols are much closer than the 7-OH groups to catalytic residue LYS144 and methyl donor AdoMet. The results of the kinetic analyses revealed that the Clint values of the compounds could be strongly affected by the C-4 substitutions, which could be partially explained by the electronic effects of the C-4 substituents and the coordination modes of 7,8- dihydroxycoumarins in the active site of COMT. These findings provide helpful guidance for further structural modification of 7,8-DHCs to improve metabolic stability. PMID- 29410836 TI - Field energetics and lung function in wild bottlenose dolphins, Tursiops truncatus, in Sarasota Bay Florida. AB - We measured respiratory flow rates, and expired O2 in 32 (2-34 years, body mass [Mb] range: 73-291 kg) common bottlenose dolphins (Tursiops truncatus) during voluntary breaths on land or in water (between 2014 and 2017). The data were used to measure the resting O2 consumption rate ([Formula: see text], range: 0.76-9.45 ml O2 min-1 kg-1) and tidal volume (VT, range: 2.2-10.4 l) during rest. For adult dolphins, the resting VT, but not [Formula: see text], correlated with body mass (Mb, range: 141-291 kg) with an allometric mass-exponent of 0.41. These data suggest that the mass-specific VT of larger dolphins decreases considerably more than that of terrestrial mammals (mass-exponent: 1.03). The average resting [Formula: see text] was similar to previously published metabolic measurements from the same species. Our data indicate that the resting metabolic rate for a 150 kg dolphin would be 3.9 ml O2 min-1 kg-1, and the metabolic rate for active animals, assuming a multiplier of 3-6, would range from 11.7 to 23.4 ml O2 min-1 kg-1.?absbreak Our measurements provide novel data for resting energy use and respiratory physiology in wild cetaceans, which may have significant value for conservation efforts and for understanding the bioenergetic requirements of this species. PMID- 29410837 TI - Trans-heteroclinic bifurcation: a novel type of catastrophic shift. AB - Global and local bifurcations are extremely important since they govern the transitions between different qualitative regimes in dynamical systems. These transitions or tipping points, which are ubiquitous in nature, can be smooth or catastrophic. Smooth transitions involve a continuous change in the steady state of the system until the bifurcation value is crossed, giving place to a second order phase transition. Catastrophic transitions involve a discontinuity of the steady state at the bifurcation value, giving place to first-order phase transitions. Examples of catastrophic shifts can be found in ecosystems, climate, economic or social systems. Here we report a new type of global bifurcation responsible for a catastrophic shift. This bifurcation, identified in a family of quasi-species equations and named as trans-heteroclinic bifurcation, involves an exchange of stability between two distant and heteroclinically connected fixed points. Since the two fixed points interchange the stability without colliding, a catastrophic shift takes place. We provide an exhaustive description of this new bifurcation, also detailing the structure of the replication-mutation matrix of the quasi-species equation giving place to this bifurcation. A perturbation analysis is provided around the bifurcation value. At this value the heteroclinic connection is replaced by a line of fixed points in the quasi-species model. But it is shown that, if the replication-mutation matrix satisfies suitable conditions, then, under a small perturbation, the exchange of heteroclinic connections is preserved, except on a tiny range around the bifurcation value whose size is of the order of magnitude of the perturbation. The results presented here can help to understand better novel mechanisms behind catastrophic shifts and contribute to a finer identification of such transitions in theoretical models in evolutionary biology and other dynamical systems. PMID- 29410838 TI - Enhanced light-harvesting by plasmonic hollow gold nanospheres for photovoltaic performance. AB - A 'sandwich'-structured TiO2NR/HGN/CdS photoanode was successfully fabricated by the electrophoretic deposition of hollow gold nanospheres (HGNs) on the surface of TiO2 nanorods (NRs). The HGNs presented a wide surface plasmon resonance character in the visible region from 540 to 630 nm, and further acted as the scatter elements and light energy 'antennas' to trap the local-field light near the TiO2NR/CdS layer, resulting in the increase of the light harvesting. An outstanding enhancement in the photochemical behaviour of TiO2NR/HGN/CdS photoanodes was attained by the contribution of HGNs in increasing the light absorption and the number of electron-hole pairs of photosensitive semiconductors. The optimized photochemical performance of TiO2NR/HGN/CdS photoanodes by using plasmonic HGNs demonstrated their potential application in energy conversion devices. PMID- 29410839 TI - Achilles tendon moment arm in humans is not affected by inversion/eversion of the foot: a short report. AB - The triceps surae primarily acts as plantarflexor of the ankle joint. However, the group also causes inversion and eversion at the subtalar joint. Despite this, the Achilles tendon moment arm is generally measured without considering the potential influence of inversion/eversion of the foot during plantarflexion. This study investigated the effect of foot inversion and eversion on the plantarflexion Achilles tendon moment arm. Achilles tendon moment arms were determined using the centre-of-rotation method in magnetic resonance images of the left ankle of 11 participants. The foot was positioned at 15 degrees dorsiflexion, 0 degrees or 15 degrees plantarflexion using a Styrofoam wedge. In each of these positions, the foot was either 10 degrees inverted, neutral or 10 degrees everted using an additional Styrofoam wedge. Achilles tendon moment arm in neutral foot position was 47.93 +/- 4.54 mm and did not differ significantly when the foot was positioned in 10 degrees inversion and 10 degrees eversion. Hence, inversion/eversion position of the foot may not considerably affect the length of the Achilles tendon moment arm. This information could be useful in musculoskeletal models of the human lower leg and foot and when estimating Achilles tendon forces during plantarflexion with the foot positioned in inversion or eversion. PMID- 29410840 TI - Novel ternary nanocomposites of MWCNTs/PANI/MoS2: preparation, characterization and enhanced electrochemical capacitance. AB - In this work, nanoflower-like MoS2 grown on the surface of multi-walled carbon nanotubes (MWCNTs)/polyaniline (PANI) nano-stem is synthesized via a facile in situ polymerization and hydrothermal method. Such a novel hierarchical structure commendably promotes the contact of PANI and electrolyte for faradaic energy storage. In the meanwhile, the double-layer capacitance of MoS2 is effectively used. The morphology and chemical composition of the as-prepared samples are characterized by scanning and transmission electron microscopies, X-ray diffraction and Fourier transform infrared spectra. The electrochemical performance of the samples is evaluated by cyclic voltammogram and galvanostatic charge-discharge measurements. It is found that the specific capacitance of the obtained MWCNTs/PANI/MoS2 hybrid is 542.56 F g-1 at a current density of 0.5 A g 1. Furthermore, the MWCNTs/PANI/MoS2 hybrid also exhibits good rate capability (62.5% capacity retention at 10 A g-1) and excellent cycling stability (73.71% capacitance retention) over 3000 cycles. PMID- 29410841 TI - Study of mixed mode fracture toughness and fracture trajectories in gypsum interlayers in corrosive environment. AB - Based on the engineering background of water dissolving mining for hydrocarbon storage in multi-laminated salt stratum, the mixed mode fracture toughness and fracture trajectory of gypsum interlayers soaked in half-saturated brine at various temperatures (20 degrees C, 50 degrees C and 80 degrees C) were studied by using CSNBD (centrally straight-notched Brazilian disc) specimens with required inclination angles (0 degrees , 7 degrees , 15 degrees , 22 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , 90 degrees ) and SEM (scanning electron microscopy). The results showed: (i) The fracture load of gypsum specimens first decreased then increased with increasing inclination angle, due to the effect of friction coefficient. When soaked in brine, the fracture toughness of gypsum specimens gradually decreased with increasing brine temperature. (ii) When soaked in brine, the crystal boundaries of gypsum separated and became clearer, and the boundaries became more open between the crystals with increasing brine temperature. Besides, tensile micro-cracks appeared on the gypsum crystals when soaked in 50 degrees C brine, and the intensity of tensile cracks became more severe when soaking in 80 degrees C brine. (iii) The experimental fracture envelopes derived from the conventional fracture criteria and lay outside these conventional criteria. The experimental fracture envelopes were dependent on the brine temperature and gradually expanded outward as brine temperature increases. (iv) The size of FPZ (fracture process zone) was greatly dependent on the damage degree of materials and gradually increased with increase of brine temperature. The study has important implication for the control of shape and size of salt cavern. PMID- 29410842 TI - Lack of multiple paternity in the oceanodromous tiger shark (Galeocerdo cuvier). AB - Multiple paternity has been documented as a reproductive strategy in both viviparous and ovoviviparous elasmobranchs, leading to the assumption that multiple mating may be ubiquitous in these fishes. However, with the majority of studies conducted on coastal and nearshore elasmobranchs that often form mating aggregations, parallel studies on pelagic, semi-solitary species are lacking. The tiger shark (Galeocerdo cuvier) is a large pelagic shark that has an aplacental viviparous reproductive mode which is unique among the carcharhinids. A total of 112 pups from four pregnant sharks were genotyped at nine microsatellite loci to assess the possibility of multiple paternity or polyandrous behaviour by female tiger sharks. Only a single pup provided evidence of possible multiple paternity, but with only seven of the nine loci amplifying for this individual, results were inconclusive. In summary, it appears that the tiger sharks sampled in this study were genetically monogamous. These findings may have implications for the genetic diversity and future sustainability of this population. PMID- 29410843 TI - Structure of semiconducting versus fast-ion conducting glasses in the Ag-Ge-Se system. AB - The transition from a semiconductor to a fast-ion conductor with increasing silver content along the Ag x (Ge0.25Se0.75)(100-x) tie line (0<=x<=25) was investigated on multiple length scales by employing a combination of electric force microscopy, X-ray diffraction, and neutron diffraction. The microscopy results show separation into silver-rich and silver-poor phases, where the Ag rich phase percolates at the onset of fast-ion conductivity. The method of neutron diffraction with Ag isotope substitution was applied to the x=5 and x=25 compositions, and the results indicate an evolution in structure of the Ag-rich phase with change of composition. The Ag-Se nearest-neighbours are distributed about a distance of 2.64(1) A, and the Ag-Se coordination number increases from 2.6(3) at x=5 to 3.3(2) at x=25. For x=25, the measured Ag-Ag partial pair distribution function gives 1.9(2) Ag-Ag nearest-neighbours at a distance of 3.02(2) A. The results show breakage of Se-Se homopolar bonds as silver is added to the Ge0.25Se0.75 base glass, and the limit of glass-formation at x?28 coincides with an elimination of these bonds. A model is proposed for tracking the breakage of Se-Se homopolar bonds as silver is added to the base glass. PMID- 29410845 TI - Grazer responses to variable macroalgal resource conditions facilitate habitat structuring. AB - Consumer responses to altered resource conditions can vary depending on dietary preference, resource characteristics and secondary resource features such as shelter. These can have cascading effects, especially if the consumed resource impacts on overall ecological functioning. In this study, we assessed the dietary composition of grazer communities following seasonal changes in the characteristics of their staple food-source (macroalgae). This was conducted in the living stromatolite pools growing along the coast of South Africa. Stable isotope mixing models suggested that following macroalgal bleaching in summer, metazoan consumers shifted their diet from predominantly macroalgae to a generalist composition. This has important implications for the integrity of the stromatolite matrix and its layered deposition. Where previously in winter stromatolite microalgae comprised a minor component of metazoan consumer diets, in summer, following a change in the resource conditions of macroalgae, microalgae featured more prominently in grazer diets. This seasonal grazing pressure on stromatolite-related resources probably promotes the pattern of annual layering observed in the stromatolite accretion. It also demonstrates a mechanism whereby grazer dietary shifts following a change in their preferred food resource can affect the ecosystem structure of their environment, specifically the stromatolite layering process which responds to microalgal growth or grazing conditions. PMID- 29410846 TI - Using sensitivity analysis to identify key factors for the propagation of a plant epidemic. AB - Identifying the key factors underlying the spread of a disease is an essential but challenging prerequisite to design management strategies. To tackle this issue, we propose an approach based on sensitivity analyses of a spatiotemporal stochastic model simulating the spread of a plant epidemic. This work is motivated by the spread of sharka, caused by plum pox virus, in a real landscape. We first carried out a broad-range sensitivity analysis, ignoring any prior information on six epidemiological parameters, to assess their intrinsic influence on model behaviour. A second analysis benefited from the available knowledge on sharka epidemiology and was thus restricted to more realistic values. The broad-range analysis revealed that the mean duration of the latent period is the most influential parameter of the model, whereas the sharka specific analysis uncovered the strong impact of the connectivity of the first infected orchard. In addition to demonstrating the interest of sensitivity analyses for a stochastic model, this study highlights the impact of variation ranges of target parameters on the outcome of a sensitivity analysis. With regard to sharka management, our results suggest that sharka surveillance may benefit from paying closer attention to highly connected patches whose infection could trigger serious epidemics. PMID- 29410847 TI - Unifying models of dialect spread and extinction using surface tension dynamics. AB - We provide a unified mathematical explanation of two classical forms of spatial linguistic spread. The wave model describes the radiation of linguistic change outwards from a central focus. Changes can also jump between population centres in a process known as hierarchical diffusion. It has recently been proposed that the spatial evolution of dialects can be understood using surface tension at linguistic boundaries. Here we show that the inclusion of long-range interactions in the surface tension model generates both wave-like spread, and hierarchical diffusion, and that it is surface tension that is the dominant effect in deciding the stable distribution of dialect patterns. We generalize the model to allow population mixing which can induce shrinkage of linguistic domains, or destroy dialect regions from within. PMID- 29410844 TI - Recent advances in multidimensional ultrafast spectroscopy. AB - Multidimensional ultrafast spectroscopies are one of the premier tools to investigate condensed phase dynamics of biological, chemical and functional nanomaterial systems. As they reach maturity, the variety of frequency domains that can be explored has vastly increased, with experimental techniques capable of correlating excitation and emission frequencies from the terahertz through to the ultraviolet. Some of the most recent innovations also include extreme cross peak spectroscopies that directly correlate the dynamics of electronic and vibrational states. This review article summarizes the key technological advances that have permitted these recent advances, and the insights gained from new multidimensional spectroscopic probes. PMID- 29410848 TI - An overlooked plant-parakeet mutualism counteracts human overharvesting on an endangered tree. AB - The exponential growth of the human population often causes the overexploitation of resources and disruption of ecological interactions. Here, we propose that the antagonist effect of humans on exploited species might be alleviated with the advent of a second predator species. We focused on the complex interactions between an endangered conifer (Araucaria araucana) and two seed exploiters: the Austral parakeet (Enicognathus ferrugineus) and human seed collectors. We tested the importance of partial seed consumption by parakeets as an escape from human seed harvesting. Although parakeets frequently ate whole seeds, a substantial proportion of the seeds found under trees were only partially eaten and avoided by human seed collectors. These seeds germinated at a similar proportion but faster than intact seeds under laboratory conditions. Our results revealed an overlooked mutualism between parakeets and an endangered tree. Incomplete seed eating by parakeets, plus selection against these eaten seeds by humans, may enhance regeneration possibilities for this conifer species subject to human seed collection, turning the scale of the antagonism-mutualism continuum to the mutualistic side. In this context, parakeets might be providing an important service in those forests subject to human harvesting by allowing a fraction of seeds to escape human predation. PMID- 29410849 TI - A prediction model of compressor with variable-geometry diffuser based on elliptic equation and partial least squares. AB - To achieve a much more extensive intake air flow range of the diesel engine, a variable-geometry compressor (VGC) is introduced into a turbocharged diesel engine. However, due to the variable diffuser vane angle (DVA), the prediction for the performance of the VGC becomes more difficult than for a normal compressor. In the present study, a prediction model comprising an elliptical equation and a PLS (partial least-squares) model was proposed to predict the performance of the VGC. The speed lines of the pressure ratio map and the efficiency map were fitted with the elliptical equation, and the coefficients of the elliptical equation were introduced into the PLS model to build the polynomial relationship between the coefficients and the relative speed, the DVA. Further, the maximal order of the polynomial was investigated in detail to reduce the number of sub-coefficients and achieve acceptable fit accuracy simultaneously. The prediction model was validated with sample data and in order to present the superiority of compressor performance prediction, the prediction results of this model were compared with those of the look-up table and back propagation neural networks (BPNNs). The validation and comparison results show that the prediction accuracy of the new developed model is acceptable, and this model is much more suitable than the look-up table and the BPNN methods under the same condition in VGC performance prediction. Moreover, the new developed prediction model provides a novel and effective prediction solution for the VGC and can be used to improve the accuracy of the thermodynamic model for turbocharged diesel engines in the future. PMID- 29410850 TI - Amorphous mesoporous GeO x anode for Na-ion batteries with high capacity and long lifespan. AB - It is recently demonstrated that amorphous Ge anode shows higher reversible Na ion storage capacity (590 mA h g-1) than crystallized Ge anode (369 mA h g-1). Here, amorphous GeO x anode is prepared by a simple wet-chemistry reduction route at room temperature. The obtained amorphous GeO x shows a porous hierarchical architecture, accompanied with a Brunauer-Emmett-Teller surface area of 159 m2 g 1 and an average pore diameter of 14 nm. This unique structure enables the GeO x anode to enhance the Na-ion/electron diffusion rate, and buffer the volume change. As anode for Na-ion battery, high reversible capacity over 400 mA h g-1, fine rate capability with a capacity of 200 mA h g-1 maintained at 3.0 A g-1 and long-term cycling stability with 270 mA h g-1 even over 1000 cycles at 1.0 A g-1 are obtained. PMID- 29410851 TI - Rapid and sensitive biomarker detection using molecular imprinting polymer hydrogel and surface-enhanced Raman scattering. AB - Biomarkers are important biochemical indicators, which could be used for identification, early diagnosis and monitoring of diseases during the course of treatment. However, biomarker diagnosis has some shortcomings such as requiring a large amount of samples, long test time and high cost, which seriously influences the correctness and timely treatment to patients. Here, a relatively fast and efficient plasmonic hot spot-localized surface imprinting of Ag spheres using biomarker template immobilization and hydrogel copolymerization is described. The technique takes a fine control of the imprinting process at the nanometre scale and provides a biosensor with high sensitivity. Proof of the opinion is established by detection of biomarker using surface-enhanced Raman scattering (SERS) spectroscopy. This work represents a valuable step towards SERS with biomarkers for cost-saving and time-saving diagnostic assay. It is expected that the new surface imprinted hydrogel plasmonic material can drive possibilities in advancing application of biomarkers in plasmonic biosensors. PMID- 29410852 TI - A 'reader' unit of the chemical computer. AB - We suggest the main principals and functional units of the parallel chemical computer, namely, (i) a generator (which is a network of coupled oscillators) of oscillatory dynamic modes, (ii) a unit which is able to recognize these modes (a 'reader') and (iii) a decision-making unit, which analyses the current mode, compares it with the external signal and sends a command to the mode generator to switch it to the other dynamical regime. Three main methods of the functioning of the reader unit are suggested and tested computationally: (a) the polychronization method, which explores the differences between the phases of the generator oscillators; (b) the amplitude method which detects clusters of the generator and (c) the resonance method which is based on the resonances between the frequencies of the generator modes and the internal frequencies of the damped oscillations of the reader cells. Pro and contra of these methods have been analysed. PMID- 29410853 TI - Controlling population of the molecular rotational state and the alignment theoretically by tailored femtosecond laser pulse. AB - We demonstrate that the population of the molecular rotational state through a stimulated impulsive Raman excitation can be controlled by tailoring the femtosecond laser pulse with a V-style phase modulation. The results show that, by precisely manipulating the modulation parameters, both the odd and even populations of the molecular rotational state can be completely suppressed or reconstructed. Meanwhile, the relative excitation between the odd and even populations can be obtained. Finally, we show that field-free molecular alignment can be controlled due to the modulation of the molecular rotational state populations. PMID- 29410854 TI - Synthesis of gypsogenin derivatives with capabilities to arrest cell cycle and induce apoptosis in human cancer cells. AB - Thirty-two gypsogenin derivatives were synthesized and screened for their cytotoxic activities. Their structures were established using IR, 1H NMR, 13C NMR, and LC-MS spectroscopic data. In MTT assays nearly all the compounds displayed good cytotoxicity in the low MUM range for several human tumour cell lines (A549, LOVO, SKOV3 and HepG2). Low IC50 values were obtained especially for the carboxamides 7a-7j, for an oxime derivative 3 and a (2,4 dinitrophenyl)hydrazono derivative 4. In particular, the IC50 values of compounds 4 (IC50 = 2.97 +/- 1.13 uMU) and 7 g (IC50 = 3.59 +/- 2.04 uMU) against LOVO cells were found to be much lower than those of the other derivatives and parent compound. These compounds were submitted to an extensive biological testing and proved compounds 4 and 7 g to act mainly by an arrest of the tumour cells in the S phase of the cell cycle. In addition, compounds 4 and 7 g triggered the apoptotic pathway in cancer cells, showing high apoptosis ratios. PMID- 29410855 TI - Modelling science trustworthiness under publish or perish pressure. AB - Scientific publication is immensely important to the scientific endeavour. There is, however, concern that rewarding scientists chiefly on publication creates a perverse incentive, allowing careless and fraudulent conduct to thrive, compounded by the predisposition of top-tier journals towards novel, positive findings rather than investigations confirming null hypothesis. This potentially compounds a reproducibility crisis in several fields, and risks undermining science and public trust in scientific findings. To date, there has been comparatively little modelling on factors that influence science trustworthiness, despite the importance of quantifying the problem. We present a simple phenomenological model with cohorts of diligent, careless and unethical scientists, with funding allocated by published outputs. This analysis suggests that trustworthiness of published science in a given field is influenced by false positive rate, and pressures for positive results. We find decreasing available funding has negative consequences for resulting trustworthiness, and examine strategies to combat propagation of irreproducible science. PMID- 29410856 TI - A glimpse of an ancient agricultural ecosystem based on remains of micromammals in the Byzantine Negev Desert. AB - It is widely believed that Byzantine agriculture in the Negev Desert (fourth to seventh century Common Era; CE), with widespread construction of terraces and dams, altered local landscapes. However, no direct evidence in archaeological sites yet exists to test this assumption. We uncovered large amounts of small mammalian remains (rodents and insectivores) within agricultural installations built near fields, providing a new line of evidence for reconstructing anthropogenic impact on local habitats. Abandonment layers furnished high abundances of remains, whereas much smaller numbers were retrieved from the period of human use of the structures. Digestion marks are present in low frequencies (20% of long bones and teeth), with a light degree of impact, which indicate the role of owls (e.g. Tyto alba) as the principal means of accumulation. The most common taxa-gerbils (Gerbillus spp.) and jirds (Meriones spp.)-occur in nearly equal frequencies, which do not correspond with any modern Negev communities, where gerbils predominate in sandy low-precipitation environments and jirds in loessial, higher-precipitation ones. Although low-level climate change cannot be ruled out, the results suggest that Byzantine agriculture allowed jirds to colonize sandy anthropogenic habitats with other gerbilids and commensal mice and rats. PMID- 29410857 TI - Using text analysis to quantify the similarity and evolution of scientific disciplines. AB - We use an information-theoretic measure of linguistic similarity to investigate the organization and evolution of scientific fields. An analysis of almost 20 M papers from the past three decades reveals that the linguistic similarity is related but different from experts and citation-based classifications, leading to an improved view on the organization of science. A temporal analysis of the similarity of fields shows that some fields (e.g. computer science) are becoming increasingly central, but that on average the similarity between pairs of disciplines has not changed in the last decades. This suggests that tendencies of convergence (e.g. multi-disciplinarity) and divergence (e.g. specialization) of disciplines are in balance. PMID- 29410858 TI - A new stem group echinoid from the Triassic of China leads to a revised macroevolutionary history of echinoids during the end-Permian mass extinction. AB - The Permian-Triassic bottleneck has long been thought to have drastically altered the course of echinoid evolution, with the extinction of the entire echinoid stem group having taken place during the end-Permian mass extinction. The Early Triassic fossil record of echinoids is, however, sparse, and new fossils are paving the way for a revised interpretation of the evolutionary history of echinoids during the Permian-Triassic crisis and Early Mesozoic. A new species of echinoid, Yunnanechinus luopingensis n. sp. recovered from the Middle Triassic (Anisian) Luoping Biota fossil Lagerstatte of South China, displays morphologies that are not characteristic of the echinoid crown group. We have used phylogenetic analyses to further demonstrate that Yunnanechinus is not a member of the echinoid crown group. Thus a clade of stem group echinoids survived into the Middle Triassic, enduring the global crisis that characterized the end Permian and Early Triassic. Therefore, stem group echinoids did not go extinct during the Palaeozoic, as previously thought, and appear to have coexisted with the echinoid crown group for at least 23 million years. Stem group echinoids thus exhibited the Lazarus effect during the latest Permian and Early Triassic, while crown group echinoids did not. PMID- 29410859 TI - Metal and polymer-mediated synthesis of porous crystalline hydroxyapatite nanocomposites for environmental remediation. AB - This study was focused on the preparation of metal and polymer-mediated porous crystalline hydroxyapatite (HAp) nanocomposites for environmental applications. Four different nano HAp systems were synthesized, namely, microwave irradiated HAp (M1), Zn doped HAp (M2), Mg-doped HAp (M3) and sodium alginate incorporated HAp (M4), and characterized using X-ray diffraction (XRD), Fourier transform infra-red spectroscopy, scanning electron microscopy, transmission electron microscopy, atomic force microscopy, nuclear magnetic resonance (NMR), X-ray fluorescence, thermogravimetric analysis and Brunauer-Emmett-Teller (BET) analyses. Systems M1-M4 showed morphologies similar to coral shapes, polymer-like interconnected structures, sponges and feathery mycelium assemblies. Using XRD, selected area electron diffraction patterns and 1H and 31P CP/MAS solid-state NMR studies, crystallinity variation was observed from highest to lowest in the order of M4 > M1 > M3 > M2. Surface area estimates using BET isotherm reflected the highest surface area for M3, and M1 > M2 > M4. Four systems of M1-M4 were used as potential adsorbent materials for the removal of metal containing azo dye from aqueous system. Adsorption data were correlated to Freundlich and Langmuir isotherm models. According to the results, the highest capacity of 212.8 mg g-1 was exhibited by M4 having mycelium like morphology with alginate groups. This study highlights the possibility of developing HAp nanocomposites for the effective removal of dye contaminants in the environment. PMID- 29410860 TI - Parallel diversifications of Cremastosperma and Mosannona (Annonaceae), tropical rainforest trees tracking Neogene upheaval of South America. AB - Much of the immense present day biological diversity of Neotropical rainforests originated from the Miocene onwards, a period of geological and ecological upheaval in South America. We assess the impact of the Andean orogeny, drainage of Lake Pebas and closure of the Panama isthmus on two clades of tropical trees (Cremastosperma, ca 31 spp.; and Mosannona, ca 14 spp.; both Annonaceae). Phylogenetic inference revealed similar patterns of geographically restricted clades and molecular dating showed diversifications in the different areas occurred in parallel, with timing consistent with Andean vicariance and Central American geodispersal. Ecological niche modelling approaches show phylogenetically conserved niche differentiation, particularly within Cremastosperma. Niche similarity and recent common ancestry of Amazon and Guianan Mosannona species contrast with dissimilar niches and more distant ancestry of Amazon, Venezuelan and Guianan species of Cremastosperma, suggesting that this element of the similar patterns of disjunct distributions in the two genera is instead a biogeographic parallelism, with differing origins. The results provide further independent evidence for the importance of the Andean orogeny, the drainage of Lake Pebas, and the formation of links between South and Central America in the evolutionary history of Neotropical lowland rainforest trees. PMID- 29410861 TI - Testing social learning of anti-predator responses in juvenile jackdaws: the importance of accounting for levels of agitation. AB - Social learning is often assumed to help young animals respond appropriately to potential threats in the environment. We brought wild, juvenile jackdaws briefly into captivity to test whether short exposures to conspecific vocalizations are sufficient to promote anti-predator learning. Individuals were presented with one of two models-a stuffed fox representing a genuine threat, or a toy elephant simulating a novel predator. Following an initial baseline presentation, juveniles were trained by pairing models with either adult mobbing calls, indicating danger, or contact calls suggesting no danger. In a final test phase with no playbacks, birds appeared to have habituated to the elephant, regardless of training, but responses to the fox remained high throughout, suggesting juveniles already recognized it as a predator before the experiment began. Training with mobbing calls did seem to generate elevated escape responses, but this was likely to be a carry-over effect of the playback in the previous trial. Overall, we found little evidence for social learning. Instead, individuals' responses were mainly driven by their level of agitation immediately preceding each presentation. These results highlight the importance of accounting for agitation in studies of anti-predator learning, and whenever animals are held in captivity for short periods. PMID- 29410862 TI - Specialized specialists and the narrow niche fallacy: a tale of scale-feeding fishes. AB - Although rare within the context of 30 000 species of extant fishes, scale feeding as an ecological strategy has evolved repeatedly across the teleost tree of life. Scale-feeding (lepidophagous) fishes are diverse in terms of their ecology, behaviour, and specialized morphologies for grazing on scales and mucus of sympatric species. Despite this diversity, the underlying ontogenetic changes in functional and biomechanical properties of associated feeding morphologies in lepidophagous fishes are less understood. We examined the ontogeny of feeding mechanics in two evolutionary lineages of scale-feeding fishes: Roeboides, a characin, and Catoprion, a piranha. We compare these two scale-feeding taxa with their nearest, non-lepidophagous taxa to identify traits held in common among scale-feeding fishes. We use a combination of micro-computed tomography scanning and iodine staining to measure biomechanical predictors of feeding behaviour such as tooth shape, jaw lever mechanics and jaw musculature. We recover a stark contrast between the feeding morphology of scale-feeding and non-scale-feeding taxa, with lepidophagous fishes displaying some paedomorphic characters through to adulthood. Few traits are shared between lepidophagous characins and piranhas, except for their highly-modified, stout dentition. Given such variability in development, morphology and behaviour, ecological diversity within lepidophagous fishes has been underestimated. PMID- 29410863 TI - Ebola could be eradicated through voluntary vaccination. AB - Ebola virus disease (EVD) is a severe infection with an extremely high fatality rate spread through direct contact with body fluids. A promising Ebola vaccine (rVSV-ZEBOV) may soon become universally available. We constructed a game theoretic model of Ebola incorporating individual decisions to vaccinate. We found that if a population adopts selfishly optimal vaccination strategies, then the population vaccination coverage falls negligibly short of the herd immunity level. We concluded that eradication of Ebola is feasible if voluntary vaccination programmes are coupled with focused public education efforts. We conducted uncertainty and sensitivity analysis to demonstrate that our findings do not depend on the choice of the epidemiological model parameters. PMID- 29410864 TI - Diversity of management strategies in Mesoamerican turkeys: archaeological, isotopic and genetic evidence. AB - The turkey (Meleagris gallopavo) represents one of the few domestic animals of the New World. While current research points to distinct domestication centres in the Southwest USA and Mesoamerica, several questions regarding the number of progenitor populations, and the timing and intensity of turkey husbandry remain unanswered. This study applied ancient mitochondrial DNA and stable isotope (delta13C, delta15N) analysis to 55 archaeological turkey remains from Mexico to investigate pre-contact turkey exploitation in Mesoamerica. Three different (sub)species of turkeys were identified in the archaeological record (M. g. mexicana, M. g. gallopavo and M. ocellata), indicating the exploitation of diverse local populations, as well as the trade of captively reared birds into the Maya area. No evidence of shared maternal haplotypes was observed between Mesoamerica and the Southwest USA, in contrast with archaeological evidence for trade of other domestic products. Isotopic analysis indicates a range of feeding behaviours in ancient Mesoamerican turkeys, including wild foraging, human provisioning and mixed feeding ecologies. This variability in turkey diet decreases through time, with archaeological, genetic and isotopic evidence all pointing to the intensification of domestic turkey management and husbandry, culminating in the Postclassic period. PMID- 29410865 TI - Preparation of hollow iron/halloysite nanocomposites with enhanced electromagnetic performances. AB - Nanostructures loaded on halloysite nanotubes (HNTs) have attracted global interest, because the nanotubular HNTs could extend the range of their potential applications. In this study, we fabricated a novel nanocomposite with hollow iron nanoparticles loaded on the surface of HNTs. The structure of the iron nanoparticles can be adjusted by ageing time. Owing to the increased remnant magnetization and coercivity values, the nanocomposites loaded with hollow iron nanoparticles showed better electromagnetic performance than that with solid iron nanoparticles. This study opens a new pathway to fabricate halloysite nanotubular nanocomposites that may gain applications in the catalytic degradation of organic pollutants and electromagnetic wave absorption. PMID- 29410866 TI - Adsorption of hexavalent chromium by polyacrylonitrile-based porous carbon from aqueous solution. AB - Owing to the unique microporous structure and high specific surface area, porous carbon could act as a good carrier for functional materials. In this paper, polyacrylonitrile (PAN)-based porous carbon materials (PPC-0.6-600, PPC-0.8-600, PPC-0.6-800 and PPC-0.8-800) were prepared by heating KOH at 600 degrees C and 800oC for the removal of Cr(VI) from aqueous solution. The adsorbent was characterized by the techniques of Fourier transform infrared spectroscopy (FT IR), elementary analysis, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and N2 adsorption techniques. The results showed that the adsorption capacity increased with decreasing pH value of the initial solution. The adsorption capacity of Cr(VI) on PPC-0.8-800 was much greater than that on other materials, and maximum adsorption capacity were calculated to be 374.90 mg g-1. Moreover, PPC-0.8-800 had superior recyclability for the removal of Cr(VI) from wastewater, about 82% of its initial adsorption capacity was retained even after five cycles. The result of kinetic simulation showed that the adsorption of Cr(VI) on the PAN-based porous carbon could be described by pseudo-second-order kinetics. The adsorption process was the ionic interaction between protonated amine groups of PPC and HCrO4- ions. PMID- 29410867 TI - Intra-tropical movements as a beneficial strategy for Palearctic migratory birds. AB - Migratory birds often move significantly within their non-breeding range before returning to breed. It remains unresolved under which circumstances individuals relocate, whether movement patterns are consistent between populations and to what degree the individuals benefit from the intra-tropical movement (ITM). We tracked adult great reed warblers Acrocephalus arundinaceus from a central and a southeastern European breeding population, which either stay at a single non breeding site, or show ITM, i.e. move to a second site. We related ITM to the normalized difference vegetation index (NDVI) describing vegetation conditions and probably reflecting food abundance for these insectivorous birds. Three quarters of birds showed ITM across the non-breeding range. We found no difference in range values and mean values of NDVI between the single non breeding sites of stationary birds and the two sites of moving birds. The vegetation conditions were better at the second sites compared to the first sites during the period which moving birds spent at the first sites. Vegetation conditions further deteriorated at the first sites during the period the moving birds resided at their second sites. Our study provides evidence that birds probably benefit from improved conditions after ITM compared to the conditions at the sites from where they departed. PMID- 29410868 TI - The flashing Brownian ratchet and Parrondo's paradox. AB - A Brownian ratchet is a one-dimensional diffusion process that drifts towards a minimum of a periodic asymmetric sawtooth potential. A flashing Brownian ratchet is a process that alternates between two regimes, a one-dimensional Brownian motion and a Brownian ratchet, producing directed motion. These processes have been of interest to physicists and biologists for nearly 25 years. The flashing Brownian ratchet is the process that motivated Parrondo's paradox, in which two fair games of chance, when alternated, produce a winning game. Parrondo's games are relatively simple, being discrete in time and space. The flashing Brownian ratchet is rather more complicated. We show how one can study the latter process numerically using a random walk approximation. PMID- 29410869 TI - The chronology of reindeer hunting on Norway's highest ice patches. AB - The melting of perennial ice patches globally is uncovering a fragile record of alpine activity, especially hunting and the use of mountain passes. When rescued by systematic fieldwork (glacial archaeology), this evidence opens an unprecedented window on the chronology of high-elevation activity. Recent research in Jotunheimen and surrounding mountain areas of Norway has recovered over 2000 finds-many associated with reindeer hunting (e.g. arrows). We report the radiocarbon dates of 153 objects and use a kernel density estimation (KDE) method to determine the distribution of dated events from ca 4000 BCE to the present. Interpreted in light of shifting environmental, preservation and socio economic factors, these new data show counterintuitive trends in the intensity of reindeer hunting and other high-elevation activity. Cold temperatures may sometimes have kept humans from Norway's highest elevations, as expected based on accessibility, exposure and reindeer distributions. In times of increasing demand for mountain resources, however, activity probably continued in the face of adverse or variable climatic conditions. The use of KDE modelling makes it possible to observe this patterning without the spurious effects of noise introduced by the discrete nature of the finds and the radiocarbon calibration process. PMID- 29410870 TI - Hierarchical VOOH hollow spheres for symmetrical and asymmetrical supercapacitor devices. AB - Hierarchical VOOH hollow spheres with low crystallinity composed of nanoparticles were prepared by a facile and template-free method, which involved a precipitation of precursor microspheres in aqueous solution at room temperature and subsequent hydrothermal reaction. Quasi-solid-state symmetric and asymmetric supercapacitor (SSC and ASC) devices were fabricated using hierarchical VOOH hollow spheres as the electrodes, and the electrochemical properties of the VOOH//VOOH SSC device and the VOOH//AC ASC device were studied by cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) and electrochemical impedance spectroscopy (EIS). Results demonstrated that the electrochemical performance of the VOOH//AC ASC device was better than that of the VOOH//VOOH SSC device. After 3000 cycles, the specific capacitance of the VOOH//AC ASC device retains 83% of the initial capacitance, while the VOOH//VOOH SSC device retains only 7.7%. Findings in this work proved that hierarchical VOOH hollow spheres could be a promising candidate as an ideal electrode material for supercapacitor devices. PMID- 29410871 TI - The evolution and anatomy of the horse manus with an emphasis on digit reduction. AB - We revisit digit reduction in the horse and propose that all five digits are partially present in the modern adult forelimb. Osteological descriptions of selected tetradactyl, tridactyl and monodactyl equids demonstrate the evolution of the forelimb. Histological, osteological and palaeontological evidence suggest that the Equus distal forelimb is more complex than traditionally conceived. The current understanding is that the horse distal forelimb consists of one complete digit (III) and two reduced splint metacarpals (II and IV). Metacarpals II and IV each exhibit a ventral ridge, which we suggest represents the undifferentiated digits I and V. These ridges are present in the tridactyl Mesohippus, but are absent in the tetradactyl Hyracotherium. The carpal articulations of the five metacarpals match those of pentadactyl taxa. Distally, the frog, a V-shaped structure on the ventral hoof represents digits II and IV, and the wings and hoof cartilages of the distal phalanx are digits I and V. We relate this revised interpretation of the Equus forelimb to Laetoli footprints, and suggest the Hipparion side impressions are created from the hooves of I and V, rather than from II and IV. We show shades of pentadactyly within the Equus manus. PMID- 29410872 TI - Visual processing: conscious until proven otherwise. AB - Unconscious perception, or perception without awareness, describes a situation where an observer's behaviour is influenced by a stimulus of which they have no phenomenal awareness. Perception without awareness is often claimed on the basis of a difference in thresholds for tasks that do and do not require awareness, for example, detecting the stimulus (requiring awareness) and making accurate judgements about the stimulus (based on unconscious processing). Although a difference in thresholds would be expected if perceptual evidence were processed without awareness, such a difference does not necessitate that this is actually occurring: a difference in thresholds can also arise from response bias, or through task differences. Here we ask instead whether the pattern of performance could be obtained if the observer were aware of the evidence used in making their decisions. A backwards masking paradigm was designed using digits as target stimuli, with difficulty controlled by the time between target and mask. Performance was measured over three tasks: detection, graphic discrimination and semantic discrimination. Despite finding significant differences in thresholds measured using proportion correct, and in observer sensitivity, modelling suggests that these differences were not the result of perception without awareness. That is, the observer was not relying solely on unconscious information to make decisions. PMID- 29410873 TI - Trophic interactions between larger crocodylians and giant tortoises on Aldabra Atoll, Western Indian Ocean, during the Late Pleistocene. AB - Today, the UNESCO World Heritage Site of Aldabra Atoll is home to about 100 000 giant tortoises, Aldabrachelys gigantea, whose fossil record goes back to the Late Pleistocene. New Late Pleistocene fossils (age ca. 90-125 000 years) from the atoll revealed some appendicular bones and numerous shell fragments of giant tortoises and cranial and postcranial elements of crocodylians. Several tortoise bones show circular holes, pits and scratch marks that are interpreted as bite marks of crocodylians. The presence of a Late Pleistocene crocodylian species, Aldabrachampsus dilophus, has been known for some time, but the recently found crocodylian remains presented herein are distinctly larger than those previously described. This indicates the presence of at least some larger crocodylians, either of the same or of a different species, on the atoll. These larger crocodylians, likely the apex predators in the Aldabra ecosystem at the time, were well capable of inflicting damage on even very large giant tortoises. We thus propose an extinct predator-prey interaction between crocodylians and giant tortoises during the Late Pleistocene, when both groups were living sympatrically on Aldabra, and we discuss scenarios for the crocodylians directly attacking the tortoises or scavenging on recently deceased animals. PMID- 29410874 TI - Differential influences of allometry, phylogeny and environment on the rostral shape diversity of extinct South American notoungulates. AB - Understanding the mechanisms responsible for phenotypic diversification, and the associated underlying constraints and ecological factors represents a central issue in evolutionary biology. Mammals present a wide variety of sizes and shapes, and are characterized by a high number of morphological convergences that are hypothesized to reflect similar environmental pressures. Extinct South American notoungulates evolved in isolation from northern mammalian faunas in highly disparate environments. They present a wide array of skeletal phenotypes and convergences, such as ever-growing dentition. Here, we focused on the origins of the rostral diversity of notoungulates by quantifying the shape of 26 genera using three-dimensional geometric morphometric analysis. We tested the influence of allometry and phylogeny on rostral shape and evaluated rates of evolutionary change in the different clades. We found strong allometric and phylogenetic signals concerning the rostral shape of notoungulates. Despite convergent forms, we observed a diffuse diversification of rostral shape, with no significant evidence of influence by large-scaled environmental variation. This contrasts with the increase in dental crown height that occurred in four late-diverging families in response to similar environmental pressures. These results illustrate the importance of considering both biological components and evolutionary rates to better understand some aspects of phenotypic diversity. PMID- 29410875 TI - Energyscapes and prey fields shape a North Atlantic seabird wintering hotspot under climate change. AB - There is an urgent need for a better understanding of animal migratory ecology under the influence of climate change. Most current analyses require long-term monitoring of populations on the move, and shorter-term approaches are needed. Here, we analysed the ecological drivers of seabird migration within the framework of the energyscape concept, which we defined as the variations in the energy requirements of an organism across geographical space as a function of environmental conditions. We compared the winter location of seabirds with their modelled energy requirements and prey fields throughout the North Atlantic. Across six winters, we tracked the migration of 94 little auks (Alle alle), a key sentinel Arctic species, between their East Greenland breeding site and wintering areas off Newfoundland. Winter energyscapes were modelled with Niche MapperTM, a mechanistic tool which takes into account local climate and bird ecophysiology. Subsequently, we used a resource selection function to explain seabird distributions through modelled energyscapes and winter surface distribution of one of their main prey, Calanus finmarchicus. Finally, future energyscapes were calculated according to IPCC climate change scenarios. We found that little auks targeted areas with high prey densities and moderately elevated energyscapes. Predicted energyscapes for 2050 and 2095 showed a decrease in winter energy requirements under the high emission scenario, which may be beneficial if prey availability is maintained. Overall, our study demonstrates the great potential of the energyscape concept for the study of animal spatial ecology, in particular in the context of global change. PMID- 29410876 TI - Experimental evidence of a pathogen invasion threshold. AB - Host density thresholds to pathogen invasion separate regions of parameter space corresponding to endemic and disease-free states. The host density threshold is a central concept in theoretical epidemiology and a common target of human and wildlife disease control programmes, but there is mixed evidence supporting the existence of thresholds, especially in wildlife populations or for pathogens with complex transmission modes (e.g. environmental transmission). Here, we demonstrate the existence of a host density threshold for an environmentally transmitted pathogen by combining an epidemiological model with a microcosm experiment. Experimental epidemics consisted of replicate populations of naive crustacean zooplankton (Daphnia dentifera) hosts across a range of host densities (20-640 hosts l-1) that were exposed to an environmentally transmitted fungal pathogen (Metschnikowia bicuspidata). Epidemiological model simulations, parametrized independently of the experiment, qualitatively predicted experimental pathogen invasion thresholds. Variability in parameter estimates did not strongly influence outcomes, though systematic changes to key parameters have the potential to shift pathogen invasion thresholds. In summary, we provide one of the first clear experimental demonstrations of pathogen invasion thresholds in a replicated experimental system, and provide evidence that such thresholds may be predictable using independently constructed epidemiological models. PMID- 29410877 TI - Reversing functional extinction of mammals prompts a rethink of paradigms about seed fate in arid Australia. AB - Functional extinction of once abundant species has frequently preceded understanding of their ecological roles. Consequently, our understanding of ecosystems is prone to shifting baselines because it often relies on observations made on depauperate species assemblages. In Australian deserts, current paradigms are that ants are the dominant granivores, mammals are unimportant seed predators and that myrmecochory in many Australian shrubs is an adaptation to increase dispersal distance and direct seeds to favourable germination sites. Here, we ask whether these paradigms could be artefacts of mammal extinction. We take advantage of a predator-proof reserve within which locally extinct native mammals have been reintroduced to compare seed removal by ants and mammals. Using foraging trays that selectively excluded mammals and ants we show that a reintroduced mammal, the woylie (Bettongia penicillata) was at least as important as ants in the removal of seeds of two shrub species (Dodonaea viscosa and Acacia ligulata). Our results provide evidence that the dominance of ants as granivores and current understanding of the adaptive benefit of myrmecochory in arid Australia may be artefacts of the functional extinction of mammals. Our study shows how reversing functional extinction can provide the opportunity to rethink contemporary understanding of ecological processes. PMID- 29410878 TI - Responses to auxin signals: an operating principle for dynamical sensitivity yet high resilience. AB - Plants depend on the signalling of the phytohormone auxin for their development and for responding to environmental perturbations. The associated biomolecular signalling network involves a negative feedback on Aux/IAA proteins which mediate the influence of auxin (the signal) on the auxin response factor (ARF) transcription factors (the drivers of the response). To probe the role of this feedback, we consider alternative in silico signalling networks implementing different operating principles. By a comparative analysis, we find that the presence of a negative feedback allows the system to have a far larger sensitivity in its dynamical response to auxin and that this sensitivity does not prevent the system from being highly resilient. Given this insight, we build a new biomolecular signalling model for quantitatively describing such Aux/IAA and ARF responses. PMID- 29410879 TI - Skipping on uneven ground: trailing leg adjustments simplify control and enhance robustness. AB - It is known that humans intentionally choose skipping in special situations, e.g. when descending stairs or when moving in environments with lower gravity than on Earth. Although those situations involve uneven locomotion, the dynamics of human skipping on uneven ground have not yet been addressed. To find the reasons that may motivate this gait, we combined experimental data on humans with numerical simulations on a bipedal spring-loaded inverted pendulum model (BSLIP). To drive the model, the following parameters were estimated from nine subjects skipping across a single drop in ground level: leg lengths at touchdown, leg stiffness of both legs, aperture angle between legs, trailing leg angle at touchdown (leg landing first after flight phase), and trailing leg retraction speed. We found that leg adjustments in humans occur mostly in the trailing leg (low to moderate leg retraction during swing phase, reduced trailing leg stiffness, and flatter trailing leg angle at lowered touchdown). When transferring these leg adjustments to the BSLIP model, the capacity of the model to cope with sudden-drop perturbations increased. PMID- 29410880 TI - Magnonic band spectrum of spin waves in an elliptical helix. AB - We show that the spin-wave spectrum in an elliptical helix has a band character. The size of the first band gap calculated using the perturbation theory is shown to scale as square root of the eccentricity. Curved magnonic waveguides of the kind considered here could be used as structural elements of future three dimensional magnonic architectures. PMID- 29410881 TI - Onwards and upwards: towards a sustainable future. PMID- 29410882 TI - Years of life lost due to bladder cancer among the inhabitants of Poland in the years 2000 to 2014. AB - Introduction: The aim of the study is to evaluate the number of years of life lost in inhabitants of Poland due to bladder cancer (BC), identify trends of the mortality and calculate the pace of change which has happened over the period of the first fifteen years of the 21st century. Material and methods: The study material was a database including 44,283 death certificates of Polish inhabitants who died due to bladder cancer in the period 2000-2014. The number of years of life lost were calculated using the SEYLL indices: SEYLLp (Standard Expected Years of Life Lost per living person) and SEYLLd (Standard Expected Years of Life Lost per death). Results: The crude death rates (CDR) index increased from 10.79 per 100,000 males in 2000 to 14.30 in 2014 (Annual Percentage Change [APC] = 2.1%, p <0.05). In women, the group value of the CDR index increased from 2.50 in 2000 to 3.83 in 2014 (APC = 2.9%, p <0.05). The standardized death rates (SDR) index fell from 23.27 in 2000 to 22.48 in 2014 (APC = -0.1%, p >0.05) in men, but rose from 3.54 in 2000 to 3.83 in 2014 (APC = 0.4%, p <0.05) in women.The SEYLLp index (per 100,000 population) due to bladder cancer in Poland increased from 202.9 in 2000 to 243.4 in 2014 (APC = 1.3%, p <0.05) in men, and from 40.4 in 2000 to 60.1 in 2014 (APC = 2.7%, p <0.05) in women. Conclusions: Despite the prolongation of patient life, as shown by the SEYLLd factor, Polish patients still lose too many years of life due to BC than compared to United States patients. PMID- 29410883 TI - The impact of the 2005 International Society of Urological Pathology Gleason grading consensus on active surveillance for prostate cancer. AB - Introduction: Current treatment plans for localized prostate carcinoma (PC) are based on core needle biopsies (CNB) classified using the Gleason score (GS). Recently, many institutions have started using the latest version of International Society of Urological Pathology (ISUP) guideline revision from 2014 for PC grading. Interestingly, this adoption is occurring without first understanding whether the 2005 ISUP revisions had a positive clinical impact. CNB based GS may underestimate tumor aggressiveness and, therefore, critically impact patient eligibility for active surveillance (AS). The 2005 ISUP recommendations bore a significant impact on the grading of Gleason 6 and 7 PCs - a range that is meaningful for AS. The objective of this study was to compare the concordance between GS in CNB and radical prostatectomy (RP) before and after the 2005 ISUP guideline revisions, with an emphasis on its clinical impact on AS. Material and methods: This was a single-center, prospective observational study. CNB were performed in a standardized manner. GS of CNB and RP specimens were compared across three time periods: 1999-2005 (pre-revision), 2006-2007 (transitional period), and 2008-2015 (post-revision). AS is usually employed in patients with GS 6 or GS 7 PC. Thus, we therefore focused on the analysis of patients with CNBs of GS <=7. Results: Between 1999 and 2015, 380 men with GS <=7 PC underwent RP at our institution (median age: 62y; median PSA: 5.8 ng/ml). Of these, 231 CNB specimens were classified as GS <=6, while 149 were GS 7.46% (pre-revision), 43% (transitional), and 54% (post-revision) of CNB with original scores <=6 were later upgraded in corresponding RP specimens (p <0.001). Conclusions: The 2005 ISUP GS revisions did not lower the rates of GS upgrades in RP specimens when compared to corresponding initial CNBs. Thus, these revisions did not improve AS selection. Future advances in molecular diagnostics may provide additional valuable information that facilitates patient enrollment in AS programs. PMID- 29410884 TI - Relationship between immunohistochemical staining extent of CD47 and histopathologic features of bladder tumor. AB - Introduction: It has been shown that CD47 is an important diagnostic and prognostic marker in many cancer types. However, the relationship between CD47 and bladder tumor stage has not been shown in previous studies. To the best of our knowledge, this is the first study investigating the association of CD47 with stages of bladder cancer. Material and methods: Surgical specimens of 175 patients were included in the study. The CD47 staining assessment was performed in the following categories; none, focal, moderate and diffuse. The statistics of the study were tested using t-test and analysis of variance. Results: We demonstrated much less CD47 staining extent in Ta tumor pathology compared to T1 and T1+T2+T3+T4 tumor pathology (p = 0.034 and p = 0.016, respectively). We also showed that the average value of CD47 staining extent with CIS+ was significantly higher compared to CIS- among NMIBC (p = 0.0248). However, no significant differences in CD47 staining pattern were observed in the following study groups: high vs. low-grade tumors in non-muscle invasive bladder cancer (NMIBC); MIBC (T2 T4) vs. NMIBC; lymph node involvement (N1-N3) vs. non-lymph node involvement (N0) in MIBC (T2-T4). Conclusions: Our study demonstrated that CD47 might have a critical role in the progression of Ta to T1 stage. Furthermore, we showed that CD47 is highly expressed in CIS+ NMIBC compared to CIS- NMIBC. Thus, differentiating stages with the help of this new potential marker may help clinicians treat bladder tumors better. Future studies to determine the role of CD47 on pathophysiology, diagnosis and prognosis of bladder tumor are warranted. PMID- 29410885 TI - Simultaneous or staged surgery in patients with kidney tumors and concomitant cardiac disease. AB - Introduction: To evaluate outcomes of simultaneous and staged surgery in patients with kidney tumors and concomitant cardiac disease. Material and methods: Between October 2001 and October 2015, fifteen patients (Group 1) underwent simultaneous surgery and fourteen patients (Group 2) underwent staged surgery. 89.7% were males (26/29), and the mean age was 60.8 +/-1.16 years. Locally advanced cancers (Stage III) were registered in the two groups in 11 vs. 3 patients (p = 0.016) and localized (Stage I) disease in 2 vs. 10 (p = 0.007), respectively. 18 patients (62%) were operated for coronary heart disease, while 10 patients (35%) underwent surgery for valvular heart disease. Nephrectomy was performed in 14rs 5 patients respectively (p = 0.003) while partial nephrectomy in 1rs 7 patients (p = 0.005). Results: In the two groups, the 30-day mortality was 13% (2 cases) and 7% (1 case), p = 1.0, and major hospital complications were observed in 3 (20%) and 2 (14%) cases, respectively, p = 0.53. The median follow-up in Group 1 and Group 2 was 87 months (range, 23.3 to 146.8 months) and 39 months (range, 3.9 to 98 months), respectively, p = 0.001. Three-year overall survival was 73.3 +/ 11.4% (95% CI 50.5-96.1) and 77.9 +/-11.3%, respectively, p = 0.70, and three year disease-free survival was 83.9 +/-10.4% and 75.0 +/-21.7%, respectively, p = 0.91. Conclusions: Simultaneous and staged surgery for kidney tumors and concomitant cardiac disease are feasible procedures. Patients with advanced tumors and complicated disease course can benefit from early intervention and consequently a simultaneous approach can be a preferred option for them. For localized renal tumors, staged surgery should be used. PMID- 29410886 TI - The role of hemostatic agents in preventing complications in laparoscopic partial nephrectomy. AB - Introduction: Nephron-sparing surgery is currently the treatment of choice for renal cell carcinoma stage T1a. During the past years, several hemostatic agents (HA) have been developed in order to reduce surgical complications. We present the results of our series and the impact of the use of HA in the prevention of surgical complications in laparoscopic partial nephrectomies (LPNs). Material and methods: We retrospectively analyzed all LPN performed in our center from 2005 to 2012. A total of 77 patients were included for analysis. Patients were divided into two groups: Group A (no use of HA) and Group B (use of HA). HA used included gelatin matrix thrombin (FloSeal) and oxidized regenerated cellulose (Surgicel). Demographics, perioperative variables, and complications were analyzed with a special interest in postoperative bleeding and urinary leakage. Results: Median age was 57.17 years old (+/-12.1), 72.7% were male, most common comorbidities were hypertension (33.8%) and diabetes mellitus (18.2%). All patients had one solitary tumor, and 87% had a tumor <=4 cm. Renal cell carcinoma was found in 79.2% of cases, and 78.7% were stage pT1a. and were used in 36 cases (46.8%). No differences were found in demographics, perioperative variables, and complications between groups. No conversions to open surgery or perioperative mortality were reported. Conclusions: We conclude that in our series the use of a hemostatic agent did not offer benefit in reducing the complication rate over sutures over a bolster. PMID- 29410887 TI - Life expectancy calculation in urology: Are we equitably treating older patients? AB - Introduction: The aim of our study was to determine the contemporary practice in the utilization of life expectancy (LE) calculations among urological clinicians. Material and methods: Members of the Irish Society of Urology (ISU) and the British Association of Urological Surgeons (BAUS) completed a questionnaire on LE utilization in urological practice. Results: The survey was delivered to 1251 clinicians and the response rate was 17% (n = 208/1251). The majority (61%, n = 127) of urologists were aware of methods available for estimated LE calculation.Seventy-one percent (n = 148) had never utilized LE analysis in clinical practice and 81% (n = 170) routinely used 'eyeballing' (empiric prediction) for estimating LE. Life expectancy tables were utilized infrequently (12%, n = 25) in making the decision for treatment in the setting of multi disciplinary meetings. Conclusions: LE is poorly integrated into treatment decision-making; not only for the management of urological patients but also in the multidisciplinary setting. Further education and awareness regarding the importance of LE is vital. PMID- 29410888 TI - What should be done to minimize pain without any sexual function deterioration in transrectal prostate biopsy? AB - Introduction: The aim of this study was to find an ideal method for the application of a transrectal ultrasound-guided prostate biopsy (TRUS-Bx) without deteriorating patient comfort. Material and methods: TRUS-Bx was applied in a total of 93 patients. Taking the application method into consideration, these patients were divided into three groups, each consisting of 31 patients. Methods applied for pain control in the different groups were compared (groups 1, 2 and 3). Age, prostate specific antigen (PSA), prostate volume, cancer detection rate, re-biopsy consent ratio, complication rates, visual analog scale (VAS), and International Index of Erectile Function (IIEF-5) scores were compared among the groups. Results: Age, PSA, prostate volume, cancer detection rate, and fever complication rate were not statistically different between the three groups. However, a statistically significant difference was detected among the groups for the VAS measured during and after TRUS-Bx, re-biopsy consent ratio, and hematuria (p <0.001, p <0.001, p <0.001, and p = 0.027, respectively). There was no detected difference in pre-operation IIEF-5 scores, but the difference in IIEF-5 scores in the first month after the operation was significant (p = 0.116, p = 0.024, respectively). Conclusions: Anal dilatation after the application of intrarectal topical anesthetic to provide anesthesia during TRUS-Bx and giving lidocaine hydrochloride with epinephrine for periprostatic nerve blockage (PNB) is a successful and effective method to maintain patient comfort, especially as it relates to pain control and sexual function. Anal dilatation seems to minimize any pain that may occur due to probe transition, and adding epinephrine as a vasopressor to the anesthetic agent chosen during the operation will be rather helpful for hemostasis control and pain that results from the needle. PMID- 29410889 TI - Minimally invasive partial cystectomy with bilateral vesico-ureteric junction resection and reimplantation for a large paraganglioma involving urinary bladder trigone. AB - Paragangliomas are neuroendocrine tumours of extra adrenal origin. Although it occurs rarely in the genitourinary system, urinary bladder is the most common site. Its diagnosis warrants complete surgical excision with lymphadenectomy in case of metastatic disease. The functional status of this tumour makes intraoperative handling challenging. Surgical resection necessitates minimal manipulation of tumour thereby mitigating intraoperative physiological jeopardy. We report the possibility of minimally invasive partial cystectomy with bilateral vesico-ureteric junction resection and re-implantation for non-malignant paraganglioma involving the bladder trigone. Intraoperative frozen section is deemed necessary to achieve tumour free margin status. PMID- 29410890 TI - A comparative assessment of irrigation and drainage characteristics for commercially available urethral catheters. AB - Introduction: We aimed to investigate irrigation and drainage characteristics of commercially available urethral catheters and determined which catheter offers the best flow characteristics. Material and methods: Twelve different commercially available urethral catheters from three companies (BardTM, RuschTM and DoverTM) were investigated to compare their irrigation and drainage properties. Irrigation port, drainage port and overall cross-sectional areas for a 24Fr 3-way catheter was measured and compared. The maximum (Qmax) and average (Qavg) irrigation and drainage flow rates for each catheter was measured for 20 40 seconds using uroflowmetry. The primary endpoint was to determine which catheter offers optimal irrigation and drainage parameters. Results: Overall cross-sectional area, irrigation port cross-sectional area, and drainage port cross-sectional area differed significantly for each 24Fr 3-way catheter assessed (p <0.001). The 24Fr 3-way Rusch SimplasticTM catheter consistently demonstrated the greatest maximal flow rate (Qmax: 5 +/-0.3 ml/s) and average flow rate (Qavg: 4.6 +/-0.2 ml/s) for irrigation. The 24Fr 3-way DoverTM catheter provided the greatest drainage properties (Qmax: 19.7 +/-2 ml/s; Q avg: 15.9 +/-5 ml/s). In the setting of continuous bladder irrigation, the 24Fr 3-way Rusch SimplasticTM catheter provided the highest irrigation rates (Qmax: 6.6 +/-1.8 ml/s; Q avg: 4.6 +/-0.9 ml/s). Conclusions: Three-way catheters demonstrate significant differences in their irrigation and drainage characteristics. The type of catheter selected should be based on the appropriate prioritization of efficient bladder irrigation versus efficient bladder drainage. PMID- 29410891 TI - Diagnostic and therapeutic recommendations for patients with nocturia. AB - Introduction: Nocturia is defined as the urge to urinate at night when the micturition was directly preceded and followed by sleep. Due to its negative impact on the quality of life of patients, an effective treatment for this disease has become a significant therapeutic challenge. The aim of this article was to explain the main risk factors for the occurrence of nocturia and to present diagnostic and therapeutic schemes in the case of nocturnal polyuria (idiopathic night time polyuria). Material and methods: A review of the literature was carried out and the available guidelines of international science societies, which provided the basis for the above recommendations, were analyzed. Results: Detailed medical history should include information concerning: lower urinary tract symptoms (including nocturia), underlying illnesses, urogenital disorders, previous surgeries and medications administered. Keeping a bladder diary is recommended. The physical examination, depending on the patient's gender, should include gynecological examination with pelvic organ prolapse assessment or prostate evaluation. In laboratory tests, a urinalysis may be used, in particular cases a cytological analysis of urine sediment may be carried out. In addition, a possible ultrasound and/or cystoscopy may be conducted. Nocturia therapy should begin with modifying dietary habits, including compliance with the fluid regimen, avoiding alcohol, coffee and tea. Moderate physical exercise is also recommended. The pharmacological treatment of nocturia caused by nocturnal polyuria is based on the use of desmopressin at a daily single dose of 25 ug for women and 50 ug for men. The use of desmopressin allows for the reduction in the number of nocturia episodes, as well as improves the overall quality of life and sleep. Treatment with desmopressin can also be considered as a form of therapy added in people with an overactive bladder or benign prostatic hyperplasia, in which nocturia is a significant clinical problem. Conclusions: Desmopressin is an effective and safe first-line treatment option in pharmacological therapy of nocturia caused by nocturnal polyuria. PMID- 29410892 TI - The relationship between serum and urinary Fetuin-A levels and kidney stone formation among kidney stone patients. AB - Introduction: Mineralization inhibitors are required to prevent the precipitation of minerals and inhibit the formation of kidney stones and other ectopic calcifications. In laboratory studies, Fetuin-A as a glycoprotein has inhibited hydroxyapatite precipitation in calcium and phosphate supersaturated solutions; however, information about patients with kidney stones is limited. The aim of this study was to investigate the association of serum and urinary Fetuin-A levels with calcium oxalate kidney stones. Material and methods: In this case control study, 30 patients with kidney stones and 30 healthy individuals without any history of urolithiasis who were referred to the urology ward of Sina Hospital of Tehran, Iran, in 2015 were entered into the study. All patients underwent computerized tomography scans. After collecting demographic information, serum and urine levels of Fetuin-A and some other calcification inhibitors and promoters, were measured and compared using T-test, Mann-Whitney and logistic regression between the two study groups. Results: Patients with kidney stones, on average, had lower levels of Serum Fetuin-A (1522.27 +/-755.39 vs. 1914.64 +/-733.76 MUg/ml; P = 0.046) as well as lower levels of Urine Fetuin A (944.62 +/-188.5 vs. 1409.68 +/-295.26 MUg/ml; P <0.001). Multivariate logistic analysis showed that urinary calcium and serum creatinine are the risk factors and Fetuin-A is a urinary protective factor for kidney stones. Conclusions: PFC Our study showed that patients with kidney stones had lower serum and urinary levels of Fetuin-A. In the logistic regression model, urinary Fetuin-A was reported as a protective factor for kidney stones. PMID- 29410893 TI - Comparative study of a new technique using nephroscope and resectoscope sheath and the percutaneous cystolithotripsy for the treatment of bladder calculus. AB - Introduction: Several minimally invasive approaches are available for the treatment of bladder stones, with each having its own advantages and disadvantages. We devised a new technique to overcome a few limitations of conventional techniques and compared its efficacy with conventional percutaneous cystolithotripsy (PCCL) technique. Material and methods: This was a randomized, open-label, prospective, controlled study conducted from July 2015 to December 2016 that included 62 patients with bladder calculus of >=2 cm in size. Patients were randomly assigned into two groups. Patients from Group 1 were treated with new a technique using a transurethral nephroscope via resectoscope outer sheath and patients from Group 2 were treated with conventional PCCL. Results: Overall, the mean (SD) age was 53.3 (11.4) years and 49.9 (12.8) years for Group 1 and 2, respectively; and stone size was 3.2 (0.8) and 3.2 (0.7), respectively. Operative time was similar in both groups (32.7 [8.7] versus 34.3 [7.0]; P = 0.428). The length of hospital stay was higher in Group 2 (2.1 [0.4]) as compared to Group 1 (1.2 [0.5]) (P = 0.000). Stones were completely cleared in all patients.Group 2 patients required more analgesics and had more complications like hematuria and wound infection. Conclusions: Results showed that cystolithotripsy with nephroscope via resectoscope sheath is an alternative to the conventional PCCL techniques as the new technique was associated with lesser complications, better cosmetic outcome and minimal analgesic requirement. PMID- 29410894 TI - The impact of urinary bladder catheterisation after ureterorenoscopic stone removal on the postoperative course. AB - Introduction: The most frequent reason for ureterorenoscopy is the necessity to remove calculi from the ureter and/or kidney. After completing this procedure the Foley catheter is inserted in the bladder. The aim of the study is to show whether catheterisation of the bladder after ureterorenoscopic stone removal in patients with a low-risk of complications is necessary and indicated. Material and methods: This is a comparative, prospective and randomized study. 100 patients meeting the assumed criteria, subjected to the ureterorenoscopy due to ureter and/or kidney stones participated in the study. The patients were divided into the experimental (Group I) and control (Group II) groups. Group I did not have a catheter, Group II was catheterised. There were two subgroups: female and male in each group. Mean values of the following parameters were calculated: intensity of postoperative pain measured by Visual Analog Pain Scale, the number of additional doses of painkillers administered after the procedure, hospital stay, occurrence of fever, significant bacteriuria, acute urinary retention and post- void retention greater than 30 ml. Results: Intensity of pain measured by the Visual Analog Scale was higher in Group II. Catheterisation does not influence: the number of additional doses of ketoprofen and pethidine administered during the 1st day after the operation, the duration of hospitalization, the occurrence of fever, significant bacteriuria, the postoperative acute urinary retention and the post-void residual urine volume. Conclusions: In patients with a low risk of postoperative complications who did not have any intraoperative complications, catheterisation of the urinary bladder increases discomfort without bringing any benefits. PMID- 29410895 TI - A ureteral stent crossing the bladder midline leads to worse urinary symptoms. AB - Introduction: To investigate the correlation between the position of a ureteral stent and stent-related symptoms, excluding the influence of ureteroscopic maneuvers. Material and methods: From January 2016 to December 2016, we analyzed 130 patients who placed a ureteral stent before ureteroscopic lithotripsy (URSL). A total of 108 patients were enrolled, including 77 (71.3%) men and 31 (28.7%) women, and the mean age was 58.9 +/-14.3 years. On the day before URSL, plain radiography (kidney, ureter, bladder X-ray [KUB]) was used to confirm the stone location and ureteral stent position. According to KUB, we defined the crossing midline group as when the distal loop of the ureteral stent was crossing the bladder midline, and the not crossing midline group as when the distal loop of the ureteral stent was not crossing the bladder midline. We assessed urinary symptoms of the two groups using the overactive bladder symptom score (OABSS) on the day before URSL. Results: The crossing midline group had a worse total OABSS (p <0.001) and worse scores for each item of daytime frequency (p = 0.047), nocturia (p <0.001), urgency (p = 0.002), and urgency incontinence (p = 0.045) than did the not crossing group. In multivariate analysis, stent position had the strongest association with the total OABSS (p = 0.002) among the other factors of age, sex, body mass index, stent side, stent diameter, stent length and stent indwelling time. Conclusions: This study shows that a ureteral stent crossing the bladder midline leads to worse urinary symptoms. Choosing the appropriate stent length for each patient is important for improving stent-related symptoms. PMID- 29410896 TI - Successful ureteroscopy for kidney stone disease leads to resolution of urinary tract infections: Prospective outcomes with a 12-month follow-up. AB - Introduction: To investigate the resolution of urinary tract infection (UTI) with the successful treatment of kidney stone disease (KSD).We reviewed the outcomes of ureteroscopy (URS) and stone treatment for patients with positive urine culture or recurrent UTIs and evaluated whether the infection resolved with the clearance of their urinary stones. Material and methods: Between March 2012 and July 2016, consecutive patients who underwent URS for stone disease with a history of recurrent UTIs or culture proven UTIs were identified from a prospective database. Data was recorded on stone free rate (SFR) and infection free rate (IFR) during the follow-up period at 3, 6 and 12-months. Results: During the study period, 103 consecutive patients with stone disease and associated UTI underwent URS over a 52-month period (mean age: 60 years, Female: Male ratio of 2:1). The mean cumulative stone size was 16 mm (range: 3-107 mm) and a positive pre-operative urine culture was found in 81 (79%) patients. While the overall SFR was 96%, the total complication rate was 12.6% (n = 13) and these were all Clavien I/II complications.At follow-up, the SFR and IFR was 96% and 88% at 3-months, and 82% and 71% at 12-months, respectively (p <0.001). While almost three-quarters of patients were stone and infection free at 12-months, the majority of those with stones recurrence also had recurrence of their UTI. Conclusions: The majority of patients will remain infection free at the 12-month follow-up if they are stone free after their initial treatment. Stone recurrence, which is more likely in high-risk patients, is also linked to the recurrence of their UTI. PMID- 29410897 TI - Inhibition of cryoglobulin synthesis as a method of positive influence on spermogram indices (clinical observations). AB - Introduction: Cold-shock precipitating proteins - cryoglobulins damage various vessels and, depending on the localization of damages, may lead to functional disorders of various organs and body systems. Evidently, cryoglobulinemia may have a negative influence on the reproductive system's condition, thus, this process requires detailed study. Material and methods: Clinical examples, indicating connection between cryoglobulinemia and spermatogenesis impairment are presented in the article. The proof is improvement of spermogram due to inhibition of cryoglobulin synthesis by the method of intradermal immunization with native autoleukocytes. Leukocytes are isolated by precipitation of a patient's heparinized peripheral venous blood in thermostat at 37 degrees S for 90-140 minutes. After precipitation, blood plasma is aspirated, leukocytes are precipitated by centrifugation. Autoleukocytes are injected in the dose 0.1 ml into 8-12 points of the skin in the back. Results: In the spermogram indices considerably improved due to the inhibition of cryoglobulin synthesis in patients with idiopathic oligoasthenoteratozoospermia. However, we have determined that in men with other forms of infertility, including severe ones, presence of an increased level of cryoglobulins significantly deteriorates prognosis considering successful correction of spermatogenesis impairment. Their elimination, in most cases, has a positive influence on spermatogenesis and makes additional conditions for efficacy improvement in the treatment of infertility. Conclusions: Examination for cryoglobulinemia should be included to methodical recommendations/instructions for examination of patients with impaired fertility, since the reduction of cryoglobulin level by means of intradermal immunization with autoleukocytes has a positive influence on spermogram indices. PMID- 29410898 TI - Subcutaneous pyelovesical bypass - Detour bypass - as a solution for ureteric obstruction. AB - Introduction: Many patients suffer from unilateral or bilateral hydronephroses caused by pelvic tumors, retroperitoneal fibrosis, occlusion due to radiation therapy or iatrogenic damage to the ureter. Currently, percutaneous nephrostomy or double J stents are primarily used. Nephrostomy deteriorates a patient's quality of life and leads to frequent infections, blockage of tubes, or bleeding, while uretral stents are associated with septicemia and irritative bladder symptoms. Thus, a useful solution is a Detour stent. Material and methods: A Detour stent consists of an outer layer made of polytetrafluoroethylene and an inner layer that is a silicone tube 17 F wide, with perforations on both ends and a radio-opaque ring on the proximal end. The ring allows for the insertion of the Detour to the kidney in the correct way. The Detour is placed subcutaneously to the kidney and to the bladder. The route is then tunneled by the large plastic hollow tube for inserting the Detour, and its distal end is sutured to the bladder. Results: Twelve patients were operated using this method, one of which received a Detour stent bilaterally. The mean follow-up was 10 months. All patients were operated previously by different methods. The average time of surgery was 78 minutes. The following complications occurred: urinary tract infections, haematoma, obstructed flow of urine through the Detour stent, prolonged urinary leakage, and pyelonephritis. Conclusions: Subcutaneous nephrovesical bypass - Detour System - is a minimally invasive, safe and effective procedure that improves quality of life with no serious complications. The Detour System allows urine to be drained in those cases where many other treatments had failed or were not feasible. PMID- 29410899 TI - Anderson-Hynes pyeloplasty in children - long-term outcomes, how long follow up is necessary? AB - Introduction: Pyeloplasty is commonly conducted in children with uretero-pelvic junction obstruction. Standard post-operational procedure involves only a short period of time after the surgery. What is the real number of complications, including those in the long-term? What is the function of the operated kidney?The aims of this study are to assess the effectiveness of pyeloplasty and to assess the suitability of conducting long term follow-up after pyeloplasty. Material and methods: 35 of 137 patients after open pyeloplasty between 1992-2006 responded to the invitation and returned for a control appointment. The median age was 8 years (range 1 month - 19 years). In 26 kidney units the disease proceeded with symptoms and in 10 cases it proceeded without symptoms. The predominant symptom was abdominal pain (n = 21). In each child both the control ultrasound and the diuretic renal scintigraphy of the kidneys were conducted. Results: Regression of symptoms after the operation was obtained in 19 kidney units (73%). Improvement in scintigraphy was observed in 23 kidney units (82.1%), improvement in ultrasound was obtained in 32 (91%) kidney units. Complications which required surgical intervention occurred in 4 (11.1%) patients. One patient required operative removal of a pyelostomy tube, 2 patients (11.1%) required repeated pyleoplasty (23 and 27 months after the operation), one child required nephrectomy due to nephrogenic arterial hypertension (after 4 years). Conclusions: Statistically, there are improvements of scintigraphic function of the kidney, improvements in ultrasound examinations, and the remission of symptoms after pyeoplasty. Most complications occur within 2 years after the surgery. Long-term follow up should be continued. PMID- 29410900 TI - Perigraft fluid collections after kidney transplantation: Does the type of donor (uncontrolled donation after circulatory death vs. donation after brain death) have a role? AB - Introduction: Perigraft fluid collection (PFC) is a common complication after kidney transplant. Its etiology is not clear and not all the causes have been identified. The influence of the type of donor has never been evaluated. Our aim was to compare the incidence, severity and management of PFC in recipients of grafts from uncontrolled donors after circulatory death (DCD) with normothermic extracorporeal membrane oxygenation (NECMO) versus recipients of grafts from donors after brain death (DBD). Material and methods: We conducted a retrospective cohort study of 300 kidney transplants performed in our center between 2007 and 2012. Patients were divided in two groups: 150 recipients of Maastricht II DCD graft and 150 recipients of the DBD graft. Incidence, severity according to Clavien scale and management were analyzed in both groups, and comparison was carried out using Chi-square. Results: Of the 300 kidney recipients analyzed, 93 (31.4%) suffered PFC, showing no difference between DBD (32.0%) and DCD (30.8%) groups (p = 0.9). Complicated PFC rate (defined as a PFC generating vascular compression, fever or urinary tract obstruction) was 22.9% in the DBD group versus 22.2% in the DCD group (p = 1); most complicated PFC were due to urinary tract obstruction (81%), with no difference between the groups (p = 1). Concerning Clavien scale, 78.5% of the PFC in our series were Clavien I, 19.4% Clavien IIIa and 2.2% Clavien IIIb, with no difference between both groups (p = 1). Conclusions: PFC is a frequent complication that appears in a third of our patients, showing no difference in the incidence or severity between DBD and uncontrolled DCD graft recipients. PMID- 29410901 TI - Can Urologists be permitted to maintain a private Social Media presence in light of the relevant Guidelines and Codes of Conduct, which govern the use of Social Media with regard to these professionals? PMID- 29410902 TI - Laparo-endoscopic stone surgery: advantages of an alternative approach. PMID- 29410903 TI - Treatment of bladder lithiasis using a percutaneous approach in a patient with Mitrofanoff conduit. PMID- 29410904 TI - Letters to the Editor. PMID- 29410905 TI - Author's Reply. PMID- 29410906 TI - Letters to the Editor. PMID- 29410907 TI - Letters to the Editor. PMID- 29410908 TI - Letters to the Editor. PMID- 29410909 TI - Letters to the Editor. PMID- 29410910 TI - Author's Reply. PMID- 29410911 TI - Performance of Laboratory Professionals Working on Malaria Microscopy in Tigray, North Ethiopia. AB - Background: Microscopic analysis of stained blood smear is the most suitable method of malaria diagnosis. However, gaps were observed among clinical laboratory professionals in microscopic diagnosis of malaria. Methods: A cross sectional study was conducted in December 2015 among 46 laboratory professionals. Data was collected via on-site assessment and panel testing. The slide panel testing was composed of positive and negative slides. The kappa score was used to estimate the agreement between participants and reference reader. Results: The overall agreement between the study participants and the reference reader in malaria detection was 79% (kappa = 0.62). Participating in refresher training on malaria microscopy (Adjusted Odds Ratio (AOR = 7, CI = 1.5-36.3)) and malaria epidemic investigation (AOR = 4.1 CI = 1.1-14.5) had statistical significant association with detection rate of malaria parasites. Conclusion: Laboratory professionals showed low performance in malaria microscopy. Most of the study participants were graded "in-training" in laboratory diagnosis of malaria. PMID- 29410912 TI - Evaluation of Predictive Factors for Successful Intravitreal Dexamethasone in Pseudophakic Cystoid Macular Edema. AB - Purpose: To determine the efficacy, safety, and predictive outcome factors for intravitreal dexamethasone implant (DEX) in pseudophakic cystoid macular edema (PCME). Methods: Retrospective, interventional, controlled study. Patients included had to have clinically significant PCME and have been treated with the DEX between 2012 and 2015. Charts and one-year data were selected consecutively, and efficacy and safety were abstracted. Visual acuity (VA) and central foveal thickness (CFT) were analysed. Results: Nineteen patient data sets were analysed. After treatment with DEX, mean VA increased significantly by 0.2 logMAR (p = 0.034), while the mean CFT was reduced significantly by 162.79 MUm (p < 0.001). Five patients receiving a combination of DEX/bevacizumab have not experienced a higher mean VA gain or CFT reduction compared to fourteen patients receiving DEX alone. Decision rules, when to combine DEX with bevacizumab, have not been defined before the study. Only posttreatment VA gains in the nonhypertensive subgroup (n = 11) were significantly better (p = 0.026). Analysis of data from diabetes patients (n = 4) versus nondiabetics yielded no significant differences in efficacy. There have been no adverse events within follow-up time. Conclusion: The use of DEX in PCME showed significant improvements in VA and CFT. The VA seems to show greater improvements in patients without hypertension. PMID- 29410913 TI - The Distribution of the Photoreceptor Outer Segment Length in a Healthy Population. AB - Purpose: To evaluate the effects of age and sex on the photoreceptor outer segment (PROS) length in healthy eyes, using spectral-domain optical coherence tomography (SD-OCT). Methods: A total of 97 eyes of 97 healthy participants (spherical equivalent < +/-1 diopters [D]) were scanned with SD-OCT. The patients were divided into 3 groups by age: group 1 (0-20 years), group 2 (21-40 years), and group 3 (41-60 years). The PROS length was defined as the distance from the inner surface of IS/OS (inner segment/outer segment) band to the inner surface of retinal pigment epithelium (RPE). Results: The mean PROS length was 52.01 +/- 3.79 MUm in females and 53.41 +/- 3.37 MUm in males (p = 0.061). The mean PROS length of the different groups was 53.70 +/- 3.18 MUm (0-20 years), 52.14 +/- 3.64 MUm (21-40 years), and 52.20 +/- 3.95 MUm (41-60 years) (p = 0.155; ANOVA test). Multiple linear regression analysis revealed a -0.039 MUm decline in PROS length per year (p = 0.074) and a -1.408 MUm decline in females (p = 0.055). Conclusion: The difference in PROS length was not statistically significant neither for age nor for gender; females tended to have a lower PROS length than males, and PROS length was slightly higher in the first two decades of life. PMID- 29410914 TI - Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AB - Very early infant diagnosis (VEID) (testing within two weeks of life), combined with rapid treatment initiation, could reduce early infant mortality. Our study evaluated turnaround time (TAT) to receipt of infants' HIV test results and ART initiation if HIV-infected, with and without birth testing availability. Data from facility records and national databases were collected for 12 facilities offering VEID, as part of an observational prospective cohort study, and 10 noncohort facilities. HIV-exposed infants born in January-June 2016 and any cohort infant diagnosed as HIV-infected at birth or six weeks were included. The median TAT from blood draw to caregiver result receipt was 76.5 days at birth and 63 and 70 days at six weeks at cohort and noncohort facilities, respectively. HIV exposed infants tested at birth were approximately one month younger when their caregivers received results versus those tested at six weeks. Infants diagnosed at birth initiated ART about two months earlier (median 6.4 weeks old) than those identified at six weeks (median 14.8 weeks). However, the long TAT for testing at both birth and six weeks illustrates the prolonged process for specimen transport and result return that could compromise the effectiveness of adding VEID to existing overburdened EID systems. PMID- 29410916 TI - Infraorbital Foramen and Pterygopalatine Fossa Location in Dry Skulls: Anatomical Guidelines for Local Anesthesia. AB - Purpose: The aim of the study was to locate the infraorbital foramen (IOF) in relation to the infraorbital margin (IOM) for proper injections of local anesthetics in skull specimens. Another aim was to determine the depth of needle penetration into pterygopalatine fossa through the greater palatine canal (GPC). Materials and Methods: 102 skull halves were used to measure the distances between (1) IOF and IOM and (2) IOF and alveolar ridge of maxilla at second premolar. Needles were inserted and bent at a 45 degrees angle, passing through the GPC at the level of hard palate. The depth of the tip of needle emerging out of GPC into pterygopalatine fossa was measured. Results: The mean distance between IOF and IOM was 6.46 +/- 1.57 mm on the right side and 6.74 +/- 1.72 mm on the left. The mean distance between IOF and alveolar bone process of the maxilla at second premolar was 29.07 +/- 3.58 mm on the right side and 29.39 +/- 3.78 mm on the left. The mean depth of penetration of the needle into the pterygopalatine fossa was similar on both sides. Conclusions: Proper identification of IOF and pterygopalatine fossa is of great significance during local anesthesia injections, due to their close proximity to vital anatomic structures. PMID- 29410915 TI - Chronic Pain and Sleep Disorders in Primary Care. AB - Background: Chronic pain (CP) and sleep disorders (SD) are highly prevalent in the general population. However, comprehensive data regarding the prevalence and characteristics of pain and SD in primary care are rare. Methods: From N = 578 patients N = 570 were included within 8 weeks (mean age: 50.8 +/- 18.7 years, females: 289). Sociodemographic data, Insomnia Severity Index (ISI), and parts of a self-report questionnaire for pain (Multidimensional German Pain Questionnaire) were recorded and additional medical information (pain medication, sleep medication) was gathered from the patient charts. Results: Of the total sample, 33.2% (n = 189) suffer from CP (pain >= 6 months) and 29.1% (n = 166) from SD. 45.5% of the CP patients suffer from SD and 26.5% from clinical insomnia (ISI >= 15). SD (beta = 0.872, SE = 0.191, t = 4,572, p < 0.001, CI [0.497; 1.246]) and older age (beta = 0.025, SE = 0.005, t = 5.135, p < 0.001, CI [0.015; 0.035]) were significantly associated with pain experience. Conclusion: About a quarter of CP patients suffer from clinical insomnia. The suggested bidirectional relation should be considered during comprehensive assessment and treatment of patients. PMID- 29410917 TI - Relationship of Common Vascular Anatomy to Cannulated Catheters. AB - Superficial veins of the upper extremity are the primary location for placement of peripheral IV catheters (PIVC). It is believed that a significant portion of PIVCs placed may cross or abut valves and branching veins or occlude a significant portion of the vein, limiting the ability to aspirate blood from the PIVC. Two separate clinical investigations using ultrasound were performed to understand the potential interaction between PIVCs and the vein lumen and the venous valves and branches of the superficial veins of the upper extremity. One study with 35 adult volunteers interrogated 210 vein segments where a PIV would likely be placed. A second pediatric study evaluated 35 vein segments central to indwelling PIVCs. The combined data from the two studies showed that over 80% of adult veins and 85% of pediatric veins can properly accommodate 20-gauge and 22 gauge PIVC, respectively. Venous valves are frequent findings, either immediately peripheral to branching veins or at periodic 5 to 7 cm points. Antegrade blood flow can be restricted by a placed PIVC, while retrograde flow is very likely to be restricted by venous valves. Together, these findings may explain the difficulty in reliable aspiration of blood from PIVC. PMID- 29410919 TI - Evaluation of Chitosan-Microcrystalline Cellulose Blends as Direct Compression Excipients. AB - This study was aimed at evaluating chitosan-microcrystalline cellulose blends as direct compression excipients. Crab shell chitosan, alpha-lactose monohydrate, and microcrystalline cellulose powders were characterized. Blends of the microcrystalline cellulose and chitosan in ratios 9 : 1, 4 : 1, 2 : 1, and 1 : 1 as direct compression excipients were made to constitute 60% of metronidazole tablets. Similar tablets containing blends of the microcrystalline cellulose and alpha-lactose monohydrate as well as those containing pure microcrystalline cellulose were also produced. The compact density, tensile strength, porosity, disintegration time, and dissolution rate of tablets were determined. Chitosan had higher moisture content (7.66%) and higher moisture sorption capacity (1.33%) compared to microcrystalline cellulose and lactose. It also showed better flow properties (Carr's index of 18.9% and Hausner's ratio of 1.23). Compact density of tablets increased but tensile strength decreased with increase in the proportion of chitosan in the binary mixtures. In contrast to lactose, the disintegration time increased and the dissolution rate decreased with increase in the proportion of chitosan. This study has shown that chitosan promotes flowability of powder mix and rapid disintegration of tablet. However, incorporation of equal proportions of microcrystalline cellulose and chitosan leads to production of extended-release tablet. Therefore, chitosan promotes tablet disintegration at low concentration and enables extended-release at higher concentration. PMID- 29410918 TI - In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice. AB - siRNA stabilized for in vivo applications is filtered and reabsorbed in the renal proximal tubule (PT), reducing mRNA expression transiently. Prior siRNA efforts have successfully prevented upregulation of mRNA in response to injury. We proposed reducing constitutive gene and protein expression of LRP2 (megalin) in order to understand its molecular regulation in mice. Using siRNA targeting mouse LRP2 (siLRP2), reduction of LRP2 mRNA expression was compared to scrambled siRNA (siSCR) in mouse PT cells. Mice received siLRP2 administration optimized for dose, administration site, carrier solution, administration frequency, and administration duration. Kidney cortex was collected upon sacrifice. Renal gene and protein expression were compared by qRT-PCR, immunoblot, and immunohistochemistry (IHC). Compared to siSCR, siLRP2 reduced mRNA expression in PT cells to 16.6% +/- 0.6%. In mouse kidney cortex, siLRP2 reduced mRNA expression to 74.8 +/- 6.3% 3 h and 70.1 +/- 6.3% 6 h after administration. mRNA expression rebounded at 12 h (160.6 +/- 11.2%). No megalin renal protein expression reduction was observed by immunoblot or IHC, even after serial twice daily dosing for 3.5 days. Megalin is a constitutively expressed protein. Although LRP2 renal mRNA expression reduction was achieved, siRNA remains a costly and inefficient intervention to reduce in vivo megalin protein expression. PMID- 29410921 TI - A Randomized Crossover Trial of a Pressure Relief Technology (SensAwakeTM) in Continuous Positive Airway Pressure to Treat Obstructive Sleep Apnea. AB - Objectives/Background: Improving adherence to CPAP devices is crucial to reduce the long-term morbidity associated with OSA. SensAwake is a unique pressure relief technology that aims to promptly reduce the pressure upon sensing irregular respiration indicative of wakefulness. The purpose of this study was to compare adherence and sleep-quality outcomes in patients treated by CPAP with and without SensAwake technology. Methods: Participants with moderate-to-severe OSA were randomized to use CPAP devices with or without SensAwake (4 weeks) before crossing over. Results: Sixty-five patients completed both arms of the trial. There were no statistically significant differences in CPAP adherence with or without SensAwake over the study period (SensAwake ON 272.67 +/- 17.06 versus SensAwake OFF 289.09 +/- 15.24; p = 0.180). SensAwake reported a significantly lower system leak, 90th percentile leak, and time spent with excessive (>60 L/min) leak. Subgroup analysis suggested a trend towards improved adherence in patients with moderate-to-severe insomnia when using SensAwake. Conclusions: Using SensAwake incurred benefit in terms of reduced leaks; however, SensAwake did not improve CPAP adherence or objective sleep quality. Further studies should investigate the accuracy of observed trends towards increased adherence using SensAwake among patients with OSA and insomnia. PMID- 29410920 TI - Novel Genetic Variants of Hepatitis B Virus in Fulminant Hepatitis. AB - Fulminant hepatitis (FH) is a life-threatening liver disease characterised by intense immune attack and massive liver cell death. The common precore stop codon mutation of hepatitis B virus (HBV), A1896, is frequently associated with FH, but lacks specificity. This study attempts to uncover all possible viral nucleotides that are specifically associated with FH through a compiled sequence analysis of FH and non-FH cases from acute infection. We retrieved 67 FH and 280 acute non-FH cases of hepatitis B from GenBank and applied support vector machine (SVM) model to seek candidate nucleotides highly predictive of FH. Six best candidates with top predictive accuracy, 92.5%, were used to build a SVM model; they are C2129 (85.3%), T720 (83.0%), Y2131 (82.4%), T2013 (82.1%), K2048 (82.1%), and A2512 (82.1%). This model gave a high specificity (99.3%), positive predictive value (95.6%), and negative predictive value (92.1%), but only moderate sensitivity (64.2%). We successfully built a SVM model comprising six variants that are highly predictive and specific for FH: four in the core region and one each in the polymerase and the surface regions. These variants indicate that intracellular virion/core retention could play an important role in the progression to FH. PMID- 29410922 TI - Unique Phrenic Nerve-Sparing Regional Anesthetic Technique for Pain Management after Shoulder Surgery. AB - Background: Ipsilateral phrenic nerve blockade is a common adverse event after an interscalene brachial plexus block, which can result in respiratory deterioration in patients with preexisting pulmonary conditions. Diaphragm-sparing nerve block techniques are continuing to evolve, with the intention of providing satisfactory postoperative analgesia while minimizing hemidiaphragmatic paralysis after shoulder surgery. Case Report: We report the successful application of a combined ultrasound-guided infraclavicular brachial plexus block and suprascapular nerve block in a patient with a complicated pulmonary history undergoing a total shoulder replacement. Conclusion: This case report briefly reviews the important innervations to the shoulder joint and examines the utility of the infraclavicular brachial plexus block for postoperative pain management. PMID- 29410923 TI - A Case of a 34-Year-Old Female with Acute Hypoxemic Respiratory Failure and Proximal Muscle Weakness. AB - Wound associated botulism is an unusual presentation. Early detection of this potentially life-threatening illness can significantly shorten length of hospital stay and improve prognosis. We present a case of a 34-year-old female with a history of heroin abuse who presented to the ED with acute respiratory failure, diplopia, and proximal muscle weakness. There was early concern for wound botulism as the instigating process. After discussion with the CDC, she was given equine serum heptavalent botulism antitoxin. Laboratory analysis later confirmed our suspicion. Symptoms improved and the patient was liberated from mechanical ventilation on day 14 and discharged from the hospital on day 23. PMID- 29410925 TI - Retroperitoneal Endometriotic Cyst Infiltrated in the Iliopsoas Incidentally Found in a Patient with Acute Back Pain. AB - We describe a rare case of retroperitoneal endometriotic cyst infiltrated in the iliopsoas incidentally found in a patient with acute back pain. Endometriosis at the pelvic peritoneum, including the Douglas pouch, has been reported often; there are few reports of cystic endometriosis in the retroperitoneal cavity. Today there are various theories regarding how endometriosis occurs. By pathological findings and lesion sites of the present case, we concluded that the endometrial tissues in the menstrual blood might metastasize lymphatically and implant and form the retroperitoneal cyst. PMID- 29410924 TI - Peripheral T-Cell Lymphoma of the Submandibular Salivary Gland as an Unusual Manifestation of Richter's Syndrome: A Case Report and Literature Review. AB - Richter's syndrome is the development of high-grade non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In most patients with Richter's syndrome, the high grade NHL is diffuse large B-cell lymphoma. Only a small minority of CLL/SLL patients develop T-cell malignancies. Herein, we describe a 40-year-old male patient presenting with peripheral T-cell lymphoma not otherwise specified (PTCL NOS) in the submandibular salivary gland, two years after the diagnosis of CLL/SLL. The PTCL-NOS consisted of small lymphocytes, which complicated diagnosis. Immunohistochemical, cytological, and molecular studies allowed the correct diagnosis of composite lymphoma (SLL/PTCL-NOS) of the submandibular salivary gland. The PTCL-NOS had a cytotoxic phenotype and aberrant expression of CD79a. There was no evidence to suggest that the PTCL-NOS of the submandibular salivary gland developed from an intimately associated submandibular lymph node or by PTCL-NOS dissemination. A review of the literature and presented case suppose that the PTCLs developed following CLL/SLL have the cytotoxic phenotype and can clinically mimic typical Richter's syndrome. PMID- 29410926 TI - The Diagnosing Challenge of a Positive ANCA Vasculitis in the Paediatric Age. AB - ANCA-positive systemic vasculitides, rare in paediatric age, present multiorganic involvement. A female teenager presented with a history of subglottic stenosis diagnosed at the age of 12. From the investigation carried out, we highlight hematoproteinuria and negative ANCAs. At 15 years old, she was admitted for gastrointestinal symptoms and respiratory distress. She presented poor peripheral perfusion, pulmonary haemorrhage, respiratory failure, and severe renal insufficiency. She was started mechanical ventilation and emergency haemodialysis. The immunological study revealed ANCA MPO positive. A presumptive diagnosis of ANCA-positive vasculitis was made, and she was started corticotherapy, cyclophosphamide, and plasmapheresis. A renal biopsy, performed later, showed crescentic glomerulonephritis with chronicity signs. Positive ANCA vasculitis may progress slowly or suddenly. The diagnosis was confirmed by a biopsy; however, we can make a presumptive diagnosis based on clinical findings and in a positive ANCA test in order to start an early treatment and decrease the associated morbimortality. PMID- 29410927 TI - Cryptogenic Cirrhosis and Hepatopulmonary Syndrome in a Boy with Hepatic Hemangioma in Botswana: A Case Report and Review of the Literature. AB - Hepatic hemangiomas are considered to be the most common benign tumors of the liver. They are often found incidentally while investigating for other causes of liver disease. Hemangiomas that are less than 10 cm are not expected to cause any problems. Typically, they do not enlarge and, apart from regular follow-up, no definitive treatment is indicated. This is a posthumous case report of a male child with a medium-sized hemangioma from infancy, complicated by cryptogenic cirrhosis and hepatopulmonary syndrome. It demonstrates the challenges of managing a child with such complicated conditions in a resource-limited setting. PMID- 29410928 TI - Pharmacological Hypotension as a Cause of Delirious Mania in a Patient with Bipolar Disorder. AB - Delirious mania is a severe but often underrecognized syndrome characterized by rapid onset of delirium, mania, and psychosis, not associated with a prior toxicity, physical illness, or mental disorder. We discuss the case of a delirious mania potentially triggered and maintained by a systemic hypotension induced by antihypertensive drugs. Symptoms recovered completely after the discontinuation of antihypertensive medications and the normalization of blood pressure levels. PMID- 29410929 TI - A Case of Midgut Volvulus Associated with a Jejunal Diverticulum. AB - Midgut volvulus in adults is a rare entity that may present with intermittent colicky abdominal pain mixed with completely asymptomatic episodes. This small bowel twist may result in complications of obstruction, ischemia, hemorrhage, or perforation. With a midgut volvulus, complications may be life-threatening, and emergent surgical intervention is the mainstay of treatment. This current case involves an 80-year-old woman with intermittent abdominal pain with increasing severity and decreasing interval of time to presentation. A CAT scan revealed mesenteric swirling with possible internal hernia. A diagnostic laparoscopy followed by laparotomy revealed a midgut volvulus, extensive adhesions involving the root of the mesentery, and a large jejunal diverticulum. The adhesions were lysed enabling untwisting of the bowel, allowing placement of the small bowel in the correct anatomic position and resection of the jejunal diverticulum. This is a rare case of midgut volvulus with intermittent abdominal pain, associated with jejunal diverticulum managed successfully. A midgut volvulus should be considered in the differential diagnosis of a patient who present with a small bowel obstruction secondary to an internal hernia, especially when a swirl sign is present on the CAT scan. PMID- 29410930 TI - A First Report of Synchronous Intracapsular and Extracapsular Hepatic Adenoma. AB - Although the gallbladder is the most common site of ectopic liver, it has been reported in many other organs, such as kidney, adrenal glands, pancreas, omentum, stomach, esophagus, mediastinum, lungs, and heart. Hepatocytes in an ectopic liver behave like normal hepatocytes; furthermore, they can be associated with the same pathological findings as those in the main liver. Ectopic liver in the gallbladder can undergo fatty change, hemosiderosis, cholestasis, cirrhosis, hemangioma, focal nodular hyperplasia, adenoma, and even carcinogenesis. The incidence of extracapsular hepatic adenoma is not known, but only two cases have been reported. Here, we provide the first case report of synchronous multiple intracapsular and extracapsular hepatic adenomas. A 60-year-old woman with multiple hepatic adenomas and one 7 * 5 * 5 cm ectopic hepatic adenoma attached to the gallbladder fundus complicated with abdominal pain is presented. PMID- 29410931 TI - Precursors to the PANSS: The BPRS and its progenitors. AB - The systematic assessment of signs and symptoms of psychopathology has roots that date back to rating scale development that began in the 1950s. This article reviews some of those rating scales. The focus is on the Brief Psychiatric Rating Scale, which is the most important precursor of the Positive and Negative Symptom Rating Scale. PMID- 29410932 TI - A Developmental History of the Positive and Negative Syndrome Scale (PANSS). AB - Psychometric instruments are products of their time-Their designs and initial purposes are influenced and shaped by the contemporary treatment regimens, context, and cultural and conceptual biases of their developers. In this review article, the authors explore the history of the most influential schizophrenia research tools that have been created over the past several decades. The authors describe the scientific concepts, cultural influences, and challenges of past and present researchers as they strive to develop better assessment tools for schizophrenia. Starting with Moore's Scheme for the Quantitative Measurement of Abnormal Emotional Condition, developed in the early 1900s, and concluding with Kay, Fiszbein, and Opler's Positive and Negative Syndrome Scale, developed in the 80s, the authors describe several scales and illustrate how each scale led to and influenced the development of a later scale. The authors hope that a better understanding of schizophrenia assessment tool evolution and limitations will assist in the development of new instruments that better address the global needs for the evaluation, research, and treatment of psychosis. PMID- 29410933 TI - Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience. AB - Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sample of people with schizophrenia was used as the data source of this study. Using regression analyses, the authors predicted the three different aspects of everyday functioning, first with just the two Positive and Negative Syndrome Scale factors and then with a global negative symptom factor. Finally, we added neurocognitive performance and functional capacity as predictors. Results: The Positive and Negative Syndrome Scale reduced emotional experience factor accounted for 21 percent of the variance in everyday social functioning, while reduced emotional expression accounted for no variance. The total Positive and Negative Syndrome Scale negative symptom factor accounted for less variance (19%) than the reduced experience factor alone. The Positive and Negative Syndrome Scale expression factor accounted for, at most, one percent of the variance in any of the functional outcomes, with or without the addition of other predictors. Implications: Reduced emotional experience measured with the Positive and Negative Syndrome Scale, often referred to as "avolition and anhedonia," specifically predicted impairments in social outcomes. Further, reduced experience predicted social impairments better than emotional expression or the total Positive and Negative Syndrome Scale negative symptom factor. In this cross-sectional study, reduced emotional experience was specifically related with social outcomes, accounting for essentially no variance in work or everyday activities, and being the sole meaningful predictor of impairment in social outcomes. PMID- 29410934 TI - Insight and Treatment Outcomes in Schizophrenia: Post-hoc Analysis of a Long term, Double-blind Study Comparing Lurasidone and Quetiapine XR. AB - Objective: The objective of this post-hoc analysis was to evaluate the effect of lurasidone and quetiapine extended-release (XR) on insight and judgment and assess the longitudinal relationships between improvement in insight and cognitive performance, functional capacity, quality of well-being, and depressive symptoms in patients with schizophrenia. Design: Clinically unstable patients with schizophrenia (N=488) were randomized to once-daily, fixed-dose treatment with lurasidone 80mg, lurasidone 160mg, quetiapine XR 600mg, or placebo, followed by a long-term, double-blind, flexible-dose continuation study involving these agents. Results: Significantly greater improvement in insight and judgment (assessed by the Positive and Negative Syndrome Scale G12 item) for the lurasidone and quetiapine XR groups, compared to the placebo group, was observed at Week 6. Over a subsequent six-month continuation period, the flexible dose lurasidone group showed significantly greater improvement in insight from acute phase baseline compared to the flexible-dose quetiapine XR group (QXR-QXR) (p=0.032). Improvement in insight was significantly correlated with improvement in cognition (p=0.014), functional capacity (p=0.006, UPSA-B), quality of well being (p=0.033, QWB), and depressive symptoms (p=0.05, Montgomery-Asberg Depression Rating Scale [MADRS] score) across treatment groups and study periods. Conclusion: In this post-hoc analysis, flexibly dosed lurasidone 40 to 160mg/d was found to be associated with significantly greater improvement in insight compared to flexibly dosed quetiapine XR 200 to 800mg/d over long-term treatment in patients with schizophrenia. Across treatment groups, improvement in insight and judgment was significantly associated with improvement in cognition, functional capacity, quality of well-being, and depressive symptoms over time. PMID- 29410935 TI - Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions: Implications for Social, Linguistic, and Cultural Consistency. AB - Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms. PMID- 29410936 TI - Disparity between General Symptom Relief and Remission Criteria in the Positive and Negative Syndrome Scale (PANSS): A Post-treatment Bifactor Item Response Theory Model. AB - Objective: Total scale scores derived by summing ratings from the 30-item PANSS are commonly used in clinical trial research to measure overall symptom severity, and percentage reductions in the total scores are sometimes used to document the efficacy of treatment. Acknowledging that some patients may have substantial changes in PANSS total scores but still be sufficiently symptomatic to warrant diagnosis, ratings on a subset of 8 items, referred to here as the "Remission set," are sometimes used to determine if patients' symptoms no longer satisfy diagnostic criteria. An unanswered question remains: is the goal of treatment better conceptualized as reduction in overall symptom severity, or reduction in symptoms below the threshold for diagnosis? We evaluated the psychometric properties of PANSS total scores, to assess whether having low symptom severity post-treatment is equivalent to attaining Remission. Design: We applied a bifactor item response theory (IRT) model to post-treatment PANSS ratings of 3,647 subjects diagnosed with schizophrenia assessed at the termination of 11 clinical trials. The bifactor model specified one general dimension to reflect overall symptom severity, and five domain-specific dimensions. We assessed how PANSS item discrimination and information parameters varied across the range of overall symptom severity (theta), with a special focus on low levels of symptoms (i.e., theta<-1), which we refer to as "Relief" from symptoms. A score of theta= 1 corresponds to an expected PANSS item score of 1.83, a rating between "Absent" and "Minimal" for a PANSS symptom. Results: The application of the bifactor IRT model revealed: (1) 88% of total score variation was attributable to variation in general symptom severity, and only 8% reflected secondary domain factors. This implies that a general factor may provide a good indicator of symptom severity, and that interpretation is not overly complicated by multidimensionality; (2) Post-treatment, 534 individuals (about 15% of the whole sample) scored in the "Relief" range of general symptom severity, but more than twice that number (n = 1351) satisfied Remission criteria (37%). 2 in 3 Remitted patients had scores that were not in a low symptom range (corresponding to Absent or Minimal item scores); (3) PANSS items vary greatly in their ability to measure the general symptom severity dimension; while many items are highly discriminating and relatively "pure" indicators of general symptom severity (delusions, conceptual disorganization), others are better indicators of specific dimensions (blunted affect, depression). The utility of a given PANSS item for assessing a patient depended on the illness level of the patient. Conclusion: Satisfying conventional Remission criteria was not strongly associated with low levels of symptoms. The items providing the most information for patients in the symptom Relief range were Delusions, Preoccupation, Suspiciousness Persecution, Unusual Thought Content, Conceptual Disorganization, Stereotyped Thinking, Active Social Avoidance, and Lack of Judgment and Insight. Lower scores on these items (item scores <=2) were strongly associated with having a low latent trait theta or experiencing overall symptom relief. The inter-rater agreement between Remission and Relief subjects suggested that these criteria identified different subsets of patients. Alternative subsets of items may offer better indicators of general symptom severity and provide better discrimination (and lower standard errors) for scaling individuals and judging symptom relief, where the "best" subset of items ultimately depends on the illness range and treatment phase being evaluated. PMID- 29410937 TI - Understanding Antipsychotic Drug Treatment Effects: A Novel Method to Reduce Pseudospecificity of the Positive and Negative Syndrome Scale (PANSS) Factors. AB - The Positive and Negative Syndrome Scale (PANSS) is the most widely used efficacy measure in acute treatment studies of schizophrenia. However, interpretation of the efficacy of antipsychotics in improving specific symptom domains is confounded by moderate-to-high correlations among standard (Marder) PANSS factors. The authors review the results of an uncorrelated PANSS score matrix (UPSM) transform designed to reduce pseudospecificity in assessment of symptom change in patients with schizophrenia. Based on a factor analysis of five pooled, placebo-controlled lurasidone clinical trials (N=1,710 patients), a UPSM transform was identified that generated PANSS factors with high face validity (good correlation with standard Marder PANSS factors), and high specificity/orthogonality (low levels of between-factor correlation measuring change during treatment). Between-factor correlations were low at baseline for both standard (Marder) PANSS factors and transformed PANSS factors. However, when measured change in symptom severity was measured during treatment (in a pooled 5 study analysis), there was a notable difference for standard PANSS factors, where changes across factors were found to be highly correlated (factors exhibited pseudospecificity), compared to transformed PANSS factors, where factor change scores exhibited the same low levels of between-factor correlation observed at baseline. At Week 6-endpoint, correlations among PANSS factor severity scores were moderate-to-high for standard factors (0.34-0.68), but continued to be low for the transformed factors (-0.22-0.20). As an additional validity check, we analyzed data from one of the original five pooled clinical trials that included other well-validated assessment scales (MADRS, Negative Symptom Assessment scale [NSA]). In this baseline analysis, UPSM-transformed PANSS factor severity scores (negative and depression factors) were found to correlate well with the MADRS and NSA. The availability of transformed PANSS factors with a high degree of orthogonality/specificity, but which retain a high degree of concurrent and face validity, can reduce pseudospecificity as a measurement confound, and should facilitate the drug development process, permitting a more accurate characterization of the efficacy of putative new agents in targeting specific symptom domains in patients with psychotic illness. PMID- 29410938 TI - Sensitivity of the Positive and Negative Syndrome Scale (PANSS) in Detecting Treatment Effects via Network Analysis. AB - Objective: The Positive and Negative Syndrome Scale is a primary outcome measure in clinical trials examining the efficacy of antipsychotic medications. Although the Positive and Negative Syndrome Scale has demonstrated sensitivity as a measure of treatment change in studies using traditional univariate statistical approaches, its sensitivity to detecting network-level changes in dynamic relationships among symptoms has yet to be demonstrated using more sophisticated multivariate analyses. In the current study, we examined the sensitivity of the Positive and Negative Syndrome Scale to detecting antipsychotic treatment effects as revealed through network analysis. Design: Participants included 1,049 individuals diagnosed with psychotic disorders from the Phase I portion of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Of these participants, 733 were clinically determined to be treatment-responsive and 316 were found to be treatment-resistant. Item level data from the Positive and Negative Syndrome Scale were submitted to network analysis, and macroscopic, mesoscopic, and microscopic network properties were evaluated for the treatment responsive and treatment-resistant groups at baseline and post-phase I antipsychotic treatment. Results: Network analysis indicated that treatment responsive patients had more densely connected symptom networks after antipsychotic treatment than did treatment-responsive patients at baseline, and that symptom centralities increased following treatment. In contrast, symptom networks of treatment-resistant patients behaved more randomly before and after treatment. Conclusions: These results suggest that the Positive and Negative Syndrome Scale is sensitive to detecting treatment effects as revealed through network analysis. Its findings also provide compelling new evidence that strongly interconnected symptom networks confer an overall greater probability of treatment responsiveness in patients with psychosis, suggesting that antipsychotics achieve their effect by enhancing a number of central symptoms, which then facilitate reduction of other highly coupled symptoms in a network like fashion. PMID- 29410939 TI - Bridging the Measurement Gap Between Research and Clinical Care in Schizophrenia: Positive and Negative Syndrome Scale-6 (PANSS-6) and Other Assessments Based on the Simplified Negative and Positive Symptoms Interview (SNAPSI). AB - There is currently a "measurement gap" between research and clinical care in schizophrenia. The main reason behind this gap is that the most widely used rating scale in schizophrenia research, the 30-item Positive and Negative Syndrome Scale (PANSS), takes so long to administer that it is rarely used in clinical practice. This compromises the translation of research findings into clinical care and vice versa. The aim of this paper is to discuss how this measurement gap can be closed. Specifically, the main points of discussion are 1) the practical problems associated with using the full 30-item PANSS in clinical practice; 2) how the brief, six-item version of the Positive and Negative Syndrome Scale (PANSS-6) was derived empirically from the full 30-item PANSS and what the initial results obtained with PANSS-6 entail; and 3) how PANSS-6 ratings, guided by the newly developed, 15-25-minute, stand-alone Simplified Negative and Positive Symptoms Interview (SNAPSI), might help bridge the measurement gap between research and clinical care in schizophrenia. The full 30 item PANSS is often used in research studies, but is too time consuming to allow for routine clinical use. Recent studies suggest that the much briefer PANSS-6 is a psychometrically valid measure of core positive and negative symptoms of schizophrenia and that the scale is sensitive to symptom improvement following pharmacological treatment. SNAPSI is a brief interview that yields the information needed to rate PANSS-6 (and other brief rating scales). We believe that PANSS-6 ratings guided by SNAPSI will help bridge the measurement gap between research and clinical care in schizophrenia. PMID- 29410940 TI - Are Shorter Versions of the Positive and Negative Syndrome Scale (PANSS) Doable? A Critical Review. AB - The Positive and Negative Syndrome Scale (PANSS) is a well-established assessment tool for measuring symptom severity in schizophrenia. Researchers and clinicians have been interested in the development of a short version of the PANSS that could reduce the burden of its administration for patients and raters. The author presents a comprehensive overview of existing brief PANSS measures, including their strengths and limitations, and discusses some possible next steps. There are two available scales that offer a reduced number of original PANSS items: PANSS-14 and PANSS-19; and two shorter versions that include six items: Brief PANSS and PANSS-6. The PANSS-6 has been tested quite extensively in established trials and appears to demonstrate high sensitivity to change and an established cut off definition for remission. Prospective testing in new antipsychotic treatment trials is still required for these shorter versions of PANSS. In addition, they need to be supplemented with interview guides, as well as provide conversion formulas to translate total scores from the short PANSS versions to the PANSS-30. Both short versions of the PANSS are essentially designed to evaluate response to antipsychotic treatment. Future PANSS scale development needs to address specific measurement of treatment-responsive positive symptoms by including treatment-sensitive items, as well as illness-phase specific PANSS tools. PMID- 29410941 TI - Positive and Negative Syndrome Scale (PANSS) Training: Challenges, Solutions, and Future Directions. AB - Rater training and the maintenance of the consistency of ratings are critical to ensuring reliability of study measures and sensitivity to changes in the course of a clinical trial. The Positive and Negative Syndrome Scale (PANSS) has been widely used in clinical trials of schizophrenia and other disorders and is considered the "gold standard" for assessment of antipsychotic treatment efficacy. The various features associated with training and calibration of this scale are complex, reflecting the intricacy and heterogeneity of the disorders that the PANSS is used to evaluate. In this article, the authors review the methods for ensuring reliability of the PANSS as well as a proposed trajectory for its use in the future. An overview of the current principles, implementation, technologies, and strategies for the best use of the PANSS; tips for how to achieve consistency among raters; and optimal training practices of this instrument are presented. PMID- 29410942 TI - The Clinical Burden of Rotavirus Gastroenteritis: A Prospective Study. AB - Background In Saudi Arabia, there is a lack of recently published, appropriately conducted epidemiological studies on rotavirus (RV) diarrhea, which emphasizes the need for up-to-date and comprehensive studies. Objective Our objective was to provide more recent data on the clinical and epidemiological characteristics as well as the economic burden of RV diarrhea among young children admitted to a tertiary care hospital in the city of Riyadh in the year prior to the initiation of the RV vaccine. Design We conducted a prospective observational study at a children's specialized hospital at King Fahad Medical City. We included children under five years of age who were hospitalized for gastroenteritis over a 12-month period from January 2012 to December 2012. Stool samples were collected on admission and tested for the presence of RV using an enzyme immunoassay. Results Of the 204 children included over the study period (mean age, 9.8 months +/- 10.2; 124 males), 102 (50%) were RV-positive. Two-thirds (69.6%) were under one year old, and 38.2% were under six months of age. RV infections occurred throughout the year, with the highest proportion occurring during the spring and summer. RV-positive diarrhea was more severe than the RV-negative diarrhea as indicated by a significantly lower bicarbonate level (68.6% versus 31.3%, P-value < 0.0001), a higher frequency of severe dehydration (11.7% versus 3%, P-value = 0.015), and longer hospital stay (mean duration, 8.78 versus 6.56 days, P-value = 0.027). In addition, the financial burden of the RV-positive cases was greater than the RV-negative cases (median 1692 USD versus 1287 USD, P-value = 0.001). Conclusion Our study shows a high prevalence of RV infections among young children admitted to the hospital for acute gastroenteritis. Furthermore, RV infections are associated with severe diarrhea and significant financial burden. PMID- 29410943 TI - Thrombotic Paradox: Ischaemic Stroke in Immune Thrombocytopaenia. A Case Report and Review. AB - Immune thrombocytopaenia (also known as idiopathic thrombocytopaenic purpura) (ITP) is a chronic condition with isolated low platelet counts. Although it is largely perceived that ITP predisposes to bleeding risks, thrombotic events, such as ischaemic strokes, do happen paradoxically in patients with ITP. A 68-year-old lady presented with right upper limb weakness and was diagnosed with an ischaemic stroke and was started on clopidogrel. She had a history of ITP. Two months later, she again had another ischaemic stroke. Prednisolone was added as her platelet count was below 50 x 109/L. Based on this case and recent case studies, we suggest the administration of antiplatelet or anticoagulant agents judiciously if the platelet count is 50 x 109/L or above with monitoring of bleeding risks. As for the management of ITP, we do agree with the general opinion that treatment is rarely required for patients with a platelet count above 50 x 109/L. We recommend a haematology consult for discussion on treatment initiation if the platelet count is below 50 x 109/L. PMID- 29410944 TI - Clinical Outcomes Observed among Biopsy Proven Lupus Nephritis Patients Treated with Mycophenolate Mofetil as First-line Therapy. AB - Background and objective The rate of end-stage renal disease from lupus nephritis has not declined, in spite of recent advances in therapeutics, such as mycophenolate mofetil (MMF). To provide insight into rates of the clinical outcomes in current practice after biopsy-proven lupus nephritis, we used a prospective cohort of the patients with newly diagnosed lupus nephritis, treated with MMF and observed their outcomes. Method Twenty systemic lupus erythematosus (SLE) patients who began mycophenolate mofetil shortly after a biopsy-confirmed diagnosis of lupus nephritis were included in the analysis. There were five patients with class III, nine with class IV, four with class III-V, one with class IV-V and two with class V lupus nephritis. The initial dose of mycophenolate mofetil was 1000 mg twice daily. If no improvement was observed, the dose was increased to 1500 mg twice daily after one month. We estimated the survival function for the time until the urine protein/creatinine reached 0.50 grams or less, after starting MMF by using an approach that accommodated interval censored data. We also evaluated the treatment response using five different sets of criteria for the response that have previously been used in the clinical trials. These included the Bristol Myers-Squibb (BMS), the American College of Rheumatology (ACR), the lupus nephritis assessment with rituximab (LUNAR ), the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS). Result We estimated that 52% of the SLE patients reached 0.50 grams of proteinuria within 51 days of starting mycophenolate mofetil (95% confidence interval 29%-74%) and 77% reached 0.50 grams or less within 260 days (95% confidence interval 57%-97%). The probability of response at 90 and 180 days was 5% and 33% (the Bristol Myers-Squibb), 26% and 57% (the American College of Rheumatology), and 11% and 28% (the lupus nephritis assessment with rituximab, the Aspreva Lupus Management Study and the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study). Conclusion The complete renal response ranged from 28% to 57% at six months in the routine clinical practice, mirroring the results in randomized clinical trials. Regardless of the response measures, the complete renal response was slow and, by most indices, reached in only a minority of the patients by the end of six months of the induction therapy. This indicates the urgent need for the faster and more effective lupus nephritis treatments. PMID- 29410945 TI - Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis. AB - Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients. PMID- 29410946 TI - Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer. AB - Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I). Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy. PMID- 29410947 TI - Before or After: Evolving Neoadjuvant Approaches to Locally Advanced Non-Small Cell Lung Cancer. AB - The treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is one of the most challenging and controversial areas of thoracic oncology. This heterogeneous group is characterized by varying tumor size and location, the potential for involvement of surrounding structures, and ipsilateral mediastinal lymph node spread. Neoadjuvant chemotherapy, administered prior to definitive local therapy, has been found to improve survival in patients with stage IIIA (N2) NSCLC. Concurrent chemoradiation has also been evaluated in phase III studies in efforts to improve control of locoregional disease. In certain instances, a tri-modality approach involving concurrent chemoradiation followed by surgery, may offer patients the best chance for cure. In this article, we provide an overview of the trials evaluating neoadjuvant therapy in patients with stage IIIA (N2) NSCLC that have resulted in current practice strategies, and we highlight the areas of uncertainty in the management of this challenging disease. We also review the current ongoing research and future directions in the management of stage IIIA (N2) NSCLC. PMID- 29410948 TI - Effects of Keratinocyte-Derived Cytokine (CXCL-1) on the Development of Theiler's Virus-Induced Demyelinating Disease. AB - CXCL-1, also called keratinocyte-derived cytokine (KC), is a predominant chemokine produced in glial cells upon infection with Theiler's murine encephalomyelitis virus (TMEV). In this study, we assessed the role of KC in the development of TMEV-induced demyelinating disease by utilizing polyclonal anti-KC antibodies as well as KC-expressing recombinant TMEV. Our results indicate that the level of KC produced after infection with TMEV or stimulation with various TLRs is significantly higher in various cells from susceptible SJL mice compared to those in cells from resistant B6 mice. SJL mice treated with rabbit anti-KC antibodies displayed accelerated development of TMEV-induced demyelinating disease, elevated viral loads in the CNS and decreased antiviral T cell responses. In addition, infection of susceptible SJL mice with recombinant KC TMEV produced biologically active KC, which resulted in the accelerated pathogenesis of demyelinating disease and elevated T cell responses to viral antigens compared to mice infected with control recombinant HEL-TMEV. These results strongly suggest that both the lack of KC during TMEV infection and the excessive presence of the chemokine promote the pathogenesis of demyelinating disease. Therefore, a balance in the level of KC during TMEV infection appears to be critically important in controlling the pathogenesis of demyelinating disease. PMID- 29410950 TI - TSEN54 Gene-Related Pontocerebellar Hypoplasia Type 2 Could Mimic Dyskinetic Cerebral Palsy with Severe Psychomotor Retardation. AB - Pontocerebellar hypoplasia (PCH) type 2 is a very rare autosomal recessive neurodegenerative disorder with prenatal onset that disrupts brain development. We present three patients (two siblings and one unrelated child) with PCH 2 linked to the most common mutation c.919G > T (p.Ala307Ser) in TSEN54 gene. The disease started soon after birth with feeding difficulties, extrapyramidal symptoms, psychomotor retardation, progressive microcephaly. Two of the patients were diagnosed with dyskinetic cerebral palsy (CP) at first. Despite the neurodegenerative character of PCH 2, the absence of regression and even some developmental progress in few patients, might erroneously lead to the incorrect diagnosis of dyskinetic CP. Megacisterna magna on brain ultrasound makes the diagnosis of PCH 2 highly probable and should prompt further imaging with MRI. MRI findings of PCH are pivotal for the diagnosis. Genetic testing for the most common mutation in TSEN54 gene should also be performed. Correct diagnosis of PCH 2 is essential not only for the prognosis of the patient, but also for prenatal diagnosis in future pregnancies. Knowledge of the clinical picture of PCH 2 will lead to correct and timely diagnosis. Advanced neuroimaging procedures and molecular genetic techniques provide valuable tools for prompt diagnosis of rare, but clinically important, neurogenetic imitators of CP. PMID- 29410951 TI - A Review of the Integrated Model of Care: An Opportunity to Respond to Extensive Palliative Care Needs in Pediatric Intensive Care Units in Under-Resourced Settings. AB - It is estimated that 6.3 million children who die annually need pediatric palliative care (PPC) and that only about 10% of them receive the attention they need because about 98% of them live in under-resourced settings where PPC is not accessible. The consultative model and the integrated model of care (IMOC) are the most common strategies used to make PPC available to critically ill children. In the consultative model, the pediatric intensive care unit (PICU) team, the patient, or their family must request a palliative care (PC) consultation with the external PC team for a PICU patient to be evaluated for special care needs. While the consultation model has historically been more popular, issues related to specialist availability, referral timing, staff's personal biases, misconceptions about PC, and other factors may impede excellent candidates from receiving the attention they need in a timely manner. Contrastingly, in the IMOC, family-centered care, PC tasks, and/or PC are a standard part of the treatment automatically available to all patients. In the IMOC, the PICU team is trained to complete critical and PC tasks as a part of normal daily operations. This review investigates the claim that the IMOC is the best model to meet extensive PPC needs in PICUs, especially in low-resource settings; based on an extensive review of the literature, we have identified five reasons why this model may be superior. The IMOC appears to: (1) improve the delivery of PPC and pediatric critical care, (2) allow clinicians to better respond to the care needs of patients and the epidemiological realities of their settings in ways that are consistent with evidence-based recommendations, (3) facilitate the universal delivery of care to all patients with special care needs, (4) maximize available resources, and (5) build local capacity; each of these areas should be further researched to develop a model of care that enables clinicians to provide pediatric patients with the highest attainable standard of health care. The IMOC lays out a pathway to provide the world's sickest, most vulnerable children with access to PPC, a human right to which they are entitled by international legal conventions. PMID- 29410952 TI - Skin Color, Cultural Capital, and Beauty Products: An Investigation of the Use of Skin Fairness Products in Mumbai, India. AB - The use of skin fairness products that frequently contain toxic ingredients is associated with significant adverse health side effects. Due to the high prevalence of use in Asian and African countries, skin fairness product use is recognized as a growing public health concern. The multi-million-dollar skin fairness product industry has also been criticized for perpetuating racism and social inequalities by reinforcing beliefs about the benefits of skin fairness for cultural capital. No quantitative studies have assessed people's beliefs about fairness and reasons for using or not using these products in India, one of the largest global markets for skin fairness products. The current study explored skin fairness product use among 1,992 women and men aged 16-60 years in the city of Mumbai, India using a self-report questionnaire. A total of 37.6% of the sample reported currently using skin fairness products, with women being two times more likely to use these products. Among current users, 17% reported past experiences of adverse side effects, and "Media/TV/Adverts" were the most common prompts for using fairness products, followed by "Friends" and "Family." Men were significantly more likely than women to endorse beliefs about fairness being more attractive and were more likely to perceive family and peers as viewing fairness as beneficial for cultural capital. There were no differences between women and men currently using products in their desire to look as fair as media celebrities. Among non-users, women were significantly more likely than men to report concerns about product efficacy and side effects as reasons for non-use, while men were significantly more likely to report socioeconomic reasons for non use. Implications of these findings are discussed in light of growing public health concerns about the use of fairness products, and potential for advocacy and public health interventions to address the use of skin fairness products. PMID- 29410953 TI - The Synergistic Antibacterial Mechanism of Gentamicin-Loaded CaCO 3 Nanoparticles. AB - In the present study, we used CaCO3 nanoparticles (CCNPs) as carriers to assess the physicochemical characteristics and antibacterial effect of gentamicin sulfate (GS)-loaded CCNPs (CGPs). The results indicated that CCNPs had relatively regular chain-like structure, and the size of the crystallites was around 62.5 nm. FT-IR analysis indicated that the GS could effectively load onto CCNPs. Meanwhile, the dosage of CCNPs would affect the drug loading and entrapment efficiency of GS. CCNPs could prolong the release of GS, and the complete release of GS from CCNPs was extended up to 24 h. Additionally, CCNPs could obviously increase the antibacterial effect of GS. The zeta potential analysis and microscopic investigations indicated that the adsorbed CCNPs could increase the damage level of bacterial cell wall and enhance the permeability of cell membranes, leading to increased bacterial death. PMID- 29410954 TI - Active Trachoma Cases in the Solomon Islands Have Varied Polymicrobial Community Structures but Do Not Associate with Individual Non-Chlamydial Pathogens of the Eye. AB - Background: Several non-chlamydial microbial pathogens are associated with clinical signs of active trachoma in trachoma-endemic communities with a low prevalence of ocular Chlamydia trachomatis (Ct) infection. In the Solomon Islands, the prevalence of Ct among children is low despite the prevalence of active trachoma being moderate. Therefore, we set out to investigate whether active trachoma was associated with a common non-chlamydial infection or with a dominant polymicrobial community dysbiosis in the Solomon Islands. Methods: We studied DNA from conjunctival swabs collected from 257 Solomon Islanders with active trachoma and matched controls. Droplet digital PCR was used to test for pathogens suspected to be able to induce follicular conjunctivitis. Polymicrobial community diversity and composition were studied by sequencing of hypervariable regions of the 16S ribosomal ribonucleic acid gene in a subset of 54 cases and 53 controls. Results: Although Ct was associated with active trachoma, the number of infections was low (cases, 3.9%; controls, 0.4%). Estimated prevalence (cases and controls, respectively) of each non-chlamydial infection was as follows: Staphylococcus aureus: 1.9 and 1.9%, Adenoviridae: 1.2 and 1.2%, coagulase negative Staphylococcus: 5.8 and 4.3%, Haemophilus influenzae: 7.4 and 11.7%, Moraxella catarrhalis: 2.3 and 4.7%, and Streptococcus pneumoniae: 7.0 and 6.2%. There was no statistically significant association between the clinical signs of trachoma and the presence or load of any of the non-Ct infections that were assayed. Interindividual variations in the conjunctival microbiome were characterized by differences in the levels of Corynebacterium, Propionibacterium, Helicobacter, and Paracoccus, but diversity and relative abundance of these specific genera did not differ significantly between cases and controls. Discussion: It is unlikely that the prevalent trachoma-like follicular conjunctivitis in this region of the Solomon Islands has a dominant bacterial etiology. Before implementing community-wide azithromycin distribution for trachoma, policy makers should consider that clinical signs of trachoma can be observed in the absence of any detectable azithromycin-susceptible organism. PMID- 29410949 TI - Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System. AB - The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS) regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by MU-opioid receptors, opiate drugs can also act through delta- and kappa-opioid receptors to modulate growth in a cell-type, region specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. To date, most studies have considered the acute effects of opiates on cellular maturation. For example, activating opioid receptors typically results in acute growth inhibition in both neurons and glia. However, with sustained opioid exposure, compensatory factors become operative, a concept that has been largely overlooked during CNS maturation. Accordingly, this article surveys prior studies on the effects of opiates on CNS maturation, and also suggests new directions for future research in this area. Identifying the cellular and molecular mechanisms underlying the adaptive responses to chronic opiate exposure (e.g., tolerance) during maturation is crucial toward understanding the consequences of perinatal opiate exposure on the CNS. PMID- 29410955 TI - A Randomized Placebo Controlled Clinical Trial to Determine the Impact of Digestion Resistant Starch MSPrebiotic(r) on Glucose, Insulin, and Insulin Resistance in Elderly and Mid-Age Adults. AB - Introduction: Type 2 diabetes (T2D) has reached epidemic proportions in North America. Recent evidence suggests that prebiotics can modulate the gut microbiome, which then plays an important role in regulating lipid metabolism, blood glucose, and insulin sensitivity. As such, prebiotics are appealing potential therapeutic strategies for prediabetes and T2D. The key objectives of this study were to determine the tolerability as well as the glucose and insulin modulating ability of MSPrebiotic(r) digestion resistant starch (DRS) in healthy mid-age (MID) and elderly (ELD) adults. Materials and methods: This was a prospective, blinded, placebo-controlled study. Prediabetes and diabetes were among the exclusion factors. ELD (>70 years) and MID (30-50 years) Canadian adults were recruited and, after 2 weeks of consuming placebo, they were randomized to consume 30 g of either MSPrebiotic(r) or placebo per day for 12 weeks. In total, 42 ELD and 42 MID participants completed the study. Blood samples were collected over the 14-week study and analyzed for glucose, lipid profile, and CRP, lipid particles, TNF-alpha, IL-10, insulin, and insulin resistance (IR). Results: At baseline, the ELD population had a significantly higher percentage (p < 0.01) with elevated glucose and significantly higher TNF alpha (p < 0.01) compared to MID adults. MSPrebiotic(r) DRS was well tolerated in both MID and ELD adults. There was a significant difference over time in blood glucose (p = 0.0301) and insulin levels (p = 0.009), as well as IR (HOMA-IR; p = 0.009) in ELD adults who consumed MSPrebiotic(r) compared to placebo. No significant changes were found in MID adults. Conclusion: Our results suggest that dietary supplementation with prebiotics such as MSPrebiotic(r) may be part of an effective strategy to reduce IR, a major risk factor for developing T2D, in the ELD. Clinical Trial Registration: NCT01977183 listed on NIH website: ClinicalTrials.gov, The metadata generated in this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/bioproject/381931). PMID- 29410956 TI - Effect of Hyperglycemia on Purinergic and Nitrergic Inhibitory Neuromuscular Transmission in the Antrum of the Stomach: Implications for Fast Gastric Emptying. AB - Background: Hyperglycemia has been reported to enhance vagovagal reflex that causes the release of inhibitory neurotransmitter, nitric oxide (NO), at the neuromuscular junction in the antrum to relax the antrum and slow gastric emptying by stimulating glucose-sensitive afferent neurons. However, hyperglycemia has also been reported to cause fast gastric emptying that may be due to suppression of the inhibitory motor neurons. Aims: The purpose of the present study was to investigate changes in inhibitory neuromuscular transmission in the gastric antrum due to hyperglycemia. Methods: Inhibitory electrical junction potentials were recorded from gastric antral muscle strips, using intracellular electrodes under non-adrenergic, non-cholinergic conditions. Studies were performed in non-hyperglycemic NOD (NH-NOD), NOD mice as they develop hyperglycemia (H-NOD) and their age-matched controls. The purinergic inhibitory junction potential (pIJP) and nitrergic IJP (nIJP) were isolated pharmacologically. Results: The control pIJP was large, around -18 mV and nIJP was small, around -9 mV. In NH-NOD the IJPs were not affected, but in H-NOD pIJP was nearly abolished and nIJP was significantly reduced. In H-NOD mice, membrane hyperpolarization caused by exogenous alpha,beta-MeATP or diethylenetriamine NO adduct was similar to that in wild-type controls (P > 0.05). H-NOD smooth muscles were significantly depolarized as compared to NH-NOD smooth muscles. Conclusion: These observations show that hyperglycemia causes suppression of purinergic and nitrergic transmission by acting on the motor neurons that form the last neuron in the vagovagal circuit. Moreover, the loss the neurotransmission is due to a defect in neurotransmitter release rather than a defect in signal transduction. Hyperglycemia also causes depolarization of smooth muscles that may increase their excitability. PMID- 29410957 TI - Time to change the single-centre approach to management of patients with tuberculosis: a novel network platform with automatic data import and data sharing. AB - Time to change the single-centre approach to TB http://ow.ly/lCeM30hBcbB. PMID- 29410958 TI - Incidence and predictive factors of lung cancer in patients with idiopathic pulmonary fibrosis. AB - The incidence and risk factors of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated. We conducted a retrospective study of 632 patients with IPF to assess the incidence and risk factors of lung cancer development. Seventy patients developed lung cancer over a median follow-up period of 3.8 years. The incidence density of lung cancer development was 25.2 cases per 1000 person-years. The most frequent type was squamous cell carcinoma (30%), the majority developed lung cancer in the peripheral lung (82.9%) and adjacent to usual interstitial pneumonia (75.7%). In a multivariate Cox regression hazard model, pack-years of smoking >=35 and coexisting emphysema were associated with lung cancer development. The 1-, 3- and 5-year all-cause mortality rates after lung cancer diagnosis were 53.5%, 78.6% and 92.9%, respectively. The incidence density of lung cancer is high in IPF patients and occurs more frequently in patients with smoking history of pack years of smoking >=35 and with coexisting emphysema. The majority of lung cancers develop adjacent to usual interstitial pneumonia. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management. PMID- 29410959 TI - Possible Estrogen Dependency in the Pathogenesis of Branchial Cleft Cysts. AB - Background: Even though branchial cleft cysts are currently accepted as a congenital anomaly, there is often a long delay until clinical presentation; branchial cleft cysts classically appear in the second to fourth decade of life. Our observation of their occurrence in three pregnant women encouraged us to contemplate a possible hormonal influence. Methods: Immunohistological analysis was performed for the evaluation of the estrogen receptor alpha (ERalpha) in paraffin-embedded tissue specimens of 16 patients with a diagnosis of branchial cleft cyst, with three of them being pregnant. Results: Expression of ERalpha was detected within epithelial cells only in branchial cleft cysts in pregnant females; moreover, higher growth fractions (Ki-67/Mib1) were found. Conclusion: The fact that the estrogen receptor was expressed only in pregnant women, in contrast to 13 investigated cases, may suggest that the high level of estrogen in pregnancy is a possible explanation for the spontaneous growth of branchial cleft cysts. PMID- 29410960 TI - In Vitro Anthelmintic Activity of Crude Extracts of Aerial Parts of Cissus quadrangularis L. and Leaves of Schinus molle L. against Haemonchus contortus. AB - Background: Haemonchus contortus, the causative agent of Haemonchosis, is the most economically important parasite in small ruminant production. Control with chemotherapy has not been successful due to rapid emergence of drug-resistant strains. There is a continuous search for alternative leads particularly from plants. The study aimed to evaluate the anthelmintic activity of crude methanolic extracts of leaves of Schinus molle and aerial parts of Cissus quadrangularis against H. contortus. Methods. Adult motility test and egg hatching inhibition assay were employed to investigate the in vitro adulticidal and egg hatching inhibitory effects of the extracts. Results: Higher concentrations of the extracts (10 and 5 mg/ml) had a significantly superior adulticidal activity (p < 0.05) compared to the negative control and lower concentration levels, which was comparable to albendazole. Similarly, the relative egg hatch inhibition efficacy of S. molle and C. quadrangularis extracts indicated a maximum of 96% and 88% egg hatch inhibition, respectively, within the 48 hrs of exposure at 1 mg/ml. Conclusion: The current study evidenced that the crude methanolic extracts of the plants have promising adulticidal and egg hatching inhibitory effects against H. contortus. PMID- 29410961 TI - The Diagnostic Roles of Cytokines in Hepatobiliary Cancers. AB - Objectives: The aim of this study was to investigate the role of several cytokines including IL-2, IL-6, IL-8, IL-10, and TNF-alpha in the diagnosis of HPB cancers. Materials and Methods: The prospective study was performed between October 2007 and September 2014. The study included 226 patients who were divided into 5 groups depending on their postoperative and histopathologic diagnosis: Control group included 30 healthy volunteers. Hepatocellular cancer (HCC) group included 24 patients diagnosed with HCC. Gallbladder cancer (GBC) group included 36 patients diagnosed with GBC. Cholangiocellular carcinoma group included 64 patients diagnosed with cholangiocellular carcinoma. Pancreatic cancer group included 72 patients diagnosed with pancreatic cancer. Serum levels of IL-2, IL 6, IL-8, IL-10, and TNF-alpha were measured using an enzyme-linked immunosorbent assay kit in accordance with the guidelines of the producer. Results: Serum TNF alpha concentration was significantly higher in the cholangiocellular carcinoma and pancreatic cancer groups compared to other groups. IL-6 and IL-10 were significantly increased in both the HCC and GBC groups, IL-2, IL-6, IL-10, and TNF-alpha in the cholangiocellular carcinoma group, and IL-2, IL-6, IL-8, and TNF alpha in the pancreatic cancer group. Conclusion: We suggest that cytokines can be used as useful markers in the diagnosis of HPB cancers. PMID- 29410962 TI - Trichomonas vaginalis Induces SiHa Cell Apoptosis by NF-kappaB Inactivation via Reactive Oxygen Species. AB - Trichomonas vaginalis induces apoptosis in host cells through various mechanisms; however, little is known about the relationship between apoptosis, reactive oxygen species (ROS), and NF-kappaB signaling pathways in the cervical mucosal epithelium. Here, we evaluated apoptotic events, ROS production, and NF-kappaB activity in T. vaginalis-treated cervical mucosal epithelial SiHa cells, with or without specific inhibitors, using fluorescence microscopy, DNA fragmentation assays, subcellular fractionation, western blotting, and luciferase reporter assay. SiHa cells treated with live T. vaginalis at a multiplicity of infection of 5 (MOI 5) for 4 h produced intracellular and mitochondrial ROS in a parasite load-dependent manner. Incubation with T. vaginalis caused DNA fragmentation, cleavage of caspase 3 and PARP, and release of cytochrome c into the cytoplasm. T. vaginalis-treated SiHa cells showed transient early NF-kappaB p65 nuclear translocation, which dramatically dropped at 4 h after treatment. Suppression of NF-kappaB activity was dependent on parasite burden. However, treatment with the ROS scavenger, N-acetyl-C-cysteine (NAC), reversed the effect of T. vaginalis on apoptosis and NF-kappaB inactivation in SiHa cells. Taken together, T. vaginalis induces apoptosis in human cervical mucosal epithelial cells by parasite-dose dependent ROS production through an NF-kappaB-regulated, mitochondria-mediated pathway. PMID- 29410963 TI - Cotransplantation of Mesenchymal Stem Cells and Immature Dendritic Cells Potentiates the Blood Glucose Control of Islet Allografts. AB - Background: Transplantation of islets is a promising alternative to treat type 1 diabetes (T1D), but graft rejection is the major obstacle to its application in clinical practice. We evaluated the effects of mesenchymal stem cells (MSCs) and immature dendritic cells (imDCs) on islet transplantation in diabetic model. Methods: The streptozotocin T1D model was established in BABL/c mice. Rat islets were isolated and identified with dithizone (DTZ) staining. MSCs and imDCs were isolated from bone marrow of syngenic mice. Islets, alone or along with MSCs and/or imDCs, were transplanted to the left kidney capsule of diabetic mice. The blood glucose levels and glycosylated hemoglobin levels after transplantation were monitored. Results: Cotransplantation significantly decreased blood glucose and glycosylated hemoglobin levels in the diabetes mice. Transplantation of 200 islets + 2 * 105 MSCs + 2 * 105 imDCs could not only restore normal blood glucose levels, but also significantly prolong graft survival for 12.6 +/- 3.48 days. Conclusions: Cotransplantation of allogenic islets with imDCs and/or MSCs can significantly promote graft survival, reverse hyperglycemia, and effectively control the glycosylated hemoglobin levels. PMID- 29410964 TI - A Comparison of Fosaprepitant and Ondansetron for Preventing Postoperative Nausea and Vomiting in Moderate to High Risk Patients: A Retrospective Database Analysis. AB - Postoperative nausea and vomiting (PONV) occur in 30-50% of patients undergoing general anesthesia and in 70-80% of high PONV risk patients. In this study, we investigated the efficacy of fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, compared to ondansetron, a selective 5-hydroxytryptamine type 3 (5 HT3) receptor antagonist, in moderate to high PONV risk patients from our previous randomized controlled trials. Patients (171 patients from 4 pooled studies) with the Apfel simplified score >= 2 and undergoing general anesthesia were randomly allocated to receive intravenous fosaprepitant 150 mg (NK1 group, n = 82) and intravenous ondansetron 4 mg (ONS group, n = 89) before induction of anesthesia. Incidence of vomiting was significantly lower in the NK1 group compared to the ONS group 0-2, 0-24, and 0-48 hours after surgery (2 versus 17%, 2 versus 28%, and 2 versus 29%, resp.). However, no significant differences in PONV, complete response, rescue antiemetic use, and nausea score were observed between groups 0-48 hours after surgery. In moderate to high PONV risk patients, fosaprepitant decreased the incidence of vomiting and was superior to ondansetron in preventing postoperative vomiting 0-48 hours after surgery. PMID- 29410965 TI - Learning and Using Abstract Words: Evidence from Clinical Populations. AB - It has been shown that abstract concepts are more difficult to process and are acquired later than concrete concepts. We analysed the percentage of concrete words in the narrative lexicon of individuals with Williams Syndrome (WS) as compared to individuals with Down Syndrome (DS) and typically developing (TD) peers. The cognitive profile of WS is characterized by visual-spatial difficulties, while DS presents with predominant impairments in linguistic abilities. We predicted that if linguistic abilities are crucial to the development and use of an abstract vocabulary, DS participants should display a higher concreteness index than both Williams Syndrome and typically developing individuals. Results confirm this prediction, thus supporting the hypothesis of a crucial role of linguistic processes in abstract language acquisition. Correlation analyses suggest that a maturational link exists between the level of abstractness in narrative production and syntactic comprehension. PMID- 29410966 TI - Antibacterial Activity of Ethanolic Extract of Syzygium polyanthum L. (Salam) Leaves against Foodborne Pathogens and Application as Food Sanitizer. AB - The aim of this study was to determine antibacterial activity of S. polyanthum L. (salam) leaves extract foodborne pathogens. All the foodborne pathogens were inhibited after treating with extract in disk diffusion test with range 6.67 +/- 0.58-9.67 +/- 0.58 mm of inhibition zone. The range of MIC values was between 0.63 and 1.25 mg/mL whereas MBC values were in the range 0.63 mg/mL to 2.50 mg/mL. In time-kill curve, L. monocytogenes and P. aeruginosa were found completely killed after exposing to extract in 1 h incubation at 4x MIC. Four hours had been taken to completely kill E. coli, S. aureus, V. cholerae, and V. parahaemolyticus at 4x MIC. However, the population of K. pneumoniae, P. mirabilis, and S. typhimurium only reduced to 3 log CFU/mL. The treated cell showed cell rupture and leakage of the cell cytoplasm in SEM observation. The significant reduction of natural microflora in grapes fruit was started at 0.50% of extract at 5 min and this concentration also was parallel to sensory attributes acceptability where application of extract was accepted by the panellists until 5%. In conclusion, S. polyanthum extract exhibits antimicrobial activities and thus might be developed as natural sanitizer for washing raw food materials. PMID- 29410967 TI - The Improvement of Laparoscopic Surgical Skills Obtained by Gynecologists after Ten Years of Clinical Training Can Reduce Peritoneal Adhesion Formation during Laparoscopic Myomectomy: A Retrospective Cohort Study. AB - Objective: To evaluate if improvement of laparoscopic skills can reduce postoperative peritoneal adhesion formation in a clinical setting. Study Design: We retrospectively evaluated 25 women who underwent laparoscopic myomectomy from January 1993 to June 1994 and 22 women who underwent laparoscopic myomectomy from March 2002 to November 2004. Women had one to four subserous/intramural myomas and received surgery without antiadhesive agents or barriers. Women underwent second-look laparoscopy for assessment of peritoneal adhesion formation 12 to 14 weeks after myomectomy. Adhesions were graded according to the Operative Laparoscopy Study Group scoring system. The main variable to be compared between the two cohorts was the proportion that showed no adhesions at second-look laparoscopy. Results: Demographic and surgical characteristics were similar between the two cohorts. No complications were observed during surgery. No adverse events were recorded during postoperative course. At second-look laparoscopy, a higher proportion of adhesion-free patients was observed in women who underwent laparoscopic myomectomy from March 2002 to November 2004 (9 out of 22) compared with women who underwent the same surgery from January 1993 to June 1994 (3 out of 25). Conclusion: The improvement of surgeons' skills obtained after ten years of surgery can reduce postoperative adhesion formation. PMID- 29410968 TI - Topical Tranexamic Acid Reduces Blood Loss in Minimally Invasive Total Knee Arthroplasty Receiving Rivaroxaban. AB - Background: It is unclear whether topical (intra-articular) or intravenous TXA reduces blood loss in minimally invasive TKA patients receiving a direct oral anticoagulant for thromboprophylaxis. This study is to investigate whether TXA given intravenously or intra-articularly is effective in reducing blood loss in minimally invasive TKA patients using rivaroxaban for thromboprophylaxis. Methods: Ninety-three patients who underwent primary minimally invasive TKA were divided into placebo group (30 patients) that received saline both intravenously and intra-articularly, intravenous (IV) group (31 patients) that received 1 g TXA intravenously, and topical group (32 patients) that received 3 g TXA in 100 ml saline intra-articularly. All patients received oral rivaroxaban of 10 mg daily for 14 days postoperatively. Results: p < 0.001 and p = 0.041. The mean total blood loss was 1131 mL (567-1845) in placebo, which was higher than that in the IV group (921 mL; range, 465-1495; p = 0.014) and the topical group (795 mL; range, 336-1350; p < 0.001). The total blood loss did not differ between the IV and the topical group (p = 0.179). Conclusion: This prospective, randomized, controlled trial demonstrated an equal efficacy of TXA in blood conservation when administered intravenously or topically in minimally invasive TKA patients receiving rivaroxaban for thromboprophylaxis. PMID- 29410969 TI - Elevated Serum Level of HMGB1 in Patients with the Antiphospholipid Syndrome. AB - Pregnancy problems are common in patients with rheumatic disease; indeed, autoimmune disorders and autoantibodies can affect pregnancy progress and lead to maternal complications. Recent studies have highlighted a close association between HMGB1, chronic inflammation, and autoimmune diseases. Thus, in this investigation, we analyzed serum levels of HMGB1, an alarmin which plays a pivotal role in inducing and enhancing immune cell function. Sera from 30 patients with antiphospholipid syndrome (11 primary and 19 secondary APS), 35 subjects with pregnancy morbidity, and 30 healthy women were analysed for HMGB1 and its putative receptor RAGE (sRAGE) by Western blot and for TNF-alpha by ELISA. Results revealed that APS patients showed significantly increased serum levels of HMGB1, sRAGE, and the proinflammatory cytokine TNF-alpha, as compared to healthy women. However, also, the pregnancy morbidity subjects showed significantly increased levels of HMGB1 and sRAGE as well as TNF-alpha compared to healthy women. Our findings suggest that in subjects with pregnancy morbidity, including obstetric APS, elevated levels of HMGB1/sRAGE may represent an alarm signal, indicating an increase of proinflammatory triggers. Further studies are needed to evaluate the role of HMGB1/sRAGE as a possible tool to evaluate the risk stratification of adverse pregnancy outcomes. PMID- 29410972 TI - Patellofemoral Instability: A Consensus Statement From the AOSSM/PFF Patellofemoral Instability Workshop. PMID- 29410974 TI - Bacteremia and Septic Arthritis due to a Nontoxigenic Strain of Clostridium difficile in a Patient With Sickle Cell Disease. AB - A 22-year-old female with sickle cell disease presented with fevers, bilateral knee pain, and lethargy. Laboratory data revealed a leukocytosis and lactic acidosis. Blood and synovial fluid cultures grew a non-toxin-producing strain of Clostridium difficile. This case highlights the fact that nontoxigenic Clostridium difficile can cause significant disease. PMID- 29410971 TI - The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer. AB - Macrophages are major cell types of the immune system, and they comprise both tissue-resident populations and circulating monocyte-derived subsets. Here, we discuss microglia, the resident macrophage within the central nervous system (CNS), and CNS-infiltrating macrophages. Under steady state, microglia play important roles in the regulation of CNS homeostasis through the removal of damaged or unnecessary neurons and synapses. In the face of inflammatory or pathological insults, microglia and CNS-infiltrating macrophages not only constitute the first line of defense against pathogens by regulating components of innate immunity, but they also regulate the adaptive arms of immune responses. Dysregulation of these responses contributes to many CNS disorders. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia and macrophages during CNS autoimmunity-multiple sclerosis and cancer-malignant glioma. We emphasize how the crosstalk between natural killer (NK) cells or glioma cells or glioma stem cells and CNS macrophages impacts on the pathological processes. Given the essential role of CNS microglia and macrophages in the regulation of all types of CNS disorders, agents targeting these subsets are currently applied in preclinical and clinical trials. We believe that a better understanding of the biology of these macrophage subsets offers new exciting paths for therapeutic intervention. PMID- 29410970 TI - The Role of NK Cells in Pig-to-Human Xenotransplantation. AB - Recruitment of human NK cells to porcine tissues has been demonstrated in pig organs perfused ex vivo with human blood in the early 1990s. Subsequently, the molecular mechanisms leading to adhesion and cytotoxicity in human NK cell porcine endothelial cell (pEC) interactions have been elucidated in vitro to identify targets for therapeutic interventions. Specific molecular strategies to overcome human anti-pig NK cell responses include (1) blocking of the molecular events leading to recruitment (chemotaxis, adhesion, and transmigration), (2) expression of human MHC class I molecules on pECs that inhibit NK cells, and (3) elimination or blocking of pig ligands for activating human NK receptors. The potential of cell-based strategies including tolerogenic dendritic cells (DC) and regulatory T cells (Treg) and the latest progress using transgenic pigs genetically modified to reduce xenogeneic NK cell responses are discussed. Finally, we present the status of phenotypic and functional characterization of nonhuman primate (NHP) NK cells, essential for studying their role in xenograft rejection using preclinical pig-to-NHP models, and summarize key advances and important perspectives for future research. PMID- 29410975 TI - Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia. AB - Background: Disease severity and outcome in community-acquired pneumonia (CAP) depend on the host and on the challenge of the causal microorganism(s). We measured levels of immunoglobulins (Igs) and complement in 257 hospitalized adults with CAP and examined the association of low levels of Igs or complement to microbial etiology, disease severity, and short-term and long-term outcome. Methods: Serum Igs were analyzed in blood samples obtained at admission and at 6 weeks postdischarge if admission levels were low. Serum complement deficiencies were screened with a total complement activity enzyme-linked immunosorbent assay (ELISA), with further analyzes performed if justified. Disease severity was assessed by the CURB-65 severity score. Short-term outcome was defined as a composite end point of intensive care unit (ICU) admission and 30-day mortality, and long-term outcome as 5-year all-cause mortality. Results: At admission, 87 (34%) patients had low levels of at least 1 Ig, with low IgG2 as the most prevalent finding (55/21%). IgG levels were lower in bacterial than viral CAP (8.48 vs 9.97 g/L, P = .023), but low Igs were not associated with microbial etiology. Fifty-five (21%) patients had low lectin pathway activity, of which 33 (13%) were mannose-binding lectin (MBL) deficient. Low admission levels of any Ig or MBL were not associated with disease severity, short-term outcome, or long term outcome. Excluding patients defined as immunocompromised from analysis did not substantially affect these results. Conclusion: In hospitalized adults with CAP, low admission levels of Igs or complement were in general not associated with microbial etiology, disease severity, short-term outcome, or long-term outcome. PMID- 29410978 TI - Prediction of Severity of Acute Pancreatitis Using Total Serum Calcium and Albumin-Corrected Calcium: A Prospective Study in Tertiary Center Hospital in Nepal. AB - Introduction: Total calcium (TC) and albumin-corrected calcium (ACC) are easily accessible AP severity tests in the Primary Health Care Center of Nepal. The aim of the study was to evaluate TC and ACC as prognostic severity markers in acute pancreatitis (AP). Methods: All patients admitted in Tribhuvan University Teaching Hospital with the diagnosis of AP were studied prospectively over a period of one year from January 2015 to January 2016. TC and ACC were measured in the first 24 hours of admission in each patient. The modified Marshall score was determined at admission and at 48 hours and at any point of time during admission as per the need of the patient. Severity of acute pancreatitis was defined as per the Revised Atlanta Classification 2012. Results: 80 patients of AP were included in the study. Among them, 14% were categorized as having severe AP. The mean total calcium was 8.22, 7.51, and 6.98 for mild, moderate, and severe AP, respectively, which was significant at 0.001. Conclusion: TC and ACC, measured within the first 24 hours, are useful severity predictors in acute pancreatitis. PMID- 29410979 TI - Ligand dynamics and protonation preferences of Rh and Ir complexes bearing an almost, but not quite, pendent base. AB - Pendent nucleophiles are essential partners in the cleavage and formation of bonds with hydrogen (e.g. protonation/deprotonation), but binding of the pendent group to the metal and the potential trapping of complexes in inactive states are a significant problem. The dipyridylmethane-based ligand framework bis(2-pyridyl) N-pyrrolidinomethane (R,pyrCPy2), bearing a hemilabile pyrrolidine moiety, has been synthesized and complexes of the type [(R,pyrCPy2)M(COD)]X (COD = 1,5 cyclooctadiene) were prepared. The solution-phase ligand dynamics and relative protonation preferences were investigated via1H NMR spectroscopy; although favorable, pendent amine binding does not kinetically inhibit pendent base protonation. Protonation at the metal (with concomitant pyrrolidine binding) has been found to be favorable for Ir, whereas N-protonation is favorable for Rh. DFT calculations predict that the RhIII hydrides have much higher relative acidities than their Ir congeners (DeltapKa ? 7-8 in CH2Cl2), and are also more acidic than the strong acid [H(OEt2)2][B(C6F5)4]. PMID- 29410976 TI - Working to Full Scope: The Reorganization of Nursing Work in Two Canadian Community Hospitals. AB - Work relationships between registered nurses (RNs) and practical nurses (LPNs) are changing as new models of nursing care delivery are introduced to create more flexibility for employers. In Canada, a team-based, hospital nursing care delivery model, known as Care Delivery Model Redesign (CDMR), redesigned a predominantly RN-based staffing model to a functional team consisting of fewer RNs and more LPNs. The scope of practice for LPNs was expanded, and unregulated health care assistants introduced. This study began from the standpoint of RNs and LPNs to understand their experiences working on redesigned teams by focusing on discourses activated in social settings. Guided by institutional ethnography, the conceptual and textual resources nurses are drawing on to understand these changing work relationships are explicated. We show how the institutional goals embedded in CDMR not only mediate how nurses work together, but how they subordinate holistic standards of nursing toward fragmented, task-oriented, divisions of care. PMID- 29410980 TI - Estimating the mean first passage time of protein misfolding. AB - Most theoretical and experimental studies confirm that proteins fold in the time scale of microseconds to milliseconds, but the kinetics of the protein misfolding remains largely unexplored. The kinetics of unfolding-folding-misfolding equilibrium in proteins is formulated in the analytical framework of the Master equation. The folded, unfolded and the misfolded state are characterized in terms of their respective contacts. The Mean First Passage Time (MFPT) to acquire the misfolded conformation from the native or folded state is derived from this equation with different boundary conditions. The MFPT is found to be practically independent of the length of the protein, the number of native contacts and the rate constant for the misfolded to the folded state. The results obtained from the survival probability are directly correlated to the age of onset and appearance of misfolding diseases in humans. PMID- 29410981 TI - Diet and microbiota linked in health and disease. AB - Diet has shaped microbiota profiles through human evolution. Traditional gut microbiomes are described to be driven by high levels of Prevotella. In the present, however, it is consistently described a lower microbial richness in urban industrialized populations compared with individuals living in rural settings, Bacteroides being predominant among urban-industrial gut microbiomes. Components of diet are highly influential in shaping the gut microbiota, being fiber, fat, proteins, polyphenols and micronutrients differentially metabolized by generalist and specialized microorganisms alone or through the phenomenon of cross-feeding. The progressive loss of microbial diversity over generations in industrialized societies along with the emerging increase of chronic non transmissible diseases have been related to the decline in the consumption of dietary fiber. Diet and derived microbial metabolites have strong implications with the development of food associated diseases such as obesity and metabolic syndrome, malnutrition and eating disorders, intestinal inflammatory diseases and colorectal cancer, among others. Still, there is a need of further studies in order to identify microbiota-related biomarkers of risk for these disorders. In turn, healthy diets and specific nutritional interventions, including increase of dietary fiber and the consumption of probiotics and prebiotics, could be valuable for restoration of beneficial bacteria and microbiota diversity capable to shift from disease to health promoting states. PMID- 29410982 TI - Carrier-doped aromatic hydrocarbons: a new platform in condensed matter chemistry and physics. AB - High-quality bulk samples of the first four polyacenes, which are naphthalene, anthracene, tetracene, and pentacene, doped with alkali metal in 1 : 1 and 1 : 2 stoichiometries were prepared and their fundamental properties were systematically studied. A new systematic understanding on the electronic states of electron-doped polyacenes sensitive to the energetic balance among on-site Coulomb repulsion, bandwidth and the Peierls instability was provided. The carrier-doped typical aromatic hydrocarbons showed a large variety of properties as well as charge transfer complexes and metal-doped fullerides. We open a new avenue for organometallic and inorganic chemistry. PMID- 29410984 TI - The role of water molecules in phototransduction of retinal proteins and G protein-coupled receptors. AB - G protein coupled receptors (GPCRs) are a key family of membrane proteins in all eukaryotes and also very important drug targets for medical intervention. The extensively studied visual pigment rhodopsin is a prime example of a family A GPCR. Its chromophore ligand retinal is covalently linked to a lysine in helix seven forming a protonated Schiff base. Interestingly, this is the same situation in other-non-GPCR-retinal proteins, like the prototype light-driven microbial proton pump bacteriorhodopsin, albeit there is no (or only a very remote) phylogenetical link. Close to the retinal ligand, several water molecules help to organise a functionally important hydrogen bond network that undergoes significant changes during photo-activation. Such water-mediated networks are also critical for ligand binding of other GPCRs and they are becoming increasingly important in drug discovery. GPCRs also contain a partially conserved water mediated hydrogen bond network that stabilises the ground state of the receptor, and rearrangement of this network leads to the stabilization of the active state. Some water molecules have a specific role in this process to appropriately orient specific residues relative to the Schiff base, and to modulate the fine structure of the transmembrane bundle, particularly near the intracellular G protein binding site. While the atomic details of these mechanisms are still missing, the recent developments in free electron lasers (FELs) are enabling us to begin to observe the changes in waters and relevant side chains shortly after photo activation at an unprecedented level of spatial and temporal resolution. PMID- 29410983 TI - Nanotopography regulates motor neuron differentiation of human pluripotent stem cells. AB - The regulation of human pluripotent stem cell (hPSC) behaviors has been mainly studied through exploration of biochemical factors. However, the current directed differentiation protocols for hPSCs that completely rely on biochemical factors remain suboptimal. It has recently become evident that coexisting biophysical signals in the stem cell microenvironment, including nanotopographic cues, can provide potent regulatory signals to mediate adult stem cell behaviors, including self-renewal and differentiation. Herein, we utilized a recently developed, large scale nanofabrication technique based on reactive-ion etching (RIE) to generate random nanoscale structures on glass surfaces with high precision and reproducibility. We report here that hPSCs are sensitive to nanotopographic cues and such nanotopographic sensitivity can be leveraged for improving directed neuronal differentiation of hPSCs. We demonstrate early neuroepithelial conversion and motor neuron (MN) progenitor differentiation of hPSCs can be promoted using nanoengineered topographic substrates. We further explore how hPSCs sense the substrate nanotopography and relay this biophysical signal through a regulatory signaling network involving cell adhesion, the actomyosin cytoskeleton, and Hippo/YAP signaling to mediate the neuroepithelial induction of hPSCs. Our study provides an efficient method for large-scale production of MNs from hPSCs, useful for regenerative medicine and cell-based therapies. PMID- 29410985 TI - Bromine-rich complexes of bismuth: experimental and theoretical studies. AB - Three novel polybromide complexes of bismuth(iii) - (2,6-MePyH)3[BiBr5(Br3)] (1), (H2bpp){[BiBr5](Br2)} (2) and (3-ClPyH)2{[BiBr5](Br2)} (3) - were synthesized. The results of an extended screening involving a set of organic cations resulting in the formation/non-formation of Bi(iii) polybromides are presented and discussed. The nature of BrBr interactions in Bi(iii) polybromides was investigated by theoretical methods, enabling the estimation of their energies. PMID- 29410986 TI - DFT modelling of a diphosphane - N-heterocyclic carbene-Rh(i) pincer complex rearrangement: a computational evaluation of the electronic effects in C-P bond activation. AB - DFT calculations confirmed that the rearrangement of a PCP-Rh-H pincer to a CCP Rh-phosphane pincer occured by C-P oxidative addition (DeltaG? = 29.5 kcal mol-1, rate-determining step), followed by P-H reductive elimination (DeltaG? = 4.8 kcal mol-1). The oxidative addition proceeded via a 3-centered transition state and is accelerated by electron-withdrawing substituents p- to the reacting C-P bond, resulting in a reaction constant (rho) of 2.12 for DeltaG? and 2.76 for DeltaH? in a Hammett-type linear free energy relationship. AIM wavefunction analyses indicated a decrease in the negative charge on the carbon bonded to Rh with a concomitant increase in the positive charge on the latter. The electronic density at the Rh-P bond critical point and the atomic charge on Rh correlate well with the Hammett constants (sigma) of the p-substituents. The replacement of the Rh bound hydride with other anions (CH3, Ph, t-Bu, OH, F, Cl, and CN) results in a decrease in the OA barrier only for CH3, which is in accordance with the experimental results. The reductive elimination occurs via a 3-centered (Rh, H, P) transition state, which adopts a conformation wherein the steric clash between the i-Pr groups is minimized, followed by recomplexation of Rh and the newly formed (i-Pr)2PH by a conformational twist around the Rh-P axis. PMID- 29410987 TI - A three-dimensional electrochemical paper-based analytical device for low-cost diagnostics. AB - Paper-based microfluidic devices with screen-printed electrodes (SPEs) for electrochemical sensing are popular for low-cost point-of-care diagnostics. The electroactive sensing area in these devices is always the irregular, bottom-SPE surface which is in contact with the analyte flowing within the paper substrate. Unfortunately, this results in an electroactive area which varies widely from sensor to sensor. In this paper, we present a three-dimensional paper-based analytical device with a hollow 3D fluid reservoir which allows for use of a more uniform top-SPE surface as the electroactive sensing area. The use of this isolated reservoir eliminates the need for dielectric inks used in conventional SPEs on paper. Our sensors are fabricated using a combination of wax-printing, screen-printing and simple folding via a cleanroom free process without the need for expensive equipment. Additionally, for the first time, we demonstrate an electrochemical paper-based analytical device with a custom designed potentiostat integrated circuit (IC) as a miniaturized reader. The versatility of the sensor is demonstrated through voltammetric, amperometric and potentiometric measurements of important biochemical analytes such as dopamine, glucose and pH. The 3D ePAD together with a custom CMOS potentiostat demonstrates a low-cost, versatile, self-contained system suitable for point-of-care diagnostic devices. PMID- 29410988 TI - Hydroperoxyl radical and formic acid formation from common DNA stabilizers upon low energy electron attachment. AB - 2-Amino-2-(hydroxymethyl)-1,3-propanediol (TRIS) and ethylenediaminetetraacetic acid (EDTA) are key components of biological buffers and are frequently used as DNA stabilizers in irradiation studies. Such surface or liquid phase studies are done with the aim to understand the fundamental mechanisms of DNA radiation damage and to improve cancer radiotherapy. When ionizing radiation is used, abundant secondary electrons are formed during the irradiation process, which are able to attach to the molecular compounds present on the surface. In the present study we experimentally investigate low energy electron attachment to TRIS and methyliminodiacetic acid (MIDA), an analogue of EDTA, supported by quantum chemical calculations. The most prominent dissociation channel for TRIS is through hydroperoxyl radical formation, whereas the dissociation of MIDA results in the formation of formic and acetic acid. These compounds are well-known to cause DNA modifications, like strand breaks. The present results indicate that buffer compounds may not have an exclusive protecting effect on DNA as suggested previously. PMID- 29410989 TI - Pneumatically actuated cell-stretching array platform for engineering cell patterns in vitro. AB - Cellular response to mechanical stimuli is a well-known phenomenon known as mechanotransduction. It is widely accepted that mechanotransduction plays an important role in cell alignment which is critical for cell homeostasis. Although many approaches have been developed in recent years to study the effect of external mechanical stimuli on cell behaviour, most of them have not explored the ability of mechanical stimuli to engineer cell alignment to obtain patterned cell cultures. This paper introduces a simple, yet effective pneumatically actuated 4 * 2 cell stretching array for concurrently inducing a range of cyclic normal strains onto cell cultures to achieve predefined cell alignment. We utilised a ring-shaped normal strain pattern to demonstrate the growth of in vitro patterned cell cultures with predefined circumferential cellular alignment. Furthermore, to ensure the compatibility of the developed cell stretching platform with general tools and existing protocols, the dimensions of the developed cell-stretching platform follow the standard F-bottom 96-well plate. In this study, we report the principle design, simulation and characterisation of the cell-stretching platform with preliminary observations using fibroblast cells. Our experimental results of cytoskeleton reorganisation such as perpendicular cellular alignment of the cells to the direction of normal strain are consistent with those reported in the literature. After two hours of stretching, the circumferential alignment of fibroblast cells confirms the capability of the developed system to achieve patterned cell culture. The cell-stretching platform reported is potentially a useful tool for drug screening in 2D mechanobiology experiments, tissue engineering and regenerative medicine. PMID- 29410990 TI - Structural determinants in the bulk heterojunction. AB - Photovoltaics is one of the key areas in renewable energy research with remarkable progress made every year. Here we consider the case of a photoactive material and study its structural composition and the resulting consequences for the fundamental processes driving solar energy conversion. A multiscale approach is used to characterize essential molecular properties of the light-absorbing layer. A selection of bulk-representative pairs of donor/acceptor molecules is extracted from the molecular dynamics simulation of the bulk heterojunction and analyzed at increasing levels of detail. Significantly increased ground state energies together with an array of additional structural characteristics are identified that all point towards an auxiliary role of the material's structural organization in mediating charge-transfer and -separation. Mechanistic studies of the type presented here can provide important insights into fundamental principles governing solar energy conversion in next-generation photovoltaic devices. PMID- 29410991 TI - NIR/blue light emission optimization of NaY1-(x+y)YbxF4:Tmy upconversion nanoparticles via Yb3+/Tm3+ dopant balancing. AB - The increased applications of lanthanide-doped upconversion nanoparticles (UCNPs) in areas such as biomedical imaging and therapy have raised the demand for high quality nanocrystals with strong and controllable luminescence intensity. Whilst several different approaches including core/shell arrangement, dye sensitization and plasmonic metallic nanostructures have been employed to improve the upconversion luminescence of UCNPs, they may be impractical for scale-up production and applications. Herein, a mathematical model that was developed using multivariate statistical analysis shows that the key to optimising the NIR and blue light emission of NaY1-(x+y)YbxF4:Tmy UCNPs is dopant balancing, where the composition of both ytterbium (Yb3+) sensitizer and thulium (Tm3+) activator is controlled in a way that the concentration and proximity of the dopants to each other can reduce cross-relaxation between Tm3+ and self-quenching that is due to sub-optimal Yb3+ concentrations, and consequently, favours efficient energy transfer between the Yb3+ sensitizers and Tm3+ activators. The data driven approach gives better understanding of the role of dopant balancing in the upconversion process and presents a general yet effective strategy to enhance the optical properties of UCNPs by manipulating the relative concentrations of the lanthanide dopants. This systematic approach will have important implications and it can be integrated with other emission enhancing strategies to produce high quality UCNPs for diverse applications in photonics, imaging, sensing, drug delivery and solar energy conversion. PMID- 29410992 TI - Kinetics of spin crossover with thermal hysteresis. AB - Non-isothermal kinetic studies of spin crossover allow establishing a reaction model of hysteretic spin state switching. PMID- 29410993 TI - Enhancement of tunneling current in phosphorene tunnel field effect transistors by surface defects. AB - The effects of the staggered double vacancies, hydrogen (H), 3d transition metals, for example cobalt, and semiconductor covalent atoms, for example, germanium, nitrogen, phosphorus (P) and silicon adsorption on the transport properties of monolayer phosphorene were studied using density functional theory and non-equilibrium Green's function formalism. It was observed that the performance of the phosphorene tunnel field effect transistors (TFETs) with an 8.8 nm scaling channel length could be improved most effectively, if the adatoms or vacancies were introduced at the source channel interface. For H and P doped devices, the upper limit of on-state currents of phosphorene TFETs were able to be quickly increased to 2465 MUA MUm-1 and 1652 MUA MUm-1, respectively, which not only outperformed the pristine sample, but also met the requirements for high performance logic applications for the next decade in the International Technology Roadmap for Semiconductors (ITRS). It was proved that the defect induced band gap states make the effective tunneling path between the conduction band (CB) and valence band (VB) much shorter, so that the carriers can be injected easily from the left electrode, then transfer to the channel. In this regard, the tunneling properties of phosphorene TFETs can be manipulated using surface defects. In addition, the effects of spin polarization on the transport properties of doped phosphorene TFETs were also rigorously considered, H and P doped TFETs could achieve a high ON current of 1795 MUA MUm-1 and 1368 MUA MUm-1, respectively, which is closer to realistic nanodevices. PMID- 29410994 TI - Butadiene as a ligand in open sandwich compounds. AB - Theoretical methods show that the lowest energy bis(butadiene)metal structures (C4H6)2M (M = Ti to Ni) have a perpendicular relative orientation of the two butadiene ligands corresponding to a tetrahedral coordination of the central metal atom to the four C[double bond, length as m-dash]C double bonds of the butadiene ligands. Distribution of the metal d electrons in the resulting tetrahedral ligand field rationalizes the predicted spin states increasing monotonically from singlet to quartet from nickel to manganese and back from quartet to singlet from manganese to titanium. PMID- 29410995 TI - "Solvent-in-salt" systems for design of new materials in chemistry, biology and energy research. AB - Inorganic and organic "solvent-in-salt" (SIS) systems have been known for decades but have attracted significant attention only recently. Molten salt hydrates/solvates have been successfully employed as non-flammable, benign electrolytes in rechargeable lithium-ion batteries leading to a revolution in battery development and design. SIS with organic components (for example, ionic liquids containing small amounts of water) demonstrate remarkable thermal stability and tunability, and present a class of admittedly safer electrolytes, in comparison with traditional organic solvents. Water molecules tend to form nano- and microstructures (droplets and channel networks) in ionic media impacting their heterogeneity. Such microscale domains can be employed as microreactors for chemical and enzymatic synthesis. In this review, we address known SIS systems and discuss their composition, structure, properties and dynamics. Special attention is paid to the current and potential applications of inorganic and organic SIS systems in energy research, chemistry and biochemistry. A separate section of this review is dedicated to experimental methods of SIS investigation, which is crucial for the development of this field. PMID- 29410996 TI - Modulation of thiol-dependent redox system by metal ions via thioredoxin and glutaredoxin systems. AB - The thioredoxin and glutaredoxin systems possess a variety of biological activities in mammalian cells, including the defense against oxidative stress, regulation of DNA synthesis, the cell cycle and the mediation of apoptosis. The thioredoxin system, comprised of NADPH, thioredoxin reductase (TrxR) and thioredoxin (Trx), exerts its activities via a disulfide-dithiol exchange reaction. Mammalian TrxRs are selenoproteins; the thiols and selenols in the active site of these enzymes confer the thioredoxin system to work as soft bases, which have a high affinity with soft acids, including numerous metal ions. In this review we focus on recent advances in the modulation of thioredoxin and glutaredoxin systems by metal ion soft acids. Numerous clinical metal-containing drugs, such as platinum- and gold-containing compounds, show inhibitory effects on the thioredoxin system, providing strategies to develop novel anti-cancer drugs. Moreover, inhibition of the Trx system by soft acids, such as mercury-, chromium- and arsenic-containing compounds cause changes in the cellular redox state and contribute to their cell toxicity. In addition, metal ions are also involved in the regulation of the glutaredoxin system. Iron ions participate in regulating Grx2 activity via iron-sulfur cluster formation. Moreover, Grx5 in mitochondria contains a 2Fe-2S cluster stabilized by GSH, which can mediate cellular iron metabolism. Collectively, these results demonstrate that metal ions are major players in regulating the Trx and Grx systems-mediated cellular redox processes and thus, provide an opportunity to understand the functions of metal ions in thiol metabolism dysfunction-related diseases. PMID- 29410997 TI - Substrate modified thermal stability of mono- and few-layer MoS2. AB - Two-dimensional semiconducting transition metal dichalcogenides have been employed as key components in various electronic devices. The thermal stability of these ultrathin materials must be carefully considered in device applications because the heating caused by current flow, light absorption, or other harsh environmental conditions is usually unavoidable. In this work, we found that the substrate plays a role in modifying the thermal stability of mono- and few-layer MoS2. Triangular etching holes, which are considered to initiate from defect sites, form on MoS2 when the temperature exceeds a threshold. On Al2O3 and SiO2, monolayer MoS2 is found to be more stable in thermal annealing than few-layer MoS2 either in atmospheric-pressure air or under vacuum; while on mica, the absolute opposite behavior exists. However, this difference due to substrates appears to vanish when using defective, chemical-vapor-deposited MoS2 samples. The substrate modification of the thermal stability of MoS2 with various thicknesses is attributed to the competition between MoS2-substrate interface interaction and MoS2-MoS2 interlayer interaction. Our findings provide important design rules for MoS2-based devices, and also potentially point to a route of controlled patterning of MoS2 with substrate engineering. PMID- 29410998 TI - The influence of like-charge attraction on the structure and dynamics of ionic liquids: NMR chemical shifts, quadrupole coupling constants, rotational correlation times and failure of Stokes-Einstein-Debye. AB - Ion pairing is one of the most fundamental atomic interactions in chemistry and biology. In contrast, pairing between like-charged ions remains an elusive concept. So far, this phenomenon was observed only for large-scaled structures, assemblies, stabilizing frameworks, or in aqueous solution wherein like-charge attraction is supported by mediating water molecules. Recently, we reported the formation of cationic clusters in pure ionic liquids (ILs) which all include hydroxyl groups (OH) for possible hydrogen bonding. In such structures like charge repulsion is overcome by cooperative hydrogen bonds. The vibrational bands in the OH-stretch region of the infrared spectra can be clearly assigned to H bonded ion pairs (c-a) or to H-bonded cationic clusters (c-c). The equilibrium between both types of ionic clusters can be controlled by using the same cation but differently strong interacting anions. In the present work, we study the influence of the cationic cluster formation on structural and dynamical NMR properties of ionic liquids, where we know that they form cationic clusters to different extent. First, we measure proton chemical shifts, delta1H, and determine deuteron quadrupole coupling constants, chiD, from a calculated relation between both NMR properties. Reliable chiD values for the liquid phase are a prerequisite for calculating reorientational correlation times, tauOH, from measured deuteron relaxation times, T1. It is shown that the correlation times are significantly influenced by the amount of cationic clusters present in the IL. The Stokes-Einstein-Debye (SED) relation is valid for the ILs wherein H bonded ion pairs (c-a) are the dominant species. With increasing cationic cluster (c-c) formation of e.g. cyclic tetramers, SED breaks down because of the structural heterogeneities. PMID- 29410999 TI - Control of the microstructure and surface chemistry of graphene aerogels via pH and time manipulation by a hydrothermal method. AB - Three-dimensional graphene aerogels of controlled pore size have emerged as an important platform for several applications such as energy storage or oil-water separation. The aerogels of reduced graphene oxide are mouldable and light weight, with a porosity up to 99.9%, consisting mainly of macropores. Graphene aerogel preparation by self-assembly in the liquid phase is a promising strategy due to its tunability and sustainability. For graphene aerogels prepared by a hydrothermal method, it is known that the pH value has an impact on their properties but it is unclear how pH affects the auto-assembly process leading to the final properties. We have monitored the time evolution of the chemical and morphological properties of aerogels as a function of the initial pH value. In the hydrothermal treatment process, the hydrogel is precipitated earlier and with lower oxygen content for basic pH values (~13 wt% O) than for acidic pH values (~20 wt% O). Moreover, ~7 wt% of nitrogen is incorporated on the graphene nanosheets at basic pH generated by NH3 addition. To our knowledge, there is no precedent showing that the pH value affects the microstructure of graphene nanosheets, which become more twisted and bent for the more intensive deoxygenation occurring at basic pH. The bent nanosheets attained at pH = 11 reduce the stacking by the basal planes and they connect via the borders, hence leading eventually to higher pore volumes. In contrast, the flatter graphene nanosheets attained under acidic pH entail more stacking and higher oxygen content after a long hydrothermal treatment. The gravimetric absorption capacity of non-polar solvents scales directly with the pore volume. The aerogels have proved to be highly selective, recyclable and robust for the absorption of nonpolar solvents in water. The control of the porous structure and surface chemistry by manipulation of pH and time will also pave the way for other applications such as supercapacitors or batteries. PMID- 29411000 TI - Solution-phase deposition of SnS thin films via thermo-reduction of SnS2. AB - Here, we demonstrate a novel solution-based route for deposition of tin monosulfide (SnS) thin films, which are emerging, non-toxic absorber materials for low-cost and large-scale PV applications via thermo-reducing Sn(iv) to Sn(ii). Upon optimizing the morphology of the SnS layer via adding a seed layer, the SnS-based hybrid solar cells show promising photocurrent conversion efficiencies. PMID- 29411001 TI - Divergent access to N-hydroxypyrroles and isoxazoles via the gold(i)- or Bronsted acid-catalysed regioselective cyclization of N-(2-trifluoromethyl-3-alkynyl) oximes. AB - The divergent regioselective cyclization of N-(2-trifluoromethyl-3-alkynyl) oximes by a suitable choice of a gold(i) or a Bronsted acid catalyst, leading to 4-trifluoromethyl-N-hydroxypyrroles or 4-trifluoromethyl-5-alkylisoxazoles was developed. In order to avoid the tedious separation of unstable N-(2 trifluoromethyl-3-alkynyl) oximes, an easy two-step, one-pot synthesis of 4 trifluoromethyl-5-alkylisoxazoles was realized via the sequential oxidation of the corresponding hydroxylamines and subsequent treatment with the reductant, sodium thiosulfate (Na2S2O3). This two-step, one-pot procedure is a complementary method for the synthesis of 4-trifluoromethyl-5-alkylisoxazole from those unstable N-(2-trifluoromethyl-3-alkynyl) oximes. PMID- 29411002 TI - Enhanced electrochemical performance of lithium ion batteries using Sb2S3 nanorods wrapped in graphene nanosheets as anode materials. AB - Antimony sulfide can be used as a promising anode material for lithium ion batteries due to its high theoretical specific capacity derived from sequential conversion and alloying lithium insertion reactions. However, the volume variation during the lithiation/delithiation process leads to capacity fading and cyclic instability. We report a facile, one-pot hydrothermal strategy to prepare Sb2S3 nanorods wrapped in graphene sheets that are promising anode materials for lithium ion batteries. The graphene sheets serve a dual function: as heterogeneous nucleation centers in the formation process of Sb2S3 nanorods, and as a structural buffer to accommodate the volume variation during the cycling process. The resulting composites exhibit excellent electrochemical performance with a highly reversible specific capacity of ~910 mA h g-1, cycling at 100 mA g 1, as well as good rate capability and cyclic stability derived from their unique structural features. PMID- 29411003 TI - Correction: The stability and generation pattern of thermally formed isocyanic acid (ICA) in air - potential and limitations of proton transfer reaction-mass spectrometry (PTR-MS) for real-time workroom atmosphere measurements. AB - Correction for 'The stability and generation pattern of thermally formed isocyanic acid (ICA) in air - potential and limitations of proton transfer reaction-mass spectrometry (PTR-MS) for real-time workroom atmosphere measurements' by Mikolaj Jan Jankowski et al., Environ. Sci.: Processes Impacts, 2016, 18, 810-818. PMID- 29411004 TI - Band alignments and heterostructures of monolayer transition metal trichalcogenides MX3 (M = Zr, Hf; X = S, Se) and dichalcogenides MX2 (M = Tc, Re; X=S, Se) for solar applications. AB - Knowledge of band alignments and heterostructure formations is fundamental for a new generation of optoelectronics based on two-dimensional layered materials. Herein, band alignments and heterostructures of IVB-VIA monolayer MX3 (M = Zr, Hf; X = S, Se) and VIIB-VIA monolayer MX2 (M = Tc, Re; X = S, Se) are calculated by density functional theory with hybrid functionals. The results indicate that for monolayer MX3, the valence bands mainly depend on the p state of the chalcogens and the conduction bands mainly depend on the d state of the transition metals. In contrast, for monolayer MX2, both valence and conduction bands depend on the d state of the transition metals. This suggests that their work functions are obviously different. Meanwhile, the characteristics of the band alignments and the planar-averaged local density of states show that ZrS3, HfS3, TcSe2 and ReS2 could be favorable candidates for photocatalytic water splitting. ZrS3, HfS3 and MX2 with the same structures are able to form type II heterostructures at their interfaces, which could be used for solar energy conversion. The power-conversion efficiency of an MX3 thin-film solar cell is approximately 16-18%, which is higher than those of MX2 thin-film solar cells. In addition, for heterostructures composed of MX3, both of the two kinds of material (M and X) play an important role in every band formation. Meanwhile, for MX2 heterostructures, almost every band depends only on a single material. The charge density difference of the heterostructures demonstrates a higher charge accumulation at the interface of MX3 heterostructures than that of MX2 heterostructures. These phenomena show that type II heterostructures formed of MX3 are more stable than those of MX2. PMID- 29411005 TI - Investigation of multi-bunching by generating multi-order fluorescence of NV center in diamond. AB - Fabricating electronics from solid-state quantum emitters is a promising strategy for the miniaturization and integration of electronic devices. However, the practical realization of solid-state quantum devices and circuits for signal transmission and processing at room temperature has remained challenging. Herein, we investigated the multi-bunching phenomenon by generating multi-order fluorescence from a pseudo-thermal source at room temperature using the nitrogen vacancy (NV) center in diamond. We demonstrate the shift in time of multi bunching by controlling the effect of dressing to realize logical gates and transistor switching operations. We also suggest the optimization of the time propagation delay (TPD) of the gate circuit by changing the boxcar gate position. PMID- 29411007 TI - An unprecedented nanocage-like and heterometallic [MoO4]-polyoxomolybdate hybrid. AB - The solvothermal oxidation of [Mo3O2(O2CCH3)6(H2O)3].ZnCl4 has been established as a general route toward [Mo4+3O4]-incorporated polyoxomolybdates (MoIV-POMs). Two unprecedented family members: the first Mo4+-Mo5+-Mo6+ nanocage cluster, Na[MoMoMoO43(OH)Py12].11H2O (1) and the first heterometallic hybrid, [MoMoZn(PO4)4(OH)2O31py3].2(C5H6N).3(C5H5N).2H2O (2) have been prepared and characterized by X-ray crystallography, elemental and DFT theoretical analyses, XPS, mass spectroscopy, cyclic voltammetry, and IR spectroscopy. PMID- 29411006 TI - Fast functionalization of ultrasound microbubbles using strain promoted click chemistry. AB - Functionalization of microbubbles (MBs) is a difficult issue due to their unstable nature. Here we report a fast and versatile method using a strain promoted alkyne-azide cycloaddition (SPAAC) click reaction for microbubble functionalization. An azadibenzocyclooctyne (DBCO) group was first introduced onto the MB surface and then an azide group into the desired ligand. Without any initiators or catalysts, essential click ligation occurred within 1 min and a majority of the reaction completed in 5 min at 37 degrees C. This fast ligation shortens the microbubble reaction time and preserves essential amounts of microbubbles for further in situ imaging and delivery of therapeutics. PMID- 29411008 TI - Manual Versus Automated Narrative Analysis of Agrammatic Production Patterns: The Northwestern Narrative Language Analysis and Computerized Language Analysis. AB - Purpose: The purpose of this study is to compare the outcomes of the manually coded Northwestern Narrative Language Analysis (NNLA) system, which was developed for characterizing agrammatic production patterns, and the automated Computerized Language Analysis (CLAN) system, which has recently been adopted to analyze speech samples of individuals with aphasia (a) for reliability purposes to ascertain whether they yield similar results and (b) to evaluate CLAN for its ability to automatically identify language variables important for detailing agrammatic production patterns. Method: The same set of Cinderella narrative samples from 8 participants with a clinical diagnosis of agrammatic aphasia and 10 cognitively healthy control participants were transcribed and coded using NNLA and CLAN. Both coding systems were utilized to quantify and characterize speech production patterns across several microsyntactic levels: utterance, sentence, lexical, morphological, and verb argument structure levels. Agreement between the 2 coding systems was computed for variables coded by both. Results: Comparison of the 2 systems revealed high agreement for most, but not all, lexical-level and morphological-level variables. However, NNLA elucidated utterance-level, sentence level, and verb argument structure-level impairments, important for assessment and treatment of agrammatism, which are not automatically coded by CLAN. Conclusions: CLAN automatically and reliably codes most lexical and morphological variables but does not automatically quantify variables important for detailing production deficits in agrammatic aphasia, although conventions for manually coding some of these variables in Codes for the Human Analysis of Transcripts are possible. Suggestions for combining automated programs and manual coding to capture these variables or revising CLAN to automate coding of these variables are discussed. PMID- 29411009 TI - Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy. AB - Purpose: Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Muller cells. Methods: Sprague Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Muller cells exposed to hyperglycemia. Results: In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-alpha and IL-6. Muller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase-1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-2'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Muller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. Conclusions: Our data demonstrate the ability of dh404 to protect the retina against diabetes-induced damage and potentially prevent vision loss. PMID- 29411010 TI - Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa. AB - Purpose: To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods: First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results: Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half sibling sister with a different father. Conclusions: The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys. PMID- 29411011 TI - Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma. AB - Purpose: Optic nerve cupping in glaucoma is characterized by remodeling of the extracellular matrix (ECM) and fibrosis in the lamina cribrosa (LC). We have previously shown that glaucoma LC cells express raised levels of ECM genes and have elevated intracellular calcium ([Ca2+]i). Raised [Ca2+]i is known to promote proliferation, activation, and contractility in fibroblasts via the calcineurin NFAT (nuclear factor of activated T-cells) signaling pathway. In this study, we examine NFAT expression in normal and glaucoma LC cells, and investigate the effect of cyclosporin A (CsA, a known inhibitor of NFAT activity) on [Ca2+]i and ECM gene expression in normal and glaucoma LC cells. Methods: [Ca2+]i was measured with dual-wavelength Ca2+ imaging and confocal microscopy using Fura-2 AM and Fluo-4 under physiological isotonic and hypotonic cell stretch treatment. Human donor LC cells were cultured under normal physiological conditions or using a glaucoma-related stimulus, oxidative stress (H2O2, 100 MUM), for 6 hours with or without CsA. NFATc3 protein levels were examined using Western blot analysis. Profibrotic ECM gene transcription (including transforming growth factor-beta1 [TGFbeta1], collagen 1A1 [Col1A1], and periostin) was analyzed using quantitative real time RT-PCR. Results: Basal and hypotonic cell membrane stretch-induced [Ca2+]i were significantly (P < 0.05) elevated in glaucoma LC cells compared to normal controls. There was a significant delay in [Ca2+]i reuptake into internal stores in the glaucoma LC cells. NFATc3 protein levels were increased in glaucoma LC cells. CsA (10 MUM) significantly inhibited the H2O2-induced expression of NFATc3 in normal and glaucoma LC cells. CsA also reduced the H2O2-induced NFATc3 dephosphorylation (and nuclear translocation), and also suppressed the H2O2 induced elevation in profibrotic ECM genes (TGFbeta1, Col1A1, and periostin), both in normal and in glaucoma LC cells. Conclusions: Intracellular Ca2+ and NFATc3 expression were significantly increased in glaucoma LC cells. CsA reduced the H2O2-induced enhancement in NFATc3 protein expression and nuclear translocation and the profibrotic gene expression both in normal and in glaucoma LC cells. Therefore, targeting the calcineurin-NFATc3 signaling pathway may represent a potential avenue for treating glaucoma-associated LC fibrosis. PMID- 29411012 TI - Utterance Duration as It Relates to Communicative Variables in Infant Vocal Development. AB - Purpose: We aimed to provide novel information on utterance duration as it relates to vocal type, facial affect, gaze direction, and age in the prelinguistic/early linguistic infant. Method: Infant utterances were analyzed from longitudinal recordings of 15 infants at 8, 10, 12, 14, and 16 months of age. Utterance durations were measured and coded for vocal type (i.e., squeal, growl, raspberry, vowel, cry, laugh), facial affect (i.e., positive, negative, neutral), and gaze direction (i.e., to person, to mirror, or not directed). Results: Of the 18,236 utterances analyzed, durations were typically shortest at 14 months of age and longest at 16 months of age. Statistically significant changes were observed in utterance durations across age for all variables of interest. Conclusion: Despite variation in duration of infant utterances, developmental patterns were observed. For these infants, utterance durations appear to become more consolidated later in development, after the 1st year of life. Indeed, 12 months is often noted as the typical age of onset for 1st words and might possibly be a point in time when utterance durations begin to show patterns across communicative variables. PMID- 29411013 TI - Gut Microbes May Shape Response to Cancer Immunotherapy. PMID- 29411014 TI - Evaluating Thrombocytopenia During Heparin Therapy. PMID- 29411015 TI - Guidelines for Patient-Reported Outcomes in Clinical Trial Protocols. PMID- 29411016 TI - Implications of Higher Than Expected Prevalence of Fetal Alcohol Spectrum Disorders. PMID- 29411018 TI - Therapy Approved for Rare Inflammatory Disease. PMID- 29411017 TI - Is Patent Foramen Ovale a Risk Factor for Perioperative Stroke? PMID- 29411019 TI - Gene Therapy for Vision Loss. PMID- 29411020 TI - New Human Insulin Analog Approved. PMID- 29411023 TI - Current Comment. PMID- 29411022 TI - To Fix the Hospital Readmissions Program, Prioritize What Matters. PMID- 29411024 TI - Progressive Massive Fibrosis in Coal Miners From 3 Clinics in Virginia. PMID- 29411025 TI - Technology as a Tool for Mental Disorders. PMID- 29411026 TI - Prophylactic Low-Dose Oxygen for Patients With Acute Stroke. PMID- 29411027 TI - Complications With Insulin Pump Therapy vs Insulin Injection Therapy. PMID- 29411028 TI - Prophylactic Low-Dose Oxygen for Patients With Acute Stroke-Reply. PMID- 29411029 TI - Technology as a Tool for Mental Disorders-Reply. PMID- 29411030 TI - Complications With Insulin Pump Therapy vs Insulin Injection Therapy-Reply. PMID- 29411033 TI - Nursemaid's Elbow (Elbow Subluxation). PMID- 29411031 TI - Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities. AB - Importance: Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples. Objective: To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States. Design, Setting, and Participants: Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled. Exposures: Alcohol consumption during pregnancy. Main Outcomes and Measures: Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation. Results: A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children. Conclusions and Relevance: Estimated prevalence of fetal alcohol spectrum disorders among first graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities. PMID- 29411032 TI - Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke. AB - Importance: Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke. Objective: To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke. Design, Setting, and Participants: Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia. Exposures: Preoperatively diagnosed PFO. Main Outcomes and Measures: Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS). Results: Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63]; P < .001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48]; P < .001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO; P = .02). Conclusions and Relevance: Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk. PMID- 29411034 TI - Oversedation of a Patient With Obstructive Sleep Apnea Prior to Imaging. PMID- 29411036 TI - I Am That Parent. PMID- 29411037 TI - Guidelines for Inclusion of Patient-Reported Outcomes in Clinical Trial Protocols: The SPIRIT-PRO Extension. AB - Importance: Patient-reported outcome (PRO) data from clinical trials can provide valuable evidence to inform shared decision making, labeling claims, clinical guidelines, and health policy; however, the PRO content of clinical trial protocols is often suboptimal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was published in 2013 and aims to improve the completeness of trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed, but it does not provide PRO-specific guidance. Objective: To develop international, consensus based, PRO-specific protocol guidance (the SPIRIT-PRO Extension). Design, Setting, and Participants: The SPIRIT-PRO Extension was developed following the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework for guideline development. This included (1) a systematic review of existing PRO-specific protocol guidance to generate a list of potential PRO-specific protocol items (published in 2014); (2) refinements to the list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) Protocol Checklist Taskforce; (3) an international stakeholder survey of clinical trial research personnel, PRO methodologists, health economists, psychometricians, patient advocates, funders, industry representatives, journal editors, policy makers, ethicists, and researchers responsible for evidence synthesis (distributed by 38 international partner organizations in October 2016); (4) an international Delphi exercise (n = 137 invited; October 2016 to February 2017); and (5) consensus meeting (n = 30 invited; May 2017). Prior to voting, consensus meeting participants were informed of the results of the Delphi exercise and given data from structured reviews evaluating the PRO protocol content of 3 defined samples of trial protocols. Results: The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce (n = 21) reduced this to 56 items, which were considered by 138 international stakeholder survey participants and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed on at a consensus meeting (n = 29 participants) and reviewed by external group of experts during a consultation period. Eleven extensions and 5 elaborations to the SPIRIT 2013 checklist were recommended for inclusion in clinical trial protocols in which PROs are a primary or key secondary outcome. Extension items focused on PRO-specific issues relating to the trial rationale, objectives, eligibility criteria, concepts used to evaluate the intervention, time points for assessment, PRO instrument selection and measurement properties, data collection plan, translation to other languages, proxy completion, strategies to minimize missing data, and whether PRO data will be monitored during the study to inform clinical care. Conclusions and Relevance: The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care. PMID- 29411040 TI - Cognitive Profiles of Finnish Preschool Children With Expressive and Receptive Language Impairment. AB - Purpose: The aim of this study was to compare the verbal and nonverbal cognitive profiles of children with specific language impairment (SLI) with problems predominantly in expressive (SLI-E) or receptive (SLI-R) language skills. These diagnostic subgroups have not been compared before in psychological studies. Method: Participants were preschool-age Finnish-speaking children with SLI diagnosed by a multidisciplinary team. Cognitive profile differences between the diagnostic subgroups and the relationship between verbal and nonverbal reasoning skills were evaluated. Results: Performance was worse for the SLI-R subgroup than for the SLI-E subgroup not only in verbal reasoning and short-term memory but also in nonverbal reasoning, and several nonverbal subtests correlated significantly with the composite verbal index. However, weaknesses and strengths in the cognitive profiles of the subgroups were parallel. Conclusions: Poor verbal comprehension and reasoning skills seem to be associated with lower nonverbal performance in children with SLI. Performance index (Performance Intelligence Quotient) may not always represent the intact nonverbal capacity assumed in SLI diagnostics, and a broader assessment is recommended when a child fails any of the compulsory Performance Intelligence Quotient subtests. Differences between the SLI subgroups appear quantitative rather than qualitative, in line with the new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) classification (American Psychiatric Association, 2013). PMID- 29411042 TI - Caring for pregnant women whose diabetes antedates pregnancy: is there room for improvement? PMID- 29411043 TI - HIF-1A gene polymorphisms and its protein level in patients with rheumatoid arthritis: a case-control study. AB - OBJECTIVES: The aim of the study was to identify HIF-1A genetic variants and their possible association with HIF-1alpha, VEGF, KDR, RORc and Foxp3 protein levels, and susceptibility to and severity of RA. METHODS: The HIF-1A gene polymorphisms were genotyped for 587 RA patients and 341 healthy individuals. The HIF-1alpha, VEGF, KDR, RORc and Foxp3serum levels were evaluated. RESULTS: Under the codominant model, the frequency of the rs12434438 GG genotype was lower in RA patients than in controls (P = 0.02). Under the recessive model (AA + AG vs GG), the association was also significant (OR 3.32; CI 1.19-9.24; P = 0.02). Overall, rs12434438 A/G and rs1951795 A/C are in almost completed linkage disequilibrium with D' = 0.96 and r2 = 0.85. The HIF-1A rs1951795 A allele was associated with rheumatoid factor (P = 0.02) and mean value of erythrocyte sedimentation rate (ESR) (P = 0.05). In RA patients with HIF-1A rs12434439 GG genotype, the parameters of disease activity such as DAS-28, VAS score, Larsen score or HAQ score were lower compared to RA patients with the HIF-1A rs12434439 AA genotype. Moreover, we also observed that Foxp3 serum levels were higher, and RORc2 serum levels were lower in RA patients with rs12434439 GG. CONCLUSION: The polymorphic HIF-1A rs12434439 GG genotype may play a protective role for RA development. PMID- 29411041 TI - Cystic fibrosis transmembrane conductance regulator-emerging regulator of cancer. AB - Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, the most common life-limiting recessive genetic disease among Caucasians. CFTR mutations have also been linked to increased risk of various cancers but remained controversial for a long time. Recent studies have begun to reveal that CFTR is not merely an ion channel but also an important regulator of cancer development and progression with multiple signaling pathways identified. In this review, we will first present clinical findings showing the correlation of genetic mutations or aberrant expression of CFTR with cancer incidence in multiple cancers. We will then focus on the roles of CFTR in fundamental cellular processes including transformation, survival, proliferation, migration, invasion and epithelial-mesenchymal transition in cancer cells, highlighting the signaling pathways involved. Finally, the association of CFTR expression levels with patient prognosis, and the potential of CFTR as a cancer prognosis indicator in human malignancies will be discussed. PMID- 29411045 TI - [Health 4.0 - how are we doing tomorrow?] AB - Digitization in healthcare is progressing steadily. While currently processes are being optimized and processes are being facilitated, the breakthrough of digital medicine is still forthcoming. Digital medicine includes applications that focus on the patient and give them the promise of better care. Many digital health applications are raising attention in traditional healthcare, as they are increasingly showing evidence.This report discusses the question of the impact of digital health applications on healthcare in the near future by evaluating the effect of software used to improve diagnosis, therapy and the communication between patients and healthcare professionals.Three key technologies have been identified that have the potential to create applications that will have a major impact on healthcare. Exemplary applications in the fields of natural language processing, deep learning and virtual reality are presented and discussed, including how the widespread use of these products can change healthcare from the perspective of the patients.The prognosis for healthcare in a digital future is obviously: we are getting better. This is due to better quality in the field of diagnosis, enabling balance in the communication between patients and healthcare professionals, and low-threshold access to healthcare, regardless of location and time. PMID- 29411046 TI - [The use of free-of-charge prescription contraceptives among women : Results of a pilot project in the German federal state of Mecklenburg-Western Pomerania]. AB - BACKGROUND: There is a connection between the receipt of unemployment benefits and the failure to use contraceptives in Germany. This study aims to understand the use of contraceptives among women entitled to unemployment benefits under the Sozialgesetzbuch II or XII (SGB II or SGB XII), prior and during an offer of contraceptives free of charge (CFOC). METHODS: The criteria for the use of CFOC (pill, intrauterine device, or ring) over a 12-month period were: age between 20 and 35 years, resident in predefined urban or rural postal codes in the German federal state of Mecklenburg-Western Pomerania, and participation in a self administered survey. Data about participants' age, education, number of children, relationship status, period of payment according to SGB II or SGB XII, the use and barriers to use of contraceptives during every occurrence of sexual intercourse, as well as the kind of contraceptives used. RESULTS: From a total of 418 women: 40.9% were single-mothers, 39.0% did not graduate school, 21.1% were childless, and 57.9% had received unemployment benefits for at least three years. Further, 21.1% rated their type of contraceptive as "less safe" or "unsafe." The most commonly cited reasons for nonregular use of contraceptives were: they are too expensive or their use is forgotten. A change in contraceptives was made by 30.9% due to the offer of CFOC. The change was associated with the number of children and the exclusive use of less safe contraceptives. DISCUSSION: CFOC seems to be attractive, especially for women with children and those who receive long-term unemployment benefits. Changing demands concerning the safety of birth control during the lives of women should be considered in the discussion about common rules for the access to CFOC. PMID- 29411047 TI - Development and Validation of a Sensitive Method for Trace Nickel Determination by Slotted Quartz Tube Flame Atomic Absorption Spectrometry After Dispersive Liquid-Liquid Microextraction. AB - In this study, dispersive liquid-liquid microextraction was systematically optimized for the preconcentration of nickel after forming a complex with diphenylcarbazone. The measurement output of the flame atomic absorption spectrometer was further enhanced by fitting a custom-cut slotted quartz tube to the flame burner head. The extraction method increased the amount of nickel reaching the flame and the slotted quartz tube increased the residence time of nickel atoms in the flame to record higher absorbance. Two methods combined to give about 90 fold enhancement in sensitivity over the conventional flame atomic absorption spectrometry. The optimized method was applicable over a wide linear concentration range, and it gave a detection limit of 2.1 ug L-1. Low relative standard deviations at the lowest concentration in the linear calibration plot indicated high precision for both extraction process and instrumental measurements. A coal fly ash standard reference material (SRM 1633c) was used to determine the accuracy of the method, and experimented results were compatible with the certified value. Spiked recovery tests were also used to validate the applicability of the method. PMID- 29411044 TI - Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine. AB - PURPOSE: Hand-held vital microscopes (HVMs) were introduced to observe sublingual microcirculatory alterations at the bedside in different shock states in critically ill patients. This consensus aims to provide clinicians with guidelines for practical use and interpretation of the sublingual microcirculation. Furthermore, it aims to promote the integration of routine application of HVM microcirculatory monitoring in conventional hemodynamic monitoring of systemic hemodynamic variables. METHODS: In accordance with the Delphi method we organized three international expert meetings to discuss the various aspects of the technology, physiology, measurements, and clinical utility of HVM sublingual microcirculatory monitoring to formulate this consensus document. A task force from the Cardiovascular Dynamics Section of the European Society of Intensive Care Medicine (with endorsement of its Executive Committee) created this consensus as an update of a previous consensus in 2007. We classified consensus statements as definitions, requirements, and/or recommendations, with a minimum requirement of 80% agreement of all participants. RESULTS: In this consensus the nature of microcirculatory alterations is described. The nature of variables, which can be extracted from analysis of microcirculatory images, is presented and the needed dataset of variables to identify microcirculatory alterations is defined. Practical aspects of sublingual HVM measurements and the nature of artifacts are described. Eleven statements were formulated that pertained to image acquisitions and quality statements. Fourteen statements addressed the analysis of the images, and 13 statements are related to future developments. CONCLUSION: This consensus describes 25 statements regarding the acquisition and interpretation of microcirculatory images needed to guide the assessment of the microcirculation in critically ill patients. PMID- 29411048 TI - Comparison of analgesic interventions for traumatic rib fractures: a systematic review and meta-analysis. AB - PURPOSE: Many studies report on outcomes of analgesic therapy for (suspected) traumatic rib fractures. However, the literature is inconclusive and diverse regarding the management of pain and its effect on pain relief and associated complications. This systematic review and meta-analysis summarizes and compares reduction of pain for the different treatment modalities and as secondary outcome mortality during hospitalization, length of mechanical ventilation, length of hospital stay, length of intensive care unit stay (ICU) and complications such as respiratory, cardiovascular, and/or analgesia-related complications, for four different types of analgesic therapy: epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks. METHODS: PubMed, EMBASE and CENTRAL databases were searched to identify comparative studies investigating epidural, intravenous, paravertebral and intercostal interventions for traumatic rib fractures, without restriction for study type. The search strategy included keywords and MeSH or Emtree terms relating blunt chest trauma (including rib fractures), analgesic interventions, pain management and complications. RESULTS: A total of 19 papers met our inclusion criteria and were finally included in this systematic review. Significant differences were found in favor of epidural analgesia for the reduction of pain. No significant differences were observed between epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks, for the secondary outcomes. CONCLUSIONS: Results of this study show that epidural analgesia provides better pain relief than the other modalities. No differences were observed for secondary endpoints like length of ICU stay, length of mechanical ventilation or pulmonary complications. However, the quality of the available evidence is low, and therefore, preclude strong recommendations. PMID- 29411051 TI - [Which psychotherapy for whom?] PMID- 29411050 TI - [Pseudarthrosis and construct failure after lumbar pedicle subtraction osteotomy : Influence of biomechanics, surgical technique, biology and avoidance strategies]. AB - There are numerous factors that can lead to construct failure and pseudarthrosis after corrective pedicle subtraction osteotomy (PSO) in the lumbar spine. Frequently, several factors are of relevance in these problematic cases. This article attempts to explain the surgical, biomechanical and biological aspects that should be understood in order to minimize the risk of pseudarthrosis and construct failure. It addresses technical varieties of the PSO procedure as well as the surgical technique, the choice of rod material and the design of multirod constructs. Biological reasons for pseudarthrosis and preventive strategies are discussed, as well as the possible contribution of low-grade infections to pseudarthrosis. The option of substituting a multilevel ALIF procedure for a PSO is another topic, as is the question of surgical indication and strategy. PMID- 29411052 TI - [Spinal cysts : Diagnostic workup and therapy]. AB - CLINICAL ISSUE: Spinal cysts can be classified as meningeal, not meningeal, and tumor-associated cysts. Due to the widespread availability of high-resolution computed tomography and magnet resonance imaging, spinal cysts can be detected with high sensitivity these days. Concerning the variety of potential cystic differential diagnoses, a precise classification is difficult and can often only be realized after surgical inspection or histological examination. PRACTICAL RECOMMENDATIONS: Spinal cysts are generally incidental findings during a routine diagnostic workup and need no further therapy. Surgical treatment can be necessary if the spinal cyst reaches a certain size and causes neurological symptoms due to the compression of the spinal cord or the nerve root. PMID- 29411053 TI - [Differential diagnosis of intracerebral and spinal cysts]. PMID- 29411049 TI - Humanized Mice as Unique Tools for Human-Specific Studies. AB - With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, "humanized" mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use. PMID- 29411055 TI - Improved neuroprotective effect of resveratrol nanoparticles as evinced by abrogation of rotenone-induced behavioral deficits and oxidative and mitochondrial dysfunctions in rat model of Parkinson's disease. AB - The objective of the present study was to evaluate the protective effect of resveratrol nanoparticles (NRSV) against rotenone-induced neurodegeneration in rats. NRSV were prepared by temperature-controlled antisolvent precipitation method and characterized for its particle size, shape, and dissolution properties. Moreover, NRSV effects compared with the free resveratrol (RSV). Animals were divided into four groups: (I) control, (II) rotenone (2 mg/kg s.c.), (III) RSV (40 mg/kg, p.o.) + rotenone, and (IV) NRSV (40 mg/kg, p.o.) + rotenone. Animals received treatments 30 min before rotenone administration for a period of 35 days. Behavioral quantifications were done using rota rod test and rearing behavior after 24 h of last dose. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH), and catalase), and complex I activity. In addition, histopathological studies were also performed. Our results showed that chronic rotenone treatment causes motor deficits, decreased rearing behavior, mitochondrial dysfunction, and oxidative stress. Furthermore, histological analysis demonstrated neuronal degeneration in rotenone-treated rats. An important finding of the present study was NRSV showed comparatively better efficacy than the RSV treatment in attenuating the rotenone-induced Parkinson's like behavioral alterations, biochemical and histological changes, oxidative stress, and mitochondrial dysfunction in rats. PMID- 29411056 TI - A novel genotoxin-specific qPCR array based on the metabolically competent human HepaRGTM cell line as a rapid and reliable tool for improved in vitro hazard assessment. AB - Although the value of the regulatory accepted batteries for in vitro genotoxicity testing is recognized, they result in a high number of false positives. This has a major impact on society and industries developing novel compounds for pharmaceutical, chemical, and consumer products, as afflicted compounds have to be (prematurely) abandoned or further tested on animals. Using the metabolically competent human HepaRGTM cell line and toxicogenomics approaches, we have developed an upgraded, innovative, and proprietary gene classifier. This gene classifier is based on transcriptomic changes induced by 12 genotoxic and 12 non genotoxic reference compounds tested at sub-cytotoxic concentrations, i.e., IC10 concentrations as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The resulting gene classifier was translated into an easy-to-handle qPCR array that, as shown by pathway analysis, covers several different cellular processes related to genotoxicity. To further assess the predictivity of the tool, a set of 5 known positive and 5 known negative test compounds for genotoxicity was evaluated. In addition, 2 compounds with debatable genotoxicity data were tested to explore how the qPCR array would classify these. With an accuracy of 100%, when equivocal results were considered positive, the results showed that combining HepaRGTM cells with a genotoxin specific qPCR array can improve (geno)toxicological hazard assessment. In addition, the developed qPCR array was able to provide additional information on compounds for which so far debatable genotoxicity data are available. The results indicate that the new in vitro tool can improve human safety assessment of chemicals in general by basing predictions on mechanistic toxicogenomics information. PMID- 29411057 TI - Biomarker monitoring for food contaminants. PMID- 29411058 TI - Diagnostic performances of intravoxel incoherent motion and conventional diffusion-weighted imaging in the differential diagnosis of benign and malignant portal vein thrombus. AB - PURPOSE: To evaluate the diagnostic accuracy of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters in the differential diagnosis of portal vein thrombus (PVT). METHODOLOGY: Thirty-five patients with PVT were enrolled in this retrospective study. Precontrast axial in-phase and out of-phase T1-weighted (W) turbo field echo (TFE), axial and coronal T2-W single shot turbo spin echo, IVIM with b values between 0 and 1300 s/mm2 and conventional DWI with b factors of 50, 400, and 800 s/mm2 with single-shot echo planar imaging, and postcontrast dynamic T1-W volumetric interpolated breath-hold examination images obtained with 1.5 T MR unit were evaluated. For quantitative analysis of conventional DWI, an ADC map was reconstructed from conventional DWI using all b values. For quantitative evaluation of IVIM, the SI was calculated from each b value. A specific software program was applied to calculate D (true diffusion coefficient), D* (pseudodiffusion coefficient associated with blood flow), and f (perfusion fraction). The differentiation between benign and malignant PVT was based on the criteria outlined in the study by Catalano et al. (Radiology 254:154-162, 2010). RESULTS: The ADC values of the malignant PVT were significantly lower than those of benign PVTs (p = 0.005). Malignant PVTs had a tendency to show higher f values in comparison with benign PVTs without statistical significance (p = 0.750). The best discriminative parameter was ADC values, which demonstrated a sensitivity of 80.0% and a specificity of 72.7% with cut-off value of 1.00 * 10-3 mm2/s. CONCLUSION: ADC values might be more superior tool than IVIM parameters in differentiation between malignant and benign PVT. PMID- 29411059 TI - The starry sky liver: multiple biliary hamartomas on MR cholangiopancreatography. PMID- 29411061 TI - ? PMID- 29411060 TI - Intraosseous venous structures adjacent to the jugular tubercle associated with an anterior condylar dural arteriovenous fistula. AB - PURPOSE: Although involvement of the osseous component with an anterior condylar dural arteriovenous fistula (AC-DAVF) has been frequently described, osseous venous structures in which AC-DAVFs develop have not been fully elucidated. We investigated osseous venous structures adjacent to the hypoglossal canal in normal controls and patients with AC-DAVFs. METHODS: The study included 50 individuals with unruptured aneurysms as normal controls and seven patients with AC-DAVFs. Osseous venous structures adjacent to the hypoglossal canal in normal controls were analyzed using computed tomography (CT) digital subtraction venography. In patients with AC-DAVFs, the fistulous pouches, draining veins, and surrounding venous structures were examined using cone beam CT. RESULTS: In 46.0% of laterals in normal controls, osseous venous structures were visualized within the jugular tubercle superomedially to the hypoglossal canal. We named these structures the jugular tubercle venous complex (JTVC). The JTVC was always continuous with the anterior condylar vein and was sometimes connected to surrounding venous channels. We detected nine fistulous pouches in the seven patients with AC-DAVFs. The fistulous pouches were in the JTVC (33.3%), anterior condylar vein (33.3%), and other venous channels within the exoccipital region (33.3%). CONCLUSION: Although the JTVC is a venous structure frequently found in normal people, it had not been investigated until now. The venous channel between the anterior condylar vein and JTVC is a common origin site for AC-DAVFs, and it was associated with 66.6% of the AC-DAVF cases in the current study. PMID- 29411062 TI - Aerogel from chemo-enzymatically oxidized fenugreek gum: an innovative delivery system of isothiazolinones biocides. AB - Aerogels of chemo-enzymatically oxidized, lyophilized fenugreek gum (EOLFG) were evaluated as "delivery system" (DS) of the microbiocide mix 5-chloro-2-methyl-4 isothiazolin-3-one (CIT) and 2-methyl-4-isothiazolin-3-one (MIT). These biocides have a broad activity spectrum and a low MIC (minimal inhibitory concentration) in the ppm range. They are approved under the EU Biocidal Product Directive for various applications, including cosmetics, are classified as skin sensitizers, and are under increasing scrutiny to limit or eliminate their use.We demonstrate that CIT/MIT can be uptaken into EOLFG aerogel corks by immersion into aqueous solutions of microbiocides, followed by blotting and re-lyophilization to generate "loaded" EOLFG aerogels. Incubation of "loaded" corks in water brings about a slow and almost complete release of the absorbed actives having the same MIC of free biocides against selected bacterial pathogens.This new biomaterial could represent an innovative DS of microbiocides and other actives for a variety of industrial, food, cosmetic, and biomedical applications. PMID- 29411064 TI - Botulinum Toxin Type A: Assessing The Effects on The Brain Stem. AB - BACKGROUND: In this study, our aim is to investigate the possible effects of Botulinum toxin type A administrations in the early and late periods on the brain stem. METHODS: Eighteen white New Zealand rabbits were used in this study with the subjects being divided into three groups. Group I received 0.05 mL sterile saline to the left anterior auricular muscles. Group II and III were injected with Botulinum toxin type A (Botox, Allergan) to the left anterior auricular muscles. Group II was sacrificed 5 days after application and Group III was sacrificed 12 weeks after application; brain stem tissues were then taken. The samples were examined with Caspase 3, 8, and 9 immunohistochemical stainings. RESULTS: In the control group with Caspase-3 immune staining, moderate-to-strong immune reactivity was seen in a small number of neurons. In the Caspase-8 and 9 immune stainings, the immune reactive neurons were seen in greater numbers when compared with the Caspase-3 immune reactive neurons. In the early and late period, groups with Caspase-8 and 9 immune stainings, the immune reactive neurons were seen in greater numbers and in the wider area when compared with the Caspase 3 immune reactive neurons. No significant differences were recognized in the Caspase immune stainings between the early and late period groups. The results were statistically supported. CONCLUSION: It was concluded that Botulinum toxin type A application did not trigger apoptosis in stem cell tissues. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29411063 TI - Multiplicity of enzymatic functions in the CAZy AA3 family. AB - The CAZy auxiliary activity family 3 (AA3) comprises enzymes from the glucose methanol-choline (GMC) family of oxidoreductases, which assist the activity of other AA family enzymes via their reaction products or support the action of glycoside hydrolases in lignocellulose degradation. The AA3 family is further divided into four subfamilies, which include cellobiose dehydrogenase, glucose oxidoreductases, aryl-alcohol oxidase, alcohol (methanol) oxidase, and pyranose oxidoreductases. These different enzymes catalyze a wide variety of redox reactions with respect to substrates and co-substrates. The common feature of AA3 family members is the formation of key metabolites such as H2O2 or hydroquinones, which are required by other AA enzymes. The multiplicity of enzymatic functions in the AA3 family is reflected by the multigenicity of AA3 genes in fungi, which also depends on their lifestyle. We provide an overview of the phylogenetic, molecular, and catalytic properties of AA3 enzymes and discuss their interactions with other carbohydrate-active enzymes. PMID- 29411066 TI - How Much Data are Good Enough? Using Simulation to Determine the Reliability of Estimating POMR for Resource-Constrained Settings. AB - INTRODUCTION: Perioperative mortality rate (POMR) is a suggested indicator for surgical quality worldwide. Currently, POMR is often sampled by convenience; a data-driven approach for calculating sample size has not previously been attempted. We proposed a novel application of a bootstrapping sampling technique to estimate how much data are needed to be collected to reasonably estimate POMR in low-resource countries where 100% data capture is not possible. MATERIAL AND METHODS: Six common procedures in low- and middle-income countries were analysed by using population database in New York and California. Relative margin of error by dividing the absolute margin of error by the true population rate was calculated. Target margin of error was +/-50%, because this level of precision would allow us to detect a moderate-to-large effect size. RESULTS AND DISCUSSION: Target margin of error was achieved at 0.3% sampling size for abdominal surgery, 7% for fracture, 10% for craniotomy, 16% for pneumonectomy, 26% for hysterectomy and 60% for C-section. POMR may be estimated with fairly good reliability with small data sampling. This method demonstrates that it is possible to use a data driven approach to determine the necessary sampling size to accurately collect POMR worldwide. PMID- 29411065 TI - The Results of In Situ Prosthetic Graft Replacement for Infected Aortic Disease. AB - BACKGROUND: Infected aortic disease is a serious clinical condition associated with significant morbidity and mortality. This study reviewed the outcomes of in situ aortic replacement with a prosthetic graft for infected aortic disease, including primary infected abdominal aortic aneurysms (PIAAA), infected aortic prosthetic grafts (IAPG), and infected aortic stent grafts (IASG). METHODS: Twenty-eight consecutive patients who underwent in situ aortic replacement with a prosthetic graft for PIAAA, IAPG, and IASG at a single center from January 2001 to December 2015 were retrospectively analyzed. Demographics, clinical characteristics, medical management, surgical procedure, and clinical outcomes were included. RESULTS: Nineteen patients with a PIAAA, three with an IAPG following open repair of abdominal aortic aneurysm (AAA), and six with an IASG following endovascular aortic repair underwent in situ prosthetic graft replacement with infected tissue and graft removal. In-hospital mortality was 7.1% (2/28). One died of bleeding on postoperative day 12, and the other died of hepatic failure on postoperative day 32. Of six patients with an IASG, two had major complications that were related to barb injury at the proximal aorta. The reinfection rate was 14.3% (4 of 28) during a mean follow-up of 35.7 months (1 142 months). All new grafts of three patients with IAPG were reinfected. The other patient became reinfected after surgery for PIAAA with iatrogenic small bowel perforation that was not detected during surgery. CONCLUSIONS: In situ graft replacement of PIAAA and IASG is feasible with acceptable outcomes, but the outcome for IAPG is questionable. PMID- 29411067 TI - American College of Surgeons Member Involvement in Global Surgery: Results from the 2015 Operation Giving Back Survey. AB - BACKGROUND: Five billion people worldwide lack access to safe surgery. American College of Surgeons (ACS) members have a strong history of humanitarian and volunteer work. Since its founding in 2004, Operation Giving Back (OGB) has served as a volunteer resource portal. This study sought to understand current activities, needs, and barriers to ACS member volunteerism, and to re-assess the role of OGB. METHODS: A 25-question electronic survey was sent to ACS members in August 2015. Utilizing branching logic, those who were involved or interested in volunteerism completed the full survey. Data were assessed using univariable analysis methods. RESULTS: Three percent (n = 1764) of those e-mailed answered the survey. Respondents were mostly men (82%), >=50 years of age (61%), and general surgeons (70%). Fifty-three percent (n = 937) reported current or past volunteer activities, and 76.5% (n = 1349) were interested in activities within three years. Approximately 84% were interested in international volunteerism and 55% in domestic volunteerism. Few (5.7%) had both training and experience in emergency and disaster response, and only 17% had institutional salary support. Eighty-two percent wished to work with OGB, and 418 indicated organizations with whom they are involved could benefit from OGB collaboration. CONCLUSIONS: Interest in surgical volunteerism among ACS member survey respondents is high. OGB has the opportunity to meet member needs by developing programmatic activities, identifying volunteer prospects, facilitating multi-institutional consortia, and leading pre-deployment training. By maximizing volunteer efforts, OGB has the potential to foster sustainable and scalable ethical practices to improve basic access to surgical care globally. PMID- 29411068 TI - Early Consequences of Pectus Excavatum Surgery on Self-Esteem and General Quality of Life. AB - BACKGROUND: An early observation after chest wall correction is direct inspection from the PE patient of their "new" thorax. Changes in self-perception may give raise to other psychological adaptations. The aim of this study was to evaluate the early changes in the fields of self-esteem, body image and QoL. METHODS: Prospective observational longitudinal multicenter cohort study. Self-esteem, emotional limitations and general health were assessed using the Child Health Questionnaire (CHQ) in patients under 18 and the World Health Organization Quality of Life Questionnaire-bref (WHOQOL-bref) was used for body image, psychological domain and overall QoL in patients over 16 years of age. Measurements were taken before surgery (T1) and 6 weeks (T2), and 6 months thereafter (T3). RESULTS: Scores on post-operative self-esteem were significantly higher compared with scores pre-operatively (p < 0.007). Also body image, psychological domain and emotional limitations showed significant improvement, respectively p < 0.001, p < 0.001, and p < 0.016. Significant improvement in the first three components was mainly achieved in the first 6 weeks post-operative. In emotional limitation, however, the largest change was between 6 weeks and 6 months. Overall quality of life in the WHOQOL-bref and general health domain in the CHQ showed no significant improvement in relation to the pre-operative scores. CONCLUSION: Post-operative PE patients after Nuss procedure showed an improved body image, increased self-esteem and increased psychological resilience in the first 6 months, with the most marked change in the first 6 weeks. Also emotional limitations changed significantly over time. The changes were not large enough to influence general QoL or general health significantly. PMID- 29411069 TI - The utility of FRAX(r) in predicting bone fractures in patients with chronic kidney disease on hemodialysis: a two-year prospective multicenter cohort study. AB - : We assessed the FRAX(r) method in 718 hemodialyzed patients in estimating increased risk of bone major and hip fractures. Over two prospective years, statistical analysis showed that FRAX(r) enables a better assessment of bone major fracture risk in these patients than any of its components and other risk factors considered in the analysis. INTRODUCTION: Despite the generally increased risk of bone fractures among patients with end-stage renal disease, no prediction models for identifying individuals at particular risk have been developed to date. The goal of this prospective, multicenter observational study was to assess the usefulness of the FRAX(r) method in comparison to all its elements considered separately, selected factors associated with renal disease and the history of falls, in estimating increased risk of low-energy major bone and hip fractures in patients undergoing chronic hemodialysis. METHODS: The study included a total of 1068 hemodialysis patients, who were followed for 2 years, and finally, 718 of them were analyzed. The risk analysis included the Polish version of the FRAX(r) calculator (without bone mineral density), dialysis vintage, mineral metabolism disorders (serum calcium, phosphate, and parathyroid hormone), and the number of falls during the last year before the study. RESULTS: Over 2 years, low-energy 30 major bone fractures were diagnosed and 13 of hip fractures among them. Area under the curve for FRAX(r) was 0.76 (95% CI 0.69-0.84) for major fractures and 0.70 (95% CI 0.563-0.832) for hip fractures. The AUC for major bone fractures was significantly higher than for all elements of the FRAX(r) calculator. In logistic regression analysis FRAX(r) was the strongest independent risk factor of assessment of the major bone fracture risk. CONCLUSIONS: FRAX(r) enables a better assessment of major bone fracture risk in ESRD patients undergoing hemodialysis than any of its components and other risk factors considered in the analysis. PMID- 29411070 TI - Saccharin fading is not required for the acquisition of alcohol self administration, and can alter the dynamics of cue-alcohol memory reconsolidation. AB - RATIONALE: Animal models of alcohol-seeking are useful for understanding alcohol addiction and for treatment development, but throughput in these models is limited by the extensive pretraining required to overcome the aversive taste of ethanol. Work by Augier et al. (Psychopharmacology 231: 4561-4568, 2014) indicates that Wistar rats will self-administer alcohol without water deprivation, exposure to sweetened ethanol solutions or intermittent access to ethanol. OBJECTIVES AND METHODS: We sought to replicate and extend the work of Augier et al. by comparing the acquisition of instrumental self-administration of ethanol in Lister-Hooded rats that had been previously saccharin faded (SF group) or not (NSF group). We also aimed to determine whether NMDA receptor antagonism with MK-801, given at memory reactivation, reduced subsequent ethanol-seeking behaviour in both groups of animals. Finally, we assessed the ethanol preference of SF and NSF rats using the two-bottle choice procedure. RESULTS: Both SF and NSF groups acquired instrumental self-administration of ethanol, though SF rats consumed fewer of the earned reinforcers. MK-801, given at memory reactivation, had different effects on NSF and SF rats: impairing the capacity of an ethanol paired conditioned stimulus (CS) to support reinstatement in NSF rats, and enhancing it in SF rats. Finally, neither SF nor NSF rats showed a preference for ethanol. CONCLUSIONS: Our data support those of Augier et al. (Psychopharmacology 231: 4561-4568, 2014) that pretraining is unnecessary for rats to acquire instrumental self-administration of ethanol. Indeed, saccharin fading may produce a weaker memory that extinguishes more readily, thus accounting for the different effects of MK-801 on SF and NSF rats. PMID- 29411071 TI - Anatomy and surgical cure of descending perineal syndrome. PMID- 29411072 TI - Prospective evaluation of the safety and feasibility of a pelvic floor dilator during active labor. AB - INTRODUCTION AND HYPOTHESIS: The objective was to assess the safety and feasibility of using a pelvic floor dilator during active labor to prevent injuries to the levator ani muscle (LAM) and perineum. METHODS: In a prospective pilot study, a pelvic floor dilator using soft pads was introduced into the vaginal canal to gradually expand the vagina, in 30 nulliparous women and in 10 controls. The primary outcomes were adverse events related to the device. Secondary outcomes were perineal lacerations after delivery, sonographically defined levator ani injury, hiatal area dimensions, and anal sphincter disruption, all at 12-20 weeks postpartum, and maximum pelvic floor dilation, time to achieve maximum dilation, and device retention rate. RESULTS: From October 2014 through November 2016, a total of 494 women were screened, and 61 consented to the study. Thirty women used the device and 27 returned for follow up. No maternal or neonatal injuries were related to use of the dilator. The average maximum dilation of the vaginal canal was 7.4 cm (SD 0.7, range 5.5-8.0). Dilation time averaged 27 min (SD 13, range 5-60). Device insertion adjustment was needed in 13 out of 30 cases (43%). Similar rates of 3th-4th degree perineal lacerations were seen in both groups. Levator ani avulsion was diagnosed in 2 out of 27 (7%) in the device group and in 1 out of 9 (11%) in the control group (p = 0.2). The rate of partial injury in the device group was 2 out of 27 (7%) vs 2 out of 9 (22%) in the comparison group (p = 0.2). CONCLUSION: The use of the pelvic floor dilator during active labor is feasible. No safety issues were identified. PMID- 29411073 TI - Demand and capacity to integrate pelvic organ prolapse and genital fistula services in low-resource settings. AB - INTRODUCTION AND HYPOTHESIS: There is a need for expanded access to safe surgical care in low- and middle-income countries (LMICs) as illustrated by the report of the 2015 Lancet Commission on Global Surgery. Packages of closely-related surgical procedures may create platforms of capacity that maximize impact in LMIC. Pelvic organ prolapse (POP) and genital fistula care provide an example. Although POP affects many more women in LMICs than fistula, donor support for fistula treatment in LMICs has been underway for decades, whereas treatment for POP is usually limited to hysterectomy-based surgical treatment, occurring with little to no donor support. This capacity-building discrepancy has resulted in POP care that is often non-adherent to international standards and in non integration of POP and fistula services, despite clear areas of similarity and overlap. The objective of this study was to assess the feasibility and potential value of integrating POP services at fistula centers. METHODS: Fistula repair sites supported by the Fistula Care Plus project were surveyed on current demand for and capacity to provide POP, in addition to perceptions about integrating POP and fistula repair services. RESULTS: Respondents from 26 hospitals in sub Saharan Africa and South Asia completed the survey. Most fistula centers (92%) reported demand for POP services, but many cannot meet this demand. Responses indicated a wide variation in assessment and grading practices for POP; approaches to lower urinary tract symptom evaluation; and surgical skills with regard to compartment-based POP, and urinary and rectal incontinence. Fistula surgeons identified integration synergies but also potential conflicts. CONCLUSIONS: Integration of genital fistula and POP services may enhance the quality of POP care while increasing the sustainability of fistula care. PMID- 29411074 TI - Bridging the Divide: Challenges and Opportunities for Public Sector Agricultural Professionals Working with Amish and Mennonite Producers on Conservation. AB - As Amish and Old Order and Conservative Mennonite (i.e., Plain) farmers increase their presence in the agricultural sector, it is crucial for public sector agricultural professionals to effectively work with them to mediate nonpoint source pollution and address issues like the hypoxic zone in the Gulf of Mexico. However, there is a dearth of research on how public sector agricultural professionals can better work with Plain producers on environmental management. There are also few training resources for those working with this key, yet hard to reach, population. Additionally, due to their religious doctrines, Plain communities strive to live apart from the "world" and may be discouraged from working with government entities and attending non-Plain people events. This study analyzes interview data from 23 Amish farmers in one region of Indiana and 18 public sector agricultural professionals from a variety of backgrounds and geographies in areas of the U.S. with heavy Plain populations. Public sector agricultural professionals identified some key agronomic challenges on Plain farms related to issues like poor pasture and manure management as well as socio cultural challenges such as restrictions on electronic and phone communication. Educators should design outreach strategies that take into consideration that faith convictions and conservation concerns may vary greatly based on the specificities of the particular Plain church group. By better understanding this population and how to work with them, public sector agricultural professionals can more effectively work towards addressing environmental problems with this under-served group. PMID- 29411075 TI - Governance Options to Enhance Ecosystem Services in Cocoa, Soy, Tropical Timber and Palm Oil Value Chains. AB - Dutch policies have advocated sustainable commodity value chains, which have implications for the landscapes from which these commodities originate. This study examines governance and policy options for sustainability in terms of how ecosystem services are addressed in cocoa, soy, tropical timber and palm oil value chains with Dutch links. A range of policies addressing ecosystem services were identified, from market governance (certification, payments for ecosystem services) to multi-actor platforms (roundtables) and public governance (policies and regulations). An analysis of policy narratives and interviews identified if and how ecosystem services are addressed within value chains and policies; how the concept has been incorporated into value chain governance; and which governance options are available. The Dutch government was found to take a steering but indirect role in all the cases, primarily through supporting, financing, facilitating and partnering policies. Interventions mainly from end-of chain stakeholders located in processing and consumption countries resulted in new market governance, notably voluntary sustainability standards. These have been successful in creating awareness of some ecosystem services and bringing stakeholders together. However, they have not fully addressed all ecosystem services or stakeholders, thus failing to increase the sustainability of value chains or of the landscapes of origin. We argue that chains sourced in tropical landscapes may be governed more effectively for sustainability if voluntary, market policy tools and governance arrangements have more integrated goals that take account of sourcing landscapes and impacts along the entire value chain. Given the international nature of these commodities. These findings have significance for debates on public-private approaches to value chain and landscape governance. PMID- 29411076 TI - Solitary testicular metastasis from prostate cancer. A case report diagnosed by PET/CT with PSMA. PMID- 29411077 TI - Regenerative therapies increase survivorship of avascular necrosis of the femoral head: a systematic review and meta-analysis. AB - PURPOSE: The aim of this study was to document the available evidence on the use of regenerative techniques for the treatment of femoral head osteonecrosis (or avascular necrosis of femoral head, AVN) and to understand their benefit compared to core decompression (CD) alone in avoiding failure and the need for total hip replacement (THR). METHODS: The search was conducted on three medical electronic databases according to PRISMA guidelines. The studies reporting number and timing of failures were included in a meta-analysis calculating cumulative survivorship with a Kaplan-Mayer curve. Moreover, the results on failures in treatment groups reported in RCT were compared with those documented in control groups, in order to understand the benefit of biological therapies compared to CD for the treatment of AVN. RESULTS: Forty-eight studies were included in this systematic review, reporting results of different types of regenerative techniques: mesenchymal stem cell implantation in the osteonecrotic area, intra-arterial infiltration with mesenchymal stem cells, implantation of bioactive molecules, or platelet-rich plasma. Overall, reported results were good, with a cumulative survivorship of 80% after ten year follow-up, and better results when regenerative treatments were combined to CD compared to CD alone (89.9% vs 70.6%, p < 0.0001). CONCLUSION: Regenerative therapies offer good clinical results for the treatment of AVN. The combination of CD with regenerative techniques provides a significant improvement in terms of survivorship over time compared with CD alone. Further studies are needed to identify the best procedure and the most suitable patients to benefit from regenerative treatments for AVN. PMID- 29411078 TI - Multivariate analysis of factors related to radiographic knee osteoarthritis based on the comparison between football players and matched nonsportsmen. AB - PURPOSE: Knee osteoarthritis (KOA) is the most common joint pathology worldwide and a major cause of later disability. It is unknown if the bone mass density (BMD) is correlated with KOA. This study aimed to investigate the prevalence of radiographic KOA among retired professional football players by comparing with matched nonsportsmen, and assess the correlation between BMD and KOA. METHODS: A cross-sectional, descriptive study was performed on a group of retired professional football players without history of knee injury. A control group of nonsporting volunteers was matched to the football player group in terms of age, height, weight, and body mass index (BMI). Uni- and multivariate analyses were performed to identify risk factors for KOA and predictors for knee function. RESULTS: Eighty-six retired male professional football players, with a mean age of 53 (51-58) years and an average period of professional career of 19.8 +/- 6.3 years, were enrolled into the study group. Eighty-six subjects were included in the control group. Radiographic KOA was more common in the control group (45.3%) than in the study group (15.1%; chi 2 = 18.633, P < 0.001). While the HSS, IKS score, and BMD of spine, femoral neck, and trochanter were all higher among sportsmen than the nonsportsmen (z = 10.250, z = 10.450, z = 7.237, z = 8.826, z = 8.776, all P < 0.001). Independent risk factors for ROA were age (55-60 + years, aOR 9.159, P < 0.001) and BMD (decrease, aOR 16.226, P = 0.001; osteoporosis, aOR 8.176, P = 0.005). The mathematical model of multiple linear regression for the HSS and IKS score were Y = 127.217-3.334 age + 8.971 BMD + 4.752 occupation and Y = 57.784-3.022 age + 7.241 BMD + 4.730 occupation, respectively. CONCLUSIONS: This study reveals that low BMD and advanced age are independent risk factors for KOA. High BMD and regular exercise have a positive impact on knee function as evaluated with the use of HSS and IKS. Our findings guarantee further study to investigate the possibility that KOA may be caused by low BMD. PMID- 29411079 TI - Activity demands and instability are the most important factors for recommending to treat ACL injuries with reconstruction. AB - PURPOSE: The purpose of the study was to (1) study and compare the factors that Swedish orthopaedic surgeons and physical therapists consider important for recommending ACL reconstruction and, (2) to assess how orthopaedic surgeons and physical therapists consider their own and each others, as well as patients', roles are in the treatment decision. METHODS: A web-based survey assessing the relevance of 21 predetermined factors, in the choice to recommend ACL reconstruction, was sent to orthopaedic surgeons and physical therapists. Respondents were also asked to rate the importance of the assessment made by themselves, the other clinician (physical therapists rated the importance of surgeons, surgeons rated the importance of physical therapists), and the patients' preferences. RESULT: Orthopaedic surgeons agreed of eight, and physical therapists of seven factors as important in the choice to recommend ACL reconstruction. The factors both groups reported as important were; "patient's wishes to return to contact/pivoting sports", "instability in physical activity", "instability in activities of daily living despite adequate rehabilitation", "physically demanding occupation", and "young age". Both professions rated their own and each others assessments as well as patient's wishes as important for the decision to recommend ACL reconstruction. CONCLUSION: Orthopaedic surgeons and physical therapists agree about factors that are important for their decision to recommend ACL reconstruction, showing that both professions share a common ground in perceptions of factors that are important in recommending ACL reconstruction. LEVEL OF EVIDENCE: Diagnostic study: Level III. PMID- 29411080 TI - Clinical and anatomic results of rotator cuff repair at 10 years depend on tear type. AB - PURPOSE: Although good short-term and mid-term outcomes are reported for rotator cuff repair, few studies have investigated long-term outcome with clinical and MRI evaluation. The hypothesis was that 10 years following repair of rotator cuff tear, the clinical and anatomic results depend on the extension of the tear. METHODS: The records of all 965 patients who underwent repair of rotator cuff tears in 2003 were retrieved. The patients were reviewed in 2014 for evaluation at a minimum follow-up of 10 years. A total of 511 patients were evaluated clinically, of whom 397 were also evaluated using MRI. There were 289 isolated supraspinatus tears (SS), 94 tears with posterior extension (P), 92 with anterior extension (A) and 36 with anteroposterior (AP) extension. RESULTS: The Constant score had significantly improved from 53.8 +/- 14.7 preoperatively to 77.7 +/- 12.1 (P < 0.0001) at 10 years, with no significant difference between the four groups. The rate of retear (Sugaya IV, V) was lower in the SS group (19%) and higher in the P (32%) and AP groups (31%). At review, infraspinatus fatty degeneration was significantly greater (Fuchs > 2) in the P (P < 0.001) and AP (P < 0.001) groups and subscapularis fatty degeneration was significantly greater (Fuchs > 2) in the A (P < 0.001) and AP (P < 0.001) groups. The rate of osteoarthritis (Samilson > 2) was significantly higher at 11% (P = 0.001) in the A group. The failure rate was significantly lower (P = 0.044) in the SS group (25%) than the massive rotator cuff tear groups (A, P and AP groups) (35%). Complications occurred in 51 shoulders (10%) and repeat surgery was required in 62 shoulders (12%), with no difference between the four groups. CONCLUSIONS: The long follow-up period of this study, large series of patients and MRI evaluation of tendon repair allowed us to demonstrate that 10 years following rotator cuff tear repair, between 68 and 81% of tendons had healed. These findings are of value in predicting response to surgical treatment. Tears with posterior extension had a higher risk of retear. However, surgical repair appeared to give a good functional outcome whatever the type of tear, despite the overall rate of complications and repeat surgery. LEVEL OF EVIDENCE: IV. PMID- 29411081 TI - Velocity-dependent transfer of adaptation in human running as revealed by split belt treadmill adaptation. AB - Animal studies demonstrate that the neural mechanisms underlying locomotion are specific to the modes and/or speeds of locomotion. In line with animal results, human locomotor adaptation studies, particularly those focusing on walking, have revealed limited transfers of adaptation among movement contexts including different locomotion speeds. Running is another common gait that humans utilize in their daily lives and is distinct from walking in terms of the underlying neural mechanisms. The present study employed an adaptation paradigm on a split belt treadmill to examine the possible independence of neural mechanisms mediating different running speeds. The adaptations learned with split-belt running resulted in aftereffects with magnitudes that varied in a speed-dependent matter. In the two components of the ground reaction force investigated, the anterior braking and posterior propulsive components exhibited different trends. The anterior braking component tended to show larger aftereffect under speeds near the slower side speed of the previously experienced split-belt in contrast to the posterior propulsive component in which the aftereffect size tended to be the largest at a speed that corresponded to the faster side speed of the split belt. These results show that the neural mechanisms underlying different running speeds in humans may be independent, just as in human walking and animal studies. PMID- 29411082 TI - When the vibrations allow for anticipating the force to be produced: an extend to Pfister et al. (2014). AB - According to the ideomotor theory, action selection is done by the mental anticipation of its perceptual consequences. If the distal information processed mainly by vision and hearing are considered essential for the representation of the action, the proximal information processed by the sense of touch and proprioception is of less importance. Recent works seem to show the opposite. Nevertheless, it is necessary to complete these results by offering a situation, more ecological, where response and effect can occur on the same effector. So, the goal of our work was to implement a more relevant spatial correspondence because to touch is not the same action that to hear or to see. To do so, participants pressed a specific key after the presentation of a stimulus. The key vibrated depending on the pressure exerted on it. In a compatible condition, high pressure on a key triggered a high vibration, while in an incompatible condition high pressure triggered a low vibration on the same effectors. As expected, the response times were faster in the compatible condition than the incompatible condition. This means that proximal information participates actively in the selection of action. PMID- 29411083 TI - Paper-based immune-affinity arrays for detection of multiple mycotoxins in cereals. AB - Mycotoxins produced by different species of fungi may coexist in cereals and feedstuffs, and could be highly toxic for humans and animals. For quantification of multiple mycotoxins in cereals, we developed a paper-based mycotoxin immune affinity array. First, paper-based microzone arrays were fabricated by photolithography. Then, monoclonal mycotoxin antibodies were added in a copolymerization reaction with a cross-linker to form an immune-affinity monolith on the paper-based microzone array. With use of a competitive immune-response format, paper-based mycotoxin immune-affinity arrays were successfully applied to detect mycotoxins in samples. The detection limits for deoxynivalenol, zearalenone, T-2 toxin, and HT-2 toxin were 62.7, 10.8, 0.36, and 0.23 MUg.kg-1, respectively, which meet relevant requirements for these compounds in food. The recovery rates were 81-86% for deoxynivalenol, 89-117% for zearalenone, 79-86% for T-2 toxin, and 78-83% for HT-2 toxin, and showed the paper-based immune affinity arrays had good reproducibility. In summary, the paper-based mycotoxin immune-affinity array provides a sensitive, rapid, accurate, stable, and convenient platform for detection of multiple mycotoxins in agro-foods. Graphical abstract Paper-based immune-affinity monolithic array. DON deoxynivalenol, HT-2 HT-2 toxin, T-2 T-2 toxin, PEGDA polyethylene glycol diacrylate, ZEN zearalenone. PMID- 29411084 TI - Comprehensive targeted and non-targeted lipidomics analyses in failing and non failing heart. AB - Myocardial infarction (MI) and subsequent progressive heart failure pathology is the major cause of death worldwide; however, the mechanism of this pathology remains unclear. The present work aimed at testing the hypothesis whether the inflammatory response is superimposed with the formation of bioactive lipid resolving molecules at the site of the injured myocardium in acute heart failure pathology post-MI. In this view, we used a robust permanent coronary ligation model to induce MI, leading to decreased contractility index with marked wall thinning and necrosis of the infarcted left ventricle. Then, we applied mass spectrometry imaging (MSI) in positive and negative ionization modes to characterize the spatial distribution of left ventricle lipids in the infarcted myocardium post-MI. After micro-extraction, liquid chromatography coupled to tandem mass spectrometry was used to confirm the structures of the imaged lipids. Statistical tools such as principal component analysis were used to establish a comprehensive visualization of lipid profile changes in MI and no-MI hearts. Resolving bioactive molecules such as resolvin (Rv) D1, RvD5, RvE3, 17-HDHA, LXA4, and 18-HEPE were detected in negative ion mode MSI, whereas phosphatidyl cholines (PC) and oxidized derivatives thereof were detected in positive ion mode. MSI-based analysis demonstrated a significant increase in resolvin bioactive lipids with comprehensive lipid remodeling at the site of infarction. These results clearly indicate that infarcted myocardium is the primary location of inflammation-resolution pathomechanics which is critical for resolution of inflammation and heart failure pathophysiology. Graphical abstract Applied scheme to determine comprehensive lipidomics in failing and non-failing heart. PMID- 29411085 TI - Detection of nanoplastics in food by asymmetric flow field-flow fractionation coupled to multi-angle light scattering: possibilities, challenges and analytical limitations. AB - We tested the suitability of asymmetric flow field-flow fractionation (AF4) coupled to multi-angle light scattering (MALS) for detection of nanoplastics in fish. A homogenized fish sample was spiked with 100 nm polystyrene nanoparticles (PSNPs) (1.3 mg/g fish). Two sample preparation strategies were tested: acid digestion and enzymatic digestion with proteinase K. Both procedures were found suitable for degradation of the organic matrix. However, acid digestion resulted in large PSNPs aggregates/agglomerates (> 1 MUm). The presence of large particulates was not observed after enzymatic digestion, and consequently it was chosen as a sample preparation method. The results demonstrated that it was possible to use AF4 for separating the PSNPs from the digested fish and to determine their size by MALS. The PSNPs could be easily detected by following their light scattering (LS) signal with a limit of detection of 52 MUg/g fish. The AF4-MALS method could also be exploited for another type of nanoplastics in solution, namely polyethylene (PE). However, it was not possible to detect the PE particles in fish, due to the presence of an elevated LS background. Our results demonstrate that an analytical method developed for a certain type of nanoplastics may not be directly applicable to other types of nanoplastics and may require further adjustment. This work describes for the first time the detection of nanoplastics in a food matrix by AF4-MALS. Despite the current limitations, this is a promising methodology for detecting nanoplastics in food and in experimental studies (e.g., toxicity tests, uptake studies). Graphical abstract Basic concept for the detection of nanoplastics in fish by asymmetric flow field-flow fractionation coupled to multi-angle light scattering. PMID- 29411086 TI - Metabolomic spectral libraries for data-independent SWATH liquid chromatography mass spectrometry acquisition. AB - High-quality mass spectral libraries have become crucial in mass spectrometry based metabolomics. Here, we investigate a workflow to generate accurate mass discrete and composite spectral libraries for metabolite identification and for SWATH mass spectrometry data processing. Discrete collision energy (5-100 eV) accurate mass spectra were collected for 532 metabolites from the human metabolome database (HMDB) by flow injection analysis and compiled into composite spectra over a large collision energy range (e.g., 10-70 eV). Full scan response factors were also calculated. Software tools based on accurate mass and predictive fragmentation were specially developed and found to be essential for construction and quality control of the spectral library. First, elemental compositions constrained by the elemental composition of the precursor ion were calculated for all fragments. Secondly, all possible fragments were generated from the compound structure and were filtered based on their elemental compositions. From the discrete spectra, it was possible to analyze the specific fragment form at each collision energy and it was found that a relatively large collision energy range (10-70 eV) gives informative MS/MS spectra for library searches. From the composite spectra, it was possible to characterize specific neutral losses as radical losses using in silico fragmentation. Radical losses (generating radical cations) were found to be more prominent than expected. From 532 metabolites, 489 provided a signal in positive mode [M+H]+ and 483 in negative mode [M-H]-. MS/MS spectra were obtained for 399 compounds in positive mode and for 462 in negative mode; 329 metabolites generated suitable spectra in both modes. Using the spectral library, LC retention time, response factors to analyze data-independent LC-SWATH-MS data allowed the identification of 39 (positive mode) and 72 (negative mode) metabolites in a plasma pool sample (total 92 metabolites) where 81 previously were reported in HMDB to be found in plasma. Graphical abstract Library generation workflow for LC-SWATH MS, using collision energy spread, accurate mass, and fragment annotation. PMID- 29411087 TI - Use of a quality control approach to assess measurement uncertainty in the comparison of sample processing techniques in the analysis of pesticide residues in fruits and vegetables. AB - In routine monitoring of foods, reduction of analyzed test portion size generally leads to higher sample throughput, less labor, and lower costs of monitoring, but to meet analytical needs, the test portions still need to accurately represent the original bulk samples. With the intent to determine minimal fit-for-purpose sample size, analyses were conducted for up to 93 incurred and added pesticide residues in 10 common fruits and vegetables processed using different sample comminution equipment. The commodities studied consisted of apple, banana, broccoli, celery, grape, green bean, peach, potato, orange, and squash. A Blixer(r) was used to chop the bulk samples at room temperature, and test portions of 15, 10, 5, 2, and 1 g were taken for analysis (n = 4 each). Additionally, 40 g subsamples (after freezing) were further comminuted using a cryomill device with liquid nitrogen, and test portions of 5, 2, and 1 g were analyzed (n = 4 each). Both low-pressure gas chromatography-tandem mass spectrometry (LPGC-MS/MS) and ultrahigh-performance liquid chromatography (UHPLC) MS/MS were used for analysis. An empirical approach was followed to isolate and estimate the measurement uncertainty contribution of each step in the overall method by adding quality control spikes prior to each step. Addition of an internal standard during extraction normalized the sample preparation step to 0% error contribution, and coefficients of variation (CVs) were 6-7% for the analytical steps (LC and GC) and 6-9% for the sample processing techniques. In practice, overall CVs averaged 9-11% among the different analytes, commodities, batches, test portion weights, and analytical and sample processing methods. On average, CVs increased up to 4% and bias 8-12% when using 1-2 g test portions vs. 10-15 g. Graphical abstract Efficient quality control approach to include sample processing. PMID- 29411089 TI - The NISTmAb Reference Material 8671 value assignment, homogeneity, and stability. AB - The NISTmAb Reference Material (RM) 8671 is intended to be an industry standard monoclonal antibody for pre-competitive harmonization of best practices and designing next generation characterization technologies for identity, quality, and stability testing. It must therefore embody the quality and characteristics of a typical biopharmaceutical product and be available long-term in a stable format with consistent product quality attributes. A stratified sampling and analysis plan using a series of qualified analytical and biophysical methods is described that assures RM 8671 meets these criteria. Results for the first three lots of RM 8671 highlight the consistency of material attributes with respect to size, charge, and identity. RM 8671 was verified to be homogeneous both within and between vialing lots, demonstrating the robustness of the lifecycle management plan. It was analyzed in concert with the in-house primary sample 8670 (PS 8670) to provide a historical link to this seminal material. RM 8671 was verified to be fit for its intended purpose as a technology innovation tool, external system suitability control, and cross-industry harmonization platform. Graphical abstract The NISTmAb Reference Material (RM) 8671 is intended to be an industry standard monoclonal antibody for pre-competitive harmonization of best practices and designing next generation characterization technologies for identity, quality, and stability testing. PMID- 29411090 TI - Combined analytical approaches to define biodistribution and biological activity of semi-synthetic berberrubine, the active metabolite of natural berberine. AB - Berberine (BBR) is a natural alkaloid obtained from Berberis species plants, known for its protective effects against several diseases. Among the primary BBR metabolites, berberrubine (M1) showed the highest plasma concentration but few and conflicting data are available regarding its concentration in biological fluids related to its new potential activity on vascular cells. A combined analytical approach was applied to study biodistribution of M1 in comparison with BBR. The optimization of sample clean-up combined with a fully validated HPLC-ESI MS/MS tailored for M1 allows sufficient detectability and accuracy to be reached in the different studied organs even when administered at low dose, comparable to that assumed by human. A predictive human vascular endothelial cell-based assay to measure intracellular xanthine oxidase has been developed and applied to study unexplored activities of M1 alongside other common activities. Results showed that oral M1 treatment exhibits higher plasma levels than BBR, reaching maximum concentration 400-fold higher than BBR (204 vs 0.5 ng/mL); moreover, M1 exhibits higher concentrations than BBR also in all the biological compartments analyzed. Noteworthy, the two compounds follow two different excretion routes: M1 through urine, while BBR through feces. In vitro studies demonstrated that M1 inhibited intracellular xanthine oxidase activity, one of the major sources of reactive oxygen species in vasculature, with an IC50 = 9.90 +/- 0.01 MUg/mL and reduced the expression of the inflammatory marker ICAM-1. These peculiar characteristics allow new perspectives to be opened up for the direct use of M1 instead of BBR in endothelial dysfunction treatment. PMID- 29411091 TI - Development of an LC-MS/MS peptide mapping protocol for the NISTmAb. AB - Peptide mapping is a component of the analytical toolbox used within the biopharmaceutical industry to aid in the identity confirmation of a protein therapeutic and to monitor degradative events such as oxidation or deamidation. These methods offer the advantage of providing site-specific information regarding post-translational and chemical modifications that may arise during production, processing or storage. A number of such variations may also be induced by the sample preparation methods themselves which may confound the ability to accurately evaluate the true modification levels. One important focus when developing a peptide mapping method should therefore be the use of sample preparation conditions that will minimize the degree of artificial modifications induced. Unfortunately, the conditions that are amenable to effective reduction, alkylation and digestion are often the same conditions that promote unwanted modifications. Here we describe the optimization of a tryptic digestion protocol used for peptide mapping of the NISTmAb IgG1kappa which addresses the challenge of balancing maximum digestion efficiency with minimum artificial modifications. The parameters on which we focused include buffer concentration, digestion time and temperature, as well as the source and type of trypsin (recombinant vs. pancreatic; bovine vs porcine) used. Using the optimized protocol we generated a peptide map of the NISTmAb which allowed us to confirm its identity at the level of primary structure. Graphical abstract Peptide map of the NISTmAb RM 8671 monoclonal antibody. Tryptic digestion was performed using an optimized protocol and followed by LC-UV-MS analysis. The trace represents the total ion chromatogram. Each peak was mapped to peptides identified using mass spectrometry data. PMID- 29411092 TI - [Shoulder instability]. PMID- 29411093 TI - A guide to classifying mitotic stages and mitotic defects in fixed cells. AB - Cell division is fundamental to life and its perturbation can disrupt organismal development, alter tissue homeostasis, and cause disease. Analysis of mitotic abnormalities provides insight into how certain perturbations affect the fidelity of cell division and how specific cellular structures, molecules, and enzymatic activities contribute to the accuracy of this process. However, accurate classification of mitotic defects is instrumental for correct interpretation of data and formulation of new hypotheses. In this article, we provide guidelines for identifying specific mitotic stages and for classifying normal and deviant mitotic phenotypes. We hope this will clarify confusion about how certain defects are classified and help investigators avoid misnomers, misclassification, and/or misinterpretation, thus leading to a unified and standardized system to classify mitotic defects. PMID- 29411096 TI - [Anifrolumab in systemic lupus erythematosus]. PMID- 29411095 TI - [Myositis-specific antibodies associated with juvenile dermatomyositis]. AB - BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune disease associated with typical skin changes and muscle weakness. Within the framework of the diagnostics, myositis-associated (MAA) and myositis-specific antibodies (MSA) can be detected. These are important for the assessment of the course of the disease and the prognosis. METHOD: In this study we searched for MAA and MSA by means of a line immunoassay in 12 currently supervised JDM patients in the Rheumatism Center Sankt Augustin. RESULTS: In 10 of the 12 patients a total of 15 myositis antibodies were detected where 3 patients each had Mi2, SRP or NXP2 antibodies, 2 had TIF-1gamma antibodies and Jo1 or Mi2beta antibodies were found in 1 patient each. Of the patients two had additional PM-Scl antibodies. In the 10 patients with detected antibodies, a good phenotype-serotype correlation was found with deviation from the phenotypes described in the literature in only 3 patients. CONCLUSION: The frequent detection of certain antibodies and the good correlation with those phenotypes described in the literature, show that the determination of MSA is an important diagnostic tool to assess the course, complications and outcome and to initiate adequate therapy at an early stage. PMID- 29411094 TI - OsPKS2 is required for rice male fertility by participating in pollen wall formation. AB - KEY MESSAGE: OsPKS2, the rice orthologous gene of Arabidopsis PKSB/LAP5, encodes a polyketide synthase that is involved in pollen wall formation in rice. In flowering plants, the pollen wall protects male gametes from various environmental stresses and pathogen attacks, as well as promotes pollen germination. The biosynthesis of sporopollenin in tapetal cell is critical for pollen wall formation. Recently, progress has been made in understanding sporopollenin metabolism during pollen wall development in Arabidopsis. However, little is known about the molecular mechanism that underlies the sporopollenin synthesis in pollen wall formation in rice (Oryza sativa). In this study, we identified that a point mutation in OsPKS2, a plant-specific type III polyketide synthase gene, caused male sterility in rice by affecting the normal progress of pollen wall formation. Two other allelic mutants of OsPKS2 were generated using the CRISPR/Cas9 system and are also completely male sterile. This result thus further confirmed that OsPKS2 controls rice male fertility. We also showed that OsPKS2 is an orthologous gene of Arabidopsis PKSB/LAP5 and has a tapetum-specific expression pattern. In addition, its product localizes in the endoplasmic reticulum. Results suggested that OsPKS2 is critical for pollen wall formation, and plays a conserved but differentiated role in sporopollenin biosynthesis from Arabidopsis. PMID- 29411097 TI - [Big data in imaging]. AB - Until now, most major medical advancements have been achieved through hypothesis driven research within the scope of clinical trials. However, due to a multitude of variables, only a certain number of research questions could be addressed during a single study, thus rendering these studies expensive and time consuming. Big data acquisition enables a new data-based approach in which large volumes of data can be used to investigate all variables, thus opening new horizons. Due to universal digitalization of the data as well as ever-improving hard- and software solutions, imaging would appear to be predestined for such analyses. Several small studies have already demonstrated that automated analysis algorithms and artificial intelligence can identify pathologies with high precision. Such automated systems would also seem well suited for rheumatology imaging, since a method for individualized risk stratification has long been sought for these patients. However, despite all the promising options, the heterogeneity of the data and highly complex regulations covering data protection in Germany would still render a big data solution for imaging difficult today. Overcoming these boundaries is challenging, but the enormous potential advances in clinical management and science render pursuit of this goal worthwhile. PMID- 29411098 TI - Quick separation and enzymatic performance improvement of lipase by ionic liquid modified Fe3O4 carrier immobilization. AB - To promote the activity and stability of immobilized porcine pancreatic lipase (PPL), novel carrier was combined with special immobilization method. Enzymatic activity was enhanced after immobilized onto ionic liquid modified magnetic Fe3O4 by electrostatic adsorption. Activity of immobilized enzyme (PPL-IM/BF4-Fe3O4@CA) reached 596 U/g PPL. Through the combination of electrostatic adsorption and embedding immobilization methods, we improve binding force between the carrier and enzyme, and further enhance the efficiency and stability of immobilized enzyme. The activity of PPL-IM/BF4-Fe3O4@CA after repeated third use was 78%. After storage at room temperature for 5 days, the residual activity was 89%. Enzymatic properties and catalytic kinetics of immobilized enzymes were studied, and the effect mechanism of ionic liquid modified Fe3O4 on PPL was revealed. The effect of ionic liquid on the carrier structure was investigated by characterization of XRD, FT-IR, SEM and TG. The mechanism and enzymatic properties of immobilized PPL via electrostatic adsorption and embedding were analyzed. A novel and efficient immobilized PPL was developed. PMID- 29411099 TI - Vitrectomy for optic disc pit maculopathy: a long-term follow-up study. AB - PURPOSE: To evaluate the clinical outcomes of vitrectomy with induction of posterior vitreous detachment for the treatment of optic disc pit maculopathy. METHODS: We retrospectively evaluated medical records and imaging studies of 11 consecutive patients with optic disc pit maculopathy who underwent vitrectomy at Sacco University Hospital, Milan, Italy, between October 2008 and December 2015. Induction of a posterior vitreous detachment (PVD) was the aim of our surgery. Intravitreal injection of ocriplasmin (Jetrea, Thrombogenics USA, Alcon/Novartis EU) was performed before surgery in three eyes of very young patients. Gas tamponade (sulfur hexafluoride (SF6) 20%) was used only in the first five cases. Main outcome measures were anatomic results as determined by optical coherence tomography and postoperative best-corrected visual acuity (BCVA). RESULTS: Before surgery, a macular detachment was present in 10 eyes and a lamellar hole of the outer retina was detected in 9 eyes. Intraoperatively, two iatrogenic paramacular holes developed in two patients during posterior hyaloid dissection. Time to PVD induction appeared to be greatly reduced in the three patients injected with ocriplasmin before surgery. Patients were followed up for a mean of 38 months (range, 18-84) after surgery. Postoperatively, one patient (9%) developed a retinal detachment that was repaired with one additional vitrectomy. Complete resolution of fluid in and under the fovea was achieved in 8 of the remaining 10 eyes (80%) without additional treatment. Reduction of the inner retinal fluid always preceded the decrease of outer retinal fluid, which in turn anticipated the absorption of macular detachment. The macular detachment resolved in a mean of 14 months after surgery. Postoperative BCVA (mean, 0.63) improved significantly compared with preoperative BCVA (mean, 0.27) (P = 0.005). Nine eyes (82%) had a postoperative BCVA of 0.5 or better. CONCLUSION: Vitrectomy with induction of PVD is a safe and successful therapeutic option for the treatment of optic disc pit maculopathy. The adjunct of ocriplasmin might facilitate the induction of PVD and reduce the risk of iatrogenic retinal holes. PMID- 29411100 TI - Role of peroxynitrite in the responses induced by heat stress in tobacco BY-2 cultured cells. AB - Temperatures above the optimum are sensed as heat stress (HS) by all living organisms and represent one of the major environmental challenges for plants. Plants can cope with HS by activating specific defense mechanisms to minimize damage and ensure cellular functionality. One of the most common effects of HS is the overproduction of reactive oxygen and nitrogen species (ROS and RNS). The role of ROS and RNS in the regulation of many plant physiological processes is well established. On the contrary, in plants very little is known about the physiological role of peroxynitrite (ONOO-), the RNS species generated by the interaction between NO and O2-. In this work, the role of ONOO- on some of the stress responses induced by HS in tobacco BY-2 cultured cells has been investigated by measuring these responses both in the presence and in the absence of 2,6,8-trihydroxypurine (urate), a specific scavenger of ONOO-. The obtained results suggest a potential role for ONOO- in some of the responses induced by HS in tobacco cultured cells. In particular, ONOO- seems implicated in a form of cell death showing apoptotic features and in the regulation of the levels of proteins involved in the response to stress. PMID- 29411101 TI - In focus in HCB. PMID- 29411102 TI - 1700108J01Rik and 1700101O22Rik are mouse testis-specific long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs; > 200 nucleotides in length) have attracted attention as fine-tuners of gene expression. However, little is known about the cell- and stage-specific expression pattern and function of lncRNAs in spermatogenesis. The purpose of this study was to identify mouse testis associated lncRNAs using a combination of computational and experimental approaches. We first used the FANTOM5 database to survey lncRNA expression in the mouse testis and performed reverse transcription quantitative polymerase chain reaction (real-time PCR) and in situ hybridization (ISH) analyses. In silico analysis showed that most of the highly expressed lncRNAs in the adult mouse testis were testis-specific lncRNAs and were expressed at and following the initiation of spermatogenesis. We selected the antisense lncRNA 1700108J01Rik and long intergenic non-coding RNA 1700101O22Rik from the most highly expressed lncRNAs in the adult testis for further analysis. Real-time PCR analysis confirmed that 1700108J01Rik and 1700101O22Rik were specifically expressed in the testis. ISH analysis revealed that the two mouse-testis-specific lncRNAs were expressed exclusively in testicular germ cells in meiotic prophase and the round spermatid stage, which coincide with the period of transcriptional reactivation during spermatogenesis. The cytoplasmic distribution of these lncRNAs revealed by ISH suggests their involvement in post-transcriptional gene regulation rather than in epigenetic or transcriptional regulation. Our data provide new insight into testis-associated lncRNAs that will be useful in expression and functional studies of spermatogenesis. PMID- 29411103 TI - Ultrastructure and biological function of matrix vesicles in bone mineralization. AB - Bone mineralization is initiated by matrix vesicles, small extracellular vesicles secreted by osteoblasts, inducing the nucleation and subsequent growth of calcium phosphate crystals inside. Although calcium ions (Ca2+) are abundant throughout the tissue fluid close to the matrix vesicles, the influx of phosphate ions (PO43 ) into matrix vesicles is a critical process mediated by several enzymes and transporters such as ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), ankylosis (ANK), and tissue nonspecific alkaline phosphatase (TNSALP). The catalytic activity of ENPP1 in osteoblasts generates inorganic pyrophosphate (PPi) intracellularly and extracellularly, and ANK may allow the intracellular PPi to pass through the plasma membrane to the outside of the osteoblasts. Although the extracellular PPi binds to growing hydroxyapatite crystals to prevent crystal overgrowth, TNSALP on the osteoblasts and matrix vesicles hydrolyzes PPi into PO43- monomers: the prevention of crystal growth is blocked, and PO43- monomers are supplied to matrix vesicles. In addition, PHOSPHO1 is thought to function inside matrix vesicles to catalyze phosphocoline, a constituent of the plasma membrane, consequently increasing PO43- in the vesicles. Accumulation of Ca2+ and PO43- inside the matrix vesicles then initiates crystalline nucleation associated with the inner leaflet of the matrix vesicles. Calcium phosphate crystals elongate radially, penetrate the matrix vesicle's membrane, and finally grow out of the vesicles to form calcifying nodules, globular assemblies of needle-shaped mineral crystals retaining some of those transporters and enzymes. The subsequent growth of calcifying nodules appears to be regulated by surrounding organic compounds, finally leading to collagen mineralization. PMID- 29411104 TI - Lingual tonsillectomy with palatal surgery for the treatment of obstructive sleep apnea in adults: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis to evaluate effects of lingual tonsillectomy with palatal surgery as a combined procedure for the treatment of obstructive sleep apnea (OSA) in adults. SEARCH METHODS: Data source: a comprehensive search of MEDLINE, Scopus, Ovid, Web of Science, and the Cochrane Library was performed through November 2017. Manual searches and subject matter expert input were also obtained. This review includes studies assessing efficacy of lingual tonsillectomy with palatal surgery as a combined procedure for the treatment of OSA in adults, who had multilevel obstruction including lingual tonsil hypertrophy, in which apnea/hypopnea index (AHI) or respiratory disturbance index (RDI) were reported. RESULTS: A total of four studies (107 patients) met our inclusion criteria. Pooled random effects analysis demonstrated a statistically significant improvement of polysomnographic respiratory events postoperatively, with average AHI reduction of 18.51 events per hour, [95% confidence interval (CI) (- 31.72, - 5.31); P = 0.006] and increase in minimal arterial oxygen saturation of 5.26 [95% CI (0.10, 10.42); P = 0.05]. The result also showed that the procedures significantly improved sleepiness resulting in an average Epworth Sleepiness Scale (ESS) reduction of 5.44 [95% CI (- 8.69, - 2.18); P = 0.001]. CONCLUSION: A combination of lingual tonsillectomy with palatal surgery may offer benefits in a selected group of OSA adults, in terms of apnea/hypopnea index, minimal arterial oxygen saturation and Epworth Sleepiness Scale. Data were based on meta-analysis of all case series with 2-6 months' follow-up. PMID- 29411106 TI - Release and uptake of pathologic alpha-synuclein. AB - Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons and formation of Lewy bodies, which are rich in aggregated alpha-synuclein (alpha-syn). Two decades of intensive research have compiled a massive body of evidence that aggregation of alpha-syn is a critical process in PD and other synucleinopathies. The dissemination of Lewy body pathology throughout the central nervous system strongly suggests a cell-to-cell transmission of alpha-syn. Although in vitro and in vivo evidence has convincingly demonstrated that aggregation-prone alpha-syn can spread from cell to cell, the exact mechanisms and the role for the disease pathology remain elusive. Except for cases of direct contact, the transmission of alpha-syn from cell to cell requires that alpha-syn is released to the extracellular space and taken up by recipient cells. Furthermore, internalized alpha-syn needs to gain access to the cytoplasm and/or target organelles of the recipient cell. Here, we review the current state of knowledge about release and uptake of alpha-syn and discuss the key questions that remain unanswered. PMID- 29411107 TI - Theoretical descriptions of novel triplet germylenes M1-Ge-M2-M3 (M1 = H, Li, Na, K; M2 = Be, Mg, Ca; M3 = H, F, Cl, Br). AB - In a quest to identify new ground-state triplet germylenes, the stabilities (singlet-triplet energy differences, DeltaES-T) of 96 singlet (s) and triplet (t) M1-Ge-M2-M3 species were compared and contrasted at the B3LYP/6-311++G**, QCISD(T)/6-311++G**, and CCSD(T)/6-311++G** levels of theory (M1 = H, Li, Na, K; M2 = Be, Mg, Ca; M3 = H, F, Cl, Br). Interestingly, F-substituent triplet germylenes (M3 = F) appear to be more stable and linear than the corresponding Cl or Br-substituent triplet germylenes (M3 = Cl or Br). Triplets with M1 = K (i.e., the K-Ge-M2-M3 series) seem to be more stable than the corresponding triplets with M1 = H, Li, or Na. This can be attributed to the higher electropositivity of potassium. Triplet species with M3 = Cl behave similarly to those with M3 = Br. Conversely, triplets with M3 = H show similar stabilities and linearities to those with M3 = F. Singlet species of formulae K-Ge-Ca-Cl and K-Ge Ca-Br form unexpected cyclic structures. Finally, the triplet germylenes M1-Ge-M2 M3 become more stable as the electropositivities of the alpha-substituents (M1 and M2) and the electronegativity of the beta-substituent (M3) increase. PMID- 29411105 TI - Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a survey of 407 children. AB - INTRODUCTION: Pyloromyotomy is the standard care for hypertrophic pyloric stenosis. The traditional approach for this procedure is a right upper quadrant transverse incision, although other "open" approaches, such as circumumbilical or periumbilical incision have been described. The more recent approach used is laparoscopic pyloromyotomy (LP), but experience feedback is still debated and its benefits remain unproven. The aim of this study was to make a review of all our LP procedures with an objective evaluation according to the literature. METHODS: A retrospective analysis of all the LPs performed in one University Children's Hospital between 1 January 1996, and 30 December 2015 was realized. Information regarding the patient's status, intraoperative and postoperative data was analyzed. RESULTS: 407 patients were included in this study. The mean operative time of the overall procedure was 24 +/- 13 min, which significantly increased with the length of the pyloric muscle (p = 0.004) and significantly impacted the full feeding time (p = 0.006). 3.4% required conversion to an open procedure during the LP. We observed a significant correlation between conversion for mucosal perforation and weight loss (p = 0.04) and between conversion for mucosal perforation and preoperative weight (p = 0.002). A redo procedure was indicated in 3.7%, for incomplete pyloromyotomy each time. The mean postoperative hospital length of stay for all procedures was 1.6 +/- 0.8 days. There were no inflammatory scars. None had incisional hernias or wound dehiscence. DISCUSSION: LP procedure appeared to be as quick as the open procedure. Our results were similar to others series for intraoperative complications. According to operative time, this technique does not have an impact on operative room utilization. Vomiting duration at presentation in HPS does not seem to have a significant impact on postoperative outcomes. LP procedure causes little pain during the postoperative period. No wound complications were registered. PMID- 29411108 TI - First detection of Cryptosporidium DNA in blood and cerebrospinal fluid of HIV infected patients. AB - Human cryptosporidiosis is an intestinal infection caused by different species belonging to the genus Cryptosporidium in both immunocompetent and immunocompromised individuals. The life cycle of Cryptosporidium sp. when affecting the digestive system is well known but the infection of other organs is less studied. Molecular methods are necessary for species and subtypes identification. The goal of this work is to propose a new approach that contributes to the diagnosis of the extra-intestinal dissemination process of Cryptosporidium infection. Cryptosporidium sp. was detected in stool and biopsy samples of two HIV-infected patients. DNA was extracted from feces, biopsy specimens, blood, and cerebrospinal fluid (CSF). All samples were analyzed by nested PCR-RFLP of the 18S rDNA, real-time PCR, and gp60 subtyping. Cryptosporidium DNA was detected in stool and tissue samples and it was also present in blood and CSF samples. Both cases were characterized as Cryptosporidium hominis subtype IeA11G3T3. This is the first report that demonstrates the presence of Cryptosporidium DNA in blood and CSF of HIV-infected patients. PMID- 29411110 TI - Rooting strategies in a subtropical savanna: a landscape-scale three-dimensional assessment. AB - In resource-limited savannas, the distribution and abundance of fine roots play an important role in acquiring essential resources and structuring vegetation patterns and dynamics. However, little is known regarding the three-dimensional distribution of fine roots in savanna ecosystems at the landscape scale. We quantified spatial patterns of fine root density to a depth of 1.2 m in a subtropical savanna landscape using spatially specific sampling. Kriged maps revealed that fine root density was highest at the centers of woody patches, decreased towards the canopy edges, and reached lowest values within the grassland matrix throughout the entire soil profile. Lacunarity analyses indicated that spatial heterogeneities of fine root density decreased continuously to a depth of 50 cm and then increased in deeper portions of the soil profile across this landscape. This vertical pattern might be related to inherent differences in root distribution between trees/shrubs and herbaceous species, and the presence/absence of an argillic horizon across this landscape. The greater density of fine roots beneath woody patches in both upper and lower portions of the soil profile suggests an ability to acquire disproportionately more resources than herbaceous species, which may facilitate the development and persistence of woody patches across this landscape. PMID- 29411109 TI - Molecular identification of Sarcocystis lutrae in the European otter (Lutra lutra) and the European badger (Meles meles) from the Czech Republic. AB - Muscular sarcosporidial infections by Sarcocystis lutrae (Apicomplexa: Sarcocystidae) from the otter (Lutra lutra) and badger (Meles meles) (Carnivora: Mustelidae) were found in the Czech Republic. As part of a diversity evaluation of Sarcocystis in wild carnivores during 2016-2017, samples of diaphragm, tongue and hind-limb muscles were collected from nine districts, examined by compression and characterized molecularly. Cyst walls were thin, with no visible protrusions, and histological sections of infected muscle tissue showed no host responses. Fourteen of 17 badgers (82% prevalence) and one otter (100% prevalence) were positive for sarcocysts. Sequence analyses at four loci (18S rRNA, 28S rRNA, ITS1 and cox1) confirmed the identity as S. lutrae. This is also the first report of a co-infection with muscular sarcocystosis and Trichinella in badger. The finding of Trichinella is important from the zoonotic point of view, since badgers are used for meat consumption. Similar and future monitoring of both parasitic taxa are needed. PMID- 29411111 TI - Functional morphology of the blood-brain barrier in health and disease. AB - The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/beta-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer's disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer's disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB. PMID- 29411112 TI - Treatment of intrabony defects with modified perforated membranes in aggressive periodontitis: a 12-month randomized controlled trial. AB - OBJECTIVE: The aim of this study was to compare the clinical and radiographic efficacy of guided tissue regeneration with a modified perforated collagen membrane (MPM) or standard collagen membrane (CM) in the treatment of intrabony defects in patients with aggressive periodontitis (AgP). MATERIALS AND METHODS: Fifteen AgP patients were included in the study. Two single intrabony defects of at least 3 mm depth with >= 6 mm probing pocket depth (PPD) from each patient were randomly assigned to either xenogenic graft plus MPM (test group) or xenogenic graft plus CM (control group). PPD, clinical attachment level (CAL), and gingival recession (GR) were recorded at baseline and at 12 months. The radiographic assessments included the measurements of defect depth (DD), change in alveolar crest position (ACP), linear defect fill (LDF), and percentage defect fill (%DF). RESULTS: After treatment, PPD, CAL, DD, and ACP values improved significantly in both groups, without statistical differences between them. However, with respect to LDF and %DF, the 12-month radiographic analysis at MPM treated sites showed a significant improvement compared to the 6-month outcomes, that was not observed at control sites (additional LDF of 0.4 +/- 0.5 mm, p = 0.010 and %DF of 6.4 +/- 7.6%, p = 0.025). CONCLUSIONS: Both strategies proved effective in the treatment of intrabony defects in patients with AgP. Nonetheless, enhanced LDF and %DF 12 months postoperatively at MPM-treated sites may stem from cellular and molecular migration from the periosteum and overlying gingival connective tissue through barrier's pores. CLINICAL RELEVANCE: Modification of CM may have positive ramifications on periodontal regeneration. PMID- 29411113 TI - Multi-site musculoskeletal pain in Swedish police: associations with discomfort from wearing mandatory equipment and prolonged sitting. AB - PURPOSE: Musculoskeletal disorders are considered as a major issue affecting the health and well-being of active duty police. Discomfort from wearing mandatory equipment and sitting for long periods of time in fleet vehicles are workload factors linked to musculoskeletal disorders in police. This study aims to determine the prevalence of multi-site musculoskeletal pain among Swedish police and to explore the possible association to discomfort experience when wearing mandatory equipment and sitting for long periods in fleet vehicles. METHODS: In this cross-sectional study responses from 4185 police were collected through a self-administered online survey including questions about physical work environment, mandatory equipment and musculoskeletal pain. Multi-site pain was determined through summing pain sites from four body regions. Binomial logistic regression was performed to explore the association between multi-site musculoskeletal pain: (1) discomfort from wearing mandatory equipment and (2) sitting for long periods in fleet vehicles. RESULTS: The prevalence of multi-site musculoskeletal pain at least 1 day per week within the previous 3 months was 41.3%. A statistically significant association between discomfort from wearing mandatory equipment and multi-site musculoskeletal pain was found; duty belt [OR 5.42 (95% CI 4.56-6.43)] as well as body armour [OR 2.69 (95% CI 2.11-3.42)]. Sitting for long periods in fleet vehicles was not significantly associated to multi-site musculoskeletal pain. CONCLUSION: Multi-site musculoskeletal pain is a considerable problem among Swedish police and modifying mandatory equipment to decrease discomfort is suggested as a potential means of decreasing the musculoskeletal pain experienced by many police officers. PMID- 29411115 TI - Abstracts From the Sixth American Cough Conference. PMID- 29411114 TI - Arrhythmia-free survival and pulmonary vein reconnection patterns after second generation cryoballoon and contact-force radiofrequency pulmonary vein isolation. AB - INTRODUCTION: The aim of this study was to compare second-generation cryoballoon and contact-force radiofrequency point-by-point pulmonary vein isolation (PVI) in atrial fibrillation (AF) patients with regard to pulmonary vein reconnection and arrhythmia-free survival. METHODS AND RESULTS: Altogether, 269 consecutive patients with drug-refractory AF undergoing PVI were included and randomly allocated to second-generation cryoballoon or contact-force point-by-point radiofrequency ablation. Median follow-up duration was 389 days (interquartile range 219-599). Mean age was 59 years (71% male); 136 patients underwent cryoballoon and 133 patients underwent radiofrequency ablation. Acute electrical PVI was 100% for both techniques. Procedure duration was significantly shorter in cryoballoon vs radiofrequency (166.5 vs 184.13 min P = 0.016). Complication rates were similar (6.0 vs 6.7%, P = 1.00). Single procedure freedom of atrial arrhythmias was significantly higher in cryoballoon as compared to radiofrequency (75.2 vs 57.4%, P = 0.013). In multivariate analysis, persistent AF, AF duration, and cryoballoon ablation were associated with freedom of atrial tachyarrhythmias. The number of repeat ablation procedures was significantly lower in the cryoballoon compared to radiofrequency (15.0 vs 24.3%, P = 0.045). At repeat ablation, pulmonary vein reconnection rate was significantly lower after cryoballoon as compared to radiofrequency ablation (36.8 vs 58.1%, P = 0.003). CONCLUSIONS: Improved arrhythmia-free survival and more durable pulmonary vein isolation is seen after PVI using second-generation cryoballoon as compared to contact-force radiofrequency, in patients with drug-refractory paroxysmal AF. Complication rates for both ablation techniques are low. PMID- 29411117 TI - Computer tomography-based morphometric analysis of the cervical spine pedicles C3 C7. AB - BACKGROUND: Our aim was to examine the specific dimensions of cervical pedicles in a large Caucasian cohort on high dissolving CT scans. METHODS: A retrospective analysis of 100 cervical spine CT scans with a maximum slice thickness of 1 mm in axial, sagittal, and coronal reconstructions was performed. The pedicle axial length (PAL), inner and outer pedicle diameter (IPD/OPD), pedicle sagittal and transverse angle (PSA/PTA), pedicle height (PH), pedicle width (PW), and the cortical thickness (COT) at different margins were measured by two independent observers. A total of 1000 cervical pedicles (C3-C7) of 52 male (age 58 +/- 17.47 years, height 177.97 +/- 8.17 cm) and 48 female patients (age 57 +/- 19.07 years, height 165.50 +/- 7.44) were measured. RESULTS: Cortical thickness at the medial limitation of the pedicle was 1.77 +/- 0.43 and 0.90 +/- 0.36 mm at the lateral limitation (p < 0.001). The mean PAL ranged from 30.5 mm at C4 level to 35.3 mm at C6 level. PW and PAL were smaller in the female than in the male patients. The smallest values for PW were at C3 with 29.17% of males and 52.88% of females < 4.5 mm. The percentage of patients with PW < 4.5 mm decreased caudally with less than 10% of pedicles below C4 in male participants and below C6 in female participants. Mean PTA ranged from 34.6 degrees to 48.02 degrees peaking at C4 and C5 levels. No gender-specific difference was found for PTA and PSA (p >= 0.13). IPD and OPD were larger in males (p < 0.001), and body height correlated significantly with IPW (p <= 0.019) and OPW (p <= 0.003). The interrater reliability was very good for PW, PH, and IPD (0.84-0.86), good for OPD, PTA, and PSA (0.64-0.79), and moderate for PAL (0.54) and cortical thickness (0.44). CONCLUSIONS: Peculiarities of pedicle dimension of this central European cohort are comparable to morphometric studies in other ethnicities. Preoperative planning before cervical pedicle screw insertion on fine-cut CT scans demonstrates good interrater reliability for all important dimensions and angulations. More than half of female patients and almost a third of male patients had a PW of less than 4.5 mm at C3 level. Even though this percentage decreases caudally, pedicle screws might not be safe to insert in a noteworthy percentage of patients. PMID- 29411118 TI - Temperature threshold models for benthic macroinvertebrates in Idaho wadeable streams and neighboring ecoregions. AB - Water temperatures are warming throughout the world including the Pacific Northwest, USA. Benthic macroinvertebrates are one of the most important and widely used indicators of freshwater impairment; however, their response to increased water temperatures and their use for monitoring water temperature impairment has been hindered by lack of knowledge of temperature occurrences, threshold change points, or indicator taxa. We present new analysis of a large macroinvertebrate database provided by Idaho Department of Environmental Quality from wadeable streams in Idaho that is to be used in conjunction with our previous analyses. This new analysis provides threshold change points for over 400 taxa along an increasing temperature gradient and provides a list of statistically important indicator taxa. The macroinvertebrate assemblage temperature change point for the taxa that decreased with increased temperatures was determined to be about 20.5 degrees C and for the taxa assemblage that increased with increased temperatures was about 11.5 degrees C. Results of this new analysis combined with our previous analysis will also be useful for others in neighboring regions where these taxa occur. PMID- 29411116 TI - [Anticancer therapy for symptom relief? : A systematic review of clinical trials in oncology]. AB - BACKGROUND: When patients suffer from incurable cancer, drug-based, systemic anticancer therapy is usually used with the aim of longer survival, while minimizing toxicity and ensuring a tolerable quality of life. It is unclear to what extent and with what degree of success systemic tumor therapy can be used to specifically improve pre-existing pain and an already compromised quality of life (QoL). METHODS: Therefore, a systematic review of oncological therapy studies (PubMed) was conducted. Only studies that identified the pain-relieving and QoL enhancing effects of systemic anticancer therapy as the primary endpoint were selected and evaluated descriptively. RESULTS: Of the 2229 abstracts identified using a piloted search string, only 13 studies met the inclusion criteria. Of these, 10 studies showed an improvement in QoL-parameters through the use of systemic tumor therapies. DISCUSSION: Only a few studies focused primarily on the improvement of parameters related to quality of life-although this is the primary therapeutic goal for many patients suffering from incurable and advanced cancer. The study results encourage regular inclusion of symptom- and QoL-related data in clinical studies and to more explicitly address the potential of systemic anticancer therapy in relieving pain and other symptoms, thereby supporting the goals of palliative care. PMID- 29411119 TI - Selective association of nonaspirin NSAIDs with risk of diverticulitis. AB - PURPOSE: The purpose of this study is to investigate the association of intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular nonaspirin NSAIDs and compare it with other risk factors for the progression of diverticulosis to diverticulitis in patients who underwent colonoscopy. METHODS: A total of 194 patients who underwent complete colonoscopy in our center between 2012 and 2016 were recruited: 144 with diverticulosis without prior diverticulitis (median age 71 years, 59.7% men) and 50 with diverticulitis (median age 64 years, 54.0% men). Data concerning current and previous medication as well as concomitant diseases were collected using a structured questionnaire and by revision of patients medical charts. RESULTS: Patients with diverticulitis were significantly (p < 0.001) younger as compared to individuals with plain diverticulosis (median age 64 versus 71 years, respectively). The intake of NSAIDs significantly (p = 0.002) increased the risk of prior diverticulitis (OR 3.2, 95% CI 1.5-6.9). In the multivariate model, both age (p < 0.001) and NSAIDs (p = 0.03) proved to be independent determinants of diverticulitis. When analyzing aspirin intake, it was not associated with diverticulitis. CONCLUSIONS: Our study demonstrates, in line with previous reports, that intake of NSAIDs is associated with diverticulitis. We show in particular that nonaspirin NSAIDs might be selectively associated with diverticulitis. These results point to divergent role of aspirin and nonaspirin NSAIDs in the development of diverticulitis. PMID- 29411120 TI - Nomogram for predicting anastomotic leakage after low anterior resection for rectal cancer. AB - PURPOSE: Anastomotic leakage after low anterior resection for rectal cancer is a critical problem. Many risk factors have been suggested and surgical techniques have improved, but anastomotic leakage remains a major postoperative challenge. This study sought to create a nomogram for precise prediction of anastomotic leakage after low anterior resection for rectal cancer. METHODS: We used data of 936 patients that had been prospectively collected by the Japanese Society for Colon and Rectal Cancer between June 2010 and February 2013. Risk factors for anastomotic leakage were identified by multivariate logistic regression analysis and used to create a nomogram. The performance of the nomogram was evaluated by using a bootstrapped-concordance index and calibration plots. RESULTS: Sex, preoperative serum albumin, tumor location and diameter, and simultaneous resection of other organs were identified as significantly associated factors that could be combined for accurate prediction of anastomotic leakage. We created a nomogram for anastomotic leakage by using these risk factors. The area under the curve was 0.72 (95% confidence interval 0.67-0.76). The nomogram had a bootstrapped-concordance index of 0.72 and was well calibrated. CONCLUSIONS: Our nomogram was a useful tool for precise prediction of anastomotic leakage after low anterior resection for rectal cancer. PMID- 29411121 TI - Spatio-temporal analysis of floating islands and their behavioral changes in Loktak Lake with respect to biodiversity using remote sensing and GIS techniques. AB - The presence of floating islands is a unique characteristic of Loktak Lake. Floating islands play a significant role in ecosystem services and ecological processes and functioning. Rapid urbanization, industrialization, and a demand for more resources have led to changes in the landscape patterns at Loktak Lake in past three decades, thereby degrading and threatening the fragile ecosystem. The aim of the present study is to assess the changes in land use practices of the Phumdis by analyzing data from the past 38 years with remote sensing techniques. Landsat images from 1977, 1988, 1999 and an Indian remote sensing image from 2015 were used to assess the land use/land cover changes. The methodology adopted is a supervised classification using the maximum likelihood technique in ERDAS software. Five land used classes were employed: open water bodies, agricultural areas, Phumdis with thick vegetation, and Phumdis with thin vegetation and settlements. The results indicate that the highest loss of land used class was in Phumdis with thin vegetation (49.38 km2) followed by Phumdis with thick vegetation (8.59 km2), while there was an overall increase in open water bodies (27.00 km2), agricultural areas (25.33 km2), and settlement (5.75 km2). Our study highlights the loss of floating islands from the Loktak as a major concern that will lead to the destruction of the only "floating national park in the world." There is a high probability of extinction of the Sangai, an important keystone species found in the Indo-Burma biodiversity hotspot, if floating islands are not protected through sustainable development. PMID- 29411122 TI - Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-beta Levels in Primary Neurons from an Alzheimer's Disease Transgenic Model. AB - PURPOSE: The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer's disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons. METHODS: Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell's protein and lipid profiles. RESULTS: Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity. CONCLUSIONS: The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis. PMID- 29411123 TI - Is There an Age Threshold for Holding Off on Testing Novel Therapies? AB - PURPOSE OF REVIEW: We will review the reasons that explain the poor accrual of elderly patients to clinical trials, then we will discuss the relevance of an age threshold for holding off on testing novel therapies. RECENT FINDINGS: Little progress has been made in enrolling elderly patients in clinical trials. Reasons to hold off on testing novel therapies in elderly patients are mainly explained by exclusion criteria and industrials' reluctance to include elderly patients for fear of negative results. No age threshold should exist for testing novel therapies as long as well-designed clinical trials are developed and requested by regulatory authorities. Furthermore, clinical trials assessing novel anticancer therapies such as targeted therapies or immune checkpoint inhibitors should be developed in elderly patients regardless of age as these therapies may present a favorable benefit-risk profile compared to chemotherapy which is often more toxic and at risk of geriatric deconditioning. PMID- 29411124 TI - Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years. AB - Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato /oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3-18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH associated mortality significantly (p = 0.0276) decreased from 66.6% (1995-2004) to 6.25% (2005-2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger. PMID- 29411125 TI - Atypical chronic lymphocytic leukemia presenting with massive IgM paraprotein. PMID- 29411126 TI - Febrile events in acute lymphoblastic leukemia: a prospective observational multicentric SEIFEM study (SEIFEM-2012/B ALL). AB - The purpose of the present study is to estimate the current incidence of febrile events (FEs) and infectious episodes in acute lymphoblastic leukemia (ALL) and evaluate the outcome. We analyzed data on all FEs in a cohort of patients affected by ALL admitted to 20 Italian hematologic centers during 21 months of observation from April 1, 2012 to December 31, 2013. Data about treatment phase, steroids, neutropenia, type and site of infection, and outcome of infection were collected. The population comprehended 271 ALL adult patients. Median age was 46 years old (range 19-75), M/F 1.1:1. We collected 179 FEs occurring during 395 different phases of treatment in 127 patients (45.3% incidence): remission induction treatment 53.1%, consolidation/maintenance 35.7%, treatment for a first or second relapse 44.3%, and refractory disease 85.7%. The incidence of FUO (fever of unknown origin) was 55/395 (13.9%). In the remaining cases, bacteria caused 92 FEs (23.2%), fungi 17 (4.3%), viruses 5 (1%). Mixed infections occurred in 10 cases mainly fungal+bacterial (9/10 cases). Neutropenia was mostly present at onset of FE (89.9% of FEs). Mortality rate was 11.7% (21/179) while 16 deaths occurred with evidence of infection (8.9%). Age > 60 years, neutropenia, poor performance status, steroids, refractory disease, and mixed infections significantly correlated with infection-related mortality. A statistically significant association with mortality was observed also for pulmonary localization and bacteremia. Our study describes the real-life epidemiological scenario of infections in ALL and identifies a subset of patients who are at higher risk for infection-related mortality. PMID- 29411127 TI - Changes in central and peripheral neuromuscular fatigue indices after concentric versus eccentric contractions of the knee extensors. AB - PURPOSE: To better understand neuromuscular characteristics of eccentric exercise induced muscle damage, this study compared between concentric (CONC) and eccentric (ECC) exercises of knee extensor muscles, and the first (ECC1) and second bouts of the eccentric exercise (ECC2) for central and peripheral parameters associated with neuromuscular fatigue. METHODS: Twelve young men performed three exercise bouts separated by at least 1 week between CONC and ECC1, and 2 weeks between ECC1 and ECC2. In each exercise, maximal voluntary concentric or eccentric contractions of the knee extensors were performed until a reduction in maximal voluntary isometric contraction (MVC) torque of at least 40% MVC was achieved immediately post-exercise. MVC torque, central (voluntary activation and normalised electromyographic activity), and peripheral neuromuscular indices (evoked torque and M-wave amplitude), and muscle soreness were assessed before (PRE), immediately after (POST), 1 h (1H), and 1-4 days after exercise (D1, D2, D3, and D4). RESULTS: MVC torque decreased at only POST for CONC (- 52.8%), but remained below the baseline at POST (- 48.6%), 1H (- 34.1%), and D1-D4 (- 34.1 to - 18.2%) after ECC1, and at POST (- 45.2%), 1H (- 24.4%) and D1 (- 13.4%) after ECC2 (p < 0.05). Voluntary activation decreased immediately after ECC1 (- 21.6%) and ECC2 (- 21.1%), but not after CONC. Electrically evoked torques decreased similarly at POST and 1H for the three conditions, but remained below the baseline at D1 only post-ECC1. CONCLUSION: These results showed that both central and peripheral factors contributed to the MVC decrease after ECC1 and ECC2, but the decrease was mainly due to peripheral factors after CONC. PMID- 29411129 TI - Associations between physical activity, resilience, and quality of life in people with inflammatory bowel disease. AB - AIM: Research has shown that moderate-to-vigorous physical activity (MVPA) is associated with higher health-related quality of life (HRQOL) in healthy individuals. Recent studies have suggested that low- to moderate-intensity physical activity can be beneficial to HRQOL in people with inflammatory bowel diseases (IBD); however, studies investigating associations between MVPA and HRQOL in this population are lacking. PURPOSE: To understand the relationships among walking, MVPA, resilience, and HRQOL in people with IBD. METHODS: People with IBD (n = 242) completed questions about physical activity, resilience and HRQOL. Pearson product-moment correlations and multiple regression analyses were used to identify associations between physical activity and HRQOL. Analysis of covariance was used to compare HRQOL over quartiles of walking and MVPA with demographic variables as covariates. RESULTS: Both walking and MVPA were independently associated with physical (beta = 0.21 and beta = 0.26, respectively; p <= 0.001) but not mental HRQOL (p > 0.05). Higher volumes of MVPA were significantly associated with physical HRQOL (quartile 1 40.3 +/- 9.0 vs. quartile 4 47.4 +/- 9.0; p < 0.001) while higher volumes of walking were associated with both physical and mental HRQOL (p <= 0.01). CONCLUSIONS: The findings suggest that engaging in higher volumes of MVPA above 150 min/week and walking, particularly above 60 min/week, are associated with improved HRQOL in people with IBD. Research would benefit from investigating participation in MVPA as a coping strategy, in a longitudinal manner, to determine which modes of activity may be most beneficial to people with IBD. PMID- 29411128 TI - Effects of sprint interval training on ectopic lipids and tissue-specific insulin sensitivity in men with non-alcoholic fatty liver disease. AB - PURPOSE: This study examined the feasibility of sprint interval exercise training (SIT) for men with non-alcoholic fatty liver disease (NAFLD) and its effects on intrahepatic triglyceride (IHTG), insulin sensitivity (hepatic and peripheral), visceral (VAT) and subcutaneous adipose tissue (ScAT). METHODS: Nine men with NAFLD (age 41 +/- 8 years; BMI 31.7 +/- 3.1 kg m-2; IHTG 15.6 +/- 8.3%) were assessed at: (1) baseline (2) after a control phase of no intervention (pre training) and (3) after 6 weeks of SIT (4-6 maximal 30 s cycling intervals, three times per week). IHTG, VAT and ScAT were measured using magnetic resonance spectroscopy or imaging and insulin sensitivity was assessed via dual-step hyperinsulinaemic-euglycaemic clamp with [6,6-D2] glucose tracer. RESULTS: Participants adhered to SIT, completing >= 96.7% of prescribed intervals. SIT increased peak oxygen uptake [[Formula: see text] peak: + 13.6% (95% CI 8.8 18.2%)] and elicited a relative reduction in IHTG [- 12.4% (- 31.6 to 6.7%)] and VAT [- 16.9% (- 24.4 to - 9.4%); n = 8], with no change in body weight or ScAT. Peripheral insulin sensitivity increased throughout the study (n = 8; significant main effect of phase) but changes from pre- to post-training were highly variable (range - 18.5 to + 58.7%) and not significant (P = 0.09), despite a moderate effect size (g* = 0.63). Hepatic insulin sensitivity was not influenced by SIT. CONCLUSIONS: SIT is feasible for men with NAFLD in a controlled laboratory setting and is able to reduce IHTG and VAT in the absence of weight loss. PMID- 29411130 TI - Sarcopenia in cancer survivors is associated with increased cardiovascular disease risk. AB - PURPOSE: The aim of this study was to assess the association between sarcopenia and cardiovascular disease (CVD) risk in cancer survivors. METHODS: We analyzed a consecutive series of 683 cancer survivors from the Korean National Health and Nutritional Exam Survey (2008-2011 years). Sarcopenia was defined as the appendicular skeletal muscle mass divided by weight (Kg) < 1 standard deviation below the sex-specific healthy population aged 20-39 years. CVD risks were assessed using the Framingham Risk Score (FRS), which were divided by tertile. Predictors of higher shift of FRS tertile by sex were calculated by stratified ordinal logistic regression analyses. RESULTS: Proportions of sarcopenia were 24.2% in males and 22.5% in females. Sarcopenic survivors were more likely to have a higher body mass index, waist circumference, blood pressure and fasting glucose level, and a lower high-density lipoprotein compared to those without sarcopenia. Sarcopenia was associated with a higher shift of FRS tertile (common odds ratio, 2.67; 95% confidence interval, 1.18-6.52, P < 0.001) in males. However, this association was not significant in female survivors. CONCLUSIONS: Sarcopenia was associated with an increased CVD risk in Korean male cancer survivors. Interventions to prevent sarcopenia may be necessary to improve cardiovascular burden in cancer survivors. PMID- 29411131 TI - Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients. AB - PURPOSE: Despite its widespread use as primary febrile neutropenia (FN) prophylaxis during chemotherapy for early-stage breast cancer, the optimal duration of daily filgrastim is unknown. Using the minimum effective duration may improve patient comfort and acceptability while reducing costs. Yet, suboptimal dosing may also negatively impact patient care. A survey was performed to obtain information regarding current practices for granulocyte colony-stimulating factor (G-CSF) use. METHODS: Canadian oncologists involved in the treatment of breast cancer patients, as well as patients who had received neo/adjuvant chemotherapy for breast cancer, were surveyed. Standardized surveys were designed to collect information on perceived reasons for G-CSF use and current practices. RESULTS: The surveys were completed by 38/50 (76%) physicians and 95/97 (98%) patients. For physicians, there was variability in the choice of chemotherapy regimens that required G-CSF support, the dose of filgrastim prescribed and the number of days prescribed. The majority of physicians reported using 5 (31.6%), 7 (47.4%), or 10 (13.2%) days of therapy. Nearly half of the patients (46.3%) recalled having experienced at least one of the chemotherapy-related complications including chemotherapy delays, dose reductions, and FN. While on filgrastim, 66.3% of patients reported myalgia and bone pain. Both physicians and patients expressed interest in participating in clinical trials designed to optimize the duration of filgrastim administration. CONCLUSIONS: Significant variability in practice exists with respect to filgrastim administration. Definitive studies are therefore required to standardize and improve care, as this has the potential to impact treatment outcomes, patient quality of life, and cost savings. PMID- 29411132 TI - What factors are associated with increased risk for prolonged postoperative opioid usage after colorectal surgery? AB - BACKGROUND: Opioid-related deaths have increased substantially over the last 10 years placing clinician's prescription practices under intense scrutiny. Given the substantial risk of opioid dependency after colorectal surgery, we sought to analyze risk of postoperative prolonged opioid use after colorectal resections. METHODS: Between 2008 and 2014, patients undergoing abdominopelvic procedure with intestinal resection at a tertiary care facility were retrospectively identified. Patient's postoperative narcotic usage including their prescriptions on discharge and their total opioid medication use was recorded. Patient variables such as demographics, surgical characteristics, and prescription use were evaluated. Finally, we developed multivariate models to identify risk factors for prolonged opioid use (> 30 days after incident surgical procedure). RESULTS: We identified 9423 recorded procedures of which 2173 consisted of abdominopelvic procedures with intestinal resection and survived > 1 year. Of these, 91% (n = 1981) were discharged on opioids, and 98% (n = 1955) of those patients filled only one prescription. A total of 92 (4%) patients remained on opioids beyond 30 days, and from this group, 25% (n = 23 patients) remained at 90 days. We found no association between postoperative complications, stoma formation, and patient's sex with risk of prolonged opioid use. However, younger age and history of chronic pain were associated with an increased risk of prolonged opioid use. The use of minimally invasive techniques also attenuated the risk of prolonged opioid use (Table 2). CONCLUSION: A small but considerable proportion of patients remain on opioids beyond 30 days. Predictors of opioid use for greater than 30 days include a history of chronic pain and younger age. The use of minimally invasive techniques reduced the risk of prolonged opioid use. We identified several immutable risk factors that predicted prolonged postoperative opioid use; however, surgeons may be able to attenuate prolonged opioid use through the use of minimally invasive techniques. PMID- 29411133 TI - Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a role for robotics? AB - BACKGROUND: The utilization of robotic platforms for general surgery procedures such as hernia repair is growing rapidly in the United States. A limited amount of data are available evaluating operative outcomes in comparison to standard laparoscopic surgery. We completed a retrospective review comparing robotic and laparoscopic ventral hernia repair to provide safety and outcomes data to help design a future prospective trial design. METHODS: A retrospective review of 215 patients undergoing ventral hernia repair (142 robotic and 73 laparoscopic) was completed at two large academic centers. Primary outcome measure evaluated was recurrence. Secondary outcomes included incidence of primary fascial closure, and surgical site occurrences. RESULTS: Propensity for treatment match comparison demonstrated that robotic repair was associated with a decreased incidence of recurrence (2.1 versus 4.2%, p < 0.001) and surgical site occurrence (4.2 versus 18.8%, p < 0.001). This may be because robotic repair was associated with increased incidence of primary fascial closure (77.1 versus 66.7%, p < 0.01). Analysis of baseline patient populations showed that robotic repairs were completed on patients with lower body mass index (28.1 +/- 3.6 versus 34.2 +/- 6.4, p < 0.001) and fewer comorbidities. CONCLUSIONS: Our retrospective data show that robotic repair was associated with decreased recurrence and surgical site occurrence. However, the differences noted in the patient populations limit the interpretability of these results. As adoption of robotic ventral hernia repair increases, prospective trials need to be designed in order to investigate the efficacy, safety, and cost effectiveness of this evolving technique. PMID- 29411134 TI - Genetic analysis of rotavirus G2P[4] strains in Pune, Western India: circulation of a novel reassortant bearing E6 NSP4 genotype. AB - In India, G2P[4] strains are known to be the second most predominant group A rotaviruses causing acute gastroenteritis among children. This study was performed to determine the diversity within VP7(G), VP4(P), VP6(I) and NSP4(E) genes of 16 G2P[4] rotavirus strains detected in children hospitalized for acute gastroenteritis in Pune, Western India during 2009-2013. Fourteen strains showed G2-P[4]-I2-E2 and two strains showed G2-P[4]-I2-E6 genotype constellation. Phylogenetic analysis showed their clustering into G2-IV-a3, P[4]-5bi/ii, I2-3ii and E2-4i/ii or E6 genotypes/lineages. These data reveal inter- and/or intra genotypic variations in a genogroup-2 constellation of G2P[4] rotavirus strains circulating in Pune, Western India, providing evidence of a novel G2P[4] reassortant bearing a rare NSP4 genotype, E6 during 2009-2013. PMID- 29411135 TI - The prevalence of hepatitis C virus infection in thalassemia patients in Iran from 2000 to 2017: a systematic review and meta-analysis. AB - One of the major infections transmitted through the bloodstream is hepatitis C virus (HCV) infection. Patients with thalassemia requiring frequent blood transfusions are at risk for HCV. Therefore, this study was conducted to determine the incidence of HCV in thalassemia patients in Iran. The following databases were searched: ISI/Web of Science, Embase, Pubmed/MEDLINE via Ovid, Scopus, as well as Iranian databases (Magiran, Irandoc and SID) from January 2000 to July 2017. The quality of the studies was evaluated using the 22-item STROBE checklist. The random model based on the DerSimonian/Laird approach was used. To assess the stability of the results, a sensitivity analysis was performed, stratifying on the basis of quality, sample size, year of publication, and geographical area of studies. Also, meta-regression analyses were carried out in terms of sample size and year of publication of studies. Fifty-two studies were included. The total number of patients included was 13,291. Based on the random model, the overall prevalence of HCV in thalassemia patients was 19% (95% CI 16 21). The results did not differ before and after sensitivity analysis. The prevalence of HCV in thalassemia patients in Iran was 19%. This figure was lower than in the neighboring countries of Iran. Screening and the use of diagnostic methods for screening blood donors are essential. In addition, the treatment of patients should be seriously addressed by the agenda of the Iranian health system. PMID- 29411136 TI - Mutation of I176R in the E coding region weakens Japanese encephalitis virus neurovirulence, but not its growth rate in BHK-21 cells. AB - Previously, we isolated the Japanese encephalitis virus (JEV) strain SCYA201201. In this study, we passed the SCYA201201 strain in Syrian baby hamster kidney (BHK 21) cells 120 times to obtain the SCYA201201-0901 strain, which exhibited an attenuated phenotype in mice. Comparison of SCYA201201-0901 amino acid sequences with those of other JEV strains revealed a single mutation, I176R, in the E coding region. Using reverse genetic technology, we provide evidence that this single E-I176R mutation does not affect virus growth in BHK-21 cells but significantly decreases JEV neurovirulence in mice. This study provides critical information for understanding the molecular mechanism of JEV attenuation. PMID- 29411137 TI - Isobavachalcone inhibits post-entry stages of the porcine reproductive and respiratory syndrome virus life cycle. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen of great economic significance that impacts the swine industry globally. Since the first report of a porcine reproductive and respiratory syndrome (PRRS) outbreak, tremendous efforts to control this disease, including various national policies and plans incorporating the use of multiple modified live-virus vaccines, have been made. However, PRRSV is still a significant threat to the swine industry, and new variants continually emerge as a result of PRRSV evolution. Several studies have shown that pandemic PRRSV strains have enormous genetic diversity and that commercial vaccines can only provide partial protection against these strains. Therefore, effective anti-PRRSV drugs may be more suitable and reliable for PRRSV control. In this study, we observed that isobavachalcone (IBC), which was first isolated from Psoralea corylifolia, had potent anti-PRRSV activity in vitro. Although many biological activities of IBC have been reported, this is the first report describing the antiviral activity of IBC. Furthermore, after a systematic investigation, we demonstrated that IBC inhibits PRRSV replication at the post-entry stage of PRRSV infection. Thus, IBC may be a candidate for further evaluation as a therapeutic agent against PRRSV infection of swine in vivo. PMID- 29411138 TI - Conferring virus resistance in tomato by independent RNA silencing of three tomato homologs of Arabidopsis TOM1. AB - The TOM1/TOM3 genes from Arabidopsis are involved in the replication of tobamoviruses. Tomato homologs of these genes, LeTH1, LeTH2 and LeTH3, are known. In this study, we examined transgenic tomato lines where inverted repeats of either LeTH1, LeTH2 or LeTH3 were introduced by Agrobacterium. Endogenous mRNA expression for each gene was detected in non-transgenic control plants, whereas a very low level of each of the three genes was found in the corresponding line. Small interfering RNA was detected in the transgenic lines. Each silenced line showed similar levels of tobamovirus resistance, indicating that each gene is similarly involved in virus replication. PMID- 29411142 TI - Mycobacterium marinum: a rare cause of chronic lymphocutaneous syndrome. AB - : We investigated the prevalence of Mycobacterium marinum lymphadenitis and describe 4 children with the disease. The database of the microbiology laboratory of a tertiary pediatric medical center was searched for all cases of nontuberculous mycobacterial lymphadenitis from 1996 to 2016. M. marinum lymphadenitis was defined as isolation of the pathogen from a lymph node or from a skin lesion with an enlarged regional lymph node. M. marinum was isolated from lymph nodes in 2 of 167 patients with nontuberculous mycobacterial lymphadenitis and from skin lesions in 2 children with skin lesions and regional reactive lymphadenitis, yielding a 2.4% prevalence of M. marinum lymphadenitis. All 4 affected children were younger than 7 years and had been referred for evaluation of enlarged lymph nodes. Preauricular/submandibular and inguinal lymph nodes (n = 2 each) were involved. Three patients had skin traumas and visited the same natural spring. The diagnosis was delayed because a history of aquatic exposure was initially missed. Two children were managed with anti-mycobacterial antibiotics and 2 by observation only. All showed good resolution. CONCLUSION: A detailed history, specifically regarding exposure to spring water sources, in cases of lymphocutaneous syndrome can point to the diagnosis of M. marinum infection. What is Known: * M. marinum can cause chronic nodular or ulcerative skin infections. * Lymphadenitis due to M. marinum has rarely been reported. What is New: * M. marinum infection can present as isolated chronic lymphadenitis; it accounts for about 2.4% of all cases of nontuberculous mycobacterial lymphadenitis and it tends to occur in noncervicofacial regions relative to infections of other nontuberculous mycobacterial species. * Careful history taking including water source exposure, especially in association with skin trauma, can point to the correct diagnosis in children with chronic lymphadenitis. PMID- 29411143 TI - Is there a gender-specific association between asthma and carotid intima media thickness in Swiss adolescents? AB - : Respiratory diseases are associated with increased cardiovascular risk in adults, but little is known on the early impact on the vasculature in youth. The SAPALDIA Youth study, the offspring study of the Swiss Study on Air Pollution and Lung and Heart Disease In Adults (SAPALDIA), investigated the association between physician-diagnosed asthma status and common carotid artery intima media thickness (CIMT). Offspring underwent standardized clinical protocols and provided information on early life factors, health, and lifestyle. The association between per subject averages of CIMT and asthma was estimated using mixed linear regression analyses adjusting for main confounders, testing for interaction with gender and age. Of 257 offspring (mean age 15 years, 53% female), 11.5% reported doctor-diagnosed asthma (male 17%, female 7%). Mean CIMT was significantly different by gender (male 0.53 mm (+/- 0.045), female 0.50 mm (+/- 0.048); p < 0.001). Interaction was highly significant by gender (p = 0.001) with significantly increased CIMT in asthmatic vs. non-asthmatics boys (difference 0.023 mm, 95% CI 0.003; 0.043), as compared to girls. CONCLUSION: Our study suggests an increased risk for early vascular change in adolescent asthmatic boys. Whereas the small number of girls limits the interpretation, the result necessitates further research into sex-specific atherosclerotic burden related to respiratory health in adolescence. What is Known: * Evidence points to a significant impact of adult respiratory disease on cardiovascular health indicators as well as on endpoints. * Inflammation is a key pathway in vascular change across the life course. What is New: * We observe an adverse association between physician-diagnosed asthma and carotid intima media thickness in adolescent boys. * Albeit a limited number of asthmatic girls, we hypothesize the gender typical timing of asthma or a higher male cardiovascular vulnerability as possible explanations for the gender-specific results. PMID- 29411144 TI - Olfactory Neuroblastoma. AB - PURPOSE OF REVIEW: To provide a comprehensive review of the literature focusing on the recent advances in the diagnosis and management of olfactory neuroblastoma. RECENT FINDINGS: Multimodality treatment is usually recommended for the majority of ONB cases. Recent advances in surgical approaches include the evolving role of endonasal endoscopic surgical resection and reconstruction. The introduction of new conformal radiation techniques has improved the outcomes and reduced treatment-related toxicity to important structures such as the eye and the brain. The role of neoadjuvant and adjuvant chemotherapy is yet to be defined. In the last two decades, there have been advances in surgical techniques with endoscopic approaches, either alone or in combination with craniotomy, gradually replacing the open traditional approaches. Prolonged surveillance is recommended for ONB due to late recurrences associated with that tumor. The role of chemotherapy and elective neck irradiation is still controversial and needs more studies to investigate their optimal role. PMID- 29411145 TI - Assessment of the trace element distribution in soils in the parks of the city of Zagreb (Croatia). AB - This paper presents the results of the preliminary testing of the selected trace elements in the soils of several parks in the city of Zagreb, Republic of Croatia. In each park, the samples were taken from several points-at various distances from the roads. The samples were taken at two different depths: 0-5 and 30-45 cm. Composite samples were done for each sampling point. Microwave-assisted wet digestion of the soil samples was performed and the determination by ICP-AES technique was done. Results obtained for Al, As, Ba, Mn, Ti, V, and K are in a good agreement with the results published in the scientific literature so far. The mass fraction values of Cd, Cr, Cu, Ni, Pb, and Zn are somewhat higher than the maximum values given in the Croatian Directive on agricultural land protection against pollution. Be, Mo, Sb, Se, and Tl in the samples were present in the concentrations that are lower than their method detection limit values. PMID- 29411146 TI - Oil-degrading properties of a psychrotolerant bacterial strain, Rhodococcus sp. Y2-2, in liquid and soil media. AB - The aim of this study was to investigate oil-degrading ability of newly isolated strain Rhodococcus Y2-2 at low temperature. Rhodococcus sp. Y2-2 was isolated from oil-contaminated soil sampled at the end of winter using a newly developed transwell plate method. In the liquid phase, the oil-degradation efficiency of strain Rhodococcus sp. Y2-2 was about 84% with an initial concentration of 1500 ppm TPH (500 ppm each of kerosene, gasoline, and diesel) when incubated for 2 weeks under optimal conditions: 10 degrees C, pH 7, and 0.5 g L- 1 inoculum. In the soil phase, the isolate showed 80% oil degradation efficiency using glucose as a carbon source, with an initial concentration of 4000 ppm TPH and the addition of water during 14 days of incubation at 10 degrees C. Additionally, the degradation efficiency of the isolate was increased by the addition of mixture of surfactant alpha olefin sulfonate and gelatin, although strain Y2-2 also produced many biosurfactant components. This study shows Rhodococcus sp. Y2 2 can degrade oil components both in liquid and soil media by consuming kerosene, gasoline, and diesel as a carbon and energy source. Therefore, the crude oil degrading ability of Rhodococcus sp. Y2-2 at low temperature provides proper bioremediation tool to clean up oil-contaminated sites especially in cold area or during winter season. PMID- 29411147 TI - Atrial Fibrillation for the Neurologist: Preventing both Ischemic and Hemorrhagic Strokes. AB - PURPOSE OF REVIEW: This review aims to help neurologists managing atrial fibrillation (AF) patients who had an ischemic stroke and/or with intracranial hemorrhage (ICH) markers, therefore at high embolic/hemorrhagic risks. RECENT FINDINGS: Implantable loop recorders have substantially improved the accuracy of AF detection. Recent research yielded a set of powerful neuroimaging markers that can stratify ICH risk. Direct oral anticoagulants (DOAC) are easier to use with a lower ICH risk than warfarin in a general AF population. Finally, the FDA approved left atrial appendage closure (LAAC) with the WATCHMAN device provides an option without the need for life-long anticoagulation. In this review, we introduce the concept of preventing both ischemic and hemorrhagic strokes in AF patients through accurate AF diagnosis and stratification of both embolic and ICH risks. LAAC can be considered in patients at higher hemorrhagic risks while warfarin/DOAC use should be individualized in the majority of AF patients at a low risk of bleeding. PMID- 29411148 TI - From a Patient Advocate's Perspective: Does Cancer Immunotherapy Represent a Paradigm Shift? AB - PURPOSE OF REVIEW: In 2016, the American Society of Clinical Oncology (ASCO) announced immunotherapy as the year's top cancer advance in its "Clinical Cancer Advances 2016: ASCO's Annual Report on Progress Against Cancer." Further, ASCO again named "Immunotherapy 2.0" as the 2017 advance of the year, emphasizing the recent, rapid pace of research into new agents that harness and enhance the innate abilities of the immune system to recognize and fight cancers-and stressing that such agents have extended the lives of many patients with late stage cancers for which there have been few treatment options. This article discusses the history of cancer immunotherapy and the recent promising advances, yet also presents a note of caution on limitations of immunotherapies, their potential harms, and the critical need for oncologists to appropriately engage with and educate patients to effectively manage their expectations. RECENT FINDINGS: Learning how to effectively harness the immune system to treat cancer represents an investigative journey of more than 100 years. However, after many failures and disappointments, this decade has seen several important successes. In 2011, the Food and Drug Administration (FDA) approved the first immunotherapy agent known as a "checkpoint inhibitor." Beginning in 2014, several additional checkpoint blockage drugs have been FDA-approved, and new indications and drug combinations have emerged. Further, on August 30, 2017, the FDA announced its first approval of a new form of immunotherapy known as CAR T cell therapy. Since the 2011 approval of the first checkpoint inhibitor, cancer immunotherapy research among the pharmaceutical industry and research institutions has exploded, with thousands of clinical trials currently taking place. The current "cancer immunotherapy revolution" is in the headlines daily and is also the primary topic of conversation among major cancer research conferences and symposia attendees. However, a once quiet voice has begun to emerge, where an increasing number of scientists, clinicians, and patient advocates are stressing the need for caution concerning the limitations and potential harms associated with cancer immunotherapy. Many oncologists, scientists, medical professional associations, and advocates agree that no recent cancer advance has been as successful, transformative, and potentially paradigm-shifting as immunotherapy. With this decade, we have seen the approval of several immunotherapy agents that have successfully treated a percentage of patients with notoriously resistant cancers, an increasing number of combination immunotherapy treatments, and new indications for approved agents. However, patients need to be aware that much of the popular media has breathlessly inflated positive outcomes of cancer immunotherapies, while neglecting to stress that just a small percentage of patients actually benefit from such treatments. Further, they often completely overlook the unique, potentially life-threatening harms that may be associated with these agents and fail to cover negative findings where immunotherapies have appeared to paradoxically accelerate cancer growth. Fortunately, the majority of journal articles presenting trial results and comprehensive review articles appropriately discuss the important limitations associated with immunotherapies, the unique spectrum of adverse effects, and the need for further research to improve our ability to identify those patients who are most likely to benefit from specific agents, sparing other patients from exposure to agents that will not be effective, yet may carry potentially life-threatening toxicities. PMID- 29411150 TI - Correction to: Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents. AB - After publication of the original article [1], the following error was reported in the Results section of the Abstract: "antifungal activity against one yeast i.e. Aspergillus niger" should read: "antifungal activity against one fungus i.e. Aspergillus niger". The authors would like to confirm all antifungal activity has been screened against fungi not yeast. PMID- 29411149 TI - Pharmacological Treatment of Attention Deficit Hyperactivity Disorder During Pregnancy and Lactation. AB - INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral problem found in 2-5% of adults. Stimulants and drugs that affect the dopaminergic, noradrenergic and/or serotonergic systems are effective treatment and are increasingly prescribed to women at child bearing age. It is consequently important that reliable information on the safety of these drugs in pregnancy is available so that appropriate therapeutic choices can be made. RESULTS: The data on stimulants (methylphenidate and amphetamines) are generally showing that there is no increase in the rate of major congenital anomalies. There are very little data on the use of atomoxetine and guanfacine in pregnancy. There are no data on the use of clonidine for ADHD but the data on its use as an antihypertensive drug have not revealed any serious adverse effect. Bupropion, when used as an antidepressant, does not seem to increase the rate of congenital anomalies. There are practically no data on the possible long-term neurodevelopmental effects of any of these drugs. Most of them are secreted in human milk, but the concentrations in infant's blood, except for clonidine and amphetamines, have been very low. Breast feeding with clonidine and amphetamines is therefore contraindicated, but there seems to be no safety concerns for the other drugs. CONCLUSION: The drugs used for the treatment of ADHD are apparently not teratogenic, but due to paucity of data, especially on the long-term neurodevelopmental outcome, the treating physician should reconsider the need of treatment during pregnancy. If needed, methylphenidate, amphetamines and bupropion are preferred drugs. PMID- 29411151 TI - Two-Pore Minimum Physiologically-based Pharmacokinetic Model to Describe the Disposition of Therapeutic Monoclonal IgG Antibody in Humans. AB - PURPOSE: The aim of this study was to develop a two-pore minimum physiologically based pharmacokinetic (mPBPK) model in describing the pharmacokinetic (PK) of therapeutic monoclonal antibody (TMAb) in human subjects. METHODS: PK data used in this study were endogenous/exogenous native IgG and two TMAbs (palivizumab and Motavizumab-YTE) in normal volunteer or familial hypercatabolic hypoproteinemia (FIHH) patient. Several important components were implemented to overcome the limitations of the early mPBPK model, e.g. two-pore model to describe the transcapillary transport of IgG from vascular to interstitial space. Six mPBPK models with different osmotic reflection coefficient (OFC) of transcapillary transport, endocytosis rates (ETR) and plasma clearance for the TMAbs/IgG were tested and the best model was selected using AICc values. RESULTS: The final model consisted of different OFC and ETR values for native IgG and TMAbs, supporting the hypothesis that the dynamics in the endosomal space had an important role in the compliant FcRn salvage mechanism to determine the clearance of TMAbs. The estimated FcRn concentration of FIHH subjects was 2.72 MUmol/l. The final two-pore mPBPK model has a better performance for native IgG than previously developed mPBPK model. CONCLUSIONS: The final two-pore mPBPK model not only overcome the limitations of the early mPBPK model but also has a better performance to describe the disposition of the IgG antibody in human subjects. PMID- 29411152 TI - Drugs in Lactation. AB - One impediment to breastfeeding is the lack of information on the use of many drugs during lactation, especially newer ones. The principles of drug passage into breastmilk are well established, but have often not been optimally applied prospectively. Commonly used preclinical rodent models for determining drug excretion into milk are very unreliable because of marked differences in milk composition and transporters compared to those of humans. Measurement of drug concentrations in humans remains the gold standard, but computer modeling is promising. New FDA labeling requirements present an opportunity to apply modeling to preclinical drug development in place of conventional animal testing for drug excretion into breastmilk, which should improve the use of medications in nursing mothers. PMID- 29411153 TI - Surface thiolation of silicon for antifouling application. AB - Thiol groups grafted silicon surface was prepared as previously described. 1H,1H,2H,2H-perfluorodecanethiol (PFDT) molecules were then immobilized on such a surface through disulfide bonds formation. To investigate the contribution of PFDT coating to antifouling, the adhesion behaviors of Botryococcus braunii (B. braunii) and Escherichia coli (E. coli) were studied through biofouling assays in the laboratory. The representative microscope images suggest reduced B. braunii and E. coli accumulation densities on PFDT integrated silicon substrate. However, the antifouling performance of PFDT integrated silicon substrate decreased over time. By incubating the aged substrate in 10 mM TCEP.HCl solution for 1 h, the fouled PFDT coating could be removed as the disulfide bonds were cleaved, resulting in reduced absorption of algal cells and exposure of non-fouled silicon substrate surface. Our results indicate that the thiol-terminated substrate can be potentially useful for restoring the fouled surface, as well as maximizing the effective usage of the substrate. PMID- 29411154 TI - Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer. AB - Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty eight patients receiving off-protocol cisplatin (50 mg/m2) in combination with docetaxel (50 mg/m2) plus cetuximab (500 mg/m2) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7-14.2) and 6.3 months (95% CI 5.7 6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted. PMID- 29411155 TI - Correction to: In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention. AB - The citation of the author name "Ah-Ng Tony Kong" in PubMed is not the author's preference. Instead of "Kong AT", the author prefers "Kong AN". PMID- 29411157 TI - Effects of melatonin on the growth and cadmium characteristics of Cyphomandra betacea seedlings. AB - To determine whether the melatonin (MT) could reduce cadmium (Cd) accumulation in Cyphomandra betacea seedlings, different concentrations of MT were added to the nutrient solution and soil to study its effects on the growth and Cd characteristics of C. betacea seedlings. Fifty micromoles per liter (MUmol/kg) of MT increased the biomass of C. betacea seedlings, but 100-200 MUmol/L (MUmol/kg) MT decreased seedling biomass in both the nutrient solution and soil cultivation experiments. The photosynthetic pigment contents showed no significant changes compared with the control when the MT dose was 150 MUmol/L (MUmol/kg) or less, while 200 MUmol/L (MUmol/kg) MT decreased the photosynthetic pigment contents. Low levels of MT improved the antioxidant enzyme activities of C. betacea seedlings, whereas high MT levels reduced them. MT increased the Cd contents in different organs of C. betacea seedlings in the nutrient solution cultivation experiment, but only 50 MUmol/kg MT increased the Cd contents in stems, leaves, and shoots of C. betacea seedlings in the soil cultivation experiment. Therefore, only low levels of MT can promote the growth of C. betacea seedlings, and MT is not suitable for reducing Cd accumulation in C. betacea seedlings. PMID- 29411158 TI - Topically Applied Ceramides Interact with the Stratum Corneum Lipid Matrix in Compromised Ex Vivo Skin. AB - PURPOSE: To determine whether formulations containing ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). METHODS: The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction. RESULTS: Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. CONCLUSIONS: Application of a formulation containing either a single ceramide or two ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide. PMID- 29411159 TI - Combined pulmonary fibrosis and emphysema predicts recurrence following surgery in patients with stage I non-small cell lung cancer. AB - The purpose of this study was to clarify the clinicopathologic characteristics of non-small cell lung cancer (NSCLC) patients with combined pulmonary fibrosis and emphysema (CPFE). We investigated the association between CPFE, the cancer survival, and the pathological features of clinical stage I NSCLC patients. Between 2005 and 2014, 218 consecutive patients with clinical stage I NSCLC underwent complete resection with systematic lymph node dissection. A univariate analysis by log-rank tests was performed to determine the risk factors for recurrence, and the Cox proportional hazards regression model was used to identify potential independent predictors. The 5-year recurrence-free proportion of patients with CPFE was 36%, which was significantly lower than in those without CPFE (82%; p < 0.001). On multivariate analysis, the presence of CPFE was one of the statistically significant independent predictors for tumor recurrence (p = 0.005). Postoperative pathological prognostic factors, including moderate or poor histological differentiation, lymphatic permeation, intratumoral vascular invasion, and lymph node metastasis, were detected more often in patients with CPFE. NSCLC patients with CPFE have histologically more invasive tumors than those without CPFE. In patients with clinical stage I NSCLC, the presence of CPFE was a statistically significant predictor of recurrence. PMID- 29411160 TI - The influence of anthropogenic edge effects on primate populations and their habitat in a fragmented rainforest in Costa Rica. AB - When a forest is fragmented, this increases the amount of forest edge relative to the interior. Edge effects can lead to loss of animal and plant species and decreased plant biomass near forest edges. We examined the influence of an anthropogenic forest edge comprising cattle pasture, coconut plantations, and human settlement on the mantled howler (Alouatta palliata), white-faced capuchin (Cebus capucinus), Central American spider monkey (Ateles geoffroyi), and plant populations at La Suerte Biological Research Station (LSBRS), Costa Rica. We predicted that there would be lower monkey encounter rate, mean tree species richness, and diameter at breast height (DBH) in forest edge versus interior, and that monkeys would show species-specific responses to edge based on diet, body size, and canopy height preferences. Specifically, we predicted that howler monkeys would show positive or neutral edge effects due to their flexible folivorous diet, large body size, and preference for high canopy, capuchins would show positive edge effects due to their diverse diet, small body size, and preference for low to middle canopy, and spider monkeys would show negative edge effects due their reliance on ripe fruit, large body size, and preference for high upper canopy. We conducted population and vegetation surveys along edge and interior transects at LSBRS. Contrary to predictions, total monkey encounter rate did not vary between the forest edge and forest interior. Furthermore, all three species showed neutral edge effects with no significant differences in encounter rate between forest edge and interior. Interior transects had significantly higher mean tree species richness than edge transects, and interior trees had greater DBH than edge trees, although this difference was not significant. These results suggest that forest edges negatively impact plant populations at La Suerte but that the monkeys are able to withstand these differences in vegetation. PMID- 29411161 TI - Cinacalcet HCl therapy in East Asian patients and rs1042636 carriers. PMID- 29411162 TI - Ensuring safe drug administration to pediatric patients with renal dysfunction: a multicenter study. AB - BACKGROUND: In pediatric patients, due to variations in baseline serum creatinine (Cr) reference values, renal dysfunctions sometimes go unnoticed. In addition, renally excreted drugs need dose adjustment while nephrotoxic drugs should be avoided altogether in patients with impaired renal function. However, most physicians are apparently unaware of these facts and may administer these drugs to vulnerable patients. METHODS: We administered a questionnaire to all physicians and pharmacists specializing in pediatric medical care at six Tokyo metropolitan government-run hospitals in Japan. RESULTS: 276 (59%) of 470 physicians and pharmacists participated. The rate of correct answers given by physicians who were asked to state the serum Cr reference range for 4-year-olds and 8-year-olds was 83 and 74%, respectively. On the other hand, the rate of correct answers given by pharmacists to the same question was only 27 and 24%, respectively. Only about 50% of physicians were aware that histamine H2-receptor antagonists and oseltamivir are renally excreted or that acyclovir and angiotensin II receptor blocker are nephrotoxic. However, most of the pharmacists recognized that histamine H2-receptor antagonists and oseltamivir are renally excreted drugs. CONCLUSIONS: For the majority of the investigated drugs, the awareness that we need to reduce dosages for patients with renal dysfunction was insufficient. To ensure safe drug administration, communication between physicians and pharmacists is paramount. There is an urgent need for the creation of a safe drug administration protocol for pediatric patients with renal dysfunction. PMID- 29411163 TI - Mordred: a molecular descriptor calculator. AB - Molecular descriptors are widely employed to present molecular characteristics in cheminformatics. Various molecular-descriptor-calculation software programs have been developed. However, users of those programs must contend with several issues, including software bugs, insufficient update frequencies, and software licensing constraints. To address these issues, we propose Mordred, a developed descriptor-calculation software application that can calculate more than 1800 two and three-dimensional descriptors. It is freely available via GitHub. Mordred can be easily installed and used in the command line interface, as a web application, or as a high-flexibility Python package on all major platforms (Windows, Linux, and macOS). Performance benchmark results show that Mordred is at least twice as fast as the well-known PaDEL-Descriptor and it can calculate descriptors for large molecules, which cannot be accomplished by other software. Owing to its good performance, convenience, number of descriptors, and a lax licensing constraint, Mordred is a promising choice of molecular descriptor calculation software that can be utilized for cheminformatics studies, such as those on quantitative structure-property relationships. PMID- 29411164 TI - Direct Growth of III-Nitride Nanowire-Based Yellow Light-Emitting Diode on Amorphous Quartz Using Thin Ti Interlayer. AB - Consumer electronics have increasingly relied on ultra-thin glass screen due to its transparency, scalability, and cost. In particular, display technology relies on integrating light-emitting diodes with display panel as a source for backlighting. In this study, we undertook the challenge of integrating light emitters onto amorphous quartz by demonstrating the direct growth and fabrication of a III-nitride nanowire-based light-emitting diode. The proof-of-concept device exhibits a low turn-on voltage of 2.6 V, on an amorphous quartz substrate. We achieved ~ 40% transparency across the visible wavelength while maintaining electrical conductivity by employing a TiN/Ti interlayer on quartz as a translucent conducting layer. The nanowire-on-quartz LED emits a broad linewidth spectrum of light centered at true yellow color (~ 590 nm), an important wavelength bridging the green-gap in solid-state lighting technology, with significantly less strain and dislocations compared to conventional planar quantum well nitride structures. Our endeavor highlighted the feasibility of fabricating III-nitride optoelectronic device on a scalable amorphous substrate through facile growth and fabrication steps. For practical demonstration, we demonstrated tunable correlated color temperature white light, leveraging on the broadly tunable nanowire spectral characteristics across red-amber-yellow color regime. PMID- 29411165 TI - Proportion of femoral hernia repairs performed for recurrence in the United States. AB - PURPOSE: Recurrence rates after femoral hernia repair (FHR) have not been reliably established in the USA. We sought to determine this trend over time. METHODS: The proportion of primary and recurrent FHRs was determined for patients age >= 18 from: ACS-NSQIP (1/2005-12/2014), Premier (1/2010-09/2015), and institutional (1/2005-12/2014) data. Trends were analyzed using a one-tailed Cochran-Armitage test. RESULTS: In the NSQIP database, 6649 patients underwent a FHR. In females, the proportion of FHRs performed for recurrence decreased from 14.0% in 2005 to 6.2% in 2014, p = 0.02. In males, there was no change: 16.7 16.1% 2005-2014 (p = 0.18). The Premier database included 4495 FHRs and our institution 315 FHRs. There was no difference for either gender over time in either data source, all p > 0.05. CONCLUSIONS: The proportion of femoral hernia repairs performed for recurrence in the USA remained relatively constant in males in two large national databases between 2005 and 2015. In females, a decrease was seen in one of the large national databases. PMID- 29411166 TI - To assess the efficacy of socket plug technique using platelet rich fibrin with or without the use of bone substitute in alveolar ridge preservation: a prospective randomised controlled study. AB - AIM: The purpose of this study is to evaluate the efficacy of Platelet Rich Fibrin (PRF) as a socket plug with or without use of Plaster of Paris (POP) as bone substitute to preserve the alveolar ridge post-extraction. MATERIAL AND METHODS: A prospective randomised single blind controlled study, was conducted for 18 months from November 2014 to May 2016 on 48 patients requiring extraction. All teeth were extracted atraumatically using periotomes and luxators without raising mucoperiosteal flap. Sockets were randomly allotted to groups A, B and C. Group A sockets were chosen as control, where figure of eight suture was placed. In group B sockets, PRF obtained by centrifugation was used as a socket plug and stabilised with figure of eight suture. Group C sockets were filled with POP and then covered with PRF. The socket was then closed with a figure of eight suture. Patients were informed of need for 6 months follow-up. RESULTS: Ninety sockets in 48 patients were subjected to our study. We found that results in the sockets where we have grafted POP showed better ridge preservation and post-operative comfort even though the difference in ridge resorption between the three groups was not statistically significant. Powered by Editorial Manager(r) and ProduXion Manager(r) from the Aries Systems Corporation. CONCLUSION: Atraumatic extraction may minimise the post-operative pain and discomfort to patient as well as the post-extraction alveolar height and width changes. The use of PRF and/or bone substitute even though clinically contributes to better post-operative healing and minimal loss of alveolar width and height, the values were not statistically significant. PMID- 29411167 TI - Investigation of adverse events associated with an off-label use of arterial stents and CE-marked iliac vein stents in the iliac vein: insights into developing a better iliac vein stent. AB - We analyzed the adverse events associated with an off-label use of arterial stents and CE-marked iliac vein stents for the treatment of iliac venous thromboembolism and investigated their relationships with the anatomical features of the iliac vein, to gain insights into the development of a better iliac vein stent. Reports of adverse events following the use of stents in the iliac vein were retrieved from the Manufacturer and User Facility Device Experience (MAUDE) database that contain suspected device-associated complications reported to the Food and Drug Administration. Data from 2006 to 2016 were investigated. The literature analysis was also conducted using PubMed, Cochrane Library, EMBASE, and Web of Science focusing on English articles published up to 4 October 2016. The analysis of 88 adverse events from the MAUDE database and 182 articles from the literature revealed that a higher number of adverse events had been reported following the use of arterial stents in the iliac vein compared to CE-marked iliac vein stents. While stent migration and shortening were reported only for the arterial stents, stent fracture and compression occurred regardless of the stent type, even though a vein does not pulsate. A study of the anatomical features of the iliac vein implies that bending, compression, and kink loads are applied to the iliac vein stents in vivo. For designing, developing, and pre clinical testing of stents intended for use in the iliac vein, the above mechanical load environments induced by the anatomical features should be considered. PMID- 29411168 TI - Advances in cardiovascular MR imaging. PMID- 29411169 TI - Subcellular storage and release mode of the novel 18F-labeled sympathetic nerve PET tracer LMI1195. AB - BACKGROUND: 18F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (18F-LMI1195) is a new class of PET tracer designed for sympathetic nervous imaging of the heart. The favorable image quality with high and specific neural uptake has been previously demonstrated in animals and humans, but intracellular behavior is not yet fully understood. The aim of the present study is to verify whether it is taken up in storage vesicles and released in company with vesicle turnover. RESULTS: Both vesicle-rich (PC12) and vesicle-poor (SK-N-SH) norepinephrine expressing cell lines were used for in vitro tracer uptake studies. After 2 h of 18F-LMI1195 preloading into both cell lines, effects of stimulants for storage vesicle turnover (high concentration KCl (100 mM) or reserpine treatment) were measured at 10, 20, and 30 min. 131I-meta-iodobenzylguanidine (131I-MIBG) served as a reference. Both high concentration KCl and reserpine enhanced 18F-LMI1195 washout from PC12 cells, while tracer retention remained stable in the SK-N-SH cells. After 30 min of treatment, 18F-LMI1195 releasing index (percentage of tracer released from cells) from vesicle-rich PC12 cells achieved significant differences compared to cells without treatment condition. In contrast, such effect could not be observed using vesicle-poor SK-N-SH cell lines. Similar tracer kinetics after KCl or reserpine treatment were also observed using 131I MIBG. In case of KCl exposure, Ca2+-free buffer with the calcium chelator, ethylenediaminetetracetic acid (EDTA), could suppress the tracer washout from PC12 cells. This finding is consistent with the tracer release being mediated by Ca2+ influx resulting from membrane depolarization. CONCLUSIONS: Analogous to 131I-MIBG, the current in vitro tracer uptake study confirmed that 18F-LMI1195 is also stored in vesicles in PC12 cells and released along with vesicle turnover. Understanding the basic kinetics of 18F-LMI1195 at a subcellular level is important for the design of clinical imaging protocols and imaging interpretation. PMID- 29411170 TI - The potential of antisense oligonucleotide therapies for inherited childhood lung diseases. AB - Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51TM) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism. PMID- 29411172 TI - Effect of laser peripheral iridotomy using argon and neodymium-YAG lasers on corneal endothelial cell density: 7-year longitudinal evaluation. AB - PURPOSE: To evaluate the changes in corneal endothelial cell density (ECD) over a 7-year period after laser peripheral iridotomy (LPI) using argon and neodymium doped yttrium aluminum garnet (Nd:YAG) lasers. STUDY DESIGN: Retrospective case series. METHODS: Eyes that underwent prophylactic LPI using argon and Nd:YAG lasers were followed up for 7 years. Central corneal endothelial cells were observed by use of noncontact specular microscopy preoperatively and at 1 and 7 years postoperatively. Changes in ECD and the associations between preoperative ECD and the total energy of the Nd:YAG laser were evaluated. RESULTS: Fifty-one eyes of 51 patients were followed up for 7 years. The ECD significantly decreased after LPI (P < 0.049), and the reduction rate at 1 year after the surgery (1.69 +/- 4.80%, 95% CI: 0.34%-3.04%) was significantly higher than the annual reduction rates after 1 year (0.17 +/- 0.85%/y, P = 0.036, 95% CI: -0.07% to 0.41%). No association was found between the preoperative ECD and the total laser energy. CONCLUSIONS: Long-term evaluation indicated that the reduction in ECD after argon-Nd:YAG laser LPI was present but small during the initial year and was negligible after 1 year. PMID- 29411171 TI - Efficacy of treat-and-extend regimen with aflibercept for pachychoroid neovasculopathy and Type 1 neovascular age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy of intravitreal aflibercept therapy using a treat-and-extend regimen on treatment-naive pachychoroid neovasculopathy (PNV) and Type 1 neovascular age-related macular degeneration (AMD). METHODS: We retrospectively studied 42 eyes with PNV and 60 eyes with Type 1 neovascular AMD. We assessed best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and total number of injections over 2 years. RESULTS: The BCVA and CMT improvements during the 2-year treatment period did not differ significantly between PNV and AMD; however, CCT decreased significantly in PNV than in AMD (P<0.05). Management of PNV required significantly fewer injections than AMD during the 2-year period (P<0.05). There were no significant differences in BCVA, CMT and CCT changes between PNV with and without polypoidal lesions (28 vs. 14 eyes) during the 2 year period. Significantly fewer injections were needed for PNV with polypoidal lesions than for PNV without (P<0.01). There were no significant differences in BCVA, CMT and CCT changes, or in the number of injections during the 2-year treatment period, between AMD with and without polypoidal lesions (30 vs. 30 eyes). CONCLUSION: Treat-and-extend regimen of intravitreal aflibercept injection may be equally effective in terms of improvement of BCVA and exudative changes both in eyes with PNV and those with Type 1 neovascular AMD requiring fewer injections for the former. Among eyes with PNV, those with polypoidal lesions needed fewer injections than those without polypoidal lesions. PMID- 29411173 TI - 'Recovery' in the Real World: Service User Experiences of Mental Health Service Use and Recommendations for Change 20 Years on from a First Episode Psychosis. AB - Little is known about how recovery oriented policy and legislative changes influence service users' perceptions of mental health care over time. Although the recovery approach is endorsed in many countries, qualitative research examining its impact on service use experiences has been lacking. This study aimed to explore this impact as well as experiences of service utilisation and suggestions for change with people diagnosed with a First Episode Psychosis between 1995 and 1999. Participants had used services during the 10 year period prior to, and 10 years post, policy and legislative shifts to the recovery approach. Semi-structured interviews were conducted with 10 participants who met criteria for 'full functional recovery' and 10 who did not. Data were analysed using Thematic Networks Analysis to develop Basic, Organising, and Global Themes. Over time, recovered participants perceived an improvement in service quality through the 'humanising' of treatment and non-recovered participants experienced their responsibility in recovery being recognised, but felt abandoned to the recovery approach. Findings suggest the importance of viewing service users as demonstrating personhood and having societal value; examining the personal meaning of psychotic experiences; and matching expectations with what services can feasibly provide. The implementation and the principal tenets of the recovery approach warrant further investigation. PMID- 29411174 TI - Synthesis, characterization, molecular docking evaluation, antiplatelet and anticoagulant actions of 1,2,4 triazole hydrazone and sulphonamide novel derivatives. AB - In the present study, a series of new hydrazone and sulfonamide derivatives of 1,2,4-triazole were synthesized. Initially three 4-substituted-5-(2-pyridyl) 1,2,4-triazole-3-thiones ZE-1(a-c) were treated with ethyl chloroacetate to get the corresponding thioesters ZE-2(a-c), which were reacted with hydrazine hydrate to the respective hydrazides ZE-3(a-c). The synthesized hydrazides were condensed with different aldehydes and p-toluene sulfonylchloride to furnish the target hydrazone derivatives ZE-4(a-c) and sulfonamide derivatives ZE-5(a-c) respectively. All the synthesized compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data. Furthermore, the new hydrazone and sulfonamide derivatives ZE-4(b-c) and ZE-5(a-b) were evaluated for their antiplatelet and anticoagulant activities. ZE-4b, ZE-4c, ZE-5a and ZE-5b inhibited arachidonic acid, adenosine diphosphate and collagen-induced platelets aggregation with IC50 values of 40.1, 785 and 10.01 (ZE-4b), 55.3, 850.4 and 10 (ZE-4c), 121.6, 956.8 and 30.1 (ZE-5a), 99.9, 519 and 29.97 (ZE-5b) respectively. Test compounds increased plasma recalcification time (PRT) and bleeding time (BT) with ZE-4c being found most effective, which at 30, 100, 300 and 1000 uM increased PRT to 84.2 +/- 1.88, 142 +/- 3.51, 205.6 +/- 5.37 and 300.2 +/- 3.48 s and prolonged BT to 90.5 +/- 3.12, 112.25 +/- 2.66, 145.75 +/- 1.60 s (P < 0.001 vs. saline group) respectively. In silico docking approach was also applied to screen these compounds for their efficacy against selected drug targets of platelet aggregation and blood coagulation. Thus in silico, in vitro and in vivo investigations of ZE-4b, ZE-4c, ZE-5a and ZE-5b prove their antiplatelet and anticoagulant potential and can be used as lead molecules for further development. PMID- 29411175 TI - Will the presence of radiological signs of tension pneumothorax affect the clinical presentation of primary spontaneous pneumothorax? AB - INTRODUCTION: Patients with primary spontaneous pneumothorax (PSP) rarely presented with radiological signs of tension pneumothorax on their presenting chest X-ray. Even though, those patients may not develop the hemodynamic instability that is seen in tension pneumothorax. The aim of this study is to elaborate whether the presence of radiological signs of tension pneumothorax in patients with PSP will affect their clinical presentation. METHODS: Retrospective study of all cases of PSP over a period from January 2007 to December 2014. The cases were divided into two groups; tension group includes cases who have radiological signs of tension pneumothorax and non-tension group who do not have those signs. The main outcome was a comparison of the hemodynamic status of both groups. RESULTS: A total of 151 cases of PSP were included in the study. Radiologic signs of tension pneumothorax were identified in 13 cases of the sample. Only one case of the tension group developed hemodynamic instability in the form of desaturation to below 92% with no statistical difference between the two groups in maintaining the hemodynamic status. CONCLUSION: In spite that PSP can be presented with radiological signs of tension pneumothorax, those patients usually maintained their hemodynamic stability. Tension pneumothorax rarely presented as consequence of PSP. PMID- 29411176 TI - Label-free imaging for T staging of gastric carcinoma by multiphoton microscopy. AB - Gastric cancer is one of the most common malignancies worldwide. The accurate diagnosis of tumor invasion depth is critical for therapeutic strategy and prognosis. Without fluorescent labelling, multiphoton microscopy (MPM) imaging could directly reveal tissue architecture based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). In this study, we aimed to explore the feasibility of MPM imaging to assess the gastric tumor morphology and infiltration. Unstained slides of 18 fresh gastric tissues with different T staging were examined by multiphoton microscopy. Morphological and quantitative analyses were both conducted. The nuclear area was defined as the area of nuclear boundary. Collagen content was defined as the ratio of SHG pixels to all pixels. Gastric normal and tumor tissues under different T stages visually presented with cellular and subcellular features on fluorescent imaging. The nuclear areas of normal and cancerous cells were 32.01 +/- 2.89 and 58.41 +/- 6.06 MUm2 (P < 0.001), respectively. Collagen content was quantified as 0.087 +/- 0.012 in normal mucosa but 0.020 +/- 0.007 in cancerous mucosa (P < 0.001). All results were in accord with the paired H&E-stained slides. Our findings suggested the convincing potential of MPM for judging T staging of gastric cancer. Without staining intervention, TPEF and SHG of MPM imaging could objectively and quantitatively indicate the subcellular and molecular changes during carcinogenesis. With the advancement of deep penetration, self-focus imaging and three-dimensional (3D) visualization, label-free MPM imaging compacted with endoscopy could be further introduced to realize the real-time in vivo assessment of tumor invasion clinically. PMID- 29411177 TI - Pseudarthrosis in adult and pediatric spinal deformity surgery: a systematic review of the literature and meta-analysis of incidence, characteristics, and risk factors. AB - We conducted a systematic review with meta-analysis and qualitative synthesis. This study aims to characterize pseudarthrosis after long-segment fusion in spinal deformity by identifying incidence rates by etiology, risk factors for its development, and common features. Pseudarthrosis can be a painful and debilitating complication of spinal fusion that may require reoperation. It is poorly characterized in the setting of spinal deformity. The MEDLINE, EMBASE, and Cochrane databases were searched for clinical research including spinal deformity patients treated with long-segment fusions reporting pseudarthrosis as a complication. Meta-analysis was performed on etiologic subsets of the studies to calculate incidence rates for pseudarthrosis. Qualitative synthesis was performed to identify characteristics of and risk factors for pseudarthrosis. The review found 162 articles reporting outcomes for 16,938 patients which met inclusion criteria. In general, the included studies were of medium to low quality according to recommended reporting standards and study design. Meta-analysis calculated an incidence of 1.4% (95% CI 0.9-1.8%) for pseudarthrosis in adolescent idiopathic scoliosis, 2.2% (95% CI 1.3-3.2%) in neuromuscular scoliosis, and 6.3% (95% CI 4.3-8.2%) in adult spinal deformity. Risk factors for pseudarthrosis include age over 55, construct length greater than 12 segments, smoking, thoracolumbar kyphosis greater than 20 degrees , and fusion to the sacrum. Choice of graft material, pre-operative coronal alignment, post-operative analgesics, and sex have no significant impact on fusion rates. Older patients with greater deformity requiring more extensive instrumentation are at higher risk for pseudarthrosis. Overall incidence of pseudarthrosis requiring reoperation is low in adult populations and very low in adolescent populations. PMID- 29411178 TI - Comment on "Modeling the cost-effectiveness of infant vaccination with pneumococcal conjugate vaccines in Germany". PMID- 29411179 TI - CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility. AB - BACKGROUND: Impaired regulatory T cell immunity plays a central role in the development of type 1 diabetes (T1D). Interleukin-2 receptor (IL-2R) signaling is essential for regulatory T cells (TREG), and cytokine-inducible SH2-containing protein (CIS) regulates IL-2R signaling as a feedback inhibitor. Previous studies identified association of CISH promoter region single nucleotide polymorphisms (SNPs) with susceptibility to infectious diseases. METHODS: Here we analyzed allele frequencies of three CISH SNPs (i.e., rs809451, rs414171, rs2239751) in a study of T1D patients (n = 260, onset age < 5 years, duration > 10 years). Minor allele frequencies were compared to a control cohort of the 1000 Genomes Project. Assigned haplotypes were determined for effects on T1D manifestation and severity. Finally, the CISH haplotype influence on cytokine signaling and function was explored in T cells from healthy donors. RESULTS: We detected similar minor allele frequencies between T1D patients and the control cohort. T1D onset age, residual serum C-peptide level, and insulin requirement were comparable between different haplotypes. Only minor differences between the haplotypes were found for in vitro cytokine (i.e., IL-2, IL-7)-induced CIS mRNA expression. STAT5 phosphorylation was induced by IL-2 or IL-7, but no differences were found between the haplotypes. TREG purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells. CONCLUSIONS: This study provides no evidence for an association of CISH promoter SNPs with susceptibility to T1D or severity of disease. In contrast to previous studies, no influence of different haplotypes on CIS mRNA expression or T cell-mediated functions was found. PMID- 29411180 TI - ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease. AB - The "A disintegrin and metalloprotease" (ADAM) family is thought to play an important role in tissue destruction and inflammatory reactions. ADAM-17 was first described as the protease responsible for tumor necrosis factor (TNF)-alpha shedding. Here, we have shown the expression of ADAM-17 in inflammatory myopathy and demonstrated the role of inflammation in interstitial lung diseases (ILD). ADAM-17 in inflammatory myopathy serum [polymyositis (n = 26), dermatomyositis (n = 34), and clinically amyopathic dermatomyositis (n = 10)] and healthy control (n = 19) was measured using enzyme-linked immunosorbent assay. The relationship between ADAM-17 and clinical data was examined. Finally, we performed immunohistological analysis to investigate the expression of ADAM-17 on the muscles of the inflammatory myopathy patients. ADAM-17 in inflammatory myopathy was significantly higher than that in healthy control (mean +/- SEM, 1048 +/- 312 and 36 +/- 18 pg/ml, respectively; p < 0.05). ADAM-17 in post-treatment with corticosteroid and/or immunosuppressant serum was significantly decreased compared with that in pre-treatment serum (1465 +/- 562 and 1059 +/- 503 pg/ml, respectively; p < 0.01). ADAM-17 was significantly positively correlated with fractalkine/CX3CL1 and CXCL16. In addition, ADAM-17 in inflammatory myopathy with ILD patients (n = 46) was significantly higher than that in non-ILD patients (n = 24) (1379 +/- 454 and 413 +/- 226 pg/ml, respectively; p < 0.05). We found the expression of ADAM-17 on muscle biopsy tissue. ADAM-17 is expressed in inflammatory myopathies especially ILD, suggesting that ADAM-17 plays a role in lung fibrosis. ADAM-17 may be a potential target in inflammatory myopathies with ILD. PMID- 29411181 TI - Biosimilars in rheumatology: recommendations for regulation and use in Middle Eastern countries. AB - The increasing availability of biosimilar medicines in Middle Eastern regions may provide an opportunity to increase the number of rheumatology patients who have access to traditionally more expensive biologic medicines. However, as well as a lack of real-world data on the use of biosimilar medicines in practice, the availability of intended copies in the region may undermine physician confidence in prescribing legitimate biosimilar medicines. There is a need for regional recommendations for healthcare professionals to ensure that biosimilar drugs can be used safely. Therefore, a literature search was performed with the aim of providing important recommendations for the regulation and use of biosimilar medicines in the Middle East from key opinion leaders in rheumatology from the region. These recommendations focus on improving the availability of relevant real-world data, ensuring that physicians are aware of the difference between intended copies and true biosimilars and ensuring that physicians are responsible for making any prescribing and switching decisions. PMID- 29411182 TI - Drug survival and effectiveness of ustekinumab in patients with psoriatic arthritis. Real-life data from the biologic Apulian registry (BIOPURE). AB - This study aims to evaluate the drug survival and effectiveness of ustekinumab in psoriatic arthritis (PsA) patients naive to biologics or inadequate responders to tumor necrosis factor (TNF-IR) inhibitors in real life. PsA patients starting ustekinumab were enrolled from 2014 to 2016. Joint involvement, peripheral or axial, Psoriatic Area Severity Index, Disease Activity Psoriatic Arthritis (DAPSA), Lee Enthesitis Index, Health Assessment Questionnaire, body mass index, comorbidities, co-therapies, mechanism of action, and causes of discontinuation of prior TNFi were collected at baseline, and 6 and 12 months. Twelve-month drug survival was evaluated by Kaplan-Meier curves. Hazard ratios (HRs) of drug discontinuation adjusted for baseline factors were estimated by multiple Cox regression analysis. Percentages of DAPSA-based remission, as crude value and adjusted for drug retention (LUNDEX index), were compared by chi2 test. Mean differences of DAPSA from baseline to 6 and 12 months were compared between naive and TNF-IR patients by ANOVA. Of 160 PsA patients starting ustekinumab, 54 were naive and 106 were TNF-IR. Twelve-month drug survival was significantly higher in naive (87%) than in TNF-IR (68%, p = 0.01). Baseline co-therapy with methotrexate did not increase the persistence on ustekinumab. Naive patients had the lowest risk of ustekinumab discontinuation (HR 0.27, p = 0.01), and the highest DAPSA based remission (34%, LUNDEX 26%). Mean differences from baseline of DAPSA was significantly greater in naive than in TNF-IR patients at 12 months (- 14.4 +/- 10 vs. - 4.1 +/- 17, p = 0.01). Our data showed that ustekinumab has a good effectiveness in real life and the best outcomes are achieved in biologic-naive PsA patients. PMID- 29411183 TI - Renal shear wave elastography for the assessment of nephron hypertrophy: a cross sectional study in chronic kidney disease. AB - PURPOSE: To investigate the association of renal elasticity to microscopic findings of nephron hypertrophy and nephrosclerosis. METHODS: Patients who underwent renal biopsy were enrolled. Renal elasticity was measured by acoustic radiation force impulse, and nephron size (glomerular volume, non-sclerotic glomerular density, and mean profile tubular area) and nephrosclerosis (globally sclerotic glomeruli and interstitial fibrosis) were estimated. Nephron hypertrophy was indicated by larger glomerular volume, larger tubular area, and lower non-sclerotic glomerular density. Nephrosclerosis was indicated by a higher percentage of globally sclerotic glomeruli and higher severity of fibrosis. RESULTS: Renal elasticity was negatively correlated with glomerular volume (r = - 0.480, P = 0.024) and mean tubular area (r = - 0.469, P = 0.028), but it was not correlated with non-sclerotic glomerular density (r = 0.205, P = 0.359), percentage of globally sclerotic glomeruli (r = 0.057, P = 0.800), and severity of fibrosis (r = 0.014, P = 0.950). In a multiple linear regression analysis, glomerular volume and mean tubular area were independently associated with renal elasticity (std beta = - 0.454, P = 0.015 and std beta = - 0.577, P = 0.007, respectively). CONCLUSION: Renal elasticity was correlated with microstructural findings of nephron hypertrophy. Measuring renal elasticity could help in detecting kidney disease. PMID- 29411184 TI - Serum cholesterol level and the rate of progression to renal failure. PMID- 29411186 TI - Exploring virulence of new and less studied species of Metarhizium spp. from Brazil for two-spotted spider mite control. AB - The two-spotted spider mite Tetranychus urticae is an important pest of strawberry crops in Brazil and many other countries. Focus for biocontrol studies involving entomopathogenic fungi has been on three species from the genus Metarhizium: M. anisopliae sensu stricto (s.s.), M. brunneum and M. robertsii. Also, the species Beauveria bassiana has been studied for spider mite control and one isolate (ESALQPL63) is commercially available in Brazil. New and undescribed Metarhizium species have been found recently in Brazil and provide a pool of isolates with potential for biocontrol in Brazil and probably also elsewhere. The mortality of adult females of T. urticae when exposed to four new Brazilian species of Metarhizium was compared to the mortality when exposed to M. anisopliae s.s., M. brunneum, M. pingshaense, M. robertsii and Beauveria bassiana ESALQPL63. Fungal suspensions were sprayed onto mites at 107 conidia/mL with 0.05% Tween 80 in laboratory bio-assays. We measured total mortality and percentage sporulating cadavers 10 days after exposure and calculated median lethal time (LT50). The lowest LT50 (4.0 +/- 0.17) was observed for mites treated with Metarhizium sp. Indet. 1 (ESALQ1638), which also performed well with respect to mortality after 10 days and capacity to sporulate from cadavers. Among the other little studied species tested, M. pingshaense (ESALQ3069 and ESALQ3222) and Metarhizium Indet. 2 (ESALQ1476) performed well and were comparable to B. bassiana (ESALQPL63). The new Metarhizium isolates and species thus showed potential for biological control. PMID- 29411187 TI - Effect of prior dengue infection on severity and outcome of Japanese encephalitis. AB - Japanese encephalitis (JE) virus and dengue virus are closely related flaviviruses but interaction between them is scarcely studied in humans. The objective of this study was to compare the outcome of JE patients who are positive and negative for dengue IgG antibodies. Patients of acute encephalitis syndrome (AES) fulfilling predecided inclusion and exclusion criteria underwent a detailed standardized workup incorporating JE IgM testing in cerebrospinal fluid (CSF) or serum. Dengue IgG in serum was tested in all. Outcomes and clinical features were compared between JE patients who were dengue IgG positive and negative in hospital and after 3 months. A total of 182 patients of JE were enrolled over 3 seasons. After excluding equivocal cases, hospital outcome was compared between 105 dengue IgG-positive and 50 dengue IgG-negative patients. Dengue IgG-positive patients had a significantly better outcome (relative risk 1.4; 95% confidence interval 1.1-1.8). On follow-up after 3 months, again, outcome was significantly better among 95 dengue IgG-positive patient than 47 dengue IgG-negative patients (relative risk 1.3; 95% confidence interval 1.01 1.8). Presence of pre-existing dengue IgG antibodies in JE patients is associated with improved outcomes. PMID- 29411188 TI - Antibiotic treatment and stewardship in the era of microbiota-oriented diagnostics. PMID- 29411189 TI - Guillain-Barre syndrome following varicella-zoster virus infection. AB - We describe the frequency, clinical features, and electrophysiological and immunological phenotypes of Guillain-Barre Syndrome (GBS) patients treated at a single institution in Bangladesh who had preceding chicken pox (primary Varicella zoster virus [VZV] infection) within 4 weeks of GBS onset. A literature review of GBS cases preceding VZV infection is also provided. Diagnosis of GBS was based on the National Institute of Neurological Disorders and Stroke criteria for GBS. Serum anti-VZV IgM and IgG antibodies were quantified by indirect chemiluminescence immunoassay (CLIA); anti-Campylobacter jejuni IgG, IgM, and IgA antibodies and anti-ganglioside GM1 IgM and IgG antibodies, by enzyme-linked immunosorbent assays. Neurophysiologic subtypes were categorized following the Hadden criteria. Of 536 patients with GBS, 7 (1.3%) had chicken pox within 4 weeks before GBS onset. Four of the seven cases were male (age range, 23 to 40 years old). All seven patients were bed-bound, six had sensory symptoms, and three required mechanical ventilation for respiratory failure. All seven patients had CSF albuminocytologic dissociation and evidence of demyelination in nerve conduction studies. Anti-VZV IgM antibodies were present and anti-GM1 and anti Campylobacter jejuni lipo-oligosaccharides (LOS) were negative in all cases. All patients had excellent outcome at 1 year (able to run). A systematic literature review of GBS cases related to VZV revealed 39 previously reported patients with comparable clinical presentations and outcomes, of which 36 had neurophysiologic evidence of demyelination. VZV infection is associated with the demyelinating subtype of GBS, clearly distinct from the axonal form of GBS that predominate in countries like Bangladesh. PMID- 29411191 TI - Diagnostic challenges in pyogenic spinal infection: an expanded role for FDG PET/CT. AB - In a preliminary investigation of FDG-PET/CT for assessment of therapy response of pyogenic spine infection, it was concluded that activity confined to the margins of a destroyed or degenerated joint with bone-on-bone contact represents nonseptic inflammation, regardless of the intensity of uptake. Only activity in bone, soft tissue, or within the epidural space represents active infection. The purpose of this investigation was to assess the performance of these pattern based interpretation criteria in a series of problem cases of proven or suspected spine infection. Eighty-two FDG-PET/CTs were done for initial diagnosis because other imaging failed to provide a definitive diagnosis and 147 FDG-PET/CTs were done to assess treatment responses. Pattern-based interpretations were compared with the clinical diagnosis based on bacterial cultures and outcomes after cessation or withholding of antibiotic therapy. Pattern-based interpretation criteria achieved a sensitivity and specificity of 98 and 100%, respectively, for initial diagnosis and a specificity of 100% for assessment of treatment response. The same data was analyzed using intensity of activity as the primary factor. Sensitivity and specificity using the intensity-based criteria were 93 and 68%, respectively, for initial diagnosis, and the specificity of a negative interpretation for therapy response was 55%. Differences from pattern-based criteria are highly significant. Pattern-based criteria perform well in problem cases with equivocal MR and for treatment response because they correctly eliminate activity from nonspecific inflammation associated with destroyed joints with bone-on-bone contact. Response occurs within a timeframe that is useful for managing antibiotic therapy. PMID- 29411193 TI - [Paraneoplastic cerebellar degeneration (PCD) - an interdisciplinary challenge in neurology, oncology and palliative care]. AB - Paraneoplastic neurological syndromes describe a very heterogeneous group of neurological disorders. Paraneoplastic cerebellar degeneration is frequently associated with gynecological tumors, lung cancer and Hodgkin lymphoma. The following case report shows the typical course of this disease as well as the diagnostic and therapeutic challenges. Furthermore the importance of interdisciplinary cooperation between neurology, oncology and palliative care for prognosis and symptom stabilization is highlighted. PMID- 29411190 TI - Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention. AB - For a long time, hand, foot and mouth disease (HFMD) was seen as a mild viral infection characterized by typical clinical manifestations that spontaneously resolved in a few days without complications. In the past two decades, HFMD has received new attention because of evidence that this disease could have clinical, epidemiological and aetiological characteristics quite different from those initially thought. In contrast to previous beliefs, it has been clarified that HFMD can be associated with complications, leading to severe neurological sequelae and, rarely, to death. This finding has led to an enormous number of studies that have indicated that several viruses in addition to those known to be causes of HFMD could be associated with the development of disease. Moreover, it was found that if some viruses were more common in some geographic areas, frequent modification of the molecular epidemiology of the infecting strains could lead to outbreaks caused by infectious agents significantly different from those previously circulating. Vaccines able to confer protection against the most common aetiologic agents in a given country have been developed. However, simultaneous circulation of more than one causative virus and modification of the molecular epidemiology of infectious agents make preparations based on a single agent relatively inadequate. Vaccines with multiple components are a possible solution. However, several problems concerning their development must be solved before adequate prevention of severe cases of HFMD can be achieved. PMID- 29411194 TI - Sarcopenia. AB - Sarcopenia is a very common, but frequently overlooked and undertreated geriatric syndrome comprising pronounced muscle mass and strength/performance loss. Estimated prevalence is between 5 and 40% in the general population, accompanied by an exponential incline with increasing age. Sarcopenia is connected to atrophy and loss of muscle fibers and motor units, affecting primarily the fast-twitch muscle fibers und their motor units. Fast-twitch muscle fibers seem to be more prone to failure of function and loss over time. Main causes for the development of sarcopenia are hormonal changes (reduced release of testosterone, estrogen, and growth hormone), nutritional deficiencies, chronic inflammation, and particularly a decrease in physical activity due to sedentary lifestyle with advancing age. Treatment options for sarcopenia comprise an active lifestyle with physical activity and exercise training, modifications of nutritional intake, and pharmacological therapies. Strength training and an adequate nutritional intake form the basis of successful sarcopenia treatment. PMID- 29411195 TI - Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors. AB - Here, we report the design and synthesis of pyrimidinyl heterocyclic compounds containing terminal electrophiles as irreversible covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of the structure-activity relationship utilizing kinase assays resulted in the identification of potent and selective JAK3 inhibitors such as T1, T8, T15, T22, and T29. Among them, T29 was verified as a promising JAK3 irreversible inhibitor that possessed the best bioactivity and selectivity against JAKs and kinases containing a cysteine in the residue analogous to Cys909 in JAK3, suggesting that covalent modification of this Cys residue allowed the identification of a highly selective JAK3 inhibitor. Moreover, T29 also displayed a significant anti inflammatory effect in ICR mice through the inhibition of increased paw thickness, which is worth further optimization to increase its potency and medicinal properties. PMID- 29411196 TI - Innovation and Integrity in Intervention Research: Conceptual Issues, Methodology, and Knowledge Translation. AB - In this article, we introduce the special issue entitled Innovation and Integrity in Intervention Science. Its focus is on essential problems and prospects for intervention research examining two related topics, i.e., methodological issues and research integrity, and challenges in the transfer of research knowledge into practice and policy. The main aims are to identify how to advance methodology in order to improve research quality, examine scientific integrity in the field of intervention science, and discuss future steps to enhance the transfer of knowledge about evidence-based intervention principles into sustained practice, routine activities, and policy decisions. Themes of the special issue are twofold. The first includes questions about research methodology in intervention science, both in terms of research design and methods, as well as data analyses and the reporting of findings. Second, the issue tackles questions surrounding the types of knowledge translation frameworks that might be beneficial to mobilize the transfer of research-based knowledge into practice and public policies. The issue argues that innovations in methodology and thoughtful approaches to knowledge translation can enable transparency, quality, and sustainability of intervention research. PMID- 29411197 TI - Young Adult Mental Health: a Prospective Examination of Service Utilization, Perceived Unmet Service Needs, Attitudes, and Barriers to Service Use. AB - Most young adults with mental health symptoms do not receive treatment or access services. It remains important to identify barriers to service utilization to improve access to care. The current study was a prospective analysis examining predictors of (a) mental health service utilization and (b) perceived unmet need for mental health services. Barriers to service utilization were examined by prior depression severity status and college student status. Participants included a subsample of young adults ages 18-23 at time of recruitment who were participating in a longitudinal monthly study who completed both baseline and a 15-month follow-up assessment (N = 622, 80% of larger study). At month 15, 23% of young adults reported receiving mental health services in the past 12 months; 26% of young adults reported a perceived unmet need for mental health services at some point in the past 12 months. There were differences in demographic and mental health predictors of service utilization and perceived unmet need for services. Women, sexual minorities, those with moderate depression, those with more impairment from depression, and perceived past year poor mental health were associated with greater likelihood of receiving services. Similar demographic characteristics were associated with greater likelihood of perceiving unmet need for services. Barriers to service utilization differed by severity of depression symptoms and student status. Young adults have distinct reasons for not accessing mental health services; addressing these to improve accessibility to care remains critical. PMID- 29411198 TI - How to mathematically optimize drug regimens using optimal control. AB - This article gives an overview of a technique called optimal control, which is used to optimize real-world quantities represented by mathematical models. I include background information about the historical development of the technique and applications in a variety of fields. The main focus here is the application to diseases and therapies, particularly the optimization of combination therapies, and I highlight several such examples. I also describe the basic theory of optimal control, and illustrate each of the steps with an example that optimizes the doses in a combination regimen for leukemia. References are provided for more complex cases. The article is aimed at modelers working in drug development, who have not used optimal control previously. My goal is to make this technique more accessible in the biopharma community. PMID- 29411199 TI - Detection of Parathyroid Autofluorescence Using Near-Infrared Imaging: A Multicenter Analysis of Concordance Between Different Surgeons. AB - BACKGROUND: Parathyroid glands (PGs) exhibit autofluorescence (AF) when excited by near-infrared laser. This multicenter study aims to analyze how this imaging could facilitate the detection of PGs during thyroidectomy and parathyroidectomy procedures. METHODS: This was a retrospective Institutional Review Board-approved analysis of prospectively collected data at three centers. Near-infrared fluorescence imaging (NIFI) was used to detect AF from PGs during thyroidectomy and parathyroidectomy procedures. Logistic regression analysis was performed to assess the utility of NIFI to identify PGs and concordance at these centers. RESULTS: Overall, 210 patients underwent total thyroidectomy (n = 95), thyroid lobectomy (n = 41), and parathyroidectomy (n = 74) (n = 70 per center). Using NIFI, AF was detected from 98% of visually identified PGs. Upon initial exploration, 46% of PGs were not visible to the naked eye due to coverage by soft tissue, but AF from these glands could be detected by NIFI without any further dissection. Overall, a median of one PG per patient was detected by NIFI in this fashion before being identified visually (p = nonsignificant between centers). On logistic regression, smaller PGs were more likely to be missed visually, but localized by AF on NIFI (odds ratio with increasing size, 0.91; p = 0.02). CONCLUSIONS: In our experience, NIFI facilitated PG identification by detecting their AF, before conventional recognition by the surgeon, in 37-67% of the time. Despite the variability in this rate across centers, there was a concordance in detecting AF from 97 to 99% of the PGs using NIFI. We suggest the incorporation of AF on NIFI alongside conventional visual cues to aid identification of PGs during neck operations. PMID- 29411200 TI - Cervicothoracoscopic Approach for Esophageal Cancer in a Patient with Right-Sided Aortic Arch. AB - BACKGROUND: Esophageal cancer frequently metastasizes to lymph nodes along the recurrent laryngeal nerve (RLN),1 therefore it is essential to dissect RLN nodes for curative esophagectomy.2 Right-sided aortic arch (RAA), a rare congenital anomaly, occurs in approximately 0.1% of adults.3 Because RAA forms a vascular ring encircling both the esophagus and the trachea at the cervicothoracic junction, its surgical anatomy is difficult to understand; hence, thoracoscopic dissection of RLN nodes is technically challenging. In this video, we applied the cervicothoracoscopic approach in a patient with esophageal squamous cell carcinoma and RAA, wherein the cervical operation was performed prior to the thoracoscopic operation.4 METHODS: A 60-year-old woman was diagnosed with stage IA esophageal squamous cell carcinoma. During preoperative evaluation, we found that she had RAA with an aberrant left subclavian artery, and therefore decided to perform esophagectomy using the cervicothoracoscopic approach. In the cervical operation, we identified the RLN and dissected the lymph node in the cervicothoracic junction. The thoracoscopic operation was then performed from the left side with the patient in the prone position. RESULTS: The operation was successful. Total operative time was 548 min, with an estimated blood loss of 220 ml. There were no intraoperative and postoperative complications, and RLN palsy did not occur. CONCLUSIONS: The vascular ring at the cervicothoracic junction in a patient with RAA made it difficult to dissect the RLN lymph nodes during oncologic esophagectomy. The cervicothoracoscopic approach enables the complete dissection of these lymph nodes and is a useful esophagectomy technique for patients with RAA. PMID- 29411201 TI - Characterization of a novel lytic bacteriophage from an industrial Escherichia coli fermentation process and elimination of virulence using a heterologous CRISPR-Cas9 system. AB - Bacterial-bacteriophage interactions are a well-studied and ecologically important aspect of microbiology. Many commercial fermentation processes are susceptible to bacteriophage infections due to the use of high-density, clonal cell populations. Lytic infections of bacterial cells in these fermentations are especially problematic due to their negative impacts on product quality, asset utilization, and fouling of downstream equipment. Here, we report the isolation and characterization of a novel lytic bacteriophage, referred to as bacteriophage DTL that is capable of rapid lytic infections of an Escherichia coli K12 strain used for commercial production of 1,3-propanediol (PDO). The bacteriophage genome was sequenced and annotated, which identified 67 potential open-reading frames (ORF). The tail fiber ORF, the largest in the genome, was most closely related to bacteriophage RTP, a T1-like bacteriophage reported from a commercial E. coli fermentation process in Germany. To eliminate virulence, both a fully functional Streptococcus thermophilus CRISPR3 plasmid and a customized S. thermophilus CRISPR3 plasmid with disabled spacer acquisition elements and seven spacers targeting the bacteriophage DTL genome were constructed. Both plasmids were separately integrated into a PDO production strain, which was subsequently infected with bacteriophage DTL. The native S. thermophilus CRISPR3 operon was shown to decrease phage susceptibility by approximately 96%, while the customized CRISPR3 operon provided complete resistance to bacteriophage DTL. The results indicate that the heterologous bacteriophage-resistance system described herein is useful in eliminating lytic infections of bacteriophage DTL, which was prevalent in environment surrounding the manufacturing facility. PMID- 29411202 TI - Regulatory and biosynthetic effects of the bkd gene clusters on the production of daptomycin and its analogs A21978C1-3. AB - Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus in an acidic peptide complex A21978C. In this complex, A21978C1-3 is most abundant and contains branched-chain fatty acyl groups, while daptomycin has a straight decanoic acyl group. The branched-chain alpha-keto acid dehydrogenase complex (BCDH complex), encoded by bkd gene clusters in Streptomyces, is responsible for the early step of converting branched-chain amino acids into branched-chain fatty acids. In a daptomycin industrial producer S. roseosporus L30, two alleles of bkd gene clusters, bkdA1B1C1/bkdA2B2C2, and a regulatory gene bkdR located upstream of bkdA2B2C2 are identified. We show that BkdR positively regulated bkdA2B2C2 expression and was negatively auto-regulated, but is not directly involved in regulation of daptomycin gene cluster expression. However, BkdR is required for both daptomycin and A21978C1-3 production. Furthermore, deletion of bkdA2B2C2 only led to partial reduction of A21978C1-3 production, while the DeltabkdA1B1C1 mutant shows very weak production of A21978C1-3, and the double bkd mutant has a similar production profile as the single DeltabkdA1B1C1 mutant, suggesting that bkdA1B1C1 gene cluster plays a dominant role in branched chain fatty acid biosynthesis. So we reveal a unique regulatory function of BkdR and genetic engineered a bkd null strain for daptomycin production with reduced impurities. PMID- 29411203 TI - Heterogeneous impacts: adverse childhood experiences and cancer screening. AB - BACKGROUND: Adverse childhood experiences (ACEs) have been associated with higher odds of cancer in adulthood. One potential explanation for this association is the impact of ACEs on cancer screening. To address this shortcoming, this study examined how ACEs were associated with current compliance and ever use of prostate, breast, cervical, and colorectal cancer screening. METHODS: Data from the 2014 Kansas Behavioral Risk Factor Surveillance System were used (n = 11,794). Logistic regressions were used to calculate odds of cancer screening behaviors from each of nine different ACE items and a count of ACEs. RESULTS: Individual ACE items were associated with lower odds of compliance with PSA screening, clinical breast exam, and pap test guidelines. Certain ACEs were associated with increased odds of compliance with colorectal cancer screening guidelines among women and lower odds of compliance among men. ACEs were associated with ever screening for PSA and ever use of colonoscopy or sigmoidoscopy among men and women. Physical abuse was most consistently associated with cancer screening, across outcomes. CONCLUSIONS: Most significant associations showed that specific ACEs were associated with lower odds of cancer screening. Therefore, efforts should be made to promote screening among those with histories of ACEs. PMID- 29411204 TI - Glucosamine use and risk of colorectal cancer: results from the Cancer Prevention Study II Nutrition Cohort. AB - PURPOSE: Use of glucosamine supplements has been associated with reduced risk of colorectal cancer (CRC) in previous studies; however, information on this association remains limited. METHODS: We examined the association between glucosamine use and CRC risk among 113,067 men and women in the Cancer Prevention Study II Nutrition Cohort. Glucosamine use was first reported in 2001 and updated every 2 years thereafter. Participants were followed from 2001 through June of 2011, during which time 1440 cases of CRC occurred. RESULTS: As has been observed in prior studies, current use of glucosamine, modeled using a time-varying exposure, was associated with lower risk of CRC (HR 0.83; 95% CI 0.71-0.97) compared to never use. However, for reasons that are unclear, this reduction in risk was observed for shorter-duration use (HR 0.68; 95% CI 0.52-0.87 for current users with <= 2 years use) rather than longer-duration use (HR 0.90; 95% CI 0.72 1.13 for current users with 3 to < 6 years of use; HR 0.99; 95% CI 0.76-1.29 for current users with >= 6 years of use). CONCLUSIONS: Further research is needed to better understand the association between glucosamine use and risk of CRC, and how this association may vary by duration of use. PMID- 29411205 TI - Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa. AB - PURPOSE: To report an unusual phenotype of retinitis pigmentosa (RP) caused by compound heterozygous mutations in SPATA7, and describe the progression over a two year follow-up period. METHODS: Retrospective case study. RESULTS: A 63-year old man with a long history of nyctalopia, progressive visual field constriction, and a recent subacute decrease in visual acuity of the left eye presented for evaluation of a suspected retinal degeneration. Multimodal retinal imaging and functional assessment with full-field electroretinogram suggested a severe rod cone dysfunction masquerading as a choroideremia-like phenotype. A vitreous opacity was found to explain recent changes in the left eye and a 25-guage vitrectomy and membrane peel was performed, yielding no change in visual acuity. Whole-exome sequencing revealed compound heterozygous variants in SPATA7 that were predicted to be pathogenic. CONCLUSIONS: Compound heterozygous c.1100A > G, p.(Y367C) and c.1102_1103delCT, p.(L368Efs*4) variants in SPATA7 manifest as an unusual RP phenotype in this case, showing extensive choroidal sclerosis and retinal pigment epithelium (RPE) atrophy with evidence of progression over two years on multimodal imaging. PMID- 29411206 TI - The toxicity of a mixture of two antiseptics, triclosan and triclocarban, on reproduction and growth of the nematode Caenorhabditis elegans. AB - Many widely used healthcare products contain antiseptics, whose persistence in aquatic environments, soils, and sediments leads to the contamination of ecosystems and adversely affects wildlife. Recently, the impact not only of high but also low doses of contaminants and mixtures of several chemicals has become a focus of concern. In this study, toxicity tests of the antiseptics triclosan (TCS) and triclocarban (TCC) were performed in an aquatic test medium using the nematode Caenorhabditis elegans. Nominal concentrations of TCS and TCC were tested in separate single-substance toxicity tests (96-h-exposure), focussing on growth and reproduction endpoints. Median effective concentrations (EC50s) from the single-substance tests were subsequently used to set up five different ratios of TCS:TCC mixtures leading to the same toxicity. Six dilutions of each mixture ratio were tested for effon reproduction of C. elegans. In the single-substance tests, TCC was about 30 times more toxic than TCS when considering effects on growth and concerning reproduction, TCC was about 50 times more toxic than TCS. For both substances, the toxic effect on reproduction was more pronounced than the one on growth. Low doses of TCS (1-10 umol L-1) stimulated reproduction by up to 301% compared to the control, which might be due to endocrine disruption or other stress-related compensation responses (hormesis). Neither antiseptic stimulated growth. In the mixtures, increasing amounts of TCC inhibited the stimulatory effects of TCS on reproduction. In addition, the interactions of TCS and TCC were antagonistic, such that mixtures displayed lower toxicity than would have been expected when TCS and TCC mixtures adhered to the principle of concentration addition. PMID- 29411207 TI - A nonspecific synergistic effect of biogenic silver nanoparticles and biosurfactant towards environmental bacteria and fungi. AB - The present study focused on the evaluation of a nonspecific synergistic effect of biogenic silver nanoparticles (AgNPs) in combination with biosurfactants against environmental bacteria and fungi. The AgNPs were synthesized in the culture supernatants of the biosurfactant producer Bacillus subtilis grown in brewery effluent, molasses or Luria-Bertani media. Antibacterial activities were tested against Gram-positive and Gram-negative bacteria, while the antifungal activity was tested against phytopathogens. The interactions between biogenic AgNPs and DNA were investigated using a cryo-TEM technique. The presence of biosurfactant significantly increased the stability of biogenic AgNPs and enhanced their antimicrobial activities. The physical properties and antimicrobial activity of biogenic AgNPs were compared with chemically synthesized Ag nanoparticles. Biogenic silver nanoparticles showed a broad spectrum of activity against bacteria and fungi. They were most active against phytopathogenic fungi and Gram-positive bacteria and less active against Gram negative bacteria. The nonspecific synergistic effect of biogenic AgNPs and biosurfactant on the phytopathogenic fungi was especially observed. In this report, the new roles of biosurfactants as a biogenic AgNPs stabilizer and enhancer of their antimicrobial properties are presented. Our results revealed that the biologically synthesized AgNPs by the biosurfactant-producing bacterium Bacillus subtilis grown on agro-industrial wastes, such as molasses and brewery effluent, could be used as a promising new nanoagent against microbes. PMID- 29411208 TI - Stool PCR for Gastrointestinal Pathogens in Patients With and Without Immune Mediated Intestinal Diseases. AB - BACKGROUND: Patients with celiac disease and inflammatory bowel disease, two immune-mediated luminal conditions, have higher rates of certain infections than healthy counterparts. The prevalence of many gastrointestinal infections in these patients, however, is unknown. AIMS: Using a novel clinical stool pathogen PCR test, we investigated the hypothesis that patients with celiac disease/inflammatory bowel disease had different distributions of diarrheal pathogens than other patients. METHODS: We performed a retrospective cohort study of outpatients who underwent stool pathogen testing with the FilmArray Gastrointestinal PCR Panel (BioFire Diagnostics, Salt Lake City, UT) at our institution from January 1 to December 31, 2015. Rates of pathogens were measured in patients with or without celiac disease/inflammatory bowel disease. RESULTS: Of 955 patients, 337 had positive test for any pathogen, with 465 bacterial, parasitic, or viral pathogens identified. One hundred and twenty-seven patients (13.3%) had celiac disease or inflammatory bowel disease, of which 29/127 (22.8%) had a positive test, compared to 308/828 other patients (37.2%) (p = 0.002). Patients with celiac disease/inflammatory bowel disease had significantly fewer viruses (1.6 vs. 8.1% of patients; p = 0.008) and parasites (0 vs. 3.3%; p = 0.039), with nonsignificant trend toward fewer bacteria (21.3 vs. 29.2%; p = 0.063). Escherichia coli species were most common in both populations. CONCLUSIONS: Stool PCR identified numerous pathogens in patients with or without celiac disease/inflammatory bowel disease. Patients with celiac disease/inflammatory bowel disease were significantly less likely to have any pathogen identified, and had significantly fewer viruses and parasites. In this population, knowledge of common pathogens can guide diagnostic evaluation and offer opportunities for treatment. PMID- 29411209 TI - Crohn's Disease in Niemann-Pick Disease Type C1: Caught in the Cross-Fire of Host Microbial Interactions. PMID- 29411212 TI - Biographies. PMID- 29411211 TI - "Bridge to the Literature"? Third-Party Genetic Interpretation Tools and the Views of Tool Developers. AB - Patients and health care consumers can obtain access to their "raw," or uninterpreted, genetic data from direct-to-consumer genetic testing companies, researchers, or providers and pursue self-directed analysis via third-party interpretation tools. Yet relatively little is known about the nature of currently available interpretation tools or the motivations of tool developers. We conducted a structured content analysis of 23 third-party interpretation tool websites and supporting information, tracking features such as types of information returned, modes of generating and presenting that information, and privacy and security measures. We additionally conducted qualitative interviews with a subset of 10 tool developers. A majority of tools (16 of 23, or 70%) offer some type of health or wellness-related information, often extracted from publicly available variant annotation databases. Half of those interviewed characterized their activities as "bridging" users to the scientific literature rather than interpretation, for which they gave a variety of scientific, ethical, and regulatory justifications. The scale, heterogeneity, and complexity of information available from third-party interpretation are unprecedented. While developers aim to enlighten and empower tool users, interpretation-free "bridging" to rapidly evolving databases may instead impose burdens on genetic counselors and other health care providers asked to provide further contextualization and explanation. PMID- 29411210 TI - Down regulation of ITGA4 and ITGA5 genes after formation of 3D spherules by human Wharton's jelly stem cells (hWJSCs). AB - Human Wharton's jelly mesenchymal stem cells (hWJSCs) are multipotent stem cells that could be aggregated into 3D spherules. ITGA4 and ITGA5 genes encode alpha4 and alpha5 subunits of integrins, respectively. In this study, we analyzed expression levels of ITGA4 and ITGA5 gene mRNAs in undifferentiated and 3D spherules forming hWJSCs in order to determine their expression pattern for possible future treatment of cancer cells in a co-culture fashion. For the purpose of obtaining hWJSCs, umbilical cords were collected from patients with caesarian section at full term delivery. The cells were then characterized according to cell surface markers using flow cytometry. Furthermore pluripotency of the obtained cells was verified. Subsequently the cells were aggregated in 3D spherules using hanging drop cultures. Expression levels of ITGA4 and ITGA5 gene mRNAs were determined by RT-PCR and Real time PCR, both in the initial undifferentiated cells and those aggregated in the spherules. The obtained hWJSCs demonstrated pluripotency, differentiating to adipogenic and osteogenic cells. They also expressed mesenchymal stem cell surface markers. Following the aggregation of these cells and formation of 3D spherules, mRNA expression levels of both genes were significantly reduced (P < 0.05) compared with the initial undifferentiated state. The results of this study demonstrated that aggregation of hWJSCs into spherules alters their expression of ITGA4 and ITGA5. The implications of such an alteration would require further research. PMID- 29411213 TI - Editorial: IMA health 2016. PMID- 29411214 TI - How (not) to think of the 'dead-donor' rule. AB - Although much has been written on the dead-donor rule (DDR) in the last twenty five years, scant attention has been paid to how it should be formulated, what its rationale is, and why it was accepted. The DDR can be formulated in terms of either a Don't Kill rule or a Death Requirement, the former being historically rooted in absolutist ethics and the latter in a prudential policy aimed at securing trust in the transplant enterprise. I contend that the moral core of the rule is the Don't Kill rule, not the Death Requirement. This, I show, is how the DDR was understood by the transplanters of the 1960s, who sought to conform their practices to their ethics-unlike today's critics of the DDR, who rethink their ethics in a question-begging fashion to accommodate their practices. A better discussion of the ethics of killing is needed to move the debate forward. PMID- 29411215 TI - The lncRNA H19 Mediates Pulmonary Fibrosis by Regulating the miR-196a/COL1A1 Axis. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by lung fibroblasts accumulation and extracellular matrix (ECM) deposition. Recently, long-noncoding RNAs (lncRNAs) have emerged as critical regulators and prognostic markers in several diseases including IPF. In the present study, we found that the expression of H19 was significantly increased in transforming growth factor-beta (TGF-beta)-induced fibroblast proliferation and bleomycin-(BLM) induced lung fibrosis (p < 0.05). We further demonstrated that H19 was a direct target of miR 196a and was associated with COL1A1 expression by sponging miR-196a. Moreover, downregulation of H19 alleviated fibroblast activation and lung fibrosis, and this effect was blocked by a miR-196a inhibitor. In conclusion, our results suggest that lncRNA H19 has a promotive effect on BLM-induced IPF, and it functions as a molecular sponge of miR-196a, which provides a novel therapeutic target for IPF. PMID- 29411216 TI - Pharmacological treatments for heart failure with preserved ejection fraction-a systematic review and indirect comparison. AB - Pharmacological interventions for heart failure with preserved ejection fraction (HFpEF) have failed to reduce mortality and hospitalization. Evidence for mineralocorticoid antagonists (MRAs), beta-adrenoceptor blockers (beta-blockers), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs)-to reduce clinical outcomes in HFpEF remains unclear. We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov for randomized controlled trials (RCTs) assessing pharmacological treatments in HFpEF diagnosed according the recommendations of the European Society of Cardiology (ESC) 2016 guidelines from inception to August, 2017. The study outcomes were mortality, hospitalization, changes in indexes of cardiac structure and function, biomarkers, and indexes of functional capacity-quality of life (QoL) assessment and 6-min walk distance test (6-MWD). The random-effects models were used to estimate pooled relative risks (RRs) for the binary outcomes and standardized mean differences for continuous outcomes, with 95% CI. A network meta-analysis using a random-effects model was employed to estimate the comparative efficacy of treatments. We included data from 15 RCTs comprising 5930 patients. There was no significant effect seen with all treatments compared with placebo and comparative efficacy of any two treatments on all outcomes assessed. However, mineralocorticoid antagonist spironolactone demonstrated a trend towards reducing mortality compared with placebo (RR 0.92; 95% CI 0.79-1.08), sildenafil (0.14; 0.01-2.78), perindopril (0.87; 0.59-1.28), and eplerenone (0.91; 0.25-3.33). Similar trends in treatment effect were observed with spironolactone on surrogate outcomes while eplerenone demonstrated a trend of superior effect in reduction of hospitalizations compared with all other drug treatment. No drug treatment demonstrated statistically significant improvement in clinical and surrogate outcomes in HFpEF diagnosed according to the ESC 2016 guideline. Spironolactone and eplerenone showed clinically relevant reduction in mortality and hospitalization respectively compared with other drug treatments. Further trials with MRAs are warranted to confirm treatment effects in HFpEF. PMID- 29411217 TI - Local and Global Visual Processing in 3-Year-Olds With and Without Autism. AB - Research on visual local and global perception in Autism Spectrum Disorder (ASD) is incomplete in young children. We investigated 35 three-year-old siblings of children with ASD, either diagnosed (n = 12) or not diagnosed (n = 23) with ASD as well as 14 controls with typical development and with no family history of ASD. Data from the local tasks Children's Embedded Figures Test, Hidden Pictures, Figure-Ground and the global tasks Closure and Fragmented Picture Test were collected. Enhanced performance on the local task Hidden Pictures differentiated children with ASD from the other groups. Implications of these results are discussed. PMID- 29411218 TI - Engineering purple rice for human health. PMID- 29411219 TI - Volunteering to Care for People with Severe Mental Illness: A Qualitative Study of the Significance of Professional and Private Life Experience. AB - Challenges in recruiting volunteers encountered by psychiatric services are barely elucidated despite a general societal increase in volunteering. The aim of the study was to explore the significance of professional and private life experiences in willingness to volunteer to care for people with severe mental illness. Focus group interviews with volunteers in the Community Family Programme was conducted, followed by thematic analysis. All interviewees had professional and/or private experience of SMI, which had a major influence on their initial willingness to volunteer. Volunteering was an opportunity to pass on their experiences and to care for SMI people in ways that were not possible in their professions. The interviewees did not distinguish between the influences of professional and/or private life experiences on their willingness to volunteer. The study demonstrates the importance of professional and/or private life experiences in initial considerations about volunteering for mental health care. The consequences for recruitment practices are discussed. PMID- 29411221 TI - Correction to: Advanced glycation end products as a source of artifacts in immunoenzymatic methods. AB - The original version of this article unfortunately contained a mistake in the author group section. Author A. Bronowicka-Szydelko's surname was inadvertently interchanged to "Szydelko-Bronowicka". PMID- 29411220 TI - Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. AB - PURPOSE OF REVIEW: This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD). RECENT FINDINGS: In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti beta7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials. Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring. The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring. PMID- 29411222 TI - Physicochemical Characterization, Glycosylation Pattern and Biosimilarity Assessment of the Fusion Protein Etanercept. AB - Etanercept is a soluble fusion protein of the tumor necrosis factor receptor (TNFR) extracellular domain, linked to an Fc part of IgG1. It possesses three N- and 13 O-glycosylation sites. Due to its complex structure, an analytical challenge is facing the development and approval of biosimilars. In the current study, physicochemical characterization using state-of-the-art analytics was performed to analyze intact and subunit masses, post-translational modifications (PTMs), higher order structure and potency of Etanercept originator Enbrel(r) and its biosimilar AltebrelTM (AryoGen Pharmed) in accordance to critical quality attributes of biopharmaceuticals. Intact mass and subunit analysis revealed a size of about 126 kDa for both biologicals. Similar glycoprotein species for the complete monomer and the Fc domain of originator and follow-on product were observed, however, small differences in lysine variants and oxidation were found. N-Glycopeptide analysis with UHPLC-QTOF-MSE confirmed the N-glycosylation sites (N149, N171 and N317) as well as Fc-specific glycosylation on N317, and TNFR specific highly sialylated glycans on N149 and N171 on both investigated products. Small quantitative variations in the N-glycan profile were detected, although the N-glycans were qualitatively similar. Four different O-glycopeptides bearing core 1-type glycans were detected. For both, N- and O-glycopeptide analysis, determination was achieved without prior cleavage of the sialic acid residues for the first time. In addition, ion mobility spectrometry data confirmed close similarity of higher-order structure of both biologics. Furthermore, a neutralization assay, investigating the impact of altered PTMs on potency, indicated that the differences within all batches are still in the acceptable range for biosimilarity. PMID- 29411223 TI - In Vitro Screening of Synthetic Fluorogenic Substrates for Detection of Cancer Procoagulant Activity. AB - Cancer procoagulant (CP), a direct activator of coagulation factor X, is among one of the tumour cell products or activities which may promote fibrin formation and has been suggested to be selectively associated with the malignant phenotype. At present, the most reliable assay for the quantification of CP activity is the three-stage chromogenic assay which utilises the ability of CP to activate factor X. In this assay, the activation of factor X leads to the formation of activated thrombin from prothrombin and the eventual hydrolyses of a thrombin chromogenic substrate which contains a p-nitroaniline leaving group. The complexity of the three-stage chromogenic assay suggests a need for a direct method of assaying CP activity. This study focuses on the design of a fluorogenic substrate that would enable the direct quantification of CP activity. The results of the study show two promising substrates for the determination of CP activity: Boc-PQVR-AMC and PQVR-AMC. Further analysis showed that Boc-PQVR-AMC could be excluded as a potential substrate for CP since it was also cleaved by collagenase. PMID- 29411224 TI - Association of generic health-related quality of life (EQ-5D dimensions) and inactivity with lung function in lung-healthy German adults: results from the KORA studies F4L and Age. AB - PURPOSE: Among patients with lung disease, decreased lung function is associated with lower health-related quality of life. However, whether this association is detectable within the physiological variability of respiratory function in lung healthy populations is unknown. We analyzed the association of each EQ-5D-3L dimension (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and self-reported physical inactivity with spirometric indices in lung-healthy adults. Modulating effects between inactivity and EQ-5D dimensions were considered. METHODS: 1132 non-smoking, apparently lung-healthy participants (48% male, aged 64 +/- 12 years) from the population-based KORA F4L and Age surveys in Southern Germany were analyzed. Associations of each EQ-5D dimension and inactivity with spirometric indices serving as outcomes (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and mid expiratory flow) were examined by linear regression, considering possible confounders. Interactions between EQ-5D dimensions (no problems/any problems) and inactivity (four categories of time spent engaging in exercise: inactive to most active) were assessed. RESULTS: Among all participants 42% reported no problems in any EQ-5D dimension, 24% were inactive and 32% exercised > 2 h/week. After adjustment, FEV1 was - 99 ml (95% CI - 166; - 32) and FVC was - 109 ml (95% CI - 195; - 24) lower among subjects with mobility problems. Comparable estimates were observed for usual activities. Inactivity was negatively associated with FVC (beta-coefficient: - 83 ml, 95% CI - 166; 0), but showed no interactions with EQ 5D. CONCLUSIONS: Problems with mobility or usual activities, and inactivity were associated with slightly lower spirometric parameters in lung-healthy adults, suggesting a relationship between perceived physical functioning and volumetric lung function. PMID- 29411225 TI - Haematological, biochemical and organ changes in broiler chickens fed varying levels of Morinda lucida (brimstone) leaf meal supplementation in the diets. AB - The aim of this study was to evaluate the effects of dietary supplementation of Morinda lucida leaf meal (MLLM) on the haematology, biochemical and organ changes of broiler chickens. One hundred and ninety-eight day-old Marshall broiler chicks were completely randomised into 6 treatments in a 3 * 2 factorial arrangement of three levels of M. lucida leaf meal supplementation (0, 0.1 and 0.2 g/kg) with or without medication. The treatment consisted of both negative (without MLLM and routine medication) and positive (containing no MLLM but with routine medication) control groups while each treatment was replicated thrice. MLLM-supplemented diets and routine medication decreased (p < 0.05) the white blood cell count compared to the negative control. Dietary supplementation with MLLM in combination with normal routine medication increased (p < 0.05) total serum protein when compared with treatment group without MLLM and routine medication. Dietary supplementation with MLLM and routine medication reduced (p < 0.05) serum creatinine concentration of the broiler chickens. Birds fed with 0.2 g/kg MLLM supplement coupled with medication and those on negative control had higher (p < 0.05) creatinine values. Serum enzyme activities reduced (p < 0.05) following supplementation. MLLM supplementation recorded no significant effect (p > 0.05) on the liver, kidney, heart and gizzard. M. lucida leaf meal can be compared to routine medication for improved health status of broiler chickens. Dietary inclusion with 0.1 g/kg MLML combined with routine medication could be used in producing healthy and safe chickens. PMID- 29411226 TI - From Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical Application. AB - Radiolabeled amino acids, their derivatives and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as radiopharmaceutical tracers. Over the past few decades, the application of molecular imaging techniques such as positron emission tomography (PET) has gained considerable importance and significance in diagnosis in today's advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochemistry facilities has progressed the production of imaging agents enabling the preparation of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while aromatic amino acids can be employed as PET tracer to study neurological disorders. This review provides a comprehensive overview of radiosynthetic and enzymatic approaches towards carbon-11 amino acids, their analogues and peptides, with focus on stereoselective reactions, and reflects upon their clinical application. PMID- 29411227 TI - Discordance, Disclosure and Normative Gender Roles: Barriers to Couple Testing Within a Community-Level HIV Self-Testing Intervention in Urban Blantyre, Malawi. AB - A community-based HIV self-testing study in Blantyre, Malawi demonstrated that not all individuals living in couples tested with their partner. We describe factors dissuading individuals in couples from self-testing with their partner. Data were drawn from qualitative study exploring consequences of HIV self-testing within couples. In-depth interviews were conducted with 33 individuals living in couples who tested alone. Participants expressed fear of dealing with HIV discordant relationships. Failure to self-test with a partner was correlated with gender, with more men than women overtly declining or unconsciously unable to have joint HIV self-test. Men feared exposure of infidelity and were often not available at home for economic reasons. Barriers to uptake of couple HIV self testing seemed to be shaped by gendered dichotomies of social-relationships. To help achieve the first 90% of the UNAIDS 90:90:90 goals, it is important to overcome structural barriers to realise the full potential of HIV self-testing. PMID- 29411228 TI - Traumatic Events and HIV Sexual Risk Behaviors Among Migrant and Non-Migrant Male Market Workers in Central Asia. AB - We examined potentially traumatic events (PTEs) and the relationship between PTEs and HIV risk behaviors among male market workers in Kazakhstan, comparing Kazakhstani to external migrants. Using respondent-driven sampling, participants were 1342 male marketplace workers in Almaty, Kazakhstan. Univariate, bivariate, and logistic regressions were conducted. We found high prevalence of PTEs among participants, and significant differences between PTEs and HIV risk by migrant status. Kazakhstanis reporting 1-2 or three-or-more traumatic events were more likely to report engaging in sex trading, compared to Kazakhstanis who reported no PTEs (OR = 3.65, CI 1.20-11.11, p = 0.022; OR = 8.17, 95% CI 2.66-25.09, p = 0.000, respectively). Kazakhstanis who reported three-or-more PTEs were more likely to report unprotected sex (OR = 2.17, CI 2.17-3.89, p = 0.009). Results did not support this relationship among external migrants. Findings underscore the need for attention on services that address trauma and HIV risk among this population and more research to understand differences by migrant status. PMID- 29411230 TI - Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure. PMID- 29411231 TI - Analysis of Chronic Granulomatous Disease in the Kavkazi Population in Israel Reveals Phenotypic Heterogeneity in Patients with the Same NCF1 mutation (c.579G>A). AB - PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47phox deficiency. METHODS: Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47phox by immunoblotting and molecular confirmation by DNA sequence analysis. RESULTS: Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47phox deficiency. CONCLUSIONS: Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusive. PMID- 29411232 TI - A Systematic Comparison of African American and Non-African American Patients on Psychosocial Aspects of Hepatitis C Infection. AB - The purpose of this study was to compare African American and non-African American hepatitis C virus (HCV) patients on self-reported symptoms of HCV liver disease and psychosocial characteristics commonly affected by it in a sample of 309 patients enrolled in a randomized controlled trial. African Americans (n = 196) rated a higher reliance on religion/spirituality for coping with HCV compared to non-African Americans. This study's findings are a basis for encouragement of public health efforts and programs to seek partnerships with African American faith and religious communities to identify and treat undiagnosed cases of HCV and promote HCV awareness. PMID- 29411233 TI - Applying Attention Restoration Theory to Understand and Address Clergy's Need to Restore Cognitive Capacity. AB - Attention Restoration Theory is applied to explore the causes and consequences of mental fatigue in clergy and suggest practical interventions to restore cognitive wellbeing. Previous research has investigated the physical and emotional health and wellbeing of clergy, but has largely neglected clergy cognitive wellbeing. Due to the demanding nature of their work, clergy are particularly susceptible to mental fatigue and depletion of their capacity to maintain attention. Symptoms include inability to focus attention, inhibit distractions, make decisions or solve problems. Mental fatigue can be overcome, and cognitive capacity restored, by spending time in restorative environments that allow directed attention to rest. PMID- 29411234 TI - Church-Based Social Support's Impact on African-Americans' Physical Activity and Diet Varies by Support Type and Source. AB - The objective of this study was to examine sources (friends, family, church members, and pastors) and type (positive or negative) of social support and their association with eating and physical activity behaviors. Study participants consisted of 41 African-American adults (78% female), with an average age of 43.5 years (standard deviation = 15.7). Participants were recruited from churches in southwest, Ohio. Mean comparisons showed family members, and friends had the highest positive and negative social support scores for healthy eating and physical activity. Pastors and church members received the lowest social support scores related to these behaviors. Using a linear regression analysis, social support in the form of physical activity rewards from family members was positively associated with fruit and vegetable consumption after adjusting for gender, age, education level, and church location. Based on these findings, future research should continue examining how different social support sources and types influence physical activity and healthy eating behaviors among African Americans. PMID- 29411235 TI - Humility, Relational Spirituality, and Well-being among Religious Leaders: A Moderated Mediation Model. AB - Prior research has demonstrated positive associations between general humility and well-being, and posited a protective effect for intellectual humility against maladjustment among religious leaders. We tested a model that extended findings on general humility to include intellectual humility among religious leaders (N = 258; M age = 42.31; 43% female; 63.7% White; 91.9% Christian affiliation). We observed a positive general humility-well-being association. Contrary to expectations, we observed risk effects for religion-specific intellectual humility. Our findings also point to the possibility that these risk effects might be attenuated by the integration of high levels of general and intellectual humility. PMID- 29411236 TI - Reply to K. Altundag. PMID- 29411237 TI - Cell growth inhibition and apoptosis in breast cancer cells induced by anti-FZD7 scFvs: involvement of bioinformatics-based design of novel epitopes. AB - BACKGROUND: FZD7 has a critical role as a surface receptor of Wnt/beta-catenin signaling in cancer cells. Suppressing Wnt signaling through blocking FZD7 is shown to decrease cell viability, metastasis and invasion. Bioinformatic methods have been a powerful tool in epitope designing studies. Small size, high affinity and human origin of scFv antibodies have provided unique advantages for these recombinant antibodies. METHODS: Two epitopes from extracellular domain of FZD7 were designed using bioinformatic methods. Specific anti-FZD7 scFvs were selected against these epitopes through panning process. The specificity of the scFvs was assessed by phage ELISA and the ability to bind to FZD7 expressing cell line (MDA MB-231) was determined by flowcytometry. Antiproliferative and apoptotic effects of the scFvs were evaluated by MTT and Annexin V/PI assays. The effects of selected scFvs on expression level of Surivin, c-Myc and Dvl genes were also evaluated by real-time PCR. RESULTS: Results demonstrated selection of two specific scFvs (scFv-I and scFv-II) with frequencies of 35 and 20%. Both antibodies bound to the corresponding peptides and cell surface receptors as shown by phage ELISA and flowcytometry, respectively. The scFvs inhibited cell growth of MDA-MB-231 cells significantly as compared to untreated cells. Growth inhibition of 58.6 and 53.1% were detected for scFv-I and scFv-II, respectively. No significant growth inhibition was detected for SKBR-3 negative control cells. The scFvs induced apoptotic effects in the MDA-MB-231 treated cells after 48 h, which were 81.6 and 74.9% for scFv-I and scFv-II, respectively. Downregulation of Surivin, c-Myc and Dvl genes were also shown after 48h treatment of cells with either of scFvs (59.3-93.8%). ScFv-I showed significant higher antiproliferative and apoptotic effects than scFv-II. CONCLUSIONS: Bioinformatic methods could effectively select potential epitopes of FZD7 protein and suggest that epitope designing by bioinformatic methods could contribute to the selection of key antigens for cancer immunotherapy. The selected scFvs, especially scFv-I, with high antiproliferative and apoptotic effects could be considered as effective agents for immunotherapy of cancers expressing FZD7 receptor including triple negative breast cancer. PMID- 29411238 TI - Hospital-Level Care at Home for Acutely Ill Adults: a Pilot Randomized Controlled Trial. AB - BACKGROUND: Hospitals are standard of care for acute illness, but hospitals can be unsafe, uncomfortable, and expensive. Providing substitutive hospital-level care in a patient's home potentially reduces cost while maintaining or improving quality, safety, and patient experience, although evidence from randomized controlled trials in the US is lacking. OBJECTIVE: Determine if home hospital care reduces cost while maintaining quality, safety, and patient experience. DESIGN: Randomized controlled trial. PARTICIPANTS: Adults admitted via the emergency department with any infection or exacerbation of heart failure, chronic obstructive pulmonary disease, or asthma. INTERVENTION: Home hospital care, including nurse and physician home visits, intravenous medications, continuous monitoring, video communication, and point-of-care testing. MAIN MEASURES: Primary outcome was direct cost of the acute care episode. Secondary outcomes included utilization, 30-day cost, physical activity, and patient experience. KEY RESULTS: Nine patients were randomized to home, 11 to usual care. Median direct cost of the acute care episode for home patients was 52% (IQR, 28%; p = 0.05) lower than for control patients. During the care episode, home patients had fewer laboratory orders (median per admission: 6 vs. 19; p < 0.01) and less often received consultations (0% vs. 27%; p = 0.04). Home patients were more physically active (median minutes, 209 vs. 78; p < 0.01), with a trend toward more sleep. No adverse events occurred in home patients, one occurred in control patients. Median direct cost for the acute care plus 30-day post-discharge period for home patients was 67% (IQR, 77%; p < 0.01) lower, with trends toward less use of home care services (22% vs. 55%; p = 0.08) and fewer readmissions (11% vs. 36%; p = 0.32). Patient experience was similar in both groups. CONCLUSIONS: The use of substitutive home-hospitalization compared to in-hospital usual care reduced cost and utilization and improved physical activity. No significant differences in quality, safety, and patient experience were noted, with more definitive results awaiting a larger trial. Trial Registration NCT02864420. PMID- 29411239 TI - Venous phase contrast-enhanced computed tomography facilitates the detection of pulmonary venous tumor thrombus. AB - A 64-year-old woman, with a history of hepatocellular carcinoma, developed recurrent metastatic lung nodules after lung metastasectomy 10 years ago. Computed tomography (CT) revealed tumors in the right middle, and left lower lobes. We planned a right middle lobectomy. Before operating, a contrast-enhanced CT in the pulmonary venous phase revealed a tumor in the pulmonary vein resembling a thrombus, indicating that the CT failed to facilitate accurate diagnosis. Following venous clamping and incision, the intravenous polypoid mass was surgically removed. As contrast-enhanced CT focuses on pulmonary arterial phases and might not detect venous lesions, we highlight the usefulness of venous phase contrast-enhanced CT for detecting pulmonary venous tumor thrombosis. Large lung metastatic carcinomas with venous extension may embolize to distant organs. Therefore, venous phase contrast-enhancement is essential for preoperative assessments of large or persisting metastatic lung tumors. PMID- 29411240 TI - Altered gray matter volume in primary insomnia patients: a DARTEL-VBM study. AB - Previous neuroimaging studies have reported brain morphological alterations and the occurrence of mental disorders in primary insomnia (PI) patients. However, studies of the effect of disrupted sleep on brain structure have showed inconsistent results. In this study, DARTEL-VBM was used to evaluate the changes in gray matter volume from 60 PI patients and 53 controls. Voxel-wise statistics was performed in two ways. One is a more liberal statistical analysis using an uncorrected P < 0. 001 with 25 voxels, and the other one is a more conservative approach using a threshold of P < 0.05, corrected for multiple comparisons using the Gaussian random field (GRF) method. Partial correlation was used to analyze the relationship between abnormal volume and clinical features. PI patients had reduced gray matter volume primarily in the right middle cingulate cortex with correction (P < 0.05). Correlation analysis showed gray matter changes in the left middle cingulate cortex were negatively associated with self-ratings for anxiety and depression. This study showed that gray matter deficits in cingulate cortex in patients with insomnia, and the decreased gray matter volume may be associated with the difficulties in emotional management due to insomnia. Functional roles of the affected regions in emotion and regulation of sleep might provide supplementary evidence and guide further research that may facilitate understanding the mechanisms underlying insomnia. PMID- 29411241 TI - Binge Eating, Loss of Control over Eating, Emotional Eating, and Night Eating After Bariatric Surgery: Results from the Toronto Bari-PSYCH Cohort Study. AB - OBJECTIVES: We explored the severity of binge eating, loss of control over eating, emotional eating, and night eating before bariatric surgery and annually for 3 years following surgery. We also assessed the impact of post-operative eating psychopathology on weight outcomes. METHODS: Eight hundred forty-four patients participated in this prospective cohort study. Demographic factors, self report measures of eating pathology (BES, NEQ, EES, EDE-Q), and weights (kg) were collected pre-surgery and annually for 3 years after surgery. RESULTS: The severity of problematic eating behaviors decreased after surgery and remained lower than baseline throughout follow-up. An increase was noted in binge eating scores (change in mean score +/- SD = 0.85 +/- 4.71; p = 0.002), emotional eating scores (2.00 +/- 13.63; p = 0.033), and loss of control eating scores (1.11 +/- 7.01; p < 0.001) after the first post-operative year that continued to the third post-operative year. There was also an increase in night eating scores between 2 and 3 years post-surgery (2.52 +/- 8.00; p = 0.01). Higher 1-year post-operative binge eating scores were a significant predictor of lower 2-year % total weight loss (beta = - 0.39, confidence interval (CI) - 1.23, - 0.16, p = 0.012). CONCLUSIONS: The severity of problematic eating behaviors decrease after bariatric surgery, but increase significantly between the first and third post operative years. Binge Eating Scale score at 1 year post-surgery was the only significant predictor of reduced percent total weight loss at 2 years. Additional prospective studies with adequate power are required to assess the progression of these eating pathologies beyond 3 years and their impact on weight outcomes beyond 2 years. PMID- 29411242 TI - Predictors of Binge Eating among Bariatric Surgery Candidates: Disinhibition as a Mediator of the Relationship Between Depressive Symptoms and Binge Eating. AB - BACKGROUND: Current and lifetime psychopathology is common in adult patients seeking bariatric surgery, with major depressive disorder and binge eating disorder affecting a higher proportion of this group than the general population. While depressive symptoms have been previously associated with eating pathology, potential mediators of this relationship are not well understood. METHODS: This study used a naturalistic, retrospective design to investigate cognitive and behavioral aspects of eating behavior (cognitive restraint, disinhibition, and hunger) as potential mediators of the relationship between depressive symptoms and binge eating within a sample of 119 adult patients (82.4% female; 96.6% white; mean age = 47 years) seeking bariatric surgery (Roux-en-Y and sleeve gastrectomy) at a large university medical center. Patients completed a standardized presurgical psychological evaluation to determine appropriateness for bariatric surgery as part of routine clinical practice. Binge eating was assessed via clinician rating (number of binge eating episodes per week) based on DSM-IV diagnostic criteria and self-report measures (Binge Eating Scale) in order to account for potential methodological differences. Depressive symptoms were assessed using the Beck Depression Inventory. RESULTS: Depressive symptoms were a significant predictor of binge eating, disinhibition, and hunger. However, only disinhibition emerged as a significant mediator of the relationship between depressive symptoms and binge eating. CONCLUSIONS: Behavioral disinhibition, or a tendency toward overconsumption of food and challenges restraining impulses associated with a loss of control eating, may represent an important variable in determining the relation between depressive symptoms and binge eating, in bariatric surgery patients. PMID- 29411243 TI - Protective Efficacy of a Pseudoalteromonas Strain in European Abalone, Haliotis tuberculata, Infected with Vibrio harveyi ORM4. AB - The hemolymph of healthy marine invertebrates is known to harbor antibiotic producing bacteria belonging to the genus Pseudoalteromonas. Such strains are potential probiotics to control infectious diseases in aquaculture. In the present study, we screened a collection of Pseudoalteromonas strains isolated from the hemolymph of oyster and mussel for antimicrobial activity against Vibrio harveyi, a pathogenic species responsible for high mortality in abalone. Subsequently, the protective efficacy of the most active strain named hCg-6 was investigated in abalone culture faced with a Vibrio harveyi ORM4 infection. First, we have controlled the Pseudoalteromonas hCg-6 safety for abalone health. To that end, animals were immersed for 4 h in Pseudoalteromonas hCg-6 suspensions in seawater. The abalone viability was monitored and Pseudoalteromonas hCg-6 was tracked by quantitative-PCR in abalone hemolymph. After immersion, no abalone death occurred while the strain hCg-6 was significantly detected in hemolymph. Therefore, the strain hCg-6 was considered safe for abalone and evaluated for its ability to protect abalone against V. harveyi (injection of 1 * 103 Vibrio per animal). A 4-h long immersion of abalone in a seawater suspension of Pseudoalteromonas hCg-6 (1 * 106 CFU mL-1) prior to infection with Vibrio harveyi significantly improved the abalone viability. Indeed, 15 days post infection, the hCg-6 treatment used increased the abalone survival rate from 16% in untreated animals to 40% in treated abalone. We hypothesized that Pseudoalteromonas hCg-6 antibacterial activity increased the hemomicrobiota shielding effect. In conclusion, Pseudoalteromonas hCg-6 is a promising anti-Vibrio strain for abalone culture. PMID- 29411244 TI - Strain Screening from Traditional Fermented Soybean Foods and Induction of Nattokinase Production in Bacillus subtilis MX-6. AB - The plasminogen-free fibrin plate assay method was used to isolate Bacillus subtilis MX-6, a strain with high production of nattokinase from Chinese douchi. The presence of aprN, a gene-encoding nattokinase, was verified with PCR method. The predicted amino acid sequence was aligned with homologous sequences, and a phylogenetic tree was constructed. Nattokinase was sublimated with ammonium sulfate, using a DEAE-Sepharose Fast Flow column, a CM-Sepharose Fast Flow column and a Sephadex G-75 gel filtration column. SDS-PAGE analysis indicated that the molecular weight of the purified nattokinase from Bacillus subtilis MX-6 was about 28 kDa. Fermentation of Bacillus subtilis MX-6 nattokinase showed that nattokinase production was maximized after 72 h; the diameter of clear zone reached 21.60 mm on the plasminogen-free fibrin plate. Nattokinase production by Bacillus subtilis MX-6 increased significantly after supplementation with supernatant I, supernatant II and soy peptone but decreased substantially after the addition of amino acids. This result indicated that the nattokinase production by B. subtilis MX-6 might be induced by soybean polypeptides. The addition of MgSO4 and CaCl2 increased B. subtilis MX-6 nattokinase production. PMID- 29411245 TI - Single Coronary Artery Anomaly: A Case Report and Review of Literature. AB - INTRODUCTION: Single coronary artery is a rare anomaly, which is usually associated with other cardiac congenital abnormalities. CASE REPORT: A 56-year old female presented with unstable angina. The patient reported complaints of typical chest pain on exertion few months prior to presentation, which progressed to become at rest. The pain was associated palpitations and dizziness. Past medical history was significant for hypertension and hyperlipidemia. Vital signs were stable. Physical examination was non-remarkable. Electrocardiogram showed normal sinus rhythm, with intermittent episodes of sinus bradycardia, and non specific T-wave changes. Trans-thoracic echocardiogram showed normal left ventricular function and no segmental wall-motion abnormalities. Selective coronary angiography showed a normal left main coronary artery arising from left coronary cusp. The left main branched to a normal left anterior descending artery and to the left circumflex artery; a large vessel which supplied also the territory of the right coronary artery (RCA) through its terminal extension. Aortography showed absence of RCA with no other vessels arising from the right or non-coronary cusps. The patient was managed conservatively and discharged home with resolution of symptoms. CONCLUSIONS: We report a rare case of isolated single coronary artery with absent RCA. The patient presented with unstable angina, and was managed conservatively. Cardiologists should be aware of this rare condition, which carries a potential risk of sudden cardiac death. PMID- 29411246 TI - A case of nodal malignant lymphoma presenting with arterial bleeding related to its duodenal penetration. AB - A 62-year-old man with a chief complaint of dysphagia visited our hospital. Enhanced computed tomography showed the tumor near the duodenal wall and lymphadenopathy in the left supraclavicular fossa and para-aortic lymph node. Upper gastrointestinal endoscopy showed an ulcer accompanied with a fistula in the anterior wall of duodenal bulb, suggesting that the tumor penetrated into duodenal wall. Biopsy from the lymph node in the left supraclavicular fossa indicated diffuse large B-cell lymphoma. Although chemotherapy was planned, massive arterial bleeding occurred from the part of duodenal penetration. Endoscopic hemostasis was unsuccessfully performed. Therefore, we performed transcathether arterial embolization for hemostasis. After the procedure, the patient received six cycles of chemotherapy, and he achieved complete response. He has been alive 5 years without recurrence. There were many cases of gastrointestinal bleeding from primary gastrointestinal lymphomas, while there were few cases with nodal involvement by malignant lymphoma resulting in bleeding from gastrointestinal tract. We herein report a case of duodenal bleeding by nodal involvement of diffuse large B-cell lymphoma with review of literature. PMID- 29411247 TI - Automatic deformable PET/MRI registration for preclinical studies based on B splines and non-linear intensity transformation. AB - PET images deliver functional data, whereas MRI images provide anatomical information. Merging the complementary information from these two modalities is helpful in oncology. Alignment of PET/MRI images requires the use of multi-modal registration methods. Most of existing PET/MRI registration methods have been developed for humans and few works have been performed for small animal images. We proposed an automatic tool allowing PET/MRI registration for pre-clinical study based on a two-level hierarchical approach. First, we applied a non-linear intensity transformation to the PET volume to enhance. The global deformation is modeled by an affine transformation initialized by a principal component analysis. A free-form deformation based on B-splines is then used to describe local deformations. Normalized mutual information is used as voxel-based similarity measure. To validate our method, CT images acquired simultaneously with the PET on tumor-bearing mice were used. Results showed that the proposed algorithm outperformed affine and deformable registration techniques without PET intensity transformation with an average error of 0.72 +/- 0.44 mm. The optimization time was reduced by 23% due to the introduction of robust initialization. In this paper, an automatic deformable PET-MRI registration algorithm for small animals is detailed and validated. Graphical abstract ?. PMID- 29411249 TI - Multi-Targeted Tyrosine Kinase Inhibitor-Induced Hyperammonemic Encephalopathy: a Report of Two Cases Using Pazopanib, Sunitinib, and Regorafenib. PMID- 29411248 TI - Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy. AB - Our previous studies demonstrated that the multifunctional agent TBN, a derivative of tetramethylpyrazine armed with a nitrone moiety, displayed high therapeutic efficacy in experimental ischemic stroke models. However, its molecular mechanisms of action underlying the neuroprotective effect need further exploration. In the present study, we found that TBN had significant activities scavenging free radicals such as .OH, O 2.- and ONOO-, inhibiting Ca2+ overload, maintaining mitochondrial function and preventing neuronal damage in primary cortical cultures. Further, TBN was effective in reducing brain infarction and ameliorating impairment of behavioral functions in the permanent middle cerebral artery occlusion (p-MCAo) rat model. TBN down-regulated the expression of pro apoptotic factors Bax, while up-regulated the expression of anti-apoptotic factor Bcl-2 and increased the expression of pro-survival factors including p-Akt and p GSK3beta in the peri-infarct cortex of p-MCAo rats. In addition, LY-294002 (a PI3K inhibitor) and MK2206 (an Akt inhibitor) significantly blocked the protective effect of TBN against OGD-induced death of cortical neurons. Taken together, the multifunctional mechanisms including scavenging free radicals, blocking calcium overload, maintaining mitochondrial function and activating the PI3K/Akt/p-GSK3beta cell survival pathway were possibly involved in the neuroprotective effects of TBN, making it a promising clinical candidate for the treatment of ischemic stroke. PMID- 29411250 TI - Exploring Mothers' Influence on Preschoolers' Physical Activity and Sedentary Time: A Cross Sectional Study. AB - Objectives Physical activity patterns can track from childhood into adulthood; therefore, establishing active behaviors early is imperative. Given the multidimensional nature of a mother's influence on their children, there is a need to utilize more comprehensive measures to assess the relationship between mother and child activity behaviors. Specifically, mothers have been identified as influencing preschoolers' activity behaviors and are often in control of organizing a family's opportunities to be active. The purpose of this study was to explore maternal influence on preschoolers' physical activity and sedentary time. Methods Preschoolers (n = 24) and their mothers (n = 24) wore ActicalTM accelerometers for 7 consecutive days (e.g., 5 weekday, 2 weekend days), and mothers completed the adapted Environmental Determinants of Physical Activity in Preschool Children-Parent Survey. Direct entry regression analyses were conducted to explore maternal influence (e.g., role modeling through mothers' activity levels, maternal support, and enjoyment of being active) on preschoolers' activity levels. Results Maternal support was found to be a significant predictor of preschoolers' light and moderate-vigorous physical activity, and sedentary time (p < .05); accounting for 37.3-46.7% of the variation. Conclusions for Practice Mothers supportive behaviors influenced preschoolers' physical activity and sedentary time. Future research is needed to investigate facilitators/barriers that mothers with preschoolers encounter with regard to providing support to be active or modeling active behaviors themselves. PMID- 29411251 TI - The Impact of a Cultural Lifestyle Intervention on Metabolic Parameters After Gestational Diabetes Mellitus A Randomized Controlled Trial. AB - OBJECTIVES: The prevalence of type 2 diabetes in Israel is increasing in all ethnic groups but most markedly in the Bedouin population. We aimed to assess the effects of a lifestyle change intervention on risk markers for type 2 diabetes after gestational diabetes mellitus (GDM). METHODS: One hundred eighty Jewish and Bedouin post-GDM women were randomly assigned to a lifestyle intervention group (IG) or a control group (CG) starting 3-4 months after delivery. The IG participated in healthy lifestyle sessions led by a dietician and a sports instructor for 24 months after delivery. The IG participants had three individual 45-min counseling sessions and four 90-min group meetings (10 women each). The dietary and exercise recommendations were culturally adapted. The primary outcome of the study was HOMA-IR. We monitored clinical and chemical biomarkers 1 and 2 years after delivery. RESULTS: After 1 and 2 years of intervention, the metabolic measures improved substantially. The intervention reduced the insulin, glucose and HOMA-IR levels in the IG compared with those in the CG (p < 0.001). CONCLUSIONS: This novel culturally tailored lifestyle intervention program significantly improved the metabolic and morphometric indices measured 1 and 2 years after delivery. These results highlight and underscore the importance of effective lifestyle change education following GDM. PMID- 29411252 TI - The Fertility Management Experiences of Australian Women with a Non-communicable Chronic Disease: Findings from the Understanding Fertility Management in Contemporary Australia Survey. AB - Introduction Despite the considerable and increasing proportion of women of reproductive age with a chronic non-communicable disease (NCD) and the potential adverse implications of many NCDs for childbearing, little is known about the fertility management experiences of women with an NCD, including their contraceptive use, pregnancy experiences and outcomes, and reproductive health care utilisation. The aim of this study was to investigate the fertility management experiences of women with an NCD and draw comparisons with women without an NCD. Method A sample of 18-50 year-old women (n = 1543) was randomly recruited from the Australian electoral roll in 2013. Of these women, 172 women reported a physical, chronic non-communicable disease: diabetes, arthritis, asthma, hypertension, heart disease, thyroid disorders, and cystic fibrosis. Respondents completed an anonymous, self-administered questionnaire. Factors associated with fertility management were identified in multivariable analyses. Results Women who reported having an NCD were significantly more likely than women who did not report an NCD to have ever been pregnant (75.9 vs. 67.5%, p = 0.034), have had an unintended pregnancy (33.47 vs. 25.5%, p = 0.026), and have had an abortion (20.3 vs. 14.2%, p = 0.044); they were less likely to consult a healthcare provider about fertility management (45.0 vs. 54.4%, p = 0.024). Similar proportions were using contraception (48.8 vs. 54.5%, p = 0.138). Conclusion The findings have implications for healthcare providers and women with an NCD and highlight the importance of addressing possible assumptions about the inability of women with an NCD to become pregnant, and ensuring women receive information about suitable methods of contraception and pre-pregnancy care. PMID- 29411253 TI - The Need to Objectively Measure Physical Activity During Pregnancy: Considerations for Clinical Research and Public Health Impact. AB - Engaging in recommended levels of physical activity during pregnancy can provide a host of physical and mental health benefits for the expecting mother and her child. However, methodological issues related to physical activity measurement have plagued many studies examining the effects of physical activity during this important life stage. Burgeoning support exists for the more widespread use of objective methods, and accelerometers specifically, for an accurate appraisal of maternal physical activity. In this commentary, we highlight discrepancies between activity estimates obtained via self-report and objective measures and describe the implications of erroneous measurement when making clinical recommendations and in conducting future physical activity and pregnancy research. Most importantly, we aim to foster academic discussion and propose a call to action requiring a paradigm shift where we acknowledge the shortcomings of self-report and move toward an empirically driven approach for physical activity measurement. Results from more high-quality research studies will help support public health messaging and facilitate trust among health care providers, clinical researchers, and expecting mothers regarding the health benefits of physical activity recommendations. PMID- 29411254 TI - Challenges Faced by Family Physicians Providing Advanced Maternity Care. AB - Introduction Maldistribution of maternity care (MC) providers in the U.S. limits access to full spectrum MC services. Obstetricians are concentrated in urban areas with many rural areas reliant on family physicians (FP) to provide MC, yet fewer FPs are providing MC. The objective of this study was to understand the challenges FPs face in gaining skills in and providing advanced MC. Methods We conducted qualitative semi-structured interviews with 51 purposively sampled key stakeholders in family medicine MC (21 family medicine-OB fellowship directors, 19 past fellows, and 10 family medicine residency directors of programs with advanced MC training). Interviews were recorded, transcribed, and analyzed using an inductive approach to qualitative content analysis. Results Three primary challenges for FPs providing advanced MC emerged from the interviews. Training: most family medicine residency programs do not provide sufficient surgical OB training, so fellowship training is an important alternative for FPs to acquire such skills. Credentialing: obtaining hospital privileges to perform cesarean sections is unpredictable and highly variable by institution. Professional relationships: "turf battles" with other MC providers can limit FPs' ability to provide care commensurate with their level of training. Discussion As the predominant provider of MC in rural and underserved areas, FPs need to be supported to provide advanced MC services. Possible strategies to accomplish this include: enhanced family medicine training in MC; policy changes to address credentialing inconsistencies; and improved team-based care for pregnant women to ensure that every woman has access to high quality MC. PMID- 29411256 TI - Congratulations to Dr. Fumio Arisaka on his 70th birthday. PMID- 29411255 TI - Advanced Maternal Age and Maternal Education Disparity in Children with Autism Spectrum Disorder. AB - Objective Previous studies have shown inconsistent results with regard to the association between advanced parental age and autism spectrum disorder (ASD). The sociodemographic status of parents has been found to be associated with children with ASD, however. Therefore, a pathway analysis was undertaken of the roles of maternal age and education in ASD diagnosis and community screening, in a national birth cohort database, using a propensity score matching (PSM) method. Method The 6- and 66-month Taiwan Birth Cohort Study dataset was used (N = 20,095). The PSM exact matching method was used to select 1700 families (ratio of 1:4 between ASD diagnosis and control) from the Taiwan Birth Cohort Study dataset. Results (1) The results from the complete dataset and the PSM exact matching dataset both show that the risk of a child being diagnosed with ASD was increased by the mother being over 40 years old. (2) Although more children of mothers with lower-than-average education were positive on screening, more children of mothers with higher-than-average education were also diagnosed with ASD. Conclusions for Practice Advanced maternal age had a higher association with the diagnosis of ASD, and maternal educational disparity was found between ASD clinical diagnosis and community screening. Community and primary medical care services should pay more attention to children of parents with lower education during ASD screening to prevent delayed diagnosis. PMID- 29411257 TI - Forty years of research on the assembly and infection process of bacteriophage. AB - This short biographical note was written as part of the lead-in material for a festschrift kindly organized for me on the occasion of my 70th birthday. The collection of articles assembled in this issue range within the spectrum of the topics covered in the special issue 'Multiscale structural biology-biophysical principles and practice ranging from biomolecules to bionanomachines.' Here I describe some of the high points of my 40 years of research science conducted in the USA, Switzerland and Japan. I also use this opportunity to express my sincerest thanks to my former colleagues and the very many contributors who so kindly contributed to this special issue. PMID- 29411258 TI - Good news, bad news. PMID- 29411259 TI - Intravitreal aflibercept for the treatment of choroidal neovascularization associated with rubella retinopathy. AB - PURPOSE: To report a case of choroidal neovascularization (CNV) associated with rubella retinopathy (RR) treated with intravitreal aflibercept. CASE PRESENTATION: A 15-year-old girl presented a complaint of visual decrease in her left eye. She had a history of hearing decrease since she was 1 year old in addition to patent ductus arteriosus. On ocular examination, the best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/400 in the left eye. Dilated fundus examinations revealed a classic salt-and-pepper appearance in both eyes and a whitish subretinal lesion with retinal hemorrhages in the left macula. Fundus fluorescein angiography (FFA) of the left eye illustrated a pattern of diffuse spotty fluorescence with an active subfoveal CNV lesion, that hyperfluoresces in the early phases of the FFA, maintains well-demarcated borders, and leaks. Spectral domain optical coherence tomography (SD-OCT) revealed thickened and elevated retinal layers at the macula due to the subretinal and intraretinal fluid with foveal and extrafoveal protruding hyper reflective lesion in the left eye. Single dose of intravitreal aflibercept was performed to the left eye and at the first month after the injection, the BCVA improved to 20/100 and the OCT revealed scar formation. At the follow-up visits, the macula was similar to those at the first month post-injection, and the BCVA was preserved. No additional injections were needed. CONCLUSION: Intravitreal aflibercept may be a treatment alternative, which provides satisfactory anatomical and functional results and leads to a better visual acuity in cases with RR complicated by CNV. PMID- 29411260 TI - A case of conjunctival MALT lymphoma: successfully treated with solely extended rituximab therapy. AB - PURPOSE: Primary ocular adnexal lymphomas are cured by radiotherapy; however, complications are frequent and relapses may occur. In this case, we aimed to report the efficacy and safety of extended systemic rituximab (anti-CD 20 monoclonal antibody) therapy of conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: In the standard regimen, rituximab is used as four consecutive weekly infusions of 375 mg/m2 in patients with low-grade lymphomas. We treated a patient who had bilateral conjunctival MALT lymphoma with rituximab 375 mg/m2 intravenously once weekly for 10 weeks as a first-line therapy. RESULTS: During the examination of the sixth week, we observed partial response of the lesions in both eyes. At the end of the tenth cure, complete remission was achieved. No local or systemic adverse effect was observed. The patient has no signs of recurrence during the 22-months follow-up period. CONCLUSION: Extended rituximab therapy may be an effective and well-tolerated first-line treatment option for bilateral conjunctival MALT lymphoma. PMID- 29411261 TI - Amentoflavone Ameliorates Abeta1-42-Induced Memory Deficits and Oxidative Stress in Cellular and Rat Model. AB - Alzheimer's disease (AD), a progressive neurodegenerative disease of the central nervous system, is the most common cause of senile dementia. This study aimed to investigate whether amentoflavone (AF), a biflavonoid compound, could exert neuroprotective activities against AD. The AD model was established by the intracranial injection of amyloid-beta (Abeta) in rat models. The effect of AF on cognitive function was examined using the Morris water maze test. Cell survival and apoptosis in the hippocampal region in an animal model were detected using Nissl staining and a terminal deoxynucleotidyl transferased UTP nick-end labeling assay, respectively. The levels of oxidant enzymes were determined by enzyme linked immunosorbent assay. Signaling molecule expressions were examined by western blotting. Our results showed that AF significantly attenuated Abeta induced deficits in neurological functions as well as neuronal cell death and apoptosis in the hippocampal region. Moreover, our findings revealed that AF increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and translocation and activated AMP-activated protein kinase (AMPK) signaling. In a cellular model of AD established by exposing PC12 cells to Abeta, our results provided further evidence that the neuroprotective activities of AF were mediated by modulating Nrf2 through AMPK/glycogen synthase kinase 3 beta signaling. AF exerts a protective effect against Abeta1-42-induced neurotoxcicity by inducing Nrf2 antioxidant pathways via AMPK signaling activation, which provided experimental evidence that AF might provide a clinical benefit to patients with AD. PMID- 29411262 TI - Analgesic Effect of Methane Rich Saline in a Rat Model of Chronic Inflammatory Pain. AB - How oxidative stress contributes to neuro-inflammation and chronic pain is documented, and methane is reported to protect against ischemia-reperfusion injury in the nervous system via anti-inflammatory and antioxidant properties. We studied whether methane in the form of methane rich saline (MS) has analgesic effects in a monoarthritis (MA) rat model of chronic inflammatory pain. Single and repeated injections of MS (i.p.) reduced MA-induced mechanical allodynia and multiple methane treatments blocked activation of glial cells, decreased IL-1beta and TNF-alpha production and MMP-2 activity, and upregulated IL-10 expression in the spinal cord on day 10 post-MA. Furthermore, MS reduced infiltrating T cells and expression of IFN-gamma and suppressed MA-induced oxidative stress (MDA and 8 OHDG), and increased superoxide dismutase and catalase activity. Thus, MS may offer anti-inflammatory and antioxidant effects to reduce chronic inflammatory pain. PMID- 29411263 TI - Naringenin Exerts Anti-inflammatory Effects in Paraquat-Treated SH-SY5Y Cells Through a Mechanism Associated with the Nrf2/HO-1 Axis. AB - Naringenin (NGN; 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one; C15H12O5), a flavanone, is found in citrus fruits and has been viewed as an antioxidant and anti-inflammatory agent. NGN is a potent inducer of the nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulates the expression of heme oxygenase-1 (HO-1), an enzyme exhibiting both antioxidant and anti-inflammatory effects. The complete mechanism by which NGN exerts anti-inflammatory actions is not completely understood yet. Therefore, we investigated here whether NGN would be able to reduce the inflammation induced by paraquat (PQ) in SH-SY5Y cells. Additionally, we analyzed the mechanism associated with the NGN-induced anti inflammatory effect. We found that a pretreatment with NGN at 80 uM for 2 h decreased the levels of pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in PQ-treated SH-SY5Y cells. The production of nitric oxide (NO.) and levels of cyclooxygenase-2 (COX-2) and of the inducible isoform of nitric oxide synthase (iNOS) were downregulated by NGN in the cells exposed to PQ. Moreover, NGN downregulated the activation of the nuclear factor-kappaB (NF-kappaB) in PQ-treated cells. The anti-apoptotic and anti-inflammatory effects promoted by NGN were abolished by ZnPP IX (a specific inhibitor of HO-1) or by knockdown of Nrf2 by small interfering RNA (siRNA). Therefore, NGN induced anti-inflammatory effects in PQ-treated SH-SY5Y cells by a mechanism associated with the Nrf2/HO-1 signaling pathway. PMID- 29411265 TI - Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder. AB - Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable disorders with an estimated co-heritability of 68%. Hundreds of common alleles have been implicated, but recently a role for rare, high-penetrant variants has been also suggested in both disorders. This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES). IBD analysis allowed to track high-risk haplotypes (IBDrisk) shared exclusively by multiple patients from different families and possibly carrying the most penetrant alleles. A total of 444 non-synonymous sequence variants, of which 137 disruptive, were identified in IBDrisk haplotypes by WES. Interestingly, gene sets previously implicated in SCZ (i.e., post-synaptic density (PSD) proteins, voltage-gated calcium channels (VGCCs), and fragile X mental retardation protein (FMRP) targets) were found significantly enriched in genes carrying IBDrisk variants. Further, IBDrisk variants were preferentially affecting genes involved in the extracellular matrix (ECM) biology and axon guidance processes which appeared to be functionally connected in the pathway derived meta-network analysis. Results thus confirm rare risk variants as key factors in SCZ and BPD pathogenesis and highlight a role for the development of neuronal connectivity in the etiology of both disorders. PMID- 29411264 TI - Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders. AB - The Miro GTPases represent an unusual subgroup of the Ras superfamily and have recently emerged as important mediators of mitochondrial dynamics and for maintaining neuronal health. It is now well-established that these enzymes act as essential components of a Ca2+-sensitive motor complex, facilitating the transport of mitochondria along microtubules in several cell types, including dopaminergic neurons. The Miros appear to be critical for both anterograde and retrograde mitochondrial transport in axons and dendrites, both of which are considered essential for neuronal health. Furthermore, the Miros may be significantly involved in the development of several serious pathological processes, including the development of neurodegenerative and psychiatric disorders. In this review, we discuss the molecular structure and known mitochondrial functions of the Miro GTPases in humans and other organisms, in the context of neurodegenerative disease. Finally, we consider the potential human Miros hold as novel therapeutic targets for the treatment of such disease. PMID- 29411267 TI - A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies. AB - Adult T-cell leukemia-lymphoma (ATL), a rare and aggressive T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1), is associated with a poor prognosis. Evidence-based standard treatment options are lacking and outcomes are generally unsatisfactory, particularly for patients with relapsed or refractory disease. Continued research is contributing to changing treatment landscape as a number of existing and investigational agents are evaluated. We describe the epidemiology of HTLV-1 and ATL, discuss the biology behind the disease, review current treatment practices and guidelines, and provide an overview of emerging therapies in ATL, with a focus on those for relapsed or refractory disease. PMID- 29411269 TI - Single-Dose Comparative Pharmacokinetics of Two Formulations of Lenalidomide 25 mg in Healthy Subjects: A Randomized Crossover Study. AB - BACKGROUND: Lenalidomide is used for the treatment of multiple myeloma in combination with dexamethasone. The purpose of this study was to compare the pharmacokinetics (PKs) and assess the bioequivalence of two formulations of lenalidomide 25 mg: Lenalid(r) 25 mg tablet (test formulation) and Revlimid(r) 25 mg capsule (reference formulation). METHODS: A randomized, single-dose, two treatment, two-period, two-sequence crossover study was conducted in 42 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for PK evaluation were collected up to 24 h post-dose and the PK parameters were estimated by non-compartmental methods. Throughout the study, tolerability was assessed on the basis of adverse events, vital signs, and clinical laboratory tests. RESULTS: The test formulation showed similar PK profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (Cmax) was 0.9995 (0.9250-1.0799) and the corresponding value for the area under the concentration-time curve from time zero to time of last quantifiable concentration (AUCt) was 0.9648 (0.9451 0.9850). Both CIs were within the conventional bioequivalence range of 0.8-1.25. The tolerability profile was not significantly different between the two formulations. CONCLUSION: This study found that the PKs of the two formulations of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation. FUNDING: Samyang Biopharmaceutical Corp. PMID- 29411266 TI - A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. AB - Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID. PMID- 29411268 TI - A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis. AB - INTRODUCTION: Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. METHODS: This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. RESULTS: All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0-t, AUC0-infinity, and Cmax were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. CONCLUSION: Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water). FUNDING: Horizon Pharma, Inc. PMID- 29411270 TI - Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design. AB - INTRODUCTION: Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH. METHODS: VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management. RESULTS: As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording ( http://laiyivens.365hy.com ) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment. CONCLUSION: VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China. TRIAL REGISTRATION: This study registered at https://clinicaltrials.gov (registration number: NCT02962297). FUNDING: Zhejiang Medicine Co., Ltd. PMID- 29411272 TI - Public support for pictorial warnings on cigarette packs: an experimental study of US smokers. AB - BACKGROUND: Understanding factors that influence public support for "nudging" policies, like pictorial cigarette pack warnings, may offer insight about how to increase such support. We sought to examine factors that influence smokers' support for requiring pictorial warnings on cigarette packs. METHODS: In 2014 and 2015, we randomly assigned 2149 adult US smokers to receive either pictorial warnings or text-only warnings on their cigarette packs for 4 weeks. The outcome examined in the current study was support for a policy requiring pictorial warnings on cigarette packs in the US. RESULTS: Support for pictorial warnings was high at baseline (mean: 3.2 out of 4). Exposure to pictorial warnings increased policy support at week 4 (beta = .05, p = .03). This effect was explained by increases in perceived message effectiveness (p < .001) and reported conversations about policy support (p < .001). Message reactance (i.e., an oppositional reaction to the warning) partially diminished the impact of pictorial warnings on policy support (p < .001). CONCLUSIONS: Exposing people to a new policy through implementation could increase public support for that policy by increasing perceived effectiveness and by prompting conversations about the policy. Reactance may partially weaken the effect of policy exposure on public support. PMID- 29411271 TI - Molecular characterization of hepatitis B virus X gene in HIV-positive South Africans. AB - Hepatitis B virus (HBV) infection is a major public health problem worldwide and the major cause of hepatocellular carcinoma (HCC) in South Africa. The role of HBV in HCC is not well understood, although the HBV X gene has been implicated as a critical factor. Data on the HBV X gene in HIV-positive South Africans are limited; thus, we investigated X gene variability in 24 HIV-infected treatment naive patients at Dr George Mukhari Academic Hospital. Quantitative and qualitative HBV DNA tests were conducted using real-time and in-house polymerase chain reaction (PCR) assays, respectively, targeting the complete HBV X gene. In house PCR-positive samples were cloned using the P-Gem T-easy vector System II and sequenced. By phylogenetic analysis, X gene sequences were classified as subgenotype A1 (n = 15), A2 (n = 4), and D1 (n = 4), and one dual infection with subgenotypes as A1 and C. The basal core promoter mutations T1753C, A1762T, and G1764A were identified in the majority of sequences. Genotype D sequences had a 6 nucleotide insertion. In conclusion, subgenotype A1 was predominant, and a rare dual infection of HBV genotype A and C was detected. The 6-nucleotide insertion could represent a unique variant in the region and highlights the need for functional studies of HBV X gene variants, particularly from resource-limited settings. PMID- 29411274 TI - Introduction to the Special Issue: Invited Papers from the 2017 APAHC Conference. AB - The 8th biennial national conference of the Association of Psychologists in Academic Health Centers (APAHC) was held in Detroit, MI, March 9-11, 2017. All speakers were invited to contribute manuscripts based on their conference presentations to this special issue of the Journal of Clinical Psychology in Medical Settings, and five presenters did so. All manuscripts were peer reviewed by experts in the field. The Conference Co-Chairs, Drs. Amy M. Williams and John A. Yozwiak, serve as Guest Editors for the special issue with Associate Editorial support from Dr. Elizabeth D. Cash. This article provides a brief overview of the rationale for the choice of the conference theme and the speakers, and a brief introduction to the articles in this special issue. PMID- 29411273 TI - Co-occurring psychosocial problems predict HIV status and increased health care costs and utilization among sexual minority men. AB - Sexual orientation related health disparities are well documented. Sexual minority men appear to be at risk for mental health problems due to the stress they experience in establishing and maintaining a minority sexual identity. These mental health issues may combine synergistically and lead to higher medical costs to society. We examine whether sexual minority specific syndemic indicators were associated with higher health care costs, health care utilization, or the risk of being HIV-infected. Health care consumers at a community health center (N = 1211) completed a brief screening questionnaire collected over 12 months. Self-reported data were linked with participants' clinical billing records. Adjusted logistic regression models identified that four syndemic indicators (suicidality, substance use, childhood sexual abuse, and intimate partner violence) were each significantly related to each other. Multiple syndemics significantly predicted higher medical care utilization and cost, and were associated with 2.5 times the risk of being HIV-infected (OR 2.49, 95% CI 1.45-4.25). Syndemic indicators did not significantly predict the number of mental health visits or costs per patient. These results confirm and extend earlier findings by relating syndemics to health services use and costs for sexual minority men. PMID- 29411275 TI - Impact of long-term fertilization practices on the soil aggregation and humic substances under double-cropped rice fields. AB - Soil organic matter (SOM) content and soil aggregation are essential components of soil structure, which plays an important role in soil quality and fertility. Also, the SOM content, aggregation, and humus substances in paddy field were affected by application of fertilization practices. However, there is still limited information about the effects of long-term different fertilization practices on soil aggregation and carbon content in the humic acid (C-HAF), fulvic acid (C-FAF), and humin (C-HUM) fractions under double-cropping rice (Oryza sativa L.) system in Southern China paddy fields. Therefore, the effects of long-term fertilizer application on soil aggregation and C-HUM, C-HAF, and C FAF contents in 0-5-, 5-10-, and 10-20-cm soil depth under double-cropped rice fields in Southern China were investigated. The experiment located at NingXiang County in Hunan Province, China begins in 1986 and the experiment includes five treatments: without fertilizer input (CK), mineral fertilizer alone (MF), rice straw residues and mineral fertilizer (RF), 30% organic matter and 70% mineral fertilizer (LOM), and 60% organic matter and 40% mineral fertilizer (HOM). The results showed that the soil total organic carbon content in paddy soils with RF, LOM, and HOM treatments was significant higher (P < 0.05) than that of the CK treatment at early and late rice maturity stages. The different sizes of soil aggregates with different fertilization treatments were decreased as HOM > LOM > RF > MF > CK. The HOM treatment had the highest percentage of soil aggregates in each size class and the CK treatment had the lowest percentage of soil aggregates in each size class in 0-5-, 5-10-, and 10-20-cm soil depth at early and late rice maturity stages. The soil C-HAF, C-FAF, and C-HUM contents were increased by long term combined application of manure with mineral fertilizer practices. Meanwhile, the results indicated that the soil C-HAF, C-FAF, and C-HUM contents with RF, LOM, and HOM treatments were significantly higher (P < 0.05) than that of the CK treatment at early and late rice maturity stages. As a result, the soil total organic carbon content, each size class of soil aggregates, and soil C-HAF, C FAF, and C-HUM contents were increased by long-term combined application of manure with mineral fertilizer in double-cropped rice fields. PMID- 29411276 TI - An efficient and reusable quaternary ammonium fabric adsorbent prepared by radiation grafting for removal of Cr(VI) from wastewater. AB - A novel quaternary ammonium polyethylene nonwoven fabric for removing chromium ions from water was prepared via radiation-induced grafting of glycidyl methacrylate and further modification with N,N'-dimethylethylenediamine. The structural and morphological characteristics of the adsorbent were analyzed using Fourier transform infrared spectroscopy (FTIR), thermogravimetry and differential thermogravimetry (TG/DTG), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The influences of several principal factors, including pH value, initial Cr(VI) concentration, contact time, and coexisting anions (including SO42-, CO32-, NO3-, PO43-, and Cl-), on adsorption performance were investigated via batch tests. The results showed that the optimum removal efficiency was 99.2% at pH 3 and the maximum adsorption quantity for Cr(VI) at 25 degrees C was 336 mg/g. The adsorption kinetic parameters were better fitted with the pseudo-second-order kinetic model, and the equilibrium data were described very well by the Freundlich isotherm model. Furthermore, the as synthesized adsorbent exhibited excellent regeneration and recyclability while maintaining high adsorption performance after five adsorption/desorption cycles. PMID- 29411277 TI - Impacts of earthworm activity on the fate of straw carbon in soil: a microcosm experiment. AB - Earthworms not only facilitate carbon (C) stabilization, but also accelerate organic matter mineralization by enhancing microbial respiration. However, the fate (mineralization vs stabilization) of newly added C by straw returning in arable lands with earthworm activity is still unclear. In the present 40 days incubation study, we incorporated artificially 13C-labeled straw into soil with and without presence of earthworms (Metaphire guillelmi). Flux measurements of CO2 from soil (mineralization) were taken regularly, while straw-derived C remaining in the soil (stabilization) was measured at the end of the incubation. There was no significant difference of the cumulative CO2 emission between earthworm presence and absence treatment. However, earthworm presence significantly decreased straw-derived cumulative CO2-C emission when compared with the treatment without earthworm. Besides, earthworm incubation led to a significantly low light fraction organic carbon (LFOC) content and straw-derived LFOC proportion. Relative to the non-earthworm treatment, straw-derived C content significantly decreased in micro-aggregates (< 0.25 mm), but increased in large macro-aggregates (> 2 mm) in the earthworm treatment. In total, only 3.8% of added straw C was assimilated by earthworm within 40 days, while most of the straw C remained in the soil. Earthworms decreased straw-derived CO2-C emission from 10.0 to 8.1% when compared with the non-earthworm treatment. In the present short period incubation experiment, compared with the soil without earthworms, the presence of Metaphire guillelmi (1) resulted a higher soil CO2 emissions, which may mainly evolved from the older SOC, and (2) stabilized more residue derived C in the soil aggregates. We therefore propose that Metaphire guillelmi may increase soil organic carbon pool turnover rates in the short term after straw returning by replacement of older SOC with newly added straw C. PMID- 29411278 TI - Occurrence, source, and ecological risk of antibiotics in Dongting Lake, China. AB - The pollution characteristics and ecological risk of 12 classified as sulfonamide, trimethoprim, quinolone, and tetracycline antibiotics in Dongting Lake, China, were studied. The total concentrations of the antibiotics ranged from 1.06 to 135.40 ng L-1 for all sampling sites. The highest average concentration was observed for sulfadiazine, followed by sulfamethoxazole. The detection frequencies (over 60%) of sulfonamides were higher than those of other antibiotics. The direct discharge of the aquaculture, livestock, and poultry wastewater might be the main pollution sources of antibiotics in the Dongting Lake. The pollution levels of antibiotics decreased in the order of East Dongting Lake > South Dongting Lake > West Dongting Lake, which may be related to the distribution and the scale of the aquaculture, livestock, and poultry sources. The seasonal changes of antibiotic concentration were relatively diversified, with the dry season generally having higher concentrations than the wet season. The results of the ecological risk assessment indicated that sulfamethoxazole, ciprofloxacin, and sarafloxacin might pose a significant risk to the aquatic organisms in Dongting Lake, especially in Potou and Nandu. This study enriches the research of emerging pollutants in freshwater lake. Graphical abstract. PMID- 29411279 TI - The recent development of advanced wastewater treatment by ozone and biological aerated filter. AB - The combination of ozone and biological aerated filter (O3/BAF) has been widely studied and applied in polishing different biological secondary effluents. O3/BAF has the advantages of high pollutants removal rate, low operating cost, and flexible combination types. The principle and combination, effect of ozone dosage and influent suspended solids (SS) on O3/BAF, applications, current research focuses, and development are discussed. The ozone can break refractory macromolecules into small and biodegradable fragments, increasing the biodegradation. It benefits the operation of BAF. The coupling of ozonation and BAF is efficient in the removal of refractory organic pollutants from different wastewaters. Ozonation can also be used as the post-treatment option after BAF to guarantee the effluent qualities. Normally, the ozone dosage varied from 5 to 125 mg/L with the contact time of 4 to 60 min, while the hydraulic retention time (HRT) of BAF is usually between 2 to 5 h when treating different biological effluents. The effluent COD is normally lower than 50 mg/L. Most of the organic micropollutants (OMPs) in the biological effluent, such as antibiotics, pharmaceuticals, personal care products, steroid hormones, and industrial chemicals, can be efficiently removed by O3/BAF. More importantly, the O3/BAF can obviously reduce the toxicity of the wastewater. The residual ozone of about 0.2 mg/L in the ozonation effluent benefits the performance of BAF. The future trends of O3/BAF are also discussed in the paper. PMID- 29411280 TI - The occurrence of selected xenobiotics in the Danube river via LC-MS/MS. AB - Having in mind that there is a general lack of monitoring plans and precaution measures in the developing countries and that the Danube is the second longest river in Europe, the estimation of the relevant concentration levels of unregulated xenobiotics is a topic of interest both on local and international level. The selected pharmaceuticals, caffeine, and benzotriazole presented in the collected water samples from seven representative locations around the territory of Novi Sad, Serbia, during 1-year period, were analyzed with the use of solid phase extraction followed by the liquid chromatography coupled with triple quad tandem mass spectrometry. The most frequently detected compounds were caffeine and carbamazepine in the concentrations up to 621 and 22.2 ng/L, respectively, while the maximum concentration of the analyzed pharmaceuticals was obtained for ibuprofen (60.1 ng/L). The presence of benzotriazole along the analyzed section of the river was confirmed in the concentration levels up to 26.7 ng/L. Although sulfamethoxazole and desmethyldiazepam were detected at trace levels (0.22 and 3.41 ng/L, respectively); the presence of these pharmaceuticals in complex mixtures should not be neglected. Due to the frequent detection caffeine, carbamazepine, ibuprofen, and benzotriazole could be proper candidate for hydrophilic anthropogenic markers for quantification of wastewater contamination in surface water in the analyzed Danube section. PMID- 29411281 TI - Using laboratory-generated biosolids to evaluate the microbial ecotoxicity of triclosan in a simulated land application scenario. AB - Land application accounts for approximately 50% of wastewater solids disposal in the USA. Yet, little is known regarding the ecological impacts of many non regulated chemicals found in biosolids. In most previous studies aimed at assessing ecological impacts, a model biosolid is generated by spiking high concentrations of the target chemical into a soil or biosolid. This approach does not account for the interaction of the chemical of interest with the solids throughout the biosolids production process (a.k.a., aging) which may impact the bioavailability and, thus, ultimate toxicity of the chemical. In the present study, using a lab-scale wastewater and digestion treatment system, we generated biosolids which contained aged triclosan and compared ecological impacts to that of spiked biosolids. Ecotoxicity was assessed based on functional and community structure changes to soil denitrifiers, microorganisms critical to nitrogen cycling. A decrease in denitrifier abundance and diversity was observed in the aged biosolids at concentrations of 17.9 +/- 1.93 MUg/kg while decreases in activity were observed at 26.9 +/- 4.6 MUg/kg. In the spiked biosolids treatment, lower denitrifier abundance, diversity, and activity were observed at triclosan (TCS) concentrations of 68.6 +/- 26.9 MUg/kg. This difference suggests a need to better understand TCS bioavailability dynamics. PMID- 29411282 TI - Microwave-assisted extraction and dyeing of chemical and bio-mordanted cotton fabric using harmal seeds as a source of natural dye. AB - The revival of cultural heritage in a form of natural colorants for textile dyeing is gaining popularity due to their soothing nature and bright shades. The present study was conducted to explore the coloring potential of harmala (Peganum harmala) seeds and to improve color strength of dye using microwave radiations followed by a mordanting process. The results showed that harmala plant seeds could be an excellent source of natural dyes for cotton dyeing if the irradiated acidified methanolic extract (RE, 4 min) is used to dye un-irradiated fabric (NRC) at 85 degrees C for 45 min using a dye bath of pH 9.0 having salt concentration of 7 g/100 mL. Alum (1%) as pre-mordants and iron (7%) as post mordants have improved the color strength in chemical mordanting more than other mordants employed. The bio-mordants employed reveal that 10% of acacia as pre-bio mordants and 7% of acacia as post-bio-mordants are effective amounts to obtain high color strength. Suggested ISO standards for colorfastness illustrate that bio-mordanting has given more excellent rating as compared to chemical mordants. It is concluded that harmala seeds have a great potential to act as a source of natural colorant for cotton dyeing under the influence of microwave radiation. PMID- 29411283 TI - Levels and distribution of cobalt and nickel in the aquatic macrophytes found in Skadar Lake, Montenegro. AB - Macrophytes react to changes in the quality of the environment in which they live (water/sediment), and they are good bioindicators of surface water conditions. In the present study, the content of the metals cobalt (Co) and nickel (Ni) was determined in the sediment, the water, and different organs of macrophytes from six localities around Lake Skadar, across four different seasons of year. The aquatic macrophytes that have been used as bioindicator species in this study are Phragmites australis (an emerged species), Ceratophyllum demersum (a submerged species), and Lemna minor (a floating species). The aim of this study was to determine the distribution of metals in macrophyte tissues and also to discover the degree of bioaccumulation of the investigated metals, depending both on the location and on the season. The content of Co and Ni in the examined parts of the macrophytes was in the range of 0.04-8.78 and 0.30-28.5 ppm, respectively. The greatest content of the investigated metal in the organs of P. australis and C. demersum was recorded at the beginning of and during the growing season. Greater concentrations of metals in the tissue of L. minor were observed at the end of the growing season. PMID- 29411284 TI - Identification of functional groups of Opuntia ficus-indica involved in coagulation process after its active part extraction. AB - Opuntia ficus-indica that belongs to the Cactaceae family and is a member of Opuntia kind has received increasing research interest for wastewater treatment by flocculation. The objectives of this study were (i) to provide more information regarding the active constituents of Opuntia spp. and (ii) to improve the extracting and using conditions of the flocculant molecules for water treatment. A classic approach by jar test experiments was used with raw and extracted material by solubilization and precipitation. The surface properties of solid material were characterized by FTIR, SEM, zeta potential measurement, and surface titration. The splitting based on the solubility of the material with pH and the titration of functional groups completed the method. The optimal pH value for a coagulation-flocculation process using cactus solid material (CSM) was 10.0 and a processing rate of 35 mg L-1. The alkaline pH of flocculation suggests an adsorption mechanism with bridging effect between particles by water-soluble extracted molecules. To validate this mechanism, an extraction water was carried out at pH = 10 (optimum of flocculation) and the solution was acidified (pH = 7) to allow precipitation of so considered active flocculant molecules. The strong flocculant property of this extract was verified, and titration of this solution showed at least one specific pKa of 9.0 +/- 0.6. This pKa corresponds to phenol groups, which could be assigned to lignin and tannin. PMID- 29411285 TI - Numerical simulation of the intra-annual evolution of beryllium-7 (7Ve) in the surface layer of the Black Sea. AB - A numerical model simulating the distribution of 7Ve in the Black Sea was developed and applied to study the spatial and temporal variations in the content of 7Be in the surface waters. Variations in the distribution of 7Ve were analyzed for the period from January to December of 2012. The average seasonal content of 7Ve in the surface layer ranges from 2.2 to 6.2 Bq m-3. The maximum concentration is typical for the eastern part of the sea in winter to spring, and the minimum concentration is typical for the central and western parts of the sea in summer. The seasonally averaged activity of 7Ve on suspended matter ranges from 440 to 1560 Bq kg-1. The highest values are observed in the sea in winter to spring, and the lowest values are typically observed in the central and western parts of the sea in summer. It was revealed that the adsorption of 7Ve on suspended matter is most significant for the evolution of the content of this radionuclide in shelf waters. PMID- 29411286 TI - Athletes with channelopathy may be eligible to play. AB - The European and Bethesda recommendations roughly state that any athlete with channelopathy is not eligible to participate in sports on a presumed risk of potentially life-threatening ventricular tachycardia or fibrillation. However, eligibility decision-making on a presumed risk of ventricular tachycardia or fibrillation is debatable. Channelopathies are primary electrical cardiac disorders and are usually transmitted as an autosomal dominant trait. Some of the channelopathies are potentially fatal in relation to exercise and predispose to life-threatening cardiac arrhythmias including ventricular tachycardia or fibrillation. Exercise, swimming, body heating and electrolyte depletion can all act as a trigger of ventricular tachycardia or fibrillation in channelopathy. However, new research mentioned a very low incidence of ventricular tachycardia or fibrillation in athletes with channelopathy challenging the decision of disqualification. Recently, the American recommendations for sports participation in athletes with a cardiovascular disorder have updated their eligibility decision-making.In this manuscript we describe the signature features of the electrocardiogram changes in channelopathies and we argue that new research data should allow for the introduction of more liberal eligibility decision-making for sports participation in athletes with channelopathy, not only in the United States but also in European countries. PMID- 29411287 TI - Mechanisms of atrial fibrillation in athletes: what we know and what we do not know. AB - Exercise is an emerging cause of atrial fibrillation (AF) in young individuals without coexisting cardiovascular risk factors. The causes of exercise-induced atrial fibrillation remain largely unknown, and conclusions are jeopardised by apparently conflicting data. Some components of the athlete's heart are known to be arrhythmogenic in other settings. Bradycardia, atrial dilatation and, possibly, atrial premature beats are therefore biologically plausible contributors to exercise-induced AF. Challenging findings in an animal model suggest that exercise might also prompt the development of atrial fibrosis, possibly due to cumulative minor structural damage after each exercise bout. However, there is very limited, indirect data supporting this hypothesis in athletes. Age, sex, the presence of comorbidities and cardiovascular risk factors, and genetic individual variability might serve to flag those athletes who are at the higher risk of exercise-induced AF. In this review, we will critically address current knowledge on the mechanisms of exercise-induced AF. PMID- 29411288 TI - Are there increased periprocedural complications with the MRI-conditional Medtronic Revo SureScan Pacing System? : A meta-analysis. AB - BACKGROUND: The use of magnetic resonance imaging (MRI)-conditional permanent pacemakers has increased significantly. In this meta-analysis, we examine the safety of MRI-conditional pacing systems in comparison with conventional systems. METHODS: An electronic search was performed using major databases, including studies that compared the outcomes of interest between patients receiving MRI conditional pacemakers (MRI group) versus conventional pacemakers (control group). RESULTS: Six studies (5 retrospective and 1 prospective non-randomised) involving 2,118 adult patients were identified. The MRI-conditional pacemakers, deployed in 969 patients, were all from a single manufacturer (Medtronic Pacing System with 5086 leads). The rate of pacemaker lead dislodgement (atrial and ventricular) was significantly higher in the MRI group (3% vs. 1%, OR 2.47 (95% CI 1.26; 4.83), p = 0.008). The MRI group had a significantly higher rate of pericardial complications (2% vs. 1%, OR 4.23 (95% CI 1.18; 15.10), p = 0.03) and a numerically higher overall complication rate in comparison with the conventional group (6% vs. 3%, OR 2.02 (95% CI 0.88; 4.66), p = 0.10) but this was not statistically significant. CONCLUSIONS: In this meta-analysis, the rates of pacemaker lead dislodgement and pericardial complications were significantly higher with the Medtronic MRI-conditional pacing system. PMID- 29411289 TI - Sudden cardiac arrest on the field of play: turning tragedy into a survivable event. AB - Sudden cardiac arrest remains the leading cause of death in exercising athletes, and recent studies have shown that it occurs more frequently than historical estimates. While out-of-hospital cardiac arrest often proves fatal, advance preparation can improve outcomes and the chance of survival. First responders to a collapsed athlete on the field of play may include team medical personnel, coaches, other athletes, officials, venue staff, emergency medical services personnel, or lay bystanders. Prompt and accurate recognition of sudden cardiac arrest, a comprehensive and rehearsed emergency action plan, early cardiopulmonary resuscitation, and immediate access to and use of an automated external defibrillator are each pivotal links in the chain of survival. This review summarises the components of an effective emergency action plan, highlights the critical role of automated external defibrillators, and reviews the diagnosis and management of sudden cardiac arrest on the field of play. PMID- 29411290 TI - Experimental Evidence that In Vivo Intracerebral Administration of L-2 Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain. AB - Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2',7'-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients. PMID- 29411292 TI - Cost-Effectiveness Analysis of Canagliflozin 300 mg Versus Dapagliflozin 10 mg Added to Metformin in Patients with Type 2 Diabetes in the United States. AB - INTRODUCTION: Agents that inhibit sodium glucose co-transporter 2 (SGLT2), including canagliflozin and dapagliflozin, are approved in the United States for the treatment of adults with type 2 diabetes mellitus (T2DM). SGLT2 inhibition lowers blood glucose by increasing urinary glucose excretion, which leads to a mild osmotic diuresis and a net loss of calories that are associated with reductions in body weight and blood pressure. This analysis evaluated the cost effectiveness of canagliflozin 300 mg versus dapagliflozin 10 mg in patients with T2DM inadequately controlled with metformin in the United States. METHODS: A 30 year cost-effectiveness analysis was performed using the validated Economic and Health Outcomes Model of T2DM (ECHO-T2DM) from the perspective of the third-party health care system in the United States. Patient demographics, biomarker values, and treatment effects for the ECHO-T2DM model were sourced primarily from a network meta-analysis (NMA) that included studies of canagliflozin and dapagliflozin in patients with T2DM on background metformin. Costs were derived from sources specific to the United States. Outcomes and costs were discounted at 3%. Sensitivity analyses that varied key model parameters were conducted. RESULTS: Canagliflozin 300 mg dominated dapagliflozin 10 mg as an add-on to metformin over 30 years, with an estimated cost offset of $13,991 and a quality adjusted life-year gain of 0.08 versus dapagliflozin 10 mg. Results were driven by the better HbA1c lowering achieved with canagliflozin, which translated to less need for insulin rescue therapy. Findings from sensitivity analyses were consistent with the base case. CONCLUSION: These results suggest that canagliflozin 300 mg is likely to provide better health outcomes at a lower overall cost than dapagliflozin 10 mg in patients with T2DM inadequately controlled with metformin from the perspective of the United States health care system. FUNDING: Janssen Scientific Affairs, LLC and Janssen Global Services, LLC. PMID- 29411293 TI - Port insertion for minimally invasive surgery: a report of practices in the Irish Republic. AB - BACKGROUND: With rapidly evolving surgical technologies, minimally invasive surgery (MIS) has become the mainstay approach for many surgeons worldwide. As laparoscopic surgery was introduced in Ireland over two decades ago, we may be encountering a higher prevalence of related complications. AIMS: This study aimed to gather data pertaining to risk factors for port-site herniation in MIS. METHODS: A 14-point anonymous questionnaire was distributed electronically between January and May 2017 to consultant and trainee laparoscopists in the Republic of Ireland. This survey related to laparoscopic volume and surgical approaches to laparoscopic port-sites. RESULTS: There were 172 eligible responses nationally. Approaches to peritoneal access included Hasson, veress (blind puncture) and SILS were 66.3, 32.6 and 1.2%, respectively. Senior surgeons and specialists in Obstetrics and Gynaecology (OBGYN) reported significantly higher utilisations of closed peritoneal access (p < 0.05). Of the participants, 119 (69.2%) reported using a bladeless trocar over a bladed type. Fascial closure was utilised in 94.2% of >= 10 mm and 2.3% of 5-mm ports using absorbable suture in 76.7%, non-absorbable suture in 14.5% and port closure devices in 8.7%. Perceptions of risk factors for PSH were not congruent with significant variations in responses between levels of expertise. CONCLUSIONS: This study demonstrates significant variations in laparoscopic port-site practices amongst surgeons nationally. The new era of practitioners may benefit from evidence-based technical workshops and guidelines to increase awareness and reduce potential complications. PMID- 29411291 TI - Post-Liver Transplantation Diabetes Mellitus: A Review of Relevance and Approach to Treatment. AB - Post-liver transplantation diabetes mellitus (PLTDM) develops in up to 30% of liver transplant recipients and is associated with increased risk of mortality and multiple morbid outcomes. PLTDM is a multicausal disorder, but the main risk factor is the use of immunosuppressive agents of the calcineurin inhibitor (CNI) family (tacrolimus and cyclosporine). Additional factors, such as pre-transplant overweight, nonalcoholic steatohepatitis and hepatitis C virus infection, may further increase risk of developing PLTDM. A diagnosis of PLTDM should be established only after doses of CNI and steroids are stable and the post operative stress has been overcome. The predominant defect induced by CNI is insulin secretory dysfunction. Plasma glucose control must start immediately after the transplant procedure in order to improve long-term results for both patient and transplant. Among the better known antidiabetics, metformin and DPP-4 inhibitors have a particularly benign profile in the PLTDM context and are the preferred oral agents for long-term management. Insulin therapy is also an effective approach that addresses the prevailing pathophysiological defect of the disorder. There is still insufficient evidence about the impact of newer families of antidiabetics (GLP-1 agonists, SGLT-2 inhibitors) on PLTDM. In this review, we summarize current knowledge on the epidemiology, pathogenesis, course of disease and medical management of PLTDM. PMID- 29411294 TI - Timed colonoscopy withdrawal, a mandatory quality measure in the era of national screening? AB - BACKGROUND: A minimum recommended withdrawal time for screening colonoscopy is recommended for by both the US Multi-Society Task Force on Colorectal Cancer and European Society of Gastrointestinal Endoscopy. AIM: To characterize the relationship between endoscopists withdrawal time at colonoscopy and polyp detection in a symptomatic cohort of patients as compared to previously untimed withdrawal. METHODS: Three experienced medical endoscopists prospectively performed 1079 colonoscopies during a 24-month period in an Irish hospital. Mean withdrawal time and individual polyp detection rate were noted. RESULTS: Introduction of mandatory withdrawal time which was monitored and documented was associated with higher polyp detection rate (33 versus 21%, p < 0.005) as compared to previously untimed withdrawal. CONCLUSION: Our findings support a monitored colonoscopy withdrawal time of at least 6 min, which correlates with higher colon polyp detection rates in a symptomatic cohort. PMID- 29411296 TI - Compliance with National Ethics Requirements for Human-Subject Research in Non biomedical Sciences in Brazil: A Changing Culture? AB - Ethics regulation for human-subject research (HSR) has been established for about 20 years in Brazil. However, compliance with this regulation is controversial for non-biomedical sciences, particularly for human and social sciences (HSS), the source of a recent debate at the National Commission for Research Ethics. We hypothesized that for these fields, formal requirements for compliance with HSR regulation in graduate programs, responsible for the greatest share of Brazilian science, would be small in number. We analyzed institutional documents (collected from June 2014 to May 2015) from 171 graduate programs at six prestigious Brazilian universities in Sao Paulo and Rio de Janeiro, the states that fund most of the science conducted in Brazil. Among these programs, 149 were in HSS. The results suggest that non-compliance with standard regulation seems to be the rule in most of these programs. The data may reflect not only a resistance from scientists in these fields to comply with standard regulations for ethics in HSR but also a disciplinary tradition that seems prevalent when it comes to research ethics in HSR. However, recent encounters between Brazilian biomedical and non biomedical scientists for debates over ethics in HSR point to a changing culture in the approach to research ethics in the country. PMID- 29411295 TI - In vitro and ex vivo characterisation of an in situ gelling formulation for sustained lidocaine release with potential use following knee arthroplasty. AB - Sustained lidocaine release via a thermoresponsive poloxamer-based in situ gelling system has the potential to alleviate pain following knee arthroplasty. A previously developed formulation showed a promising drug release profile in synthetic phosphate-buffered saline (PBS). To support the translation of this formulation, ex vivo characterisation was warranted. This study therefore aimed (1) to modify the previously developed formulation to reduce the burst release, (2) to compare the release behaviour into ex vivo human intra-articular fluid (IAF) and PBS and (3) to determine the formulation spread in an ex vivo human knee using magnetic resonance imaging (MRI). All formulations provided sustained release out to 72 h; polyvinyl pyrrolidone was the most effective additive yielding a small yet significant decrease (p < 0.05) in the burst release. Release of lidocaine from the formulation occurred significantly faster into IAF compared to PBS (1.4 times greater release in the first 24 h), correlating with faster rates of gel erosion in IAF. Injection was easily achieved through a 21 gauge (G) needle into the synovial space of a human cadaveric knee, and MRI scans revealed effective spreading of the formulation throughout the joint cavity. The pattern of spread is promising for the drug to reach the widespread nerve endings in the joint capsule; the effect of this spread on release in an in vivo setting will be the subject of future studies. The demonstrated properties indicate that the in situ gelling formulation has the potential to be used clinically to treat post-operative pain following knee arthroplasty. PMID- 29411298 TI - Mentoring: Giving Forward While Giving Back. PMID- 29411297 TI - Trypanosoma brucei Plimmer & Bradford, 1899 is a synonym of T. evansi (Steel, 1885) according to current knowledge and by application of nomenclature rules. AB - Proper application of the principles of biological nomenclature is fundamental for scientific and technical communication about organisms. As other scientific disciplines, taxonomy inherently is open to change, thus species names cannot be final and immutable. Nevertheless, altering the names of organisms of high economical, medical, or veterinary importance can become a complex challenge between the scientific need to have correct classifications, and the practical ideal of having fixed classifications. Trypanosoma evansi (Steel, 1885), T. brucei Plimmer & Bradford, 1899 and T. equiperdum Doflein, 1901 are important parasites of mammals. According to current knowledge, the three names are synonyms of a single trypanosome species, the valid name of which should be T. evansi by the mandatory application of the Principle of Priority of zoological nomenclature. Subspecies known as T. brucei brucei Plimmer & Bradford, 1899, T. b. gambiense Dutton, 1902 and T. b. rhodesiense Stephens & Fantham, 1910 should be referred to respectively as T. evansi evansi (Steel, 1885), T. e. gambiense and T. e. rhodesiense. The polyphyletic groupings so far known as T. evansi and T. equiperdum should be referred respectively to as surra- and dourine-causing strains of T. e. evansi. Likewise, trypanosomes so far known as T. b. brucei should be referred to as nagana-causing strains of T. e. evansi. Though it modifies the scientific names of flagship human and animal parasites, the amended nomenclature proposed herein should be adopted because it reflects phylogenetic and biological advancements, fixes errors, and is simpler than the existing classificatory system. PMID- 29411299 TI - A rare CALR variant mutation and a review of CALR in essential thrombocythemia. AB - Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm characterized by megakaryocyte hyperplasia, thrombocytosis, thrombotic and hemorrhagic complications, and potential transformation into myelofibrosis and acute myeloid leukemia. The vast majority of cases are driven by a somatic mutation in JAK2, CALR, or MPL. CALR, a gene that codes for the calcium-binding chaperone calreticulin, is the predominant mutation in patients with non-mutated JAK2 essential thrombocythemia, accounting for 20-25% of the overall somatic mutation frequency in ET. In this brief review of ET, we introduce a rare CALR mutation through a case presentation of a 58-year-old man with diffuse pulmonary emboli in the setting of thrombocytosis. We subsequently characterize the main types of CALR mutations and their value in diagnosis and prognosis of disease course, and lastly discuss the current clinical approach to ET. PMID- 29411300 TI - The sound of air: point-of-care lung ultrasound in perioperative medicine. AB - PURPOSE: Lung ultrasound (LUS) has emerged as an effective and accurate goal directed diagnostic tool that can be applied in real time for the bedside assessment of patients with respiratory symptoms and signs. Lung ultrasound has definite and easily recognized findings and has been shown to outperform physical examination and chest radiography for the diagnosis and monitoring of many pulmonary and pleural conditions. In this article, we review the principles of LUS image acquisition and interpretation, summarizing key terms and sonographic findings. PRINCIPAL FINDINGS: Although LUS is easy to learn, adequate training and performance in an organized fashion are crucial to its clinical effectiveness and to prevent harm. Therefore, we review normal LUS findings and propose step wise approaches to the most common LUS diagnoses, such as pneumothorax, pleural effusion, interstitial syndrome, and lung consolidation. We highlight potential pitfalls to avoid and review a recently published practical algorithm for LUS use in clinical practice. CONCLUSIONS: Because of the unique physical properties of the lungs, only a careful and systematic analysis of both artifacts and anatomical images allows accurate interpretation of sonographic findings. Future studies exploring the use of software for automatic interpretation, quantitative methods for the assessment of interstitial syndrome, and continuous monitoring devices may further simplify and expand the use of this technique at the bedside in acute medicine and the perioperative setting. PMID- 29411303 TI - Combination of Intra-Hematomal Hypodensity on CT and BRAIN Scoring Improves Prediction of Hemorrhage Expansion in ICH. AB - BACKGROUND: Hematoma expansion (HE) occurs in 1/3 of ICH patients and is associated with poor outcome. Intra-hematomal hypodensity (IHH) on CT has been reported to predict HE, as has the "BRAIN" score. We sought to assess the predictive value of these markers alone and in combination. METHODS: We performed a retrospective single-center study of ICH patients with CT < 6 h from onset. Two blinded neurologists assessed IHH on initial CT. Two HE definitions were examined: > 6 ml and > 6 ml or > 33%. Multivariable logistic regression was used to determine the relationship between IHH and HE. Predictive value of the BRAIN score alone and integrated with IHH was assessed. RESULTS: In 122 included patients, median ICH volume was 13 ml, median time to CT 2.0 h; HE > 6 ml occurred in 31% and > 6 ml/> 33% in 43% of subjects. IHH were identified in 61% of patients with moderate inter-rater agreement (kappa = 0.59). In multivariable analysis, IHH was associated with HE using > 6 ml definition (OR 8.3, 95% CI, 2.6 32.8, P < 0.001) but not using the > 6 ml/> 33% definition (OR 1.9, 95% CI 0.84 4.3, P = 0.12). Rate of HE (> 6 ml) increased across increasing BRAIN score quartiles (Q1:11%, Q2:23%, Q3:43%, Q4:57%, P for trend < 0.001). Rate of HE > 6 ml in patients with BRAIN score >= 10 and IHH was 55%, with either alone was 33%, and with neither was 3%. CONCLUSIONS: Combining IHH on non-contrast CT and a simple clinical BRAIN score is a potentially powerful way to predict those patients at very high and very low risk of HE. PMID- 29411302 TI - Long-Term Health Effects and Underlying Biological Mechanisms of Developmental Exposure to Arsenic. AB - PURPOSE OF REVIEW: Exposure to inorganic arsenic (iAs) via drinking water represents a significant global public health threat with chronic exposure associated with cancer, skin lesions, neurological impairment, and cardiovascular diseases. Particularly susceptible populations include the developing fetus and young children. This review summarizes some of the critical studies of the long term health effects and underlying biological mechanisms related to developmental exposure to arsenic. It also highlights the complex factors, such as the sex of the exposed individual, that contribute to susceptibility to the later life health effects of iAs. RECENT FINDINGS: Studies in animal models, as well as human population-based studies, have established that prenatal and early life iAs exposures are associated with long-term effects, and many of these effects display sexually dimorphic responses. As an underlying molecular basis, recent epidemiologic and toxicologic studies have demonstrated that changes to the epigenome may play a key mechanistic role underlying many of the iAs-associated health outcomes. Developmental exposure to iAs results in early and later life health effects. Mechanisms underlying these outcomes are likely complex, and include disrupted key biological pathways with ties to the epigenome. This highlights the importance of continued research, particularly in animal models, to elucidate the important underpinnings (e.g., timing of exposure, metabolism, dose) of these complex health outcomes and to identify the biological mechanisms underlying sexual dimorphism in iAs-associated diseases. Future research should investigate preventative strategies for the protection from the detrimental health endpoints associated with early life exposure to iAs. Such strategies could include potential interventions focused on dietary supplementation for example the adoption of a folate-rich diet. PMID- 29411301 TI - Emerging Biomarkers in Cutaneous Melanoma. AB - Earlier identification of aggressive melanoma remains a goal in the field of melanoma research. With new targeted and immune therapies that have revolutionized the care of patients with melanoma, the ability to predict progression and monitor or predict response to therapy has become the new focus of research into biomarkers in melanoma. In this review, promising biomarkers are highlighted. These biomarkers have been used to diagnose melanoma as well as predict progression to advanced disease and response to therapy. The biomarkers take various forms, including protein expression at the level of tissue, genetic mutations of cancer cells, and detection of circulating DNA. First, a brief description is provided about the conventional tissue markers used to stage melanoma, including tumor depth. Next, protein biomarkers, which provide both diagnostic and prognostic information, are described. This is followed by a discussion of important genetic mutations, microRNA, and epigenetic modifications that can provide therapeutic and prognostic material. Finally, emerging serologic biomarkers are reviewed, including circulating melanoma cells and exosomes. Overall the goal is to identify biomarkers that aid in the earlier identification and improved treatment of aggressive melanoma. PMID- 29411304 TI - Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review. AB - PURPOSE: Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects. METHODS: MEDLINE and Scopus databases were searched (up to 31st October 2017). RESULTS: Nine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene. CONCLUSIONS: The presence of diabetes does not alter anti osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction. PMID- 29411305 TI - Association of glycaemic variability evaluated by continuous glucose monitoring with diabetic peripheral neuropathy in type 2 diabetic patients. AB - PURPOSE: Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes, is linked to glycaemic derangements. Glycaemic variability, as a pattern of glycaemic derangements, is a key risk factor for diabetic complications. We investigated the association of glycaemic variability with DPN in a large-scale sample of type 2 diabetic patients. METHODS: In this cross-sectional study, we enrolled 982 type 2 diabetic patients who were screened for DPN and monitored by a continuous glucose monitoring (CGM) system between February 2011 and January 2017. Multiple glycaemic variability parameters, including the mean amplitude of glycaemic excursions (MAGE), mean of daily differences (MODD), standard deviation of glucose (SD), and 24-h mean glucose (24 h MG), were calculated from glucose profiles obtained from CGM. Other possible risks for DPN were also examined. RESULTS: Of the recruited type 2 diabetic patients, 20.1% (n = 197) presented with DPN, and these patients also had a higher MAGE, MODD, SD, and 24-h MG than patients without DPN (p < 0.001). Using univariate and multiple logistic regression analyses, MAGE and conventional risks including diabetic duration, HOMA-IR, and hemoglobin A1c (HbA1c) were found to be independent contributors to DPN, and the corresponding odds ratios (95% confidence interval) were 4.57 (3.48-6.01), 1.10 (1.03-1.17), 1.24 (1.09-1.41), and 1.33 (1.15-1.53), respectively. Receiver operating characteristic analysis indicated that the optimal MAGE cutoff value for predicting DPN was 4.60 mmol/L; the corresponding sensitivity was 64.47%, and the specificity was 75.54%. CONCLUSIONS: In addition to conventional risks including diabetic duration, HOMA IR and HbA1c, increased glycaemic variability assessed by MAGE is a significant independent contributor to DPN in type 2 diabetic patients. PMID- 29411307 TI - Interprofessional Communication Concerning Work-Related Musculoskeletal Disorders: A Qualitative Study. AB - Purpose Understanding and treating musculoskeletal disorders (MSDs) requires coordination between the numerous healthcare professionals involved, including occupational physicians (OPs), general practitioners (GPs) and social insurance physicians (SIPs). The main objective of this study was to assess communication between OPs, GPs and SIPs in the management of MSDs. Methods This is a qualitative study in the form of semi-structured interviews with OPs in the French region of Brittany. The interviews were conducted until data saturation was achieved. The interviews were fully coded and analysed thematically using NVivo(r) software. Results The interviews were carried out among 17 OPs from companies and external occupational healthcare services who treated employees from various activity sectors. Different communication channels were used depending on the interlocutor, though they were mainly contacted by mail or phone. Most of the communication passed through the patient, either verbally or in writing. No major failure was detected in communication between the various types of practitioners, but instances of communication were influenced by various factors such as differences in perception, representation and objectives, as well as by how well the physicians knew each other. A number of instances of non communication were found. Conclusion This study showed that patients play a key role in the interactions between different practitioners. It also revealed that different types of professional relationships depend on the objectives of the various interlocutors, which in turn vary according to their roles and competences. PMID- 29411308 TI - Pope Innocent XI's renal stones: an example of medical correspondence. PMID- 29411309 TI - HCV and kidney transplant in the era of new direct-acting antiviral agents (DAAs). PMID- 29411306 TI - Relaxin activates AMPK-AKT signaling and increases glucose uptake by cultured cardiomyocytes. AB - PURPOSE: Many evidences show that the hormone relaxin plays a pivotal role in the physiology and pathology of the cardiovascular system. This pleiotropic hormone exerts regulatory functions through specific receptors in cardiovascular tissues: in experimental animal models it was shown to induce coronary vasodilation, prevent cardiac damage induced by ischemia/reperfusion and revert cardiac hypertrophy and fibrosis. A tight relationship between this hormone and important metabolic pathways has been suggested, but it is at present unknown if relaxin could regulate cardiac metabolism. Our aim was to study the possible effects of relaxin on cardiomyocyte metabolism. METHODS: Neonatal rat cardiomyocytes were treated with relaxin and (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays (MTT) were performed to assess metabolic activity; while 2-deoxy D-[3H] glucose and BODIPY-labelled fatty acid incorporations were analyzed to measure glucose and fatty acid uptakes, and western blot was utilized to study the intracellular signaling pathways activated by the hormone. RESULTS: We observed that relaxin at 10 ng/ml was able to increase the level of metabolic activity of cultured neonatal rat cardiomyocytes; the rate of 2-deoxy-D [3H]glucose incorporation demonstrated that relaxin also induced an increase in glucose uptake. First evidence is also offered that relaxin can activate the master energy sensor and regulator AMPK in cardiomyocytes. Moreover, the treatment of cardiomyocytes with relaxin also induced dose-dependent increases in ERK1/2, AKT, and AS160 phosphorylation. That raise in AS160 phosphorylation induced by relaxin was prevented by the pretreatment with AMPK and AKT pathways inhibitors, indicating that both molecules play important roles in the relaxin effects reported. CONCLUSION: Relaxin can regulate cardiomyocyte metabolism and activate AMPK, the central sensor of energy status that maintains cellular energy homeostasis, and also ERK and AKT, two molecular sensing nodes that coordinate dynamic responses of the cell's metabolic responses. PMID- 29411310 TI - Polypharmacy in Home Care in Europe: Cross-Sectional Data from the IBenC Study. AB - BACKGROUND: Home care (HC) patients are characterized by a high level of complexity, which is reflected by the prevalence of multimorbidity and the correlated high drug consumption. This study assesses prevalence and factors associated with polypharmacy in a sample of HC patients in Europe. METHODS: We conducted a cross-sectional analysis on 1873 HC patients from six European countries participating in the Identifying best practices for care-dependent elderly by Benchmarking Costs and outcomes of community care (IBenC) project. Data were collected using the interResident Assessment Instrument (interRAI) instrument for HC. Polypharmacy status was categorized into three groups: non polypharmacy (0-4 drugs), polypharmacy (5-9 drugs), and excessive polypharmacy (>= 10 drugs). Multinomial logistic regressions were used to identify variables associated with polypharmacy and excessive polypharmacy. RESULTS: Polypharmacy was observed in 730 (39.0%) HC patients and excessive polypharmacy in 433 (23.1%). As compared with non-polypharmacy, excessive polypharmacy was directly associated with chronic disease but also with female sex (odds ratio [OR] 1.58; 95% confidence interval [CI] 1.17-2.13), pain (OR 1.51; 95% CI 1.15-1.98), dyspnea (OR 1.37; 95% CI 1.01-1.89), and falls (OR 1.55; 95% CI 1.01-2.40). An inverse association with excessive polypharmacy was shown for age (OR 0.69; 95% CI 0.56-0.83). CONCLUSIONS: Polypharmacy and excessive polypharmacy are common among HC patients in Europe. Factors associated with polypharmacy status include not only co-morbidity but also specific symptoms and age. PMID- 29411311 TI - Relationship between 25 hydroxyvitamin D and lipid profile in Lebanese school children. AB - PURPOSE: Limited information is available regarding the association of vitamin D and lipid profile in pediatric populations. The objective of this cross-sectional study is to determine the prevalence of vitamin D deficiency in a large sample of Lebanese schoolchildren and to evaluate the relationship between vitamin D and lipid profile. METHODS: 969 Lebanese schoolchildren (505 boys and 464 girls) aged 8-18 years were recruited from 10 schools of different socioeconomic status (SES). Non-fasting total cholesterol, triglycerides and HDL-Cholesterol (HDL-C) were measured. Non-HDL-C was calculated. RESULTS: The prevalence of 25(OH)D deficiency (level below 20 ng/ml) is 56.6% (48.1% in boys, 65.7% in girls). There is no significant relationship between 25(OH)D levels and age. 25(OH)D is inversely correlated with BMI in the total population, and in boys and girls (p < 0.0001, p = 0.001 and p = 0.001, respectively) and is higher in children from high SES schools and during the summer season (p < 0.0001 in both cases). 25(OH)D is inversely correlated with triglycerides and non-HDL-C in the total population and in boys and girls (p < 0.0001 for all), and positively correlated with HDL-C in the total population and in boys but not in girls (p = 0.001, p < 0.0001 and p = 0.1, respectively). In a multilinear regression analysis, in the overall population, 25(OH)D is independently associated with sex, season, school's SES, BMI, triglycerides and non-HDL-C. In boys, the association with BMI and season is non-significant. CONCLUSION: An independent relationship is observed between 25(OH)D and cardiometabolic risk factors in the pediatric Lebanese population Further studies are needed to evaluate the long-term consequences of this relationship. PMID- 29411312 TI - "Madonna of the carnation": Leonardo da Vinci (1452-1519). PMID- 29411313 TI - MYOD and HAND transcription factors have conserved recognition sites in mTOR promoter: insights from in silico analysis. AB - mTOR regulates multiple cellular processes that are critical for proper maintenance of cell growth and development. However, mechanisms and factors responsible for transcriptional regulation of mTOR are partially known. To identify different transcription factor binding sites in promoter region of mTOR, we performed in silico phylogenetic foot printing analysis of diverse set of human orthologs. Phylogenetic tree for the orthologs was generated to establish the evolutionary relationships among them. Conserved binding sites among the species were predicted by tool MEME. The predicted conserved sites were further analyzed for binding of transcription factors by MatInspector program. Predicted TFs were then integrated with known physical interactions and coexpression data to decipher the important transcriptional regulators of mTOR signaling. Our study suggests that motifs AGGCGGG (+ 15 to + 21) and GGCGGC (+ 60 to + 65) are highly conserved across the species and are recognition sequence for HAND and MYOD transcription factors, respectively. Also these two transcription factors show direct physical interaction in protein-protein interaction map, indicating their regulatory role on expression of mTOR for control of myogenesis. Our study provides novel clues on differential regulation of mTOR under diverse environmental conditions. PMID- 29411314 TI - Feasibility and preliminary efficacy of an exercise telephone counseling intervention for hematologic cancer survivors: a phase II randomized controlled trial. AB - BACKGROUND: Supervised exercise interventions produce the largest improvements in patient-reported outcomes in cancer survivors but their scalability has been questioned. Telephone counseling has been proposed as a more feasible alternative but its impact on exercise behavior and health outcomes have been modest. Basing telephone counseling exercise (TCE) interventions on the theoretical advances described in the multi-process action control framework (M-PAC) may improve these outcomes. PURPOSE: To assess the feasibility and preliminary efficacy of a M-PAC based TCE intervention for increasing aerobic exercise behavior in hematologic cancer survivors (HCS). METHODS: We recruited 51 HCS who were randomized to either a weekly TCE group (n = 26) or a self-directed exercise (SDE) group (n = 25). Participants completed online measures of self-reported aerobic exercise behavior, quality of life (QoL), fatigue, and program satisfaction at baseline and post-intervention (12 weeks). RESULTS: Adherence to the TCE intervention was 93% and retention was 100%. Participants receiving TCE increased their weekly aerobic exercise by 218 min compared to 93 min in the SDE group [mean-adjusted between-group difference (MBGDadj) = 139, 95%CI = 65 to 213, p < .001, effect size (d) = 2.19]. Clinically meaningful QoL improvements favored the TCE group for mental health (MBGDadj = 3.7, 95%CI = - 0.4 to 7.9, p = .08, d = 0.42) and mental health component (MBGDadj = 3.6, 95%CI = - 0.8 to 8.1, p = .10, d = 0.35) subscales. CONCLUSIONS: The 12-week TCE intervention substantially increased exercise behavior and may have meaningfully improved QoL in HCS. IMPLICATIONS FOR CANCER SURVIVORS: Though more definitive trials are needed, remote TCE interventions based on the M-PAC may improve exercise behavior and QoL in HCS and perhaps other cancer survivor groups. TRIAL REGISTRATION NUMBER: Clinical Trials ID: NCT03052777. PMID- 29411316 TI - Nuclear cardiology in the literature: A selection of recent, original research papers. PMID- 29411315 TI - Inflammation Strikes Again: Frailty and HIV. AB - PURPOSE OF REVIEW: As a consequence of antiretroviral therapy, the proportion of older HIV-infected adults is increasing, with a concomitant shift in burden of illness to age-related syndromes and disease. Frailty is an age-related syndrome of increased vulnerability to stress, predictive of major adverse clinical outcomes among HIV-infected and uninfected persons alike. Understanding frailty pathogenesis is critical to developing interventions to improve health outcomes in HIV. Here, we review the current evidence for the relationship between inflammation and frailty in HIV, and the potential for novel, inflammation targeted interventions. RECENT FINDINGS: Dysregulated inflammation has been consistently associated with frailty in elderly HIV-uninfected persons. Dysregulated inflammation is also central to HIV pathophysiology and several recent studies have demonstrated the important association of inflammation with frailty in HIV. Some evidence suggests that anti-inflammatory therapies may be effective in ameliorating the adverse impact of frailty among aging HIV-infected adults, though further investigation is necessary. Inflammation has been implicated in frailty in HIV infection, and improved understanding of the role that inflammation plays in frailty pathogenesis is key to the development of effective therapies to slow or prevent frailty in the vulnerable HIV-infected population. PMID- 29411317 TI - Nutraceuticals: A Review. AB - Skin aging is continuously influenced by various internal and external factors such as the biologic progression of cells, ultraviolet (UV) radiation, tobacco, nutritional deficiencies, and hormonal imbalances that lead to the degradation of skin cells. Through the degradation of skin cells, free radicals and inflammation weaken repair mechanisms and result in collagen and elastic fiber breakdown. The appearance of aging skin is highlighted by skin roughness, wrinkling, pigmentation change, telangiectasias, loss of elasticity, and decreased firmness, all of which are accelerated by these internal and external factors. Throughout the years, nutraceuticals have been studied to delay and fight against these internal and external factors, many of which are found in foods and byproducts consumed naturally. The aim of this review is to aid dermatologists in understanding the mechanism of action of popular nutraceuticals and their possible efficacy in antiaging and skin health. PMID- 29411318 TI - Policy Options for Infliximab Biosimilars in Inflammatory Bowel Disease Given Emerging Evidence for Switching. AB - Biosimilars are becoming increasingly available internationally as patents expire on the originator biologic drugs they are intended to copy. Although substitution policies seen with generic drugs are being considered as a means to reduce expenditures on biologics, some biosimilars pose particular challenges in that the act of substitution may eventually lead to increased rates of therapeutic failure. As evidence requirements from regulators do not directly address this challenge, switch trials of biosimilars have emerged that may provide further answers. Using infliximab in inflammatory bowel disease as an example, we critically examine emerging evidence from two key switch trials (NOR-SWITCH and NCT020968610) and discuss the clinical and economic implications of these and what policy options may be most reasonable for payers. Options include reimbursing biosimilars for only newly diagnosed patients, using product-listing agreements to manage uncertainty, or using tiered co-payments or other incentives to promote biosimilar use. PMID- 29411319 TI - [The conversation with the patient is essential for good pharmacotherapeutic care]. AB - Frail elderly with polypharmacy are at greater risk of preventable medication related health damage. To improve medication safety, the healthcare field prepared, in consultation with the Dutch Health Care Inspectorate, a number of guidelines and standards containing conditions for safe prescribing. According to these standards the active involvement of patients by health care professionals is essential for good pharmacotherapeutic care. However, two studies with patients show that there is still room for improvement. According to patients, they can be (even) better informed about changes in their medication. Also the caregivers could communicate more clearly who is the central contact point and who is ultimately responsible for the medication. Patients are not sufficiently informed on this. Furthermore, there is uncertainty about how and why medication reviews are performed. More explanation to patients about this is desirable. In addition, patients experience that keeping their medication list up to date and transferring medication data between health care providers could be improved. Finally, a group of patients welcomes the opportunity to co-decide on changes in their medication. In order to prescribe safely, it is crucial that caregivers actively involve patients in pharmacotherapeutic care and really enter into conversation with them about their medication. PMID- 29411320 TI - The Role of Tendon Transfers for Irreparable Rotator Cuff Tears. AB - PURPOSE OF REVIEW: This review aims to describe the tendon transfer options for treating irreparable rotator cuff tears (RCTs). Options for transfer include latissimus dorsi and lower trapezius transfers for posterior-superior RCTs and pectoralis major and latissimus dorsi transfer for anterior-superior RCTs. RECENT FINDINGS: While the latissimus dorsi tendon transfer has historically been performed for posterosuperior RCTs, the lower trapezius transfer is a more anatomic option and has demonstrated promising results in recent studies. Similarly, the pectoralis major transfer has historically been the tendon transfer of choice for anterosuperior RCTs. However, the latissimus dorsi tendon transfer has recently been shown to be a safe and anatomic tendon transfer for subscapularis insufficiency. The treatment of irreparable RCTs involves complex decision making. Tendon transfer procedures can restore the glenohumeral joint force couples, allowing restoration of near-normal shoulder kinematics. Benefits include reliable pain relief, increased function, and increased strength. Proper selection of donor tendon is crucial, and the principles of tendon transfer procedures must be adhered to for maximal benefit. PMID- 29411321 TI - Natural History of Degenerative Rotator Cuff Tears. AB - PURPOSE OF REVIEW: In the past several years, there have been significant advances in our understanding of the natural history of rotator cuff disease. Studies have continued to provide valuable insight into the clinical, radiographic, and anatomic features of these atraumatic tears. Our purpose is to summarize the findings and contributions from these recent high-quality studies. RECENT FINDINGS: Current research has continued to describe and provide understanding into the natural history of atraumatic rotator cuff disease, including symptom progression, tear enlargement, and the development of arthritis. This knowledge has allowed identification of tears with higher risk of disease progression. Additionally, studies have investigated, with long-term healing data, whether the natural history of degenerative rotator cuff tears can be altered with surgical intervention. Recent studies have shown encouraging mid to long-term healing data and clinical outcome scores for smaller tears in younger patients with minimal fatty infiltration. Future research should focus on obtaining long-term healing data, functional outcome data, and refining surgical indications for rotator cuff repair. Identifying patients with specific tear characteristics amendable to healing will allow us to provide a long-term, durable repair, thus interrupting the natural history of degenerative rotator cuff disease. PMID- 29411323 TI - Alcohol consumption after laparoscopic sleeve gastrectomy: 1-year results. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (SG) represents, at present, the most performed bariatric procedure worldwide with excellent long-term results on weight loss and comorbidities control. After the gastrectomy procedure, together with hormonal modification, several changes in taste and habits occur, including the potential modification in alcohol consumption. The aim of this prospective study was to determine the frequency and the amount of alcohol use before and after SG using a modified version of the Alcohol Use Disorder Identification Test (AUDIT) at 1-year follow-up and eventually to evaluate relationships between different ages and sexes. MATERIALS AND METHODS: A total of 142 patients were prospectively enrolled and evaluated before and 1 year after SG with a modified AUDIT. The exclusion criteria were as follows: history of alcohol abuse, presence of psychopathology or cognitive impairments, diabetes mellitus type II decompensated, or previous gastrointestinal, liver, and pancreatic resective surgery. Subgroup analyses were performed between male and female and between under and over 40 years old. RESULTS: The median AUDIT score decreased from 2.70 (range 1-18) before surgery to 1.38 (range 1-7) after 1 year of SG, indicating a marked reduction in alcohol use. The most consumed alcoholic drink was beer (36.6%/n = 52) while after surgery the consumption of beer decreased considerably (21.1%/n = 30). The frequency of alcohol consumption also decreased: at baseline 45% of patients consumed alcoholic drinks "from 2 to 4 times per month", whereas 26 and 39.4% consumed alcohol "never" and "less than once a month," respectively. After surgery, nobody consumed more then six alcoholic drinks. No differences were found between the subgroups in terms of alcohol consumption and social behavior. CONCLUSIONS: The alcohol preference is modified and decreased 1 year after SG and this could be related to the strict nutritional follow-up and to the hormonal changes. Studies with large samples and long-term follow-up are needed to confirm our data. LEVEL OF EVIDENCE: IV. PMID- 29411322 TI - The Role of Biologic Therapy in Rotator Cuff Tears and Repairs. AB - PURPOSE OF REVIEW: The purpose of this review was to establish the foundation of the major biologic adjuvants to rotator cuff repairs and review recent scientific findings. RECENT FINDINGS: Platelet-rich plasma (PRP) overall has no significant impact on functional outcomes and repair integrity, but may be more advantageous in small to medium tears. Further studies should focus on leukocyte-rich versus poor preparations and the use of PRP in patients that are high risk for repair failure. Biologic and synthetic patches or augments provide mechanical stability for large and massive rotator cuff tears and decrease re-tear rates. Mesenchymal stem cells have demonstrated improved healing rates without an impact on outcomes. Cytokines and growth factors show promise in animal models, but require human trials to further evaluate. In massive or revision repairs, allograft or synthetic patch augmentation should be considered. Platelet-rich plasma may have benefit in smaller tears. Further studies are needed to evaluate the value of mesenchymal stem cells and various cytologic chemical signals. PMID- 29411324 TI - Chronic Exposure to Fluoride During Gestation and Lactation Increases Mandibular Bone Volume of Suckling Rats. AB - We aimed to investigate the effect of maternal exposure to NaF on mandibular bone microarchitecture and phosphocalcic plasma parameters of the offspring. For this purpose, 10-, 15-, and 21-day-old pups (n = 6-8 per group) from two groups of mothers, control and NaF 50mg/L treated dams, were used. Plasma calcium (Ca) and phosphorus (P) levels and alkaline phosphatase activity (ALP) were measured. Fluoride concentration (F-) in bone and in stomach content was measured using potentiometry after isothermal distillation. Morphometric, histological, and histomorphometric analyses of the jaw bones were performed. Plasma Ca and P levels and ALP activity increased in 10-day and decreased in 21-day-old pups from NaF-treated mothers. Fluoride concentration in stomach content samples of 15- and 21-day-old nursing pups from mothers exposed to NaF in their drinking water was higher compared to that observed in control dam offspring. Mandibular F- content was higher in 21-day-old pups born to F--exposed dams compared to those observed in age-matched control pups. Mandibular area increased in 21-day-old pups born to treated mothers as compared to controls. Mandibular bone volume BV/TV (%) was higher in offspring from NaF-exposed dams than in controls at all the studied times. The increase in bone volume after exposure to F- was concomitant with the increase in trabecular thickness and the decrease in trabecular separation. Altogether, our results showed that exposure to NaF during gestation and lactation increased mandibular area and bone volume of pups, with concomitant changes in phosphocalcic parameters associated with the bone modeling process. PMID- 29411325 TI - Vascular dysfunction of postural tachycardia syndrome in children. AB - BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance, and its incidence in children is approximately 6.8% [1]. The pathogenesis of POTS is complex with multiple, overlapping, interacting pathophysiological mechanisms. Although the specific pathogenic mechanism has remained perplexing, with the discovery of various gasotransmitters and biological peptides, the vascular dysfunction has aroused overwhelming attention. DATA SOURCES: On the basis of searching in a wide range of recent original literatures, we reviewed the pathogenesis of vascular dysfunction in children with POTS. RESULTS: The flow-mediated vasodilation of POTS patients was greater than that of healthy controls, and the vasodilator factors were increased in patients with POTS under basal condition or under a standing position, while the vasoconstriction factors were reduced. CONCLUSIONS: Vascular dysfunction, as one of pathogenesis in pediatric POTS patients, affects the occurrence and development of diseases through a variety of factors. PMID- 29411326 TI - Plasma adrenomedullin level in children with obesity: relationship to left ventricular function. AB - BACKGROUND: Obese children are at increased risk for abnormal cardiac structure and function. Little is known about adrenomedullin (AM), a cytokine produced in various organs and tissues, as a biomarker of cardiac hypertrophy in obese children. This study aimed to assess the plasma AM levels in a cohort of obese children and its relationship to left ventricular (LV) functions. METHODS: The study included 60 obese children and 60 non-obese children matched for age and gender as control group. Blood pressure, serum lipid profile, fasting glucose, insulin and plasma AM and the homeostatic model assessment of insulin resistance (HOMA-IR) were measured. Cardiac dimensions and LV functions were assessed using conventional echocardiography. RESULTS: Compared to control subjects, obese children had higher blood pressure (P = 0.01), insulin (P = 0.001), HOMA-IR (P = 0.001), and AM (P = 0.001). Moreover, obese children had higher LV mass index (LVMI) (P = 0.001), indicating LV hypertrophy; prolonged isovolumic relaxation times (P = 0.01), prolonged mitral deceleration time (DcT) (P = 0.01) and reduced ratio of mitral E-to-mitral A-wave peak velocity (P = 0.01), indicating LV diastolic dysfunction. Laboratory abnormalities were only present in children with LV hypertrophy. In multivariate analysis in obese children with LV hypertrophy, AM levels were positively correlated with LVMI [odds ratio (OR) 1.14, 95% confidence interval (Cl) 1.08-1.13, P = 0.0001] and mitral DcT (OR 2.25, 95% CI 1.15-2.05, P = 0.01) in the presence of higher blood pressure and HOMA-IR. A cut-off value of AM at 52 pg/mL could differentiate obese children with and without left ventricular hypertrophy at a sensitivity of 94.32% and specificity of 92.45%. CONCLUSIONS: Plasma AM levels may be elevated in obese children particularly those with LV hypertrophy and is correlated with higher blood pressure and insulin resistance. Measurement of plasma AM levels in obese children may help to identify those at high risk of developing LV hypertrophy and dysfunction. PMID- 29411327 TI - Gene variants of the phosphatidylcholine synthesis pathway do not contribute to RDS in the Chinese population. AB - BACKGROUND: To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. METHODS: We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants. RESULTS: We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang populations (0.0045 vs. 0.0064, respectively, P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous variants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB; F341L was also not previously reported in exome sequencing project. CONCLUSIONS: The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1, CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research. PMID- 29411328 TI - Hyperuricemia is associated with short-term outcomes in elderly patients with acute myocardial infarction. AB - BACKGROUND: Although a lot of studies have shown serum uric acid (SUA) could be a marker of adverse prognosis in patients with acute myocardial infarction, the role of SUA as a risk factor for myocardial infarction is controversial. This study aimed to evaluate the association between hyperuricemia and short-term outcomes of elderly patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: Six hundred and seventy-three elderly patients (>= 60 years) were divided into high-SUA-level group (group H: N = 168) and low-SUA level group (group L: N = 505) according to the SUA levels on admission. The following primary end points were evaluated within 30 days of AMI. The adverse events included postoperative angina pectoris, heart failure (Killip class >= II), and death. The comparisons were made between two groups in clinical and angiographic characteristics. RESULTS: The incidences of postoperative angina pectoris, heart failure, and the total adverse cardiovascular events were significantly higher in group H than in group L. But the incidence of death was similar between groups. In group H, heart rate (HR), systolic and diastolic blood pressure, SUA, homocysteine (HCY), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and creatine kinase myocardial band (CKMB) peak were clearly higher compared with those in group L. The results of logistic regression showed that the incidence of 30-day adverse events was closely related to TG, HCY and SUA. CONCLUSIONS: An elevated SUA level may be related to the short-term outcomes and seems to be an independent predictor of 30-day cardiovascular events in elderly patients with STEMI. PMID- 29411329 TI - Geriatricians and the older emergency general surgical patient: proactive assessment and patient centred interventions. Salford-POP-GS. AB - Increasing numbers of older patients require Emergency admission under General Surgery (EGS). This is a group of heterogeneous and often complex individuals with varying degrees of multimorbidity, polypharmacy, functional, mobility and cognitive impairment. Our article describes the benefits of comprehensive assessment coupled with patient-centred multiprofessional interventions and timely discharge planning. We discuss diverse service models and describe our experience in the planning, development and consolidation of a perioperative service for older EGS patients. PMID- 29411330 TI - Declining incidence in fall-induced deaths of older adults: Finnish statistics during 1971-2015. AB - BACKGROUND: Fall-induced deaths of elderly people are a major problem. AIM AND METHODS: Using the Official Cause-of-Death Statistics of Finland, we aimed to determine the current trends in the number and age-adjusted incidence (per 100,000 persons) of fall deaths among older Finns by taking into account 50 years or older persons who died because of a fall-induced injury in 1971-2015. RESULTS: Among men, the number of fall-induced deaths increased considerably between 1971 and 2003 (from 162 in 1971 to 564 in 2003), while thereafter, this number has been relatively stable (579 deaths in 2015). Men's age-adjusted incidence of fall deaths rose from 45.6 in 1971 to 69.5 in 1998, after which it stayed relatively stable until 2005 (69.9). Since 2005, this figure has shown a steady, deep decline (only 45.1 in 2015). Among women, the number of fall-induced deaths increased considerably between 1971 and 1998 (from 279 in 1971 to 563 in 1998), while thereafter, this number has been relatively stable (532 deaths in 2015). In sharp contrast to men, women's age-adjusted incidence of fall-induced deaths has been declining since the early 1970s, the incidence being 82.6 in 1971 while only 33.0 in 2015. A steady, deep decline started in 1998. CONCLUSIONS: Among 50 years or older Finns the number of fall-induced deaths increased considerably from the early 1970s until the late 1990s but stabilized thereafter. In the new millennium, the age-adjusted incidence of these deaths has started to decline in both sexes. Despite this we have to effectively continue the falls prevention efforts, because our elderly population will grow rapidly in the near future. PMID- 29411331 TI - Association of pre-operative medication use with post-surgery mortality and morbidity in oncology patients receiving comprehensive geriatric assessment. AB - BACKGROUND: Comprehensive geriatric assessment (CGA) has become a predictor for elderly cancer patients in post-surgical complications, including post-discharge institutionalization and mortality. AIMS: To determine whether pre-operative medication use is associated with post-operative morbidity and mortality in oncology patients receiving CGA. METHODS: Patients aged 65 years or older who were scheduled for cancer surgery and presented for CGA were included in the present study. Baseline characteristics of patients were collected from electrical medical records, and pre-operative medication review was performed. The primary outcome was death within 30 days after surgery and post-discharge institutionalization. RESULTS: A total of 475 cancer patients were included. Among them, three patients died within 30 days after surgery and 14 patients were discharged to another institution. All patients who died within 30 days after surgery had polypharmacy with marginal significance (P = 0.087). Multivariate analysis models were constructed using significant factors for post-surgery institutionalization from univariate analysis: Model I (polypharmacy and transfusion), Model II (polypharmacy and infection), and Model III (polypharmacy, transfusion, and infection). Infection was the most significant factor. Its adjusted odds ratio was as large as 11.1 and attributable risk was almost 91%. In pre-surgery medication use, only polypharmacy showed significant association with post-discharge institutionalization. Attributable risk of polypharmacy was around 75%. CONCLUSIONS: It is possible that pre-operative medication use has impact on death and post-discharge institutionalization in geriatric oncology patients, further highlighting the importance of medication optimization for elderly patients with cancer surgery. PMID- 29411332 TI - A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened. AB - We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 nmf164 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Slight inflammation also occasionally occurred with saline inhalation. There was no difference between the saline treated, HPBCD-treated, and untreated Npc1 nmf164 homozygous mice for weight, balance beam performance, or coat hanger performance. Interestingly, there was a trend to longer survival in the HPBCD-treated Npc1 nmf164 homozygous mice, which, when combined with the survival times of the saline-treated survivals (each of which was not different), became significant. PMID- 29411333 TI - A Review of Childhood Behavioral Problems and Disorders in the Development of Obesity: Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and Beyond. AB - PURPOSE OF REVIEW: Given the high rates of pediatric and adult obesity, it is imperative to identify early risk factors that might contribute to excess weight gain. This review aims to investigate the relationship between childhood behavioral problems with the development and persistence of obesity. Specifically, this review highlights the association of obesity with (1) neurocognitive constructs, such as executive functioning and inhibition/impulsivity, and (2) disorders commonly diagnosed in childhood, including attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). RECENT FINDINGS: Consistent evidence supports a relationship between childhood behavioral problems, executive functioning, inhibition/impulsivity, ADHD, and ASD with obesity across the lifespan. Longitudinal studies suggest behavior problems, neurocognitive functioning deficits, and ADHD symptoms in childhood predict weight gain over time. Identifying risk factors in childhood that promote obesity may help develop targeted intervention and prevention programs. Additional research should elucidate mechanisms that account for these relationships. PMID- 29411335 TI - Evolving Role of Natriuretic Peptides from Diagnostic Tool to Therapeutic Modality. AB - Natriuretic peptides (NP) are widely recognized as key regulators of blood pressure, water and salt homeostasis. In addition, they play a critical role in physiological cardiac growth and mediate a variety of biological effects including antiproliferative and anti-inflammatory effects in other organs and tissues. The cardiac release of NPs ANP and BNP represents an important compensatory mechanism during acute and chronic cardiac overload and during the pathogenesis of heart failure where their actions counteract the sustained activation of renin-angiotensin-aldosterone and other neurohormonal systems. Elevated circulating plasma NP levels correlate with the severity of heart failure and particularly BNP and the pro-peptide, NT-proBNP have been established as biomarkers for the diagnosis of heart failure as well as prognostic markers for cardiovascular risk. Despite activation of the NP system in heart failure it is inadequate to prevent progressive fluid and sodium retention and cardiac remodeling. Therapeutic approaches included administration of synthetic peptide analogs and the inhibition of NP-degrading enzyme neutral endopeptidase (NEP). Of all strategies only the combined NEP/ARB inhibition with sacubitril/valsartan had shown clinical success in reducing cardiovascular mortality and morbidity in patients with heart failure. PMID- 29411334 TI - Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes. AB - Across the years the CCNs have been increasingly implicated in the development of obesity, diabetes and its complications. Evidence for this is currently derived from their dysregulation in key metabolic pathological states in humans, animal and in vitro models, and also pre-clinical effects of their bioactivities. CCN2 is the best studied in this disease process and the other CCNs are yet to be better defined. Key steps where CCNs may play a pathogenic metabolic role include: (i) obesity and insulin resistance, where CCN2 inhibits fat cell differentiation in vitro and CCN3 may induce obesity and insulin resistance; (ii) elevated blood glucose levels to diabetes mellitus onset, where CCN2 may contribute to pancreatic beta cell and islet function; and (iii) in diabetes complications, such as nephropathy, retinopathy, liver disease (NAFLD/NASH), CVD and diabetes with heart failure. In contrast, CCN1, CCN2 and possibly CCN3, may have a reparative role in wound healing in diabetes, and CCN2 in islet cell development. In terms of CCN2 regulation by a diabetes metabolic environment and related mechanisms, the author's laboratory and others have progressively shown that advanced glycation-end products, protein kinase C isoforms, saturated fatty acids, reactive oxygen species and haemodynamic factors upregulate CCN2 in relevant cell and animal systems. Recent data has suggested that CCN2, CCN3 and CCN6 may affect energy homeostasis including in regulating glycolysis and mitochondrial function. This paper will address the current data implicating CCNs in diabetes and its complications, focusing on recent aspects with translational clinical relevance and future directions. PMID- 29411336 TI - Central Sleep Apnea with Cheyne-Stokes Breathing in Heart Failure - From Research to Clinical Practice and Beyond. AB - Characterized by periodic crescendo-decrescendo pattern of breathing alternating with central apneas, Central sleep apnea (CSA) with Cheyne-Stokes Breathing represents a highly prevalent, yet underdiagnosed comorbidity in chronic heart failure (CHF). A diverse body of evidence demonstrates increased morbidity and mortality in the presence of CSB. CSB has been described in both CHF patients with preserved and reduced ejection fraction, regardless of drug treatment. Risk factors for CSB are older age, male gender, high BMI, atrial fibrillation and hypocapnia.The pathophysiology of CSB has been explained by the loop gain theory, where a controller (the respiratory center) and a plant (the lungs) are operating in a reciprocal relationship (negative feedback) to regulate a key parameter (partial pressure of carbon dioxide (pCO2)). The temporal interaction between these elements is dependent on the circulatory delay. Increased chemosensitivity/chemoresponsiveness of the respiratory center and/or augmented ascending non- CO2 stimuli from the C-fibers in the lungs (interstitial pulmonary edema), overly efficient ventilation when breathing at low volumes and prolonged circulation time are involved. An alternative hypothesis of CSB being an adaptive response of the failing heart has its merits as well. The clinical manifestation of CSB is usually poor, lacking striking symptoms and complaints. Witnessed apneas and snoring are infrequently reported by the sleep partner. Sometimes patients may report poor sleep quality with frequent awakenings, paroxysmal nocturnal dyspnea and frequent urination at night. Standard instrumental and laboratory studies, performed in CHF patients, may present clues to the presence of CSB. Concentric remodeling of the left ventricle and dilated left atrium (echocardiography), high BNP and C-reactive protein levels, increased ventilation carbon dioxide output (VEVCO2) and lower end-tidal CO2 (cardiopulmonary exercise testing), reduced diffusion capacity (pulmonary function testing) and hypocapnia (blood-gas analysis) may indicate the presence of CSB.CSB and cardiovascular disease are probably linked through bidirectional causality. Cyclic variations in heart rate, blood pressure, respiratory volume, partial pressure of arterial oxygen (pO2) and pCO2 lead to sympathetic-adrenal activation. The latter worsens ventricular energetism and survival of cardiomyocytes and exerts antiarhythmogenic effects. It causes cardiac remodeling, potentiating the progression and the lethal outcome in CHF patients. Several treatment modalities have been proposed in CSB. The most commonly used are continuous positive airway pressure (CPAP), adaptive servoventilation (ASV) and nocturnal home oxygen therapy (HOT). Novel therapies like nocturnal supplemental CO2 and phrenic nerve stimulation are being tested recently. The current treatment recommendations (by the American Academy of Sleep Medicine) are for CPAP and HOT as standard therapies, while ASV is an option only in patients with EF > 45%. BPAP (bilevel device) remains an option only when there is no adequate response to previous modes of treatment. Acetazolamide and theophylline are options only after failing the above modalities and if accompanied by a close follow-up. PMID- 29411339 TI - Evaluation of complications developing during and after transvaginal ultrasound - guided oocyte retrieval. AB - OBJECTIVES: To investigate the complications of the oocyte retrieval procedure currently used in in vitro fertilisation. MATERIAL AND METHODS: We examined 1.031 patients who underwent oocyte retrieval in the IVF unit of our hospital for complications developed during and after the procedure. RESULTS: No complications developed related to sedation or general anaesthesia. Vaginal bleeding was observed in 3.1% of the patients. There was no intra-abdominal bleeding or pelvic organ injuries requiring surgery. Two patients developed pelvic abscesses. Ovarian hyperstimulation syndrome (OHSS) occurred in 1.45% of the patients. Almost all of the patients tolerated the oocyte retrieval process well. After the procedure, only 2% of the patients described their pain as severe, and 0.4% as the worst pain they had ever experienced. CONCLUSIONS: The most common complication during oocyte retrieval is vaginal bleeding, which is largely controlled by buffer application. In conclusion, the oocyte retrieval process can be considered a safe procedure. PMID- 29411337 TI - Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review. AB - INTRODUCTION: Interleukin-13 and interleukin-4 are type-II cytokines signalling through the shared type II interleukin-4 receptor. As a result of their structural similarity, interleukin-13 and interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. OBJECTIVE: This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of interleukin-13 alone or interleukin-13 and interleukin-4 in combination. METHODS: We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of interleukin 13/interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the interleukin-13/interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. RESULTS: Aside from expected evidence that inhibition of interleukin-13 and interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the interleukin-13 pathway alone or the combined interleukin-13/interleukin-4 pathways. CONCLUSIONS: Although our findings are reassuring, long-term safety assessments of biologics that target the interleukin-13/interleukin-4 pathways currently in clinical development are needed. PMID- 29411338 TI - A Multi-hospital Before-After Observational Study Using a Point-Prevalence Approach with an Infusion Safety Intervention Bundle to Reduce Intravenous Medication Administration Errors. AB - INTRODUCTION: We previously found a high rate of errors in the administration of intravenous medications using smart infusion pumps. OBJECTIVES/DESIGN: An infusion safety intervention bundle was developed in response to the high rate of identified errors. A before-after observational study with a prospective point prevalence approach was conducted in nine hospitals to measure the preliminary effects of the intervention. MAIN OUTCOME MEASURES: Primary outcome measures were overall errors and medication errors, with the secondary outcome defined as potentially harmful error rates. RESULTS: We assessed a total of 418 patients with 972 medication administrations in the pre-intervention period and 422 patients with 1059 medication administrations in the post-intervention period. The overall error rate fell from 146 to 123 per 100 medication administrations (p < 0.0001), and the medication error rate also decreased from 39 to 29 per 100 medication administrations (p = 0.001). However, there was no significant change in the potentially harmful error rate (from 0.5 to 0.8 per 100 medication administrations, p = 0.37). An intervention component aiming to reduce labeling not-completed errors was effective in reducing targeted error rates, but other components of the intervention bundle did not show significant improvement in the targeted errors. CONCLUSION: Development and implementation of the intervention bundle was successful at reducing overall and medication error rates, but some errors remained and the potentially harmful error rate did not change. The error rate reductions were not always correlated with the specific individual interventions. Further investigation is needed to identify the best strategies to reduce the remaining errors. CLINICAL TRIALS REGISTRATION: Registered at ClinicalTrials.gov, identifier: NCT02359734. PMID- 29411340 TI - Neuropilin 1 in uterine leiomyosarcoma. Clinical and pathological analysis. AB - OBJECTIVES: The role of angiogenesis in leiomyosarcomas still remains unclear. The aim of this study was to evaluate the NRP1 expression in the leiomyosarcoma tissues and to find the relations between its expression and the clinical features. MATERIAL AND METHODS: The study group consisted of 50 patients with diagnosis of the uterine leiomyosarcoma. Clinical and follow up data were collected. Using immunohistochemical methods the expression of NRP1 was detected. RESULTS: The lack of NRP1 expression was found in 14 cases, positive (weak or moderate) expression was noted in 36 cases. The significantly higher expression of NRP1 was observed in more severe clinical stages in comparison to lower stages of the disease. The significantly shorter survival of patients with the positive expression of NRP1 in leiomyosarcoma was observed. CONCLUSIONS: The expression of NRP1 is associated with clinical advancement and worse prognosis in uterine LMS. Neuropilin 1 can be widely used as a postoperative survival predictor for the patients suffering from uterine LMS. PMID- 29411341 TI - Does IGF-1 play a role in the biology of ovarian cancer? AB - OBJECTIVES: The aim of the study was to investigate serum concentrations of the insulin-like growth factor-1 in women with ovarian cancer and healthy controls, and to compare free IGF-1 levels with selected clinical and pathological param eters. Correlation analysis was used to measure the following: IGF-1 concentration and Ca125; IGF-1 level and the height of the OC patients. MATERIAL AND METHODS: The study included 70 patients with OC and 50 healthy controls. Serum concentrations of free IGF-1 were measured in all subjects. Routine diagnostic tests (CBC and USG and Ca125) were performed. RESULTS: Significantly higher serum concentrations of free IGF-1 were found in the study group as compared to controls. No statistically significant relationships between IGF-1 serum concentrations and tumor differentiation, histological type, and disease stage were detected. No statistically significant correlations between IGF-1 and Ca125 level or between IGF-1 and growth of OC patients were found. CONCLUSIONS: Serum IGF-1 participates in the etiopathogenesis of ovarian cancer in menstruating women, while local synthesis of this factor and other components of the autocrine loop of the IGF-1 system play a greater role in their post menopausal peers. PMID- 29411342 TI - Impact of experimental diabetes and chronic hypoxia on rat fetal body weight. AB - OBJECTIVES: The aim of the study is to determine the impact of the experimental diabetes and the chronic hypoxia on pregnancy development and rat fetal body weight. MATERIAL AND METHODS: The experiment was performed on female Wistar rats. Animals were divided into the experimen-tal groups. I - Controls, II - Untreated diabetes, III - Insulin-treated diabetes, IV - No diabetes with chronic hypoxia, V - Untreated diabetes and chronic hypoxia, VI - Insulin- treated diabetes and chronic hypoxia. Diabetes was induced in groups II, III, V and VI with intraperitoneal injection of streptozocin (STZ) at a dose of 40 mg/kg. Chronic hypoxia was induced by placing dams (groups IV, V and VI) in conditions of 10.5% oxygen and 89.5%. Insulin was administered subcutaneously at the dose of 9 IU/kg. Starting from the 6th day after STZ injection and chronic hypoxia conditions animals were caged together for 12 hours for 3 consecutive days to ensure fertilization. On day 21 of gestation the animals were decapitated, the fetuses were removed and weighted. RESULTS: Mean fetal body weight in separate groups were: I - 5.38 g, II - 6.04g, III - 5.32g, IV- 5.56 g, V - 3.45 g, VI - 6.23 g. CONCLUSIONS: Pre-existing type 1 diabetes does not affect fetal body weight compared to healthy newborn control rats. Pro-longed hypoxia does not impact on fetal body weight. Chronic hypoxia during pregnancy complicated with untreated type 1 diabetes mellitus leads to significant reduction of fetal body weight. Insulin treatment reversed the detrimental effect of chronic hypoxia on fetal development. PMID- 29411343 TI - Does reactive hypoglycemia during the 100 g oral glucose tolerance test adversely affect perinatal outcomes? AB - OBJECTIVES: To determine whether pregnant women who have reactive hypoglycemia during the 100 g oral glucose toler-ance test (OGTT) are at an increased risk of poor pregnancy outcomes. MATERIAL AND METHODS: We retrospectively analyzed perinatal data from 413 women who underwent a 3 h OGTT at 24-28 weeks of gestation and gave birth in our clinics between January 2012 and December 2014. RESULTS: According to OGTT results, the majority of the subjects were normoglycemic (n = 316, 76.5%), while 49 (11.9%) were diagnosed with gestational diabetes, and 33 (8.0%) had single high glucose values. Reactive hypoglycemia was de-tected in only 15 patients (3.6%). The mean age of the women in the reactive hypoglycemia group was significantly lower than that of the women in the gestational diabetes and single high glucose value groups (26.4 +/- 4.4 years, 31.4 +/- 5.4 years, and 31.8 +/- 4.3 years, respectively; p < 0.05). The newborns of the women in the reactive hypoglycemia group had higher rates of APGAR scores < 7, increased admission to the neonatal intensive care unit (NICU), and lower birth weights compared with the other groups (p < 0.001, p < 0.001, and p = 0.009, respectively). CONCLUSION: Reactive hypoglycemia during the 3 h 100 g OGTT is significantly associated with low APGAR scores, low birth weights, and prenatal admission to the NICU. Therefore, pregnant women who develop hypoglycemia during the 100 g OGTT performed at 24-28 weeks of gestation should receive attentive follow-up care to decrease the possibility of adverse perinatal outcomes. PMID- 29411344 TI - Maternal and perinatal outcomes of dichorionic diamniotic twin pregnancies diagnosed with vanishing twin syndrome: a retrospective analysis from a single clinical center. AB - OBJECTIVES: Multiple pregnancies are known to be associated with adverse maternal and perinatal complications. How-ever, data regarding the outcomes of spontaneously reduced twin pregnancies are limited. In the current study we aimed to evaluate the consequences of the vanishing twin syndrome (VTS) in dichorionic diamniotic twin pregnancies for both mother and baby in our perinatal center. MATERIAL AND METHODS: A total of 711 pregnancies were included into the study. 51 cases of vanishing twin syndrome constituted Group 1, 235 cases of normal twins constituted Group 2, and 425 singleton pregnancies formed Group 3. The pregnancies that had multifetal reduction and monochorionic twinning were excluded from both study group and twin control group. The collected data were as follows: age, gravidity, parity, gestational week at birth, delivery route, birth weight, obstetric complications, and maternal and perinatal outcomes. RESULTS: No significant difference was observed between the groups regarding mean maternal age (p > 0.05). Mean birth weight, gestational age at birth and preterm birth ratio were significantly lower in the Group 2 when compared with Group 1 and Group 3 (all p < 0.001). Adverse perinatal outcomes including very low birth weight (VLBV) and low Apgar scores were more common in Group 1 (p < 0.05), but no significant difference was found between the groups in terms of neona-tal intensive care unit admission and perinatal mortality ratios (p > 0.05). Obstetric complications such as preeclampsia, gestational diabetes and intrauterine growth restriction were significantly higher in Group 2 than in Group 1 and Group 3 (all p < 0.05). However, severe maternal morbidities were similar among three groups (p = 0.141). CONCLUSIONS: VTS is seems to be associated with VLBV and low Apgar scores. However, the incidence of severe maternal and perinatal morbidity and mortality in pregnancies with VTS is similar to other pregnancies. PMID- 29411345 TI - Psychosomatic symptoms of the Couvade syndrome in Finnish and Polish expectant fathers. AB - OBJECTIVES: The aim of the study was to assess the occurrence of symptoms associated with the Couvade syndrome in two groups of men of Polish and Finnish nationality, and to perform a comparative analysis. MATERIAL AND METHODS: The study was conducted in two groups of men (expectant fathers): 51 Poles and 40 Finns using a self-constructed questionnaire prepared in Polish and English languages. The statistical analysis was performed in Micro-soft Office Excel 2010 and Statistica 12. The Pearson's test was calculated, and the statistical significance level was p < 0.05. RESULTS: The most common physical symptoms reported by the Polish men were weight gain (78%) and gastric disorders (80%), whereas the Finns most frequently declared weight gain (60%). As for emotional symptoms, mood swings (p = 0.0001) and sleep disorders (p = 0.00004) were significantly more common in the Poles, whilst the Finns experienced frustration (p = 0.0403) and nervousness (p = 0.01579) significantly more frequently. The Finnish respondents more often used profes-sional forms of preparation for childbirth and parenthood (p = 0.00229). CONCLUSIONS: Psychosomatic symptoms of the Couvade syndrome are significantly more common in Polish than in Finnish expectant fathers. Compared with Polish fathers, Finns significantly more frequently attend ante-natal classes. Ante-natal care should encompass education of men as they do experience the symptoms of the Couvade syndrome during their wives'/partners' pregnancies. PMID- 29411346 TI - Post-menopausal vulvovaginal atrophy - an overview of the current treatment options. AB - Sex hormone deficiency in post-menopausal women causes changes in the lower urinary tract. Vulvovaginal atrophy is a pathology resulting from those changes. VVA has a negative effect on the quality of life therefore prompting a search for new therapeutic options. The aim of this article is to summarize the current treatment modalities, both hormonal and non-hormonal for post-menopausal vaginal atrophy. Topical oestrogen therapy remains the "golden standard". Alternatives, although promising, require well-designed control studies. PMID- 29411347 TI - Child sexual abuse as an etiological factor of overweight and eating disorders - considerations for primary health care providers. AB - Despite the recognition of the clinical importance of child sexual abuse, primary health care providers are often not ad-equately prepared to perform medical evaluations and diagnose child sexual maltreatment. Paper presents basic symptoms and signs of CSA, which may suggest the need for further patient's diagnosis and referral. Since the great majority of sexually abused children do not have any abnormal physical findings, special attention is paid to the silent warning signs of CSA, such as changes in attitude towards own body and eating habits. Numerous studies suggest that victims of CSA may develop obesity or eating disorders of various forms and intensities. PMID- 29411348 TI - Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. AB - OBJECTIVE: To determine the frequency of older Americans with epilepsy receiving concomitant prescriptions for antiepileptic drugs (AEDs) and non-epilepsy drugs (NEDs) which could result in significant pharmacokinetic (PK) interaction, and to assess the contributions of racial/ethnic, socioeconomic, and demographic factors. METHODS: Retrospective analyses of 2008-2010 Medicare claims for a 5% random sample of beneficiaries >=67 years old in 2009 augmented for minority representation. Prevalent cases had >=1 ICD-9 345.x or >=2 ICD-9 780.3x, and >=1 AED. Among them, incident cases had no seizure/epilepsy claim codes nor AEDs in preceding 365 days. Drug claims for AEDs, and for the 50 most common NEDs within +/- 60 days of the index epilepsy date were tabulated. Interacting pairs of AEDs/NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. RESULTS: Interacting drug pairs affecting NED efficacy were found in 24.5% of incident, 39% of prevalent cases. Combinations affecting AED efficacy were found in 20.4% of incident, 29.3% of prevalent cases. Factors predicting higher interaction risk included having >= 1 comorbidity, being eligible for Part D low Income Subsidy, and not living in the northeastern US. Protective factors were Asian race/ethnicity, and treatment by a neurologist. SIGNIFICANCE: A substantial portion of older epilepsy patients received NED-AED combinations that could cause important PK interactions. The lower frequency among incident vs. prevalent cases may reflect changes in prescribing practices. Avoidance of interacting AEDs is feasible for most persons because of the availability of newer drugs. PMID- 29411349 TI - Lumbopelvic Pain and Threats to Walking Ability in Well-Functioning Older Adults: Findings from the Baltimore Longitudinal Study of Aging. AB - OBJECTIVES: To examine the potential contribution of severity of lumbopelvic pain (LPP) in well-functioning older adults to poorer walking efficiency, lack of endurance, slower gait speed, and decline in these mobility parameters over 1 to 5 years. DESIGN: Longitudinal analysis of Baltimore Longitudinal Study of Aging data. SETTING: National Institute on Aging, Clinical Research Unit, Baltimore, Maryland. PARTICIPANTS: Well-functioning men and women aged 60 to 89 (N=878). MEASUREMENTS: An interviewer-administered questionnaire was used to ascertain reported presence and severity of back and hip pain in the preceding 12 months and reported walking ability, including ease of walking a mile. Certified examiners assessed usual gait speed, the energetic cost of walking (oxygen consumption, mL per kg/m), and time taken to walk 400 m as quickly as possible. Covariates included sex, age, age-squared, race, height, weight, exercise, and smoking. RESULTS: Overall, 31.4% had mild LPP, and 15.7% had moderate to severe LPP. In adjusted analyses, reported walking ability (p<.001), endurance walk performance (p=.007), and energetic cost of walking (p=.049) were worse with increasing LPP severity. Usual gait speed did not vary according to LPP (p=.31). Longitudinally, over an average 2.3 years, persons with new or sustained LPP had worse follow-up level, greater mean decline, and higher likelihood of meaningful decline in reported walking ability than persons free of LPP or whose LPP resolved. Walking performance did not differ according to LPP follow-up status. CONCLUSION: LPP was common in well-functioning older adults and was associated with greater energetic cost of walking and poorer perceived and observed walking endurance. The longitudinal effect of LPP is unclear, but worsening perception of walking ability and its contribution to future mobility loss warrants further attention. PMID- 29411350 TI - Counteraction ability of TMAO toward different denaturing agents. AB - Differential scanning calorimetry measurements performed on RNase A in aqueous binary solutions containing different concentrations of urea, tetramethylurea, guanidinium chloride, and guanidinium thiocyanate, and in aqueous ternary solutions, containing the same denaturants plus 1 M trimethylamine N-oxide, TMAO, demonstrate that the latter has a general counteracting ability at pH 7.0, but not at pH 4.0. Experimental data rule out the idea that counteraction originates from direct interactions between TMAO molecules and denaturing agents. A rationalization is provided on the basis of a theoretical approach grounded on the solvent-excluded volume effect, whose magnitude depends on the density of aqueous solutions. PMID- 29411351 TI - Comparative safety and efficacy of topical mometasone furoate with other topical corticosteroids. AB - Derivatives of hydrocortisone, such as mometasone furoate, a (2') furoate-17 ester with chlorine substitutions at positions 9 and 21, have been designed to improve efficacy and reduce the incidence of adverse effects. An extensive literature search of MEDLINE, Embase and other databases was conducted to review the safety and efficacy of various formulations of topical mometasone furoate. Mometasone furoate exhibits high potency with greater anti-inflammatory activity and a longer duration of action than betamethasone. In clinical trials, mometasone furoate shows comparable or significantly better efficacy, depending on the comparator, in all indications studied in both adults and children. It is well tolerated with only transient, mild to moderate local adverse effects. It is characterised by low systemic availability due to its high lipophilicity, low percutaneous absorption and rapid hepatic biotransformation, and consequently has no significant effect on the hypothalamic-pituitary-adrenal axis. The molecular biotransformation of mometasone furoate in the skin results in a lower affinity with dermal cells than epidermal cells, which contributes to its low atrophogenicity. Sensitisation to mometasone furoate is low. Overall, mometasone furoate is a highly efficacious potent corticosteroid with a low risk of both local and systemic adverse effects. PMID- 29411352 TI - Risk of depression among patients with acne in the U.K.: a population-based cohort study. PMID- 29411353 TI - Group Education and Multidisciplinary Management for Chronic Headaches Among Adolescents in a Military Treatment Facility: A Retrospective Chart Review. AB - OBJECTIVE: To assess the effect of group education on the frequency of chronic headaches among adolescents. BACKGROUND: Chronic headaches are a common problem among adolescents with significant psychosocial morbidity. Brief education on lifestyle interventions to decrease headache frequency has established benefits among adult patients but is less proven among adolescents. METHODS: This study is a chart review examining our experience with a group education program for 155 adolescents, aged 12-17 years old, enrolled in the U.S. military medical system with at least 3 months of chronic headaches who were referred to a headache evaluation clinic. The primary outcome of our study was self-reported number of days with a headache in the previous 30 days based on patient recall. We used a paired samples t-test to measure the change in headache frequency between the frequency reported at the headache class and follow-up more than 6 months after the class. RESULTS: Most of the adolescents seen in the program were female (114/155 [73.5%]) and suffered from migraine headaches (108/155 [69.8%]). Severe headache-related disability was reported by 40.6% of subjects (63/155). Subjects reported an average of 19 days with headache during the previous 30 days. Females and patients with higher headache-related disability reported a higher number of days with headache. Participation in the group education was associated with an 11.5 (SD 11.9, P < .001) day decrease in the frequency of headaches during the previous 30 days at follow-up at least 6 months after the class, with largest decline seen in patients with the highest level of migraine-related disability at baseline. CONCLUSION: Based on our retrospective chart review study, group education on headache evaluation and lifestyle management has potential as an effective, low-cost intervention for treatment of chronic headaches among adolescents. PMID- 29411354 TI - 3D quantitative comparative analysis of long bone diaphysis variations in microanatomy and cross-sectional geometry. AB - Long bone inner structure and cross-sectional geometry display a strong functional signal, leading to convergences, and are widely analyzed in comparative anatomy at small and large taxonomic scales. Long bone microanatomical studies have essentially been conducted on transverse sections but also on a few longitudinal ones. Recent studies highlighted the interest in analyzing variations of the inner structure along the diaphysis using a qualitative as well as a quantitative approach. With the development of microtomography, it has become possible to study three-dimensional (3D) bone microanatomy and, in more detail, the form-function relationships of these features. This study focused on the selection of quantitative parameters to describe in detail the cross-sectional shape changes and distribution of the osseous tissue along the diaphysis. Two-dimensional (2D) virtual transverse sections were also performed in the two usual reference planes and results were compared with those obtained based on the whole diaphysis analysis. The sample consisted in 14 humeri and 14 femora of various mammalian taxa that are essentially terrestrial. Comparative quantitative analyses between different datasets made it possible to highlight the parameters that are strongly impacted by size and phylogeny and the redundant ones, and thus to estimate their relevance for use in form-function analyses. The analysis illustrated that results based on 2D transverse sections are similar for both sectional planes; thus if a strong bias exists when mixing sections from the two reference planes in the same analysis, it would not problematic to use either one plane or the other in comparative studies. However, this may no longer hold for taxa showing a much stronger variation in bone microstructure along the diaphysis. Finally, the analysis demonstrated the significant contribution of the parameters describing variations along the diaphysis, and thus the interest in performing 3D analyses; this should be even more fruitful for heterogeneous diaphyses. In addition, covariation analyses showed that there is a strong interest in removing the size effect to access the differences in the microstructure of the humerus and femur. This methodological study provides a reference for future quantitative analyses on long bone inner structure and should make it possible, through a detailed knowledge of each descriptive parameter, to better interpret results from the multivariate analyses associated with these studies. This will have direct implications for studies in vertebrate anatomy, but also in paleontology and anthropology. PMID- 29411355 TI - A Diary Study of Basic Psychological Needs and Daily Headache Experience. AB - OBJECTIVE: A diary study was conducted to investigate the relationships between headache activity and basic psychological needs satisfaction. METHODS: One hundred sixteen young adults (M age = 19.17 (SD = 2.90); 81.7% female; 75.9% Caucasian) completed an online daily diary of headache activity and needs satisfaction for 3 weeks. Data were analyzed using hierarchical linear modeling. RESULTS: On days when headache occurred, participants reported decreased needs satisfaction of competence (gamma10 = -0.18, P = .014) and relatedness (gamma10 = -0.24, P = .003), and a marginal but not significant reduction in autonomy (gamma10 = -0.13, P = .067). Additionally, more severe headaches were associated with decreased needs satisfaction in autonomy (gamma10 = -0.08, P = .009), competence (gamma10 = -0.08, P = .011), and relatedness (gamma10 = -0.09, P = .005). Presence of a headache diagnosis did not moderate the relationship between headache occurrence and basic needs satisfaction (all Ps >= .24). CONCLUSIONS: This preliminary study is the first to show that headache is related to reduced basic psychological needs satisfaction, providing a potential account for one mechanism by which headache may negatively affect quality of life. Further research is needed to extend these findings to larger samples of migraine sufferers to enable more thorough between-group comparisons of headache-related burden on basic needs satisfaction. These findings may be informative for treatment approaches that focus on outcomes beyond mere symptom reduction. PMID- 29411356 TI - Enhancing group cognitive-behavioral therapy for hoarding disorder with between session Internet-based clinician support: A feasibility study. AB - OBJECTIVE: Hoarding disorder (HD) is difficult to treat. In an effort to increase efficacy and engagement in cognitive-behavioral therapy (CBT), we developed and evaluated a novel intervention comprising group CBT combined with between-session Internet-based clinician support for people with HD. METHOD: Twenty participants with HD received group CBT combined with an Internet-support system enabling therapist-participant communication between group sessions. RESULTS: The treatment was associated with a significant reduction on the Saving Inventory Revised (SI-R) and a large effect size (Cohen's d = 1.57) was found at posttreatment. Treatment gains were maintained at the 3-month follow-up. Group attendance was high and no participants dropped out from treatment prematurely. Between-session motivational support from the therapist was most frequently mentioned as the main strength of the system. CONCLUSION: The results of this study support adding Internet-based clinician support to group CBT for HD to increase treatment adherence and, potentially, improve the overall efficacy of CBT. PMID- 29411357 TI - Iodine-containing supplement use by pregnant women attending antenatal clinics in Western Australia. AB - BACKGROUND: Iodine requirements increase during pregnancy and although national recommendations for daily iodine supplementation (150 ug) exist, there is no research related to the uptake of these recommendations by pregnant women in Western Australia. AIMS: To investigate the use of iodine-containing supplements and associations with their use in a sample of Western Australian pregnant women. MATERIALS AND METHODS: A cross-sectional study was conducted on pregnant women attending antenatal clinics in a public tertiary hospital for women and neonates in Perth during 2012 and 2013 (n = 425). Women completed a self-administered questionnaire. Frequencies and percentages were obtained for categorical variables and chi2 tests conducted to assess associations between iodine containing supplement use and sociodemographic and pregnancy-related factors. RESULTS: A total of 24% of pregnant women reported using iodine-containing supplements prior to pregnancy compared to 66% during the previous two months. Age and maternal income were associated with use prior to pregnancy only (P = 0.004 and P = 0.031) and first pregnancy was associated with use during pregnancy only (P = 0.006). Ethnicity and reporting use in the first two trimesters were associated with the use of iodine supplements both in the year prior to pregnancy (P = 0.002 and P = 0.020, respectively) and during pregnancy (P < 0.001 and P = 0.001, respectively). CONCLUSIONS: Two-thirds of women reported use of iodine containing supplements during pregnancy, within the range reported for other Australian states. One-quarter reported use prior to pregnancy. Public health strategies are required to promote awareness of the importance of iodine and supplementation both before and during the entire pregnancy. PMID- 29411358 TI - Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. AB - Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre hospital administration of the drug. The measured concentration was 28.7 (21.5 38.5 [8.7-89.0]) MUg.ml-1 . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations. PMID- 29411359 TI - Comparison of laryngeal morbidities with modified reinforced silicone tube intubation guided over a bougie vs. a guidewire: novel assessment with voice analysis. AB - Semi-rigid flexible introducer-guided tracheal intubation is associated with pharyngolaryngeal morbidities. We compared the practice of railroading a newly described modified reinforced silicone tracheal tube with a built-in guide channel in its wall over a non-kinking guidewire with railroading the same tube over a disposable bougie, with respect to pharyngolaryngeal morbidities. One hundred and twenty-four ASA 1 and 2 adults were randomly assigned to undergo bougie-guided (n = 62) or wire-guided (n = 62) intubation under general anaesthesia. All patients were assessed for postoperative pharyngolaryngeal complaints. In addition, voice parameters (fundamental frequency, shimmer, jitter and harmonic noise ratio) with vowels 'a' and 'i' were analysed pre-operatively and 24 h postoperatively. The success of first-attempt intubation and the associated haemodynamic response were also recorded. A higher incidence of pharyngolaryngeal complaints was seen in the bougie group, 48.3%, 95%CI (35.9 60.9%) when compared with wire-guided group 28.3%, 95%CI (18.0-40.6%), p = 0.01. Postoperatively, all the voice parameters were significantly more affected when compared with their pre-operative value in the bougie-guided group (p < 0.05) but not in the wire-guided group. The success of first-attempt intubation was similar in both groups. Wire-guided orotracheal intubation was associated with a lower incidence of pharyngolaryngeal complaints and effect on voice when compared with bougie-guided intubation. PMID- 29411360 TI - Efficacy of group cognitive rehabilitation therapy in multiple sclerosis. AB - OBJECTIVE: Cognitive impairment occurs in 40%-65% of patients with multiple sclerosis (MS). Several techniques for cognitive rehabilitation (CR) in these patients have been evaluated; however, the results have been controversial. In this study, we investigated the efficacy of group compensatory CR in patients with MS-related cognitive impairment. MATERIALS AND METHODS: Thirty-four female patients with diagnosed relapsing-remitting MS and evidence of impaired cognitive function were included and randomized to intervention (n = 17) and control (n = 17) groups. CR intervention consisted of eight 2-hour sessions of comprehensive group CR over a 4-week period that focused on improvement of memory, attention, and executive function. As placebo, the control group received the same number of non-therapeutic group sessions. Assessment of cognitive function was performed before intervention (pretest), at the end of intervention (post-test), and 3 months later (follow-up). RESULTS: The study population included 34 patients with a mean age of 35.5 years. Statistical comparison of memory assessments at 3-month follow-up showed significantly higher scores in the CR group than in the control group (93.33 vs 86.40 for Addenbrooke's Cognitive Examination test and 16.58 vs 12.00 for visual memory, 19.32 vs 14.05 for verbal memory, and 51.28 vs 44.41 for general scores on the Memory Functioning Questionnaire test, respectively). Wisconsin card sorting test score comparison showed significantly lower total time consumption in the CR group than in the control group (308.1 vs 340.8 seconds, respectively). Behavior rating inventory of executive function-adult scores in all four subtests were significantly higher in the CR group than in the control group (40.25 vs 55.4 for behavioral regulation index, 51.16 vs 68.6 for metacognition index, and 97.41 vs 124.00 for global executive composite, respectively). Attention was the only domain in which we did not observe any significant variation between groups in terms of post-test and follow-up scores. CONCLUSION: This study supports the efficacy of group CR in the improvement of cognitive function in patients with MS. PMID- 29411361 TI - Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo. AB - One of the crucial challenges in the clinical management of cancer is the resistance to chemotherapeutics. We recently demonstrated that the Hedgehog receptor Patched, which is overexpressed in many recurrent and metastatic cancers, is a multidrug transporter for chemotherapeutic agents such as doxorubicin. The present work provides evidences that Patched is expressed in adrenocortical carcinoma (ACC) patients, and is a major player of the doxorubicin efflux and the doxorubicin resistance in the human ACC cell line H295R. We discovered that methiothepin inhibits the doxorubicin efflux activity of Patched. This drug-like molecule enhances the cytotoxic, pro-apoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells which endogenously overexpress Patched, and thereby mitigates the resistance of these cancer cells to doxorubicin. Moreover, we report that in mice the combination of methiothepin with doxorubicin prevents the development of xenografted ACC tumors more efficiently than doxorubicin alone by enhancing the accumulation of doxorubicin specifically in tumors without obvious undesirable side effects. Our results suggest that the use of an inhibitor of Patched drug efflux such as methiothepin in combination with doxorubicin could be a promising therapeutic option for adrenocortical carcinoma, and most likely also for other Patched-expressing cancers. PMID- 29411362 TI - The analgesic efficacy of forced coughing during cervical punch biopsy: A prospective randomised controlled study. AB - INTRODUCTION: Cervical punch biopsies are a common ambulatory procedure, performed routinely by gynaecologists. The aim of the present study was to assess the efficacy of forced coughing as a pain-reducing technique during cervical punch biopsy compared to a control group. MATERIALS AND METHODS: The study was a prospective randomised-control trial. The study group comprised 90 women who underwent cervical punch biopsies during investigation of abnormal Pap test results. The women were randomly assigned to 'cough' and control groups. Pain was measured on a 10 cm visual analogue scale (VAS) during different stages of the procedure. RESULTS: VAS pain score during biopsies was significantly lower in the 'cough' group. The median pain level in the 'cough' group was 1.5, compared to 4.0 in the control group. Eighty percent of the women in the 'cough' group reported a pain level of 2.0 or less compared to 40% of the women in the 'control' group (P = 0.0002). In the second biopsy, 69% of the women reported VAS <= 2.0 in the cough group compared to 28% of the patients in the control group. Forced coughing was shown both to reduce anxiety regarding the prospect of future cervical procedures and to decrease patients' desires for future pain management. This was true for 32% of the women in the 'control' group compared to 12% of the women in the 'cough' group (P = 0.05). CONCLUSION: Forced coughing provides significant pain relief during cervical punch biopsy and reduces the patients' fears and desires for pain medications in future procedures. PMID- 29411363 TI - Migraine Action Plan (MAP). PMID- 29411364 TI - Erratum. PMID- 29411365 TI - Frequency of Headache in Mitochondrial Disorders. PMID- 29411367 TI - Erratum. PMID- 29411366 TI - Case Report of the Safety Assessment of Transcranial Magnetic Stimulation Use in a Patient With Cardiac Pacemaker: To Pulse or Not to Pulse? AB - BACKGROUND: Single-pulse transcranial magnetic stimulation (sTMS) is an emerging neuromodulation method reported to be useful in migraine. Despite a low propensity for side effects, some concern with its use in patients with cardiac pacemakers has been expressed. CASE: We present a patient with chronic migraine with a cardiac pacemaker, who had tried unsuccessfully several migraine preventives with either poor efficacy or tolerability. With involvement of the cardiology team, we tested the effect of sTMS on her pacemaker and found it to be a safe and effective option for her. CONCLUSION: Having regard to the risk/benefit ratio of sTMS, its use in patients with disabling migraine in the presence of a cardiac pacemaker can be carefully evaluated and may represent a useful therapeutic option. PMID- 29411368 TI - Frequency of Headache in Mitochondrial Disorders: A Response. PMID- 29411370 TI - P-Hacking in Headache Research. PMID- 29411369 TI - Fibromyalgia Among Patients With Chronic Migraine and Chronic Tension-Type Headache: A Multicenter Prospective Cross-Sectional Study - A Response. PMID- 29411371 TI - The Complex Aura of Nikola Tesla. PMID- 29411372 TI - Fibromyalgia Among Patients With Chronic Migraine and Chronic Tension-Type Headache: A Multicenter Prospective Cross-Sectional Study: A Comment. PMID- 29411373 TI - Introducing the Migraine Action Plan. PMID- 29411375 TI - Corrigendum. PMID- 29411374 TI - A Survey of Neurologists on Postconcussion Syndrome. AB - BACKGROUND AND OBJECTIVES: Postconcussion syndrome (PCS) has been controversial for more than 150 years. As there have not been any surveys of PCS among neurologists in the United States since 1992, another was performed using most of the prior items to assess current opinions and practices and whether there have been any changes since 1992. METHODS: Two hundred and eighty-nine neurologists attending the Texas Neurological Society 20th Annual Winter Conference continuing medical education meeting in 2017 were supplied the survey instrument with registration materials. The 25 item instrument (including 7 new items) contained items on demographics, definitions, causation, prognosis, medicolegal aspects, testing, and treatment. Forty percent of attendees completed the survey. RESULTS: The majority of respondents agree with the following: PCS is a clearly defined syndrome with a solid basis for determining prognosis with an organic basis; accept the authenticity of patients' reports of symptoms; effective treatment is available for headaches lasting 3 months or more; headaches persist in over 20% 1 year after injury; and cognitive rehabilitation is effective. The majority of the respondents do not agree with the following: symptoms improve in a relatively short period of time and quickly resolve once litigation is settled; effective treatment is available for PCS; and return to play guidelines are strongly evidence based. 68.4% disagree with the following: I would support my son or grandson (or if you do not have one, relative's or friend's) playing football. [Correction added on February 9, 2018, after first online publication: "One year after injury" deleted.] CONCLUSIONS: There has been growing acceptance of the organicity of PCS among neurologists in the last 25 years. There is significant concern over the long-term sequelae of concussion as most respondents would not recommend that their son or grandson play football. PMID- 29411376 TI - Erratum. PMID- 29411377 TI - Memory decline from hippocampal electrodes? Let's not forget statistics and study design. PMID- 29411378 TI - Response: Memory decline from hippocampal electrodes? Let's not forget statistics and study design. PMID- 29411379 TI - Valuing and understanding fish populations in the Anthropocene: key questions to address. AB - Research on the values of fish populations and fisheries has primarily focused on bio-economic aspects; a more nuanced and multidimensional perspective is mostly neglected. Although a range of social aspects is increasingly being considered in fisheries research, there is still no clear understanding as to how to include these additional values within management policies nor is there a cogent appreciation of the major knowledge gaps that should be tackled by future research. This paper results from a workshop held during the 50th anniversary symposium of the Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017. Here, we aim to highlight the current knowledge gaps on the values of fish populations and fisheries thus directing future research. To this end, we present eight questions that are deeply relevant to understanding the values of fish populations and fisheries. These can be applied to all habitats and fisheries, including freshwater, estuarine and marine. PMID- 29411381 TI - Ectomycorrhizal host specificity in a changing world: can legacy effects explain anomalous current associations? AB - Despite the importance of ectomycorrhizal (ECM) fungi in forest ecosystems, knowledge about the ecological and co-evolutionary mechanisms underlying ECM host associations remains limited. Using a widely distributed group of ECM fungi known to form tight associations with trees in the family Pinaceae, we characterized host specificity among three unique Suillus-host species pairs using a combination of field root tip sampling and experimental bioassays. We demonstrate that the ECM fungus S. subaureus can successfully colonize Quercus hosts in both field and glasshouse settings, making this species unique in an otherwise Pinaceae-specific clade. Importantly, however, we found that the colonization of Quercus by S. subaureus required co-planting with a Pinaceae host. While our experimental results indicate that gymnosperms are required for the establishment of new S. subaureus colonies, Pineaceae hosts are locally absent at both our field sites. Given the historical presence of Pineaceae hosts before human alteration, it appears the current S. subaureus-Quercus associations represent carryover from past host presence. Collectively, our results suggest that patterns of ECM specificity should be viewed not only in light of current forest community composition, but also as a legacy effect of host community change over time. PMID- 29411380 TI - Allergic contact stomatitis caused by propolis candies. PMID- 29411382 TI - Differences in Neuropsychological Functioning Between Homicidal and Nonviolent Schizophrenia Samples. AB - Few studies have compared performance on neurocognitive measures between violent and nonviolent schizophrenia samples. A better understanding of neurocognitive dysfunction in violent individuals with schizophrenia could increase the efficacy of violence reduction strategies and aid in risk assessment and adjudication processes. This study aimed to compare neuropsychological performance between 25 homicide offenders with schizophrenia and 25 nonviolent schizophrenia controls. The groups were matched for age, race, sex, and handedness. Independent t-tests and Mann-Whitney U-tests were used to compare the schizophrenia groups' performance on measures of cognition, including composite scores assessing domain level functioning and individual neuropsychological tests. Results indicated the violent schizophrenia group performed worse on measures of memory and executive functioning, and the Intellectual Functioning composite score, when compared to the nonviolent schizophrenia sample. These findings replicate previous research documenting neuropsychological deficits specific to violent individuals with schizophrenia and support research implicating fronto-limbic dysfunction among violent offenders with schizophrenia. PMID- 29411384 TI - A novel antisense long noncoding RNA, TWISTED LEAF, maintains leaf blade flattening by regulating its associated sense R2R3-MYB gene in rice. AB - Natural antisense long noncoding RNAs (lncRNAs) are widespread in many organisms. However, their biological functions remain largely unknown, particularly in plants. We report the identification and characterization of an endogenous lncRNA, TWISTED LEAF (TL), which is transcribed from the opposite strand of the R2R3 MYB transcription factor gene locus, OsMYB60, in rice (Oryza sativa). TL and OsMYB60 were found to be coexpressed in many different tissues, and the expression level of TL was higher than that of OsMYB60. Downregulation of TL by RNA interference (RNAi) and overexpression of OsMYB60 resulted in twisted leaf blades in transgenic rice. The expression level of OsMYB60 was significantly increased in TL-RNAi transgenic plants. This suggests that TL may play a cis regulatory role on OsMYB60 in leaf morphological development. We also determined that the antisense transcription suppressed the sense gene expression by mediating chromatin modifications. We further discovered that a C2H2 transcription factor, OsZFP7, is an OsMYB60 binding partner and involved in leaf development. Taken together, these findings reveal that the cis-natural antisense lncRNA plays a critical role in maintaining leaf blade flattening in rice. Our study uncovers a regulatory mechanism of lncRNA in plant leaf development. PMID- 29411385 TI - Biogeographic constraints to marine conservation in a changing climate. AB - The siting of protected areas to achieve management and conservation objectives draws heavily on biogeographic concepts of the spatial distribution and connectivity of species. However, the marine protected area (MPA) literature rarely acknowledges how biogeographic theories underpin MPA and MPA network design. We review which theories from biogeography have been incorporated into marine spatial planning and which relevant concepts have yet to be translated to inform the next generation of design principles. This biogeographic perspective will only become more relevant as climate change amplifies these spatial and temporal dynamics, and as species begin to shift in and out of existing MPAs. The scale of climate velocities predicted for the 21st century dwarfs all but the largest MPAs currently in place, raising the possibility that in coming decades many MPAs will no longer contain the species or assemblages they were established to protect. We present a number of design elements that could improve the success of MPAs and MPA networks in light of biogeographic processes and climate change. Biogeographically informed MPA networks of the future may resemble the habitat corridors currently being considered for many terrestrial regions. PMID- 29411383 TI - Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone. AB - KEY POINTS: In isolated resistance arteries, endothelial modulation of vasoconstrictor responses to alpha1 -adrenoceptor agonists occurs via a process termed myoendothelial feedback: localized inositol trisphosphate (InsP3 ) dependent Ca2+ transients activate intermediate conductance Ca2+ -activated K+ (IKCa ) channels, hyperpolarizing the endothelial membrane potential to limit further reductions in vessel diameter. We demonstrate that IKCa channel-mediated myoendothelial feedback limits responses of isolated mesenteric arteries to noradrenaline and nerve stimulation, but not to the thromboxane A2 mimetic U46619 or to increases in intravascular pressure. In contrast, in the intact mesenteric bed, although responses to exogenous noradrenaline were limited by IKCa channel mediated myoendothelial feedback, release of NO and activation of endothelial small conductance Ca2+ -activated K+ (SKCa ) channels in response to increases in shear stress appeared to be the primary mediators of endothelial modulation of vasoconstriction. We propose that (1) the functional contribution of myoendothelial feedback to arterial tone is determined by the nature of the vasoconstrictor stimulus, and (2) although IKCa channel-mediated myoendothelial feedback may contribute to local control of arterial diameter, in the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction. ABSTRACT: Constriction of isolated resistance arteries in response to alpha1 -adrenoceptor agonists is limited by reciprocal engagement of inhibitory endothelial mechanisms via myoendothelial feedback. In the current model of feedback, agonist stimulation of smooth muscle cells results in localized InsP3 -dependent Ca2+ transients that activate endothelial IKCa channels. The subsequent hyperpolarization of the endothelial membrane potential then feeds back to the smooth muscle to limit further reductions in vessel diameter. We hypothesized that the functional contribution of InsP3 -IKCa channel-mediated myoendothelial feedback to limiting arterial diameter may be influenced by the nature of the vasoconstrictor stimulus. To test this hypothesis, we investigated the functional role of myoendothelial feedback in modulating responses of rat mesenteric resistance arteries to the adrenoceptor agonist noradrenaline, the thromboxane A2 mimetic U46619, increases in intravascular pressure and stimulation of perivascular sympathetic nerves. In isolated arteries, responses to noradrenaline and stimulation of sympathetic nerves, but not to U46619 and increases in intravascular pressure, were modulated by IKCa channel-dependent myoendothelial feedback. In the intact mesenteric bed perfused under conditions of constant flow, responses to exogenous noradrenaline were modulated by myoendothelial feedback, but shear stress-induced release of NO and activation of endothelial SKCa channels appeared to be the primary mediators of endothelial modulation of vasoconstriction to agonists and nerve stimulation. Thus, we propose that myoendothelial feedback may contribute to local control of diameter within arterial segments, but at the level of the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction. PMID- 29411386 TI - The wisdom of the body: Listeners' autonomic arousal distinguishes between spontaneous and posed vocal emotions. AB - It has been the matter of much debate whether perceivers are able to distinguish spontaneous vocal expressions of emotion from posed vocal expressions (e.g., emotion portrayals). In this experiment, we show that such discrimination can be manifested in the autonomic arousal of listeners during implicit processing of vocal emotions. Participants (N = 21, age: 20-55 years) listened to two consecutive blocks of brief voice clips and judged the gender of the speaker in each clip, while we recorded three measures of sympathetic arousal of the autonomic nervous system (skin conductance level, mean arterial blood pressure, pulse rate). Unbeknownst to the listeners, the blocks consisted of two types of emotional speech: spontaneous and posed clips. As predicted, spontaneous clips yielded higher arousal levels than posed clips, suggesting that listeners implicitly distinguished between the two kinds of expression, even in the absence of any requirement to retrieve emotional information from the voice. We discuss the results with regard to theories of emotional contagion and the use of posed stimuli in studies of emotions. PMID- 29411387 TI - A novel experimental system using the liverwort Marchantia polymorpha and its fungal endophytes reveals diverse and context-dependent effects. AB - Fungal symbioses are ubiquitous in plants, but their effects have mostly been studied in seed plants. This study aimed to assess the diversity of fungal endophyte effects in a bryophyte and identify factors contributing to the variability of outcomes in these interactions. Fungal endophyte cultures and axenic liverwort clones were isolated from wild populations of the liverwort, Marchantia polymorpha. These collections were combined in a gnotobiotic system to test the effects of fungal isolates on the growth rates of hosts under laboratory conditions. Under the experimental conditions, fungi isolated from M. polymorpha ranged from aggressively pathogenic to strongly growth-promoting, but the majority of isolates caused no detectable change in host growth. Growth promotion by selected fungi depended on nutrient concentrations and was inhibited by coinoculation with multiple fungi. The M. polymorpha endophyte system expands the resources for this model liverwort. The experiments presented here demonstrate a wealth of diversity in fungal interactions even in a host reported to lack standard mycorrhizal symbiosis. In addition, they show that some known pathogens of vascular plants live in M. polymorpha and can confer benefits to this nonvascular host. This highlights the importance of studying endophyte effects across the plant tree of life. PMID- 29411388 TI - First isolation of Weissella ceti responsible for outbreaks of weissellosis in farmed rainbow trout in Japan. PMID- 29411389 TI - 40 years of PCE: A successful recipe to take into the future. PMID- 29411390 TI - Amoebicidal activity of curcumin on Entamoeba histolytica trophozoites. AB - OBJECTIVES: This study was undertaken to investigate the amoebicidal potential of curcumin on Entamoeba histolytica, as well as its synergistic effect with metronidazole. METHODS: Entamoeba histolytica trophozoites were exposed to 100, 200 and 300 MUm of curcumin, for 6, 12 and 24 h. Consequently, the viability of cells was determined by trypan blue exclusion test. All specimens were further analysed by scanning electron microscopy. For drug combination experiment, the Chou-Talalay method was used. KEY FINDINGS: Curcumin affected the growth and cell viability in a time- and dose-dependent manner. The higher inhibitory effects were observed with 300 MUm at 24 h; 65.5% of growth inhibition and only 28.8% of trophozoites were viable. Additionally, curcumin also altered adhesion and the morphology of the trophozoites. Scanning electron microscopy revealed treated trophozoites with damages on the membrane, size alterations and parasites with loss of cellular integrity. In addition, the combination of curcumin + metronidazole exhibited a synergistic effect; the activity of both drugs was improved. CONCLUSIONS: This is the first report evaluating the effectiveness of curcumin against E. histolytica. Our results suggest that CUR could be considered for evaluation in future pharmacological studies as a promising amoebicidal agent or as complementary therapy. PMID- 29411391 TI - Alteronol induces cell cycle arrest and apoptosis via increased reactive oxygen species production in human breast cancer T47D cells. AB - OBJECTIVE: Emerging evidence showed that alteronol has a potential antitumour effect in several tumour cells. However, the antitumour effect of alteronol on breast cancer has not been reported. This study investigated the mechanisms of alteronol-induced cell proliferation inhibition in human breast cancer T47D cells. METHODS: After treatment with alteronol, T47D cell proliferation was examined by MTT assay. The cell cycle distribution, cell apoptosis, reactive oxygen species level and mitochondrial membrane potential were evaluated via flow cytometry. Next, the protein levels of cyclin B1, cdc2, p21, p-cyclin B1, p-cdc2, p53, Bax, Bcl-2 and cytochrome c were analysed using Western blot analysis. Meanwhile, the mRNA levels of cyclin B1, cdc2, p21 and p53 were examined by qRT PCR. KEY FINDINGS: Our data showed that alteronol inhibited the proliferation of T47D cells via inducing G2-phase arrest and cell apoptosis. Compared with control group, alteronol significantly increased ROS level and triggered mitochondrial dysfunction in alteronol-treated T47D cells. Further studies showed that the mRNA and protein levels of cdc2 and cyclin B1 were downregulated, while the mRNA and protein levels of p21, p53, p-cyclin B1, p-cdc2 and cytochrome c were upregulated. In addition, the expression level of Bax was increased, and the expression level of Bcl-2 was decreased. CONCLUSIONS: Alteronol induced T47D cell cycle arrest and cell apoptosis through increasing ROS production and triggering mitochondrial dysfunction, and subsequently inhibiting T47D cell proliferation. PMID- 29411392 TI - Evaluation Of A Powder-Free DNA Extraction Method For Skeletal Remains. AB - Bones are often recovered in forensic investigations, including missing persons and mass disasters. While traditional DNA extraction methods rely on grinding bone into powder prior to DNA purification, the TBone Ex buffer (DNA Chip Research Inc.) digests bone chips without powdering. In this study, six bones were extracted using the TBone Ex kit in conjunction with the PrepFiler(r) BTATM DNA extraction kit (Thermo Fisher Scientific) both manually and via an automated platform. Comparable amounts of DNA were recovered from a 50 mg bone chip using the TBone Ex kit and 50 mg of powdered bone with the PrepFiler(r) BTATM kit. However, automated DNA purification decreased DNA yield (p < 0.05). Nevertheless, short tandem repeat (STR) success was comparable across all methods tested. This study demonstrates that digestion of whole bone fragments is an efficient alternative to powdering bones for DNA extraction without compromising downstream STR profile quality. PMID- 29411393 TI - Culturally embedded health beliefs, self-care and the use of anti-ageing medicine among Australian and Japanese older adults. AB - Adopting Kleinman's and Lock's ideas that there are cultural variations in understandings of health care and the medicalisation of ageing bodies, this study compares and contrasts older adults' use of anti-ageing medicine in two cultural settings. Based on 42 interviews conducted in Australia and Japan with adults aged 60 and over, findings revealed distinct pathways to initiating anti-ageing medicine use between the two cohorts which reflect different attitudes to the medicalisation of ageing in the two settings. In Australia where consultation of medical doctors for major and minor ailments is routine for many older adults, supplement use was initiated on doctor's advice, or reactionary, in that dissatisfaction with doctors' advice was the impetus. By contrast, many Japanese elders did not seek the advice of medical practitioners for minor health issues, considering them instead to be part of a natural process of ageing, and viewed their supplement use as co-extensive with their use of Shokuji-ryohou or a traditional corrective diet. Despite these cultural differences, both the Australian and Japanese elders resisted more extreme manifestations of the biomedicalisation of ageing and took anti-ageing medicine to ward off the perceived danger of surgery in later life. PMID- 29411394 TI - The "next generation" reference laboratory? PMID- 29411395 TI - Surveys of blood collection and utilization. PMID- 29411396 TI - Remote emergency release of blood products using a custom iPad application. PMID- 29411397 TI - Anti-RhD reduces levels of detectable RhD antigen following anti-RhD infusion. PMID- 29411399 TI - Twiddler's syndrome in an adolescent female with an apheresis port. PMID- 29411400 TI - CeBr3 scintillators for 4 He prompt gamma spectroscopy: Results from a Monte Carlo optimization study. AB - PURPOSE: Range uncertainties limit the potential of charged particle therapy. In vivo and online range verification techniques could increase the confidence in the dose delivery distribution and lead to more conformal treatments. Prompt gamma imaging and prompt gamma spectroscopy (PGS) have been demonstrated for such a purpose. The successful application of these techniques requires the development of a dedicated detector system optimized to the radiation energy ranges and the intensity. In this work, we investigated a detector system based on CeBr3 crystals capable of performing spectroscopy of the prompt gamma radiation induced by 4 He beams. METHODS: We performed Monte Carlo simulations to optimize the detector system. The study was carried out both with the Geant4 toolkit and the FLUKA package. The simulated system consisted of a primary crystal for spectroscopy and secondary crystals for noise reduction in anticoincidence (AC). For comparison purposes, we considered a configuration without AC crystals. We first defined the dimensions of the primary cerium bromide (CeBr3 ) crystal and the secondary bismuth germanate (BGO) or CeBr3 crystals. We then evaluated their detection performance for monoenergetic gamma radiation up to 7 MeV in such way that the probability of the photo-peak detection was maximized in comparison to the number of escape peak and Compton events. We simulated realistic prompt gamma radiation spectra induced by 4 He beams on homogeneous targets (water, graphite, and aluminum) and on implants (water with an aluminum insert). Finally, we tested the performances of the optimized systems in the detection of the realistic gamma spectra. The quantitative analysis was accomplished by comparing the signal-to-noise ratio between the different configurations and the ability to resolve the discrete reactions. RESULTS: We present the optimized dimensions for the primary CeBr3 crystals with and without AC shielding. The specific values are given over a wide range of crystal volumes. The results show an optimal primary CeBr3 crystal with an approximately diameter to length ratio of 1 without AC shielding and 0.5 with AC shielding. The secondary BGO and CeBr3 should have a transverse dimension of 3 and 4.56 cm, respectively. The analysis of the prompt gamma spectra from 4 He beams highlighted the presence of specific discrete reactions not observed in 1 H studies, for example, 12 C transition 0+ (7.65 MeV) ->2+ (4.44 MeV). This reaction is responsible for the generation of the 3.21 MeV prompt gamma peak. The optimized primary crystal provides a significant increase in the signal-to-noise ratio together with an improved resolution of the discrete gamma lines, especially in the high-energy region. The detection configuration with an optimized anticoincidence crystal improved the signal-to-noise ratio up to a factor of 3.5. CONCLUSIONS: This work provides the optimal geometry for primary and secondary crystals to be used in range verification through PGS. The simulations show that such a PGS system may allow for the simultaneous detection of the discrete lines from a thin metal implant within a water phantom. PMID- 29411401 TI - Treatment patterns, costs, and mortality among Medicare beneficiaries with CIED infection. AB - BACKGROUND: Cardiac implantable electronic device (CIED) infection is a serious adverse event, but there are limited contemporary real-world data on treatment pathways and associated costs in the Medicare population following diagnosis of CIED infection. Hence, this study evaluates postinfection treatment pathways and associated healthcare expenditures and mortality among Medicare fee-for-service beneficiaries with CIED infection. METHODS: Retrospective cohort analysis of 5,401 beneficiaries who developed a device-related infection in the year following implantation/upgraded CIED (1/1/2010-12/31/2012). Patients were followed-up to 12 months/death following diagnosis of infection and were divided into mutually exclusive groups based on whether they underwent CIED system removal (Group I), or no CIED system intervention (Group II; IIA with or IIB without infection hospitalization). All-cause healthcare resource utilization/expenditures were also measured. RESULTS: In the year following infection, 64.1% of patients underwent device extraction, of who 2,109 (39.0%) had their device replaced (Group IA) and 1,355 (25.1%) had their device extracted without replacement (Group IB); 62.2% of patients were hospitalized and 25.3% of patients died. Mean Medicare payments-per-patient for facility-based services by group were: IA = $62,638 (standard deviation [SD]: $46,830), IB = $50,079 (SD: $45,006), IIA = $77,397 (SD: $79,130), and IIB = $22,856 (SD: $31,167). CONCLUSIONS: Hospitalizations were the largest cost driver; infection-related costs, including cost of extraction/replacement, accounted for >50% of expenditures for patients with surgical/hospital intervention. Management of CIED infection in Medicare beneficiaries is associated with high healthcare expenditures in the year following infection. Additional measures to prevent device infection are needed to improve the outcomes and reduce costs in these patients. PMID- 29411402 TI - Safety, tolerability, and efficacy evaluation of the SlimME device for circumference reduction. AB - OBJECTIVE: To assess the short- and long-term thermal impact of subclinical and clinical regimens of a single, non-invasive uniform ultrasound treatment session on subcutaneous adipose tissue (SAT). STUDY DESIGN: Prospective, open-label, single-arm, split-side study. METHODS: Patients (n = 17) were subjected to uniform ultrasound treatment, delivered in a single session with the SlimME device. The device was set to one of four treatment regimens, which differed in their durations and energy fluences during the raise and maintenance phases. Up to six abdominal regions were treated, with six patients receiving a different treatment on each side of the abdomen. Safety was assessed by measuring skin surface temperature, evaluating expected skin responses immediately and 30 min after treatment and via patient ratings of pain and discomfort. Efficacy of raising and then maintaining SAT temperatures at 48 degrees C, was determined by routinely measuring SAT temperatures during the treatment session and by histological analysis of samples collected 7 (n = 13) or 90 (n = 4) days after treatment. RESULTS: Trace to mild erythema was observed in up to 48% of the treated zones, which, in most cases, resolved within 30 minutes. No significant rise in mean skin surface temperature (<=26.5 degrees C) was recorded following any of the four tested regimens. Overall, patients reported tolerability to treatment, with the highest mean pain score registered for the moderate and high intensity regimens (4.4 +/- 1.5 and 4.9 +/- 1.4, respectively). Mean SAT temperatures did not exceed 48.4 +/- 2.5 degrees C and were effectively maintained throughout the maintenance phase of the treatment session. Low-energy fluence led to localized fat coagulative necrotic lesions, surrounded by subacute rim of inflammation, while high-energy fluence induced fat coagulative necrosis alongside granulomatous panniculitis, which resolved within 90 days. CONCLUSION: The tested uniform ultrasound regimens elicited SAT temperature elevations, with a subsequent energy-dependent increase in degree of fat necrosis. At the same time, the unique design spared the surrounding tissue from thermal damage and was associated with minimal discomfort. Taken together, the SlimME device constitutes an effective tool for destruction of stubborn hypodermal fat deposits. Lasers Surg. Med. (c) 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID- 29411403 TI - Occupational rhinitis and occupational asthma: Association or progression? AB - BACKGROUND: Occupational asthma is the most frequently reported occupational respiratory disease in registries, and is often co-diagnosed with occupational rhinitis. We undertook a systematic review of the English-language epidemiologic literature linking these two conditions, with emphasis on progression from occupational rhinitis to occupational asthma. METHODS: PubMed and Embase were queried in a series of structured searches designed to identify studies comparing occupational asthma and occupational rhinitis incidence or prevalence in occupationally exposed individuals. RESULTS: The searches yielded a total of 109 unique citations, 15 of which yielded inferential data on the occupational rhinitis-asthma relationship. Nine of fifteen studies showed statistically significant associations between the occurrence of occupational rhinitis and occupational asthma among individual workers. CONCLUSIONS: Limited data support the notion that occupational rhinitis precedes the development of occupational asthma, particularly when high-molecular-weight (HMW) agents are involved. The relationship between the two conditions could not be evaluated in many relevant studies due to a lack of cross-tabulation of individual cases. PMID- 29411404 TI - Review article: the evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis. AB - BACKGROUND AND AIMS: PSC is an autoimmune biliary inflammatory disorder that is often associated with inflammatory bowel disease (IBD), with 50%-75% of patients with PSC having coexisting IBD, most commonly ulcerative colitis. Currently, no medical therapies have been shown to improve the disease course or slow its progression. However, ongoing research has resulted in a growing interest in the use of antibiotics for treatment of PSC, of which vancomycin is the most studied. In this review, we summarise the current evidence on the use of vancomycin in PSC and comment on future research areas of interest. METHODS: A comprehensive PUBMED and EMBASE literature search for articles on vancomycin, PSC, therapeutic options and microbiome was performed. RESULTS: Two randomised clinical trials, three case series and two case reports were included in the study. These include uncontrolled data from at least 98 patients that include promising improvements in biochemistry and imaging. Optimal dosing regimens are unclear. CONCLUSION: Vancomycin is one of the most studied antibiotics used in the treatment of PSC with promising results. There is not currently sufficient evidence to support treatment recommendations. Further research is needed to establish if vancomycin is a PSC treatment. PMID- 29411405 TI - Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. AB - BACKGROUND: Fibrosis in ulcerative colitis has remained largely unexplored despite its clinical implications. AIMS: This cross-sectional study was aimed at characterising the presence, anatomical location and degree of ulcerative colitis associated fibrosis and its possible link to clinical parameters. METHODS: Seven hundred and six individual tissue cross-sections derived every 10 cm along the length of 89 consecutive Ulcerative colitis colectomy specimens were examined and compared to Crohn's disease colitis, diverticular disease and uninvolved areas from colorectal cancer patients. Degree of inflammation, fibrosis and morphometric measurements of all layers of the intestinal wall were evaluated. Three gastrointestinal pathologists independently assessed colon sections stained with haematoxylin and eosin, Masson trichrome and Sirius red. Clinical data were collected prospectively. RESULTS: Submucosal fibrosis was detected in 100% of ulcerative colitis colectomy specimens, but only in areas affected by inflammation. Submucosal fibrosis was associated with the severity of intestinal inflammation (Spearman correlations rho (95% confidence interval): 0.58 (P < 0.001) and histopathological changes of chronic mucosal injury, but not active inflammation. Colectomy for refractory disease rather than presence of dysplasia was associated with increased fibrosis and a thicker muscularis mucosae, whereas a thinner muscularis mucosae was associated with anti-tumour necrosis factor therapy. No feature on endoscopic mucosal biopsies could predict the underlying amount of fibrosis or the thickness of the muscularis mucosae. CONCLUSIONS: A significant degree of fibrosis and muscularis mucosae thickening should be considered as common complications of chronic progressive ulcerative colitis. These features may have clinical consequences such as motility abnormalities and increased wall stiffness. PMID- 29411406 TI - APOE epsilon4 is also required in TREM2 R47H variant carriers for Alzheimer's disease to develop. PMID- 29411407 TI - Pressure tensor for electrostatic interaction calculated by fast multipole method with periodic boundary condition. AB - A microscopic expression of the pressure tensor using the fast multipole method (FMM) with periodic boundary conditions has been derived. The pressure tensor calculated using this expression has been compared with that obtained using the Ewald method with high accuracy. The precision of the pressure tensor can be controlled as a function of expansion order p of FMM. Using the calculated pressure tensor, the constant pressure molecular dynamics calculation with fully fluctuating cell can be performed for anisotropic systems such as crystals, metals, liquid crystals, glasses, polymers, lipid bilayers, and interfacial regions between two phases. (c) 2018 Wiley Periodicals, Inc. PMID- 29411408 TI - Exploratory and Confirmatory Analyses in Sentence Processing: A Case Study of Number Interference in German. AB - Given the replication crisis in cognitive science, it is important to consider what researchers need to do in order to report results that are reliable. We consider three changes in current practice that have the potential to deliver more realistic and robust claims. First, the planned experiment should be divided into two stages, an exploratory stage and a confirmatory stage. This clear separation allows the researcher to check whether any results found in the exploratory stage are robust. The second change is to carry out adequately powered studies. We show that this is imperative if we want to obtain realistic estimates of effects in psycholinguistics. The third change is to use Bayesian data-analytic methods rather than frequentist ones; the Bayesian framework allows us to focus on the best estimates we can obtain of the effect, rather than rejecting a strawman null. As a case study, we investigate number interference effects in German. Number feature interference is predicted by cue-based retrieval models of sentence processing (Van Dyke & Lewis, 2003; Vasishth & Lewis, 2006), but it has shown inconsistent results. We show that by implementing the three changes mentioned, suggestive evidence emerges that is consistent with the predicted number interference effects. PMID- 29411409 TI - The impact of electric fields on testis physiopathology, sperm parameters and DNA integrity-The role of resveratrol. AB - This study investigated the long-term effects of electric fields (EF) which might cause physiopathological or morphological changes in the testis tissues of rats. We assumed that using resveratrol (RES) might reduce harmful effects of the EF. Thirty-two male Wistar Albino rats were randomly divided into four groups with eight animals in each; control, EF, EF + RES and RES. Malondialdehyde (MDA), superoxide dismutase, catalase, glutathione peroxidase and histopathological parameters were evaluated in testis tissue. Epididymal sperm count, motility and DNA damage were studied. Total testosterone, follicle-stimulating hormone, luteinising hormone, estradiol and growth hormone levels were evaluated in the plasma samples. EF caused statistically significant increase in MDA levels, body weight and DNA damage. A significant decrease was detected in sperm count and motility. The histopathological examination of the testes showed the germ cell decrease in the seminiferous epithelium with oedema and vascular congestion in the interstitial tissue. In immunohistochemical examination, the increase in the apoptotic cells number was detected. RES partially ameliorated biochemical, histopathological and immunohistochemical findings in the EF + RES group. These findings clearly demonstrated that EF can cause damage in rat testis. RES can ameliorate the damage caused by EF. PMID- 29411410 TI - Discontinuities and disruptions in drug dosage guidelines for the paediatric population. AB - AIMS: This study investigates paediatric drug dosage guidelines with the aim of investigating their agreement with body surface area (BSA) scaling principles. METHODS: A total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration, frequency and dose per age bracket from 0 to 18 years. Drug treatments were categorized as follows: (1) The same dose recommendation in milligrams per kilogram (mg kg-1 ) for all age/weights; (2) Change in the mg kg-1 dosing according to age/weight; (3) Change in dose in mg according to age/weight; (4) Change from mg kg-1 dosing to a dose in mg according to age/weight; (5) The same recommendation for all age/weight groups in mg; or (6) BSA dosing. Example drugs were selected to illustrate dose progression across ages. RESULTS: Most drug treatments (63%) have the same mg kg 1 dose for all age/weight groups, 14% are dosed in mg kg-1 across all ages with dose changes according to age/weight, 13% were dosed in mg across all ages with dose changes, 10% switched from mg kg-1 to a set dose in mg, 4.2% have the same dose in mg for all age and weight groups and 2.2% are dosed according to BSA. CONCLUSIONS: Paediatric dosage guidelines are based on weight-based formulas, available dosing formulations and prior patterns of use. Substantial variation from doses predicted by BSA scaling are common, as are large shifts in recommended doses at age thresholds. Further research is required to determine if better outcomes could be achieved by adopting biologically based scaling of paediatric doses. PMID- 29411411 TI - Emergency department utilisation for inflammatory bowel disease in the United States from 2006 to 2014. AB - BACKGROUND: Despite advances in treatment, patients with inflammatory bowel disease (IBD) frequently require emergency department (ED) visits and hospitalisations. AIMS: To analyse trends in ED visits and subsequent hospitalisations for IBD in the United States (US). METHODS: Data were analysed from the Nationwide Emergency Department Sample (NEDS) years 2006-2014. The NEDS is the largest all-payer ED database in the US, weighted to represent 135 million visits/year. IBD was identified using ICD-9 codes for Crohn's disease (CD) or ulcerative colitis (UC). Surgeries were identified using procedure codes. RESULTS: The frequency of IBD-ED visits increased 51.8%, from 90 846 visits in 2006 to 137 946 in 2014, which was statistically significant in linear regression. For comparison, all-case ED use between 2006 and 2014 increased 14.8%. In-patient hospitalisations from the ED decreased 12.1% for IBD (from 64.7% rate of hospitalisation from the ED in 2006 to 52.6% in 2014), with a UC:CD ratio of 1.2:1 in 2006 and 1.3:1 in 2014. Chi-square analysis revealed that this was a significant decrease. Surgery rates also showed a statistically significant decrease. The mean ED charge per patient rose 102.5% and the aggregate national cost of IBD-ED visits increased 207.5%. CD accounted for over twice as many visits as UC in both years. UC, age, male gender, highest income quartile, private insurance, Medicaid/Medicare, and tobacco use were associated with in patient admissions. CONCLUSIONS: The number of ED visits due to IBD and associated charges have continued to rise, while the rates of in-patient hospitalisations referred from the ED and surgeries have decreased. PMID- 29411412 TI - Necrobiosis lipoidica with mucin deposition in a patient with autoimmune thyroiditis. PMID- 29411413 TI - Sensitivity and specificity of a briefer version of the Cambridge Cognitive Examination (CAMCog-Short) in the detection of cognitive decline in the elderly: An exploratory study. AB - OBJECTIVE: To create a reduced and briefer version of the widely used Cambridge Cognitive Examination (CAMCog) battery as a concise cognitive test to be used in primary and secondary levels of health care to detect cognitive decline. Our aim was to reduce the administration time of the original test while maintaining its diagnostic accuracy. METHODS: On the basis of the analysis of 835 CAMCog tests performed by 429 subjects (107 controls, 192 mild cognitive impairment [MCI], and 130 dementia patients), we extracted items that most contributed to intergroup differentiation, according to 2 educational levels (<=8 and >8 y of formal schooling). RESULTS: The final 33-item "low education" and 24-item"high education" CAMCog-Short correspond to 48.5% and 35% of the original version and yielded similar rates of accuracy: area under ROC curves (AUC) > 0.9 in the differentiation between controls * dementia and MCI * dementia (sensitivities > 75%; specificities > 90%); AUC > 0.7 for the differentiation between controls and MCI (sensitivities > 65%; specificities > 75%). CONCLUSIONS: The CAMCog-Short emerges as a promising tool for a brief, yet sufficiently accurate, screening tool for use in clinical settings. Further prospective studies designed to validate its diagnostic accuracy are needed. PMID- 29411414 TI - Whole genome association study of brain-wide imaging phenotypes: A study of the ping cohort. AB - Neuropsychological disorders have a biological basis rooted in brain function, and neuroimaging data are expected to better illuminate the complex genetic basis of neuropsychological disorders. Because they are biological measures, neuroimaging data avoid biases arising from clinical diagnostic criteria that are subject to human understanding and interpretation. A challenge with analyzing neuroimaging data is their high dimensionality and complex spatial relationships. To tackle this challenge, we introduced a novel distance covariance tests that can assess the association between genetic markers and multivariate diffusion tensor imaging measurements, and analyzed a genome-wide association study (GWAS) dataset collected by the Pediatric Imaging, Neurocognition, and Genetics (PING) study. We also considered existing approaches as comparisons. Our results showed that, after correcting for multiplicity, distance covariance tests of the multivariate phenotype yield significantly greater power at detecting genetic markers affecting brain structure than standard mass univariate GWAS of individual neuroimaging biomarkers. Our results underscore the usefulness of utilizing the distance covariance to incorporate neuroimaging data in GWAS. PMID- 29411415 TI - Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals. AB - PURPOSE: To probe the cardiac metabolism of carbohydrates and short chain fatty acids simultaneously in vivo following the injection of a hyperpolarized 13 C labeled substrate mixture prepared using photo-induced nonpersistent radicals. METHODS: Droplets of mixed [1-13 C]pyruvic and [1-13 C]butyric acids were frozen into glassy beads in liquid nitrogen. Ethanol addition was investigated as a means to increase the polarization level. The beads were irradiated with ultraviolet light and the radical concentration was measured by ESR spectroscopy. Following dynamic nuclear polarization in a 7T polarizer, the beads were dissolved, and the radical-free hyperpolarized solution was rapidly transferred into an injection pump located inside a 9.4T scanner. The hyperpolarized solution was injected in healthy rats to measure cardiac metabolism in vivo. RESULTS: Ultraviolet irradiation created nonpersistent radicals in a mixture containing 13 C-labeled pyruvic and butyric acids, and enabled the hyperpolarization of both substrates by dynamic nuclear polarization. Ethanol addition increased the radical concentration from 16 to 26 mM. Liquid-state 13 C polarization was 3% inside the pump at the time of injection, and increased to 5% by addition of ethanol to the substrate mixture prior to ultraviolet irradiation. In the rat heart, the in vivo 13 C signals from lactate, alanine, bicarbonate, and acetylcarnitine were detected following the metabolism of the injected substrate mixture. CONCLUSION: Copolarization of two different 13 C-labeled substrates and the detection of their myocardial metabolism in vivo was achieved without using persistent radicals. The absence of radicals in the solution containing the hyperpolarized 13 C-substrates may simplify the translation to clinical use, as no radical filtration is required prior to injection. PMID- 29411416 TI - Decrease in eosinophils infiltrating into the skin of patients with dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid. AB - Bullous pemphigoid (BP) is an acquired autoimmune blistering disease in which autoantibodies against epitopes in the basement membrane zone of the skin such as BP180 or BP230 are produced. Dipeptidyl peptidase (DPP)-4 inhibitors have become commonly used to treat diabetes. As DPP-4 inhibitors are more commonly prescribed for diabetes, BP related to DPP-4 inhibitors has been reported and has attracted attention. Therefore, we retrospectively investigated patients who were diagnosed with BP in order to examine characteristics of DPP-4 inhibitor-related BP (nine patients; median age, 85 years) in comparison with non-DPP-4 inhibitor-related BP (21; median age, 85 years). There was no significant difference in Bullous Pemphigoid Disease Area Index between DPP-4 inhibitor-related BP patients and non DPP-4 inhibitor-related BP patients, except for erosions/blisters score in mucosa. Laboratory tests revealed no significant differences between DPP-4 inhibitor-related BP patients and non-DPP-4 inhibitor-related BP patients in total white blood cell count, eosinophil count, neutrophil count and the titer of anti-BP180 antibody. The number of eosinophils infiltrating into the skin was significantly lower in patients with DPP4 inhibitor-related BP than in patients with non-DPP4 inhibitor-related BP. Our results showed that DPP-4 inhibitor related BP has some distinct pathological characteristics from BP not associated with DPP-4 inhibitor. PMID- 29411417 TI - Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. AB - DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long-term survival, because of the availability of effective salvage therapies. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases. PMID- 29411418 TI - Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial). PMID- 29411420 TI - From the Editors. PMID- 29411421 TI - Tanycytes and hypothalamic control of energy metabolism. AB - Studies from a number of areas of neuroendocrinology indicate that hypothalamic tanycytes play a key role in control of energy metabolism. First, profound annual changes in gene expression have been identified in these unusual glial cells in seasonal mammals, for example in genes relating to the transport and metabolism of thyroid hormone into the hypothalamus. The consequent changes in local thyroid hormone availability in the hypothalamus have been shown experimentally to regulate annual cycles in energy intake, storage and expenditure in seasonal species. This is reflected in overt seasonal changes in appetite, body fat composition and torpor. Second, studies in laboratory rodents demonstrate that hypothalamic tanycytes possess transport mechanisms and receptors that indicate they have a cellular function as nutrient sensors. Ex vivo studies with organotypic tanycyte cultures confirm that acute changes in nutrient availability alter calcium and purinergic signalling within and between tanycytes. Finally, tanycytes are components of a stem cell niche in the hypothalamus whose activity can be regulated by the nutritional environment. Experimental depletion of cell division in the hypothalamus alters the homeostatic response to nutrient excess in mice raised in high fat diets. These convergent lines of evidence suggest that tanycytes are nutrient and metabolite sensors that impact upon plasticity and neuronal function in the surrounding hypothalamus, and consequently have an important role in energy intake and expenditure. PMID- 29411423 TI - The anatomy of the perineal branch of the sciatic nerve. AB - A "perineal" branch of the sciatic nerve has been visualized during surgery, but there is currently no description of this nerve branch in the literature. Our study investigates the presence and frequency of occurrence of perineal innervation by the sciatic nerve and characterizes its anatomy in the posterior thigh. Fifteen cadavers were obtained for dissection. Descriptive results were recorded and analyzed statistically. Twenty-one sciatic nerves were adequately anatomically preserved. Six sciatic nerves contained a perineal branch. Five sciatic nerves had a branch contributing to the perineal branch of the posterior femoral cutaneous (PFC) nerve. In specimens with adequate anatomical preservation, the perineal branch of the sciatic nerve passed posterior to the ischial tuberosity in three specimens and posterior to the conjoint tendon of the long head of biceps femoris and semitendinosus muscles (conjoint tendon) in one. In specimens in which the perineal branch of the PFC nerve received a contribution from the sciatic nerve, the branch passed posterior to the sacrotuberous ligament in one case and posterior to the conjoint tendon in three. Unilateral nerve anatomy was found to be a poor predictor of contralateral anatomy (Cohen's kappa = 0.06). Our study demonstrates for the first time the presence and frequency of occurrence of the perineal branch of the sciatic nerve and a sciatic contribution to the perineal branch of the PFC nerve. Clinicians should be cognizant of this nerve and its varying anatomy so their practice is better informed. Clin. Anat. 31:357-363, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29411422 TI - Wnt signaling regulates proliferation and differentiation of radial glia in regenerative processes after stab injury in the optic tectum of adult zebrafish. AB - Zebrafish have superior abilities to generate new neurons in the adult brain and to regenerate brain tissue after brain injury compared with mammals. There exist two types of neural stem cells (NSCs): neuroepithelial-like stem cells (NE) and radial glia (RG) in the optic tectum. We established an optic tectum stab injury model to analyze the function of NSCs in the regenerative condition and confirmed that the injury induced the proliferation of RG, but not NE and that the proliferated RG differentiated into new neurons after the injury. We then analyzed the involvement of Wnt signaling after the injury, using a Wnt reporter line in which canonical Wnt signaling activation induced GFP expression and confirmed that GFP expression was induced specifically in RG after the injury. We also analyzed the expression level of genes related to Wnt signaling, and confirmed that endogenous Wnt antagonist dkk1b expression was significantly decreased after the injury. We observed that Wnt signal inhibitor IWR1 treatment suppressed the proliferation and differentiation of RG after the injury, suggesting that up-regulation of Wnt signaling in RG after the stab injury was required for optic tectum regeneration. We also confirmed that Wnt activation by treatment with GSK3beta inhibitor BIO in uninjured zebrafish induced proliferation of RG in the optic tectum. This optic tectum stab injury model is useful for the study of the molecular mechanisms of brain regeneration and analysis of the RG functions in physiological and regenerative conditions. PMID- 29411424 TI - Positional relationship between the pectoralis major and external abdominal oblique muscles for consideration during dual-plane breast augmentation. AB - During dual plane breast augmentation (DPBA), the costal origin of the pectoralis major (the PM) should be cut to ensure appropriate coverage and positioning of an implant. However, surgeons sometimes make inappropriate planar incisions and insufficient muscular incisions because the external abdominal oblique (the EAO) muscle partially overlaps the lateral portion of the PM. The goal of this study was to clarify the positional relationship between the PM and EAO with the aim of improving the accuracy of implant and muscular incisions during DPBA. Forty sides of 20 embalmed and fresh cadavers were dissected. The midline and midclavicular line (MCL) were used as reference lines for measurements. We clarified the overlapping patterns between the PM and EAO, and measured the distances from the MCL to the borders of those two muscles. The costal part of the PM originated from the 5th (25%), 6th (70%), or 7th rib (5%), respectively. The distances from the MCL to the lateral border of the PM at the 4th, 5th, and 6th ribs were 49.8 mm, 30.5 mm, and 6.3 mm, respectively. In 90% of the specimens, the PM and the EAO overlapped near the MCL. The width of the overlapping portion between the PM and EAO was about 25 mm. This study is one of the first to suggest an innovative approach for explaining the positional relationships between the PM and EAO. Our findings can be useful for surgeons attempting to produce optimal outcomes in DPBA, especially in procedures that involve patients of different races. Clin. Anat. 31:339-346, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29411425 TI - Urotherapy in children with dysfunctional voiding and the responsiveness of two condition-specific questionnaires. AB - AIMS: We sought to establish the responsiveness of the Dutch Vancouver Symptom Score for Dysfunctional Elimination Syndrome (VSSDES) and Pediatric urinary incontinence Quality of life (PinQ) questionnaires. Secondary, we evaluated the outcome of urotherapy extended for children with dysfunctional voiding (DV). METHODS: This cross-sectional multicenter study was done in one tertiary and two community hospitals. Children with DV were included, also when refractory to previous urotherapeutic treatment. The questionnaires were completed before and after urotherapy. The primary outcome measure was the responsiveness of the Dutch VSDESS and PinQ. Secondary outcome was the initial success (defined by the International Children's Continence Society) of extended urotherapy. RESULTS: Between June 2014 and May 2016, 64 children (median age 7 years, IQR 6-10) received urotherapy (median 18 weeks, IQR 11-28). In contrast to the VSSDES, the PinQ showed good responsiveness. For children and parents, respectively, the area under the ROC-curve was 0.79 (P = 0.01) and 0.72 (P = 0.03) for the PinQ and 0.50 (P = 0.98) and 0.55 (P = 0.62) for the VSSDES. Fifty children received extended urotherapy, 27 had complete, and 14 had partial response. Sixteen children had been refractory to previous treatment; four showed complete, and six showed partial response. CONCLUSION: The PinQ is able to detect clinically important changes in continence-specific quality of life after treatment. We support the use of the VSSDES questionnaire in addition to the current diagnostics for the diagnosis of DV. Extended urotherapy showed to be a successful treatment for children with DV, also for those who had received previous unsuccessful treatment. PMID- 29411427 TI - Infant case of tinea faciei caused by Microsporum canis. PMID- 29411426 TI - Integrating eQTL data with GWAS summary statistics in pathway-based analysis with application to schizophrenia. AB - Many genetic variants affect complex traits through gene expression, which can be exploited to boost statistical power and enhance interpretation in genome-wide association studies (GWASs) as demonstrated by the transcriptome-wide association study (TWAS) approach. Furthermore, due to polygenic inheritance, a complex trait is often affected by multiple genes with similar functions as annotated in gene pathways. Here, we extend TWAS from gene-based analysis to pathway-based analysis: we integrate public pathway collections, expression quantitative trait locus (eQTL) data and GWAS summary association statistics (or GWAS individual level data) to identify gene pathways associated with complex traits. The basic idea is to weight the SNPs of the genes in a pathway based on their estimated cis effects on gene expression, then adaptively test for association of the pathway with a GWAS trait by effectively aggregating possibly weak association signals across the genes in the pathway. The P values can be calculated analytically and thus fast. We applied our proposed test with the KEGG and GO pathways to two schizophrenia (SCZ) GWAS summary association data sets, denoted by SCZ1 and SCZ2 with about 20,000 and 150,000 subjects, respectively. Most of the significant pathways identified by analyzing the SCZ1 data were reproduced by the SCZ2 data. Importantly, we identified 15 novel pathways associated with SCZ, such as GABA receptor complex (GO:1902710), which could not be uncovered by the standard single SNP-based analysis or gene-based TWAS. The newly identified pathways may help us gain insights into the biological mechanism underlying SCZ. Our results showcase the power of incorporating gene expression information and gene functional annotations into pathway-based association testing for GWAS. PMID- 29411428 TI - Pacemaker therapy in low-birth-weight infants. AB - Infants born with complete atrioventricular block (CAVB) and fetal bradycardia are frequently born with low birth weight. Three low-birth-weight CAVB infants underwent temporary pacemaker implantation, followed by permanent single-chamber pacemaker implantation at median body weights of 1.7 and 3.2 kg, respectively. All infants caught up with their growth curves and had >3 years of estimated residual battery life. This two-stage strategy was successful in facilitating permanent pacemaker implantation in low-birth-weight babies. Placement of single chamber pacemaker on the apex of the left ventricle appears to be associated with longer battery lifespan. PMID- 29411429 TI - Anatomical variations of the insular gyri: A morphological study and proposal of unified classification. AB - The locations of gyral landmarks vary among individuals. This can be crucial during local landmark-based mapping of the human cortex, so the aim of the present study was to establish criteria for classifying the morphological variability of the human insula. The study was conducted on 50 isolated, randomly selected adult cadaveric hemispheres, fixed in 10% formalin, and preserved in 70% ethanol (24 right and 26 left hemispheres). A thorough rating system, including bifid form (i.e., divided on top), branching or hypoplasia, was used to analyze the insular gyri. The number of all insular gyri ranged from four to six (mean = 5.16, SD = 0.65). Within the anterior lobule, the number of short gyri ranged from two to four (mean = 3.3, SD = 0.54). The middle short gyrus was the most variable. It was well-developed in 25 of the 50 cases (50%). Within the posterior lobule there were one or two long insular gyri (mean = 1.88, SD = 0.32). In 48 cases (96%), the anterior long gyrus was well-developed. A complete lack of the posterior long gyrus was noted in six of the 50 cases (12%). In conclusions, the accessory, the middle short, and the posterior long gyri of the insula were the most variable. The middle short gyrus was well-developed in only half of the cases. The number of insular gyri found in horizontal sections of the brain does not necessarily indicate their true number. Clin. Anat. 31:347-356, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29411430 TI - Giant left atrium. PMID- 29411431 TI - Stable and Efficient Organo-Metal Halide Hybrid Perovskite Solar Cells via pi Conjugated Lewis Base Polymer Induced Trap Passivation and Charge Extraction. AB - High-quality pinhole-free perovskite film with optimal crystalline morphology is critical for achieving high-efficiency and high-stability perovskite solar cells (PSCs). In this study, a p-type pi-conjugated polymer poly[(2,6-(4,8-bis(5-(2 ethylhexyl) thiophen-2-yl)-benzo[1,2-b:4,5-b'] dithiophene))-alt-(5,5-(1',3'-di-2 thienyl-5',7'-bis(2-ethylhexyl) benzo[1',2'-c:4',5'-c'] dithiophene-4,8-dione))] (PBDB-T) is introduced into chlorobenzene to form a facile and effective template agent during the anti-solvent process of perovskite film formation. The pi conjugated polymer PBDB-T is found to trigger a heterogeneous nucleation over the perovskite precursor film and passivate the trap states of the mixed perovskite film through the formation of Lewis adducts between lead and oxygen atom in PBDB T. The p-type semiconducting and hydrophobic PBDB-T polymer fills in the perovskite grain boundaries to improve charge transfer for better conductivity and prevent moisture invasion into the perovskite active layers. Consequently, the PSCs with PBDB-T modified anti-solvent processing leads to a high-efficiency close to 20%, and the devices show excellent stability, retaining about 90% of the initial power conversion efficiency after 150 d storage in dry air. PMID- 29411432 TI - Laser Irradiation of Metal Oxide Films and Nanostructures: Applications and Advances. AB - Recent technological advances in developing a diverse range of lasers have opened new avenues in material processing. Laser processing of materials involves their exposure to rapid and localized energy, which creates conditions of electronic and thermodynamic nonequilibrium. The laser-induced heat can be localized in space and time, enabling excellent control over the manipulation of materials. Metal oxides are of significant interest for applications ranging from microelectronics to medicine. Numerous studies have investigated the synthesis, manipulation, and patterning of metal oxide films and nanostructures. Besides providing a brief overview on the principles governing the laser-material interactions, here, the ongoing efforts in laser irradiation of metal oxide films and nanostructures for a variety of applications are reviewed. Latest advances in laser-assisted processing of metal oxides are summarized. PMID- 29411433 TI - Iron Carbides and Nitrides: Ancient Materials with Novel Prospects. AB - Iron carbides and nitrides have aroused great interest in researchers, due to their excellent magnetic properties, good machinability and the particular catalytic activity. Based on these advantages, iron carbides and nitrides can be applied in various areas such as magnetic materials, biomedical, photo- and electrocatalysis. In contrast to their simple elemental composition, the synthesis of iron carbides and nitrides still has great challenges, particularly at the nanoscale, but it is usually beneficial to improve performance in corresponding applications. In this review, we introduce the investigations about iron carbides and nitrides, concerning their structure, synthesis strategy and various applications from magnetism to the catalysis. Furthermore, the future prospects are also discussed briefly. PMID- 29411434 TI - Activity levels of preterm children at seven years of age. PMID- 29411435 TI - Empirical single sample quantification of bias and variance in Q-ball imaging. AB - PURPOSE: The bias and variance of high angular resolution diffusion imaging methods have not been thoroughly explored in the literature and may benefit from the simulation extrapolation (SIMEX) and bootstrap techniques to estimate bias and variance of high angular resolution diffusion imaging metrics. METHODS: The SIMEX approach is well established in the statistics literature and uses simulation of increasingly noisy data to extrapolate back to a hypothetical case with no noise. The bias of calculated metrics can then be computed by subtracting the SIMEX estimate from the original pointwise measurement. The SIMEX technique has been studied in the context of diffusion imaging to accurately capture the bias in fractional anisotropy measurements in DTI. Herein, we extend the application of SIMEX and bootstrap approaches to characterize bias and variance in metrics obtained from a Q-ball imaging reconstruction of high angular resolution diffusion imaging data. RESULTS: The results demonstrate that SIMEX and bootstrap approaches provide consistent estimates of the bias and variance of generalized fractional anisotropy, respectively. The RMSE for the generalized fractional anisotropy estimates shows a 7% decrease in white matter and an 8% decrease in gray matter when compared with the observed generalized fractional anisotropy estimates. On average, the bootstrap technique results in SD estimates that are approximately 97% of the true variation in white matter, and 86% in gray matter. CONCLUSION: Both SIMEX and bootstrap methods are flexible, estimate population characteristics based on single scans, and may be extended for bias and variance estimation on a variety of high angular resolution diffusion imaging metrics. PMID- 29411436 TI - Color Changes of a Full-Color Emissive ESIPT Fluorophore in Response to Recognition of Certain Acids and Their Conjugate Base Anions. AB - 2-(1,3-Benzothiazol-2-yl)-4-methoxy-6-(1,4,5-triphenyl-1H-imidazol-2-yl)phenol (BTImP) is an excited-state intramolecular proton transfer (ESIPT) fluorophore, containing an acid-stimuli-responsive intramolecular hydrogen bond (H-bond) that can switch from the central phenolic proton to the imidazole (Im) or benzothiazole (BT) nitrogen atoms. Here, we demonstrate that BTImP shows full color (red, green, blue, and white) emission upon the addition of different concentrations of HClO4 or, with time, after the addition of HBF4 . It also shows thermally dependent color changes from pink through white to blue in a narrow temperature range of 25-60 degrees C. 1 H and 15 N NMR measurements suggest that, after the green fluorescent BTImP is protonated at its Im nitrogen atom, a conjugate base anion coordinates to the imidazolium (HIm+ ) proton, forming two types of complexes with different coordination states. One state shows a significantly Stokes-shifted red emission resulting from ESIPT at the BT side, whereas the other shows a typical Stokes-shifted blue emission, probably caused by interaction of the anion with the phenolic proton, which breaks the H-bond on the BT side. BF4- and ClO4- are effective in forming such a blue emitter, whereas Cl- and PF6- are not; this behavior depends on whether the anion can fit into the bidentate binding site consisting of HIm+ and the phenolic hydroxy group. PMID- 29411437 TI - Influence of immunogenetics, sex and body condition on the cutaneous microbial communities of two giant salamanders. AB - The complex association between hosts and microbial symbionts requires the implementation of multiple approaches to evaluate variation in host physiology. Within amphibians, heterogeneity in immunogenetic traits and cutaneous microbiota is associated with variation in disease resistance. Ozark (Cryptobranchus alleganiensis bishopi) and eastern hellbenders (C. a. alleganiensis) provide a model system to assess variation in host traits and microbial communities. Ozark hellbenders have experienced declines throughout their range, are federally endangered and experience wound retardation that is absent in the eastern subspecies. Previous microbial investigations indicate differentiation in the composition of the skin microbiota of both hellbender subspecies, but it is not clear whether these patterns are concurrent with diversity in the major histocompatibility complex (MHC) genes. We characterized the MHC IIB and the skin microbiota of hellbenders in Missouri, where both subspecies co-occur though not sympatric. We compared the microbiota composition and MHC diversity between both subspecies and investigated whether individual-level MHC diversity, sex and body condition were associated with microbiota composition. Overall, MHC IIB diversity was lower in Ozark hellbenders compared to the eastern subspecies. Multivariate statistical comparisons identified microbiota differentiation between Ozark and eastern hellbenders. MHC IIB allele presence/absence, allele divergence, body composition and sex defined grouping of hellbender microbiotas within populations. Differentiation of the cutaneous microbiotas and MHC IIB genes between eastern and Ozark hellbenders suggests that differences exist in immunity between the two subspecies. This study demonstrates how simultaneous assessments of host genetic traits and microbiotas can inform patterns of microbial community structure in natural systems. PMID- 29411438 TI - A rapid fluorogenic GPCR-beta-arrestin interaction assay. AB - Detection of protein-protein interactions involved in signal transduction in live cells and organisms has a variety of important applications. We report a fluorogenic assay for G protein-coupled receptor (GPCR)-beta-arrestin interaction that is genetically encoded, generalizes to multiple GPCRs, and features high signal-to-noise because fluorescence is absent until its components interact upon GPCR activation. Fluorescence after protease-activated receptor-1 activation developed in minutes and required specific serine-threonine residues in the receptor carboxyl tail, consistent with a classical G protein-coupled receptor kinase dependent beta-arrestin recruitment mechanism. This assay provides a useful complement to other in vivo assays of GPCR activation. PMID- 29411440 TI - Integrating genomic and phenotypic data to evaluate alternative phylogenetic and species delimitation hypotheses in a recent evolutionary radiation of grasshoppers. AB - Although resolving phylogenetic relationships and establishing species limits are primary goals of systematics, these tasks remain challenging at both conceptual and analytical levels. Here, we integrated genomic and phenotypic data and employed a comprehensive suite of coalescent-based analyses to develop and evaluate competing phylogenetic and species delimitation hypotheses in a recent evolutionary radiation of grasshoppers (Chorthippus binotatus group) composed of two species and eight putative subspecies. To resolve the evolutionary relationships within this complex, we first evaluated alternative phylogenetic hypotheses arising from multiple schemes of genomic data processing and contrasted genetic-based inferences with different sources of phenotypic information. Second, we examined the importance of number of loci, demographic priors, number and kind of phenotypic characters and sex-based trait variation for developing alternative species delimitation hypotheses. The best-supported topology was largely compatible with phenotypic data and showed the presence of two clades corresponding to the nominative species groups, one including three well-resolved lineages and the other comprising a four-lineage polytomy and a well-differentiated sister taxon. Integrative species delimitation analyses indicated that the number of employed loci had little impact on the obtained inferences but revealed the higher power provided by an increasing number of phenotypic characters and the usefulness of assessing their phylogenetic information content and differences between sexes in among-taxa trait variation. Overall, our study highlights the importance of integrating multiple sources of information to test competing phylogenetic hypotheses and elucidate the evolutionary history of species complexes representing early stages of divergence where conflicting inferences are more prone to appear. PMID- 29411439 TI - Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation. AB - Cellular stress like ER and oxidative stress are the principle causative agents of various proteinopathies. Multifunctional protein PARK7/DJ-1 provides protection against cellular stress. Recently, insulin/IGF also has emerged as a neuro-protective molecule. However, it is not known whether DJ-1 and insulin/IGF complement each other for cellular protection in response to stress. In this study, we show for the first time, that in human and mouse neuronal cell lines, down regulation of DJ-1 for 48 h leads to compensatory upregulation of insulin/IGF signaling (IIS) pathway genes, namely, insulin receptor, insulin receptor substrate, and Akt under normal physiological conditions as well as in cellular stress conditions. Moreover, upon exogenous supply of insulin there is a marked increase in the IIS components both at gene and protein levels leading to down regulation and inactivation of GSK3beta. By immunoprecipitation, it was observed that Sirt3 mediated deacetylation and activation of FoxO3a could not occur under DJ-1 downregulation. Transient DJ-1 downregulation also led to Akt mediated increased phosphorylation and nuclear exclusion of FoxO3a. When DJ-1 was downregulated increased interaction of Sirt3 with IRS2 was observed leading to its activation resulting in IIS upregulation. Thus, transient downregulation of DJ-1 leads to stimulation of IIS pathway by Sirt3 mediated IRS2 activation. Consequently, antiapoptotic program is triggered in neuronal cells via Akt GSK3beta-FoxO3a axis. (c) 2018 BioFactors, 44(3):224-236, 2018. PMID- 29411441 TI - Excitons and Trions in One-Photon- and Two-Photon-Excited MoS2 : A Study in Dispersions. AB - Herein, various dispersions of MoS2 obtained by means of liquid phase exfoliation are spectroscopically, (spectro-) electrochemically, and microscopically characterized. At the core of these studies are transient absorption assays. Importantly, small-angle X-ray scattering measurements are employed to corroborate the exfoliated character of the MoS2 flakes in dispersion, on the one hand, and to correlate the results with TEM, AFM, and Raman characterization in the solid state, on the other. It is, then, demonstrated that transient absorption spectroscopy responds sensitively not only to changes in the sample preparation but also to instrumental and environmental parameters. It is documented that the spectroscopic features and their underlying lifetimes are tuneable on the femto-, pico-, and nanosecond scales by changing, for example, the centrifugation speed, the pump fluence, or the temperature. In other words, transient absorption spectroscopy provides an in situ method to quantitatively characterize liquid dispersions of MoS2 without facing the problems of reaggregated samples due to their drying for microscopic assays. The most far reaching results stem from resonantly and nonresonantly changing the pump fluence to characterize either single- or multiple-excited-state species such as excitons, trions, and bi-/multiexcitons and to follow their formation and deactivation pattern. PMID- 29411442 TI - Gene expression profiling across ontogenetic stages in the wood white (Leptidea sinapis) reveals pathways linked to butterfly diapause regulation. AB - In temperate latitudes, many insects enter diapause (dormancy) during the cold season, a period during which developmental processes come to a standstill. The wood white (Leptidea sinapis) is a butterfly species distributed across western Eurasia that shows photoperiod-induced diapause with variation in critical day length across populations at different latitudes. We assembled transcriptomes and estimated gene expression levels at different developmental stages in experimentally induced directly developing and diapausing cohorts of a single Swedish population of L. sinapis to investigate the regulatory mechanisms underpinning diapause initiation. Different day lengths resulted in expression changes of developmental genes and affected the rate of accumulation of signal molecules, suggesting that diapause induction might be controlled by increased activity of monoamine neurotransmitters in larvae reared under short-day light conditions. Expression differences between light treatment groups of two monoamine regulator genes (DDC and ST) were observed already in instar III larvae. Once developmental pathways were irreversibly set at instar V, a handful of genes related to dopamine production were differentially expressed leading to a significant decrease in expression of global metabolic genes and increase in expression of genes related to fatty acid synthesis and sequestration. This is in line with a time-dependent (hour-glass) model of diapause regulation where a gradual shift in the concentration of monoamine neurotransmitters and their metabolites during development of larvae under short-day conditions leads to increased storage of fat, decreased energy expenditures, and ultimately developmental stasis at the pupal stage. PMID- 29411443 TI - Near-Infrared Excitation/Emission and Multiphoton-Induced Fluorescence of Carbon Dots. AB - Carbon dots (CDs) have significant potential for use in various fields including biomedicine, bioimaging, and optoelectronics. However, inefficient excitation and emission of CDs in both near-infrared (NIR-I and NIR-II) windows remains an issue. Solving this problem would yield significant improvement in the tissue penetration depth for in vivo bioimaging with CDs. Here, an NIR absorption band and enhanced NIR fluorescence are both realized through the surface engineering of CDs, exploiting electron-acceptor groups, namely molecules or polymers rich in sulfoxide/carbonyl groups. These groups, which are bound to the outer layers and the edges of the CDs, influence the optical bandgap and promote electron transitions under NIR excitation. NIR-imaging information encryption and in vivo NIR fluorescence imaging of the stomach of a living mouse using CDs modified with poly(vinylpyrrolidone) in aqueous solution are demonstrated. In addition, excitation by a 1400 nm femtosecond laser yields simultaneous two-photon-induced NIR emission and three-photon-induced red emission of CDs in dimethyl sulfoxide. This study represents the realization of both NIR-I excitation and emission as well as two-photon- and three-photon-induced fluorescence of CDs excited in an NIR-II window, and provides a rational design approach for construction and clinical applications of CD-based NIR imaging agents. PMID- 29411444 TI - The role of hybridization during ecological divergence of southwestern white pine (Pinus strobiformis) and limber pine (P. flexilis). AB - Interactions between extrinsic factors, such as disruptive selection and intrinsic factors, such as genetic incompatibilities among loci, often contribute to the maintenance of species boundaries. The relative roles of these factors in the establishment of reproductive isolation can be examined using species pairs characterized by gene flow throughout their divergence history. We investigated the process of speciation and the maintenance of species boundaries between Pinus strobiformis and Pinus flexilis. Utilizing ecological niche modelling, demographic modelling and genomic cline analyses, we illustrated a divergence history with continuous gene flow. Our results supported an abundance of advanced generation hybrids and a lack of loci exhibiting steep transition in allele frequency across the hybrid zone. Additionally, we found evidence for climate associated variation in the hybrid index and niche divergence between parental species and the hybrid zone. These results are consistent with extrinsic factors, such as climate, being an important isolating mechanism. A build-up of intrinsic incompatibilities and of coadapted gene complexes is also apparent, although these appear to be in the earliest stages of development. This supports previous work in coniferous species demonstrating the importance of extrinsic factors in facilitating speciation. Overall, our findings lend support to the hypothesis that varying strength and direction of selection pressures across the long lifespans of conifers, in combination with their other life history traits, delays the evolution of strong intrinsic incompatibilities. PMID- 29411445 TI - Progress toward Catalytic Micro- and Nanomotors for Biomedical and Environmental Applications. AB - Synthetic micro- and nanomotors (MNMs) are tiny objects that can autonomously move under the influence of an appropriate source of energy, such as a chemical fuel, magnetic field, ultrasound, or light. Chemically driven MNMs are composed of or contain certain reactive material(s) that convert chemical energy of a fuel into kinetic energy (motion) of the particles. Several different materials have been explored over the last decade for the preparation of a wide variety of MNMs. Here, the discovery of materials and approaches to enhance the efficiency of chemically driven MNMs are reviewed. Several prominent applications of the MNMs, especially in the fields of biomedicine and environmental science, are also discussed, as well as the limitations of existing materials and future research directions. PMID- 29411446 TI - Factors associated with nicotine replacement therapy use among hospitalised smokers. AB - INTRODUCTION AND AIMS: Nicotine replacement therapy (NRT) is recommended as a smoking cessation aid for hospitalised smokers. We examined factors associated with NRT use during hospitalisation and after discharge, and NRT uptake when systematically offered free of cost. DESIGN AND METHODS: A nested analysis was conducted using data from a clinical trial that evaluated the effectiveness of a pharmacist-led smoking cessation intervention in 600 hospitalised smokers. RESULTS: NRT was used at least once by 285 (48%) participants during hospitalisation and by 287 (48%) participants during the 12 months post discharge. Heavy smokers and those who expressed interest in using NRT for their next quit attempt at baseline interview were more likely to use NRT during hospitalisation [odds ratio (OR) 1.94, 95% confidence interval (CI) 1.38, 2.74; OR 2.09, 95% CI 1.48, 2.95] and after discharge (OR 1.70, 95% CI 1.20, 2.41; OR 1.97, 95% CI 1.39, 2.79). Those using six or more medications were more likely to use NRT during hospitalisation (OR 1.65, 95% CI 1.05, 2.61). Post-discharge NRT users were more likely to have been initially admitted for a respiratory or cardiac problem (OR 1.51, 95% CI 1.05, 2.18). When NRT was offered free of cost to a subset of patients (n = 300), 157 (52%) used NRT during hospitalisation. Nicotine dependence and interest in using NRT predicted its use (OR 2.26, 95% CI 1.38, 3.70; OR 2.58, 95% CI 1.58, 4.20). DISCUSSION AND CONCLUSIONS: Targeting heavy smokers, those with cardio-respiratory conditions and those interested in using NRT regardless of regimen complexity could improve NRT uptake. PMID- 29411447 TI - Transcriptomics reveal transgenerational effects in purple sea urchin embryos: Adult acclimation to upwelling conditions alters the response of their progeny to differential pCO2 levels. AB - Understanding the mechanisms with which organisms can respond to a rapidly changing ocean is an important research priority in marine sciences, especially in the light of recent predictions regarding the pace of ocean change in the coming decades. Transgenerational effects, in which the experience of the parental generation can shape the phenotype of their offspring, may serve as such a mechanism. In this study, adult purple sea urchins, Strongylocentrotus purpuratus, were conditioned to regionally and ecologically relevant pCO2 levels and temperatures representative of upwelling (colder temperature and high pCO2 ) and nonupwelling (average temperature and low pCO2 ) conditions typical of coastal upwelling regions in the California Current System. Following 4.5 months of conditioning, adults were spawned and offspring were raised under either high or low pCO2 levels, to examine the role of maternal effects. Using RNA-seq and comparative transcriptomics, our results indicate that differential conditioning of the adults had an effect on the gene expression patterns of the progeny during the gastrula stage of early development. For example, maternal conditioning under upwelling conditions intensified the transcriptomic response of the progeny when they were raised under high versus low pCO2 conditions. Additionally, mothers that experienced upwelling conditions produced larger progeny. The overall findings of this study are complex, but do suggest that transgenerational plasticity in situ could act as an important mechanism by which populations might keep pace with rapid environmental change. PMID- 29411448 TI - Host-associated bacterial community succession during amphibian development. AB - Amphibians undergo significant developmental changes during their life cycle, as they typically move from a primarily aquatic environment to a more terrestrial one. Amphibian skin is a mucosal tissue that assembles communities of symbiotic microbiota. However, it is currently not well understood as to where amphibians acquire their skin symbionts, and whether the sources of microbial symbionts change throughout development. In this study, we utilized data collected from four wild boreal toad populations (Anaxyrus boreas); specifically, we sampled the skin bacterial communities during toad development, including eggs, tadpoles, subadults and adults as well as environmental sources of bacteria (water, aquatic sediment and soil). Using 16S rRNA marker gene profiling coupled with SourceTracker, we show that while primary environmental sources remained constant throughout the life cycle, secondary sources of boreal toad symbionts significantly changed with development. We found that toad skin communities changed predictably across development and that two developmental disturbance events (egg hatching and metamorphosis) dictated major changes. Toad skin communities assembled to alternative stable states following each of these developmental disturbances. Using the predicted average rRNA operon copy number of the communities at each life stage, we showed how the skin bacterial communities undergo a successional pattern whereby "fast-growing" (copiotroph) generalist bacteria dominate first before "slow-growing" (oligotroph) specialized bacteria take over. Our study highlights how host-associated bacterial community assembly is tightly coupled to host development and that host-associated communities demonstrate successional patterns akin to those observed in free living bacteria as well as macrofaunal communities. PMID- 29411449 TI - CAIDE Dementia Risk Score, Alzheimer and cerebrovascular pathology: a population based autopsy study. AB - BACKGROUND: CAIDE Dementia Risk Score is a tool for estimating dementia risk in the general population. Its longitudinal associations with Alzheimer or vascular neuropathology in the oldest old are not known. AIM: To explore the relationship between CAIDE Dementia Risk Score at baseline and neuritic plaques, neurofibrillary tangles, cerebral infarcts and cerebral amyloid angiopathy (CAA) after up to 10-year follow-up in the Vantaa 85 + population. METHODS: Study population included 149 participants aged >=85 years, without dementia at baseline, and with available clinical and autopsy data. Methenamine silver staining was used for beta-amyloid and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, CAA and alpha synuclein pathologies. The CAIDE Dementia Risk Score was calculated based on scores for age, sex, BMI, total cholesterol, systolic blood pressure, physical activity and APOEepsilon4 carrier status (range 0-18 points). RESULTS: A CAIDE Dementia Risk Score above 11 points was associated with more cerebral infarctions up to 10 years later: OR (95% CI) was 2.10 (1.06-4.16). No associations were found with other neuropathologies. CONCLUSION: In a population of elderly aged >=85 years, higher CAIDE Dementia Risk Score was associated with increased risk of cerebral infarcts. PMID- 29411450 TI - Assessing niche partitioning of co-occurring sibling bat species by DNA metabarcoding. AB - Niche partitioning through foraging is a mechanism likely involved in facilitating the coexistence of ecologically similar and co-occurring animal species by separating their use of resources. Yet, this mechanism is not well understood in flying insectivorous animals. This is particularly true of bats, where many ecologically similar or cryptic species coexist. The detailed analysis of the foraging niche in sympatric, cryptic sibling species provides an excellent framework to disentangle the role of specific niche factors likely involved in facilitating coexistence. We used DNA metabarcoding to determine the prey species consumed by a population of sympatric sibling Rhinolophus euryale and Rhinolophus mehelyi whose use of habitat in both sympatric and allopatric ranges has been well established through radio tracking. Although some subtle dietary differences exist in prey species composition, the diet of both bats greatly overlapped (Ojk = 0.83) due to the consumption of the same common and widespread moths. Those dietary differences we did detect might be related to divergences in prey availabilities among foraging habitats, which prior radio tracking on the same population showed are differentially used and selected when both species co occur. This minor dietary segregation in sympatry may be the result of foraging on the same prey-types and could contribute to reduce potential competitive interactions (e.g., for prey, acoustic space). Our results highlight the need to evaluate the spatial niche dimension in mediating the co-occurrence of similar insectivorous bat species, a niche factor likely involved in processes of bat species coexistence. PMID- 29411451 TI - New Phosphorus-Doped Perovskite Oxide as an Oxygen Reduction Reaction Electrocatalyst in an Alkaline Solution. AB - Because of their structural and compositional flexibility, perovskite oxides represent an attractive alternative electrocatalyst class to precious metals for the oxygen reduction reaction (ORR); an important reaction in fuel cells and metal-air batteries. Partial replacement of the original metal cation with another cation, namely, doping, can be used to tailor the ORR activity of perovskite, for which a metal has been exclusively used as the dopant component in the past. Herein, phosphorus is proposed as a non-metal dopant for the cation site to develop a new perovskite family with the formula of La0.8 Sr0.2 Mn1-x Px O3-delta (x=0, 0.02, 0.05, and 0.1; denoted as LSM, LSMP0.02, LSMP0.05, and LSMP0.1, respectively). Powder XRD patterns reveal that the solubility of phosphorus in the perovskite structure is around 0.05. Rotating ring-disk electrode experiments in the form of linear-sweep voltammetry scans demonstrated the best ORR performance for LSMP0.05, and also revealed close to a four-electron ORR pathway for all four compositions. A chronoamperometric test (9000 s) and 500 cycle accelerated durability test demonstrated higher durability for LSMP0.05 relative to that of LSM and the commercial 20 wt % Pt/C catalyst. The higher ORR activity for LSMP0.05 is attributed to the optimised average valence of Mn, as evidenced by combined X-ray photoelectron spectroscopy and soft X-ray absorption spectroscopy data. Doping phosphorus into perovskites is an effective way to develop high-performance electrocatalysts for ORR. PMID- 29411452 TI - Effects of controlled dehydration on sleep quality and quantity: A polysomnographic study in healthy young adults. AB - Dehydration is associated with several alternations in body homeostasis involving both physiological and mental aspects. In addition some studies have reported a negative effect of dehydration on subjectively assessed sleep-related parameters. The aim of the current study was to examine for the first time the effect of controlled dehydration on sleep quality and quantity using the gold-standard method of polysomnography. Twelve healthy male volunteers participated in this study (23.4 +/- 0.8 years). Participants performed an in-house full polysomnographic assessment in two different occasions taking place in random order: (i) in a dehydrated state; and (ii) in a euhydrated state. In the dehydration scenario, the participants were allowed to consume only 1.25 L of non caffeinated fluids, while during the euhydrated state participants had to drink at least 3 L of non-caffeinated fluids during the last 24 hr before the polysomnographic study. Urine specific gravity was assessed by refractrometry on collection day in order to assess hydration status. Participants who did not fulfil the hydration criteria were rescheduled. All participants successfully completed the two polysomnographic studies without any complaints or adverse effects reported. No significant differences were found in any of the examined indices of sleep quality and quantity between the dehydration and euhydration scenarios (p > .05). This is the first study to show that controlled mild dehydration does not seem to affect sleep quality and quantity in young healthy adults. More research is necessary to further verify these conclusions and assess whether other parameters are involved in the manifestation of sleep disturbances. PMID- 29411453 TI - Afebrile seizures in infants: Never forget magnesium! PMID- 29411454 TI - Sex-specific patterns in cortical and trabecular bone microstructure in the Kirsten Skeletal Collection, South Africa. AB - OBJECTIVES: The purpose of this study was to provide bone histomorphometric reference data for South Africans of the Western Cape who likely dealt with health issues under the apartheid regime. METHODS: The 206 adult individuals (n female = 75, n male = 131, mean = 47.9 +/- 15.8 years) from the Kirsten Skeletal Collection, U. Stellenbosch, lived in the Cape Town metropole from the late 1960s to the mid-1990s. To study age-related changes in cortical and trabecular bone microstructure, photomontages of mid-thoracic rib cross-sections were quantitatively examined. Variables include relative cortical area (Rt.Ct.Ar), osteon population density (OPD), osteon area (On.Ar), bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp). RESULTS: All cortical variables demonstrated significant relationships with age in both sexes, with women showing stronger overall age associations. Peak bone mass was compromised in some men, possibly reflecting poor nutritional quality and/or substance abuse issues throughout adolescence and early adulthood. In women, greater predicted decrements in On.Ar and Rt.Ct.Ar suggest a structural disadvantage with age, consistent with postmenopausal bone loss. Age-related patterns in trabecular bone microarchitecture are variable and difficult to explain. Except for Tb.Th, there are no statistically significant relationships with age in women. Men demonstrate significant negative correlations between BV/TV, Tb.N, and age, and a significant positive correlation between Tb.Sp and age. CONCLUSIONS: This research highlights sex-specific differences in patterns of age-related bone loss, and provides context for discussion of contemporary South African bone health. While the study sample demonstrates indicators of poor bone quality, osteoporosis research continues to be under-prioritized in South Africa. PMID- 29411456 TI - Into the wild-WAMBAM goes to Canada. AB - The sixth Wild Animal Models Bi-Annual Meeting was held in July 2017 in Quebec, with 42 participants. This report documents the evolution of questions asked and approaches used in evolutionary quantitative genetic studies of wild populations in recent decades, and how these questions and approaches were represented at the recent meeting. We explore how ideas from previous meetings in this series have developed to their present states, and consider how the format of the meetings may be particularly useful at fostering the rapid development and proliferation of ideas and approaches. PMID- 29411455 TI - Can social partnerships influence the microbiome? Insights from ant farmers and their trophobiont mutualists. AB - Mutualistic interactions with microbes have played a crucial role in the evolution and ecology of animal hosts. However, it is unclear what factors are most important in influencing particular host-microbe associations. While closely related animal species may have more similar microbiota than distantly related species due to phylogenetic contingencies, social partnerships with other organisms, such as those in which one animal farms another, may also influence an organism's symbiotic microbiome. We studied a mutualistic network of Brachymyrmex and Lasius ants farming several honeydew-producing Prociphilus aphids and Rhizoecus mealybugs to test whether the mutualistic microbiomes of these interacting insects are primarily correlated with their phylogeny or with their shared social partnerships. Our results confirm a phylogenetic signal in the microbiomes of aphid and mealybug trophobionts, with each species harbouring species-specific endosymbiont strains of Buchnera (aphids), Tremblaya and Sodalis (mealybugs), and Serratia (both mealybugs and aphids) despite being farmed by the same ants. This is likely explained by strict vertical transmission of trophobiont endosymbionts between generations. In contrast, our results show the ants' microbiome is possibly shaped by their social partnerships, with ants that farm the same trophobionts also sharing strains of sugar-processing Acetobacteraceae bacteria, known from other honeydew-feeding ants and which likely reside extracellularly in the ants' guts. These ant-microbe associations are arguably more "open" and subject to horizontal transmission or social transmission within ant colonies. These findings suggest that the role of social partnerships in shaping a host's symbiotic microbiome can be variable and is likely dependent on how the microbes are transmitted across generations. PMID- 29411458 TI - The state medical virology is in. PMID- 29411457 TI - Changes in structural network are associated with cortical demyelination in early multiple sclerosis. AB - The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age-matched controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T1 and T2 * high-resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion-weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease-duration: 0-1 year, 1-2 years, 2-3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 * 10-8 ) and connectivity metrics (p < 10-4 ). We observed significant cortical myelin loss in the shorter disease duration cohorts (0-1 year, p = .0015), and an increase in connectivity in the longer disease-duration cohort (2-3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis. PMID- 29411459 TI - Anchoring and Upgrading Ultrafine NiPd on Room-Temperature-Synthesized Bifunctional NH2 -N-rGO toward Low-Cost and Highly Efficient Catalysts for Selective Formic Acid Dehydrogenation. AB - Hydrogen is widely considered to be a sustainable and clean energy alternative to the use of fossil fuels in the future. Its high hydrogen content, nontoxicity, and liquid state at room temperature make formic acid a promising hydrogen carrier. Designing highly efficient and low-cost heterogeneous catalysts is a major challenge for realizing the practical application of formic acid in the fuel-cell-based hydrogen economy. Herein, a simple but effective and rapid strategy is proposed, which demonstrates the synthesis of NiPd bimetallic ultrafine particles (UPs) supported on NH2 -functionalized and N-doped reduced graphene oxide (NH2 -N-rGO) at room temperature. The introduction of the ?NH2 ?N group to rGO is the key reason for the formation of the ultrafine and well dispersed Ni0.4 Pd0.6 UPs (1.8 nm) with relatively large surface area and more active sites. Surprisingly, the as-prepared low-cost NiPd/NH2 -N-rGO dsiplays excellent hydrophilicity, 100% H2 selectivity, 100% conversion, and remarkable catalytic activity (up to 954.3 mol H2 (mol catalyst)-1 h-1 ) for FA decomposition at room temperature even with no additive, which is much higher than that of the best catalysts so far reported. PMID- 29411460 TI - Leishmania mexicana can utilize amino acids as major carbon sources in macrophages but not in animal models. AB - Leishmania parasites target macrophages in their mammalian hosts and proliferate within the mature phagolysosome compartment of these cells. Intracellular amastigote stages are dependent on sugars as a major carbon source in vivo, but retain the capacity to utilize other carbon sources. To investigate whether amastigotes can switch to using other carbon sources, we have screened for suppressor strains of the L. mexicana Deltalmxgt1-3 mutant which lacks the major glucose transporters LmxGT1-3. We identified a novel suppressor line (Deltalmxgt1 3s2 ) that has restored growth in rich culture medium and virulence in ex vivo infected macrophages, but failed to induce lesions in mice. Deltalmxgt1-3s2 amastigotes had lower rates of glucose utilization than the parental line and primarily catabolized non-essential amino acids. The increased mitochondrial metabolism of this line was associated with elevated levels of intracellular reactive oxygen species, as well as increased sensitivity to inhibitors of the tricarboxylic acid (TCA) cycle, including nitric oxide. These results suggest that hardwired sugar addiction of Leishmania amastigotes contributes to the intrinsic resistance of this stage to macrophage microbicidal processes in vivo, and that these stages have limited capacity to switch to using other carbon sources. PMID- 29411462 TI - Delayed gastric emptying and altered antrum protein metabolism during activity based anorexia. AB - BACKGROUND: Anorexia nervosa, a restrictive eating disorder, is often associated with gastrointestinal disorders, particularly a delayed gastric emptying. However, the mechanisms remained poorly documented. Thus, we aimed to evaluate gastric emptying and antrum protein metabolism in the Activity-Based Anorexia model (ABA). METHODS: Females C57Bl/6 mice were randomized into 3 groups: Control, ABA, and Limited Food Access (LFA). Food access has been progressively limited from 6 h/day at day 6 to 3 h/day at day 9 and until day 17. ABA mice had free access to an activity wheel. Gastric emptying was assessed. On gastric extracts, a proteomic analysis was performed, as well as an evaluation of protein synthesis and protein oxidation. KEY RESULTS: Both LFA and ABA mice exhibited a delayed gastric emptying compared with Controls (P < .05). Proteomic approach revealed 15 proteins that were differentially expressed. Among these proteins, we identified 2 clusters of interest contributing to (i) the organization of muscle fiber with ACTA2, VCL, KRT19, KRT8, and DES proteins and (ii) "heat shock proteins" with STIP1, HSPD1, and HSPA8 proteins. ABA mice specifically exhibited an increased rate of gastric oxidized proteins. CONCLUSIONS AND INFERENCES: Delayed gastric emptying observed in anorectic conditions appears to be secondary to malnutrition. However, an oxidative stress is specifically present in the stomach of ABA mice. Its role remains to be further studied. PMID- 29411463 TI - Promoting evidence-based urinary incontinence management in acute nursing and rehabilitation care-A process evaluation of an implementation intervention in the orthopaedic context. AB - RATIONALE, AIMS, AND OBJECTIVES: The risk of developing urinary incontinence (UI) is associated with older age and hip surgery. There has been limited focus on factors that promote evidence-based UI practice in the orthopaedic context. The aim of this study was to evaluate an implementation intervention to support evidence-based practice for UI in patients aged 65 or older undergoing hip surgery. METHODS: A 3-month intervention was delivered in 2014 to facilitate the implementation of UI knowledge in orthopaedic units in 2 hospitals in Sweden. Each unit appointed a multidisciplinary team of nurses and physiotherapists or occupational therapists to facilitate the implementation. The teams were supported by external facilitators who shared knowledge about UI and implementation science. Interviews, nonparticipant observations, and audits of patient records were performed. RESULTS: Prior to the intervention, there was no use of guidelines regarding UI. The intervention raised the internal facilitators' awareness of UI risks associated with hip surgery. As internal facilitators shared this information with their peers, staff awareness of UI increased. The teams of internal facilitators described needing additional time and support from managers to implement evidence-based UI care. A management initiative triggered by the intervention increased the documentation of UI and urinary problems in 1 unit. CONCLUSION: To promote evidence-based practice related to safe procedures for older people in hospital care, there is a need to better understand strategies that successfully facilitate knowledge implementation. This study suggests that a multiprofessional team approach is promising for instigating a process towards evidence-based management of UI. PMID- 29411464 TI - Vocabulary growth rate from preschool to school-age years is reflected in the connectivity of the arcuate fasciculus in 14-year-old children. AB - The acquisition of language involves the functional specialization of several cortical regions. Connectivity between these brain regions may also change with the development of language. Various studies have demonstrated that the arcuate fasciculus was essential for language function. Vocabulary learning is one of the most important skills in language acquisition. In the present longitudinal study, we explored the influence of vocabulary development on the anatomical properties of the arcuate fasciculus. Seventy-nine Chinese children participated in this study. Between age 4 and age 10, they were administered the same vocabulary task repeatedly. Following a previous study, children's vocabulary developmental trajectories were clustered into three subgroups (consistently good, catch-up, consistently poor). At age 14, diffusion tensor imaging data were collected. Using ROI-based tractography, the anterior, posterior and direct segments of the bilateral arcuate fasciculus were delineated in each child's native space. Group comparisons showed a significantly reduced fractional anisotropy in the left arcuate fasciculus of children in the consistently poor group, in particular in the posterior and direct segments of the arcuate fasciculus. No group differences were observed in the right hemisphere, nor in the left anterior segment. Further regression analyses showed that the rate of vocabulary development, rather than the initial vocabulary size, was a specific predictor of the left arcuate fasciculus connectivity. PMID- 29411461 TI - Spatiotemporal integration of looming visual and tactile stimuli near the face. AB - Real-world objects approaching or passing by an observer often generate visual, auditory, and tactile signals with different onsets and durations. Prompt detection and avoidance of an impending threat depend on precise binding of looming signals across modalities. Here we constructed a multisensory apparatus to study the spatiotemporal integration of looming visual and tactile stimuli near the face. In a psychophysical experiment, subjects assessed the subjective synchrony between a looming ball and an air puff delivered to the same side of the face with a varying temporal offset. Multisensory stimuli with similar onset times were perceived as completely out of sync and assessed with the lowest subjective synchrony index (SSI). Across subjects, the SSI peaked at an offset between 800 and 1,000 ms, where the multisensory stimuli were perceived as optimally in sync. In an fMRI experiment, tactile, visual, tactile-visual out-of sync (TVoS), and tactile-visual in-sync (TViS) stimuli were delivered to either side of the face in randomized events. Group-average statistical responses to different stimuli were compared within each surface-based region of interest (sROI) outlined on the cortical surface. Most sROIs showed a preference for contralateral stimuli and higher responses to multisensory than unisensory stimuli. In several bilateral sROIs, particularly the human MT+ complex and V6A, responses to spatially aligned multisensory stimuli (TVoS) were further enhanced when the stimuli were in-sync (TViS), as expressed by TVoS < TViS. This study demonstrates the perceptual and neural mechanisms of multisensory integration near the face, which has potential applications in the development of multisensory entertainment systems and media. PMID- 29411465 TI - Association mapping reveals candidate loci for resistance and anaemic response to an emerging temperature-driven parasitic disease in a wild salmonid fish. AB - Even though parasitic infections are often costly or deadly for the host, we know very little which genes influence parasite susceptibility and disease severity. Proliferative kidney disease is an emerging and, at elevated water temperatures, potentially deadly disease of salmonid fishes that is caused by the myxozoan parasite Tetracapsuloides bryosalmonae. By screening >7.6 K SNPs in 255 wild brown trout (Salmo trutta) and combining association mapping and Random Forest approaches, we identified several candidate genes for both the parasite resistance (inverse of relative parasite load; RPL) and the severe anaemic response to the parasite. The strongest RPL-associated SNP mapped to a noncoding region of the congeneric Atlantic salmon (S. salar) chromosome 10, whereas the second strongest RPL-associated SNP mapped to an intronic region of PRICKLE2 gene, which is a part of the planar cell polarity signalling pathway involved in kidney development. The top SNP associated with anaemia mapped to the intron of the putative PRKAG2 gene. The human ortholog of this gene has been associated with haematocrit and other blood-related traits, making it a prime candidate influencing parasite-triggered anaemia in brown trout. Our findings demonstrate the power of association mapping to pinpoint genomic regions and potential causative genes underlying climate change-driven parasitic disease resistance and severity. Furthermore, this work illustrates the first steps towards dissecting genotype-phenotype links in a wild fish population using closely related genome information. PMID- 29411466 TI - Writing fluency in patients with low-grade glioma before and after surgery. AB - BACKGROUND: Low-grade glioma (LGG) is a type of brain tumour often situated in or near areas involved in language, sensory or motor functions. Depending on localization and tumour characteristics, language or cognitive impairments due to tumour growth and/or surgical resection are obvious risks. One task that may be at risk is writing, both because it requires intact language and memory function and because it is a very complex and cognitively demanding task. The most commonly reported language deficit in LGG patients is oral lexical-retrieval difficulties, and poor lexical retrieval would be expected to affect writing fluency. AIMS: To explore whether writing fluency is affected in LGG patients before and after surgery and whether it is related to performance on tasks of oral lexical retrieval. METHODS & PROCEDURES: Twenty consecutive patients with presumed LGG wrote a narrative and performed a copy task before undergoing surgery and at 3-month follow-up using keystroke-logging software. The same tasks were performed by a reference group (N = 31). The patients were also tested using the Boston Naming Test (BNT) and word-fluency tests before and after surgery. Writing fluency was compared between the patients and the reference group, and between the patients before and after surgery. Relationships between performance on tests of oral lexical retrieval and writing fluency were investigated both before and after surgery. OUTCOME & RESULTS: Different aspects of writing fluency were affected in the LGG patients both before and after surgery. However, when controlling for the effect of typing speed, the LGG group differed significantly from the reference group only in the proportion of pauses within words. After surgery, a significant decline was seen in production rate and typing speed in the narrative task, and a significant increase was seen in pauses before words. Strong positive relationships were found between oral lexical retrieval and writing fluency both before and after surgery. CONCLUSIONS & IMPLICATIONS: Although aspects of writing fluency were affected both before and after surgery, the results indicate that typing speed is an important factor behind the pre surgery differences. However, the decline in overall productivity and the increase in pauses before words after surgery could be related to a lexical deficit. This is supported by the finding that oral lexical-retrieval scores were strongly correlated with writing fluency. However, further exploration is needed to identify the language and cognitive abilities affecting writing processes in LGG patients. PMID- 29411467 TI - Rheumatic fever: The rebound phenomenon returns. PMID- 29411469 TI - EQ-5D-5L: Smaller steps but a major step change? PMID- 29411470 TI - Development of a language screening instrument for Swedish 4-year-olds. AB - BACKGROUND: The Swedish Program for health surveillance of preschool children includes screening of language and communication abilities. One important language screening is carried out at age 4 years as part of a general screening conducted by health nurses at child health centres. The instruments presently in use for this screening mainly focus on expressive phonology. This may result in both over-referral of children with phonological difficulties and under-referral of children with language disorders (LDs), involving difficulties with vocabulary, grammar and/or language comprehension. Previous research has proposed non-word repetition as a clinical marker for LD. It has also been found that higher predictive power is achieved when non-word repetition is combined with the assessment of lexical/semantic skills. Taking these findings into account, the construction of a language screening instrument may yield more adequate referrals to speech-language therapists (SLTs). AIMS: To construct a new standardized language screening instrument for 4-year-olds and to test its properties. METHODS & PROCEDURES: An instrument was developed and revised after piloting. A population of 352 children was screened at the regular 4-year check-up by 11 health nurses. The final sample consisted of 328 children aged 46-53 months (23% multilingual). Children performing below a preliminary cut-off were referred to an SLT (n = 52). Five SLTs carried out an assessment on average within 5 weeks using a gold standard language test battery. Children who screened negatively were followed up with a parent questionnaire at age 5;6. OUTCOMES & RESULTS: Thirty-one true-positives and 11 false-positives were identified after SLT assessment. A further six children were identified as false-negatives (two through referral to an SLT and four through parent questionnaire at age 5;6). A receiver-operating characteristics curve with a C statistic of .94 was calculated. Based on optimal cut-off, the sensitivity of the screening instrument was found to be .84, and specificity was .96. Multilingual children performed similar to monolingual children; boys performed significantly lower than girls; and children with a family history of language-related problems performed lower than those without. Interrater reliability was high, as was Cronbach's alpha. CONCLUSIONS & IMPLICATIONS: The screening instrument seems sufficiently valid for its purpose to identify children who need further assessment by an SLT. A follow up study including SLT assessment for all children to check for false-negatives would be interesting in future, as would studies comparing results from the 4 year screening with those from earlier screens. PMID- 29411472 TI - Pulse oximetric assessment of anatomical vascular contribution to tissue perfusion in the gastric conduit. AB - BACKGROUND: Tubularized stomach is a common substitute used after oesophageal resection. The risk for gastric conduit ischemia, as well as the mechanisms and dynamics for the occurrence of deficient tissue perfusion during the critical construction of a gastric tube, is poorly understood. METHODS: Twenty-nine patients that underwent oesophagectomy were studied with transmural pulse oximetry of different parts of the stomach, and at predefined preparatory steps during the construction of the gastric conduit. RESULTS: After ligation of the left gastric artery (LGA), a reduction to 83.5% in tissue saturation was observed. Three patients (10.3%) had a sustained saturation despite ligation at this point. During final preparation of the gastric tube, and after stapling of the minor curvature, saturation fell to 76.5%. Saturation increased significantly to 80.0% 2 h after the stapling, just before construction of the anastomosis (P = 0.021). There was no association between the level of oxygen saturation and the risk of anastomotic dehiscence. CONCLUSION: During gastric tube construction for oesophageal replacement, conduit perfusion, measured as oxygen saturation with pulse oximetry, decreases significantly. The main cause of this reduction seems to be ligation of the LGA and the final stapling of the gastric tube. Future studies are needed to establish the clinical implications of this finding. PMID- 29411471 TI - Oscillatory dynamics in the dorsal and ventral attention networks during the reorienting of attention. AB - The ability to reorient attention within the visual field is central to daily functioning, and numerous fMRI studies have shown that the dorsal and ventral attention networks (DAN, VAN) are critical to such processes. However, despite the instantaneous nature of attentional shifts, the dynamics of oscillatory activity serving attentional reorientation remain poorly characterized. In this study, we utilized magnetoencephalography (MEG) and a Posner task to probe the dynamics of attentional reorienting in 29 healthy adults. MEG data were transformed into the time-frequency domain and significant oscillatory responses were imaged using a beamformer. Voxel time series were then extracted from peak voxels in the functional beamformer images. These time series were used to quantify the dynamics of attentional reorienting, and to compute dynamic functional connectivity. Our results indicated strong increases in theta and decreases in alpha and beta activity across many nodes in the DAN and VAN. Interestingly, theta responses were generally stronger during trials that required attentional reorienting relative to those that did not, while alpha and beta oscillations were more dynamic, with many regions exhibiting significantly stronger responses during non-reorienting trials initially, and the opposite pattern during later processing. Finally, stronger functional connectivity was found following target presentation (575-700 ms) between bilateral superior parietal lobules during attentional reorienting. In sum, these data show that visual attention is served by multiple cortical regions within the DAN and VAN, and that attentional reorienting processes are often associated with spectrally specific oscillations that have largely distinct spatiotemporal dynamics. PMID- 29411473 TI - Morphological and chemical changes in human deciduous dentin after phosphoric acid, self-etching adhesive and Er: YAG laser conditioning. AB - The morphological and chemical changes in deciduous dentin produced by different conditioning protocols were evaluated in this in vitro study. Eighty primary dentin samples were divided into eight groups (n = 10): G1, acid etching; G2, self-etching adhesive; G3, G4, Er: YAG laser irradiation at 25.5 and 38.2 J cm-2 , respectively; 10 Hz and spray irrigation. Groups 5, 6, 7, and 8 were irradiated at previous densities, and then phosphoric acid or self-etching adhesive conditioning was applied. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) were used to evaluate chemical and morphological changes. Paired t-test and One-way ANOVA were used for statistical analysis (p <= 0.05). All samples showed different morphology with specific characteristics according to the conditioning protocol. Changing element concentration values are expressed in atomic percent (at %). After conditioning, there were statistically significant differences (p <= 0.05) for p at% and Ca/P in all groups; highlighting the following additional findings by group: G1, G7, and G8 showed changes in all elements studied, G2 presented a decrease in C at% and increased Ca at%, G3 and G4 exhibited at% changes in C, trace elements and Ca. Furthermore, G5 showed at% changes in O and trace elements; while G6 changes were observed on C at%, O at% and trace elements at%. Dentin morphology and chemical composition varied in accordance with the conditioning protocol, with characteristics specific for each one that could have clinical implications for the retention and bond strength performance of adhesive materials. PMID- 29411475 TI - Fibers with Hyper-Crosslinked Functional Porous Frameworks. AB - The incorporation of robust porous frameworks into polymer fibers with handleable morphologies and flexible chemical compositions exhibits significant advantages for device fabrication in a wide range of applications. However, the soft linear polymeric chains of the fibers make the generation of nanopores extremely challenging. Herein, a facile synthetic strategy based on a combination of functional monomer grafting and hyper-crosslinking technology is developed for the porous engineering of polymeric fibers. In this methodology, the nanoporous framework originating from the hyper-crosslinking of aromatic monomers is covalently grafted onto fibers, which is beneficial to retaining their unique fiber morphology and to preserving their excellent mechanical properties. Moreover, this promising protocol can be further extended to the porous functionalization of polymeric matrices with diverse morphologies for target specific applications. PMID- 29411474 TI - Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients. AB - The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood. Observations have previously identified existence of a CHL carrier state that demonstrated variable outcomes based upon the organ which was transplanted. Data defining the incidence and outcome of CHL in pediatric KTx are not well described. The charts of children undergoing isolated KTx at Children's Hospital of Pittsburgh between January 2000 and December 2014 were retrospectively reviewed. EBV loads in the peripheral blood were routinely measured as part of surveillance protocols at our center. CHL was defined as the presence of high load for >50% of samples for >=6 months. PTLD was defined histologically using WHO definitions. Of 188 isolated KTx recipients, we identified a total of 16 (8%) children who developed CHL carrier state. No patient developed EBV-driven late-onset PTLD. Age at the time of KTx was significantly lower in the CHL group (median 3.9 years, interquartile range: IQR 2.9-6.6, P = .0004). Children in the CHL group were more likely to be EBV seronegative prior to KTx (94%, 15/16), compared to the UVL and LVL groups (55% and 50%, respectively, P < .002). The median duration of CHL carrier state was 20 months (IQR 10.7-35.8). Fifteen of the 16 CHL carriers experienced spontaneous resolution of CHL carrier state. Children in the CHL group were younger at the time of primary EBV infection (P = .023). Finally, antiviral medication was not effective in either preventing or decreasing the EBV viral load in blood (P = .84). Overall incidence of late-onset PTLD is very low compared to heart and intestinal transplant, even though KTx recipients can develop CHL carrier state. The CHL carriers in KTx recipients were EBV-seronegative prior to transplant and were younger both at the time of KTx and at the time of primary EBV infection compared to those in the UVL and HVL groups. Antivirals did not prevent EBV infection or decrease EBV viral loads. PMID- 29411476 TI - Integration of speech and gesture in aphasia. AB - BACKGROUND: Information from speech and gesture is often integrated to comprehend a message. This integration process requires the appropriate allocation of cognitive resources to both the gesture and speech modalities. People with aphasia are likely to find integration of gesture and speech difficult. This is due to a reduction in cognitive resources, a difficulty with resource allocation or a combination of the two. Despite it being likely that people who have aphasia will have difficulty with integration, empirical evidence describing this difficulty is limited. Such a difficulty was found in a single case study by Cocks et al. in 2009, and is replicated here with a greater number of participants. AIMS: To determine whether individuals with aphasia have difficulties understanding messages in which they have to integrate speech and gesture. METHODS & PROCEDURES: Thirty-one participants with aphasia (PWA) and 30 control participants watched videos of an actor communicating a message in three different conditions: verbal only, gesture only, and verbal and gesture message combined. The message related to an action in which the name of the action (e.g., 'eat') was provided verbally and the manner of the action (e.g., hands in a position as though eating a burger) was provided gesturally. Participants then selected a picture that 'best matched' the message conveyed from a choice of four pictures which represented a gesture match only (G match), a verbal match only (V match), an integrated verbal-gesture match (Target) and an unrelated foil (UR). To determine the gain that participants obtained from integrating gesture and speech, a measure of multimodal gain (MMG) was calculated. OUTCOMES & RESULTS: The PWA were less able to integrate gesture and speech than the control participants and had significantly lower MMG scores. When the PWA had difficulty integrating, they more frequently selected the verbal match. CONCLUSIONS & IMPLICATIONS: The findings suggest that people with aphasia can have difficulty integrating speech and gesture in order to obtain meaning. Therefore, when encouraging communication partners to use gesture alongside language when communicating with people with aphasia, education regarding the types of gestures that would facilitate understanding is recommended. PMID- 29411477 TI - Effects of a 24-hr-shift-related short-term sleep deprivation on cardiac function: A cardiac magnetic resonance-based study. AB - Fatigue and sleep deprivation are common phenomena, especially among medical professionals and shift workers. Studies have proven that short episodes of sleep deprivation can lead to sympathetic hyperactivity with an elevation in blood pressure, heart rate, and an increased secretion of stress hormones (e.g. cortisol, noradrenaline, thyroid hormones). In this study investigating cardiac strain in 20 healthy subjects undergoing short-term sleep deprivation, it could be shown for the first time that 24-hr-shift-related short-term sleep deprivation leads to a significant increase in cardiac contractility, blood pressure, heart rate and stress hormone secretion. These findings may help better understand how workload and shift duration affect public health, and lay the foundation for further investigations. PMID- 29411478 TI - A subunit of the HOPS endocytic tethering complex, FgVps41, is important for fungal development and plant infection in Fusarium graminearum. AB - The signals by which eukaryotic cells communicate with the environment are usually mediated by vesicle trafficking to be attenuated or terminated. However, vesicle trafficking-mediated signal transmission during interactions between pathogens and host plants is poorly understood. Here, we identified and characterized the vacuole sorting protein FgVps41, which is the yeast HOPS tethering complex subunit Vps41 homolog in Fusarium graminearum. Targeted gene deletion demonstrated that FgVps41 is important for vegetative growth, asexual/sexual development, conidial morphology, plant infection and deoxynivalenol production. Cellular localization and cytological examinations revealed that FgVps41 localizes to early/late endosomes and vacuole membrane, and is recruited to prevacuolar compartments and vacuole membrane by interacting with FgRab7 in F. graminearum. Furthermore, we found FgVps41 mediates vacuole membrane fusion and sorting of FgApeI, a cargo protein involving in the cytosol-to-vacuole targeting pathway. In addition, we found that FgVps41 interacts with FgYck3, a vacuolar type I casein kinase, which regulates vesicle fusion in the AP-3 pathway. Deletion of FgYck3 showed similar phenotypes to the DeltaFgvps41 mutant, and both FgRab7 and FgYck3 regulate the normal localization of FgVps41. Collectively, our results demonstrate that FgVps41 acts as a HOPS tethering complex subunit and is important for the development of infection-related morphogenesis in F. graminearum. PMID- 29411479 TI - Achieving Simultaneous CO2 and H2 S Conversion via a Coupled Solar-Driven Electrochemical Approach on Non-Precious-Metal Catalysts. AB - Carbon dioxide (CO2 ) and hydrogen sulfide (H2 S) are generally concomitant with methane (CH4 ) in natural gas and traditionally deemed useless or even harmful. Developing strategies that can simultaneously convert both CO2 and H2 S into value-added products is attractive; however it has not received enough attention. A solar-driven electrochemical process is demonstrated using graphene encapsulated zinc oxide catalyst for CO2 reduction and graphene catalyst for H2 S oxidation mediated by EDTA-Fe2+ /EDTA-Fe3+ redox couples. The as-prepared solar driven electrochemical system can realize the simultaneous conversion of CO2 and H2 S into carbon monoxide and elemental sulfur at near neutral conditions with high stability and selectivity. This conceptually provides an alternative avenue for the purification of natural gas with added economic and environmental benefits. PMID- 29411480 TI - Genome re-sequencing and simple sequence repeat markers reveal the existence of divergent lineages in the Canadian Puccinia striiformis f. sp. tritici population with extensive DNA methylation. AB - Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is an important disease in Canada. The worldwide genetic structure of Pst populations have been characterized, excluding Canada. Here, we elucidated the genetic structure of the western Canadian Pst population using molecular markers, revealing the presence of four divergent lineages with predominantly clonal structure. In the worldwide context, two previously reported lineages were identified: PstS0 (22%), representing an old Northwestern-European and PstS1 (35%), an invasive warm-temperature adapted. Additionally, two new, unreported lineages, PstPr (9%) and PstS1-related (35%), were detected, which produced more telia than other lineages and had double the number of unique recombination events. The PstPr was a recent invasion, and likely evolved in a diverse, recombinant population as it was closely related to the PstS5, PstS7/Warrior, PstS8/Kranich, and PstS9 lineages originating from sexually recombining populations in the centre of diversity. The DNA methylation analysis revealed DNA methyltransferase1-homologs, providing compelling evidence for epigenetic regulation and as a first report, an average of ~5%, 5hmC in the Puccinia epigenome merits further investigation. The divergent lineages in the Canadian Pst population with the potential for genetic recombination, as well as epigenetic regulation needs consideration in the context of pathogen adaptation and management. PMID- 29411481 TI - Glycoside hydrolase DisH from Desulfovibrio vulgaris degrades the N acetylgalactosamine component of diverse biofilms. AB - Biofilms of sulfate-reducing bacteria (SRB) produce H2 S, which contributes to corrosion. Although bacterial cells in biofilms are cemented together, they often dissolve their own biofilm to allow the cells to disperse. Using Desulfovibrio vulgaris as a model SRB, we sought polysaccharide-degrading enzymes that disperse its biofilm. Using a whole-genome approach, we identified eight enzymes as putative extracellular glycoside hydrolases including DisH (DVU2239, dispersal hexosaminidase), an enzyme that we demonstrated here, by utilizing various p nitrooligosaccharide substrates, to be an N-acetyl-beta-D-hexosaminidase. For N acetyl-beta-D-galactosamine (GalNAc), Vmax was 3.6 umol of p-nitrophenyl/min (mg protein)-1 and Km was 0.8 mM; the specific activity for N-acetyl beta-D glucosamine (GlcNAc) was 7.8 umol of p-nitrophenyl/min (mg protein)-1 . Since GalNAc is one of the three exopolysaccharide matrix components of D. vulgaris, purified DisH was found to disperse 63 +/- 2% biofilm as well as inhibit biofilm formation up to 47 +/- 4%. The temperature and pH optima are 60 degrees C and pH 6, respectively; DisH is also inhibited by copper and is secreted. In addition, since polymers of GalNAc and GlcNAc are found in the matrix of diverse bacteria, DisH dispersed biofilms of Pseudomonas aeruginosa, Escherichia coli and Bacillus subtilis. Therefore, DisH has the potential to inhibit and disperse a wide-range of biofilms. PMID- 29411482 TI - Whorl pattern keratopathies in veterinary and human patients. AB - The course travelled by corneal epithelial cells from their stem cell niche at the limbus toward the vertex of the cornea is normally not evident due to their transparency, but in certain conditions, the epithelial cells can be rendered visible to the clinician. In such cases, the pathway taken by epithelial cells can manifest as a whorl pattern described using a variety of terms including hurricane keratitis/keratopathy, vortex keratopathy, whorl keratopathy, cornea verticillata, and at times, named after causative agents as exemplified by amiodarone keratopathy. Here, we briefly discuss the terminology used and the spectrum of conditions that can result in keratopathies with whorl patterns in human patients. We review the manifestations of such patterns in veterinary patients and discuss the state of understanding of the underlying forces that create the whorl distribution of epithelial cells on the ocular surface. PMID- 29411483 TI - Extraocular muscle architecture in hawks and owls. AB - OBJECTIVE: A complete and accurate understanding of extraocular muscle function is important to the veterinary care of the avian eye. This is especially true for birds of prey, which rely heavily on vision for survival and yet are prone to ocular injury and disease. To better understand the function of extraocular muscles in birds of prey, we studied extraocular muscle architecture grossly and histologically. ANIMALS STUDIED: This sample was composed of two each of the following species: red-tailed hawk (Buteo jamaicensis), Harris's hawk (Parabuteo unicinctus), great horned owl (Bubo virginianus), and barn owl (Tyto alba). PROCEDURES: All extraocular muscles were dissected and weighed. To analyze muscle fiber architecture, the superior oblique and quadratus muscles were dissected, weighed, and sectioned at 5 MUm thickness in the transverse plane. We calculated the physiologic cross-sectional area and the ratio of muscle mass to predicted effective maximum tetanic tension. RESULTS AND CONCLUSIONS: Hawk and owl extraocular muscles exhibit significant physiological differences that play roles in ocular movements and closure of the nictitating membrane. Owls, which do not exhibit extraocular movement, have muscle architecture suited to stabilize the position of a massive, tubular eye that protrudes significantly from the orbit. Hawks, which have a more globose eye that is largely contained within the orbit, do not require as much muscular stability and instead have muscle architecture that facilitates rapid eye movement. PMID- 29411485 TI - Leaving surgical training: some of the reasons are in surgery. AB - In 2014, the Royal Australasian College of Surgeons identified, through internal analysis, a considerable attrition rate within its Surgical Education and Training programme. Within the attrition cohort, choosing to leave accounted for the majority. Women were significantly over-represented. It was considered important to study these 'leavers' if possible. An external group with medical education expertise were engaged to do this, a report that is now published and titled 'A study exploring the reasons for and experiences of leaving surgical training'. During this time, the Royal Australasian College of Surgeons came under serious external review, leading to the development of the Action Plan on Discrimination, Bullying and Sexual Harassment in the Practice of Surgery, known as the Building Respect, Improving Patient Safety (BRIPS) action plan. The 'Leaving Training Report', which involved nearly one-half of all voluntary 'leavers', identified three major themes that were pertinent to leaving surgical training. Of these, one was about surgery itself: the complexity, the technical, decision-making and lifestyle demands, the emotional aspects of dealing with seriously sick patients and the personal toll of all of this. This narrative literature review investigates these aspects of surgical education from the trainees' perspective. PMID- 29411484 TI - Risk factors for postoperative ileus after colorectal cancer surgery: methodological issues. PMID- 29411486 TI - Severe insulin resistance in disguise: A familial case of reactive hypoglycemia associated with a novel heterozygous INSR mutation. AB - AIM: Hypoglycemia in childhood is very rare and can be caused by genetic mutations or insulin-secreting neoplasms. Postprandial hypoglycemia has previously been associated with insulin receptor (INSR) gene mutations. We aimed to identify the cause of postprandial hypoglycemia in a 10-year-old boy. SUBJECTS: We studied the symptomatic proband and his apparently asymptomatic mother and elder brother. All of them were lean. METHODS: Metabolic screening of the proband included a 5-hour oral glucose tolerance test (OGTT), angio-magnetic resonance imaging, and 18 F-dihydroxyphenylalanine positron emission tomography/computed tomography imaging of the pancreas. INSR gene sequencing and in vitro functional studies of a novel INSR mutation were also undertaken. RESULTS: Fasting hyperinsulinemia was detected during metabolic screening, and 5 hour OGTT showed hypoglycemia at 240' in the proband, his mother, and brother. Pancreatic imaging showed no evidence of neoplasia. Acanthosis nigricans with high fasting insulin levels in the proband suggested severe insulin resistance and prompted INSR gene sequencing, which revealed the novel, heterozygous p.Phe1213Leu mutation in the patient and his family members. In vitro studies showed that this mutation severely impairs insulin receptor function by abolishing tyrosine kinase activity and downstream insulin signaling. CONCLUSIONS: The identification of etiological cause of hypoglycemia in childhood may be challenging. The combination of fasting hyperinsulinemia with acanthosis nigricans in a lean subject with hypoglycemia suggests severe insulin resistance and warrants INSR gene screening. PMID- 29411487 TI - Technique, postoperative complications, and visual outcomes of phacoemulsification cataract surgery in 21 penguins (27 eyes): 2011-2015. AB - OBJECTIVE: To describe surgical technique, postoperative complications, and visual outcome in penguins after phacoemulsification lens extraction surgery. ANIMALS STUDIED: Twenty-one penguins (27 eyes) that had phacoemulsification from 2011 to 2015 at Animal Eye Associates. Species included are as follows: 14 southern Rockhopper (18 eyes, 66.6%), 4 Gentoo (4 eyes, 19%), 2 King (3 eyes, 9.5%), and 1 Chinstrap penguin (2 eyes, 4.8%). Eleven of the penguins were females, and 10 were males with average age at the time of surgery being 27.5 years (range of 22-31 years). PROCEDURE: This is a retrospective study of phacoemulsification cataract surgery patients from 2011 to 2015. Visual outcome was evaluated by veterinary ophthalmologists at postoperative recheck examinations and subjectively by penguin keepers using individual bird surveys and paired t tests for statistical analysis. RESULTS: All eyes were functionally visual after surgery and at the time of last follow-up. Based on keeper surveys, 81% (17/21) of penguins showed immediate improvements in overall quality of life and 90% (19/21) of penguins exhibited improvement in mobility and behavior within their exhibit following cataract removal. Of the 14 penguins that received 1:5 intracameral atracurium during surgery, 10 (71.4%) had moderate mydriasis, 1 (7.1%) had minimal mydriasis, and 3 (21.4%) showed no effect to the pupil. Seventy percent of the cases had phacoemulsification times less than 60 seconds/eye; the mean time was 72 seconds. Sixteen eyes (59.3%) underwent anterior capsulotomy only, planned anterior and posterior capsulotomies were performed in 3 eyes (11.1%), and the entire lens capsule was removed due to capsular fibrosis and wrinkling in 8 eyes (29.6%). The most common short-term postoperative complication was temporary mild blepharospasm and/or epiphora, reported in 8 eyes (29.6%) from 7 penguins (33.3%). Long-term complications, 2-6 years postoperatively, included posterior synechiation resulting in dyscoria (10 of 24 eyes, 41.7%) and capsular fibrosis in all penguins with residual lens capsule (19/19, 100%). CONCLUSION: The prognosis for vision and behavioral improvement after phacoemulsification surgery in penguins is good, with low incidence of vision-threatening complications. PMID- 29411488 TI - Regioselective Cyclotrimerization of Terminal Alkynes Using a Digermyne. AB - The catalytic activation of small neutral molecules followed by the formation of C-C bonds is a highly important method to increase the complexity and/or value of simple starting materials. Reported is an isolable digermyne, a compound with a Ge=Ge bond, which acts as a precatalyst for the cyclotrimerization of terminal arylacetylenes to afford the corresponding 1,2,4-triarylbenzenes with absolute regioselectivity. The results demonstrate that bespoke main-group-element compounds can catalytically activate and transform small neutral organic molecules and induce the formation of C-C bonds. PMID- 29411489 TI - Comparison of three methods for measuring height in rehabilitation inpatients and the impact on body mass index classification: An open prospective study. AB - AIM: To compare standing height, estimated current height and demi-span estimated height and examine their impact on body mass index (BMI) classification. METHODS: Cross-sectional data was collected on 104 patients admitted to an adult rehabilitation ward and seen by the dietitian. Patient's standing, estimated current height and demi-span estimated height were collected and grouped by age: 19-64 and >=65 years. RESULTS: The limits of agreement (95% confidence interval) for estimated current height compared with standing height were +9.9 cm and -7.9 cm, in contrast to +8.7 cm and -14.3 cm for demi-span estimated height. Demi-span underestimated height when compared with standing height in both age groups, 19 64 years: (mean +/- SD) 3.0 +/- 6.5 cm (P = 0.001, n = 68) and >= 65 year age group 4.0 +/- 6.0 cm (P < 0.001, n = 36), resulting in a significantly greater mean BMI (analysis of variance P < 0.001, P = 0.02). In the 19-64 and >=65 year age groups, 3% (2/68) and 10% (4/36) of patients, respectively, had a different BMI classification using demi-span estimated height compared with standing height. CONCLUSIONS: Estimated current height is a simple and practical alternative if standing height is unable to be obtained when performing a nutrition assessment. Demi-span estimated height should be used with caution when calculating BMI to assess nutritional status, particularly in the elderly. PMID- 29411490 TI - Validation of the Malnutrition Screening Tool for use in a Community Rehabilitation Program. AB - AIM: The aim of the present study was to determine if the Malnutrition Screening Tool (MST) is valid for use within the Community Rehabilitation Program (CRP) setting. Secondary outcome measures were to assess malnutrition prevalence in the CRP population and to determine trends between malnutrition and age, body mass index (BMI) and falls history. METHODS: This study used a cross-sectional design. All clients admitted to a Melbourne metropolitan CRP during the study period had the MST completed at intake. A total of 160 participants were then selected at random and a Subjective Global Assessment (SGA) was completed by an experienced dietitian. Participants were classified as well nourished or malnourished, and this result was compared to their MST score. Data analysis was completed to determine the predictive value of the MST compared to SGA, which was expressed using sensitivity, specificity, positive and negative predictive values. RESULTS: Out of the 160 participants, 34.0% were identified as malnourished. The MST achieved a sensitivity of 72.2% and a specificity of 83.8% with positive predictive value of 69.6% and negative predictive value of 85.4% compared to the SGA. Participants in the malnourished group were older and had a lower BMI (P < 0.05). CONCLUSIONS: Considering the demographics and needs of the CRP population group and the predictive value of the MST compared to SGA, it can be concluded that the MST is a valid screening tool for use in this population and has relatively low burden to complete. Consequently, the MST could be included in the client initial needs identification to be completed when admitted to the program. PMID- 29411491 TI - Cost evaluation of providing evidence-based dietetic services for weight management in adults: In-person versus eHealth delivery. AB - AIM: To compare the theoretical costs of best-practice weight management delivered by dietitians in a traditional, in-person setting compared to remote consultations delivered using eHealth technologies. METHODS: Using national guidelines, a framework was developed outlining dietitian-delivered weight management for in-person and eHealth delivery modes. This framework mapped one-on one patient-dietitian consultations for an adult requiring active management (BMI >= 30 kg/m2 ) over a one-year period using both delivery modes. Resources required for both the dietitian and patient to implement each treatment mode were identified, with costs attributed for material, fixed, travel and personnel components. The resource costs were categorised as either establishment or recurring costs associated with the treatment of one patient. RESULTS: Establishment costs were higher for eHealth compared to in-person costs ($1394.21 vs $90.05). Excluding establishment costs, the total (combined dietitian and patient) cost for one patient receiving best-practice weight management for 12 months was $560.59 for in-person delivery, compared to $389.78 for eHealth delivery. Compared to the eHealth mode, a higher proportion of the overall recurring delivery costs was attributed to the patient for the in-person mode (46.4% and 33.9%, respectively). CONCLUSIONS: Although it is initially more expensive to establish an eHealth service mode, the overall reoccurring costs per patient for delivery of best-practice weight management were lower compared to the in-person mode. This theoretical cost evaluation establishes preliminary evidence to support alternative obesity management service models using eHealth technologies. Further research is required to determine the feasibility, efficacy and cost-effectiveness of these models within dietetic practice. PMID- 29411492 TI - Dietetic intervention for inpatients on fluid-only diets helps to achieve nutritional requirements. AB - AIM: The present study aimed to assess whether dietetic intervention helps patients on fluid-only diets to meet their energy and protein requirements. This topic has not been previously investigated. METHODS: A quasi-experimental study of 57 patients receiving fluid-only diets was conducted at The Townsville Hospital. The fluid consumption of participants was observed over 24 hours and was used to calculate total energy and protein intakes. The percentage of protein and energy requirements met was compared between patients receiving dietetic intervention and patients who were not. RESULTS: Patients receiving dietetic interventions met a higher percentage of their energy requirements (75.88) than the control group (18.10) based on median intakes (P < 0.001). Patients receiving dietetic intervention also met a higher percentage of their protein requirements (75.99) than the control group (13.80) based on median intakes (P < 0.001). Stratification for age, body mass index (BMI) and fluid diet type showed no change in effect. CONCLUSIONS: This study shows that dietetic intervention enabled patients on fluid-only diets to meet up to 80% more of their energy requirements and up to 95% more of their protein requirements. These results were consistent across age, BMI and fluid diet type. The significance of these differences has resulted in a change of clinical practice at the study hospital. All patients on fluid-only diets for three days or longer are now blanket referred for dietetic intervention. PMID- 29411493 TI - Food, nutrition and ageing in the twenty-first century. PMID- 29411494 TI - Post-pyloric feeding tube placement in critically ill patients: Extending the scope of practice for Australian dietitians. AB - AIM: To determine whether the placement of a post-pyloric feeding tube (PPFT) can be taught safely and effectively to a critical care dietitian. METHODS: This is a prospective observational study conducted in an adult intensive care unit (ICU). The intervention consisted of 19 attempts at post-pyloric intubation by the dietitian. The 10 'learning' attempts were performed by the dietitian under the direction of an experienced (having completed in excess of 50 successful tube placements) user. A subsequent nine 'consolidation' attempts were performed under the responsibility of the intensive care consultant on duty. The primary outcome measures were success (i.e. tip of the PPFT being visible in or distal to the duodenum on X-ray) and time (minutes) to PPFT placement. Patients were observed for adverse events per standard clinical practice. RESULTS: A total of 19 post pyloric tube placements were attempted in 18 patients (52 (23-70) years, ICU admission diagnoses: trauma n = 4; respiratory failure n = 3; and burns, pancreatitis and renal failure n = 2 each). No adverse events occurred. Most (75%) patients were sedated, and mechanically ventilated. Prokinetics were used to assist tube placement in 11% (2/19) of attempts, both of which were successful. Placement of PPFT was successful in 58% (11/19) of attempts. Whilst training, the success rate was 40% (4/10) compared with 78% (7/9) once training was consolidated (P = 0.17). In the successful attempts, the mean time to placement was 11.0 minutes (3.9-27.1 minutes). CONCLUSIONS: A dietitian can be trained to safely and successfully place PPFT in critically ill patients. PMID- 29411495 TI - Efficacy of a telephone-based medical nutrition program on blood lipid and lipoprotein metabolism: Results of Our Healthy Heart. AB - AIM: Derangements in blood lipid and lipoprotein metabolism are one of the leading causes of coronary heart disease (CHD). Therapeutic lifestyle changes such as diet and exercise are often prescribed to improve blood lipid and lipoprotein characteristics, but the efficacy of a telephone-based health coaching program has not been thoroughly explored. Our purpose was to examine effects of the Our Healthy Heart (OHH) Program on blood lipid and lipoprotein characteristics of individuals with mixed dyslipidaemia. METHODS: Cholesterol content of serum very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density (HDL) subfractions and apolipoprotein concentrations were measured by vertical-density ultracentrifugation (Vertical Auto Profile (VAP)) from 1522 individuals with mixed dyslipidaemia (age 18-99 years, body mass index (BMI) 25-40, 62.7% female). Telephone-based health coaching (OHH, n = 722) or standard care (Control, n = 800) was provided for six months followed by VAP to evaluate changes in lipid and lipoprotein concentrations. Controls were obtained from individuals with similar blood lipid/lipoprotein characteristics who did not participate in the OHH Program. Coaches collected baseline self-reported data on anthropometrics, food intake and exercise. Participants in the OHH group were then prescribed a hypocaloric 500 kcal/day caloric deficit with encouragement to participate in physical activity. A two-way ANOVA was used to examine differences between groups over time, with results presented as means +/- standard deviation. RESULTS: Health coaching significantly decreased serum concentrations of apoB100 (104.5 +/- 25.8-94.3 +/- 24.8 mg/dL), shifted LDL pattern size from B to A or A/B in over 60% of the OHH group and decreased cholesterol content of all VLDL subfractions (P < 0.05) compared to the control. CONCLUSIONS: Telephone-based health coaching recommendations to reduce dietary energy intake and increase physical activity produced significant improvements in cholesterol content of atherogenic lipoproteins, which are known to increase CHD risk. PMID- 29411496 TI - Taxonomic patterns in the nitrogen assimilation of soil prokaryotes. AB - Nitrogen (N) is frequently a limiting nutrient in soil; its availability can govern ecosystem functions such as primary production and decomposition. Assimilation of N by microorganisms impacts the availability of N in soil. Despite its established ecological significance, the contributions of microbial taxa to N assimilation are unknown. Here we measure N uptake and use by microbial phylotypes and taxonomic groups within a diverse assemblage of soil microbes through quantitative stable isotope probing (qSIP) with 15 N. Following incubation with 15 NH4+, distinct patterns of 15 N assimilation among taxonomic groups were observed. For instance, glucose addition stimulated 15 N assimilation in most members of Actinobacteria and Proteobacteria but generally decreased 15 N use by Firmicutes and Bacteriodetes. While NH4+ is considered a preferred and universal source of N to prokaryotes, the majority (> 80%) of N assimilation in our soils could be attributed to a handful of active orders. Characterizing N assimilation of taxonomic groups with 15 N qSIP may provide a basis for understanding how microbial community composition influences N availability in the environment. PMID- 29411497 TI - The effects of two different types of bandage contact lenses on the healthy canine eye. AB - OBJECTIVE: To compare two types of bandage contact lenses on the healthy canine eye. ANIMALS STUDIED: Six healthy Beagles. PROCEDURES: Two different types of bandage contact lenses (single sized human silicone contact lens 'PureVision 2' (Bausch & Lomb Incorporated, Rochester, NY, USA) and specially designed veterinary hydrogel contact lens 'AcriVet Pat D' (Bausch & Lomb Incorporated) were placed in 12 eyes of healthy Beagle dogs. Retention times and the effects of the lenses regarding irritation of the eye, changes in tear production, impact of contact lenses on tonometric readings, and cytologic and microbiological alterations of the canine eye were investigated. RESULTS: Mean retention times for veterinary hydrogel lenses with special dimensions were significantly shorter (2 days) than for one size human silicon lenses (8.8 days). Irritation scores were overall low for both types of lenses apart from one human lens causing severe irritation and keratoconjunctivitis as a sequel to folding and displacement. Tear production remained stable in human contact lenses. Intraocular pressure readings with a contact lens in place were only slightly altered; the most accurate readings were obtained through a human lens with an applanation tonometer. Cytology revealed a slight, nonsignificant increase in neutrophilic granulocytes with both types of lenses; the microflora did not change significantly. DISCUSSION: Human silicone lenses have significantly longer retention times and are less expensive than veterinary hydrogel lenses. In regard to irritation, bacterial growth and inflammation, both types of lenses can be recommended for use in canine eyes. PMID- 29411498 TI - Authors' reply re: Safety and effectiveness of female tubal sterilisation by hysteroscopy, laparoscopy or laparotomy: a register-based study. PMID- 29411499 TI - Stress-induced pyruvate accumulation contributes to cross protection in a fungus. AB - It is commonly observed that microorganisms subjected to a mild stress develop tolerance not only to higher doses of the same stress but also to other stresses a phenomenon called cross protection. The mechanisms for cross protection have not been fully revealed. Here, we report that heat shock induced cross protection against UV, oxidative and osmotic/salt stress conditions in the cosmopolitan fungus Metarhizium robertsii. Similarly, oxidative and osmotic/salt stresses also induced cross protection against multiple other stresses. We found that oxidative and osmotic/salt stresses produce an accumulation of pyruvate that scavenges stress-induced reactive oxygen species and promotes fungal growth. Thus, stress induced pyruvate accumulation contributes to cross protection. RNA-seq and qRT PCR analyses showed that UV, osmotic/salt and oxidative stress conditions decrease the expression level of pyruvate consumption genes in the trichloroacetic acid cycle and fermentation pathways leading to pyruvate accumulation. Our work presents a novel mechanism for cross protection in microorganisms. PMID- 29411500 TI - Novel, diverse RNA viruses from Mediterranean isolates of the phytopathogenic fungus, Rosellinia necatrix: insights into evolutionary biology of fungal viruses. AB - To reveal mycovirus diversity, we conducted a search of as-yet-unexplored Mediterranean isolates of the phytopathogenic ascomycete Rosellinia necatrix for virus infections. Of seventy-nine, eleven fungal isolates tested RNA virus positive, with many showing coinfections, indicating a virus incidence of 14%, which is slightly lower than that (approximately 20%) previously reported for extensive surveys of over 1000 Japanese R. necatrix isolates. All viral sequences were fully or partially characterized by Sanger and next-generation sequencing. These sequences appear to represent isolates of various new species spanning at least 6 established or previously proposed families such as Partiti-, Hypo-, Megabirna-, Yado-kari-, Fusagra- and Fusarividae, as well as a newly proposed family, Megatotiviridae. This observation greatly expands the diversity of R. necatrix viruses, because no hypo-, fusagra- or megatotiviruses were previously reported from R. necatrix. The sequence analyses showed a rare horizontal gene transfer event of the 2A-like protease domain between a dsRNA (phlegivirus) and a positive-sense, single-stranded RNA virus (hypovirus). Moreover, many of the newly detected viruses showed the closest relation to viruses reported from fungi other than R. necatrix, such as Fusarium spp., which are sympatric to R. necatrix. These combined results imply horizontal virus transfer between these soil-inhabitant fungi. PMID- 29411502 TI - Isolation and genomic characterization of Novimethylophilus kurashikiensis gen. nov. sp. nov., a new lanthanide-dependent methylotrophic species of Methylophilaceae. AB - Recently, it has been found that two types of methanol dehydrogenases (MDHs) exist in Gram-negative bacterial methylotrophs, calcium-dependent MxaFI-MDH and lanthanide-dependent XoxF-MDH and the latter is more widespread in bacterial genomes. We aimed to isolate and characterize lanthanide-dependent methylotrophs. The growth of strain La2-4T on methanol, which was isolated from rice rhizosphere soil, was strictly lanthanide dependent. Its 16S rRNA gene sequence showed only 93.4% identity to that of Methylophilus luteus MimT , and the name Novimethylophilus kurashikiensis gen. nov. sp. nov. is proposed. Its draft genome (ca. 3.69 Mbp, G + C content 56.1 mol%) encodes 3579 putative CDSs and 84 tRNAs. The genome harbors five xoxFs but no mxaFI. XoxF4 was the major MDH in the cells grown on methanol and methylamine, evidenced by protein identification and quantitative PCR analysis. Methylamine dehydrogenase gene was absent in the La2 4T genome, while genes for the glutamate-mediated methylamine utilization pathway were detected. The genome also harbors those for the tetrahydromethanopterin and ribulose monophosphate pathways. Additionally, as known species, isolates of Burkholderia ambifaria, Cupriavidus necator and Dyadobacter endophyticus exhibited lanthanide dependent growth on methanol. Thus, lanthanide can be used as an essential growth factor for methylotrophic bacteria that do not harbor MxaFI-MDH. PMID- 29411501 TI - Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death. AB - BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate. We found higher levels of cell death in the medial nasal and the lateral nasal processes at E10.5 in association with higher levels of p53 in the double mutant embryos. We also found higher levels of pSmad1/5/9 in the lateral nasal processes at E10.5 in the double mutant embryos. Western analyses revealed that double mutant embryos showed similar degrees of upregulation of pSmad1/5/9 with caBmpr1a or Tak1-cKO embryos while the double mutant embryos showed higher levels of phospho-p38 than caBmpr1a or Tak1-cKO embryos at E17.5, but not at E10.5. It suggested that deletion of Tak1 aggravates the craniofacial deformities of the caBmpr1a mutants by increasing p53 and phospho-p38 at different stage of embryogenesis. PMID- 29411503 TI - Ultrathin Palladium Nanomesh for Electrocatalysis. AB - An ordered mesh of palladium with a thickness of about 3 nm was synthesized by a solution-based oxidative etching. The ultrathin palladium nanomeshes have an interconnected two-dimensional network of densely arrayed, ultrathin quasi nanoribbons that form ordered open holes. The unique mesoporous structure and high specific surface area make these ultrathin Pd nanomeshes display superior catalytic performance for ethanol electrooxidation (mass activity of 5.40 Am g-1 and specific activity of 7.09 mA cm-2 at 0.8 V vs. RHE). Furthermore, the regular mesh structure can be applied to support other noble metals, such as platinum, which exhibits extremely high hydrogen evolution reaction (HER) activity and durability. PMID- 29411504 TI - Proof-of-concept study of vertical augmentation using block-type allogenic bone grafts: A preclinical experimental study on rabbit calvaria. AB - This study aimed to quantify the healing following vertical augmentation of allogenic bone blocks with/without recombinant human bone morphogenetic protein-2 (rhBMP-2) on rabbit calvaria. Experiments were performed using allogenic bone blocks which were grafted bilaterally with or without rhBMP-2 on 20 rabbit calvaria, and these animals were divided to four groups according to the use of rhBMP-2 and healing periods (2 and 8 weeks; n = 10 in each group). Onlay-type bone blocks (8 mm in diameter and 5 mm high) were fixed with a self-tapping screw after removing the cortex in the control group, and the same protocol was applied with the addition of soaking the bone blocks with rhBMP-2 for 15 min in the test group. Radiographic and histologic analyses were performed after 2 or 8 weeks to evaluate the volumetric stability and bone regeneration within the grafted area. The radiographic analysis revealed that the height of the allogenic bone block decreased but its volume was maintained from 2 to 8 weeks in both the control and test groups. The histologic results demonstrated a statistically significant increase in new bone area in the test group, especially in the lower region adjacent to the preexisting calvarial floor. The amount of newly formed bone in all regions of the augmented bone blocks in both the control and test groups was greater at 8 weeks than at 2 weeks. In conclusion, the vertically grafted allogenic bone block maintained its volume with new bone formation, and this was accelerated by the addition of rhBMP-2. These findings indicate that allogenic bone block soaked with rhBMP-2 could be a useful candidate biomaterial for vertical augmentation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2700-2707, 2018. PMID- 29411505 TI - Transcriptomics of aged Drosophila motor neurons reveals a matrix metalloproteinase that impairs motor function. AB - The neuromuscular junction (NMJ) is responsible for transforming nervous system signals into motor behavior and locomotion. In the fruit fly Drosophila melanogaster, an age-dependent decline in motor function occurs, analogous to the decline experienced in mice, humans, and other mammals. The molecular and cellular underpinnings of this decline are still poorly understood. By specifically profiling the transcriptome of Drosophila motor neurons across age using custom microarrays, we found that the expression of the matrix metalloproteinase 1 (dMMP1) gene reproducibly increased in motor neurons in an age-dependent manner. Modulation of physiological aging also altered the rate of dMMP1 expression, validating dMMP1 expression as a bona fide aging biomarker for motor neurons. Temporally controlled overexpression of dMMP1 specifically in motor neurons was sufficient to induce deficits in climbing behavior and cause a decrease in neurotransmitter release at neuromuscular synapses. These deficits were reversible if the dMMP1 expression was shut off again immediately after the onset of motor dysfunction. Additionally, repression of dMMP1 enzymatic activity via overexpression of a tissue inhibitor of metalloproteinases delayed the onset of age-dependent motor dysfunction. MMPs are required for proper tissue architecture during development. Our results support the idea that matrix metalloproteinase 1 is acting as a downstream effector of antagonistic pleiotropy in motor neurons and is necessary for proper development, but deleterious when reactivated at an advanced age. PMID- 29411506 TI - A simple technique to improve calculated skin dose accuracy in a commercial treatment planning system. AB - Radiation dermatitis during radiotherapy is correlated with skin dose and is a common clinical problem for head and neck and thoracic cancer patients. Therefore, accurate prediction of skin dose during treatment planning is clinically important. The objective of this study is to evaluate the accuracy of skin dose calculated by a commercial treatment planning system (TPS). We evaluated the accuracy of skin dose calculations by the anisotropic analytical algorithm (AAA) implemented in Varian Eclipse (V.11) system. Skin dose is calculated as mean dose to a contoured structure of 0.5 cm thickness from the surface. The EGSnrc Monte Carlo (MC) simulations are utilized for the evaluation. The 6, 10 and 15 MV photon beams investigated are from a Varian TrueBeam linear accelerator. The accuracy of the MC dose calculations was validated by phantom measurements with optically stimulated luminescence detectors. The calculation accuracy of patient skin doses is studied by using CT based radiotherapy treatment plans including 3D conformal, static gantry IMRT, and VMAT treatment techniques. Results show the Varian Eclipse system underestimates skin doses by up to 14% of prescription dose for the patients studied when external body contour starts at the patient's skin. The external body contour is used in a treatment planning system to calculate dose distributions. The calculation accuracy of skin dose with Eclipse can be considerably improved to within 4% of target dose by extending the external body contour by 1 to 2 cm from the patient's skin. Dose delivered to deeper target volumes or organs at risk are not affected. Although Eclipse treatment planning system has its limitations in predicting patient skin dose, this study shows the calculation accuracy can be considerably improved to an acceptable level by extending the external body contour without affecting the dose calculation accuracy to the treatment target and internal organs at risk. This is achieved by moving the calculation entry point away from the skin. PMID- 29411508 TI - Sub-Tenon's anesthesia for canine cataract surgery. AB - OBJECTIVE: To test a sub-Tenon's anesthesia technique in dogs as an alternative to systemic neuromuscular blockade to aid in canine cataract surgery under general anesthesia. PROCEDURES: A prospective controlled clinical study was performed involving 12 dogs undergoing bilateral cataract surgery under general anesthesia. One eye was randomly assigned to have phacoemulsification and prosthetic lens implantation performed with sub-Tenon's anesthesia (STA), and the control eye had surgery performed with systemic neuromuscular blockade (NMB). Intraocular pressure (IOP) was measured immediately before and after STA administration. Globe position, globe rotation, pupillary dilation, and vitreal expansion were assessed for both STA and NMB eyes during surgery. RESULTS: Sub Tenon's anesthesia produced a globe position suitable for cataract surgery with the degree of vitreal expansion not significantly different to control NMB eyes. STA produced greater anterior globe displacement than NMB in all cases. STA had no significant effect on IOP. CONCLUSION: Sub-Tenon's anesthesia was an effective alternative to systemic neuromuscular blockade for canine cataract surgery and may be beneficial for surgical exposure in deep orbited breeds. PMID- 29411507 TI - The contribution of physical fitness to individual and ethnic differences in risk markers for type 2 diabetes in children: The Child Heart and Health Study in England (CHASE). AB - BACKGROUND: The relationship between physical fitness and risk markers for type 2 diabetes (T2D) in children and the contribution to ethnic differences in these risk markers have been little studied. We examined associations between physical fitness and early risk markers for T2D and cardiovascular disease in 9- to 10 year-old UK children. METHODS: Cross-sectional study of 1445 9- to 10-year-old UK children of South Asian, black African-Caribbean and white European origin. A fasting blood sample was used for measurement of insulin, glucose (from which homeostasis model assessment [HOMA]-insulin resistance [IR] was derived), glycated hemoglobin (HbA1c), urate, C-reactive protein (CRP), and lipids. Measurements of blood pressure (BP) and fat mass index (FMI) were made; physical activity was measured by accelerometry. Estimated VO2 max was derived from a submaximal fitness step test. Associations were estimated using multilevel linear regression. RESULTS: Higher VO2 max was associated with lower FMI, insulin, HOMA IR, HbA1c, glucose, urate, CRP, triglycerides, LDL-cholesterol, BP and higher HDL cholesterol. Associations were reduced by adjustment for FMI, but those for insulin, HOMA-IR, glucose, urate, CRP, triglycerides and BP remained statistically significant. Higher levels of insulin and HOMA-IR in South Asian children were partially explained by lower levels of VO2max compared to white Europeans, accounting for 11% of the difference. CONCLUSIONS: Physical fitness is associated with risk markers for T2D and CVD in children, which persist after adjustment for adiposity. Higher levels of IR in South Asians are partially explained by lower physical fitness levels compared to white Europeans. Improving physical fitness may provide scope for reducing risks of T2D. PMID- 29411509 TI - Initial experience with the use of fractional flow reserve in the hemodynamic evaluation of transplant renal artery stenosis. AB - OBJECTIVE: To describe and standardize an original protocol for fractional flow reserve (FFR) pre and postangioplasty in an initial series of patients with clinically manifested transplant renal artery stenosis (TRAS). BACKGROUND: There is no data in the literature about the use of FFR in TRAS. METHODS: Patients with TRAS detected in a noninvasive study were referred to diagnostic angiography and stenosis considered visually severe (>= 60%) were included. After selective cannulation, a PressureWire 0.014" (CertusTM-St. Jude Medical) was advanced to the distal portion of the vessel. Resting Pd/Pa ratio (ratio of mean distal to lesion and mean proximal pressures) and translesional systolic pressure gradient were obtained and FFR and hyperemic translesional systolic and mean pressure gradients (HSG and HMG) were registered after papaverine induced maximum hyperemia-pre and poststent implantation. Creatinine levels and office blood pressure measurements were registered at the baseline, 6 and 12 months after intervention. RESULTS: Ten consecutive patients had successful stent implantation and were included. After treatment, significant increase in FFR (0.76 +/- 0.09 vs. 0.96 +/- 0.04, P < 0.001) and reduction in systolic hyperemic gradients ( 41.40 +/- 19.18, P < 0.001) and mean (-24.00 +/- 11.65, P < 0.001) were observed. A strong negative correlation was observed between FFR and percent stenosis diameter-%SD (r = -0.89, P < 0.001) and HSG (r = -0.9, P < 0.001) as well as a strong positive correlation between FFR and baseline Pd/Pa ratio (r = 0.9, P < 0.001). CONCLUSION: FFR was a well-tolerated, valid and reproducible tool during percutaneous intervention for TRAS. Good correlation was observed between FFR and others hemodynamic parameters of lesion severity. PMID- 29411510 TI - The pH dependency of N-converting enzymatic processes, pathways and microbes: effect on net N2 O production. AB - Nitrous oxide (N2 O) is emitted during microbiological nitrogen (N) conversion processes, when N2 O production exceeds N2 O consumption. The magnitude of N2 O production vs. consumption varies with pH and controlling net N2 O production might be feasible by choice of system pH. This article reviews how pH affects enzymes, pathways and microorganisms that are involved in N-conversions in water engineering applications. At a molecular level, pH affects activity of cofactors and structural elements of relevant enzymes by protonation or deprotonation of amino acid residues or solvent ligands, thus causing steric changes in catalytic sites or proton/electron transfer routes that alter the enzymes' overall activity. Augmenting molecular information with, e.g., nitritation or denitrification rates yields explanations of changes in net N2 O production with pH. Ammonia oxidizing bacteria are of highest relevance for N2 O production, while heterotrophic denitrifiers are relevant for N2 O consumption at pH > 7.5. Net N2 O production in N-cycling water engineering systems is predicted to display a 'bell-shaped' curve in the range of pH 6.0-9.0 with a maximum at pH 7.0 7.5. Net N2 O production at acidic pH is dominated by N2 O production, whereas N2 O consumption can outweigh production at alkaline pH. Thus, pH 8.0 may be a favourable pH set-point for water treatment applications regarding net N2 O production. PMID- 29411511 TI - The mechanism for the radioprotective effects of zymosan-A in mice. AB - It proved that Zymosan-A protected the haematopoietic system from radiation induced damage via Toll-Like Receptor2 in our previous study. In this study, we investigated the potential mechanism for the radioprotective effects of Zymosan A. The mice were treated with Zymosan-A (50 mg/kg, dissolved in NS) via peritoneal injection 24 and 2 hours before ionizing radiation. Apoptosis of bone marrow cells and the levels of IL-6, IL-12, G-CSF and GM-CSF were evaluated by flow cytometry assay. DNA damage was determined by gamma-H2AX foci assay. In addition, RNA sequencing was performed to identify differentially expressed genes (DEGs). Zymosan-A protected bone marrow cells from radiation-induced apoptosis, up-regulated IL-6, IL-12, G-CSF and GM-CSF in bone marrow cells. Zymosan-A also protected cells from radiation-induced DNA damage. Moreover, RNA sequencing analysis revealed that Zymosan-A induced 131 DEGs involved in the regulation of immune system process and inflammatory response. The DEGs were mainly clustered in 18 KEGG pathways which were also associated with immune system processes. Zymosan-A protected bone marrow cells from radiation-induced apoptosis and up regulated IL-6, IL-12, G-CSF and GM-CSF. Moreover, Zymosan-A might also exhibit radioprotective effects through regulating immune system process and inflammatory response. These results provided new knowledge regarding the radioprotective effect of Zymosan-A. PMID- 29411513 TI - Unraveling the Raman Enhancement Mechanism on 1T'-Phase ReS2 Nanosheets. AB - 2D transition metal dichalcogenides materials are explored as potential surface enhanced Raman spectroscopy substrates. Herein, a systematic study of the Raman enhancement mechanism on distorted 1T (1T') rhenium disulfide (ReS2 ) nanosheets is demonstrated. Combined Raman and photoluminescence studies with the introduction of an Al2 O3 dielectric layer unambiguously reveal that Raman enhancement on ReS2 materials is from a charge transfer process rather than from an energy transfer process, and Raman enhancement is inversely proportional while the photoluminescence quenching effect is proportional to the layer number (thickness) of ReS2 nanosheets. On monolayer ReS2 film, a strong resonance enhanced Raman scattering effect dependent on the laser excitation energy is detected, and a detection limit as low as 10-9 m can be reached from the studied dye molecules such as rhodamine 6G and methylene blue. Such a high enhancement factor achieved through enhanced charge interaction between target molecule and substrate suggests that with careful consideration of the layer-number-dependent feature and excitation-energy-related resonance effect, ReS2 is a promising Raman enhancement platform for sensing applications. PMID- 29411512 TI - Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs. AB - Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection-derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR-122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection-associated extrahepatic comorbidities. PMID- 29411514 TI - HSPA12B promotes functional recovery after ischaemic stroke through an eNOS dependent mechanism. AB - Stroke is the leading cause of disability worldwide. HSPA12B, a heat-shock protein recently identified expression specifically in endothelial cells, is able to promote angiogenesis. Here, we have investigated its effects on functional recovery at chronic phase of ischaemic stroke. Ischaemic stroke was induced by 60 min. of middle cerebral artery occlusion in transgenic mice with overexpression of HSPA12B (HSPA12B Tg) and wild-type littermates (WT). HSPA12B Tg mice demonstrated a significant higher survival rate than WT mice within 28 days post stroke. Significant improved neurological functions, increased spontaneous locomotor activity and decreased anxiety were detected inHSPA12B Tg mice compared with WT controls within 21 days post-stroke. Stroke-induced hippocampal degeneration was attenuated in HSPA12B Tg mice examined at day 28 post-stroke. Interestingly, HSPA12B Tg mice showed enhanced peri-infarct angiogenesis (examined 28 days post-stroke) and hippocampal neurogenesis (examined 7 days post stroke), respectively, compared to WT mice. The stroke-induced eNOS phosphorylation and TGF-beta1 expression were augmented in HSPA12B Tg mice. However, administration with eNOS inhibitor L-NAME diminished the HSPA12B-induced protection in neurological functional recovery and mice survival post-stroke. The data suggest that HSPA12B promoted functional recovery and survival after stroke in an eNOS-dependent mechanism. Targeting HSPA12B expression may have a therapeutic potential for the stroke-evoked functional disability and mortality. PMID- 29411515 TI - SIRT1/FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells. AB - Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro-inflammatory responses. Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA. SIRT1, FoxO3 and NF-kappaB nuclear accumulation, SIRT1 deacetylase activity, IL-8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed. In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls. Furthermore, CSE reduced FoxO3 expression only in PBECs from controls. In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF-kappaB binding to the IL-8 gene promoter thus increasing IL-8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis. Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF-kappaB. FoxO3 siRNA treatment increased IL-8 and decreased CCL20 expression in 16HBE. In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF-kappaB activity and inducing pro inflammatory responses. PMID- 29411516 TI - Type II toxin/antitoxin system ParESO /CopASO stabilizes prophage CP4So in Shewanella oneidensis. AB - Toxin/antitoxin (TA) loci are commonly found in mobile genetic elements such as plasmids and prophages. However, the physiological functions of these TA loci in prophages and cross-regulation among these TA loci remain largely unexplored. Here, we characterized a newly discovered type II TA pair, ParESO /CopASO , in the CP4So prophage in Shewanella oneidensis. We demonstrated that ParESO /CopASO plays a critical role in the maintenance of CP4So in host cells after its excision. The toxin ParESO inhibited cell growth, resulting in filamentous growth and eventually cell death. The antitoxin CopASO neutralized the toxicity of ParESO through direct protein-protein interactions and repressed transcription of the TA operon by binding to a DNA motif in the promoter region containing two inverted repeats [5'-GTANTAC (N)3 GTANTAC-3']. CopASO also repressed transcription of another TA system PemKSO /PemISO in megaplasmid pMR-1 of S. oneidensis through binding to a highly similar DNA motif in its promoter region. CopASO homologs are widely spread in Shewanella and other Proteobacteria, either as a component of a TA pair or as orphan antitoxins. Our study thus illustrated the cross-regulation of the TA systems in different mobile genetic elements and expanded our understanding of the physiological function of TA systems. PMID- 29411517 TI - Design, Synthesis, and Anti-HIV-1 Evaluation of a Novel Series of 1,2,3,4 Tetrahydropyrimidine-5-Carboxylic Acid Derivatives. AB - A series of tetrahydropyrimidine derivatives (2a - 2l) were designed, synthesized, and screened for anti-HIV-1 properties based on the structures of HIV-1 gp41 binding site inhibitors, NB-2 and NB-64. A computational study was performed to predict the pharmacodynamics, pharmacokinetics, and drug-likeness features of the studied molecules. Docking studies revealed that the carboxylic acid group in the molecules forms salt bridges with either Lys574 or Arg579. Physiochemical properties (e.g., molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, and number of rotatable bonds) of the synthesized compounds confirmed and exhibited that these compounds were within the range set by Lipinski's rule of five. Compounds 2e and 2k with 4-chlorophenyl substituent and 4-methylphenyl group at C(4) position of the tetrahydropyrimidine ring was the most potent one among the tested compounds. This suggests that these compounds may serve as leads for development of novel small-molecule HIV-1 inhibitors. PMID- 29411518 TI - A retrospective study of radiation dose measurements comparing different cath lab X-ray systems in a sample population of patients undergoing percutaneous coronary intervention for chronic total occlusions. AB - OBJECTIVES: A retrospective study was performed to investigate if the generation of X-ray system used was an independent factor for radiation dose in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: PCI procedures for CTOs are known to be associated with higher doses of radiation. The authors suspected progressive reductions in radiation doses for CTO PCI as newer X-ray systems were introduced into clinical practice. METHODS: Procedures performed over a five-year period by three interventional cardiologists were retrospectively reviewed. Five different X-ray systems were used across three hospital sites. These included: Axiom Artis and Coroskop HIP (both Siemens), Innova (GE), Allura Xper FD 10, and Allura Clarity FD 10 (both Philips). Procedural and demographic data including body mass index (BMI; kg/m2 ), fluoroscopy time (min), and dose area product (DAP; cGycm2 ) were collated for each procedure. Statistical analysis was performed to compare the influence each X-ray system would have on DAP values after BMI and fluoroscopy time were controlled for. RESULTS: In total, 860 procedures were analyzed. Mean fluoroscopy time was 40.00 +/- 19.99 min, mean BMI was 29.90 +/- 5.13 kg/m2 , mean DAP 11,980 +/- 7,947 cGycm2 . Log values of DAP were used to normalize results in a general linear model. A significant statistical difference in DAP between X-ray systems was demonstrated after fluoroscopy time and BMI were controlled for (P <= 0.001). CONCLUSION: There is a significant impact on DAP values resulting from the generation of X-ray system used, measured during PCI for CTOs, with the most modern systems producing the lowest radiation doses. PMID- 29411519 TI - Semitendinosus and patellar tendons shear modulus evaluation by supersonic shearwave imaging elastography. AB - PURPOSE: Shear modulus (MU) is directly correlated to the tissue stiffness and can predict the tendon ultimate force to failure. With the knee extended 0 degrees (K0), semitendinosus tendon (ST) is tensioned while patellar tendon (PT) is relaxed. At 80o , knee flexion (K80) tendons present an opposite stress pattern; however, the relation between ST and PT MU in both situations was not studied yet. METHOD: We accessed the MU of the ST and PT at 0o and 80o knee flexion by supersonic shear wave imaging (SSI) elastography from 18 healthy males. Relative MU indexes were calculated for relaxed and tensioned conditions. RESULT: The average MU for ST was MUST-K0 = 197.62 +/- 31.93 kPa and MUST-K80 = 77.76 +/- 30.08. For TP, values were MUTP-K0 = 23.45 +/- 5.89 and MUTP-K80 = 113.92 +/- 57.23 kPa. Relative MU indexes were calculated for relaxed (IR = MUST K80 /MUTP-K0 ) and tensioned conditions (IT = MUST-K0 /MUPT-K80 ). The relative MU indexes were IR = 3.63 +/- 1.50 and IT = 2.00 +/- 0.96 (P<0.05). CONCLUSION: Semitendinosus tendon MU was significantly higher than PT MU in both tensioned and relaxed positions. This can predict a higher ultimate force to failure and a less elastic behaviour in ST grafts when compared to PT grafts. This new parameter could aid physicians in graft choice previous to anterior cruciate ligament reconstruction. PMID- 29411520 TI - Randomized investigator-blinded comparative study of moisturizer containing 4-t butylcyclohexanol and licochalcone A versus 0.02% triamcinolone acetonide cream in facial dermatitis. AB - BACKGROUND: Facial dermatitis can result from various conditions, some of which are of a chronic and relapsing nature. The use of topical corticosteroid therapy may lead to additional adverse effects. OBJECTIVE: To compare the efficacy of moisturizer containing 4-t-butylcyclohexanol, which acts as a sensitivity regulator, and licochalcone A, an anti-inflammatory agent from the licorice plant Glycyrrhiza inflata, with that of 0.02% triamcinolone acetonide (TA) for the treatment of facial dermatitis. METHODS: This was a randomized, prospective, investigator-blinded study. Eighty participants with mild to moderate facial dermatitis were randomly treated with either the test facial moisturizer or 0.02% TA twice daily for the first 2 weeks. For the subsequent 2 weeks, all patients used only the test moisturizer. Clinical assessment by investigators, bioengineering measurements, patients' subjective evaluation, and clinical photography were performed at baseline, week 2, and week 4. RESULTS: Both treatments showed a statistically significant improvement with regard to physician clinical assessment, skin hydration, transepidermal water loss, and patient-assessed visual analog scale after 2 and 4 weeks of treatment compared with baseline. The test facial moisturizer produced better skin hydration than TCS. The improvement in TEWL after 4 weeks of using the test moisturizer was comparable with 2-week treatment with 0.02% TA cream. However, subjective evaluation by patients indicated that TA more rapidly improved sensation sensitivity. CONCLUSION: The test facial moisturizer was slower than 0.02% TA in improving facial dermatitis, but showed greater benefit in erythema control and skin hydration. PMID- 29411521 TI - Words fail: Lesion-symptom mapping of errors of omission in post-stroke aphasia. AB - Impaired object naming is a core deficit in post-stroke aphasia, which can manifest as errors of commission - producing an incorrect word or a non-word - or as errors of omission - failing to attempt to name the object. Detailed behavioural, computational, and neurological investigations of errors of commission have played a key role in the development of neurocognitive models of word production. In contrast, the neurocognitive basis of omission errors is radically underspecified despite being a prevalent phenomenon in aphasia and other populations. The prevalence of omission errors makes their neurocognitive basis important for characterizing an individual's deficits and, ideally, for personalizing treatment and evaluating treatment outcomes. This study leveraged established relationships between lesion location and errors of commission to investigate omission errors in picture naming. Omission error rates from the Philadelphia Naming Test for 123 individuals with post-stroke aphasia were analysed using support vector regression lesion-symptom mapping. Omission errors were most strongly associated with left frontal and mid-anterior temporal lobe lesions. Computational model analysis further showed that omission errors were positively associated with impaired semantically driven lexical retrieval rather than phonological retrieval. These results suggest that errors of omission in aphasia predominantly arise from lexical-semantic deficits in word retrieval and selection from a competitor set. PMID- 29411522 TI - Mapping the CLEC12A expression on myeloid progenitors in normal bone marrow; implications for understanding CLEC12A-related cancer stem cell biology. AB - The C-type lectin domain family 12, member A (CLEC12A) receptor has emerged as a leukaemia-associated and cancer stem cell marker in myeloid malignancies. However, a detailed delineation of its expression in normal haematopoiesis is lacking. Here, we have characterized the expression pattern of CLEC12A on the earliest stem- and myeloid progenitor subsets in normal bone marrow. We demonstrate distinct CLEC12A expression in the classically defined myeloid progenitors, where on average 39.1% (95% CI [32.5;45.7]) of the common myeloid progenitors (CMPs) expressed CLEC12A, while for granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors (MEPs), the average percentages were 81.0% (95% CI [76.0;85.9]) and 11.9% (95% CI [9.3;14.6]), respectively. In line with the reduced CLEC12A expression on MEPs, functional assessment of purified CLEC12A+/- CMPs and MEPs in the colony-forming unit assay demonstrated CLEC12A+ subsets to favour non-erythroid colony growth. In conclusion, we provide evidence that the earliest CLEC12A+ cell in the haematopoietic tree is the classically defined CMP. Furthermore, we show that CLEC12A-expressing CMPs and MEPs are functionally different than their negative counterparts. Importantly, these data can help determine which cells will be spared during CLEC12A-targeted therapy, and we propose CLEC12A to be included in future studies of myeloid cancer stem cell biology. PMID- 29411523 TI - First report of the use of long-tapered sirolimus-eluting coronary stent for the treatment of chronic total occlusions with the hybrid algorithm. AB - BACKGROUND: Coronary chronic total occlusions (CTO) usually coexist with diffusely diseased coronary segments proximal and/or distal to the CTO segment. During percutaneous treatment of CTO, multiple overlapping stents are often needed to treat these long lesions. OBJECTIVES: Aim of this study is to report the first use of long, tapered coronary sirolimus-eluting stents (SES) in this setting. METHODS AND RESULTS: This is a retrospective analysis of 100 consecutive patients undergoing CTO recanalization following the hybrid algorithm. Procedural success rate was 89% (11 failures). Among the successful cases, "conventional" drug-eluting stents(DES) were used in 40(44.9%) patients, while in 49(55%) patients long-tapered SES were attempted with a success rate of 98% (1 cross-over to regular stents). Total stent length in the long-tapered DES group was higher compared to the "conventional" stenting group (76 +/- 28 mm vs 46 +/- 22 mm, P < .001), with a similar total number of stent (1.6 +/- 0.8 vs 1.9 +/- 0.8). At quantitative coronary analysis, proximal and distal segment involvement was more extended in patients undergoing long-tapered stenting, with longer overall lesion length. No differences in periprocedural complications and clinical outcomes at a mean follow-up of 303 +/- 179 days were observed. CONCLUSIONS: The use of long tapered coronary DES is technically feasible and safe for the percutaneous treatment of CTOs, especially for patients presenting with long lesions. PMID- 29411524 TI - Beam profile assessment in spectral CT scanners. AB - In this paper, we present a method that uses a combination of experimental and modeled data to assess properties of x-ray beam measured using a small-animal spectral scanner. The spatial properties of the beam profile are characterized by beam profile shape, the angular offset along the rotational axis, and the photon count difference between experimental and modeled data at the central beam axis. Temporal stability of the beam profile is assessed by measuring intra- and interscan count variations. The beam profile assessment method was evaluated on several spectral CT scanners equipped with Medipix3RX-based detectors. On a well calibrated spectral CT scanner, we measured an integral count error of 0.5%, intrascan count variation of 0.1%, and an interscan count variation of less than 1%. The angular offset of the beam center ranged from 0.8 degrees to 1.6 degrees for the studied spectral CT scanners. We also demonstrate the capability of this method to identify poor performance of the system through analyzing the deviation of the experimental beam profile from the model. This technique can, therefore, aid in monitoring the system performance to obtain a robust spectral CT; providing the reliable quantitative images. Furthermore, the accurate offset parameters of a spectral scanner provided by this method allow us to incorporate a more realistic form of the photon distribution in the polychromatic-based image reconstruction models. Both improvements of the reliability of the system and accuracy of the volume reconstruction result in a better discrimination and quantification of the imaged materials. PMID- 29411525 TI - New Methoxyflavone from Casimiroa sapota and the Biological Activities of Its Leaves Extract against Lead Acetate Induced Hepatotoxicity in Rats. AB - Flavonoids are agents with strong antioxidant properties and ameliorate many diseases associated with oxidative stress. Leaves of Casimiroa sapota were investigated for components and antioxidant/anti-inflammatory activities against lead acetate ((AcO)2 Pb) induced hepatotoxicity in rats. Three groups of male albino rats were administrated orally with vehicle or C. sapota (100 and 200 mg/kg b.w/day) for 28 days; other group was injected with sub-acute dose (100 mg/kg b.w/day) of (AcO)2 Pb. Three protective groups were injected with (AcO)2 Pb (100 mg/kg b.w/day) for 7 days at day 22 after treatment with either C. sapota (100 or 200 mg/kg b.w/day) or silymarin (SILY) for 28 days. We isolated and identified, from C. sapota, a new compound for the 1st time in nature; 5,6,2',3' tetramethoxyflavone in addition to the rare compound 5,6,3'-trimethoxyflavone (second report of isolation from nature) and the known compound 5,6,2',3',4' pentamethoxyflavone. There is an improvement in all hemato-biochemical parameters, antioxidant defense system and anti-inflammatory cytokines of protective groups, which received C. sapota in dose dependent manner. The percentage of changes in all parameters measured in (AcO)2 Pb groups that received vehicle, CS100, CS200 or SILY were 109.2, 37.3, 12.5%, and 1.2% compared with the healthy control group. The C. sapota groups confer a better antioxidant activity by preventing oxidative stress and inflammation in (AcO)2 Pb treated rats. The compounds isolated are responsible at least in part for the observed protective effects. PMID- 29411526 TI - Assessment of multi-criteria optimization (MCO) for volumetric modulated arc therapy (VMAT) in hippocampal avoidance whole brain radiation therapy (HA-WBRT). AB - This study compared the dosimetric performance of (a) volumetric modulated arc therapy (VMAT) with standard optimization (STD) and (b) multi-criteria optimization (MCO) to (c) intensity modulated radiation therapy (IMRT) with MCO for hippocampal avoidance whole brain radiation therapy (HA-WBRT) in RayStation treatment planning system (TPS). Ten HA-WBRT patients previously treated with MCO IMRT or MCO-VMAT on an Elekta Infinity accelerator with Agility multileaf collimators (5-mm leaves) were re-planned for the other two modalities. All patients received 30 Gy in 15 fractions to the planning target volume (PTV), namely, PTV30 expanded with a 2-mm margin from the whole brain excluding hippocampus with margin. The patients all had metastatic lesions (up to 12) of variable sizes and proximity to the hippocampus, treated with an additional 7.5 Gy from a simultaneous integrated boost (SIB) to PTV37.5. The IMRT plans used eight to eleven non-coplanar fields, whereas the VMAT plans used two coplanar full arcs and a vertex half arc. The averaged target coverage, dose to organs-at risk (OARs) and monitor unit provided by the three modalities were compared, and a Wilcoxon signed-rank test was performed. MCO-VMAT provided statistically significant reduction of D100 of hippocampus compared to STD-VMAT, and Dmax of cochleas compared to MCO-IMRT. With statistical significance, MCO-VMAT improved V30 of PTV30 by 14.2% and 4.8%, respectively, compared to MCO-IMRT and STD-VMAT. It also raised D95 of PTV37.5 by 0.4 Gy compared to both MCO-IMRT and STD-VMAT. Improved plan quality parameters such as a decrease in overall plan Dmax and total monitor units (MU) were also observed for MCO-VMAT. MCO-VMAT is found to be the optimal modality for HA-WBRT in terms of PTV coverage, OAR sparing and delivery efficiency, compared to MCO-IMRT or STD-VMAT. PMID- 29411527 TI - Heterogeneity-based, multiple mechanisms in the resistance to osimertinib (AZD9291): A case report. AB - Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post-osimertinib progression. PMID- 29411528 TI - Alterations in the gut microbiota of patients with acquired immune deficiency syndrome. AB - Acquired immune deficiency syndrome (AIDS), caused by infection with human immunodeficiency virus (HIV), is associated with gastrointestinal disease, systemic immune activation and changes in the gut microbiota. Here, we aim to investigate the gut microbiota patterns of HIV-infected individuals and HIV uninfected individuals in populations from South China. We enrolled 33 patients with HIV (14 participants treated with highly active antiretroviral therapy [HAART] for more than 3 months; the remaining 19 individuals had not received treatment) and 35 healthy controls (HC) for a cross-sectional comparison of gut microbiota using stool samples. Gut microbial communities were profiled by sequencing the bacterial 16S rRNA genes. Dysbiosis was more common among patients with AIDS compared with healthy individuals. Dysbiosis was characterized by decreased alpha-diversity, low mean counts of Bacteroidetes, Faecalibacterium, Prevotella, Bacteroides vulgatus, Dialister and Roseburia inulnivorans, and high mean counts of Proteobacteria, Enterococcus, Streptococcus, Lactobacillus, Lachnociostridium, Ruminococcus gnavus and Streptococcus vestibularis. Increased abundance of Bacilli was observed in homosexual patients. Proteobacteria were higher among heterosexual patients with HIV infections. Tenericutes were higher among patients with history of intravenous drug abuse. Restoration of gut microbiota diversity and a significant increase in abundance of Faecalibacterium, Blautia and Bacteroides were found in patients receiving HAART compared to those who did not receive. HIV infection-associated dysbiosis is characterized by decreased levels of alpha-diversity and Bacteroidetes, increased levels of Proteobacteria and the alterations of gut microbiota correlate with the route of HIV transmission. The imbalanced faecal microbiota of HIV infection is partially restored after therapy. PMID- 29411529 TI - Three-dimensional printing CT-derived objects with controllable radiopacity. AB - PURPOSE: The goal of this work was to develop phantoms for the optimization of pre-operative computed tomography (CT) scans of the prostate artery, which are used for embolization planning. METHODS: Acrylonitrile butadiene styrene (ABS) pellets were doped with barium sulfate and extruded into filaments suitable for 3D printing on a fused deposition modeling (FDM) printer. Cylinder phantoms were created to evaluate radiopacity as a function of doping percentage. Small diameter tree phantoms were created to assess their composition and dimensional accuracy. A half-pelvis phantom was created using clinical CT images, to assess the printer's control over cortical bone thickness and cancellous bone attenuation. CT-derived prostate artery phantoms were created to simulate complex, contrast-filled arteries. RESULTS: A linear relationship (R = 0.998) was observed between barium sulfate added (0%-10% by weight), and radiopacity (-31 to 1454 Hounsfield Units [HU]). Micro-CT scans showed even distribution of the particles, with air pockets comprising 0.36% by volume. The small vessels were found to be oversized by a consistent amount of 0.08 mm. Micro-CT scans revealed that the phantoms' interiors were completely filled in. The maximum HU values of cortical bone in the phantom were lower than that of the filament, a result of CT image reconstruction. Creation of cancellous bone regions with lower HU values, using the printer's infill parameter, was successful. Direct volume renderings of the pelvis and prostate artery were similar to the clinical CT, with the exception that the surfaces of the phantom objects were not as smooth. CONCLUSIONS: It is possible to reliably create FDM 3D printer filaments with predictable radiopacity in a wide range of attenuation values, which can be used to print dimensionally accurate radiopaque objects derived from CT data. Phantoms of this type can be quickly and inexpensively developed to assess and optimize CT protocols for specific clinical applications. PMID- 29411530 TI - Diagnosis and management of rare inferior vena cava leiomyosarcoma guided by a novel minimally invasive vascular biopsy technique. AB - Primary vascular tumors such as vascular leiomyosarcomas are rare, but exhibit markedly different characteristics than tumors that invade the vasculature from a secondary source. Establishing a diagnosis is essential in determining the appropriate treatment plan, but obtaining a histologic specimen may prove challenging and carry significant risks. Minimally invasive endovascular biopsy techniques can be pivotal in the diagnosis-and thus in the management-of vascular tumors. We present a case of a primary inferior vena cava leiomyosarcoma, not able to be adequately assessed by noninvasive imaging and deemed too risky to be approached with traditional percutaneous biopsy techniques. Accurate diagnosis of such tumors is critical, as the success of surgical resection, although high risk, depends greatly upon the type, location, and extent of malignancy. PMID- 29411532 TI - A randomized clinical trial to evaluate the stain removal efficacy of a sodium phytate dentifrice formulation. AB - OBJECTIVES: Phytate is an organic, cyclic polyphosphate analogous to linear condensed polyphosphates used as stain removal agents. This study investigated stain removal efficacy of an experimental sodium phytate-containing dentifrice compared to a reference dentifrice. METHODS: An experimental, moderate abrasivity (relative dentine abrasivity [RDA] ~130) antisensitivity fluoride dentifrice containing sodium phytate (0.85% w/w as the hexasodium salt) (n = 111) was compared to a reference, marketed, low-abrasivity (RDA ~ 43), anti-sensitivity fluoride dentifrice (n = 113), both containing 1150 ppm fluoride as sodium fluoride. Primary efficacy variables were between-treatment differences in extrinsic dental stain of anterior teeth after 6 and 12 weeks' twice-daily use, using Lobene stain index (MacPherson modification, MLSI) mean area (A) and intensity (I) scores. Comparisons included whole-tooth and hard-to-reach areas (gingival, interproximal, body of lingual). RESULTS: At both 6- and 12-week timepoints, MLSI (A * I) scores for total area and hard-to-reach areas for the experimental dentifrice were statistically significantly lower than baseline (P < .0001 for all). This was demonstrated for the reference dentifrice at 6 weeks only, for total, interproximal (P < .0001 for both), and body of lingual (P = .0395) scores. Compared with the reference, the experimental dentifrice had statistically significantly lower MLSI scores at both 6 and 12 weeks for all outcome variables including both total MLSI (A * I) and hard-to reach areas (P < .0001 in all cases). Products were generally well-tolerated. CONCLUSIONS: Differences between treatments were considered clinically differentiable. Sodium phytate may therefore be a suitable additive ingredient to improve tooth stain control performance within an otherwise conventional dentifrice formulation. CLINICAL SIGNIFICANCE: Following 6 and 12 weeks brushing, clinically differentiable differences were shown in stain index scores with an experimental dentifrice containing sodium phytate compared to a reference dentifrice without sodium phytate. Sodium phytate may therefore be a suitable additive ingredient to improve tooth stain control performance within an otherwise conventional dentifrice formulation. PMID- 29411531 TI - Aspirin and clopidogrel high on-treatment platelet reactivity and genetic predictors in peripheral arterial disease. AB - OBJECTIVES: Our aims were to examine the prevalence and genetic predictors of aspirin and clopidogrel high on-treatment platelet reactivity (HoTPR), and associated adverse cardiovascular outcomes in patients with peripheral arterial disease (PAD). BACKGROUND: The association of aspirin and clopidogrel HoTPR with outcomes in PAD remains unclear. METHODS: This is a prospective cohort study of patients with angiographically documented PAD involving carotid and lower extremity arteries. Aspirin and clopidogrel HoTPR (using the VerifyNow Assay) and associated genetic predictors were compared to clinical outcomes. The primary end point was a composite of major adverse cardiovascular events: all-cause mortality, myocardial infarction, stroke, target vessel revascularization (TVR) and limb-loss in patients who underwent extremity intervention. RESULTS: The study was stopped prematurely due to slow patient enrolment. Of 195 patients enrolled, the primary analysis was performed in 154 patients taking both drugs. Aspirin HoTPR was present in 31 (20%) and clopidogrel HoTPR in 76 (49%) patients. There was a trend toward more primary composite outcome events with PRU >= 235 (52% freedom-from-event rate vs. 70% for PRU < 235; P = 0.09). TVR was higher in those with PRU >= 235 (20 vs. 6%, unadjusted P = 0.02). There was no association between aspirin HoTPR and combined outcomes. Single nucleotide polymorphisms in serum paraoxonase/arylesterase 1 (PON1) gene was associated with aspirin HoTPR (P = 0.005) while SNP in phospholipase A2, group III (PLA2G3) gene was associated with clopidogrel HoTPR (P = 0.002). CONCLUSION: Clopidogrel HoTPR was significantly associated with TVR, while aspirin HoTPR was not associated with adverse clinical outcomes in patients with PAD. PMID- 29411533 TI - Habitat filtering of bacterioplankton communities above polymetallic nodule fields and sediments in the Clarion-Clipperton zone of the Pacific Ocean. AB - Deep-sea mining of commercially valuable polymetallic nodule fields will generate a seabed sediment plume into the water column. Yet, the response of bacterioplankton communities, critical in regulating energy and matter fluxes in marine ecosystems, to such disturbances is unknown. Metacommunity theory, traditionally used in general ecology for macroorganisms, offers mechanistic understanding on the relative role of spatial differences compared with local environmental conditions (habitat filtering) for community assembly. We examined bacterioplankton metacommunities using 16S rRNA amplicons from the Clarion Clipperton Zone (CCZ) in the eastern Pacific Ocean and in global ocean transect samples to determine sensitivity of these assemblages to environmental perturbations. Habitat filtering was the main assembly mechanism of bacterioplankton community composition in the epi- and mesopelagic waters of the CCZ and the Tara Oceans transect. Bathy- and abyssopelagic bacterioplankton assemblages were mainly assembled by undetermined metacommunity types or neutral and dispersal-driven patch-dynamics for the CCZ and the Malaspina transect. Environmental disturbances may alter the structure of upper-ocean microbial assemblages, with potentially even more substantial, yet unknown, impact on deep sea communities. Predicting such responses in bacterioplankton assemblage dynamics can improve our understanding of microbially-mediated regulation of ecosystem services in the abyssal seabed likely to be exploited by future deep sea mining operations. PMID- 29411534 TI - Extracellular vesicles have variable dose-dependent effects on cultured draining cells in the eye. AB - The role of extracellular vesicles (EVs) as signal mediators has been described in many biological fields. How many EVs are needed to deliver the desired physiological signal is yet unclear. Using a normal trabecular meshwork (NTM) cell culture exposed to non-pigmented ciliary epithelium (NPCE)-derived EVs, a relevant model for studying the human ocular drainage system, we addressed the EVs dose-response effects on the Wnt signaling. The objective of the study was to investigate the dosing effects of NPCE-derived EVs on TM Wnt signaling. EVs were isolated by PEG 8000 method from NPCE and RPE cells (used as controls) conditioned media. Concentrations were determined by Tunable Resistive Pulse Sensing method. Various exosomes concentration were incubated with TM cells, for the determination of mRNA (beta-Catenin, Axin2 and LEF1) and protein (beta Catenin, GSK-3beta) expression using real-time quantitative PCR and Western blot, respectively. Exposure of NTM cells for 8 hrs to low EVs concentrations was associated with a significant decreased expression of beta-Catenin, GSK-3beta, as opposed to exposure to high exosomal concentrations. Pro-MMP9 and MMP9 activities were significantly enhanced in NTM cells treated with high EV concentrations of (X10) as compared to low EV concentrations of either NPCE- or RPE-derived EVs and to untreated control. Our data support the concept that EVs biological effects are concentration-dependent at their target site. Specifically in the present study, we described a general dose-response at the gene and MMPs activity and a different dose-response regarding key canonical Wnt proteins expression. PMID- 29411535 TI - Near-infrared spectroscopy detects age-related differences in skeletal muscle oxidative function: promising implications for geroscience. AB - Age is the greatest risk factor for chronic disease and is associated with a marked decline in functional capacity and quality of life. A key factor contributing to loss of function in older adults is the decline in skeletal muscle function. While the exact mechanism(s) remains incompletely understood, age-related mitochondrial dysfunction is thought to play a major role. To explore this question further, we studied 15 independently living seniors (age: 72 +/- 5 years; m/f: 4/11; BMI: 27.6 +/- 5.9) and 17 young volunteers (age: 25 +/- 4 years; m/f: 8/9; BMI: 24.0 +/- 3.3). Skeletal muscle oxidative function was measured in forearm muscle from the recovery kinetics of muscle oxygen consumption using near-infrared spectroscopy (NIRS). Muscle oxygen consumption was calculated as the slope of change in hemoglobin saturation during a series of rapid, supra-systolic arterial cuff occlusions following a brief bout of exercise. Aging was associated with a significant prolongation of the time constant of oxidative recovery following exercise (51.8 +/- 5.4 sec vs. 37.1 +/- 2.1 sec, P = 0.04, old vs. young, respectively). This finding suggests an overall reduction in mitochondrial function with age in nonlocomotor skeletal muscle. That these data were obtained using NIRS holds great promise in gerontology for quantitative assessment of skeletal muscle oxidative function at the bed side or clinic. PMID- 29411536 TI - Use of the 22C3 anti-programmed death-ligand 1 antibody to determine programmed death-ligand 1 expression in cytology samples obtained from non-small cell lung cancer patients. AB - BACKGROUND: Pembrolizumab monotherapy is a standard-of-care treatment for the first- and second-line treatment of advanced non-small cell lung cancer with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) values >= 50% and >= 1%, respectively. PD-L1 testing with the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx companion assay has been validated on tumor tissue with the Dako Autostainer Link 48 (ASL48). 22C3 anti-PD-L1 antibody-based laboratory-developed tests (LDTs) compatible with other autostainers and cytology samples are essential to support pembrolizumab treatment decisions across institutions globally. METHODS: ASL48 and BenchMark Ultra LDTs were optimized for the evaluation of cytology samples through comparisons with cell lines with known PD L1 expression levels (strong, moderate, and negative). The PD-L1 TPS was then evaluated for 70 paired biopsy and cytology samples (bronchial washes, n = 40; pleural effusions, n = 30) with these LDTs. Biopsy and cytology LDT TPS values were also compared with a subset of biopsy samples (n = 37) evaluated with the PD L1 IHC 22C3 pharmDx assay on the ASL48. RESULTS: Intraclass correlation coefficients of 0.884 to 0.898 were observed for biopsy samples versus cytology samples with the ASL48 and BenchMark Ultra LDTs. Concordance was high, regardless of the TPS cut point (<1% vs >= 1% and <50% vs >= 50%), sample type (pleural effusion vs bronchial wash), or tumor histology (adenocarcinoma vs squamous cell carcinoma). Concordance was high for each LDT versus the PD-L1 IHC 22C3 pharmDx assay. CONCLUSIONS: ASL48 and BenchMark Ultra 22C3 antibody concentrate-based LDTs have been validated for PD-L1 testing in cytology samples, and they will support reliable, high-quality PD-L1 testing across regions globally. Cancer Cytopathol 2018;126:264-74. (c) 2018 American Cancer Society. PMID- 29411538 TI - SPION-mediated miR-141 promotes the differentiation of HuAESCs into dopaminergic neuron-like cells via suppressing lncRNA-HOTAIR. AB - In this study, a bioinformatics analysis and luciferase reporter assay revealed that microRNA-141 could silence the expression of lncRNA-HOTAIR by binding to specific sites on lncRNA-HOTAIR. We used superparamagnetic iron oxide nanoparticles (SPIONs) to mediate the high expression of microRNA-141 (SPIONs@miR 141) in human amniotic epithelial stem cells (HuAESCs), which was followed by the induction of the differentiation of HuAESCs into dopaminergic neuron-like cells (iDNLCs). qPCR, western blot, immunofluorescence staining and HPLC all suggested that SPION-mediated overexpression of miR-141 could promote an increased expression of brain-derived neurotrophic factor (BDNF), DAT and 5-TH in HuAESC derived iDNLCs. The RIP and ChIP assay also showed that overexpression of miR-141 could significantly inhibit the recruitment and binding of lncRNA-HOTAIR to EZH2 on BDNF gene promoter. cDNA microarray analysis revealed that the expression levels of 190 genes were much higher in iDNLCs than in HuAESCs. Finally, a protein interaction network analysis and identification showed that in the iDNLC group with SPIONs@miR-141, factors that interact with BDNF, such as FGF8, SHH, NTRK3 and CREB1, all showed significantly higher expression levels compared with those in the SPIONs@miR-Mut. Therefore, this study confirmed that the highly efficient expression of microRNA-141 mediated by SPIONs could improve the efficiency of HuAESCs differentiation into dopaminergic neuron-like cells. PMID- 29411537 TI - Developmental and sex differences in tetramethylenedisulfotetramine (TMDT) induced syndrome in rats. AB - Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide considered a chemical threat agent. Symptoms of intoxication include seizures leading to status epilepticus and death. While children and women have been often the victims, no studies exist investigating the neurotoxic effects of TMDT in developing individuals or females. Thus, we performed such an investigation in developing Sprague-Dawley rats of both sexes in order to identify potential age- or sex-dependent vulnerability to TMDT exposure. Subcutaneous injection was chosen as the preferred route of TMDT exposure. EEG recordings confirmed the seizure activity observed in both postnatal day 15 (P15) and adult rats. Additionally, P15 rats displayed greater sensitivity to TMDT than postnanatal day 25 or adult animals. Seizures were generally more severe in females compared to males. Barrel rotations accompanied convulsions in P25 and adult, but sparsely in P15 rats. Adults developed barrel rolling less frequently than P25 population. Neuronal cell death was not present in 24-h TMDT survivors at any age or sex tested. A seizure rechallenge with flurothyl 7 days following TMDT exposure demonstrated longer latencies to the first clonic seizure but a faster progression into the tonic-clonic seizure in P15 and adult survivors as compared to their vehicle-injected counterparts. In conclusion, the youngest age group represents the most vulnerable population to the TMDT-induced toxidrome. Females appear to be more vulnerable than males. TMDT exposure promotes seizure spread and progression in survivors. These findings will help to establish sex- and age specific treatment strategies for TMDT-exposed individuals. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 403-416, 2018. PMID- 29411540 TI - Editorial: The American College of Rheumatology White Paper on Biosimilars: It Isn't All White-There Is Some Gray and Black. PMID- 29411539 TI - Association between glutathione peroxidase 1 codon 198 variant and the occurrence of breast cancer in Rwanda. AB - BACKGROUND: Glutathione peroxidase 1 gene (GPX1) is one of the antioxidant enzyme that remove the reactive oxygen species in a continuous process. Since the identification of a well-characterized functional polymorphism named p.Pro198Leu (rs1050450 C>T) in GPX1 gene, abundant studies have evaluated the association between p.Pro198Leu polymorphism and tumor risk in diverse population. But, the available results related to breast cancer are conflicting and absent in Africa. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Rwanda population to determine whether it is associated with the risk of developing breast cancer. METHODS: Genomic DNA from peripheral blood leukocytes of 41 patients with breast cancer and 42 healthy controls were enrolled and genotyped GPX1 Pro198Leu polymorphism by PCR amplification and DNA sequencing. RESULTS: No significant difference in the frequencies of Pro/Pro (49%) and Pro/Leu (51%) genotypes in cancer cases and in controls (50% each) were found. The allelic frequencies of Pro and Leu were 74% versus 26% and 75% versus 25% in breast cancer cases and controls respectively. No association was observed in allele frequencies of Pro and Leu, and familial history. Only an overall association of GPX1 Pro198Leu with grade of cancer (Pro/Leu vs. Pro/Pro: p = .0200) was detected. CONCLUSION: The result of this study suggested that GPX1 Pro198Leu polymorphism could not be a risk factor for breast cancer in Rwanda. However, large-scale studies on the effect of this polymorphism on the factors disturbing the redox homeostasis are needed for conclusive understanding. PMID- 29411541 TI - Exploring an alternative approach to Lyme disease surveillance in Maryland. AB - In Maryland, Lyme disease (LD) is a reportable disease and all laboratories and healthcare providers are required to report to the local health department. Given the volume of LD reports and effort required for investigation, surveillance for LD is burdensome and subject to underreporting. We explored the utility of International Classification of Diseases, 9th Revision, Clinical Modification (administrative) codes for use with LD surveillance. We aimed to collect the administrative codes for a 10% sample of 2009 LD reports (n = 474) from 292 facilities stratified by case classification (confirmed, probable, suspected and not a case). Sixty-three per cent (n = 184) of facilities responded to the survey, and 341 different administrative codes were obtained for 91% (n = 430) of sampled reports. The administrative code for Lyme disease (088.81) was the most commonly reported code (133/430 patients) among sampled reports; while it was used for 62 of 151 (41%) confirmed cases, it was also used for 48 of 192 (25%) not a case reports (sensitivity 41% and specificity 73%). A combination of nine codes was developed with sensitivity of 74% and specificity of 37% when compared to not a case reports. We conclude that the administrative code for LD alone has low ability to identify LD cases in Maryland. Grouping certain codes improved sensitivity, but our results indicate that administrative codes alone are not a viable surveillance alternative for a disease with complex manifestations such as LD. PMID- 29411542 TI - Prevalence of psychotic-like experiences and their correlations with internalizing problems: A study of early adolescents in rural area in Karawang, Indonesia. AB - INTRODUCTION: Adolescents who live in rural areas have been found to experience more mental health problems than those who live in urban areas. In Indonesia, adolescents who live in rural areas have limited facilities to access mental health services. On the other hand, there is still a strong belief in the rural communities that mental health problems are the consequence of demonic possession, having committed a sin, lack of faith, etc. Rural communities tend to seek traditional remedies such as advice from traditional healers or witchdoctors. Unfortunately, previous studies have indicated that the onset of most mental health problems is during adolescence, and this includes psychotic symptoms that are often manifested as psychotic-like experiences (PLEs). METHODS: The Strength and Difficulties Questionnaire was used to examine internalizing problems. PLEs were used to examine psychotic symptoms. Data were collected in 3 junior high schools in Karawang. A total of 270 adolescents (aged between 11 and 16 years old) who live in the rural area in Karawang participated in this research. RESULTS: The study found that the prevalence of adolescents with at least 2 symptoms of PLEs was 7%. The result of the study indicated that there is no significant correlation between psychotic-like experiences and internalizing problems (r = .075, P = .22). DISCUSSION: PLEs significantly correlated with peer relationship problems rather than with internalizing problems. Further investigation is needed to examine the factors that contribute to PLEs in rural settings. PMID- 29411543 TI - Lumped-parameter models of the pulmonary vasculature during the progression of pulmonary arterial hypertension. AB - A longitudinal study of monocrotaline-induced pulmonary arterial hypertension (PAH) was carried out in Sprague-Dawley rats to investigate the changes in impedance (comprising resistance and compliance) produced by elevated blood pressure. Using invasively measured blood flow as an input, blood pressure was predicted using 3- and 4-element Windkessel (3WK, 4WK) type lumped-parameter models. Resistance, compliance, and inductance model parameters were obtained for the five different treatment groups via least-squares errors. The treated animals reached levels of hypertension, where blood pressure increased two folds from control to chronic stage of PAH (mean pressure went from 24 +/- 5 to 44 +/- 6 mmHg, P < 0.0001) but blood flow remained overall unaffected. Like blood pressure, the wave-reflection coefficient significantly increased at the advanced stage of PAH (0.26 +/- 0.09 to 0.52 +/- 0.09, P < 0.0002). Our modeling efforts revealed that resistances and compliance changed during the disease progression, where changes in compliance occur before the changes in resistance. However, resistance and compliance are not directly inversely related. As PAH develops, resistances increase nonlinearly (Rd exponentially and R at a slower rate) while compliance linearly decreases. And while 3WK and 4WK models capture the pressure flow relation in the pulmonary vasculature during PAH, results from Akaike Information Criterion and sensitivity analysis allow us to conclude that the 3WK is the most robust and accurate model for this system. Ninety-five percent confidence intervals of the predicted model parameters are included for the population studied. This work establishes insight into the complex remodeling process occurring in PAH. PMID- 29411544 TI - The metabolic pathways utilized by Salmonella Typhimurium during infection of host cells. AB - Only relatively recently has research on the metabolism of intracellular bacterial pathogens within their host cells begun to appear in the published literature. This reflects in part the experimental difficulties encountered in separating host metabolic processes from those of the resident pathogen. One of the most genetically tractable and thoroughly studied intracellular bacterial pathogens, Salmonella enterica serovar Typhimurium (S. Typhimurium), has been at the forefront of metabolic studies within eukaryotic host cells. In this review, we offer a synthesis of what has been discovered to date regarding the metabolic adaptation of S. Typhimurium to survival and growth within the infected host. We discuss many studies in the context of techniques used, types of host cells, how host metabolites contribute to intracellular survival and proliferation of the pathogen and how bacterial metabolism affects the virulence and persistence of the pathogen. PMID- 29411545 TI - The microbial contribution to reactive oxygen species dynamics in marine ecosystems. AB - This review surveys the current state of knowledge of the concentrations, sources and sinks of reactive oxygen species (ROS) in the ocean. Both abiotic and biotic factors contribute to ROS dynamics in seawater, and ROS can feature prominently in marine microbe-microbe interactions. The sun plays a key role in the production of ROS in the ocean, and consequently ROS concentrations are typically maximal in the sun-exposed surface. However, microbes can also contribute significantly to extracellular ROS. Production of superoxide is widespread within the microbial community, and may benefit the producers as antimicrobial agents or perhaps more generally, as a means of nutrient scavenging. Decomposition of hydrogen peroxide is a community-wide activity, though some members may play less significant roles in this process. The more reactive forms of ROS, singlet oxygen and the hydroxyl radical, may be less important as microbial stressors, as they tend to react with the chemicals in seawater before they can contact the cells. However, exceptions may exist for microbes attached to singlet oxygen-generating sinking particulate matter. Extracellular ROS thus plays an important role in the ecology of marine microbes, the full extent to which we are only beginning to appreciate. PMID- 29411546 TI - Cross-protection from hydrogen peroxide by helper microbes: the impacts on the cyanobacterium Prochlorococcus and other beneficiaries in marine communities. AB - Hydrogen peroxide (HOOH) is a reactive oxygen species, derived from molecular oxygen, that is capable of damaging microbial cells. Surprisingly, the HOOH defence systems of some aerobes in the oxygenated marine environments are critically depleted, relative to model aerobes. For instance, the gene encoding catalase is absent in the numerically dominant photosynthetic cyanobacterium, Prochlorococcus. Accordingly, Prochlorococcus is highly susceptible to HOOH when exposed as pure cultures. Pure cultures do not exist in the marine environment, however. Catalase-positive community members can remove HOOH from the seawater medium, thus lowering the threat to Prochlorococcus and any other member that likewise lacks their own catalase. This cross-protection may constitute a loosely defined symbiosis, whereby the catalase-positive helper cells may benefit through the acquisition of nutrients released by the beneficiaries such as Prochlorococcus. Other members of the community that may be helped by the catalase-positive cells may include some lineages of Synechococcus - the sister genus of Prochlorococcus - as well as some lineages of SAR11 and ammonia oxidizing archaea and bacteria. The co-occurrence of catalase-positive and negative members suggests that cross-protection from HOOH-mediated oxidative stress may play an important role in the construction of the marine microbial community. PMID- 29411547 TI - The Science Behind Biosimilars: Entering a New Era of Biologic Therapy. PMID- 29411548 TI - Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder. AB - Social impairment is one of the major symptoms in multiple psychiatric disorders, including autism spectrum disorder (ASD). Accumulated studies indicate a crucial role for the gut microbiota in social development, but these mechanisms remain unclear. This review focuses on two strategies adopted to elucidate the complicated relationship between gut bacteria and host social behavior. In a top down approach, researchers have attempted to correlate behavioral abnormalities with altered gut microbial profiles in rodent models of ASD, including BTBR mice, maternal immune activation (MIA), maternal valproic acid (VPA) and maternal high fat diet (MHFD) offspring. In a bottom-up approach, researchers use germ-free (GF) animals, antibiotics, probiotics or pathogens to manipulate the intestinal environment and ascertain effects on social behavior. The combination of both approaches will hopefully pinpoint specific bacterial communities that control host social behavior. Further discussion of how brain development and circuitry is impacted by depletion of gut microbiota is also included. The converging evidence strongly suggests that gut microbes affect host social behavior through the alteration of brain neural circuits. Investigation of intestinal microbiota and host social behavior will unveil any bidirectional communication between the gut and brain and provide alternative therapeutic targets for ASD. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 474-499, 2018. PMID- 29411549 TI - Is Omalizumab a Problem-Solving Remedy in Severe Asthma? PMID- 29411550 TI - Dog and Cat Allergies: Current State of Diagnostic Approaches and Challenges. AB - Allergies to dogs and cats affect 10%-20% of the population worldwide and is a growing public health concern as these rates increase. Given the prevalence of detectable dog and cat allergens even in households without pets, there is a critical need to accurately diagnose and treat patients to reduce morbidity and mortality from exposure. The ability to diagnose cat sensitization is good, in contrast to dogs. Component resolved diagnostics of sensitization to individual allergenic proteins will dramatically improve diagnosis. This review focuses on the current state of knowledge regarding allergies to dogs and cats, recent advances, therapies such as subcutaneous immunotherapy, and discusses important areas to improve diagnosis and therapy. PMID- 29411551 TI - Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization? AB - Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-delta and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future. PMID- 29411552 TI - Therapeutic Effect of Omalizumab in Severe Asthma: A Real-World Study in Korea. AB - PURPOSE: Omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, has proved to be effective for the treatment of severe asthma. However, there is no direct evidence of effectiveness of omalizumab in Korean patients with severe asthma. We sought to evaluate the real-world effectiveness of omalizumab in Korean adult patients suffering from severe asthma and to identify predictors of favorable response. METHODS: A retrospective analysis of electrical medical records was performed on severe allergic asthmatic patients with omalizumab treatment group (OT group) for more than 6 months between March 2008 and February 2016. Propensity score matching was applied to define the standardized treatment control group (STC group) treated without omalizumab. Asthma-related outcomes were compared between the 2 groups, and analyzed before and after omalizumab use in the OT group. Responders to treatment were defined as patients showing >50% reduction in asthma exacerbations and/or systemic steroid requirement during the outcome period. RESULTS: One hundred twenty-four patients with severe asthma (62 in the OT group; 62 in the STC group) were enrolled in the study. Proportion of patients having the reduction of asthma exacerbation (53.2% vs 35.5%, P=0.015) and the rate of responders (67.7% vs 41.9%, P=0.007) were significantly higher in the OT group than in the STC group. Significant reductions were noted in asthma exacerbation (P=0.006), hospitalization (P=0.009), hospitalization days (P=0.006), systemic corticosteroid requirements (P=0.027), and sputum eosinophil count (P=0.031) in OT group compared with STC group. There were no significant differences in changes of forced expiratory volume in the 1 second (FEV1) levels between the 2 groups. No predictors of responders were found for omalizumab treatment. CONCLUSIONS: Omalizumab can reduce exacerbations/hospitalization/systemic steroid burst in Korean adult patients with severe asthma. PMID- 29411553 TI - Dyspnea Perception During Induced Bronchoconstriction Is Complicated by the Inhaled Methacholine in Children With Clinical Asthma. AB - PURPOSE: Dyspnea is not widely utilized as an indicator of asthma provocation despite its universal presentation. We hypothesized that dyspnea severity was proportionate with the lung function decline, methacholine dose-step, and the degree of bronchial hyperresponsiveness (BHR). METHODS: We retrospectively analyzed 73 children's bronchial provocation test data with an assessment of dyspnea at every dose-step. Dyspnea severity was scored using a modified Borg (mBorg) scale. A linear mixed effect analysis was performed to evaluate the relationship between the mBorg scale, the percentage fall in the forced expiratory volume in 1 second (FEV1) (DeltaFEV1%), the methacholine dose-step, and the degree of BHR (BHR grade). RESULTS: Subjects were divided into 5 BHR groups based on their last methacholine dose-steps. The mBorg scores did not differ significantly among BHR groups (P=0.596, Kruskal-Wallis test). The linear mixed effect analysis showed that DeltaFEV1% was affected by the methacholine dose-step (P<0.001) and BHR grade (P<0.001). The mBorg score was affected by the dose-step (P<0.001) and BHR grade (P=0.019). We developed a model to predict the mBorg score and found that it was affected by the methacholine dose-step and DeltaFEV1%, elevating it by a score of 0.039 (chi2 [1]=21.06, P<0.001) and 0.327 (chi2 [1]=47.45, P<0.001), respectively. A significant interaction was observed between the methacholine dose-step and DeltaFEV1% (chi2 [1]=16.20, P<0.001). CONCLUSIONS: In asthmatic children, inhaled methacholine, as well as the degree of BHR and lung function decline, may affect dyspnea perception during the bronchial provocation test. If we wish to draw meaningful information from dyspnea perception, we have to consider various complicating factors underlying it. PMID- 29411554 TI - Are Registration of Disease Codes for Adult Anaphylaxis Accurate in the Emergency Department? AB - PURPOSE: There has been active research on anaphylaxis, but many study subjects are limited to patients registered with anaphylaxis codes. However, anaphylaxis codes tend to be underused. The aim of this study was to investigate the accuracy of anaphylaxis code registration and the clinical characteristics of accurate and inaccurate anaphylaxis registration in anaphylactic patients. METHODS: This retrospective study evaluated the medical records of adult patients who visited the university hospital emergency department between 2012 and 2016. The study subjects were divided into the groups with accurate and inaccurate anaphylaxis codes registered under anaphylaxis and other allergy-related codes and symptom related codes, respectively. RESULTS: Among 211,486 patients, 618 (0.29%) had anaphylaxis. Of these, 161 and 457 were assigned to the accurate and inaccurate coding groups, respectively. The average age, transportation to the emergency department, past anaphylaxis history, cancer history, and the cause of anaphylaxis differed between the 2 groups. Cutaneous symptom manifested more frequently in the inaccurate coding group, while cardiovascular and neurologic symptoms were more frequently observed in the accurate group. Severe symptoms and non-alert consciousness were more common in the accurate group. Oxygen supply, intubation, and epinephrine were more commonly used as treatments for anaphylaxis in the accurate group. Anaphylactic patients with cardiovascular symptoms, severe symptoms, and epinephrine use were more likely to be accurately registered with anaphylaxis disease codes. CONCLUSIONS: In case of anaphylaxis, more patients were registered inaccurately under other allergy-related codes and symptom related codes rather than accurately under anaphylaxis disease codes. Cardiovascular symptoms, severe symptoms, and epinephrine treatment were factors associated with accurate registration with anaphylaxis disease codes in patients with anaphylaxis. PMID- 29411555 TI - Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients. AB - PURPOSE: In order to gain an insight into determinants of reported variability in immune responses to respiratory viruses in human bronchial epithelial cells (HBECs) from asthmatics, the responses of HBEC to viral infections were evaluated in HBECs from phenotypically heterogeneous groups of asthmatics and in healthy controls. METHODS: HBECs were obtained during bronchoscopy from 10 patients with asthma (6 atopic and 4 non-atopic) and from healthy controls (n=9) and grown as undifferentiated cultures. HBECs were infected with parainfluenza virus (PIV)-3 (MOI 0.1) and rhinovirus (RV)-1B (MOI 0.1), or treated with medium alone. The cell supernatants were harvested at 8, 24, and 48 hours. IFN-alpha, CXCL10 (IP 10), and RANTES (CCL5) were analyzed by using Cytometric Bead Array (CBA), and interferon (IFN)-beta and IFN-lambda1 by ELISA. Gene expression of IFNs, chemokines, and IFN-regulatory factors (IRF-3 and IRF-7) was determined by using quantitative PCR. RESULTS: PIV3 and RV1B infections increased IFN-lambda1 mRNA expression in HBECs from asthmatics and healthy controls to a similar extent, and virus-induced IFN-lambda1 expression correlated positively with IRF-7 expression. Following PIV3 infection, IP-10 protein release and mRNA expression were significantly higher in asthmatics compared to healthy controls (median 36.03 fold). No differences in the release or expression of RANTES, IFN-lambda1 protein and mRNA, or IFN-alpha and IFN-beta mRNA between asthmatics and healthy controls were observed. However, when asthmatics were divided according to their atopic status, HBECs from atopic asthmatics (n=6) generated significantly more IFN lambda1 protein and demonstrated higher IFN-alpha, IFN-beta, and IRF-7 mRNA expressions in response to PIV3 compared to non-atopic asthmatics (n=4) and healthy controls (n=9). In response to RV1B infection, IFN-beta mRNA expression was lower (12.39-fold at 24 hours and 19.37-fold at 48 hours) in non-atopic asthmatics compared to atopic asthmatics. CONCLUSIONS: The immune response of HBECs to virus infections may not be deficient in asthmatics, but seems to be modified by atopic status. PMID- 29411557 TI - Electronic Consultation Support System for Radiocontrast Media Hypersensitivity Changes Clinicians' Behavior. AB - PURPOSE: Patients with a history of radiocontrast media (RCM) hypersensitivity can be overlooked, resulting in repeated reactions. Therefore, a consultation support system for RCM hypersensitivity has been in operation at Seoul National University Bundang Hospital since December 2011. We analyzed the effect of this system on physicians' practice. METHODS: A retrospective study was conducted on patients with previous RCM reactions (December 1, 2010 to November 30, 2012). The control period was December 2010 to November 2011, and the intervention period was December 2011 to November 2012. The primary outcome was the composite outcome of premedication and consultation. Premedication was defined as preventive medication prescribed by the physician who ordered RCM-enhanced computed tomography (CT) at the same time. The secondary outcome was the recurrence rate after using the consultation support system. RESULTS: A total of 189 clinicians prescribed 913 CT scans during the control period and 225 clinicians performed 1,153 examinations during the intervention period. The odds ratio (OR) of achieving the composite outcome increased significantly after use of the consultation support system (OR, 1.54; 95% confidence interval [CI], 1.15-2.05). Clinicians in both medical (OR, 1.48; 95% CI, 1.06-2.07) and surgical (OR, 2.07; 95% CI, 1.24-3.46) departments showed significant changes in their behavior, whereas those in the emergency department did not (OR, 1.07; 95% CI, 0.41-2.78). Professors (OR, 1.47; 95% CI, 1.06-2.04) and trainees (OR, 1.97, 95% CI, 1.22 3.18) showed significant changes in their behavior toward patients with previous RCM reactions. The behavior of 86 clinicians who ordered CT scans during both the control and intervention periods was unchanged. CONCLUSIONS: The consultation support system for those with previous RCM hypersensitivity reactions changed physicians' practice patterns and decreased recurrent RCM hypersensitivity reactions as well. PMID- 29411556 TI - Dog and Cat Allergies and Allergen Avoidance Measures in Korean Adult Pet Owners Who Participated in a Pet Exhibition. AB - PURPOSE: This study evaluated dog and cat allergies and their association with allergen avoidance measures in Korean adults. METHODS: The study population consisted of 537 adults who currently kept dogs or cats and participated in a pet exhibition in Korea. The subjects were asked to complete questionnaires regarding pet ownership, allergen avoidance, and allergy symptoms, and underwent skin prick tests. They were considered to have a dog or cat allergy if they suffered from one or more of allergy symptoms during contact with their pets. RESULTS: In total, 103 of 407 dog owners (25.3%) and 45 of 130 cat owners (34.6%) had a dog or cat allergy, respectively. Dog owners kept 1.3+/-1.5 dogs; this number did not differ according to the presence of dog allergy. Dog owners with a dog allergy had owned their dogs longer than those without (88.0+/-72.0 vs 67.5+/-72.7 months, P<0.05). Cat owners kept 2.1+/-3.6 cats; this number did not differ according to the presence of cat allergy, nor did the duration of cat ownership. Cat owners with a cat allergy had facial contact and slept with their cats less frequently (8.6+/-11.9 vs 18.3+/-27.0 times/day, P<0.01; 71.1% vs 81.2%, P<0.05); however, they had their cats shaved and beds cleaned less frequently than those without (1.8+/-3.3 vs 3.2+/-4.4 times/year, P<0.05; 1.5+/-1.5 vs 3.9+/-6.0 times/month, P<0.01). CONCLUSIONS: Cat owners with a cat allergy tried to minimize contact with their cats, but efforts to avoid indoor cat allergens were lower than those without. In comparison, dog owners with a dog allergy had kept their dogs for longer time than those without; however, current contact with their dogs and allergen avoidance measures did not differ between the 2 groups. PMID- 29411558 TI - Interactions Between Bisphenol A Exposure and GSTP1 Polymorphisms in Childhood Asthma. AB - PURPOSE: Bisphenol A (BPA) exposure may increase the risk of asthma. Genetic polymorphisms of oxidative stress-related genes, glutathione S-transferases (GSTM1, GSTP1), manganese superoxide dismutase, catalase, myeloperoxidase, and microsomal epoxide hydrolase may be related to BPA exposure. The aim is to evaluate whether oxidative stress genes modulates associations of BPA exposure with asthma. METHODS: We conducted a case-control study comprised of 126 asthmatic children and 327 controls. Urine Bisphenol A glucuronide (BPAG) levels were measured by ultra-performance liquid chromatography/tandem mass spectrometry, and genetic variants were analyzed by a TaqMan assay. Information on asthma and environmental exposure was collected. Analyses of variance and logistic regressions were performed to determine the association of genotypes and urine BPAG levels with asthma. RESULTS: BPAG levels were significantly associated with asthma (adjusted odds ratio [aOR], 1.29 per log unit increase in concentration; 95% confidence interval [CI], 1.081.55). Compared to the GG genotype, children with a GSTP1 AA genotype had higher urine BPAG concentrations (geometric mean [standard error], 12.72 [4.16] vs 11.42 [2.82]; P=0.036). In children with high BPAG, the GSTP1 AA genotype was related to a higher odds of asthma than the GG genotype (aOR, 4.84; 95% CI, 1.0223.06). CONCLUSIONS: GSTP1 variants are associated with urine BPA metabolite levels. Oxidative stress genes may modulate the effect of BPA exposure on asthma. PMID- 29411559 TI - Intralymphatic Immunotherapy Alleviates Allergic Symptoms During Allergen Exposure in Daily Life. PMID- 29411560 TI - Benefits of Nasal Cellulose Powder Application Depend on the Type of Allergen Sensitization in Allergic Rhinitis. PMID- 29411561 TI - A Case of Intraoperative Anaphylaxis Caused by Bovine-Derived Thrombin. AB - Intraoperative bovine-derived topical thrombin is still widely used for hemostasis during surgery. A 38-year-old woman with chronic spontaneous urticaria was referred to the orthopedic surgery department for herniated disk and myelopathy. During the first stage of operation, bovine-derived thrombin powder soaked in Gelfoam was used as a hemostatic aid. After 30 minutes, the patient developed anaphylactic shock with systemic skin rash and angioedema. Repeated intravenous bolus and infusion of vasopressor were carried out, and her blood pressure normalized. Skin test and specific immunoglobulin E test showed positive results for bovine thrombin and beef, respectively. During the second stage of operation (After 10 days from first stage of operation), bovine-derived thrombin powder was excluded and the operation was successful without any unexpected events. Therefore, bovine thrombin should be used with caution because it might cause anaphylaxis. PMID- 29411563 TI - Review of technological advancements in calibration systems for laser vision correction. AB - Using PubMed and our internal database, we extensively reviewed the literature on the technological advancements in calibration systems, with a motive to present an account of the development history, and latest developments in calibration systems used in refractive surgery laser systems. As a second motive, we explored the clinical impact of the error introduced due to the roughness in ablation and its corresponding effect on system calibration. The inclusion criterion for this review was strict relevance to the clinical questions under research. The existing calibration methods, including various plastic models, are highly affected by various factors involved in refractive surgery, such as temperature, airflow, and hydration. Surface roughness plays an important role in accurate measurement of ablation performance on calibration materials. The ratio of ablation efficiency between the human cornea and calibration material is very critical and highly dependent on the laser beam characteristics and test conditions. Objective evaluation of the calibration data and corresponding adjustment of the laser systems at regular intervals are essential for the continuing success and further improvements in outcomes of laser vision correction procedures. PMID- 29411562 TI - Limulus amoebocyte lysate test via an open-microcavity optical biosensor. AB - Almost since its discovery, Limulus amoebocyte lysate (LAL) testing has been an important part of the pharmaceutical quality control toolkit. It allows for in vitro endotoxin testing, which has replaced tests using animals, such as using rabbits' thermal response to judge pyrogenicity of test samples, thus leading to a less expensive and faster test of parenteral pharmaceuticals and medical devices that contact blood or cerebrospinal fluid. However, limited by the detection mechanisms of the LAL assays currently used in industry, further improvement in their performance is challenging. To address the growing demand on optimizing LAL assays for increased test sensitivity and reduced assay time, we have developed an LAL assay approach based on a detection mechanism that is different from those being used in industry, namely, gel-clot, turbidimetric, and chromogenic detection. Using a unique open-microcavity photonic-crystal biosensor to monitor the change in the refractive index due to the reaction between LAL regents and endotoxins, we have demonstrated that this approach has improved the LAL assay sensitivity by 200 times compared with the commercial standard methods, reduced the time needed for the assay by more than half, and eliminated the necessity to incubate the test samples. This study opens up the possibility of using the significantly improved LAL assays for a wide range of applications. PMID- 29411564 TI - 'In the Bleak Midwinter'. PMID- 29411565 TI - ? PMID- 29411566 TI - ? PMID- 29411567 TI - ? PMID- 29411568 TI - ? PMID- 29411569 TI - The importance of the 'little' things. PMID- 29411570 TI - ? PMID- 29411571 TI - ? PMID- 29411572 TI - ? PMID- 29411573 TI - ? PMID- 29411574 TI - Better care, fewer suicides? PMID- 29411575 TI - ? PMID- 29411576 TI - ? PMID- 29411577 TI - ? PMID- 29411578 TI - ? PMID- 29411579 TI - Structured measures against infections in nursing homes. PMID- 29411580 TI - ? PMID- 29411581 TI - ? PMID- 29411583 TI - ? PMID- 29411584 TI - ? PMID- 29411586 TI - ? PMID- 29411585 TI - Experiences of the bereaved in connection with the suicide of young men. AB - BACKGROUND: On average 110 men under 35 years of age take their own lives in Norway each year. Few receive health assistance in the period prior to the suicide, and little research exists on contact with assistance agencies for persons who take their own lives, beyond studies of the number of doctor visits before the death. This study aimed to obtain knowledge of relatives' need for assistance from the health services, both to identify suicide risk and motivate them to seek help in life crises. MATERIAL AND METHOD: Sixty-one in-depth interviews with the bereaved next of kin of young men (18-30 years) were analysed using interpretative phenomenological analysis. RESULTS: The bereaved perceived the generally accepted assumption that suicide is attributable to mental illness as an obstacle to identifying suicide risk. Most of the bereaved saw no signs of mental illness before the suicide. The suicide crisis was associated with relational factors. The bereaved who had harboured the thought that a suicide risk existed found that it was not enough to urge the suicidal person to seek health assistance. Improved knowledge of suicide and seeking health assistance were measures that were proposed. INTERPRETATION: The findings challenge the current prevention model. Healthcare personnel as well as the general population should be better informed that mental illness is neither a sufficient nor a necessary factor to explain suicide, even though a higher risk of suicide is associated with some mental disorders. PMID- 29411587 TI - ? PMID- 29411588 TI - ? PMID- 29411590 TI - ? PMID- 29411589 TI - ? PMID- 29411591 TI - ? PMID- 29411592 TI - ? PMID- 29411594 TI - Neglected tropical diseases - the present and the future. PMID- 29411595 TI - ? PMID- 29411596 TI - ? PMID- 29411597 TI - Developing a vaccine for leishmaniasis: how biology shapes policy. PMID- 29411598 TI - Zika Immunoassay Based on Surface-Enhanced Raman Scattering Nanoprobes. AB - Zika virus (ZIKV) was considered a public health emergency of international concern after the 2015 outbreak. Serological tests based on immunoassay platforms is one of the methods applied on the diagnosis of ZIKV and Dengue virus (DENV). However, the high limits of detection (LOD) and the cross-reactivity between ZIKV and DENV are still limitations in immunological tests. In order to tackle these issues, we have designed an immune-specific assay based on surface-enhanced Raman scattering (SERS) nanoprobes. Gold shell-isolated nanoparticles (Au-SHINs) were synthesized with 100 nm Au nanoparticles and 4 nm silica shell thickness coated with Nile Blue (Raman reporter). Then, the SERS nanoprobes were wrapped in a final silica shell and functionalized with monoclonal anti-ZIKV NS1 antibodies. Concentrations of ZIKV NS1 down to 10 ng/mL were probed free of cross-reactivity with DENV NS1 antigens. PMID- 29411599 TI - Synchrotron Radiation Microcomputed Tomography Guided Chromatographic Analysis for Displaying the Material Distribution in Tablets. AB - One unusual and challenging scientific field that has received only cursory attention to date is the three-dimensional (3D) microstructure and spatial distribution of drug(s) and formulation materials in solid dosage forms. This study aims to provide deeper insight into the relationships between the microstructure of multiple-unit pellet system (MUPS) tablets and the spatial distribution of the active pharmaceutical ingredient (API) and excipients to facilitate the design of quantitative models for drug delivery systems. Synchrotron radiation X-ray microcomputed tomography (SR-MUCT) was established as a 3D structure elucidation technique, which, in conjunction with liquid chromatography coupled to mass spectrometry (LC-MS) or liquid chromatography with evaporative light-scattering detector (LC-ELSD) enables chemical analysis of tablets. On the basis of the specific interior construction of theophylline MUPS tablets, the spatial distribution of materials was acquired by quantifying microregion samples that had been validated by SR-MUCT for their locations in the MUPS tablets. The 3D structure of the MUPS tablets was catalogued as three structural domains: a matrix layer (ML), a protective cushion layer (PCL), and pellets (PL). Compared with the components in the ML, components in the PL had a larger proportion of theophylline, sucrose, and diethyl phthalate and a smaller proportion of lactose and sodium lauryl sulfate, whereas glyceryl monostearate was found to account for a large portion of the PCL. Microstructural characterization-guided zonal chemical determination represents a new approach for quality assessment and the development of drug delivery systems with in-depth insight into their constituent layers on a new scale. PMID- 29411600 TI - Porous Particle-Reinforced Bioactive Gelatin Scaffold for Large Segmental Bone Defect Repairing. AB - Large segmental bone defect repairing remains a big challenge in clinics, and synthetic bone grafts suitable for this purpose are still highly demanded. In this article, hydrophilic composite scaffolds (bioactive hollow particle (BHP) gel scaffold) composed of bioactive hollow nanoparticles and cross-linked gelatin have been developed. The bioactive nanoparticles have a porous structure as well as high specific surface area; thus, they interact strongly with gelatin to overcome the swelling problem that a hydrophilic polymer scaffold will usually face. With this combination, these BHP-gel scaffolds showed porous structure and mechanical properties similar to those of the cancellous bone. They also showed excellent bioactivity and cell growth promotion performance in vitro. The best of them, namely, 10BHP-gel scaffold, was evaluated in vivo on a rat femur model, where it was found that the 5 mm segmental bone defect almost healed with new bone tissue formed in 12 weeks and the scaffold itself degraded at the same time. Thus, 10BHP-gel scaffold may become a potential bone graft for large segmental bone defect healing in the future. PMID- 29411601 TI - Origin of Reduced Open-Circuit Voltage in Highly Efficient Small-Molecule-Based Solar Cells upon Solvent Vapor Annealing. AB - In this study, we demonstrate that remarkably reduced open-circuit voltage in highly efficient organic solar cells (OSCs) from a blend of phenyl-C61-butyric acid methyl ester and a recently developed conjugated small molecule (DPPEZnP THD) upon solvent vapor annealing (SVA) is due to two independent sources: increased radiative recombination and increased nonradiative recombination. Through the measurements of electroluminescence due to the emission of the charge transfer state and photovoltaic external quantum efficiency measurement, we can quantify that the open-circuit voltage losses in a device with SVA due to the radiative recombination and nonradiative recombination are 0.23 and 0.31 V, respectively, which are 0.04 and 0.07 V higher than those of the as-cast device. Despite of the reduced open-circuit voltage, the device with SVA exhibited enhanced dissociation of charge-transfer excitons, leading to an improved short circuit current density and a remarkable power conversion efficiency (PCE) of 9.41%, one of the best for solution-processed OSCs based on small-molecule donor materials. Our study also clearly shows that removing the nonradiative recombination pathways and/or suppressing energetic disorder in the active layer would result in more long-lived charge carriers and enhanced open-circuit voltage, which are prerequisites for further improving the PCE. PMID- 29411602 TI - Biodegradable Drug-Loaded Hydroxyapatite Nanotherapeutic Agent for Targeted Drug Release in Tumors. AB - Tumor-targeted drug delivery systems have been increasingly used to improve the therapeutic efficiency of anticancer drugs and reduce their toxic side effects in vivo. Focused on this point, doxorubicin (DOX)-loaded hydroxyapatite (HAP) nanorods consisting of folic acid (FA) modification (DOX@HAP-FA) were developed for efficient antitumor treatment. The DOX-loaded nanorods were synthesized through in situ coprecipitation and hydrothermal method with a DOX template, demonstrating a new procedure for drug loading in HAP materials. DOX could be efficiently released from DOX@HAP-FA within 24 h in weakly acidic buffer solution (pH = 6.0) because of the degradation of HAP nanorods. With endocytosis under the mediation of folate receptors, the nanorods exhibited enhanced cellular uptake and further degraded, and consequently, the proliferation of targeted cells was inhibited. More importantly, in a tumor-bearing mouse model, DOX@HAP-FA treatment demonstrated excellent tumor growth inhibition. In addition, no apparent side effects were observed during the treatment. These results suggested that DOX@HAP FA may be a promising nanotherapeutic agent for effective cancer treatment in vivo. PMID- 29411603 TI - Palindromic Molecule Beacon-Based Cascade Amplification for Colorimetric Detection of Cancer Genes. AB - A highly sensitive and selective colorimetric assay based on a multifunctional molecular beacon with palindromic tail (PMB) was proposed for the detection of target p53 gene. The PMB probe can serve as recognition element, primer, and polymerization template and contains a nicking site and a C-rich region complementary to a DNAzyme. In the presence of target DNA, the hairpin of PMB is opened, and the released palindromic tails intermolecularly hybridize with each other, triggering the autonomous polymerization/nicking/displacement cycles. Although only one type of probe is involved, the system can execute triple and continuous polymerization strand displacement amplifications, generating large amounts of G-quadruplex fragments. These G-rich fragments can bind to hemin and form the DNAzymes that possess the catalytic activity similar to horseradish peroxidase, catalyzing the oxidation of ABTS by H2O2 and producing the colorimetric signal. Utilizing the newly proposed sensing system, target DNA can be detected down to 10 pM with a linear response range from 10 pM to 200 nM, and mutant target DNAs are able to be distinguished even by the naked eye. The desirable detection sensitivity, high specificity, and operation convenience without any separation step and chemical modification demonstrate that the palindromic molecular beacon holds the potential for detecting and monitoring a variety of nucleic acid-related biomarkers. PMID- 29411604 TI - Fe Stabilization by Intermetallic L10-FePt and Pt Catalysis Enhancement in L10 FePt/Pt Nanoparticles for Efficient Oxygen Reduction Reaction in Fuel Cells. AB - We report in this article a detailed study on how to stabilize a first-row transition metal (M) in an intermetallic L10-MPt alloy nanoparticle (NP) structure and how to surround the L10-MPt with an atomic layer of Pt to enhance the electrocatalysis of Pt for oxygen reduction reaction (ORR) in fuel cell operation conditions. Using 8 nm FePt NPs as an example, we demonstrate that Fe can be stabilized more efficiently in a core/shell structured L10-FePt/Pt with a 5 A Pt shell. The presence of Fe in the alloy core induces the desired compression of the thin Pt shell, especially the two atomic layers of Pt shell, further improving the ORR catalysis. This leads to much enhanced Pt catalysis for ORR in 0.1 M HClO4 solution (at both room temperature and 60 degrees C) and in the membrane electrode assembly (MEA) at 80 degrees C. The L10-FePt/Pt catalyst has a mass activity of 0.7 A/mgPt from the half-cell ORR test and shows no obvious mass activity loss after 30 000 potential cycles between 0.6 and 0.95 V at 80 degrees C in the MEA, meeting the DOE 2020 target (<40% loss in mass activity). We are extending the concept and preparing other L10-MPt/Pt NPs, such as L10-CoPt/Pt NPs, with reduced NP size as a highly efficient ORR catalyst for automotive fuel cell applications. PMID- 29411605 TI - Investigation of Agonist Recognition and Channel Properties in a Flatworm Glutamate-Gated Chloride Channel. AB - Glutamate-gated chloride channels (GluCls) are neurotransmitter receptors that mediate crucial inhibitory signaling in invertebrate neuromuscular systems. Their role in invertebrate physiology and their absence from vertebrates make GluCls a prime target for antiparasitic drugs. GluCls from flatworm parasites are substantially different from and are much less understood than those from roundworm and insect parasites, hindering the development of potential therapeutics targeting GluCls in flatworm-related diseases such as schistosomiasis. Here, we sought to dissect the molecular and chemical basis for ligand recognition in the extracellular glutamate binding site of SmGluCl-2 from Schistosoma mansoni, using site-directed mutagenesis, noncanonical amino acid incorporation, and electrophysiological recordings. Our results indicate that aromatic residues in ligand binding loops A, B, and C are important for SmGluCl-2 function. Loop C, which differs in length compared to other pentameric ligand gated ion channels (pLGICs), contributes to ligand recognition through both an aromatic residue and two vicinal threonine residues. We also show that, in contrast to other pLGICs, the hydrophobic channel gate in SmGluCl-2 extends from the 9' position to the 6' position in the channel-forming M2 helix. The 6' and 9' positions also seem to control sensitivity to the pore blocker picrotoxin. PMID- 29411606 TI - Detection and Sourcing of Gluten in Grain with Multiple Floating-Gate Transistor Biosensors. AB - We report a chemically tunable electronic sensor for quantitation of gluten based on a floating-gate transistor (FGT) architecture. The FGTs are fabricated in parallel and each one is functionalized with a different chemical moiety designed to preferentially bind a specific grain source of gluten. The resulting set of FGT sensors can detect both wheat and barley gluten below the gluten-free limit of 20 ppm (w/w) while providing a source-dependent signature for improved accuracy. This label-free transduction method does not require any secondary binding events, resulting in a ca. 45 min reduction in analysis time relative to state-of-the-art ELISA kits with a simple and easily implemented workflow. PMID- 29411607 TI - Dynamic Photoelectrochemical Device Using an Electrolyte-Permeable NiO x/SiO2/Si Photocathode with an Open-Circuit Potential of 0.75 V. AB - As a thermodynamic driving force obtained from sunlight, the open-circuit potential (OCP) in photoelectrochemical cells is typically limited by the photovoltage ( Vph). In this work, we establish that the OCP can exceed the value of Vph when an electrolyte-permeable NiO x thin film is employed as an electrocatalyst in a Si photocathode. The built-in potential developed at the NiO x/Si junction is adjusted in situ according to the progress of the NiO x hydration for the hydrogen evolution reaction (HER). As a result of decoupling of the OCP from Vph, a high OCP value of 0.75 V (vs reversible hydrogen electrode) is obtained after 1 h operation of HER in an alkaline electrolyte (pH = 14), thus outperforming the highest value (0.64 V) reported to date with conventional Si photoelectrodes. This finding might offer insight into novel photocathode designs such as those based on tandem water-splitting systems. PMID- 29411608 TI - Visible-Light-Induced Radical Cascade Cyclization: Synthesis of the ABCD Ring Cores of Camptothecins. AB - A new strategy for constructing indolizino[1,2-b]quinolin-9(11H)-ones (ring cores of camptothecins) from readily available isocyanoarenes and N-(alkyl-2-yn-1 yl)pyridin-2(1H)-ones has been developed through a visible-light-induced radical cascade cyclization process. The reaction proceeds under mild conditions with fair to excellent yields. The easy introduction of substituents for both reactants and the broad functional group tolerance of the reaction make it a straightforward route to the cores of the marketed camptothecins and their derivatives. PMID- 29411609 TI - Diffusion of Benzene and Alkylbenzenes in Nonpolar Solvents. AB - The translational diffusion constants, D, of benzene and a series of alkylbenzenes have been determined in n-pentadecane, 2,6,10,14 tetramethylpentadecane (pristane), 2,2,4,4,6,8,8-heptamethylnonane (isocetane), and 2,6,10,15,19,23-hexamethyltetracosane (squalane) using capillary flow techniques. The solutes' D values are compared with the predictions of a cylinder diffusion model as are those for (a) benzene and alkylbenzenes in n-nonane, n decane, n-dodecane, and supercritical CO2 and (b) n-alkanes and 1-alkenes in n hexane, n-heptane, n-octane, benzene, and toluene. The D values for benzene and the alkylbenzenes also are compared with the predictions of lollipop diffusion for which the phenyl ring is the candy and the alkyl chain is the handle. Both models give an average difference of less than 4% between experimental and calculated diffusion constants in solvents whose viscosities vary by a factor of more than 600 when benzene and toluene (as solutes) are omitted; the comparisons include 150 and 85 D values for the cylinder and lollipop models, respectively. The differences increase when benzene and toluene are included and are most likely because of their shapes and the shapes assumed by the models. The agreement with the models indicates that the chains of the alkylbenzenes and 1 alkenes, like those of the n-alkanes, are relatively extended. The D values for several of the solutes also are fitted to a modification of the Stokes-Einstein relation that varies their dependence on viscosity instead of chain dimensions. PMID- 29411610 TI - Quaternary Pavonites A1+xSn2-xBi5+xS10 (A+ = Li+, Na+): Site Occupancy Disorder Defines Electronic Structure. AB - The field of mineralogy represents an area of untapped potential for the synthetic chemist, as there are numerous structure types that can be utilized to form analogues of mineral structures with useful optoelectronic properties. In this work, we describe the synthesis and characterization of two novel quaternary sulfides A1+xSn2-xBi5+xS10 (A = Li+, Na+). Though not natural minerals themselves, both compounds adopt the pavonite structure, which crystallizes in the C2/m space group and consists of two connected, alternating defect rock-salt slabs of varying thicknesses to create a three-dimensional lattice. Despite their commonalities in structure, their crystallography is noticeably different, as both structures have a heavy degree of site occupancy disorder that affects the actual positions of the atoms. The differences in site occupancy alter their electronic structures, with band gap values of 0.31(2) eV and 0.07(2) eV for the lithium and sodium analogues, respectively. LiSn2Bi5S10 exhibits ultralow thermal conductivity of 0.62 W m-1 K-1 at 723 K, and this result is corroborated by phonon dispersion calculations. This structure type is a promising host candidate for future thermoelectric materials investigation, as these materials have narrow band gaps and intrinsically low thermal conductivities. PMID- 29411611 TI - Triethanolamine-Modified Gold Nanoparticles Synthesized by a One-Pot Method and Their Application in Electrochemiluminescent Immunoassy. AB - In many electrochemiluminescent (ECL) systems, coreactants play crucial roles in the redox-induced light emission process at the electrode surface. In this work, a novel and environment-friendly nanoplatform for ECL immunosensing enabled by triethanolamine (TEOA)-modified gold nanoparticles (TEOA@AuNPs) is reported. The monodisperse TEOA@AuNPs are fabricated by one-pot synthesis using TEOA as both reducing and stabilizing agent. Then the TEOA@AuNPs-modified electrode not only acted as coreactant for Ru(bpy)32+ ECL system but also provided a carrier for antibody 1 to form label-free immunosensor through an interaction between antigen and antibody. The unique structure of the TEOA@AuNPs loaded a large amount of coreactant of Ru(bpy)32+, which shortened the electron-transfer distance from the AuNPs surface to the appended TEOA molecules, thereby greatly enhancing the ECL efficiency and amplifying the ECL signal. In addition, Ru(bpy)32+-doped silica (RuSiO2) nanoparticles and antibody 2 were combined to form a composite for labels and a sandwich-type ECL immunosensor has been constructed. The possible mechanism of those ECL systems have also been proposed and confirmed by the EC-MS hyphenated technique. The human cardiopathy biomarker, cardiac troponin I (cTnI), was detected in a wide linear concentration range and the limit of detection (LOD) was 34 or 5.5 fg mL-1 by using the proposed label-free or labeling ECL immunoassay method. PMID- 29411612 TI - Aviation-Related Impacts on Ultrafine Particle Number Concentrations Outside and Inside Residences near an Airport. AB - Jet engine exhaust is a significant source of ultrafine particles and aviation related emissions can adversely impact air quality over large areas surrounding airports. We investigated outdoor and indoor ultrafine particle number concentrations (PNC) from 16 residences located in two study areas in the greater Boston metropolitan area (MA, USA) for evidence of aviation-related impacts. During winds from the direction of Logan International Airport, that is, impact sector winds, an increase in outdoor and indoor PNC was clearly evident at all seven residences in the Chelsea study area (~4-5 km from the airport) and three out of nine residences in the Boston study area (~5-6 km from the airport); the median increase during impact-sector winds compared to other winds was 1.7-fold for both outdoor and indoor PNC. Across all residences during impact-sector and other winds, median outdoor PNC were 19 000 and 10 000 particles/cm3, respectively, and median indoor PNC were 7000 and 4000 particles/cm3, respectively. Overall, our results indicate that aviation-related outdoor PNC infiltrate indoors and result in significantly higher indoor PNC. Our study provides compelling evidence for the impact of aviation-related emissions on residential exposures. Further investigation is warranted because these impacts are not expected to be unique to Logan airport. PMID- 29411613 TI - Rapid Affinity Enrichment of Human Apolipoprotein A-I Associated Lipoproteins for Proteome Analysis. AB - Isolation of high density lipoproteins (HDL) for structural and functional studies typically relies on ultracentrifugation techniques, which are time consuming and difficult to scale. With emerging interest in the clinical relevance of HDL structure and function to cardiovascular disease, a significant gap exists between current and desirable sample preparation throughput. To enable proteomic studies of HDL with large clinical cohorts, we have developed an affinity enrichment approach that relies on the association of histidine-tagged, lipid free ApoA-I with HDL followed by standard metal chelate chromatography. Characterization of the resulting affinity-enriched ApoA-I associated lipoprotein (AALP) pool using biochemical, electrophoretic, and proteomic analysis demonstrates that the isolated material is closely related in structural features, lipid content, protein complement, and relative protein distribution to HDL isolated by ultracentrifugation using sequential density adjustment. The simplicity of the method provides avenues for high-throughput analysis of HDL associated proteins. PMID- 29411615 TI - Protein Nanosheet Mechanics Controls Cell Adhesion and Expansion on Low-Viscosity Liquids. AB - Adherent cell culture typically requires cell spreading at the surface of solid substrates to sustain the formation of stable focal adhesions and assembly of a contractile cytoskeleton. However, a few reports have demonstrated that cell culture is possible on liquid substrates such as silicone and fluorinated oils, even displaying very low viscosities (0.77 cSt). Such behavior is surprising as low viscosity liquids are thought to relax much too fast (=40 dB, interval between onset and treatment <=30 days). They received systemic prednisolone (100 mg followed by tapered doses) combined with intratympanic injection of dexamethasone (4 mg/ml). Intratympanic injection was performed 4 times (days 1, 2, 4, and 7) in 92 patients (92 ears) or 2 times (days 1 and 2) in 99 patients (100 ears). The hearing outcomes were evaluated at 1 week from the start of treatment and 1 to 2 months after the completion of treatment. RESULTS: There was no significant difference in hearing outcomes between the 4- and 2-injection groups at either time point. Multiple regression analysis also showed that the hearing level after treatment did not depend on the total number of intratympanic steroid injections. CONCLUSION: These results indicate that a protocol using only 2 intratympanic steroid injections exerts a sufficient effect on the hearing outcomes of ISSNHL. This simplified treatment protocol would be greatly beneficial to relieve the physical and mental stress of patients. PMID- 29411624 TI - Healthy living for healthcare workers: It is time to set an example. PMID- 29411625 TI - Mortality among people living with HIV/AIDS with non-small-cell lung cancer in the modern HAART Era. AB - People living with HIV (PLWHA) with adequate access to modern combination antiretroviral therapy (cART) are living longer and experiencing reduced AIDS related morbidity and mortality. However, increases in non-AIDS related conditions, such as certain cancers, have accompanied these therapeutic advances over time. As such, our study objective was to determine the impact of HIV on all cause and lung cancer-specific mortality amongst PLWHA with diagnoses of non small-cell lung cancer (NSCLC) and HIV-negative individuals with NSCLC. This analysis was inclusive of PLWHA on and off cART over the age of 19 years and a 10% comparison sample from the BC population >=19 years, over a 13-year period (2000-2013). Kaplan-Meier estimates, Cox PH models, and competing risk analysis for all-cause and cause-specific mortality (respectively) compared PLWHA to HIV negative individuals, controlling for age, gender, cancer stage, co-morbidities; and nadir CD4 count, viral load, and injection drug use for a HIV-positive specific analysis. We identified 71 PLWHA and 2463 HIV-negative individuals diagnosed with NSCLC between 2000 and 2013. PLWHA with NSCLC were diagnosed at a significantly younger age than HIV-negative individuals (median age 57 vs 71 years, p < 0.01). We found no significant difference in lung cancer-specific mortality. However, in multivariate analysis, HIV was associated with greater all cause mortality (adjusted hazard ratio [aHR]:1.44; 95% confidence interval [CI]: 1.08-1.90), with median survival of 4 months for PLWHA, and 10 months for HIV negative. Higher nadir CD4 count was protective against mortality (aHR: 0.33, 95% CI: 0.17-0.64) amongst PLWHA in multivariate analysis. Our analysis suggests that PLWHA in the modern cART era experience similar lung cancer survival outcomes compared to the general BC population with NSCLC. However, we also observed significantly higher all-cause mortality among PLWHA with NSCLC, which may warrant further inquiry into the role of HIV in exacerbating mortality among PLWHA with comorbidities and cancer. PMID- 29411626 TI - Sex differences in adherence to guidelines in aspirin prescription in a population of low-risk cardiovascular patients. PMID- 29411627 TI - Transgenic proteins rich in valine or glycine are concerns for heart disease patients. PMID- 29411628 TI - Neuropsychological performance in patients with asymptomatic HIV-1 infection. AB - Human immunodeficiency virus (HIV-1) infection and acquired immunodeficiency syndrome (AIDS) lead to neurocognitive disorders; however, there is still much knowledge to be gained regarding HIV-associated neurocognitive disorders. The purpose of this study was to assess the cognitive performance, instrumental activities of daily living, depression, and anxiety in patients with asymptomatic HIV-1 infections compared with seronegative participants without neurocognitive impairment. We studied a sample consisted of 60 patients with asymptomatic HIV-1 infections and 60 seronegative participants without neurocognitive impairment from the city of Barranquilla, Colombia, with a mean age of 36.07 years. A protocol of neuropsychological and psychopathological tests was applied to the participants. The group of patients with asymptomatic HIV infections significantly underperformed on tasks that assessed global cognitive screening, attention span, learning, phonemic verbal fluency, auditory-verbal comprehension, information processing speed, cognitive flexibility, and motor skills compared to the group of seronegative participants. No significant differences were found in memory, visual confrontation naming, vocabulary, inhibition, and instrumental activities of daily living. Additionally, the patients with asymptomatic HIV-1 infection had a higher anxiety index than the seronegative participants, but no significant difference was found in depression. A correlation was found between depression and anxiety. In conclusion, the patients with asymptomatic HIV-1 infection had lower cognitive performances than the seronegative participants in the cognitive functions mentioned above and more anxiety but still performed the instrumental activities of daily living. PMID- 29411629 TI - Clinical Texting Among Medical Trainees of the University of British Columbia [Formula: see text]. AB - We believe cellphone text messages are commonly used in medical practice whether in rural or urban settings and that clinical photos are often attached to them. Our interest is the use of this technology to provide dermatology service to rural and remote British Columbia. Concern has been expressed about the security of confidential information and adequacy of privacy protection in such an application. We have found little published information about the extent of texting in rural and remote settings (and none in our jurisdiction) or the number and nature of privacy breaches that have actually occurred as a result. To obtain such information, we first set out to survey medical practitioners about their actual use. The results reported here are from medical trainees enrolled with the University of British Columbia who are in both rural and urban settings. PMID- 29411630 TI - Serial measures of microparticles during intense physical activity in untrained subjects with different endothelial abnormalities: new useful biomarkers for individual evaluation? PMID- 29411631 TI - The ambiguity of physical activity, exercise and atrial fibrillation. AB - Although commonly associated with cardiovascular disease or other medical conditions, atrial fibrillation may also occur in individuals without any known underlying conditions. This manifestation of atrial fibrillation has been linked to extensive and long-term exercise, as prolonged endurance exercise has shown to increase prevalence and risk of atrial fibrillation. In contrast, more modest physical activity is associated with a decreased risk of atrial fibrillation, and current research indicates a J-shaped association between atrial fibrillation and the broad range of physical activity and exercise. This has led to the hypothesis that the mechanisms underlying an increased risk of atrial fibrillation with intensive exercise are different from those underlying a reduced risk with moderate physical activity, possibly linked to distinctive characteristics of the population under study. High volumes of exercise over many years performed by lean, healthy endurance trained athletes may lead to cardiac (patho)physiological alterations involving the autonomic nervous system and remodelling of the heart. The mechanisms underlying a reduced risk of atrial fibrillation with light and moderate physical activity may involve a distinctive pathway, as physical activity can potentially reduce the risk of atrial fibrillation through favourable effects on cardiovascular risk factors. PMID- 29411632 TI - Video-assisted thoracoscopic thymectomy for thymoma: a single-center experience. AB - Background Thymoma is a primary tumor derived from the epithelial cells of the thymus, which is commonly seen in the mediastinum. Surgical thymectomy is the radical treatment for thymoma. The recent introduction of video-assisted thoracoscopic surgery has improved the quality of thymectomy surgery. The clinical characteristics of thymoma and the outcomes of video-assisted thoracoscopic thymectomy in Vietnamese patients are still lacking. The objectives of this study were to investigate the clinical and laboratory characteristics of thymoma and to evaluate the early results of video-assisted thoracoscopic thymectomy for thymoma in Vietnamese patients. Methods All 53 thymoma patients with or without myasthenia gravis who underwent video-assisted thoracoscopic thymectomy in Military Hospital 103, Vietnam, from October 2013 to July 2017 were included. Results The mean age was 46.5 7.1 years, and the female/male ratio was 1.2:1. Myasthenia gravis, mostly stage IIA, was present in 84.9% of patients. There was no hospital mortality or major postoperative complication. The mean operative time was 65 min, intensive care unit stay was 22 +/- 5 h, and postoperative hospital stay was 7.5 +/- 1.7 days. Conclusion Thoracoscopic thymectomy for thymoma in Vietnamese patients achieved improved cosmesis and was safe for both non-myasthenia gravis and myasthenia gravis patients. PMID- 29411633 TI - Harlequin syndrome following upper lobectomy. AB - A 58-year-old women developed unilateral facial flushing and sweating on the left side of her face immediately after a right thoracotomy upper lobectomy and paravertebral block. She was diagnosed with Harlequin syndrome in the absence of any other neurological signs or symptoms. She had recovered completely from this episode on follow-up. PMID- 29411634 TI - Undifferentiated thymic carcinoma with intracranial metastasis in a two-year-old. AB - Thymic carcinoma with central nervous system involvement is very rare in children. A 27-month-old girl presented with a unilateral squint, vomiting, and behavioral changes. Imaging studies showed a silent anterior mediastinal mass and a large metastatic mass at the base of the skull. Biopsy of the anterior mediastinal mass confirmed an undifferentiated tumor consistent with thymic carcinoma. The child died within 3 months of the onset of symptoms, due to progression of the disease. These lethal tumors of unknown histogeneses and etiology are aggressive in nature, resistant to therapy, and have a rapidly fatal course. PMID- 29411635 TI - Surgery for tricuspid regurgitation in a case of anomalous systemic venous return. AB - A 75-year-old woman presented with severe tricuspid regurgitation requiring surgical repair. She had extremely rare anomalies in systemic venous return in spite of situs solitus: persistent left superior vena cava with absent right superior vena cava, infrahepatic inferior vena cava interruption, and hemiazygos continuation to a persistent left superior vena cava. These unusual systemic venous anomalies had significantly enlarged the coronary sinus, and the stretched coronary sinus orifice changed the geometry of the tricuspid annulus and triggered tricuspid regurgitation. There were technical difficulties in establishing cardiopulmonary bypass and achieving successful tricuspid valve repair. PMID- 29411636 TI - Cut-down outperforms complete percutaneous transcatheter valve implantation. AB - Background The ideal approach for transfemoral transcatheter aortic valve implantation is still widely debated. The objective of this study was to compare access and bleeding complications of complete percutaneous versus the surgical cut-down approach for transfemoral transcatheter aortic valve implantation. Methods The study included 667 consecutive patients from November 2008 to December 2016, 466 in the percutaneous group and 201 in the cut-down group. There were no significant differences in baseline characteristics between the 2 groups. Primary study endpoints were vascular access site and bleeding complications according to the Valve Academic Research Consortium II criteria. Results Mean procedure time was shorter in the cut-down group: 93.5 +/- 22.0 (percutaneous) vs. 69 +/- 19 min (cut-down), p < 0.001. The rate of access complications was higher in the percutaneous group: 20.4% (95/466) vs. 8.5% (17/201), p = 0.037; with predominantly minor complications in the percutaneous cohort: 14.4% (67/466) vs. 2.5% (5/201), p = 0.04. Bleeding complications were more frequent in the percutaneous group: 21.9% (102/466) vs. 4.5% (9/201), p = 0.01. Hospital mortality was 5.2% in the percutaneous group and 1.9% in the cut-down group ( p = 0.075). Conclusions Surgical cut-down provided controlled access and resulted in fewer access site and bleeding complications. Nonetheless, major access complications were not significantly different between the two cohorts. The two approaches must be seen as complementary techniques. A portfolio containing both techniques is the only way to provide a tailor-made and patient-orientated approach ensuring the safest access based on the individual vessel condition. PMID- 29411637 TI - Ictal headache: Insights from two cases. AB - BACKGROUND: We report the first literature description of ictal epileptic headaches closely mimicking glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. CASE 1: A 37-year-old man complained of short-lasting, electric-shock like headache, confined to the pharynx. During the episodes, he could not speak because he felt "words blocked at the throat". An EEG recorded epileptic discharges concomitant with headache; a brain MRI disclosed frontal polymicrogyria. CASE 2: A 66-year-old man complained of short-lasting, right periocular headache, associated with ipsilateral ptosis, conjunctival injection and lacrimation. Some episodes were followed by tonic contraction of the right facial and limb muscles; on one occasion, headache was followed by a generalized seizure. A brain MRI revealed hippocampal abnormalities. DISCUSSION: These cases highlight the complex relationship between headache and epilepsy, and suggest a possible contribution of cortical structures to the genesis of paroxysmal headaches such as glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. PMID- 29411638 TI - The role of the brainstem in migraine: Potential brainstem effects of CGRP and CGRP receptor activation in animal models. AB - Background Migraine is a severe debilitating disorder of the brain that is ranked as the sixth most disabling disorder globally, with respect to disability adjusted life years, and there remains a significant unmet demand for an improved understanding of its underlying mechanisms. In conjunction with perturbed sensory processing, migraine sufferers often present with diverse neurological manifestations (premonitory symptoms) that highlight potential brainstem involvement. Thus, as the field moves away from the view of migraine as a consequence of purely vasodilation to a greater understanding of migraine as a complex brain disorder, it is critical to consider the underlying physiology and pharmacology of key neural networks likely involved. Discussion The current review will therefore focus on the available evidence for the brainstem as a key regulator of migraine biology and associated symptoms. We will further discuss the potential role of CGRP in the brainstem and its modulation for migraine therapy, given the emergence of targeted CGRP small molecule and monoclonal antibody therapies. Conclusion The brainstem forms a functional unit with several hypothalamic nuclei that are capable of modulating diverse functions including migraine-relevant trigeminal pain processing, appetite and arousal regulatory networks. As such, the brainstem has emerged as a key regulator of migraine and is appropriately considered as a potential therapeutic target. While currently available CGRP targeted therapies have limited blood brain barrier penetrability, the expression of CGRP and its receptors in several key brainstem nuclei and the demonstration of brainstem effects of CGRP modulation highlight the significant potential for the development of CNS penetrant molecules. PMID- 29411639 TI - Prospective memory is dysfunctional in migraine without aura. AB - Introduction Prospective memory is the ability to carry out a delayed intended action, so to maintain and retrieve future plans, goals and activities. Deficits of prospective memory negatively impact on patients and caregivers' everyday living and determine poor adherence to treatment. Since frontal regions are involved in both event- and time-based prospective memory tasks and are impaired in migraine without aura, defects of prospective memory might occur in migraine without aura patients; until now this issue has not been investigated. The aim of the current study was to explore time- versus event-based prospective memory in migraine without aura. Patients and methods Ninty-one consecutive migraine without aura patients and 84 healthy subjects were enrolled in the study. They underwent a standardized measure of prospective memory evaluating both time-based and event-based prospective memory, and the Montreal Cognitive Assessment assessing global cognitive status. Moreover, all participants completed the Beck Depression Inventory-II and a self-administered version of the Apathy Evaluation Scale, to assess severity of depressive symptoms and apathy, respectively. Results Migraine without aura and healthy subjects did not differ on demographic aspects (i.e. age, education and gender). However, individuals with migraine without aura demonstrated impaired prospective memory performance compared to healthy subjects, with a greater impairment demonstrated for the time-based tasks. Within the migraine without aura group, no significant association was found between prospective memory performance and clinical scores, apathy, and depression. Conclusions Individuals with migraine without aura experience particular difficulty executing a future intention; therefore, migraine without aura is associated with dysfunction of prospective memory. PMID- 29411640 TI - Screening for possible oligogenic pathogenesis in Chinese sporadic ALS patients. AB - We investigated all coding regions of 17 known amyotrophic lateral sclerosis (ALS)-related genes in 311 sporadic ALS patients who were of Chinese ancestry using next-generation sequencing technology. All nonsynonymous variants identified were confirmed by Sanger sequencing. 29 (9.32%) patients harbored at least one pathogenic or likely pathogenic variants. Nine (2.8%) patients harbored two or three variants which frequency <1% in population databases that may be related to oligogenic pathogenesis. A higher allele frequency was observed in East Asian than in European patients for the majority variants identified in this screening, which may indicate that genetic factors are responsible for the different clinical characteristics between Chinese and European ALS patients. Our study reports the results of extensive genetic screening and is the first to investigate the possible oligogenic pathogenesis in Chinese sporadic ALS patients. These findings are useful for exploring ALS pathogenesis and treatment strategies. PMID- 29411641 TI - Smart Pens Will Improve Insulin Therapy. PMID- 29411642 TI - Effects of dietary inclusion of macauba seed cake meal on performance, caecotrophy traits and in vitro evaluations for growing rabbits. AB - The objective was to evaluate the inclusion of macauba seed cake (MSC) meal in diets for growing rabbits by assessing their growth and slaughtering performance, haematological traits, nutritional contribution of caecotrophs, in vitro digestibility, degradability and fermentation parameters. A total of 88 rabbits were distributed to four groups with 22 animals each and fed diets containing 0, 50, 100 and 150 g/kg of MSC, respectively. The in vitro assays were conducted employing cecum inoculum on the same dietary treatments. The inclusion of MSC yielded a quadratic effect on in vitro dry matter digestibility (p < 0.001). The maximum amount of produced gas was raised linearly with the inclusion of MSC (p = 0.016). MSC linearly reduced several variables as the nutritional contribution of caecotrophs in dry matter (p = 0.017) and crude protein (p = 0.014), live weight at 51 d (p = 0.024), body weight gain (p = 0.039), average daily feed intake (ADFI) (p = 0.001) and feed conversion ratio (FCR) (p = 0.007) in the first period evaluated (30-50 d); furthermore the ADFI and FCR the second (51-72 d) and whole period (30-72 d) (p < 0.001). MSC addition caused a quadratic effect on white blood cells count (p = 0.026) and a linear decrease of eosinophils (p = 0.045). In conclusion, the inclusion of up to 150 g/kg of MSC improves the in vitro digestibility and fermentation potential of the diets, reflecting on the ADFI and FCR of the animals, although adverse effects are observed on the weight of the commercial carcass and nutritive contribution of the caecotrophs. PMID- 29411643 TI - MDN-0171, a new medermycin analogue from Streptomyces albolongus CA-186053. AB - A new medermycin derivative, MDN-0171 (1), and two known structurally related compounds, medermycin (2) and antibiotic G15-F (3) were isolated from the acetone extract of culture broths of the marine-derived Streptomyces albolongus strain CA 186053. Their structures were determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). Compounds 2 and 3 accounted for the antimicrobial activity (against methicillin-resistant Staphylococcus aureus and Escherichia coli) previously detected in the crude extract of this actinomycete. PMID- 29411644 TI - Genitourinary syndrome of menopause. Prevalence and quality of life in Spanish postmenopausal women. The GENISSE study. AB - OBJECTIVE: To determine the prevalence of genitourinary syndrome of menopause (GSM) and urogynecological conditions associated with menopause, and to evaluate the impact of GSM on quality of life in a cohort of Spanish postmenopausal women. METHODS: Multicenter, cross-sectional, and observational study involving 430 women. RESULTS: The prevalence of GSM was 70%. GSM was diagnosed in 60.2% of women with no known diagnosis of vulvovaginal atrophy or GSM. Most prevalent symptoms were vaginal dryness (93.3%) and reduced lubrication with sexual activity (90.0%). Most prevalent signs were decreased moisture (93.7%) and loss of vaginal rugae (78.4%). GSM was significantly associated with stress or mixed urinary incontinence, overactive bladder, and vaginal prolapse. Symptoms showed a low-moderate impact on quality of life, mainly in sexual functioning and self concept and body image. CONCLUSIONS: The GSM is very prevalent in Spanish postmenopausal women, affecting up to 70% of those consulting the gynecologist. Despite the high prevalence of symptoms and signs and its impact on the women's well-being, GSM remains underdiagnosed and undertreated. Given its relationship with urogynecological conditions, it seems necessary to provide an adequate evaluation of postmenopausal women for identifying potential co-morbidities and providing most adequate treatments. An adequate management of GSM will contribute to an improvement in the quality of life of these women. PMID- 29411645 TI - Application of the MALDI Biotyper to clinical microbiology: progress and potential. AB - INTRODUCTION: The introduction of the MALDI Biotyper in laboratories substantially changed microbiology practice, this has been called a revolution. The system accelerated diagnostic while costs were reduced and accuracy was increased. In just a few years MALDI-TOF MS became the first-line identification tool for microorganisms. Ten years after its introduction, more than 2000 MALDI Biotyper systems are installed in laboratories which are performing routine diagnostic, and the number is still increasing. Areas covered: This article summarises changes in clinical microbiology introduced by the MALDI Biotyper and its effects, as it has been published in peer reviewed articles found in PubMed. Further, the potential of novel developments to increase the value of the system is described. Expert commentary: The MALDI Biotyper has significantly improved clinical microbiology in the area of microorganism identification. Now new developments and applications, e.g. for typing and resistance testing, might further increase its value in clinical microbiology. The systems might get the central diagnostic analyser which is getting integrated into the widely automated microbiology laboratories of the future. PMID- 29411646 TI - Why does a high-fat diet increase cancer risk? PMID- 29411647 TI - Cytotoxic constituents from Vicia monantha subsp. monantha seeds. AB - Chemical investigation of Vicia monantha subsp. monantha Retz. revealed isolation of one new hydroxy- fatty acid (6) identified as (6-Z, 10-E)-9-hydroxy henicosa 6,10-dienoic acid in addition to six known metabolites; hexadecanoic acid (1), beta-sitosterol (2), beta-amyrin (3), beta-sitosterol-glucoside (4), 2,3 dihydroxypropyl tetradecanoate (5) and (Z)-9-hydroxypentadec-6-enoic acid (7). The cytotoxic effect of the isolated compounds was assessed by MTT assay using lung cancer A-549, prostate cancer PC3, breast cancer MCF-7, colon cancer HCT-116 and liver cancer HepG2 cell lines. Only compounds 1, 2, and 4 showed cytotoxic effect on HCT-116 cells where compound 2 was the most active with IC50 value of 22.61 MUg/mL. In addition, compounds 1, 2, 3, and 4 showed promising cytotoxic effect on MCF-7 cells with IC50 values of 21.03, 15.42, 10.089, and 11.34 MUg/mL, respectively. PMID- 29411648 TI - Expanding the boundary of biocatalysis: design and optimization of in vitro tandem catalytic reactions for biochemical production. AB - Biocatalysts have been increasingly used in the synthesis of fine chemicals and medicinal compounds due to significant advances in enzyme discovery and engineering. To mimic the synergistic effects of cascade reactions catalyzed by multiple enzymes in nature, researchers have been developing artificial tandem enzymatic reactions in vivo by harnessing synthetic biology and metabolic engineering tools. There is also growing interest in the development of one-pot tandem enzymatic or chemo-enzymatic processes in vitro due to their neat and concise catalytic systems and product purification procedures. In this review, we will briefly summarize the strategies of designing and optimizing in vitro tandem catalytic reactions, highlight a few representative examples, and discuss the future trend in this field. PMID- 29411649 TI - Alteration in microRNA-155 level correspond to severity of coronary heart disease. AB - Cardiovascular diseases are a consequence of genetic and epigenetic interactions. Inflammation contributes toward the initiation and progression of atherosclerotic lesions. Previous studies have shown that microRNA (miR) 155 plays a role in cardiovascular disease, including the prevention of inflammatory infiltration, regulation of autophagy, and participation of immunoreactions. However, the change of miR-155 level in the development of atherosclerosis remains to be determined. The initial objective of this study was that CHD patients would have altered serum miR-155 level. We also aim to identify whether circulating miR-155 content could be used as a predictor for severity of coronary atherosclerosis. Sample was collected from 300 CHD patients and 100 controls. Quantitative real time PCR analysis was utilized on RNA isolated from plasma. Expression of miR-155 was identified on the basis of the quartiles of the Gensini score, and association between the microRNA and CHD was analyzed. CHD patients had higher miR-155 level in comparison to controls (p < .001), and the miRNA content significantly increased following an increasing Gensini score (p < .001). Gensini score was significantly associated with miR-155 expression (r = 0.6124, p < .001). Our findings suggest that interaction between circulating miR-155 expressions with classical risk factors of atherosclerotic lesions, and serum miR 155 content may serve as a novel biomarker for evaluating severity of CHD. PMID- 29411650 TI - Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery. AB - The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 23 full factorial design was performed using Design Expert(r) software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 +/- 0.40%) and a very small micellar size (33.23 +/- 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ. PMID- 29411651 TI - High-fat diet and colorectal cancer: myths and facts. PMID- 29411652 TI - The safety of pharmacologic treatment for pediatric obesity. AB - INTRODUCTION: Pediatric obesity is a serious public health concern. Five medications have been approved by the Food and Drug Administration (FDA) for chronic weight management in adults with obesity, when used as an adjunct to lifestyle modification. Orlistat is the only FDA-approved medication for pediatric patients aged 12 years and above. Areas covered: This paper summarizes safety and efficacy data from clinical trials of weight loss medications conducted among pediatric samples. Relevant studies were identified through searches in PubMed. Expert opinion: Orlistat, as an adjunct to lifestyle modification, results in modest weight losses and may be beneficial for some pediatric patients with obesity. However, gastrointestinal side effects are common and may limit use. In adults taking orlistat, rare but severe adverse events, including liver and renal events, have been reported. Recent pediatric pharmacokinetic studies of liraglutide have demonstrated similar safety and tolerability profiles as found in adults, with gastrointestinal disorders being the most common adverse events. Clinical trials are needed of liraglutide, as well as other medications for obesity, that systematically evaluate their risks and benefits in pediatric patients. PMID- 29411653 TI - Cardiac regeneration in a newborn: what does this mean for future cardiac repair research? PMID- 29411654 TI - Eribulin therapy for the treatment of patients with advanced soft tissue sarcoma. AB - Eribulin is a structurally simplified, synthetic macrocyclic ketone analog of halichondrin B, which is a natural, polyether macrolide derived from marine sponges. Eribulin exerts its cytotoxicity by its unique microtubule dynamics inhibitory action. Eribulin was approved in 2010 by the US FDA as a third-line therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. In 2016, it was approved for treatment of metastatic liposarcoma for patients who have progressed with anthracycline treatment. In this article, we review the pharmacokinetics, mechanism of action of eribulin with focus on preclinical and clinical data in sarcoma and also the role of miRNAs in soft tissue sarcomas. PMID- 29411655 TI - Investigational drug therapies for coeliac disease - where to from here? AB - INTRODUCTION: Despite decades of research and a detailed knowledge of the immunopathological basis of coeliac disease (CD), adherence to a lifelong gluten free diet (GFD) remains the single proven and available treatment. The increasing prevalence of CD combined with variable adherence to the GFD in a significant proportion of patients demands new therapeutic strategies. Areas covered: Trial registries, clinicaltrials.gov, pharmaceutical company website searches as well as published data from PubMed and conference proceedings were used to extract the most recent outcomes for CD therapeutics. This article aims to review the available therapies from a pathophysiological approach, and propose future directions in this interesting yet largely unfulfilled area of research. Expert opinion: Increasingly, the GFD is being challenged by its availability, palatability, practicality and now even efficacy in some populations. Whilst the causative antigens have been well described, it is clear that treatment based on the removal of these immunostimulatory peptides from the diet is far more complex than early experience in CD treatment implied. Despite burgeoning interest and research in experimental therapies for CD over the past twenty years, the only therapy showing promise as a true alternative to a GFD is that of the induction of tolerance via a vaccine. PMID- 29411656 TI - Adapting Evidence-Based Teen Pregnancy Programs to Be LGBT-Inclusive: Lessons Learned. AB - CONTEXT: Lesbian, gay, bisexual, and transgender (LGBT) youth show higher rates of sexual risk behaviors than heterosexual and cisgender youth; yet, most school based sexual health education is largely heteronormative and cisnormative and does not recognize the spectrum of sexual and gender identity. New York City's Departments of Health and Education collaborated to create an LGBT-inclusive supplement to the Reducing the Risk curriculum and implement it in 21 South Bronx high schools. METHOD: Teachers completed an electronic survey to report the number of students reached and an online log to measure curriculum adherence. Students were administered an anonymous 74-item pre- and posttest to measure demographics, sexual health knowledge, and student satisfaction with the curriculum. Chi-square and t tests were used to assess differences in student demographics and changes in knowledge scores. RESULTS: Reducing the Risk was implemented in 21 schools reaching 230 classes and 5,673 students; with 161 classes receiving the supplement. Teachers reported completing an average of 70% of LGBT supplement activities. Students who received the supplement reported higher satisfaction and greater knowledge scores than students who did not. CONCLUSION: New York City experience shows that being more inclusive of LGBT teens while implementing preexisting evidence-based sexual and reproductive health programs is possible and replicable. PMID- 29411657 TI - Tips for reading patents: a concise introduction for scientists. AB - Many commercial and academic institutions protect their commercially valuable research information using patents, making the patent literature a rich and early source of cutting-edge research. While scientists and students often create the data that finds its way into patents, some rarely read the patent literature. Here, we provide an informal and brief collection of hints and tips that may assist scientists and students who do not regularly read the patent literature to locate the key scientific findings that are disclosed by patentees. These tips will introduce the reader to: (i) the general structure of patents and the sections of the patents that scientists and students may find particularly helpful; and (ii) a few factors to keep in mind when using data disclosed in the patent literature, such as patent lifespans, jurisdictions and the patent review processes. Although this is not a comprehensive and complete guide to reading patents, the accessible nature of this informal introduction to patent reading should assist scientists and students to make more effective use of the cutting edge research disclosed in patent specifications. PMID- 29411658 TI - Antioxidant properties and anti-mutagenic potential of Piper Cubeba fruit extract and molecular docking of certain bioactive compounds. AB - Spices and herbs are recognized as sources of natural antioxidants and thus play an important role in the chemoprevention of diseases and aging. Piper cubeba is one among them and known for its medicinal properties for decades. Various biological activities are associated with its extract and phytocompounds. However, the anti-mutagenic activity of antioxidant rich extract is less explored. In this study, we performed the fraction-based antioxidant activity of P. cubeba using four different assays and evaluated the anti-mutagenic activity of most potent antioxidant fraction using Salmonella typhimurium tester strains against four mutagens (methyl methanesulfonate [MMS], sodium azide [SA], benzo(a)pyrene, and 2-aminoflourene) respectively. Among all tested fractions at 25-200 ug/ml, ethanolic extract revealed highest antioxidant activity and significant anti-mutagenicity against both direct and indirect acting mutagens at least one tester strain. Phytochemical analysis by gas chromatography-mass spectrometry (GC/MS) revealed the presence of various phytocompounds including copaene, isocaryophyllene, alpha-cubebene, etc. Molecular docking studies on DNA binding interactions of GC/MS detected phytocompounds highlight the possible mode of binding. In summary, these in vitro studies have provided the scientific basis for validation of using this plant in the traditional system of medicine and highlighted the need for exploring the role of various compounds for therapeutic efficacy. On the other hand, synergistic interaction among phytocompounds is to be explored to optimize or standardize the extracts for the exploitation in modern phytomedicine. PMID- 29411659 TI - Safety and efficacy of miltefosine monotherapy and pentoxifylline associated with pentavalent antimony in treating mucosal leishmaniasis. AB - INTRODUCTION: Mucosal Leishmaniasis (ML) is a difficult to treat and severe form of Leishmaniasis. In general, more than 40% of subjects with ML have therapeutic failure upon the use of pentavalent antimony (Sbv) at 20mg/kg/day during 30 days. Additionally, Sbv is a toxic drug that requires parenteral administration, and many patients will need several courses to be cured. In cases that cannot be treated or cured by Sbv, the alternative is amphotericin B, another toxic and parenteral drug. As a consequence, many ML patients will be cured only after years of disease and may present several morbidities due to the aggressiveness of the disease or toxicity related to the treatment. Areas covered: We aimed to review clinical trials with Miltefosine or Sbv associated with pentoxifylline in the treatment of ML. Expert commentary: There are few studies to define more effective and safer therapy in mucosal disease caused by Leishmania, with an urgent need to supporting and funding well designed trials. Miltefosine monotherapy, as well as pentoxifylline combined with Sbv are promising therapeutic approaches to increase the cure rate of this neglected disease. PMID- 29411660 TI - Patient engagement in health technology assessment: what constitutes 'meaningful' and how we might get there. PMID- 29411661 TI - Novel pharmacotherapy for the treatment of hospital-acquired and ventilator associated pneumonia caused by resistant gram-negative bacteria. AB - INTRODUCTION: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP. Areas covered: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed. Expert opinion: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated. PMID- 29411662 TI - Empowerment, environment and person-centred care: A qualitative study exploring the hospital experience for adults with cognitive impairment. AB - It is acknowledged that there are many challenges to ensuring a positive hospital experience for patients with cognitive impairment. The study ('Improving hospital care for adults with cognitive impairment') aimed to explore the positive and negative experiences of older adults with cognitive impairment (dementia and delirium) and their relatives and/or carers, during an acute hospital stay, from admission to discharge, using a qualitative, case study methodology. Six participants with cognitive impairment, eight relatives and 59 members of the health care team were recruited. Data was collected via ethnographic, observational periods at each stage of the hospital journey and through the use of semi-structured interviews with relatives, carers and health care staff including: medical staff; nursing staff; physiotherapists and ward managers. Interpretive phenomenological analysis was used to facilitate data analysis. 52 hours 55 minutes of ethnographic observations and 18 interviews with ward staff and relatives were undertaken. Three superordinate themes emerged from the data as crucial in determining the quality of the hospital experience: valuing the person; activities of empowerment and disempowerment and the interaction of environment with patient well-being. Whether the patient's hospital experience was positive or negative was powerfully influenced by family involvement and ward staff actions and communication. Participants identified a requirement for a ward based activity service for patients with cognitive impairment. Further research must be undertaken focusing on the development of ward based activities for patients with cognitive impairment, alongside a move towards care which explores measures to improve and expand relative involvement in hospital care. PMID- 29411663 TI - The impact of life story work on person-centred care for people with dementia living in long-stay care settings in Ireland. AB - The potential of life story work to add quality to dementia care is widely acknowledged. Whether this potential is always realised in practice and under what circumstances is less clear. This paper explores whether knowing the person's life story enhances healthcare professionals' understanding of the person with dementia and whether this understanding impacts on the person's care. In-depth interviews were conducted with 11 registered nurses and 12 healthcare assistants who had used life story work with people with dementia living in long stay care settings. Data were analysed using the constant comparative technique. Engaging in life story work enabled staff to see the person behind the dementia. Understanding (as opposed to knowing) the person with dementia's life story changed staff's thinking on what is important when delivering care to people with dementia, with staff giving concrete examples of changes in how they delivered care to the person with dementia and what they considered important when delivering that care. It was concluded that life story work can facilitate a shift to person centred dementia care but how it is implemented matters if this outcome is to be achieved. PMID- 29411664 TI - Salivary gland ultrasonography findings are associated with clinical, histological, and serologic features of Sjogren's syndrome. AB - OBJECTIVE: Salivary gland ultrasonography (SGUS) has been applied in the diagnosis of Sjogren's syndrome (SS). The aim of this study is to investigate the association of SGUS findings with clinical, histological, and serologic features of SS. METHODS: A total of 104 patients with suspected SS underwent SGUS for evaluation of salivary gland involvement. Patients with primary SS were determined according to the classification criteria for SS. The parenchymal inhomogeneity of bilateral parotid and submandibular glands was graded from 0 (homogeneity) to 4 (gross inhomogeneity). Receiver operating characteristic curve analysis was performed to compare the diagnostic performance of different SGUS scoring methods. Clinical and serologic features were compared between groups classified by SGUS score. The association between SGUS and these features of SS was explored by multivariable linear regression analysis. RESULTS: Study participants were predominantly women (96.2%) and had a mean age of 54.1 years. Eighty-seven patients and 88 patients with primary SS were identified based on AECG criteria and ACR/EULAR classification criteria for SS, respectively. Among the different scoring methods, the sum of the grades of four salivary glands (range 0-16) had the best diagnostic performance, with sensitivity of 77.3% and specificity of 87.5% (cutoff value, 7) for distinguishing primary SS from sicca non-SS. SGUS score was associated with focus score in labial salivary gland biopsy (beta = 0.240, p = 0.033) and anti-Ro/SSA serology (beta = 0.283, p = 0.016) and inversely associated with unstimulated whole salivary flow (beta = 0.298, p = 0.011). CONCLUSION: Ultrasonography of major salivary glands is associated with histopathology of minor salivary glands, serology of SS, and salivary gland function. PMID- 29411665 TI - Immunomodulatory potential of recombinant filarial protein, rWbL2, and its therapeutic implication in experimental ulcerative colitis in mouse. AB - OBJECTIVE: Immunomodulation by helminth proteins has potential therapeutic implications in inflammatory bowel disease. In the present study, we have explored the therapeutic effect of a RAL family protein of filarial parasite Wuchereria bancrofti i.e., rWbL2 protein against DSS induced colitis in a mouse model. MATERIALS AND METHODS: Anti-inflammatory activity of rWbL2 on mice peritoneal exudate cells was analyzed under in vitro condition. The colitis mice were treated intraperitoneally (i.p.) with rWbL2 in increasing doses (10 ug, 25 ug, and 50 ug) on days 4, 5, and 6. Disease severity was assessed by disease activity index (DAI), macroscopic and histopathological scores, and enzyme myeloperoxidase activity (MPO) in the colon. The response of the cultured splenocytes from treated mice to Con-A stimulation, in terms of ELISA-based assessment of the protein followed by the assessment of mRNA expression of cytokines, was measured by real-time PCR analysis. RESULT: rWbL2 protein showed anti-inflammatory activity in vitro. Treatment with rWbL2 (at 25 ug/dose) effectively attenuated disease severity by reducing weight loss, DAI, mucosal edema, colon damage, and MPO activity. This therapeutic effect was found to be associated with increased release of anti-inflammatory cytokine IL-10 and decreased release of pro-inflammatory cytokine IFN-gamma and TNF-alpha by the splenocytes of treated mice followed by stimulation with Con-A. CONCLUSIONS: These results provide evidence of the strong immunomodulatory potential of rWbL2 protein implicating its therapeutic application against ulcerative colitis. PMID- 29411666 TI - ASXL1 mutations in AML are associated with specific clinical and cytogenetic characteristics. AB - Mutations of ASXL1 are early events in acute myeloid leukemia (AML) leukemogenesis and have been associated with unfavorable prognosis. In this study, we investigated the type and frequency of ASXL1 mutations in a large cohort of patients with de novo or secondary AML (s-AML) and looked for correlations with cytogenetic findings and disease features. ASXL1 mutations were associated with older age, s-AML and higher peripheral leukocytosis. We observed more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations but a negative correlation with myelodysplastic syndromes (MDS) related cytogenetic abnormalities, especially -5/del(5q) and -7/del(7q). ASXL1 mutations were also found in other genetically defined AML subgroups such as those with t(9;22), inv(3)/t(3;3), t(8;21) or t(15;17); however, none of our inv(16) cases carried ASXL1 mutations. We detected two previously unreported ASXL1 mutations, p.IIe593Val and p.Cys688Tyr. Our findings suggest that ASXL1 mutations tend to cluster with specific clinical and cytogenetic profiles of AML patients. PMID- 29411667 TI - Prognosis of patients with ascites after PleurX insertion: an observational study. AB - OBJECTIVE: To evaluate the safety of PleurX in cirrhotic patients with refractory ascites. METHODS: We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period. RESULTS: We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p = .23 and .96, respectively). Mortality was higher in patients with malignant ascites (p= .01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups. CONCLUSION: PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings. PMID- 29411668 TI - Twelve tips to promote a feedback culture with a growth mind-set: Swinging the feedback pendulum from recipes to relationships. AB - Feedback in medical education has traditionally showcased techniques and skills of giving feedback, and models used in staff development have focused on feedback providers (teachers) not receivers (learners). More recent definitions have questioned this approach, arguing that the impact of feedback lies in learner acceptance and assimilation of feedback with improvement in practice and professional growth. Over the last decade, research findings have emphasized that feedback conversations are complex interpersonal interactions influenced by a multitude of sociocultural factors. However, feedback culture is a concept that is challenging to define, thus strategies to enhance culture are difficult to pin down. In this twelve tips paper, we have attempted to define elements that constitute a feedback culture from four different perspectives and describe distinct strategies that can be used to foster a learning culture with a growth mind-set. PMID- 29411669 TI - CK7/CK20 Double-Negative Pulmonary Enteric Adenocarcinoma With Histopathological Evaluation of Transformation Zone Between Enteric Adenocarcinoma and Conventional Pulmonary Adenocarcinoma. AB - We report a rare case of pulmonary enteric adenocarcinoma (PEA) exhibiting a immunohistochemical feature of CK7/CK20 double-negativity by evaluating the transformation zone between PEA and conventional pulmonary adenocarcinoma (CPA). A 75-year-old man was found to have a mass, 40 mm in diameter, in the right lower lobe on chest computed tomography, and underwent right lower lobectomy. Histologically, the tumor was composed of a PEA and CPA component. The dominant PEA component had medium to large complex glands with tall columnar cells with eosinophilic cytoplasm and brush-border. The CPA component comprised small to medium glands with cuboidal cells. Moreover, intermediate glands (INT), which had cuboidal to tall columnar cells, with morphological features between PEA and CPA, was also observed in the transformation area. Immunohistochemically, the PEA component was negative for CK7, CK20, and TTF-1, and positive for CDX2 and SATB2 (weak): the CPA component was negative for CK20, CDX2, and SATB2, and positive for CK7 and TTF-1: the INT were negative for SATB2, with intermingled positive signals for CK7, CK20, TTF-1, and CDX2. The final diagnosis was PEA based on the CPA component and not colorectal carcinoma. To distinguish CK7-negative PEA from metastatic colorectal carcinoma, careful examination for a CPA component is very useful along with clinical information. There are no reports that discuss about process of oncogenesis, de novo sequence or transformation from CPA of PEA. This is the first reported case of CK7/CK20 double-negative PEA, with analysis of the transformation zone between PEA and CPA components. PMID- 29411670 TI - Mindfulness in severe and persistent mental illness: a systematic review. AB - OBJECTIVE: This systematic review summarises the current state of research on mindfulness in SPMI, given the pressing need to provide alternative, scalable and cost-effective treatment modalities for patients with severe and persistent mental illness (SPMI). METHODS: Articles included mindfulness-based interventions for SPMI. Excluded articles included qualitative studies, acceptance and compassion therapies, case reports and reviews. Studies were identified by searching the databases Medline, Embase and PsycINFO. RESULTS: Six randomised controlled trials, seven prospective studies and one retrospective study were identified. Clinical improvements were observed on psychotic symptoms, and on improvements of depression symptoms, cognition, mindfulness, psycho-social and vocational factors. CONCLUSIONS: Findings suggest that mindfulness is feasible for individuals with SPMI, and displays potential benefits in outcomes aside from psychotic symptoms. The effects of mindfulness in psychotic symptoms needs further investigation in larger definitive studies using methodological rigor and thorough assessments of other psychiatric populations who are also representative of SPMI. PMID- 29411672 TI - Management of fracture-dislocations of the little finger carpometacarpal joint: a systematic review. AB - Fracture-dislocations of the carpometacarpal joint (CMCJ) of the little ray involve dorsal subluxation of the metacarpal base and they may be associated with injury of neighbouring CMCJs. Different treatment options are described, with no clear consensus on their management. This study presents a systematic review of comparative studies describing the management of these injuries. A bespoke search strategy was applied across multiple databases. Results were screened against specified stepwise inclusion criteria and data were extracted independently by two authors with discrepancy resolution by a third. Of 437 search results, six comparative studies were identified. Comparisons included non-operative or early mobilization versus fixation K-wires or open reduction and internal fixation. Conclusions were mixed; all studies had critical or significant risks of bias (using the ROBINS-I tool) and there was heterogeneity between studies. PMID- 29411671 TI - Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation. AB - Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood. Here we demonstrate for the first time that adipose-derived stromal/stem cells (ASCs) induced to an adipogenic or osteogenic lineage have differences in strand preference (-3p and -5p) for miRNAs originating from the same primary transcript. Furthermore, evaluation of miRNA expression in ASCs demonstrates alterations in both miRNA strand preference and 5'seed site heterogeneity. Additionally, we show that during stem cell differentiation there are alterations in expression of genes associated with the miRNA biogenesis pathway. Quantitative RT-PCR demonstrated changes in the Argonautes (AGO1-4), Drosha, and Dicer at intervals of ASC adipogenic and osteogenic differentiation compared to untreated ASCs. Specifically, we demonstrated altered expression of the AGOs occurring during both adipogenesis and osteogenesis, with osteogenesis increasing AGO1-4 expression and adipogenesis decreasing AGO1 gene and protein expression. These data demonstrate changes to components of the miRNA biogenesis pathway during stromal/stem cell differentiation. Identifying regulatory mechanisms for miRNA processing during ASC differentiation may lead to novel mechanisms for the manipulation of lineage differentiation of the ASC through the global regulation of miRNA as opposed to singular regulatory mechanisms. PMID- 29411673 TI - 20 years of rheumatoid hand surgery: what did I learn? AB - Rheumatoid arthritis is one common form of inflammatory arthritis that affects about 1% of the population. Few conditions in hand surgery have undergone such fundamental changes within the last two decades as rheumatoid arthritis has with regard to clinical presentations and treatments. This article provides a personal practice-guided review of the author's decision making and treatment for patients with rheumatoid arthritis in the past two decades. PMID- 29411674 TI - Is This Kid a Likely Experimenter or a Likely Persister? An Analysis of Individual-Level and Family-Level Risk Factors Predicting Multiple Offending Among a Group of Adjudicated Youth. AB - To implement effective diversion programs and determine for a well-suited intervention strategy, ascertaining who, among the adjudicated youth, is more likely to involve in multiple offending, rather than desisting after an initial delinquent behavior, is of great significance. The overall objective of this study, therefore, is to contribute to the existing knowledge on assessing the risks for multiple offending during juvenile adjudication processes. In this regard, this study examined the predicting powers of several individual-level and family-level risk factors on multiple offending during adolescence, based on a data set derived from court-ordered social examination reports (SERs) on 400 adjudicated youth in Turkey. Two binomial regression models were implemented to test the predictor values of various risk factors from these two domains. Results indicated the following as significant predictors of multiple offending among the subjects: younger age of onset in delinquency, dropping out of school, having delinquent/drug abusing (risky) friends, being not able to share problems with the family, increased number of siblings, and having a domestically migrated family. Conclusively, these findings were compared with the existing literature, and the policy implications and recommendations for future research were discussed. PMID- 29411675 TI - PCSK9 inhibitors: a non-statin cholesterol-lowering treatment option. AB - Elevated low-density lipoprotein cholesterol (LDL-C) plays a major role in the development of atherosclerotic cardiovascular disease. Statins are the first-line treatment to lower LDL-C in patients with hypercholesterolemia; however, some high cardiovascular risk patients may have inadequate responses to statin therapy or are intolerant to statins, and may need additional and/or alternative non statin therapies to further reduce their LDL-C levels. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of circulating LDL-C levels, have received considerable attention as promising non statin therapeutic options for the management of hypercholesterolemia. This review provides a brief overview of the history and science of PCSK9 inhibitors, focusing on two PCSK9 monoclonal antibodies that have been approved by the US Food and Drug Administration: alirocumab and evolocumab. Recently released and forthcoming clinical trial data will be discussed, as well as the practical application of patient populations that may benefit from PCSK9 inhibitors. Finally, the recent expert recommendations regarding the use of PCSK9 inhibitors and other non-statin therapies to treat patients with inadequate LDL-C-lowering on statin therapy will be summarized. PMID- 29411676 TI - Health systems flattening - the failed promises of decentralisation in Mozambique. AB - Over the past decade, health systems strengthening (HSS) has become a global health imperative. As an answer to the influence of large-scale initiatives and NGOs, HSS represents a backlash against disease-specific projects and funding. Depicted as a positive evolution, HSS advertises local autonomy, and a turn away from donor-driven agendas. Central to this shift was the hope that 'vertical' funding, especially for HIV/AIDS, could be better used to build up the 'crumbling core' of health infrastructure in sub-Saharan Africa. As part of the change in Mozambique, HIV specialty clinics known as 'day hospitals' were decentralised (closed down) nationwide. Done in the name of efficiency and increased treatment coverage, the full impacts of this remain uncharted. In this article, I critique the ethical adequacy of HSS as a reorganising principle, pointing out the pursuit not of robust health systems, but of easily monitored ones instead. Occurring alongside performance-based financing, HSS invites the removal of specialty services, exposing health systems to additional shaping by outside forces. Based on ethnography with HIV support groups, I suggest HSS was an inevitable policy choice, but partially coercive. Such changes are neither counter-hegemonic nor capable of ameliorating foreign distortions in the developing world. PMID- 29411677 TI - Factors contributing to motorcycle fatal crashes on National Highways in India. AB - This study analyses fatal crash patterns, and identifies the risk factors contributing to motorcycle versus non-motorcycle fatal crashes using binomial logistic regression on two-, four- and six-lane National Highways (NHs) in India utilizing police fatal crash data. The distribution of victims' mode by striking vehicles shows that percentage share of striking vehicles (truck) against the victims' vehicles (motorcycle) is 44%, 52% and 37% on two-lane NH-8, four-lane NH 24 and six-lane NH-1, respectively. Nine explanatory variables pertaining to fatal crash, victim, roadway and environment are considered for the model (using combined data of cited three NHs). The results of the logistic regression model (motorcycle versus non-motorcycle fatal crashes) show that for variable 'collision type', likelihood of occurrence of 'rear-end', 'sideswipe' and 'head on' fatal crashes are 42-times, 35-times and 25-times more than 'hit pedestrian' respectively. Similarly, for variable 'number of vehicle', likelihood is thrice as 'single-vehicle' than 'two or more vehicles'; and, for variable 'number of lane', probability is more on 'two-lane' NH-8 than 'four-lane' NH-24. Based on the study results, it is recommended to upgrade two-lane (undivided carriageway) to four-lane (divided carriageway) NHs to reduce 'head-on' collision. PMID- 29411679 TI - Pulmonary Atresia With an Intact Ventricular Septum: Preoperative Physiology, Imaging, and Management. AB - Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare complex cyanotic congenital heart disease with heterogeneous morphological variation. Prenatal diagnosis allows for developing a safe plan for delivery and postnatal management. While transthoracic echocardiography allows for detailed delineation of the cardiac anatomy, additional imaging modalities such as computed tomography, magnetic resonance imaging, and catheterization may be necessary to further outline features of the cardiac anatomy, specifically coronary artery anatomy. The size of the tricuspid valve and right ventricular cavity as well as the presence of right ventricle-dependent coronary circulation help to dichotomize between biventricular repair versus univentricular palliation or heart transplantation, as well as predicting the expected survival. The delineation and understanding of these features help to dictate both medical and surgical management. PMID- 29411678 TI - Dysregulated lipid storage and its relationship with insulin resistance and cardiovascular risk factors in non-obese Asian patients with type 2 diabetes. AB - The prevalence of non-obese type 2 diabetes in Asians is up to 50%. This review aims to summarize the role of regional fat in the development of insulin resistance and cardiovascular risk in non-obese Asian type 2 diabetes as well as the role of intra-pancreatic fat and beta-cell dysfunction. The body fat content of non-obese Asian type 2 diabetic patients is not different from that of non diabetic subjects but the proportion of intra-abdominal and intra-hepatic fat are greater. Visceral fat contributes to insulin resistance and cardiovascular risk in non-obese Asian type 2 diabetes. Intra-hepatic fat and the hypertrophic abdominal subcutaneous adipocytes are associated with insulin resistance and cardiovascular risk in non-obese, non-diabetic Asian subjects. It may be true in non-obese Asian type 2 diabetic patients. The role of intra-myocellular lipid and insulin resistance is uncertain. Intra-pancreatic fat may not be involved in beta cell dysfunction in non-obese Asian type 2 diabetes. PMID- 29411680 TI - Road traffic crashes and built environment analysis of crash hotspots based on local police data in Galle, Sri Lanka. AB - Road traffic crashes (RTCs) are a leading cause of death and disability. In low- and middle-income countries, vulnerable road users are commonly involved in injurious RTCs. This study describes epidemiological and built environment analysis (BEA) of in Galle, Sri Lanka. After ethical and police permission, police data were collected and descriptive statistics tabulated. Spatial analysis identified hot spots and BEA was conducted at each location. Seven hundred and fifty-two victim data from 389 reported RTCs were collected. Most victims were male (91%) 21-50 years of age (>70%). Forty-nine percent of RTCs were non grievous. Crashes commonly included motorcycles (33.9%), three-wheelers (18.3%) or cars (14.4%). Most victims were drivers (33.4%) or pedestrians (21.3%). Factors contributing to RTCs include aggressive driving (44.5%) or speeding (42.7%). All hotspots were in urban areas, and most were at intersections (63%). Further analysis of hot spots is necessary to identify areas for intervention. PMID- 29411681 TI - Assessment of sedation level for endoscopic retrograde cholangiopancreatography - a prospective validation study. AB - BACKGROUND AND AIMS: There is no consensus on how to assess the depth of sedation for endoscopic retrograde cholangiopancreatography (ERCP). This study was carried out in order to evaluate different methods of assessment of depth of sedation: bispectral index (BiS), modified Richmond Agitation/Sedation Scale (mRASS), modified Ramsay Sedation Scale (mRSS) and modified Observer Assessment of Alertness and Sedation (mOAAS) and their applicability to clinical practice. METHODS: Two hundred patients were recruited. Sedation was given by standard clinical practice using propofol sedation or patient controlled sedation. Sedation was assessed on all patients using the above-mentioned methods. BiS was considered the reference point for sedation scales. Cronbach's alpha was calculated to determine the consistency of different scales in respect to each other and prediction probability and Spearman's correlation coefficients of sedation scales were calculated to show the relationship between sedation scales and BiS. RESULTS: All scales showed high reliability with overall Cronbach's alpha 0.943. Dropping scales suggested better consistency between mOAAS, mRSS and mRASS than with BiS. Spearman's correlation and prediction probability showed similar results with all tested scales: mOAAS (0.695, 0.739), mRSS (0.673, 0.735), mRASS (0.683, 0.738), p < .01 for all scales. CONCLUSIONS: All tested methods were found to be reliable in the assessment of the depth of sedation when compared with each other. However, mRASS, mRSS and mOAAS require the patient to respond to verbal or tactile stimulus, which may impair execution of ERCP, whereas BiS information is collected directly from electroencephalogram and thus may be preferable in clinical setting. PMID- 29411682 TI - The Experience of Persons With Multiple Sclerosis Using MS INFoRm: An Interactive Fatigue Management Resource. AB - We aimed to understand participants' experiences with a self-guided fatigue management resource, Multiple Sclerosis: An Interactive Fatigue Management Resource ( MS INFoRm), and the extent to which they found its contents relevant and useful to their daily lives. We recruited 35 persons with MS experiencing mild to moderate fatigue, provided them with MS INFoRm, and then conducted semistructured interviews 3 weeks and 3 months after they received the resource. Interpretive description guided the analysis process. Findings indicate that participants' experience of using MS INFoRm could be understood as a process of change, influenced by their initial reactions to the resource. They reported experiencing a shift in knowledge, expectations, and behaviors with respect to fatigue self-management. These shifts led to multiple positive outcomes, including increased levels of self-confidence and improved quality of life. These findings suggest that MS INFoRm may have a place in the continuum of fatigue management interventions for people with MS. PMID- 29411683 TI - Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease. AB - We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31. PMID- 29411684 TI - Are precues effective in proactively controlling taboo interference during speech production? AB - This research investigated whether precues engage proactive control to reduce emotional interference during speech production. A picture-word interference task required participants to name target pictures accompanied by taboo, negative, or neutral distractors. Proactive control was manipulated by presenting precues that signalled the type of distractor that would appear on the next trial. Experiment 1 included one block of trials with precues and one without, whereas Experiment 2 mixed precued and uncued trials. Consistent with previous research, picture naming was slowed in both experiments when distractors were taboo or negative compared to neutral, with the greatest slowing effect when distractors were taboo. Evidence that precues engaged proactive control to reduce interference from taboo (but not negative) distractors was found in Experiment 1. In contrast, mixing precued trials in Experiment 2 resulted in no taboo cueing benefit. These results suggest that item-level proactive control can be engaged under certain conditions to reduce taboo interference during speech production, findings that help to refine a role for cognitive control of distraction during speech production. PMID- 29411685 TI - A confirmative clinimetric analysis of the 36-item Family Assessment Device. AB - BACKGROUND: The Family Assessment Device (FAD) is a 60-item questionnaire widely used to evaluate self-reported family functioning. However, the factor structure as well as the number of items has been questioned. A shorter and more user friendly version of the original FAD-scale, the 36-item FAD, has therefore previously been proposed, based on findings in a nonclinical population of adults. AIMS: We aimed in this study to evaluate the brief 36-item version of the FAD in a clinical population. METHODS: Data from a European multinational study, examining factors associated with levels of family functioning in adult cancer patients' families, were used. Both healthy and ill parents completed the 60-item version FAD. The psychometric analyses conducted were Principal Component Analysis and Mokken-analysis. RESULTS: A total of 564 participants were included. Based on the psychometric analysis we confirmed that the 36-item version of the FAD has robust psychometric properties and can be used in clinical populations. CONCLUSIONS: The present analysis confirmed that the 36-item version of the FAD (18 items assessing 'well-being' and 18 items assessing 'dysfunctional' family function) is a brief scale where the summed total score is a valid measure of the dimensions of family functioning. This shorter version of the FAD is, in accordance with the concept of 'measurement-based care', an easy to use scale that could be considered when the aim is to evaluate self-reported family functioning. PMID- 29411686 TI - What is at stake? Exploring the moral experience of stigma with Indian Australians and Anglo-Australians living with depression. AB - This article applies the framework of moral experience to examine the cultural experience of stigma with Indian-Australians and Anglo-Australians living with depression in Melbourne, Australia. To date few studies have examined this dynamic in relation to mental illness and culture, and no studies have applied this framework in a culturally comparative way. Based on 58 in-depth interviews with people with depression recruited from the community, we explicate how stigma modulates what is at stake upon disclosure of depression, participants' lived experience following that disclosure, and how practices of health-seeking become stigmatised. Findings show that the social acceptance of depression jars against participants' experience of living with it. Denialism and fear of disclosure were overwhelming themes to emerge from our analysis with significant cultural differences; the Anglo-Australians disclosed their depression to family and friends and encountered significant resistance about the legitimacy of their illness. In contrast, many Indian-Australians, especially men, did not disclose their illness for fear of a damaged reputation and damaged social relations. For Indian-Australians, social relations in the community were at stake, whereas for Anglo-Australians workplace relations (but not community relations) were at stake. Participants' experiences in these settings also influenced their patterns of health-seeking behaviors and age and inter-generational relationships were important mediators of stigma and social support. These findings illuminate how stigma, culture, and setting are linked and they provide critical information necessary to identify and develop customised strategies to mitigate the harmful effects of stigma in particular cultural groups. PMID- 29411687 TI - Simultaneous anaerobic oxidation/partial nitrification-denitrification for cost effective and efficient removal of organic carbon and nitrogen from highly polluted streams. AB - Laboratory bench-scale anoxic/aerobic reactors with complete mix and continuous flow conditions were operated with high-strength synthetic wastewater to achieve simultaneous COD and nitrogen removal. High concentrations of organic carbon and nitrogen can be found in slaughterhouse, dairy, and food processing wastewaters, and also in some landfill leachates. Therefore, the goal of this study is to find a simple, efficient, reliable, cost-effective, and general solution for organic carbon and ammonia removal from streams with high influent concentrations of more than 5000 mg/L COD and 250 mg/L NH3-N. The highest COD (97%) and NH3-N (91%) removal efficiencies were obtained with initial COD and ammonia concentrations of 5211 mg/L and 262.8 mg/L NH3-N with volumetric loading rates of 11.26 kg COD/m3 d and 0.57 kg NH3-N/m3 d for COD and ammonia, respectively. Anaerobic oxidation is the main COD removal pathway in a simultaneous anaerobic oxidation/partial nitrification-denitrification (SAO/PND) system, and nitrogen removal significantly occurs via bacterial assimilation and partial nitrification denitrification pathways. There are several advantages for this proposed SAO/PND system from a practical point of view, such as feasibility of simultaneous COD and nitrogen removal in a single reactor; simple operation; flexibility and practicality of this system as a general solution and cost effectiveness. PMID- 29411688 TI - Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current treatment strategies? AB - INTRODUCTION: Approved medications for relapsing-remitting multiple sclerosis have shown to be effective in terms of their anti-inflammatory potential. However, it is also crucial to evaluate what long-term effects a patient can expect from current MS drugs in terms of preventing neurodegeneration. Here we aim to provide an overview of the current treatment strategies in MS with a specific focus on potential neuroprotective effects. Areas covered: Randomized, double-blind and placebo or referral-drug controlled phase 2a/b and phase 3 trials were examined; non-blinded phase 4 studies (extension studies) were included to provide long-term data, if not otherwise available. Endpoints considered were expanded disability status scale, various neuropsychological tests, percent brain volume change and T1-hypointense lesions as well as multiple sclerosis functional composite, confirmed disease progression, and no evidence of disease activity. Expert commentary: Overall, neuroprotective functions of classical MS therapeutics are not sufficiently investigated, but available data show limited effects. Thus, further research and development in neuroprotection are warranted. When counselling patients, potential long-term beneficial effects should be presented more conservatively. PMID- 29411689 TI - Tumor necrosis and >20 mitoses per 50 high-power fields can distinguish 'very high-risk' and 'highest-risk' within 'high-risk' gastric gastrointestinal stromal tumor. AB - AIM: We aimed to investigate the optimal criteria for classifying higher risk forms of gastric gastrointestinal stromal tumor (gGIST). MATERIALS & METHODS: A total of 246 high-risk gGIST patients were enrolled. Univariate and multivariate analyses were conducted to determine the association between clinicopathological features and overall survival. Appropriate cut-off values were calculated to identify those at higher risk of gGIST. RESULTS: Multivariate and univariate analyses revealed that tumor necrosis and mitotic counts are independent risk factors for overall survival. The optimal cut-off value of mitotic counts was 20. Patients with both necrosis and >20 mitoses/50 high-power fields were worse than those with either one. CONCLUSION: Tumor necrosis and >20 mitoses/50 high-power fields are independent risk factors for high-risk gGIST. Patients with both risk factors indicate worse prognosis. PMID- 29411690 TI - A new selection method to increase the health benefits of CVD prevention strategies. AB - Background Cardiovascular disease (CVD) prevention is commonly focused on providing individuals at high predicted CVD risk with preventive medication. Whereas CVD risk increases rapidly with age, current risk-based selection of individuals mainly targets the elderly. However, the lifelong (preventable) consequences of CVD events may be larger in younger individuals. The purpose of this paper is to investigate if health benefits from preventive treatment may increase when the selection strategy is further optimised. Methods Data from three Dutch cohorts were combined ( n = 47469, men:women 1:1.92) and classified into subgroups based on age and gender. The Framingham global risk score was used to estimate 10-year CVD risk. The associated lifelong burden of CVD events according to this 10-year CVD risk was expressed as quality-adjusted life years lost. Based on this approach, the additional health benefits from preventive treatment, reducing this 10-year CVD risk, from selecting individuals based on their expected CVD burden rather than their expected CVD risk were estimated. These benefits were expressed as quality-adjusted life years gained over lifetime. Results When using the current selection strategy (10% risk threshold), 32% of the individuals were selected for preventive treatment. When the same proportion was selected based on burden, more younger and fewer older individuals would receive treatment. Across all individuals, the gain in quality-adjusted life years was 217 between the two strategies, over a 10-year time horizon. In addition, when combining the strategies 5% extra eligible individuals were selected resulting in a gain of 628 quality-adjusted life years. Conclusion Improvement of the selection approach of individuals can help to reduce further the CVD burden. Selecting individuals for preventive treatment based on their expected CVD burden will provide more younger and fewer older individuals with treatment, and will reduce the overall CVD burden. PMID- 29411691 TI - Prospective memory in idiopathic REM sleep behavior disorder with or without mild cognitive impairment: a preliminary study. AB - OBJECTIVE: The ability to execute delayed intentions, known as prospective memory (PM), is crucial to everyday living. PM failures are reported in mild cognitive impairment (MCI) and Parkinson's disease, however, no study to date has investigated PM functioning in individuals at high risk of developing these conditions, precisely those diagnosed with idiopathic REM sleep behavior disorder (iRBD). We aimed to assess PM in iRBD according to patients' cognitive status and to determine the underlying nature of their difficulties. METHOD: Fifty-eight participants, including 20 healthy controls (HC) and 38 polysomnographic confirmed iRBD patients with (iRBD-MCI = 13) or without (iRBD-nMCI = 25) MCI participated in this study. Following a neuropsychological assessment, PM was evaluated using a self-administered questionnaire (PRMQ), a simple clinical measure (envelope test), and a laboratory cue salience task. RESULTS: No significant group differences were noted on the PRMQ and envelope test. On the PM laboratory task, non-parametric analyses revealed better detection accuracy in HC than both iRBD groups for all high and low salient cues. While iRBD-nMCI and iRBD MCI patients performed similarly on the high salient condition, the latter showed significant difficulty in detecting low salient cues. Multiple regression analyses revealed executive dysfunction as the best predictor to significantly account for differences in the low salient condition in iRBD. CONCLUSION: PM difficulties in iRBD are most important in patients with MCI (vs without MCI) and may be attributed to a gradual alteration in executive mechanisms. PM impairment could act as a promising indicator of early cognitive dysfunction in iRBD. PMID- 29411692 TI - Polyvictimization and Girls' Involvement in the Juvenile Justice System: Investigating Gender-Differentiated Patterns of Risk, Recidivism, and Resilience. AB - A recent dramatic rise in girls' arrests has increased our need to examine whether our models of youth justice system involvement need to be differentiated by gender. Polyvictimization, in particular, has been implicated as a powerful predictor of youth problem behavior. However, recent research suggests that polyvictimization is associated with youth involvement in the justice system in ways that differ for girls at the levels of the independent variables (i.e., the sources of risk), the dependent variables (i.e., youth outcomes), and the mediators of these associations (i.e., the purported mechanisms that account for these relations). The present critique describes growth points in the current research with the goal of suggesting promising directions for future investigations. In particular, gaps are noted regarding our understanding of the specific forms of polyvictimization that affect traumatized girls' development, especially given the highly disproportionate prevalence of sexual abuse among justice-involved girls. In addition, increased attention is needed to gender differences in the timing of victimization and the onset of risky behavior, as well as the nature of trauma-linked youth offenses and recidivism, which research also suggests may differ for boys and girls. Furthermore, a new body of research on psychophysiological reactivity promises to shed light on gender differences in trauma response, resilience, and risk. Finally, the importance acknowledging the intersection of polyvictimization, gender, and race is noted. The article ends with a discussion of the ways in which understanding gender differences and similarities can inform gender-responsive approaches to prevention and intervention efforts. PMID- 29411693 TI - Opening Remarks. PMID- 29411694 TI - Why Polyvictimization Matters. AB - The five important papers in this series reflect the evolving state of research on violence and victimization. Their findings and methods underscore the importance of studying poly-victimization as the more encompassing genesis of harm across stages of development, rather than singular, isolated events. That is, children and youth who experience one type of violence are more likely than not to have experienced (or will experience) many others. Poly-victimized children become victims of further abuse and trauma and, in turn, are at increased risk of becoming perpetrators toward peers and future partners. These five papers incorporate a wider lens that is more inclusive of gender minority and ethnic minority youth, as well as underserved populations such as youth served by the juvenile justice systems (especially girls). Important developments were described in terms of recruiting difficult-to-reach populations, and ways to screen for psychological maltreatment in the background of youths. These papers demonstrate how the field is moving away from narrowly focused studies of violence/victimization, toward a more integrative, person-centered strategy. Such a strategy looks for common elements, such as healthy relationship development, that move us closer to common causes and solutions. These solutions should involve universal prevention via our education system that promotes well-being, enhances resilience, and reduces poly-victimization for all youth. PMID- 29411695 TI - Poly-Victimization and Peer Harassment Involvement in a Technological World. AB - This article explores the ways poly-victimized youth (those experiencing multiple different types of victimization over the course of 1 year) use technology to interact with peers. Particular attention is given to the peer harassment victimization and perpetration experiences of poly-victimized youth compared with less victimized and non-victimized youth-both overall and through technology. Data were collected as part of the Technology Harassment Victimization (THV) study; a national survey of 791 youth, ages 10 to 20 across the United States. Study results document the heightened risks that poly-victimized youth experience when interacting with peers. Low and high poly-victimized youth were both at significantly greater risk of being dual victims and perpetrators of peer harassment when compared with non-victimized youth even after taking into account other potentially explanatory factors. This was not found to be the case for less victimized youth. This was true for high poly-victims and technology-involved harassment risk as well. There were indications that poly-victimized youth were interacting with peers in more intense and risky ways in general using new technology. The increase in attention to poly-victimization in recent years has importantly identified the detrimental role that experiencing different forms of victimization have on youth. This study not only adds to that literature but suggests that there is an opportunity to interrupt additional victimization by understanding how poly-victimized youth interact with peers before and during adolescence. Although preliminary, the differences in technology use by poly victimized youth versus others suggest that more information is needed to understand how they are relating to peers in both positive and risky ways in this environment. PMID- 29411696 TI - From Poly-Victimization to Poly-Strengths: Understanding the Web of Violence Can Transform Research on Youth Violence and Illuminate the Path to Prevention and Resilience. AB - For many years, an overly "siloed" approach has hampered efforts to understand violence and minimize the societal burden of violence and victimization. This article discusses the limitations of an overly specialized approach to youth violence research, which has focused too much on violence in particular contexts, such as the family or the school. Instead, a child-centered approach is needed that comprehensively assesses all exposures to violence. This concept of the total cumulative burden of violence is known as poly-victimization. The poly victimization framework reveals that many youth are entangled in a web of violence, experiencing victimization in multiple settings by multiple perpetrators. This more accurate view of children's exposure to violence has many advantages for advancing our scientific understanding of violence. Perhaps somewhat surprisingly, this more comprehensive view also points to new insights for resilience and prevention. This includes recognizing a parallel concept, "poly-strengths," which captures the number of resources and assets children and their families can use to help insulate youth from violence (prevention) or assist in coping and promoting well-being after victimization (intervention). Reconceptualizing how resilience is defined and understood among youth populations can help alleviate the true societal burden of youth victimization. PMID- 29411697 TI - Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014-2017). AB - INTRODUCTION: To deal with the rapid emergence of drug resistance challenges, together with the difficulty to eradicate the virus, off-target effects and significant cumulative drug toxicities, it is still imperative to develop next generation anti-HIV agents with novel chemical classes or new mechanisms of action. Areas covered: We primarily focused on current strategies to discover novel anti-HIV agents. Moreover, examples of anti-HIV lead compounds were mainly selected from recently patented publications (reported between 2014 and 2017). In particular, 'privileged structure'-focused substituents decorating approach, scaffold hopping, natural-product diversification and prodrug are focused on. Furthermore, exploitation of new compounds with unexplored mechanisms of action and medicinal chemistry strategies to deplete the HIV reservoir were also described. Perspectives that could inspire future anti-HIV drug discovery are delineated. Expert opinion: Even if a large number of patents have been disclosed recently, additional HIV inhibitors are still required, especially novel chemical skeletons displaying a unexploited mechanism of action. Current medicinal chemistry strategies are inadequate, and appropriate and new methodologies and technologies should be exploited to identify novel anti-HIV drug candidates in a time- and cost- effective manner. PMID- 29411698 TI - Lenalidomide in non-deletion 5q lower-risk myelodysplastic syndromes: a glass quarter full or three quarters empty? PMID- 29411701 TI - A retrospective study of the neuropathology and diagnosis of naturally occurring feline infectious peritonitis. AB - Feline infectious peritonitis (FIP) is one of the most important viral diseases of cats worldwide. Our study describes the neuropathology and the diagnostic features of 26 cases of FIP in domestic cats. The average age of affected individuals was 11.8 mo, and there was no sex or breed predisposition. Clinical neurologic signs were noted in 22 cases, and rabies was clinically suspected in 11 cases. Twenty cats had lesions in multiple organs, and 6 cats had lesions only in the brain. Gross neuropathologic changes occurred in 15 cases and consisted of hydrocephalus (10 cases), cerebellar herniation through the foramen magnum (6 cases), cerebral swelling with flattening of gyri (2 cases), and accumulation of fibrin within ventricles (2 cases) or leptomeninges (1 case). Histologically, 3 main distinct distributions of neuropathologic changes were observed, namely periventricular encephalitis (12 cases), rhombencephalitis (8 cases), and diffuse leptomeningitis with superficial encephalitis (6 cases). Fresh tissue samples were submitted for fluorescent antibody testing (FAT) after autopsy in 17 cases, and positive results were found in only 7 cases. Immunohistochemistry (IHC) for feline coronavirus confirmed the diagnosis in all 26 cases. IHC appears to be a more sensitive and reliable test for confirmation of FIP than is FAT. PMID- 29411700 TI - How will telemedicine change clinical practice in chronic obstructive pulmonary disease? AB - Within telehealth there are a number of domains relevant to pulmonary care: telemonitoring, teleassistance, telerehabilitation, teleconsultation and second opinion calls. In the last decade, several studies focusing on the effects of various telemanagement programs for patients with chronic obstructive pulmonary disease (COPD) have been published but with contradictory findings. From the literature, the best telemonitoring outcomes come from programs dedicated to aged and very sick patients, frequent exacerbators with multimorbidity and limited community support; programs using third-generation telemonitoring systems providing constant analytical and decisionmaking support (24 h/day, 7 days/week); countries where strong community links are not available; and zones where telemonitoring and rehabilitation can be delivered directly to the patient's location. In the near future, it is expected that telemedicine will produce changes in work practices, cultural attitudes and organization, which will affect all professional figures involved in the provision of care. The key to optimizing the use of telemonitoring is to correctly identify who the ideal candidates are, at what time they need it, and for how long. The time course of disease progression varies from patient to patient; hence identifying for each patient a 'correct window' for initiating telemonitoring could be the correct solution. In conclusion, as clinicians, we need to identify the specific challenges we face in delivering care, and implement flexible systems that can be customized to individual patients' requirements and adapted to our diverse healthcare contexts. PMID- 29411702 TI - Practical Guidelines for Perioperative Hypersensitivity Reactions. AB - Perioperative hypersensitivity reactions constitute a first-line problem for anesthesiologists and allergists. Therefore, hospitals should have a consensus protocol for the diagnosis and management of these reactions. However, this kind of protocol is not present in many hospitals, leading to problems with treatment, reporting of incidents, and subsequent etiological diagnosis. In this document, we present a systematic review of the available scientific evidence and provide general guidelines for the management of acute episodes and for referral of patients with perioperative hypersensitivity reactions to allergy units. Members of the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) have created this document in collaboration with members of the Spanish Anesthesia Society (SEDAR). A practical algorithm is proposed for the etiologic diagnosis, and recommendations are provided for the management of hypersensitive patients. PMID- 29411703 TI - Social Media as a Tool for the Management of Food Allergy in Children. AB - BACKGROUND: Food allergy markedly impairs quality of life, and avoiding the offending food requires extensive patient education. Social media have been proven a useful source of information for other chronic conditions. Our aim was to describe how pediatric patients with food allergy and their families are using social media. METHODS: We performed a cross-sectional study in the pediatric allergy unit of a tertiary hospital. Patients with food allergy were questioned about their disease and their use of social media. The survey was completed by the patients themselves in the case of those aged over 13 years and by parents or guardians in the case of younger patients. RESULTS: We included 193 patients (162 guardians, 31 adolescents). Social media were used by 109 guardians (67.3%) and 29 adolescents (90.3%), of whom 30.3% and 6.9%, respectively, used them for food allergy-related purposes. The most popular websites were Facebook for guardians (52.2%) and YouTube for teenagers (80.6%). Having cow's milk and/or egg allergy was the only feature related to using social media for food allergy. Using social media for information on food allergy did not correlate with the frequency of recent reactions, self-scored knowledge about food allergy, or opinion on evidence-based or alternative therapies for the disease. CONCLUSIONS: Most patients and guardians of patients with food allergy used social media. However, only a small portion accessed used them to increase their knowledge of the disease. PMID- 29411704 TI - [Genetic association analyses of the endocannabinoid system on anxious phenotype]. AB - BACKGROUND: Accumulating data confirmed that the endocannabinoid system (ECS) is involved in the regulation of stress response and emotional processes, therefore ECS became an important pharmacological target as a potential anxiolytic. Although unequivocal data from animal studies confirmed the relevancy of the ECS in anxious phenotype, human genetic data are poorly available in the literature in this field. In the presented studies we tested possible associations between anxious phenotype and the cannabinoid receptor 1 and the fatty acid amide hydrolase gene polymorphisms. METHODS: Almost 900 subjects were involved in our study from the general population. Anxious phenotype was measured by the State Trait Anxiety Inventory (STAI) and the anxious subscale of the Brief Symptom Inventory (BSI-ANX). Genetic polymorphisms were genotyped from buccal mucosa samples' DNA by MassArray Sequenom technic. General linear models and post hoc tests were performed for statistical analyses. RESULTS: Phenotypic variances were not dependent on single marker's effect. However, interaction analyses provided significant results. Carriers of GG genotype of the rs2180619 scored significantly higher on the STAI-T scale in presence of SS genotype of 5-HTTLPR compared to other allelic variants (p=0.0006). SS genotype together with GG genotype meant almost a 5-fold risk to be anxious (OR=4.64, 95% CI: 1.7-12.71). In case of the C385A polymorphism of FAAH gene, A allele was associated with high scores of the BSI-ANX and the STAI-T if there were multiple childhood traumas in the anamnesis compared to C allele (pinteract=0.00002; pinteract=0.0023; respectively). CONCLUSION: Our results confirmed earlier positive data on the association between ECS and anxious phenotype. According to our findings ECS plays a significant role in the pathomechanism of anxious disorders by a complex mechanism of genetic interaction with the serotonin transporter gene and childhood traumas. PMID- 29411705 TI - [Vascular endothelial growth factor (VEGF) as a potential biomarker in major depressive disorder]. AB - BACKGROUND: There is growing evidence that vascular endothelial growth factor (VEGF) plays a crucial role in neurodevelopment and regeneration. Several data support that intact VEGF pathway is indispensable for therapeutic effect of antidepressants, any disruption of VEGF signaling can result treatment resistance. In our study we investigated the peripherial blood VEGF level before and 4-week after antidepressant treatment in patients with major depressive episode and we compared VEGF levels between responders and non-responders. METHODS: We recruited 34 patients diagnosed with major depression disorder rom our department. Depressive symptoms were followed by the Montgomery Asberg Depression Scale. Level of VEGF was measured from peripheral plasma by ELISA technic. For comparisons we performed general linear models and Mann-Whitney U tests. RESULTS: Baseline VEGF level was significantly higher in the non-responder subgroup compared to responders (p=0.017). In regression analyses the baseline and end-point VEGF levels were correlated with end-point MADRS (p=0.03; p=0.02, respectively). In our sample the higher baseline VEGF level was correlated with 2.75 times greater chance for treatment resistance in non-responders compared to responders. CONCLUSION: Our results confirm the significant role of VEGF signaling in the pathomechanism of major depression disorder. These data suggest that high baseline VEGF level can be a predictor for lack of therapy response, thus VEGF can be regarded as a potential biomarker for treatment resistance in major depression disorder. PMID- 29411706 TI - [Maternal bonding style, cholinergic receptor gene polymorphisms in association with smoking-related depressive symptoms]. AB - : Backgorund: There is accumulating evidence on the association between the cholinergic system and nicotine dependence (ND) in the literature and the bidirectional relationship of ND and depression. However, the molecular background of the development of ND and related affective phenotype is not clear. METHODS: We recruited 255 tretament-seeking smokers into our study. For phenotyping assessments we used the Fagerstrom Nicotine Dependence Test; The Minnessotta Nicotine Withdrawal Scale; the Zung Self-Rating Depression Scale and the Parental Bonding Instrument. DNA was isolated from buccal mucosa sample and CHRNA4 and CHRNB2 gene SNPs were genotyped with MassArray Sequenom techniques. For statistical analyses ANOVA test, Mann-Whitney U test, linear regression, two step cluster analyses and hapscore tests were performed. RESULTS: Two-step cluster analysis revealed 3 well-differentiated subgroups among smokers based on phenotypic characteristics. One subgroup was associated with the highest withdrawal and depressive scores. Frequency of the risk haplotype of CHRNA4 was significantly higher in this subgroup (p=0.019). Further, lifetime prevalence of major depression was also significantly higher in this subgroup. Besides, CHRNB2 gen variants showed a significant interacting effect with maternal bonding style on suicide thoughts (p=0.005). CONCLUSIONS: Our results confirmed the genetic effect of CHRNA4 and CHRNB2 on smoking-related depression. These findings suggest that a genetically vulnerable subgroup can be distinguished among smokers and this subphenotype is more prone to withdrawal and depressive symptoms. Our data suggest that suicidal risk depends on both CHRNB2 gene variants and maternal bonding style. Pharmacogenetic concerns of CHRNA4 and CHRNB2 genes might be significant considering suicide as side effect of quitting therapy. Further pharmacogenetic investigations are requierd to clarify this possibility. PMID- 29411707 TI - [Psychobiological background and clinical aspects of the placebo effect in psychiatry]. AB - The placebo-effect is present in almost every field of medicine, however, in the assessment of the effect of psychotropic drugs it is a major problem. The rise of the placebo-effect in clinical trials is observed during the last decades, in spite of all efforts to introduce new methods in clinical trials to overcome this problem and the number of studies aiming to unveil the mechanisms that lie in the background that this phenomenon have risen. A considerable amount of data has accumulated regarding the psychobiological background of placeboeffect, however, the details of underlying mechanisms are still not clear. Furthermore, the lack of objective tools for the assessment of the phenotypic changes during the treatment of psychiatric disorders makes it even more difficult to differentiate the symptom intensity changes related to drug response from the placebo effect. The consequences of this scarcity of information concerning the background of placebo-effect may hinder the development of new compounds, having enormous medical, scientific and economical disadvantages. In this review we summarise the psychobiological mechanisms in the background of placebo effect and its impact on clinical trials. PMID- 29411708 TI - [From stone-craved genes to Michelangelo: significance and different aspects of gene-environment interaction]. AB - Although genetic studies have improved a lot in recent years, without clinical relevance sometimes their significance is devalued. Reviewing the major milestones of psychogenomics it can be seen that break-through success is just a question of time. Investigations of direct effect of genetic variants on phenotypes have not yielded positive findings. However, an important step was taken by adapting the gene-environment interaction model. In this model genetic vulnerability stepped into the place of "stone craved" pathology. Further progress happened when studies of environmental factors were combined with genetic function (epigenetics). This model provided the possibility for investigation of therapeutic interventions as environmental factors and it was proven that effective treatments exert a modifying effect on gene expression. Moreover, recent developments focus on therapeutic manipulation of gene function (e.g. chemogenetics). Instead of "stone craved" genes up-to-date dynamically interacting gene function became the basis of psychogenomics in which correction of the expression is a potential therapeutic tool. Keeping in mind these trends and developments, there is no doubt that genetics will be a fundamental part of daily clinical routine in the future. PMID- 29411709 TI - Impact of event positioning algorithm on performance of a whole-body PET scanner using one-to-one coupled detectors. AB - The advent of silicon photomultipliers (SiPMs) has introduced the possibility of increased detector performance in commercial whole-body PET scanners. The primary advantage of these photodetectors is the ability to couple a single SiPM channel directly to a single pixel of PET scintillator that is typically 4 mm wide (one to-one coupled detector design). We performed simulation studies to evaluate the impact of three different event positioning algorithms in such detectors: (i) a weighted energy centroid positioning (Anger logic), (ii) identifying the crystal with maximum energy deposition (1st max crystal), and (iii) identifying the crystal with the second highest energy deposition (2nd max crystal). Detector simulations performed with LSO crystals indicate reduced positioning errors when using the 2nd max crystal positioning algorithm. These studies are performed over a range of crystal cross-sections varying from 1 * 1 mm2 to 4 * 4 mm2 as well as crystal thickness of 1 cm to 3 cm. System simulations were performed for a whole-body PET scanner (85 cm ring diameter) with a long axial FOV (70 cm long) and show an improvement in reconstructed spatial resolution for a point source when using the 2nd max crystal positioning algorithm. Finally, we observe a 30 40% gain in contrast recovery coefficient values for 1 and 0.5 cm diameter spheres when using the 2nd max crystal positioning algorithm compared to the 1st max crystal positioning algorithm. These results show that there is an advantage to implementing the 2nd max crystal positioning algorithm in a new generation of PET scanners using one-to-one coupled detector design with lutetium based crystals, including LSO, LYSO or scintillators that have similar density and effective atomic number as LSO. PMID- 29411710 TI - Translating secondary electrospray ionization-high-resolution mass spectrometry to the clinical environment. AB - While there has been progress in making use of breath tests to guide clinical decision making, the full potential of exhaled breath analysis still remains to be exploited. Here we summarize some of the reasons why this is the case, what we have done so far to overcome some of the existing obstacles, and our vision of how we think breath analysis will play a more prominent role in the coming years. In particular, we envision that real-time high-resolution mass spectrometry will provide valuable information in biomarker discovery studies. However, this can only be achieved by a coordinated effort, using standardized equipment and methods in multi-center studies to eventually deliver tangible advances in the field of breath analysis in a clinical setting. Concrete aspects such as sample integrity, compound identification, quantification and standardization are discussed. Novel secondary electrospray ionization developments with the aim of facilitating inter-groups comparisons and biomarker validation studies are also presented. PMID- 29411711 TI - Microstructure and in vivo characterization of multi-channel nerve guidance scaffolds. AB - In a previous study, we demonstrated a novel manufacturing approach to fabricate multi-channel scaffolds (MCS) for use in spinal cord injuries (SCI). In the present study, we extended similar materials processing technology to fabricate significantly longer (5X) porous poly caprolactone (PCL) MCS and evaluated their efficacy in 1 cm sciatic peripheral nerve injury (PNI) model. Due to the increase in MCS dimensions and the challenges that may arise in a longer nerve gap model, microstructural characterization involved MCS wall permeability to assess nutrient flow, topography, and microstructural uniformity to evaluate the potential for homogeneous linear axon guidance. It was determined that the wall permeability dramatically varied from 0.02 +/- 0.01 * 10-13 to 21.7 +/- 11.4 * 10 13 m2 for 50% and 70% porous PCL, respectively. Using interferometry, the porous PCL surface roughness was determined to be 10.7 +/- 1.2 MUm, which is believed to be sufficient to promote cell integration. Using micro computed tomography, the 3D MCS microstructure was determined to be uniform over 1 cm with an open lumen volume of 44.6% +/- 3.6%. In vivo implantation, in the rat sciatic nerve model, over 4 weeks, demonstrated that MCS scaffolds maintained structural integrity, were biocompatible, and supported linear axon guidance and distal end egress over 1 cm. Taken together, this study demonstrated that MCS technology previously developed for the SCI is also relevant to longer nerve gap PNI. PMID- 29411712 TI - Average stopping powers for electron and photon sources for radiobiological modeling and microdosimetric applications. AB - This study concerns calculation of the average electronic stopping power for photon and electron sources. It addresses two problems that have not yet been fully resolved. The first is defining the electron spectrum used for averaging in a way that is most suitable for radiobiological modeling. We define it as the spectrum of electrons entering the sensitive to radiation volume (SV) within the cell nucleus, at the moment they enter the SV. For this spectrum we derive a formula that combines linearly the fluence spectrum and the source spectrum. The latter is the distribution of initial energies of electrons produced by a source. Previous studies used either the fluence or source spectra, but not both, thereby neglecting a part of the complete spectrum. Our derived formula reduces to these two prior methods in the case of high and low energy sources, respectively. The second problem is extending electron spectra to low energies. Previous studies used an energy cut-off on the order of 1 keV. However, as we show, even for high energy sources, such as 60Co, electrons with energies below 1 keV contribute about 30% to the dose. In this study all the spectra were calculated with Geant4 DNA code and a cut-off energy of only 11 eV. We present formulas for calculating frequency- and dose-average stopping powers, numerical results for several important electron and photon sources, and tables with all the data needed to use our formulas for arbitrary electron and photon sources producing electrons with initial energies up to ~1 MeV. PMID- 29411714 TI - Effects of tissue processing on bioactivity of cartilage matrix-based hydrogels encapsulating osteoconductive particles. AB - In the treatment of severe traumatic brain injury (TBI), decompressive craniectomy is commonly used to remove a large portion of calvarial bone to allow unimpeded brain swelling. Hydrogels have the potential to revolutionize TBI treatment by permitting a single-surgical intervention, remaining pliable during brain swelling, and tuned to regenerate bone after swelling has subsided. With this motivation, our goal is to present a pliable material capable of regenerating calvarial bone across a critical size defect. We therefore proposed the use of a methacrylated solubilized decellularized cartilage (MeSDCC) hydrogel encapsulating synthetic osteogenic particles of hydroxyapatite nanofibers, bioglass microparticles, or added rat bone marrow-derived mesenchymal stem cells (rMSCs) for bone regeneration in critical-size rat calvarial defects. Fibrin hydrogels were employed as a control material for the study. MeSDCC hydrogels exhibited sufficient rheological performance for material placement before crosslinking ([Formula: see text] > 500 Pa), and sufficient compressive moduli post-crosslinking (E > 150 kPa). In vitro experiments suggested increased calcium deposition for cells seeded on the MeSDCC material; however, in vivo bone regeneration was minimal in both MeSDCC and fibrin groups, even with colloidal materials or added rMSCs. Minimal bone regeneration in the MeSDCC test groups may potentially be attributed to cartilage solubilization after decellularization, in which material signals may have degraded from enzymatic treatment. Looking to the future, an improvement in the bioactivity of the material will be crucial to the success of bone regeneration strategies for TBI treatment. PMID- 29411715 TI - Evaluation of fractioned nitric oxide in chronic cough patients. AB - INTRODUCTION: Cough exceeding 3-8 weeks was defined as chronic cough in various guides. Asthma is the most common cause of chronic-specific cough. Causes other than asthma include prolonged bacterial bronchitis and upper airway cough syndrome (UACS). Nitric oxide (NO) causes vascular smooth muscle relaxation, bronchodilation, and oxidant effects via its metabolite, peroxynitrite. An increase in NO results in inflammation, vasodilatation, and bronchial edema. MATERIALS AND METHODS: The study group included 90 patients aged 6-17 years selected from individuals presenting to the Pediatric Immunology and Allergic Diseases Clinic with cough persisting for 4 weeks and 30 other patients representing to the control group. Patients with a history of premature birth and long-term ventilatory support, neuromotor retardation, or chronic lung and heart disease received systemic corticosteroid therapy in the previous 4 weeks, a chest deformity, with any chronic disease or received immunotherapy were excluded from the study. RESULTS: The most common diagnosis among the 90 patients in this study was asthma, observed in 27 (30%). Fractional exhaled NO values were highest in the asthma group at 39.5 +/- 26.6 parts per billion (ppb) and lowest in the UACS group at 11.6 +/- 4.0 ppb. Values in the control group were 17.8 +/- 11.1 ppb. The differences between the groups were statistically significant (P < 0.001). CONCLUSION: Fractional exhaled NO measurement can be used as a quick and reliable diagnostic method in patients presenting with chronic cough due to its high positive predictive value, its practical nature, the fact that it is a noninvasive method and that it does not require the use of medication. PMID- 29411713 TI - Using biomaterials to modulate chemotactic signaling for central nervous system repair. AB - Chemotaxis enables cellular communication and movement within the body. This review focuses on exploiting chemotaxis as a tool for repair of the central nervous system (CNS) damaged from injury and/or degenerative diseases. Chemokines and factors alone may initiate repair following CNS injury/disease, but exogenous administration may enhance repair and promote regeneration. This review will discuss critical chemotactic molecules and factors that may promote neural regeneration. Additionally, this review highlights how biomaterials can impact the presentation and delivery of chemokines and growth factors to alter the regenerative response. PMID- 29411716 TI - Effect of color shading procedures and cyclic loading on the biaxial flexural strength of zirconia. AB - PURPOSE: Zirconia is the most preferred ceramic restoration in posterior areas because of its flexural strength. The aim of the study is the evaluation of biaxial flexural strength of different colored zirconium oxide core materials after cyclic loading. MATERIAL AND METHODS: Zirconia discs (12 mm diameter and 1.2 mm thickness) were divided into 6 groups of 12 discs each. Groups were colored according to the Vita Classic shade guide: A3 and D4. One group was not colored and left as control. Each group was randomly divided into subgroups and subjected to mechanical cycling prior to biaxial flexural strength test. Cyclic loading was applied as 50 N loads for 20,000 times for the loaded groups. Samples were subjected to biaxial flexural strength test in a universal testing machine with a crosshead speed of 1 mm/min. Two-way analysis of variance (ANOVA) and Tukey's HSD tests were used for comparisons of the groups. RESULTS: Biaxial flexural strength values did not vary significantly depending on coloring procedure or loading process tested (p>.05). XRD analysis displayed that the monoclinic volume fraction of zirconia was highest in cyclic loaded D4 and was lowest in non-loaded control group. The SEM image revealed that A3 color solution created metallic coloring pigments at grain boundaries. CONCLUSIONS: Coloring procedures and cyclic loading did not affect the biaxial flexural strength of zirconia core material; however, microstructural analysis displays changes, which may weaken the zirconia structure on the long term. PMID- 29411717 TI - Evaluation of two different rapid maxillary expansion surgical techniques and their effects on the malar complex based on 3d cone-beam computed tomography. AB - : We compared and evaluated the effects of two techniques used for surgically assisted rapid maxillary expansion (SARME) using three-dimensional (3D) cone-beam computed tomography, focusing on changes in soft and hard tissue in the malar region. A conventional Le Fort I osteotomy group (10 patients, mean age: 19.3 years) and a high Le Fort I group (12 patients, mean age: 20.4 years) underwent 3D analyses. Changes in hard and soft tissue of the malar region were compared. The average increases in the bone malar width and soft malar width in the high Le Fort I group between the pre- and postoperative periods were 1.43 +/- 1.23 and 1.39 +/- 1.19 mm, respectively. The average increases in the bone malar depth on the right and left sides in the high Le Fort I group were 1.34 +/- 0.81 and 1.60 +/- 0.54 mm, respectively. Progress in hard tissues did not reflect significant changes in soft tissue. CONTEXT: Effects of high Le Fort I SARME on the malar complex. AIMS: To compare and evaluate the effects of two techniques used for SARME, using 3D cone-beam computed tomography, focusing on changes in hard and soft tissues in the malar region. SETTINGS AND DESIGN: A conventional Le Fort I osteotomy group (10 patients, mean age: 19.3 years) and a high Le Fort I group (12 patients, mean age: 20.4 years). METHODS AND MATERIAL: Each group underwent 3D analyses, and changes in hard and soft tissues of the malar region were compared. STATISTICAL ANALYSIS USED: The SPSS software (ver. 15.0 for Windows) was used. The Kolmogorov-Smirnov test, Student's t test, and paired-samples test were conducted. RESULTS: The average increases in the bone malar width and soft malar width in the high Le Fort I group between the pre- and postoperative periods were 1.43 +/- 1.23 and 1.39 +/- 1.19 mm, respectively. The average increases in the bone malar depth on the right and left sides in the high Le Fort I group were 1.34 +/- 0.81 and 1.60 +/- 0.54 mm, respectively. CONCLUSIONS: Progress in hard tissues did not reflect significant changes in soft tissue. PMID- 29411718 TI - Glucose pump test can be used to measure blood flow rate of native arteriovenous fistula in chronic hemodialysis. AB - PURPOSE: In chronic hemodialysis patients, the low flow of vascular access may leads to inadequate dialysis, increased rate of hospitalization, morbidity, and mortality. It was found that surveillance should be performed for native arteriovenous (AV) should not be performed for AV graft in various studies. However, surveillance was done in graft AV fistulas in most studies. Doppler ultrasonography (US) was suggested for surveillance of AV fistulas by the last vascular access guideline of National Kidney Foundation Disease Outcomes Quality Initiative (NKF KDOQI). The aim of study is to determine whether glucose pump test (GPT) is used for surveillance of native AV fistulas by using Doppler US as reference. METHODS: In 93 chronic hemodialysis patients with native AV fistula, blood flow rates were measured by Doppler US and GPT. For GPT, glucose was infused to 16 mL/min by pump and was measured at basal before the infusion and 11 s after the start of the infusion by glucometer. Doppler US was done by an expert radiologist. Used statistical tests were Mann-Whitney U test, Friedman test, regression analysis, and multiple regression analysis. RESULTS: Median values of blood flow rates measured by GPT (707 mL/min) and by Doppler US (700 mL/min) were not different (Z = 0.414, P = 0.678). Results of GPT and Doppler US measurements were positive correlate by regression analysis. The mean GPT value of diabetic patients (n = 39; 908 mL/min) was similar to that of nondiabetic patients (n = 54; 751 mL/min; Z = 1.31, P = 0.188). GPT values measured at three different dialysis session did not differ from each other that by Friedman test (F = 0.92, P = 0.39). This showed that GPT was stable and reliable. CONCLUSIONS: Glucose pump test can be used to measure blood flow rate of native AV fistula. GPT is an accurate and reliable test. PMID- 29411719 TI - Gender differences and demographics and type of cardiac device over a 10-year period. AB - AIMS: This study aims to review the influence of gender-specific differences and patient demographics on cardiac device and pacing mode selection over a 10-year period. METHODS: We retrospectively reviewed patients who underwent first implantation of the cardiac device between January 1, 2006 and June 31, 2016. RESULTS: During the study period, 704 patients underwent first cardiac device implantation. Number of patients undergoing pacemaker was 452 and number of patients undergoing implantable cardioverter defibrillator/cardiac resynchronization therapy and defibrillator (ICD/CRT-D) was 252. Patients undergoing pacemaker were 49.9% female with mean age 72.36+11.1. The most common indication was atrioventricular block (AVB) (84%) in both genders. The most frequently used pacing modes were VVI (70.8%), but over a 10-year period pacemaker selection shifted from VVI to DDD pacemakers. Patients undergoing ICD/CRT-D were 19.7% female with mean age 62.5+10.8. The most common indications for ICD/CRT-D was ischemic cardiomyopathy (ICMP) (55.0%). The rate of male patients was higher in patients who have received device therapy for dilated cardiomyopathy (DCMP) or ICMP, whereas the rate of female patients was higher in hypertrophic cardiomyopathy (HCMP) patients. The most common used implanted system was VVI-ICD (60.6%). CONCLUSIONS: The present study demonstrated that there was no significant difference between female and male patients in pacing mode selection, mostly VVI pacing mode was chosen; however, over a 10-year period pacemaker selection shifted from VVI to DDD pacemakers. Female patients had less ICD/CRT-D implantation than male patients. PMID- 29411720 TI - Evaluation of Candida Albicans biofilm formation on various parts of implant material surfaces. AB - AIMS: Candida albicans adhesion to any oral substrata is the first and essential stage in forming a pathogenic fungal biofilm. In general, yeast cells have remarkable potential to adhere to host surfaces, such as teeth or mucosa, and to artificial, non-biological surfaces, such as dental materials. C. albicans adhesion to denture materials is widely recognized as the main reason for the development of stomatitis. This study compared the susceptibility of different parts of the implant system with C. albicans adhesion. MATERIAL AND METHODS: Each material maintained contact with C. albicans suspension, and biofilm formations around the implant materials were evaluated. To evaluate the biofilm formation, the XTT technique and scanning electron microscopy (SEM) were used. RESULTS: In general, a fine biofilm layer of C. albicans species was found on the surface of all examined materials. However, when examining the SEM images, candidal growth was significantly lower on the surfaces of the gingival former, abutment, and machined surface implant samples. According to the colorimetric assay (XTT), the gingival former samples revealed the lowest quantity of biofilms formed (median XTT value, 0.0891) (P < 0.001). The abutment and machined surface implant samples had low XTT values with similar values. The highest median colorimetric XTT values (0.1741), significantly higher than those of the other materials (P < 0.001), were for the bone level implant samples. CONCLUSIONS: This finding emphasizes implant treatment would be chosen complacency in patients who are prone to oral candidosis, medically compromised patients under immunosuppression, and patients with tumor who are being treated with chemotherapy or radiation. PMID- 29411721 TI - Effect of a galactagogue herbal tea on breast milk production and prolactin secretion by mothers of preterm babies. AB - BACKGROUND AND OBJECTIVES: Poor breast milk production is the most frequent cause of breastfeeding failure in preterm babies. The aim of our study is to evaluate the effect of herbal tea mixture containing stinging nettle (Natal, Hipp) on breast milk production and serum prolactin levels of mothers, and weight gain of preterm babies. MATERIALS AND METHODS: We enrolled mothers and their babies who were less than 37 gestational week and less than 2000 g, fed with orogastric tube without any contraindication of enteral feeding in neonatal intensive care unit between November 2010 and June 2011. The mothers of treatment group (n = 32) were consuming commercially available herbal mixture tea for 1 week. The mothers control group (n = 21) received only the same advice on supportive measures as group I. Mothers in the placebo group (n = 32) were given fruit tea for 1 week. The daily breast milk production of mothers and weight gain of preterm babies were recorded. Also, serum prolactin levels of the mothers were measured. RESULTS: Increase of the milk production from the first to the seventh day was more prominent in mothers using herbal tea mixture. Increased rate in the amount of milk was 80% in the treatment, 34.3% in the placebo and 30% in the control group (P = 0.000). There was no statistically significant difference in weight gain of babies between the two groups, due to formula feeding in case of insufficient breast milk. Serum prolactin levels of the mothers at the beginning and on the seventh day showed no significant difference. CONCLUSIONS: In mothers with premature babies and who are treated in neonatal intensive care unit, consumption of galactogogue herbal tea will increase lactation and prevent lack of human milk without any adverse effect. PMID- 29411722 TI - Gabapentin pretreatment for propofol and rocuronium injection pain: A randomized, double-blind, placebo-controlled study. AB - AIM: This prospectively-planned, randomized, double-blind and placebo-controlled study aims to evaluate the effect of 1200 mg gabapentin premedication on the incidence and severity of propofol and rocuronium injection pain. METHOD: One hundred patients, between 18-60 years of age and ASA I-II for elective surgery planned under general anaesthetic, were randomized and divided into two groups. Two hours before the operation, the patients were given either a placebo tablet (Group P, n = 50) or 1200 mg gabapentin tablet (Group G, n = 50). On the back of the non-dominant hand, a vein was opened using a 20 G cannula , 0.9% NaCl was begun and preoxygenation was provided. For anaesthesia induction, 1% propofol at 800 ml/hr infusion rate was administered for 20 s. Propofol injection pain was evaluated up to the 20th second and recorded using a scale between 0 and 3 developed by McCrirrick and HunteR The remaining propofol dose (2.5 mg/kg), 5 ml saline and 0.6 mg/kg rocuronium were injected in that order over 10 seconds and rocuronium injection pain response was evaluated with a four point scale. RESULTS: Pain after propofol infusion average score (degree >= 1) (Group G = 0.5; Group P = 1.0) and incidence (Group G = 46%; Group P = 68%); and average withdrawal movements response score linked to rocuronium injection pain (>= 1 response) (Group G = 0.3; Group P = 1.2) and incidence (Group G = 20%; Group P = 80%) were detected to be significantly lower in the gabapentin group compared to the placebo group (p < 0.001). CONCLUSION: Premedication with 1200 mg gabapentin 2 hours before propofol and rocuronium injection reduced the incidence and severity of injection pain. PMID- 29411723 TI - Diagnostic role of neutrophil-lymphocyte ratio in oral cavity cancers. AB - AIM: In this study, we aimed to evaluate the diagnostic role of neutrophil lymphocyte ratio (NLR) and other hemogram parameters in differentiating nonmalignant oral cavity lesions from oral cavity cancers. METHODS: Ninety-five patients who were performed oral cavity biopsy between the years 2013 and 2015 were retrospectively reviewed. The control group comprised consecutive 70 patients who underwent septoplasty/septorhinoplasty procedures. Inclusion criteria were to be available with common blood count (CBC) just prior to procedure. The hemogram parameters including NLR were compared between the groups. RESULTS: Lymphocyte count and mean platelet volume (MPV) were found to be significantly decreased in oral cavity squamous cell carcinoma (SCC) and in other oral cavity cancers (OCCs) compared with benign oral cavity lesions and control group. In contrast, NLR revealed significantly higher in OCCs and in oral SCC compared with nonmalignant oral cavity lesions and control group. The receiver operating characteristics curve analysis suggested cutoff value of 2.88 for NLR in predicting malignancy [area under curve (AUC) 0.756, sensitivity 51%, specificity 88%]. CONCLUSIONS: NLR was first shown to be significantly elevated in oral cavity cancers and in oral cavity SCC in this study. In our opinion, NLR may be helpful in identifying the oral cavity lesions at high risk for harboring malignancy. PMID- 29411725 TI - Vascular endothelial growth factor in pleural effusions and correlation with radiologic and biochemical parameters. AB - INTRODUCTION: Pleural effusion is a common clinical problem with management difficulties. The aim of this study is to evaluate vascular endothelial growth factor (VEGF) in differential diagnosis of pleural effusions and the presence of correlation between radiological features and biochemical properties. MATERIALS AND METHODS: The study included patients with pleural effusion. VEGF levels in the pleural fluid were measured by enzyme-linked immunosorbent assay. RESULTS: A total of 97 patients who had exudative pleural effusion related to lung cancer (n = 17), nonpulmonary malignancies (n = 25), mesothelioma (n = 9), pneumonia (n = 14), tuberculosis (n = 8), miscellaneous causes (n = 6), and transudative effusion (n = 18) were included. Pleural VEGF levels were higher in exudative effusions with respect to transudative effusions (P < 0.001) and in effusions related to malignancies versus benign causes (P < 0.001). Pleural VEGF was inversely correlated with pleural fluid glucose and pH levels and had positive correlation with lactate dehydrogenase, protein levels (P < 0.001), hematocrit, and eosinophil values in the pleura (P < 0.05). Pleural VEGF levels were also higher in patients with massive effusions and pleural thickening (both P < 0.001). CONCLUSIONS: The overlap of pleural VEGF levels between the groups may limit the value of VEGF in discriminating between malignant versus benign and exudative versus transudative effusions; however, it may be a useful adjunct to various methods. The VEGF levels in pleural fluid seem to be related to the degree of inflammation and pleural invasion. PMID- 29411724 TI - A Prospective, randomized study comparing 7-day and 14-day quadruple therapies as first-line treatments for helicobacter pylori infection in patients with functional dyspepsia. AB - OBJECTIVE: Standard triple therapy for Helicobacter pylori has a low eradication rate in Turkey. The aim of this study was to evaluate and compare the effectiveness of 7-day and 14-day lansoprazole, amoxicillin, clarithromycin, and bismuth subsalicylate (LACB) treatment regimens as first-line H. pylori eradication therapies. MATERIALS AND METHODS: This study included 70 patients with symptoms of dyspepsia and a positive H. pylori stool antigen test (SAT). Thirty-five patients received the modified quadruple therapy regimen for 7 days (LACB-7) whereas the remaining 35 patients received the treatment for 14 days (LACB-14). Eradication was assessed by SAT 1 month after the end of therapy. RESULTS: A total of 64 patients completed the therapy. The cumulative per protocol (PP) and intention-to-treat (ITT) eradication rates were 89% (n = 57/64) and 81.4% (n = 57/70), respectively. Both the PP and ITT eradication rates were superior in the LACB-14 group, compared with the LACB-7 group (PP: 90.6% vs. 87.5%; ITT: 81.4% vs. 80%, respectively), but these differences were not statistically significant (P = 0.689). CONCLUSIONS: Both the 7-day and 14-day first-line LACB therapies provided a high cure rate, were well tolerated, and were equally effective against H. pylori infection in Turkey. PMID- 29411726 TI - Association between the oxidative status, Vitamin D levels and respiratory function in asthmatic children. AB - AIM: We studied the relationship between plasma concentrations of oxidative system markers, vitamin D, and respiratory functions in children with asthma. MATERIALS AND METHODS: Ninety one children aged 6-17 years with stable asthma seen in the clinic had the serum concentrations of oxidative system markers [total antioxidant capacity (TAC), total oxidative status (TOS), paraoxonase-1 activity (PON-1), and 25-hydroxyvitamin D3] and respiratory functions were measured. RESULTS: There was no statistical correlation between TAC and age and FEV1. There was a significant positive correlation between TAC and 25(OH)D3 (r = 0.214, P = 0.021), TAC and TOS (r = 0.218, P = 0.007), TAC and PON-1 (r = 0.230, P = 0.028), TAC and IgE (r = 0.194, P = 0.033), and inverse correlation between TAC and PEF (r = -0.208, P = 0.024). In the backward multiple regression analysis, 25(OH)D3 (t = 2.613, P = 0.011), age (t = -2.158, P = 0.034), TOS (t = 2.158, P = 0.000), and OSI index (t = -13.859 P = 0.000) maintained an independent relationship with TAC (r = 0.858, r2 = 0.737, F = 21.436, P = 0.000). CONCLUSION: Oxidative stress correlates with the serum vitamin D concentrations. Clinical trials are required to confirm that increasing serum 25OHD may improve asthma control, as measured by clinical and oxidative stress markers. PMID- 29411727 TI - Effect of titanium-prepared platelet-rich fibrin treatment on the angiogenic biomarkers in gingival crevicular fluid in infrabony defects of patients with chronic periodontitis: A randomized controlled clinical trial. AB - AIM: The aim of this double-blinded, randomized, controlled clinical study was to investigate the effect of titanium-prepared platelet-rich fibrin (T-PRF) treatment on the angiogenic biomarkers in gingival crevicular fluid (GCF) in infrabony defects of patients with chronic periodontitis. MATERIALS AND METHODS: Twenty five systemically healthy participants who complied with inclusion criteria with periodontal infrabony defects were recruited. In each patient, the infrabony defect of one side of arch was designated as control group (allograft), whereas the infrabony defect on the contralateral side of same arch was designated as test group (allograft + T-PRF). The therapy methods (test or control) were randomly decided. GCF samples were collected at baseline (presurgery) and then the 3rd, 7th, 14th, and 30th days after surgery. Platelet derived growth factor (PDGF)-BB, vascular endothelial growth factor (VEGF)-A, fibroblast growth factor (FGF)-2, anjiogenin (ANG), angiostatin (ANT) in the GCF samples were measured using human enzyme-linked immunosorbent assay kits. RESULTS: In both groups, total amounts of PDGF-BB, VEGF-A, FGF-2, ANG, and ANT peaked in the GCF samples obtained at the early postoperative day (day 3) and decreased over time in the samples obtained at the 7th, 14th, and 30th days postsurgery. There were no significant differences between groups for the total amounts of PDGF-BB, VEGF-A, FGF-2, ANG, and ANT at all evaluation periods. CONCLUSION: Application of T-PRF combined with allograft in infrabony defects of patients with chronic periodontitis had no significant effects on angiogenic biomarkers in GCF. PMID- 29411728 TI - A comparative scanning electron microscopy evaluation of smear layer removal with chitosan and MTAD. AB - : The aim of the present study was to compare the efficacy of chitosan and MTAD for the smear layer removal from the root canal through a scanning electron microscope (SEM). Thirty teeth were randomly divided into three groups according to the final irrigants: 0.2% chitosan, MTAD, saline (control group). After the mechanical preparation, the samples were irrigated with saline (control group), 0.2% chitosan and MTDA respectively. Then, the samples were split and the smear layer at the apical, middle, and coronal thirds of each root canal was imaged using SEM. The statistical analysis was performed using the Kruskal-Wallis test and the Mann-Whitney U test (alpha = 5%). The difference between chitosan and MTDA was statistically significant in the apical region (p < 0.05), no significant difference was obtained in the coronal and middle regions in these two experiment groups (p > 0.05). The control group exhibited the lowest efficacy in smear layer removal in all regions. Thus, from the result of the present study, we may conclude that chitosan was more effective in smear layer removal than MTAD especially in the apical third. CONTEXT: Irrigation, which serves a variety of purposes including antibacterial action, tissue dissolution, cleaning and chelating, plays a centric role in the final success of root canal treatment. Thus, more and more attention has been put on the improvement and development of various irrigation techniques or systems. AIMS: The aim of the present study was to compare the efficacy of chitosan and MTAD for the smear layer removal from the root canal through scanning electron microscopy (SEM). SETTINGS AND DESIGN: Thirty single-canal premolars were instrumented with rotary-files and then, randomly assigned to test groups which were irrigated with chitosan and MTDA, and control group was treated with saline. Thereafter, the efficacy of smear layer removal was evaluated by SEM. MATERIALS AND METHODS: Thirty teeth were randomly divided into three groups according to the final irrigants: 0.2% chitosan, MTAD, saline (control group). After the mechanical preparation, the samples were irrigated with saline (control group), 0.2% chitosan and MTDA respectively. Then, the samples were split and the smear layer at the apical, middle, and coronal thirds of each root canal was imaged using SEM. STATISTICAL ANALYSIS USED: Kruskal-Walli test and Mann-Whitney U test Results: The difference between chitosan and MTDA was statistically significant in the apical regions (p < 0.05), no significant difference was obtained in the coronal and middle regions in these two experiment groups (p > 0.05). The control group exhibited the lowest efficacy in smear layer removal in all regions. CONCLUSION: Thus, from the result of present study, we may conclude that chitosan was more effective in smear layer removal than MTAD, especially in the apical third. PMID- 29411729 TI - Fecal carriage of extended-spectrum beta-lactamase and ampc beta-lactamase producing enterobacteriaceae in a turkish community. AB - BACKGROUND: Community-acquired infection caused by extended-spectrum beta lactamase (ESBL)-producing microorganisms has an increasing frequency. AIM: The aim of this study was to determine the fecal carriage of ESBL and AmpC beta lactamase-producing Enterobacteriaceae in community and to investigate cefotaxime M (CTX-M) genes among ESBL isolates. MATERIALS AND METHODS: A total of 1402 fecal specimens which were collected from outpatients included in the study. ESBL screening, ESBL production, and AmpC beta-lactamase detection were performed. Matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) was used for identification of species. Antibiotic susceptibilities of the isolates were detected by disk diffusion method. CTX-M beta-lactamase genes were investigated by polymerase chain reaction. RESULTS: During the study period, a total of 1402 fecal samples were analysed with ESBL screening test and 490 Enterobacteriaceae strains isolated from these samples (Escherichia coli [n = 461, 94.1%], Klebsiella pneumoniae [n = 25, 5.1%], and Enterobacter cloacae [n = 4, 0.8%]). Fecal carriage of ESBL-producing Enterobacteriaceae in the community was 34.3%. AmpC beta-lactamases were detected in 26 (5.3%), and the frequency of CTX-M was found as 96.9%. The resistance rates of the E. coli strains to fluoroquinolones, trimethoprim-sulfamethoxazole, and carbapenems were 31.2%, 33.3%, and 0%, respectively. CONCLUSION: The relative high prevalence of fecal carriage of ESBL producing bacteria in community warrants further study in this field including developing policies about antimicrobial use and close monitoring of resistance patterns. PMID- 29411730 TI - Where we are in the fight against Hepatitis B Infection; Trends in Hepatitis B virus seroprevalence in Black Sea Region of Turkey. AB - CONTEXT: To determine new strategies for complete coverage of hepatitis B virus (HBV) vaccination, every country needs to take into concern factors of infection transmission in its own region. AIMS: The aim of this study was to investigate the seroprevalence of hepatitis B among all age groups in northern Turkey using HBsAg and anti-HBs serological markers. MATERIALS AND METHODS: The laboratory records of a total of 101648 patients of all ages attending a tertiary level hospital in Samsun, a Black Sea coastal city, between January 2014 and May 2016 were evaluated retrospectively. RESULTS: HBsAg and anti-HBs seropositivity was found to be 4% and 38.3%, respectively. There was a significant difference between HBsAg (chi2 = 209.08; P = 0.00), anti-HBs (chi2 = 124.12; P = 0.00) seropositivity, and immunization status. Although we found a statically difference between men and women (chi2 = 32.2 P = 0.00) for HBsAg seropositivity, there was no significant difference for anti-HBs (P = 0.22). In 1998, the universal infant immunization program changed the HBV epidemiology in Turkey, and resulted in an apparent trend towards reduced disease levels. However, prevalence of HBV infection is still high in adolescent and young adults. CONCLUSIONS: Therefore, a catch-up immunization program, education, and follow-up policy for these groups, in addition to routine infant immunization, will decrease the HBV infection rate, reducing morbidity and mortality rates, and will help to reduce hepatitis B transmission in Turkey. PMID- 29411731 TI - Bonding strength of universal adhesives to Er,Cr:YSGG Laser-Irradiated Dentin. AB - OBJECTIVES: Universal adhesives have been recently introduced for use as self etch or etch-and-rinse adhesives depending on the dental substrate and clinical condition. However, their bonding effectiveness to laser-irradiated dentin is still not well known. Therefore, the aim of this study was to compare the shear bond strength (SBS) of two universal adhesives (Single Bond Universal, Nova Compo B Plus) applied following laser-etching with SBS of the same adhesives applied in self-etch and acid-etch modes, respectively. MATERIALS AND METHODS: Sixty bovine incisors were used to obtain the flattened dentin surfaces. Specimens were divided into two groups according to universal adhesives. Each universal adhesive was applied with one of the following modes, self-etch, acid-etch, or laser-etch (n = 10). Er,Cr:YSGG laser was used for laser-etching with 1.5 W-20 Hz parameters. After adhesive applications and composite buildups, SBS was determined after storage in water for 24 h using a universal testing machine with a crosshead speed of 0.5 mm/min. Failure modes were evaluated using a stereomicroscope. Data were analyzed using two-way of analyses of variances (ANOVA) (P = 0.05). RESULTS: Two-way ANOVA revealed that adhesive had no effect on SBS (P > 0.05), but application mode significantly influenced SBS (P < 0.001). Laser-etch significantly increased SBS for NCP when compared to self-etch mode, whereas laser-etch provided similar SBS with self-etch mode for SBU. CONCLUSIONS: The influence of different application modes on dentin bond strength of universal adhesives was dependent on the adhesive material. CLINICAL SIGNIFICANCE: For universal adhesives, laser etching may provide some benefits on bonds strength but this would depend on product. PMID- 29411732 TI - Street drug use among emergency patients in a Public Hospital in Turkey. AB - BACKGROUND: Country-specific numbers of street drug (SD) users are well documented. However, little data exists regarding these patients' clinical presentations and outcomes in the emergency department (ED). Therefore, management of these patients in the emergency setting is still a subject of debate. OBJECTIVES: The aim of this study is to determine the symptoms and signs of SD users presenting to the ED, and to report the substances, treatments, and outcomes. MATERIALS AND METHODS: In this single-center study, symptoms, clinical findings, diagnoses, and outcomes of patients who reported to have used SDs or were diagnosed as SD users were investigated within a 1-year study period. Chi square and Mann-Whitney U tests were performed to compare independent variables. RESULTS: Mean age of the 425 study patients was 25 +/- 9 years (range: 12-64 years), and 6.1% (n = 26) of the patients were females. SDs used before presentation to the ED were mostly synthetic cannabinoids and "ecstasy." Overall prevalence of SD user admissions in ED was 0.24%. The most common presenting complaint was weakness/faintness in 21.1% (n = 90). Depressed level of consciousness was the most common physical sign (33.3%, n = 142). Incidences of altered mental status were significantly higher among ecstasy and/or bonsai users (n = 14, 27.5%; P = 0.027 and n = 46, 64.8%; P < 0.001, respectively), compared to other SD users. While 23.1% (n = 98) of the SD users did not warrant any medical intervention, 6.6% of the users (n = 28) underwent advanced life support. CONCLUSIONS: Self-reported SD users were mostly young males who were treated symptomatically and discharged. Almost one-third-mostly ecstasy and bonsai users had depressed level of consciousness and required resuscitation. PMID- 29411733 TI - Preoperative platelettolymphocyte ratio as a prognostic factor in geriatric patients with proximal femoral fractures. AB - INTRODUCTION: The aim of this study was to investigate whether the platelet to lymphocyte ratio is a prognostic factor in geriatric patients who underwent surgery for proximal femoral fractures. MATERIALS AND METHODS: Clinical and laboratory data of 288 patients who underwent surgery for proximal femoral fracture were analysed. The patients were divided into six groups on the basis of sex (male and female) and survival duration after the operation (death within the first 6 months, death between the 6 and 12 months, survival for more than 12 months). Pre-operative platelet/lymphocyte ratios of these groups were compared. RESULTS: Of 288 patients, 187 were female and 101 were male. There was no significant difference between the groups with regard to age (p = 0.123 female groups) (p = 0.207 male groups). Although the preoperative platelet to lymphocyte ratio was higher in patients who died within 12 months than in those who survived beyond that, this platelet/lymphocyte ratio was statistically significant in females who died in the first 6 months (p = 0.038). CONCLUSION: A high preoperative platelet to lymphocyte ratio may be associated with high risk of mortality in patients who were operated for proximal femoral fracture. PMID- 29411734 TI - Giant pericardial cyst with a growing feature. AB - Pericardial cysts are rare and benign lesions of the heart. They are usually asymptomatic and diagnosed incidentally on echocardiography or chest X-ray. In this report, we present an extremely rare case of a symptomatic giant pericardial cyst (11.6 cm * 10.6 cm * 8 cm) of a 55-year-old male patient who was admitted to our cardiology clinic. A thoracic computed tomography (CT) in 2013 revealed a giant pericardial cyst. However, at that time, the patient was asymptomatic and follow-up was recommended. Recent thoracic CT and magnetic resonance imaging demonstrated a significantly growing feature of this cyst with impending possible complications. PMID- 29411735 TI - The importance of early diagnosis of gardner's syndrome in dental examination. AB - Gardner syndrome (GS) is a rare genetic disorder. Dentists play an important role in diagnosis considering that craniomaxillofacial osteomas are a major criteria for GS. We report a 26-year-old male patient who referred to our department with toothache. On routine panoramic radiographic examination, multiple radiopaque masses were detected incidentally. In addition, on extraoral examination, a soft tissue tumor was detected on his shoulder. The patient was referred to the gastroenterology department and intestinal polyps were detected in the colon. Histopathology report revealed malignant changes in the intestinal polyps. Early colectomy, which is a life-saving operation, was possible because of our early diagnosis. PMID- 29411736 TI - Depression and posttraumatic stress disorder among road traffic accident victims managed in a tertiary hospital in Southern Nigeria: The methodological issue. PMID- 29411737 TI - Chlorhexidine-induced anaphylaxis occurring in the workplace in a health-care worker: case report and review of the literature. AB - BACKGROUND: Chlorhexidine has been widely used in the occupational field as an effective antiseptic and disinfectant, especially in the health-care services. Several cases of allergic reactions to chlorhexidine have been reported, both in the general population and in workers. OBJECTIVES: To describe a case of occupational chlorhexidine-induced severe anaphylaxis that occurred in the workplace in a health-care worker (HCW) and to update the literature on chlorhexidine as a possible occupational allergen. METHODS: We report a case of a severe anaphylactic reaction that occurred in the workplace in a 63-year-old man, who had worked as a dentist for over 20 years. We also carried out a systematic review of the literature according to the PRISMA guidelines. No time or language filters were applied. Only occupational case-reports and case-series were included. RESULTS: The causative role of chlorhexidine was suspected owing to the presence of chlorhexidine-containing products in the workplace. Positive results on the Basophil Activation Test confirmed the diagnosis of immediate chlorhexidine-induced hypersensitivity reaction and excluded a role of other disinfectants. No other causes of anaphylaxis were suspected. Our systematic literature review identified 14 cases of occupational chlorhexidine-induced allergy among HCWs; in these cases, the clinical presentation was mild and the symptoms resolved. No cases of systemic reactions in the workplace were reported. CONCLUSIONS: This is the first report of chlorhexidine-induced severe anaphylaxis occurring in the workplace. This case report underlines the importance of investigating and being aware of individual and environmental risk factors in the occupational field, which can cause, albeit infrequently, severe reactions with serious consequences. PMID- 29411739 TI - [Pathogenetic aspects of the development of acute focal cerebral ischemia]. AB - Current concepts on the main mechanisms of brain damage in ischemic stroke are considered. Chemical regulation of physiological and pathological processes of maintaining cellular pool is supported by a multistep system that included compounds of different structure and complexity. A complex assessment and comparison of the processes taking place during the development of acute local cerebral ischemia (necrosis, apoptosis, autoimmune inflammatory reaction, neuroplasticity) can help in the objectification and prognosis of individual characteristics of the course and outcome of ischemic stroke. Understanding of the cascade of events that occur during the acute ischemic damage is critical for determining current and future diagnostic and therapeutic approaches. PMID- 29411738 TI - Surgical Management of Distal Biceps Tendon Anatomical Reinsertion Complications: Iatrogenic Posterior Interosseous Nerve Palsy. AB - BACKGROUND Although iatrogenic posterior interosseous nerve (PIN) palsy is an uncommon complication of ruptured distal biceps brachii tendon surgical anatomical reinsertion, it is the most severe complication leading to functional limitation. The present study investigated possible types of PIN palsy as a postoperative complication of anatomical distal biceps tendon reinsertion, and aimed to clinically assess patients at 2 years after its surgical treatment. MATERIAL AND METHODS The studied sample comprised 7 male patients diagnosed with an iatrogenic PIN palsies after anatomical reinsertion of the distal biceps tendon, who were referred to the reference center for management of a peripheral nervous system injury. The nerve injury was intraoperatively evaluated. The clinical assessment used the Medical Research Council (MRC) System for motor recovery, and the Quick Disability of the Arm, Shoulder, and Hand (Quick DASH) was performed before the surgical treatment of the PIN injuries and at 2 years postoperatively. In all studied cases, electromyography was performed preoperatively and postoperatively. RESULTS The comparison of the preoperative (x=1.43+/-0.53) and postoperative (x=4.71+/-0.49) results of the motor recovery of the PIN demonstrated a statistically significant improvement (p<0.001). Moreover, the results of functional assessments with the use of the Quick DASH questionnaire significantly improved (p<0.001) postoperatively (x=6.14+/-6.86) compared to the preoperative evaluations (x=54.29+/-12.05). CONCLUSIONS The PIN palsies as complications of the surgical anatomical reinsertion of ruptured distal biceps brachii resulted from mechanical nerve compression or direct intraoperative damage. The 2-year outcomes justified the clinical use of surgical management for iatrogenic PIN palsy. PMID- 29411740 TI - [Complex assessment of the contribution of genetic factors to the risk of ischemic stroke]. AB - AIM: To develop a method of the complex assessment of genetic risk for ischemic stroke (IS) and evaluate its effectiveness. MATERIAL AND METHODS: Genotyping of 182 patients with atherothrombotic and cardioembolic subtypes of IS and 360 healthy individuals of 48 single nucleotide polymorphic loci (SNP) associated with the risk of II and its subtypes was performed. RESULTS AND CONCLUSION: In each group of SNPs, composite indicators of genetic risk of IS in groups of patients and healthy controls were identified. Differences between the calculated values of the genetic risk in these groups were significant (p <0,05). The quality of the binary classification validated by ROC-analysis confirmed the predictive potential of the proposed method of risk calculation for determining the genetic predisposition to the development of IS. PMID- 29411741 TI - [The role of pre-stroke cognitive disorders in the formation of post-stroke cognitive impairment]. AB - AIM: To identify pre-stroke cognitive disorders and assess their influence on the post-stroke neuropsychological status of the patient. MATERIAL AND METHODS: The study included 103 patients in an acute state of ischemic stroke in the carotid system. Cognitive functions were assessed with MoCA and IQCODE. All patients are evaluated for the presence of vascular risk factors and their relationship to the cognitive impairment. RESULTS AND CONCLUSION: According to the MoCA, 89 (86.4%) patients in the acute state of ischemic stroke had cognitive impairment of varying severity. Out of 103 patients, 55 (53.4%) had cognitive impairment prior to onset of stoke, mostly of mild severity. Among the main risk factors that correlated with the presence of pre-stroke cognitive impairment were age, heart rhythm disturbances and heart failure. PMID- 29411742 TI - [Indicators of homeostasis, inflammation and homocysteine in ischemic stroke in the young age]. AB - AIM: To determine indicators of homeostasis, inflammation and homocysteine in the young-aged patients with ischemic stroke (IS) of different genesis in the subacute and chronic stages. MATERIAL AND METHODS: Out of 218 patients with IS (mean age 34.7+/-8.7 years), 55 had stroke due to dissection of the inner carotid or the spinal artery, 28 due to cardioembolia, 38 due to antiphospholipid syndrome (APS), 16 due to cerebral arteritis; 85 patients were classified as having cryptogenic stroke, including 23 with noncerebral thrombosis (coagulopathy of unknown etiology) and 62 with no thrombosis. The control group included 28 healthy people matched for age and sex. RESULTS: There were 1) an increase in von Willebrand factor and coagulation factor VIII as well as a decrease in plasminogen and an increase in plasmin-inhibitor in IS caused by thrombosis (APS, cardioembolia, coagulopathy of unknown etiology); 2) alterations in erythrocyte aggregation and deformity in cryptogenic stroke; 3) mild or moderate hyperhomocysteinemia, with the exception of patients with APS and arteritis. Linear regression analysis confirmed these relationships. Discriminant analysis identified the clusters of parameters characteristic of APS (an increase in (aPTT), plasminogen, blood sedimentation rate, C-reactive protein) and cardioembolia (decreased protein C and increased hematocrit). CONCLUSION: The laboratory markers associated with cerebral thrombosis can be used for identification of a prothrombotic state as a cause of IS in the young age. Moderate hyperhomocysteinemia is a risk factor but not a cause of IS. The increase of inflammatory markers in APS suggests a role of infection in its development. PMID- 29411743 TI - [Prognostic significance of indices of platelets aggregation and interleukin 1beta in the acute period of ischemic stroke]. AB - AIM: To determine the prognostic significance of indices of platelet aggregation (PA) and the level of interleukin IL-1beta in the outcome of ischemic stroke (IS). MATERIAL AND METHODS: One hundred and eight patients were studied. According to disease outcome, two groups of patients were identified: survivors (group 1) and patients with fatal outcome (group 2). Patients were examined in the very early stage (the 1st day of hospitalization) and in the early stage (the 7th day of hospitalization) of IS. The level of interleukin IL-1beta in blood serum was defined by enzyme immunoassay method. PA was measured by nephelometric method. RESULTS AND CONCLUSION: According to PA indices, a posteriori prognosis of fatal outcome was 10%, but according to IL-1beta indices, it was 0.90%. Consequently, the prognostic significance of PA indices with regard to fatal outcome of IS patients in the acute period is higher than that of IL-1b indices. Taking into consideration the expenses of both methods of diagnosis, the authors conclude that with regard to economic availability, PA measurement as a prognostic-diagnostic method is more acceptable in clinical practice. PMID- 29411744 TI - [The experimental strategies in the study of ischemic stroke]. AB - Literature data and own experience in the studies of experimental stroke methodology are reviewed. Advantages and disadvantages of the common models of focal ischemia used in the laboratory practice are discussed in details. The advantages of the filament occlusion of the middle cerebral artery in rats as the most adequate model of human stroke are substantiated. The authors suggest a modification of this variant using an additional coagulation of the pterygopalatine artery that allows the exclusion of the retrograde and collateral blood flow into the inner carotid artery after ligation of the common and external carotid arteries. PMID- 29411745 TI - [Preclinical studies of drugs on animal stroke models]. AB - Preclinical studies are studies using experimental models of stroke in animals as well as on neurons, cell neuronal cultures and surviving brain slices. They directed both towards testing the efficacy and evaluation of the mechanisms of action of drugs, and the study of the mechanisms of ischemic damage to search for new targets for stroke treatment. This article shows the basic principles of the organization and planning of animal models of ischemic stroke. Modeling of cerebral ischemia on the different models and animal species, the modern principles of assessment of brain damage are considered as well. PMID- 29411746 TI - [Cerebroprotective activity of metformin, gosogliptin, citicoline and a novel GPR119 agonist in cerebral ischemia under experimental diabetes mellitus]. AB - : Hypoglycemic agents of some groups: sodium-glucose cotransporter type 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists reduce the risk and/or severity of cardiovascular diseases. Studies of such properties are currently focused on metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors. Agonists of GPR119 receptor, increasing the secretion of GLP-1 and insulin, are also actively studied as hypoglycemic drugs with endothelial and cerebroprotective potential. AIM: To evaluate the cerebroprotective activity of metformin, gosogliptin, citicoline and an agonist of GPR119 (ZB-16) in middle cerebral artery occlusion (MCAO) in animals with 4-week streptozotocin nicotinamide-induced diabetes. MATERIAL AND METHODS: A study included 73 male rats. Hypoglycemic agents and ZB-16 were administered on the first day of diabetes and citicoline was administered after MCAO. Cerebroprotective effect was evaluated using Garcia, Combs and D'Alecy score test, 'Rotarod' and 'open field' test, as well as the infarct volume and severity of brain edema measurement. RESULTS AND CONCLUSION: Preventive administration of metformin resulted in the pronounced hypoglycemic activity without a significant cerebroprotective effect in subsequent brain ischemia modelling. Administration of substances with incretin activity (gosogliptin and, in particular, ZB-16) in addition to the hypoglycemic action promoted a significant reduction of infarct volume, brain edema and severity of neurologic deficit of the surviving animals. At the same time, the introduction of citicoline without proper glycemic control didn't reduce the brain ischemia severity. PMID- 29411747 TI - [A neuroprotective action of carnosine in conditions of experimental focal cerebral ischemia-reperfusion]. AB - AIM: To assess neuroprotective properties of preventive injections of carnosine in experimental focal cerebral ischemia in rats. MATERIAL AND METHODS: A focal ischemia in Wistar rats induced by the 60 min-occlusion of the middle cerebral artery with the following 24h-reperfusion was used. Animals received carnosine mixed with ration in daily dose of 150 mg/kg of body mass during 7 days before surgery. RESULTS AND CONCLUSION: Carnosine decreased the size of the lesion by 20%, neurological deficit by 43% with a simultaneous increase in the antioxidant status of blood plasma and brain tissue compared to the animals of the control group. The authors showed for the first time the neuroprotective effect of low dose of carnosine (150 mg/kg of body mass) mixed with ration used in preventive treatment courses in the experimental focal cerebral ischemia-reperfusion model. PMID- 29411748 TI - [A study of the efficacy and safety of L-carnitine in patients with ischemic stroke in the early rehabilitation period]. AB - AIM: To evaluate the efficacy and safety of L-carnitine injections in patients with ischemic stroke (IS) in the rehabilitation period. MATERIAL AND METHODS: Sixty patients in the early rehabilitation period of IS were stratified into two groups. Patients of group 1 received elcar, the 100 mg/ml solution for intravenous and intramuscular injection, in dose of 500 mg intramuscular 2 times a day during 7 days, with the second course after 10 days, in the complex treatment of the 2nd stage of poststroke rehabilitation. Patients of group 2 received conventional therapy. Treatment efficacy was assessed at end points: 1st visit (the 1 st day of treatment), 2nd visit (the 7-10th day), 3rd visit (28-30th day).The following scales were used: NIHSS, the Barthel index, MFI-20, HADS, the Visual Analogue Scale. RESULTS AND CONCLUSION: L-carnitine significantly improved the quality of life of the patients. The frequency of complaints of cerebral and somatic character decreased significantly which was combined with a reduction in the severity of neurological deficit on the NIHSS. Moreover, the decreased levels of general asthenia and psychoemotional defect were observed that resulted in the reduction of the percentage of patients who needed help according to the Barthel index. PMID- 29411749 TI - [Pathogenesis of chronic disorders of cerebral circulation]. AB - Chronic disorders of cerebral circulation are a common syndrome, in the pathogenesis of which the important role play structural and functional alterations in large and small arteries, autoregulation of cerebral circulation and the level of systemic arterial pressure. Drugs that increase cerebral blood flow and restore the ability to its autoregulation are used, among others, in treatment of patients with CRMC. The possibility of using nicergoline (sermion) for the treatment of patients with CRMK is considered. PMID- 29411750 TI - [Modern strategies of protection of hypoxic-ischemic brain damage]. AB - Nowadays, there are two complementary approaches to treatment of patients with ischemic stroke: reperfusion and neuroprotection. The main purpose of neuroprotection is to intervene ischemic cascade at every stage of the pathological process and thus avoid the death of nerve cells and expand the therapeutic window for reperfusion therapy. The use of drugs with neurotrophic, antioxidant and neuroregenerative effects is pathogenically explained at all stages of post stroke rehabilitation. Ethylmethylhydroxypyridine succinate (mexidol) is a derivative of succinic acid with antihypoxic, membrane protective, nootropic, anticonvulsant and sedative action. The majority of researchers confirmed the positive effect of mexidol expressed as the marked regression of neurological deficit and wider opportunities for further early rehabilitation. The results of the randomized double blind multicenter placebo-controlled, parallel-group trial of the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA) were published in 2017. The results of the study showed the best positive dynamics of neurological function recovery in case of timely treatment with mexidol with the following two month therapy. The safety of the long-term use of mexidol was confirmed. PMID- 29411751 TI - [A regional experience of the optimization of neurological care for the rural population]. AB - At present, the problem of disparity of healthcare, including neurological care, in urban and rural settings is highly relevant. Medical care after acute stroke or other chronic disabling diseases (epilepsy, Parkinson's disease) in rural settings is quite challenging due to the lack of access to specialized medical treatment facilities, low level of resources in medical and obstetric centers, low quality of healthcare, personnel turnover in rural healthcare and insufficient coverage of population with outpatient follow-up services. The most promising optimization approaches, which proved to be effective both abroad and in the Russian Federation, including Tyumen district, are the development of multidisciplinary mobile teams and telemedicine. Introduction of these approaches provides an increased access of rural population to specialized medical care, which leads to improvement in overall population health status. PMID- 29411753 TI - [Interview with professor E.I. Bogdanov]. PMID- 29411752 TI - [The dynamics of shoulder joint function in patients with hemiparesis in the acute period of carotid stroke]. AB - AIM: To evaluate the recovery of shoulder joint function in patients with hemiparesis in the acute period of hemispheric stroke on the basis of the analysis of electromyography (fEMG) of the muscles of this region before and after rehabilitation measures, including targeted training with biofeedback (BFB). MATERIAL AND METHODS: Three groups of 25 people each were studied. Patients of the physical therapy (PT) group received standard treatment and physical therapy; patients of the PT+BFB group received BFB training in addition to PT; the control group consisted of people without neurological and orthopedic symptoms. A clinical study and EMG of the muscles of the shoulder girdle during testing movements was performed. RESULTS: On the side of paresis, the function of muscles was characterized by a decrease in the bioelectric activity (movement amplitude was decreased as well) and later phase of the maximum EMG activity compared to the norm. The time of maximum EMG activity had a trend towards the shift to the normal values during the treatment process, but the difference reached a statistically significant level not for all muscles and all movements. There were variants of the functions of the paretic muscles accompanied by the increased EMG activity. In the early stages (up to 21 days) of stroke, no significant changes in the EMG activity of shoulder girdle muscles were observed. The PT+BFB group showed better results than the PT group not only in the onset of activity, but also in the reduction of the amplitude when performing the same movement that indirectly suggested the more optimal inclusion of muscles in the motor act. In the period of acute hemispheric stroke, there were changes not only in the EMG activity of muscles of the affected side, but also of the contralateral side. CONCLUSION: A fEMG of the muscles is a more sensitive and informative method of the diagnosis of disorders of motor function and assessment of recovery process of the muscles of the shoulder joint in patients with hemiparesis. PMID- 29411754 TI - [The new 2017 European society of cardiology (ESC) guidelines: important changes for introduction into clinical practice]. AB - The paper gives an overview of the European Society of Cardiology (ESC) guidelines updated in 2017. The revised and amended guidelines for areas, such as dual antiplatelet therapy (DAT), treatment of patients with ST-segment elevation myocardial infarction (STEMI), and management of patients with valvular heart disease and peripheral artery disease, were presented in late summer of this year. The authors of this paper present an independent analysis and discussion of new data on the key issues of diagnosis and treatment in patients in the above areas. The recommendations on DAT pay special attention to the timing of the therapy and to the choice of its drugs. The updated data on the treatment of patients with STEMI accurately determine the time to percutaneous coronary interventions, approaches to revascularization; the updates touch upon fibrinolytic therapy and new approaches to lipid-lowering therapy too. Recommendations for the management of patients with peripheral artery atherosclerosis propose for the first time a section devoted to the choice of antiplatelet therapy (an antiaggregant and/or an anticoagulant) depending on the clinical situation. PMID- 29411755 TI - [Anticoagulant therapy in patients with atrial fibrillation and reduced kidney function of diabetic and non-diabetic etiologies]. AB - AIM: To evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and stages I-III chronic kidney disease (CKD). SUBJECTS AND METHODS: The cohort parallel-group study included 92 patients with AF and stages I-III diabetic and non-diabetic CKD, who were treated with DOACs (dabigatran, rivaroxaban, or apixaban) and vitamin K antagonists (warfarin). The follow-up duration was 12 months. RESULTS: Thromboembolic events and bleeding, which required patient hospitalization or blood transfusions, were not recorded during 1-year follow-up. There was no clinically significant progression of CKD in the groups of therapy with vitamin K antagonists or DOACs. Just the same, a more intense decrease in glomerular filtration rate and a high rate of hemorrhagic complications were revealed in the subgroup of patients with diabetes mellitus (DM) versus those with non-diabetic CKD. CONCLUSION: In patients with non-valvular AF and diabetic and non-diabetic CKD, the use of DOACs effectively and safely prevents thromboembolic events, irrespective of the stage of CKD. At the same time, in patients taking anticoagulants, CKD progresses more rapidly in the presence of DM than in its absence, regardless of a specific anticoagulant. Hemorrhagic complications are more common in patients with AF, DM, and CKD, which requires more frequent monitoring of their kidney function. PMID- 29411756 TI - [Multislice spiral computed tomography of the heart in dilated cardiomyopathy: possibilities in the verification of myocarditis (in comparison with myocardial biopsy) and in the evaluation of prognosis]. AB - AIM: To investigate whether intravenous contrast-enhanced multislice spiral computed tomography (computed tomography) (MSCT) versus myocardial morphological examination can diagnose myocarditis and the non-inflammatory causes of dilated cardiomyopathy (DCM) and evaluate prognosis in patients with the latter. SUBJECTS AND METHODS: A study group consisted of 130 patients, including 95 men (46.8+/ 11.9 years), with DCM (mean left ventricular (LV) end-diastolic dimension (EDD), 6.6+/-0.8 cm; mean LV ejection fraction (EF), 29.8+/-9.3%; NYHA functional class (FC) III (II; III)). All the patients underwent intravenous contrast-enhanced 320 slice CT of the heart; myocardial morphological examination was made in 48 patients (endomyocardial biopsy in 29 patients, intraoperative biopsy in 7, and autopsy in 9, and study of the explanted heart in 3). In addition, cardiotropic viral DNA in the blood and myocardium and the level of anticardiolipin antibodies were determined; echocardiography (in all the patients), scintigraphy (n = 45), magnetic resonance imaging (MRI) (n = 21), and coronary angiography (CG) (n = 46), and a genetic consultation were performed. A comparison group comprised 20 patients, including 14 men (69.3+/-9.2 years), with coronary atherosclerosis (40% or more stenoses) according to MSCT findings in the absence of criteria for DCM (mean LV EDD, 4.8+/-0.5 cm; mean LV EF, 59.4+/-4.6%). RESULTS: Morphological/comprehensive examination showed that myocarditis as a cause of DCM was diagnosed in 76 (65%) patients; its concurrence with genetic cardiomyopathies was in 17 more patients (17%). MSCT of the heart revealed lower accumulation areas in 2 (1.5%) patients (type 1 based on the proposed rating scale), delayed myocardial contrast agent accumulation (DMCAA) in 81 (62.3%): subendocardial accumulation (type 2) in 8, intramyocardial accumulation in 4 (type 3), subepicardial accumulation in 52 (type 4), and transmural accumulation in 15 (type 5); DMCAA was not noted in 49 patients. DMCAA was not found in the comparison group. As compared with biopsy, the sensitivity, specificity, predictive value of positive and negative results of the tests in detecting active myocarditis for all the types of DMCAA were 77.4, 47.1, 72.7, and 53.3%, respectively; those for types 3-5 of DMCAA were 77.4, 52.9, 75.0, and 56.3%; those in detecting all the morphological types of myocarditis were 68.3, 28.6, 84.8, and 13.3%, and those for types 3-5 were 65.9, 28.6, 84.4, and 12.5%, respectively. Comparison of the data of MSCT and those of comprehensive examination in all the patients with DCM, the diagnostic significance in detecting myocarditis for all the types of DMCAA was 70.6, 67.9, 88.9 and 38.8%, respectively; that for DMCAA types 3-5 was 60.8, 67.9, 87.3, and 32.3%. In the study group, MSCT also identified the non-compacted myocardium (n = 31 (23.8%)), coronary atherosclerosis (n = 31 (23%)), which is confirmed by CG findings in 15 patients. The patients with DMCAA significantly more frequently showed a relationship with previous infection, acute onset, significantly higher NYHA FCs, end-diastolic and end-systolic LV volumes, and insignificantly lower LV EF. During a mean follow-up periods of 12 (6; 37.25) months, the overall mortality rate was 17.7% (23 deaths); the death + transplantation index was 20% (n = 26). All the types of DMCAA were found to be significantly related to prognosis: in the DMCAA group, the mortality rate was 21.5% versus 7.8% in the non-DMCAA group (odds ratio 3.22; 95% confidence interval, 1.02 to 10.21; p < 0.05). CONCLUSION: MSCT with the assessment of delayed contrast enhancement (and simultaneous CT coronary angiography) can be used for the non-invasive diagnosis of myocarditis in patients with DCM, including that in the presence of contraindications to MRI. DMCAA correlates with the presence of myocarditis, its activity, the degree of functional disorders, and prognosis. PMID- 29411757 TI - [Nocturnal pulse oximetry indicators in the evaluation of obstructive sleep apnea syndrome in outpatients with concomitant diseases of the upper respiratory tract and overweight]. AB - AIM: By using mathematical modeling, to evaluate the impact of upper respiratory tract diseases, retro- and micrognathia, and body mass index (BMI) on nocturnal pulse oximetry indicators (oxygen saturation level and oxygen desaturation index) in outpatients examined for suspected obstructive sleep apnea syndrome (OSAS). SUBJECTS AND METHODS: The study enrolled 260 subjects with a mean age of 47.8+/ 12.0 years. All the examinees underwent outpatient pulse oximetry screening during nocturnal sleep because of suspected OSAS. Multislice spiral computed tomography was carried out to assess the paranasal sinuses and nasal septum. BMI was calculated. Variance factor analysis using an original programming application intended to create binary and ternary dispersion complexes was employed as a main mathematical tool. RESULTS: There were statistically significantly sets of risk factors for OSAS: nasal septum deviation + increased BMI + male gender = 68.66%; chronic allergic rhinitis + increased BMI + male gender = 63.09%; retromicrognathia + increased BMI + male ganger = 59.48%; and chronic tonsillitis + increased BMI + male gander = 60.88%. Higher BMI and male gender are a most statistically significant set of risk factors. CONCLUSION: Pulse oximetry screening during nocturnal sleep in snoring patients with suspected OSAS in combination with an assessment of age, sex, BMI, ENT comorbidity, retro- and micrognathia can predict the severity of the disease and serve as a basis for elaborating an OSAS screening program. PMID- 29411758 TI - [A retrospective historical study evaluating the safe use of current antidepressants in cardiology practice]. AB - AIM: To confirm the data available in the literature on the cardiac safety of antidepressants. SUBJECTS AND METHODS: The archival data of 146 case histories were retrospectively analyzed. A study sample consisted of 96 cardiac inpatients regularly taking an antidepressant for more than 3 days during treatment for the underlying cardiovascular disease. The safe use of antidepressants was evaluated in terms of initial electrocardiogram (ECG) QTc interval changes, systolic and diastolic blood pressures (BP) (SBP and DBP), heart rate (HR), and hemorrhagic complications. The data obtained over periods of 3- and 6-8 days were analyzed. RESULTS: The sample showed no clinically significant ECG QTc interval changes when taking regularly antidepressants within 8 days. Analysis of the dynamics of BP and HR in patients receiving antidepressants revealed no statistically significant differences in these indicators before and 3 and 6-8 days after drug administration. No case of hemorrhagic complications was seen in the study group taking antidepressants. CONCLUSION: The investigation generally confirms the high cardiac safety of new-generation antidepressants within at least the first week of therapy. Noteworthy are the low daily drug dosages (relatively specified in the instructions) that are sufficient for most cardiac patients with depressive disorders and an additional factor for minimizing adverse reactions. PMID- 29411759 TI - [The clinical efficacy of allergen-specific immunotherapy with water-salt extracts and adjuvant allergens for atopic asthma with household sensitization]. AB - AIM: To evaluate the clinical and economic efficiency of allergen-specific immunotherapy (ASIT); to comparatively analyze the efficiency of various therapy regimens for atopic asthma. SUBJECTS AND METHODS: The clinical and economic efficiency of asthma therapy using ASIT with water-salt allergen extracts or the adjuvant drug alustal 'mite allergen' and only with medicines were comparatively analyzed. The investigation enrolled 156 patients with mild and moderate atopic asthma, household allergy. In Group 1 (n = 57), ASIT was performed using the classical scheme by subcutaneous injection of house dust mite allergen (JSC 'I.I. Mechnikov Biomed', Russia). In Group 2 (n = 43), ASIT was conducted using the alustal 'mite allergen' (Stallergenes, France). Group 3 (n = 56) received only medical therapy. RESULTS: ASIT with both water-salt allergen extracts and the adjuvant allergen alustal is an effective treatment for mild and moderate atopic asthma. ASIT greatly reduces the need for anti-inflammatory treatment and the use of symptomatic drugs and improves the physical and psychoemotional indicators of quality of life in patients. The economic benefit of ASIT is delayed, but its use significantly reduces financing costs. CONCLUSION: ASIT is a reasonable, highly effective and ultimately cost-effective treatment in patients with atopic asthma. A variety of drugs for ASIT can choose schemes that are convenient and acceptable for each patient, which allows wider use of this treatment. PMID- 29411760 TI - [Enteral tube feeding in adult patients with cystic fibrosis and respiratory failure]. AB - AIM: To evaluate the efficiency of nocturnal hyperalimentation in adult patients with cystic fibrosis (CF) and respiratory failure. SUBJECTS AND METHODS: The investigation enrolled 17 patients older than 18 years (mean age, 25.6+/-4.2 years) diagnosed with very severe CF (forced expiratory volume in one second (FEV1), < 30%; body mass index (BMI), < 18.5 kg/m2); all the patients were on the waiting list for lung transplantation. Nutritional status and pulmonary function parameters, such as body weight, height, BMI, and FEV1, were measured at baseline, before and 6 and 9 months after tube feeding. RESULTS: The study group showed a considerable increase in body weight and BMI after 6 and 9 months. The change in lung function was statistically insignificant. Lung transplantation was successfully conducted in 5 patients; 4 died while on the waiting list; the cause of death was respiratory failure. CONCLUSION: Supplemental PEG tube feeding improves the nutritional status (BMI, body weight) of patients with very severe CF. PMID- 29411761 TI - [Annual blood pressure dynamics and weather sensitivity in women]. AB - AIM: To study the annual cycle of blood pressure (BP) and weather sensitivity in normotensive women aged 20-59 years. SUBJECTS AND METHODS: The same group of 25 non-smoking women who had been living in the European North of Russia (62 degrees N, 51 degrees E) almost since their birth and were engaged in moderate intensity mental labor was daily examined. During a year, there were 11823 blood pressure measurements using the Korotkoff technique; heart rate was calculated by palpation. These meteorological parameters were taken at the websites: http://meteo.infospace.ru and ftp://ftp.ngdc.noaa.gov/stp/geomagnetic_data/indices/kp_ap. The statistical significance of differences in the indicators was determined using the Fisher's test and the Newman-Keuls test. The study used a correlation analysis with the calculation of the Spearman's rank correlation coefficient. RESULTS: The maximum systolic and diastolic BP values were revealed in February and January, respectively. The minimum values of systolic BP were detected in July; those of diastolic BP were in August. An individual-based analysis of sensitivity to environmental variations showed that about 88% of the women responded to atmospheric temperature; nearly 44% did to geomagnetic activity; almost 24% were sensitive to relative air humidity, and about 16% of the women were to atmospheric pressure. CONCLUSION: The dynamics of systolic and diastolic BP in the annual cycle of women depends on meteorological factors and suggests that there is a change in the priorities of its control in different periods of a year. PMID- 29411762 TI - [Association of FOXP3 gene -3279 C>A polymorphism with the risk of pulmonary sarcoidosis]. AB - AIM: To investigate the association of the polymorphic marker -3279 C>A of the FOXP3 gene with the risk of pulmonary sarcoidosis (PS) and to estimate the transcription level of this gene in the carriers of different genotypes of this polymorphic marker. SUBJECTS AND METHODS: The investigation included 99 patients of Russian ethnicity (mean age, 45.41+/-1.31 years) living in the Republic of Karelia, who were diagnosed with persistent PS, and 116 healthy donors (mean age, 42.06+/-1.30 years) in the control group. The alleles and genotypes of the polymorphic marker -3279 C>A of the FOXP3 gene were identified using polymerase chain reaction (PCR)-restriction fragment length polymorphism. The number of transcripts of the studied gene in the peripheral blood leukocytes of healthy donors and PS patients was determined with real-time PCR. RESULTS: The control group and the PS patient one had no statistically significant differences in the distribution of the frequencies of alleles and genotypes by the polymorphic marker -308G>A of the FOXP3 gene (p > 0.05). The number of FOXP3 gene transcripts was not statistically significantly different in the peripheral blood leukocytes of patients with PS and control individuals. No statistically significant differences were observed in the mRNA expression levels in the above-mentioned gene in the carriers of different genotypes by the polymorphic marker -3279 C>A of the FOXP3 gene in all examined groups. CONCLUSION: The polymorphic marker 3279 C>A of the FOXP3 gene is unassociated with the risk of PS. PMID- 29411763 TI - [ACOS: Clinical and functional features The Russian formulation mesalazine (kansalazine) in the therapy of ulcerative colitis]. AB - AIM: To investigate the clinical and functional parameters in patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) versus those with chronic obstructive pulmonary disease (COPD) and asthma. SUBJECTS AND METHODS: A total of 129 people were examined. 51 patients with ACOS were followed up in Group 1; Group 2 included 38 patients with severe asthma; Group 3 consisted of 40 patients with severe COPD. All the patients underwent clinical examination: history data collection, physical examination, evaluation of disease symptoms, and study of respiratory function (spirometry, body plethysmography). RESULTS: ACOS is clinically characterized by considerable demands for emergency drugs and by more frequent asthmatic fits and exacerbations, which require hospitalization. The parameters of bronchial resistance in ACOS were established to be increased throughout the follow-up period and to be comparable with those in patients with COPD. In the patients with ACOS, the severity of pulmonary hyperinflation was associated with increased demands for emergency drugs (r=0.59; p=0.015). Fixed bronchial obstruction in ACOS can be caused by smoking intensity and duration associated with increased bronchial resistance in expiration (r=0.51; p=0.003) and intrathoracic volume (r=0.71; p=0.0001); as well as increased body mass index (p<0.001) and disease duration, which were interrelated with a reduction in the forced expiratory volume in one second/forced vital capacity ratio (r=-0.63; p=0.001 and r=-0.71; p=0.0034, respectively). CONCLUSION: Patients with ACOS show more severe clinical manifestations and a substantial increase in functional residual capacity and intrathoracic volume throughout the follow-up period, suggesting that the distal bronchi are impaired and pulmonary hyperinflation develops. PMID- 29411764 TI - [Characteristics of the course of gastric and duodenal ulcer disease concurrent with duodenal insufficiency]. AB - AIM: To comprehensively study the course of gastric ulcer disease (GUD) and duodenal ulcer disease (DUD) concurrent with chronic duodenal insufficiency (CDI). MATERIAL AND METHODS: Ulcer disease (UD) was verified on the basis of the results of clinical and fibrogastroduodenoscopic examinations. The data of contrast duodenography and cavitary manometry were used to identify CDI. Gastroduodenal motor activity was investigated using the peripheral electrogastrograph EGG-4M. The results of pH measurements were employed to assess the state of gastric acid secretion and duodenal pH values. RESULTS: A comprehensive examination was made in 106 patients with UD concurrent with CDI (a study group) and 30 UD patients without CDI (a comparison group). Epigastric pain was noted in the patients with GUD in the study and comparison groups (91.5 and 84.6%, respectively), but the pain was mainly aching in the patients with concomitant CDI and more intense (77.8%) in those without this condition. In the study group, heartburn was more common in patients with GUD and DUD (75.3 and 71.4%, respectively) than in those with UD in the comparison group (28.5 and 37.5%, respectively). Helicobacter pylori tests were positive in 23.8% of the patients in the study group and in 57.2% in the comparison group. Electrogastrography indicated that the patients with GUD and CDI had bradygastria and hypokinesis on an empty stomach; the electrical activity was reduced after eating. In the comparison group, tachygastria and hyperkinesis were detected on an empty stomach; these postprandial indicators were elevated. H. pylori tests were positive in 34.7% of the patients with DUD and CDI and in 63.6% of those with DUD without CDI. The postprandial electrical activity increased in patients with DUD and decreased in the comparison group. The specific features of changes in gastric and duodenal pH values in GUD and DUD concurrent with CDI in comparison with the isolated course of UD. CONCLUSION: The immediate and long term follow-ups show that GUD and DUD concurrent with CDI run a more persistent course; the time of ulcer healing increases and the periods of remission decrease. PMID- 29411765 TI - [Evaluation of the efficacy of pregabalin in the therapy of chronic pain in patients with knee osteoarthritis]. AB - AIM: To evaluate the efficacy of pregabalin in the therapy of chronic pain in patients with knee osteoarthritis (KOA). SUBJECTS AND METHODS: The study enrolled 60 patients with KOA and neuropathic pain component (NPC) (Douleur Neuropathique en 4 questions (DN4) questionnaire scores, >4) who were randomized into two groups to receive aceclofenac or aceclofenac + pregabalin for 5 weeks. All the patients underwent clinical and neurological examinations, assessment of the functional WOMAC index, pain intensity at rest and during movement, and diagnosis of neuropathic pain (NP) (DN4 and Pain DETECT questionnaires). RESULTS: Both groups were observed to have positive changes in the studied parameters; however, combination therapy using an anticonvulsant drug (pregabalin) showed a more pronounced positive effect against not only NPC, but also the functional activity (WOMAC) and severity of pain (visual analogue scale). CONCLUSION: Combination therapy using pregabalin in KOA patients having the signs of NP is more effective than monotherapy with nonsteroidal anti-inflammatory drugs (aceclofenac). PMID- 29411766 TI - [Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy]. AB - AIM: To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy. SUBJECTS AND METHODS: The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016. RESULTS: The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p <= 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss. CONCLUSION: Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied. PMID- 29411767 TI - [Effect of an angiotensin-converting-enzyme inhibitor on the plasma concentration of cytokines and vasoactive molecules in patients with coronary heart disease and hypertension]. AB - AIM: To investigate the plasma concentrations of cytokines and vasoactive molecules in patients with coronary heart disease (CHD) in the presence of hypertension in relation to the angiotensin-converting-enzyme (ACE) inhibitor level reflecting the degree of renin-angiotensin-aldosterone system (RAAS) inhibition. SUBJECTS AND METHODS: 72 patients with NYHA functional class (FC) II III angina pectoris and 40 healthy persons at the age of 47-65 years were examined in a controlled cohort study. Enzyme immunoassay was employed to determine the serum concentrations of interleukins (IL) (IL-2, IL-12, IL-17A, and IL-24), the vasoactive molecules of bradykinin, serotonin, ACE, angiotensin-II (AT-II), NO, and endothelin-1 (ET-1), and plasma renin activity. In addition, the plasma level of the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro was used as a marker for ACE inhibition. RESULTS: The patients with CHD occurring in the presence of hypertension compared with the apparently healthy individuals displayed decreased ET-1 and NO production along with elevated levels of serotonin, AT-II, as well as IL-17A and IL-12. The found changes were accompanied by reduced renin activity. Thus, the individuals with low ACE inhibitor levels showed more pronounced production of the proinflammatory cytokine IL-17A, as well as high plasma concentrations of ACE and NO. The high ACE inhibitor level that reflects patient adherence to appropriate antihypertensive therapy is associated with the reduced production of IL-2 and with the minimum serum levels of ACE, AT-II, and NO, being characterized by the high production of IL-12 and serotonin at the same time. CONCLUSION: In patients with CHD and hypertension, the high plasma enzyme inhibitor concentration that reflects the activity of appropriate antihypertensive therapy, by contributing to the strengthening of the mechanisms of relaxation of blood vessels, is associated with the risk for proinflammatory activation of whole blood cells and platelets. The mean ACE inhibitor levels that reflect moderate RAAS suppression and are characterized by a relatively low proinflammatory activation of mononuclear cells may be more preferable than the maximum ones, from the point of view of slowing the progression of the subclinical inflammatory process of the vascular wall and preventing possible CHD exacerbations. This determines the feasibility of estimating the plasma level of an ACE inhibitor to control the depth of inhibition of RAAS activity. PMID- 29411768 TI - [Implantable cardioverter defibrillators in the prevention of sudden cardiac death]. AB - The article highlights the role of implantable cardioverter defibrillators (ICDs) in the primary and secondary prevention of sudden cardiac death. It considers the results of multicenter studies comparing the efficacy of antiarrhythmic drugs and implantable devices in the primary and secondary prevention of sudden cardiac death, including that in patients with nonischemic cardiomyopathy and discusses quality of life in patients with ICDs. PMID- 29411769 TI - [Role of neutrophil dysfunction in the pathogenesis of systemic lupus erythematosus]. AB - Neutrophil dysfunction plays a considerable role.in systemic lupus erythematosus (SLE) The protective function of neutrophils is carried out through various mechanisms: isolation of granular antimicrobial peptides (gAMP), microbial phagocytosis with subsequent degradation via reactive oxygen species inside the phagolysosomes; as well as bactericidal action due to the release of networks from chromatin and gAMP, also called neutrophil extracellular traps (NECTs). The development of neutropenia in SLE has multiple causes, including the formation of antibodies directly to leukocytes; that of neutralizing autoantibodies to the growth factors of neutrophils and cells - myeloid precursors; bone marrow suppression; involvement of neutrophils in the processes of apoptosis and NETosis. Neutrophils in SLE are characterized by reduced phagocytic ability and pathological oxidative activity. In SLE, there is a decrease in the ability to remove the products of neutrophil apoptosis, which is correlated with disease activity. SLE patients are noted to have a higher expression level of the genes specific for low-density granulocytes, an abnormal immature neutrophil population. The impaired processes of formation of NECTs and removal NETosis products play a substantial role in the pathogenesis of SLE. It is shown that the abnormal formation of NECTs also causes endothelial injury and increases the risk of thromboses. The design of novel drugs that act on the specific parts of the formation of NECTs or contribute to their removal from the extracellular environment can propel therapy for SLE and other autoimmune diseases to new heights. There is evidence for further investigations of neutrophil-mediated pathogenetic processes in SLE in order to identify potential therapeutic targets and to understand the mechanisms of action of drugs used in clinical practice. PMID- 29411770 TI - [Alirocoumab: new perspectives of lipid-lowering therapy]. AB - Alirocoumab (Praluent) is a fully human monoclonal antibody against proprotein covertase subtilisin/kexin type 9 (PCSK9). The data of ODYSSEY Phases II and III clinical trials demonstrate the high efficacy of alirocoumab in lowering the level of low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia, with a considerable advantage over control groups (placebo, ezetimibe or modified statin therapy) in both monotherapy and combination therapy with statins and other lipid-lowering agents. Alirocoumab provides additional lipid-lowering effects against other atherogenic fractions of cholesterol, including non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a). The agent show high safety and good tolerability and it can be considered as the drug of choice for patients who have not reached their target LDL cholesterol levels after statin therapy and have statin intolerance and familial heterozygous hypercholesterolemia. There are now the preliminary results of a secondary analysis of data from the ODYSSEY LONG TERM study, suggesting that alirocoumab therapy may be accompanied by a lower risk of cardiovascular events. The final results will be provided after the data of a study of cardiovascular outcomes after therapy with alirocoumab versus placebo (ODYSSEY OUTCOMES) are published. PMID- 29411771 TI - [Melatonin and hypertension: a possible role in combination therapy]. AB - This literature review gives the results of clinical trials studying the association of the level of endogenous melatonin and blood pressure (BP), the effects of exogenous melatonin on BP (particularly at night) in relation to the used rapid- or controlled-release formulation of melatonin. PMID- 29411772 TI - [Diagnosis and treatment of pulmonary hypertension: from the point of view of 2017]. AB - Pulmonary hypertension (PH) is a group of diseases characterized by increased pulmonary vascular resistance (PVR). Regardless of its cause, PH leads to right ventricular failure and premature death. Recent advances in the diagnosis and treatment of PH have prompted the elaboration of new guidelines for the diagnosis and treatment of PH. This paper provides a brief overview of major achievements in diagnostic and treatment approaches in patients PH. PMID- 29411773 TI - [A fixed-dose lisinopril+amlodipine+rosuvastatin combination: prospects for its use in patients with hypertension and concomitant dyslipidemia]. AB - In Russia, target blood pressure (BP) levels are achieved in only 14.4% of men and in 30.9% of women. The need for combination therapy of hypertension is as high as 70.7%. There are well-known benefits of combined antihypertensive therapy allowing for higher efficiency and better tolerability. One of the current combinations is a combination of an angiotensin-converting enzyme inhibitor and a calcium antagonist, which have pronounced protective activity and metabolic neutrality. Fixed-dose combinations have substantial advantages over free ones, contributing to improving patient compliance with the used treatment regimen. Dyslipidemia is present in 60.7% of the hypertensive patients. Nonetheless, only 9.7% of Russian patients with coronary heart disease take statins and control of lipid levels remains very poor. The review discusses whether the use of the triple combination lisinopril + amlodipine + rosuvastatin is reasonable from the standpoint of evidence-based medicine. There are literature data suggesting the high value of this fixed-dose combination in the context of organ protection and the reduced risk of cardiovascular events. PMID- 29411776 TI - Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination. AB - This corrects the article DOI: 10.1038/mi.2017.81. PMID- 29411775 TI - Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium. AB - Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-lambda (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-lambda production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-lambda, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics. PMID- 29411774 TI - GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. AB - The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIgamma and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIgamma and beta-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43-/- mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIgamma and defensins in mice. Furthermore, SCFA induced RegIIIgamma and beta-defensins in intestinal epithelial enteroids generated from WT but not GPR43-/- mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIgamma and beta-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis. PMID- 29411778 TI - Erratum: Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. AB - This corrects the article DOI: 10.1038/nature23481. PMID- 29411777 TI - Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity. AB - Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer's patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant. PMID- 29411779 TI - Erratum: Host and viral traits predict zoonotic spillover from mammals. AB - This corrects the article DOI: 10.1038/nature22975. PMID- 29411781 TI - Assessment of occupational exposure to gaseous peracetic acid. AB - OBJECTIVES: In order to assess short-term exposure to peracetic acid (PAA) in disinfection processes, the Authors compared 4 industrial hygiene monitoring methods to evaluate their proficiency in measuring airborne PAA concentrations. MATERIAL AND METHODS: An active sampling by basic silica gel impregnated with methyl p-tolyl sulfoxide (MTSO), a passive solid phase micro-extraction technique using methyl p-tolyl sulfide (MTS) as on-fiber derivatization reagent, an electrochemical direct-reading PAA monitor, and a novel visual test strip PAA detector doped with 2,2'-azino-bis (3-ethylbenzothiazoline)-6-sulfonate were evaluated and tested over the range of 0.06-16 mg/m3, using dynamically generated PAA air concentrations. RESULTS: The linear regression analysis of linearity and accuracy showed that the 4 methods were suitable for PAA monitoring. Peracetic acid monitoring in several use applications showed that the PAA concentration (1.8 mg/m3) was immediately dangerous to life or health as proposed by the National Institute of Occupational Safety and Health, and was frequently exceeded in wastewater treatment (up to 7.33 mg/m3), and sometimes during food and beverage processes and hospital high-level disinfection operations (up to 6.8 mg/m3). CONCLUSIONS: The methods were suitable for the quick assessment of acute exposure in PAA environmental monitoring and can assist in improving safety and air quality in the workplace where this disinfectant is used. These monitoring methods allowed the evaluation of changes to work out practices to reduce PAA vapor concentrations during the operations when workers are potentially overexposed to this strong antioxidant agent. Int J Occup Med Environ Health 2018;31(4):527-535. PMID- 29411780 TI - Corrigendum: Complex pectin metabolism by gut bacteria reveals novel catalytic functions. AB - This corrects the article DOI: 10.1038/nature21725. PMID- 29411782 TI - Dechlorination of chlorobenzene on vanadium-based catalysts for low-temperature SCR. AB - Chlorobenzene (CB) inhibits SCR activity of V-based catalysts at low temperature, though the adsorption amount is small. NH3 adsorption increases due to the break in the C-Cl bond during CB oxidation. The dissociated Cl- ions provide extra Bronsted acid sites, leading to the formation of inactive NH4Cl. Ce and Mn improve dechlorination, forming more NH4Cl on the catalyst surface. PMID- 29411783 TI - Assembly of [Cu2(COO)4] and [M3(MU3-O)(COO)6] (M = Sc, Fe, Ga, and In) building blocks into porous frameworks towards ultra-high C2H2/CO2 and C2H2/CH4 separation performance. AB - A porous MOF platform (SNNU-65s) formed by creatively combining paddle-wheel-like [Cu2(COO)4] and trigonal prismatic [M3(MU3-O)(COO)6] building blocks was designed herein. The mixed and high-density open metal sites and the OH-functionalized pore surface promote SNNU-65s to exhibit ultra-high C2H2 uptake and separation performance. Impressively, SNNU-65-Cu-Ga stands out for the highest C2H2/CO2 (18.7) and C2H2/CH4 (120.6) selectivity among all the reported MOFs at room temperature. PMID- 29411784 TI - Reduced graphene oxide doped predominantly with CF2 groups as a superior anode material for long-life lithium-ion batteries. AB - A fluorine-doped reduced graphene oxide (F-rGO), predominantly in the form of CF2 groups, was synthesized using the reduced-graphene-oxide precursor devoid of residual hydroxyl and carboxyl groups through a solvothermal process. The vacancies and defects accompanying the formation of the highly stable and electrochemically inert CF2 groups contribute to the excellent cycling stability of F-rGO, when it is applied as the anode material in a lithium-ion battery. PMID- 29411785 TI - Compression of multidimensional NMR spectra allows a faster and more accurate analysis of complex samples. AB - We propose an approach to efficiently compress and denoise multidimensional NMR spectral data, improving their corresponding storage, handling, and analysis. This method has been tested with 2D homonuclear, 2D and 3D heteronuclear, and 2D phase-sensitive NMR spectral data and shown to be especially powerful for 2D NMR metabolomics studies. PMID- 29411786 TI - Fluorescence enhancement mediated by high-index-faceted Pt nanocrystals: roles of crystal structures. AB - In this work, we report studies that focus on correlating fluorescence enhancement with crystal structures, using Pt nanoparticles as a demonstration. Both experimental and theoretical calculation results provide evidence to support an interesting phenomenon that high-index structures, especially step atoms, contribute in enhancing fluorescence signals. PMID- 29411791 TI - Self-assembly of small-molecule fumaramides allows transmembrane chloride channel formation. AB - This study reports the formation of self-assembled transmembrane anion channels by small-molecule fumaramides. Such artificial ion channel formation was confirmed by ion transport across liposomes and by planar bilayer conductance measurements. The geometry-optimized model of the channel and Cl- ion selectivity within the channel lumen was also illustrated. PMID- 29411792 TI - The synthesis of amphiphilic polyethyleneimine/calcium phosphate composites for bispecific T-cell engager based immunogene therapy. AB - Bispecific T-cell engagers (BiTEs) are single chain variable fragments with specific structures, which could connect the surface antigen on cancer cells and CD3 ligands on T cells, and then engage the T cells for cancer immunotherapy. In this report, a novel organic-inorganic hybrid gene delivery system composed of stearic acid modified polyethyleneimine (stPEI) and calcium phosphate (CaP) was used to deliver MC.DNA into cells to express BiTE antibodies. This gene delivery system exhibits high transfection efficiency, long-term effects and low cytotoxicity in vitro. Furthermore, the gene production, anti-IGF1R/CD3 bispecific T-cell engager, exhibited a rapid redirection activity in T cells to induce cancer cell apoptosis. In summary, the results confirmed that stPEI-CaP could be an efficient gene delivery system for BiTE encoding MC.DNA based gene immunotherapy. PMID- 29411793 TI - Expeditious synthesis of polyacetylenic water hemlock toxins and their effects on the major GABAA receptor isoform. AB - Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4pi-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives. PMID- 29411794 TI - Optical absorption and photoconductivity in iodine-excess ionic liquids: the case of 1-alkyl-3-methyl imidazolium iodides. AB - We investigated the optical absorption and photoconductivity of iodine-excess ionic liquids (ILs) based on 1-alkyl-3-methyl imidazolium iodide ([Cnmim][I]; n = 3, 4, and 6). The iodide concentration m was 2 ? m ? 8, which was determined by the molar fraction [Cnmim]+ : [Im]- = 1 : m. By adding iodine, an absorption edge shifted from 282 nm in the UV region to around 600 nm in the visible-light region. The optical bandgaps Eo decreased gradually from 2.3 eV to 1.9 eV with increasing m from 2 to 8. The alkyl-side chain lengths of the cations have little effect on the Eo. This experimental result was confirmed by ab initio molecular orbital calculations. The effects were reflected in the photoconductivity of the ILs, as expected. [C4mim][Im] exhibited greater photo-induced electron generation compared with [C3mim][Im] and [C6mim][Im]. The photoconductivity in both [C3mim][Im] and [C6mim][Im] increased slightly with increasing m. The trend of photoconductivity in [C4mim][Im] exhibited an N-shaped form. The highest photoconductivity 1.6 was observed in [C4mim][I8]. PMID- 29411795 TI - Modulating the properties of multi-functional molecular devices consisting of zigzag gallium nitride nanoribbons by different magnetic orderings: a first principles study. AB - Using the non-equilibrium Green's function formalism in combination with density functional theory, we calculated the spin-dependent electronic properties of molecular devices consisting of pristine and hydrogen-terminated zigzag gallium nitride nanoribbons (ZGaNNRs). Computational results show that the proposed ZGaNNR models display multiple functions with perfect spin filtering, rectification, and a spin negative differential resistance (sNDR) effect. Spin dependent transport properties, spin density and transmission pathways with applied bias values were calculated to understand the spin filter and the sNDR effect. The spin filtering efficiency can be up to -100% or 100% within a large range of biases, and a dual spin filtering effect can also be found in these model devices. The highest rectification ratio reaches 4.9 * 109 in spin-down current of ZGaNNRs with only the passivated nitrogen edge, and only ZGaNNRs with the passivated gallium edge exhibit an obvious sNDR behavior with the largest peak to valley current ratio of 1.25 * 107. The proposed hydrogenated ZGaNNRs can be preferred materials for realizing oscillators, memory circuits and fast switching applications. PMID- 29411796 TI - The gelation influence on diffusion and conductivity enhancement effect in renewable ionic gels based on a LMWG. AB - This paper reports the interdisciplinary study on molecular dynamics, ionic interactions and electrical conductivity in a quaternary ammonium salt (TMABr) ionogel based on a low molecular weight gelator (LMWG) in a wide range of electrolyte molar concentrations. The thermal scanning conductometry (TSC) was used to investigate the electric properties of the ionogels. The prepared TMABr/H2O/LMWG ionogel exhibits better ion transport properties than the dissociated TMA+ cation in solution. The enhanced ionic conductivity effect (EICE) was observed in the concentration range of the TMABr salt up to 1 M. To investigate the transport properties of the TMA+ cation and solvent molecules in the gel and sol phase, the NMR diffusiometry method was used. The field-cycling relaxometry method (FFC NMR) was applied to study the local motions of the electrolyte at the surface of the gelator matrix. On the basis of the obtained data, the higher ionic conductivity observed in the gel phase has been related to the microstructure of the gel matrix. The possible explanation for the origin of this effect has been given. The investigated system is a thermally reversible physical gel, all registered data were reproducible upon transforming the sample from gel to sol and back to the gel state, confirming the enhancement effect as a permanent property of the investigated ionogels. Therefore, the EICE has been proposed to be used as an internal sensor to monitor the condition of the ionogel phase, thus making them smart materials. PMID- 29411797 TI - Patterned polyaniline encapsulated in titania nanotubes for electrochromism. AB - In this article, we report the preparation of a TiO2 nanotube array (TNA) film used as a transparent electrochromic material and a TNA/polyaniline patterned hybrid electrochromic film utilized as an information display material. The TNA film was fabricated by an anodizing process, and a surface patterned TNA with extreme wettability contrast (hydrophilic/hydrophobic) on a TNA surface through self-assembly (SAM) and photocatalytic lithography is fabricated. Then the TNA/polyaniline hybrid film was prepared by electrodeposition of aniline in an aqueous solution. Finally, the electrochromic properties of the TNA film and the TNA/polyaniline hybrid film were investigated. Compared with neat TNA film and polyaniline (PANI) films, the hybrid film shows a much higher optical contrast in the near infrared range. The TNA/polyaniline hybrid film shows higher coloration efficiencies of 24.4 cm2 C-1 at a wavelength of 700 nm and 17.1 cm2 C-1 at a wavelength of 1050 nm compared to the TNA coloration efficiency. The color switching time (20.9 s or 22.9 s) of TNA/polyaniline is faster than TNA. PMID- 29411798 TI - Ab initio kinetic Monte Carlo simulation of seeded emulsion polymerizations of styrene. AB - Seeded emulsion polymerizations of styrene are modeled on the basis of a detailed kinetic scheme accounting for the chain length and conversion dependence of termination rate coefficients. A holistic kinetic Monte Carlo approach was developed, which simulates the elemental reactions in the aqueous phase, the transfer of radicals into individual particles, and the radical polymerization in each particle based on a complete kinetic model. Experimentally-derived particle size distributions are used as input for the simulations. The required rate coefficients were taken from literature. Without any adjustment of this data a very good agreement between simulation results and experimental data is found. The validation of the model is performed based on monomer conversion - time data and full molar mass distributions. PMID- 29411799 TI - Investigating multicolour photochromic behaviour of AgCl and AgI thin films loaded with silver nanoparticles. AB - Multicolour photochromic behaviour in light-sensitive Ag-AgCl and Ag-AgI thin films at room temperature was investigated and compared. Although it seemed that the Ag-Ag halide thin films have similar optical properties, their optical responses to a monochromatic laser beam are completely different. It is shown that Ag-AgCl thin film changes its colour under light irradiation to the same colour of the incident light, regardless of the polarization state of the laser beam. In contrast, the Ag-AgI thin film changes to complementary colours of the incident beam. The different optical behaviours of Ag-AgCl and Ag-AgI thin films are due to the different electrical properties of AgCl and AgI thin films. Moreover, the multicolour photochromic behaviour is due to the changes of absorption spectra and surface morphology of silver nanoparticles on silver-haide thin film. These changes are the result of excitation of localized surface plasmon resonance of silver nanoparticles by the laser beam and charge transfer between silver nanoparticles and silver-halide thin films. PMID- 29411800 TI - Nonvolatile ternary resistive switching memory devices based on the polymer composites containing zinc oxide nanoparticles. AB - Nonvolatile ternary memory devices were fabricated from the composites polymer blends containing zinc oxide (ZnO) nanoparticles. When applying a negative bias on the top electrode, the fabricated devices with a simple sandwich structure of indium tin oxide (ITO)/composite polymer/aluminum (Al) exhibited three distinct resistance states, which could be labeled as "OFF", "ON1" and "ON2" for ternary data storage application. The ITO/polystyrene (PS) + ZnO/Al devices can endure 3 * 104 read-cycles and exhibit a retention time of 104 s. The resistance temperature dependence at different resistance states was investigated to confirm the temperature-dependent properties. The resistance of the "OFF" and "ON1" state reveals negative temperature dependence, manifesting a typical semiconductor characteristic. The resistance of the "ON2" state exhibits positive temperature dependence, showing metallic properties. PMID- 29411801 TI - Tuning the singlet fission relevant energetic levels of quinoidal bithiophene compounds by means of backbone modifications and functional group introduction. AB - Efficient singlet fission (SF) has been obtained in quinoidal bithiophene, end capped with dicyanomethylene groups (QBT). However, QBT suffers from low triplet state energy [E(T1)] because of its biradicaloid nature, which results in a great driving force for SF but also a large loss of energy during the SF process. This is not favorable for the application of SF in solar cells. Modifications to the molecular structure of QBT were performed to optimize the SF relevant excited state energy levels and its diradical character in the present study. This includes chalcogen replacement, the fusing of the heterocyclic ring between the two thiophene rings, and the introduction of side substituents. Detailed analysis focused on the correlation between the molecular structure of the QBT derivatives and their diradical character y0, bond length alternation (BLA), molecular orbitals, and SF relevant excited state energy levels. The results show that electron-donating substituents, particularly groups introduced at the inner beta positions of the thiophene ring, can increase E(T1) and reduce the energy loss of SF significantly under the premise of exothermic SF. These results would be beneficial to the development of new SF candidates for application in solar cells. PMID- 29411802 TI - Polydopamine films change their physicochemical and antimicrobial properties with a change in reaction conditions. AB - The morphology and physicochemical properties of polydopamine are not totally inherent and undergo changes with differing reaction conditions like the choice of solvent used for polymerization. The polymerisation of dopamine to polydopamine carried out in different solvents like sodium hydroxide, sodium bicarbonate, PBS and Tris leads to polydopamine with exceptionally different morphological and physicochemical features with each solvent. Additionally, the different physicochemical characteristics and morphologies bestow the polymer films with different extents of antimicrobial activity. Moreover, the findings supported by chemical evidence from X-ray photoelectron spectroscopy reveal that higher antibacterial activities were obtained against E. coli and S. aureus with polydopamine films prepared by Tris and NaOH solvent induced polymerization. The antibacterial activity observed in saline was found to be higher than that in PBS medium for both E. coli and S. aureus. The higher antibacterial activity of polydopamine films prepared in Tris and NaOH solvents was attributed to the covalent incorporation of -OH groups on the surface provided by nucleophilic Tris and NaOH solvents during the polymerisation process. The distinct physicochemical and morphological changes were supported by the results from contact angle measurements, FE-SEM, EDAX, AFM, and XPS analysis. The present finding provides insight into the different chemistry, morphologies and properties of the designed polydopamine films with controlled antibacterial/antifouling properties. Additionally, new insights into the mechanism of formation, physicochemical changes in morphology and properties of polydopamine coatings were revealed. PMID- 29411803 TI - Origin of the overpotentials for HCOO- and CO formation in the electroreduction of CO2 on Cu(211): the reductive desorption processes decide. AB - Electroreduction of CO2 on Cu surface provides the potential in producing hydrocarbons and other multi-carbon products. However, a comprehensive understanding of the potential-related mechanism is required to improve the product selectivity as well as to reduce the overpotentials. Herein, we systematically characterize the potential effect on the complete reaction pathways to CO and HCOO- on the Cu(211) surface. Reaction free energy and activation barrier are computed as functions of electric potential. It is found that chemical adsorption state of CO2 is effectively stabilized by the substrate, which is expected to be dominant at potentials below -0.27 V vs. SHE, much earlier than that previously reported on Cu(100). Considering that the activation barriers of the other surface processes are small enough to be overcome at room temperature, the large reductive desorption free energies of OH- and HCOO- are suggested as the origin of high overpotentials. PMID- 29411804 TI - Study of low temperature chlorine atom initiated oxidation of methyl and ethyl butyrate using synchrotron photoionization TOF-mass spectrometry. AB - The initial oxidation products of methyl butyrate (MB) and ethyl butyrate (EB) are studied using a time- and energy-resolved photoionization mass spectrometer. Reactions are initiated with Cl radicals in an excess of oxygen at a temperature of 550 K and a pressure of 6 Torr. Ethyl crotonate is the sole isomeric product that is observed from concerted HO2-elimination from initial alkylperoxy radicals formed in the oxidation of EB. Analysis of the potential energy surface of each possible alkylperoxy radical shows that the CH3CH(OO)CH2C([double bond, length as m-dash]O)OCH2CH3 (RgammaO2) and CH3CH2CH(OO)C([double bond, length as m dash]O)OCH2CH3 (RbetaO2) radicals are the isomers that could undergo this concerted HO2-elimination. Two lower-mass products (formaldehyde and acetaldehyde) are observed in both methyl and ethyl butyrate reactions. Secondary reactions of alkylperoxy radicals with HO2 radicals can decompose into the aforementioned products and smaller radicals. These pathways are the likely explanation for the formation of formaldehyde and acetaldehyde. PMID- 29411805 TI - Dynamics and ionic conductivity of ionic liquid crystals forming a hexagonal columnar mesophase. AB - For the first time, the molecular mobility of two linear-shaped tetramethylated guanidinium triflate ionic liquid crystals (ILCs) having different lengths of alkyl chains was investigated using a combination of broadband dielectric spectroscopy (BDS) and specific heat spectroscopy (SHS). By self-assembly, these ILCs can form a hexagonal ordered mesophase besides plastic crystalline phases and the isotropic state. Three dielectric active processes were found using BDS for both samples. At low temperatures, a gamma-process in the plastic crystalline state is observed which is assigned to localized fluctuations of methyl groups including nitrogen atoms in the guanidinium head. At higher temperatures but still in the plastic crystalline state, an alpha1-process takes place. An alpha2 process was detected using SHS but with a completely different temperature dependence of the relaxation times than that of the alpha1-relaxation. This result is discussed in detail, and different molecular assignments of the processes are suggested. At even higher temperatures, electrical conductivity is detected and an increase in the DC conductivity by four orders of magnitude at the phase transition from the plastic crystalline to the hexagonal columnar mesophase is found. This result is traced to a change in the charge transport mechanism from a delocalized electron hopping in the stacked aromatic systems (in the plastic phase) to one dominated by an ionic conduction in the quasi-1D ion channels formed along the supermolecular columns in the ILC hexagonal mesophases. PMID- 29411806 TI - Osmotic contribution to the flow-driven tube formation of copper-phosphate and copper-silicate chemical gardens. AB - We have produced hollow copper-containing precipitate tubes using a flow injection technique, and characterized their linear and volume growth. It is shown that the ratio of the volume increase rate to that of pumping is constant independent of the chemical composition. It is also found that osmosis significantly contributes to the tube growth, since the inward flux of chemical species dominates during the precipitate pattern formation. The asymmetric hydrodynamic field coupled with the inherent concentration and pH gradients results in different particle morphology on the two sides of the precipitate membrane. While the tubes have a smooth outer surface, the inner walls are covered with nanoflowers for copper phosphate and with nanoballs for copper silicate. PMID- 29411807 TI - Mitochondria-based aircraft carrier enhances in vivo imaging of carbon quantum dots and delivery of anticancer drug. AB - The application of engineered bacteria-based drug delivery vehicles to treat cancer has been practiced for more than a century. Mitochondria, evolutionarily originated from bacteria, are ubiquitous, semi-autonomous cellular organelles. In this study, we present the first exploration of using mitochondria as a delivery system of carbon quantum dots (CQDs) for in vivo imaging and administration of the anticancer drug doxorubicin (DOX). The results show that mitochondria as carriers are compatible with CQD loading and preserve the optical properties of CQDs. Moreover, the mitochondria delivery system can improve the CQD bio distribution in organs and prolong the retention time of CQDs after intravenous injection. Furthermore, mitochondria loaded with doxorubicin hydrochloride (Mito DOX) show an enhanced therapeutic effect compared to free DOX. The mitochondria based "aircraft" system may be a promising novel therapeutic platform with high potential for biological imaging and drug delivery to fight cancer and other diseases. PMID- 29411808 TI - Extraordinary sensitivity for H2S and Fe(iii) sensing in aqueous medium by Al-MIL 53-N3 metal-organic framework: in vitro and in vivo applications of H2S sensing. AB - An Al(iii) metal-organic framework (MOF) called Al-MIL-53-N3 (1) was synthesized under solvothermal reaction conditions using Al(NO3)3.9H2O and H2BDC-N3 (H2BDC-N3 = 2-azido-1,4-benzenedicarboxylic acid) ligand in a DMF/water (DMF = N,N dimethylformamide) mixture. Phase purity was checked by performing X-ray powder diffraction, infrared spectroscopy and thermogravimetric analysis. Thermogravimetric analysis suggests that 1 is highly stable up to 300 degrees C under air atmosphere. The activated 1 (called 1') showed a very fast fluorescence response to H2S (turn-on) and Fe(iii) ions (turn-off) in an aqueous medium with excellent sensitivity and selectivity even in the presence of other potentially intrusive analytes. In the presence of H2S, the conversion of the azide moiety to amine is responsible for the fluorescence turn-on properties. On the other hand, the partial replacement of framework Al(iii) ions by Fe(iii) can be assigned for the selective detection behavior to Fe(iii) ions. The detection limits (90.47 nM for H2S and 0.03 MUM for Fe(iii) ions in water) of 1' are lower than those of the formerly reported MOF type of fluorescent sensors. The 1'-loaded J774A.1 macrophage cells are healthy and respond to intracellular H2S to exhibit strong blue fluorescence, confirming its suitability to detect H2S inside the cells. In addition, 1' can detect H2S in human blood plasma (HBP) and sulfide ions in real water samples. These features make 1' a very promising candidate for the on-site sensing of Fe(iii) ions and the detection of intracellular and extracellular H2S. PMID- 29411809 TI - The emerging era of supramolecular polymeric binders in silicon anodes. AB - Silicon (Si) anode is among the most promising candidates for the next-generation high-capacity electrodes in Li-ion batteries owing to its unparalleled theoretical capacity (4200 mA h g-1 for Li4.4Si) that is approximately 10 times higher than that of commercialized graphitic anodes (372 mA h g-1 for LiC6). The battery community has witnessed substantial advances in research on new polymeric binders for silicon anodes mainly due to the shortcomings of conventional binders such as polyvinylidene difluoride (PVDF) to address problems caused by the massive volume change of Si (300%) upon (de)lithiation. Unlike conventional battery electrodes, polymeric binders have been shown to play an active role in silicon anodes to alleviate various capacity decay pathways. While the initial focus in binder research was primarily to maintain the electrode morphology, it has been recently shown that polymeric binders can in fact help to stabilize cracked Si microparticles along with the solid-electrolyte-interphase (SEI) layer, thus substantially improving the electrochemical performance. In this review article, we aim to provide an in-depth analysis and molecular-level design principles of polymeric binders for silicon anodes in terms of their chemical structure, superstructure, and supramolecular interactions to achieve good electrochemical performance. We further highlight that supramolecular chemistry offers practical tools to address challenging problems associated with emerging electrode materials in rechargeable batteries. PMID- 29411810 TI - N,N-Disubstituted-N'-acylthioureas as modular ligands for deposition of transition metal sulfides. AB - First row transition metal complexes (Ni, Co, Cu, Zn) with N,N-disubstituted-N' acylthiourea ligands have been synthesized and characterized. Bis(N,N-diisopropyl N'-cinnamoylthiourea)nickel was found to have the lowest onset temperature for thermal decomposition. Thin film deposition of Ni, Co, and Zn sulfides by aerosol assisted chemical vapor deposition from their respective N,N-diisopropyl-N' cinnamoylthiourea complexes at 350 degrees C has been demonstrated. PMID- 29411811 TI - Bright green-to-yellow emitting Cu(i) complexes based on bis(2-pyridyl)phosphine oxides: synthesis, structure and effective thermally activated-delayed fluorescence. AB - A family of brightly luminescent dinuclear complexes of [Cu(MU2-X)(N^N)]2 type (X = I or SCN) has been synthesized in 76-90% yields by the reaction of bis(2 pyridyl)phosphine oxides (N^N) with the corresponding Cu(i) salts. The X-ray diffraction study reveals that the Cu2I2 core of the [Cu(MU2-I)(N^N)]2 complexes has either a butterfly- or rhomboid-shaped structure, while the eighth-membered [Cu()Cu] ring in the [Cu2(SCN)2(N^N)]2 complexes is nearly planar. In the solid state, these compounds exhibit a strong green-to-yellow emission (lambda = 536 592 nm) with high PLQYs (up to 63%) and short lifetimes (1.9-10.0 MUs). The combined photophysical and DFT study indicates that the ambient-temperature emission of the complexes obtained can be assigned to the thermally activated delayed fluorescence (TADF) from the 1(M + X)LCT excited state, while at 77 K, phosphorescence from the 3(M + X)LCT state is likely observed. PMID- 29411812 TI - The roles of buckled geometry and water environment in the excitonic properties of graphitic C3N4. AB - The exciton plays a crucial role in two-dimensional materials involved in photocatalytic water splitting, where its properties are determined not only by the material itself, but also by the surrounding water environment. By the framework of many-body perturbation theory, we investigated the excitonic effects in pure and water-adsorbed g-C3N4. It is shown that the excitonic properties are very sensitive to the geometry of g-C3N4 and the adsorption of water molecules. Firstly, the optical band gap, i.e. the first bright excitonic energy of pure g C3N4 decreases remarkably from a high symmetry planar structure (3.8 eV) to a P1 buckled configuration (2.7 eV). Secondly, the hydrogen bonds between water and g C3N4 induce the generation of interface excitons. With a reduced binding energy (at least 0.2 eV), interface excitons can contribute to a more efficient separation of electrons and holes. Our work provides an insight into the excitation mechanism of 2D photocatalysts in a real environment. PMID- 29411813 TI - Oxidized Co-Sn nanoparticles as long-lasting anode materials for lithium-ion batteries. AB - Herein, we present the synthesis and systematic comparison of Sn- and Co-Sn-based nanoparticles (NPs) as anode materials for lithium-ion batteries. These nanomaterials were produced via inexpensive routes combining wet chemical synthesis and dry mechanochemical methods (ball milling). We demonstrate that oxidized, nearly amorphous CoSn2Ox NPs, in contrast to highly crystalline Sn and CoSn2 NPs, exhibit high cycling stability over 1500 cycles, retaining a capacity of 525 mA h g-1 (92% of the initial capacity) at a high current density of 1982 mA g-1. Moreover, when cycled in full-cell configuration with LiCoO2 as the cathode, such CoSn2Ox NPs deliver an average anodic capacity of 576 mA h g-1 over 100 cycles at a current of 500 mA g-1, with an average discharge voltage of 3.14 V. PMID- 29411814 TI - Theoretical kinetic study of the formic acid catalyzed Criegee intermediate isomerization: multistructural anharmonicity and atmospheric implications. AB - We performed a theoretical study on the double hydrogen shift isomerization reaction of a six carbon atom Criegee intermediate (C6-CI), catalyzed by formic acid (HCOOH), to produce vinylhydroperoxide (VHP), C6-CI + HCOOH -> VHP + HCOOH. This Criegee intermediate can serve as a surrogate for larger CIs derived from important volatile organic compounds like monoterpenes, whose reactivity is not well understood and which are difficult to handle computationally. The reactant HCOOH exerts a pronounced catalytic effect on the studied reaction by lowering the barrier height, but the kinetic enhancement is hindered by the multistructural anharmonicity. First, the rigid ring-structure adopted by the saddle point to facilitate simultaneous transfer of two atoms does not allow the formation of as many conformers as those formed by the reactant C6-CI. And second, the flexible carbon chain of C6-CI facilitates the formation of stabilizing intramolecular C-HO hydrogen bonds; this stabilizing effect is less pronounced in the saddle point structure due to its tightness and steric effects. Thus, the contribution of the reactant C6-CI conformers to the multistructural partition function is larger than that of the saddle point conformers. The resulting low multistructural anharmonicity factor partially cancels out the catalytic effect of the carboxylic acid, yielding in a moderately large rate coefficient, k(298 K) = 4.9 * 10-13 cm3 molecule-1 s-1. We show that carboxylic acids may promote the conversion of stabilized Criegee intermediates into vinylhydroperoxides in the atmosphere, which generates OH radicals and leads to secondary organic aerosols, thereby affecting the oxidative capacity of the atmosphere and ultimately the climate. PMID- 29411815 TI - Borophene hydride: a stiff 2D material with high thermal conductivity and attractive optical and electronic properties. AB - Two-dimensional (2D) structures of boron atoms, so-called borophene, have recently attracted remarkable attention. In a recent exciting experimental study, a hydrogenated borophene structure was realized. Motivated by this success, we conducted extensive first-principles calculations to explore the mechanical, thermal conduction, electronic and optical responses of borophene hydride. The mechanical response of borophene hydride was found to be anisotropic, with an elastic modulus of 131 N m-1 and a high tensile strength of 19.9 N m-1 along the armchair direction. Notably, it was shown that by applying mechanical loading the metallic electronic character of borophene hydride can be altered to direct band gap semiconducting, very appealing for application in nanoelectronics. The absorption edge of the imaginary part of the dielectric function was found to occur in the visible range of light for parallel polarization. Finally, it was estimated that this novel 2D structure at room temperature can exhibit high thermal conductivities of 335 W mK-1 and 293 W mK-1 along the zigzag and armchair directions, respectively. Our study confirms that borophene hydride shows an outstanding combination of interesting mechanical, electronic, optical and thermal conduction properties, which are promising for the design of novel nanodevices. PMID- 29411816 TI - Synergy of polypyrrole and carbon x-aerogel in lithium-oxygen batteries. AB - A crucial step in the development of lithium-oxygen (Li-O2) batteries is to design an oxygen cathode with high catalytic activity and stable porous structure. Achieving such design requires an integrated strategy in which porosity, conductivity, catalytic activity, and mechanical durability are all considered in a battery system. Here, we develop polypyrrole-coated carbon x aerogels with macroscopic 3D architecture, and demonstrate their potential as oxygen cathodes for Li-O2 batteries. This material, a novel and mechanically strong composite aerogel with polymer-cross-linked structure, not only provides effective pores that allow to store the discharge products and open channels for better oxygen diffusion, but also forms a robust 3D catalytic network that promotes both oxygen reduction and evolution reactions with improved mechanical and electrochemical stability. This work highlights the synergy between the 3D porous, conductive carbon aerogel framework and the polypyrrole catalytic layer, which maintains stable catalytic activity without deactivation and provides a more effective gas-liquid-solid interface for rapid oxygen absorption and diffusion, thereby leading to significant improvements in the capacity, rate capability and cycle life of the cathode. PMID- 29411817 TI - Stereoselective synthesis of natural product inspired carbohydrate fused pyrano[3,2-c]quinolones as antiproliferative agents. AB - Pyrano[3,2-c]quinolone structural motifs are commonly found in natural products with diverse biological activities. As part of a research programme aimed at developing the efficient synthesis of natural product-like small molecules, we designed and developed the microwave assisted, facile stereoselective synthesis of two series of carbohydrate fused pyrano[3,2-c]quinolone derivatives (n = 23) starting from 2-C-formyl galactal and 2-C-formyl glucal, reacting with various 4 hydroxyquinolones in shorter reaction times (15-20 min). The antiproliferative activity of these synthesized pyrano[3,2-c]quinolones was determined against MCF 7 (breast) and HepG2 (liver) cancer cells. The selected library members displayed low micromolar (3.53-9.68 MUM) and selective antiproliferative activity. These findings on carbohydrate fused pyrano[3,2-c]quinolone derivatives are expected to provide new leads for anticancer drug discovery. PMID- 29411818 TI - Ferrimagnetism in manganese-rich gallium and aluminium spinels due to mixed valence Mn2+-Mn3+ states. AB - Stoichiometric (MnGa2O4 and MnAl2O4) and Mn-rich (Mn1.3Ga1.7O4 and Mn1.4Al1.6O4) spinels with a small inversion degree (0.14-0.21) were obtained via a co precipitation route followed by calcination of the as-synthesized coprecipitates at 700-1000 degrees C under different gas atmospheres (air, N2 or argon). In situ synchrotron XRD at elevated temperatures reveals the conditions for synthesizing phase-pure materials. The stoichiometry of the samples is confirmed by inductively coupled plasma optical emission spectrometry as well as by structure refinement of neutron diffraction data of phase-pure specimens. XANES characterization reveals the average oxidation state of manganese to be +2.2 and 2.3 in Mn1.3Ga1.7O4 and Mn1.4Al1.6O4 spinels, respectively. The mixed Mn2+-Mn3+ valence states are responsible for the ferrimagnetic properties of Mn1.3Ga1.7O4 and Mn1.4Al1.6O4 samples below 48 and 55 K, respectively, as well as for a smaller optical bandgap when compared to stoichiometric spinels. PMID- 29411819 TI - A high-performance asymmetric supercapacitor based on vanadyl phosphate/carbon nanocomposites and polypyrrole-derived carbon nanowires. AB - A novel asymmetric supercapacitor device in an aqueous electrolyte is fabricated using a vanadyl phosphate/carbon nanocomposite as the positive electrode and a polypyrrole-derived carbon nanowire as the negative electrode. The vanadyl phosphate/carbon nanocomposites are synthesized by a simple two-step approach in which layered VOPO4.2H2O is first intercalated by dodecylamine and then annealed at high temperature, leading to the in situ carbonization of the intercalated dodecylamine. It is found that the sample in which the incorporated carbon with a high degree of graphitization exhibits a high specific capacitance of 469 F g-1 at a current density of 1 A g-1 and excellent rate performance (retained 77% capacitance at 10 A g-1). A polypyrrole-derived carbon nanowire is synthesized by the direct carbonization of nanowire-shaped polypyrrole, revealing a rough surface of nanowire-like frameworks and good electrochemical behavior. Taking advantage of both positive and negative materials, the assembled asymmetric supercapacitor device exhibits a high energy density of 30.6 W h kg-1 at a high power density of 813 W kg-1 in a wide voltage region of 0-1.6 V, as well as a good electrochemical stability (84.3% capacitance retention after 5000 cycles). The present work can shed light on the fabrication of novel asymmetric supercapacitors with high-performance. PMID- 29411820 TI - Structure-based discovery of new maternal embryonic leucine zipper kinase inhibitors. AB - Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3.52 MUM and 178.3 nM, respectively. In vitro cell-based assays revealed that 16 has no effect on the growth of various types of cancer cells, but has the potential to inhibit cancer cell migration and invasion. Western blotting analyses revealed that 16 suppresses the phosphorylation of focal adhesion kinase (FAK), a downstream molecule of MELK, which is a key kinase in regulating cancer cell migration and invasion. PMID- 29411821 TI - Small-molecule anticancer agents kill cancer cells by harnessing reactive oxygen species in an iron-dependent manner. AB - In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species in an iron-dependent manner. Results of the preliminary studies are consistent with the recently described cell death mechanism ferroptosis. Studies are in progress to confirm ferroptosis as the cell death mechanism and to identify the specific molecular targets of these small molecule anticancer agents. PMID- 29411822 TI - Intramolecular Morita-Baylis-Hillman reaction as a strategy for the construction of tricyclic sesquiterpene cores. AB - Starting from a common polyfunctionalized bicyclo[3.2.1]octane-6,8-dione intermediate, a concise synthetic route to tricyclic cores found in quadrane, suberosane, cedrane and related sesquiterpenes was developed using a Morita Baylis-Hillman intramolecular reaction as a key step. PMID- 29411823 TI - Photoelectrodes based on 2D opals assembled from Cu-delafossite double-shelled microspheres for an enhanced photoelectrochemical response. AB - Although a unique light-harvesting property was recently demonstrated in a photocathode based on 2-dimensional (2D) opals of CuFeO2-shelled SiO2 microspheres, the performance of a monolayer of ultra-thin CuFeO2-shelled microspheres is limited by ineffective charge separation. Herein, we propose an innovative design rule, in which an inner CuFeO2/outer CuAlO2 double-shelled heterojunction is formed on each partially etched microsphere to obtain a hexagonally assembled 2D opal photoelectrode. Our Cu-delafossite double-shelled photocathode shows a dramatically improved charge separation capability, with a 9 fold increase in the photocurrent compared to that of the single-shelled counterpart. Electrochemical impedance spectroscopy clearly confirms the reduced charge transport/transfer resistance associated with the Cu-delafossite double shelled photocathode, while surface photovoltage spectra reveal enhanced polarization of the photogenerated carrier, indicating improved charge separation capability with the aid of the heterojunction. Our finding sheds light on the importance of heterojunction interfaces in achieving optimal charge separation in opal architectures as well as the inner-shell/electrolyte interface to expedite charge separation/transport. PMID- 29411824 TI - Organogels composed of trifluoromethyl anthryl cyanostyrenes: enhanced emission and self-assembly. AB - A series of alpha-cyanostyrenes bearing anthracene and electron withdrawing trifluoromethyl units were designed and synthesized. The alpha-cyanostyrene skeleton favors aggregation induced enhanced emission behavior due to the restriction of intramolecular rotations. Remarkably, the anthryl cyanostyrenes bearing simple trifluoromethyl (CF3) substituents form stable organogels with enhanced fluorescence emission compared to their solution state. In water, the CF3 substituted anthrylstyrenes self-assemble into entangled fibrous nano/microstructures through intermolecular H-bonding, pi-pi stacking and cyano substituent interactions. The morphological features of the aggregates and the gels were substantiated using scanning electron microscopy, TEM, and powder XRD measurements. The stability of the gels was assessed using rheology investigations. PMID- 29411825 TI - High thermoelectric performance of graphite nanofibers. AB - Graphite nanofibers (GNFs) have been demonstrated to be a promising material for hydrogen storage and heat management in electronic devices. Here, by means of first-principles and transport simulations, we show that GNFs can also be an excellent material for thermoelectric applications thanks to the interlayer weak van der Waals interaction that induces low thermal conductance and a step-like shape in the electronic transmission with mini-gaps, which are necessary ingredients to achieve high thermoelectric performance. This study unveils that the platelet form of GNFs in which graphite layers are perpendicular to the fiber axis can exhibit outstanding thermoelectric properties with a figure of merit ZT reaching 3.55 in a 0.5 nm diameter fiber and 1.1 in a 1.1 nm diameter one. Interestingly, by introducing 14C isotope doping, ZT can even be enhanced up to more than 5, and more than 8 if we include the effect of finite phonon mean free path, which demonstrates the amazing thermoelectric potential of GNFs. PMID- 29411826 TI - Moldable biomimetic nanoscale optoelectronic platforms for simultaneous enhancement in optical absorption and charge transport. AB - Nano-scale patterns such as those found on the exterior surface of the eyes of certain nocturnal insects have far-reaching implications in terms of optoelectronic device design. The advantage of using these patterns for optoelectronic enhancement in photovoltaic light harvesting has been less explored due to the lack of suitable engineered materials to easily fabricate such nanostructures. Here, an attempt is made to realize these complex patterns using a self-assembly based molding process on hitherto unexplored robust structural epoxies with excellent repeatability and scalability to a larger area. The incorporation of these patterns in the substrate shows nearly a 50% broadband drop in the specular reflectance of the nanostructured substrate. Furthermore, it is demonstrated that by tweaking the bio-inspired patterns on the interior side of a light harvesting device, it is possible to obtain a broadband improvement in the external quantum efficiency in the spectral window between 350 and 650 nm leading to a significant improvement of up to 49% in the photocurrent density in the structured devices. From our experiment and simulations, it is observed that this enhancement stems from a combination of two effects: first, a broadband drop in the specular reflectance exceeding 70%, arising from trapped surface plasmon polariton modes, and second, an improved charge separation in the structured device arising due to perturbed built-in electric fields. Furthermore, the simulations which take into account the interfacial nano-scale morphology show that for absorbers with low carrier mobilities, a significant improvement in the photocurrent and in the fill factor is simultaneously possible. Overall, this work demonstrates a combination of tweaked bio-mimetic design and the use of unconventional robust structural materials as nanostructured optoelectronic substrates. This effort can bridge the gap between naturally evolved designs and practical optoelectronics to enhance the performance. PMID- 29411827 TI - Synthesis of high performance N-doped carbon coated Li2ZnTi3O8via a NTA-assisted solid-state route. AB - N-Doped carbon coated Li2ZnTi3O8 (LZTO@C-N) anodes have been successfully synthesized via a simple NTA-assisted solid-state method using NTA as C and N sources, as well as a chelating agent. It is shown that the N element can be doped into carbon. The N-doped carbon greatly benefits the electrochemical performance of LZTO@C-N. The initial capacities of 276.5, 271.3 and 231.9 mA h g 1 are delivered at 2, 3 and 5 A g-1, respectively, for LZTO@C-N-2 with a carbon content of 4.89%. 186.0, 177.3 and 159.7 mA h g-1 are still maintained at the 100th cycle, respectively. The good electrochemical performance of the LZTO@C-N-2 electrode at high current densities is due to its proper specific surface area and particle size, low charge-transfer resistance, and high lithium diffusion coefficient. PMID- 29411828 TI - Two-dimensional delocalized states in organometallic bis-acetylide networks on Ag(111). AB - The electronic structure of surface-supported organometallic networks with Ag-bis acetylide bonds that are intermediate products in the bottom-up synthesis of graphdiyne and graphdiyne-like networks were studied. Scanning tunneling microscopy (STM) and spectroscopy (STS) reveal a frontier, unoccupied electronic state that is delocalized along the entire organometallic network and proves the covalent nature of the Ag-bis-acetylide bonds. Density-functional theory (DFT) calculations corroborate the spatial distribution of the observed delocalized state and attribute it to band mixing of carbon and silver atoms combined with n doping of the metal surface. The metal-bis-acetylide bonds are typical metal organic bonds with mixed character containing covalent and strong ionic contributions. Moreover, the organometallic networks exhibit a characteristic graphene-like band structure with linear band dispersion at each K point. PMID- 29411829 TI - Water soluble hydrophobic peptoids via a minor backbone modification. AB - Peptoids - oligomers of N-substituted glycine - are an important class of peptide mimics that are widely used in areas ranging from biology and medicine to metal binding and catalysis. The utility of peptoids, however, especially for applications in aqueous solutions, is often hampered by the hydrophobic nature of their sequences dictated by structural and functional requirements. Herein we describe a simple method to solubilize hydrophobic peptoids in water without modifying their original sequences, via the insertion of biocompatible and low cost piperazine or homopiperazine groups at the N- or C-terminus of the peptoid backbone. We show that our method can be applied for the production of alpha-, beta- and azapeptoids, which display high water solubility for long periods of time. Moreover, circular dichroism (CD) spectroscopy revealed that the incorporation of piperazine groups within alpha-peptoids, having chiral naphthyl monomers, beta-peptoids and unstructured azapeptoids results in peptoids that exhibit high conformational order in water. PMID- 29411830 TI - Metal-ion responsive reversible assembly of DNA origami dimers: G-quadruplex induced intermolecular interaction. AB - We present a novel metal-ion stimulated organization of DNA origami nanostructures by employing G-quadruplexes as stimuli-responsive bridges. The reversible assembly process of DNA origami was the result of conformational changes between the G-quadruplex and its single-strand state induced by monovalent cations. This study might stimulate a new design of responsive DNA based intelligent nanomaterials. PMID- 29411831 TI - Modeling compressive behavior of open-cell polymerized high internal phase emulsions: effects of density and morphology. AB - The compressive behavior of poly(HIPE) foams was studied using the developed micromechanics based computational model. The model allowed identifying the morphological parameters governing the foam compressive behavior. These parameters comprise: (i) foam density, (ii) Sauter mean diameter of voids calculated from the morphological analysis of the polydispersed microstructure of poly(HIPE), and (iii) polymer/strut characteristic size identified as the height of the curvilinear triangular cross-section. The model prediction compared closely with the experiments and considered both the linear and plateau regions of the compressive poly(HIPE) behavior. The computational model allows the prediction of structure-property relationships for poly(HIPE) foams with various relative densities and open cell microstructure using the input parameters obtained from the morphology characterization of the poly(HIPE). The simulations provide a pathway for understanding how tuning the manufacturing process can enable the optimal foam morphology for targeted mechanical properties. PMID- 29411832 TI - [Yb(AAZTA)(H2O)]-: an unconventional ParaCEST MRI probe. AB - An unexpectedly slow exchange rate has been observed for the coordinated water molecule of [Yb(AAZTA)(H2O)]- using 1H-NMR and CEST-MRI studies. This made it possible for the first time to exploit the bound water molecule of a LnIII complex with carboxylic donor groups for CEST imaging. This result envisages the development of a new family of thermodynamically stable ParaCEST probes based on anionic chelates. PMID- 29411833 TI - Drag crisis moderation by thin air layers sustained on superhydrophobic spheres falling in water. AB - We investigate the effect of thin air layers naturally sustained on superhydrophobic surfaces on the terminal velocity and drag force of metallic spheres free falling in water. The surface of 20 mm to 60 mm steel or tungsten carbide spheres is rendered superhydrophobic by a simple coating process that uses a commercially available hydrophobic agent. By comparing the free fall of unmodified spheres and superhydrophobic spheres in a 2.5 meter tall water tank, it is demonstrated that even a very thin air layer (~1-2 MUm) that covers the freshly dipped superhydrophobic sphere can reduce the drag force on the spheres by up to 80%, at Reynolds numbers from 105 to 3 * 105, owing to an early drag crisis transition. This study complements prior investigations on the drag reduction efficiency of model gas layers sustained on heated metal spheres falling in liquid by the Leidenfrost effect. The drag reduction effects are expected to have significant implications for the development of sustainable air layer-based energy saving technologies. PMID- 29411834 TI - Photochromism of a spiro-functionalized diarylethene derivative: multi-colour fluorescence modulation with a photon-quantitative photocyclization reactivity. AB - A spiro-functionalized photochromic diarylethene derivative showed multi-colour fluorescence modulation with a photon-quantitative photocyclization reactivity and high thermal stability. PMID- 29411835 TI - C6' steric bulk of cinchona alkaloid enables an enantioselective Michael addition/annulation sequence toward pyranopyrazoles. AB - A catalytic asymmetric Michael addition/annulation process between pyrazolones and enynones towards enantioenriched pyranopyrazoles was developed. Key features include the development of a cinchona alkaloid with C6' steric bulk as a competent catalyst and the observation of a unique stereospecific deuteration alpha to the keto group via a conducted tour pathway. PMID- 29411836 TI - Synthesis of (d)-erythrose from glycolaldehyde aqueous solutions under electric field. AB - The formation of the first C-C bonds from formaldehyde represents the rate limiting step of the formose reaction. However, the free-energy surface associated with such a process has never been determined in condensed phase. By means of ab initio molecular dynamics and metadynamics techniques here we report on the free-energy landscape underlying the synthesis of glycolaldehyde from a formaldehyde aqueous solution. Moreover, numerical samples of formaldehyde (both neat and in water solution) and of glycolaldehyde (both neat and in aqueous solution) have been exposed to intense electric fields. The application of electrostatic gradients strongly prevents the formaldehyde umpolung and catalyzes the formation of C-O-bonded polymers in formaldehyde-containing samples. However, when the field is applied on glycolaldehyde aqueous solutions, new C-C bonds are formed and (d)-erythrose is synthesized. This way, a numerical Miller-like experiment led to the formation of a prebiotically relevant (d)-tetrose from ubiquitarious molecules such as glycolaldehyde and water. PMID- 29411837 TI - Viscoelasticity of dense suspensions of thermosensitive microgel mixtures undergoing colloidal gelation. AB - Dense suspensions of temperature (T)-sensitive poly(N-isopropyl acrylamide) (N) and poly(N-isopropyl methacrylamide) (NM) microgel mixtures with different volume transition temperatures (T and T, respectively; T < T) exhibit a characteristic T dependent viscoelasticity due to T-induced changes in the type of interparticle interaction as well as the volume fraction of each gel. In the range of T < T, where the swollen microgels with repulsive interparticle interactions are densely packed, the equilibrium modulus (G) decreases upon heating due entirely to the packing effect, i.e., a reduction in the total volume fraction of the microgels (phi). At T > T where the attractive interparticle interactions between dehydrated and hydrophobic microgels emerge, the suspensions show solid-like elastic properties due to the network-like flocculation of the shrunken microgels (colloidal gelation), even when phi becomes considerably lower than the threshold for randomly close packing. The T-dependence of G shows a minimum at a characteristic temperature (TB; TB > T) due to the competition between the repulsive interparticle interactions from the packing effect and electrostatic force, and the attractive interactions from the hydrophobicity. The TB in N/NM mixture suspensions shifts to a higher value with a decrease in N content in the mixtures (XN), accompanied by a discontinuous-like change at a specific value of XN (XN*). The TB at every value of XN agrees approximately with the temperature where the total volume fraction of the attractive hydrophobic microgels is 0.3 regardless of microgel type (N or NM). The discontinuous-like variation in TB at XN* reflects the change in the network-like flocculation particles, from only attractive N microgels in the high XN regime, to the attractive N and NM microgel mixtures in the moderate XN regime. The requirement of the repulsive electrostatic force with an appropriate strength for the stability of the network like flocculation is also demonstrated using the PNIPAM-co-fumaric acid (NF) microgel suspensions at various pH. PMID- 29411838 TI - Polar organometallic strategies for regioselective C-H metallation of N heterocyclic carbenes. AB - N-Heterocyclic carbenes (NHCs) have become indispensable ligands across a broad swathe of the synthetic and catalytic landscape, not in small part due to their ease of electronic and steric tunability. One of the latest additions to this important family of ligands are anionic NHCs, which have become valuable precursors to access abnormal NHC complexes as well as shown great potential for further NHC functionalisation. Deprotonative metallation has emerged as one of the most versatile methodologies to access anionic NHCs, where judicious choice of reaction conditions and metallating agents can finely tune the regioselectivity of the reaction. This Feature Article focuses on the recent emergence of s-block metal-mediated NHC metallations and the new opportunities this methodology offers. PMID- 29411839 TI - Thermally activated motion of a contact line over defects. AB - At the nanometer scale, the motion of a contact line separating a dry from a wet region is limited by the presence of surface heterogeneities that pin it. Here we revisit the seminal model proposed by Joanny and de Gennes to include the influence of thermal noise and viscosity using a Langevin model with two degrees of freedom: the average position of the contact line and its distortion. We identify the conditions under which the dynamics in a velocity-driven experiment can in fact be described by a constant forcing at small scale. We then relate the asymptotic properties of the relation between force and contact line velocity to the properties of the defects. In particular, we show that Kramers' approximation misses the strong asymmetry between advancing and receding directions. Finally, we show how to use the model to fit experimental data and extract the salient features of the surface energy landscape. PMID- 29411840 TI - Carbonate esters turn camptothecin-unsaturated fatty acid prodrugs into nanomedicines for cancer therapy. AB - We report that carbonate esters could turn hydrophobic camptothecin (CPT) unsaturated fatty acid prodrugs into nanoaggregates in aqueous solution. The active CPT could be rapidly released once triggered by a reductive stimulus when a carbonate ester was combined with a disulfide bond, resulting in a potent in vivo antitumor activity. PMID- 29411841 TI - Real-time monitoring of the aggregation of Alzheimer's amyloid-beta via1H magic angle spinning NMR spectroscopy. AB - Proton magic-angle-spinning NMR used for real-time analysis of amyloid aggregation reveals that mechanical rotation of Abeta1-40 monomers increases the rate of formation of aggregates, and that the increasing lag-time with peptide concentration suggests the formation of growth-incompetent species. EGCG's ability to shift off-pathway aggregation is also demonstrated. PMID- 29411842 TI - Valence, loop formation and universality in self-assembling patchy particles. AB - Patchy particles have emerged as an attractive model to mimic phase separation and self-assembly of globular proteins solutions, colloidal patchy particles, and molecular fluids where directional interactions are operative. In our previous work, we extensively explored the coupling of directional and isotropic interactions on both the phase separation and self-assembly in a system of patchy particles with five spots. Here, we extend this work to consider different patch valences and isotropic interaction strengths with an emphasis on self-assembly. Although the location of self-assembly transition lines in the temperature density plane depend on a number of parameters, we find universal behavior of cluster size that is dependent only on the probability of a spot being bound, the patch valence, and the density. Using these principles, we quantify both the mass distribution and the shape for all clusters, as well as clusters containing loops. Following the logical implications of these results, combined with a simplified version of a mean-field theory that incorporates Flory-Stockmayer theory, we find a universal curve for the temperature dependence of cluster mass and a universal curve for the fraction of clusters that contain loops. As the curves are dependent on the particle valence, such results provide a method for parameterizing patchy particle models using experimental data. PMID- 29411843 TI - Active ideal sedimentation: exact two-dimensional steady states. AB - We consider an ideal gas of active Brownian particles that undergo self-propelled motion and both translational and rotational diffusion under the influence of gravity. We solve analytically the corresponding Smoluchowski equation in two space dimensions for steady states. The resulting one-body density is given as a series, where each term is a product of an orientation-dependent Mathieu function and a height-dependent exponential. A lower hard wall is implemented as a no-flux boundary condition. Numerical evaluation of the suitably truncated analytical solution shows the formation of two different spatial regimes upon increasing Peclet number. These regimes differ in their mean particle orientation and in their variation of the orientation-averaged density with height. PMID- 29411844 TI - In situ synchrotron radiation X-ray diffraction studies on molecular aggregation structure of nylon 12 films during bulge testing. AB - It is desirable to establish a method for evaluating mechanical properties, such as modulus and strength, of micrometer and sub-micrometer thick polymer films. Bulge tests, where bulge deformation is imposed on films by the pressure of an inert gas, are suitable for satisfying this demand. However, very few studies on polymer films exist in the literature. In this study, bulge testing equipment for in situ synchrotron radiation wide-angle X-ray diffraction (WAXD) measurements is designed and used to study the relationship between the molecular aggregation structure and the mechanical properties of a crystalline nylon 12 (Ny12) film during bulge testing. Isothermally crystallized and quenched Ny12 films exhibited stress-strain curves similar to those obtained by conventional uniaxial elongation. In situ WAXD measurements during bulge testing revealed that the lattice extension of the crystallites is clearly dependent on crystallinity. Concretely, crystallites in the isothermally crystallized film show higher elastic properties than those in the quenched one. The results of the molecular aggregation structure, including the crystal structure and the amorphous chain surrounding the crystallites, of the films during bulge deformation firstly obtained in this study must be useful for designing toughened polymer films. PMID- 29411846 TI - Synthesis of low-oxidation-state germanium clusters comprising a functional anchor group - synthesis and characterization of [(Ge0)5(Ge-R)3(Ge-(CH2)n CH[double bond, length as m-dash]CH2)] with R = Si(SiMe3)3. AB - The first alkenyl-functionalized, uncharged deltahedral germanium clusters [{Si(SiMe3)3}3Ge9(CH2)nCH[double bond, length as m-dash]CH2] (n = 1 or 3) comprising five Ge0 atoms are presented. All compounds were NMR-spectroscopically and mass-spectrometrically characterized. [{Si(SiMe3)3}3Ge9(CH2)3CH[double bond, length as m-dash]CH2] was further characterized by X-ray structure analysis and Raman spectroscopy. Temperature-dependent NMR studies reveal dynamic behavior for both compounds in solution at room temperature. The propenyl derivative [{Si(SiMe3)3}3Ge9CH2CH[double bond, length as m-dash]CH2] undergoes fast decomposition in solution. The possibility of the comparatively stable pentenyl substituted Ge9 cluster as a candidate for follow-up reactions is highlighted. PMID- 29411848 TI - Highly durable Cu-based electrodes from a printable nanoparticle mixture ink: flash-light-sintered, kinetically-controlled microstructure. AB - Recently, printable nanomaterials have drawn tremendous attention for low-cost, large-area electronics applications. In particular, metallic nanoparticles that can facilitate the formation of highly functioning electrodes are indispensable constituent nanomaterials. In this paper, we propose printable mixed inks comprising multicomponent ingredients of Cu, Ni and Cu/Cu10Sn3 core/shell nanoparticles. It is clearly revealed that a characteristic morphology appropriate to highly conductive and durable Cu-based electrodes can be derived easily in a timescale of about 1 ms through an instantaneous flash-light sintering process, resulting in a resistivity of 49 MUOmega cm and normalized resistance variation of around 1 (after 28 days under a harsh environment of 85 degrees C temperature and 85% humidity). In addition, it is demonstrated that highly functioning electrodes can be formed on thermally vulnerable polyethylene terephthalate (PET) substrates by incorporating an ultrathin optical/thermal plasmonic barrier layer. PMID- 29411851 TI - Syntheses and evaluation of new acridone derivatives for selective binding of oncogene c-myc promoter i-motifs in gene transcriptional regulation. AB - We synthesized a series of acridone derivatives for specific binding ligands of i motifs. Subsequent evaluations showed that B19 could selectively bind to and stabilize the c-myc promoter i-motif without significant binding to the G quadruplex and duplex DNA. This caused down-regulation of c-myc transcription and expression, resulting in tumor cell apoptosis. PMID- 29411852 TI - Asymmetric mesoporous silica nanoparticles as potent and safe immunoadjuvants provoke high immune responses. AB - Asymmetric mesoporous silica nanoparticles with a head-tail structure are potent immunoadjuvants for delivering a peptide antigen, generating a higher antibody immune response in mice compared to their symmetric counterparts. PMID- 29411854 TI - Correction: Comparison of air samplers for determination of isocyanic acid and applicability for work environment exposure assessment. AB - Correction for 'Comparison of air samplers for determination of isocyanic acid and applicability for work environment exposure assessment' by Mikolaj Jan Jankowski et al., Environ. Sci.: Processes Impacts, 2017, 19, 1075-1085. PMID- 29411855 TI - Gel-based supramolecular ON-OFF switch from aryl-triazolyl peptides with excellent chiro-optical, thixotropic, and self-healing characteristics. AB - Systematic structure-property optimization of an achiral gelator (aryl-triazolyl homo dipeptide, 1.0) through a fragment replacement approach led to the identification of a new chiral system (aryl-triazolyl dipeptide 1.4 having leucine as the C-terminal residue) which exhibits consistent and perfectly reversible chiro-optical responses on sol-gel transition that can work like an ON OFF switch. The gelator 1.4 could also direct the assembly of 1.0 in a sergeant soldier mode to give similar CD responses. In addition, its gels are mouldable, self-healing and highly thixotropic, making it important from an application standpoint. PMID- 29411856 TI - Improving methyl ketone production in Escherichia coli by heterologous expression of NADH-dependent FabG. AB - We previously engineered Escherichia coli to overproduce medium- to long-chain saturated and monounsaturated methyl ketones, which could potentially be applied as diesel fuel blending agents or in the flavor and fragrance industry. Recent efforts at strain optimization have focused on cofactor balance, as fatty acid derived pathways face the systematic metabolic challenge of net NADPH consumption (in large part, resulting from the key fatty acid biosynthetic enzyme FabG [beta ketoacyl-ACP reductase]) and net NADH production. In this study, we attempted to mitigate cofactor imbalance by heterologously expressing NADH-dependent, rather than NADPH-dependent, versions of FabG identified in previous studies. Of the four NADH-dependent versions of FabG tested in our previously best-reported methyl ketone-producing strain (EGS1895), the version from Acholeplasma laidlawii (Al_FabG) showed the greatest increase in methyl ketone yield in shake flasks (35 75% higher than for an RFP negative-control strain, depending on sugar loading). An improved strain (EGS2920) attained methyl ketone titers during fed-batch fermentation of 5.4 +/- 0.5 g/L, which were, on average, ca. 40% greater than those for the base strain (EGS1895) under fermentation conditions optimized in this study. Shotgun proteomic data for strains EGS2920 and EGS1895 during fed batch fermentation were consistent with the goal of alleviating NADPH limitation through expression of Al_FabG. For example, relative to strain EGS1895, strain EGS2920 significantly upregulated glucose-6-phosphate isomerase (directing flux into glycolysis rather than the NADPH-producing pentose phosphate pathway) and downregulated MaeB (a NADP+ -dependent malate dehydrogenase). Overall, the results suggest that heterologous expression of NADH-dependent FabG in E. coli may improve sustained production of fatty acid-derived renewable fuels and chemicals. PMID- 29411857 TI - Follow-up of a randomised phase II study of chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: impact on allogeneic haematopoietic stem cell transplantation. PMID- 29411858 TI - Photo-switchable microbial fuel-cells. AB - Regulation of Bio-systems in a clean, simple, and efficient way is important for the design of smart bio-interfaces and bioelectronic devices. Light as a non invasive mean to control the activity of a protein enables spatial and temporal control far superior to other chemical and physical methods. The ability to regulate the activity of a catalytic enzyme in a biofuel-cell reduces the waste of resources and energy and turns the fuel-cell into a smart and more efficient device for power generation. Here we present a microbial-fuel-cell based on a surface displayed, photo-switchable alcohol dehydrogenase. The enzyme was modified near the active site using non-canonical amino acids and a small photo reactive molecule, which enables reversible control of enzymatic activity. Depending on the modification site, the enzyme exhibits reversible behavior upon irradiation with UV and visible light, in both biochemical, and electrochemical assays. The change observed in power output of a microbial fuel cell utilizing the modified enzyme was almost five-fold, between inactive and active states. PMID- 29411859 TI - Split trehalase as a versatile reporter for a wide range of biological analytes. AB - In health care, biosensors are envisioned as universal diagnostic devices with AAAA characteristics (i.e., available for anything, anywhere, anytime, to anyone). Despite numerous attempts to develop such a diagnostic device, none have managed to fulfill all four criteria and be commercialized. Glucometers, the most successful class of biosensor currently marketed monitor blood glucose concentrations. Their performance in clinical samples, including sensitivity and specificity, has been optimized and they are small and relatively inexpensive. We aimed to develop a technology that uses this existing biosensor, but adds versatility in detection of a wide range of analytes. Herein, we report the periplasmic trehalase of E. coli as a novel split enzyme reporter capable of converting a wide variety of analytes into glucose. Conditional complementation of trehalase fragments induced by detection of analytes, resulting in trehalose hydrolysis and glucose production, was used to detect antibodies and bacterial cells. We also demonstrated retention of split TreA activity in undiluted clinical samples. In conclusion, a trehalase-based biosensor platform offers a versatile and convenient method for point-of-care applications as it does not require sample preparation or handling and can be integrated with existing glucometers or sensors. PMID- 29411860 TI - Self-management for bronchiectasis. AB - BACKGROUND: Bronchiectasis is a long term respiratory condition with an increasing rate of diagnosis. It is associated with persistent symptoms, repeated infective exacerbations, and reduced quality of life, imposing a burden on individuals and healthcare systems. The main aims of therapeutic management are to reduce exacerbations and improve quality of life. Self-management interventions are potentially important for empowering people with bronchiectasis to manage their condition more effectively and to seek care in a timely manner. Self-management interventions are beneficial in the management of other airways diseases such as asthma and COPD (chronic obstructive pulmonary disease) and have been identified as a research priority for bronchiectasis. OBJECTIVES: To assess the efficacy, cost-effectiveness and adverse effects of self-management interventions for adults and children with non-cystic fibrosis bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Specialised Register of trials, clinical trials registers, reference lists of included studies and review articles, and relevant manufacturers' websites up to 13 December 2017. SELECTION CRITERIA: We included all randomised controlled trials of any duration that included adults or children with a diagnosis of non-cystic fibrosis bronchiectasis assessing self-management interventions delivered in any form. Self-management interventions included at least two of the following elements: patient education, airway clearance techniques, adherence to medication, exercise (including pulmonary rehabilitation) and action plans. DATA COLLECTION AND ANALYSIS: Two review authors independently screened searches, extracted study characteristics and outcome data and assessed risk of bias for each included study. Primary outcomes were, health-related quality of life, exacerbation frequency and serious adverse events. Secondary outcomes were the number of participants admitted to hospital on at least one occasion, lung function, symptoms, self-efficacy and economic costs. We used a random effects model for analyses and standard Cochrane methods throughout. MAIN RESULTS: Two studies with a total of 84 participants were included: a 12-month RCT of early rehabilitation in adults of mean age 72 years conducted in two centres in England (UK) and a six month proof-of-concept RCT of an expert patient programme (EPP) in adults of mean age 60 years in a single regional respiratory centre in Northern Ireland (UK). The EPP was delivered in group format once a week for eight weeks using standardised EPP materials plus disease-specific education including airway clearance techniques, dealing with symptoms, exacerbations, health promotion and available support. We did not find any studies that included children. Data aggregation was not possible and findings are reported narratively in the review.For the primary outcomes, both studies reported health-related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ), but there was no clear evidence of benefit. In one study, the mean SGRQ total scores were not significantly different at 6 weeks', 3 months' and 12 months' follow-up (12 months mean difference (MD) -10.27, 95% confidence interval (CI) -45.15 to 24.61). In the second study there were no significant differences in SGRQ. Total scores were not significantly different between groups (six months, MD 3.20, 95% CI -6.64 to 13.04). We judged the evidence for this outcome as low or very low. Neither of the included studies reported data on exacerbations requiring antibiotics. For serious adverse events, one study reported more deaths in the intervention group compared to the control group, (intervention: 4 of 8, control: 2 of 12), though interpretation is limited by the low event rate and the small number of participants in each group.For our secondary outcomes, there was no evidence of benefit in terms of frequency of hospital admissions or FEV1 L, based on very low-quality evidence. One study reported self-efficacy using the Chronic Disease Self-Efficacy scale, which comprises 10 components. All scales showed significant benefit from the intervention but effects were only sustained to study endpoint on the Managing Depression scale. Further details are reported in the main review. Based on overall study quality, we judged this evidence as low quality. Neither study reported data on respiratory symptoms, economic costs or adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether self-management interventions benefit people with bronchiectasis. In the absence of high-quality evidence it is advisable that practitioners adhere to current international guidelines that advocate self-management for people with bronchiectasis.Future studies should aim to clearly define and justify the specific nature of self-management, measure clinically important outcomes and include children as well as adults. PMID- 29411861 TI - The first Seriatum study of growth by R. E. Scammon. AB - Richard E. Scammon's article, "The First Seriatim Study of Human Growth," provided one of the best-known visuals in the field of human biology. Scammon resurrected longitudinal height data of one child from Buffon's Histoire Naturelle, converted them to metric, and plotted these measurements as a function of age. The result was the first graph of one individual's growth curve from birth to 18 years of age. This image was subsequently reproduced in numerous texts on human growth and biology. Published in 1927, Scammon's article provides a snapshot of the state of growth research at the time and gives a (literal) picture of the future of human biology. The graph of the growth of one child symbolizes the importance of process and variation in biological anthropology. PMID- 29411862 TI - A phase 1 dose-finding study of intravenous L-citrulline in sickle cell disease: a potential novel therapy for sickle cell pain crisis. PMID- 29411863 TI - When is a sentinel node biopsy indicated for patients with primary melanoma? Comment on the 'Australian guidelines for the management of cutaneous melanoma'. PMID- 29411864 TI - 'Role of sentinel lymph node biopsy as a staging procedure in patients with melanoma: A critical appraisal' by Omgo E Nieweg, Alan Cooper and John F Thompson. PMID- 29411865 TI - Purification, characterization, and N-glycosylation of recombinant butyrylcholinesterase from transgenic rice cell suspension cultures. AB - Recombinant butyrylcholinesterase produced in a metabolically regulated transgenic rice cell culture (rrBChE) was purified to produce a highly pure (95%), active form of enzyme. The developed downstream process uses common manufacturing friendly operations including tangential flow filtration, anion exchange chromatography, and affinity chromatography to obtain a process recovery of 42% active rrBChE. The purified rrBChE was then characterized to confirm its comparability to the native human form of the molecule (hBChE). The recombinant and native enzyme demonstrated comparable enzymatic behavior and had an identical amino acid sequence. However, rrBChE differs in that it contains plant-type complex N-glycans, including an alpha-1,3 linked core fucose, and a beta-1,2 xylose, and lacking a terminal sialic acid. Despite this difference, rrBChE is demonstrated to be an effective stoichiometric bioscavenger for five different organophosphorous nerve agents in vitro. Together, the efficient downstream processing scheme and functionality of rrBChE confirm its promise as a cost effective alternative to hBChE for prophylactic and therapeutic use. PMID- 29411866 TI - Leaf N resorption efficiency and litter N mineralization rate have a genotypic tradeoff in a silver birch population. AB - Plants enhance N use efficiency by resorbing N from senescing leaves. This can affect litter N mineralization rate due to the C:N-ratio requirements of microbial growth. We examined genotypic links between leaf N resorption and litter mineralization by collecting leaves and litter from 19 Betula pendula genotypes and following the N release of litter patches on forest ground. We found significant genotypic variation for N resorption efficiency, litter N concentration, cumulative three-year patch N-input and litter N release with high broad-sense heritabilities (H2 = 0.28-0.65). The genotype means of N resorption efficiency varied from 46% to 65% and correlated negatively with the genotype means of litter N concentration, cumulative patch N-input and litter N release. NH4+ yield under patches had a positive genotypic correlation with the cumulative patch N-input. During the first year of litter decomposition, genotypes varied from N immobilization (max 2.71 mg/g dry litter) to N release (max 1.41 mg/g dry litter), creating a genotypic tradeoff between the N conserved by resorption and the N available for root uptake during the growing season. We speculate that this tradeoff is one likely reason for the remarkably wide genotypic range of N resorption efficiencies in our birch population. PMID- 29411867 TI - WITHDRAWN: Systemic treatments for metastatic cutaneous melanoma. AB - BACKGROUND: Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation.Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. OBJECTIVES: To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. SEARCH METHODS: Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. SELECTION CRITERIA: Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. DATA COLLECTION AND ANALYSIS: Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. MAIN RESULTS: No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma.Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine. PMID- 29411869 TI - Is cortisol production in response to an acute stressor associated with diurnal cortisol production during adolescence? AB - The goal of the current study was to examine the extent to which cortisol responding to an acute stressor is related to diurnal cortisol patterns during adolescence. Participants were 105 adolescents (10-17 years of age) who experienced a robust social-evaluative stressor and provided saliva samples (before and immediately after, as well as 10, 20, and 30 min after the stressor) to assess both cortisol reactivity and recovery and also provided saliva samples (at wake-up, 30 min after wake-up, 4 pm, and at bedtime) on two consecutive days to measure diurnal cortisol production. Dual process latent growth curve models, one for cortisol reactivity and one for diurnal cortisol, indicated that dampened cortisol reactivity and prolonged cortisol recovery (i.e., less cortisol produced during reactivity but more cortisol produced during recovery) were associated with dampened decreases in cortisol production across the day, suggesting that adolescents are likely to show attenuation in multiple components of HPA axis functioning. PMID- 29411868 TI - Ethnic density and cancer: A review of the evidence. AB - Accumulating data suggest that factors in the social environment may be associated with cancer-related outcomes. Ethnic density, defined as the proportion of racial/ethnic minority individuals residing in a given geographic area, is 1 of the most frequently studied social environment factors, but studies on ethnic density and cancer have yielded inconsistent findings. Thus, the objective of the current review was to summarize the extant data on ethnic density and cancer-related outcomes (cancer risk, stage at diagnosis, and mortality) with the aim of identifying pathways by which ethnic density may contribute to outcomes across populations. In general, the findings indicated an association between ethnic density and increased risk for cancers of infectious origin (eg, liver, cervical) but lower risk for breast and colorectal cancers, particularly among Hispanic and Asian Americans. Hispanic ethnic density was associated with greater odds of late-stage cancer diagnosis, whereas black ethnic density was associated with greater mortality. In addition, this review highlights several methodological and conceptual issues surrounding the measurement of ethnic neighborhoods and their available resources. Clarifying the role of neighborhood ethnic density is critical to developing a greater understanding of the health risks and benefits accompanying these environments and how they may affect racial and ethnic disparities in cancer-related outcomes. Cancer 2018;124:1877-903. (c) 2018 American Cancer Society. PMID- 29411870 TI - Specific glycine to alanine mutation eliminates dynamic interaction of polymeric GlyT1a N-terminus with Coomassie Brilliant Blue G-250. AB - We previously found that multimeric GlyT1aN16 protein exhibits increased diffusion in a polyacrylamide gel and shows an unusual time-dependent absorbance rearrangement, as revealed by the Bradford assay. Here, we find that glycine to alanine mutation eliminates the absorbance shift, but not the altered diffusion properties of GlyT1aN16, indicating that these two phenomena are not interconnected. The absorbance shift is apparent with both native and urea denatured GlyT1aN16, suggesting that the effect is either not dependent on protein structure, or the required structure is restored very quickly following denaturant removal. In the far-UV spectra, circular dichroism (CD) curves for both wild-type and mutated GlyT1aN16 are under the zero line, indicating largely unstructured character. However, a significant shift of the mutant CD curve suggests possible microstructural heterogeneity. Deconvolution of the CD data indicates a potential 3-fold increase in isolated helical content, which would inhibit an absorbance shift, as we demonstrated previously. These results suggest that, in addition to protein quantification, Coomassie Brilliant Blue G-250 can be used to reveal certain properties of the secondary structure of proteins. PMID- 29411871 TI - End-state comfort in two object manipulation tasks: Investigating how the movement context influences planning in children, young adults, and older adults. AB - The movement context (pantomime, pantomime with image/object as guide, and actual use) has been shown to influence end-state comfort-the propensity to prioritize a comfortable final hand position over an initially comfortable one-across the lifespan. The present study aimed to assess how the movement context (pantomime, using a dowel as the tool, and actual use) influences end-state comfort when acting with objects (glass/hammer) that differ in use-dependent experience. Children (ages 6-11, n = 70), young adults (n = 21), and older adults (n = 21) picked up an overturned glass to pour water and a hammer to hit a nail, where the handle faced away from the participant. End-state comfort was assessed in each movement context. Findings provide support for an increase in end-state comfort with age, adult-like patterns at age 10, and no difference between older adults and 8- to 9-year-old children. In addition, this work revealed that perception of "graspability" led to an increase in end-state comfort in the hammering task; therefore, suggesting our ability to act with objects and tools in the environment is influenced by use-dependent experience and object perception. Results add to our understanding of changes in motor planning abilities with age, and factors underlying these changes. PMID- 29411872 TI - Ascorbic Acid-Based Oxygen Scavenger in Active Food Packaging System for Raw Meatloaf. AB - : A nonferrous oxygen scavenger (NFOS) comprising activated carbon and sodium l ascorbate was developed to enhance the preservative efficacy of raw meatloaves. To determine the optimum formulation of activated carbon and sodium l-ascorbate, NFOSs with varying ratios of components (1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, and 1:2, w/w) were prepared and their oxygen-scavenging volumes were measured over 4 d at 25 degrees C. Assays of oxygen-scavenging capacities indicated that the optimum NFOS formulation of activated carbon and sodium l-ascorbate was achieved at a ratio of 1:1.6 (w/w). Finally, the optimal NFOS sachet was applied to packaging of raw meatloaves and its oxygen-scavenging capacity was periodically analyzed. Moreover, microbiological changes (including total aerobic bacteria, lactic acid bacteria, and yeasts and molds) and an effect on lipid oxidation during the storage were examined at 4 degrees C for 4 d. The meatloaves packaged with NFOS sachet had lower thiobarbituric acid reactive substances and microbiological changes than control meatloaves, indicating the practical utility in the food packaging industry. PRACTICAL APPLICATION: Oxygen-scavenging sachets containing iron powder have been generally used although those have several problems. Therefore, to solve them, an ascorbic acid-based oxygen scavenger composed of activated carbon and sodium l-ascorbate was newly developed. It did not only inhibit lipid oxidation but also reduce microbial growth in meatloaves. It could be used as a promising packaging material to protect meat products from lipid oxidation and microbial contamination. PMID- 29411873 TI - Modeling Transfer of Vibrio Parahaemolyticus During Peeling of Raw Shrimp. AB - : This study aimed to qualify the transfer of Vibrio parahaemolyticus during the shrimp peeling process via gloves under 3 different scenarios. The 1st 2 scenarios provided quantitative information for the probability distribution of bacterial transfer rates from (i) contaminated shrimp (6 log CFU/g) to non contaminated gloves (Scenario 1) and (ii) contaminated gloves (6 log CFU/per pair) to non-contaminated shrimp (Scenario 2). In Scenario 3, bacterial transfer from contaminated shrimp to non-contaminated shrimp in the shrimp peeling process via gloves was investigated to develop a predictive model for describing the successive bacterial transfer. The range of bacterial transfer rate (%) in Scenarios 1 and 2 was 7% to 91.95% and 0.04% to 12.87%, respectively, indicating that the bacteria can be transferred from shrimp to gloves much easier than that from gloves to shrimp. A Logistic (1.59, 0.14) and Triangle distribution (-1.61, 0.12, 1.32) could be used to describe the bacterial transfer rate in Scenarios 1 and 2, respectively. In Scenario 3, a continuously decay patterning with fluctuations as the peeling progressed has been observed at all inoculation levels of the 1st shrimp (5, 6, and 7 log CFU/g). The bacteria could be transferred easier at 1st few peels, and the decreasing bacterial transfer was found in later phase. Two models (exponential and Weibull) could describe the successive bacterial transfer satisfactorily (pseudo-R2 > 0.84, RMSE < 1.23, SEP < 10.37). The result of this study can provide information regarding cross contamination events in the seafood factory. PRACTICAL APPLICATION: This study presented that Vibrio parahaemolyticus cross-contamination could be caused by gloves during the shrimp peeling process. The bacterial transfer rate distribution and predictive model derived from this work could be used in risk assessment of V. parahaemolyticus to ensure peeled shrimp safety. PMID- 29411875 TI - Parameters critical for the effector mechanism of anti-CD20 antibodies revisited. PMID- 29411874 TI - Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma. PMID- 29411876 TI - Wide skin markings pattern: melanoma descriptor or patient-related factor?: reply from the authors. PMID- 29411877 TI - Contrasting acclimation abilities of two dominant boreal conifers to elevated CO2 and temperature. AB - High latitude forests will experience large changes in temperature and CO2 concentrations this century. We evaluated the effects of future climate conditions on 2 dominant boreal tree species, Pinus sylvestris L. and Picea abies (L.) H. Karst, exposing seedlings to 3 seasons of ambient (430 ppm) or elevated CO2 (750 ppm) and ambient temperatures, a + 4 degrees C warming or a + 8 degrees C warming. Pinus sylvestris responded positively to warming: seedlings developed a larger canopy, maintained high net CO2 assimilation rates (Anet ), and acclimated dark respiration (Rdark ). In contrast, carbon fluxes in Picea abies were negatively impacted by warming: maximum rates of Anet decreased, electron transport was redirected to alternative electron acceptors, and thermal acclimation of Rdark was weak. Elevated CO2 tended to exacerbate these effects in warm-grown Picea abies, and by the end of the experiment Picea abies from the +8 degrees C, high CO2 treatment produced fewer buds than they had 3 years earlier. Treatments had little effect on leaf and wood anatomy. Our results highlight that species within the same plant functional type may show opposite responses to warming and imply that Picea abies may be particularly vulnerable to warming due to low plasticity in photosynthetic and respiratory metabolism. PMID- 29411878 TI - The breakdown of genomic ancestry blocks in hybrid lineages given a finite number of recombination sites. AB - When a lineage originates from hybridization genomic blocks of contiguous ancestry from different ancestors are fragmented through genetic recombination. The resulting blocks are delineated by so called junctions, which accumulate with every generation that passes. Modeling the accumulation of ancestry block junctions can elucidate processes and timeframes of genomic admixture. Previous models have not addressed ancestry block dynamics for chromosomes that consist of a finite number of recombination sites. However, genomic data typically consist of informative markers that are interspersed with fragments for which no ancestry information is available. Hence, repeated recombination events may occur between markers, effectively removing existing junctions. Here, we present an analytical treatment of the dynamics of the mean number of junctions over time, taking into account the number of recombination sites per chromosome, population size, genetic map length, and the frequency of the ancestral species in the founding hybrid swarm. We describe the expected number of junctions using equidistant molecular markers and estimate the number of junctions using random markers. This extended theory of junctions thus reflects properties of empirical data and can serve to study the genomic patterns following admixture. PMID- 29411879 TI - Understanding drug interactions with St John's wort (Hypericum perforatum L.): impact of hyperforin content. AB - OBJECTIVE: The aim of this study was to review herb-drug interaction studies with St John's wort (Hypericum perforatum L.) with a focus on the hyperforin content of the extracts used in these studies. METHODS: PUBMED was systematically searched to identify studies describing pharmacokinetic interactions involving St John's wort. Data on study design and the St John's wort extract or product were gathered to extract hyperforin content and daily dose used in interaction studies. KEY FINDINGS: This analysis demonstrates that significant herb-drug interactions (resulting in a substantial change in systemic exposure) with St John's wort products were associated with hyperforin daily dosage. Products that had a daily dose of <1 mg hyperforin were less likely to be associated with major interaction for drugs that were CYP3A4 or p-glycoprotein substrates. Although a risk of interactions cannot be excluded even for low-dose hyperforin St. John's wort extracts, the use of products that result in a dose of not more than 1 mg hyperforin per day is recommended to minimise the risk of interactions. CONCLUSIONS: This review highlights that the significance of herb-drug interactions with St John's wort is influenced by the nature of the herbal medicines product, particularly the hyperforin content. PMID- 29411880 TI - Indirect presentation in the thymus limits naive and regulatory T-cell differentiation by promoting deletion of self-reactive thymocytes. AB - Acquisition of T-cell central tolerance involves distinct pathways of self antigen presentation to thymocytes. One pathway termed indirect presentation requires a self-antigen transfer step from thymic epithelial cells (TECs) to bone marrow-derived cells before the self-antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context-dependent, potentially due to variation in self-antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane bound transgenic self-antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow-derived antigen-presenting cells, insHEL mediated thymocyte deletion was abolished, whereas thyroHEL-mediated deletion occurred at a later stage of thymocyte development and Foxp3+ regulatory T-cell differentiation increased. Indirect presentation increased the strength of T-cell receptor signalling that both self-antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self-reactive thymocytes. PMID- 29411882 TI - Cloning, expression, and characterization of thermal-stable and pH-stable agarase from mangrove sediments. AB - AgaM1, a beta-agarase belonging to glycoside hydrolases family 16 (GH16), was cloned from the environmental DNA of mangrove sediments. The gene agaM1 is 2136 bp in length and encodes a protein of 712 amino acids. The properties of recombinant AgaM1 (rAgaM1) were studied using prokaryotic expression. The optimum temperature and pH were 50 degrees C and 7.0, respectively, and rAgaM1 exhibited a high adaptability to wide ranges of temperature and pH. A relatively high activity was retained at from 30 to 60 degrees C and from pH 6.0 to 9.0. Thermal stability was showed more than 70% relative activity after pre-incubation at 40 degrees C for 60 h. Outstanding pH stability were observed for rAgaM1 from pH 5.0 to 10.0 after pre-incubation for 60 h. Thin-layer chromatography revealed neoagarotetraose (NA4) and neoagarohexaose (NA6) were the end-products of rAgaM1 degraded agarose. Besides, rAgaM1 were found with a Km of 1.82 mg ml-1 and a Vm of 357.14 U mg-1 for agarose. The Km was smaller than those of most agarases reported previously. This discrepancy revealed the high affinity of rAgaM1 to agarose. Overall, the results indicated the potential of rAgaM1 in future industrial application. PMID- 29411881 TI - Green synthesized silver nanoparticles demonstrating enhanced in vitro and in vivo antibiofilm activity against Candida spp. AB - Candida species are opportunistic fungal pathogens, which are known for their biofilm associated infections on implanted medical devices in clinical settings. Broad spectrum usage of azole groups and other antifungal agents leads to the occurrence of drug resistance among Candida species. Most of the antifungal agents have failed to treat the biofilm mediated Candida infections. In the present study, silver nanoparticles (AgNPs) were synthesized using Dodonaea viscosa and Hyptis suoveolens methanolic leaf extracts and characterized by ultraviolet-visible absorption spectroscopy, X-ray diffraction analysis, Fourier transform infrared spectroscopy and Scanning electron microscopy, Dynamic light scattering, and Zeta potential analysis. The main goal of this study was to assess the AgNPs for their antibiofilm efficacy against Candida spp. through microscopic analysis and in vitro virulence assays. The results revealed that AgNPs strongly inhibited more than 80% biofilm formed by Candida spp. Furthermore, the AgNPs also reduced the yeast-to-hyphal transition, exopolysaccharide biosynthesis, secreted aspartyl proteinase production which are the major virulence factors of Candida species. This study reveals that biosynthesized AgNPs can be considered for the treatment of biofilm related Candida infections. PMID- 29411884 TI - Blastic plasmacytoid dendritic cell neoplasm with unusual morphology, MYC rearrangement and TET2 and DNMT3A mutations. PMID- 29411883 TI - Lethality Prediction for Escherichia Coli O157:H7 and Uropathogenic E. coli in Ground Chicken Treated with High Pressure Processing and Trans-Cinnamaldehyde. AB - : Pathogenic Escherichia coli, intestinal (O157:H7) as well as extraintestinal types (for example, Uropathogenic E. coli [UPEC]) are commonly found in many foods including raw chicken meat. The resistance of E. coli O157:H7 to UPEC in chicken meat under the stresses of high hydrostatic Pressure (HHP, also known as HPP-high pressure processing) and trans-cinnamaldehyde (an essential oil) was investigated and compared. UPEC was found slightly less resistant than O157:H7 in our test parameter ranges. With the addition of trans-cinnamaldehyde as an antimicrobial to meat, HPP lethality enhanced both O157:H7 and UPEC inactivation. To facilitate the predictive model development, a central composite design (CCD) was used to assess the 3-parameter effects, that is, pressure (300 to 400 MPa), trans-cinnamaldehyde dose (0.2 to 0.5%, w/w), and pressure-holding time (15 to 25 min), on the inactivation of E. coli O157:H7 and UPEC in ground chicken. Linear models were developed to estimate the lethality of E. coli O157:H7 (R2 = 0.86) and UPEC (R2 = 0.85), as well as dimensionless nonlinear models. All models were validated with data obtained from separated CCD combinations. Because linear models of O157:H7 and UPEC had similar R2 and the significant lethality difference of CCD points was only 9 in 20; all data were combined to generate models to include both O157:H7 and UPEC. The results provide useful information/tool to predict how pathogenic E. coli may survive HPP in the presence of trans-cinnamaldehyde and to achieve a great than 5 log CFU/g reduction in chicken meat. The models may be used for process optimization, product development and to assist the microbial risk assessment. PRACTICAL APPLICATION: The study provided an effective means to reduce the high hydrostatic pressure level with incorporation of antimicrobial compound to achieve a 5-log reduction of pathogenic E. coli without damaging the raw meat quality. The developed models may be used to predict the high pressure processing lethality (and process optimization), product development (ingredient selection), and to assist the microbial risk assessment. PMID- 29411885 TI - Comment on Eckberg et al. 2016. PMID- 29411886 TI - Supplementation of quercetin for advanced DNA integrity in bull semen cryopreservation. AB - The aim of this study was to identify the effects of adding quercetin (Q) to Tris extender in order to identify levels of oxidative stress in bull sperm after freeze thawing. Ejaculates were collected via artificial vagina from Holstein bulls. Semen was divided into five tools and diluted to a final concentration of 15 * 106 spermatozoa/ml with the Tris extender containing Q (25, 50, 100 and 200 MUg/ml) and no additive (control; C). All examples were equilibrated at 4 degrees C during 4 hr then were loaded into 0.25-ml straws and frozen using a controlled rate. Sperm motility and motility characteristics were determined using the computer-assisted semen analyser. Sperm membrane integrity was assessed using the hypoosmotic swelling test. Sperm chromatin integrity was investigated using the single cell gel electrophoresis. Total antioxidant capacities were performed colorimetrically. Q supplementation used as an antioxidant did not produce better results in the proportion of sperm progressive and total motility, plasma membrane integrity and sperm abnormalities. Q supplementation exhibited the favourable tail length, tail DNA and tail moment. In conclusion, when whole parameters are considered, Q25 can be added to the Tris extender due to its positive effect on sperm DNA integrity and no adverse effect on the progressive and total motilities of sperm. PMID- 29411887 TI - Infant feeding-related maternity care practices and maternal report of breastfeeding outcomes. AB - BACKGROUND: Evidence-based maternity practices and policies can improve breastfeeding duration and exclusivity. Maternity facilities report practices through the Maternity Practices in Infant Nutrition and Care (mPINC) survey, but individual outcomes, such as breastfeeding duration and exclusivity, are not collected. METHODS: mPINC data on maternity care practices for 2009 were linked to data from the 2009 Pregnancy Risk Assessment Monitoring System (PRAMS), which collects information on mothers' behaviors and experiences around pregnancy. We calculated total mPINC scores (range 0-100). PRAMS data on any and exclusive breastfeeding at 8 weeks were examined by total mPINC score quartile. RESULTS: Of 15 715 women in our sample, 53.7% were breastfeeding any at 8 weeks, and 29.3% were breastfeeding exclusively. They gave birth at 1016 facilities that had a mean total mPINC score of 65/100 (range 19-99). Care dimension subscores ranged from 41 for facility discharge care to 81 for breastfeeding assistance. In multivariable analysis adjusting for covariates, a positive relationship was found between total mPINC score quartile and both any breastfeeding (quartile 2: odds ratio [OR] 1.40 [95% confidence interval {CI} 1.08-1.83], quartile 3: OR 1.50 [95% CI 1.15-1.96], quartile 4: OR 2.12 [95% CI 1.61-2.78] vs quartile 1) and exclusive breastfeeding (quartile 3: OR 1.41 [95% CI 1.04-1.90], quartile 4: OR 1.89 [95% CI 1.41-2.55] vs quartile 1) at 8 weeks. CONCLUSIONS: These data demonstrate that evidence-based maternity care practices and policies are associated with better breastfeeding outcomes. Maternity facilities may evaluate their practices and policies to ensure they are helping mothers achieve their breastfeeding goals. PMID- 29411888 TI - The ameliorative effects of Ginkgo biloba on apoptosis, LH-R expression and sperm morphology anomaly in testicular torsion and detorsion. AB - Torsion/detorsion (T/D) induces testicular damages in both germinal epithelial and interstitial tissues. Ginkgo biloba extract (GbE) exerts antioxidant and free radical scavenger. We investigated the effect of GbE on testicular tissues, Leydig and sperm cells in rats injured with T/D. Twenty-eight Wistar albino rats were randomly assigned into four groups (Control, GbE, Treatment: T/D+GbE, T/D). T/D performed to the rats in torsion, treatment received GbE (50 mg/kg) 1 hr before T/D, GbE group received only GbE (50 mg/kg) and control was defined as sham group. After T/D, the testes along with epididymis were removed and processed. LH-R expression, apoptosis, sperm morphology and histopathological damage scores were determined for each group. Testicular T/D caused significant increases in apoptosis and sperm morphology anomaly, and a significant decrease in Johnsen's testicular biopsy scores, LH-R expression of Leydig cell and normal sperm cell count. GbE ameliorated testicular histopathology and caused significant increases in LH-R expression, normal sperm cell count in the treated and particularly GbE group. Consequently, GbE may prevent testicular injury and enhance Leydig and sperm cell activity following both T/D and normal situation owing to its antioxidant, anti-apoptotic, free radical scavenger and anti inflammatory effects. PMID- 29411889 TI - Thiol-disulphide homoeostasis as an oxidative stress marker in men with varicocele. AB - Oxidative stress is the most common factor leading to infertility in men with varicocele. Reactive oxygen species and other markers of oxidative stress are measured to predict the extent of oxidative stress. Thiol groups are important antioxidants and essential molecules protecting organism against the harmful effects of reactive oxygen species. Thiol-disulphide homoeostasis is a unique, easy and new method to demonstrate oxidative stress. The aim of this study was to determine thiol-disulphide homoeostasis as an oxidative stress marker in infertile men with varicocele. The hormonal profile and parameters of thiol disulphide homoeostasis were studied in 46 infertile men with varicocele, 70 fertile men with varicocele and 37 fertile controls. Infertile men with varicocele had significantly higher disulphide concentrations and disulphide/native thiol, disulphide/total thiol and native/total thiol ratios than those of fertile men with varicocele and fertile controls. According to these results, the blood plasma of patients with varicocele contains excessive oxidative stress, even in men with normospermia, and therefore, thiol-disulphide homoeostasis may be useful as an oxidative stress marker in men with varicocele. PMID- 29411890 TI - Breastfeeding and the substance-exposed mother and baby. AB - BACKGROUND: Breastfeeding rates are typically low for women with a substance-use disorder. This is despite the specific benefits of breastfeeding to alleviate the severity of neonatal abstinence syndrome and the well-documented generic advantages. This study explored the feasibility of in-hospital, tailored breastfeeding support for the substance-exposed mother and baby. METHODS: This was a mixed-methods feasibility study undertaken in Scotland from April 2014 to May 2015. Women with a substance-use disorder either received standard Baby Friendly Initiative care only or were given additional support which included a dedicated breastfeeding support worker, personalized capacity-building approach, and a low-stimuli environment for 5 days. Feasibility outcome measures were maternal recruitment, satisfaction and acceptability of support, breastfeeding on fifth postnatal day, and severity of neonatal abstinence syndrome. RESULTS: Fourteen mother-infant dyads participated. Intervention participants demonstrated higher rates of continued breastfeeding and reported a greater degree of satisfaction with support and confidence in their breastfeeding ability. Maternal experience of health care practices, attitudes, and postnatal environment influenced their perceptions of breastfeeding support. Breastfed infants were less likely to require pharmacotherapy for neonatal withdrawal and had a shorter hospital stay. CONCLUSIONS: The findings highlight the feasibility of tailored breastfeeding support for the substance-exposed mother and baby and endorse the promotion and support of breastfeeding for this group. Future research should include a statistically powered randomized controlled trial to evaluate clinical efficacy. PMID- 29411891 TI - Effect of gestational diabetes mellitus on testis and pancreatic tissues of male offspring. AB - The purpose of this study was to determine the effect of gestational diabetes mellitus (GDM) on some reproductive characteristics, testicular and pancreatic oxidative status and pancreatic endocrine receptor densities of male offspring at post-pubertal stage. A total of 36 1-day-old Wistar Albino male offspring including 12 pups of nontreated mothers (control group), 14 pups of 40 mg/kg STZ injected mothers (STZ-40 group) and 10 pups of 60 mg/kg STZ-injected mothers (STZ 60 group) were used. The offspring were euthanised on post-natal day 60, their blood, reproductive organs and pancreatic tissues were obtained and examined. When compared with the control group, there was a significant decrease in body and absolute reproductive organ weights, serum testosterone level, testicular and pancreatic catalase activities, pancreatic glutathione level, epididymal sperm concentration of both STZ-40 and STZ-60 groups as well as in testicular glutathione level of only STZ-60 group. Significant increases were determined in testicular and pancreatic malondialdehyde level and glutathione peroxidase activity in both groups and in fasting serum glucose of only STZ-60 group in comparison with the control group. Although some histopathological damages were observed in testes of both STZ-40 and STZ-60 groups, there were no detectable differences between the groups in density of insulin, glucagon and somatostatin receptors in pancreas. In conclusion, GDM has negative effects on reproductive efficiency and testicular-pancreatic tissue oxidant/antioxidant balance of male offspring at post-pubertal stage. PMID- 29411892 TI - Identification of novel translocation between short arm of chromosome 4 and long arm of chromosome 6 in an infertile man using Interphase Chromosome Profiling (ICP). AB - Conventional cytogenetics has always been a favourite to detect chromosomal aberrations. Carriers of chromosomal translocation are often phenotypically normal but are infertile. Couples are often advised to go for karyotyping, but culture failure or improper metaphase spread with poor banding often makes the analysis difficult. We report here a novel translocation between short arm of chromosome 4 and long arm of chromosome 6 in an infertile man using an advanced molecular cytogenetic technique of Interphase Chromosome Profiling (ICP). PMID- 29411893 TI - Genome-wide association study for reproductive traits in a Large White pig population. AB - Using the PorcineSNP80 BeadChip, we performed a genome-wide association study for seven reproductive traits, including total number born, number born alive, litter birth weight, average birth weight, gestation length, age at first service and age at first farrowing, in a population of 1207 Large White pigs. In total, we detected 12 genome-wide significant and 41 suggestive significant SNPs associated with six reproductive traits. The proportion of phenotypic variance explained by all significant SNPs for each trait ranged from 4.46% (number born alive) to 11.49% (gestation length). Among them, 29 significant SNPs were located within known QTL regions for swine reproductive traits, such as corpus luteum number, stillborn number and litter size, of which one QTL region associated with litter size contained the ALGA0098819 SNP for total number born. Subsequently, we found that 376 functional genes contained or were near these significant SNPs. Of these, 14 genes-BHLHA15, OCM2, IL1B2, GCK, SMAD2, HABP2, PAQR5, GRB10, PRELID2, DMKN, GPI, GPIHBP1, ADCY2 and ACVR2B-were considered important candidates for swine reproductive traits based on their critical roles in embryonic development, energy metabolism and growth development. Our findings contribute to the understanding of the genetic mechanisms for reproductive traits and could have a positive effect on pig breeding programs. PMID- 29411895 TI - SUMOylation: One small modification for proteins, multiple giant problems for mankind. PMID- 29411894 TI - Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF-1alpha-VEGF pathway in oxygen-induced retinopathy mice. AB - Retinopathy of prematurity (ROP) is a retinopathy characterized by retinal neovascularization (RNV) occurring in preterm infants treated with high concentrations of oxygen and may lead to blindness in severe cases. Currently, anti-VEGF therapy is a major treatment for ROP, but it is costly and may cause serious complications. The previous study has demonstrated that melatonin exerted neuroprotective effect against retinal ganglion cell death induced by hypoxia in neonatal rats. However, whether melatonin is anti-angiogenic and neuroglial protective in the progression of ROP remains unknown. Thus, this study was to investigate the effect of melatonin on RNV and neuroglia in the retina of oxygen induced retinopathy (OIR) mice. The results showed a reduction in retinal vascular leakage in OIR mice after melatonin treatment. Besides, the size of retinal neovascular and avascular areas, the number of preretinal neovascular cell nuclei, and the number of proliferative vascular endothelial cells within the neovascular area were significantly decreased in mice treated with melatonin. After oxygen-induced injury, the density of astrocytes was decreased, accompanied by morphologic and functional changes of astrocytes. Besides, retinal microglia were also activated. Meanwhile, the levels of inflammatory factors were elevated. However, these pathologic processes were all hindered by melatonin treatment. Furthermore, HIF-1alpha-VEGF pathway was activated in the retina of OIR mice, yet was suppressed in melatonin-treated OIR mice retinas. In conclusion, melatonin prevented pathologic neovascularization, protected neuroglial cells, and exerts anti-inflammation effect via inhibition of HIF-1alpha-VEGF pathway in OIR retinas, suggesting that melatonin could be a promising therapeutic agent for ROP. PMID- 29411896 TI - 1 H and 13 C NMR characterization of 1,3,4-oxadiazole derivatives. PMID- 29411897 TI - The immunopathogenic and immunomodulatory effects of interleukin-12 in periodontal disease. AB - Interleukin 12 (IL-12) is an inflammatory cytokine that promotes the response of the immune system. This cytokine has been implicated as a potent stimulator of several diseases characterized by inflammatory-induced bone destruction, such as rheumatoid arthritis and periodontitis. Yet, the exact role of IL-12 in the development and progress of periodontitis has not been clarified. Several studies have demonstrated a positive correlation between the level of IL-12 and the severity of periodontal destruction. Deletion of IL-12 in mice with periodontitis significantly suppressed the level of bone destruction. Interestingly, next to a role in modulating the pathogenesis, IL-12 also has immunological-regulatory properties. This cytokine induces expression of immunosuppressive molecules, such as indoleamine-pyrrole 2,3-dioxygenase (IDO). Thus, these findings suggest both negative and positive influences of IL-12 in periodontal disease. It is currently proposed that the diversity of action of cytokines is a molecular key which regulates biological development and homeostasis. Accordingly, the actions of IL 12 might be one of the mechanisms that regulate homeostasis of periodontal tissue during and following inflammation. Therefore, this article aims to review both destructive and protective functionalities of IL-12 with an emphasis on periodontal disease. PMID- 29411898 TI - Insight into old and new pure shift nuclear magnetic resonance methods for enantiodiscrimination. AB - Enantiodiscrimination and their quantification using nuclear magnetic resonance (NMR) spectroscopy has always been a subject of great interest. Proton is the nucleus of choice for enantiodiscrimination due to its high sensitivity and ubiquitous presence in nature. Despite its advantages, enantiodiscrimination suffers from extensive signal splitting by the proton-proton scalar couplings, which give complex multiplets that spread over a frequency range of some tens of hertz. These multiplets often overlap, further complicating interpretation of the spectra and quantifications. In the present review, we discuss some of the recent developments in the pure shift 1 H NMR based methods for enantiomer resolution and enantiodiscrimination. We also compare various pure shift methods used for enantiodiscrimination and measurement of enantiomeric excess, considering the fact that conventional 1 H NMR fails to provide any detailed insight. PMID- 29411900 TI - In vivo comparison of medialized dome and anatomic patellofemoral geometries using subject-specific computational modeling. AB - Successful outcome following total knee arthroplasty (TKA) with patella resurfacing is partly determined by the restoration of patellofemoral (PF) function and recovery of the quadriceps mechanism. The current study compared two patellar TKA geometries (medialized dome and anatomic) to determine their impact on PF mechanics and quadriceps function. In-vivo, subject-specific patellar mechanics were evaluated using a sequential experimental and modeling approach. First, stereo radiography, marker-based motion capture, and force plate data were collected for TKA patients (10 dome, 10 anatomic) performing a knee extension and lunge. Second, subject-specific, whole-body, musculoskeletal models, including 6 degrees-of-freedom (DOF) knee joint kinematics, were created for each subject and activity to predict quadriceps forces. Last, finite element models of each subject and activity were created to predict PF kinematics, patellar loading, moment arm, and patellar tendon angle. Differences in mechanics between dome and anatomic patients were highlighted during load-bearing (lunge) activity. Anatomic subjects demonstrated greater PF flexion angles (avg. 11 +/- 3 degrees ) compared to dome subjects during lunge. Similar to the natural knee, contact locations on the patella migrated inferior to superior as the knee flexed in anatomic subjects, but remained relatively superior in dome subjects. Differences in kinematics and contact location likely contributed to altered mechanics with anatomic subjects presenting greater load transfer from the quadriceps to the patellar tendon in deep flexion (>75 degrees ), and dome subjects demonstrating larger contact forces during lunge. Although there was substantial patient variability, evaluations of PF mechanics suggested improved quadriceps function and more natural kinematics in the anatomic design. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1910-1918, 2018. PMID- 29411901 TI - Reactive Oxygen Species: Radical Factors in the Evolution of Animal Life: A molecular timescale from Earth's earliest history to the rise of complex life. AB - Introduction of O2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O2 also presented major challenges as O2 and many of its derived reactive oxygen species (ROS) are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to play a major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. PMID- 29411899 TI - Quantity and Diversity: Simulating Early Word Learning Environments. AB - The words in children's language learning environments are strongly predictive of cognitive development and school achievement. But how do we measure language environments and do so at the scale of the many words that children hear day in, day out? The quantity and quality of words in a child's input are typically measured in terms of total amount of talk and the lexical diversity in that talk. There are disagreements in the literature whether amount or diversity is the more critical measure of the input. Here we analyze the properties of a large corpus (6.5 million words) of speech to children and simulate learning environments that differ in amount of talk per unit time, lexical diversity, and the contexts of talk. The central conclusion is that what researchers need to theoretically understand, measure, and change is not the total amount of words, or the diversity of words, but the function that relates total words to the diversity of words, and how that function changes across different contexts of talk. PMID- 29411902 TI - Japan Gastroenterological Endoscopy Society guidelines for endoscopic papillary large balloon dilation. AB - The Japan Gastroenterological Endoscopy Society has developed the 'EPLBD Clinical Practice Guidelines' as fundamental guidelines based on new scientific techniques. EPLBD is a treatment method that has recently become widely used for choledocolithiasis. The evidence level in this field is usually low, and in many instances, the recommendation grading has to be determined on the basis of expert consensus. At this point, the guidelines are divided into the following six sections according to the 'EST Clinical Practice Guidelines': (i) Indications, (ii) procedures, (iii) special cases, (iv) procedure-related adverse events, (v) treatment outcomes, and (vi) postoperative follow up observation. PMID- 29411903 TI - Solutions to wildlife laundering in Indonesia: reply to Janssen and Chng 2018. PMID- 29411904 TI - Triple Noncovalent-Interaction-Containing Supramolecular Polymer Vesicle Chemosensors with Dynamically Tunable Detection Ranges. AB - Chemosensors (CSs) with dynamically tunable detection ranges have important significance for their expansion in practical applications; however, most CSs possess an unchangeable detection limit. In this work, we report the first example of a supramolecular polymer vesicle (SPV) chemosensor with a dynamically tunable detection range. SPVs containing porphyrin (PP) moieties and beta cyclodextrin (beta-CD)/azobenzene (Azo) host-guest interactions were first constructed. The obtained SPVs were used to detect Zn2+ with a high selectivity and sensitivity over a wide detection limit range of 8.67*10-9 to 1.99*10-11 under UV light irradiation. The corresponding sensing mechanism was attributed to the synergistic effects of the triple noncovalent interactions, including the metal-ligand coordination of PP/Zn2+ and the double host-guest interactions of beta-CD/Azo and beta-CD/PP. PMID- 29411905 TI - FOXO1 targeting by capsaicin reduces tissue damage after testicular torsion. AB - Testicular torsion-related oxidative stress causes a sequential chain of DNA damage, lipid peroxidation and cell death that leads to the derangement in the sperm functions and infertility. Capsaicin that has been applied for pain relief and cancer prevention possesses antioxidant properties which can be exploited to confer cell survival under ischaemic testis damage. Wistar male rats weighing 150 200 g were randomly divided into four groups: (i) sham group (all procedures except torsion of testis), (ii) ischaemia group (TT group), (iii) three TT groups treated with different dose of capsaicin (TT + different doses of Cap) and (iv) three control groups treated with different doses of capsaicin (100, 500 and 1000 ug/ml). Capsaicin administration significantly decreased the expression of pro apoptotic factors and increased the expression of anti-apoptotic factors. Likewise, the expression of FOXO1 is significantly increased by higher doses of the capsaicin. Histological assessment by H&E and TUNEL method also exhibited an improved testicular morphology and decreased apoptosis in testes. These results suggested clinical potential for capsaicin in treatment of testicular torsion by targeting FOXO1 and apoptotic pathways. PMID- 29411906 TI - Triarylamine-Cored Dendritic Molecular Gel for Efficient Colorometric, Fluorometric, and Impedometeric Detection of Picric Acid. AB - Detection of nitroaromatics at ultralow concentration is a major security concern in defense, forensics, and environmental science. To this end, a new triarylamine cored dendritic gelator (OGR) was synthesized, which produced thermoreversible, thixotropic, and fluorescent gels in n-octanol. On gelation, both pi-pi* transitions and the emission peak of the gelator show redshifts with a 4.5-fold increase of fluorescence intensity in the gel state indicating J-aggregation. The nitrogen lone-pair electrons of OGR make it a donor, and electron transfer occurs to acceptor nitroaromatics causing fluorescence quenching, which is further promoted due to its acidity. The Stern-Volmer rate constants measured for different nitroaromatics showed that it senses picric acid (PA) best. The contact mode technique with OGR-treated paper strips can allow naked-eye detection of PA under UV light down to 10-11 m concentration within 30 s. Reusability of the gel is achieved by treating OGR@PAx with NaOH solution. Impedance spectroscopic results indicated a decrease of both charge-transport resistance and Warburg impedance on successive addition of PA. The limits of detection of PA determined from fluorescence and impedance measurements match well. Thus, the OGR gel is a reusable, low-cost, specific sensor for PA by naked-eye colorimetric, fluorescence, and impedance techniques. PMID- 29411907 TI - A Synthetic Approach for the Rapid Preparation of BODIPY Conjugates and their use in Imaging of Cellular Drug Uptake and Distribution. AB - A solid-phase synthetic (SPS) method was developed for the preparation of BODIPY labeled bioactive compounds that allows for fast and simple synthesis of conjugates for use in fluorescent microscopy. The approach was used to visualize cellular uptake and distribution of cytotoxic triterpenes in cancer cells. PMID- 29411908 TI - A Highly Stretchable Transparent Self-Powered Triboelectric Tactile Sensor with Metallized Nanofibers for Wearable Electronics. AB - Recently, the quest for new highly stretchable transparent tactile sensors with large-scale integration and rapid response time continues to be a great impetus to research efforts to expand the promising applications in human-machine interactions, artificial electronic skins, and smart wearable equipment. Here, a self-powered, highly stretchable, and transparent triboelectric tactile sensor with patterned Ag-nanofiber electrodes for detecting and spatially mapping trajectory profiles is reported. The Ag-nanofiber electrodes demonstrate high transparency (>70%), low sheet resistance (1.68-11.1 Omega ?-1 ), excellent stretchability, and stability (>100% strain). Based on the electrode patterning and device design, an 8 * 8 triboelectric sensor matrix is fabricated, which works well under high strain owing to the effect of the electrostatic induction. Using cross-locating technology, the device can execute more rapid tactile mapping, with a response time of 70 ms. In addition, the object being detected can be made from any commonly used materials or can even be human hands, indicating that this device has widespread potential in tactile sensing and touchpad technology applications. PMID- 29411909 TI - Gene expression profiles of the meniscus avascular phenotype: A guide for meniscus tissue engineering. AB - Avascular (Avas) meniscus regeneration remains a challenge, which is partly a consequence of our limited knowledge of the cells that maintain this tissue region. In this study, we utilized microarrays to characterize gene expression profiles of intact human Avas meniscus tissue and of cells following culture expansion. Using these data, we examined various 3D culture conditions to redifferentiate Avas cells toward the tissue phenotype. RNA was isolated from either the tissue directly or following cell isolation and 2 weeks in monolayer culture. RNA was hybridized on human genome arrays. Differentially expressed (DE) genes were identified by ranking analysis. DAVID pathway analysis was performed and visualized using STRING analysis. Quantitative PCR (qPCR) on additional donor menisci (tissues and cells) were used to validate array data. Avas cells cultured in 3D were subjected to qPCR to compare with the array-generated data. A total of 387 genes were DE based on differentiation state (>3-fold change; p < 0.01). In Avas-cultured cells, the upregulated pathways included focal adhesion, ECM receptor interaction, regulation of actin cytoskeleton, and PDGF Signaling. In 3D cultured Avas cells, TGFbeta1 or combinations of TGFbeta1 and BMP6 were most effective to promote an Avas tissue phenotype. THBS2 and THBS4 expression levels were identified as a means to denote meniscus cell phenotype status. We identified the key gene expression profiles, new markers and pathways involved in characterizing the Avas meniscus phenotype in the native state and during in vitro dedifferentiation and redifferentiation. These data served to screen 3D conditions to generate meniscus-like neotissues. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1947-1958, 2018. PMID- 29411910 TI - Paratesticular seminoma: echographic features and histological diagnosis with review of the literature. AB - Primary extratesticular seminomas exceptionally occur in the epididymis or in the paratesticular region/spermatic cord. Some old papers included poor histological description or insufficient photographic documentation, reducing the number of faithful cases: an up-to-date systematic review is lacking. We report the 4th primary seminoma of the paratesticular region/spermatic cord in a 35-year-old man, including the first echographic description. We provide review of the literature and etiopathogenetic discussion. Ultrasound examination showed a right paratesticular, solid, heterogeneous mass (iso-hypoechoic with hyperechoic striae; peri- and intra-lesional vascular signals) with no testicular involvement: the paratesticular origin was confirmed by pathological examination. Despite careful gross examination and extensive sampling, the 6.5-cm extratesticular tumor revealed only one microscopic focus with minimal invasion (<2 mm) of the atrophic testicular parenchyma. Intratubular germ cell neoplasia or morphologic features of a regressed testicular tumor (fibrosis/scar, necrosis, hyalinization, calcification, inflammation) were not found. Primary seminomas of the paratesticular region/spermatic cord occurred at an older mean age and presented as bigger lesions if compared to the 9 primary epididymal seminomas reported in literature. Clinical-pathological correlation and accurate sampling are mandatory for a correct diagnosis. PMID- 29411911 TI - Dianionic Carbon-Bridged Scandium-Copper/Silver Heterobimetallic Complexes: Synthesis, Bonding, and Reactivity. AB - Alkylidene-bridged scandium-copper/silver heterobimetallic complexes were synthesized and structurally characterized. The complexes contain different Sc-C and M-C (M=CuI , AgI ) bonds. The reactivity of the scandium-copper heterobimetallic complex was also studied, which reveals that the heterobimetallic complex is a reaction intermediate for the transmetalation of akylidene group from ScIII to CuI . The scandium-copper heterobimetallic complex also undergoes an addition reaction with CO, resulting in the formation of a new C=C double bond. DFT calculations were used to study the bonding and the subsequent reactivity with CO of the scandium-copper heterobimetallic complex. It clearly demonstrates a cooperative effect between the two metal centers through the formation of a direct Sc???Cu interaction that drives the reactivity with CO. PMID- 29411912 TI - Meeting the meiotic challenge: Specializations in mammalian oocyte spindle formation. AB - Oocytes uniquely accumulate cytoplasmic constituents to support early embryogenesis. This unique specialization is accompanied by acquisition of a large size and by execution of asymmetric meiotic divisions that preserve precious ooplasm through the expulsion of minimal size polar bodies. While often taken for granted, these basic features of oogenesis necessitate unique specializations of the meiotic apparatus. These include a chromatin-sourced RanGTP gradient that restricts spindle size by defining a spatial domain where meiotic spindles form, acentriolar centrosomes that rely on microtubule organizing centers to form spindle poles, and an actin-based mechanism for asymmetric spindle positioning. Additionally, localized protein synthesis to support spindle formation is achieved in the spindle forming region, whilst protein synthesis is reduced elsewhere in the ooplasm. This is achieved through enrichment of spindle-related mRNAs in the spindle forming region combined with local PLK1-mediated phosphorylation and inactivation of the translational repressor EIF4EBP1. This allows PLK1 to function as an important regulatory nexus through which endogenous and exogenous signals can impact spindle formation and function, and highlights the important role that PLK1 may have in maintaining oocyte quality and fertility. PMID- 29411913 TI - A novel role of the corticotrophin-releasing hormone regulating peptide, teneurin C-terminal associated peptide 1, on glucose uptake into the brain. AB - Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signalling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotrophin releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurones, where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy-dependent, this suggests that TCAP has the potential to regulate glucose uptake because glucose is the primary energy substrate in brain, and neurones require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of the present study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated 18 F deoxyglucose (FDG) uptake into brain tissue was assessed in male wild-type Wistar rats by functional positron emission tomography. TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3 days and decreased blood glucose after 1 week. This is corroborated by a decreased serum concentration of insulin and an increased serum concentration of glucagon. In immortalised hypothalamic neurones, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and mitogen activated protein kinase/ERK phosphorylation events. Taken together, these data demonstrate that TCAP-1 increases glucose metabolism in neurones, and may represent a peptide signalling agent that regulated glucose uptake before insulin and related peptides. PMID- 29411914 TI - Enantiospecific Three-Component Alkylation of Furan and Indole. AB - Furan- and indole-derived boronate complexes react with alkyl iodides under radical (photoredox) or polar (SN 2) conditions to generate three-component alkylation products with high efficiency and complete stereospecificity. The methodology allows the incorporation of versatile functional groups such as nitriles, ketones, esters, sulfones, and amides, providing rapid access to complex chiral heteroaromatic molecules in enantioenriched form. Interestingly, while indolyl boronate complexes react directly with alkyl halides in a polar pathway, furyl boronates require photoredox catalysis. Careful mechanistic analysis revealed that the boronate complex not only serves as a substrate in the reaction but also acts as a reductive quencher for the excited state of the photocatalyst. PMID- 29411916 TI - Neural androgen receptors affect the number of surviving new neurones in the adult dentate gyrus of male mice. AB - Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurones within the hippocampus is modulated by the action of androgen via the androgen receptor (AR); however, it is not known whether this holds true in mice. Furthermore, the evidence is mixed regarding whether androgens act in neural tissue or via peripheral non-neural targets to promote new neurone survival in the hippocampus. We evaluated whether the action of androgen via AR underlies the survival of new neurones in mice, and investigated whether increasing AR selectively in neural tissue would increase new neurone survival in the hippocampus. We used the cre-loxP system to overexpress AR only in neural tissues (Nestin-AR). These males were compared with wild-type males, as well as control males with 1 of the 2 mutations required for overexpression. Mice were gonadectomised and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU) and for 37 days (following BrdU injection), mice were treated with oil or dihydrotestosterone (DHT). Using immunohistochemistry, proliferation (Ki67) and survival (BrdU) of new neurones were both evaluated in the dorsal and ventral dentate gyrus. Dihydrotestosterone treatment increased the survival of new neurones in the entire hippocampus in wild-type mice and control mice that only have 1 of 2 necessary mutations for transgenic expression. However, DHT treatment did not increase the survival of new neurones in mice that overexpressed AR in neural tissue. Cell proliferation (Ki67) and cell death (pyknotic cells) were not affected by DHT treatment in wild-type or transgenic males. These results suggest that androgens act via neural AR to affect hippocampal neurogenesis by promoting cell survival; however, the relationship between androgen dose and new neurone survival is nonlinear. PMID- 29411915 TI - Zinc-Containing Radical Anions via Single Electron Transfer to Donor-Acceptor Adducts. AB - Reactions of [Cp*2 Fe] with the Lewis acid [Zn(C6 F5 )2 ] in the presence of [(PhC(S)S)2 ], 9,10-phenanthrenedione or 4,5-pyrenedione yield the salt [Cp*2 Fe][(PhC(S)S)Zn(C6 F5 )2 ] 1, [Cp*2 Fe][((C14 H8 O2 )Zn(C6 F5 )2 )?] 4, and [Cp*2 Fe][((C16 H8 O2 )Zn(C6 F5 )2 )?] 5, respectively. The latter two species represent the first examples of isolable zinc-containing radical anions. While [(PhC(S)S)2 ] binds weakly to [Zn(C6 F5 )2 ], the diones afford the isolable adducts [(C14 H8 O2 )Zn(C6 F5 )2 ] 2 and [(C16 H8 O2 )Zn(C6 F5 )2 ] 3. Cyclic voltammetry and computational studies support the view that 4 and 5 are formed via single electron transfer (SET) to the donor-acceptor adducts, 2 and 3, respectively. Subsequent treatment of 4 and 5 with [NC5 H4 NMe2 ] affords [Zn(C6 F5 )2 (NC5 H4 NMe2 )2 ] with liberation of the dione, and regeneration of [Cp*2 Fe]. PMID- 29411917 TI - Selectivity Modulation and Structure of alpha/aza-beta3 Cyclic Antimicrobial Peptides. AB - Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing alpha- and aza-beta3 -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic alpha/aza-beta3 -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse gamma- and N-N turns (hydrazino turns), a unique feature due to the aza-beta3 residues. The alpha amino acid side chains form a cluster on one face of the ring, while the aza beta3 -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach. PMID- 29411918 TI - Esophageal dysmotility according to Chicago classification v3.0 vs v2.0: Implications for association with reflux, bolus clearance, and allograft failure post-lung transplantation. AB - BACKGROUND: Proximal reflux and incomplete transit of boluses swallowed are risk factors for obstructive chronic lung allograft dysfunction (o-CLAD) post-lung transplantation (LTx). Likewise, so is esophagogastric junction outflow obstruction (EGJOO), but not hypo-contractility, when diagnosed using Chicago Classification (CC) v3.0. Given, peristaltic breaks as defined using CCv2.0 can prolong esophageal clearance, both swallowed and refluxed, but which are deemed within normality using CCv3.0, our aim was to determine whether hypo contractility as diagnosed using CCv2.0, influences the association with reflux, along with its clearance, and that of boluses swallowed, and thus its association to allograft failure. METHODS: Esophageal motility abnormalities were classified using CC v3.0 and v2.0 in 50 patients post-LTx (26 female, 55 years (20-73 years)). RESULTS: Reclassification from CCv3.0 to v2.0 resulted in 7 patients with normal motility being reclassified to hypo-contractility (n = 6) or hyper contractility (n = 1); 2 patients with hypo-contractility to normal motility; and 3 patients with EGJOO without hyper-contractility to EGJOO with hyper contractility. The main consequence of reclassification was that the sub-group exhibiting hypo-contractility became more likely to have abnormal numbers of reflux events (P = .025) and incomplete bolus transit (P = .002) than those with normal motility using CCv2.0; associations not seen using CCv3.0. Irrespective of CC used only patients with EGJOO appeared more likely to develop o-CLAD than those with normal motility (P < .05). CONCLUSIONS: Irrespective of CC used, o CLAD appears linked to EGJOO. CCv2.0 however, accentuates the increased reflux and incomplete bolus transit associated with hypo-contractility post-LTx, suggesting that these motor abnormalities, though considered minor, may be of importance after lung transplant. PMID- 29411919 TI - Logging and fire regimes alter plant communities. AB - Disturbances are key drivers of plant community composition, structure, and function. Plant functional traits, including life forms and reproductive strategies are critical to the resilience and resistance of plant communities in the event of disturbance. Climate change and increasing anthropogenic disturbance are altering natural disturbance regimes globally. When these regimes shift beyond the adaptive resilience of plant functional traits, local populations and ecosystem functions can become compromised. We tested the influence of multiple disturbances, of varying intensity and frequency, on the composition and abundance of vascular plant communities and their respective functional traits (life forms and reproductive strategies) in the wet sclerophyll, Mountain Ash Eucalyptus regnans forests of southeastern Australia. Specifically, we quantified the effect of the type and number of disturbances (including fires, clearcut logging, and salvage logging) on plant community composition. We found that clearcut and salvage logging and the number of fires significantly influenced plant community composition and functional traits. Specifically, multiple fires resulted in lower populations of species that depend on on-site seeding for persistence. This includes the common tree species Eucalyptus regnans, Pomaderris aspera, and Acacia dealbata. In contrast, clearcut and salvage logged sites supported abundant on-site seeder species. However, species that depend on resprouting by surviving individuals, such as common and keystone "tree ferns" Dicksonia antarctica and Cyathea australis, declined significantly. Our data have important implications for understanding the relationship between altered disturbance regimes and plant communities and the respective effects on ecosystem function. In a period of rapid global environmental change, with disturbances predicted to increase and intensify, it is critical to address the impact of altered disturbance regimes on biodiversity. PMID- 29411920 TI - Time-Dependent ATR-FTIR Spectroscopic Studies on Fatty Acid Diffusion and the Formation of Metal Soaps in Oil Paint Model Systems. AB - The formation of metal soaps (metal complexes of saturated fatty acids) is a serious problem affecting the appearance and structural integrity of many oil paintings. Tailored model systems for aged oil paint and time-dependent attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy were used to study the diffusion of palmitic acid and subsequent metal soap crystallization. The simultaneous presence of free saturated fatty acids and polymer-bound metal carboxylates leads to rapid metal soap crystallization, following a complex mechanism that involves both acid and metal diffusion. Solvent flow, water, and pigments all enhance metal soap crystallization in the model systems. These results contribute to the development of paint cleaning strategies, a better understanding of oil paint degradation, and highlight the potential of time-dependent ATR-FTIR spectroscopy for studying dynamic processes in polymer films. PMID- 29411921 TI - Successful cryoablation of breast cancer. AB - The current standard of care for screen-detected breast cancers is surgical excision. Cryotherapy is a promising non- surgical alternative treatment for these cancers and is performed under local anesthesia as an outpatient, circumventing the risks that come with an operation. New research also shows promising results for the treatment of breast cancer when cryotherapy is combined with immune modulation as it may help prevent tumor recurrence. We herein report a case of breast cancer treated successfully with cryoablation. A brief literature review of cryoablation as a treatment for breast cancer is added. PMID- 29411922 TI - Regulating Higher-Order Organization through the Synergy of Two Self-Sorted Assemblies. AB - The extracellular matrix (ECM) is the natural fibrous scaffold that regulates cell behavior in a hierarchical manner. By mimicking the dynamic and reciprocal interactions between ECM and cells, higher-order molecular self-assembly (SA), mediated through the dynamic growth of scaffold-like nanostructures assembled by different molecular components, was developed. Designed and synthesized were two self-sorted coumarin-based gelators, a peptide molecule and a benzoate molecule, which self-assemble into nanofibers and nanobelts, respectively, with different dynamic profiles. Upon the dynamic growth of the fibrous scaffold assembled from peptide gelators, nanobelts assembled from benzoate gelators transform into a layer-by-layer nanosheet, reaching ninefold increase in height. By using light and an enzyme, the spatial-temporal growth of the scaffold can be modified, leading to in situ height regulation of the higher-order architecture. PMID- 29411923 TI - Sac1, a lipid phosphatase at the interface of vesicular and nonvesicular transport. AB - The lipid phosphatase Sac1 dephosphorylates phosphatidylinositol 4-phosphate (PI4P), thereby holding levels of this crucial membrane signaling molecule in check. Sac1 regulates multiple cellular processes, including cytoskeletal organization, membrane trafficking and cell signaling. Here, we review the structure and regulation of Sac1, its roles in cell signaling and development and its links to health and disease. Remarkably, many of the diverse roles attributed to Sac1 can be explained by the recent discovery of its requirement at membrane contact sites, where its consumption of PI4P is proposed to drive interorganelle transfer of other cellular lipids, thereby promoting normal lipid homeostasis within cells. PMID- 29411924 TI - Mechanistic Exploration of the Transmetalation and Reductive Elimination Events Involving PdIV -Abnormal NHC Complexes in Suzuki-Miyaura Coupling Reactions: A DFT Study. AB - A comprehensive DFT (M06-L-D3(SMD)/BS2//M06-L/BS1 level) investigation has been carried out to explore in detail the mechanism of the transmetalation and reductive elimination reactions of abnormal N-heterocyclic carbene (aNHC) palladium(IV) complexes within the framework of Suzuki-Miyaura cross-coupling reactions. Emphasis was placed on the role of base and the effect of countercations on the critical transmetalation and reductive elimination events involving palladium(IV) complexes. Of the two competing roles of the base, the route involving boronate formation followed by halide exchange prevails over that of direct halide exchange for the intermediates [PdIV (aNHC)(OMe)2 Cl]- Na+ (pathway A), [PdIV (aNHC)(OMe)(Cl)2 ]- Na+ (pathway B), and [PdIV (aNHC)Cl3 ]- Na+ (pathway C) emanating from the oxidative addition reaction. The results of the calculations are in accordance with our previous theoretical findings of favorable energetics for palladium intermediates incorporating two coordinated methoxy groups. The negative role played by the countercation in the transmetalation step is mainly due to the overstabilization of the pre transmetalation intermediate, which is in line with experimental kinetic results. The anionic complexes exhibit greater affinity for the transmetalation and reductive elimination reactions than the neutral variants. PMID- 29411925 TI - A boundary current drives synchronous growth of marine fishes across tropical and temperate latitudes. AB - Entrainment of growth patterns of multiple species to single climatic drivers can lower ecosystem resilience and increase the risk of species extinction during stressful climatic events. However, predictions of the effects of climate change on the productivity and dynamics of marine fishes are hampered by a lack of historical data on growth patterns. We use otolith biochronologies to show that the strength of a boundary current, modulated by the El Nino-Southern Oscillation, accounted for almost half of the shared variance in annual growth patterns of five of six species of tropical and temperate marine fishes across 23 degrees of latitude (3000 km) in Western Australia. Stronger flow during La Nina years drove increased growth of five species, whereas weaker flow during El Nino years reduced growth. Our work is the first to link the growth patterns of multiple fishes with a single oceanographic/climate phenomenon at large spatial scales and across multiple climate zones, habitat types, trophic levels and depth ranges. Extreme La Nina and El Nino events are predicted to occur more frequently in the future and these are likely to have implications for these vulnerable ecosystems, such as a limited capacity of the marine taxa to recover from stressful climatic events. PMID- 29411926 TI - Cry1 deficiency leads to testicular dysfunction and altered expression of genes involved in cell communication, chromatin reorganization, spermatogenesis, and immune response in mouse testis. AB - Cryptochrome (Cry)1 is essential for generating circadian rhythm in central and many peripheral oscillators; however, its role in male reproduction remains unclear. We investigated this question using Cry1 knockout (KO) mice. We found that Cry1 is necessary for normal testicular function: Cry1 deficiency increased testicular germ cell apoptosis and decreased sperm count. A transcriptome analysis showed that the expression levels of 375 genes-including 12 encoding micro (mi)RNAs-were altered in the testis of Cry1 KO mice relative to wild-type controls. A bioinformatics analysis revealed that the differentially expressed genes were related to important biological processes including cell-cell communication, metabolism, chromatin reorganization, spermatogenesis, and the immune response. An integrative analysis of miRNA-mRNA networks suggested that the 12 dysregulated miRNAs may contribute to testis disorders through negative regulation of their target mRNAs expression in testis, and interestingly, all the 12 miRNAs are predicted to target core circadian clock components. These results provide the first evidence of a correlation between dysregulation of Cry1 and male reproductive defects in mice, indicating that Cry1 plays a critical role in maintaining normal testicular function. PMID- 29411927 TI - Oral contraception in adolescents with type 1 diabetes and its association with cardiovascular risk factors. A multicenter DPV study on 24 011 patients from Germany, Austria or Luxembourg. AB - OBJECTIVE: To investigate differences in cardiovascular risk factors and metabolic control in girls with type 1 diabetes with or without use of oral contraceptives (OC) from the multicenter "diabetes prospective follow-up" (DPV) registry. METHODS: Twenty-four thousand eleven adolescent girls (13 to < 18 years of age) from Germany, Austria or Luxembourg with type 1 diabetes from the DPV registry were included in this cross-sectional study. Multivariable regression models were applied to compare clinical characteristics (hemoglobin A1c [HbA1C ], blood pressure, serum lipids, body mass index) and lifestyle factors (smoking, physical inactivity, alcohol consumption) between girls with or without OC use. Confounders: age, diabetes duration and migration background. STATISTICAL ANALYSIS: SAS 9.4. RESULTS: In girls with type 1 diabetes and OC use, clinical characteristics and lifestyle factors were less favorable compared to non-users. Differences were most pronounced for the prevalence of dyslipidemia (OC-users: 40.0% vs non-users: 29.4; P < .0001) and the number of smokers (OC-users: 25.9% vs non-users: 12.5%; P < .0001). OC use, sociodemographic characteristics and lifestyle factors explained between 1 and 7% of the population variance in serum lipids and blood pressure. The use of OC explained a small additional proportion in all variables considered (<1%). CONCLUSIONS: OC use in adolescent girls with type 1 diabetes was associated with a poorer cardiovascular risk profile. Biological risk factors were partly explained by a clustering of sociodemographic and lifestyle factors with a small additional contribution of OC use. Prescription of OC should therefore be combined with a screening for cardiovascular risk factors and targeted education. PMID- 29411928 TI - Suspected thrombotic microangiopathy in a child with Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. PMID- 29411929 TI - The battle of two ions: Ca2+ signalling against Na+ stress. AB - Soil salinity adversely affects plant growth, crop yield and the composition of ecosystems. Salinity stress impacts plants by combined effects of Na+ toxicity and osmotic perturbation. Plants have evolved elaborate mechanisms to counteract the detrimental consequences of salinity. Here we reflect on recent advances in our understanding of plant salt tolerance mechanisms. We discuss the embedding of the salt tolerance-mediating SOS pathway in plant hormonal and developmental adaptation. Moreover, we review newly accumulating evidence indicating a crucial role of a transpiration-dependent salinity tolerance pathway, that is centred around the function of the NADPH oxidase RBOHF and its role in endodermal and Casparian strip differentiation. Together, these data suggest a unifying and coordinating role for Ca2+ signalling in combating salinity stress at the cellular and organismal level. PMID- 29411930 TI - Physicochemical characterization of pectinase activity from Bacillus spp. and their accessory role in synergism with crude xylanase and commercial cellulase in enzyme cocktail mediated saccharification of agrowaste biomass. AB - AIM: The aim of this study was to evaluate the physicochemical properties of the crude pectinase activity from three Bacillus isolates of ruminant dung origin and study their synergism with crude xylanases from the same Bacillus spp. and a commercial cellulase to evaluate their accessory role in improved biomass saccharification. METHODS AND RESULTS: Pectinolytic crude culture filtrate obtained from three ruminant dung isolates, Bacillus safensis M35, Bacillus altitudinis R31 and Bacillus altitudinis J208, on crude pectin containing medium possessed polygalacturonate hydrolase, pectate lyase and pectin lyase activities. Studies regarding their stability under various temperature and pH conditions revealed their mild acidic to alkaline and mesophilic nature with enzyme activity falling within the pH range 6.0-9.0 and temperature range 30-60 degrees C. The pectinase activity was categorized as endolytic as it brought about ~50% reduction in relative viscosity of pectic polymer within initial 10 min of incubation. Synergism of pectinase activity with crude xylanase activities and/or commercial cellulase was clearly demonstrated as ~1.6 to ~1.9-fold increase in agrowaste biomass saccharification was obtained confirming the role of pectinases as accessory enzymes. CONCLUSION: Synergism of the broad-spectrum endopectinase activity obtained from three Bacillus isolates with accessory crude xylanases from the same isolates and commercial cellulase enhanced the agrowaste saccharification and confirmed the accessory role of crude pectinase as they formed an efficient enzyme cocktail functioning in a contributive manner for improvement of agrowaste biomass saccharification. SIGNIFICANCE AND IMPACT OF THE STUDY: Mesophilic crude endopectinases obtained from Bacillus spp. isolated from ruminant dung possessed activity in broad pH and temperature ranges as well as broad substrate specificity. Moreover, their synergism with crude xylanase and Primfast(r) 200 cellulase demonstrated the potential to form efficient enzyme cocktail for application in plant biomass saccharification process. PMID- 29411931 TI - Neuroprotective Mechanisms of Glucagon-like Peptide-1-based Therapies in Ischaemic Stroke: A Systematic Review based on Pre-Clinical Studies. AB - Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP 1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP 4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative stress and apoptosis. GLP-1RAs significantly reduced infarct volume when administered acutely, but not later after stroke. The reported effects of DPP-4Is on infarct volume were inconsistent. GLP-1-RAs reliably improved functional outcome, but the effects on cerebral blood flow were inconclusive. These neuroprotective effects were often attributed to activation of the GLP-1 receptor, but non-GLP-1R-mediated effects have also been suggested. Both GLP-1RAs and DPP-4Is significantly affected inflammation, oxidative stress and apoptosis in animal stroke models; however, data from clinical trials only report therapeutic efficacy for GLP-1RAs. Thus, GLP-1RA administration is the most promising treatment to pursue for patients at risk of stroke or immediately after stroke. Future studies should address acute and prophylactic treatments in stroke patients with and without diabetes. PMID- 29411932 TI - Screening for Selective Protein Inhibitors by Using the IANUS Peptide Array. AB - Finding new road blacks: A peptidic inhibitor of calcineurin (CaN)-mediated nuclear factor of activated T cells (NFAT) dephosphorylation, which is developed through a template-assisted IANUS (Induced orgANisation of strUcture by matrix assisted togethernesS) peptide array, is cell permeable and able to block the translocation of green fluorescent protein-NFAT fusion protein (GFP-NFAT) into the nucleus after stimulation. PMID- 29411933 TI - Regiospecific ortho-C-H Allylation of Benzoic Acids. AB - A carboxylate-directed ortho-C-H functionalization has been developed and it allows the regiospecific introduction of allyl residues to benzoic acids. In the presence of a [Ru(p-cymene)Cl2 ]2 and K3 PO4 , benzoic acids react with allyl acetates at only 50 degrees C to give the corresponding ortho-allylbenzoic acids. The protocol is generally applicable to both electron-rich and electron poor benzoic acids in combination with linear and branched allyl acetates. The products can be further functionalized in situ, for example, by double-bond migration, lactonization, or decarboxylation. PMID- 29411934 TI - Water Soluble Antioxidant Dextran-Quercetin Conjugate with Potential Anticancer Properties. AB - Quercetin, a naturally occurring potent antioxidant, is limited in therapeutic use, owing to its poor water solubility and stability. Herein, a method of conjugating quercetin to an aldehyde functionalized dextran via an HCl catalyzed condensation reaction to yield a water soluble quercetin functionalized polymer is reported. The prepared conjugate is characterized by 1 H and 1 H-13 C heteronuclear single quantum correlation (HSQC) NMR, which demonstrate that conjugation occurs via both the A- and B-rings of quercetin. The degree of quercetin functionalization can be tuned by varying the reaction temperature and/or the concentration of the HCl catalyst. However, as temperatures and HCl concentrations are increased above 40 degrees C and 2 m, respectively, the increase in functionalization is accompanied by an increase in the oxidation of the conjugated quercetin and a decrease in polymer yield. The prepared conjugate is shown to have improved stability compared with native quercetin while maintaining substantial free-radical scavenging activity. Anticancer activity is evaluated in vitro in a neuroblastoma cell line. The dextran-aldehyde-quercetin conjugate prepared at 40 degrees C and 2 m HCl is shown to be cytotoxic to neuroblastoma cells (SH-SY5Y-IC50 = 123 ug mL-1 and BE(2)-C-IC50 = 380 ug mL-1 ) but shows no activity against nonmalignant MRC-5 cells at concentrations up to 400 ug mL-1 . PMID- 29411935 TI - Determining the Optimized Interlayer Separation Distance in Vertical Stacked 2D WS2 :hBN:MoS2 Heterostructures for Exciton Energy Transfer. AB - The 2D semiconductor monolayer transition metal dichalcogenides, WS2 and MoS2 , are grown by chemical vapor deposition (CVD) and assembled by sequential transfer into vertical layered heterostructures (VLHs). Insulating hBN, also produced by CVD, is utilized to control the separation between WS2 and MoS2 by adjusting the layer number, leading to fine-scale tuning of the interlayer interactions within the VLHs. The interlayer interactions are studied by photoluminescence (PL) spectroscopy and are demonstrated to be highly sensitive to the input excitation power. For thin hBN separators (one to two layers), the total PL emission switches from quenching to enhancement by increasing the laser power. Femtosecond broadband transient absorption measurements demonstrate that the increase in PL quantum yield results from Forster energy transfer from MoS2 to WS2 . The PL signal is further enhanced at cryogenic temperatures due to the suppressed nonradiative decay channels. It is shown that (4 +/- 1) layers of hBN are optimum for obtaining PL enhancement in the VLHs. Increasing thickness beyond this causes the enhancement factor to diminish, with the WS2 and MoS2 then behaving as isolated noninteracting monolayers. These results indicate how controlling the exciton generation rate influences energy transfer and plays an important role in the properties of VLHs. PMID- 29411936 TI - Relationship between cancer-related traumatic stress and family milestone achievement in adolescent and young adult survivors of childhood cancer. AB - Late physical and emotional effects of cancer treatment pose a burden for adolescent and young adult survivors of childhood cancer, including family milestone achievement. This brief report examined links between ongoing cancer related post-traumatic stress symptoms (CR-PTSS) and family milestone achievement. Survivors (n = 51; Mage = 24.73, SD = 8.20) completed CR-PTSS and family formation questionnaires. Descriptive statistics, univariate parameter constraints, and correlation analyses examined relations among study variables. Ongoing intrusive thoughts and hyperarousal were negatively linked to family identity development and family achievement. Findings from the present study provide support that ongoing CR-PTSS may be a barrier to family formation. PMID- 29411938 TI - The effect of Baby-friendly status on exclusive breastfeeding in U.S. hospitals. AB - In 2014, a leading hospital accreditation agency, mandated hospitals publicly report their exclusive breastfeeding (EBF) rates. This new regulation provided an opportunity to explore differences in EBF outcomes using a standardized definition across a large hospital sample in the United States. The purpose of this study was to examine the relationships between population demographics and the Baby-friendly (BF) hospital designation on EBF rates in hospitals throughout the United States. We obtained EBF rates from 121 BF hospitals and 1,608 hospitals without the BF designation. Demographic variables were computed using census tract data for the population surrounding each hospital. Relationships were explored using linear regression. We found that EBF rates were positively correlated with a bachelor's degree, log income, and those who identified as White or Asian and negatively correlated with those without college attendance, individuals living below the poverty line, and those who identified as African American or Hispanic. For all models, the BF designation of a hospital was associated with higher EBF rates (p < 0.01; effect sizes, 0.11-0.49) with the exception of the model containing log income. Using a multiple linear regression model that was allowed to contain more than one independent variable, we were able to explain 22% of the variability in EBF rates. The BF hospital designation was associated with significantly higher EBF rates independent of demographic variables. Support for hospitals to attain the BF hospital designation is a meaningful public health goal. PMID- 29411937 TI - Nephrin as a biomarker of sickle cell glomerulopathy in Malawi. AB - BACKGROUND: Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD. PROCEDURES: We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease. RESULTS: Among children with sickle cell anemia, 24.8% had a urine albumin creatinine ratio of 30 mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut point of 622 ng/mg, the 50th percentile, was associated with a 45.8 times greater odds of having albuminuria in children with nephrinuria above this value. Further analysis revealed this urinary NCR cut-point to have 96% sensitivity, 64% specificity, 47% positive predictive value, and 98% negative predictive value for the presence of albuminuria. CONCLUSIONS: These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD. PMID- 29411939 TI - Surprise, Recipes for Surprise, and Social Influence. AB - Surprising people can provide an opening for influencing them. Surprises garner attention, are arousing, are memorable, and can prompt shifts in understanding. Less noted is that, as a result, surprises can serve to persuade others by leading them to shifts in attitudes. Furthermore, because stories, pictures, and music can generate surprises and those can be widely shared, surprise can have broad social influence. People also tend to share surprising items with others, as anyone on social media has discovered. This means that in addition to broadcasting surprising information, surprising items can also spread through networks. The joint result is that surprise not only has individual effects on beliefs and attitudes but also collective effects on the content of culture. Items that generate surprise need not be random or accidental. There are predictable methods or recipes for generating surprise. One such recipe is discussed, the repetition-break plot structure, to explore the psychological and social possibilities of examining surprise. Recipes for surprise offer a useful means for understanding how surprise works and offer prospects for harnessing surprise to a wide array of ends. PMID- 29411940 TI - Analysis of basidiomycete pigments in situ by Raman spectroscopy. AB - Basidiomycetes, that is, mushroom-type fungi, are known to produce pigments in response to environmental impacts. As antioxidants with a high level of unsaturation, these compounds can neutralize highly oxidative species. In the event of close contact with other microbes, the enzymatically controlled pigment production is triggered and pigment secretion is generated at the interaction zone. The identification and analysis of these pigments is important to understand the defense mechanism of fungi, which is essential to counteract an uncontrolled spread of harmful species. Usually, a detailed analysis of the pigments is time consuming as it depends on laborious sample preparation and isolation procedures. Furthermore, the applied protocols often influence the chemical integrity of the compound of interest. A possibility to noninvasively investigate the pigmentation is Raman microspectroscopy. The methodology has the potential to analyze the chemical composition of the sample spatially resolved at the interaction zone. After the acquisition of a representative spectroscopic library, the pigment production by basidiomycetes was monitored for during response to different fungi and bacteria. The presented results describe a very efficient noninvasive way of pigment analysis which can be applied with minimal sample preparation. PMID- 29411941 TI - Preserved re-experience of discrete emotions: Amnesia and executive function. AB - Amnesic patients can re-experience emotions elicited by forgotten events, suggesting that brain systems for episodic and emotional memory are independent. However, the range of such emotional memories remains under-investigated (most studies employing just positive-negative emotion dyads), and executive function may also play a role in the re-experience of emotions. This is the first investigation of the intensity of the emotional re-experience of a range of discrete emotions (anger, fear, sadness, and happiness) for a group of amnesic patients. Twenty Korsakoff syndrome (KS) patients and 20 neurologically normal controls listened to four novel emotional vignettes selectively eliciting the four basic emotions. Emotional experience was measured using pen-and-paper Visual Analogue Mood Scales and episodic memory using verbal recollections. After 30 min, the recollection of stories was severely impaired for the patient group, but the emotional re-experience was no different from that of controls. Notably, there was no relationship between episodic recall and the intensity of the four emotions, such that even profoundly amnesic patients reported moderate levels of the target emotion. Exploratory analyses revealed negative correlations between the intensity of basic emotions and executive functions (e.g., cognitive flexibility and response inhibition) for controls but not patients. The results suggest that discrete emotions can be re-experienced independently of episodic memory, and that the re-experience of certain discrete emotions appears to be dampened by executive control. KS patients with absent or mild cognitive symptoms should benefit from emotion-regulation interventions aimed at reducing the recognized affective burden associated with their episodic memory deficit. PMID- 29411942 TI - Laser-induced breakdown spectroscopy-Raman: An effective complementary approach to analyze renal-calculi. AB - Presence of renal-calculi (kidney stones) in human urethra is being increasingly diagnosed over the last decade and is considered as one of the most painful urological disorders. Accurate analysis of such stones plays a vital role in the evaluation of urolithiasis patients and in turn helps the clinicians toward exact etiologies. Two highly complementary laser-based analytical techniques; laser induced breakdown spectroscopy (LIBS) and micro-Raman spectroscopy have been used to identify the chemical composition of different types of renal-calculi. LIBS explores elemental characteristics while Raman spectroscopy provides molecular details of the sample. This complete information on the sample composition might help clinicians to identify the key aspects of the formation of kidney stones, hence assist in therapeutic management and to prevent recurrence. The complementarity of both techniques has been emphasized and discussed. LIBS spectra of different types of stones suggest the probable composition of it by virtue of the major, minor and trace elements detected from the sample. However, it failed to differentiate the crystalline form of different hydrates of calcium oxalate stone. This lacuna was overcome by the use of Raman spectroscopy and these results are compared with conventional chemical analysis. PMID- 29411943 TI - Trends of child undernutrition in rural Ecuadorian communities with differential access to roads, 2004-2013. AB - Road access can influence protective and risk factors associated with nutrition by affecting various social and biological processes. In northern coastal Ecuador, the construction of new roads created a remoteness gradient among villages, providing a unique opportunity to examine the impact of roads on child nutritional outcomes 10 years after the road was built. Anthropometric and haemoglobin measurements were collected from 2,350 children <5 years in Esmeraldas, Ecuador, from 2004 to 2013 across 28 villages with differing road access. Logistic generalized estimating equation models assessed the longitudinal association between village remoteness and prevalence of stunting, wasting, underweight, overweight, obesity, and anaemia. We examined the influence of socio economic characteristics on the pathway between remoteness and nutrition by comparing model results with and without household-level socio-economic covariates. Remoteness was associated with stunting (OR = 0.43, 95% CI [0.30, 0.63]) and anaemia (OR = 0.56, 95% CI [0.44, 0.70]). Over time, the prevalence of stunting was generally decreasing but remained higher in villages closer to the road compared to those farther away. Obesity increased (0.5% to 3%) over time; wasting was high (6%) but stable during the study period. Wealth and education partially explained the better nutritional outcomes in remote vs. road villages more than a decade after some communities gained road access. Establishing the extent to which these patterns persist requires additional years of observation. PMID- 29411944 TI - The Unforeseen Consequences of Interacting With Non-Native Speakers. AB - Sociolinguistic research shows that listeners' expectations of speakers influence their interpretation of the speech, yet this is often ignored in cognitive models of language comprehension. Here, we focus on the case of interactions between native and non-native speakers. Previous literature shows that listeners process the language of non-native speakers in less detail, because they expect them to have lower linguistic competence. We show that processing the language of non native speakers increases lexical competition and access in general, not only of the non-native speaker's speech, and that this leads to poorer memory of one's own speech during the interaction. We further find that the degree to which people adjust their processing to non-native speakers is related to the degree to which they adjust their speech to them. We discuss implications for cognitive models of language processing and sociolinguistic research on attitudes. PMID- 29411945 TI - Molecular Engineering of Photoacoustic Performance by Chalcogenide Variation in Conjugated Polymer Nanoparticles for Brain Vascular Imaging. AB - As conjugated polymer nanoparticles (CPNs) have attracted growing interest as photoacoustic (PA) imaging contrast agents, revelation of the relationship between the molecular structure of conjugated polymers and PA property is highly in demand. Here, three donor-acceptor-structured conjugated polymer analogs are designed, where only a single heteroatom of acceptor units changes from oxygen to sulfur to selenium, allowing for systematic investigation of the molecular structure-PA property relationship. The absorption and PA spectra of these CPNs can be facilely tuned by changing the heteroatoms of the acceptor units. Moreover, the absorption coefficient, and in turn the PA signal intensity, decreases when the heteroatom changes from oxygen to sulfur to selenium. As these CPNs exhibit weak fluorescence and similar photothermal conversion efficiency (~70%), their PA intensities are approximately proportional to their absorption coefficients. The in vivo brain vasculature imaging in this study also demonstrates this trend. This study provides a simple but efficient strategy to manipulate the PA properties of CPNs through changing the heteroatom at key positions. PMID- 29411946 TI - Spatio-temporal map for early cancer detection: Proof of concept. AB - A spatio-temporal map of human cervical tissue is obtained from time-resolved fluorescence images with the dynamic contrast enhanced through principal component analysis (PCA) for clear demarcation of regions of normal and pre cancerous conditions. Changes in the properties of fluorescence in different environments are captured through fluorescence lifetime maps in the human cervical tissue sample. The correlation embodied in the second principal component (PC) representing sectorial information free of background of the first PC, segregates fluorescence activities, as illustrated in the PC maps. It significantly enhances the contrast of the images which are majorly handicapped by the variations in fluorophore environment. The result is validated on phantoms, mimicking the changes in the environment of normal and abnormal tissues. This spatio-temporal map illustrates the potential of time resolved auto fluorescence imaging of cervical tissue in combination with PCA to clearly demarcate normal and abnormal regions with enhanced contrast. PMID- 29411947 TI - Silk Fibroin-Based Fibrous Anal Fistula Plug with Drug Delivery Function. AB - The aim of this work is to develop a drug-loaded silk fibroin fibrous membrane (DSFM) that can be attached to the surface of an anal fistula plug to improve the treatment of Crohn's disease (CD). Curcumin (CUR) and 5-aminosalicylic acid (5 ASA)-loaded silk fibroin (SF) membranes are coaxially electrospun onto the surface of a braided silk filament plug. The membranes show a predominant structure of random coil and silk I conformation. The concentration of CUR/5-ASA (weight ratio of 1/1) in the SF solution is optimized to 0.4, 0.9, and 1.9 wt%. The morphologies, secondary structures, and in vitro drug release properties of the membranes are examined. Sectional images of fibers in the membranes show core shell structures. The coaxial electrospinning process does not alter the chemical characteristics of the drugs. The dual-drugs encapsulated in the membranes are released in a steady and sustainable manner, and the cumulative release rate is improved by the increased drug loading. The membranes exhibit no cytotoxicity, thereafter increase the viability of human fibroblasts on the DSFMs. These SF membranes with core-shell structure and functional encapsulation of CUR and 5-ASA should be useful for further studies toward the treatment of CD. PMID- 29411948 TI - Challenges of identifying unpublished data from clinical trials: Getting the best out of clinical trials registers and other novel sources. AB - Clinical trial data are essential for assessments of the effectiveness of health care interventions. Information about ongoing or completed, but not yet formally published, trials has been more difficult to identify until the development of clinical trials registers and portals. This paper summarises research evidence on identifying sources of trial data, how and when to search those sources, and which future developments may enhance access to and retrieval of unpublished trial evidence. We conducted a literature search for relevant studies and provide a narrative review of the evidence from these studies. Clinical trial data can be found in resources including clinical trials registers, regulatory agency sources, health technology assessment websites and manufacturers' websites, and submissions for regulatory approval. The challenges of searching these resources are described. Trials registers are relatively unsophisticated in terms of their search interfaces, and searchers need to adapt to each individual register. There is overlap across registers, but little research on the degree and nature of overlap and how best to search. Despite these challenges, trials registers and other resources can be rich sources of additional unique trial data, which may not be available from journal reports. New initiatives, such as OpenTrials, aim to consolidate and link all structured data and documentation related to clinical trials. No single resource gives access to all trials, and multiple registers should be searched as sensitively as possible. Searching is challenging and should be adequately resourced. Information specialists should monitor new developments which may reduce the challenges over the coming years. PMID- 29411949 TI - Discrimination of malignant and normal kidney tissue with short wave infrared dispersive Raman spectroscopy. AB - Renal mass biopsy is still controversial due to imperfect accuracy. Raman spectroscopy (RS) demonstrated promise as an in vivo real-time, nondestructive diagnostic tool in many malignancies. Short wave infrared (SWIR) RS has the potential to improve on previous RS systems for renal mass diagnosis. The aim of this study is to evaluate a SWIR RS system in differentiating normal and malignant renal samples. Measurements were acquired using a benchtop RS system with excitation wavelength at 1064 nm and an InGaAs array detector. Processed spectra were classified with a Bayesian machine learning algorithm, sparse multinomial logistic regression. Sensitivity and receiver operating characteristic curve analyses evaluated the classifier accuracy. Accuracy of the classifier was 92.5% with sensitivity and specificity of 95.8% and 88.8%, respectively. For posterior probability of malignant class assignment, the area under the ROC curve is 0.94 (95% confidence interval: 0.89-0.99, P < .001). SWIR RS accurately differentiated normal and malignant kidney tumors. RS has the potential to be used as a diagnostic tool in kidney cancer. PMID- 29411950 TI - Long-term deepened snow promotes tundra evergreen shrub growth and summertime ecosystem net CO2 gain but reduces soil carbon and nutrient pools. AB - Arctic climate warming will be primarily during winter, resulting in increased snowfall in many regions. Previous tundra research on the impacts of deepened snow has generally been of short duration. Here, we report relatively long-term (7-9 years) effects of experimentally deepened snow on plant community structure, net ecosystem CO2 exchange (NEE), and soil biogeochemistry in Canadian Low Arctic mesic shrub tundra. The snowfence treatment enhanced snow depth from 0.3 to ~1 m, increasing winter soil temperatures by ~3 degrees C, but with no effect on summer soil temperature, moisture, or thaw depth. Nevertheless, shoot biomass of the evergreen shrub Rhododendron subarcticum was near-doubled by the snowfences, leading to a 52% increase in aboveground vascular plant biomass. Additionally, summertime NEE rates, measured in collars containing similar plant biomass across treatments, were consistently reduced ~30% in the snowfenced plots due to decreased ecosystem respiration rather than increased gross photosynthesis. Phosphate in the organic soil layer (0-10 cm depth) and nitrate in the mineral soil layer (15-25 cm depth) were substantially reduced within the snowfences (47 70 and 43%-73% reductions, respectively, across sampling times). Finally, the snowfences tended (p = .08) to reduce mineral soil layer C% by 40%, but with considerable within- and among plot variation due to cryoturbation across the landscape. These results indicate that enhanced snow accumulation is likely to further increase dominance of R. subarcticum in its favored locations, and reduce summertime respiration and soil biogeochemical pools. Since evergreens are relatively slow growing and of low stature, their increased dominance may constrain vegetation-related feedbacks to climate change. We found no evidence that deepened snow promoted deciduous shrub growth in mesic tundra, and conclude that the relatively strong R. subarcticum response to snow accumulation may explain the extensive spatial variability in observed circumpolar patterns of evergreen and deciduous shrub growth over the past 30 years. PMID- 29411951 TI - A systematic review of interventions using cue-automaticity to improve the uptake of preventive healthcare in adults: applications to dental visiting. AB - OBJECTIVE: Since behaviour is underpinned by both cognitive and automatic processes, psychological interventions aiming to instigate or modify habitual behaviour (cue-automaticity interventions) offer an alternative to the more commonly used (mainly educational) strategies to increase preventive healthcare use. Theory suggests that low socio-economic (SES) groups are especially likely to benefit. Cue-automaticity describes how repetition of behaviour, initiated by a particular 'cue', in a constant context, leads to the automatic instigation and/or execution of behaviour. Our primary objective was to assess the effectiveness of cue-automaticity interventions to improve the uptake of adult preventive healthcare, and to consider how this might be applied to the design of interventions to promote preventive dental visiting. BASIC RESEARCH DESIGN: An electronic search, with citation snowballing, of cue-automaticity interventions to influence adult preventive healthcare use was undertaken. RESULTS: Searching identified 11,888 titles and abstracts. Paper screening left 26 papers, of which 6 RCTs met the inclusion criteria. All 6 incorporated an Implementation Intention (I-I) component. Four studies involved cancer screening and 2 involved vaccination programmes. Five studies showed a significantly positive increase in preventive healthcare use, while one did not. CONCLUSIONS: Whilst few studies using cue-automaticity to underpin the promotion of preventive care use have been undertaken, studies that do exist have promising results. As cue-automaticity interventions may be of particular benefit to low SES groups, research is needed to investigate whether cue-automaticity interventions can translate into reducing inequalities in attendance for dental check-ups. PMID- 29411952 TI - Plasma transfusions prior to insertion of central lines for people with abnormal coagulation. AB - The mission of the Cochrane Nursing Care Field (CNCF) is to improve health outcomes through increasing the use of the Cochrane Library and supporting Cochrane's role by providing an evidence base for nurses and healthcare professionals who deliver, lead or research nursing care. The CNCF produces Cochrane Corner columns, summaries of recent nursing-care-relevant Cochrane Reviews that are regularly published in collaborating nursing-related journals. Information on the processes CNCF has developed can be accessed at: cncf.cochrane.org/evidence-transfer-program-review-summaries. This is a Cochrane review summary of: Hall DP, Estcourt LJ, Doree C et al ( 2016 ) Plasma transfusions prior to insertion of central lines for people with abnormal coagulation. Cochrane Database of Systematic Reviews. Issue 9. CD011756. doi: 10.1002/14651858.CD011756.pub2. PMID- 29411953 TI - Exploring the use of high-fidelity simulation training to enhance clinical skills. AB - The use of interprofessional simulation training to enhance nursing students' performance of technical and non-technical clinical skills is becoming increasingly common. Simulation training can involve the use of role play, virtual reality or patient simulator manikins to replicate clinical scenarios and assess the nursing student's ability to, for example, undertake clinical observations or work as part of a team. Simulation training enables nursing students to practise clinical skills in a safe environment. Effective simulation training requires extensive preparation, and debriefing is necessary following a simulated training session to review any positive or negative aspects of the learning experience. This article discusses a high-fidelity simulated training session that was used to assess a group of third-year nursing students and foundation level 1 medical students. This involved the use of a patient simulator manikin in a scenario that required the collaborative management of a deteriorating patient. PMID- 29411954 TI - Supporting people who experience intimate partner violence. AB - Intimate partner violence (IPV) is a significant issue in health and social care. Nurses may encounter individuals in healthcare settings who experience IPV, and they have an important role in supporting these people by providing person centred care. It is important that nurses understand the complex issues involved in IPV, including those related to its presentation and effects on physical and psychological health. Nurses should also be aware of factors such as lack of knowledge among healthcare professionals and the challenge for some individuals of disclosing IPV, which can affect nurses' ability to identify and support those who experience IPV. PMID- 29411955 TI - Key role of public health in improving health situation of the population PMID- 29411957 TI - Making HIPPA Work for Consumers:Teach Consumers to Fish (For Health Records) and They'll Have Information for a Lifetime. PMID- 29411956 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. PMID- 29411958 TI - Becoming a Data Master. PMID- 29411959 TI - How MACRA Changes Him. PMID- 29411960 TI - New Spin on Organic Radical Batteries-An Isoindoline Nitroxide-Based High-Voltage Cathode Material. AB - Organic electrode materials are a highly promising and environmentally benign class of battery materials with radical polymers being at the forefront of this research. Herein, we report the first example of the 1,1,3,3 tetramethylisoindolin-2-yloxyl class of nitroxides as an organic electrode material and the synthesis and application of a novel styrenic nitroxide polymer, poly(5-vinyl-1,1,3,3-tetramethylisoindolin-2-yloxyl) (PVTMIO). The polymer was synthesized from the precursor monomer, 2-methoxy-5-vinyl-1,1,3,3 tetramethylisoindoline, and subsequent oxidative deprotection yielded the electroactive radical species. Cyclic voltammetry revealed a high oxidation potential of 3.7 V versus Li, placing it among the top of the nitroxide class of electrode materials. The suitability of PVTMIO for utilization in a high-voltage organic radical battery was confirmed with a discharge capacity of 104.7 mAh g-1, high rate performance, and stability under cycling conditions (90% capacity retention after 100 cycles), making it one of the highest reported organic p dopable cathode materials. PMID- 29411961 TI - Interface Engineering via Photopolymerization-Induced Phase Separation for Flexible UV-Responsive Phototransistors. AB - Interface engineering has been recognized to be substantially critical for achieving efficient charge separation, charge carrier transport, and enhanced device performance in emerging optoelectronics. Nevertheless, precise control of the interface structure using current techniques remains a formidable challenge. Herein, we demonstrate a facile and versatile protocol wherein in situ thiol-ene click photopolymerization-induced phase separation is implemented for constructing heterojunction semiconductor interfaces. This approach generates continuous mountainlike heterojunction interfaces that favor efficient exciton dissociation at the interface while providing a continuous conductive area for hole transport above the interface. This facile low-temperature paradigm presents good adaptability to both rigid and flexible substrates, offering high performance UV-responsive phototransistors with a normalized detectivity up to 6.3 * 1014 cm Hz1/2 W-1 (also called jones). Control experiments based on ex situ photopolymerization and in situ thermal polymerization are also implemented to demonstrate the superiority of this novel paradigm. PMID- 29411962 TI - Oxygen Impurities Link Bistability and Magnetoresistance in Organic Spin Valves. AB - Vertical crossbar devices based on manganite and cobalt injecting electrodes and a metal-quinoline molecular transport layer are known to manifest both magnetoresistance (MR) and electrical bistability. The two effects are strongly interwoven, inspiring new device applications such as electrical control of the MR and magnetic modulation of bistability. To explain the device functionality, we identify the mechanism responsible for electrical switching by associating the electrical conductivity and the impedance behavior with the chemical states of buried layers obtained by in operando photoelectron spectroscopy. These measurements revealed that a significant fraction of oxygen ions migrate under voltage application, resulting in a modification of the electronic properties of the organic material and of the oxidation state of the interfacial layer with the ferromagnetic contacts. Variable oxygen doping of the organic molecules represents the key element for correlating bistability and MR, and our measurements provide the first experimental evidence in favor of the impurity driven model describing the spin transport in organic semiconductors in similar devices. PMID- 29411963 TI - Metal-Organic Framework Modified Glass Substrate for Analysis of Highly Volatile Chemical Warfare Agents by Paper Spray Mass Spectrometry. AB - Paper spray mass spectrometry has been shown to successfully analyze chemical warfare agent (CWA) simulants. However, due to the volatility differences between the simulants and real G-series (i.e., sarin, soman) CWAs, analysis from an untreated paper substrate proved difficult. To extend the analytical lifetime of these G-agents, metal-organic frameworks (MOFs) were successfully integrated onto the paper spray substrates to increase adsorption and desorption. In this study, several MOFs and nanoparticles were tested to extend the analytical lifetimes of sarin, soman, and cyclosarin on paper spray substrates. It was found that the addition of either UiO-66 or HKUST-1 to the paper substrate increased the analytical lifetime of the G-agents from less than 5 min detectability to at least 50 min. PMID- 29411964 TI - Enhanced Chemotherapeutic Efficacy of Paclitaxel Nanoparticles Co-delivered with MicroRNA-7 by Inhibiting Paclitaxel-Induced EGFR/ERK pathway Activation for Ovarian Cancer Therapy. AB - Chemotherapy-induced activation of cell survival pathways leads to drug resistance. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in many biological pathways. Paclitaxel (PTX) is one of the first-line chemotherapy drugs for ovarian cancer, and it induces the activation of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway that leads to tumor cell proliferation, survival, invasion, and drug resistance. MicroRNA-7 (miR-7) has the ability to suppress the EGFR/ERK pathway. To sensitize chemotherapy, we developed monomethoxy(poly(ethylene glycol))-poly(d,l-lactide- co-glycolide)-poly(l-lysine) nanoparticles for the simultaneous co-delivery of PTX and miR-7. The resulting PTX/miR-7 nanoparticles (P/MNPs) protect miRNA from degradation, possess a sequential and controlled release of drugs, improve the transfection efficiency of miRNA, decrease the half-maximal inhibitory concentration of PTX, and increase the apoptosis of ovarian cancer cells. The chemotherapeutic efficacy of PTX is prominently enhanced in vitro and in vivo via the inhibition of PTX-induced EGFR/ERK pathway activation by miR-7. Our studies in P/MNPs reveal a novel paradigm for a dual-drug-delivery system of chemotherapeutics and gene therapy in treating cancers. PMID- 29411965 TI - Hollow Pt-Functionalized SnO2 Hemipill Network Formation Using a Bacterial Skeleton for the Noninvasive Diagnosis of Diabetes. AB - Hollow-structured nanomaterials are presented as an outstanding sensing platform because of their unique combination of high porosity in both the micro- and nanoscale, their biocompatibility, and flexible template applicability. Herein, we introduce a bacterial skeleton method allowing for cost-effective fabrication with nanoscale precision. As a proof-of-concept, we fabricated a hollow SnO2 hemipill network (HSHN) and a hollow Pt-functionalized SnO2 hemipill network (HPN). A superior detecting capability of HPN toward acetone, a diabetes biomarker, was demonstrated at low concentration (200 ppb) under high humidity (RH 80%). The detection limit reaches 3.6 ppb, a level satisfying the minimum requirement for diabetes breath diagnosis. High selectivity of the HPN sensor against C6H6, C7H8, CO, and NO vapors is demonstrated using principal component analysis (PCA), suggesting new applications of HPN for human-activity monitoring and a personal healthcare tool for diagnosing diabetes. The skeleton method can be further employed to mimic nanostructures of biomaterials with unique functionality for broad applications. PMID- 29411966 TI - Pt-Bi Antibonding Interaction: The Key Factor for Superconductivity in Monoclinic BaPt2Bi2. AB - In the search for superconductivity in a BaAu2Sb2-type monoclinic structure, we have successfully synthesized the new compound BaPt2Bi2, which crystallizes in the space group P21/m (No. 11; Pearson symbol mP10) according to a combination of powder and single-crystal X-ray diffraction and scanning electron microscopy. A sharp electrical resistivity drop and large diamagnetic magnetization below 2.0 K indicates it owns superconducting ground state. This makes BaPt2Bi2 the first reported superconductor in a monoclinic BaAu2Sb2-type structure, a previously unappreciated structure for superconductivity. First-principles calculations considering spin-orbit coupling indicate that Pt-Bi antibonding interaction plays a critical role in inducing superconductivity. PMID- 29411968 TI - Discovery of Plasmodium (M)TRAP-Aldolase Interaction Stabilizers Interfering with Sporozoite Motility and Invasion. AB - As obligate, intracellular parasites, Plasmodium spp. rely on invasion of host cells in order to replicate and continue their life cycle. The parasite needs to traverse the dermis and endothelium of blood vessels, invade hepatocytes and red blood cells, traverse the mosquito midgut, and enter the salivary glands to continue the cycle of infection and transmission. To traverse and invade cells, the parasite employs an actomyosin motor at the core of a larger invasion machinery complex known as the glideosome. The complex is comprised of multiple protein-protein interactions linking the motor to the internal cytoskeletal network of the parasite and to the extracellular adhesins, which directly contact the host tissue or cell surface. One key interaction is between the cytoplasmic tails of the thrombospondin related anonymous protein (TRAP) and aldolase, a bridging protein to the motor. Here, we present results from screening the Medicines for Malaria Venture (MMV) library of 400 compounds against this key protein-protein interaction. Using a surface plasmon resonance screen, we have identified several compounds that modulate the dynamics of the interaction between TRAP and aldolase. These compounds have been validated in vitro by studying their effects on sporozoite gliding motility and hepatocyte invasion. One of the MMV compounds identified reduced invasion levels by 89% at the lowest concentration tested (16 MUM) and severely inhibited gliding at even lower concentrations (5 MUM). By targeting protein-protein interactions, we investigated an under-explored area of parasite biology and general drug development, to identify potential antimalarial lead compounds. PMID- 29411969 TI - Diagnosing and Understanding Angiostrongyliasis, A Zoonotic Cause of Meningitis. AB - Eosinophilic meningitis caused by Angiostrongylus cantonensis is spreading worldwide, and it can manifest as a severe neurological disease. Angiostrongyliasis is a food- and water-borne parasitosis that usually exhibits a seasonal and circumscribed geographical distribution. To improve control and treatment of these infections, further studies of transmission dynamics under natural conditions and the development of better diagnostic tools and treatment options are needed. PMID- 29411967 TI - Drosophila as a Model System for Neurotransmitter Measurements. AB - Drosophila melanogaster, the fruit fly, is an important, simple model organism for studying the effects of genetic mutations on neuronal activity and behavior. Biologists use Drosophila for neuroscience studies because of its genetic tractability, complex behaviors, well-known and simple neuroanatomy, and many orthologues to human genes. Neurochemical measurements in Drosophila are challenging due to the small size of the central nervous system. Recently, methods have been developed to measure real-time neurotransmitter release and clearance in both larvae and adults using electrochemistry. These studies have characterized dopamine, serotonin, and octopamine release in both wild type and genetic mutant flies. Tissue content measurements are also important, and separations are predominantly used. Capillary electrophoresis, with either electrochemical, laser-induced fluorescence, or mass spectrometry detection, facilitates tissue content measurements from single, isolated Drosophila brains or small samples of hemolymph. Neurochemical studies in Drosophila have revealed that flies have functioning transporters and autoreceptors, that their metabolism is different than in mammals, and that flies have regional, life stage, and sex differences in neurotransmission. Future studies will develop smaller electrodes, expand optical imaging techniques, explore physiological stimulations, and use advanced genetics to target single neuron release or study neurochemical changes in models of human diseases. PMID- 29411970 TI - E-H Bond Activation and Insertion Processes in the Reactions of the Unsaturated Hydride [W2Cp2(MU-H)(MU-PPh2)(NO)2]. AB - The reactions of the title complex (1) with different p-block element (E) molecules was examined. Compound 1 reacted with BH3.THF at room temperature to give the trihydride [W2Cp2(MU-H)H2(MU-PPh2)(NO)2], which formally results from hydrogenation of 1, a reaction that actually does not take place when neat dihydrogen is used. Clean E-H bond oxidative addition, however, took place when 1 was reacted with HSnPh3, to give the related dihydride stannyl derivative [W2Cp2(MU-H)H(MU-PPh2)(NO)2(SnPh3)]. In contrast, the reaction of 1 with HSPh involved H2 elimination to give the thiolate-bridged complex [W2Cp2(MU-SPh)(MU PPh2)(NO)2], while that with (p-tol)C(O)H resulted in insertion of the aldehyde to yield the related alkoxide complex [W2Cp2{MU-OCH2(p-tol)}(MU-PPh2)(NO)2]. Insertion also prevailed in the reactions of 1 with CNtBu, which, however, involved the competitive formation of new C-H or N-H bonds, to give a mixture of formimidoyl and aminocarbyne derivatives, [W2Cp2(MU-kappa1:eta2-HCNtBu)(MU PPh2)(NO)2] (W-W = 3.0177(2) A) and [W2Cp2{MU-C(NHtBu)}(MU-PPh2)(NO)2] (W-W = 2.9010(4) A), respectively, even though the latter was thermodynamically preferred, according to density functional theory calculations. The former represents the first structurally characterized complex displaying a formimidoyl or iminoacyl ligand in the alkenyl-like MU-kappa1:eta2 coordination mode. The reaction of 1 with diazomethane proceeded with N2 elimination and C-H coupling to yield the agostic methyl-bridged complex [W2Cp2(MU-kappa1:eta2-CH3)(MU PPh2)(NO)2] (calculated W-W = 2.923 A), whereas the reaction with N2CH(SiMe3) proceeded with insertion of the diazoalkane to give the corresponding hydrazonide complex [W2Cp2{MU-NH(NCHSiMe3)}(MU-PPh2)(NO)2] (W-W = 2.8608(4) A). The latter was converted under alkaline conditions to the methyldiazenide derivative [W2Cp2{MU-N(NMe)}(MU-PPh2)(NO)2] (W-W = 2.8730(2) A), in a process involving hydrolysis of the C-Si bond coupled with a 1,3-H shift from N to C. PMID- 29411971 TI - Efficient Quantum-Dot Light-Emitting Diodes Employing Thermally Activated Delayed Fluorescence Emitters as Exciton Harvesters. AB - Utilization of triplet excitons plays a key role in obtaining highly efficient quantum-dot light-emitting diodes (QD-LEDs). However, to date, only phosphorescent materials have been implemented to harvest triplet excitons in QD LEDs. In this work, we introduced a thermally activated delayed fluorescence (TADF) emitter, 4,5-di(9H-carbazol-9-yl)phthalonitrile (2CzPN), doped into poly(N vinylcarbazole) (PVK) as an exciton harvester in red QD-LEDs by solution processing. As a result, electrons leaking to the PVK layer will be trapped by 2CzPN to form long-lifetime TADF excitons in the 2CzPN:PVK layer, and then this harvested exciton energy can be effectively transferred to the adjacent QDs by the Forster resonance energy-transfer process. The fabricated red CdSe/CdS core/shell QD-LEDs show a maximum luminescence efficiency of 17.33 cd/A and longer lifetime. Our results demonstrate that the TADF sensitizer would be a promising candidate to develop highly efficient QD-LEDs. PMID- 29411972 TI - 3D Fiber-Network-Reinforced Bicontinuous Composite Solid Electrolyte for Dendrite free Lithium Metal Batteries. AB - Replacement of flammable organic liquid electrolytes with solid Li+ conductors is a promising approach to realize excellent performance of Li metal batteries. However, ceramic electrolytes are either easily reduced by Li metal or penetrated by Li dendrites through their grain boundaries, and polymer electrolytes are also faced with instability on the electrode/electrolyte interface and weak mechanical property. Here, we report a three-dimensional fiber-network-reinforced bicontinuous solid composite electrolyte with flexible Li+-conductive network (lithium aluminum titanium phosphate (LATP)/polyacrylonitrile), which helps to enhance electrochemical stability on the electrode/electrolyte interface by isolating Li and LATP and suppress Li dendrites growth by mechanical reinforcement of fiber network for the composite solid electrolyte. The composite electrolyte shows an excellent electrochemical stability after 15 days of contact with Li metal and has an enlarged tensile strength (10.72 MPa) compared to the pure poly(ethylene oxide)-bistrifluoromethanesulfonimide lithium salt electrolyte, leading to a long-term stability and safety of the Li symmetric battery with a current density of 0.3 mA cm-2 for 400 h. In addition, the composite electrolyte also shows good electrochemical and thermal stability. These results provide such fiber-reinforced membranes that present stable electrode/electrolyte interface and suppress lithium dendrite growth for high safety all-solid-state Li metal batteries. PMID- 29411973 TI - Redox Capacitive Assaying of C-Reactive Protein at a Peptide Supported Aptamer Interface. AB - Electrochemical immunosensors offer much in the potential translation of a lab based sensing capability to a useful "real world" platform. In previous work we have introduced an impedance-derived electrochemical capacitance spectroscopic analysis as supportive of a reagentless means of reporting on analyte target capture at suitably prepared mixed-component redox-active, antibody-modified interfaces. Herein we directly integrate receptive aptamers into a redox charging peptide support in enabling a label-free low picomolar analytical assay for C reactive protein with a sensitivity that significantly exceeds that attainable with an analogous antibody interface. PMID- 29411974 TI - Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. AB - Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium. PMID- 29411975 TI - Affinity-Based Screen for Inhibitors of Bacterial Transglycosylase. AB - The rise of antibiotic resistance has created a mounting crisis across the globe and an unmet medical need for new antibiotics. As part of our efforts to develop new antibiotics to target the uncharted surface bacterial transglycosylase, we report an affinity-based ligand screen method using penicillin-binding proteins immobilized on beads to selectively isolate the binders from complex natural products. In combination with mass spectrometry and assays with moenomycin A and salicylanilide analogues (1-10) as reference inhibitors, we isolated four potent antibacterials confirmed to be benastatin derivatives (11-13) and albofungin (14). Compounds 11 and 14 were effective antibiotics against a broad-spectrum of Gram-positive and Gram-negative bacteria, including Acinetobacter baumannii, Clostridium difficile, Staphylococcus aureus, and drug-resistant strains with minimum inhibitory concentrations in the submicromolar to nanomolar range. PMID- 29411976 TI - Synthesis and Characterizations of Macrocyclic Cr(III) and Co(III) 1-Ethynyl Naphthalene and 9-Ethynyl Anthracene Complexes: An Investigation of Structural and Spectroscopic Properties. AB - Reported herein are the syntheses and structural and emission spectroscopic characterizations of new CrIII(HMC) and CoIII(cyclam) complexes bearing fluorophore alkynyl ligands, where HMC and cyclam are 5,5,7,12,12,14-hexamethyl 1,4,8,11-tetraazacyclotetradecane and 1,4,8,11-tetraazacyclotetradecane, respectively. Two Cr(III) bis-1-ethynylnaphthalene (C2Np) complexes, trans [Cr(HMC)(C2Np)2]Cl ([1]Cl) and cis-[Cr(HMC)(C2Np)2]Cl ([2]Cl), were prepared from the reactions between trans/cis-[Cr(HMC)Cl2]Cl and lithium 1-ethynylnaphthalene (LiC2Np) in yields of 73 and 66%, respectively. Also investigated are CoIII(cyclam) complexes bearing both C2Np and C2ANT (ANT = 9-anthryl), namely [Co(cyclam)(C2Ar)Cl]Cl (Ar = ANT ([3]Cl), Np ([4]Cl)), [Co(cyclam)(C2Np)(NCCH3)](OTf)2 ([5](OTf)2), and [Co(cyclam)(C2Np)2]OTf ([6]OTf). Complexes [3]Cl (72%) and [4]Cl (67%) were prepared from the reaction between [Co(cyclam)Cl2]Cl and Me3SiC2ANT or Me3SiC2Np, respectively, in the presence of triethylamine. The reaction of [4]Cl with excess silver triflate in CH3CN yielded complex [5](OTf)2 (78%), which was reacted with HC2Np in the presence of triethylamine to form complex [6]OTf in 39% yield. Single crystal X-ray diffraction studies of [1]+, [3]+, [4]+, and [6]+ revealed a pseudo-octahedral geometry around the Cr(III) or Co(III) center with the tetraaza-macrocyclic ligand occupying the equatorial plane and the alkynyl- and/or chloro-ligand occupying the apical positions. The absorption spectra of complexes [1]+ and [2]+ display structured d-d bands between 400 and 550 nm, a feature that is absent in the d-d absorption of the Co(III) complexes [3]+-[6]+. Contrasting emission behaviors were observed: the Cr(III) complexes display metal-centered phosphorescence, while the Co(III) species exhibit ligand-based fluorescence. Time-delayed phosphorescence measurements revealed lifetimes of 447 and 97 MUs for [1]+ and [2]+ at 77 K, respectively, and a room temperature lifetime of 218 MUs for [1]+. PMID- 29411977 TI - From Lead(II) Dithiocarbamate Precursors to a Fast Response PbS Positive Temperature Coefficient Thermistor. AB - PbS submicron crystals were formed by thermolysis of two different lead dithiocarbamate complexes. These precursors were readily synthesized and fully characterized, and in situ synchrotron powder diffraction experiments were performed to characterize their decomposition. The structure and purity of resultant PbS was examined using scanning electron and transmission electron microscopies, powder X-ray diffraction, and infrared spectroscopy. Submicron crystalline PbS was used to create a new PbS thermistor with excellent sensitivity and an ultrarapid thermal response time. PMID- 29411979 TI - How Do Ring Size and pi-Donating Thiolate Ligands Affect Redox-Active, alpha Imino-N-heterocycle Ligand Activation? AB - Considerable effort has been devoted to the development of first-row transition metal catalysts containing redox-active imino-pyridine ligands that are capable of storing multiple reducing equivalents. This property allows abundant and inexpensive first-row transition metals, which favor sequential one-electron redox processes, to function as competent catalysts in the concerted two-electron reduction of substrates. Herein we report the syntheses and characterization of a series of iron complexes that contain both pi-donating thiolate and pi-accepting (alpha-imino)-N-heterocycle redox-active ligands, with progressively larger N heterocycle rings (imidazole, pyridine, and quinoline). A cooperative interaction between these complementary redox-active ligands is shown to dictate the properties of these complexes. Unusually intense charge-transfer (CT) bands, and intraligand metrical parameters, reminiscent of a reduced (alpha-imino)-N heterocycle ligand (L*-), initially suggested that the electron-donating thiolate had reduced the N-heterocycle. Sulfur K-edge X-ray absorption spectroscopic (XAS) data, however, provides evidence for direct communication, via backbonding, between the thiolate sulfur and the formally orthogonal (alpha-imino)-N heterocycle ligand pi*-orbitals. DFT calculations provide evidence for extensive delocalization of bonds over the sulfur, iron, and (alpha-imino)-N-heterocycle, and TD-DFT shows that the intense optical CT bands involve transitions between a mixed Fe/S donor, and (alpha-imino)-N-heterocycle pi*-acceptor orbital. The energies and intensities of the optical and S K-edge pre-edge XAS transitions are shown to correlate with N-heterocycle ring size, as do the redox potentials. When the thiolate is replaced with a thioether, or when the low-spin S = 0 Fe(II) is replaced with a high-spin S = 3/2 Co(II), the N-heterocycle ligand metrical parameters and electronic structure do not change relative to the neutral L0 ligand. With respect to the development of future catalysts containing redox active ligands, the energy cost of storing reducing equivalents is shown to be lowest when a quinoline, as opposed to imidazole or pyridine, is incorporated into the ligand backbone of the corresponding Fe complex. PMID- 29411978 TI - Structural Rationale for the Enhanced Catalysis of Nonenzymatic RNA Primer Extension by a Downstream Oligonucleotide. AB - Nonenzymatic RNA primer extension by activated mononucleotides has long served as a model for the study of prebiotic RNA copying. We have recently shown that the rate of primer extension is greatly enhanced by the formation of an imidazolium bridged dinucleotide between the incoming monomer and a second, downstream activated monomer. However, the rate of primer extension is further enhanced if the downstream monomer is replaced by an activated oligonucleotide. Even an unactivated downstream oligonucleotide provides a modest enhancement in the rate of reaction of a primer with a single activated monomer. Here we study the mechanism of these effects through crystallographic studies of RNA complexes with the recently synthesized nonhydrolyzable substrate analog, guanosine 5'-(4 methylimidazolyl)-phosphonate (ICG). ICG mimics 2-methylimidazole activated guanosine-5'-phosphate (2-MeImpG), a commonly used substrate in nonenzymatic primer extension experiments. We present crystal structures of primer-template complexes with either one or two ICG residues bound downstream of a primer. In both cases, the aryl-phosphonate moiety of the ICG adjacent to the primer is disordered. To investigate the effect of a downstream oligonucleotide, we transcribed a short RNA oligonucleotide with either a 5'-ICG residue, a 5' phosphate or a 5'-hydroxyl. We then determined crystal structures of primer template complexes with a bound ICG monomer sandwiched between the primer and each of the three downstream oligonucleotides. Surprisingly, all three oligonucleotides rigidify the ICG monomer conformation and position it for attack by the primer 3'-hydroxyl. Furthermore, when GpppG, an analog of the imidazolium bridged intermediate, is sandwiched between an upstream primer and a downstream helper oligonucleotide, or covalently linked to the 5'-end of the downstream oligonucleotide, the complex is better preorganized for primer extension than in the absence of a downstream oligonucleotide. Our results suggest that a downstream helper oligonucleotide contributes to the catalysis of primer extension by favoring a reactive conformation of the primer-template-intermediate complex. PMID- 29411980 TI - Dynamics of Surfactant Clustering at Interfaces and Its Influence on the Interfacial Tension: Atomistic Simulation of a Sodium Hexadecane-Benzene Sulfonate-Tetradecane-Water System. AB - The process of equilibration of the tetradecane-water interface in the presence of sodium hexadecane-benzene sulfonate is studied using intensive atomistic molecular dynamics simulations. Starting as an initial point with all of the surfactants at the interface, it is obtained that the equilibration time of the interface (several microseconds) is orders of magnitude higher than previously reported simulated times. There is strong evidence that this slow equilibration process is due to the aggregation of surfactants molecules on the interface. To determine this fact, temporal evolution of interfacial tension and interfacial formation energy are studied and their temporal variations are correlated with cluster formation. To study cluster evolution, the mean cluster size and the probability that a molecule of surfactant chosen at random is free are obtained as a function of time. Cluster size distribution is estimated, and it is observed that some of the molecules remain free, whereas the rest agglomerate. Additionally, the temporal evolution of the interfacial thickness and the structure of the surfactant molecules on the interface are studied. It is observed how this structure depends on whether the molecules agglomerate or not. PMID- 29411981 TI - Correction to "Detection of Curvature-Radius-Dependent Interfacial pH/Polarity for Amphiphilic Self-Assemblies: Positive versus Negative Curvature". PMID- 29411982 TI - Glucose Responsive Rheological Change and Drug Release from a Novel Worm-like Micelle Gel Formed in Cetyltrimethylammonium Bromide/Phenylboronic Acid/Water System. AB - A novel glucose (Glc)-responsive gel formed by worm-like micelles (WLMs) has the potential to provide a self-regulating insulin delivery system. We have prepared a WLM gel system using 75 mM cetyltrimethylammonium bromide, 75 mM phenylboronic acid, and water. At pH 9.4, this gel-like system was highly viscous and supported its own weight, and dynamic viscoelasticity measurement indicated that it contained long and entangled WLMs. The visual observation of gels prepared to include >6 mM Glc revealed that these adopted a sol-like appearance, whereas those prepared to include a control compound (2-10 mM diethylene glycol) retained their gel-like appearance. The storage modulus ( G') of this system decreased as the Glc concentration increased (2-10 mM), indicating a gradual shortening of the WLMs. In vitro release was evaluated using a test compound (fluorescein isothiocyanate dextran) in a microsized flow system. By 120 min, the release of this compound from the WLM gel was around 27-fold greater in the presence of 100 mM Glc than without Glc or with 100 mM diethylene glycol. This demonstrated the successful preparation of a WLM gel that showed an altered drug release rate, depending on Glc concentration. PMID- 29411983 TI - Synthesis of Polyaryl-Substituted Olefins via a Rh(III)-Catalyzed One-Pot Reaction Using N-Phenoxyacetamides, Ketones, and Hydrazines. AB - A Rh(III)-catalyzed one-pot reaction of N-phenoxyacetamides, ketones, and hydrazines for a facile access to disubstituted and trisubstituted ethylenes is reported. In this method, various ketones are transformed into donor-donor diazo compounds, which engage in insertion with N-phenoxyacetamides, following beta-H elimination under Rh(III) catalysis to generate (E)-polyaryl-substituted olefins. This chemistry features simple starting materials, mild reaction conditions, and good functional group tolerance. PMID- 29411984 TI - Two Fungicides Alter Reproduction of the Small Brown Planthopper Laodelphax striatellus by Influencing Gene and Protein Expression. AB - Aside from their intended actions, fungicides can drive pest insect outbreaks due to virtually continuous use and pest evolution. Small brown planthopper (SBPH), Laodelphax striatellus, outbreaks occurred recently in many provinces in China, with devastating rice losses. Because exposure to the fungicide jinggangmycin (JGM) increased reproduction of the brown plant hopper, Nilaparvata lugens, via its influence on fatty acid synthase, we posed the hypothesis that JGM and carbendazim (CBM) influence SBPH reproduction via their influence on enzymes involved in other aspects of lipid metabolism. Exposure to the fungicide CBM stimulated SBPH reproduction (egg-laying up by 78%) and to another fungicide, JGM, led to decreased egg-laying (down by 47.3%). These inverse effects are mediated by down-regulated expression of l-3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) in JGM-treated females and up-regulated expression of hydroxysteroid dehydrogenase-like protein 2-like (HSD) in CBM-treated females. RNAi knockdown of, separately, LCHAD and HSD led to reduced egg-laying (down by 52% for dsLCHAD and by 73% for dsHSD). dsLCHAD, dsHSD, and JGM treatments also led to severely reduced ovarian development in experimental SBPH, with shorted and thinned valvula and lack of egg cells in ovaries. Valvula of CBM-treated females enlarged, with banana-shaped eggs in ovaries. These data strongly support our hypothesis. PMID- 29411985 TI - Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Bronsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective alpha-Alkylation of Quinolinylmethanols with Enals. AB - A strategy for the facile construction of the chiral quinolinylmethanolic structure, a core featured in cinchona alkaloids, is reported. A new reactivity is harnessed by TfOH-promoted chemoselective activation of alpha-C-H over O-H bond in quinolinylmethanols. The new reactivity is successfully engineered with an iminium catalysis in a synergistic manner to create a powerful conjugate addition-cyclization cascade process for synthesis of chiral quinoline derived gamma-butyrolactones in good yields and with good to excellent enantioselectivities. The method enables the first total synthesis of natural product broussonetine in three steps. PMID- 29411986 TI - Anion Relay Enabled [3 + 3]-Annulation of Active Methylene Isocyanides and Ene Yne-Ketones. AB - A new anion relay enabled [3 + 3]-annulation of active methylene isocyanides and conjugated ene-yne-ketones was developed for the efficient and straightforward synthesis of biologically valuable furo[3,2-c]pyridine derivatives. In this transformation, a sequential through-bond and through-space anion relay chemistry cascade is involved, which is initiated by an intermolecular Michael addition. Three new bonds and two rings are sequentially constructed from readily available acyclic precursors. PMID- 29411987 TI - Construction of Benzene Rings by Copper-Catalyzed Cycloaddition Reactions of Oximes and Maleimides: An Access to Fused Phthalimides. AB - A useful Cu-catalyzed cycloaddition protocol for the construction of benzene rings has been achieved. The reactions, utilizing readily available oximes and maleimides as starting materials, proceed under mild reaction conditions to generate a series of structurally interesting fused-phthalimides that are difficult to be prepared by conventional methods. PMID- 29411988 TI - Complete splenic embolization for the treatment of refractory ascites after liver transplantation. AB - Refractory ascites is an uncommon complication that may develop postoperatively after liver transplantation. The diagnosis and treatment of this condition is a real challenge. We report two cases of patients who underwent a transplant due to cryptogenic cirrhosis and developed refractory ascites during the immediate postoperative period. This is a serious complication associated with decreased survival by up to one year and a reduced quality of life. After ruling out the main causes of ascites, a portal hyperflow was a potential etiology. This condition perpetuates itself with splenic circulation and brings about a reduction in the hepatic arterial flow. Therefore, if arterial blood flow to the spleen is diminished, venous return and portal circulation will be reduced and arterial blood flow will improve. Splenic artery embolization is a procedure introduced many years ago for the management of splenic artery steal syndrome and small-for-size living donor liver transplantation. This procedure is performed in order to reduce portal hyperflow and consequently, ascites. In conclusion, splenic artery embolization is a therapeutic option for the treatment of refractory ascites after liver transplantation. PMID- 29411990 TI - Diagnosis and management of hepatic encephalopathy. AB - Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE. PMID- 29411991 TI - Patient pathway: the ideal approach. AB - Hepatic encephalopathy (HE) can be a devastating complication of cirrhosis, affecting patients and their families. Multidisciplinary community and specialist teams must work together with patients and their families to recognise HE, identify and treat problems early, and minimise time spent unwell or in hospital. Primary care provides an ideal setting for patient education and reinforcement of the salient points on self-care. In the acute setting, the use of care pathways can ensure that the critical aspects of pharmacological, dietetic and supportive care are offered in a timely fashion to reduce morbidity and mortality. This article discusses strategies that can be used in primary and secondary care to help teams deliver excellent practice in HE management. PMID- 29411989 TI - Fecal microbiota transplantation in refractory or recurrent Clostridium difficile infection: a real-life experience in a non-academic center. AB - AIM: this study aimed to describe the efficacy and safety of fecal microbiota transplantation (FMT) for the treatment of refractory and recurrent Clostridium difficile infection (CDI). METHODS: this was an observational study of patients with refractory or recurrent CDI treated with FMT between June 2014 and January 2017. Primary and secondary outcomes were the resolution of diarrhea without CDI recurrence within two months after one or more FMT. A descriptive analysis was performed. RESULTS: thirty-four FMT were performed in 28 patients, 88.2% (n = 30) using an upper route with a gastroscopy and 11.8% (n = 4) with colonoscopy; 50% (n = 17) of FMT were due to recurrent CDI and 50% (n = 17) were due to refractory CDI. The overall cure rate of upper FMT was 87.5% (21/24) and 100% (4/4) when colonoscopy was performed. A cure was achieved after one FMT in 88% (22/25) of cases and after two or more FMT in 8% (2/25) of cases, resulting in an overall cure rate of 96% (24/25). No severe adverse events were reported. CONCLUSION: FMT constitutes an effective and safe approach for the management of refractory and recurrent CDI, with an overall cure rate of 96% and no reported severe adverse events. PMID- 29411992 TI - Improving Quality of Care for People with Hepatic Encephalopathy. PMID- 29411993 TI - Hepatic encephalopathy: causes and health-related burden. AB - Patients with cirrhosis are at risk of hepatic encephalopathy (HE). While its pathogenesis is not fully understood, the circulation of increased levels of ammonia through the bloodstream to the brain is thought to be a key causative factor. The ammonia penetrates the blood-brain barrier, ultimately leading to cerebral oedema. This can result in cognitive impairments, which can exhibit in multiple ways, adversely affecting quality of life for both patients and their families. The need for hospitalisation and longer hospital stays associated with HE has cost implications for the health service. Treatment revolves around the reduction of ammonia levels in the bloodstream. PMID- 29411994 TI - Anticancer metallodrugs: where is the next cisplatin? AB - Despite the severe side effects and the emergence of drug resistance, the use of DNA-targeting platinum drugs remains strong either alone or in a combination chemotherapy regimen. New strategies and formulations are being explored in the design of anticancer metal complexes that exhibit nonclassical modes of action, selectively hit precise biomolecular targets or are even able to induce immunogenic anticancer activity. These developments will ameliorate the systemic toxicity of metal-based drugs and widen the range of treatable cancers. PMID- 29411995 TI - Cyclic lipodepsipeptides: time for a concerted action to unlock their application potential? PMID- 29411996 TI - Emergence of Depressive Symptoms from Kindergarten to Sixth Grade. AB - This study documents the emergence of symptoms of anxiety and depression in a community sample of school-age children and describes the temporal progression of symptoms leading to depressive episodes. Caregivers of 468 seventh graders reported retrospectively the manifestation of 14 symptoms of depression and anxiety in their children from kindergarten through sixth grade. The sample was balanced by sex and reflected the racial and economic diversity of the urban school district. Childhood period prevalence was calculated for each symptom, and discrete time survival analyses compared likelihoods of early symptom emergence in children who did and did not meet diagnostic criteria for major depressive disorder (MDD) by ninth grade. Symptom prevalence ranged between 20% (excessive guilt) and 50% (concentration problems) during the elementary school years. The 4 year period prevalence of MDD was 8.9%, 95% confidence interval [6.5%, 12.1%]. Low energy, excessive worry, excessive guilt, anhedonia, social withdrawal, and sadness or depressed mood were each associated with a significantly higher likelihood of onset of MDD. Compared to girls, boys were more likely to exhibit sad mood, fatigue, and trouble concentrating. Children who later met criteria for MDD demonstrated a significantly higher likelihood of showing core features of depressive and anxiety disorders during their elementary school years. The findings underscore the importance of recognizing early signs and developing interventions to help children manage early symptoms and prevent later psychiatric illness. PMID- 29411997 TI - Does Music Matter? A Look at the Issues and the Evidence. AB - Does music matter? Judging from the ever-diminishing support for music education in public funding, the message is that it is just a frill to be cast aside for more pressing needs. The pleasure of listening to music is worthy in itself and reason enough for support, but what happens when people are more deeply engaged, such as when they learn to read music and play an instrument? Can more material rewards follow for cognition, language, and emotion, and for social and physical well-being? This essay presents an overview of issues and evidence from a broad range of disciplines and age groups. PMID- 29411998 TI - Understanding and Reducing Sexual Prejudice in Jamaica: Theoretical and Practical Insights From a Severely Anti-Gay Society. AB - Jamaica has earned an international reputation for severe sexual prejudice perhaps disproportionately so compared to other severely anti-LGBT (lesbian, gay, bisexual, and transgender) societies. Until recently, however, no quantitative empirical research had investigated Jamaica's sexual prejudice, leaving the prejudice poorly understood and methods of reducing it unclear. This article reviews empirical research on Jamaican anti-LGBT prejudice from the past 15 years. It situates Jamaica within the global context, explains the current understanding of the severity and nature of the problem, evaluates solutions currently being explored, and suggests promising strategies based on available evidence. Importantly, this article also reflects on lessons learned from Jamaica that are relevant for other severely anti-LGBT societies. PMID- 29411999 TI - Field Evidence Supporting Conventional Onion Curing Practices as a Strategy To Mitigate Escherichia coli Contamination from Irrigation Water. AB - The Produce Safety Rule of the U.S. Food Safety Modernization Act includes restrictions on the use of agricultural water of poor microbiological quality. Mitigation options for poor water quality include the application of an irrigation-to-harvest interval of <4 days; however, dry bulb onion production includes an extended irrigation-to-harvest interval (<30 days). This study evaluated conventional curing practices for mitigating Escherichia coli contamination in a field setting. Well water inoculated with rifampin-resistant E. coli (1, 2, or 3 log CFU/mL) was applied to onion fields (randomized block design; n = 5) via drip tape on the final day of irrigation. Onions remained undisturbed for 7 days and were then lifted to the surface to cure for an additional 21 days before harvest. Water, onions, and soil were tested for presence of rifampin-resistant E. coli. One day after irrigation, 13.3% of onions (20 of 150) receiving the poorest quality water (3 log CFU/mL) tested positive for E. coli; this prevalence was reduced to 4% (6 of 150 onions) after 7 days. Regardless of inoculum level, E. coli was not detected on any onions beyond 15 days postirrigation. These results support conventional dry bulb onion curing practices as an effective strategy to mitigate microbiological concerns associated with poor quality irrigation water. PMID- 29412001 TI - Training the Anesthesiologist Trainer: Enhancing the Quality of Feedback during Human Patient Simulations. AB - An essential piece of anesthesiologist training is attending resident feedback sessions. Yet, few attending anesthesiologists have formal teaching education and little time to acquire it. In this field experiment, attending physicians were randomly assigned to a control group or to receive 30 minutes of feedback training inspired by Implicit Person Theory (IPT). As such, IPT training encouraged physicians to praise process-oriented learning while discouraging performance-oriented mindsets. Attending physicians then observed residents participate in a human patient simulation (HPS) activity and provided residents with feedback. Content and statistical analyses revealed trained attending physicians praised learning goals and challenged performance goals more often than untrained physicians during feedback sessions. Thus, the training provides a rapid method of enhancing the quality of attending physicians' training communication. PMID- 29412000 TI - Measurement of the perfusion fraction in brain tumors with intravoxel incoherent motion MR imaging: validation with histopathological vascular density in meningiomas. AB - OBJECTIVE: To evaluate the quantification performance of the perfusion fraction (f) measured with intravoxel incoherent motion (IVIM) MR imaging in a comparison with the histological vascular density in meningiomas. METHODS: 29 consecutive patients with meningioma (59.0 +/- 16.8 years old, 8 males and 21 females) who underwent a subsequent surgical resection were examined with both IVIM imaging and a histopathological analysis. IVIM imaging was conducted using a single-shot SE-EPI sequence with 13 b-factors (0, 10, 20, 30, 50, 80, 100, 200, 300, 400, 600, 800, 1000 s mm-2) at 3T. The perfusion fraction (f) was calculated by fitting the IVIM bi-exponential model. The 90-percentile f-value in the tumor region-of-interest (ROI) was defined as the maximum f-value (f-max). Histopathological vascular density (%Vessel) was measured on CD31-immunostainted histopathological specimens. The correlation and agreement between the f-values and %Vessel was assessed. RESULTS: The f-max (15.5 +/- 5.5%) showed excellent agreement [intraclass correlation coefficient (ICC) = 0.754] and a significant correlation (r = 0.69, p < 0.0001) with the %Vessel (12.9 +/- 9.4%) of the tumors. The Bland-Altman plot analysis showed excellent agreement between the f max and %Vessel (bias, -2.6%; 95% limits of agreement, from -16.0 to 10.8%). The f-max was not significantly different among the histological subtypes of meningioma. CONCLUSION: An excellent agreement and a significant correlation were observed between the f-values and %Vessel. The f-value can be used as a noninvasive quantitative imaging measure to directly assess the vascular volume fraction in brain tumors. Advances in knowledge: The f-value measured by IVIM imaging showed a significant correlation and an excellent agreement with the histological vascular density in the meningiomas. The f-value can be used as a noninvasive and quantitative imaging measure to directly assess the volume fraction of capillaries in brain tumors. PMID- 29412002 TI - Close pathological correlations between chronic kidney disease and reproductive organ-associated abnormalities in female cotton rats. AB - Cotton rat ( Sigmodon hispidus) is a useful experimental rodent for the study of human infectious diseases. We previously clarified that cotton rats, particularly females, developed chronic kidney disease characterized by cystic lesions, inflammation, and fibrosis. The present study investigated female-associated factors for chronic kidney disease development in cotton rats. Notably, female cotton rats developed separation of the pelvic symphysis and hypertrophy in the vaginal parts of the cervix with age, which strongly associated with pyometra. The development of pyometra closely associated with the deterioration of renal dysfunction or immunological abnormalities was indicated by blood urea nitrogen and serum creatinine or spleen weight and serum albumin/globulin ratio, respectively. These parameters for renal dysfunction and immunological abnormalities were statistically correlated. These phenotypes found in the female reproductive organs were completely inhibited by ovariectomy. Further, the female cotton rats with pyometra tended to show more severe chronic kidney disease phenotypes and immunological abnormalities than those without pyometra; these changes were inhibited in ovariectomized cotton rats. With regard to renal histopathology, cystic lesions, inflammation, and fibrosis were ameliorated by ovariectomy. Notably, the immunostaining intensity of estrogen receptor alpha and estrogen receptor beta were weak in the healthy kidneys, but both estrogen receptors were strongly induced in the renal tubules showing cystic changes. In conclusion, the close correlations among female reproductive organ-associated abnormalities, immunological abnormalities, and renal dysfunction characterize the chronic kidney disease features of female cotton rats. Thus, the cotton rat is a unique rodent model to elucidate the pathological crosstalk between chronic kidney disease and sex-related factors. Impact statement The increasing number of elderly individuals in the overall population has led to a concomitant age related increase in chronic kidney disease. Moreover, the global prevalence of patients with chronic kidney disease is gradually increasing, which poses a serious public health problem. The limited number of spontaneous chronic kidney disease animal models, which resemble chronic kidney disease pathogenesis in elderly individuals, is a major limitation in the development of experimental and curative medicines for chronic kidney disease. This pathological study clarified that sex-related factors, including hormones, and abnormalities of the female reproductive system, such as pyometra, are closely associated with chronic kidney disease development by using cotton rats ( Sigmodon hispidus). Further, ovariectomy inhibited the phenotypes of the female reproductive system, immunological abnormalities, and chronic kidney disease. Thus, this laboratory rodent serves as a novel and useful spontaneous chronic kidney disease model to elucidate the candidate disease factors and the pathogenesis of chronic kidney disease both in human and experimental medicine. PMID- 29412003 TI - Sympathetic arousal as a marker of chronicity in childhood stuttering. AB - PURPOSE: This study investigated whether sympathetic activity during a stressful speaking task was an early marker for stuttering chronicity. METHOD: Participants were 9 children with persisting stuttering, 23 children who recovered, and 17 children who do not stutter. Participants performed a stress-inducing picture naming task and skin conductance was measured across three time points. RESULTS: Findings indicated that at the initial time point, children with persisting stuttering exhibited higher sympathetic arousal during the stressful speaking task than children whose stuttering recovered. CONCLUSIONS: Findings are taken to suggest that sympathetic activity may be an early marker of heightened risk for chronic stuttering. PMID- 29412004 TI - Neural Response to Pleasant Pictures Moderates Prospective Relationship Between Stress and Depressive Symptoms in Adolescent Girls. AB - Adolescent girls are at increased risk for depression, which is thought to result from the interaction of biological vulnerabilities and life stressors common to adolescent girls. A blunted late positive potential (LPP) to emotional stimuli (i.e., pleasant and unpleasant) has been associated with depressive symptoms and risk. The current study of adolescent girls examines the moderating effects of the LPP, a candidate biomarker of depression, of the link between life stress and increases in depressive symptoms over 1 year. We measured LPP to pleasant and unpleasant pictures from the International Affective Picture Set among 143 predominantly Caucasian adolescent girls ages 8 to 14, who also reported on the frequency of common life stressors. Self-reported depressive symptoms were assessed both at baseline and 1 year after the initial lab visit. The LPP to pleasant pictures moderated the relationship between baseline life stressors and the change in depressive symptoms. Specifically, life stress was associated with increases in depressive symptoms when the LPP to pleasant pictures was blunted, whereas life stress was associated with decreases in depressive symptoms when the LPP to pleasant pictures was potentiated. These effects showed some specificity to family and school-related stressors and to anhedonic and efficacy-related depressive symptoms. A similar pattern, though not statistically significant, was found for the LPP to unpleasant pictures. Together, these findings suggest that the LPP to pleasant pictures may represent a useful biomarker in identifying individuals at greatest risk of experiencing depressive symptoms following stress. PMID- 29412005 TI - Citizen Science to Communicate about Public Health Messages: The Reach of a Playful Online Survey on Sitting Time and Physical Activity. AB - : There is a lack of research on how to communicate public health guidelines. Citizen science (CS) has been an effective way to involve the public in research. This study analyses the reach of a well-established CS experiment, launched during an annual national science event, to understand if it could be used as communication strategy for public health issues. A short playful online survey contained tailored health-related messages associated to an "animal totem" profile, based on the combination of sitting and physical activity levels (koala: high sitting, low activity; gorilla: high sitting, high activity; zebra: low sitting, low activity; bee: low sitting, high activity). Tweets, radio interviews, radio and online advertisements, press articles, and a press conference were used to promote the CS experiment. Google Analytics and Facebook Graph API (application programming interface) (use and spread of experiment) and descriptive statistics (attributes of adults completing the experiment) were used. A total of 6,246 adults completed the experiment, with a peak of views (n = 5,103) and completions (n = 1,209) a couple of days before the event. Completers were mostly female (65.8%), on average 37.5 years old, and had a healthy body mass index (23.8 kg/m2). Nearly half (46.4%) had the most beneficial profile ("bee"), 26.5% had the least healthy profile ("koala"). CS as part of a national science event is a good platform for health communication as 1 in 1,000 Flemish adults were reached. However, those completing the experiment were not representative of the general Flemish adult population and reported to be more physically active. ABBREVIATIONS: API: application programming interface; BMI: body mass index; CVD: cardiovascular disease; METs: metabolic equivalents. PMID- 29412006 TI - Gadolinium as an MRI contrast agent. AB - MRI contrast is often enhanced using a contrast agent. Gd3+-complexes are the most widely used metallic MRI agents, and several types of Gd3+-based contrast agents (GBCAs) have been developed. Furthermore, recent advances in MRI technology have, in part, been driven by the development of new GBCAs. However, when designing new functional GBCAs in a small-molecular-weight or nanoparticle form for possible clinical applications, their functions are often compromised by poor pharmacokinetics and possible toxicity. Although great progress must be made in overcoming these limitations and many challenges remain, new functional GBCAs with either small-molecular-weight or nanoparticle forms offer an exciting opportunity for use in precision medicine. PMID- 29412007 TI - Eye Tracking as a Marker of Hyperphagia in Prader-Willi Syndrome. AB - This study examined the feasibility of eye tracking measures as markers of hyperphagia in 42 children and adults with Prader-Willi syndrome (PWS). Gaze data collected during free visual exploration of complex displays revealed that food images may not have an overall superior salience in PWS. However, increased attention to food in the context of other high-interest items was associated with higher scores on caregiver reports of hyperphagia. The study also provided preliminary evidence of test-retest reliability of eye tracking measures, suggesting that gaze characteristics may be a promising objective marker of food related interests in PWS. PMID- 29412008 TI - Subtraction CT angiography in head and neck with low radiation and contrast dose dual-energy spectral CT using rapid kV-switching technique. AB - OBJECTIVE: To investigate the application of low radiation and contrast dose spectral CT angiology using rapid kV-switching technique in the head and neck with subtraction method for bone removal. METHODS: This prospective study was approved by the local ethics committee. 64 cases for head and neck CT angiology were randomly divided into Groups A (n = 32) and B (n = 32). Group A underwent unenhanced CT with 100 kVp, 200 mA and contrast-enhanced CT with spectral CT mode with body mass index-dependent low dose protocols. Group B used conventional helical scanning with 120 kVp, auto mA for noise index of 12 HU (Hounsfield unit) for both the unenhanced and contrast-enhanced CT. Subtraction images were formed by subtracting the unenhanced images from enhanced images (with the 65 keV enhanced spectral CT image in Group A). CT numbers and their standard deviations in aortic arch, carotid arteries, middle cerebral artery and air were measured in the subtraction images. The signal-to-noise ratio and contrast-to-noise ratio for the common and internal carotid arteries and middle cerebral artery were calculated. Image quality in terms of bone removal effect was evaluated by two experienced radiologists independently and blindly using a 4-point system. Radiation dose and total iodine load were recorded. Measurements were statistically compared between the two groups. RESULTS: The two groups had same demographic results. There was no difference in the CT number, signal-to-noise and contrast-to-noise ratio values for carotid arteries and middle cerebral artery in the subtraction images between the two groups (p > 0.05). However, the bone removal effect score [median (min-max)] in Group A [4 (3-4)] was rated better than in Group B [3 (2-4)] (p < 0.001), with excellent agreement between the two observers (kappa > 0.80). The radiation dose in Group A (average of 2.64 mSv) was 57% lower than the 6.18 mSv in Group B (p < 0.001). The total iodine intake in Group A was 13.5g, 36% lower than the 21g in Group B. CONCLUSION: Spectral CT imaging with rapid kV-switching in the subtraction angiography in head and neck provides better bone removal with significantly reduced radiation and contrast dose compared with conventional subtraction method. Advances in knowledge: This novel method provides better bone removal with significant radiation and contrast dose reduction compared with the conventional subtraction CT, and maybe used clinically to protect the thyroid gland and ocular lenses from unnecessary high radiation. PMID- 29412009 TI - Development of a carboplatin derivative conjugated with a collagen-like triple helical peptide. AB - AIM: The development of a platinum anticancer agent that has improved efficacy by efficient delivery to a tumor and that suppresses side effects has been investigated. Arginine-rich triple-helical peptides are promising drug carriers because of their stability in body fluids and cell-penetrating activity. RESULTS: We synthesized a carboplatin derivative conjugated with an arginine-rich triple helical peptide. This derivative released platinum under acidic conditions or in the presence Cl- ions. Administration of this derivative to P388 tumor-bearing mice showed comparable survival rates to twice the dose of carboplatin, which was attributed to a longer mean residence time by pharmacokinetics analysis. CONCLUSION: The collagen-like triple-helical peptide was an efficient carrier of a platinum anticancer agent because of a modification to its pharmacokinetic profile. PMID- 29412010 TI - Decoupling of the Occipitotemporal Cortex and the Brain's Default-Mode Network in Dyslexia and a Role for the Cingulate Cortex in Good Readers: A Brain Imaging Study of Brazilian Children. AB - The goal of the present study was to investigate intrinsic and reading-related brain function associated with dyslexia and typical readers in monolingual Brazilian children. Two fMRI studies were carried out: a resting-state and a word reading study. The results show (a) underconnectivity between the occipitotemporal region (visual word form area) and the brain's default-mode network in dyslexic readers and (b) more activation of the anterior cingulate cortex for typical readers relative to dyslexic readers. The findings provide evidence for brain connectivity and function differences in an underrepresented population in fMRI studies of dyslexia; the results suggest atypical intrinsic function, and differences in directed attention processes in dyslexia. PMID- 29412011 TI - Embedded performance validity indicator for children: California Verbal Learning Test - Children's Edition, forced choice. AB - Performance validity testing in children undergoing neuropsychological testing is a growing research area. Accurate identification of performance validity is necessary to avoid invalid assessment conclusions. In the present research, a forced choice (FC) trial was created for the California Verbal Learning Test - Children's Edition (CVLT-C), modeled after the established California Verbal Learning Test - Second Edition (CVLT-II) FC trial. Distractor words were taken directly from the CVLT-II FC Standard Form, with about half being concrete (n = 8) and half abstract (n = 7). The order of the items was organized similarly to the CVLT-II FC to ensure that items from within the same category were not sequential. The Test of Memory Malingering was administered for comparison, and three embedded measures that have previously been validated in adults were also calculated. The CVLT-C FC trial was administered to 40 children, aged 6-16 (M = 12.08, SD = 3.13). Average full scale IQ was 97.3 (SD = 12.41, range = 71-123). Ninety-three percent of examinees performed perfectly on the CVLT-C FC, suggesting high specificity, which is similar to findings for the CVLT-II FC normative group (90%). Results from other embedded measures are also presented. PMID- 29412013 TI - Moral Incongruence and Pornography Use: A Critical Review and Integration. AB - Internet pornography use (IPU) remains a controversial topic within sexual behavior research fields. Whereas some people report feeling dysregulated in their use of pornography, mental health and medical communities are divided as to whether IPU can be addictive. The present review sought to examine this issue more closely, with a focus on how variables other than pornography use, such as moral disapproval and moral incongruence (i.e., feeling as if one's behaviors and one's values about those behaviors are misaligned), might specifically contribute to self-perceived problems around pornography use. Through an examination of recent literature, the present work reviews evidence that moral incongruence about IPU is a common phenomenon and that it is associated with outcomes relevant to current debates about pornography addiction. Specifically, moral incongruence regarding IPU appears to be associated with greater distress about IPU, greater psychological distress in general, greater reports of problems related to IPU, and greater reports of perceived addiction to IPU. The implications of this body of evidence for both clinical and research communities are discussed, and future directions for research are considered. PMID- 29412012 TI - Application of an assay Cascade methodology for a deep preclinical characterization of polymeric nanoparticles as a treatment for gliomas. AB - Glioblastoma multiforme (GBM) is the most devastating primary brain tumor due to its infiltrating and diffuse growth characteristics, a situation compounded by the lack of effective treatments. Currently, many efforts are being devoted to find novel formulations to treat this disease, specifically in the nanomedicine field. However, due to the lack of comprehensive characterization that leads to insufficient data on reproducibility, only a reduced number of nanomedicines have reached clinical phases. In this context, the aim of the present study was to use a cascade of assays that evaluate from physical-chemical and structural properties to biological characteristics, both in vitro and in vivo, and also to check the performance of nanoparticles for glioma therapy. An amphiphilic block copolymer, composed of polyester and poly(ethylene glycol; PEG) blocks, has been synthesized. Using a mixture of this copolymer and a polymer containing an active targeting moiety to the Blood Brain Barrier (BBB; Seq12 peptide), biocompatible and biodegradable polymeric nanoparticles have been prepared and extensively characterized. In vitro studies demonstrated that nanoparticles are safe for normal cells but cytotoxic for cancer cells. In vivo studies in mice demonstrated the ability of the Seq12 peptide to cross the BBB. Finally, in vivo efficacy studies using a human tumor model in SCID mice resulted in a significant 50% life span increase, as compared with non-treated animals. Altogether, this assay cascade provided extensive pre-clinical characterization of our polymeric nanoparticles, now ready for clinical evaluation. PMID- 29412014 TI - Albendazole solution formulation via vesicle-to-micelle transition of phospholipid-surfactant aggregates. AB - OBJECTIVE: To reveal the physicochemical mechanisms governing the solubilization of albendazole in surfactant and phospholipid-surfactant solutions and, on this basis, to formulate clinically relevant dose of albendazole in solution suitable for parenteral delivery. SIGNIFICANCE: (1) A new drug delivery system for parenteral delivery of albendazole is proposed, offering high drug solubility and low toxicity of the materials used; (2) New insights on the role of surface curvature on albendazole solubilization in surfactant and surfactant-phospholipid aggregates are provided. METHODS: The effect of 17 surfactants and 6 surfactant phospholipid mixtures on albendazole solubility was studied. The size of the colloidal aggregates was determined by light-scattering. The dilution stability of the proposed formulation was assessed by experiments with model human serum. RESULTS: Anionic surfactants increased very strongly drug solubility at pH = 3 (up to 4 mg/mL) due to strong electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. This effect was observed with all anionic surfactants studied, including sodium dodecyl sulfate, double chain sodium dioctylsulfosuccinate (AOT), and the bile salt sodium taurodeoxycholate. The phospholipid-surfactant mixture of 40% sodium dipalmitoyl phosphatidylglycerol +60% AOT provided highest albendazole solubilization (4.4 mg/mL), smallest colloidal aggregate size (11 nm) and was stable to dilution with model human serum at (and above) 1:12 ratio. CONCLUSIONS: A new albendazole delivery system with high drug load and low toxicity of the materials used was developed. The high solubility of albendazole was explained with vesicle-to micelle transition due to the larger interfacial curvature preferred for albendazole solubilization locus. PMID- 29412015 TI - Differentiation of Malignant and Benign Adrenal Lesions With Delayed CT: Multivariate Analysis and Predictive Models. AB - OBJECTIVE: The purpose of this study is to identify imaging and patient parameters that affect the diagnostic performance of delayed contrast-enhanced CT for distinguishing malignant from benign adrenal lesions larger than 1 cm in adult patients and to derive predictive models. MATERIALS AND METHODS: This retrospective study assessed 97 pathologically proven adrenal lesions that had undergone unenhanced, portal venous, and 15-minute delayed CT. Quantitatively, single-parameter evaluations of lesion attenuation (in Hounsfield units) and absolute percentage enhancement washout (APEW) and relative percentage enhancement washout (RPEW) were performed. In addition, descriptive CT features (lesion size, margin definition, heterogeneity vs homogeneity, fat, and calcification) and patients' demographic characteristics and medical history of malignancy were evaluated for association with lesion status using multiple logistic regression with stepwise model selection. Areas under the ROC curve (Az) were determined for univariate and multivariate analyses. Leave-one-lesion-out cross-validation was applied to ascertain the predictive performance of single parameter and multivariate evaluations. RESULTS: The Az values for unenhanced attenuation, portal venous attenuation, delayed attenuation, APEW, and RPEW were 0.835, 0.534, 0.847, 0.792, and 0.871, respectively. Multivariate analyses revealed that portal venous attenuation, delayed attenuation, and APEW were significant features, with an Az of 0.923 when combined. The addition of the descriptive CT features increased the Az to 0.938; patient age and a history of malignancy were additional significant factors, increasing the Az to 0.956 and 0.972, respectively. The combined predictive classifier yielded 89% accuracy under cross-validation, compared with the best commonly applied single-parameter evaluation (77% for RPEW < 40%). CONCLUSION: Multivariate imaging evaluation applied to delayed contrast-enhanced CT alone, with or without patient characteristics, improves diagnostic performance for characterizing adrenal lesions beyond those of single-parameter evaluations. Predictive formulas assessing the probabilities of lesion benignity or malignancy are provided. PMID- 29412016 TI - Reactions to Both Nonionic Iodinated and Gadolinium-Based Contrast Media: Incidence and Clinical Characteristics. AB - OBJECTIVE: The objective or our study was to assess the incidence rate and clinical characteristics of allergiclike reactions in patients who received both nonionic iodinated contrast medium (ICM) and gadolinium-based contrast medium (GBCM). MATERIALS AND METHODS: Acute allergiclike reactions in patients who received both ICM and GBCM to nonionic ICM or GBCM injections during a 5-year period were analyzed. Allergy preparation was not administered when patients received a different type of contrast material. Acute allergiclike reactions to both ICM and GBCM were evaluated. RESULTS: Of 302,858 contrast injections (155,234 ICM and 147,624 GBCM) during a 5-year period, 1006 (752 ICM and 254 GBCM) acute allergiclike contrast reactions were reported. The overall rate of reaction to ICM was 0.48% (95% CI, 0.45-0.52%), and the overall rate of reaction to GBCM was 0.17% (95% CI, 0.15-0.19%). A total of 19,237 patients received at least one ICM injection and one GBCM injection, with a total of 56,310 injections (19,237 initial injections and 37,073 subsequent injections). Nine patients had reactions to both ICM and GBCM with the primary reaction rate of 9/19,237 (incidence rate, 0.047%; 95% CI, 0.044-0.050%), and the secondary reaction rate of 9/37,073 (incidence rate, 0.024%; 95% CI, 0.023-0.026%). All secondary reactions in patients who had a reaction to both ICM and GBCM were mild. None of the patients required medication for the treatment of the secondary reaction. CONCLUSION: An allergiclike reaction to both nonionic ICM and GBCM was an extremely rare event that presented as a mild acute reaction without significant clinical consequences despite the fact that an allergy preparation was not administered. PMID- 29412017 TI - Transcatheter Arterial Chemoembolization With or Without Radiofrequency Ablation: Outcomes in Patients With Barcelona Clinic Liver Cancer Stage B Hepatocellular Carcinoma. AB - OBJECTIVE: The objective of our study was to clarify the indications for transcatheter arterial chemoembolization (TACE) of the hepatic artery combined with radiofrequency ablation (RFA), which we refer to as "TACE-RFA," for patients with hepatocellular carcinoma (HCC) beyond the Milan criteria. This study assessed the prognoses of patients with intermediate-stage HCC, which we defined as Barcelona Clinic Liver Cancer (BCLC) stage B (hereafter referred to as BCLC B), according to the BCLC-B substages through treatment in a multicenter study. MATERIALS AND METHODS: Two-hundred thirty patients with intermediate-stage HCC who were treated from January 2000 to December 2015 were enrolled. These patients were divided into four classes (B1-B4) according to the Bolondi classification. Between these substages, the prognosis of patients who underwent TACE-RFA was compared with that of patients who underwent TACE, the latter of which is the suggested standard therapy for patients with BCLC-B HCC. RESULTS: TACE-RFA and hepatic resection survival curves were better than those of TACE (p < 0.001 for TACE-RFA vs TACE). In particular, for substages B1 and B2, the overall survival rates of patients who underwent TACE-RFA were significantly higher than those who underwent TACE (B1, p < 0.001 for TACE-RFA vs TACE; B2, p = 0.015 for TACE-RFA vs TACE). CONCLUSION: The indications for TACE-RFA may be expanding to BCLC-B HCC. For patients with disease classified as substages B1 and B2, TACE-RFA may be a better treatment modality than TACE alone. PMID- 29412018 TI - Single-Contrast CT for Detecting Bowel Injuries in Penetrating Abdominopelvic Trauma. AB - OBJECTIVE: Many centers advocate use of triple-contrast (IV, oral, and rectal) CT for assessing hemodynamically stable patients with penetrating abdominopelvic trauma. Enteric contrast material has several disadvantages, leading our practice to pursue use of single-contrast (IV) CT. We conducted a retrospective review of electronic medical records at our institution to assess the accuracy of single contrast CT for diagnosing bowel injuries in cases of penetrating abdominopelvic trauma. MATERIALS AND METHODS: We retrospectively reviewed patients who presented to our emergency department between January 1, 2004, and March 1, 2014, with penetrating abdominopelvic trauma, underwent an abdominopelvic CT, and had surgery performed thereafter. We reviewed pertinent emergency department records for details regarding the site of injury, the number of injuries per patient, and the type of weapon used. We correlated CT reports with operative notes for presence and sites of bowel injury. RESULTS: A total of 274 patients (median age, 27 years old) met our inclusion criteria; 77% had sustained gunshot wounds (GSWs). CT showed bowel injury in 173 cases; surgery revealed bowel injury in 162 cases. CT had 142 true-positive, 31 false-positive, 81 true-negative, and 20 false-negative cases, resulting in sensitivity of 88%, specificity of 72%, positive predictive value of 82%, and negative predictive value of 80% for detecting bowel injuries. CT had the highest sensitivity and specificity in patients with multiple GSWs (94% and 79%, respectively) and those with injuries to the stomach and rectum. CONCLUSION: Single-contrast CT can show bowel injuries in patients with penetrating abdominopelvic trauma with accuracy comparable with that reported for triple-contrast CT. PMID- 29412019 TI - Improving Performance of Mammographic Breast Positioning in an Academic Radiology Practice. AB - OBJECTIVE: The purpose of this project was to achieve sustained improvement in mammographic breast positioning in our department. MATERIALS AND METHODS: Between June 2013 and December 2016, we conducted a team-based performance improvement initiative with the goal of improving mammographic positioning. The team of technologists and radiologists established quantitative measures of positioning performance based on American College of Radiology (ACR) criteria, audited at least 35 mammograms per week for positioning quality, displayed performance in dashboards, provided technologists with positioning training, developed a supportive environment fostering technologist and radiologist communication surrounding mammographic positioning, and employed a mammography positioning coach to develop, improve, and maintain technologist positioning performance. Statistical significance in changes in the percentage of mammograms passing the ACR criteria were evaluated using a two-proportion z test. RESULTS: A baseline mammogram audit performed in June 2013 showed that 67% (82/122) met ACR passing criteria for positioning. Performance improved to 80% (588/739; p < 0.01) after positioning training and technologist and radiologist agreement on positioning criteria. With individual technologist feedback, positioning further improved, with 91% of mammograms passing ACR criteria (p < 0.01). Seven months later, performance temporarily decreased to 80% but improved to 89% with implementation of a positioning coach. The overall mean performance of 91% has been sustained for 23 months. The program cost approximately $30,000 to develop, $42,000 to launch, and $25,000 per year to maintain. Almost all costs were related to personnel time. CONCLUSION: Dedicated performance improvement methods may achieve significant and sustained improvement in mammographic breast positioning, which may better enable facilities to pass the recently instated Enhancing Quality Using the Inspection Program portion of a practice's annual Mammography Quality Standards Act inspections. PMID- 29412020 TI - Phyllodes Tumor of the Breast: Ultrasound-Pathology Correlation. AB - OBJECTIVE: The purpose of this study is to evaluate the sonographic and histopathologic features distinguishing benign from borderline and malignant phyllodes tumors. MATERIALS AND METHODS: The ultrasound examinations of women with pathologically proven phyllodes tumors from 2004 to 2011 were retrospectively reviewed. The sonographic features of benign, borderline, and malignant phyllodes tumors were compared and analyzed using the American College of Radiology's BI-RADS ultrasound lexicon. Fisher exact test and Wilcoxon rank sum test were used for statistical analysis. RESULTS: Fifty-nine women were included in the study; 28 benign (47%), 19 malignant (32%), and 12 borderline (20%) phyllodes tumors were identified. Significant univariate predictors of increased risk of borderline or malignant phyllodes tumors were patient age greater than 55 years (p = 0.014), irregular lesion shape (p = 0.011), and longest lesion dimension greater than 7 cm (p = 0.0022) at sonography. No significant differences were observed in lesion margins, boundaries, echo patterns, or posterior acoustic features. CONCLUSION: There is substantial overlap in the sonographic features of benign and borderline or malignant phyllodes tumors. Understanding the clinical and sonographic features of phyllodes tumors may aid the radiologist in predicting biological behavior, including the likelihood of benign versus borderline or malignant phyllodes tumors at pathologic analysis. PMID- 29412021 TI - Cardiogenic shock: the next frontier in acute cardiovascular care! PMID- 29412022 TI - Tailor-made pH-sensitive polyacrylic acid functionalized mesoporous silica nanoparticles for efficient and controlled delivery of anti-cancer drug Etoposide. AB - A multifaceted therapeutic platform has been proposed for controlled delivery of Etoposide (ETS) leading to a synergistic advantage of maximum therapeutic efficacy and diminished toxicity. A state of the art pH responsive nanoparticles (NPs) MSNs-PAA consisting of mesoporous silica nanoparticles core and polymeric shell layers, were developed for controlled release of model anti-cancer drug ETS. Graft onto strategy was employed and amination served as an interim step, laying a vital foundation for functionalization of the MSN core with hydrophilic and pH responsive polyacrylic acid (PAA). MCM-41-PAA were investigated as carriers for loading and regulated release of ETS at different pH for the first time. The PAA-MSNs contained 20.19% grafted PAA as exhibited by thermogravimetric analysis (TGA), which enormously improved the solubility of ETS in aqueous media. The synthesized PAA-MSNs were characterized by various techniques viz, SEM-EDS, TEM, BET, FT-IR and powder XRD. ETS was effectively loaded into the channels of PAA-MSN via electrostatic interactions. The cumulative release was much rapid at extracellular tumor (6.8) and endosomal pH (5.5) than that of blood pH (7.4). Hemolysis study was done for the prepared NPs. MTT assay results showed that the drug-loaded ETS-MCM-41-PAA NPs were more cytotoxic to both prostate cancer cells namely PC-3 and LNCaP than free ETS, which was attributed to their slow and sustained release behavior. The above results confirmed that PAA-MSN hold a great potential as pH responsive carriers with promising future in the field of cancer therapy. PMID- 29412023 TI - Using the care hours per patient day tool: one hospital's experience. AB - This article examines one hospital's journey to improve the way in which the nursing workforce was used. A clear message in Lord Carter's review for the Department of Health ( Carter, 2016 ) was to drive efficiency and work towards being the 'model hospital'. With the introduction of the care hours per patient day, a new rota management system, and a review of the establishment tool used, the hospital has developed a way of real time tracking of nursing time against patient care needs on a ward-by-ward basis. The trust also used a newly developed establishment tool to triangulate and articulate particular patient care requirements. PMID- 29412024 TI - Improving student nurses' confidence in managing the acutely ill patient. AB - AIM: the Acute Illness Management (AIM) course was introduced into NHS trusts across Greater Manchester in 2002/03 for registered nurses. In preparation for the transition from student to registered nurse, the AIM course was then included in the final year of the undergraduate nursing programme. The aim of this study was to evaluate the impact of the AIM course on student nurses' confidence in managing the acutely ill patient. METHOD: a quantitative approach was adopted. Ethical approval was granted by the Research and Ethics committee at the University of Salford. RESULTS: a total of 192 student nurses attended the AIM course; 94% of the students completed a pre-course questionnaire and 100% completed the post-course questionnaire. CONCLUSION: the evidence suggests a significant increase in the student nurses' confidence in recognising, responding and managing an acutely ill patient following the one-day course. PMID- 29412025 TI - Information for clinical staff considering writing for a professional journal. AB - Alan Glasper, Editor in Chief, Comprehensive Child and Adolescent Nursing, and Ian Peate, Editor in Chief, British Journal of Nursing, describe a systematic approach to writing for publication. PMID- 29412026 TI - Caring for and cleansing a baby's skin. PMID- 29412027 TI - Help for men with cancer. PMID- 29412028 TI - A review of isolation practices and procedures in healthcare settings. AB - The notion of 'isolation' in infectious diseases refers to the possibility of people known or suspected to be infected from the wider population, and has historically been used to control and prevent the spread of infectious diseases. Isolation practices in healthcare settings evolved over the 20th century resulting in a focus on the disruption of known routes of potential transmission. There was renewed attention to infection prevention and control (IPC) in the UK at the turn of the 20th century after high-profile reports acknowledged the importance of IPC as a key indicator of high-quality clinical care, and the impact of healthcare-acquired infections. There has been a shift away from isolation wards towards isolation in single rooms on general wards. For infections that are spread by the airborne, droplet or contact routes, placing the patient in single-room isolation is considered to be an important component of transmission-based precautions (TBPs). However, in practice isolation is complex and a number of challenges are involved in implementing IPC procedures. PMID- 29412029 TI - Link lecturers' views on supporting student nurses who have a learning difficulty in clinical placement. AB - BACKGROUND: literature that reports the experiences of facilitating reasonable adjustments for student nurses who have a learning difficulty (LD) in clinical placement from the viewpoint of link lecturers is limited and warrants further exploration. Research aim: to explore link lecturers' views on reasonable adjustments in clinical placement and whether they are confident with their own knowledge of the processes involved. METHODOLOGY: data were collected using interviews with three link lecturers from three fields of nursing (adult, child and mental health). Audio-recorded interviews were transcribed, coded and thematically analysed. FINDINGS: three main themes were identified: student engagement, clarity of link lecturer role and external barriers. CONCLUSION: findings demonstrate that link lecturers have some confidence with their own knowledge of the processes involved with supporting student nurses with an LD in clinical placement, but these processes are complex with many barriers preventing successful facilitation of available reasonable adjustments. PMID- 29412030 TI - Managing patients with an acute dermatological emergency. PMID- 29412031 TI - Surrogacy: why the Law Commission is reviewing current arrangements. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, considers the reasons why the Law Commission is consulting on changing the law relating to surrogacy. PMID- 29412032 TI - Multiple sclerosis: dealing with complex treatment decisions. PMID- 29412033 TI - Never events in the NHS. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses the recently revised NHS Never Events policy and framework. PMID- 29412034 TI - Winter pressures and a safety checklist. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, discusses the Emergency Department Safety Checklist, some of the results after implementation and how it can help with increased emergency department admissions. PMID- 29412035 TI - Measles: what you can do. PMID- 29412037 TI - Communication is a two-way street. AB - In her final blog, Clare Price-Dowd, Senior Programme Lead, NHS Leadership Academy, discusses what good communication means and the difference this can make to patients. PMID- 29412036 TI - Understanding the impact of eating disorders: using the reflecting team as a learning strategy for students. AB - This article outlines how the application of a reflecting team from systemic family therapy practice was used as a learning strategy for a postgraduate programme for healthcare students. The programme was designed to increase the students' skills, knowledge and awareness of the needs of people with eating disorders, and their families. There were some benefits to this learning strategy. Students reported that the use of a reflecting team enabled them to gain a deep understanding of the emotional impact of eating disorders on individuals and their carers. However, as this method of learning was new to the students, they needed some initial instruction on the approach. During the programme of study, it became evident that the health professionals were deeply affected by the experiences of people with eating disorders. This would suggest that possibly it was the presence of the sufferers themselves as part of the reflecting team that provided the pivotal learning opportunity, rather than the reflecting team per se. PMID- 29412038 TI - Why education matters: reflections on the last 50 years. AB - Elizabeth Rosser, Professor of Nursing and acting Executive Dean of Faculty, Bournemouth University, reflects on her own nursing journey and the importance of nurse education. PMID- 29412039 TI - The power of inspiration on a paediatriac oncology unit. AB - Sophie Kelly, Third Year Student, MA Nursing, Children and Young People, University of Salford, looks back at what she learned from a placement she was initially apprehensive about. PMID- 29412040 TI - How 70 years of healthcare policy has shaped the NHS. AB - Emeritus Professor Alan Glasper, University of Southampton, investigates the relationship between UK health policy and changes in the pattern of care delivery by nurses since the NHS was created 70 years ago. PMID- 29412042 TI - Musculoskeletal pain and menopause. AB - Musculoskeletal pain, arthralgia and arthritis are all more common in women, and their frequency increases with age and in some appears to be associated with the onset of menopause. The clinical assessment, investigation and management of women presenting with musculoskeletal pain, arthralgia or arthritis at the time of menopause are reviewed. Common causes of arthralgia and arthritis in this population are discussed. The epidemiological and trials evidence for the effects of hormone replacement therapy on musculoskeletal pain and arthritis (primarily from RCTs of HRT for other menopausal symptoms) are discussed. Lastly, the possible underlying aetiological roles of sex hormones including estrogen, and their deficiency, in predisposing to musculoskeletal pain and arthritis are overviewed. Although the association appears strong, a causal link between estrogen deficiency and musculoskeletal pain or different types of arthritis is lacking; there have been few studies specifically within this group of symptomatic patients, and there is much still to understand about musculoskeletal pain and arthritis at the time of the menopause, and about how we might prevent or treat this. PMID- 29412043 TI - Acute Crisis Care for Patients with Mental Health Crises: Initial Assessment of an Innovative Prehospital Alternative Destination Program in North Carolina. AB - OBJECTIVE: Emergency Departments (ED) are overburdened with patients experiencing acute mental health crises. Pre-hospital transport by Emergency Medical Services (EMS) to community mental health and substance abuse treatment facilities could reduce ED utilization and costs. Our objective was to describe characteristics, treatment, and outcomes of acute mental health crises patients who were transported by EMS to an acute crisis unit at WakeBrook, a North Carolina community mental health center. METHODS: We performed a retrospective cohort study of patients diverted to WakeBrook by EMS from August 2013-July 2014. We abstracted data from WakeBrook medical records and used descriptive statistics to quantify patient characteristics, diagnoses, length of stay (LOS), and 30-day recidivism. RESULTS: A total of 226 EMS patients were triaged at WakeBrook. The median age was 38 years, 55% were male, 58% were white, and 38% were uninsured. The most common chief complaints were suicidal ideation or self-harm (46%) and substance abuse (19%). The most common diagnoses were substance-related and addictive disorders (42%), depressive disorders (32%), and schizophrenia spectrum and other psychotic disorders (22%). Following initial evaluation, 28% of patients were admitted to facilities within WakeBrook, 40% were admitted to external psychiatric facilities, 18% were stabilized and discharged home, 5% were transferred to an ED within 4 hours for further medical evaluation, and 5% refused services. The median LOS at WakeBrook prior to disposition was 12.0 hours (IQR 5.4-21.6). Over a 30-day follow-up period, 60 patients (27%) had a return visit to the ED or WakeBrook for a mental health issue. CONCLUSIONS: A dedicated community mental health center is able to treat patients experiencing acute mental health crises. LOS times were significantly shorter compared to regional EDs. Successful broader programmatic implementation could improve care quality and significantly reduce the volume of patients treated in the ED for acute mental health disorders. PMID- 29412044 TI - An Exotic Hitchhiker: A Case Report of Importation into Connecticut from Africa of the Human Parasitizing Tick, Hyalomma truncatum (Acari: Ixodidae). AB - We report the importation into Connecticut, U.S.A., of an exotic tick, Hyalomma truncatum (Koch) (Acari: Ixodidae), on a human with recent travel history to Africa. The tick was identified using key morphological characters and through DNA sequencing. This case report highlights continuing risk associated with the importation of exotic tick vectors of medical and veterinary significance on international travelers returning to the United States from abroad. PMID- 29412045 TI - The risk of cervical atypia in oral contraceptive users. AB - BACKGROUND: The interactions of oral contraceptive (OC) use, risk of human papillomavirus (HPV) infection and associated cellular atypia are complex. We investigated the association between history of OC-use, and cytological or histopathological abnormalities in a cohort of non-HPV vaccinated originally 16 17-year-old women participating the PATRICIA trial for 4 years. METHODS: The total number of hepatitis A-virus (control) vaccine recipients participating in the clinical PATRICIA trial in Finland was 2399. Nine-hundred and ninety-nine women returned questionnaires on living conditions-life habits and sexual health after completing the study. Mean age at answering the questionnaire at the end of the clinical trial was 22 years. Age at sexual debut varied between 12 and 16 years for majority of the women. Cervical cytological samples were obtained every 6 months throughout the PATRICIA trial. The relative risk of cervical atypia associated with time since start of oral contraceptives use was calculated as odds ratio (OR) with 95% confidence interval (CI) using logistic regression. RESULTS: Compared to never-users, the smoking and age-at-sexual-debut adjusted relative risk of cervical intraepithelial neoplasia grade 1 (CIN1) in women who had started the use of oral contraceptives for more than 1 year was low (OR 0.2, 95% CI: 0.1-0.7). Risk of cytological atypia was also reduced (OR 0.6) albeit not significantly (95% CI: 0.3-1.3). CONCLUSIONS: Use of oral contraceptives does not increase the risk of cervical atypia but when established might instead be protective. PMID- 29412046 TI - Leading by example: The role of accreditors in promoting interprofessional collaborative practice. PMID- 29412049 TI - Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies? AB - Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referred to as cancer hallmarks. Although nowadays the catalog of cancer hallmarks is quite broad, the most common and obvious of them are 1) uncontrolled proliferation, 2) resistance to programmed cell death (apoptosis), 3) tissue invasion and metastasis, and 4) sustained angiogenesis. Among the genes affected by cancer, those encoding ion channels are present. Membrane proteins responsible for signaling within cell and among cells, for coupling of extracellular events with intracellular responses, and for maintaining intracellular ionic homeostasis ion channels contribute to various extents to pathophysiological features of each cancer hallmark. Moreover, tight association of these hallmarks with ion channel dysfunction gives a good reason to classify them as special type of channelopathies, namely oncochannelopathies. Although the relation of cancer hallmarks to ion channel dysfunction differs from classical definition of channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties, in a broader context of the disease state, to which pathogenesis ion channels essentially contribute, such classification seems absolutely appropriate. In this review the authors provide arguments to substantiate such point of view. PMID- 29412050 TI - Polluted Morality: Air Pollution Predicts Criminal Activity and Unethical Behavior. AB - Air pollution is a serious problem that affects billions of people globally. Although the environmental and health costs of air pollution are well known, the present research investigates its ethical costs. We propose that air pollution can increase criminal and unethical behavior by increasing anxiety. Analyses of a 9-year panel of 9,360 U.S. cities found that air pollution predicted six major categories of crime; these analyses accounted for a comprehensive set of control variables (e.g., city and year fixed effects, population, law enforcement) and survived various robustness checks (e.g., balanced panel, nonparametric bootstrapped standard errors). Three subsequent experiments involving American and Indian participants established the causal effect of psychologically experiencing a polluted (vs. clean) environment on unethical behavior. Consistent with our theoretical perspective, results revealed that anxiety mediated this effect. Air pollution not only corrupts people's health, but also can contaminate their morality. PMID- 29412047 TI - PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer. AB - Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation. PMID- 29412051 TI - Prehospital Analgesia for Pediatric Trauma Patients in Iraq and Afghanistan. AB - BACKGROUND: Previous studies have evaluated prehospital analgesia during combat operations in Iraq and Afghanistan, but were limited to the adult population. However, a significant portion of the casualties of those conflicts were children. We describe the prehospital analgesia administered to wartime pediatric trauma patients. METHODS: We queried the Department of Defense Trauma Registry (DODTR) for all pediatric patients (<18 years of age) admitted to United States and Coalition fixed-facility hospitals in Iraq and Afghanistan from January 2007 to January 2016. We divided pediatric patients into 2 groups: those that had documentation of receipt of analgesic drugs in the prehospital setting (n = 618) and those who had not received analgesia before reaching a fixed-facility (n = 2,821). For characterization of drug administration, we grouped patients into those receiving acetaminophen, NSAID, fentanyl, ketamine, morphine, or other analgesics (e.g., hydromorphone, tramadol, etc.). RESULTS: During the study period, there were 3,439 pediatric encounters with documentation of 703 instances of analgesia administrations to 618 patients (17.9% of total pediatric encounters). Of the subjects receiving analgesic agents, 46.2% (n = 325) received morphine, 30.4% (n = 214) received fentanyl, 17.4% (n = 122) received ketamine, 1.8% (n = 13) received acetaminophen, and 2.8% (n = 20) received a non-steroidal anti-inflammatory drug. The remaining 9 administrations consisted of methoxyflourane (1), nalbuphine (2), hydromorphone (3), and tramadol (3). An injury severity score (ISS) >15 increased the odds of receiving an analgesic agent (OR 1.26, 95% CI 1.02-1.56). Additionally, there was an association between analgesia administration and the following prehospital interventions: wound dressing, tourniquet, intravenous (IV) line placement, intraosseous line placement, IV fluids, intubation, and external warming. CONCLUSIONS: Overall, a low proportion of pediatric trauma subjects within this population received analgesia in the prehospital environment. The most common analgesic medication administered was morphine. Those receiving analgesic agents had more severe injuries and higher rates of concomitant interventions. These results highlight the potential need for Tactical Combat Casualty Care guidelines specifically providing recommendations for analgesia administration among pediatric patients. PMID- 29412052 TI - Integrating the social determinants of health into two interprofessional courses: Findings from a pilot study. AB - Five colleges and universities in Upstate New York, United States, created the 'Route-90 Collaborative' to support faculty implementing the Institute of Medicine's (IOM) Framework for Educating Health Professionals to Address the Social Determinants of Health. The two courses described herein used a flipped classroom approach in which students from 14 different nations were responsible for facilitating individual classes. This descriptive study used an educational intervention in two interprofessional courses - reproductive health and global health - based on the IOM Framework into two courses. The evaluation used quantitative and open-ended text response data from students. Course evaluations indicated the students found the courses helped them to learn more about health issues and service delivery in various countries, expand their knowledge base on sociocultural and ecological influences on health care, and broaden their perspectives on various health topics so they will be able to provide higher quality healthcare. Although this is the first effort of our Collaborative to implement the Framework, given the student feedback, we believe implementing the Framework in various courses has the potential to enhance healthcare service delivery and reduce the negative impact of social determinants of health. PMID- 29412053 TI - Design of a new artificial breathing system for simulating the human respiratory activities. AB - The purpose of this work is the conception and implementation of an artificial active respiratory system that allows the simulation of human respiratory activities. The system consists of two modules, mechanical and electronical. The first one represents a cylindrical lung adjustable in resistance and compliance. This lung is located inside a transparent thoracic box, connected to a piston that generates variable respiratory efforts. The parameters of the system, which are pressure, flow and volume, are measured by the second module. A computer application was developed to control the whole system, and enables the display of the parameters. A series of tests were made to evaluate the respiratory efforts, resistances and compliances. The results were compared to the bibliographical studies, allowing the validation of the proposed system. PMID- 29412054 TI - Design of a stabilisation platform for Parkinson's disease patient. AB - There are an increased number of patients all over the world suffering from postural tremors and rest tremors, the types of tremors associated with Parkinson's disease and other neurodegenerative diseases such as amyotrophic lateral sclerosis. Currently, there is no cure for such disease and patients have to deal with their condition to continue their life normally with the existing of some helpful instruments. This work presents a self-stabilising Parkinson's disease (PD) Tray (platform) that can help them to carry objects that they hold with their hand. The proposed design includes a mechanical platform and en electronic system to control the tray and inhibits any vibrations of the base plate of the tray. An algorithm was developed that would take positional data from an Inertia movement sensors IMU, compute angles in degrees from its Euler angle raw data and then use those angles to control three servo motors in a direction counter to the changes in the IMU's position. The platform, was capable of stabilising the base of the tray such that objects placed in it would not be dropped. The tray was tested on simulating conditions and the result should that the mean absolute value of the acceleration values in X and Y directions were reduced from 2.23 m/sec2 to 0.26 m/sec2 in the X direction and from 1.41 m/sec2 to 0.34 m/sec2 in the Y direction. PMID- 29412048 TI - Arginase: A Multifaceted Enzyme Important in Health and Disease. AB - The arginase enzyme developed in early life forms and was maintained during evolution. As the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. The urea cycle provides protection against excess ammonia, while l-ornithine is needed for cell proliferation, collagen formation, and other physiological functions. In mammals, increases in arginase activity have been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system and also to dysfunction of the immune system and cancer. Two important aspects of the excessive activity of arginase may be involved in diseases. First, overly active arginase can reduce the supply of l arginine needed for the production of nitric oxide (NO) by NO synthase. Second, too much l-ornithine can lead to structural problems in the vasculature, neuronal toxicity, and abnormal growth of tumor cells. Seminal studies have demonstrated that increased formation of reactive oxygen species and key inflammatory mediators promote this pathological elevation of arginase activity. Here, we review the involvement of arginase in diseases affecting the cardiovascular, renal, and central nervous system and cancer and discuss the value of therapies targeting the elevated activity of arginase. PMID- 29412055 TI - Prenatal Stress as a Risk-and an Opportunity-Factor. AB - Two separate lines of research indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity and (b) that these postnatal phenotypes are associated with increased susceptibility to both positive and negative developmental experiences. Therefore, prenatal stress may increase sensitivity to the rearing environment. We tested this hypothesis by manipulating prenatal stress and rearing-environment quality, using a cross fostering paradigm, in prairie voles. Results showed that prenatally stressed voles, as adults, displayed the highest behavioral and physiological reactivity when cross-fostered to low-contact (i.e., low-quality) rearing but the lowest behavioral and physiological reactivity when cross-fostered to high-contact (i.e., high-quality) rearing; non-prenatally stressed voles showed no effect of rearing condition. Additionally, while neither prenatal stress nor rearing condition affected oxytocin receptor binding, prenatally stressed voles cross fostered to high-contact rearing showed the highest vasopressin-1a receptor binding in the amygdala. Results indicate that prenatal stress induces greater environmental sensitivity, making it both a risk and an opportunity factor. PMID- 29412057 TI - Mitophagy in Cardiomyocytes and in Platelets: A Major Mechanism of Cardioprotection Against Ischemia/Reperfusion Injury. AB - Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of mitophagy and highlight the role of mitophagy in cardioprotection. PMID- 29412058 TI - The Metabolic Flexibility of Hovering Vertebrate Nectarivores. AB - Foraging hummingbirds and nectar bats oxidize both glucose and fructose from nectar at exceptionally high rates. Rapid sugar flux is made possible by adaptations to digestive, cardiovascular, and metabolic physiology affecting shared and distinct pathways for the processing of each sugar. Still, how these animals partition and regulate the metabolism of each sugar and whether this occurs differently between hummingbirds and bats remain unclear. PMID- 29412060 TI - Physiology in Perspective: Homeostasis and Survival. PMID- 29412056 TI - Breathing: Motor Control of Diaphragm Muscle. AB - Breathing occurs without thought but is controlled by a complex neural network with a final output of phrenic motor neurons activating diaphragm muscle fibers (i.e., motor units). This review considers diaphragm motor unit organization and how they are controlled during breathing as well as during expulsive behaviors. PMID- 29412059 TI - Role of Astrocytic Mitochondria in Limiting Ischemic Brain Injury? AB - Until recently, astrocyte processes were thought to be too small to contain mitochondria. However, it is now clear that mitochondria are found throughout fine astrocyte processes and are mobile with neuronal activity resulting in positioning near synapses. In this review, we discuss evidence that astrocytic mitochondria confer selective resiliency to astrocytes during ischemic insults and the functional significance of these mitochondria for normal brain function. PMID- 29412063 TI - A Mixed Methods Review of Education and Patient Navigation Interventions to Increase Breast and Cervical Cancer Screening for Rural Women. AB - Reviews have assessed studies of breast and cervical cancer screening access and utilization for rural women, but none analyze interventions to increase screening rates. A mixed methods literature search identified studies of breast and/or cervical cancer prevention education and patient navigation interventions for rural women. Rural areas need greater implementation and evaluation of screening interventions as these services address the challenges of delivering patient centered cancer care to un-/underserved communities. The lack of intervention studies on breast and cervical cancer education and patient navigation programs compared to urban studies highlights the need for validation of these programs among diverse, rural populations. PMID- 29412064 TI - A Study of the Impact of the Commonly Used Female Contraceptive Methods in Egypt on Female Sexual Function. AB - Temporary methods of female contraception are commonly practiced in Egypt, but an increased total fertility rate was recently reported. Impaired female sexual function (FSF) due to contraceptive use can be a reason for irregular use/discontinuation. This study aimed at identifying the type(s) of the commonly used contraceptive method(s) in Egypt that can impair FSF. The sexual function of women on some form of temporary contraceptive was compared to that of women not using contraceptives. All participants answered the Arabic translation of the 19 item Female Sexual Function Index questionnaire. Furthermore, participants on contraceptives answered a global question: Did the use of the contraceptive impact your sexual function? Participants on contraceptives were subgrouped into Copper-T intrauterine devices (IUDs), progestin injectable (medroxyprogesterone 400 mg), combined oral pills (COP; 30 ug ethinylestradiol and 150 ug levonorgestrel), and progestin-only pills (POP; 750 ug levonorgestrel). According to this study, neither the IUDs nor the COP impaired FSF. However, the progestin only contraceptives were associated with impairment of FSF; the injectable was worse than the POP. Accordingly, counseling about the potential sexual risks of the available contraceptive methods is recommended. Impaired FSF due to contraceptive use can be addressed by a trial of an alternative method to avoid discontinuation. PMID- 29412061 TI - Circadian Etiology of Type 2 Diabetes Mellitus. AB - The epidemic of Type 2 diabetes mellitus necessitates development of novel therapeutic and preventative strategies to attenuate expansion of this debilitating disease. Evidence links the circadian system to various aspects of diabetes pathophysiology and treatment. The aim of this review will be to outline the rationale for therapeutic targeting of the circadian system in the treatment and prevention of Type 2 diabetes mellitus and consequent metabolic comorbidities. PMID- 29412065 TI - A simplified treatment algorithm for treating thoracic and lumbar spine trauma. AB - Context Current treatment of TLST should consider injury morphology, neurological status, clinical status (pain and disability) and also multimodal radiological evaluation (MMRE) with CT, MRI and dynamic/ standing plain radiographs. Methods A narrative literature review was performed to propose a treatment algorithm to guide the management of thoracolumbar spinal trauma (TLST). In order to classify injuries and surgical indications, we utilized the two most recent classification systems (TLICS and new AO spine classification) and related recent literature. Results Injuries were categorized into three groups according to stability: 1) Stable injuries, 2) Potentially unstable injuries/ delayed instability or 3) Clearly unstable injuries. Stable injuries included most of AO type A fractures without neurological deficit, mild clinical symptoms and without risk factors for late deformity. Potentially unstable injuries generally included patients without neurological deficits but with some risk factors for late deformity or with severe clinical symptoms. Surgery may be recommended in this group. Finally, clearly unstable injuries are those with spinal dislocations and/ or with neurological deficits, especially in the setting of persistent neural tissue compression, requiring early surgical treatment. Conclusions The proposed treatment algorithm is intended to help surgeons select the best treatment modality for their patients, categorizing injuries according to their main characteristics into one of these three groups. Further studies addressing the reliability and safety of this algorithm are necessary. PMID- 29412066 TI - Alkalinity and external carbon requirements for denitrification-nitrification of coke wastewater. AB - The Industrial Emissions Directive requires that coke wastewater is treated to reach an effluent with < 50 mg/L total nitrogen (TN). A shortage of alkalinity (3.6 mg as CaCO3/mg [Formula: see text]) in the wastewater limited nitrification to 45%. Various compounds were tested as a source of additional alkalinity, with optimal results being found for sodium carbonate, which enabled 95% nitrification at 300 mg/L (as CaCO3). Sodium bicarbonate led to incomplete ammonia oxidation (76%) whilst soda ash prevented nitrite oxidation. Addition of sodium hydroxide enabled 98% nitrification but was associated with [Formula: see text] accumulation. Ammonia and nitrite oxidation had optimal pH ranges of 7.0-8.3 and 5.5-6.8, respectively. As organic carbon concentrations in coke wastewater are at times insufficient for effective denitrification external organic carbon was also considered to enhance denitrification. A laboratory-scale anoxic-aerobic activated sludge process was used to investigate glycerol and acetic acid as carbon sources. Glycerol was associated with a low biomass production (0.18 mg of biomass produced per 1 mg of glycerol) and mixed liquor suspended solids (MLSS) declined from 2235 to 750 mg/L leading to incomplete nitrification (< 30%) and an effluent TN of 59 mg/L. Acetic acid had a higher biomass production (0.31 mg of biomass produced per 1 mg of acetic acid) maintaining stable MLSS concentrations (3137 mg/L). Overall, a denitrification-nitrification process with alkalinity (Na2CO3 at 300 mg/L) and acetic acid dosing enabled an effluent TN of 24 mg/L. PMID- 29412062 TI - Vagal Interoceptive Modulation of Motivated Behavior. AB - In addition to regulating the ingestion and digestion of food, sensory feedback from gut to brain modifies emotional state and motivated behavior by subconsciously shaping cognitive and affective responses to events that bias behavioral choice. This focused review highlights evidence that gut-derived signals impact motivated behavior by engaging vagal afferents and central neural circuits that generally serve to limit or terminate goal-directed approach behaviors, and to initiate or maintain behavioral avoidance. PMID- 29412067 TI - Systems theory as a framework for examining a college campus-based support program for the former foster youth. AB - Increased attention to former foster youth pursuing post-secondary education has resulted in the creation of college campus based support programs to address their need. However, limited empirical evidence and theoretical knowledge exist about these programs. This study seeks to describe the application of systems theory as a framework for examining a college campus based support program for former foster youth. In-depth semi-structured interviews were conducted with 32 program stakeholders including students, mentors, collaborative members, and independent living program staff. Using qualitative data analysis software, holistic coding techniques were employed to analyze interview transcripts. Then applying principles of extended case method using systems theory, data were analyzed. Findings suggest systems theory serves as a framework for understanding the functioning of a college campus based support program. The theory's concepts help delineate program components and roles of stakeholders; outline boundaries between and interactions among stakeholders; and identify program strengths and weakness. Systems theory plays an important role in identifying intervention components and providing a structure through which to identify and understand program elements as a part of the planning process. This study highlights the utility of systems theory as a framework for program planning and evaluation. PMID- 29412068 TI - Assessing the perceptions and attitudes among geriatric resource nurses: Evaluating the NICHE program at a large academic medical center. AB - The national Nurses Improving Care for Healthsystem Elders (NICHE) program and the geriatric resource nurse (GRN) model promote training a geriatric nursing workforce to serve in hospitals and elsewhere. Literature exists on the NICHE program but this is the first to study the opinions, attitudes, and perceptions of GRNs in practice. Our organization's hybrid GRN model, first adopted in 1999, combines materials from national NICHE program with homegrown resources and has GRNs practicing in a wide range of clinical specialties. This descriptive study, using survey design and administrative data, examined GRNs trained prior to 2017 to assess their (i) demographic, employment, and other characteristics; (ii) satisfaction with components of training program; (iii) ability to apply new knowledge and skills in practice; (iv) perceived support from leadership; and (v) perceived barriers encountered. Program outcomes, such as completion rates and workplace satisfaction, as well as areas for improvement and recommendation for future research, are also discussed. PMID- 29412069 TI - The effect of wearing jeans on maximum static lifting strength for men and women at various exertion heights. AB - This study collected maximum static lifting strength (MSLS) data from 13 males and 13 females at an exertion height of 10-100 cm above the floor (in 10-cm increments) in wearing athletic shorts and wearing jeans conditions. Knee angles were also examined when participants performed the MSLS tasks. Results showed that gender, pant type and exertion height significantly affected participants' MSLS and corresponding knee angle. The effect of wearing jeans primarily occurred at 10-40 cm; meanwhile, male participants tended to stoop while exerting force. This substantially decreased their MSLS (55 N). For female participants in this exertion height range, no significant difference was found in knee angles; accordingly, wearing jeans only slightly affected their MSLS. In summary, wearing jeans had a noticeable effect on the MSLS of male participants, who should be particularly careful when performing lifting tasks at a height of less than 50 cm above the floor. PMID- 29412070 TI - Implications of human trafficking in Asia: a scoping review of aftercare initiatives centered on economic development. AB - The trafficking of persons is one of the most egregious violations of human rights in modern society. Given the disproportionate effects across demographic categories of age and gender, as well as concentrated impacts within the developing world, there is a strong need for research and literature on program effectiveness and appropriate aftercare efforts for those persons whose lives and livelihoods have been impacted by trafficking. The purpose of this article is to provide a scoping review of what is known about effectively helping survivors of human trafficking experiencing lack of economic opportunity and the implications for practice and future research regarding the absence of literature. From over 14,000 initial search results, this article focuses on those initiatives (N = 16) that support economic development of the individual or family after being trafficked. Implications arising from the review for trafficking policy, areas for further research, and implications for practitioners are highlighted and discussed. PMID- 29412071 TI - Patient predictors and utilization of health services within a medical home for homeless persons. AB - BACKGROUND: The Veterans Health Administration (VHA) established a patient centered medical home model of care for veterans experiencing homelessness called a Homeless Patient Aligned Care Team (HPACT) to improve engagement with primary care and reduce utilization of hospital-based services. To evaluate the impact of the HPACT model, this study compares the number and type of health care visits in the 12 months before and after enrollment in HPACT at one VHA facility, and explores patient characteristics associated with increases and decreases in visits. METHODS: Chart reviews of VHA medical records were conducted for all patients enrolled in an HPACT in Pittsburgh, Pennsylvania, between May 2012 and December 2013 (N = 179). Multivariable mixed-effect logistic regressions estimated differences in having any visit in the 0-6 months and 7-12 months before and after HPACT enrollment, and multinomial logistic regressions predicted increases or decreases versus no change in number of visits over 12 months. RESULTS: Compared with 0-6 months prior to HPACT, patients were more likely to visit primary care in the 0-6 months (adjusted odds ratio [aOR] = 4.91, 95% confidence interval [CI] = 2.94-8.20) and 7-12 months (aOR = 2.30, 95% CI = 1.42 3.72) following HPACT. Patients were less likely to visit the emergency department (ED) or to be hospitalized in the 0-6 months (aOR = 0.57, 95% CI = 0.34-0.94; and aOR = 0.55, 95% CI = 0.25-0.76) and 7-12 months (aOR = 0.43, 95% CI = 0.33-0.91; and aOR = 0.45, 95% CI = 0.26-0.80) following HPACT. Patients were less likely to visit mental health (aOR = 0.35, 95% CI = 0.20-0.60) and addiction specialists (aOR = 0.39, 95% CI = 0.18-0.84) in the 7-12 months following HPACT. Overall, 59% of patients had increases in primary care visits following HPACT. Female patients and those with self-housing were less likely to have increases versus no change in primary care visits (adjusted relative risk ratio [aRRR] = 0.15, 95% CI = 0.03-0.74; and aRRR = 0.35, 95% CI = 0.14-0.90). CONCLUSIONS: An integrated HPACT model was successful in engaging homeless veterans in primary care for 1 year, potentially contributing to reductions in ED use. More tailored approaches may be needed for vulnerable populations experiencing homelessness, including homeless women. PMID- 29412072 TI - The missing link: Finding space for gerontology content into university curricula in South Africa. AB - The rapid increase in the global elderly population has been widely documented in both demographic and popular literature in recent decades. Population estimates produced by the national statistical service of South Africa in 2017 show that the proportion of elderly (60 years and older) in South Africa is growing fast, reaching 8.1% of the total population in 2017. The country is set to experience a doubling of the population over the age of 65 by the year 2020. Similar to their counterparts in the developed world, tertiary institutions throughout Africa too are faced with the challenge of training professionals capable of understanding and responding to the socioeconomic consequences, social priorities, and complex needs of an increasing aging population. The right set of policies can equip individuals, families, and societies to address the challenges of an aging population. After conducting an extensive literature review, we recommend that policy-makers in South Africa should look into ways that will enable them to meet the many challenges of an aging population in the coming decades. One way to address this issue would be to include gerontology content into the curricula of programs in the humanities and social sciences. PMID- 29412073 TI - Evidence for a Change in the Sex Ratio of Children Referred for Gender Dysphoria: Data from the Center of Expertise on Gender Dysphoria in Amsterdam (1988-2016). PMID- 29412074 TI - Macroplastique and Botox are superior to Macroplastique alone in the management of neurogenic vesicoureteric reflux in spinal cord injury population with presumed healthy bladders. AB - CONTEXT/OBJECTIVE: Vesico-ureteric reflux(VUR) is a known complication of neuropathic bladder in spinal cord injury(SCI) population. Bulking agents such as Macroplastique are new minimally-invasive treatment option for VUR with good results. The aim of this study is to assess the efficacy of Macroplastique alone or in combination with Botox(BTX-A), in managing VUR in SCI population with presumed healthy bladders and correlate the pre-and post-injection urodynamic findings with the outcome. DESIGN: Retrospective comparative study. PARTICIPANTS: SCI patients with VUR and presumed health bladders (normo-compliant, low filling pressures), treated with macroplastique alone or in combination with BTX-A, who had pre and post-intervention Video-urodynamics (VUDS) and followed up for at least 12 months. INTERVENTIONS: Macroplastique and BTX-A injections, VUDS. OUTCOME MEASURES: The primary end point was the overall treatment rate of VUR at 3 months and the secondary outcomes were the success rate (treated + improved) and the comparison of urodynamic parameters (pre-and post-injection). RESULTS: We studied 34 intervention-naive SCI patients. 19 had only Macroplastique (Group 1) and 15 had Macroplastique and BTX-A (Group 2). The overall treatment rate was 65.4% for group 1 and 88.9% for group 2 (P = 0.029). The overall success rate (treated + improved) was 80.8% and 94.4% respectively (P = 0.123). The comparison of follow up VUDS parameters showed a statistically significant rise in the detrusor pressure of group 1 (34.04cmH2O vs.19.2cmH2O, P = 0.008) and a drop in compliance (19.8mls/cmH2O vs.26.3mls/cmH2O, P = 0.018) as compared to baseline. CONCLUSION: The combination of BTX-A and Macroplastique is more effective that Macroplastique alone in the management of secondary VUR in SCI patients with presumed healthy bladders. PMID- 29412075 TI - PCSK9 inhibition for LDL lowering and beyond - implications for patients with peripheral artery disease. AB - Low-density lipoprotein cholesterol (LDL-C) has been proven to be a causal factor of atherosclerosis and, along with other triggers like inflammation, the most frequent reason for peripheral arterial disease. Moreover, a linear correlation between LDL-C concentration and cardiovascular outcome in high-risk patients could be established during the past century. After the development of statins, numerous randomized trials have shown the superiority for LDL-C reduction and hence the decrease in cardiovascular outcomes including mortality. Over the past decades it became evident that more intense LDL-C lowering, by either the use of highly potent statin supplements or by additional cholesterol absorption inhibitor application, accounted for an even more profound cardiovascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serin protease with effect on the LDL receptor cycle leading to its degradation and therefore preventing continuing LDL-C clearance from the blood, is the target of a newly developed monoclonal antibody facilitating astounding LDL-C reduction far below to what has been set as target level by recent ESC/EAS guidelines in management of dyslipidaemias. Large randomized outcome trials including subjects with PAD so far have been able to prove significant and even more intense cardiovascular risk reduction via further LDL-C debasement on top of high intensity statin medication. Another approach for LDL-C reduction is a silencing interfering RNA muting the translation of PCSK9 intracellularly. Moreover, PCSK9 concentrations are elevated in cells involved in plaque composition, so the potency of intracellular PCSK9 inhibition and therefore prevention or reversal of plaques may provide this mechanism of action on PCSK9 with additional beneficial effects on cells involved in plaque formation. Thus, simultaneous application of statins and PCSK9 inhibitors promise to reduce cardiovascular event burden by both LDL-C reduction and pleiotropic effects of both agents. PMID- 29412076 TI - Repeated-sprint performance and plasma responses following beetroot juice supplementation do not differ between recreational, competitive and elite sprint athletes. AB - PURPOSE: There is an ongoing debate whether highly trained athletes are less responsive to the ergogenic properties of nitrate. We assessed the effects of nitrate supplementation on plasma nitrate and nitrite concentrations and repeated sprint performance in recreational, competitive and elite sprint athletes. METHODS: In a randomized double-blinded cross-over design, recreational cyclists (n = 20), national talent speed-skaters (n = 22) and Olympic-level track cyclists (n = 10) underwent two 6-day supplementation periods; 140 mL/d nitrate-rich (BR; ~800 mg/d) and nitrate-depleted (PLA; ~0.5 mg/d) beetroot juice. Blood samples were collected and three 30-s Wingate tests were performed. RESULTS: Plasma nitrate and nitrite concentrations were higher following BR vs PLA (P < .001), with no differences between sport levels (all P > .10). Peak power over the three Wingates was not different between BR and PLA (1338 +/- 30 vs 1333 +/- 30 W; P = .62), and there was no interaction between treatment (BR-PLA) and Wingate number (1-2-3; P = .48). Likewise, mean power did not differ between BR and PLA (P = .86). In contrast, time to peak power improved by ~2.8% following BR vs PLA (P = .007). This improvement in BR vs PLA was not different between Wingate 1, 2 and 3. Moreover, the effects of BR vs PLA did not differ between sport levels for any Wingate parameter (all P > .30). CONCLUSION: The plasma and repeated-sprint performance responses to beetroot juice supplementation do not differ between recreational, competitive and elite sprint athletes. Beetroot juice supplementation reduces time to reach peak power, which may improve the capacity to accelerate during high-intensity and sprint tasks in recreational as well as elite athletes. PMID- 29412077 TI - Transient Effects of Anesthesia on Leukocyte Apoptosis and Monocyte Cytokine Stimulation: A Clinical Study. AB - The effects of anesthetics on immune cell apoptosis and cytokine stimulation were studied in a prospective study. American Society of Anesthesiologists I/II patients underwent elective inguinal hernia repair or varicose veins stripping surgery and were randomized to either epidural anesthesia (n = 14) or general anesthesia with sevoflurane (n = 19) or propofol (n = 15). Blood was sampled before anesthesia induction (T0), at the end of surgery (T1), and 6 h later (T2). Apoptosis was determined by ANNEXIN-V staining of white blood cells; monocytes were isolated and stimulated for cytokine production. Results were compared with 10 healthy volunteers well-matched for age and gender. Apoptosis of lymphocytes and monocytes was increased in the epidural and sevoflurane groups at T2. Propofol group had increased production of interleukin-6 at T1 and sevoflurane and epidural groups had decreased production of tumor necrosis factor-alpha at T2. Results emphasize the modulation of immune function by epidural and sevoflurane but not propofol anesthesia in a clinical setting. PMID- 29412078 TI - Computerized Cuff Pressure Algometry as Guidance for Circumferential Tissue Compression for Wearable Soft Robotic Applications: A Systematic Review. AB - In this article, we review the literature on quantitative sensory testing of deep somatic pain by means of computerized cuff pressure algometry (CPA) in search of pressure-related safety guidelines for wearable soft exoskeleton and robotics design. Most pressure-related safety thresholds to date are based on interface pressures and skin perfusion, although clinical research suggests the deep somatic tissues to be the most sensitive to excessive loading. With CPA, pain is induced in deeper layers of soft tissue at the limbs. The results indicate that circumferential compression leads to discomfort at ~16-34 kPa, becomes painful at ~20-27 kPa, and can become unbearable even below 40 kPa. PMID- 29412079 TI - Modeling and Experimental Evaluation of Bending Behavior of Soft Pneumatic Actuators Made of Discrete Actuation Chambers. AB - In this article, we have established an analytical model to estimate the quasi static bending displacement (i.e., angle) of the pneumatic actuators made of two different elastomeric silicones (Elastosil M4601 with a bulk modulus of elasticity of 262 kPa and Translucent Soft silicone with a bulk modulus of elasticity of 48 kPa-both experimentally determined) and of discrete chambers, partially separated from each other with a gap in between the chambers to increase the magnitude of their bending angle. The numerical bending angle results from the proposed gray-box model, and the corresponding experimental results match well that the model is accurate enough to predict the bending behavior of this class of pneumatic soft actuators. Further, by using the experimental bending angle results and blocking force results, the effective modulus of elasticity of the actuators is estimated from a blocking force model. The numerical and experimental results presented show that the bending angle and blocking force models are valid for this class of pneumatic actuators. Another contribution of this study is to incorporate a bistable flexible thin metal typified by a tape measure into the topology of the actuators to prevent the deflection of the actuators under their own weight when operating in the vertical plane. PMID- 29412080 TI - Novel Design of a Soft Lightweight Pneumatic Continuum Robot Arm with Decoupled Variable Stiffness and Positioning. AB - Soft robot arms possess unique capabilities when it comes to adaptability, flexibility, and dexterity. In addition, soft systems that are pneumatically actuated can claim high power-to-weight ratio. One of the main drawbacks of pneumatically actuated soft arms is that their stiffness cannot be varied independently from their end-effector position in space. The novel robot arm physical design presented in this article successfully decouples its end-effector positioning from its stiffness. An experimental characterization of this ability is coupled with a mathematical analysis. The arm combines the light weight, high payload to weight ratio and robustness of pneumatic actuation with the adaptability and versatility of variable stiffness. Light weight is a vital component of the inherent safety approach to physical human-robot interaction. To characterize the arm, a neural network analysis of the curvature of the arm for different input pressures is performed. The curvature-pressure relationship is also characterized experimentally. PMID- 29412081 TI - Artificial Heliotropism and Nyctinasty Based on Optomechanical Feedback and No Electronics. AB - Although plants are typically not considered an inspiration for designing motile robots, they do perform a variety of intricate motion patterns, including diurnal cycles of sun tracking (heliotropism) and leaf opening (nyctinasty). In real plants, these motions are controlled by complex, feedback-based biological mechanisms that, to date, have been mimicked only in computer-controlled artificial systems. This work demonstrates both heliotropism and nyctinasty in a system in which few simple, but strategically positioned thermo-responsive springs and lenses form a feedback loop controlling these motions and substantiating a behavioral analogy to "plants." In particular, this feedback allows the "artificial plant" to reach and stabilize at a metastable position in which the solar flux on the "plants" and the solar power "leaves" are maximized. Unlike many soft robotic systems, our "plants" are completely autonomous, in that, they do not require any external controls or power sources. Bioinspired designs such as this could be of interest for soft robotic systems in which materials alone-rather than power-consuming electronic circuitry-control the motions. PMID- 29412082 TI - The Structure, Design, and Closed-Loop Motion Control of a Differential Drive Soft Robot. AB - This article presents the structure, design, and motion control of an inchworm inspired pneumatic soft robot, which can perform differential movement. This robot mainly consists of two columns of pneumatic multi-airbags (actuators), one sensor, one baseboard, front feet, and rear feet. According to the different inflation time of left and right actuators, the robot can perform both linear and turning movements. The actuators of this robot are composed of multiple airbags, and the design of the airbags is analyzed. To deal with the nonlinear performance of the soft robot, we use radial basis function neural networks to train the turning ability of this robot on three different surfaces and create a mathematical model among coefficient of friction, deflection angle, and inflation time. Then, we establish the closed-loop automatic control model using three-axis electronic compass sensor. Finally, the automatic control model is verified by linear and turning movement experiments. According to the experiment, the robot can finish the linear and turning movements under the closed-loop control system. PMID- 29412083 TI - Reducing Actuator Requirements in Continuum Robots Through Optimized Cable Routing. AB - Continuum manipulators offer many advantages compared to their rigid-linked counterparts, such as increased degrees of freedom and workspace volume. Inspired by biological systems, such as elephant trunks and octopus tentacles, many continuum manipulators are made of multiple segments that allow large-scale deformations to be distributed throughout the body. Most continuum manipulators currently control each segment individually. For example, a planar cable-driven system is typically controlled by a pair of cables for each segment, which implies two actuators per segment. In this article, we demonstrate how highly coupled crossing cable configurations can reduce both actuator count and actuator torque requirements in a planar continuum manipulator, while maintaining workspace reachability and manipulability. We achieve highly coupled actuation by allowing cables to cross through the manipulator to create new cable configurations. We further derive an analytical model to predict the underactuated manipulator workspace and experimentally verify the model accuracy with a physical system. We use this model to compare crossing cable configurations to the traditional cable configuration using workspace performance metrics. Our work here focuses on a simplified planar robot, both in simulation and in hardware, with the goal of extending this to spiraling-cable configurations on full 3D continuum robots in future work. PMID- 29412084 TI - Fiber-Reinforced Origamic Robotic Actuator. AB - A novel pneumatic soft linear actuator Fiber-reinforced Origamic Robotic Actuator (FORA) is proposed with significant improvements on the popular McKibben-type actuators, offering nearly doubled motion range, substantially improved force profile, and significantly lower actuation pressure. The desirable feature set is made possible by a novel soft origamic chamber that expands radially while contracts axially when pressurized. Combining this new origamic chamber with a reinforcing fiber mesh, FORA generates very high traction force (over 150N) and very large contractile motion (over 50%) at very low input pressure (100 kPa). We developed quasi-static analytical models both to characterize the motion and forces and as guidelines for actuator design. Fabrication of FORA mostly involves consumer-grade three-dimensional (3D) printing. We provide a detailed list of materials and dimensions. Fabricated FORAs were tested on a dedicated platform against commercially available pneumatic artificial muscles from Shadow and Festo to showcase its superior performances and validate the analytical models with very good agreements. Finally, a robotic joint was developed driven by two antagonistic FORAs, to showcase the benefits of the performance improvements. With its simple structure, fully characterized mechanism, easy fabrication procedure, and highly desirable performance, FORA could be easily customized to application requirements and fabricated by anyone with access to a 3D printer. This will pave the way to the wider adaptation and application of soft robotic systems. PMID- 29412085 TI - Compliant Buckled Foam Actuators and Application in Patient-Specific Direct Cardiac Compression. AB - We introduce the use of buckled foam for soft pneumatic actuators. A moderate amount of residual compressive strain within elastomer foam increases the applied force ~1.4 * or stroke ~2 * compared with actuators without residual strain. The origin of these improved characteristics is explained analytically. These actuators are applied in a direct cardiac compression (DCC) device design, a type of implanted mechanical circulatory support that avoids direct blood contact, mitigating risks of clot formation and stroke. This article describes a first step toward a pneumatically powered, patient-specific DCC design by employing elastomer foam as the mechanism for cardiac compression. To form the device, a mold of a patient's heart was obtained by 3D printing a digitized X-ray computed tomography or magnetic resonance imaging scan into a solid model. From this model, a soft, robotic foam DCC device was molded. The DCC device is compliant and uses compressed air to inflate foam chambers that in turn apply compression to the exterior of a heart. The device is demonstrated on a porcine heart and is capable of assisting heart pumping at physiologically relevant durations (~200 ms for systole and ~400 ms for diastole) and stroke volumes (~70 mL). Although further development is necessary to produce a fully implantable device, the material and processing insights presented here are essential to the implementation of a foam-based, patient-specific DCC design. PMID- 29412086 TI - An Ultralightweight and Living Legged Robot. AB - In this study, we describe the most ultralightweight living legged robot to date that makes it a strong candidate for a search and rescue mission. The robot is a living beetle with a wireless electronic backpack stimulator mounted on its thorax. Inheriting from the living insect, the robot employs a compliant body made of soft actuators, rigid exoskeletons, and flexure hinges. Such structure would allow the robot to easily adapt to any complex terrain due to the benefit of soft interface, self-balance, and self-adaptation of the insect without any complex controller. The antenna stimulation enables the robot to perform not only left/right turning but also backward walking and even cessation of walking. We were also able to grade the turning and backward walking speeds by changing the stimulation frequency. The power required to drive the robot is low as the power consumption of the antenna stimulation is in the order of hundreds of microwatts. In contrast to the traditional legged robots, this robot is of low cost, easy to construct, simple to control, and has ultralow power consumption. PMID- 29412088 TI - Gemstracker Expertise team Rotterdam arm and hand: Web-based monitoring of physical, social and emotional functioning in patients with upper limb amputations. AB - BACKGROUND AND AIM: Patient-reported outcome measures are increasingly used to evaluate effectiveness of treatment. However, the use of 'paper and pencil' questionnaires is time-consuming for both patients and healthcare specialists. Therefore, the aim of this project was to develop a custom-built web-based monitoring system. TECHNIQUE: We incorporated reliable and valid questionnaires on all domains of human functioning as described in the World Health Organization's Classification of Functioning, Disability and Health (ICF and ICF CY). The method of remote follow-up enables long-term evaluation of PROMs. We specified monitoring protocols for both children and adults, split for different age groups with emphasis on health-related quality of life. DISCUSSION: Time efficient evaluation of PROMs may lead to higher compliance and an increase of client-centred practice. Moreover, evaluating PROMs facilitates patient empowerment and enables patients to make informed decisions about their treatment and healthcare needs. Clinical relevance We developed a web-based system for evaluation of PROMs. The system has enabled better informed decision-making for our clients. PMID- 29412090 TI - Editorial: Trent International Prosthetics Symposium Special Issue. PMID- 29412089 TI - Investigating the uncanny valley for prosthetic hands. AB - BACKGROUND: In 1970, Mori hypothesised the existence of an 'uncanny valley', whereby stimuli falling short of being fully human are found to be creepy or eerie. OBJECTIVES: To investigate how eerie people find different prosthetic hands and whether perceptions of eeriness can be accounted for by categorical ambiguity. STUDY DESIGN: Students participated in computerised experiments during which photographic images of hands were presented. METHODS: We compared photographs of prosthetic hands pre-selected as more (H+) or less human-like (H ), as well as mechanical and real hands. Participants rated the hands for eeriness and human-likeness, as well as performing a speeded classification (human/non-human) and location judgment (control) task. RESULTS: The H- prosthetic hands were rated as more eerie than the H+ prosthetic, mechanical and real hands, and this was unaffected by hand orientation. Participants were significantly slower to categorise the H+ prosthetic hands compared to the H- prosthetic and real hands, which was not due to generally slower responses to the H+ prosthetic hands (control task). CONCLUSION: People find prosthetic hands to be eerie, most consistently for less human-like prosthetic hands. This effect is not driven by ambiguity about whether to categorise the prosthetic hand as human or artificial. Clinical relevance More obviously artificial, less-realistic, prosthetic hands consistently generate a sense of eeriness, while more realistic prosthetic hands avoid the uncanny valley, at least on initial viewing. Thus, greater realism in prosthetic design may not always incur a cost, although the role of movement and cutaneous input requires further investigation. PMID- 29412091 TI - The Finnish healthcare services lean management. AB - Purpose The purpose of this paper is to discuss health services managers' experiences of management in a special health-care unit and development efforts from the point of view of the Lean method. Additionally, the aim is to deepen the knowledge of the managers' work and nature of the Lean method development processes in the workplace. The research focuses on those aspects and results of Lean method that are currently being used in health-care environments. Design/methodology/approach These data were collected through a number of thematic interviews. The participants were nurse managers ( n = 7) and medical managers ( n = 7) who applied Lean management in their work at the University Hospital in the Northern Ostrobothnia Health Care District. The data were analysed with a qualitative content analysis. Findings A common set of values in specialized health-care services, development of activities and challenges for management in the use of the Lean manager development model to improve personal management skills. Practical implications Managers in specialized health-care services can develop and systematically manage with the help of the Lean method. This emphasizes assumptions, from the point of view of management, about systems development when the organization uses the Lean method. The research outcomes originate from specialized health-care settings in Finland in which the Lean method and its associated management principles have been implemented and applied to the delivery of health care. Originality/value The study shows that the research results and in-depth knowledge on Lean method principles can be applied to health-care management and development processes. The research also describes health services managers' experiences of using the Lean method. In the future, these results can be used to improve Lean management skills, identify personal professional competencies and develop skills required in development processes. Also, the research findings can be used in the training of health services managers in the health-care industry worldwide and to help them survive the pressure to change repeatedly. PMID- 29412092 TI - The role of the psychological contract in the motivation of nurses. AB - Purpose Although private health care is regarded as providing a premium quality experience for both patients and staff alike, it is not without its daily challenges for health professionals. This study aims to explore the psychological contract of nurses to develop a greater understanding of how employee-employer interaction impacts motivation levels. Design/methodology/approach Data were gathered through semi-structured interviews with thirteen nurses at a private hospital in South Africa. Five nursing managers were interviewed to provide a management perspective. Thematic analysis was used to identify the salient elements of the psychological contract and to establish connections with motivational features. Findings The psychological contract of nurses was balanced in nature, contained predominantly relational elements and was characterized by the need for manager support, leadership and autonomy. Motivation was a by product of fulfilment and was enhanced by a combination of tangible and intangible rewards. Practical implications Nursing managers should recognize their role in caring for the wellbeing of their staff and should be trained accordingly. Equipping nurses with the necessary tools to work autonomously, as well as acknowledging their skills, will stimulate confidence and improve motivation. Originality/value This study makes an important contribution to the existing literature on the psychological contract of nurses within the health care system. It provides insight into relationship-based mechanisms that can be used to improve the motivation of nurses and thus impact the overall quality of patient care. PMID- 29412093 TI - Authentic leadership in healthcare: a scoping review. AB - Purpose The purpose of this paper is to review peer-reviewed original research articles on authentic leadership (AL) in health care to identify potential research gaps and present recommendations for future research. The objectives are to examine and map evidence of the main characteristics, research themes and methodologies in the studies. AL is a leader's non-authoritarian, ethical and transparent behaviour pattern. Design/methodology/approach A scoping review with thematic analysis was conducted. A three-step search strategy was used with database and manual searches. The included studies were composed of English language peer-reviewed original research articles referring to both AL and health care. Findings In total, 29 studies were included. The studies favoured Canadian nurses in acute care hospitals. AL was understood as its original definition. The review identified four research themes: well-being at work, patient care quality, work environment and AL promotion. Quantitative research methodology with the authentic leadership questionnaire and cross-sectional design were prevalent. Research limitations/implications Future research needs more variation in research themes, study populations, settings, organisations, work sectors, geographical origins and theory perspectives. Different research methodologies, such as qualitative and mixed methods research and longitudinal designs, should be used more. Originality/value This is presumably the first literature review to map the research on AL in health care. PMID- 29412094 TI - The need to succeed - learning experiences resulting from the implementation of value-based healthcare. AB - Purpose The aim of this study has been to explore learning experiences from the two first years of the implementation of value-based healthcare (VBHC) at a large Swedish University Hospital. Design/methodology/approach An explorative design was used in this study. Individual open-ended interviews were carried out with 19 members from four teams implementing VBHC. Qualitative analysis was used to analyse the verbatim transcripts of the interviews. Findings Three main themes pinpointing learning experiences emerged through the analysis: resource allocation to support implementation, anchoring to create engagement and dedicated, development-oriented leadership with power of decision. Resource allocation included the need to set aside time and administrative resources and also the need to adjust essential IT-systems. The work of anchoring to create engagement involved both patients and staff and was found to be a never-ending task calling for deep commitment. The hospital top management's explicit decision to implement VBHC facilitated the implementation process, but the team leaders' lack of explicit management mandate was experienced as obstructing the process. The development process contributed not only to single-loop learning but also to double-loop learning. Originality/value Learning experiences drawn from implementing VBHC have not been studied before, and thus the results of this study could be of importance to managers and administrators wanting to implement this concept in their respective organizations. PMID- 29412095 TI - Return on investment in healthcare leadership development programs. AB - Purpose Strong leadership has been shown to foster change, including loyalty, improved performance and decreased error rates, but there is a dearth of evidence on effectiveness of leadership development programs. To ensure a return on the huge investments made, evidence-based approaches are needed to assess the impact of leadership on health-care establishments. As a part of a pan-Canadian initiative to design an effective evaluative instrument, the purpose of this paper was to identify and summarize evidence on health-care outcomes/return on investment (ROI) indicators and metrics associated with leadership quality, leadership development programs and existing evaluative instruments. Design/methodology/approach The authors performed a scoping review using the Arksey and O'Malley framework, searching eight databases from 2006 through June 2016. Findings Of 11,868 citations screened, the authors included 223 studies reporting on health-care outcomes/ROI indicators and metrics associated with leadership quality (73 studies), leadership development programs (138 studies) and existing evaluative instruments (12 studies). The extracted ROI indicators and metrics have been summarized in detail. Originality/value This review provides a snapshot in time of the current evidence on ROI indicators and metrics associated with leadership. Summarized ROI indicators and metrics can be used to design an effective evaluative instrument to assess the impact of leadership on health-care organizations. PMID- 29412096 TI - Nurses' leadership self-efficacy, motivation, and career aspirations. AB - Purpose This paper aims to test a model examining precursors and outcomes of nurses' leadership self-efficacy, and their aspirations to management positions. Design/methodology/approach A cross-sectional survey of 727 registered nurses across Canada was conducted. Structural equation modelling using Mplus was used to analyse the data. Findings Results supported the hypothesized model: chi2(312) = 949.393; CFI = 0.927; TLI = 0.919; RMSEA = 0.053 (0.049-0.057); SRMR 0.044. Skill development opportunities ( beta = 0.20), temporary management roles ( beta = 0.12) and informal mentoring ( beta = 0.11) were significantly related to nurses' leadership self-efficacy, which significantly influenced motivation to lead ( beta = 0.77) and leadership career aspirations ( beta = 0.23). Motivation to lead was significantly related to leadership career aspirations ( beta = 0.50). Practical implications Nurses' leadership self-efficacy is an important determinant of their motivation and intention to pursue a leadership career. Results suggest that nurses' leadership self-efficacy can be influenced by providing opportunities for leadership mastery experiences and mentorship support. Leadership succession planning should include strategies to enhance nurses' leadership self-efficacy and increase front-line nurses' interest in leadership roles. Originality value With an aging nurse leader workforce, it is important to understand factors influencing nurses' leadership aspirations to develop and sustain nursing leadership capacity. This research study makes an important contribution to the nursing literature by showing that nurses' leadership self-efficacy appears to be an important determinant of their motivation to lead and desire to pursue a career as a nurse leader. PMID- 29412097 TI - Exploring team working and shared leadership in multi-disciplinary cancer care. AB - Purpose The purpose of this paper is to explore the relevance of shared leadership to multi-disciplinary cancer care. It examines the policy background and applies concepts from shared leadership to this context. It includes discussion of the implications and recommendations. Design/methodology/approach This is a conceptual paper examining policy documents and secondary literature on the topic. While it focuses on the UK National Health Services, it is also relevant to other countries given they follow a broadly similar path with regard to multi-disciplinary working. Findings The paper suggests that shared leadership is a possible way forward for multi-disciplinary cancer care, particularly as policy developments are supportive of this. It shows that a shared perspective is likely to be beneficial to the further development of multi-disciplinary working. Research limitations/implications Adopting shared leadership needs to be explored further using appropriate empirical research. Practical implications The paper offers comments on the implications of introducing shared leadership and makes recommendations including being aware of the barriers to its implementation. Originality/value The paper offers an alternative view on leadership in the health-care context. PMID- 29412098 TI - Leadership in crisis situations: merging the interdisciplinary silos. AB - Purpose Complex clinical situations, involving multiple medical specialists, create potential for tension or lack of clarity over leadership roles and may result in miscommunication, errors and poor patient outcomes. Even though copresence has been shown to overcome some differences among team members, the coordination literature provides little guidance on the relationship between coordination and leadership in highly specialized health settings. The purpose of this paper is to determine how different specialties involved in critical medical situations perceive the role of a leader and its contribution to effective crisis management, to better define leadership and improve interdisciplinary leadership and education. Design/methodology/approach A qualitative study was conducted featuring purposively sampled, semi-structured interviews with 27 physicians, from three different specialties involved in crisis resource management in pediatric centers across Canada: Pediatric Emergency Medicine, Otolaryngology and Anesthesia. A total of three researchers independently organized participant responses into categories. The categories were further refined into conceptual themes through iterative negotiation among the researchers. Findings Relatively "structured" (predictable) cases were amenable to concrete distributed leadership - the performance by micro-teams of specialized tasks with relative independence from each other. In contrast, relatively "unstructured" (unpredictable) cases required higher-level coordinative leadership - the overall management of the context and allocations of priorities by a designated individual. Originality/value Crisis medicine relies on designated leadership over highly differentiated personnel and unpredictable events. This challenges the notion of organic coordination and upholds the validity of a concept of leadership for crisis medicine that is not reducible to simple coordination. The intersection of predictability of cases with types of leadership can be incorporated into medical simulation training to develop non-technical skills crisis management and adaptive leaderships skills. PMID- 29412099 TI - Developing accreditation for community based surgery: the Irish experience. AB - Purpose Carrying out minor surgery procedures in the primary care setting is popular with patients, cost effective and delivers at least as good outcomes as those performed in the hospital setting. This paper aims to describe the central role of clinical leadership in developing an accreditation system for general practitioners (GPs) undertaking community-based surgery in the Irish national setting where no mandatory accreditation process currently exists. Design/methodology/approach In all, 24 GPs were recruited to the GP network. Ten pilot standards were developed addressing GPs' experience and training, clinical activity and practice supporting infrastructure and tested, using information and document review, prospective collection of clinical data and a practice inspection visit. Two additional components were incorporated into the project (patient satisfaction survey and self-audit). A multi-modal evaluation was undertaken. A majority of GPs was included at all stages of the project, in line with the principles of action learning. The steering group had a majority of GPs with relevant expertise and representation of all other actors in the minor surgery arena. The GP research network contributed to each stage of the project. The project lead was a GP with minor surgery experience. Quantitative data collected were analysed using Predictive Analytic SoftWare. Krueger's framework analysis approach was used to analyse the qualitative data. Findings A total of 9 GPs achieved all standards at initial review, 14 successfully completed corrective actions and 1 GP did not achieve the required standard. Standards were then amended to reflect findings and a supporting framework was developed. Originality/value The flexibility of the action-learning approach and the clinical leadership design allowed for the development of robust quality standards in a short timeframe. PMID- 29412100 TI - The EIS Model: A Pilot Investigation of a Multidisciplinary Sex Therapy Treatment. AB - Marital couples not experiencing a satisfying sexual relationship are less satisfied in their overall relationship. There is, however, a paucity of controlled outcome studies researching the effectiveness of sex therapy interventions. This study was a pilot investigation of a new manual-based sex therapy called the EIS (empathy, intimacy, and sexual satisfaction) model. Results showed significant improvement in sexual and marital satisfaction, marital intimacy, and verbal sexual intimacy for men and women, and sexual function for women. Effect sizes were large for these variables and posttreatment differences. Results provide initial support for the theory and interventions of the EIS model. Treatment should include addressing vulnerable communication, relational intimacy, conflict resolution, sexual functioning, sexual medicine care, and sensual and sexual skills. PMID- 29412101 TI - Decreased ERp57 Expression in WAG/Rij Rats Thalamus and Cortex: Possible Correlation with Absence Epilepsy. AB - BACKGROUND: The role of intracellular proteins in the pathogenesis of absence epilepsy were mentioned. These proteins are thought to be related to energy generation, signal transduction, inflammation processes and membrane conductance. OBJECTIVES: The investigation of protein profile of the genetically epileptic rat brains was the main subject of this study. METHODS: For this, a 2D-gel electrophoresis based comparative proteome analysis was performed using thalamus tissue of genetic absence epileptic WAG/Rij and age matched Wistar rats. Regulated spots displaying differences in their abundance were identified using MALDI-TOF/TOF. Among the six spots (DHRS9, BR44, HINT1, CREM, SPRE and PDIA3/ERp57) the highest mascot score was attributed to ERp57 a neuroprotective/neurodegenerative system associated protein. Western Blot analyses were performed to validate changes occurring at ERp57 in thalamus and also identify changes in fronto-parietal cortex. RESULTS: Reductions in the expression levels of ERp57 were detected in the thalamic and the fronto-parietal brain regions of the WAG/Rij rats in comparison to Wistar rats. CONCLUSION: Such difference might be associated with the pathogenic mechanisms dictating the absence epilepsy. Lower levels of ERp57 may be playing an important role in the development of spontaneous seizures activity seen in the absence epileptic WAG/Rij rats strain. PMID- 29412102 TI - Cloning, Expression, Purification and Characterization of Oligomeric States of the Native 5HT2A G-Protein-Coupled Receptor. AB - BACKGROUND: The 5HT2A G-Protein Coupled Receptor (GPCR) is an important family of receptors involved in an array of neuromodulatory functions. Their dysregulation has been implicated in a number of psychiatric diseases. In spite of the importance of this GPCR, high resolution structure and mechanistic details of its function is unknown. Cholesterol plays an important role in the function of many receptors and reduced cholesterol levels can lead to disruption of serotonergic pathways. However, the role of cholesterol in the formation of GPCR oligomers has not been previously shown for this receptor. Given that receptor dimers have been shown to be the functional unit of this receptor, it is important to investigate the effect of cholesterol in the oligomeric state of 5HT2A receptor. OBJECTIVES: The main objective of this work is to clone, over-express and purify the 5HT2A receptor and investigate the effect of cholesterol in its oligomer formation. METHODS: The 5HT2A receptor (5HT2AR) DNA construct was subcloned into pFastBac-HT vector and the purified bacmid was used to transfect healthy Sf9 cells. After subsequent passages, a high titer baculovirus was used for over-expression in Sf9 cells. To verify whether the over-expressed receptor was localized in the membrane or cytosolic fraction, cells with and without baculoviral infection were analyzed by immunocytochemistry. Subsequently, the over-expression conditions required to obtain sufficient quantity of the receptor was optimized followed by the optimization of the purification conditions. Finally, the culture was scaled up and the receptor was purified by affinity chromatography. The over-expression of the receptor was checked by Western blotting and purity was analyzed by Coomassie stained SDS PAGE. Cryo-electron microscopy experiments were performed on the purified receptor in presence and absence of cholesterol and at multiple concentrations to rule out any concentration dependent effect on the oligomer formation. RESULTS: Immunocytochemistry experiments showed prominent nuclear staining; however, bright green staining along the cell membrane was observed only for the infected cells, suggesting appropriate trafficking of majority of the over-expressed receptors to the cell membrane. Results of cryoelectron microscopy show that the receptor with cholesterol had particles that were bigger in size (~11 - 12 nm) compared to the dimension of known GPCR homologs. In contrast, the receptor after removal of cholesterol revealed a uniform distribution of smaller particles (~5 - 6 nm) that is approximately half the size of 5HT2AR particles with cholesterol. Comparing the 2D average views of detergent encapsulated 5HT2AR particles with the overall dimensions of other 5HT receptor analogs, we show that while a 5HT2AR dimer more closely matches the dimensions of particles with CHS, only a monomer can be fit to particles without CHS. Importantly, even at higher receptor concentration and particle density, the size for 5HT2AR particles without CHS remains the same, suggesting that dimerization is unlikely an effect of concentration. CONCLUSION: Our results indicated that 5HT2A receptor primarily forms a dimer in presence of cholesterol whereas it predominantly forms a monomer when cholesterol is removed. PMID- 29412103 TI - Nanotechnology Inspired Advanced Engineering Fundamentals for Optimizing Drug Delivery. AB - BACKGROUND: Drug toxicity and inefficacy are commonly experienced problems with drug therapy failure. To face these problems, extensive research work took place aiming to design new dosage forms for drug delivery especially nanoparticulate systems. These systems are designed to increase the quantity of the therapeutic molecule delivered to the desired site concurrently with reduced side effects. In order to achieve this objective, nanocarriers must principally display suitable drug vehiculization abilities and a controlled biological destiny of drug molecules. Only the intelligent design of the nanomedicine will accomplish these fundamentals. METHODS: The present review article is dedicated to the discussion of the important fundamentals to be considered in the fabrication of nanomedicines. These include the therapeutic agent, the imaging agent, the nanocarrier and the functionalization moieties. Special consideration is devoted to the explanation and compilation of highly potential fabrication approaches assisting how to control the in vivo destiny of the nanomedicine. Finally, some nanotechnology-based drug delivery systems, for the development of nanomedicine, are also discussed. RESULTS: The nanotechnology-based drug delivery systems show remarkable outcomes based on passive and active targeting as well as improvement of the drug pharmacodynamic and pharmacokinetic profiles. Multifunctional nanocarrier concept affords a revolutionary drug delivery approach for maximizing the efficacy, safety and monitoring the biological fate of the therapeutic molecule. CONCLUSION: Nanomedicines may enhance the efficacy of therapeutic molecules and reduce their toxic effects. Meanwhile, further research works are required to rightly optimize (and define) the effectiveness, nanotoxicity, in vivo destiny and feasibility of these nanomedicines which, from a preclinical standpoint, are actually promising. PMID- 29412104 TI - Radiation-Induced Pulmonary Epithelial-Mesenchymal Transition: A Review on Targeting Molecular Pathways and Mediators. AB - BACKGROUND: Radiotherapy is the most widely used treatment method for average and advanced lung cancer patients. Moreover, the clinical toxicities caused by radiotherapy are categorized into acute radiation pneumonitis and late pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is a complex physiological process involves many signaling molecules and proteins like adaptor proteins, and transcriptional factors. It was identified as a significant mechanism for fibrosis, wound healing and also cancer. A variety of biomarkers have appeared in radiation-induced lung EMT, some of which are acquired (N-cadherin, vimentin and fibronectin, etc.) and some of which are repressed during the transition of epithelial cells (E-cadherin, zona occludens-1). OBJECTIVE: In the current review, we highlighted the radiation-induced lung EMT signaling pathway and their mediators. We also discuss the EMT in cancer, fibrosis and its epigentics. RESULTS: Radiation-induced lung EMT is controlled by numerous signaling pathways like MAPK, NF-kB, Wnt, microRNAs and histone modifications. Transcriptional factors such as Snail, slug, twist, ZEB1 (Zinc finger E-box binding-1) and ZEB2 (Zinc finger E-box binding-2) proteins are inducers linking radiation-induced EMT and fibrosis. Epigenetic modulations are heritable changes in the structure and function of the genome that occurs without any change in the sequence. Several approaches showed the role of epigenetic modifications and its inhibitors in controlling fibrosis and cancer. Only limited reports are focused on understanding the epigenetic regulations of radiation-induced lung EMT. CONCLUSION: The current review focused on recent findings regarding radiation induced lung fibrosis and EMT, thus provides some information on important signaling pathways, its subsequent expression of genes and proteins involved in EMT. This review also discussed various inhibitors that could be used to treat EMT related diseases, i.e., fibrosis, cancer. PMID- 29412106 TI - Antimicrobial Activity of Diazenyl Derivatives: An Update. AB - The development of new antimicrobial drugs is a very challenging task owing to the rapidly developing drug resistance among the existing drugs. The hybridization of active and novel compounds is a commonly used approach to combat this situation. The azo linkage (N=N) is successfully used to link two bioactive moieties to enhance the therapeutic effects. The hybrid derivatives linked by azo linkage have shown their activity by acting on target proteins in microorganisms, cell wall inhibitors, DHPS inhibitors, RNA Editing Ligase 1 inhibitors, the general protein secretory (Sec) pathway inhibitors, neuraminidase inhibitors, etc. The current review covers the general enzymes and regulatory pathways in microorganisms targeted by diazenyl compounds and recent developments pertaining to diazenyl derivatives as antimicrobial agents during the last five years. This information will prove useful to the researchers for the development of novel antimicrobial agents by slight modifications in active derivatives with improved activities. PMID- 29412105 TI - Tocotrienols Regulate Bone Loss through Suppression on Osteoclast Differentiation and Activity: A Systematic Review. AB - BACKGROUND: There are accumulating studies reporting that vitamin E in general exhibits bone protective effects. This systematic review, however discusses the effects of a group of vitamin E isomers, tocotrienols in preventing bone loss through osteoclast differentiation and activity suppression. OBJECTIVE: This review is aimed to discuss the literature reporting the effects of tocotrienols on osteoclasts, the cells specialized for resorbing bone. RESULTS: Out of the total 22 studies from the literature search, only 11 of them were identified as relevant, which comprised of eight animal studies, two in vitro studies and only one combination of both. The in vivo studies indicated that tocotrienols improve the bone health and reduce bone loss via inhibition of osteoclast formation and resorption activity, which could be through regulation of RANKL and OPG expression as seen from their levels in the sera. This is well supported by data from the in vitro studies demonstrating the suppression of osteoclast formation and resorption activity following treatment with tocotrienol isomers. CONCLUSION: Thus, tocotrienols are suggested to be potential antioxidants for prevention and treatment of bone-related diseases characterized by increased bone loss. PMID- 29412107 TI - Genetic Mechanisms of Antibiotic Resistance and the Role of Antibiotic Adjuvants. AB - The ever increasing number of multidrug-resistant microorganism pathogens has become a great and global public health threat. Antibiotic mechanisms of action and the opposing mechanisms of resistance are intimately associated, but comprehension of the biochemical and molecular functions of such drugs is not a simple exercise. Both the environment, and genetic settings contribute to alterations in phenotypic resistance (natural bacterial evolution), and make it difficult to control the emergence and impacts of antibiotic resistance. Under such circumstances, comprehension of how bacteria develop and/or acquire antibiotic resistance genes (ARG) has a critical role in developing propositions to fight against these superbugs, and to search for new drugs. In this review, we present and discuss both general information and examples of common genetic and molecular mechanisms related to antibiotic resistance, as well as how the expression and interactions of ARGs are important to drug resistance. At the same time, we focus on the recent achievements in the search for antibiotic adjuvants, which help combat antibiotic resistance through deactivation of bacterial mechanisms of action such as beta-lactamases. Recent advances involving the use of anti-resistance drugs such as: efflux pump inhibitors; anti-virulence drugs; drugs against quorum sensing; and against type II/III secretion systems are revealed. Such antibiotic adjuvants (as explored herein) collaborate against the problems of antibiotic resistance, and may restore or prolong the therapeutic activity of known antibiotics. PMID- 29412108 TI - Learning from Nature: Bioinspired Strategies Towards Antimicrobial Nanostructured Systems. AB - Microbial contamination still remains a major issue of the modern era, due to the widespread of drug-resistant pathogens. This has prompted researchers to come up with novel antimicrobial systems that could overcome antibiotic-resistance. In this context, nature can provide inestimable source of inspiration to design high performance multifunctional materials with potent activity against drug-resistant pathogens. Actually, integrating the bio-inspired-approach with nanotechnology can provide cutting-edge solutions for drug-resistant infections. In this context, this review will examine recent advances in the development of bio inspired antimicrobial nanostructures. Advantages of bioinspired approach to nanomaterials over conventional routes have been highlighted. Generally, bionspired synthesis can be carried out either by mimicking the functions of natural materials/ structures or by mimicking the biological processes employed to produce substances or materials. The review provides an overview of both strategies as applied to the synthesis of inorganic, organic as well as hybrid nanostructures. Antimicrobial efficacy and biological properties of these systems have been highlighted. Antimicrobial and antibiofouling nanostructured surfaces are also discussed. PMID- 29412110 TI - The Sesamum indicum Rhizosphere Associated Bacterium: A Source of Antifungal Compound. AB - BACKGROUND: The impact of fungal infections on human health has increased considerably within a past few decades. Although drugs with antifungal properties are available, but they are less effective and are associated with side effects. OBJECTIVE AND METHOD: To screen the bacterial isolates from Sesamum indicum and to investigate the antifungal activity of the screened bacterial isolates against Aspergillus sp. Co-culture assay and agar overlay were used to scrutinize the anti-Aspergillus activity. Furthermore, optimization of media and growth conditions to enhance the production of anti-Aspergillus compound. RESULTS: Several bacterial cultures were isolated from Sesamum indicum rhizosphere collected from Mandi (H.P.) India. These bacterial cultures were assayed for antifungal activity against Aspergillus species i.e. A. fumigatus and A. niger. Two most potent strains were chosen for more detailed analyses. The biochemical characterization and 16S ribosomal RNA sequencing revealed that Burkholderia sp. strain RC1 and Acinetobacter pittii strain RC2 exhibit strong similarity (100%) with Burkholderia sp. SR2-07 and Acinetobacter sp. strain 3-59. Additionally, it was also validated that RC1 and RC2 showed significant difference in the production of anti-Aspergillusactivity under altered growth conditions. CONCLUSION: Results from this study recommend that plant rhizosphere remains a rich hotspot for delivering a novel antifungal compounds. PMID- 29412111 TI - Efficacy of P2Y12 Receptor Blockers After Myocardial Infarction and Genetic Variability of their Metabolic Pathways. AB - BACKGROUND: Various antiplatelet drugs are used following Acute Coronary Syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes Pglycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation. Common gain-of-function or loss-of-function alleles of CYP2C19 gene are associated with lower or higher platelet reactivity that may impact clinical outcomes of clopidogrel treatment. Prasugrel is considered to be less dependent on CYP2C19 variability as it is also metabolized by other CYP450 isoforms. Some studies, however, showed the relevance of CYP2C19 variants for platelet reactivity during prasugrel treatment as well. Ticagrelor is metabolized mainly by CYP3A4, which does not show functionally relevant genetic variability. Its concentrations may be modified by the variants of Pglycoprotein gene ABCB1. While no substantial difference between the clinical efficacy of prasugrel and ticagrelor has been documented, both of them have been shown to be superior to clopidogrel in post-ACS treatment. This can be partially explained by lower variability at each step of their metabolism. It is probable that factors influencing the pharmacokinetics of both drugs, including genetic factors, may predict the clinical efficacy of antiplatelet treatment in personalized medicine. CONCLUSION: We summarize the pharmacokinetics and pharmacogenetics of P2Y12 inhibitors with respect to their clinical effects in post-myocardial infarction treatment. PMID- 29412112 TI - Novel Direct Anticoagulants and Atherosclerosis. AB - Coagulation factors can affect cellular processes that include inflammatory signaling by acting on endothelial protease activated receptors, vascular smooth muscle and inflammatory cells beyond the coagulation cascade. This is important in the pathogenesis of atherosclerosis. Accordingly, experimental data points to beneficial effects of coagulation protease inhibitors on the attenuation of atherosclerosis progression in animal models. However, available clinical data do not support the use of anticoagulants as an add-on treatment of atherosclerosis. New clinical studies are needed with a better selection of patients to clarify the role of novel direct anticoagulants in the management of atherosclerosis. PMID- 29412109 TI - New Benzothiazole-based Thiazolidinones as Potent Antimicrobial Agents. Design, synthesis and Biological Evaluation. AB - BACKGROUND: Thiazole and benzothiazole derivatives, as well as thiazolidinones are very important scaffolds in medicinal chemistry. Literature has revealed that they possess a wide spectrum of biological activities including antimicrobial activity. OBJECTIVE: The goal of this paper is the designing of new benzothiazole based thiazolidinones and the evaluation of their biological activities. METHODS: The designed compounds were synthesized using classical organic synthesis methods. The antimicrobial activity was evaluated using the method of microdilution. RESULTS: The twelve newly synthesized compounds showed antimicrobial properties. All compounds appeared to be more active than ampicillin in most studied strains and in some cases, more active than streptomycin. Antifungal activity, in most cases was also better than the reference drugs ketoconazole and bifonazole. The prediction of cytotoxicity revealed that the synthesized compounds were not toxic (LD50 350-1000 mg/kg of body weight). Docking studies on the antibacterial activity confirmed the biological results. CONCLUSION: The twelve new compounds were synthesized and studied for their antimicrobial activity. The compounds appeared to be promising antimicrobial agents and could be the lead compounds for new, more potent drugs. According to the docking prediction, the compounds could be MurB inhibitors. PMID- 29412113 TI - Screening for Rare Genetic Variants Associated with Atherosclerosis: Opportunity for Personalized Medicine. AB - Atherosclerosis and its clinical manifestations is a leading cause of disease burden worldwide. Currently, most of the individuals carrying a strong predisposition to complications of atherosclerosis because of monogenic dyslipidaemias remain undiagnosed and consequently are not given an opportunity for prevention. Therefore, one of the main public health challenges remains the identification of individuals with significantly increased risk for atherosclerosis due to monogenic predisposition. Next-Generation Sequencing (NGS) has revolutionized genetic testing in symptomatic patients. Although new genomic technologies are still developing, and evidence on the use of this methodology for screening purposes is still lacking, genome testing might provide a powerful tool for the identification of individuals at risk. This may pave the way for the implementation of personalized medicine in the field of atherosclerosis prevention. In this review, we discuss the potential of genetic screening for atherosclerosis prevention and present the potential target of 17 genes responsible for monogenic dyslipidaemias associated with atherosclerosis. PMID- 29412114 TI - Caveolin-1 in Stroke Neuropathology and Neuroprotection: A Novel Molecular Therapeutic Target for Ischemic-Related Injury. AB - Cardiovascular disease and associated cerebral stroke are a global epidemic attributed to genetic and epigenetic factors, such as diet, life style and an increasingly sedentary existence due to technological advances in both the developing and developed world. There are approximately 5.9 million stroke related deaths worldwide annually. Current epidemiological data indicate that nearly 16.9 million people worldwide suffer a new or recurrent stroke yearly. In 2014 alone, 2.4% of adults in the United States (US) were estimated to experience stroke, which is the leading cause of adult disability and the fifth leading cause of death in the US There are 2 main types of stroke: Hemorrhagic (HS) and ischemic stroke (IS), with IS occurring more frequently. HS is caused by intra cerebral hemorrhage mainly due to high blood pressure, while IS is caused by either embolic or thrombotic stroke. Both result in motor impairments, numbness or abnormal sensations, cognitive deficits, and mood disorders (e.g. depression). This review focuses on the 1) pathophysiology of stroke (neuronal cell loss, defective blood brain barrier, microglia activation, and inflammation), 2) the role of the membrane protein caveolin- 1 (Cav-1) in normal brain physiology and stroke-induced changes, and, 3) we briefly discussed the potential therapeutic role of Cav-1 in recovery following stroke. PMID- 29412115 TI - Genetic Variations and Subclinical Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus. AB - Atherosclerosis and its cardiovascular complications are the main cause of death in diabetic patients. Patients with diabetes mellitus have a greater than 10-fold risk of cardiovascular disease in their lifetime. The carotid Intima-Media Thickness (cIMT), a surrogate marker for the presence and progression of atherosclerosis, predicts future cardiovascular events in asymptomatic subjects with Type 2 Diabetes Mellitus (T2DM). This review focuses on genetic variants that contribute to the pathobiology of subclinical atherosclerosis in the setting of T2DM. Specifically, we devoted our attention to wellstudied genes selected for their relevance for atherosclerosis. These include: The Renin-Angiotensin- Aldosterone System (RAAS), Apolipoprotein E (ApoE), Methylenetetrahydrofolate Reductase (MTHFR) and pro-inflammatory genes. The ever-growing availability of advanced genotyping technologies has made Genome-Wide Association Studies (GWAS) possible. Although several bioinformatics tools have been developed to manage and interpret the huge amounts of data produced, there has been limited success in the many attempts to uncover the biological meaning of the novel susceptibility loci for atherosclerosis. PMID- 29412116 TI - Prevention of Vascular Complications in Diabetes Mellitus Patients: Focus on the Arterial Wall. AB - In Diabetes Mellitus (DM), hyperglycaemia and insulin resistance progressively lead to both microvascular and macrovascular complications. Whereas the incidence of microvascular complications is closely related to tight glycaemic control, this does not apply to macrovascular complications. Hyperglycaemia influences many interweaving molecular pathways that initially lead to increased oxidative stress, increased inflammation and endothelial dysfunction. The latter represents the initial in both types of vascular complications; it represents the "obligatory damage" in microvascular complications development and only "introductory damage" in macrovascular complications development. Other risk factors, such as arterial hypertension and dyslipidaemia, also play an important role in the progression of macrovascular complications. All these effects accumulate and lead to functional and structural arterial wall damage. In the end, all factors combined lead to the promotion of atherosclerosis and consequently major adverse cardiovascular events. If we accept the pivotal role of vascular wall impairment in the pathogenesis and progression of microvascular and macrovascular complications, treatment focused directly on the arterial wall should be one of the priorities in prevention of vascular complications in patients with DM. In this review, an innovative approach aimed at improving arterial wall dysfunction is described, which may show efficacy in clinical studies. In addition, the potential protective effects of current treatment approaches targeting the arterial wall are summarised. PMID- 29412117 TI - Review of the Methods to Obtain Paediatric Drug Safety Information: Spontaneous Reporting and Healthcare Databases, Active Surveillance Programmes, Systematic Reviews and Meta-analyses. AB - BACKGROUND: Knowledge of drugs safety collected during the pre-marketing phase is inevitably limited because the randomized clinical trials (RCTs) are rarely designed to evaluate safety. The small and selective groups of enrolled individuals and the limited duration of trials may hamper the ability to characterize fully the safety profiles of drugs. Additionally, information about rare adverse drug reactions (ADRs) in special groups is often incomplete or not available for most of the drugs commonly used in the daily clinical practice. In the paediatric setting several highimpact safety issues have emerged. Hence, in recent years, there has been a call for improved post-marketing pharmacoepidemiological studies, in which cohorts of patients are monitored for sufficient time in order to determine the precise risk-benefit ratio. OBJECTIVE: In this review, we discuss the current available strategies enhancing the post marketing monitoring activities of the drugs in the paediatric setting and define criteria whereby they can provide valuable information to improve the management of therapy in daily clinical practice including both safety and efficacy aspects. The strategies we cover include the signal detection using international pharmacovigilance and/or healthcare databases, the promotion of active surveillance initiatives which can generate complete, informative data sets for the signal detection and systematic review/meta-analysis. CONCLUSION: Together, these methods provide a comprehensive picture of causality and risk improving the management of therapy in a paediatric setting and they should be considered as a unique tool to be integrated with post-marketing activities. PMID- 29412118 TI - Antibody Administration for Bone Tissue Engineering: A Systematic Review. AB - BACKGROUND: Currently, antibodies are progressively applied in medicine for different purposes, including diagnostic and therapeutic indications. Over twenty monoclonal antibodies utilized for many therapeutic reasons from therapy of cancers, immune disorders, and osteoporosis to localized bony defects. In addition, therapeutic antibodies represented various findings in bone tissue engineering. OBJECTIVES: The current study aims to systematically review the available literature on antibody assisted bone regeneration in animal models. METHODS: A through electronic search was conducted from January 1992 to June 2017 limited to English language publications on administrations of antibodies for bone regeneration. Data extraction was ere performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Twenty studies were selected and analyzed in this systematic review. Among these studies, six articles reported in vitro results in addition to in vivo evaluations. The data is tabulated according to the route of administrations as locally administrated antibody which includes anti-bone morphogenetic protein 2 (anti-BMP2) and systemic administrated antibodies, which include anti sclerostin and anti- Dickkopf-1 (DKK1). Data are summarized and reported by the following variables: Type of study, types of cells for in vitro investigations, types of animal models and defects characteristics, types of scaffolds used in the defect site, duration of follow-ups; and outcomes of assessments. CONCLUSIONS: A novel approach of administration of antibodies demonstrated promising results for bone tissue engineering. However, more investigations, particularly in larger animals, are required for their further possible clinical administration. PMID- 29412119 TI - Sodium-glucose Cotransporter 2 Inhibitors and Ischemic Stroke. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with substantially increased risk for cardiovascular events, including ischemic stroke. In turn, ischemic stroke represents a leading cause of mortality and long-term disability worldwide. The recent class of glucose-lowering agents is sodium-glucose cotransporter 2 (SGLT-2) inhibitors, which act through inhibition of glucose reabsorption in the kidney, resulting in glucose excretion without stimulating insulin release. Accumulating data suggests that these agents improve multiple risk factors for ischemic stroke except their glucose-lowering effect. OBJECTIVE: In the present review, the pleiotropic actions of SGLT-2 inhibitors are summarized and their potential implications on ischemic stroke prevention are discussed. METHODS: We performed a comprehensive search of the literature in terms of SGLT-2 inhibitors efficacy on ischemic stroke and traditional risk factors of cerebrovascular disease. RESULTS: Several studies consistently showed that SGLT-2 inhibitors reduce blood pressure, induce weight loss, increase high density lipoprotein cholesterol levels and reduce triglyceride levels. In addition, they improve several emerging cardiovascular risk factors, most notably arterial stiffness, albuminuria and oxidative stress. However, in the only trial that evaluated the effects of these agents on the incidence of ischemic stroke, empagliflozin did not reduce the risk of first or recurrent stroke despite a significant reduction in cardiovascular and all-cause mortality. CONCLUSION: Despite the multiple pleiotropic effects of SGLT-2 inhibitors, these agents do not appear to affect stroke risk. Ongoing large trials with longer follow-up will evaluate whether the pleiotropic effects of this class will translate into benefits in ischemic stroke prevention. PMID- 29412120 TI - Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis; from Pathophysiology to Clinical Practice. AB - BACKGROUND: SGLT-2 inhibitors are a novel class of antidiabetic drugs, recently approved for the treatment of patients with T2DM. Their cardioprotective and renoprotective action, along with their beneficial effects on metabolic parameters, makes them an attractive therapeutic option. Since 2015, when the US FDA issued warning regarding the increased risk of euDKA in the setting of SGLT-2 inhibitors administration, a vivid discussion upon the direct connection between this novel class and the major metabolic complication of diabetes mellitus is still ongoing. OBJECTIVES: To present the underlying pathophysiology, associating SGLT-2 inhibitors and euDKA, and clinical data both in T1DM and in T2DM patients, in order to understand the clinical background which favors the development of euDKA. METHOD: We conducted a comprehensive research of the relevant literature regarding the association between SGLT-2 inhibitors in clinical practice and the events of diabetic ketoacidosis, mainly euglycemic. RESULTS: Randomized controlled trials, meta-analyses, case series and case reports shed light on this possible connection, the background that favors euDKA, and the mediating pathophysiologic mechanisms. Many of those euDKA events developed in patients with T1DM, due to off-label use of SGLT-2 inhibitors, or in patients previously misdiagnosed as having T2DM, who in fact suffered from LADA. CONCLUSION: SGLT-2 inhibitors certainly predispose to euDKA, but it is unclear if, as certain precipitating factors are usually recognized on the background, DKA would also occur in the absence of an SGLT-2 inhibitor. Further investigation is required in order to establish or not SGLT- 2 inhibitors as causative factors of euDKA. PMID- 29412121 TI - Sodium-glucose Cotransporter 2 Inhibitors: Impact on Body Weight and Blood Pressure Compared with other Antidiabetic Drugs. AB - BACKGROUND: Sodium-glucose co-transporters 2 inhibitors have emerged as a novel antidiabetic class of drugs offering significant ameliorating effects on a variety of cardiovascular risk factors, secondary to their mechanism of action, including blood pressure and body weight. OBJECTIVE: The purpose of this article is to discuss available data on the impact of SGLT-2 inhibitors on blood pressure and body weight compared with other available anti-diabetic drugs and to present potential mechanisms mediating these effects. METHODS: A comprehensive review of the literature was performed to identify studies examining the effects of SGLT-2 inhibitors on blood pressure and body weight. RESULTS: SGLT-2 inhibition has been related with a mild decrease in blood pressure of approximately 3-5mmHg in systolic and 1-2mmHg in diastolic blood pressure. These data have been confirmed with 24h ambulatory measurements, as well. Furthermore, given the loss of calories in the urine, a mild decrease in body weight is anticipated, as well. Studies with this class of drugs noted a reduction in body weight of 2 to 3 kg, similar to the loss noted with the use of glucagon-like peptide 1 analogues, the only class of drugs that has offered significant reductions in body weight so far. Consclusion: The beneficial effects of the SGLT-2 inhibition on an abundance of cardiovascular risk factors, including blood pressure and body weight, have created great expectations for potential benefits from the cardiovascular events standpoint, a theory that was confirmed in the two available cardiovascular studies of this promising class of drugs. PMID- 29412122 TI - Sodium-glucose Cotransporter 2 Inhibitors: Nephroprotective Impact on Diabetic Kidney Disease. AB - BACKGROUND: Diabetic nephropathy is a crucial microvascular complication of diabetes mellitus that is associated with elevated cardiovascular risk. SGLT-2 inhibitors are a new class of hypoglycemic drugs that positively affect several risk factors of cardiorenal damage. OBJECTIVES: The study aimed to review and critically discuss available data on the association of SGLT-2 inhibitors treatment with kidney function, progress of diabetic kidney disease, and renal related outcomes, as well to unveil potential mechanisms of action that mediate such effects. METHOD: We conducted a comprehensive search of the literature on the renal related effects of SGLT-2 inhibitors, to compose a narrative mini review. RESULTS: The administration of SGLT-2 inhibitors was observed to exert beneficial effects on a wide cluster of risk factors of chronic kidney disease, such as hyperglycemia, blood pressure, serum uric acid, and body weight. Data from the first two large, randomized, clinical trials of SGLT-2 inhibitors conducted to address the renal related outcomes of SGLT-2 inhibitors suggest substantial benefits on estimated glomerular filtration rate decline and albuminuria. CONCLUSION: The initial data suggest clinically meaningful benefits of the SGLT-2 inhibitors in diabetic patients in relevance with chronic kidney disease. Future, well-designed randomised clinical trials need to be further investigated such as nephroprotective outcomes, that if confirmed, could lead to new perspectives in the management of diabetic nephropathy. PMID- 29412123 TI - Sodium-glucose Cotransporter 2 Inhibitors: The Pleiotropic Mechanisms of Actions. AB - BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of oral antidiabetic drugs. So far, there are three agents approved for use in Europe and in the USA, two in Japan and another four agents under testing. OBJECTIVE: The purpose of this study is to describe the mechanism of action and the favorable and adverse effects of SGLT-2 inhibitors. METHOD: A thorough review of literature indexed in PubMed, Scopus and Cochrane databases were conducted. Original papers, review papers and their relevant references in English, from 2005 to February 2017, were included. RESULTS: The main mechanism of action is the glycosuria induced by the inhibition of SGLT-2, located in the early segment of the proximal convoluted tubule. Along with large amounts of glucose, sodium, water and uric acid are also excessively excreted in urine. These actions have various, both desired and adverse, consequent implications in kidneys, blood pressure, cardiovascular system and other systems. Moreover, SGLT-2 inhibitors act directly to organs other than the kidneys, as SGLT-2 can be expressed there. CONCLUSION: The underlying mechanisms responsible for the SGLT-2 inhibitor actions, are pleiotropic and occur in the kidneys, as well as in other target organs. The comprehension of these mechanisms, not only permits us to understand their actions better, but it could also help us to predict more of their undisclosed favorable actions, as well as their rare adverse effects. PMID- 29412124 TI - Sodium-glucose Cotransporter 2 Inhibitors: Glucose Lowering Against other Hypoglycemic Agents. AB - BACKGROUND: The treatment of diabetes remains challenging over the decades, even after the introduction of numerous novel drugs of different classes. Most patients with type 2 diabetes require a combination of multiple agents and eventually the use of insulin. The newest antidiabetic drugs, possibly with the most pleiotropic actions after metformin are the sodium-glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i). This class has a unique mechanism inhibiting the glucose reabsorption in the proximal tubule of the kidney. OBJECTIVE: The purpose of this review is to critically discuss the beneficial effect of SGLT-2i on glycemic control as monotherapy or in combination with other hypoglycemic agents. METHODS: A systematic review of randomised clinical trials on SGLT-2i vs placebo, other glucoselowering drugs or insulin was performed, and studies assessing glycemic control, mainly expressed through glycated hemoglobin and fasting plasma glucose levels (FPG) were included in the review. Electronic and manual searches on MEDLINE, EMBASE and Cochrane Library were performed. RESULTS: In our review, we mainly focused on dapagliflozin, empaglifozin and canagliflozin. All agents exhibited a sufficient reduction of HbA1c as well as FPG. CONCLUSIONS: SGLT-2i are a reliable second-line therapy of T2DM, since they can be combined safely with metformin, sulfonylures, incretin mimetics, insulin as well as in triple combinations. In many studies, they were prioritised as monotherapy with satisfying effects regarding HbA1c and FPG level reductions. PMID- 29412126 TI - Quantification of Radiation Exposure of Non-Dominant Index for the Surgeon Performing Sentinel Lymph-Node Removal Procedure. AB - BACKGROUND: Sentinel lymph-node scintigraphy is a useful method for accurate staging of different tumors and a helpful tool in personalized therapy for oncological patients. The radiation exposure for surgical staff has been a concern since the sentinel lymph-node detection method was developed. OBJECTIVE: The objective of the study was to determine and quantify the exposure to radiation of the non-dominant index for the surgeon performing sentinel lymph node removal and to determine, if there is an irradiation risk imposed during the surgical procedure. METHOD: We performed a study over a period of one year, where we evaluated the exposure of surgeon's non-dominant index during 196 sentinel lymph-node removal procedures. The pharmaceutical was administrated via subcutaneous injection in four peritumoral or perilesional injection sites. The equipment we used consisted of EuroProbe3 for sentinel lymph-node detection and ring TLD dosimeter placed on the surgeon's non-dominant index. RESULTS: The clinical distribution was: 104 melanomas, 84 breast carcinomas, 6 vulvar carcinomas and 2 penial carcinomas. The administered activity showed an average of 39.55 MBq (SD +/- 1.96) Tc-99m nanoalbumin compound. The non-dominant index exposure ranged between 0.10 mSv and 0.13 mSv/month with a cumulative dose of 1.31 mSv/year, thus 6.69 uSv per procedure. CONCLUSION: The surgeon received a minimal dose for the non-dominant index. The values we recorded did not pose any additional concerns or restrictions, the exposure being under the limits and constraints established by regulations, close to the detectability limit of the dosimeter. The procedure is safe in terms of radiation protection, respecting the limitation and optimization principles. PMID- 29412127 TI - Investigating the Association Between miR-608 rs4919510 and miR-149 rs2292832 with Colorectal Cancer in Iranian Population. AB - BACKGROUND: Single Nucleotide Polymorphisms (SNPs) in microRNA (miRNA) networks may serve as diagnostic and prognostic biomarkers of a variety of diseases such as cancer. Some studies have been performed to examine associations between miR 149 and miR-608 polymorphisms and susceptibility to colorectal cancer, but the results remain controversial and race-dependent. OBJECTIVE: The aim of our study was to investigate the association of miR-608 (rs4919510) and miR- 149 (rs2292832) with colorectal cancer and its clinical features in a sample of Iranian population. METHODS: This retrospective study was conducted on 76 CRC cases and 70 controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) method. To confirm the RFLP process, 10% of the PCR products were validated by direct sequencing. RESULTS: Our findings showed significant correlation between adjusted data of rs2292832 with sex and age in TT genotype (OR= 5.148, 95% CI=1.081 +/- 24.511, P=0.04). Distribution of rs4919510 polymorphism was not significantly different between controls and patients (CG, adjusted OR= 1.243, 95% CI=0.546 +/- 2.831; P=0.604 and GG, adjusted OR= 0.249, 95% CI=0.063 +/- 0.959; P=0.05). On the other hand, our results showed that a significant correlation was present between metastatic clinicopathological features and miR-608 (rs4919510) polymorphism (P=0.044). CONCLUSION: Our findings reveal that genotypes of rs2292832 and rs4919510 are not associated with risk of colorectal cancer in Iranian population. Moreover, the CC genotype of rs4919510 contributes to the metastatic features of the colorectal cancer. PMID- 29412129 TI - [Usefulness of CGH-array and SNP-array for the etiological diagnosis of premature ovarian insufficiency]. AB - Premature ovarian insufficiency (POI) defined by the cessation of ovarian function before the age of 40 years and the increase of gonadotropins (> 25 UI/l) occurs in approximately 1-5% of women. Different mechanisms are responsible for POI: chemotherapy, radiotherapy, environmental factors or genetic causes but most frequently no cause is identified. In order to determine the etiology of POI, cytogenetic analyses such as karyotype are performed. The karyotype allows to identify abnormalities of the number of chromosomes as well as abnormalities of the structure such as translocations, deletions or insertions of a size greater than 5-10 Mb... Turner syndrome is the most frequent genetic cause of POI and deletions of the long arm of the X chromosome are other causes of POI identified by the karyotype. However, the resolution of the karyotype is low and other cytogenetic techniques were developed such as all genome microarray analysis. This technique includes CGH-array and SNP-array and allows to identify gain or loss of chromosomal material as small as 10 kb but not the balanced structural rearrangements. Different studies using microarray analysis in cohorts of patients presenting with POI identify candidate genes responsible for POI. Furthermore, they allowed to identify a recurrent microdeletion, which includes the CPEB1 gene, located in 15q25.2 in about 1.5% of patients with POI. PMID- 29412125 TI - The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2. AB - Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer. CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury. By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research. Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis. PMID- 29412130 TI - [CRISPR-Cas9, germinal cells and human embryo]. AB - The performance of the molecular tool using CRISPR-Cas9, which makes it possible to induce targeted modifications of the DNA, has found numerous applications in research and open promising prospects in human clinic. CRISPR-Cas9 has been widely used to generate transgenic animals after targeted modification of the genome at the zygotic stage. It was also tested on human embryos on an experimental basis. Although there are potential medical indications that may justify a targeted modification of the embryo or germ cell genome, the uncertainties regarding the efficacy and safety of the method do not allow us to consider implementing such germline gene therapy in the short-term. However, it is necessary to weigh the scientific and ethical issues involved in this approach. PMID- 29412128 TI - Variation in Immune-Related microRNAs Profile in Human Milk Amongst Lactating Women. AB - BACKGROUND: Human Milk (HM) is a biological fluid representing the first nutrient for newborns. It directly impacts the development of the infant's immune system. In this concern, specific microRNAs (miRNAs) such as hsa-miR-21, hsa-miR-181a, hsa-miR-150 and hsa-miR-223 are known to be involved in the innate and acquired immune response. OBJECTIVE: Herein, these miRNAs were evaluated in frozen and pasteurized samples of human colostrum and HM in order to elucidate the distribution and the expression profile of these biological mediators in both biological fluids. METHODS: Using quantitative approach qRT-PCR, we analyzed immune-related microRNAs in both, colostrum and HM. RESULTS: Our study provided evidence of a comparable profile of immune specific miRNAs in colostrum and HM. Although we detected all the four miRNAs tested, we point out the prevalence of hsamiR- 181a and hsa-miR-223 indicative to act on T and granulocytes cell populations as selective targets. Therefore, these biomolecules could affect newborn's immune homeostasis at early stages of life. While, variation in immune related miRNAs was found in HM amongst lactating women, it was not evidenced in colostrum. Of interest, pasteurization procedure did not alter the distribution or the expression profile of the miRNAs tested in both colostrum and HM. Herein, we also proposed a simple method to determine the quantity of these biomolecules in biological fluids. CONCLUSION: Considering, this evidence the variation in immune-related miRNAs should be take into account and could be relevant for preterm and hospitalized infants who usually received pasteurized HM from donors. PMID- 29412131 TI - [Stretch-induced axon growth: a universal, yet poorly explored process]. AB - The growth of axons is a key step in neuronal circuit assembly. The axon starts elongating with the migration of its growth cone in response to molecular signals present in the surrounding embryonic tissues. Following the formation of a synapse between the axon and the target cell, the distance which separates the cell body from the synapse continues to increase to accommodate the growth of the organism. This second phase of elongation, which is universal and crucial since it contributes to an important proportion of the final axon size, has been historically referred to as "stretch-induced axon growth". It is indeed likely to result from a mechanical tension generated by the growth of the body, but the underlying mechanisms remain poorly characterized. This article reviews the experimental studies of this process, mainly analysed on cultured neurons so far. The recent development of in vivo imaging techniques and tools to probe and perturb mechanical forces within embryos will shed new light on this universal mode of axonal growth. This knowledge may inspire the design of novel tissue engineering strategies dedicated to brain and spinal cord repair. PMID- 29412132 TI - [Protein-protein interacting networks, their structures and disease-related mutations]. AB - In recent years, the comparison of protein interactomes has identified conserved modules, that could represent functional nuclei with a common ancestry. Within this context, recent analyses of protein-protein interacting networks have led to a debate on the influence of the experimental method on the quality and biological pertinence of these data. It is crucial to understand the measure in which divergence between networks of different species reflect sampling biases in respective experimental methods, as opposed to topological features dictated by biological functionality. This aspect requires novel, precise and practical mathematical tools, to quantify and compare high resolution networks. To this end, we have studied the relationship between pools of aleatory graphs and real biological signalization networks, while stressing the number of graph cycles in the networks, which represent complexes in experimental protein interactomes. By combining methods for graph and algorithm dynamics to count the loops, we evaluate the relative importance of the loops in biological networks in comparison with network analyses. PMID- 29412133 TI - [IGoR: a tool for learning and simulating the random generation of antigen receptors]. AB - Antigen receptors, which form the base of the adaptive immune system, are created stochastically by a DNA editing process called V(D)J recombination. As high throughput sequencing enables to study the repertoire of these receptors, it is now possible to learn the probabilistic laws of this random process, and to use them to analyse receptors of interest, generate synthetic repertoires to create controls, or aid the identification of receptors that are specific to diseases, with possible applications for medical diagnostics. This article describes how these tasks can be performed using the IGoR software, which can learn statistical models from data, annotate existing sequences, or generate new synthetic ones with the same laws as the recombination process. PMID- 29412134 TI - [Nextflow, an efficient tool to improve computation numerical stability in genomic analysis]. AB - Reproducing routine bioinformatics analysis is challenging owing to a combination of factors hard to control for. Nextflow is a flow management framework that uses container technology to insure efficient deployment and reproducibility of computational analysis pipelines. Third party pipelines can be ported into Nextflow with minimum re-coding. We used RNA-Seq quantification, genome annotation and phylogeny reconstruction examples to show how two seemingly irreproducible analyzes can be made stable across platforms when ported into Nextflow. PMID- 29412135 TI - [From sequence variability to structural and functional prediction: modeling of homologous protein families]. AB - Thanks to next-generation sequencing, the number of sequenced genomes grows rapidly, providing in particular ample examples for the sequence variability between homologous proteins. This article discusses data-driven probabilistic sequence models, which are able to extract a multitude of information from sequence data alone, including (i) structural features like residue-residue contacts, which are formed in the folded protein, (ii) protein-protein interaction interfaces and (iii) phenotypic effects of amino-acid substitutions in proteins. PMID- 29412136 TI - Micropattern differentiation of mouse pluripotent stem cells recapitulates embryo regionalized cell fate patterning. AB - During gastrulation epiblast cells exit pluripotency as they specify and spatially arrange the three germ layers of the embryo. Similarly, human pluripotent stem cells (PSCs) undergo spatially organized fate specification on micropatterned surfaces. Since in vivo validation is not possible for the human, we developed a mouse PSC micropattern system and, with direct comparisons to mouse embryos, reveal the robust specification of distinct regional identities. BMP, WNT, ACTIVIN and FGF directed mouse epiblast-like cells to undergo an epithelial-to-mesenchymal transition and radially pattern posterior mesoderm fates. Conversely, WNT, ACTIVIN and FGF patterned anterior identities, including definitive endoderm. By contrast, epiblast stem cells, a developmentally advanced state, only specified anterior identities, but without patterning. The mouse micropattern system offers a robust scalable method to generate regionalized cell types present in vivo, resolve how signals promote distinct identities and generate patterns, and compare mechanisms operating in vivo and in vitro and across species. PMID- 29412137 TI - Salient experiences are represented by unique transcriptional signatures in the mouse brain. AB - It is well established that inducible transcription is essential for the consolidation of salient experiences into long-term memory. However, whether inducible transcription relays information about the identity and affective attributes of the experience being encoded, has not been explored. To this end, we analyzed transcription induced by a variety of rewarding and aversive experiences, across multiple brain regions. Our results describe the existence of robust transcriptional signatures uniquely representing distinct experiences, enabling near-perfect decoding of recent experiences. Furthermore, experiences with shared attributes display commonalities in their transcriptional signatures, exemplified in the representation of valence, habituation and reinforcement. This study introduces the concept of a neural transcriptional code, which represents the encoding of experiences in the mouse brain. This code is comprised of distinct transcriptional signatures that correlate to attributes of the experiences that are being committed to long-term memory. PMID- 29412138 TI - Simultaneous two-photon imaging and two-photon optogenetics of cortical circuits in three dimensions. AB - The simultaneous imaging and manipulating of neural activity could enable the functional dissection of neural circuits. Here we have combined two-photon optogenetics with simultaneous volumetric two-photon calcium imaging to measure and manipulate neural activity in mouse neocortex in vivo in three-dimensions (3D) with cellular resolution. Using a hybrid holographic approach, we simultaneously photostimulate more than 80 neurons over 150 MUm in depth in layer 2/3 of the mouse visual cortex, while simultaneously imaging the activity of the surrounding neurons. We validate the usefulness of the method by photoactivating in 3D selected groups of interneurons, suppressing the response of nearby pyramidal neurons to visual stimuli in awake animals. Our all-optical approach could be used as a general platform to read and write neuronal activity. PMID- 29412139 TI - Role of the visual experience-dependent nascent proteome in neuronal plasticity. AB - Experience-dependent synaptic plasticity refines brain circuits during development. To identify novel protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we conducted a quantitative proteomic screen of the nascent proteome in response to visual experience in Xenopus optic tectum using bio-orthogonal metabolic labeling (BONCAT). We identified 83 differentially synthesized candidate plasticity proteins (CPPs). The CPPs form strongly interconnected networks and are annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs revealed the requirement for eukaryotic initiation factor three subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity in tectal neurons and behavioral plasticity in tadpoles. These results demonstrate that the nascent proteome is dynamic in response to visual experience and that de novo synthesis of machinery that regulates RNA splicing and protein translation is required for experience-dependent plasticity. PMID- 29412142 TI - Heterogeneous asymmetric recombinase polymerase amplification (haRPA) for rapid hygiene control of large-volume water samples. AB - Hygiene of drinking water is periodically controlled by cultivation and enumeration of indicator bacteria. Rapid and comprehensive measurements of emerging pathogens are of increasing interest to improve drinking water safety. In this study, the feasibility to detect bacteriophage PhiX174 as a potential indicator for virus contamination in large volumes of water is demonstrated. Three consecutive concentration methods (continuous ultrafiltration, monolithic adsorption filtration, and centrifugal ultrafiltration) were combined to concentrate phages stepwise from 1250 L drinking water into 1 mL. Heterogeneous asymmetric recombinase polymerase amplification (haRPA) is applied as rapid detection method. Field measurements were conducted to test the developed system for hygiene online monitoring under realistic conditions. We could show that this system allows the detection of artificial contaminations of bacteriophage PhiX174 in drinking water pipelines. PMID- 29412140 TI - Translational control of ERK signaling through miRNA/4EHP-directed silencing. AB - MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signaling cascade in mammalian cells. PMID- 29412141 TI - Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci. AB - Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis. PMID- 29412143 TI - Enriching behavioral ecology with reinforcement learning methods. AB - This article focuses on the division of labor between evolution and development in solving sequential, state-dependent decision problems. Currently, behavioral ecologists tend to use dynamic programming methods to study such problems. These methods are successful at predicting animal behavior in a variety of contexts. However, they depend on a distinct set of assumptions. Here, we argue that behavioral ecology will benefit from drawing more than it currently does on a complementary collection of tools, called reinforcement learning methods. These methods allow for the study of behavior in highly complex environments, which conventional dynamic programming methods do not feasibly address. In addition, reinforcement learning methods are well-suited to studying how biological mechanisms solve developmental and learning problems. For instance, we can use them to study simple rules that perform well in complex environments. Or to investigate under what conditions natural selection favors fixed, non-plastic traits (which do not vary across individuals), cue-driven-switch plasticity (innate instructions for adaptive behavioral development based on experience), or developmental selection (the incremental acquisition of adaptive behavior based on experience). If natural selection favors developmental selection, which includes learning from environmental feedback, we can also make predictions about the design of reward systems. Our paper is written in an accessible manner and for a broad audience, though we believe some novel insights can be drawn from our discussion. We hope our paper will help advance the emerging bridge connecting the fields of behavioral ecology and reinforcement learning. PMID- 29412144 TI - Early life stress determines the effects of glucocorticoids and stress on hippocampal function: Electrophysiological and behavioral evidence respectively. AB - Exposure to early-life adversity may program brain function to prepare individuals for adaptation to matching environmental contexts. In this study we tested this hypothesis in more detail by examining the effects of early-life stress - induced by raising offspring with limited nesting and bedding material from postnatal days 2-9 - in various behavioral tasks and on synaptic function in adult mice. Early-life stress impaired adult performance in the hippocampal dependent low-arousing object-in-context recognition memory task. This effect was absent when animals were exposed to a single stressor before training. Early-life stress did not alter high-arousing context and auditory fear conditioning. Early life stress-induced behavioral modifications were not associated with alterations in the dendritic architecture of hippocampal CA1 pyramidal neurons or principal neurons of the basolateral amygdala. However, early-life stress reduced the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and glutamate release probability specifically in hippocampal CA1 neurons, but not in the basolateral amygdala. These ex vivo effects in the hippocampus were abolished by acute glucocorticoid treatment. Our findings support that early-life stress can hamper object-in-context learning via pre- and postsynaptic mechanisms that affect hippocampal function but these effects are counteracted by acute stress or elevated glucocorticoid levels. PMID- 29412145 TI - Trends in diabetes prevalence among Korean adults based on Korean National Health and Nutrition Examination Surveys III-VI. AB - AIMS: The purpose of this study was to investigate trends in diabetic prevalence over the past 11 years using Korea National Health and Nutrition Examination Survey (KNHANES) data. In addition, we aimed to examine trends in diagnosed and undiagnosed diabetes after stratification. METHODS: We used data from the KNHANES III (2005), IV (2007-2009), V (2010-2012), and VI (2013-2015). 46,157 participants were included in this study. Diabetes was defined as follows: (1) an answer of 'yes' to whether the participants had ever been diagnosed with diabetes by a physician, (2) fasting plasma glucose (FPG) >=126 mg/dL, or (3) taking oral hypoglycemic agents or insulin. All sampling and weight variables were stratified, and analysis to account for the complex sampling design. The prevalence of diabetes was standardized by the 2005 Korean Housing Census. RESULTS: In men, the crude prevalence of total and undiagnosed diabetes were significantly increased with KNHANES phase (P for trend = 0.002 and 0.004, respectively). The age-standardized prevalence of total, diagnosed and undiagnosed diabetes of both sexes increased with the KNHANES phase (all P for trend < 0.001). Compared with the KNHANES III, the age-adjusted odds ratios (ORs) for the crude-prevalence of undiagnosed diabetes in KNHANES IV, V, and VI were 1.00 (0.72-1.41), 1.08 (0.78-1.51), and 1.42 (1.04-1.96) for men. CONCLUSIONS: The prevalence of total, diagnosed and undiagnosed diabetes steadily increased and public efforts should focus on screening for the detection of diabetes, especially in men. PMID- 29412146 TI - Predictive factors for birth weight of newborns of mothers with gestational diabetes mellitus. AB - AIMS: To evaluate the predictive factors of birth weight (BW) of newborns of women with gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was performed among pregnant women with GDM treated in a public maternity unit, Brazil. We selected 283 pregnant women, with nutritional follow-up initiated till the 28th gestational week, singleton pregnancy, without chronic diseases and with birth weight information of the newborns. The predictive factors of BW were identified by multivariate linear regression. RESULTS: Mean maternal age was 31.2 +/- 5.8 years; 64.4% were non-white; 70.1% were pre-gestational overweight or obese. Mean BW was 3234.3 +/- 478.8 g. An increase of 1 kg of weight in the first and third trimesters increased BW by 21 g (p = 0.01) and 27 g (p = 0.03), respectively. Similarly, the other predictive factors of BW were pre-gestational body mass index (beta = 17.16, p = 0.02) and postprandial plasma glucose in the third trimester (beta = 4.14, p = 0.008), in the model adjusted by gestational age at delivery (beta = 194.68, p < 0.001). CONCLUSIONS: The best predictors of BW were gestational age at birth, and maternal pre-gestational and gestational anthropometric characteristics. Maternal glycaemic levels may also influence BW. The results may contribute to a review of prenatal routines for pregnant women with GDM. PMID- 29412147 TI - Evaluation of chest compression artefact removal based on rhythm assessments made by clinicians. AB - AIM: To evaluate the performance of a state-of-the-art cardiopulmonary resuscitation (CPR) artefact suppression method by assessing to what extent the filtered electrocardiogram (ECG) can be correctly diagnosed by emergency medicine doctors. METHODS: A total of 819 ECG segments were used. Each segment contained two consecutive 10 s intervals, an artefact free interval and an interval corrupted by CPR artefacts. Each ECG segment was digitally processed to remove CPR artefacts using an adaptive filter. Each ECG segment was split into artefact free and filtered intervals, randomly reordered for dissociation, and independently offered to four reviewers for rhythm annotation. The rhythm annotations of the artefact-free intervals were considered as the gold standard against which the rhythm annotations of the filtered intervals were evaluated. For the filtered intervals, the rater agreement (kappa, Kappa score) with the gold standard, the sensitivity and the specificity were computed individually for each reviewer, and jointly through the majority decision of the pool of reviewers (DPR). These results were also compared to those obtained using a commercial shock advisory algorithm (SAA). RESULTS: The agreement between each reviewer and the gold standard was moderate ranging between kappa = 0.41-0.64. The sensitivities and specificities ranged between 64.3-95.0%, and 70.0-95.9%, respectively. The agreement for the DPR was substantial with kappa = 0.64 (0.62 0.66), a sensitivity of 90.6%, and a specificity of 85.6%. For the SAA, the agreement was fair with kappa = 0.33 (0.31-0.35), a sensitivity of 90.3%, and a specificity of 66.4%. CONCLUSION: Clinicians outperformed the SAA, but specificities remained below the specifications recommended by the American Heart Association. Visual assessment of the filtered ECG by clinicians is not reliable enough, and varies greatly among clinicians. Results considerably improve by considering the consensus decision of a pool of clinicians. PMID- 29412149 TI - Topical timolol for an iris hemangioma. AB - Extraocular infantile hemangiomas have been shown to respond to oral and topical beta blockers, while there is little literature regarding the management of intraocular infantile hemangiomas with beta blockers. This case report discusses the management of an iris hemangioma with topical timolol, a treatment previously unreported in the literature. PMID- 29412148 TI - Ginsenoside F1 suppresses astrocytic senescence-associated secretory phenotype. AB - Senescence is one of the hallmarks of aging and identified as a potential therapeutic target in the treatment of aging and aging-related diseases. Senescent cells accumulate with age in a variety of human tissues where they develop a complex senescence-associated secretory phenotype (SASP). SASP in brain could contribute to age-related inflammation and chronic neurodegenerative diseases. We confirmed that senescent astrocytes express a characteristic of SASP in vitro by human cytokine antibody array. Ginsenoside F1 suppresses the SASP from astrocytes induced by d-galactose via suppressing p38MAPK-dependent NF kappaB activity. A specific inhibitor of p38MAPK, SB203580 significantly decreased the secretion of IL-6 and IL-8, the major components of SASPs. Additionally, treatment of senescent astrocytes with NF-kappaB inhibitor, BAY 11 7092, also suppressed the secretion of IL-6 and IL-8, suggesting NF-kappaB was required for SASP. Importantly, conditioned media from senescent astrocytes promoted the migration of glioblastoma cells, such as U373-MG, U251-MG and U87-MG assessed by scratch wound healing. This migration was significantly decreased by F1 treatment in senescent astrocytes. Interestingly, IL-8, the main mediator regulating glioblastoma cell invasion, was suppressed in both transcriptional and protein level. Herein, we propose ginsenoside F1 as a potential therapeutic strategy for reducing the deleterious contribution of senescent astrocytes in aged brain and related diseases. PMID- 29412150 TI - Airsoft gun-related ocular injuries: long-term follow-up. AB - PURPOSE: To describe the long-term ocular effects of airsoft gun pellet injuries. METHODS: The present study extends by 7-10 years the results of a 2010 study on the acute ocular findings related to airsoft gun pellet injuries in 59 patients, wherein we found a variety of anterior and posterior segment injuries, including hyphema (66%), corneal edema (61%), corneal erosions (59%), and traumatic mydriasis (25%), as well as retinal edema in (22%), retinal hemorrhages and mild vitreous hemorrhage in (2.1%), and, in 1 patient, elevated intraocular pressure and traumatic cataract. RESULTS: Of the 59 patients in the original study, up-to date medical records were available for 26 (44%; 20 males). The mean follow-up time was 8 years (range, 7.2-10.3 years); the mean age, 17.1 years. Persistent abnormal findings included traumatic cataract in 3 cases (11.5%) and iris dialysis in 1 case (3.8%). In all traumatic cataract cases, cataract was not present at the time of initial examination after injury. Final mean best corrected visual acuity was 0.92 (range 0.67-1.0), logMAR 0.03 (range 0.18-0). CONCLUSIONS: While most acute airsoft gun-related ocular injuries are transient, some patients may develop significant and potentially sight-threatening ocular damage, even in the absence of significant pathologic findings at the time of the injury. Long-term follow-up on these patients is advisable. PMID- 29412151 TI - Physico-chemical properties of aqueous drug solutions: From the basic thermodynamics to the advanced experimental and simulation results. AB - The physical chemical properties of aqueous solutions of model compounds are illustrated in relation to hydration and solubility issues by using three perspectives: thermodynamic, spectroscopic and molecular dynamics simulations. The thermodynamic survey of the fundamental backgrounds of concentration dependence and experimental solubility results show some peculiar behavior of aqueous solutions with several types of similar solutes. Secondly, the use of a variety of experimental spectroscopic devices, operating under different experimental conditions of dimension and frequency, has produced a large amount of structural and dynamic data on aqueous solutions showing the richness of the information produced, depending on where and how the experiment is carried out. Finally, the use of molecular dynamics computational work is presented to highlight how the different types of solute functional groups and surface topologies organize adjacent water molecules differently. The highly valuable contribution of computer simulation studies in providing molecular explanations for experimental deductions, either of a thermodynamic or spectroscopic nature, is shown to have changed the current knowledge of many aqueous solution processes. While this paper is intended to provide a collective view on the latest literature results, still the presentation aims at a tutorial explanation of the potentials of the three methodologies in the field of aqueous solutions of pharmaceutical molecules. PMID- 29412152 TI - Development and validation of a novel diagnostic nomogram model based on tumor markers for assessing cancer risk of pulmonary lesions: A multicenter study in Chinese population. AB - PURPOSE: This study aimed to build a valid diagnostic nomogram for assessing the cancer risk of the pulmonary lesions identified by chest CT. PATIENTS AND METHODS: A total of 691 patients with pulmonary lesions were recruited from three centers in China. The cut-off value for each tumor marker was confirmed by minimum P value method with 1000 bootstrap replications. The nomogram was based on the predictive factors identified by univariate and multivariate analysis. The predictive performance of the nomogram was measured by concordance index and calibrated with 1000 bootstrap samples to decrease the overfit bias. We also evaluated the net benefit of the nomogram via decision curve analysis. Finally, the nomogram was validated externally using a separate cohort of 305 patients enrolled from two additional institutions. RESULTS: The cut-off for CEA, SCC, CYFRA21-1, pro-GRP, and HE4 was 4.8 ng/mL, 1.66 ng/mL, 1.83 ng/mL, 56.55 pg/mL, and 63.24Lpmol/L, respectively. Multivariate logistic regression model (LRM) identified tumor size, CEA, SCC, CYFRA21-1, pro-GRP, and HE4 as independent risk factors for lung cancer. The nomogram based on LRM coefficients showed concordance index of 0.901 (95% CI: 0.842-0.960; P < 0.001) for lung cancer in the training set and 0.713 (95% CI: 0.599-0.827; P < 0.001) in the validation set. Decision curve analysis reported a net benefit of 87.6% at 80% threshold probability superior to the baseline model. CONCLUSION: Our diagnostic nomogram provides a useful tool for assessing the cancer risk of pulmonary lesions identified in CT screening test. PMID- 29412153 TI - Increased expression of GGN promotes tumorigenesis in bladder cancer and is correlated with poor prognosis. AB - Bladder cancer has shown great challenge for people's life. Traditional therapeutics against bladder cancer including surgery could not bring much benefit for patients, particularly for the late stage patients. So it is necessary to keep in mind why and how bladder cancer cells survive in our body. In this study, we explored the function and the molecular mechanism of GGN gene in bladder cancer. GGN was shown to be expressed at a high level in bladder cancer tissues compared to the control and was associated with the unsatisfactory survival rate of patients. GGN was also expressed abundantly in bladder cancer cell lines such as T24, 5637 and BIU87. Then GGN was knocked down in 5637 cells and T24 cells at both RNA and protein level. In accordance, aberrant growth and proliferation were demonstrated in bladder cancer cells. The ability of migration and invasion of bladder cancer cells was also inhibited. The in vivo data further proved that the xenograft tumor growth was dramatically suppressed by GGN knockdown. Then we demonstrated that the level of IkappaB, bax and truncated caspase3 was upregulated after GGN was knocked down in 5637 cells. In contrast, expression level of NFkappaB, IKK, c-Myc, cyclin D1 and Bcl-2 was reduced. Further, the phosphorylation level of IkappaB was also downregulated. These data suggest that NFkappaB/caspase3-mediated apoptosis signaling was regulated by GGN. Conclusively, GGN played a tumor-promoting role in bladder cancer through regulation of NFkappaB/caspase3-mediated apoptosis signaling. This study provides a new clue for the treatment of patients with bladder cancer. PMID- 29412154 TI - Quantification of anisotropy and orientation in 3D electron microscopy and diffusion tensor imaging in injured rat brain. AB - Diffusion tensor imaging (DTI) reveals microstructural features of grey and white matter non-invasively. The contrast produced by DTI, however, is not fully understood and requires further validation. We used serial block-face scanning electron microscopy (SBEM) to acquire tissue metrics, i.e., anisotropy and orientation, using three-dimensional Fourier transform-based (3D-FT) analysis, to correlate with fractional anisotropy and orientation in DTI. SBEM produces high resolution 3D data at the mesoscopic scale with good contrast of cellular membranes. We analysed selected samples from cingulum, corpus callosum, and perilesional cortex of sham-operated and traumatic brain injury (TBI) rats. Principal orientations produced by DTI and 3D-FT in all samples were in good agreement. Anisotropy values showed similar patterns of change in corresponding DTI and 3D-FT parameters in sham-operated and TBI rats. While DTI and 3D-FT anisotropy values were similar in grey matter, 3D-FT anisotropy values were consistently lower than fractional anisotropy values from DTI in white matter. We also evaluated the effect of resolution in 3D-FT analysis. Despite small angular differences in grey matter samples, lower resolution datasets provided reliable results, allowing for analysis of larger fields of view. Overall, 3D SBEM allows for more sophisticated validation studies of diffusion imaging contrast from a tissue microstructural perspective. PMID- 29412155 TI - Development of novel tasks for studying view-invariant object recognition in rodents: Sensitivity to scopolamine. AB - The capacity to recognize objects from different view-points or angles, referred to as view-invariance, is an essential process that humans engage in daily. Currently, the ability to investigate the neurobiological underpinnings of this phenomenon is limited, as few ethologically valid view-invariant object recognition tasks exist for rodents. Here, we report two complementary, novel view-invariant object recognition tasks in which rodents physically interact with three-dimensional objects. Prior to experimentation, rats and mice were given extensive experience with a set of 'pre-exposure' objects. In a variant of the spontaneous object recognition task, novelty preference for pre-exposed or new objects was assessed at various angles of rotation (45 degrees , 90 degrees or 180 degrees ); unlike control rodents, for whom the objects were novel, rats and mice tested with pre-exposed objects did not discriminate between rotated and un rotated objects in the choice phase, indicating substantial view-invariant object recognition. Secondly, using automated operant touchscreen chambers, rats were tested on pre-exposed or novel objects in a pairwise discrimination task, where the rewarded stimulus (S+) was rotated (180 degrees ) once rats had reached acquisition criterion; rats tested with pre-exposed objects re-acquired the pairwise discrimination following S+ rotation more effectively than those tested with new objects. Systemic scopolamine impaired performance on both tasks, suggesting involvement of acetylcholine at muscarinic receptors in view-invariant object processing. These tasks present novel means of studying the behavioral and neural bases of view-invariant object recognition in rodents. PMID- 29412156 TI - Tanshinone modulates the expression of Bcl-2 and Bax in cardiomyocytes and has a protective effect in a rat model of myocardial ischemia-reperfusion. AB - OBJECTIVE: To investigate the protective activity of tanshinone in a rat model of myocardial ischemia-reperfusion and determine its effect on the expression of Bcl 2 and Bax in cardiomyocytes. METHODS: We established a rat model of myocardial ischemia-reperfusion. Rats were randomly divided into blank (no surgery); saline; and low-dose (2 mg/ml), medium-dose (15 mg/ml), and high-dose (50 mg/ml) tanshinone groups. We measured heart rate and troponin (cTnI) levels, performed TUNEL to detect cardiomyocyte apoptosis, and detected LDH and CK-MB activities in serum by ELISA. We performed RT-qPCR and western blot to detect the expression of Bcl-2 and Bax mRNA and protein in cardiomyocytes. RESULTS: Rats treated with tanshinone experienced more stable heart rate after ischemia-reperfusion compared with those in the saline control group. cTnI decreased after ischemia-reperfusion in mice injected with tanshinone, while cTnI in saline-treated mice increased significantly compared with that in the blank control group. TUNEL staining showed that there were greater apoptotic cardiomyocytes in the saline group, but the tanshinone groups showed fewer apoptotic cardiomyocytes. LDH and CK-MB activities were significantly increased after reperfusion in the saline group (p<0.01) and also in the low- and medium-dose tanshinone groups (p<0.05). However, no significant differences were found in the high-dose tanshinone group (p>0.05). The expression levels of Bcl-2 mRNA and protein in cardiomyocytes of rats were higher in the three tanshinone groups in a dose-sensitive manner than those in the blank and saline groups (p<0.05). By contrast, the expression levels of Bax mRNA and protein were reduced in the three tanshinone groups in a dose sensitive manner compared to those in the blank and saline groups (p<0.05). CONCLUSION: Tanshinone shows a protective effect in a dose-dependent manner in a rat model of myocardial ischemia-reperfusion, suggesting its potential therapeutic use. PMID- 29412157 TI - Two sample comparisons including zero-inflated continuous data: A parametric approach with applications to microarray experiment. AB - Micro-array experiments are important fields in molecular biology where zero values mixed with a continuous outcome are frequently encountered leading to a mixed distribution with a clump at zero. Comparison of two mixed populations, e.g. of a control and a treated group; of two groups with different types of cancer, to name a few, are often encountered in these contexts. Fairly skewed distribution of the continuous part coupled with small sample sizes are issues of main concern to be attended for the quality of inference in such situations while popularly used nonparametric methods rely on asymptotic distribution of the underlying test statistics which are valid only under large sample sizes. We address the aforementioned issues via a newly proposed exact test for location scale family distributions and Generalized pivot quantity (GPQ) based parametric test procedures for non-location-scale distributions. Simulation based assessment showed their superior performance with respect to size and power in comparison to the popular two-part tests (Wilcoxon rank sum, t-test, Kolmogrov-Smirnov, Ansari Bradley and Sigel-Tukey) more prominently for small sample sizes. PMID- 29412158 TI - Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD. PMID- 29412159 TI - Molecular characteristics of the spike gene of porcine epidemic diarrhoea virus strains in Eastern China in 2016. AB - The outbreak of piglet diarrhoea caused by porcine epidemic diarrhoea virus (PEDV) began to spread in Southern China in late 2010 and resulted in significant economic losses throughout the country. To determine the prevalence and the molecular characteristics of common PEDV strains in China, 1272 faeces and small intestine samples in pigs were collected from 17 provinces and inspected for PEDV; the full-length spike (S) gene of 18 detected PEDV strains collected from five eastern provinces were sequenced and analysed. The epidemiological data revealed that the PEDV-positive rate in diarrhoea specimens was 28.93%. Phylogenetic analysis of the S genes showed that the CH-JSYC-1-2016 strain was clustered into a G2-a subgroup (US and Asian non-S-INDEL), and other seventeen virus strains was clustered into a new subgroup G2-b (Chinese non-S-INDEL). The G2-b subgroup only contained Chinese PEDV strains that were isolated after 2014. Compared with the CV777 vaccine strain, Eastern China PEDVs were genetically distinct and had various amino acid differences in the neutralizing epitope domain of the S protein, as well as different patterns of predicted high specificity N-glycosylation sites. The prevalence of Chinese non-S-INDEL strains may be responsible for the immunization failure by using currently available commercial vaccines (based on attenuated CV777 strain), and the development of novel vaccines based on these newly identified PEDV variants may contribute to the control of PED outbreaks in China. PMID- 29412161 TI - Comparative experimental study of Brucella melitensis and its lipopolysaccharide in mouse model infected via subcutaneous route of exposure. AB - Brucella melitensis is a major zoonotic pathogen in which lipopolysaccharide (LPS) is believed to play a major role in the diseases pathogenesis. To study the immunopathophysiological aspects, we established a mouse model experimentally infected with whole cell of B. melitensis and its lipopolysaccharide via subcutaneous route of exposure. Eighty four mice, BALB/c, both sexes with equal gender distribution and 6-8 weeks-old were randomly assigned into 3 groups. Group 1 (n = 36) were subcutaneoulsy inoculated with 0.4 mL 109 of B. melitensis while group 2 (n = 36) were subcutaneously challenged with 0.4 mL 109 of LPS. Group 3 (n = 12) was challenged subcuatneously with phosphate buffered saline and served as a control group. Animals were observed for clinical signs, haematological and histopathological analysis for a period of 24 days post-inoculation. Our results revealed that B. melitensis infected group demonstrated significant clinical signs and histopathological evidence than LPS infected group. However, both infected groups showed elevated levels of interleukins (IL-1beta & IL6), antibody levels (IgM & IgG) as early as 3 days post-infection with predominance in LPS infected group. For hormone analysis, low levels of progesterone, estradiol and testosterone were observed in both B. melitensis and LPS challenged groups throughout the study period. Moreover, in B. melitensis infected groups, the organism was re-isolated from the organs and tissues of gastrointestinal, respiratory and reproductive systems; thereby confirming the possible transmission of the disease dynamics. Moreover, LPS stimulated significantly the innate and acquired immune system without significant systemic dysfunction suggesting the potentiality of the protective properties of this component as an alternative vaccine for brucellosis infection. This report is the first detailed investigation comparing the infection progression and host responses in relation to the immunopathophysiological aspects in mouse model after subcutaneous inoculation with B. melitensis and its lipopolysaccharide. PMID- 29412160 TI - Visfatin regulates the production of lipopolysaccharide-induced inflammatory cytokines through p38 signaling in murine macrophages. AB - Visfatin plays an important role in regulation of inflammatory cytokines. However, the role of visfatin under bacterial stress condition is not fully explored yet. Therefore, the present study was conducted for the better understanding of the regulation mechanism of visfatin on the production of inflammatory cytokines under lipopolysaccharide (LPS) stress in RAW264.7 murine macrophages. Enzyme Linked Immuno-sorbent Assay (ELISA) results showed that, as compared to the control group, visfatin significantly up-regulated the levels of interleukin (IL)-1beta, IL-6, IL-10, tumor necrosis factor (TNF)-alpha (P < 0.05). Compared to the LPS group, the levels of IL-1beta, IL-10, TNF-alpha was down-regulated in visfatin + LPS group (P < 0.05). After adding p38 inhibitor, SB203580 to culture, the production of IL-1beta, IL-6, IL-10, TNF-alpha was significantly reduced as compared to visfatin only (P < 0.01). The results showed that visfatin may regulate the production of IL-1beta, IL-6, IL-10, TNF-alpha through the p38 signaling pathway. As compared to the PBS group, phosphorylayed p38 (P-p38) level in visfatin group was significantly decreased (P < 0.05). Compared with LPS group, P-p38 level was significantly decreased in visfatin + LPS group (P < 0.05). Hence, it is concluded that visfatin can significantly increase the levels of IL-1beta, IL-10 and TNF-alpha in normal conditions, while their levels significantly decrease during inflammation. Moreover, visfatin participates in the inflammatory response through the p38 mitogen-activated protein kinase (MAPK) signal pathway by the up-regulation of p38 and down regulation of P-p38 levels. PMID- 29412162 TI - Diagnostic performance of different perfusion algorithms for the detection of angiographical spasm. AB - PURPOSE: To assess the diagnostic utility of different perfusion algorithms for the detection of angiographical terial spasm. METHOD: During a 2-year period, 45 datasets from 29 patients (54.2+/-10,75y, 20F) with suspected cerebral vasospasm after aneurysmal subarachnoid hemorrhage were included. Volume Perfusion CT (VPCT), Non-enhanced CT (NCT) and angiography were performed within 6hours post ictus. Perfusion maps were generated using a maximum slope (MS) and a deconvolution-based approach (DC). Two blinded neuroradiologists independently evaluated MS and DC maps regarding vasospasm-related perfusion impairment on a 3 point Likert-scale (0=no impairment, 1=impairment affecting <50%, 2=impairment affecting >50% of vascular territory). A third independent neuroradiologist assessed angiography for presence and severity of arterial narrowing on a 3-point Likert scale (0=no narrowing, 1=narrowing affecting <50%, 2=narrowing affecting>50% of artery diameter). MS and DC perfusion maps were evaluated regarding diagnostic accuracy for angiographical arterial spasm with angiography as reference standard. Correlation analysis of angiography findings with both MS and DC perfusion maps was additionally performed. Furthermor, the agreement between MS and DC and inter-reader agreement was assessed. RESULTS: DC maps yielded significantly higher diagnostic accuracy than MS perfusion maps (DC:AUC=.870; MS:AUC=.805; P=0.007) with higher sensitivity for DC compared to MS (DC:sensitivity=.758; MS:sensitivity=.625). DC maps revealed stronger correlation with angiography than MS (DC: R=.788; MS: R=694;=<0.001). MS and DC showed substantial agreement (Kappa=.626). Regarding inter-reader analysis, (almost) perfect inter-reader agreement was observed for both MS and DC maps (Kappa>=981). CONCLUSION: DC yields significantly higher diagnostic accuracy for the detection of angiographic arterial spasm and higher correlation with angiographic findings compared to MS. PMID- 29412163 TI - The protective effect of nicorandil on cardiomyocyte apoptosis after coronary microembolization by activating Nrf2/HO-1 signaling pathway in rats. AB - BACKGROUND: Myocardial apoptosis is considered to be the chief cause of progressive cardiac dysfunction induced by coronary microembolization (CME), and the Nrf2/HO-1 signaling pathway is involved in CME-induced myocardial apoptosis. Nicorandil (NIC) has multiple beneficial cardiovascular effects on myocardial injury. Therefore, this study was undertaken to analyze the role of NIC pretreatment in the inhibiting myocardial apoptosis after CME in rats. METHODS: Forty rats were divided into Sham group, CME group, CME plus NIC (NIC) group, and CME plus AAV9-Nrf2 (AAV9-Nrf2) group (n = 10 per group). CME-induced myocardial apoptosis model was established through injecting plastic microspheres (42 MUM) into the left ventricle except the Sham group. NIC group received nicorandil 3 mg/(kg.d) for 7 days before the operation. Cardiac function was assessed by echocardiography. The mRNA expression level of Nrf2 was detected by RT-PCR. The protein expression levels of Nrf2, HO-1, Bcl-2, Bax and cleaved caspase-3 were detected by Western blot. The size of the microinfarction area was measured by HBFP staining; myocardial apoptosis was analyzed by TUNEL staining. RESULTS: Compared with the sham group, the cardiac function and the expression level of Nrf2, HO-1 and Bcl-2were decreased, while myocardial apoptosis and the expression of Bax and cleaved caspase-3 were increased in the CME group. Compared with the CME group, cardiac function was significantly improved, the expression levels of Nrf2, HO-1, and Bcl-2 were increased, the expression of Bax and cleaved caspase-3 were decreased, and the myocardial apoptosis was attenuated in the NIC group and AAV9-Nrf2 group. CONCLUSION: NIC pretreatment effectively inhibit CME-induced myocardial apoptosis and improve cardiac function. The protective effects are mediated through the activation of the Nrf2/HO-1 signaling in cardiomyocytes. PMID- 29412164 TI - SGK1 inhibits PM2.5-induced apoptosis and oxidative stress in human lung alveolar epithelial A549 cells. AB - Emerging evidence demonstrated that particulate matter 2.5 (PM2.5) is an important environmental risk factor for lung diseases. Serum- and glucocorticoid inducible kinase 1(SGK1) was reported to be a crucial factor for cell survival. However, the role of SGK1 in PM2.5-induced cell injury is still unclear. In this work, we firstly found that the expression of SGK1 was decreased in PM2.5-treated human lung alveolar epithelial (A549) cells by western blot. In addition, overexpression of SGK1 significantly attenuated A549 cell apoptosis and reduced the reactive oxygen species (ROS) generation induced by PM2.5. Moreover, we found that PM2.5 exposure significantly promoted the ERK1/2 activation and inhibited the AKT activation, whereas overexpression of SGK1 could reverse that. Finally, the results of the rescue experiment showed that MK2206 (AKT inhibitor) could rescue the impact of SGK1 on A549 cell apoptosis, while PD98059 (ERK1/2 inhibitor) could not further aggravate the impact. Taken together, our results suggest that SGK1 inhibits PM2.5-induced cell apoptosis and ROS generation via ERK1/2 and AKT signaling pathway in human lung alveolar epithelial A549 cells. PMID- 29412165 TI - SED-SEEP Consensus document on the use of continuous glucose monitoring in Spain. PMID- 29412166 TI - Efflux inhibition by IWR-1-endo confers sensitivity to doxorubicin effects in osteosarcoma cells. AB - Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnks1/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin. We found that IWR-1-endo significantly inhibited cellular efflux, as measured by cellular retention of Calcein AM and doxorubicin. In a model of doxorubicin resistant osteosarcoma, pre-treatment with IWR-1-endo strongly sensitized to doxorubicin. This sensitization reduced the doxorubicin IC50 in doxorubicin-resistant cells, but not in chemotherapy naive cells and caused doxorubicin-treated cells to accumulate at the G2/M checkpoint. Further, we found that sensitization with IWR-1-endo produced increased gammaH2AX foci formation, indicating increased DNA damage by doxorubicin. Taken together, our findings show that IWR-1-endo increases cellular responses to doxorubicin, by blocking efflux transport in a drug-resistant model of osteosarcoma. PMID- 29412167 TI - Effectiveness of Client-Centered "Tune-Ups" on Community Reintegration, Mobility, and Quality of Life After Stroke: A Randomized Controlled Trial. AB - OBJECTIVE: To explore the effectiveness of a 2-week client-centered rehabilitation intervention (tune-up) delivered 6 months after inpatient discharge on community reintegration at 1 year in people with stroke. DESIGN: A multicenter randomized controlled trial with 2 groups: an intervention ("tune up") group and a control group having the same exposure to assessment. SETTING: Three research laboratories. PARTICIPANTS: Participants (N=103) with hemiparetic stroke recruited from inpatient rehabilitation units at the time of discharge. INTERVENTIONS: Participants randomized to the tune-up group received 1-hour therapy sessions in their home 3times/wk for 2 weeks at 6 months postdischarge focusing on identified mobility-related goals. A second tune-up was provided at 12 months. MAIN OUTCOME MEASURES: Community reintegration measured by the Subjective Index of Physical and Social Outcome at 12 months and secondary outcomes included the Berg Balance Scale and measures of mobility and health related quality of life up to 15 months. RESULTS: At 12 months, both groups showed significant improvement in community reintegration (P<.05), a trend evident at all time points, with no difference between groups (mean difference, 0.5; 95% confidence interval, -1.8 to 2.7; P=.68). Similarly, a main effect of time reflected improvement in mobility-related and quality of life outcomes for both groups (P<=.0.5), but no group differences (P>=.30). CONCLUSIONS: All participants in the tune-up group met or exceeded at least 1 mobility-related goal; however, the intervention did not differentially improve community reintegration. The improvements in mobility and quality of life over the 15-month postdischarge period may be secondary to high activity levels in both study groups and exposure to regular assessment. PMID- 29412168 TI - On the Reporting of Experimental and Control Therapies in Stroke Rehabilitation Trials: A Systematic Review. AB - OBJECTIVE: To use the Centralized Open-Access Rehabilitation database for Stroke to explore reporting of both experimental and control interventions in randomized controlled trials for stroke rehabilitation (including upper and lower extremity therapies). DATA SOURCES: The Centralized Open-Access Rehabilitation database for Stroke was created from a search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Cumulative Index of Nursing and Allied Health from the earliest available date to May 31, 2014. STUDY SELECTION: A total of 2892 titles were reduced to 514 that were screened by full text. This screening left 215 randomized controlled trials in the database (489 independent groups representing 12,847 patients). DATA EXTRACTION: Using a mixture of qualitative and quantitative methods, we performed a text-based analysis of how the procedures of experimental and control therapies were described. Experimental and control groups were rated by 2 independent coders according to the Template for Intervention Description and Replication criteria. DATA SYNTHESIS: Linear mixed-effects regression with a random effect of study (groups nested within studies) showed that experimental groups had statistically more words in their procedures (mean, 271.8 words) than did control groups (mean, 154.8 words) (P<.001). Experimental groups had statistically more references in their procedures (mean, 1.60 references) than did control groups (mean, .82 references) (P<.001). Experimental groups also scored significantly higher on the total Template for Intervention Description and Replication checklist (mean score, 7.43 points) than did control groups (mean score, 5.23 points) (P<.001). CONCLUSIONS: Control treatments in stroke motor rehabilitation trials are underdescribed relative to experimental treatments. These poor descriptions are especially problematic for "conventional" therapy control groups. Poor reporting is a threat to the internal validity and generalizability of clinical trial results. We recommend authors use preregistered protocols and established reporting criteria to improve transparency. PMID- 29412169 TI - Fever of unknown origin due to Legionnaires' disease: A diagnostic challenge. PMID- 29412170 TI - Propranolol disrupts consolidation of emotional memory in Lymnaea. AB - The therapeutic efficacy of the synthetic beta-adrenergic receptor blocker, propranolol, for the treatment of post-traumatic stress disorder (PTSD) is currently being debated. Mixed results have been published regarding propranolol's ability to disrupt the consolidation and reconsolidation of memories. Here, we use the invertebrate model Lymnaea to study propranolol's ability to disrupt consolidation of memories formed under varying various types of stress which cause differing degrees of emotional memory. We show that when propranolol is administered immediately following operant conditioning, only the consolidation process of memories enhanced by individual stressors (i.e. a non emotional memory) is susceptible to disruption. However, when propranolol is administered prior to training, only memories enhanced by a combination of stressors leading to an emotional memory are susceptible to disruption. These data suggest that the time of propranolol administration, as well as the type of memory formed play a key role in propranolol's ability to obstruct memory consolidation. PMID- 29412171 TI - Roles of short fibulins, a family of matricellular proteins, in lung matrix assembly and disease. AB - Cyclical inflation of the lungs depends on the elasticity of lung parenchymal tissues, a mechanical property that is largely determined by elastic fibers and collagen fibers contained therein. Breakdown of elastic fibers in lungs and lack of the ability to repair damaged elastic fibers causes emphysema, and excessive collagen fibrillogenesis in lung parenchyma is critical for the pathogenesis of lung fibrosis. Recent studies revealed that fibulin-3, 4, and 5, which are matricellular proteins collectively termed "short fibulins" or "elastic fibulins", play crucial roles in the assembly of elastic fibers. Although these fibulins are closely related paralogs with very similar domain structures and sequences, they have independent molecular functions in elastogenesis, as evidenced by different phenotypes in their gene-knockout mice and in patients with mutations in these genes. More recently, emerging evidence suggests that fibulin-4 is also necessary for fibrillar collagen assembly. In this review, I focus on the roles of short fibulins and their associating molecules in the assembly of elastic fibers and collagen fibers. Human diseases caused by mutations in the genes for these molecules are also reviewed. These matricellular proteins could be novel therapeutic targets for emphysema and lung fibrosis. PMID- 29412172 TI - In vitro pharmacology of ambroxol: Potential serotonergic sites of action. AB - AIMS: Ambroxol is a muco-active agent with multiple, clinically relevant effects in the airway. Despite its widespread use and well documented clinical efficacy, there are few data on its mechanism of action and receptor pharmacology beyond sodium channel blockade and inhibition of guanylate cyclase. Accordingly, in vitro studies were conducted to determine its overall receptor pharmacology and possible sites of action. MATERIALS AND METHODS: In vitro radioligand binding/enzyme inhibition studies were conducted at 62 receptors, ion channels and enzymes using standard techniques. Additional in vitro studies were conducted to establish the potency of ambroxol at selected sites. KEY FINDINGS: These studies indicate that ambroxol has affinity for the 5-HT3 serotonin receptor, as well as affinity for the 5-HT serotonin transporter (SERT), with IC50 values of 17,600 nM and 19,500 nM respectively. In vitro functional studies in isolated guinea pig colon indicate that ambroxol is a 5-HT3 serotonin receptor antagonist with an IC50 value of 36,000 nM. SIGNIFICANCE: Together, these studies indicate that ambroxol may exert its beneficial properties via antagonism of the 5-HT3 serotonin receptor and/or inhibition of serotonin uptake (5-HT transport: SERT), in addition to its reported effects at the sodium channel and guanylate cyclase. PMID- 29412173 TI - Three lysophosphatidic acids with a distinct long chain moiety differently affect cell differentiation of human colon epithelial cells to goblet cells. AB - AIM: The intestinal mucus layer helps maintain intestinal homeostasis. In this study, we investigated the effects of lysophosphatidic acids (LPA) on differentiation of human colon carcinoma cell line, HT-29, to goblet cells with and without sodium butyrate, a known differentiation factor for intestinal cells. MAIN METHODS: Number and average size of cells with goblet-like morphology in five photographs per dish were measured for assessment of differentiation of HT 29 cells to goblet cells as well as their relative portion of surface of to whole surface area of the photograph. KEY FINDINGS: Our results revealed that 18:1 LPA enhanced butyrate-induced differentiation of HT-29 cells. Because increased mRNA expression of LPA5 and decreased mRNA expression of LPA6 were observed in HT-29 cells after treatment with butyrate, we explored the effects of alkyl LPA and 20:4 LPA, which show preferentially higher affinities to LPA5 and LPA6, respectively. As a result, the cell differentiation to goblet cell was increased by alkyl LPA but decreased by 20:4 LPA. Further, alkyl LPA and 18:1 LPA, but not 20:4 LPA, were found to reduce the numbers of cells surviving after incubation in a standard culture medium containing 10% fetal calf serum. SIGNIFICANCE: We suggest that the three LPAs positively and negatively affect the differentiation of HT-29 cells to goblet cells, which may be associated with their reduced survival through the activation of distinct LPA receptor(s). PMID- 29412174 TI - Whole-genome sequencing enabling the detection of a colistin-resistant hypermutating Citrobacter werkmanii strain harbouring a novel metallo-beta lactamase VIM-48. AB - Citrobacter spp. harbouring metallo-beta-lactamases (MBLs) have been reported from various countries and different sources, but their isolation from clinical specimens remains a rare event in Europe. MBL-harbouring Enterobacteriaceae are considered a major threat in infection control as therapeutic options are often limited to colistin. In this study, whole-genome sequencing was applied to characterise five clinical isolates of multidrug-resistant Citrobacter werkmanii obtained from rectal swabs. Four strains possessed a class 1 integron with a novel blaVIM-48 MBL resistance gene and the aminoglycoside acetyltransferase gene aacA4, whilst one isolate harboured a blaIMP-8 MBL. Resistance to colistin evolved in one strain isolated from a patient who had received colistin orally for 8 days. Genomic comparison of this strain with a colistin-susceptible pre treatment isolate from the same patient revealed 66 single nucleotide polymorphisms (SNPs) and 26 indels, indicating the presence of a mutator phenotype. This was confirmed by the finding of a SNP in the mutL gene that led to a significantly truncated protein. Additionally, an amino acid change from glycine to serine at position 53 was observed in PmrA. Mutations in the pmrA gene have been previously described as mediating colistin resistance in different bacterial species and are the most likely reason for the susceptibility change observed. To the best of our knowledge, this is the first description of a colistin-resistant Citrobacter spp. isolated from a human sample. This study demonstrates the power of applying next-generation sequencing in a hospital setting to trace and understand evolving resistance at the level of individual patients. PMID- 29412176 TI - Functional characterization of Helicoverpa armigera trehalase and investigation of physiological effects caused due to its inhibition by Validamycin A formulation. AB - Trehalase catalyzes hydrolysis of trehalose and plays a crucial role in insect metabolism. In the present study, phylogenetic analysis and multiple sequence alignment suggested that H. armigera trehalase-1 (HaTre-1) is closely related to other soluble trehalases with conserved signature features and functional sites. We have expressed and purified recombinant HaTre-1 having Vmax ~0.16mM/min and KM ~1.34mM. Inhibition kinetics and Microscale thermophoresis illustrated competitive inhibition of HaTre-1 by Validamycin A having Ki ~3nM and KD ~542nM, respectively. Docking studies of HaTre-1 with Validamycin A indicated that it binds at the active site with multiple hydrogen bonds. Ingestion of Validamycin A resulted in impediment of H. armigera growth and developmental defects. Treated larvae showed concentration dependent decrease in fecundity. It also led to total inhibition of ex-vivo trehalase activity and down-regulation of gene expression of HaTre-1. Relatively high insect mortality was observed on tomato plants sprayed with combination of Validamycin A with Azadirachta indica (neem) and Pongamia pinnata (karanj) oil as compared to the individual treatments. This report has re-emphasized trehalase inhibition as a potential insecticidal strategy and also recommends Validamycin A as a prospective value-added ingredient to commercial bio-pesticide formulations. PMID- 29412177 TI - Medulloblastoma with myogenic and/or melanotic differentiation does not align immunohistochemically with the genetically defined molecular subgroups. AB - The World Health Organization classification of central nervous system neoplasms (2016 update) recognizes 4 histological variants and genetically defined molecular subgroups within medulloblastoma (MB). MB with myogenic differentiation is one of the rare variants, which is usually recognized as a pattern alongside the known histological variants. Because of its rarity, less is known about its molecular landscape and importantly about its placement in the current molecular schema. We aimed to analyze this rare variant for expression of 3 immunohistochemical markers conventionally used in molecular stratification of MB. Demographic profile and imaging details with survival outcome were also analyzed. Sixty-five MB cases were molecularly stratified using immunohistochemical markers (YAP1, GAB1, beta-catenin). MB with myogenic differentiation and MB cases showing variable immunoreactivity with the above 3 antibodies were further evaluated for smooth muscle actin, desmin, myogenin, and HMB45. Seven cases were categorized as MB with myogenic and/or melanotic differentiation. Age ranged from 2 to 40 years with a male-to-female ratio of 1:1.3. In 4 cases, myogenic or melanotic differentiation was evident on histology, whereas in 3, differentiation was highlighted only with muscle markers. Interestingly, all 7 cases showed variable immunoreactivity with 3 molecular markers and did not follow the conventionally accepted algorithm used for molecular stratification. Follow-up period ranged from 9 to 57 months. Overall survival revealed a varied pattern, with 3 deaths and 4 patients being alive with no evidence of disease at last follow-up. Our results provide evidence that these variants are distinct and do not align immunohistochemically with the currently recognized genetic subgroups. PMID- 29412175 TI - Optimization of the microwave-assisted enzymatic extraction of Rosa roxburghii Tratt. polysaccharides using response surface methodology and its antioxidant and alpha-d-glucosidase inhibitory activity. AB - An extraction assay applying microwave-assisted enzymatic treatment for polysaccharides in Rosa roxburghii was developed using response surface methodology. The process parameters were optimized using Plackett-Burman (PB) design and central composite design to enhance the Rosa roxburghii polysaccharide extraction yield. Specific conditions (microwave power, 575W; microwave time, 18min; liquid-to-material ratio, 13.5:1mL/g; and enzyme dose, 6.5g/mL) generated an experimental yield of 36.21+/-0.62%, which closely agreed with the predicted value of 35.75%. Purification with a DEAE-52 cellulose column generated two fractions, PR-1 (from 6.2*103 to 7.4KDa) and PR-2 (from 559.8 to 106.6KDa). Subsequently, the antioxidant activity and alpha-d-glucosidase inhibitory activity of the two polysaccharide fractions were assessed; PR-1 exhibited stronger antioxidant activity and alpha-d-glucosidase inhibitory activity than PR 2. Finally, the monosaccharide composition of PR-1 was determined by HPLC using a 1-phenyl-3-methyl-5-pyrazolone precolumn derivatization method. The result showed that PR-1 contained mannose, ribose, rhamnose, glucosamine hydrochloride, glucuronic acid, galacturonic acid, glucose, galactose, arabinose and fucose with molar percentages of 2.1%, 0.54%, 2.1%, 0.26%, 1.5%, 22.7%, 24.0%, 26.4%, 19.6% and 0.89%, respectively. PMID- 29412178 TI - Cysteinyl leukotriene receptor 1 regulates glucose-stimulated insulin secretion (GSIS). AB - Insulin resistance is an important pathological hallmark of type 2 diabetes mellitus. Glucose-stimulated insulin secretion (GSIS) plays a key role in maintaining blood glucose levels within normal range. Impaired GSIS has been associated with type 2 diabetes, however, the underlying molecular mechanisms remain largely unknown. Cysteinyl leukotriene receptor 1 (cysLT1R) is an important G protein-coupled receptor mediating the biological functions of cysteinyl leukotrienes (cys-LTs). Little is known about the effects of cysLT1R in insulin secretion and pathogenesis of T2DM. In the present study, we aimed to define the physiological functions of cysLT1R in GSIS in MIN6 beta-cells. Using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, we found that cysLT1R was expressed in pancreatic MIN6 beta-cells. We also reported that glucose increased the expression of cysLT1R in MIN6 cells. Additionally, the cysLT1R antagonist montelukast promoted GSIS in a dose dependent manner, however, the cysLT1R agonist LD4 inhibited GSIS, suggesting an antagonistic effect of cysLT1R on GSIS. Silencing of cysLT1R by transfection with cysLT1R siRNA enhanced GSIS while overexpression of cysLT1R reduced GSIS in pancreatic MIN6 beta-cells. Mechanistically, we found that the Arf6/Cdc42/Rac1 pathway was involved in this process. Collectively, our findings highlight the essential role of cysLT1R in suppressing pancreatic insulin secretion, and potentially provided a new insight into understanding the mechanical regulation of glucose homeostasis. PMID- 29412179 TI - High-frequency spectral ultrasound imaging (SUSI) visualizes early post-traumatic heterotopic ossification (HO) in a mouse model. AB - PURPOSE: Early treatment of heterotopic ossification (HO) is currently limited by delayed diagnosis due to limited visualization at early time points. In this study, we validate the use of spectral ultrasound imaging (SUSI) in an animal model to detect HO as early as one week after burn tenotomy. METHODS: Concurrent SUSI, micro CT, and histology at 1, 2, 4, and 9weeks post-injury were used to follow the progression of HO after an Achilles tenotomy and 30% total body surface area burn (n=3-5 limbs per time point). To compare the use of SUSI in different types of injury models, mice (n=5 per group) underwent either burn/tenotomy or skin incision injury and were imaged using a 55MHz probe on VisualSonics VEVO 770 system at one week post injury to evaluate the ability of SUSI to distinguish between edema and HO. Average acoustic concentration (AAC) and average scatterer diameter (ASD) were calculated for each ultrasound image frame. Micro CT was used to calculate the total volume of HO. Histology was used to confirm bone formation. RESULTS: Using SUSI, HO was visualized as early as 1week after injury. HO was visualized earliest by 4weeks after injury by micro CT. The average acoustic concentration of HO was 33% more than that of the control limb (n=5). Spectroscopic foci of HO present at 1week that persisted throughout all time points correlated with the HO present at 9weeks on micro CT imaging. CONCLUSION: SUSI visualizes HO as early as one week after injury in an animal model. SUSI represents a new imaging modality with promise for early diagnosis of HO. PMID- 29412181 TI - Clinical application of Bruker Biotyper MALDI-TOF/MS system for real-time identification of KPC production in Klebsiella pneumoniae clinical isolates. PMID- 29412180 TI - As You Eat It: Effects of Prenatal Nutrition on Asthma. AB - Asthma most frequently develops early in life, and increased recognition of the role of lifestyle and environmental factors in asthma susceptibility raises the possibility that dietary exposures during pregnancy may influence the risk of asthma in offspring. This review discusses the latest evidence with regard to the effect of diet during pregnancy on childhood asthma risk, including potential mechanisms, outcomes of randomized clinical trials, and results from observational studies. Vitamin D and polyunsaturated fatty acid intake during pregnancy are highlighted as areas with large and growing bodies of literature to support a potential role in prenatal modulation of subsequent asthma risk. Several other nutritional interventions are under active investigation, and recommendations regarding dietary modifications during pregnancy will likely need to be personalized based on factors such as maternal smoking and genetic variants. Although nutrition during pregnancy is uniquely challenging to investigate, and definitive recommendations cannot be made without additional high-quality evidence and knowledge regarding long-term effects of interventions, the modifiable nature of the diet and sizeable potential reduction of morbidity supports ongoing research to determine how to optimize nutrition during pregnancy to prevent asthma in offspring. PMID- 29412182 TI - Draft genome sequence of a CTX-M-8, CTX-M-55 and FosA3 co-producing Escherichia coli ST117/B2 isolated from an asymptomatic carrier. AB - OBJECTIVES: Asymptomatic carriers can act as reservoirs of multidrug-resistant (MDR) bacteria. The aim of this study was to describe the draft genome sequence of a MDR Escherichia coli lineage recovered from a faecal sample of a healthy carrier. METHODS: Genomic DNA was sequenced on an Illumina NextSeq platform. Sequence reads were de novo assembled using CLC Genomics Workbench and the whole genome sequence was evaluated through bioinformatics tools available from the Center of Genomic Epidemiology as well as additional in silico analysis. RESULTS: The genome size was calculated as 5178340 bp, with 5442 protein-coding sequences and 5492 total genes. Presence of the blaCTX-M-8, blaCTX-M-55 and fosA3 genes was detected in addition to other antimicrobial resistance genes. Interestingly, the strain was assigned to serotype O8:H4-fimH97 and was classified within the highly virulent phylogroup B2. CONCLUSION: This draft genome can provide helpful information to elucidate genetic features that contribute to colonisation and adaptation of MDR and virulent pathogens in asymptomatic carriers. PMID- 29412184 TI - Molecular epidemiology, evolution and phylogeny of foot-and-mouth disease virus. AB - Foot-and-mouth disease virus (FMDV) is responsible for one of the most economically important infectious diseases of livestock. The virus spreads very easily and continues to affect many countries (mainly in Africa and Asia). The risks associated with the introduction of FMDV result in major barriers to trade in animals and their products. Seven antigenically distinct forms of the virus are known, called serotypes, but serotype C has not been detected anywhere for many years and may now be extinct. The serotypes have been further divided into topotypes (except for serotype Asia-1 viruses, which comprise a single topotype), genotypes, lineages and sub-lineages, which are usually restricted to specific geographical regions. However, sometimes, trans-regional spread of some strains occurs. Due to the error-prone replication of the RNA genome, the virus continuously evolves and new strains frequently arise (e.g. with modified antigenicity). Using nucleotide sequencing technologies, this rapid evolution of the viral genome can be followed. This allows the tracing of virus transmission pathways within an outbreak of disease if (near) full-length genome sequences can be generated. Furthermore, the movement of distinct virus lineages, from one country to another can be analyzed. Some important examples of the spread of new strains of FMD virus are described. PMID- 29412183 TI - Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review. AB - : Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. PERSPECTIVE: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions. PMID- 29412185 TI - Day surgery versus Outpatient setting for endovenous laser ablation treatment. A prospective cohort study. AB - OBJECTIVES: The traditional surgical approach to the treatment of the superficial venous insufficiency requires at least 12 h of post-operative monitoring and this often means the necessity of an overnight hospitalization. The introduction of new, less invasive techniques (i.e endovenous laser ablation) reduces the hospitalization stay in a Day Surgery setting. However, the increasing skills of the operators and the patient's selection, allows to propose endovenous laser ablation in an Outpatient setting. The aim of this study is to evaluate the activity of a single high-volume center. METHOD: We enrolled 112 consecutive patients with great sapehous vein insufficiency and indication to endothermal laser ablation, 57 operations (51%) were performed in Day Surgery setting and 55 (49%) in Outpatient setting according to endovascular laser ablation's criteria. Past medical history, CEAP classification, VCSS score, type of symptoms and intervention's data were collected. Post-operative results (success and complications rates, patient's functional and aesthetic satisfaction) were evaluated at 7 and 30 days after intervention. A QoL questionnaire (CIVIQ) was submitted to the patients 30 days after surgery. RESULTS: We did not observe a statistically significant difference between the two groups concerning treatment results and complications onset. The QoL assessment did not differed significantly, except for over 65-year old patients undergoing outpatient treatment that showed a better QoL compared to those undergoing the same treatment in Day Surgery (p 0.05). CONCLUSIONS: The endothermal laser ablation technique allows a safe, comfortable and faster management of the venous disease in Outpatient setting. This would further reduce the costs of the treatment while preserving the functional and aesthetic results and the low complication rate of the Day Surgery setting. PMID- 29412186 TI - Cyclic RGD functionalized liposomes encapsulating urokinase for thrombolysis. AB - : Thrombosis, a critical event in blood vessels, not only is associated with myocardial infarction and stroke, but also accounts for considerable morbidity and mortality. Thrombolytic drugs are usually applied to the treatment of acute myocardial infarction, acute cerebral infarction and pulmonary embolism. However, thrombolytic drugs show limited efficacy in clinical practice because of the short half-life in plasma and systemic side effects. In this study, the cyclic RGD (cRGD) functionalized liposomes were prepared to encapsulate urokinase, a cheap and widely used thrombolytic drug in clinic and better thrombolysis efficacy was achieved. The flow cytometry analysis showed that the cRGD liposomes could bind to the activated platelets while not to the resting platelets. In vitro release study revealed that the release percentage reached plateau in about 5 h with 60% urokinase being released from liposomes. Results from the in vitro thrombolysis experiments demonstrated a good thrombolysis potential of the cRGD urokinase liposomes. The in vivo thrombolysis study demonstrated that the cRGD liposomes could significantly reduce the dose of urokinase by 75% while achieving the equivalent thrombolysis effect as the free urokinase in mouse mesenteric thrombosis model. In conclusion, the cRGD liposomes encapsulating urokinase hold great promise in clinic for better thrombolytic efficacy. STATEMENT OF SIGNIFICANCE: In this paper, the cRGD liposomes were prepared to encapsulate urokinase for targeted thrombolysis therapy. The cRGD liposomes could specifically bind to the activated platelets and could stably and continuously release its loaded urokinase. The mouse mesenteric thrombosis model was established to evaluate the thrombolysis effect of the cRGD urokinase liposomes. The results demonstrated that the cRGD liposomes could improve the thrombolytic efficacy by almost 4-fold over free urokinase. In conclusion, the cRGD liposomes encapsulating urokinase had great potential for the clinical treatment of thrombosis. PMID- 29412187 TI - How does sagittal imbalance affect the appropriateness of surgical indications and selection of procedure in the treatment of degenerative scoliosis? Findings from the RAND/UCLA Appropriate Use Criteria study. AB - BACKGROUND CONTEXT: Degenerative lumbar scoliosis (DLS) is often associated with sagittal imbalance, which may affect patients' health outcomes before and after surgery. The appropriateness of surgery and preferred operative approaches has not been examined in detail for patients with DLS and sagittal imbalance. PURPOSE: The goals of this article were to describe what is currently known about the relationship between sagittal imbalance and health outcomes among patients with DLS and to determine how indications for surgery in patients with DLS differ when sagittal imbalance is present. STUDY DESIGN/SETTING: This study included a literature review and an expert panel using the RAND/University of California at Los Angeles (UCLA) Appropriateness Method. METHODS: To develop appropriate use criteria for DLS, researchers at the RAND Corporation recently employed the RAND/UCLA Appropriateness Method, which involves a systematic review of the literature and multidisciplinary expert panel process. Experts reviewed a synopsis of published literature and rated the appropriateness of five common operative approaches for 260 different clinical scenarios. In the present work, we updated the literature review and compared panelists' ratings in scenarios where imbalance was present versus absent. This work was funded by the Collaborative Spine Research Foundation, a group of surgical specialty societies and device manufacturers. RESULTS: On the basis of 13 eligible studies that examined sagittal imbalance and outcomes in patients with DLS, imbalance was associated with worse functional status in the absence of surgery and worse symptoms and complications postoperatively. Panelists' ratings demonstrated a consistent pattern across the diverse clinical scenarios. In general, when imbalance was present, surgery was more likely to be appropriate or necessary, including in some situations where surgery would otherwise be inappropriate. For patients with moderate to severe symptoms and imbalance, a deformity correction procedure was usually appropriate and frequently necessary, except in some patients with severe risk factors for complications. Conversely, procedures that did not correct imbalance, when present, were usually inappropriate. CONCLUSIONS: Clinical experts agreed that sagittal imbalance is a major factor affecting both when surgery is appropriate and which type of procedure is preferred among patients with DLS. PMID- 29412188 TI - Do findings identified on magnetic resonance imaging predict future neck pain? A systematic review. AB - BACKGROUND CONTEXT: Magnetic resonance imaging (MRI) has the potential to identify pathology contributing to neck pain. However, the importance of findings on MRI remains unclear. PURPOSE: We aimed to investigate whether findings on cervical spine MRI predict future neck pain. STUDY DESIGN: A systematic review was carried out. PATIENT SAMPLE: People with or without neck pain comprised the study sample. OUTCOME MEASURES: Clinically important neck pain outcomes such as pain and disability. METHODS: The review protocol was registered on PROSPERO [CRD42016049228]. MEDLINE, CINAHL, and EMBASE databases were searched. Prospective cohort studies investigating the association between baseline MRI findings and clinical outcome were included. Cohorts with serious underlying diseases as the cause of their neck pain were excluded. Associations between MRI findings and neck pain outcomes were extracted from the included studies. RESULTS: A total of 12 studies met all inclusion criteria. Eight studies presented data on participants with current neck pain, two studies included a mixed sample, and two studies included a sample of participants with no current neck pain. Because of the heterogeneity between the studies in terms of MRI findings, populations, and clinical outcomes investigated, it was not possible to pool the results. No consistent associations between MRI findings and future outcomes were identified. Single studies of populations with neck pain reported significant associations for neck muscle fatty infiltrate (risk ratio [RR]: 21.00, 95% confidence interval [CI]: 2.97-148.31) with persistent neck disability; disc protrusion (mean difference ranged from -1.83 to -2.88 on a 10 point pain scale), and disc degeneration (RR: 0.59; 95% CI: 0.36-0.98) with neck pain. In a population without pain, the development of foraminal stenosis over a 10-year period was associated with development of neck pain (RR: 2.99; 95% CI: 1.23-7.23). CONCLUSION: The limited number, heterogeneity, and small sample size of the included studies do not permit definitive conclusions on the association between MRI findings of the cervical spine with future neck pain. PMID- 29412189 TI - Stability, elastic and electronic properties of a novel BN2 sheet with extended hexagons with N-N bonds. AB - A new B-N monolayer material (BN2) consisting of a network of extended hexagons is predicted using density functional theory. The distinguishable nature of this 2D material is found to be the presence of the bonded N atoms (N-N) in the lattice. Analysis of the phonon dispersion curves show this phase of BN2 to be stable. The calculated elastic properties exhibit anisotropic mechanical properties that surpass graphene in the armchair direction. The BN2 monolayer is metallic with in-plane p states dominating the Fermi level. Novel applications resulting from a strong anisotropic mechanical strength together with the metallic properties of the BN2 sheet with the extended hexagons with N-N bonds may enable future innovation at the nanoscale. PMID- 29412190 TI - Transport theory for femtosecond laser-induced spin-transfer torques. AB - Ultrafast demagnetization of magnetic layers pumped by a femtosecond laser pulse is accompanied by a nonthermal spin-polarized current of hot electrons. These spin currents are studied here theoretically in a spin valve with noncollinear magnetizations. To this end, we introduce an extended model of superdiffusive spin transport that enables the treatment of noncollinear magnetic configurations, and apply it to the perpendicular spin valve geometry. We show how spin-transfer torques arise due to this mechanism and calculate their action on the magnetization present, as well as how the latter depends on the thicknesses of the layers and other transport parameters. We demonstrate that there exists a certain optimum thickness of the out-of-plane magnetized spin current polarizer such that the torque acting on the second magnetic layer is maximal. Moreover, we study the magnetization dynamics excited by the superdiffusive spin-transfer torque due to the flow of hot electrons employing the Landau-Lifshitz-Gilbert equation. Thereby we show that a femtosecond laser pulse applied to one magnetic layer can excite small-angle precessions of the magnetization in the second magnetic layer. We compare our calculations with recent experimental results. PMID- 29412193 TI - Erratum: Predictors of Intraocular Pressure After Phacoemulsification in Primary Open-Angle Glaucoma Eyes with Wide Versus Narrower Angles (An American Ophthalmological Society Thesis). AB - [This corrects the article on p. T6 in vol. 115, PMID: 29147104.]. PMID- 29412191 TI - Reversing the direction of galvanotaxis with controlled increases in boundary layer viscosity. AB - Weak external electric fields (EFs) polarize cellular structure and direct most migrating cells (galvanotaxis) toward the cathode, making it a useful tool during tissue engineering and for healing epidermal wounds. However, the biophysical mechanisms for sensing weak EFs remain elusive. We have reinvestigated the mechanism of cathode-directed water flow (electro-osmosis) in the boundary layer of cells, by reducing it with neutral, viscous polymers. We report that increasing viscosity with low molecular weight polymers decreases cathodal migration and promotes anodal migration in a concentration dependent manner. In contrast, increased viscosity with high molecular weight polymers does not affect directionality. We explain the contradictory results in terms of porosity and hydraulic permeability between the polymers rather than in terms of bulk viscosity. These results provide the first evidence for controlled reversal of galvanotaxis using viscous agents and position the field closer to identifying the putative electric field receptor, a fundamental, outside-in signaling receptor that controls cellular polarity for different cell types. PMID- 29412194 TI - Correction to 'Walking with wider steps changes foot placement control, increases kinematic variability and does not improve linear stability'. AB - [This corrects the article DOI: 10.1098/rsos.160627.]. PMID- 29412195 TI - In situ examination of a charged amino acid-induced structural change in lipid bilayers by sum frequency generation vibrational spectroscopy. AB - The interactions between amino acids (AAs) and membranes represent various short range and long-range interactions for biological phenomena; however, they are still poorly understood. In this study, we used cationic lysine and arginine as AA models, and systematically investigated the interactions between charged AAs and lipid bilayers using sum frequency generation vibrational spectroscopy (SFG VS) in situ and in real time. The AA-induced dynamic structural changes of the lipid bilayer were experimentally monitored using the spectral features of CD2, CD3, the lipid head phosphate, and carbonyl groups in real time. Time-dependent SFG changes in the structure of the lipid bilayer provide direct evidence for the different interactions of lysine and arginine with the membrane. It was found that the discrepancy between lysine and arginine in binding with the lipid bilayer is due to the nature of the terminal functional groups. Arginine exhibits a more drastic impact on the membrane than lysine. SFG responses of the acyl chains, phosphate groups, and carbonyl groups provide evidence that the interaction between AAs and the membrane most likely follows an electrostatics and hydrogen bond-induced defect model. This work presents an exemplary method for comprehensive investigations of interactions between membranes and other functionally significant substances. PMID- 29412196 TI - Temperature-dependent phase evolution of copper-oxide thin-films on Au(111). AB - The formation of ultrathin copper oxide layers on an Au(111) surface is explored with scanning tunneling microscopy and density functional theory. Depending on the thermal treatment of as-grown Cu-O samples, a variety of thin-film morphologies is observed. Whereas 1D oxide stripes with Au[112[combining macron]] and Au[11[combining macron]0] orientation emerge at 450 and 550 K annealing, respectively, a planar (2 * 2) Cu-O network with specific domain structure develops at higher temperature. The latter is ascribed to a Cu3O2 honeycomb lattice with oxygen ions alternatingly located in surface and interface positions. Strain minimization and a thermodynamic preference for Cu-rich edges lead to the formation of structurally well-defined boundaries, delimiting either triangular, elongated or stripe-like Cu3O2 domains. The low-temperature phases compirse complex arrangements of hexagonal and square Cu-O units, similar to those found in Cu2O(111) and (100) surfaces, respectively. The transitions between different thin-film phases are driven by Cu dissolution in the gold crystal and O2 evaporation and therefore accompanied by a thinning of the oxide layer with increasing temperature. PMID- 29412197 TI - On-surface synthesis: a promising strategy toward the encapsulation of air unstable ultra-thin 2D materials. AB - 2D black phosphorus (BP) and transition metal chalcogenides (TMCs) have beneficial electronic, optical, and physical properties at the few-layer limit. However, irreversible degradation of exfoliated or chemical vapor deposition grown ultrathin BP and TMCs like GaSe via oxidation under ambient conditions limits their applications. Herein, the on-surface growth of an oxidation resistant 2D thin film of a metal coordination polymer is demonstrated by multiscale simulations. We show that the preparation of such heterostructures can be conducted in solution, in which pristine BP and GaSe present better stability than in an air environment. Our calculations reveal that the interaction between the polymer layer and 2D materials is dominated by van der Waals forces; thus, the electronic properties of pristine BP and GaSe are well preserved. Meanwhile, the isolation from oxygen and water can be achieved by monolayer polymers, due to the nature of their close-packed layers. Our facile strategy for enhancing the environmental stability of ultrathin materials is expected to accelerate efforts to implement 2D materials in electronic and optoelectronic applications. PMID- 29412198 TI - Recent advances in three-dimensional graphene based materials for catalysis applications. AB - Over the past few decades, two-dimensional graphene based materials (2DGMs) have piqued the interest of scientists worldwide, and the exploration of their potential applications in catalysis, sensors, electronic devices and energy storage due to their extraordinary physical and chemical properties has rapidly progressed. As for these 2DGMs, there is a complementary need to assemble 2D building blocks hierarchically into more complicated and hierarchical three dimensional graphene-based materials (3DGMs). Such a capability is vitally crucial in order to design sophisticated and multi-functional catalysts with tailorable properties. This comprehensive review describes some important recent advances with respect to 3DGMs, including their preparation methods, characterization and applications in catalysis, e.g., photocatalysis, electrocatalysis, organic catalysis, and CO oxidation. The importance of the relationship between the structure and catalytic performance, a topic which has become a central focus of research in order to develop high-performance catalytic systems, is discussed. Likely future developments and their associated challenges are proposed and discussed. PMID- 29412199 TI - Plasmonic nanoparticles embedded in single crystals synthesized by gold ion implantation for enhanced optical nonlinearity and efficient Q-switched lasing. AB - We report on the synthesis of embedded gold (Au) nanoparticles (NPs) in Nd:YAG single crystals using ion implantation and subsequent thermal annealing. Both linear and nonlinear absorption of the Nd:YAG crystals have been enhanced significantly due to the embedded Au NPs, which is induced by the surface plasmon resonance (SPR) effect in the visible light wavelength band. Particularly, through a typical Z-scan system excited by a femtosecond laser at 515 nm within the SPR band, the nonlinear absorption coefficients of crystals with Au NPs have been observed to be nearly 5 orders of magnitude larger than that without Au NPs. This giant enhancement of nonlinear absorption properties is correlated with the saturable absorption (SA) effect, which is the basis of passive Q-switching or mode-locking for pulsed laser generation. In addition, the linear and nonlinear absorption enhancement could be tailored by varying the fluence of implanted Au+ ions, corresponding to the NP size and concentration modulation. Finally, the Nd:YAG wafer with embedded Au NPs has been applied as a saturable absorber in a Pr:LuLiF4 crystal laser cavity, and efficient pulsed laser generation at 639 nm has been realized, which presents superior performance to the MoS2 saturable absorber based system. This work opens an avenue to enhance and modulate the nonlinearities of dielectrics by embedding plasmonic Au NPs for efficient pulsed laser operation. PMID- 29412200 TI - Temperature-tunable wettability on a bioinspired structured graphene surface for fog collection and unidirectional transport. AB - We designed a type of smart bioinspired wettable surface with tip-shaped patterns by combining polydimethylsiloxane (PDMS) and graphene (PDMS/G). The laser etched porous graphene surface can produce an obvious wettability change between 200 degrees C and 0 degrees C due to a change in aperture size and chemical components. We demonstrate that the cooperation of the geometrical structure and the controllable wettability play an important role in water gathering, and surfaces with tip-shaped wettability patterns can quickly drive tiny water droplets toward more wettable regions, so making a great contribution to the improvement of water collection efficiency. In addition, due to the effective cooperation between super hydrophobic and hydrophilic regions of the special tip shaped pattern, unidirectional water transport on the 200 degrees C heated PDMS/G surface can be realized. This study offers a novel insight into the design of temperature-tunable materials with interphase wettability that may enhance fog collection efficiency in engineering liquid harvesting equipment, and realize unidirectional liquid transport, which could potentially be applied to the realms of microfluidics, medical devices and condenser design. PMID- 29412201 TI - Unusual photoresponses in the upper critical solution temperature of polymer solutions mediated by changes in intermolecular interactions in an azo-doped liquid crystalline solvent. AB - Photoinduced changes in the upper critical solution temperature (UCST) were investigated for polymer solutions in an azobenzene-doped liquid crystal solvent. The UCST of poly(methyl methacrylate) (PMMA) and polystyrene (PS) solutions dropped upon irradiation with UV light, which induces trans-cis photoisomerization of the doped azo dye. In the case of PMMA solutions, the photoinduced drop in UCST was significantly larger than that expected from previous studies using azo-based polymers and common solvents. Moreover, the UCST of PS solutions also decreased under photoirradiation, in a direction opposite to that expected from the contribution of polarity. X-ray diffraction data of the solvent suggest that the decreased intermolecular interaction in the solvent (i.e. larger distance between the solvent molecules) is responsible for the photoresponsive behavior of the UCST. The proposed mechanism is consistent with the Flory-Huggins theory. Using such photoresponses in the UCST, the isothermal transition between 2-phase and 1-phase states by photoirradiation was demonstrated. PMID- 29412202 TI - Low energy electron-induced decomposition of (eta5-Cp)Fe(CO)2Mn(CO)5, a potential bimetallic precursor for focused electron beam induced deposition of alloy structures. AB - The production of alloyed nanostructures presents a unique problem in focused electron beam induced deposition (FEBID). Deposition of such structures has historically involved the mixing of two or more precursor gases in situ or via multiple channel gas injection systems, thereby making the production of precise, reproducible alloy compositions difficult. Promising recent efforts to address this problem have involved the use of multi-centred, heterometallic FEBID precursor species. In this vein, we present here a study of low-energy electron interactions with cyclopentadienyl iron dicarbonyl manganese pentacarbonyl ((eta5 Cp)Fe(CO)2Mn(CO)5), a bimetallic species with a polyhapto ligand (Cp) and seven terminal carbonyl ligands. Gas phase studies and coupled cluster calculations of observed low-energy electron-induced reactions were conducted in order to predict the performance of this precursor in FEBID. In dissociative electron attachment, we find single CO loss and cleavage of the Fe-Mn bond, leading to the formation of [Mn(CO)5]-, to be the two dominant channels. Contributions through further CO loss from the intact core and the formation of [Mn(CO)4]- are minor channels. In dissociative ionization (DI), the fragmentation is significantly more extensive and the DI spectra are dominated by fragments formed through the loss of 5 and 6 CO ligands, and fragments formed through cleavage of the Fe-Mn bond accompanied by substantial CO loss. The gas phase fragmentation channels observed are discussed in relation to the underlying processes and their energetics, and in context to related surface studies and the likely performance of this precursor in FEBID. PMID- 29412203 TI - The effect of surface charge on oral absorption of polymeric nanoparticles. AB - Surface charge plays an important role in determining the interactions of nanoparticles with biological components. Substantial studies have demonstrated that surface charge affects the fate of nanoparticles after intravenous administration; however, few studies have investigated the effect of surface charge on the bioavailability and absorption of nanoparticles after oral administration. In this study, polymeric nanoparticles with a similar particle size and surface polyethylene glycol (PEG) density, but with varying surface charges (positive, negative and neutral), were developed to study the effect of surface charge on the oral absorption of polymeric nanoparticles. The nanoparticles were constructed from polyethylene glycol-block-polylactic acid (PEG-PLA) with the incorporation of lipid components with different charges. Our results suggested that the positive surface charge facilitated the cellular uptake and transport of nanoparticles through both Caco-2 cells in vitro and small intestinal epithelial cells in vivo. The positively charged nanoparticles showed a favorable distribution in the small intestine, and significantly improved the oral bioavailability. This study presents valuable information towards the design of nanoparticles for improved oral drug delivery. PMID- 29412204 TI - The nitrogen concentration effect on Ce doped SiOxNy emission: towards optimized Ce3+ for LED applications. AB - Ce-Doped SiOxNy films are deposited by magnetron reactive sputtering from a CeO2 target under a nitrogen reactive gas atmosphere. Visible photoluminescence measurements regarding the nitrogen gas flow reveal a large emission band centered at 450 nm for a sample deposited under a 2 sccm flow. Special attention is paid to the origin of such an emission at high nitrogen concentration. Different emitting centers are suggested in Ce doped SiOxNy films (e.g. band tails, CeO2, Ce clusters, Ce3+ ions), with different activation scenarios to explain the luminescence. X-ray photoelectron spectroscopy (XPS) reveals the exclusive presence of Ce3+ ions whatever the nitrogen or Ce concentrations, while transmission electron microscopy (TEM) shows no clusters or silicates upon high temperature annealing. With the help of photoluminescence excitation spectroscopy (PLE), a wide excitation range from 250 nm up to 400 nm is revealed and various excitations of Ce3+ ions are proposed involving direct or indirect mechanisms. Nitrogen concentration plays an important role in Ce3+ emission by modifying Ce surroundings, reducing the Si phase volume in SiOxNy and causing a nephelauxetic effect. Taking into account the optimized nitrogen growth parameters, the Ce concentration is analyzed as a new parameter. Under UV excitation, a strong emission is visible to the naked eye with high Ce3+ concentration (6 at%). No saturation of the photoluminescence intensity is observed, confirming again the lack of Ce cluster or silicate phase formation due to the nitrogen presence. PMID- 29412205 TI - Challenges and advances in the computational modeling of biological phosphate hydrolysis. AB - Phosphate ester hydrolysis is fundamental to many life processes, and has been the topic of substantial experimental and computational research effort. However, even the simplest of phosphate esters can be hydrolyzed through multiple possible pathways that can be difficult to distinguish between, either experimentally, or computationally. Therefore, the mechanisms of both the enzymatic and non enzymatic reactions have been historically controversial. In the present contribution, we highlight a number of technical issues involved in reliably modeling these computationally challenging reactions, as well as proposing potential solutions. We also showcase examples of our own work in this area, discussing both the non-enzymatic reaction in aqueous solution, as well as insights obtained from the computational modeling of organophosphate hydrolysis and catalytic promiscuity amongst enzymes that catalyze phosphoryl transfer. PMID- 29412206 TI - Origin of enhancement in Raman scattering from Ag-dressed carbon-nanotube antennas: experiment and modelling. AB - The D- and G-band Raman signals from random arrays of vertically aligned, multi walled carbon nanotubes are significantly enhanced (up to ~14*) while the signal from the underlying Si substrate is simultaneously attenuated (up to ~6*) when the nanotubes are dressed, either capped or coated, with Ag. These Ag-induced counter-changes originate with the difference in geometry of the nanotubes and planar Si substrate and contrast in the Ag depositions on the substrate (essentially thin film) and the nanotube (nano-particulate). The surface integral equation technique is used to perform detailed modelling of the electromagnetic response of the system in a computationally efficient manner. Within the modelling the overall antenna response of the Ag-dressed nanotubes is shown to underpin the main contribution to enhancement of the nanotube Raman signal with hot-spots between the Ag nanoparticles making a subsidiary contribution on account of their relatively weak penetration into the nanotube walls. Although additional hot-spot activity likely accounts for a shortfall in modelling relative to experiment it is nonetheless the case that the significant antenna driven enhancement stands in marked contrast to the hot-spot dominated enhancement of the Raman spectra from molecules adsorbed on the same Ag-dressed structures. The Ag-dressing procedure for amplifying the nanotube Raman output not only allows for ready characterisation of individual nanotubes, but also evidences a small peak at ~1150 cm-1 (not visible for the bare, undressed nanotube) which is suggested to be due to the presence of trans-polyacetylene in the structures. PMID- 29412207 TI - Molecular dynamics of the halloysite nanotubes. AB - We report large-scale and long-time molecular dynamics simulations demonstrating the transformation of a single kaolin alumosilicate sheet to a halloysite nanotube. The models we consider contain up to 5 * 105 atoms, which is two orders of magnitude larger than that used in previous theoretical works. It was found that the temperature plays a crucial role in the formation of the rolled geometry of the halloysite. For the models with periodic boundary conditions, we observe the tendency to form twin-tube structures, which is confirmed experimentally by atomic force microscopy imaging. The molecular dynamics calculations show that the rate of the rolling process is very sensitive to the choice of the winding axis and varies from 5 ns to 25 ns. The effects of the open boundary conditions and the initial form of the kaolin alumosilicate sheet are discussed. Our simulation results are consistent with experimental TEM and AFM halloysite tube imaging. PMID- 29412208 TI - Wearable energy sources based on 2D materials. AB - Wearable energy sources are in urgent demand due to the rapid development of wearable electronics. Besides flexibility and ultrathin thickness, emerging 2D materials present certain extraordinary properties that surpass the properties of conventional materials, which make them advantageous for high-performance wearable energy sources. Here, we provide a comprehensive review of recent advances in 2D material based wearable energy sources including wearable batteries, supercapacitors, and different types of energy harvesters. The crucial roles of 2D materials in the wearable energy sources are highlighted. Based on the current progress, the existing challenges and future prospects are outlined and discussed. PMID- 29412209 TI - A DFT+U study of the catalytic degradation of 1,2-dichloroethane over CeO2. AB - The catalytic degradation of 1,2-dichloroethane (DCE) at CeO2(111) was investigated using periodic density functional theory calculations corrected by on-site Coulomb interactions. From thorough calculations of possible elementary steps, we are able to identify the lowest energy reaction pathway for the catalytic oxidation of DCE at CeO2(111). It proceeds via two successive C-Cl bond breaking processes to form adsorbed CH2CH2 species, and after further dehydrogenation and C-C bond scission, the surface species are finally oxidized to CO2 and H2O. The surface oxygen vacancies were found to be important for the catalytic decomposition of DCE, by providing the adsorption sites, as well as for charge transfer to favor C-Cl bond breaking. We are also able to illustrate the effect of H2O on the catalytic activity of CeO2(111) for DCE oxidation. PMID- 29412210 TI - Aerogel materials with periodic structures imprinted with cellulose nanocrystals. AB - Novel aerogel materials with periodic structures derived from chiral nematic liquid crystalline cellulose nanocrystals (CNCs) are reported. The liquid crystalline structure of phase-separated CNCs is locked by a simple solvent exchange method or silica condensation. Both cellulose and silica/cellulose aerogel materials were obtained after critical point drying, and subsequent calcination of the silica/cellulose composite afforded a silica aerogel with periodic order. Gas adsorption and electron microscopy studies revealed that these materials have high surface areas and a unique chiral nematic structure imparted from the helicoidal CNC template. This is a new, scalable approach to aerogel materials with highly anisotropic structures. The high porosity and periodic, chiral features of these new materials may make them suitable for applications that require anisotropic properties or as hard templates for the construction of other ordered aerogels. PMID- 29412211 TI - Gold nanoclusters with bright near-infrared photoluminescence. AB - The increase in nonradiative pathways with decreasing emission energy reduces the luminescence quantum yield (QY) of near-infrared photoluminescent (NIR PL) metal nanoclusters. Efficient surface ligand chemistry can significantly improve the luminescence QY of NIR PL metal nanoclusters. In contrast to the widely reported but modestly effective thiolate ligand-to-metal core charge transfer, we show that metal-to-ligand charge transfer (MLCT) can be used to greatly enhance the luminescence QY of NIR PL gold nanoclusters (AuNCs). We synthesized water-soluble and colloidally stable NIR PL AuNCs with unprecedentedly high QY (~25%) upon introduction of triphenylphosphonium moieties into the surface capping layer. By using a combination of spectroscopic and theoretical methods, we provide evidence for gold core-to-ligand charge transfer occurring in AuNCs. We envision that this work can stimulate the development of these unusually bright AuNCs for promising optoelectronic, bioimaging, and other applications. PMID- 29412212 TI - Porous gold nanocluster-decorated manganese monoxide nanocomposites for microenvironment-activatable MR/photoacoustic/CT tumor imaging. AB - Stimuli-responsive nanoprobes that integrate multi-modal imaging capacities are highly desirable for precise tumor visualization. Herein, novel porous gold nanocluster-decorated manganese monoxide nanocomposites (MnO@Au NCs) were synthesized via a facile approach. The porous gold nanocluster layer was germinated on the surface of the as-prepared MnO@DMSA NPs through simple reduction of chloroauric acid in the presence of hydroxylamine hydrochloride. The MnO@Au NCs could be effectively internalized by tumor cells and slowly release Mn2+ ions within the acidic tumor microenvironment, improving the visualization of the tumor morphology. Benefitting from the porous architecture, the enhanced accessibility of Mn centers to proximal water molecules greatly augmented T1 weighted MRI contrast capacity. Compared with the conventional Mn-based contrast agents, the porous Au nanoclusters on MnO@Au NCs could delay the release of Mn2+ ions and thus effectively prolong the diagnostic time window. The broad near infrared absorption of MnO@Au NCs features a high photoacoustic imaging depth than that of conventional gold nanospheres. Moreover, the Au nanoclusters exhibited desirable X-ray computed tomography contrast and rapid clearance from the living body. The as-prepared MnO@Au NCs hold great potential for accurate tumor imaging. PMID- 29412213 TI - Stereoselective synthesis of a Podophyllum lignan core by intramolecular reductive nickel-catalysis. AB - A Ni-catalyzed reductive cascade to a diastereocontrolled construction of THN[2,3 c]furan, is developed. The mild reaction conditions led to the tolerance of broad functional groups that can be placed in almost every position of this skeleton with good yields. The conformational control for the observed trans- or cis-fused selectivity during this tandem cyclization-coupling is also proposed. PMID- 29412214 TI - Alkylating probes for the G-quadruplex structure and evaluation of the properties of the alkylated G-quadruplex DNA. AB - The G-quadruplex structure has been found in biologically significant regions of the genomic DNA, including the telomere and promoter regions, and is known to play an important role in a number of biological processes. In this paper, we report the development of alkylating probes for the G-quadruplex structure and evaluation of the properties of the modified G-quadruplex structure. PMID- 29412218 TI - Thinning regimes and initial spacing for Eucalyptus plantations in Brazil. AB - This study focuses on the effects of different thinning regimes on clonal Eucalyptus plantations growth. Four different trials, planted in 1999 and located in Bahia and Espirito Santo States, were used. Aside from thinning, initial planting density, and post thinning fertilization application were also evaluated. Before canopy closure, and therefore before excessive competition between trees took place, it was found that stands planted under low densities (667 trees per hectare) presented a lower mortality proportion when compared to stand planted under higher densities (1111 trees per hectare). However, diameter growth prior to thinning operations was not statistically different between these two densities, presenting an overall mean of 4.9 cm/year. After canopy closure and the application of the thinning treatments, it was found that thinning regimes beginning early in the life of the stand and leaving a low number of residual trees presented the highest diameter and height growth. Unthinned treatments and thinning regimes late in the life of the stand (after 5.5 years), leaving a large number of residual trees presented the highest values of basal area production. The choice of the best thinning regime for Eucalyptus clonal material will vary according to the plantation objective. PMID- 29412219 TI - Ash content, carbon and C/N ratio in parica in function of NPK fertilization. AB - Fertilization in areas of forest plantations is needed to supplement plants' nutritional needs until harvest. An experiment was performed to check the influence of fertilization on levels of ash, carbon and C/N relation in Schizolobium amazonicum. Soil liming was performed and fertilization occurred after 15 days of incubation. S. amazonicum seedlings were produced and submitted to fertilization with N, P and K: N = 0, 40, 80 and 120 kg ha-1; P2O5 = 0, 50, 100 and 200 kg ha-1; K2O = 0, 50, 100 and 200 kg ha-1. The plants were measured after 180 days. The seedlings of 20 treatments with the highest increase in height and diameter were transplanted to the field. Soil was fertilized and limestone was spread; seedlings were distributed into randomized blocks, with six replications. After 12 months, the plants were removed to determine ash, organic carbon, C/N relation contents. The ashes were submitted to digestion to determine nutrient concentrations. Fertilization influenced the levels of ash and organic carbon and C/N relation in S. amazonicum. Results indicate that the species has a potential for energy production. PMID- 29412220 TI - Erratum: Health-related quality of life of patients with squamous cell carcinoma: a comparison according to tumor location. Braz Oral Res. 2017;31:e105. AB - [This corrects the article doi: 10.1590/1807-3107BOR-2017.vol31.0105]. PMID- 29412221 TI - Culture of human dental pulp cells at variable times post-tooth extraction. AB - The aim of this study was to investigate the viability of human dental pulp cells from extracted teeth kept at standard room temperature and atmospheric pressure for different periods of time. Twenty-one healthy permanent teeth were used. They were divided into five groups according to the expected time from extraction to processing. One group was tested immediately after extraction; the other groups were each tested at one of the following time points: 30 minutes, 1 hour, 2 hours, and 5 hours post-extraction. Cell morphology was analysed by light microscopy; cell proliferation was analysed using MTT assay and by counting the viable cells in a haemocytometer. Similar results were observed in all groups (p < 0.05). A delay of up to five hours for tooth processing and tissue collection does not preclude the establishment of dental pulp cell cultures, affect the morphology of these cells, or reduce their proliferative potential. PMID- 29412222 TI - Evaluation of adaptation of ceramic inlays using optical coherence tomography and replica technique. AB - Optical coherence tomography (OCT) has generally been used as a nondestructive technique to evaluate integrities of composite restorations. We investigated marginal and internal adaptations of ceramic inlay restorations with OCT and compared them to results with the silicone replica technique. Round-shaped class I cavities were prepared on 16 human maxillary first premolar teeth. Ceramic inlays were fabricated. Silicone replicas from inlays were obtained and sectioned to measure marginal and internal adaptations with a stereomicroscope (Leica Dfc 295, Bensheim, Germany). Inlays were cemented on respective teeth. Marginal and internal adaptations were then measured with the OCT system (Thorlabs, New Jersey, USA) in 200- MUm intervals. Replica and OCT measurements were compared with independent samples t-tests. A paired t-test was used to evaluate the marginal and internal adaptations of each group (p < 0.05). Marginal and internal adaptations were 100.97 +/- 31.36 and 113.94 +/- 39.75 MUm, respectively, using the replica technique and 28.97 +/- 17.86 and 97.87 +/- 21.83 MUm, respectively, using OCT. The differences between the techniques were significant (p = 0.00 and p = 0.01, respectively). On evaluation within the groups, internal adaptation values were found to be significantly higher than the marginal adaptation values for the replica technique (p = 0.00) and OCT (p = 0.00). Therefore, the replica and OCT techniques showed different results, with higher values of marginal and internal adaptation found with the replica technique. Marginal and internal adaptation values of ceramic inlays, whether measured by replica or OCT techniques, were within clinically acceptable limits. PMID- 29412223 TI - Effect on adhesion of a nanocapsules-loaded adhesive system. AB - This study aimed to evaluate the in situ degree of conversion, contact angle, and immediate and long-term bond strengths of a commercial primer and an experimental adhesive containing indomethacin- and triclosan-loaded nanocapsules (NCs). The indomethacin- and triclosan-loaded NCs, which promote anti-inflammatory and antibacterial effects through controlled release, were incorporated into the primer at a concentration of 2% and in the adhesive at concentrations of 1, 2, 5, and 10%. The in situ degree of conversion (DC, n=3) was evaluated by micro-Raman spectroscopy. The contact angle of the primer and adhesive on the dentin surface (n = 3) was determined by an optical tensiometer. For the microtensile bond strength uTBS test (12 teeth per group), stick-shaped specimens were tested under tensile stress immediately after preparation and after storage in water for 1 year. The data were analyzed using two-way ANOVA, three-way ANOVA and Tukey's post hoc tests with alpha=0.05. The use of the NC-loaded adhesive resulted in a higher in situ degree of conversion. The DC values varied from 75.07 +/- 8.83% to 96.18 +/- 0.87%. The use of NCs in only the adhesive up to a concentration of 5% had no influence on the bond strength. The contact angle of the primer remained the same with and without NCs. The use of both the primer and adhesive with NCs (for all concentrations) resulted in a higher contact angle of the adhesive. The longitudinal MUTBS was inversely proportional to the concentration of NCs in the adhesive system, exhibiting decreasing values for the groups with primer containing NCs and adhesives with increasing concentrations of NCs. Adhesives containing up to 5% of nanocapsules and primer with no NCs maintained the in situ degree of conversion, contact angle, and immediate and long-term bond strengths. Therefore, the NC-loaded adhesive can be an alternative method for combining the bond performance and therapeutic effects. The use of an adhesive with up to 5% nanocapsules containing indomethacin and triclosan and a primer with no nanocapsules maintained the long-term bond performance. PMID- 29412224 TI - Therapeutic effect of Aloe vera and silver nanoparticles on acid-induced oral ulcer in gamma-irradiated mice. AB - Radiation combined injury, a life-threatening condition, has higher mortality than simple radiation injury. The aim of the present study was to analyze the efficiency of Aloe vera and silver nanoparticles in improving the healing of ulcerated oral mucosa after irradiation. Thirty male Albino mice were divided into five groups: control, radiation, Aloe vera (AV), silver nanoparticles (NS), and AV+NS. The mice were exposed to whole body 6Gy gamma-radiation. After one hour, 20% acetic acid was injected into the submucosal layer of the lower lip for ulcer induction. The animals received topical treatment with the assigned substances for 5 days. Lip specimens were subjected to hematoxylin and eosin and anti alpha-smooth muscle actin immunohistochemical staining. Results demonstrated occurance of ulcer three days post irradiation in all groups except in the AV+NS group where only epithelial detachment was developed. After seven days, data revealed persistent ulcer in radiation group, and almost normal epithelium in the AV+NS group. A significant reduction of epithelial thickness was detected in all groups at the third day as compared to control. At the seventh day, only the AV+NS group restored the epithelial thickness. Area percent of alpha-smooth muscle actin expression was significantly decreased in radiation group at the third day followed by significant increase at the seventh day. However, all treatment groups showed significant increase in alpha-smooth muscle actin at the third day, which decreased to normal level at the seventh day. Our study demonstrated the efficiency of Aloe vera and silver nanoparticles in enhancing ulcer healing after irradiation. PMID- 29412225 TI - Evaluation of the association of bruxism, psychosocial and sociodemographic factors in preschoolers. AB - The aim of the present study was to evaluate factors associated with sleep bruxism in five-year-old preschool children. A preschool-based cross-sectional study was conducted with 761 pairs of children and their parents/caregivers. Sleep bruxism was diagnosed using a questionnaire administered to the parents/caregivers, who also answered questionnaires addressing sociodemographic data and parent's/caregiver's sense of coherence. Clinical oral evaluations of the children to determine dental caries, traumatic dental injuries, malocclusion and tooth wear were performed by two researchers who had undergone a training exercise (interexaminer Kappa: 0.70 to 0.91; intraexaminer Kappa: 0.81 to 1.00). Descriptive analysis and logistic regression for complex samples were carried out (alpha = 5%). The prevalence of sleep bruxism among the preschool children was 26.9%. The multivariate analysis revealed that bruxism was associated with poor sleep quality (OR = 2.93; 95 CI: 1.52-5.65) and tooth wear (OR = 2.34; 95%CI: 1.39-3.96). In the present study, sleep bruxism among preschool children was associated with tooth wear and poor sleep quality of the child. In contrast, psychosocial aspects (sense of coherence) were not associated with sleep bruxism. PMID- 29412226 TI - Association between the macroscopic characteristics of the umbilical cord, high risk pregnancy and neonatal repercussions. AB - OBJECTIVE: To verify the association between the macroscopic characteristics of the umbilical cord, high-risk pregnancy and neonatal repercussions. METHOD: A cross-sectional study carried out from January 2012 to January 2015 in a public maternity hospital in Goiania/GO. The study population consisted of 126 recent puerperal women with diagnosis of high-risk pregnancy, and 139 clinically normal women (control group). Macroscopic features of the umbilical cord, maternal, fetal and neonatal diseases, gestational age, Apgar score, birth weight, head circumference and parity were evaluated. Data were descriptively analyzed. RESULTS: 265 puerperal women and their respective newborns participated in the study. The most frequent characteristics of the umbilical cord of those with high risk pregnancy and those from the control group were the absence of true knots (97.6% and 2.4%, respectively), length between 35 and 70 centimeters and paracentral insertion (81.7% and 18.3%). A statistical difference was observed between the high-risk pregnancy group and extremes of maternal age (p=0.004). CONCLUSION: The analysis and description of the characteristics of the umbilical cord carried out by the nurse lend important information about the neonatal prognosis. This evaluation subsidizes clinical practice and seeks to ensure the safety of the (mother-baby) binomial throughout the perinatal period. PMID- 29412227 TI - Validation of the Echelle Douleur Inconfort Nouveau-Ne for Brazilian culture. AB - OBJECTIVE: To evaluate the reliability and validity of the Brazilian version of the Echelle Douleur Inconfort Nouveau-Ne, which measures prolonged pain in neonates. METHOD: A methodological study carried out with 96 neonates. The Brazilian versions of the Echelle Douleur Inconfort Nouveau-Ne and the Children's and Infants' Postoperative Pain Scale were used for data collection. For reliability, equivalence measured by intraobserver agreement and homogeneity were considered. To evaluate the validity, the convergent construct approach was considered correlating the Brazilian versions of the Echelle Douleur Inconfort Nouveau-Ne and the Children's and Infants' Postoperative Pain Scale. RESULTS: In assessing reliability, the coefficient of agreement between observers varied between 0.64 and 0.85 for the items that make up the instrument, and 0.96 for the total score. Cronbach's alpha was 0.82. Regarding the convergent validity evaluation, Spearman correlation coefficient between the values found for both scales was 0.79 (p< 0.0001). CONCLUSION: The Brazilian version of the Echelle Douleur Inconfort Nouveau-Ne is a reliable and valid instrument for assessing prolonged pain in neonates. PMID- 29412228 TI - The protective effect of dexmedetomidine in a rat ex vivo lung model of ischemia reperfusion injury. AB - PURPOSE: To investigate the effect of dexmedetomidine (Dex) in a rat ex vivo lung model of ischemia-reperfusion injury. METHODS: An IL-2 ex vivo lung perfusion system was used to establish a rat ex vivo lung model of ischemia-reperfusion injury. Drugs were added to the perfusion solution for reperfusion. Lung injury was assessed by histopathological changes, airway pressure (Res), lung compliance (Compl), perfusion flow (Flow), pulmonary venous oxygen partial pressure (PaO2), and lung wet/dry (W/D) weight ratio. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), 78 kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured, respectively. RESULTS: The introduction of Dex attenuated the post-ischemia reperfusion lung damage and MDA level, improved lung histology, W/D ratio, lung injury scores and SOD activity. Decreased mRNA and protein levels of GRP78 and CHOP compared with the IR group were observed after Dex treatment. The effect of Dex was dosage-dependence and a high dose of Dex (10 nM) was shown to confer the strongest protective effect against lung damage (P<0.05). Yohimbine, an alpha2 receptor antagonist, significantly reversed the protective effect of Dex in lung tissues (P<0.05). CONCLUSION: Dex reduced ischemia-reperfusion injury in rat ex vivo lungs. PMID- 29412229 TI - Influence of biomaterials on scintigraphic diagnosis of periprosthetic infections. Ceftizoxime-99m technetium model. AB - PURPOSE: To compare the influence of two metallic implants in the diagnosis of periprosthetic infection using 99m technetium-labeled ceftizoxime. METHODS: Twenty rats were randomly divided into four groups, which received sterile and contaminated titanium and stainless steel implants. After 3 weeks, scintilographic images were obtained using a gamma chamber. Radioactivity counts were obtained for the region of interest (ROI) on the operated and non-operated paws. RESULTS: Groups A, B, and C showed homogenous distribution of the radiopharmaceutical. Hyper uptake was observed in the operated paw from group D. The ROI target count was higher in the two groups with stainless steel implants. Among the control groups, the count was higher in the stainless steel group. Furthermore, among the contaminated groups, the uptake was higher in the stainless steel group, with a significant difference. The target: non-target ratio was significantly lower in the control and contaminated groups with both titanium and stainless steel, but the comparison between control groups and contaminated groups was only significant in the former. The cpm/g observed after a decay of 48h showed statistically significant differences between groups. CONCLUSION: Different biomaterials used in implants have an influence on the results of scintigraphy with 99mTc-CFT. PMID- 29412230 TI - Protective effect of dexmedetomidine against myocardial ischemia-reperfusion injury in rabbits. AB - PURPOSE: To investigate the influence of dexmedetomidine on myocardial ischemia reperfusion injury (IRI) in rabbits. METHODS: Twenty-four New Zealand white rabbits were randomly divided into two equal-sized groups: IRI group (group IR) and dexmedetomidine group (group D). Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), left ventricular diastolic pressure (LVDP), +dp/dtmax, -dp/dtmax, and t-dp/dtmax were recorded and calculated at the following time points: before (T0) and after (T1) dexmedetomidine infusion, after 30-min ischemia (T2), and after 120-min reperfusion (T3). The levels of plasma endothelin 1 (ET-1), thromboxane A2 (TXA2), and platelet activating factor (PAF); area of myocardial infarction (MI); and no-reflow area were evaluated. RESULTS: SBP, DBP, LVSP, LVEDP, LVDP, and +dp/dtmax at T3 were higher in group D than in group IR (P<0.05). The average no reflow area in group IR was significantly smaller than that in group D (14+/-3% vs. 38+/-5%, P=0.0116). The ET-1, TXA2, and PAF levels at T2 and T3 were higher than those at T0 in both groups (P<0.05). CONCLUSION: Dexmedetomidine could reduce the magnitude of ischemic myocardial no-reflow area and protect the myocardium with ischemia-reperfusion injury. PMID- 29412231 TI - The effects of subcutaneous injection of nicotine on osseointegration of machined and anodized implants in rabbits. AB - PURPOSE: To evaluate the influence of subcutaneous injection nicotine in osseointegration process on different implant surfaces. METHODS: Twenty-two male rabbits were distributed into two groups according to the subcutaneous injections: (1) nicotine 3 mg/day/kg and (2) 0.9 % NaCI 3 mL/day/kg, three times a day; subgroups were then designated-machined and anodized implants were placed in the right and left tibia bones, respectively. The animals were submitted euthanasia after periods of eight weeks to determine nicotine and cotinine levels, alkaline phosphatase and biomechanical analysis. RESULTS: The plasmatic levels of nicotine and cotinine were 0.5 +/- 0.28 ng/mL and 9.5 +/- 6.51 ng/mL, respectively. The alkaline phosphatase analyses in blood levels in control group were observed 40.8 +/- 11.88 UI/L and 40.75 +/- 12.46 UI/L, for the surfaces machined and anodized, respectively. In the test group was observed levels 37.9 +/- 4.84 UI/L, for both implant surfaces. No significant differences were observed between control and test groups and between the implant surfaces regarding alkaline phosphatase blood levels. For biomechanics, no significant differences were observed in control group between the machined (25+/-8.46 Ncm) or anodized (31.2 +/- 6.76 Ncm) implants. However, the treatment with nicotine induced higher torque than control in both machined (38.3 +/- 13.52 Ncm) and anodized (35.5 +/- 14.17 Ncm) implants, with p = 0.0024 and p = 0.0121, respectively. CONCLUSION: Subcutaneous injection of nicotine following implant insertion didn't have effect on osseointegration, independently from the implant surface. PMID- 29412232 TI - Laparoscopic versus open pylorus-preserving pancreatoduodenectomy. The first meta analyse of retrospective matched cases. AB - PURPOSE: To compare the safety, feasibility, and short-term clinical benefits of laparoscopic pylorus-preserving pancreaticoduodenectomy (L-PPPD) to open pylorus preserving pancreaticoduodenectomy (O-PPPD) through retrospective matched cases. METHODS: Web of Science, Cochrane, PubMed, CNKI were searched systematically identify studies published between January and December 2017 comparing L-PPPD to O-PPPD. The meta-analysis was performed by using Review Manager 5.3. RESULTS: Two studies matched the selection criteria, including 108 (50%) cases of laparoscopic pylorus-preserving pancreaticoduodenectomy and 108(50%) cases of open pylorus preserving pancreaticoduodenectomy. None of the included studies were randomized, which were both retrospective matched cases. There was no difference in the incidence of postoperative pancreatic fistula, blood loss, diet start and lymph nodes. However, L-PPPD has a shorter hospital stay (p=0.0003) and O-PPPD has a shorter operative time (p=0.02) and tend to decrease the delayed gastric emptying. CONCLUSIONS: The perioperative safety of laparoscopic surgery, which also has advantages of minimal invasion and shorter hospital stay, is comparable to that of open surgery. Laparoscopic surgery could be operated if the patients matched the indication and operation difficulty is not so great. However, blind pursuits of L-PPPD should be restrained because there is no essential difference between these two in terms of feasibility, safety and short-term complication. PMID- 29412233 TI - Thoracotomy compared to laparotomy in the traumatic diaphragmatic hernia. Systematic review and proportional methanalysis. AB - PURPOSE: To evaluate the most used approach to treat traumatic diaphragmatic ruptures, and in which one the requirement to assess the second cavity is more frequent. METHODS: Systematic review, observational studies. Outcomes: moment of approach, most commonly via addressed and the requirement to open the other cavity. Bases searched: Lilacs, Pubmed, Embase, Clinicaltrials.gov and Web of Science. Statistical analysis: StatsDirect 3.0.121 software. RESULTS: Sixty eight studies (2023 participants) were included. Approach in acute phase was performed four times more than in chronic phase. Approach: abdominal 65% (IC 95% 63-67%), thoracic 23% (IC 95% 21-24%), abdominal in the acute phase 75% (IC 95% 71-78%), and chronic 24% (IC 95% 19-29%), thoracic in the acute phase 12% (IC 95% 10-14%) and chronic 69% (IC 95% 63-74%). Thorax opening in the abdominal approach: 10% (95% CI 8-14%). Abdomen opening in the thoracic approach: 15% (95% CI 7-24%). CONCLUSIONS: The most common approach was the abdominal. The approach in the acute phase was more common. In the acute phase the abdominal approach is more frequent than the thoracic approach. In the chronic phase the thoracic approach is more frequent than the abdominal one. The requirement to open the second cavity was similar in both approaches. PMID- 29412234 TI - Combination of preoperative pulmonary and nutritional preparation for esophagectomy. AB - PURPOSE: To compare pulmonary and nutritional parameters before and after inspiratory muscle training (IMT) and enteral feeding support in patients with esophageal disease undergoing preoperative outpatient follow-up. METHODS: Thirty patients with a mean age of 55.83 years, 16 men and 14 women, were included. Pulmonary assessment consisted of the measurement of MIP, MEP, and spirometry. Anthropometric measurements and laboratory tests were performed for nutritional assessment. After preoperative evaluation, inspiratory muscle training and enteral nutrition support were started. A p<0.05 was considered statistically significant. RESULTS: After an outpatient follow-up period of 4 weeks, a significant increase in MIP (-62.20 +/- 25.78 to -81.53 +/- 23.09), MEP (73.4 +/- 31.95 to 90.33 +/- 28.39), and FVC (94.86 +/- 16.77 to 98.56 +/- 17.44) was observed. Regarding the anthropometric variables, a significant increase was also observed in BMI (20.18 +/- 5.04 to 20.40 +/- 4.69), arm circumference (23.38 +/- 3.28 to 25.08 +/- 4.55), arm muscle circumference (21.48 +/- 3.00 to 22.07 +/- 3.36), and triceps skinfold thickness (5.62 +/- 2.68 to 8.33 +/- 6.59). CONCLUSION: Pulmonary and nutritional preparation can improve respiratory muscle strength, FVC and anthropometric parameters. However, further studies are needed to confirm the effectiveness of this preoperative preparation. PMID- 29412235 TI - Abdominal cavity simulator for skill progression in videolaparoscopic sutures in Brazil. AB - PURPOSE: To develop and test a model of teaching by means of an abdominal cavity simulator. METHODS: This study had two stages: development of a teaching model and an experimental prospective study that aimed to evaluate the residents' competence. The participants were divided into 3 groups: first-year resident, second-year resident, and senior surgeon. The two groups of resident physicians received training in the simulator, under instructor supervision for skill acquisition, according to the model proposed in first stage. The surgeons did not receive this intervention. The correlations and associations were verified through simple and multiple linear regressions. The learning curves were analysed using Cox regression models. The impact of the epidemiological characteristics was tested. RESULTS: All residents reached the maximum score at the end of 16 steps and were comparable to the experimental (p<0.001). CONCLUSION: Residents who underwent training using the methodology of the proposed teaching model, which is based on realistic simulation, acquired proficiency in the accomplishment of endosutures in up to 16 hours of training in the laboratory. PMID- 29412236 TI - Assessment of a new kind of surgical simulator. The physical surgical simulator. AB - PURPOSE: To evaluate whether the use of the physical surgical simulator may benefit the development of laparoscopic skills. METHODS: Ten medical students were divided into two groups: the first one performed ten weekly training sessions with a physical surgical simulator - ETX A2 LAP and, afterwards, one laparoscopic cholecystectomy in a porcine model, while the second group performed only a laparoscopic cholecystectomy. Both groups were compared regarding bleeding, total surgical time, time to perform each surgical step and qualitative parameters, based on a previously validated tool. RESULTS: There was no difference in any of the evaluated parameters. CONCLUSION: We did not find any evidence of benefit in the use of the physical simulator for surgical performance in medical students. PMID- 29412237 TI - Technical innovation: Intragastric Single Port Sleeve Gastrectomy (IGSG). A feasibility survival study on porcine model. AB - PURPOSE: To perform technically the laparoscopic sleeve gastrectomy (LSG) using a unique Intragastric Single Port (IGSG) in animal swine model, evidencing an effective and safe procedure, optimizing the conventional technique. METHODS: IGSG was performed in 4 minipigs, using a percutaneous intragastric single port located in the pre-pyloric region. The gastric stapling of the greater curvature started from the pre-pyloric region towards the angle of His by Endo GIATM system and the specimen was removed through the single port. In the postoperative day 30, the animals were sacrificed and submitted to autopsy. RESULTS: All procedures were performed without conversion, and all survived 30 days. The mean operative time was 42 min. During the perioperative period no complications were observed during invagination and stapling. No postoperative complications occurred. Post mortem examination showed no leaks or infectious complications. CONCLUSION: Intragastric Single Port is a feasible procedure that may be a suitable alternative technique of sleeve gastrectomy for the treatment of morbid obesity. PMID- 29412238 TI - Prognostic Accuracy of the GRACE Score in Octogenarians and Nonagenarians with Acute Coronary Syndromes. AB - BACKGROUND: The GRACE Score was derived and validated from a cohort in which octogenarians and nonagenarians were poorly represented. OBJECTIVE: To test the accuracy of the GRACE score in predicting in-hospital mortality of very elderly individuals with acute coronary syndromes (ACS). METHODS: Prospective observational study conducted in the intensive coronary care unit of a tertiary center from September 2011 to August 2016. Patients consecutively admitted due to ACS were selected, and the very elderly group was defined by age >= 80 years. The GRACE Score was based on admission data and its accuracy was tested regarding prediction of in-hospital death. Statistical significance was defined by p value < 0,05. RESULTS: A total of 994 individuals was studied, 57% male, 77% with non ST elevation myocardial infarction and 173 (17%) very elderly patients. The mean age of the sample was 65 +/- 13 years, and the mean age of very elderly patients subgroup was 85 +/- 3.7 years. The C-statistics of the GRACE Score in very elderly patients was 0.86 (95% CI = 0.78 - 0.93), with no difference when compared to the value for younger individuals 0.83 (95% CI = 0.75 - 0.91), with p = 0.69. The calibration of the score in very elderly patients was described by chi2 test of Hosmer-Lemeshow = 2.2 (p = 0.98), while the remaining patients presented chi2 = 9.0 (p = 0.35). Logistic regression analysis for death prediction did not show interaction between GRACE Score and variable of very elderly patients (p = 0.25). CONCLUSION: The GRACE Score in very elderly patients is accurate in predicting in-hospital ACS mortality, similarly to younger patients. PMID- 29412239 TI - Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease. AB - BACKGROUND: Metabolic syndrome (MS) is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. OBJECTIVES: To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS). METHODS: Patients (n = 116, 68% males) aged 56 (9) years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1), methylenotetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (ENOS), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), apolipoprotein C3 (APOC3), lipoprotein lipase (LPL) were analysed by polymerase chain reaction (PCR) technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. RESULTS: Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 +/- 1.5 vs. 13.0 +/- 1.6, p = 0.066), with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078). CONCLUSIONS: The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease. PMID- 29412240 TI - Leisure-Time Physical Activity, but not Commuting Physical Activity, is Associated with Cardiovascular Risk among ELSA-Brasil Participants. AB - BACKGROUND: Despite reports in the literature that both leisure-time physical activity (LTPA) and commuting physical activity (CPA) can promote health benefits, the literature lacks studies comparing the associations of these domains of physical activity with cardiovascular risk scores. OBJECTIVE: To investigate the association between LTPA and CPA with different cardiovascular risk scores in the cohort of the Longitudinal Study of Adult Health ELSA-Brasil. METHODS: Cross-sectional study with data from 13,721 participants of both genders, aged 35-74 years, free of cardiovascular disease, from ELSA Brazil. Physical activity was measured using the International Physical Activity Questionnaire (IPAQ). Five cardiovascular risk scores were used: Framingham score - coronary heart disease (cholesterol); Framingham score - coronary heart disease (LDL-C); Framingham score - cardiovascular disease (cholesterol); Framingham score - cardiovascular disease (body mass index, BMI); and pooled cohort equations for atherosclerotic cardiovascular disease (ASCVD). Associations adjusted for confounding variables between physical activity and different cardiovascular risk scores were analyzed by logistic regression. Confidence interval of 95% (95%CI) was considered. RESULTS: LTPA is inversely associated with almost all cardiovascular risk scores analyzed, while CPA shows no statistically significant association with any of them. Dose-response effect in association between LTPA and cardiovascular risk scores was also found, especially in men. CONCLUSIONS: LTPA was shown to be associated with the cardiovascular risk scores analyzed, but CPA not. The amount of physical activity (duration and intensity) was more significantly associated, especially in men, with cardiovascular risk scores in ELSA-Brasil. PMID- 29412241 TI - Oral Anticoagulation in Atrial Fibrillation: Development and Evaluation of a Mobile Health Application to Support Shared Decision-Making. AB - BACKGROUND: Atrial fibrillation is responsible for one in four strokes, which may be prevented by oral anticoagulation, an underused therapy around the world. Considering the challenges imposed by this sort of treatment, mobile health support for shared decision-making may improve patients' knowledge and optimize the decisional process. OBJECTIVE: To develop and evaluate a mobile application to support shared decision about thromboembolic prophylaxis in atrial fibrillation. METHODS: We developed an application to be used during the clinical visit, including a video about atrial fibrillation, risk calculators, explanatory graphics and information on the drugs available for treatment. In the pilot phase, 30 patients interacted with the application, which was evaluated qualitatively and by a disease knowledge questionnaire and a decisional conflict scale. RESULTS: The number of correct answers in the questionnaire about the disease was significantly higher after the interaction with the application (from 4.7 +/- 1.8 to 7.2 +/- 1.0, p < 0.001). The decisional conflict scale, administered after selecting the therapy with the app support, resulted in an average of 11 +/- 16/100 points, indicating a low decisional conflict. CONCLUSIONS: The use of a mobile application during medical visits on anticoagulation in atrial fibrillation improves disease knowledge, enabling a shared decision with low decisional conflict. Further studies are needed to confirm if this finding can be translated into clinical benefit. PMID- 29412242 TI - Development and Psychometric Validation of HIPER-Q to Assess Knowledge of Hypertensive Patients in Cardiac Rehabilitation. AB - BACKGROUND: The absence of instruments capable of measuring the level of knowledge of hypertensive patients in cardiac rehabilitation programs about their disease reflects the lack of specific recommendations for these patients. OBJECTIVE: To develop and validate a questionnaire to evaluate the knowledge of hypertensive patients in cardiac rehabilitation programs about their disease. METHODS: A total of 184 hypertensive patients (mean age 60.5 +/- 10 years, 66.8% men) were evaluated. Reproducibility was assessed by calculation of the intraclass correlation coefficient using the test-retest method. Internal consistency was assessed by the Cronbach's alpha and the construct validity by the exploratory factorial analysis. RESULTS: The final version of the instrument had 17 questions organized in areas considered important for patient education. The instrument proposed showed a clarity index of 8.7 (0.25). The intraclass correlation coefficient was 0.804 and the Cronbach's correlation coefficient was 0.648. Factor analysis revealed five factors associated with knowledge areas. Regarding the criterion validity, patients with higher education level and higher family income showed greater knowledge about hypertension. CONCLUSION: The instrument has a satisfactory clarity index and adequate validity, and can be used to evaluate the knowledge of hypertensive participants in cardiac rehabilitation programs. PMID- 29412243 TI - Epidemiological aspects of human and canine visceral leishmaniasis in State of Alagoas, Northeast, Brazil. AB - : Zoonotic visceral leishmaniasis (ZVL), caused by protozoans of the genus Leishmania, it is a worldwide of great importance disease. In the northeast region of Brazil, the state of Alagoas has an endemic status for ZVL. Thus, this work aimed to analyze the epidemiological situation of human and canine visceral leishmaniasis in Alagoas, Northeast, Brazil, from 2007 to 2013. We conducted a descriptive, observational, retrospective study using secondary data from the Notifiable Diseases Information System, the Center of Zoonosis Control of Maceio, and the Central Laboratory of Public Health of Alagoas. During the studied period, it was observed that the highest incidence of human visceral leishmaniasis was in 2011 and the lowest in 2013. On the other hand, canine visceral leishmaniasis had its highest incidence in 2007 and its lowest in 2012. Of the 55 municipalities in the State of Alagoas that showed human visceral leishmaniasis (HVL), Sao Jose da Tapera presented an average of 4.4 cases over the past five years, being classified as of intense transmission. Regarding canine visceral leishmaniasis, in the same studied period, 45,112 dogs were examined in the State, of which 4,466 were positive. It resulted, thus, in a 9.9% positivity rate. CONCLUSIONS: Our data are important because canine infection is an important risk factor for the human disease. PMID- 29412244 TI - Effect of watershed land use on water quality: a case study in Corrego da Olaria Basin, Sao Paulo State, Brazil. AB - The water quality is related to the hydrologic and limnologic properties of ground and surface water, and significant efforts have been made to monitor water sources to understand the effects of land use changes in agricultural areas, with significant socioeconomic activities. The objective of this study was to evaluate the qualitative aspects of surface water in subbasins related to land use. Samples were analyzed in terms of physical and chemical parameters on monthly discrete water quality sampling in four representative sites at first order subbasin streams, located at the Polo Regional Centro Norte, Pindorama County, State of Sao Paulo, Brazil. The land use classification was made by visual detection technique in a multispectral satellite data obtained from LandSat8- spectral bands of the OLI sensor. The watershed was classified into major land cover/use classes and overlay maps generated in ArcGIS 10 indicated a significant shift from natural vegetation to agriculture activities. Water quality monitoring was according to the brazilian protocol and the results were submitted to analysis of variance (ANOVA). The values obtained differ significantly at each sampling point - subbasins, reflecting the effects of land use on water quality. Soil conservation management is important to optimize soil use in order to contribute to the control of water pollution and the formulation of a public policy is necessary for the conservation of water and soil resources. PMID- 29412245 TI - Effect of irrigation at critical stages on the phenology of flowering and fruiting of the cactus Opuntia spp. AB - This paper briefly reports some effects of irrigations at two critical periods on the phenology of three varieties of cactus pear cultivated in Agadir area: the spineless varieties 'Aissa' and 'Moussa' and the thorny one 'Achefri'. In the first year experiments (2010-2011) treatments of irrigation used were: (T1) 0 mm, (T2) 30 mm during flowering and 30 mm during fruit enlargement and (T3) 30 mm only during fruit enlargement. In the 2nd year experiments, irrigation treatments were: (T1) 0 mm, (T2) 60 mm during flowering and 60 mm during fruit enlargement and (T3) 60 mm only during fruit enlargement. Treatments of irrigation were applied between mid-April and mid-June in the 1st year experiments and in February and May in the 2nd year experiments. Results of the first year experiments showed that the emission of buds was higher in the thorny variety than in the spineless ones (more than 6 emitted buds/cladode vs less than 4.5 in the spineless varieties). In the second year, irrigation increased the emission of buds in the three varieties (more than 7 emitted buds/cladode for each T2 and T3 of all varieties vs not more than 5 for T1) and the duration of the flowering phase of these varieties. However, irrigation did not modify the proportions of fruits reaching commercial maturity during the early or the late period of maturation. PMID- 29412246 TI - Potential of natural repellents methylanthranilate and anthraquinone applied on maize seeds and seedlings against house sparrow (Passer domesticus) in captivity. AB - Various bird pests caused severe economic losses to valuable crops and fruit orchards all over the world. Among the birds, house sparrow is also considered to cause heavy plunder, not only to seeds of crops but also seedlings especially in organic farming. In present study two bird repellents, methylanthranilate and anthraquinone tested against house sparrows on maize seeds and seedlings in aviary conditions. Trial group in aviary-I, the treated maize seeds and seedlings with different doses of both bird repellents, control group in aviary-II, untreated seeds and seedlings were provided for three hours in the early morning. In each aviary, two closed circuit cameras were also installed to monitor the behavioral responses against different concentrations of both chemical repellents. Statistical analysis showed that there existed highly significant (P<0.01) variations among the trial and control groups for seeds and seedlings. By comparing both repellents, significant (P<0.05) differences were detected and anthraquinone showed better efficacy when compared to methylanthranilate, but in maize seedlings both repellents equal repellent properties. Non-significant (P>0.05) differences were observed in different grading of both natural chemical repellents for maize seeds while significant (P<0.05) variations were noticed for maize seedlings when provided to sparrows. By videotaped behavior sparrows presented manifest head juddering and feather upsetting activities by consumption of treated seeds and seedlings with higher concentrations of both natural bird repellents. PMID- 29412247 TI - Black and white teas as potential agents to combine with amphotericin B and protect red blood cells from amphotericin B-mediated toxicity. AB - Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with black tea or white tea and protective of citotoxic effect. The present study shows that white and black teas have additive effects with amphotericin B against some species Candida. In addition, the combination of white and black tea with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that white and black tea is a potential agent to combine with amphotericin for antifungal efficacy and to reduce the amphotericin dose to lessen side effects. PMID- 29412248 TI - Histopathology of Andean Potato (Solanum tuberosum Andigenum group) varieties parasitized by the false root-knot nematode, Nacobbus aberrans. AB - Landraces of the Solanum tuberosum Andigenum group are abundant and diverse. They are a valuable genetic resource possessing resistance to pests, diseases, and environmental stresses. In the Andean region, populations of the false root-knot nematode Nacobbus aberrans became specialized to infect native potatoes, being one of the major limiting factors affecting this crop. A better understanding of the host plant-parasite interactions is important in order to select tolerant or resistant plants to be included in management programs. Despite the close of association of N. aberrans with potato, and the great diversity of the S. tuberosum Andigenum group, few histopathological studies have been conducted. The aim of this work was to analyze histological alterations induced by different Argentine populations of the nematode in naturally infested roots of four Andean potato varieties (Collareja, Negra Imilla, Ojo de Senorita and Colorada). All the varieties showed hyperplastic tissue in the central zone of galls, where syncytia developed in close association with the nematode female. Syncytia were composed of modified hyperplastic tissue and parenchyma xylem cells. The results showed differences among varieties in their response to nematode populations, with Ojo de Senorita and Negra Imilla being the most susceptible ones. This study is the first describing histopathological alterations induced by N. aberrans in susceptible Andean potato landraces. PMID- 29412249 TI - Exogenous niacin treatment increases NADPH oxidase in kiwifruit. AB - Kiwifruit are a popular fruit worldwide; however, plant growth is threatened by abiotic stresses such as drought and high temperatures. Niacin treatment in plants has been shown to increase NADPH levels, thus enhancing abiotic stresses tolerance. Here, we evaluate the effect of niacin solution spray treatment on NADPH levels in the kiwifruit cultivars Hayward and Xuxiang. We found that spray treatment with niacin solution promoted NADPH and NADP+ levels and decreased both O2.- production and H2O2 contents in leaves during a short period. In fruit, NADPH contents increased during early development, but decreased later. However, no effect on NADP+ levels has been observed throughout fruit development. In summary, this report suggests that niacin may be used to increase NADPH oxidases, thus increasing stress-tolerance in kiwifruit during encounter of short-term stressful conditions. PMID- 29412250 TI - Susceptibility of cariogenic microorganisms to phytoconstituents. AB - This study aimed to evaluate the in vitro antibacterial activity of the phytochemicals thymol, linalool, and citronellol against Streptococcus mutans, Streptococcus salivarius and Streptococcus oralis. Disk diffusion screening on solid medium and measurement of the diameter of the bacterial growth inhibition halos was the technique utilized. The Minimum Inhibitory Concentration (MIC) of the substances was determined using serial substance dilutions and microdilution technique in Brain Heart Infusion culture medium. After incubation for 24 hours in an oven at 37 degrees C, plate reading was completed and confirmed by visual method using 2,3,5 triphenyl tetrazolium chloride dye. The Minimum Bactericidal Concentration (MBC) was determined from MIC subcultures. Assays were performed in triplicate, and chlorhexidine was used as a positive control. The diameters in mm of the growth inhibition halos ranged between 7.3 and 10.7 for S. mutans, 7.3 and 10.0 for S. oralis, and 8.2 and 9.8 for S. salivarius. The MIC and MBC values obtained converged, ranging from maximum values in the presence of Linalool (1,250.0 mg/mL, 2,500.0 mg/mL and 2,500.0 mg/mL, respectively, for S. mutans, S. oralis, and S. salivarius); and minimum values with Thymol (312.5 MUg/ml, 156.2 MUg/mL and 156.2 MUg/ml, respectively for S. mutans, S. oralis, and S. salivarius). All the tested phytochemicals displayed antibacterial activity, thus representing substances with potential applications in preventing tooth decay. PMID- 29412251 TI - Reports of new wing color polymorphism and taxonomic information to cercopids (Auchenorrhyncha: Cercopidae) from upland rice crop, Para State, Brazil. AB - Cercopidae is one of the largest families of the spittlebug superfamily Cercopoidea. Most spittlebugs species are characterized by bright color patterns. Thus, this study evaluated for the first time the Cercopidae species collected in rice crops, Novo Progresso, Para state, Brazil. Insects were collected weekly between November/2010 and March/2011 from areas without (WA) and with agrochemical applications (AA). Four species were recorded: Deois incompleta (Walker, 1851) (71 specimens in WA area and 50 in AA area); Mahanarva spectabilis (Distant, 1909) (39 specimens in WA area and 39 in AA area); Mahanarava tristis (Fabricius, 1803) (26 specimens in WA area and 20 in AA area); Zulia pubescens (Fabricius, 1803) (11 specimens in WA area and four in AA area). The species collected displayed pronounced color polymorphism when compared with the color patterns of the same species from other regions. This makes correct identification more difficult for these species. Therefore, taxonomic and diagnostic informations provided in this study will help in the correct identification, control and monitoring of these insects in future studies. Besides that, we recommend monitoring in rice fields and further study of the biology and ecology of cercopids in Brazil to assess the potential of these species as rice pests. PMID- 29412252 TI - Identification and susceptibility of clinical isolates of Candida spp. to killer toxins. AB - Although invasive infections and mortality caused by Candida species are increasing among compromised patients, resistance to common antifungal agents is also an increasing problem. We analyzed 60 yeasts isolated from patients with invasive candidiasis using a PCR/RFLP strategy based on the internal transcribed spacer (ITS2) region to identify different Candida pathogenic species. PCR analysis was performed from genomic DNA with a primer pair of the ITS2-5.8S rDNA region. PCR-positive samples were characterized by RFLP. Restriction resulted in 23 isolates identified as C. albicans using AlwI, 24 isolates as C. parapsilosis using RsaI, and 13 as C. tropicalis using XmaI. Then, a group of all isolates were evaluated for their susceptibility to a panel of previously described killer yeasts, resulting in 75% being susceptible to at least one killer yeast while the remaining were not inhibited by any strain. C. albicans was the most susceptible group while C. tropicalis had the fewest inhibitions. No species-specific pattern of inhibition was obtained with this panel of killer yeasts. Metschnikowia pulcherrima, Pichia kluyveri and Wickerhamomyces anomalus were the strains that inhibited the most isolates of Candida spp. PMID- 29412253 TI - New evidence of the evolutionary relationship of the flavida complex with the genus Panstrongylus (Hemiptera, Triatominae) by karyosystematic. PMID- 29412254 TI - Reservoir longitudinal gradient promotes ordered losses on diversity and density of Ephemeroptera community. AB - Reservoir operations alter, eliminate or restrain the natural hydrologic cycles. Biotic community has become subject to these non-cyclic events, responding by reducing the species diversity. Ephemeroptera species present distinct responses to environmental deterioration such that poses this assemblage between the most useful groups in biomonitoring programs. We hypothesized an alteration in beta diversity at the longitudinal species gradient, which will be influenced mainly by species losses between zones. Changes in temporal beta diversity is also expected, but the main drivers of such alterations will be the species turnover between the sampling period. Ephemeroptera community was monitored in nine sampling points from Itaipu Reservoir, where were installed three sets of substrates composed by a float and 2 wooden substrates. We took biological samples in triplicates monthly, from June-01 to August-02. Our initial hypothesis was partially supported and with significant variations only for spatial approach, between the Reservoir zones. The generated ordering from Non-Metric Dimensional Scale - NMDS - corroborated with spatial analyzes, with the formation of two groups along the gradient zonation of the reservoir. The temporal ordination showed no clear pattern. As expected, the contribution to beta diversity was different for our two approaches, such that the loss of species was more important along the spatial gradient and despite of no significant result, the species replacement was more important among months. The spatial results lead us to infer that differences in limnological characteristics between zones are important for determining differences in Ephemeroptera composition and can reflect the dependency degree of the species in relation to the lentic and sometimes-lotic conditions, mainly in the riverine zone of reservoirs. On the other hand, the absence of a temporal pattern can be result of chaotic variations in the physical and chemical attributes imposed by the reservoir operation, disrupting continuity of the biota and natural succession processes. PMID- 29412255 TI - ? AB - Edward Cope's neo-Lamarckist theory operated with an alternative mechanism to natural selection. For him, increases or decreases of the ontogenic stages produce characteristics that could be generated and integrated into the organism through the inheritance of acquired characters. Increasing body complexity, or not, this mechanism increased adaptive capacity. This could be interpreted as biological progress in a manner similar to the interpretation made by proponents of synthetic evolutionary theory. But unlike the latter, neo-Lamarkism relegated natural selection to a secondary role. This study aims to clarify the position of Cope in relation to the phenomenon of biological progress, as well as his strongly adaptational approach, proposing that this has been an indirect contribution to the articulation of the new evolutionary synthesis. PMID- 29412256 TI - Parliamentary debates on death with dignity in Argentina: the rights of terminal patients on the legislative agenda, 1996-2012. AB - This article examines the regulation on terminal patients' rights in Argentina at two points in time: the first attempts to regulate end-of-life rights (1996), and the "death with dignity" law passed by the National Congress (2011-2012). Comparative analysis allows us to observe variations among the individuals and situations included in the legislation, as well as in the conceptualization of autonomy and the interventions that is considered lawful refuse. The political context and the differential way that "death with dignity" entered the legislative agenda in each period determined the public's construction of the problem and thus the extent and result of the debates. PMID- 29412257 TI - The tropics, science, and leishmaniasis: an analysis of the circulation of knowledge and asymmetries. AB - The article investigates the process of circulation of knowledge which occurred during the first decades of the twentieth century between the South American researchers Edmundo Escomel (Peru) and Alfredo Da Matta (Brazil) and the Europeans Alphonse Laveran (France) and Patrick Manson (England) with regard to the definition and validation of espundia as a disease specific to South America, while simultaneously the need to insert this illness into the newly created group of diseases called the "leishmaniasis" was proposed. Sharing recent concerns in considering historical research beyond the limits imposed by the Nation-state as a category that organizes narratives, it dialogs with some apologists of global and transnational history, situating this specific case within this analytical perspective. PMID- 29412258 TI - The black scourge? Race and the Rockefeller Foundation's tuberculosis commission in interwar Jamaica. AB - From 1927 to 1942, the Rockefeller Foundation ran a tuberculosis commission in Jamaica that researched the epidemiology of the disease, examined the efficacy of a vaccine with heat-killed tubercle bacilli, and offered basic treatment to tuberculosis sufferers. Drawing upon diaries and scientific writings by the staff employed by the commission, among other sources, this article explores the role that race played in the tuberculosis commission. It assesses how race shaped the research conducted by the commission, how it informed staff interactions and staff/patient relations, and the clash and/or confluence of "imported" and local racial ideas in the commission's work. PMID- 29412259 TI - An imperial laboratory: the investigation and treatment of treponematoses in occupied Haiti, 1915-1934. AB - This article examines anti-treponematoses work as part of US occupation public health policy in Haiti, a unique event in the history of international health. Yaws was highly prevalent in Haiti, but occupation doctors initially ignored it because of its close association with syphilis and stigmas attached to sexually transmitted disease. This changed when C.S. Butler asserted that yaws was "innocent" and that the two diseases should therefore be considered as one. Treatment increased as an anti-treponematoses campaign was now believed to hold great benefits for the occupation's paternalist and strategic aims, even though it ultimately failed. This work reflected Haiti's status as a public health "laboratory" which affected Haitian medicine for years to come and significantly influenced future campaigns aimed at disease eradication. PMID- 29412260 TI - Liberating the people from their "loathsome practices:" public health and "silent racism" in post-revolutionary Bolivia. AB - After the Movimiento Nacionalista Revolucionario (MNR) took power in the 1952 National Revolution, the party expanded rural public health programs to address what early twentieth-century elites called the "Indian problem:" the idea that indigenous culture was an impediment to Bolivia's modernization. After 1952, the MNR used public health as a project of cultural assimilation, and state-sponsored health programs sought to culturally whiten the population by transforming personal habits. This essay analyzes the language with which health workers discussed the indigenous population to show that despite the regime's intention to move away from defining the rural population on racial terms, medical and political elites continued to define indigenous customs as an obstacle to progress and a remnant of an antiquated past. PMID- 29412261 TI - Not a polar island: yellow fever, Spanish medical research, and the struggle for scientific and political hegemony in late nineteenth century Cuba. AB - This paper explores questions related to yellow fever and the political destiny of Cuba in the late nineteenth century. A forgotten therapeutic device to treat the disease invented in that period, the "polar chamber" (camara polar), provides a useful standpoint for reconstructing the tradition of Spanish yellow fever research in Cuba, a topic largely neglected by the medical historiography. The failed history of this device can also illuminate the complex struggle for scientific hegemony between Spanish, Cuban, and US institutions and researchers. Finally, we focus on the politics of the polar chamber by analyzing how this invention intended to provide a particular solution for the complex, threefold struggle for Cuba's political future. PMID- 29412262 TI - [From oral history to the research film: the audiovisual as a tool of the historian]. AB - An analytical essay of the process of image production, audiovisual archive formation, analysis of sources, and creation of the filmic narrative of the four historiographic films that form the DVD set Passados presentes (Present pasts) from the Oral History and Image Laboratory of Universidade Federal Fluminense (Labhoi/UFF). From excerpts from the audiovisual archive of Labhoi and the films made, the article analyzes: how the problem of research (the memory of slavery, and the legacy of the slave song in the agrofluminense region) led us to the production of images in a research situation; the analytical shift in relation to the cinematographic documentary and the ethnographic film; the specificities of revisiting the audiovisual collection constituted by the formulation of new research problems. PMID- 29412263 TI - Zika and Aedes aegypti: new and old challenges. AB - Infection with the zika virus had a great impact not only on pregnant women and newborns, but also on public health, on popular ideas about Aedes aegypti and with respect to women's social rights. The objective of this paper is to identify this impact and the historical, social and health changes of the disease and the legacy of the zika virus. Interventions by researchers from different specialties foster conditions for more comprehensive investigations into future epidemic threats in Brazil and Latin America. This dialogue took place after the seminar "Aedes aegypti: past and future health emergencies," organized by the Casa de Oswaldo Cruz, when we talked with some speakers and other leading researchers about the history and challenges of Aedes aegypti and zika. PMID- 29412264 TI - [A history of missing historians? A call for historiographical reflection]. PMID- 29412265 TI - [Rethinking the "wager on life:" toward environmental sociology in the twenty first century]. PMID- 29412266 TI - [Eradication of Aedes aegypti: new perspectives on international health cooperation in the Americas]. PMID- 29412267 TI - [The magic of technologies and frontiers: a comment on Beyond Imported Magic]. PMID- 29412268 TI - ? AB - [This corrects the article doi: 10.1590/S0104-59702017000300012]. PMID- 29412269 TI - Health, zika and politics. PMID- 29412270 TI - Cuadernos Medico Sociales from Rosario, Argentina, and other Latin American social medicine journals from the 1970s and 1980s. AB - In the 1970s and 1980s, a series of journals were founded to disseminate ideas from Latin American social medicine in various countries across the continent, during the early stage of a movement that would later become institutionalized in Brazil under the name "collective medicine." In this article, we look at the principal characteristics of those endeavors: Revista Centroamericana de Ciencias de la Salud, Saude em Debate, Salud Problema, Revista Latinoamericana de Salud and Cuadernos Medico Sociales. We focus in particular on Cuadernos Medico Sociales, published in Rosario, Argentina. We analyze the conditions under which this publication emerged, the editorial processes it followed, and the central role played by Carlos Bloch, its founder and managing editor. PMID- 29412271 TI - [Delicious, healthy, and good for digestion: medical discourse present in the consumption of fruit, preserves, and compotes in sixteenth-century Portuguese America]. AB - One of the major challenges the European colonizers faced in sixteenth-century Portuguese America was adaptation to their new environment, especially nutritional obstacles. Obtaining the human body's daily calorie requirements may have been one of the more strenuous tasks in colonial dynamics. Their diets were composed of what was available; in this context, native fruits took on an important role, especially when consumed in the form of compotes and preserves. Our goal is to highlight the importance of colonial sweets, identify how they were consumed, and show the relationship between this activity and the medical discourse which was present in sixteenth-century Europe. PMID- 29412272 TI - Medical translators and the idea of translation in Portugal in the late eighteenth century: the case of books on medicine. AB - This study demonstrates how translations into Portuguese influenced the publishing market in the late eighteenth century and sheds light on the establishment of standard Portuguese. Focusing specifically on medical texts translated into Portuguese from published works or manuscripts between 1770 and 1810, the translators' - and occasionally the editors' - paratexts in the translated books on medicine and pharmacy are investigated and cross-referenced against reports written by the censors on the same works, themselves physicians appointed by the censorship bodies or physicians/censors, in a bid to seek out answers, however incomplete they may be, to questions about the circulation of the printed word, the spread of scientific knowledge, and the debates concerning the definition of the Portuguese language. PMID- 29412273 TI - Facing austerity: the decline in health access and quality of care for patients with cancer in Portugal. AB - In April 2011, Portugal called on the European Union for a financial bailout due to its debt crisis, and counterbalanced this rescue with various austerity measures. Within the Portuguese public health system (Servico Nacional de Saude, SNS) these measures were swiftly applied on a large scale, and in turn led to increasing difficulties among the health professionals within the SNS with regard to the use of diagnostics, treatments, and medications for patients, as well as growing obstacles to regular clinical consultations. Through media analysis of Portuguese health policy related to cancer and statements from professionals in the SNS, this article expresses the concerns of these health providers and explores how this situation is negatively impacting the lives of those who deal with this disease every day. PMID- 29412274 TI - [The San Juan de Dios Hospital and its workers: the social life of a hospital and the health crisis in Colombia]. AB - This article describes some significant events of the fifteen years of struggle (1999-2014) of a group of women for the reactivation of the San Juan de Dios Hospital and to stay on as workers after the neoliberal reforms in Colombia. The ethnography presented proposes tools for the understanding of the moral dimensions forged from a conflict for the recognition of rights and shows that the hospital, more than being an architectural complex, is a language activated by the workers to affirm their humanity, a vehicle for the symbolic elaboration of a cause and a means to understand the construction of collectives based on emotional terminology. PMID- 29412275 TI - The technopolitics of climate change: climate models, geopolitics, and governmentality. AB - Based on an empirical study of climate modeling at Brazil's Instituto Nacional de Pesquisas Espaciais, the article explores how climate modeling represents a pragmatic government approach in the realm of climate change. The discussion begins with how this pragmatic approach serves the purposes of the geopolitical action of the State within the international framework of global climate knowledge production. It then shows how modeling engenders forms of interpretation of climate change phenomena and future impacts on the local scale and finds expression in governmental rationalities of a biopolitical nature. In short, the discussion is how the technoscience of climate modeling is constructed as a governmental technology and rationality (governmentality) of the State, a process I call the technopolitics of climate change. PMID- 29412276 TI - Oral history and memories of Hansen's disease patients in two Colombian leper colonies: life trajectories, conflicts and resistance strategies. AB - The paper examines the oral history of Hansen's disease in two Colombian communities that were leper colonies until 1961. The oral history around the disease allows us to connect individuals' memories with collective memory. This history remains an oral one, and few academic studies have documented it. We use oral history as a qualitative research method in order to analyze how the patients and those who lived alongside them positioned themselves in terms of the disease and how it permeated their entire existence, re-signifying the concepts of health and disease, normality and abnormality. We examine how, over the course of their lives, they engaged in resistance strategies that allowed them to get closer to normality, in their own sociocultural terms. PMID- 29412277 TI - Family and crisis: contributions of the systemic thinking for family care. PMID- 29412278 TI - Primary care assessment from a male population perspective. AB - OBJECTIVE: to evaluate the quality of primary health care from the perspective of the male population. METHOD: a cross-sectional descriptive-evaluative study conducted at the family health units of Teresina, Piaui, Brazil, with the male population being interviewed through the Primary Care Assessment Tool (PCAT). RESULTS: 301 participants with mean age of 51.34 years, married, incomplete elementary school and monthly income between one and two minimum wages. The evaluation was positive for the following care domains: utilization, information system and longitudinality. The features access, comprehensiveness of care, service available and service provided, family centeredness and community orientation obtained a negative evaluation. CONCLUSION: the features of primary care are unsatisfactory, indicating the need to expand access to services offered and to qualify care for male users. PMID- 29412279 TI - Social representations of undergraduates about the education through work for health program. AB - OBJECTIVE: analyze the social representation of undergraduates from the health area in which were scholars of PET-Saude of the UFRJ-Macae Professor Aloisio Teixeira Campus about this program and its contribution to the respective professional training. METHOD: This is an exploratory, descriptive study, with a qualitative approach. A total of 38 undergraduates participated, and a professional socioeconomic questionnaire and semi-structured interview were used to collect data. To analyze the data, thematic content analysis was used. RESULTS: The results showed that PET-Saude integrates undergraduates, health professionals and community, seeking the interdisciplinarity and the interrelation of those involved, articulating the scientific knowledge with the common sense for the transformation of the health service. CONCLUSION: The program encourages population's empowerment and the critical, reflexive thinking of undergraduates and professionals about the health-disease process and acts as a source of transformations in the training of health professionals in response to the demands of the Unified Health System (SUS). PMID- 29412280 TI - Palliative therapy in adults with cancer: a cross-sectional study. AB - OBJECTIVE: To characterize the socioeconomic and clinical profile of adult cancer patients in palliative therapy. METHOD: Cross-sectional study in an oncology hospital in Parana, with 124 adult patients who started palliative therapy in the period from Jan. 2 to June 30, 2015. RESULTS: Of the participating population, 60.5% were women, 68.5% white, 48.4% married, 72.6% catholic and with income of one to two minimum wages. Non-smokers, 45.2%, non-alcoholics 75%, and 92% had Performance Status 1 and 2. The predominant primary diagnosis was breast cancer, with previous chemotherapy and radiotherapy. The sites of metastasis were lung/mediastinum/bronchi and lymph nodes. CONCLUSION: The socioeconomic and clinical context characterized the profile of adult patients in palliative therapy. The demand arising from the increase in cases of advanced cancer requires nursing care at all stages of treatment. PMID- 29412281 TI - Patient participation in hand hygiene among health professionals. AB - OBJECTIVE: To investigate the perception and attitude of health professionals (HPs) about the patient participation in hand hygiene (HH). METHOD: A cross sectional study with 150 HPs from a university hospital in Brazil. A descriptive analysis was conducted. RESULTS: Simple hand hygiene was the preferred method of HPs, rather than hand rubbing with alcohol-based solutions. A total of 83.3% of the HPs supported the patient participation in reminding them about HH, but 48% reported that they would feel uncomfortable; 45.3%, comfortable; and 20.7% were familiar with the "Patients for Patient Safety" program. CONCLUSION: HPs showed limited knowledge about HH, opposing recommendations on the topic. The contradiction between the HPs acceptance and attitude when questioned by the patient regarding HH was revealed, reflecting a lack of knowledge about the WHO program and the need to implement educational practices in health. PMID- 29412282 TI - The use of Facebook in health education: perceptions of adolescent students. AB - OBJECTIVE: understand the perceptions of adolescent students regarding the use of Facebook social media in sexual and reproductive health learning in the Family Health Strategy. METHOD: a qualitative, descriptive study developed with 96 adolescents from a public school and a private school in Fortaleza-CE who concluded an educational intervention using Facebook. The information was collected in the online environment itself, as well as in a questionnaire applied in person. For the collection and analysis of this information, netnography was used. RESULTS: Facebook contributed to the sexual and reproductive health education in an interactive, playful and practical way, reducing the embarrassment of some adolescents to converse on the subject, and brought adolescents closer to the health service, by strengthening their bond with Health professionals. FINAL CONSIDERATIONS: health professionals should recognize that such virtual spaces on the Internet offer potential for the production of health care, especially among adolescents. PMID- 29412283 TI - The daily lives of people with Parkinson's disease. AB - OBJECTIVE: To understand the daily lives of people with Parkinson's disease. METHOD: Qualitative research, using as methodological and theoretical referential the Grounded Theory and Symbolic Interactionism, respectively. The in-depth interview was conducted with 30 people with Parkinson's disease. RESULTS: From data analysis, three themes were selected: Living with the disease - living with the treatment and changes in lifestyle; Modifying of one's job performance - revealing incapacity for work and the need to anticipate retirement and; Living with the stigma - the feeling of prejudice against the disease and the perceived limitations of the health services. FINAL CONSIDERATIONS: Living with a chronic and non-transferable disease encompasses social, physical and cultural effects, along with the personal experiences of each unique individual. This study assists the improvement of care to people with the disease, because the care practice emerges from the interactions between the subjects. PMID- 29412284 TI - The free spirit: spiritualism meanings by a Nursing team on psychiatry. AB - OBJECTIVE: To analyze the meanings attributed by nursing professionals in psychiatry to spirituality and its relationship with care. METHOD: Clinical qualitative, with appreciation of symbolic meanings. We interviewed 18 individuals for a semi-structured script of open questions and the data were analyzed in the light of psychoanalytic hermeneutics. The discussion was undertaken with the overlap of understanding of the sacred symbol, psychological and the meaning of life. RESULTS: Different spiritualities are interposed by personal restlessness and the experience of transience. Spirituality aids in social functions, personal balance and commitment to endure the anguish of transience. Among professionals, it has been shown as an ethical-combative attitude to evil forms, but there is a restriction in dealing with patients' spirituality. FINAL CONSIDERATIONS: The meanings pointed to the limits of human reason, resembling caregivers and patients in subjective conditions by which they avoid spirituality in psychiatry. It is suggested that spiritual attention be given to professionals. PMID- 29412285 TI - Disability retirement among university public servants: epidemiological profile and causes. AB - OBJECTIVE: To identify the epidemiological profile and causes of disability pensions for university public servants. METHOD: A cross-sectional and descriptive study, carried out with 40 retired employees due to disability of a public university. Sociodemographic, occupational and clinical data were obtained. The analyses were stratified according to gender, considering a significance level of 5%. RESULTS: Disability pensions were more frequent among women (72.5%), aged up to 60 years (77.5%). Mental and behavioral disorders were mainly responsible for pensions (35%). There was a significant difference between the sexes (p <= 0.05) for the variables: educational level, function performed by the worker and presence of dependents. CONCLUSION: The epidemiological profile showed a higher frequency of female, married/stable marital status, aged between 51 and 60 years and up to 12 years of schooling. Chronic degenerative diseases were predominant among the causes for disability pensions. PMID- 29412286 TI - Workload of nurses: observational study of indirect care activities/interventions. AB - OBJECTIVE: Observe the workflow of nurses in hospitalization units identifying indirect care activities/interventions; measure the frequency and average time spent in performing them; and to verify the associations between average time of the activities interventions grouped into categories and per hospitalization unit. METHOD: Observational exploratory study using the timed technique. It was conducted in medical, surgical and specialized clinic units of a teaching hospital in the northwest of Sao Paulo Brazil, with 16 attending nurses as participants. RESULTS: 90 hours of observation were performed, of which 58% (52 hours and 10 minutes) were related to indirect care activities of the patients. The most frequent activities/interventions were: "Communication" - 1,852 (44.1%), mean 34.6 (SD = 54); "Walking" - 1,023 (24.3%), mean 22 (SD = 49.2); and "Documentation" - 663 (15.8%), mean 82.7 (SD = 144.4). CONCLUSION: These findings favor a redesign of the work process and foster the need to update and refine the current workload measurement instruments. PMID- 29412287 TI - Construction and validation of clinical contents for development of learning objects. AB - OBJECTIVE: to describe the process of construction and validation of clinical contents for health learning objects, aimed at patients in the treatment of head and neck cancer. METHOD: descriptive, methodological study. The development of the script and the storyboard were based on scientific evidence and submitted to the appreciation of specialists for validation of content. The agreement index was checked quantitatively and the suggestions were qualitatively evaluated. RESULTS: The items described in the roadmap were approved by 99% of expert experts. The suggestions for adjustments were inserted in their entirety in the final version. The free-marginal kappa statistical test, for multiple evaluators, presented value equal to 0.68%, granting a substantial agreement. CONCLUSION: The steps taken in the construction and validation of the content for the production of educational material for patients with head and neck cancer were adequate, relevant and suitable for use in other subjects. PMID- 29412288 TI - Critical defining characteristics for nursing diagnosis about ineffective breastfeeding. AB - OBJECTIVE: To investigate the Nursing diagnostic accuracy measures and to propose a model to use defining characteristics in order to judge the nursing diagnosis of ineffective breastfeeding. METHOD: Cross-sectional study with a sample of 73 binomials mom-child hospitalized in a maternity ward of an University Hospital, from July to August of 2014. RESULTS: The diagnostic predominance rate was 58.9%. The characteristics that best meet the needs of logistic regression model were: discontinuance of breast sucking; infant's inability of seizing the areola-nipple region correctly; infant's crying one hour after breastfeeding and inappropriate milk supply perceived. CONCLUSION: Breastfeeding process is dynamic; diagnostic judgement may suffer some changes according to the time data are collected; the defining characteristics are the best predictors if associated with models and rules of use. PMID- 29412289 TI - Calf circumference: clinical validation for evaluation of muscle mass in the elderly. AB - OBJECTIVE: To validate calf circumference as a technology for assessing muscle mass in the elderly. METHOD: Cross-sectional study with 132 elderly people from Goiania, Goias, Brazil. Decreased muscle mass was determined by the skeletal muscle mass index (IME) using Dual Energy X-Ray Absortometry (DEXA). The cutoff circumferences (CC) cutoff points to indicate muscle mass decrease were estimated by ROC curve, sensitivity, specificity and accuracy. RESULTS: The most accurate cut-off points for detecting decreased muscle mass in the elderly were 34 cm for men (sensitivity: 71.5%, specificity: 77.4%) and 33 cm for women (sensitivity: 80.0%; specificity: 84.6%). CONCLUSION: CC can be used as a measure for early identification of muscle mass decrease in routine evaluations of the elderly in primary care. PMID- 29412290 TI - Patients' knowledge about medication prescription in the emergency service. AB - OBJECTIVE: To identify which orientations were received by the patient about the medication prescription and which professional performed it; to evaluate the patients' knowledge about prescription drugs and to correlate it to socioeconomic variables, comorbidities, and the frequency with which the patient seeks emergency service; and to evaluate the knowledge about the medication prescribed after the health care. METHOD: This was a cross-sectional study on 304 patients that received emergency service's discharge along with medication prescription. Applied instruments: sociodemographic characterization and evaluation of the knowledge about the prescribed medication. We used a descriptive and inferential analysis. RESULTS: Most subjects had no doubts about how or for how long to take the medication; and presented questions about adverse reactions and what to do in case of forgetting to take the medication doses. There was a significant association between age; educational level; comorbidity; the frequency of emergency service's use; and knowledge about medications. CONCLUSION: a total of 48% of the patients declared to need information about adverse effects and what to do if they forget to take the medication. PMID- 29412291 TI - Burnout and nursing work environment in public health institutions. AB - OBJECTIVE: to identify associations between the Burnout domains and the characteristics of the work environment. METHOD: cross-sectional study with 745 nurses from 40 public health institutions in Sao Paulo. Nursing Work Index Revised (NWI-R) and Maslach Burnout Inventory were used. Similar institutions according to NWI-R were grouped by clustering and the Anova and Bonferroni tests were used in the comparative analyzes. RESULTS: there was significant and moderate correlation between emotional exhaustion and autonomy, control over the environment and organizational support; between reduced personal accomplishment, autonomy and organizational support; and between depersonalization and autonomy. The group that presented the worst conditions in the work environment differed on emotional exhaustion from the group with most favorable traits. CONCLUSION: emotional exhaustion was the trait of Burnout that was more consistently related to the group of institutions with more unfavorable working conditions regarding autonomy, organizational support and control over the environment. PMID- 29412293 TI - Non-frail elderly people and their license to drive motor vehicles. AB - OBJECTIVE: to analyse the link between the non-frailty condition and the results of driving license for elderly people to drive motor vehicles. METHOD: cross sectional study with data collection in the sample period from August 2015 to March 2016. Study performed with 347 elderlies (>=60 years). RESULTS: 180 (51.9%) of the participants were classified as non-frail. 48 (26.7%) of them were considered capable to drive, 121 (67.2%) capable to drive with restrictions and 11 (6.1%) temporarily uncapable. No significant relation was found between the non-frailty conditions and the results of the motor vehicles driving license study (p=0.557). CONCLUSION: The absence of physical frailty does not necessarily points out that the elderly are able to drive motor vehicles. Tracking the frailty subsidizes preventive interventions, which seek to interfere positively in the act of driving. This is an unprecedented study in nursing and it highlights an essential field for the performance of gerontological nursing. PMID- 29412292 TI - Practice of use of diapers in hospitalized adults and elderly: cross-sectional study. AB - OBJECTIVE: analyze the practice of use of diapers in adults and elderly in hospital. METHOD: observational cross-sectional study, with a sample of 105 participants assigned according to the data collection period, from September 2013 to January 2014, in the surgical clinic wards in a University Hospital. RESULTS: it was observed that 38% of the 105 participants of the study did not need the use of diapers. 18% used it because they were disabled and 16% had their cognitive system damaged. As they were hospitalized, it was identified that 51.4% of patients were there ranging from 02 to 10 days, and 60% used diapers for the same period. It is also identified that long term urinary catheter (24.8%), as technology associated to diapers in the urinary control and to pressure ulcers (12.4%), being the main complication. CONCLUSION: the use of diapers did not have specific criteria to be selected. For this, it was proposed an "Evaluation Scale of Diapers Use in Adults", as for indication as for its monitoring to help the study transposal for the nursing practice. PMID- 29412294 TI - Accuracy of the defining characteristics in nursing diagnoses of Hyperthermia in newborns. AB - OBJECTIVE: to clinically validate the accuracy of the defining characteristics in nursing diagnoses of Hyperthermia in newborns. METHOD: a cross-sectional study conducted in units of medium and high risk in a maternity from the city of Fortaleza-CE. A total of 216 newborns were evaluated to identify the defining characteristics of diagnoses. A latent class model with random effects was used to measure sensitivity and specificity. RESULTS: Hyperthermia was present in 5.6% of the sample. The characteristics lack of suction maintenance (31.3%); skin warm to touch (25.5%); lethargy (24.2%); and tachypnea (21.4%) were the most frequent. Stupor presented higher sensitivity (99.9%) and specificity (100%) while vasodilation characteristics, irritability and lethargy only showed significant values for specificity (92.7%, 91.6% and 74.3%, respectively). CONCLUSION: four characteristics of high specificity contribute to Hyperthemia. However, stupor is the only one with significant sensitivity to identify it at its early-stage. PMID- 29412295 TI - Costs of examinations performed in a hospital laboratory in Chile. AB - OBJECTIVE: To determine the total average costs related to laboratory examinations performed in a hospital laboratory in Chile. METHOD: Retrospective study with data from July 2014 to June 2015. 92 examinations classified in ten groups were selected according to the analysis methodology. The costs were estimated as the sum of direct and indirect laboratory costs and indirect institutional factors. RESULTS: The average values obtained for the costs according to examination group (in USD) were: 1.79 (clinical chemistry), 10.21 (immunoassay techniques), 13.27 (coagulation), 26.06 (high-performance liquid chromatography), 21.2 (immunological), 3.85 (gases and electrolytes), 156.48 (cytogenetic), 1.38 (urine), 4.02 (automated hematological), 4.93 (manual hematological). CONCLUSION: The value, or service fee, returned to public institutions who perform laboratory services does not adequately reflect the true total average production costs of examinations. PMID- 29412296 TI - Perception of nursing workers humanization under intensive therapy. AB - OBJECTIVE: understand the perception of nursing workers working in the Intensive Care Unit (ICU) regarding humanization in the work environment. METHOD: we used the reference of phenomenology, structure of the phenomenon. Participated 25 nursing professionals working in an adult ICU of a university hospital, through focused interviews, answering the guiding question: What do you understand by humanization of the working conditions of the nursing team working in the ICU? RESULTS: the analysis revealed the themes: humanization in the ICU; working condition in the ICU; management of people in the ICU and management process in the ICU. FINAL CONSIDERATIONS: humanization is necessary through the change of the work environment and the managerial process, privileging the participatory management model as a way to transform theory into practice and value the worker. PMID- 29412297 TI - Construction and validation of forms: systematization of the care of people under hemodialysis. AB - OBJECTIVE: create and validate forms to subsidize the systematization of nursing care with people on hemodialysis. METHOD: institutional case study to support the systematization of assistance from the construction of forms for data collection, diagnoses, interventions and nursing results, using cross-mapping, Risner's reasoning, Neuman's theory, taxonomies of diagnoses, interventions and nursing results with application in clinical practice and validation by focal group with specialist nurses. RESULTS: 18 people on hemodialysis and 7 nurses participated. Consensus content of form matter with specialist nurses in the area (Crombach 0.86). The papers captured 43 diagnoses, 26 interventions and 78 nursing results depicting human responses in their singularities. FINAL CONSIDERATIONS: the validated forms fill a gap by enabling the capture of human responses from people on hemodialysis and by subsidizing the planning of nursing care on a scientific basis. PMID- 29412298 TI - Body consciousness of people with intestinal stomach: A phenomenological study. AB - OBJECTIVE: to describe the bodily awareness of people with stomies. METHOD: a descriptive study with a qualitative approach, carried out in the Ostomized Association of the State of Ceara, through semi-structured interviews with ten people with intestinal stomies, according to Merleau-Ponty's phenomenological thinking. RESULTS: two categories of analysis emerged: The body that I have, in which the sensations of deficiency, imperfection and bad odor add to the feeling of strangeness towards one's own body, affecting the way of being in the world of each deponent; and The body that others perceive, in which the stoma is seen as an embarrassing and complex experience, since it hampers daily activities and conviviality with other people. FINAL CONSIDERATIONS: The corporeal consciousness of Being-Stomp-in-the-world requires the movement to reconstruct the senses of the body from the body I have and from that which others perceive. PMID- 29412299 TI - Spiritual well-being and hope in the preoperative period of cardiac surgery. AB - OBJECTIVE: To characterize relations between spiritual well-being and hope of patients in the preoperative period of cardiac surgery. METHOD: Exploratory cross sectional study with quantitative approach, performed in the infirmaries of a reference hospital in cardiology. We evaluated 69 patients hospitalized in preoperative period of myocardial revascularization, valve repair or replacement. RESULTS: We verified that patients hold relevant scores of hope and welfare in all areas, being the existential well-being significantly lower than the religious one. The average of the spiritual well-being score was below the required to be considered high. There was no significant correlation between welfare and hope. CONCLUSION: Nurses should develop a watchful eye to these issues, be trained in specific protocols of spiritual anamnese and use the real moments of care to strengthen the patients. PMID- 29412300 TI - Validation and reliability of the scale Self-efficacy and their child's level of asthma control. AB - OBJECTIVE: To evaluate the psychometric properties in terms of validity and reliability of the scale Self-efficacy and their child's level of asthma control: Brazilian version. METHOD: Methodological study in which 216 parents/guardians of children with asthma participated. A construct validation (factor analysis and test of hypothesis by comparison of contrasted groups) and an analysis of reliability in terms of homogeneity (Cronbach's alpha) and stability (test retest) were carried out. RESULTS: Exploratory factor analysis proved suitable for the Brazilian version of the scale (Kaiser-Meyer-Olkim index of 0.879 and Bartlett's sphericity with p < 0.001). The correlation matrix in factor analysis suggested the removal of item 7 from the scale. Cronbach's alpha of the final scale, with 16 items, was 0.92. CONCLUSION: The Brazilian version of Self efficacy and their child's level of asthma control presented psychometric properties that confirmed its validity and reliability. PMID- 29412301 TI - The nurses' work process in different countries: an integrative review. AB - OBJECTIVE: To analyze the characteristics of nurses' work process in different countries. METHOD: We have used the integrative review method and selected 84 publications (articles, theses and dissertations) in national and foreign thesis banks and databases. We analyzed the evidence based on dialectical materialism. RESULTS: The rejection of managerial tasks hides the singularity of nurses' work, due to the failure to understand the inseparable nature of managerial and healthcare tasks, given that it is what provides the expertise to coordinate the nursing work process and guide the healthcare work processes. The social and technical division is present in the work process in all countries studied, albeit in different ways. The nurse's position in the healthcare work process is subordinated to that of the physician. CONCLUSION: The characteristics are similar. The rejection of the dual nature of the work by nurses themselves due to alienation results in the non-recognition of their own work. PMID- 29412302 TI - Integrative literature review: sleep patterns in infants attending nurseries. AB - OBJECTIVE: To identify evidence available in the literature about sleep patterns of infants attending nurseries. METHOD: An integrative review of studies published in Portuguese, English or Spanish available in full text on LILACS, CINAHL, and PubMed databases. The following descriptors sono, lactente and creches or bercarios (in Portuguese) and sleep, infant and childcare or nurseries were used for LILACS, CINAHL and Pubmed, respectively. Nine studies were selected and analyzed. RESULTS: The main component explored in the studies about sleep pattern is the sleep position of the infants, due to its association with sudden infant death syndrome. The results pointed to the need to promote and develop written guidelines regarding behavioral practices to reduce the risk of this phenomenon. CONCLUSION: Evidence has identified sleep issues, mainly regarding the sleep position of the infant and the environment where the infant sleeps, showing that it is critical to set routines and interventions to improve the quality of sleep care of infants attending nurseries. PMID- 29412303 TI - Conceptual definitions of indicators for the nursing outcome "Knowledge: Fall Prevention". AB - OBJECTIVE: to construct conceptual definitions for indicators of nursing outcome Knowledge: Fall Prevention, selected for evaluation of hospitalized patients with the nursing diagnosis Risk for falls. METHOD: integrative literature review performed in the LILACS, MEDLINE and Web of Science databases, comprising articles published in English, Spanish and Portuguese languages from 2005 to 2015. RESULTS: the final sample of the study was composed of 17 articles. The conceptualizations were constructed for 14 indicators of nursing outcome Knowledge: Fall Prevention focused on hospitalized patients. CONCLUSION: the theoretical support of the Nursing Outcomes Classification (NOC), through the process of constructing the conceptual definitions of the indicators of its results, allows nurses to accurately implement this classification in clinical practice and to evaluate the effectiveness of their interventions through the change of the patients' status over time. PMID- 29412304 TI - Problematization Methodology and Convergent Healthcare Research: praxis proposal in research. AB - OBJECTIVE: Presenting theoretical subsidies for the nursing care practice based on the possibility of convergence between research practice and educational practice. METHOD: The Convergent Healthcare Research was developed from February to August 2015, with an intersectoral working group formed by 32 participants, including health, social services and public safety professionals. Ten group meetings were organized, based on the Problematization Methodology with Maguerez's Arch. RESULTS: The reflection-action movement resulted in the shared (re)building of the flowchart of care to women subjected to a situation of violence, as a device for communication between the services. FINAL CONSIDERATIONS: The research practice based on the Problematization Methodology with Maguerez's Arch proved to be useful and viable in qualitative research, which has as purpose the transformation of the reality studied. PMID- 29412305 TI - Journal Club: a group of research experience. AB - INTRODUCTION: the Journal Club (JC) is a teaching and learning strategy developed by individuals who meet to discuss scientific articles in periodicals. OBJECTIVE: to describe the experience of the JC strategy at the Group for Studies and Research in Health Services Administration and Nursing Management (Gepag). METHOD: case studies or scientific research demonstration mode of practical experience for the understanding and justification of facts. RESULTS: Gepag JC emerged in 2008 and, in 2014, was computerized with the Google Drive(r), in order to increase its scope and optimize the Group>s meetings. From April to May 2014, the instrument was tested and adjusted, resulting in advancements. FINAL CONSIDERATIONS: the advantages involved optimizing the time of meetings, facilitation of access to publications of interest to the Group and creating the database to support future research. PMID- 29412306 TI - Clinical and epidemiological teaching of dengue through simulated practice. AB - OBJECTIVE: to describe the experience of clinical teaching on dengue and the practice of epidemiological surveillance using problematization methodology. METHOD: report of experience on educational activity with undergraduate nursing students, held in March 2016, at a public university in the city of Sao Paulo, conceived in four stages: dialogic lecture, active search of Aedes aegypti, case study and simulation of nursing consultation to individuals with dengue. RESULTS: The activity allowed to retrieve previous knowledge about the disease, respond to exercises that addressed different clinical situations and epidemiological surveillance, including in situ evaluation of possible mosquito outbreaks, and discuss the need to expand prevention and health of the individual and the community, the impact of the media in the dissemination of cases and the coping difficulties experienced in the different levels of attention. CONCLUSION: the methodology adopted enabled qualified training of students to cope with dengue. PMID- 29412307 TI - The Tidal Model: analysis based on Meleis's perspective. AB - OBJECTIVE: To critically reflect on the conceptual components of the Tidal Model in the application of the mental healthcare process. METHOD: Critical analysis based on the Models of Theory Analysis, focused on the clarity and consistency of the theoretical components of the Tidal Model. RESULTS: The clarity of the theory was verified through the demonstration of the following components: functional, presuppositions, concepts and propositions. The consistency is due to the possibility of proven application in several countries with different populations. CONCLUSION: There is a vast field of research and possibilities of application in the Brazilian nursing consultation, in search of usefulness and support in nursing care. PMID- 29412308 TI - Statistically, What's the Chance of a Breach? PMID- 29412309 TI - [Intersexuality: between knowledge and interventions]. AB - This study proposes to reflect on the links between knowledge production and its daily effects on the field of sexuality, based on intersexuality as a contemporary issue. Intersexuality is an interesting object of analysis for such reflection, since it allows exploring the interfaces between knowledge production on sexuality, power relations between professionals, intersex persons, and their families, use of embodiment technologies, conceptions of the normal and natural body, formation of subjectivities, and the shaping of a new social, political, and moral order heavily associated with subjects' biological constitution. The reflections proposed here originated from a qualitative study in a public healthcare institution serving as a reference for intersex persons in Rio de Janeiro, Brazil, focusing especially on the discourses of physicians involved in the care for intersex individuals. PMID- 29412310 TI - Hypercompetition and research integrity. PMID- 29412311 TI - [Investigation of an outbreak of acute Chagas disease outside the Amazon Region, in Rio Grande do Norte State, Brazil, 2016]. AB - The aim of this article was to confirm and describe an outbreak of acute Chagas disease involving oral transmission in the western region of Rio Grande do Norte State, Brazil. This was a descriptive case series study in which the data sources were medical records and interviews with suspected cases from September 16 to November 19, 2015. An entomological investigation was conducted in the probable sites of infection for acute Chagas disease cases. Eighteen cases of acute Chagas disease were confirmed in residents of four municipalities (counties) in Rio Grande do Norte State. The most frequently reported signs and symptoms were fever and weakness (n = 18), followed by myalgia (n = 17), prostration, loss of appetite, and edema of the lower limbs (n = 15). Median duration of fever was 20 days (range: 6 to 45 days). Fifteen cases were confirmed by the laboratory criterion and three by epidemiological link with consistent clinical characteristics. All confirmed cases reported having consumed sugar cane juice from the same mill. A total of 110 triatomines were captured on the plantation where the sugar cane had been crushed for juice. The insects were found in the peridomicile, in stacks of firewood and close to the sugar cane mill. The majority of the captured specimens were Triatoma brasiliensis and showed a natural infection rate of 63%. The Chagas disease outbreak was confirmed with oral transmission via ingestion of sugar cane juice contaminated with infected triatomines, as evidenced by the epidemiological link between the investigated cases and the entomological survey in the probable site where the infection occurred. PMID- 29412312 TI - Burden of disease from lower limb amputations attributable to diabetes mellitus in Santa Catarina State, Brazil, 2008-2013. AB - The objective was to estimate the burden of disease from lower limb amputations attributable to diabetes mellitus in Santa Catarina State, Brazil, from 2008 to 2013. A descriptive epidemiological study was performed by calculating disability adjusted life years (DALY). Burden of disease was high, more than 8,000 DALY in men and women. Disability accounted for 93% of DALY and mortality for 7.5%. The burden in men was 5,580.6 DALY, almost double that in women (2,894.8), and the share of the years lost due to disability (YLD) component in men pushed this rate to 67.6% of total DALY. Men live longer following amputation, so they lose more years of healthy life (65.8%), while mortality is higher in women (61%). DALY rates were not distributed homogeneously across the state. The intensification of evaluation, planning, and development of cost-effective strategies for prevention and health education for diabetic foot should be oriented according to higher male vulnerability. PMID- 29412313 TI - [Presence and extent of primary care characteristics under different models for children's healthcare]. AB - The aim of this study is to compare traditional primary care units and family health units to determine which of the two models is better oriented towards primary care for children, considering the existence and scope of essential and intermediate attributes of primary care. We interviewed a total of 1,484 parents and guardians of children under 10 years of age enrolled in family health units in Joao Pessoa, Paraiba State, Brazil, as well as in traditional primary care units in Cascavel, Parana State, Brazil, and mixed primary care units in Londrina, Parana State, Brazil. The Primary Care Assessment Tool Brazil, children's version, was used for this purpose. The parametric one-way ANOVA test was used to identify statistically significant differences between the models of care, followed by the Tukey post hoc multiple comparison test to identify which model presented differences. The study design's limitations notwithstanding, the findings raised the hypothesis that mixed primary care units were the model best oriented to primary care for children. The difference may relate to the fact that the different models belonged to different municipalities, without the possibility of adjusting the variables linked to the different contexts in the variables. Thus, this hypothesis may be proven by future studies with more robust designs and expanded to include other users and health professionals. PMID- 29412314 TI - [Association between socioeconomic, health, and primary care conditions and hospital morbidity due to waterborne diseases in Brazil]. AB - The current study aimed to assess the association between socioeconomic conditions, basic sanitation, and coverage by family health teams and hospitalizations for waterborne diseases. The analysis of socioeconomic conditions and sanitation was based on an ecological study with data from the Brazilian National Household Sample Survey (PNAD) and the Brazilian Health Informatics Departament (DATASUS) database (observations for the States and Federal District) for the year 2013. Associations between family health teams and hospitalization were assessed by simple regressions, with data from DATASUS and the Department of Primary Care of Ministry of Health from 1998 to 2014. Connection to the public sewage system, low schooling, and family health team coverage were significantly associated (p < 0.05) with hospitalizations for waterborne diseases. Based on attributable risk analysis, for Brazil as a whole in 2013, 57,574 (16.3%) of hospital admissions for waterborne diseases could have been avoided by adequate sewage disposal, which would also have avoided BRL 20,372,559.90 in treatment costs and 172,722 days lost to hospitalization. The results emphasize the importance of integrated sanitation policies, education, and health care that consider regional inequalities, thereby contributing to improvement of the population's health conditions. PMID- 29412315 TI - Environmental factors associated with canine visceral leishmaniasis in an area with recent introduction of the disease in the State of Rio de Janeiro, Brazil. AB - The study assessed the association between environmental characteristics obtained by remote sensing and prevalence of canine visceral leishmaniasis (CVL) in the neighborhood of Jacare, an area with recent introduction of the disease in the municipality (county) of Niteroi, Rio de Janeiro State, Brazil. This was a cross sectional study to assess CVL prevalence, defined as a positive result in the dual path platform (DPP) rapid immunochromatographic assay, confirmed by immunoenzymatic assay (IEA). The study included 97 dogs, with 21.6% CVL prevalence. CVL prevalence was higher in dogs with contact with another dog, opossum, marmoset, or hedgehog, as well as history of culling of other dogs with CVL from the household. In the multivariate analysis, adjusted for the dog's sex and age, dogs in areas with sparse vegetation showed fivefold higher prevalence of Leishmania infantum infection compared to dogs in areas with less vegetation (OR = 5.72; 95%CI: 1.47-22.20). Meanwhile, less urbanized areas, characterized as commercial or low-income residential areas, identified by remote sensing as those with high density of gray structures, were associated with lower CVL prevalence (OR = 0.09; 95%CI: 0.01-0.92). The higher prevalence of infection in dogs living alongside wild animals and in areas with more vegetation and lower prevalence in more urbanized areas suggest a rural transmission pattern for CVL in this area. PMID- 29412316 TI - When rarity is an asset: political activism for the rights of persons with rare diseases in the Brazilian Unified National Health System. PMID- 29412317 TI - [Territory, places, and health: resizing spatiality in public health]. AB - The aim of this study is to extend the reading of the health-disease process from the territorial perspective. Theoretical production on the link between health and the environment should go beyond medical typologies and their emphasis on the distribution of environmental risks (physical, biological, and chemical) to acknowledge the social and subjective production of territories. In order to make progress with this theoretical production, public health should draw on the integration of concepts from the social sciences such as the appropriation of space, territory-territorialities, and places. In terms of scale, it should also focus on micro-territories, since the scenario of local territories and places of daily living are where lifestyles, illness, and the construction of health materialize. PMID- 29412318 TI - Predicting survival function and identifying associated factors in patients with renal insufficiency in the metropolitan area of Maringa, Parana State, Brazil. AB - Renal insufficiency is a serious medical and public health problem worldwide. Recently, although many surveys have been developed to identify factors related to the lifetime of patients with renal insufficiency, controversial results from several studies suggest that researches should be conducted by region. Thus, in this study we aim to predict and identify factors associated with the lifetime of patients with chronic renal failure (CRF) in the metropolitan area of Maringa, Parana State, Brazil, based on the generalized additive models for location, scale and shape (GAMLSS) framework. Data used in this study were collected from the Maringa Kidney Institute and comprehends 177 patients (classified with CRF and mostly being treated under the Brazilian Unified National Health System) enrolled in a hemodialysis program from 1978 up to 2010. By using this approach, we concluded that in other regions, gender, kidney transplant indicator, antibodies to hepatitis B and antibodies to hepatitis C are significant factors that affect the expected lifetime. PMID- 29412319 TI - A socio-historical approach to policy analysis: the case of the Brazilian Workers' Food Policy. AB - Policy analyses based on traditional or structuralist definitions of the state are important, but they have some limitations for explaining processes related to policymaking, implementation, and results. Bourdieusian sociology links the analysis to objective and subjective dimensions of social practices and can help elucidate these phenomena. This article provides such empirical evidence by analyzing the social genesis of a Brazilian policy that currently serves 18 million workers and was established by the state in 1976 through the Fiscal Incentives Program for Workers' Nutrition (PIFAT/PAT). The study linked the analysis of the trajectory of social agents involved in the policy's formulation to the historical conditions that allowed the policy to exist in the first place. Although the literature treats the policy as a workers' food program (PAT), the current study showed that it actually represented a new model for paying financial subsidies to companies that provided food to their employees, meanwhile upgrading the commercial market for collective meals. The study further showed that the program emerged as an administrative policy, but linked to economic agents. The program became a specific social space in which issues related to workers' nutrition became secondary, but useful for disguising what had been an explicit side of its genesis, namely its essentially fiscal nature. PMID- 29412320 TI - Effects of social protection on tuberculosis treatment outcomes in low or middle income and in high-burden countries: systematic review and meta-analysis. AB - Tuberculosis (TB) is a poverty infectious disease that affects millions of people worldwide. Evidences suggest that social protection strategies (SPS) can improve TB treatment outcomes. This study aimed to synthesize such evidences through systematic literature review and meta-analysis. We searched for studies conducted in low- or middle-income and in high TB-burden countries, published during 1995 2016. The review was performed by searching PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect and LILACS. We included only studies that investigated the effects of SPS on TB treatment outcomes. We retained 25 studies for qualitative synthesis. Meta-analyses were performed with 9 randomized controlled trials, including a total of 1,687 participants. Pooled results showed that SPS was associated with TB treatment success (RR = 1.09; 95%CI: 1.03-1.14), cure of TB patients (RR = 1.11; 95%CI: 1.01-1.22) and with reduction in risk of TB treatment default (RR = 0.63; 95%CI: 0.45-0.89). We did not detect effects of SPS on the outcomes treatment failure and death. These findings revealed that SPS might improve TB treatment outcomes in lower-middle-income economies or countries with high burden of this disease. However, the overall quality of evidences regarding these effect estimates is low and further well-conducted randomized studies are needed. PMID- 29412321 TI - [Cost analyses of medical care for schizophrenia and depression in Mexico, 2005 2013]. AB - The study aimed to analyze the costs of medical care for mental disorders in the Mexican health system. This was a retrospective cross-sectional evaluation study. As markers for the problem, the study selected two of the principal psychological processes in mental disorders in recent years: depression and schizophrenia. Annual accumulated incidence was identified based on epidemiological reporting by type of institution in 2005-2013. The mean annual case management cost was determined with the instrumentation and consensus technique, identifying the production functions, types of inputs, costs, and amounts of inputs ordered, concentrated in the mean case matrix. Finally, an econometric adjustment factor was applied to control the inflationary effect for each year in the study period. Mean annual case management cost was USD 2,216.00 for schizophrenia and USD 2,456.00 for depression. All the institutions in the Mexican health system showed upward and constant epidemiological and economic trends. The total cost for the two disorders in the last year of the period (2013) was USD 39,081,234.00 (USD 18,119,877.00 for schizophrenia and USD 20,961,357.00 for depression). The largest impact for the two disorders combined was in institutions serving the population without health insurance (USD 24,852,321.00) versus the population with private insurance (USD 12,891,977.00). The cost of meeting the demand for services for the two disorders differs considerably between institutions that treat the population with private health service versus the population without, and is higher in the latter. The study's epidemiological and economic indicators provide evidence for decision-making in the use and allocation of healthcare resources for these two disorders in the coming years. PMID- 29412322 TI - [Association between serum zinc level and hypercholesterolemia and insulin resistance in Brazilian children]. AB - The objective of the study was to assess the association between serum zinc level and cardiometabolic factors in prepubertal Brazilian children. This was a cross sectional study in a representative sample of schoolchildren 8 to 9 years of age in public and private urban schools in Vicosa, Minas Gerais State, Brazil. Body composition was assessed with dual-energy x-ray absorptiometry. The study measured serum glucose, insulin, total cholesterol, high and low density lipoprotein cholesterol, triglycerides, apolipoproteins A (Apo A) and B, uric acid, leptin, homocysteine, ultrasenstive C-reactive protein, and serum zinc. Arterial pressure was measured with automatic inflation equipment. Zinc deficiency was observed in 1.3% of the children. Girls showed the worst cardiometabolic profile, with higher prevalence of increased android fat, triglycerides, insulin resistance, leptin, zinc, and Apo A. In the first tertile of serum zinc concentration, prevalence of insulin resistance was 96% higher (PR = 1.96; 95%CI: 1.04-3.66) and hypercholesterolemia was 23% lower (PR = 0.77; 95%CI: 0.61-0.96) than in the reference category (grouped 2nd and 3rd tertiles of serum zinc concentration). Despite the low prevalence of zinc deficiency, insulin resistance was more prevalent in children in the lowest third of serum zinc concentration. It is important to prevent cardiometabolic alterations in childhood, especially insulin resistance, with an emphasis on serum zinc level. PMID- 29412323 TI - Contextual and individual factors associated with dissatisfaction with public emergency health services in Brazil, 2011-2012. AB - The Brazilian network of emergency care, in recent years, has shown significant progress. The objective was to evaluate contextual and individual factors associated with the satisfaction with public emergency health services. This was a cross-sectional multilevel study carried out between June 2011 and January 2012. Data were collected via telephone at the ombudsman's office of the Brazilian Unified National Health System (SUS). Telephone numbers were randomly selected from a telephone company database. Health services, socioeconomic, and individual demographic variables were evaluated, in addition to information about the municipalities. The outcome variable was dissatisfaction with public emergency health services in Brazil. Multilevel logistic regression was performed and 7,027 individuals from 61 municipalities answered the survey. The prevalence of perceived dissatisfaction was 48.1% (95%CI: 46.9-49.3). Variables that remained significantly associated with the outcome are: age up to 20 years, 16 or more years of education, lives in the Central region, non-resolved demands, longer waiting times, and accessing emergency in a primary care service. Prevalence of a perceived dissatisfaction is predominantly associated with care's waiting time and the length needed to resolve the demand. PMID- 29412324 TI - [Women's experience with cesareans in Uruguay: the woman's right to be accompanied by a person of her choice and difficulties with enforcement]. AB - The article aims to analyze how women are accompanied by a trusted person during cesareans, as guaranteed under Law 17,386 on "accompanying persons during labor and childbirth", enacted in Uruguay in 2001. The findings are part of a larger study on the experience and meaning of cesareans for Uruguayan women. An exploratory, descriptive qualitative methodology was used for this purpose. The technique involved in-depth interviews with 31 women whose cesareans were performed in their first pregnancy in the city and greater metropolitan area of Montevideo. Based on the findings, the conclusion is that having a trusted accompanying person during labor and childbirth is experienced by women as a factor for emotional protection given the anxieties generated by a major surgery like a cesarean. Nevertheless, for the women interviewed in the study, "being accompanied" was not a continuous process, but characterized by a series of separations, both from the accompanying persons and from their children, causing anxiety, anguish, ambivalent feelings towards the newborn infant, and difficulties in mother-infant bonding, especially in the immediate postpartum. PMID- 29412325 TI - [Views of health system administrators, professionals, and users concerning the electronic health record and facilitators and obstacles to its implementation]. AB - The design and deployment of complex technologies like the electronic health record (EHR) involve technical, personal, social, and organizational issues. The Brazilian public and private scenario includes different local and regional initiatives for implementation of the electronic health record. The Brazilian Ministry of Health also has a proposal to develop a national EHR. The current study aimed to provide a comprehensive view of perceptions by health system administrators, professionals, and users concerning their experiences with the electronic health record and their opinions of the possibility of developing a national EHR. This qualitative study involved 28 semi-structured interviews. The results revealed both the diversity of factors that can influence the implementation of an electronic health record and the existence of convergences and aspects that tend to be valued differently according to the different points of view. Key aspects include discussions on the electronic health record's attributes and it impact on healthcare, especially in the case of local electronic health records, concerns over costs and confidentiality and privacy pertaining to electronic health records in general, and the possible implications of centralized versus decentralized data storage in the case of a national EHR. The interviews clearly showed the need to establish more effective communication among the various stakeholders, and that the different perspectives should be considered when drafting and deploying an EHR at the local, regional, and national levels. PMID- 29412326 TI - [Hospitalizations due to complications of pregnancy and maternal and perinatal outcomes in a cohort of pregnant women in the Brazilian Unified National Health System in Sao Paulo, Brazil]. AB - Maternal morbidity, fetal mortality, and neonatal mortality are important indicators of maternal and child health. The study aimed to describe maternal and perinatal outcomes (low birth weight, prematurity, fetal and neonatal deaths, postpartum hospitalizations, and readmission of newborns) in a cohort of pregnant women whose deliveries were covered by the Brazilian Unified National Health System (SUS) in the city of Sao Paulo, Brazil, in the second semester of 2012. We obtained a retrospective cohort of 55,404 pregnant women with deterministic and probabilistic linkage of data from the Hospital Information System of the SUS (SIH/SUS), Information System on Live Births (SINASC), Mortality Information System (SIM), and National Registry of Health Establishments (CNES) databases. Hospitalizations due to obstetric complications occurred in 4.3% of the women. The most frequent diagnoses were infection, hypertensive disease of pregnancy, and diabetes. Hospitalizations prior to childbirth were more common in pregnant women 35 years or older and those with a history of multiple pregnancies and low schooling. Postpartum hospitalizations were three times greater and maternal mortality was nine times greater in pregnant women with a history of previous hospitalization due to obstetric complications. Adverse perinatal outcomes (fetal and neonatal mortality and low birth weight) were twice as frequent in infants of women with previous hospitalization when compared to those without. A similar pattern was seen in hospitalization of newborns soon after birth and in hospital readmission. Adverse maternal and perinatal outcomes were more frequent in pregnant women with a history of previous hospitalization. PMID- 29412327 TI - [Social Healthcare Organizations: a phenomenological expression of healthcare privatization in Brazil]. AB - The study analyzed the expansion of Social Healthcare Organizations (OSS in Portuguese) in Brazil from 2009 to 2014. The ten largest OSS were measured according to their budget funding and their qualifications as non-profit organizations were explored, considering evidence of their expansion and consolidation in the management and provision of health services via strategies proper to for-profit private enterprises. The study is descriptive and exploratory and was based on public-domain documents. In their relations with government, the OSS have benefited from legal loopholes and incentives and have expanded accordingly. There has been a recent trend for these organizations to simultaneously apply for status as charitable organizations, thereby ensuring multiple opportunities for fundraising and additional tax incentives, permission to invest financial surpluses in the capital market, and remunerate their boards of directors. These organizations tend to concentrate in technology-dense hospital services, with clauses concerning increasing financial transfers to the detriment of other regulatory clauses, and special contract modalities for enabling services that are absolutely strategic for the overall functioning of the Brazilian Unified National Health System. Thus, in this study, the OSS are one component of the Health Economic and Industrial Complex, acting in management, provision, and regulation of services in a scenario of intensive commodification of health and the transfer of public funds to the private sector. PMID- 29412329 TI - Characteristics of the environmental microscale and walking and bicycling for transportation among adults in Curitiba, Parana State, Brazil. AB - The aim of this study was to analyze the association between the characteristics of the built and social and environmental microscale and walking and bicycling for transportation in adults in Curitiba, Parana State, Brazil. A cross-sectional study was performed in 2009 with a household survey that included 1,419 adults. Objective evaluation of environment was performed on the resident's street segments, using an instrument for systematic observation consisting of six dimensions: "land use", "public transportation", "streetscape", "conditions and aesthetics", "places for walking and bicycling", and "social environment". The score for each dimension was obtained as the sum of positive items related to physical activity. The items for "public transportation" (>= 1 items) and "places for walking and bicycling on the streets" (>= 3 items) were dichotomized, while the scores for the other items were classified in tertiles. Walking and bicycling for transportation were assessed with the International Physical Activity Questionnaire (IPAQ). The data were analyzed using multilevel Poisson regression. Medium "streetscape" score was inversely associated with walking >= 150min/week (PR = 0.60; 95%CI: 0.40-0.91; VPC = 12%) and bicycling (PR = 0.54; 95%CI: 0.29 0.99; VPC = 60%). In conclusion, only "streetscape" was associated with walking and bicycling for transportation in adults. PMID- 29412328 TI - [Programmatic vulnerability in leprosy control: gender-related patterns in Bahia State, Brazil]. AB - The aim of this study was to analyze operational indicators and time trends in leprosy control from a gender perspective in Bahia State, Brazil, from 2001 to 2014. This was a time series study based on epidemiological data on leprosy from the Brazilian National System of Diseases of Notification, using joinpoint Poisson and polynomial regression. Of the 40,054 new cases of leprosy, 47.1% of the recorded contacts were not examined, with a significant upward trend, especially in women (average annual percentage change - AAPC = 5.6; 95%CI: 3.5; 7.7) when compared to men (AAPC = 3.0; 95%CI: 0.5; 5.6). The proportion of cure in the 2003-2014 cohort was 85%, with a downward trend, especially in men (AAPC = -0.5; 95%CI: -0.9; 0.0), compared to women (AAPC = -0.4; 95%CI: -0.7; -0.1). Treatment dropout rate was 5.5%, with a more significant downward trend in women (AAPC = -4.9; 95%CI: -8.7; -1.1) than in men (AAPC = -2.7; 95%CI: -4.4; -1.0). Relapse was recorded in 3.8% of all the entries during the same period; women showed a significant downward trend (AAPC = -2.2; 95%CI: -3.3; -1.0) and men a significant upward trend (AAPC = 4.9; 95%CI: 2.9; 6.8). Polynomial regression analysis was consistent with joinpoint regression. Leprosy in Bahia State shows operational indicators with significant magnitude and time trends, especially in the male population. Health services' insufficient performance in conducting contact surveillance and longitudinal care reveal various dimensions of vulnerability. PMID- 29412330 TI - Contribution of chronic diseases to the prevalence of disability in basic and instrumental activities of daily living in elderly Brazilians: the National Health Survey (2013). AB - This study's objective was to assess the contribution of selected chronic diseases to the prevalence of disability in elderly Brazilians, based on data from the National Health Survey (PNS 2013). Disability was defined as some degree of difficulty in performing ten activities, considering three levels: (i) without disability; (ii) disabled only in some instrumental activity of daily living (IADL); and (iii) disabled in some basic activity of daily living (BADL). The multinomial additive hazards model was the attribution method used to assess the contribution of each self-reported chronic condition (hypertension, diabetes, arthritis, stroke, depression, heart disease, and lung disease) to the prevalence of disability in this population, stratified by sex and age bracket (60 to 74 years and 75 or older). Study participants included 10,537 elderly Brazilians with a mean age of 70.0 years (SD = 7.9 years) and predominance of women (57.4%). Prevalence rates for disability in at least one IADL and at least one BADL were 14% (95%CI: 12.9; 15.1) and 14.9% (95%CI: 13.8; 16.1), respectively. In general, the contribution of chronic diseases to prevalence of disability was greater in younger elderly (60 to 74 years) and in the group with greatest severity (disabled in BADL), highlighting the relevance of stroke and arthritis in men, and arthritis, hypertension, and diabetes in women. This knowledge can help orient health services to target specific groups, considering age, sex, and current illnesses, aimed at preventing disability in the elderly. PMID- 29412331 TI - [Compliance with guidelines by state plans for food and nutritional security in Brazil]. AB - A descriptive and documental study was performed from August to October 2016 to analyze compliance by state plans for food and nutritional security (PlanSAN) with the guidelines set by the Brazilian National Policy for Food and Nutritional Security (PNSAN). The state plans were accessed via the websites of the Inter Ministerial Chamber for Food and Nutritional Security (CAISAN) or the state governments, plus complementary data collection at the state level. All the states of Brazil joined the National System for Food and Nutritional Security (SISAN), while fewer than half (13 states, 48%) had drafted their plans. Of these, 5 (38%) of the PlanSAN had schedules that coincided with the same state's pluriannual plan, 5 (38%) of the PlanSAN specified the budget requirements for meeting the proposed targets, 7 (54%) specified mechanisms for monitoring the plan, and only 2 (15%) defined methodologies for monitoring food and nutritional security. The recent existence of (and adherence to) the CAISAN appear to be related to the lack of state plans in half the states. Although most of the states that did have plans met some of the guidelines laid out by the PNSAN, these mechanisms become weak and impractical when they lack earmarked budget funds to meet their targets. Since the PNSAN is structurally inter-sectorial, the development of plans requires collective work by various government departments. Importantly, the items analyzed here are all guidelines, which implies the need for mechanisms to monitor their actual implementation. PMID- 29412332 TI - ? AB - [This corrects the article doi: 10.1590/0102-311x00037316]. PMID- 29412333 TI - ERRATUM: Observatorio sobre as Estrategias da Industria do Tabaco: uma nova perspectiva para o monitoramento da interferencia da industria nas politicas de controle do tabaco no Brasil e no mundo. AB - [This corrects the article doi: 10.1590/0102-311x00148515]. PMID- 29412334 TI - Gender differences of cannabis smoking on serum leptin levels: population-based study. AB - OBJECTIVE: To evaluate the serum leptin levels in cannabis smokers. METHODS: This was a cross-sectional population-based study of participants between the ages of 18 and 35 years. The data were collected through a self-administered questionnaire covering sociodemographic data and the use of psychoactive substances. Leptin levels were measured using a commercial ELISA kit. RESULTS: Of the 911 participants, 6.7% were identified as cannabis smokers and had significantly lower leptin levels (p = 0.008). When stratified by gender, there was a significant decrease in leptin levels among male smokers (p = 0.039). CONCLUSION: Cannabis smoking was linked to leptin levels in men, suggesting that the response to biological signals may be different between men and women. PMID- 29412335 TI - Art therapy as an adjuvant treatment for depression in elderly women: a randomized controlled trial. AB - OBJECTIVE: There are few quantitative studies on art therapy for the treatment of depression. The objective of this study was to evaluate if art therapy is beneficial as an adjuvant treatment for depression in the elderly. METHODS: A randomized, controlled, single-blind study was carried out in a sample of elderly women with major depressive disorder (MDD) stable on pharmacotherapy. The experimental group (EG) was assigned to 20 weekly art therapy sessions (90 min/session). The control group (CG) was not subjected to any adjuvant intervention. Patients were evaluated at baseline and after 20 weeks, using the Geriatric Depression Scale (GDS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and cognitive measures. RESULTS: Logistic regression analysis adjusted for age revealed that women in EG (n=31) had significant improvement in GDS (p = 0.007), BDI (p = 0.025), and BAI (p = 0.032) scores as compared with controls (n=25). No difference was found in the cognitive measures. CONCLUSION: Art therapy as an adjunctive treatment for MDD in the elderly can improve depressive and anxiety symptoms. CLINICAL TRIAL REGISTRATION: RBR-2YXY7Z. PMID- 29412336 TI - Psychiatric disorders in adolescents with type 1 diabetes: a case-control study. AB - OBJECTIVES: To study the prevalence of psychiatric disorders in adolescents with and without type 1 diabetes, the factors associated with its presence, and to test the reliability of a screening tool for use in clinical settings. METHODS: Eighty-one adolescents were enrolled in this case-control study, including 36 diabetic participants and 45 controls. Clinical and sociodemographic data were collected and psychiatric symptoms and diagnoses were obtained from adolescents and their parents using a screening tool (Strengths & Difficulties Questionnaire) and a semi-structured interview (Development and Well-Being Assessment). RESULTS: Psychiatric disorders were identified in 22.2% of the sample (30.56% among diabetic adolescents vs. 15.56% of controls: OR = 2.39, 95%CI 0.82-6.99; p = 0.11). Overweight (body mass index percentile >= 85) was the only factor associated with psychiatric disorder (OR = 3.07; 95%CI 1.03-9.14; p = 0.04). Compared to the semi-structured interview, the screening instrument showed 80% sensitivity, 96% specificity, 88.9% positive predictive value and 92.3% negative predictive value for the presence of psychiatric diagnoses in adolescents. CONCLUSION: Psychiatric morbidity was high in this sample of adolescents, especially among those with diabetes. Routine use of the Strengths and Difficulties Questionnaire can help with early detection of psychiatric disorders in this at-risk group. PMID- 29412337 TI - The presentation of the mind-brain problem in leading psychiatry journals. AB - OBJECTIVE: The mind-brain problem (MBP) has marked implications for psychiatry, but has been poorly discussed in the psychiatric literature. This paper evaluates the presentation of the MBP in the three leading general psychiatry journals during the last 20 years. METHODS: Systematic review of articles on the MBP published in the three general psychiatry journals with the highest impact factor from 1995 to 2015. The content of these articles was analyzed and discussed in the light of contemporary debates on the MBP. RESULTS: Twenty-three papers, usually written by prestigious authors, explicitly discussed the MBP and received many citations (mean = 130). The two main categories were critiques of dualism and defenses of physicalism (mind as a brain product). These papers revealed several misrepresentations of theoretical positions and lacked relevant contemporary literature. Without further discussion or evidence, they presented the MBP as solved, dualism as an old-fashioned or superstitious idea, and physicalism as the only rational and empirically confirmed option. CONCLUSION: The MBP has not been properly presented and discussed in the three leading psychiatric journals in the last 20 years. The few articles on the topic have been highly cited, but reveal misrepresentations and lack of careful philosophical discussion, as well as a strong bias against dualism and toward a materialist/physicalist approach to psychiatry. PMID- 29412339 TI - Validation of the Mnemonic Similarity Task - Context Version. AB - OBJECTIVE: Pattern separation (PS) is the ability to represent similar experiences as separate, non-overlapping representations. It is usually assessed via the Mnemonic Similarity Task - Object Version (MST-O) which, however, assesses PS performance without taking behavioral context discrimination into account, since it is based on pictures of everyday simple objects on a white background. We here present a validation study for a new task, the Mnemonic Similarity Task - Context Version (MST-C), which is designed to measure PS while taking behavioral context discrimination into account by using real-life context photographs. METHODS: Fifty healthy subjects underwent the two MST tasks to assess convergent evidence. Instruments assessing memory and attention were also administered to study discriminant evidence. The test-retest reliability of MST-C was analyzed. RESULTS: Weak evidence supports convergent validity between the MST C task and the MST-O as measures of PS (rs = 0.464; p < 0.01); PS performance assessed via the MST-C did not correlate with memory or attention; a moderate test-retest reliability was found (rs = 0.595; p < 0.01). CONCLUSION: The MST-C seems useful for assessing PS performance conceptualized as the ability to discriminate complex and realistic spatial contexts. Future studies are welcome to evaluate the validity of the MST-C task as a measure of PS in clinical populations. PMID- 29412338 TI - Clinical practice guidelines for post-stroke depression in China. AB - Post-stroke depression (PSD) is a very common complication that leads to increased physical disability, poor functional outcome, and higher mortality. Therefore, early detection and treatment are very important. Since there are currently no specific guidelines for this disorder in China, the purpose of this study was to develop PSD guidelines and provide suggestions for clinicians and related workers. PMID- 29412340 TI - First detection of dengue virus in the saliva of immunocompetent murine model. AB - The lack of an experimental animal model for the study of dengue pathogenesis is a limiting factor for the development of vaccines and drugs. In previous studies, our group demonstrated the susceptibility of BALB/c mice to infection by dengue virus (DENV) 1 and 2, and the virus was successfully isolated in several organs. In this study, BALB/c mice were experimentally infected intravenously with DENV 4, and samples of their saliva were collected. Viral RNA extracted from the saliva samples was subjected to qRT-PCR, with a detection limit of 0.002 PFU/mL. The presence of DENV-4 viral RNA was detected in the saliva of two mice, presenting viral titers of 109 RNA/mL. The detection of DENV RNA via saliva sampling is not a common practice in dengue diagnosis, due to the lower detection rates in human patients. However, the results observed in this study seem to indicate that, as in humans, detection rates of DENV RNA in mouse saliva are also low, correlating the infection in both cases. This study reports the first DENV detection in the saliva of BALB/c immunocompetent mice experimentally infected with non-neuroadapted DENV-4. PMID- 29412341 TI - Leishmania (Viannia) braziliensis isolated from the saliva of patients in a cutaneous leishmaniasis-endemic area of northeastern Brazil. AB - Several studies have described the use of non-invasive collection methods, mostly based on the detection of parasite DNA, for diagnosis. However, no Leishmania specimens have been isolated from saliva. Here, we report the first isolation of Leishmania braziliensis from the saliva of humans with cutaneous leishmaniasis but without lesions on their mucosa. The isolates were obtained from salivary fluid inoculated in hamsters and were tested by multilocus enzyme electrophoresis. Seven samples from 43 patients suspected of having the disease were identified for in vivo culture. These findings suggest that saliva is a clinical sample that allows the isolation of Leishmania sp. PMID- 29412342 TI - In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195. AB - BACKGROUND: Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO) levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent. OBJECTIVE: To evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro. METHODS: The viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 uM). Additionally, intracellular parasite viability was evaluated to determine IC50 values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 uM). Infected macrophages were then treated with PK11195 (25-100 uM) to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-gamma. FINDINGS: Median IC50 values for PK11195 were 14.2 uM for L. amazonensis, 8.2 uM for L. major, and 3.5 uM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron microscopy revealed some morphological alterations suggestive of autophagy. Interestingly, MCP-1 and superoxide levels were reduced in L. amazonensis-infected macrophages treated with PK11195. MAIN CONCLUSIONS: PK11195 causes the killing of amastigotes in vitro by mechanisms independent of inflammatory mediators and causes morphological alterations within Leishmania parasites, suggestive of autophagy, at doses that are non-toxic to macrophages. Thus, this molecule has demonstrated potential as an anti-leishmanial agent. PMID- 29412343 TI - The influence of a light and dark cycle on the egg laying activity of Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae). AB - BACKGROUND: The epidemiological importance of the mosquito Aedes aegypti as a vector of multiple human pathogens has generated a growing number of studies on the physiology and behaviour of its blood-feeding females. The activity of oviposition is one of the critical elements contributing to the expansion of Ae. aegypti's populations. Although there is a vast literature about oviposition behaviour, significant specific knowledge about egg viability and female fertility under light and dark conditions is still lacking. OBJECTIVES: We studied, in controlled laboratory conditions, the effect that light and dark cycles have on the efficiency of oviposition by Ae. aegypti females. METHODS: Physiological assays were performed using synchronised eggs obtained from forced egg laying. The number and viability of eggs was analysed under three different light/dark regimes: LD12:12 (12 h of light and 12 h of dark), DD (constant darkness) and LL (constant light). FINDINGS AND CONCLUSIONS: Our results show that females prefer to lay their eggs in dark conditions, but maximising the number and viability of eggs requires the occurrence of a light/dark cycle. Ongoing research on this theme has the potential of contributing to the proposition of new strategies for control based on the failure of egg laying and hatching. PMID- 29412345 TI - Characterisation of an ABC transporter of a resistant Candida glabrata clinical isolate. AB - BACKGROUND: Candida glabrata ranks second in epidemiological surveillance studies, and is considered one of the main human yeast pathogens. Treatment of Candida infections represents a contemporary public health problem due to the limited availability of an antifungal arsenal, toxicity effects and increasing cases of resistance. C. glabrata presents intrinsic fluconazole resistance and is a significant concern in clinical practice and in hospital environments. OBJECTIVE: The aim of this study was to characterise the azole resistance mechanism presented by a C. glabrata clinical isolate from a Brazilian university hospital. METHODS: Azole susceptibility assays, chemosensitisation, flow cytometry and mass spectrometry were performed. FINDINGS: Our study demonstrated extremely high resistance to all azoles tested: fluconazole, voriconazole, posaconazole and itraconazole. This isolate was chemosensitised by FK506, a classical inhibitor of ABC transporters related to azole resistance, and Rhodamine 6G extrusion was observed. A mass spectrometry assay confirmed the ABC protein identification suggesting the probable role of efflux pumps in this resistance phenotype. MAIN CONCLUSIONS: This study emphasizes the importance of ABC proteins and their relation to the resistance mechanism in hospital environments and they may be an important target for the development of compounds able to unsettle drug extrusion. PMID- 29412346 TI - Vaccination strategies and results for tackling the measles outbreak in Ceara State, Brazil, 2013-2015. AB - This study describes the experience and results of the vaccination strategies developed for tackling the measles outbreak in Ceara State, Brazil, from December 2013 to September 2015. Strategies of routine vaccination, community immunity, and vaccination campaigns were conducted, along with searching of unvaccinated people, through rapid monitoring of immunization coverage and scanning. To describe the results, primary data collected in field activities and secondary data on vaccination in a population aged from six months to 49 years, available at the Information System of the National Immunization Program (IS-NIP), were used. The immunization coverage achieved was of >95%. However, this coverage is only administrative and may not represent reality, hence the importance of implementing the nominal information system of the National Immunization Program. PMID- 29412344 TI - Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland. AB - BACKGROUND: Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. OBJECTIVES: We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. METHODS: We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. FINDINGS: Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI) = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3%) patient, of whom 244 (27.0%; 95% CI = 24.2-30.0%) were positive. Eight (28.6%; 95% CI = 15.3-47.1%) of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000) or with Chagasic cardiomyopathy (p = 0.729). Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. CONCLUSIONS: Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection. PMID- 29412347 TI - Microcephaly in Piaui, Brazil: descriptive study during the Zika virus epidemic, 2015-2016. AB - OBJECTIVE: to describe the occurrence and characteristics of microcephaly cases in Piaui, Brazil, during an epidemic of Zika virus infection in 2015-2016. METHODS: descriptive study using data of live births from January/2015 to January/2016, obtained from the Information System on Live Births (Sinasc), the Public Health Events Registry (RESP) and the active search for medical records; mothers and live births were tested for dengue, chikungunya, and Zika, besides syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpes (STORCH). RESULTS: of the 75 microcephaly cases, 34 were related to congenital infectious process; microcephaly prevalence was of 13.6/10 thousand live births; imaging exams confirmed that 34 live births presented calcifications, 23 had cerebral atrophies, 14 had lissencephaly, 12 had ventriculomegaly and 6 had dysgenesis; none tested positive for STORCH, dengue or chikungunya; 1 was IgM positive for Zika. CONCLUSION: there was an outbreak of microcephaly in Piaui, possibly related to infection during pregnancy Zika virus. PMID- 29412348 TI - Quality of records on sexual violence against women in the Information System for Notifiable Diseases (Sinan) in Santa Catarina, Brazil, 2008-2013. AB - OBJECTIVE: to describe the quality of records on cases of sexual violence against women, reported in the Information System for Notifiable Diseases (Sinan), in Santa Catarina State, Brazil, from 2008 to 2013. METHODS: normative assessment with data from records of sexual violence cases against women (>=10 years old); data quality was described according to the dimensions 'non-duplicity' (acceptable when >95%), 'completeness' (good when >75%), and 'consistency' (excellent when >90.0%) of information. RESULTS: 2,010 cases of sexual violence against women were studied, after the exclusion of four duplicate records; the percentage of non-duplicity was 99.9% (acceptable); of completeness was 93.3% (good) and of consistency was 98.9% (excellent). CONCLUSION: the results presented point out the usefulness of Sinan as a source of information for the surveillance of sexual violence against women and for planning actions to tackle this type of aggression. PMID- 29412349 TI - Dental caries in peoples of Xingu Indigenous Park, Brazil, 2007 and 2013. AB - OBJECTIVE: to describe the prevalence of dental caries and the supply of dental care in the population of Xingu Indigenous Park, Brazil, at 5, 12 and 15-19 years old, in 2007 and 2013. METHODS: cross-sectional study panel, with secondary data provided by the Indigenous Special Sanitary District of Xingu and Project Xingu. RESULTS: 368 indigenous people were examined in 2007 and 423 in 2013; there was no significant difference between the means of the number of decayed, missing and filled teeth at 5 years (6.43 [2007], 5.85 [2013]; p=0.29), and at 12 years (2.54 [2007], 2.78 [2013]; p=0.81); this difference was significant at 15-19 years (6.89 [2007], 4.65 [2013]; p<0.01); the dental care index decreased from 21.7 to 7.1%, 44.1 to 16.4%, and 63.1 to 41.1%, respectively at 5, 12, and 15-19 years. CONCLUSION: the prevalence of caries remained high in children, with a reduction in adolescents (15-19 years old); there was a decrease in the supply of dental care. PMID- 29412350 TI - Sociodemographic characteristics and time series of mortality due to suicide among elderly individuals in Bahia State, Brazil, 1996-2013. AB - OBJECTIVE: to describe sociodemographic aspects and time evolution of mortality due to suicide among elderly individuals in Bahia State, Brazil, from 1996 to 2013. METHODS: time series descriptive and ecological study, with data from the Mortality Information System (SIM); Prais-Winsten regression was used for trend analysis and to calculate annual percent change (APC). RESULTS: 858 deaths due to suicide were identified in elderly in Bahia; 85.4% were men, and 53.8% were in the 60-69 age group; 64.3% of deaths resulted from hanging/strangulation, followed by self-poisoning by pesticides and chemical products (13.1%); there was an increasing trend in suicide mortality rate in the general elderly population (APC 11.0; 95%CI 6.9;15.3) and in the male sex (APC 12.1; 95%CI 7.1;17.3), whilst in the female population it remained stable. CONCLUSION: in Bahia, mortality due to suicide among elderly individuals presented an increasing trend in the period studied and was higher among males. PMID- 29412351 TI - Assessment of the production of cervical cancer care procedures in the Brazilian National Health System in 2015. AB - OBJECTIVE: to assess the procedures production of screening, diagnostic investigation and precursor lesions treatment for cervical cancer in the Brazilian National Health System (SUS). METHODS: normative evaluation with calculation of estimates of need based on national screening guidelines in two scenarios: organized (1) and opportunistic (2) screening; data were obtained from the SUS Ambulatory Care Information System and the Cervical Cancer Information System. RESULTS: considering the scenario 1, the production of cytopathologic exams (-46,9%) and biopsies (-44.9%) was below the necessary in Brazil, whereas colposcopy (61.3%) and precursor lesions treatments (37.4%) were above; in scenario 2, biopsies were below the necessary (-48.5%) whilst colposcopy (193.9%) and precursor lesions treatments (28.4%) were above. CONCLUSION: there were deficits in cytopathologic exams and biopsies and excess of colposcopies and treatment of precursor lesions in Brazil. PMID- 29412352 TI - Angiostrongylus spp. in the Americas: geographical and chronological distribution of definitive hosts versus disease reports. AB - BACKGROUND: Angiostrongyliasis is an infection caused by nematode worms of the genus Angiostrongylus. The adult worms inhabit the pulmonary arteries, heart, bronchioles of the lung, or mesenteric arteries of the caecum of definitive host. Of a total of 23 species of Angiostrongylus cited worldwide, only nine were registered in the American Continent. Two species, A. cantonensis and A. costaricensis, are considered zoonoses when the larvae accidentally parasitise man. OBJECTIVES: In the present study, geographical and chronological distribution of definitive hosts of Angiostrongylus in the Americas is analysed in order to observe their relationship with disease reports. Moreover, the role of different definitive hosts as sentinels and dispersers of infective stages is discussed. METHODS: The study area includes the Americas. First records of Angiostrongylus spp. in definitive or accidental hosts were compiled from the literature. Data were included in tables and figures and were matched to geographic information systems (GIS). FINDINGS: Most geographical records of Angiostrongylus spp. both for definitive and accidental hosts belong to tropical areas, mainly equatorial zone. In relation to those species of human health importance, as A. cantonensis and A. costaricensis, most disease cases indicate a coincidence between the finding of definitive host and disease record. However, in some geographic site there are gaps between report of definitive host and disease record. In many areas, human populations have invaded natural environments and their socioeconomic conditions do not allow adequate medical care. MAIN CONCLUSIONS: Consequently, many cases for angiostrongyliasis could have gone unreported or unrecognised throughout history and in the nowadays. Moreover, the population expansion and the climatic changes invite to make broader and more complete range of observation on the species that involve possible epidemiological risks. This paper integrates and shows the current distribution of Angiostrongylus species in America, being this information very relevant for establishing prevention, monitoring and contingency strategies in the region. PMID- 29412353 TI - Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment. AB - BACKGROUND: The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES: Study the anti Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS: The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS: The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS: These results suggest the studied combinations could be used in the treatment of Chagas disease. PMID- 29412354 TI - Mycobacterium tuberculosis promotes genomic instability in macrophages. AB - BACKGROUND: Mycobacterium tuberculosis is an intracellular pathogen, which may either block cellular defensive mechanisms and survive inside the host cell or induce cell death. Several studies are still exploring the mechanisms involved in these processes. OBJECTIVES: To evaluate the genomic instability of M. tuberculosis-infected macrophages and compare it with that of uninfected macrophages. METHODS: We analysed the possible variations in the genomic instability of Mycobacterium-infected macrophages using the DNA breakage detection fluorescence in situ hybridisation (DBD-FISH) technique with a whole human genome DNA probe. FINDINGS: Quantitative image analyses showed a significant increase in DNA damage in infected macrophages as compared with uninfected cells. DNA breaks were localised in nuclear membrane blebs, as confirmed with DNA fragmentation assay. Furthermore, a significant increase in micronuclei and nuclear abnormalities were observed in infected macrophages versus uninfected cells. MAIN CONCLUSIONS: Genomic instability occurs during mycobacterial infection and these data may be seminal for future research on host cell DNA damage in M. tuberculosis infection. PMID- 29412355 TI - Paracoccidioidomycosis due to Paracoccidioides brasiliensis S1 plus HIV co infection. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is one of the most important systemic mycoses in Latin America and the leading fungal cause of mortality in non immunosuppressed individuals in Brazil. However, HIV/PCM co-infection can increase the clinical severity in these co-infected patients. This co-infection is rarely reported in the literature mainly because of the different epidemiological profiles of these infections. Furthermore, PCM is a neglected and non-notifiable disease, which may underestimate the real importance of this disease. The advent of molecular studies on the species of the genus Paracoccidioides has expanded the knowledge regarding the severity and the clinical spectrum in PCM. In this context, the development of studies to describe the association of the Paracoccidioides phylogenetic cryptic species in vulnerable populations, such as HIV-infected patients, appears relevant. OBJECTIVE: To describe the clinical, epidemiological, therapeutic and prognostic aspects in HIV/PCM co-infected patients, along with the molecular identification of the Paracoccidioides species involved in these cases. METHODS: The investigators performed a molecular and clinical retrospective study involving HIV/PCM co-infected patients, from a reference centre for PCM care in the endemic area of Rio de Janeiro, Brazil, from 1998 to 2015. Molecular identification of the fungal strains was done by amplification of partial sequences of arf and gp43 genes. FINDINGS: Of 89 patients diagnosed with PCM by fungal isolation in the culture, a viable isolate was recovered for molecular analysis from 44 patients. Of these 44 patients, 28 (63.6%) had their serum samples submitted for enzyme immunoassay tests for screening of HIV antibodies, and 5 (17.9%) had a positive result. All cases were considered severe, with a variable clinical presentation, including mixed, acute/subacute clinical forms and a high rate of complications, requiring combination therapy. Paracoccidioides brasiliensis S1 was the species identified in all cases. CONCLUSIONS: HIV/PCM co-infection can change the natural history of this fungal disease. The authors reinforce the need to include HIV screening diagnostic tests routinely for patients with PCM. PMID- 29412356 TI - Sensitivity of diagnostic methods for Mansonella ozzardi microfilariae detection in the Brazilian Amazon Region. AB - BACKGROUND: The human filarial worm Mansonella ozzardi is highly endemic in the large tributaries of the Amazon River. This infection is still highly neglected and can be falsely negative when microfilariae levels are low. OBJECTIVES: This study investigated the frequency of individuals with M. ozzardi in riverine communities in Coari municipality, Brazilian Amazon. METHODS: Different diagnostic methods including polymerase chain reaction (PCR), blood polycarbonate membrane filtration (PCMF), Knott's method (Knott), digital thick blood smears (DTBS) and venous thick blood smears (VTBS) were used to compare sensitivity and specificity among the methods. Data were analysed using PCMF and Bayesian latent class models (BLCM) as the gold standard. We used BLCM to calculate the prevalence of mansonelliasis based on the results of five diagnostic methods. FINDINGS: The prevalence of mansonelliasis was 35.4% by PCMF and 30.1% by BLCM. PCR and Knott methods both possessed high sensitivity. Sensitivity relative to PCMF was 98.5% [95% confidence interval (CI): 92.0 - 99.7] for PCR and 83.5% (95% CI: 72.9 - 90.5) for Knott. Sensitivity derived by BLCM was 100% (95% CI 93.7 - 100) for PCMF, 100% (95% CI: 93.7 - 100) for PCR and 98.3% (95% CI: 90.6 - 99.9) for Knott. The odds ratio of being diagnosed as microfilaremic increased with age but did not differ between genders. Microfilariae loads were higher in subjects aged 30 - 45 and 45 - 60 years. MAIN CONCLUSIONS: PCMF and PCR were the best methods to assess the prevalence of mansonelliasis in our samples. As such, using these methods could lead to higher prevalence of mansonelliasis in this region than the most commonly used method (i.e., thick blood smears). PMID- 29412357 TI - Identification of the alpha-enolase P46 in the extracellular membrane vesicles of Bacteroides fragilis. AB - BACKGROUND: Members of the Bacteroides fragilis group are the most important components of the normal human gut microbiome, but are also major opportunistic pathogens that are responsible for significant mortality, especially in the case of bacteraemia and other severe infections, such as intra-abdominal abscesses. Up to now, several virulence factors have been described that might explain the involvement of B. fragilis in these infections. The secretion of extracellular membrane vesicles (EMVs) has been proposed to play a role in pathogenesis and symbiosis in gram-negative bacteria, by releasing soluble proteins and other molecules. In B. fragilis, these vesicles are known to have haemagglutination and sialidosis activities, and also contain a capsular polysaccharide (PSA), although their involvement in virulence is still not clear. OBJECTIVE: The aim of this study was to identify proteins in the EMV of the 638R B. fragilis strain by mass spectrometry, and also to assess for the presence of Bfp60, a surface plasminogen (Plg) activator, previously shown in B. fragilis to be responsible for the conversion of inactive Plg to active plasmin, which can also bind to laminin-1. METHODS: B. fragilis was cultured in a minimum defined media and EMVs were obtained by differential centrifugation, ultracentrifugation, and filtration. The purified EMVs were observed by both transmission electron microscopy (TEM) and immunoelectron microscopy (IM). To identify EMV constituent proteins, EMVs were separated by 1D SDS-PAGE and proteomic analysis of proteins sized 35 kDa to approximately 65 kDa was performed using mass spectrometry (MALDI-TOF MS). FINDINGS: TEM micrographs proved the presence of spherical vesicles and IM confirmed the presence of Bfp60 protein on their surface. Mass spectrometry identified 23 proteins with high confidence. One of the proteins from the B. fragilis EMVs was identified as an enolase P46 with a possible lyase activity. MAIN CONCLUSIONS: Although the Bfp60 protein was not detected by proteomics, alpha-enolase P46 was found to be present in the EMVs of B. fragilis. The P46 protein has been previously described to be present in the outer membrane of B. fragilis as an iron-regulated protein. PMID- 29412358 TI - Feline sporotrichosis: associations between clinical-epidemiological profiles and phenotypic-genotypic characteristics of the etiological agents in the Rio de Janeiro epizootic area. AB - BACKGROUND: Sporotrichosis is caused by species of the genus Sporothrix. From 1998 to 2015, 4,703 cats were diagnosed at the Fundacao Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil. Even after the description of the Sporothrix species, the characterisation of feline isolates is not performed routinely. OBJECTIVES: To characterise the clinical isolates from cats at the species level and correlate them with the clinical and epidemiological characteristics of the cats. METHODS: Forty seven Sporothrix spp. isolates from cats assisted at Fiocruz from 2010 to 2011 were included. Medical records were consulted to obtain the clinical and epidemiological data. The isolates were identified through their morphological and physiological characteristics. T3B polymerase chain reaction (PCR) fingerprinting was used for molecular identification of the species. FINDINGS: In phenotypic tests, 34 isolates were characterised as S. brasiliensis, one as S. schenckii and 12 as Sporothrix spp. PCR identified all isolates as S. brasiliensis. MAIN CONCLUSIONS: S. brasiliensis is the only etiological agent of feline sporotrichosis in Rio de Janeiro to date. None association was found between the isolates and the clinical and epidemiological data. In addition, we strongly recommend the use of molecular techniques for the identification of isolates of Sporothrix spp. PMID- 29412359 TI - Potential application of rLc36 protein for diagnosis of canine visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is fatal if left untreated. Infected dogs are important reservoirs of the disease, and thus specific identification of infected animals is very important. Several diagnostic tests have been developed for canine VL (CVL); however, these tests show varied specificity and sensitivity. The present study describes the recombinant protein rLc36, expressed by Leishmania infantum, as potential antigen for more sensitive and specific diagnosis of CVL based on an immunoenzymatic assay. The concentration of 1.0 MUg/mL of rLc36 enabled differentiation of positive and negative sera and showed a sensitivity of 85% and specificity of 71% (with 95% confidence), with an accuracy of 76%. PMID- 29412360 TI - Lutzomyia umbratilis from an area south of the Negro River is refractory to in vitro interaction with Leishmania guyanensis. AB - BACKGROUND: Lutzomyia umbratilis, the vector for Leishmania guyanensis in northern South America, has been found naturally infected with L. guyanensis only in areas north of the Negro and Amazon rivers. While populations of this sand fly species are also found in areas south of these rivers, these populations have never been reported to be infected and/or transmitting L. guyanensis. However, no studies on the corresponding host-parasite interactions are available. OBJECTIVES: This study evaluated the interaction between Lu. guyanensis promastigotes and field-collected Lu. umbratilis sand flies from Rio Preto da Eva and Manacapuru, which are located to the north and south, respectively, of the Negro River. METHODS: Procyclic and metacyclic attachment was quantified using an in vitro system. FINDINGS: Low attachment of parasites to the midguts of insects collected from Manacapuru was detected. Conversely, greater binding of metacyclic parasites was observed in the midguts of insects collected from Rio Preto da Eva, and this attachment was more pronounced than that observed for procyclics (p < 0.03). MAIN CONCLUSIONS: The Lu. umbratilis population from an area south of the Negro River has lower in vitro interaction with L. guyanensis. The higher attachment of L. guyanensis to midguts of insects from Rio Preto da Eva may suggest better vector competence. These findings are in accordance with previously reported epidemiological information of American cutaneous leishmaniasis (ACL) transmission in the Amazon. PMID- 29412361 TI - Entomopathogenic fungi and their potential for the management of Aedes aegypti (Diptera: Culicidae) in the Americas. AB - Classical biological control has been used extensively for the management of exotic weeds and agricultural pests, but never for alien insect vectors of medical importance. This simple but elegant control strategy involves the introduction of coevolved natural enemies from the centre of origin of the target alien species. Aedes aegypti - the primary vector of the dengue, yellow fever and Zika flaviviruses - is just such an invasive alien in the Americas where it arrived accidentally from its West African home during the slave trade. Here, we introduce the concept of exploiting entomopathogenic fungi from Africa for the classical biological control of Ae. aegypti in the Americas. Fungal pathogens attacking arthropods are ubiquitous in tropical forests and are important components in the natural balance of arthropod populations. They can produce a range of specialised spore forms, as well as inducing a variety of bizarre behaviours in their hosts, in order to maximise infection. The fungal groups recorded as specialised pathogens of mosquito hosts worldwide are described and discussed. We opine that similar fungal pathogens will be found attacking and manipulating Ae. aegypti in African forests and that these could be employed for an economic, environmentally-safe and long-term solution to the flavivirus pandemics in the Americas. PMID- 29412362 TI - Can whitening toothpastes maintain the optical stability of enamel over time? AB - Besides the effects on the health of individuals, cigarette smoking can also interfere with the appearance of their teeth. To evaluate the effect of cigarette smoking-toothbrushing-cycling (CSTC) with whitening toothpastes on the roughness and optical behavior of bovine enamel for eight weeks. Thirty bovine dentin/enamel discs, 8.0 mm in diameter and 2.0 mm thick, were randomly divided into three groups according to the toothpastes: whitening (Colgate Luminous White - CW and Oral B 3D White - OW), and a non-whitening (Colgate - C). The roughness, color (CIE L*a*b* system), translucency and gloss were measured before and after the specimens were submitted to CSTC. The topography of the specimens was analyzed by scanning electron microscopy. During the first week, the specimens were daily subjected to the consumption of 20 cigarettes and brushed (40 strokes/100 g) with the toothpastes' slurries. Thereafter, the CSTC was weekly applied in an accumulated model (140 cigarettes/280 strokes) for seven weeks. The data were submitted to two-way ANOVA, Tukey's HSD test, and paired-t test (alpha=0.05). The three toothpastes produced significant changes in roughness, color, translucency and gloss (p<0.05). After eight weeks, the roughness and the gloss produced by the three toothpastes were similar (p>0.05), while OW produced the lowest color change and the translucency of C was lower than that of CW (p<0.05). The three toothpastes produced a significant decrease in L* values and a significant increase in a* values after eight weeks (p<0.05). No significant difference in the b* coordinate was found for OW (p=0.13) There were topographic changes in the enamel surfaces. The whitening toothpastes increased the roughness, changed the topography and were not able to maintain the optical stability of enamel exposed over eight weeks. PMID- 29412363 TI - Preemptive use of etodolac on tooth sensitivity after in-office bleaching: a randomized clinical trial. AB - This study determined the effectiveness of the preemptive administration of etodolac on risk and intensity of tooth sensitivity and the bleaching effect caused by in-office bleaching using 35% hydrogen peroxide. Fifty patients were selected for this tripleblind, randomized, crossover, and placebo-controlled clinical trial. Etodolac (400 mg) or placebo was administrated in a single-dose 1 hour prior to the bleaching procedure. The whitening treatment with 35% hydrogen peroxide was carried out in two sessions with a 7-day interval. Tooth sensitivity was assessed before, during, and 24 hours after the procedure using the analog visual scale and the verbal rating scale. Color alteration was assessed by a bleach guide scale, 7 days after each session. Relative risk of sensitivity was calculated and adjusted by session, while overall risk was compared by the McNemar's test. Data on the sensitivity level of both scales and color shade were subjected to Friedman, Wilcoxon, and Mann-Whitney tests, respectively (alpha=0.05). The preemptive administration of etodolac did not affect the risk of tooth sensitivity and the level of sensitivity reported, regardless of the time of evaluation and scale used. The sequence of treatment allocation did not affect bleaching effectiveness, while the second session resulted in additional color modification. The preemptive administration of etodolac in a single dose 1 hour prior to in-office tooth bleaching did not alter tooth color, and the risk and intensity of tooth sensitivity reported by patients. A single-dose preemptive administration of 400 mg of etodolac did not affect either risk of tooth sensitivity or level of sensitivity reported by patients, during or after the in office tooth bleaching procedure. PMID- 29412364 TI - Reliability of light microscopy and a computer-assisted replica measurement technique for evaluating the fit of dental copings. AB - The aim of this in vitro study was to assess the reliability of two measurement systems for evaluating the marginal and internal fit of dental copings. Sixteen CAD/CAM titanium copings were produced for a prepared maxillary canine. To modify the CAD surface model using different parameters (data density; enlargement in different directions), varying fit was created. Five light-body silicone replicas representing the gap between the canine and the coping were made for each coping and for each measurement method: (1) light microscopy measurements (LMMs); and (2) computer-assisted measurements (CASMs) using an optical digitizing system. Two investigators independently measured the marginal and internal fit using both methods. The inter-rater reliability [intraclass correlation coefficient (ICC)] and agreement [Bland-Altman (bias) analyses]: mean of the differences (bias) between two measurements [the closer to zero the mean (bias) is, the higher the agreement between the two measurements] were calculated for several measurement points (marginal-distal, marginal-buccal, axial-buccal, incisal). For the LMM technique, one investigator repeated the measurements to determine repeatability (intra-rater reliability and agreement). For inter-rater reliability, the ICC was 0.848-0.998 for LMMs and 0.945-0.999 for CASMs, depending on the measurement point. Bland-Altman bias was -15.7 to 3.5 MUm for LMMs and -3.0 to 1.9 MUm for CASMs. For LMMs, the marginal-distal and marginal-buccal measurement points showed the lowest ICC (0.848/0.978) and the highest bias (-15.7 MUm/-7.6 MUm). With the intra-rater reliability and agreement (repeatability) for LMMs, the ICC was 0.970-0.998 and bias was -1.3 to 2.3 MUm. LMMs showed lower interrater reliability and agreement at the marginal measurement points than CASMs, which indicates a more subjective influence with LMMs at these measurement points. The values, however, were still clinically acceptable. LMMs showed very high intra rater reliability and agreement for all measurement points, indicating high repeatability. PMID- 29412365 TI - Effects of mineral trioxide aggregate, BiodentineTM and calcium hydroxide on viability, proliferation, migration and differentiation of stem cells from human exfoliated deciduous teeth. AB - The aim of the study was to evaluate the effects of the capping materials mineral trioxide aggregate (MTA), calcium hydroxide (CH) and BiodentineTM (BD) on stem cells from human exfoliated deciduous teeth (SHED) in vitro. SHED were cultured for 1 - 7 days in medium conditioned by incubation with MTA, BD or CH (1 mg/mL), and tested for viability (MTT assay) and proliferation (SRB assay). Also, the migration of serum-starved SHED towards conditioned media was assayed in companion plates, with 8 MUm-pore-sized membranes, for 24 h. Gene expression of dentin matrix protein-1 (DMP-1) was evaluated by reverse-transcription polymerase chain reaction. Regular culture medium with 10% FBS (without conditioning) and culture medium supplemented with 20% FBS were used as controls. MTA, CH and BD conditioned media maintained cell viability and allowed continuous SHED proliferation, with CH conditioned medium causing the highest positive effect on proliferation at the end of the treatment period (compared with BD and MTA) (p<0.05). In contrast, we observed increased SHED migration towards BD and MTA conditioned media (compared with CH) (p<0.05). A greater amount of DMP-1 gene was expressed in MTA group compared with the other groups from day 7 up to day 21. Our results show that the three capping materials are biocompatible, maintain viability and stimulate proliferation, migration and differentiation in a key dental stem cell population. PMID- 29412366 TI - Effect of filler size and filler loading on wear of experimental flowable resin composites. AB - The relationship between wear resistance and filler size or filler loading was clarified for the universal resin composite; however, their relationship in flowable resin composites has not been clarified. The purpose of this study was to investigate the effect of filler size and filler loading on wear of experimental flowable resin composites by using a cyclic loading device. Nine experimental flowable resin composites consisting of three different sizes (70, 200 and 400 nm) and loading (50, 55 and 60 wt%) of filler were prepared. Bowl shaped cavities were prepared on a flat surface of ceramic blocks using a No. 149 regular cut diamond point. The cavities were treated with a silane coupling agent and an all-in-one adhesive and then filled with each experimental flowable resin composite. The restored surfaces were finished and polished with a 1500-grit silicon carbide paper. The specimens were subjected to an in vitro two-body wear test using a cyclic loading device. The localized worn surfaces were evaluated at 10,000, 20,000, 30,000, and 40,000 cycles using a computer-controlled three dimensional measuring microscope (n=5). The volumetric wear loss of the materials was calculated automatically by the equipment. Data were statistically analyzed with two-way ANOVA and post hoc Tukey test. Two-way ANOVA showed that the filler size significantly influenced wear volume (p<0.003), but the filler loading did not have a significant effect (p>0.05). A post hoc Tukey test detected significant differences in filler size between 70 nm and 400 nm, and 200 nm and 400 nm (p<0.007). The experimental flowable resin composite containing a mean filler size of 400 nm exhibited significantly lower wear resistance in two-body wear compared with those containing mean filler sizes of 200 nm or 70 nm. PMID- 29412367 TI - Oral health-related quality of life of children with oral clefts and their families. AB - Oral health problems can influence people's Quality of Life (QoL) because of pain, discomfort, limitations, and other esthetics problems, affecting their social life, feeding, daily activities, and the individual's well-being. To compare oral health-related quality of life (OHRQoL) of children with and without oral clefts and their families. 121 children aged from 2 to 6 years, from both sexes, enrolled in the treatment routine of the Pediatric Dentistry Clinics of a Dental School and a Hospital for Cleft Treatment were divided into two groups: Group 1 - children with cleft lip and palate; Group 2 - children without cleft lip and palate. The OHRQoL was assessed using the validated Portuguese version of the Early Childhood Oral Health Impact Scale (B-ECOHIS). The questionnaire was answered individually, only once, at a private place. Mann-Whitney U test was used to verify differences between groups. Spearman's Rho test was used to associate sex and age with quality of life. The level of significance was set at 5% (p<0.05). According to the parents' perception on the OHRQoL of children with and without cleft lip and palate, oral health of children with oral clefts (Group 1) had a statistically significant impact on OHRQoL. The correlation of sex with impact on OHRQoL did not show statistically significant differences. On the other hand, the higher the age the higher the impact on QoL. The group comparison revealed that the cleft lip and palate negatively impacted on OHRQoL of 2 to 6 year-old children and their parents. PMID- 29412368 TI - Effects of orofacial myofunctional therapy on masticatory function in individuals submitted to orthognathic surgery: a randomized trial. AB - OBJECTIVES: The esthetic and functional results of orthognathic surgery of severe dentofacial deformities are predictable, however there are differences regarding the effects on stomatognathic system. The aim was to investigate the effects of orofacial myofunctional therapy (OMT) on the masticatory function in individuals with dentofacial deformity submitted to orthognathic surgery (OGS). MATERIAL AND METHODS: Forty-eight individuals (18-40 years) were evaluated, 14 undergoing OMT (treated group-TG), 10 without this treatment (untreated group-UTG) and 24 in a control group with normal occlusion; for clinical aspects the data of an individual was missed (n=46). Chewing was performed using the Expanded protocol of orofacial myofunctional evaluation with scores (OMES-E). Muscle tone and mobility were also analyzed before (P0), three (P1) and six months (P2) after OGS. Surface electromyography of the masseter and temporalis muscles was performed, considering the parameters amplitude and duration of act and cycle, and the number of masticatory cycles. The OMT consisted of ten therapeutic sessions along the postoperative period. The results were compared using parametric and non-parametric tests. RESULTS: TG showed higher scores in P1 and P2 than P0; for the masticatory type the scores in P2 were significantly higher than P0. In addition, the proportion of individuals with adequate tone of lower lip and adequate tongue mobility for TG increased significantly from P1 and P2 in relation to P0. The EMG results showed a decrease in act and cycle duration in P2 in relation to P0 and P1 for the TG; furthermore the values were close to controls. An increase in the number of cycles from P0 to P2 was also observed, indicating faster chewing, which may be attributed to an improvement of balanced occlusion associated with OMT. CONCLUSION: There were positive effects of OMT on the clinical and electromyography aspects of chewing in individual submitted to orthognathic surgery. PMID- 29412369 TI - Quality of infant care in primary health services in Southern and Northeastern Brazil. AB - OBJECTIVE: To assess the quality of the health care provided to children aged under one year old performed by primary health services in the South and Northeast regions of Brazil. METHODS: This is a cross-sectional, population-based study carried out in 2010 with 7,915 children aged from one to four years, whose homes are located in the areas of health service coverage. We described the prevalence of procedures and guidelines, such as weight and height measurement, vaccination, newborn blood spot screening, evaluation of umbilical cord, instruction on breastfeeding and introduction of new food, and their respective 95% confidence intervals. The differences were analyzed using the chi-square test of heterogeneity and linear trend. We considered the main outcome of high-quality infant care if the child had received all recommended procedures and guidelines in the first year of life. For this analysis, we used the Poisson regression considering hierarchical model. RESULTS: There was low prevalence for the instruction on breastfeeding in the first week of life (58.8%, 95%CI 57.5-60.0) and on the introduction of new food in the fourth month care. The prevalence of high-quality in childcare was 42.0% (95%CI 40.5-43.5). The adjusted analysis according to hierarchical model indicated greater probability of this outcome in the Northeast region (PR = 1.17, 95%CI 1.09-1.26), in smaller municipalities (PR = 1.17, 95%CI 1.03-1.33), and in municipalities with 50,000 and 99,000 inhabitants (PR = 1.20, 95%CI 1.09-1.34). CONCLUSIONS: The Northeast region has higher-quality infant care services, which can be explained by the consolidation of the Family Health Strategy in that region. PMID- 29412370 TI - Why precision medicine is not the best route to a healthier world. AB - Precision medicine has been announced as a new health revolution. The term precision implies more accuracy in healthcare and prevention of diseases, which could yield substantial cost savings. However, scientific debate about precision medicine is needed to avoid wasting economic resources and hype. In this commentary, we express the reasons why precision medicine cannot be a health revolution for population health. Advocates of precision medicine neglect the limitations of individual-centred, high-risk strategies (reduced population health impact) and the current crisis of evidence-based medicine. Overrated "precision medicine" promises may be serving vested interests, by dictating priorities in the research agenda and justifying the exorbitant healthcare expenditure in our finance-based medicine. If societies aspire to address strong risk factors for non-communicable diseases (such as air pollution, smoking, poor diets, or physical inactivity), they need less medicine and more investment in population prevention strategies. PMID- 29412371 TI - Trend of oral and pharyngeal cancer mortality in Brazil in the period of 2002 to 2013. AB - OBJECTIVE: To analyze the trend of oral and pharyngeal cancer mortality rates in the period of 2002 to 2013 in Brazil according to sex, anatomical site, and macroregion of the country. METHODS: The mortality data were obtained from the Mortality Information System and the population data were obtained from the Brazilian Institute of Geography and Statistics. The trend of the rates standardized by sex and age was calculated using the Prais-Winsten estimation, and we obtained the annual percentage change and the respective 95% confidence intervals, analyzed according to sex, macroregion, and anatomical site. RESULTS: The average coefficient of oral cancer mortality was 1.87 per 100,000 inhabitants and it remained stable during the study period. The coefficient of pharyngeal cancer mortality was 2.04 per 100,000 inhabitants and it presented an annual percentage change of -2.6%. Approximately eight in every 10 deaths occurred among men. There was an increase in the rates of oral cancer in the Northeast region (annual percentage change of 6.9%) and a decrease in the Southeast region (annual percentage change of -2.9%). Pharyngeal cancer mortality decreased in the Southeast and South regions with annual percentage change of -4.8% and -5.1% respectively. Cancer mortality for tonsil, other major salivary glands, hypopharynx, and other and unspecified parts of mouth and pharynx showed a decreasing trend while the other sites presented stability. CONCLUSIONS: Pharyngeal cancer mortality decreased in the period of 2002 to 2013. Oral cancer increased only in the Northeast region. Mortality for tonsil cancer, other major salivary glands, hypopharynx, and other and ill-defined sites in the lip, oral cavity, and pharynx decreased. PMID- 29412372 TI - Descriptive study of the Specialized Care of the Spanish Health System. AB - OBJECTIVE: The objective of this study is to analyze the trend of the Key Indicators of the National Health System of Spain and its autonomous communities, related to Specialized Care, from the publication of the Law of Cohesion and Quality. METHODS: This is an ecological study of temporary series of Spain and its autonomous communities from 2003 to 2014. We have analyzed 10 indicators related to Specialized Care (percentage of expenditure, professionals, waiting lists, surgical activity, average duration, infections, and mortality) using the Prais-Winsten regression method. We have obtained data from the health information system of the Spanish Ministry of Health, Social Services, and Equality. RESULTS: Specialized care expenditure (APC = 0.059, 95%CI 0.041-0.074), number of medical professionals (APC = 0.0006, 95%CI 0.0003-0.0009) and nursing professionals (APC = 0.001, 95%CI 0.0005-0.0016), hospital infections (APC = 0.0003, 95%CI 0.0002-0.0004), and in-hospital mortality (APC = 0.0008, 95%CI 0.0006-0.001) had an increasing trend in Spain. Average duration presented a decreasing trend (APC = -0.0017, 95%CI -0.002- -0.0014). The trend of waiting lists (specialized appointment and non-urgent surgical interventions) was static. The trend of these indicators varied in the Autonomous Communities. CONCLUSIONS: We have observed a non-compliance with the principles of equity and quality of the services offered. Increased aging, technological development, and inadequate strategies taken to reduce health costs may be the main causes. PMID- 29412373 TI - Use of electronic immunization registry in the surveillance of adverse events following immunization. AB - OBJECTIVE: To describe adverse events following vaccination (AEFV) of children under two years old and analyze trend of this events from 2000 to 2013, in the city of Araraquara (SP), Brazil. METHODS: This is a descriptive study conducted with data of the passive surveillance system of AEFV that is available in the electronic immunization registry (EIR) of the computerized medical record of the municipal health service (Juarez System). The study variables were: age, gender, vaccine, dose, clinical manifestations and hospitalization. We estimated rates using AEFV as numerator and administered doses of vaccines as denominator. The surveillance sensitivity was estimated by applying the method proposed by the Centers for Disease Control and Prevention. We used Prais-Winsten regression with a significance level of 5.0%. RESULTS: The average annual rate of AEFV was 11.3/10,000 administered doses, however without a trend in the study period (p=0.491). Most cases occurred after the first dose (41.7%) and among children under one year of age (72.6%). Vaccines with pertussis component, yellow fever and measles-mumps-rubella were the most reactogenic. We highlighted the rates of hypotonic-hyporesponsive episodes and convulsion that were 4.1/10,000 and 1.5/10,000 doses of vaccines with pertussis component, respectively, most frequently in the first dose; 60,0% of cases presented symptoms in the first 24 hours after vaccination, however, 18.6% showed after 96 hours. The sensitivity of surveillance was 71.9% and 78.9% for hypotonic-hyporesponsive episodes and convulsion, respectively. CONCLUSIONS: The EIR-based AEFV surveillance system proved to be useful and highly sensitive to describe the safety profile of vaccines in a medium-sized city. It was also shown that the significant increase of the vaccines included in the basic vaccination schedule in childhood in the last decade did not alter the high safety standard of the National Immunization Program. PMID- 29412374 TI - The general movement assessment in non-European low- and middle-income countries. AB - Abnormal general movements are among the most reliable markers for cerebral palsy. General movements are part of the spontaneous motor repertoire and are present from early fetal life until the end of the first half year after term. In addition to its high sensitivity (98%) and specificity (91%), the assessment of general movements is non-invasive and time- and cost-efficient. It is therefore ideal for assessing the integrity of the young nervous system, most notably in lowresource settings. Studies on the general movements assessment in low- and middle-income countries such as China, India, Iran, or South Africa are still rare but increasing. In Brazil, too, researchers have demonstrated that the evaluation of general movements adds to the functional assessment of the young nervous system. Applying general movements assessment in vulnerable populations in Brazil is therefore highly recommended. PMID- 29412375 TI - Effectiveness of breast cancer screening policies in countries with medium-low incidence rates. AB - Chile has lower breast cancer incidence rates compared to those in developed countries. Our public health system aims to perform 10 biennial screening mammograms in the age group of 50 to 69 years by 2020. Using a dynamic programming model, we have found the optimal ages to perform 10 screening mammograms that lead to the lowest lifetime death rate and we have evaluated a set of fixed inter-screening interval policies. The optimal ages for the 10 mammograms are 43, 47, 51, 54, 57, 61, 65, 68, 72, and 76 years, and the most effective fixed inter-screening is every four years after the 40 years. Both policies respectively reduce lifetime death rate in 6.4% and 5.7% and the cost of saving one life in 17% and 9.3% compared to the 2020 Chilean policy. Our findings show that two-year inter-screening interval policies are less effective in countries with lower breast cancer incidence; thus we recommend screening policies with a wider age range and larger inter-screening intervals for Chile. PMID- 29412376 TI - Breastfeeding and behavior disorders among children and adolescents: a systematic review. AB - OBJECTIVE: This systematic review study aimed to assess the evidence available for the association between breastfeeding and behavior disorders in childhood and adolescence. METHODS: The search was carried out in the PubMed, Lilacs, and PsycINFO databases up to December 2016. Inclusion criteria were as follows: prospective, retrospective and cross-sectional studies assessing the association between breastfeeding and behavior disorders in childhood or adolescence, using psychometric tests, carried out in humans and published in Portuguese, English, or Spanish. The search was performed in several stages by two independent researchers using pre-established criteria. RESULTS: Eighteen studies met the inclusion criteria. Breastfeeding for a period equal to or higher than three or four months seemed to be inversely associated with total behavior and conduct disorders in childhood; however, the association remains unclear for other behavior disorders. Only four studies assessed behavior disorders in adolescence, and when an association was found, it was likely to be positive. The duration of breastfeeding seemed to be more important than the exclusive or non-exclusive pattern of breastfeeding. CONCLUSIONS: Breastfed children for at least three to four months had fewer total behavior and conduct disorders in childhood. Further studies are needed to better understand this association, particularly in adolescence and involving other behavioral profiles. PMID- 29412377 TI - Tuberculosis and latent infection in employees of different prison unit types. AB - OBJECTIVE: Estimate the prevalence of active tuberculosis and latent tuberculosis infection among the staff that is in contact and the staff that is not in contact with prisoners, and investigate factors associated with latent tuberculosis infection in this population. METHODS: Observational cross-sectional study, conducted from 2012 to 2015, in employees of different prison units in the municipality of Franco da Rocha, SP. It consisted of the application of a questionnaire, application and reading of the tuberculin test, sputum smear microscopy, sputum culture, and radiological examination. The association between the qualitative variables was calculated by the Pearson's chi-squared test. The sociodemographic and clinical-epidemiological factors related to the latent tuberculosis infection were evaluated by the logistic regression with the odds ratios (OR) calculation and their respective intervals with 95% of confidence (95%CI). RESULTS: A total of 1,059 employees were examined, 657 (62.0%) of prisons, 249 (23.5%) of CASA Foundation units and 153 (14.5%) of custodial and psychiatric treatment hospitals. The tuberculin test was applied and read for 945 (89.2%) professionals. Of these, 797 (84.3%) were contacts of detainees and 148 (15.7%) were not. Among prison staff, the factors associated with latent tuberculosis infection were: contact with detainee (OR = 2.12, 95%CI 1.21-3.71); male gender (OR = 1.97, 95%CI 1.19-3.27); between 30 and 39 years old (OR = 2.98, 95%CI 1.34-6.63), 40 to 49 years old (OR = 4.32, 95%CI 1.94-9.60), and 50 to 59 years old (OR = 3.98, 95%CI 1.68-9.43); nonwhite color or race (OR = 1.89, 95%CI 1.29-2.78); and smoker (OR = 1.64, 95%CI 1.05-2.55). There were no positive test on sputum smear microscopy and culture. Of the 241 (22.8%) professionals who underwent radiological examination, 48 (19.9%) presented alterations of which 11 were suspected of tuberculosis. CONCLUSIONS: Prison employees who have direct contact with detainees are 2.12 times more likely to become infected with Mycobacterium tuberculosis in the work environment and consequently to become ill with tuberculosis and should be targeted for disease prevention and control. PMID- 29412379 TI - Muscle, inflammation and metabolic health: is irisin the missing link? PMID- 29412378 TI - Evaluation of the effects of a diabetes educational program: a randomized clinical trial. AB - OBJECTIVE: Evaluate the effectiveness of a diabetes mellitus educational program in primary health care. METHODS: This cluster randomized trial was conducted in a sample of 470 people with type 2 diabetes mellitus from eight health units, randomly assigned to two groups: intervention (n = 231) and control (n = 239). The intervention group participated in the educational program composed of three strategies: group education, home visit, and telephone intervention. Simultaneously, the control group was monitored individually. Group monitoring took place over nine months in the year 2012. Clinical evaluations were performed at the initial time (T0), three (T3), six (T6) and nine (T9) months after the beginning of the intervention. RESULTS: After nine months of follow-up, 341 users remained in the study, 171 in the control group and 170 in the intervention group. The average age of users was 60.6 years. In both groups, statistically significant differences were observed in mean HbA1c levels over the follow-up time (p < 0.05). However, the mean HbA1c level at T3, T6 and T9 times were significantly lower among the people in the intervention group (p < 0.05). CONCLUSIONS: The educational program model developed was effective to improve the glycemic control of the intervention group participants. PMID- 29412380 TI - Poor glycemic control can lead to an early appearance of atherosclerosis in patients with type 1 diabetes - Can this be avoided by effective educational programs? PMID- 29412381 TI - Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk. AB - OBJECTIVE: Thus, the aim of this study was to compare if higher or smaller fibronectin type 3 domain-containing protein 5 (FNDC5)/irisin levels are associated with inflammatory and metabolic markers, caloric/macronutrient intake, physical fitness and type 2 diabetes mellitus (T2DM) risk in obese middle-aged men, and also to correlate all variables analyzed with FNDC5/irisin. SUBJECTS AND METHODS: On the basis of a cluster study, middle-aged obese men (IMC: 31.01 +/- 1.64 kg/m2) were divided into groups of higher and smaller levels of FNDC5/irisin. The levels of leptin, resistin, adiponectin, tumor necrosis factor alpha (TNFalpha), interleukin 6 and 10 (IL6, IL10), lipopolysaccharide (LPS), glucose, insulin, glycated hemoglobin, insulin resistance and sensibility, lipid profile, risk of T2DM development, body composition, rest energy expenditure, caloric/macronutrient intake and physical fitness were measured. RESULTS: The higher FNDC5/ irisin group presented improved insulin sensibility (homeostasis model assessment - sensibility (HOMA-S) (p = 0.01) and QUICKI index (p < 0.01)), insulin (p = 0.02) and triglyceride levels (p = 0.01), lower insulin resistance (homeostasis model assessment - insulin resistance (HOMA-IR) (p = 0.01), triglycerides/glucose (TYG index) (p = 0.02), neck circumference (p = 0.02), risk of T2DM development (p = 0.02), tendency to decrease serum resistin (p = 0.08) and significant lower LPS levels (p = 0.02). Inverse correlations between FNDC5/irisin and body weight (r -0.46, p = 0.04), neck circumference (r -0.51, p = 0.02), free fat mass (r -0.49, p = 0.02), triglycerides (r -0.43, p = 0.05) and risk of developing T2DM (r -0.61, p = 0.04) were observed. CONCLUSIONS: These results suggest that higher FNDC5/irisin levels in obese middle-aged men are related to a better metabolic profile and lower risk of T2DM development and serum LPS, a potential inducer of insulin resistance. PMID- 29412382 TI - Thyroid disorders in obese patients. Does insulin resistance make a difference? AB - OBJECTIVE: The aim of this study was to evaluate the association between insulin resistance and thyroid pathology in obese patients, and compare the results between insulin-resistant and noninsulin-resistant patients. SUBJECTS AND METHODS: Obese/nondiabetic patients, aged 18-70 years, attending the outpatient endocrinology service for 2 years were consecutively included. We evaluated the patients' fasting plasma glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), thyroid-stimulating hormone (TSH), free thyroxine (FT4), antithyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (Tg-Ab), and thyroid ultrasound. RESULTS: We included 82 patients with a mean age 44.21 +/- 12.67 years. The thyroid disorders encountered and their prevalences were: hypothyroidism (14.6%, 95% confidence interval [CI] 8.6-23.8%), hyperthyroidism (1.2%, 95% CI 2.0-6.6%), goiter (28.0%, 95% CI 19.5-3.6%), thyroid nodules (35.4%, 95% CI 25.9-46.2%), and Hashimoto's thyroiditis (32.9%, 95% CI 23.7-43.7%). HOMA-IR correlated positively with TSH levels (r = 0.24, p = 0.028), and this correlation remained after adjustment for body mass index (BMI), waist/hip ratio (WHR), serum cortisol, subcutaneous fat thickness (SFT), visceral fat thickness (VFT), triglycerides, gamma-glutamyl transpeptidase (GGT), and alanine aminotransferase (ALT) in multivariate regression analysis (b = 0.207, 95% CI, 0.09-0.385, p = 0.023). TSH levels were significantly higher in patients with HOMA-IR >= 2.5 than in those with HOMA-IR < 2.5 (2.03 MUIU/mL, interquartile range [IQR] 1.59-2.69 MUIU/mL) versus 1.59 MUIU/mL, IQR 0.94-2.26 MUIU/mL, p = 0.023). CONCLUSIONS: The most prevalent thyroid disorder in patients attending our endocrinology clinic for investigation of obesity was thyroid nodules. One in seven patients had hypothyroidism. Our findings suggest that TSH levels correlate with insulin resistance in obese patients. PMID- 29412383 TI - Metastatic lymph node characteristics as predictors of recurrence/persistence in the neck and distant metastases in differentiated thyroid cancer. AB - OBJECTIVE: The aim of this study was to evaluate the association between this characteristic and outcomes in patients with lymph node metastasis in a Brazilian cohort. SUBJECTS AND METHODS: This study examined a retrospective cohort of adult patients diagnosed with differentiated thyroid cancer and lymph node metastases from 1998 to 2015 in two referral centers. Number, location, size and extranodal extension (ENE) of metastatic lymph nodes were assessed and correlated with response to initial therapy. RESULTS: A greater number of metastatic nodes, larger size, presence of lateral neck disease and ENE were all associated with a lower probability of achieving an excellent response to initial therapy (p <= 0.05 for all these parameters). Local recurrent disease had a significant association with lymph node number (6 in the recurrence/persistence group versus 4 in the non-recurrent group; p = 0.02) and ENE (19.2 versus 75%, p = 0.03). Lateral neck disease was the only characteristic associated with distant metastasis and was present in 52.1% of the group without metastasis and 70.4% of the group with metastasis (p = 0.001). CONCLUSION: The lymph node characteristics were associated with response to initial therapy and neck recurrence/persistence, confirming the importance of the analysis of these factors in risk stratification in a Brazilian population and its possible use to tailor initial staging and long term follow-up. PMID- 29412384 TI - Thyroglobulin levels before radioactive iodine therapy and dynamic risk stratification after 1 year in patients with differentiated thyroid cancer. AB - OBJECTIVES: We sought to assess the relationship between stimulated thyroglobulin (sTg) before radioactive iodine therapy (RIT), and the dynamic risk stratification 1 year after treatment, and to establish the utility of the sTg as a predictor of response to therapy in these patients. A retrospective chart review of patients with differentiated thyroid cancer (DTC) who underwent RIT after surgery and were followed for at least 1 year, was carried out. SUBJECTS AND METHODS: Patients were classified according to the dynamic risk stratification 1 year after initial treatment. The sTg values before RIT were compared among the groups. ROC curve analysis was performed. RESULTS: Fifty-six patients were enrolled (mean age 44.7 +/- 14.4 years, 80.7% had papillary carcinoma). Patients with excellent response had sTg = 2.1 +/- 3.3 ng/mL, those with indeterminate response had sTg = 8.2 +/- 9.2 ng/mL and those with incomplete response had sTg = 22.4 +/- 28.3 ng/mL before RIT (p = 0.01). There was a difference in sTg between excellent and incomplete response groups (p = 0.009) while no difference was found between indeterminate and either excellent or incomplete groups. The ROC curve showed an area under the curve of 0.779 assuming a sTg value of 3.75 ng/mL. CONCLUSION: Our study results suggest that the higher the sTg before RIT, the greater the likelihood of an incomplete response to initial treatment. A sTg cut-off of 3.75 ng/mL was found to be a good predictor of response to initial treatment in patients with DTC. PMID- 29412385 TI - Serum selenium and selenoprotein-P levels in autoimmune thyroid diseases patients in a select center: a transversal study. AB - OBJECTIVE: Selenium (Se) supplementation has been used to help prevent the progression of Graves' ophthalmopathy (GO) and autoimmune thyroid diseases (AITD) patients. We investigated Se serum and selenoprotein P (SePP) levels in Graves' disease (GD) with and without GO, Hashimoto's thyroiditis (HT) patients and in 27 control individuals (C). SUBJECTS AND METHODS: We studied 54 female and 19 male patients: 19 with GD without GO, 21 GD with GO, 14 with HT and 19 with HT+LT4. Se values were measured using graphite furnace atomic absorption spectrophotometry. Serum SePP levels were measured by ELISA. RESULTS: Median Se levels were similar among all groups; GD patients: 54.2 (46.5-61.1 MUg/L), GO: 53.6 (43.5-60.0 MUg/L), HT: 51.9 (44.6-58.5 MUg/L), HT+LT4 54.4 (44-63.4) and C group patients: 56.0 (52.4-61.5 MUg/L); P = 0.48. However, serum SePP was lower in GO patients: 0.30 (0.15-1.05 MUg/mL) and in HT patients: 0.35 (0.2-1.17 MUg/mL) compared to C group patients: 1.00 (0.564.21 MUg/mL) as well as to GD patients: 1.19 (0.62-2.5 MUg/mL) and HT+LT4 patients: 0.7 (0,25-1.95); P = 0.002. Linear regression analysis showed a significant relationship between SePP and TPOAb values (r = 0.445, R2 = 0.293; P < 0.0001). Multiple regression analysis found no independent variables related to Se or SePP. CONCLUSION: A serum Se concentration was lower than in some other countries, but not significantly among AITD patients. The low serum SePP levels in GO and HT patients seems to express inflammatory reactions with a subsequent increase in Se-dependent protein consumption remains unclear. PMID- 29412386 TI - Laparoscopic sleeve gastrectomy in severely obese adolescents: effects on metabolic profile. AB - OBJECTIVE: The objective was to conduct clinical and metabolic evaluations of obese adolescents before and after laparoscopic sleeve gastrectomy (LSG) (up to 24 months). SUBJECTS AND METHODS: This was designed as a retrospective, descriptive series of cases study, conducted in Instituto da Crianca, Sao Paulo, Brazil. Analysis of clinical and laboratory data from 22 obese adolescents between 14 and 19 years old submitted to LSG between 2007 and 2014. Patients had BMI > 40 kg/m2 or BMI > 35 kg/m2 with comorbidities. Anthropometric, clinical and laboratory assessments were performed: before surgery, 6, 12, 18, and 24 months after surgery. We assessed weight loss and metabolic changes up to 24 months after LSG. RESULTS: The mean preoperative weight and BMI were 128.5 kg (SD = 23.1) and 46.5 kg/m2 (SD = 74), respectively. There was an average weight loss of 34.5 kg in the first 12 months' post LSG, corresponding to a 60% excess weight loss (EWL), as well as an average reduction in BMI of 12.3 kg/m2. However, after 24 months, the average EWL was 45%, corresponding to an average weight regain (WR) of 13.3 kg (15%) within two years. LSG improved dyslipidemia in 67.8% of patients, a significant remission of hepatic steatosis 47% and 37.7% systemic arterial hypertension; type 2 diabetes remission was complete. CONCLUSIONS: LSG proved to be a safe and effective procedure and seems to be the new hope for the obesity epidemic. PMID- 29412387 TI - Relationships between adiponectin levels, the metabolic syndrome, and type 2 diabetes: a literature review. AB - Elevated hepatic glucose production, impaired insulin secretion, and insulin resistance - abnormalities of glucose metabolism typically found in subjects with obesity - are major factors underlying the pathogenesis of type 2 diabetes (DM2) and the metabolic syndrome (MS). Adiponectin is a major regulator of glucose and lipid homeostasis via its insulin-sensitizing properties, and lower levels seems to be associated with the development of DM2 and MS. The purpose of this review is to clarify the mechanisms whereby adiponectin relates to the development of DM2 and MS and the association between polymorphisms of the adiponectin gene, circulating levels of the hormone, and its relationships with DM2. In addition, the impact of dietary lipids in the circulating levels of adiponectin will be addressed. According to the literature, circulating adiponectin levels seem to decrease as the number of MS components increases. Lower adiponectin concentrations are associated with higher intra-abdominal fat content. Therefore, adiponectin could link intra-abdominal fat with insulin resistance and development of MS. Therapeutic strategies that target the MS and its components, such as lifestyle modification through physical activity and weight loss, have been shown to increase adiponectin concentrations. Possible roles of diets containing either low or high amounts of fat, or different types of fat, have been analyzed in several studies, with heterogeneous results. Supplementation with n-3 PUFA modestly increases adiponectin levels, whereas conjugated linoleic acid supplementation appears to reduce concentrations when compared with unsaturated fatty acid supplementation used as an active placebo. PMID- 29412388 TI - Effect of biliopancreatic diversion on sleep quality and daytime sleepiness in patients with obesity and type 2 diabetes. AB - OBJECTIVE: The poor quality of sleep and the deprivation thereof have been associated with disruption of metabolic homeostasis, favoring the development of obesity and type 2 diabetes (T2DM). We aimed to evaluate the influence of biliopancreatic diversion (BPD) surgery on sleep quality and excessive daytime sleepiness of obese patients with T2DM, comparing them with two control groups consisting of obese and normal weight individuals, both normal glucose tolerant. SUBJECTS AND METHODS: Forty-two women were divided into three groups: LeanControl (n = 11), ObeseControl (n = 13), and ObeseT2DM (n = 18). The LeanC and ObeseC groups underwent all tests and evaluations once. The ObeseT2DM underwent BPD and were reassessed after 12 months. Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were applied before and 12 months after BPD. RESULTS: Before surgery, there was less daytime sleepiness in LeanC group (p = 0.013) compared with ObeseC and T2DMObese groups. The two obese groups did not differ regarding daytime sleepiness, demonstrating that the presence of T2DM had no influence on daytime sleepiness. After surgery, the daytime sleepiness (p = 0.002) and the sleep quality (p = 0.033) improved. The score for daytime sleepiness of operated T2DMObese group became similar to LeanC and lower than ObeseC (p = 0.047). CONCLUSION: BPD surgery has positively influenced daytime sleepiness and sleep quality of obese patients with T2DM, leading to normalization of daytime sleepiness 12 months after surgery. These results reinforce previously identified associations between sleep, obesity and T2DM in view of the importance of sleep in metabolic homeostasis, quality of life and health. PMID- 29412389 TI - High prevalence of insulin resistance among Brazilian chronic hepatitis C patients. AB - OBJECTIVE: This study aims to estimate the prevalence of insulin resistance (IR) among chronic hepatitis C (CHC) patients and their related laboratory and demographic data. SUBJECTS AND METHODS: In this study, non-diabetic CHC patients referred to Viral Hepatitis Ambulatories from Rio de Janeiro (Brazil) donated blood samples. Insulin was measured using a chemiluminescence immunoassay. IR was determined by HOMA-IR, where HOMA-IR > 2 was defined as IR. RESULTS: A total of 214 CHC patients were recruited (123 females aged 53.6 years +/- 10.9 years). IR was present in 133 patients (62.1%) and was associated in bivariate analysis to higher mean values of age (p = 0.040), triglycerides (p = 0.032), glucose (p = 0.000), insulin (p = 0.000), waist circumference (p = 0.001), and body mass index (p = 0.007); however, none of these variables were significant in the multivariate analysis. CONCLUSIONS: The high prevalence of IR was observed among CHC patients, and there was no difference in clinical or laboratory parameters when both groups were compared in the multivariate analysis. This high IR prevalence could lead to a high risk for development of cardiovascular disease and metabolic disorders. PMID- 29412390 TI - Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing. AB - Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene. PMID- 29412391 TI - More than kin, less than kind: one family and the many faces of diabetes in youth. AB - Identification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin). We found a Gly178Ala substitution in exon 5 of GCK gene in three individuals co-segregating with diabetes, and type 1 diabetes was identified in two other individuals based on clinical and laboratory data. One individual with previous gestational diabetes and other with prediabetes were also described. We discuss difficulties in defining etiology of hyperglycemia in youth in clinical practice, especially monogenic forms of diabetes, in spite of the availability of several genetic, laboratory, and clinical tools. PMID- 29412392 TI - Coexistence of diffuse large B-cell lymphoma and papillary thyroid carcinoma in a patient affected by Hashimoto's thyroiditis. AB - Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. On the contrary, primary thyroid lymphoma (PTL) is a rare disease, accounting for 2% to 5% of all thyroid malignancies. Despite several cases in which both PTC and PTL arise in the setting of Hashimoto's thyroiditis (HT), the coexistence of both tumors in HT patients is very rare. Herein we report the case of a 66-year-old woman with long-standing nodular HT under replacement therapy, who presented with a fast, painless enlargement in the right anterior side of the neck. Thyroid ultrasonography demonstrated increased growth of a hypoechoic nodule in the right lobe measuring 32 * 20 mm. A total thyroidectomy was performed, and histology revealed a diffuse large B-cell lymphoma (DLBCL) on a background of florid HT. Moreover, a unifocal papillary microcarcinoma, classical variant (7 mm, pT1aNxMx), was discovered. The patient was then treated with chemotherapy for the PTL, but she did not undergo radioactive iodine ablation treatment for the microPTC as per guidelines. Two years after surgery, the patient had no evidence of recurrence of either malignancy. This rare case highlights the importance of monitoring HT patients with nodular lesions, especially if they have long standing disease. In addition, PTL should be considered for differential diagnosis in elder HT patients who present with sudden thyroid enlargement. PMID- 29412393 TI - Long-term illness and suffering: contributions from the Social and Human Sciences in Health. PMID- 29412394 TI - Biographical ruptures and flows in the family experience and trajectory of children with cystic fibrosis. AB - Biographical disruption (BD) became a core concept of sociological studies on the chronic illness experience by showing how this event can be strongly affected by ruptures in the ways of living and organizing the biographical trajectory through narratives. Critical reviews have pointed out that the widespread use of this concept was not sufficiently attentive to its analytical limits, e.g. addressing experiences of children with genetic diseases, when biographic flows (BF) rather than BD would be probably found. In this paper, we employed the concepts of BD and BF to analyze the relationships between the illness trajectories of children with cystic fibrosis (CF) and the experiences of their parents, taking into account the narratives about their histories and family contexts, drawn from semi structured interviews with 10 children with CF and 14 family members. The results pointed to potentialities and limits of the concepts of BD and BF for the analysis undertaken in this study. We conclude that both concepts can be applied to the analysis of family experience involving child genetic diseases, provided that this occurs in a critical and sensitive way to subjects and contexts investigated, keeping in mind the more broader theoretical concerns. PMID- 29412395 TI - [Family Therapeutic Trajectories: rare hereditary diseases involving long-term suffering]. AB - This article analyzes common elements in the trajectory of people affected by rare hereditary diseases in Brazil, focusing on the search for diagnosis and treatment, and the reproducibility in the family. Rare diseases affect 65 people in every 100 thousand. These are usually chronic and degenerative conditions, many incurable or without effective treatment. About 80% of rare diseases are genetic in origin and can be inherited. This fact has important implications for family health care policies, reproduction, and care for clinical conditions that, in some cases, spanned generations. To analyze the data, two theoretical axes are articulated: family and kinship studies, and analyzes of long-term suffering. The research investigated people affected by rare hereditary diseases and their families, in the political scenarios in which these actors circulate, such as patient associations, scientific congresses and public hearings. There is evidence of the need to build a continuous agenda on rare diseases in Brazil capable of effectively promoting universal and integral access of the affected persons to the public health system, and seeking for solutions to alleviate suffering that threatens the very continuity of the family. PMID- 29412396 TI - "The Death of Ivan Ilyich" and multiple dimensions of illness. AB - The short story "The Death of Ivan Ilyich" (1886), Leo Tolstoy (1828-1910) provides key elements for a reflection on the meaning of long-term illness. Based on Tolstoy's short story the present paper analyzes the multiple dimensions of the process of illness. It starts with the argument that illness is not an a priori totality, but a trajectory of associations between the sick person, the doctor, family members, friends and caregivers. Acting, being affected, thinking and feeling all come together in the development of these associations. The analysis of the Ivan Ilyich's illness will consider the following points: (a) illness as otherness and incomprehensibility (growing unfamiliarity with one's body and the stages by which the body is gradually objectified); (b) illness as trajectories in an field of practices that involves the development of skills and the "education of attention"; (c) modes of health care as a set of techniques, objects and discourses that are put together or associated throughout trajectories concerned with the establishment of health. Long-term illness is therefore a mode of immersion of the sick person in networks of relations that come to be a part of her everyday life. PMID- 29412397 TI - Experience of people living with the Berardinelli-Seip Syndrome in the Brazilian Northeast. AB - This paper analyzes the experience of people living with the Berardinelli-Seip Syndrome in the Brazilian Northeast. This qualitative study was developed with eleven informants, namely, nine people living with the syndrome and two mothers. Information was gathered using participant observation, social characterization and semi-structured interviews. Data were analyzed by means of a thematic coding technique. Two categories emerged: (1) 'the secret is to shut your mouth': food management in daily life; and (2) 'Ah, is it a transvestite?' body, gender, and masculinization. We concluded that, in the experience of the informants, their negotiations and creativity translated into strategies for food management that integrated tastes, values, habits, biomedical prescriptions and pleasures involved in commensality situations. Regarding corporeality, it has been shown that representations and experiences with the body show gender inequalities, insofar as women become privileged targets of stigmas, prejudices and discrimination in adult life. PMID- 29412398 TI - [Impacts of long-term illness: experience of young adults with Acute Myeloid Leukemia]. AB - This article analyzes the tangible and intangible impacts involved in the experience of young adults diagnosed with a long-term illness, namely Acute Myeloid Leukemia. It follows on from broader research, inspired by the Phenomenology of Alfred Schutz. The data were obtained through in-depth interviews with four young adults, aged between 20 and 28, who were in the maintenance phase of cancer treatment between November 2013 and January 2014 in the State of Mato Grosso. The results focus on striking aspects of the impacts of the experience during the process of becoming aware of the illness in which the diagnosis provoked feelings mobilized by ideas regarding a serious illness. This is followed by the impacts on appearance due to the treatment, especially hair loss and day-to-day coping strategies, as well as weight gain or loss. Finally, there is the marked impact of the imminence of death due to the lethality of the disease and the testimony of the occurrence in friends and family, but also for the survivors. The impacts are the effects and transformations in the lives of people and their relations and evoke (re)actions, however, they are diluted in the experience composing it, and not being homogeneous, its approach addresses the singularity encountered in contextualized biographies. PMID- 29412399 TI - [Legitimacy and non-legitimacy of experiences of long-term suffering and illness]. AB - This paper discusses the legitimacy and non-legitimacy of selected experiences of long-term illness and suffering, which are, or are not, considered diseases by medical diagnoses, such as pain, chronic fatigue, and "high blood pressure" using international and national sociological and anthropological research in health. It explores their implications, reflexes and ambiguities for the identity, moral and physical suffering perceived by the subjects and in their relationship with others and with the health services. This is a text about select research on the theme. It concludes that the ill persons are moved by actions and significance about their experience with the physical and moral suffering that are, or are not, legitimate for them, but that jeopardize their lives and biographies, and are expressed in their language and emotions, reflected in their social relations and also in their identity of being, or not being, ill. The legitimacy and non legitimacy of these experiences have implications for health care, which require further ethnographic research. PMID- 29412400 TI - [Is "associativism" good for one's health? The case of rare diseases]. AB - Based on the question of an inspiring work - "Is the Market good for one's Health?", this paper poses a similar question, centered on "associativism" (belonging to a labor group or association) and the field of rare diseases. Starting from the research carried out in the scope of the Master's Degree in Sociology of the School of Economics of the University of Coimbra, this text puts into perspective the formulations created for the field of genetic conditions that, mainly, depart from a Eurocentric vision. The field of rare diseases is analyzed, identifying the roles, relationships and motivations of the different actors, namely, civil associations, pharmaceutical industry, academy, government, and families. The analysis highlights the preponderance of the market and the production of medicines, identifying a governance model - Utility Model of Care - in which the person who suffers and his/her family are left devoid of their subjectivity and transmuted into medication and market agents. PMID- 29412401 TI - Interview: The chronic conditions approach by the Unified Health System. AB - The interview explains the analysis of Eugenio Vilaca Mendes regarding the importance of chronic conditions in the morbidity and mortality profile and its impact on the Unified Health System (SUS) in Brazil. It points out which measures should be prioritized, in the interviewee's view, for the improvement of the SUS in order to qualify the care offered to the patients of these conditions, and finally brings a set of considerations formulated by him regarding the organizaton of access to Primary Care the health. PMID- 29412402 TI - [Nutritional and sociodemographic characteristics of nursing mothers: a systematic review]. AB - A systematic review of nutritional and sociodemographic characteristics of nursing mothers, using the published literature from 2004 to 2014 in the Biblioteca Virtual de Saude and Medline databases. Using the following key words, 561 articles were identified: "Human Milk" and "Milk Banks"; keywords: "Profile," "Nutritional," "Milk Donor," "Nursing Mother" and "Nursing Mothers"; available abstracts; date and language. From these, 84.1% were excluded for not dealing with the established subject, 1.8% for being a review and 7.5% for the unavailability of abstracts for study. Thirty-seven articles were selected, of which 18.9% analyzed the profile of the HM donor. Of the total, 89.2% reported age, the majority between 20 and 30 years of age. The level of schooling was mentioned in 32.4% ranging from elementary school and higher education. With respect to income, a higher prevalence of low socioeconomic status was observed. About the nutritional status, 45.9% of the studies measured the body mass index and 29.4% reported the predominance of excess weight. There were deficiencies, particularly of vitamin A, with frequencies between 9% and 26%. A majority of young adult mothers, varied schooling, low income and nutritional deficiencies were noted, demanding interventions to improve health and increase HM donations. PMID- 29412403 TI - [Perception scales of validated food insecurity: the experience of the countries in Latin America and the Caribbean]. AB - The scope of this systematic review was to compare the food insecurity scales validated and used in the countries in Latin America and the Caribbean, and analyze the methods used in validation studies. A search was conducted in the Lilacs, SciELO and Medline electronic databases. The publications were pre selected by titles and abstracts, and subsequently by a full reading. Of the 16,325 studies reviewed, 14 were selected. Twelve validated scales were identified for the following countries: Venezuela, Brazil, Colombia, Bolivia, Ecuador, Costa Rica, Mexico, Haiti, the Dominican Republic, Argentina and Guatemala. Besides these, there is the Latin American and Caribbean scale, the scope of which is regional. The scales ranged from the standard reference used, number of questions and diagnosis of insecurity. The methods used by the studies for internal validation were calculation of Cronbach's alpha and the Rasch model; for external validation the authors calculated association and /or correlation with socioeconomic and food consumption variables. The successful experience of Latin America and the Caribbean in the development of national and regional scales can be an example for other countries that do not have this important indicator capable of measuring the phenomenon of food insecurity. PMID- 29412404 TI - Murder and actual bodily harm in Itaborai, Brazil: analysis at different scales. AB - An ecological study aimed at analyzing homicide rates and actual bodily harm was conducted in Itaborai, in the years 2010 to 2011. The entire municipality was used in the study covering critical and non-critical areas. The data came from the Information System for the Public Security Institute in Rio de Janeiro state. The territories were identified and defined by referring to studies on illegal occupations of areas. The snowballing method was used for the social recognition of poor conditions. The morphological differentiation of urban and housing standards marked the locations. The areas were georeferenced, and the problems were located geographically and organized according to their corresponding critical area. We calculated the municipal rates using population estimates from IBGE. For the critical areas, we obtained estimates of the number of households multiplied by a factor equal to the average household density in the corresponding census tract. There was a decrease in homicide rates and a rise in actual bodily harm in Itaborai. We also found that there was an increased risk of bodily injury in critical areas with the worst living conditions, suggesting the existence of social inequalities that make certain social spaces more vulnerable to incidents involving violent injuries. PMID- 29412405 TI - Association between life events after diagnosis of breast cancer and metastasis. AB - The objective was to examine the association between life events post diagnosis of breast cancer and metastasis. Cross-sectional study with 300 women attending a reference hospital in oncology in the Espirito Santo. Was used the instrument Life Events Units-LEU/VAS to evaluate life events reported by women. Data were analyzed by using the nonparametric Wilcoxon and chi-square tests. It was performed odds ratio calculation for the variables associated with metastasis. It was found that 21% of the sample reported at least one life event post diagnosis. Of the 46 women who developed metastases, 20 reported one or more life events (p = 0.001). The odds ratio calculated shows that having life events post diagnosis increases by 2.59 (1,37 - 4,91; p = 0,003) times the chance of developing metastasis. When considering the time between diagnosis and the onset of metastasis there was a median of 18.0 months. The study shows a relationship between life events and metastasis, however emphasize the importance of a more complex analysis to better understand the impacts of these events on the onset and progression of breast cancer. PMID- 29412406 TI - Psychological demand and control of the work process of public university servants. AB - This cross-sectional research aimed to analyze the psychological demand and work control self-reported by the Education Administrative Technicians of a public university. This is a complete sample selection consisting of 833 Education Administrative Technicians who self-completed a questionnaire with questions structured in 2013/2014. A descriptive bivariate analysis was performed with the calculation of psychosocial stress at work, using the Demand-Control Model quadrants categorized as: low-demand work (low-demand and high-control), reference group, passive work (low-demand and low-control), active work (high demand and high-control), high-demand (high-demand and low-control) - group with the highest exposure. The study complies with all ethical and legal research requirements involving human beings. There was a predominance of the category of workers performing passive work (n = 319, 39.7%), low work demand (n = 274, 34.1%), high work demand (n = 116, 14.4%) and active work (n = 95, 11.8%). There were contributions from the investigation on the health of these workers insofar as they provided a diagnosis of the category. There is a recommendation for such data to support interventions to empower them and retailor jobs. PMID- 29412407 TI - Oral health outcomes: the association of clinical and socio-dental indicators to evaluate dental caries in preschool children. AB - Dental caries is a public health problem that impacts oral health related to quality of life (OHRQoL). This study aimed to evaluate the outcome of dental caries in children by associating clinical and socio-dental indicators. A cross sectional study was carried out with 2 to 6-year-old children who attended public day care centers in a city in the Southeast Region of Brazil. After sample calculation, 446 children were randomly selected by eligibility criteria. Two professionals evaluated dental caries using WHO (2013) criteria and classified subjects according to early childhood caries (ECC) severity. Parents/care- givers answered a characterization questionnaire and self-reported socio-dental indicator (B-ECO-HIS). The prevalence of dental caries was 33.7%. The children with high severity of ECC had 5 times higher chance of suffering an impact on OHRQoL. The one way ANOVA test showed that the impact on OHRQoL (ECOHIS scores) was associated with ECC. The outcome dental caries in oral health presented high prevalence as clinical indicator and high impact on OHRQoL as socio dental indicator. Clinical and socio-dental indicators should be evaluated together. PMID- 29412408 TI - Identifying mothers' intention to place infant in supine sleep position: a population-based study. AB - This study aimed to identify mother's opinion on infant sleep position and the factors associated with the intention to place the infant in the supine position in the municipality of Rio Grande, Southern Brazil. A standardized questionnaire was applied to all mothers residing in this municipality who gave birth to a child in the only two local maternity wards from January 1 to December 31, 2010. Chi-square test was used to compare proportions, along with a Poisson regression with robust adjustment in the multivariate analysis. The effect measure used was prevalence ratio (PR). Of the 2,395 mothers interviewed (972% of the total), 20.5% (95%CI: 18.4%-21.6%) intended to place the newborn to sleep in the supine position. This prevalence varied from 11% (95%CI: 8.1-13.7) for mothers with three or more children to 35% (CI95%: 31.1-40.2) among those with 12 or more years of schooling. After adjusted analysis, younger mothers with higher education and household income who performed prenatal care in the private system or who have had three or more children had significantly higher PR to place the baby to sleep in the supine position compared to others. Campaigns encouraging this practice should focus primarily on older mothers of lower socioeconomic level and performing prenatal care in PHC facilities. PMID- 29412409 TI - [Factors associated with the use of dental health services]. AB - This paper seeks to analyze the factors associated with the use of dental health services (UDHS) by adults in the city of Corrientes, Argentina. A cross-sectional study was conducted. Information concerning the study variables was collected via a home survey. The sample size was established with a 95% confidence interval level (381 individuals). A simple random sampling design was used, which was complemented with a non-probability quota sampling. The data was analyzed using SPSS version 21.0 and Epidat version 3.1 softwares. Socio-economic level, dental health coverage, perception of oral health care, perception of oral health, knowledge about oral health, and oral hygiene habits were significantly associated with the UDHS over the last twelve months. These same factors, excluding dental health coverage and knowledge about oral health, were associated with the UDHS for routine dental check-ups. Measures should be implemented to increase the UDHS for prevention purposes in men and women of all socio-economic levels, particularly in less-privileged individuals. PMID- 29412410 TI - Construct validity and internal consistency in the Leisure Practices Scale (EPL) for adults. AB - This study proposes and analyzes the construct validity and internal consistency of the Leisure Practices Scale (EPL). This survey seeks to identify the preferences and involvement in in different leisure practices in adults. The instrument was formed based on the cultural leisure content (artistic, manual, physical, sports, intellectual, social, tourist, virtual and contemplation/leisure). The validation process was conducted with: a) content analysis by leisure experts, who evaluated the instrument for clarity of language and practical relevance, which allowed the calculation of the content validity coefficient (CVC); b) reproducibility test-retest with 51 subjects to calculate the temporal variation coefficient; c) internal consistency analysis with 885 participants. The evaluation presented appropriate coefficients, both with respect to language clarity (CVCt = 0.883) and practical relevance (CVCt = 0.879). The reproducibility coefficients were moderate to excellent. The scale showed adequate internal consistency (0.72). The EPL has psychometric quality and acceptable values in its structure, and can be used to investigate adult involvement in leisure activities. PMID- 29412411 TI - Evaluation of institutional foster care services for children and adolescents in Recife. AB - This study aimed to evaluate the structure and process of institutional foster care services for the protection of children and adolescents who are victims of neglect and/or violence in Recife. A semi-structured questionnaire was applied to those responsible for the services. Variables frequency were calculated and the following implementation level classification system adopted: critical, when compliance was less than 40% of the recommended standards; inadequate, 40-59%; acceptable, 60%-89%; adequate and excellent, 90-100%. The qualitative analysis consisted in interviews with one manager from the Judiciary and three managers from the Executive. Of the five philanthropic institutions investigated, two had an excellent standard structure; two were acceptable and one inadequate. Among public institutions, one was considered inadequate and the others acceptable. Regarding the process, one institution was found to be excellent and the others acceptable. The content analysis identified that the greatest challenges to introduction of the measures envisaged in the Child and Adolescent Statute are drug use, family geographical remoteness, lack of integration with other institutions and staff turnover. PMID- 29412412 TI - Hospitalizations for diabetes mellitus and the Family Health Strategy, Parana, Brazil, 2000-2012. AB - The aim of this study was to identify trends in hospitalization for diabetes mellitus and their correlation with the Family Health Strategy (FHS) coverage in the state of Parana, by Health District (HD), between 2000 and 2012. It is an ecological study based on secondary data from the Hospital Information System of the Brazilian Unified Health System and the Primary Care Department. There was downward trend for general admission rates (from 10.2 to 9.0/10,000 inhabitants), but upward trend for some HDs. No correlation was observed between admission rates and the FHS coverage for the state. However, there was strong inverse correlation for Paranagua, Metropolitan, Foz do Iguacu and Umuarama HDs, and strong and direct correlation for Pato Branco, Campo Mourao, Cianorte, Telemaco Borba and Ivaipora HDs. Overall, hospitalizations for diabetes mellitus proved to be decreasing and without correlation with FHS coverage; however, there were differences according to HDs. PMID- 29412413 TI - [Oldenburg Burnout Inventory - validation of a new way to measure Burnout in Brazil]. AB - This study sought to validate the Oldenburg Burnout Inventory (OLBI) measurement scale in Brazil. The methodology included data collection through a quantitative survey with 273 people. Structural equation modeling was used for data analysis. The scale was validated after being subjected to all statistical assumptions, reducing the original 16 to 13 variables resulting in an enhanced measurement capacity of the Burnout syndrome than the original scale. This study contributes a scale adapted to Brazil to study the health of the worker, since it provides a way to measure a syndrome responsible for problems of various types, with impacts both inside and outside organizations. PMID- 29412414 TI - Analysis of cases of gestational and congenital syphilis between 2008 and 2010 in Fortaleza, State of Ceara, Brazil. AB - This study analyzes the reported cases of syphilis in pregnant women and the possible outcomes for fetuses and the newborn in Fortaleza, Ceara. It is a cross sectional study that analyzed 175 reported cases of syphilis in pregnant women matched with the corresponding reports of congenital syphilis during the years 2008-2010. Descriptive statistics with absolute and relative frequencies, central tendency and dispersion measures, and the Pearson's chi-square test were used to analyze the statistical significance using the p-value <0.05. Sociodemographic variables of pregnant/postpartum women, the assistance provided to newborns and the outcome of cases were analyzed. The results showed the occurrence of syphilis in young women with more than 85% of inappropriate treatment, 62.9% of untreated sexual partners or lack of statistics and high percentages of non-realization of the recommended tests for congenital syphilis investigation in children. Among the fetuses, five were stillborn, one miscarried and there were three neonatal deaths. The lack of adequate treatment of pregnant women may be associated with morbidity and mortality of fetuses, maintaining this infection as a burden on the list of public health problems. PMID- 29412415 TI - Factors associated with submission to HIV rapid test in childbirth care. AB - Rapid HIV tests are used in maternity hospitals to prevent mother-to-child transmission. This study aimed to analyze factors associated with submission to the rapid HIV test (outcome). This is a cross-sectional study conducted in 2009 in 15 hospitals from the Rio de Janeiro's Unified Health System (SUS) by interviewing a representative sample of 835 pregnant women hospitalized for birth and by verifying medical records. Adjusted prevalence ratios were obtained by Poisson regression according to a hierarchical model, and variables associated with the outcome (p <= 0.05) remained in the final model. According to medical records (MR), 79.6% of mothers were submitted to rapid HIV test and, according to interviews (INT), 55.7%. At the distal level, the lack of a partner (MR), having >= 6 residents at home (MR) and non-white skin color (INT) were associated with a higher prevalence of the outcome. At the intermediate level, not having a negative HIV serology from prenatal care (MR and INT) was associated with a higher prevalence of the outcome, as well as PHC prenatal care (MR) and lack of prenatal care (INT). At the proximal level, delivery in a hospital not certified as Baby-Friendly was associated with a higher prevalence of outcome (MR and INT). PMID- 29412416 TI - Assessment of the way in which entries are filled out in Child Health Records and the quality of the entries according to the type of health services received by the child. AB - The scope of this study was to assess the way Child Health Records (CHRs) are filled out and the association between the quality of entries and type of service used to monitor the health of children. It involved a cross-sectional study with a stratified sample - proportional for the nine Health Districts of Belo Horizonte, State of Minas Gerais - of 3- to 5-year-old children selected on Child Vaccination Campaign Day in 2014. Interviews with parents including observation of the 21 CHR items were conducted. The dependent variable was defined by the quality of the CHR entry (satisfactory/unsatisfactory), where satisfactory entries were > 60%. The independent variables were the type of service for monitoring child health, demographic and health conditions of the mother and child and healthcare treatment received by the child, with the participation of 367 (96.10%) parents. The prevalence of unsatisfactory entries was 55.5%. No significant association was found between quality of entry and type of healthcare. Unsatisfactory entries were associated with gestational age < 37 weeks, lack of access to information about the CHR and the absence of parental entries on the CHR. The CHR has been unsatisfactorily employed as a tool for monitoring health, irrespective of the type of service used by the child. PMID- 29412417 TI - Factors associated with child sexual abuse confirmation at forensic examinations. AB - The aim of this study is identify potential factors associated with child sexual abuse confirmation at forensic examinations. The forensic files of children under 12 years of age reporting sexual abuse at the Nina Rodrigues Institute of Forensic Medicine in Salvador, Bahia, Brazil between January 2008 and December 2009 were reviewed. A multivariate analysis was conducted to identify factors associated with finding evidence of sexual abuse in forensic examinations. The proportion of cases confirmed by the forensic physician based on material evidence was 10.4%. Adjusted analysis showed that the variables place of birth, type of abuse reported, family relationship between the child and the perpetrator, and the interval between the reported abuse and the forensic examination were not independently associated with finding forensic evidence of sexual abuse. A report of penetration was associated with a five-fold greater likelihood of confirmation, while the victim being 10-11 years of age was associated with a two-fold of abuse confirmation than younger children. These findings should be taken into consideration when drawing up guidelines for the multidisciplinary evaluation of children suspected of being victims of sexual abuse and in deciding whether to refer the child for forensic examination. PMID- 29412418 TI - Prevalence and factors associated with hypertriglyceridemic waist in the elderly: a population-based study. AB - To identify the prevalence and factors associated with hypertriglyceridemic waist (HW) in community-dwelling elderly people in northeast Brazil. Population-based cross-sectional study. Some 316 elderly (>= 60 years) people of both sexes participated in this study. Data were collected using a questionnaire, based on that used in the Health, Welfare and Aging Study (SABE), in addition to blood tests, blood pressure measurements and anthropometric measurements. The hypertriglyceridemic waist condition was diagnosed using high values of triglycerides (>= 150 mg/dl) and waist circumference increased >= 88 and >= 102 cm for women and men, respectively. Logistic regression analysis was used to compare the hypertriglyceridemic waist and associated factors, significance level of 5%. The prevalence of hypertriglyceridemic waist (HW) was 27.1%. The logistic regression model (OR) adjusted showed the condition of HW associated to the feminine sex (OR 4.19), to the insufficiently active elderly (OR 2.41) and with overweight (OR 4.06). A high prevalence (27.1%) of hypertriglyceridemic waist was observed, indicating the female sex, physical inactivity and overweight as key factors associated with hypertriglyceridemic waist in community-dwelling elderly people. PMID- 29412419 TI - [Gestational history and prenatal care characteristics of adolescent and adult mothers in a maternity hospital in the interior of Minas Gerais, Brazil]. AB - The scope of this research was to analyze the gestational history and prenatal care characteristics of adolescent and adult mothers in a maternity hospital located in a city in Minas Gerais, which is a hospital of reference in the macro region of health of Jequitinhonha. It involved a descriptive cross-sectional study. A total of 327 mothers were interviewed between May 2013 and March 2014 using a semi-structured questionnaire. With a sample of 255, the number of adult women was predominant. With respect to prenatal care, 324 pregnant women had medical appointments. In terms of the location for prenatal care, 79.2% of adolescents were attended in the public health service, while that percentage was 60.4% among adult women. Regarding the type of birth, 54.7% of mothers had normal delivery and 45% had cesarean section. Among adolescents, there was a higher percentage of normal delivery compared to adult women and this data had a statistically significant relationship with the age of the pregnant women. With respect to gestational age at birth, 85.9% had full-term deliveries, 13.5% had preterm delivery and 0.6% had post-term delivery. It was revealed that adolescent mothers were at a disadvantage compared to the other mothers in terms of both socioeconomic characteristics and prenatal care received. PMID- 29412420 TI - [Satisfaction levels of users and verification of the knowledge of pharmacists in public pharmacies in the State of Espirito Santo, Brazil]. AB - The scope of this study was to determine the satisfaction levels of users of public pharmacies and verify the knowledge of pharmacists in relation to dispensing of medicines. This is a descriptive study, conducted in municipalities in the State of Espirito Santo, in the period from May to August 2013. Data were collected using a structured questionnaire and SPSS20 software was used for statistical analysis. The Student t or ANOVA test was used for data with normal distribution, while the Mann-Whitney or Kruskal-Wallis test was applied for data without normal distribution. The Spearman correlation was used to evaluate patient satisfaction with the service time and the waiting time. The significance level for the tests was 5%. The main results obtained were the high level of dissatisfaction among users and the correlation with the waiting time to be attended. Apart from this, the knowledge of pharmacists in relation to the medication dispensed was classified as satisfactory/regular. The conclusion drawn is that actions are necessary in the management of pharmaceutical service to address the expectations of users in the dispensation of drugs. PMID- 29412421 TI - [The prevalence of common mental disorders and associated factors among the elderly in a Brazilian city]. AB - With advancing age, the presence of psychic morbidities is more frequent and jeopardizes the quality of life of the population. The scope of this study was to estimate the prevalence and factors associated with Common Mental Disorders (CMD) in the elderly population resident in a municipality. It involved a cross sectional study with 310 elderly people residing in Ibicui in the State of Bahia. A questionnaire assessing sociodemographic characteristics, lifestyle, health status and screening for CMD (Self-Reporting Questionnaire - SRQ-20) was used. For statistical analysis, Poisson regression was used, with calculation of prevalence ratios, confidence intervals (95%) and p <= 0.05 significance level. The general prevalence of CMD was 55.8%. The female individuals who reported rheumatism presented higher prevalence of CMD. It is recommended that prevention and control of these morbidities among the elderly population of the municipality should be implemented. PMID- 29412422 TI - The Territorial Dimension of Sewage Networks: the Case of Recreio dos Bandeirantes, Rio de Janeiro, Brazil. AB - The urban suburbs of Brazilian cities have grown without an adequate sanitation infrastructure. Different social groups try to overcome these shortcomings seeking local sanitation alternatives at individual or community levels, contrasting with the universal model of sewage networks. This study was developed in the suburban neighborhood of Recreio dos Bandeirantes, Rio de Janeiro, Brazil, in order to analyze the installation process of the sewage system under a territorial approach. Data facilitated the construction of territorial schemes related to conflicts during the implementation of sewage networks in this neighborhood, where middle class groups and favela residents coexist with environmental preservation areas, beaches and commercial activities. This work revealed the need for contextualized sanitation information made available by the Brazilian Institute of Geography and Statistics (IBGE) and state sewage collection company, which conceal these conflicts or the representation of residents about their sanitation problems. Overlapping territorial managing functions should be considered as one of the factors responsible for the conflicts identified in the neighborhood. Further studies are suggested as methodological complementation and data update. PMID- 29412423 TI - Health-related quality of life of adolescent students. AB - This study aimed to evaluate the perception of health related quality of life (HRQoL) of adolescent students. This is a cross-sectional study with 807 adolescents aged 10 to 17 years from two public schools of Niteroi and four private schools of Rio de Janeiro and Sao Goncalo. Information on HRQoL was obtained by a reduced version of the Kidscreen questionnaire with 27 items. Student t tests were used to assess the perception of HRQoL stratified by type of school, gender, age and ownership of assets. We used linear regression models to evaluate HRQoL settings. In general, the evaluated adolescents evidenced a good HRQoL. However, results show significant differences in the perception of each HRQoL realm between subgroups. Private school adolescents had better HRQoL compared to public schools in all Kidscreen-27 realms. Older adolescents, those from public school and those with lower ownership of assets had lower HRQoL values in most realms, particularly in the 'Autonomy and Relationship with Parents' realm. Disclosure of the differentiated profile of HRQoL among adolescents is the first step towards developing action strategies in the school environment that prioritize the most vulnerable groups. PMID- 29412424 TI - ? PMID- 29412425 TI - FIRST POSTPARTUM HOME VISIT: A PROTECTIVE STRATEGY FOR EXCLUSIVE BREASTFEEDING. AB - OBJECTIVE: To investigate the influence of the first postpartum visit, family income, pacifier habit, number of siblings and birth weight on the maintenance of exclusive breastfeeding in infants aged one week up to six months. METHODS: In this cross-sectional study, data were collected through a survey, which included social and demographic characteristics of the families and the breastfeeding practice in children aged one week to six months, who received care at family health units in the municipality of Vitoria de Santo Antao, Pernambuco, Northeast Brazil, between December 2014 and February 2015. Prevalence ratio was used to indicate how many times the outcome prevalence was increased by the influence of the studied variables, as well as a binary logistic regression model for the analysis and reliability of the results. RESULTS: The prevalence of exclusive breastfeeding was 41.7%. Family income, pacifier habit, number of siblings and birth weight did not show statistical association with the maintenance of exclusive breastfeeding. However, the absence of postpartum home visits adversely influenced the outcome (p=0.009). The children who received home visits had a higher chance of being exclusively breastfed for six months or more (PR 2.28, 95%CI 1.17-4.42). In the logistic regression, only the visit showed significance to estimate the probability of exclusive breastfeeding. CONCLUSIONS: The absence of postpartum home visits negatively influenced the duration of exclusive breastfeeding. This finding fills a gap in the knowledge of determinants of exclusive breastfeeding and may guide the planning of local strategies and actions to promote, protect and support exclusive breastfeeding. PMID- 29412426 TI - SELECTIVE DORSAL RHIZOTOMY IN CEREBRAL PALSY: SELECTION CRITERIA AND POSTOPERATIVE PHYSICAL THERAPY PROTOCOLS. AB - OBJECTIVE: To identify selection criteria for selective dorsal rhizotomy (SDR) in cerebral palsy, to analyze the instruments used for evaluation, and to describe the characteristics of physical therapy in postoperative protocols. DATA SOURCES: Integrative review performed in the following databases: SciELO, PEDro, Cochrane Library, and PubMed. The terms in both Portuguese and English for "cerebral palsy", "selective dorsal rhizotomy", and "physical therapy" were used in the search. Studies whose samples enrolled individuals with cerebral palsy who had attended physical therapy sessions for selective dorsal rhizotomy according to protocols and describing such protocols' characteristics were included. Literature reviews were excluded and there was no restriction as to period of publication. DATA SYNTHESIS: Eighteen papers were selected, most of them being prospective cohort studies with eight-month to ten-year follow-ups. In most studies, the instruments of assessment encompassed the domains of functions, body structure, and activity. The percentage of posterior root sections was close to 50%. Primary indications for SDR included ambulatory spastic diplegia, presence of spasticity that interfered with mobility, good strength of lower limbs and trunk muscles, no musculoskeletal deformities, dystonia, ataxia or athetosis, and good cognitive function. Postoperative physical therapy is part of SDR treatment protocols and should be intensive and specific, being given special emphasis in the first year. CONCLUSIONS: The studies underline the importance of appropriate patient selection to obatin success in the SDR. Postoperative physical therapy should be intensive and long-term, and must necessarily include strategies to modify the patient's former motor pattern. PMID- 29412427 TI - ASSOCIATION OF NUTRITIONAL STATUS WITH LUNG FUNCTION AND MORBIDITY IN CHILDREN AND ADOLESCENTS WITH CYSTIC FIBROSIS: A 36-MONTH COHORT STUDY. AB - OBJECTIVE: To evaluate the association between nutritional status, lung function and morbidity in a 36-month cohort in children and adolescents with cystic fibrosis. METHODS: Prospective cohort of children and adolescents with cystic fibrosis aged 1-15 years. At the baseline, the nutritional status was determined by weight-for-height and body mass index-for-age for children <2 years and >=2 years, respectively, and classified as: nutritional failure, nutritional risk and acceptable; and by the 50th percentile, according to the World Health Organization (WHO) growth charts. Lung function was assessed by forced expiratory volume in one second (FEV1). Morbidity was determined by the presence of infection and hospitalization by pulmonary exacerbation. Risk ratio and 95% confidence interval (95%CI) were calculated, being significant when p<0.05. RESULTS: We evaluated 38 children and adolescents (median age 3.8 years). Patients that were classified as having nutritional failure at baseline had a RR of 5.00 (95%CI 1.49; 16.76) to present impaired lung function after 36 months. Those classified bellow the 50th percentile had a RR of 4.61 (95%CI 0.89; 23.81) to present the same outcome. Nutritional status was not a risk factor for morbidity in this cohort. CONCLUSIONS: Nutritional deficit was associated with impaired lung function, but not with morbidity in children and adolescents with cystic fibrosis. PMID- 29412428 TI - ACUTE RESPIRATORY DISEASES IN BRAZILIAN CHILDREN: ARE CAREGIVERS ABLE TO DETECT EARLY WARNING SIGNS? AB - OBJECTIVE: To assess the level of caregiver knowledge about respiratory signs and symptoms of acute respiratory infection (ARI) as well as their ability to detect the early warning signs and need for medical assistance in children referred to an emergency service. METHODS: This is a prospective, cross-sectional study. A standardized questionnaire with questions on the perception of the severity of ARI signs and symptoms was applied to caregivers of pediatric patients assisted in the emergency room of a university hospital from August 2011 to May 2012. Chi square and Student's t-tests were used to determine which variables contributed with caregivers' recognition of severity of acute respiratory diseases. RESULTS: 499 caregivers were interviewed. The most cited causes of ARI were flu syndrome (78.6%), common cold (73.9%), pharyngitis (64.1%), and pneumonia (54.5%). Fever (34.1%) and cough (15.8%) were major reasons for referral to hospital. The most cited signs of severity recognized by caregivers were fever (99.6%), dyspnea (91.4%), wheezing (86.4%), adynamia (80.2%), coughing (79.8%), and tachypnea (78.6%). Children's history of respiratory diseases (p=0.002), caregiver's age (p=0.010) and marital status (p=0.014) were significantly associated with tachypnea, the most severe ARI symptom. CONCLUSIONS: Although caregivers of children can recognize ARI most important signs and symptoms, they are unable to judge severity, which may delay medical care and early treatment. PMID- 29412429 TI - ASSOCIATION BETWEEN FRACTION OF EXHALED NITRIC OXIDE AND SPIROMETRY DATA AND CLINICAL CONTROL OF ASTHMA IN CHILDREN AND ADOLESCENTS. AB - OBJECTIVE: To evaluate the association between fraction of exhaled nitric oxide (FeNO) values and forced expiratory volume in the first second (FEV1) and the level of asthma control, as proposed by the Global Initiative for Asthma (GINA), in asthmatic children and adolescents attended at the National Institute of Women, Children and Adolescents Health Fernandes Figueira of Fundacao Oswaldo Cruz (IFF/FIOCRUZ). METHODS: This was a cross-sectional study, with a review of medical records of 90 asthmatics between 7 and 17 years old, who were followed up at the IFF/FIOCRUZ Asthma Outpatient Clinic and were referred to perform respiratory function tests (RFT)between March 2013 and September 2014. After classification according to GINA, patients performed complete spirometry and FeNO measurement. Subsequently, they were separated into two groups: regular and non regular inhaled corticosteroid (ICS) use, regardless of the ventilatory pattern in spirometry. RESULTS: The association between FEV1 values and the degree of asthma control according to GINA (p=0.001) was observed in all patients, regardless of ICS use, but there was no association between FEV1 and levels of FeNO. CONCLUSIONS: The correlation observed between GINA and FEV1 reinforces the importance of spirometry in the clinical follow-up of these patients. Although no association was found between the value of FeNO and the degree of asthma control and FEV1, FeNO may be an early method to detect airway inflammation, even before the symptoms and spirometric changes. PMID- 29412430 TI - NEONATAL SEPSIS: MORTALITY IN A MUNICIPALITY IN SOUTHERN BRAZIL, 2000 TO 2013. AB - OBJECTIVE: To describe the neonatal mortality coefficient attributed to sepsis and other causes, and to report the maternal, neonatal and death characteristics of newborn infants that died in the city of Londrina, Parana, in Southern Brazil. METHODS: This is a cross-sectional study with a time series analysis. Neonatal deaths that contained neonatal sepsis records in any field of the death certificate between the years 2000 and 2013 were studied. The years were grouped into biennia, and cause specific neonatal mortality coefficient was calculated, according to the International Classification of Diseases, 10th revision. Results are expressed as prevalence ratio and 95% confidence interval (95CI%). For bivariate analysis, p<0.05 was considered significant. RESULTS: Among the 745 deaths, 229 (30.7%) had sepsis, with a neonatal mortality coefficient of 7.5 per one thousand livebirths. Sepsis was involved in 2.3 deaths per 1,000 live births. The main underlying causes were conditions originated in the perinatal period and congenital malformations. Sepsis was associated with pre-eclampsia, urinary tract infection, Apgar in the 1st and 5th minutes, and occurrence of late death. In the descriptive trend analysis, there was an increased proportion of mothers aged 35 years or older and with eight or more schooling years. Prenatal coverage was high, but a little more than half of the mothers attended seven or more medical appointments. CONCLUSIONS: In the 14 years analyzed, the prenatal care was identified as a preventive measure against maternal and fetal disorders and the advanced maternal age was associated with neonatal mortality. PMID- 29412431 TI - CHEMERIN AND FACTORS RELATED TO CARDIOVASCULAR RISK IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW. AB - OBJECTIVE: To review findings on chemerin and factors related to cardiovascular risk in children and adolescents. DATA SOURCE: A systematic review was performed, according to the standards proposed by the PRISMA guideline, on PubMed, Science Direct, and Lilacs databases. The descriptor "chemerin" was used in combination with "children" and "adolescent", no time limit applied. The research encompassed only original articles written in English, conducted with human subjects - the adult and elderly populations excluded -, as well as literature reviews, brief communications, letters, and editorials. DATA SYNTHESIS: After independent analyses of the studies by two reviewers, seven articles meeting the eligibility criteria, published between 2012 and 2016, remained for the review. Cross sectional, prospective, cohort, and case-control studies were included. The importance of chemerin adipokines on the risk factors for cardiovascular disease is demonstrated by its association with obesity and diabetes mellitus, as well as clinical, anthropometric, and biochemical parameters. However, the strength of evidence from these studies is relatively low, due to their heterogeneity, with several limitations such as small samples and consequent lack of representativeness, lack of standardization in dosage methods, cross-sectional design of most studies, and impossibility of extrapolating results. CONCLUSIONS: The deregulation of chemerin caused by increased adipose tissue may contribute to the development of cardiovascular diseases, suggesting that this adipokine may play a significant role in early identification of individuals at risk. PMID- 29412432 TI - BONE GEOMETRY AND PHYSICAL ACTIVITY IN CHILDREN AND ADOLESCENTS: SYSTEMATIC REVIEW. AB - OBJECTIVE: To perform a systematic review on the practice of physical activity and/or sports in health and its influence on bone geometry of healthy children and adolescents. DATA SOURCE: The method used as reference was the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Databases searched for articles published from 2006 to 2016, with "Bone geometry" AND (Sport* OR Exercise* OR "Physical Activity") as descriptors, were PubMed, BIREME/LILACS and SciELO. DATA SYNTHESES: After the selection, 21 articles were included. Most studies stated that practice of physical activity and/or sports was beneficial for bone geometry and bone mineral density. Only two studies presented values of bone parameters for control individuals better than those of swimmers. Physical activities and sports studied were: gymnastics (n=7), rhythmic gymnastics (n=2), tennis (n=1), soccer (n=3), capoeira (n=1), swimming (n=4), cycling (n=0), jumping activities (n=2), studies relating physical activity with isokinetic peak torque (n=1), physical activity measured by questionnaire (n=4), and additional physical education classes (n=2). CONCLUSIONS: Among the sports and physical activities found, gymnastics, soccer, and more intense physical activity assessed by questionnaires were mentioned along with better results in bone geometry compared to the absence of physical activity, whereas swimming and jumping exercises did not influence it. Therefore, sports activities with weight bearing and those practiced more frequently and intensively are beneficial for bone geometry. PMID- 29412433 TI - CONTENT VALIDATION OF EDUCATIONAL MATERIAL ON HEALTHY EATING FOR CHILDREN UNDER TWO YEARS OF AGE. AB - OBJECTIVE: To validate the content of an educational material aimed at mothers and caregivers on healthy feeding for children less than two years of age. METHODS: Quantitative study for content validation of an educational material containing three educational modules and respective folders, elaborated on the basis of official references for healthy feeding for children under two years old and adapted to the Brazilian context. Content validation was made through consensus conference in two stages by seven experts. RESULTS: In the first stage, an individual and anonymous evaluation was made and the items analyzed by the seven experts averaged seven or more, with standard deviation below three. However, some items in the educational modules (operational and adherence) and Leaflet I (motivation and culture) reached cut-off values. The second stage involved a face-to-face meeting with five of the seven experts, expressing their opinions and seeking for a new consensus. The items whose results were close to the cut-off had an expressive increase in importance and consensus level after the meeting. CONCLUSIONS: The quantitative data obtained after the consensus meetings were superior to the predefined cut-offs, and the content of the proposed educational material was consensually validated by all participating experts. The consensus conference was an efficient methodological technique to build and validate educational instruments. PMID- 29412434 TI - INFLUENCE OF BREASTFEEDING ON CONSUMPTION OF SWEETENED BEVERAGES OR FOODS. AB - OBJECTIVE: To verify whether breastfeeding is associated with lower prevalence of consumption of sweetened beverages or foods in infants. METHODS: This is a cross sectional study with data collected from the Survey on Prevalence of Breastfeeding conducted in Brazilian municipalities in 2008. A representative sample of 14,326 infants aged 6 to 11.9 months of age, residents of 75 municipalities in the State of Sao Paulo, Southeastern Brazil, was studied. The influence of breastfeeding on the consumption of sweetened beverages or food products was analyzed by multilevel Poisson regression. Variables with p<0.20 in the crude analysis were included in the multilevel analysis. RESULTS: Most infants were on breastfeeding (56.1%). The prevalence of sweetened drinks or foods consumption was 53.3%. The consumption of sweetened products was shown to be less prevalent among breastfed infants after adjustment for confounding factors (PR 0.87; 95%CI 0.83-0.91). CONCLUSIONS: Breastfeeding was associated with lower consumption of sweetened beverages or foods. As an additional effect of actions aimed at promoting breastfeeding, a decrease in intake of sweetened products is expected among infants. PMID- 29412435 TI - ACRODERMATITIS ENTEROPATHICA: CLINICAL MANIFESTATIONS AND PEDIATRIC DIAGNOSIS. AB - OBJECTIVE: To report a case of acrodermatitis enteropathica, a rare disease with autosomal recessive inheritance. CASE DESCRIPTION: An 11-month-old boy was presenting symmetrical erythematous and yellowish-brownish crusted lesions on his face, feet, hands and knees, intermittent diarrhea, fever, and recurrent infections since the age of six months. He was thin and had scarce hair on the scalp. The serum zinc level was measured and a reduced level of 27.0 mcg/dL (normal range: 50.0-120.0) was identified. Oral supplementation with 2.0 mg/kg/day of zinc sulfate was immediately initiated. A rapid and progressive improvement of symptoms was observed. The symptoms reappeared with an attempt to stop supplementation. COMMENTS: Recognizing and properly treating acrodermatitis enteropathica is important to prevent complications. PMID- 29412436 TI - Implications of ICD-10 for Sarcopenia Clinical Practice and Clinical Trials: Report by the International Conference on Frailty and Sarcopenia Research Task Force. AB - Establishment of an ICD-10-CM code for sarcopenia in 2016 was an important step towards reaching international consensus on the need for a nosological framework of age-related skeletal muscle decline. The International Conference on Frailty and Sarcopenia Research Task Force met in April 2017 to discuss the meaning, significance, and barriers to the implementation of the new code as well as strategies to accelerate development of new therapies. Analyses by the Sarcopenia Definitions and Outcomes Consortium are underway to develop quantitative definitions of sarcopenia. A consensus conference is planned to evaluate this analysis. The Task Force also discussed lessons learned from sarcopenia trials that could be applied to future trials, as well as lessons from the osteoporosis field, a clinical condition with many constructs similar to sarcopenia and for which ad hoc treatments have been developed and approved by regulatory agencies. PMID- 29412437 TI - An International Position Statement on the Management of Frailty in Diabetes Mellitus: Summary of Recommendations 2017. AB - AIM: The International Position Statement provides the opportunity to summarise all existing clinical trial and best practice evidence for older people with frailty and diabetes. It is the first document of its kind and is intended to support clinical decisions that will enhance safety in management and promote high quality care. METHODS: The Review Group sought evidence from a wide range of studies that provide sufficient confidence (in the absence of grading) for the basis of each recommendation. This was supported by a given rationale and key references for our recommendations in each section, all of which have been reviewed by leading international experts. Searches for any relevant clinical evidence were generally limited to English language citations over the previous 15 years. The following databases were examined: Embase, Medline/PubMed, Cochrane Trials Register, Cinahl, and Science Citation. Hand searching of 16 key major peer-reviewed journals was undertaken by two reviewers (AJS and AA) and these included Lancet, Diabetes, Diabetologia, Diabetes Care, British Medical Journal, New England Journal of Medicine, Journal of the American Medical Association, Journal of Frailty and Aging, Journal of the American Medical Directors Association, and Journals of Gerontology - Series A Biological Sciences and Medical Sciences. RESULTS: Two scientific supporting statements have been provided that relate to the area of frailty and diabetes; this is accompanied by evidence-based decisions in 9 clinical domains. The Summary has been supported by diagrammatic figures and a table relating to the inter-relations between frailty and diabetes, a frailty assessment pathway, an exercise-based programme of intervention, a glucose-lowering algorithm with a description of available therapies. CONCLUSIONS: We have provided an up to date evidence-based approach to practical decision-making for older adults with frailty and diabetes. This Summary document includes a user-friendly set of recommendations that should be considered for implementation in primary, community-based and secondary care settings. PMID- 29412438 TI - The Vicious Cycle of Myostatin Signaling in Sarcopenic Obesity: Myostatin Role in Skeletal Muscle Growth, Insulin Signaling and Implications for Clinical Trials. AB - The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials. PMID- 29412439 TI - New Simplified Screening Method for Postprandial Hypotension in Older People. AB - BACKGROUND: Postprandial hypotension (PPH) is an important disorder in the older people that remain underdiagnosed. The reference PPH diagnostic method is too demanding, because blood pressure (BP) needs to be measured 8 times in 2 hours. OBJECTIVES: Our primary objective was to define a new simplified PPH diagnostic method and to evaluate its performances. DESIGN: We conducted a cross-sectional study. SETTING: Two geriatric rehabilitation units in France. PARTICIPANTS: 104 patients (70 women, 34 men) with high risk of PPH were included. MEASUREMENTS: BP was measured twice before the midday meal in seated position at the table, and every 15 minutes for 90 minutes after the end of the meal. Receiver Operating Characteristic curves were plotted for each postprandial BP measure to determine the best postprandial measure in terms of sensitivity and specificity. The optimal diagnostic threshold was calculated with Youden's index according to BP difference before and after the meal. RESULTS: A new simplified diagnostic method is proposed: a decrease of at least 10 mmHg systolic BP between BP measures before the meal and 75 minutes after the end of the meal. This new method had a sensitivity of 82% (95%CI 66 - 92) and a specificity of 91% (95%CI 81 - 97). CONCLUSION: This new diagnostic method is fast, efficient and suitable for everyday use. It could improve PPH diagnosis in older people. Larger studies are needed to validate it. PMID- 29412440 TI - Precipitants of Delirium in Older Inpatients Admitted in Surgery for Post-Fall Hip Fracture: An Observational Study. AB - BACKGROUND: Hip fractures precipitate several acute adverse outcomes in elderly people, thus leading to chronic adverse outcomes. OBJECTIVES: The objective of our study was to examine the clinical characteristics associated with incident delirium in community dwelling elderly individuals who have a hip fracture. DESIGN: Retrospective observational cohort study. SETTING: Data was collected from an academic tertiary hospital affiliated with McGill University. PARTICIPANTS: 114 elderly individuals who were above 65 years of age, who underwent surgery for a fractured hip. MEASUREMENTS: The main outcome variable was incident delirium, which was assessed by chart reviews of notes and observations recorded by nurses and physicians when patients were admitted post operatively to the surgical unit. Covariates included age, sex, length of stay, delay to surgery, number of medical comorbidities, number of medications and hip fracture location, and were extracted from medical records. Baseline mobility and functional status, preoperative cognitive impairment, postoperative complications, regular psychotropic medications, psychotropic medications in hospital, and location of discharge were also assessed through chart review. RESULTS: The results demonstrated that 17.5% of participants with a diagnosis of delirium had a longer length of hospitalization (p = 0.01), a lower baseline functional status (p = 0.03) and pre-operative cognitive impairment (p = 0.01). Patients receiving new psychotropic medications in hospital were more likely to have delirium (OR = 4.6, p = 0.01) which was independent of pre-operative cognitive impairment. CONCLUSION: We have shown that an association exists between psychotropic medication prescription and incident delirium in patients with hip fractures, even when adjusting for cognitive impairment. Hence, the prescription of psychotropic drugs should be judicious in these patients so as minimize the risk of adverse outcomes. PMID- 29412441 TI - Impact of Sarcopenia on One-Year Mortality among Older Hospitalized Patients with Impaired Mobility. AB - OBJECTIVES: However, the information regarding the impact of sarcopenia on mortality in older individuals is rising, there is a lack of knowledge concerning this issue among geriatric hospitalized patients. Therefore, aim of the present study was to investigate the associations between sarcopenia and 1-year mortality in a prospectively recruited sample of geriatric inpatients with different mobility and dependency status. DESIGN AND SETTING: Sarcopenia was diagnosed using the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP). Hand grip strength and skeletal muscle mass were measured using Jamar dynamometer and bioelectrical impedance analysis, respectively. Physical function was assessed with the Short Physical Performance Battery. Dependency status was defined by Barthel-Index (BI). Mobility limitation was defined according to walking ability as described in BI. The survival status was ascertained by telephone interview. RESULTS: The recruited population comprised 198 patients from a geriatric acute ward with a mean age of 82.8 +/- 5.9 (70.2% females). 50 (25.3%) patients had sarcopenia, while 148 (74.7%) had no sarcopenia. 14 (28%) patients died among sarcopenic subjects compared with 28 (19%) non-sarcopenic subjects (P=0.229). After adjustment for potential confounders, sarcopenia was associated with increased mortality among patients with limited mobility prior to admission (n=138, hazard ratio, HR: 2.52, 95% CI: 1.17-5.44) and at time of discharge (n=162, HR: 1.93, 95% CI: 0.67-3.22). In a sub-group of patients with pre-admission BI<60 (n=45), <70 (n=73) and <80 (n=108), the risk of death was 3.63, 2.80 and 2.55 times higher in sarcopenic patients, respectively. In contrast, no significant relationships were observed between sarcopenia and mortality across the different scores of BI during admission and at time of discharge. CONCLUSION: Sarcopenia is significantly associated with higher risk of mortality among sub-groups of older patients with limited mobility and impaired functional status, independently of age and other clinical variables. PMID- 29412442 TI - Preliminary Study on Prevalence and Associated Factors with Sarcopenia in a Geriatric Hospitalized Rehabilitation Setting. AB - The reported prevalence of sarcopenia has shown a wide range, crucially based on the diagnostic criteria and setting. This cross-sectional study evaluated the prevalence of sarcopenia and sought to identify factors associated with sarcopenia on admission in a specialized geriatric rehabilitation setting based on the newly developed the Asian Working Group for Sarcopenia algorithm. Among 87 participants (mean age, 76.05 +/- 7.57 years), 35 (40.2%) were classified as showing sarcopenia on admission. Prevalence was high, particularly among participants >=80 years old, with tendencies toward lower body mass index, smoking habit, lower cognitive function, and greater functional impairment compared with the non-sarcopenic group. Identification of sarcopenia in elderly patients before rehabilitation and consideration of risk factors may prove helpful in achieving rehabilitation outcomes. PMID- 29412443 TI - Muscle Quality Improves with Extended High-Intensity Resistance Training after Hip Fracture. AB - BACKGROUND: Muscle mass deficits endure after hip fracture. Strategies to improve muscle quality may improve mobility and physical function. It is unknown whether training after usual care yields muscle quality gains after hip fracture. OBJECTIVES: To determine whether muscle quality improves after hip fracture with high-intensity resistance training and protein supplementation. DESIGN: Case series. SETTING: University of Utah Skeletal Muscle Exercise Research Facility. PARTICIPANTS: 17 community-dwelling older adults, 3.6+/-1.1 months post-hip fracture, recently discharged from usual-care physical therapy (mean age 77.0+/ 12.0 years, 12 female), enrolled. INTERVENTION: Participants underwent 12 weeks (3x/week) of unilaterally-biased resistance training. METHODS/MATERIALS: Participants were measured via a 3.0 Tesla whole-body MR imager for muscle lean and intramuscular adipose tissue (IMAT) of the quadriceps before and after resistance training. Peak isometric knee extension force output was measured with an isokinetic dynamometer. Muscle quality was calculated by dividing peak isometric knee extension force (N) by quadriceps lean muscle mass (cm2). In addition, common physical function variables were measured before and after training. RESULTS: Surgical and nonsurgical lean quadriceps muscle mass improved among participants (mean change: 2.9 cm2+/-1.4 cm2, and 2.7 cm2+/-1.3 cm2, respectively), while IMAT remained unchanged. Peak force improved in the surgical limb by 43.1+/-23N, with no significant change in the nonsurgical limb. Significant gains in physical function were evident after training. CONCLUSION: Participants recovering from hip fracture demonstrated improvements in muscle mass, muscle strength, and muscle quality in the surgical limb after hip fracture. These were in addition to gains made in the first months after fracture with traditional care. Future studies should determine the impact that muscle quality has on long-term functional recovery in this population. PMID- 29412444 TI - Frailty and Neurodegenerative Disease: Anticipating the Future, Expanding the Framework. AB - An array of technologies for preventing and treating age-related neural decline and disease are currently under development. A clear framework for how to identify groups in need of such inventions is needed. An encompassing concept of frailty could provide a solid basis for such purposes. Concepts of frailty, including physical and cognitive frailty, are currently applied in clinical settings, and in research and development. The terminology facilitates identifying processes of age-related physical and cognitive decline. However, age related neurodegenerative diseases do not fit the conceptual framework of frailty. A terminology of frailty can and should be developed that connects aging, cognitive decline, and neurodegenerative disease. Such a framework needs to (a) adequately account for the effects that the processes of aging have on neural decline and disease, and (b) be helpful in identifying relevant groups of users and patients. PMID- 29412445 TI - 8th International Conference on Frailty and Sarcopenia Research (ICFSR), March 1 3, 2018, Miami, USA, Symposia, Conference, Oral communications. PMID- 29412447 TI - Surgical treatment of multiple ipsilateral breast cancers. PMID- 29412448 TI - Reaching out to the surgical community in China. PMID- 29412449 TI - Use of aspirin and bleeding-related complications after hepatic resection. AB - BACKGROUND: The operative risk of hepatectomy under antiplatelet therapy is unknown. This study sought to assess the outcomes of elective hepatectomy performed with or without aspirin continuation in a well balanced matched cohort. METHODS: Data were retrieved from a multicentre prospective observational study. Aspirin and control groups were compared by non-standardized methods and by propensity score (PS) matching analysis. The main outcome was severe (Dindo Clavien grade IIIa or more) haemorrhage. Other outcomes analysed were intraoperative transfusion, overall haemorrhage, major morbidity, comprehensive complication index (CCI) score, thromboembolic complications, ischaemic complications and mortality. RESULTS: Before matching, there were 118 patients in the aspirin group and 1685 in the control group. ASA fitness grade, cardiovascular disease, previous history of angina pectoris, angioplasty, diabetes, use of vitamin K antagonists, cirrhosis and type of hepatectomy were significantly different between the groups. After PS matching, 108 patients were included in each group. There were no statistically significant differences between the aspirin and control groups in severe haemorrhage (6.5 versus 5.6 per cent respectively; odds ratio (OR) 1.18, 95 per cent c.i. 0.38 to 3.62), intraoperative transfusion (23.4 versus 23.7 per cent; OR 0.98, 0.51 to 1.87), overall haemorrhage (10.2 versus 12.0 per cent; OR 0.83, 0.35 to 1.94), CCI score (24 versus 28; P = 0.520), major complications (23.1 versus 13.9 per cent; OR 1.82, 0.92 to 3.79) and 90-day mortality (5.6 versus 4.6 per cent; OR 1.21, 0.36 to 4.09). CONCLUSION: This observational study suggested that aspirin continuation is not associated with a higher rate of bleeding-related complications after elective hepatic surgery. PMID- 29412450 TI - Intrathoracic versus cervical anastomosis and predictors of anastomotic leakage after oesophagectomy for cancer. AB - BACKGROUND: Studies comparing the anastomotic leak rate in patients with an intrathoracic versus a cervical anastomosis after oesophagectomy are equivocal. The aim of this study was to compare clinical outcome after oesophagectomy in patients with an intrathoracic or cervical anastomosis, and to identify predictors of anastomotic leakage in a nationwide audit. METHODS: Between January 2011 and December 2015, all consecutive patients who underwent oesophagectomy for cancer were identified from the Dutch Upper Gastrointestinal Cancer Audit. For the comparison between an intrathoracic and cervical anastomosis, propensity score matching was used to adjust for potential confounders. Multivariable logistic regression modelling with backward stepwise selection was used to determine independent predictors of anastomotic leakage. RESULTS: Some 3348 patients were included. After propensity score matching, 654 patients were included in both the cervical and intrathoracic anastomosis groups. An intrathoracic anastomosis was associated with a lower leak rate than a cervical anastomosis (17.0 versus 21.9 per cent; P = 0.025). The percentage of patients with recurrent nerve paresis was also lower (0.6 versus 7.0 per cent; P < 0.001) and an intrathoracic anastomosis was associated with a shorter median hospital stay (12 versus 14 days; P = 0.001). Multivariable analysis revealed that ASA fitness grade III or higher, chronic obstructive pulmonary disease, cardiac arrhythmia, diabetes mellitus and proximal oesophageal tumours were independent predictors of anastomotic leakage. CONCLUSION: An intrathoracic oesophagogastric anastomosis was associated with a lower anastomotic leak rate, lower rate of recurrent nerve paresis and a shorter hospital stay. Risk factors for anastomotic leak were co-morbidities and proximal tumours. PMID- 29412451 TI - Prevalence and factors associated with postpartum depression in women from single child families. AB - OBJECTIVE: To investigate the prevalence of postpartum depression (PPD) and its associated factors among women without siblings from south China. METHODS: A cross-sectional study was conducted involving 468 mothers from single-child families who were assessed at 6 weeks after childbirth at a tertiary hospital in Guangzhou, China, from June 2015 to July 2016. The Chinese version of the Edinburgh Postnatal Depression Scale and a self-designed questionnaire regarding risk factors were administered to all participants. RESULTS: The prevalence of PPD in women from single-child families was 56.2%. A multivariate logistic regression model identified the following pregnancy-related and psychological risk factors: unplanned pregnancy (odds ratio [OR] 2.35, 95% confidence interval [CI] 1.73-3.32), being a first-time mother (OR 3.00, 95% CI 1.73-4.93), poor mother-in-law relationship (OR 3.15, 95% CI 2.93-3.36), and poor family support (OR 2.13, 95% CI 1.84-2.45). Sociodemographic characteristics were not associated with the development of PPD. CONCLUSION: The development of PPD in women from single-child families is an important public health concern. Health practitioners should offer psychoeducation and culturally sensitive counseling during the postpartum period, and the screening of mood disorders from the prenatal to the postpartum period should be covered by maternity insurance. PMID- 29412452 TI - Screening for fetal and neonatal alloimmune thrombocytopenia - lessons learned from a Norwegian screening program. PMID- 29412453 TI - Meta-analysis of delayed gastric emptying after pylorus-preserving versus pylorus resecting pancreatoduodenectomy. AB - BACKGROUND: Delayed gastric emptying (DGE) is a frequent complication after pylorus-preserving pancreatoduodenectomy. Recent studies have suggested that resection of the pylorus is associated with decreased rates of DGE. However, superiority of pylorus-resecting pancreatoduodenectomy was not shown in a recent RCT. This meta-analysis summarized evidence of the effectiveness and safety of pylorus-preserving compared with pylorus-resecting pancreatoduodenectomy. METHODS: RCTs and non-randomized studies comparing outcomes of pylorus-preserving and pylorus-resecting pancreatoduodenectomy were searched systematically in MEDLINE, Web of Science and CENTRAL. Random-effects meta-analyses were performed and the results presented as weighted odds ratios (ORs) or mean differences with their corresponding 95 per cent confidence intervals. Subgroup analyses were performed to account for interstudy heterogeneity between RCTs and non-randomized studies. RESULTS: Three RCTs and eight non-randomized studies with a total of 992 patients were included. Quantitative synthesis across all studies showed superiority for pylorus-resecting pancreatoduodenectomy regarding DGE (OR 2.71, 95 per cent c.i. 1.48 to 4.96; P = 0.001) and length of hospital stay (mean difference 3.26 (95 per cent c.i. -1.04 to 5.48) days; P = 0.004). Subgroup analyses including only RCTs showed no significant statistical differences between the two procedures regarding DGE, and for all other effectiveness and safety measures. CONCLUSION: Pylorus-resecting pancreatoduodenectomy is not superior to pylorus-preserving pancreatoduodenectomy for reducing DGE or other relevant complications. PMID- 29412454 TI - Antioxidant Properties of Astaxanthin in Oil-in-Water Emulsions with Differently Charged Emulsifiers Under Chlorophyll Photosensitization. AB - : The antioxidative or prooxidative properties of astaxanthin at the concentrations of 0, 10, and 100 MUM were determined in oil-in-water (O/W) emulsions containing neutral, anionic, and cationic emulsifiers, which was Tween 20, sodium dodecyl sulfate, cetyltrimethylammonium bromide (CTAB), respectively, under chlorophyll photosensitization. The oxidative parameters and headspace volatiles were analyzed in O/W emulsions. In the 24 h period of visible light irradiation, 100 MUM of astaxanthin acted as an antioxidant in O/W emulsions containing neutral and anionic emulsifiers. However, astaxanthin in O/W emulsions with a cationic emulsifier was neither an antioxidant nor a prooxidant. The profiles of volatile compounds showed that astaxanthin served as a singlet oxygen quencher in O/W emulsions containing neutral and anionic emulsifiers. However, in O/W emulsion with a cationic emulsifier, astaxanthin was neither a singlet oxygen quencher nor a free radical scavenger because prooxidant properties of CTAB overwhelmed the antioxidant effects of astaxanthin. Therefore, the antioxidant properties of astaxanthin were influenced by the emulsifier charges in O/W emulsions. PRACTICAL APPLICATION: Astaxanthin is a lipid-soluble pigment and has antioxidant, anticancer, and anti-inflammatory properties and beneficial effects on cardiovascular diseases. Many lipid-based foods are displayed on the shelves in the markets under fluorescent light. The addition of astaxanthin can extend the shelf life of O/W emulsion type foods such as beverage and dressing products under visible light irradiation. Also, oxidative stability in emulsion type foods containing astaxanthin rich natural ingredients can be predicted. PMID- 29412455 TI - Hypocholesterolemic Effects of Kenaf Seed Oil, Macroemulsion, and Nanoemulsion in High-Cholesterol Diet Induced Rats. AB - : This study aimed to evaluate the effect of kenaf seed oil (KSO), kenaf seed oil in-water macroemulsion (KSOM), kenaf seed oil-in-water nanoemulsions (KSON), and emulsifier mixtures (EM) on serum lipid profile, liver oxidative status, and histopathological changes in high-cholesterol fed rats. Stability and characteristic of KSOM and KSON were carried out prior to in vivo study. Forty two Sprague-Dawley rats were divided into 7 groups (6 rats each) and induced hypercholesterolemia by feeding high cholesterol diet (HCD) for 14 days prior to treatments. Different treatments were introduced on day 15 to 29 while supplemented with HCD and removal of HCD during treatment on day 30 to 43, except for HCD group. Body weight and serum lipid profiles were measured at 3 different points: after hypercholesterolemia was induced, on day 29, and at the end of the experiment. Relative liver weight, atherogenic index, coronary risk index, and fecal total bile acids were also determined at the end of experiment. KSON showed significantly higher stability than KSOM and FTIR exhibited good encapsulation of KSO after 1.5 years of storage. Serum total cholesterol, low density lipoprotein cholesterol, lipid peroxidation levels in HCD group without treatment were significantly higher compared to normal control group and all treatment groups. All samples demonstrated hypocholesterolemic effect, but KSON exhibited higher efficiency in cholesterol-lowering properties, weight control and decreased liver fat as confirmed by histopathological evaluation. The overall results revealed that the efficacy of different treatments was in descending order of KSON, KSO, KSOM, and EM. PRACTICAL APPLICATION: Kenaf seed oil-in-water nanoemulsion (KSON) has the potential to be used as a natural alternative to the synthetic hypocholesterolemic drug in the future. However, larger sample size and clinical trial are needed to confirm on this potential application. In addition, treatment with KSON was suggested to prevent cardiovascular disease and fatty liver. PMID- 29412456 TI - Cortical thickness patterns as state biomarker of anorexia nervosa. AB - OBJECTIVE: Only few studies have investigated cortical thickness in anorexia nervosa (AN), and it is unclear whether patterns of altered cortical thickness can be identified as biomarkers for AN. METHOD: Cortical thickness was measured in 19 adult women with restricting-type AN, 24 individuals recovered from restricting-type AN (REC-AN) and 24 healthy controls. Those individuals with current or recovered from AN had previously shown altered regional cortical volumes across orbitofrontal cortex and insula. A linear relevance vector machine learning algorithm estimated patterns of regional thickness across 24 subdivisions of those regions. RESULTS: Region-based analysis showed higher cortical thickness in AN and REC-AN, compared to controls, in the right medial orbital (olfactory) sulcus, and greater cortical thickness for short insular gyri in REC-AN versus controls bilaterally. The machine-learning algorithm identified a pattern of relatively higher right orbital, right insular and left middle frontal cortical thickness, but lower left orbital, right middle and inferior frontal, and bilateral superior frontal cortical thickness specific to AN versus controls (74% specificity and 74% sensitivity, chi2 p < .004); predicted probabilities differed significantly between AN and controls (p < .023). No pattern significantly distinguished the REC-AN group from controls. CONCLUSIONS: Higher cortical thickness in medial orbitofrontal cortex and insula probably contributes to higher gray matter volume in AN in those regions. The machine learning algorithm identified a mixed pattern of mostly higher orbital and insular, but relatively lower superior frontal cortical thickness in individuals with current AN. These novel results suggest that regional cortical thickness patterns could be state markers for AN. PMID- 29412458 TI - Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the MU-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model. AB - Conventional opioids bind to MU-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and beta-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the MU-opioid receptor that differentially activates G-protein coupling while mitigating beta-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score. Phase 1 data consisted of 145 subjects (88% male, 12% female), who received single doses of oliceridine ranging between 0.15 and 7 mg, as well as multiple doses ranging from 0.4 to 4.5 mg every 4-6 hours. Sixteen of these subjects were CYP2D6 poor metabolizers, who have lower oliceridine clearance than extensive metabolizers. Approximately 265 subjects (10% male, 90% female) came from the phase 2 study, in which they received active doses ranging from 0.5 to 4 mg every 3-4 hours. The final model was a 3-compartment model that included covariates of body weight, sex, and CYP2D6 status. The PD model was an indirect response model linked to plasma oliceridine concentrations and included the placebo pain response over the 48-hour treatment period. The EC50 for oliceridine on pain relief was estimated as 10.1 ng/mL (95%CI, 8.4-12.1 ng/mL). Model qualification showed that the model robustly reproduced the original data. PMID- 29412457 TI - Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies. AB - Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes (CRISs) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pretreatment biopsies from multiple regions or at different time points, remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n = 543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n = 10), (iv) multi-regional biopsies from colon tumours (n = 29 biopsies, n = 7 tumours), and (v) pretreatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n = 44). Compared to previous results obtained using CRC resection material, we demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p = 0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p = 0.003 and p = 0.02, respectively). These findings have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29412459 TI - Shelf to Health: Does Product Innovation Change National Estimates of Dietary Impacts? AB - : This paper presents a simulation process to augment nutrition surveillance in the United States which incorporates product innovation data. Traditional point estimates of nutritional quality in a food category are compared to those based on distributions of nutrient compositions using product-level variability seen in the market. Nationally representative consumption patterns provide dietary intakes. Cookies are used as an example food category. Nutrient composition data from Global New Product Database (GNPD) for 5259 cookies launched 2005 to 2012 were matched to dietary intakes from 2005 to 2012 National Health and Nutrition Examination Survey (NHANES) over the 2 y cycles of NHANES for 8284 cookie consumers. Average dietary intakes from traditional NHANES and GNPD-based estimations produced similar mean values for energy, carbohydrates, sugars, total fat, and protein. Saturated fat, fiber and cholesterol contributions using new product compositions were significantly higher than traditional NHANES approaches, estimates of sodium were significantly lower. These differences become pronounced when comparing adult and child consumption patterns and over time. This process also simulated trans fat consumption estimates not traditionally available within NHANES. On average cookies contributed 0.3 g/d (range 0 to 4.1 g/d). Much variability in food composition is seen in the market which is shown to influence estimates of the national diet. PRACTICAL APPLICATION: Numerous factors drive changes in the food supply, including health trends, firm strategic choices, and food policy. This evolution presents a challenge for dietary assessments and nutrition monitoring. The public health impact of variability in nutritional composition, subpopulation consumption patterns and market dynamics are particularly difficult to evaluate and are shown to influence estimates of the national diet. PMID- 29412460 TI - Revisiting the Mechanism of Hydrolysis of Betanin. AB - Betanin (betanidin 5-O-beta-D-glucoside) is a water-soluble plant pigment used as a color additive in food, drugs and cosmetic products. Despite its sensitivity to light and heat, betanin maintains appreciable tinctorial strength in low acidic and neutral conditions, where the color of other plant pigments, such as anthocyanins, quickly fades. However, betanin is an iminium natural product that experiences acid- and base-catalyzed hydrolysis to form the fairly stable betalamic acid and cyclo-DOPA-5-O-beta-D-glucoside. Here, we show that the decomposition of betanin in aqueous phosphate solution pH 2-11 is subject to general base catalysis by hydrogen phosphate ion and intramolecular general acid and base catalysis, providing new insights on the mechanism of betanin hydrolysis. UV/Vis absorption spectrophotometry, 1 H NMR spectroscopy and mass spectrometry were used to investigate product formation. Furthermore, theoretical calculations support the hypothesis that the nitrogen atom of the tetrahydropyridine ring of betanin is doubly protonated, as observed for structurally simpler amino dicarboxylic acids. Our results contribute to the study of betanin and other pigments belonging to the class of betalains and to deepen the knowledge on the chemical properties of imino acids as well as on iminium-catalyzed modifications of carbonyl compounds in water. PMID- 29412461 TI - Influence of Expectation Measure on the Sensory Acceptance of Petit Suisse Product. AB - : The consumer's expectation has an important role in the consumption of food products. It is one of the factors that influence the perception of sensory attributes and interact with the physiological, behavioral and cognitive factors influencing consumer decisions. The present study aimed to analyze the influence of consumer's expectations on the acceptance of Petit Suisse. Products of 4 different brands were used for the sensory analysis, 2 international brands and 2 regional ones. The 9-point regular hedonic scale was employed to carry out affective sensory and expectation measure tests (with and without product information). Concerning the present research, photos of the packaging of each product were printed in color and presented to the participants. These photos displayed the following pieces of information: the product brand, pictures, colors, product name, nutritional information and date of manufacture. International samples obtained higher grades when presented with their packaging, and obtained lower values both in the blind test and in the real expectation test evaluation. It can be concluded that the sensory analysis of the expectation measure showed that the brand influences the acceptance of the product, for the consumer's expectations for international brands had positively confirmed and disconfirmed acceptance. PRACTICAL APPLICATION: This study generated a significant contribution, especially for companies that aim for a wider market. The application of sensory analysis with a focus on expectation measure, it shows that the brand determines the purchase, based on the results of this study. Therefore, the product's visual identity must be invested in; it must arouse children and adults' attention. That is, it reinforces that the image of the product, the label and what it arouses in the consumers are extremely important for the final choice. PMID- 29412462 TI - Effects of Processing Conditions During Manufacture on Retronasal-Aroma Compounds from a Milk Coffee Drink. AB - : To develop a ready-to-drink (RTD) milk coffee retaining the original coffee flavor, the effects of processing conditions during manufacture on retronasal arma (RA) compounds from the milk coffee were investigated by gas chromatography mass spectrometry using an RA simulator (RAS). Thirteen of 46 detected compounds in the RAS effluent (RAS compounds) decreased significantly following pH adjustment of coffee (from pH 5.1 to 6.8) and 5 compounds increased. RAS compounds from coffee tended to decrease through the pH adjustment and subsequent sterilization. Significantly higher amounts of 13 RAS compounds were released from the milk coffee produced using a blending-after-sterilization (BAS) process without the pH adjustment than from that using a blending-before-sterilization (BBS) process with the pH adjustment. In BAS-processed milk coffee, significantly lower amounts of 8 high-volatility compounds and 1H-pyrrole were released from coffee containing infusion-sterilized (INF) milk than from coffee containing plate-sterilized (PLT) milk, whereas 3 low-volatility compounds were released significantly more from coffee using PLT milk. Principal component analysis revealed that the effect of the manufacturing process (BAS, BBS, or homemade (blending unsterilized coffee without pH adjustment with sterilized milk)) on milk coffee volatiles was larger than that of the sterilization method (INF or PLT) for milk, and that the sterilization method could result in different RAS volatile characteristics in BAS and homemade processes. In conclusion, a BAS process was found to be superior to a BBS process for the manufacture of an RTD milk coffee that retains volatile characteristics similar to that of a homemade milk coffee. PRACTICAL APPLICATION: Ready-to-drink (RTD) milk coffee manufactured using the conventional blending-before-sterilization process does not retain its original coffee flavor due to pH adjustment of the coffee during the process. The new blending-after-sterilization (BAS) process enabled the production of RTD milk coffee whose volatiles are closer to that of homemade milk coffee, as demonstrated by the results of RAS-GC-MS analysis. The BAS process has already been applied to the manufacture of RTD milk coffees in Japan. PMID- 29412463 TI - The Drug-Drug Interaction Profile of Presatovir. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUCinf ), and decreased by rifampin (40.3% in Cmax and 82.5% in AUCinf ) and efavirenz (55.7% in AUCinf ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment. PMID- 29412464 TI - Effects of bentonite Bgp35b-p on the gut microbiota of mice fed a high-fat diet. AB - BACKGROUND: Bentonite is a natural clay mineral with health-promoting effects due to its high adsorption abilities with high cation-exchange capacity. Previously, we found an anti-obesity effect for Bgp35b-p bentonite produced in South Korea, where its high adsorbent ability of dietary lipids possibly partially removed the lipidic environment in the gut (unpublished). It is hypothesized that Bgp35b-p affects the intestinal microbial community, and thus the microbial changes were investigated via next-generation sequencing targeting the bacterial 16S rRNA gene and bioinformatics using QIIME (Quantitative Insights Into Microbial Ecology) were performed on feces of C57BL/6 male mice fed a high-fat diet (HFD) with the Bgp35b-p. RESULTS: The HFD caused microbial dysbiosis, characterized by a decrease in the relative abundance of Bacteroidetes and an increase in abundance of Firmicutes and Proteobacteria. It was found that HFD + Bgp35b-p led to significant changes in the microbial compositions of family-level bacteria known as short-chain fatty-acid-producing bacteria. The relative abundance of Ruminococcaceae was significantly increased, and the abundances of Clostridiaceae and Lachnospiraceae were decreased by HFD + Bgp35b-p, shifting close to that in mice fed a normal diet. CONCLUSION: Bgp35b-p induced compositional changes in intestinal microbiota, which can be considered as a prebiotic effect, thus suggesting that bentonite may be a potential prebiotic functional supplement. (c) 2018 Society of Chemical Industry. PMID- 29412466 TI - Giant reed genotypes from temperate and arid environments show different response mechanisms to drought. AB - Studies at the root level and how the root-shoot interactions may influence the whole crop performance of giant reed (Arundo donax L.) under limited water conditions are largely missing. In the present study, we illustrate the effects of water stress on some phenotypic traits at the root-shoot levels of two giant reed genotypes (from Morocco and Northern Italy) that were reported to have different adaptive hydraulic stem conductivities despite the limited genetic variability of the species. The trial was carried out in 1 m3 rhizotrons (1 * 1 * 1 m) for two consecutive growing seasons. As expected, both genotypes showed an effective behavior to contrast water shortage; however, the Moroccan genotype showed a higher leaf water potential, a lower root length density (RLD) and thinner roots in the upper soil layer (0-20 cm), and similar to control RLD values at deep soil layers (40-60 cm). On the other hand the Italian genotype showed the opposite pattern; that is no drought (DR) effects in RLD and root diameter at upper soil layers and reduced RLD in deep layers, thus revealing different DR adaptation characteristics between two genotypes. This DR adaptation variability might bring new insights on DR tolerance of giant reed identifying potential traits aimed to improve the integral plant functioning, to a more efficient use of water resources, and to a more effective crop allocation to targeted stressful conditions under a climate change scenario that foresees the increase of DR periods. PMID- 29412467 TI - Heavy Episodic Drinking Trajectories Among Underage Young Adult Women: The Role of Feminine Norms. AB - BACKGROUND: Heavy episodic drinking (HED; 4 or more drinks in a 2-hour period) in U.S. college women has increased by 40% in the past 30 years. This dramatic shift suggests that women are "closing the gender gap" and are drinking at rates similar to men. Multidimensional feminine norms, or beliefs and expectations about what it means to be a woman, are theoretically promising and gender relevant factors that may help account for within-group differences in problematic drinking patterns among this increasingly at-risk group. The aim of this study was to identify distinct developmental trajectories of HED among underage young adult women and examine the gender-relevant factors that predict these typologies. METHODS: Growth mixture modeling was used to identify latent trajectory classes of HED over the course of a year (3 time points) in 700 underage (Wave 1, Mage = 18, SD = 0.32) young adult women from a Mid-Atlantic university in the United States. Logistic regression analyses evaluated feminine norm endorsement, sorority status, perceived peer norms, expectancies, alcohol related consequences, and marijuana use as predictors of the latent trajectory classes. RESULTS: About 64.4% of underage women reported engaging in HED. Three HED latent trajectory classes were identified as follows: (i) High Risk, (31%) reported weekly HED over the course of the year; (ii) Monthly HED (33.4%) reported engaging in HED roughly once a month; and (iii) Abstainers (35.6%) reported no HED over the course of the year. The High-Risk class reported significantly more alcohol-related problems and marijuana use than the other trajectory classes. The multidimensional feminine norms of sexual fidelity and appearance were significantly associated with the latent trajectory classes even when controlling for well-established correlates of drinking. CONCLUSIONS: High risk drinking typologies were identified in underage women, and these trajectories were related to feminine norms. Prevention and intervention programs targeting gender-relevant factors may help reduce problematic drinking and marijuana use among underage women engaging in problematic patterns of drinking. PMID- 29412465 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei of appendicular and extra-appendicular origin. AB - BACKGROUND: The prognostic value of the primary neoplasm responsible for pseudomyxoma peritonei (PMP) remains poorly studied. The aim of this study was to determine the prognosis for patients with extra-appendicular PMP (EA-PMP) treated optimally with complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: All patients treated for PMP with CCRS and HIPEC between 1994 and 2016 were selected retrospectively from a French multicentre database. Patients with EA-PMP had pathologically confirmed non neoplastic appendices and were matched in a 1 : 4 ratio with patients treated for appendicular PMP (A-PMP), based on a propensity score. RESULTS: Some 726 patients were identified, of which 61 (EA-PMP group) were matched with 244 patients (A-PMP group). The origins of primary tumours in the EA-PMP group included the ovary (45 patients), colon (4), urachus (4), small bowel (1), pancreas (1) and unknown (6). The median peritoneal carcinomatosis index was comparable in EA-PMP and A-PMP groups (15.5 versus 18 respectively; P = 0.315). In-hospital mortality (3 versus 2.9 per cent; P = 1.000) and major morbidity 26 versus 25.0 per cent; P = 0.869) were also similar between the two groups. Median follow-up was 66.9 months. The 5 year overall survival rate was 87.8 (95 per cent c.i. 83.2 to 92.5) per cent in the A-PMP group and 87 (77 to 96) per cent in the EA-PMP group. The 5-year disease-free survival rate was 66.0 (58.7 to 73.4) per cent and 70 (53 to 83) per cent respectively. CONCLUSION: Overall and disease-free survival following treatment with CCRS and HIPEC is similar in patients with pseudomyxoma peritonei of appendicular or extra-appendicular origin. PMID- 29412468 TI - PtxtPME1 and homogalacturonans influence xylem hydraulic properties in poplar. AB - While the xylem hydraulic properties, such as vulnerability to cavitation (VC), are of paramount importance in drought resistance, their genetic determinants remain unexplored. There is evidence that pectins and their methylation pattern are involved, but the detail of their involvement and the corresponding genes need to be clarified. We analyzed the hydraulic properties of the 35S::PME1 transgenic aspen that ectopically under- or over-express a xylem-abundant pectin methyl esterase, PtxtPME1. We also produced and analyzed 4CL1::PGII transgenic poplars expressing a fungal polygalacturonase, AnPGII, under the control of the Ptxa4CL1 promoter that is active in the developing xylem after xylem cell expansion. Both the 35S::PME1 under- and over-expressing aspen lines developed xylem with lower-specific hydraulic conductivity and lower VC, while the 4CL1::PGII plants developed xylem with a higher VC. These xylem hydraulic changes were associated with modifications in xylem structure or in intervessel pit structure that can result in changes in mechanical behavior of the pit membrane. This study shows that homogalacturonans and their methylation pattern influence xylem hydraulic properties, through its effect on xylem cell expansion and on intervessel pit properties and it show a role for PtxtPME1 in the xylem hydraulic properties. PMID- 29412469 TI - Variation in the angiosperm ionome. AB - The ionome is defined as the elemental composition of a subcellular structure, cell, tissue, organ or organism. The subset of the ionome comprising mineral nutrients is termed the functional ionome. A 'standard functional ionome' of leaves of an 'average' angiosperm, defined as the nutrient composition of leaves when growth is not limited by mineral nutrients, is presented and can be used to compare the effects of environment and genetics on plant nutrition. The leaf ionome of a plant is influenced by interactions between its environment and genetics. Examples of the effects of the environment on the leaf ionome are presented and the consequences of nutrient deficiencies on the leaf ionome are described. The physiological reasons for (1) allometric relationships between leaf nitrogen and phosphorus concentrations and (2) linear relationships between leaf calcium and magnesium concentrations are explained. It is noted that strong phylogenetic effects on the mineral composition of leaves of angiosperm species are observed even when sampled from diverse environments. The evolutionary origins of traits including (1) the small calcium concentrations of Poales leaves, (2) the large magnesium concentrations of Caryophyllales leaves and (3) the large sulphur concentrations of Brassicales leaves are traced using phylogenetic relationships among angiosperm orders, families and genera. The rare evolution of hyperaccumulation of toxic elements in leaves of angiosperms is also described. Consequences of variation in the leaf ionome for ecology, mineral cycling in the environment, strategies for phytoremediation of contaminated land, sustainable agriculture and the nutrition of livestock and humans are discussed. PMID- 29412470 TI - Stability constants of adducts of succinate copper(II) complexes with beta cyclodextrin determined by capillary electrophoresis. AB - Cyclodextrins (CD) form inclusion complexes with different "guests" owing to the fact that the shape of the CD molecule is a truncated cone with a hydrophobic cavity. The adducts of CD with metal complexes remain scantily explored. In this study, the stability constants of the adducts between succinate copper(II) complexes and beta-CD was determined using capillary electrophoresis. The beta-CD concentration in background electrolytes (BGE) was found to influence on the effective electrophoretic mobility of the copper(II) complexes in succinate BGEs. It was shown that succinic acid and its anions and copper(II) ions did not form a significant amount of the inclusion complexes with beta-CD and the mobility change was caused by the adduct formation between succinate copper(II) complexes and beta-CD. The stability constants of these adducts were determined at 25 degrees S and ionic strength of 0.100 M: log beta(CuL22- /beta-CD) = 1.76 +/- 0.06, log beta(CuL0 /beta-CD) = 0.98 +/- 0.09. The [CuHL]+ and [CuHL2 ]- species were found to do not form adducts with beta-CD. PMID- 29412471 TI - Untargeted profiling of Glycyrrhiza glabra extract with comprehensive two dimensional liquid chromatography-mass spectrometry using multi-segmented shift gradients in the second dimension: Expanding the metabolic coverage. AB - Metabolic profiling of Glycyrrhiza glabra using comprehensive two-dimensional liquid chromatography (LC * LC) coupled with photodiode array (PDA) and mass spectrometry (MS) detection is described. The separation was conducted under reversed-phase conditions, using a combination of first dimension (1 D) 150 mm microbore cyano column utilising 2.7 MUm diameter (dp ) particles, and second dimension (2 D) 50 mm superficially porous octadecylsilica column with 2.7 MUm dp particles. A multi-segmented shift gradient (MSG) for the 2 D separation was developed, and the orthogonality achieved was compared with other modes of gradients, such as full in-fraction, and shift gradient systems. Results demonstrated a significant expansion of metabolic coverage using MSG in 2 D, providing the highest measure of orthogonality compared to other gradient modes. Compound identifications were performed by employing complementary data from PDA and MS detection, with reference to structural group-type distribution in 2D space. A total of ca. 120 compounds were detected, and among them 37 were tentatively identified, distributed over the chemical families of glycosylated flavanones, triterpene saponins, and others. In comparison with one-dimensional LC, the total number of compounds detected was ca. 2-fold greater when LC * LC was employed. To the best of our knowledge, this is the first demonstration of the MSG mode in LC * LC, representing a powerful strategy to expand the metabolic coverage for analysis of plant-derived extracts, containing a multitude of different phytochemical classes. PMID- 29412472 TI - Current methods for mycotoxins analysis and innovative strategies for their reduction in cereals: an overview. AB - Mycotoxins are secondary metabolites produced by moulds in food that are considered a substantial issue in the context of food safety, due to their acute and chronic toxic effects on animals and humans. Therefore, new accurate methods for their identification and quantification are constantly developed in order to increase the performance of extraction, improve the accuracy of identification and reduce the limit of detection. At the same time, several industrial practices have shown the ability to reduce the level of mycotoxin contamination in food. In particular, a decrease in the amount of mycotoxins could result from standard processes naturally used for food processing or by procedures strategically introduced during processing, with the specific aim of reducing the amount of mycotoxins. In this review, the current methods adopted for accurate analyses of mycotoxins in cereals (aflatoxins, ochratoxins, trichothecenes, fumonisins) are discussed. In addition, both conventional and innovative strategies adopted to obtain safer finished products from common cereals intended for human consumption will be explored and analysed. (c) 2018 Society of Chemical Industry. PMID- 29412473 TI - Ancient rice cultivar extensively replaces phospholipids with non-phosphorus glycolipid under phosphorus deficiency. AB - Recycling of phosphorus (P) from P-containing metabolites is an adaptive strategy of plants to overcome soil P deficiency. This study was aimed at demonstrating differences in lipid remodelling between low-P-tolerant and -sensitive rice cultivars using lipidome profiling. The rice cultivars Akamai (low-P-tolerant) and Koshihikari (low-P-sensitive) were grown in a culture solution with [2 mg l-1 (+P)] or without (-P) phosphate for 21 and 28 days after transplantation. Upper and lower leaves were collected. Lipids were extracted from the leaves and their composition was analysed by liquid chromatography/mass spectrometry (LC-MS). Phospholipids, namely phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and phosphatidylinositol (PI), lysophosphatidylcholine (lysoPC), diacylglycerol (DAG), triacylglycerol (TAG) and glycolipids, namely sulfoquinovosyl diacylglycerol (SQDG), digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG) and 1,2-diacyl-3-O-alpha-glucuronosyl glycerol (GlcADG), were detected. GlcADG level was higher in both cultivars grown in -P than in +P and the increase was larger in Akamai than in Koshihikari. DGDG, MGDG and SQDG levels were higher in Akamai grown in -P than in +P and the increase was larger in the upper leaves than in the lower leaves. PC, PE, PG and PI levels were lower in both cultivars grown in -P than in +P and the decrease was larger in the lower leaves than in the upper leaves and in Akamai than in Koshihikari. Akamai catabolised more phospholipids in older leaves and synthesised glycolipids in younger leaves. These results suggested that extensive phospholipid replacement with non-phosphorus glycolipids is a mechanism underlying low-P-tolerance in rice cultivars. PMID- 29412474 TI - Sex-dependent reductions in high molecular weight adiponectin during acute hyperinsulinemia are prevented with endurance training in older females. AB - OBJECTIVE: The high molecular weight (HMW) adiponectin isoform is considered the active form of adiponectin and is linked to insulin sensitivity and the reduced risk of developing cardiovascular disease. The purpose of the first study was to determine the effects of age and sex on the plasma HMW adiponectin response to acute hyperinsulinemia, and secondly determine whether either endurance or resistance exercise training could affect this response. DESIGN AND PARTICIPANTS: Twenty-six healthy males (19-84 years) and twenty-six healthy females (18-76 years) were recruited and matched for BMI to examine the effects of sex and age on the plasma adiponectin response to a 2-hour hyperinsulinemic-euglycemic clamp. To examine the effects of exercise training, a subgroup of young (<35 years) and aged (>55 years) individuals were randomized into a 12-week endurance or resistance training programme and had their adiponectin response to hyperinsulinemia measured before and after training. High molecular weight (HMW) and total adiponectin were measured by ELISA. RESULTS: In response to hyperinsulinemia, plasma HMW adiponectin decreased in females (-9%, P < .005), but not males. After 12 weeks of endurance training, the response of plasma HMW adiponectin to hyperinsulinemia increased in older females (36%, P < .05) only. Resistance training had no effect on the plasma adiponectin response to hyperinsulinemia. Despite no age or sex differences at baseline, skeletal muscle AdipoR1 increased in response to endurance training (~120%, P < .001) and resistance training (~38%, P < .05), regardless of age or sex. CONCLUSION: The inhibitory action of hyperinsulinemia on plasma HMW adiponectin occurs in females but not males, irrespective of age. Twelve weeks of endurance training protects older females against the hyperinsulinemic inhibition of plasma HMW adiponectin, which could promote healthy ageing. PMID- 29412476 TI - Soluble MHC class II-driven therapy for a systemic lupus erythematosus murine experimental in vitro and in vivo model. AB - Taking into consideration the multiparametric nature of systemic lupus erythematosus (SLE), the severity and variability of symptoms and the lack of effective therapeutic approaches, this study took advantage of the recently described role of soluble major histocompatibility complex class II (sMHCII) molecules in maintaining tolerance to the organism and attempted to apply sMHCII proteins as a treatment to murine SLE experimental models in vitro as well as in vivo. After breaking tolerance to DNA in vitro, which was accompanied by development of specific anti-dsDNA antibodies, syngeneic or allogeneic sMHCII molecules, purified from healthy mouse serum, could significantly reduce the specific antibody levels and drive the system towards immunosuppression, as assessed by specific marker analysis on T cells and cytokine production by flow cytometry and ELISA, respectively. The in vivo experimental model consisted of pristane-induced SLE symptoms to BALB/c mice, which developed maximal levels of anti-dsDNA 2 months after pristane inoculation. Syngeneic or allogeneic sMHCII administration could alleviate pristane-induced symptoms, significantly decrease specific anti-dsDNA antibody production and develop immunosuppression to the host, as manifested by increase of CD4 + CTLA-4 + and CD4 + CD25 + cell populations in the spleen. Thus, the results presented in this study introduced the ability of sMHCII proteins to suppress specific autoantigen response, opening new areas of research and offering novel therapeutic approaches to SLE with expanding features to other autoimmune diseases. PMID- 29412475 TI - Review concludes that specific recommendations are needed to harmonise the provision of fresh mother's milk to their preterm infants. AB - AIM: There are no specific recommendations for using a mother's fresh milk for her preterm infant. We reviewed the available evidence on its collection, storage and administration. METHODS: The working group of the French Neonatal Society on fresh human milk use in preterm infants searched the MEDLINE database and Cochrane Library up to June 2017 for papers published in English or French. They specifically analysed 282 papers providing information on prospective, retrospective and clinical studies and examined guidelines from various countries. RESULTS: The review concluded that fresh mother's own milk should be favoured in accordance with the latest recommendations. However, it must be carried out under stringent conditions so that the expected benefits are not offset by risks related to different practices. The working group has summarised the best conditions for feeding preterm infants with human milk, balancing high nutritional and immunological quality with adequate virological and bacteriological safety. Professionals must provide parents with the necessary conditions to establish breastfeeding, together with specific and strong support. CONCLUSION: Based on their review, the working group has made specific recommendations for using fresh mother's own milk under careful conditions, so that the expected benefits are not offset by risks related to practices. PMID- 29412477 TI - CCR5 RNA Pseudoknots: Residue and Site-Specific Labeling correlate Internal Motions with microRNA Binding. AB - Conformational dynamics of RNA molecules play a critical role in governing their biological functions. Measurements of RNA dynamic behavior sheds important light on sites that interact with their binding partners or cellular stimulators. However, such measurements using solution-state NMR are difficult for large RNA molecules (>70 nt; nt=nucleotides) owing to severe spectral overlap, homonuclear 13 C scalar couplings, and line broadening. Herein, a strategic combination of solid-phase synthesis, site-specific isotopic labeled phosphoramidites, and enzymatic ligation is introduced. This approach allowed the position-specific insertion of isotopic probes into a 96 nt CCR5 RNA fragment. Accurate measurements of functional dynamics using the Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion (RD) experiments enabled extraction of the exchange rates and populations of this RNA. NMR chemical shift perturbation analysis of the RNA/microRNA-1224 complex indicated that A90-C1' of the pseudoknot exhibits similar changes in chemical shift observed in the excited state. This work demonstrates the general applicability of a NMR-labeling strategy to probe functional RNA structural dynamics. PMID- 29412478 TI - Relativistic heavy atom effect on 13 C NMR chemical shifts initiated by adjacent multiple chalcogens. AB - In this paper, we have investigated the cumulative peculiarity of the "heavy atom on light atom" effect on the 13 C NMR chemical shifts, initiated by the adjacent chalcogens. For this purpose, the most accurate hybrid computational scheme for the calculation of chemical shifts of carbon nuclei, directly bonded with several heavy chalcogens, is introduced and attested on the representative series of molecules. The best hybrid scheme combines the nonrelativistic coupled cluster based approach with the different types of corrections, including vibrational, solvent, and relativistic. The dependences of the total relativistic corrections to carbon shielding constants in 2 series of model compounds, namely, X?13 C?Y (X, Y = O, S, Se, Te) and C(XH)m (YH)n (ZH)p (QH)s H1-m H1-n H1-p H1-s (X, Y, Z, Q = S, Se, Te and m, n, p, s = 0, 1), on the total atomic number of the adjacent chalcogens have been obtained. PMID- 29412479 TI - Fast and Selective Heavy Metal Removal by a Novel Metal-Organic Framework Designed with In-Situ Ligand Building Block Fabrication Bearing Free Nitrogen. AB - Fast and effective adsorbents for the selective removal of HgII and PbII ions were prepared by the reaction of Zn(NO3 )2 ?6H2 O, H2 BDC, and N1 ,N2 bis(pyridin-4-ylmethylene) ethane-1,2-diamine (L) that yields an unprecedented two-dimensional layer-based supramolecular framework, {Zn(BDC)(L*)}?DMF (TMU-40), by solvothermal reaction. The formation of this framework involved an in situ C=C coupling of L to L* [L*=5,6-di(pyridin-4-yl)-1,2,3,4-tetrahydropyrazine]. As L* contains free nitrogen atoms, direct reaction of L* and metals led to metallated products. Post-synthetic modification of this novel MOF (TMU-40) with H2 O2 gives a new framework (O-TMU-40) by same structure and different ligand, which also bears free nitrogen atoms. FTIR spectra, TGA analysis, X-ray diffraction, Zeta Potential analysis and 1 H NMR spectroscopy were used to characterize the prepared frameworks. The TMU-40 and O-TMU-40 frameworks were used for heavy-metal removal from aqueous solutions. Maximum adsorption values of 269 mg g-1 for HgII with TMU-40 and 215 mg g-1 for PbII with O-TMU-40 were achieved in 10 min at 298 Kwithout changes in the pH of the adsorption medium with pseudo-second order kinetics based on the Langmuir model. The extremely fast kinetics of TMU-40 means this adsorbent can reduce heavily contaminated water containing HgII concentrations of 40 ppm down to the acceptable limit of 2 ppb. PMID- 29412480 TI - Direct and Indirect Effects of Perceived Stigma on Posttraumatic Growth in Gay Men and Lesbian Women in Chile. AB - This study examined the direct and indirect effects of perceived stigma on posttraumatic growth (PTG) in a sample of gay men and lesbian women in Chile, with coping strategies (positive reappraisal, social support seeking, and active coping strategies) as intermediate variables. Data from 467 gay men (57.4%) and lesbian women (42.6%) were analyzed. A respondent-driven sampling (RDS) method was used. The hierarchical regression analysis indicated the important predictive role of active coping, beta = .23, and positive reappraisal, beta = .45, in PTG, R2 = .31, p < .001, f2 = 0.16. Results revealed that, in the presence of positive reappraisal coping as an intermediate variable, partial indirect effects are detected between perceived stigma and PTG. Seeking instrumental social support did not produce indirect effects between perceived stigma and PTG, whereas active coping produced partial indirect effects. These findings suggest that the positive reappraisal of a traumatic experience is essential for reporting personal growth. Implications of these more complex relations for counseling interventions and further research are discussed. PMID- 29412481 TI - Catalytic Enantioselective Synthesis of Highly Functionalized Pentafluorosulfanylated Pyrrolidines. AB - The first catalytic asymmetric synthesis of highly functionalized pentafluorosulfanylated pyrrolidines is described. The method, based on a 1,3 dipolar cycloaddition reaction of aryl and heteroaryl-substituted glycine Schiff bases with pentafluorosulfanyl acrylic esters, gave access to a broad range of pyrrolidines bearing aryl, naphtyl, and heteroaryl groups. By using Xing-Phos as a catalyst, the corresponding products were obtained in good yields, good to high regioselectivity, and excellent diastereo- and enantioselectivities (up to 98 % ee). This methodology allowed the preparation of enantioenriched SF5 compounds for the first time using an enantioselective approach. PMID- 29412482 TI - Establishment of magnetic resonance imaging 3D reconstruction technology of orbital soft tissue and its preliminary application in patients with thyroid associated ophthalmopathy. AB - OBJECTIVE: Effective management of thyroid-associated ophthalmopathy (TAO) requires precise identification of the disease activity period as it is responsive to immunosuppressive treatment. Quantitative evaluations of orbital soft tissue are useful for analysing disease stages. We aimed to establish a method for orbital soft tissue volume calculation based on magnetic resonance imaging (MRI) data using 3D reconstruction technology. Furthermore, we validated the accuracy and precision of this method and investigated volume differences between patients with TAO and healthy individuals. MATERIALS AND METHODS: Using Mimics software for 3D reconstruction based on orbital MRI data, we quantitatively measured orbital fat volume (FV) and extraocular muscle volume (MV) using a manual phantom, and in patients with TAO and healthy volunteers (n = 10 each). The phantom was made using a combination of butter and chicken muscle and 2 observers measured its volume. Volume calculations were compared to a previously established standard volume. One observer measured a typical TAO case 10 times to calculate intra-observer variability while 3 observers independently measured 10 patients with TAO each to calculate interobserver variability. Orbital soft tissue volumes between 10 patients with TAO and 10 healthy individuals were compared. RESULTS: The precision of calculations for the phantom between the 2 observers varied from -4.60% to -2.78% for FV and between -4.13% to 0.71% for MV. Mean differences among repetitive calculations were lower than 4%, except during measurement of MV, which was 5.84%. The intraclass correlation coefficient varied from 0.976 to 0.996. FV was 15.53 +/- 3.06 mL in patients with TAO and 11.32 +/- 1.68 mL(P = .001)in healthy individuals, while MV was 3.19 +/- 0.82 mL in patients with TAO and 2.45 +/- 0.57 mL(P = .030)in healthy individuals. CONCLUSIONS: This method of calculating orbital soft tissue volumes based on MRI data and 3D reconstruction is both reliable and accurate as it yielded significant differences in tissue volume between patients with TAO and healthy individuals. PMID- 29412483 TI - Does including colour-blind men enhance search and rescue teams? PMID- 29412484 TI - Observational study found that even small variations in light can wake up very preterm infants in a neonatal intensive care unit. AB - AIM: This prospective observational study evaluated the behavioural responses of very preterm infants to spontaneous light variations. METHODS: We measured spontaneous light variations in the incubators of 27 very preterm infants, with a median gestational age of 28 weeks (range 26-31 weeks), over 10 hours. All of them had been admitted to the neonatal care unit of the Strasbourg University Hospital, France, between April 2008 and July 2009. Two independent raters examined changes in the infants' behavioural states using video recordings. The percentage of awakenings was recorded when there were light variations and during control periods with no changes. RESULTS: We analysed 275 periods following light variations and 275 control periods. The overall percentage of awakenings was greater during periods following a change in light than during control periods (16.3% vs 11%, p = 0.03). The extent of light protection affected the percentage of awakenings. In mild light protection, there were more awakenings following changes in light than in control periods (25.6% vs 6.7%, p = 0.01). This difference was not found in high light protection. CONCLUSION: Very preterm infants can be woken up by small variations in light, when the light protection in their incubator is insufficient. PMID- 29412485 TI - Advancing the management of obstructive airways diseases through translational research. AB - Obstructive airways diseases (OAD) represent a huge burden of illness world-wide, and in spite of the development of effective therapies, significant morbidity and mortality related to asthma and COPD still remains. Over the past decade, our understanding of OAD has improved vastly, and novel treatments have evolved. This evolution is the result of successful translational research, which has connected clinical presentations of OAD and underlying disease mechanisms, thereby enabling the development of targeted treatments. The next challenge of translational research will be to position these novel treatments for OAD for optimal clinical use. At the same time, there is great potential in these treatments providing even better insights into disease mechanisms in OAD by studying the effects of blocking individual immunological pathways. To optimize this potential, there is a need to ensure that translational aspects are added to randomized clinical trials, as well as real-world studies, but also to use other trial designs such as platform studies, which allow for simultaneous assessment of different interventions. Furthermore, demonstrating clinical impact, that is research translation, is an increasingly important component of successful translational research. This review outlines concepts of translational research, exemplifying how translational research has moved management of obstructive airways diseases into the next century, with the introduction of targeted, individualized therapy. Furthermore, the review describes how these therapies may be used as research tools to further our understanding of disease mechanisms in OAD, through translational, mechanistic studies. We underline the current need for implementing basic immunological concepts into clinical care in order to optimize the use of novel targeted treatments and to further the clinical understanding of disease mechanisms. Finally, potential barriers to adoption of novel targeted therapies into routine practice and how these may be overcome are described. PMID- 29412486 TI - Chromosomal inversions promote genomic islands of concerted evolution of Hsp70 genes in the Drosophila subobscura species subgroup. AB - Heat-shock (HS) assays to understand the connection between standing inversion variation and evolutionary response to climate change in Drosophila subobscura found that "warm-climate" inversion O3+4 exhibits non-HS levels of Hsp70 protein like those of "cold-climate" OST after HS induction. This was unexpected, as overexpression of Hsp70 can incur multiple fitness costs. To understand the genetic basis of this finding, we have determined the genomic sequence organization of the Hsp70 family in four different inversions, including OST , O3+4 , O3+4+8 and O3+4+16 , using as outgroups the remainder of the subobscura species subgroup, namely Drosophila madeirensis and Drosophila guanche. We found (i) in all the assayed lines, the Hsp70 family resides in cytological locus 94A and consists of only two genes, each with four HS elements (HSEs) and three GAGA sites on its promoter. Yet, in OST, the family is comparatively more compact; (ii) the two Hsp70 copies evolve in concert through gene conversion, except in D. guanche; (iii) within D. subobscura, the rate of concerted evolution is strongly structured by inversion, being higher in OST than in O3+4 ; and (iv) in D. guanche, the two copies accumulated multiple differences, including a newly evolved "gap-type" HSE2. The absence of concerted evolution in this species may be related to a long-gone-unnoticed observation that it lacks Hsp70 HS response, perhaps because it has evolved within a narrow thermal range in an oceanic island. Our results point to a previously unrealized link between inversions and concerted evolution, with potentially major implications for understanding genome evolution. PMID- 29412487 TI - The association and potentially destructive role of Th9/IL-9 is synergistic with Th17 cells by elevating MMP9 production in local lesions of oral lichen planus. AB - BACKGROUND: This study was to investigate association and potentially destructive role of Th9/IL-9 and their synergistic interaction with Th17 cells in elevating MMP9 production in local lesions of oral lichen planus (OLP) patients. METHODS: Oral mucosal tissues were obtained from OLP patients and healthy controls (HC) and then divided into an epithelial part (EP) or a lamina propria part (LP). Both EP and LP subsets were assessed for IL-9 and MMP9 mRNA levels by real-time quantitative PCR (qPCR). Flow cytometry was used to detect the CD4+ T helper subset Th9 (IL-9+ IL-17- CD4+ ) and Th17 (IL-9- IL-17+ CD4+ ) in co-cultured CD4+ Th cells and oral keratinocytes of OLP. IL-9, IL-17, and MMP9 in co-culture supernatant were detected by ELISA. RESULTS: The qPCR results demonstrated that IL-9 and MMP9 mRNA levels were positively correlated in OLP lesions, and both significantly elevated in EP and LP lesions of erosive type OLP. Th9 and Th17 cells were significantly elevated in co-cultures of CD4+ Th cells and keratinocytes, and MMP9, IL-9, and IL-17 levels were simultaneously increased. In vitro, recombinant human IL-17 treatment significantly enhanced MMP9 protein and mRNA levels, while a synergistic effect of IL-9 and IL-17 was not observed. However, further results showed Th17 cells, IL-17, and MMP9 were increased significantly when recombinant IL-9 was added to the cultured CD4+ T cells. CONCLUSION: This study demonstrated that Th9/IL-9 can induce elevated levels of MMP9 to aggravate OLP disease severity, which may occur directly through increasing Th17 levels or indirectly through a synergistic role with Th17. PMID- 29412488 TI - Influence of peanut matrix on stability of allergens in gastric-simulated digesta: 2S albumins are main contributors to the IgE reactivity of short digestion-resistant peptides. AB - BACKGROUND: Most food allergens sensitizing via the gastrointestinal tract are stable proteins that are resistant to pepsin digestion, in particular major peanut allergens, Ara h 2 and Ara h 6. Survival of their large fragments is essential for sensitizing capacity. However, the immunoreactive proteins/peptides to which the immune system of the gastrointestinal tract is exposed during digestion of peanut proteins are unknown. Particularly, the IgE reactivity of short digestion-resistant peptides (SDRPs; <10 kDa) released by gastric digestion under standardized and physiologically relevant in vitro conditions has not been investigated. OBJECTIVE: The aim of this study was to investigate and identify digestion products of major peanut allergens and in particular to examine IgE reactivity of SDRPs released by pepsin digestion of whole peanut grains. METHODS: Two-dimensional gel-based proteomics and shotgun peptidomics, immunoblotting with allergen-specific antibodies from peanut-sensitized patients, enzyme-linked immunosorbent inhibition assay and ImmunoCAP tests, including far ultraviolet circular dichroism spectroscopy were used to identify and characterize peanut digesta. RESULTS: Ara h 2 and Ara h 6 remained mostly intact, and SDRPs from Ara h 2 were more potent in inhibiting IgE binding than Ara h 1 and Ara 3. Ara h 1 and Ara h 3 exhibited sequential digestion into a series of digestion-resistant peptides with preserved allergenic capacity. A high number of identified SDRPs from Ara h 1, Ara h 2 and Ara h 3 were part of short continuous epitope sequences and possessed substantial allergenic potential. CONCLUSION AND CLINICAL RELEVANCE: Peanut grain digestion by oral and gastric phase enzymes generates mixture of products, where the major peanut allergens remain intact and their digested peptides have preserved allergenic capacity highlighting their important roles in allergic reactions to peanut. PMID- 29412490 TI - Extensive transcriptional variation poses a challenge to thermal stress biomarker development for endangered corals. AB - As climate changes, sea surface temperature anomalies that negatively impact coral reef organisms continue to increase in frequency and intensity. Yet, despite widespread coral mortality, genetic diversity remains high even in those coral species listed as threatened. While this is good news in many ways, it presents a challenge for the development of biomarkers that can identify resilient or vulnerable genotypes. Taking advantage of three coral restoration nurseries in Florida that serve as long-term common garden experiments, we exposed over 30 genetically distinct Acropora cervicornis colonies to hot and cold temperature shocks seasonally and measured pooled gene expression responses using RNAseq. Targeting a subset of 20 genes, we designed a high-throughput qPCR array to quantify expression in all individuals separately under each treatment with the goal of identifying predictive and/or diagnostic thermal stress biomarkers. We observed extensive transcriptional variation in the population, suggesting abundant raw material is available for adaptation via natural selection. However, this high variation made it difficult to correlate gene expression changes with colony performance metrics such as growth, mortality and bleaching susceptibility. Nevertheless, we identified several promising diagnostic biomarkers for acute thermal stress that may improve coral restoration and climate change mitigation efforts in the future. PMID- 29412491 TI - A semiarid fruit agroecosystem as a conservation-friendly option for small mammals in an anthropized landscape in Mexico. AB - Many studies have addressed the potential of low-input agroecosystems for biological conservation. However, most have been carried out on annual agroecosystems in temperate, developed countries. As agricultural surface will increase and natural protected areas alone will not warrant the conservation of biodiversity, it is crucial to include different types of agroecosystems in research and conservation efforts. In Mexico, perennial, low-input, fruit oriented nopal orchards (Opuntia spp.), one of the few crops suitable for semiarid areas, are the 10th out of 61 most important fruit crops grown in the country. We assessed their value for conservation in an anthropized landscape by comparing their rodent assemblages with those in adjacent habitats and determined the influence of the latter on the rodent communities inside them. We live trapped rodents in 12 orchards and adjacent natural xeric shrubland, grassland, and cropland. We captured 19 different species, of which 17 used the orchards. Four are Mexican endemics. Orchards have higher alpha diversity, species richness, and abundance than cropland and grassland and are not different from shrubland. The dominant rodent species are the same in orchards and shrubland, and where these two meet they integrate into one habitat. Within-habitat quality is a critical driver of the composition and diversity of rodent communities in the orchards studied, and the neighboring habitats do not modify them substantially. Increasing within-patch heterogeneity beyond a certain level is at the expense of habitat integrity and produces small-scale fragmentation reducing habitat quality. At a landscape scale, orchards contribute importantly to regional rodent diversity compared with other land use types, and appear to increase habitat connectivity between patches of shrubland. Orchards' higher alpha diversity would give them higher ecological resilience and make them better suited than grassland and cropland to contribute to the conservation of local biota. Nopal orchards should be considered conservation allies and incorporated in regional conservation plans. Regrettably, their future is unwarranted as producers face low revenues and lack of governmental support. Our confirmation that orchards have an important, positive impact on biodiversity can be used as a strong argument to lobby for incentives to safeguard this environmental friendly, low-input agroecosystem. PMID- 29412489 TI - Preclinical optimization of antibody-based radiopharmaceuticals for cancer imaging and radionuclide therapy-Model, vector, and radionuclide selection. AB - Intact antibodies and their truncated counterparts (eg, Fab, scFv fragments) are generally exquisitely specific and selective vectors, enabling recognition of individual cancer-associated molecular phenotypes against a complex and dynamic biomolecular background. Complementary alignment of these advantages with unique properties of radionuclides is a defining paradigm in both radioimmunoimaging and radioimmunotherapy, which remain some of the most adept and promising tools for cancer diagnosis and treatment. This review discusses how translational potency can be maximized through rational selection of antibody-nuclide couples for radioimmunoimaging/therapy in preclinical models. PMID- 29412492 TI - Histogram analysis of stretched-exponential and monoexponential diffusion weighted imaging models for distinguishing low and intermediate/high gleason scores in prostate carcinoma. AB - BACKGROUND: Noninvasive measures to evaluate the aggressiveness of prostate carcinoma (PCa) may benefit patients. PURPOSE: To assess the value of stretched exponential and monoexponential diffusion-weighted imaging (DWI) for predicting the aggressiveness of PCa. STUDY TYPE: Retrospective study. SUBJECTS: Seventy five patients with PCa. FIELD STRENGTH: 3T DWI examinations were performed using b-values of 0, 500, 1000, and 2000 s/mm2 . ASSESSMENT: The research were based on entire-tumor histogram analysis and the reference standard was radical prostectomy. STATISTICAL TESTS: The correlation analysis was programmed with Spearman's rank-order analysis between the histogram variables and Gleason grade group (GG). Receiver operating characteristic (ROC) regression was used to analyze the ability of these histogram variables to differentiate low-grade (LG) from intermediate/high-grade (HG) PCa. RESULTS: The percentiles and mean of apparent diffusion coefficient (ADC) and distributed diffusion coefficient (DDC) were correlated with GG (rho: 0.414-0.593), while there was no significant relation among alpha value, skewnesses, and kurtosises with GG (rho:0.034-0.323). HG tumors (ADC:484 +/- 136, 592 +/- 139, 670 +/- 144, 788 +/- 146, 895 +/- 141 mm2 /s; DDC: 410 +/- 142, 532 +/- 172, 666 +/- 193, 786 +/- 196, 914 +/- 181 mm2 /s) had lower values in the 10th , 25th , 50th , 75th percentiles and means than LG tumors (ADC: 644 +/- 779, 737 +/- 84, 836 +/- 83, 919 +/- 82, 997 +/- 107 mm2 /s; DDC: 552 +/- 82, 680 +/- 94, 829 +/- 112, 931 +/- 106, 1045 +/- 100 mm2 /s). However, there was no difference between LG and HG tumors in alpha value (0.671 +/- 0.041 vs. 0.633 +/- 0.114), kurtosises (ADC 0.09 vs. 0.086; DDC -0.033 vs. 0.317), or skewnesses (ADC -0.036 vs. 0.073; DDC -0.063 vs. 0.136). The above statistics were P < 0.01. ADC10 with AUC = 0.840 and DDC10 with AUC = 0.799 were similar in discriminating between LG and HG PCa at P < 0.05. DATA CONCLUSION: Histogram variables of DDC and ADC may predict the aggressiveness of PCa, while alpha value does not. The abilities of ADC10 and DDC10 to discriminate LG from HG tumors were similar, and both better than their respective means. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:491-498. PMID- 29412493 TI - Direct N-Glycofunctionalization of Amides with Glycosyl Trichloroacetimidate by Thiourea/Halogen Bond Donor Co-Catalysis. AB - Using a halogen bond (XB) donor and Schreiner's thiourea as cooperative catalysts, various amides, including the asparagine residues of several peptides, were directly coupled with glycosyl trichloroacetimidates to give unique N acylorthoamides in good yields. Synthetic applications of N-acylorthoamides, including rearrangement to the corresponding beta-N-glycoside, were also demonstrated. PMID- 29412494 TI - The rising tide of Acanthamoeba keratitis in Auckland, New Zealand: a 7-year review of presentation, diagnosis and outcomes (2009-2016). AB - IMPORTANCE: Acanthamoeba is an increasingly prevalent cause of vision-threatening microbial keratitis. BACKGROUND: To assess the incidence, clinical presentation, diagnosis and outcomes of patients with Acanthamoeba keratitis (AK) in Auckland, New Zealand over a 7-year period. DESIGN: Retrospective observational consecutive case series. PARTICIPANTS: Fifty-eight eyes of 52 patients diagnosed with AK. METHODS: All cases of AK were identified using a cross-referenced search of clinical, laboratory and pharmacy records from March 2009 to May 2016. MAIN OUTCOME MEASURES: Demographic and clinical data were collected including age, gender, risk factors, clinical manifestations, initial diagnosis, diagnostic investigations, treatment, presenting and final visual acuity and surgical interventions. RESULTS: Contact lens (CL) use was noted in 96% of unilateral and 100% of bilateral cases. The mean duration of symptoms at presentation was 21 days and the mean duration from presentation to definitive diagnosis was 14 days. Initial diagnosis was recorded as CL-related keratitis in 70.6%, viral keratitis in 15.5% and AK in 12.0%. The diagnosis was confirmed with In vivo confocal microscopy (IVCM) in 67.2%, corneal scrape in 22.4%, corneal biopsy in 1.7% and clinically in 8.6%. IVCM sensitivity was 83.0%. Surgical intervention was required in four patients, all with delayed diagnosis (range 63-125 days). The incidence of AK has more than doubled when compared with the preceding 7-year period. CONCLUSIONS AND RELEVANCE: AK is a rare vision-threatening protozoal infection with rapidly-increasing incidence in New Zealand, predominantly affecting CL users. Diagnosis is often challenging and when delayed is associated with worse outcomes. IVCM offers rapid diagnosis with high sensitivity. PMID- 29412495 TI - Evaluation of treatment outcomes in patients with supraglottic laryngeal cancer in Ontario, Canada: A population-based study. AB - BACKGROUND: Supraglottic laryngeal carcinoma has an entirely different etiology, clinical presentation, and prognosis compared to glottis cancer but the only evidence for the use of concurrent chemotherapy with radiotherapy (CRT) is the 5.4% 5-year improvement in overall survival (OS) for the combined laryngeal site. METHOD: We conducted a retrospective population-based study using administrative data to compare OS, disease-specific survival (DSS), laryngectomy-free survival, and laryngoesophageal dysfunction-free survival over time and by treatment for all patients with supraglottic laryngeal carcinoma diagnosed between January 1, 1990, and December 31, 2014, in Ontario, Canada. RESULTS: There was no improvement over time in OS (hazard ratio [HR] 1.006; P = .90), DSS (HR 1.031; P = .65), or laryngoesophageal dysfunction-free survival (P = .39). The patients selected for CRT had similar OS (HR 1.04; P = .66), laryngectomy-free survival (HR 0.95; P = .23), and laryngoesophageal dysfunction-free survival (P = .79) compared with patients undergoing radiotherapy. CONCLUSION: The addition of CRT by head and neck oncologists in Ontario, Canada, did not improve outcomes for the "real world" patients with supraglottic laryngeal carcinoma. PMID- 29412497 TI - Ultrarare marine microbes contribute to key sulphur-related ecosystem functions. AB - The description of a rare biosphere within microbial communities has created great interest because microbes play a fundamental role in the functioning of all ecosystems on earth. Despite recent progress in understanding the ecology of the rare biosphere, the concept itself is still discussed, and fundamental questions remain. Here, we target the seed bank compartment of the rare biosphere, assess the level of rarity at which micro-organisms are still able to colonize an ecosystem and investigate whether rare species are functionally redundant. Using an original experimental design where wood in aquaria was inoculated with increasingly diluted coastal seawater, we show that bacteria that represented as few as 0.00000002% of the cells in the environment (or 1 cell in 10 L of seawater) were still able to grow and play key roles within the ecosystem. Our experiment further showed that some bacteria can be replaced by others that have the potential to fulfil the same metabolic tasks. This finding suggests some functional redundancy within bacterial species. However, when ultrarare bacteria were progressively removed, productivity was reduced, and below a certain threshold some processes were lost, and the function of the ecosystem was altered. Overall the study shows that bacteria that are not detected by high throughput sequencing approaches are nevertheless viable and able to colonize new ecosystems, suggesting the need to consider ultrarare microbes in the marine environment. PMID- 29412496 TI - Characterization of active and infiltrative tumorous subregions from normal tissue in brain gliomas using multiparametric MRI. AB - BACKGROUND: Targeted localized biopsies and treatments for diffuse gliomas rely on accurate identification of tissue subregions, for which current MRI techniques lack specificity. PURPOSE: To explore the complementary and competitive roles of a variety of conventional and quantitative MRI methods for distinguishing subregions of brain gliomas. STUDY TYPE: Prospective. POPULATION: Fifty-one tissue specimens were collected using image-guided localized biopsy surgery from 10 patients with newly diagnosed gliomas. FIELD STRENGTH/SEQUENCE: Conventional and quantitative MR images consisting of pre- and postcontrast T1 w, T2 w, T2 FLAIR, T2 -relaxometry, DWI, DTI, IVIM, and DSC-MRI were acquired preoperatively at 3T. ASSESSMENT: Biopsy specimens were histopathologically attributed to glioma tissue subregion categories of active tumor (AT), infiltrative edema (IE), and normal tissue (NT) subregions. For each tissue sample, a feature vector comprising 15 MRI-based parameters was derived from preoperative images and assessed by a machine learning algorithm to determine the best multiparametric feature combination for characterizing the tissue subregions. STATISTICAL TESTS: For discrimination of AT, IE, and NT subregions, a one-way analysis of variance (ANOVA) test and for pairwise tissue subregion differentiation, Tukey honest significant difference, and Games-Howell tests were applied (P < 0.05). Cross validated feature selection and classification methods were implemented for identification of accurate multiparametric MRI parameter combination. RESULTS: After exclusion of 17 tissue specimens, 34 samples (AT = 6, IE = 20, and NT = 8) were considered for analysis. Highest accuracies and statistically significant differences for discrimination of IE from NT and AT from NT were observed for diffusion-based parameters (AUCs >90%), and the perfusion-derived parameter as the most accurate feature in distinguishing IE from AT. A combination of "CBV, MD, T2 _ISO, FLAIR" parameters showed high diagnostic performance for identification of the three subregions (AUC ~90%). DATA CONCLUSION: Integration of a few quantitative along with conventional MRI parameters may provide a potential multiparametric imaging biomarker for predicting the histopathologically proven glioma tissue subregions. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:938-950. PMID- 29412498 TI - Functional connectivity in replicated urban landscapes in the land snail (Cornu aspersum). AB - Urban areas are highly fragmented and thereby exert strong constraints on individual dispersal. Despite this, some species manage to persist in urban areas, such as the garden snail, Cornu aspersum, which is common in cityscapes despite its low mobility. Using landscape genetic approaches, we combined study area replication and multiscale analysis to determine how landscape composition, configuration and connectivity influence snail dispersal across urban areas. At the overall landscape scale, areas with a high percentage of roads decreased genetic differentiation between populations. At the population scale, genetic differentiation was positively linked with building surface, the proportion of borders where wooded patches and roads appeared side by side and the proportion of borders combining wooded patches and other impervious areas. Analyses based on pairwise genetic distances validated the isolation-by-distance and isolation-by resistance models for this land snail, with an equal fit to least-cost paths and circuit-theory-based models. Each of the 12 landscapes analysed separately yielded specific relations to environmental features, whereas analyses integrating all replicates highlighted general common effects. Our results suggest that urban transport infrastructures facilitate passive snail dispersal. At a local scale, corresponding to active dispersal, unfavourable habitats (wooded and impervious areas) isolate populations. This work upholds the use of replicated landscapes to increase the generalizability of landscape genetics results and shows how multiscale analyses provide insight into scale-dependent processes. PMID- 29412499 TI - Substance P ameliorates tumor necrosis factor-alpha-induced endothelial cell dysfunction by regulating eNOS expression in vitro. AB - OBJECTIVE: The aim of this study was to explore the beneficial effects of SP on NO production and inflammation-induced vascular endothelium cell death. METHODS: To mimic the inflammatory environment, TNF-alpha was treated with HUVECs, and SP was added prior to TNF-alpha to determine its protective effect. WST-1 assay was performed to detect cell viability. NO level in conditioned medium was measured by Griess Reagent System. The protein level of cleaved caspase-3, eNOS, and phosphorylated Akt was detected by Western blot analysis. RESULTS: TNF-alpha declined endothelial cell viability by downregulating Akt and NO production. TNF alpha-induced cell death was reliably restored by NO, confirming the requirement of NO for cell survival. By contrast, pretreatment of SP attenuated TNF-alpha induced cellular apoptosis, accompanied by an increase in the phosphorylation of Akt, eNOS expression, and NO production. Blockage of NK-1R, phosphorylated Akt or eNOS by CP-96345, A6730, or L-NAME entirely eliminated the effect of SP. CONCLUSIONS: SP can protect the vascular endothelium against inflammation-induced damage through modulation of the Akt/eNOS/NO signaling pathway. PMID- 29412500 TI - Gelatin-genipin-based biomaterials for skeletal muscle tissue engineering. AB - Skeletal muscle engineering aims at tissue reconstruction to replace muscle loss following traumatic injury or in congenital muscle defects. Skeletal muscle can be engineered by using biodegradable and biocompatible scaffolds that favor myogenic cell adhesion and subsequent tissue organization. In this study, we characterized scaffolds made of gelatin cross-linked with genipin, a natural derived cross-linking agent with low cytotoxicity and high biocompatibility, for tissue engineering of skeletal muscle. We generated gelatin-genipin hydrogels with a stiffness of 13 kPa to reproduce the mechanical properties characteristic of skeletal muscle and we show that their surface can be topographically patterned through soft lithography to drive myogenic cells differentiation and unidirectional orientation. Furthermore, we demonstrate that these biomaterials can be successfully implanted in vivo under dorsal mouse skin, showing good biocompatibility and slow biodegradation rate. Moreover, the grafting of this biomaterial in partially ablated tibialis anterior muscle does not impair muscle regeneration, supporting future applications of gelatin-genipin biomaterials in the field of skeletal muscle tissue repair. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2763-2777, 2018. PMID- 29412501 TI - Region-specific ischemia, neovascularization and macular oedema in treatment naive proliferative diabetic retinopathy. AB - IMPORTANCE: Region-specific pathology in proliferative diabetic retinopathy enhances our understanding and management of this disease. BACKGROUND: To investigate non-perfusion, neovascularization and macular oedema. DESIGN: A cross sectional, observational, non-randomized study. PARTICIPANTS: Consecutive 43 eyes of 27 treatment-naive patients. METHODS: Ultra-widefield fluorescein angiography for studying specific zones, that is, far-peripheral zone, mid-peripheral zone and central retina (cr), and spectral-domain optical coherence tomography for analysing thickness of macular layers. MAIN OUTCOME MEASURES: Non-perfusion index (NPI) and neovascularization index (NVI) in different zones, thickness of cr, retinal nerve fibre layer, ganglion cell layer (GCL), inner nuclear layer (INL) and outer plexiform layer in parafoveal regions. RESULTS: The NPI of far periphery and NVI of mid-periphery were the highest by one-way analysis of variance testing. Ischemic retina defined as high NPI in far-periphery was significantly related to macular oedema via a binary classification approach (P < 0.05). The ischemic retina was correlated with a decreased thickness of both retinal nerve fibre and GCL (P < 0.05); macular oedema was correlated with increased INL thickness (P < 0.0001). CONCLUSIONS AND RELEVANCE: The region specific correlation of NPI of far-periphery and NVI of mid-periphery, but not with central retinal thickness, suggests different pathogeneses of neovascularization and macular oedema. Retinal nerve fibre layer and GCL, both biomarkers of diabetic retinal neuronopathy, are associated with retinal ischemia, but not with macular oedema, suggesting that diabetic microangiopathy and neuronopathy possess distinct pathogenic pathways. The strong correlation between macular oedema and INL indicates that intracellular oedema is a determining factor of diabetic macular oedema. PMID- 29412502 TI - The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes: a cohort and nested case-control study. AB - OBJECTIVE: To obtain evidence of the effects of metformin and statins on the incidence of ovarian cancer in women with type 2 diabetes (T2D). DESIGN: A retrospective cohort study and nested case-control study. SETTING: The data were obtained from a diabetes database (FinDM) combining information from several nationwide registers. POPULATION: A cohort of 137 643 women over 40 years old and diagnosed with T2D during 1996-2011 in Finland. METHODS: In full cohort analysis Poisson regression was used to estimate the hazard ratios (HR) in relation to ever use of metformin, insulin other oral anti-diabetic medication or statins. In the nested case-control analysis 20 controls were matched to each case of ovarian cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different medications. The estimates were adjusted for age and duration of T2D. MAIN OUTCOME MEASURE: Incidence of ovarian cancer. RESULTS: In all, 303 women were diagnosed with ovarian cancer during the follow up. Compared with other forms of oral anti-diabetic medication, metformin (HR 1.02, 95% CI: 0.72-1.45) was not found to be associated with the incidence of ovarian cancer. Neither was there evidence for statins to affect the incidence (HR 0.99, 95% CI: 0.78-1.25). In nested case-control analysis the results were essentially similar. CONCLUSIONS: No evidence of an association between the use of metformin or statins and the incidence of ovarian cancer in women with T2D was found. TWEETABLE ABSTRACT: No evidence found for metformin or statins reducing the incidence of ovarian cancer. PMID- 29412504 TI - Preventive dental management of osteonecrosis of the jaws related to zoledronic acid treatment. AB - OBJECTIVE: To evaluate the effect of preventive dental management on reducing the incidence and delaying the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients treated with intravenous zoledronic acid (ZA). MATERIALS AND METHODS: This single-center clinical study included 255 patients with cancer monitored over a 6-year period. Patients received dental treatment prior to (group A) or after (group B) the initiation of ZA therapy. Dental treatments performed, incidence proportion (IP), and incidence rate (IR) in both groups were analyzed using significance tests. BRONJ onset was estimated using the Kaplan Meier estimator and log-rank test. Independent risk factors to develop BRONJ were evaluated using Cox regression analysis models. RESULTS: Thirty-seven patients suffered from BRONJ (IP = 14.5%), 7.3% in group A and 36.5% in group B (p = .000). The IR was 0.007 patients/month in group B and 0.004 in group A. BRONJ free survival at 3 years was 97% in group A and 66% in group B. Survival curves were significant (p = .056) according to log-rank test. Multivariate Cox models showed that dental extractions (p = .000) were significant. CONCLUSIONS: BRONJ occurred significantly in patients who underwent dental extractions after the initiation of ZA and did not accomplish a preventive dental program. PMID- 29412503 TI - Transcriptome-wide comparison of selenium hyperaccumulator and nonaccumulator Stanleya species provides new insight into key processes mediating the hyperaccumulation syndrome. AB - To obtain better insight into the mechanisms of selenium hyperaccumulation in Stanleya pinnata, transcriptome-wide differences in root and shoot gene expression levels were investigated in S. pinnata and related nonaccumulator Stanleya elata grown with or without 20 MUm selenate. Genes predicted to be involved in sulphate/selenate transport and assimilation or in oxidative stress resistance (glutathione-related genes and peroxidases) were among the most differentially expressed between species; many showed constitutively elevated expression in S. pinnata. A number of defence-related genes predicted to mediate synthesis and signalling of defence hormones jasmonic acid (JA, reported to induce sulphur assimilatory and glutathione biosynthesis genes), salicylic acid (SA) and ethylene were also more expressed in S. pinnata than S. elata. Several upstream signalling genes that up-regulate defence hormone synthesis showed higher expression in S. pinnata than S. elata and might trigger these selenium mediated defence responses. Thus, selenium hyperaccumulation and hypertolerance in S. pinnata may be mediated by constitutive, up-regulated JA, SA and ethylene mediated defence systems, associated with elevated expression of genes involved in sulphate/selenate uptake and assimilation or in antioxidant activity. Genes pinpointed in this study may be targets of genetic engineering of plants that may be employed in biofortification or phytoremediation. PMID- 29412505 TI - Labor and Delivery Nursing Experience: A Prerequisite for Midwifery Education? PMID- 29412506 TI - No evidence of association of oxytocin polymorphisms with breastfeeding in 2 independent samples. AB - Oxytocin has an important function in breastfeeding via its role in the milk ejection reflex and in attachment and bonding processes. Genetic factors account for a significant part of the individual differences in breastfeeding behavior. OXT and OXTR have been proposed as gene candidates for breastfeeding. Previous studies have focused on certain single-nucleotide polymorphisms (SNPs) within these genes, finding null or inconsistent results. The present study analyses the associations between a wide coverage of polymorphisms in OXT and OXTR and breastfeeding duration from 2 large and independent unselected samples comprising a total of 580 and 2112 female twin mothers from the Murcia Twin Registry (Spain) and QIMR Berghofer Medical Research Institute (Australia), respectively. A total of 19 SNPs in OXT and 137 in OXTR SNPs were covered in both samples. Effects of the OXT and OXTR polymorphisms on breastfeeding duration were calculated by means of linear regression controlling for age at survey time, educational level, interaction between age and educational level and principal components of genetic ancestry. The analyses were conducted independently in the 2 samples and also meta-analyzed. Although some SNPs were associated at an alpha level of .05 with breastfeeding, they did not survive multiple testing correction. We conclude that SNPs within or nearby OXT and OXTR are unlikely to have large effects on breastfeeding behavior. PMID- 29412508 TI - Proteomics Analysis of the Adhesion Activity of Lactobacillus acidophilus ATCC 4356 Upon Growth in an Intestine-Like pH Environment. AB - Many health effects of Lactobacillus acidophilus are desirable among these the adhesion ability is vital to enhance the possibility of colonization and stabilization associated with the gut mucosal barrier. In this study, the growth characteristics and the adhesion activity of L. acidophilus in the intestine-like pH environment (pH 7.5) are identified. The number of bacteria adhering to the HT 29 cells is found with a gradual increase trend (pH 5.5-7.5). This also leads to the morphological changes of L. acidophilus after exposure to different pH environments. Furthermore, with the help of the isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis, 207 proteins are detected differentially expressed at pH of 7.5. The use of GO analysis and KEGG analysis indicates three essential pathways related to the cell envelope peptide-glycan biosynthesis, carbohydrate metabolism, and amino acid metabolism are obviously changed. Adhesion related surface protein fmtB and PrtP are upregulated in pH 7.5 group. While the moonlight proteins like pyruvate kinase, which binds specifically to the mucin layer and inhibits the adhesive activity of L. acidophilus, is found downregulated. These results could be useful to understand the adhesion mechanism of L. acidophilus adapting for the gut mucosal barrier in the intestinal environment. PMID- 29412507 TI - Long-term evaluation of vascular grafts with circumferentially aligned microfibers in a rat abdominal aorta replacement model. AB - Long-term results of implants in small animal models can be used to optimize the design of grafts to further promote tissue regeneration. In previous study, we fabricated a poly(E-caprolactone) (PCL) bi-layered vascular graft consisting of an internal layer with circumferentially aligned microfibers and an external layer with random nanofibers. The circumferentially oriented vascular smooth muscle cells (VSMCs) were successfully regenerated after the grafts were implanted in rat abdominal aorta for 3 months. Here we investigated the long-term (18 months) performance of the bi-layered grafts in the same model. All the grafts were patent. No thrombosis, aneurysm, or stenosis occurred. The endothelium maintained complete. However, most of circumferentially oriented VSMCs migrated to luminal surface of the grafts to form a neointima with uniform thickness. Accordingly, extracellular matrix including collagen, elastin, and glycosaminoglycan displayed high density in neointima layer while with low density in the grafts wall because of the incomplete degradation of PCL. A small amounts of calcification occurred in the grafts. The contraction and relaxation function of regenerated neoartery almost disappeared. These data indicated that based on the structure design, many other factors of grafts should be considered to achieve the regenerated neoartery similar to the native vessels after long term implantation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2596-2604, 2018. PMID- 29412509 TI - Current Level of Fish Consumption is Associated with Mortality in Chinese but not US Adults: New Findings From Two Nationwide Cohort Studies With 14 and 9.8 Years of Follow-Up. AB - SCOPE: Whether dietary fish consumption is linked to mortality remains unclear. We aim to investigate the association of fish consumption with mortality in Chinese and US nationwide populations. METHODS AND RESULTS: We utilize data from China Health and Nutrition Survey (CHNS, n = 14 117) and National Health and Nutrition Examination Survey (NHANES, n = 33 221) including NHANES III conducted in 1988-1994 and continuous NHANES 1999-2010. Cox proportional hazards regression is used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 14 and 9.8 years for CHNS and NHANES, 1007 and 5209 deaths are documented, respectively. Among Chinese adults, increased fish intake is significantly associated with decreased total mortality. The multivariable adjusted HRs (95% CIs) across increasing categories of fish intake are 0.45 (0.36 0.56), 0.72 (0.60-0.86), and 0.70 (0.59-0.85) (p trend < 0.0001). However, fish intake is not associated with total mortality among US adults (p trend = 0.21). We only detected a borderline inverse association between fish intake and stroke mortality (p trend = 0.05), whereas a positive association with diabetes mortality in the third category of fish intake in NHANES. CONCLUSION: In these two nationwide cohort studies, fish consumption is associated with a reduced risk of total mortality for Chinese but not US populations. PMID- 29412510 TI - Otolaryngologist adherence to the AAO-HNSF Allergic Rhinitis Clinical Practice Guideline. AB - BACKGROUND: In February 2015, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNSF) published the Allergic Rhinitis Clinical Practice Guideline (AR-CPG). The objective of this study was to assess otolaryngologists' perception of the accuracy and adherence to the AR-CPG. METHODS: A survey was distributed to fellows of the American Academy of Otolaryngic Allergy and members of the American Academy of Otolaryngology-Head and Neck Surgery Foundation. A total of 601 otolaryngologists responded. The survey evaluated otolaryngologists' demographic data, perception of the accuracy of the guideline, and adherence to the guideline action statements. RESULTS: The majority of respondents were actively practicing (544 [90.5%]), for a duration of 11-30 years (308 [51.2%]), in a private practice setting (387 [64.4%]). The cohort was largely fellowship trained (348 [57.9%]) and had reviewed the guideline (428 [71.2%]). Most respondents perceived the guideline as being correct "a great deal" (295 [69.7%]) and deviated from the guideline "only a little" (302 [71.6%]). High rates of adherence to the strong guideline recommendations were observed. Respondents "always/most of the time" recommended intranasal steroids (581 [97.6%]), and oral antihistamines (439 [74%]) as primary therapy. Otolaryngologists in practice for longer were more likely to deviate from the guideline recommendations by obtaining sinonasal imaging (p = 0.007) and recommending oral leukotriene receptor antagonists as primary therapy (p = 0.0001). CONCLUSION: Overall perception of the correctness of and adherence to the AR-CPG was high in this cohort. Targeted education resources should be provided to otolaryngologists in practice for longer in efforts to reduce harmful or unnecessary variations in care. PMID- 29412511 TI - Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations. AB - BACKGROUND & AIMS: Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status. METHODS: We compared plasma bile acids in 17 ABCB11-mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasis patients by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasis patients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB11, and 8 healthy controls, for further verification. RESULTS: The overall hydrophobicity indices of total bile acids in both the ABCB11-mutated group (11.89 +/- 1.07 min) and the undiagnosed cholestasis group (11.46 +/- 1.07 min) were lower than those of healthy controls (13.69 +/- 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid (LCA), tauro-LCA, glyco-LCA and hyocholic acid was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestasis patients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001). CONCLUSIONS: Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases. PMID- 29412512 TI - Performance of Preformed Au/Cu Nanoclusters Deposited on MgO Powders in the Catalytic Reduction of 4-Nitrophenol in Solution. AB - The deposition of preformed nanocluster beams onto suitable supports represents a new paradigm for the precise preparation of heterogeneous catalysts. The performance of the new materials must be validated in model catalytic reactions. It is shown that gold/copper (Au/Cu) nanoalloy clusters (nanoparticles) of variable composition, created by sputtering and gas phase condensation before deposition onto magnesium oxide powders, are highly active for the catalytic reduction of 4-nitrophenol in solution at room temperature. Au/Cu bimetallic clusters offer decreased catalyst cost compared with pure Au and the prospect of beneficial synergistic effects. Energy-dispersive X-ray spectroscopy coupled with aberration-corrected scanning transmission electron microscopy imaging confirms that the Au/Cu bimetallic clusters have an alloy structure with Au and Cu atoms randomly located. Reaction rate analysis shows that catalysts with approximately equal amounts of Au and Cu are much more active than Au-rich or Cu-rich clusters. Thus, the interplay between the Au and Cu atoms at the cluster surface appears to enhance the catalytic activity substantially, consistent with model density functional theory calculations of molecular binding energies. Moreover, the physically deposited clusters with Au/Cu ratio close to 1 show a 25-fold higher activity than an Au/Cu reference sample made by chemical impregnation. PMID- 29412513 TI - Determination of peripheral neuropathy in high-fat diet fed low-dose streptozotocin-treated female C57Bl/6J mice and Sprague-Dawley rats. AB - AIMS/INTRODUCTION: Peripheral neuropathy is a common complication of diabetes and also occurs in 30% of human obese individuals with impaired glucose tolerance. Even though peripheral neuropathy affects both sexes, most pre-clinical studies have been carried out using male rodents. The aim of the present study was to create diet-induced obesity and type 2 diabetes in female rats and mice in order to examine the development of peripheral neuropathy. MATERIALS AND METHODS: At 12 weeks-of-age, rats and mice were separated into three groups. Two groups or rats and mice were fed a 60-kcal% high-fat diet for 12 weeks (rats) or 8 weeks (mice). To induce type 2 diabetes, one group of high-fat diet-fed rats and mice were treated with a low dose of streptozotocin. Analyses of multiple neural end-points were carried out 12 weeks later. RESULTS: Glucose utilization was impaired in diet-induced obese female rats and mice, as was a number of neurological end points including nerve conduction velocity, intraepidermal and subepithelial corneal nerve fiber densities, and thermal and mechanical sensitivity. When female diet-induced obese rats or mice were made hyperglycemic, glucose utilization and sensory nerve density of the skin and cornea, as well as thermal and mechanical sensitivity, were more significantly impaired compared with diet induced obese female rodents. CONCLUSIONS: These studies show that diet-induced obese and type 2 diabetic female rodents develop peripheral neuropathy that is similar to that occurring in male rodents. However, for female rats, more aggressive treatment is required to induce dietary obesity. PMID- 29412514 TI - Effects of Parent-Implemented Early Start Denver Model Intervention on Chinese Toddlers with Autism Spectrum Disorder: A Non-Randomized Controlled Trial. AB - : To evaluate the effects of a 26-week, high-intensity, parent-implemented Early Start Denver Model (P-ESDM) intervention on developmental outcomes, severity of autism spectrum disorder (ASD), and parental stress of ASD toddlers in China. Subjects in P-ESDM group (n = 23) were recruited from 1.5- to 2.5-year-old toddlers who were screened positive in Xuhui and Minhang Districts and were diagnosed with ASD. A community (comparison) group of age-matched toddlers with ASD (n = 20) was recruited from other areas. Subjects of the P-ESDM group attended 1.5-hr parent coaching per week for 26 weeks, and those in the community group received interventions available from communities. Assessments were conducted at baseline (T1) and 26 weeks later (T2). After adjusting for baseline differences between the two groups, P-ESDM group demonstrated greater improvement than the community group in general development, especially in Language domain. Neither group demonstrated significant change in ASD severity, but the P-ESDM group showed greater improvement in social affect, parent-reported social communication and symbolic play than community group did. Finally, parents in P ESDM group experienced decreased parenting stress while those in community group showed an opposite trend, though the differences did not reach significant association with the P-ESDM intervention. Chinese toddlers with ASD receiving 26 weeks of P-ESDM via regular coaching sessions showed significant greater improvement than those receiving community interventions in multiple aspects of development including social communications. These findings add support to the importance of providing early screening, diagnosis, and immediate referral for evidence-based interventions to improve outcome of young children with ASD. Autism Res 2018, 11: 654-666. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The development of early screening and diagnosis of autism spectrum disorder (ASD) in China has highlighted the importance of early intervention for young children with ASD. Our current study demonstrated that parent-implemented Early Start Denver Model (P-ESDM) via coaching from professionals improved developmental outcomes, especially in the language domain, and social communicational behaviors of Chinese toddlers with ASD. P-ESDM may help parents in China provide effective early intervention to their children with ASD via improving their skills when they are still at a waiting list for services or lack access to intervention, and has the potential to alleviate their parenting stress. PMID- 29412515 TI - l-Methionine anti-biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor. AB - BACKGROUND: Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l-Methionine is an amino acid with reported biofilm-inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co-treatment with ivacaftor and l-methionine can reduce the formation of Pseudomonas aeruginosa biofilms. METHODS: P aeruginosa (PAO-1 strain) biofilms were studied in the presence of l-methionine and/or ivacaftor. For static biofilm assays, PAO-1 was cultured in a 48-well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter-GloTM assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs. RESULTS: l-Methionine (0.5 MUM) significantly reduced PAO-1 biofilm mass (32.4 +/- 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 MUg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 MUg/mL), a synergistic anti-biofilm effect was noted at 0.05 MUM and 0.5 MUM of l-methionine (two-way analysis of variane, p = 0.0415) compared with corresponding concentrations of l-methionine alone. CONCLUSION: Ivacaftor enhanced the anti-biofilm activity of l-methionine against the PAO-1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l methionine combinations for P aeruginosa sinusitis are planned. PMID- 29412516 TI - Risk factors for failure of early recovery from pancreatoduodenectomy despite the use of enhanced recovery after surgery protocols and a physical aging score to predict postoperative risks. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are beneficial for pancreatoduodenectomy (PD). Our aim was to evaluate risk factors associated with ERAS protocol failure after PD. METHODS: Clinical variables of 187 patients managed using ERAS protocols between April 2011 and April 2017, including non early recovery (non-ER) patients, with complications or requiring a hospital stay >=15 days, and early recovery (ER) patients, were compared. A physical aging (PA) score was devised to predict postoperative risks. RESULTS: Independent risk factors of complications were a pre-albumin level <=18 mg/dl (odds ratio (OR) 2.197; 95% confidence interval (CI) 1.052-4.622), and an American Society of Anesthesiologists (ASA) score >=II (OR 2.195; 95% CI 1.052-4.746). Independent risk factors for hospital stay >=15 days (P < 0.001) were age >=70 years (OR 2.438; 95% CI 1.122-5.299) and an ASA score >=II (OR 2.348; 95% CI 1.109-4.968). The PA score included age, ASA score, and pre-albumin level. The complication rate for each PA score was as follows: score "0", 12.1%; score "1", 18.2%; score "2", 26.9%; score "3", 30.8%; and score ">=4", 47.2%. CONCLUSIONS: Advanced age, poor nutrition, and serious illnesses can cause ERAS protocol failure. The PA score is effective for predicting postoperative progress. PMID- 29412517 TI - Plasma Proteomic Signatures in Early Chronic Obstructive Pulmonary Disease. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and abnormal inflammatory response of the lungs to inhaled noxious particles or gases. We used a proteomic approach with 2-DE followed by MALDI TOF-MS analyses in order to identify potential biomarkers in the early stages of the disease: global initiative for chronic obstructive pulmonary disease (GOLD) stage mild and moderate. EXPERIMENTAL DESIGN: Blood plasma was collected from 43 patients with mild and moderate COPD as well as from 43 age- and sex-matched control subjects. Proteome analysis was based on 2D-Page followed by MALDI-TOF MS identifications. Validation was made on two significant proteins by western blotting. RESULTS: The analyses revealed 29 between-group differences in expressed spots, belonging to 20 unique proteins. These proteins are involved in inflammation (haptoglobin, Ig alpha-1 chain C), blood coagulation and complement pathways (prothrombin, complement 4-B, ApoH), oxidative stress (ceruloplasmin, vitamin D binding protein, and serotransferrin), and lipoprotein/lipid metabolism (apolipoprotein A-I, and apolipoprotein E). CONCLUSION AND CLINICAL RELEVANCE: These results indicate that specific proteomic signatures can be detected and useful in terms of treatment selection and in early COPD patient monitoring. PMID- 29412518 TI - Atrium-specific ion channels in the zebrafish-A role of IKACh in atrial repolarization. AB - AIM: The zebrafish has emerged as a novel model for investigating cardiac physiology and pathology. The aim of this study was to investigate the atrium specific ion channels responsible for shaping the atrial cardiac action potential in zebrafish. METHODS: Using quantitative polymerase chain reaction, we assessed the expression level of atrium-specific potassium channels. The functional role of these channels was studied by patch clamp experiments on isolated atrial and ventricular cardiomyocytes and by optical mapping of explanted adult zebrafish hearts. Finally, surface ECGs were recorded to establish possible in vivo roles of atrial ion channels. RESULTS: In isolated adult zebrafish hearts, we identified the expression of kcnk3, kcnk9, kcnn1, kcnn2, kcnn3, kcnj3 and kcnj5, the genes that encode the atrium-specific K2P , KCa 2.x and Kir 3.1/4 (KACh ) ion channels. The electrophysiological data indicate that the acetylcholine-activated inward-rectifying current, IKACh, plays a major role in the zebrafish atrium, whereas K2P 3.1/9.1 and KCa 2.x channels do not appear to be involved in regulating the action potential in the zebrafish heart. CONCLUSION: We demonstrate that the acetylcholine-activated inward-rectifying current (IKACh ) current plays a major role in the zebrafish atrium and that the zebrafish could potentially be a cost-effective and reliable model for pharmacological testing of atrium-specific IKACh modulating compounds. PMID- 29412522 TI - ? PMID- 29412519 TI - High-Throughput DNA sequencing of ancient wood. AB - Reconstructing the colonization and demographic dynamics that gave rise to extant forests is essential to forecasts of forest responses to environmental changes. Classical approaches to map how population of trees changed through space and time largely rely on pollen distribution patterns, with only a limited number of studies exploiting DNA molecules preserved in wooden tree archaeological and subfossil remains. Here, we advance such analyses by applying high-throughput (HTS) DNA sequencing to wood archaeological and subfossil material for the first time, using a comprehensive sample of 167 European white oak waterlogged remains spanning a large temporal (from 550 to 9,800 years) and geographical range across Europe. The successful characterization of the endogenous DNA and exogenous microbial DNA of 140 (~83%) samples helped the identification of environmental conditions favouring long-term DNA preservation in wood remains, and started to unveil the first trends in the DNA decay process in wood material. Additionally, the maternally inherited chloroplast haplotypes of 21 samples from three periods of forest human-induced use (Neolithic, Bronze Age and Middle Ages) were found to be consistent with those of modern populations growing in the same geographic areas. Our work paves the way for further studies aiming at using ancient DNA preserved in wood to reconstruct the micro-evolutionary response of trees to climate change and human forest management. PMID- 29412521 TI - Longitudinal outcomes of patients enrolled in a phase Ib clinical trial of the adipose-derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Cell-based therapies have been used for the management of several diseases, holding promising results. Few studies have evaluated their use in chronic lung diseases. Idiopathic pulmonary fibrosis (IPF) remains a lethal disease although new therapies have emerged the recent years. We have recently published a phase I study of 14 patients receiving endobronchially adipose-derived stem cells (ADSCs). The aim of this report is to assess the outcome for our patients' population. PATIENTS AND METHODS: Patients who originally participated in this phase I study were followed up until the time of death. Pulmonary function tests as well as disease progression and survival time points were recorded. RESULTS: After first administration, a significant functional decline was observed as assessed by the changes (delta-Delta) of diffusion capacity for carbon monoxide (DLco) (mean DeltaDLco = 6.2%, P = .04) and forced vital capacity (FVC) (mean DeltaFVC = 6%, P = .029) at 18 and at 24 months, respectively. Median overall progression-free survival was 26 months and median overall survival was 32 months. All patients were alive for at least 2 years (survival rate, 100%) after first administration. Twelve patients (85.7%) died owing to disease progression. None of the patients experienced tumor development. CONCLUSIONS: Significant functional decline occurred at 24 months after first administration. The median survival and time to progression are in line with the published epidemiologic data. Further clinical trials complemented by mechanistic studies are sorely needed to delineate the role of ADSCs in IPF pathogenesis and treatment. PMID- 29412520 TI - Socio-economic status and time trends associated with early ART initiation following primary HIV infection in Montreal, Canada: 1996 to 2015. AB - INTRODUCTION: Guidelines regarding antiretroviral therapy (ART) initiation in HIV infection have varied over time, with the 2015 World Health Organization recommendation suggesting ART initiation at the time of diagnosis regardless of CD4 T-cell counts. Herein, we investigated the influence of socio-demographic and clinical factors in addition to time trends on early ART initiation among participants of the Montreal Primary HIV Infection Study. METHODS: The Montreal Primary HIV Infection Study is a prospective cohort established in three community medical centres (CMCs) and two university medical centres (UMCs). Recently diagnosed HIV-infected adults were categorized as receiving early (vs. delayed) ART if ART was initiated within 180 days of the baseline visit. Associations between early ART initiation and socio-demographic, socio-economic and behavioural information were examined. Independent associations of factors linked with early ART initiation were determined using multivariable binary logistic regression analysis. RESULTS: A total of 348 participants had a documented date of HIV acquisition of <180 days. The median interquartile range (IQR) age of participants was 35 (28; 42) years and the majority were male (96%), having paid employment (63%), men who have sex with men (MSM) (78%) and one to four sexual partners in the last three months (70%). Participants presented with a median IQR HIV plasma viral load of 4.6 (3.7; 5.3) log10 copies/ml, CD4 count of 510 (387; 660) cells/MUl and were recruited in CMCs (52%) or UMCs (48%). Early ART initiation was observed in 47% of the participants and the trend followed a V shaped curve with peaks in 1996 to 1997 (89%) and 2013 to 2015 (88%) with a dip in 2007 to 2009 (22%). Multivariable analyses showed that having a paid employment adjusted odds ratio (aOR: 2.43; 95% CI: 1.19, 4.95), lower CD4 count (aOR per 50 cell increase: 0.93; 95% CI: 0.87, 0.99) and care at UMCs (aOR: 2.03; 95% CI: 1.06 to 3.90) were independently associated with early ART initiation. CONCLUSIONS: Early ART initiation during primary HIV infection was associated with diminished biological prognostic factors and calendar time mirroring evolution of treatment guidelines. In addition, socio-economic factors such as having a paid employment, contribute to early ART initiation in the context of universal access to care in Canada. PMID- 29412523 TI - [A phenomenological approach of bodily experience]. AB - Phenomenology suggests that the clinician should not only focus on the patient's body as it can be objectively grasped, and not only on the patient's inner, psychic world, notably the representations and fears about the body, but should also explore the patient's body as it is experienced and lived, what we call the " bodily experience ". PMID- 29412524 TI - [Physicians as narrators : story(ies) of the medical experience]. AB - This article focuses on the subjectivity and lived experience of those who nowadays practice medicine, by relying on the stories that physicians tell about themselves and their practices. Such narratives disclose what is at stake in clinical practice and in physicians themselves. They are therefore a meaningful source to understand how physicians perceive the personal and professional challenges they face daily in a changing medical context. PMID- 29412525 TI - [The hospital as space and as territory]. AB - Space is lived individually and collectively and can become a source of existential affectation, especially when the lived experience is modified by disease. The fact that the hospital is also a place of territorialisation can potentiate this affectation, with at times surprising consequences. We aim - based on a reflection about the relationship patients and clinicians establish with the territory of the hospital- to identify some psychological and existential issues at stake with regard to space as a social construction. PMID- 29412526 TI - [Obsessive compulsive disorder and deep brain stimulation, a future so close]. AB - The obsessive compulsive disorder (OCD) is a psychiatric disorder with a high prevalence (2-3 %), frequently causing a disabling condition. Drug and psychotherapeutic treatment is generally effective. However about 1/3 of the patients are treatment-resistant, suffering from chronic psychological distress with important sociofunctional repercussions. The identification of dysfunctional neural networks in this disease opens the door to the use of neuromodulation techniques, as deep brain stimulation (DBS). We discuss the clinical results of subthalamic nucleus DBS and the involvement of this nucleus in the pathophysiology of OCD. We emphasize the importance to confirm these results with a larger number of patients and to determine the benefits regarding the quality of life of implanted patients. PMID- 29412527 TI - [Psychotropic and liver enzyme's perturbation, conduct to hold]. AB - Drug-induced liver injury (DILI) represents a complex clinical problem, both in terms of diagnosis and of therapeutic approach. When the suspected treatment is a psychotropic drug, the role of the liaison psychiatrist is not limited to the re adaptation of the drug treatment. In this article, with a clinical case as an example, we will discuss the issues to deal with facing a perturbation of liver enzymes in a patient on psychotropic treatment. The risk and benefit assessment of a therapeutic window, as well as the overall care of the patient at the general hospital will be detailed. PMID- 29412528 TI - [Prevention of suicide at Emergency Room: from the " Interpersonal Theory of Suicide " to the connectedness]. AB - Suicidal behavior (SB) has a dramatic epidemiological and clinical relevance in Switzerland. Both official reports and literature highlight SB prevention as a priority and recommend adopting new approaches, inspired by psychological models and ensuing in pragmatic interventions. Moreover, Emergency Room's (ER) role as a critical link in SB prevention chain is encouraged. Based on " Interpersonal Theory of Suicide ", " impossible situation ", and connectedness constructs, such interventions could be realized at ER through m-Health applications, with the main aim of reinforcing the patient's feeling of connectedness to his context. However, these applications have to be used with a critical view, because in no case they can be assimilated to clinical evaluation or human presence and interaction in the therapeutic relation. PMID- 29412530 TI - ? PMID- 29412531 TI - ? PMID- 29412529 TI - [Adult scoliosis: surgical management]. AB - Adult scoliosis is a common condition. Symptoms could be very debilitating. Surgical management requires a clear assessment of the functional impact of scoliosis, the failure of conservative treatments and precise analysis of radiological investigations (full spine views, dynamic X-rays and MRI). Surgical techniques (anterior and posterior approaches, minimal invasive techniques, osteotomies, all spine instrumentation) must be tailored to each patient. The main goals of surgery are treatment of symptoms, correction of deformity in coronal and sagittal plane and achievement of a solid fusion. Despite a high rate of complications, surgical treatment of adult scoliosis is associated with a better quality of life for patients. PMID- 29412533 TI - ? PMID- 29412532 TI - ? PMID- 29412535 TI - ? PMID- 29412534 TI - ? PMID- 29412536 TI - Introducing outpatient parenteral antimicrobial therapy in a children's hospital. AB - Outpatient parenteral antimicrobial therapy (OPAT) offers an alternative to inpatient care for delivering intravenous antibiotics in patients' homes or in a day care clinic setting. It was first introduced in North America in the 1970s and has evolved over the years, starting with the adult population and now moving to the paediatric population ( Chapman 2013 ). OPAT has the potential to offer excellent, patient-centred, high-quality care to treat a wide variety of infectious conditions in patients who are medically stable and do not need hospitalisation. For children and young people OPAT has the potential for families to resume their normal lives: returning to work, school and home. Paediatric OPAT (P-OPAT) is being implemented across the UK, with five centres now established. This article reports on the implementation of P-OPAT at Sheffield Children's NHS Foundation Trust (Sheffield Children's) in June 2016, highlighting the challenges and successes. PMID- 29412538 TI - Avoiding errors when administering injectable phenytoin to a child in status epilepticus. AB - Errors often occur in the prescribing, preparing, administering and monitoring of intravenous phenytoin ( NHS Improvement 2016 ). Following two fatal incidents involving injectable phenytoin, with contributing factors such as wrong weight estimation, a disregard for existing phenytoin prescriptions and confusion about the final concentration, an alert was issued by NHS Improvement in 2016. This article explores research into the use of injectable phenytoin and why adverse events occur when it is used. The article will inform nurses and doctors who work with children in acute settings about the risks associated with using injectable phenytoin and implications for practice on how to negate these risks. Applying this knowledge to nursing practice can result in reduced adverse events, and a safer and more effective care environment. PMID- 29412537 TI - Health promotion for young people with profound and multiple learning disabilities. AB - Research confirms that children and young people with severe learning disabilities do not have the same level of access to high-quality care, health education and health promotion activities as children and young people without disabilities. This article discusses a quality improvement, action research project to investigate alternative approaches to health promotion that enhance the health and well-being of children and young people with complex neurodisabilities. The project involved assessment of school records and completion by staff of an eight-question survey. It found that the proactive approach of school nurses in raising awareness and understanding through questioning was positively received, and reinforced how meaningful and relevant information could be delivered to these young people. The project also had unexpected benefits, including more integrated team working, increased knowledge, greater awareness and understanding of the importance of health promotion participation, and student satisfaction. PMID- 29412540 TI - Big Data Requires Information Governance. PMID- 29412539 TI - Understanding fluid homeostasis in infants and children: part 1. AB - Fluid requirements differ between infants and children. It is important for children's nurses to understand the principles of fluid mechanics and apply this understanding to ensure each child's state of hydration, and thereby preserve their safety and well-being. This two-part article aims to introduce the concept of fluid balance and electrolytes to children's nursing students, help them identify what is normal and what is not, and provide guidance on what actions should be taken when problems occur. It may also be useful for registered nurses to use for revalidation. PMID- 29412541 TI - HIM Using mHealth to Teach Patients Why and How to Access Health Records. PMID- 29412542 TI - Formalized Structure and Strategic Alignment--the Keys to IG Success. PMID- 29412543 TI - Improved Patient Engagement for LGBT Populations: Addressing Factors related to Sexual Orientation/Gender Identity for Effective Health Information Management. PMID- 29412544 TI - New Study Illuminates the Ongoing Road to ICD-10 Productivity and Optimization. PMID- 29412545 TI - [The assessment of the quality of water from sources of decentralized water supply of Ekaterinburg and surrounding areas]. AB - The availability of high-quality drinking water is currently the one out of the most acute problems in the Russian Federation. There was performed an analysis of the chemical composition of drinking water from sources of decentralized supply of inhabitants of the city of Yekaterinburg and the surrounding areas. Average values of indices of the water quality in the wells for individual use in the district of the city of Yekaterinburg not go beyond the standards, with the exception of manganese content. In some sources there were revealed elevated values of chromatic level, oxidability, hardness, content of iron, nitrates, barium, dry residue, ammonium nitrogen, silicon. Percentage of sources that do not meet hygienic requirements on a number of indices can reach 21-23%. PMID- 29412546 TI - [The problem of iodine deficiency and its solution in the republic of Belarus]. AB - The problem of iodine deficiency is relevant to the Republic of Belarus. It's confirmed by virtually commonly found geophysical iodine deficiency in soils and waters. Data on iodine deficiency initiated the development of a state strategy for the elimination of iodine deficiency in the population. This strategy determined the mandatory use of iodized salt only in the country in the food industry and catering as the main event for the elimination of iodine deficiency. The aim of this work was a comprehensive evaluation of the results of the implementation of the strategy for elimination of iodine deficiency among the population of the Republic of Belarus. Medical monitoring of the assessment of the efficacy showed the decrease in the incidence of simple non-toxic goiter in adolescents from 1215,23 per 100,000 population in 1998 to 341,25 in 2013 (3.6 times), and indices ofprimary morbidity rate in children fell by 2.9 times. Over the period from 1998 primary morbidity rate of simple nontoxic goiter decreased significantly in adults from 379.9 to 31,71 people per 100,000 of the population in 2013 respectively (almost 12 times). Data of the assessment of ioduria in Belarus indicate that 89.2% of children enrolled in the study have iodine excretion of more than 100 pg/L. Thus, in the Republic of Belarus there was achieved the level of an adequate intake of iodine with foodstuffs. This model ofprevention of iodine deficiency, as well as the traditional approach based on the adoption of the law, is a versatile and cost-effective mode. PMID- 29412547 TI - PCA3 rs544190G>A and prostate cancer risk in an eastern Chinese population. AB - BACKGROUND: The association of prostate cancer antigen 3 (PCA3) polymorphism (SNP, rs544190G>A) with metastatic prostate cancer in European descent has been reported. Our aim of the current study was to re-validate the effect of PCA3 polymorphism on prostate cancer risk in an Eastern Chinese population and then estimate possible genetic discrepancies among population. MATERIALS AND METHODS: Taqman assay was employed to determine genotype of SNP rs544190 in 1015 ethnic Han Chinese patients with prostate cancer and 1032 cancerfree controls. Simultaneously, odds ratios (OR) and 95% confidence intervals (95%CI) for risk relationship were calculated by logistic regression models. RESULTS: The statistically significant relationship between PCA3 rs544190G>A and higher prostate cancer risk was not found. Stratification analysis revealed that there was no remarkable association of rs544190 variant AG/AA genotype with prostate cancer risk in every subgroup, except for patients with Gleason score <=7(3+4). CONCLUSION: Although the results demonstrated that SNP rs544190 was not involved in prostate cancer risk in Eastern Chinese descent, unlike in European population, these might have clinical implications on prostate cancer heterogeneity around the World. To validate these findings, well-designed studies with different ethnic populations are warranted. PMID- 29412548 TI - Flexible ureterorenoscopy is associated with less stone recurrence rates over Shockwave lithotripsy in the management of 10-20 millimeter lower pole renal stone: medium follow-up results. AB - PURPOSE: To identify the role of shock wave lithotripsy (SWL) and flexible ureterorenoscopy (f-URS) on the stone recurrence, in the management of 10-20 millimeter lower pole stone (LPS) with medium follow-up outcomes. MATERIALS AND METHODS: The patients' charts which were treated with SWL or f-URS for LPS between January 2011 and September 2013 were analyzed, retrospectively. Patients who had a solitary 10-20mm LPS were enrolled into the study. In both procedures, patient was accepted as stone free, if complete stone clearance was achieved in the 3rd month abdominal computed tomography. Only patients with a stone free status were evaluated in follow-ups. RESULTS: The stone-free rate was 77.9% (88/113 patients) for the SWL group and 89% (114/128 patients) for the f-URS group (p=0.029). Stone recurrence was detected in 28 (35.4%) patients in SWL group and in 17 (17.2%) patients in f-URS group (p=0.009). Stone types and 24 hour urine sample results were similar between groups (p=0.123 vs p=0.197, respectively). Multivariate regression analysis revealed that f-URS procedure and absence of abnormality in 24 hour urine analysis significantly decreased stone recurrence in medium term follow-up (p=0.001 and p<0.001, respectively). CONCLUSIONS: Our study showed for the first time, that patients which underwent f URS for LPS, faced less stone recurrence, independent from diet regimen and metabolic evaluation in medium term follow-up. Additionally, presence of abnormality in 24 hour urine analysis increase the stone recurrence risk in follow-ups. PMID- 29412549 TI - Salvage surgical procedure for artificial sphincter extrusion. AB - : Case Hypothesis: Surgical removal is the standard treatment for artificial sphincter extrusion. However in some specific situations is possible to maintain the prosthesis with good results. CASE REPORT: We report a 60 years old patient presenting sphincter pump extrusion one month after artificial urinary sphincter (AUS) AMS 800TM placement for treating post-radical prostatectomy urinary incontinence (PRPUI). He also had a penile prosthesis implant one year before that was replaced in the same surgery the sphincter was implanted. As patient refused sphincter removal and there were no signals of active infection he was treated by extensive surgical washing with antibiotics and antiseptics. Pump was repositioned in the opposite side of the scrotum. Patient had good evolution with sphincter activation 50 days later. After 10 months of follow up, patient is socially continent and having regular sexual intercourse. Savage surgery may be an option in select cases of artificial sphincter extrusion. Promising future implications: Like in some patients with penile prosthesis some patients with artificial sphincter extrusion can be treated without removing the device. This may be a line of research about conservative treatment of artificial sphincter complications. PMID- 29412550 TI - Review of post bariatric surgery effects on common genitourinary physiology. AB - BACKGROUND: Obesity is a worldwide challenging health problem. Weight loss through medical management of obesity has not always been successful, thus, giving rise to the need for surgical intervention. Bariatric surgery has been shown to be helpful for morbidly obese patients. However, studies have also shown the effect of surgery on stone formation, fertility and erectile function. This review summarizes the main findings of several studies that analyze stone formation and fertility in men as well as erectile function post bariatric surgery. The underlying pathophysiologic alterations post bariatric surgery include increased absorption of oxalate leading to hyperoxaluria, hypocitraturia and increased urinary calcium oxalate supersaturation. Contradicting data exist on the effect of bariatric surgery on fertility and erectile function. Further studies are needed to analyze the mechanisms. PMID- 29412551 TI - Laparoscopic approach to pheochromocytoma in pregnancy: case report. AB - A 32-year-old 22-week pregnant hypertensive woman with sporadic episodes of headaches, sweating, and facial flushing was diagnosed with pheochromocytoma through biochemical and imaging tests. Perioperative management included a multidisciplinary approach, symptom stabilization with alpha blockade followed by beta blockade, and tumor resection by laparoscopic adrenalectomy at 24 weeks gestation. The diagnosis was confirmed by histopathological examination and immunohistochemistry tests. The decision for surgical removal of the tumor was based on maternal symptoms, tumor size, gestational age, the possibility of doing a laparoscopy, and the expertise of the surgical team. PMID- 29412552 TI - [Influence of radiating and chemical loads on changes of biochemical indices of the endocrine homeostasis in inhabitants from ecologically various areas of the Bryansk region]. AB - There ecologic-hygienic ranging of all 27 areas of the Bryansk region was performed with the using of the innovative methodical approach with taking into account the integrated indices of total pollution of all objects of the environment. The analysis of results of the performed biochemical researches with studying of indices of the endocrine homeostasis in residents of ecologically various areas has allowed to evolve thyrotropic hormone TTH (Qcalc=2,4 at K=1,96) and thyroid hormone ST4 (Qcalc=3,684 at K=1,96) as biological markers of the negative impact of technogenic-chemical contamination of environment on human health. PMID- 29412553 TI - [Cytogenetic indices of buccal epithelium in schoolchildren residing in territories with different levels of the air pollution]. AB - In the article there are contained the results of the study of ambient air of the regional center, urban-type settlement, and buccal epithelium in 87 schoolchildren aged of 11-13 years. Schoolchildren residing in the regional center were shown to be more susceptible to the exposure to such toxicants as carbon monoxide, nitrogen oxide, fluorhydric acid, chlorine and its compounds, sulfur dioxide, formaldehyde contained in the ambient air. In this group of students if compared with students who live in the village, there were revealed more pronounced cytogenetic deteriorations in oral mucosal epitheliocytes: cells with micronuclei, different forms of protrusion of the core, dual-core cell mitosis, kariokynesis, apoptotic bodies significantly more common occur, that can speak about both not only of cytogenetic instability, but and the degree of environmental genotoxicity, in particular, ambient air. There was noted the tendency to increase the level of cytogenetic damage and destruction of the nucleus in the group of girls in comparison with boys. PMID- 29412555 TI - 2017 CPT Coding Update. PMID- 29412554 TI - [Trace element status in old people of European and Asian parts of the North of Russia]. AB - To determine age-relatedpeculiarities of trace element system in oldpeople, residing in different natural and geographical regions, the content of 25 trace elements in hair samples of women from Arkhangelsk (average age is 87,0+/-0,98 years) and Magadan (average age is 80,1+/-1,25 years) was determined by spectrometric methods. In both groups there was established element misbalance characterized by lower concentration of such essential elements as Ca, Mg, Co, Cu and higher concentration of Na. The excess of K and Zn is more expressed in hair of female residents of Arkhangelsk in comparison with the city of Magadan there was revealed significantly more higher content of aluminum, boron, silicon, in the city of Magadan there are significantly higher concentrations of selenium and tin. According to the frequency of occurrence the excess of elements in the body of residents of the city of Arkhangelsk is comparable to that of residents of the city of Magadan, but has its own features. In Arkhangelsk there is more pronounced the excess ofpotassium, there was found high content of zinc, whereas in the city of Magadan there was revealed an excess of manganese and arsenic. Square of the figure, reflecting the deficiency of elements in female residents of the city of Magadan is more than in the city of Arkhangelsk, which is manifested by larger deficiency of chromium, zinc, iron. Identified regional differences in the content of macro- and microelements are related to biogeochemical and ecological features of the regions, which can determine the specifics of the aging diseases and time of their occurrence. PMID- 29412557 TI - Keep Out: Unsecured PHI Inside. PMID- 29412556 TI - [Research of the air environment in cafes and restaurants, where a nargile is smoked]. AB - By means of special devices there was performed research of air in premises of 17 cafes and restaurants where nargile is smoking. In the premises during the day and more there was evaluated a concentration of the following markers of tobacco smoke: carbon monoxide (CO), nicotine, tobacco smoke particles PM2,5 andpolycyclic aromatic hydrocarbons (PAHs). In the air of the examined enterprises the concentration of the major markers of tobacco smoke was established to exceed by several times acceptable and safe levels. At that in cafes and restaurants where nargile smoking the higher concentration of CO and PAHs was on average significantly more frequently than in a cafes with a rare nargile smoking. The data obtained can be used to refute the opinion on the safety of nargile smoking and tobacco smoke from the nargiles. All modern legislative and administrative measures to restrict and ban tobacco smoking should be extend to smoking nargile. PMID- 29412558 TI - [The impact of socio-economic factors and lifestyle on the health of the population in the Voronezh region]. AB - There are presented results of research of the impact of socio-economic factors, environmental factors and lifestyle on the health of the population. Among the socio-economic indices there are analyzed: the health expenditure; per capita income; living wage; the cost of the minimum food basket; the percentage ofpersons with income below the subsistence minimum; the amount of living space per person; the percentage of apartments that do not have running water; the percentage of apartments that do not have sewage systems; the proportion of living space, equipped with central heating; housing area per overall per capita at the end of the year. Also there are considered negative lifestyle factors: the abuse of alcohol and tobacco. The results of the study allow to select factors of the negative character and to identify measures for their elimination for the improvement ofpublic health. PMID- 29412559 TI - [Experimental evaluation of the impact of low doses of the herbicide 2,4-D in drinking water on some indices of lipid and immune status]. AB - There were studied features of the manifestation of incoming with potable water nontoxic doses of the herbicide 2,4-D on the body mass index, some indices of lipid metabolism and immune system in different types of diets in the experiment in rats. There was shown a significant gain in body weight of animals, and MDA and leptin level in the serum under the action of a herbicide in conjunction with a high-calorie diet. In all experimental groups there was noted the increased level of total cholesterol, tendency to the increase of LDL cholesterol. Under the action of the herbicide there was noted an increase of IL-6, TNF-a and the numbers of leukocytes and, on the contrary, the reduction of the number of thymocytes and kariocytes in thymus and spleen. PMID- 29412560 TI - Is HIPAA Outdated? While Coverage Gaps and Growing Breaches Raise Industry Concern, Others Argue HIPAA is Still Effective. PMID- 29412561 TI - How Small Organizations Handle HIPAA Compliance. PMID- 29412562 TI - Things Privacy Officers Can Do Today to Defend Against a CYBERATTACK. PMID- 29412563 TI - Are You Ready for a HIPAA Audit? PMID- 29412564 TI - HIM Prepped to Shape the Future of Population Health through HIE. PMID- 29412565 TI - Standards for Safety, Security, and Interoperability of Medical Devices in an Integrated Health Information Environment. PMID- 29412566 TI - IG Case Study: Utah Health Information Network's Information Asset Inventory. PMID- 29412567 TI - Making Amendments to Health Records (2017 Update). PMID- 29412568 TI - Pneumonia and COPD Reporting in the Inpatient Setting. PMID- 29412569 TI - [In process]. PMID- 29412570 TI - [In process]. PMID- 29412571 TI - New CPT Codes Describe Emerging Technologies in the Treatment of Heart Failure. PMID- 29412572 TI - [In process]. PMID- 29412573 TI - [In process]. PMID- 29412574 TI - [In process]. PMID- 29412575 TI - [In process]. PMID- 29412627 TI - [In process]. PMID- 29412628 TI - Health IT Preparing for 'The Big One.' PMID- 29412629 TI - [In process]. PMID- 29412630 TI - [In process]. PMID- 29412631 TI - [In process]. PMID- 29412632 TI - [In process]. PMID- 29412633 TI - Harnessing Cell Dynamic Responses on Magnetoelectric Nanocomposite Films to Promote Osteogenic Differentiation. AB - The binding of cell integrins to proteins adsorbed on the material surface is a highly dynamic process critical for guiding cellular responses. However, temporal dynamic regulation of adsorbed proteins to meet the spatial conformation requirement of integrins for a certain cellular response remains a great challenge. Here, an active CoFe2O4/poly(vinylidene fluoride-trifluoroethylene) nanocomposite film, which was demonstrated to be an obvious surface potential variation (Delta V ~ 93 mV) in response to the applied magnetic field intensity (0-3000 Oe), was designed to harness the dynamic binding of integrin-adsorbed proteins by in situ controlling of the conformation of adsorbed proteins. Experimental investigation and molecular dynamics simulation confirmed the surface potential-induced conformational change in the adsorbed proteins. Cells cultured on nanocomposite films indicated that cellular responses in different time periods (adhesion, proliferation, and differentiation) required distinct magnetic field intensity, and synthetically programming the preferred magnetic field intensity of each time period could further enhance the osteogenic differentiation through the FAK/ERK signaling pathway. This work therefore provides a distinct concept that dynamically controllable modulation of the material surface property fitting the binding requirement of different cell time periods would be more conducive to achieving the desired osteogenic differentiation. PMID- 29412634 TI - Magnetic Nanomaterials: Chemical Design, Synthesis, and Potential Applications. AB - Magnetic nanomaterials (MNMs) have attracted significant interest in the past few decades because of their unique properties such as superparamagnetism, which results from the influence of thermal energy on a ferromagnetic nanoparticle. In the superparamagnetic size regime, the moments of nanoparticles fluctuate as a result of thermal energy. To understand the fundamental behavior of superparamagnetism and develop relevant potential applications, various preparation routes have been explored to produce MNMs with desired properties and structures. However, some challenges remain for the preparation of well-defined magnetic nanostructures, including exchange-coupled nanomagnets, which are considered as the next generation of advanced magnets. In such a case, effective synthetic methods are required to achieve control over the chemical composition, size, and structure of MNMs. For instance, liquid-phase chemical syntheses, a set of emerging approaches to prepare various magnetic nanostructures, facilitate precise control over the nucleation and specific growth processes of nanomaterials with diverse structures. Among them, the high-temperature organic phase method is an indispensable one in which the microstructures and physical/chemical properties of MNMs can be tuned by controlling the reaction conditions such as precursor, surfactant, or solvent amounts, reaction temperature or time, reaction atmosphere, etc. In this Account, we present an overview of our progress on the chemical synthesis of various MNMs, including monocomponent nanostructures (e.g., metals, metal alloys, metal oxides/carbides) and multicomponent nanostructures (heterostructures and exchange-coupled nanomagnets). We emphasize the high-temperature organic-phase synthetic method, on which we have been focused over the past decade. Notably, multicomponent nanostructures, obtained by growing or incorporating different functional components together, not only retain the functionalities of each single component but also possess synergic properties that emerge from interfacial coupling, with improved magnetic, optical, or catalytic features. Herein, potential applications of MNMs are covered in three representative areas: biomedicine, catalysis, and environmental purification. Regarding biomedicine, MNMs can detect or target biological entities after being modified with specific biomolecules, and they can be applied to magnetic resonance imaging, imaging-guided drug delivery, and photothermal therapy. Apart from their magnetic features, the catalytic performance of some MNMs resulting from their highly specific chemical components and surface structure will be briefly introduced, highlighting its impact in the methanol oxidation reaction, the oxygen reduction reaction, the oxygen and hydrogen evolution reactions, and the Fischer-Tropsch synthesis. Finally, environmental purification, primarily for water remediation, will be highlighted with two main aspects: the effective capture of bacteria and the removal of adverse ions in wastewater. We hope that this Account will clarify the progress on the controllable preparation of MNMs with specific compositions, sizes, and structures and generate broad interest in the realms of biomedicine and catalysis as well as in environmental issues and other potential applications. PMID- 29412635 TI - Integration of Inverse Supercritical Fluid Extraction and Miniaturized Asymmetrical Flow Field-Flow Fractionation for the Rapid Analysis of Nanoparticles in Sunscreens. AB - We report the use of inverse supercritical fluid extraction (SFE) and miniaturized asymmetrical flow field-flow fractionation (mAF4) for the preparation and subsequent analysis of titanium dioxide nanoparticles in model and commercial sunscreens. The approach allows for the fast and reliable fractionation and sizing of TiO2 nanoparticles and their quantitation in commercial products. This new method represents a powerful and efficient tool for the verification of nanoparticle content in a wide range of matrixes, as demanded by recently introduced regulatory requirements. Furthermore, the use of carbon dioxide as an environmentally friendly solvent is in line with the increasing need for ecologically compatible analytical techniques. PMID- 29412636 TI - Colorimetric and Fluorescent Detecting Phosgene by a Second-Generation Chemosensor. AB - Because of the current shortage of first-generation phosgene sensors, increased attention has been given to the development of fluorescent and colorimetric based methods for detecting this toxic substance. In an effort focusing on this issue, we designed the new, second-generation phosgene chemosensor 1 and demonstrated that it undergoes a ring-opening reaction with phosgene in association with color and fluorescent changes with a detection limit of 3.2 ppb. Notably, in comparison with the first-generation sensor RB-OPD, 1 not only undergoes a much faster response toward phosgene with an overall response time within 2 min, but it also generates no byproducts during the sensing process. Finally, sensor 1 embedded nanofibers were successfully fabricated and used for accurate and sensitive detection of phosgene. PMID- 29412637 TI - Method for the Determination of Iodide in Dried Blood Spots from Newborns by High Performance Liquid Chromatography Tandem Mass Spectrometry. AB - Dried blood spots (DBS), collected for newborn screening programs in the United States, have been used to screen for congenital metabolic diseases in newborns for over 50 years. DBS provide an easy and inexpensive way to collect and store peripheral blood specimens and present an excellent resource for studies on the assessment of chemical exposures in newborns. In this study, a selective and sensitive method was developed for the analysis of iodide in DBS by high performance liquid chromatography electrospray tandem mass spectrometry. Accuracy, inter- and intraday precision, matrix effects, and detection limits of the method were determined. Further validation of the method was accomplished by concurrent analysis of whole blood and fortified blood spotted on a Whatman 903 filter card. A significant positive correlation was found between measured concentrations of iodide in venous whole blood and the same blood spotted as DBS. The method limit of detection was 0.15 ng/mL iodide. The method was further validated by the analysis of a whole blood sample certified for iodide levels (proficiency testing sample) by spotting on a filter card. Twenty DBS samples collected from newborns in New York State were analyzed to demonstrate the applicability of the method. The measured concentrations of iodide in whole blood of newborns from New York State ranged between 8), and the water ligands of the Co(II) complexes are not deprotonated at neutral pH. All complexes produce CEST peaks through either alcohol OH or amide NH proton exchange. The water ligands exchange too rapidly to produce a CEST effect as shown by variable-temperature 17O NMR spectroscopy studies. The complexes with available coordination sites for inner-sphere water ligands produce large paramagnetic shifts and broadening of the 17O resonances of bulk water, whereas the encapsulated complexes show much less shifting and broadening of 17O resonances. All complexes produce substantial paramagnetic shifts of the 1H resonances of bulk water, which is promising for the development of supramolecular CEST agents. PMID- 29412654 TI - Activity of Topotecan toward the DNA/Topoisomerase I Complex: A Theoretical Rationalization. AB - Topotecan (TPT) is a nontoxic anticancer drug characterized by a pH-dependent lactone/carboxyl equilibrium. TPT acts on the covalently bonded DNA/topoisomerase I (DNA/TopoI) complex by intercalating between two DNA bases at the active site. This turns TopoI into a DNA-damaging agent and inhibits supercoil relaxation. Although only the lactone form of the drug is active and effectively inhibits TopoI, both forms have been co-crystallized at the same location within the DNA/TopoI complex. To gain further insights into the pH-dependent activity of TPT, the differences between two TPT:DNA/TopoI complexes presenting either the lactone (acidic pH) or the carboxyl (basic pH) form of TPT were studied by means of molecular dynamic simulations, quantum mechanical/molecular mechanical calculations, and topological analysis. We identified two specific amino acids that have a direct relationship with the activity of the drug, i.e., lysine 532 (K532) and asparagine 722 (N722). K532 forms a stable hydrogen bond bridge between TPT and DNA only when the drug is in its active lactone form. The presence of the active drug triggers the formation of an additional stable interaction between DNA and protein residues, where N722 acts as a bridge between the two fragments, thus increasing the binding affinity of DNA for TopoI and further slowing the release of DNA. Overall, our results provide a clear understanding of the activity of the TPT-like class of molecules and can help in the future design of new anticancer drugs targeting topoisomerase enzymes. PMID- 29412655 TI - The Nature of the Heavy Alkaline Earth Metal-Hydrogen Bond: Synthesis, Structure, and Reactivity of a Cationic Strontium Hydride Cluster. AB - The molecular strontium hydride [(Me3TACD)3Sr3(MU3-H)2][SiPh3] (2) was isolated as the dark red benzene solvate 2.C6H6 in 69% yield from the reaction of [Sr(SiPh3)2(thf)3] (1') with (Me3TACD)H (1,4,7-trimethyl-1,4,7,10 tetraazacyclododecane). This reaction can be considered as a redox process, with the Bronsted acidic amine proton in (Me3TACD)H transformed into the hydride by the anion [SiPh3]-. Trace amounts of water resulted in the formation of [(Me3TACD)3Sr3(MU3-H)(MU3-OH)][SiPh3] (2*), which cocrystallized with 2. Single crystal X-ray diffraction of 2 revealed a substitutional disorder of a bridging hydride with a hydroxide ligand. Hydride complex 2 was also obtained by hydrogenolysis of [(Me3TACD)Sr(SiPh3)] (3), although pure 3 proved difficult to isolate. In the presence of a 2-fold excess of (Me3TACD)H, the reaction with disilyl 1' gave [(Me3TACD)SiPh3] (4). Complex 2 underwent facile H/D exchange with D2 (1 bar), with the anion [SiPh3]- decomposing concurrently. In the reaction of 2 with 1,1-diphenylethylene (DPE), the anion [SiPh3]- was added to the C?C bond in DPE to give [(Me3TACD)3Sr3H2][Ph2CCH2SiPh3] (5), whereas the cationic cluster [(Me3TACD)3Sr3H2]+ remained unchanged. 9-Fluorenone underwent one-electron reduction with 2 to give the paramagnetic ketyl complex [{(Me3TACD)H}Sr(OC13H8*)2(thf)2] (6). These strontium compounds are structurally similar to the lighter calcium congeners, but more reactive, in particular with regard to fast H/D exchange and [SiPh3]- anion decomposition. DFT studies on the cationic hydride clusters suggest a more pronounced covalent character for strontium compared to calcium. Disilyl 1, strontium diketyl 6, and the calcium congener of 6, [{(Me3TACD)H}Ca(OC13H8.)2] (10), were also characterized by X-ray diffraction. PMID- 29412656 TI - Melting Transition of Oriented DNA Fibers Submerged in Poly(ethylene glycol) Solutions Studied by Neutron Scattering and Calorimetry. AB - The influence of molecular confinement on the melting transition of oriented Na DNA fibers submerged in poly(ethylene glycol) (PEG) solutions has been studied. The PEG solution exerts an osmotic pressure on the fibers which, in turn, is related to the DNA intermolecular distance. Calorimetry measurements show that the melting temperature increases and the width of the transition decreases with decreasing intermolecular distance. Neutron scattering was used to monitor the integrated intensity and width of a Bragg peak from the B-form of DNA as a function of temperature. The data were quantitatively analyzed using the Peyrard Bishop-Dauxois model. The experiments and analysis showed that long segments of double-stranded DNA persist until the last stages of melting and that there appears to be a substantial increase of the DNA dynamics as the melting temperature of the DNA is approached. PMID- 29412657 TI - Synthesis and Electrocatalytic Activity of Ammonium Nickel Phosphate, [NH4]NiPO4.6H2O, and beta-Nickel Pyrophosphate, beta-Ni2P2O7: Catalysts for Electrocatalytic Decomposition of Urea. AB - Electrocatalytic decomposition of urea for the production of hydrogen, H2, for clean energy applications, such as in fuel cells, has several potential advantages such as reducing carbon emissions in the energy sector and environmental applications to remove urea from animal and human waste facilities. The study and development of new catalyst materials containing nickel metal, the active site for urea decomposition, is a critical aspect of research in inorganic and materials chemistry. We report the synthesis and application of [NH4]NiPO4.6H2O and beta-Ni2P2O7 using in situ prepared [NH4]2HPO4. The [NH4]NiPO4.6H2O is calcined at varying temperatures and tested for electrocatalytic decomposition of urea. Our results indicate that [NH4]NiPO4.6H2O calcined at 300 degrees C with an amorphous crystal structure and, for the first time applied for urea electrocatalytic decomposition, had the greatest reported electroactive surface area (ESA) of 142 cm2/mg and an onset potential of 0.33 V (SCE) and was stable over a 24-h test period. PMID- 29412658 TI - Total Synthesis of (-)-Chromodorolide B By a Computationally-Guided Radical Addition/Cyclization/Fragmentation Cascade. AB - The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four contiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst, and employs equimolar amounts of the two addends. Computational studies guided the development of this central step of the synthesis and provide insight into the origin of the observed stereoselectivity. PMID- 29412659 TI - Retinoic Acid Receptor-Related Orphan Receptor gammat (RORgammat) Agonists as Potential Small Molecule Therapeutics for Cancer Immunotherapy. AB - The recent success of PD-1/PD-L1 antibodies for advanced cancer treatment has led to the conclusion that activating the immune system can be employed to fight cancer. These results also encourage the development of small molecule immunomodulators for cancer immunotherapy. RORgammat is a key transcription factor mediating Th17 cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. Since RORgammat agonists have been shown to increase basal activity of RORgammat and promote Th17 cell differentiation, development of RORgammat agonists could provide a unique approach to cancer immunotherapy. In this review, we summarize RORgammat sterol and synthetic agonists, analyze the common ground of their mode of actions, and discuss the potential role of RORgammat agonists as small molecule therapeutics for cancer immunotherapy. PMID- 29412660 TI - Role of the Cysteine 81 Residue of Macrophage Migration Inhibitory Factor as a Molecular Redox Switch. AB - Macrophage migration inhibitory factor (MIF) is a pro-inflammatory and tumor promoting cytokine that occurs in two redox-dependent immunologically distinct conformational isoforms. The disease-related structural isoform of MIF (oxMIF) can be specifically and predominantly detected in the circulation of patients with inflammatory diseases and in tumor tissue, whereas the ubiquitously expressed isoform of MIF (redMIF) is abundantly expressed in healthy and diseased subjects. In this article, we report that cysteine 81 within MIF serves as a "switch cysteine" for the conversion of redMIF to oxMIF. Modulating cysteine 81 by thiol reactive agents leads to significant structural rearrangements of the protein, resulting in a decreased beta-sheet content and an increased random coil content, but maintaining the trimeric quaternary structure. This conformational change in the MIF molecule enables binding of oxMIF-specific antibodies BaxB01 and BaxM159, which showed beneficial activity in animal models of inflammation and cancer. Crystal structure analysis of the MIF-derived EPCALCS peptide, bound in its oxMIF-like conformation by the Fab fragment of BaxB01, revealed that this peptide adopts a curved conformation, making the central thiol protein oxidoreductase motif competent to undergo disulfide shuffling. We conclude that redMIF might reflect a latent zymogenic form of MIF, and formation of oxMIF leads to a physiologically relevant, i.e., enzymatically active, state. PMID- 29412661 TI - Stereoselective Synthesis of 3,3-Disubstituted Oxindoles and Spirooxindoles via Allylic Alkylation of Morita-Baylis-Hillman Carbonates of Isatins with Cyclic Sulfamidate Imines Catalyzed by DABCO. AB - An efficient, organocatalytic, and ecofriendly method has been developed for the quick construction of a wide array of 3,3-disubstituted oxindoles in good to excellent yields and diastereomeric ratio (up to <=96:4) with excellent functional group tolerance via an allylic alkylation reaction of cyclic sulfamidate imines with a number of MBH carbonates of isatins in 2-MeTHF as an environmentally benign solvent at room temperature using 5 mol % of DABCO. Furthermore, a metal-free-based one-shot synthesis of a medicinally promising polycyclic spirooxindole with an all-carbon spirocenter has been achieved with outstanding dr value (up to <=99:1). PMID- 29412662 TI - Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics. AB - In this paper, 26 natural polymyxin components and a new derivative S2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E2, E2-Val, A2, M2, D2, and S2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E2, M2, and S2 was similar to that of polymyxin E. Compound S2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S2 could be a new drug candidate. PMID- 29412663 TI - Aqueous OH Radical Reaction Rate Constants for Organophosphorus Flame Retardants and Plasticizers: Experimental and Modeling Studies. AB - Aqueous .OH reaction rate constants ( kOH) for organophosphate esters (OPEs) are essential for assessing their environmental fate and removal potential in advanced oxidation processes (AOPs). Herein experimental and in silico approaches were adopted to obtain kOH values for a variety of OPEs. The determined kOH for 18 OPEs varies from 4.0 * 108 M-1 s-1 to 1.6 * 1010 M-1 s-1. Based on the experimental kOH values, a quantitative structure-activity relationship model that involves molecular structural information on the number of heavy atoms, content index, and the most negative charge of C atoms was developed for predicting kOH of other OPEs. Furthermore, appropriate density functional theory (DFT) and solvation models were selected, which together with transition state theory were employed to predict kOH of three representative OPEs. The deviation between the DFT calculated and the experimental kOH values ( kcal/ kexp) is within 2. Half-lives of the OPEs were estimated to be 0.5-22791.3 days in natural waters and 0.044-19.7 s in AOPs, indicating the OPEs are potentially persistent in natural waters and can be quickly eliminated by AOPs. The determined kOH values and the in silico methods offer a scientific base for assessing OPEs fate in aquatic environments. PMID- 29412664 TI - Growth Mechanism of SiC CVD: Surface Etching by H2, H Atoms, and HCl. AB - Silicon carbide is a wide bandgap semiconductor with unique characteristics suitable for high temperature and high power applications. Fabrication of SiC epitaxial layers is usually performed using chemical vapor deposition (CVD). In this work, we use quantum chemical density functional theory (B3LYP and M06-2X) and transition state theory to study etching reactions occurring on the surface of SiC during CVD in order to combine etching effects to the surface kinetic model for SiC CVD. H2, H atoms and HCl gases are chosen in the study as the most likely etchants responsible for surface etching. We consider etchings of four surface sites, namely CH3(ads), SiH3CH2(ads), SiH2(CH2)2(ads), and SiH(CH2)3(ads), which represent four subsequent snapshots of the surface as the growth proceeds. We find that H atoms are the most effective etchant on CH3(ads) and SiH3CH2(ads), which represent the first and second steps of the growth. HCl and H2 are shown to be much less effective than H atoms and produce the etching rate constants which are ~104 and ~107 times slower. In comparison to CH3(ads), SiH3CH2(ads) is shown to be less stable and more susceptible to etchings. Unlike the first and second steps of the growth, the third and fourth steps (i.e., SiH2(CH2)2(ads) and SiH(CH2)3(ads)) are stable and much less susceptible to any of the three etchants considered. This implies that the growth species become more stable via forming Si-C bonds with another surface species. The formation of a larger surface cluster thus helps stabilizing the growth against etchings. PMID- 29412665 TI - Catalysis in a Cationic Coordination Cage Using a Cavity-Bound Guest and Surface Bound Anions: Inhibition, Activation, and Autocatalysis. AB - The Kemp elimination (reaction of benzisoxazole with base to give 2 cyanophenolate) is catalyzed in the cavity of a cubic M8L12 coordination cage because of a combination of (i) benzisoxazole binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2 cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface. PMID- 29412666 TI - Influence of Water on Carbon Dioxide and Room Temperature Ionic Liquid Dynamics: Supported Ionic Liquid Membrane vs the Bulk Liquid. AB - The influence of water on the dynamics of a room temperature ionic liquid (RTIL), 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EmimNTf2), and CO2 in the RTIL was studied in the bulk liquid and a supported ionic liquid membrane (SILM) using two-dimensional infrared (IR) and IR polarization selective pump probe spectroscopies. In the water-saturated bulk EmimNTf2, the complete orientational randomization and structural spectral diffusion (SSD) of CO2 became faster than in the dry EmimNTf2. In the poly(ether sulfone) SILM, only the longer time components of the SSD became faster in the water-saturated RTIL; the complete orientational randomization remained similar to the dry RTIL in the SILM. The implication is that the presence of water in EmimNTf2 contained in the SILM facilitates the fluctuation of globally modified RTIL structure in the pores, but the local RTIL environments are relatively unaffected. PMID- 29412667 TI - Superconductivity in a New 1144-Type Family of (La,Na)AFe4As4 (A = Rb or Cs). AB - We discovered novel Fe-based superconductors (FeSCs) (La,Na)AFe4As4, where A = Rb or Cs, and characterized their superconducting properties. (La,Na)AFe4As4 is a so called 1144-type compound with a tetragonal unit cell classified into space group P4/mmm (no. 123). The lattice constants are a = 3.861(1) A and c = 13.26(1) A for (La,Na)RbFe4As4 and a = 3.880(1) A and c = 13.60(1) A for (La,Na)CsFe4As4. The Rietveld refinement results on the powder X-ray diffraction suggest that the La/Na ratio is rather fixed as La:Na = 0.44(5):0.56(5). The electrical resistivity and magnetic susceptibility show superconducting transition at 25.5 K for (La,Na)RbFe4As4 and 24.0 K for (La,Na)CsFe4As4. The superconducting transition temperature (Tc) of (La,Na)AFe4As4 is comparable with that of 122-type (La,Na)Fe2As2 and lower than that of typical 122-type or 1144-type FeSCs by more than 10 K. The possible reasons for lower Tc are discussed in terms of the structural modification, carrier concentration, and chemical disorder.